PMID- 25010993 TI - Catalytic conversion of aryl triazenes into aryl sulfonamides using sulfur dioxide as the sulfonyl source. AB - Various sulfonamides have been synthesized from triazenes and sulfur dioxide. In the presence of just a catalytic amount of BF3.OEt2, a series of 1-aryl-triazenes were converted into sulfonyl hydrazines in good to excellent yields. When using CuCl2 as the catalyst, the corresponding sulfonamides can be produced from the 1 aryl triazenes in good yields. PMID- 25010992 TI - Effects of subconcussive head trauma on the default mode network of the brain. AB - Although they are less severe than a full blown concussive episodes, subconcussive impacts happen much more frequently and current research has suggested this form of head trauma may have an accumulative effect and lead to neurological impairment later in life. To investigate the acute effects that subconcussive head trauma may have on the default mode network of the brain resting-state, functional magnetic resonance was performed. Twenty-four current collegiate rugby players were recruited and all subjects underwent initial scanning 24 h prior to a scheduled full contact game to provide a baseline. Follow-up scanning of the rugby players occurred within 24 h following that game to assess acute effects from subconcussive head trauma. Differences between pre game and post-game scans showed both increased connectivity from the left supramarginal gyrus to bilateral orbitofrontal cortex and decreased connectivity from the retrosplenial cortex and dorsal posterior cingulate cortex. To assess whether or not a history of previous concussion may lead to a differential response following subconcussive impacts, subjects were further divided into two subgroups based upon history of previous concussion. Individuals with a prior history of concussion exhibited only decreased functional connectivity following exposure to subconcussive head trauma, while those with no history showed increased connectivity. Even acute exposure to subconcussive head trauma demonstrates the ability to alter functional connectivity and there is possible evidence of a differential response in the brain for those with and without a history of concussion. PMID- 25010994 TI - Editorial. Developmental perspectives of autism. PMID- 25010995 TI - Development and evaluation of an interactive simulation module to train the use of an electrosurgical device. AB - BACKGROUND: The purpose of this study was to develop and evaluate an interactive Web-based training module for electrosurgery and use of an electrosurgical device. MATERIALS AND METHODS: The training module consists of a theoretical part, a device tutorial, and an assessment. For evaluation, participants were recruited at the surgical departments from a university hospital and a non university teaching hospital and were divided into a training group and a control group. All participants performed the same theoretical and practical tests. The training participants first completed the module before they performed the tests. The control participants immediately performed the tests. Results were compared between the training and control participants. To evaluate face validity, the training participants filled out a questionnaire on their opinion about the module. RESULTS: In total, 39 participants were enrolled in the study: 20 in the training group and 19 in the control group. The training group answered significantly more theoretical questions correctly (15.7 versus 9.7; P<.001) and made significantly fewer errors in the practical test (2.2 versus 5.6; P=.007). The participants in the training group rated the usefulness and characteristics of the module with high marks. All of them indicated the module to be of additive value to surgical training programs. CONCLUSIONS: Training with an interactive Web-based module has a positive effect on both theoretical and practical competence regarding electrosurgery and use of an electrosurgical device. This module was rated positively by the participants and was indicated to be a useful addition to surgical training programs. PMID- 25010996 TI - Minimalist, standard and no footwear on static and dynamic postural stability following jump landing. AB - In recreational sports, uncushioned, light-weight and minimalist shoes are increasingly used to imitate barefoot situations. Uncertainty exists whether these shoes provide sufficient stability during challenging movements. In this randomised crossover study, 35 healthy distance runners performed jump landing stabilisation and single-leg stance tests on a force plate, using four conditions in random order: barefoot, uncushioned minimalist shoes, cushioned ultraflexible shoes and standard running shoes. Ground reaction force (GRF) and centre of pressure (COP) data were used to determine unilateral jump landing stabilisation time and COP sway velocity during single-leg stance. Repeated measures analysis of variance revealed significant footwear interactions for medial-lateral (p < 0.001) and anterior-posterior COP sway velocity during standing (p < 0.001). The barefoot condition produced significantly greater postural sway velocities (p < 0.001) compared to all footwear conditions. No significant effects were found for jump landing stabilisation time. In conclusion, the results of this study indicate that increased shoe flexibility and reduced sole support have no, or only minor influence on static and dynamic postural control, and therefore, may not increase the risk of traumatic events during sports activities. However, barefoot conditions should be considered carefully when adequate postural control is needed. PMID- 25010997 TI - Implementation and outcomes of the New York State YMCA diabetes prevention program: a multisite community-based translation, 2010-2012. AB - INTRODUCTION: Weight loss and physical activity achieved through the Diabetes Prevention Program (DPP) have been shown to reduce type 2 diabetes risk among individuals with prediabetes. The New York State Young Men's Christian Association (YMCA) delivered the 16-week evidence-based model at 14 YMCAs. A mixed methods process and outcomes evaluation was conducted. METHODS: Most participants were referred by clinicians and were encouraged to achieve 5% to 7% weight loss. Participants were weighed weekly; additional data were gathered from participant surveys and focus groups and staff surveys and interviews. RESULTS: Participants (N = 254) lost a mean of 9 pounds (P < .001), or 4.2% of body weight, by program completion; 40% achieved 5% or more weight loss and 25% achieved 7% or more weight loss. Ten months after baseline, 61% of participants reported 5% or more weight loss and 48% reported 7% or more weight loss. In multivariate models, weight loss was negatively associated with black race (16 weeks: adjusted odds ratio [AOR], 0.190, P = .002; 10 months: AOR, 0.244, P = .005) and positively associated with attendance (16 weeks: AOR, 18.699, P < .001; 10 months: AOR, 2.808, P = .024). Participants reported improvements in health and lifestyle changes after program completion. Factors contributing to program success included coaches who motivated participants, the group setting, curriculum, and program duration. However, sociodemographic diversity was limited. CONCLUSION: Outcomes demonstrate the potential for effectively implementing the DPP in community-based settings. Findings also suggest the need for replications among a broader population. PMID- 25010998 TI - Physician weight recommendations for overweight and obese firefighters, United States, 2011-2012. AB - INTRODUCTION: National guidelines state that health care professionals (HCPs) should advise patients on the importance of maintaining a healthy weight. Firefighters have high rates of obesity, and cardiovascular events are the leading cause of line-of-duty deaths in firefighters. This study assessed the association of age and body mass index (BMI) with HCP weight recommendations among male firefighters. METHODS: We used data on self-reported HCP weight recommendations and measured BMI from a 2011-2012 national sample of male firefighters (N = 1,002). HCP recommendations were recorded as no advice, maintain, gain, or lose weight, and BMI was categorized as normal (<25.0 kg/m(2)), overweight (25.0-29.9 kg/m(2)), class I obese (30.0-34.9 kg/m(2)), and class II or III obese (>=35.0 kg/m(2)). We used multinomial logistic regression to estimate the odds of receiving weight advice by age and BMI categories. RESULTS: Most firefighters (96%) reported visiting an HCP in the past year. Most (69%) firefighters and 48% of class I to III obese firefighters reported receiving no weight advice. Higher BMI predicted HCP advice to lose weight (odds ratio class I obese vs normal weight: 12.98; 95% confidence interval: 5.38 31.34). Younger firefighters were less likely to receive weight loss advice than older firefighters, except among those who were class II or III obese. CONCLUSIONS: HCPs are important sources of health information for firefighters. Overweight and obese firefighters, particularly those who are younger, do not consistently receive HCP advice to lose weight. This marks a missed opportunity to prevent further weight gain and reduce obesity-related health outcomes. PMID- 25010999 TI - Socioecologic factors as predictors of readiness for self-management and transition, medication adherence, and health care utilization among adolescents and young adults with chronic kidney disease. AB - INTRODUCTION: The objective of our study was to determine the socioecologic factors that predict readiness for self-management and transition from pediatric to adult health care services, adherence to taking medications, and health care utilization among adolescents and young adults with chronic kidney disease. METHODS: We enrolled 52 adolescents and young adults aged 13 to 21 (96.5% participation). Participants were administered measures that examined: socioecologic factors, individualized education plans or 504 plans, readiness for self-management and transition (the University of North Carolina TRxANSITION scale), triangulated measures of adherence to taking medications (parent reported, physician reported, and medication-possession ratios), and health care utilization (number of visits to the emergency department, number of inpatient admissions, and number of inpatient days in the previous year). RESULTS: Overall, our sample had moderate levels of readiness for self-management and transition, high rates of parent- and physician-reported medication adherence, and high rates of health care utilization. Age was a significant positive predictor of readiness for self-management and transition. Compared with participants who had private health insurance, participants who had public insurance had more emergency department visits, inpatient admissions, and inpatient days, and lower rates of physician-reported medication adherence. Participants who did not have an individualized education plan or 504 plan had significantly more emergency department visits, inpatient admissions, and inpatient days. CONCLUSION: Socioecologic factors play an important role in readiness for self-management and transition, medication adherence, and health care utilization in pediatric patients with chronic kidney disease. Age, insurance status, and having an individualized education plan or 504 plan may be key factors. PMID- 25011000 TI - Severe obesity among children in New York City public elementary and middle schools, school years 2006-07 through 2010-11. AB - INTRODUCTION: Although studies have shown that childhood obesity overall is on the decline among New York City (NYC) public school children, the prevalence of severe childhood obesity has not been studied. METHODS: We used height and weight measurements of 947,765 NYC public school students aged 5 to 14 years in kindergarten through 8th grade (K-8), from school years 2006-07 through 2010-11. We used age- and sex-specific body mass index (BMI) percentiles according to Centers for Disease Control and Prevention growth charts to define childhood obesity (BMI >= 95th percentile) and severe childhood obesity (BMI >=120% of 95th percentile) and to identify biologically implausible values (BIV). Multivariable logistic models tested for trends in obesity and severe obesity prevalence. To evaluate misclassification, we recalculated prevalence estimates for the most recent school year (2010-11) including the student records identified as BIV who were also declared severely obese (BMI >= 120% of 95th percentile). We refer to this subgroup of BIVs as "high BIV." RESULTS: Severe obesity among NYC public school students in grades K-8 decreased 9.5% from the 2006-07 school year (6.3%) to the 2010-11 school year (5.7%), and obesity decreased 5.5% (from 21.9% to 20.7%). The prevalence of severe obesity and obesity was highest among minority, poor, and male children. Severe obesity declined in prevalence among every subgroup, with the greatest effect among white students and wealthy students. Severe obesity prevalence increased with age, and obesity prevalence peaked among those aged 7 to 10 years. For the 2010-11 school year, including high BIVs increased severe obesity prevalence from 5.7% to 6.6% and increased obesity prevalence from 20.7% to 21.5%. CONCLUSION: Among all subgroups of NYC public school children in grades K-8, the reduction in severe obesity was greater than the reduction in overall obesity. Efforts to decrease obesity in NYC have affected the severely obese; however, monitoring of this specific subgroup should continue because of differences in trends and greater health risks. PMID- 25011001 TI - Placing workplace wellness in proper context: value beyond money. PMID- 25011002 TI - Acute effects of a loaded warm-up protocol on change of direction speed in professional badminton players. AB - It has previously been shown that a loaded warm-up may improve power performances. We examined the acute effects of loaded dynamic warm-up on change of direction speed (CODS), which had not been previously investigated. Eight elite badminton players participated in three sessions during which they performed vertical countermovement jump and CODS tests before and after undertaking the dynamic warm-up. The three warm-up conditions involved wearing a weighted vest (a) equivalent to 5% body mass, (b) equivalent to 10% body mass, and (c) a control where a weighted vest was not worn. Vertical jump and CODS performances were then tested at 15 seconds and 2, 4, and 6 minutes post warm-up. Vertical jump and CODS significantly improved following all warm-up conditions (P < .05). Post warm-up vertical jump performance was not different between conditions (P = .430). Post warm-up CODS was significantly faster following the 5% (P = .02) and 10% (P < .001) loaded conditions compared with the control condition. In addition, peak CODS test performances, independent of recovery time, were faster than the control condition following the 10% loaded condition (P = .012). In conclusion, the current study demonstrates that a loaded warm-up augmented CODS, but not vertical jump performance, in elite badminton players. PMID- 25011003 TI - Effects of thermal fluctuations and fluid compressibility on hydrodynamic synchronization of microrotors at finite oscillatory Reynolds number: a multiparticle collision dynamics simulation study. AB - We investigate the emergent dynamical behavior of hydrodynamically coupled microrotors by means of multiparticle collision dynamics (MPC) simulations. The two rotors are confined in a plane and move along circles driven by active forces. Comparing simulations to theoretical results based on linearized hydrodynamics, we demonstrate that time-dependent hydrodynamic interactions lead to synchronization of the rotational motion. Thermal noise implies large fluctuations of the phase-angle difference between the rotors, but synchronization prevails and the ensemble-averaged time dependence of the phase angle difference agrees well with analytical predictions. Moreover, we demonstrate that compressibility effects lead to longer synchronization times. In addition, the relevance of the inertia terms of the Navier-Stokes equation are discussed, specifically the linear unsteady acceleration term characterized by the oscillatory Reynolds number ReT. We illustrate the continuous breakdown of synchronization with the Reynolds number ReT, in analogy to the continuous breakdown of the scallop theorem with decreasing Reynolds number. PMID- 25011004 TI - Effects of agave nectar versus sucrose on weight gain, adiposity, blood glucose, insulin, and lipid responses in mice. AB - Agave nectar is a fructose-rich liquid sweetener derived from a plant, and is often promoted as a low glycemic alternative to refined sugar. However, little scientific research has been conducted in animals or humans to determine its metabolic and/or health effects. The aim of this study was to explore the influence of agave nectar versus sucrose on weight gain, adiposity, fasting plasma blood glucose, insulin, and lipid levels. Eighteen (n=18) male ICR mice (33.8+/-1.6 g) were divided into two groups (n=6 for agave nectar and n=12 for sucrose) and provided free access to one of two diets of equal energy densities differing only in a portion of the carbohydrate provided. Diets contained 20% carbohydrate (by weight of total diet) from either raw agave nectar or sucrose. Epididymal fat pads were excised, and blood was collected after 34 days. Weight gain (4.3+/-2.2 vs. 8.4+/-3.4 g), fat pad weights (0.95+/-0.54 vs. 1.75+/-0.66 g), plasma glucose (77.8+/-12.2 vs. 111.0+/-27.9 mg/dL), and insulin (0.61+/-0.29 vs. 1.46+/-0.81 ng/mL) were significantly lower (P<=.05) for agave nectar-fed mice compared to sucrose-fed mice respectively. No statistically significant differences in total cholesterol or triglycerides were detected. These results suggest that in comparison to sucrose, agave nectar may have a positive influence on weight gain and glucose control. However, more research with a larger sample of animals and/or with human subjects is warranted. PMID- 25011006 TI - Innovative interventions to promote behavioral change in overweight or obese individuals: A review of the literature. AB - The overweight and obesity trends have risen over the past few decades, placing significant burdens on health care in terms of increased morbidity and cost. Behavioral change therapy is an effective treatment strategy and includes goal setting, self-monitoring, problem solving, and reinforcement tactics. Traditionally, behavior change therapy has been delivered using face-to-face counseling along with paper and pen recording of dietary intake and physical activity. The current advances in technology provide opportunities to deliver interventions using cellphones, internet, and active video games. These new methods to deliver behavior change for the management and prevention of obesity are being developed in order to increase access, improve convenience, decrease cost, and increase participant engagement. In this review, we present new approaches to promote behavior changes in the management of obesity. Currently available data show promising results. However, future research is needed to address study limitations and implementation challenges of these innovative interventions. PMID- 25011007 TI - Characterization of a shortened model of diet alternation in female rats: effects of the CB1 receptor antagonist rimonabant on food intake and anxiety-like behavior. AB - The prevalence of eating disorders and obesity in western societies is epidemic and increasing in severity. Preclinical research has focused on the development of animal models that can mimic the maladaptive patterns of food intake observed in certain forms of eating disorders and obesity. This study was aimed at characterizing a recently established model of palatable diet alternation in female rats. For this purpose, females rats were fed either continuously with a regular chow diet (Chow/Chow) or intermittently with a regular chow diet for 2 days and a palatable, high-sucrose diet for 1 day (Chow/Palatable). Following diet cycling, rats were administered rimonabant (0, 0.3, 1, 3 mg/kg intraperitoneally) during access to either palatable diet or chow diet and were assessed for food intake and body weight. Finally, rats were pretreated with rimonabant (0, 3 mg/kg, intraperitoneally) and tested in the elevated plus maze during withdrawal from the palatable diet. Female rats with alternating access to palatable food cycled their intake, overeating during access to the palatable diet and undereating upon returning to the regular chow diet. Rimonabant treatment resulted in increased chow hypophagia and anxiety-like behavior in Chow/Palatable rats. No effect of drug treatment was observed on the compulsive eating of palatable food in the diet-cycled rats. The results of this study suggest that withdrawal from alternating access to the palatable diet makes individuals vulnerable to the anxiogenic effects of rimonabant and provides etiological factors potentially responsible for the emergence of severe psychiatric side-effects following rimonabant treatment in obese patients. PMID- 25011009 TI - How nutritional status signalling coordinates metabolism and lignocellulolytic enzyme secretion. AB - The utilisation of lignocellulosic plant biomass as an abundant, renewable feedstock for green chemistries and biofuel production is inhibited by its recalcitrant nature. In the environment, lignocellulolytic fungi are naturally capable of breaking down plant biomass into utilisable saccharides. Nonetheless, within the industrial context, inefficiencies in the production of lignocellulolytic enzymes impede the implementation of green technologies. One of the primary causes of such inefficiencies is the tight transcriptional control of lignocellulolytic enzymes via carbon catabolite repression. Fungi coordinate metabolism, protein biosynthesis and secretion with cellular energetic status through the detection of intra- and extra-cellular nutritional signals. An enhanced understanding of the signals and signalling pathways involved in regulating the transcription, translation and secretion of lignocellulolytic enzymes is therefore of great biotechnological interest. This comparative review describes how nutrient sensing pathways regulate carbon catabolite repression, metabolism and the utilisation of alternative carbon sources in Saccharomyces cerevisiae and ascomycete fungi. PMID- 25011010 TI - Fusarium graminearum PKS14 is involved in orsellinic acid and orcinol synthesis. AB - The available genome sequences show that the number of secondary metabolite genes in filamentous fungi vastly exceeds the number of known products. This is also true for the global plant pathogenic fungus Fusarium graminearum, which contains 15 polyketide synthase (PKS) genes, of which only 6 have been linked to products. To help remedy this, we focused on PKS14, which has only been shown to be expressed during plant infections or when cultivated on rice or corn meal (RM) based media. To enhance the production of the resulting product we introduced a constitutive promoter in front of PKS14 and cultivated two of the resulting mutants on RM medium. This led to the production of two compounds, which were only detected in the PKS14 overexpressing mutants and not in the wild type or PKS14 deletion mutants. The two compounds were tentatively identified as orsellinic acid and orcinol by comparing spectroscopic data (mass spectroscopy and chromatography) to authentic standards. NMR analysis of putative orcinol isolated from the PKS14 overexpressing mutant supported our identification. Orcinol and orsellinic acid, not previously detected in Fusarium, have primarily been detected in lichen fungi. Orsellinic acid is hypothesized to be the PKS release product which is transformed to orcinol through decarboxylation. Phylogenetic analyses of PKSs placed PKS14 in a subclade of known OA synthases. Expression analysis by microarray of 55 experiments identified seven genes near PKS14 that were expressed in a similar manner. One of the seven genes encodes a predicted carboxylase, which could be responsible for transforming orsellinic acid to orcinol. PMID- 25011008 TI - Fungal model systems and the elucidation of pathogenicity determinants. AB - Fungi have the capacity to cause devastating diseases of both plants and animals, causing significant harvest losses that threaten food security and human mycoses with high mortality rates. As a consequence, there is a critical need to promote development of new antifungal drugs, which requires a comprehensive molecular knowledge of fungal pathogenesis. In this review, we critically evaluate current knowledge of seven fungal organisms used as major research models for fungal pathogenesis. These include pathogens of both animals and plants; Ashbya gossypii, Aspergillus fumigatus, Candida albicans, Fusarium oxysporum, Magnaporthe oryzae, Ustilago maydis and Zymoseptoria tritici. We present key insights into the virulence mechanisms deployed by each species and a comparative overview of key insights obtained from genomic analysis. We then consider current trends and future challenges associated with the study of fungal pathogenicity. PMID- 25011011 TI - The role of the de novo pyrimidine biosynthetic pathway in Cryptococcus neoformans high temperature growth and virulence. AB - Fungal infections are often difficult to treat due to the inherent similarities between fungal and animal cells and the resulting host toxicity from many antifungal compounds. Cryptococcus neoformans is an opportunistic fungal pathogen of humans that causes life-threatening disease, primarily in immunocompromised patients. Since antifungal therapy for this microorganism is limited, many investigators have explored novel drug targets aim at virulence factors, such as the ability to grow at mammalian physiological temperature (37 degrees C). To address this issue, we used the Agrobacterium tumefaciens gene delivery system to create a random insertion mutagenesis library that was screened for altered growth at elevated temperatures. Among several mutants unable to grow at 37 degrees C, we explored one bearing an interruption in the URA4 gene. This gene encodes dihydroorotase (DHOase) that is involved in the de novo synthesis of pyrimidine ribonucleotides. Loss of the C. neoformans Ura4 protein, by targeted gene interruption, resulted in an expected uracil/uridine auxotrophy and an unexpected high temperature growth defect. In addition, the ura4 mutant displayed phenotypic defects in other prominent virulence factors (melanin, capsule and phospholipase) and reduced stress response compared to wild type and reconstituted strains. Accordingly, this mutant had a decreased survival rate in macrophages and attenuated virulence in a murine model of cryptococcal infection. Quantitative PCR analysis suggests that this biosynthetic pathway is induced during the transition from 30 degrees C to 37 degrees C, and that transcriptional regulation of de novo and salvage pyrimidine pathway are under the control of the Ura4 protein. PMID- 25011012 TI - The influence of infant-caregiver experiences on amygdala Bdnf, OXTr, and NPY expression in developing and adult male and female rats. AB - Previous work with various animal models has demonstrated that alterations in the caregiving environment produce long-term changes in anxiety-related and social behaviors, as well as amygdala gene expression. We previously introduced a rodent model in which the timing and duration of exposure to maltreatment or nurturing care outside the home cage can be controlled to assess neurobiological outcomes. Here we sought to determine whether our brief experimental conditions produce changes in gene expression within the developing and adult amygdala. Using a candidate gene approach, we examined fold mRNA changes for the Brain-derived neurotrophic factor (Bdnf), Oxytocin receptor (OXTr), and Neuropeptide Y (NPY) genes, which are all highly expressed in the amygdala and play important roles in anxiety-related and social behaviors. In adults, significant group differences were detected for only Bdnf, with higher levels of Bdnf mRNA for females that had been exposed to maltreatment and males exposed to nurturing care outside the home cage relative to littermate controls. For pups, significant group differences were detected for only OXTr, with lower levels of OXTr mRNA in females exposed to maltreatment. Finally, for adolescents, maltreated-females showed significant changes in Bdnf (decreased), OXTr (decreased), and NPY (increased) mRNA relative to controls. These data illustrate the ability of brief, but repeated exposure to different caregiving environments during the first postnatal week to have long term effects on gene expression within the developing and adult amygdala, especially for females. PMID- 25011013 TI - Serum total p-cresylsulfate level is associated with abnormal QTc interval in stable angina patients with early stage of renal failure. AB - BACKGROUND: p-Cresylsulfate (PCS), a protein-bound uraemic retention solute, is known to cause endothelial dysfunction and possibly plays a role in coronary atherosclerosis. Furthermore, the association among serum total PCS, major adverse cardiovascular events, and all-cause mortality were also found in previous studies. However, little is known about the relationship between total PCS level and prolonged QT interval. We assessed whether serum total PCS level is related with prolonged QT interval by measuring 12-lead electrocardiogram (ECG) recording in stable angina patients with early stage of renal failure. METHODS: Serum total PCS concentrations were measured by using the Ultra Performance LC System in 154 consecutive stable angina patients. A 12-lead ECG recording was obtained from each subject. RESULTS: Patients with abnormal corrected QT (QTc) interval have higher median serum total PCS levels than patients with normal QTc interval. Statistically significant associations were observed between the serum total PCS levels and the QTc interval (r=0.217, P=0.007). Using multivariate and trend analyses, serum total PCS level was independently associated with QTc prolongation. CONCLUSIONS: This study indicates that serum total PCS levels are significantly higher in the presence of abnormal QTc interval and are associated with the QTc prolongation. Whether total PCS plays a role in the pathogenesis of QTc prolongation requires future investigation. PMID- 25011014 TI - Soft-landing ion mobility of silver clusters for small-molecule matrix-assisted laser desorption ionization mass spectrometry and imaging of latent fingerprints. AB - Matrix-assisted laser desorption ionization (MALDI) imaging is gaining popularity, but matrix effects such as mass spectral interference and damage to the sample limit its applications. Replacing traditional matrices with silver particles capable of equivalent or increased photon energy absorption from the incoming laser has proven to be beneficial for low mass analysis. Not only can silver clusters be advantageous for low mass compound detection, but they can be used for imaging as well. Conventional matrix application methods can obstruct samples, such as fingerprints, rendering them useless after mass analysis. The ability to image latent fingerprints without causing damage to the ridge pattern is important as it allows for further characterization of the print. The application of silver clusters by soft-landing ion mobility allows for enhanced MALDI and preservation of fingerprint integrity. PMID- 25011015 TI - Deformation behavior of metastable beta-type Ti-25Nb-2Mo-4Sn alloy for biomedical applications. AB - The deformation behavior of metastable beta-type Ti-25Nb-2Mo-4Sn (wt%) alloy subjected to different thermo-mechanical treatments was discussed by the combining results from transmission electron microscope, tensile test and in-situ synchrotron X-ray diffraction. Visible "double yielding" behavior, which is characterized by the presence of stress-plateau, was observed in the solution treated specimen. Upon a cold rolling treatment, the Ti-25Nb-2Mo-4Sn alloy performs nonlinear deformation because of the combined effects of elastic deformation and stress-induced alpha" martensitic transformation. After the subsequent annealing, the beta phase is completely stabilized and no stress induced martensitic transformation takes place on loading due to the inhibitory effect of grain boundaries and dislocations on martensitic transformation. As a result, the annealed specimen exhibits linear elastic deformation. PMID- 25011016 TI - Nanotube dispersion and polymer conformational confinement in a nanocomposite fiber: a joint computational experimental study. AB - A combination of computational and experimental methods was implemented to understand and confirm that conformational changes of a polymer [specifically polyacrylonitrile (PAN)] vary with the dispersion quality and confinement between single-wall carbon nanotubes (SWNT) in the composite fibers. A shear-flow gel spinning approach was utilized to produce PAN-based composite fibers with high concentration (i.e., loading of 10 wt %) of SWNT. Dispersion qualities of SWNT ranging from low to high were identified in the fibers, and their effects on the structural morphologies and mechanical properties of the composites were examined. These results show that, as the SWNT dispersion quality in terms of distribution in the fiber and exfoliation increases, PAN conformations were confined to the extended-chain form. Full atomistic computational results show that the surface interaction energy between isolated PAN and SWNT was not preferred, leading to the self-agglomeration of PAN. However, confinement of the polymer chains between SWNT bundles or individual tubes (i.e., molecular crowding) resulted in large increases in the PAN-SWNT interaction energy. In other words, the crowding of polymer chains by the SWNT at high concentrations can promote extended-chain conformational development during fiber spinning. This was also evidenced experimentally by the observance of significantly improved PAN orientation and crystallization in the composite. Ultimately this work provides fundamental insight toward the specific structural changes capable at the polymer/nanotube interface which are important toward improvement of the effective contribution of the SWNT to the mechanical performance of the composite. PMID- 25011017 TI - Relationship between serum levels of angiopoietin-related growth factor and metabolic risk factors. AB - Angiopoietin-related growth factor (AGF, also known as angiopoietin-like protein 6) has been introduced as a novel hepatocyte-derived factor, which antagonizes obesity and insulin resistance in mice. However, human studies show conflicting results and are limited to a small cohort of patients. In the current study, we therefore sought to investigate AGF serum levels in a large metabolically well characterized cohort. AGF serum concentrations were determined by commercial enzyme-linked immunosorbent assay in 697 patients of a cohort from Eastern Germany (Sorbs). Correlations of AGF serum levels with clinical and biochemical measures of glucose and lipid metabolism, as well as markers of renal function, were investigated. In nondiabetic subjects (n=627), AGF was positively correlated with markers of insulin resistance and negatively correlated with high-density lipoprotein cholesterol in univariate analyses (p<0.05). After adjustment for age, gender, and body mass index, none of these factors remained independently associated with AGF, neither in nondiabetic subjects nor in patients with type 2 diabetes mellitus (T2DM) (n=70). However, we confirmed existing data of significantly higher AGF concentrations in patients with T2DM as compared to controls in this large cohort. Circulating AGF is elevated in subjects with T2DM and related to the type of antidiabetic treatment, but is not independently associated with anthropometric parameters, indices of insulin sensitivity and secretion, or a number of other adipokines. PMID- 25011018 TI - Increased protein and mRNA expression of resistin after dexamethasone administration. AB - Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype. PMID- 25011020 TI - An irresolute linker: separation, and structural and spectroscopic characterization of the two linkage isomers of a Ru(ii)-(2-(2'-pyridyl)pyrimidine 4-carboxylic acid) complex. AB - For the first time the two linkage isomers of a Ru(ii) complex with 2-(2' pyridyl)pyrimidine-4-carboxylic acid (cppH) - that form in comparable amounts - have been fully characterized individually. The X-ray structure of each isomer is related to its NMR spectrum in solution. PMID- 25011019 TI - Effect of long term vitamin D supplementation on biomarkers of inflammation in Latino and African-American subjects with pre-diabetes and hypovitaminosis D. AB - Low vitamin D levels are associated with minority subjects, the metabolic syndrome, and inflammation. The effect of vitamin D supplementation on markers of inflammation has not been well studied. The aim of the study was to evaluate the effects of high doses of vitamin D supplementation for 1 year on serum biomarkers of inflammation in Latino and African-American subjects with pre-diabetes and hypovitaminosis D. Latino (n=69) and African-American (n=11) subjects who had both pre-diabetes and hypovitaminosis D with a mean age of 52.0 years, a BMI of 32.7 kg/m(2), and 70% of whom were females, were randomized to receive weekly doses (mean+/-SD) of vitamin D (85 300 IU+/-16 000) or placebo oil for 1 year. Serum levels of interleukin-6, tumor necrosis factor, highly sensitive C-reactive protein), plasminogen activator inhibitor 1, and insulin-like growth factor-1 were measured at baseline, 6, and 12 months. Serum 25-OH vitamin D levels of 22 ng/ml at baseline quickly rose to nearly 70 ng/ml in subjects receiving vitamin D and did not change in the placebo group. Two-way repeated measures ANOVA showed no differences between the 2 groups in any of the 5 selected parameters. High dose vitamin D supplementation for 1 year in minority subjects with pre-diabetes and hypovitaminosis D failed to affect serum biomarkers of inflammation.Clinical trial reg. no.: NCT00876928, clinicaltrials.gov. PMID- 25011021 TI - The occurrence of iron-deficiency anemia in children with type 1 diabetes. AB - OBJECTIVE: A higher risk for iron deficiency, which can lead to anemia, has been noticed in children with early stages of type 1 diabetes. Anemia in diabetes is not uncommon and thus may contribute to disease complications. The aim of the study was to determine the influence of type 1 diabetes incidence on the manifestation of iron-deficiency anemia. MATERIALS AND METHODS: The study included 100 children with type 1 diabetes, aged 6 to 17 years. The diagnosis of type 1 diabetes in all patients was made on the basis of clinical symptoms and, at a later stage, on the basis of the occurrence of islet cell autoantibodies. The patients were divided into groups according to the duration of the disease: those with newly diagnosed type 1 diabetes (ND), those who have the disease for 1 to 3 years (FMD), those who have it for 4 to 6 years (SMD), and those who have it for more than 6 years (LD). Morphological parameters of blood have been measured by means of the flame atomic absorption spectrometry method: red blood cells (RBC), hemoglobin (HGB), acetylated HGB, hematocrit (HCT), RBC volume (mean corpuscular volume [MCV]), HGB mass in RBC (mean corpuscular HGB [MCH]), mean HGB content in RBC (MCH concentration), and serum iron concentration. RESULTS: In the ND children, significantly lower concentrations of HCT and HGB as well as the amount of RBC and MCV have been shown, in comparison with the children who have type 1 diabetes longer: for HGB, compared with the FMD children; for HCT, compared with the SMD and LD children; for RBC, compared with the LD children; and for MCV, compared with the SMD children. Some significant inverse correlation has been observed in the MCH concentration in comparison with the children who have type 1 diabetes for more than 1 year. It has been shown that, when compared with the FMD, SMD, and LD children, more ND children are characterized by the coexistence of at least 3 reduced values of the morphological blood parameters associated with iron-deficiency anemia (26%, 17%, 7%, and 3%, respectively). At the same time, it has been found that the mean iron concentration in the blood serum of the ND group is significantly lower than that of the SMD and LD groups. CONCLUSIONS: The incidence of anemia in the early stages of the disease justifies conducting the screening in all children with type 1 diabetes and taking appropriate preventive measures toward the patients at risk for iron-deficiency anemia. PMID- 25011022 TI - Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides. AB - Differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopies as well as theoretical computations were applied to investigate inter- and intramolecular interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least physically stable of all studied samples. Dielectric measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of density functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC molecules become very weak or are eventually broken. Simultaneously, strong H bonds between the matrix and API are formed. This observation was used to explain the physical stability of the investigated solid dispersions. Finally, solubility measurements revealed that the solubility of IMC can be enhanced by the use of acetylated carbohydrates, although the observed improvement is marginal due to strong interactions. PMID- 25011023 TI - A simple method for detecting vitrectomy infusion line position in hazy media, in case of poor visualization. AB - PURPOSE: To introduce a simple and practical method for detecting vitrectomy infusion line position in a hazy media. METHODS: The position of the infusion cannula was evaluated before and during vitrectomy in 17 eyes of 17 patients with hazy media. This procedure was performed by using the light pipe inserted partially into the cannula and determining the color of transmitted light into the vitreous cavity. Dark red or brownish color was considered as suprachoroidal placement and bright whitish color as the correct position of the cannula tip. RESULTS: In 13 patients, the position of the cannula was considered as a precise position by using the aforementioned method at the beginning of the operation, and vitrectomy was performed without any infusion line-related complications. In two cases, the incorrect placement of the infusion cannula was confirmed with this technique, and the cannula was reinserted and repositioned. In two cases, secondary slippage of the cannula in suprachoroidal space was detected by using this method during vitrectomy, and another cannula was tried in another position. CONCLUSION: Using the color of light pipe inserted partially into the cannula is a safe and simple method for evaluating the position of the infusion line in the eye. PMID- 25011024 TI - Spontaneous peripheral migration of subfoveal perfluorocarbon. PMID- 25011025 TI - Optical coherence tomography-based ranibizumab monotherapy for retinal angiomatous proliferation in Korean patients. AB - PURPOSE: To evaluate the visual outcome of optical coherence tomography-based ranibizumab monotherapy in Korean patients with retinal angiomatous proliferation and identify prognostic factors of visual outcome. METHODS: A prospective single arm clinical study of 31 retinal angiomatous proliferation patients who underwent 3 consecutive monthly intravitreal ranibizumab injections was conducted. Additional treatment was given based on optical coherence tomography at monthly follow-ups over 24 months. RESULTS: Best-corrected visual acuity improved from 48.7 +/- 19.3 to 56.3 +/- 19.1 letters at 24 months (P = 0.010). Total cumulative numbers of injection were 5.5 +/- 2.2 and 7.7 +/- 3.4 times at 12 and 24 months, respectively. Older age, larger choroidal neovascularization size, and poor initial best-corrected visual acuity were associated with poor visual outcome. Final best-corrected visual acuity was significantly worse with Stage 3 disease (70.4 +/- 5.1, 62.3 +/- 11.6, 46.2 +/- 22.3 letters improved in each stage; P = 0.015). Among factors associated with poor visual outcome, only the stage of retinal angiomatous proliferation remained statistically significant on multiple linear regression analysis (P = 0.006). Although baseline best-corrected visual acuity was similar, Stage 3 patients exhibited limited visual improvement despite anatomical improvement, and more recurrences requiring more injections. CONCLUSION: Retinal angiomatous proliferation may be successfully managed with ranibizumab monotherapy in Korean patients, with the number of treatments required comparable to other forms of neovascular age-related macular degeneration. However, visual improvement was limited in late-stage RAP. PMID- 25011026 TI - Surgical outcomes of florid diabetic retinopathy treated with antivascular endothelial growth factor. AB - PURPOSE: To evaluate the effectiveness of vitreoretinal surgery combined with antivascular endothelial growth factor therapy to treat florid diabetic retinopathy, a rare and severe form of diabetic retinopathy in young patients. METHODS: Retrospective observational case series including 61 eyes of 45 patients operated on for florid diabetic retinopathy over the past 5 years, with preoperative or intraoperative intravitreal injection of bevacizumab. Cases were classified into three stages of disease severity, according to the extension of the fibrovascular membranes. Main outcome measures were mean change in visual acuity, anatomical outcome, and surgical complications. RESULTS: After a mean follow-up of 20.3 months, the mean visual acuity significantly increased from +1.7 logMAR before surgery to +0.8 logMAR after surgery (P < 0.01). The visual gain was significant in Stages I and II (P < 0.05) but not significant in Stage III. A flat retina without silicone oil was achieved in 84% of eyes. Eight eyes (13%) progressed to neovascular glaucoma and/or phthisis despite repeated surgeries. CONCLUSION: Vitrectomy combined with antivascular endothelial growth factor therapy allows both favorable visual and anatomical outcomes in this rapidly evolving disease. Prognosis remains poor in severe stages, suggesting that the earlier the surgery performed, the better is the visual prognosis. PMID- 25011027 TI - Evaluation of the safety of sclerotomy incision in patients with choroidal colobomas with/without associated microcornea. AB - PURPOSE: Whether the position of the ora serrata is normal in patients with choroidal colobomas remains unknown. The aim of this study was to measure the distance between the ora serrata and limbus in these patients and define safe sclerotomy sites for standard three-port pars plana vitrectomy. METHODS: Twelve patients with choroidal colobomas with normal corneas (Group 1) and 11 patients with choroidal colobomas with microcornea (Group 2) were included in the study. Twelve patients with simple retinal detachment served as control subjects. All participants underwent vitrectomy. The distance between the limbus and ora serrata, corneal diameter, and ocular axial length were measured. RESULTS: The average corneal diameter was 10.9 mm in Group 1, 7.9 mm in Group 2, and 11.4 mm in the control group. The average distance between the limbus and ora serrata was 6.3 mm in Group 1, 7.6 mm in Group 2, and 6.2 mm in the control group. There were significant differences in the distance between the limbus and ora serrata among the 3 groups (analysis of variance test, P < 0.05). CONCLUSION: Our study confirmed that it is safe to perform a sclerotic puncture 4 mm posterior to the limbus for vitrectomy in patients with choroidal colobomas with or without microcornea. PMID- 25011028 TI - Differential diagnosis of macular edema of different pathophysiologic origins by spectral domain optical coherence tomography. AB - PURPOSE: To develop a classification approach based solely on spectral domain optical coherence tomography to differentiate macular edema (ME) of different disease entities and to determine underlying pathology. METHODS: A cross sectional study including 153 participants: 27 with Irvine-Gass, 31 with uveitic ME, 24 with ME after branch retinal vein occlusion, 13 with central retinal vein occlusion, 44 with diabetic ME, and 14 controls. Spectral domain optical coherence tomography was graded according to a standardized reading protocol. Grading characteristics were: ME pattern in the central line (horizontal/vertical) and in volume scans, distribution of cysts in Early Treatment Diabetic Retinopathy Study grid, morphologic features, and quantitative parameters such as individual layer thickness. The parameters in a best-fitting multivariate model were evaluated for reliability to predict the underlying pathology using a leave-one-out crossover-validation analysis. To evaluate clinical reliability, two masked clinicians graded spectral domain optical coherence tomography images according to the assessed parameters. RESULTS: The best-fitting multivariate model revealed that microfoci, ME pattern in vertical line scan, and foveal retinal nerve fiber layer thickness are the best indicators of the underlying pathology of ME. Classification accuracy of this model was 96%, mean cross-validated test classification accuracy was 84% (r2 = 0.95, P < 0.0001). Clinical relevance was examined with 2 independent readers, yielding classification accuracies of 86% in both cases. CONCLUSION: Macular edema demonstrates characteristic patterns, morphologic features, and layer thicknesses dependent on the underlying disease process. Diagnostic recognition of these features may allow clinical and automated disease identification based primarily on spectral domain optical coherence tomography analysis. PMID- 25011029 TI - To the editor. PMID- 25011030 TI - To the editor. PMID- 25011031 TI - To the editor. PMID- 25011032 TI - To the editor. PMID- 25011033 TI - Reply: To PMID 24509489. PMID- 25011034 TI - Reply: To PMID 24531737. PMID- 25011035 TI - Chiral effect at protein/graphene interface: a bioinspired perspective to understand amyloid formation. AB - Protein misfolding to form amyloid aggregates is the main cause of neurodegenerative diseases. While it has been widely acknowledged that amyloid formation in vivo is highly associated with molecular surfaces, particularly biological membranes, how their intrinsic features, for example, chirality, influence this process still remains unclear. Here we use cysteine enantiomer modified graphene oxide (GO) as a model to show that surface chirality strongly influences this process. We report that R-cysteine modification suppresses the adsorption, nucleation, and fiber elongation processes of Abeta(1-40) and thus largely inhibits amyloid fibril formation on the surface, while S-modification promotes these processes. And surface chirality also greatly influences the conformational transition of Abeta(1-40) from alpha-helix to beta-sheet. More interestingly, we find that this effect is highly related to the distance between chiral moieties and GO surface, and inserting a spacer group of about 1-2 nm between them prevents the adsorption of Abeta(1-40) oligomers, which eliminates the chiral effect. Detailed study stresses the crucial roles of GO surface. It brings novel insights for better understanding the amyloidosis process on surface from a biomimetic perspective. PMID- 25011036 TI - A longitudinal study of emotional intelligence training for otolaryngology residents and faculty. AB - IMPORTANCE: Emotions underlie and influence physician communications and relationships with patients and colleagues. Training programs to enhance emotional attunement, or emotional intelligence (EI), for physicians and assess training effects are scarce. OBJECTIVE: To assess whether an EI training program for otolaryngology residents and faculty affects patient satisfaction. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal, cohort study of physician residents and faculty in an EI training program at the Department of Otolaryngology, University of Kansas Medical Center, with annual training from 2005 to 2011. INTERVENTIONS: Three levels of interventions included 4 years of repeated EI assessment, 7 years of highly interactive EI training with high risk/high-stress simulations, and ongoing modeling and mentoring of EI skills by faculty. MAIN OUTCOMES AND MEASURES: Four levels of outcome of the EI training were assessed with the following questions: Did participants enjoy the program? Could they apply the training to their practice? Did it change their behavior? Did it affect patient satisfaction? The Emotional Quotient Inventory (EQ-i) was administered to faculty and residents, and the Press Ganey Patient Satisfaction Survey was completed by patients. RESULTS: Ninety-seven percent of participants (103 of 106) reported that they enjoyed the programs, and 98% (104 of 106) reported that they have or could have applied what they learned. Participants demonstrated improvement in mean EQ-i scores from 102.19 (baseline/pretraining) to 107.29 (posttraining and assessment 1 year later; change, 6.71; 95% CI, 3.44 9.98). This increase was sustained in successive years, and these results were supported with linear growth curve analysis. The total department mean EQ-i score in pretraining year 2005 was 104.29 ("average" range), with posttraining scores in the "high average" range (112.46 in 2006, 111.67 in 2007, and 113.15 in 2008). An increase in EQ-i scores and EI training corresponded with an increase in patient satisfaction scores. Percentile rank patient satisfaction scores before EI training ranged from 85% to 90%; after training, scores ranged from 92% to 99%. CONCLUSIONS AND RELEVANCE: Emotional intelligence training positively influences patient satisfaction and may enhance medical education and health care outcome. PMID- 25011037 TI - Older persons and compromised decisional capacity: the role of public policy in defining and developing core professional competencies. AB - Issues frequently arise concerning the cognitive and emotional ability of older individuals to make certain legally significant decisions. In confronting these issues, the professional involvement of both attorneys and physicians (and other health care professionals), acting both individually and collaboratively, is desirable. This article describes the possible contributions of public policy in developing, through fostering innovations in medical and legal education, core competencies for physicians and attorneys that are essential to improving interprofessional collaboration on behalf of older individuals suspected of being compromised in their ability to make certain significant decisions. Additionally, ideas are suggested to address certain aspects of the current policy environment that may inhibit attorneys and physicians from optimal interprofessional interaction in this sphere. PMID- 25011038 TI - Design and synthesis of coumarin-3-acylamino derivatives to scavenge radicals and to protect DNA. AB - In this study, a series of coumarin-3-acylamino derivatives containing phenethylamine moiety or tyramine moiety were synthesized and their antioxidant activities were evaluated by Cu(2+)/glutathione(GSH)-, OH- and 2,2'-azobis(2 amidinopropane hydrochloride)(AAPH)-induced oxidation of DNA. It was found that both hydroxyl and ortho-methoxy groups at A ring, hydroxyl group at B ring and peptide bond can enhance the abilities of coumarin-3-acylamino derivatives to protect DNA against OH- and AAPH-induced oxidation. Moreover, these coumarin-3 acylamino derivatives were employed to scavenge 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+)). We found that tyramine moiety, hydroxyl and ortho-methoxy are the key groups to enhance the activities of antioxidants to quench ABTS(+). Therefore, tyramine linked with coumarin-3-carboxyl acid which containing hydroxyl and ortho-methoxy exhibited powerful antioxidant abilities. PMID- 25011039 TI - Synthesis, structure, spectroscopic and ferroelectric properties of an acentric polyoxotungstate containing 1:2-type [Sm(alpha-PW11O39)2]11- fragment and D proline components. AB - An organic-inorganic hybrid mono-Sm(III) substituted phosphotungstate KNa3[HPro]7[Sm(alpha-PW11O39)2].Pro.18H2O (1) (Pro=D-proline) has been synthesized in the conventional aqueous solution and structurally characterized by elemental analyses, inductively coupled plasma atomic emission spectrometry (ICP-AES) analyses, IR spectra, UV spectra, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and single-crystal X-ray diffraction. The molecule of 1 consists of a classical 1:2-type [Sm(alpha-PW11O39)2](11-) fragment and free D-proline components. It should be pointed out that the synergistic action between the in-situ formed chiral [Sm(alpha-PW11O39)2](11-) fragment and chiral D-proline components results in the formation of the chiral 1. The luminescence emission of 1 reveals three characteristic bands that derive from the (4)G5/2->(6)H5/2, (4)G5/2->(6)H7/2 and (4)G5/2->(6)H9/2 transitions of the Sm(III) cation as well as the synergistic contribution of the O->W transitions of [alpha-PW11O39](7-) moieties and a pi(*)-n or pi(*)-pi transitions of Pro. Its ferroelectric behavior has been measured. PMID- 25011040 TI - Determination of N-acetylation degree in chitosan using Raman spectroscopy. AB - Application of Raman spectroscopy in determination of the acetylation degree (DA) of chitosan has been developed. The spectra of several chitosan samples characterized by different DD (degree of deacetylation) in the range 50-100% have been measured. The integral intensities of the bands assigned to the vibrations of amine group and glucosidic ring were used to calculate the DA from the intensity ratio. The assignment of the bands to the respective normal modes of chitosan was based on the DFT quantum chemical calculations. This method has a number of advantages over other techniques. It is fast and does not require purification of the sample nor require dissolution of the chitosan in any solvent. PMID- 25011041 TI - Vibrational spectroscopic studies, normal co-ordinate analysis, first order hyperpolarizability, HOMO-LUMO of midodrine by using density functional methods. AB - The FTIR (4000-400 cm(-1)), FT-Raman (4000-100 cm(-1)) and UV-Visible (400-200 nm) spectra of midodrine were recorded in the condensed state. The complete vibrational frequencies, optimized geometry, intensity of vibrational bands and atomic charges were obtained by using Density Functional Theory (DFT) with the help of 6-311++G(d,p) basis set. The first order hyperpolarizability (beta) and related properties (MU, alpha and Deltaalpha) of this molecular system were calculated by using DFT/6-311++G(d,p) method based on the finite-field approach. The assignments of the vibrational spectra have been carried out with the help of Normal Co-ordinate Analysis (NCA) following the scaled quantum mechanical force methodology. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using NBO analysis. From the recorded UV-Visible spectrum, the electronic properties such as excitation energies, oscillator strength and wavelength are calculated by DFT in water and gas methods using 6-311++G(d,p) basis set. The calculated HOMO and LUMO energies confirm that charge transfer occurs within the molecule. Besides MEP, NLO and thermodynamic properties were also calculated and interpreted. The electron density-based local reactivity descriptor such as Fukui functions was calculated to explain the chemical selectivity or reactivity site in midodrine. PMID- 25011042 TI - A study of vibrational spectra and investigations of charge transfer and chemical bonding features of 2-chloro benzimidazole based on DFT computations. AB - Benzimidazoles are bicyclic heteroatomic molecules. Polycyclic heteroatomic molecules have extensive coupling of different modes leading to strong coupling of force constants associated with the various chemical bonds of the molecules. To carry out a detailed vibrational spectroscopic analysis of such a bicyclic heteroatomic molecule, FT-IR and FT-Raman spectra of 2-chloro benzimidazole (CBZ) have been recorded in the condensed phase. Density Functional Theory calculations in the B3LYP/6-31G(*) level have been carried out to determine the optimized geometry and vibrational frequencies. In order to obtain a close agreement between theoretical and observed frequencies and hence to perform a reliable assignment, the theoretical DFT force field was transformed from Cartesian to local symmetry co-ordinates and then scaled empirically using SQM methodology. The SQM treatment resulted in a RMS deviation of 9.4 cm(-1). For visual comparison, the observed and calculated spectra are presented on a common wavenumber scale. From the NBO analysis, the electron density (ED) charge transfers in the sigma(*) and pi(*) antibonding orbitals and second order delocalization energies E((2)) confirms the occurrence of intramolecular charge transfer (ICT) within the molecule. The calculated Homo and Lumo energies show that charge transfer occurs within the molecule. The results obtained from the vibrational, NBO and HOMO-LUMO analyses have been properly tabulated. PMID- 25011043 TI - Spectroscopic, potentiometric and theoretical studies of novel imino-phenolate chelators for Fe(III). AB - The present study was targeted to explore the binding properties of two strong chelators for Fe(III) based on tripodal-iminophenolate moiety. Complexation behavior of the tripodal systems cis-cis cyclohexane-1,3,5-tricarboxylic acid tris-({2-[(2-hydroxy-benzylidene)-amino]-ethyl}-amide (CYCOENSAL, L(1)) and cis cis cyclohexane-1,3,5-tricarboxylic acid tris-({3-[(2-hydroxy-benzylidene)-amino] propyl}-amide (CYCOPNSAL, L(2)) is described. Three protonation constants obtained are assigned for three hydroxyl groups of aromatic ring were employed for the evaluation of the formation constants of the metal complexes. Both ligands liberate three protons each forming monomeric complexes of type FeLH3, FeLH2, FeLH and FeL (L=L(1) and L(2)). The first species FeLH3 depicted at low pH, where the ligands were coordinated through three imine nitrogen and other species form subsequently from FeLH3 in steps upon deprotonation and coordination of the phenolic oxygen giving encapsulated tris(phenolate) complexes. The probable structures of the metal complexes formed in solution were proposed through molecular modeling calculations. L(2) was observed to be highly selective towards Fe(III) as compared to L(1). PMID- 25011044 TI - Investigation of trypsin-CdSe quantum dot interactions via spectroscopic methods and effects on enzymatic activity. AB - The paper presents the interactions between trypsin and water soluble cadmium selenide (CdSe) quantum dots investigated by spectrophotometric methods. CdSe quantum dots have strong ability to quench the intrinsic fluorescence of trypsin by a static quenching mechanism. The quenching has been studied at three different temperatures where the results revealed that electrostatic interactions exist between CdSe quantum dots and trypsin and are responsible to stabilize the complex. The Scatchard plot from quenching revealed 1 binding site for quantum dots by trypsin, the same has been confirmed by making isothermal titrations of quantum dots against trypsin. The distance between donor and acceptor for trypsin CdSe quantum dot complexes is calculated to be 2.8 nm by energy transfer mechanisms. The intrinsic fluorescence of CdSe quantum dots has also been enhanced by the trypsin, and is linear for concentration of trypsin ranging 1-80 MUl. All the observations evidence the formation of trypsin-CdSe quantum dot conjugates, where trypsin retains the enzymatic activity which in turn is temperature and pH dependent. PMID- 25011045 TI - Structural and photophysical properties of HPPCO (4-hydroxy-5-phenyl-6H pyrido[3,2,1-jk]carbazol-6-one) derivatives. AB - Proton-substitution effects of 4-hydroxy-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-6 one (HPPCO) on structural and photophysical properties were presented. HPPCO crystallized in the orthorhombic space group Pbca with an intermolecular hydrogen bonding between OH and oxygen atom of the carbonyl. The proton-substituted derivatives, 6-oxo-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-4-yl acetate (OPPCA) and 6-oxo-5-phenyl-6H-pyrido[3,2,1-jk]carbazol-4-yl benzoate (OPPCB), crystallized in the monoclinic P21/c space group. For OPPCA and OPPCB, a weak interaction between carbonyl oxygen atom in the substituted group and carbon atom in the fused ring was responsible for three-dimensional arrangements. In addition, 6-oxo-5-phenyl 6H-pyrido[3,2,1-jk]carbazol-4-yl furan-2-carboxylate (OPPCF), and 6-oxo-5-phenyl 6H-pyrido[3,2,1-jk]carbazol-4-yl naphthoate (OPPCN) were also synthesized. HPPCO and the four derivatives excited by ultraviolet (UV) light produced blue emission. Proton substitution of the OH group significantly increased the radiative transitions and moderately decreased the non-radiative transitions. Consequently the luminescence quantum yields of the derivatives enhanced more than 4.6-fold, no matter what the groups were substituted. Structural and optical properties were further determined using density functional theory (DFT) and ZINDO calculations. The planar structure of the pyridocarbazole-fused ring resulted in pi->pi(*) electronic transitions within the main frame, with an additional transition from the n(O) of carbonyl to the pi(*) of the main frame. The three excited states that arose from these transitions were responsible for the blue luminescence. PMID- 25011046 TI - Clinical consequences of Tityus bahiensis and Tityus serrulatus scorpion stings in the region of Campinas, southeastern Brazil. AB - Scorpion stings account for most envenomations by venomous animals in Brazil. A retrospective study (1994-2011) of the clinical consequences of Tityus scorpion stings in 1327 patients treated at a university hospital in Campinas, southeastern Brazil, is reported. The clinical classification, based on outcome, was: dry sting (no envenoming), class I (only local manifestations), class II (systemic manifestations), class III (life-threatening manifestations, such as shock and/or cardiac failure requiring inotropic/vasopressor agents, and/or respiratory failure), and fatal. The median patient age was 27 years (interquartile interval = 15-42 years). Scorpions were brought for identification in 47.2% of cases (Tityus bahiensis 27.7%; Tityus serrulatus 19.5%). Sting severity was classified and each accounted for the following percentage of cases: dry stings - 3.4%, class I - 79.6%, class II - 15.1%, class III - 1.8% and fatal 0.1%. Pain was the primary local manifestation (95.5%). Systemic manifestations such as vomiting, agitation, sweating, dyspnea, bradycardia, tachycardia, tachypnea, somnolence/lethargy, cutaneous paleness, hypothermia and hypotension were detected in class II or class III + fatal groups, but were significantly more frequent in the latter group. Class III and fatal cases occurred only in children <15 years old, with scorpions being identified in 13/25 cases (T. serrulatus, n = 12; T. bahiensis, n = 1). Laboratory blood abnormalities (hyperglycemia, hypokalemia, leukocytosis, elevations in serum total CK, CK-MB and troponin T, bicarbonate consumption and an increase in base deficit and blood lactate), electrocardiographic changes (ST segment) and echocardiographic alterations (ventricular ejected fraction <54%) were frequently detected in class III patients. Seventeen patients developed pulmonary edema, 16 had cardiac failure and seven had cardiogenic shock. These results indicate that most scorpion stings involved only local manifestations, mainly pain; the greatest severity was associated with stings by T. serrulatus and in children <15 years old. PMID- 25011047 TI - Recent progress on the structure and function of the TrkH/KtrB ion channel. AB - Members of the Superfamily of K(+) Transporters (SKT) are integral membrane proteins that mediate the uptake of ions into non-animal cells. Although these proteins are homologous to the well-characterized K(+) channel family, relatively little was known about their transport and gating mechanisms until the recent determination of crystal structures for two SKT proteins, TrkH and KtrB. These structures reveal that the SKT proteins are channels, containing a flexible loop in the middle of the permeation pathway that may act as a gate. Two different conformational changes have been observed for the associated gating rings, suggesting different mechanisms of regulation by the binding of nucleotides. PMID- 25011048 TI - Editorial comment. PMID- 25011049 TI - Editorial comment. PMID- 25011050 TI - Editorial comment. PMID- 25011051 TI - Preparation of inorganic/organic polymer hybrid microcapsules with high encapsulation efficiency by an electrospray technique. AB - Microcapsules composed of calcium phosphate and chitosan were prepared in a single step by electrospraying. An aqueous solution containing calcium chloride and chitosan was electrosprayed into a phosphate solution to form a calcium phosphate shell on the sprayed droplets. The resulting microcapsules were 350 MUm in average diameter. Investigation using fluorescently labeled chitosan and XRD measurements revealed that the shells of the microcapsules were composed of calcium phosphate (mainly hydroxyapatite) and chitosan. Instead of chitosan, poly(diallyldimethylammonium chloride) and polyethylene glycol were also available for microcapsule production by electrospraying. Variations in the electrospraying conditions resulted in a variety of microcapsule shapes. Various types of substrates were successfully encapsulated in microcapsules with a high encapsulation efficiency (more than 80%). Finally, we succeeded in the encapsulation of living yeast cells in microcapsules, and observed their growth within these microcapsules. PMID- 25011054 TI - Rerouting radical cascades: intercepting the homoallyl ring expansion in enyne cyclizations via C-S scission. AB - The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3 exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C-C bond fragmentation. The interception of the intermediate 5-exo-trig product via beta-scission of a properly positioned weak C S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu3Sn-functionalized naphthalenes. PMID- 25011053 TI - miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties. AB - Renal cell carcinoma (RCC) is an aggressive disease, with 35% chance of metastasis. The 'cancer stem cell' hypothesis suggests that a subset of cancer cells possess stem cell properties and is crucial in tumor initiation, metastasis and treatment resistance. We isolated RCC spheres and showed that they exhibit cancer stem cell/ tumor initiating cell-like properties including the formation of self-renewing spheres, high tumorigenicity and the ability to differentiate to cell types of the original tumor. Spheres showed increased expression of stem cell-related transcription factors and mesenchymal markers. miRNAs were differentially expressed between RCC spheres and their parental cells. Inhibition of miR-17 accelerated the formation of RCC spheres which shared molecular characteristics with the spontaneous RCC spheres. Target prediction pointed out TGFbeta pathway activation as a possible mechanism to drive RCC sphere formation. We demonstrate that miR-17 overexpression interferes with the TGFbeta-EMT axis and hinders RCC sphere formation; and validated TGFBR2 as a direct and biologically relevant target during this process. Thus, a single miRNA may have an impact on the formation of highly tumorigenic cancer spheres of kidney cancer. PMID- 25011055 TI - Intermolecular stabilization of 3,3'-diamino-4,4'-azoxyfurazan (DAAF) compressed to 20 GPa. AB - The room temperature stability of 3,3'-diamino-4,4'-azoxyfurazan (DAAF) has been investigated using synchrotron far-infrared, mid-infrared, Raman spectroscopy, and synchrotron X-ray diffraction (XRD) up to 20 GPa. The as-loaded DAAF samples exhibited subtle pressure-induced ordering phenomena (associated with positional disorder of the azoxy "O" atom) resulting in doubling of the a-axis, to form a superlattice similar to the low-temperature polymorph. Neither high pressure synchrotron XRD, nor high pressure infrared or Raman spectroscopies indicated the presence of structural phase transitions up to 20 GPa. Compression was accommodated in the unit cell by a reduction of the c-axis between the planar DAAF layers, distortion of the beta-angle of the monoclinic lattice, and an increase in intermolecular hydrogen bonding. Changes in the ring and -NH2 deformation modes and increased intermolecular hydrogen bonding interactions with compression suggest molecular reorganizations and electronic transitions at ~ 5 GPa and ~ 10 GPa that are accompanied by a shifting of the absorption band edge into the visible. A fourth-order Birch-Murnaghan fit to the room temperature isotherm afforded an estimate of the zero-pressure isothermal bulk modulus, K0 = 12.4 +/- 0.6 GPa and its pressure derivative K0' = 7.7 +/- 0.3. PMID- 25011056 TI - Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo. AB - Adrenocorticotropic hormone (ACTH) production by pituitary corticotroph adenomas is the main cause of Cushing's disease. A drug that targets pituitary ACTH secreting adenomas would aid treatment of Cushing's disease. Octreotide, a somatostatin receptor type 2 (SSTR2)-preferring somatostatin analogue, has no effect on ACTH secretion in patients with Cushing's disease. The multiligand SOM230 (pasireotide) displays a much higher affinity for SSTR1 and SSTR5 than octreotide and suppresses ACTH secretion in cultures of human corticotroph tumors to a greater extent than octreotide. In the present in vitro and in vivo study, we determined the effect of SOM230 on ACTH production and cell proliferation of AtT-20 corticotroph tumor cells. SOM230 decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and ACTH levels in the culture medium of these cells, suggesting that SOM230 suppresses ACTH synthesis and secretion in corticotroph tumor cells. SOM230 also decreased cell proliferation and both cyclic adenosine monophosphate response element-binding protein and Akt phosphorylation in AtT-20 cells. SSTR5 knockdown inhibited the SOM230-induced decreases in cell proliferation. Fluorescence-activated cell sorting analyses revealed that SOM230 did not attenuate cell cycle progression. Tumor weight in mice xenografted with AtT-20 cells and treated with SOM230 was significantly lower than in AtT-20 xenografted control mice. SOM230 also significantly decreased plasma ACTH levels, and POMC and pituitary tumor transforming gene mRNA levels in the tumor cells. Thus, SOM230 inhibits ACTH production and corticotroph tumor cell proliferation in vitro and in vivo. PMID- 25011058 TI - Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis feedback system. AB - Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100MUg/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA. PMID- 25011057 TI - Transcriptome analysis of human adipocytes implicates the NOD-like receptor pathway in obesity-induced adipose inflammation. AB - Adipose tissue inflammation increases with obesity, but adipocyte vs. immune cell contributions are unclear. In the present study, transcriptome analyses were performed on highly-purified subcutaneous adipocytes from lean and obese women, and differentially expressed genes/pathways were determined in both adipocyte and stromal vascular fraction (SVF) samples. Adipocyte but not SVF expression of NOD like receptor pathway genes, including NLRP3 and PYCARD, which regulate caspase-1 mediated IL-1beta secretion, correlated with adiposity phenotypes and adipocyte class II major histocompatibility complex (MHCII) gene expression, but only MHCII remained after adjusting for age and body mass index. IFNgamma stimulated adipocyte MHCII, NLRP3 and caspase-1 expression, while adipocyte MHCII-mediated CD4(+) T cell activation, an important factor in adipose inflammation, induced IFNgamma-dependent adipocyte IL-1beta secretion. These results uncover a dialogue regulated by interactions among T cell IFNgamma and adipocyte MHCII and NLRP3 inflammasome activity that appears to initiate and escalate adipose tissue inflammation during obesity. PMID- 25011059 TI - Chemical constituents from Myristica fragrans fruit. AB - A neolignan, erythrosurinamensin and a diaryl phenyl propanoid, virolane were isolated from Myristica fragrans for the first time. Apart from these two, previously known steroids, other lignans and neolignans were isolated from the fruit pericarp of M. fragrans. The structures of the compounds were identified by employing various spectroscopic methods. PMID- 25011061 TI - Phase behaviour of PMMA-b-PHEMA with solvents methanol and THF: modelling and comparison to the experiment. AB - Self-consistent field theory is used to model the self-assembly of a symmetric PMMA-block-PHEMA in the presence of two solvents, methanol and tetrahydrofuran (THF). The model predictions are compared to our experimental results of solvent vapour annealing of thin polymer films, where the sequence of cylinder to gyroid (or micelles) to lamellar phases was found upon increasing the methanol-THF ratio and for particular extents of film swelling. The Hansen solubility parameters are used to estimate the Flory-Huggins interaction parameters (chi) needed in the theoretical model. However, because enacting the experimental range of high (chi)N values is computationally prohibitive, the use of moderate (chi)N values is compensated by employing larger values of the solvent-to-polymer size ratio (alpha). This approach is validated by showing that the predicted phase diagrams exhibit qualitatively similar trends whether (chi)N or alpha is increased. Using such an approach, the theory predicts a cylinder to gyroid to lamellar transition on increasing the THF-methanol ratio, a trend consistent with that observed in the experiments. PMID- 25011060 TI - Quantitative evaluation of Radix Paeoniae Alba sulfur-fumigated with different durations and purchased from herbal markets: simultaneous determination of twelve components belonging to three chemical types by improved high performance liquid chromatography-diode array detector. AB - In this study, a improved high performance liquid chromatography-diode array detector (HPLC-DAD) method for simultaneous quantification of twelve major components belonging to three chemical types was developed and validated, and was applied to quantitatively compare the quality of Radix Paeoniae Alba (RPA) sulfur fumigated with different durations and purchased from commercial herbal markets. The contents of paeoniflorin, benzoylpaeoniflorin, oxypaeoniflorin, benzoic acid and paeonol decreased whereas that of paeoniflorin sulfonate increased in RPA with the extending of sulfur-fumigation duration. Different levels of paeoniflorin sulfonate were determined in ten of seventeen commercial RPA samples, indicating that these ten samples may be sulfur-fumigated with different durations. Moreover, the relative standard deviation of the contents of each component was higher in the commercial sulfur-fumigated RPA samples than that in commercial non-fumigated RPA samples, and the percentage of the total average content of monoterpene glycosides in the determined analytes was higher in the decoctions of commercial sulfur-fumigated RPA than that in commercial non fumigated RPA samples. All these results suggested that the established method was precise, accurate and sensitive enough for the global quality evaluation of sulfur-fumigated RPA, and sulfur-fumigation can not only change the proportions of bioactive components, but also cause the reduction of the quality consistency of both raw materials and aqueous decoctions of RPA. PMID- 25011062 TI - Reconstruction of intracortical whisker-evoked local field potential from electrocorticogram using a model trained for spontaneous activity in the rat barrel cortex. AB - Electrocorticogram (ECoG) has provided neural information from the cortical surfaces, is widely used in clinical applications, and expected to be useful for brain-machine interfaces. Recent studies have defined the relationship between neural activity in deep layers of the cerebral cortex and ECoG. However, it is still unclear whether this relationship is shared across different brain states. In this study, spontaneous activity and whisker-evoked responses in the barrel cortex of anesthetized rats were recorded with a 32-channel ECoG electrode array and 32-channel linear silicon probe electrodes, respectively. Spontaneous local field potentials (LFPs) at various depths could be reconstructed with high accuracy (R>0.9) by a linear weighted summation of spontaneous ECoG. Current source density analysis revealed that the reconstructed LFPs correctly represented laminar profiles of current sinks and sources as well as the raw LFP. Moreover, when we applied the spontaneous activity model to reconstruction of LFP from the whisker-related ECoG, high accuracy of reconstruction could be obtained (R>0.9). Our results suggest that the ECoG carried rich information about synaptic currents in the deep layers of the cortex, and the same reconstruction model can be applied to estimate both spontaneous activity and whisker-evoked responses. PMID- 25011063 TI - C6 deficiency does not alter intrinsic regeneration speed after peripheral nerve crush injury. AB - Peripheral nerve injury leads to Wallerian degeneration, followed by regeneration, in which functionality and morphology of the nerve are restored. We previously described that deficiency for complement component C6, which prevents formation of the membrane attack complex, slows down degeneration and results in an earlier recovery of sensory function after sciatic nerve injury compared to WT animals. In this study, we determine whether C6(-/-) rats have an intrinsic trait that affects sciatic nerve regeneration after injury. To study the contribution of complement activation on degeneration and regeneration with only minimal effect of complement activation, a crush injury model with only modest complement deposition was used. We compared the morphological and functional aspects of crushed nerves during degeneration and regeneration in C6(-/-) and WT animals. Morphological changes of myelin and axons showed similar degeneration and regeneration patterns in WT and C6(-/-) injured nerves. Functional degeneration and regeneration, recorded by ex vivo electrophysiology and in vivo foot flick test, showed that the timeline of the restoration of nerve conduction and sensory recovery also followed similar patterns in WT and C6(-/-) animals. Our findings suggest that C6 deficiency by itself does not alter the regrowth capacity of the peripheral nerve after crush injury. PMID- 25011064 TI - European survey on laboratory preparedness, response and diagnostic capacity for Crimean-Congo haemorrhagic fever, 2012. AB - Crimean-Congo haemorrhagic fever (CCHF) is an infectious viral disease that has (re-)emerged in the last decade in south-eastern Europe, and there is a risk for further geographical expansion to western Europe. Here we report the results of a survey covering 28 countries, conducted in 2012 among the member laboratories of the European Network for Diagnostics of 'Imported' Viral Diseases (ENIVD) to assess laboratory preparedness and response capacities for CCHF. The answers of 31 laboratories of the European region regarding CCHF case definition, training necessity, biosafety, quality assurance and diagnostic tests are presented. In addition, we identified the lack of a Regional Reference Expert Laboratory in or near endemic areas. Moreover, a comprehensive review of the biosafety level suitable to the reality of endemic areas is needed. These issues are challenges that should be addressed by European public health authorities. However, all respondent laboratories have suitable diagnostic capacities for the current situation. PMID- 25011065 TI - Rapid spread of the novel respiratory syncytial virus A ON1 genotype, central Italy, 2011 to 2013. AB - Respiratory infections positive for human respiratory syncytial virus (RSV) subtype A were characterised in children admitted to hospitals in Rome and Ancona (Italy) over the last three epidemic seasons. Different strains of the novel RSV A genotype ON1, first identified in Ontario (Canada) in December 2010, were detected for the first time in Italy in the following 2011/12 epidemic season. They bear an insertion of 24 amino acids in the G glycoprotein as well as amino acid changes likely to change antigenicity. By early 2013, ON1 strains had spread so efficiently that they had nearly replaced other RSV-A strains. Notably, the RSV peak in the 2012/13 epidemic season occurred earlier and, compared with the previous two seasons, influenza-like illnesses diagnoses were more frequent in younger children; bronchiolitis cases had a less severe clinical course. Nonetheless, the ON1-associated intensive care unit admission rate was similar, if not greater, than that attributable to other RSV-A strains. Improving RSV surveillance would allow timely understanding of the epidemiological and clinicopathological features of the novel RSV-A genotype. PMID- 25011066 TI - Letter to the editor: cutaneous diphtheria in a migrant from an endemic country in east Africa, Austria May 2014. PMID- 25011069 TI - ECDC publishes a directory of online resources for prevention and control of antimicrobial resistance and healthcare-associated infections. PMID- 25011070 TI - Is plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) determination in donors and recipients predictive of renal function after kidney transplantation? AB - OBJECTIVES: Delayed graft function (DGF) is still a major issue in kidney transplantation. Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) were evaluated in a population of kidney donors and recipients to investigate their performance to predict early renal function. DESIGN AND METHODS: Plasma (pNGAL) and urine (uNGAL) samples were obtained from donors before organ procurement, and from recipients before transplantation, and then 6, 24 and 48h after the procedure. Kidney transplantations were performed from both living donors (LDs, n=17) and deceased donors (DDs, n=80). Recovery of renal function was evaluated as the time to reach serum creatinine <2mg/l or glomerular filtration rate (GFR)>40mL/min. Logistic regression was used to assess the ability of different variables to predict the occurrence of DGF. RESULTS: Plasma NGAL levels were significantly lower in LDs than in DDs. No episodes of DGF were recorded among LD kidney recipients, but DGF was observed in 25% of patients in the DD group. There was no correlation between donor pNGAL and uNGAL values and the occurrence of post-transplant DGF. Recipient pNGAL performed better than uNGAL in terms of predicting DGF occurrence. Donor pNGAL and uNGAL values did not influence the time needed to reach serum creatinine levels of <2mg/dl after transplantation. When time to reach eGFR of >40mL/min is considered, only donor uNGAL seems to be a predictor of graft function recovery. However, recipient pNGAL values obtained 24 and 48h after transplantation, but not uNGAL values, were found to be a significant predictor of graft function recovery. CONCLUSIONS: Plasma NGAL level determination in recipients, but not in donors, proved to be a reliable predictor of DGF occurrence and renal function restoration, but too long for an interval to be able to compete with biomarkers currently used in clinical practice. PMID- 25011071 TI - Blood distribution of bortezomib and its kinetics in multiple myeloma patients. AB - OBJECTIVES: Pharmacokinetic disposition of bortezomib in the blood has not been fully characterized in humans. This study aimed to evaluate the blood distribution of bortezomib and its kinetics in multiple myeloma patients. DESIGN AND METHOD: Eighteen multiple myeloma patients receiving bortezomib-dexamethasone combination therapy were enrolled. Blood specimens were drawn just before bortezomib administration on days 1 and 8 in the second and third cycles and after discontinuation. The relationships between bortezomib concentration and blood components were evaluated. RESULTS: Bortezomib concentration in the blood on day 1 was higher than that on day 8 in the second cycle. No difference was observed in bortezomib blood concentrations between day 8 in the second and third cycles. The bortezomib concentration in the blood and blood cells was 3- and 7 fold higher than that in plasma. Bortezomib concentration in the blood was correlated with the red blood cell count. The half-life of bortezomib in the blood was 23days. CONCLUSION: Bortezomib was taken up into red blood cells to only a limited extent and eliminated in parallel to the red blood cells' lifespan. The turnover of red blood cells can affect the pharmacokinetic disposition of bortezomib in multiple myeloma patients. PMID- 25011072 TI - Mitochondrial and ER-targeted eCALWY probes reveal high levels of free Zn2+. AB - Zinc (Zn2+) ions are increasingly recognized as playing an important role in cellular physiology. Whereas the free Zn2+ concentration in the cytosol has been established to be 0.1-1 nM, the free Zn2+ concentration in subcellular organelles is not well-established. Here, we extend the eCALWY family of genetically encoded Forster Resonance Energy Transfer (FRET) Zn2+ probes to permit measurements in the endo(sarco)plasmic reticulum (ER) and mitochondrial matrix. Deployed in a variety of mammalian cell types, these probes reveal resting mitochondrial free [Zn2+] values of ~300 pM, somewhat lower than in the cytosol but 3 orders of magnitude higher than recently reported using an alternative FRET-based sensor. By contrast, free ER [Zn2+] was found to be >=5 nM, which is >5000-fold higher than recently reported but consistent with the proposed role of the ER as a mobilizable Zn2+ store. Treatment of beta-cells or cardiomyocytes with sarco(endo)plasmic reticulum Ca2+-ATPase inhibitors, mobilization of ER Ca2+ after purinergic stimulation with ATP, or manipulation of ER redox, exerted no detectable effects on [Zn2+]ER. These findings question the previously proposed role of Ca2+ in Zn2+ mobilization from the ER and suggest that high ER Zn2+ levels may be an important aspect of cellular homeostasis. PMID- 25011073 TI - Procedure for the characterization of radon potential in existing dwellings and to assess the annual average indoor radon concentration. AB - Risk assessment due to radon exposure indoors is based on annual average indoor radon activity concentration. To assess the radon exposure in a building, measurement is generally performed during at least two months during heating period in order to be representative of the annual average value. This is because radon presence indoors could be very variable during time. This measurement protocol is fairly reliable but may be a limiting in the radon risk management, particularly during a real estate transaction due to the duration of the measurement and the limitation of the measurement period. A previous field study defined a rapid methodology to characterize radon entry in dwellings. The objective of this study was at first, to test this methodology in various dwellings to assess its relevance with a daily test. At second, a ventilation model was used to assess numerically the air renewal of a building, the indoor air quality all along the year and the annual average indoor radon activity concentration, based on local meteorological conditions, some building characteristics and in-situ characterization of indoor pollutant emission laws. Experimental results obtained on thirteen individual dwellings showed that it is generally possible to obtain a representative characterization of radon entry into homes. It was also possible to refine the methodology defined in the previous study. In addition, numerical assessments of annual average indoor radon activity concentration showed generally a good agreement with measured values. These results are encouraging to allow a procedure with a short measurement time to be used to characterize long-term radon potential in dwellings. PMID- 25011074 TI - Environmental hazards and distribution of radioactive black sand along the Rosetta coastal zone in Egypt using airborne spectrometric and remote sensing data. AB - High-resolution airborne gamma ray spectrometry, conducted in 2003, was used to estimate radioactive elements spatial abundance along the Rosetta coastal zone area. It was noticed that both Uranium and Thorium are concentrated in the black sand deposits along the beach. In contrary, Potassium was observed in high level abundance at the cultivated Nile Delta lands due to the accumulated usage of fertilizers. Exposure Rate (ER), Absorbed Dose Rate (ADR) and Annual Effective Dose Rate (AEDR) were calculated to evaluate the radiation background influence in human. Results indicated that the human body in the study sites is subjected to radiation hazards exceeds the accepted limit for long duration exposure. In addition, the areas covered by the highest concentration of Uranium and Thorium show the highest level of radiogenic heat production. Detection the environmental hazards of the radioactive black sands in the study site encouraged this research to monitor the spatial and temporal distribution of these sediments. The Landsat Thematic Mapper images acquired in 1990, 2003 and 2013 were analyzed using remote sensing image processing techniques. Image enhancements, classification and changes detection indicated a positive significant relationship between the patterns of coastline changes and distribution of the radioactive black sand in the study sites. The radioactive black sands are usually concentrated in the eroded areas. Therefore, in 1990 high concentration of the radioactive black sands were observed along the eastern and western flanks of the Rosetta promontory. Distribution of these sediments decreased due to the construction of the protective sea walls. Most of the radioactive black sands are transported toward the east in Abu Khashaba bay under the effect of the longshore currents and toward the west in Alexandria and Abu Quir bay under the action of the seasonal reverse currents. PMID- 25011075 TI - Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration. AB - Mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, whilst unloading in microgravity can cause reduced tissue regeneration, possibly through effects on stem cell tissue progenitors. To test the specific hypothesis that mechanical unloading alters differentiation of bone marrow mesenchymal and hematopoietic stem cell lineages, we studied cellular and molecular aspects of how bone marrow in the mouse proximal femur responds to unloading in microgravity. Trabecular and cortical endosteal bone surfaces in the femoral head underwent significant bone resorption in microgravity, enlarging the marrow cavity. Cells isolated from the femoral head marrow compartment showed significant down-regulation of gene expression markers for early mesenchymal and hematopoietic differentiation, including FUT1(-6.72), CSF2(-3.30), CD90(-3.33), PTPRC(-2.79), and GDF15(-2.45), but not stem cell markers, such as SOX2. At the cellular level, in situ histological analysis revealed decreased megakaryocyte numbers whilst erythrocytes were increased 2.33 fold. Furthermore, erythrocytes displayed elevated fucosylation and clustering adjacent to sinuses forming the marrow-blood barrier, possibly providing a mechanistic basis for explaining spaceflight anemia. Culture of isolated bone marrow cells immediately after microgravity exposure increased the marrow progenitor's potential for mesenchymal differentiation into in-vitro mineralized bone nodules, and hematopoietic differentiation into osteoclasts, suggesting an accumulation of undifferentiated progenitors during exposure to microgravity. These results support the idea that mechanical unloading of mammalian tissues in microgravity is a strong inhibitor of tissue growth and regeneration mechanisms, acting at the level of early mesenchymal and hematopoietic stem cell differentiation. PMID- 25011076 TI - A pilot validation of a modified Illness Perceptions Questionnaire designed to predict response to cognitive therapy for psychosis. AB - BACKGROUND AND OBJECTIVES: Clinical responsiveness to cognitive behavioural therapy for psychosis (CBTp) varies. Recent research has demonstrated that illness perceptions predict active engagement in therapy, and, thereby, better outcomes. In this study, we aimed to investigate the psychometric properties of a modification of the Illness Perceptions Questionnaire (M-IPQ) designed to predict response following CBTp. METHODS: Fifty-six participants with persistent, distressing delusions completed the M-IPQ; forty before a brief CBT intervention targeting persecutory ideation and sixteen before and after a control condition. Additional predictors of outcome (delusional conviction, symptom severity and belief inflexibility) were assessed at baseline. Outcomes were assessed at baseline and at follow-up four to eight weeks later. RESULTS: The M-IPQ comprised two factors measuring problem duration and therapy-specific perceptions of Cure/Control. Associated subscales, formed by summing the relevant items for each factor, were reliable in their structure. The Cure/Control subscale was also reliable over time; showed convergent validity with other predictors of outcome; predicted therapy outcomes; and differentially predicted treatment effects. LIMITATIONS: We measured outcome without an associated measure of engagement, in a small sample. Findings are consistent with hypothesis and existing research, but require replication in a larger, purposively recruited sample. CONCLUSIONS: The Cure/Control subscale of the M-IPQ shows promise as a predictor of response to therapy. Specifically targeting these illness perceptions in the early stages of cognitive behavioural therapy may improve engagement and, consequently, outcomes. PMID- 25011077 TI - Inflamm-aging does not simply reflect increases in pro-inflammatory markers. AB - Many biodemographic studies use biomarkers of inflammation to understand or predict chronic disease and aging. Inflamm-aging, i.e. chronic low-grade inflammation during aging, is commonly characterized by pro-inflammatory biomarkers. However, most studies use just one marker at a time, sometimes leading to conflicting results due to complex interactions among the markers. A multidimensional approach allows a more robust interpretation of the various relationships between the markers. We applied principal component analysis (PCA) to 19 inflammatory biomarkers from the InCHIANTI study. We identified a clear, stable structure among the markers, with the first axis explaining inflammatory activation (both pro- and anti-inflammatory markers loaded strongly and positively) and the second axis innate immune response. The first but not the second axis was strongly correlated with age (r=0.56, p<0.0001, r=0.08 p=0.053), and both were strongly predictive of mortality (hazard ratios per PCA unit (95% CI): 1.33 (1.16-1.53) and 0.87 (0.76-0.98) respectively) and multiple chronic diseases, but in opposite directions. Both axes were more predictive than any individual markers for baseline chronic diseases and mortality. These results show that PCA can uncover a novel biological structure in the relationships among inflammatory markers, and that key axes of this structure play important roles in chronic disease. PMID- 25011078 TI - A novel model-based adaptive control strategy for step-feed SBRs dealing with influent fluctuation. AB - A novel model-based adaptive control strategy for step-feed sequence batch reactors (SBRs) was developed and compared with traditional fixed-parameters control strategy and statically optimal parameters control strategy under influent fluctuation period. The SBR was operated with automatic alteration of the operating parameters based on the numerical calculation results of fully coupled activated sludge model (FCASM). Since the influent fluctuated from one cycle to another, model-based adaptive control strategy was applied to optimize the operating parameters of the SBR accordingly. By using the model-based adaptive control strategy, the average removal efficiencies for total nitrogen (TN) and total phosphorus (TP) achieved in fluctuation tests were over 84% and 98%, respectively. Compared to traditional fixed-parameters strategy, the TN removal efficiency was improved by 25.11%. PMID- 25011079 TI - Hydrolysis of ionic cellulose to glucose. AB - Hydrolysis of ionic cellulose (IC), 1,3-dimethylimidazolium cellulose phosphite, which could be synthesized from cellulose and dimethylimidazolium methylphosphite ([Dmim][(OCH3)(H)PO2]) ionic liquid, was conducted for the synthesis of glucose. The reaction without catalysts at 150 degrees C for 12h produced glucose with 14.6% yield. To increase the hydrolysis yield, various acid catalysts were used, in which the sulfonated active carbon (AC-SO3H) performed the best catalytic activity in the IC hydrolysis. In the presence of AC-SO3H, the yields of glucose reached 42.4% and 53.9% at the reaction condition of 150 degrees C for 12h and 180 degrees C for 1.5h, respectively; however the yield decreased with longer reaction time due to the degradation of glucose. Consecutive catalyst reuse experiments on the IC hydrolysis demonstrated the catalytic activity of AC-SO3H persisted at least through four successive uses. PMID- 25011080 TI - Enhanced bioelectricity generation by improving pyocyanin production and membrane permeability through sophorolipid addition in Pseudomonas aeruginosa-inoculated microbial fuel cells. AB - Improvement on electron shuttle-mediated extracellular electron transfer (EET) is of great potential to enhance the power output of MFCs. In this study, sophorolipid was added to enhance the performance of Pseudomonas aeruginosa inoculated MFC by improving the electron shuttle-mediated EET. Upon sophorolipid addition, the current density and power density increased ~ 1.7 times and ~ 2.6 times, respectively. In accordance, significant enhancement on pyocyanin production (the electron shuttle) and membrane permeability were observed. Furthermore, the conditions for sophorolipid addition were optimized to achieve maximum pyocyanin production (14.47 +/- 0.23 MUg/mL), and 4 times higher power output was obtained compared to the control. The results substantiated that enhanced membrane permeability and pyocyanin production by sophorolipid, which promoted the electron shuttle-mediated EET, underlies the improvement of the energy output in the P. aeruginosa-inoculated MFC. It suggested that addition of biosurfactant could be a promising way to enhance the energy generation in MFCs. PMID- 25011081 TI - Application of Anaerobic Digestion Model No. 1 to describe the syntrophic acetate oxidation of poultry litter in thermophilic anaerobic digestion. AB - A molecular analysis found that poultry litter anaerobic digestion was dominated by hydrogenotrophic methanogens which suggests that bacterial acetate oxidation is the primary pathway in the thermophilic digestion of poultry litter. IWA Anaerobic Digestion Model No. 1 (ADM1) was modified to include the bacterial acetate oxidation process in the thermophilic anaerobic digestion (TAD). Two methods for ADM1 parameter estimation were applied: manual calibration with non linear least squares (MC-NLLS) and an automatic calibration using differential evolution algorithms (DEA). In terms of kinetic parameters for acetate oxidizing bacteria, estimation by MC-NLLS and DEA were, respectively, km 1.12 and 3.25 +/- 0.56 kg COD kg COD(-1)d(-1), KS 0.20 and 0.29 +/- 0.018 kg COD m(-3) and Yac-st 0.14 and 0.10 +/- 0.016 kg COD kg COD(-1). Experimental and predicted volatile fatty acids and biogas composition were in good agreement. Values of BIAS, MSE or INDEX demonstrate that both methods (MC-NLLS and DEA) increased ADM1 accuracy. PMID- 25011082 TI - LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. AB - Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations in the LKB1 tumor suppressor are common in NSCLC. Genetic and mechanistic analysis has defined LKB1-deficient NSCLC tumors as a phenotypically distinct subpopulation of NSCLC with potential avenues for therapeutic gain. In expanding on previous work indicating hypersensitivity of LKB1-deficient NSCLC cells to 2-deoxy-D-glucose (2DG), we find that 2DG has in vivo efficacy in LKB1 deficient NSCLC using transgenic murine models of NSCLC. Deciphering of the molecular mechanisms behind this phenotype reveals that loss of LKB1 in NSCLC cells imparts increased sensitivity to pharmacological compounds that aggravate ER stress. In comparison to NSCLC cells with functional LKB1, treatment of NSCLC cells lacking LKB1 with the ER stress activators (ERSA), tunicamycin, brefeldin A or 2DG, resulted in aggravation of ER stress, increased cytotoxicity, and evidence of ER stress-mediated cell death. Based upon these findings, we suggest that ERSAs represent a potential treatment avenue for NSCLC patients whose tumors are deficient in LKB1. PMID- 25011083 TI - Immediate and two-year outcomes after EVAR in "on-label" and "off-label" neck anatomies using different commercially available devices. analysis of the experience of two Italian vascular centers. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) has fast become the therapeutic strategy of choice for abdominal aortic aneurysms (AAAs). Nowadays, the most important limit to the effectiveness of this technique is represented by complex anatomical situations, especially regarding the morphology of the proximal sealing zone. The aim of this study was to evaluate the 2-year outcome of unselected, real-world patients with "off-label" (off-L) proximal necks treated in 2 high-volume Italian vascular centers. METHODS: A double-center study was conducted on a prospectively compiled computerized database between January 2010 and December 2011. One hundred and ninety-six consecutive elective surgery patients were analyzed and divided into 2 groups ("on-label" [on-L] and "off-L" necks) on the basis of their aortic neck anatomy. The neck was classified as an "off-L neck" in the presence of: (1) a noncylindrical neck, (2) an angulated neck, (3) a short neck, and (4) an enlarged neck. The end points were 30-day and 2-year technical and clinical success, evaluated in terms of freedom from reintervention and death. RESULTS: One hundred and thirty-three elective patients were treated by standard EVAR in the presence of an "off-L" proximal neck anatomy. Technical success was achieved in all cases in both groups. Six (9.5%) unplanned adjunctive procedures were necessary in the on-L group and 16 (12%) in the off-L group (P = ns). Perioperative endoleaks, reinterventions, stent-graft migration rates, and AAA-related deaths were null. A multivariate analysis was performed to evaluate the subgroups of patients with 2 or > 2 anatomic factors that indicate a challenging neck. In patients with 2 such factors, a significant difference was observed in terms of intraoperative adjunctive procedures, intraoperative endoleaks, and all-cause mortality: 26.7% vs. 9.9% (P = 0.048), 6.7% vs. 0.5% (P = 0.023), and 13.3% vs. 1.1% (P = 0.0012), respectively. The same differences became increasingly evident when analyzing patients with > 2 criteria: 50% vs. 10% (P = 0.0022), 16.7% vs. 0.5% (P < 0.001), and 16.7% vs. 1.0% (P = 0.01). No AAA-related deaths or AAA ruptures were reported in either group at the end of the 2-year follow-up. High-flow endoleaks, stent-graft migration, and, consequently, reintervention were more frequent in the off-L group, but none of these parameters reached statistical significance. CONCLUSIONS: Our experience seems to show that the off-L use of EVAR could be considered effective for the treatment of patients unfit for open surgery. In patients with more than one anatomical proximal neck feature contraindicating open surgery, the rate of immediate complications and reinterventions was higher, but this did not affect the clinical benefit and success at 2-year follow-up. PMID- 25011084 TI - A survey of perioperative management of major lower limb amputations: current UK practice. AB - BACKGROUND: A Quality Improvement Framework has been formulated aiming to reduce the perioperative mortality of patients undergoing major lower limb amputations as this is unacceptably high. Surgical site infections (SSI) have a significant impact on the morbidity and mortality of this group of patients. This study aimed to establish whether consensus exists among UK consultant vascular surgeons regarding perioperative management of major lower limb amputations and review current evidence regarding the prevention of SSI. METHODS: A postal questionnaire, which had previously been piloted, was sent to consultant members of the Vascular Society. It comprised 17 questions to establish their current perioperative practice and the estimated incidence of SSI within their patient cohort. The chi-squared test was used to establish the impact of skin preparation, dressings, and closure technique on infection rates. RESULTS: A total of 168 consultants responded to the questionnaire-a response rate of 37.2%. The median-reported infection rate was in the range of 6-10%. 95.8% of respondents always give antibiotics. The majority of respondents use aqueous betadine (44.6%). The majority of respondents close the skin with subcuticular continuous sutures (58.3%). The preferred dressing for both above- and below-knee amputations was a stump bandage (62.5% and 61.9%, respectively). No statistically significant difference was seen in the reported infection when examined in relation to skin preparation, closure method, or dressings used. CONCLUSIONS: It appears that there is currently little consensus on the perioperative management of patients undergoing major lower limb amputation. Further studies in the form of randomized control trials are required to facilitate decision making and optimize patient outcome. PMID- 25011085 TI - Impact of elevated perioperative fasting blood glucose on carotid artery stenting outcomes. AB - BACKGROUND: Carotid artery stenting (CAS) for high-risk individuals is accepted practice. An impaired fasting hyperglycemia (IFG) is often associated with poor procedural outcomes after other percutaneous procedures. The clinical outcomes of CAS for patients with elevated fasting blood sugar (FBS) are not well defined. METHODS: A database of patients undergoing CAS was sampled from 2000 to 2009. An IFG was defined as plasma glucose > 110 mg/dL. Life table analyses were performed to assess time-dependent outcome differences between those patients with and without IFG. The outcomes of freedom from restenosis, occlusion, death, recurrent symptoms, and neurologic event were calculated. Cox proportional hazard analysis or Fisher's exact test was performed to identify factors associated with outcomes. RESULTS: During the study period 322 patients underwent 345 CAS procedures. The mean follow-up was 4.6 years. A total of 196 patients (61%) were male. The indications for CAS were neurologic symptoms in high-risk patients in 23% and asymptomatic high-risk in the remainder. Fifty-nine percent had an IFG but only 30% had a history of diabetes mellitus (DM). Patients with an IFG were more likely to suffer a major adverse event (MAE; death, myocardial infarction, stroke; 12% vs. 26%, <= 110 vs. > 110, respectively, at 5 years, P = 0.021 by chi squared analysis) in the 90-day perioperative period. By life table analysis, there were no differences between normal and IFG patients with regards to freedom from occlusion or target vessel revascularization. The long-term MAE rate was significantly worse in patients with an IFG, driven by decreased survival and stroke rates. Patients carrying the diagnosis of DM had equivalent outcomes to non-DM patients (67 +/- 5% vs. 62 +/- 7%, <= 110 vs. >110, respectively, at 5 years, P = 0.84). The presence of metabolic syndrome and/or the combination of diabetes and metabolic syndrome in the IFG group were drivers of increasing poor MAE rates. CONCLUSIONS: Patients with IFG undergoing CAS are at a greater risk for periprocedural morbidity and worse MAE in both the short and long term. The diagnosis of DM does not have a similar impact on outcomes. A current IFG, as opposed to a history of DM, should be considered an important risk factor when determining the suitability for CAS. PMID- 25011086 TI - Popliteal venous aneurysms: characteristics, management strategies, and clinical outcomes--a modern single-center series. AB - BACKGROUND: Popliteal vein aneurysm (PVA) may be an incidental finding on imaging, but often presents in the context of acute venous thromboembolism (VTE). The role of anticoagulation with or without surgical excision versus expectant management is ill defined. METHODS: In this single-center, retrospective, cohort study, patient records from January 2002 to December 2013 were queried for terminology consistent with PVA. Demographic data and clinical outcomes were extracted via chart review. RESULTS: A total of 21 patients with PVA were identified (57% male). Mean follow-up was 38 +/- 31 months. Mean PVA diameter was 2.5 +/- 1.1 cm; 67% were saccular (with the remainder being fusiform), 19% contained thrombus, 67% were left sided, and bilateral PVA was present in 24% of cases. At the time of PVA diagnosis, 14% had pulmonary embolism. Treatment consisted of observation only (62%), anticoagulation (19%), surgery (5%), or both anticoagulation and surgery (14%). There were no recurrences of VTE once treated, although there was 1 acute deep venous thrombosis in a patient who was managed conservatively. Two patients had recurrent PVA after surgery, and there were 2 surgical complications (transient foot drop and hematoma). CONCLUSIONS: PVA is associated with VTE. Based on our series, it is unclear if incidentally discovered PVA (without VTE) warrants treatment with anticoagulation and/or surgical repair. Further multicenter studies are needed to establish the indications for safety and durability of surgery. PMID- 25011087 TI - A simple technique to prevent torsion and other obstructions of autogenous vein conduits. AB - During a bypass or a transposed fistula, there is a risk of twisting or torsion of the vein within the tunnel, which may not be easily apparent when incomplete. When valvulotomes are used some nonobstructing leaflets or flaps may remain. These mechanical problems may go undetected at the time and may cause hemodynamic changes, act as a nucleus for thrombosis, or obstruction postoperatively. These may result in early graft failure. A simple technique to prevent and treat twisting and other obstructions in autogenous venous conduits is described. Use of this method has helped the authors to avoid acute obstructions in vein bypasses and transposed dialysis access fistulas. PMID- 25011088 TI - Incidence and relevance of groin incisional complications after aortobifemoral bypass grafting. AB - BACKGROUND: Aortobifemoral bypass (ABFB) for aortoiliac occlusive disease (AIOD) is traditionally accompanied by substantial groin incisional morbidity, which poses a threat to an underlying prosthetic graft. We performed a study to investigate the frequency and define the clinical course and significance of such problems. METHODS: One hundred twenty consecutive patients undergoing primary elective ABFB for AIOD were enrolled in a prospective study. The healing of groin wounds was systematically assessed, the occurrence of incisional complications of any type noted, and their clinical course and economic consequences documented and analyzed. RESULTS: Early postoperative complications (30 days) affected 35 (15%) groin wounds in 29 (24.8%) patients. Lymph fistulas/lymphoceles were observed in 15 (6.4%), infection in 11 (4.7%), and noninfectious wound dehiscence in 9 (3.8%) of groin incisions. The only significant predictor of groin healing impairment was preoperative length of stay. Groin incision-related morbidity significantly increased the duration and cost of hospitalization. Sixty percent of groin healing problems were diagnosed after discharge and they represented the most common cause for early readmissions. CONCLUSIONS: The incidence of groin wound complications after ABFB is considerable, their financial impact significant, and delayed onset frequent. Femoral incisional morbidity after ABFB still represents an unremitting nuisance, necessitating further improvements in preventive strategies and techniques and strict adherence to conventional ones, including the minimization of preoperative length of stay. PMID- 25011089 TI - Which model yields more ischemia-reperfusion organ injury? PMID- 25011090 TI - Circulating interleukin-6 levels are associated with abdominal aortic aneurysm presence: a meta-analysis and meta-regression of case-control studies. AB - BACKGROUND: In a number of relatively small-size studies, investigators have measured and compared circulating interleukin-6 (IL-6) levels in cases with abdominal aortic aneurysm (AAA) and controls without AAA to assess its possible role in the pathogenesis or progression of AAA. To summarize the present evidence for an association between circulating IL-6 levels and AAA presence, we performed a meta-analysis of case-control studies that compared circulating IL-6 levels between patients with AAA and subjects without AAA. METHODS: MEDLINE and EMBASE were searched through December 2013 using Web-based search engines (PubMed and OVID). Eligible studies were case-control studies of patients with AAA and subjects without AAA reporting circulating IL-6 levels. For each study, data regarding plasma or serum IL-6 levels in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Mixed-effects (unrestricted maximum likelihood) meta-regression analyses were performed to determine whether the differences in circulating IL-6 levels were modulated by the prespecified factors. RESULTS: Our search identified 13 eligible studies enrolling a total of 1,029 cases with AAA and 924 controls without AAA. Pooled analysis of the 13 studies demonstrated significantly greater circulating IL-6 levels in the AAA group than those in the control group (random effects SMD 0.59; 95% CI 0.37-0.80; P for effect < 0.00001; P for heterogeneity < 0.0000). The meta-regression coefficient for the mean age (P = 0.10196) and the proportion of current smokers (P = 0.29893) was not statistically significant. That for the mean AAA diameter, however, was significantly positive (coefficient 0.02789; 95% CI 0.00778-0.04800; P = 0.00657), and that for the proportion of men was significantly negative (coefficient -0.01823; 95% CI -0.03202 to -0.00445; P = 0.00952). CONCLUSIONS: Circulating IL-6 levels are greater in patients with AAA than those in subjects without AAA, which suggest that greater circulating IL-6 levels are associated with AAA presence. As the mean AAA diameter and the proportion of men increase, circulating IL-6 levels in patients with AAA are respectively more and less greater than those in controls without AAA. PMID- 25011091 TI - Mechanical thrombectomy with Trerotola compared with catheter-directed thrombolysis for treatment of acute iliofemoral deep vein thrombosis. AB - BACKGROUND: Mechanical thrombectomy (MT) of acute deep vein thrombosis (DVT) is safe and effective in reducing thrombus burden. MT utilizing a percutaneous thrombectomy device confers a great advantage because it may reduce both the dose of the thrombolytic agent and the overall procedure time compared with a conventional catheter-directed thrombolysis (CDT). We examined the results of MT using the Trerotola device and evaluated factors affecting patient outcome. METHODS: This retrospective study was performed using data from a database of patients who had undergone treatment for an acute iliofemoral DVT from January 2005 to December 2011, at 2 institutions. The patients' clinical characteristics and procedures were compared, and the outcomes of treatment with the Trerotola in the MT group were compared with those obtained with CDT. RESULTS: There were a total of 98 DVTs (left 76; right 22) in 90 patients (34 men); 53 DVTs were treated with MT and 45 with CDT. There were no statistical differences in the clinical characteristics among the MT with CDT, MT only and CDT group. Inferior vena cava filters were placed in 93 DVTs (95%), and iliac vein stenting was used in 64 (65%). Symptom improvement was seen in 78% (18 limbs) of the MT group, 80% (24 limbs) of the MT with CDT group, and 71% (32 limbs) of the CDT group (P = 0.498). The procedure time was shorter in the MT with CDT group (18.2 +/- 8.2 hr) or in the MT only group (2.7 +/- 2.0 hr) compared with the CDT group (29.3 +/- 9.4 hr; P < 0.001). Urokinase dose was lower in MT only (0 million units) or in the MT with CDT group (5.13 +/- 3.72 million units) than in the CDT group (7.51 +/- 4.54 million units; P < 0.001). There was no difference in complications during the procedures or in primary patency rate during the follow-up period (mean 16.0 +/- 19.1 months; range: 0-78 months). CONCLUSIONS: MT with the Trerotola device for acute iliofemoral DVT required shorter procedure times and lower urokinase doses than conventional CDT, while providing the same results. PMID- 25011092 TI - Comparison of surgical and endovascular salvage procedures for juxta-anastomotic stenosis in autogenous wrist radiocephalic arteriovenous fistula. AB - BACKGROUND: Although dysfunctional radiocephalic arteriovenous fistulas (RCAVFs) are typically treated surgically, the endovascular approach is also considered suitable. The aim of this retrospective study was to compare the cumulative patency rates following surgical and endovascular salvaging of dysfunctional RCAVFs, and to evaluate whether the maturity of vascular access sites at the time of treatment influenced the outcomes. METHODS: A total of 60 patients underwent surgical or endovascular salvage treatment for juxta-anastomotic stenosis of autogenous wrist RCAVFs: 35 patients underwent proximal neo-anastomosis and 25 underwent percutaneous transluminal angioplasty (PTA). RESULTS: Clinical and anatomical success rates were, respectively, 100% and 97.1% in the surgery group, and 100% and 96.0% in the angioplasty group (P = 0.81). The post-treatment restenosis rate was higher in the angioplasty group (n = 11, 46.0%) than in the surgery group (n = 8, 22.8%), without reaching statistical significance (P = 0.15). In a Kaplan-Meier analysis, the primary and assisted primary patency rates were significantly higher in the surgery group (P = 0.036 and P = 0.026, respectively), but there was no significant difference in secondary patency rates between the groups (P = 0.52). When stratified by RCAVF maturity at the time of treatment, no significant difference was noted in primary patency rates between the treatment groups. After adjusting for other variables, the relative risk of restenosis was significantly higher in the angioplasty group (hazard ratio 2.56; 95% confidence interval 1.02-6.46; P = 0.046). CONCLUSIONS: Post-treatment primary and assisted primary patency rates after proximal neo-anastomosis were significantly higher than after PTA, and RCAVF maturity did not influence the outcomes. PMID- 25011093 TI - Does mechanical filtration of intraoperative cell salvage effectively remove titanium debris generated during instrumented spinal surgery? An in vitro analysis. AB - BACKGROUND CONTEXT: Instrumented fusion of the spine is a surgery commonly performed to stabilize vertebrae causing pain and to correct anatomic deformities. Such surgery can create substantial blood loss. Autotransfusion is a means to limit homologous blood transfusion in this setting. However, a dilemma is created when the high-speed drill used for bone removal comes in contact with implanted titanium spinal hardware. A clinician at this point is forced to decide between two options: to discontinue autotransfusion to avoid the potential transfusion of titanium fragments while risking blood loss and the need for homologous transfusion or to continue autotransfusion while risking transfusion of titanium fragments back into circulation. PURPOSE: To conclusively identify whether titanium fragments created by a high-speed drill are able to pass through standard autotransfusion microaggregate blood filters. STUDY DESIGN: A positive and negatively controlled experiment with blinded sample analysis. OUTCOMES MEASURES: The presence or absence of titanium alloy on a filter with detection by energy-dispersive X-ray spectroscopy (EDX). METHODS: A mock autotransfusion setup was devised for in vitro filtering. Six investigational and two control experiments were conducted. Titanium fragments generated by a high-speed drill were aspirated with saline and filtered with standard autotransfusion reservoirs and microaggregate blood filters. A final filter with a 1-MUm pore size was placed distal to the blood filters. After filtration was complete, this final filter was analyzed using EDX. RESULTS: The presence of titanium was confirmed by EDX on five of six investigational filters. The positive and negative control filters were analyzed by EDX and tested positive and negative, respectively, for titanium. CONCLUSIONS: Standard 40 MUm reservoir and blood microaggregate filters do not eliminate the smallest fragments of titanium generated by contact between a high-speed drill and a titanium hardware. The mass of titanium able to elude filtration is very small. The impact of transfusing blood contaminated with such a small mass of titanium is not known. PMID- 25011094 TI - Physical activity and associations with computed tomography-detected lumbar zygapophyseal joint osteoarthritis. AB - BACKGROUND CONTEXT: There are no previous epidemiologic studies examining associations between physical activity and imaging-detected lumbar zygapophyseal joint osteoarthritis (ZJO) in a community-based sample. PURPOSE: To determine whether physical activity is associated with prevalent lumbar ZJO on computed tomography (CT). STUDY DESIGN/SETTING: A community-based cross-sectional study. PATIENT SAMPLE: Four hundred twenty-four older adults from the Framingham Heart Study. OUTCOME MEASURES: Participants received standardized CT assessments of lumbar ZJO at the L2-S1 levels. Severe lumbar ZJO was defined according to the presence and/or degree of joint space narrowing, osteophytosis, articular process hypertrophy, articular erosions, subchondral cysts, and intra-articular vacuum phenomenon. This definition of lumbar ZJO was based entirely on CT imaging findings and did not include any clinical criteria such as low back pain. METHODS: Physical activity was measured using the Physical Activity Index, which estimate hours per day typically spent in these activity categories: sleeping, sitting, slight activity, moderate activity, and heavy activity. Participants reported on usual frequency of walking, running, swimming, and weightlifting. We used multivariable logistic regression to examine associations between self reported activity and severe lumbar ZJO, while adjusting for key covariates including age, sex, height, and weight. RESULTS: In multivariable analyses, ordinal categories of heavy physical activity duration per day were significantly associated with severe lumbar ZJO (p for trend=.04), with the greatest risk observed for the category 3 or more hours per day, odds ratio 2.13 (95% confidence interval [CI] 0.97-4.67). When heavy activity was modeled as a continuous independent variable, each hour was independently associated with 1.19 times the odds of severe lumbar ZJO (95% CI 1.03-1.38, p=.02). Less vigorous types of physical activity and the type of exercise were not associated with severe lumbar ZJO. Older age, lesser height, and greater weight were independently and significantly associated with severe lumbar ZJO. In multivariable models predicting lumbar ZJO, neither model discrimination nor reclassification improved with the addition of physical activity variables, compared with a multivariable model including age, sex, height, and weight. CONCLUSIONS: Our findings demonstrate a statistically significant cross-sectional association between heavy physical activity and CT-detected severe lumbar ZJO. However, the additional discriminatory capability of heavy physical activity above and beyond that contributed by other factors was negligible. PMID- 25011095 TI - Tuberculosis of ultralong segmental thoracic and lumbar vertebrae treated by posterior fixation and cleaning of the infection center through a cross-window. AB - BACKGROUND CONTEXT: Surgical treatment of thoracolumbar tuberculosis (TB) aims at spinal cord decompression, focus debridement, spine stability, and deformity correction. However, several problems exist in treating multiple segmental thoracolumbar TB, including reducing surgical trauma with effective incision exposure; ensuring the effective long-armed fixation, and maintaining the possibility for revisionary surgery in cases of treatment failure. PURPOSE: To investigate the clinical efficacy and surgical technique of the single posterior midline approach for screw-rod fixation and debridement through the sacrospinalis muscle outer cross-window to treat multiple segmental thoracolumbar spinal TB. STUDY DESIGN: A retrospective cohort study. PATIENT SAMPLE: A group of 17 patients with spinal TB after surgical treatment, with a mean follow-up of 27.9 months (range, 18-48 months). OUTCOME MEASURES: Neurologic recovery, Cobb angle, and graft union assessed by the Moon standard. METHODS: This study was approved by the local ethical committee and recruited patients from January, 2005 to January, 2011. We used a posterior midline incision for internal fixation of a pedicle screw system in the gap of the longissimus and spinal multifidus. Anterior lesion debridement and interbody fusions were performed through bilateral cross-windows in the outer edge of the sacrospinalis muscle. Using this technique, we treated 17 patients (10 men; aged 19 to 68 years; mean 39.8 years) with spinal TB involving more than four vertebrae. Nerve damage was classified by the Frankel classification. All patients were treated with regular anti-TB chemotherapy and were followed for 18 to 48 (mean: 27.9 months) months. RESULTS: The mean (range) for operative time was 4.7 (3.6-6.3) hours, for blood loss during surgery was 1,100 (850-2,300) mL, and for time of interbody fusion was 6.3 (4 to 11) months. The Cobb angle correction rate is 67.1%. Nine of 11 patients' neurologic function returned to normal, which was statistically significant (p=.004). There was no TB recurrence or internal fixation failure. CONCLUSIONS: Combined with anti-TB chemotherapy, the discussed surgical technique can show improved lesion clearance, decompression of the anterior aspect of the spine, bone graft fusion, internal fixation of outside lesions, drainage and lead to positive treatment outcomes. PMID- 25011096 TI - The impact of generalized joint laxity on the occurrence and disease course of primary lumbar disc herniation. AB - BACKGROUND CONTEXT: Generalized joint laxity (GJL) has been associated with spine related disorders such as low back pain, accelerated disc degeneration, and recurrence after discectomy surgery for primary lumbar disc herniation (p-LDH). Generalized joint laxity might be a causative factor of p-LDH, but this relationship is poorly understood. In addition, the impact of GJL on outcomes after the treatment for p-LDH has not been reported. PURPOSE: To explore relationship between GJL and p-LDH and to compare clinical and radiological outcomes post-therapy in p-LDH patients with or without GJL. STUDY DESIGN: A retrospective comparative study. PATIENT SAMPLE: The study group included 203 males, and the control group included 362 males who were matched for age, race, and body mass index with the study group. OUTCOME MEASURES: The primary outcome was the presence or absence of GJL according to the Beighton scale. The secondary outcome measures included the clinical outcome according to a visual analog scale and the Oswestry disability index and the radiological outcome. METHODS: We compared baseline data between groups, and we evaluated the impact of GJL on outcomes after different types of several treatment for LDH. RESULTS: The prevalence of GJL was significantly higher in the study group (10.8%) than in the matched control group (4.4%) (p=.003). In multivariate logistic regression analysis, GJL was the only significant predictor (p=.012). For all treatment methods, patients with GJL had worse clinical outcomes than did patients without GJL. In the patients treated with lumbar discectomy surgery, the differential Cobb value at the last follow-up was higher in the GJL patients than in the non GJL patients (p=.001). CONCLUSIONS: Generalized joint laxity was closely related to p-LDH and may be a causative factor. In addition, patients with GJL had worse clinical and radiological outcomes than patients without GJL. Consequently, GJL should be evaluated preoperatively, and this information should be communicated to p-LDH patients with GJL. PMID- 25011097 TI - Transient expression of rabies virus glycoprotein (RVGP) in Drosophila melanogaster Schneider 2 (S2) cells. AB - The transient transfection process has been developed to allow rapid production of recombinant proteins. In this paper, we describe the transient expression of recombinant rabies virus glycoprotein (RVGP) in Drosophila melanogaster Schneider 2 (S2) cells. Different cell transfection reagents were evaluated, together with the effects of different cell cultivation procedures on RVGP expression. Yields of RVGP in the range 50-90ng/10(7) cells were obtained in multi-well plate transfection experiments, where it was observed that RVGP expression was linked to the DNA concentration. RVGP expression was 1.3 times higher using 10MUg rather than 5MUg of DNA. Inhibition of RVGP expression was observed at higher concentrations of DNA, with DNA concentrations above 15MUg decreasing RVGP expression 1.5-fold for cells transfected with polyethylenimine (PEI) and 1.6 fold for cells transfected with cationic lipid. The results of shake flask transfection indicated that S2 cells were more effectively transfected in suspension than under static conditions. RVGP yields of 182.2ng/10(7) cells (PEI), 201ng/10(7) cells (calcium phosphate), and 215ng/10(7) cells (cationic lipid) were obtained for S2 cell suspension cultures. The highest volumetric RVGP concentration (309ng/mL) was found for cells transfected with cationic lipid. This value was 1.21 and 1.16 times higher, respectively, than for cells transfected with PEI (253.4ng/mL) and calcium phosphate (237.2ng/mL). There was little effect of transfection on the kinetics of cell growth, with growth rates of 1.12 and 1.19d(-1) for transfected and control cells, respectively. In spinner flasks, the expression of RVGP was 150 and 138ng/10(7) cells for transfection using PEI and calcium phosphate, respectively. A comparison of the different transfection reagents (calcium phosphate, cationic lipid, and cationic polymer) showed no significant differences in RVGP expression when shake flasks were used. Overall, the data indicated that transient expression in D. melanogaster S2 cells is a practical way of synthesizing RVGP for use in structural and functional studies. PMID- 25011098 TI - A proteomic view of cell physiology of the industrial workhorse Bacillus licheniformis. AB - Bacillus licheniformis is known for its high protein secretion capacity and is being applied extensively as a host for the industrial production of enzymes such as proteases and amylases. In its natural environment as well as in fermentation processes the bacterium is often facing adverse conditions such as oxidative or osmotic stress or starvation for nutrients. During the last years detailed proteome and transcriptome analyses have been performed to study the adaptation of B. licheniformis cells to various stresses (heat, ethanol, oxidative or salt stress) and starvation conditions (glucose, nitrogen or phosphate starvation). A common feature of the response to all tested conditions is the downregulation of many genes encoding house-keeping proteins and, consequently, a reduced synthesis of the corresponding proteins. Induction of the general stress response (sigma(B) regulon) is only observed in cells subjected to heat, ethanol or salt stress. This paper summarizes our current knowledge on general and specific stress and starvation responses of this important industrial bacterium. The importance of selected marker genes and proteins for the monitoring and optimization of B. licheniformis based fermentation processes is discussed. PMID- 25011099 TI - Heterologous pathway for the production of L-phenylglycine from glucose by E. coli. AB - The aproteinogenic amino acid L-phenylglycine (L-Phg) is an important side chain building block for the preparation of several antibiotics and taxol. To biosynthesis L-Phg from glucose, an engineered Escherichia coli containing L-Phg synthetic genes was firstly developed by an L-phenylalanine producing chassis supplying phenylpyruvate. The enzymes HmaS (L-4-hydroxymandelate synthase), Hmo (L-4-hydroxymandelate oxidase) and HpgT (L-4-hydroxyphenylglycine transaminase) from Amycolatopsis orientalis as well as Streptomyces coelicolor were heterologously expressed in E. coli and purified to evaluate their abilities on L Phg formation. HpgT conversing phenylglyoxylate to L-Phg uses an unusual amino donor L-phenylalanine, which releases another phenylpyruvate as the substrate of HmaS. Thus, a recycle reaction was developed to maximize the utilization of precursor phenylpyruvate. To amplify the accumulation of L-Phg, the effects of attenuating L-phenylalanine transamination was investigated. After deletion of tyrB and aspC, L-Phg yield increased by 12.6-fold. The limiting step in the L-Phg biosynthesis was also studied; the L-Phg yield was further improved by 14.9-fold after enhancing hmaS expression. Finally, by optimizing expression of hmaS, hmo and hpgT and attenuation of L-phenylalanine transamination, the L-Phg yield was increased by 224-fold comparing with the original strain. PMID- 25011100 TI - Measles virus takes a two-pronged attack on PP1. AB - During viral infection, RIG-I-like receptors (RLRs) are activated upon dephosphorylation by the phosphatase PP1, resulting in type I interferon production. In this issue, Davis et al. (2014) and Mesman et al. (2014) show that measles virus inhibits this antiviral response by targeting PP1 and thus preventing RLR dephosphorylation and activation. PMID- 25011101 TI - The public health policy implications of understanding metabiosis. AB - In this issue of Cell Host & Microbe, Siegel et al. (2014) report that colonization of Streptococcus pneumoniae is facilitated by coinfection with influenza virus through utilization of sialic acids cleaved by the viral neuraminidase. The implications of this finding for use of influenza antivirals to prevent flu-related complications are discussed. PMID- 25011102 TI - Type VI secretion system helps find a niche. AB - Type VI secretion systems (T6SSs) deliver toxins into target cells and thus play a role in bacterial warfare. In this issue of Cell Host & Microbe, Ma et al. (2014) demonstrate that T6SS-dependent attack during interbacterial competition in the host context enables niche colonization by Agrobacterium tumefaciens. PMID- 25011103 TI - Monocyte-plasmablast crosstalk during dengue. AB - Dengue virus infection induces a dramatic expansion of B cell plasmablasts. In this issue, Kwissa et al. (2014) begin with transcriptomic analysis and then integrate studies in human clinical samples, nonhuman primates, and coculture of primary human cells to identify a role for CD14(+)CD16(+) monocytes in generating plasmablast responses during dengue virus infection. PMID- 25011104 TI - Interactions between HIV-1 and the cell-autonomous innate immune system. AB - HIV-1 was recognized as the cause of AIDS in humans in 1984. Despite 30 years of intensive research, we are still unraveling the molecular details of the host pathogen interactions that enable this virus to escape immune clearance and cause immunodeficiency. Here we explore a series of recent studies that consider how HIV-1 interacts with the cell-autonomous innate immune system as it navigates its way in and out of host cells. We discuss how these studies improve our knowledge of HIV-1 and host biology as well as increase our understanding of transmission, persistence, and immunodeficiency and the potential for therapeutic or prophylactic interventions. PMID- 25011105 TI - Antagonism of the phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5. AB - The cytosolic sensor MDA5 is crucial for antiviral innate immune defense against various RNA viruses including measles virus; as such, many viruses have evolved strategies to antagonize the antiviral activity of MDA5. Here, we show that measles virus escapes MDA5 detection by targeting the phosphatases PP1alpha and PP1gamma, which regulate MDA5 activity by removing an inhibitory phosphorylation mark. The V proteins of measles virus and the related paramyxovirus Nipah virus interact with PP1alpha/gamma, preventing PP1-mediated dephosphorylation of MDA5 and thereby its activation. The PP1 interaction with the measles V protein is mediated by a conserved PP1-binding motif in the C-terminal region of the V protein. A recombinant measles virus expressing a mutant V protein deficient in PP1 binding is unable to antagonize MDA5 and is growth impaired due to its inability to suppress interferon induction. This identifies PP1 antagonism as a mechanism employed by paramyxoviruses for evading innate immune recognition. PMID- 25011106 TI - Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC SIGN-mediated inhibition of PP1 phosphatases. AB - Dendritic cells (DCs) are targets of measles virus (MV) and play central roles in viral dissemination. However, DCs express the RIG-I-like receptors (RLRs) RIG-I and Mda5 that sense MV and induce type I interferon (IFN) production. Given the potency of this antiviral response, RLRs are tightly regulated at various steps, including dephosphorylation by PP1 phosphatases, which induces their activation. We demonstrate that MV suppresses RIG-I and Mda5 by activating the C-type lectin DC-SIGN and inducing signaling that prevents RLR dephosphorylation. MV binding to DC-SIGN leads to activation of the kinase Raf-1, which induces the association of PP1 inhibitor I-1 with GADD34-PP1 holoenzymes, thereby inhibiting phosphatase activity. Consequently, GADD34-PP1 holoenzymes are unable to dephosphorylate RIG I and Mda5, hence suppressing type I IFN responses and enhancing MV replication. Blocking DC-SIGN signaling allows RLR activation and suppresses MV infection of DCs. Thus, MV subverts DC-SIGN to control RLR activation and escape antiviral responses. PMID- 25011107 TI - Maintenance and replication of the human cytomegalovirus genome during latency. AB - Human cytomegalovirus (HCMV) can establish latent infection in hematopoietic progenitor cells (HPCs) or CD14 (+) monocytes. While circularized viral genomes are observed during latency, how viral genomes persist or which viral factors contribute to genome maintenance and/or replication is unclear. Previously, we identified a HCMV cis-acting viral maintenance element (TR element) and showed that HCMV IE1 exon 4 mRNA is expressed in latently infected HPCs. We now show that a smaller IE1 protein species (IE1x4) is expressed in latently infected HPCs. IE1x4 protein expression is required for viral genome persistence and maintenance and replication of a TR element containing plasmid (pTR). Both IE1x4 and the cellular transcription factor Sp1 interact with the TR, and inhibition of Sp1 binding abrogates pTR amplification. Further, IE1x4 interacts with Topoisomerase IIbeta (TOPOIIbeta), whose activity is required for pTR amplification. These results identify a HCMV latency-specific factor that promotes viral chromosome maintenance and replication. PMID- 25011108 TI - Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. AB - Much of the mortality attributed to influenza virus is due to secondary bacterial pneumonia, particularly from Streptococcus pneumoniae. However, mechanisms underlying this coinfection are incompletely understood. We find that prior influenza infection enhances pneumococcal colonization of the murine nasopharynx, which in turn promotes bacterial spread to the lungs. Influenza accelerates bacterial replication in vivo, and sialic acid, a major component of airway glycoconjugates, is identified as the host-derived metabolite that stimulates pneumococcal proliferation. Influenza infection increases sialic acid and sialylated mucin availability and enhances desialylation of host glycoconjugates. Pneumococcal genes for sialic acid catabolism are required for influenza to promote bacterial growth. Decreasing sialic acid availability in vivo by genetic deletion of the major airway mucin Muc5ac or mucolytic treatment limits influenza induced pneumococcal replication. Our findings suggest that higher rates of disease during coinfection could stem from influenza-provided sialic acid, which increases pneumococcal proliferation, colonization, and aspiration. PMID- 25011109 TI - A BTLA-mediated bait and switch strategy permits Listeria expansion in CD8alpha(+) DCs to promote long-term T cell responses. AB - Listeria monocytogenes infected CD8alpha(+) DCs in the spleen are essential for CD8(+) T cell generation. CD8alpha(+) DCs are also necessary for Listeria expansion and dissemination within the host. The mechanisms that regulate CD8alpha(+) DCs to allow Listeria expansion are unclear. We find that activating the B and T lymphocyte attenuator (BTLA), a coinhibitory receptor for T cells, suppresses, while blocking BTLA enhances, both the primary and memory CD8 T cell responses against Listeria. Btla(-/-) mice have lower effector and memory CD8(+) T cells while paradoxically also being more resistant to Listeria. Although bacterial entry into Btla(-/-) CD8alpha(+) DCs is unaffected, Listeria fails to expand within these cells. BTLA signaling limits Fas/FasL-mediated suppression of Listeria expansion within CD8alpha(+) DCs to more effectively alert adaptive immune cells. This study uncovers a BTLA-mediated strategy used by the host that permits Listeria proliferation to enable increasing T cell responses for long term protection. PMID- 25011110 TI - STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting. AB - Variant surface antigens play an important role in Plasmodium falciparum malaria pathogenesis and in immune evasion by the parasite. Although most work to date has focused on P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1), two other multigene families encoding STEVOR and RIFIN are expressed in invasive merozoites and on the infected erythrocyte surface. However, their role during parasite infection remains to be clarified. Here we report that STEVOR functions as an erythrocyte-binding protein that recognizes Glycophorin C (GPC) on the red blood cell (RBC) surface and that its binding correlates with the level of GPC on the RBC surface. STEVOR expression on the RBC leads to PfEMP1-independent binding of infected RBCs to uninfected RBCs (rosette formation), while antibodies targeting STEVOR in the merozoite can effectively inhibit invasion. Our results suggest a PfEMP1-independent role for STEVOR in enabling infected erythrocytes at the schizont stage to form rosettes and in promoting merozoite invasion. PMID- 25011111 TI - Genome-wide functional analysis of Plasmodium protein phosphatases reveals key regulators of parasite development and differentiation. AB - Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria. PMID- 25011112 TI - Immunomodulation in cancer. AB - We have to strengthen our 'chess-playing skills' when using immunotherapeutic approaches in cancer treatment: know the cancerous opponent, study its evolution and have an eye for its weaknesses. Besides tumor cells, other pieces on the board are stromal cells, endothelial cells and different immune cells. Some of these immune cells, like helper and cytotoxic T cells, natural killer (T) cells and mature dendritic cells are of help, others like regulatory T cells and myeloid-derived suppressor cells belong to the opponent, while macrophages and neutrophils can belong to both. A personalized approach, by selecting the optimal treatment from the myriad of possibilities based on biomarker findings, is essential to attack that particular cancer at that moment. We have to adapt the strategy to the changing positions created by the opponent. Using all these skills, we might control cancer growth in the future. PMID- 25011113 TI - Extinction of cue-evoked drug-seeking relies on degrading hierarchical instrumental expectancies. AB - There has long been need for a behavioural intervention that attenuates cue evoked drug-seeking, but the optimal method remains obscure. To address this, we report three approaches to extinguish cue-evoked drug-seeking measured in a Pavlovian to instrumental transfer design, in non-treatment seeking adult smokers and alcohol drinkers. The results showed that the ability of a drug stimulus to transfer control over a separately trained drug-seeking response was not affected by the stimulus undergoing Pavlovian extinction training in experiment 1, but was abolished by the stimulus undergoing discriminative extinction training in experiment 2, and was abolished by explicit verbal instructions stating that the stimulus did not signal a more effective response-drug contingency in experiment 3. These data suggest that cue-evoked drug-seeking is mediated by a propositional hierarchical instrumental expectancy that the drug-seeking response is more likely to be rewarded in that stimulus. Methods which degraded this hierarchical expectancy were effective in the laboratory, and so may have therapeutic potential. PMID- 25011114 TI - Bioaccumulation and risk assessment of per- and polyfluoroalkyl substances in wild freshwater fish from rivers in the Pearl River Delta region, South China. AB - Per- and polyfluoroalkyl substances (PFASs) are used in various industries, which results in their ubiquitous occurrence in the environment. This study determined the concentrations of eighteen PFASs in muscle and liver of nine wild freshwater fish species collected from rivers in the Pearl River Delta (PRD) region, South China, and assessed their bioaccumulation and potential health risks to local people. The results showed that eight and twelve PFASs were detected in the fish muscle and liver samples, respectively. Perfluorooctane sulfonate (PFOS) was found to be the predominant PFAS both in muscle and liver with its highest concentrations of 79ng/g wet weight (ww) in muscle and 1500ng/g ww in liver, followed by Perfluoroundecanoic acid (PFUnDA) and Perfluorotridecanoic acid (PFTrDA) with trace concentrations. The mean PFOS concentrations in fish muscle and liver tissues of the nine collected species ranged from 0.40ng/g in mud carp to 25ng/g in snakehead, and from 5.6ng/g in mud carp to 1100ng/g in snakehead, respectively. Significant positive correlations were found among PFASs both in water and fish, indicating a similar pollution source for these PFASs. In tilapia samples, PFOS concentrations showed an increasing trend with increasing length and weight, but no significant difference between genders. Bioaccumulation factors (logBAF) in fish for the PFASs were in the range from 2.1 to 5.0. The calculated hazard ratios (HR) of PFOS for all fishes were in the range of 0.05 2.8, with four out of nine species (tilapia, chub, leather catfish and snakehead) having their HR values more than 1.0. The results suggest that frequent consumption of these four fish species may pose health risks to local population. PMID- 25011115 TI - Heavy metals in water, sediments and submerged macrophytes in ponds around the Dianchi Lake, China. AB - Through retaining runoff and pollutants such as heavy metals from surrounding landscapes, ponds around a lake play an important role in mitigating the impacts of human activities on lake ecosystems. In order to determine the potential for heavy metal accumulation of submerged macrophytes, we investigated the concentrations of 10 heavy metals (i.e., As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) in water, sediments, and submerged macrophytes collected from 37 ponds around the Dianchi Lake in China. Our results showed that both water and sediments of these ponds were polluted by Pb. Water and sediments heavy metal concentrations in ponds received urban and agricultural runoff were not significantly higher than those in ponds received forest runoff. This result indicates that a large portion of heavy metals in these ponds may originate from atmospheric deposition and weathering of background soils. Positive relationships were found among heavy metal concentrations in submerged macrophytes, probably due to the coaccumulation of heavy metals. For most heavy metals, no significant relationships were found between submerged macrophytes and their water and sediment environments. The maximum concentrations of Cr, Fe and Ni in Ceratophyllum demersum were 4242, 16,429 and 2662mgkg(-1), respectively. The result suggests that C. demersum is a good candidate species for removing heavy metals from polluted aquatic environments. PMID- 25011116 TI - Protective effect of shrimp carotenoids against ammonia stress in common carp, Cyprinus carpio. AB - This study is aimed at evaluating the protective effect of shrimp carotenoids on ammonia stress in common carp. Crude carotenoid extract from shrimp exoskeleton, astaxanthin and astaxanthin ester fractionated from crude extract was fed to the common carp fingerlings at 100 and 200ppm concentration by incorporating carotenoids into feed. Experimental and control fish were then exposed to sublethal dose of ammonia. Serum total antioxidant status (TAS), activities of superoxide dismutase (SOD) and catalase were measured to determine the effect of dietary carotenoid on defense status of fish. Activities of aspartate transaminase (AST) and alanine transaminase (ALT) were measured to determine the protective effect of carotenoids against tissue damage caused by the ammonia stress. TAS, catalase and SOD activity was higher in tissues from fish fed with the diet containing astaxanthin rich and astaxanthin ester rich extract compared to fish fed with control diet. TAS reduced in the tissues considerably after exposure to ammonia. However, TAS was still higher in tissues from fish fed with carotenoid containing diet than in tissues from fish fed with control diet. Eventhough there was an increase in the activities of ALT and AST due to stress by ammonia toxicity in all groups, fish fed with astaxanthin extract had lower activities and also prevented lipid peroxidation in the tissues. In conclusion, shrimp carotenoid increased the resistance of common carp fingerlings to ammonia induced stress. PMID- 25011117 TI - Integrated assessment of oxidative stress and DNA damage in earthworms (Eisenia fetida) exposed to azoxystrobin. AB - Azoxystrobin has been widely used in recent years. The present study investigated the oxidative stress and DNA damage effects of azoxystrobin on earthworms (Eisenia fetida). Earthworms were exposed to different azoxystrobin concentrations in an artificial soil (0, 0.1, 1, and 10mg/kg) and sampled on days 7, 14, 21, and 28. Superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POD), glutathione-S-transferase (GST), reactive oxygen species (ROS), and malondialdehyde (MDA) content were measured by an ultraviolet spectrophotometer to determine the antioxidant responses and lipid peroxidation. Single cell gel electrophoresis (SCGE) was used to detect DNA damage in the coelomocytes. Compared with these in the controls, earthworms exposed to azoxystrobin had excess ROS accumulation and greater SOD, POD, and GST activity while the opposite trend occurred for CAT activity. MDA content increased after 14-day exposure, and DNA damage was enhanced with an increase in the concentration of azoxystrobin. In conclusion, azoxystrobin caused oxidative stress leading to lipid peroxidation and DNA damage in earthworms. PMID- 25011118 TI - Effect of sub-acute exposure to nickel nanoparticles on oxidative stress and histopathological changes in Mozambique tilapia, Oreochromis mossambicus. AB - The aim of the present study was to assess the oxidative stress, antioxidant response and histopathological changes of nickel nanoparticles (Ni NPs) exposure (14 days) in Mozambique tilapia, Oreochromis mossambicus. Ni NPs were synthesized by metal salt reduction method and characterized by X-ray diffraction (XRD) and Transmission electron microscopy (TEM). The XRD peaks at 44 degrees , 51 degrees and 76 degrees were indexed to the (111), (200) and (220) Bragg's reflections of cubic structure of Nickel, respectively. The crystallite sizes were calculated using Scherrer's formula applied to the major intense peaks and found to be the size of 56nm. TEM images showed that the synthesized Ni NPs are spherical in shape. Biochemical analysis indicated that the superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activity was significantly affected by Ni NPs treated O. mossambicus. Reduced antioxidant enzymes and the contents of antioxidants were lowered in the liver and gills of fishes treated with Ni NPs. After 14 days of exposure, a significant accumulation of Ni in the Ni NPs in experimental group was observed in the gill and skin tissues, with the highest levels found in the liver. Ni NPs exposed fish showed nuclear hypertrophy (NH), nuclear degeneration (ND), necrosis (NC) and irregular-shaped nuclei were observed in liver tissue. The hyperplasia of the gill epithelium (GE), lamellar fusion of secondary lamellae (LF), dilated marginal channel (MC), epithelial lifting (EL) and epithelial rupture were observed in gill tissue. Degeneration in muscle bundles (DM), focal area of necrosis (NC) vacuolar degeneration in muscle bundles (VD), edema between muscle bundles (ED) and splitting of muscle fibers were noticed in skin tissue. Further ecotoxicological evaluation will be made concerning the risk of Ni NPs on aquatic environment. PMID- 25011119 TI - Application of Taguchi L32 orthogonal array design to optimize copper biosorption by using Spaghnum moss. AB - In this work, Taguchi L32 experimental design was applied to optimize biosorption of Cu(2+) ions by an easily available biosorbent, Spaghnum moss. With this aim, batch biosorption tests were performed to achieve targeted experimental design with five factors (concentration, pH, biosorbent dosage, temperature and agitation time) at two different levels. Optimal experimental conditions were determined by calculated signal-to-noise ratios. "Higher is better" approach was followed to calculate signal-to-noise ratios as it was aimed to obtain high metal removal efficiencies. The impact ratios of factors were determined by the model. Within the study, Cu(2+) biosorption efficiencies were also predicted by using Taguchi method. Results of the model showed that experimental and predicted values were close to each other demonstrating the success of Taguchi approach. Furthermore, thermodynamic, isotherm and kinetic studies were performed to explain the biosorption mechanism. Calculated thermodynamic parameters were in good accordance with the results of Taguchi model. PMID- 25011120 TI - Brevibacillus sp. KUMAs2, a bacterial isolate for possible bioremediation of arsenic in rhizosphere. AB - Arsenic (As) contamination of soil and water has been considered as a major global environmental issue during last few decades. Among the various methods so far reported for reclamation of As contaminated rhizosphere soil, bioremediation using bacteria has been found to be most promising. An As resistant bacterial isolate Brevibacillus sp. KUMAs2 was obtained from As contaminated soil of Nadia, West Bengal, India, which could resist As(V) and As(III) a maximum of 265mM and 17mM, respectively. The strain could remove ~40 percent As under aerobic culture conditions. As resistant property in KUMAs2 was found to be plasmid-borne, which carried both As oxidizing and reducing genes. The strain could promote chilli plant growth under As contaminated soil environment by decreasing As accumulation in plant upon successful colonization in the rhizosphere, which suggests the possibility of using this isolate for successful bioremediation of As in the crop field. PMID- 25011121 TI - Response to copper bromide exposure in Vicia sativa L. seeds: analysis of genotoxicity, nucleolar activity and mineral profile. AB - Copper bromide (CuBr2) effects on seed germination and plantlet development of Vicia sativa L. are evaluated through mitotic index, chromosome aberrations, nucleolar activity and mineral profile. CuBr2 induces a significant presence of micronuclei, sticky and c-metaphases, anaphase bridges and chromosome breaks. Increased number of nucleoli and scattering of AgNOR proteins from the nucleolus in the nuclear surface at CuBr2 1mM and in the cytoplasm at CuBr2 5mM, goes along with the decrease of root growth. In V. sativa embryo the content of many macro and micronutrients increases up to copper 1mM in agreement with reserve mobilization while at CuBr2 5mM some elements are present in lower amount. We hypothesize that inhibitory effects observed at 5mM are due either to a nutrient shortage or to a direct influence of copper on root cell division, evidenced by low mitotic index, high occurrence of chromosome aberrations and loss of material from the nucleolus. PMID- 25011122 TI - Metabolites analysis, metabolic enzyme activities and bioaccumulation in the clam Ruditapes philippinarum exposed to benzo[a]pyrene. AB - A study was performed on clams (Ruditapes philippinarum) exposed to 0.03, 0.3 and 3MUg/L benzo[a]pyrene (B[a]P) for 21 days. B[a]P metabolite contents, activities of aryl hydrocarbon hydroxylase (AHH), 7-ethoxyresorufin O-deethylase (EROD), epoxide hydrolase (EH), dihydrodiol dehydrogenase (DD), glutathione-S-transferase (GST), sulfotransferase (SULT) and uridinediphosphate glucuronyltransferase (UGT) and B[a]P bioaccumulation were assayed in gills and digestive glands. Results showed that the order of B[a]P phase I metabolite contents was 9-hydroxy B[a]P>B[a]P-1,6-dione>B[a]P-7,8-dihydrodiol, and the concentration of B[a]P-7,8 dihydrodiol sulfate conjugates was higher than that of B[a]P-7,8-dihydrodiol glucuronide conjugates. B[a]P accumulation and the activities of AHH, EROD, EH, DD, SULT and UGT increased first and then reached equilibrium. GST activity was induced first and then depressed. The concentration of B[a]P was far higher than that of its metabolites. Besides, there were no significant differences between enzyme activities in gills and those in digestive glands. These results provided information on B[a]P metabolic mechanism in bivalve and scientific data for pollution monitoring and food security. PMID- 25011123 TI - Biosorption of nickel by Lysinibacillus sp. BA2 native to bauxite mine. AB - The current scenario of environmental pollution urges the need for an effective solution for toxic heavy metal removal from industrial wastewater. Bioremediation is the most cost effective process employed by the use of microbes especially bacteria resistant to toxic metals. In this study, Lysinibacillus sp. BA2, a nickel tolerant strain isolated from bauxite mine was used for the biosorption of Ni(II). Lysinibacillus sp. BA2 biomass had isoelectric point (pI) of 3.3. The maximum negative zeta potential value (-39.45) was obtained at pH 6.0 which was highly favourable for Ni(II) biosorption. 238.04mg of Ni(II) adsorbed on one gram of dead biomass and 196.32mg adsorbed on one gram of live biomass. The adsorption of Ni(II) on biomass increased with time and attained saturation after 180min with rapid biosorption in initial 30min. The Langmuir and Freundlich isotherms could fit well for biosorption of Ni(II) by dead biomass while Langmuir isotherm provided a better fit for live biomass based on correlation coefficient values. The kinetic studies of Ni(II) removal, using dead and live biomass was well explained by second-order kinetic model. Ni(II) adsorption on live biomass was confirmed by SEM-EDX where cell aggregation and increasing irregularity of cell morphology was observed even though cells were in non-growing state. The FTIR analysis of biomass revealed the presence of carboxyl, hydroxyl and amino groups, which seem responsible for biosorption of Ni(II). The beads made using dead biomass of Lysinibacillus sp. BA2 could efficiently remove Ni(II) from effluent solutions. These microbial cells can substitute expensive methods for treating nickel contaminated industrial wastewaters. PMID- 25011124 TI - Antioxidant defense responses in Mytella guyanensis (Lamarck, 1819) exposed to an experimental diesel oil spill in Paranagua Bay (Parana, Brazil). AB - We evaluated the effects of diesel oil on the bivalve Mytella guyanensis using biomarkers of oxidative stress (glutathione S-transferase, glutathione peroxidase, and reduced glutathione) after an experimental in situ spill in a mangrove area in southern Brazil. A linear model was developed for the Multiple Before-After Control-Impact (MBACI) experimental design to assess the significance of biological responses. Control and impacted sites were sampled seven and two days before as well as two and seven days after the spill. With the exception of a late response of reduced glutathione (GSH) levels on day seven, none of the biomarkers were significantly altered by the impact. This result was attributed to the high environmental variability of the experimental sites combined with a low sensitivity of Mytella guyanensis to diesel oil at short time scales. The high resistance of M. guyanensis suggests that its antioxidant response is triggered only after a medium- to long-term exposure to contaminants. PMID- 25011125 TI - Stereoselective metabolism, distribution, and bioaccumulation brof triadimefon and triadimenol in lizards. AB - In this research, Chinese lizards (Eremias argus) were chosen as laboratory animal to evaluate the stereoselectivity in the processes of metabolism, distribution, and bioaccumulation of triadimefon. A validated chiral high performance liquid chromatography coupled with triple quadruple mass spectrometry (HPLC-MS/MS) method was developed for determining enantiomers' residues of parent compound triadimefon and its metabolite triadimenol in lizard blood and tissues. Pharmacokinetic results of single-does exposure suggested that S-(+)-triadimefon was metabolized easier than R-(-)-triadimefon, and RR-(+)-triadimenol was the main metabolic product of triadimefon. During the continuous exposure of two dose (40mg/kg(bw).d and 200mg/kg(bw).d), enantiomers of triadimefon and triadimenol were detected in all body compartments, with the highest triadimefon concentrations in brain. However, the triadimenol concentrations were not significantly different among the compartments. The concentrations of RS-(+) triadimenol were negative correlated with concentrations of RR-(+)-triadimenol both in blood (r=-0.775, p=0.024) and liver (r=-0.834, p=0.02) in 200mg/kg(bw).d group, which indicates that chiral conversion between enantiomers of triadimenol might exist in the metabolic process of triadimefon. In all the processes, the enantiomer fractions (EFs) of R-(-)-triadimefon and RR-(+)-triadimenol were significantly different from their natural ratios, 0.5 and 0.1, respectively, which proved that metabolism, bioaccumulation, and distribution of triadimefon and triadimenol in lizards were enantioselective. These results help enrich and supplement the knowledge of the stereoselective behaviour of triadimefon and triadimenol in reptile. PMID- 25011126 TI - Assessment of biotic response to heavy metal contamination in Avicennia marina mangrove ecosystems in Sydney Estuary, Australia. AB - Mangrove forests act as a natural filter of land-derived wastewaters along industrialized tropical and sub-tropical coastlines and assist in maintaining a healthy living condition for marine ecosystems. Currently, these intertidal communities are under serious threat from heavy metal contamination induced by human activity associated with rapid urbanization and industrialization. Studies on the biotic responses of these plants to heavy metal contamination are of great significance in estuary management and maintaining coastal ecosystem health. The main objective of the present investigation was to assess the biotic response in Avicennia marina ecosystems to heavy metal contamination through the determination of metal concentrations in leaves, fine nutritive roots and underlying sediments collected in fifteen locations across Sydney Estuary (Australia). Metal concentrations (especially Cu, Pb and Zn) in the underlying sediments of A. marina were enriched to a level (based on Interim Sediment Quality Guidelines) at which adverse biological effects to flora could occasionally occur. Metals accumulated in fine nutritive roots greater than underlying sediments, however, only minor translocation of these metals to A. marina leaves was observed (mean translocation factors, TFs, for all elements <0.13, except for Mn). Translocation factors of essential elements (i.e., common plant micro-nutrients, Cu, Ni, Mn and Zn) were greater than non-essential elements (As, Cd, Co, Cr and Pb), suggesting that A. marina mangroves of this estuary selectively excluded non-essential elements, while regulating essential elements and limiting toxicity to plants. This study supports the notion that A. marina mangroves act as a phytostabilizer in this highly modified estuary thereby protecting the aquatic ecosystem from point or non-point sources of heavy metal contamination. PMID- 25011127 TI - [Outstanding aspects of hepatic amebiasis. 1965]. PMID- 25011128 TI - [The importance of amniography in the study of chronic fetal distress. 1968]. PMID- 25011129 TI - Pfizer wins ruling that blocks generic pregabalin until 2018. PMID- 25011131 TI - National initiative to cultivate the next generation of palliative care leaders. PMID- 25011130 TI - New drug treatment reduces chronic pain following shingles. PMID- 25011132 TI - Palliative care page added to MedlinePlus. PMID- 25011133 TI - Public notification: Arth-Q contains hidden drug ingredient. PMID- 25011134 TI - Chronic pain patients should ask questions: the ASA Choosing Wisely list. PMID- 25011135 TI - AGA seeks to reduce preventable GI health issues. PMID- 25011136 TI - New video public service announcement (PSA) flipbook. PMID- 25011137 TI - Nearly two thirds of states lack rescue drug and Good Samaritan overdose laws. PMID- 25011138 TI - Health information exchange reduces use of repeated diagnostic imaging for back pain. PMID- 25011139 TI - National Pain Foundation reformed. PMID- 25011140 TI - India amends Drug Act to simplify access to pain medicines. PMID- 25011141 TI - WHO develops resolution on access to pain medications. PMID- 25011142 TI - Physicians are the primary source of opioids for chronic abusers. PMID- 25011143 TI - CPAP becomes member based. PMID- 25011144 TI - FDA approves oxycodone and acetaminophen extended-release tablets. PMID- 25011145 TI - Opioids prescriptions stabilizing after 5-fold increase in 10-year span. PMID- 25011146 TI - Atlas of Palliative Care Services in Latin America. PMID- 25011147 TI - FDA approves Topamax for migraine prevention in adolescents. PMID- 25011153 TI - [1. The goals and objectives of "war time military evening meetings". Friedrich Trendelenburg]. PMID- 25011156 TI - [German prize for patient safety presented for the 1st time - Patient Safety Action Group selects 3 projects out of 70 submissions]. PMID- 25011157 TI - [Memorandum on use of information technology in drug therapy: challenges and recommendations]. PMID- 25011158 TI - Medical devices; general and plastic surgery devices; classification of the nonabsorbable expandable hemostatic sponge for temporary internal use. Final order. AB - The Food and Drug Administration (FDA) is classifying the nonabsorbable expandable hemostatic sponge for temporary internal use into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the nonabsorbable expandable hemostatic sponge for temporary internal use classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 25011159 TI - International Conference on Harmonisation; guidance on Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 6 on Uniformity of Dosage Units General Chapter; availability. Notice. AB - The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 6: Uniformity of Dosage Units General Chapter.'' The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guidance provides the results of the ICH Q4B evaluation of the Uniformity of Dosage Units General Chapter harmonized text from each of the three pharmacopoeias (United States, European, and Japanese) represented by the Pharmacopoeial Discussion Group (PDG). The guidance conveys recognition of the three pharmacopoeial methods by the three ICH regulatory regions and provides specific information regarding the recognition. The guidance is intended to recognize the interchangeability between the local regional pharmacopoeias, thus avoiding redundant testing in favor of a common testing strategy in each regulatory region. The guidance is in the form of an annex to the core guidance on the Q4B process entitled ''Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions'' (core ICH Q4B guidance). PMID- 25011160 TI - Medicare program; additional extension of the payment adjustment for low-volume hospitals and the Medicare-dependent hospital (MDH) program under the hospital Inpatient Prospective Payment Systems (IPPS) for acute care hospitals for fiscal year 2014. Extension of a payment adjustment and a program. AB - This document announces changes to the payment adjustment for low-volume hospitals and to the Medicare-dependent hospital (MDH) program under the hospital inpatient prospective payment systems (IPPS) for the second half of FY 2014 (April 1, 2014 through September 30, 2014) in accordance with sections 105 and 106, respectively, of the Protecting Access to Medicare Act of 2014 (PAMA). PMID- 25011161 TI - Dental devices; reclassification of blade-form endosseous dental implant. Final order. AB - The Food and Drug Administration (FDA) is issuing a final order to reclassify the blade-form endosseous dental implant, a preamendments class III device, into class II (special controls). On its own initiative, based on new information, FDA is revising the classification of blade-form endosseous dental implants. PMID- 25011162 TI - Changes to scheduling and appearing at hearings. Final rules. AB - These final rules explain how a claimant may object to appearing at a hearing via video teleconferencing, or to the time and place of a hearing. These final rules adopt, with further clarification regarding our good cause exception, the notice of proposed rulemaking (NPRM) that we published in the Federal Register on June 27, 2013. We expect that these final rules will have a minimal impact on the public, help ensure the integrity of our programs, and allow us to administer our programs more efficiently. PMID- 25011163 TI - Ninety-day waiting period limitation. Final rules. AB - These final regulations clarify the maximum allowed length of any reasonable and bona fide employment-based orientation period, consistent with the 90-day waiting period limitation set forth in section 2708 of the Public Health Service Act, as added by the Patient Protection and Affordable Care Act (Affordable Care Act), as amended, and incorporated into the Employee Retirement Income Security Act of 1974 and the Internal Revenue Code. PMID- 25011164 TI - Final priority; National Institute on Disability and Rehabilitation Research- Rehabilitation and Research Training Centers. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for the Rehabilitation Research and Training Center (RRTC) Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for an RRTC on Employment for Individuals with Intellectual and Developmental Disabilities. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2014 and later years. We take this action to focus research attention on areas of national need. We intend for this priority to contribute to improved employment outcomes of individuals with intellectual and developmental disabilities. PMID- 25011165 TI - Final priority; National Institute on Disability and Rehabilitation Research- Rehabilitation Research and Training Centers. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority under the Rehabilitation Research and Training Center (RRTC) Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, this notice announces a priority for an RRTC on Improving Employment Outcomes for Individuals with Psychiatric Disabilities. We take this action to focus research attention on an area of national need. We intend this priority to contribute to improved employment outcomes for individuals with psychiatric disabilities. PMID- 25011167 TI - CQC map highlights lack of places of safety for young people. PMID- 25011166 TI - Fighting the mental battle. PMID- 25011168 TI - Government commits to give mental health training to all healthcare professionals. PMID- 25011170 TI - Fighting the mental battle. PMID- 25011171 TI - Cafe culture. PMID- 25011172 TI - All in the game. PMID- 25011173 TI - Welfare writes. PMID- 25011174 TI - Outside the box. PMID- 25011175 TI - The bigger picture. PMID- 25011176 TI - A child in mind. PMID- 25011177 TI - Crisis resolution teams: how are they performing? PMID- 25011178 TI - Legal eye. PMID- 25011179 TI - Network. PMID- 25011180 TI - Animal instincts. PMID- 25011181 TI - Viewpoint. PMID- 25011183 TI - Searching for the rush. PMID- 25011182 TI - Stratified medicine in psychiatry: what service users, carers and the public think. PMID- 25011184 TI - On the record. PMID- 25011185 TI - Timothy Danforth Baker, MD 1925-2013. PMID- 25011186 TI - The value of volunteering. PMID- 25011187 TI - Helping independent practices thrive in a rapidly changing industry. PMID- 25011188 TI - Death by a thousand codes. PMID- 25011189 TI - ICD-10: how did we get here, or what are we doing? PMID- 25011190 TI - ICD-10: the final nail in the coffin for our profession? PMID- 25011191 TI - There's no code for quality care. PMID- 25011192 TI - Documentation, documentation, documentation. The key to ICD-10 readiness. PMID- 25011193 TI - ICD-10: navigating a successful transition. PMID- 25011194 TI - The truth about ICD-10 and your EMR vendor. PMID- 25011195 TI - ICD-10: are your practice management & billing systems ready? PMID- 25011196 TI - What are payors doing to implement ICD-10? PMID- 25011197 TI - ICD-10 personal perspective: what's eating doctor grape? PMID- 25011198 TI - The Curator of the Dead and the Sheriff of London. PMID- 25011199 TI - [Additional external radiotherapy to multiple metastases originating from thymic neuroendocrine tumor following peptide receptor radionuclide therapy: a case report]. AB - We describe the case of a 60-year-old man suffering from an advanced thymic neuroendocrine tumor with left supraclavicular lymph node and multiple bone metastases. The patient initially underwent systemic therapy with somatostatin analogues. Thereafter, peptide receptor radionuclide therapy (PRRT) was considered because the lesions had remained stable despite the pharmacological therapy. PRRT was performed 10 months after the initial treatment in a European hospital. Eighteen months after the treatment, cranial nerve palsy arising from skull base metastases and Horner's syndrome induced by left supraclavicular lymph node metastases became exacerbated. Therefore, a course of external radiotherapy was performed with palliative intent in our hospital. During the radiotherapy planning, the biodistribution of 111In-octreotide was examined to determine whether the absorbed dose of the previous PRRT was acceptable. As a result, external radiotherapy was performed, and an acute radiation reaction was observed; the severity of the reaction was typical of reactions to neck radio therapy. The treatment course of the present case was considered to be instructive because PRRT cannot be performed in Japan at present. PMID- 25011200 TI - Iliopubic subcutaneous plate osteosynthesis for osteoporotic fractures of the anterior pelvic ring. An alternative to the supra-acetabular external fixator. AB - The majority of fractures of the anterior pelvic ring is treated non-operatively. However, a number of patients do not get pain free and cannot be mobilized. Since the supra-acetabular external fixator is associated with significant complications we developed an alternative technique based on recent anatomical studies. This article is a clinical feasibility study to evaluate a novel stabilization technique for fractures of the anterior pelvic ring in the elderly patient. This technique obtains rapid pain reduction and early ambulation in this group of patients. PMID- 25011201 TI - [Radioinduced brain cyst: case report]. AB - We present a case of intraparenchymal radioinduced cyst of the brain observed in our department. It is a rare and relatively benign pathology which is usually treated conservatively or by surgery. We emphasize long-term imaging follow up in patients treated by radiosurgery, which can lead to the demonstration of multiple adverse events such as tumefactive cyst formation. PMID- 25011202 TI - [Incidence of colorectal carcinoma and patient survival in the Grand-Duchy of Luxembourg]. AB - As in many other Western countries, colorectal cancer is one of the most common malignant tumours in Luxembourg. It is thus an important target for prevention measures. In light of the discussions on the introduction of organized screening programmes in Luxembourg a description of the current cancer incidence and relative survival rates, as well as a comparison with neighbouring countries are important. The tumour incidence is comparable to that in other countries with similar socio-economic development. The standardized incidence rate (world population) in 2010 was 26.4 and 44.4 per 100,000 for women and men, respectively. In some, but not all, Western European countries, a decreasing trend of the standardized incidence is emerging. No such trend is currently observed in Luxembourg. The mortality and relative survival rates are comparable to those in other European countries. The proportion of colorectal carcinomas of stages T1 + T2, 18.7% in the years 2000 to 2011, is markedly lower in Luxembourg than for example in Rhineland -Palatinate (29.4%), while the proportion of carcinomas of stage T4 is higher (17.4% versus 13.9%). This suggests that further successes in prevention are possible and illustrates the benefits of an organized screening colonoscopy program compared with opportunistic screening. PMID- 25011203 TI - [Percutaneous aortic valve replacement using the Direct Flow Medical system: results of the Luxembourg registry]. AB - Percutaneous aortic valve replacement (TAVI) is one of the most innovative procedure in interventional cardiology. The Direct Flow Medical transcatheter aortic valve (DFM) is a new nonmetallic valve which allows perfect repositioning and valve retrieval prior to the final deployment. This study is a prospective non-randomized evaluation of the DFM system in the Luxembourg registry. The study focused on 15 patients who received between March 2013 and October 2013 a percutaneous aortic valve replacement by DFM prosthesis. All clinical and echocardiographic data have been collected prospectively. Fifteen inoperable patients with severe aortic stenosis were evaluated. The average age of our population was 83 +/- 4.16 years, mean STS score was 16%. 46% of patients were in NYHA class III and 33.3% in NYHA class IV. Mean ejection fraction was 59% +/- 12.7, the average mean gradient was 52.86 +/- 18.5 mm Hg and mean aortic orifie was 0.63 +/- 0.15 cm2. Procedural success rate was 100%. The mean trans- valvular gradient decreased from 52.86 +/- 18.5 mm Hg to 12 +/- 4.2 mm Hg (p < 0.001). The average hospital stay was 14 +/- 7.6 days. The non-fatal major event rate at one month was 33.3%. The mortality rate at one month was limited to 6.6%. These results allow us to confirm the efficacy and safety of the DFM valve. PMID- 25011204 TI - NOAC and intracerebral bleeding--presentation of four cases and review of the literature. AB - AF might be a life threatening disease. Patients have been under oral antithrombotic treatment in order to avoid thrombotic events. Although this treatment proved to be effective in the last decades there was always the inconvenience of a regular blood control. In the last months NOACs have been flooding the market promising to be as effective as their older concurrents in certain circumstances and highlighting the fact that the control of INR has become obsolete. However, as there is no specific antidote up to date, NOACs might present a life threatening event in case of an intracerebral haemorrhage. The brain surgeons might find themselves in a difficult situation when they have to decide whether to operate on a patient with a compromised haemostasis or not. We present four patients who were treated with NOACs for AF. Three of them were admitted with intracerebral haemorrhage in our neurosurgical unit from January to October 2013. The fourth patient bled one week after stopping his treatment with NOAC. Furthermore we take a closer look to the existing literature and try to portray the issue from a neurosurgical point of view. PMID- 25011205 TI - Case report: exertional heat stroke after moderate effort as a neurological emergency. AB - Exertional heat stroke can occur even after moderate efforts in persons predisposed to the condition. Consequences can be far-reaching, potentially leading to multi-organ failure and possibly death. We discuss the case of a 23 year old army recruit presenting with altered consciousness and hyperthermia after a training march. Following initial clinical improvement, rising CK and liver enzyme levels as well as increasing INR were recorded. Facing the risk of multi-organ failure, the patient was transferred to a specialized ICU. The condition could be stabilized without recurring to molecular adsorbent recirculation system (MARS). Exertional heat stroke must be readily recognized as such for correct treatment to be initiated. A multi-disciplinary approach is urgently warranted. PMID- 25011206 TI - Culture in America. PMID- 25011207 TI - Colorectal cancer screening: the role of perceived susceptibility, risk and cultural illness beliefs among American Indians. AB - PURPOSE: Colorectal cancer (CRC) disproportionately affects American Indians and is a leading cause of mortality despite being treatable when detected early. METHODS: An explanatory model to guide a CRC screening education media campaign was developed from survey and focus group data collected at three American Indian communities (n = 29) in California. Project data was analyzed using Chi Square, Fisher's Exact Test and thematic analysis. RESULTS: Low perceived susceptibility due to low harm value, cultural illness beliefs, and competing priorities likely lead to poor CRC screening behavior, placing American Indians at high risk for CRC mortality. PMID- 25011208 TI - The relationship of prejudicial attitudes to psychological, social, and physical well-being within a sample of college students in the United States. AB - This study examined the relationship of prejudicial attitudes to psychological, social, and physical well-being among 495 college students in the Northeast region of the United States. Prejudicial attitudes included racism, sexism, homophobia, physical disability bias, weight/body-size bias, and anti-immigrant sentiment. As a secondary objective, we examined the associations among the various forms of prejudice and their relationship to key demographic and personal characteristics. We also examined the associations between psychological, social, and physical well-being. The results indicated that specific forms of prejudice, especially racism and sexism, were negative correlates of psychological, social, and/or physical well-being. The results also indicated that there may exist a prejudicial syndrome, linking diverse forms of prejudice. Furthermore, poor functioning in one area of well-being (e.g., psychological health) is related to poor functioning in other areas of well-being (social and physical health). Overall, this study provides important implications for future research and prevention programs in the area of prejudice and well-being. PMID- 25011209 TI - Multiethnic perspectives on mainstream America. AB - The terms mainstream America and mainstream American are often used but infrequently defined. The purpose of this study was to explore definitions of these terms among a multiethnic sample of 158 college students. Two major themes emerged from a qualitative analysis: 1) an exclusionary definition as U.S.-born, dominated by Whites and of Judeo-Christian faith versus the predominant, more inclusive, contemporary definition of sharing American values and practices within a diverse society and 2) a contrast between highly critical comments (weakened family ties, moral decay, racism) and favorable comments (opportunity, helpfulness, openness and inclusiveness). Responses by ethnic group were also reported. PMID- 25011210 TI - Examination of cultural knowledge and provider sensitivity in nurse managed health centers. AB - It is important to examine empirical evidence of cultural competence among health care providers and to understand how it is assessed from an organizational context. There is a dearth of information about these concepts. Given its relevance to caring for diverse patient populations, the purpose of this paper is to present findings from a mixed method study which conducted a general cultural assessment survey of Nurse Managed Health Centers (NMHCs) that were affiliates of the National Nursing Centers Consortium. Findings enabled the authors to formulate recommendations that could strengthen the cultural competence of staff Organizational leadership and advanced practice nurses would benefit from more intentional efforts to increase proficiency of NMHC staff members in their cultural knowledge and sensitivity skills when delivering care to the populations they serve. PMID- 25011211 TI - [Dear Colleagues! Tocolysis in preterm labor]. PMID- 25011212 TI - [Tocolysis in preterm labour--current recommendations]. AB - Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists- fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations. PMID- 25011213 TI - COX-2 expression pattern is related to ovarian cancer differentiation and prognosis, but is not consistent with new model of pathogenesis. AB - OBJECTIVE: Numerous studies suggest that cyclooxygenase-2 (COX-2) is overexpressed in cancer. Our objective was to investigate the relationship between COX-2 expression in ovarian carcinoma and clinicopathological factors. An emphasis was put on the association with the new pattern of tumorigenesis that divides tumors into type I--less aggressive, and type II--more aggressive one. The prognostic significance of COX-2 expression was evaluated. METHODS: Ovarian cancer tissues were obtained from 65 patients in FIGO III stage (23 with type I and 42 with type II ovarian cancer). COX-2 expression was evaluated by immunohistochemistry. The statistical analysis was performed in order to assess the connection between COX-2 expression and characteristic factors of ovarian cancer patients as well as the new division for type I and type II ovarian cancer RESULTS: COX-2 expression was detected in 91% of tissue samples. It was markedly elevated in well differentiated tumors (p = 0.0041). The platinum-resistant tumors had significantly higher expression of COX-2 (p = 0.0337). There was no difference between COX-2 expression in type I and type II ovarian cancer (p = 0.6720). The COX-2 staining was not associated to age, CA125 level, the presence of ascites or any special histological type. An increased expression of COX-2 was an unfavorable prognostic factor for overall survival (p = 0.0369) and progression-free survival (p = 0.0218). Multivariate analysis confirmed that COX 2 overexpression is an independent unfavorable prognostic factor of shorter progression-free survival (p = 0.048). CONCLUSIONS: COX-2 expression is an unfavorable prognostic factor for progression-free survival and overall survival in ovarian cancer There is no relationship between COX-2 expression in ovarian cancer tissue and the examined model of ovarian cancer pathogenesis. PMID- 25011214 TI - Barriers in entering treatment among women with urinary incontinence. AB - OBJECTIVE: The aim of the study was to identify barriers in help seeking behaviors among women with urinary incontinence UI. MATERIALS AND METHODS: The study was performed using the method of diagnostic enquiry by means of questionnaire and interview among two groups of patients. The first group of women aged 47-79 years consisted of 80 members of the Association of People with Urinary Incontinence "Uroconti". The second group included 61 females aged 26-81 years admitted to the Urodynamic Laboratory of Gynecology and Oncology Clinic at the University Hospital in Krakow. RESULTS: Patients with stress urinary incontinence (SUI) reported to the doctor on average after 4 years, patients with urgency urinary incontinence (UUI), after 3 years, patients with a mixed form of urinary incontinence (MUI), after 6 years, and with overflow incontinence, after 10 years from the appearance of first symptoms. Anxiety shame, the conviction that symptoms of UI are a normal age related state, as well as the conviction that the symptoms are temporary significantly affected the delay in seeking medical consultation. Most of the surveyed women made the decision to undertake treatment themselves, and their main motive was the escalation of symptoms. The majority (89.4%) of women surveyed alleviated the symptoms of urinary incontinence without the help of a doctor sometimes using methods detrimental to their health. CONCLUSION: The identification of help seeking barriers and reaching out to risk groups is essential for early diagnose and effective treatment of women with urinary incontinence. PMID- 25011215 TI - The influence of soybean extract on the expression level of selected drug transporters, transcription factors and cytochrome P450 genes encoding phase I drug-metabolizing enzymes. AB - OBJECTIVE: Soybean phytoestrogens, such as genistein and daidzein, reduce climacteric symptoms and the risk of certain chronic diseases such as cancer and cardiovascular diseases. Despite their widespread use in functional foods and dietary supplements, there is very little data available on their safety and herb drug interactions, especially with antineoplastic agents. Hence, the aim of our study was to assess the effects of soybean extracts on the expression level of CYP genes and their transcriptional factors. We also investigated the effect of soybean on the mRNA level of transporters, such as P-glycoprotein (MDRI) and multidrug resistance-associated proteins (MRP1, MRP2). MATERIALS AND METHODS: Wistar rats were fed a standardized soybean extract (100 mg/kg, p.o.). cDNA was synthesized from total RNA isolated from different tissues (liver and intestinal epithelium) using reverse transcription. Gene expression level was analyzed by RT PCR method. RESULTS: We demonstrated a significant increase of CYP1A1 mRNA level (by 89%, p = 0.002 and 125%, p = 0.004) as compared with the control group. An increase of AHR and CAR expression after 10 days was also observed (by 60%, p < 0.001 and 52%, p > 0.05, respectively). Additionally an inductive effect for CYP2D1 by 22% (p = 0.008), Mdr1a by 267% (p < 0.0001), Mdr2b by 86% (p < 0.00001), Mrp1 by 9-fold (p < 0.0001), Mrp2 by 83% (p < 0.0001) in the liver and for Mrp2 by 35% (p < 0.001) in the intestinal epithelium, was evaluated. A significant decrease of mRNA level was observed for CYP3A1 (human CYP3A4) in the liver and Mdr1b in the intestinal epithelium. Moreove, we also showed a slight decrease in the amount of mRNA for CAR, PXR and ARNT after 3 days. CONCLUSIONS: Our results suggest that Glycine max may change the expression level of CYPs, especially CYP3A4 and CYP1A 7, involved in biotransformation of xenobiotics (drugs, procarcinogens) and may participate in clinically significant interactions with drugs metabolized by these enzymes. Moreover an increase of CYP1A1 (homologue to human CYPIA 1) mRNA level may not only reduce the carcinogenicity of foreign compounds, but may also activate some compounds to their carcinogenicity In case of transporters, it is considered that an increase of their expression in the body may lead to increased fetoprotection. Also, it may reduce both, the exposure of sensitive tissues (e.g. brain, placenta) to xenobiotics and treatment effectiveness of certain diseases. Hence, the search for a safe substance that could effectively modulate transporter activity especially in the treatment of certain hormone -dependent disorders, e.g. osteoporosis and breast cancer occurring mainly in postmenopausal period, continues. PMID- 25011216 TI - Usefulness of three dimensional transvaginal ultrasonography and hysterosalpingography in diagnosing uterine anomalies. AB - INTRODUCTION: Uterine anomalies may lead to infertility recurrent miscarriage, preterm labour intrauterine growth restriction and post-partum haemorrhage. Infertility and recurrent miscarriage are relatively common problems in the female population. Diagnostic algorithms in such cases include the evaluation of uterine anatomy Magnetic resonance imaging (MRI) is the most accurate technique for visualizing the female genitourinary tract anatomy but as it is expensive and not readily available, it is not useful in everyday practice. Hysterosalpingography (HSG) is a frequently performed procedure that plays an important role in evaluating the uterus and fallopian tubes. The most typical indication for HSG is infertility and recurrent miscarriage, which are common problems in the female population. However this procedure is invasive, exposes the patient to ionizing radiation, carries a risk of complications and does not show the external contour of the uterus, which is essential for differentiating uterine anomalies. Three dimensional transvaginal ultrasound (3D TV USG) is a noninvasive and quick, imaging method that may be used in diagnosing uterine anomalies. This method allows evaluate the external contours of the uterus, making it comparable to MRI. OBJECTIVE AND METHODS: In this study we discuss the advantages and disadvantages of HSG and 3D TV USG in diagnosing uterine anomalies. Additionally we present the results of HSG and 3D TV USG of 155 patients referred to our Department because of infertility and/or suspected uterine anomalies. RESULTS: After performing HSG, in the studied group 118 patients were diagnosed with a normal uterus, 4 with unicornuate (including 1 patient with an unicornuate uterus, with rudimentary horn), and 6 with didelphys uterus. In 22 cases, due to the lack of evaluation of external contour of the uterus, we could not differentiate arcuate, septate and bicornuate uterus. After performing 3D TV USG we confirmed the HSG diagnosis and precise differentiated 22 disputable cases. 8 with arcuate, 11 with septate (2 complete and 9 partial) and 3 with complete bicornuate uterus. In 5 patients, severe pain and lack of cooperation during HSG made the acquisition of diagnostic X-ray images impossible. In these cases 3D TV USG allowed the anatomic assessment of the uterus, a normal uterus was found in all of them. All uterine anomalies were then confirmed by hysteroscopy and/or laparoscopy CONCLUSIONS: Basing on a review of the literature and our results, we conclude that HSG is not the optimal method for diagnosing uterine anomalies, while 3D TV USG can accurately show the uterus anomalies and may become an alternative method to MRI. PMID- 25011217 TI - Intra- and inter-observer variability of evaluation of uterine cervix elastography images during pregnancy. AB - OBJECTIVES: To evaluate reproducibility and repeatability of the assessment of elastography images of the uterine cervix using an Elastography Index. MATERIAL AND METHODS: Elastography images of the uterine cervix were obtained. Numeric scale called Elastography Index, previously published by the authors, was used to describe parts of the cervix. A total of 282 images were evaluated twice by an experienced and twice by an inexperienced operator RESULTS: Reproducibility and repeatability of the evaluation of internal and external os and cervical canal were over 90%. Inter-assay coefficient of variation was 1.84%, 6.76% and 7.27% respectively and 5.84% for anterior and 16.74% for posterior wall. Analysis of the second evaluation only of both operators revealed no significant difference for posterior wall as well (F-test; p = 0.09). CONCLUSION: Authors proved satisfactory reproducibility and repeatability of subjective assessment of elastography images of uterine cervix during pregnancy with the use of Elastography Index in the hands of experienced and inexperienced observer PMID- 25011218 TI - Histomorphometry and detection of glycosaminoglycans in the endocervical epithelium of pregnant rats after local administration of hyaluronidase. AB - OBJECTIVE: The aim of the study was to detect the presence of glycosaminoglycans and to investigate histomorphometric aspects of the endocervical epithelium in pregnant rats after local administration of hyaluronidase. MATERIALS AND METHODS: Ten pregnant rats were randomly distributed into two groups. On day 18 of pregnancy 1 mL of distilled water and 0.02 mL of hyaluronidase were administered to the control group (CG) and the study group (SG), respectively On day 20 the rats were sacrificed, followed by dissection and removal of the uterine cervix, which was prepared for histomorphometry (endocervical epithelium thickness and leucocyte infiltration) and for immunohistochemistry with alcian blue reaction and its respective blockers. The paired Student t test was used to compare the groups. RESULTS: The SG was characterized by reduced epithelial thickness (mean: 291.01 +/- 71.1 vs. 764.30 +/- 50.94; p < 0.0001) and a larger number of eosinophils (mean: 3.72 +/- 1.60 vs. 0.54 +/- 0.70; p < 0.0001). Alcian blue staining (pH 0.5) indicated a very strong reaction (3+) for the CG. With pH 2.5, the staining was also very intense (4+) in the CG. With methylation, both groups showed negative reactions after alcian blue staining (pH 2.5). With the methylation reaction followed by saponification and with enzymatic digestion of the lamina, staining showed a weak reaction (1+) in both groups. CONCLUSION: The SG presented with significant alterations related to the reduction of epithelial thickness and an increase in leucocyte infiltration. Furthermore, the use of hyaluronidase resulted in a significant decrease of the sulfated glycosaminoglycans. PMID- 25011219 TI - Urinary tract infection in pregnant population, which empirical antimicrobial agent should be specified in each of the three trimesters? AB - OBJECTIVE: We aimed to investigate the bacterial profile and the adequacy of antimicrobial treatment in pregnant women with urinary tract infection. MATERIAL AND METHODS: This retrospective observational study was conducted with 753 pregnant women who needed hospitalization because of UTI in each of the three trimesters. Midstream urine culture and antimicrobial susceptibility tests were evaluated. RESULTS: E. Coli was the most frequently isolated bacterial agent (82.2%), followed by Klebsiella spp. (11.2%). In each of the three trimesters, E. Coli remained the most frequently isolated bacterium (86%, 82.2%, 79.5%, respectively), followed by Klebsiella spp. (9%, 11.6%, 12.2%, respectively). Enterococcus spp. were isolated as a third microbial agent, with 43 patients (5.7%) in the three trimesters. The bacteria were found to be highly sensitive to fosfomycin, with 98-99% sensitivity for E.Coli and 88-89% for Klebsiella spp. and for Enterococcus spp. 93-100% nitrofurantoin sensitivity for each of the three trimesters. CONCLUSIONS: We demonstrated that E. Coli and Klebsiella spp. are the most common bacterial agents isolated from urine culture of pregnant women with UTI in each of the three trimesters. We consider fosfomycin to be the most adequate first-line treatment regimen due to high sensitivity to the drug, ease of use and safety for use in pregnancy PMID- 25011220 TI - [Screening for ovarian cancer in BRCA1/BRCA2 mutations carriers]. AB - Worldwide screening for early detection of ovarian cancer in both, the general population and the group of women at high risk for ovarian cancer including BRCA genes mutations carriers, has proven to be ineffective. The recommended screening methods, including a pelvic examination, transvaginal ultrasound, and CA125 performed biannually continue to fail due to their relatively low sensitivity specificity and positive predictive value tests, as well as the fact that cancer is still detected in advanced stages (FIGO III/IV). However proteomic techniques and the ongoing search for more sensitive and specific biomarkers to increase effectiveness of screening tests for ovarian cancer bring new hope. We reviewed the current literature on screening for ovarian cancer in BRCA genes mutations carriers. PMID- 25011221 TI - [Active periodontitis as a potential risk factor of preferm delivery]. AB - The influence of active periodontitis on the incidence of preterm delivery has been widely described in numerous scientific papers. Studies suggest that an implementation of a periodontal treatment during pregnancy is not only safe for both, the mother and the child, but it also has a beneficial effect on the pregnancy and embryo-fetal development, consequently reducing morbidity and mortality among premature infants. Therefore, mandatory dental examinations in pregnant women may facilitate early implementation of periodontal treatment and reduce the rates of preterm delivery PMID- 25011222 TI - Endometriosis in a post-laparoscopic scar--case report and literature review. AB - Endometriosis is an estrogen-dependent, chronic disease consisting in implantation and hyperplasia of the endometrium outside of the uterine cavity Endometriosis in post-laparoscopic scars applies to approx. 0.5-7% of the extraorganic locations of the disease. The purpose of the paper was to describe medical management and literature review for endometriosis in a post-laparoscopic scar. Two lesions located near the insertion site for the lower trocars were removed along with the border of healthy tissue. At the time of publication of this paper the patient did not report any complaints. In conclusion, each limited lesion in the subcutaneous tissue, with pain intensifying during menstruation, should suggest an initial diagnosis of scar endometriosis, regardless of patient age and type of surgery PMID- 25011223 TI - Pulmonary CT angiography in the diagnosis of pulmonary embolism in pregnancy--a case report. AB - This paper describe the case of pulmonary thromboembolism (PTE) in pregnancy diagnosed by angio CT The clinical diagnosis of PTE in normal population is difficult. In pregnancy is even more complicated, because physiologic changes of pregnancy can mimic signs and symptoms of PTE. Our patient presented dyspnoea, breathing effort and cyanosis of the mouth at admission. In the check-up there was a distinct murmur just under the heart and tachycardia 115 bpm. The Doppler examination of the venous vessels of the lower extremities was normal. Echocardiography revealed features of right ventricular failure. Due to increased level of D-dimers and echocardiographic features of right-ventricular overload, the suspicion of pneumonic embolism was made. Therefore, in order to verify the initial diagnosis the decision of pulmonary CT angiography was made with the radiological protection of the fetus. This study revealed pulmonary embolism in the form of numerous defects in the contrast fillings of the pulmonary arteries. CT pulmonary angiography is the first imaging test of choice in general population who is suspected to have PTE. However there is no consensus what should be preferred during pregnancy. In this paper the diagnostic concepts and an evidence-based guidelines were discussed in case of PTE in pregnancy as well as its side effects including teratogenicity and oncogenicity. In each case, the risks and benefits must be compared before a decision is taken. In case of thrombosis symptoms in the lower extremities, ultrasound should be taken as the next step, otherwise chest X-ray must be performed. In patients with normal chest X-ray the next step should be scintigraphy but if chest X-ray is abnormal, angio CT is preferred. PMID- 25011224 TI - [Recommendations of the Polish Gynecological Society concerning docosahexaenoic acid supplementation in the prevention of preterm birth]. PMID- 25011225 TI - [Four measures of treatment compliance among patients recovering from psychotic episodes--a comparative study]. AB - OBJECTIVES: Patient compliance influences results of treatment of mental disorders. The study compares four measures of treatment adherence. METHODS: 103 subjects were examined in the early remission from an acute psychotic (schizophrenic or schizoaffective) crisis. Compared was patient's compliance assessed by two simple scales: 5-point POP (patient's self-rating) and 7-point POK (clinician's rating) as well as by two composite questionnaires: the Drug Attitude Inventory (DAI-10) and the Medication Adherence Rating Scale (MARS). The ROC curve was used to compare sensitivity and specificity of DAI-10 and MARS scores as predictors of simple ratings. RESULTS: The percentage of patients who complied ranged between 42.8% to 62% (20.4-26.2% with stringent criteria applied). The POK shows a stronger correlation with the POP (0.50) than with the results of DAL-10 (0.30) or MARS (0.32). The POP correlated low with DAI-10 (0.23) and MARS (0.32). The correlation between MARS and DAI-10 was relatively high (0.67). Their reliability (Cronbach's a coefficient) only moderately exceeded the satisfactory level (DAI-10: alpha = 0.76) or approximated it (MARS: alpha = 0.61). Area under the curve (AUC) suggested comparable and significant diagnostic value of the DAI-10 and MARS. Scores extending 7.5 points indicated their optimal relation between sensitivity and specificity in predicting the clinician or patient ratings. CONCLUSIONS: Approximately one in two (one in four assuming the more demanding criteria) of the subjects complied with treatment recommendations. The correlation between the results of the questionnaires was relatively high, though moderate between the simple ratings. DAI-10 and MARS showed moderate reliability, sensitivity and specificity. PMID- 25011226 TI - [The effect of two predictors' interaction on short- and long-term treatment outcomes of schizophrenia]. AB - OBJECTIVES: To monitor the effect of interaction of duration of untreated psychosis (DUP) and expressed emotion (EE) on treatment outcomes in schizophrenia. METHODS: 56 individuals diagnosed with schizophrenia were assessed at 4 time points. The number of relapses, the number and duration of rehospitalizations and the severity of symptoms were assessed at index hospitalization and at 3, 7 and 12-year follow-ups. RESULTS: No correlation was found between DUP and EE measured at index hospitalization. Over the 12-year period the number of rehospitalizations for individuals with short DUP and low EE did not increase, as opposed to those with short DUP and with high EE. In the group with long DUP, the number of rehospitalizations increased irrespectively of EE level. The positive syndrome in the group with short DUP and high EE was less severe than in individuals with long DUP and high EE. Analogous differences appeared in the group with low EE. CONCLUSIONS: 1) No correlation was found between DUP and EE at index hospitalization. 2) Number of rehospitalizations and intensity of positive symptoms proved to be associated over time with the interaction of DUP and EE. 3) Long-time observation and multiple assessments allow to obtain more reliable results. PMID- 25011227 TI - [The analysis of the bipolarity features in students of arts and the students of technology]. AB - BACKGROUND: The aim of the research was to assess the prevalence of the bipolar spectrum features among students of a variety of faculties, by dividing them arbitrarily into 'art' or 'technology' cohorts. MATERIAL AND METHODS: 120 subjects were examined, including 57 students of arts, and 63 students of technology. The tools used included a basic socio-demographic questionnaire and the Hirschfeld Mood Disorder Questionnaire (MDQ). RESULTS: The bipolar spectrum features (as identified by the MDQ responses) were significantly more prevalent among the students of arts, as compared to the students of technology (28.2% vs. 4.8%, p < or = 0.001; OR = 7.8; CI 95%: 2.13-28.51; p < 0.01). Moreover, in comparison to the students of technology, the students of arts were more likely to: 1) report mood patterns of intermittent 'highs' and 'lows' (49.1% vs. 15.9%, p < or = 0.0001; OR = 5.11; CI 95%: 2.18-11.99; p < or = 0.001); 2) seek for psychiatric or psychological support (12.3% vs. 1.5%; p < or = 0.05; OR = 5.2; CI 95%: 1.79-15.21; p < or = 0.01); 3) have a history of utilisation of psychotropic medications (31% vs. 7.9%, p < or = 0.001; OR = 8.7; CI 95%: 1.03-72.9; p < or = 0.05). They were also more likely to use psychoactive substances (other than alcohol). CONCLUSIONS: The considerable prevalence of the bipolarity features (as measured by the MDQ), combined with higher prevalence of intermittent periods of elevated or depressed mood, higher likelihood of seeking for psychiatric or psychological treatment, and higher prevalence of using psychoactive medications/substances in the cohort of the students of arts indicate a significant association between artistic talents and creativity, and the bipolar spectrum disorders. PMID- 25011228 TI - [Dynamics of depression symptoms after myocardial infarction--the importance of changes in hope]. AB - AIM: The mechanism of dynamics of depression symptoms after myocardial infarction (MI) during six months was examined with reference to (a) whether the changes in coping strategies mediate the effect of changes in cognitive appraisal on changes in the level of depression, and (b) whether this mediation is moderated by the changes in hope. METHODS: Cognitive appraisal (threat/harm, challenge), hope, coping strategies (problem-, emotion- and avoidance-focused) and depression were assessed two times among 173 cardiac patients: a few days after first MI and then six months later. RESULTS: Only emotion-focused coping partly mediated the relationship between changes in threat/harm appraisal and changes in depression (both direct and indirect effects were positive). The effect of changes in challenge appraisal on depression was only direct and negative. Both direct effects were moderated by the level of changes in hope: the associations between changes in appraisal and depression were significant only when hope do not change or decreased in time. CONCLUSIONS: Associations between dynamics of appraisal and depression during six months after MI were more direct and depended on changes in hope. PMID- 25011229 TI - [Sexual dysfunction in men in the first 9 months after myocardial infarction]. AB - OBJECTIVES: The aim of the study is to assess the frequency of sexual dysfunction in men after myocardial infarction (MI). METHODS: 62 men were asked to fill IIEF 15 to assess sexual dysfunction 3 and 9 months after MI. RESULTS. Erectile dysfunction (ED), orgasmic dysfunction, decreased sexual desire, decreased intercourse satisfaction, decreased overall satisfaction were recognized respectively by: 61.3%, 24.2%, 62.9%, 71%, 54.8% of men 3 months after MI, and 51.6%, 17.7%, 58.1%, 77.4%, 59.7% of men 9 months after MI. Men with ED had higher serum CRP (5.8 vs. 3.8; p = 0.04) and creatinine (1 vs. 0.9; p = 0.04) levels in the peri-infarction period and higher serum BNP (47.4 vs. 24.6; p = 0.04) measured 3 months after MI than men without ED. They had also higher serum testosterone levels than men without ED (12.6 vs. 10.6; p = 0.03). Men with decreased sexual desire had significantly lower serum DHEAs (dehydroepiandrosterone sulfate) levels in the peri-infarction period than men with normal sexual desire (191.1 vs. 224.3; p = 0.044). Men with ED 9 months after MI had higher serum CRP levels in the peri-infarction period (7.5 vs. 4.6; p = 0.0371). Men with orgasmic dysfunction had lower left ventricular ejection fraction (EF) measured in the peri-infarction period (0.4 vs. 0.5; p = 0.0318). CONCLUSIONS: 1. Men with ED have higher serum CRP and creatinine levels in the peri-infarction period. 2. DHEAs level has an influence on sexual desire and on erectile function after MI. 3. BNP level in post-MI patients affects erectile function. 4. EF has an impact on orgasmic function. PMID- 25011230 TI - [Parental attitudes recollected by patients and neurotic disorders picture- sexuality-related and sexuality-unrelated symptoms]. AB - OBJECTIVES: To evaluate the risks associated with non-optimal characteristics of the picture of parents in the patient's memories, concerning the sexuality related symptoms and other areas of neurotic disorders. METHODS: Coexistence of memories of parental attitudes and the current symptoms were analyzed on the basis of KO"0" Checklist and Life Inventory completed prior to treatment in the day hospital for neurotic disorders. RESULTS: In questionnaires, obtained from 2582 females and 1347 males between 1980-2002, there was a significant incidence of memories of adverse parental attitudes, the feeling of not being loved, the parent indifference, rejection. Regression analysis showed a significant relationship between the parental attitudes and symptoms, for instance reluctance of men to sexual contacts coexisted (OR = 3.41) with hostile mother's attitude, the same association in women was weaker (OR = 1.64) but still significant. Also, the absence of mother in childhood was associated with a risk of disruptions in the conduct of intercourse (erectile dysfunction or pain) in women (OR = 2.43) and men (OR = 3.29). Other analyzed symptoms, also sexuality -unrelated, though weaker and less frequently, were associated with non-optimal pictures of parents, e.g. pessimism in women with the hostile mother (OR = 1.97). Higher global severity of symptoms was associated with non-optimal parental attitudes. CONCLUSIONS: The type of recollected attitudes of parents was associated with a higher incidence of symptoms, primarily in the field of sexuality, and with other selected symptoms, as well as with higher global symptom level. The results indicate importance of life circumstances in the development of psychopathology and encourage to further research. PMID- 25011231 TI - [The perception of the relationship between parents, patterns of attachment and psychopathological symptoms in girls in late adolescence]. AB - AIM: The paper presents a study concerning perception of relationship between parents, attachment patterns between adolescents and parents and their influence on intensity of psychopathology symptoms in nonclinical adolescent women. METHOD: The study examined 75 nonclinical women in late adolescent (17-19 years old). Participants completed Parental Bonding Instrument, Youth Self Report Form and simple survey containing additional questions. RESULTS: The study revealed that the girls in late adolescence who perceived parents relationship as not good presented more psychopathology symptoms. The study also revealed that the adolescents who perceived their parents as less care and more controlled have more psychopathology symptoms. Maternal care was a predictor of lower levels of withdrawal, anxiety and depression. Paternal care was a predictor of lower levels of somatic complaints and thought disorders. Maternal control was a predictor of higher levels of attention disorders and aggressive behavior. Paternal control was a predictor of greater severity of social problems. CONCLUSIONS: The results are generally consistent with the data from literature. Perceived by adolescents family aspects such as parents quality relationship and attachment have significant influenced on the intensity ofpsychopathology symptoms: internalizing and externalizing symptoms, withdrawal, anxiety and depression, social problems, thought disorder, impaired concentration and aggressive behavior. PMID- 25011232 TI - [The influence of unreconciled grief in the family on the functioning and development of a child]. AB - The aim of the work is to present the influence of unreconciled grief in a family for functioning and growth of a child. The paper is based on some examples of clinical work from the field of family therapy, where developmental problems of children followed their carer's inability to cope with death and bereavement. Presented cases from family therapy serve as examples of possible therapeutic interventions in such situations. They show examples of developmental disturbances and psychopathology of the child who stays in relationship with deeply bereaved intimates. PMID- 25011233 TI - [Research on the role of life events in bipolar disorder]. AB - This review focuses on latest research regarding the role of life events in bipolar disorder. Description of important patients experiences and mechanisms, according to which they operate, is the key issue in diagnostics, therapy, prevention and planning of further studies. Definitions of life events differ depending on theoretical conceptions. At the same time they can be divided on the basis of time relation between the occurrence of event and disorder. Events that can play important role in bipolar disorders are the following: early childhood traumas, early loss of important family member and current stressful events. Taking the latter into account, positive experiences connected with performances can affect manic symptoms, and negative events--depressive ones. The other group of important life events in this context consists of life events that are dependent on the patients' psychopathology. Hypotheses of kindling, "manic denial" or stress-diathesis model can explain mechanisms of these relations. The role of life events is probably modified by personality, temperament and coping mechanisms. Congruency of life events with personality styles is being underlined. There is a substantial lack of research in this field. Their integration with knowledge of genetic vulnerability and connection with neurobiological base with life events' reactions (e.g. catechol-o-methyl transferase, BDNFVal66Met genotype) is needed. Further research require consideration of methodological issues, like research plans and models (that will make integration of knowledge from different studies fields possible) or specific diagnostic methods. PMID- 25011234 TI - [Autoaggressive behaviour with patients suffering from type 1 diabetes treated at the Clinic for Psychiatry and Psychotherapy Developmental Age--description of cases]. AB - AIM: The aim of this study was to observe autoagressive behaviour with patients suffering from type 1 diabetes hospitalized in The Child Psychiatry Department of The Paediatric Centre in Sosnowiec. METHOD: Analysis of clinical cases, medical documentation and literature. RESULTS: Patients suffered from type 1 diabetes. On account of mental disorders they required treatment in a psychiatric ward. In the course of their hospitalization the appearance of various autoagressive behaviour were observed--the sick deliberately gave a dose of insulin improperly, apply an inadequate diet, and also self-mutilated themselves. CONCLUSIONS: Described patients by their own illness (type 1 diabetes) in a self-destructive way coped with negative emotions. Autoagressive behaviour were their way of coping with stress, communicating experienced problems to others, they also helped in reducing inner tension. Through autoagression patients express anger, guilt, shame, loneliness, inner emptiness, a lack of confidence or humiliation. The period of adolescence, female gender and the presence of chronic disease are the factors that could intensify the difficulties described. PMID- 25011235 TI - [Role of leptin in eating disorders--current concept]. AB - Eating disorders constitute a dynamically developing group of diseases, in which only some have well-established diagnostic criteria, e.g. anorexia nervosa or bulimia nervosa. Many symptoms of eating disorders are hard to be qualified to any known disorder from that group, and quantity and diversity of symptoms connected to eating grow systematically. It makes the work of clinicians and psychotherapists more difficult, as well as hampers communication between specialists. It is also a challenge for scientists to create new qualifications based on known and theoretical pathomechanisms connected to disruptions in food intake regulation. PMID- 25011236 TI - [Extraction techniques for analysis of venlafaxine and its metabolites in biological matrices]. AB - Venlafaxine (VEN), which was introduced into therapy in 1990s is one of the most often used antidepressants. The monitoring of its concentration in the organism is recommended, particularly in the case when a patient suffers of others illnesses and is treated with different drugs, which can interfere with VEN. The most popular diagnostic material for the determination of VEN level is blood. The present study is the review of actual reports on the methods of extraction of VEN and its metabolite from blood and other human diagnostic materials, like saliva and urine, and also from animals tissues. The paper shows the classic extraction methods, such as liquid-liquid extraction and solid-phase extraction. It also contains the modifications of these methods such as liquid-phase microextraction and cloud point extraction. According to the literature it can be stated that the best recovery of VEN and its main metabolite, O-demethylvenlafaxine, was obtained when the liquid-liquid extraction was used. The new, modified methods of extraction, are cost-effective, owing to the reduced use of solvents and also smaller volume of diagnostic material, but the results of the analysis, especially the recovery of the analytes, were lower than those obtained by classic methods of extraction. PMID- 25011237 TI - [Planning disorders in men with schizophrenia and in men with localized frontal lobe lesions]. AB - AIM: Planning disorders have been observed in people with frontal lobe lesions for many decades. There's also growing body of evidence of frontal dysfunction in people with schizophrenia. The aim of this study is to compare the planning abilities in men with schizophrenia, men with localized frontal lobe lesions and healthy men. METHOD: A sample of 90 men participated in the study. They were divided into three groups: men with schizophrenia (n = 30), men with localized frontal lobe lesions (n = 30) and healthy men (n = 30) as a control group. Planning abilities were assessed with a clinical trial based on Tower of London task. RESULTS: Significant differences in ToL measures were found between controls and men with schizophrenia (Trials solved: p < 0.01; Trials solved perfectly: p < 0.05; Execution time: p < 0.001) and between controls and men with frontal lobe lesions (Trials solved: p < 0.001; Thinking time: p < 0.05; Execution time: p < 0.001). No significant differences were found between schizophrenia and frontal lobe lesion groups. CONCLUSIONS: Similar deficits in planning and solving problems, which require planning, may be observed in men with schizophrenia and men with frontal lobe lesions. In both groups time spent on thinking is less effective than in healthy men. Not only quantitative, but also qualitative assessment should be carried when examining patients' performance on Tower of London task. PMID- 25011238 TI - [The importance of hope in coping with schizophrenia]. AB - Hope is an important dimension of psychological functioning, the source of strength in existential challenges both in health and illness. It is already known that hope is connected with the subjective well-being in people suffering from schizophrenia. Therefore, increasing hope is a promising goal of therapeutic interventions. On the other hand, multiple definitions of hope and methodological differences in the approach to the subject do not lead to determining therapeutic indications, useful in clinical practice. Most scientific projects about hope in people with schizophrenia concentrate on description of mechanisms influencing the patients welfare or determining the relationships between hope intensification and other factors. The paper reviews the concepts of hope and related psychometric techniques and presents the results of research on hope in people with schizophrenia. The presented studies are focused mainly on relationships between hope and psychopathology, the recovery and well-being of the patients. Continuing the research in this topic and analysis of current data may contribute to beneficial changes in the treatment of schizophrenia PMID- 25011239 TI - [Sense of humour in schizophrenia--ability of humour reception and possibilities of its application in therapeutic interventions]. AB - The existing research on sense of humour in schizophrenia is focused on two main areas, mainly, assessment of patients' abilities to understand and appreciate humour and denoting the possibilities of its application in therapeutic programs concentrating on the improvement of patients' functionality and preventing illness relapses. The vast majority of the conclusions from the above mentioned research corroborate the opinion on the usefulness of developing and reinforcing sense of humour in schizophrenia, emphasizing its beneficial effect on the patients' quality of life, above all, in terms of reducing aggression, anxiety and depression as well as improving general life satisfaction and social functioning. At the same time numerous research indicate low reception of humour in schizophrenia which can negatively influence its effective usage in therapeutic interventions. Further constraint with regard to the therapy can constitute an intensified fear for being laughed at, which has been confirmed in numerous empirical reports. Therefore, it seems that addressing humorous therapeutic interventions to the above mentioned group of patients requires especially careful planning taking into consideration its cognitive and affective limitations in the perception of humour and intensified fear for being laughed at. PMID- 25011240 TI - [Anti-aquaporin-4 antibody-positive optic neuropathy--an ophthalmologist's perspective]. PMID- 25011241 TI - [Ocular surface squamous neoplasia: analysis of 34 cases]. AB - PURPOSE: To evaluate location, treatment and clinical course in cases of ocular surface squamous neoplasia (OSSN). METHODS: Thirty-four cases with OSSN [conjunctival intraepithelial neoplasia (CIN) 17 cases; squamous cell carcinoma (SCC) 17 cases] treated in Kyushu University hospital from 2000 to 2011 were retrospectively studied. RESULT: Lesions of CIN were observed in the conjunctiva bulbar in sixteen cases (16/17), and in eleven of those, the lesions were seen in the nasal part (nasal : lateral = 11 : 6). The lesions of eight SCC cases (8/17) were observed in the conjunctiva bulbar, of seven cases (7/17) were observed in the conjunctiva palpebral, and of two cases (2/17) in the fornical conjunctiva. Significantly far more cases of SCC in the conjunctiva bulbar were seen in the nasal part compared to the lateral part (nasal : lateral = 7 : 1). Most SCC lesions in the conjunctiva palpebral and fornix were observed in the upper eyelid (upper : lower = 6 : 3). CIN were treated by excision in nine cases (9/17), excision after topical chemotherapy in three cases (3/ 17), and topical chemotherapy in 5 cases (5/17). Nine SCC patients were treated by excision (9/17), four by excision after topical chemotherapy (4/17), and four by radiotherapy (4/17). Three cases of CIN and one case of SCC had recurrence and needed further treatment. CONCLUSION: The use of preoperative chemotherapy and radiotherapy for OSSN patients seems useful for a good outcome. PMID- 25011242 TI - [Dysthyroid optic neuropathy in pregnancy]. AB - BACKGROUND: While development of thyroid eye disease is rarely observed in pregnant women, here we report three cases of pregnant patients with severe dysthyroid optic neuropathy (DON). CASE: Case 1, a 30 year-old woman with thyroid eye disease diagnosed during pregnancy and DON occurring at eight months. Visual acuity was 0.05 in right eye and 0.8 in left. Case 2, a 32 year-old woman with Graves' disease diagnosed during pregnancy and DON occurring at five months. Visual acuity was 0.2 in right eye and 0.09 in left. In cases 1 and 2, since no permission for therapy during pregnancy was obtained from either patient, systemic steroid therapy was performed after delivery. Case 3, a 31 year-old woman with Graves' disease diagnosed during pregnancy. At nine months, DON was diagnosed in both eyes. Visual acuity was 0.07 in right eye and 0.2 in left. An organized systemic steroid therapy following delivery at the end of a normal gestational period was performed. In all three patients, higher levels of thyroid antibodies were observed while thyroid function remained controlled. CONCLUSION: DON developed in pregnant woman with Graves' disease who have higher levels of thyroid antibodies. A close coordination between internists and obstetricians is required for appropriate treatment, including systemic steroid therapy. PMID- 25011243 TI - [A case report of malignant lymphoma receiving infliximab therapy with Behcet's disease]. AB - BACKGROUND: To report a case of malignant lymphoma occurring in Behcet's disease (BD) with infliximab therapy. CASE: A 62-year-old man was diagnosed with BD in 1997. Despite treatment with colchicine, cyclosporine and prednisolone, he had frequent bilateral posterior ocular attacks. He was started on infliximab in August 2007 and for 6 months had no ocular attacks. Cyclosporine was therefore reduced. After 4 years of infliximab administration, he had neither ocular attacks nor general symptoms. However, he had general malaise and weight loss from the end of March 2012. Peripheral blood examination showed abnormal cells, so we terminated the infliximab. Bone marrow aspiration showed diffuse proliferation of medium to large lymphoid cells, and the histological diagnosis was diffuse large B-cell lymphoma. He was treated with 8 cycles of chemotherapy and 4 times intrathecal chemotherapy, and is now in remission. After termination of infliximab, he had no further ocular attacks. CONCLUSION: Although malignant lymphoma associated with BD is rare, attending ophthalmologists need to keep it in mind. PMID- 25011244 TI - [Good agricultural practice (GAP) of Chinese materia medica (CMM) for ten years: achievements, problems and proposals]. AB - This paper aims to summarize the achievements during the implementation process of good agricultural practice (GAP) in Chinese Materia Medica (CMM), and on basis of analyzing the existing problems of GAP, to propose further implementation of GAP in TCM growing. Since the launch of GAP in CMM growing ten years ago, it has acquired great achievements, including: (1) The promulgation of a series of measures for the administration of the GAP approval in the CMM growing; (2) The expanded planting area of CMM; (3) The increased awareness of standardized CMM growing among farmers and enterprises; (4) The establishment of GAP implementation bases for CMM growing; (5) The improvement of theory and methodology for CMM growing; (6) The development of a large group of experts and scholars in GAP approval for CMM production. The problems existing in the production include: (1) A deep understanding of GAP and its certification is still needed; (2) The distribution of the certification base is not reasonable; (3) The geo-economics effect and the backward farming practices are thought to be the bottlenecks in the standardization of CMM growing and the scale production of CMM; (4) Low comparative effectiveness limits the development of the GAP; (5) The base of breeding improved variety is blank; (6) The immature of the cultivation technique lead to the risk of production process; (7) The degradation of soil microbial and the continuous cropping obstacle restrict the sustainable development of the GAP base. To further promote the health and orderly GAP in the CMM growing, the authors propose: (1) To change the mode of production; (2) To establish a sound standard system so as to ensure quality products for fair prices; (3) To fully consider the geo-economic culture and vigorously promote the definite cultivating of traditional Chinese medicinal materials; (4) To strengthen the transformation and generalization of basic researches and achievements, in order to provide technical support for the CMM production; (5) To deepen the understanding of GAP, to vigorously promote ecological planting and precision agriculture, in order to overcome the continuous cropping obstacle. The authors think that despite the fact that we are still facing with a huge array of management and technological problems, the GAP in the CMM growing has already enjoyed widespread support and showed great potential. In the future, with people's deeper understanding of GAP and the great progress of the science and technology, the GAP will constantly be fused with the theory, methodology and technology in the modern agriculture like precision agriculture, eco-agriculture and etc. PMID- 25011245 TI - [Chemical constituents from a Tibetan medicine Meconopsis horridula]. AB - A phytochemical investigation on the aerial parts of a Tibetan medicine Meconopsis horridula, by solvent extraction, repeated chromatographies on silica gel, Sephadex LH-20, and preparative TLC techniques, led to the isolation of 9 compounds. By spectroscopic analysis and comparison of its 1H and 13C-NMR data with those in literatures, their structures were identified as oleracein E(1), N ( trans-p-coumaroyl) tyramine (2), chrysoeriol (3), apigenin (4), hydnocarpin (5), p-coumaric acid glucosyl ester (6), stigmast-5-ene-3beta-ylformate (7), 3beta-hydroxy-7alpha-ethoxy-24beta-ethylcholest-5-ene (8), and beta-sitosterol (9), respectively, among which compounds 6-8 were isolated from the genus for the first time,and 1,3 were isolated from the species for the first time. A MTT method was applied to evaluate the cytotoxic activity of compounds 14 against the human hepatocellular liver carcinoma cell line (HepG2), and compound 1 showed significant cytotoxicity against HepG2,with its inhibitory rate of 52.2% at 10 micromol x L(-1). PMID- 25011246 TI - [Subacute toxicity and chemical analysis of Tibetan medicine Oxytropis falcata]. AB - Four different extracts of Oxytropis falcata, including the aerial aqueous extract, and the underground aqueous extract, the aerial lipophilic extract, and the underground lipophilic extract were prepared and then administrated orally to mice at the maximum dose (50 g x kg(-1) x d(-1) calculated by raw material) for fifteen days respectively. Compared with the control group, which was administrated of 1.0% tween-80, the treatment groups did not show significant differences in appearance and behavior. However, the organcoefficient, blood biochemical indicator and pathological section results showed that the lipophilic extracts of the aerial and underground parts of O. flacata showed mild injury to the liver of mice, while the aerial and underground aqueous extracts and the underground lipophilic extract showed mild toxicity to the kidney of male mice. Chemical analysis showed that the lipophilic extracts of the aerial and underground parts, especially aerial lipophilic extract, consisted of large amount of flavonoid aglycones with little amount of polysaccharides and proteins, while the aqueous extracts contained much polysaccharides and proteins with almost no flavonoid aglycones detected. PMID- 25011247 TI - [Chemical constituents from whole plants of Aconitum tanguticum (III)]. AB - Nineteen compounds were isolated from the whole plants of Aconitum tanguticum by various of chromatographic techniques and their structures were determined through spectral analysis (1D, 2D-NMR and MS) and comparison with the literature data. These compounds were identified as 5-hydroxymethy furfural (1), 5 acetoxymethyl furfural (2), pyrrolezanthine [5-hydroxymethyl-1-[2-(4 hydroxyphenyl) -ethyl] -1H-pyrrole-2-carbaldehyde] (3), lichiol B (4), phthalic acid dibutyl ester (5), 3, 4-dihydroxy phenylethanol (6), 3, 4-dihydroxy phenylethanol glucoside (7), salidroside (8), p-hydroxy phenylethanol (9), p hydroxybenzoie acid glucoside (10), p-hydroxybenzoic acid (11), gastrodin (12), 1 (3, 4-dimethoxyphenyl) -1, 2-ethanediol (13), p-hydroxy benzaldehyde (14), p hydroxy acetophenone (15), 3, 4-dihydroxy phenyl ethyl acetate (16), syringic aldehyde (17), ethyl beta-D-fructopyranoside (18), and p-hydroxybenzoic acid methyl ester (19). Compounds 3 and 4 were isolated from the Ranunculaceae family for the first time, and compounds 2, 6 and 9-19 were isolated from the Aconitum genus for the first time, and compounds 1 and 5 were isolated from the species for the first time. PMID- 25011248 TI - [Chemical constituents of Tibetan medicine kandrakari (I)]. AB - In order to illuminate the effective compounds in Tibetan medicine kandrakari, chemical composition of dry stems of Rubus amabilis were studied by means of various chromatographic techniques, leading to the isolation of 11 compounds. On the basis of spectroscopic data, their structures were elucidated as 1,8 dihydroxy-3,7-dimethoxyxanthone (1), 1-hydroxy-3,7,8-trimethoxyxanthone (2), 1,8 dihydroxy-3,5-dim ethoxyxanthone (3), kaempfero-3-O-(6"-trans-p-coumaroyl) -beta D-glucopyranoside (4), quercetin (5), kaempferol (6), hyperoside (7), luteolin-7 O-beta-D-glucopy ranoside (8), apigenin-7-O-beta-D-glucopyranoside (9), isovitexin-7-O-glucoside (10), and procyanidin B4 (11). Compounds 1-3 were isolated from the Rubus genus for the first time,and compounds 1-6, 10-11 were isolated from R. amabilis for the first time. PMID- 25011249 TI - [HPLC-fingerprint-based quality evaluation on a Tibetan medicine Phyllanthus emblica and its tannin parts]. AB - This study is to establish the fingerprint for Phyllanthus emblica and their tannin parts from different habitats by HPLC for its quality control. The determination was carried out on a Diamonsil C18 (4.6 mm x 250 mm, 5 microm) column, with methanol-0.2% glacial acetic acid as mobile phase with gradient elution at a flow rate of 1 mL x min(-1). The temperature was maintained at 30 degrees C and the detected wavelength is 260 nm, Thirteen chromatographic peaks were extracted as the common peaks of the fingerprint of P. emblica, and eleven as the common peaks of P. emblica tannin parts, and five peaks were identified by comparing with referent samples. The fingerprints of 8 samples were compared and classified by similarity evaluation, cluster analysis and principal component analysis (PCA). The similarity degrees of eight P. emblica were between 0.763 and 0.993, while tannin parts were between 0.903 and 0.991. All the samples of P. emblica and their tannin parts were classified into 3 categories. The method was so highly reproducible, simple and reliable that it could provide basis for quality control and evaluation of P. emblica from different habitats. PMID- 25011250 TI - [A powder X-ray diffractometry for detection of Tibetan medicine Zuotai]. AB - A robust, direct, rapid and non-destructive X-ray diffraction crystallography method for detecting the Tibetan medicine Zuotai is presented. Powder samples of Zuotai, cinnabar and calomel were unambiguously characterized using powder X-ray diffractometry (PXRD) by comparing a practical identification of metacinnabar in the analyzed material, which confirmed the present of metacinnabar in Zuotai. At the same time, 11 strong lines in the fingerprint of Zuotai were selected to indicate the effective constituents of Zuotai, which were listed in the form of d ( I/I0 )%: metacinnabar 3.356 4/100, 2.061 4/55.0, 2.911 8/35.0, 1.760 1/37.0, 1.339 5/12.0, 1.304 5/10.0, 1.192 0/10.0, 1.683 4/7.0, 1.458 0/5.6. sulfur 3.824 4/100, 3.197 5/40.2, 3.442 2/38.1, 3.095 6/19.7, 5.690 9/16.8, 2.851 0/16.3, 2.414 4/11.3. The results showed that mercury chemical state is metacinnabar with sulfur in Tibetan medicine Zuotai. This method should be supplemented to quality control of rare traditonal Chinese medicine. PMID- 25011251 TI - [UFLC-PDA fingerprint of Tibetan medicine Pterocephalus hookeir]. AB - This study was aimed to establish an UFLC fingerprint of Tibetan medicine Pterocephalus hookeir samples from different habitats. UFLC-PDA was adopted to analyse 21 batches of P. hookeir samples from different habitats. The chromatographic condition was as follow: Agilent proshell 120 SB-C18 column (4.6 mm x 100 mm, 2.7 microm) eluted with the mobile phases of acetonitrile and 0.2% phosphoric acid water in gradient mode. The flow rate was 1.0 mL x min(-1), and the detection wavelength was set at 238 nm. The fingerprints of 21 batches P. hookeir were carried out by similarity comparation, and 15 chromatographic peaks were extracted as the common peaks of fingerprint, of which 5 peaks were identified as chlorogenic acid, loganin, sweroside, sylvestroside III, triplostoside A. The similarity degrees of 18 batchs of samples were above 0.9, and the other 3 batchs of samples were below 0.9. This is the first established fingerprint of P. hookeir by using UFLC-PDA. This method has good precision, stability and repeatability that it could provide basis for quality control and evaluation of P. hookeir. PMID- 25011252 TI - [Phytochemical and pharmacological advance on Tibetan medicinal plants of Corydalis]. AB - It was estimated that about 428 species of genus Corydalis are distributed all worldwide, with about 298, especially 10 groups and 219 species being uniquely spread in China. The genus Corydalis have been widely employed as folk medicines in China, especially as traditional Tibetan medicines, for treatment of fever, hepatitis, edema, gastritis, cholecystitis, hypertension and other diseases. The phytochemical studies revealed that isoquinoline alkaloids are its major bioactive ingredients. The extensive biological researches suggested its pharmacological activities and clinic applications against cardiovascular diseases and central nervous system, antibacterial activities, analgesic effects, anti-inflammatory, anti-oxidation and anti-injury for hepatocyte, and so on. As an effort in promoting the research of pharmacodynamic ingredients, this article presents an overview focusing on the distribution, phytochemical and pharmacological results of Corydalis species that have been applied in traditional Tibetan medicinal, hopefully to provide a reference for the new Tibetan medicine development from Corydalis plant resource. PMID- 25011253 TI - [Exploration of property theory of Tibetan medicine]. AB - Tibetan Herbal medicine has its own complete theory based on five sources doctrine. And the theories of "Liuwei", "Baxing" and "Shiqi Gongxiao" formed the basic core components of the property theory of Tibetan medicine. However, books and literature of Tibetan medicine have never been systematically expounded and discussed about it specially which thus will limit the further development of Tibetan medicine theory. In this thesis, we firstly introduced three basic core components of the property theory-the "Liu Wei", "Baxing", and "Shiqi Gongxiao" and their interactions as well. At the same time, the links and similarities between the theory of Tibetan medicine and Chinese medicine theory were compared. The job of the thesis done above is to lay the foundation for further systematic reveal and development of Tibetan medicine theory. PMID- 25011254 TI - [Development history of methodology of Chinese medicines' authentication]. AB - This paper reviewed the emergence process of the subject and methodology of Chinese Medicines' Authentication. Based on the research progress and major achievements acquired in research of each methodology including identification of origin, description, microscopic, physical, chemical and biological characteristics of Chinese medicines, it is expounded that the development process of each methodology combined modem digital technology, information science and its own characteristics. And the development direction is further described for methodology of Chinese Medicines' Authentication towards systematization and informationization. PMID- 25011255 TI - [Construction of plant expression vectors with PMI gene as selection marker and their utilization in transformation of Salvia miltiorrhiza f. alba]. AB - OBJECTIVE: To construct plant expression pCAMBIA1301-PMI by substituting PMI for hygromycin resistance gene in pCAMBIA1301 and obtain transgenic Salvia miltiorrhiza f. alba using PMI-mannose selection system. METHOD: The 6 phosphomannose isomerase gene (PMI) of Escherichia coli was amplified by PCR. Sequence analysis showed that it shared 100% amino acids identities with the sequences of PMI genes isolates reported in the NCBI. Based on pCAMBIA1305, the plant expression pCAMBIA1305-PMI was constructed successfully by substituting PMI for hygromycin resistance gene in pCAMBIA1305. pCAMBIA1305-PMI was transformed into Agrobacterium tumefaciens LBA4404, and then the leaves of S. miltiorrhiza f. alba were inoculated in LBA4404 with pCAMBIA1305-PMI. RESULT: Plant expression pCAMBIA1301-PMI was successfully constructed and the leaves of S. miltiorrhiza f. alba inoculated in LBA4404 with pCAMBIA1305-PMI were selected on medium supplemented with a combination of 20 g x L(-1) mannose and 10 g x L(-1) sucrose as a carbon source. The transformation efficiency rate was 23.7%. CONCLUSION: Genetic transformation was confirmed by PCR, indicating that a new method for obtaining transgenic S. miltiorrhiza f. alba plants was developed using PMI mannose selection system. PMID- 25011256 TI - [Optimization of expression and purification of recombinant Salvia miltiorrhiza WRKY1 protein in Escherichia coli]. AB - WRKY transcription factor is one of the Zinc finger proteins which contains a highly conserved WRKY domain and is a family of the plant-specific transcription factor. The plasmid pET28a-SmWRKY1 harboring Salvia miltiorrhiza WRKY1 (SmWRKY1) gene was successfully transformed and expressed in Escherichia coli BL21 (DE3). The conditions on protein expression of SmWRKY1 in E. coli, including induction duration, temperature, IPTG concentration and the E. coli concentration were optimized. The results showed that the highest protein expression of SmWRKY1 was obtained at 24 hours after the E. coli was cultured in the presence of 0.2 mol x L(-1) IPTG at 20 degrees C with A600 values of 1.0-1.5. This recombinant histidine-tagged protein was expressed at 2.454 g x L(-1) as inclusion body, which was first extracted using urea, and then purified by Ni2+ affinity chromatography and identified by SDS-PAGE. The expression of SmWRKY1 in E. coli was further confirmed by western blotting analysis. PMID- 25011257 TI - [SSR information in Erigeron breviscapus transcriptome and polymorphism analysis]. AB - OBJECTIVE: The SSR information in the transcriptome of Erigeron breviscapus was analyzed in this study, in order to further develop new functional genes SSR markers laid a solid foundation. METHOD: SSR loci were searched in all of 52,060 unigenes by using est_timmer. Perl program and SSR primers were designed by Primer3. Furthermore, 36 pairs of primers were randomly selected for the polymorphism analysis on 13 Erigeron breviscapus plants collected from different places. RESULT: A total of 3639 SSRs were found in the transcriptome of Erigeron breviscapus, distributed in 3260 unigenes with the distribution frequency of 6.99%. Di-nucleotide repeat was the main type, account for as much as 34.41% of all SSRs, followed by mono-nucleotide (31.41%) and tri-nucleotide repeat motif (28.08%). The di-nucleotide repeat motifs of AT/AT and AC/GT were the predominant repeat types (28.71%). The tri-nucleotide repeat motifs of AAT/AT was the predominant repeat types (7.94%). For validation the availability of those SSR primers, we randomly selected 36 pairs of primers for PCR amplification. Among them, 34 pair primers (94.44%) produced clear and reproductive bands, 19 pair primers showed polymorphism (52.78%), and 13 Erigeron breviscapus plants were divided into 2 groups. CONCLUSION: There are numerous SSRs in Erigeron breviscapus transcriptome with high frequency and various types, this will provide abundant candidate molecular markers for genetic diversity study and genetic map in this plant. PMID- 25011258 TI - [Index components contents in honeysuckle change trend at different time in a day and different stubbles in a year]. AB - The index components contents of different time and different stubbles in honeysuckle were measured by HPLC, and were analysis by using the method of SPSS. Results showed that the content of index ingredients of different time had differences, and firstly decreased, then increased with time. The content of index ingredients of different stubbles had significantly differences, and firstly decreased, then increased with time. The chlorogenic acid contents were 2.059%-3.593%. The luteolosid contents were 0.110%-0.171%. Results indicated that the best picking buds time is before seven o'clock in the morning and evening at before and after seven o'clock, the index component content is higher. Picking buds in spring and at autumn index component content is higher; Picking buds in summer index component content is low. The experiment provides theoretical support for quality control in the whole process of the honeysuckle harvested and comprehensive utilization of honeysuckle. PMID- 25011259 TI - [Study and evaluation of preparation of silybin PLGA microspheres by stainless steel membrane emulsification technique]. AB - OBJECTIVE: The aim of the present study was to prepare uniform-sized silybin loaded poly (lactic-co-glycolic acid) (PLGA) microspheres in study of silybin with stainless steel membrane. METHOD: Silybin PLGA microspheres were prepared by stainless steel membrane emulsification. The preparation conditions were optimized by single-factor test and orthogonal experiment, and evaluating the mean diameters, the particle size distribution, drug loading, entrapment efficiency and morphology of microsphere. RESULT: Prepared microspheres were round and surface was smooth. The mean diameter was (4.961 +/- 0.56) microm. The span was (1.75 +/- 0.18). The entrapment efficiency was (54.997 +/- 4.05)% and the average drug loading was (23.6 +/- 1.70)%. CONCLUSION: The stainless steel membrane emulsification can be used to prepare the silybin PLGA microspheres. The mean diameters of the silybin PLGA microspheres can be controlled in certain level. Stainless steel membrane emulsification has great potentiality exploitation and utilization. PMID- 25011260 TI - [Preparation of total alkaloids from Sophora alopecuroides freeze-dried powders and investigation of its antitumor effects]. AB - OBJECTIVE: To investigate molding technology of total alkaloids from Sophora alopecuroides freeze-dried powders and observe its inhibition effects on liver transplantation tumor in mice. METHOD: With color, clarity, water-soluble and formability as indexes, single factor tests were adopted to screen type and amount of filler, the concentration of total alkaloids in drug liquid, pH in order to determine optimum prescription of total alkaloids from S. alopecuroides freeze-dried powders, the lowest melting point was determined and freeze drying curve was drafted. Mice hepatoma H22 ascites tumor strain was sterile inoculated in right axillary subcutaneous of mice, and antitumor effect of total alkaloids from S. alopecuroides freeze-dried powders on liver transplantation tumor H22 in mice. RESULT: When selected 80 g x L(-1) as mannitol as filler, the concentration of total alkaloids in drug liquid was 25 g x L(-1) and pH 6.5-7.5, freeze-dried effect was optimum with fast reconstitute speed. Average inhibition rate of the big (120 mg x kg(-1)) and medium (60 mg x kg(-1)) dose group of total alkaloids from S. alopecuroides freeze-dried powders on liver transplantation tumor H22 in mice were 56.08% and 35.49%, respectively. CONCLUSION: Preparation technology was reasonable, reproducible and stable, total alkaloids from S. alopecuroides freeze dried powders had significant antitumor effect and showed a dose-effect relationship. PMID- 25011261 TI - [Preparation of curcumin-loaded long-circulating liposomes and its pharmacokinetics in rats]. AB - Curcumin has a wide spectrum of pharmaceutical properties such as antitumor, antioxidant, antiamyloid, and anti-inflammatory activity. However, poor aqueous solubility and low bioavailability of curcumin are major challenge in its development as a useful drug. To overcome many of these problems, curcumin-loaded long-circulating liposomes (Cur-LCL) were prepared by the ethanol injection method. Morphology of Cur-LCL was observed by transmission electron microscope, mean particle size and Zeta potential were detected by laser particle size analyzer, entrapment efficiency and drug loading were evaluated by ultracentrifugation. The drug release behavior in vitro and pharmacokinetic behavior in rats of Cur-LCL were investigated with curcumin (Cur) and curcumin liposomes (Cur-Lips) as control. The results showed that the mean diameter of Cur LCL was 110 nm, the Zeta potential was -5.8 mV. The entrapment efficiency and drug loading of Cur-LCL was 80.25%, 2.06%, respectively. The release behavior in vitro studied by dialysis in PBS buffer showed significant sustained release profile that 48.95% Cur were released from Cur-LCL in 7 h, 88.92% in 24 h. The pharmacokinetic parameters showed that compared with Cur and Cur-Lips, the t(1/2beta) of Cur-LCL was extended to 13 and 1.8-fold, respectively. Besides, the AUC values was significantly increased (P < 0.01), and the clearance was evidently decreased (P < 0.01). These results from in vitro and in vivo indicated that Cur-LCL were able to realize controlled drug release and increase circulation time. PMID- 25011262 TI - [Study on oral absorption enhancers of astragalus polysaccharides]. AB - Astragalus polysaccharides was lounded to 4-(2-aminoethylphenol), followed by labeling the APS-Tyr with fluorescein-5-isothiocyanate (FITC) at the secondary amino group. The absorption enhancement effects of low molecular weight chitosan and protamine on astragalus polysaccharides were evaluated via Caco-2 cell culture model. The results show that the fluorecent labeling compound has good stability and high sensitivity. On the other hand low molecular weight chitosan and protamine also can promoted absorption of the astragalus polysaccharides without any cytotoxity, and the absorption increase was more significant with increasing the amount of low molecular weight chitosan and protamine. At the same time, the low molecular weight chitosan has slightly better effect. The transepithelial electric resistance (TEER) of Caco-2 cells show that absorption enhancers could improve its membrane transport permeability by opening tight junctions between cells and increasing the cell membrane fluidity. PMID- 25011263 TI - [Optimization of processing technology for xanthii fructus by UPLC fingerprint technique and contents of toxicity ingredient]. AB - The experiment's aim was to optimize the processing technology of Xanthii Fructus which through comparing the difference of UPLC fingerprint and contents of toxicity ingredient in water extract of 16 batches of processed sample. The determination condition of UPLC chromatographic and contents of toxicity ingredient were as follows. UPLC chromatographic: ACQUITY BEH C18 column (2.1 mm x 100 mm, 1.7 microm) eluted with the mobile phases of acetonitrile and 0.1% phosphoric acidwater in gradient mode, the flow rate was 0.25 mL x min(-1) and the detection wavelength was set at 327 nm. Contents of toxicity ingredient: Agilent TC-C18 column (4.6 mm x 250 mm, 5 microm), mobile phase was methanol-0.01 mol x L(-1) sodium dihydrogen phosphate (35: 65), flow rate was 1.0 mL x min(-1), and detection wavelength was 203 nm. The chromatographic fingerprints 16 batches of samples were analyzed in using the similarity evaluation system of chromatographic, fingerprint of traditional Chinese medicine, SPSS16.0 and SIMCA13.0 software, respectively. The similarity degrees of the 16 batches samples were more than 0.97, all the samples were classified into four categories, and the PCA showed that the peak area of chlorogenic acid, 3,5 dicaffeoylquinic acid and caffeic acid were significantly effect index in fingerprint of processed Xanthii Fructus sample. The outcome of determination showed that the toxicity ingredient contents of all samples reduced significantly after processing. This method can be used in optimizing the processing technology of Xanthii Fructus. PMID- 25011264 TI - [Effect of ligustrazine on reverse cholesterol transport in foam cells]. AB - OBJECTIVE: To discuss the intervention effect of ligustrazine on ox-LDL-induced foam cells from the perspective of reverse cholesterol transport. METHOD: RAW264.7 cultured in vitro was induced with 20 mg x L(-1) ox-LDL to establish the foam cell model, and intervened with ligustrazine. The lipid accumulation in cells was observed by the oil red O dyeing. The changes in total cholesterol and cholesterol ester in the cells were detected with the colorimetric method. The fluorescent quantitative PCR and Western blot were used to detect the mRNA expressions of PPARgamma, LXRalpha and ABCA1. RESULT: Ligustrazine could reduce total cholesterol and cholesterol ester in foam cells, inhibit the lipid accumulation, and increase the mRNA and protein expressions of PPARgamma, LXRalpha and ABCA1. CONCLUSION: Ligustrazine can promote the reverse cholesterol transport by increasing the gene expressions of PPARgamma, LXRalpha and ABCA1. PMID- 25011265 TI - [Experimental study on aging effect of Angelica sinensis polysaccharides combined with cytarabine on human leukemia KG1alpha cell lines]. AB - The latest findings of our laboratory showed that Angelica sinensis polysaccharide (ASP) showed a definite effect in regulating the aging of hematopoietic stem cells. Leukemia is a type of malignant hematopoietic tumor in hematopoietic stem cells. There have been no relevant reports about ASP's effect in regulating the aging of leukemia cells. In this study, human acute myeloid leukemia (AML) KG1alpha cell lines in logarithmic growth phase were taken as the study object, and were divided into the ASP group, the cytarabine (Ara-C) group, the ASP + Ara-C group and the control group. The groups were respectively treated with different concentration of ASP, Ara-C and ASP + Ara-C for different periods, with the aim to study the effect of ASP combined with Ara-C in regulating the aging of human acute myeloid leukemia KG1alpha cell lines and its relevant mechanism. The results showed that ASP, Ara-C and ASP + Ara-C could obviously inhibit KG1alpha cell proliferation in vitro, block the cells in G0/G1 phase. The cells showed the aging morphological feature. The percentage of positive stained aging cells was dramatically increased, and could significantly up-regulate the expression of aging-related proteins P16 and RB, which were more obvious in the ASP + Ara-C group. In conclusion, the aging mechanism of KG1alpha cell induced by ASP and Ara-C may be related to the regulation of the expression of aging-related proteins, suggesting that the combined administration of ASP and anticancer drugs plays a better role in the treatment of leukemia . PMID- 25011266 TI - [Chemo-preventive effect of Angelica sinensis' supercritical extracts on AOM/DSS induced mouse colorectal carcinoma associated with inflammation]. AB - To study the chemo-preventive effect of the supercritical extracts from Angelica sinensis (SFE-AS) on induced colorectal carcinoma in mice by using the AOM/DSS induced male mice colorectal carcinoma model, and discuss its possible action mechanism. Male Balb/c mice were subcutaneously injected with single dose of azoxymethane (AOM, 10 mg x kg(-1) body weight). One week later, they were given 2% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colorectal carcinoma. Each drug group was orally administered with supercritical extracts from Angelica sinensis at 15, 30, 60 mg x kg(-1) until the 17th week. The tumor incidence rate of the SFE-AS group, mice tumor-bearing quantity and tumor-bearing volume of the SFE-AS group were lower than that of the AOM/DSS model control group, which may be related with the significant reduction of PCNA, COX-2, iNOS in the AOM/DSS-induced mouse colorectal carcinoma model associated with inflammation by SFE-AS. According to the results of this study, SFE-AS showed an intervention effect in the incidence and development of AOM/DSS-induced mouse colorectal carcinoma associated with inflammation, and could be further used in chemo-preventive studies on human colorectal carcinoma. PMID- 25011267 TI - [Study on multi-target optimization of prescription dose of Mahuang decoction]. AB - OBJECTIVE: To optimize the prescription dose of Mahuang decoction in a multi target manner, in order to provide reference for the quantitative optimization of the prescription dose of the traditional Chinese medicine compound. METHOD: The number of diaphoretic spots in rats, the tracheal antispasmodic rate in guinea pigs and the writhing times by acetic acid in mice were taken as the indexes for evaluating the diaphoretic, antispasmodic and analgesic effects. According to the experimental results of the 16 orthogonal combination prescriptions, a mathematical dose-effect model was built by support vector regression (SVR) and quadratic response surface regression (RSR) respectively. The multi-target optimization was achieved by elitist non-dominated sorting genetic algorithm (NSGA-II) and entropy weight TOPSIS method. RESULT: The optimal dose of Mahuang decoction after being optimized by SVR modeling contained 17.71 g of Ephedrae Herba, 9.57 g of Cinnamomi Ramulus, 11.75 g of Armeniacae Semen Amarum and 4.39 g of Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle. The optimized result by RSR modeling contained 13.37 g of Ephedrae Herba, 11.61 g of Cinnamomi Ramulus, 11.98 g of Armeniacae Semen Amarum and 5.67 g of Glycyrrhizae Radix et Rhizoma Praeparate Cum Melle. SVR was superior to RSR in both of the forecast capacity and optimization results. CONCLUSION: SVR-NSGA-II-TOPSIS method could be adopted for the multi-target optimization for the dose of Mahuang decoction and other traditional Chinese medicine compounds. It is proved to be the optimal prescription with the best efficacy, and could provide scientific quantitative basis for determining the dose of traditional Chinese medicine compound prescriptions and developing new traditional Chinese medicines. PMID- 25011268 TI - [Role of ERK/FoxO3a signal axis in inhibitory effect of vitexin 1 (VB-1) in HepG2 cell proliferation]. AB - OBJECTIVE: To investigate whether the ERK/FoxO3a signal axis could induce the inhibitory effect of vitexin 1 (VB-1) in HepG2 cell proliferation. METHOD: The MTT method was adopted to observe the effect of different concentrations of VB-1 on human hepatoma carcinoma cell line HepG2 and immortalized human embryo liver cell line L-02. The cell growth was assessed by the clone formation assay. The protein phosphorylation levels of ERK1/2 and FoxO3a were measured by the western blot. RESULT: VB-1 inhibited the viability of HepG2 cell line in a concentration dependent manner, with a weak effect on L-02 cell line. VB-1 could effectively inhibit the anchorage-dependent growth of HepG2 cells, and reduce the expression levels of pERK1/2 and pFoxO3a in a concentration-dependent manner. MEK1/2 inhibitor PD98059 could enhance VB-1' s effect in inhibiting HepG2 cell proliferation and ERK1/2, FoxO3a phosphorylation. CONCLUSION: VB-1 inhibits the proliferative activity of hepatoma carcinoma cell line HepG2 by blocking the ERK/FoxO3a signal axis. PMID- 25011269 TI - [Study on inhibitory effect of different extract fractions from longdan xiegan decoction on biofilms of Candida albicans]. AB - OBJECTIVE: To observe the inhibitory effect of different extract fractions from Longdan Xiegan decoction on biofilms of Candida albicans, and discuss its possible mechanism. METHOD: The micro-dilution method and the XTT reduction assay were adopted to explore the antifungal activity of different extract fractions from Longdan Xiegan decoction and detect the inhibitory effect of different extracts on biofilms of C. albicans. The expression quantity of the adhesion related gene ALS1 and hypha formation SUN41 were detected by qRT-PCR. RESULT: The MICs of extracts from Longdan Xiegan decoction, including petroleum ether, water, butanol, methanol and ethyl acetate, against C. albicans were > 1 000, > 1 000, > 1 000, 125, 125 mg x L(-1). The SMIC50 against biofilms of C. albicanswere > 1 000, > 1000, > 1 000, 500, 500 mg x L(-1). The SMIC50 were > 1 000, > 1 000, > 1 000, > 1 000 and 1 000 mg x L(-1). 1 000 mg x L(-1) ethyl acetate extracts could considerably inhibit the expression of the adhesion related gene ALS1 and hypha formation SUN41. CONCLUSION: The ethyl acetate extract showed the greatest activity against Candida albicans biofilms. PMID- 25011270 TI - [Study on material base of Carthamus tinctorius with antioxidant effect based on selective knock-out]. AB - OBJECTIVE: To establish a method for studying efficacious materials of traditional Chinese medicines from an overall perspective. METHOD: Carthamus tinctorius was taken the example. Its major components were depleted by preparing liquid chromatography. Afterwards, the samples with major components depleted were evaluated for their antioxidant effect, so as to compare and analyze the major efficacious materials of C. tinctorius with antioxidant activity and the contributions. RESULT: Seven major components were depleted from C. tinctorius samples, and six of them were identified with MS data and control comparison. After all of the samples including depleted materials are compared and evaluated for their antioxidant effect, the findings showed that hydroxysafflor yellow A, anhydrosafflor yellow B and 6-hydroxykaempferol-3, 6-di-O-glucoside-7-O glucuronide were the major efficacious materials. CONCLUSION: This study explored a novel and effective method for studying efficacious materials of traditional Chinese medicines. Through this method, we could explain the direct and indirect contributions of different components to the efficacy of traditional Chinese medicines, and make the efficacious material expression of traditional Chinese medicines clearer. PMID- 25011271 TI - [Comparative metabonomics study on urine in rat treated by Angelica sinensis volatile oil]. AB - Metabonomics was employed to investigate the effect of Angelica sinensis volatile oil (ASVO) to the endogenous metabolites of normal rats, and to reveal the possible ways of metabolism in rats caused by ASVO. The fifty male Waster rats were randomly divided into five groups (each consists of 10 rats), such as control group, high dose group of ASVO, middle dose group of ASVO, low dose group of ASVO, and Aspirin group. They were given 0.9% saline, 0.352 mL x kg(-1) ASVO, 0.176 mL x kg(-1) ASVO, 0.088 mL x kg(-1) ASVO and ASP respectively with the equal volume of 0.2 mL. Drugs and vehicle were given for 3 successive days. The urine was collected at 12, 24, 36, 48 h after modeling with metabolic cages. Rat urine metabolic fingerprint in different stages was analyzed using GC-MS, based on which the principal component analysis (PCA)and orthogonal partial least squares discriminant analysis (OPLS-DA) models were established for metabonomic analysis. Potential biomarkers were screened by using variable importance in the projection (VIP) and T test. It was revealed that the middle dose of ASVO at 36 h induces a substantial change in rat urine. Compared with control group, seven kinds of endogenous metabolites in ASP group and ASVO group change significantly (P < 0.05), among which aconitic acid, succinic acid, citric acid, alpha-ketone glutaric acid, glycine and malic acid content had an upward trend (P < 0.05) and prostaglandin content had a downward trend (P < 0.01). The mechanism of ASVO and ASP have the similarity. It is likely that ASVO intervenes the metabolic process by affecting the energy, amino acid and lipid metabolism. Our work also indicates that rats administrated with ASVO can increase the energy metabolism of the body, induce the production of inflammatory substances and strengthen the body's immune ability. The result has also provide a proof for futher interpret ASVO pharmacological effects. PMID- 25011272 TI - [Study on PK-PD characteristics of ginsenoside Rg1 and Rb1, in rats with myocardial ischemia following intravenous administration of shengmai injection]. AB - It is the objective of this paper to study pharmacokinetics-pharmacodynamics (PK PD) characteristics of ginsenoside Rg1 and Rb1 on the effect of inducing nitric oxide (NO) release after intravenous administration of Shengmai injection to rats with myocardial ischemia. The model of myocardial ischemia rats was produced by subcutaneous injection of isoproterenol. The serum samples were collected at different time points after intravenous administration of Shengmai injection to rats with the dose of 10.8 mL x kg(-1). The concentrations of ginsenoside Rg1 and Rb1 in serum were determined, and then the concentration-time curves were drawn. Pharmacokinetic parameters of ginsenoside Rg1 and Rb1 were calculated after the construction of pharmacokinetic models. Meanwhile, NO2- and NO3-, the metabolites of NO, in serum were determined, and then the effect-time curve was drawn. The combined PK-PD model was established based on the theory of effect compartment by Sheiner et al. Then pharmacodynamic parameters were calculated. The results indicated that the pharmacokinetics of ginsenoside Rg1 and Rb1 conformed to a two compartment model. Ginsenoside Rg1 and Rb1 exhibited quick and slow elimination in rats respectively. The effect of Shengmai injection on inducing NO release did not relate directly with and lagged behind the concentrations of ginsenoside Rg1 and Rb1 in serum. The effect exhibited good correlation with ginsenoside Rg1 and Rb1 levels in effect compartment. The relationship between effect and serum concentration fits Sigmoid-E(max) model. This study successfully established the combined PK-PD model of ginsenoside Rg1 and Rb1 after intravenous administration of Shengmai injection to rats. The model can efficiently predict the concentration and effect of Shengmai injection in vivo. PMID- 25011273 TI - [Study on excretion of 20 (S) -protopanaxadiolocotillol type epimers in rats]. AB - Gindenosides are the active ingredients of Panax ginseng. 20 (S) protopanaxadiolocotillol type epimers are the main metabolites of 20 (S) protopanaxadiol. The previous studies showed that there are stereoselectivity difference in pharmacodynamics and pharmacokinetics between 24R-epimer and 24S epimer. The purpose of this study was to explore the excretion of the epimers in bile, feces and urine of rat. Liquid chromatography tandem mass spectrometry method has been performed for determination of 24R-epimer and 24S-epimer in bile, feces and urine. 24R-epimer or 24S-epimer was intragastric administered to rats at a single dose of 10 mg x kg(-1). Results showed that after administration the recovery of 24R-epimer and 24S-epimer in feces was 17.69% and 17.09%, respectively, while both of the two epimers were hardly detected in urine. The 48 h cumulative biliary excretion rate of 24R-epimer was 8.01% after administration, while only 1.47% for 24S-epimer. It indicated that there are stereoselectivity in biliary excretion of the epimers with intragastric administration. PMID- 25011274 TI - [Clinical research of safflower injection on hibernating myocardial revascularization]. AB - Coronary artery disease (CAD) is one of the leading causes of death. Safflower attracts great attention owing to its anti-ischemia/reperfusion injury effect. Ninety-three patients with CAD were included and randomized into safflower treatment group, PCI group and control group. Low-dose dobutamine stress echocardiography (DSE) was performed to measure end-systolic volume (ESV), end diastolic volume (EDV), left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) to determine the recovery of hibernating myocardium and cardiac function in all patients before treatment and after 3-month follow-up. The study was to investigate the effects of safflower on hibernating myocardial revascularization and cardiac function. It was found that LVEF was significantly improved, while the ESV and WMSI were significantly reduced after 2-week treatment in safflower and PCI treatment groups. No significant differences were found between safflower and PCI treatment groups in ESV, EDV, WMSI and LVEF after treatment Safflower injection effectively improved hibernating myocardial function. PMID- 25011275 TI - [Impact on evaluation of clinical efficacy of traditional Chinese medicine for level in soft targets of processing technology]. AB - Traditional Chinese medicine (TCM) is a very practical subject, which has its unique theoretical system and clinical characteristics. In the course of clinical practice, the exact clinical efficacy is the key of existence and development. But the existing evaluation system is difficult to objectively evaluate the clinical efficacy of TCM. Therefore, how to objectively evaluate the clinical efficacy and get definitive evidence is the focus of the evaluation of clinical efficacy of TCM. Relative to modern medicine, TCM is more concerned about the changes of feelings and clinical symptoms of the patient in the course of the evolution of the disease. Soft targets mainly used for the evaluation of the clinical efficacy of symptoms and functional activity of the disease. The level in soft targets of processing technology is often used methods in clinical evaluation. But it has often produced the phenomenon which the results of the evaluation is mutual contradiction, which will ultimately affect the effect of evaluation of clinical efficacy of TCM. In order to better evaluate the clinical efficacy of TCM, in the process of adoption of soft targets, it clearly identify it's role, highlighting the characteristics of interventions on disease, and as much as possibly avoid the level in soft targets of processing technology to real assess clinical efficacy of TCM. PMID- 25011276 TI - [Prescription parsing of miao medicine Polygonum capitatum and kelintong capsule]. AB - By literature survey searching references and parsing prescriptions, the auther has analyze the clinical advantage of Miao medicine in the treatment of symptom heat stranguria. Guizhou Miao medicine Polygonum capitatum has many advantages such as resources and clinical. After companying with Phellodendri Cortex, the compound prescription plays the pharmacological activity of antipyretic and diuretic, especially for the symptom heat stranguria, damp and hot junction based in the bladder. Miao medicine Kelintong capsule showed clinical advantage in the treatment of symptom heat stranguria, having a clinical advantage in improving the overall effectiveness and improve the overall aspects of the patient's symptoms. PMID- 25011277 TI - [Analysis on influential factors in China's exports of primary and semi-finished products of traditional Chinese medicine to ASEAN]. AB - Two regression models, based on panel data over the period of 2000-2011, are built and used to analyze what factors determine China's exports of primary and semi-finished products of traditional Chinese medicine to ASEAN. The results indicate that, China GDP, the ratio of ASEAN to China GDP per capita, average export price, the ratio of state-owned assets to total assets, have a significant positive influence on the export volumes of primary products of Chinese medicine. At the same time, RMB appreciation, the ratio of three kinds of foreign-invested assets to total assets, China-ASEAN Early Harvest Program, ASEAN-China Free Trade Area have a significant negative influence. In respect of the export volumes of semi-finished products of Chinese medicine, the significant influential factors are ASEAN GDP and the ratio of ASEAN to China GDP per capita. The former is positive and the latter is negative. In order to optimize the commodity composition of experts, it is needed to increase export volumes of both primary and semi-finished products of Chinese medicine. According to the analysis above, some proposals are put forward, such as, improving the performance of foreign capital, playing an exemplary and leading role in technological innovation by state-owned enterprises, taking advantage of bargaining power of suppliers, increasing outward foreign direct investment. PMID- 25011278 TI - [Acquisition and storage methods for image data collected in Chinese medicine resources survey]. AB - The acquisition and storage of the image data are important in the Chinese medicine resources survey, and it is important data and evidence for the process and the results. The image data of the Chinese medicinal materials' habitat, original plant or animal, processing in habitat, commodity form, the relative contents and workshop scenarios in the investigation are important for the compiling of the Color Atlas of National Chinese Medicine Resources, mapping the digital scattergram of the Chinese medicine resources, establishing the digital Chinese medicine plant herbarium and acquiring the documentary of the Chinese medicine resource survey. The content, procedures and methods of the video data collecting have been related and analyzed in this article to provide reference for the Chinese medicine resources survey. PMID- 25011279 TI - [Uncontrolled factors of blood pressure in essential hypertension: from "patient's high blood pressure" to "hypertensive patient"]. AB - Hypertension is a significant medical and public health issue which puts an enormous burden on health care resources and the community. It is a chronic medical condition in which the systemic arterial blood pressure (BP) is elevated. Serious complications including cardiovascular and cerebrovascular diseases would be preventable if the rise in BP with age could be prevented or diminished. The majority of hypertensive patients require long-term treatment. Oral antihypertensive drugs, lifestyle modification including exercise and dietary modification are milestones for hypertension therapy. However, the control rate of hypertension hasn't reached the expected requirements currently. "Three lows" status quo, just low awareness, low treatment, and low control, are still the major problems confronting modern medicine. Recently, uncontrolled factors of blood pressure are widely concerned, which include insomnia, constipation, mood disorders, exogenous, etc. What's more, the control strategies of hypertension should not only pay close attention to "patient's high blood pressure", but also to "hypertensive patient". Therefore, the treatment of uncontrolled factors of blood pressure plays an important role in hypertensive therapy, which could be further research priorities. PMID- 25011280 TI - [Analysis of multicomponent drug metabolism used in clinical pharmacy research of traditional Chinese medicine]. AB - Multicomponent drug metabolism can be defined as a research area that, rather than pharmacokinetics and pharmacodynamics, is a concerted dynamic metabolic variation of one component in several other compounds circumstance with the interaction of transport protein and drug metabolizing enzymes, and the study of the dynamic course of multiple components must be simultaneously determined. By the use of multicomponent drug metabolism in the clinical pharmacy research of traditional Chinese medicine (TCM), it can become a useful tool with the integration of the overall dialectical method and the concrete molecular approach. PMID- 25011281 TI - [Reasearch on evolution and transition of processing method of fuzi in ancient and modern times]. AB - Fuzi is a medicine used for rescuing from collapse by restoring yang as well as a famous toxic traditional Chinese medicine. In order to ensure the efficacy and safe medication, Fuzi has mostly been applied after being processed. There have been different Fuzi processing methods recorded by doctors of previous generations. Besides, there have also been differences in Fuzi processing methods recorded in modern pharmacopeia and ancient medical books. In this study, the authors traced back to medical books between the Han Dynasty and the period of Republic of China, and summarized Fuzi processing methods collected in ancient and modern literatures. According to the results, Fuzi processing methods and using methods have changed along with the evolution of dynasties, with differences in ancient and modern processing methods. Before the Tang Dynasty, Fuzi had been mostly processed and soaked. From Tang to Ming Dynasties, Fuzi had been mostly processed, soaked and stir-fried. During the Qing Dynasty, Fuzi had been mostly soaked and boiled. In the modem times, Fuzi is mostly processed by being boiled and soaked. Before the Tang Dynasty, a whole piece of Fuzi herbs or their fragments had been applied in medicines; Whereas their fragments are primarily used in the modern times. Because different processing methods have great impacts on the toxicity of Fuzi, it is suggested to study Fuzi processing methods. PMID- 25011282 TI - [Water use of re-vegetation pioneer tree species Schima superba and Acacia mangium in hilly land of South China]. AB - The xylem sap flows of two pioneer tree species, i.e., Acacia mangium and Schima superba, in degraded hill lands of South China, were continually monitored with Granier' s thermal dissipation probes during 2004-2007 and 2008-2012, respectively, and their seasonal transpiration changes at different tree age levels were compared. The results showed that the annual transpiration of both species increased with tree ages, and S. superba demonstrated a higher value than A. mangium. The average annual whole-tree transpiration of S. superba (7014.76 kg) was higher than that of A. mangium (3704.97 kg). A. mangium (511.46-1802.17 kg) had greater seasonal variation than S. superba (1346.48-2349.35 kg). The standard regression coefficients (beta) of transpiration (Eh), photosynthetically active radiation (PAR) and vapor pressure deficit (VPD) for both species increased with soil moisture, suggesting the increase of soil moisture generated a greater sensitivity of plants to environmental factors. Partial correlation analysis revealed that soil moisture played an important role in the seasonal variation of transpiration of both species. The optimum soil moistures of S. superba and A. mangium were 0.22-0.40 and 0.29-0.30 (V/V), respectively, indicating the native pioneer species S. superba better adapted to water deficit compared with exotic pioneer species A. mangium. PMID- 25011283 TI - [Characteristics of carbon storage and its allocation in Erythrophleum fordii plantations with different ages]. AB - Carbon storage and its allocation of 7-, 29- and 32-year-old Erythrophleum fordii plantation ecosystems in Guangxi were studied on the basis of biomass survey. The results showed that the carbon contents in different organs of E. fordii, ranging from 509.0 to 572.4 g x kg(-1), were in the order of stem > branch > root > bark > leaf. No significant differences in carbon content were observed among the shrub, herb and litter layers of the E. fordii plantations with different ages. Carbon content in the soil layer (0-100 cm) decreased with increasing the soil depth, but increased with increasing the stand age. The carbon storage of the arbor layer was 21.8, 100.0 and 121.6 t x hm(-2) for 7-, 29- and 32-year-old stands, respectively, and the order of carbon storage allocation in different organs was same as the order of carbon content. The 7-, 29- and 32-year-old E. fordii plantation ecosystems stored carbon at 132.6, 220.2 and 242.6 t x hm(-2), respectively. The arbor layer and soil layer were the main carbon pools, accounting for more than 97% of carbon storage in the ecosystem. Carbon storage allocation increased in arbor layer but decreased in soil layer with increasing the stand age. The influence of stand age on carbon storage allocation in shrub, herb and litter layers did not show a obvious regular pattern. PMID- 25011284 TI - [Stoichiometric characteristics of plant and soil C, N and P in different forest types in depressions between karst hills, southwest China]. AB - The stoichiometric properties of plant carbon (C), nitrogen (N) and phosphorus (P) and their relationships with soil were studied in six dominant plant communities in three forest types, i.e., plantation forest, secondary forest and primary forest in depressions between karst hills, southwest China. The C, N and P contents of both plant and soil had significant differences among the different forest types. Soil C and N contents were the highest in the secondary forest and the lowest in the plantation forest. Soil P content was the highest in the plantation forest and the lowest in the primary forest. Plant C and P contents were in the order of plantation forest > primary forest > secondary forest, and plant N content was the highest in the plantation forest and the lowest in the primary forest. Soil N:P,C:P and plant C:P ratios were significantly higher in the primary forest than in the other two forest types. There were no significant difference for the soil C:N ratio among the three forest types. Plant N:P ratio was the highest in the secondary forest and the lowest in the plantation forest. Plant C:N ratio was in the order of primary forest > plantation forest > secondary forest. There were significantly positive linear correlations between N and P contents, C:N and C:P ratios, C:P and N:P ratios of arbor leaves in the different forest types, and significant negative linear correlations between plant C:N and N:P ratios, and between soil C:N and N:P ratios. There were no significant correlations between plant and soil C, N, P contents and C:P ratio, suggesting that the supply of C, N and P from soil had little influence on plant C, N and P contents. PMID- 25011285 TI - [Soil carbon and nitrogen storage of different land use types in northwestern Shanxi Loess Plateau]. AB - The soil organic carbon (SOC) and total nitrogen (TN) storage under five different land use patterns, i. e. , poplar and Caragana microphylla plantation, C. microphylla artificial shrubland, poplar plantation, bare land and cropland were studied in the hilly [ness Plateau of northwestern Shanxi. The results showed that the contents, densities and storage of SOC and TN varied remarkably under the different land-use patterns. Soil carbon and nitrogen contents and storage in the 0-20 cm soil layer were significantly higher in the 20-40 cm and 40-60 cm soil layers under each of the five land use patterns. In the same soil layer, the contents and densities of SOC and TN under the five land use patterns were in the order of poplar and C. microphylla plantation > C. microphylla artificial shrubland > poplar plantation > bare land > cropland. The SOC storage in the 0-60 cm soil layer was in the order of poplar and C. microphylla plantation (30.09 t x hm(-2)) > C. microphylla artificial shrubland (24.78 t x hm(-2)) > poplar plantation (24.14 t x hm(-2)) > bare land (22.06 t x hm(-2)) > cropland (17.59 t x hm(-2)). Soil TN storage had the same trend as SOC storage, and TN storage in the 0-60 cm soil layer was the highest (4.94 t x hm(-2)) in poplar and Caragana microphylla plantation, followed by C. microphylla artificial shrubland (3.53 t x hm(-2)), poplar plantation (3.51 t x hm(-2)), bare land (3.40 t x hm(-2)), and cropland (2.71 t x hm(-2)). Poplar and C. microphylla plantation and C. microphylla artificial shrubland were the good land use patterns in the process of vegetation construction and ecological restoration in the hilly Loess Plateau of northwestern Shanxi. PMID- 25011286 TI - [Responses of Manglietia glauca growth to soil nutrients and climatic factors]. AB - Tree height and diameter of breast height (DBH) as growth characteristics of Manglietia glauca introduced from Vietnam were measured at many sites in south China and responses of M. glauca growth to soil nutrients and climatic factors were analyzed in this study. Annual average increments of tree height and DBH among different planted sites had significant differences. Annual average increments of tree height and DBH had significant positive correlation with soil total N and P, available N and P, but no significant correlation with soil organic matter, total K, available K, indicating that soil N and P contents could be the main affecting factors for the growth of M. glauca. Annual average increment of tree height had significant difference, but annual average increment of DBH had no significant difference at different altitudes. Annual average increment of tree height increased with the altitude from 150 to 550 m, the maximum was at the altitude of 550 m, and then it decreased. It indicated that the most appropriate altitude for M. glauca introduction is 550 m. Annual average increments of tree height and DBH had significant negative correlation with annual average temperature and > or = 10 degrees C accumulated temperature, and significant positive correlation with annual average precipitation, suggesting that annual mean temperature, > or = 10 degrees C accumulated temperature and annual average precipitation could be the main climatic factors influencing the growth of M. glauca. PMID- 25011287 TI - [Climate suitability for tea growing in Zhejiang Province]. AB - It is important to quantitatively assess the climate suitability of tea and its response to climate change. Based on meteorological indices of tea growth and daily meteorological data from 1971 to 2010 in Zhejiang Province, three climate suitability models for single climate factors, including temperature, precipitation and sunshine, were established at a 10-day scale by using the fuzzy mathematics method, and a comprehensive climate suitability model was established with the geometric average method. The results indicated that the climate suitability was high in the tea growth season in Zhejiang Province, and the three kinds of climate suitability were all higher than 0.6. As for the single factor climate suitability, temperature suitability was the highest and sunshine suitability was the lowest. There were obvious inter-annual variations of tea climate suitability, with a decline trend in the 1970s, less variation in the 1980s, and an obvious incline trend after the 1990s. The change tendency of climate suitability for spring tea was similar with that of annual climate suitability, lower in the 1980s, higher in the 1970s and after the 1990s. However, the variation amplitude of the climate suitability for spring tea was larger. The climate suitability for summer tea and autumn tea showed a decline trend from 1971 to 2010. PMID- 25011288 TI - [Spatial pattern of forest biomass and its influencing factors in the Great Xing'an Mountains, Heilongjiang Province, China]. AB - Based on field inventory data and vegetation index EVI (enhanced vegetation index), the spatial pattern of the forest biomass in the Great Xing'an Mountains, Heilongjiang Province was quantitatively analyzed. Using the spatial analysis and statistics tools in ArcGIS software, the impacts of climatic zone, elevation, slope, aspect and vegetation type on the spatial pattern of forest biomass were explored. The results showed that the forest biomass in the Great Xing'an Mountains was 350 Tg and spatially aggregated with great increasing potentials. Forest biomass density in the cold temperate humid zone (64.02 t x hm(-2)) was higher than that in the temperate humid zone (60.26 t x hm(-2)). The biomass density of each vegetation type was in the order of mixed coniferous forest (65.13 t x hm(-2)) > spruce-fir forest (63.92 t x hm(-2)) > Pinus pumila-Larix gmelinii forest (63.79 t x hm(-2)) > Pinus sylvestris var. mongolica forest (61.97 t x hm(-2)) > Larix gmelinii forest (61.40 t x hm(-2)) > deciduous broadleaf forest (58.96 t x hm(-2)). With the increasing elevation and slope, the forest biomass density first decreased and then increased. The forest biomass density in the shady slopes was greater than that in the sunny slopes. The spatial pattern of forest biomass in the Great Xing' an Mountains exhibited a heterogeneous pattern due to the variation of climatic zone, vegetation type and topographical factor. This spatial heterogeneity needs to be accounted when evaluating forest biomass at regional scales. PMID- 25011289 TI - [Evaluation of root and bud cold hardiness of wine grape varieties based on temperature-injury relation]. AB - A system for differential thermal analysis (DTA) was applied for low temperature exotherms (LTE) analysis of roots and buds of eight wine grape varieties, and the temperature-injury (LT-I) regression functions of buds, phloem and xylem of roots were established to evaluate the cold hardiness of roots and buds of the different varieties. The order of phloem 50% lethal temperature of the eight grapevines was Marselan > Cabernet Franc > Cabernet Sauvignon > Petit Manseng > Chardonnay > Cabernet Gernischt > Italian Riesling > Xiongyuebai. The xylem 50% lethal temperature of the different cultivars was in the order of Marselan > Chardonnay > Cabernet Sauvignon > Petit Manseng > Cabernet Franc > Cabernet Gernischt > Italian Riesling > Xiongyuebai. The order of bud 50% lethal temperature was Cabernet Sauvignon > Petit Manseng > Cabernet Gernischt > Cabernet Franc > Chardonnay > Italian Riesling > Marselan > Xiongyuebai. A comprehensive evaluation on cold hardiness of the different varieties was conducted by fuzzy membership function. For roots, Marselan was the poorest, and Xiongyuebai was the best. For buds, Cabernet Sauvignon, Cabernet Franc, Petit Manseng and Cabernet Gernischt were poorer, while Italian Riesling and Xiongyuebai were better. PMID- 25011290 TI - [Citrus boron nutrient level and its impact factors in the Three Gorges Reservoir region of Chongqing, China]. AB - To investigate the level of boron nutrient in citrus and its impact factors, a total of 954 citrus leaf samples and 302 soil samples were collected from representative orchards in the 12 main citrus production counties in the Three Gorges Reservoir region of Chongqing to determine the boron content in citrus leaves, as well as the relationships between leaf boron content with soil available boron content, soil pH value, cultivar, rootstock and the age of tree. Results indicated that the leaf samples from 41.6% orchards (< 35 mg x kg(-1)) and the soil samples from 89.4% orchards (< 0.5 mg x kg(-1)) were boron insufficient. The correlation of leaf boron content and soil available boron content was not significant. The soil pH, cultivar, rootstock and the age of tree did affect the leaf boron content. The leaves from the orchards with soil pH of 4.5-6.4 demonstrated significantly higher boron contents than with the soil pH of 6.5-8.5. The leaf boron contents in the different cultivars was ranged as Satsuma mandarin > pomelo > valencia orange > sweet orange > tangor > navel orange. The citrus on trifoliate orange and sour pomelo rootstocks had significantly higher leaf boron contents than on Carrizo citrange and red tangerine rootstocks. Compared with the adult citrus trees (above 8 year-old), 6.6% more of leaf samples of younger trees (3 to 8 year-old) contained boron contents in the optimum range (35-100 mg x kg(-1)). PMID- 25011291 TI - [Effects of field border length for irrigation on photosynthetic characteristics, dry matter accumulation and water use efficiency of wheat]. AB - With the high-yielding winter wheat cultivar Jimai 22 as test material, a three year field experiment was conducted to examine the effects of border length for irrigation on flag leaf water potential, photosynthetic characteristics, dry matter accumulation and distribution of wheat. In the 2010-2011 growing season, six treatments were installed, i. e., the field border length was designed as 10 m (L10), 20 m (L20), 40 m (L40), 60 m (L60), 80 m (L80) and 100 m (L100). In the 2011-2012 and 2012-2013 growing seasons, the field border length was designed as 40 m (L40), 60 m (L60), 80 m (L80) and 100 m (L100). The results showed that the average relative soil water content of the 0-200 cm soil layer was presented as L80, L60>L100>L40>L20>L10 at anthesis in the 2010-2011 growing season and as L80, L60>L100>L40 in the 2011-2012 and 2012-2013 growing seasons. At 11 d and 21 d after anthesis, the water potential, net photosynthetic rate and transpiration rate of flag leaf were presented as L80, L100>L60>L40>L20, L10, and as L80>L60, L100>L40, L20, L10 at 31 d after anthesis. The coefficients of variability both of the dry matter accumulation at anthesis and maturity and of grain yield in different regions of L80 field were lower than those of L100. The average dry matter accumulation, dry matter accumulation after anthesis and the contribution to grain of L80 were dramatically higher than those of L100, L40, L20 and L10. L80 had the highest average grain yield and water use efficiency, being the best treatment for irrigation in our study. PMID- 25011292 TI - [Effects of plant polysaccharides-containing compound agents on yield and matter accumulation and transportation of winter wheat]. AB - A field experiment was conducted to study the effects of foliar spraying of three kinds of compound agents [plant polysaccharides (P1), plant polysaccharides plus 5-aminolevulinic acid (P2), and plant polysaccharides plus 5-aminolevulinic acid and dimethylpiperidinium chloride (P3)] at the initial flowering stage of winter wheat on its yield components, sucrose content, soluble sugar content, the accumulation and translocation of dry matter, nitrogen and phosphorus. The grain number per spike and kilo-grains mass of winter wheat increased with the spray of the compound agents. The grain yield increased by more than 8.5% compared with the control. Within 20 days after spraying the three compound agents, the sucrose content of flag leaf had an obvious increase. Compared with the control, P1 and P3 increased the soluble sugar content by more than 4.5% and 11.0%, respectively. P3 enhanced the accumulations of post-anthesis dry matter, nitrogen and phosphorus by 48.5%, 116.9% and 18. 1%, respectively. Correspondingly, contributions of accumulated post-anthesis dry matter and nutrient to grain yield increased significantly. Whereas, the contribution of translocated pre-anthesis nutrient to grain yield in P3 treatment was smaller than in the other treatments. The high yield of winter wheat was related to the regulation of photosynthetic product supply in vegetative organ, the increased soluble sugar content in grain, and the accumulation of post-anthesis dry matter and nutrient regulated by the plant polysaccharides-containing compound agent. PMID- 25011293 TI - [Characteristics of ammonium N and nitrate N accumulation in dryland soil in relation with wheat yield]. AB - A total of eleven field trials in Yongshou, Shaanxi Province and seven in Luoyang, Henan Province were conducted with two treatments (without N as control and with 150 kg N x hm(-2) addition). The wheat biomass and seed yield were determined, and so were the nitrate and ammonium N concentrations in five layers (0-20, 20-40, 40-60, 60-80, 80-100 cm) at each trial site. Results showed that soil ammonium concentrations in the two provinces were very low while nitrate N concentrations were relatively high. Soil nitrate N occupied 91% of the total mineral N, and exhibited the same trend as the total mineral N in reflecting soil N supplying capacity. Without N application, the cumulative nitrate N amounts in the 0-40, 0-60, 0-80 and 0-100 cm layers in Yongshou were significantly correlated with wheat biomass and seed yield while no such correlation existed in Luoyang. With N addition, the relations of cumulative nitrate N of the different layers to wheat biomass and yield were greatly declined in Yongshou whereas those of Luoyang were changed to be negative. The yield increases were significantly correlated with the amount of nitrate N accumulated in the 0-80 and 0-100 cm layers of the two sites under N addition. Wheat mainly depended on nitrate N from the 0-20 cm layer at seedling stage, 0-40 cm at reviving, and 0-60 cm at elongation stages, and could utilize 0-100 cm nitrate N at maturity. After wheat harvest, the concentration of ammonium N was not significantly different from the initial value while that of nitrate N greatly decreased. PMID- 25011294 TI - [Effect of waterlogging on leaf senescence characteristics of summer maize in the field]. AB - Taking two summer maize hybrids Zhengdan 958 (ZD958) and Denghai 605 (DH605) as experimental materials, a field experiment was conducted to explore the effects of waterlogging for different durations (3 and 6 days) on leaf senescence characteristics of summer maize at the three-leaf stage (V3), six-leaf stage (V6), and 10 days after the tasseling stage (10VT). Results showed that superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities and soluble protein content decreased significantly after waterlogging. However, the content of malondialdehyde (MDA) increased significantly by 35.3% and 34.1% for DH605 and ZD958, respectively. The leaf chlorophyll content and grain yield of summer maize decreased significantly after waterlogging. The grain yields of DH605 and ZD958 after waterlogging for 6 days at V3 were most seriously affected, which were decreased by 32.1% and 35.2%, respectively. Overall, the summer maize was most susceptible to the effect of waterlogging at V3, followed by V6 and 10VT, and the influence extent increased with the increase of waterlogging duration. PMID- 25011295 TI - [Impact of different tillage practices on soil organic carbon and water use efficiency under continuous wheat-maize binary cropping system]. AB - Base on an 8-year field experiment, the effects of tillage practices coupled with or without straw return on the soil organic carbon (SOC) and water use efficiency (WUE) were investigated in Guanzhong Plain during the growing seasons from 2008 to 2009. The results showed that conservation tillage practices (sub-soiling, SS; rotary tillage, RT; no-till, NT) improved the SOC, WUE and crop yield compared with conventional tillage (CT), among which, SS coupled with straw return had the highest increment, with increase in SOC content of the 0-30 cm soil layer, WUE and crop yield by 19.5%, 16.9% and 20.5%, respectively. The NT practice effectively increased the SOC content of the 0-10 cm soil layer. Conclusively, under the current soil and climatic conditions in Guanzhong Plain, sub-soiling coupled with straw return is the most efficient tillage practice for promoting SOC accumulation, increasing water-use efficiency and yield. PMID- 25011296 TI - [Characteristics of distribution and transportation of rice genotype with high nitrogen utilization efficiency at the late growth stage]. AB - Taking a high nitrogen utilization efficiency rice genotype (NUE(H)) as test material and a low nitrogen utilization efficiency genotype (NUE(L)) as control, a pot experiment was carried out with nitrogen treatments of 100 (low) and 200 mg x kg(-1) (normal), to analyze the differences in nitrogen accumulation distribution, translocation and transport efficiency between the two genotypes. The results showed that NUE(H) could still maintain a high yield and a high nitrogen utilization efficiency at the low rate of nitrogen fertilization, with the grain yield being 1.75 times of that of NUE(L), and the nitrogen recovery efficiency of 50.9% compared with 36.4% for NUE(L). Compared to the normal nitrogen fertilization rate, the low nitrogen fertilization rate promoted the nitrogen accumulation by 34.2%, 2.5% and 0.5% in NUE(H) at the flowering, filling and mature stages, while decreased by 23.5% and 15.6% in NUE(L) at filling and mature stages, respectively. Nitrogen accumulation distribution in organs of NUE(H) was in the order of leaf > stem > root > spike, spike > leaf > stem > root, and spike > stem > leaf > root at the flowering, filling and mature stages, respectively. With the advancement of growth period, the nitrogen accumulation in spike increased obviously. At the two nitrogen fertilization rates, nitrogen transfer was ordered as leaf > stem > root for NUE(H), and stem > leaf > root for NUE(L), and nitrogen transfer efficiencies of NUE(H) were 50.8%, 60.3%, which were as 1.67 and 1.55 times as that of NUE(L), respectively. It could be concluded that the higher nitrogen transport efficiency of NUE(H) leaves laid a good foundation for the construction of grain after heading. PMID- 25011297 TI - [Dynamics simulation on plant growth, N accumulation and utilization of processing tomato at different N fertilization rates]. AB - Three field experiments were conducted to simulate the dynamics of aboveground biomass, N accumulation and utilization of drip-irrigated processing tomatoes at different N fertilization rates (0, 75, 150, 300, 450, or 600 kg x hm(-2)). The results showed that Logistic models best described the changes in aboveground biomass, N accumulation, and utilization of accumulated N efficiency with the physiological development time (PDT). Rapid accumulation of N began about 4-6 d (PDT) earlier than the rapid accumulation of aboveground biomass. The momentary utilization rate of N (NMUR) increased after emergence, reached a single peak, and then decreased. The N accumulation, aboveground biomass and yield were highest in the 300 kg x hm(-2) treatment. The quadratic model indicated that application rate of 349 to 382 kg N x hm(-2) was optimum for drip-irrigated processing tomatoes in northern Xinjiang. PMID- 25011298 TI - [Effects of different NO3- concentrations on the growth and antioxidant enzyme systems of strawberry seedlings]. AB - The effects of different NO3- concentrations (CK, 16 mmol x L(-1) NO3-; T1, 48 mmol x L(-1) NO3-; T2, 96 mmol x L(-1) NO3-; T3, 144 mmol x L(-1) NO3-) on the growth properties and antioxidant enzymes activities of strawberry seedlings were studied by sand culture. The results indicated that the plant height, leaf area, dry matter accumulation and root/shoot ratio of strawberry seedlings in T1, T2 and T3 were significantly decreased compared to the control (CK) after 15 days of treatment. The plant heights in T1, T2 and T3 decreased by 16.1%, 36.8% and 43.9%, and the areas of functional leaf decreased by 19.7%, 34.3% and 47.5% respectively, compared to the control. With the increasing NO3- concentration, the malondialdehyde (MDA), proline, soluble protein content and relative electronic leakage of the strawberry seedlings first increased and then decreased, but all those parameters in T1, T2 and T3 were higher than in the control. The activities of antioxidant enzymes, superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX) in both root and leaf, and catalase (CAT) in the root first increased and then decreased, but the CAT activity in the leaf gradually decreased with the increasing NO3 concentration. In T3, the activity of SOD in both root and leaf, APX in the root were lower than in the control. In sum, the osmolytes of strawberry seedlings increased and the plants become weaker under nitrate stress, and some antioxidant enzymes in strawberry seedlings increased at the low level of nitrate stress and decreased at the high level. The strawberry plants were stunted when growing under 48 mmol x L(-1) NO(3 ) condition. PMID- 25011299 TI - [Effects of bamboo biochar addition on temperature rising, dehydration and nitrogen loss during pig manure composting]. AB - Composting is an effective way to realize the treatment and recycling of livestock manure. However, traditional composting process has the problems of slow temperature rising, poor dehydration effect and serious nitrogen loss. Composting experiments of pig manure were carried out to investigate the influence of different rates of bamboo biochar addition on the temperature rising speed, dehydration effect and nitrogen loss during the composting process. The results showed that the addition of bamboo biochar could shorten the temperature rising time of the pile by 24-48 h, increase the dehydration rate by 13.6%-21.4%, and prolong the lasting time of the thermophilic phase by 216-264 h. The NH(4+) N, NO(3-)-N, and total nitrogen contents in the pile were higher under the treatments with bamboo biochar amendment than under the control, and moreover, the nitrogen fixation percentage increased by 28.3%-65.4% as compared to the control. PMID- 25011300 TI - [Characteristics of phosphorus adsorption and desorption of soils from wetlands recovered from farmlands in Caizi Lake]. AB - In this study, topsoil samples were collected from wetlands recovered from farmlands respectively for 3, 5, 9 and 11 years around Caizi Lake, Anhui, China. Their characteristics of adsorption and desorption of phosphorus were examined with comparison to soils sampled from an adjacent vegetable farmland and a non cultivated wetland. Phosphorus adsorption curves of all studied soils could be modeled by Langmuir and Freundlich equations (P < 0.01). The maximum P adsorption (Xm), adsorption constant K and maximum buffer capacity (MBC) of all the 6 soil samples were in the ranges of 478-1074 mg x kg(-1), 0.14-0.61 and 68.6-661.5 mg x kg(-1), respectively. These three parameters all tented to increase with the recovered years but did not reach the values of the non-cultivated wetland. However, the P desorption rate ranging from 6.2% to 14.6%, increased first and then decreased with the recovered years and was significantly higher than that of the non-cultivated wetland. It was concluded that the P immobilization would increase with the recovery years of cultivated wetlands, which could be affected by the soil organic carbon and clay contents of the wetland soil. PMID- 25011301 TI - [Effects of long-term fertilization on evolution of S forms in a red soil and a black soil]. AB - Sulfur (S) forms in two contrasting soils (a red soil and a black soil) under different long-term fertilization treatments (from 1990 to 2011) from the National Long-term Monitoring Network of Soil Fertility and Fertilizer Effects of China were investigated using a fractionation scheme in order to explore the distribution and transportation of S with different forms in the soils. The soil samples were collected from the topsoil (0-20 cm) and subsoil (20-40 cm) horizons that were treated with no fertilizers (CK), nitrogen, phosphorus, and potassium fertilizers (NPK), or NPK plus organic manures (MNPK) since 1990. The results indicated that when compared with the CK, total S contents in the topsoil layers treated with NPK and MNPK were increased by 42% and 33% for the red soil, and by 6% and 76% for the black soil, respectively, while the total S in the subsoil layer was less affected by the fertilization treatments and obviously lower than in the topsoil layer except for the red soil treated with NPK. The main forms of inorganic S in the red soil and black soil were found to be available S and HCl extracted S, respectively. The application of NPK and MNPK increased the available S by 447% and 102% in the topsoil layer of the red soil compared with CK, and facilitated the transportation of available S into the lower depth. In contrast, NPK and MNPK only increased the available S by 54% and 93% in the topsoil layer of the black soil, and showed a slight influence on available S in the subsoil. The organic S forms were predominantly composed of ester S and residual S in the two soils. Under long-term fertilization, the residual S significantly increased over 32% and 55% in the topsoil and subsoil layers, respectively, compared with CK. The ester S and carbon-bonded S, which were relatively active, were less affected by the fertilization treatments, but positively related to the level of organic carbon in each soil (P < 0.05). In addition, the results from the long-term experiments indicated that the contribution of S input from atmospheric deposition was significant and should not be neglected. PMID- 25011302 TI - [Ecological risk assessment of human activity of rapid economic development regions in southern Jiangsu, China: a case study of Dantu District of Zhenjiang City]. AB - This article investigated the spatiotemporal variation of landscape ecological risk in Dantu District of Zhenjiang City with statistical method based on the ETM remote sensing data in 2000 and 2005, and the TM remote sensing data in 2010, and quantitative index of regional ecological risk assessment was established with the employment of landscape index, so as to enhance the ecosystem management, prevent and reduce the regional ecological risk in southern Jiangsu with rapid economic development. The results showed that the fragmentations, divergence, and ecological losses of natural landscape types, such as forestland, wetland, waters, etc., were deteriorated with the expansion of built-up lands from 2000 to 2010. The higher ecological risk zone took up 5.7%, 9.0%, and 10.2% of the whole region in 2000, 2005, and 2010, respectively, which mainly distributed in the plain hilly region. During the study period, the area aggravating to the higher ecological risk zone was approximately 296.2 km2, 48% of the whole region. The ecological risk rose up in most of the region. The interference of rapid economic development to landscape patterns was even more intensive, with obvious spatial differences in ecological risk distribution. The measures of exploiting resources near the port, utilizing natural wetlands, constructing industrial parks, and rapid urbanization, etc., intensified the ecological risk and accelerated the conversion rate. Prompt strategies should be established to manage the ecological risk of this region. PMID- 25011303 TI - [The Chinese urban metabolisms based on the emergy theory]. AB - By using emergy indices of urban metabolisms, this paper analyzed 31 Chinese urban metabolisms' systematic structures and characteristics in 2000 and 2010. The results showed that Chinese urban metabolisms were characterized as resource consumption and coastal external dependency. Non-renewable resource emergy accounted for a higher proportion of the total emergy in the inland cities' urban metabolisms. The emergy of imports and exports accounted for the vast majority of urban metabolic systems in metropolises and coastal cities such as Beijing and Shanghai, showing a significant externally-oriented metabolic characteristic. Based on that, the related policies were put forward: to develop the renewable resource and energy industry; to improve the non-renewable resource and energy utilization efficiencies; to optimize the import and export structure of services, cargo and fuel; and to establish the flexible management mechanism of urban metabolisms. PMID- 25011304 TI - [Evaluation of ecosystem service value and strategies for ecological design in land consolidation: a case of land consolidation project in Da'an City, Jilin Province, China]. AB - Land consolidation, as one of the major driving forces for the changes of land use/cover, has significant impacts on landscape patterns, ecological functions, and ecosystem services. In this paper, a land consolidation project conducted in Da'an City, Jinlin Province, China, was selected to evaluate the ecosystem service values before and after land consolidation at three spatial scales, i. e., village, town, and county. The results indicated that the land consolidation with the goal to increase the area of cultivated land might cause the decrease of the saline and alkaline land, grassland, and wetland. In addition, land consolidation resulted in the reduction of the total ecosystem service values at varying degree at the three scales. Compared to the pre-consolidation status, the total post-consolidation ecosystem service values at the village, town and county scales were 7.96, 843.01 and 1205.86 million yuan, and reduced by 10.5%, 14.2% and 33.1%, respectively. Based on the evaluation of ecosystem service value, strategies of landscape ecological design were discussed to improve the ecological functions and to provide the guidance for the sustainable development of land consolidation. PMID- 25011305 TI - [Forest lighting fire forecasting for Daxing'anling Mountains based on MAXENT model]. AB - Daxing'anling Mountains is one of the areas with the highest occurrence of forest lighting fire in Heilongjiang Province, and developing a lightning fire forecast model to accurately predict the forest fires in this area is of importance. Based on the data of forest lightning fires and environment variables, the MAXENT model was used to predict the lightning fire in Daxing' anling region. Firstly, we studied the collinear diagnostic of each environment variable, evaluated the importance of the environmental variables using training gain and the Jackknife method, and then evaluated the prediction accuracy of the MAXENT model using the max Kappa value and the AUC value. The results showed that the variance inflation factor (VIF) values of lightning energy and neutralized charge were 5.012 and 6.230, respectively. They were collinear with the other variables, so the model could not be used for training. Daily rainfall, the number of cloud-to-ground lightning, and current intensity of cloud-to-ground lightning were the three most important factors affecting the lightning fires in the forest, while the daily average wind speed and the slope was of less importance. With the increase of the proportion of test data, the max Kappa and AUC values were increased. The max Kappa values were above 0.75 and the average value was 0.772, while all of the AUC values were above 0.5 and the average value was 0. 859. With a moderate level of prediction accuracy being achieved, the MAXENT model could be used to predict forest lightning fire in Daxing'anling Mountains. PMID- 25011306 TI - [Effects of phytase transgenic corn planting on soil nematode community]. AB - A healthy soil ecosystem is essential for nutrient cycling and energy conversion, and the impact of exogenous genes from genetically modified crops had aroused wide concerns. Phytase transgenic corn (i. e., the inbred line BVLA430101) was issued a bio-safety certificate on 27 September 2009 in China, which could improve the efficiency of feed utilization, reduce environmental pollution caused by animal manure. In this study, the abundance of trophic groups, community structure and ecological indices of soil nematodes were studied over the growing cycle of phytase transgenic corn (ab. transgenic corn) and control conventional parental corn (ab. control corn) in the field. Totally 29 and 26 nematode genera were isolated from transgenic corn and control corn fields, respectively. The abundances of bacterivores and omnivores-predators, the total number of soil nematodes, and the Shannon index (H) were significantly greater under transgenic corn than under control corn, while the opposite trend was found for the relative abundance of herbivores and the maturity index (Sigma MI) of soil nematodes. Repeated-measures analysis of variance (ANOVA) did not detect any significant effects of transgenic corn on the composition and abundance of nematode trophic groups and ecological indices of soil nematodes. Furthermore, the Student-T test showed that the abundances of bacterivores and omnivores-predators and the total number of soil nematodes during the milk-ripe stage were significant higher in the transgenic corn field than in the control corn field. The effects of transgenic corn planting on soil nematodes might be related to the increase in the nitrogen content of field soil under transgenic corn compared to control corn. PMID- 25011307 TI - [Effects of vegetable cultivation years on microbial biodiversity and abundance of nitrogen cycling in greenhouse soils]. AB - The effects of facility vegetable cultivation years (three, nine, fourteen or seventeen years) on biodiversity and abundance of soil microorganisms, such as bacteria, ammonia oxidizing bacteria (AOB) and nirK type denitrifying bacteria, in the greenhouse soils in Wuwei of Gansu Province, China were determined by the combined analyses of terminal restriction fragment length polymorphism (T-RFLP) and real-time quantitative PCR. The results showed that the dominant population structure and abundance of bacteria, AOB, nirK type denitrifying bacteria in the soils were significantly different from those in the farmland fields. The dominant population also changed with the cultivation years. With the increase of vegetable cultivation years, the abundance of 16S rRNA and nirK gene in the 0-20 cm soil layer first increased and then decreased, with the maximum values of 9.67 x 10(9) and 2.30 x 10(7) copies x g(-1) soil at year 14 and year 9, being as 1.51 and 1.52 times of that of the 3-year, respectively. However, the abundance of amoA gene showed an opposite trend. The amoA gene copy number in the 14-year sample was 3.28 x 10(7) copies x g(-1) soil, which was only 45.7% of that of the 3-year. These results illustrated that the ecological adaptation mechanisms of the different functional microorganisms involved in nitrogen cycling had significant differences in the facility vegetable soils, and provided a base for further researches on exploring and explaining the characteristics and adaptation mechanisms of microorganisms in greenhouse soil. PMID- 25011308 TI - [Effects of arbuscular mycorrhizal fungi on root system morphology and sucrose and glucose contents of Poncirus trifoliata]. AB - The effects of inoculation with Glomus mosseae, G. versiforme, and their mixture on plant growth, root system morphology, and sucrose and glucose contents of trifoliate orange (Poncirus trifoliata L.) were studied by pot culture. The results showed that all the inoculated treatments significantly increased the plant height, stem diameter, leaf number, and shoot and root biomass. In addition, the mycorrhizal treatments significantly increased the number of 1st, 2nd, and 3rd lateral roots. Inoculation with arbuscular mycorrhizal fungi significantly increased the root projected area, surface area, volume, and total root length (mainly 0-1 cm root length), but decreased the root average diameter. Meanwhile, G. versiforme showed the best effects. Mycorrhizal inoculation significantly increased the leaf sucrose and root glucose contents, but decreased the leaf glucose and root sucrose contents. Owing to the 'mycorrhizal carbon pool' in roots, inoculation with arbuscular mycorrhizal fungi resulted in high glucose content and low sucrose content of roots, which would facilitate the root growth and development, thereby the establishment of better root system morphology of host plants. PMID- 25011309 TI - [Inhibition effects and mechanisms of the entophytic fungus Trichoderma harzianum LH-7 from Aloe barbadensis]. AB - Inhibition spectrum and antagonistic mechanism of an endophytic fungus Trichoderma harzianum LH-7, isolated from wild medicinal plant Aloe barbadensis, were investigated by in vitro culture methods against 9 kinds of plant pathogens. The results showed that nutrient competition and hyper-parasitism were the two primarily antagonist approaches that strain LH-7 adopted to inhibit the tested plant pathogens with a significant inhibition rate of 62.4%-88.4%. Moreover, the active compound from metabolites of LH-7 could cause pathogen mycelial deformities, cell wall rupture and conidial malformation, leading to the effective inhibition on pathogens growth and reproduction. PMID- 25011310 TI - [Biotypes and phylogenetic analysis of Bemisia tabaci (Hemiptera: Aleyrodidae) in China]. AB - Bemisia tabaci (Genn.) (Hemiptera: Aleyrodidae) is considered taxonomically as a species complex and could cause serious damages to crops by directly feeding on phloem and/or indirectly transmission of plant viruses. In this study, biotypes and phylogenetic relationships of 33 geographic populations of B. tabaci collected from nine provinces of China in 2010 and 2011 were studied based on the mitochondrial COI gene. The results showed there were a total of six biotypes of B. tabaci (B, Q, ZHJ-1, ZHJ-3, An and Nauru) recovered in China and the geographical distribution of these six biotypes was uneven. Phylogenetic analysis showed that biotype An B. tabaci from Taiwan clustered together with Hainan biotype An populations, indicating these two geographic populations might originate from a same ancestor. In addition, biotype B B. tabaci in China had a 99% genetical similarity compared to that from France and Uganda. However, relationships of biotype Q on the phylogenetic tree were divided into two different clusters. One was occupied with the population from China and Western Mediterranean Sea countries (France and Morocco) and the other contained biotype Q populations from Eastern Mediterranean Sea countries (Israel and Turkey). Overall, the results suggested that biotype Q B. tabaci in China was genetically similar to that from Western Mediterranean Sea countries and it could be highly possible that Chinese biotype Q B. tabaci originated from Western Mediterranean Sea areas. PMID- 25011311 TI - [Accumulation of lead in Spodoptera exigua (Hubner) and its impact on the population]. AB - The heavy metals pollution is one of the ecological problems which have been paid close attention to Spodoptera exigua Hubner, one of the key pests on vegetables and cotton in the Yangtze River and its southern area in China, has broken out more frequently in recent years. In this study, accumulation of Pb2+ in S. exigua and its excretion were detected when fed with artificial diets with different Pb2+ concentrations (0.3, 1.2, 4.8, 19.2 and 76.8 mg x kg(-1), respectively). Life table was constructed according to the survival and growth of different stages of S. exigua. The effect of lead on three successive generations of beet armyworm was studied using the life table in the laboratory. It was found that the Pb2+ contents were significantly different when S. exigua was reared at different Pb2+ concentrations in the same generation in a significant dose dependent manner. The concentration of Pb2+ increased with prolonging the stress time at the same time. The Pb2+ concentrations at the three developmental stages of beet armyworm followed the order of larvae > adult > pupa. The beet armyworm could excrete heavy metals by means of faeces, prepupa exuviate and puparium, and the concentrations of Pb2+ in faeces and prepupa exuviate were far higher than in puparium. According to the survival rates of different developmental stages, the female ratios and the egg numbers, the laboratory population life table was constructed. It showed that low doses of Pb2+ promoted the growth of the population, and high doses inhibited the growth, and the index of population trend (I) declined more rapidly with the increase of stress time. The study could provide references for long-term and objective assessment of heavy metal hazard and its effect on the populations of important agricultural pests. PMID- 25011312 TI - [Effects of host stage of Phenacoccus solenopsis Tinsley on the fitness of the offspring of Aenasius bambawalei Hayat]. AB - To understand the effects of host stage on the fitness of the offspring Aenasius bambawalei Hayat, the sex ratio and body size of their offsprings parasitizing Phenacoccus solenopsis Tinsley of different stages (3rd instar nymph and adult) were determined under the laboratory conditions of (27 +/- 1) degree C, RH (70 +/ 5)% and 14L:10D. Sex ratio, body length and hind tibia length of the offsprings of A. bambawalei parasitizing the P. solenopsis adult females were significantly higher compared to those parasitizing the 3rd instar mealybugs. The hind tibia length of the offspring wasp was closely related to the body length. The body size of the parasitised 3rd instar mealybugs affected the size of the offspring wasp of A. bambawalei significantly, while such relationship was not found between the adult female of mealybugs and the offspring wasp. PMID- 25011313 TI - [Effect of locomotion and feeding on metabolic mode of juvenile lenok, Brachymystax lenok (Pallas) under different water temperatures]. AB - To investigate the effect of locomotion and feeding on the metabolic mode of juvenile lenok, Brachymystax lenok (Pallas) under different water temperatures, the pre-exercise oxygen consumption rate (MO2p), active oxygen consumption rate (MO2a), metabolic scope (MS), critical swimming speed (Uc) and swimming metabolic rate of both fasting and fed fish were measured at five temperature levels (4 degrees C, 8 degrees C, 12 degrees C, 16 degrees C and 20 degrees C) and ten flow velocities with saturated dissolved oxygen (> 8.0 mg x L(-1)). The results showed that the MO2p and MO2a of the feeding group were significantly higher (P < 0.05) than the fasting group under different temperatures, and the increases in MO2p and MO2a at 4 degrees C, 8 degrees C, 12 degrees C, 16 degrees C and 20 degrees C were 15%, 47%, 30%, 43% and 8%, and 12%, 23%, 21%, 36% and 7%, respectively. No significant differences were observed for Uc and MS between the fasting and the feeding groups (P > 0.05), but the MS showed a trend of decline with increase in water temperature. Swimming metabolic rate of fish was increased with increasing the flow velocity, and further increase of flow velocity resulted in a decline in swimming metabolic rate, and the swimming metabolic rate of the feeding group was significantly higher than that of the fasting group (P < 0.05). The metabolic rate increased with increasing the swimming speed up to 70% Uc, and then decreased with increasing the swimming speed up to Uc. It was concluded that, under certain temperature, the maximum metabolic rate was induced by exercise and feeding; the metabolic rate exhibited the additive metabolic mode before increasing to the maximum and thereafter, the metabolic rate induced by feeding reduced with decreasing the swimming metabolic rate, exhibiting the locomotion prioritized mode. PMID- 25011314 TI - [Anaerobic biodegradation of phthalic acid esters (Paes) in municipal sludge]. AB - Phthalic acid esters (PAEs), a class of organic pollutants with potent endocrine disrupting properties, are widely present in municipal sludge. Study of PAEs biodegradation under different anaerobic biological treatment processes of sludge is, therefore, essential for a safe use of sludge in agricultural practice. In this study, we selected two major sludge PAEs, i.e. di-n-butyl phthalate (DBP) and di-(2-enthylhexyl) phthalate (DEHP), to investigate their biodegradation behaviors in an anaerobic sludge digestion system and a fermentative hydrogen production system. The possible factors influencing PAEs biodegradation in relation to changes of sludge properties were also discussed. The results showed that the biodegradation of DBP reached 99.6% within 6 days, while that of DEHP was 46.1% during a 14-day incubation period in the anaerobic digestion system. By comparison, only 19.5% of DBP was degraded within 14 days in the fermentative hydrogen production system, while no degradation was detected for DEHP. The strong inhibition of the degradation of both PAEs in the fermentative hydrogen production system was ascribed to the decreases in microbial biomass and ratios of gram-positive bacteria/gram-negative bacteria and fungi/ bacteria, and the increase of concentrations of volatile fatty acids (e. g. acetic acid, propionic acid and butyric acid) during the fermentative hydrogen-producing process. PMID- 25011315 TI - [Aquatic ecological risk assessment of microcystins and nitrogen pollution based on species sensitivity distribution]. AB - Species sensitivity distributions (SSDs) methods in both forward and reverse modes were used to evaluate the ecological risk and determine the contaminant concentration threshold for the protection of aquatic species and ecological quality. In this study, the existing toxicity data of freshwater organisms were fitted to SSD functions to estimate the hazardous concentrations for 5% of the species (HC5) for microcystins, ammonia and nitrite, and the ecological risk of their mixtures. The potentially affected fractions (PAFs) of various concentrations of microcystins, ammonia and nitrite were also calculated. Results showed that microcystins exhibited a higher ecological risk than ammonia and nitrite. The HC5 value for microcystins exposure was 19.22 microg x L(-1) whereas the HC5 values for ammonia and nitrite exposure were 6583.94 microg x L(-1) and 334.33 microg x L(-1), respectively. The sensitivity of freshwater organisms varied with exposed concentrations of microcystins, ammonia and nitrite. Crustaceans were more sensitive than fishes to microcystins, and less sensitive than fishes to nitrite when the concentrations of microcystins and nitrite were below 125.04 microg x L(-1) and 2989.40 microg x L(-1), respectively, and vice versa when exposed to higher concentrations of microcystins and nitrite. No significant difference was observed for the sensitivities of fishes and crustaceans exposed to ammonia. In studies with selected lakes in China, our results showed that the ecological risk in both Tai and Hongfeng lakes exceeded the permissible HC5 threshold, and the multiple substance potentially affected fractions (msPAFs) of microcystins, ammonia and nitrite were 2.6%-5.6%, indicating that the ecological risk of their mixtures was more threatening than each individual contaminant being investigated. PMID- 25011316 TI - [A comparative study of different sampling designs in fish community estimation]. AB - The study of fishery community ecology depends on quality and quantity of data collected from well-designed sampling programs. The optimal sampling design must be cost-efficient, and the sampling results have been recognized as a significant factor affecting resources management. In this paper, the performances of stationary sampling, simple random sampling and stratified random sampling in estimating fish community were compared based on computer simulation by design effect (De), relative error (REE) and relative bias (RB). The results showed that, De of stationary sampling (average De was 3.37) was worse than simple random sampling and stratified random sampling (average De was 0.961). Stratified random sampling performed best among the three designs in terms of De, REE and RB. With the sample size increased, the design effect of stratified random sampling decreased but the precision and accuracy increased. PMID- 25011317 TI - [Changes of non-structural carbohydrates and its impact factors in trees: a review]. AB - Non-structural carbohydrates (NSCs) are an important energy source for the metabolism of plants. The size of the NSC pool is likely to mirror the overall carbon supply status and its dynamics strongly influences physiological processes in plants. In order to predict the response and adaptation of trees to climate change, this review summarized the current understanding of NSC pool in trees, and mainly focused on its seasonal and spatial variation for analyzing the relationships between environmental factors and NSC allocation. Moreover, the response and adaptation strategies of NSC pool in trees to climate change were also discussed. Finally, some suggestions were proposed for the potential study orientation of NSC pool in trees in future climate conditions. PMID- 25011318 TI - [Ecological function and application of toxin beta-ODAP in grass pea (Lathyrus sativus)]. AB - Grass pea (Lathyrus sativus) is a legume with various adverse adaptability and rich nutrition. However, it can lead to the human and animal neurotoxicity after long-term consumption due to its neurotoxin, beta-N-oxalyl-L-alpha, beta diaminopropionic acid (beta-ODAP), limiting its utilization. This paper summarized the influences of beta-ODAP on osmotic adjustment and growth regulation in grass pea under drought stress, the research progress in analysis methods, toxicological mechanisms and practical utility of beta-ODAP, and the breeding strategies for low- and zero-beta-ODAP. Beta-ODAP synthesis was found to be abundant in grass pea under drought stress and its content was enhanced gradually with the increasing extent of drought stress. beta-ODAP could supply nitrogen for plant growth and seed development, scavenge reactive oxygen species (ROS), involve in osmotic adjustment as a soluble amino acid, transport zinc-ions as a carrier molecule, and impact nodule development. However, increasing the content of sulfur-containing amino acids (methionine and cysteine) could decrease the level of toxicity of grass pea. There were a lot of investigations on collecting genetic resources, cross breeding, tissue culture, and gene manipulation for low- and zero-toxin in grass pea in recent years. Although beta ODAP could induce excitotoxicity by damaging intracellular Ca2+ homeostasis and as glutamate analogues, it has medicinal value on hemostasis and anti-tumor. PMID- 25011319 TI - [Research advance in the function of quorum sensing in the biological aggregates]. AB - Quorum sensing is a microbial phenomenon that microorganisms use signal molecules to perceive environmental conditions and regulate specific gene expressions. As the communication function of quorum sensing is increasingly highlighted in the microbial field, researches on quorum sensing in the formation process of biological aggregates (biofilm and granules) attract wide attentions. The paper reviewed autoinducers (AI) classification and the corresponding regulation methods in quorum sensing, and provided an up-to-date account on research progress of AIs regulating biological aggregates formation and structural stability. New territories and future of quorum sensing were also outlined. PMID- 25011320 TI - [Contribution of fungi to soil nitrous oxide emission and their research methods: a review]. AB - Nitrous oxide is an important greenhouse gas. Soil is one major emission source of N2O, which is a by-product of microorganisms-driven nitrification and denitrification processes. Extensive research has demonstrated archaea and bacteria are the predominant contributors in nitrification and denitrification. However, fungi may play a predominant role in the N transformation in a certain soil ecosystem. The fungal contribution to N2O production has been rarely investigated. Here, we reviewed the mechanism of N2O production by soil fungi. The mechanisms of denitrification, autotrophic and heterotrophic nitrification and their key microbes and functional genes were described, respectively. We discriminated the differences in denitrification between bacteria and fungi and discussed the methods being used to determine the contribution of fungi to soil N2O emission, including selective inhibitors, 15N stable isotope probing, isolation and pure culturing and uncultured molecular detection methods. The existing problems and research prospects were also presented. PMID- 25011321 TI - [Copper in methane oxidation: a review]. AB - Methane bio-oxidation plays an important role in the global methane balance and warming mitigation, while copper has a crucial function in methane bio-oxidation. On one side, copper is known to be a key factor in regulating the expression of the genes encoding the two forms of methane monooxygenases (MMOs) and is the essential metal element of the particulate methane monooxygenase (pMMO). On the other side, the content and fractionation of copper in the environment have great effects on the distribution of methanotrophs and their metabolic capability of methane and non-methane organic compounds, as well as on the copper-specific uptake systems in methanotrophs. Thus, it is meaningful to know the role of copper in methane bio-oxidation for comprehensive understanding of this process and is valuable for guiding the application of methanotrophs in greenhouse gas removal and pollution remediation. In this paper, the roles of copper in methane oxidation were reviewed, including the effect of copper on methanotrophic community structure and activity, the expression and activity of MMOs as well as the copper uptake systems in methanotrophs. The future studies of copper and methane oxidation were also discussed. PMID- 25011322 TI - [Application of microfluidics in aquatic environmental pollution analysis]. AB - Recently, a new type of chip technology, microfluidics, has received global attention for its rapid analysis speed, low reagent consumption, small size and simple operation, etc. Based on a micro-channel network and supported by a Micro Electro-Mechanic System (MEMS), this technology integrates all the functions of a laboratory into one small piece of chip, which is called "lab on the chip". This paper presented a brief introduction about microfluidics and its representative developments. Future prospects in the aspects of instrument miniaturization, system integration, chip materials, and detection techniques, as well as the implementation of microfluidics in aquatic environmental pollutant analysis were thoroughly discussed. Some problems faced now were put forward. With the rapid progress in the microfluidics, a universal low-cost microchip capable of high speed multi-channel detection and integrated with many kinds of detection methods would be the research focus in the future. PMID- 25011323 TI - Secondary gain, Gone with the Wind & the SGR. PMID- 25011324 TI - Kansas legislature passes health care cost transparency bill: real time explanation of benefits. PMID- 25011325 TI - The skinny on obesity. PMID- 25011326 TI - Providing patient-centered care, education & research to benefit Missouri. PMID- 25011327 TI - Doctors extending their education: why an MBA? Is it a degree of success? PMID- 25011329 TI - Getting comfortable with near-death experiences. My unimaginable journey: a physician's near-death experience. PMID- 25011328 TI - Getting comfortable with death. Palliative care begins at home. AB - Palliative care is multidimensional care of patients with life-limiting diseases concurrent with active disease management, together with support for their caregivers. Components of primary palliative care include management of physical and psychological symptoms and discussions about goals of care and end of life wishes. Primary care physicians and all specialty physicians should provide primary palliative care for their chronically ill patients. This paper reviews the benefits of palliative care and provides resources for its implementation. PMID- 25011330 TI - Marathon study runs on. PMID- 25011331 TI - Medicare advantage: blame the physicians, and then fire them. PMID- 25011332 TI - In reply. PMID- 25011333 TI - Acute generalized exanthematous pustulosis reported due to loxosceles envenomation may be secondary to azithromycin therapy. PMID- 25011334 TI - Dr. Mueller and fellow authors reply. PMID- 25011336 TI - News from Missouri Medicine. PMID- 25011335 TI - Expert counseling needed at end-of-life. PMID- 25011337 TI - Developmental & behavioral health care integration between pediatricians & pediatric behavioral health specialists. PMID- 25011338 TI - On collaboration. PMID- 25011339 TI - Driven by evidence: diagnosis and treatment for children with autism spectrum disorders. AB - As the prevalence of autism spectrum disorders increases, practitioners across the state of Missouri face an increasing need to understand and provide evidence based clinical care for these children and families. We describe the breadth of diagnosis and treatment services offered at Children's Mercy Hospital (Kansas City, Missouri), one of the designated Missouri Autism Centers, to demonstrate a model of implementation for evidence-based practice. Finally, we discuss relevant clinical considerations and provide resources for physicians to assist in the care and education of their patients. PMID- 25011340 TI - The ADHD Clinic: a collaborative model of care. AB - Hyperactivity Disorder (ADHD) is a common chronic and often life-persistent neurobehavioral disorder. At Children's Mercy Hospital, collaboration between a developmental-behavioral pediatrician and a behavioral psychologist, both of whom specialize in ADHD, allows the use of both medication and behavior modification which are recommended by the American Academy of Pediatrics and which are equally effective as stand-alone therapies. Children who receive both of these treatment modalities also fare better than those who receive only medication in a number of areas. This article will describe our collaborative clinic model and will address considerations of parent preference about these therapeutic approaches. PMID- 25011341 TI - A refresher on Tourette syndrome. AB - Tourette Syndrome (TS) is recognized as a more common neurodevelopmental disorder than once thought. In this article we present an update on TS including the DSM-5 revised criteria, new findings in the genetics of TS, treatment advances such as new medications for tics and the use of new tools including Cognitive Behavioral Intervention for Tics (CBIT). We also explore supportive services for the ongoing care of patients using nursing education and family therapy. PMID- 25011342 TI - Treating our youngest patients: psychotropic medications in early childhood. AB - Over the past several decades there have been multiple studies indicating that infants, toddlers and preschoolers who develop emotional and behavioral problems may not simply outgrow their problems. Early intervention is ideal, and may help to maximize long-term functioning. When other interventions fail or do not fully address the symptoms, psychotropic medications can be very helpful, even in the preschool years. With limited scientific research in this population, the use of psychotropic medications in very young children can be challenging. The judicious use of these agents in this population will be discussed, including weighing the risks and benefits of prescribing to these most vulnerable patients. PMID- 25011343 TI - Implementing motivational interviewing in a pediatric hospital. AB - Motivational Interviewing is a collaborative style of communication designed to strengthen a person's own motivation and commitment to change. We report on our ongoing efforts to implement motivational interviewing to address health behavior change among several patient populations in our pediatric hospital, including sexual risk reduction among adolescents, increased self-care for patients with spina bifida, increased adherence for adolescents with Type 1 diabetes, and facilitation with transition from pediatric to adult care among gastroenterology patients. PMID- 25011344 TI - No guts, no glory: models of integrated care within a GI subspecialty practice. AB - The focus in pediatric medicine has shifted from a concentration on mortality and morbidity to a more comprehensive view encompassing the physical, social, and psychological aspects of health. What follows is a description of four integrated, collaborative care clinics within the GI subspecialty at Children's Mercy Kansas City that specifically address this trend in pediatric healthcare. With these descriptions, we hope to inform broader acceptance and utilization of similar models across other pediatric populations. PMID- 25011345 TI - Neonatal circumcision: new recommendations & implications for practice. AB - Neonatal male circumcision is the most common surgical procedure performed on pediatric patients. While the rate of neonatal circumcision in the United States has been dropping, circumcision continues to be frequent, ranging from 42% to 80% among various populations. While the cultural debate over circumcision continues, recent evidence of medical benefits led to a revision of the American Academy of Pediatrics (AAP) circumcision policy statement. In contrast to the 1999 AAP policy statement, the 2012 policy asserts that the preventive benefits of neonatal circumcision outweigh the risk of the procedure, which is well tolerated when performed by trained professionals, under sterile conditions, and with appropriate pain management. This Circumcision Policy Statement has also been endorsed by the American College of Obstetricians and Gynecologists and a similar policy statement is in place from the American Urologic Association. Despite the new recognized health benefits found by the 2012 Task Force of Circumcision (TFOC), circumcision remains controversial even among medical professionals. Other well recognized medical organizations including The American Academy of Family Practice and some international pediatric societies have not adopted such a strong endorsement of circumcision. The policy statements from these organizations continue to more closely resemble the 1999 AAP policy statement that stated, "Existing scientific evidence demonstrates potential medical benefits of newborn male circumcision; however, these data are not sufficient to recommend routine neonatal circumcision." In this review we will summarize historical, cultural and ethical factors in neonatal circumcision and briefly compare common surgical techniques including anesthesia. In addition, we will discuss recent information regarding the benefits and risks of neonatal circumcision. Finally, we will discuss the financial reimbursement of practitioners and the benefits of standardized circumcision curriculum for trainees. PMID- 25011346 TI - Pediatric pain management: a review. AB - Although the occurrence of pain in hospitalized children is common, assessment and treatment of pain presents unique challenges to practitioners who care for pediatric patients. Knowledge of drug mechanisms as well as metabolic differences in infants and children compared with adults is necessary for the successful treatment of acute and chronic pain syndromes. Recent reports of adverse events in children receiving both opioid and non-opioid analgesics have prompted re examination of some long standing pain medication regimens and prescribing practices. We review advances in diagnosis and management of pain in pediatric populations. PMID- 25011347 TI - Safety and efficacy of electronic cigarettes: a review. AB - Tobacco smoking remains the highest cause of preventable deaths worldwide. Electronic cigarettes have recently become popular as nicotine alternatives. With public use on the rise and recent tobacco industry interest, field experts and regulatory agencies voiced concerns about their safety and unregulated production. Electronic cigarettes are safer than conventional cigarettes and at least as safe as other approved nicotine replacement therapies. Further evidence is needed as their popularity increases amidst controversy over safety and efficacy. PMID- 25011348 TI - State of the association: presidential address. PMID- 25011349 TI - Presidential inaugural address progress or just complexity? PMID- 25011350 TI - In memoriam Professor Dr Albert Oehling. PMID- 25011351 TI - Trends in hypersensitivity drug reactions: more drugs, more response patterns, more heterogeneity. AB - Hypersensitivity drug reactions (HDRs) vary over time in frequency, drugs involved, and clinical entities. Specific reactions are mediated by IgE, other antibody isotypes (IgG or IgM), and T cells. Nonspecific HDRs include those caused by nonsteroidal anti-inflammatory drugs (NSAIDs). beta-Lactams--the most important of which are amoxicillin and clavulanic acid--are involved in specific immunological mechanisms. Fluoroquinolones (mainly moxifloxacin, followed by ciprofloxacin and levofloxacin) can also induce HDRs mediated by IgE and T cells. In the case of radio contrast media, immediate reactions have decreased, while nonimmediate reactions, mediated by T cells, have increased. There has been a substantial rise in hypersensitivity reactions to antibiotics and latex in perioperative allergic reactions to anesthetics. NSAIDs are the most frequent drugs involved in HDRs. Five well-defined clinical entities, the most common of which is NSAID-induced urticaria/angioedema, have been proposed in a new consensus classification. Biological agents are proteins including antibodies that have been humanized in order to avoid adverse reactions. Reactions can be mediated by IgE or T cells or they may be due to an immunological imbalance. Chimeric antibodies are still in use and may have epitopes that are recognized by the immune system, resulting in allergic reactions. PMID- 25011352 TI - Tolerability during double-blind randomized phase I trials with the house dust mite allergy immunotherapy tablet in adults and children. AB - BACKGROUND AND OBJECTIVE: The orodispersible house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) is being developed for the treatment of HDM respiratory allergic disease. The objective of the 2 phase I trials was to investigate tolerability and the acceptable dose range of HDM SLIT-tablet treatment in adults and children with HDM respiratory allergic disease. PATIENTS AND METHODS: The trials were randomized, multiple-dose, dose-escalation, double blind, placebo-controlled phase I trials including patients with HDM-induced asthma, with or without rhinoconjunctivitis. Both trials were registered in EudraCT (Trial 1: 2005-002151-41; Trial 2: 2007-000402-67). Trial 1 included 71 adults (18-63 years) and trial 2 included 72 children (5-14 years). Both trials included 6 dose groups that were randomized 3:1 to active treatment or placebo once daily for 28 days. Adverse events (AEs) were coded in MedDRA (version 8.1 or later). Immunological variables included specific IgE and IgE-blocking factor. RESULTS: No serious AEs were reported. In trial 1 (maximum dose, 32 development units [DU]), 1 patient in the 16 DU group discontinued due to AEs. The entire 32 DU group was discontinued as 1 patient had a severe adverse reaction. In trial 2 (maximum dose, 12 DU), no patients discontinued prematurely. The most frequently reported AEs were mild application-site related events. The total number of events was dose-related within each trial. HDM SLIT-tablet treatment induced changes in immunological parameters in a dose-dependent manner. CONCLUSIONS: These trials demonstrate that doses up to 12 DU of HDM SLIT-tablet were tolerated in the selected populations, and thus are suitable for further clinical investigations in adults and children with HDM respiratory allergic disease. PMID- 25011353 TI - The allergenic structure of the thaumatin-like protein Ole e 13 is degraded by processing of raw olive fruits. AB - BACKGROUND: The thaumatin-like protein (TLP) Ole e 13 in raw olive fruit is responsible for occupational allergy in olive oil mill workers. However, these workers do not experience allergic symptoms after ingestion of edible olive. OBJECTIVES: To analyze the presence of IgE-reactive TLP in raw and edible olive fruit and to assess the allergenic potency of both sources. METHODS: The content of TLP in raw and edible olive fruit protein extracts was analyzed using immunoblotting with sera from allergic patients and with olive TLP-specific IgG. The structural and immunological stability of TLP were assayed using immunoblotting after treatment of both raw olive and purified TLP with 0.25 M NaOH solution for 24 hours. Olive pollen extract was investigated by immunoblotting for TLP content. RESULTS: The TLP contained in raw olive fruit was not present in edible olives as a result of maceration before human consumption. No TLP was detected in olive pollen using specific IgG or sera from patients allergic to olive fruit. Sera from patients allergic to olive pollen did not react with purified TLP. CONCLUSIONS: IgE-reactive TLP is not present in edible olive, thus explaining the low number of patients allergic to this highly consumed fruit. Patients allergic to olive pollen are not sensitized toTLP and, therefore, not expected to be at risk of food allergy to olive fruit or TLP plant sources. PMID- 25011354 TI - Spirometric and exhaled nitric oxide reference values in preschool children from the community of Navarra. AB - BACKGROUND AND OBJECTIVE: Preschool children can perform quality, reproducible spirometric maneuvers, provided appropriate equipment is used and specially trained nursing staff training are available. However, use of spirometry for the diagnosis and follow-up of preschool children with respiratory diseases remains limited in clinical practice, because consensus on test quality and acceptability criteria and reference data are lacking. We initiated the present study with the aim of developing reference equations, since tables of normal values for this age group are not available in our area. PATIENTS AND METHODS: The study population comprised healthy preschool children in our community. Normal values for exhaled nitric oxide in this age range were assessed. Regression equations were constructed using univariate and multivariate models. RESULTS: A total of 114 healthy preschool children aged 3 to 6 years were enrolled. According to the criteria of the American Thoracic Society/European Respiratory Society, 60 children were able to perform acceptable and reproducible spirometric maneuvers. The best correlations were observed for the untransformed linear regression model that included height. The correlation coefficients for forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV0.5 were 0.89, 0.88, and 0.86, respectively. The regression equations for the calculation of reference values were as follows: FVC = -2.6 + 0.036 x height, cm FEV1 = -2.04 + 0.029 x height, cm FEV0.5 = -1.53 + 0.022 x height, cm. We obtained fraction of inhaled nitric oxygen (FeNO) values for 56 children. The mean (SD) value was 11 (4.9) ppb. CONCLUSIONS: Most preschool children in our area were able to perform quality spirometry maneuvers. We obtained regression equations that allowed us to calculate the reference ranges in our population and the distribution of normal FeNO values. PMID- 25011355 TI - Identification of Plantago lanceolata pollen allergens using an immunoproteomic approach. AB - BACKGROUND: Airborne Plantago pollen triggers respiratory allergies in Mediterranean countries. OBJECTIVES: We aimed to study sensitization in patients with seasonal respiratory allergy and identify proteins of Plantago lanceolata pollen that could be responsible for hypersensitivity reactions in sensitized patients. We also determined the airborne pollen concentration of Plantago species from 2004 to 2011. METHODS: IgE-binding proteins were analyzed and characterized using 1D and 2D gel electrophoresis and immunoblotting with sera from individuals sensitized to P lanceolata pollen extracts, mass spectrometry analysis, and protein data mining. We used aerobiological methods to study airborne pollen. RESULTS: P lanceolata pollen accounts for 3% of the annual pollen spectrum in the air of Porto. Of a total of 372 patients, 115 (31%) showed specific IgE levels to P lanceolata pollen extracts. All sera from P lanceolata allergic patients recognized 8 prominent groups of IgE-reactive allergens. Separation of proteins using 2D gel electrophoresis followed by identification with mass spectrometry revealed the presence of other IgE-reactive components that could be involved in sensitization. CONCLUSIONS: We detected proteins in P lanceolata pollen extracts that, to our knowledge, have not yet been studied and could worsen sensitization to this weed pollen species. The proteins identified were involved in a variety of cellular functions. By applying 2D electrophoresis and immunoblotting with a pool of 2 sera from different P lanceolata-allergic patients, we obtained a more detailed characterization of the P lanceolata allergen profile. PMID- 25011356 TI - Severe combined immunodeficiency in Brazil: management, prognosis, and BCG associated complications. AB - BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression. PMID- 25011357 TI - Usefulness of specific-IgG4 to Hymenoptera venom in the natural history of hymenoptera stings. PMID- 25011358 TI - Occupational asthma caused by exposure to Ceratitis capitata (Mediterranean fruit fly). PMID- 25011359 TI - Recurrent anaphylaxis associated with solitary bee sting (Hymenoptera: Megachilidae) in a patient with mastocytosis. PMID- 25011360 TI - Prediction of the evolution of common variable immunodeficiency: HLA typing for patients with selective IgA deficiency. PMID- 25011361 TI - Successful treatment of systemic cytomegalovirus infection in severe combined immunodeficiency using allogeneic bone marrow transplantation followed by adoptive immunotherapy. PMID- 25011362 TI - Proteins responsible for nut allergies. PMID- 25011363 TI - Analysis of the IgE response to pine nut allergens in Italian allergic patients. PMID- 25011364 TI - Allergy to red meat in adulthood: a case report. PMID- 25011365 TI - Pork-cat syndrome as a cause of occupational asthma. PMID- 25011366 TI - Clinical pearls in interpreting 24-hour ECG. AB - Interpreting a 24-hour ambulatory electrocardiogram (AECG) is important for the evaluation of patients with suspected arrhythmic events. Clinical pearls in interpreting the 24-hr ECG are presented in this article. PMID- 25011367 TI - Risk stratification for coronary artery disease using pharmacological stress tests. AB - Cardiac stress testing is frequently used for diagnosis of coronary artery disease and for risk stratification which can facilitate decision making and help in the overall management of patients with known or suspected coronary disease. Exercise remains the preferred stress modality and should be performed when feasible but it is often contraindicated, impractical or unable to provide the needed information. In these circumstances pharmacologic stress tests can provide a wealth of prognostic data and should be performed instead of non-diagnostic or suboptimal exercise stress tests. Here we will review the use of pharmacologic stress tests including the indications for ordering them and the different stress agents and imaging modalities that can be utilized with emphasis on practical information that the primary care physician and general practitioner need on a daily basis in their practice. PMID- 25011368 TI - The role of cardiac magnetic resonance imaging in patients with ischemic heart disease. AB - Over the last decade, cardiovascular magnetic resonance (CMR) imaging has emerged as a powerful non-invasive imaging modality with pivotal role in the evaluation and management of patients with coronary artery disease. In particular, it quantifies ventricular function, detects myocardial ischemia and scar, visualizes myocardial edema and hemorrhage. CMR provides high resolution images that are not limited by acoustic window, and without the use of radiation or iodine contrast, hence being an attractive alternative to other non-invasive modalities. In this paper we present four different cases illustrating the role of CMR in the diagnosis of patients with known or suspected coronary artery disease, how it provides prognostic information and may guide or alter the management. PMID- 25011369 TI - Trends in nutritional intakes and nutrition-related cardiovascular disease risk factors in Lebanon: the need for immediate action. AB - AIM: To examine the burden of cardiovascular disease (CVD) risk factors and their association with dietary variables in the Lebanese population while reviewing secular trends in the population's nutritional intakes and nutrition-related CVD risk factors. METHODS: Data on CVD risk factors and food consumption patterns in Lebanon were collected from scholarly papers, including individual studies and systematic review articles. Electronic databases were searched using combinations of key terms. RESULTS: The prevalence of obesity in Lebanon followed an alarming increasing trend over time, paralleled by an escalation in the prevalence of hypertension, diabetes and hyperlipidemia. Food consumption surveys illustrate an increasing trend in energy intake and the proportion of energy derived from fat and animal products, with a concomitant decrease in carbohydrates and cereals intakes. CONCLUSION: The shift towards an atherogenic diet coupled with the alarming increase in nutrition-related cardiovascular risk factors suggest that the Lebanese population is at an increased risk for CVDs. This should alert to the importance of formulating multicomponent intervention strategies at both the individual and population levels to halt the progression of nutrition-related diseases in the country, while highlighting the need for immediate public health efforts to promote the adoption of healthy dietary habits. PMID- 25011370 TI - Dietary patterns in cardiovascular diseases prevention and management: review of the evidence and recommendations for primary care physicians in Lebanon. AB - The objective of this paper is to discuss the advantages of using the dietary pattern approach in evaluating the role of diet in cardiovascular diseases (CVD) prevention and management and to report on the association between major dietary patterns and CVD risk factors among Lebanese adults. The significance of this type of research to primary care physicians is also highlighted. The dietary pattern approach overcomes the inconsistent findings of single nutrient analysis in evaluating diet-disease associations, takes into consideration the synergistic effects of nutrients, and provides culture specific recommendations. Using data from the national Nutrition and Non-Communicable Disease Risk Factor Survey, we appraised the association of dietary patterns with CVD risk factors among Lebanese adults. Two major dietary patterns were identified: Western pattern, characterized by high intake of fast food sandwiches, desserts, and carbonated beverages and the traditional Lebanese pattern, characterized by high intakes of fruits and vegetables, olives and olive oil, and traditional dishes. Only the Western pattern was associated with increased risk of obesity (abdominal obesity), hyperglycemia and the metabolic syndrome. These findings demonstrated the valuable results that can be obtained using the dietary patterns approach in evaluating the association between diet and CVD risk factors and provided evidence that this approach can be used as a tool to push for desirable dietary changes in the country. PMID- 25011371 TI - [Towards the accreditation of anesthesiologists in Lebanon]. PMID- 25011372 TI - [Linear insertion of atrioventricular valves in children with and without Down's syndrome]. AB - OBJECTIVE: Study various parameters encountered in the linear insertion of the atrioventricular valves (LIAVV) in patients with and without Down's syndrome (DS). MATERIAL: A group of patients (n = 6240) aged from 0 to 16 years with and without congenital heart disease (CHD) registered over 6 years (1.07.2005 30.06.2011) in the National Registry of the Pediatric and Congenital Heart Disease of the Society of Cardiology in Lebanon. METHOD: Children were divided in two groups; Group I: children with DS and group II: children without DS. In the two groups, the frequency of LIAVV whether isolated or associated with other CHD (excluding the atrioventricular canal), the distribution boy-girl and the various associated cardiac anomalies were studied. We used nonparametric tests for comparing the two groups. The p value < 0.05 was considered significant. RESULTS: Group I consists of 155 patients including 31 (20%) with LIAVV, isolated in 22 cases (14.2%) and associated with CHD in 9 cases (5.8%). Group II was composed of 5995 patients; the incidence of LIAVV was 0.2% (14 patients) with apvalue < 0.00001. Regarding sex, there was a marked male predominance: respectively 78% and 56% in groups I and II. In patients with isolated LIAVV, 86% of patients were males. Family history of DS is found in 3/7 children without T21 with isolated LIAVV. A patient, in whom an atrial septal defect ostium primum type with LIAVV was diagnosed during the first month of life, has seen his septal defect closed spontaneously five months later. CONCLUSION: Encountered predominantly among a male population, the isolated LIAVV is less frequent in children without DS but often with family history of Down's syndrom. PMID- 25011373 TI - E. coli, K. pneumoniae and K. oxytoca community-acquired infections susceptibility to cephalosporins and other antimicrobials in Lebanon. AB - OBJECTIVES: Cephalosporin resistance in Enterobacteriaceae has become an international concern. This article studies the distribution and trends of resistance of E. coli and Klebsiella species isolated from clinical specimens representing community-acquired infections. METHODS: E. coli, K. pneumoniae and K. oxytoca specimen strains were collected from patients presenting to three acute care hospitals in Lebanon. The study period extended from January 2010 to January 2011 and included patients presenting with community-acquired infections only. Automated microbiological system (VITEK 2) was used for identification and antimicrobial susceptibilities. RESULTS: Data from consecutive non-duplicate 589 E. coli, 54 K. pneumoniae and 40 K. oxytoca strains were collected of which 69.5%, 74.0% and 67.5% were susceptible to 3rd generation cephalosporins (3GC), respectively. Out of the 3GC-resistant E. coli strains, around 90% were susceptible to nitrofurantoin, 46% were susceptible to trimethoprim/sulfamethoxazole (TMP/SMX) and 53% to ciprofloxacin. The patterns of antimicrobial susceptibility in the two Klebsiella species did not parallel those in the E. coli strains. Yet, the number of Klebsiella strains was much lower than that of E. coli. Of note is that the 3GC-resistant strains of both Klebsiella species were less susceptible to nitrofurantoin compared to the overall groups reaching a maximum of 30%. However, susceptibility to TMP/SMX was much higher reaching 79% and that of ciprofloxacin reaching 86%. CONCLUSION: Clinical specimens of E. coli, Klebsiella pneumoniae and Klebsiella oxytoca, causing community-acquired infections in Lebanon showed that these organisms are significantly resistant to many antibiotics. These patterns of resistance were mainly to internationally recommended drugs for empiric treatment of community acquired infections like community-acquired urinary tract infections (UTIs) and intra-abdominal infections. Therefore, continuous antimicrobial susceptibility surveillance is advisable to track emerging resistance in Enterobacteriaceae and national guidelines would be tailored accordingly. PMID- 25011374 TI - Extraction of a tunneled jugular defibrillator lead via a superior approach. AB - Extraction of cardiac implantable electrical devices (CIED) is becoming an increasing necessity. Infection is among the most frequent and serious complications associated with the surge of CIED implants. We describe the extraction of an infected cardiac resynchronization therapy-defibrillator (CRT-D) in a patient with a tunneled implantable cardioverter defibrillator (ICD) lead implanted from the right jugular vein. PMID- 25011375 TI - Jogging-induced spontaneous peri-renal hemorrhage: a rare urologic emergency. AB - Spontaneous peri-renal hemorrhage (SPH), also known as Wunderlich's syndrome, is an uncommon and rare urologic emergency, which could become life-threatening, requiring immediate diagnosis and management. The diagnosis can be challenging, even with new imaging modalities, and management can vary from conservative approach, to surgical intervention. We present a case of jogging-induced SPH diagnosed using CT scan that was managed conservatively, with follow-up for up to five years using CT imaging studies. PMID- 25011376 TI - Rhinoliths: an unusual diagnosis of nasal obstruction. AB - In our modern medical practice, rhinoliths are a rare occurrence, but they ought to be considered in the differential diagnosis of a long-standing nasal obstruction. They are known to cause unilateral nasal discharge, facial pain, headache, epistaxis, and nasal obstruction. We present two cases that we encountered in our practice, and discuss them with a review of the existing literature. PMID- 25011377 TI - SLIT: indications, follow-up, and management. AB - Specific sublingual immunotherapy (SLIT) has been proved to be a safe and effective approach in respiratory allergy. However, further research is required on aspects such as patient selection, use of optimal dosing, effects on asthma, long-term effects, and management of adverse reactions. In addition, the widely heterogeneous nature of studies on SLIT performed to date and the application of the criteria for subcutaneous immunotherapy make it difficult for the prescribing clinician to draw accurate and useful conclusions. Therefore, the QUASAR Group (QUality in the Administration of SLIT in Allergic Rhinitis), which comprises allergologists with broad clinical experience in SLIT, investigated the latest research findings and available data on this approach. Working parties were formed in 3 different categories: selection of candidates for SLIT, treatment efficacy, and adverse reactions. We performed a PubMed search for articles that were representative of each category and found 850. From these, we finally selected 266 articles, which were reviewed to retrieve data on SLIT. Evidence for each clinical question was graded according to the Oxford classification. The resulting text was evaluated on 3 occasions by all the members of the group until the final version was agreed upon. In this version, we review available evidence on SLIT, particularly with pollens, which is the subject of most articles. In areas where evidence is insufficient, an alternative agreed upon by the members of the QUASAR group is presented. Finally, we propose algorithms for selecting candidates for SLIT and for management of adverse events. PMID- 25011378 TI - Analyzing support of postnatal transition in term infants after c-section. AB - BACKGROUND: Whereas good data are available on the resuscitation of infants, little is known regarding support of postnatal transition in low-risk term infants after c-section. The present study was performed to describe current delivery room (DR) management of term infants born by c-section in our institution by analyzing videos that were recorded within a quality assurance program. METHODS: DR- management is routinely recorded within a quality assurance program. Cross-sectional study of videos of term infants born by c-section. Videos were analyzed with respect to time point, duration and number of all medical interventions. Study period was between January and December 2012. RESULTS: 186 videos were analyzed. The majority of infants (73%) were without support of postnatal transition. In infants with support of transition, majority of infants received respiratory support, starting in median after 3.4 minutes (range 0.4-14.2) and lasting for 8.8 (1.5-28.5) minutes. Only 33% of infants with support had to be admitted to the NICU, the remaining infants were returned to the mother after a median of 13.5 (8-42) minutes. A great inter- and intra individual variation with respect to the sequence of interventions was found. CONCLUSIONS: The study provides data for an internal quality improvement program and supports the benefit of using routine video recording of DR-management. Furthermore, data can be used for benchmarking with current practice in other centers. PMID- 25011379 TI - Systematic review and meta-analysis of published randomized controlled trials comparing purse-string vs conventional linear closure of the wound following ileostomy (stoma) closure. AB - OBJECTIVE: The objective of this article is to systematically analyse the randomized, controlled trials comparing the effectiveness of purse-string closure (PSC) of an ileostomy wound with conventional linear closure (CLC). METHODS: Randomized, controlled trials comparing the effectiveness of purse-string closure vs conventional linear closure (CLC) of ileostomy wound in patients undergoing ileostomy closure were analysed using RevMan(r), and the combined outcomes were expressed as risk ratio (RR) and standardized mean difference (SMD). RESULTS: Three randomized, controlled trials, recruiting 206 patients, were retrieved from medical electronic databases. There were 105 patients in the PSC group and 101 patients in the CLC group. There was no heterogeneity among included trials. Duration of operation (SMD: -0.18; 95% CI: -0.45, 0.09; z = 1.28; P < 0.20) and length of hospital stay (SMD: 0.01; 95% CI: -0.26, 0.28; z = 0.07; P < 0.95) was statistically similar following both approaches of ileostomy wound closure. The risk of surgical site infection (OR, 0.10; 95% CI: 0.03, 0.33; z = 3.78; P < 0.0001) was significantly reduced when ileostomy wound was closed using PSC technique. CONCLUSION: PSC technique for ileostomy wound is associated with a reduced risk of surgical site infection apparently without influencing the duration of operation and length of hospital stay. PMID- 25011380 TI - The 'Malawi device': a durable, reusable, low cost device from own materials for emergency ventilation during percutaneous tracheostomy. AB - The use of a tracheostomy is routine in current intensive care practice to facilitate weaning patients requiring prolonged respiratory support from mechanical ventilation. Percutaneous tracheostomy has become an established technique with an acceptable risk profile in appropriately selected patients, and has the advantage that it can be performed at the bedside without the need for an operating theatre. This is particularly relevant in a resource-poor setting. Ideally, percutaneous tracheostomy requires the presence of two skilled persons; one to perform the tracheostomy while the other controls the airway and withdraws the endo-tracheal tube at the appropriate time. This is not always possible in a resource poor setting with limited manpower. Without two operators, it is possible for the tracheal tube to become displaced before the completion of the tracheostomy with potentially disastrous consequences. We describe a method by which the airway and ventilation can be maintained if accidental tracheal extubation occurs before completion of a percutaneous tracheostomy. The 'Malawi Device', a cheap and simple modification of readily available equipment, enables a single operator to maintain the airway and ventilate the patient when the above scenario occurs. PMID- 25011381 TI - The impact of cannabis use on clinical outcomes in recent onset psychosis. AB - BACKGROUND: There are inconsistencies in findings as to whether cannabis use has a negative impact on clinical outcomes for people with established psychosis. Effects may be more evident on patients with recent onset psychosis. AIM: To investigate the relationship between cannabis use and clinical outcome, including whether change in cannabis use affects psychotic symptoms, affective symptoms, functioning and psychotic relapse in a sample of people in early psychosis with comorbid cannabis abuse or dependence. METHODS: One hundred and ten participants were examined prospectively with repeated measures of substance use antecedent to psychopathology at baseline, 4.5, 9, and 18 months. We used random intercept models to estimate the effects of cannabis dose on subsequent clinical outcomes and whether change in cannabis use was associated with change in outcomes. RESULTS: There was no evidence of a specific association between cannabis use and positive symptoms, or negative symptoms, relapse or hospital admissions. However, a greater dose of cannabis was associated with subsequent higher depression and anxiety. Change in the amount of cannabis used was associated with statistically significant corresponding change in anxiety scores, but not depression. Additionally, reductions in cannabis exposure were related to improved patient functioning. CONCLUSIONS: Reducing cannabis may be directly associated with improvements in anxiety and functioning, but not other specific symptoms. PMID- 25011382 TI - Rehydration conditions for isolation of high quality RNA from the lichen Lobaria pulmonaria. AB - BACKGROUND: The poikilohydric nature of lichens enables them to survive repeated episodes of desiccation by utilizing water when it becomes available. During rehydration, RNA-degrading endonucleases may be released, reducing RNA quantity and quality. Re-generation of a steady-state condition where RNA quantity and quality no longer fluctuate establishes a framework for development of new hypotheses for future investigations. Using Lobaria pulmonaria as a model species, the objective of this study was to compare the effect of different rehydration conditions on the quantity and quality of RNA from the rehydrated thallus. FINDINGS: Spectrophotometric measurements of total RNA and cDNA were performed for samples prepared from dry lichen or lichen after rehydration (0.5 h, 1 h, 2 h, 4 h or 24 h), with limited light and dark conditions, and at three temperatures (15 degrees C, 20 degrees C or 32 degrees C) for some of these conditions. The results showed that rehydration of the thallus for 4 h at 20 degrees C in light yielded the highest concentration and quality of RNA. A higher RNA concentration was obtained in light than in dark conditions, but the RNA quality was unaffected. CONCLUSIONS: This study suggests that allowance of 4 h for thallus rehydration should be adequate to ensure complete recovery of transcription. After 4 h at 20 degrees C further studies can be carried out on the RNA in this model species. PMID- 25011383 TI - First described case of coma triggered by retrograde venous air embolism: an exceptional but potentially life-threatening situation. PMID- 25011385 TI - Predicting the effects of environment and management on cotton fibre growth and quality: a functional-structural plant modelling approach. AB - In general, the quality of fruits depends on local conditions experienced by the fruit during its development. In cotton, fruit quality, and more specifically the quality of the fibre in the fruit, depends on interactions between fruit position in the plant architecture, temperature and agronomic practices, such as sowing time, mulching with plastic film and topping of the plant's main stem and branches. To quantify this response of cotton fibre quality to environment and management, we developed a simulation model of cotton growth and development, CottonXL. Simulation of cotton fibre quality (strength, length and micronaire) was implemented at the level of each individual fruit, in relation to thermal time (represented by physiological age of the fruit) and prevailing temperature during development of each fruit. Field experiments were conducted in China in 2007 to determine model parameters, and independent data on cotton fibre quality in three cotton producing regions in China were used for model validation. Simulated values for fibre quality closely corresponded to experimental data. Scenario studies simulating a range of management practices predicted that delaying topping times can significantly decrease fibre quality, while sowing date and film mulching had no significant effect. We conclude that CottonXL may be used to explore options for optimizing cotton fibre quality by matching cotton management to the environment, taking into account responses at the level of individual fruits. The model may be used at plant, crop and regional levels to address climate and land-use change scenarios. PMID- 25011384 TI - Effects of weight management by exercise modes on markers of subclinical atherosclerosis and cardiometabolic profile among women with abdominal obesity: a randomized controlled trial. AB - BACKGROUND: Few studies have examined the differential effects of weight management by exercise mode on subclinical atherosclerosis. We hypothesized that 3 modes of aerobic, resistance, and combination exercises have differential effects on the flow-mediated dilation (FMD), carotid-femoral pulse wave velocity (PWV), and carotid intima-media thickness (IMT) as well as cardiometabolic profile in weight management. METHODS: A randomized, single-blind trial (ISRCTN46069848) was conducted in Seoul, South Korea between November 2011 and December 2012. Randomized participants were 110 women with abdominal obesity (aerobic group n = 50; resistance group n = 30; combination exercise group n = 30). The treatment period was 12 months with 3-month follow up: A diet-alone intervention for the first 3 months and a diet-plus-exercise intervention for the next 9 months according to exercise modes. The exercise training was designed with an intensity of 50-70% heart rate reserve for 3 days a week in 60-minute long sessions for 9 months, consisting of 30-minute treadmill and 30-minute bike exercises for aerobic group; upper and lower body exercises with an intensity target of 2 sets and 8-12 repetitions for resistance group; 30-minute resistance and consecutive 30-minute aerobic exercises for combination group. RESULTS: Ninety-two and 49 participants were analyzed for modified intention-to-treat analysis and per-protocol (PP) analysis, respectively. The 3 exercise modes had no significant differential effects on FMD, PWV, and IMT over time; however, the combination group was found to have significantly lower levels of fasting glucose than the aerobic group (p = .034) in the PP analysis. Nevertheless, we observed significant time effects such as reductions in PWV (p = .048) and IMT (p = .018) in cubic and quadratic trends, respectively, and improvements in body weight, waist circumference, low-density and high-density lipoprotein cholesterol levels, fasting glucose levels, and cardiorespiratory fitness in linear, quadratic, or cubic trends. CONCLUSIONS: For women with abdominal obesity, a combination of aerobic and resistance exercises may be preferable to a single exercise mode for effective glucose control. Regardless of exercise mode, exercise interventions combined with dietary interventions in weight management may be beneficial in reducing the risk of subclinical atherosclerosis and cardiometabolic risk. PMID- 25011386 TI - Anger in pathological gambling: clinical, psychopathological, and personality correlates. AB - The aim of this study was to explore the association between pathological gambling (PG) and anger by assessing whether psychopathology and personality are related to PG and to evaluate gender differences. The sample comprised 71 PGs and 37 healthy controls. Anger, psychopathology and personality were assessed with the STAXI-2, SCL-90-R and TCI-R respectively. Gender did not affect anger expression after stratifying by diagnostic condition (p > .05). Among PG patients, anger, psychopathology and personality measures were correlated with good effect-size (r > .30). Scores in the Anger Temperament (B = 0.21, p = .038) and Anger External-Expression (B = 0.27, p = .029) scales were positively associated with PG severity scores. Anger expression in PG should be considered in future treatment programs. PMID- 25011387 TI - Interleukin-6 in renal disease and therapy. AB - Interleukin (IL)-6 has become a major target for clinical intervention in various autoimmune conditions. Here, drugs including the humanized anti-IL-6 receptor (IL 6R) antibody tocilizumab emphasize the clinical importance of IL-6 in driving disease and poor patient outcomes. During the course of this review, we will outline the biology surrounding IL-6 and discuss the impact of IL-6 in renal disease and the clinical complications associated with renal replacement therapies and transplantation. We will also consider the merit of IL-6 measurement as a prognostic indicator and provide a clinical perspective on IL-6 blocking therapies in renal disease. PMID- 25011388 TI - Chronic intake of proanthocyanidins and docosahexaenoic acid improves skeletal muscle oxidative capacity in diet-obese rats. AB - Obesity has become a worldwide epidemic. The cafeteria diet (CD) induces obesity and oxidative-stress-associated insulin resistance. Polyunsaturated fatty acids and polyphenols are dietary compounds that are intensively studied as products that can reduce the health complications related to obesity. We evaluate the effects of 21 days of supplementation with grape seed proanthocyanidins extract (GSPE), docosahexaenoic-rich oil (DHA-OR) or both compounds (GSPE+DHA-OR) on skeletal muscle metabolism in diet-obese rats. The supplementation with different treatments did not reduce body weight, although all groups used more fat as fuel, particularly when both products were coadministered; muscle beta-oxidation was activated, the mitochondrial functionality and oxidative capacity were higher, and fatty acid uptake gene expressions were up-regulated. In addition to these outcomes shared by all treatments, GSPE reduced insulin resistance and improved muscle status. Both treatments increased 5'-AMP-activated protein kinase (AMPK) phosphorylation, which was consistent with higher plasma adiponectin levels. Moreover, AMPK activation by DHA-OR was also correlated with an up-regulation of peroxisome proliferator-activated receptor alpha (Pparalpha). GSPE+DHA-OR, in addition to activating AMPK and enhancing fatty acid oxidation, increased the muscle gene expression of uncoupling protein 2 (Ucp2). In conclusion, GSPE+DHA-OR induced modifications that improved muscle status and could counterbalance the deleterious effects of obesity, and such modifications are mediated, at least in part, through the AMPK signaling pathway. PMID- 25011389 TI - Data mining with molecular design rules identifies new class of dyes for dye sensitised solar cells. AB - A major deficit in suitable dyes is stifling progress in the dye-sensitised solar cell (DSC) industry. Materials discovery strategies have afforded numerous new dyes; yet, corresponding solution-based DSC device performance has little improved upon 11% efficiency, achieved using the N719 dye over two decades ago. Research on these dyes has nevertheless revealed relationships between the molecular structure of dyes and their associated DSC efficiency. Here, such structure-property relationships have been codified in the form of molecular dye design rules, which have been judiciously sequenced in an algorithm to enable large-scale data mining of dye structures with optimal DSC performance. This affords, for the first time, a DSC-specific dye-discovery strategy that predicts new classes of dyes from surveying a representative set of chemical space. A lead material from these predictions is experimentally validated, showing DSC efficiency that is comparable to many well-known organic dyes. This demonstrates the power of this approach. PMID- 25011390 TI - From ordinary to blue emission in peralkylated n-oligosilanes: the calculated structure of delocalized and localized singlet excitons. AB - Excited singlet state structures believed to be responsible for the Franck-Condon allowed and the strongly Stokes-shifted (blue) emissions in linear permethylated oligosilanes (Si(n)Me(2n+2)) have been found and characterized with time dependent density functional (TD-DFT) methods for chain lengths 4 <= n <= 16. For chain lengths with n > 7, the S1 relaxed structures closely resemble the S0 equilibrium structures where all valence angles are tetrahedral and all backbone dihedral angles are transoid. At chain lengths with n < 8 more strongly distorted structures with one long Si-Si bond built from silicon 3p orbitals are encountered. The large Stokes shift is due more to a large destabilization of the ground state than the relaxation in the S1 excited state. For n = 7, both types of minima were located, exactly reproducing the borderline between the large radius and the small-radius self-trapped excitons known from experiments. PMID- 25011391 TI - Combining immunofluorescence with in situ proximity ligation assay: a novel imaging approach to monitor protein-protein interactions in relation to subcellular localization. AB - The in situ Proximity Ligation Assay (PLA) is suited for visualizing protein protein interactions and post-translational protein modifications in both tissue sections and in vitro cell cultures. Accurate identification and quantification of protein-protein interactions are critical for in vitro cell analysis, especially when studying the dynamic involvement of proteins in various processes, including cell proliferation, differentiation, and apoptosis. Here, we monitored the interactions between protein kinase-Czeta (PKCzeta) and Bcl10 protein in untreated and etoposide (VP-16)-treated C4-I cells by means of a new combined morphological approach and validated it by taking stock of our previous proteomic and biochemical work (Chiarini et al. in J Proteome Res 11:3996-4012, 2012). We first analyzed the colocalization of PKCzeta and Bcl10 proteins through classical immunofluorescent colocalization analysis. On the basis of these results, we developed a novel imaging approach combining immunofluorescence (IF) techniques with in situ PLA to identify the PKCzeta.Bcl10 complexes at the level of a specific subcellular compartment, i.e., the nuclear envelope (NE). By this means, we could show that the amount of PKCzeta.Bcl10 complexes localized at the NE of C4-I cells during proliferation or after treatment with VP-16 closely corresponded to our previous purely biochemical results. Hence, the present findings demonstrate that the combination of in situ PLA with classical IF detection is a novel powerful analytical tool allowing to morphologically demonstrate new specific protein-protein interactions at level of subcellular organelles, the complexes functions of which can next be clarified through proteomic/biochemical approaches. PMID- 25011392 TI - Ketogenic diet in patients with Lennox-Gastaut syndrome. AB - PURPOSE: The ketogenic diet (KD) has been used as an alternative to antiepileptic drugs (AEDs) for patients with refractory epilepsy. Lennox-Gastaut syndrome (LGS) belongs to the group of epileptic encephalopathies that often prove refractory to AED treatment. In this prospective study we assess the efficacy and tolerability of the KD in patients with LGS. METHODS: Between March 1, 1990 and April 1, 2013, 61 patients who met diagnostic criteria of LGS were seen at our department. Twenty of them were placed on the KD and followed for a minimum of 16 months. RESULTS: The children had previously received a mean of 6.5 different AEDs and were on a mean of 2.5 AEDs when the diet was started. Eighteen months after initiating the diet, fifteen of the initial patients (75%) remained on the diet; three patients (15%) were seizure free, three (15%) had a 75-99% decrease in seizures, two (10%) had a 50-74% decrease in seizures, and the remaining seven children (35%) had a <50% decrease in seizures. Three seizure-free patients were tapered off the diet after remaining seizure free. In the three patients who had a 75-99% decrease in seizures AEDs were reduced. CONCLUSION: The KD is an effective and well-tolerated treatment option for patients with LGS, not only for those with cryptogenic, but also for those with structural LGS. The diet should be considered early in the course of this syndrome. PMID- 25011393 TI - A small molecule that induces reactive oxygen species via cellular glutathione depletion. AB - Induction of excessive levels of reactive oxygen species (ROS) by small-molecule compounds has been considered a potentially effective therapeutic strategy against cancer cells, which are often subjected to chronic oxidative stress. However, to elucidate the mechanisms of action of bioactive compounds is generally a time-consuming process. We have recently identified NPD926, a small molecule that induces rapid cell death in cancer cells. Using a combination of two comprehensive and complementary approaches, proteomic profiling and affinity purification, together with the subsequent biochemical assays, we have elucidated the mechanism of action underlying NPD926-induced cell death: conjugation with glutathione mediated by GST, depletion of cellular glutathione and subsequent ROS generation. NPD926 preferentially induced effects in KRAS-transformed fibroblast cells, compared with their untransformed counterparts. Furthermore, NPD926 sensitized cells to inhibitors of system x(c)-, a cystine-glutamate antiporter considered to be a potential therapeutic target in cancers including cancer stem cells. These data show the effectiveness of a newly identified ROS inducer, which targets glutathione metabolism, in cancer treatment. PMID- 25011395 TI - Combined conjugated esterified estrogen plus methyltestosterone supplementation and risk of breast cancer in postmenopausal women. AB - OBJECTIVES: Testosterone supplementation is being prescribed increasingly to treat symptoms of hormone deficiency in pre- and postmenopausal women; however, studies of the association of testosterone therapy, alone or in combination with estrogen, with risk of breast cancer are limited. The current study assessed the association of combination conjugated esterified estrogen and methyltestosterone (CEE+MT) use and breast cancer risk in postmenopausal women in the Women's Health Initiative (WHI). STUDY DESIGN: At Year 3 of follow-up, women in the WHI observational study (N=71,964) provided information on CEE+MT use in the past two years, duration of use, and the brand name of the product. In addition, in each of years 4-8, women were asked whether they had used CEE+MT in the previous year. After 10 years of follow-up, 2832 incident breast cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of CEE+MT use (irrespective of use of other hormones) and of exclusive CEE+MT use in relation to breast cancer risk. RESULTS: Neither CEE+MT use nor exclusive use of CEE+MT was associated with risk: multivariable-adjusted HR 1.06, 95% CI 0.82-1.36 and HR 1.22, 95% CI 0.78 1.92, respectively. Among women with a natural menopause, the HR for exclusive use was 1.32 (95% CI 0.68-2.55). There was no indication of an association when repeated measures of CEE+MT use were included in a time-dependent covariates analysis. CONCLUSION: The present study, the largest prospective study to date, did not show a significant association of CEE+MT supplementation and risk of breast cancer. PMID- 25011394 TI - Uptake and metabolism of iron oxide nanoparticles in brain cells. AB - Magnetic iron oxide nanoparticles (IONPs) are used for various applications in biomedicine, for example as contrast agents in magnetic resonance imaging, for cell tracking and for anti-tumor treatment. However, IONPs are also known for their toxic effects on cells and tissues which are at least in part caused by iron-mediated radical formation and oxidative stress. The potential toxicity of IONPs is especially important concerning the use of IONPs for neurobiological applications as alterations in brain iron homeostasis are strongly connected with human neurodegenerative diseases. Since IONPs are able to enter the brain, potential adverse consequences of an exposure of brain cells to IONPs have to be considered. This article describes the pathways that allow IONPs to enter the brain and summarizes the current knowledge on the uptake, the metabolism and the toxicity of IONPs for the different types of brain cells in vitro and in vivo. PMID- 25011396 TI - Vascular cognitive impairment in dementia. AB - Vascular risk factors and cerebrovascular disease are common causes of dementia. Shared risk factors for vascular dementia and Alzheimer's disease, as well as frequent coexistence of these pathologies in cognitively impaired older people, suggests convergence of the aetiology, prevention and management of the commonest dementias affecting older people. In light of this understanding, the cognitive impairment associated with cerebrovascular disease is an increasingly important and recognised area of the medicine of older people. Although the incidence of cerebrovascular events is declining in many populations, the overall burden associated with brain vascular disease will continue to increase associated with population ageing. A spectrum of cognitive disorders related to cerebrovascular disease is now recognised. Cerebrovascular disease in older people is associated with specific clinical and imaging findings. Although prevention remains the cornerstone of management, the diagnosis of brain vascular disease is important because of the potential to improve clinical outcomes through clear diagnosis, enhanced control of risk factors, lifestyle interventions and secondary prevention. Specific pharmacological intervention may also be indicated for some patients with cognitive impairment and cerebrovascular disease. However the evidence base to guide intervention remains relatively sparse. PMID- 25011397 TI - Oxidative stress and organ damages. AB - Oxidative stress plays a pivotal role in various pathological conditions, including hypertension, pulmonary hypertension, diabetes, and chronic kidney disease, with high levels of oxidative stress in target organs such as the heart, pancreas, kidney, and lung. Oxidative stress is known to activate multiple intracellular signaling, which induces apoptosis or cell overgrowth, leading to organ dysfunction. As such, targeting oxidative stress is thought to be effective in protecting against organ damage, and measuring oxidative stress status may serve as a biomarker in diverse disease states. Several new intrinsic anti oxidative or pro-oxidative factors have recently been reported, and are potential new targets. In the present review, we focus on diabetes, pulmonary hypertension, and renal dysfunction, and their relation with new targets - adrenomedullin, oxidized LDL, and mineralocorticoid receptor. PMID- 25011398 TI - Scientific forum topic: translating knowledge to practice in childhood dysarthria. PMID- 25011399 TI - Individual and environmental contributions to treatment outcomes following a neuroplasticity-principled speech treatment (LSVT LOUD) in children with dysarthria secondary to cerebral palsy: a case study review. AB - This study describes the use of a neuroplasticity-principled speech treatment approach (LSVT((r))LOUD) with children who have dysarthria secondary to cerebral palsy. To date, the authors have treated 25 children with mild-to-severe dysarthria, a continuum of gross and fine motor functions, and variable cognitive abilities. From this data set, two case studies are presented that represent as weak or strong responders to LSVT LOUD. These case studies demonstrate how individual and environmental features may impact immediate and lasting responses to treatment. Principles that drive activity-dependent neuroplasticity are embedded in LSVT LOUD and may contribute to positive therapeutic and acoustic outcomes. However, examination of the response patterns indicated that intensity (within and across treatment sessions) is necessary but not sufficient for change. Weak responders may require a longer treatment phase, better timing (e.g., developmentally, socially), and a more prominent desire to communicate successfully during daily activities. Strong responders appear to benefit from the intensity and saliency of treatment as well as from intrinsic and extrinsic rewards for using the trained skills for everyday communication. Finally, possibilities are presented for technological solutions designed to promote accessibility to the intensive task repetition and maintenance required to drive lasting changes. PMID- 25011400 TI - Association between objective measurement of the speech intelligibility of young people with dysarthria and listener ratings of ease of understanding. AB - PURPOSE: This study aimed to investigate the association between listeners' ratings of how much effort it took to understand the speech of young people with cerebral palsy and the percentage of words listeners actually understood. METHOD: Thirty-one young people with dysarthria and cerebral palsy (16 males, 15 females; mean age = 11 years, SD = 3) were audio recorded repeating single words and producing speech. Objective measures of intelligibility were calculated for multiple familiar and unfamiliar listeners using a forced choice paradigm for single words and verbatim orthographic transcriptions for connected speech. Listeners rated how much effort it took to understand speech in each condition using a 5-point ordinal ease of listening (EOL) scale. RESULTS: Agreement on EOL within rater groups was high (ICC > 0.71). An effect of listener was observed for familiar listeners, but not for unfamiliar listeners. EOL agreement between familiar and unfamiliar listeners was weak-moderate (ICC = 0.46). EOL predicted the percentage of speech actually understood by familiar and unfamiliar listeners (r > 0.56, p < 0.001 for all predictions). Strongest associations between EOL and intelligibility were observed for speakers with mild and profound impairments. CONCLUSIONS: The findings of this study demonstrate that listeners can judge how well they have understood dysarthric speech. EOL is associated with listener familiarity, speech task and speech impairment severity. EOL is appropriate for use in clinical practice as a measure of communication activity. PMID- 25011401 TI - Criterion-related validity of the Test of Children's Speech sentence intelligibility measure for children with cerebral palsy and dysarthria. AB - PURPOSE: To evaluate the criterion-related validity of the TOCS+ sentence measure (TOCS+, Hodge, Daniels & Gotzke, 2009 ) for children with dysarthria and CP by comparing intelligibility and rate scores obtained concurrently from the TOCS+ and from a conversational sample. METHOD: Twenty children (3 to 10 years old) diagnosed with spastic cerebral palsy (CP) participated. Nineteen children also had a confirmed diagnosis of dysarthria. Children's intelligibility and speaking rate scores obtained from the TOCS+, which uses imitation of sets of randomly selected items ranging from 2-7 words (80 words in total) and from a contiguous 100-word conversational speech were compared. RESULTS: Mean intelligibility scores were 46.5% (SD = 26.4%) and 50.9% (SD = 19.1%) and mean rates in words per minute (WPM) were 90.2 (SD = 22.3) and 94.1 (SD = 25.6), respectively, for the TOCS+ and conversational samples. No significant differences were found between the two conditions for intelligibility or rate scores. Strong correlations were found between the TOCS+ and conversational samples for intelligibility (r = 0.86; p < 0.001) and WPM (r = 0.77; p < 0.001), supporting the criterion validity of the TOCS+ sentence task as a time efficient procedure for measuring intelligibility and rate in children with CP, with and without confirmed dysarthria. CONCLUSION: The results support the criterion validity of the TOCS+ sentence task as a time efficient procedure for measuring intelligibility and rate in children with CP, with and without confirmed dysarthria. Children varied in their relative performance on the two speaking tasks, reflecting the complexity of factors that influence intelligibility and rate scores. PMID- 25011402 TI - The rhetoric of cancer. AB - BACKGROUND: Research involving the discovery of novel anticancer drugs and treatments hold precedence among the general public. However, investigating the etiology and epidemiology of malignancies can have a significant effect on reducing the prevalence of cancer in society. Understanding risk factors that drive neoplastic development can provide educated individuals the opportunity to avoid such catalysts. METHODS: Literature searches were conducted on prominent magazine and newspaper sources to analyze the accuracy and relevance the material had toward cancer prevention. Additionally, two professionals involved in oncology were interviewed to gain a more personal view of the population's knowledge on cancer awareness and prevention. RESULTS: The lack of attention paid to the understanding of cancer and its subsequent prevention has resulted in fundamental misconceptions that facilitate the development of neoplastic growths. CONCLUSIONS: Addressing the lack of attention paid to cancer awareness and prevention through proper education can have a significant effect on limiting the impact cancer has on society. PMID- 25011403 TI - Maternal reproductive history, fertility treatments and folic acid supplementation in the risk of childhood acute leukemia: the ESTELLE study. AB - PURPOSE: To investigate the potential involvement of fertility treatments and other conditions of becoming pregnant (infertility, getting pregnant on birth control, maternal history of fetal loss) and folic acid supplements in the etiology of childhood leukemia (CL). METHODS: The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 of acute myeloblastic leukemia (AML)] diagnosed in France in 2010-2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. The odds ratios (OR) and their 95% confidence intervals were estimated using unconditional regression models adjusted for potential confounders. RESULTS: CL was not associated with difficulty in becoming pregnant [OR 0.9 (0.7-1.2)], in vitro fertilisation [OR 0.6 (0.3-1.5)] or the use of any fertility treatment [OR 0.8 (0.5-1.1)] for the index pregnancy. CL was not significantly associated with becoming pregnant on contraception [OR 1.2 (0.8-1.8)], but a positive association was observed for third generation oral contraception [OR 4.3 (1.2-16.2)]; however, the result is based on small numbers. Folic acid supplementation during pregnancy was not associated with CL, but an inverse borderline association was observed for supplementation initiated in the 3 months preceding pregnancy [OR 0.7 (0.5-1.0)]. In addition, maternal histories of stillbirth and miscarriage were associated with ALL [OR 2.6 (1.1-5.9)] and AML [OR 1.8 (1.1-2.8)], respectively. CONCLUSIONS: The findings do not suggest that infertility and fertility treatments are risk factors for CL. They suggest that maternal histories of stillbirth and miscarriage may be more frequent among mothers of CL cases and that folic acid supplementation during preconception may reduce the risk of CL. PMID- 25011404 TI - Breast screening: an obsessive compulsive disorder. AB - Population-based mammographic screening, founded on the premise that 'early is better than late,' has been adopted in several countries but has been the subject of controversy since its inception. Findings and interpretation of clinical trials data vary considerably, with disagreement on the outcome and value of such a procedure. In recent years, misgivings are being voiced from many quarters, not just about the benefits but about the potential harms of mass screening. The many are being screened for the benefit of the few. Even this might be acceptable, but the realization that a significant proportion of women with screen detected cancers that will potentially not cause them harm, and who are very likely receiving unnecessary treatment, has sparked further concern. Many are calling for re-assessment of the age of commencement and periodicity if not complete cessation of indiscriminate screening. An aspect of great concern is that screening is being vigorously advocated by many healthcare workers, the media, and lay persons alike without proper awareness or appreciation of the consequences. Although some National Health Department leaflets are now presenting a truer picture, there is still a distinct lack of transparency to allow women to distinguish perception from reality and to make informed choices. How many would elect to be screened if they knew that for every one woman who is notionally saved by early detection, anywhere from 2 to 10 otherwise healthy women are being turned into breast cancer patients? PMID- 25011406 TI - Subarachnoid hemorrhage and intracerebral hematoma caused by aneurysms of the anterior circulation: influence of hematoma localization on outcome. AB - Additional space-occupying intracerebral hematoma (ICH) in patients suffering from subarachnoid hemorrhage (SAH) is a known predictor for poor outcome. Emergent clot evacuation might be mandatory. However, data concerning the influence of ICH location on outcome is scarce. Therefore, we analyzed the influence of ICH location on clinical course and outcome in patients with SAH and additional ICH. One hundred seventy-four patients were treated with aneurysmal SAH and additional ICH between September 1999 and May 2012. Information including patient characteristics, treatment, and radiological findings were prospectively entered into a database. Patients were stratified according to ICH location and neurological outcome. Neurological outcome was assessed according to modified Rankin Scale (mRS). ICH location was temporal (58.6 %), frontal (28.7 %), and perisylvian ICH (12.6 %); 63.8 % presented in poor admission status and favorable outcome was achieved in 35.6 %. In the multivariate analysis, favorable outcome was associated with young age, ICH <50 ml, and good admission status. The location of ICH was not associated with outcome. The current data confirms that a significant number of patients with ICH after aneurysm rupture achieve favorable outcome. Prognostic factor for favorable outcome are "age," "size of the hematoma," and "admission status." The location of the ICH seems not to be associated with outcome. PMID- 25011407 TI - Gender differences in emotions, forgiveness and tolerance in relation to political violence. AB - This study, which forms part of a broader research project, analyzes gender differences in: the intensity of diverse emotions, the justification of violence, attitudes towards the terrorist group ETA, forgiveness and tolerance. Participants comprised 728 people (45.5% men and 54.5% women) resident in either Basque Country or Navarra (Spain), representative of all national identities and political ideologies existing in this context. An ad hoc questionnaire was designed and administered between November 2005 and February 2006, a short time before ETA declared a ceasefire. Women reported more intensity in fear for political reasons and scored higher in two of the six measures of empathy included in the study (empathy with prisoners and empathy with those who suffer and think like oneself). Men scored higher in positive emotionality, indifference and Schadenfreude. Women perceived apology and forgiveness as more necessary elements for achieving peace than men. These results suggest that it may be beneficial for women to play a more prominent role in relation to the resolution of intergroup conflicts such as the one existing in the Basque Country. PMID- 25011408 TI - Brain networks and their origins. Comment on "Understanding brain networks and brain organization" by Luiz Pessoa. PMID- 25011409 TI - Interprosthetic femoral fractures treated with locking plate. AB - PURPOSE: Interprosthetic fractures are challenging to manage. Although treatment of femoral fractures around a single implant has been described, there is little literature for treatment of interprosthetic femoral fractures. This study analyses the management and outcomes of 15 patients with interprosthetic femoral fractures treated with locking plates. METHODS: A retrospective chart review was conducted of 17 patients with interprosthetic femur fracture treated with locking plates from 2002 to 2013. Patient demographics and comorbidities were collected. Preoperatively, patients were classified with the Vancouver or Su classification system. Intraoperative use of bone graft and/or cerclage cables was also examined. Clinical and radiographic outcomes were evaluated for union, time to full weight bearing, return to preinjury level of activity, and pain assessed with visual analog scale (VAS). RESULTS: There were 15 patients with interprosthetic fractures meeting criteria for this study. Average patient age was 80.53 (range, 61-92) years. Bone grafting was used in 23.5% (four of 17) and cerclage cables in 29.4% (five of 17). Patients achieved complete union and return to full weight bearing an average of 4.02 (range, two to six) months later. Average VAS pain score was 1.00 (range, zero to six). All patients returned to their preoperative ambulatory status. CONCLUSION: Locking plates could achieve satisfactory results for interprosthetic fractures. Considering an individual's fracture type, bone quality and protheses to determine the appropriate plate length and optional use of cerclage and/or bone graft was essential. In this limited sample size, interprosthetic fractures occurred at similar rates at the supracondylar region and diaphysis. PMID- 25011410 TI - Comparison of ulnar nerve repair according to injury level and type. AB - PURPOSE: The aim of the study was to evaluate the results of epiperineural suture repaired primary (clean transaction injury, massive soft-tissue associated injury) and secondary (delayed partial injury) ulnar nerve injuries according to lesion level and type. METHODS: Forty-two patients diagnosed with ulnar nerve injury between January 2008 and January 2012 were involved in the study. Ulnar nerve lesions were classified according to the level of injury into three types: type 1--lesion located above the flexor carpi ulnaris branch; type 2--lesion located between the flexor carpi ulnaris and the flexor digitorum profundus III and IV; type 3--lesion located below the flexor digitorum profundus III and IV and no more than 10 cm distal from the elbow crease. Additionally, ulnar nerve lesions were classified according to type into three groups: group 1 (n 17)- clean transaction injury; group 2 (n 14)--massive soft-tissue associated injury; group 3 (n 11)--delayed partial clean transaction injury. In follow-up evaluations, sensory and motor recovery was analysed with the most common Highet scale modified by Dellon et al. Functional results were evaluated according to the Disability of Arm, Shoulder, and Hand (DASH) score at final follow-up. RESULTS: There were no statistically significant differences between groups according to men/women ratio, mean age, mean follow-up period and ulnar-nerve injury level. The DASH score was significantly better in the clean transaction injury group than the other groups and significantly better for type 3 than types 1 and 2 injuries in all groups. Sensory recovery of type 1 and 3 injuries in the massive soft-tissue associated injury group was significantly worse than the other groups. The worst motor recovery was evaluated in type 1 injury and the best in type 3 injury according to injury level. According to group, motor recovery of the massive soft-tissue associated group was significantly worse than the other groups in all injury types. There were no statistically significant differences between clean transaction injury and delayed partial clean transaction injury groups in all injury types. CONCLUSIONS: Prognostic factors that influenced motor-sensory recovery and functional results were found in interval between trauma and reconstruction, injury level (worse results from proximal to distal) and mechanism of injury (worse results from massive soft tissue injury to clear, sharp-tissue injury). PMID- 25011411 TI - Prospective collection of error data in orthopaedic and trauma surgery procedures. AB - PURPOSE: The frequency, type and consequences of errors in orthopaedic and trauma surgery procedures should be analysed. METHODS: In a level II trauma centre, errors and intraoperative complications were prospectively recorded concerning type, severity, preventability and consequences. The error-related time delay was also noted. RESULTS: In 2012, 984 operative cases could be evaluated over six months: 744 elective and 240 emergency procedures. A total 107 errors (10.8%) in 72 procedures were recorded. There were 78 nonmedical/organisational, nine medical and 20 combined errors. Clinical consequences were seen in 1% of errors. The error rate was higher in emergency procedures. Time delays were involved in two thirds of the errors (on average 8.5 minutes). CONCLUSION: Typical patient- and procedure-related errors can be detected by consequent documentation and analysis. It may help to develop sufficient strategies of error prevention. Because of the often-seen time delay, error prevention may help save time and costs. PMID- 25011412 TI - Midterm clinical and radiographic results of the medial pivot total knee system. AB - PURPOSE: The ADVANCE(r) Medial Pivot Knee System was designed with a highly congruent medial compartment and a less conforming lateral compartment to more closely mimic the kinematics of the normal knee. The purpose of this study was to evaluate the midterm clinical and radiographic outcomes of this total knee arthroplasty (TKA) system. METHODS: Between January 1998 and December 2006, 421 primary TKAs were performed in 373 subjects using this system and a surgical technique that resects the posterior cruciate ligament. Of these, 365 TKAs in 320 subjects were available for a follow-up visit occurring at a mean of 5.3 years. Subjects were evaluated using Knee Society Scores, range of motion, and radiographic review. RESULTS: The average Knee Society clinical score was 95.5 at final follow-up, with 358 (98%) TKAs having excellent or good results. Range of motion increased from a preoperative mean of 115 to 119 degrees at final follow up. Component survivorship, excluding revisions for infection or trauma, was 96.6% at five years. CONCLUSIONS: This study demonstrates subjects implanted with the ADVANCE(r) Medial Pivot Knee System achieved satisfactory clinical and radiographic midterm outcomes. PMID- 25011413 TI - Academic context and perceived mental workload of psychology students. AB - The excessive workload of university students is an academic stressor. Consequently, it is necessary to evaluate and control the workload in education. This research applies the NASA-TLX scale, as a measure of the workload. The objectives of this study were: (a) to measure the workload levels of a sample of 367 psychology students, (b) to group students according to their positive or negative perception of academic context (AC) and c) to analyze the effects of AC on workload. To assess the perceived AC, we used an ad hoc questionnaire designed according to Demand-Control-Social Support and Effort-Reward Imbalance models. Using cluster analysis, participants were classified into two groups (positive versus negative context). The differences between groups show that a positive AC improves performance (p < .01) and reduces feelings of overload (p < .02), temporal demand (p < .02), and nervousness and frustration (p < .001). Social relationships with peers and teachers, student autonomy and result satisfaction were relevant dimensions of the AC (p < .001 in all cases). PMID- 25011414 TI - Statistical power calculations for mixed pharmacokinetic study designs using a population approach. AB - Simultaneous modelling of dense and sparse pharmacokinetic data is possible with a population approach. To determine the number of individuals required to detect the effect of a covariate, simulation-based power calculation methodologies can be employed. The Monte Carlo Mapped Power method (a simulation-based power calculation methodology using the likelihood ratio test) was extended in the current study to perform sample size calculations for mixed pharmacokinetic studies (i.e. both sparse and dense data collection). A workflow guiding an easy and straightforward pharmacokinetic study design, considering also the cost effectiveness of alternative study designs, was used in this analysis. Initially, data were simulated for a hypothetical drug and then for the anti-malarial drug, dihydroartemisinin. Two datasets (sampling design A: dense; sampling design B: sparse) were simulated using a pharmacokinetic model that included a binary covariate effect and subsequently re-estimated using (1) the same model and (2) a model not including the covariate effect in NONMEM 7.2. Power calculations were performed for varying numbers of patients with sampling designs A and B. Study designs with statistical power >80% were selected and further evaluated for cost effectiveness. The simulation studies of the hypothetical drug and the anti malarial drug dihydroartemisinin demonstrated that the simulation-based power calculation methodology, based on the Monte Carlo Mapped Power method, can be utilised to evaluate and determine the sample size of mixed (part sparsely and part densely sampled) study designs. The developed method can contribute to the design of robust and efficient pharmacokinetic studies. PMID- 25011415 TI - Hoopoes color their eggs with antimicrobial uropygial secretions. AB - Uropygial gland secretions are used as cosmetics by some species of birds to color and enhance properties of feathers and teguments, which may signal individual quality. Uropygial secretions also reach eggshells during incubation and, therefore, may influence the coloration of birds' eggs, a trait that has attracted the attention of evolutionary biologists for more than one century. The color of hoopoe eggs typically changes along incubation, from bluish-gray to greenish-brown. Here, we test experimentally the hypothesis that dark uropygial secretion of females is responsible for such drastic color change. Moreover, since uropygial secretion of hoopoes has antimicrobial properties, we also explore the association between color and antimicrobial activity of the uropygial secretion of females. We found that eggs stayed bluish-gray in nests where female access to the uropygial secretion was experimentally blocked. Furthermore, experimental eggs that were maintained in incubators and manually smeared with uropygial secretion experienced similar color changes that naturally incubated eggs did, while control eggs that were not in contact with the secretions did not experience such color changes. All these results strongly support the hypothesis that female hoopoes use their uropygial gland secretion to color the eggs. Moreover, saturation of the uropygial secretion was associated with antimicrobial activity against Bacillus licheniformis. Given the known antimicrobial potential of uropygial secretions of birds, this finding opens the possibility that in scenarios of sexual selection, hoopoes in particular and birds in general signal antimicrobial properties of their uropygial secretion by mean of changes in egg coloration along incubation. PMID- 25011416 TI - Nest defenses and egg recognition of yellow-bellied prinia against cuckoo parasitism. AB - Parasites may, in multi-parasite systems, block the defenses of their hosts and thus thwart host recognition of parasites by frequency-dependent selection. Nest defenses as frontline may block or promote the subsequent stage of defenses such as egg recognition. We conducted comparative studies of the defensive strategies of a host of the Oriental cuckoo Cuculus optatus, the yellow-bellied prinia Prinia flaviventris, in mainland China with multiple species of cuckoos and in Taiwan with a single cuckoo species. Cuckoo hosts did not exhibit aggression toward cuckoos in the presence of multiple cuckoo species but showed strong aggressive defenses of hosts directed toward cuckoos in Taiwan. Furthermore, the cuckoo host in populations with a single cuckoo species was able to distinguish adults of its brood parasite, the Oriental cuckoo, from adult common cuckoos (Cuculus canorus). This represents the first case in which a cuckoo host has been shown to specifically distinguish Oriental cuckoo, from other Cuculus species. Hosts ejected eggs at a higher rate in a single cuckoo species system than in a multi-species cuckoo system, which supports the strategy facilitation hypothesis. Granularity analysis of variation in egg phenotype based on avian vision modeling supported the egg signature hypothesis in hosts because Taiwanese prinias increased consistency in the appearance of their eggs within individual hosts thus favoring efficient discrimination against cuckoo eggs. This study significantly improves our knowledge of intraspecific variation in antiparasitism behavior of hosts between single- and multi-cuckoo systems. PMID- 25011417 TI - Is pentraxin 3 a new cardiovascular risk marker in polycystic ovary syndrome? AB - BACKGROUND/AIMS: Polycystic ovary syndrome (PCOS) patients have an increased rate of subclinical inflammation, which plays a role in the pathogenesis of atherosclerosis. Pentraxin 3 (PTX3) is an inflammatory mediator which belongs to the same family as the well-established cardiovascular biomarker C-reactive protein (CRP). The present study was performed to investigate plasma PTX3 levels in patients with PCOS and to determine the relationship between PTX3 and other known cardiovascular risk factors. METHODS: 40 patients with PCOS and 40 age- and BMI-matched healthy controls were included in the study. The groups were divided into subgroups according to BMI. Insulin resistance indexes, lipid profile, CRP and PTX3 levels were analyzed. RESULTS: There was no difference for insulin resistance indexes and lipid profile between the PCOS and control groups. CRP levels were significantly higher in obese PCOS and control subjects than in lean subjects, whereas no difference in PTX3 concentrations was observed between subgroups. CONCLUSION: PTX3 and CRP levels were similar in the PCOS group compared with the non-PCOS control group. PMID- 25011418 TI - Outcomes of very-low-birth-weight infants exposed to maternal clinical chorioamnionitis: a multicentre study. AB - BACKGROUND: Chorioamnionitis is a recognized risk factor of preterm delivery; however, controversy still persists concerning the relationship between maternal inflammation and neonatal morbidity and mortality. OBJECTIVE: To determine the incidence of clinical chorioamnionitis and its relationship to morbidity and mortality among very-low-birth-weight (VLBW) infants. METHODS: This was a retrospective analysis of prospectively collected data of VLBW neonates <= 32 weeks' gestational age (GA) admitted to collaborating units in the Spanish SEN1500 Network between January 2008 and December 2011. Clinical chorioamnionitis was defined by obstetricians based on clinical findings, and neonatal outcomes were compared between exposed and non-exposed infants by multivariate logistic regression analysis. RESULTS: During the study period, 11,464 VLBW newborns were admitted to our units and 10,026 were <= 32 weeks' GA. Among them, 8,330 (83.1%) had complete data and were included. Of these, 1,480 (17.8%) were exposed to maternal clinical chorioamnionitis. The incidence was higher at lower GA and, after adjusting for confounding factors, exposed infants had higher risks of early-onset neonatal sepsis (EONS) (10.0 vs. 2.8%; aOR 3.102; 95% CI 2.306-4.173; p < 0.001) and necrotizing enterocolitis (NEC) (11.2 vs. 7.7%; aOR 1.300; 95% CI 1.021-1.655; p < 0.033), but lower risks of patent ductus arteriosus (PDA) (43.2 vs. 34.9%; aOR 0.831; 95% CI 0.711-0.971; p < 0.02) and late-onset bacterial sepsis (LONS) (36.6 vs. 32.5%; aOR 0.849; 95% CI 0.729-0.989; p < 0.035). There were no differences in mortality between the groups. CONCLUSIONS: The incidence of maternal clinical chorioamnionitis is inversely related to GA at delivery, and in VLBW infants <= 32 weeks' GA it is associated with higher risks of EONS and NEC, but lower risks of PDA and LONS. We did not found differences in survival. PMID- 25011419 TI - Catalan and Hungarian validation of the Zuckerman-Kuhlman-Aluja Personality Questionnaire (ZKA-PQ). AB - The goal of this study was to examine the cross-cultural validity and reliability of the Zuckerman-Kuhlman-Aluja Personality Questionnaire (ZKA-PQ) - a recently published instrument for assessing the Zuckerman's Alternative Five Factor Personality Model - in Catalan and Hungarian speaking populations. The samples consisted of 1,564 subjects from Catalonia and 1,647 from Hungary. Results showed a clear five-factor structure and acceptable alpha reliabilities of the ZKA-PQ in both countries. Facets alpha average was 80.35 and 74.10 for Catalans and Hungarians respectively. The factorial congruency coefficients indicated that both structures were equivalent, with a global value of .97. However, the robust structure obtained with EFA yielded poor fit indices in the subsequent CFA. Altogether, the psychometric findings were similar to those obtained in the original validation study carried out in Spanish and English populations. Main country differences were found only in Neuroticism factor, with Hungarians scoring significantly lower that Catalans. Nevertheless, country, sex and age explained only 18.6 % of Neuroticism variance (adjusted R squared = .186). Country differences had only medium effect size [F(1, 3188) = 292, p < .001, eta2 = .084 1 ]. PMID- 25011420 TI - Parahisian pacing: technique, utility, and pitfalls. AB - Several observations and maneuvers in the electrophysiology (EP) laboratory are employed to identify whether retrograde ventriculoatrial conduction is via the atrioventricular (AV) node or an accessory pathway. Parahisian pacing is a unique maneuver where there is no change in the position of the catheter, the position of the stimulating electrode, nor the cycle length for pacing, but rather the pacing output is varied. The primary value for parahisian pacing is to distinguish between a septal accessory pathway and AV nodal conduction. However, more nuanced but just as reliable interpretation is possible to also help identify free-wall accessory pathways, intermittently conducting pathways, multiple accessory pathways, and various combinations of pathway and AV nodal retrograde conduction. In this review, we discuss the importance of correct technique and explain with examples some uncommon, yet instructive, findings when performing parahisian pacing. PMID- 25011421 TI - Associations between program outcomes and adherence to Social Cognitive theory tasks: process evaluation of the SHED-IT community weight loss trial for men. AB - BACKGROUND: Despite rising international rates of obesity, men remain reluctant to participate in weight loss research. There is a lack of evidence to guide the development of effective weight loss interventions that engage men. The objective of this study was to provide a comprehensive process evaluation of the SHED-IT (Self-Help, Exercise and Diet using Information Technology) weight loss program for men, as delivered in the SHED-IT community weight loss trial, and to identify key components associated with success. METHODS: In an assessor-blinded randomised controlled trial, 159 overweight and obese men (BMI 25.0-40.0 kg/m2) were randomised to one of two gender-tailored weight loss interventions with no face-to-face contact, or a control group. The interventions were informed by Bandura's Social Cognitive Theory (SCT) with men encouraged to complete a Support Book containing SCT-based tasks including goal setting, reward setting, creation of social support strategies and self-monitoring of: i) weight, ii) physical activity, and iii) diet. At post-test, compliance with SCT tasks was examined and men also completed a process evaluation questionnaire. RESULTS: Both SHED-IT intervention groups demonstrated greater weight loss during the intervention compared to the control, with no difference between intervention groups. Most men engaged with the SCT tasks although compliance declined over time and utilisation of social support networks and reward selection was poor. In a multiple regression model, the number of goals set (beta [95% CI] = -0.3 [-0.6, -0.1], p = 0.01) and the number of weight records documented (beta [95% CI] = -0.2 [-0.4, 0.0], p = 0.03) independently predicted weight loss. The process evaluation indicated that men found the programs to be supportive, enjoyable and beneficial. CONCLUSIONS: This process evaluation provides valuable information to inform the development of obesity treatment strategies that engage men. Future studies with men should include a strong focus on self-monitoring and goal setting to enhance behaviour change and improve treatment effects. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000699066. PMID- 25011422 TI - Real-world use of fingolimod in patients with relapsing remitting multiple sclerosis: a retrospective study using the national multiple sclerosis registry in Kuwait. AB - BACKGROUND: Fingolimod is an oral sphingosine-1-phosphate-receptor modulator, which has demonstrated efficacy in clinical trials and has recently been approved for multiple sclerosis (MS) treatment in Kuwait. Post-marketing studies are important to demonstrate real-life efficacy and safety. OBJECTIVE: The objective of this study was to examine the efficacy and safety of fingolimod treatment in a clinical setting. METHODS: Using the national Kuwait MS registry, relapsing remitting MS patients who had been prescribed fingolimod for >=6 months were retrospectively identified. Three-monthly clinical evaluations and 6-monthly magnetic resonance imagings (MRIs) were performed. Patient status pre- and post treatment was compared using chi-square and Student t-tests. RESULTS: A total of 175 patients were included: 75.4 % female (n = 132); mean age 33.3 +/- 9.2 years; mean disease duration 7.2 +/- 5.2 years; mean fingolimod use 21.7 +/- 9.1 months. Most had used previous disease-modifying therapy (78.9 %; n = 138), mainly interferons (66.9 %; n = 117). Twenty-three patients (11.4 %) discontinued/withdrew fingolimod; of whom eight had relapses. The proportion of relapse-free patients improved significantly (86.3 % vs. 32.6 %; p < 0.001), while the proportion of patients with MRI activity decreased (18.3.6 % vs. 77.7 %; p < 0.001). Mean expanded disability status scale (EDSS) score at the last visit improved when compared with pre-treatment (2.26 +/- 1.49 vs. 2.60 +/- 1.44; p = 0.03). Forty-three (24.6 %) patients experienced adverse events; headaches and lymphopenia were the most commonly reported adverse events. CONCLUSION: Fingolimod treatment was associated with reduced relapse and MRI activity, and an improved EDSS score. Discontinuation/withdrawal rates and adverse events were low. Fingolimod presents a promising treatment for MS in Kuwait. PMID- 25011423 TI - Outdoor thermal physiology along human pathways: a study using a wearable measurement system. AB - An outdoor summer study on thermal physiology along subjects' pathways was conducted in a Japanese city using a unique wearable measurement system that measures all the relevant thermal variables: ambient temperature, humidity, wind speed (U) and short/long-wave radiation (S and L), along with some physio psychological parameters: skin temperature (T skin), pulse rate, subjective thermal sensation and state of body motion. U, S and L were measured using a globe anemo-radiometer adapted use with pedestrian subjects. The subjects were 26 healthy Japanese adults (14 males, 12 females) ranging from 23 to 74 years in age. Each subject wore a set of instruments that recorded individual microclimate and physiological responses along a designated pedestrian route that traversed various urban textures. The subjects experienced varying thermal environments that could not be represented by fixed-point routine observational data. S fluctuated significantly reflecting the mixture of sunlit/shade distributions within complex urban morphology. U was generally low within urban canyons due to drag by urban obstacles such as buildings but the subjects' movements enhanced convective heat exchanges with the atmosphere, leading to a drop in T skin. The amount of sweating increased as standard effective temperature (SET*) increased. A clear dependence of sweating on gender and body size was found; males sweated more than females; overweight subjects sweated more than standard/underweight subjects. T skin had a linear relationship with SET* and a similarly clear dependence on gender and body size differences. T skin of the higher-sweating groups was lower than that of the lower-sweating groups, reflecting differences in evaporative cooling by perspiration. PMID- 25011424 TI - Effects of behavioral response and vaccination policy on epidemic spreading--an approach based on evolutionary-game dynamics. AB - How effective are governmental incentives to achieve widespread vaccination coverage so as to prevent epidemic outbreak? The answer largely depends on the complex interplay among the type of incentive, individual behavioral responses, and the intrinsic epidemic dynamics. By incorporating evolutionary games into epidemic dynamics, we investigate the effects of two types of incentives strategies: partial-subsidy policy in which certain fraction of the cost of vaccination is offset, and free-subsidy policy in which donees are randomly selected and vaccinated at no cost. Through mean-field analysis and computations, we find that, under the partial-subsidy policy, the vaccination coverage depends monotonically on the sensitivity of individuals to payoff difference, but the dependence is non-monotonous for the free-subsidy policy. Due to the role models of the donees for relatively irrational individuals and the unchanged strategies of the donees for rational individuals, the free-subsidy policy can in general lead to higher vaccination coverage. Our findings indicate that any disease control policy should be exercised with extreme care: its success depends on the complex interplay among the intrinsic mathematical rules of epidemic spreading, governmental policies, and behavioral responses of individuals. PMID- 25011425 TI - Immunoglobulin replacement therapy: a twenty-year review and current update. AB - OBJECTIVE: The expansion of immunoglobulin replacement to multiple disease entities marks a decade-long advancement in immune therapy. Parallel to its extension, the characteristics and composition of immunoglobulin products have diversified. The aim of this study was to summarize a 20-year comprehensive literature review of currently commercially available immunoglobulin products, particularly examining individual product properties in a comparative format. Data Sources/Study Selections: The literature review was performed using PubMed and Ovid, screening a time span of 2 decades. Both authors reviewed the obtained articles for acceptable quality, and the selection was narrowed down based on criteria for randomized clinical and therapeutic trials. RESULTS: Product specific characteristics in terms of purification strategy, stabilizers, composition, and viral inactivation were found among the immunoglobulin products investigated. Such differing characteristics manifest in their variable clinical safety and efficacy as assessed by the comparative product analysis. In subgroups of patients, subcutaneous immunoglobulin therapy may be an alternative to intravenous immunoglobulin (IVIG) therapy with an equal efficacy and a lower number of systemic adverse events. CONCLUSION: Only few comprehensive clinical synopses are available to clearly demonstrate the differences in IVIG products despite the widespread clinical use of the therapy. This review defines significant characteristics of individual immunoglobulin products, noting important differences in product development and application and allowing informed clinical decisions to match a product with patients' risk factors and comorbidity. This balanced approach to gammaglobulin replacement therapy is imperative to produce the highest clinical efficacy and lowest number of adverse events. PMID- 25011426 TI - Ribonucleoprotein therapy in Alzheimer's disease? PMID- 25011427 TI - Epidemiology and molecular characterization of methicillin-resistant Staphylococcus aureus nasal carriage isolates from bovines. AB - BACKGROUND: Staphylococcus aureus is a common bacterium usually found on skin and mucous membranes of warm blooded animals. Resistance in S. aureus has been increasingly reported though depending on the clonal lineage. Indeed, while hospital acquired (HA)-methicillin resistant S. aureus (MRSA) are typically multi resistant, community associated (CA)-MRSA are by large more susceptible to many antibiotics. Although S. aureus isolated from animals are often susceptible to most antibiotics, multi-resistant livestock associated (LA)-MRSA have been recovered from bovine mastitis.In this study, we investigated the prevalence and types of MRSA present in the nose of healthy bovines of different age groups and rearing practices. Since no validated methods for MRSA isolation from nasal swabs were available, we compared two isolation methods. Molecular characterization was performed by means of spa-typing, MLST, SCCmec typing and microarray analysis for the detection of antimicrobial resistance and virulence genes. RESULTS: MRSA between herd prevalence in bovines was estimated at 19.8%. There was a marked difference between rearing practices with 9.9%, 10.2% and 46.1% of the dairy, beef and veal calve farms respectively being MRSA positive. No significant difference was observed between both isolation methods tested. Most isolates were ST398 spa type t011 or closely related spa types. Few ST239 spa type t037 and t388 and ST8 spa type t121 were also found. SCCmec types carried by these strains were mainly type IV(2B), IV(2B&5) and type V. Type III and non-typeable SCCmec were recovered to a lesser extent. All isolates were multi-resistant to at least two antimicrobials in addition to the expected cefoxitin and penicillin resistance, with an average of resistance to 9.5 different antimicrobials. Isolates selected for microarray analysis carried a broad range of antimicrobial resistance and virulence genes. CONCLUSION: MRSA were mainly present in veal farms, compared to the lower prevalence in dairy or beef farms. Multi-resistance in these strains was high. Though mainly CC398 spa t011 was found, the genetic diversity was higher than what was found for pigs in Belgium. CC8 strains, a typically human lineage but also recently found also in association with bovines, has been retrieved here also. PMID- 25011428 TI - Combination of in situ preconcentration and on-site analysis for phosphate monitoring in fresh waters. AB - Excess nutrients of phosphorus and nitrogen would lead to adverse impacts on a water body. It is important that their concentrations in a dynamic water ecosystem are measured accurately and constantly for an early warning before occurrences of algal blooms and for environmental management. Nevertheless, on site measurements by existing technologies are often limited by the inherent sensitivities. In this study, a portable system for dissolved phosphate monitoring in freshwater based on the diffusive gradients in thin films (DGT) technique was developed. A polydiallydimethylammonium chloride (PDA) aqueous solution and a dialysis membrane were used as a binding phase and a diffusive layer in this preconcentration device, respectively. The binding properties of the PDA solution were evaluated in solutions of different pH (3 to 9) and varying concentrations of anions (2.0-20 mM). The amount of phosphates preconcentrated in the devices was measured by ultraviolet-visible (UV) spectroscopy to obtain the concentrations in waters without elution steps. The devices were validated in synthetic river water with good agreement with the theoretical prediction and in natural river water. A system combining this preconcentration device and a compact detection chamber equipped with a pair of light emitting diodes (LED) was studied in lab synthetic solutions for on-site monitoring of phosphate concentrations and their fluctuations. PMID- 25011429 TI - Validating an ontology-based algorithm to identify patients with type 2 diabetes mellitus in electronic health records. AB - BACKGROUND: Improving healthcare for people with chronic conditions requires clinical information systems that support integrated care and information exchange, emphasizing a semantic approach to support multiple and disparate Electronic Health Records (EHRs). Using a literature review, the Australian National Guidelines for Type 2 Diabetes Mellitus (T2DM), SNOMED-CT-AU and input from health professionals, we developed a Diabetes Mellitus Ontology (DMO) to diagnose and manage patients with diabetes. This paper describes the manual validation of the DMO-based approach using real world EHR data from a general practice (n=908 active patients) participating in the electronic Practice Based Research Network (ePBRN). METHOD: The DMO-based algorithm to query, using Semantic Protocol and RDF Query Language (SPARQL), the structured fields in the ePBRN data repository were iteratively tested and refined. The accuracy of the final DMO-based algorithm was validated with a manual audit of the general practice EHR. Contingency tables were prepared and Sensitivity and Specificity (accuracy) of the algorithm to diagnose T2DM measured, using the T2DM cases found by manual EHR audit as the gold standard. Accuracy was determined with three attributes - reason for visit (RFV), medication (Rx) and pathology (path) - singly and in combination. RESULTS: The Sensitivity and Specificity of the algorithm were 100% and 99.88% with RFV; 96.55% and 98.97% with Rx; and 15.6% and 98.92% with Path. This suggests that Rx and Path data were not as complete or correct as the RFV for this general practice, which kept its RFV information complete and current for diabetes. However, the completeness is good enough for this purpose as confirmed by the very small relative deterioration of the accuracy (Sensitivity and Specificity of 97.67% and 99.18%) when calculated for the combination of RFV, Rx and Path. The manual EHR audit suggested that the accuracy of the algorithm was influenced by data quality such as incorrect data due to mistaken units of measurement and unavailable data due to non documentation or documented in the wrong place or progress notes, problems with data extraction, encryption and data management errors. CONCLUSION: This DMO based algorithm is sufficiently accurate to support a semantic approach, using the RFV, Rx and Path to define patients with T2DM from EHR data. However, the accuracy can be compromised by incomplete or incorrect data. The extent of compromise requires further study, using ontology-based and other approaches. PMID- 25011430 TI - Enhancing life prospects of socially vulnerable youth through sport participation: a mixed methods study. AB - BACKGROUND: Sport participation has been associated with improved life prospects such as academic performance and employability prospects. As such, promoting sport participation might be a way to increase life prospects, especially for socially vulnerable youth because they are less physically active than their peers. However, the evidence for the causal effect of sport participation on these outcomes is still limited and little is known about factors that play a role in this possible effect. The aim of this study is four-fold. First, the causal effect of sport participation on life prospects is studied and the underlying mechanisms of this relation are explored. Secondly, the life experiences of the youngsters in the sport context, that may contribute to skill development, are studied. Thirdly, social conditions for a positive effect are explored, as sport is likely to have a positive effect under specific conditions. Fourthly, this study aims to provide insights on the elements of successful partnerships between youth care organisations and local sport clubs. METHODS AND DESIGN: This protocol reports on a mixed method study. An intervention that aims to increase the sport participation of socially vulnerable youth, between 12-23 years old, is implemented in three regions of a Rotterdam youth care organisation. The youngsters in the two control regions receive care-as-usual. The main outcome variables, collected via questionnaires, are the life prospect, sense of coherence and self-regulation skills of the youngsters after 6 and 18 months of follow-up. The Motivational Climate Scale is administered to explore the social conditions for a positive effect and interviews are conducted with sport coaches to explore their role in skill development. Interviews with the youngsters are conducted to gain insight on the life experiences that may lead to skill development. The elements of successful partnerships are collected during interviews with youth care professionals, sport coaches and other stakeholders in the sport context. DISCUSSION: The results of this study can support efforts of youth care organisations and local sport clubs to improve the life prospects of socially vulnerable youth through sport participation. TRIAL REGISTRATION: Trialregister.nl NTR4621 Date of Registration: 2 June 2014. PMID- 25011431 TI - Ten-year longitudinal study of thyroid function in children with Down's syndrome. AB - BACKGROUND/AIMS: The natural history of thyroid function in children with Down's syndrome is relatively unknown. We hypothesized that in these patients the occurrence of thyroid dysfunction rises during development. METHODS: Thyroid function was assessed yearly in 145 children with Down's syndrome, all followed from birth up to 10 years of age. Heteroskedastic binary and ordinary logistic regression for repeated measures was used to evaluate the relationship of thyroid function with continuous time. RESULTS: Congenital hypothyroidism was detected in 7% of cases. The probability of acquired thyroid dysfunction increased from 30% at birth to 49% at 10 years (p < 0.001). The subclinical hypothyroidism was nearly stable during the follow-up. The probability of hypothyroidism increased from 7 to 24% at 10 years (p < 0.001). Positive anti-thyroglobulin antibodies were associated with higher odds of more severe hypothyroidism (odds ratio 3.6). Positive anti-thyroid peroxidase antibodies were a better predictor of more severe hypothyroidism (odds ratio 6.1). Diffuse hypoechogenicity on thyroid ultrasound was found in 34 out of 145 children. CONCLUSION: The probability of thyroid dysfunction increasing during development is higher than previously reported. Such children should be carefully monitored annually to early identify thyroid dysfunction. PMID- 25011432 TI - Abnormal downward gaze and cold caloric examination due to propofol: a case study. AB - BACKGROUND: An adolescent girl had isolated abnormal downward gaze and oculovestibular (cold caloric) testing during propofol administration, prompting concern for brainstem abnormality. PATIENT: An otherwise healthy 16-year-old girl presented after an intentional hanging. Brainstem reflexes were normal except that both eyes exhibited tonic downward gaze on initial examination. After propofol was suspended for 30 minutes in order to evaluate her level of responsiveness, her eyes normalized to midposition from tonic downward gaze. With reinitiation of propofol, the eyes returned to the former downward position. C collar stabilization prohibited the usual oculocephalic (doll's eyes) evaluation. Right-sided cold water instillation resulted in right eye exodeviation to the right with minimal medial movement of the left eye to the right. After left-sided cold water instillation, the left eye deviated downward with minimal medial deviation of the right eye. She was extubated and off sedatives within 48 hours of admission, and normal ocular motility returned. CONCLUSION: This patient exhibited abnormal ocular motility and cold caloric response with single-agent propofol exposure. The remainder of her cranial nerve examination was normal, and her normal imaging studies and prompt resolution led us to suspect a propofol effect. Physicians should be aware of the pharmacologic alterations of ocular motility and cold caloric testing when propofol is administered. PMID- 25011433 TI - Effects of neuromuscular electrical stimulation on the wrist and finger flexor spasticity and hand functions in cerebral palsy. AB - PURPOSE: To evaluate the effects of neuromuscular electrical stimulation on wrist range of motion, wrist and finger flexor spasticity, and hand functions in patients with unilateral cerebral palsy. METHOD: Twenty-four children with unilateral spastic cerebral palsy (14 boys and 10 girls) between the ages of 5 and 14 years were randomized into neuromuscular electrical stimulation and control groups. Conventional exercises were applied, and static volar wrist-hand orthosis was administered to all patients 5 days a week for 6 weeks. Additionally, 30-minute neuromuscular electrical stimulation sessions were applied to the wrist extensor muscles in the neuromuscular electrical stimulation group. Patients were evaluated by Zancolli Classification System, Manual Ability Classification System, and Abilhand-Kids Test. RESULTS: Compared with baseline, a significant increase was evident in active wrist extension angle at the fourth and sixth weeks in both groups (all P < 0.001), more prominent in the neuromuscular electrical stimulation group at the fourth and sixth weeks (P = 0.015 and P = 0.006, respectively). A decrease was observed in the spasticity values in the neuromuscular electrical stimulation group at the fourth and sixth weeks (P = 0.002 and P = 0.001, respectively) and in the control group only at the sixth week (P = 0.008). Abilhand-Kids values improved only in the neuromuscular electrical stimulation group (P < 0.001). CONCLUSION: Neuromuscular electrical stimulation application in addition to conventional treatments is effective in improving active wrist range of motion, spasticity, and hand functions in cerebral palsy. PMID- 25011434 TI - OTC gene in ornithine transcarbamylase deficiency: clinical course and mutational spectrum in seven Korean patients. AB - BACKGROUND: Ornithine transcarbamylase deficiency, an inborn error of metabolism, is the most common urea cycle disorder and is caused by mutations in the OTC gene located on Xp21. In this study, the clinical and genetic characteristics of seven Korean patients with ornithine transcarbamylase deficiency were analyzed. METHODS: During 2009-2012, a total of seven patients (three male and four female patients) from six unrelated families were diagnosed with ornithine transcarbamylase deficiency by biochemical or molecular analysis. OTC gene sequencing analysis was performed in six of these patients. Clinical manifestations, clinical courses, and the results of genetic studies were reviewed retrospectively. RESULTS: The median follow-up period for the seven patients with ornithine transcarbamylase deficiency was 44 months (11.9-150 months). Clinical manifestations of ornithine transcarbamylase deficiency included vomiting and seizure, which were the most frequent signs at admission. Two of the four heterozygous female patients (50%) experienced severe neurological sequelae. The early onset male patient characterized severe neurological deficits. The late-onset male patient recovered completely from acute encephalopathy and coma without any neurological deficits. Direct sequencing and multiplex ligation-dependent probe amplification analysis of OTC gene revealed five different mutations. Of these mutations, two were novel (c.867 3T>C and c.664_667delinsAC). CONCLUSION: Ornithine transcarbamylase deficiency was genetically heterogeneous in the seven Korean patients with confirmed ornithine transcarbamylase deficiency diagnosis by biochemical findings and/or genetic analysis, together with two novel mutations in the OTC gene. We hope that these data will contribute to a better understanding of the clinical course and distinct molecular genetic characteristics of Korean patients with ornithine transcarbamylase deficiency. PMID- 25011435 TI - Neurocutaneous melanosis: an illustrative patient. PMID- 25011436 TI - High-dose rosuvastatin treatment for multifocal stroke in trauma-induced cerebral fat embolism syndrome: a case report. AB - BACKGROUND: Fat embolism syndrome is a life-threatening condition with treatment centering on the provision of excellent supportive care and early fracture fixation. No pharmacologic intervention has yet shown any clear benefit. We used high-dose rosuvastatin specifically for its anti-inflammatory effects to treat a patient with severe fat embolism syndrome. We also suggest that magnetic resonance imaging and transcranial Doppler studies are helpful in establishing the diagnosis and for monitoring the patient's course. PATIENT: A 17-year-old boy developed severe cerebral fat embolism syndrome with multifocal strokes after sustaining bilateral femur fractures. RESULTS: In spite of profound and prolonged neurological impairment, our patient experienced dramatic recovery by the time he was discharged from inpatient rehabilitation several weeks after his initial injury. Magnetic resonance imaging revealed the classic "starfield" pattern of infarcts on diffusion-weighted sequences early in the illness. Additionally, serial transcranial Doppler studies demonstrated dramatically elevated microembolic events that resolved completely during the course of treatment. CONCLUSION: We feel that the acute administration of high-dose rosuvastatin early in the development of our patient's illness may have contributed to his ultimate recovery. Therapeutic guidelines cannot be extrapolated from a single patient, but our experience suggests that statin therapy could be potentially beneficial for individuals with severe fat embolism syndrome, and this approach deserves further clinical evaluation. Additionally, the diagnosis and monitoring of cerebral involvement in fat embolism syndrome is facilitated by both magnetic resonance imaging and transcranial Doppler studies. PMID- 25011437 TI - Prognostic usefulness of derived T2-weighted fetal magnetic resonance imaging measurements in congenital diaphragmatic hernia. AB - OBJECTIVE: To determine the usefulness of various parameters based on T2-weighted fetal magnetic resonance (MR) imaging measurements of the uninvolved lung for the neonatal prognosis of congenital diaphragmatic hernia (CDH). MATERIAL AND METHODS: We used ultrasonography and MR imaging to study 28 fetuses with CDH. We retrospectively analyzed a) on fetal ultrasonography, the observed-to-expected lung to head ratio (O/E LHR) and the position of the liver, and b) on fetal MR imaging, the lung-liver signal ratio (LLSR) and the lungcerebrospinal fluid ratio (L/CSF SR). To determine the prognostic value of these parameters, we compared them with the following postnatal parameters: survival, pulmonary hypertension, need for oxygen supplementation, and need for extracorporeal membrane oxygenation. RESULTS: We found significant differences between O/E LHR and the need for postnatal extracorporeal membrane oxygenation (P=.033) and postnatal survival (P=.01). We also found significant differences in LLSR between fetuses that survived more than 45 days and those that died within 45 days (1.91 vs. 2.56; P=.039). CONCLUSIONS: In fetuses with CDH, the LLSR correlates with postnatal survival and can potentially be used as a prognostic parameter in CDH. PMID- 25011438 TI - Polyoxometalate-functionalized metal-organic frameworks with improved water retention and uniform proton-conducting pathways in three orthogonal directions. AB - Polyoxometalate-functionalized metal-organic frameworks featuring uniform proton conducting pathways in three orthogonal directions, good water retention and stability were prepared. The proton conductivity of the hybrid material was observed to increase by 5 orders of magnitude compared to that of the parent material HKUST-1. PMID- 25011439 TI - FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in Europe and a leading cause of cancer-related death. Almost 50% of patients with CRC develop liver metastases, which heralds a poor prognosis unless metastases can be downsized to surgical resection or ablation. The FOXFIRE trial examines the hypothesis that combining radiosensitising chemotherapy (OxMdG: oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres(r); Sirtex Medical Limited, North Sydney, Australia) as a first-line treatment for liver dominant metastatic CRC will improve clinical outcomes when compared to OxMdG chemotherapy alone. METHODS/DESIGN: FOXFIRE is an open-label, multicentre, randomised controlled trial of OxMdG with or without the addition of SIRT (1:1 randomisation). Eligible adult patients have histologically confirmed colorectal adenocarcinoma, liver metastases measurable on computed tomography scan and untreatable by either surgical resection or local ablation, and they may have limited extra-hepatic disease, defined as <=5 nodules in the lung and/or one other metastatic site which is amenable to future definitive treatment. Eligible patients may have received adjuvant chemotherapy following resection of the primary tumour, but are not permitted to have previously received chemotherapy for metastatic disease, and must have a life expectancy of >=3 months and a WHO performance status of 0-1. The primary outcome is overall survival. Secondary outcomes include progression free survival (PFS), liver-specific PFS, patient reported outcomes, safety, response rate, resection rate and cost-effectiveness. FOXFIRE shares a combined statistical analysis plan with an international sister trial called SIRFLOX. DISCUSSION: This trial is establishing a network of SIRT centres and 'feeder' chemotherapy-only centres to standardise the delivery of SIRT across the whole of the UK and to provide greater equity of access to this highly specialised liver-directed therapy. The FOXFIRE trial will establish the potential role of adding SIRT to first-line chemotherapy for unresectable liver metastatic colorectal cancer, and the impact on current treatment paradigms for metastatic CRC. TRIAL REGISTRATION: ISRCTN83867919. PMID- 25011440 TI - Fit-for-purpose curated database application in mass spectrometry-based targeted protein identification and validation. AB - BACKGROUND: Mass spectrometry (MS) is a very sensitive and specific method for protein identification, biomarker discovery, and biomarker validation. Protein identification is commonly carried out by comparing MS data with public databases. However, with the development of high throughput and accurate genomic sequencing technology, public databases are being overwhelmed with new entries from different species every day. The application of these databases can also be problematic due to factors such as size, specificity, and unharmonized annotation of the molecules of interest. Current databases representing liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based searches focus on enzyme digestion patterns and sequence information and consequently, important functional information can be missed within the search output. Protein variants displaying similar sequence homology can interfere with database identification when only certain homologues are examined. In addition, recombinant DNA technology can result in products that may not be accurately annotated in public databases. Curated databases, which focus on the molecule of interest with clearer functional annotation and sequence information, are necessary for accurate protein identification and validation. Here, four cases of curated database application have been explored and summarized. FINDINGS: The four presented curated databases were constructed with clear goals regarding application and have proven very useful for targeted protein identification and biomarker application in different fields. They include a sheeppox virus database created for accurate identification of proteins with strong antigenicity, a custom database containing clearly annotated protein variants such as tau transcript variant 2 for accurate biomarker identification, a sheep-hamster chimeric prion protein (PrP) database constructed for assay development of prion diseases, and a custom Escherichia coli (E. coli) flagella (H antigen) database produced for MS-H, a new H-typing technique. Clearly annotating the proteins of interest was essential for highly accurate, specific, and sensitive sequence identification, and searching against public databases resulted in inaccurate identification of the sequence of interest, while combining the curated database with a public database reduced both the confidence and sequence coverage of the protein search. CONCLUSION: Curated protein sequence databases incorporating clear annotations are very useful for accurate protein identification and fit-for purpose application through MS-based biomarker validation. PMID- 25011441 TI - Developing a scale to measure family dynamics related to long-term care, and testing that scale in a multicenter cross-sectional study. AB - BACKGROUND: As Japan's population ages, more frail elderly people are cared for by members of their family. The dynamics within such families are difficult to study, in part because they are difficult to quantify. We developed a scale for assessing family dynamics related to long-term care. Here we report on the development of that scale, and we present the results of reliability testing and validation testing. METHODS: Two primary-care specialists drafted questions about family dynamics, and discussed them with other primary-care physicians and clinical researchers. The final questionnaire asked about four problems or undesirable situations: disengagement (emotional distance), scapegoating (inappropriate blame), transfer of problems across generations (transfer of unnecessary burden from older to younger generations, trans-generationally displaced revenge), and undesirable behavior (co-dependence). Next, at six general-medicine clinics, doctors evaluated families that had a caregiver and a patient requiring long-term care. The results were analyzed by factor analysis. Cronbach's alpha was computed, and criterion-related validation tests were done with three types of criteria: relationship before caregiving, ability to do activities of daily living (ADL), and the duration of care. RESULTS: Results were obtained from 199 families. Among the caregivers, 79% were women and their mean age was 63 years. Among the patients, 71% were women and their mean age was 84 years. The results of factor analysis indicated that the scale was unidimensional. Cronbach's alpha was 0.73. Not having a good relationship before caregiving was associated with significantly worse family dynamics scores, as was greater dependence regarding ADL. CONCLUSIONS: We developed a scale that enables physicians to assess the dynamics of families with a patient and a family caregiver. The scale's scores are reliable and the results of validation testing were generally good. This scale holds promise as a tool both for research and for primary-care practice. PMID- 25011443 TI - Metabolite markers of incident CKD risk. PMID- 25011442 TI - Serum metabolomic profiling and incident CKD among African Americans. AB - BACKGROUND AND OBJECTIVES: Novel biomarkers that more accurately reflect kidney function and predict future CKD are needed. The human metabolome is the product of multiple physiologic or pathophysiologic processes and may provide novel insight into disease etiology and progression. This study investigated whether estimated kidney function would be associated with multiple metabolites and whether selected metabolomic factors would be independent risk factors for incident CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 1921 African Americans free of CKD with a median of 19.6 years follow-up among the Atherosclerosis Risk in Communities Study were included. A total of 204 serum metabolites quantified by untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry was analyzed by both linear regression for the cross-sectional associations with eGFR (specified by the Chronic Kidney Disease Epidemiology Collaboration equation) and Cox proportional hazards model for the longitudinal associations with incident CKD. RESULTS: Forty named and 34 unnamed metabolites were found to be associated with eGFR specified by the Chronic Kidney Disease Epidemiology Collaboration equation with creatine and 3 indoxyl sulfate showing the strongest positive (2.8 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, 2.1 to 3.5) and negative association (-14.2 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, -17.0 to -11.3), respectively. Two hundred four incident CKD events with a median follow-up time of 19.6 years were included in the survival analyses. Higher levels of 5-oxoproline (hazard ratio, 0.70; 95% confidence interval, 0.60 to 0.82) and 1,5-anhydroglucitol (hazard ratio, 0.68; 95% confidence interval, 0.58 to 0.80) were significantly related to lower risk of incident CKD, and the associations did not appreciably change when mutually adjusted. CONCLUSIONS: These data identify a large number of metabolites associated with kidney function as well as two metabolites that are candidate risk factors for CKD and may provide new insights into CKD biomarker identification. PMID- 25011444 TI - Total cholesterol and neuropsychiatric symptoms in Alzheimer's disease: the impact of total cholesterol level and gender. AB - BACKGROUND: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are a major factor in nursing home placement and a primary cause of stress for caregivers. Elevated cholesterol has been linked to psychiatric disorders and has been shown to be a risk factor for AD and to impact disease progression. The present study investigated the relationship between cholesterol and NPS in AD. METHODS: Data on cholesterol and NPS from 220 individuals (144 females, 76 males) with mild-to-moderate AD from the Texas Alzheimer's Research and Care Consortium (TARCC) cohort were analyzed. The total number of NPS and symptoms of hyperactivity, psychosis, affect and apathy were evaluated. Groups based on total cholesterol (TC; >=200 vs. <200 mg/dl) were compared with regard to NPS. The impact of gender was also assessed. RESULTS: Individuals with high TC had lower MMSE scores as well as significantly more NPS and more symptoms of psychosis. When stratified by gender, males with high TC had significantly more NPS than females with high TC or than males or females with low TC. CONCLUSION: The role of elevated cholesterol in the occurrence of NPS in AD appears to be gender and symptom specific. A cross-validation of these findings will have implications for possible treatment interventions, especially for males with high TC. PMID- 25011445 TI - Which should be the essential components of stroke centers in Japan? A survey by questionnaires sent to the directors of facilities certified by the Japan stroke society. AB - BACKGROUND: We conducted a survey by questionnaire to identify the essential components of stroke centers in Japan and compared our results with the European Expert Survey. METHODS: In 2007, a questionnaire was mailed to the directors of 740 facilities certified by the Japan Stroke Society to ask their opinion on the essential components of comprehensive stroke centers (CSC), primary stroke centers (PSC) and any hospital ward (AHW) admitting acute stroke patients. The directors were asked to provide 1 of the following 6 possible answers regarding 112 components: 'irrelevant'; 'useful but not necessary'; 'desirable'; 'important but not absolutely necessary'; 'absolutely necessary', or 'question unclear or ambiguous'. The components considered 'absolutely necessary' by more than 75% of the respondents were compared between our survey and the European Expert Survey. In addition, we compared the rates of neurosurgeons and neurologists who answered 'absolutely necessary' with regard to each component. RESULTS: Responses were obtained from 428 directors (57.8% response rate). Among these respondents, 298 (69.6%) were neurosurgeons. There was no component considered 'absolutely necessary' for AHW by more than 75% of the respondents, and this was similar to the results of the European Expert Survey. The following components were considered 'absolutely necessary' for PSC in our survey: brain CT scanning 24 h a day, 7 days a week (24/7); automated monitoring of the ECG, pulse oximetry, blood pressure and breathing, and respiratory support. In both our survey and the European Expert Survey, the essential components for CSC were as follows: physiotherapist; brain CT scanning 24/7; monitoring of the ECG, pulse oximetry and blood pressure; carotid surgery; angioplasty and stenting, and intravenous recombinant tissue plasminogen activator protocols. The components multidisciplinary stroke team, stroke-trained nurse, ultrasonography, collaboration with an outside rehabilitation center, stroke pathway and clinical research were deemed essential only in the European Expert Survey. However, MRI 24/7, MR angiography 24/7, conventional angiography 24/7, respiratory support as well as most neuroendovascular and neurosurgical treatments were considered necessary for CSC by more than 75% of the respondents in our survey. Analyzing the responses from only neurologists reduced the differences between our survey and the European Expert Survey. CONCLUSIONS: The present study indicated the essential components expected for stroke centers in Japan. Our survey demonstrated that more emphasis was likely to be placed on installations than on a dedicated stroke team and the use of stroke care maps. In addition, the results of this study may reflect some characteristics of the stroke care environment in Japan, such as the predominance of neurosurgeons and widespread use of MRI. PMID- 25011446 TI - Dr. Roy Bakay and the modern era of neurosurgical mentorship. PMID- 25011447 TI - Spanish adaptation of the Illinois Sexual Harassment Myth Acceptance. AB - Sexual harassment is among the most serious forms of gender violence, and what all violent acts have in common are the many myths associated with them. Three studies were conducted to adapt a Spanish version of the Illinois Sexual Harassment Myth Acceptance (ISHMA) scale, which assesses myths about sexual harassment. The first study aimed to, for the first time, present psychometric data on the Spanish version of the ISHMA. The participants were 339 college students. After adapting the items and measuring their content validity, we examined the test's dimensional structure, statistically analyzed the items, and determined the instrument's reliability (alpha = .91 for the total scale and between .77 and .84 for the different dimensions). Study 2 involved 326 adult participants from the general population and its objective was to evaluate the scale's dimensional structure through confirmatory factor analysis (chi2 143 = 244.860, p < .001; GFI = .952; CFI = .958; RMSEA = .034 [.026 - .041]). The third study was conducted in order to measure convergent validity in both students and adults from the general population. Differences by gender were found in all dimensions being the females' means higher than males (Cohen's d between .38 and .62). Our findings suggest the Spanish version of the ISHMA is a useful instrument to study myths about sexual harassment. PMID- 25011448 TI - Physicians' engagement in dual practices and the effects on labor supply in public hospitals: results from a register-based study. AB - BACKGROUND: Physician dual practice, a combination of public and private practice, has attracted attention due to fear of reduced work supply and a lack of key personnel in the public system, increase in low priority treatments, and conflicts of interest for physicians who may be competing for their own patients when working for private suppliers. In this article, we analyze both choice of dual practice among hospital physicians and the dual practices' effect on work supply in public hospitals. METHODS: The sample consisted of 12,399 Norwegian hospital physicians working in public hospitals between 2001 and 2009. We linked hospital registry data on salaries and hospital working hours with data from national income and other registries covering non-hospital income, including income from dual work, cohabiting status, childbirths and socioeconomic characteristics. Our dataset also included hospital variables describing i.e. workload. We estimated odds ratio for choosing dual practice and the effects of dual practice on public working hours using different versions of mixed models. RESULTS: The percentage of physicians engaged in dual practice fell from 35.1% for men and 17.6% for women in 2001 to 25.0% and 14.2%, respectively, in 2009. For both genders, financial debt and interest payments were positively correlated and having a newborn baby was negatively correlated with engaging in dual practice. Larger family size and being cohabitating increased the odds ratio of dual practice among men but reduced it for women. The most significant internal hospital factor for choosing dual practice was high wages for extended working hours, which significantly reduced the odds ratio for dual practice. The total working hours in public hospitals were similar for both those who did and did not engage in dual practice; however, dual practice reduced public working hours in some specialties. CONCLUSION: Economic factors followed by family variables are significant elements influencing dual practice. Although our findings indicate that engagement in dual practice by public hospital physicians in a well regulated market may increase the total labor supply, this may vary significantly between medical specialties. PMID- 25011449 TI - Novel Cul3 binding proteins function to remodel E3 ligase complexes. AB - BACKGROUND: Cullins belong to a family of scaffold proteins that assemble multi subunit ubiquitin ligase complexes to recruit protein substrates for ubiquitination via unique sets of substrate adaptor, such as Skp1 or Elongin B, and a substrate-binding protein with a conserved protein-protein interacting domain, such as leucine-rich repeats (LRR), a WD40 domain, or a zinc-finger domain. In the case of the Cullin3 (Cul3), it forms a BTB-Cul3-Rbx1 (BCR) ubiquitin ligase complex where it is believed that a BTB domain-containing protein performs dual functions where it serves as both the substrate adaptor and the substrate recognition protein. RESULTS: Tandem affinity purification and LC/MS-MS analysis of the BCR complex led to the identification of 10,225 peptides. After the SEQUEST algorithm and CDART program were used for protein identification and domain prediction, we discovered a group of Cul3-bound proteins that contain either the LRR or WD40 domain (CLWs). Further biochemical analysis revealed that the LRR domain-containing CLWs could bind both Cul3 and BTB domain-containing proteins. The dual binding role for the LRR domain containing CLWs results in causing the BTB-domain protein to become a substrate instead of an adaptor.To further distinguish potential substrates from other components that are part of the BCR ubiquitin ligase complex, we altered the parameters in the SEQUEST algorithm to select for peptide fragments with a modified lysine residue. This method not only identifies the potential substrates of the BCR ubiquitin ligase complex, but it also pinpoints the lysine residue in which the post-translational modification occurs. Interestingly, none of the CLWs were identified by this method, supporting our hypothesis that CLWs were not potential substrates but rather additional components of the BCR ubiquitin ligase complex. CONCLUSION: Our study identified a new set of Cul3-binding proteins known as CLWs via tandem affinity purification and LC/MS-MS analysis. Subsequently, our biochemical analysis revealed that some CLWs modify binding of BTB domain-containing proteins to the complex, causing degradation of the BTB domain-containing protein. As these CLWs were excluded from our list of substrates, we propose that CLWs serve as unique Cul3 binding proteins that provide an alternative regulatory mechanism for the complex. PMID- 25011451 TI - Alcohol and cardiovascular disease. PMID- 25011452 TI - An elderly woman with postprandial abdominal pain. PMID- 25011453 TI - Thyroid hormone levels and incident chronic kidney disease in euthyroid individuals: the Kangbuk Samsung Health Study. AB - BACKGROUND: Overt and subclinical hypothyroidism are associated with higher levels of serum creatinine and with increased risk of chronic kidney disease (CKD). The prospective association between thyroid hormones and kidney function in euthyroid individuals,however, is largely unexplored. METHODS: We conducted a prospective cohort study in 104 633 South Korean men and women who were free of CKD and proteinuria at baseline and had normal thyroid hormone levels and no history of thyroid disease or cancer. At each annual or biennial follow-up visit, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxin (FT4) levels were measured by radioimmunoassay. The study outcome was incident CKD, defined as an estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: After a median follow-up of 3.5 years, 1032 participants developed incident CKD.There was a positive association between high-normal levels of TSH and increased risk of incident CKD. In fully-adjusted models including baseline eGFR, the hazard ratio comparing the highest vs the lowest quintiles of TSH was 1.26 [95% confidence interval (CI) 1.02 to 1.55; P for linear trend=0.03]. In spline models, FT3 levels below 3 pg/ml were also associated with increased risk of incident CKD. There was no association between FT4 levels and CKD. CONCLUSIONS: In a large cohort of euthyroid men and women, high levels of TSH and low levels of FT3, even within the normal range, were modestly associated with an increased risk of incident CKD. PMID- 25011454 TI - Cohort Profile: Footprints in Time, the Australian Longitudinal Study of Indigenous Children. AB - Indigenous Australians experience profound levels of disadvantage in health, living standards, life expectancy, education and employment, particularly in comparison with non-Indigenous Australians. Very little information is available about the healthy development of Australian Indigenous children; the Longitudinal Study of Indigenous Children (LSIC) is designed to fill this knowledge gap.This dataset provides an opportunity to follow the development of up to 1759 Indigenous children. LSIC conducts annual face-to-face interviews with children (aged 0.5-2 and 3.5-5 years at baseline in 2008) and their caregivers. This represents between 5% and 10% of the total population of Indigenous children in these age groups, including families of varied socioeconomic and cultural backgrounds. Study topics include: the physical, social and emotional well-being of children and their caregivers; language; culture; parenting; and early childhood education.LSIC is a shared resource, formed in partnership with communities; its data are readily accessible through the Australian Government Department of Social Services (see http://dss.gov.au/lsic for data and access arrangements). As one of very few longitudinal studies of Indigenous children, and the only national one, LSIC will enable an understanding of Indigenous children from a wide range of environments and cultures. Findings from LSIC form part of a growing infrastructure from which to understand Indigenous child health. PMID- 25011455 TI - Cohort Profile: The Yorkshire Health Study. AB - The Yorkshire Health Study is a longitudinal observational regional health study collecting health information on the residents from the Yorkshire and Humberside region in England. The second wave of data collection is currently under way. The study aims to inform National Health Service (NHS) and local authority health related decision making in Yorkshire, with wider implications from findings as well. The first wave contains records for 27 806 individuals (2010-12), aged between 16 and 85, from one part of Yorkshire (South Yorkshire), with the second wave expanding data collection to the whole of the Yorkshire and Humberside region. Data were collected on current and long-standing health, health care usage and health-related behaviours, with a particular focus on weight and weight management. The majority of individuals have also given consent for record linkage with routine clinical data, allowing the linking to disease diagnosis, medication use and health care usage. The study encourages researchers to utilize the sample through the embedding of randomized controlled trials, other controlled trials and qualitative studies. To access the anonymized data or use the sample to recruit participants to studies, researchers should contact Clare Relton (c.relton@sheffield.ac.uk). PMID- 25011450 TI - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. AB - OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 ( 1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to 0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health. PMID- 25011456 TI - Generation and characterization of a new mammalian cell line continuously expressing virus-like particles of Japanese encephalitis virus for a subunit vaccine candidate. AB - BACKGROUND: Japanese encephalitis virus (JEV) is the most important cause of epidemic encephalitis in most Asian regions. There is no specific treatment available for Japanese encephalitis, and vaccination is the only effective way to prevent JEV infection in humans and domestic animals. The purpose of this study is to establish a new mammalian cell line stably and efficiently expressing virus like particle of JEV for potential use of JEV subunit vaccine. RESULTS: We generated a new cell clone (BJ-ME cells) that stably produces a secreted form of Japanese encephalitis virus (JEV) virus-like particle (VLP). The BJ-ME cells were engineered by transfecting BHK-21 cells with a code-optimized cDNA encoding JEV prM and E protein expression plasmid. Cell line BJ-ME can stably produces a secreted form of Japanese encephalitis virus virus-like particle (JEV-VLP) which contains the JEV envelope glycoprotein (E) and membrane protein (M). The amount of JEV-VLP antigen released into the culture fluid of BJ-ME cells was as high as 15-20 MUg/ml. JEV-VLP production was stable after multiple cell passages and 100% cell expression was maintained without detectable cell fusion or apoptosis. Cell culture fluid containing the JEV-VLP antigen could be harvested five to seven times continuously at intervals of 4-6 days while maintaining the culture. Mice immunized with the JEV-VLP antigen with or without adjuvant developed high titers of neutralizing antibodies and 100% protection against lethal JEV challenge. CONCLUSION: These results suggest that the recombinant JEV-VLP antigen produced by the BJ-ME cell line is an effective, safe and affordable subunit Japanese encephalitis vaccine candidate, especially for domestic animals such as pig and horse. PMID- 25011457 TI - Cancers of the lung, head and neck on the rise: perspectives on the genotoxicity of air pollution. AB - Outdoor air pollution has been recently classified as a class I human carcinogen by the World Health Organization (WHO). Cumulative evidence from across the globe shows that polluted air is associated with increased risk of lung, head and neck, and nasopharyngeal cancers--all of which affect the upper aerodigestive tract. Importantly, these cancers have been previously linked to smoking. In this article, we review epidemiologic and experimental evidence of the genotoxic and mutagenic effects of air pollution on DNA, purportedly a key mechanism for cancer development. The alarming increase in cancers of the upper aerodigestive tract in Asia suggests a need to focus government efforts and research on reducing air pollution, promoting clean energy, and investigating the carcinogenic effects of air pollution on humans. PMID- 25011459 TI - The incidences and mortalities of major cancers in China, 2010. AB - To estimate the cancer incidences and mortalities in China in 2010, the National Central Cancer Registry (NCCR) of China evaluated data for the year of 2010 from 145 qualified cancer registries covering 158,403,248 people (92,433,739 in urban areas and 65,969,509 in rural areas). The estimates of new cancer cases and cancer deaths were 3,093,039 and 1,956,622 in 2010, respectively. The percentage of morphologically verified cases were 67.11%; 2.99% of incident cases were identified through death certification only, with the mortality to incidence ratio of 0.61. The crude incidence was 235.23/100,000 (268.65/100,000 in males and 200.21/100,000 in females). The age-standardized rates by Chinese standard population (ASR China) and by world standard population (ASR world) were 184.58/100,000 and 181.49/100,000, respectively, with a cumulative incidence (0 74 years old) of 21.11%. The crude cancer mortality was 148.81/100,000 (186.37/100,000 in males and 109.42/100,000 in females). The ASR China and ASR world were 113.92/100,000 and 112.86/100,000, respectively, with a cumulative mortality of 12.78%. Lung, breast, gastric, liver, esophageal, colorectal, and cervical cancers were the most common cancers. Lung, liver, gastric, esophageal, colorectal, breast, and pancreatic cancers were the leading causes of cancer deaths. The coverage of cancer registration has rapidly increased in China in recent years and may reflect more accurate cancer burdens among populations living in different areas. Given the increasing cancer burden in the past decades, China should strengthen its cancer prevention and control. PMID- 25011458 TI - Epidemiologic studies of particulate matter and lung cancer. AB - Particulate matter (PM) plays an important role in air pollution, especially in China. European and American researchers conducted several cohort-based studies to examine the potential relationship between PM and lung cancer and found a positive association between PM and lung cancer mortality. In contrast, the results regarding PM and lung cancer risk remain inconsistent. Most of the previous studies had limitations such as misclassification of PM exposure and residual confounders, diminishing the impact of their findings. In addition, prospective studies on this topic are very limited in Chinese populations. This is an important problem because China has one of the highest concentrations of PM in the world and has had an increased mortality risk due to lung cancer. In this context, more prospective studies in Chinese populations are warranted to investigate the relationship between PM and lung cancer. PMID- 25011460 TI - The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors. AB - Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS GCTs. PMID- 25011461 TI - Giant myxoinflammatory fibroblastic sarcoma with bone invasion: a very rare clinical entity and literature review. AB - Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade, malignant soft tissue tumor that is usually observed in the extremities of adult patients. Magnetic resonance imaging findings for this tumor type have rarely been reported. We report a case involving the distal left femur of a middle-aged man and tumoral invasion of the bone, which, to our knowledge, has been previously described only once. He was treated with distal femoral tumor resection and reconstruction with a modular prosthesis. Histopathologic diagnosis confirmed MIFS. We reviewed literature of the diagnostic imaging and bone invasion findings associated with this tumor type. PMID- 25011462 TI - Support groups and cardiac rehabilitation: effects of partner participation on anxiety and depression. AB - This study analyzes the effect on levels of patient anxiety and depression of a partner joining a cardiac rehabilitation program support group, also taking into account the sex of the patient. The study was undertaken using a two-group comparison design with pre-and post-test measures in non-equivalent groups. The sample comprised patients in the cardiac rehabilitation program (CRP) at the Ramon y Cajal Hospital, Madrid (Spain). Analysis of covariance (ANCOVA) showed direct effects of sex and partner participation in support groups on the anxiety trait. Similarly, interaction effects were observed between the sex variable and partner participation. These results indicate the pertinence of designing separate groups for patients and partners. PMID- 25011463 TI - Brushing cytology of the biliary tract: bile juice from the ERCP sheath tube provides cell-rich smear samples. AB - OBJECTIVES: To improve the diagnostic accuracy of bile smear cytology, we assessed two cell-yielding procedures. STUDY DESIGN: One hundred and forty-one patients with biliary stricture underwent endoscopic retrograde cholangiopancreatography (ERCP) and conventional brush sampling. The cytologist cut the brush head off the support wire, centrifuged it directly in tissue culture medium for 1 min at 3,000 rpm, centrifuged the medium again and then smeared the cell pellet onto slides. The remaining sheath tube was then cut into 12-cm segments, which were centrifuged in a centrifuge tube for 1 min at 3,000 rpm, collected and submitted for cytospin preparation. RESULTS: The final histopathological diagnoses based on surgery, biopsy or clinical progression were evaluated for sensitivity, specificity and accuracy. Using conventional smears alone, the sensitivity, specificity and accuracy in patients with biliary stricture were 66.1, 80.7 and 68.8%, respectively. For conventional smears, brush washing and sheath tube contents together, the sensitivity improved to 73.9%, specificity to 100% and accuracy to 78.7%. In the patients with bile duct carcinoma, the sensitivity, specificity and accuracy were 87.3, 100 and 90.7%, respectively. CONCLUSION: Superior diagnostic accuracy was achieved when conventional smear procedures were combined with the two new procedures. PMID- 25011464 TI - Molecular simulation of N-acetylneuraminic acid analogs and molecular dynamics studies of cholera toxin-Neu5Gc complex. AB - Cholera toxin (CT) is an AB5 protein complex secreted by the pathogen Vibrio cholera, which is responsible for cholera infection. N-acetylneuraminic acid (NeuNAc) is a derivative of neuraminic acid with nine-carbon backbone. NeuNAc is distributed on the cell surface mainly located in the terminal components of glycoconjugates, and also plays an important role in cell-cell interaction. In our current study, molecular docking and molecular dynamic (MD) simulations were implemented to identify the potent NeuNAc analogs with high-inhibitory activity against CT protein. Thirty-four NeuNAc analogs, modified in different positions C 1/C-2/C-4/C-5/C-7/C-8/C-9, were modeled and docked against the active site of CT protein. Among the 34 NeuNAc analogs, the analog Neu5Gc shows the least extra precision glide score of -9.52 and glide energy of -44.71 kcal/mol. NeuNAc analogs block the CT active site residues HIS:13, ASN:90, LYS:91, GLN:56, GLN:61, and TRP:88 through intermolecular hydrogen bonding. The MD simulation for CT Neu5Gc docking complex was performed using Desmond. MD simulation of CT-Neu5Gc complex reveals the stable nature of docking interaction. PMID- 25011465 TI - Obesity and appetite genes. PMID- 25011467 TI - Pathology or normal variant: what constitutes a delay in puberty? AB - Puberty is a complex maturation process that begins during fetal life and persists until the acquisition of reproduction function. The fundamental event that activates puberty occurs in the hypothalamus. A complex neuron network stimulates GnRH secretion, which stimulates pituitary gonadotropin secretion and then gonadal steroid secretion. Pubertal delay is defined as the presentation of clinical signs of puberty 2-2.5 SD later than in the normal population. Three major groups of etiopathogeneses are described: (1) hypogonadotropic hypogonadism, (2) hypergonadotropic hypogonadism, and (3) constitutional delay of puberty (CDP) - the most common cause of delayed puberty in boys. The differential diagnosis between CDP and isolated hypogonadotropic hypogonadism remains difficult. Mechanisms of pubertal timing are now better understood and genetic or epigenetic causes can explain some pubertal delays. However, there are still unexplained mechanisms. Treatment of delayed puberty is necessary to ensure full pubertal development for the adolescent and in case of hypogonadism, to restore fertility. Finally, precocious diagnosis of hypogonadism is primordial but can be difficult during childhood and in cases of partial hypogonadism. The study of genetic pubertal diseases or of different animal models could help to discover new diagnostic or therapeutic tools. PMID- 25011469 TI - Reasons for smoking among tri-ethnic daily and nondaily smokers. AB - INTRODUCTION: Nondaily smokers experience adverse effects from tobacco use, yet they have been understudied compared to daily smokers. Understanding how reasons for smoking (RS) differ by smoking level, gender, and race/ethnicity could inform tailored interventions. METHODS: A cross-sectional survey was administered through an online panel survey service to 2,376 current smokers who were at least 25 years of age. The sample was stratified to obtain equal numbers of 3 racial/ethnic groups (African American [AA], Latino, and White) across smoking level (native nondaily, converted nondaily, daily light, and daily moderate/heavy). RESULTS: A 7-factor structure of a 20-item Modified Reasons for Smoking Scale (MRSS) was confirmed (each subscale alpha > 0.80). Each factor of the MRSS varied by smoking level, with nondaily smokers endorsing all RS less frequently than daily smokers (p < .0001). The 4 smoker subgroups incrementally differed from one another (p < .05) with several exceptions between converted nondaily and daily light smokers. Males reported stronger RS on 5 out of 7 reasons (p < .05). Females had higher scores on tension reduction/relaxation (p < .0001). Latinos reported stronger RS than Whites and AAs on all reasons (p < .05) except for tension reduction/relaxation (p > .05). AAs and Whites were comparable on all RS (p > .05). CONCLUSIONS: The present study highlights considerable variability across smoking level, gender, and race/ethnicity in strength of RS. Addressing subgroup differences in RS may contribute to more sensitive and effective prevention and treatment efforts. PMID- 25011468 TI - Neural signatures of autism spectrum disorders: insights into brain network dynamics. AB - Neuroimaging investigations of autism spectrum disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD sub-populations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data. PMID- 25011470 TI - Impairment of translation in neurons as a putative causative factor for autism. AB - BACKGROUND: A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage. PRESENTATION OF THE HYPOTHESIS: We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins. TESTING THE HYPOTHESIS: A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models. IMPLICATIONS OF THE HYPOTHESIS: It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence. REVIEWERS: This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev. PMID- 25011471 TI - Anti-inflammatory effect of caffeine is associated with improved lung function after lipopolysaccharide-induced amnionitis. AB - BACKGROUND: Although caffeine enhances respiratory control and decreases the need for mechanical ventilation and resultant bronchopulmonary dysplasia, it may also have anti-inflammatory properties in protecting lung function. OBJECTIVE: We hypothesized that caffeine improves respiratory function via an anti-inflammatory effect in lungs of a lipopolysaccharide (LPS)-induced pro-inflammatory amnionitis rat pup model. METHODS: Caffeine was given orally (10 mg/kg/day) from postnatal day (p)1 to p14 to pups exposed to intra-amniotic LPS or normal saline. Expression of IL-1beta was assessed in lung homogenates at p8 and p14, and respiratory system resistance (Rrs) and compliance (Crs) as well as CD68 cell counts and radial alveolar counts were assessed at p8. RESULTS: In LPS-exposed rats, IL-1beta and CD68 cell counts both increased at p8 compared to normal saline controls. These increases in pro-inflammatory markers were no longer present in caffeine-treated LPS-exposed pups. Rrs was higher in LPS-exposed pups (4.7 +/- 0.9 cm H2O/ml.s) at p8 versus controls (1.6 +/- 0.3 cm H2O/ml.s, p < 0.01). LPS-exposed pups no longer exhibited a significant increase in Rrs (2.8 +/ 0.5 cm H2O/ml.s) after caffeine. Crs did not differ significantly between groups, although radial alveolar counts were lower in both groups of LPS-exposed pups. CONCLUSIONS: Caffeine promotes anti-inflammatory effects in the immature lung of prenatal LPS-exposed rat pups associated with improvement of Rrs, suggesting a protective effect of caffeine on respiratory function via an anti inflammatory mechanism. PMID- 25011472 TI - Ready for a milk shake? PMID- 25011473 TI - CaMKII in cardiometabolic disease. PMID- 25011474 TI - Hepatogenic and neurogenic differentiation of bone marrow mesenchymal stem cells from abattoir-derived bovine fetuses. AB - BACKGROUND: Mesenchymal stem cells (MSC) are multipotent progenitor cells characterized by their ability to both self-renew and differentiate into tissues of mesodermal origin. The plasticity or transdifferentiation potential of MSC is not limited to mesodermal derivatives, since under appropriate cell culture conditions and stimulation by bioactive factors, MSC have also been differentiated into endodermal (hepatocytes) and neuroectodermal (neurons) cells. The potential of MSC for hepatogenic and neurogenic differentiation has been well documented in different animal models; however, few reports are currently available on large animal models. In the present study we sought to characterize the hepatogenic and neurogenic differentiation and multipotent potential of bovine MSC (bMSC) isolated from bone marrow (BM) of abattoir-derived fetuses. RESULTS: Plastic-adherent bMSC isolated from fetal BM maintained a fibroblast like morphology under monolayer culture conditions. Flow cytometric analysis demonstrated that bMSC populations were positive for MSC markers CD29 and CD73 and pluripotency markers OCT4 and NANOG; whereas, were negative for hematopoietic markers CD34 and CD45. Levels of mRNA of hepatic genes alpha-fetoprotein (AFP), albumin (ALB), alpha1 antitrypsin (alpha1AT), connexin 32 (CNX32), tyrosine aminotransferase (TAT) and cytochrome P450 (CYP3A4) were up-regulated in bMSC during a 28-Day period of hepatogenic differentiation. Functional analyses in differentiated bMSC cultures evidenced an increase (P < 0.05) in albumin and urea production and glycogen storage. bMSC cultured under neurogenic conditions expressed NESTIN and MAP2 proteins at 24 h of culture; whereas, at 144 h also expressed TRKA and PrPC. Levels of MAP2 and TRKA mRNA were up-regulated at the end of the differentiation period. Conversely, bMSC expressed lower levels of NANOG mRNA during both hepatogenic and neurogenic differentiation processes. CONCLUSION: The expression patterns of linage-specific markers and the production of functional metabolites support the potential for hepatogenic and neurogenic differentiation of bMSC isolated from BM of abattoir-derived fetuses. The simplicity of isolation and the potential to differentiate into a wide variety of cell lineages lays the foundation for bMSC as an interesting alternative for investigation in MSC biology and eventual applications for regenerative therapy in veterinary medicine. PMID- 25011476 TI - Spatial simulation of land use based on terrestrial ecosystem carbon storage in coastal Jiangsu, China. AB - This paper optimises projected land-use structure in 2020 with the goal of increasing terrestrial ecosystem carbon storage and simulates its spatial distribution using the CLUE-S model. We found the following: The total carbon densities of different land use types were woodland > water area > cultivated land > built-up land > grassland > shallows. Under the optimised land-use structure projected for 2020, coastal Jiangsu showed the potential to increase carbon storage, and our method was effective even when only considering vegetation carbon storage. The total area will increase by reclamation and the original shallows will be exploited, which will greatly increase carbon storage. For built-up land, rural land consolidation caused the second-largest carbon storage increase, which might contribute the most as the rural population will continue to decrease in the future, while the decrease of cultivated land will contribute the most to carbon loss. The area near the coastline has the greatest possibility for land-use change and is where land management should be especially strengthened. PMID- 25011475 TI - The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. AB - BACKGROUND: Patients with ER-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites. Aryl hydrocarbon receptor (AHR) ligands show promise as antimetastatic drugs for estrogen receptor (ER)-negative breast cancer. METHODS: Triple negative MDA-MB-231 breast cancer cells were treated with eight AHR-active pharmaceuticals including 4-hydroxtamoxifen, flutamide leflunomide, mexiletine, nimodipine, omeprazole, sulindac and tranilast, and the effects of these compounds on cell proliferation (MTT assay) and cell migration (Boyden chamber assay) were examined. The role of the AHR in mediating inhibition of MDA-MB-231 cell invasion was investigated by RNA interference (RNAi) and knockdown of AHR or cotreatment with AHR agonists. Lung metastasis of MDA-MB-231 cells was evaluated in mice administered cells by tail vein injection and prometastatic gene expression was examined by immunohistochemistry. RESULTS: We showed that only the proton pump inhibitor omeprazole decreased MDA-MB-231 breast cancer cell invasion in vitro. Omeprazole also significantly decreased MDA-MB-231 cancer cell metastasis to the lung in a mouse model (tail vein injection), and in vitro studies showed that omeprazole decreased expression of at least two prometastatic genes, namely matrix metalloproteinase-9 (MMP-9) and C-X-C chemokine receptor 4 (CXCR4). Results of RNA interference studies confirmed that omeprazole-mediated downregulation of CXCR4 (but not MMP-9) was AHR-dependent. Chromatin immunoprecipitation assays demonstrated that omeprazole recruited the AHR to regions in the CXCR4 promoter that contain dioxin response elements (DREs) and this was accompanied by the loss of pol II on the promoter and decreased expression of CXCR4. CONCLUSIONS: AHR-active pharmaceuticals such as omeprazole that decrease breast cancer cell invasion and metastasis may have important clinical applications for late stage breast cancer chemotherapy. PMID- 25011477 TI - Impact of smoking on the quantity and quality of antibodies induced by human papillomavirus type 16 and 18 AS04-adjuvanted virus-like-particle vaccine - a pilot study. AB - BACKGROUND: The AS04-adjuvanted bivalent L1 virus-like-particle (VLP) vaccine (CervarixTM) against infection with human papillomavirus (HPV) types 16/18 holds great promise to prevent HPV16/18 infections and associated neoplasias, but it is important to rule out significant co-factors of the neoplasias like smoking. METHODS: We conducted a pilot study to compare the quantity and quality of HPV16/18 antibody response at baseline and 7 months post vaccination in 104 non smoking and 112 smoking female participants vaccinated at 0, 1 and 6 months with CervarixTM (55 and 48 study participants) or with Hepatitis A vaccine (HAVRIXTM) (48 and 64 participants, respectively). These 216 women were a sub-sample of 4808 baseline 16- to 17-year old Finnish women initially enrolled in the double-blind, randomized controlled phase III PATRICIA trial. Following end-of-study unblinding in 2009 they were randomly chosen out of all the participants of the three major Finnish PATRICIA study sites in the Helsinki metropolitan area (University of Helsinki, N = 535, and Family Federation Finland, N = 432) and Tampere (University of Tampere, N = 428). Following enrolment, serum samples were collected at month 0 and month 7 post 1st vaccination shot, and were analysed for levels and avidity of IgG antibodies to HPV16 and HPV18 using standard and modified (4 M urea elution) VLP ELISAs. RESULTS: We found that at month 7 post vaccination women who smoked (cotinine level > 20 ng/ml) had levels of anti HPV16/18 antibodies comparable to those of non-smoking women. Low-avidity HPV16/18 IgG antibodies were observed in 16% of the vaccinated women, and active smoking conferred a three-fold increased risk (95% CI 1.0-9.3) of having the low avidity antibodies. CONCLUSION: Our data suggest that while smoking does not interfere with the quantity of vaccine-induced peak IgG levels, it may affect the avidity of IgG induced by HPV16/18 vaccination. PMID- 25011480 TI - Metal-organic frameworks (MOFs). PMID- 25011479 TI - Knowledge and acceptability of Chlamydia trachomatis screening among pregnant women and their partners; a cross-sectional study. AB - BACKGROUND: Chlamydia trachomatis infections in pregnancy can cause maternal disease, adverse pregnancy outcomes and neonatal disease, which is why chlamydia screening during pregnancy has been advocated. The effectiveness of a screening program depends on the knowledge of health care professionals, women and partners and the acceptability for screening of the target population. We assessed the knowledge of chlamydia infection among pregnant women and their partners in the Netherlands, their attitudes towards testing, and their experiences of being offered a chlamydia test. In addition, we evaluated the association between participants' background characteristics and knowledge of chlamydia. METHODS: Pregnant women aged <= 30 years and their partners (regardless of their age) attending one of the participating primary midwifery care practices in the Netherlands were invited to participate. All participants completed a questionnaire, pregnant women provided a vaginal swab and partners provided a urine sample to test for C. trachomatis. RESULTS: In total, 383 pregnant women and 282 partners participated in the study of whom 1.9% women and 2.6% partners tested chlamydia positive. Participants had high levels of awareness (92.8%) of chlamydial infection. They were knowledgeable about the risk of chlamydia infection; median knowledge score was 9.0 out of 12.0. Lower knowledge scores were found among partners (p-value <0.001), younger aged (p-value 0.02), non western origin (p-value <0.001), low educational level (p-value <0.001), and no history of sexually transmitted infections (p-value <0.001). In total, 78% of respondents indicated that when pregnant women are tested for chlamydia, their partners should also be tested; 54% believed that all women should routinely be tested. Pregnant women more often indicated than partners that testing partners for chlamydial infection was not necessary (p-value <0.001). The majority of pregnant women (56.2%) and partners (59.2%) felt satisfied by being offered the test during antenatal care. CONCLUSION: Pregnant women and their partners were knowledgeable about chlamydial infection, found testing, both pregnant women and their partners, for chlamydia acceptable and not stigmatizing. PMID- 25011478 TI - A systematic review of the evidence that brain structure is related to muscle structure and their relationship to brain and muscle function in humans over the lifecourse. AB - BACKGROUND: An association between cognition and physical function has been shown to exist but the roles of muscle and brain structure in this relationship are not fully understood. A greater understanding of these relationships may lead to identification of the underlying mechanisms in this important area of research. This systematic review examines the evidence for whether: a) brain structure is related to muscle structure; b) brain structure is related to muscle function; and c) brain function is related to muscle structure in healthy children and adults. METHODS: Medline, Embase, CINAHL and PsycINFO were searched on March 6th 2014. A grey literature search was performed using Google and Google Scholar. Hand searching through citations and references of relevant articles was also undertaken. RESULTS: 53 articles were included in the review; mean age of the subjects ranged from 8.8 to 85.5 years old. There is evidence of a positive association between both whole brain volume and white matter (WM) volume and muscle size. Total grey matter (GM) volume was not associated with muscle size but some areas of regional GM volume were associated with muscle size (right temporal pole and bilateral ventromedial prefrontal cortex). No evidence was found of a relationship between grip strength and whole brain volume however there was some evidence of a positive association with WM volume. Conversely, there is evidence that gait speed is positively associated with whole brain volume; this relationship may be driven by total WM volume or regional GM volumes, specifically the hippocampus. Markers of brain ageing, that is brain atrophy and greater accumulation of white matter hyperintensities (WMH), were associated with grip strength and gait speed. The location of WMH is important for gait speed; periventricular hyperintensities and brainstem WMH are associated with gait speed but subcortical WMH play less of a role. Cognitive function does not appear to be associated with muscle size. CONCLUSION: There is evidence that brain structure is associated with muscle structure and function. Future studies need to follow these interactions longitudinally to understand potential causal relationships. PMID- 25011481 TI - IRE1 inhibition perturbs the unfolded protein response in a pancreatic beta-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis. AB - BACKGROUND: The Akita mutation (C96Y) in the insulin gene results in early onset diabetes in both humans and mice. Expression of mutant proinsulin (C96Y) causes endoplasmic reticulum (ER) stress in pancreatic beta-cells and consequently the cell activates the unfolded protein response (UPR). Since the proinsulin is terminally misfolded ER stress is irremediable and chronic activation of the UPR eventually activates apoptosis in some cells. Here we analyzed the IRE1-dependent activation of genes in response to misfolded proinsulin production in an inducible mutant proinsulin (C96Y) insulinoma cell line. RESULTS: The IRE1 endoribonuclease inhibitors 4MU8c and MKC-3946 prevented the splicing of the XBP1 mRNA in response to ER stress caused by mutant proinsulin production. Microarray expression analysis and qPCR validation of select genes revealed that maximal upregulation of many UPR genes in response to mutant proinsulin production required IRE1, although most were still increased above control. Interestingly, neither degradation of misfolded proinsulin via ER-associated degradation (ERAD), nor apoptosis induced by prolonged misfolded proinsulin expression were affected by inhibiting IRE1. CONCLUSIONS: Although maximal induction of most UPR genes requires IRE1, inhibition of IRE1 does not affect ERAD of misfolded proinsulin or predispose pancreatic beta-cells expressing misfolded proinsulin to chronic ER stress-induced apoptosis. PMID- 25011482 TI - Interferon regulatory factor 5 genetic variants are associated with cardiovascular disease in patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction. Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders. In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients. METHODS: Three IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA. Among them, 390 (18.2%) had experienced CV events. The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression. RESULTS: Male sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population. Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively). Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012). CONCLUSIONS: Our results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA. PMID- 25011483 TI - Infarct patterns, collaterals and likely causative mechanisms of stroke in symptomatic intracranial atherosclerosis. AB - BACKGROUND: There are limited data on the specific mechanisms of stroke in patients with intracranial atherosclerotic stenosis (ICAS). We undertook this study to describe infarct patterns and likely mechanisms of stroke in a large cohort of patients with ICAS, and to evaluate the relationship of these infarct patterns to angiographic features (collaterals, stenosis location and stenosis severity). METHODS: We evaluated infarct patterns in the territory of a stenotic intracranial artery on neuroimaging performed at baseline and during follow-up if a recurrent stroke occurred in patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. We defined the likely mechanism of stroke (artery-to-artery embolism, perforator occlusion, hypoperfusion or mixed) according to the site of ICAS and based on the infarct patterns on neuroimaging. Collaterals were assessed using American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grades, and stenosis severity using the WASID trial's measurement technique. We evaluated the association of infarct patterns with angiographic features using chi(2) tests. RESULTS: The likely mechanisms of stroke based on the infarct patterns at baseline in the 136 patients included in the study were artery-to artery embolism (n = 69; 50.7%), perforator occlusion (n = 34; 25%), hypoperfusion (n = 12; 8.8%) and mixed (n = 21; 15.5%). Perforator-occlusive infarcts were more frequent in the posterior circulation, and mixed patterns were more prevalent in the anterior circulation (both p < 0.01). Most of the mixed patterns in the anterior circulation combined small pial or scattered multiple cortical infarcts with infarcts in border-zone regions, especially the cortical ones. Isolated border-zone infarcts were not significantly associated with a poor grading for collaterals or the severity of stenosis. Among 47 patients with a recurrent infarct during follow-up, the infarct patterns suggested an artery-to artery embolic mechanism in 29 (61.7%). CONCLUSIONS: Artery-to-artery embolism is probably the most common mechanism of stroke in both the anterior and the posterior circulations in patients with ICAS. An extension of intracranial atherosclerosis at the site of stenosis into adjacent perforators also appears to be a common mechanism of stroke, particularly in the posterior circulation, whereas hypoperfusion as the sole mechanism is relatively uncommon. Further research is important to accurately establish the specific mechanisms of stroke in patients with ICAS, since preliminary data suggest that the underlying mechanism of stroke is an important determinant of prognosis. PMID- 25011484 TI - I-DAQ: a new test to assess direct and indirect aggression free of response bias. AB - Self-reports of aggression are deeply impacted by response bias, especially by social desirability, but there are no specific methods for controlling this bias. Furthermore, despite the importance of the subject few instruments have been designed to assess both direct and indirect forms of aggression. The aim of the present research was to develop a brief measure that comprises both forms of aggression and which makes it possible to obtain scores free of social desirability and acquiescence effects. The scales were created using recently developed methods for controlling response bias effects in a sample of 750 participants over a wide age range. The items were chosen by a panel of judges from among the best of the existing aggression measures. Confirmatory factor analysis showed the expected three factor structure (CFI = .98; AGFI = .97 and RSMEA = .078, 90% C.I. = .074 - .083) and the scales showed good psychometric properties in that they had good reliability (ranging from thetaxx = .77 to thetaxx = .83), and convergent and criterion validity. PMID- 25011485 TI - Self-assembled LiFePO4 nanowires with high rate capability for Li-ion batteries. AB - Controlling the dimensions in the nanometer scale of olivine-type LiFePO4 has been regarded as one of the most effective strategies to improve its electrochemical performance for Li-ion batteries. In this communication, we demonstrate a novel LiFePO4 nanoarchitecture, which is composed of self-assembled single-crystalline nanowires and exhibits good rate capability with a reversible capacity of ~110 mA h g(-1) at a current rate of 30 C, and a stable capacity retention of ~86% after 1000 cycles at a current rate of 10 C. PMID- 25011486 TI - Respiratory bronchiolitis-interstitial lung disease. AB - Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is a rare, mild inflammatory pulmonary disorder that occurs almost exclusively in current or former heavy smokers, usually between the third and sixth decades, most likely with no gender predilection. The onset is usually insidious with exertional dyspnea and persistent cough, which may be non-productive, developing over a course of weeks or months. RB-ILD may also be diagnosed in asymptomatic patients with functional impairment and chest radiograph or high-resolution computed tomography (HRCT) abnormalities. Histologically, RB-ILD is characterized by the accumulation of yellow-brown pigmented macrophages within the lumens of respiratory bronchioles and alveolar ducts, associated with a patchy submucosal and peribronchiolar chronic inflammation. Common findings also include mild bronchiolar and peribronchiolar alveolar fibrosis that expands contiguous alveolar septa and leads to architectural distortion as well as centrilobular emphysema. Chest radiographs in patients with RB-ILD typically show fine reticulonodular interstitial opacities, while on HRCT central and peripheral bronchial wall thickening, centrilobular nodules, and ground-glass opacities associated with upper lobe centrilobular emphysema are most frequently reported. Pulmonary function testing may be normal but usually demonstrates mixed, predominantly obstructive abnormalities, often combined with hyperinflation and usually associated with a mild to moderate reduction in carbon monoxide diffusion capacity (DLco). The course of RB-ILD is heterogeneous. Some patients respond favorably to corticosteroids and/or smoking cessation, but often there is no functional improvement and the disease progresses despite smoking cessation and treatment. PMID- 25011487 TI - Multiple sclerosis-related trigeminal neuralgia: a prospective series of 43 patients treated with gamma knife surgery with more than one year of follow-up. AB - BACKGROUND: Trigeminal neuralgia (TN) related to multiple sclerosis (MS) is more difficult to manage pharmacologically and surgically. OBJECTIVE: This article aims to evaluate the safety and efficacy of Gamma Knife surgery (GKS) in this special group of patients. METHODS: Between July 1992 and November 2010, 43 cases with more than 1 year of follow-up were operated with GKS for TN related to MS and prospectively evaluated in the Timone University Hospital, Marseille, France. Radiosurgery using the Gamma Knife (model B or C or Perfexion) was performed. A single 4-mm isocenter was positioned at a median distance of 8 mm (range 5.7 14.7) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 75-90) was delivered. RESULTS: The median follow-up period was 53.8 months (12-157.1). Thirty-nine patients (90.7%) were initially pain free. Their actuarial probability of remaining pain free without medication at 6 months, 1, 3, 5 and 10 years was 87.2, 71.8, 43.1, 38.3 and 20.5%, respectively, and remained stable till 12 years. The hypoesthesia actuarial rate at 6 months, 1 and 2 years was 11.5, 11.5 and 16%, and remained stable till 12 years. CONCLUSIONS: GKS proved safe and effective in this special group of patients. PMID- 25011488 TI - Health-seeking behaviour of male foreign migrant workers living in a dormitory in Singapore. AB - BACKGROUND: Foreign workers' migrant status may hinder their utilisation of health services. This study describes the health-seeking behaviour and beliefs of a group of male migrant workers in Singapore and the barriers limiting their access to primary healthcare. METHODS: A cross-sectional study of 525 male migrant workers, >= 21 years old and of Indian, Bangladeshi or Myanmar nationality, was conducted at a dormitory via self-administered questionnaires covering demographics, prevalence of medical conditions and health-seeking behaviours through hypothetical scenarios and personal experience. RESULTS: 71% (95%CI: 67 to 75%) of participants did not have or were not aware if they had healthcare insurance. 53% (95%CI: 48 to 57%) reported ever having had an illness episode while in Singapore, of whom 87% (95%CI: 82 to 91%) saw a doctor. The number of rest days was significantly associated with higher probability of having consulted a doctor for their last illness episode (p = 0.026), and higher basic monthly salary was associated with seeing a doctor within 3 days of illness (p = 0.002). Of those who saw a doctor, 84% (95%CI: 79 to 89%) responded that they did so because they felt medical care would help them to work better. While 55% (95%CI: 36 to 73%) said they did not see a doctor because the illness was not serious, those with lower salaries were significantly more likely to cite inadequate finances (55% of those earning < S$500/month). In hypothetical injury or illness scenarios, most responded that they would see the doctor, but a sizeable proportion (15% 95%CI: 12 to 18%) said they would continue to work even in a work-related injury scenario that caused severe pain and functional impairment. Those with lower salaries were significantly more likely to believe they would have to pay for their own healthcare or be uncertain about who would pay. CONCLUSIONS: The majority of foreign workers in this study sought healthcare when they fell ill. However, knowledge about health-related insurance was poor and a sizeable minority, in particular those earning < S$500 per month, may face significant issues in accessing care. PMID- 25011489 TI - A quantum dot based electrochemiluminescent immunosensor for the detection of pg level phenylethanolamine A using gold nanoparticles as substrates and electron transfer accelerators. AB - This study reports the development of an electrochemiluminescent (ECL) immunosensor for ultrasensitive detection of phenylethanolamine A (PA) based on CdSe quantum dots (QDs) and gold nanoparticles (GNPs). The GNPs/ovalbumin-PA/anti PA-QD immunosensor was fabricated layer by layer using GNPs as substrates and electron transport accelerators. The use of GNPs greatly enhanced the sensitivity for detecting PA due to the excellent electron transportation ability and the large surface area of GNP carriers allowing several binding events of ovalbumin PA on each nanosphere. Transmission electron microscopy images (TEM), photoluminescence spectra, ultraviolet-visible absorption spectra and dynamic light scattering (DLS) were used to characterize the QDs and GNPs. The sensor was characterized with electrochemical impedance spectra (EIS), and a strong ECL emission of the modified electrode could be observed during the cathodic process of S2O8(2-) and QDs in air-saturated PBS buffer containing 0.1 M K2S2O8 and 0.1 M KCl (pH 7.4). With a competitive immunoassay format, the ECL signal depended linearly on the logarithm of the phenylethanolamine A concentration within a range of 0.02 ng mL(-1) to 50 ng mL(-1), and the detection limit was 0.0047 ng mL(-1), much lower than those reported in the literature. This ECL immunosensor is rapid, simple and sensitive with acceptable precision, and it will extend the application of QD ECL in immunoassays of beta-agonists and open new avenues for the detection of food additive residues in the future. PMID- 25011490 TI - Health-related quality of life and self-efficacy of managing behavior problems for family caregivers of vascular dementia and Alzheimer's disease patients. AB - BACKGROUND: Little is known about the differences in patients' behavioral problems and health outcomes of family caregivers of patients with vascular dementia (VaD) and Alzheimer's disease (AD). METHODS: A secondary analysis of baseline data on a subsample of caregiver-dementia patient dyads in a randomized clinical trial. RESULTS: Family caregivers of VaD patients reported higher self efficacy than caregivers of AD patients in handling verbally nonaggressive and verbally aggressive behaviors. Caregivers of VaD patients had poorer health related quality of life (HRQoL) than caregivers of AD patients considering role disability due to physical health problems, bodily pain, social function, and physical component summary. Greater self-efficacy was associated with better mental health-related outcomes for family caregivers of VaD patients, and better self-care ability of VaD patients was associated with better caregiver mental health-related outcomes. Caring for a patient with more severe dementia predicted poor physical health-related outcomes in role disability due to physical health problems, but better overall mental health (mental component summary) for caregivers. CONCLUSION: This study is the first to examine and compare the behavioral problems of AD and VaD patients in a Chinese population, along with their family caregivers' self-efficacy and health outcomes. Family caregivers of patients with VaD might warrant specific attention to their HRQoL, with interventions developed to enhance their self-efficacy. PMID- 25011491 TI - Attributions of blame to battered women when they are perceived as feminists or as "difficult to deal with". AB - This study aimed to analyze the influence of victim-related and observer-related factors in victim blaming of battered women. Two hundred and forty six college students participated. They were asked to read a scenario describing a hypothetical case of physical violence perpetrated by a man against his partner. Depending on the experimental condition, the victim was described either as a feminist and/or as exhibiting difficulties in her relationship with others or not. A hierarchical regression analysis was performed with victim blaming as dependent variable. Participants' hostile sexism positively predicted victim blaming when the victim was described as a feminist and as a "difficult to deal with" woman (p < .001). In addition, men, but not women, high in hostile sexist attitudes placed more blame on the victim when she was presented as a feminist woman (p < .001). These results underscore the importance of victim-related and observer-related factors, and of their interaction, in blaming the victim of gender-based violence. PMID- 25011492 TI - How do climate-linked sex ratios and dispersal limit range boundaries? AB - BACKGROUND: Geographic ranges of ectotherms such as reptiles may be determined strongly by abiotic factors owing to causal links between ambient temperature, juvenile survival and individual sex (male or female). Unfortunately, we know little of how these factors interact with dispersal among populations across a species range. We used a simulation model to examine the effects of dispersal, temperature-dependent juvenile survival and sex determining mechanism (temperature-dependent sex determination (TSD) and genotypic sex determination (GSD)) and their interactions, on range limits in populations extending across a continuous range of air temperatures. In particular, we examined the relative importance of these parameters for population persistence to recommend targets for future empirical research. RESULTS: Dispersal influenced the range limits of species with TSD to a greater extent than in GSD species. Whereas male dispersal led to expanded species ranges across warm (female-producing) climates, female dispersal led to expanded ranges across cool (male-producing) climates. Two-sex dispersal eliminated the influence of biased sex ratios on ranges. CONCLUSION: The results highlight the importance of the demographic parameter of sex ratio in determining population persistence and species range limits. PMID- 25011494 TI - Influence of thigh activation on the VO2 slow component in boys and men. AB - PURPOSE: During constant work rate exercise above the lactate threshold (LT), the initial rapid phase of pulmonary oxygen uptake (VO2) kinetics is supplemented by an additional VO2 slow component (VO2Sc) which reduces the efficiency of muscular work. The VO2Sc amplitude has been shown to increase with maturation but the mechanisms are poorly understood. We utilized the transverse relaxation time (T2) of muscle protons from magnetic resonance imaging (MRI) to test the hypothesis that a lower VO2 slow component (VO2Sc) amplitude in children would be associated with a reduced muscle recruitment compared to adults. METHODS: Eight boys (mean age 11.4 +/- 0.4) and eight men (mean age 25.3 +/- 3.3 years) completed repeated step transitions of unloaded-to-very heavy-intensity (U -> VH) exercise on a cycle ergometer. MRI scans of the thigh region were acquired at rest and after VH exercise up to the VO2Sc time delay (ScTD) and after 6 min. T2 for each of eight muscles was adjusted in relation to cross-sectional area and then summed to provide the area-weighted SigmaT2 as an index of thigh recruitment. RESULTS: There were no child/adult differences in the relative VO2Sc amplitude [Boys 14 +/ 7 vs. Men 18 +/- 3 %, P = 0.15, effect size (ES) = 0.8] during which the change (?) in area-weighted SigmaT2 between the ScTD and 6 min was not different between groups (Boys 1.6 +/- 1.2 vs. Men 2.3 +/- 1.1 ms, P = 0.27, ES = 0.6). A positive and strong correlation was found between the relative VO2Sc amplitude and the magnitude of the area-weighted ?SigmaT2 in men (r = 0.92, P = 0.001) but not in boys (r = 0.09, P = 0.84). CONCLUSIONS: This study provides evidence to show that progressive muscle recruitment (as inferred from T2 changes) contributes to the development of the VO2Sc during intense submaximal exercise independent of age. PMID- 25011495 TI - Acute increases in intraluminal pressure improve vasodilator responses in aged soleus muscle feed arteries. AB - PURPOSE: We tested the hypothesis that exposure to an acute increase in intraluminal pressure, to mimic pressure associated with a bout of exercise, improves nitric oxide (NO)-mediated endothelium-dependent dilation in aged soleus muscle feed arteries (SFA) and that improved endothelial function would persist after a 2 h recovery period. METHODS: SFA from young (4-month) and old (24-month) Fischer 344 rats were cannulated and pressurized at 90 (P90) or 130 (P130) cmH2O for 60 min. At the end of the treatment period, pressure in the P130 SFA was lowered to 90 cmH2O for examination of endothelium-dependent [flow or acetylcholine (ACh)] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation. To determine the role of NO, vasodilator responses were assessed in the presence of N (omega)-nitro-L-arginine (L-NNA). To determine whether the effects of pressure persisted following a recovery period at normal pressure, SFA were pressurized to 130 cmH2O for 60 min and subsequently lowered to 90 cmH2O for 2 h before assessing function. RESULTS: ACh- and flow-induced dilations were impaired in old SFA. Treatment with increased pressure for 60 min improved ACh- and flow-induced dilations in old SFA. SNP-induced dilation was improved in old and young SFA. The beneficial effect of pressure treatment on ACh- and flow induced dilation in old SFA was blocked by L-NNA and was not present following a 2 h recovery period. CONCLUSION: These results indicate that an acute increase in intraluminal pressure improves NO-mediated endothelium-dependent dilation in aged SFA; however, the beneficial effect does not persist after 2 h. PMID- 25011493 TI - Hands and feet: physiological insulators, radiators and evaporators. AB - The purpose of this review is to describe the unique anatomical and physiological features of the hands and feet that support heat conservation and dissipation, and in so doing, highlight the importance of these appendages in human thermoregulation. For instance, the surface area to mass ratio of each hand is 4 5 times greater than that of the body, whilst for each foot, it is ~3 times larger. This characteristic is supported by vascular responses that permit a theoretical maximal mass flow of thermal energy of 6.0 W (136 W m(2)) to each hand for a 1 degrees C thermal gradient. For each foot, this is 8.5 W (119 W m(2)). In an air temperature of 27 degrees C, the hands and feet of resting individuals can each dissipate 150-220 W m(2) (male-female) of heat through radiation and convection. During hypothermia, the extremities are physiologically isolated, restricting heat flow to <0.1 W. When the core temperature increases ~0.5 degrees C above thermoneutral (rest), each hand and foot can sweat at 22-33 mL h(-1), with complete evaporation dissipating 15-22 W (respectively). During heated exercise, sweat flows increase (one hand: 99 mL h(-1); one foot: 68 mL h( 1)), with evaporative heat losses of 67-46 W (respectively). It is concluded that these attributes allow the hands and feet to behave as excellent radiators, insulators and evaporators. PMID- 25011496 TI - Neuromuscular electrical stimulation via the peroneal nerve is superior to graduated compression socks in reducing perceived muscle soreness following intense intermittent endurance exercise. AB - PURPOSE: A novel technique of neuromuscular electrical stimulation (NMES) via the peroneal nerve has been shown to augment limb blood flow which could enhance recovery following exercise. The present study examined the effects of NMES, compared to graduated compression socks on muscle soreness, strength, and markers of muscle damage and inflammation following intense intermittent exercise. METHODS: Twenty-one (age 21 +/- 1 years, height 179 +/- 7 cm, body mass 76 +/- 9 kg,) healthy males performed a 90-min intermittent shuttle running test on three occasions. Following exercise, the following interventions were applied: passive recovery (CON), graduated compression socks (GCS) or NMES. Perceived muscle soreness (PMS) and muscle strength (isometric maximal voluntary contraction of knee extensors and flexors) were measured and a venous blood sample taken pre exercise and 0, 1, 24, 48 and 72 h following exercise for measurement of creatine kinase (CK) and Lactate dehydrogenase (LDH) activity and IL-6 and CRP concentrations. RESULTS: PMS increased in all conditions immediately, 1 and 24 h post-exercise. At 24 h PMS was lower in NMES compared to GCS and CON (2.0 +/- 1.6, 3.2 +/- 2.1, 4.6 +/- 2.0, respectively). At 48 h PMS was lower in NMES compared to CON (1.3 +/- 1.5 and 3.1 +/- 1.8, respectively). There were no differences between treatments for muscle strength, CK and LDH activity, IL-6 and CRP concentrations. CONCLUSIONS: The novel NMES technique is superior to GCS in reducing PMS following intense intermittent endurance exercise. PMID- 25011498 TI - Latin American students and language learning in Catalonia: what does the linguistic interdependence hypothesis show us? AB - The massive arrival in Spain of students of immigrant origin has visibly altered the traditional configuration of schools, where ethnic, cultural and linguistic diversity is becoming increasingly manifest. This situation is worth being mentioned insofar as it affects all the different autonomous communities in the country, even more clearly Catalonia, where the educational system is organized under the parameters of bilingual education. One of the theoretical constructs supporting this educational model is the Linguistic Interdependence Hypothesis, developed by Jim Cummins at the beginning of the 1980s. According to the author, whenever the instruction in a given language (Lx) takes place under certain conditions, competence acquired in this language can be transferred onto another (Ly). Bearing this theoretical construct in mind, our study focuses on a sample of 237 Spanish-speaking subjects (123 native and 114 immigrant students) who completed a series of parallel tests evaluating their skills in Catalan and Spanish. Drawing on the data analyzed we can conclude that the Hypothesis accounts for the results in both native and immigrant students with the same L1. PMID- 25011497 TI - Efficacy and safety of neoadjuvant chemotherapy with concurrent liposomal encapsulated doxorubicin, paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive breast cancer in clinical practice. AB - BACKGROUND: Based on previous results obtained with non-pegylated liposomal encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR. METHODS: Patients received six cycles of TLC-D99 (50 mg/m(2) every 3 weeks), paclitaxel (80 mg/m(2) weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla. RESULTS: Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5% of patients and 14.5% had inflammatory BC. Conservative surgery was performed in 46.8% of the patients and pCR was achieved in 63% (95% CI 50.5 75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5%; P = 0.028). Forty-five patients (72.6%) completed study treatment and 80.6% received at least five treatment cycles. No patients developed congestive heart failure and 14.5% of patients showed a >= 10 % decrease in the left ventricular ejection fraction. CONCLUSION: The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2 positive BC. PMID- 25011499 TI - Dynamics of silver nanoparticle release from wound dressings revealed via in situ nanoscale imaging. AB - The use of silver nanoparticles (AgNPs) in textiles for enhanced anti-microbial properties has led to concern about their release and impact on both human and environmental health. Here a novel method for in situ visualization of AgNP release from silver-impregnated wound dressings is introduced. By combining an environmental scanning electron microscope, a gaseous analytical detector and a peltier cooling stage, this technique provides near-instantaneous nanoscale characterization of interactions between individual water droplets and AgNPs. We show that dressings with different silver application methods have very distinct AgNP release dynamics. Specifically, water condensation on dressings with AgNP deposited directly on the fiber surface resulted in substantial and rapid AgNP release. By comparison, AgNP release from wound dressing with nanoparticles grown, not deposited, from the fiber surface was either much slower or negligible. Our methodology complements standard bulk techniques for studying of silver release from fabrics by providing dynamic nanoscale information about mechanisms governing AgNP release from individual fibers. Thus coupling these nano and macro-scale methods can provide insight into how the wound dressing fabrication could be engineered to optimize AgNP release for different applications. PMID- 25011500 TI - Low frequency magnetic force augments hepatic differentiation of mesenchymal stem cells on a biomagnetic nanofibrous scaffold. AB - Liver tissue engineering using polymeric nanofibrous scaffold and stem cells holds great promises for treating end-stage liver failures. The aim of this study was to evaluate hepatic trans-differentiation potential of human mesenchymal stem cells (hMSCs) on a biomagnetic electrospun nanofibrous scaffold fabricated from a blend of poly-L-lactide (PLLA), collagen and fibrin-rich blood clot, under the influence of a low frequency magnetic field. The scaffold was characterized for surface properties, biochemical and biomechanical parameters and bio-magnetic behaviour. Cell proliferation assay revealed that the scaffold was suitable for hMSCs adhesion and proliferation. Hepatic trans-differentiation potential of hMSCs was augmented on nanofibrous scaffold in magnetic field exposure group compared to control groups, as evident by strong expression of hepatocyte specific markers, albumin release, urea synthesis and presence of an inducible cytochrome P450 system. Our results conclude that biomagnetic scaffold of PLLA/collagen/blood clot augments hepatic trans-differentiation of hMSCs under magnetic field influence. PMID- 25011501 TI - Interaction between the transcription factor AtTIFY4B and begomovirus AL2 protein impacts pathogenicity. AB - The begomovirus AL2 protein is a transcriptional activator, a silencing suppressor, and inhibitor of basal defense. AL2 forms a complex at the CP promoter, through interaction with a plant-specific DNA-binding protein, Arabidopsis PEAPOD2 (also known as TIFY4B). AtTIFY4B has three domains (PPD, TIFY and CCT_2) conserved between homologs from different plant species. We confirmed that the AL2 protein from Tomato golden mosaic virus and Cabbage leaf curl virus interacts with TIFY4B from Arabidopsis, tomato and Nicotiana benthamiana in the nucleus of plant cells. Bimolecular Fluorescence Complementation demonstrated that the interaction involves both the TIFY and CCT_2 domains. Surprisingly, amino acids 84-150 can prevent AtTIFY4B from localizing to the nucleus, and interaction with AL2 results in some of the protein re-entering the nucleus. When AtTIFY4B is over-expressed, we observe an increase in mean latent period, where systemic symptoms are detected on average, 4 days later than in mock treated plants. This appears to be a consequence of reduced viral DNA titers, possibly related to the role of TIFY4B in cell cycle arrest. Our results point to a potential role for TIFY4B in host defense against geminiviruses. Expression of TIFY4B in N. benthamiana increases in response to geminivirus infection, which would result in suppression of proliferation, reducing viral replication. Geminiviruses may counter this defense response through an interaction between AL2 and TIFY4B, which would inhibit TIY4B function. The consequence of this inhibition would be failure to arrest the cell cycle, providing an environment conducive for geminivirus replication. PMID- 25011502 TI - Monitoring of pesticide residues in human breast milk from Punjab, India and its correlation with health associated parameters. AB - This study was undertaken to determine the present status of pesticide residues in breast milk from Punjab. A total of 127 breast milk samples were analyzed and pesticide residues were detected in 25 % of the milk samples. Residues of cyfluthrin, fenvalerate, cypermethrin, profenophos, gamma-HCH, beta-HCH, chlorpyriphos, monocrotophos, p,p' DDE and phosalone were detected with mean levels of 63.04, 11.69, 3.63, 2.66, 2.64, 2.29, 1.91, 1.63, 0.56 and 0.29 ng g( 1), respectively. Cyfluthrin was leading pesticide detected in breast milk contributing 31.28 % to the total residue load. It was observed that the residue levels were decreasing with increase in parity and age of mother and cyfluthrin had highest mean concentration of 90.63 ng g(-1) in the first parity and 21.11 ng g(-1) in youngest age group. Residue levels were higher in urban population than the rural population although, statistically non-significant difference was found between the two (p > 0.05). PMID- 25011503 TI - Occurrence of glyphosate in water bodies derived from intensive agriculture in a tropical region of southern Mexico. AB - Glyphosate is an agrochemical widely used to control weeds. However, glyphosate spreads to water bodies by spray-drift, run-off and leaching, potentially causing detrimental effects on non-target biota. There is no information on the occurrence of this herbicide in water bodies near crop fields in Mexico, although it is the most commonly used pesticide in this country. To fill this gap, we quantified glyphosate in water bodies from twenty-three locations, including natural protected areas and agricultural areas in southern Mexico, during the dry and the rainy seasons. We expected (1) higher concentrations during the dry season due to reduced dilution by precipitation and, (2) absence of glyphosate in the protected areas. In agreement with our expectation, concentration of glyphosate was higher during the dry season (up to 36.7 MUg/L). Nonetheless, glyphosate was detected in all samples-including natural protected areas. These results emphasize the need for an evaluation of the impact of glyphosate on native species as well as regulate its use. PMID- 25011504 TI - [Comparison of interferon-gamma release assays and adenosine deaminase of pleural fluid for the diagnosis of pleural tuberculosis]. AB - OBJECTIVE: To compare the diagnostic performance of interferon gamma releasing assays (T-SPOT. TB) and adenosine deaminase (ADA) in pleural tuberculosis, and therefore to evaluate the value of T-SPOT. TB in a high tuberculosis burden country. METHODS: From June 2011 to November 2012, 111 patients with pleural fluid in Beijing Chest Hospital, Capital Medical University were enrolled prospectively and categorized as culture/biopsy-confirmed pleural tuberculosis group (n = 59) and non-pleural tuberculosis group (n = 52). Patients with uncertain diagnosis and clinically diagnosed pleural tuberculosis were excluded from the study. Pleural fluid T-SPOT. TB and ADA measurements were performed, in addition to other routine laboratory tests. Continuous variables (spot forming cells, SFCs) were compared using nonparametric Mann-Whitney U test. Comparisons between proportions were performed using Chi-squared test. RESULTS: The receiver operating characteristic (ROC) curve and cut-off value of pleural fluid T-SPOT. TB were established according to spot forming cells (SFC) between culture/biopsy confirmed pleural tuberculosis group and non-pleural tuberculosis group (216 SFC/10(6) pleural fluid mononuclear cells). The sensitivity of pleural fluid T SPOT. TB and ADA was 91.5% (54/59) and 71.2% (42/59), respectively. The specificity was 90.4% (47/52) and 92.0% (46/50), respectively. The sensitivity of pleural fluid T-SPOT. TB was significantly higher than that of ADA (chi(2) = 8.045, P < 0.01). There was no significant difference of specificity between pleural fluid T-SPOT. TB and ADA (chi(2) = 0.000, P > 0.05). The area under the ROC curve was 0.912 for pleural fluid T-SPOT. TB and 0.903 for ADA. The sensitivity of combination diagnosis of ADA and pleural fluid T-SPOT. TB decreased to 67.8% (40/59), but the specificity increased to 100.0% (50/50). CONCLUSIONS: Pleural fluid T-SPOT. TB are relatively accurate supplementary assays for the diagnosis of pleural tuberculosis in this high tuberculosis burden country, and the combination of pleural fluid ADA and T-SPOT. TB is of diagnostic value. PMID- 25011505 TI - [Evaluation of the RNA simultaneous amplification and testing for detection of rifampin resistance in Mycobacterium tuberculosis]. AB - OBJECTIVE: To establish and evaluate a method for detection of rifampin resistance in Mycobacterium tuberculosis (M. tuberculosis) by the RNA simultaneous amplification and testing (SAT). METHODS: RNA probe and primer of reverse transcription with T7 promoter targets pre-16S rRNA were designed, and the isothermal RNA amplification at 42 degrees C was performed for real-time detection of the levels of pre-16S rRNA in drug exposed MTB. Twenty clinical isolates were detected by the SAT after treatment with rifampicin 1, 2 and 3 d in order to determine the best drug effect time. Fifty clinical isolates with known drug susceptibility results were used to determine the best cutoff value of rifampicin drug susceptibility by SAT. In total, 128 clinical isolates were detected by SAT to evaluate the accuracy compared with the Bactec MGIT 960. RESULTS: The best drug effect time and cutoff value for the detection of rifampin resistance by SAT were 2 d and 2.95. With the result of Bactec MGIT 960 as the reference, the sensitivity and the specificity of the assay was 100% (51/51) and 97.4% (75/77), respectively. CONCLUSIONS: The isothermal RNA amplification assay is a highly sensitive and specific tool for the detection of rifampicin resistance in M. tuberculosis, and therefore, it may be a new method to detect rifampicin resistance in M. tuberculosis. PMID- 25011506 TI - [Assessment of positive end-expiratory pressure induced lung volume change by ultrasound in mechanically ventilated patients]. AB - OBJECTIVE: To investigate the value of lung ultrasound for assessing positive end expiratory pressure (PEEP) -induced lung volume change in mechanically ventilated patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) . METHODS: Eighteen patients with ALI or ARDS were prospectively studied. P-V curves and lung ultrasound were performed at PEEP 12, 8, 4 and 0 cm H2O (1 cm H2O = 0.098 kPa). PEEP-induced lung volume change was measured using the P-V curve method and lung ultrasound. RESULTS: Four lung ultrasound entities were defined: consolidation, multiple irregularly spaced B lines, multiple abutting B lines and normal aeration.For each of the 12 lung regions examined, PEEP-induced ultrasound changes were measured and an lung ultrasound score (LUS) was calculated. A highly significant correlation was found between PEEP-induced lung volume change measured by P-V curves and LUS change (r = 0.82, P < 0.01) . A statistically significant correlation was found between LUS change and PEEP induced increase in PaO2 (r = 0.66, P < 0.01). CONCLUSION: PEEP-induced lung volume change can be adequately estimated with bedside lung ultrasound. Since lung ultrasound cannot assess PEEP-induced lung hyperinflation, it should not be the sole method for PEEP titration. PMID- 25011507 TI - [The clinicopathological analysis of pulmonary parenchymal involvement of multicentric giant lymph node hyperplasia (Castleman's disease)]. AB - OBJECTIVE: To observe the clinicopathological features of pulmonary parenchymal involvement of multicentric Castleman's disease(MCD). METHODS: Retrospective analysis was carried out for 6 patients of MCD with pulmonary parenchymal involvement who had been admitted to Peking Union Medical College Hospital from July 2008 to March 2013. Relevant literatures were reviewed. The diagnosis was established by surgical lung biopsy and all specimens were fixed in neutral formalin and embedded in paraffin. Sections were cut for HE and immunohistochemical stain. B cell and T cell gene rearrangement were tested in 3 cases. RESULTS: These 6 patients (all females) aged 31-68 years, with a median of 49.5 years. The presenting symptoms were fever (4/6), cough (3/6), and lymphadenopathy (6/6). Laboratory study showed elevated ESR (5/6) and CRP (4/6), and hypergammaglobulinaemia (2/6). Chest CT showed multiple nodules with perilymphatic distribution and ground-glass opacity (GGO). Pathologically, there were 5 cases of plasma cell type and 1 case of hyaline vascular type. The plasma cell variant showed dense mature plasma cell infiltration in pulmonary interstitium. The hyaline vascular variant was characterized by the presence of regressed germinal centers and broad concentric mantle zones. The gene arrangement tests were all negative. During the follow-up period (range: 2-60 months; mean: 31 months), 2 cases with plasma cell type received CHOP chemotherapy and then remained stable. One case with hyaline vascular type received CHOP chemotherapy but died due to deterioration of the disease. CONCLUSIONS: In the thorax, Castleman's disease usually manifests as hilar and mediastinal lymph node enlargement. Pulmonary parenchymal involvement by MCD is very rare. It is mostly seen in the elderly female, and can manifest with systemic symptoms. Chest CT usually reveals multiple nodules and GGO. It shows similar morphological characteristics to those found in lymph nodes. Immunohistochemistry and gene rearrangement test can help to differentiate it from other pulmonary lymphoproliferative diseases. PMID- 25011508 TI - [Primary hyperparathyroidism with metastatic pulmonary calcification: a case report and review of literature]. AB - OBJECTIVE: To highlight the characteristics of metastatic pulmonary calcification(MPC) of a patient with primary hyperparathyroidism. METHODS: The clinical, radiological, pathological and (99)mTc-MDP bone scanning data of the patient with primary hyperparathyroidism were studied and relevant literature was reviewed. RESULTS: This 56 year-old female patient presented with cough and shortness of breath. The chest CT scan showed multiple, bilateral infiltrates and calcification in the left lung and ventricular wall. Transbronchial lung biopsy was performed, and the pathological study showed that there was diffuse calcification in the alveoli and alveolar septa.(99)mTc-MDP bone-scanning showed pulmonary uptake mostly. The patient showed significant clinical and radiological improvement after surgical removal of the parathyroid gland. CONCLUSIONS: Patients of primary hyperparathyroidism with respiratory symptoms were easily misdiagnosed as primary pulmonary diseases.(99)mTc-MDP bone-scanning can be used to help differentiate MPC from other diseases with similar clinical and radiological findings, thus allowing prompt therapy. PMID- 25011509 TI - [Effects of platelet-derived growth factor on the function of smooth muscle cells from different orders of pulmonary artery]. AB - OBJECTIVE: To explore the functional responses of normal rat pulmonary artery smooth muscle cells (PASMCs) from different orders of pulmonary artery to the platelet-derived growth factor (PDGF). METHODS: The pulmonary artery branches were gently isolated from Sprague-Dawley rats (250-350 g) and eventually cut into three groups according to the vascular grading: the proximal pulmonary arteries, including pulmonary trunk and the first order branches of intrapulmonary arteries;the middle pulmonary arteries, including the second to third orders of intrapulmonary arteries;the distal pulmonary arteries, including the forth to fifth orders of intrapulmonary arteries. PASMCs from the three groups of vessels were isolated and cultured in DMEM. Cells were identified by immunofluorescence stained smooth muscle cell markers alpha-SMA, S100A4 and Calponin antibody. Cell proliferation was quantified by using 0.5 g/L methyl thiazolyl tetrazolium (MTT) assay. Western blot was used for detecting the protein expression level of proliferating cell nuclear antigen (PCNA) in PASMCs. Wound healing test was employed for cell migration assay. RESULTS: All of the three groups of cells positively expressed alpha-SMA, S100A4 and Calponin marker and no obvious differences were found in the appearance among the three groups. Under control condition (cultured in DMEM+2%FBS), three groups of PASMCs showed similar cell proliferation rate (137.0 +/- 12.1)%, (166.1 +/- 23.6)%, (156.8 +/- 2.5)%. The expression level of PCNA by Western blot was (0.42 +/- 0.10), (0.55 +/- 0.18), (0.48 +/- 0.28), respectively. The numbers of cells migrating to blank areas of the three groups were (49 +/- 14), (68 +/- 13) and (71 +/- 7). The above results were not significantly different. While after incubation with PDGF (10 ug/L, 48 h), the proliferation rate of middle and distal groups were (215.7 +/- 17.8)% and (195.2 +/- 6.6)%, higher than that of the proximal group(167.0 +/- 14.4)%, (P < 0.01). In middle and distal groups, the expression level of PCNA were (0.93 +/- 0.11) and (1.21 +/- 0.14) respectively, which were higher than that in the proximal group (0.62 +/- 0.03), (P < 0.001). The number of cells migrating to blank areas of the middle and distal groups were (194 +/- 46), (171 +/- 16), and exhibited increased migration ability compared to the proximal group (67 +/- 21), (P < 0.01). CONCLUSION: These results suggest that PASMCs from different orders of pulmonary arteries have different responses to PDGF stimulation. This will help to understand the possible mechanism for that under same pathophysiological stimulus, different orders of pulmonary arteries may have different responses. PMID- 25011510 TI - [The expression of SIRT1 in brainstem of rats in different types of hypoxia and its significance]. AB - OBJECTIVE: To explore the correlation between SIRT1 expression in brainstem and apnea hypopnea index and the effect of hypoxia on SIRT1 expression in rats. METHODS: Thirty-three healthy Sprague-Dawley(SD) rats underwent sleep monitoring and SIRT1 protein in brainstems was measured by Western blot. The correlation of sleep apnea index and SIRT1 protein level in brainstem was analysed. Another 36 adult male SD rats were randomly and equally divided into 4 groups: normal control (NC) group, continuous hypoxia (CH) group, intermittent hypoxia (IH) group and intermittent hypoxia with hypercapnia (IHH) group. The expression of SIRT1 protein of the lower brainstems of the 4 groups were measured by Western blot. RESULTS: The level of SIRT1 in the brainstem was negatively correlated with the frequency of spontaneous sleep apnea in REM(r = -0.617, P < 0.001) while positively correlated with the frequency of post sigh sleep apnea in REM (r = 0.535, P < 0.01). The relative expression level of SIRT1 in NC, CH, IH, IHH group were (1.4 +/- 1.0), (1.4 +/- 0.6), (2.5 +/- 1.0) , (1.6 +/- 1.2), respectively. There was a significant difference in the SIRT1 level among groups (F = 2.964, P < 0.05) . CONCLUSIONS: The rats with lower level of SIRT1 may have lower anti oxidative stress capability which results in higher frequency of spontaneous sleep apnea. Under the circumstance of hypoxia, the fact that the expression of SIRT1 protein was elevated may be a protective mechanism. PMID- 25011511 TI - [Pharmacologic ascorbate treatment of influenza in vivo]. AB - OBJECTIVE: To investigate the effects of pharmacologic ascorbate (vitamin C) against Influenza A/CA/7/09 (H1N12009). METHODS: BALB/c mice inoculated intranasally with influenza virus were treated with ascorbate (3 mg/g) twice daily by intraperitoneal (i.p.) injection for up to 14 d. Control groups received an equivalent volume of normal saline. Body weights were measured daily. To quantify the level of viral replication in the respiratory tract, the mice were euthanized and lungs removed and prepared as whole lung homogenates.Viral titers were determined by TCID50 assay in MDCK cells. Cytokine titers were determined by ELISA following the manufacturer's protocol (IL-1beta, IL-6, TNF-alpha, IFN alpha). For lung histopathologic evaluation, lungs were fixed with 10% neutral buffered formalin at time of isolation, and then coded, processed into paraffin blocks, sectioned onto glass slides and stained (hematoxylin and eosin).Slides were examined and scored by a pathologist. RESULTS: Mice infected with influenza virus and treated with pharmacologic ascorbate had higher survival and less weight loss, and had lung viral titers reduced by as much as 10 to 100-fold compared to the controls. Pathologic study of the lungs showed that the treated animals had little inflammation (bronchiolitis, perivasculitis, alveolitis, and vasculitis) compared to the controls.IL-1, IL-6, and IFN-alpha lung levels were lower in the treated animals compared to the controls. CONCLUSION: Pharmacologic ascorbate is a pro-oxidant that eliminates influenza virus in the lung, and therefore reduces lung inflammation and lowers death rate in this mouse model. PMID- 25011512 TI - [Tanshinone IIA sulfonate upregulated pulmonary artery smooth muscle peroxisome proliferator-activated receptor gamma expression in monocrotaline induced pulmonary hypertension rat]. AB - OBJECTIVE: To investigate the effect of sodium tanshinone IIA sulfonate (STS) on rat right ventricular systolic pressure (RVSP), mean right ventricular pressure (MRVP), right ventricular hypertrophy index [RV/(LV+S)], pulmonary vascular remodeling, and PPARgamma protein expression in pulmonary artery smooth muscle of monocrotaline (MCT) induced rat pulmonary hypertension model. METHODS: The pulmonary hypertension model was established by subcutaneously injection of MCT, and the rats were treated with or without STS for 21 days. After that, RVSP, mRVP and RV/(LV+S) were measured. Lung histopathological sections were prepared, and the lumen area, the wall thickness and arterial radius of pulmonary arteries were quantified using the Image Pro Plus 6.0 software. PPARgamma protein expression in rat pulmonary artery smooth muscle was detected by Western blot. RESULTS: Compared with control group, the RVSP, mRVP were significantly increased in MCT group (P < 0.05), while in the MCT+STS group, it was decreased from (81.2 +/- 1.9) and (28.6 +/- 2.0) mmHg to (35.4 +/- 8.3) and (14.1 +/- 5.4) mmHg, respectively (P < 0.05). The RV/(LV+S) of MCT group was (0.57 +/- 0.04), markedly higher than those of control group and control+STS group (0.33 +/- 0.02) and (0.34 +/- 0.02) , respectively, P < 0.05, while in MCT+STS group, the RV/(LV+S) was (0.43 +/- 0.02), lower than that of MCT group (P < 0.05) ;The luminal area/total area of MCT group decreased to (27 +/- 6)%compared with control rats (56.00 +/- 3.00) % (P < 0.05) . The wall thickness/artery radius (WT%) of MCT group increased from (20 +/- 4) % (control group) to (40 +/- 3) % (P < 0.05) .In MCT+STS treated rats, luminal area/ total area and WT% were (39.0 +/- 2.0) %and (31.0 +/- 2.0) %, both statistically different from MCT group (P < 0.05) . The level of PPARgamma protein in pulmonary artery smooth muscle of MCT group was (48 +/- 4) %, lower than control group (100 +/- 0) % (P < 0.05) .In the MCT+STS group, PPARgamma protein expression was recovered (102 +/- 3) %, (P < 0.05) . CONCLUSION: STS markedly decreased RVSP,MRVP, RV/(LV+S) and pulmonary vascular remodeling in MCT induced pulmonary hypertension rat, and PPARgamma might be targeted as a key molecule during STS treatment. PMID- 25011513 TI - [Relevant research of the relationship between polymorphism of NPSR1 and bronchial asthma and anxiety]. PMID- 25011514 TI - [Role of fluid shift in the pathogenesis of obstructive sleep apnoea]. PMID- 25011515 TI - Pathologic complete remission after preoperative high-dose-rate brachytherapy in patients with operable cervical cancer: preliminary results of a prospective randomized multicenter study. AB - The role of preoperative intrauterine brachytherapy (BT) in the multidisciplinary treatment of early stage cervical carcinoma (ESCC) is controversial. In 2005, a prospective randomized multicenter study was initiated in Hungary in order to explore the potential advantages of preoperative high-dose-rate (HDR) BT. In this article we evaluate the efficiency of preoperative HDR BT by the rate of pathologic complete remission (pCR) in the first 185 patients enrolled in the study at the National Institute of Oncology and at the Uzsoki Municipal Cancer Center in collaboration with the 1st Department of Gynaecology and Obstetrics of Semmelweis University, Budapest, Hungary. In arm A, patients received 2x8Gy preoperative intracavitary HDR BT, while in arm B no preoperative treatment was given. In both arms patients underwent radical Wertheim (Piver III) hysterectomy. The pCR rate was 25.7% after preoperative HDR BT, while it was only 11.2% with surgery alone (p=0.03), in these cases the tumor was eliminated during the diagnostic excision or conisation. The rate of positive surgical margins was 1.5% after preoperative BT, while it was as high as 11.4% without preoperative RT (p=0.02). There was no significant difference in the local tumor control (LTC), distant metastases free survival (DMFS) and overall survival (OS) between the two arms. According to our preliminary results preoperative intracavitary HDR BT significantly increases the rate of pCR and decreases the rate of positive surgical margins in patients with ESCC. Longer follow-up is required to establish the possible impact of pCR on the ultimate LTC and OS. PMID- 25011517 TI - Minister defends controversial NHS Health Checks programme. PMID- 25011516 TI - Executive functioning deficits in preschool children with Fetal Alcohol Spectrum Disorders. AB - Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the vast majority of available evidence comes from school-age children and adolescents. Very little is known about EF during the critical developmental period prior to 6 years of age in FASD. We evaluated EF in 39 children with FASD (3.0-5.5 years) and a comparison group of 50 age-matched, nonexposed controls. Measures included the EF Scale for Early Childhood and a Delay of Gratification task. Compared to age-matched controls, preschool children with FASD had impairments on the EF Scale and showed more impulsivity on the Delay of Gratification task. To confirm the EF Scale finding, FASD group performance was compared to a separate normative dataset (N = 1,400). Those with FASD performed below normal (M = -0.57, SD = 0.92). Within the FASD group, IQ was correlated with the EF Scale (partial r = .60, p = .001) and Delay of Gratification (partial r = .58, p = .005). EF Scale performance did not differ significantly across levels of FASD severity (fetal alcohol syndrome [FAS], partial FAS, or alcohol-related neurobehavioral disorder [ARND]). However, compared to normative data, those with FAS had the largest deficits (M = -0.91 SD from the mean, SE = 0.23), followed by partial FAS (M = -0.66 SD from the mean, SE = 0.26), then ARND (M = -0.36 SD from the mean, SE = 0.20). These novel data show that EF deficits manifest well before the age of 6 years in children with FASD, that they occur across the spectrum, and that EF may be most impaired in children with more severe forms of FASD and/or lower IQs. PMID- 25011518 TI - Fluorescent ligands and energy transfer in photoactive ruthenium-bipyridine complexes. AB - Ruthenium bis(bipyridine) complexes have proved to be useful as phototriggers for visible and IR-light photodelivery of molecules. They usually expel one ligand heterolytically upon absorption of blue or green light. However, their absorption capabilities at wavelengths longer than 500 nm are poor. Through coordination of fluorescent ligands to the Ru center, it is possible to establish an energy transfer pathway that allows these kinds of complexes to extend the range of photoactivation up to yellow wavelengths. We introduce a study of this effect in several complexes of the family using a modified Rhodamine as fluorescent ligand with different coordinated linkers. The observed trends show that a rational design of fluorophore-enhanced Ru-bpy phototriggers is possible and that photolysis efficiency can be increased by choosing the right combination of ligands. PMID- 25011519 TI - Dropout from care among HIV-infected patients enrolled in care at a tertiary HIV care center in Chennai, India. AB - Long-term follow-up of persons infected with HIV infection is essential to optimize clinical outcomes. However, limited data exist on the rates of dropout (DO) from HIV care and factors associated with DO especially from resource limited settings. We conducted a retrospective analysis of the data available at YRGCARE, a private HIV care provider in south India that has registered over 15,000 HIV-infected persons since its inception in 1993. We included 7995 patients who registered for care between 1 January 2004 and 31 December 2009. A dropout was defined as a person who registered for care during this period and had not been seen in the clinic for >1 year. Logistic regression was used to examine factors associated with DO from clinical care. The median age of the patients registered for care was 34 years; 66% were male and 83% were married. The overall DO rate was 38.1 per 100 person-years - the majority of the DOs occurred within 6 months from registration. In multivariate analyses, patients who were enrolled in clinical studies/projects entitling them to free medications and retention staff (Odds Ratio [OR]: 0.65) or were on antiretroviral therapy (ART; OR: 0.37) or had a CD4 > 350 at the last visit (OR: 0.20) were significantly less likely to DO from clinical care. We observed a high rate of DO from clinical care at this tertiary HIV clinic in Chennai, India. Making ART available free of charge in the private sector and providing incentives/benefits for attending clinic visits as is routinely done in clinical trials might help improve retention. PMID- 25011520 TI - Determinants of quality of life during induction therapy in pediatric acute lymphoblastic leukemia. AB - PURPOSE: Improvement in survival of pediatric acute lymphoblastic leukemia (ALL) has increased the attention to quality of life (QoL) . QoL is impaired during maintenance treatment, but little is known about QoL during induction therapy. Identification of patients with poor QoL during induction will provide opportunities for early interventions, and may subsequently improve future QoL. This national multi-center study aimed to assess QoL and its determinants during ALL induction treatment. METHODS: Proxy reports of the Child Health Questionnaire (CHQ) and the PedsQL cancer version were collected. Child, treatment, and parental characteristics were analyzed as potential determinants in a multiple regression model. RESULTS: One hundred thirty parents of children participated (response rate 82 %), median child age was 5.7 years and 48 % were female. QoL, as measured with the CHQ, was significantly lower than the norm, the effect sizes were large, and the differences were clinically relevant. Physical QoL was more often affected than psychosocial QoL. Regression models could be constructed for 4/ 10 CHQ scales and 6/ 8 PedsQL cancer scales, accounting for 7 to 36 % of the variance in scores. Impaired QoL was most often associated with older children, girls, and time since diagnosis. Also, father respondents seem to have a lower QoL perception compared to mother respondents although this needs to be confirmed in future research. CONCLUSIONS: Specific counseling for subsets of patients with a higher risk of low QoL during the early phases of therapy is warranted. PMID- 25011521 TI - Clinical implications of malnutrition in childhood cancer patients--infections and mortality. AB - PURPOSE: In childhood cancer patients, malnutrition has been proposed to increase infection rates and reduce survival. We investigated whether malnutrition at diagnosis and during treatment and weight loss during treatment are prognostic factors for infection rates and survival, within a heterogeneous childhood cancer population. METHODS: From two previous studies, all children <=18 years of age diagnosed with cancer between October 2004 and October 2011 were included in this study. Data regarding BMI, infections, and survival were retrieved. Patients with a BMI z-score lower than -2.0 were classified as malnourished. Weight loss more than 5% was considered relevant. RESULTS: Two hundred sixty-nine childhood cancer patients were included in this study. At diagnosis, 5.2% of all patients were malnourished. These patients showed worse survival than those who were well nourished (hazard ratio (HR) = 3.63, 95% confidence interval (CI) = 1.52-8.70, p = 0.004). Malnourishment at 3 months after diagnosis (3.3% of all patients) also showed worse survival (HR = 6.34, 95% CI = 2.42-16.65, p < 0.001). Weight loss of more than 5% in the first 3 months after diagnosis was related to increased occurrence of febrile neutropenic episodes with bacteremia in the first year after diagnosis (odds ratio (OR) = 3.05, 95 % CI = 1.27-7.30, p = 0.012). CONCLUSION: We found that malnourishment in the initial phase of therapy is associated with worse survival in childhood cancer patients. In addition, we found for the first time that weight loss during treatment is associated with increased presence of febrile neutropenic episodes with bacteremia. This underlines the importance of optimal feeding designs in childhood cancer patients. PMID- 25011524 TI - Development of avian external genitalia: interspecific differences and sexual differentiation of the male and female phallus. AB - Avian genitalia, particularly in waterfowl, are extremely diverse. Penis morphology varies among species, and penis length and elaboration are associated with the frequency of forced extra-pair copulations, yet the developmental mechanisms responsible for this variation are unknown. In addition, females have a small phallic structure that is homologous to the male phallus, but little is known about when or how sexual differentiation takes place. To determine whether species-specific genital morphologies and sexual differentiation occur during duck embryonic development, we characterized development from the onset of genital tubercle initiation through stages of sexual differentiation in 3 species. Pekin and Laysan ducks have long, thick penises, whereas those of Mandarin ducks are shorter and thinner. Development of the genital tubercle is similar throughout the pre-hatching period across the 3 species, suggesting that differences in penis morphology arise post-hatching. We observed that male and female phallus development is similar at early stages, but the female phallus later regresses. Then, we compared male and female genital development between ducks and chickens, which develop a non-intromittent penis. We found that external genital development in male and female chickens resembles that of female ducks, which raises the possibility that male phallus development became feminized during galliform evolution. PMID- 25011525 TI - Non-specific lipid transfer proteins: a protein family in search of an allergenic pattern. PMID- 25011526 TI - Roles of CXCL5 on migration and invasion of liver cancer cells. AB - Inflammatory factors play a vital role in the progression of liver cancer, although exact factors and related mechanisms still remain unclear. The present study aimed at screening inflammatory factors related to liver cancer metastasis and investigating the potential mechanism by which cancer cells are recruited. We screened and validated inflammatory factors by microarray and RT-PCR. Small interfering RNA (siRNA) and recombinant protein were used to assess CXCL5 effects on the movement of liver cancer cells (LCCs). Our screening microarray demonstrated over-expression of CXCL5 in LCCs with high metastatic potentials. CXCL5 increased LCCs migration and invasion, probably through autocrine and paracrine mechanisms. CXCL5-CXCR2 and ERK1/2 pathways could play critical roles in the regulation of LCCs migration. Our data indicates that LCCs per se may act as the producer and receptor of CXCL5 responsible for liver cancer migration and invasion. PMID- 25011527 TI - The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Although the etiology of ASD remains elusive, converging lines of research indicate that mitochondrial dysfunction may play a substantive role in disease pathophysiology. Without an established causal link, the generation of therapeutic targets for ASD has been relatively unsuccessful and has focused solely on individual symptoms. The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has previously been used for the treatment of intractable epilepsy and is known to enhance mitochondrial function. The purpose of this study was to determine if the KD could reverse the social deficits and mitochondrial dysfunction identified in the prenatal valproic acid (VPA) rodent model of ASD. Sprague-Dawley dams were administered VPA or saline on gestational day 12.5. The pups were treated with the KD or their standard diet (SD) for 10 days beginning on postnatal day 21 (PD21). On PD35 juvenile play behavior was tested with the play-fighting paradigm and rats were then sacrificed for mitochondrial bioenergetic analysis. The offspring exposed to VPA prenatally demonstrated a significant decrease in the number of play initiations/attacks and this was reversed with the KD. Prenatal VPA exposure also disrupted the pattern of play responses; VPA/SD animals used complete rotations more often than saline control animals. Treatment with the KD did not affect the number of complete rotations. In addition, while prenatal exposure to VPA altered mitochondrial respiration, the KD was able to restore aspects of bioenergetic dysfunction. As the KD was able to modify complex social behaviors and mitochondrial respiration, it may be a useful treatment option for ASD. Future studies will need to examine the effectiveness of the KD to reverse the two additional core deficits of ASD and to explore various treatment regimens to determine optimal treatment duration and formulation. PMID- 25011529 TI - A treatment planning study comparing Elekta VMAT and fixed field IMRT using the varian treatment planning system eclipse. AB - BACKGROUND: The newest release of the Eclipse (Varian) treatment planning system (TPS) includes an optimizing engine for Elekta volumetric-modulated arc therapy (VMAT) planning. The purpose of this study was to evaluate this new algorithm and to compare it to intensity-modulated radiation therapy (IMRT) for various disease sites by creating single- and double-arc VMAT plans. METHODS: A total of 162 plans were evaluated in this study, including 38 endometrial, 57 head and neck, 12 brain, 10 breast and 45 prostate cancer cases. The real-life IMRT plans were developed during routine clinical cases using the TPS Eclipse. VMAT plans were generated using a preclinical version of Eclipse with tumor-region-specific optimizing templates without interference of the operator: with one full arc (1A) and with two full arcs (2A), and with partial arcs for breast and prostate with hip implant cases. All plans were evaluated based on target coverage, homogeneity and conformity. The organs at risk (OARs) were analyzed according to plan objectives, such as the mean and maximum doses. If one or more objectives were exceeded, the plan was considered clinically unacceptable, and a second VMAT plan was created by adapting the optimization penalties once. RESULTS: Compared to IMRT, single- and double-arc VMAT plans showed comparable or better results concerning the target coverage: the maximum dose in the target for 1A is the same as that for IMRT; for 2A, an average reduction of 1.3% over all plans was observed. The conformity showed a statistically significant improvement for both 1A (+3%) and 2A (+6%). The mean total body dose was statistically significant lower for the considered arc techniques (IMRT: 16.0 Gy, VMAT: 15.3 Gy, p < 0.001). However, the sparing of OARs shows individual behavior that depends strongly on the different tumor regions. A clear difference is found in the number of monitor units (MUs) per plan: VMAT shows a reduction of 31%. CONCLUSION: These findings demonstrate that based on optimizing templates with minimal interaction of the operator, the Eclipse TPS is able to achieve a plan quality for the Elekta VMAT delivery technique that is comparable to that of fixed-field IMRT. Plans with two arcs show better dose distributions than plans with one arc. PMID- 25011528 TI - Imaging the role of amyloid in PD dementia and dementia with Lewy bodies. AB - Cognitive impairment and dementia are significant sequelae of Parkinson disease (PD) and comprise a key feature of dementia with Lewy bodies (DLB), a disease with similar clinical and neuropathological features. Multiple independent causes have been implicated in PD dementia (PDD) and DLB, among them the accumulation of beta-amyloid, a neuropathological hallmark of Alzheimer disease. Over the last decade, PET imaging has emerged as a viable method to measure amyloid burden in the human brain and relate it to neurodegenerative diseases. This article reviews what amyloid imaging has taught us about PDD and DLB. Current data suggest that brain amyloid deposition tends to be more marked in DLB, yet contributes to cognitive impairment in both DLB and PD. These results are broadly consistent with neuropathology and CSF studies. beta-Amyloid may interact synergistically with other pathological processes in PD and DLB to contribute to cognitive impairment. PMID- 25011530 TI - Climate sensitivity runs and regional hydrologic modeling for predicting the response of the greater Florida Everglades ecosystem to climate change. AB - It is important to understand the vulnerability of the water management system in south Florida and to determine the resilience and robustness of greater Everglades restoration plans under future climate change. The current climate models, at both global and regional scales, are not ready to deliver specific climatic datasets for water resources investigations involving future plans and therefore a scenario based approach was adopted for this first study in restoration planning. We focused on the general implications of potential changes in future temperature and associated changes in evapotranspiration, precipitation, and sea levels at the regional boundary. From these, we developed a set of six climate and sea level scenarios, used them to simulate the hydrologic response of the greater Everglades region including agricultural, urban, and natural areas, and compared the results to those from a base run of current conditions. The scenarios included a 1.5 degrees C increase in temperature, +/-10 % change in precipitation, and a 0.46 m (1.5 feet) increase in sea level for the 50-year planning horizon. The results suggested that, depending on the rainfall and temperature scenario, there would be significant changes in water budgets, ecosystem performance, and in water supply demands met. The increased sea level scenarios also show that the ground water levels would increase significantly with associated implications for flood protection in the urbanized areas of southeastern Florida. PMID- 25011531 TI - Defining the reference condition for wadeable streams in the Sand Hills subdivision of the Southeastern Plains ecoregion, USA. AB - The Sand Hills subdivision of the Southeastern Plains ecoregion has been impacted by historical land uses over the past two centuries and, with the additive effects of contemporary land use, determining reference condition for streams in this region is a challenge. We identified reference condition based on the combined use of 3 independent selection methods. Method 1 involved use of a multivariate disturbance gradient derived from several stressors, method 2 was based on variation in channel morphology, and method 3 was based on passing 6 of 7 environmental criteria. Sites selected as reference from all 3 methods were considered primary reference, whereas those selected by 2 or 1 methods were considered secondary or tertiary reference, respectively. Sites not selected by any of the methods were considered non-reference. In addition, best professional judgment (BPJ) was used to exclude some sites from any reference class, and comparisons were made to examine the utility of BPJ. Non-metric multidimensional scaling indicated that use of BPJ may help designate non-reference sites when unidentified stressors are present. The macroinvertebrate community measures Ephemeroptera, Plecoptera, Trichoptera richness and North Carolina Biotic Index showed no differences between primary and secondary reference sites when BPJ was ignored. However, there was no significant difference among primary, secondary, and tertiary reference sites when BPJ was used. We underscore the importance of classifying reference conditions, especially in regions that have endured significant anthropogenic activity. We suggest that the use of secondary reference sites may enable construction of models that target a broader set of management interests. PMID- 25011532 TI - Residential preferences for river network improvement: an exploration of choice experiments in Zhujiajiao, Shanghai, China. AB - River networks have both ecological and social benefits for urban development. However, river networks have suffered extensive destruction as a result of urbanization and industrialization, especially in China. River restoration is a growth business but suffers poor efficiency due to a lack of social understanding. Assessing the benefits of river system restoration and recognizing public preferences are critical for effective river ecosystem restoration and sustainable river management. This study used a choice experiment with a multinomial logit model and a random parameter logit model to assess respondents' cognitive preferences regarding attributes of river networks, and their possible sources of heterogeneity. Results showed that riverfront condition was the attribute most preferred by respondents, while stream morphology was the least preferred. Results also illustrated that the current status of each of three river network attributes was not desirable, and respondents would prefer a river network with a "branch pattern," that is "limpid with no odor," and "accessible with vegetation." Estimated willingness to pay was mainly affected by household monthly income, residential location, and whether respondents had household members engaged in a water protection career. The assessment results can provide guidance and a reference for managers, sponsors, and researchers. PMID- 25011533 TI - The stakeholder preference for best management practices in the Three Gorges Reservoir Region. AB - A qualitative analysis of in-depth interviews with 92 farmers and 42 policy managers in Wuxi County, the Three Gorges Reservoir Region, was conducted to identify stakeholder preferences for alternative best management practices (BMPs) and to determine the factors that affect their acceptance. Policy manager support for most of the practices was relatively stronger than support by farmers, except for the grade stabilization structure (GSS), hillside ditch (HD) and constructed wetland alternative, owing to their perceptions of soil benefits, economic advantages and environmental advantages. Farmers opposed those practices that occupied cultivated lands or changed the conventional planting methods, such as field border, conservation tillage (CT) and contour buffer strips. They tended to accept the BMPs with off-farm pollution reduction, such as GSS, riparian forest buffer and HD, and the BMPs associated with soil benefits, such as nutrient management and Terrace. The result that almost all respondents did not accept CT differed from reports in the existing literature. There is a significant correlation between the acceptance of some BMPs and the townships where the farmers lived (P <= 0.05). The environmental conditions and social factors would affect farmer support for BMPs, including local soil conditions, farming methods, economic income, education level and age. The economic advantages of the BMPs were the main motivation for farmers to accept the practices. Furthermore, intensive education efforts, financial incentives or economic subsidies may promote the adoption of the BMPs in our study area. PMID- 25011534 TI - Quantification of stenotic mitral valve area and diagnostic accuracy of mitral stenosis by dual-source computed tomography in patients with atrial fibrillation: comparison with cardiovascular magnetic resonance and transthoracic echocardiography. AB - This study aimed to evaluate the utility of dual-source computed tomography (DSCT) for quantification of the mitral valve area (MVA) in patients with atrial fibrillation (AF) and mitral stenosis (MS) and to compare the results of DSCT with those of cardiovascular magnetic resonance (CMR) and transthoracic echocardiography (TTE). One hundred-two patients with AF and MS who had undergone electrocardiography-gated DSCT, TTE and CMR prior to operation were retrospectively enrolled. The MVA was planimetrically determined by DSCT, CMR, and TTE, as well as by Doppler TTE using the pressure half-time method (TTE-PHT). Agreement, relationship between measurements, and the highest accuracy were evaluated using Bland-Altman, Pearson correlation, and receiver operating characteristic analyses. The MVA on DSCT (mean, 1.27 +/- 0.27 cm(2)) was significantly larger than that on CMR (1.15 +/- 0.28 cm(2), P < 0.05), TTE planimetry and TTE-PHT (1.16 +/- 0.28 and 1.07 +/- 0.30 cm(2), respectively; P < 0.05). TTE-planimetry had better correlation with planimetry on DSCT and CMR (r = 0.65 and 0.67, respectively; P < 0.05) than TTE-PHT (r = 0.51 and 0.55, respectively; P < 0.05). Using an MVA of 1.0 cm(2) on TTE-planimetry and TTE-PHT as the reference, the optimal thresholds for detecting severe MS on DSCT was 1.19 cm(2). The planimetry of the MVA measured by DSCT may be a reliable, alternative method for the quantification of MS in patients with AF. PMID- 25011535 TI - Dual-energy cardiac computed tomography for differentiating cardiac myxoma from thrombus. AB - Although intra-cardiac masses are rare, diagnosis and refined characterization of these masses are important because of the different therapeutic strategies used to treat these lesions. The purpose of this study was to evaluate the diagnostic value of dual-energy cardiac computed tomography (CCT) for differentiating cardiac myxomas from thrombi. Our institutional review board approved this study, and patients provided informed consent. We prospectively enrolled 37 patients who had an intra-cardiac mass on echocardiography or computed tomography (CT). All patients underwent dual-energy CCT. For quantitative analysis, the CT attenuation density and iodine concentration of the intra-cardiac mass were measured on CT images. The Mann-Whitney test was used to evaluate differences in the mean CT attenuation density and the mean iodine concentrations between the cardiac myxoma and thrombus groups. Pathological results or follow-up with echocardiography was used to make the final diagnosis. There were a total of 17 cardiac myxomas and 20 thrombi. On CT, the mean CT numbers were not significantly different between cardiac myxomas and cardiac thrombi (91.7 +/- 11.6 HU vs. 85.2 +/- 10.9 HU, respectively, P = 0.241), whereas, the mean iodine concentration (mg/ml) was significantly different between cardiac myxomas and cardiac thrombi (3.53 +/- 0.72 vs. 1.37 +/- 0.31, respectively, P < 0.001). Dual-energy CCT using a quantitative analytic methodology can be used to differentiate between cardiac myxomas and thrombi. PMID- 25011536 TI - Label-free voltammetric aptasensor for the sensitive detection of microcystin-LR using graphene-modified electrodes. AB - The development of successful biosensing platforms is highly dependent upon the biorecognition properties of the recognition receptor and the sensitivity of the transducer of the binding signal. The integration of the high affinity and specificity of DNA aptamers with the unique properties of the carbon nanomaterial graphene offers an excellent avenue for sensitive and selective biosensing architectures. In this work, a highly sensitive and selective aptasensor which utilizes an unlabeled DNA aptamer assembled on a graphene electrode for microcystin-LR detection was developed. A facile strategy was used for the aptasensor fabrication on the basis of the noncovalent assembly of DNA aptamer on graphene-modified screen printed carbon electrodes. Assembly of the DNA aptamer on the graphene-modified electrodes caused a marked drop in the square wave voltammetric reduction signal of the [Fe(CN)6](4-/3-) redox couple. The presence of microcystin-LR, on the other hand, caused a dose-responsive increase in peak current, allowing the quantification of microcystin-LR through the measurement of peak current change. Under optimal conditions, the detection limit of the developed aptasensor was 1.9 pM in buffer, a concentration much lower than those offered by previously reported biosensors for microcystin-LR. The developed aptasensor also exhibited excellent selectivity for microcystin-LR with no detectable cross-reactivity to okadaic acid, microcystin-LA, and microcystin-YR. Moreover, the proposed aptasensor has been applied for the analysis of spiked tap water and fish samples showing good recovery percentages. This novel, simple, high-performance, and low-cost detection platform would facilitate the routine monitoring of microcystin-LR in real samples. PMID- 25011537 TI - Translational selection in human: more pronounced in housekeeping genes. AB - BACKGROUND: Translational selection is a ubiquitous and significant mechanism to regulate protein expression in prokaryotes and unicellular eukaryotes. Recent evidence has shown that translational selection is weakly operative in highly expressed genes in human and other vertebrates. However, it remains unclear whether translational selection acts differentially on human genes depending on their expression patterns. RESULTS: Here we report that human housekeeping (HK) genes that are strictly defined as genes that are expressed ubiquitously and consistently in most or all tissues, are under stronger translational selection. CONCLUSIONS: These observations clearly show that translational selection is also closely associated with expression pattern. Our results suggest that human HK genes are more efficiently and/or accurately translated into proteins, which will inevitably open up a new understanding of HK genes and the regulation of gene expression. REVIEWERS: This article was reviewed by Yuan Yuan, Baylor College of Medicine; Han Liang, University of Texas MD Anderson Cancer Center (nominated by Dr Laura Landweber) Eugene Koonin, NCBI, NLM, NIH, United States of America Sandor Pongor, International Centre for Genetic Engineering and biotechnology (ICGEB), Italy. PMID- 25011538 TI - Individual education, area income, and mortality and recurrence of myocardial infarction in a Medicare cohort: the National Longitudinal Mortality Study. AB - BACKGROUND: The Medicare program provides universal access to hospital care for the elderly; however, mortality disparities may still persist in this population. The association of individual education and area income with survival and recurrence post Myocardial Infarction (MI) was assessed in a national sample. METHODS: Individual level education from the National Longitudinal Mortality Study was linked to Medicare and National Death Index records over the period of 1991-2001 to test the association of individual education and zip code tabulation area median income with survival and recurrence post-MI. Survival was partitioned into 3 periods: in-hospital, discharge to 1 year, and 1 year to 5 years and recurrence was partitioned into two periods: 28 day to 1 year, and 1 year to 5 years. RESULTS: First MIs were found in 8,043 women and 7,929 men. In women and men 66-79 years of age, less than a high school education compared with a college degree or more was associated with 1-5 year mortality in both women (HRR 1.61, 95% confidence interval 1.03-2.50) and men (HRR 1.37, 1.06-1.76). Education was also associated with 1-5 year recurrence in men (HRR 1.68, 1.18-2.41, < High School compared with college degree or more), but not women. Across the spectrum of survival and recurrence periods median zip code level income was inconsistently associated with outcomes. Associations were limited to discharge-1 year survival (RR lowest versus highest quintile 1.31, 95% confidence interval 1.03-1.67) and 28 day-1 year recurrence (RR lowest versus highest quintile 1.72, 95% confidence interval 1.14-2.57) in older men. CONCLUSIONS: Despite the Medicare entitlement program, disparities related to individual socioeconomic status remain. Additional research is needed to elucidate the barriers and mechanisms to eliminating health disparities among the elderly. PMID- 25011541 TI - Mechano-responsive polymer solutions based on CO2 supersaturation: shaking induced phase transitions and self-assembly or dissociation of polymeric nanoparticles. AB - Mechanical stimulation of supersaturated aqueous CO2 solutions is accompanied by a pH increase within seconds. In solutions of tailored homo- and AB diblock copolymers this is exploited to induce micelle formation, or, taking advantage of an aqueous upper critical solution temperature transition, nanoparticle disassembly. PMID- 25011540 TI - Inflammatory expression profiles in monocyte-to-macrophage differentiation in patients with systemic lupus erythematosus and relationship with atherosclerosis. AB - INTRODUCTION: Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes' expression is related to atherosclerosis in SLE. METHODS: Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined. RESULTS: Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors. CONCLUSIONS: Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis. PMID- 25011539 TI - Therapeutic targeting of microRNAs: current status and future challenges. AB - MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that have crucial roles in regulating gene expression. Increasing evidence supports a role for miRNAs in many human diseases, including cancer and autoimmune disorders. The function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies for several diseases. In this Review we summarize our current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides, discuss various in vivo delivery strategies and analyse ongoing challenges to ensure the specificity and efficacy of therapeutic oligonucleotides in vivo. Finally, we review current progress on the clinical development of miRNA-targeting therapeutics. PMID- 25011542 TI - Retrospective analysis of severe neutropenia in patients receiving concomitant administration of docetaxel and clarithromycin. AB - BACKGROUND: Neutropenia is one of the most important dose-limiting toxicities of docetaxel. Docetaxel is metabolized by cytochrome P450 3A4 (CYP3A4). Clarithromycin, a potent inhibitor of CYP3A4, is occasionally used in combination with docetaxel. The aim of this study was to evaluate whether the risk of severe neutropenia induced by docetaxel was increased by concomitant administration of clarithromycin. METHODS: Patients with advanced lung cancer receiving docetaxel were identified from an electronic medical record system and divided into 2 groups: concomitant administration of clarithromycin and no concomitant administration of clarithromycin. The proportion of patients experiencing grade 4 neutropenia between the 2 groups was compared. Potential risk factors associated with grade 4 neutropenia were also examined using univariate and multivariate logistic regression analyses. RESULTS: One hundred and fifty-eight patients were analysed. Grade 4 neutropenia was more frequently detected in the patients receiving clarithromycin than in those not receiving the drug (63.2 vs. 35.3%; p = 0.025). Multivariate analysis showed that co-administration of clarithromycin [odds ratio (OR) 4.98; p = 0.004], pre-treatment absolute neutrophil count (OR 2.62; p = 0.011) and female gender (OR 2.75; p = 0.029) resulted in an increase in the incidence of grade 4 neutropenia. CONCLUSIONS: This study shows that concomitant administration of clarithromycin potentiated docetaxel-induced myelosuppression. PMID- 25011543 TI - Spatiotemporal characteristics of pandemic influenza. AB - BACKGROUND: Prediction of timing for the onset and peak of an influenza pandemic is of vital importance for preventive measures. In order to identify common spatiotemporal patterns and climate influences for pandemics in Sweden we have studied the propagation in space and time of A(H1N1)pdm09 (10,000 laboratory verified cases), the Asian Influenza 1957-1958 (275,000 cases of influenza-like illness (ILI), reported by local physicians) and the Russian Influenza 1889-1890 (32,600 ILI cases reported by physicians shortly after the end of the outbreak). METHODS: All cases were geocoded and analysed in space and time. Animated video sequences, showing weekly incidence per municipality and its geographically weighted mean (GWM), were created to depict and compare the spread of the pandemics. Daily data from 1957-1958 on temperature and precipitation from 39 weather stations were collected and analysed with the case data to examine possible climatological effects on the influenza dissemination. RESULTS: The epidemic period lasted 11 weeks for the Russian Influenza, 10 weeks for the Asian Influenza and 9 weeks for the A(H1N1)pdm09. The Russian Influenza arrived in Sweden during the winter and was immediately disseminated, while both the Asian Influenza and the A(H1N1)pdm09 arrived during the spring. They were seeded over the country during the summer, but did not peak until October-November. The weekly GWM of the incidence moved along a line from southwest to northeast for the Russian and Asian Influenza but northeast to southwest for the A(H1N1)pdm09. The local epidemic periods of the Asian Influenza were preceded by falling temperature in all but one of the locations analysed. CONCLUSIONS: The power of spatiotemporal analysis and modeling for pandemic spread was clearly demonstrated. The epidemic period lasted approximately 10 weeks for all pandemics. None of the pandemics had its epidemic period before late autumn. The epidemic period of the Asian Influenza was preceded by falling temperatures. Climate influences on pandemic spread seem important and should be further investigated. PMID- 25011544 TI - Long-lasting changes in brain activation induced by a single REAC technology pulse in Wi-Fi bands. Randomized double-blind fMRI qualitative study. AB - The aim of this randomized double-blind study was to evaluate in healthy adult subjects, with functional magnetic resonance imaging (fMRI), long lasting changes in brain activation patterns following administration of a single, 250 milliseconds pulse emitted with radio-electric asymmetric conveyer (REAC) technology in the Wi-Fi bands. The REAC impulse was not administered during the scan, but after this, according to a protocol that has previously been demonstrated to be effective in improving motor control and postural balance, in healthy subjects and patients. The study was conducted on 33 healthy volunteers, performed with a 1.5 T unit while operating a motor block task involving cyclical and alternating flexion and extension of one leg. Subsequently subjects were randomly divided into a treatment and a sham treatment control group. Repeated fMRI examinations were performed following the administration of the REAC pulse or sham treatment. The Treated group showed cerebellar and ponto-mesencephalic activation components that disappeared in the second scan, while these activation components persisted in the Sham group. This study shows that a very weak signal, such as 250 milliseconds Wi-Fi pulse, administered with REAC technology, could lead to lasting effects on brain activity modification. PMID- 25011545 TI - Myofibroblastic stromal reaction and lymph node status in invasive breast carcinoma: possible role of the TGF-beta1/TGF-betaR1 pathway. AB - BACKGROUND: The microenvironment modulates tissue specificity in the normal breast and in breast cancer. The stromal loss of CD34 expression and acquisition of SMA myofibroblastic features may constitute a prerequisite for tumor invasiveness in breast carcinoma. The aim of the present study is to examine the stromal expression of CD34 and SMA in cases of invasive ductal carcinoma and to try to demonstrate the role played by the TGF-beta 1 et TGF-beta R1 pathway in the transformation of normal breast fibrocytes into myofibroblasts. METHODS: We carried out an immunohistochemical study of CD34, SMA, TGF-beta and TGF-beta R1 on a series of 155 patients with invasive ductal carcinoma. We also treated a breast fibrocytes cell line with TGF-beta1. RESULTS: We found a loss of stromal expression of CD34 with the appearance of a myofibroblastic reaction in almost 100% cases of invasive ductal carcinoma. The strong stromal expression of SMA correlates with the presence of lymph node metastases. We were also able to show a greater expression of TGF-beta in the tumor cells as well as a higher expression of TGF- beta R1 in the tumor stroma compared to normal breast tissue. Finally, we demonstrated the transformation of breast fibrocytes into SMA positive myofibroblasts after being treated with TGF-beta1. CONCLUSIONS: Our study demonstrated that a significant tumor myofibroblastic reaction is correlated with the presence of lymph node metastasis and that this myofibroblastic reaction can be induced by TGF-beta1. Future research on fibrocytes, myofibroblasts, TGF-beta and stromal changes mechanisms is essential in the future and may potentially lead to new treatment approaches. PMID- 25011546 TI - The history of Chagas disease. AB - The ancestor of Trypanosome cruzi was probably introduced to South American via bats approximately 7-10 million years ago. When the first humans arrived in the New World, a sylvatic cycle of Chagas disease was then already well established. Paleoparasitological data suggests that human American trypanosomiasis originated in the Andean area when people founded the first settlements in the coastal region of the Atacama Desert. Identification of T. cruzi as the etiological agent and triatome bugs as the transmission vector of Chagas disease occurred within a few years at the beginning of the 20th century. History also teaches us that human activity leading to environmental changes, in particular deforestation, is the main cause for the spread of Chagas disease. Recently, migration of T. cruzi infected patients has led to a distribution of Chagas disease from Latin America to non-endemic countries in Europe, North America and western Pacific region. PMID- 25011547 TI - Comparative photo-release of nitric oxide from isomers of substituted terpyridinenitrosylruthenium(II) complexes: experimental and computational investigations. AB - The 4'-(2-fluorenyl)-2,2':6',2''-terpyridine (FT) ligand and its cis(Cl,Cl)- and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6) complexes have been synthesized. Both isomers were separated by HPLC and fully characterized by (1)H and (13)C NMR. The X-ray diffraction crystal structures were solved for FT (Pna21 space group, a = 34.960(4), b = 5.9306(7), c = 9.5911(10) A), and trans(Cl,Cl) [Ru(II)(FT)Cl2(NO)](PF6).MeOH (P1[combining macron] space group, a = 10.3340(5), b = 13.0961(6), c = 13.2279(6) A, alpha = 72.680(2), beta = 70.488(2), gamma = 67.090(2) degrees ). Photo-release of NO radicals occurs under irradiation at 405 nm, with a quantum yield of 0.31 and 0.10 for cis(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6) and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6), respectively. This significant difference is likely due to the trans effect of Cl(-), which favors the photo release. UV-visible spectroscopy and cyclic voltammetry indicate the formation of ruthenium(iii) species as photoproducts. A density functional theory (DFT) analysis provides a rationale for the understanding of the photo-physical properties, and allows relating the weakening of the Ru-NO bond, and finally the photo-dissociation, to HOMO -> LUMO excitations. PMID- 25011548 TI - Did the new French pay-for-performance system modify benzodiazepine prescribing practices? AB - BACKGROUND: French general practitioners (GPs) were enrolled in a new payment system in January 2012. As part of a national agreement with the French National Ministry of Health, GPs were asked to decrease the proportion of patients who continued their benzodiazepine treatment 12 weeks after its initiation and to decrease the proportion of patients older than 65 who were prescribed long half life benzodiazepines. In return, GPs could expect an extra payment of up to 490 euros per year. This study reports the evolution of the corresponding prescribing practices of French GPs during that period regarding patients who were prescribed a benzodiazepine for the first time. METHODS: The national healthcare system's administrative database was used to report the longitudinal follow-up of two historical cohorts of French patients from the Pays de la Loire area. STUDY PATIENTS: The "2011" and "2012" cohorts included all patients who initiated benzodiazepine regimens from April 1 to June 30 in 2011 and 2012, respectively.The primary outcomes were the proportion of those study patients who continued benzodiazepine treatment after 12 weeks and the proportion of study patients >65 years who were prescribed long half-life benzodiazepines.Analyses were performed using a multi-level regression. RESULTS: In total, 41,436 and 42,042 patients initiated benzodiazepine treatment in 2011 and 2012, respectively. A total of 18.97% of patients continued treatment for more than 12 weeks in 2012, compared with 18.18% in 2011. In all, 27.43% and 28.06% of patients >65 years continued treatment beyond 12 weeks in 2011 and 2012, respectively. The proportion of patients >65 years who were prescribed long half life benzodiazepines decreased from 53.5% to 48.8% (p < 0.005) due to an increase in short half-life benzodiazepine prescriptions. Patients >65 years who were prescribed short half-life benzodiazepines were more likely to continue treatment after 12 weeks (p < 0.005). CONCLUSIONS: Despite the pay-for-performance strategy, the number of short half-life benzodiazepine prescriptions increased between 2011 and 2012, and the number of long half-life benzodiazepine initiations remained unchanged. Reducing the proportion of long half-life benzodiazepine prescriptions might be counterproductive because prescribing short half-life benzodiazepines was associated with higher rates of continuation beyond the recommended duration. PMID- 25011549 TI - Exposure to volatile organic compounds in healthcare settings. AB - OBJECTIVES: To identify and summarise volatile organic compound (VOC) exposure profiles of healthcare occupations. METHODS: Personal (n=143) and mobile area (n=207) evacuated canisters were collected and analysed by a gas chromatograph/mass spectrometer to assess exposures to 14 VOCs among 14 healthcare occupations in five hospitals. Participants were volunteers identified by their supervisors. Summary statistics were calculated by occupation. Principal component analysis (PCA) was used to reduce the 14 analyte inputs to five orthogonal factors and identify occupations that were associated with these factors. Linear regressions were used to assess the association between personal and mobile area samples. RESULTS: Exposure profiles differed among occupations; ethanol had the highest geometric mean (GM) among nursing assistants (~4900 and ~1900 ug/m(3), personal and area), and 2-propanol had the highest GM among medical equipment preparers (~4600 and ~2000 ug/m(3), personal and area). The highest total personal VOC exposures were among nursing assistants (~9200 ug/m(3)), licensed practical nurses (~8700 ug/m(3)) and medical equipment preparers (~7900 ug/m(3)). The influence of the PCA factors developed from personal exposure estimates varied by occupation, which enabled a comparative assessment of occupations. For example, factor 1, indicative of solvent use, was positively correlated with clinical laboratory and floor stripping/waxing occupations and tasks. Overall, a significant correlation was observed (r=0.88) between matched personal and mobile area samples, but varied considerably by analyte (r=0.23-0.64). CONCLUSIONS: Healthcare workers are exposed to a variety of chemicals that vary with the activities and products used during activities. These VOC profiles are useful for estimating exposures for occupational hazard ranking for industrial hygienists as well as epidemiological studies. PMID- 25011551 TI - Involuntary detrusor contraction is a frequent finding in patients with recurrent urinary tract infections. AB - OBJECTIVE: To check whether subtle voiding dysfunction is related to recurrent urinary tract infection (rUTI). METHODS: 254 consecutive patients with at least four episodes of urinary tract infection (UTI) were studied. At least three repeat urodynamic evaluations with an additional ice water test to maximize the detection of involuntary detrusor contraction (IDC) were used. Stress urinary incontinence cases were used as controls. Nonparametric univariate and multivariate analyses were used for statistics. RESULTS: IDC was detected in 83.6% of patients in the rUTI group and in 31.7% in the control group. IDC was <15 cm H2O in 54.7% whereas high-amplitude (>50 cm H2O) IDC was observed in 6.8% in the rUTI group. Female urinary tract obstruction was diagnosed in 16.8% of patients in the rUTI group and in 7.9% in the control group. Residual volume, PdetQmax and Qmax were not predictive of UTI recurrence. Symptoms were similar in both groups. CONCLUSIONS: Patients with rUTI present with covert bladder dysfunctions represented by detrusor overactivity. PMID- 25011550 TI - Histone deacetylase expression patterns in developing murine optic nerve. AB - BACKGROUND: Histone deacetylases (HDACs) play important roles in glial cell development and in disease states within multiple regions of the central nervous system. However, little is known about HDAC expression or function within the optic nerve. As a first step in understanding the role of HDACs in optic nerve, this study examines the spatio-temporal expression patterns of methylated histone 3 (K9), acetylated histone 3 (K18), and HDACs 1-6 and 8-11 in the developing murine optic nerve head. RESULTS: Using RT-qPCR, western blot and immunofluorescence, three stages were analyzed: embryonic day 16 (E16), when astrocyte precursors are found in the optic stalk, postnatal day 5 (P5), when immature astrocytes and oligodendrocytes are found throughout the optic nerve, and P30, when optic nerve astrocytes and oligodendrocytes are mature. Acetylated and methylated histone H3 immunoreactivity was co-localized in the nuclei of most SOX2 positive glia within the optic nerve head and adjacent optic nerve at all developmental stages. HDACs 1-11 were expressed in the optic nerve glial cells at all three stages of optic nerve development in the mouse, but showed temporal differences in overall levels and subcellular localization. HDACs 1 and 2 were predominantly nuclear throughout optic nerve development and glial cell maturation. HDACs 3, 5, 6, 8, and 11 were predominantly cytoplasmic, but showed nuclear localization in at least one stage of optic nerve development. HDACs 4, 9 and10 were predominantly cytoplasmic, with little to no nuclear expression at any time during the developmental stages examined. CONCLUSIONS: Our results showing that HDACs 1, 2, 3, 5, 6, 8, and 11 were each localized to the nuclei of SOX2 positive glia at some stages of optic nerve development and maturation and extend previous reports of HDAC expression in the aging optic nerve. These HDACs are candidates for further research to understand how chromatin remodeling through acetylation, deacetylation and methylation contributes to glial development as well as their injury response. PMID- 25011552 TI - Transformational leadership in the local police in Spain: a leader-follower distance approach. AB - Based on the transformational leadership theory (Bass, 1985), the aim of the present study was to analyze the differences in leadership styles according to the various leading ranks and the organizational follower-leader distance reported by a representative sample of 975 local police members (828 male and 147 female) from Valencian Community (Spain). Results showed differences by rank (p < .01), and by rank distance (p < .05). The general intendents showed the most optimal profile of leadership in all the variables examined (transformational leadership behaviors, transactional-leadership behaviors, laissez-faire behaviors, satisfaction with the leader, extra effort by follower, and perceived leadership effectiveness). By contrast, the least optimal profiles were presented by intendents. Finally, the maximum distance (five ranks) generally yielded the most optimal profiles, whereas the 3-rank distance generally produced the least optimal profiles for all variables examined. Outcomes and practical implications for the workforce dimensioning are also discussed. PMID- 25011553 TI - Prevention of Salmonella contamination of finished soybean meal used for animal feed by a Norwegian production plant despite frequent Salmonella contamination of raw soy beans, 1994-2012. AB - BACKGROUND: Salmonella contaminated animal feed is a major source for introducing Salmonella into the animal derived food chain. Because soybeans frequently are contaminated with Salmonella, soybean meal used as animal feed material, a by product of a "crushing plant" which produces oil from soybeans, can be important source of Salmonella in the animal feed. RESULTS: During the 19-year period, 34% of samples collected during unloading of ships delivering soybeans yielded Salmonella; the proportion of samples from ships that yielded Salmonella varied from 12-62% each year. Dust samples from all shiploads from South America yielded Salmonella. In total 94 serovars of Salmonella were isolated, including nine (90%) of the EU 2012 top ten serovars isolated from clinical cases of salmonellosis in humans, including major animal pathogenic serovars like Spp. Typhimurium and Enteritidis. CONCLUSIONS: This study shows that a HAACP-based control program in a soybean crushing plant can produce Salmonella free soybean meal despite frequent Salmonella contamination of raw soybeans. That approach is suggested as an effective way to minimize the risk of Salmonella exposure of the animal feed mills and contamination of the subsequent animal feed chain. PMID- 25011554 TI - In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. AB - Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. PMID- 25011555 TI - Light-induced collective pseudospin precession resonating with Higgs mode in a superconductor. AB - Superconductors host collective modes that can be manipulated with light. We show that a strong terahertz light field can induce oscillations of the superconducting order parameter in NbN with twice the frequency of the terahertz field. The result can be captured as a collective precession of Anderson's pseudospins in ac driving fields. A resonance between the field and the Higgs amplitude mode of the superconductor then results in large terahertz third harmonic generation. The method we present here paves a way toward nonlinear quantum optics in superconductors with driving the pseudospins collectively and can be potentially extended to exotic superconductors for shedding light on the character of order parameters and their coupling to other degrees of freedom. PMID- 25011557 TI - Aflatoxin exposure may not play a role in liver cancer development in Mongolia. AB - BACKGROUND/AIMS: The incidence of hepatocellular carcinoma (HCC) in Mongolia is growing at an alarming rate. Traditional dried food was suggested as the major reason for high HCC numbers, due to possible aflatoxin contamination during manufacturing. We thus aimed to measure aflatoxin concentrations in Mongolian food samples. METHODS: Samples of traditional Mongolian food ('aaruul', dried meat, and dried noodles; in total 11 samples) were collected and shipped to Germany. The food samples were analyzed for aflatoxins by extraction, immunoaffinity purification, and subsequent HPLC with fluorescence detection. RESULTS: The traditional Mongolian food samples did not contain any detectable amounts of aflatoxin. CONCLUSION: Since Mongolian food does not contain aflatoxins, the cause for the increasing HCC incidence in Mongolia is probably due to a high prevalence of viral hepatitides. Further studies to identify the reason for this development are warranted. PMID- 25011558 TI - Assessment of a self-regulated learning intervention. AB - Following a pretest-posttest design with no control group, this paper evaluates the efficacy of an intervention program. Consisting of twelve sessions, the program endeavored to increase knowledge and use of self-regulated learning strategies, as well as study time, in 277 first-year students in the Spanish secondary education system. The intervention's efficacy was assessed in terms of three variables: knowledge of self-regulated learning strategies, use of self regulated learning strategies, and study time. The results of post-intervention data analysis indicate that statistically significant changes occurred in students' knowledge of self-regulated learning strategies and weekly study time, but not in their use of self-regulated learning strategies. When the sample was stratified into three groups (high, moderate, and low) according to baseline scores on the dependent variables, our findings show that students in the lower group profited most from the intervention on all three variables. This suggests that participation in the program is especially useful for at-risk students (i.e. those with little knowledge and use of effective learning strategies). PMID- 25011559 TI - Quinoxaline, its derivatives and applications: A State of the Art review. AB - Quinoxaline derivatives are an important class of heterocycle compounds, where N replaces some carbon atoms in the ring of naphthalene. Its molecular formula is C8H6N2, formed by the fusion of two aromatic rings, benzene and pyrazine. It is rare in natural state, but their synthesis is easy to perform. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the quinoxaline and quinoxaline derivatives, associated medical and biomedical value as well as industrial value. Modifying quinoxaline structure it is possible to obtain a wide variety of biomedical applications, namely antimicrobial activities and chronic and metabolic diseases treatment. PMID- 25011560 TI - Molecular structure of the NQTrp inhibitor with the Alzheimer Abeta1-28 monomer. AB - The self-assembly of the amyloid-beta (Abeta) peptide of various amino acid lengths into senile plaques is one hallmark of Alzheimer's disease pathology. In the past decade, many small molecules, including NQTrp, have been identified to reduce aggregation and toxicity. However, due to the heterogeneity of the conformational ensemble of Abeta with drugs, we lack detailed structures of the transient complexes. Following our previous simulation of the monomer of Abeta1 28, here we characterize the equilibrium ensemble of the Abeta1-28 monomer with NQTrp by means of extensive atomistic replica exchange molecular dynamics simulations using a force field known to fold diverse proteins correctly. While the secondary structure content and the intrinsic disorder of the whole peptides are very similar and the lifetimes of the salt-bridges remain constant, the population of beta-hairpin is reduced by a factor of 1.5 and the population of alpha-helix in the region 17-24 is increased by a factor of two upon NQTrp binding. These two factors, which impact the free energy barrier for nucleation, provide a first explanation for the reported reduced Abeta1-40/1-42 aggregation kinetics in the presence of NQTrp. Backbone and side-chain interactions of Abeta with NQTrp may also inhibit Abeta-Abeta contacts. The fraction of free Abeta1-28 monomer is, however, on the order of 20-25% at 17.5 mM, and this shows that the affinity of NQTrp is low and hence its inhibitory activity is not very strong. This inhibitor can be improved to reduce the formation of dimer, a critical step in aggregation and toxicity. PMID- 25011562 TI - Puzzling over protein cysteine phosphorylation--assessment of proteomic tools for S-phosphorylation profiling. AB - Cysteine phosphorylation has recently been discovered in both prokaryotic and eukaryotic systems, and is thought to play crucial roles in signaling and regulation of cellular responses. This article explores the topics of chemical stability of this type of structural modification and the resulting issues regarding affinity enrichment of S-phosphopeptides and their mass spectrometry based detection in the course of general proteomics studies. Together, this work suggests that the current advances in phosphoproteomic methodologies provide adequate tools for investigating protein cysteine phosphorylation and appear to be immediately available for practical implementation. The article provides useful information necessary for designing experiments in the emerging cysteine phosphoproteomics. The examples of methodological proposals for S-linked phosphorylation detection are included herein in order to stimulate development of new approaches by the phosphoproteomic community. PMID- 25011561 TI - Modelling mechanism of calcium oscillations in pancreatic acinar cells. AB - We present a simple model for calcium oscillations in the pancreatic acinar cells. This model is based on the calcium release from two receptors, inositol trisphosphate receptors (IPR) and ryanodine receptors (RyR) through the process of calcium induced calcium release (CICR). In pancreatic acinar cells, when the Ca2+ concentration increases, the mitochondria uptake it very fast to restrict Ca(2+) response in the cell. Afterwards, a much slower release of Ca2+ from the mitochondria serves as a calcium supply in the cytosol which causes calcium oscillations. In this paper we discuss a possible mechanism for calcium oscillations based on the interplay among the three calcium stores in the cell: the endoplasmic reticulum (ER), mitochondria and cytosol. Our model predicts that calcium shuttling between ER and mitochondria is a pacemaker role in the generation of Ca2+ oscillations. We also consider the calcium dependent production and degradation of (1,4,5) inositol-trisphosphate (IP3), which is a key source of intracellular calcium oscillations in pancreatic acinar cells. In this study we are able to predict the different patterns of calcium oscillations in the cell from sinusoidal to raised-baseline, high frequency and low-frequency baseline spiking. PMID- 25011563 TI - Genetically engineered Thompson Seedless grapevine plants designed for fungal tolerance: selection and characterization of the best performing individuals in a field trial. AB - The fungi Botrytis cinerea and Erysiphe necator are responsible for gray mold and powdery mildew diseases, respectively, which are among the most devastating diseases of grapes. Two endochitinase (ech42 and ech33) genes and one N-acetyl beta-D-hexosaminidase (nag70) gene from biocontrol agents related to Trichoderma spp. were used to develop a set of 103 genetically modified (GM) 'Thompson Seedless' lines (568 plants) that were established in open field in 2004 and evaluated for fungal tolerance starting in 2006. Statistical analyses were carried out considering transgene, explant origin, and plant response to both fungi in the field and in detached leaf assays. The results allowed for the selection of the 19 consistently most tolerant lines through two consecutive years (2007-2008 and 2008-2009 seasons). Plants from these lines were grafted onto the rootstock Harmony and established in the field in 2009 for further characterization. Transgene status was shown in most of these lines by Southern blot, real-time PCR, ELISA, and immunostrips; the most tolerant candidates expressed the ech42-nag70 double gene construct and the ech33 gene from a local Hypocrea virens isolate. B. cinerea growth assays in Petri dishes supplemented with berry juices extracted from the most tolerant individuals of the selected population was inhibited. These results demonstrate that improved fungal tolerance can be attributed to transgene expression and support the iterative molecular and physiological phenotyping in order to define selected individuals from a population of GM grapevines. PMID- 25011564 TI - Interaction of diet and the masou salmon Delta5-desaturase transgene on Delta6 desaturase and stearoyl-CoA desaturase gene expression and N-3 fatty acid level in common carp (Cyprinus carpio). AB - The masou salmon Delta5-desaturase-like gene (D5D) driven by the common carp beta actin promoter was transferred into common carp (Cyprinus carpio) that were fed two diets. For P1 transgenic fish fed a commercial diet, Delta6-desaturase-like gene (D6D) and stearoyl-CoA desaturase (SCD) mRNA levels in muscle were up regulated (P < 0.05) 12.7- and 17.9-fold, respectively, and the D6D mRNA level in the gonad of transgenic fish was up-regulated 6.9-fold (P < 0.05) compared to that of non-transgenic fish. In contrast, D6D and SCD mRNA levels in transgenic fish were dramatically down-regulated (P < 0.05), 50.2- and 16.7-fold in brain, and 5.4- and 2.4-fold in liver, respectively, in comparison with those of non transgenic fish. When fed a specially formulated diet, D6D and SCD mRNA levels in muscle of transgenic fish were up-regulated (P < 0.05) 41.5- and 8.9-fold, respectively, and in liver 6.0- and 3.3-fold, respectively, compared to those of non-transgenic fish. In contrast, D6D and SCD mRNA levels in the gonad of transgenic fish were down-regulated (P < 0.05) 5.5- and 12.4-fold, respectively, and D6D and SCD mRNA levels in the brain were down-regulated 14.9- and 1.4-fold (P < 0.05), respectively, compared to those of non-transgenic fish. The transgenic common carp fed the commercial diet had 1.07-fold EPA, 1.12-fold DPA, 1.07-fold DHA, and 1.07-fold higher observed total omega-3 fatty acid levels than non-transgenic common carp. Although these differences were not statistically different (P > 0.05), there were significantly (P < 0.10) higher omega-3 fatty acid levels when considering the differences for all of the individual omega-3 fatty acids. The genotype * diet interactions observed indicated that the potential of desaturase transgenesis cannot be realized without using a well designed diet with the needed amount of substrates. PMID- 25011566 TI - Synchrotron X-ray phase nano-tomography-based analysis of the lacunar-canalicular network morphology and its relation to the strains experienced by osteocytes in situ as predicted by case-specific finite element analysis. AB - Osteocytes are hypothesized to regulate bone remodeling guided by both biological and mechanical stimuli. Morphology of the lacunar-canalicular network of osteocytes has been hypothesized to be strongly related to the level of mechanical loading and to various bone diseases. Finite element modeling could help to better understand the mechanosensation process by predicting the physiological strain environment. The aims of this study were to (i) quantify the lacunar-canalicular morphology in the cortex of the human femur; (ii) predict the in situ local deformations around and in osteocytes by means of case-specific finite element models; and (iii) investigate the potential relationship between morphology and deformations. Human femoral cortical bone samples were imaged using synchrotron X-ray phase nano-tomography with 50 nm voxel size. Rectangular volumes of interest were selected to contain single osteocyte lacunae and the surrounding matrix. Lacunar-canalicular morphology was quantified and the cell geometry was artificially reconstructed based on a priori assumptions. Finite element models of the volumes of interest were generated, containing the extracellular matrix, osteocyte and peri-cellular matrix, and subjected to uniaxial compression. The morphological analysis revealed that canalicular number was dictated by lacunar size, that the spacing of canaliculi fell within a narrow range, suggesting that these pores are well distributed throughout the bone matrix and indicated the trend that lacunae at the outer osteon boundary were less elongated than others. No apparent relationship was found between the morphological parameters and the predicted strains. The globally applied strain was amplified locally by factors up to 10 and up to 70 in the extracellular matrix and the in cells, respectively. Cell deformations were localized mainly at the body-dendrite junctions, with magnitudes reaching the in vitro stimulatory threshold reported for osteocytes. PMID- 25011565 TI - Development and characterization of a new inbred transgenic rat strain expressing DsRed monomeric fluorescent protein. AB - The inbred rat is a suitable model for studying human disease and because of its larger size is more amenable to complex surgical manipulation than the mouse. While the rodent fulfills many of the criteria for transplantation research, an important requirement is the ability to mark and track donors cells and assess organ viability. However, tracking ability is limited by the availability of transgenic (Tg) rats that express suitable luminescent or fluorescent proteins. Red fluorescent protein cloned from Discosoma coral (DsRed) has several advantages over other fluorescent proteins, including in vivo detection in the whole animal and ex vivo visualization in organs as there is no interference with autofluorescence. We generated and characterized a novel inbred Tg Lewis rat strain expressing DsRed monomeric (DsRed mono) fluorescent protein under the control of a ubiquitously expressed ROSA26 promoter. DsRed mono Tg rats ubiquitously expressed the marker gene as detected by RT-PCR but the protein was expressed at varying levels in different organs. Conventional skin grafting experiments showed acceptance of DsRed monomeric Tg rat skin on wild-type rats for more than 30 days. Cardiac transplantation of DsRed monomeric Tg rat hearts into wild-type recipients further showed graft acceptance and long-term organ viability (>6 months). The DsRed monomeric Tg rat provides marked cells and/or organs that can be followed for long periods without immune rejection and therefore is a suitable model to investigate cell tracking and organ transplantation. PMID- 25011567 TI - Optimistic and defensive-pessimist students: differences in their academic motivation and learning strategies. AB - In addition to cognitive and behavioral strategies, students can also use affective-motivational strategies to facilitate their learning process. In this way, the strategies of defensive-pessimism and generation of positive expectations have been widely related to conceptual models of pessimism-optimism. The aim of this study was to describe the use of these strategies in 1753 secondary school students, and to study the motivational and strategic characteristics which differentiated between the student typologies identified as a result of their use. The results indicated a higher use of the generation of positive expectations strategy (optimism) (M = 3.40, SD = .78) than the use of the defensive pessimism strategy (M = 3.00, SD = .78); a positive and significant correlation between the two strategies (r = .372, p = .001); their relationship with adequate academic motivation and with the use of learning strategies. Furthermore, four student typologies were identified based on the use of both strategies. Lastly, we propose a new approach for future work in this line of research. PMID- 25011556 TI - HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. AB - Antiretroviral treatment (ART) of HIV infection suppresses viral replication. Yet if ART is stopped, virus reemerges because of the persistence of infected cells. We evaluated the contribution of infected-cell proliferation and sites of proviral integration to HIV persistence. A total of 534 HIV integration sites (IS) and 63 adjacent HIV env sequences were derived from three study participants over 11.3 to 12.7 years of ART. Each participant had identical viral sequences integrated at the same position in multiple cells, demonstrating infected-cell proliferation. Integrations were overrepresented in genes associated with cancer and favored in 12 genes across multiple participants. Over time on ART, a greater proportion of persisting proviruses were in proliferating cells. HIV integration into specific genes may promote proliferation of HIV-infected cells, slowing viral decay during ART. PMID- 25011569 TI - Studies of the microbial metabolism of flavonoids extracted from the leaves of Diospyros kaki by intestinal bacteria. AB - Flavonoid glycosides are metabolized by intestinal bacteria, giving rise to a wide range of phenolic acids that may exert systemic effects in the body. The microbial metabolism of flavonoids extracted from the leaves of Diospyros kaki (FLDK) by intestinal bacteria was investigated in vitro. High-performance liquid chromatography/linear trap quadrupole orbitrap mass spectrometry was performed to analyze the metabolites of flavonoids in vivo using Xcalibur2.1 software. The results showed that the levels of flavonoid glycosides and flavonoid aglycones decreased rapidly in the process of microbial metabolism by intestinal bacteria in vitro, and the metabolic rate may be related to the concentration of intestinal bacteria in the culture solution. In vivo metabolites of FLDK were detected in rat plasma and urine after oral administration of FLDK. Eight flavonoids were identified in the urine, and three were identified in the plasma; however, flavonoid aglycones were not found in the plasma. PMID- 25011568 TI - The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. AB - BACKGROUND: Pragmatic trials compare the effects of different decisions in usual clinical practice. OBJECTIVES: To develop and evaluate methods to implement simple pragmatic trials using routinely collected electronic health records (EHRs) and recruiting patients at the point of care; to identify the barriers and facilitators for general practitioners (GPs) and patients and the experiences of trial participants. DESIGN: Two exemplar randomised trials (Retropro and eLung) with qualitative evaluations. SETTING: Four hundred and fifty-nine English and Scottish general practices contributing EHRs to a research database, of which 17 participated in the trials. PARTICIPANTS: Retropro aimed to recruit 300 patients with hypercholesterolaemia and high cardiovascular risk and eLung aimed to recruit 150 patients with a chronic obstructive pulmonary disease exacerbation. INTERVENTIONS: Retropro randomised between simvastatin and atorvastatin and eLung between immediate antibiotics and deferred or non-use. eLung recruited during an unscheduled consultation using EHR flagging. MAIN OUTCOME MEASURE: Successful trial completion with implementation of information technology (IT) system for flagging and data processing and documentation of operational and scientific experiences. DATA SOURCES: EHR research database. RESULTS: The governance approval process took over 3 years. A total of 58.8% of the practices (n = 270) expressed interest in participating. The number of interested practices dropped substantially with each stage of the governance process. In Retropro, 6.5% of the practices (n = 30) were eventually approved and 3.7% (n = 17) recruited patients; in eLung, these numbers were 6.8% (n = 31) and 1.3% (n = 6) respectively. Retropro successfully completed recruitment (301 patients) whereas eLung recruited 31 patients. Retropro recruited 20.6% of all statin starters in recruiting practices and 1.1% in the EHR database; the comparable numbers for eLung were 32.3% and 0.9% respectively. The IT system allowed for complex eligibility criteria with central on and off control of recruitment and flagging at a practice. Good Clinical Practice guidelines, governance and consent procedures were found to have substantially affected the intended simple nature of the trials. One qualitative study of 13 clinicians found that clinicians were generally positive about the principle of computerised trial recruitment (flagging during consultation). However, trials which did not include patients with acute illness were favoured. The second qualitative process evaluation interviewed 27 GPs about their actual experiences, including declining, recruiting and non-recruiting GPs. Opportunistic patient recruitment during a routine GP consultation was found to be the most controversial element. The actual experiences of recruiting patients during unscheduled consultation were generally more positive than the hypothetical views of GPs. Several of the recruiting GPs reported the process took 5 minutes and was straightforward and feasible on most occasions. Almost all GPs expressed their strong support for the use of EHRs for trials. Ten eLung participants were interviewed, all of whom considered it acceptable to be recruited during a consultation and to use EHRs for trials. CONCLUSIONS: EHR point-of-care trials are feasible, although the recruitment of clinicians is a major challenge owing to the complexity of trial approvals. These trials will provide substantial evidence on clinical effectiveness only if trial interventions and participating clinicians and patients are typical of usual clinical care and trials are simple to initiate and conduct. Recommendations for research include the development of evidence and implementation of risk proportionality in trial governance and conduct. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33113202 and ISRCTN72035428. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and the Wellcome Trust and will be published in full in Health Technology Assessment; Vol. 18, No. 43. See the NIHR Journals Library website for further project information. PMID- 25011570 TI - Contribution of CNT1 and ENT1 to ribavirin uptake in human hepatocytes. AB - The objective of this study was to investigate the contributions of a sodium dependent concentrative nucleoside transporter (CNT) 1 and an equilibrative nucleoside transporter (ENT) 1 to ribavirin uptake in human hepatocytes. The initial studies in oocytes expressing CNT1 and ENT1 showed increases in ribavirin uptake, indicating that ribavirin was a substrate for both CNT1 and ENT1. The CNT1- and ENT1-mediated ribavirin uptake showed concentration dependency with the following kinetics parameters: Km 26.3 MUM and Vmax 426.2 fmol/min/oocyte for CNT1; Km 70.5 MUM and Vmax 134.3 fmol/min/oocyte for ENT1. Ribavirin uptake clearance in six human hepatocytes ranged from 21.3 to 300.7 MUL/min. Estimation of the contributions of CNT1 and ENT1 to the hepatic uptake of ribavirin by using a relative activity factor method indicated that the relative contribution of ENT1 to the ribavirin uptake was 82.8 +/- 3.9%. Real-time polymerase chain reaction analysis of CNT1 and ENT1 expressions in the hepatocytes showed that ENT1 mRNA expression was closely correlated with ribavirin uptake (R = 0.95, P = 0.003) while CNT1 was not. The findings indicated that ENT1 was the major transporter controlling the hepatic uptake of ribavirin. PMID- 25011571 TI - Ionic liquid effects on nucleophilic aromatic substitution reactions from QM/MM simulations. AB - Nucleophilic aromatic substitution (SNAr) reactions are particularly sensitive to medium effects and have been reported to benefit from ionic liquids. The SNAr reaction between cyclic secondary amines (i.e., piperidine, pyrrolidine, and morpholine) and the 2-L-5-nitrothiophene (para-like) and 2-L-3-nitrothiophene (ortho-like) isomers, where L = bromo, methoxy, phenoxy, and 4-nitrophenoxy, has been computationally investigated in 1-butyl-3-methylimidazolium tetrafluoroborate and hexafluorophosphate [BMIM][BF4] and [BMIM][PF6], respectively. QM/MM Monte Carlo simulations utilizing free-energy perturbation theory were used to characterize the solute-solvent interactions over the addition-elimination reaction pathway. Energetic and structural analyses determined that the improved SNAr reactivity in [BMIM][BF4] and [BMIM][PF6] can be attributed to (1) an enhanced nucleophilicity of the cyclic amines in the ionic liquids with an order of Pyr >= Pip > Mor, (2) beneficial pi(+)-pi interactions between the BMIM cations and the aromatic rings present on the substrate that enhanced coplanarity between the thiophene ring and the aromatic substituents, resulting in a larger positive charge on the reacting ipso carbon, and (3) a highly ordered ionic liquid clathrate formation that, despite an entropy penalty, provided reduced activation free-energy barriers derived from an increasing number of solvent ions favorably interacting with the emerging charge separation at the rate-limiting addition step. PMID- 25011572 TI - Long-term complete remission of multiple extranodal natural killer/T-cell-type posttransplant lymphoproliferative disorder after surgical resection: a case report. AB - BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life threatening complication of organ transplantation that results from immunosuppression therapy. Most cases of PTLD derive from the B-cell lineage. T cell PTLD, particularly natural killer (NK)/T-cell PTLD, is quite rare; only a few cases have been described. CASE REPORT: A 42-year-old woman received a living related renal allograft from her father. Sixteen years after transplantation, the patient presented with a 1-week history of low-grade fever and epigastralgia. Computed tomography revealed intestinal masses and a right upper lung lobe mass. Gallium scintigraphy showed uptake in the abdominal mass. Epstein-Barr virus related antibody was not detected in the patient's serum sample. We performed extirpation of the jejunum and ileum tumors. The pathologic findings showed that these 2 tumors were NK/T-cell lymphoma. After the operation, the lung mass rapidly enlarged, and right upper lobectomy was performed. The right upper lung lobe tumor showed the same histopathologic findings as the small bowel tumor. The final histologic diagnosis was established as multiple extranodal NK/T cell type PTLD of the small bowel and right upper lung lobe. CONCLUSIONS: After reduction of the immunosuppressive agent, no recurrence of PTLD has been observed for the past 9 years. PMID- 25011573 TI - Time-averaged albumin predicts the long-term prognosis of IgA nephropathy patients who achieved remission. AB - BACKGROUND: Primary IgA nephropathy (IgAN) is the most common form of idiopathic glomerulonephritis worldwide. Although most patients are able to achieve remission with the current therapy, a large number of patients will still progress to end-stage renal disease. This study aimed to evaluate kidney disease progression and the risk factors for progression in IgAN patients who achieved remission. METHODS: Patients from a prospective database with IgAN were included in this study. All the subjects had achieved a complete remission (CR) or partial remission (PR) following 6 months of therapy. Renal survival and the relationship between the clinical parameters and composite renal outcomes were assessed. RESULTS: The study comprised 878 IgAN patients recruited between January 2005 and December 2010. Overall, 632 patients were enrolled in this study. The data from the 369 patients who achieved remission were analyzed; the mean follow-up time was 49 months. The median serum creatinine (SCr) concentration at baseline was 91.3 MUmol/L, and the time-averaged creatinine (TA-SCr) was 91.8 MUmol/L. The mean serum albumin (ALB) level at baseline was 39.4 g/L, and the time-averaged serum albumin (TA-ALB) was 42.1 g/L. Multivariate Cox regression analyses revealed that the TA-ALB and TA-SCr levels were independently associated with the composite renal outcome. The patients with a TA-SCr value > 120 MUmol/L and a TA ALB level < 38 g/L were less likely to recover from renal progression. CONCLUSION: The strong predictive relationship of low TA-ALB and high TA-SCr levels with progression observed in this study suggests that TA-ALB may serve as a marker of the long-term renal prognosis of IgAN patients who have achieved remission. PMID- 25011574 TI - Incidental papillary fibroelastoma of the tricuspid valve. AB - Primary cardiac tumors are very rare, papillary fibroelastoma (PFE) being the second most common benign tumor of the heart in previous series. However, as a consequence of increased imaging examinations, incidental PFE may represent the most common cardiac tumor. Their clinical presentation varies from incidental asymptomatic masses to severe life-threatening cardiovascular complications necessitating emergency surgery. Here we report the diagnostic evaluation and successful surgical resection of such a cardiac tumor in a 67-year-old woman. Histology confirmed diagnosis of a papillary fibroelastoma. This report demonstrates it's necessary to include cardiac tumors in the differential diagnosis of subtle and non-specific cardiothoracic symptoms. PMID- 25011575 TI - Distinct determinants of long-term and short-term survival in critical illness. AB - PURPOSE: To identify the determinants of short-term and long-term survival in adult patients admitted to intensive care units (ICUs). METHODS: This population based, observational cohort study included all eleven adult ICUs in the Winnipeg Health Region of Manitoba, Canada, analyzing initial ICU admissions during the period 1999-2010 of all Manitobans >=17 years old. Analysis included Kaplan-Meier survival curves and multivariable regression models of 30-day mortality and post 90-day survival among those who survived to day 90. We used likelihood ratios to compare the predictive power of clusters of variables in these models. RESULTS: After 33,324 initial ICU admissions, mortality rates within 30 and 90 days were 15.9 and 19.5 %, respectively. The survival curve demonstrated an early phase with a high rate of death, followed by a markedly lower death rate that was only clearly established after several months. 30-day mortality was predominantly determined by characteristics of the acute illness; with its relative contribution set at 1.00, the next largest contributors were age (0.19) and comorbidity (0.16). In contrast, post-90-day mortality was mainly determined by age (relative contribution 1.00) and comorbidity (0.95); the next largest contributor was characteristics of acute illness (0.28). CONCLUSIONS: We observed two phases of survival related to critical illness. Short-term mortality was mainly determined by the acute illness, but its effect decayed relatively rapidly. Mortality beyond 3 months, among those who survived to that point, was mainly determined by age and comorbidity. Recognition of these findings is relevant to discussions with patients and surrogates about achievable goals of care. PMID- 25011576 TI - Family presence during cardiopulmonary resuscitation: an opportunity for meaning making in bereavement. PMID- 25011577 TI - Self-reported acne is not associated with prostate cancer. AB - OBJECTIVE: Some studies have suggested an inverse association between acne vulgaris and the acne-related bacterium Propionibacterium acnes and prostate cancer (PCa). Self-reported acne might be an easily obtainable marker to identify men at relatively low risk of PCa and might be incorporated into PCa risk calculators. This study aimed to evaluate the association between self-reported acne and PCa in a large case-referent study. METHODS AND MATERIALS: The case group comprised 942 patients with PCa recruited from a population-based cancer registry in 2003 to 2006, 647 of whom met the criteria for aggressive PCa. The referents (n = 2,062) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions about acne. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using multivariable logistic regression for PCa and aggressive PCa as separate end points, while adjusting for age and family history of PCa. RESULTS: A history of acne was reported by 320 cases (33.9%) and 739 referents (35.8%). Self-reported acne was significantly associated neither with PCa (adjusted OR = 0.95, 95% CI: 0.80-1.12) nor with aggressive PCa (adjusted OR = 0.97, 95% CI: 0.80-1.18). CONCLUSION: Self-reported acne is not suitable as a marker to identify men at low risk of aggressive PCa. PMID- 25011578 TI - Biliary complications after pancreaticoduodenectomy: skinny bile ducts are surgeons' enemies. AB - BACKGROUND: The aim of this study was to determine the incidence and predisposing factors of biliary complications (BCs) after pancreaticoduodenectomy (PD) and report our experience in managing these BCs. Pancreatic surgery, particularly PD, has benefited from improvements in operative techniques and postoperative care and is currently safer in terms of mortality. However, the morbidity associated with PD remains high, including frequent complications such as delayed gastric emptying and pancreatic fistulas. Rarer but important BCs are those that manifest as bile leaks (BLs) and biliary strictures (BSs). METHODS: Between April 2005 and December 2011, a total of 397 patients underwent PD at two centers. All data were retrospectively studied with respect to age, gender, pancreatic pathology, neoadjuvant treatment, preoperative biliary stenting, intraoperative data, postoperative pancreatic fistula, BL and BS rates, and mortality. The management of BCs was also analyzed. RESULTS: Thirty patients experienced a BC: 13 BLs (3.3 %) and 17 BSs (4.3 %). A thin bile duct (<5 mm), measured during surgery, was the only predisposing factor for developing a BL or a BS. The management of the BLs consisted of surveillance in six patients (46 %), percutaneous drainage of bilioma in four patients (31 %), and reintervention in three patients (23 %). No patient with a BS had surgery as the frontline treatment: the initial management consisted of an endoscopic procedure, a percutaneous procedure, or medical treatment. Four patients (23.5 %) underwent surgical treatment after failure of nonsurgical procedures. CONCLUSIONS: The only identified predictive factor of BC, either a BS or a BL, was a thin bile duct. Although the noninvasive technique was the treatment of choice initially, reintervention was required in almost 25 % of the cases. PMID- 25011579 TI - Advances in European sea bass genomics and future perspectives. AB - Only recently available sequenced and annotated teleost fish genomes were restricted to a few model species, none of which were for aquaculture. The application of marker assisted selection for improved production traits had been largely restricted to the salmon industry and genetic and Quantitative Trait Loci (QTL) maps were available for only a few species. With the advent of next generation sequencing the landscape is rapidly changing and today the genomes of several aquaculture species have been sequenced. The European sea bass, Dicentrarchus labrax, is a good example of a commercially important aquaculture species in Europe for which in the last decade a wealth of genomic resources, including a chromosomal scale genome assembly, physical and linkage maps as well as relevant QTL have been generated. The current challenge is to stimulate the uptake of the resources by the industry so that the full potential of this scientific endeavor can be exploited and produce benefits for producers and the public alike. PMID- 25011580 TI - Attenuated psychosis syndrome: don't jump the gun. AB - Attenuated psychosis syndrome (APS) was introduced in DSM-5 as a condition for further study. A number of concerns have been raised regarding APS, including its validity as a clinical entity, issues relating to stigma, the potential that it is an unnecessary diagnosis of what might be a self-limiting phase of attenuated psychotic symptoms, and treatment implications of the diagnosis. The current paper presents a number of conceptual and practical issues that should be addressed in deciding whether APS should be accepted as an official diagnosis in subsequent editions of DSM. These include the problem of transferring the established validity of 'at-risk' criteria to APS given some non-trivial differences between the criteria sets, the relationship between attenuated psychotic symptoms and other presenting non-psychotic disorders, the difficulties of operationalising the subthreshold or 'attenuated' concept in standard clinical practice, and the likelihood of the diagnosis leading to overprescription of antipsychotic medication for this group of patients. PMID- 25011581 TI - Plough fracture of the anterior arch of the atlas: a biomechanical investigation. AB - PURPOSE: "Plough" fracture, in which the odontoid ploughs through and causes a high-energy shear fracture of the anterior arch of the atlas, has been documented in clinical case studies and classified as clinically unstable. Our objectives were to develop a biomechanical model to simulate atlantal plough fracture and investigate injury mechanisms. METHODS: Horizontally aligned head impacts into a padded barrier were simulated using a human upper cervical spine specimen (occiput through C3) mounted to a surrogate torso mass on a sled and carrying a surrogate head. We divided 13 specimens into 3 groups based upon head-impact location: upper forehead in the midline, upper lateral side of the forehead, and upper lateral side of the head. Post-impact fluoroscopy and anatomical dissection documented the injuries. Time-history biomechanical responses were determined for neck loads, accelerations, and motions. RESULTS: A single specimen sustained a plough fracture variant to the atlantal anterior arch due to impact to the upper forehead and continued forward torso momentum. Horizontal velocity of C3 at the time of forehead impact was 2.7 m/s. This specimen had an anteriorly displaced fracture fragment consisting of the inferior portion of the atlantal anterior arch together with multiple complete fractures of the axis. Peak force occurred first at the impact barrier (1,903.0 N; 47 ms) followed by the neck (1,715.9 N; 58 ms). Forward translation ended at 48 ms for the head and 72 ms for the C3 vertebra. CONCLUSIONS: Our present results, though preliminary, indicate that plough fracture of the anterior arch of the atlas likely occurred immediately following or simultaneously with associated axis fractures at approximately 58 ms following impact to the upper forehead. The present injury response data highlighted the role of load transfer from torso momentum to the upper cervical spine to produce anterior shear force and forward displacement of the dens and bony fragment of the anterior arch of the atlas relative to the C1 ring. PMID- 25011582 TI - The influence of cervical plate fixation with either autologous bone or cage insertion on radiographic and patient-rated outcomes after two-level anterior cervical discectomy and fusion. AB - PURPOSE: We aimed to identify technique-related factors influencing radiographic and patient-rated outcomes after two-level anterior cervical discectomy with fusion (ACDF) using either cage or autologous bone, with or without anterior plate fixation (APF). METHODS: This single center study was nested within the Eurospine Spine Tango data acquisition system. INCLUSION CRITERIA: consecutive two-level ACDF patients (2004-2012) presenting with signs of degenerative cervical radiculopathy or myelopathy. Before and 12 month postoperatively, patients completed the multidimensional Core Outcome Measures Index (COMI); at 12 months postoperatively they also rated the global treatment outcome (GTO) and their satisfaction with care. Cervical lordosis and segmental height were assessed radiographically preoperatively, immediately postoperatively, and at the last follow-up (LFU) (18.2 +/- 13.3 months). RESULTS: One hundred and forty-four consecutive patients (113 with APF) were included. The use of APF versus stand alone methods was associated with significantly increased segmental height (by 2.6 +/- 2.6 versus 1.5 +/- 2.4 mm, p = 0.04) and preservation of lordosis (by 2.7 +/- 4.4 degrees versus -1.7 +/- 5 degrees , p < 0.0001) at LFU, with comparable clinical outcome (COMI score reduction >=3.1-point). Multiple regression controlling for potential confounders revealed that APF (p = 0.0004) and cage (p = 0.001) were associated with greater segmental height at LFU; APF was associated with a greater lordosis angle at LFU (p < 0.0001). Greater increase in segmental height at LFU (p = 0.02) was associated with a better GTO. CONCLUSIONS: Adding APF was associated with greater segmental height and preservation of lordosis in two-level ACDF, especially using bone autograft, but also for cage. Clinical outcome was comparable for all groups. Though the surgical technique per se did not determine clinical outcome, patients achieving a greater segmental height difference showed a significantly better GTO. PMID- 25011583 TI - Predictors of kyphotic deformity in osteoporotic vertebral compression fractures: a radiological study. AB - PURPOSE: To report the radiological predictors of kyphotic deformity in osteoporotic vertebral compression fractures (OVCF). METHODS: This is a retrospective study of 64 consecutive patients with OVCF. We studied the radiographic features in the immediate post-injury image of patients, who developed significant (more than 30 degrees ) segmental kyphotic deformity at final follow-up and compared them with those patients who did not. RESULTS: Thirty-three (82.5%) out of 40 patients with fracture at thoracolumbar (TL) junction, 5 (33.3%) patients out of 15 with fracture at lumbar (L) spine and 7 (77.7%) patients out of 9 with fracture at thoracic (T) spine developed significant segmental kyphotic deformity. Forty-one (75.9%) [TL-33 (80.5%), L-4 (33.33%) and T-4 (80%)] out of 54 [TL-37 (68.51%), L-12 (22.23%) and T-5 (9.26%)] patients with superior endplate fracture developed significant segmental kyphotic deformity. Forty patients (86.9%) [TL-28 (70%), L-6 (15%) and T-6 (15%)] out of 46 [TL-32 (69.56%), L-8 (17.4%) and T-6 (13.04%)] with anterior cortical wall fracture developed significant segmental kyphotic deformity. Five patients (71.42%) [TL-2 (40%) and T-3 (60%)] out of 7 [TL-02 (28.58%), L-01 (14.28%), T-04 (57.14%)] with adjacent level fracture developed significant segmental kyphotic deformity. The average immediate post-injury kyphosis of 11 degrees (5 degrees 25 degrees ) increased to 29 degrees (15 degrees -50 degrees ) at final follow up. CONCLUSION: Progressive segmental kyphotic collapse following an OVCF seems unavoidable. Patients with TL junction and superior endplate fracture are probably at the highest risk for significant segmental kyphotic deformity. PMID- 25011584 TI - Extensive laminectomy for multilevel cervical stenosis with ligamentum flavum hypertrophy: more than 10 years follow-up. AB - PURPOSE: The aim of this research was to evaluate the long-term results of extensive laminectomy for the treatment of cervical spondylotic myelopathy due to multilevel cervical stenosis (MCS) with ligamentum flavum hypertrophy (LFH). METHODS: From January 2000 to December 2002, a total of 91 patients who underwent extensive laminectomy for MCS with LFH were included in this study to investigate the long-term outcome of this surgical option. All patients were presenting moderate-to-severe preoperative cervical myelopathy. The patients with cervical lordosis, without cervical kyphosis and instability, were included in our study through preoperative radiological examination. Clinical outcomes were evaluated by the Japanese Orthopedic Association (JOA) scoring system and by recovery rate (RR). The changes in curvature of cervical spine were determined by cervical curvature index (CCI). Range of motion (ROM) of the cervical spine was assessed by measuring the C2-7 Cobb angle on flexion and extension. The anteroposterior diameters and the drift-back distance of the spinal cord were calculated using the MRI image. The axial pain was measured by a visual analogue scale (VAS). Statistical analysis was performed using paired t test with significance set at P < 0.05. RESULTS: Ninety-one (83 %) of the 109 patients completed the follow-up in this study. The mean duration of follow-up was 12.1 years. The preoperative JOA scores in these patients averaged 6.8, and the postoperative scores at the final follow-up averaged 14.5 (average RR 68.4 %). The CCI decreased significantly from 20.8 +/- 2.1 preoperatively to 11.5 +/- 1.8 at last follow-up (t = 15.31, P < 0.01). The cervical ROM at C2-7 decreased from 42.7 degrees before surgery to 20.4 degrees at the final follow-up (t = 21.16, P < 0.01). The increased anteroposterior diameters at the level of maximum compression together with the significant drift-back distance of the spinal cord suggested that decompression was complete. The postoperative VAS score suggested that the axial pain was mild (1.4 +/- 0.8). CONCLUSIONS: A series of clinical results were obtained after the extensive laminectomy for a long-term follow-up period exceeding 10 years. The extensive laminectomy may be an option for an alternative procedure for treatment of MCS with LFH. PMID- 25011586 TI - Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients. AB - BACKGROUND: Recently, a consensus Bullous Pemphigoid Disease Area Index (BPDAI) was proposed to measure therapeutic outcomes in bullous pemphigoid (BP). OBJECTIVE: To compare BPDAI with other clinical parameters of disease activity at baseline and to describe the variations of BPDAI during the initial phase of treatment. METHODS: Thirty BP patients were included and followed for 1 year. BPDAI was assessed at baseline and on days 30, 90 and 360 by the same investigator. Concomitantly, the number of daily new blisters, the skin surface area of erythematous/eczematous/urticarial plaques and blisters/erosions, total lesion area (TLA), pruritus score and mucosal involvement were recorded. RESULTS: At baseline, BPDAI was 46.7 +/- 25 (mean +/- SD); it was well correlated with erythematous/eczematous/urticarial skin surface (r = 0.63), TLA (r = 0.83), number of daily new blisters (r = 0.7; p <= 0.0002) and anti-BP180 autoantibodies (r = 0.49; p = 0.006), but not with anti-BP230 autoantibodies. For the 8 patients with severe BP at baseline, the mean BPDAI was 76.5, versus 35.9 for moderate BP (p = 0.0007). A value of 56 was proposed as a cut-off value for severe BP. BPDAI decreased to 11.9 +/- 8.7, 10.7 +/- 12.7 and 2.5 +/- 4.1 on days 30, 90 and 360, respectively. CONCLUSION: BPDAI rapidly decreased during the early treatment stage of BP with variations almost totally conditioned by the skin activity component. PMID- 25011585 TI - Peroxiredoxin-1 protects estrogen receptor alpha from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer. AB - INTRODUCTION: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. METHODS: An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. RESULTS: In ER positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ERalpha protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ERalpha protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ERalpha levels in breast cancer cells. CONCLUSIONS: PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ERalpha loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer. PMID- 25011587 TI - [Animal welfare and the use of laboratory animals in scientific research]. PMID- 25011588 TI - [Diagnosis of cystic echinococcosis in faeces scattered in areas of Puna and Quebrada. Province of Jujuy, Argentina]. AB - Echinococcosis is a parasitic disease common in livestock, caused by the cestode Echinococcus granulosus, the dog being the principal definitive host. The province of Jujuy is an endemic area located in the Northwest of Argentina. Due to the restricted ecological conditions of Quebrada and Puna, the most important activity of the population is formal cattle pastoralism and transhumance, especially of sheep and camelids. The dog acquires the double function of company and shepherd in these communities. The objective of the present study was to conduct a diagnosis of the situation in areas of La Quebrada and Puna where the circulation of E. granulosus is suspected. Five hundred and twenty three (523) samples of canine fecal material scattered in the environment were collected from 2002 to 2012. Prevalence varied from 2% in Susques to 27.7% in Humahuaca, the largest in the province. In Tumbaya, prevalence was 21% in the year 2007, reaching 0% in the year 2010 but increasing again to 10.5% in the year 2011. These results may be related to health education on preventive measures and mass deworming held prior to sample taking in the year 2010. A prevalence between 19.4% and 2% was observed in the rest of the regions studied, suggesting that a lack of strategies for echinococcosis control has allowed the spread of the disease. PMID- 25011589 TI - Seroprevalence and major antigens recognized by sera from Trypanosoma cruzi infected dogs from Jalisco, Mexico. AB - Chagas disease is a major endemic disease caused by the protozoan parasite Trypanosoma cruzi. This parasitic disease is widely distributed throughout Latin America, affecting 10 million people. There are also reports of canine infection in the southern part of the United States. Dogs are considered the predominant domestic reservoir for T. cruzi in many areas of endemicity. In Mexico, dog infection by this parasite has been poorly studied. In this work 209 dogs from six villages in Jalisco, Mexico, were assessed to detect anti-T. cruzi antibodies by ELISA and Western blot. Seventeen (17) seropositive dogs (8.1 %) were detected by both tests, representing a seropositive value similar to that found in some southern states of Mexico where the infection is present. No statistical differences were observed concerning the age and sex of infected and non-infected dogs. The major antigens recognized by positive sera were 26, 32, 66 and 80kDa. These proteins are candidates to develop a specific diagnostic method for canine Chagas. No antibodies against HSP16 protein were found in T. cruzi seropositive sera. This is the first report of canine serology of Chagas disease in this central part of Mexico. This report will contribute to the knowledge of the infection status of domestic reservoirs in the state of Jalisco, Mexico. PMID- 25011591 TI - [Utility of MALDI-TOF MS for the identification of anaerobic bacteria]. AB - The analysis by MALDI-TOF MS (Matrix-assited laser desorption/ionization time-of flight mass spectrometry) has become a reference method for the identification of microorganisms in Clinical Microbiology. However, data on some groups of microorganisms are still controversial. The aim of this study is to determine the utility of MALDI-TOF MS for the identification of clinical isolates of anaerobic bacteria. One-hundred and six anaerobic bacteria isolates were analyzed by MALDI TOF MS and by conventional biochemical tests. In those cases where identification by conventional methodology was not applicable or in the face of discordance between sequencing methodologies, 16 S rRNA gene sequence analysis was performed. The conventional method and MALDI-TOF MS agreed at genus and species level by 95.3 %. Concordance in gram-negative bacilli was 91.4% and 100% among gram positive bacilli; there was also concordance both in the 8 isolates studied in gram-positive cocci and in the single gram-negative cocci included. The data obtained in this study demonstrate that MALDI-TOF MS offers the possibility of adequate identification of anaerobic bacteria. PMID- 25011590 TI - [Cystic echinococcosis in dogs and children in the province of Rio Negro, Argentina]. AB - Cystic echinococcosis (CE) is an endemic disease in the province of Rio Negro, Argentina. The control program against CE has developed monitoring surveillance systems. Currently, the coproELISA/Western blot (WB) test is used to determine transmission in livestock farms (epidemiological units or EU) from collected dry field-dispersed dog feces. The objective was to evaluate the prevalence of CE on livestock farms and its relationship with CE cases in children aged 0-14 years. Canine fecal samples were obtained from randomly selected livestock farms and processed by the coproELISA/WB test. Furthermore, new cases in children in the same age group mentioned above were identified. In 278 EU, 571 samples of canine feces were obtained. There were 37 positive samples for coproELISA/WB (6.5%) and the presence of transmission was demonstrated in 37 EU (13.3%). There were no significant differences (p=0.9) with the survey conducted in the period 2003-2004 while there were significant differences (p=0.02) with the EU survey of native populations conducted in 2009-2010. With respect to animal density in the work area, the EU yielding negative results had an average of 2 dogs (SD 2.1) per EU while in the EU having positive results the average was 3 dogs (SD 4.2), showing statistically significant differences (p=0.02). In children under 15 years of age, 12 cases were diagnosed. This study has identified, on average, that the cases of hydatid disease are closer in the positive fields than in the negative fields (p=0.00307).The coproELISA/WB test allowed to identify the dispersion of CE on livestock farms and its relationship with the occurrence of cases in children in 2009-2010. PMID- 25011593 TI - [Evaluation of Vitek 2 for the identification of Candida yeasts]. AB - The aim of this investigation was to evaluate the performance of Vitek 2 YST cards (bioMerieux, Inc., Hazelwood, MO, USA) for the identification of yeasts of the genus Candida. A total of 168 isolates were analyzed and the results were compared to those of the API 20 C AUX (24%) o API ID 32 C (76%) kits (bioMerieux, Marcy L'Etoile, France). Each isolate was grown in chromogenic agar and in corn meal agar (Oxoid, UK) to observe its micromorphology. C. albicans and C. dublininesis were identified by additional biochemical and molecular tests. The agreement observed was 98.3%. Only three isolates were incorrectly identified by Vitek 2: one strain of C .tropicalis and one strain of C. krusei were identified as C. parapsilosis by YST while one strain of C. krusei was identified with low discrimination. The average time for obtaining results was 18.25 h. Vitek 2 is a simple, safe and useful system for the identification of significant Candida species. PMID- 25011592 TI - Hemolytic uremic syndrome with mild renal involvement due to Shiga toxin producing Escherichia coli (STEC) O145 strain. AB - Hemolytic uremic syndrome (HUS) is a disorder characterized by the presence of the classic triad: microangiopathic hemolytic anemia, thrombocytopenia and acute renal injury. HUS without acute renal failure can be confused with other hematologic diseases. An infantile HUS caused by a Shiga-toxin-producing Escherichia coli (STEC) O145 strain carrying genotype stx2, ehxA, eae subtype beta1 is herein reported. The infant did not require dialysis during the acute stage of HUS, evolved favorably, maintained normal blood pressure and normal renal function and had no recurrence until the last control. This could be due to several factors, such as the characteristics of infecting STEC strain and a reduction in host susceptibility to renal injury. This report highlights the regional participation of non-O157 STEC in childhood diseases and the importance of performing active surveillance for all forms of HUS. PMID- 25011594 TI - [Evaluation of the VITEK 2 system (AST-YSO1 cards) for antifungal susceptibility testing against different Candida species]. AB - The aim of this investigation was to evaluate the results of antifungal susceptibility for various Candida species using the Vitek 2 semi-automated system (AST-YSO1 cards, bioMerieux), and to compare them with those obtained by the CLSI (Clinical and Laboratory Standards Institute) broth microdilution reference method (Document M27-A3,2008). The essential agreement (EA) was > 90%, except for Candida glabrata against voriconazole (VCZ); and for Candida krusei against fluconazole (FCZ). The overall categorical agreement (CA) was > 90% when FCZ was evaluated and 89.5% at 24h and 80.7% at 48 h for VCZ. The average time for obtaining results was 15.5h. Minor errors were 7.8% at 24h and 6.1% at 48 h for FCZ, and 10.5% at 24h and 19.3% at 48 h for VCZ. There was only one very major error for FCZ against Candida parapsilosis and no major errors were observed. For amphotericin B, only three isolates showed MICs >= 2 MUg/ml. The Vitek 2 system detected the MIC value for various Candida species and showed excellent agreement with the reference method proposed by the CLSI. PMID- 25011596 TI - [Characterization of enteropathogenic Escherichia coli (EPEC) strains isolated during the chicken slaughtering process]. AB - In Argentina, EPEC is one of the most prevalent agents isolated from children with diarrhea. Because contamination with this pathotype could occur during slaughter, the aim of this study was to isolate and characterize EPEC strains obtained from live animals (cloacae), eviscerated carcasses, washed carcasses and water from chillers. Twenty nine isolates of atypical EPEC were characterized. These isolates presented a wide variety of serotypes, some of which (O2:H40, O8:H19 and O108:H9) had been reported in other animal species. Serotype O45:H8, previously isolated from children with diarrhea was also found. Isolates of serotypes O2:H40, O108:H9 and O123:H32 were detected at different stages of the slaughtering process, suggesting that the process is not adequately performed. This latter fact highlights the importance of reinforcing control and hygienic measures at different stages of the chicken slaughtering process in order to reduce microbial contamination. PMID- 25011595 TI - Detection of Mycoplasma canadense and Mycoplasma californicum in dairy cattle from Argentina. AB - Different species of Mycoplasma can affect bovine cattle, causing several diseases. PCR sequencing and further analysis of the 16S-23S rRNA ITS region have shown a significant interspecies variability among Mollicutes. Sixteen suspected isolates of Mycoplasma spp. obtained from milk samples from dairy herds were amplified (16S-23S rRNA ITS region). Fourteen out of those 16 suspected Mycoplasma spp. isolates were PCR-positive. To confirm the identity of Mycoplasma bovis, these 14 isolates were tested by another species-specific PCR. Seven of the isolates rendered a positive result. The products of 16S-23S rRNA ITS PCR from one isolate that was identified as M. bovis and from two other isolates, identified as non- M. bovis were randomly selected, sequenced and analyzed. The three sequences (A, B and C) showed 100% similarity with M. bovis, Mycoplasma canadense and Mycoplasma californicum respectively. PMID- 25011597 TI - [Survival of VTEC O157 and non-O157 in water troughs and bovine feces]. AB - Verotoxin-producing Escherichia coli (VTEC) is the etiologic agent of hemolytic uremic syndrome (HUS), which typically affects children ranging in age from six months to five years old. Transmission is produced by consumption of contaminated food, by direct contact with animals or the environment and from person to person. In previous studies we determined that the environment of a dairy farm is a non-animal reservoir; thus, we proposed to study the survival of 4 VTEC isolates (O20:H19; O91:H21; O157:H7 and O178:H19) in sterile water troughs and bovine feces by viable bacteria count and detection of virulence genes by PCR. It was demonstrated that the survival of different VTEC isolates (O157 and non-O157) varied in terms of their own characteristics as well as of the environmental conditions where they were found. The main differences between isolates were their survival time and the maximal counts reached. The competitive and adaptive characteristics of some isolates increase the infection risk for people that are visiting or working on a farm, as well as the risk for reinfection of the animals and food contamination. PMID- 25011598 TI - [Mycotrophic capacity and efficiency of microbial consortia of arbuscular mycorrhizal fungi native of soils from Buenos Aires province under contrasting management]. AB - We characterized the infective and sporulation capacities of microbial consortia of arbuscular mycorrhizal fungi (AMF) native of Buenos Aires province (Argentina) and determined if some soil characteristics and mycorrhizal parameters could allow to select potentially beneficial inocula. Soil samples were selected from seven locations in Buenos Aires province all under agricultural (A) and pristine (P) conditions. The AMF were multiplied and mycorrhizal root colonization of trap plants was observed at 10 weeks of growth. Spore number in field was low; however, after multiplication spore density accounted for 80-1175 spores per 100g of soil. The principal component analysis showed that the P and Fe soil contents are the main modulators of infectivity and sporulation capacity. The mycorrhizal potential was determined in three locations, being high in Pristine Loberia and Agricultural Trenque Lauquen and low in Junin. Agricultural Loberia (AL) and Pristine Loberia (PL) inocula were selected and their efficiency was evaluated under controlled conditions. Even though shoot dry matter increases after inoculation was not significant (p>0.05) mycorrhizal response was greater than 40% for tomato and 25% for corn, particularly after inoculation with inocula from the agricultural management. These results could be associated to the incipient development of mycorrhizae in both species. Additional research should be conducted to further develop our findings in order to determine the factors involved in the selection of efficient inocula. PMID- 25011600 TI - [Quantification of parasites in aquatic environments in the Province of Salta, Argentina]. AB - Microbiological pollution of recreational waters is a major problem for public health as it may transmit waterborne diseases. To assess water quality, current legislation only requires limits for bacterial indicators; however, these organisms do not accurately predict the presence of parasites. Small number of parasites is usually present in water and although they are capable of causing disease, they may not be high enough to be detected. Detection therefore requires water samples to be concentrated. In this work three recreational aquatic environments located in the province of Salta were monitored over one year. For parasite quantification, water samples were collected every three months and concentrated by ultrafiltration. Detection was performed by microscopy. In addition, monthly monitoring was carried out in each aquatic environment: physicochemical variables were measured in situ and bacteriological counts were determined by traditional microbiological techniques. Of 14 parasites identified, at least nine were detected in each aquatic environment sampled. While bacteriological contamination decreased in most cases during winter (76-99%), parasites were present year-round, becoming a continual threat to public health. Thus, we here propose that it is necessary to use specific parasitological indicators to prevent waterborne disease transmission. Our results suggest that Entamoeba would be a suitable indicator as it was found in all environments and showed minimal seasonal variation. The results obtained in this study have epidemiological relevance and will allow decision-makers to propose solutions for water protection in order to care for population health. PMID- 25011599 TI - Optimization of laccase production by two strains of Ganoderma lucidum using phenolic and metallic inducers. AB - Ganoderma lucidum (Curtis) P. Karst is a white rot fungus that is able to degrade the lignin component in wood. The ability of two strains of this species to produce the ligninolytic enzyme laccase was assessed. After the evaluation of induction with heavy metals and phenolic compounds, it was found that among the tested substances, copper and ferulic acid are the best laccase inducers. It was also observed that the two types of inducers (phenolic and metallic) produce different electrophoretic patterns of laccase activity. Optimized concentrations of inducers were obtained through a factorial design and the thermal stability of optimized supernatants was studied at a wide range of acidic pH. We found that the enzyme is more thermostable at higher pH values. PMID- 25011601 TI - [Lichtheimia sp. in an immunodepressed patient]. PMID- 25011602 TI - The relationship between psychological symptoms, lung function and quality of life in children and adolescents with non-cystic fibrosis bronchiectasis. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between psychological symptoms and quality of life (QOL) and clinical variables in a cohort of children and adolescents with non-cystic fibrosis (non-CF) bronchiectasis. METHODS: Seventy-six patients (aged 8-17years) participated in this study. Questionnaires were used to evaluate the psychological status and QOL of the patients and healthy controls. The patient and control groups were divided into child and adolescent groups to exclude the effect of puberty on psychological status. RESULTS: No significant difference was found between patient and control groups for mean depression and trait anxiety scores. Only the child-rated physical health QOL scores were significantly lower for patients than the controls. Also, excepting physical health scores in adolescent group, all of the parent-rated QOL scores were significantly lower in both group and total subjects. Regarding determinants of QOL, age of children and FEV1/FVC percent predicted had positive effects, while dyspnea severity and trait anxiety had negative effects, for the sample as a whole. CONCLUSIONS: Non-CF bronchiectasis is associated with poorer QOL in childhood. The impact of the disease on QOL occurs through both clinical and psychological variables. PMID- 25011603 TI - Persistent oral human papillomavirus infection is associated with smoking and elevated salivary immunoglobulin G concentration. AB - BACKGROUND: Prevalence and risk factors for human papillomavirus (HPV) persistence in oral mucosa are largely unknown. Furthermore, the antiviral effects of saliva in the outcome of oral HPV infections are unexplored. OBJECTIVES: To compare the levels of selected salivary defence proteins in women with a persistent oral HPV infection and in those without any signs of oral HPV. Lifestyle factors including the use of oral contraceptives, oral sex, smoking and alcohol drinking habits were also assessed. STUDY DESIGN: This nested case control study of the Finnish Family HPV Study included 60 women with a persistent oral HPV infection and 117 women who remained HPV DNA negative throughout a 6 year follow-up. Whole saliva samples and oral scrapings for HPV testing were collected at the same visit. The oral HPV status was related to salivary concentrations of lactoferrin, lysozyme, IgA, IgG, total protein and sodium as well as to the use of oral contraceptives, oral sex, smoking and alcohol drinking habits. RESULTS: Women with a persistent oral HPV infection had higher salivary levels of IgG (p=0.007) and lysozyme (p=0.002, when adjusted to the total protein concentration), than those without an HPV infection. Lactoferrin and IgA concentrations were not related to the HPV-status. Smoking increased the risk of a persistent oral HPV infection (p=0.020), but the oral HPV status was not related to other life-style factors studied. CONCLUSIONS: Smoking is a risk factor for a persistent oral HPV infection. Oral HPV infection may be associated with increased concentrations of salivary IgG and lysozyme. PMID- 25011604 TI - Antibiotic rotation strategies to reduce antimicrobial resistance in Gram negative bacteria in European intensive care units: study protocol for a cluster randomized crossover controlled trial. AB - BACKGROUND: Intensive care units (ICU) are epicenters for the emergence of antibiotic-resistant Gram-negative bacteria (ARGNB) because of high rates of antibiotic usage, rapid patient turnover, immunological susceptibility of acutely ill patients, and frequent contact between healthcare workers and patients, facilitating cross-transmission.Antibiotic stewardship programs are considered important to reduce antibiotic resistance, but the effectiveness of strategies such as, for instance, antibiotic rotation, have not been determined rigorously. Interpretation of available studies on antibiotic rotation is hampered by heterogeneity in implemented strategies and suboptimal study designs. In this cluster-randomized, crossover trial the effects of two antibiotic rotation strategies, antibiotic mixing and cycling, on the prevalence of ARGNB in ICUs are determined. Antibiotic mixing aims to create maximum antibiotic heterogeneity, and cycling aims to create maximum antibiotic homogeneity during consecutive periods. METHODS/DESIGN: This is an open cluster-randomized crossover study of mixing and cycling of antibiotics in eight ICUs in five European countries. During cycling (9 months) third- or fourth-generation cephalosporins, piperacillin-tazobactam and carbapenems will be rotated during consecutive 6-week periods as the primary empiric treatment in patients suspected of infection caused by Gram-negative bacteria. During mixing (9 months), the same antibiotics will be rotated for each consecutive antibiotic course. Both intervention periods will be preceded by a baseline period of 4 months. ICUs will be randomized to consecutively implement either the mixing and then cycling strategy, or vice versa. The primary outcome is the ICU prevalence of ARGNB, determined through monthly point-prevalence screening of oropharynx and perineum. Secondary outcomes are rates of acquisition of ARGNB, bacteremia and appropriateness of therapy, length of stay in the ICU and ICU mortality. Results will be adjusted for intracluster correlation, and patient- and ICU-level variables of case-mix and infection-prevention measures using advanced regression modeling. DISCUSSION: This trial will determine the effects of antibiotic mixing and cycling on the unit-wide prevalence of ARGNB in ICUs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01293071 December 2010. PMID- 25011605 TI - Effect of an isoenergetic traditional Mediterranean diet on the high-density lipoprotein proteome in men with the metabolic syndrome. AB - BACKGROUND/AIMS: The objective of this preliminary study was to examine the impact of the Mediterranean diet (MedDiet) on the high-density lipoprotein (HDL) proteome in men with the metabolic syndrome (MetS). METHODS: Twenty-six men with the MetS first consumed a standardized baseline North American isoenergetic control diet (5 weeks) and then consumed an isoenergetic MedDiet (5 weeks), both in full feeding condition. The HDL fraction was isolated by ultracentrifugation at the end of each diet and the HDL proteome assessed by isobaric tags for relative and absolute quantitation and mass spectrometry. RESULTS: Of all proteins identified within HDL, only 3 showed significant changes in relative abundance after the MedDiet versus the control diet, including a reduction in inflammation-related inter-alpha-trypsin inhibitor heavy chain H4 (fold change: 0.62) and hemoglobin subunits alpha (fold change: 0.40) and beta (fold change: 0.46). Other HDL-bound proteins associated with functions related to lipid metabolism/cholesterol homeostasis, oxidation, coagulation, complement activation and immunity were unchanged after consumption of the MedDiet for 5 weeks. CONCLUSIONS: Changes in the HDL proteome may explain, at least partly, the well known anti-inflammatory effect ascribed to the MedDiet. Otherwise, short-term consumption of the MedDiet seems to have little impact on other features of the HDL proteome in men with the MetS. PMID- 25011608 TI - Freestanding 3D mesoporous Co3O4@carbon foam nanostructures for ethanol gas sensing. AB - Metal oxide materials have been widely used as gas-sensing platforms, and their sensing performances are largely dependent on the morphology and surface structure. Here, freestanding flower-like Co3O4 nanostructures supported on three dimensional (3D) carbon foam (Co3O4@CF) were successfully synthesized by a facile and low-cost hydrothermal route and annealing procedure. The morphology and structure of the nanocomposites were studied by X-ray diffraction, X-ray photoelectron spectroscopy, energy-dispersive spectroscopy, and scanning electron microscopy (SEM). The SEM characterizations showed that the skeleton of the porous carbon foam was fully covered by flower-like Co3O4 nanostructures. Moreover, each Co3O4 nanoflower is composed of densely packed nanoneedles with a length of ~10 MUm, which can largely enhance the surface area (about 286.117 m(2)/g) for ethanol sensing. Gas sensor based on the as-synthesized 3D Co3O4@CF nanostructures was fabricated to study the sensing performance for ethanol at a temperature range from 180 to 360 degrees C. Due to the 3D porous structure and the improvement in sensing surface/interface, the Co3O4@CF nanostructure exhibited enhanced sensing performance for ethanol detection with low resistance, fast response and recovery time, high sensitivity, and limit of detection as low as 15 ppm at 320 degrees C. The present study shows that such novel 3D metal oxide/carbon hybrid nanostructures are promising platforms for gas sensing. PMID- 25011606 TI - 2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride protects against beta amyloid-induced activation of the apoptotic cascade in cultured cortical neurons. AB - Aggregated beta-amyloid, implicated in the pathogenesis of Alzheimer's disease (AD), induces neurotoxicity by evoking a cascade of oxidative damage-dependent apoptosis in neurons. We investigated the molecular mechanisms underlying the protective effect of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377) against the beta-amyloid (Abeta25-35)-induced primary cortical neuronal cell neurotoxicity. Treatment with KHG26377 attenuated the Abeta25-35 induced apoptosis by decreasing the Bax/Bcl-2 ratio and suppressing the activation of caspase-3. A marked increase in calcium influx and in the level of reactive oxygen species together with a decrease in glutathione levels was found after Abeta25-35 exposure; however, KHG26377 treatment reversed these changes in a concentration-dependent manner. In addition, KHG26377 significantly suppressed Abeta25-35-induced toxicity concomitant with a reduction in the activation of extracellular signal-regulated kinases 1 and 2 and nuclear factor kappa B. The KHG26377-induced protection of neuronal cells against Abeta toxicity was also mediated by suppressing the expression of glycogen synthase kinase-3beta, increasing the levels of beta-catenin, and reducing the levels of phosphorylated tau. Our findings suggest that KHG26377 may modulate the neurotoxic effects of beta-amyloid and provide a rationale for treatment of AD. PMID- 25011609 TI - Tuning pharmacokinetics and biodistribution of a targeted drug delivery system through incorporation of a passive targeting component. AB - Major challenges in the development of drug delivery systems (DDSs) have been the short half-life, poor bioavailability, insufficient accumulation and penetration of the DDSs into the tumor tissue. Understanding the pharmacokinetic (PK) parameters of the DDS is essential to overcome these challenges. Herein we investigate how surface chemistry affects the PK profile and organ distribution of a gold nanoparticle-based DDS containing both a passive and active targeting moiety via two common routes of administration: intravenous and intraperitoneal injections. Using LC/MS/MS, ELISA and INAA we report the half-life, peak plasma concentrations, area under the curve, ability to cross the peritoneal barrier and biodistribution of the nanoconjugates. The results highlight the design criteria for fine-tuning the PK parameters of a targeted drug delivery system that exploits the benefits of both active and passive targeting. PMID- 25011611 TI - Facile preparation of black Nb4+ self-doped K4Nb6O17 microspheres with high solar absorption and enhanced photocatalytic activity. AB - Black Nb(4+) self-doped K4Nb6O17 microspheres were prepared for the first time through a facile UV light photoreduction method. By the introduction of Nb(4+), the defective K4Nb6O17 can harvest the full spectrum of visible light as well as near-infrared light. The black K4Nb6O17 microspheres showed improved visible light-driven photocatalytic H2 production activity. Importantly, the present synthetic approach is also applicable to the preparation of other Nb(4+) self doped niobates. PMID- 25011612 TI - Exercise-referral scheme to promote physical activity among hypertensive patients: design of a cluster randomized trial in the Primary Health Care Units of Mexico's Social Security System. AB - BACKGROUND: Although the benefits of physical activity (PA) on to prevent and manage non-communicable diseases are well known, strategies to help increase the levels of PA among different populations are limited. Exercise-referral schemes have emerged as one effective approach to promote PA; however, there is uncertainty about the feasibility and effectiveness of these schemes in settings outside high-income countries. This study will examine the effectiveness of a scheme to refer hypertensive patients identified in Primary Health Care facilities (PHCU) of the Mexican social security institution to a group PA program offered in the same institution. METHODS AND DESIGN: We will describe the methods of a cluster randomized trial study designed to evaluate the effectiveness of an exercise referral scheme to increasing physical activity in hypertensive patients compared to a non-referral scheme. Four PHCU were selected for the study; the PHCU will take part as the unit of randomization and sedentary hypertensive patients as the unit of assessment. 2 PHCU of control group (GC) will provide information to hypertensive patients about physical activity benefits and ways to increase it safely. 2 PHCU of intervention group (IG) will refer patients to sports facilities at the same institution, to follow a group based PA program developed to increase the PA levels with a designed based on the Transtheoretical Model and Social Cognitive Theory. To evaluate the effects of the intervention as well as short-term maintenance of the intervention's effects, PA will be assessed at baseline, at 24 and 32 weeks of follow-up.The main outcome will be the difference before and after intervention in the percentage of participants meeting recommended levels of PA between and within intervention and control groups. PA will be measured through self-report and with objective measure by accelerometer. DISCUSSION: This study will allow us to evaluate a multidisciplinary effort to link the primary care and community-based areas of the same health care system. Our findings will provide important information about the feasibility and effectiveness of an exercise-referral scheme and will be useful for decision-making about the implementation of strategies for increasing PA among hypertensive and other clinical populations in Mexico and Latin America. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01910935. Date of registration: 07/05/2013. PMID- 25011613 TI - Dietary vitamin E in White Leghorn layer breeder hens: a strategy to combat aflatoxin B1-induced damage. AB - Mycotoxins are unavoidable contaminants of animal and human feed and food respectively. This study was designed to investigate the protective activity of vitamin E (Vit E) in White Leghorn breeder hens and their progeny against aflatoxin B1 (AFB1)-induced damage. The results indicated a significant decrease in egg production and quality in the groups exposed to dietary AFB1. A detectable amount of AFB1 residue appeared in the eggs during the first week of mycotoxin exposure at levels >= 2.5 mg kg(-1), which reached its peak (0.403 +/- 0.04 ng/g [mean +/- standard deviation]) during the second week of the experiment (in the group fed 10 mg kg(-1)). Feeding Vit E + AFB1 resulted in higher AFB1 residues (0.467 +/- 0.03) when compared with the hens fed AFB1 alone. The resistance of red blood cells to oxidative damage was decreased, while embryonic mortalities and deformities were increased in the AFB1-fed groups. The protective effect of Vit E on these parameters was noted in the groups fed lower doses of AFB1. After the withdrawal of mycotoxin-contaminated feed, most of the parameters returned towards normal within 2 weeks, except AFB1 residues that were still detectable. From the findings of this study one can conclude that the addition of Vit E in the diet of hens provided only partial protection against AFB1-induced damage. PMID- 25011614 TI - Caffeine inhibits migration in glioma cells through the ROCK-FAK pathway. AB - AIMS: Glioma is the most malignant brain tumor that has the ability to migrate and invade the CNS. In this study, we investigated the signaling mechanism of caffeine on the migration of glioma cells. METHODS: The effect of caffeine on cell migration was evaluated using Transwell and wound healing assays. The expression of the focal adhesion complex as it related to cell migration was assayed using Western blotting and immunostaining. RESULTS: Caffeine decreased the migration of rat C6 and human U87MG glioma cells and down-regulated the expression of phosphorylated focal adhesion kinase (p-FAK) and p-paxillin. Caffeine also decreased p-FAK staining at the edge of glioma cells and disassembled actin stress fibers. Additionally, caffeine elevated expression of phosphorylated myosin light chain (p-MLC), an effect that could be blocked by Y27632, a rho-associated protein kinase (ROCK) inhibitor, but not myosin light chain kinase inhibitor, ML-7. Y27632 also inhibited the caffeine-reduced expression of p-FAK and p-paxillin as well as cell migration. CONCLUSION: Caffeine decreased the migration of glioma cell through the ROCK-focal adhesion complex pathway; this mechanism may be useful as part of clinical therapy in the future. PMID- 25011615 TI - BiOsimilaRs in the management of anaemia secondary to chemotherapy in HaEmatology and Oncology: results of the ORHEO observational study. AB - BACKGROUND: The approval of epoetin biosimilars in the European Union requires extensive scientific evaluation and stringent regulatory procedures, including post-marketing studies. The ORHEO (place of biOsimilaRs in the therapeutic management of anaemia secondary to chemotherapy in HaEmatology and Oncology) study was an observational, longitudinal, multicentre study performed in France to evaluate the efficacy and safety of biosimilar epoetins for the treatment of chemotherapy-induced anaemia (CIA) in the clinical setting. METHODS: Patients >18 years with CIA (haemoglobin [Hb] <11 g/dL) in association with solid tumours, lymphoma or myeloma and eligible for treatment with an epoetin biosimilar were included in this study. Patient characteristics were recorded at baseline along with anaemia-related information, such as observed and target Hb (as chosen by the treating clinician), brand and dose of epoetin biosimilar prescribed, and details of any other treatments. Patients were then followed-up at 3 and 6 months. The primary endpoint was Hb response (defined as Hb reaching >=10 g/dL, an increase of Hb >=1 g/dL since inclusion visit or reaching physician-defined target Hb, with no blood transfusions in the 3 weeks prior to measurement). Other endpoints included adverse events, achievement of target Hb and associated treatments. RESULTS: Overall, 2333 patients >18 years (mean age 66.5 years) with CIA (haemoglobin [Hb] <11 g/dL) in association with solid tumours, lymphoma or myeloma and eligible for biosimilar epoetin treatment were included. 99.9% of patients received epoetin zeta (median dose 30,000 IU/week). Mean baseline Hb was 9.61 g/dL, with 35.6% of patients having moderate anaemia (Hb 8-9.5 g/dL). Hb response was achieved in 81.6% and 86.5% of patients at 3 and 6 months, respectively. Overall mean change in Hb level was 1.52 +/- 1.61 and 1.72 +/- 1.61 g/dL at 3 and 6 months, respectively. Transfusion and thromboembolic event rates were 9.4% and 2.4% at 3 months, and 5.8% and 1.5% at 6 months, respectively. CONCLUSIONS: Epoetin zeta was effective and well tolerated in the management of CIA in patients with solid tumours, lymphoma and myeloma. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT02140736 (date of registration: 14 May 2014). PMID- 25011616 TI - Controlled synthesis of hierarchical TiO2 nanoparticles on glass fibres and their photocatalytic performance. AB - This paper reports the synthesis of novel photocatalysts consisting of TiO2 nanoparticles and glass fibres (GF) using a two-step process. The method involves the hydrolysis of titanium tetrachloride in the presence of GF and a following hydrothermal process under alkaline conditions. Various techniques are employed to characterize the morphology, structure and crystallinity of TiO2 on the fibre surface. The results show that depending on the experiment setups, TiO2 nanoparticles exhibit spherical or flake-like morphology, forming characteristic hierarchical structures along with flexible GF. Flake-like TiO2/GF exhibits much enhanced photocatalytic activity thanks to the large surface area and the hetero junction of anatase and TiO2-B phases observed in its structure. An interesting observation is that the alkali treatment of GF leads to the formation of porous structures on the fibre surface, facilitating the adsorption-concentration promoted photocatalytic process. The removal ratio of the organic dye by employing TiO2/GF remains more than 80% after six cyclic runs, showing the reusability of photocatalysts in real application. The novelty of this work lies in the synergy arising from materials with unique morphologies, structures and availabilities as well as capabilities in separating photogenerated electron-hole pairs, which have not been specifically considered previously in photocatalytic semiconductors. PMID- 25011617 TI - Spotted fever Rickettsia species in Hyalomma and Ixodes ticks infesting migratory birds in the European Mediterranean area. AB - BACKGROUND: A few billion birds migrate annually between their breeding grounds in Europe and their wintering grounds in Africa. Many bird species are tick infested, and as a result of their innate migratory behavior, they contribute significantly to the geographic distribution of pathogens, including spotted fever rickettsiae. The aim of the present study was to characterize, in samples from two consecutive years, the potential role of migrant birds captured in Europe as disseminators of Rickettsia-infected ticks. METHODS: Ticks were collected from a total of 14,789 birds during their seasonal migration northwards in spring 2009 and 2010 at bird observatories on two Mediterranean islands: Capri and Antikythira. All ticks were subjected to RNA extraction followed by cDNA synthesis and individually assayed with a real-time PCR targeting the citrate synthase (gltA) gene. For species identification of Rickettsia, multiple genes were sequenced. RESULTS: Three hundred and ninety-eight (2.7%) of all captured birds were tick-infested; some birds carried more than one tick. A total number of 734 ticks were analysed of which 353 +/- 1 (48%) were Rickettsia-positive; 96% were infected with Rickettsia aeschlimannii and 4% with Rickettsia africae or unidentified Rickettsia species. The predominant tick taxon, Hyalomma marginatum sensu lato constituted 90% (n = 658) of the ticks collected. The remaining ticks were Ixodes frontalis, Amblyomma sp., Haemaphysalis sp., Rhipicephalus sp. and unidentified ixodids. Most ticks were nymphs (66%) followed by larvae (27%) and adult female ticks (0.5%). The majority (65%) of ticks was engorged and nearly all ticks contained visible blood. CONCLUSIONS: Migratory birds appear to have a great impact on the dissemination of Rickettsia-infected ticks, some of which may originate from distant locations. The potential ecological, medical and veterinary implications of such Rickettsia infections need further examination. PMID- 25011618 TI - An in silico structural insights into Plasmodium LytB protein and its inhibition. AB - In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3 methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new anti-malarial compounds or inhibitors. Here a systematic in silico study has been conducted to get an insight into the structure of Plasmodium lytB as well as its affinities towards different inhibitors. We used comparative modeling technique to predict the three-dimensional (3D) structure of Plasmodium LytB taking Escherichia coli LytB protein (PDB ID: 3KE8) as template and the model was subsequently refined through molecular dynamics (MD) simulation. A large ligand data-set containing diphospate group was subjected for virtual screening against the target using GOLD 5.2 program. Considering the mode of binding and affinities, 17 leads were selected on basis of binding energies in comparison to its substrate HMBPP (Gold.Chemscore.DG: -20.9734 kcal/mol). Among them, five were discarded because of their inhibitory activity towards other human enzymes. The rest 12 potential leads carry all the properties of any "drug like" molecule and the knowledge of Plasmodium LytB-inhibitory mechanism which can provide valuable support for the anti-malarial-inhibitor design in future. PMID- 25011619 TI - Varying degrees of nonlinear mechanical behavior arising from geometric differences of urogynecological meshes. AB - Synthetic polypropylene meshes were designed to restore pelvic organ support for women suffering from pelvic organ prolapse; however, the FDA released two notifications regarding potential complications associated with mesh implantation. Our aim was to characterize the structural properties of Restorelle and UltraPro subjected to uniaxial tension along perpendicular directions, and then model the tensile behavior of these meshes utilizing a co-rotational finite element model, with an imbedded linear or fiber-recruitment local stress-strain relationship. Both meshes exhibited a highly nonlinear stress-strain behavior; Restorelle had no significant differences between the two perpendicular directions, while UltraPro had a 93% difference in the low (initial) stiffness (p=0.009) between loading directions. Our model predicted that early alignment of the mesh segments in the loading direction and subsequent stretching could explain the observed nonlinear tensile behavior. However, a nonlinear stress strain response in the stretching regime, that may be inherent to the mesh segment, was required to better capture experimental results. Utilizing a nonlinear fiber recruitment model with two parameters A and B, we observed improved agreement between the simulations and the experimental results. An inverse analysis found A=120 MPa and B=1.75 for Restorelle (RMSE=0.36). This approach yielded A=30 MPa and B=3.5 for UltraPro along one direction (RMSE=0.652), while the perpendicular orientation resulted in A=130 MPa and B=4.75 (RMSE=4.36). From the uniaxial protocol, Restorelle was found to have little variance in structural properties along these two perpendicular directions; however, UltraPro was found to behave anisotropically. PMID- 25011620 TI - Predicting timing of foot strike during running, independent of striking technique, using principal component analysis of joint angles. AB - As 3-dimensional (3D) motion-capture for clinical gait analysis continues to evolve, new methods must be developed to improve the detection of gait cycle events based on kinematic data. Recently, the application of principal component analysis (PCA) to gait data has shown promise in detecting important biomechanical features. Therefore, the purpose of this study was to define a new foot strike detection method for a continuum of striking techniques, by applying PCA to joint angle waveforms. In accordance with Newtonian mechanics, it was hypothesized that transient features in the sagittal-plane accelerations of the lower extremity would be linked with the impulsive application of force to the foot at foot strike. Kinematic and kinetic data from treadmill running were selected for 154 subjects, from a database of gait biomechanics. Ankle, knee and hip sagittal plane angular acceleration kinematic curves were chained together to form a row input to a PCA matrix. A linear polynomial was calculated based on PCA scores, and a 10-fold cross-validation was performed to evaluate prediction accuracy against gold-standard foot strike as determined by a 10 N rise in the vertical ground reaction force. Results show 89-94% of all predicted foot strikes were within 4 frames (20 ms) of the gold standard with the largest error being 28 ms. It is concluded that this new foot strike detection is an improvement on existing methods and can be applied regardless of whether the runner exhibits a rearfoot, midfoot, or forefoot strike pattern. PMID- 25011621 TI - Scaling and kinematics optimisation of the scapula and thorax in upper limb musculoskeletal models. AB - Accurate representation of individual scapula kinematics and subject geometries is vital in musculoskeletal models applied to upper limb pathology and performance. In applying individual kinematics to a model's cadaveric geometry, model constraints are commonly prescriptive. These rely on thorax scaling to effectively define the scapula's path but do not consider the area underneath the scapula in scaling, and assume a fixed conoid ligament length. These constraints may not allow continuous solutions or close agreement with directly measured kinematics. A novel method is presented to scale the thorax based on palpated scapula landmarks. The scapula and clavicle kinematics are optimised with the constraint that the scapula medial border does not penetrate the thorax. Conoid ligament length is not used as a constraint. This method is simulated in the UK National Shoulder Model and compared to four other methods, including the standard technique, during three pull-up techniques (n=11). These are high performance activities covering a large range of motion. Model solutions without substantial jumps in the joint kinematics data were improved from 23% of trials with the standard method, to 100% of trials with the new method. Agreement with measured kinematics was significantly improved (more than 10 degrees closer at p<0.001) when compared to standard methods. The removal of the conoid ligament constraint and the novel thorax scaling correction factor were shown to be key. Separation of the medial border of the scapula from the thorax was large, although this may be physiologically correct due to the high loads and high arm elevation angles. PMID- 25011622 TI - Computational simulations of flow dynamics and blood damage through a bileaflet mechanical heart valve scaled to pediatric size and flow. AB - Despite pressing needs, there are currently no FDA approved prosthetic valves available for use in the pediatric population. This study is performed for predictive assessment of blood damage in bileaflet mechanical heart valves (BMHVs) with pediatric sizing and flow conditions. A model of an adult-sized 23 mm St. Jude Medical (SJM) Regent(TM) valve is selected for use in simulations, which is scaled in size for a 5-year old child and 6-month old infant. A previously validated lattice-Boltzmann method (LBM) is used to simulate pulsatile flow with thousands of suspended platelets for cases of adult, child, and infant BMHV flows. Adult BMHV flows demonstrate more disorganized small-scale flow features, but pediatric flows are associated with higher fluid shear stresses. Platelet damage in the pediatric cases is higher than in adult flow, highlighting thrombus complication dangers of pediatric BMHV flows. This does not necessarily suggest clinically important differences in thromboembolic potential. Highly damaged platelets in pediatric flows are primarily found far downstream of the valve, as there is less flow recirculation in pediatric flows. In addition, damage levels are well below expected thresholds for platelet activation. The extent of differences here documented between the pediatric and adult cases is of concern, demanding particular attention when pediatric valves are designed and manufactured. However, the differences between the pediatric and adult cases are not such that development of pediatric sized valves is untenable. This study may push for eventual approval of prosthetic valves resized for the pediatric population. Further studies will be necessary to determine the validity and potential thrombotic and clinical implications of these findings. PMID- 25011623 TI - Evaluation of a microcolony growth monitoring method for the rapid determination of ethambutol resistance in Mycobacterium tuberculosis. AB - BACKGROUND: Due to the increasing prevalence of Mycobacterium tuberculosis strains resistant to one or more antibiotics, there is a need for new quantitative culture methods both for drug susceptibility testing and for validation of mutations putatively associated with drug resistance. We previously developed a (myco) bacterial culture method, in which multiple growing microcolonies are monitored individually. Transfer of the growing microcolonies to selective medium allows the effect on the growth rate of each individual colony to be determined. As entire growing colonies are exposed to antibiotics rather than re-subbed, a second lag phase is avoided and results are obtained more rapidly. Here we investigate the performance of the microcolony method to differentiate between ethambutol (EMB) resistant, intermediate and susceptible strains. METHODS: One week old microcolonies from a reference panel of four strains with known EMB susceptibility were transferred to different concentrations of EMB. Growth rates during the 1st 2 days of exposure were used to set up classification criteria to test and classify a blinded panel of 20 tuberculosis strains with different susceptibilities. RESULTS: For 18 strains (90%) reference culture results corresponded to our classifications based on data collected within 9 days of inoculation. A single strain was classified as Intermediate instead of Susceptible, and 1 strain could not be classified due to a contamination. CONCLUSIONS: Using a microcolony growth monitoring method we were able to classify, within 9 days after inoculation, a panel of strains as EMB susceptible, intermediate or resistant with 90% correlation to the reference methods. PMID- 25011624 TI - Performance of coumarin-derived dendrimer-based fluorescence-linked immunosorbent assay (FLISA) to detect malaria antigen. AB - BACKGROUND: Due to limitation of conventional malaria diagnostics, including microscopy, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA), alternative accurate diagnostics have been demanded for improvement of sensitivity and specificity. METHODS: Serially diluted Plasmodium LDH antigens, Plasmodium falciparum-infected human red blood cells (RBC) derived from in vitro culture or patient's samples were used for evaluation of the performance of fluorescence-linked immunosorbent assay (FLISA). Microscopic examination was used to determine parasite density and the performance of FLISA was compared to ELISA. Finally, sensitivity and specificity of FLISA was determined by human specimens infected with P. falciparum, Plasmodium vivax, Toxoplasma gondii, and amoebae. RESULTS: As a result of FLISA, the fluorescent intensity was highly correlated with antigen amount and FLISA was more sensitive than ELISA. FLISA detected at least 0.01 ng/ml of pLDH antigen, which showed 1,000-fold higher sensitivity than ELISA. In vitro-cultured P. falciparum was detected up to 20 parasite number/MUL in FLISA but 5120 parasite number/MULin sandwich ELISA. In vitro P. falciparum-infected RBC number was highly correlated with fluorescent intensity (R2 = 0.979), showing that FLISA was reliable for detection of P. falciparum and available for quantification of parasite numbers. Furthermore, eighteen patient samples infected with P. falciparum (n = 9) and P. vivax (n = 9) showed 100% of sensitivity (18/18). FLISA showed 96.3% of specificity (26/27) because one sample of patient blood infected with T. gondii gave a false positive reactivity among healthy donors (n = 9), T. gondii-infected patients (n = 9), and amoeba-infected patients (n = 9). CONCLUSION: FLISA has a keen and high performance to detect malaria antigen, suggesting a potential assay as malaria immunodiagnostic. PMID- 25011625 TI - Physical perceptions and self-concept in athletes with muscle dysmorphia symptoms. AB - Individuals affected by Muscle Dysmorphia (MD; body image disorder based on the sub estimation of muscle size), practice weightlifting in order to alleviate their muscular dissatisfaction. Although physical activity is associated with increased physical self-perception, we assume that this was not reproduced in full in people with MD. The study sample consisted of 734 weightlifters and bodybuilders, 562 men and 172 women, who completed the Escala de Satisfaccion Muscular, the Physical Self-Concept Questionnaire, and from whom measures of body fat and Fat -Free Mass Index (FFMI) were obtained. The results showed that people suffering from MD symptoms, overall, have poorer physical self-concept perceptions (F = 18.46 - 34.77, p < .01). PMID- 25011626 TI - Differential introgression among loci across a hybrid zone of the intermediate horseshoe bat (Rhinolophus affinis). AB - BACKGROUND: Hybrid zones formed by the secondary contact of divergent lineages represent natural laboratories for studying the genetic basis of speciation. Here we tested for patterns of differential introgression among three X-linked and 11 autosomal regions to identify candidate loci related to either reproductive isolation or adaptive introgression across a hybrid zone between two Chinese mainland subspecies of the intermediate horseshoe bat Rhinolophus affinis: R. a. himalayanus and R. a. macrurus. RESULTS: Our results support the previous suggestion that macrurus formed when a third subspecies (R. a. hainanus) recolonized the mainland from Hainan Island, and that himalayanus is the ancestral taxon. However, this overall evolutionary history was not reflected in all loci examined, with considerable locus-wise heterogeneity seen in gene tree topologies, levels of polymorphism, genetic differentiation and rates of introgression. Coalescent simulations suggested levels of lineage mixing seen at some nuclear loci might result from incomplete lineage sorting. Isolation with migration models supported evidence of gene flow across the hybrid zone at one intronic marker of the hearing gene Prestin. CONCLUSIONS: We suggest that phylogenetic discordance with respect to the species tree seen here is likely to arise via a combination of incomplete lineage sorting and a low incidence of introgression although we cannot rule out other explanations such as selection and recombination. Two X-linked loci and one autosomal locus were identified as candidate regions related to reproductive isolation across the hybrid zone. Our work highlights the importance of including multiple genomic regions in characterizing patterns of divergence and gene flow across a hybrid zone. PMID- 25011627 TI - Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence. AB - The relevant role in cancer played by the tyrosine kinase receptor encoded by the MET oncogene led to the development of specific inhibitors, some of which are now in advanced phases of clinical trials. Previous experience has shown that the main limit to the efficacy of most targeted treatments is the advent of resistance. Mechanisms underlying resistance to MET-specific small tyrosine kinase inhibitors (TKIs) have been already described, while nothing is known about resistance to MET monoclonal antibodies, nor about bypassing resistance to chemical TKIs by antibodies or vice-versa. EBC1 lung cancer cells are MET addicted as a consequence of gene amplification and thus sensitive to MET inhibitors, including the monovalent form of a MET monoclonal antibody (MV-DN30). We generated cells resistant to this antibody and found that resistance was due to a further increase of gene copy number and a dramatic overexpression of the MET receptor. Such an excess of expression saturated the 'shedding' activity of MV-DN30, and prevented both the efficient down-regulation of the MET receptor from the surface and the inhibition of the ensuing constitutive activation. Notably, antibody-resistant cells remained MET-'addicted' and were still sensitive to MET TKIs. Moreover, antibody-resistant cells became 'drug dependent', since the removal of MV-DN30 led them to death due to excess of signal. In the mirror experiment, cells made resistant to MET-specific TKIs were still sensitive to treatment with the antibody MV-DN30. These findings suggest that a discontinuous, combined treatment by antibodies and chemical kinase inhibitors may increase the clinical response and bypass resistance to anti-MET targeted therapies. PMID- 25011629 TI - Propofol-based sedation in gastrointestinal endoscopy: getting safer and safer. PMID- 25011630 TI - Depressive symptoms and suicidal ideation in adolescents accompanying a parent in recyclable trash collection. AB - The relationship between mental health and poverty has been well documented in adults. However, few studies have addressed how low socioeconomic status and psychosocial vulnerabilities may influence depressive symptoms in adolescents. The current study was carried out in a non-randomly selected sample of 239 adolescents whose parents work as ragpickers (waste collectors for recycling) in Brazil. In-person interviews were conducted, and the presence of depressive symptoms and suicidal ideation were assessed using the Children's Depression Inventory (CDI). We observed that 23% (CI +/- 5.34) of the adolescents presented with depressive symptoms and 35% (CI +/- 6.05) had suicidal ideation. Fatigue or loss of energy (p = .012) and irritable mood (p = .013) were significantly higher among boys than girls according to DSM-IV criteria. However, we found no gender differences in DSM-IV criteria for Major Depressive Disorders (MDD) or Dysthymic Disorder (DD) in diminished interest or pleasure, weight loss or weight gain, decreased appetite, sleep problems, feelings of worthlessness, diminished concentration or ability to think, recurrent thoughts of death, suicidal ideation, or low self-esteem. There were no significant gender differences in total CDI score, however a greater percentage of girls presented with depressed mood than boys (29.9% vs. 17.1%, p < .05). PMID- 25011628 TI - How much do we know about the coupling of G-proteins to serotonin receptors? AB - Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several G-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different pathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search was performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public databases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues. Only a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible thousands suggested by expression data analysis have been examined experimentally. In addition this has mostly been obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions have not been explored, our findings suggest additional possible interactions that should be examined based on our expression data analysis. PMID- 25011631 TI - Glycoconjugated porphyrin dimers as robust ratiometric temperature sensors. AB - We report the properties of glycoconjugated porphyrin dimers behaving as highly sensitive ratiometric temperature sensors in water. This effect results from interactions between carbohydrate and water altering molecular relaxation kinetics leading to temperature sensitive dual emission. These dimers are robust ratiometric fluorescent probes over a large temperature window (20-90 degrees C). PMID- 25011633 TI - Incidence of postoperative deep vein thrombosis after robotic-assisted laparoscopic prostatectomy: a prospective study in Chinese patients. AB - OBJECTIVE: To investigate the incidence of deep vein thrombosis (DVT) in Chinese patients undergoing robotic-assisted laparoscopic radical prostatectomy (RALP) for prostate cancer and the need for prophylactic anticoagulation. METHODS: From August 2007 to September 2010, patients with prostate cancer undergoing RALP in our center were prospectively recruited for the study. Perioperative parameters, including patients' age, disease stage and pathology, and intraoperative findings were collected. All patients underwent Doppler ultrasonographic evaluation of their bilateral lower limbs on postoperation day 3 for any evidence of DVT. The incidence of and possible predisposing factors for DVT were determined. RESULTS: One hundred and nine consecutive patients were recruited during the study period. The incidence rate of post-RALP DVT was 16.9 % (18 cases), with only one patient (1 %) developing above-knee DVT. No patient developed DVT-associated complications during follow-up. Patients with DVT were older (69.2 +/- 4.4 vs. 65 +/- 5.8 years old; p = 0.05), had greater intraoperative blood loss (775 vs. 264.7 ml; p = 0.001) and required lengthier hospitalization (8.1 vs. 6.0 days; p = 0.013). However, no difference in smoking history, body mass index, history of diabetes, lymph node dissection or disease stage was observed between patients with and without DVT. CONCLUSIONS: The post-RALP incidence of DVT in Chinese populations is not low. However, the majority of DVT cases are below the knee level and asymptomatic. PMID- 25011632 TI - Assembly and stability of Salmonella enterica ser. Typhi TolC protein in POPE and DMPE. AB - In this work we assessed the suitability of two different lipid membranes for the simulation of a TolC protein from Salmonella enterica serovar Typhi. The TolC protein family is found in many pathogenic Gram-negative bacteria including Vibrio cholera and Pseudomonas aeruginosa and acts as an outer membrane channel for expulsion of drug and toxin from the cell. In S. typhi, the causative agent for typhoid fever, the TolC outer membrane protein is an antigen for the pathogen. The lipid environment is an important modulator of membrane protein structure and function. We evaluated the conformation of the TolC protein in the presence of DMPE and POPE bilayers using molecular dynamics simulation. The S. typhi TolC protein exhibited similar conformational dynamics to TolC and its homologues. Conformational flexibility of the protein is seen in the C-terminal, extracellular loops, and alpha-helical region. Despite differences in the two lipids, significant similarities in the motion of the protein in POPE and DMPE were observed, including the rotational motion of the C-terminal residues and the partially open extracellular loops. However, analysis of the trajectories demonstrated effects of hydrophobic matching of the TolC protein in the membrane, particularly in the lengthening of the lipids and subtle movements of the protein's beta-barrel towards the lower leaflet in DMPE. The study exhibited the use of molecular dynamics simulation in revealing the differential effect of membrane proteins and lipids on each other. In this study, POPE is potentially a more suitable model for future simulation of the S. typhi TolC protein. PMID- 25011635 TI - Pain related catastrophizing on physical limitation in rheumatoid arthritis patients. Is acceptance important? AB - The experience of Rheumatoid Arthritis (RA) includes significant suffering and life disruption. This cross-sectional study examined the associations between pain, catastrophizing, acceptance and physical limitation in 55 individuals (11 males and 44 female; Mean age = 54.37; SD = 18.346), from the Portuguese population with (RA) 2 years after the diagnosis; also explored the role of acceptance as a mediator process between pain, catastrophizing and physical limitation. Results showed positive correlation between pain and catastrophizing (r = .544; p <= .001), and also between pain and 2-years' physical limitation (r = .531; p <= .001) Results also showed that acceptance was negatively correlated with physical limitation 2 years after the diagnosis (r = -.476; p <= .001). Path analysis was performed to explore the direct effect of pain (beta = -.393; SD = .044; Z = 3.180; p <= .001) and catastrophizing (n.sig.) on physical limitation and also to explore the buffer effect of acceptance in this relationship (indirect effect beta = -.080). Results showed that physical limitation is not necessarily a direct product of pain and catastrophizing but acceptance was also involved. Pain and catastrophizing are associated but the influence of catastrophizing on physical limitation is promoted by low levels of acceptance. Results emphasize the relevance of acceptance as the emotional regulation process by which pain and catastrophizing influence physical functioning and establish the basic mechanism by which pain and catastrophizing operate in a contextual based perspective. Also the study results offer a novel approach that may help behavioral health and medical providers prevent and treat these conditions. PMID- 25011634 TI - Formation and development of maxillary first molars with delayed eruption. AB - Cases of congenitally missing and delayed eruption of the maxillary first molar are rare. However, in recent years, we have experienced cases of suspected delayed eruption of or congenitally missing first molars. The purpose of this study was to analyze the formation of delayed erupted maxillary first molars (M1) (>2 standard deviations), which play important roles in occlusion, and normal eruption of the maxillary first molars (U6). The frequency of M1 among patients born between 1974 and 1994 in one institution with a clear total patient number and personal oral histories was 1.55 % [80 % bilateral eruption in 8 of 806 male patients (0.99 %) and 23 of 1195 female patients (1.92 %)]. To evaluate the formation and eruption of M1 according to Moorrees's tooth formation stages, panoramic X-ray films were obtained every year for 73 patients with M1 from 3 institutions (20 male and 53 female patients, total 131 M1s) without systematic histories or genetic disorders. The development/growth curve of M1 was fitted to both the logistic curve and U6 curve. The M1 development/growth curve was started behind with U6 curve; however, the straight part of the M1 curve exhibited steep inclination compared with the straight part of the U6 curve. The curve of the eruption pathway of M1 also exhibited a sigmoid S shape. These results indicate that the development and migration speed of M1 are faster than that of U6, excluding the delayed start point. These results may help orthodontists in treatment planning for patients with M1. PMID- 25011636 TI - Placental mesenchymal dysplasia, a case of intrauterine sudden death. AB - Placental mesenchymal dysplasia (PMD) is a rare condition presenting with enlarged, multicystic placenta like molar changes. Although PMD usually features a normal fetus and the pregnancy often extends into the third trimester, PMD is clinically significant lesion with high rates of FGR, IUFD, and is associated with Beckwith-Wiedemann syndrome (BWS). We report a 30-year old woman at her first pregnancy with intrauterine sudden death at 31 weeks of gestation. The vesicular lesion in her uterus was detected at 10 weeks on ultrasound. The fetus was normal size without any anomaly on ultrasound and normal trophoblastic vascularization by Doppler study during the pregnancy. As the pregnancy advanced, the vesicular lesion decreased in size and no fetal abnormalities were detected. At 28 weeks of gestation an ultrasound detected dilated periumbilical chorionic vessels. We didn't detect severe FGR or abnormal trophoblastic vascularization. At 31 weeks of gestation an intrauterine sudden death of a normal-sized fetus without any anomaly occurred. The placenta was enlarged, and microscopic morphology confirmed a diagnosis of PMD. The chorionic vessels were cirsoid, dilated and tortuous. We determined the rupture of expanded periumbilical chorionic vessels led to fetal death. PMID- 25011637 TI - The long-term effects of red light-emitting diode irradiation on the proliferation and differentiation of osteoblast-like MC3T3-E1 cells. AB - Low level laser therapy (LLLT) affects various biological processes, and it is said that the non-coherent light of the light-emitting diode (LED) has a similar action. The purpose of this study was to examine the effects of LED light on the proliferation and differentiation of osteoblasts-like MC3T3-E1 cells cultured in osteogenic differentiation medium (ODM) over the long term. Cells were irradiated with red LED light of 630 nm at three doses; 0.5J/cm2, 1.5J/cm2 or 3.0J/cm2 for the cell proliferation activity assay, and at 0.5J/cm2 for the osteogenic differentiation activity assay. The former activity was checked by counting the number of viable cells using Trypan blue dye. The latter activity was evaluated by alkaline phosphatase (ALP) staining and examining the mRNA expression of the osteopontin (OPN) gene using real-time quantitative PCR. The number of viable MC3T3-E1 cells showed a tendency to increase after the irradiation at all three energy densities in comparison with a non-irradiation group (control group). In particular, there was a remarkable 3.34-fold increase in the group irradiated with 3.0J/cm2 on day 7 after starting the culture. On culture day 15, there was a tendency for the red LED irradiation group (0.5 J/cm2) to exhibit more staining for ALP than the control group, and the expression of OPN was significantly higher in the irradiation group on culture day 16. In conclusion, low level red LED light can enhance MC3T3-E1 cell proliferation and osteogenic differentiation when the cells are cultured for a relatively long time. PMID- 25011638 TI - Increased levels of interleukin-6 in tracheal aspirate fluid are indicative of fetal inflammation in ventilated extremely low gestational age newborns. AB - OBJECTIVE: To determine whether increased serum and/or tracheal aspirate fluid (TAF) levels of IL-6 at birth are associated with fetal inflammation in ventilated extremely low gestational age newborns (ELGAN). METHOD: A total of 36 ELGAN who required mechanical ventilation were enrolled in this study. The patients were classified into two groups: 19 infants who displayed histological evidence of funisitis, which is a marker of fetal inflammation, (funisitis group) and 17 infants without funisitis (comparison group). TAF samples were obtained during routine endotracheal suctioning performed within 2 hours of birth. RESULTS: The funisitis group exhibited significantly higher TAF IL-6 levels than the comparison group (2245 vs. 113 pg/mg total protein; p<0.001). The serum IL-6 levels of the funisitis group were also significantly elevated compared with those of the comparison group (median: 737 vs. 136 pg/mL, p=0.017). Receiver operating characteristic curve analysis of the association between IL-6 levels and the presence of funisitis revealed that the TAF IL-6 concentration had a higher area under the curve (0.947) than the serum IL-6 concentration (0.719). At a cut-off value of 216 pg/mg total protein, the TAF IL-6 level exhibited sensitivity and specificity values of 94.7% and 86.7%, respectively, for detecting funisitis. CONCLUSION: Elevated TAF IL-6 levels at birth are strongly associated with funisitis. The TAF IL-6 concentration is a useful marker for detecting fetal inflammation in ventilated ELGAN. PMID- 25011639 TI - Diagnostic approach to cardiac amyloidosis. AB - Amyloidosis is a relatively rare disease that may be underdiagnosed and could affect the entire human body. Many organs may be affected, which could increase the morbidity and mortality. Cardiac involvement is the leading cause of poor prognosis. Patients with cardiac amyloidosis are usually admitted with heart failure. The clinical presentation varies greatly, and using the correct approach is important in identifying cardiac amyloidosis. A 51-year-old man was diagnosed with chronic heart failure. He had increased brain natriuretic peptide levels, a low ejection fraction, and left and right ventricular hypertrophy with granular sparkling as seen by echocardiography. These findings led us to perform a cardiac biopsy that confirmed the diagnosis of cardiac amyloidosis. Further investigation revealed that the patient had amyloid light-chain type amyloidosis due to multiple myeloma. He is now undergoing the 3rd phase of chemotherapy. Congo-red stain is usually used by physicians to histologically confirm amyloidosis, with which apple-green birefringence indicates amyloid deposits. Other stains such as direct fast scarlet (DFS) and hematoxylin-eosin (HE) can also confirm the presence of amyloid deposits. In the present case, DFS and HE were used, both of which suggested amyloid deposits surrounding myocardial cells. The use of a combination of stains can increase the diagnostic sensitivity and specificity of amyloidosis. However, the typical echocardiographic appearances would be enough to diagnose cardiac amyloidosis when it is impossible for the patient to undergo a cardiac biopsy, if an additional histological specimen from another tissue such as abdominal fat confirms amyloidosis. PMID- 25011640 TI - Incretin attenuates diabetes-induced damage in rat cardiac tissue. AB - Glucagon-like peptide-1 (GLP-1), as a member of the incretin family, has a role in glucose homeostasis, its receptors distributed throughout the body, including the heart. The aim was to investigate cardiac lesions following diabetes induction, and the potential effect of GLP-1 on this type of lesions and the molecular mechanism driving this activity. Adult male rats were classified into: normal, diabetic, 4-week high-dose exenatide-treated diabetic rats, 4-week low dose exenatide-treated diabetic rats, and 1-week exenatide-treated diabetic rats. The following parameters were measured: in blood: glucose, insulin, lactate dehydrogenase (LDH), total creatine kinase (CK), creatine kinase MB isoenzyme (CK MB), and CK-MB relative index; in cardiac tissue: lipid peroxide (LPO) and some antioxidant enzymes. The untreated diabetic group displayed significant increases in blood level of glucose, LDH, and CK-MB, and cardiac tissue LPO, and a significant decrease in cardiac tissue antioxidant enzymes. GLP-1 supplementation in diabetic rats definitely decreased the hyperglycemia and abolished the detrimental effects of diabetes on the cardiac tissue. The effect of GLP-1 on blood glucose and on the heart also appeared after a short supplementation period (1 week). It can be concluded that GLP-1 has beneficial effects on diabetes induced oxidative cardiac tissue damage, most probably via its antioxidant effect directly acting on cardiac tissue and independent of its hypoglycemic effect. PMID- 25011641 TI - S2O8(2-)/UV-C and H2O2/UV-C treatment of Bisphenol A: assessment of toxicity, estrogenic activity, degradation products and results in real water. AB - The performance of S2O8(2-)/UV-C and H2O2/UV-C treatments was investigated for the degradation and detoxification of Bisphenol A (BPA). The acute toxicity of BPA and its degradation products was examined with the Vibrio fischeri bioassay, whereas changes in estrogenic activity were followed with the Yeast Estrogen Screen (YES) assay. LC and LC-MS/MS analyses were conducted to determine degradation products evolving during photochemical treatment. In addition, BPA spiked real freshwater samples were also subjected to S2O8(2-)/UV-C and H2O2/UV-C treatment to study the effect of a real water matrix on BPA removal and detoxification rates. BPA removal in pure water was very fast (?7 min) and complete via both H2O2/UV-C and S2O8(2-)/UV-C treatment, accompanied with rapid and significant mineralization rates ranging between 70% and 85%. V.fischeri bioassay results indicated that degradation products being more toxic than BPA were formed at the initial stages of H2O2/UV-C whereas a rapid and steady reduction in toxicity was observed during S2O8(2-)/UV-C treatment in pure water. UV-C treatment products exhibited a higher estrogenic activity than the original BPA solution while the estrogenicity of BPA was completely removed during H2O2/UV C and S2O8(2-)/UV-C treatments parallel to its degradation. 3-methylbenzoic and 4 sulfobenzoic acids, as well as the ring opening products fumaric, succinic and oxalic acids could be identified as degradation products. BPA degradation required extended treatment periods (>20 min) and TOC removals were considerably retarded (by 40%) in the raw freshwater matrix most probably due to its natural organic matter content (TOC=5.1 mg L(-1)). H2O2/UV-C and S2O8(2-)/UV-C treatment in raw freshwater did not result in toxic degradation products. PMID- 25011642 TI - Computational study of bacterial membrane disruption by cationic biocides: structural basis for water pore formation. AB - The development of biocides as disinfectants that do not induce bacterial resistance is crucial to health care since hospital-acquired infections afflict millions of patients every year. Recent experimental studies of a class of cationic biocides based on the phenylene ethynylene backbone, known as OPEs, have revealed that their biocidal activity is accompanied by strong morphology changes to bacterial cell membranes. In vitro studies of bacterial membrane mimics have shown changes to the lipid phase that are dependent on the length and orientation of the cationic moieties on the backbone. This study uses classical molecular dynamics to conduct a comprehensive survey of how oligomers with different chemical structures interact with each other and with a bacterial cell membrane mimic. In particular, the ability of OPEs to disrupt membrane structure is studied as a function of the length of the biocides and the orientation of their cationic moieties along the backbone of the molecule. The simulation results show that the structure of OPEs radically affects their interactions with a lipid bilayer. Biocides with branched cationic groups form trans-membrane water pores regardless of their backbone length, while only 1-1.5 nm of membrane thinning is observed with biocides with cationic groups on their terminal ends. The molecular dynamics simulations provide mechanistic details at the molecular level of the interaction of these biocidal oligomers and the lipid bilayer and corroborate experimental findings regarding observed differences in membrane disruption by OPEs with different chemical structures. PMID- 25011643 TI - Does a thrombin-based topical haemostatic agent reduce blood loss and transfusion requirements after total knee revision surgery? A randomized, controlled trial. AB - PURPOSE: The aim of the present study was to assess the efficacy of a thrombin based topical haemostatic in reducing blood requirements after total knee replacement (TKR) revision surgery. METHODS: This prospective, randomized, controlled study was designed to evaluate the haemostatic efficacy and safety of a thrombin-based topical haemostatic (Floseal) versus standard treatment in patients receiving total knee revision arthroplasty. The decrease in haemoglobin values postsurgery and the blood units transfused were recorded. The decision to transfuse was made by a surgeon blinded to the patient's group allocation. RESULTS: Forty-eight patients were enroled in the study; twenty-four patients each were randomized to the treatment and control groups, respectively. The median decrease in haemoglobin concentration on the first postoperative day was 2.2 g/dL in the treatment group and 2.7 g/dL in the control group. A significant reduction in units of blood transfused was also observed in the treatment group compared with the control group [1.1 +/- 1.13 (range 0-4) vs. 1.9 +/- 1.41 (range 0-5) blood units; P = 0.04]. No major treatment-related adverse events were recorded in the study. CONCLUSIONS: This study shows that a thrombin-based topical haemostatic reduces the need for blood transfusion in TKR revision surgery. CLINICAL RELEVANCE: A thrombin-based topical haemostatic agent can be an appropriate solution to enhance haemostasis and vessel sealing at the operative site in TKR revision surgery, in order to reduce the need for blood transfusion after surgery. LEVEL OF EVIDENCE: II. PMID- 25011645 TI - Transcatheter embolotherapy with N-butyl cyanoacrylate for ectopic varices. AB - PURPOSE: To address technical feasibility and clinical outcome of transcatheter embolotherapy with N-butyl cyanoacrylate (NBCA) for bleeding ectopic varices. METHODS: The institutional review board approved this retrospective study and waived informed consent. From January 2004 to June 2013, a total of 12 consecutive patients received transcatheter embolotherapy using NBCA for bleeding ectopic varices in our institute. Clinical and radiologic features of the endovascular procedures were comprehensively reviewed. RESULTS: Preprocedural computed tomography images revealed ectopic varices in the jejunum (n = 7), stoma (n = 2), rectum (n = 2), and duodenum (n = 1). The 12 procedures consisted of solitary embolotherapy (n = 8) and embolotherapy with portal decompression (main portal vein stenting in 3, transjugular intrahepatic portosystemic shunt in 1). With regard to vascular access, percutaneous transhepatic access (n = 7), transsplenic access (n = 4), and transjugular intrahepatic portosystemic shunt tract (n = 1) were used. There was no failure in either the embolotherapy or the vascular accesses (technical success rate, 100 %). Two patients died within 1 month from the procedure from preexisting fatal medical conditions. Only one patient, with a large varix that had been partially embolized by using coils and NBCA, underwent rebleeding 5.5 months after the procedure. The patient was retreated with NBCA and did not undergo any bleeding afterward for a follow-up period of 2.5 months. The remaining nine patients did not experience rebleeding during the follow-up periods (range 1.5-33.2 months). CONCLUSION: Transcatheter embolotherapy using NBCA can be a useful option for bleeding ectopic varices. PMID- 25011644 TI - Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus. AB - BACKGROUND: Mouse visual thalamus has emerged as a powerful model for understanding the mechanisms underlying neural circuit formation and function. Three distinct nuclei within mouse thalamus receive retinal input, the dorsal lateral geniculate nucleus (dLGN), the ventral lateral geniculate nucleus (vLGN), and the intergeniculate nucleus (IGL). However, in each of these nuclei, retinal inputs are vastly outnumbered by nonretinal inputs that arise from cortical and subcortical sources. Although retinal and nonretinal terminals associated within dLGN circuitry have been well characterized, we know little about nerve terminal organization, distribution and development in other nuclei of mouse visual thalamus. RESULTS: Immunolabeling specific subsets of synapses with antibodies against vesicle-associated neurotransmitter transporters or neurotransmitter synthesizing enzymes revealed significant differences in the composition, distribution and morphology of nonretinal terminals in dLGN, vLGN and IGL. For example, inhibitory terminals are more densely packed in vLGN, and cortical terminals are more densely distributed in dLGN. Overall, synaptic terminal density appears least dense in IGL. Similar nuclei-specific differences were observed for retinal terminals using immunolabeling, genetic labeling, axonal tracing and serial block face scanning electron microscopy: retinal terminals are smaller, less morphologically complex, and more densely distributed in vLGN than in dLGN. Since glutamatergic terminal size often correlates with synaptic function, we used in vitro whole cell recordings and optic tract stimulation in acutely prepared thalamic slices to reveal that excitatory postsynaptic currents (EPSCs) are considerably smaller in vLGN and show distinct responses following paired stimuli. Finally, anterograde labeling of retinal terminals throughout early postnatal development revealed that anatomical differences in retinal nerve terminal structure are not observable as synapses initially formed, but rather developed as retinogeniculate circuits mature. CONCLUSIONS: Taken together, these results reveal nuclei-specific differences in nerve terminal composition, distribution, and morphology in mouse visual thalamus. These results raise intriguing questions about the different functions of these nuclei in processing light-derived information, as well as differences in the mechanisms that underlie their unique, nuclei-specific development. PMID- 25011646 TI - Can silicon partially alleviate micronutrient deficiency in plants? A review. AB - Silicon protects plants against various biotic and abiotic stresses, including metal toxicity. Under a high metal concentration, Si can externally decrease metal availability to the plant by its precipitation in the growth media, and Si also affects the metal distribution inside the plant, diminishing the damage. Could Si also protect plants against metal deficiency stress? Recently, the physiological role of Si in relation to micronutrients deficiency symptoms has been assessed in several plant species in hydroponics. In cucumber, Si supply mitigated the symptoms of Fe deficiency, but this effect was not clear under Zn- or Mn-deficiency conditions. The main factor controlling this beneficial effect seems to be the Si contribution to the formation of metal deposits in the root and/or leaves apoplast and its role in their following remobilization when required. The enhancement of the content of long-distance transport molecules (such as citrate) due to Si addition should also contribute to the metal transport from root to shoot, which will diminish deficiency symptoms. PMID- 25011648 TI - [Pharmacokinetic alterations in pregnancy and use of therapeutic drug monitoring]. AB - Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency. PMID- 25011647 TI - Effect of dietary prebiotic supplementation on advanced glycation, insulin resistance and inflammatory biomarkers in adults with pre-diabetes: a study protocol for a double-blind placebo-controlled randomised crossover clinical trial. AB - BACKGROUND: Advanced glycation endproducts (AGEs) contribute to the development of vascular complications of diabetes and have been recently implicated in the pathogenesis of diabetes. Since AGEs are generated within foodstuffs upon food processing, it is increasingly recognised that the modern diet is replete with AGEs. AGEs are thought to stimulate chronic low-grade inflammation and promote oxidative stress and have been linked to the development of insulin resistance. Simple therapeutic strategies targeted at attenuating the progression of chronic low-grade inflammation and insulin resistance are urgently required to prevent or slow the development of type 2 diabetes in susceptible individuals. Dietary modulation of the human colonic microbiota has been shown to confer a number of health benefits to the host, but its effect on advanced glycation is unknown. The aim of this article is to describe the methodology of a double-blind placebo controlled randomised crossover trial designed to determine the effect of 12 week consumption of a prebiotic dietary supplement on the advanced glycation pathway, insulin sensitivity and chronic low-grade inflammation in adults with pre diabetes. METHODS/DESIGN: Thirty adults with pre-diabetes (Impaired Glucose Tolerance or Impaired Fasting Glucose) aged between 40-60 years will be randomly assigned to receive either 10 grams of prebiotic (inulin/oligofructose) daily or 10 grams placebo (maltodextrin) daily for 12 weeks. After a 2-week washout period, study subjects will crossover to receive the alternative dietary treatment for 12 weeks. The primary outcome is the difference in markers of the advanced glycation pathway carboxymethyllysine (CML) and methylglyoxal (MG) between experimental and control treatments. Secondary outcomes include HbA1c, insulin sensitivity, lipid levels, blood pressure, serum glutathione, adiponectin, IL-6, E-selectin, myeloperoxidase, C-reactive protein, Toll-like Receptor 4 (TLR4), soluble receptor for AGE (sRAGE), urinary 8-isoprostanes, faecal bacterial composition and short chain fatty acid profile. Anthropometric measures including BMI and waist circumference will be collected in addition to comprehensive dietary and lifestyle data. DISCUSSION: Prebiotics which selectively stimulate the growth of beneficial bacteria in the human colon might offer protection against AGE-related pathology in people at risk of developing type 2 diabetes. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000130763. PMID- 25011650 TI - Plasma copeptin is associated with type 2 diabetes in men but not in women in the population-based KORA F4 study. AB - Elevated plasma CT-pro-vasopressin (copeptin) has been described as biomarkers for type 2 diabetes (T2D) and the metabolic syndrome (MetS), which, however, was not confirmed by all studies. Here, we analyzed the association of copeptin with T2D, MetS and MetS components in the population-based KORA F4 study. Plasma copeptin concentrations were analyzed in 1,554 study participants. We used fractional polynomial selection procedures to check for nonlinearity of the associations between copeptin and T2D and HbA1c, respectively. In logistic regression models, we investigated associations between copeptin and T2D, MetS and its components according to IDF criteria. In the fractional polynomial approach, linear models fitted best for copeptin. In multivariable adjusted models, copeptin as a continuous variable was associated with T2D and HbA1c only in men (OR = 1.38 per standard deviation, 95 % CI 1.13-1.70 for T2D). Comparing the top quartile Q4 versus Q1-3, elevated copeptin was associated with T2D (OR 2.70, 95 % CI 1.60-4.59) in men but not in women (OR 0.98, 95 % CI 0.52-1.83). Copeptin was not significantly associated with MetS, central obesity, triglycerides and reduced HDL cholesterol. A significant association with copeptin was observed for hypertension in women (OR 1.59, 95 % CI 1.08-2.33) and glucose dysfunction according to IDF criteria in men (OR 1.63, 95 % CI 1.14 2.34). In the KORA F4 study, copeptin was significantly associated with T2D only in men, whereas hypertension was associated with copeptin in women. No other components of the MetS were related to elevated copeptin. PMID- 25011649 TI - Endogenous kisspeptin tone is a critical excitatory component of spontaneous GnRH activity and the GnRH response to NPY and CART. AB - BACKGROUND/AIMS: Kisspeptin is the major excitatory regulator of gonadotropin releasing hormone (GnRH) neurons and is responsible for basal GnRH/LH release and the GnRH/LH surge. Although it is widely assumed, based on mutations in kisspeptin and Kiss1R, that kisspeptin acts to sustain basal GnRH neuronal activity, there have been no studies to investigate whether endogenous basal kisspeptin tone plays a direct role in basal spontaneous GnRH neuronal excitability. It is also of interest to examine possible interactions between endogenous kisspeptin tone and other neuropeptides that have direct effects on GnRH neurons, such as neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART), since the activity of all these neuropeptides changes during states of negative energy balance. METHODS: Loose cell-attached and whole-cell current patch-clamp recordings were made from GnRH-GFP neurons in hypothalamic slices from female and male rats. RESULTS: Kisspeptin activated GnRH neurons in a concentration-dependent manner with an EC50 of 3.32 +/- 0.02 nM. Surprisingly, a kisspeptin antagonist, Peptide 347, suppressed spontaneous activity in GnRH neurons, demonstrating the essential nature of the endogenous kisspeptin tone. Furthermore, inhibition of endogenous kisspeptin tone blocked the direct activation of GnRH cells that occurs in response to antagonism of NPY Y5 receptor or by CART. CONCLUSIONS: Our electrophysiology studies suggest that basal endogenous kisspeptin tone is not only essential for spontaneous GnRH neuronal firing, but it is also required for the net excitatory effects of other neuropeptides, such as CART or NPY antagonism, on GnRH neurons. Therefore, endogenous kisspeptin tone could serve as the linchpin in GnRH activation or inhibition. PMID- 25011651 TI - Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz. AB - OBJECTIVES: Growing evidence associates the non-nucleoside reverse transcriptase inhibitor efavirenz with several adverse events. Newer antiretrovirals, such as the integrase inhibitor raltegravir, the non-nucleoside reverse transcriptase inhibitor rilpivirine and the protease inhibitor darunavir, claim to have a better toxicological profile than efavirenz while producing similar levels of efficacy and virological suppression. The objective of this study was to determine the in vitro toxicological profile of these three new antiretrovirals by evaluating their effects on the mitochondrial and cellular parameters altered by efavirenz in hepatocytes and neurons. METHODS: Hep3B cells and primary rat neurons were treated with clinically relevant concentrations of efavirenz, darunavir, rilpivirine or raltegravir. Parameters of mitochondrial function, cytotoxicity and oxidative and endoplasmic reticulum stress were assessed using standard cell biology techniques. RESULTS: None of the new compounds altered the mitochondrial function of hepatic cells or neurons, while efavirenz decreased mitochondrial membrane potential and enhanced superoxide production in both cell types, effects that are known to significantly compromise the functioning of mitochondria, cell viability and, ultimately, cell number. Of the four drugs assayed, efavirenz was the only one to alter the protein expression of LC3-II, an indicator of autophagy, and CHOP, a marker of endoplasmic reticulum stress and the unfolded protein response. CONCLUSIONS: Darunavir, rilpivirine and raltegravir do not induce toxic effects on Hep3B cells and primary rat neurons, which suggests a safer hepatic and neurological profile than that of efavirenz. PMID- 25011652 TI - Comment on: Glycopeptide use is associated with increased mortality in Enterococcus faecalis bacteraemia. PMID- 25011653 TI - Translational research strategy: an essential approach to fight the spread of antimicrobial resistance. AB - Translation research strategy in infectious diseases, combining the results from basic research with patient-orientated research, aims to bridge the gap between laboratory findings and clinical infectious disease practice to improve disease management. In an era of increasing antimicrobial resistance, there are four main areas of clinical and scientific uncertainty that need to be urgently addressed by translational research: (i) early diagnosis of antibiotic-resistant infections and the appropriateness of empirical antibiotic therapy; (ii) the identification of reservoirs of antibiotic-resistant pathogens; (iii) the development of new antibiotics with lower propensities to evoke resistance; and (iv) the development of new non-antibiotic drugs to be used in the prevention of the spread of resistant bacterial strains. Strict European collaboration among major stakeholders is therefore essential. Appropriate educational tools to train a new generation of scientists with regard to a multifaceted approach to antimicrobial resistance research should be developed. Key areas include the support and implementation of European networks focused on translational research and related education activities, making potential therapeutics more attractive to investors and helping academic investigators to determine whether new molecules can be developed with clinical applicability. PMID- 25011654 TI - TNF-alpha levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects. AB - BACKGROUND: Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long term antiretroviral therapy normalizes inflammatory alterations compared with HIV uninfected persons of different age is not known. METHODS: We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects. RESULTS: Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-alpha and IFN-gamma levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-alpha levels, which persisted as high as those in elderly non-survivor controls. CONCLUSIONS: Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-alpha levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART. PMID- 25011655 TI - Antimicrobial resistance, genetic resistance determinants for ceftriaxone and molecular epidemiology of Neisseria gonorrhoeae isolates in Nanjing, China. AB - OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major problem worldwide. This study investigated the AMR, genetic ceftriaxone resistance determinants and molecular epidemiology of N. gonorrhoeae in Nanjing, China. METHODS: N. gonorrhoeae isolates were collected in 2007 (n = 198) and 2012 (n = 80). The susceptibility to ceftriaxone, spectinomycin, ciprofloxacin and tetracycline was determined using an agar-dilution method. The ceftriaxone resistance determinants penA, mtrR and penB were examined using sequencing. N. gonorrhoeae multi-antigen sequence typing (NG-MAST) was performed for molecular epidemiology. RESULTS: All isolates were resistant to ciprofloxacin, 42.4% produced beta-lactamase and 34.9% showed high-level resistance to tetracycline (MIC >=16 mg/L). In total, 5.4% of isolates were resistant to ceftriaxone; however, all of these isolates were obtained in 2007 and the susceptibility to ceftriaxone appeared to have increased. All isolates were susceptible to spectinomycin. No penA mosaic alleles were found. Non-mosaic penA alleles with A501T and G542S alterations, an H105Y alteration in mtrR and an A102D/N alteration in porB1b were statistically associated with decreased susceptibility or resistance to ceftriaxone. The most prevalent NG-MAST sequence types (STs) were ST568 (n = 13), ST270 (n = 9) and ST421 (n = 7). ST270 was the most common ST in isolates with decreased susceptibility or resistance to ceftriaxone. CONCLUSIONS: Ceftriaxone, ideally 500 mg and together with azithromycin (1-2 g), should be recommended for treatment of gonorrhoea in Nanjing, China. However, N. gonorrhoeae strains with resistance to ceftriaxone have been found in Nanjing. NG MAST and ceftriaxone resistance determinant analysis can be valuable to supplement the antimicrobial resistance surveillance in China, which needs to be further strengthened. PMID- 25011657 TI - Acne smart club: an educational program for patients with acne. AB - OBJECTIVE: To evaluate adherence to therapy in acne patients using mobile phones and Short Message Service (SMS) to communicate. METHODS: 160 patients were randomly assigned to two groups: the SMS group received 2 text messages twice a day for a period of 12 weeks; the control group did not receive any messages. Before and after 12 weeks, the following evaluations were performed in all patients: digital photographs, the Global Acne Grading System, the Dermatology Life Quality Index, the Cardiff Acne Disability Index, the doctor-patient relationship evaluated through the Patient-Doctor Depth-of-Relationship Scale, and the adherence to treatment evaluated by asking patients how many days a week they had followed the therapy. For statistical analysis we used Student's t test. RESULTS: The SMS group had a better improvement of all parameters compared to the control group. CONCLUSION: Adherence and compliance are higher for patients who are included in a strategy of control. PMID- 25011656 TI - Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study. AB - INTRODUCTION: Severe infections in intensive care patients show high morbidity and mortality rates. Linezolid is an antimicrobial drug frequently used in critically ill patients. Recent data indicates that there might be high variability of linezolid serum concentrations in intensive care patients receiving standard doses. This study was aimed to evaluate whether standard dosing of linezolid leads to therapeutic serum concentrations in critically ill patients. METHODS: In this prospective observational study, 30 critically ill adult patients with suspected infections received standard dosing of 600 mg linezolid intravenously twice a day. Over 4 days, multiple serum samples were obtained from each patient, in order to determine the linezolid concentrations by liquid chromatography tandem mass spectrometry. RESULTS: A high variability of serum linezolid concentrations was observed (range of area under the linezolid concentration time curve over 24 hours (AUC24) 50.1 to 453.9 mg/L, median 143.3 mg*h/L; range of trough concentrations (Cmin) < 0.13 to 14.49 mg/L, median 2.06 mg/L). Furthermore, potentially subtherapeutic linezolid concentrations over 24 hours and at single time points (defined according to the literature as AUC24 < 200 mg*h/L and Cmin < 2 mg/L) were observed for 63% and 50% of the patients, respectively. Finally, potentially toxic levels (defined as AUC24 > 400 mg*h/L and Cmin > 10 mg/L) were observed for 7 of the patients. CONCLUSIONS: A high variability of linezolid serum concentrations with a substantial percentage of potentially subtherapeutic levels was observed in intensive care patients. The findings suggest that therapeutic drug monitoring of linezolid might be helpful for adequate dosing of linezolid in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01793012. Registered 24 January 2013. PMID- 25011658 TI - HBV-associated cryoglobulinemic vasculitis: remission after antiviral therapy with entecavir. AB - BACKGROUND/AIMS: Cryoglobulinemic vasculitis remains an uncommon complication of hepatitis B virus infection. METHODS: We report the case of a 40-years old female Chinese patient with chronic hepatitis B developing cryoglobulinemic vasculitis with multiple organ involvement (liver, kidney, and skin) coupled with weakness, arthralgias, haemolytic anaemia, and autoimmune thyroiditis. She received entecavir mono-therapy at dose adjusted for estimated glomerular filtration rate. RESULTS: Within five months of entecavir treatment, hepatitis B viraemia decreased below the limit of detection with normal serum amino-transferase levels, HBeAg clearance occurred, vasculitis regressed with disappearance of purpura and ascites; in addition, renal function normalized and nephritic syndrome remitted. After a five-year follow-up, the patient is asymptomatic with intact kidney function, proteinuria in the normal range, and normal liver biochemistry, despite the antiviral treatment was withdrawn and the patient remained HBsAg positive. CONCLUSIONS: This is the second case of hepatitis B virus-related cryoglobulinemic vasculitis successfully treated with entecavir suggesting that effective antiviral therapy may counteract both the hepatic and extra-hepatic manifestations of infection by hepatitis B virus. PMID- 25011659 TI - 18F-fluoro-deoxy-glucose-positron emission tomography/computed tomography in diagnosis of head and neck squamous cell carcinoma: a systematic review and meta analysis. AB - 18F-fluoro-deoxy-glucose-positron emission tomography/computed tomography-scan (PET/CT) is used increasingly for detection of cancer. Precise diagnostic assessment of tumour extension in head and neck squamous cell carcinoma (HNSCC) is of critical importance for ensuring that patients receive proper treatment. Preliminary studies have shown divergent results of PET/CT in diagnosis and staging of HNSCC. The aims of this study were (1) to systematically review and meta-analyse published data about the diagnostic accuracy of PET/CT for diagnosing patients with HNSCC and (2) to compare the diagnostic accuracy of PET/CT with that of standard conventional imaging (SCI). METHODS: A systematic literature search in the PubMed, Embase and Cochrane databases on publications of PET/CT diagnostics of HNSCC from January 2005 to July 2013 was carried out. All retrieved studies were reviewed and qualitatively analysed. Along with the calculated pooled sensitivity and specificity of PET/CT and SCI, bubble- and summary receiver operating characteristics (SROC) plots were created. FINDINGS: Two meta-analyses of diagnostic accuracy were conducted. The first, on PET/CT, included 987 patients distributed across nine studies. The second, on SCI, included 517 patients participating in a total of six studies among those comparing PET/CT to SCI. The meta-analyses showed a pooled sensitivity of 89.3% (95% confidence interval [95% CI]: 83.4-93.2%) and specificity of 89.5% (95% CI: 82.9-93.7%) for PET/CT and correspondingly, a pooled sensitivity and specificity of 71.6% (95% CI: 44.3-88.9%) and 78.0% (95%CI: 30.2-96.7%) for SCI. A graphical comparison to SCI showed a clear difference in favour of PET/CT. INTERPRETATION: PET/CT is highly accurate in diagnosing patients suffering from HNSCC. PMID- 25011660 TI - Child drowning prevention in the Philippines: the beginning of a conversation. AB - This study describes a process to explore factors which contribute to child drowning deaths and allows the development of appropriate strategies to prevent similar deaths in a selected site in the Northern Philippines. Data collection techniques used in obtaining baseline data include: review of drowning mortality records; key informant interviews; focus group discussions; and community walk throughs. Risk factors identified which could or did contribute to drowning events were: proximity to bodies of water; inadequate child supervision; lack of information/awareness of prevention strategies; and lack of drowning prevention programme(s). Measures on how to prevent drowning deaths were explored and initial interventions were implemented through a committee convened by the community. These interventions include: community education sessions; capability building measures; redesigning of community wells; development of playpens; and use of barriers. Community engagement is a crucial element in the development and implementation of any health programme. This study demonstrates that by engaging and working with the community action occurs, however, there is a need to conduct further evaluation activities to determine if the actions by the community continued beyond the project and have resulted in a decrease in drowning. One of the strengths of the process described is that it is culturally appropriate and site-specific and allows the community to find the solutions itself. Exploration and delivery of further projects in larger areas is required to reduce drowning in the Philippines. An imperative is the evaluation which will provide valuable information on whether barriers are a sustainable and acceptable means of prevention to the community in the long term. PMID- 25011661 TI - Effects of cold exposure on autonomic changes during the last rapid eye movement sleep transition and morning blood pressure surge in humans. AB - BACKGROUND: Various studies have linked the occurrence of cardiovascular events and low ambient temperatures as well as the morning blood pressure surge (MBPS). We hypothesized that low ambient temperatures produce a higher sympathetic change during the last rapid eye movement (REM) sleep transition and that this may play an important role in cold-related cardiovascular events. METHODS: All experiments were carried out on 12 healthy male adults, aged 24.00+/-0.74 years, who participated in two experimental conditions randomly (>1 day apart): warm (23 degrees C) and cold (16 degrees C). Blood pressure (BP) was measured every 30 min for 24 h by autonomic ambulatory BP monitoring. The electroencephalograms, electrocardiograms, ambient temperature, near-body temperature, and physical activity were recorded by miniature polysomnography for 24 h. RESULTS: The cold conditions resulted in: (i) higher MBPS than under warm conditions; (ii) significant and greater sympathetic index changes during the sleep-wake transition than during cover-to-uncover and supine-to-sit position tests; (iii) the non-REM-REM transition-related sympathetic elevation during the cold conditions being significantly higher in late sleep period than in early sleep period; (iv) at 1h prior to morning awakening, the value of total power of heart rate variability changes being significantly negatively correlated with the changes of near-body temperature; and (v) significantly higher arousal index and shorter average interval of REM periods than in warm conditions. CONCLUSION: Cold exposure elevates the amplitude of MBPS and is associated with late sleep stage transition sympathetic activation, which might have important implications for cold-related cardiovascular events. PMID- 25011662 TI - Predictors and patterns of insomnia symptoms in OSA before and after PAP therapy. AB - OBJECTIVE: Identify factors that predict improvement versus persistence of insomnia symptoms following treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy. METHODS: Archival data from 68 PAP treated sleep apnea patients aged 25-83 were analyzed using nonparametric tests and stepwise regression to assess the relationships between insomnia symptoms, multiple OSA variables, and PAP use over time. RESULTS: Pretreatment insomnia symptom severity (ISS; b = -0.72, p < 0.001), PAP average use (b = -0.01, p = 0.01) and respiratory disturbance index (RDI; b = -0.02, p = 0.03) predict change in insomnia following PAP therapy. Forty-five percent (24/53) of the subjects with moderate to severe insomnia at pretreatment reported no/mild symptoms after PAP therapy and were considered improved. Improved subjects had lower pretreatment ISS (p < 0.001), higher RDI (p = 0.01), and higher average PAP use (p < 0.035) than subjects with persistent insomnia. Number of medications and comorbidities were similar between improved and persistent groups. New onset of insomnia symptoms occurred in 13% (2/15) of the patients with no/mild pretreatment insomnia. CONCLUSIONS: Although ISS declines following PAP treatment, 55% of OSA patients have persistent moderate to severe symptoms despite treatment. More severe OSA is linked to higher likelihood of insomnia improvement and the effect of PAP therapy on insomnia may be mediated by OSA severity. Persistent insomnia is unrelated to medication use or comorbidities and may represent an independent, self-sustaining disorder requiring targeted intervention. PMID- 25011664 TI - Yttrium-catalysed dehydrocoupling of alanes with amines. AB - We report [Y{N(SiMe3)2}3] as a precatalyst for the dehydrocoupling of sterically demanding amines with beta-diketiminate stabilised aluminium dihydrides. While simple fluorinated anilines readily undergo Al-H/N-H dehydrocoupling under thermal conditions, catalytic methods are required to achieve reasonable rates of reaction for ortho-substituted anilines or hindered aliphatic amines. PMID- 25011665 TI - Metallization of double-stranded DNA triggered by bound galactose-modified naphthalene diimide. AB - Naphthalene diimide (NDI) derivatives bearing galactose moieties through different spacers, NDI-DS1 and NDI-DS2, were synthesized by the click reaction of the acetylene derivatives of NDI with galactose azide. They bound to double stranded DNA with threading intercalation, as confirmed by the topoisomerase I assay and circular dichroism spectroscopy. The binding affinities of these ligands were on the order of 10(5) M(-1) with several-fold higher affinity for double-stranded DNA than for single-stranded DNA. The silver mirror reaction on the double-stranded DNA bound to these ligands afforded silver nanowires that were converted to gold nanowires. In the atomic force microscopy measurements, the increased height of DNA areas on a mica plate was observed in the case of double-stranded DNA after NDI-DS2 treatment and subsequently silver mirror reaction, whereas the increased height of DNA areas was not observed in the case of single-stranded DNA after the same treatment. PMID- 25011666 TI - Antimicrobial resistance and class 1 and 2 integrons in Escherichia coli from meat turkeys in Northern Italy. AB - This study is aimed at determining the antimicrobial resistance (AMR) and the presence of class 1 and 2 integrons in 48 avian pathogenic Escherichia coli (APEC) strains isolated from meat turkeys during three sequential production cycles. Thirty avian faecal E. coli (AFEC) strains from the first cycle were also analysed. Strains were tested for AMR against 25 antimicrobials by disk diffusion test and were screened for the presence of integrons and associated gene cassettes by polymerase chain reaction followed by sequencing. Genetic relatedness of isolates was established by pulsed-field gel electrophoresis. High levels of resistance were detected to tetracyclines, penicillins and sulphonamides in APEC and AFEC. Resistance to aminoglycosides, fluoroquinolones, cephalosporins and phenicols was variable, based on the antimicrobial drug and the isolate (APEC vs. AFEC). Full susceptibility to colistin was detected. Multidrug resistance of up to seven antimicrobial classes was exhibited by APEC (93.8%) and AFEC (100%). Nearly 44% of strains tested positive for class 1 and/or class 2 integrons containing the dfrA, aadA and sat2 genes, alone or in combination, coding for streptomycin/spectinomycin, trimethoprim and streptothricin resistance, respectively. The estX and orfF genes of unknown function were also detected. A significant association was found between the presence of integrons and the resistance to aminoglycosides and potentiated sulphonamides. The results of this study showed that AMR, multidrug resistance and class 1 and 2 integrons are widespread among pathogenic and commensal E. coli from Italian turkeys. More attention should be addressed to limit the use of antimicrobials in turkeys and the AMR of turkey E. coli. PMID- 25011667 TI - Motor task performance under vibratory feedback early poststroke: single center, randomized, cross-over, controlled clinical trial. AB - Stroke rehabilitation is far from meeting patient needs in terms of timing, intensity and quality. This study evaluates the efficacy and safety of an innovative technological tool, combining 3D motion analysis with targeted vibratory feedback, on upper-limb task performance early poststroke (<4 weeks). The study design was a two-sequence, two-period, randomized, crossover trial (NCT01967290) in 44 patients with upper-limb motor deficit (non-plegic) after medial cerebral artery ischemia. Participants were randomly assigned to receive either the experimental session (repetitive motor task under vibratory feedback and 3D motor characterization) or the active comparator (3D motor characterization only). The primary outcome was the number of correct movements per minute on a hand-to-mouth task measured independently. Vibratory feedback was able to modulate motor training, increasing the number of correct movements by an average of 7.2/min (95%CI [4.9;9.4]; P < 0.001) and reducing the probability of performing an error from 1:3 to 1:9. This strategy may improve the efficacy of training on motor re-learning processes after stroke, and its clinical relevance deserves further study in longer duration trials. PMID- 25011668 TI - 4-Phenylbutyric acid increases GLUT4 gene expression through suppression of HDAC5 but not endoplasmic reticulum stress. AB - BACKGROUND: The chemical chaperone 4-phenylbutyric acid (4-PBA) has been shown to relieve endoplasmic reticulum (ER) stress. Therefore, it improves insulin sensitivity and promotes glucose metabolism in skeletal muscle. Glucose transporter type 4 (GLUT4), as a major glucose transporter protein, plays a central role in glucose metabolism. Until now, it has been unclear whether 4-PBA affects GLUT4 gene expression and thus, contributes to glucose metabolism. METHODS: C2C12 myotubes were treated with 4-PBA, tunicamycin or butyrate and subjected to Western blot and RT-PCR. RESULTS: 4-PBA-treated C2C12 myotubes increased GLUT4 expression and promoted glucose metabolism. Most interestingly, GLUT4 gene expression induced by 4-PBA was not associated with ER stress even in the presence of tunicamycin, an ER stress inducer. Moreover, we also found that 4 PBA inhibited histonedeacetylase 5 (HDAC5) expression in C2C12 myotubes, resulting in hyperacetylation of the histone H3 at the myocyte enhancer factor 2 (MEF2) binding site. This increased the binding of MEF2A to the site on the GLUT4 promoter, resulting in increased GLUT4 expression. CONCLUSIONS: Our data indicate that 4-PBA increases GLUT4 expression by acetylating the MEF2 site to increase the MEF2A binding through a mechanism that involves suppression of the HDAC5 pathway, but without involving ER stress. PMID- 25011670 TI - AC driven magnetic domain quantification with 5 nm resolution. AB - As the magnetic storage density increases in commercial products, e.g. the hard disc drives, a full understanding of dynamic magnetism in nanometer resolution underpins the development of next-generation products. Magnetic force microscopy (MFM) is well suited to exploring ferromagnetic domain structures. However, atomic resolution cannot be achieved because data acquisition involves the sensing of long-range magnetostatic forces between tip and sample. Moreover, the dynamic magnetism cannot be characterized because MFM is only sensitive to the static magnetic fields. Here, we develop a side-band magnetic force microscopy (MFM) to locally observe the alternating magnetic fields in nanometer length scales at an operating distance of 1 nm. Variations in alternating magnetic fields and their relating time-variable magnetic domain reversals have been demonstrated by the side-band MFM. The magnetic domain wall motions, relating to the periodical rotation of sample magnetization, are quantified via micromagnetics. Based on the side-band MFM, the magnetic moment can be determined locally in a volume as small as 5 nanometers. The present technique can be applied to investigate the microscopic magnetic domain structures in a variety of magnetic materials, and allows a wide range of future applications, for example, in data storage and biomedicine. PMID- 25011669 TI - Environmental and cultural correlates of physical activity parenting practices among Latino parents with preschool-aged children: Ninos Activos. AB - BACKGROUND: Latino children are at high risk of becoming obese. Physical activity (PA) can help prevent obesity. Parents can influence children's PA through parenting practices. This study aimed to examine the independent contributions of (1) sociodemographic, (2) cultural, (3) parent perceived environmental, and (4) objectively measured environmental factors, to PA parenting practices. METHODS: A cross-sectional sample of Latino parents (n = 240) from Harris County, TX in 2011 2012 completed validated questionnaires to assess PA parenting practices, acculturation, familism, perception of their neighborhood environment, and demographics. Home addresses were mapped and linked to Census block-level crime and traffic data. Distance to the closest park was mapped by GIS. Regression models were built in a hierarchical step-wise fashion. RESULTS: Combined models showed R2 of 6.8% to 38.9% for different parenting practices. Significant correlations included sociodemographic variables with having outdoor toys available, psychological control, and promotion of inactivity. Cultural factors correlated with PA safety concern practices. Perceived environmental attributes correlated with five of seven parenting practices, while objectively-measured environmental attributes did not significantly correlate with PA parenting practices. CONCLUSION: Interventions promoting PA among Latino preschoolers may need to address the social-ecological context in which families live to effectively promote PA parenting, especially parents' perceptions of neighborhoods. PMID- 25011671 TI - Gemcitabine and docetaxel for epithelioid sarcoma: results from a retrospective, multi-institutional analysis. AB - OBJECTIVE: Epithelioid sarcoma (ES) presents unique clinical features in comparison to other sarcoma subtypes. Data regarding the benefits of chemotherapy are very limited. Combination regimens using gemcitabine and docetaxel (Gem/Doce) have proven to be effective, especially in uterine and nonuterine leiomyosarcoma. Yet, there is no available data on the efficacy of Gem/Doce in ES. METHODS: A retrospective analysis of the three participating institutions was performed. Twenty-eight patients with an ES diagnosis presented at one of the participating institutions between 1989 and 2012. Of this group, 17 patients received chemotherapy. RESULTS: Patients' median overall survival (OS) after the beginning of palliative chemotherapy was 21 months, and the 1-year OS was 87%. Twelve patients received Gem/Doce with a clinical benefit rate of 83%. The median progression-free survival (PFS) was 8 months for all patients receiving Gem/Doce. The best response was complete remission in 1 patient and partial remission in 6 patients. All 6 patients receiving Gem/Doce as a first-line treatment showed measurable responses with a median PFS of 9 months. CONCLUSIONS: In this retrospective study, Gem/Doce was an effective chemotherapeutic regimen for ES. Prospective studies are needed to better assess the effects of this combination drug therapy. PMID- 25011672 TI - Editor's Introduction. PMID- 25011673 TI - Intimate Partner Physical and Sexual Violence and Outcomes of Unintended Pregnancy Among National Samples of Women From Three Former Soviet Union Countries. AB - The article examines the relationship between intimate partner violence (IPV) and unintended pregnancy among nationally representative samples of women in three former Soviet Union countries. Women who experienced physical and/or sexual IPV from their current or most recent husband or living together partner demonstrated higher risks of unintended last pregnancy, either terminated through abortion (in Azerbaijan, Moldova, and Ukraine) or resulting in unintended live birth (in Ukraine). IPV prevention components should be integrated into reproductive health programs to reduce the risk of unintended births and abortions among women living with abusive partners in these former Soviet Union countries. PMID- 25011674 TI - Displaced African Female Survivors of Conflict-Related Sexual Violence: Challenges for Mental Health Providers. AB - Conflict throughout Africa has created havoc for many. This overwhelming chaos has led to the disintegration of social order and generated widespread gender based violence. As a result, African women have become casualties, experienced brutal acts of sexual violence, and been forced into exile. Drawing on the tribulations of displaced African female survivors of conflict-related sexual violence, this article discusses these women's experiences and highlights the barriers and struggles encountered while seeking refuge. The article concludes by exploring the challenges of providing culturally informed, strength-focused mental health services to these women as they rebuild their lives in a new sociocultural context. PMID- 25011675 TI - The Laws Have Changed, But What About the Police? Policing Domestic Violence in Bosnia and Herzegovina. AB - Despite having received gender sensitivity and domestic violence (DV) education in the post-war reformation era, anecdotal evidence from across Bosnia and Herzegovina indicates that most police officers view DV as a private family affair and continue to hold negative attitudes toward women and DV victims. This study assessed these claims by examining gender and DV attitudes held by 137 Bosnian police officers. It was hypothesized that officers who received DV training would be less likely to hold sexist attitudes toward women or view DV as justifiable compared with untrained officers. Results, as well as policy implications and suggestions for future research, are presented. PMID- 25011676 TI - Are Collaborations Enough? Professionals' Knowledge of Victim Services. AB - Service providers must be aware of community resources to make referrals, and yet studies have found providers to be less knowledgeable of services other than their own. This article describes a survey of 279 domestic violence, victim assistance, law enforcement, legal professionals, public health, and mental health professionals who were asked about a range of services for victims of domestic violence. Results indicated that groups had less knowledge of some services, notably, special services provided by domestic violence shelters and Temporary Assistance to Needy Families (TANF), food, and goods. Perceptions of service availability differed across professional groups in terms of overall health, law enforcement, and shelter services. Results call for purposeful interprofessional communication and cross-training. PMID- 25011677 TI - Policymaking Under Uncertainty: Routine Screening for Intimate Partner Violence. AB - Intimate partner violence (IPV) is a significant public health issue affecting around three million U.S. women during their lifetimes; this article provides guidance to policymakers on addressing IPV. In 2011, an Institute of Medicine panel recommended routine IPV screening for women and adolescents as part of comprehensive preventive care services, which is in conflict with the 2004 U.S. Preventive Services Task Force recommendations. The current evidence base for policymaking suffers weaknesses related to study design, which should be addressed in future research. Meanwhile, policymakers should consider available evidence in their settings, assess local needs, and make recommendations where appropriate. PMID- 25011678 TI - An effective and well-tolerated strategy in recurrent and/or metastatic head and neck cancer: successive lines of active chemotherapeutic agents. AB - BACKGROUND: The combination platinum, 5-fluorouracil (5-FU) and cetuximab is the standard first-line regimen of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Due to the toxicity of this treatment, alternative therapies are often offered to patients. The aim of this study was to evaluate the overall survival obtained with a first line chemotherapy adapted to patients functional status and the administration of all active drugs within successive lines of chemotherapy. METHODS: This series included a total of 194 patients with recurrent and/or metastatic HNSCC treated from 2006 to 2011 in a single institution where the administration of successive lines of chemotherapies has been the standard clinical approach. Treatment was administered according to clinical practice guidelines. RESULTS: Most patients received at least two treatment lines. Only 11 patients (6%) were treated with a combination of cisplatin, 5-FU and cetuximab in front line, but most patients received at least one platinum-based regimen (n = 154 patients, 78%); 162 (82%) received taxanes, 36 (18%) received 5-FU, 27 (14%) received capecitabine, 67 (34%) received methotrexate and 134 (68%) received cetuximab. The median overall survival was 9.8 months (95% CI: 8.1-11.4 months) and reached 13.1 months among the subgroup of 131 patients eligible for inclusion in a clinical trial. CONCLUSION: The survival outcomes of patients treated in the first-line setting with chemotherapy regimens adapted to their functional status, followed by several subsequent regimens were comparable with published outcomes of patients treated by platinum, 5-FU and cetuximab. PMID- 25011679 TI - Can epidemic detection systems at the hospital level complement regional surveillance networks: case study with the influenza epidemic? AB - BACKGROUND: Early knowledge of influenza outbreaks in the community allows local hospital healthcare workers to recognise the clinical signs of influenza in hospitalised patients and to apply effective precautions. The objective was to assess intra-hospital surveillance systems to detect earlier than regional surveillance systems influenza outbreaks in the community. METHODS: Time series obtained from computerized medical data from patients who visited a French hospital emergency department (ED) between June 1st, 2007 and March 31st, 2011 for influenza, or were hospitalised for influenza or a respiratory syndrome after an ED visit, were compared to different regional series. Algorithms using CUSUM method were constructed to determine the epidemic detection threshold with the local data series. Sensitivity, specificity and mean timeliness were calculated to assess their performance to detect community outbreaks of influenza. A sensitivity analysis was conducted, excluding the year 2009, due to the particular epidemiological situation related to pandemic influenza this year. RESULTS: The local series closely followed the seasonal trends reported by regional surveillance. The algorithms achieved a sensitivity of detection equal to 100% with series of patients hospitalised with respiratory syndrome (specificity ranging from 31.9 and 92.9% and mean timeliness from -58.3 to 20.3 days) and series of patients who consulted the ED for flu (specificity ranging from 84.3 to 93.2% and mean timeliness from -32.3 to 9.8 days). The algorithm with the best balance between specificity (87.7%) and mean timeliness (0.5 day) was obtained with series built by analysis of the ICD-10 codes assigned by physicians after ED consultation. Excluding the year 2009, the same series keeps the best performance with specificity equal to 95.7% and mean timeliness equal to -1.7 day. CONCLUSIONS: The implementation of an automatic surveillance system to detect patients with influenza or respiratory syndrome from computerized ED records could allow outbreak alerts at the intra-hospital level before the publication of regional data and could accelerate the implementation of preventive transmission-based precautions in hospital settings. PMID- 25011680 TI - Ruthenium(ii) complexes containing functionalised beta-diketonate ligands: developing a ferrocene mimic for biosensing applications. AB - Three series of ruthenium complexes with the general formula Ru(bpy)n(beta diketonato)3-n (bpy = 2,2'-bipyridine, n = 0, 1, 2) were prepared and investigated using cyclic voltammetry and UV-vis spectroscopy. Variation of both the number and electronic demand of the beta-diketonato ligands resulted in well defined modulation of the potential at which oxidation of the metal centre occurred. The observed potentials were shown to be in good agreement with calculated ligand electrochemical parameters. A novel ruthenium(ii) complex with electrochemical behaviour similar to that of ferrocene was identified. PMID- 25011681 TI - Unfolding and aggregation of a glycosylated monoclonal antibody on a cation exchange column. Part II. Protein structure effects by hydrogen deuterium exchange mass spectrometry. AB - Hydrogen-deuterium exchange mass spectrometry (HX-MS) with proteolytic fragmentation is used to determine patterns of unfolding, as measured by increased solvent exposure, with peptide-level resolution for a glycosylated monoclonal antibody both when eluted from a tentacle-type cation exchange column (Fractogel EMD SO3-) and while bound to the resin. Two peaks are obtained when the bound protein is eluted with either a NaCl gradient or with two NaCl steps at increasing concentration. The first, early eluting peak contains only monomeric species whose structure is consistent with the native monomer. The second, late eluting peak contains a mixture of monomeric and aggregated species. The monomeric species in this mixture is also found to have a structure consistent with that of the native mAb, showing no evidence of increased solvent exposure. The aggregated species show instead significant unfolding in areas of the protein structure contained within the Fc region. The same peptides that exhibit the greatest level of solvent exposure in the aggregated species are also found in the fraction of protein that elutes from the resin only at high salt concentration, indicating that the aggregates are formed when the strongly-bound unfolded intermediate is desorbed at high salt. There is no evidence that the unfolded intermediate, formed while the protein is bound on the resin, is present in any of the eluted fractions indicating that, upon desorption from the resin, the intermediate either quickly refolds or forms aggregates which end-up co eluting with the refolded protein at high salt concentrations. PMID- 25011682 TI - Adherence to artemether-lumefantrine drug combination: a rural community experience six years after change of malaria treatment policy in Tanzania. AB - BACKGROUND: Adherence to multidosing is challenging worldwide. This study assessed the extent of adherence to multidosing artemether-lumefantrine (ALu) in a rural community in Tanzania, six years after switching from single dose policy of sulphadoxine-pyrimethamine. METHODS: This study was a prospective observational, open label, non-randomized study involving 151 patients with uncomplicated malaria recruited at Fukayosi dispensary in Bagamoyo district in Tanzania. Patients treated with ALu were visited at home on day 3 for interview on drug intake, capillary blood sample collection for microscopy and ALu tablets count. Venous blood samples (2 ml) for determination of blood lumefantrine concentrations and blood slides for microscopy were collected on day-7. Kappa's coefficient was used to assess agreement between pill count and self-report. Adherence was categorized depending on the tablets remaining and what the patient reported. Only those with empty blister pack available but no tablet remaining and reported taking all six doses of ALu at a correct dose and correct time were regarded as definite adherent. The rest were either probable adherent or probable non-adherent. RESULTS: Only 14.9% of the patients were definite adherent the rest took the drug at incorrect time or did not finish the tablets. Out of 90 patients with analysed plasma samples for lumefantrine blood concentrations, 13/90 (14.4.0%) had lumefantrine concentrations <175 ng/ml. There was no difference in mean lumefantrine concentration in the patients who stated to have taken all doses as required (561.61 ng/ml 95% CI = 419.81-703.41) compared to those who stated to have not adhered well to drug intake (490.95 ng/ml, 95% CI = 404.18 577.7074 (p = 0.643). None of the patients had detectable parasites by microscopy on day-3 and day-7 regardless of adherence status and the level of day-7 blood lumefantrine. There was strong agreement between the self-reported responses on drug intake and pill-counts (kappa coefficient = 0.955). Age, sex, education and place where first dose was taken were associated with adherence. CONCLUSIONS: The overall adherence six years after the change of malaria treatment policy was low. It is, therefore, important to continuously monitor the level of adherence to treatment in order to get the current situation and institute corrective measures on time. PMID- 25011683 TI - The Association between Patient-Centered Attributes of Care and Patient Satisfaction. AB - BACKGROUND AND OBJECTIVE: Little is known about the attributes of care that most strongly impact satisfaction in real-world settings where patients' limited medical knowledge may restrict their ability to ascertain the true quality of care. We therefore examined the association between patient-centered attributes of physician care (thoroughness, explanation, and listening), in-office waiting time, and patient satisfaction. METHODS: We used the Community Tracking Study Household Survey, a US nationally representative dataset (n = 71,594). Using logistic regression models, we analyzed the association between patient ratings of care attributes and patient satisfaction for the total sample and by subgroups, according to health status, physician type, and visit type. RESULTS: Patients' perception of excellent or very good care attributes was strongly associated with being very satisfied with care received (thoroughness of care, odds ratio [OR] 2.64, 95 % confidence interval [CI] 2.31-3.02; listening, OR 2.04, 95 % CI 1.77-2.36; explanation, OR 1.63, 95 % CI 1.42-1.86), as was a waiting time of <=10 min (OR 1.50, 95 % CI 1.39-1.63). The effect magnitude of thoroughness on satisfaction is particularly strong relative to high-quality listening and explanation among respondents in poor health, and for whom the most recent office visit was to see a generalist or for curative care. CONCLUSIONS: Thoroughness of care was the strongest determinant of patient satisfaction, followed by physician listening and explanation. Especially with patients' improved access to current medical information, it is important for physicians to recognize that excellent communication cannot serve as a substitute for high quality, thorough care. PMID- 25011684 TI - Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment. AB - BACKGROUND: Previous studies have shown that class-I histone deacetylase (HDAC) 8 mRNA is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. Using urothelial cancer cell lines we evaluated whether specific targeting of HDAC8 might be a therapeutic option in bladder cancer treatment. METHODS: We conducted siRNA-mediated knockdown and specific pharmacological inhibition of HDAC8 with the three different inhibitors compound 2, compound 5, and compound 6 in several urothelial carcinoma cell lines with distinct HDAC8 expression profiles. Levels of HDAC and marker proteins were determined by western blot analysis and mRNA levels were measured by quantitative real-time PCR. Cellular effects of HDAC8 suppression were analyzed by ATP assay, flow cytometry, colony forming assay and migration assay. RESULTS: Efficient siRNA-mediated knockdown of HDAC8 reduced proliferation up to 45%. The HDAC8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (IC50 9 - 21 MUM). Flow cytometry revealed only a slight increase in the sub-G1 fraction indicating a limited induction of apoptosis. Expression of thymidylate synthase was partly reduced; PARP-cleavage was not detected. The influence of the pharmacological inhibition on clonogenic growth and migration show a cell line- and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. CONCLUSIONS: Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. Accordingly, HDAC8 on its own is not a promising drug target in bladder cancer. PMID- 25011686 TI - Interaction effects of the COMT and DRD4 genes with anxiety-related traits on selective attention. AB - The study investigated whether the DRD4 and COMT genes can modify relations between trait anxiety and selective attention. Two hundreds and sixty-six subjects performed a visual search task in which they had to find words looking through a sheet with rows of letters. After finishing the first sheet the subject was presented the second one, this time with an instruction to perform the task as quickly and accurate as possible. To study top-down attention, the number of correctly identified words (accuracy) and the time for completion of each trial were analyzed. To study bottom-up attention, the letters 'o' and 'n' were written in green, whilst the others were in black, and subjects were asked whether they had noticed that 2-3 minutes after the task completion. Genotypes for the COMT Val158Met and DRD4 VNTR-48 polymorphisms and TCI Harm Avoidance and MMPI Depression scales' scores were obtained as well. High anxious individuals showed a more pronounced increase in accuracy in the second trial and more profound processing of irrelevant stimuli (colored letters). There was a significant interaction effect of DRD4 and Harm avoidance on the accuracy dynamics F(1, 210), = 7.65, p = .006, eta2 = .04. Among DRD4 long allele carriers, high anxious subjects significantly improved accuracy (p = .013) and tended to slow speed, while those with lower Harm avoidance demonstrated the opposite trend. These effects were more robust in less educated individuals. It was concluded that the DRD4 polymorphism may modify the influence of trait anxiety on the speed-accuracy tradeoff. PMID- 25011687 TI - Endocrine and mood responses to two working days in female teachers. AB - Currently, a considerable amount of work stress is present in school teachers, one of the occupational groups with the highest levels of job strain and burnout. As chronic stress produces significant modifications in emotional adjustment and neuroendocrine functioning, we aimed to investigate the role of these work stress constructs in the endocrine and mood responses of a group of female teachers during two working days (WD) at different moments in the academic year. We studied mood as well as levels of cortisol and testosterone, representative of a predominant catabolic or anabolic balance. Our results showed that higher "control" was associated with higher positive mood (p = .028 on WD1 and p = .057 on WD2) and salivary testosterone (Tsal) (p = .022 on WD1), whereas "demands" and "total job strain" were related to negative mood (p = .011 and p = .015, respectively). Participants with higher scores on "total burnout" and "emotional exhaustion" also had higher negative mood (p < .05 in all cases). Depersonalization correlated positively with negative mood (p = .019 and p = .006 on WD1 and WD2, respectively). Finally, personal accomplishment showed an inverse relationship with negative mood (p = .038 on WD2). These results are useful for job risk prevention and interventions that should focus on the control dimension of the job strain questionnaire and on personal accomplishment from the burnout scale. PMID- 25011685 TI - Rapid evolution of BRCA1 and BRCA2 in humans and other primates. AB - BACKGROUND: The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers. RESULTS: To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection. CONCLUSIONS: While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed. PMID- 25011688 TI - Diagnostic and functional structure of a high-resolution thyroid nodule clinic: an efficiency model. PMID- 25011689 TI - Alexithymia and gastrointestinal-specific anxiety in moderate to severe irritable bowel syndrome. AB - OBJECTIVE: Gastrointestinal-specific anxiety (GSA) and alexithymia are two psychological constructs that may contribute to severity of irritable bowel syndrome (IBS). We aimed to investigate their independent contribution in predicting the level of severity in a group of patients with moderate to severe IBS. METHOD: A sample of 177 consecutive IBS patients (49.2% with moderate and 50.8% with severe IBS), diagnosed with Rome III criteria, were evaluated for IBS symptoms, alexithymia, GSA, psychological distress, and psychosocial functioning with validated scales. RESULTS: IBS severity was highly associated to both alexithymia (r=0.61) and GSA (r=0.66), that were also associated to each other (r=0.64). Severe IBS patients scored significantly different than moderate IBS patients to all scales in the expected direction. Multiple and hierarchical regression analyses showed that IBS severity was predicted at a similar degree by alexithymia and GSA, controlled for IBS symptoms, psychological distress, and psychosocial functioning. Effect sizes showed that the highest IBS severity scores were obtained by patients with high alexithymia alone (d=1.16) or combined with higher GSA (d=1.45). CONCLUSION: Alexithymia and GSA were closely related to each other and associated to IBS severity, thus suggesting a common basis of emotional dysregulation. However, alexithymia (particularly the facets of difficulty identifying and describing feelings) resulted to be a stronger predictor of IBS severity than GSA, thus suggesting that impaired affective awareness may reflect on the clinical manifestations of IBS. PMID- 25011690 TI - Comorbidity in obsessive-compulsive disorder (OCD): a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is often associated with significant psychiatric comorbidity. Comorbid disorders include mood and anxiety disorders as well as obsessive-compulsive spectrum disorders (OCSDs). This paper aims to investigate comorbidity of DSM Axis I-disorders, including OCSDs, in patients with OCD from 10 centers affiliated with the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). METHODS: This is a cross sectional study of comorbidity of Axis I disorders including OCSDs in 457 outpatients with primary OCD (37% male; 63% female), with ages ranging from 12 to 88years (mean: 39.8+/-13). Treating clinicians assessed Axis I disorders using the Mini International Neuropsychiatric Interview and assessed OCSDs using the Structured Clinical Interview for OCD related/spectrum disorders (SCID-OCSD). RESULTS: In terms of the OCSDs, highest comorbidity rates were found for tic disorder (12.5%), BDD (8.71%) and self-injurious behavior (7.43%). In terms of the other Axis I-disorders, major depressive disorder (MDD; 15%), social anxiety disorder (SAD; 14%), generalized anxiety disorder (GAD; 13%) and dysthymic disorder (13%) were most prevalent. DISCUSSION: High comorbidity of some OCSDs in OCD supports the formal recognition of these conditions in a separate chapter of the nosology. Rates of other Axis I disorders are high in both the general population and in OCSDs, indicating that these may often also need to be the focus of intervention in OCD. PMID- 25011691 TI - The impact of mood episodes and duration of illness on cognition in bipolar disorder. AB - OBJECTIVE: A number of studies showed cognitive impairment in bipolar patients but few researches have studied the impact of mood episodes or duration of illness on neuropsychological functioning. METHODS: Cognitive functioning was examined in 110 bipolar 1 outpatients with different mood state (mania, major depression, mixed episode and euthymia). The neuropsychological battery included The Visual Search Test, Trail Making Test, Corsi Test, Frontal Assessment Battery (FAB), Cognitive Estimation Task (CET) and Tower of London and it assessed attention, memory and executive/planning functions. Failures in the different cognitive tests were compared between groups using chi(2) tests with Bonferroni's corrections. Finally a binary logistic regression was performed in order to find an eventual association between age and duration of illness and CET bizarreness. RESULTS: All the symptomatic patients (manic, depressed, mixed) failed more frequently The Visual Search Test in comparison with euthymics (chi(2)=9.882, df=3, p=0.017, phi=0.30; rate of failures: manic patients 32.2%, depressed patients 30.6%, euthymics 0%, mixed patients 18.2%). CET was performed worse by manic and euthymic patients (chi(2)=10.086, df=3, p=0.015, phi=0.31; rate of failures: manic patients 46.4%, depressed patients 22.9%, euthymics 52.1%, mixed patients 18.2%). Finally, a longer duration of illness was found to be predictive of more bizarreness at CET (OR=1.06, p=0.01). CONCLUSIONS: Bipolar patients present impairment in different cognitive domains even in euthymic phases. Frontal dysfunction might be associated with a long duration of illness as shown by number of bizarreness at CET in chronic bipolar patients. PMID- 25011692 TI - Erythropoiesis-stimulating agent use among non-dialysis-dependent CKD patients before and after the trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) using a large US health plan database. AB - BACKGROUND: In a landmark study, TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) examined the use of erythropoiesis-stimulating agent (ESA) therapy to treat anemia among patients with chronic kidney disease (CKD) and found no benefit compared to placebo. STUDY DESIGN: A retrospective observational design was used to determine the impact of TREAT on clinical practice. SETTING & PARTICIPANTS: A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and 4. FACTOR: ESA prescribing 2 years before and after publication of TREAT. OUTCOMES: Rate of ESA prescribing for ESA-naive and -prevalent cohorts. MEASUREMENTS: (1) Monthly ESA prescribing in the 2 years before and after publication of TREAT (ordinary least squares regression), (2) adjusted likelihood of prescribing ESA after TREAT (clustered logistic regression), and (3) probability of receiving ESA therapy based on anemia status (chi(2) test). RESULTS: For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage 3: change of slope, -0.08 [P<0.001]; stage 4: change of slope, -0.16 [P<0.001]). ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin levels <10g/dL, only 25% of patients with CKD stage 3 and 33% of patients with stage 4 were prescribed ESAs 2 years after TREAT, a notable 50% decline. After adjusting for all covariates, the probability of prescribing ESAs was 35% lower during the 2-year period after versus before publication of TREAT (OR, 0.65; 95% CI, 0.63-0.67). LIMITATIONS: The cumulative effect of adverse safety concerns in the period before TREAT also influenced physician prescribing of ESA therapy and could not be separated from the influence of TREAT. CONCLUSIONS: TREAT appears to be a watershed study that was followed by a marked decline in ESA prescribing for patients with CKD. PMID- 25011693 TI - Angiotensin blockade and progressive loss of kidney function in hemodialysis patients: a randomized controlled trial. AB - BACKGROUND: Glomerular filtration rate (GFR) declines during long-term dialysis treatment. In peritoneal dialysis, blockade of the renin-angiotensin-aldosterone system reduces GFR decline. Observational studies suggest that similar treatment may preserve kidney function in hemodialysis (HD). STUDY DESIGN: A multicenter, randomized, placebo-controlled, double-blinded trial, with 1-year follow-up. SETTING & PARTICIPANTS: Adult HD patients with urine output >300mL/24h, HD vintage less than 1 year, and cardiac ejection fraction >30%. Patients were included from 6 HD centers. INTERVENTION: Patients were randomly assigned to placebo or the angiotensin II receptor blocker irbesartan, 300mg daily. Target systolic blood pressure (BP) was 140mm Hg. OUTCOMES & MEASUREMENTS: Primary outcomes were change in GFR measured as the mean of creatinine and urea renal clearance together with urine volume. Secondary outcomes were change in albuminuria, renin-angiotensin II-aldosterone hormone plasma levels, and time to anuria. RESULTS: Of 82 patients randomly assigned (41 patients in each group), 56 completed 1 year of treatment. The placebo and irbesartan groups were comparable at baseline in terms of sex balance (26 vs 30 men), mean age (62 vs 61 years), median HD vintage (137 vs 148 days), mean HD time (10 vs 11h/wk), median urine volume (1.19 vs 1.26L/d), and mean GFR (4.8 vs 5.7mL/min/1.73m(2)). The target BP level was reached in both groups and BP did not differ significantly between groups over time. Adverse-event rates were similar. GFR declined by a mean of 1.7 (95% CI, 1.2-2.3) and 1.8 (95% CI, 1.1-2.4) mL/min/1.73m(2) per year in the placebo and irbesartan groups, respectively. Mean difference (baseline values minus value at 12 months) between groups was -0.0 (95% CI, -0.8 to 0.8). In each group, 4 patients became anuric. LIMITATIONS: GFR decline rates were lower than expected, reducing the power. CONCLUSIONS: At equal BP levels, we found that irbesartan treatment did not affect the decline in GFR or urine volume significantly during 1 year of treatment in HD patients. Irbesartan treatment was used safely in the studied population. PMID- 25011694 TI - Capsules with a hierarchical shell structure assembled by aminoglycosides and DNA via the kinetic path. AB - Aminoglycosides are capable of expelling water molecules when forming a complex with DNA via electrostatic interaction. The "water-proof" nature of the complex leads to the formation of capsules, which possess hierarchical shell structures with a smooth and rigid outer layer and a viscoelastic inner layer. PMID- 25011695 TI - Current understanding of genomic DNA of porcine circovirus type 2. AB - Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases in swine and is also described as the modulator of host immunity that exacerbates the clinical outcome of many bacterial and viral infections. To date, it has caused increasingly larger losses in the pig industry worldwide. The genomic DNA of PCV2 is predicted to contain 11 open reading frames (ORFs) and at least seven potential ORFs-encoding proteins larger than 5 kDa. Currently, however, only five virally encoded proteins (Rep, Rep', Cap, ORF3, and ORF4 protein) have been identified in PCV2 replication. In the present review, we strive to discuss the current understanding of the genomic DNA of PCV2 with the purpose of providing insight into the scientific basis of the pathogenesis of PCV2 and the prevention of its infection. PMID- 25011696 TI - Modelling the structure of full-length Epstein-Barr virus nuclear antigen 1. AB - Epstein-Barr virus is a clinically important human virus associated with several cancers and is the etiologic agent of infectious mononucleosis. The viral nuclear antigen-1 (EBNA1) is central to the replication and propagation of the viral genome and likely contributes to tumourigenesis. We have compared EBNA1 homologues from other primate lymphocryptoviruses and found that the central glycine/alanine repeat (GAr) domain as well as predicted cellular protein (USP7 and CK2) binding sites are present in homologues in the Old World primates, but not the marmoset, suggesting that these motifs may have co-evolved. Using the resolved structure of the C-terminal one-third of EBNA1 (homodimerization and DNA binding domain), we have gone on to develop monomeric and dimeric models in silico of the full-length protein. The C-terminal domain is predicted to be structurally highly similar between homologues, indicating conserved function. Zinc could be stably incorporated into the model, bonding with two N-terminal cysteines predicted to facilitate multimerisation. The GAr contains secondary structural elements in the models, while the protein binding regions are unstructured, irrespective of the prediction approach used and sequence origin. These intrinsically disordered regions may facilitate the diversity observed in partner interactions. We hypothesize that the structured GAr could mask the disordered regions, thereby protecting the protein from default degradation. In the dimer conformation, the C-terminal tails of each monomer wrap around a proline-rich protruding loop of the partner monomer, providing dimer stability, a feature which could be exploited in therapeutic design. PMID- 25011697 TI - An insight into the biophysical characterization of insoluble collagen aggregates: implication for arthritis. AB - Misfolding and aggregation of proteins is involved in some of the most prevalent neurodegenerative disorders. The importance of collagen stems from the fact that it is one of the dominant component used for tissue engineering and drug delivery applications and is a major component of skin, tendon, bone and other connective tissues. A systematic investigation on the conformation of collagen at various concentrations of glyoxal is studied by various biophysical techniques such as Trp fluorescence, ANS binding, Circular dichroism (CD), ATR-FTIR, Congo red (CR) assay, Rayleigh light scattering and Turbidity measurements. At 60% (v/v) glyoxal, collagen retains native-like secondary structure, altered Trp environment and high ANS fluorescence, characteristic of molten globule (MG) state. At 80% (v/v) glyoxal, insoluble collagen aggregates are detected as confirmed by decrease in Trp and ANS fluorescence, increase in non-native beta sheet structure as evident from far-UV CD and FTIR spectra, increase in Thioflavin T fluorescence, Rayleigh light scattering, Turbidity measurements, as well as red shift in CR absorbance. PMID- 25011698 TI - Effects of metabolic pathway precursors and polydimethylsiloxane (PDMS) on poly (gamma)-glutamic acid production by Bacillus subtilis BL53. AB - The aims of this study were to evaluate the effects of the addition of metabolic precursors and polydimethylsiloxane (PDMS) as an oxygen carrier to cultures of Bacillus subtilis BL53 during the production of gamma-PGA. Kinetics analyses of cultivations of different media showed that B. subtilis BL53 is an exogenous glutamic acid-dependent strain. When the metabolic pathway precursors of gamma PGA synthesis, L-glutamine and a-ketoglutaric acid, were added to the culture medium, production of the biopolymer was increased by 20 % considering the medium without these precursors. The addition of 10 % of the oxygen carrier PDMS to cultures caused a two-fold increase in the volumetric oxygen mass transfer coefficient (kLa), improving gamma-PGA production and productivity. Finally, bioreactor cultures of B. subtilis BL53 adopting the combination of optimized medium E, added of glutamine, alpha-ketoglutaric acid, and PDMS, showed a productivity of 1 g L(-1) h(-1) of g-PGA after only 24 h of cultivation. Results of this study suggest that the use of metabolic pathway precursors glutamine and a-ketolgutaric acid, combined with the addition of PDMS as an oxygen carrier in bioreactors, can improve gamma-PGA production and productivity by Bacillus strains . PMID- 25011699 TI - Do thoughts have sound? Differences between thoughts and auditory hallucinations in schizophrenia. AB - Cognitive theories about auditory hallucinations maintain that inner speech is erroneously interpreted as coming from an external source. Few first-hand accounts of patients' experiences have been made, so there is limited knowledge of the process through which patients distinguish their auditory verbal hallucinations (AVHs) from ordinary thoughts. 89 individuals diagnosed with schizophrenia, some experiencing acute hallucinatory symptomatology (Sz-AVHs) and some who were not (Sz-noAVHs), were assessed along with 48 individuals from the general population using the Auditory Hallucinations Assessment Questionnaire (AHAQ; Cuevas-Yust, Rodriguez Martin, Ductor Recuerda, Salas Azcona, & Leon Gomez, 2006). The Schz-AVHs group reported hearing ordinary thoughts at the same volume as their auditory hallucinations (p = .53) and spoken words (p = .89). In contrast, the Sz-noAVHs and general population samples reported hearing spoken words louder than their own thoughts (p = .002; p = .04). In comparison to these last two groups, the Sz-AVHs group described the sound of their thoughts as louder. These findings are consistent with the cognitive hypothesis of auditory verbal hallucinations. Confusion identifying the source of auditory hallucinations could be due, in part, to "hearing" one's thoughts at the same volume as auditory hallucinations and spoken words. PMID- 25011701 TI - The effects of epidural/spinal opioids in labour analgesia on neonatal outcomes: a meta-analysis of randomized controlled trials. AB - PURPOSE: Epidural/spinal opioids are increasingly used to relieve parturients' pain in labour. Some studies indicate that opioids can induce side effects in neonates, such as respiratory depression and neurobehavioural changes. This meta analysis aimed to clarify the effects of opioids in labour analgesia on neonates. SOURCE: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASETM were searched for relevant randomized controlled trials (RCTs). The neonatal data of Apgar scores, Neurological and Adaptive Capacity Scores (NACS), and umbilical cord pH values were extracted. Statistical analyses were carried out using Review Manager 5.2 and Stata((r)) 10. PRINCIPAL FINDINGS: Twenty-one trials with 2,859 participants were included in our meta-analysis. No difference in the incidence of Apgar scores < 7 was shown between the opioid and control groups at one minute (risk difference [RD] 0.0%, 95% confidence interval [CI]: 3.0 to 2.0, P = 0.78; I (2) = 0%, 95% CI: 0 to 50) and at five minutes (RD -1.0%, 95% CI: -2.0 to 1.0, P = 0.31; I(2) = 0%, 95% CI: 0 to 50). No significant differences were found in the NACS at two hours (mean difference [MD] -0.35, 95% CI: -1.70 to 1.01, P = 0.62; I(2) = 0%, 95% CI: 0 to 79) and at 24 hr (MD -0.45, 95% CI: -1.36 to 0.46, P = 0.33; I(2) = 3%, 95% CI: 0 to 26). Also, no significant differences were found in umbilical cord artery pH (MD -0.02, 95% CI: -0.06 to 0.03, P = 0.48; I(2) = 80%, 95% CI: 46 to 92) and vein pH (MD -0.03, 95% CI: -0.07 to 0.00, P = 0.08; I(2) = 77%, 95% CI: 36 to 91). No significant publication bias was found. CONCLUSION: The common doses of fentanyl and sufentanil used with an epidural/spinal technique in labour analgesia are safe for neonates up to 24 hr after delivery. In future studies, more attention should be paid to the long-term side effects in neonates. PMID- 25011700 TI - Gastric subserous space islet transplantation: techniques and initial results in diabetic inbred Lewis rats. AB - BACKGROUND: Implantation site is an important factor affecting the effect of islet transplantation. In the literature, the gastric subserous space (GSS) is rarely used as the implantation site of islets. Our present study reports the initial results with a limited numbers of islets transplanted into the GSS in Lewis rats and compares the outcomes between the GSS and the liver. MATERIAL AND METHODS: STZ was used to induce diabetes in Lewis rats, using a limited numbers of islets from the donors of the same species transplanted into the GSS and also into the portal vein (PV). Fasting blood glucose levels were measured and the transplanted insulin-positive islets were detected using immunohistochemical method. RESULTS: The fasting blood glucose levels were significantly reduced compared with that in the pre-transplantation period in rats of the GSS group. Oral glucose tolerance testing (OGTT) on day 28 after transplantation revealed an excellent functional capacity. Insulin-positive islets were identified in the stomach throughout the study. However, we found no difference in fasting blood glucose between pre- and post-transplantation and no insulin-positive islets were discovered in rats of the PV group. CONCLUSIONS: Under the treatment of a limited numbers of islets, the gastric subserous space reveals a preferable capacity for glycometabolism of STZ-induced Lewis diabetic rats compared with the portal vein. PMID- 25011702 TI - Hidden scale invariance in condensed matter. AB - Recent developments show that many liquids and solids have an approximate "hidden" scale invariance that implies the existence of lines in the thermodynamic phase diagram, so-called isomorphs, along which structure and dynamics in properly reduced units are invariant to a good approximation. This means that the phase diagram becomes effectively one-dimensional with regard to several physical properties. Liquids and solids with isomorphs include most or all van der Waals bonded systems and metals, as well as weakly ionic or dipolar systems. On the other hand, systems with directional bonding (hydrogen bonds or covalent bonds) or strong Coulomb forces generally do not exhibit hidden scale invariance. The article reviews the theory behind this picture of condensed matter and the evidence for it coming from computer simulations and experiments. PMID- 25011703 TI - Postoperative pain outcomes after transvaginal mesh revision. AB - INTRODUCTION AND HYPOTHESIS: Although the current literature discusses mesh complications including pain, as well as suggesting different techniques for removing mesh, there is little literature regarding pain outcomes after surgical removal or revision. The purpose of this study is to determine if surgical removal or revision of vaginal mesh improves patient's subjective complaints of pelvic pain associated with original placement of mesh. METHODS: After obtaining approval from the Vanderbilt University Medical Center Institutional Review Board, a retrospective review of female patients with pain secondary to previous mesh placement who underwent excision or revision of vaginal mesh from January 2000 to August 2012 was performed. Patient age, relevant medical history including menopause status, previous hysterectomy, smoking status, and presence of diabetes, fibromyalgia, interstitial cystitis, and chronic pelvic pain, was obtained. Patients' postoperative pain complaints were assessed. RESULTS: Of the 481 patients who underwent surgery for mesh revision, removal or urethrolysis, 233 patients met our inclusion criteria. One hundred and sixty-nine patients (73 %) reported that their pain improved, 19 (8 %) reported that their pain worsened, and 45 (19 %) reported that their pain remained unchanged after surgery. Prior history of chronic pelvic pain was associated with increased risk of failure of the procedure to relieve pain (OR 0.28, 95 % CI 0.12-0.64, p = 0.003). CONCLUSIONS: Excision or revision of vaginal mesh appears to be effective in improving patients' pain symptoms most of the time. Patients with a history of chronic pelvic pain are at an increased risk of no improvement or of worsening pain. PMID- 25011704 TI - Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease. AB - BACKGROUND: The substantia nigra (SN) midbrain nucleus is constitutively iron rich. Iron levels elevate further with age, and pathologically in Parkinson's disease (PD). Iron accumulation in PD SN involves dysfunction of ceruloplasmin (CP), which normally promotes iron export. We previously showed that ceruloplasmin knockout (CP KO) mice exhibit Parkinsonian neurodegeneration (~30% nigral loss) by 6 months, which is prevented by iron chelation. Here, we explored whether known iron-stressors of the SN (1) aging and (2) MPTP, would exaggerate the lesion severity of CP KO mice. FINDINGS: We show that while 5 month old CP KO mice exhibited nigral iron elevation and loss of SN neurons, surprisingly, aging CP KO mice to 14 months did not exacerbate iron elevation or SN neuronal loss. Unlike young mice, iron chelation therapy in CP KO mice between 9-14 months did not rescue neuronal loss. MPTP exaggerated iron elevation in young CP KO mice but did not increase cell death when compared to WTs. CONCLUSIONS: We conclude that there may exist a proportion of substantia nigra neurons that depend on CP for protection against iron neurotoxicity and could be protected by iron-based therapeutics. Death of the remaining neurons in Parkinson's disease is likely caused by parallel disease mechanisms, which may call for additional therapeutic options. PMID- 25011705 TI - Intronic and plasmid-derived regions contribute to the large mitochondrial genome sizes of Agaricomycetes. AB - Sizes of mitochondrial genomes vary extensively between fungal species although they typically contain a conserved set of core genes. We have characterised the mitochondrial genome of the conifer root rot pathogen Heterobasidion irregulare and compared the size, gene content and structure of 20 Basidiomycete mitochondrial genomes. The mitochondrial genome of H. irregulare was 114, 193 bp and contained a core set of 15 protein coding genes, two rRNA genes and 26 tRNA genes. In addition, we found six non-conserved open reading frames (ORFs) and four putative plasmid genes clustered in three separate regions together with 24 introns and 14 intronic homing endonuclease genes, unequally spread across seven of the core genes. The size differences among the 20 Basidiomycetes can largely be explained by length variation of intergenic regions and introns. The Agaricomycetes contained the nine largest mitochondrial genomes in the Basidiomycete group and Agaricomycete genomes are significantly (p < 0.001) larger than the other Basidiomycetes. A feature of the Agaricomycete mitochondrial genomes in this study was the simultaneous occurrence of putative plasmid genes and non-conserved ORFs, with Cantharellus cibarius as only exception, where no non-conserved ORF was identified. This indicates a mitochondrial plasmid origin of the non-conserved ORFs or increased mitochondrial genome dynamics of species harbouring mitochondrial plasmids. We hypothesise that two independent factors are the driving forces for large mitochondrial genomes: the homing endonuclease genes in introns and integration of plasmid DNA. PMID- 25011706 TI - Effect of ketoprofen on pre-weaning piglet mortality on commercial farms. AB - The effect of ketoprofen on pre-weaning piglet mortality was evaluated in a large scale study on commercial farms. Sows (n= 1486) from 15 farms were included. Half of the sows received 3 mg/kg ketoprofen in a single intramuscular administration within 12 h after farrowing. The other half remained untreated. Pre-weaning mortality was lower in the ketoprofen-treated group than in the control group (8.43% vs. 10.24%, respectively; P= 0.010). The major impact of ketoprofen on mortality was seen between days 2 and 7 postpartum (mortality rates of 2.75% vs. 4.02% for treated and control groups, respectively; P= 0.001). In addition, ketoprofen treatment was associated with a higher number of piglets weaned per litter than when no treatment was given (10.0 vs. 9.84, respectively; P= 0.012). PMID- 25011707 TI - Surveillance of diarrhoea in small animal practice through the Small Animal Veterinary Surveillance Network (SAVSNET). AB - Using the Small Animal Veterinary Surveillance Network (SAVSNET), a national small animal disease-surveillance scheme, information on gastrointestinal disease was collected for a total of 76 days between 10 May 2010 and 8 August 2011 from 16,223 consultations (including data from 9115 individual dogs and 3462 individual cats) from 42 premises belonging to 19 UK veterinary practices. During that period, 7% of dogs and 3% of cats presented with diarrhoea. Adult dogs had a higher proportional morbidity of diarrhoea (PMD) than adult cats (P <0.001). This difference was not observed in animals <1 year old. Younger animals in both species had higher PMDs than adult animals (P < 0.001). Neutering was associated with reduced PMD in young male dogs. In adult dogs, miniature Schnauzers had the highest PMD. Most animals with diarrhoea (51%) presented having been ill for 2-4 days, but a history of vomiting or haemorrhagic diarrhoea was associated with a shorter time to presentation. The most common treatments employed were dietary modification (66% of dogs; 63% of cats) and antibacterials (63% of dogs; 49% of cats). There was variability in PMD between different practices. The SAVNET methodology facilitates rapid collection of cross-sectional data regarding diarrhoea, a recognised sentinel for infectious disease, and characterises data that could benchmark clinical practice and support the development of evidence based medicine. PMID- 25011708 TI - Ask not what your journal can do for you - ask what you can do for it. PMID- 25011709 TI - Comparison of tiletamine and zolazepam pharmacokinetics in tigers (Panthera tigris) and leopards (Panthera pardus): do species differences account for adverse effects in tigers? AB - Serious post-operative neurological complications of unknown aetiology are reported in tigers after immobilisation using tiletamine and zolazepam. These complications may arise from the persistent effects of tiletamine or active metabolites of tiletamine or zolazepam. Concentrations of tiletamine, zolazepam and some metabolites were measured using high performance liquid chromatography mass spectrometry in plasma from captive tigers (n = 8) and leopards (n = 9; an unaffected species, for comparison) during anaesthesia for routine clinical procedures. The zolazepam:tiletamine (Z:T) ratio was calculated. Peak concentrations occurred at 9-33 min and ranged from 83.5 to 379.2 ng/mL for tiletamine and 301.1 to 1239.3 ng/mL for zolazepam after correction for dose by weight. There were no significant differences between tigers and leopards. The Z:T ratio was generally <5 and did not differ between species. In both tigers and leopards, zolazepam metabolism appeared to be primarily via demethylation. There was evidence for hydroxylation in leopards, but much less in tigers than leopards. No major differences between the species in parent pharmacokinetics were identified. The metabolism of tiletamine could not be defined with any degree of certainty for either species. PMID- 25011710 TI - Mechanisms underlying the inhibitory effect of the feed contaminant deoxynivalenol on glucose absorption in broiler chickens. AB - Deoxynivalenol (DON), a major contaminant of cereals and grains, is of public health concern worldwide and has been shown to reduce the electrogenic transport of glucose. However, the full effects of Fusarium mycotoxins on nutrient absorption are still not clear. The aim of this study was to investigate whether decreased nutrient absorption was due to specific effects on transporter trafficking in the intestine and whether inhibition of phosphoinositol-3-kinase (PI-3-kinase) affected the electrogenic jejunal transport of glucose. Jejunal mucosa of 6-week-old broiler chickens were mounted in Ussing chambers and treated with DON, wortmannin (a specific inhibitor of PI-3-kinase), DON + wortmannin, phlorizin and cytochalasin B. DON was found to decrease the short-circuit current (Isc) after glucose addition. A similar decline in Isc after glucose addition was observed following pre-application of wortmannin, or phlorizin (Na(+)/glucose co transporter, SGLT1 inhibitor). The results indicate that DON decreased glucose absorption in the absence of wortmannin or phlorizin but had no additional effect on glucose absorption in their presence. Glucose transport was not affected by cytochalasin B (facilitative glucose transporter, GLUT2 inhibitor). The study provides evidence that the suppressive effect of DON on the electrogenic transport of glucose may be due to an inhibitory activity of the PI3 kinase pathway and intestinal SGLT1. Furthermore, the effect of cytochalasin B on glucose transport in chicken tissues differs from that in mammals. PMID- 25011711 TI - Pharmacokinetic profiles of the analgesic drug flupirtine in cats. AB - Flupirtine (FLU) is a non-opioid analgesic drug with no antipyretic or antiphlogistic effects, used in the treatment of a wide range of pain states in human beings. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate to recommend its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy cats. Six mixed breed adult cats were randomly assigned to two treatment groups using an open, single dose, two-treatment, two-phase, paired, cross-over design (2 * 2 Latin-square). Group 1 (n = 3) received a single dose of 5 mg/kg of FLU injected IV into the jugular vein. Group 2 (n = 3) received the same dose via PO route. The wash out period was 1 week. Blood samples (1 mL) were collected at assigned times and plasma was then analysed by a validated HPLC method. No adverse effects at the point of injection and no behavioural changes or alterations in health parameters were observed in the animals during or after the study (up to 7 days after the full study). After IV administration, FLU was detectable in plasma up to 36 h. After PO administration, FLU plasma concentrations were lower than those following IV administration, but they were detectable over the same time range. The terminal part of both mean pharmacokinetic curves showed a similar trend of elimination. The oral bioavailability was approximately 40%. This is the first study of FLU in an animal species of veterinary interest and it could pave the way for the use of this active ingredient in the veterinary field. PMID- 25011712 TI - Duplex PCR for differentiation of the vaccine strain Brucella suis S2 and B. suis biovar 1 from other strains of Brucella spp. AB - Immunisation with attenuated Brucella spp. vaccines prevents brucellosis, but may also interfere with diagnosis. In this study, a duplex PCR was developed to distinguish Brucella suis vaccine strain S2 from field strains of B. suis biovar 1 and other Brucella spp. The PCR detected 60 fg genomic DNA of B. suis S2 or biovar 1 field strains and was able to distinguish B. suis S2 and wild-type strains of B. suis biovar 1 among 76 field isolates representing all the common species and biovars, as well as four vaccine strains, of Brucella. PMID- 25011713 TI - Heritability of epistaxis in the Australian Thoroughbred racehorse population. AB - Post exercise epistaxis, the manifestation of a severe form of exercise-induced pulmonary haemorrhage (EIPH), has been observed in many equine racing populations. Although multiple analyses have suggested that non-genetic factors may lead to the development of this condition, relatively little consensus has been reached regarding its genetic aetiology. The objective of this study was to provide insight into both genetic and non-genetic factors that may contribute to the expression of epistaxis in the Australian Thoroughbred racing population. Racing records and reported epistaxis occurrences were acquired for 117,088 horses entered in races and official barrier trials from 1 August 2000 until 22 February 2011. Heritability was estimated using two different logistic generalised linear mixed models (lifetime epistaxis risk h(2) = 0.27 and individual race epistaxis risk h(2) = 0.50). Sex, age, and year of birth were shown to be significant; however, trainer, jockey, race distance, condition of the track (i.e. 'going'), racecourse, track surface, number of race starters, year and month of race were not significant. Evidence suggests genetic and non genetic links to EIPH expressed as epistaxis. PMID- 25011714 TI - Ventricular arrhythmias in the North American multidisciplinary study of ARVC: predictors, characteristics, and treatment. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with sudden cardiac death. However, the selection of patients for implanted cardioverter-defibrillators (ICDs), as well as programming of the ICD, is unclear. OBJECTIVES: The objective of this study was to identify predictors, characteristics, and treatment of ventricular arrhythmias in patients with ARVC. METHODS: The Multidisciplinary Study of Right Ventricular Cardiomyopathy established the North American ARVC Registry and enrolled patients with a diagnosis of ARVC. Patients were followed prospectively. RESULTS: Of 137 patients enrolled, 108 received ICDs. Forty-eight patients had 502 sustained episodes of ventricular arrhythmias, including 489 that were monomorphic and 13 that were polymorphic. In the patients with ICDs, independent predictors of ventricular arrhythmias in follow-up included spontaneous sustained ventricular arrhythmias before ICD implantation and T-wave inversions inferiorly. The only independent predictor for life-threatening arrhythmias, defined as sustained ventricular tachycardia (VT) >=240 beats/min or ventricular fibrillation, was a younger age at enrollment. Anti-tachycardia pacing (ATP), independent of the cycle length of the VT, was successful in terminating 92% of VT episodes. CONCLUSIONS: In the North American ARVC Registry, the majority of ventricular arrhythmias in follow up are monomorphic. Risk factors for ventricular arrhythmias were spontaneous ventricular arrhythmias before enrollment and a younger age at ICD implantation. ATP is highly successful in terminating VT, and all ICDs should be programmed for ATP, even for rapid VT. PMID- 25011715 TI - Defining arrhythmic risk and defibrillator therapy in ARVC: shocking rhythm? PMID- 25011716 TI - Predictors of permanent pacemaker implantation in patients with severe aortic stenosis undergoing TAVR: a meta-analysis. AB - BACKGROUND: Atrioventricular (AV) conduction disturbances requiring permanent pacemaker (PPM) implantation may complicate transcatheter aortic valve replacement (TAVR). Available evidence on predictors of PPM is sparse and derived from small studies. OBJECTIVES: The objective of this study was to provide summary effect estimates for clinically useful predictors of PPM implantation after TAVR. METHODS: We performed a systematic search for studies that reported the incidence of PPM implantation after TAVR and that provided raw data for the predictors of interest. Data on study, patient, and procedural characteristics were abstracted. Crude risk ratios (RRs) and 95% confidence intervals for each predictor were calculated by use of random effects models. Stratified analyses by type of implanted valve were performed. RESULTS: We obtained data from 41 studies that included 11,210 TAVR patients, of whom 17% required PPM implantation after intervention. The rate of PPM ranged from 2% to 51% in individual studies (with a median of 28% for the Medtronic CoreValve Revalving System [MCRS] and 6% for the Edwards SAPIEN valve [ESV]). The summary estimates indicated increased risk of PPM after TAVR for men (RR: 1.23; p < 0.01); for patients with first-degree AV block (RR: 1.52; p < 0.01), left anterior hemiblock (RR: 1.62; p < 0.01), or right bundle branch block (RR: 2.89; p < 0.01) at baseline; and for patients with intraprocedural AV block (RR: 3.49; p < 0.01). These variables remained significant predictors when only patients treated with the MCRS bioprosthesis were considered. The data for ESV were limited. Unadjusted estimates indicated a 2.5-fold higher risk for PPM implantation for patients who received the MCRS than for those who received the ESV. CONCLUSIONS: Male sex, baseline conduction disturbances, and intraprocedural AV block emerged as predictors of PPM implantation after TAVR. This study provides useful tools to identify high-risk patients and to guide clinical decision making before and after intervention. PMID- 25011717 TI - Pacemaker after transcatheter aortic valve replacement: unexpected, but not infrequent outcome. PMID- 25011718 TI - Prognostic significance of LGE by CMR in aortic stenosis patients undergoing valve replacement. AB - BACKGROUND: Prior studies have shown that late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) can detect focal fibrosis in aortic stenosis (AS), suggesting that it might predict higher mortality risk. OBJECTIVES: This study was conducted to evaluate whether LGE-CMR can predict post-operative survival in patients with severe AS undergoing aortic valve replacement (AVR). METHODS: We prospectively evaluated survival (all-cause and cardiovascular disease related) according to LGE-CMR status in 154 consecutive AS patients (96 men; mean age: 74 +/- 6 years) without a history of myocardial infarction undergoing surgical AVR and in 40 AS patients undergoing transcatheter aortic valve replacement (TAVR). RESULTS: LGE was present in 29% of patients undergoing surgical AVR and in 50% undergoing TAVR. During a median follow-up of 2.9 years, 21 patients undergoing surgical AVR and 20 undergoing TAVR died. In surgical AVR, the presence of LGE predicted higher post-operative mortality (odds ratio: 10.9; 95% confidence interval [CI]: 1.2 to 100.0; p = 0.02) and worse all-cause survival (73% vs. 88%; p = 0.02 by log-rank test) and cardiovascular disease related survival (85% vs. 95%; p = 0.03 by log-rank test) on 5-year Kaplan-Meier estimates of survival after surgical AVR. Multivariate Cox analysis identified the presence of LGE (hazard ratio: 2.8; 95% CI: 1.3 to 6.9; p = 0.025) and New York Heart Association functional class III/IV (hazard ratio: 3.2; 95% CI: 1.1 to 8.1; p < 0.01) as the sole independent predictors of all-cause mortality after surgical AVR. The presence of LGE also predicted higher all-cause mortality (p = 0.05) and cardiovascular disease related mortality (p = 0.03) in the subgroup of patients without angiographic coronary artery disease (n = 110) and higher cardiovascular disease related mortality in 25 patients undergoing transfemoral TAVR. CONCLUSIONS: The presence of LGE indicating focal fibrosis or unrecognized infarct by CMR is an independent predictor of mortality in patients with AS undergoing AVR and could provide additional information in the pre-operative evaluation of risk in these patients. PMID- 25011719 TI - On fibrosis, prognosis, and the unique role of CMR: a paradigm shift from "bright is dead" to "bright is bad". PMID- 25011721 TI - Mortality in the PARTNER trials: transfemoral is better. PMID- 25011720 TI - Comprehensive analysis of mortality among patients undergoing TAVR: results of the PARTNER trial. AB - BACKGROUND: Patients with severe aortic stenosis (AS) who were deemed too high risk or inoperable for conventional aortic valve replacement (AVR) in the PARTNER (Placement of Aortic Transcatheter Valves) trial were randomized to transcatheter aortic valve replacement (TAVR) versus AVR (PARTNER-A arm) or standard therapy (PARTNER-B arm). OBJECTIVES: This study compared when and how deaths occurred after TAVR versus surgical AVR or standard therapy. METHODS: The PARTNER-A arm included 244 transfemoral (TF) and 104 transapical (TA) TAVR patients, and 351 AVR patients; the PARTNER-B arm included 179 TF-TAVR patients and 179 standard therapy patients. Deaths were categorized as cardiovascular, noncardiovascular, or uncategorizable, and were characterized by multiphase hazard modelling. RESULTS: In the PARTNER-A arm, the risk of death peaked after randomization in the TA-TAVR and AVR groups, falling to low levels commensurate with the U.S. population within 3 months. Early risk was less in TF-TAVR patients, resulting in initial superior survival; between 12 and 18 months, risk increased, such that within 2 years, TF-TAVR and AVR patients had similar survival rates. Cardiovascular, noncardiovascular, and uncategorizable deaths for TF-TAVR were 37%, 43%, and 20%, respectively, versus 22%, 41%, and 37%, respectively, for TA TAVR and 33%, 43%, and 24%, respectively, for AVR. In the PARTNER-B arm, risk with standard therapy was 60% per year; TF-TAVR reduced risk to 20% per year, resulting in 0.5 years of life added within 2.5 years. CONCLUSIONS: In inoperable AS patients, TAVR substantially reduced the risk of cardiovascular death. In high risk patients, TA-TAVR and AVR were associated with elevated peri-procedural risk more than with TF-TAVR, although cardiovascular death was higher after TF-TAVR. Therefore, TF-TAVR should be considered the standard of care for severely symptomatic inoperable patients or those at high risk of noncardiovascular mortality after conventional surgery. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). PMID- 25011722 TI - Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study. AB - BACKGROUND: The EVEREST II (Endovascular Valve Edge-to-Edge REpair STudy) High Risk registry and REALISM Continued Access Study High-Risk Arm are prospective registries of patients who received the MitraClip device (Abbott Vascular, Santa Clara, California) for mitral regurgitation (MR) in the United States. OBJECTIVES: The purpose of this study was to report 12-month outcomes in high risk patients treated with the percutaneous mitral valve edge-to-edge repair. METHODS: Patients with grades 3 to 4+ MR and a surgical mortality risk of >=12%, based on the Society of Thoracic Surgeons risk calculator or the estimate of a surgeon coinvestigator following pre-specified protocol criteria, were enrolled. RESULTS: In the studies, 327 of 351 patients completed 12 months of follow-up. Patients were elderly (76 +/- 11 years of age), with 70% having functional MR and 60% having prior cardiac surgery. The mitral valve device reduced MR to <=2+ in 86% of patients at discharge (n = 325; p < 0.0001). Major adverse events at 30 days included death in 4.8%, myocardial infarction in 1.1%, and stroke in 2.6%. At 12 months, MR was <=2+ in 84% of patients (n = 225; p < 0.0001). From baseline to 12 months, left ventricular (LV) end-diastolic volume improved from 161 +/- 56 ml to 143 +/- 53 ml (n = 203; p < 0.0001) and LV end-systolic volume improved from 87 +/- 47 ml to 79 +/- 44 ml (n = 202; p < 0.0001). New York Heart Association functional class improved from 82% in class III/IV at baseline to 83% in class I/II at 12 months (n = 234; p < 0.0001). The 36-item Short Form Health Survey physical and mental quality-of-life scores improved from baseline to 12 months (n = 191; p < 0.0001). Annual hospitalization rate for heart failure fell from 0.79% pre-procedure to 0.41% post-procedure (n = 338; p < 0.0001). Kaplan Meier survival estimate at 12 months was 77.2%. CONCLUSIONS: The percutaneous mitral valve device significantly reduced MR, improved clinical symptoms, and decreased LV dimensions at 12 months in this high-surgical-risk cohort. (Endovascular Valve Edge-to-Edge REpair STudy [EVERESTIIRCT]; NCT00209274). PMID- 25011723 TI - Treatment for mitral regurgitation: which one are we talking about? PMID- 25011725 TI - The 3 pathways of translational medicine: an evolution to a call-and-response method. PMID- 25011724 TI - Review of clinical practice guidelines for the management of LDL-related risk. AB - Managing risk related to low-density lipoprotein (LDL) is vital in therapy for patients at risk for atherosclerotic cardiovascular disease (ASCVD) events given its important etiologic role in atherogenesis. Despite decades of research showing reduction of ASCVD risk with multiple approaches to lowering of LDL cholesterol, there continue to be significant gaps in care with inadequate numbers of patients receiving standard of care lipid-lowering therapy. Confusion regarding implementation of the multiple published clinical practice guidelines has been identified as one contributor to suboptimal management of LDL-related risk. This review summarizes the current guidelines for reduction of LDL-related cardiovascular risk provided by a number of major professional societies, which have broad applicability to diverse populations worldwide. Statements have varied in the process and methodology of development of recommendations, the grading system for level and strength of evidence, the inclusion or exclusion of expert opinion, the suggested ASCVD risk assessment tool, the lipoproteins recommended for risk assessment, and the lipoprotein targets of therapy. The similarities and differences among important guidelines in the United States and internationally are discussed, with recommendations for future strategies to improve consistency in approaches to LDL-related ASCVD risk and to reduce gaps in implementation of evidence-based therapies. PMID- 25011726 TI - Where Is the American College of Cardiology heading?: a PINNACLE Registry case study. PMID- 25011727 TI - Handheld ultrasound and diagnosis of cardiovascular disease at the bedside. PMID- 25011728 TI - Multiple measures of dispositional global/local bias predict attentional blink magnitude. AB - When the second of two targets (T2) is presented temporally close to the first target (T1) in a rapid serial visual presentation stream, accuracy to identify T2 is markedly reduced-an attentional blink (AB). While most individuals show an AB, Dale and Arnell (Atten Percept Psychophys 72(3):602-606, 2010) demonstrated that individual differences in dispositional attentional focus predicted AB performance, such that individuals who showed a natural bias toward the global level of Navon letter stimuli were less susceptible to the AB and showed a smaller AB effect. For the current study, we extended the findings of Dale and Arnell (Atten Percept Psychophys 72(3):602-606, 2010) through two experiments. In Experiment 1, we examined the relationship between dispositional global/local bias and the AB using a highly reliable hierarchical shape task measure. In Experiment 2, we examined whether three distinct global/local measures could predict AB performance. In both experiments, performance on the global/local tasks predicted subsequent AB performance, such that individuals with a greater preference for the global information showed a reduced AB. This supports previous findings, as well as recent models which discuss the role of attentional breadth in selective attention. PMID- 25011729 TI - Need and disparities in primary care management of patients with diabetes. AB - BACKGROUND: An aging population means that chronic illnesses, such as diabetes, are becoming more prevalent and demands for care are rising. Members of primary care teams should organize and coordinate patient care with a view to improving quality of care and impartial adherence to evidence-based practices for all patients. The aims of the present study were: to ascertain the prevalence of diabetes in an Italian population, stratified by age, gender and citizenship; and to identify the rate of compliance with recommended guidelines for monitoring diabetes, to see whether disparities exist in the quality of diabetes patient management. METHODS: A population-based analysis was performed on a dataset obtained by processing public health administration databases. The presence of diabetes and compliance with standards of care were estimated using appropriate algorithms. A multilevel logistic regression analysis was applied to assess factors affecting compliance with standards of care. RESULTS: 1,948,622 Italians aged 16+ were included in the study. In this population, 105,987 subjects were identified as having diabetes on January 1st, 2009. The prevalence of diabetes was 5.43% (95% CI 5.33-5.54) overall, 5.87% (95% CI 5.82-5.92) among males, and 5.05% (95% CI 5.00-5.09) among females. HbA1c levels had been tested in 60.50% of our diabetic subjects, LDL cholesterol levels in 57.50%, and creatinine levels in 63.27%, but only 44.19% of the diabetic individuals had undergone a comprehensive assessment during one year of care. Statistical differences in diabetes care management emerged relating to gender, age, diagnostic latency period, comorbidity and citizenship. CONCLUSIONS: Process management indicators need to be used not only for the overall assessment of health care processes, but also to monitor disparities in the provision of health care. PMID- 25011731 TI - Adaption of cardio-respiratory balance during day-rest compared to deep sleep--an indicator for quality of life? AB - Heart rate and breathing rate fluctuations represent interacting physiological oscillations. These interactions are commonly studied using respiratory sinus arrhythmia (RSA) of heart rate variability (HRV) or analyzing cardiorespiratory synchronization. Earlier work has focused on a third type of relationship, the temporal ratio of respiration rate and heart rate (HRR). Each method seems to reveal a specific aspect of cardiorespiratory interaction and may be suitable for assessing states of arousal and relaxation of the organism. We used HRR in a study with 87 healthy subjects to determine the ability to relax during 5 day resting periods in comparison to deep sleep relaxation. The degree to which a person during waking state could relax was compared to somatic complaints, health related quality of life, anxiety and depression. Our results show, that HRR is barely connected to balance (LF/HF) in HRV, but significantly correlates to the perception of general health and mental well-being as well as to depression. If relaxation, as expressed in HRR, during day-resting is near to deep sleep relaxation, the subjects felt healthier, indicated better mental well-being and less depressive moods. PMID- 25011730 TI - Obsessive Compulsive Treatment Efficacy Trial (OCTET) comparing the clinical and cost effectiveness of self-managed therapies: study protocol for a randomised controlled trial. AB - BACKGROUND: UK National Institute of Health and Clinical Excellence guidelines for obsessive compulsive disorder (OCD) specify recommendations for the treatment and management of OCD using a stepped care approach. Steps three to six of this model recommend treatment options for people with OCD that range from low intensity guided self-help (GSH) to more intensive psychological and pharmacological interventions. Cognitive behavioural therapy (CBT), including exposure and response prevention, is the recommended psychological treatment. However, whilst there is some preliminary evidence that self-managed therapy packages for OCD can be effective, a more robust evidence base of their clinical and cost effectiveness and acceptability is required. METHODS/DESIGN: Our proposed study will test two different self-help treatments for OCD: 1) computerised CBT (cCBT) using OCFighter, an internet-delivered OCD treatment package; and 2) GSH using a book. Both treatments will be accompanied by email or telephone support from a mental health professional. We will evaluate the effectiveness, cost and patient and health professional acceptability of the treatments. DISCUSSION: This study will provide more robust evidence of efficacy, cost effectiveness and acceptability of self-help treatments for OCD. If cCBT and/or GSH prove effective, it will provide additional, more accessible treatment options for people with OCD. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN73535163. Date of registration: 5 April 2011. PMID- 25011732 TI - Reversion by vitamin E treatment of the oxidative damage but not of the advancement in reproductive senescence produced by neonatal hypoxia or hypoxia ischemia in female rats. AB - BACKGROUND/AIMS: Few studies address the long-term consequences of perinatal hypoxia (H), a frequent birth complication. Previously we described advanced reproductive senescence (premature loss of regular cyclicity) in female rats subjected to perinatal H or H plus unilateral ischemia (HI) associated with changes in the hypothalamic expression of estrogen and opioid receptors. Our aim is to explore whether hypothalamic inflammation and oxidative damage mediate these reproductive alterations. METHODS: Female rats were subjected on postnatal day (PND) 7 to H (6.5% O2 for 50 min) or HI (H + right carotid artery ligature) and inflammation/oxidative damage markers, such as iNOS, nNOS, insulin-like growth factor (IGF) system expression, glial reaction and macrophage invasion in the medial basal hypothalamus-preoptic area (GFAP Western blot and immunohistochemistry, ED1 immunohistochemistry), were determined. The effect of antioxidant treatment with vitamin E (VE; 1.5 mg/rat on PND 4, 6 and 8) was also explored. RESULTS: No significant cellular inflammatory reactions were observed although GFAP protein was significantly increased at early times after injury. Forty-eight hours after injury iNOS, nNOS and IGF-I mRNA decreased in the HI group, and nNOS in the H group. IGFBP-3 mRNA increased in HI rats at 48 h and 30 days, while it fell at 7 days postinjury in both groups. VE treatment prevented the effects of HI on oxidation/inflammation markers, but did not prevent the premature onset of reproductive senescence or the altered hormone receptors expression. CONCLUSION: These results suggest that the oxidative and inflammatory damage caused by perinatal H or HI may not be responsible for the late-onset reproductive abnormalities. PMID- 25011733 TI - Carotid endarterectomy and carotid artery stenting: changing paradigm during 10 years in a high-volume centre. AB - BACKGROUND: We analysed the results of internal carotid artery (ICA) stenosis treatment at our institution over the last 10 years according to treatment modalities (carotid endarterectomy [CEA] vs carotid artery stenting [CAS]). Furthermore, we compared our results of treatment prior to the EVA-3S study being implemented into our practice (2003-2007) and after that (2008-2012). METHOD: During the years 2003-2012, a total of 1,471 procedures were performed for ICA stenosis. CEA was done in 815 cases and CAS in 656 cases. The primary outcome was disabling stroke (mRS > 2) or myocardial infarction (MI) within 30 days after treatment. Secondary outcomes were frequency of transient ischaemic attacks (TIAs), minor strokes (stroke without impaired activities of daily living [ADL]) and any other significant complication. Comparisons of the results before and after 2008 were performed. RESULTS: Major mortality and morbidity were divided according to treatment groups; reached 1.0 % in the CEA group and 3.0 % in the CAS group, p = 0.004. Minor stroke was recorded at 1.8 % and 2.7 % in the CEA and CAS, p = 0.245. TIAs in 1.0 % (CEA) and 4.7 % (CAS), p < 0.001. Any complication in 11.9 % (CEA) and 13.3 % (CAS), p = 0.401. In the overall results (i.e. CEA and CAS together), we found in 2008-2012 a decrease of incidence of TIAs (from 30/840 to 9/631, p = 0.011) and any complications (from 120/840 to 64/631, p = 0.017). CONCLUSIONS: CEA performed in a high-volume centre is a safe procedure in properly indicated patients. In all subgroup analyses, CEA fared better than or at least of equal benefit as CAS. Since 2008, the frequency of TIAs and other complications decreased significantly. This study supports an idea of CEA being the first choice of treatment and CAS being reserved for strictly selected cases, such as re-stenosis after a previous carotid procedure, carotid dissection, ICA stenosis after radiotherapy, previous major neck surgery, contralateral cranial nerve palsy or tandem stenosis. PMID- 25011908 TI - Surgical revascularization in structural orthotopic bone allograft increases bone remodeling. AB - BACKGROUND: Osseous defects reconstructed with cryopreserved structural allografts are poorly revascularized and therefore are prone to nonunion, infection, deterioration of mechanical properties, and fracture. Whether this can be mitigated by specific interventions such as intramedullary surgical revascularization has been incompletely evaluated. QUESTIONS/PURPOSES: We aimed to study surgical revascularization as a means to improve bone remodeling in cryopreserved allograft. Second, we questioned whether spatial histomorphometric differences occur in cortical bone areas after intramedullary surgical revascularization. Third, biomechanical properties of the graft-recipient construct in surgically revascularized allograft were compared with those of conventional allografts. METHODS: Allografts were harvested from 10 Brown Norway rats, cryopreserved, and transplanted orthotopically in a 10-mm defect in two groups of 10 Lewis rats each (major histocompatibility mismatch). In the control group, no surgical revascularization was performed, whereas in the experimental group, a saphenous arteriovenous bundle was transposed in the bone marrow cavity. Bone remodeling was measured with histomorphometry, histology, and microcomputed tomography at 16 weeks. Spatial differences were analyzed with histomorphometry. To determine biomechanical properties, load at failure and structural stiffness in bending were evaluated by the three-point bend testing. In both groups, normal values of the contralateral femur also were analyzed. RESULTS: Surgically revascularized allografts had increased bone remodeling (bone formation rate to bone surface ratio: 130 +/- 47 um(3)/um(2)/year versus 44 +/- 43 um(3)/um(2)/year, p = 0.006) and higher cortical osteocyte counts (18.6% +/- 12.7% versus 3.1% +/- 2.8%, p = 0.002) than nonrevascularized grafts. In nonrevascularized grafts, the bone formation rate to bone surface ratio was 35% of the contralateral normal values, whereas in surgically revascularized grafts, the bone formation rate to bone surface ratio in the grafts exceeded the contralateral values (110%). Microcomputed tomography did not show differences in bone volume between groups, however in both groups, bone volume was less in grafts compared with the contralateral femurs. Inner cortical bone formation rate to bone surface ratio was greater in surgically revascularized grafts (65 +/- 30 um(3)/um(2)/year versus 13 +/- 16 um(3)/um(2)/year in the control group, p = 0.012). Outer cortical bone formation rate to bone surface ratio also increased in surgically revascularized grafts (49 +/- 31 um(3)/um(2)/year versus 19 +/- 21 um(3)/um(2)/year, p = 0.032). No differences were found in load at failure and structural stiffness between both groups. In the control group, load at failure and structural stiffness were lower in grafts than in the contralateral femurs (p = 0.004 and p = 0.02, respectively). In the experimental group, surgically revascularized grafts also had lower load at failure and structural stiffness than the contralateral femurs (p = 0.008 and p = 0.02, respectively). CONCLUSIONS: Surgical revascularization of large segmental allografts improved bone remodeling and viability without an adverse effect on total bone volume or bending strength and stiffness in this short-term analysis. CLINICAL RELEVANCE: Cryopreserved allografts remain largely necrotic and are associated with a high rate of complications. Surgical revascularization increases graft healing which could contribute to graft survival with time. PMID- 25011909 TI - CORR Insights(r): Obesity does not affect survival outcomes in extremity soft tissue sarcoma. PMID- 25011910 TI - MKRN3 mutations in familial central precocious puberty. AB - Loss-of-function mutations in the gene encoding the makorin RING finger protein 3 (MKRN3) have recently been reported to underlie familial cases of central precocious puberty (CPP). The imprinted MKRN3 gene is expressed only from the paternal allele, and mutations inherited from the father affect boys and girls equally, which is in contrast to the known female preponderance in idiopathic CPP. By screening a series of 6 families and 1 male patient with idiopathic CPP, we identified 2 further families carrying loss-of-function mutations in MKRN3, the previously reported variant c.475_476insC (p.Ala162Glyfs*14) and a novel one, c.331G>T (p.Glu111*). We conclude that MKRN3 mutations appear to be a frequent cause of familial CPP and, considering the imprinted mode of inheritance, may also account for a certain proportion of isolated CPP cases. Remarkably, four out of six MKRN3 mutations described so far encode either a stop codon or a frameshift followed by a premature stop codon. Consequently, there may be less severe mutations that possibly associate with more subtle phenotypes, which could even explain variation within the physiological range. Mutation screening in larger cohorts is necessary in order to estimate the real prevalence of MKRN3 mutations in idiopathic CPP. PMID- 25011911 TI - 7,9-Diaryl-1,6,8-trioxaspiro[4.5]dec-3-en-2-ones: readily accessible and highly potent anticancer compounds. AB - 7,9-Diaryl-1,6,8-trioxaspiro[4.5]dec-3-en-2-ones are a recently described group of spirocyclic butenolides that can be generated rapidly and as a single diastereomer through a cascade process between gamma-hydroxybutenolides and aromatic aldehydes. The following outlines our findings that these spirocycles are potently cytotoxic and have a dramatic structure-function profile that provides excellent insight into the structural features required for this potency. PMID- 25011912 TI - Docking based virtual screening and molecular dynamics study to identify potential monoacylglycerol lipase inhibitors. AB - Monoacylglycerol lipase (MAGL) is one of the key enzymes of the endocannabinoid system (ECS). It hydrolyzes one of the major endocannabinoid, 2 arachidonoylglycerol (2-AG), an endogenous full agonist at G protein coupled cannabinoid receptors CB1 and CB2. Numerous studies showed that MGL inhibitors are potentially useful for the treatment of pain, inflammation, cancer and CNS disorders. These provocative findings suggested that pharmacological inhibition of MAGL function may confer significant therapeutic benefits. In this study, we presented hybrid ligand and structure-based approaches to obtain a novel set of virtual leads as MAGL inhibitors. The constraints used in this study, were Glide score, binding free energy estimates and ADME properties to screen the ZINC database, containing approximately 21 million compounds. A total of seven virtual hits were obtained, which showed significant binding affinity towards MAGL protein. Ligand, ZINC24092691 was employed in complex form with the protein MAGL, for molecular dynamics simulation study, because of its excellent glide score, binding free energy and ADME properties. The RMSD of ZINC24092691 was observed to stay at 0.1 nm (1 A) in most of the trajectories, which further confirmed its ability to inhibit the protein MAGL. The hits were then evaluated for their ability to inhibit human MAGL. The compound ZINC24092691 displayed the noteworthy inhibitory activity reducing MAGL activity to 21.15% at 100 nM concentration, with an IC50 value of 10 nM. PMID- 25011913 TI - Synthesis of sulfonamides with effective inhibitory action against Porphyromonas gingivalis gamma-carbonic anhydrase. AB - New benzenesulfonamides incorporating GABA or N-alpha-acetyl-L-lysine scaffolds as well as guanidine functionalities as water solubilizing moieties were obtained, using 4-aminoethyl/methyl-benzenesulfonamide and metanilamide/sulfanilamide as zinc-binding motives. The new compounds were medium potency inhibitors of the widespread cytosolic human carbonic anhydrase (CA, EC 4.2.1.1) isoforms I and II and more effective inhibitors (KIs low nanomolar range) of the bacterial gamma-CA from the oral pathogen Porphyromonas gingivalis. These sulfonamides may be useful tools for understanding the physiological role of bacterial CAs in pathogenesis of some infectious disease. PMID- 25011914 TI - In vitro induction of apoptosis by isosclerone from marine-derived fungus Aspergillus fumigatus. AB - In the present study, we investigated the apoptotic effects of isosclerone from marine-derived fungi on human breast cancer MCF-7 cells. Treatment with isosclerone exhibited a characteristic feature of apoptosis including significant cytotoxicity and DNA fragmentation in cancer cells. In addition, The apoptosis induction abilities of the isosclerone was studied by analyzing the expression of caspase-3, -8 and -9, Bcl-2 family, NF-kappa-B P50, P65, and IKK proteins. Western blot and RT-PCR analysis have indicated that isosclerone induce cancer cells apoptosis through down-regulated Bcl-2 family and up-regulated caspases, and activating the NF-kappa-B signaling pathway. Our data demonstrate that isosclerone specifically binds to crystal structure of apoptosis regulator BCL-2 and pseudo-activated procaspase-3 proteins through down-regulated Bcl-2 family and up-regulated caspases, and activating the NF-kappa-B signaling pathway. Our proof-of-principle study should have a positive impact on future drug discovery. PMID- 25011915 TI - 2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists. AB - A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode. PMID- 25011916 TI - Clinical and biological determinants of kidney outcomes in a population-based cohort study. AB - BACKGROUND/AIMS: Prospective studies on factors associated with adverse kidney outcomes in European general populations are scant. Also, few studies consider the potential confounding effect of baseline kidney function. METHODS: We used baseline (2003-2006) and 5-year follow-up data of adults from the general population to evaluate the effect of baseline kidney function and proteinuria on the association of clinical, biological (e.g. uric acid, homocysteine, cytokines), and socioeconomic factors with change in kidney function, rapid decline in kidney function, and incidence of chronic kidney disease (CKD). Estimated glomerular filtration rate (eGFR) and urinary albuminuria-to-creatinine ratio (UACR) were collected. Kidney outcomes were modeled using multivariable regressions. RESULTS: A total of 4,441 subjects were included in the analysis. Among participants without CKD at baseline, 11.4% presented rapid decline in eGFR and/or incident CKD. After adjustment for baseline eGFR and log UACR, only age (Odds Ratio; 1.25 [95%CI 1.18-1.33]), diabetes (OR 1.48 [1.03-2.13]), education (OR middle vs. high 1.51 [1.08-2.11]) and log ultrasensitive CRP (OR 1.16 [1.05 1.22]) were associated with rapid decline in eGFR or incident CKD. Baseline log UACR (OR 1.18 [1.06-1.32]) but not eGFR was associated with rapid decline in eGFR and/or incident CKD. CONCLUSION: In addition to age and diabetes, education and CRP levels are associated with adverse kidney outcomes independently of baseline kidney function. PMID- 25011917 TI - Recent advances in trifluoromethylation of organic compounds using Umemoto's reagents. AB - The incorporation of fluorine-containing moieties into organic compounds is of great importance in pharmaceutical, agricultural, and materials science. Within these organofluorides, the trifluoromethyl group is one of the most important motifs. In recent years, the trifluoromethyl group has attracted more and more attention, and many trifluoromethylated compounds have been found to possess special activities. However, until now, only a few methods have been developed to achieve this efficiently using Umemoto's reagents. This review highlights recent developments in the direct introduction of a trifluoromethyl group into organic compounds with Umemoto's reagents. Seven approaches to the trifluoromethylation of organic compounds are summarized: (i) trifluoromethylation of arenes, (ii) trifluoromethylation of alkenes, (iii) trifluoromethylation of terminal alkynes, (iv) deoxygenative trifluoromethylation of benzylic xanthates, (v) trifluoromethylation of ketoesters, (vi) trifluoromethylation of aryl boronic acids and aromatic amines (synthesis of ArCF3) and (vii) trifluoromethylation of biphenyl isocyanide derivatives. PMID- 25011918 TI - Composite titanium dioxide nanomaterials. PMID- 25011919 TI - Hypoxia turns genotypic female medaka fish into phenotypic males. AB - Hypoxia caused by eutrophication is amongst the most pressing global problems in aquatic systems. Notably, more than 400 "dead zones" have been identified worldwide, resulting in large scale collapse of fisheries and major changes in the structure and trophodynamics. Recent studies further discovered that hypoxia can also disrupt sex hormone metabolism and alter the sexual differentiation of fish, resulting in male biased F1 generations and therefore posing a threat to the sustainability of natural populations. However, it is not known whether, and if so how, hypoxia can also change the sex ratio in vertebrates that have sex determining XX/XY chromosomes. Using the Japanese medaka (Oryzias latipes) as a model, we demonstrate, for the first time, that hypoxia can turn genotypic female fish with XX chromosomes into phenotypic males. Over half of the XX females exposed to hypoxia exhibit male secondary sexual characteristics and develop testis instead of ovary. We further revealed that hypoxia can: (a) down-regulate the vasa gene, which controls proliferation of primordial germ cells and gonadal sex differentiation into ovary, and (b) up-regulate the DMY gene which resides at the sex-determining locus of the Y chromosome, and direct testis differentiation. This is the first report that hypoxia can directly act on genes that regulate sex determination and differentiation, thereby turning genotypic females into phenotypic males and leading to a male-dominant F1 population. PMID- 25011920 TI - Experimental evaluation of the contribution of acidic pH and Fe concentration to the structure, function and tolerance to metals (Cu and Zn) exposure in fluvial biofilms. AB - An indoor channel system was colonised with fluvial biofilms to study the chronic effects of high Fe and SO4(2-) concentrations and acidic pH, the water chemistry in the surrounding streams of Aljustrel mining area (Alentejo, Portugal), and their contribution to community (in)tolerance to metal toxicity by short-term experiments with Cu and Zn. Biofilms were subjected to four different treatments during 8 weeks: high Fe and SO4(2-) concentrations (1 mg Fe l(-1)+ 700 mg SO4(2-) l(-1)) and acidic pH, high Fe and SO4(2-) at alkaline pH; lower Fe and SO4(2-) at acidic pH: and lower Fe and SO4(2-) concentrations at alkaline pH as negative control. During chronic exposure, acidic pH affected growth negatively, based on low values of algal biomass and the autotrophic index, high values of the antioxidant enzyme activities and low diversity diatom communities, dominated by acidophilic species (Pinnularia aljustrelica) in acidic treatments, being the effects more marked with high Fe and SO4(2-). Co-tolerance to metals (Cu and Zn) was also shown in biofilms from the acidic treatments, contrasting with the higher sensitivity observed in the alkaline treatments. We can conclude that the Aljustrel mining area acidic environment limits algal growth and exerts a strong selection pressure on the community composition which is in turn, more tolerant to metal exposure. PMID- 25011921 TI - Optimization of NRU assay in primary cultures of Eisenia fetida for metal toxicity assessment. AB - Coelomocytes, immunocompetent cells of lumbricids, have received special attention for ecotoxicological studies due to their sensibility to pollutants. Their in vitro responses are commonly quantified after in vivo exposure to real or spiked soils. Alternatively, quantifications of in vitro responses after in vitro exposure are being studied. Within this framework, the present study aimed at optimizing the neutral red uptake (NRU) assay in primary culture of Eisenia fetida coelomocytes for its application in soil toxicity testing. Optimized assay conditions were: earthworm depuration for 24 h before retrieving coelomocytes by electric extrusion; 2 * 10(5) seeded cells/well (200 ul) for the NRU assay and incubation for 1 h with neutral red dye. Supplementation of the culture medium with serum was not compatible with the NRU assay, but coelomocytes could be maintained with high viability for 3 days in a serum-free medium without replenishment. Thus, primary cultures were used for 24 h in vitro toxicity testing after exposure to different concentrations of Cd, Cu, Ni and Pb (ranging from 0.1 to 100 MUg/ml). Primary cultures were sensitive to metals, the viability declining in a dose-dependent manner. The toxicity rank was, from high to low, Pb > Ni > Cd > Cu. Therefore, it can be concluded that the NRU assay in coelomocytes in primary cultures provides a sensitive and prompt response after in vitro exposure to metals. PMID- 25011922 TI - Breeding near a landfill may influence blood metals (Cd, Pb, Hg, Fe, Zn) and metalloids (Se, As) in white stork (Ciconia ciconia) nestlings. AB - Cadmium, lead, mercury, selenium, iron, zinc and arsenic levels were measured in blood samples from 59 free-ranging white stork nestlings from colonies located in three different environmental conditions in Western Spain. The reference colony was situated in "Llanos de Caceres y Sierra de Fuentes", an Area of Special Interest for Bird Protection. A second colony was located close to (4.9 km) an urban landfill and a third one was close to both an intensive agricultural area and an urban landfill (1.5 km). Blood samples were diluted and elemental analysis was performed using inductively coupled plasma mass spectrometer. In all cases, the essential metals zinc and iron were found at the highest mean concentrations followed by lead > selenium > mercury > arsenic > cadmium. Regarding toxic metals, the highest concentrations were found for lead (ranging from 23.27 to 146.4 ug/L) although in all cases the concentrations were lower than those considered to cause subclinical effects. The metals levels detected in the chick's blood were not related to the previously reported levels in the soil next to the colonies, which may indicate that landfills are the main source of metals in white stork nestlings. The present data showed that metal levels in white stork chicks may be influenced by the use of landfills as feeding areas by the parents. However, more studies on the metal content in the feed of white stork and the influence of the distance to the landfill are necessary to establish the causality of these findings. PMID- 25011923 TI - Sublethal and transgenerational effects of insecticides in developing Trichogramma galloi (Hymenoptera: Trichogrammatidae) : toxicity of insecticides to Trichogramma galloi. AB - This study assessed the transgenerational effects of insecticides in developing Trichogramma galloi (Hymenoptera: Trichogrammatidae). Laboratory bioassays were performed in which five insecticides were sprayed on egg-larval, pre-pupal and pupal stages of the parasitoid. The interaction between insecticides and development stages of the parasitoid was not significant for the rate of F0 emergence. All insecticides significantly reduced the emergence of wasps, with the lowest emergence observed when they were applied to the pupal stage. For the sex ratio, only spinosad applied to the pre-pupal stage and triflumuron applied on the egg-larval and pre-pupal stages did not differ from the controls. Triflumuron applied to pre-pupae did not lead to any difference in the parasitism rate of the treated generation (F0) when compared to the control. There were no significant differences among survival curves for females of F0 when all insecticides were sprayed on the egg-larval stage. Both concentrations of lambda cyhalothrin + thiamethoxam reduced female pre-pupal survival, and all treatments reduced female pupal survival. In addition, we observed a transgenerational effect of the insecticides on emergence and sex ratio of next generation (F1). Lambda-cyhalothrin + thiamethoxam (Min) applied to the pre-pupae and pupae, the maximum rate of the same insecticides applied to the egg-larvae and pre-pupae, and spinosad applied to pre-pupae all significantly reduced the adults emergence of T. galloi F1 generation. Only triflumuron did not alter the F1 sex ratio. These bioassays provide a basis for better understanding the effects of insecticide use on beneficial parasitoids. PMID- 25011924 TI - Exposure to neonicotinoids influences the motor function of adult worker honeybees. AB - Systemic pesticides such as neonicotinoids are commonly used on flowering crops visited by pollinators, and their use has been implicated in the decline of insect pollinator populations in Europe and North America. Several studies show that neonicotinoids affect navigation and learning in bees but few studies have examined whether these substances influence their basic motor function. Here, we investigated how prolonged exposure to sublethal doses of four neonicotinoid pesticides (imidacloprid, thiamethoxam, clothianidin, dinotefuran) and the plant toxin, nicotine, affect basic motor function and postural control in foraging-age worker honeybees. We used doses of 10 nM for each neonicotinoid: field-relevant doses that we determined to be sublethal and willingly consumed by bees. The neonicotinoids were placed in food solutions given to bees for 24 h. After the exposure period, bees were more likely to lose postural control during the motor function assay and fail to right themselves if exposed to imidacloprid, thiamethoxam, clothianidin. Bees exposed to thiamethoxam and nicotine also spent more time grooming. Other behaviours (walking, sitting and flying) were not significantly affected. Expression of changes in motor function after exposure to imidacloprid was dose-dependent and affected all measured behaviours. Our data illustrate that 24 h exposure to sublethal doses of neonicotinoid pesticides has a subtle influence on bee behaviour that is likely to affect normal function in a field setting. PMID- 25011925 TI - Weekday and weekend sedentary time and physical activity in differentially active children. AB - OBJECTIVES: To investigate whether weekday-weekend differences in sedentary time and specific intensities of physical activity exist among children categorised by physical activity levels. DESIGN: Cross-sectional observational study. METHODS: Seven-day accelerometer data were obtained from 810 English children (n=420 girls) aged 10-11 years. Daily average minday(-1) spent in moderate to vigorous physical activity were calculated for each child. Sex-specific moderate to vigorous physical activity quartile cut-off values categorised boys and girls separately into four graded groups representing the least (Q1) through to the most active (Q4) children. Sex- and activity quartile-specific multilevel linear regression analyses analysed differences in sedentary time, light physical activity, moderate physical activity, vigorous physical activity, and moderate to vigorous physical activity between weekdays and weekends. RESULTS: On weekdays Q2 boys spent longer in light physical activity (p<0.05), Q1 (p<0.001), Q2 boys (p<0.01) did significantly more moderate physical activity, and Q1-Q3 boys accumulated significantly more vigorous physical activity and moderate to vigorous physical activity than at weekends. There were no significant differences in weekday and weekend sedentary time or physical activity for Q4 boys. On weekdays Q2 and Q3 girls accumulated more sedentary time (p<0.05), Q1 and Q2 girls did significantly more moderate physical activity (p<0.05), and Q1 Q3 girls engaged in more vigorous physical activity (p<0.05) and more moderate to vigorous physical activity (p<0.01) than at weekends. Q4 girls' sedentary time and physical activity varied little between weekdays and weekends. CONCLUSIONS: The most active children maintained their sedentary time and physical activity levels at weekends, while among less active peers weekend sedentary time and physical activity at all intensities was lower. Low active children may benefit most from weekend intervention strategies. PMID- 25011926 TI - Facile regiospecific synthesis of 2,3-disubstituted indoles from isatins. AB - A facile regiospecific synthesis of 2,3-disubstituted indoles from isatins has been developed. Nucleophilic addition of Grignard reagents to commercially available isatins, followed by reduction with borane, afforded an array of structurally diverse 2,3-disubstituted indoles in moderate to good yields. The method described herein represents a novel and very simple approach to synthesize various 2,3-disubstituted indoles, extremely important structural motifs in the pharmaceutical industry and medicinal chemistry. PMID- 25011928 TI - Hydrocarbonoclastic biofilms based on sewage microorganisms and their application in hydrocarbon removal in liquid wastes. AB - Attempts to establish hydrocarbonoclastic biofilms that could be applied in waste hydrocarbon removal are still very rare. In this work, biofilms containing hydrocarbonoclastic bacteria were successfully established on glass slides by submerging them in oil-free and oil-containing sewage effluent for 1 month. Culture-dependent analysis of hydrocarbonoclastic bacterial communities in the biofilms revealed the occurrence of the genera Pseudomonas, Microvirga, Stenotrophomonas, Mycobacterium, Bosea, and Ancylobacter. Biofilms established in oil-containing effluent contained more hydrocarbonoclastic bacteria than those established in oil-free effluent, and both biofilms had dramatically different bacterial composition. Culture-independent analysis of the bacterial flora revealed a bacterial community structure totally different from that determined by the culture-dependent method. In microcosm experiments, these biofilms, when used as inocula, removed between 20% and 65% crude oil, n-hexadecane, and phenanthrene from the surrounding effluent in 2 weeks, depending on the biofilm type, the hydrocarbon identity, and the culture conditions. More of the hydrocarbons were removed by biofilms established in oil-containing effluent than by those established in oil-free effluent, and by cultures incubated in the light than by those incubated in the dark. Meanwhile, the bacterial numbers and diversities were enhanced in the biofilms that had been previously used in hydrocarbon bioremediation. These novel findings pave a new way for biofilm-based hydrocarbon bioremediation, both in sewage effluent and in other liquid wastes. PMID- 25011927 TI - Up-regulation of hepatic alpha-2-HS-glycoprotein transcription by testosterone via androgen receptor activation. AB - BACKGROUND/AIMS: Fetuin-A (alpha-2-HS-glycoprotein, AHSG), a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone. METHODS: HepG2 cells were treated with testosterone and androgen receptor antagonist flutamide, and were silenced with androgen receptor siRNA. To test the in vivo relevance, male mice were subjected to androgen deprivation therapy (ADT) for 7 weeks. AHSG mRNA levels were determined by quantitative RT-PCR and fetuin-A protein abundance by Western blotting. RESULTS: In HepG2 cells, AHSG mRNA expression and fetuin-A protein abundance were both up-regulated following testosterone treatment. The human alpha- 2-HS-glycoprotein gene harbors putative androgen receptor response elements in the proximal 5 kb promoter sequence relative to TSS. The effect of testosterone on AHSG mRNA levels was abrogated by silencing of the androgen receptor in HepG2 cells. Moreover, treatment of HepG2 cells with the androgen receptor antagonist flutamide in presence of endogenous ligands in the medium significantly down-regulated AHSG mRNA expression and fetuin-A protein abundance. In addition, ADT of male mice was followed by a significant decrease of hepatic Ahsg mRNA expression and fetuin-A protein levels. CONCLUSIONS: Testosterone participates in the regulation of hepatic fetuin-A expression, an effect mediated, at least partially, by androgen receptor activation. PMID- 25011929 TI - Stimulation of a singlet superconductivity in SFS weak links by spin-exchange scattering of cooper pairs. AB - Josephson junctions with a ferromagnetic metal weak link reveal a very strong decrease of the critical current compared to a normal metal weak link. We demonstrate that in the ballistic regime the presence of a small region with a non-collinear magnetization near the center of a ferromagnetic weak link restores the critical current inherent to the normal metal. The above effect can be stimulated by additional electrical bias of the magnetic gate which induces a local electron depletion of ferromagnetic barrier. The underlying physics of the effect is the interference phenomena due to the magnetic scattering of the Cooper pair, which reverses its total momentum in the ferromagnet and thus compensates the phase gain before and after the spin-reversed scattering. In contrast with the widely discussed triplet long ranged proximity effect we elucidate a new singlet long ranged proximity effect. This phenomenon opens a way to easily control the properties of SFS junctions and inversely to manipulate the magnetic moment via the Josephson current. PMID- 25011930 TI - Update on human rabies in a dog- and fox-rabies-free country. AB - Rabies is responsible for 50,000 deaths per year worldwide. Mainland France has been officially freed from rabies in non-flying animals since 2001. METHOD: We wanted to provide an update on the French situation, using published data, and describe possible options since official guidelines are lacking. RESULTS: Post exposure prophylaxis (PEP) (early and careful cleaning and dressing of the wound, vaccination, and in case of high-risk exposure, injection of specific anti-rabies immunoglobulins) is known to be efficient except in rare cases. It is recommended after grade II contact (+specific immunoglobulins in immunodepressed patients), or grade III contact (vaccination+immunoglobulins). DISCUSSION: Mainland France being rabies-free, 3 options may be considered in case of bite by a dog or a cat that cannot be monitored in France: (a) consider the risk of rabies as null, so no PEP should be administrated, whatever the severity of bites; (b) consider there is a weak but lethal risk, so the international recommendations should be applied, using immunoglobulins in some cases; (c) consider that the risk is extremely low but cannot be excluded, and that the patient should be vaccinated to be protected, but without adding immunoglobulins (whether in case of grade II or III bites). CONCLUSION: There are no national guidelines for rabies in France, and so the physician managing the patient is the one who will decide to treat or not. PMID- 25011931 TI - Increasing the provision of mental health care for vulnerable, disaster-affected people in Bangladesh. AB - BACKGROUND: Bangladesh has the highest natural disaster mortality rate in the world, with over half a million people lost to disaster events since 1970. Most of these people have died during floods or cyclones, both of which are likely to become more frequent due to global climate change. To date, the government's post disaster response strategy has focused, increasingly effectively, on the physical needs of survivors, through the provision of shelter, food and medical care. However, the serious and widespread mental health consequences of natural disasters in Bangladesh have not yet received the attention that they deserve. This Debate article proposes a practical model that will facilitate the provision of comprehensive and effective post-disaster mental health services for vulnerable Bangladeshis on a sustainable basis. DISCUSSION: A series of socially determined factors render the women and the poor of Bangladesh particularly vulnerable to dying in natural disasters; and, for those who survive, to suffering from some sort of disaster-related mental health illness. For women, this is largely due to the enforced gender separation, or purdah, that they endure; while for the poor, it is the fact that they are, by definition, only able to afford to live in the most climatically dangerous, and under-served parts of the country. Although the disasters themselves are brought by nature, therefore, social determinants increase the vulnerability of particular groups to mental illness as a result of them. While deeply entrenched, these determinants are at least partially amenable to change through policy and action. SUMMARY: In response to the 2004 Indian Ocean tsunami, the World Health Organisation developed a framework for providing mental health and psychosocial support after major disasters, which, we argue, could be adapted to Bangladeshi post-cyclone and post-flood contexts. The framework is community-based, it includes both medical and non-clinical components, and it could be adapted so that women and the poor are actively sought out and provided for. After training, these services could be run by Bangladesh's pre-existing 50,000-strong Cyclone Preparedness Programme workforce, alongside the country's extensive network of community-based health workers. PMID- 25011933 TI - Estimation of savings of life-years and cost from early detection of cervical cancer: a follow-up study using nationwide databases for the period 2002-2009. AB - BACKGROUND: Few studies consider both the survival and financial benefits of detection of invasive cervical cancer (ICC) at earlier stages. This study estimated the savings in life-years and costs from early diagnosis of cervical cancer using an ex post approach. METHODS: A total of 28,797 patients diagnosed with cervical cancer in the period 2002-2009 were identified from the National Cancer Registry of Taiwan, and linked to the National Mortality Registry until the end of 2011. Life expectancies (LE) for cancer at different stages were estimated using a semi-parametric extrapolation method. The expected years of life lost (EYLL) for cancer were calculated by subtracting the LE of the cancer cohort from that of the age-and sex-matched general population. The mean lifetime costs after diagnosis paid by the single-payer National Health Insurance during (NHI) 2002-2010 were estimated by multiplying average monthly expenditures by the survival probabilities and summing up over lifetime. RESULTS: ICC at stages 1 to 4 had an average EYLL of 6.33 years, 11.64 years, 12.65 years, and 18.61 years, respectively, while the related lifetime costs paid by the NHI were $7,020, $10,133, $11,120, and $10,015 US dollars, respectively; the younger the diagnosis age, the higher the savings with regard to EYLL. The mean lifetime costs of managing cervical cancer were generally lower for the earlier stages compared with stages 3 and 4. CONCLUSIONS: Early detection of ICC saves lives and reduces healthcare costs. These health benefits and monetary savings can be used for cost effectiveness assessments and the promotion of regular proactive screening, especially among older women. PMID- 25011932 TI - Cell migration on planar and three-dimensional matrices: a hydrogel-based perspective. AB - The migration of cells is a complex process that is dependent on the properties of the surrounding environment. In vivo, the extracellular environment is complex with a wide range of physical features, topographies, and protein compositions. There have been a number of approaches to design substrates that can recapitulate the complex architecture in vivo. Two-dimensional (2D) substrates have been widely used to study the effect of material properties on cell migration. However, such substrates do not capture the intricate structure of the extracellular environment. Recent advances in hydrogel assembly and patterning techniques have enabled the design of new three-dimensional (3D) scaffolds and microenvironments. Investigations conducted on these matrices provide growing evidence that several established migratory trends obtained from studies on 2D substrates could be significantly different when conducted in a 3D environment. Since cell migration is closely linked to a wide range of physiological functions, there is a critical need to examine migratory trends on 3D matrices. In this review, our goal is to highlight recent experimental studies on cell migration within engineered 3D hydrogel environments and how they differ from planar substrates. We provide a detailed examination of the changes in cellular characteristics such as morphology, speed, directionality, and protein expression in 3D hydrogel environments. This growing field of research will have a significant impact on tissue engineering, regenerative medicine, and in the design of biomaterials. PMID- 25011934 TI - FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study. AB - OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled. DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included. RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV. CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab. PMID- 25011935 TI - Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. AB - BACKGROUND: Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. METHODS: We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. RESULTS: A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82-212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. CONCLUSIONS: Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy. PMID- 25011936 TI - Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease. AB - OBJECTIVE: Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease. DESIGN: BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6(-/-)) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets. RESULTS: BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6(-/-) compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6(-/-) mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs. CONCLUSIONS: Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy. PMID- 25011937 TI - Targeting tumour necrosis factor receptor 1 assembly reverses Th17-mediated colitis through boosting a Th2 response. AB - OBJECTIVE: The soluble preligand assembly domain (PLAD) of tumour necrosis factor receptor 1 (TNFR1) interferes with receptor trimerisation to block downstream signalling, and mediates Th17 suppression. We explored the therapeutic potential of recombinant PLAD.Fc protein on a spontaneous experimental colitis. DESIGN: A T cell-specific BLIMP-1 knockout mouse model with mixed Th1/Th17 responses, resembling human Crohn's disease (CD) was established, and its colitogenic phenotype was characterised. Mice, 9 weeks old, were treated with PLAD.Fc protein at 5 mg/kg of body weight twice per week for 16 weeks, and presence of colitis was monitored by the appearance of diarrhoea, weight loss, and by histological colonic scoring. Activation status, cytokine profiles, and transcription factors in T cells were further analysed. RESULTS: The colitogenic phenotype in BLIMP-1 knockout mice was alleviated when an interleukin (IL)-23 knockdown transgene was introduced, indicating a therapeutic potential by downregulating IL-23-Th17 axis in these knockout mice. In PLAD.Fc-treated group, the mouse body weight remained stable and only mild disease scores were revealed. The percentage of naive CD4 T cells was increased and that of effector/memory CD4 T cells was decreased after PLAD.Fc-treatment. Moreover, the levels of IFN-gamma, IL-17, IL-21, IL-22, IL 23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-alpha were diminished. Strikingly, Th2-associated cytokines (IL-4, IL-13 and IL-10) in sera, as well as percentages of Th2 cells, were increased in PLAD.Fc-treated mice. However, PLAD.Fc-mediated suppression of effector phenotypes in Th1/Th17 was abrogated after neutralising IL-10. CONCLUSIONS: The Th2 cytokine milieu induced by PLAD.Fc rebalanced T-helper cell subsets and conferred a protection against colitis in BLIMP-1 knockout mice. PMID- 25011938 TI - Phase II multicentered study of low-dose everolimus plus cisplatin and weekly 24 hour infusion of high-dose 5-fluorouracil and leucovorin as first-line treatment for patients with advanced gastric cancer. AB - OBJECTIVE: This phase II trial investigates the efficacy and safety of low-dose everolimus in combination with cisplatin-fluorouracil chemotherapy in patients with advanced gastric cancer. METHODS: Eligible patients with chemotherapy-naive advanced gastric cancer received low-dose everolimus (10 mg p.o. on days 1, 8 and 15) plus cisplatin and a weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL) chemotherapy (cisplatin 35 mg/m(2) intravenous infusion for 24 h on days 1 and 8, 5-fluorouracil 2,000 mg/m(2) and leucovorin 300 mg/m(2) intravenous infusion for 24 h on days 1, 8 and 15) every 28 days. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: Forty patients (19 men; 21 women; median age, 54.1 years; range, 33.7-73.3 years) received a median of 6 (range, 1 30; 95% CI, 4.9-8.0) cycles of study treatment. The ORR was 52.5% (21 confirmed partial response). The median progression-free survival and overall survival were 6.9 (95% CI, 4.9-8.4) and 10.5 (95% CI, 8.6-12.3) months, respectively. Most adverse events were mild. CONCLUSION: Adding low-dose everolimus to cisplatin HDFL chemotherapy failed to increase the ORR as in a preplanned statistical assumption but may prolong progression-free survival in treatment-naive advanced gastric cancer patients. PMID- 25011940 TI - Mapping risk of plague in Qinghai-Tibetan Plateau, China. AB - BACKGROUND: Qinghai-Tibetan Plateau of China is known to be the plague endemic region where marmot (Marmota himalayana) is the primary host. Human plague cases are relatively low incidence but high mortality, which presents unique surveillance and public health challenges, because early detection through surveillance may not always be feasible and infrequent clinical cases may be misdiagnosed. METHODS: Based on plague surveillance data and environmental variables, Maxent was applied to model the presence probability of plague host. 75% occurrence points were randomly selected for training model, and the rest 25% points were used for model test and validation. Maxent model performance was measured as test gain and test AUC. The optimal probability cut-off value was chosen by maximizing training sensitivity and specificity simultaneously. RESULTS: We used field surveillance data in an ecological niche modeling (ENM) framework to depict spatial distribution of natural foci of plague in Qinghai Tibetan Plateau. Most human-inhabited areas at risk of exposure to enzootic plague are distributed in the east and south of the Plateau. Elevation, temperature of land surface and normalized difference vegetation index play a large part in determining the distribution of the enzootic plague. CONCLUSIONS: This study provided a more detailed view of spatial pattern of enzootic plague and human-inhabited areas at risk of plague. The maps could help public health authorities decide where to perform plague surveillance and take preventive measures in Qinghai-Tibetan Plateau. PMID- 25011939 TI - High energy density rechargeable magnesium battery using earth-abundant and non toxic elements. AB - Rechargeable magnesium batteries are poised to be viable candidates for large scale energy storage devices in smart grid communities and electric vehicles. However, the energy density of previously proposed rechargeable magnesium batteries is low, limited mainly by the cathode materials. Here, we present new design approaches for the cathode in order to realize a high-energy-density rechargeable magnesium battery system. Ion-exchanged MgFeSiO4 demonstrates a high reversible capacity exceeding 300 Ah . g(-1) at a voltage of approximately 2.4 V vs. Mg. Further, the electronic and crystal structure of ion-exchanged MgFeSiO4 changes during the charging and discharging processes, which demonstrates the (de)insertion of magnesium in the host structure. The combination of ion exchanged MgFeSiO4 with a magnesium bis(trifluoromethylsulfonyl)imide-triglyme electrolyte system proposed in this work provides a low-cost and practical rechargeable magnesium battery with high energy density, free from corrosion and safety problems. PMID- 25011941 TI - High selectivity towards small copper ions by a preorganized phenanthroline derived tetradentate ligand and new insight into the complexation mechanism. AB - A preorganized tetradentate phenanthroline-derived amide ligand, N,N'-diethyl N,N'-ditolyl-2,9-dicarboxamide-1,10-phenanthroline (Et-Tol-DAPhen), was found to show high selectivity towards small copper ions, which might be due to the change of the coordination mechanism from tetradentate to terdentate mode. PMID- 25011942 TI - A comparison of five malaria transmission models: benchmark tests and implications for disease control. AB - BACKGROUND: Models for malaria transmission are usually compared based on the quantities tracked, the form taken by each term in the equations, and the qualitative properties of the systems at equilibrium. Here five models are compared in detail in order to develop a set of performance measures that further illuminate the differences among models. METHODS: Five models of malaria transmission are compared. Parameters are adjusted to correspond to similar biological quantities across models. Nine choices of parameter sets/initial conditions are tested for all five models. The relationship between malaria incidence in humans and (1) malaria incidence in vectors, (2) man-biting rate, and (3) entomological inoculation rate (EIR) at equilibrium is tested for all models. A sensitivity analysis for all models is conducted at all parameter sets. Overall sensitivities are ranked for each of the five models. A set of simple control interventions is tested on two of the models. RESULTS: Four of these models behave consistently over a set of nine choices of parameters and initial conditions, with one behaving significantly differently. Two of the models do not match reported entomological inoculation rate data well. The sensitivity profiles, although consistently having similar top parameters, vary not only between models but among choices of parameters and initial conditions. A numerical experiment on two of the models illustrates the effect of these differences on control strategies, showing significant differences between models in predicting which of the control measures are more effective. CONCLUSIONS: A set of benchmark tests based on performance measures are developed to be used on any proposed malaria transmission model to test its overall behaviour in comparison to both other models and data sets. PMID- 25011943 TI - Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the "adipose tissue expandability" hypothesis. AB - OBJECTIVE: The presence of large subcutaneous adipocytes in obesity has been proposed to be linked with insulin resistance and type 2 diabetes through the "adipose tissue expandability" hypothesis, which holds that large adipocytes have a limited capacity for expansion, forcing lipids to be stored in nonadipose ectopic depots (skeletal muscle, liver), where they interfere with insulin signaling. This hypothesis has, however, been largely formulated by cross sectional findings and to date has not been prospectively demonstrated in the development of insulin resistance in humans. RESEARCH DESIGN AND METHODS: Twenty nine men (26.8 +/- 5.4 years old; BMI 25.5 +/- 2.3 kg/m(2)) were fed 40% more than their baseline requirement for 8 weeks. Before and after overfeeding, insulin sensitivity was determined using a two-step hyperinsulinemic-euglycemic clamp. Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) were measured by (1)H-MRS and abdominal fat by MRI. Subcutaneous abdominal adipose and skeletal muscle tissues were collected to measure adipocyte size and markers of tissue inflammation. RESULTS: Subjects gained 7.6 +/- 2.1 kg (55% fat) and insulin sensitivity decreased 18% (P < 0.001) after overfeeding. IHL increased 46% from 1.5% to 2.2% (P = 0.002); however, IMCL did not change. There was no association between adipocyte size and ectopic lipid accumulation. Despite similar weight gain, subjects with smaller fat cells at baseline had a greater decrease in insulin sensitivity, which was linked with upregulated skeletal muscle tissue inflammation. CONCLUSIONS: In experimental substantial weight gain, the presence of larger adipocytes did not promote ectopic lipid accumulation. In contrast, smaller fat cells were associated with a worsened metabolic response to overfeeding. PMID- 25011944 TI - Renal hyperfiltration is associated with glucose-dependent changes in fractional excretion of sodium in patients with uncomplicated type 1 diabetes. AB - OBJECTIVE: Renal hyperfiltration is a common abnormality associated with diabetic nephropathy in patients with type 1 diabetes (T1D). In animal models, increased proximal tubular sodium reabsorption results in decreased distal sodium delivery, tubuloglomerular feedback activation, afferent vasodilatation, and hyperfiltration. The role of tubular factors is less well understood in humans. The aim of the current study was therefore to compare the fractional sodium excretion (FENa) in hyperfiltering (T1D-H) versus normofiltering (T1D-N) patients and healthy control (HC) subjects, as well as the role of ambient hyperglycemia on FENa. RESEARCH DESIGN AND METHODS: Blood pressure, renal function (inulin for glomerular filtration rate [GFR], and paraaminohippurate for effective renal plasma flow), FENa, and circulating neurohormones were measured in T1D-H (n = 28, GFR >=135 mL/min/1.73 m(2)), T1D-N (n = 30), and HC (n = 35) subjects during clamped euglycemia. Studies were repeated in a subset of patients during clamped hyperglycemia. RESULTS: During clamped euglycemia, T1D-H exhibited lower FENa than T1D-N and HC subjects (0.64 +/- 0.06% vs. 0.91 +/- 0.12% and 0.90 +/- 0.10%, P < 0.05). During clamped hyperglycemia, FENa increased (Delta + 0.88 +/- 0.22% vs. Delta + 0.02 +/- 0.21%; between-group effect, P = 0.01) significantly in T1D H, whereas FENa did not change in T1D-N. When treated as continuous variables, elevated GFR values were associated with hyperglycemia-induced increases in FENa (R(2) = 0.20, P = 0.007). CONCLUSIONS: Patients with uncomplicated T1D-H exhibit lower FENa under euglycemic conditions, which may help to identify patients with hyperfiltration outside of a controlled laboratory setting. Increased FENa in T1D H but not T1D-N under clamped hyperglycemic conditions suggests that the mechanisms responsible for increased sodium reabsorption leading to hyperfiltration can be saturated. PMID- 25011945 TI - Cultures of diabetic foot ulcers without clinical signs of infection do not predict outcomes. AB - OBJECTIVE: We examined associations between ulcer bioburden and ulcer outcomes in neuropathic diabetic foot ulcers (DFUs) that lacked clinical signs of infection. RESEARCH DESIGN AND METHODS: Three dimensions of bioburden (i.e., microbial load, microbial diversity, and the presence of likely pathogens) were measured at baseline using swab cultures obtained by Levine's technique. Subjects were assessed every 2 weeks for 26 weeks to determine the rate of healing and development of infection-related complications. Foot ulcers were off-loaded using total-contact casts and routinely debrided. To establish associations between bioburden and rate of healing, Cox proportional hazards and least squares regression were used after adjusting for ulcer depth, surface area, and duration. RESULTS: A total of 77 subjects completed the study. Sixty-five (84.4%) had ulcers that healed during follow-up; weeks-to-closure ranged from 2 to 26 (median 4.0). Mean (+/- SD) percent reduction in surface area/week was 25.0% (+/- 23.33). Five (6.5%) of the DFUs developed an infection-related complication. None of the bioburden dimensions (i.e., microbial load, microbial diversity, or presence of likely pathogens) was significantly associated with weeks-to-closure or percent reduction in surface area per week. Weeks-to-closure was best predicted by ulcer duration, depth, and surface area (c-statistic = 0.75). CONCLUSIONS: Culturing DFUs that showed no clinical signs of infection had no predictive value for outcomes of DFUs managed with total-contact casts and routine debridement. These findings support recommendations of the Infectious Disease Society of America that culturing and antibiotics should be avoided in treating DFUs that show no clinical signs of infection. PMID- 25011946 TI - Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. AB - OBJECTIVE: Mealtime insulin is commonly added to manage hyperglycemia in type 2 diabetes when basal insulin is insufficient. However, this complex regimen is associated with weight gain and hypoglycemia. This study compared the efficacy and safety of exenatide twice daily or mealtime insulin lispro in patients inadequately controlled by insulin glargine and metformin despite up-titration. RESEARCH DESIGN AND METHODS: In this 30-week, open-label, multicenter, randomized, noninferiority trial with 12 weeks prior insulin optimization, 627 patients with insufficient postoptimization glycated hemoglobin A1c (HbA1c) were randomized to exenatide (10-20 ug/day) or thrice-daily mealtime lispro titrated to premeal glucose of 5.6-6.0 mmol/L, both added to insulin glargine (mean 61 units/day at randomization) and metformin (mean 2,000 mg/day). RESULTS: Randomization HbA1c and fasting glucose (FG) were 8.3% (67 mmol/mol) and 7.1 mmol/L for exenatide and 8.2% (66 mmol/mol) and 7.1 mmol/L for lispro. At 30 weeks postrandomization, mean HbA1c changes were noninferior for exenatide compared with lispro (-1.13 and -1.10%, respectively); treatment differences were -0.04 (95% CI -0.18, 0.11) in per-protocol (n = 510) and -0.03 (95% CI -0.16, 0.11) in intent-to-treat (n = 627) populations. FG was lower with exenatide than lispro (6.5 vs. 7.2 mmol/L; P = 0.002). Weight decreased with exenatide and increased with lispro (-2.5 vs. +2.1 kg; P < 0.001). More patients reported treatment satisfaction and better quality of life with exenatide than lispro, although a larger proportion of patients with exenatide experienced treatment emergent adverse events. Exenatide resulted in fewer nonnocturnal hypoglycemic episodes but more gastrointestinal adverse events than lispro. CONCLUSIONS: Adding exenatide to titrated glargine with metformin resulted in similar glycemic control as adding lispro and was well tolerated. These findings support exenatide as a noninsulin addition for patients failing basal insulin. PMID- 25011947 TI - Real-time continuous glucose monitoring among participants in the T1D Exchange clinic registry. AB - OBJECTIVE: To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA1c, severe hypoglycemia [SH], and diabetic ketoacidosis [DKA]). RESEARCH DESIGN AND METHODS: Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real time CGM during the prior 30 days. RESULTS: Nine percent of participants used CGM (6% of children <13 years old, 4% of adolescents 13 to <18 years, 6% of young adults 18 to <26 years, and 21% of adults >=26 years). CGM use was more likely with higher education, higher household income, private health insurance, longer duration of diabetes, and use of insulin pump (P < 0.01 all factors). CGM use was associated with lower HbA1c in children (8.3% vs. 8.6%, P < 0.001) and adults (7.7% vs. 7.9%, P < 0.001). In adults, more frequent use of CGM (>=6 days/week) was associated with lower mean HbA1c. Only 27% of users downloaded data from their device at least once per month, and <=15% of users reported downloading their device at least weekly. Among participants who used CGM at baseline, 41% had discontinued within 1 year. CONCLUSIONS: CGM use is uncommon but associated with lower HbA1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use. PMID- 25011948 TI - Diabetes-related distress, insulin dose, and age contribute to insulin-associated weight gain in patients with type 2 diabetes: results of a prospective study. AB - OBJECTIVE: The determinants of insulin-associated weight gain in type 2 diabetes mellitus (T2DM) are partly unknown. Therefore, we conducted a prospective study to identify predictors of insulin-associated weight gain. RESEARCH DESIGN AND METHODS: In patients with T2DM, we assessed physical activity by accelerometry and measured diabetes-related distress by questionnaires before and 6 and 12 months after starting insulin therapy. Glycemic control (HbA1c) and insulin dose were monitored. RESULTS: After 12 months of insulin therapy, mean body weight had increased by 3.0 +/- 2.5 kg (P < 0.001). The drop in HbA1c was correlated with insulin-associated weight gain. With the use of a multiple linear regression model, a cluster of variables was identified that significantly related to weight gain. Diabetes-related distress, initial insulin dose, and the increase of insulin dose during the course of the study as well as age appeared to be important predictors of weight gain after initiation of insulin therapy. Physical activity (measured as MET) decreased from 1.40 +/- 0.04 at baseline to 1.32 +/- 0.04 MET (P < 0.05) but was not significantly related to weight changes. CONCLUSIONS: Diabetes-related distress, initial and titration of insulin dose, and age all significantly predict insulin-associated weight gain. After the initiation of insulin therapy, physical activity decreased significantly, but this did not determine weight gain over the first 12 months. Our study findings may have clinical implications. PMID- 25011949 TI - Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes. AB - OBJECTIVE: Previous studies demonstrated that the anti-CD3 monoclonal antibody otelixizumab, administered at a total dose of 48-64 mg, can slow the loss of C peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients. RESEARCH DESIGN AND METHODS: A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed meal tolerance test at month 12. RESULTS: The change in 2-h C-peptide AUC was not different between placebo-treated patients and otelixizumab-treated patients ( 0.20 vs. -0.22 nmol/L, P = 0.81). Secondary end points, including HbA1c, glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/10(6) peripheral blood mononuclear cells) in the otelixizumab group, in contrast with previously published studies at higher doses of otelixizumab. CONCLUSIONS: Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control. PMID- 25011950 TI - Increased cardiometabolic risk factors and inflammation in adipose tissue in obese subjects classified as metabolically healthy. AB - OBJECTIVE: It has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non-metabolically healthy counterparts. However, the validity of this concept has recently been challenged, since it may not translate into lower morbidity and mortality. The aim of the current study was to compare the cardiometabolic/inflammatory profile and the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in patients categorized as having MHO or metabolically abnormal obesity (MAO). RESEARCH DESIGN AND METHODS: We performed a cross-sectional analysis to compare the cardiometabolic/inflammatory profile of 222 MHO and 222 MAO patients (62% women) matched by age, including 255 lean subjects as reference (cohort 1). In a second cohort, we analyzed the adipokine profile and the expression of genes involved in inflammation and extracellular matrix remodeling in visceral adipose tissue (VAT; n = 82) and liver (n = 55). RESULTS: The cardiometabolic and inflammatory profiles (CRP, fibrinogen, uric acid, leukocyte count, and hepatic enzymes) were similarly increased in MHO and MAO in both cohorts. Moreover, above 30%of patients classified as MHO according to fasting plasma glucose exhibited IGT or T2D [corrected]. The profile of classic (leptin, adiponectin, resistin) as well as novel (serum amyloid A and matrix metallopeptidase 9) adipokines was almost identical in MHO and MAO groups in cohort 2. Expression of genes involved in inflammation and tissue remodeling in VAT and liver showed a similar alteration pattern in MHO and MAO individuals. CONCLUSIONS: The current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals. PMID- 25011951 TI - Glycation of fetal hemoglobin reflects hyperglycemia exposure in utero. AB - OBJECTIVE: The lifetime risk of metabolic diseases in offspring of women with gestational diabetes mellitus (GDM) depends, at least in part, on the impact of glycemic fetal programming. To quantify this impact, we have developed and validated a unique mass spectrometry method to measure the percentage of glycated hemoglobin in cord blood. RESEARCH DESIGN AND METHODS: This case-control study includes 37 GDM women and 30 pregnant women with normal glucose tolerance (NGT). RESULTS: Glycation of the alpha-chain (Glalpha) was higher in neonates from GDM (2.32 vs. 2.20%, P < 0.01). Glalpha strongly correlated with maternal A1C measured at delivery in the overall cohort (r = 0.67, P < 0.0001) as well as in each group (GDM: r = 0.66, P < 0.0001; NGT: r = 0.50, P = 0.01). CONCLUSIONS: Thus, Glalpha may reflect hyperglycemic exposure during the last weeks of fetal development. Future studies will confirm Glalpha is a predictive biomarker of prenatally programmed lifetime metabolic health and disease. PMID- 25011952 TI - Lipid profiling reveals different therapeutic effects of metformin and glipizide in patients with type 2 diabetes and coronary artery disease. AB - OBJECTIVE: We recently demonstrated a beneficial effect of metformin compared with glipizide in type 2 diabetic patients regarding cardiovascular outcomes for 3-year treatment in the SPREAD-DIMCAD study. However, the potential mechanism for the clinical effects remains unclear. Here, we performed a comprehensive lipidomics study to evaluate the different lipid metabolites in serum samples obtained from participants in this study. RESEARCH DESIGN AND METHODS: Liquid chromatography-quadrupole time of flight-mass spectrometry was used to evaluate the different lipid metabolites in serum samples obtained from the participants (21 patients in glipizide group and 23 patients in metformin group) before and after each year of treatment (at 0 [baseline], 1, 2, and 3 years of study drug administration). RESULTS: A total of 118 serum lipid molecular species was identified and quantified. During treatment, metformin induced a substantially greater change in serum lipid species compared with glipizide, especially at the 2- and 3-year time points (with 2, 11, and 12 lipid species being significantly different between the groups after each year of treatment [1, 2, or 3 years], P < 0.05). Among the significantly changed lipid species, three lipid metabolites were linked to long-term composite cardiovascular events (adjusted P < 0.05). After treatment, triacylglycerols (TAGs) of a relatively higher carbon number showed a clearly increased trend in metformin group compared with the glipizide group, whereas the changes in TAGs with different double bonds were minimal. CONCLUSIONS: Our findings revealed the differential therapeutic effects of metformin and glipizide on comprehensive lipidomics, which were comparable with their different long-term effects on cardiovascular outcomes. PMID- 25011953 TI - Clinical features and pharmacotherapy of childhood monoamine neurotransmitter disorders. AB - Childhood neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the monoamine neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, neurotransmitter disorders are frequently misdiagnosed. The diagnosis of neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for monoamine neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase monoamine substrate availability, boost enzyme co factor levels, reduce monoamine breakdown, and replace depleted levels of monoamines with pharmacological analogs as clinically indicated. Most monoamine neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa's syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood monoamine neurotransmitter disorders. PMID- 25011954 TI - Chromosome-breakage genomic instability and chromothripsis in breast cancer. AB - BACKGROUND: Chromosomal breakage followed by faulty DNA repair leads to gene amplifications and deletions in cancers. However, the mere assessment of the extent of genomic changes, amplifications and deletions may reduce the complexity of genomic data observed by array comparative genomic hybridization (array CGH). We present here a novel approach to array CGH data analysis, which focuses on putative breakpoints responsible for rearrangements within the genome. RESULTS: We performed array comparative genomic hybridization in 29 primary tumors from high risk patients with breast cancer. The specimens were flow sorted according to ploidy to increase tumor cell purity prior to array CGH. We describe the number of chromosomal breaks as well as the patterns of breaks on individual chromosomes in each tumor. There were differences in chromosomal breakage patterns between the 3 clinical subtypes of breast cancers, although the highest density of breaks occurred at chromosome 17 in all subtypes, suggesting a particular proclivity of this chromosome for breaks. We also observed chromothripsis affecting various chromosomes in 41% of high risk breast cancers. CONCLUSIONS: Our results provide a new insight into the genomic complexity of breast cancer. Genomic instability dependent on chromosomal breakage events is not stochastic, targeting some chromosomes clearly more than others. We report a much higher percentage of chromothripsis than described previously in other cancers and this suggests that massive genomic rearrangements occurring in a single catastrophic event may shape many breast cancer genomes. PMID- 25011955 TI - Suicidal ideation, depression and quality of life in the elderly: study in a gerontopsychiatric consultation. AB - The global increase in elderly population all over the world, especially in Portugal, justifies the importance of mental health study in this age group. The aim of this study was to characterize the elderly patients in Gerontopsychiatry Consultation of Centro Hospitalar Sao Joao in Porto, related to socio-demographic aspects, physical and global disabilities, depression, suicidal ideation and quality of life, and to explore the association between suicidal ideation, depression, and quality of life and global and functional disability. In this cross-sectional study, 155 patients were recruited consecutively, with a final sample of 75 subjects (59 women and 16 men) without cognitive deficits and a mean age of 72.8 (SD = 6.04). Concerning the depression level measured with the Geriatric Depression Scale (Barreto et al., 2008) it was found that 66.7% presented severe depression and suicidal ideation (M = 41.96, SD = 36.38), a value considered with a potential risk of suicide using the Suicidal Ideation Questionnaire (Ferreira & Castela, 1999). The elderly also perceived their quality of life as low, revealing global disability assessed with the EasyCare- Elderly Assessment (Sousa & Figueiredo, 2000a). A significant positive correlation was also found between depression and suicidal ideation (rs =.71, p < .001), as well as quality of life (rs = .50, p < .001), and suicidal ideation with quality of life (rs = .40, p < .001). The data obtained in this study corroborate the results found in other studies. PMID- 25011956 TI - Grammatical Comprehension in Spanish-speaking children with Specific Language Impairment (SLI). AB - The Grammatical Structures Comprehension Test (CEG) was used to analyze grammatical comprehension problems in native Spanish-speaking children with Specific Language Impairment (SLI). The test is divided into 20 blocks containing the most common grammatical structures in Spanish. Our objective was to establish whether the CEG was sensitive in detecting these problems and whether there were differential patterns in grammatical comprehension between children with SLI (14 participants) and two control groups: a chronological control group (CC) with 14 participants and a linguistic control group (LC) also with 14 participants. We found significant differences between the SLI group and the chronological control participants (Box's M = 63.080, F = 1, 159, p = .238), with a correct classification rate of 85.7 % in the discriminant function analysis. These differences did not occur in all the blocks, in which we identified a range of different performance patterns that varied according to the structures being analyzed. This work helps to clarify certain questions about grammatical comprehension in children with SLI and contributes to the debate on delay vs. "delay within the delay". PMID- 25011957 TI - Magnetic resonance standard for cavernous sinus hemangiomas: proposal for a diagnostic test. AB - BACKGROUND: By definition, a cavernous sinus is a vascular plexus. A hemangioma is a vascular tumor which is rich in vascular plexus and caused by vascular deformity or tumor-like proliferation. Radiosurgery can effectively control the growth of smaller cavernous sinus hemangiomas (CSHs). This paper aimed to quantify the MRI characteristics of CSHs which provided a basis for further treatment. METHODS: A retrospective analysis was conducted of the MRI characteristics of 133 cavernous sinus lesion patients between January 2006 and December 2009, and none of them was diagnosed without histology. Two groups were set apart according to the pathological results: a CSH group (24 patients) and a non-CSH group (109 patients). The latter was further divided into 3 categories: a meningioma group (33 patients), a neurilemmoma group (37 patients) and a miscellaneous group (39 patients). A single-factor chi(2) analysis was performed to analyze the data on the 12 MRI characteristics. RESULTS: T2-weighted ultrahigh signal, signal uniformity, dumbbell-like appearance and infiltration of the sellar region were considered statistically significant for the differentiation of CSHs from non-CSHs. If these 4 items served as the diagnostic criteria, the sensitivity, specificity and accuracy was 87.5, 96.3 and 94.7%, respectively. CONCLUSION: Smaller CSHs can be treated by radiosurgery directly, without performance of a pathological biopsy. PMID- 25011958 TI - Neighborhoods and adolescent health-risk behavior: an ecological network approach. AB - This study integrates insights from social network analysis, activity space perspectives, and theories of urban and spatial processes to present an novel approach to neighborhood effects on health-risk behavior among youth. We suggest spatial patterns of neighborhood residents' non-home routines may be conceptualized as ecological, or "eco"-networks, which are two-mode networks that indirectly link residents through socio-spatial overlap in routine activities. We further argue structural configurations of eco-networks are consequential for youth's behavioral health. In this study we focus on a key structural feature of eco-networks--the neighborhood-level extent to which household dyads share two or more activity locations, or eco-network reinforcement--and its association with two dimensions of health-risk behavior, substance use and delinquency/sexual activity. Using geographic data on non-home routine activity locations among respondents from the Los Angeles Family and Neighborhood Survey (L.A.FANS), we constructed neighborhood-specific eco-networks by connecting sampled households to "activity clusters," which are sets of spatially-proximate activity locations. We then measured eco-network reinforcement and examined its association with dimensions of adolescent health risk behavior employing a sample of 830 youth ages 12-17 nested in 65 census tracts. We also examined whether neighborhood level social processes (collective efficacy and intergenerational closure) mediate the association between eco-network reinforcement and the outcomes considered. Results indicated eco-network reinforcement exhibits robust negative associations with both substance use and delinquency/sexual activity scales. Eco network reinforcement effects were not explained by potential mediating variables. In addition to introducing a novel theoretical and empirical approach to neighborhood effects on youth, our findings highlight the importance of intersecting conventional routines for adolescent behavioral health. PMID- 25011959 TI - [Detailed docking of "phospholipid" biological metabolizing pathway]. AB - OBJECTIVE: To construct protein functional network according to the physiological process in vivo and functionally based distinct families, to understand biological functions, and to make wise decisions. METHODS: We described here a very effective strategy combining with multiple-docking and protein-ligand binding-affinity fingerprint method to generate bio-functional network and pathway and reveal the protein "unknown" functions and their relationship. RESULTS: Totally 27 sets of proteins and 28 bio-active molecules were used to reconstruct the possible phospholipids metabolic network by computational simulation strategy. The protein-ligand network reconstruction and pathway based drug design showed that the direct interaction investigation might be effective in complex biological system study. CONCLUSION: Even for weak and moderate interactions in the real biology system, the relationship between each other can be achieved by fingerprint analysis based on multiple-docking data. The results of these calculations give valuable insight into the pathway and the function relationship among these proteins. This method can be a very useful tool for protein classification, target selection, and inhibitor design. PMID- 25011960 TI - [hMSH2 aberrant expression in patients with sporadic colorectal cancer in Xinjiang]. AB - OBJECTIVE: To explore the significance of hMSH2 aberrant expression in patients with sporadic colorectal cancer in Xinjiang Uygur Autonomous Region. METHODS: Clinicopathological parameters and postoperative samples of 327 patients with sporadic colorectal cancer were collected in Xinjiang Uygur Autonomous Region. Immunohistochemistry PV-9000 two-step method was performed to measure hMSH2 expression in the postoperative pathologic specimens. Prognostic value of hMSH2 expression was evaluated. RESULTS: Thirty-five (10.7%) patients showed aberrant nuclear staining of hMSH2 expression. The patients with aberrant expression of hMSH2 showed better prognosis than the normal expression group, with significant difference (P<0.05). CONCLUSION: In Xinjiang, aberrant hMSH2 expression can be regarded as an independent prognostic factor in patients with sporadic colorectal cancer. PMID- 25011961 TI - [Plasma amino acid profiling of "same symptom for different disease" in Uyghur medicine based on high-performance liquid chromatography]. AB - OBJECTIVE: To determine the plasma amino acid metabolism of "same symptom for different diseases" in different cancer patients in Uyghur medicine. METHODS: Plasma amino acid concentration was tested by high-performance liquid chromatography (HPLC) in cancer patients with different symptom, and the spectral profiles were subjected to a t-test for statistical significance. RESULTS: Compared with the healthy group, lung cancer, cervical cancer, breast cancer and gastric cancer patients with abnormal Savda had lower concentration of plasma amino acids except some amino acids. Lung cancer patients with abnormal Savda had higher concentration of plasma phenylalanine, serine, cystine, valine, isoleucine, leucine and aspartic acid than Unsavda patients (P<0.05). Cervical cancer patients with abnormal Savda had low concentration of plasma arginine, but higher concentration of plasma cystine than Unsavda patients (P<0.05). Breast cancer patients with abnormal Savda had higher concentration of plasma leucine, serine, taurine, cystine, tyrosine, valine, isoleucine and asparagine than Unsavda patients (P<0.05). Gastric cancer patients with abnormal Savda had high concentration of plasma cystine but lower concentration of plasma phenylalanine, threonine and arginine than Unsavda patients (P<0.05). CONCLUSION: Different tumor patients with abnormal Savda have common characteristics and significant differences. PMID- 25011962 TI - [Diabetic cardiomyopathy in medical examination patients with impaired glucose tolerance and Type 2 diabetes]. AB - OBJECTIVE: To investigate the change of diabetic cardiomyopathy in patients with impaired glucose tolerance (IGT) and Type 2 diabetes (T2DM) and its influencing factors. METHODS: Patients with IGT and T2DM were divided into an IGT group (n=314), a T2DM group (n=368) and an NC group (400 normal subjects). The left ventricular ejection fractions (LVEF) and the interventricular septal depth (IVSd) were measured by Doppler echocardiography. The general information and blood biochemistry were also collected during the corresponding time period. RESULTS: Compared with the NC group, waist circumference (WC), bodymass index (BMI), premature family history of cardiovascular disease, the serum levels of fasting plasma glucose (FPG), HbA1c, TC, TG, hyperlipidemia, BUN and Cr significantly increased (P<0.01) in the IGT and T2DM groups. Compared with the NC group and the IGT group, the LVEF significantly decreased (P<0.01) and the IVSd significantly increased (P<0.01) in the T2DM group. The LVEF and IVSd did not have obvious difference between the NC group and the IGT group. Pearson correlation analysis showed a negative correlation between LVEF and HbA1c, TC and duration of disease (P<0.01); but a positive correlation between IVSd and WC, BMI, HbA1c and duration of disease, and a negative correlation between IVSd and HDL (P<0.05). In the multiple linear stepwise regression, HbA1c and duration of disease showed a significant association with both LVEF and IVSd (P<0.05). CONCLUSION: T2DM has a close association with cardiomyopathy. HbA1c and duration of disease are the independent predictors for LVEF and IVSd. PMID- 25011963 TI - [Measurement of Rho-kinase and CD4+CD25+ regulatory T cells in the peripheral blood in asthmatic patients]. AB - OBJECTIVE: To determine the levels of Rho-kinase and CD4+CD25+ regulatory T cells in patients with asthma, and the relationship between Rho-kinase and CD4+CD25+ regulatory T cells. METHODS: We included 16 patients with moderate to severe asthma in the research group and 14 healthy people as the control group. The levels of Rho-kinase in the 2 groups were measured by ELISA. The level of CD4+CD25+ regulatory T cells in the 2 groups was measured by flow cytometry. The pulmonary function was measured by spirometer. RESULTS: The level of Rho-kinase in the research group was higher than that in the healthy controls (P<0.05). The level of CD4+CD25+ regulatory T cells in the healthy controls was higher than that of the research group (P<0.05). There was no correlation between the level of Rho-kinase in the peripheral blood of the 2 groups and forced expiratiory volume at the first second/ forced vital capacity (FEV1%) (r=-0.491, P>0.05). The level of CD4+CD25+ regulatory T cells in the peripheral blood of the 2 groups showed a positive correlation with FEV1% (r=0.380, P=0.038). There was no correlation between the level of Rho-kinase and the level of CD4+CD25+ regulatory T cells in the peripheral blood of the 2 groups (r=-0.438, P>0.05). CONCLUSION: Rho-kinase and CD4+CD25+ regulatory T cells may play a key role in the pathogenesis of asthma. PMID- 25011964 TI - [Potential detrimental effect of soy isoflavones on testis sertoli cells]. AB - OBJECTIVE: To determine the effect of soy isoflavones on cell proliferation and the transcription levels of follicle-stimulating hormone receptor (FSHR), inhibin alpha (INHalpha), INHbetaB, androgen binding protein (ABP), transferrin (Tf) and vimentin in testis sertoli cells in SD rats. METHODS: Sertoli cells were cultured in vitro, exposed to daidzein at 0.03, 0.3, 3, and 30 MUmol/L and genistein at 0.05, 0.5, 5 and 50 MUmol/L, respectively. MTT was used to detect the proliferation of sertoli cells. Real-time PCR was used to detect the relative mRNA expressions of FSHR, INHalpha, INHbetaB, ABP, Tf and vimentin. RESULTS: Compared with control groups, cell proliferation and the relative mRNA expression levels of INHbetaB and ABP in the treated cells showed no significant alternation. The INHalpha mRNA expression levels were increased in 0.3 and 3 MUmol/L Dai and 0.05 MUmol/L Gen, while the mRNA expression levels of FSHR were downregulated in 30 MUmol/L Dai and Gen at all concentrations. Tf mRNA expression levels were downregulated in 30 MUmol/L Dai and 5 MUmol/L and 50 MUmol/L Gen, and the mRNA expression levels of vimentin were downregulated in 3 and 30 MUmol/L Dai and 50 MUmol/L Gen. CONCLUSION: Soy Isoflavones may have potential detrimental effect on the male reproductive system, as they may impact the function of sertoli cells by downregulating the transcription levels of some important proteins. PMID- 25011965 TI - [Detecting chromosomal aberrations in myelodysplastic syndrome with fluorescence in situ hybridization and conventional cytogenetic analysis]. AB - OBJECTIVE: To detect chromosomal abnormalities in myelodysplastic syndrome (MDS) patients by fluorescence in situ hybridization (FISH) and conventional cytogenetic analysis (CCA). METHODS: FISH and CCA were performed in 100 patients who were diagnosed with MDS by conventional detection of bone marrow smear and bone marrow biopsy, and were followed up. RESULTS: Forty-eight (48%) patients showed chromosomal abnormalities. The positive rate of -5/5q-, 20q-, +8, -7/7q-, and -Y was 16%, 15%, 12%, 11%, and 5%, respectively, and that of CCA was 11%. The positive rate of molecular genetics abnormalities detected by FISH was obviously higher than that of CCA (P<0.01) and the combination of FISH and CCA increased the detection rate to 49%. The follow-up showed that the prognosis of patients with normal FISH results was significantly better than the abnormal ones. A correlation between complex karyotypes and poor prognosis was observed. Abnormality of -7/7q- was found closely correlated with the higher risk of acute leukemia and death. CONCLUSION: Chromosomal abnormalities have been found in 49 MDS patients. Common chromosomal abnormalities in MDS patients include -5/5q-, 20q-, +8 and -7/7q-. FISH combined with CCA can improve the detection rate of chromosomal aberrations in MDS. FISH is more sensitive than CCA for detection and can be used as an important basis for prognostic assessment for MDS. PMID- 25011966 TI - [Multi-slice CT angiography in the diagnosis of lesions of mesenteric artery and mesenteric vein]. AB - OBJECTIVE: To evaluate the value of multi-slice CT angiography (MSCTA) in the diagnosis of super mesenteric artery (SMA) and super mesenteric vein (SMV), and discuss the 3D reconstruction method for detecting mesenteric vessel lesions. METHODS: Thirty-three patients suffering from mesenteric vessel diseases were analyzed. There were 14 SMA lesions, including 9 thromboses, 3 dissecting aneurysms, 1 pseudoaneurysm, and 1 malrotation. There were 19 SMV thromboses. The 3D reconstruction included volume rendering (VR), maximum intensity projection (MIP), and multi-planner reformation (MPR). RESULTS: The lesions appeared clear by MSCTA in the 33 patients. The SMA thrombosis was shown clear in the MIP in all 9 patients, and only 4 of them were detected in the VR. There was significant difference between MIP andVR in detecting SMA thrombosis (P=0.0294). Three dissecting aneurysms were best shown in the MPR; 1 pseudoaneurysm and 1 malrotation were clearly manifested in the VR. The thrombosis of SMV was clearly shown by both MIP and MPR in all 19 patients. Collateral vessels were clearly shown in the MIP in 12 patients; the collateral vessels were detected by VR only in 5, and the other 7 failed to show the collateral vessels. There was significant difference between the MIP and the VR in showing lateral collateral vessels (P=0.0046). CONCLUSION: Both lesions of SMA and SMV can be detected by MSCTA. MIP is an ideal reconstruction method for SMA thrombosis and collateral vessels around the SMV. PMID- 25011967 TI - [Fetal pulmonary venous Doppler flow patterns in hypoplastic left heart syndrome]. AB - OBJECTIVE: To discuss the value of fetal pulmonary venous Doppler flow patterns in hypoplastic left heart syndrome (HLHS). METHODS: Forty-six HLHS and 180 normal singleton fetuses at 24+0 to 37+6 weeks of gestation were enrolled in this study. The blood flow of pulmonary vein (PV) was detected by color Doppler ultrasound. The systolic wave of ventricle (S-wave), diastolic wave of ventricle (D-wave), atrial contraction wave (A-wave) and S/D ratio of PV were measured. The statistical difference in the above parameters between HLHS and normal fetuses was compared. The diagnosis was also confirmed by autopsy in still birth or postnatal follow-up when the baby was alive. RESULTS: The PV blood flow in HLHS fetuses had a high possibility of reversed A wave, and the velocity of S wave and S/D ratio were higher than the matched normal controls (P<0.001). There were 3 types of PV blood flow patterns among all fetuses with HLHS. Both the cases with right to left shunt through foramen ovale (FO) and the cases with restricted left to right shunt at FO showed the triphasic patterns of PV with antegrade S wave, D wave and retrograde A wave. However, the latter had a higher velocity of retrograde A wave (P<0.001), lower D wave (P<0.001), and obviously elevated S wave and S/D ratio (P<0.001). The cases with intact interatrial septum showed short and apparent pulsatile back and forth blood flow in the PV, which displayed as absence of D wave. CONCLUSION: The 3 types of PV blood flow patterns in the fetuses with HLHS reflect the severity of hypertension in the left atrium, which is extremely vital for the prognosis and the perinatal treatment plan. PMID- 25011968 TI - [Meta-analysis of total thyroidectomy for multinodular goiter]. AB - OBJECTIVE: To systematically evaluate the efficiency and safety of total thyroidetomy (including near-total tyhroidectomy) versus subtotal thyroidectomy for multinodular goiter. METHODS: The literatures were searched from Cochrane Library, PubMed, Embase, Chinese Biological Medical Datebase, Chinese National Knowledge Infrastructure, and Chinese Science and Technology Journal Full-text Database as of November 2013. We included all randomizad controlled trials on total (including near-total) versus subtotal thyroidectomy in the treatment of multinodular goiter. The collecting of data and quality assessment were respectively completed by 2 researchers. RevMan5.1 software was used for Meta analysis. RESULTS: We collected 7 literatures conforming to the standard, incuding 2 192 patients. The Metaanalysis outcomes showed that total thyroidectomy was associated with lower nodule recurrence rate (OR=0.13, 95% CI: 0.07-0.22, P<0.001) and higher in transient hypoparathyroidism rate (OR=2.33, 95% CI: 1.72-3.17, P<0.001). However, no statistical difference was seen comparing total and subtotal thyroidectomy in permanent recurrent laryngeal nerve paralysis rate (OR= 0.81, 95% CI: 0.24-2.74, P=0.74) and permanent hypoparathyroidism rate (OR=2.94, 95% CI: 0.48- 18.11, P=0.24). CONCLUSION: Nodule recurrence rate of total thyroidectomy for multinodular goiter is lower than subtotal thyroidectomy and does not increase permanent complications. PMID- 25011969 TI - [Surgical correction of post-traumatic thoracolumbar kyphotic deformity with posterior transpedicular limited osteotomy technique]. AB - OBJECTIVE: To evaluate the clinical outcome of surgical management for post traumatic thoracolumbar kyphotic deformity with single-stage posterior transpedicularlimited osteotomies. METHODS: From March 2007 to May 2010, 17 patients with post-traumatic thoracolumbar kyphotic deformity treated with posterior limited transpedicular osteotomy were admitted. The preoperative Cobb angle was 41 degrees -62 degrees (52.5 degrees +/-6.4 degrees ). Sagittal balance was evaluated by the standing lateral films measuring the C7 plumb line distance (C7 PLD) from the posterior superior corner of S1. The C7 PLD was 18-58 (41.2 +/-12.4) mm in the sagittal plane. The preoperative oswestry disability index (ODI) was 42-50 (45.7 +/-2.7), and the average preoperative visual analogue scale (VAS) was 8-10 (8.8 +/-0.7). The American Spinal Injury Association (ASIA) impairment scale was used to assess the neurological deficits, and grade C in 1 patient, grade D in 7 and grade E in 9 patients. The operation time, blood loss, complications, post-operative Cobb angle, ODI and VAS score at the follow-up were collected and analyzed. RESULTS: The average duration of postoperative follow-up was 24-53 (34.5 +/-7.1) months. The operation time was 180-400 (287.1 +/-65.9) min, with an blood loss of 350-1 300 (838.2 +/-276.4) mL. The postoperative kyphotic angle was 3 degrees -12 degrees (6.1 degrees +/-3.0 degrees ), and it was 7.5 degrees +/-2.6 degrees at the final follow-up evaluation. The postoperative C7PLD was (3.6 +/-3.9) mm and it was (3.4 +/-2.3) mm at the final follow-up evaluation. Postoperatively, the ASIA impairment scale was grade D in 4 and grade E in 13 patients. At the final follow-up ODI and VAS were reduced to an average of 5.2 +/-2.4 and 2.4 +/-1.0, respectively. Cerebrospinal fluid leakage was found in 2 patients, deep wound infection in 1, and intercostal neuralgia in 2. All the complications were relieved after conservative medical therapy. One patient received additional surgery at postoperative 12 weeks due to breakage of posterior implants. Another screw pullout case was treated with reinsertion of larger screws at postoperative 4 months. Solid fusion was confirmed by plain film and CT scan in all patients within 1 year after the surgery. CONCLUSION: Single staged posterior transpedicular limited osteotomies is safe and effective to correct post-traumatic thoracolumbar kyphotic deformity. PMID- 25011970 TI - [Association between interleukin-18 and Global Registry of Acute Coronary Events score in patients with acute coronary syndrome]. AB - OBJECTIVE: To determine the correlation between interleukin-18 (IL-18) level and Global Registry of Acute Coronary Events (GRACE) risk score as well as risk stratification in patients with acute coronary syndrome (ACS), and to determine the clinical prognostic value of IL-18 for major adverse cardiac events (MACE) in ACS patients. METHODS: A total of 150 ACS patients were subjected to risk assessment and stratification with GRACE risk score. All ACS patients received conventional treatments and MACE was recorded. Plasma IL-18 was measured by enzyme-linked immunosorbent assay and the relationship between plasma IL-18 level and GRACE scores in ACS patients was analyzed. Predictive accuracy of IL-18 level and GRACE risk score for MACE were determined by receiver operating characteristic curve and the corresponding area under the curve. RESULTS: According to GRACE risk stratification, IL-18 level was significantly elevated in the high risk group (>140) compared with that in the middle risk group (109-140; P<0. 05), while IL-18 level was significantly elevated in the middle risk group compared with that in the low risk group (<=108; P<0. 05). According to the IL-18 level, patients were stratified into 4 groups by quartile (from the lowest to the highest, Q1-Q4). Compared with Q1-Q3 groups, the GRACE risk score and percentage of high risk patients were the highest in the Q4 group (P<0.05). Receiver operating characteristic curve analysis showed that IL-18 level was positively related with GRACE risk score and that the area under the curve of IL-18 level and GRACE risk score for predicting MACE in hospital patients were 0.887 and 0.914, respectively. CONCLUSION: Both IL-18 level and GRACE risk score are valuable parameters for risk of MACE in patients with ACS. IL-18 may be an important biomarker in the prognosis of ACS patients. PMID- 25011971 TI - [Cross-sectional study on high-normal blood pressure and chronic kidney disease in occupational physical examination population in Changsha]. AB - OBJECTIVE: To investigate the relationship between high-normal blood pressure and chronic kidney disease (CKD) in occupational physical examination population in Changsha. METHODS: With a convenient sampling method, a cross-sectional survey of representative sample of 11 274 white collar workers was conducted in Changsha between March 2011 and May 2011 in a large comprehensive hospital. All subjects were assigned into 4 groups: a normal blood pressure group, a high-normal blood pressure group, an undiagnosed hypertension group, and a diagnosed hypertension group. Anthropometry, blood pressure, blood sample and urine sample were measured with standard instruments and methodology for all the subjects. Multiple logistic regression analysis was used to identify risk factors for CKD. RESULTS: The prevalence of CKD in the normal blood pressure, high-normal blood pressure, undiagnosed hypertension, and diagnosed hypertension were 3.31%, 6.60%, 11.78%, and 17.35%, respectively. The prevalence of CKD in males was significantly higher than that in females (P<0.01). For males with high-normal blood pressure, the CKD risk was significantly greater (OR, 1.30; 95% CI:1.03 - 1.63) than those with optimal blood pressure. The logistic regression analysis showed that there was an additive effect of hyperuricemia on CKD risk in men with high-normal blood pressure compared with men with optimal blood pressure (OR, 2.25; 95% CI, 1.59 - 3.19; P<0.05). CONCLUSION: The prevalence of CKD in people with the high-normal blood pressure is 6.60% in occupational physical examination population in Changsha. CKD is a high risk for men with highnormal blood pressure and hyperuricemia is an independent risk factor. PMID- 25011973 TI - [Effect of standardized PICC training and management on the clinical effect and complication of catheterization]. AB - OBJECTIVE: To determine the clinical effect of standardized training and management of peripherally inserted central catheter (PICC) and catheter-related complications. METHODS: A total of 610 patients were divided into a control group and an observation group, the control group (n=300) were catheterized by trainees who received "short-term intensive training", the observation group (n=310) by "system standardized training and management". The clinical efficacy of catheterization and the rate of catheter-related complications were compared. RESULTS: There was significant difference in the one-time puncture success rate, one-time cannulation success rate, the time for operation and the pain score between the 2 groups (all P<0.01), and there was also significant difference in the occurrence of catheter extrusion, plug, arrhythmia, catheter-related thrombosis, phlebitis, puncture point effusion and catheter-related infection between the 2 groups (all P<0.05). CONCLUSION: Standardized PICC training and management can improve the effect of catheterization and reduce the incidence of PICC-related complication. PMID- 25011972 TI - [Effect of curcumin on the expression of p-STAT3 and IkappaB in db/db mice]. AB - OBJECTIVE: To determine the effect of curcumin on diabetic nephropathy in db/db mice and its possible mechanism. METHODS: Ten female db/db mice were randomly divided into 2 groups: one was treated with curcumin at 200 mg/(kg.d) and the other was a placebo group. Five age-matched db/m mice were grouped as the controls. In the curcumin group, curcumin was administered to db/db mice for 18 weeks. At the end of the experiment, the blood glucose and albumin were measured, and the kidney tissue sections were stained with PAS to observe the pathological changes. The expression of collagen IV and FN in the kidney was detected by immunohitochemistry staining. Western blot was used to detect the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and IkappaB in the kidney. RESULTS: Compared with db/m mice, the weight and blood glucose of db/db mice were markedly increased, accompanied with heavy proteinuria, glomerulus hypertrophy, mesangial area expansion, thickening of basement membrane and ECM deposition. The phosphorylation of STAT3 was upregulated and the degradation of IkappaB was increased. Compared with the db/db mice, curcumin significantly decreased the urinary albumin, inhibited the phosphorylation of STAT3 and the degradation of IkappaB, and reduced the expression of collagen IV and FN in the kidney. CONCLUSION: Curcumin can obviously decrease albuminuria and attenuate glomerular sclerosis in diabetic db/db mice by inhibiting phosphorylation of STAT3 and degradation of IkappaB. PMID- 25011974 TI - [Bladder interstitial cells and pathophysiology]. AB - Bladder interstitial cell (IC) is a cell, which lacks thick filaments and dense bodies but with incomplete basement membrane, rough endoplasmic reticulum and golgi apparatus. IC is divided into 4 subtypes: lamina propria IC, intramuscular IC, IC between the detrusor bundles and perivascular IC. There are different ion currents and related activation pathways in the lamina propria IC and intramuscular IC. Ca2+ signaling pathways play an important role in the communication between IC and detrusor. Any bladder lesions affecting the ion current and Ca2+ signaling pathways can lead to bladder dysfunction. The bladder lesions include bladder outlet obstruction, bladder pain syndrome, interstitial cystitis, neurogenic bladder and diabetes. Imatinib mesylate is currently an available treatment target in IC, and electrical stimulation of acupuncture therapy is a new direction. PMID- 25011976 TI - A kinetically protected pyrene: molecular design, bright blue emission in the crystalline state and aromaticity relocation in its dicationic species. AB - Sterically congested tetraarylpyrenes exhibited emission in both solution and the solid state. The monocationic species of pyrene 1 could be isolated because of the reasonably protected system. The aromaticity of 1 relocates from the biphenyl part to the naphthalene unit upon two-electron oxidation. PMID- 25011975 TI - PET imaging of cardiac wound healing using a novel [68Ga]-labeled NGR probe in rat myocardial infarction. AB - PURPOSE: Peptides containing the asparagine-glycine-arginine (NGR) motif bind to aminopeptidase N (CD13), which is expressed on inflammatory cells, endothelial cells, and fibroblasts. It is unclear whether radiolabeled NGR-containing tracers could be used for in vivo imaging of the early wound-healing phase after myocardial infarction (MI) using positron emission tomography (PET). PROCEDURES: Uptake of novel tracer [(68)Ga]NGR was assessed together with [(68)Ga]arginine glycine-aspartic acid ([(68)Ga]RGD) and 2-deoxy-2-[(18) F]fluoro-D-glucose after myocardial ischemia/reperfusion (MI/R) injury using MU-PET and autoradiography, and relative expressions of CD13 and integrin beta3 were assessed in fibroblasts, inflammatory cells, and endothelial cells by immunohistochemistry. RESULTS: In the infarcted myocardium, uptake of [(68)Ga]NGR was maximal from days 3 to 7 after MI/R, and correlated with fibroblast and inflammatory cell infiltration as well as [(68)Ga]RGD uptake. CONCLUSIONS: [(68)Ga]NGR allows noninvasive and sequential determination of CD13 expression in fibroblasts and inflammatory cells by PET. This will facilitate monitoring of CD13 in the individual wound healing processes, allowing patient-specific therapies to improve outcome after MI. PMID- 25011977 TI - "We don't know her history, her background": adoptive parents' perspectives on whole genome sequencing results. AB - Exome sequencing and whole genome sequencing (ES/WGS) can provide parents with a wide range of genetic information about their children, and adoptive parents may have unique issues to consider regarding possible access to this information. The few papers published on adoption and genetics have focused on targeted genetic testing of children in the pre-adoption context. There are no data on adoptive parents' perspectives about pediatric ES/WGS, including their preferences about different kinds of results, and the potential benefits and risks of receiving results. To explore these issues, we conducted four exploratory focus groups with adoptive parents (N = 26). The majority lacked information about their children's biological family health history and ancestry, and many viewed WGS results as a way to fill in these gaps in knowledge. Some expressed concerns about protecting their children's future privacy and autonomy, but at the same time stated that WGS results could possibly help them be proactive about their children's health. A few parents expressed concerns about the risks of WGS in a pre-adoption context, specifically about decreasing a child's chance of adoption. These results suggest that issues surrounding genetic information in the post-adoption and ES/WGS contexts need to be considered, as well as concerns about risks in the pre-adoption context. A critical challenge for ES/WGS in the context of adoption will be balancing the right to know different kinds of genetic information with the right not to know. Specific guidance for geneticists and genetic counselors may be needed to maximize benefits of WGS while minimizing harms and prohibiting misuse of the information in the adoption process. PMID- 25011978 TI - A survey of genetic counselors about the needs of 18-25 year olds from families with hereditary breast and ovarian cancer syndrome. AB - As a result of modern treatments, the life of women who test positive for BRCA mutations may be plotted along the arc of preventive medicine rather than the slope of diagnostics. Despite evidence supporting the benefits of risk reduction, protocols for early detection and prevention among women from families affected by hereditary breast and ovarian cancer (HBOC) are not yet proven, and clinical trials have not been undertaken for patients aged 18 to 25. The absence of psychosocial data may leave genetic counselors without uniform guidance on how to manage the care of these patients. This project sought to investigate perspectives on counseling 18-25 year-old patients from families with hereditary cancer syndromes, with specific emphasis on HBOC, given their unique developmental, familial, and medical challenges. Certified genetic counselors were recruited through the NSGC's Cancer Genetics Special Interest Group listserv. Researchers constructed an online survey which included 41 items and elicited information about: counselor demographics, training, and practice settings; approaches to cancer risk assessment; and common challenges in work with 18- to 25-year-old patients. The survey was also informed by previous work by researchers with 18 to 25-year-olds with BRCA gene mutations. Eighty-six surveys were completed. Researchers used a combination of grounded theory and content analysis for open-ended responses, supported and triangulated with statistical analysis to maximize the interpretation of data. Genetic counselors who responded to this survey experience 18-25 year old patients presenting for cancer risk assessment differently than older patients, and some reported adapting their counseling style to address these differences. Respondents differed in the extent to which they felt well-versed in the developmental needs of patients in this age group. Respondents aged 39 and under reported feeling familiar with this stage in life, having more recently completed it; respondents aged 40 and over reported they were less familiar with, and more interested in learning about, this age group. A primary challenge in cancer risk assessment of these patients, reported primarily by counselors aged 39 and under, is navigating family dynamics in counseling sessions and addressing the developmentally labile young adult. With respect to BRCA-related cancer risk, where penetrance is incomplete, onset in early adulthood is rare. Evidence-based treatment/prevention options exist, but providers may not have clarity regarding how or when to provide directive counsel. A rich understanding of the themes inherent in how people grow and change over time might enhance the counselor's capacity to assess patients and their family members. The integration of a developmental approach to genetic counseling has the potential to reduce the imperative for non-directive counseling. PMID- 25011979 TI - Assessment of the standard forensic procedure for the evaluation of psychological injury in intimate-partner violence. AB - In judicial terms, a victim refers to any person who has suffered injury arising from an action or omission of an action that constitutes an offence, and the burden of proof lies with the prosecution. A review of Spanish judicial judgements underscored that the lack of evidence of psychological injury in cases of intimate-partner violence (IPV) accounted for approximately 40% of acquittals. Thus, the Spanish standard of proof for the forensic evaluation of psychological injury i.e., the MMPI-2 and the unstructured interview were assessed in order to determine if they met the statutory requirement for the assessment of psychological injury and the differential diagnosis of feigning. The results of the comparison of 51 women victims of IPV with firm convictions against their aggressors, and 54 women mock victims of IPV showed that the F, K, Fb, Fp and Ds scales, and the F-K index discriminated significantly and with medium and large effect sizes, between adjudicated and mock victims. However, the results did not provide a valid decision criterion for forensic settings i.e., false negatives (identifying feigner as honest protocols) were not classified correctly. In conclusion, the standard forensic procedure for the evaluation of psychological injury in cases of IPV did not constitute valid proof for judges who acquitted defendants on the grounds of not proven due to the lack of evidence of psychological injury. PMID- 25011980 TI - Is a targeted and planned GP intervention effective in cardiovascular disease prevention? A randomized controlled trial. AB - BACKGROUND: The optimal intensity and duration of the intervention to achieve sustained risk reduction in patients at high and very high cardiovascular (CV) risk still need to be established. The aim of this study was to evaluate the impact of general practitioner's (GP's) systematic and planned intervention on total CV risk reduction and a change in individual CV risk factors. MATERIAL AND METHODS: This was a cluster-randomized trial (ISRCTN31857696) including 64 practices and 3245 patients aged >=40. The participating GPs and their examinees were randomized into an intervention or to a control group (standard care). Intervention group practitioners followed up their examinees during 1, 3, 6, 12, and 18 months. The main outcome measures were change in proportion of patients with low, moderate, high, and very high CV risk, and change in individual CV risk factors from the first to the second registration. RESULTS: The proportion of patients with very high CV risk was lower in the intervention group, the same as of patients with high blood pressure, total and LDL cholesterol, and increased intake of alcohol. The mean systolic (-1.49 mmHg) and diastolic (-1.57 mmHg) blood pressure, triglycerides (-0.18 mmol/L), body mass index (-0.22), and waist (-0.4 cm) and hip circumference (-1.08 cm) was reduced significantly in the intervention group. There was no additional impact in the intervention group of other tested CV risk factors. CONCLUSIONS: Systematic and planned GP's intervention in CVD prevention reduces the number of patients with very high total CV risk and influences a change in lifestyle habits. PMID- 25011981 TI - Macroscopic modeling for heat and water vapor transfer in dry snow by homogenization. AB - Dry snow metamorphism, involved in several topics related to cryospheric sciences, is mainly linked to heat and water vapor transfers through snow including sublimation and deposition at the ice-pore interface. In this paper, the macroscopic equivalent modeling of heat and water vapor transfers through a snow layer was derived from the physics at the pore scale using the homogenization of multiple scale expansions. The microscopic phenomena under consideration are heat conduction, vapor diffusion, sublimation, and deposition. The obtained macroscopic equivalent model is described by two coupled transient diffusion equations including a source term arising from phase change at the pore scale. By dimensional analysis, it was shown that the influence of such source terms on the overall transfers can generally not be neglected, except typically under small temperature gradients. The precision and the robustness of the proposed macroscopic modeling were illustrated through 2D numerical simulations. Finally, the effective vapor diffusion tensor arising in the macroscopic modeling was computed on 3D images of snow. The self-consistent formula offers a good estimate of the effective diffusion coefficient with respect to the snow density, within an average relative error of 10%. Our results confirm recent work that the effective vapor diffusion is not enhanced in snow. PMID- 25011982 TI - Alterations in luteal production of androstenedione, testosterone, and estrone, but not estradiol, during mid- and late pregnancy in pigs: effects of androgen deficiency. AB - Recently, we have found that flutamide-induced androgen deficiency altered progesterone production in the porcine corpus luteum (CL) during mid- and late pregnancy. Herein, we tested whether flutamide administration subsequently influences androgen and estrogen metabolism in the CL of pregnancy. Pregnant gilts were treated with flutamide between Days 43 and 49 (GD50F), 83 and 89 (GD90F), or 101 and 107 (GD108F) of gestation. Corpora lutea (CLs) were collected from treated and nontreated (control) pigs. The concentrations of androstenedione (A4), testosterone (T), estrone (E1), and estradiol (E2) together with the levels of expression of mRNAs and proteins for cytochrome P450 17alpha-hydroxylase/c17 20 lyase (CYP17A1), 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), cytochrome P450 aromatase (CYP19A1), and 17beta-hydroxysteroid dehydrogenase type 7 (17beta-HSD7) were measured in the CL of control and flutamide-treated animals. Steroidogenic enzymes were also immunolocalized in luteal tissues. The luteal concentrations of A4 and T were higher in the GD50F (P = 0.006, P = 0.03) and GD108F (P = 0.005, P = 0.035) groups, but lower in the GD90F (P = 0.004, P = 0.014) group. The E1 level was greater only in the GD90F (P = 0.03) and GD108F (P = 0.035) groups, whereas E2 concentration was not affected by flutamide treatment. Increased luteal CYP17A1 mRNA and protein expression was found in the GD50F (P = 0.002, P = 0.03) and GD108F (P = 0.0026, P = 0.03) groups, but reduced in the GD90F (P = 0.002, P = 0.03) group. mRNA of 17beta-HSD1 was upregulated in the GD50F (P = 0.0005) group, but downregulated in the GD90F (P = 0.002) and GD108F (P = 0.0005) groups. In contrast, 17beta-HSD1 protein expression was higher in the GD50F and GD108F (P = 0.03) groups, but lower in the GD90F (P = 0.03) group. Both CYP19A1 mRNA and protein levels were greater in the GD90F (P = 0.001, P = 0.028) and GD108F (P = 0.005, P = 0.03) groups. Neither 17beta-HSD7 mRNA nor protein level were affected by flutamide exposure. Both CYP17A1 and 17beta-HSD1 were immunolocalized exclusively in small luteal cells, whereas CYP19A1 and 17beta-HSD7 were found in large luteal cells of control and flutamide treated CLs. Overall, flutamide administration led to the alterations in A4, T, and E1, but not in E2, production in the CL of pregnancy in pigs, probably because of disrupted steroidogenic enzymes expression. These changes suggest that androgens are important modulators of luteal function during pregnancy in pigs. PMID- 25011983 TI - The effects of exclusion of progesterone or Day 0 GnRH from a GnRH, prostaglandin, GnRH + progesterone program on synchronization of ovulation in pasture-based dairy heifers. AB - This study evaluated the effect of removing the GnRH injection on Day 0 or the progesterone (P4) device from a GnRH, PGF2alpha, GnRH (GPG) + P4 program on follicular dynamics and synchronization of ovulation in dairy heifers. Friesian and Friesian * Jersey heifers, in autumn 2009 (n = 35) and spring 2010 (n = 38), were randomly allocated to one of three estrus synchronization programs. The first group (GPG + P4) received 100 MUg GnRH on Day 0, a P4-releasing intravaginal device from Days 0 to 7, 500 MUg PGF2alpha on Day 7, and 100 MUg GnRH on Day 9, followed by fixed-time artificial insemination 16 to 20 hours later. The program for group 2 (GPG) was the same as group 1 with the exclusion of the P4 device. Group 3 (P + G + P4) was treated the same as group 1, except for the absence of the GnRH treatment on Day 0. Ultrasonography was performed on Days 0, 1, 2, 3, and 7 and then at 12 hourly intervals on Days 9 to 11. Dominant follicle size was affected by both treatment and day, and there was also a significant interaction (P < 0.02) between treatment and day. Mean dominant follicle size was larger in the heifers treated with P + G + P4 on Days 1 to 3 than those treated with GPG + P4 (P < 0.02) and, on Day 2, than those treated with GPG (P = 0.005). However, on Day 7, mean dominant follicle size was larger in heifers treated with GPG than heifers treated with P + G + P4 (P = 0.03). The emergence of a new follicular wave was later in heifers treated with P + G + P4 than heifers, which received a GnRH injection on Day 0 (4.3 +/- 0.7 days, compared with combined GPG + P4 and GPG 3.0 +/- 0.3 days; P = 0.03). The proportion of heifers that ovulated within the first 48 hours after the Day 9 injection of GnRH was not affected by treatment (GPG, 81%; GPG + P4, 84%; and P + G + P4, 100% [including early ovulation]; P = 0.11). The timing of the ovulation was not different between treatments (P = 0.97). PMID- 25011984 TI - Osteoporosis as an independent risk factor for silent brain infarction and white matter changes in men and women: the PRESENT project. AB - SUMMARY: Previous studies have not demonstrated a relationship between osteoporosis and cerebral infarction in the community, especially in men. We found that osteoporosis may be an independent risk factor for brain white matter change/silent infarction in men, as well as in women. PURPOSE: We aimed to study the relationship between low bone mineral density (BMD) and brain white matter changes and/or silent infarcts (WMC/SI). METHODS: This was a community-based, cross-sectional study supported by the regional government. Bone mineral density measurements and brain computed tomography were performed in 646 stroke- and dementia-free subjects (aged 50-75 years). RESULTS: After adjustment for age, hypertension, diabetes mellitus, dyslipidemia, and current smoking status, the odds ratio (OR) of risk for WMC and/or SI was 1.8 in the osteopenia group (95 % confidence interval [CI] 1.15-2.77; P = 0.01) and 2.2 in the osteoporosis group (95 % CI 1.42-3.55; P < 0.001). Among men, the OR was 1.8 (95 % CI 0.72-4.62; P = 0.21) and 3.8 (95 % CI 1.63-8.86; P = 0.002), and in women, the OR was 1.9 (95 % CI 1.15-2.78; P = 0.010) and 2.2 (95 % CI 1.42-3.55; P = 0.001), respectively. CONCLUSIONS: Severe bone mass loss may be an independent risk factor for brain WMC/SI in men and women. Low BMD may cause brain WMC/SI in the step that leads to stroke. Although there are well-designed studies on the prevention of cerebral infarction in patients with brain WMC/SI, a specific prevention method, such as aspirin, should be used for patients with low BMD who have WMC/SI. Screening for low BMD as an independent vascular risk factor in healthy subjects may be required to prevent stroke. PMID- 25011985 TI - Impact of multidisciplinary hip fracture program on timing of surgery in elderly patients. AB - The effect of patient characteristics and organizational and system factors on time to surgery were studied using Emilia Romagna Region database and hospital survey. The results showed that the implementation of a Hip Fracture Program significantly increased the probability of early surgery while single intervention had only slight effect INTRODUCTION: The purpose of this study is to evaluate the effect of formal Hip Fracture Program (HFP) on timing of surgery in hip fracture older patients. METHODS: This is a retrospective cohort study based on Emilia Romagna administrative databases. Data on organizational and system factor were also obtained through a hospital survey. A multilevel logistic regression analysis was carried out to assess the effect of covariates on early surgery, taking into account patient level, hospital level, and trust level variability. RESULTS: From 1 January to 31 December 2011, 5,520 subjects over 65 years old underwent surgical repair for hip fracture in Emilia Romagna. The mean waiting time to surgery was 3.4 +/- 12.3 days, and the overall percentage of patients operated within 2 days was 52.2%. In the adjusted multilevel logistic model, significant risk factors affecting the timing of surgical intervention at patient level were age, comorbidity, day of admission, and antiplatelet or warfarin therapy while no significant single variables were found at hospital level including dedicated operation theater, hospital volume, dedicated orthogeriatric beds, and geriatrician involvement. The most significant variable was the implementation of HFP at trust level that increased three times the probability of early surgery after adjusting for confounding variables (OR 3.216, 95% CI 0.582-6.539). CONCLUSIONS: Several modifiable organizational factors may affect the proportion of patients with hip fracture undergoing early surgery. This study suggests that the development and the implementation of an evidence based HFP at trust level are a key point of the strategy of quality of care. PMID- 25011986 TI - Differences in persistency with teriparatide in patients with osteoporosis according to gender and health care provider. AB - This analysis investigated the persistence of teriparatide for treatment of osteoporosis in 829 patients according to gender and health care provider treated with teriparatide. This study showed that female patients were less persistent than males and those patients treated in the practices of orthopedic surgeons were more treatment persistent than patients treated in general practitioner (GP) practices. INTRODUCTION: The optimal persistency of teriparatide (TPTD) is of the upmost importance to ensure fracture risk reduction and pain relief. Data reporting on gender-specific or health care provider-dependent differences on health care provider-dependent persistence is currently lacking. METHODS: We analyzed a large dataset extracted from the Disease Analyzer database (IMS Health, Germany). Out of a dataset of 15 million patients, we identified patients with osteoporosis who received first-time teriparatide prescriptions from January 2005 to December 2012. RESULTS: All 829 patients (677 females and 152 males) were included in the study. The patients were treated by 214 general practitioners (GPs) and 143 orthopedic surgeons. After 18 months of follow-up, 39.5 % of the female and 34 % of the male patients discontinued their treatment (p = 0.0308). We found a significant difference in the discontinuation rate of patients treated by orthopedic surgeons (35.0 %) compared to patients treated by GPs (44.2 %) (p = 0.0445). Additionally, at the end of the 18 months of follow up, 39.4 % of female and 47.8 % of male patients were still on treatment. We found a highly significant decreased risk for treatment discontinuation in patients with fractures prior to treatment initiation compared to those without such fractures (hazard ratio (HR) 0.77; 95 % confidence interval (CI) 0.66-0.90). There was a significantly increased risk of treatment discontinuation for female patients (HR 1.38; 95 % CI 1.10-1.74) compared to male patients. CONCLUSIONS: In conclusion, female patients presented higher discontinuation rates of TPTD compared to males. Patients treated in the practices of orthopedic surgeons were more persistent than patients treated in GP practices. TPTD persistence in patients with osteoporosis is higher than with antiresorptives but is still suboptimal and needs to be improved to ensure fracture risk reductions comparable to randomized controlled trial (RCT) results. PMID- 25011987 TI - Predictors of hospitalisations for heart failure and mortality in patients with pulmonary hypertension associated with left heart disease: a systematic review. AB - OBJECTIVES: Left heart disease (LHD) is the main cause of pulmonary hypertension (PH), but little is known regarding the predictors of adverse outcome of PH associated with LHD (PH-LHD). We conducted a systematic review to investigate the predictors of hospitalisations for heart failure and mortality in patients with PH-LHD. DESIGN: Systematic review. DATA SOURCES: PubMed MEDLINE and SCOPUS from inception to August 2013 were searched, and citations identified via the ISI Web of Science. STUDY SELECTION: Studies that reported on hospitalisation and/or mortality in patients with PH-LHD were included if the age of participants was greater than 18 years and PH was diagnosed using Doppler echocardiography and/or right heart catheterisation. Two reviewers independently selected studies, assessed their quality and extracted relevant data. RESULTS: In all, 45 studies (38 from Europe and USA) were included among which 71.1% were of high quality. 39 studies were published between 2003 and 2013. The number of participants across studies ranged from 46 to 2385; the proportion of men from 21% to 91%; mean/median age from 63 to 82 years; and prevalence of PH from 7% to 83.3%. PH was consistently associated with increased mortality risk in all forms of LHD, except for aortic valve disease where findings were inconsistent. Six of the nine studies with data available on hospitalisations reported a significant adverse effect of PH on hospitalisation risk. Other predictors of adverse outcome were very broad and heterogeneous including right ventricular dysfunction, functional class, left ventricular function and presence of kidney disease. CONCLUSIONS: PH is almost invariably associated with increased mortality risk in patients with LHD. However, effects on hospitalisation risk are yet to be fully characterised; while available evidence on the adverse effects of PH have been derived essentially from Caucasians. PMID- 25011988 TI - Unmasking health determinants and health outcomes for urban First Nations using respondent-driven sampling. AB - OBJECTIVE: Population-based health information on urban Aboriginal populations in Canada is limited due to challenges with the identification of Aboriginal persons in existing health data sets. The main objective of the Our Health Counts (OHC) project was to work in partnership with Aboriginal stakeholders to generate a culturally relevant, representative baseline health data set for three urban Aboriginal communities in Ontario, Canada. DESIGN: Respondent-driven sampling (RDS). SETTING: Hamilton, Ontario, Canada. PARTICIPANTS: The OHC study, in partnership with the De dwa da dehs ney >s Aboriginal Health Access Centre (DAHC), recruited 554 First Nations adults living in Hamilton using RDS. RESULTS: Among First Nations adults living in Hamilton, 78% earned less than $20 000 per year and 70% lived in the lowest income quartile neighbourhoods. Mobility and crowded living conditions were also highly prevalent. Common chronic diseases included arthritis, hypertension, diabetes and chronic obstructive pulmonary disease and rates of emergency room access were elevated. CONCLUSIONS: RDS is an effective sampling method in urban Aboriginal contexts as it builds on existing social networks and successfully identified a population-based cohort. The findings illustrate striking disparities in health determinants and health outcomes between urban First Nations individuals and the general population which have important implications for health services delivery, programming and policy development. PMID- 25011989 TI - Medicines management support to older people: understanding the context of systems failure. AB - OBJECTIVES: Changing demographics and pressures on the healthcare system mean that more older people with complex medical problems need to be supported in primary and community care settings. The challenge of managing medicines effectively in frail elderly patients is considerable. Our research investigates what can go wrong and why, and seeks insight into the context that might set the scene for system failure. SETTING: North London; a district general hospital and surrounding health authorities. PARTICIPANTS: 7 patients who had been admitted to hospital and 16 informants involved in their care. DESIGN: Patients with preventable medication-related admissions were identified in an occurrence screening study. An accident investigation approach was used to create case studies from accounts of staff involved in each patient's care prior to their admission. Structured analysis of case studies according to the accident investigation approach was complemented by a separate analysis of interviews using open coding with constant comparison to identify and illustrate higher level contextual themes. OUTCOMES: The study sheds light on care management problems, their causes and the context in which care management problems and their causes have occurred. RESULTS: Care management problems were rooted in issues with decision-making, information support and communications among staff members and between staff, patients and carers. Poor judgement, slips and deviations from best practice were attributed to task overload and complexity. Within general practice, at the interface with community services and with hospitals, we identified disruption to traditional intraprofessional and interprofessional roles, assumptions, channels and media of communication which together created conditions that might compromise patient safety. CONCLUSIONS: New ways of working driven by the ethos of productivity are disrupting traditional intraprofessional and interprofessional roles, assumptions, channels and media of communication. Concomitant improvements in communications technology, process and protocol are urgently required to offset potentially serious risks to patient safety. PMID- 25011990 TI - Factors associated with failure of enhanced recovery protocol in patients undergoing major hepatobiliary and pancreatic surgery: a retrospective cohort study. AB - OBJECTIVE: This study examined the risk factors associated with failure of enhanced recovery protocol after major hepatobiliary and pancreatic (HBP) surgery. SETTING AND PARTICIPANTS: A retrospective cohort of 194 adult patients undergoing major HBP surgery at a university hospital in Hong Kong was followed up for 30 days. The patients were from a larger cohort study of 736 consecutive adults with preoperative urinary cotinine concentration to examine the association between passive smoking and risk of perioperative respiratory complications and postoperative morbidities. OUTCOME MEASURES: The primary outcome was failure of enhanced recovery protocol. This was defined as a composite measure of the following events: intensive care unit (ICU) stay more than 24 h after surgery, unplanned admission to ICU within 30 days after surgery, hospital readmission, reoperation and mortality. RESULTS: There were 25 failures of enhanced recovery after HBP surgery (12.9%, 95% CI 8.5% to 18.4%). After adjusting for elective ICU admission, smokers (relative risk (RR ) 2.21, 95% CI 1.10 to 4.46), high preoperative alanine transaminase/glutamic-pyruvic transaminase (RR 3.55,95% CI 1.68 to 7.49) and postoperative morbidities (RR 2.69, 95% CI 1.30 to 5.56) were associated with failures of enhanced recovery in the generalised estimating equation risk model. Compared with those managed successfully, failures stayed longer in ICU (median 19 vs 25 h, p<0.001) and in hospital for postoperative care (median 7 vs 13 days, p=0.003). CONCLUSIONS: Smokers and patients having high preoperative alanine transaminase/glutamic pyruvic transaminase concentration or have a high risk of postoperative morbidities are likely to fail enhanced recovery protocol in HBP surgery programmes. PMID- 25011991 TI - Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. AB - INTRODUCTION: Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST). METHODS AND ANALYSIS: FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 umol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3. ETHICS AND DISSEMINATION: FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal. TRIAL REGISTRATION NUMBER: FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728). PMID- 25011992 TI - Public perceptions of cancer: a qualitative study of the balance of positive and negative beliefs. AB - OBJECTIVES: Cancer's insidious onset and potentially devastating outcomes have made it one of the most feared diseases of the 20th century. However, advances in early diagnosis and treatment mean that death rates are declining, and there are more than 30 million cancer survivors worldwide. This might be expected to result in more sanguine attitudes to the disease. The present study used a qualitative methodology to provide an in-depth exploration of attitudes to cancer and describes the balance of negative and positive perspectives. DESIGN: A qualitative study using semistructured interviews with thematic analysis. SETTING: A university in London, UK. PARTICIPANTS: 30 participants (23-73 years), never themselves diagnosed with cancer. RESULTS: Accounts of cancer consistently incorporated negative and positive views. In almost all respondents, the first response identified fear, trauma or death. However, this was followed-sometimes within the same sentence-by acknowledgement that improvements in treatment mean that many patients can survive cancer and may even resume a normal life. Some respondents spontaneously reflected on the contradictions, describing their first response as a 'gut feeling' and the second as a more rational appraisal-albeit one they struggled to believe. Others switched perspective without apparent awareness. CONCLUSIONS: People appear to be 'in two minds' about cancer. A rapid, intuitive sense of dread and imminent death coexists with a deliberative, rational recognition that cancer can be a manageable, or even curable, disease. Recognising cancer's public image could help in the design of effective cancer control messages. PMID- 25011993 TI - The Canadian survey of health, lifestyle and ageing with multiple sclerosis: methodology and initial results. AB - OBJECTIVE: People with multiple sclerosis (MS) are living longer so strategies to enhance long-term health are garnering more interest. We aimed to create a profile of ageing with MS in Canada by recruiting 1250 (5% of the Canadian population above 55 years with MS) participants and focusing data collection on health and lifestyle factors, disability, participation and quality of life to determine factors associated with healthy ageing. DESIGN: National multicentre postal survey. SETTING: Recruitment from Canadian MS clinics, MS Society of Canada chapters and newspaper advertisements. PARTICIPANTS: People aged 55 years or older with MS symptoms more than 20 years. OUTCOME MEASURES: Validated outcome measures and custom-designed questions examining MS disease characteristics, living situation, disability, comorbid conditions, fatigue, health behaviours, mental health, social support, impact of MS and others. RESULTS: Of the 921 surveys, 743 were returned (80.7% response rate). Participants (mean age 64.6+/ 6.2 years) reported living with MS symptoms for an average of 32.9+/-9.5 years and 28.6% were either wheelchair users or bedridden. There was only 5.4% missing data and 709 respondents provided optional qualitative information. According to data derived from the 2012 Canadian Community Health Survey of Canadians above 55 years of age, older people with MS from this survey sample are about eight times less likely to be employed full-time. Older people with MS were less likely to engage in regular physical activity (26.7%) compared with typical older Canadians (45.2%). However, they were more likely to abstain from alcohol and smoking. CONCLUSIONS: Despite barriers to participation, we were able to recruit and gather detailed responses (with good data quality) from a large proportion of older Canadians with MS. The data suggest that this sample of older people with MS is less likely to be employed, are less active and more disabled than other older Canadians. PMID- 25011994 TI - Parenting roles and knowledge in neonatal intensive care units: protocol of a mixed methods study. AB - INTRODUCTION: There is a strong focus on the translation of scientific knowledge into evidence-based practice when dealing with very preterm births. The aim is to standardise and rationalise healthcare. The incorporation of parents' perspectives with respect to the organisation of care and technical interventions in neonatal intensive care units (NICUs) is needed. This study aims to analyse the repertoire of meanings, knowledge and emotions actualised by the parents of very preterm infants hospitalised in NICUs in the decision process regarding parental care, treatment options and uses of information sources. METHODS AND ANALYSIS: This is a mixed-methods, observational study. The methodological strategy will rely on: (1) Ethnographic observation, carried out in a level III NICU located in the North of Portugal, during 6 months; (2) NICU-based surveys of mothers and fathers of very preterm infants born between July 2013 and June 2014 and admitted at the seven public level III NICUs of the Northern Health Region of Portugal; (3) Single and couple semistructured interviews to a subsample of mothers and fathers of very preterm infants, 4 months after birth. Inferential statistics will be used to analyse the quantitative data and content analysis, with an iterative and reflexive process and will be implemented to assess qualitative data. ETHICS AND DISSEMINATION: The study protocol was approved by the National Data Protection Commission and the Ethics Committee of all the hospitals involved. The current project will contribute to develop resources for enriched good medical practices in the context of neonatal services through integrating insights from social sciences, public health, epidemiology and ethics. The expected dissemination actions are effective tools in designing strategies that aim to develop family-centred care and to improve medical practices in the context of neonatal services. PMID- 25011995 TI - The management of postoperative reflux in congenital esophageal atresia tracheoesophageal fistula: a systematic review. AB - PURPOSE: Esophageal atresia (EA), with or without tracheoesophageal fistula (TEF), is associated with postoperative gastroesophageal reflux (GER). We performed a systematic review of the literature regarding routine anti-reflux medication post EA-TEF repair and its impact on postoperative GER and associated complications. METHODS: A comprehensive search was conducted using MEDLINE, EMBASE, CINHAL, CENTRAL (Cochrane library) electronic databases and gray literature. Full-text screening was performed in duplicate. Included articles reported a primary diagnosis of EA-TEF, a secondary diagnosis of postoperative GER, and primary treatment of GER with anti-reflux medications. RESULTS: Screening of 2,910 articles resulted in 25 articles (1,663 patients) for analysis. Most were single-center studies (92%) and retrospective (76%); there were no randomized control trials. Fifteen studies named the class of anti-reflux agent used, 3 the duration of therapy, and none either the dose prescribed or number of doses. Complications were inconsistently reported. Anti-reflux surgery was performed in 433/1,663 (26.0%) patients. Average follow-up was 53.2 months (14 studies). CONCLUSION: The quality of literature regarding anti-reflux medication for GER post EA-TEF repair is poor. There are no well-outlined algorithms for anti-reflux agents, doses, or duration of therapy. Standardized protocols and reliable reporting are necessary to develop guidelines to better manage postoperative GER in EA-TEF patients. PMID- 25011996 TI - Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma. AB - The role of the microenvironment in high-grade lymphoma is not well defined. In this report, we employ immunohistochemistry to characterise programmed death-1 (PD-1/CD279) and FoxP3 expression in 70 cases of diffuse large B-cell lymphoma (DLBCL). PD-1 is a surface marker characteristic of follicular helper T-cells whilst FoxP3 is characteristic of Tregs. We demonstrate variable infiltration with CD4(+) T-cells (<10 to >50 % of all lymph node cells) and PD-1(hi) cells (0.1 to 1.5 % of all cells). CD4(+) T-cells can be distributed in clusters or more diffusely and PD-1(hi) cells, but not FoxP3(+) cells, are found in rosettes around lymphoma cells. Cases with high CD4(+) T-cell numbers tended to have higher numbers of both PD-1(hi) and FoxP3(+) cells. Cases with total CD4(+) T cell, PD-1(hi) and FoxP3(+) numbers above the median associate with better clinical outcome. Overall, we demonstrate that infiltration by CD4(+) T-cells, including both FoxP3(+) and PD-1(hi) subsets, correlates with prognosis in DLBCL. In distinction to previous reported series, patients (91 %) were treated with rituximab-containing regimens, suggesting that the effects of CD4+ T-cell infiltration are maintained in the rituximab era. This work suggests that determinants of total CD4(+) T-cell infiltration, either molecular characteristics of the lymphoma or the patients' immune system, and not individual T-cell subsets, correlate with clinical outcome. PMID- 25011997 TI - Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). AB - The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor beta1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT. PMID- 25011998 TI - Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors. AB - BACKGROUND/AIMS: The occurrence and clinical relevance of DNA hypermethylation and global hypomethylation in pancreatic neuroendocrine tumours (PanNETs) are still unknown. We evaluated the frequency of both epigenetic alterations in PanNETs to assess the relationship between methylation profiles and chromosomal instability, tumour phenotypes and prognosis. METHODS: In a well-characterized series of 56 sporadic G1 and G2 PanNETs, methylation-sensitive multiple ligation dependent probe amplification was performed to assess hypermethylayion of 33 genes and copy number alterations (CNAs) of 53 chromosomal regions. Long interspersed nucleotide element-1 (LINE-1) hypomethylation was quantified by pyrosequencing. RESULTS: Unsupervised hierarchical clustering allowed to identify a subset of 22 PanNETs (39%) exhibiting high frequency of gene-specific methylation and low CNA percentages. This tumour cluster was significantly associated with stage IV (p = 0.04) and with poor prognosis in univariable analysis (p = 0.004). LINE-1 methylation levels in PanNETs were significantly lower than in normal samples (p < 0.01) and were approximately normally distributed. 12 tumours (21%) were highly hypomethylated, showing variable levels of CNA. Interestingly, only 5 PanNETs (9%) were observed to show simultaneously LINE-1 hypomethylation and high frequency of gene-specific methylation. LINE-1 hypomethylation was strongly correlated with advanced stage (p = 0.002) and with poor prognosis (p < 0.0001). In the multivariable analysis, low LINE-1 methylation status and methylation clusters were the only independent significant predictors of outcome (p = 0.034 and p = 0.029, respectively). CONCLUSION: The combination of global DNA hypomethylation and gene hypermethylation analyses may be useful to define distinct subsets of PanNETs. Both alterations are common in PanNETs and could be directly correlated with tumour progression. PMID- 25011999 TI - Enamel matrix derivative protein enhances production of matrixmetalloproteinase-2 by osteoblasts. AB - BACKGROUND: Matrix metalloproteinases (MMPs) degrade the extracellular matrix (ECM) and regulate remodeling and regeneration of bone. Enamel matrix derivative (EMD) protein has been used clinically for periodontal regeneration, although its molecular mechanisms are not clear. We evaluated the role of matrix metalloproteinases (MMPs) in regulating EMD-dependent degradation of gelatin on oeoblast-like cell line MG63. METHODS: MG-63 cells (osteoblast cell line) were incubated with 100 MUg/ml EMD protein in the presence or absence of MMP-2 tissue inhibitor for 20 h followed by incubation on DQ-gelatin-coated plates for 4 h. MG 63 cells (1 * 10(6)) were preincubated with SB203580 for 30 min at 37 degrees C and were then placed in 100 MUg/ml EMD protein for 24 h. Conditioned media were collected and detected by Western blot analysis. RESULTS: EMD protein enhanced cell-mediated degradation of gelatin, which was inhibited by the MMP inhibitor TIMP-2. Furthermore, MMP-2 was produced by MG63 cells in response to EMD protein in a P38 MAPK-dependent manner. In addition, blocking of p38 MAPK activation by SB203580 significantly inhibited generation of the active form of MMP-2. CONCLUSION: P38 MAPK pathway promotes expression MMP-2 in EMD activated osteoblasts, which in turn stimulates periodontal regeneration by degrading matrix proteins in periodontal connective tissue. PMID- 25012000 TI - CpG-ODNs induced changes in cytokine/chemokines genes expression associated with suppression of infectious bronchitis virus replication in chicken lungs. AB - The process of virus replication in host cells is greatly influenced by the set of cytokines, chemokines and antiviral substances activated as a result of host virus interaction. Alteration of cytokines profiles through manipulation of the innate immune system by innate immune stimulants may be helpful in inhibiting virus replication in otherwise permissive cells. The aim of present studies was to characterize innate immune responses capable of inhibiting infectious bronchitis virus (IBV) replication in chicken lungs after in ovo administration of CpG ODN. In our experiments, CpG ODN 2007 or PBS solution was injected on 18th embryonic day (ED) via the chorioallontoic route. CpG ODN and PBS inoculated embryos were challenged with virulent IBV on the 19th ED. Lung tissue samples from experimental chicks were analysed for cytokines/chemokines gene expression at 24h, 48h, and 72h, post infection. Our data showed significant differential up regulation of IFN-gamma, IL-8 (CXCLi2) and MIP-1beta genes and suppression of IL 6 gene expression being associated with inhibition of IBV replication in lungs tissue retrieved from embryos pre-treated with CpG ODN. It is expected that understanding of the innate immune modulation of target tissues by the virus and innate immune stimulants will be helpful in identification of valuable targets for development of novel, safe, effective and economical control strategies against IBV infection in chickens. PMID- 25012001 TI - The COMET Initiative database: progress and activities from 2011 to 2013. AB - The Core Outcome Measures in Effectiveness Trials (COMET) Initiative database is an international repository of studies relevant to the development of core outcome sets. By the end of 2013, it included a unique collection of 306 studies. The website is increasingly being used, with more than 12,000 visits in 2013 (a 55% increase over 2012), 8,369 unique visitors (a 53% increase) and 6,844 new visitors (a 48% increase). There has been a rise in visits from outside the United Kingdom, with 2,405 such visits in 2013 (30% of all visits). By December 2013, a total of 4,205 searches had been completed, with 2,139 in 2013 alone. PMID- 25012002 TI - Monocrural flaccid paralysis following asthmatic attack (post asthmatic amyotrophy) - case report & minireview. PMID- 25012003 TI - Perindopril and residual chronic subdural hematoma volumes six weeks after burr hole surgery: a randomized trial. AB - OBJECTIVE: Recurrence rates of between 5% and 25% have been reported following surgery for chronic subdural hematoma (CSH). A previous study showed that the treatment with angiotensin converting enzyme (ACE) inhibitors decreases the risk of recurrence. To test the effects of ACE inhibitors on the recurrence CSH and CSH remnant six weeks after surgery, we conducted a prospective double-blinded randomized controlled clinical trial on patients with CSHs from July 2009 until October 2012. PATIENTS AND METHODS: Patients eligible for burr hole surgery for CSH were randomized into either an ACE inhibitor perindopril 5mg or placebo treatment daily for three months prior to surgery. Cerebral CT scans were performed after six weeks, and clinical follow-ups were performed three months after surgery. Additionally, a retrospective analysis of the data and CT scans from all nonrandomized patients from the same time period was performed. RESULTS: Forty-seven patients were included in the randomized study. The patients' preoperative Glasgow Coma Scale scores were 15. None of the patients in the randomized group developed a recurrence after surgery. Measurements of the sizes of the CSH before and six weeks after surgery revealed no difference between the placebo and perindopril-treated groups. In the retrospective group (245 patients), there was no correlation between the risk of recurrence and ACE inhibitor treatment. CONCLUSION: Our data suggest that perindopril does not diminish the size of residual CSHs six weeks after burr hole surgery and that ACE inhibitors do not decrease the risk of CSH recurrence. PMID- 25012004 TI - Comparing the accuracy of different smell identification tests in Parkinson's disease: relevance of cultural aspects. AB - OBJECTIVE: The aim of this study is to determine the usefulness of the University of Pennsylvania smell identification test (UPSIT), sniffin sticks (SS-16) and brief smell identification test (B-SIT) to assess smell identification in the Mexican population and its accuracy in discriminating subjects with Parkinson's disease (PD). METHODS: We included 199 nondemented PD subjects and 199 control subjects matched by gender. Smell identification was tested using the UPSIT and SS-16. Our group obtained B-SIT data from a previous report. RESULTS: The mean number of UPSIT items correctly identified by controls was 27.3+/-6; the PD group had a mean score of 19.4+/-6. UPSIT had a sensitivity of 82% with a specificity of 66% for a cut-off score of <=25 for detection of PD. The mean number of SS-16 items correctly identified by controls was 10.3+/-2.2, while the PD group had 7.4+/-2.8 correct answers. For SS-16, sensitivity was 77.8% and specificity of 71.2% when using a cut-off value of <=9. Lemon, turpentine and rose had an identification rate below the 25th percentile for all three tests. Odors with an identification rate above the 75th percentile include banana for all three tests, and gasoline, onion and chocolate for UPSIT and B-SIT. CONCLUSION: The sensitivity and specificity of the smell tests that were evaluated were lower in comparison to other published reports. Cultural biases and smell familiarity may influence the test results. The development of a true cross-culturally adapted smell identification test is warranted may improve test accuracy. PMID- 25012005 TI - Pharmacoresistant epilepsy in hypomelanosis of Ito: palliative surgical treatment with modified anatomic posterior quadrantic resection. PMID- 25012006 TI - Spontaneous arteriovenous fistula of the superficial temporal artery: Diagnosis and treatment. AB - OBJECTIVES: Despite the increasing reports of traumatic and iatrogenic arteriovenous fistulas (AVFs) of the superficial temporal artery (STA), the spontaneous origination of fistulas is extremely rare, and very little is known about their natural development. Spontaneous AVFs of the STA have the characteristic findings of an expanding, painless pulsatile mass and a palpable thrill with or without a vascular murmur. PATIENTS AND METHODS: This article describes five patients with AVFs of the STA with no history of a head injury. Four of them were treated successfully either by surgical resection or by endovascular embolization. These five illustrative cases with their medium-term follow-up results are reported. RESULTS: In two patients, we successfully used a single-balloon alone to occlude the fistula without any complications; the patients experienced no recurrences during the clinical follow-up. In the other two patients, we carefully identified and ligated all of the involved feeding arteries and draining veins, which was followed by an excision of the lesion. At the 6-month follow-up, the patients were doing very well, with no evidence of AVF recurrences or new neurological complaints. CONCLUSIONS: AVFs of the STA can be detected via a computed tomography angiogram (CTA) or by intra-arterial angiography alone. Intra-arterial angiography, however, remains the definitive type of investigation. AVF may be treated either by surgical ligation and excision under a local or general anesthetic or by endovascular embolization. The former modality has been the most common method of treating the lesion in the vast majority of reports. However, endovascular embolization also appears to be suitable for treating this condition. PMID- 25012007 TI - Median-evoked somatosensory potentials in severe brain injury: does initial loss of cortical potentials exclude recovery? AB - OBJECTIVE: In patients with severe brain injury (SBI) median-evoked somatosensory potentials (M-SSEP) serve as a prognostic tool. Bilateral loss of cortical responses (BLCR) is usually thought to be a reliable marker of poor prognosis. Prognostic accuracy to predict a poor outcome depends on the cause of coma and is best in hypoxic-ischemic encephalopathy (HIE) reaching almost 100% which is in contrast to patients with other etiologies of coma, especially traumatic brain injury (TBI). Only little evidence exists on the possibility of electrophysiological recovery of BLCR in repeated or serial SSEP-examinations and detailed functional outcome in these cases. METHODS: 28 patients (78.6% male, 21.4% female, mean age 43.1+/-18.6 years) from our in-patient early (post-acute) neurorehabilitation center with BLCR in their first M-SSEP were re-examined after a mean interval of 66+/-55.8 days. SBI was caused by different etiologies. We retrospectively analyzed (a) the recovery rate from BLCR in consecutive M-SSEP and (b) the detailed functional outcome of those patients with recovered cortical responses. RESULTS: 14/28 (50%) patients with primarily BLCR showed re-occurrence of cortical potentials, either uni- or bilaterally. Of the 14 patients, one died due to a non-neurological cause. Of the remaining 13 patients 6 - most of them suffering from traumatic brain injury (TBI) - could be transferred to further continuing neurorehabilitation and achieved good functional long-term outcome. BLCR in HIE still had a poor prognosis with none of our patients achieving an outcome better than vegetative state. CONCLUSIONS: Electrophysiological recovery from primarily BLCR seems possible and is accompanied by good functional outcome in a relevant number of patients. Thus caution is warranted in predicting a poor prognosis based predominantly on SSEP, especially in patients with TBI. Focusing SSEP-examination on the early days after severe brain injury and performing only one examination in the case of BLCR may lead to systematic underestimation of the possibility of recovery. PMID- 25012008 TI - Overlapping stents for blood blister-like aneurysms of the internal carotid artery. AB - OBJECTIVE: Blood blister-like aneurysms (BBAs) are unique due to their high risk of recurrent bleeding associated with their fragile neck. The best treatment for BBAs is still controversial. This paper sought to evaluate the safety and efficacy of stent-assisted coiling and subsequent overlapping stents (SAC+OS) in the treatment of BBAs. METHODS: Fifteen consecutive patients with ruptured BBAs managed with SAC+OS were enrolled in this study. The clinical characteristics, procedural data, angiographic outcome, and follow-up results were reviewed. RESULTS: SAC+OS were successfully performed in all 15 cases. The instant angiographic result was total occlusion in 6 cases, residual neck in 7 cases, and residual aneurysm in 2 cases. Angiographic follow-ups revealed total occlusion in all 6 cases treated by triple or quadruple stents, and 6 of 9 cases treated by double stents. Major recanalization was detected in 3 cases treated by double stents. The modified Rankin Scale score at 4-52 months follow-up (23.8 months on average) was 0 in 6 cases, 1 in 8 cases, and 3 in one case. CONCLUSION: Stent assisted coiling and subsequent overlapping stents are feasible and safe for BBAs. It can be helpful to further decrease the risk of recanalization with more stents. Early angiographic follow-up within 2 weeks is recommended. PMID- 25012009 TI - Application of endovascular coiling and subsequent Onyx 34 embolization in anterior communicating artery aneurysms with adjacent hematoma. AB - OBJECTIVE: Small anterior communicating artery aneurysms with recurrent bleeding and adjacent hematoma may have a high risk of post-operative rebleeding. This clinical study summarizes our preliminary experience with this subset of aneurysms, which were treated with endovascular coiling and subsequent Onyx 34 embolization. METHODS: We retrospectively reviewed the data of 9 patients suffering from small anterior communicating artery aneurysms treated with the combination of coils and Onyx. The clinical characteristics, angiographic outcomes, and follow-up results are reviewed. RESULTS: Endovascular coiling and Onyx embolization were successfully accomplished in all 9 cases. The Raymond scale ratings of the treatments are all class I with the parent arteries kept patent. One patient died of severe brain edema on the 5th post-operative day. The modified Rankin scale (mRS) score for the other 8 patients at follow-ups (6m to 26m, 15.8m on average) was 0 in 5 cases, 1 in 2 cases, and 3 in 1 case. Seven of 8 patients (87.5%) underwent angiographic follow-up that demonstrated persistent durable occlusion with no recanalization. CONCLUSIONS: Endovascular coiling and subsequent Onyx 34 embolization may be effective in treating anterior communicating artery aneurysms with adjacent hematoma. Further studies with larger sample size and adequate follow-up are required to verify its safety and efficacy as well as to evaluate the long-term outcome. PMID- 25012010 TI - Progressive multifocal leukoencephalopathy in a patient with pre-clinical primary biliary cirrhosis. PMID- 25012011 TI - Galea-pericranium dural closure: can we safely avoid sealants? AB - OBJECTIVE: Dural closure is one of the most critical steps in neurosurgical procedures as it prevents many common postoperative complications. Methods of dural closure include the use of allogenic, autogenic, xenogenic, absorbable or synthetic materials together with sealant/glues or hemostatic compounds. Most common autogenic graft is galea-pericranium. This study aims to demonstrate how the intrinsic properties of the galea-pericranium make effectively useless the application of any glue in order to ensure the watertight integrity of the graft. PATIENTS AND METHODS: 276 cases were included in the study. Postoperative dural closure related complication in patients subjected to duraplasty were analysed in three groups undergoing different duraplasty techniques: galea-pericranium graft without sealants, galea-pericranium graft plus sealant, non-autologous dural patch plus sealant. RESULTS: No statistically significant differences between the three groups were observed in terms of subcutaneous fluid collection rate, CSF fistulas, brain abscesses, subdural empyemas, wound dehiscence, radiotherapic sequelae. CONCLUSIONS: Our study shows that galea-pericranium alone (without sealants) is comparable to other duraplasty techniques that involve the use of sealants or of non-autologous pathches in terms of long term postoperative results. PMID- 25012012 TI - The squares test as a measure of hand function in multiple sclerosis. AB - Deterioration of hand function can be important in multiple sclerosis (MS). The standard way of assessing hand function in MS is the 9-hole peg test (9HPT), one of the three components of the MS functional composite measure. In this study we examine the squares test (ST), a test of hand function that is used extensively in handedness research. We evaluated reproducibility of the ST in 49 healthy controls, and both discriminatory power and concurrent validity of the ST in 38 MS patients and 18 age and gender matched controls. The ST proved to be a reliable and easy to administrate paper-and-pencil test of hand function. The ST showed a high and highly significant correlation with the standard 9HPT over a broad range of Expanded Disability Status Scale (EDSS) scores, and had high discriminatory power, also comparable to the 9HPT. Therefore, the ST is a candidate test for use in composite measures of MS related functional deficits for clinical practice and in clinical trials. PMID- 25012013 TI - Cervical intramedullary metastasis from cerebral glioblastoma multiforme: case report. PMID- 25012014 TI - Response to antiepileptic drugs in partial epilepsy with structural lesions on MRI. AB - OBJECTIVE: Although partial epilepsy with structural lesions on MRI (lesional epilepsy) is less favorably responsive to antiepileptics than those without structural lesions on MRI, the response to antiepileptics in lesional epilepsy is a heterogeneous condition. There is growing evidence that the extent of epileptic network beyond the visible lesion on MRI may be related with the response to antiepileptics. The aims of this study are to clarify whether (1) the epilepsy network beyond the visible lesion on MRI, or (2) duration of lesional epilepsy on MRI are related with the response to antiepileptics or not. METHODS: The inclusion criteria for this study were (1) having structural lesions on MRI, (2) taking antiepileptics for at least 1 year, and (3) age >=13 years old. The definition for drug-resistance epilepsy was a failure of adequate trials of two tolerated, appropriately chosen and used antiepileptics to achieve sustained seizure freedom. The duration was defined as the interval between the start of antiepileptics and the last follow-up. We defined the lesion-plus group as the structural lesions on MRI that has wider spread of epileptic network beyond the visible lesions on MRI, such as hippocampal sclerosis and malformation of cortical development. Lesion-restriction group was defined as the epileptic network being believed to be limited on the structural lesions. RESULTS: We found 234 patients with lesional epilepsy, who met the inclusion criteria. Of these 234 patients, 115 patients were male (49%) and 119 patients were female (51%). The median age was 22 years old (range 13-78 years old) and the median duration was 131 months (range 12-516 months). Forty percent (90/234 patients) were intractable to antiepileptics. Of the structural lesions on MRI, hippocampal sclerosis was most frequent (N=90). Other structural lesions were malformation of cortical development (N=38), cerebromalatic lesions related with trauma (N=34), tumor (N=19), cystic lesion (N=15), cerebral infarction (N=11), vascular malformation (N=10), and other miscellaneous lesion (N=24). Lesion-plus group had significantly higher drug-resistance epilepsy than cystic lesions on MRI (60/128 vs. 2/15, p=0.013 by Fisher's exact test). There was a tendency of having more drug-resistance epilepsy in the lesion-plus group than the lesion-restriction group (56/121 vs. 30/89, p=0.09 by Chi-square test). The median duration in drug resistance epilepsy was significantly longer than that of medically controlled epilepsy (178 months (range 23-516 months) vs 102 months (range 12-479 months), p<0.0001 by Mann-Whitney test). In addition, duration was only the significant variable associated with drug-resistance epilepsy in lesional epilepsy by multiple logistic regression analysis (p=0.02 for overall model fit). CONCLUSION: In lesional epilepsy, hippocampal sclerosis and malformation of cortical development are more intractable to antiepileptics, reflecting wider epileptic network beyond the visible lesion. In addition, the response to antiepileptics may be expected to decrease when the duration is prolonged. PMID- 25012015 TI - A case of ipsilateral chin-eyelid synkinesis after brain trauma without peripheral facial nerve lesion. PMID- 25012016 TI - Functional magnetic resonance imaging of motor and language for preoperative planning of neurosurgical procedures adjacent to functional areas. AB - OBJECTIVE: Functional magnetic resonance imaging (fMRI) for motor and language mapping is used for presurgical planning. This study aimed to evaluate the value of fMRI in clinical routine for preoperative planning of brain surgery adjacent to functional brain areas. METHODS: Thirty-seven consecutive patients with brain lesions adjacent to sensomotor and/or language functional areas underwent fMRI prior to planned brain surgery on a 3T MRI scanner for identification of motor in all and language functional areas in 29 patients. Analysis software installed on the MRI console was used for rapid image analysis and direct visualization. All fMRI results were analyzed according to the use for preoperative planning. RESULTS: fMRI data analysis and visualization was possible in less than 10min. In 35 patients fMRI of motor cortex and in 25 patients fMRI of language could be performed due to the patient's compliance. In 34 patients motor activity could be clearly identified in the precentral gyrus. The dominant hemisphere could be identified clearly in 22 cases. In 18 patients direct anatomical correlation of the activity maps to the speech area of Broca and/or Wernicke could be made. Resection surgery was performed in all patients. 11 patients underwent awake surgery with intraoperative cortical stimulation. CONCLUSION: fMRI for clinical routine is a reliable and rapid method for identification of functional brain areas prior to brain surgery adjacent to functional areas. This method allows direct monitoring of the data quality and visualization without being time consuming. Knowledge about the relation of functional areas to the brain lesions improves the preoperative planning, the operation strategy and decision making with patients. PMID- 25012017 TI - Impact of aneurysm location on hemorrhage risk. AB - INTRODUCTION: Recent studies have reinforced anterior communicating (AComm) artery location as a significant risk factor for aneurysm rupture in addition to posterior circulation/posterior communicating (PComm) artery location. However, studies stratifying aneurysm location in greater detail are sparse. METHODS: We reviewed the records of 747 consecutive patients with 1013 aneurysms seen at our institution over a 7 year period, noting aneurysm location and rupture status at the time of presentation. RESULTS: High proportions of ruptured aneurysms were seen among frontopolar/pericallosal (59%, OR 3.07, p=0.011), vertebral/posteroinferior cerebellar (PICA; 53%, OR 2.49, p=0.0037), AComm (50%, OR 2.46, p<0.0001), and PComm aneurysms (44%, OR 1.77, p=0.0016). Low proportions of ruptured aneurysms were seen among superior hypophyseal artery (SHA; 6%, OR 0.12, p=0.0001), internal carotid artery (ICA) bifurcation (12%, OR 0.27, p=0.0012), and ophthalmic artery aneurysms (15%, OR 0.33, p=0.0002). The proportion of ruptured PComm aneurysms demonstrated a trend toward being greater than anterior choroidal artery aneurysms (OR 2.14, p=0.09); however the proportion was significantly greater among anterior choroidal artery aneurysms as compared to nonPComm intradural ICA aneurysms (OR 2.78, p=0.03). Notably, the lower rupture rate of SHA aneurysms as compared to ophthalmic artery aneurysms neared statistical significance (OR 0.38, p=0.10). CONCLUSION: Aneurysm location has a significant impact on risk of rupture and should be stratified in greater detail in future studies of aneurysm natural history. PMID- 25012018 TI - Prognostic factors of clinical outcome after neuronavigation-assisted hematoma drainage in patients with spontaneous intracerebral hemorrhage. AB - OBJECTIVE: The prognostic factors that contribute to outcome after navigation assisted drainage in patients with spontaneous intracerebral hemorrhage (ICH) have not been defined. We compared the characteristics and clinical outcomes of patients with spontaneous ICHs who underwent neuronavigation-assisted hematoma drainage. METHODS: Forty-seven patients were enrolled from January 2004 to August 2013. The patients were divided into two groups according to Glasgow Outcome Scale (GOS) scores: the good- (GOS 4-5) and poor-outcome (GOS 1-3) groups. A variety of factors, characteristics, and clinical outcomes were analyzed. RESULTS: Among the 47 patients, 16 and 31 showed good and poor outcomes, respectively. The mortality rate was 4.3%. Patients' ages, horizontal and vertical diameters and volume of the hematoma on the initial brain computed tomography scan, and the initial Glasgow Coma Scale (GCS) scores were significantly different between the two groups (P<0.05). Ages less than 60 years, smaller horizontal and vertical diameters of the hematoma, less initial hematoma volume, higher initial GCS scores, and the absence of intraventricular hemorrhages were significantly associated with good outcome (P<0.05). Among these factors, initial hematoma volume was a borderline prognostic factor (odds ratio [OR], 0.951; 95% confidence interval [CI], 0.904-1.001; P=0.054), whereas initial GCS score was a significant prognostic factor (OR, 2.737; 95% CI, 1.371-5.465; P=0.004), in the multivariate analysis. CONCLUSION: Initial GCS score and hematoma volume were important prognostic factors of clinical outcome in patients with spontaneous ICHs who underwent navigation-assisted drainage. Such factors should be carefully considered before patients are treated with navigation assisted hematoma drainage. PMID- 25012019 TI - The clinical experience of recurrent central nervous system hemangioblastomas. AB - OBJECTIVE: Hemangioblastomas (HBLs) of the central nervous system are benign vascular tumors that may occur sporadically or in von Hippel-Lindau disease (VHLD). We analyzed the clinical and radiological findings of HBLs focusing on recurrence. MATERIAL AND METHODS: From 1998 to 2012, 36 patients with HBLs were treated. Twenty nine patients (80.6%, mean age 46.7 years) had sporadic HBLs and seven (19.4%, mean age 39 years) had HBLs associated with VHLD. Initially, the mass was totally removed in 32 patients, subtotally in one and partially in one, and gamma knife radiosurgery was done in two patients. The mean duration of follow-up was 48.4 months. We retrospectively analyzed the clinical and radiologic findings. RESULTS: The location of cerebellum and brainstem was common. The HBLs of spinal cord and cerebral hemisphere were related with VHLD. The common radiologic findings of sporadic HBLs showed a cyst with a mural nodule in 15 patients (51.7%) and pure solid lesion in eight (27.6%). In HBLs related with VHLD, five of seven patients had multiple lesions and pure solid mass was common. Three (10.3%) and two (28.6%) patients showed recurrence in sporadic and VHLD-related HBLs, respectively. Two totally resected mural nodules on the cyst showed recurrence with similar radiologic findings 3 years later in sporadic HBLs. In recurred HBLs related with VHLD, one pure solid mass and one mural nodule on cyst showed the local recurrences after the total resection 8 years later and associated with distant recurrence. CONCLUSIONS: All patients should be more specifically followed to detect local and distant recurrence, even if the clinical course was benign and mass was totally removed. PMID- 25012020 TI - Treatment of traumatic spondylolisthesis of the lower cervical spine with concomitant bilateral facet dislocations: risk of respiratory deterioration. AB - BACKGROUND: This study aimed to retrospectively examine 36 cases of bilateral cervical facet dislocations (BCFD) of the lower cervical spine who were at risk for respiratory deterioration. METHODS: The cases of 36 subjects with BCFD of the lower cervical spine who failed to achieve closed reduction were retrospectively studied. The extents of neurological injuries included posterior neck pain without neurological deficit (n=2), incomplete spinal cord injury (ISCI) (n=21), and complete spinal cord injury (CSCI) (n=13). RESULTS: Among the subjects, 26 (72.22%) had dyspnea, 6 required mechanical ventilation due to respiratory muscle paralysis, 11 required tracheostomy, and 9 required intubation. All patients received posterior approach reduction, stabilization, and fusion treatment for BCFD in one operative session. For the 26 quadriparetic patients with dyspnea, priority was given to treating their respiratory problems. For the other 10 patients without dyspnea, surgical treatment for irreducible lower cervical spine dislocation was given priority. After an average follow-up period of 63 months, 21 complications were found, but all patients exhibited fusion. Twenty-one patients with ISCI exhibited improvements in their conditions of 1 or 2 grades on the American Spinal Injury Association scale, whereas those with CSCI did not improve. All 26 apnea cases improved. The majority (26) of the 36 cases with BCFD of the lower cervical spine suffered dyspnea. CONCLUSIONS: Although further study is required, our study suggests that the posterior surgical approach to the cervical spine is safe and effective for patients with traumatic spondylolisthesis of the lower cervical spine concomitant with BCFD who are at risk of respiratory deterioration. PMID- 25012021 TI - Sellar and parasellar lesions - clinical outcome in 61 children. AB - OBJECTIVE: To evaluate clinical outcome in a 10-year consecutive series of children operated for sellar and parasellar tumors with special focus on neuropsychology and endocrinology. PATIENTS AND METHODS: We analyzed 61 children (30 female) under 18 years of age (mean age 9.9, range 1 month-17 years) operated between 2000 and 2010. Medical records were evaluated retrospectively; postoperative histologic diagnoses included 20 craniopharyngiomas, 17 gliomas, 6 pituitary adenomas and 18 rare tumor entities. RESULTS: Of 61 patients, 58 (95%) were still alive at last follow-up. Three patients died, all due to progression of malignant rhabdoid tumors. Postoperative clinical morbidity consisted of endocrinological (66%), visual (60.7%) and other neurological deficits (55.9%) after a mean follow-up of 44 months. When compared to all other tumor entities in this series, craniopharyngiomas were associated with high rates of gross-total resection (p=0.008), frequent progression of residual tumor (p=0.005) scotomas (p=0.013), persistent diabetes insipidus (p<0.001), and panhypopituitarism (p<0.001). Surgically treated gliomas showed higher rates of motor weakness (p=0.004), double vision (p<0.001), and milder forms of endocrinopathy (single hormone deficits, p=0.02). In general, deterioration in school performance was associated with multiple surgeries (p=0.018) and radiotherapy (p=0.021). CONCLUSION: Excellent overall survival in these patients is possible, however malignant rhabdoid tumors have a poor prognosis. Aggressive treatment is associated with significant morbidity. Children operated for craniopharyngioma showed an expected high rate of endocrine deterioration, whereas glioma patients had higher incidences of motor weakness and double vision. The treating physicians should be well aware of all these considerable postoperative deficits, especially when facing interdisciplinary management decisions, and for the informed consent discussions with the patient and the parents. PMID- 25012022 TI - Chemoprophylaxis for venous thromboembolism in traumatic brain injury: a review and evidence-based protocol. AB - Venous thromboembolism (VTE) is a recognized source of morbidity and mortality in patients suffering traumatic brain injury (TBI). While traumatic brain injury is a recognized risk factor for the development of VTE, its presence complicates the decision to begin anticoagulation due to fear of exacerbating the intracranial hemorrhagic injury. The role of chemoprophylaxis in this setting is poorly defined, leading to a wide variability in clinical practice. A comprehensive review of the literature was performed in an effort to summarize relevant data and construct a chemoprophylaxis protocol to be implemented in a Level I Trauma Center. The review reveals robust evidence regarding the safety and efficacy of chemoprophylaxis in the setting of TBI following demonstration of a stable intracranial injury. In light of this data, a protocol is assembled that, in the absence of predetermined exclusion criteria, will initiate chemoprophylaxis within 24h after the demonstration of a stable intracranial injury by computed tomography (CT). PMID- 25012023 TI - Minimally invasive key-hole approach for the surgical treatment of single and multiple brain metastases. AB - The role of surgical management in the setting of multiple brain metastases is controversial. Although the role of surgical resection in single brain metastases is well stated, in multiple brain metastases whole brain radiation therapy remains a mainstay of treatment. In this series, the authors evaluate the efficacy of minimally invasive neurosurgical techniques in the resection of brain metastases with a particular focus on multiple metastases. 57 patients who underwent surgical resection of brain metastases with a key-hole approach, were analyzed for surgical success, complications, neurological deficits, functional outcome and overall survival. 187 brain metastases were detected. The majority of patients improved in KPS postoperatively at 6 weeks (80.6%) and 3 months follow up (62.5%). Mean overall survival was 14.2 months with a 1 year survival rate of 44%. According to univariate analysis, poor systemic control of cancer, tumor extending to both lobar and deep brain, lower extent of resection and symptomatic tumor resection were found to be associated with poorer survival. With the use of minimally invasive neurosurgery, aggressive management of multiple metastases leads to minimal postoperative stay, improvement in quality of life and overall survival. Patient overall survival is dependent on recursive partitioning analysis (RPA) class, and should be used to guide management. PMID- 25012024 TI - Evaluate the serum cortisol in patients with intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: The level of stress hormones, especially cortisol reflects stroke severity and acts as an early risk assessment of the severity of disease and prognosis. There are few neuroendocrine change and prognostic value data in patients with spontaneous supratentorial intracerebral hemorrhage (ICH). The present study aimed to evaluate the prognostic value of cortisol in patients with acute ICH. METHODS: In a prospective observational study including 61 consecutive patients with supratentorial ICH, the morning (8 a.m.) serum cortisol level and afternoon (4 p.m.) serum cortisol level were measured to determine their value to predict functional outcome and mortality within 90 days. RESULTS: Cortisol levels were increased in patients with an unfavorable functional outcome as compared to patients with a favorable functional outcome within 90 days (8 a.m. p<0.001; 4 p.m. p<0.001), and in patients who died within 90 days as compared to survivors (8 a.m. p<0.001; 4 p.m. p=0.003). For functional outcome prediction, receiver-operating-characteristics revealed an area under the curve (AUC) on admission for cortisol (8 a.m.: AUC 0.86 (95% CI 0.77-1.00)), which was statistically not different from the National Institutes of Health Stroke Scale (NIHSS) (p=0.20) or ICH score (p=0.84). For mortality prediction, cortisol had an AUC of 0.87 (95% CI 0.67-1.00), which was statistically not different from the NIHSS (p=0.58) or ICH score (p=0.68). CONCLUSIONS: In our small cohort of patients with acute ICH, elevated cortisol was associated with increased mortality and worse outcome. If confirmed in a larger study, the morning serum cortisol may be used as an additional prognostic factor in ICH patients. PMID- 25012025 TI - Clinically relevant complications related to posterior atlanto-axial fixation in atlanto-axial instability and their management. AB - BACKGROUND: The Magerl transarticular technique and the Harms-Goel C1 lateral mass-C2 isthmic screw technique are the two most commonly used surgical procedures to achieve fusion at C1-C2 level for atlanto-axial instability. Despite recent technological advances with an increased safety, several complications may still occur, including vascular lesions, neurological injuries, pain at the harvested bone graft site, infections, and metallic device failure. METHODS: We retrospectively analyzed all patients (n=42 cases) undergoing a Harms Goel C1-C2 fixation surgery with polyaxial C1 lateral mass screws and C2 isthmic screws at two different institutions between 2003 and 2012 and report clinical and radiological complications. One patient was lost to follow-up. The mean follow-up of the remaining 41 patients was 18.7 months (range 12-90). A clinically relevant complication was defined as a complication determining the onset of a new neurological deficit or requiring the need for a revision surgery. RESULTS: A total of 14 complications occurred in 10 patients (24.4% of 41 patients). Greater occipital nerve neuralgia was evident in 4 patients (9.8%). All but one completely resolved at the end of the follow-up. Persistent neck pain was reported by 3 patients (7.3%), hypoesthesia by 1 patient (2.4%), and anesthesia in the C2 area on both sides in 1 patient (2.4%). Furthermore, a superficial, a deep, and a combined superficial and deep wound infection occurred in 1 patient each (2.4%). One patient (2.4%) had pain at the iliac bone graft donor site for several weeks with spontaneous resolution. A posterior progressive intestinal herniation through the iliac scar was seen in 1 case (2.4%), which required surgical repair. No vascular damages occurred. Altogether, 5/41 patients (12.2%) had a clinically relevant complication including 4 patients necessitating a revision surgery at the C1-C2 level (9.8%). CONCLUSIONS: Atlanto-axial fixation surgery remains a challenging procedure because of the proximity of important neurovascular structures. Nevertheless, on the basis of our current experience, the C1 lateral mass-C2 isthmic screw technique appears to be safe with a low incidence of clinically relevant complications. Postoperative C2 neuralgia, as the most frequent problem, is due to surgical manipulation during preparation of the C1 screw entry point. PMID- 25012026 TI - Poor outcomes of elderly patients undergoing multimodality intra-arterial therapy for acute ischemic stroke. AB - OBJECTIVE: The incidence of acute ischemic stroke is highest in the elderly. Information regarding outcomes of elderly patients undergoing different modalities of intra-arterial therapy (IAT) for acute ischemic stroke (AIS) is scarce and conflicting. This study compares the safety, technical efficacy and outcomes of elderly patients (>=80 years) to non-elderly patients (<80 years) who underwent multimodality IAT. METHODS: From a registry of consecutive patients treated with IAT for AIS at our institution over a 3.5-year period, patients with anterior circulation occlusions aged >=80 years were compared to the patients <80 years. RESULTS: Between 2008 and 2012, 24 patients >=80 years (elderly) and 95 patients <80 years (non-elderly) received IAT for anterior circulation occlusions. In the elderly, there were more females (66.7% vs. 28.4%, p=<0.001) and atrial fibrillation (58.3% vs. 25.2%, p=0.003). Between the 2 groups, there was no difference in NIHSS score (17.2 vs. 16.3, p=0.17), THRIVE score (4.21 vs. 4.39, p=0.633), recanalization rate (70.1% vs. 85.3%, p=0.13), or severe reperfusion hemorrhages (8.3% vs. 4.2%, p=0.425). There was no significant difference in 3-month mortality (33.3% vs. 16.8%, p=0.28); however, fewer elderly patients reached good 3-month outcome (0% vs. 40.0%, p=<0.001). After controlling for baseline factors, only female gender (OR 5.3, 95% CI 1.7-16.7; p=0.04) and higher 3-month mRS (OR 1.6; 95% CI 1.1-2.40; p=0.008) were independently associated with elderly age. CONCLUSION: Despite similar safety profiles and recanalization rates, elderly patients had poor functional outcomes after IAT. Intra-arterial therapy in the elderly should be pursued very cautiously only after careful analysis of the risks and benefits for each patient. PMID- 25012027 TI - Cerebral blood flow velocity underestimates cerebral blood flow during modest hypercapnia and hypocapnia. AB - To establish the accuracy of transcranial Doppler ultrasound (TCD) measures of middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) as a surrogate of cerebral blood flow (CBF) during hypercapnia (HC) and hypocapnia (HO), we examined whether the cross-sectional area (CSA) of the MCA changed during HC or HO and whether TCD-based estimates of CBFV were equivalent to estimates from phase contrast (PC) magnetic resonance imaging. MCA CSA was measured from 3T magnetic resonance images during baseline, HO (hyperventilation at 30 breaths/min), and HC (6% carbon dioxide). PC and TCD measures of CBFV were measured during these protocols on separate days. CSA and TCD CBFV were used to calculate CBF. During HC, CSA increased from 5.6 +/- 0.8 to 6.5 +/- 1.0 mm(2) (P < 0.001, n = 13), while end-tidal carbon dioxide partial pressure (PETCO2) increased from 37 +/- 3 to 46 +/- 5 Torr (P < 0.001). During HO, CSA decreased from 5.8 +/- 0.9 to 5.3 +/- 0.9 mm(2) (P < 0.001, n = 15), while PetCO2 decreased from 36 +/- 4 to 23 +/- 3 Torr (P < 0.001). CBFVs during baseline, HO, and HC were compared between PC and TCD, and the intraclass correlation coefficient was 0.83 (P < 0.001). The relative increase from baseline was 18 +/- 8% greater (P < 0.001) for CBF than TCD CBFV during HC, and the relative decrease of CBF during HO was 7 +/- 4% greater than the change in TCD CBFV (P < 0.001). These findings challenge the assumption that the CSA of the MCA does not change over modest changes in PETCO2. PMID- 25012028 TI - Acute cardiopulmonary effects induced by the inhalation of concentrated ambient particles during seasonal variation in the city of Sao Paulo. AB - Ambient particles may undergo modifications to their chemical composition as a consequence of climatic variability. The determination of whether these changes modify the toxicity of the particles is important for the understanding of the health effects associated with particle exposure. The objectives were to determine whether low levels of particles promote cardiopulmonary effects, and to assess if the observed alterations are influenced by season. Mice were exposed to 200 MUg/m(3) concentrated ambient particles (CAPs) and filtered air (FA) in cold/dry and warm/humid periods. Lung hyperresponsiveness, heart rate, heart rate variability, and blood pressure were evaluated 30 min after each exposure. After 24 h, blood and tissue samples were collected. During both periods (warm/humid and cold/dry), CAPs induced alterations in red blood cells and lung inflammation. During the cold/dry period, CAPs reduced the mean corpuscular volume levels and increased erythrocytes, hemoglobin, mean corpuscular hemoglobin concentration, and red cell distribution width coefficient variation levels compared with the FA group. Similarly, CAPs during the warm/humid period decreased mean corpuscular volume levels and increased erythrocytes, hemoglobin, hematocrit, and red cell distribution width coefficient variation levels compared with the FA group. CAPs during the cold/dry period increased the influx of neutrophils in the alveolar parenchyma. Short-term exposure to low concentrations of CAPs elicited modest but significant pulmonary inflammation and, to a lesser extent, changes in blood parameters. In addition, our data support the concept that changes in climate conditions slightly modify particle toxicity because equivalent doses of CAPs in the cold/dry period produced a more exacerbated response. PMID- 25012029 TI - Circulating angiogenic cell population responses to 10 days of reduced physical activity. AB - Circulating angiogenic cells (CACs) are a diverse group that have been identified as predictors of cardiovascular health and are inversely proportional to cardiovascular disease (CVD) outcomes. Inactivity is a growing concern in industrialized nations and is an independent risk factor for CVD. There is limited evidence regarding the impact of reduced physical activity (rPA) on different CAC populations. The purpose of this study was to evaluate the effect of objectively monitored rPA with maintained energy balance on two CAC populations (CFU and CD34(+) cells), intracellular nitric oxide (NOi), and genes related to NO production in active, healthy men. Participants (age 25 +/- 2.9 yr) refrained from structured physical activity for 10 days, which was reflected by a significant reduction in time in vigorous + very vigorous intensity activity (P = 0.03). Sedentary time tended to increase (P = 0.06) with rPA. CFU CACs have been characterized as mainly monocytic and lymphocytic cells. We found significant reductions in both the number of CFU CACs (-35.69%, P = 0.01) and CFU CAC NOi ( 33.84%, P = 0.03). Neither NOi nor the number of CD34(+) cells, which are hematopoietic and endothelial progenitors, changed with rPA. We found no significant differences in NO-related gene expression or oxidative stress-related gene expression with rPA in either CAC type. Therefore, we conclude that although various CAC populations have been related to vascular health, regular physical activity is necessary to maintain CAC NOi and the vulnerability of CACs to short term reductions in physical activity is population specific. PMID- 25012030 TI - A method of switching the signal in an MRI phantom based on trace ion currents. AB - A method for electrically changing the hydrogen nuclear magnetic resonance (NMR) signal intensity in a magnetic resonance imaging (MRI) phantom is presented. The method is based on creating local magnetic field inhomogeneities from impurity ion currents in a polar hydrocarbon. The effect is demonstrated using the propylene carbonate on an NMR spectrometer and an MRI scanner. This effect is largest when the electric field is applied perpendicular to the static magnetic field in magnetic resonance, and is linear with applied voltage. The applicability of a switchable signal in an MRI phantom is demonstrated with a spin-echo, echo planar imaging sequence where the MRI signal is changed between blocks of 10 images in a series of 200 images. This technique may find applications in inter and intra platform fMRI quality control. PMID- 25012031 TI - Regulation of some salt defense-related genes in relation to physiological and biochemical changes in three sugarcane genotypes subjected to salt stress. AB - Sugarcane (Saccharum officinale L.; Poaceae) is a sugar-producing plant widely grown in tropic. Being a glycophytic species, it is very sensitive to salt stress, and salinity severely reduces growth rate and cane yield. The studies investigating the regulation of salt defense metabolite-related genes in relation to final biochemical products in both susceptible and tolerant genotypes of sugarcane are largely lacking. We therefore investigated the expression levels of sugarcane shaggy-like kinase (SuSK), sucrose transporter (SUT), proline biosynthesis (pyrolline-5-carboxylate synthetase; P5CS), ion homeostasis (NHX1), and catalase (CAT2) mRNAs, and contents of Na(+), soluble sugar, and free proline in three sugarcane genotypes (A19 mutant, K88-92, and K92-80) when subjected to salt stress (200 mM NaCl). The relative expression levels of salt defense-related genes in salt-stressed plantlets of sugarcane cv. K88-92 were upregulated in relation to salt exposure times when compared with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as housekeeping gene. In addition, final biochemical products, i.e., low Na(+), sucrose enrichment, and free proline accumulation, were evidently demonstrated in salt-stressed plantlets. Chlorophyll b, total chlorophyll, total carotenoid concentrations, and maximum quantum yield of PSII (F v/F m) in positive check (K88-92) were maintained under salt stress, leading to high net photosynthetic rate (P n) and growth retention (root length, fresh weight, and leaf area). In contrast, photosynthetic abilities in negative check, K92-80, and A19 mutant lines grown under salt stress declined significantly in comparison to control, leading to a reduction in P n and an inhibition of overall growth characters. The study concludes that the genetic background of sugarcane cv. K88-92 may further be exploited to play a key role as parental clone for sugarcane breeding program for salt-tolerant purposes. PMID- 25012032 TI - [The increasing burden of chronic respiratory diseases in women. An expanding area of research]. PMID- 25012033 TI - [Features of asthma in women: what is the relationship with hormonal status?]. AB - INTRODUCTION: The prevalence and control of asthma are modulated by hormonal changes in women, suggesting an influence of sex hormones on the airways. BACKGROUND: The blood levels of both oestrogens and progesterone can modulate airway tone and inflammation. Asthma prevalence changes at puberty and the menopause, events also associated with modifications of adipose tissue and behaviour. Changes in lung function and asthma control are well documented during the menstrual cycle. However, an effect of hormone therapy on asthma control has not been demonstrated. PERSPECTIVE: The effect of a targeted hormonal therapeutic intervention in menopausal asthma, a phenotype, which is frequently particularly severe, or in premenstrual asthma, should be evaluated by randomized trials. CONCLUSION: Involvement of sex hormones and their cyclical variations in the characteristics of asthma in women is probable, despite lack of convincing data. However, no definitive protective or deleterious effect can be assigned. Complex interactions with adipose tissue, airways anatomy and the domestic or working environment must be taken into account to explain these differences. PMID- 25012034 TI - [Asthma in the elderly]. AB - Asthma is a common condition in the elderly although often confounded with chronic obstructive pulmonary disease (COPD) in this population. Asthma in the elderly seems to represent a specific phenotype characterized by more severe, but often less perceived, airway obstruction, a neutrophilic or mixed-type of airway inflammation and frequent comorbidities. Patients aged 65 years and over have an increased asthma-related morbidity and mortality compared to younger patients, probably due to difficulties in regard to diagnosis, assessment of the disease severity and treatment. Research is urgently needed to determine the optimal treatment of the aged patient. In this document we will review the state of knowledge on this topic and discuss the challenges of multidisciplinary asthma management in the elderly. PMID- 25012035 TI - [Cannabis smoking and lung cancer]. AB - Cannabis is the most commonly smoked illicit substance in the world. It can be smoked alone in plant form (marijuana) but it is mainly smoked mixed with tobacco. The combined smoking of cannabis and tobacco is a common-place phenomenon in our society. However, its use is responsible for severe pulmonary consequences. The specific impact of smoking cannabis is difficult to assess precisely and to distinguish from the effect of tobacco. Marijuana smoke contains polycyclic aromatic hydrocarbons and carcinogens at higher concentration than tobacco smoke. Cellular, tissue, animal and human studies, and also epidemiological studies, show that marijuana smoke is a risk factor for lung cancer. Cannabis exposure doubles the risk of developing lung cancer. This should encourage clinicians to identify cannabis use and to offer patients support in quitting. PMID- 25012036 TI - [COPD and perception of the new GOLD document in Europe. Workshop from the Societe de pneumologie de langue francaise (SPLF)]. AB - INTRODUCTION: The organization of care for chronic non-infectious diseases, notably COPD, is a common preoccupation in developed countries in which this disease is among the main causes of mortality and disability. We report a summary of a workshop organized on this theme in April 2013 by the Societe de pneumologie de langue francaise. BACKGROUND: Experts from several European countries presented the organizational practices for the management of COPD in their countries, in particular the detection of the disease and the systems of care. The common objectives were to obtain better motivation to stop smoking, earlier detection of the disease and education in the recognition of the signs of exacerbation and their severity. The experts agreed that mass detection is of little benefit and difficult to organize. Early individual screening is preferable on the basis of precise, easily identified criteria. The classification recommended by the GOLD committee since 2011 does not seem to be adopted universally throughout Europe. If there is a real improvement over the previous classification due to taking into account clinical criteria, quality of life and exacerbations, criticisms have arisen concerning the choice of certain pathways and therapeutic recommendations not based on prospective studies with a high level of evidence. CONCLUSION: European experiences concerning the management of COPD are varied and complementary. One remaining question is who to screen: all subjects at risk (all smokers, all occupations at risk), only symptomatic subjects, subjects with severe and disabling symptoms? PMID- 25012038 TI - [Physiological significance and interpretation of plasma lactate concentration and pH in clinical exercise testing]. AB - According to a widely accepted model, based on the theory of the anaerobic threshold (AT), the increase in plasma lactate concentration which develops after the first ventilatory threshold (VT1, considered as an AT) is due to compensation for insufficient aerobic metabolism by anaerobic glycolysis, with accumulation of lactic acid resulting in a decrease in pH. Bicarbonate is the main buffer of protons (>90%) producing non-metabolic CO2 in muscle and thus increasing the CO2 flux to the lungs. This phenomenon, along with the low pH, triggers hyperventilation. Because of this model, great importance has been placed on plasma lactate and pH. We argue that this importance is excessive and these variables should be used with caution in the interpretation of clinical exercise testing, because the model based on AT is not valid: there is no aerobic failure above VT1 and, thus, there is no evidence of an AT; the increase in plasma lactate does not reflect anaerobiosis but is the marker of the increase in the error signal needed for the stimulation of mitochondrial respiration; bicarbonate is not the main buffer during exercise (these are proteins and phosphocreatine breakdown in the muscle; hemoglobin in the blood); non-metabolic CO2 is not produced in the muscle but in the lung because of the low pH and hyperventilation (the control of which remains unknown); and the flux of CO2 to the lung does not increase at faster rate after than before VT1. PMID- 25012039 TI - [Chest physical therapy of the distal lung. Mechanical basis of a new paradigm]. AB - Recent medical literature has shown that there has been renewed interest focused on the small airways deep in the lung tissue. Although there is involvement of the distal airways at an early stage in mucus secreting lung diseases, no specific chest physical therapy (CPT) manoeuver has been proposed for small airways clearance. A four-tier classification of CPT has been established with identification of its benefits at each level of a monoalveolar respiratory tract model. The usual expiratory techniques directed towards the upper and middle respiratory tract are not applicable to the small airways and new paradigm is proposed appropriate to their specific mechanical characteristics. This comprises a slow resistive inspiratory manoeuver in the lateral position. Clinical auscultation of the lung is the cornerstone of the validation and follow-up of the technique. PMID- 25012037 TI - [Adjuvant surgical resection for multidrug-resistant tuberculosis: A review]. AB - INTRODUCTION: The frequency of multi and extensively drug resistant pulmonary tuberculosis (MDR/XDR-TB) is increasing worldwide, with major issues related to treatment modalities and outcome. In this setting, the exact benefits associated with surgical resection are still unknown. METHODS: We performed a literature review to determine the indications, morbidity, mortality and bacteriological success associated with the surgical management of MDR/XDR-TB patients. RESULTS: Altogether, 177 publications dealing with surgical resection and MDR/XDR-TB have been analyzed, including 35 surgical series and 24 cohort studies summarized in one meta-analysis. The surgical series reported success rates from 47% to 100%, complication rates from 0 to 29%, and mortality rates from 0 to 8%. The published meta-analysis reported a statistically significant association between surgical resection and treatment success (OR 2.24, IC95% 1.68-2.97). However, all these studies were associated with selection bias. International consensual guidelines included a multidisciplinary assessment in a reference centre, a personalized and prolonged antibiotic treatment and a medico-surgical discussion on a case-to-case basis. PERSPECTIVES: These guidelines are now applied for the management of patients with MDR/XDR-TB in our centre. Further studies are required to avoid further increase in the burden of MDR/XDR-TB and to establish the optimal timing of medical and surgical treatments. PMID- 25012040 TI - [Epidemiology of obstructive sleep apnoea syndrome]. AB - INTRODUCTION: Epidemiological cohorts based on population samples, established in the 1990s, have helped to clarify the prevalence of obstructive sleep apnoea syndrome (OSAS) and to identify key risk factors and co-morbidities. STATE OF KNOWLEDGE: OSAS is a common disease whose prevalence increases with age. Its main risk factor is obesity, but familial and genetic predisposition may also promote the condition. The association of OSAS with increased cardiovascular mortality has been known for several years and has been confirmed by recent data from epidemiological cohorts showing increased mortality including an increased incidence of coronary events and stroke in particular in men aged below 70 years. Recent studies also show an independent association between OSAS and cancer mortality. CONCLUSIONS: OSAS is a common disease whose prevalence continues to increase with the increase of obesity in the population. Large epidemiological studies have shown an independent relationship between OSAS and cardiovascular diseases, metabolic disorders and more recently cancer. PMID- 25012041 TI - Protective mechanism of Panax notoginseng saponins on rat hemorrhagic shock model in recovery stage. AB - To explore protective mechanism of Panax notoginseng saponins (PNS) on rat hemorrhagic shock model in recovery stage. 72 Wistar rats were selected and divided into control group, model group and PNS group with 24 rats in each group. 200 mg/kg PNS was injected intravenously at 60 min of hemorrhagic shock stage in PNS groups. Changes of endotoxin, MPO, IL-6, SOD, MDA and TNF alpha were observed at 30 and 120 min of recovery stage by ELISA; water content of lung and intestine was detected; HE staining was applied to observe morphological change of intestinal mucosa, kidney, liver and lung; western blot was used to detect intercellular adhesion molecule-1 (ICAM-1) level in lung tissue and intestine tissue. At 30 min and 120 min of recovery stage, MDA, MPO, endotoxin, TNF alpha and IL-6 levels significantly increased in model group compared with control group, however SOD level significantly decreased, the difference was statistically significant (P < 0.05); PNS dose-dependently decreased MDA, MPO, endotoxin, TNF alpha and IL-6 levels, and increased SOD level, which was statistically significant (P < 0.05); In results of water content detection, water content in lung tissue and intestine tissue was significantly higher than in control group, however, after being treated with PNS, the water content was significantly decreased; HE staining showed the morphologic change of lung tissue cells; Western blot showed that in lung tissue and intestine tissue, ICAM-1 level in model group was significantly higher than in control group, and it was lower in PNS group than in model group. PNS can increase SOD activity, decrease levels of MDA, endotoxin and MPO, decrease expression of TNF alpha and IL-6, and decrease water content in lung tissue and intestine tissue. Thus, PNS is protective to rat hemorrhagic shock model by anti oxidative stress and anti inflammatory pathways, and ICAM-1 may play an important role in the mechanism. PMID- 25012042 TI - Urological results after fetal myelomeningocele repair in pre-MOMS trial patients at the Children's Hospital of Philadelphia. AB - INTRODUCTION: Myelomeningocele patients deal with multiple medical issues, including lower extremity neurological deficits, bowel and bladder incontinence and the sequelae of hydrocephalus secondary to a Chiari II malformation. In utero intervention holds the promise of reversing some of the sequelae and improving outcome. MATERIAL AND METHODS: Between 1998 and 2003 (preceding the formal Management of Myelomeningocele Study, MOMS), an initial group of 58 patients underwent in utero repair of their myelomeningocele between 21 and 25 weeks' gestation. Long-term (5-year) follow-up has occurred in this cohort of patients. Previous reports have documented decreased incidence of ventriculoperitoneal shunting and neuromotor functioning, showing improved outcomes compared with historical controls. RESULTS: Overall, 4 fetal deaths occurred, while the majority of patients returned for follow-up for up to 5 years after closure. Phone follow-up has also been conducted for those who could not return. To date, 10 patients (18.5%) have successfully toilet-trained, while 2 patients have bowel continence and 1 has bladder continence but requires enemas; 2 patients who successfully toilet-trained developed spinal dermoid cysts requiring surgical resection. DISCUSSION: Historically, in utero repair of myelomeningocele patients yields a greater percentage of patients who have achieved continence compared with those undergoing postnatal repair. The MOMS trial will compare contemporary urological outcomes of those patients undergoing either prenatal or postnatal repair in a randomized fashion. The results of this trial showed a decreased need for ventriculoperitoneal shunting in those patients who underwent in utero repair as well as an improvement in lower extremity function. PMID- 25012043 TI - Adding low-field magnetic stimulation to noninvasive electromagnetic neuromodulatory therapies. PMID- 25012044 TI - Bridging the gap: combining somatic and psychological interventions. PMID- 25012045 TI - Deep brain stimulation in major depression: plastic changes of 5 hydroxytryptamine neurons. PMID- 25012046 TI - Impact of trastuzumab treatment beyond disease progression for advanced/metastatic breast cancer on survival - results from a prospective, observational study in Germany. AB - OBJECTIVES: Evidence suggests that continued trastuzumab therapy beyond progression (TBP) may provide additional survival benefit. Within the framework of an observational prospective study of patients with advanced/metastatic breast cancer receiving trastuzumab in routine clinical practice, we had the opportunity to examine the effect of TBP in a large population. PATIENTS AND METHODS: Among a total of 1843 trastuzumab-treated patients, a sub-cohort of 418 fulfilled the selection criteria for the TBP analysis: 261 continued trastuzumab and 157 discontinued. Logrank tests and Cox models were used to compare survival and identify prognostic factors. RESULTS: Survival from progression was significantly longer in those patients continuing trastuzumab treatment beyond disease progression (TBP: median 22.1 months; no TBP: median 14.9 months; HR = 0.64; P = 0.00021). In addition to TBP, a positive endocrine receptor status, a longer relapse-free interval, no visceral metastasis, no concomitant chemotherapy during first-line treatment, and first-line response were independently significant prognostic variables for longer survival on multivariate analysis. CONCLUSION: The hitherto limited evidence for TBP benefit from randomized studies was confirmed. While a number of strong disease-related predictors for survival after first progression could be identified, the positive effect of trastuzumab continuation retained statistical significance in a multivariate model. PMID- 25012047 TI - Is breast cancer from Sub Saharan Africa truly receptor poor? Prevalence of ER/PR/HER2 in breast cancer from Kenya. AB - OBJECTIVES: Studies on ER/PR/HER2 in breast cancer from Sub Saharan Africa (SSA) are fraught with inconsistencies in the prevalence of hormone receptor status. In Kenya, ER/PR/HER2 for breast cancers is not part of routine assessment and available in only three to four centers across the country. Variability in methodology and interpretation makes comparison between data difficult. Our aim was to accurately determine the prevalence of ER/PR/HER2 using standardized techniques and double reporting. Prognostic tumor parameters were also correlated with clinical features and receptor status. MATERIALS AND METHODS: Consecutive invasive breast cancers (IBC) accrued between September 2011 and December 2012 were analyzed at Aga Khan University Hospital, Nairobi (AKUHN). Tumor blocks were stained for ER/PR/HER2 on an automated platform. Double reporting of ER/PR/HER2 was done using the Allred system and the ASCO/CAP guidelines respectively. RESULTS: A total of 301 cases of IBC were analyzed for pathology and ER/PR/HER2. The age range of patients was 19-94 years with a median of 47.5 years. Invasive ductal carcinoma (NOS) was the most common histologic type (84.2%). ER positivity was seen in 72.8%, PR in 64.8% and HER2 in 17.6% of all cases. Triple negative breast cancers (TNBC) constituted 20.2% of the cases. There was a significant association between receptor status and histologic grade (p < 0.001) and statistically significant trend of increasing pathological stage of tumor (pT) associated with TNBC (p = 0.020). CONCLUSIONS: We present a definitive prospective analysis of ER/PR/HER2 from a single center and demonstrate that prevalence of receptor status from SSA is comparable with that in the West. PMID- 25012048 TI - Impact of common treatments given in the perinatal period on the developing brain. AB - BACKGROUND: Over the last decades, considerable progress has been made in the perinatal management of high-risk preterm neonates, changing the landscape of pathological conditions associated with neurological impairments. Major focal destructive lesions are now less common, and the predominant neuropathological lesion is diffuse white-matter damage in the most immature infants. Similarly, over the last few years, we have observed a trend towards a decrease in neurological impairment in the absence of treatments specifically aimed at neuroprotection. OBJECTIVES: We examined whether recent changes in treatment strategies in perinatal care during the perinatal period could have had an indirect beneficial impact on the occurrence of brain lesions and their consequences. METHODS: Thus, we reviewed the effects of the most common treatments administered during the perinatal period to the mother or to very preterm infants on brain damage and neurocognitive follow-up. RESULTS: Antenatal steroids and exogenous surfactant are the two main treatments capable of leading to neuroprotection in very preterm infants. Randomized controlled trials are currently investigating the effects of inhaled nitric oxide and erythropoietin, while antenatal magnesium sulphate and caffeine are also likely to provide some neuroprotection, but this needs to be further investigated. Finally, other common treatments against pain, haemodynamic failure and patent ductus arteriosus have conflicting or no effects on the developing brain. CONCLUSION: While specific neuroprotective drugs are still awaited, recent advances in perinatal care have been associated with an unexpected but significant decrease in the incidence of both severe brain lesions and neurological impairment. PMID- 25012049 TI - P,N,N-pincer nickel-catalyzed cross-coupling of aryl fluorides and chlorides. AB - P,N,N-Pincer nickel complexes [Ni(Cl){N(2-R2PC6H4)(2'-Me2NC6H4)}] (R = Ph, 3a; R = Pr(i), 3b; R = Cy, 3c) were synthesized and their catalysis toward the Kumada or Negishi cross-coupling reaction of aryl fluorides and chlorides was evaluated. Complex 3a effectively catalyzes the cross-coupling of (hetero)aryl fluorides with aryl Grignard reagents at room temperature. Complex 3a also catalyzes the cross-coupling of (hetero)aryl chlorides and arylzinc reagents at 80 degrees C with low catalyst loadings and good functional group compatibility. PMID- 25012050 TI - Influence of glutathione and glutathione S-transferases on DNA interstrand cross link formation by 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the active anticancer moiety generated by laromustine. AB - Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short lived (t1/2 ~ 30 s) chloroethylating agent that can generate high yields of oxophilic electrophiles responsible for the chloroethylation of the O-6 position of guanine in DNA. These guanine O-6 alkylations are believed to be responsible for the therapeutic effects of 90CE and its prodrugs. Thus, 90CE demonstrates high selectivity toward tumors with diminished levels of O(6)-alkylguanine-DNA alkyltransferase (MGMT), the resistance protein responsible for O(6)-alkylguanine repair. The formation of O(6)-(2-chloroethyl)guanine lesions ultimately leads to the generation of highly cytotoxic 1-(N(3)-cytosinyl),-2-(N(1)-guaninyl)ethane DNA interstrand cross-links via N(1),O(6)-ethanoguanine intermediates. The anticancer activity arising from this sequence of reactions is thus identical to this component of the anticancer activity of the clinically used chloroethylnitrosoureas. Herein, we evaluate the ability of glutathione (GSH) and other low molecular weight thiols, as well as GSH coupled with various glutathione S-transferase enzymes (GSTs) to attenuate the final yields of cross links generated by 90CE when added prior to or immediately following the initial chloroethylation step to determine the major point(s) of interaction. In contrast to studies utilizing BCNU as a chloroethylating agent by others, GSH (or GSH/GST) did not appreciably quench DNA interstrand cross-link precursors. While thiols alone offered little protection at either alkylation step, the GSH/GST couple was able to diminish the initial yields of cross-link precursors. 90CE exhibited a very different GST isoenzyme susceptibility to that reported for BCNU, this could have important implications in the relative resistance of tumor cells to these agents. The protection afforded by GSH/GST was compared to that produced by MGMT. PMID- 25012051 TI - Night work and breast cancer risk in a general population prospective cohort study in The Netherlands. AB - Experimental studies in animals indicate that disruption of the circadian rhythm is carcinogenic, and night work has been suggested to be a probable breast cancer cause in humans. Findings among humans, however are inconsistent, often gathered with retrospective study designs, and only based on specific populations, such as nurses. We used data on night work collected in the Dutch Labor Force Surveys of 1996 until 2009, and individually linked these with National registers on hospital admission. Among 285,723 women without breast cancer at baseline, 2,531 had a hospital admission for breast cancer during an average of 7 years of follow up in the registers. Occasional and regular night work were not associated with the risk of hospital admission for breast cancer (adjusted hazard ratios 1.04; 95 % confidence interval 0.85-1.27, and 0.87; 0.72-1.05, respectively). Working more hours per week, or more years in a job entailing night work did not show increased breast cancer risks. Hazard ratios neither differed between nurses and women with other occupations. Our results show no association of night work with incident breast cancer, and suggest that night work generally does not increase the risk of breast cancer among women in the Dutch working population. PMID- 25012052 TI - Immediate closure of paravalvular leak after transcatheter aortic valve implantation. PMID- 25012053 TI - Traumatic subclavian arterial thrombosis presenting with cerebral infarct--a case report. AB - Subclavian artery thrombosis is a rare complication of sternoclavicular fractures. Also, cerebral infarcts caused by subclavian artery thrombosis, post trauma, is very unusual. We report the case of a 49 year-old female patient presenting with traumatic subclavian arterial thrombosis and cerebral infarction secondary to a fractured manubrium with posteriorly displaced right clavicle and retrograde thromboembolisation. PMID- 25012054 TI - Statins in CHF. PMID- 25012055 TI - Tragal cartilage shield tympanoplasty: our technique and results in 612 cases. AB - CONCLUSION: This study reveals that tragal cartilage tympanoplasty is a reliable technique, it has a high degree of graft take, and the tympanic re-aeration and hearing results are satisfactory. OBJECTIVE: Cartilage is the grafting material of choice in advanced pathologies of the middle ear while the indications for its routine use remain controversial. The purpose of this study was to report our long-term experience with the 'tragal cartilage shield' tympanoplasty. METHODS: This was a retrospective case series. The study was conducted on 612 adult patients from January 2003 until January 2012. We evaluated graft take, pure-tone average air-bone gap (PTA-ABG), postoperative aeration, and complications. The mean postoperative follow-up was 68 months. RESULTS: Sex, age, and tobacco smoke did not have any impact on postoperative results. Graft take was achieved in 99.35% of patients; there were no immediate postoperative complications. The overall average preoperative PTA-ABG was 44.95 +/- 7.77 dB, whereas 1 year after surgery it was 10.66 +/- 5.41 dB (p < 0.0001). Statistically significant improvement was observed up to 10 years after surgery. Moreover, we obtained a good tympanic ventilation (1 year after surgery, the average aeration score was 9.09 +/- 1.93), which was stable up to 10 years. PMID- 25012056 TI - Postural stability in subjects with whiplash injury symptoms: results of a pilot study. AB - CONCLUSIONS: Posturographic tests can be used to assess and confirm the body's imbalance in subjects with whiplash injury. Further studies with larger cohorts are necessary to confirm this pilot study. OBJECTIVES: To verify through a posturographic exam the qualitative and quantitative alterations of postural stability in subjects with previous cervical trauma in comparison with healthy subjects. METHODS: A total of 42 subjects were analysed for the study; 22 as the control group (NM) and 20 (WM) with a positive anamnesis of whiplash injury from 3 to 12 month from diagnosis through a force platform. Centre of pressure (CoP) movements of the two groups with their eyes open and closed were recorded. RESULTS: During the closed eye test, the subjects with cervical injuries displayed a significant increase in the anterior-posterior oscillation velocity (p < 0.05) compared with the control group, with a significant reduction (p < 0.01) of the ratio between the shifting length (SL) of CoP on the polygon support and the total envelope area (EA, mm(2)) of CoP movements in the polygon support (SL/EA-ratio, mm(-1)). PMID- 25012057 TI - Management of cervical lymph nodes for cN0 advanced glottic laryngeal carcinoma and its long-term results. AB - CONCLUSIONS: Cervical lymph node metastatic rates tend to increase by T stage in cN0 glottic laryngeal carcinoma (GLC). Moreover, cervical lymph node metastasis (LNM) shows a sequential pattern according to the regions involved and LNM affects the prognosis. OBJECTIVES: To investigate factors that contribute to LNM of N0 (cN0) T2-T4 GLC and their effect on prognosis. METHODS: A total of 212 GLC patients who had been admitted between December 2002 and January 2013 were retrospectively analyzed. They included 202 men and 10 women, median age 58.6 years (range 29-85 years), whose identified tumor stages included T2 (n = 81), T3 (n = 67), and T4 (n = 64). Relevant factors of cervical LNM were analyzed; multivariate analyses and receiver operating characteristic (ROC) curve were carried out to predict the metastasis and prognosis. RESULTS: The overall metastatic rate of N0 GLC was 14.6%. T staging and pathological classification were the risk factors for LNM. Metastatic rates for levels II, III, and IV were 10.2%, 14.6%, and 2.5%, respectively. Approximate 4.2% of patients experienced LNM with no recurrence of laryngeal cancer. Overall 3- and 5-year survival rates were 85% and 80%, respectively, compared with 66% and 57%, respectively, among patients with LNM. The inter-group survival curve comparison was statistically significant (p = 0.012). PMID- 25012058 TI - Improved green-light-emitting pyrotechnic formulations based on tris(2,2,2 trinitroethyl)borate and boron carbide. AB - Green-light-emitting pyrotechnic compositions based on tris(2,2,2 trinitroethyl)borate (TNEB) and boron carbide have been investigated. The best performing formulations were found to be insensitive to various ignition stimuli, and exhibited very high spectral purities and luminosities compared to previously reported green-light-emitting formulations. PMID- 25012059 TI - Prognosis of medically treated patients at least 80 years old with severe sclerotic aortic stenosis. AB - BACKGROUND: The prevalence of severe sclerotic aortic stenosis (ScAS) in those at least ?80 years old has been increasing in Japan; however, the prognosis of these Japanese patients without surgical treatment has not been reported. METHODS AND RESULTS: Ninety consecutive patients with medically treated severe ScAS were prospectively studied. To assess further event-free survival rate (EFSR) from either cardiac (heart failure or cardiac death) events or noncardiac deaths, they were divided into three groups based on aortic valve area (AVA) at the initial diagnosis (group A: AVA?0.6cm(2), group B: 0.6cm(2)485,000 cytosine positions within the human genome. RESULTS: Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors. In 80% of cases, the hypermethylator status was retained in both the early and late tumor of the same patient, indicating limited alterations to genome-wide methylation during progression and that the CIMP phenotype is an early event. Analysis of hypermethylated loci identified 218 genes frequently methylated across grade II, III and IV tumors indicating a possible role in sGBM tumorigenesis. Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles. We also identified 180 genes that were methylated only in sGBM. Further analysis of these genes may lead to a better understanding of the pathology of sGBM vs pGBM. CONCLUSION: This is the first study to have documented genome-wide methylation changes within paired early/late astrocytic gliomas on such a large CpG probe set, revealing a number of genes that maybe relevant to secondary gliomagenesis. PMID- 25012073 TI - Cell-secreted flavins bound to membrane cytochromes dictate electron transfer reactions to surfaces with diverse charge and pH. AB - The variety of solid surfaces to and from which microbes can deliver electrons by extracellular electron transport (EET) processes via outer-membrane c-type cytochromes (OM c-Cyts) expands the importance of microbial respiration in natural environments and industrial applications. Here, we demonstrate that the bifurcated EET pathway of OM c-Cyts sustains the diversity of the EET surface in Shewanella oneidensis MR-1 via specific binding with cell-secreted flavin mononucleotide (FMN) and riboflavin (RF). Microbial current production and whole cell differential pulse voltammetry revealed that RF and FMN enhance EET as bound cofactors in a similar manner. Conversely, FMN and RF were clearly differentiated in the EET enhancement by gene-deletion of OM c-Cyts and the dependency of the electrode potential and pH. These results indicate that RF and FMN have specific binding sites in OM c-Cyts and highlight the potential roles of these flavin cytochrome complexes in controlling the rate of electron transfer to surfaces with diverse potential and pH. PMID- 25012075 TI - Agreement between QuantiFERON(r)-TB Gold In-Tube and the tuberculin skin test and predictors of positive test results in Warao Amerindian pediatric tuberculosis contacts. AB - BACKGROUND: Interferon-gamma release assays have emerged as a more specific alternative to the tuberculin skin test (TST) for detection of tuberculosis (TB) infection, especially in Bacille Calmette-Guerin (BCG) vaccinated people. We determined the prevalence of Mycobacterium tuberculosis infection by TST and QuantiFERON(r)-TB Gold In-Tube (QFT-GIT) and assessed agreement between the two test methods and factors associated with positivity in either test in Warao Amerindian children in Venezuela. Furthermore, progression to active TB disease was evaluated for up to 12 months. METHODS: 163 HIV-negative childhood household contacts under 16 years of age were enrolled for TST, QFT-GIT and chest X-ray (CXR). Follow-up was performed at six and 12 months. Factors associated with TST and QFT-GIT positivity were studied using generalized estimation equations logistic regression models. RESULTS: At baseline, the proportion of TST positive children was similar to the proportion of children with a positive QFT-GIT (47% vs. 42%, p = 0.12). Overall concordance between QFT-GIT and TST was substantial (kappa 0.76, 95% CI 0.46-1.06). Previous BCG vaccination was not associated with significantly increased positivity in either test (OR 0.68, 95% CI 0.32-1.5 for TST and OR 0.51, 95% CI 0.14-1.9 for QFT-GIT). Eleven children were diagnosed with active TB at baseline. QFT-GIT had a higher sensitivity for active TB (88%, 95% CI 47-98%) than TST (55%, 95% CI 24-83%) while specificities were similar (respectively 58% and 55%). Five initially asymptomatic childhood contacts progressed to active TB disease during follow-up. CONCLUSION: Replacement of TST by the QFT-GIT for detection of M. tuberculosis infection is not recommended in this resource-constrained setting as test results showed substantial concordance and TST positivity was not affected by previous BCG vaccination. The QFT-GIT had a higher sensitivity than the TST for the detection of TB disease. However, the value of the QFT-GIT as an adjunct in diagnosing TB disease is limited by a high variability in QFT-GIT results over time. PMID- 25012076 TI - Repolarization lability measured on 10-second ECG by spatial TT' angle: reproducibility and agreement with QT variability. AB - BACKGROUND: Reproducibility of spatial TT' angle on the 10-second ECG and its agreement with QT variability has not been previously studied. METHODS: We analyzed 2 randomly selected 10-second segments within 3-minute resting orthogonal ECG in 172 healthy IDEAL study participants (age 38.1+/-15.2years, 50% male, 94% white). Repolarization lability was measured by the QT variance (QTV), short-term QT variability (STV(QT)), and spatial TT' angle. Bland-Altman analysis was used to assess the agreement between different log-transformed metrics of repolarization lability, and to assess the reproducibility. RESULTS: The heart rate showed a very high reproducibility (bias 0.14%, Lin's rho_c=0.99). As expected, noise suppression by averaging improves reproducibility. Agreement between two 10-second LogQTV was poor (bias -0.04; 95% limits of agreement [ 1.89; 1.81]), while LogSTV(QT) (0.04 [-1.01; 1.10]), and especially LogTT' angle (-0.009 [-0.84; 0.82]) was better. CONCLUSION: TT' angle is a satisfactory reproducible metric of repolarization lability on the 10-second ECG. PMID- 25012074 TI - Effect of adhesion and chemokine presentation on T-lymphocyte haptokinesis. AB - Motility is critical for the function of T-lymphocytes. Motility in T-lymphocytes is driven by the occupancy of chemokine receptors by chemokines, and modulated by adhesive interactions. However, it is not well understood how the combination of adhesion and chemokine binding affects T-lymphocyte migration. We used microcontact printing on polymeric substrates to measure how lymphocyte migration is quantitatively controlled by adhesion and chemokine ligation. Focusing only on random motion, we found that T-lymphocytes exhibit biphasic motility in response to the substrate concentration of either ICAM-1 or VCAM-1, and generally display more active motion on ICAM-1 surfaces. Furthermore, we examined how the combination of the homeostatic chemokines CCL19 and CCL21 contribute to motility. By themselves, CCL19 and CCL21, ligands for CCR7, elicit biphasic motility, but their combination synergistically increases CCR7 mediated chemokinesis on ICAM-1. By presenting CCL21 with ICAM-1 on the surface with soluble CCL19, we observed random motion that is greater than what is observed with soluble chemokines alone. These data suggest that ICAM-1 has a greater contribution to motility than VCAM-1 and that both adhesive interactions and chemokine ligation work in concert to control T-lymphocyte motility. PMID- 25012077 TI - Electrocardiographic left ventricular hypertrophy and the risk of adverse cardiovascular events: a critical appraisal. AB - This review covers selected electrocardiographic left ventricular hypertrophy (ECG-LVH) studies which have evaluated their prognostic value for adverse cardiovascular (CVD) events. Most ECG-LVH studies have used echocardiographic left ventricular mass (Echo-LVM) as the gold standard for evaluating ECG-LVH criteria. More recently, LVM from magnetic resonance imaging (MRI-LVM) has evolved as the new gold standard. The reported risk of adverse CVD events is generally highest for ECG-LVH criteria which combine high amplitude QRS criteria with repolarization abnormalities such as in LV strain pattern. Evolving coronary heart disease (CHD) may account in part for the increased risk for ECG-LVH. However, one large coronary arteriography study found that 5-year survival was significantly lower in coronary artery disease (CAD) patients with ECG-LVH than without LVH regardless of CAD status. The utility of Echo-LVH as a standard is limited by the large intra- and inter-reader variability and the lack of standardization of allometric formulations for adjustment of LVM to body size. Newer evaluation data with MRI-LVM as the standard show that for most ECG criteria CVD event rates are significantly higher for study subgroups with ECG LVH than those without ECG-LVH. However, the performance results differ when comparing the risk for CVD events from those for the overall LVH classification accuracy according to sensitivity and specificity. Large short-term variability of ECG amplitudes due to electrode placement variability is a common limiting factor for ECG-LVH criteria performance regardless of the gold standard. Clinical trials for hypertension control rely largely on monitoring Echo-LVH rather than ECG-LVH. PMID- 25012078 TI - Malaria outbreaks in China (1990-2013): a systematic review. AB - BACKGROUND: China has already achieved remarkable accomplishments in shrinking the malaria burden since the mid-20th Century. The country now plans to eliminate malaria by the year 2020. Looking at the dynamics of malaria outbreaks during the last decades might provide important information regarding the potential challenges of such an elimination strategy and might help to avoid mistakes of the past. METHODS: A systematic review of the published literature (English and Chinese) was conducted to identify malaria outbreaks during the period 1990 until 2013 in China. The main causes of outbreaks as described in these papers were categorized according to whether they were related to population migration, environmental factors, vector and host related factors, and operational problems of the health services. RESULTS: The review identified 36 malaria outbreaks over the 23-year study period, on which sufficient information was available. They mainly occurred in southern and central China involving 12 provinces/autonomous regions. More than half of all outbreaks (21/36, 58%) were attributed at least in part to population migration, with malaria importation to non- or low-endemic areas from high-endemic Chinese areas (13/15) or endemic countries (2/15) having been the most frequent reason (15/21, 71%). Other main causes were problems of the health services (15/36, 42%), in particular poor malaria case management (10/15, 67%), environmental factors (7/36, 19%), and vector and host related factors (5/36, 14%). CONCLUSIONS: Beside a number of other challenges, addressing population movement causing malaria appears to be of particular importance to the national malaria programme. Strengthening of surveillance for malaria and early radical treatment of cases should thus be considered among the most important tools for preventing malaria outbreaks and for the final goal of malaria elimination in China. PMID- 25012080 TI - Investigation of polymerase chain reaction assays to improve detection of bacterial involvement in bovine respiratory disease. AB - Bovine respiratory disease (BRD) causes severe economic losses to the cattle farming industry worldwide. The major bacterial organisms contributing to the BRD complex are Mannheimia haemolytica, Histophilus somni, Mycoplasma bovis, Pasteurella multocida, and Trueperella pyogenes. The postmortem detection of these organisms in pneumonic lung tissue is generally conducted using standard culture-based techniques where the presence of therapeutic antibiotics in the tissue can inhibit bacterial isolation. In the current study, conventional and real-time polymerase chain reaction (PCR) assays were used to assess the prevalence of these 5 organisms in grossly pneumonic lung samples from 150 animals submitted for postmortem examination, and the results were compared with those obtained using culture techniques. Mannheimia haemolytica was detected in 51 cases (34%) by PCR and in 33 cases (22%) by culture, H. somni was detected in 35 cases (23.3%) by PCR and in 6 cases (4%) by culture, Myc. bovis was detected in 53 cases (35.3%) by PCR and in 29 cases (19.3%) by culture, P. multocida was detected in 50 cases (33.3%) by PCR and in 31 cases (20.7%) by culture, and T. pyogenes was detected in 42 cases (28%) by PCR and in 31 cases (20.7%) by culture, with all differences being statistically significant. The PCR assays indicated positive results for 111 cases (74%) whereas 82 cases (54.6%) were culture positive. The PCR assays have demonstrated a significantly higher rate of detection of all 5 organisms in cases of pneumonia in cattle in Northern Ireland than was detected by current standard procedures. PMID- 25012079 TI - The effects of statin medications on aerobic exercise capacity and training adaptations. AB - The incidence of myopathy increases dramatically in statin users who also exercise, likely limiting the positive impact of this lifesaving medication. New evidence also indicates that statin use can directly compromise aerobic exercise capacity; however, we are just beginning to understand the interactions of statins with exercise training and adaptations. This review focuses on the interactions of statins with aerobic exercise capacity and training adaptations to summarize the available information and draw attention to the gaps in our current knowledge in this area. PubMed, Web of knowledge, and Google scholar databases were searched between January 2000 and December 2013 using the following terms and their combinations: statins, exercise, aerobic capacity, endurance training, adaptations. The reference lists of the relevant articles were also scanned for additional information. Considering the widespread use of statins and the need for exercise for cardiovascular health, a better understanding of the interactions of these interventions as well as practical solutions are needed to reduce statin adverse effects associated with exercise. PMID- 25012081 TI - Analytical confirmation of Xanthium strumarium poisoning in cattle. AB - Xanthium strumarium, commonly referred to as "cocklebur," rarely causes poisoning in cattle. When mature, this robust, annual weed bears numerous oval, brownish, spiny burs. Only the seeds in the burs and young seedlings (cotyledonary leaves) contain the toxic principle, carboxyatractyloside. In the Frankfort district of the Free State Province of South Africa, a herd of 150 Bonsmara cows were allowed to graze on the banks of a small river, where mature cocklebur was growing. Four cows died while grazing in this relatively small area. Clinical signs ranged from recumbency, apparent blindness, and hypersensitivity to convulsive seizures. During necropsy, burs completely matted with ingesta were located in the rumen content. The most distinctive microscopic lesions were severe, bridging centrilobular to midzonal hepatocyte necrosis and hemorrhage. Ultrastructurally, periacinar hepatocytes were necrotic, and novel electron-dense cytoplasmic needle like crystals were observed, often in close association with peroxisomes. Carboxyatractyloside concentrations were determined using liquid chromatography high-resolution mass spectrometry (LC-HRMS). Carboxyatractyloside was present in rumen contents at 2.5 mg/kg; in burs removed from the rumen at 0.17 mg/kg; in liver at 66 ng/g, and was below the limit of quantitation in the kidney sample, estimated at approximately 0.8 ng/g. Based on the presence of the plants on the riverbank, the history of exposure, the clinical findings, the presence of burs in the rumen, and the microscopic and ultrastructural lesions, X. strumarium poisoning in the herd of cattle was confirmed and was supported by LC-HRMS. PMID- 25012082 TI - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry for rapid identification of Brachyspira species isolated from swine, including the newly described "Brachyspira hampsonii". AB - The Brachyspira species traditionally associated with swine dysentery and other diarrheal diseases in pigs are Brachyspira hyodysenteriae, Brachyspira pilosicoli, and, to a lesser extent, Brachyspira murdochii. "Brachyspira hampsonii" is a recently proposed novel species that causes clinical disease similar to that caused by B. hyodysenteriae. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems are increasingly available in veterinary diagnostic laboratories, are less expensive, and are faster than traditional microbiological and molecular methods for identification. Thirty-three isolates associated with Brachyspira species of importance to swine were added to an existing MALDI-TOF MS database library. In total, species included in the library were: B. hyodysenteriae, "B. hampsonii" clades I and II, Brachyspira innocens, Brachyspira intermedia, B. murdochii, and B. pilosicoli. A comparison between MALDI-TOF MS and nox sequencing was completed on 176 field isolates. Of the 176 field isolates, 174 (98.9%) matched species identification by both methods. Thirty field isolates were identified by both methods as "B. hampsonii". Twenty-seven of the 30 (90%) "B. hampsonii" field isolates matched clade designation in both assays. The nox sequencing identified 26 as "B. hampsonii" clade I and 4 as clade II. Comparatively, MALDI-TOF MS identified 25 of the 30 as "B. hampsonii" clade I and 5 as clade II. The current study indicates MALDI-TOF MS is a reliable tool for the identification of swine Brachyspira species; however, final clade designation for "B. hampsonii" may still require molecular techniques. PMID- 25012083 TI - Intranuclear coccidiosis caused by Cyclospora spp. in calves. AB - Intranuclear coccidiosis in 3 calves is described. Two calves with no genetic relationship were kept in the same pen, and the third calf was on another farm. The animals suffered from watery diarrhea or severe emaciation. Histologic examination showed epithelial desquamation (cases 1 and 2) or atrophy (case 3) of the jejunal villi. Coccidial meronts or merozoites were present in the nuclei of the majority of villus epithelial cells. There were rare intranuclear macrogametocytes, macrogametes, microgametocytes, microgametes, and oocysts in cases 1 and 2, but these were more easily observed in case 3. Parasite 18S ribosomal RNA sequences from case 1 showed 99.5% sequence identity with Cyclospora sp. Guangzhou 1, which has been found in fecal samples of cattle from China. In addition to the molecular results in one of the cases, the fact that the microgametocytes and oocysts were noticeably smaller in size than those of Eimeria alabamensis in all cases indicates the close association between Cyclospora and the 3 cases described herein. PMID- 25012084 TI - Incremental prediction and moderating role of the perceived emotional intelligence over aggressive behavior. AB - The aim of this research was to explore the influence of Perceived Emotional Intelligence (PEI) on aggression dimensions (Physical Aggression, Verbal Aggression, Hostility, and Anger) above and beyond the effects of gender, age, and personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience), as well as the moderating role of PEI on the relationship between personality and aggressive behavior, among young adults. The Trait Meta-Mood Scale, the Big-Five Inventory, and the Aggression Questionnaire were administered to a 313 Spanish community sample, comprised of both males (39.0%) and females (61.0%), ranging from 14 to 69 years old (X = 24.74; SD = 9.27). Controlling the effects of age, gender, and personality, PEI dimensions (Attention, Clarity and Repair) accounted for 3% of the variance (p < .05) in Verbal Aggression and Hostility. Interaction analysis showed that all PEI subscales moderated the relationship between four out of the Big-Five personality dimensions (Extraversion, Agreeableness, Neuroticism, and Openness to Experience) and the aggression dimensions. Particularly, the interaction between Attention and Extraversion and between Clarity and Neuroticism were significant predictors of Total Aggression (b = .67, t(313) = 2.35, p < .05; b = -.71, t(313) = -2.50, p < .05). The results show evidence of the predictive and incremental validity of PEI dimensions on aggressive behavior among young adults and of the moderating role of PEI on the personality-aggression relationship. PMID- 25012085 TI - Dual transcriptomics of virus-host interactions: comparing two Pacific oyster families presenting contrasted susceptibility to ostreid herpesvirus 1. AB - BACKGROUND: Massive mortality outbreaks affecting Pacific oyster (Crassostrea gigas) spat in various countries have been associated with the detection of a herpesvirus called ostreid herpesvirus type 1 (OsHV-1). However, few studies have been performed to understand and follow viral gene expression, as it has been done in vertebrate herpesviruses. In this work, experimental infection trials of C. gigas spat with OsHV-1 were conducted in order to test the susceptibility of several bi-parental oyster families to this virus and to analyze host-pathogen interactions using in vivo transcriptomic approaches. RESULTS: The divergent response of these oyster families in terms of mortality confirmed that susceptibility to OsHV-1 infection has a significant genetic component. Two families with contrasted survival rates were selected. A total of 39 viral genes and five host genes were monitored by real-time PCR. Initial results provided information on (i) the virus cycle of OsHV-1 based on the kinetics of viral DNA replication and transcription and (ii) host defense mechanisms against the virus. CONCLUSIONS: In the two selected families, the detected amounts of viral DNA and RNA were significantly different. This result suggests that Pacific oysters are genetically diverse in terms of their susceptibility to OsHV-1 infection. This contrasted susceptibility was associated with dissimilar host gene expression profiles. Moreover, the present study showed a positive correlation between viral DNA amounts and the level of expression of selected oyster genes. PMID- 25012087 TI - Perceptual priming and reading speed among fourth grade children. AB - This study evaluated the perceptual priming in fourth grade primary school children using a word-fragment completion task. The children were classified into two categories according to their reading speed: high and low. Using several sub scales of the WISC-IV, their working memory was measured, and their total IQ was estimated, in order to control for their effects on priming. The statistical analyses showed that children with high reading speed were significantly better at word-fragment completion and showed greater priming (p < .01); in other words, the prior processing of the words from which the fragments came produced a greater benefit in the performance of the word-fragment completion task. A regression model was developed to explain reading speed based on the following variables: perceptual priming, working memory and percentage of completed fragments belonging to words not previously processed (adjusted R 2 = 0.64). PMID- 25012086 TI - Darbepoetin-alpha accelerates neovascularization and engraftment of extrahepatic colorectal metastases. AB - PURPOSE: Erythropoietin and its analogue darbepoetin (DPO)-alpha have been shown to improve liver function and regeneration after partial hepatectomy (Phx). However, previous experimental studies have also shown that DPO significantly enhances Phx-induced engraftment of colorectal liver metastases by increasing neovascularization and tumor cell proliferation. Therefore, the present study analyzed whether DPO affects engraftment and neovascularization of extrahepatic colorectal metastases after major hepatectomy. METHODS: Green fluorescent protein transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Animals received a single dose of DPO (10 ug/kg body weight) at the day of tumor cell implantation (day 0). Phosphate buffered saline-treated animals served as controls. To study whether the effect of DPO is influenced by Phx, additional animals with and without DPO treatment underwent 70% Phx at day 0. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied repetitively over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry. RESULTS: In nonhepatectomized animals, DPO significantly accelerated tumor cell engraftment and slightly enhanced tumor neovascularization. Tumor cell migration and host tissue infiltration were not affected by DPO. In hepatectomized animals, DPO slightly enhanced tumor growth and significantly accelerated tumor neovascularization, but did not affect tumor cell migration and infiltration. CONCLUSION: The present study indicates that DPO accelerates extrahepatic engraftment of colorectal cancer cells, most probably by stimulating the process of neovascularization. PMID- 25012088 TI - Medical diagnosis in resource-poor tropical countries. AB - When working in healthcare centers in developing countries where diagnostic resources are limited, clinical skills are of considerable importance. This study presents the diagnostic tools available in resource-poor areas. Anamnesis and physical examination are key components for reaching a correct diagnosis. The laboratory has at its disposal hemograms, basic blood chemistry and urinalysis. The available basic microbiological tests are the study of fresh feces, smears for malaria, direct smears for bacilli in sputum and Gram staining of clinical exudates. Basic radiography of the chest, abdomen, bones and soft tissues are of considerable usefulness but are not available in all centers. Ultrasonography can be of considerable usefulness due to its simplicity and versatility. The diagnosis in low resource conditions should sharpen our clinical skills and should be supported by the use of additional basic tests. PMID- 25012089 TI - [The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature]. AB - BACKGROUND: The role of nipple-sparing mastectomy (NSM) for breast cancer is controversial as there is concern regarding its oncological safety and complication rate. We carried out a review of the literature to quantify the incidence of occult nipple malignancy in breast cancer, identify the factors influencing occult nipple malignancy, quantify locoregional recurrence rates and quantify NSM complication rates. METHODS: A search of the literature was performed using PubMed. Keywords used were "mastectomy", "nipple involvement", "nipple-sparing mastectomy", "skin-sparing mastectomy" "occult nipple malignancy" "occult nipple disease" "breast cancer recurrence". Articles were analyzed regarding incidence of occult nipple malignancy, potential factors influencing the incidence of occult malignancy and recurrence/complications following NSM. The incidence of occult nipple disease was compared between groups using Chi(2) or Fisher's exact tests for categorical variables and Student's t-tests for continuous variables. P values were considered significant<0.05. We identified nearly 30 studies compiling nearly 10 000 cases examining the rate of occult nipple malignancy and 23 studies compiling 2300 cases providing information on the rate of local recurrence after NSM. RESULTS: The overall rate of occult nipple malignancy was 11.5 %. Primary tumour characteristics influencing occult nipple malignancy were tumour-nipple distance<2cm, grade, lymph node metastasis, lymphovascular invasion, HER2 positive, ER/PR negative, tumour size>5cm, retro areolar/central location and multicentric tumours. The overall nipple recurrence rate following NSM was 0.9 %, skin flap recurrence rate was 4.2 %. Full and partial thickness nipple necrosis rates were 2.9 % and 6.3 % respectively. CONCLUSION: NSM for primary breast cancer is appropriate in carefully selected patients. All patients should have retro-areolar sampling. There is strong evidence to suggest that suitable cases are well circumscribed single or multifocal lesions that have a TND>2cm. Tumours should be graded 1-2 and not have LVI, axillary node metastasis or HER2 positivity. PMID- 25012090 TI - Collaboratively reframing mental health for integration of HIV care in Ethiopia. AB - BACKGROUND: Integrating mental health with general medical care can increase access to mental health services, but requires helping generalists acquire a range of unfamiliar knowledge and master potentially complex diagnostic and treatment processes. METHOD: We describe a model for integrating complex specialty care with generalist/primary care, using as an illustration the integration of mental health into hospital-based HIV treatment services in Ethiopia. Generalists and specialists collaboratively developed mental health treatments to fit the knowledge, skills and resources of the generalists. The model recognizes commonalities between mental health and general medical care, focusing on practical interventions acceptable to patients. It was developed through a process of literature review, interviews, observing clinical practice, pilot trainings and expert consultation. Preliminary evaluation results were obtained by debriefing generalist trainees after their return to their clinical sites. RESULTS: In planning interviews, generalists reported discomfort making mental health diagnoses but recognition of symptom groups including low mood, anxiety, thought problems, poor child behaviour, seizures and substance use. Diagnostic and treatment algorithms were developed for these groups and tailored to the setting by including possible medical causes and burdens of living with HIV. First-line treatment included modalities familiar to generalists: empathetic patient-provider interactions, psychoeducation, cognitive reframing, referral to community supports and elements of symptom-specific evidence-informed counselling. Training introduced basic skills, with evolving expertise supported by job aides and ongoing support from mental health nurses cross-trained in HIV testing. Feedback from trainees suggested the programme fit well with generalists' settings and clinical goals. CONCLUSIONS: An integration model based on collaboratively developing processes that fit the generalist setting shows promise as a method for incorporating complex, multi-faceted interventions into general medical settings. Formal evaluations will be needed to compare the quality of care provided with more traditional approaches and to determine the resources required to sustain quality over time. PMID- 25012091 TI - Heart rate variability is augmented in patients with positional obstructive sleep apnea, but only supine LF/HF index correlates with its severity. AB - PURPOSE: Data on cardiac autonomic functioning, as expressed by heart rate variability (HRV), in patients with positional obstructive sleep apnea (p-OSA) disorder are lacking. The purpose of the study was to compare HRV indices between sleep segments derived from supine body position and another body position with and without apneic events, respectively. Our intention was to find some correlation between HRV indices and the pathophysiological characteristics of the corresponding temporal period. METHODS: Nocturnal polysomnograms derived from twenty-seven patients (22 men) with documented positional apnea were retrospectively reviewed. Patients never treated for OSA and free from diseases/drugs altering HRV were examined. Data from total sleep studies were collected. Two N2 sleep segments, from supine body position with sleep-disordered breathing (SDB) and another body position without SDB were analyzed. Apneic events (namely, apneas, hypopneas, and respiratory effort-related arousals (RERAs)), arousals, number of desaturations, minimum pulse oximetry (SaO2min), time domain variables (average RR, SDNN, SDSD, RMSSD, pNN50, and HRV triangular index) and frequency domain variables (VLF, LF, HF, TP, LF/HF) were recorded for both temporal periods. RESULTS: With the exception of average RR and HF, all other variables were significantly higher in segments with SDB. Only LF/HF_supine ratio was positively correlated with the apneic_supine_index (t = 3.13, p < 0.01) and negatively correlated with SaO2min (t = -2.9, p < 0.01) and the desaturation_supine_index (t = -2.5, p = 0.02). Arousals were negatively correlated with SaO2min (t = -2.8, p < 0.01). CONCLUSIONS: SDB augments autonomic tone in patients with p-OSA, but only LF/HF correlates with its severity and might be used as a screening tool in the future. On the contrary, parasympathetic tone, as reflected by HF, remains constant in both periods. PMID- 25012092 TI - A fluorescent probe for site I binding and sensitive discrimination of HSA from BSA. AB - A fluorescent probe DH1 has been successfully developed to detect HSA via site I non-covalent bonding. DH1 shows a dramatic fluorescence enhancement towards HSA without interference from other proteins. The molecular docking method, for the first time, was utilized to provide deep insight into the sensing mechanism of the probe. Moreover, probe DH1 was successfully used to detect trace HSA in healthy human urine. PMID- 25012093 TI - A combination of topical antiseptics for the treatment of sore throat blocks voltage-gated neuronal sodium channels. AB - Amylmetacresol and dichloro-benzylalcohol are ingredients of lozenges used for the treatment of sore throat. In a former in vitro study, a local anaesthetic like effect of these substances has been described. Since amylmetacresol and dichloro-benzylalcohol are co-administered in over-the-counter lozenges, the intention of this study is to evaluate the in vitro effects of the combination of these compounds on the voltage-gated sodium channel. We analysed the block of inward sodium currents induced by the combination of amylmetacresol, dichloro benzylalcohol and the local anaesthetic lidocaine. Tonic and use-dependent block and effects on the inactivated channel state of the neuronal sodium channel were examined. Therefore, the alpha-subunit of the voltage-gated NaV1.2 sodium channel was heterologously expressed in HEK 293 cells in vitro. Inward sodium currents were investigated in the whole-cell configuration of the patch-clamp technique. The combination of amylmetacresol and dichloro-benzylalcohol and the combination of amylmetacresol and lidocaine induced a block of resting and inactivated sodium channels both displaying a pronounced block at the inactivated channel state. In addition, the combination of all three compounds also resulted in a voltage dependent block of inward sodium currents. While use-dependent block by co application of amylmetacresol and dichloro-benzylalcohol was moderate (<20 %), lidocaine and amylmetacresol induced a robust use-dependent block (up to 50 %). This study demonstrates local anaesthetic-like effects of a combination of amylmetacresol and dichloro-benzylalcohol as established ingredients of lozenges. In the presence of amylmetacresol, dichloro-benzylalcohol and lidocaine, a prominent block of inward sodium currents is apparent. PMID- 25012094 TI - Prognostic value of 11C-choline PET/CT and CT for predicting survival of bladder cancer patients treated with radical cystectomy. AB - BACKGROUND: In patients with bladder cancer (BCa) preoperative staging with (11)C choline positron emission tomography-computed tomography (PET/CT) could be used to derive prognostic information and hence stratify patients preoperatively with respect to disease management. METHODS: From June 2004 to May 2007, 44 patients with localized BCa were staged with (11)C-choline PET/CT before radical cystectomy. The results of imaging were correlated to overall survival (OS) and cumulative incidence of cancer-specific death (CSD). RESULTS: There was no statistically significant difference in OS and CSD between the patient groups when stratified for organ-confined versus non-organ-confined disease or lymph node involvement defined by either (11)C-choline PET/CT (OS: p = 0.262, hazard ratio [HR] = 1.60; p = 0.527, HR = 0.76; CSD: p = 0.144, HR = 2.25; p = 0.976, HR = 0.98) or CT (OS: p = 0.518, HR = 1.34; p = 0.228, HR = 1.67; CSD: p = 0.323, HR = 1.90; p = 0.136, HR = 2.38). The limitation of this study is the small number of included patients. CONCLUSION: In our prospective trial neither CT nor (11)C choline PET/CT were able to sufficiently predict OS or CSD in BCa patients treated with radical cystectomy albeit trends and moderately increased HRs could be demonstrated without significant differences between CT or (11)C-choline PET/CT. However, these trends might prove statistically significant in bigger patient cohorts. Therefore initial transsectional imaging might be of clinical relevance in respect to prognosis and could play a role in the counseling of BCa patients. PMID- 25012095 TI - Evaluation of corneal epithelial and stromal thickness in keratoconus using spectral-domain optical coherence tomography. AB - PURPOSE: We sought to assess the corneal thickness of the epithelium and stroma in keratoconic and normal eyes by spectral-domain optical coherence tomography (SD-OCT). METHODS: Fifty-seven keratoconic and 20 normal eyes were studied. The eyes were examined by SD-OCT, and the keratoconic eyes were subdivided into 2 groups: those showing only smooth corneal thinning and corneal protrusion on the image (KC1 group) and those showing abnormalities in the Bowman layer or in the stroma, or in both (KC2 group). The thicknesses at the corneal vertex and at the superior, inferior, nasal, and temporal cornea 1.5 mm from the corneal vertex in the KC1 group were compared with those in the normal group. The OCT findings in the KC2 group were described. RESULTS: The epithelial thickness at the corneal vertex and at the inferior and temporal cornea, and the stromal thickness at all points were significantly thinner in the KC1 group than in the normal group (p < 0.05). The epithelial and stromal thicknesses at the corneal vertex were significantly correlated in the KC1 group and the normal group (r (2) = 0.427, p < 0.0001).The epithelial thickness in the KC2 group was not uniform owing to Bowman layer scarring, stromal scars, and secondary corneal amyloidosis. CONCLUSIONS: Although epithelial thinning is associated with stromal thinning, when the cornea remains clear, the epithelial thickness may vary because of the irregularity of the stroma beneath the epithelium in patients with keratoconus. PMID- 25012096 TI - Hemodynamic response in a geographical word naming verbal fluency test. AB - Functional hemodynamic response was studied in a new Verbal Fluency Task (VFT) that demanded the production of geographical words while fMRI data was obtained. Participants completed 7 trials with a total duration of 2 min. 20 s. Four simple arithmetic subtraction trials were alternated with 3 geographical naming trials. Each trial had a duration of 20 s. Brain activity was contrasted between both conditions and significant differences (p < .05, Family Wise Error correction) were observed in the prefrontal medial gyrus, typically associated with word retrieval and phonological awareness, and in the parahippocampal gyrus, posterior cingulate cortex and lingual gyrus, areas related to spatial cognition. These results indicate that geographic VFT could be incorporated into a browser of cognitive processes using VFT considering its specific relationship with spatial cognition. Further investigations are proposed, taking special interest in the gender variable and eliminating phonological restrictions, because the evoked Argentinean cities and towns ended in a consonant letter. PMID- 25012097 TI - [RESAOLAB: West African network of laboratories to enhance the quality of clinical biology]. AB - The Fondation Merieux, in partnership with the Ministries of Health of Burkina Faso, Mali and Senegal, implemented for four years a project to reinforce the laboratory sector in the three participating countries: the RESAOLAB project (West African Network of Biomedical Analysis Laboratories).The objective of RESAOLAB project, in partnership with the WHO Office for West Africa and the West African Health Organization, was to strengthen the systems of biomedical laboratories to improve diagnostic services, access, monitoring and management of infectious diseases. Following the successful results achieved under the RESAOLAB project and due to the demand of the neighbour countries ministries, the RESAOLAB project is now extended to four other countries of the West African region: Benin, Guinea-Conakry, Niger and Togo. The RESAOLAB project has become the RESAOLAB programme, its purpose is to strengthen the quality of the medical biology services thanks to a regional and transversal approach. PMID- 25012098 TI - Traditional and alternative community food security interventions in Montreal, Quebec: different practices, different people. AB - Food insecurity is steadily increasing in developed countries. Traditional interventions adopted to tackle food insecurity, like food banks, address the urgent need for food. By contrast, alternative interventions, such as community gardens and kitchens, are oriented towards social integration and the development of mutual aid networks. The objective of this paper is to examine whether the populations served by traditional and alternative interventions in food security differ according to measures of vulnerability. We studied newly registered participants to food security interventions. Participants were selected from a random sample of food security community organizations in a two-stage cluster sampling frame. The categorizing variable was participation in a community organization providing either traditional interventions or alternative interventions. Seven measures of vulnerability were used: food security; perceived health; civic participation; perceived social support of the primary network, social isolation, income and education. Regression multilevel models were used to assess associations. 711 participants in traditional interventions and 113 in alternative interventions were enrolled in the study. Between group differences were found with respect to food insecurity, health status perception, civic participation, education and income, but not with respect to social isolation or perceived social support from primary social network. Traditional and alternative food security interventions seem to reach different populations. Participants in traditional interventions were found to have less access to resources, compared to those in alternative interventions. Thus, new participants in traditional interventions may have higher levers of vulnerability than those in alternative interventions. PMID- 25012099 TI - E/A ratio before cardiac resynchronization therapy predicts left ventricle reverse remodeling. AB - AIM: Clinical experience shows that about 2 out of 3 patients with indication to resynchronization therapy (CRT) may have improvements in NYHA class, echocardiographic parameters and survival. However, specific clinical or technical parameters that identify responder patients have not yet been found. Aim of the present study was to assess the efficacy of CRT and to estimate the predictive value of specific echocardiographic parameters. METHODS: All patients who underwent CRT from January 2004 till June 2009, at our Institution, were clinically examined and evaluated by echo and ECG before implant. Between January and February 2010, among a population of 55 patients (41 M, 14F, mean age 66.3+/ 5.9), 42 patients (33 M) were considered in the final multiparametric analysis. Of the 13 excluded patients, 6 died, 2 underwent cardiac transplantation and 5 were lost to follow-up. Basal characteristics of the study population were: ischemic etiology in 15 out of 42 patients, back-up defibrillation in 39 patients. The mean follow-up period was 26.2+/-13.0 months. Patients had been classified as CRT responders if they showed an inverse left ventricle (LV) remodeling, defined as a 10% reduction of end-diastolic diameter (LVEDD) compared to the basal measure. RESULTS: Echo parameters significantly improved after CRT: LVEDD was significantly (P<0.05) reduced (basal vs. CRT: 76+/-7 mm vs. 64+/-10 mm, P=0.00004); basal ejection fraction (EF) was 21+/-5% vs. 37+/-14% after CRT (P=0.00001); mitral regurgitation (MR) (grading from 1 to 4) was 2.8+/-0.6 vs. 2.3+/-0.9 (P=0.00998); QRS duration was 157+/-25 ms vs. 135+/-23 ms (P=0.00036), and NYHA class 2.6+/-0.5 vs. 2.1+/-0.4, P=0.00006). Only a positive trend of the E/A ratio was observed (P=0.088). Among 42 patients, 24 (57%) had an inverse LV remodeling and were defined as CRT responders. By comparing responder with no responder patients, the basal values of echo parameters like EF, LVEDD, MR, QRS, NYHA class were similar in the two groups; while E/A was statistically different between the two groups (P=0.02), being less severe in responder patients. CONCLUSION: Our experience confirms that about 2 out of 3 patients are responder to CRT and their clinical improvements remain stable in a long term follow-up. Patients with a less severe E/A ratio are more likely to improve their clinical condition as shown by the reverse remodeling measured through the LVEDD. PMID- 25012100 TI - (99m)Tc-DTPA scintigraphy assesses the absence of glomerular filtration rate impairment of Aliskiren in high-risk hypertensive subjects. A 12-month follow-up study. AB - AIM: Glomerular filtration rate (GFR) is commonly calculated using the modification of diet in renal disease (MDRD) and Cockroft-Gault (CG) formulas and recently by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm and not directly measured, so that the real impact of antihypertensive therapy on GFR could not be well defined. In this study, the effect of Aliskiren on the GFR measured by radionuclide clearance of 99mTc-diethylene triamine penta acetic acid (DTPA) was investigated. METHODS: In 106 hypertensive subjects (53% men) aged 61.9+/-12.7 years with uncontrolled blood pressure (BP) receiving at least 2 antihypertensive medications, Aliskiren was added once-daily at a dose of 150-300 mg for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while 24-hours ambulatory BP and GFR (in mL/min/1.73 m2) were evaluated at baseline and at the end of the follow-up. Analysis of variance for repeated measures of BP, GFR and microalbuminuria was provided. RESULTS: With the use of Aliskiren a significant reduction of BP and microalbuminuria was found (P<0.0001). Only in male population, a significant reduction in GFR calculated with CKD-EPI (82.4+/-15 vs. 78.6+/-18.2, P<0.01) and CG (81.6+/-29.5 vs. 74.2+/-28.4, P<0.0001) formulas was observed. This impairment of GFR was not found either with MDRD formula (70.5+/-19.6 vs. 68.3+/-23.4) or by radionuclide clearance (62.4+/-18.6 vs. 61.4+/-20.5). CONCLUSION: This study seems to demonstrate that the efficacy on BP control of Aliskiren is not accompanied by an impairment of GFR. In order to evaluate the effect of Aliskiren on GFR scintigraphy technique or MDRD formula resulted to be the most accurate methods. PMID- 25012101 TI - Review of current technologies for thromboembolism management. AB - Percutaneous thrombectomy is being widely used as a sole therapy or as an adjunct to other therapies for the management of thrombotic occlusions in arteries, veins and grafts. Various techniques used can be broadly classified under percutaneous aspiration thrombectomy, pull-back thrombectomy and trapping, recirculation mechanical thrombectomy, direct contact/non-recirculation thrombectomy and direct or indirect ultrasound thrombectomy. In the following article, we will provide a review of these techniques describing the commonly utilized devices and their characteristics. PMID- 25012102 TI - Reverse platypnoea-orthodeoxia syndrome in association with an ascending aortic aneurysm: a case report. PMID- 25012103 TI - Flecainide in patient with aggressive catecholaminergic polymorphic ventricular tachycardia due to novel RYR2 mutation. PMID- 25012104 TI - Syncope as presentation of recurrent Tako-Tsubo cardiomyopathy. PMID- 25012105 TI - [Influence of cognition on treatment outcome in geriatric patients: association between MMSE and gain in activities of daily living]. AB - BACKGROUND: Cognitive impairment or dementia influence the results of geriatric treatment. The aim of the study was to quantify this influence. PATIENTS AND METHODS: Data of 2527 patients from the years 2006 to 2009 were analysed in order to quantify the influence of cognition measured with the Mini Mental Status Examination (MMSE) on the improvement of activities of daily living as reflected by the Functional Independence Measure (FIM). RESULTS: Impaired cognition is accompanied by a lower FIM score on admission and on discharge. But the improvement of the FIM of slightly cognitively impaired patients (MMSE 20-26) is the same as in patients without cognitive impairment (MMSE 27-30). Patients with a MMSE below 20 points have smaller improvements in their FIM score but nevertheless 40 % of the patients with a MMSE of 10-19 and still 30 % of the patients with a MMSE of 0-9 points show better improvements than the average of all patients. CONCLUSION: Patients with a MMSE below 20 should not generally be excluded from geriatric treatment, but individual factors should be considered. PMID- 25012106 TI - [Frailty from the rehabilitation medicine point of view]. AB - BACKGROUND: Frailty syndrome exerts an increasing challenge to health care systems. Thus, rehabilitative interventions should be taken to prevent or slow this syndrome. METHODS: Based on the definitions of frailty and rehabilitation, the present work gives an overview of current treatment options. The methodology and evidence for device-assisted training forms such as neuromuscular electrical stimulation or mechanical muscle stimulation are discussed. The use of various forms of training for frail patients is critically discussed. RESULTS: Among other things, age- and disease-related changes in skeletal muscle play a central role in the development of frailty. Progressive strength training is an evidence based rehabilitative strategy to improve function. Since this form of strength training can be a vigorous exercise especially for the elderly and infirmed, it can be offered as an alternative form of training. PMID- 25012107 TI - [Effectiveness of geriatric rehabilitation in the oldest old: evaluation of South German observational data]. AB - BACKGROUND: Geriatric rehabilitation might be the only way for the very old to maintain their participation in social life, since in many cases self care, everyday skills and basic activities of daily living can only be recovered by an integrative treatment approach using a multiprofessional team setting. At the same time limited financial resources in health care have to be considered to make appropriate allocation decisions in geriatric rehabilitation. PURPOSE: The goal of this work was to determine whether chronological age is a limiting factor for functional outcome in geriatric rehabilitation. MATERIALS AND METHODS: Data from the state of Baden-Wurttemberg (KODAS data set) from the years 2005-2011 for nonagenarians and data for centenarians from the Geriatrics in Bavaria database (GiB-DAT) project from the years 2003-2011 were compared to the data of the younger seniors undergoing geriatric rehabilitation. For the KODAS data collection, 31 geriatric rehabilitation clinics in Baden-Wurttemberg were involved. The GiB-DAT project included 59 geriatric rehabilitation clinics in Bavaria. Both databases compare the results of the geriatric assessment at the beginning and at the end of geriatric rehabilitation. RESULTS: The analyzed data are presented with regard to the functional outcome in the very elderly and are discussed with respect to policy implications. PMID- 25012110 TI - [Communications of the Federal Association of Geriatrics]. PMID- 25012113 TI - Identification of dorsal-ventral hippocampal differentiation in neonatal rats. AB - The adult hippocampal formation (HF) is functionally, connectionally, and transcriptionally differentiated along the dorsal-ventral axis. At birth, the hippocampus appears shortened along its dorsal-ventral axis. We therefore questioned at what postnatal age the differentiated dorsal-ventral hippocampus is present. We first established that the ventral tissue in the short postnatal hippocampus remains ventral in the adult-like hippocampus. Second, using anatomical tracing techniques we report that, within the first postnatal week, the main input from the entorhinal cortex (EC) to HF is topographically organized. The terminal distribution of this input along the dorsal-ventral axis of HF was related to a dorsolateral-to-ventromedial axis of origin in EC, thus reflecting adult topography. Finally, we examined gene expression along the dorsal-ventral axis in the developing hippocampus. We found that several genes that were differentially enriched in the adult dorsal and ventral hippocampus were similarly enriched in the dorsal and ventral hippocampal poles at birth. The differentially expressed genes relate to different molecular pathways and biomarkers of disease. Taken together, these data lead us to conclude that the entire dorsal-ventral axis of HF is present at birth showing adult-like functional differentiation. Moreover, our findings indicate that the neonatal ventral hippocampus is enriched with biomarkers associated with mental illnesses. These include schizophrenia, affective and anxiety disorders, disorders previously deemed as ventral hippocampal associated disorders, as well as alcoholism. Our results thus suggest an early developmental susceptibility of the ventral HF to mental illness. PMID- 25012114 TI - Glutamatergic phenotype of glucagon-like peptide 1 neurons in the caudal nucleus of the solitary tract in rats. AB - The expression of a vesicular glutamate transporter (VGLUT) suffices to assign a glutamatergic phenotype to neurons and other secretory cells. For example, intestinal L cells express VGLUT2 and secrete glutamate along with glucagon-like peptide 1 (GLP1). We hypothesized that GLP1-positive neurons within the caudal (visceral) nucleus of the solitary tract (cNST) also are glutamatergic. To test this, the axonal projections of GLP1 and other neurons within the cNST were labeled in rats via iontophoretic delivery of anterograde tracer. Dual immunofluorescence and confocal microscopy was used to visualize tracer-, GLP1-, and VGLUT2-positive fibers within brainstem, hypothalamic, and limbic forebrain nuclei that receive input from the cNST. Electron microscopy was used to confirm GLP1 and VGLUT2 immunolabeling within the same axon varicosities, and fluorescent in situ hybridization was used to examine VGLUT2 mRNA expression by GLP1-positive neurons. Most anterograde tracer-labeled fibers displayed VGLUT2-positive varicosities, providing new evidence that ascending axonal projections from the cNST are primarily glutamatergic. Virtually all GLP1-positive varicosities also were VGLUT2-positive. Electron microscopy confirmed the colocalization of GLP1 and VGLUT2 immunolabeling in axon terminals that formed asymmetric (excitatory type) synapses with unlabeled dendrites in the hypothalamus. Finally, in situ hybridization confirmed that GLP1-positive cNST neurons express VGLUT2 mRNA. Thus, hindbrain GLP1 neurons in rats are equipped to store glutamate in synaptic vesicles, and likely co-release both glutamate and GLP1 from axon varicosities and terminals in the hypothalamus and other brain regions. PMID- 25012115 TI - NCD Countdown 2025: accountability for the 25 * 25 NCD mortality reduction target. PMID- 25012116 TI - Adverse outcomes after total and unicompartmental knee replacement in 101,330 matched patients: a study of data from the National Joint Registry for England and Wales. AB - BACKGROUND: Total knee replacement (TKR) or unicompartmental knee replacement (UKR) are options for end-stage osteoarthritis. However, comparisons between the two procedures are confounded by differences in baseline characteristics of patients undergoing either procedure and by insufficient reporting of endpoints other than revision. We aimed to compare adverse outcomes for each procedure in matched patients. METHODS: With propensity score techniques, we compared matched patients undergoing TKR and UKR in the National Joint Registry for England and Wales. The National Joint Registry started collecting data in April 1, 2003, and is continuing. The last operation date in the extract of data used in our study was Aug 28, 2012. We linked data for multiple potential confounders from the National Health Service Hospital Episode Statistics database. We used regression models to compare outcomes including rates of revision, revision/reoperation, complications, readmission, mortality, and length of stay. FINDINGS: 25,334 UKRs were matched to 75,996 TKRs on the basis of propensity score. UKRs had worse implant survival both for revision (subhazard ratio [SHR] 2.12, 95% CI 1.99-2.26) and for revision/reoperation (1.38, 1.31-1.44) than TKRs at 8 years. Mortality was significantly higher for TKR at all timepoints than for UKR (30 day: hazard ratio 0.23, 95% CI 0.11-0.50; 8 year: 0.85, 0.79-0.92). Length of stay, complications (including thromboembolism, myocardial infarction, and stroke), and rate of readmission were all higher for TKR than for UKR. INTERPRETATION: In decisions about which procedure to offer, the higher revision/reoperation rate of UKR than of TKR should be balanced against a lower occurrence of complications, readmission, and mortality, together with known benefits for UKR in terms of postoperative function. If 100 patients receiving TKR received UKR instead, the result would be around one fewer death and three more reoperations in the first 4 years after surgery. FUNDING: Royal College of Surgeons of England and Arthritis Research UK. PMID- 25012117 TI - Patient safety after partial and total knee replacement. PMID- 25012118 TI - 45-day mortality after 467,779 knee replacements for osteoarthritis from the National Joint Registry for England and Wales: an observational study. AB - BACKGROUND: Understanding the risk factors for early death after knee replacement could help to reduce the risk of mortality after this procedure. We assessed secular trends in death within 45 days of knee replacement for osteoarthritis in England and Wales, with the aim of investigating whether any change that we recorded could be explained by alterations in modifiable perioperative factors. METHODS: We took data for knee replacements done for osteoarthritis in England and Wales between April 1, 2003, and Dec 31, 2011, from the National Joint Registry for England and Wales. Patient identifiers were used to link these data to the national mortality database and the Hospital Episode Statistics database to obtain details of death, sociodemographics, and comorbidity. We assessed mortality within 45 days by Kaplan-Meier analysis and assessed the role of patient and treatment factors by Cox proportional hazards models. FINDINGS: 467,779 primary knee replacements were done to treat osteoarthritis during 9 years. 1183 patients died within 45 days of surgery, with a substantial secular decrease in mortality from 0.37% in 2003 to 0.20% in 2011, even after adjustment for age, sex, and comorbidity. The use of unicompartmental knee replacement was associated with substantially lower mortality than was total knee replacement (hazard ratio [HR] 0.32, 95% CI 0.19-0.54, p<0.0005). Several comorbidities were associated with increased mortality: myocardial infarction (HR 3.46, 95% CI 2.81 4.14, p<0.0005), cerebrovascular disease (3.35, 2.7-4.14, p<0.0005), moderate/severe liver disease (7.2, 3.93-13.21, p<0.0005), and renal disease (2.18, 1.76-2.69, p<0.0005). Modifiable perioperative risk factors, including surgical approach and thromboprophylaxis were not associated with mortality. INTERPRETATION: Postoperative mortality after knee replacement has fallen substantially between 2003 and 2011. Efforts to further reduce mortality should concentrate more on older patients, those who are male and those with specific comorbidities, such as myocardial infarction, cerebrovascular disease, liver disease, and renal disease. FUNDING: National Joint Registry for England and Wales. PMID- 25012119 TI - Dental fear, tobacco use and alcohol use among university students in Finland: a national survey. AB - BACKGROUND: Tobacco- and alcohol use are associated with psychological problems. Individuals with high dental fear also more often report other psychological problems than do those with lower level of dental fear. We evaluated the association between dental fear and tobacco- and alcohol use while controlling for age, gender, general mood and feelings in social situations. METHODS: The data (n = 8514) were collected from all universities in Finland with an electronic inquiry sent to all first-year university students. Dental fear was measured with the question: "How afraid are you of visiting a dentist?" with reply alternatives "Not at all", "Somewhat" and "Very". Regularity of tobacco use was determined with the question: "Do you smoke or use snuff?", with reply alternatives "Not at all", "Occasionally" and "Daily". The Alcohol Use Disorders Identification Test (AUDIT) was used for determination of alcohol use; an AUDIT sum score of 8 or more indicated hazardous, harmful or dependent alcohol use. The statistical tests used were Chi-square tests and Multiple logistic regression analyses. RESULTS: When controlled for age, gender, alcohol use, general mood and feelings in social situations, those who used tobacco regularly were more likely to have high dental fear than were those who used tobacco occasionally or not at all. When controlled for age, gender, general mood and feelings in social situations, those with hazardous, harmful or dependent alcohol use were more likely to have high dental fear than were those with low-risk of alcohol use, the association between alcohol use and dental fear was not strong. When tobacco use was added into this model, alcohol use was no longer statistically significantly associated with dental fear. CONCLUSIONS: The findings of this study support the suggestion that some people may have common vulnerability factors linked to tobacco use, alcohol use, and dental fear. PMID- 25012120 TI - Involvement of JAK/STAT signaling in the effect of cornel iridoid glycoside on experimental autoimmune encephalomyelitis amelioration in rats. AB - In the present study, we investigated the therapeutic benefit of cornel iridoid glycoside (CIG), the main component extracted from Cornus officinalis, in experimental autoimmune encephalomyelitis (EAE) rats. CIG was intragastrically administered daily after EAE initiation for 20days and reduced disease severity, incidence, disease onset and ongoing paralysis. Histopathological staining showed that CIG could reduce T cell entry to the central nervous system and microglia activation, increased brain-derived neurotrophic factor (BDNF) expression and mature oligodendrocytes, and decreased oligodendrocyte progenitor cells (OPCs). Also, CIG treatment inhibited brain JAK/STAT1/3 and reduced proinflammatory cytokines. CIG might be a novel potential therapeutic agent for multiple sclerosis (MS). PMID- 25012121 TI - Using a partially randomized patient preference study design to evaluate the therapeutic effect of acupuncture and cupping therapy for fibromyalgia: study protocol for a partially randomized controlled trial. AB - BACKGROUND: Conducting randomized controlled trials on traditional Chinese non drug therapies has been limited by factors such as patient preference to specific treatment modality. The aim of this study is to investigate the feasibility of applying a partially randomized patient preference (PRPP) trial model in evaluating the efficacy of two types of traditional Chinese medicine therapies, acupuncture and cupping, for fibromyalgia while accounting for patients' preference of either therapeutic modality. METHODS: This protocol was approved by the Institutional Ethics Committee of affiliated Dongfang Hospital, Beijing University of Chinese Medicine (approval number: 2013052104-2). One hundred participants with fibromyalgia will be included in this study. Diagnosis of fibromyalgia will be based on the American College of Rheumatology criteria. Before treatment, participants will be interviewed for their preference toward acupuncture or cupping therapy. Fifty participants with no preference will be randomly assigned to one of the two groups and another 50 participants with strong preference to either acupuncture or cupping will receive what they choose. For acupuncture and cupping therapy, the main acupoints used will be tender points (Ashi). Treatment will be three times a week for 5 consecutive weeks with a follow-up period of 12 weeks. Outcome measures will be qualitative (patient expectation and satisfaction) and quantitative (pain intensity, quality of life, depression assessment). TRIAL REGISTRATION NUMBER: NCT01869712 (in clinicaltrials.gov, on 22nd May 2013). PMID- 25012122 TI - Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms. AB - BACKGROUND/AIMS: O(6)-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. METHODS: We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. RESULTS: In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. CONCLUSION: Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine. PMID- 25012123 TI - Kynurenic acid inhibits colon cancer proliferation in vitro: effects on signaling pathways. AB - Kynurenic acid (KYNA), a tryptophan metabolite, inhibits proliferation of several cancer cell lines including colon cancer, renal cancer and glioblastoma cells. Previous studies reported that inhibitory properties of KYNA may be related to interactions of KYNA with cell cycle regulators and signaling proteins. However, the exact molecular interaction of KYNA with signaling pathways in colon cancer cells has not been studied to date. The molecular mechanism of KYNA activity towards colon cancer cells may be of great importance taking into consideration that KYNA is present in several tissues and physiological fluids, including gastrointestinal tract, and it is also present in various products of human diet. In this study, the inhibitory effect of KYNA on activation of phosphoinositide 3 kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways in colon adenocarcinoma HT-29 cells was revealed. KYNA decreased phosphorylation of Akt, ERK 1/2 and p38 kinases in HT-29 cells. Interestingly, the study revealed also unexpected effect of KYNA on Wnt pathway in HT-29 cells. KYNA in millimolar concentrations increased protein expression of beta-catenin. However, the nuclear translocation of beta-catenin in HT-29 cells exposed to KYNA was not observed. Moreover, KYNA 1 mM increased antiproliferative properties of inhibitors of signaling pathways: wortmannin, PD98059, SB202190 and IWR-1. Taking into consideration these results, KYNA may be seen as a potential chemopreventive agent in colon cancer or supportive agent in standard cancer chemotherapy. However, the interactions between KYNA, Wnt signaling pathway and beta-catenin need further studies to exclude potential effect of KYNA on colon carcinogenesis. PMID- 25012125 TI - Legionella pneumophila type IV effectors hijack the transcription and translation machinery of the host cell. AB - Intracellular bacterial pathogens modulate the host response to persist and replicate inside a eukaryotic cell and cause disease. Legionella pneumophila, the causative agent of Legionnaires' disease, is present in freshwater environments and represents one of these pathogens. During coevolution with protozoan cells, L. pneumophila has acquired highly sophisticated and diverse strategies to hijack host cell processes. It secretes hundreds of effectors into the host cell, and these manipulate host signaling pathways and key cellular processes. Recently it has been shown that L. pneumophila is also able to alter the transcription and translation machinery of the host and to exploit epigenetic mechanisms in the cells it resides in to counteract host responses. PMID- 25012124 TI - A serine protease homolog negatively regulates TEP1 consumption in systemic infections of the malaria vector Anopheles gambiae. AB - Clip domain serine protease homologs are widely distributed in insect genomes and play important roles in regulating insect immune responses, yet their exact functions remain poorly understood. Here, we show that CLIPA2, a clip domain serine protease homolog of Anopheles gambiae, regulates the consumption of the mosquito complement-like protein TEP1 during systemic bacterial infections. We provide evidence that CLIPA2 localizes to microbial surfaces in a TEP1-dependent manner whereby it negatively regulates the activity of a putative TEP1 convertase, which converts the full-length TEP1-F form into active TEP1cut. CLIPA2 silencing triggers an exacerbated TEP1-mediated response that significantly enhances mosquito resistance to infections with a broad class of microorganisms including Plasmodium berghei, Escherichia coli and the entomopathogenic fungus Beauveria bassiana. We also provide further evidence for the existence of a functional link between TEP1 and activation of hemolymph prophenoloxidase during systemic infections. Interestingly, the enhanced TEP1 mediated immune response in CLIPA2 knockdown mosquitoes correlated with a significant reduction in fecundity, corroborating the existence of a trade-off between immunity and reproduction. In sum, CLIPA2 is an integral regulatory component of the mosquito complement-like pathway which functions to prevent an overwhelming response by the host in response to systemic infections. PMID- 25012126 TI - Palliative care development in the Asia-Pacific region: an international survey from the Asia Pacific Hospice Palliative Care Network (APHN). AB - BACKGROUND: Although palliative care is an important public healthcare issue worldwide, the current situation in the Asia-Pacific region has not been systematically evaluated. OBJECTIVES: This survey aimed to clarify the current status of palliative care in the Asia-Pacific region. METHODS: Questionnaires were sent to a representative physician of each member country/region of the Asia Pacific Hospice Palliative Care Network (APHN). The questionnaire examined palliative care service provision, information regarding physician certification in palliative care, the availability of essential drugs for palliative care listed by the International Association for Hospice and Palliative Care (IAHPC) and the regulation of opioid-prescribing practice. RESULTS: Of the 14 member countries/regions of the APHN, 12 (86%) responded. Some form of specialist palliative care services had developed in all the responding countries/regions. Eight member countries/regions had physician certifications for palliative care. Most essential drugs for palliative care listed by the IAHPC were available, whereas hydromorphone, oxycodone and transmucosal fentanyl were unavailable in most countries/regions. Six member countries/regions required permission to prescribe and receive opioids. CONCLUSIONS: The development of palliative care is in different stages across the surveyed countries/regions in the Asia-Pacific region. Data from this survey can be used as baseline data for monitoring the development of palliative care in this region. PMID- 25012127 TI - A brief etymology of the collateral circulation. AB - It is well known that the protective capacity of the collateral circulation falls short in many individuals with ischemic disease of the heart, brain, and lower extremities. In the past 15 years, opportunities created by molecular and genetic tools, together with disappointing outcomes in many angiogenic trials, have led to a significant increase in the number of studies that focus on: understanding the basic biology of the collateral circulation; identifying the mechanisms that limit the collateral circulation's capacity in many individuals; devising methods to measure collateral extent, which has been found to vary widely among individuals; and developing treatments to increase collateral blood flow in obstructive disease. Unfortunately, accompanying this increase in reports has been a proliferation of vague terms used to describe the disposition and behavior of this unique circulation, as well as the increasing misuse of well-ensconced ones by new (and old) students of collateral circulation. With this in mind, we provide a brief glossary of readily understandable terms to denote the formation, adaptive growth, and maladaptive rarefaction of collateral circulation. We also propose terminology for several newly discovered processes that occur in the collateral circulation. Finally, we include terms used to describe vessels that are sometimes confused with collaterals, as well as terms describing processes active in the general arterial-venous circulation when ischemic conditions engage the collateral circulation. We hope this brief review will help unify the terminology used in collateral research. PMID- 25012128 TI - Cross talk between vascular smooth muscle cells and monocytes through interleukin 1beta/interleukin-18 signaling promotes vein graft thickening. AB - OBJECTIVE: Interleukin (IL)-1beta and IL-18 are key proinflammatory cytokines that play important roles in the pathophysiology of vein graft remodeling. However, the mechanism of IL-1beta/IL-18 production and its role in the development of graft remodeling remain unclear. APPROACH AND RESULTS: IL-1beta/IL 18 were rapidly expressed in venous interposition grafts. Vascular smooth muscle cell (VSMC) death and monocytic inflammasome activation occurred in grafted veins. Necrotic VSMCs induced the expression of IL-1beta, IL-18, and other inflammasome-associated proteins in monocytes, which was partially inhibited by their antagonist, recombinant IL-1ra-Fc-IL-18bp. Activated monocytes stimulated proliferation of VSMCs by activating cell growth-related signaling molecules (AKT, STAT3, ERK1/2, and mTOR [AKT/protein kinase B, signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, mammalian target of rapamycin]) and increasing production of platelet-derived growth factor-bb; these effects were suppressed by IL-1ra-Fc-IL-18bp. Activated monocytes also promoted migration of VSMCs, which was independent of IL-1beta/IL 18 signaling. Importantly, administration of IL-1ra-Fc-IL-18bp inhibited activation of cell growth-related signaling molecules, VSMC proliferation, and vein graft thickening in vivo. CONCLUSIONS: Our work identified an interaction among necrotic VSMCs, monocytes, and viable VSMCs through IL-1beta/IL-18 signaling, which might be exploited as a therapeutic target in vein graft remodeling. PMID- 25012129 TI - Neutrophil extracellular traps promote thrombin generation through platelet dependent and platelet-independent mechanisms. AB - OBJECTIVE: Activation of neutrophils by microbial or inflammatory stimuli results in the release of neutrophil extracellular traps (NETs) that are composed of DNA, histones, and antimicrobial proteins. In purified systems, cell-free DNA (CFDNA) activates the intrinsic pathway of coagulation, whereas histones promote thrombin generation through platelet-dependent mechanisms. However, the overall procoagulant effects of CFDNA/histone complexes as part of intact NETs are unknown. In this study, we examined the procoagulant potential of intact NETs released from activated neutrophils. We also determined the relative contribution of CFDNA and histones to thrombin generation in plasmas from patients with sepsis. APPROACH AND RESULTS: NETs released from phorbyl myristate-activated neutrophils enhance thrombin generation in platelet-poor plasma. This effect was DNA dependent (confirmed by DNase treatment) and occurred via the intrinsic pathway of coagulation (confirmed with coagulation factor XII- and coagulation factor XI-depleted plasma). In platelet-rich plasma treated with corn trypsin inhibitor, addition of phorbyl myristate-activated neutrophils increased thrombin generation and shortened the lag time in a toll-like receptor-2- and toll-like receptor-4-dependent mechanism. Addition of DNase further augmented thrombin generation, suggesting that dismantling of the NET scaffold increases histone mediated, platelet-dependent thrombin generation. In platelet-poor plasma samples from patients with sepsis, we found a positive correlation between endogenous CFDNA and thrombin generation, and addition of DNase attenuated thrombin generation. CONCLUSIONS: These studies examine the procoagulant activities of CFDNA and histones in the context of NETs. Our studies also implicate a role for the intrinsic pathway of coagulation in sepsis pathogenesis. PMID- 25012130 TI - F-actin-anchored focal adhesions distinguish endothelial phenotypes of human arteries and veins. AB - OBJECTIVE: Vascular endothelial-cadherin- and integrin-based cell adhesions are crucial for endothelial barrier function. Formation and disassembly of these adhesions controls endothelial remodeling during vascular repair, angiogenesis, and inflammation. In vitro studies indicate that vascular cytokines control adhesion through regulation of the actin cytoskeleton, but it remains unknown whether such regulation occurs in human vessels. We aimed to investigate regulation of the actin cytoskeleton and cell adhesions within the endothelium of human arteries and veins. APPROACH AND RESULTS: We used an ex vivo protocol for immunofluorescence in human vessels, allowing detailed en face microscopy of endothelial monolayers. We compared arteries and veins of the umbilical cord and mesenteric, epigastric, and breast tissues and find that the presence of central F-actin fibers distinguishes the endothelial phenotype of adult arteries from veins. F-actin in endothelium of adult veins as well as in umbilical vasculature predominantly localizes cortically at the cell boundaries. By contrast, prominent endothelial F-actin fibers in adult arteries anchor mostly to focal adhesions containing integrin-binding proteins paxillin and focal adhesion kinase and follow the orientation of the extracellular matrix protein fibronectin. Other arterial F-actin fibers end in vascular endothelial-cadherin-based endothelial focal adherens junctions. In vitro adhesion experiments on compliant substrates demonstrate that formation of focal adhesions is strongly induced by extracellular matrix rigidity, irrespective of arterial or venous origin of endothelial cells. CONCLUSIONS: Our data show that F-actin-anchored focal adhesions distinguish endothelial phenotypes of human arteries from veins. We conclude that the biomechanical properties of the vascular extracellular matrix determine this endothelial characteristic. PMID- 25012131 TI - Suppressor of cytokine signaling 1-derived peptide inhibits Janus kinase/signal transducers and activators of transcription pathway and improves inflammation and atherosclerosis in diabetic mice. AB - OBJECTIVE: Activation of Janus kinase/signal transducers and activators of transcription (STAT) pathway by hyperglycemia and dislypidemia contributes to the progression of diabetic complications, including atherosclerosis. Suppressor of cytokine signaling (SOCS) proteins negatively regulate Janus kinase/STAT and have emerged as promising target for anti-inflammatory therapies. We investigated whether a cell-permeable lipopeptide corresponding to the kinase inhibitory region of SOCS1 could reduce atherosclerosis in diabetic mice and identified the mechanisms involved. APPROACH AND RESULTS: Streptozotocin-induced diabetic apolipoprotein E-deficient mice (aged 8 and 22 weeks) were given intraperitoneal injections of vehicle, SOCS1-derived peptide, or control mutant peptide for 6 to 10 weeks. SOCS1 therapy suppressed STAT1/STAT3 activation in atherosclerotic plaques of diabetic mice and significantly reduced lesion size at both early and advanced stages of lesion development compared with vehicle group. Plaque characterization demonstrated that SOCS1 peptide decreased the accumulation of lipids, macrophages, and T lymphocytes, whereas increasing collagen and smooth muscle cell content. This atheroprotective effect was accompanied by systemic (reduced proinflammatory Ly6C(high) monocytes and splenic cytokine expression) and local (reduced aortic expression of chemokines and cytokines) mechanisms, without impact on metabolic parameters. In vitro, SOCS1 peptide dose dependently inhibited STAT1/STAT3 activation and target gene expression in vascular smooth muscle cells and macrophages and also suppressed cytokine-induced cell migration and adhesion processes. CONCLUSIONS: SOCS1-based targeting Janus kinase/STAT restrains key mechanisms of atherogenesis in diabetic mice, thereby preventing plaque formation and increasing plaque stability. Approaches to mimic native SOCS1 functions may have a therapeutic potential to retard the progression of diabetic complications. PMID- 25012132 TI - Retinal vasculopathy is reduced by dietary salt restriction: involvement of Glia, ENaCalpha, and the renin-angiotensin-aldosterone system. AB - OBJECTIVE: Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin-angiotensin-aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin-angiotensin aldosterone system is involved. We examined whether a low-salt (LS) diet influenced vascular and glial cell injury and the renin-angiotensin-aldosterone system in ischemic retinopathy. APPROACH AND RESULTS: Pregnant Sprague Dawley rats were fed LS (0.03% NaCl) or normal salt (0.3% NaCl) diets, and ischemic retinopathy was induced in the offspring. An LS diet reduced retinal neovascularization and vaso-obliteration, the mRNA and protein levels of the angiogenic factors, vascular endothelial growth factor, and erythropoietin. Microglia, which influence vascular remodeling in ischemic retinopathy, were reduced by LS as was tumor necrosis factor-alpha. Macroglial Muller cells maintain the integrity of the blood-retinal barrier, and in ischemic retinopathy, LS reduced their gliosis and also vascular leakage. In retina, LS reduced mineralocorticoid receptor, angiotensin type 1 receptor, and renin mRNA levels, whereas, as expected, plasma levels of aldosterone and renin were increased. The aldosterone/mineralocorticoid receptor-sensitive epithelial sodium channel alpha (ENaCalpha), which is expressed in Muller cells, was increased in ischemic retinopathy and reduced by LS. In cultured Muller cells, high salt increased ENaCalpha, which was prevented by mineralocorticoid receptor and angiotensin type 1 receptor blockade. Conversely, LS reduced ENaCalpha, angiotensin type 1 receptor, and mineralocorticoid receptor expression. CONCLUSIONS: An LS diet reduced retinal vasculopathy, by modulating glial cell function and the retinal renin-angiotensin-aldosterone system. PMID- 25012133 TI - Perivascular adipose tissue, potassium channels, and vascular dysfunction. AB - Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of adipokines and the release of other thus far unidentified factors, this recently discovered adipose tissue modulates vascular regulation and the myogenic response. After the discovery of its ability to diminish the vessel's response to vasoconstrictors, a new paradigm established adipose-derived relaxing factor (ADRF) as a paracrine smooth muscle cells' potassium channel opener that could potentially help combat vascular dysfunction. This review will discuss the role of ADRF in vascular dysfunction in obesity and hypertension, the different potassium channels that can be activated by this factor, and describes new pharmacological tools that can mimic the ADRF effect and thus can be beneficial against vascular dysfunction in cardiovascular disease. PMID- 25012135 TI - Role of biomechanical forces in stem cell vascular lineage differentiation. AB - Mechanical forces have long been known to play a role in the maintenance of vascular homeostasis in the mature animal and in developmental regulation in the fetus. More recently, it has been shown that stem cells play a role in vascular repair and remodeling in response to biomechanical stress. Laminar shear stress can directly activate growth factor receptors on stem/progenitor cells, initiating signaling pathways leading toward endothelial cell differentiation. Cyclic strain can stimulate stem cell differentiation toward smooth muscle lineages through different mechanisms. In vivo, blood flow in the coronary artery is significantly altered after stenting, leading to changes in biomechanical forces on the vessel wall. This disruption may activate stem cell differentiation into a variety of cells and cause delayed re-endothelialization. Based on progress in the research field, the present review aims to explore the role of mechanical forces in stem cell differentiation both in vivo and in vitro and to examine what this means for the application of stem cells in the clinic, in tissue engineering, and for the management of aberrant stem cell contribution to disease. PMID- 25012134 TI - Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. AB - Atherosclerosis preferentially occurs in arterial regions exposed to disturbed flow, in part, due to alterations in gene expression. MicroRNAs (miRNAs) are small, noncoding genes that post-transcriptionally regulate gene expression by targeting messenger RNA transcripts. Emerging evidence indicates that alteration of flow conditions regulate expression of miRNAs in endothelial cells both in vitro and in vivo. These flow-sensitive miRNAs, known as mechano-miRs, regulate endothelial gene expression and can regulate endothelial dysfunction and atherosclerosis. MiRNAs such as, miR-10a, miR-19a, miR-23b, miR-17-92, miR-21, miR-663, miR-92a, miR-143/145, miR-101, miR-126, miR-712, miR-205, and miR-155, have been identified as mechano-miRs. Many of these miRNAs were initially identified as flow sensitive in vitro and were later found to play a critical role in endothelial function and atherosclerosis in vivo through either gain-of function or loss-of-function approaches. The key signaling pathways that are targeted by these mechano-miRs include the endothelial cell cycle, inflammation, apoptosis, and nitric oxide signaling. Furthermore, we have recently shown that the miR-712/205 family, which is upregulated by disturbed flow, contributes to endothelial inflammation and vascular hyperpermeability by targeting tissue inhibitor of metalloproteinase-3, which regulates metalloproteinases and a disintegrin and metalloproteinases. The mechano-miRs that are implicated in atherosclerosis are termed as mechanosensitive athero-miRs and are potential therapeutic targets to prevent or treat atherosclerosis. This review summarizes the current knowledge of mechanosensitive athero-miRs and their role in vascular biology and atherosclerosis. PMID- 25012136 TI - Haploinsufficiency of the insulin-like growth factor-1 receptor enhances endothelial repair and favorably modifies angiogenic progenitor cell phenotype. AB - OBJECTIVES: Defective endothelial regeneration predisposes to adverse arterial remodeling and is thought to contribute to cardiovascular disease in type 2 diabetes mellitus. We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R) is a negative regulator of insulin sensitivity and nitric oxide bioavailability. In this report, we examined partial deletion of the IGF1R as a potential strategy to enhance endothelial repair. APPROACH AND RESULTS: We assessed endothelial regeneration after wire injury in mice and abundance and function of angiogenic progenitor cells in mice with haploinsufficiency of the IGF1R (IGF1R(+/-)). Endothelial regeneration after arterial injury was accelerated in IGF1R(+/-) mice. Although the yield of angiogenic progenitor cells was lower in IGF1R(+/-) mice, these angiogenic progenitor cells displayed enhanced adhesion, increased secretion of insulin-like growth factor-1, and enhanced angiogenic capacity. To examine the relevance of IGF1R manipulation to cell-based therapy, we transfused IGF1R(+/-) bone marrow-derived CD117(+) cells into wild-type mice. IGF1R(+/-) cells accelerated endothelial regeneration after arterial injury compared with wild-type cells and did not alter atherosclerotic lesion formation. CONCLUSIONS: Haploinsufficiency of the IGF1R is associated with accelerated endothelial regeneration in vivo and enhanced tube forming and adhesive potential of angiogenic progenitor cells in vitro. Partial deletion of IGF1R in transfused bone marrow-derived CD117(+) cells enhanced their capacity to promote endothelial regeneration without altering atherosclerosis. Our data suggest that manipulation of the IGF1R could be exploited as novel therapeutic approach to enhance repair of the arterial wall after injury. PMID- 25012137 TI - Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. AB - OBJECTIVE: In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). APPROACH AND RESULTS: Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A2A/A1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation. CONCLUSIONS: Ticagrelor, but not clopidogrel, reduces myocardial IS. The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and COX2 activity. PMID- 25012138 TI - Enhanced catalysis and enantioselective resolution of racemic naproxen methyl ester by lipase encapsulated within iron oxide nanoparticles coated with calix[8]arene valeric acid complexes. AB - In this study, two types of nanoparticles have been used as additives for the encapsulation of Candida rugosa lipase via the sol-gel method. In one case, the nanoparticles were covalently linked with a new synthesized calix[8]arene octa valeric acid derivative (C[8]-C4-COOH) to produce new calix[8]arene-adorned magnetite nanoparticles (NP-C[8]-C4-COOH), and then NP-C[8]-C4-COOH was used as an additive in the sol-gel encapsulation process. In the other case, iron oxide nanoparticles were directly added into the sol-gel encapsulation process in order to interact electrostatically with both C[8]-C4-COOH and Candida rugosa lipase. The catalytic activities and enantioselectivities of two novel encapsulated lipases (Enc-NP-C[8]-C4-COOH and Enc-C[8]-C4-COOH@Fe3O4) in the hydrolysis reaction of racemic naproxen methyl ester were evaluated. The results showed that the activity and enantioselectivity of the lipase were improved when the lipase was encapsulated in the presence of calixarene-based additives. Indeed, the encapsulated lipases have an excellent rate of enantioselectivity, with E = 371 and 265, respectively, as compared to the free enzyme (E = 137). The lipases encapsulated with C[8]-C4-COOH and iron oxide nanoparticles (Enc-C[8]-C4 COOH@Fe3O4) retained more than 86% of their initial activities after 5 repeated uses and 92% with NP-C[8]-C4-COOH. PMID- 25012139 TI - Historic records on the commercial production of infant formula. AB - Industrialized food production first appeared in 1856, pioneered by Borden in the USA, Liebig in Germany, Nestle in Switzerland, and Mellin in the UK. Their products differed remarkably and deviated from human and cow's milk, and physicians discussed the importance of minute variations in protein, fat and carbohydrates. Proprietary formulas were free of bacteria, and the companies prospered with mass production, international marketing and aggressive advertising. From 1932 on, medical societies restricted advertising to the laity. In 1939 Williams in Singapore and in 1970 Jelliffe in Jamaica suspected that commercial formula may be increasing infant mortality in the Third World. Breastfeeding continued to decline during the early 20th century, falling in 1970 below 10% in the USA. The Swiss 'Third World Group' and the US 'Infant Formula Action Coalition' linked infant mortality and industry marketing in the Third World. The controversy of 1970-1984 led to the WHO Code, which regulated the advertising and marketing of baby food. This was one of several public health statements contributing to the resurgence of breastfeeding. PMID- 25012140 TI - Tuberculosis monoresistance and culture conversion in smokers. PMID- 25012141 TI - False memory for context activates the parahippocampal cortex. AB - Previous studies have reported greater activity in the parahippocampal cortex during true memory than false memory, which has been interpreted as reflecting greater sensory processing during true memory. However, in these studies, sensory detail and contextual information were confounded. In the present fMRI study, we employed a novel paradigm to dissociate these factors. During encoding, abstract shapes were presented in one of two contexts (i.e., moving or stationary). During retrieval, participants classified shapes as previously "moving" or "stationary." Critically, contextual processing was relatively greater during false memory ("moving" responses to stationary items), while sensory processing was relatively greater during true memory ("moving" responses to moving items). Within the medial temporal lobe, false memory versus true memory produced greater activity in the parahippocampal cortex, whereas true memory versus false memory produced greater activity in the hippocampus. The present results indicate that the parahippocampal cortex mediates contextual processing rather than sensory processing. PMID- 25012142 TI - A modular designed copolymer with anti-thrombotic activity and imaging capability. AB - Through a modular ROMP (ring-opening metathesis polymerization) strategy, a random copolymer with anti-thrombotic activity and imaging capability has been constructed from RGD, rhodamine B and PEG modified norbornene monomers. As we expected, these tri-component polynorbornenes exhibit significant enhancement in anti-thrombotic efficacy and bioavailability in vivo. PMID- 25012143 TI - Molybdenum distributions and variability in drinking water from England and Wales. AB - An investigation has been carried out of molybdenum in drinking water from a selection of public supply sources and domestic taps across England and Wales. This was to assess concentrations in relation to the World Health Organization (WHO) health-based value for Mo in drinking water of 70 MUg/l and the decision to remove the element from the list of formal guideline values. Samples of treated drinking water from 12 water supply works were monitored up to four times over an 18-month period, and 24 domestic taps were sampled from three of their supply areas. Significant (p < 0.05) differences were apparent in Mo concentration between sources. Highest concentrations were derived from groundwater from a sulphide-mineralised catchment, although concentrations were only 1.5 MUg/l. Temporal variability within sites was small, and no seasonal effects (p > 0.05) were detected. Tap water samples collected from three towns (North Wales, the English Midlands, and South East England) supplied uniquely by upland reservoir water, river water, and Chalk groundwater, respectively, also showed a remarkable uniformity in Mo concentrations at each location. Within each, the variability was very small between houses (old and new), between pre-flush and post-flush samples, and between the tap water and respective source water samples. The results indicate that water distribution pipework has a negligible effect on supplied tap water Mo concentrations. The findings contrast with those for Cu, Zn, Ni, Pb, and Cd, which showed significant differences (p < 0.05) in concentrations between pre-flush and post-flush tap water samples. In two pre flush samples, concentrations of Ni or Pb were above drinking water limits, although in all cases, post-flush waters were compliant. The high concentrations, most likely derived from metal pipework in the domestic distribution system, accumulated during overnight stagnation. The concentrations of Mo observed in British drinking water, in all cases less than 2 MUg/l, were more than an order of magnitude below the WHO health-based value and suggest that Mo is unlikely to pose a significant health or water supply problem in England and Wales. PMID- 25012144 TI - Seasonality in the distribution of dinoflagellates with special reference to harmful algal species in tropical coastal environment, Bay of Bengal. AB - A study was carried out in the coastal waters of Kalpakkam, southeast coast of India, to find out the seasonal variation in dinoflagellate community structure. Samples were collected for a period of 4 years during 2006-2010. During the study 69 species of dinoflagellates were encountered among which Ceratium furca and Prorocentrum micans were most common during all the seasons. Genus Ceratium was found to be the most diverse one with 23 species which was followed by genus Protoperidinium with 16 species. Of 69 species, 27 species were considered as dominant based on their abundance during pre-monsoon (PRM), monsoon (MON) and post-monsoon (POM) periods. Relatively high density and diversity of dinoflagellates were encountered during the PRM period as compared to the MON and POM periods. Abundance pattern of dinoflagellates for three seasons showed the following trend: PRM > POM > MON. Salinity showed a positive correlation with dinoflagellate community showing its importance in dinoflagellate growth and sustenance. Ammonia and phosphate developed negative correlation with dinoflagellate density indicating the utilization of these nutrients by the dinoflagellate community. The presence of three dinoflagellate associations, broadly representing the three seasons experienced at this location, was evident from the cluster analysis. The study revealed presence of 19 relatively abundant toxic/red tide forming dinoflagellate species in the coastal waters of Kalpakkam. PMID- 25012145 TI - Application of a toxicity test battery integrated index for a first screening of the ecotoxicological threat posed by ports and harbors in the southern Adriatic Sea (Italy). AB - Ports and harbors may represent a threat for coastal ecosystems due to pollutant inputs, especially those derived from maritime activities. In this study, we report a first assessment of the ecotoxicological threat posed by six ports and harbors of opposite coastal regions, Apulia and Albania, in the southern Adriatic Sea (Italy). A bioassay battery consisting of four different species representing different trophic levels, algae Dunaliella tertiolecta, bacteria Vibrio fischeri, crustacean Artemia salina, and echinoids Paracentrotus lividus, has been used to assess sediment elutriates, pore waters, and sediment suspensions. Two different approaches of toxicity data integration, worst case and integrated index, have been used to determine the most appropriate procedure for the investigated sites. All sites with the worst case approach showed high toxicity levels. The chronic test with algae was the most sensitive identifying the highest effects in the battery. This effect can be attributable to contaminants derived from antifouling paints. The sediments, evaluated with V. fischeri test, often showed toxicity not found in the aqueous matrices of the same sites and that can be mainly linked to organic compounds. The test battery used in this study allowed us to perform a preliminary screening of the ecotoxicological risk of the studied area. In fact, the species utilized for toxicity tests responded differently to the investigated samples, showing different sensitivity. The test battery integrated index did not allow highlighting the differences among the sites and showed a general high ecotoxicological risk. A larger number of tests with higher sensitivity together with a tailored attribution of weights to endpoints and matrices will improve the final site evaluation. PMID- 25012146 TI - MicroRNA-205 regulates the calcification and osteoblastic differentiation of vascular smooth muscle cells. AB - OBJECTIVES: We investigated the role of miR-205 in the osteogenic differentiation of vascular smooth muscle cells (VSMCs). METHODS: Osteogenic differentiation of human aortic smooth muscle cells (HASMCs) was induced by 10 mM beta glycerophosphate (beta-GP). Alizarin Red S staining, alkaline phosphatase (ALP) activity and osteocalcin secretion were used to determine osteogenic differentiation of HASMCs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to measure the expression of miR-205 in HASMCs. RESULTS: The expression of endogenous miR-205 was decreased in HASMCs during beta glycerophosphate-induced calcification. Overexpression of miR-205 inhibited the differentiation of HASMCs into osteoblast-like cells, as evidenced by a decrease in ALP activity, osteocalcin secretion, and Runx2 expression, whereas miR-205 depletion enhanced osteoblastic differentiation of HASMCs. Runx2 and Smad1 were identified as direct targets of miR-205 by computational analysis and experimental assays. CONCLUSION: The present study shows that miR-205 may negatively regulate the beta-glycerophosphate-induced calcification of HASMCs, at least partially by targeting Runx2 and Smad1. PMID- 25012148 TI - Nicotine and health. AB - Nicotine, an alkaloid derived from the leaves of tobacco plants (Nicotiana tabacum and Nicotiana rustica) is the primary addictive agent in tobacco products.(1,2) There are different ways of administering the various products including smoking cigarettes, chewing tobacco, holding moist snuff in the mouth, inhaling dry snuff through the nose, inhaling smoke from a waterpipe and inhaling vapour from an electronic cigarette.(3-6) It can be difficult differentiating the effects of nicotine from the many other toxic substances these products also contain. Here we review the pharmacological effects of nicotine but we will not review the well-known harmful effects of cigarettes, where it is primarily the toxins and carcinogens in tobacco smoke rather than the nicotine that cause illness and death.(7) A future article will consider the use of electronic cigarettes. PMID- 25012149 TI - ?Teriflunomide for multiple sclerosis. AB - ?Teriflunomide (Aubagio-Genzyme Therapeutics), the main metabolite of the disease modifying anti-rheumatic drug leflunomide,1 is an immunomodulatory agent with anti-inflammatory properties.2 It is a new oral treatment licensed for adults with relapsing-remitting multiple sclerosis. Here we discuss the evidence for its effectiveness and safety, and consider its place in therapy. PMID- 25012147 TI - Current status specifiers for patients at clinical high risk for psychosis. AB - BACKGROUND: Longitudinal studies of the clinical high risk (CHR) syndrome for psychosis have emphasized the conversion vs non-conversion distinction and thus far have not focused intensively on classification among non-converters. The present study proposes a system for classifying CHR outcomes over time when using the Structured Interview for Psychosis-risk Syndromes and evaluates its validity. METHOD: The system for classifying CHR outcomes is referred to as "current status specifiers," with "current" meaning over the month prior to the present evaluation and "specifiers" indicating a set of labels and descriptions of the statuses. Specifiers for four current statuses are described: progression, persistence, partial remission, and full remission. Data from the North American Prodromal Longitudinal Study were employed to test convergent, discriminant, and predictive validity of the current status distinctions. RESULTS: Validity analyses partly supported current status distinctions. Social and role functioning were more impaired in progressive and persistent than in remitted patients, suggesting a degree of convergent validity. Agreement between CHR current statuses and current statuses for a different diagnostic construct (DSM IV Major Depression) was poor, suggesting discriminant validity. The proportion converting to psychosis within a year was significantly higher in cases meeting progression criteria than in those meeting persistence criteria and tended to be higher than in those meeting full remission criteria, consistent with a degree of predictive validity. DISCUSSION: CHR syndrome current status specifiers could offer a potentially valid and useful description of current clinical status among non-converters. Study in additional samples is needed. PMID- 25012150 TI - The importance of personality and parental styles on optimism in adolescents. AB - Some studies have suggested that personality factors are important to optimism development. Others have emphasized that family relations are relevant variables to optimism. This study aimed to evaluate the importance of parenting styles to optimism controlling for the variance accounted for by personality factors. Participants were 344 Brazilian high school students (44% male) with mean age of 16.2 years (SD = 1) who answered personality, optimism, responsiveness and demandingness scales. Hierarchical regression analyses were conducted having personality factors (in the first step) and maternal and paternal parenting styles, and demandingness and responsiveness (in the second step) as predictive variables and optimism as the criterion. Personality factors, especially neuroticism (beta = -.34, p < .01), extraversion (beta = .26, p < .01) and agreeableness (beta = .16, p < .01), accounted for 34% of the optimism variance and insignificant variance was predicted exclusively by parental styles (1%). These findings suggest that personality is more important to optimism development than parental styles. PMID- 25012151 TI - Simple multiplex real-time PCR for rapid detection of common 16S rRNA methyltransferase genes. AB - We have developed a real-time multiplex PCR assay to detect the three most common 16S rRNA methyltransferase genes (armA, rmtB and rmtC), which encode problematic high-level resistance to all clinically-relevant aminoglycoside antibiotics. All results were consistent with published conventional PCR assays and these genes still appear rare in Australia. PMID- 25012152 TI - Radical cystectomy and ileal orthotopic bladder substitution after radical retropubic prostatectomy: functional and oncological results. AB - Men with good functional results following radical retropubic prostatectomy (RRP) and requiring radical cystectomy (RC) for subsequent bladder carcinoma seldom receive orthotopic bladder substitution. Four patients aged 62-72 years (median 67 years), who had undergone RRP for prostate cancer of stage pT2bN0M0 Gleason score 6 (n = 1), pT2cN0M0 Gleason score 5 and 6 (n = 2) and pT3bN0M0 Gleason score 7 (n = 1) 27 to 104 months before, developed urothelial bladder carcinoma treated with RC and ileal orthotopic bladder substitution. After radical prostatectomy three were continent and one had grade I stress incontinence, and three achieved intercourse with intracavernous alprostadil injections. Follow-up after RC ranged between 27 and 42 months (median 29 months). At the 24-month follow-up visit after RC daily urinary continence was total (0 pad) in one patient, two used one pad for mild leakage, and one was incontinent following endoscopic incision of anastomotic stricture. One patient died of progression of bladder carcinoma, while the other three are alive without evidence of disease. The three surviving patients continued to have sexual intercourse with intracavernous alprostadil injections. Men with previous RRP have a reasonable chance of maintaining a satisfactory functional outcome following RC and ileal orthotopic bladder substitution. PMID- 25012155 TI - Carboplatin and paclitaxel treatment is effective in advanced anal cancer. AB - BACKGROUND: The development of distant metastases of squamous cell carcinoma of the anal canal (SCCA) is rare but has a poor prognosis. A combination of carboplatin and paclitaxel is commonly used for treating squamous cell cancer in different organs, but its efficacy in advanced SCCA is unclear. The objective of this study is to determine the tolerability and outcome of patients with advanced SCCA on carboplatin plus paclitaxel treatment at the Moffitt Cancer Center. METHODS: Retrospective analysis was conducted by looking at records from the Moffitt Cancer Center Tumor Registry from January 2007 to January 2012. Eligible patients had to have a diagnosis of SCCA and have received carboplatin plus paclitaxel every 3 weeks as part of the treatment plan. RESULTS: Eighteen patients fulfilled the criteria; 14 were initially diagnosed with early-stage disease and received concurrent chemoradiation, but then relapsed. Median age was 56 years. Upon diagnosis of metastatic disease, 12 patients received carboplatin plus paclitaxel as a first-line treatment. Five patients had received prior systemic chemotherapy regimens and 1 had received prior local regional therapy. The response rate was high at 53% including 3 patients who achieved a complete response. Median overall survival was 12.19 months. CONCLUSIONS: Carboplatin and paclitaxel treatment shows encouraging activity in advanced SCCA. PMID- 25012153 TI - Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells. AB - BACKGROUND: Vinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells. METHODS: Human bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to mesenchymal markers and apoptosis. The role of the proteasome in controlling cell cell adhesion was studied using the proteasome inhibitor MG132. RESULTS: We show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation. CONCLUSIONS: Our findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis. PMID- 25012156 TI - Applying novel methods to assess clinical outcomes: insights from the TRILOGY ACS trial. AB - AIMS: Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side. METHODS AND RESULTS: The traditional time-to-first-event, Andersen Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72 0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events. CONCLUSION: This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common. CLINICAL TRIAL REGISTRATION: NCT00699998. PMID- 25012157 TI - High frequency of potential entrapment gaps in beds in an acute hospital. AB - OBJECTIVE: dimensional guidelines for bedrails have been developed to minimise the risk of patient entrapment within the bed. We examined whether bedrails in a large Irish teaching hospital complied with these standards. DESIGN AND SETTING: survey of 60 accessible beds in six hospital wards. METHODS: a specialised cone and cylinder tool that mimics the size and weight of a small adult neck and head was used to determine gaps in the four zones most associated with entrapment. RESULTS: the number of failures for each zone was 15 beds for zone 1 (any space between the perimeters of the rail); 42 beds for zone 2 (the space under the rail); 41 beds for zone 3 (the space between the inside surface of the bedrail and the mattress) and 13 beds for zone 4 (the space between the mattress and rail at the end of the rail). Failures were more common with hydraulic adjusted than with electric profiling beds. Mattresses that were the wrong size (usually too narrow) or too soft and bedrails that were loose or were poorly maintained accounted for many failures. CONCLUSION: many beds used in our hospital did not comply with dimensional standards to minimise entrapment risks. This emphasises the need for careful selection of patients for whom bedrails are to be used as well as the need for monitoring and maintenance of bed systems. PMID- 25012158 TI - Prevalence and predictors of bedrail use in an acute hospital. AB - OBJECTIVE: to determine the prevalence and predictors of bedrail use in an acute hospital. DESIGN AND SETTING: overnight survey in a University teaching hospital. SUBJECTS: Three-hundred and twenty-seven beds and patients in 14 wards. METHODS: data were collected on bedrail use and on the bed system, ward and patient characteristics. Medical, nursing and physical therapy notes were examined and the night and day nurses and, if necessary, the doctors and therapists caring for the patient interviewed to determine patients' diagnoses, functional and cognitive status. RESULTS: there were 133 (40.7%) beds with one or more raised rails. Independent predictors of bedrail use were use of electric profiling beds, confusion, reduced alertness and any difficulty with transferring from bed. The most common reported indication for bedrail use was 'to prevent rolling out of bed' (59%); 'to prevent getting out of bed' was recorded in 11% of cases. Use of bedrails was judged inappropriate in 27/133 (20.3%) patients and in 14/43 (32.6%) patients with abnormal mental status; misuse was particularly common in those with confusion or agitation [13/34 (38.2%)]. Failure to use bedrails was potentially inappropriate in 32/194 (16.5%) of those without bedrails. CONCLUSION: this study using individual patient data shows that the use of electric profiling beds, abnormal mental states and difficulty transferring from bed are the main predictors of bedrail use in acute hospitals. Inappropriate use of bedrails is common in those with cognitive impairment or with agitation. PMID- 25012159 TI - Fracture risk assessment before and after resolution of endogenous hypercortisolism: is the FRAX(r) algorithm useful? AB - PURPOSE: Fracture risk data following curative treatment of Cushing's syndrome (CS) are scarce and the role of bisphosphonates in bone recovery after remission is controversial. We evaluated the effects of hypercortisolism remission in bone recovery in CS. Then, we assessed if the FRAX((r)) algorithm calculated before the cure can predict fracture risk after cure. METHODS: Thirty-six patients with CS were retrospectively investigated. Bone turnover markers, bone mineral density (BMD) at the lumbar spine (L1-L4) and left femur (both neck and total hip were considered), and fracture risk using FRAX((r)) algorithm with femoral neck BMD were evaluated at diagnosis and after a median follow-up of 24 months (range 12 108 months) from hypercortisolism remission. Data about bone active therapy were analyzed. RESULTS: Hypercortisolism remission was associated with the improvement of all densitometric parameters and with the reduction of fracture risk. The percentage change in BMD and the fracture risk were not significantly different in bisphosphonate-treated vs. untreated patients. During follow-up, three fractured patients at baseline exhibited a new vertebral fracture. A baseline 10 year probability of major osteoporotic fractures (FRAX((r)) Major) of 17 % was able to predict the occurrence of a new vertebral fracture during follow-up after cure with 100 % sensitivity, 77 % specificity, 81 % positive predictive value and 100 % negative predictive value. CONCLUSIONS: Osteoporosis and fracture risk may be reversible after curative treatment of CS, regardless of bisphosphonate therapy. We suggest applying the FRAX((r)) algorithm to all active CS patients using a baseline FRAX((r)) Major of 17 % as "intervention threshold". PMID- 25012160 TI - Epidemic characteristics of hemorrhagic fever with renal syndrome in China, 2006 2012. AB - BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses is a serious public health problem in China. The National Notifiable Disease Surveillance System (NNDSS) was established online by China CDC in 2004 and rodent surveillance sites were adjusted to 40 sites in 22 provinces in 2005. Here we analyzed the surveillance data of both human cases and rodents host during 2006-2012 to examine the epidemic trends of HFRS in recent years in China. METHODS: Records on HFRS human cases and surveillance data of rodents host from 2006 to 2012 were analyzed. Phylogenetic tree based on complete sequence of M segment of 58 virus isolates was constructed and analyzed to make a better understanding of the molecular diversity of hantaviruses in China. RESULTS: During 2006-2012, a total of 77558 HFRS human cases and 866 deaths were reported with the average annual incidence rate of 0.83 cases/100,000 population and case fatality rate of 1.13%. 84.16% of the total cases were clustered in 9 provinces and mainly reported in spring and autumn-winter seasons. HFRS incidence in males was over 3 times higher than in females and farmers still accounted for the largest proportion. The average density of rodents was relatively stable from 2006 to 2012. Apodemus agrarius and Rattus norvegicus were predominant in wild field and residential area, respectively. Both hantaviruses carrying and infection rates in rodents had a rapid increase in 2012. Phylogenetic analysis showed that at least six clades of Hantaan virus and five of Seoul virus were prevalent in China. CONCLUSION: HFRS in China was still a natural focal disease with relatively high morbidity and fatality and its distribution and epidemic trends had also changed. Surveillance measures, together with prevention and control strategies should be improved and strengthened to reduce HFRS infection in China. PMID- 25012161 TI - Worker compensation injuries among the Aboriginal population of British Columbia, Canada: incidence, annual trends, and ecological analysis of risk markers, 1987 2010. AB - BACKGROUND: Aboriginal people in British Columbia (BC) have higher injury incidence than the general population, but information is scarce regarding variability among injury categories, time periods, and geographic, demographic and socio-economic groups. Our project helps fill these gaps. This report focuses on workplace injuries. METHODS: We used BC's universal health care insurance plan as a population registry, linked to worker compensation and vital statistics databases. We identified Aboriginal people by insurance premium group and birth and death record notations. We identified residents of specific Aboriginal communities by postal code. We calculated crude incidence rate and Standardized Relative Risk (SRR) of worker compensation injury, adjusted for age, gender and Health Service Delivery Area (HSDA), relative to the total population of BC. We assessed annual trend by regressing SRR as a linear function of year. We tested hypothesized associations of geographic, socio-economic, and employment-related characteristics of Aboriginal communities with community SRR of injury by multivariable linear regression. RESULTS: During the period 1987-2010, the crude rate of worker compensation injury in BC was 146.6 per 10,000 person-years (95% confidence interval: 146.4 to 146.9 per 10,000). The Aboriginal rate was 115.6 per 10,000 (95% CI: 114.4 to 116.8 per 10,000) and SRR was 0.88 (95% CI: 0.87 to 0.89). Among those living on reserves SRR was 0.79 (95% CI: 0.78 to 0.80). HSDA SRRs were highly variable, within both total and Aboriginal populations. Aboriginal males under 35 and females under 40 years of age had lower SRRs, but older Aboriginal females had higher SRRs. SRRs are declining, but more slowly for the Aboriginal population. The Aboriginal population was initially at lower risk than the total population, but parity was reached in 2006. These community characteristics independently predicted injury risk: crowded housing, proportion of population who identified as Aboriginal, and interactions between employment rate and income, occupational risk, proportion of university-educated persons, and year. CONCLUSIONS: As employment rates rise, so has risk of workplace injury among the Aboriginal population. We need culturally sensitive prevention programs, targeting regions and industries where Aboriginal workers are concentrated and demographic groups that are at higher risk. PMID- 25012162 TI - Integration of microfluidics into the synthetic biology design flow. AB - One goal of synthetic biology is to design and build genetic circuits in living cells for a range of applications. Major challenges in these efforts include increasing the scalability and robustness of engineered biological systems and streamlining and automating the synthetic biology workflow of specification design-assembly-verification. We present here a summary of the advances in microfluidic technology, particularly microfluidic large scale integration, that can be used to address the challenges facing each step of the synthetic biology workflow. Microfluidic technologies allow precise control over the flow of biological content within microscale devices, and thus may provide more reliable and scalable construction of synthetic biological systems. The integration of microfluidics and synthetic biology has the capability to produce rapid prototyping platforms for characterization of genetic devices, testing of biotherapeutics, and development of biosensors. PMID- 25012163 TI - HDL cholesterol, apolipoproteins, and cardiovascular risk in hemodialysis patients. AB - High concentrations of HDL cholesterol are considered to indicate efficient reverse cholesterol transport and to protect from atherosclerosis. However, HDL has been suggested to be dysfunctional in ESRD. Hence, our main objective was to investigate the effect of HDL cholesterol on outcomes in maintenance hemodialysis patients with diabetes. Moreover, we investigated the associations between the major protein components of HDL (apoA1, apoA2, and apoC3) and end points. We performed an exploratory, post hoc analysis with 1255 participants (677 men and 578 women) of the German Diabetes Dialysis study. The mean age was 66.3 years and the mean body mass index was 28.0 kg/m(2). The primary end point was a composite of cardiac death, myocardial infarction, and stroke. The secondary end point included all-cause mortality. The mean duration of follow-up was 3.9 years. A total of 31.3% of the study participants reached the primary end point and 49.1% died from any cause. HDL cholesterol and apoA1 and apoC3 quartiles were not related to end points. However, there was a trend toward an inverse association between apoA2 and all-cause mortality. The hazard ratio for death from any cause in the fourth quartile compared with the first quartile of apoA2 was 0.63 (95% confidence interval, 0.40 to 0.89). The lack of an association between HDL cholesterol and cardiovascular risk may support the concept of dysfunctional HDL in hemodialysis. The possible beneficial effect of apoA2 on survival requires confirmation in future studies. PMID- 25012164 TI - A pathogenetic role for endothelin-1 in peritoneal dialysis-associated fibrosis. AB - In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits low-grade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF beta1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-beta1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-beta1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-beta1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF beta1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PD associated dysfunction. PMID- 25012165 TI - Renal F4/80+ CD11c+ mononuclear phagocytes display phenotypic and functional characteristics of macrophages in health and in adriamycin nephropathy. AB - Conventional markers of macrophages (Mfs) and dendritic cells (DCs) lack specificity and often overlap, leading to confusion and controversy regarding the precise function of these cells in kidney and other diseases. This study aimed to identify the phenotype and function of renal mononuclear phagocytes (rMPs) expressing key markers of both Mfs and DCs. F4/80(+)CD11c(+) cells accounted for 45% of total rMPs in normal kidneys and in those from mice with Adriamycin nephropathy (AN). Despite expression of the DC marker CD11c, these double positive rMPs displayed the features of Mfs, including Mf-like morphology, high expression of CD68, CD204, and CD206, and high phagocytic ability but low antigen presenting ability. F4/80(+)CD11c(+) cells were found in the cortex but not in the medulla of the kidney. In AN, F4/80(+)CD11c(+) cells displayed an M1 Mf phenotype with high expression of inflammatory mediators and costimulatory factors. Adoptive transfer of F4/80(+)CD11c(+) cells separated from diseased kidney aggravated renal injury in AN mice. Furthermore, adoptive transfer of common progenitors revealed that kidney F4/80(+)CD11c(+) cells were derived predominantly from monocytes, but not from pre-DCs. In conclusion, renal F4/80(+)CD11c(+) cells are a major subset of rMPs and display Mf-like phenotypic and functional characteristics in health and in AN. PMID- 25012166 TI - Multiple genes of the renin-angiotensin system are novel targets of Wnt/beta catenin signaling. AB - Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor (LEF)-binding sites, and beta-catenin induced the binding of LEF-1 to these sites in kidney tubular cells. Overexpression of either beta-catenin or different Wnt ligands induced the expression of all RAS genes. Conversely, a small-molecule beta-catenin inhibitor ICG-001 abolished RAS induction. In a mouse model of nephropathy induced by adriamycin, either transient therapy or late administration of ICG-001 abolished established proteinuria and kidney lesions. ICG-001 inhibited renal expression of multiple RAS genes in vivo and abolished the expression of other Wnt/beta-catenin target genes. Moreover, ICG-001 therapy restored expression of nephrin, podocin, and Wilms' tumor 1, attenuated interstitial myofibroblast activation, repressed matrix expression, and inhibited renal inflammation and fibrosis. Collectively, these studies identify all RAS genes as novel downstream targets of Wnt/beta catenin. Our results indicate that blockade of Wnt/beta-catenin signaling can simultaneously repress multiple RAS genes, thereby leading to the reversal of established proteinuria and kidney injury. PMID- 25012167 TI - Colony-stimulating factor-1: a potential biomarker for lupus nephritis. AB - A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increased serum or urine CSF-1 levels in patients with cutaneous, serositis, and musculoskeletal disease; however, the increase in CSF-1 levels was far greater in LN. Moreover, an elevation in serum or urine CSF-1 levels correlated with increasing intrarenal CSF-1 expression and histopathology. By longitudinally tracking patients, we found that elevated serum CSF-1 heralded the initial onset of disease, and a rise in serum or urine CSF-1 predicted recurrences of LN before clinical evidence of glomerular dysfunction and conventional serologic measures, even in patients with other manifestations of SLE. These findings indicate that serial monitoring for a rise in serum or urine CSF-1 levels in patients with SLE reflects kidney histopathology and may predict renal disease activity and the onset and recurrence of LN more accurately than conventional laboratory measures. PMID- 25012168 TI - Akt1-mediated fast/glycolytic skeletal muscle growth attenuates renal damage in experimental kidney disease. AB - Muscle wasting is frequently observed in patients with kidney disease, and low muscle strength is associated with poor outcomes in these patients. However, little is known about the effects of skeletal muscle growth per se on kidney diseases. In this study, we utilized a skeletal muscle-specific, inducible Akt1 transgenic (Akt1 TG) mouse model that promotes the growth of functional skeletal muscle independent of exercise to investigate the effects of muscle growth on kidney diseases. Seven days after Akt1 activation in skeletal muscle, renal injury was induced by unilateral ureteral obstruction (UUO) in Akt1 TG and wild type (WT) control mice. The expression of atrogin-1, an atrophy-inducing gene in skeletal muscle, was upregulated 7 days after UUO in WT mice but not in Akt1 TG mice. UUO-induced renal interstitial fibrosis, tubular injury, apoptosis, and increased expression of inflammatory, fibrosis-related, and adhesion molecule genes were significantly diminished in Akt1 TG mice compared with WT mice. An increase in the activating phosphorylation of eNOS in the kidney accompanied the attenuation of renal damage by myogenic Akt1 activation. Treatment with the NOS inhibitor L-NAME abolished the protective effect of skeletal muscle Akt activation on obstructive kidney disease. In conclusion, Akt1-mediated muscle growth reduces renal damage in a model of obstructive kidney disease. This improvement appears to be mediated by an increase in eNOS signaling in the kidney. Our data support the concept that loss of muscle mass during kidney disease can contribute to renal failure, and maintaining muscle mass may improve clinical outcome. PMID- 25012169 TI - Renal angiotensin-converting enzyme upregulation: a prerequisite for nitric oxide synthase inhibition-induced hypertension? PMID- 25012170 TI - Renal angiotensin-converting enzyme is essential for the hypertension induced by nitric oxide synthesis inhibition. AB - The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the gamma isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition. PMID- 25012171 TI - Can muscle-kidney crosstalk slow progression of CKD? PMID- 25012172 TI - Antagonism of canonical Wnt/beta-catenin signaling: taking RAS blockade to the next level? PMID- 25012173 TI - Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines. AB - Although APOL1 gene variants are associated with nephropathy in African Americans, little is known about APOL1 protein synthesis, uptake, and localization in kidney cells. To address these questions, we examined APOL1 protein and mRNA localization in human kidney and human kidney-derived cell lines. Indirect immunofluorescence microscopy performed on nondiseased nephrectomy cryosections from persons with normal kidney function revealed that APOL1 protein was markedly enriched in podocytes (colocalized with synaptopodin and Wilms' tumor suppressor) and present in lower abundance in renal tubule cells. Fluorescence in situ hybridization detected APOL1 mRNA in glomeruli (podocytes and endothelial cells) and tubules, consistent with endogenous synthesis in these cell types. When these analyses were extended to renal-derived cell lines, quantitative RT-PCR did not detect APOL1 mRNA in human mesangial cells; however, abundant levels of APOL1 mRNA were observed in proximal tubule cells and glomerular endothelial cells, with lower expression in podocytes. Western blot analysis revealed corresponding levels of APOL1 protein in these cell lines. To explain the apparent discrepancy between the marked abundance of APOL1 protein in kidney podocytes observed in cryosections versus the lesser abundance in podocyte cell lines, we explored APOL1 cellular uptake. APOL1 protein was taken up readily by human podocytes in vitro but was not taken up efficiently by mesangial cells, glomerular endothelial cells, or proximal tubule cells. We hypothesize that the higher levels of APOL1 protein in human cryosectioned podocytes may reflect both endogenous protein synthesis and APOL1 uptake from the circulation or glomerular filtrate. PMID- 25012174 TI - Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome. AB - Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8+/-0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient. PMID- 25012175 TI - Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway. AB - AKI is associated with increased morbidity, mortality, and cost of care, and therapeutic options remain limited. Reactive oxygen species are critical for the genesis of ischemic AKI. Stanniocalcin-1 (STC1) suppresses superoxide generation through induction of uncoupling proteins (UCPs), and transgenic overexpression of STC1 inhibits reactive oxygen species and protects from ischemia/reperfusion (I/R) kidney injury. Our observations revealed high AMP-activated protein kinase (AMPK) activity in STC1 transgenic kidneys relative to wild-type (WT) kidneys; thus, we hypothesized that STC1 protects from I/R kidney injury through activation of AMPK. Baseline activity of AMPK in the kidney correlated with the expression of STCs, such that the highest activity was observed in STC1 transgenic mice followed (in decreasing order) by WT, STC1 knockout, and STC1/STC2 double-knockout mice. I/R in WT kidneys increased AMPK activity and the expression of STC1, UCP2, and sirtuin 3. Inhibition of AMPK by administration of compound C before I/R abolished the activation of AMPK, diminished the expression of UCP2 and sirtuin 3, and aggravated kidney injury but did not affect STC1 expression. Treatment of cultured HEK cells with recombinant STC1 activated AMPK and increased the expression of UCP2 and sirtuin 3, and concomitant treatment with compound C abolished these responses. STC1 knockout mice displayed high susceptibility to I/R, whereas pretreatment of STC1 transgenic mice with compound C restored the susceptibility to I/R kidney injury. These data suggest that STC1 is important for activation of AMPK in the kidney, which mediates STC1-induced expression of UCP2 and sirtuin 3 and protection from I/R. PMID- 25012176 TI - An economic evaluation of rt-PA locking solution in dialysis catheters. AB - In a recent randomized trial, weekly recombinant tissue plasminogen activator (rt PA), 1 mg per lumen, once per week, and twice-weekly heparin as a locking solution (rt-PA/heparin) resulted in lower risks of hemodialysis catheter malfunction and catheter-related bacteremia compared with thrice-weekly heparin (heparin alone). We collected detailed costs within this trial to determine how choice of locking solution would affect overall health care costs, including the cost of locking solutions and all other relevant medical costs over the course of the 6-month trial. Nonparametric bootstrap estimates were used to derive 95% confidence intervals (CIs) and mean cost differences between the treatment groups. The cost of the locking solution was higher in patients receiving rt PA/heparin, but this was partially offset by lower costs for managing complications. Overall, the difference in unadjusted mean cost for managing patients with rt-PA/heparin versus heparin alone was Can$323 (95% CI, -$935 to $1581; P=0.62). When the costs were extrapolated over a 1-year time horizon using decision analysis, assuming ongoing rt-PA effectiveness, the overall costs of the strategies were similar. This finding was sensitive to plausible variation in the frequency and cost of managing patients with catheter-related bacteremia, and whether the benefit of rt-PA on catheter-related bacteremia was maintained in the long term. In summary, we noted no significant difference in the mean overall cost of an rt-PA/heparin strategy as a locking solution for catheters compared with thrice-weekly heparin. Cost savings due to a lower risk of hospitalization for catheter-related bacteremia partially offset the increased cost of rt-PA. PMID- 25012177 TI - Phagocyte NADPH oxidase restrains the inflammasome in ANCA-induced GN. AB - ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL 1beta generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody mediated disease model, mice transplanted with either gp91(phox)-deficient or p47(phox)-deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1beta levels compared with mice transplanted with wild-type bone marrow. IL-1beta receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1beta generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1beta generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1beta generation were inversely related in human monocytes. Furthermore, transplantation of gp91(phox)/caspase-1 double deficient bone marrow rescued the accelerated NCGN phenotype in gp91(phox) bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants. PMID- 25012179 TI - Protein-bound uremic toxins induce tissue remodeling by targeting the EGF receptor. AB - Indoxyl sulfate and p-cresol sulfate have been suggested to induce kidney tissue remodeling. This study aimed to clarify the molecular mechanisms underlying this tissue remodeling using cultured human proximal renal tubular cells and half nephrectomized mice treated with indoxyl sulfate or p-cresol sulfate as study models. Molecular docking results suggested that indoxyl sulfate and p-cresol sulfate dock on a putative interdomain pocket of the extracellular EGF receptor. In vitro spectrophotometric analysis revealed that the presence of a synthetic EGF receptor peptide significantly decreased the spectrophotometric absorption of indoxyl sulfate and p-cresol sulfate. In cultured cells, indoxyl sulfate and p cresol sulfate activated the EGF receptor and downstream signaling by enhancing receptor dimerization, and increased expression of matrix metalloproteinases 2 and 9 in an EGF receptor-dependent manner. Treatment of mice with indoxyl sulfate or p-cresol sulfate significantly activated the renal EGF receptor and increased the tubulointerstitial expression of matrix metalloproteinases 2 and 9. In conclusion, indoxyl sulfate and p-cresol sulfate may induce kidney tissue remodeling through direct binding and activation of the renal EGF receptor. PMID- 25012178 TI - GIV/girdin links vascular endothelial growth factor signaling to Akt survival signaling in podocytes independent of nephrin. AB - Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Galpha-interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Galphai3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Galphai3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Galphai3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases. PMID- 25012181 TI - Fast spatial ancestry via flexible allele frequency surfaces. AB - MOTIVATION: Unique modeling and computational challenges arise in locating the geographic origin of individuals based on their genetic backgrounds. Single nucleotide polymorphisms (SNPs) vary widely in informativeness, allele frequencies change non-linearly with geography and reliable localization requires evidence to be integrated across a multitude of SNPs. These problems become even more acute for individuals of mixed ancestry. It is hardly surprising that matching genetic models to computational constraints has limited the development of methods for estimating geographic origins. We attack these related problems by borrowing ideas from image processing and optimization theory. Our proposed model divides the region of interest into pixels and operates SNP by SNP. We estimate allele frequencies across the landscape by maximizing a product of binomial likelihoods penalized by nearest neighbor interactions. Penalization smooths allele frequency estimates and promotes estimation at pixels with no data. Maximization is accomplished by a minorize-maximize (MM) algorithm. Once allele frequency surfaces are available, one can apply Bayes' rule to compute the posterior probability that each pixel is the pixel of origin of a given person. Placement of admixed individuals on the landscape is more complicated and requires estimation of the fractional contribution of each pixel to a person's genome. This estimation problem also succumbs to a penalized MM algorithm. RESULTS: We applied the model to the Population Reference Sample (POPRES) data. The model gives better localization for both unmixed and admixed individuals than existing methods despite using just a small fraction of the available SNPs. Computing times are comparable with the best competing software. AVAILABILITY AND IMPLEMENTATION: Software will be freely available as the OriGen package in R. CONTACT: ranolaj@uw.edu or klange@ucla.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25012180 TI - Physical and functional links between anion exchanger-1 and sodium pump. AB - Anion exchanger-1 (AE1) mediates chloride-bicarbonate exchange across the plasma membranes of erythrocytes and, via a slightly shorter transcript, kidney epithelial cells. On an omnivorous human diet, kidney AE1 is mainly active basolaterally in alpha-intercalated cells of the collecting duct, where it is functionally coupled with apical proton pumps to maintain normal acid-base homeostasis. The C-terminal tail of AE1 has an important role in its polarized membrane residency. We have identified the beta1 subunit of Na(+),K(+)-ATPase (sodium pump) as a binding partner for AE1 in the human kidney. Kidney AE1 and beta1 colocalized in renal alpha-intercalated cells and coimmunoprecipitated (together with the catalytic alpha1 subunit of the sodium pump) from human kidney membrane fractions. ELISA and fluorescence titration assays confirmed that AE1 and beta1 interact directly, with a Kd value of 0.81 MUM. GST-AE1 pull-down assays using human kidney membrane proteins showed that the last 11 residues of AE1 are important for beta1 binding. siRNA-induced knockdown of beta1 in cell culture resulted in a significant reduction in kidney AE1 levels at the cell membrane, whereas overexpression of kidney AE1 increased cell surface sodium pump levels. Notably, membrane staining of beta1 was reduced throughout collecting ducts of AE1-null mouse kidney, where increased fractional excretion of sodium has been reported. These data suggest a requirement of beta1 for proper kidney AE1 membrane residency, and that activities of AE1 and the sodium pump are coregulated in kidney. PMID- 25012182 TI - repfdr: a tool for replicability analysis for genome-wide association studies. AB - MOTIVATION: Identification of single nucleotide polymorphisms that are associated with a phenotype in more than one study is of great scientific interest in the genome-wide association studies (GWAS) research. The empirical Bayes approach for discovering whether results have been replicated across studies was shown to be a reliable method, and close to optimal in terms of power. RESULTS: The R package repfdr provides a flexible implementation of the empirical Bayes approach for replicability analysis and meta-analysis, to be used when several studies examine the same set of null hypotheses. The usefulness of the package for the GWAS community is discussed. AVAILABILITY AND IMPLEMENTATION: The R package repfdr can be downloaded from CRAN. CONTACT: ruheller@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25012183 TI - Effects of high-intensity intermittent running exercise in overweight children. AB - This study examined the effects of a 6-week intermittent exercise training, at different intensities, on body composition, functional walking and aerobic endurance in overweight children. Forty-eight overweight children (age: 10.4 +/- 0.9 years) were randomly assigned to either intervention or control group. Lower and higher intensity intermittent exercise groups (LIIE and HIIE) performed intermittent running three times a week. LIIE performed more intervals at a lower intensity [16 intervals at 100% of individual maximal aerobic speed (MAS), 8 minutes in total], and HIIE performed fewer intervals at a higher intensity (12 intervals at 120% of MAS, 6 minutes in total). Each interval consisted of a 15 second run at the required speed, followed by a 15-second passive recovery. After 6 weeks, HIIE had a significantly (p < 0.05) higher percentage reduction in sum of skinfolds (i.e. calf and triceps), and significantly (p < 0.05) fewer steps during the functional obstacle performance, as compared with LIIE and control group. Significant improvement (p < 0.05) was found in intermittent aerobic endurance for HIIE as compared to the control group. Higher intensity intermittent training is an effective and time-efficient intervention for improving body composition, functional walking and aerobic endurance in overweight children. PMID- 25012185 TI - Service-Enriched Housing: The Staying at Home Program. AB - INTRODUCTION: The purpose of this research was to determine whether service enriched housing (i.e., the Staying at Home [SAH] program) in publicly subsidized buildings for low-income older adults influenced resident outcomes. METHOD: Eleven elderly high-rise buildings were used. Seven buildings had the SAH program and four did not. Information was collected from resident questionnaires, housing managers data, and medical information. A total of 10 desired outcomes were proposed as part of SAH (e.g., health improvements, receive more non institutional services, receive more preventive services, and be less likely to be institutionalized). Information was collected over the course of the SAH program every 6 months from December 2008 through June 2011. RESULTS: Overall, 736 surveys were completed by SAH program participants and 399 were completed by control group participants. Seven of the ten desired outcomes were achieved, and in 3 of the ten cases, no differences between the SAH group and control group were identified. The program was also beneficial with respect to cost savings. CONCLUSION: On the basis of these findings, the SAH program should be viewed as a success. In this case, service-enriched housing for elders in high-rise buildings would appear to be beneficial. PMID- 25012184 TI - PEDF and PEDF-derived peptide 44mer protect cardiomyocytes against hypoxia induced apoptosis and necroptosis via anti-oxidative effect. AB - Pigment epithelium-derived factor (PEDF) has many biological activities. But it's not known whether PEDF and its functional peptides could protect against hypoxia induced cell death and the mechanisms are still unclear. We used cultured H9c2 cells and primary cardiomyocytes to show that apoptosis and necroptosis were significantly increased after hypoxia. Both PEDF and its fuctional peptides 44mer reduced apoptosis and necroptosis rates and inhibited the expression of cleaved caspase 3 and receptor-interacting protein 3 (RIP3). Furthermore, PEDF and 44mer could up-regulate super oxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels, promote clearing of reactive oxygen species (ROS) and malondialdehyde (MDA). While, 34mer, another functional peptides had no effect on cell apoptosis and necroptosis. Hereby this is the first evidence that PEDF and its functional peptide 44mer protect cultured H9c2 cells and primary cardiomyocytes against apoptosis and necroptosis under hypoxic condition via the anti-oxidative mechanism. PMID- 25012186 TI - Adverse conditions at the workplace are associated with increased suicide risk. AB - OBJECTIVE: The present study addressed potential harms of a negative working environment for employed subjects. The main aim was to evaluate if adverse working conditions and job strain are related to an increase in suicide mortality. METHODS: The study population consisted of 6817 participants drawn from the MONICA/KORA Augsburg, Germany, surveys conducted in 1984-1995, being employed at baseline examination and followed up on average for 12.6 years. Adverse working conditions were assessed by an instrument of 16 items about chronobiological, physical and psychosocial conditions at the workplace, job strain was assessed as defined by Karasek. Suicide risks were estimated by Cox regression adjusted for suicide-related risk factors. RESULTS: A number of 28 suicide cases were observed within follow-up. High levels of adversity in chronobiological/physical working conditions significantly increased the risk for suicide mortality (HR 3.28, 95% CI 1.43-7.54) compared to low/intermediate levels in a model adjusted for age, sex and survey (p value 0.005). Additional adjustment for living alone, low educational level, smoking, high alcohol consumption, obesity and depressed mood attenuated this effect (HR 2.73) but significance remained (p value 0.022). Adverse psychosocial working conditions and job strain, in contrast, had no impact on subsequent suicide mortality risk (p values > 0.200). CONCLUSIONS: A negative working environment concerning chronobiological or physical conditions at the workplace had an unfavourable impact on suicide mortality risk, even after controlling for relevant suicide related risk factors. Employer interventions aimed to improve workplace conditions might be considered as a suitable means to prevent suicides among employees. PMID- 25012187 TI - Phenomenology of OCD: lessons from a large multicenter study and implications for ICD-11. AB - This study aimed to investigate the phenomenology of obsessive-compulsive disorder (OCD), addressing specific questions about the nature of obsessions and compulsions, and to contribute to the World Health Organization's (WHO) revision of OCD diagnostic guidelines. Data from 1001 patients from the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders were used. Patients were evaluated by trained clinicians using validated instruments, including the Dimensional Yale-Brown Obsessive-Compulsive Scale, the University of Sao Paulo Sensory Phenomena Scale, and the Brown Assessment of Beliefs Scale. The aims were to compare the types of sensory phenomena (SP, subjective experiences that precede or accompany compulsions) in OCD patients with and without tic disorders and to determine the frequency of mental compulsions, the co-occurrence of obsessions and compulsions, and the range of insight. SP were common in the whole sample, but patients with tic disorders were more likely to have physical sensations and urges only. Mental compulsions occurred in the majority of OCD patients. It was extremely rare for OCD patients to have obsessions without compulsions. A wide range of insight into OCD beliefs was observed, with a small subset presenting no insight. The data generated from this large sample will help practicing clinicians appreciate the full range of OCD symptoms and confirm prior studies in smaller samples the degree to which insight varies. These findings also support specific revisions to the WHO's diagnostic guidelines for OCD, such as describing sensory phenomena, mental compulsions and level of insight, so that the world-wide recognition of this disabling disorder is increased. PMID- 25012188 TI - Response to letter from Lipsitz et al. PMID- 25012189 TI - Difference in cerebral and peripheral hemodynamics among term and preterm infants during the first three days of life. AB - BACKGROUND: The relationship between cerebral and peripheral hemodynamics during the early postnatal period has not been clarified. OBJECTIVES: To evaluate cerebral and peripheral oxygenation and blood volumes between term and preterm infants during the first 3 days of life. MATERIALS AND METHODS: We performed near infrared time-resolved spectroscopy on 32 term infants (term group) and 40 preterm infants (preterm group), with an optode placed on their forehead and upper arm. The cerebral blood volume (CBV), peripheral blood volume (PBV), cerebral Hb oxygen saturation (cSO2) and peripheral Hb oxygen saturation (pSO2) were measured at 3-6, 12, 24, 48 and 72 h after birth. RESULTS: The CBV in the term group (2.45 +/- 0.47 ml/100 g) was significantly higher than that in the preterm group (1.97 +/- 0.33 ml/100 g). In contrast to the CBV, the PBV in the preterm group (3.63 +/- 0.76 ml/100 g) was significantly higher than that in the term group (3.26 +/- 0.56 ml/100 g). In the preterm group, there was a significant positive relationship between the CBVs and PBVs at each time point except at 72 h after birth. Despite the differences in blood volumes, there were no differences in the cSO2 and pSO2 between the two groups. CONCLUSIONS: The contrasting results in the CBV and PBV between the term and preterm infants might be explained by differences in the maturation of the physiological mechanism to control CBV and PBV. PMID- 25012190 TI - The structure of the catalytic domain of a plant cellulose synthase and its assembly into dimers. AB - Cellulose microfibrils are para-crystalline arrays of several dozen linear (1->4) beta-d-glucan chains synthesized at the surface of the cell membrane by large, multimeric complexes of synthase proteins. Recombinant catalytic domains of rice (Oryza sativa) CesA8 cellulose synthase form dimers reversibly as the fundamental scaffold units of architecture in the synthase complex. Specificity of binding to UDP and UDP-Glc indicates a properly folded protein, and binding kinetics indicate that each monomer independently synthesizes single glucan chains of cellulose, i.e., two chains per dimer pair. In contrast to structure modeling predictions, solution x-ray scattering studies demonstrate that the monomer is a two-domain, elongated structure, with the smaller domain coupling two monomers into a dimer. The catalytic core of the monomer is accommodated only near its center, with the plant-specific sequences occupying the small domain and an extension distal to the catalytic domain. This configuration is in stark contrast to the domain organization obtained in predicted structures of plant CesA. The arrangement of the catalytic domain within the CesA monomer and dimer provides a foundation for constructing structural models of the synthase complex and defining the relationship between the rosette structure and the cellulose microfibrils they synthesize. PMID- 25012191 TI - Insights into the localization and function of the membrane trafficking regulator GNOM ARF-GEF at the Golgi apparatus in Arabidopsis. AB - GNOM is one of the most characterized membrane trafficking regulators in plants, with crucial roles in development. GNOM encodes an ARF-guanine nucleotide exchange factor (ARF-GEF) that activates small GTPases of the ARF (ADP ribosylation factor) class to mediate vesicle budding at endomembranes. The crucial role of GNOM in recycling of PIN auxin transporters and other proteins to the plasma membrane was identified in studies using the ARF-GEF inhibitor brefeldin A (BFA). GNOM, the most prominent regulator of recycling in plants, has been proposed to act and localize at so far elusive recycling endosomes. Here, we report the GNOM localization in context of its cellular function in Arabidopsis thaliana. State-of-the-art imaging, pharmacological interference, and ultrastructure analysis show that GNOM predominantly localizes to Golgi apparatus. Super-resolution confocal live imaging microscopy identified GNOM and its closest homolog GNOM-like 1 at distinct subdomains on Golgi cisternae. Short term BFA treatment stabilizes GNOM at the Golgi apparatus, whereas prolonged exposures results in GNOM translocation to trans-Golgi network (TGN)/early endosomes (EEs). Malformed TGN/EE in gnom mutants suggests a role for GNOM in maintaining TGN/EE function. Our results redefine the subcellular action of GNOM and reevaluate the identity and function of recycling endosomes in plants. PMID- 25012193 TI - A general metal free approach to alpha-ketoamides via oxidative amidation diketonization of terminal alkynes. AB - A novel catalytic system TMSOTf/I2/DMSO for the oxidative coupling of terminal alkynes with virtually any primary/secondary amine leading to alpha-ketoamides has been developed. The reaction possibly proceeds via iminium ion formation, wherein DMSO acts as a solvent as well as an oxidizing agent. PMID- 25012192 TI - LNK1 and LNK2 are transcriptional coactivators in the Arabidopsis circadian oscillator. AB - Transcriptional feedback loops are central to the architecture of eukaryotic circadian clocks. Models of the Arabidopsis thaliana circadian clock have emphasized transcriptional repressors, but recently, Myb-like REVEILLE (RVE) transcription factors have been established as transcriptional activators of central clock components, including PSEUDO-RESPONSE REGULATOR5 (PRR5) and TIMING OF CAB EXPRESSION1 (TOC1). We show here that NIGHT LIGHT-INDUCIBLE AND CLOCK REGULATED1 (LNK1) and LNK2, members of a small family of four LNK proteins, dynamically interact with morning-expressed oscillator components, including RVE4 and RVE8. Mutational disruption of LNK1 and LNK2 function prevents transcriptional activation of PRR5 by RVE8. The LNKs lack known DNA binding domains, yet LNK1 acts as a transcriptional activator in yeast and in planta. Chromatin immunoprecipitation shows that LNK1 is recruited to the PRR5 and TOC1 promoters in planta. We conclude that LNK1 is a transcriptional coactivator necessary for expression of the clock genes PRR5 and TOC1 through recruitment to their promoters via interaction with bona fide DNA binding proteins such as RVE4 and RVE8. PMID- 25012194 TI - Main outcomes of a newborn hearing screening program in Belgium over six years. AB - OBJECTIVE: To present the outcomes of the newborn hearing screening program in Belgium (French-speaking area) since its implementation and to analyze its evolution between 2007 and 2012 in the neonatal population without reported risk factors for hearing loss. METHODS: The study was descriptive and based on a retrospective analysis of six annual databases (2007-2012) from the newborn hearing screening program. The main outcomes were identified: prevalence of reported hearing impairment; coverage rates (first and second test, follow-up); proportions of conclusive screening tests; referral rate. Each outcome was presented for the six years and by year of birth. Chi-squares were used to study differences in the various outcomes according to time. RESULTS: Over the six years, 264,508 newborns were considered as eligible for the screening. Hearing impairment was confirmed in 1.410/00 (n = 374) of them, with significant disparities from year to year, between 0.670/00 and 1.940/00. Analysis of the screening process showed that only 92.71% (n = 245,219) of the eligible newborns underwent a first hearing test. This coverage rate varied greatly over time: at the beginning, less than 90% of the newborns had a first test and it rose to almost 95%. After the two screening steps, 2.40% (n = 6340) of the newborns were referred to an ENT doctor; the referral rate slightly decreased during the first years of the program and then stabilized around 2.4%. Over the period, only 62.21% of the referred newborns had a follow-up; the follow-up rate was particularly low for the first year (44.91%) and then strongly increased (+19.52% in 2008) but never exceeded 70%. CONCLUSIONS: Outcome measures for the newborn hearing screening program in Belgium are lower than the benchmarks released by the Joint Committee on Infant Hearing. Nevertheless, the evolution of the outcome measures since the implementation of the program has been positive, particularly during the first years. At some point, most of the outcome measures decreased or at least did not change any further. The motivation and commitment of the professionals have to be supported in a variety of ways to improve outcome measures and thus, the quality of the program. PMID- 25012195 TI - Second branchial cleft fistulae: patient characteristics and surgical outcome. AB - BACKGROUNDS: Second branchial cleft anomalies predispose to recurrent infections, and surgical resection is recommended as the treatment of choice. There is no clear consensus regarding the timing or surgical technique in the operative treatment of these anomalies. Our aim was to compare the effect of age and operative techniques to patient characteristics and treatment outcome. METHODS: A retrospective study of pediatric patients treated for second branchial sinuses or fistulae during 1998-2012 at two departments in our academic tertiary care referral center. Comparison of patient characteristics, preoperative investigations, surgical techniques and postoperative sequelae. RESULTS: Our data is based on 68 patients, the largest series in the literature. One-fourth (24%) of patients had any infectious symptoms prior to operative treatment. Patient demographics, preoperative investigations, use of methylene blue, or tonsillectomy had no effect on the surgical outcome. There were no re-operations due to residual disease. Three complications were observed postoperatively. CONCLUSIONS: Our patient series of second branchial cleft sinuses/fistulae is the largest so far and enables analyses of patient characteristics and surgical outcomes more reliably than previously. Preoperative symptoms are infrequent and mild. There was no difference in clinical outcome between the observed departments. Performing ipsilateral tonsillectomy gave no outcome benefits. The operation may be delayed to an age of approximately three years when anesthesiological risks are and possible harms are best avoided. Considering postoperative pain and risk of postoperative hemorrhage a routine tonsillectomy should not be included to the operative treatment of second branchial cleft fistulae. PMID- 25012196 TI - Fourth branchial cleft anomaly: management strategy in acute presentation. AB - OBJECTIVES: Branchial malformations are common congenital head and neck lesions usually diagnosed in childhood during the first decade of life. Acute presentation is usually managed with conservative protocols before a definitive surgical procedure although the risk of life-treating septic complications may influence the physician's decision. Surgery is the treatment of choice with the removal of the lesion alone, nevertheless more aggressive approaches must be considered in complicated cases. Selective neck dissection including the removal of part of the thyroid lobe with the congenital lesion should be considered as the "ultima ratio" treatment to avoid recurrence. METHODS: We reviewed literature and report our experience concerning two patients with fourth branchial cleft sinus. RESULTS: A three-year-old child with a clinical history of recurrent neck abscess was referred to our department after several drainages performed in another centre. A three-year-old child referred to our department for a left side lower primary neck abscess. In both cases the diagnosis of a complicated fourth cleft remnant was confirmed by rigid endoscopic visualization of the mucosal orifice of the sinus in the pyriform fossa. Surgical management during acute presentation was challenging; in one patient the early fasciitis required an emergency procedure to remove the infected sinus that were strictly adherent to the deep vascular-nervous axis. CONCLUSION: Surgery was the definitive treatment in both cases and at 12 and 25 months follow-up respectively no recurrences were observed. PMID- 25012197 TI - Making Me Feel Comfortable: Developing Trust in the Nurse for Mexican Americans. AB - Trust (confianza) is an important component of patient-centered care and culturally competent care and a major element in the Hispanic culture. The aim of this study was to conceptualize the process of the development of interpersonal trust by hospitalized patients in their nurses. Using the grounded theory method, English-speaking Mexican American patients (N = 22) were interviewed. The core category was Making Me Feel Comfortable. The cyclical process included a beginning stage (Having Needs, Relying on the Nurse), middle stage (Coming Across to Me, Taking Care of Me, Connecting), and end point (Feeling Confianza) with two outcomes (Confiding in the Nurse, Taking Away the Negative). Anytime there was a negative element during the middle stage, this element halted any further development of trust with the nurse. Unique findings were related to Hispanic cultural values of familism and personalismo. The findings have implications which impact patient safety and quality care. PMID- 25012198 TI - Screening to Treatment: Obstacles and Predictors in Perinatal Depression (STOP PPD) in the Dallas Healthy Start program. AB - Healthy Start programs have made tremendous contributions toward improving the health of mothers and infants through the screening and early detection of perinatal depression. In a collaborative partnership with the Dallas Healthy Start (DHS) program, this pilot study investigated rates of follow-up to systematic referrals for the treatment of perinatal depression in the DHS, as well as identified specific barriers and predictors or treatment follow-up. Results of this study support strengthening existing community-based treatment programs for perinatal depression. PMID- 25012199 TI - Are metabolically healthy obese individuals really healthy? AB - Obesity has become one of the major public health concerns of the past decades, because it is a key risk factor for type 2 diabetes, cardiovascular diseases, dyslipidemia, hypertension, and certain types of cancer, which may lead to increased mortality. Both treatment of obesity and prevention of obesity-related diseases are frequently not successful. Moreover, a subgroup of individuals with obesity does not seem to be at an increased risk for metabolic complications of obesity. In this literature, this obesity subphenotype is therefore referred to as metabolically healthy obesity (MHO). Importantly, individuals with MHO do not significantly improve their cardio-metabolic risk upon weight loss interventions and may therefore not benefit to the same extent as obese patients with metabolic comorbidities from early lifestyle, bariatric surgery, or pharmacological interventions. However, it can be debated whether MHO individuals are really healthy, especially since there is no general agreement on accepted criteria to define MHO. In addition, overall health of MHO individuals may be significantly impaired by several psycho-social factors, psychosomatic comorbidities, low fitness level, osteoarthritis, chronic pain, diseases of the respiratory system, the skin, and others. There are still open questions about predictors, biological determinants, and the mechanisms underlying MHO and whether MHO represents a transient phenotype changing with aging and behavioral and environmental factors. In this review, the prevalence, potential biological mechanisms, and the clinical relevance of MHO are discussed. PMID- 25012200 TI - Epidemiology of hormonal contraceptives-related venous thromboembolism. AB - For many years, it has been well documented that combined hormonal contraceptives increase the risk of venous thromboembolism (VTE). The third-generation pill use (desogestrel or gestodene (GSD)) is associated with an increased VTE risk as compared with second-generation (levonorgestrel) pill use. Other progestins such as drospirenone or cyproterone acetate combined with ethinyl-estradiol (EE) have been investigated. Most studies have reported a significant increased VTE risk among users of these combined oral contraceptives (COCs) when compared with users of second-generation pills. Non-oral combined hormonal contraception, such as the transdermal patch and the vaginal ring, is also available. Current data support that these routes of administration are more thrombogenic than second-generation pills. These results are consistent with the biological evidence of coagulation activation. Overall, the estrogenic potency of each hormonal contraceptive depending on both EE doses and progestin molecule explains the level of thrombotic risk. Some studies have shown a similar increased VTE risk among users of COCs containing norgestimate (NGM) as compared with users of second-generation pill. However, for this combination, biological data, based on quantitative assessment of sex hormone-binding globulin or haemostasis parameters, are not in agreement with these epidemiological results. Similarly, the VTE risk associated with low doses of EE and GSD is not biologically plausible. In conclusion, newer generation formulations of hormonal contraceptives as well as non-oral hormonal contraceptives seem to be more thrombogenic than second-generation hormonal contraceptives. Further studies are needed to conclude on the combinations containing NGM or low doses of EE associated with GSD. PMID- 25012201 TI - Impulse control behaviours in patients with Parkinson's disease after subthalamic deep brain stimulation: de novo cases and 3-year follow-up. AB - OBJECTIVE: To document the occurrence of impulse control behaviours (ICBs) in patients with Parkinson's disease after 3 years of continuous deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: Detailed neurological and ICB assessments were performed before STN DBS and up to 3 years after implant. RESULTS: 13 out of 56 patients (23.2%) had ICBs at baseline; they took higher doses of dopamine agonists (DAA). Three years after implant 11 had fully remitted with a 60.8% reduction of DAA medication; the remaining two, who had a similar medication reduction, had only compulsive eating, having recovered from hypersexuality. Six of the 43 patients without ICBs at baseline (14%) developed transient de novo ICBs after implant; none of them had ICBs at the 3 year observation. CONCLUSIONS: ICBs were abolished in patients 3 years after STN DBS and DAA dosages were lowered. New ICBs may occur after implant and are transient in most cases. Compulsive eating may be specifically related to STN stimulation. PMID- 25012203 TI - Optimal number of strata for the stratified methods in computerized adaptive testing. AB - Test security can be a major problem in computerized adaptive testing, as examinees can share information about the items they receive. Of the different item selection rules proposed to alleviate this risk, stratified methods are among those that have received most attention. In these methods, only low discriminative items can be presented at the beginning of the test and the mean information of the items increases as the test goes on. To do so, the item bank must be divided into several strata according to the information of the items. To date, there is no clear guidance about the optimal number of strata into which the item bank should be split. In this study, we will simulate conditions with different numbers of strata, from 1 (no stratification) to a number of strata equal to test length (maximum level of stratification) while manipulating the maximum exposure rate that no item should surpass (r max ) in its whole domain. In this way, we can plot the relation between test security and accuracy, making it possible to determine the number of strata that leads to better security while holding constant measurement accuracy. Our data indicates that the best option is to stratify into as many strata as possible. PMID- 25012202 TI - Effect of subthalamic nucleus deep brain stimulation on dual-task cognitive and motor performance in isolated dystonia. AB - OBJECTIVE: Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor complications of Parkinson's disease (PD) but may worsen specific cognitive functions. The effect of STN DBS on cognitive function in dystonia patients is less clear. Previous reports indicate that bilateral STN stimulation in patients with PD amplifies the decrement in cognitive-motor dual-task performance seen when moving from a single-task to dual-task paradigm. We aimed to determine if the effect of bilateral STN DBS on dual-task performance in isolated patients with dystonia, who have less cognitive impairment and no dementia, is similar to that seen in PD. METHODS: Eight isolated predominantly cervical patients with dystonia treated with bilateral STN DBS, with average dystonia duration of 10.5 years and Montreal Cognitive Assessment score of 26.5, completed working memory (n-back) and motor (forced-maintenance) tests under single-task and dual-task conditions while on and off DBS. RESULTS: A multivariate, repeated-measures analysis of variance showed no effect of stimulation status (On vs Off) on working memory (F=0.75, p=0.39) or motor function (F=0.22, p=0.69) when performed under single-task conditions, though as working memory task difficulty increased, stimulation disrupted the accuracy of force-tracking. There was a very small worsening in working memory performance (F=9.14, p=0.019) when moving from single task to dual-tasks when using the 'dual-task loss' analysis. CONCLUSIONS: This study suggests the effect of STN DBS on working memory and attention may be much less consequential in patients with dystonia than has been reported in PD. PMID- 25012204 TI - Habitat use by giant panda in relation to man-made forest in Wanglang Nature Reserve of China. AB - To evaluate the effectiveness of human restoration in species conservation, in this study, we undertook a field survey of giant panda (Ailuropoda melanoleuca) habitat and man-made forest habitat in Wanglang Nature Reserve of China. Our results revealed that giant panda did not use the man-made forest in this area so far, and that there were significant differences between the giant panda habitat and the man-made forest habitat. Compared with giant panda habitat, the man-made forest habitat was characterized by lower shrub coverage, thinner trees and lower bamboo density. To improve the effectiveness of human restoration, the habitat requirement of giant panda should be fully consider in the whole process of habitat restoration. PMID- 25012205 TI - Ant cuticular response to phthalate pollution. AB - Phthalates are common atmospheric contaminants used in the plastic industry. Ants have been shown to constitute good bioindicators of phthalate pollution. Hence, phthalates remain trapped on ant cuticles which are mostly coated with long-chain hydrocarbons. In this study, we artificially contaminated Lasius niger ants with four phthalates: dibutyl phthalate (DBP), diisobutyl phthalate (DiBP), di(2 ethylhexyl) phthalate (DEHP), and benzyl butyl phthalate (BBP). The first three have previously been found on ants in nature in Touraine (France), while the fourth has not. The four phthalates disappeared rapidly (less than 5 days) from the cuticles of live ants. In contrast, on the cuticles of dead ants, DEHP quantities remained unchanged over time. These results indicate that phthalates are actively absorbed by the cuticles of live ants. Cuticular absorption of phthalates is nonspecific because eicosane, a nonnatural hydrocarbon on L. niger cuticle, was similarly absorbed. Ants are important ecological engineers and may serve as bioindicators of ecosystem health. We also suggest that ants and more generally terrestrial arthropods may contribute to the removal of phthalates from the local environment. PMID- 25012206 TI - A field study on phytoremediation of dredged sediment contaminated by heavy metals and nutrients: the impacts of sediment aeration. AB - Compared to traditional chemical or physical treatments, phytoremediation has proved to be a cost-effective and environmentally sound alternative for remediation of contaminated dredged sediment. A field study was conducted in a sediment disposal site predominantly colonized by Typha angustifolia under different sediment moisture conditions to estimate the phytoremediation effects of dredged sediment. The moisture content was 37.30 % and 48.27 % in aerated and waterlogged sediment, respectively. Total nitrogen (TN) content was higher in the waterlogged sediment than in the aerated sediment. The total Cd contents were lower in aerated sediment, which was mainly resulted from the lower exchangeable fraction of Cd. The bioaccumulation of P, Cu and Pb in T. angustifolia was promoted by waterlogging, and the belowground tissue concentrations and accumulation factors (AFs) of Cu were higher than that of other metals, which can be explained by that Cu is an essential micronutrient for plants. Consistent with many previous studies, T. angustifolia showed higher metal levels in roots than in above-ground tissues at both the sediment conditions. Due to the improved biomass produced in the aerated sediment, the removals of nutrients and the metals by plant harvest were higher from aerated sediment than from waterlogged sediment. It was indicated that maintaining the dredged sediment aerated can avoid release risk and plant uptake of metals, while the opposite management option can promote phytoextraction of these contaminants. PMID- 25012207 TI - Capability of the natural microbial community in a river water ecosystem to degrade the drug naproxen. AB - The present work aims at evaluating the ability of the River Tiber natural microbial community to degrade naproxen in water samples collected downstream from a wastewater treatment plant. For this purpose, different water microcosms were set up (microbiologically active vs sterile ones) and treated with naproxen (100 MUg/L) alone or in the co-presence of gemfibrozil in order to evaluate if the co-presence of the latter had an influence on naproxen degradation. The experiment was performed in the autumn and was compared with the same experimental set performed in spring of the same year to highlight if seasonal differences in the river water influenced the naproxen degradation. Pharmaceutical concentrations and microbial analysis (total cell number, viability, and microbial community composition) were performed at different times in the degradation experiments. The overall results show that the natural microbial community in the river water had a key role in the naproxen degradation. In fact, although there was a transient negative effect on the natural microbial community in all the experiments (3 h after adding the pharmaceutical), the latter was able to degrade naproxen within about 40 days. On the contrary, no decrease in the pharmaceutical concentration was observed in the sterile river water. Moreover, the co-presence of the two drugs lengthened the naproxen lag phase. As regards the natural microbial community composition detected by Fluorescence in situ Hybridization, Alpha and Gamma-Proteobacteria increased when the pharmaceutical halved, suggesting their role in the degradation. This study shows that with the concentration studied, naproxen was degraded by the natural microbial populations collected from a river chronically contaminated by this pharmaceutical. PMID- 25012208 TI - Effect of dietary supplementation of essential oils mixture on performance, eggshell quality, hatchability, and mineral excretion in quail breeders. AB - The main aim of this study was to investigate the effect of six different levels (0, 50, 100, 200, 400, and 600 mg/kg) of phytogenic feed additive containing a mixture essential oils from thyme, black cumin, fennel, anise and rosemary on performance, eggshell quality, reproductive traits, and mineral excretion in quail breeders. In this trial, a total of 60 male and 120 female quails, 91 days old, were randomly distributed in six experimental groups. During the 60-day experiment period, birds were fed with six treatment diets. Performances, eggshell qualities, hatchability, and mineral excretion data were evaluated at the end of the experiment. Results showed that the different dietary levels of essential oil mixture had no significant effect on performance parameters, damaged eggs, eggshell weight, fertility, hatchability of fertile eggs, hatchability of set eggs, and lead and boron excretion. On the other hand, 50 mg/kg supplementation of essential oil mixture (EOM) significantly improved egg breaking strength and eggshell thickness, and ash, calcium, phosphorus, magnesium, manganese, zinc, and cadmium excretion was significantly depressed in quail breeders supplemented with the two higher doses (400 or 600 mg/kg) of EOM. These results concluded that supplementing diets with EOM improved egg-breaking strength and decreased excretion of minerals in breeder quails. PMID- 25012209 TI - An approach to determining functional parameters of microperiphyton fauna in colonization surveys for marine bioassessment based on rarefaction curves. AB - The functional parameters, i.e., the estimated equilibrium species number (S eq), the colonization rate constant, and the time taken to reach 90 % of S eq (T 90), of microperiphyton fauna have been widely used to determine the water quality status in aquatic ecosystems. The objective of this investigation was to develop a protocol for determining functional parameters of microperiphyton fauna in colonization surveys for marine bioassessment based on rarefaction and regression analyses. The temporal dynamics in species richness of microperiphyton fauna during the colonization period was analyzed based on a dataset of periphytic ciliates in Chinese coastal waters of the Yellow Sea. The results showed that (1) based on observed species richness and estimated maximum species numbers, a total of 16 glass slides were required in order to achieve coefficients of variation of <5 % in the functional parameters; (2) the rarefied average species richness and functional parameters showed weak sensitivity to sampling effort; (3) the temporal variations in average species richness were well-fitted to the MacArthur Wilson model; and (4) the sampling effort of ~8 glass slides was sufficient to achieve coefficients of variation of <5 % in equilibrium average species number (AvS eq), colonization rate (AvG), and the time to reach 90 % of AvS eq (AvT 90) based on the average species richness. The findings suggest that the AvS eq, AvG, and AvT 90 values based on rarefied average species richness of microperiphyton might be used as reliable ecological indicators for the bioassessment of marine water quality in coastal habitats. PMID- 25012210 TI - Dendritic tree extraction from noisy maximum intensity projection images in C. elegans. AB - BACKGROUND: Maximum Intensity Projections (MIP) of neuronal dendritic trees obtained from confocal microscopy are frequently used to study the relationship between tree morphology and mechanosensory function in the model organism C. elegans. Extracting dendritic trees from noisy images remains however a strenuous process that has traditionally relied on manual approaches. Here, we focus on automated and reliable 2D segmentations of dendritic trees following a statistical learning framework. METHODS: Our dendritic tree extraction (DTE) method uses small amounts of labelled training data on MIPs to learn noise models of texture-based features from the responses of tree structures and image background. Our strategy lies in evaluating statistical models of noise that account for both the variability generated from the imaging process and from the aggregation of information in the MIP images. These noisy models are then used within a probabilistic, or Bayesian framework to provide a coarse 2D dendritic tree segmentation. Finally, some post-processing is applied to refine the segmentations and provide skeletonized trees using a morphological thinning process. RESULTS: Following a Leave-One-Out Cross Validation (LOOCV) method for an MIP databse with available "ground truth" images, we demonstrate that our approach provides significant improvements in tree-structure segmentations over traditional intensity-based methods. Improvements for MIPs under various imaging conditions are both qualitative and quantitative, as measured from Receiver Operator Characteristic (ROC) curves and the yield and error rates in the final segmentations. In a final step, we demonstrate our DTE approach on previously unseen MIP samples including the extraction of skeletonized structures, and compare our method to a state-of-the art dendritic tree tracing software. CONCLUSIONS: Overall, our DTE method allows for robust dendritic tree segmentations in noisy MIPs, outperforming traditional intensity-based methods. Such approach provides a useable segmentation framework, ultimately delivering a speed-up for dendritic tree identification on the user end and a reliable first step towards further morphological characterizations of tree arborization. PMID- 25012211 TI - Center of pressure trajectory differences between shod and barefoot running. AB - This study examined differences in center of pressure (COP) trajectories between shod and barefoot running. Ten habitually shod runners ran continuous laps under both shod and barefoot conditions. The COP trajectory was calculated in the global coordinate system but then transformed to the anatomic coordinate system of the foot. The anterior-posterior and medio-lateral positions and excursions of the COP, as well as the most medial location and percent stand at which it occurred were examined. Additionally, external eversion moments and ground reaction forces were assessed. Compared to the shod condition, in the barefoot condition the COP was located more anteriorly early in stance and the COP was located significantly more medially at most time points across stance. There were no differences in external eversion moments during early stance or peak ground reaction forces between conditions. Future studies on mechanical or epidemiological differences between shod and barefoot running may find the COP trajectory an informative parameter to examine. PMID- 25012213 TI - Influence of a bridging group and the substitution effect of bis(1,2,4-triazine) N-donor extractants on their interactions with a Np(V) cation. AB - The present theoretical study provides a realistic evaluation of the equilibrium structure, reaction modes, and bonding characteristics of a variety of neptunyl complexes formed with bis(triazinyl) N-donor extractants, which differ in their bridging groups such as pyridine, bipyridines, and orthophenanthroline, corresponding to the ligands (L) of tridentate bis(triazinyl)pyridines and tetradentate bis(triazinyl)bipyridines and bis(triazinyl)-1,10-phenanthrolines (BTPhens), respectively. Our calculations show that coordination of [NpO2](+) to tetradentate ligands is more favorable than that to tridentate ones no matter in a gas, aqueous, or organic phase. The presence of nitrate ions can enhance the coordination ability of neptunyl and stabilize the neutral NpO2L(NO3) complexes in thermodynamics. Our studies indicate that the complexation reaction mode [NpO2(H2O)n](+) + L + NO3(-) -> NpO2L(NO3) + nH2O is the most probable at the interface between water and the organic phase. The contribution of an orthophenanthroline bridging group is relatively more pronounced compared to its pyridine counterpart in ligand-exchange reaction. Complexation reactions of hydrated neptunyl with C2-BTPhen and BTPhen assisted by a nitrate ion are favorable thermodynamically, resulting from the least deformation of the ligand and strong complexation stability. The quantum theory of atoms-in-molecules and charge decomposition analysis suggest that electron delocalization and charge transfer are the main reasons responsible for stabilization of the tetradentate complexes and reveal a strong ionic feature of the Np-ligand bonds. Inspection of the frontier molecular orbitals reveals a distinct 5f orbital (Np) interaction with ligand atoms, implying the extent of f-based covalency. Our study may facilitate the rational design of ligands toward the improvement of their binding ability with Np(V) and more efficient separation of Np in spent nuclear fuels. PMID- 25012212 TI - Oil accumulation mechanisms of the oleaginous microalga Chlorella protothecoides revealed through its genome, transcriptomes, and proteomes. AB - BACKGROUND: Microalgae-derived biodiesel is a promising substitute for conventional fossil fuels. In particular, the green alga Chlorella protothecoides sp. 0710 is regarded as one of the best candidates for commercial manufacture of microalgae-derived biofuel. This is due not only to its ability to live autotrophically through photosynthesis, but also to its capacity to produce a large amount of biomass and lipid through fermentation of glucose. However, until the present study, neither its genome sequence nor the platform required for molecular manipulations were available. RESULTS: We generated a draft genome for C. protothecoides, and compared its genome size and gene content with that of Chlorella variabilis NC64A and Coccomyxa subellipsoidea C-169. This comparison revealed that C. protothecoides has a reduced genome size of 22.9 Mbp, about half that of its close relatives. The C. protothecoides genome encodes a smaller number of genes, fewer multi-copy genes, fewer unique genes, and fewer genome rearrangements compared with its close relatives. In addition, three Chlorella specific hexose-proton symporter (HUP)-like genes were identified that enable the consumption of glucose and, consequently, heterotrophic growth. Furthermore, through comparative transcriptomic and proteomic studies, we generated a global perspective regarding the changes in metabolic pathways under autotrophic and heterotrophic growth conditions. Under heterotrophic conditions, enzymes involved in photosynthesis and CO2 fixation were almost completely degraded, either as mRNAs or as proteins. Meanwhile, the cells were not only capable of quickly assimilating glucose but also showed accelerated glucose catabolism through the upregulation of glycolysis and the tricarboxylic acid (TCA) cycle. Moreover, the rapid synthesis of pyruvate, upregulation of most enzymes involved in fatty acid synthesis, and downregulation of enzymes involved in fatty acid degradation favor the synthesis of fatty acids within the cell. CONCLUSIONS: Despite similarities to other Chlorella, C. protothecoides has a smaller genome than its close relatives. Genes involved in glucose utilization were identified, and these genes explained its ability to grow heterotrophically. Transcriptomic and proteomic results provided insight into its extraordinary ability to accumulate large amounts of lipid. The C. protothecoides draft genome will promote the use of this species as a research model. PMID- 25012215 TI - Representative seroprevalences of human and livestock brucellosis in two Mongolian provinces. AB - Mongolia implemented a brucellosis livestock mass vaccination campaign from 2000 to 2009. However, the number of human cases did not decline since 2004 and the current epidemiological situation in Mongolia was uncertain. The objective of this study was to estimate the representative seroprevalences of humans and livestock in two provinces in view of their comparison with officially reported data. A representative cross-sectional study using cluster sampling proportional to size in humans, sheep, goats, cattle, yaks, horses, camels and dogs was undertaken to assess the apparent seroprevalence in humans and animals. A total of 8054 livestock and dog sera and 574 human sera were collected in Sukhbaatar and Zavkhan provinces. Human and animal sera were tested with the Rose Bengal and ELISA tests. The overall apparent seroprevalence of brucellosis was 27.3% in humans (95% CI 23.7-31.2%), 6.2% (95% CI 5.5-7.1%) in sheep, 5.2% (95% CI 4.4 5.9%) in goats, 16.0% (95% CI 13.7-18.7%) in cattle, 2.5% (95% CI 0.8-7.6%) in camels, 8.3 (95% CI 6.0-11.6%) in horses and 36.4% (95% CI 26.3-48.0%) in dogs. More women than men were seropositive (OR = 1.7; P < 0.0014). Human seroprevalence was not associated with small ruminant and cattle seroprevalence at the nomadic camp (hot ail) level. Annual incidence of clinical brucellosis, inferred from the seroprevalence using a catalytic model, was by a factor of 4.6 (1307/280) in Sukhbaatar and by a factor of 59 (1188/20) in Zavkhan. This represents a 15-fold underreporting of human brucellosis in Mongolia. The lack of access to brucellosis diagnostic testing at the village level hinders rural people from receiving appropriate treatment. In conclusion, this study confirms the high seroprevalence of human and livestock brucellosis in Mongolia. Stringent monitoring and quality control of operational management of a nationwide mass vaccination of small and large ruminants is warranted to assure its effectiveness. More research is needed to understand the complex animal-human interface of brucellosis transmission at different scales from farm to provincial level. PMID- 25012219 TI - The E3 ligase RNF34 is a novel negative regulator of the NOD1 pathway. AB - BACKGROUND/AIMS: To identify the regulator of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and its regulatory function. METHODS AND RESULTS: We performed a yeast two-hybrid screening assay and identified the E3 ligase RNF34 as a candidate partner of NOD1. Using co-immunoprecipitation (co-IP) and glutathione S transferase (GST)-pull down assays, we further confirmed that RNF34 is associated with NOD1. Western blotting showed that RNF34 downregulated the stability of NOD1 and promoted its ubiquitination. Functional analysis demonstrated that RNF34 overexpression inhibited NOD1-dependent activation of nuclear factor-kappa B (NF-kappaB), whereas knockdown of RNF34 using small interfering RNA increased NF-kappaB activation following stimulation from NOD1 overexpression or transfection of gamma-D-glutamyl-meso-diaminopimelic acid. CONCLUSION: These findings confirm that RNF34 is a negative regulator of the NOD1 pathway through direct interaction and ubiquitination of NOD1, and suggest a novel regulatory mechanism of NOD1. PMID- 25012216 TI - A neuronal function of the tumor suppressor protein merlin. AB - Mutagenic loss of the NF2 tumor suppressor gene encoded protein merlin is known to provoke the hereditary neoplasia syndrome, Neurofibromatosis type 2 (NF2). In addition to glial cell-derived tumors in the PNS and CNS, disease-related lesions also affect the skin and the eyes. Furthermore, 60% of NF2 patients suffer from peripheral nerve damage, clinically referred to as peripheral neuropathy. Strikingly, NF2-associated neuropathy often occurs in the absence of nerve damaging tumors, suggesting tumor-independent events. Recent findings indicate an important role of merlin in neuronal cell types concerning neuromorphogenesis, axon structure maintenance and communication between axons and Schwann cells. In this review, we compile clinical and experimental evidences for the underestimated role of the tumor suppressor merlin in the neuronal compartment. PMID- 25012220 TI - Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. PMID- 25012222 TI - Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. PMID- 25012223 TI - Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old. AB - Alzheimer's disease, which is defined pathologically by abundant amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to Alzheimer's disease, including cerebrovascular disease and hippocampal sclerosis. Although definite Alzheimer's disease pathology can distinguish dementia from normal individuals, the pathologies underlying cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of Alzheimer's disease pathology, cerebrovascular disease, hippocampal sclerosis and the altered expression of three synaptic proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of 'The 90+ Study' who came to autopsy, including participants with dementia (n = 84), those with cognitive impairment but no dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage, cerebrovascular disease, hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-binding protein (TDP 43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and cognitive impairment groups. Comparing the cognitive impairment and dementia groups, synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the cognitive impairment and dementia groups. All measures distinguished the dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in synaptophysin, a high Braak stage and the presence of TDP-43 and hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology, hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with cognitive impairment, we conclude that those with cognitive impairment, but no dementia, are indistinguishable from cognitively normal subjects based on the measures reported here. PMID- 25012225 TI - PE with ST-segment elevation in leads V1-3 and AVR treated successfully by catheter directed high-dose bolus thrombolytic therapy during CPR. AB - A 55-year-old man presented with the emergency department after having a short syncopal episode and angina during the exertion for 1 month. His initial electrocardiogram showed minimal ST-segment changes on precordial leads. While waiting for the laboratory tests, abruptly, the patient went into cardiopulmonary arrest. After a short resuscitation, a new electrocardiogram revealed ST-segment elevations in leads V1-3 and AVR, mimicking an anteroseptal myocardial infarction. Although, the angiography showed severe coronary artery disease, coronary flow was normal and main branches of pulmonary artery were almost fully occluded by large pulmonary emboli. Recombinant tissue plasminogen activator bolus (25 mg) was given 2 times at 5-minute intervals immediately into pulmonary artery by pig-tail catheter under the cardiopulmonary resuscitation. The patient had an excellent response to high-dose bolus thrombolytic therapy. We conclude that in the case of massive pulmonary embolism with small chance of resuscitation, the catheter-directed high-dose bolus injection of recombinant tissue plasminogen activator could enrich the therapeutical possibilities. PMID- 25012226 TI - Non-typeable Haemophilus influenzae, an under-recognised pathogen. AB - Non-typeable Haemophilus influenzae (NTHi) is a major cause of mucosal infections such as otitis media, sinusitis, conjunctivitis, and exacerbations of chronic obstructive pulmonary disease. In some regions, a strong causal relation links this pathogen with infections of the lower respiratory tract. In the past 20 years, a steady but constant increase has occurred in invasive NTHi worldwide, with perinatal infants, young children, and elderly people most at risk. Individuals with underlying comorbidities are most susceptible and infection is associated with high mortality. beta-lactamase production is the predominant mechanism of resistance. However, the emergence and spread of beta-lactamase negative ampicillin-resistant strains in many regions of the world is of substantial concern, potentially necessitating changes to antibiotic treatment guidelines for community-acquired infections of the upper and lower respiratory tract and potentially increasing morbidity associated with invasive NTHi infections. Standardised surveillance protocols and typing methodologies to monitor this emerging pathogen should be implemented. International scientific organisations need to raise the profile of NTHi and to document the pathobiology of this microbe. PMID- 25012224 TI - A data-driven model of biomarker changes in sporadic Alzheimer's disease. AB - We demonstrate the use of a probabilistic generative model to explore the biomarker changes occurring as Alzheimer's disease develops and progresses. We enhanced the recently introduced event-based model for use with a multi-modal sporadic disease data set. This allows us to determine the sequence in which Alzheimer's disease biomarkers become abnormal without reliance on a priori clinical diagnostic information or explicit biomarker cut points. The model also characterizes the uncertainty in the ordering and provides a natural patient staging system. Two hundred and eighty-five subjects (92 cognitively normal, 129 mild cognitive impairment, 64 Alzheimer's disease) were selected from the Alzheimer's Disease Neuroimaging Initiative with measurements of 14 Alzheimer's disease-related biomarkers including cerebrospinal fluid proteins, regional magnetic resonance imaging brain volume and rates of atrophy measures, and cognitive test scores. We used the event-based model to determine the sequence of biomarker abnormality and its uncertainty in various population subgroups. We used patient stages assigned by the event-based model to discriminate cognitively normal subjects from those with Alzheimer's disease, and predict conversion from mild cognitive impairment to Alzheimer's disease and cognitively normal to mild cognitive impairment. The model predicts that cerebrospinal fluid levels become abnormal first, followed by rates of atrophy, then cognitive test scores, and finally regional brain volumes. In amyloid-positive (cerebrospinal fluid amyloid beta1-42 < 192 pg/ml) or APOE-positive (one or more APOE4 alleles) subjects, the model predicts with high confidence that the cerebrospinal fluid biomarkers become abnormal in a distinct sequence: amyloid-beta1-42, phosphorylated tau, total tau. However, in the broader population total tau and phosphorylated tau are found to be earlier cerebrospinal fluid markers than amyloid-beta1-42, albeit with more uncertainty. The model's staging system strongly separates cognitively normal and Alzheimer's disease subjects (maximum classification accuracy of 99%), and predicts conversion from mild cognitive impairment to Alzheimer's disease (maximum balanced accuracy of 77% over 3 years), and from cognitively normal to mild cognitive impairment (maximum balanced accuracy of 76% over 5 years). By fitting Cox proportional hazards models, we find that baseline model stage is a significant risk factor for conversion from both mild cognitive impairment to Alzheimer's disease (P = 2.06 * 10(-7)) and cognitively normal to mild cognitive impairment (P = 0.033). The data-driven model we describe supports hypothetical models of biomarker ordering in amyloid-positive and APOE-positive subjects, but suggests that biomarker ordering in the wider population may diverge from this sequence. The model provides useful disease staging information across the full spectrum of disease progression, from cognitively normal to mild cognitive impairment to Alzheimer's disease. This approach has broad application across neurodegenerative disease, providing insights into disease biology, as well as staging and prognostication. PMID- 25012227 TI - Analyses of sublittoral macrobenthic community change in a marine nature reserve using similarity profiles (SIMPROF). AB - Sublittoral macrobenthic communities in the Skomer Marine Nature Reserve (SMNR), Pembrokeshire, Wales, were sampled at 10 stations in 1993, 1996, 1998, 2003, 2007 and 2009 using a Day grab and a 0.5 mm mesh. The time series is analysed using Similarities Profiles (SIMPROF) tests and associated methods. Q-mode analysis using clustering with Type 1 SIMPROF addresses multivariate structure among samples, showing that there is clear structure associated with differences among years. Inverse (r-mode) analysis using Type 2 SIMPROF decisively rejects a hypothesis that species are not associated with each other. Clustering of the variables (species) with Type 3 SIMPROF identifies groups of species which covary coherently through the time-series. The time-series is characterised by a dramatic decline in abundances and diversity between the 1993 and 1996 surveys. By 1998 there had been a shift in community composition from the 1993 situation, with different species dominating. Communities had recovered in terms of abundance and species richness, but different species dominated the community. No single factor could be identified which unequivocally explained the dramatic changes observed in the SMNR. Possible causes were the effects of dispersed oil and dispersants from the Sea Empress oil spill in February 1996 and the cessation of dredge-spoil disposal off St Annes Head in 1995, but the most likely cause was severe weather. With many species, and a demonstrable recovery from an impact, communities within the SMNR appear to be diverse and resilient. If attributable to natural storms, the changes observed here indicate that natural variability may be much more important than is generally taken into account in the design of monitoring programmes. PMID- 25012230 TI - On the origin of ionicity in ionic liquids. Ion pairing versus charge transfer. AB - In this paper we show by using static DFT calculations and classical molecular dynamics simulations that the charge transfer between ionic liquid ions plays a major role in the observed discrepancies between the overall mobility of the ions and the observed conductivities of the corresponding ionic liquids, while it also directly suppresses the association of oppositely charged ions, thus the ion pairing. Accordingly, in electrochemical applications of these materials it is important to consider this reduction of the total charges on the ions, which can greatly affect the performance of the given process or device in which the ionic liquid is used. By slightly shifting from the salt-like to a molecular liquid like system via the decreased charges, the charge transfer also fluidizes the ionic liquid. We believe that this vital information on the molecular level structure of ionic liquids offers a better understanding of these materials, and allows us to improve the a priori design of ionic liquids for any given purpose. PMID- 25012228 TI - A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine. AB - BACKGROUND: The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria. METHODS: Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios. RESULTS: Vaccine induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow up in some individuals. CONCLUSIONS: Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy. PMID- 25012231 TI - Recognizing the bank robber and spotting the difference: emotional state and global vs. local attentional set. AB - In two experiments (161 participants in total), we investigated how current mood influences processing styles (global vs. local). Participants watched a video of a bank robbery before receiving a positive, negative or neutral induction, and they performed two tasks: a face-recognition task about the bank robber as global processing measure, and a spot-the-difference task using neutral pictures (Experiment-1) or emotional scenes (Experiment-2) as local processing measure. Results showed that positive mood induction favoured a global processing style, enhancing participants' ability to correctly identify a face even when they watched the video before the mood-induction. This shows that, besides influencing encoding processes, mood state can be also related to retrieval processes. On the contrary, negative mood induction enhanced a local processing style, making easier and faster the detection of differences between nearly identical pictures, independently of their valence. This dissociation supports the hypothesis that current mood modulates processing through activation of different cognitive styles. PMID- 25012232 TI - Rheology and simulation of 2-dimensional clathrin protein network assembly. AB - Clathrin is a three-legged protein complex that assembles into lattice structures on the cell membrane and transforms into fullerene-like cages during endocytosis. This dynamic structural flexibility makes clathrin an attractive building block for guided assembly. The assembly dynamics and the mechanical properties of clathrin protein lattices are studied using rheological measurements and theoretical modelling in an effort to better understand two dynamic processes: protein adsorption to the interface and assembly into a network. We find that percolation models for protein network formation are insufficient to describe clathrin network formation, but with Monte Carlo simulations we can describe the dynamics of network formation very well. Insights from this work can be used to design new bio-inspired nano-assembly systems. PMID- 25012233 TI - Plasma metabonomics study on Chinese medicine syndrome evolution of heart failure rats caused by LAD ligation. AB - BACKGROUND: Chinese medicine syndromes (Zheng) in many disease models are not clearly characterized or validated, and the concepts of Chinese medicine syndromes are confounding and controversial. Metabonomics has been applied to the evaluation and classification of the Chinese medicine syndromes both in clinical and nonclinical studies. In this study, we aim to investigate the evolution of the Chinese medicine syndrome in myocardial infarction induced heart failure and to confirm the feasibility of the Zheng classification by plasma metabonomics in a syndrome and disease combination animal model. METHODS: The heart failure (HF) model was induced by ligation of the left anterior descending coronary artery (LAD) in Sprague-Dawley rats. The rats were divided into the following two groups: the HF model group (LAD ligation) and the sham operated group. GC-MS was used with pattern recognition technology and principal component analysis (PCA) to analyze the plasma samples at 4, 21 and 45 day after operation. RESULTS: It was determined that the period from 7 to 28 days was the stable time window of ischemic heart failure with qi deficiency and blood stasis syndrome (QDBS), and the qi deficiency syndrome occurred at 1 to 4 days and 45 to 60 days after operation. The results exhibited 5 plasma metabolite changes in the same trend at 4 and 21 day after the LAD operation, 7 at 21 and 45 day, and 2 at 4 and 45 day. No metabolite showed the same change at all of the 3 time points. At day 21 (the QDBS syndrome time point) after operation, 4 plasma metabolites showed the same trends with the results of our previous study on patients with the blood stasis syndrome. CONCLUSIONS: The syndrome diagnosis is reliable in the HF rat model in this study. Plasma metabolites can provide a basis for the evaluation of Chinese medicine syndrome animal models. PMID- 25012234 TI - A high copy number of FCGR3B is associated with psoriasis vulgaris in Han Chinese. AB - BACKGROUND: Copy number variations of FCGR3B are associated with several immune related diseases such as systemic lupus erythematosus, rheumatoid arthritis and primary Sjogren's syndrome. Little is known about the association between FCGR3B copy number variants and psoriasis. OBJECTIVE: To investigate whether FCGR3B copy number variants are associated with susceptibility to psoriasis vulgaris in the Chinese Han population. METHODS: 343 psoriasis vulgaris patients and 574 healthy individuals were recruited as cases and controls. TaqMan(r) Copy Number Assays were performed to quantify the copy numbers in the FCGR3B locus. CopyCaller v1.0 software and R (version 2.15.3) were used to do the subsequent statistical analysis. RESULTS: A significant association between psoriasis vulgaris and a high copy number (>2) of FCGR3B was observed (odds ratio = 1.63, 95% confidence interval 1.09-2.45, p < 0.02). However, the low copy number of FCGR3B was not significantly associated with psoriasis vulgaris. CONCLUSION: A high copy number of FCGR3B is associated with psoriasis vulgaris in Han Chinese. PMID- 25012236 TI - The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies. AB - RATIONALE: Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia. OBJECTIVES: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated. RESULTS: The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release. CONCLUSIONS: The actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms. PMID- 25012238 TI - Femtosecond laser 3D micromachining: a powerful tool for the fabrication of microfluidic, optofluidic, and electrofluidic devices based on glass. AB - Femtosecond lasers have unique characteristics of ultrashort pulse width and extremely high peak intensity; however, one of the most important features of femtosecond laser processing is that strong absorption can be induced only at the focus position inside transparent materials due to nonlinear multiphoton absorption. This exclusive feature makes it possible to directly fabricate three dimensional (3D) microfluidic devices in glass microchips by two methods: 3D internal modification using direct femtosecond laser writing followed by chemical wet etching (femtosecond laser-assisted etching, FLAE) and direct ablation of glass in water (water-assisted femtosecond laser drilling, WAFLD). Direct femtosecond laser writing also enables the integration of micromechanical, microelectronic, and microoptical components into the 3D microfluidic devices without stacking or bonding substrates. This paper gives a comprehensive review on the state-of-the-art femtosecond laser 3D micromachining for the fabrication of microfluidic, optofluidic, and electrofluidic devices. A new strategy (hybrid femtosecond laser processing) is also presented, in which FLAE is combined with femtosecond laser two-photon polymerization to realize a new type of biochip termed the ship-in-a-bottle biochip. PMID- 25012235 TI - Implementing evidence-based recommended practices for the management of patients with mild traumatic brain injuries in Australian emergency care departments: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Mild head injuries commonly present to emergency departments. The challenges facing clinicians in emergency departments include identifying which patients have traumatic brain injury, and which patients can safely be sent home. Traumatic brain injuries may exist with subtle symptoms or signs, but can still lead to adverse outcomes. Despite the existence of several high quality clinical practice guidelines, internationally and in Australia, research shows inconsistent implementation of these recommendations. The aim of this trial is to test the effectiveness of a targeted, theory- and evidence-informed implementation intervention to increase the uptake of three key clinical recommendations regarding the emergency department management of adult patients (18 years of age or older) who present following mild head injuries (concussion), compared with passive dissemination of these recommendations. The primary objective is to establish whether the intervention is effective in increasing the percentage of patients for which appropriate post-traumatic amnesia screening is performed. METHODS/DESIGN: The design of this study is a cluster randomised trial. We aim to include 34 Australian 24-hour emergency departments, which will be randomised to an intervention or control group. Control group departments will receive a copy of the most recent Australian evidence-based clinical practice guideline on the acute management of patients with mild head injuries. The intervention group will receive an implementation intervention based on an analysis of influencing factors, which include local stakeholder meetings, identification of nursing and medical opinion leaders in each site, a train-the trainer day and standardised education and interactive workshops delivered by the opinion leaders during a 3 month period of time. Clinical practice outcomes will be collected retrospectively from medical records by independent chart auditors over the 2 month period following intervention delivery (patient level outcomes). In consenting hospitals, eligible patients will be recruited for a follow-up telephone interview conducted by trained researchers. A cost-effectiveness analysis and process evaluation using mixed-methods will be conducted. Sample size calculations are based on including 30 patients on average per department. Outcome assessors will be blinded to group allocation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612001286831 (date registered 12 December 2012). PMID- 25012237 TI - Effects of vitamin D on parathyroid hormone and clinical outcomes in peritoneal dialysis: a narrative review. AB - Vitamin D deficiency is very prevalent in dialysis and peritoneal dialysis (PD) patients show lower levels of cholecalciferol (25(OH)D3) than hemodialysis patients. We conducted a systematic narrative review to assess the effects of vitamin D therapy on control of secondary hyperparathyroidism and clinical outcomes induced by vitamin D pleiotropic effects. Medline database was searched for cohort and intervention studies reporting data on vitamin D (all sterols including synthetic analogs) and peritoneal dialysis without language restriction. Two authors independently extracted data. Twenty-nine observational and eleven interventional studies were identified for inclusion (1,036 subjects). PTH levels decreased in twenty-nine studies, increased in one study and remained stable in ten studies. Thirty-three studies analyzed the oral route for vitamin D administration, ten the intraperitoneal, one the subcutaneous and one the intravenous. A significant decrease of peritonitis risk was observed in two studies. Proteinuria decreased in four studies and remained stable in one study. Peritoneal protein loss decreased in one study and was stable in two studies. Studies on the therapeutic effects of vitamin D in PD are limited and describe small population samples. Moreover, vitamin D compounds do not consistently reduce PTH levels. The administration of active vitamin D in PD may have interesting pleiotropic effects such as decreasing proteinuria and peritoneal protein loss. According to these effects, vitamin D could help to preserve residual renal function and ensure efficient peritoneal membrane dialysance. PMID- 25012239 TI - Correspondence on "Possible spontaneous PFO closure after thrombus trapped in PFO", Antonia Schulz et al., Clin Res Cardiol 2014; 103:333-335. PMID- 25012240 TI - Risk prediction with triglycerides in patients with stable coronary disease on statin treatment. AB - BACKGROUND: The aim of the prospective Homburg Cream and Sugar study was to analyze the role of fasting and postprandial serum triglycerides (TG) as risk modifiers in patients with coronary artery disease (CAD). METHODS AND RESULTS: A sequential oral triglyceride and glucose tolerance test was developed to obtain standardized measurements of postprandial TG kinetics and glucose in 514 consecutive patients with stable CAD confirmed by angiography (95% were treated with a statin). Fasting and postprandial TG predicted the primary outcome measure of cardiovascular death and hospitalizations after 48 months follow-up (fasting TG >150 vs. <106 mg/dl: Hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.31 2.45, p = 0.0001; area under the curve >1120 vs. <750 mg/dl/5 hr: HR 1.78, 95% CI 1.29-2.45, p = 0.0003). Parameters of the postprandial TG increase did not improve risk prediction compared to fasting TG. The number of cardiovascular deaths and myocardial infarctions was higher in the upper tertile of fasting TG (HR 1.79, 95%-CI 1.04-3.09, p = 0.03). Risk prediction by TG was independent of traditional risk factors, medication, glucose metabolism, LDL- and HDL cholesterol. Total cholesterol, LDL- and HDL-cholesterol concentrations were not associated with the primary outcome. CONCLUSIONS: Fasting serum triglycerides >150 mg/dl independently predict cardiovascular events in patients with coronary artery disease on guideline-recommended medication. Assessment of postprandial TG does not improve risk prediction compared to fasting TG in these patients. PMID- 25012241 TI - Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established. METHOD: We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed. RESULTS: Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity. CONCLUSION: We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs. PMID- 25012242 TI - Downregulation of tumor suppressor menin by miR-421 promotes proliferation and migration of neuroblastoma. AB - Neuroblastoma, featured by a high rate of spontaneous remissions, is the most common extra-cranial solid tumor in infants and children. Numerous reports have demonstrated that MicroRNAs (miRNAs) play essential roles in cancer progression, including cell proliferation, apoptosis, invasion, metastasis and angiogenesis. miR-421 functions as an onco-miR in some malignancies. However, its role in neuroblastoma remains poorly understood. In the present study, we found that miR 421 was increased in neuroblastoma tissues compared with matched adjacent normal tissues. Forced overexpression of miR-421 substantially enhanced cell proliferation, cell-cycle progression, migration, and invasion of neuroblastoma cells. At the molecular level, tumor suppressor menin was found to be a target of miR-421. Furthermore, downregulation of menin by small interfering RNA oligos exhibited similar effects with overexpression of miR-421. On the other hand, overexpression of menin partially reversed the proliferative effects of miR-421 in neuroblastoma cells. Collectively, miR-421 may promote neuroblastoma cell growth and motility partially by targeting menin. PMID- 25012243 TI - IL-17 gene polymorphism is associated with susceptibility to gastric cancer. AB - We conducted a case-control study to investigate the role of three common IL-17A and IL-17F single nucleotide polymorphisms (SNPs) on the susceptibility to gastric cancer. A case-control study was conducted using a Chinese study population of 462 gastric cancer subjects and 462 controls. Polymerase chain reaction restriction fragment length of polymorphism (PCR-RFLP) was taken to genotype rs2275913, rs763780, and rs3748067 within the IL-17 gene. When comparing demographic characteristics of gastric cancer between gastric cancer cases and control groups, cancer cases were more likely to be cigarette smokers and alcohol drinkers, have cancer history in the first relatives, and have higher infection rate of Helicobacter pylori. By conditional regression analysis, individuals carrying IL-17 rs2275913 GA, AA genotype, and A allele were associated with an increased gastric cancer risk. Those carrying rs3748067 CC genotype and C allele had a significantly increased risk for the development of gastric cancer. Moreover, rs2275913 and rs3748067 variations had association with cigarette smoking, alcohol drinking, and H. pylori infection on the risk of gastric cancer. These results suggest that rs2275913 and rs3748067 variations significantly increase gastric cancer risk in a Chinese population. PMID- 25012244 TI - Biological and clinical implications of endocan in gastric cancer. AB - Endocan overexpression has been reported to be associated with poor prognosis in various cancer types such as breast cancer, kidney cancer, and lung cancer. However, the biological and prognostic significance of endocan in gastric cancer remains unknown. Here, we investigated the expression status of endocan in gastric cancer. Endocan expression status was determined in 255 gastric cancer specimens by immunohistochemical staining. The association of endocan protein with clinicopathological parameters and prognosis was subsequently determined. The oncogenic role of endocan in gastric cancer was examined using a small interfering RNA (siRNA) approach. Spearman regression correlation analysis showed that endocan expression was associated with the pathological tumor stage. In Cox regression analysis, endocan expression was found to be an independent prognostic factor for survival. Endocan promoted gastric cancer cell proliferation. Our findings indicate that endocan is a potential target for therapeutic intervention in gastric cancer. PMID- 25012245 TI - MicroRNA-27b suppresses growth and invasion of NSCLC cells by targeting Sp1. AB - Non-small cell lung cancer (NSCLC) is the major cause of cancer death worldwide. Increasing evidence shows that microRNAs (miRNAs), evolutionally conserved non coding RNAs, are widely involved in the development and progression of NSCLC. Aberrant alteration of miRNAs expression has been implicated in NSCLC initiation and progression. Herein, we studied the role of miR-27b in NSCLC cells. We found that miR-27b was significantly decreased in several NSCLC cell lines. Forced overexpression of miR-27 inhibited both the growth and invasion of NSCLC cells. Furthermore, we identified Sp1 transcription factor (Sp1) as a target of miR-27b in NSCLC cells. Moreover, we found that miR-27 suppressed growth and invasion of NSCLC cells partially by targeting Sp1. Our data indicate that miR-27b may play a critical role in the development of NSCLC. PMID- 25012248 TI - Comparing patients' and surgeons' perceptions: statistics and reference standards. PMID- 25012247 TI - Transcriptional landscape of repetitive elements in normal and cancer human cells. AB - BACKGROUND: Repetitive elements comprise at least 55% of the human genome with more recent estimates as high as two-thirds. Most of these elements are retrotransposons, DNA sequences that can insert copies of themselves into new genomic locations by a "copy and paste" mechanism. These mobile genetic elements play important roles in shaping genomes during evolution, and have been implicated in the etiology of many human diseases. Despite their abundance and diversity, few studies investigated the regulation of endogenous retrotransposons at the genome-wide scale, primarily because of the technical difficulties of uniquely mapping high-throughput sequencing reads to repetitive DNA. RESULTS: Here we develop a new computational method called RepEnrich to study genome-wide transcriptional regulation of repetitive elements. We show that many of the Long Terminal Repeat retrotransposons in humans are transcriptionally active in a cell line-specific manner. Cancer cell lines display increased RNA Polymerase II binding to retrotransposons than cell lines derived from normal tissue. Consistent with increased transcriptional activity of retrotransposons in cancer cells we found significantly higher levels of L1 retrotransposon RNA expression in prostate tumors compared to normal-matched controls. CONCLUSIONS: Our results support increased transcription of retrotransposons in transformed cells, which may explain the somatic retrotransposition events recently reported in several types of cancers. PMID- 25012246 TI - Increased EphB2 expression predicts cholangiocarcinoma metastasis. AB - The activation of Ephrin (Eph) receptors, the largest tyrosine kinase families of cell surface receptor, has recently been addressed in human cholangiocarcinoma (CCA). Therefore, the present study aimed to investigate the role of Eph receptors and its ligands in CCA. Of all 50 cases of human CCA tested, immunohistochemical staining demonstrated that EphB2, EphB4, ephrinB1, and ephrinB2 were 100 % positive in CCA tissues with overexpressions of the above proteins as 56, 56, 70, and 48 % of cases, respectively. High expression of EphB2 was significantly correlated with the metastatic status of patients (P = 0.027). We also found that the high co-expression level of EphB2/ephrinB1 or EphB2/ephrinB2 were significantly correlated with the metastatic status of the patients (P = 0.034 and P = 0.024). Furthermore, we showed that the high co expression level of EphB4/MVD and ephrinB1/MVD were significantly correlated with the metastasis status of CCA patients (P = 0.012 and P = 0.029). We further demonstrated that the EphB2 suppression using siRNA significantly reduced CCA cell migration by decreasing the phosphorylation of focal adhesion kinase (FAK) and paxillin. In conclusion, the upregulation of EphB2 receptors and its specific ligands (ephrinB1 and ephrinB2) leads to CCA metastasis. Suppression of EphB2 expression as well as inhibition of its downstream signaling proteins might serve as possible therapeutic strategies in human CCA. PMID- 25012249 TI - Mohs micrographic surgery for dermatofibrosarcoma protuberans (DFSP): a single centre series of 76 patients treated by frozen-section Mohs micrographic surgery with a review of the literature. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade sarcoma that typically presents with local invasion but rarely metastasises. Surgical excision remains the first-line treatment for DFSP. There are no randomised controlled or prospective studies comparing wide local excision (WLE) with Mohs micrographic surgery (MMS), but available evidence from the retrospective studies and case series available has consistently shown higher recurrence rates for standard surgery and WLE than for MMS. Combined recurrence rates of data within the last 20 years for WLE have been reported at 7.3% compared with 1.1% for MMS. Our aim was to review the clinical details and recurrence rates of DFSP cases treated with frozen-section MMS in our centre between 1996 and February 2013. The relevant data were collected from the case notes. It involved 76 patients with nine of these patients lost to follow-up. In the remaining 67 (67/76) cases, the recurrence rate was 1.5% during the mean follow-up period of 50 months (2-132). This is comparable to recurrence rates for the MMS in the literature [20,21]. Our series is the largest series for frozen-section MMS reported to date. Based on these findings and the current literature evidence, we advocate MMS as the treatment of choice for DFSP in all locations. PMID- 25012250 TI - Drinking water source and human Toxoplasma gondii infection in the United States: a cross-sectional analysis of NHANES data. AB - BACKGROUND: Toxoplasma gondii imparts a considerable burden to public health. Human toxoplasmosis can be life-threatening in immunocompromised individuals, has been associated with psychiatric disorders, and can cause severe congenital pathologies, spontaneous abortion, or stillbirth. Environmental modes of transmission contributing to the incidence of human toxoplasmosis are poorly understood. We sought to examine National Health and Nutrition Examination Survey (NHANES) data for risk factors associated with T. gondii seroprevalence. METHODS: T. gondii serology results reported for Continuous NHANES survey years 1999-2004 and 2009-10 were examined. To explore associations with toxoplasmosis seropositivity, covariates of interest were selected a priori, including source and home treatment of tap water. Associations between potential risk factors and evidence of IgG antibodies against T. gondii were assessed using multivariable logistic regression. RESULTS: Among 23,030 participants with available T. gondii serology across 8 years of continuous NHANES survey data (1999-2004; 2009-2010), persons born outside the United States were significantly more likely to be seropositive, and seropositivity was inversely associated with years spent in the United States. Among US-born participants, participants with homes on well water (both those who used at-home water treatment devices and those who did not), as well as participants with public/private company-provided tap water who did not use at-home water treatment devices, were significantly more likely to be seropositive compared to participants who used home treatment devices on tap water provided by a private or public water company. A comparative subpopulation analysis revealed age-adjusted seroprevalence among US-born persons 12-49 yrs old significantly declined to 6.6% (95% CI, 5.2-8.0) (P <0.0001) in 2009-10, compared to previously published reports for NHANES data from 1988-1994 (14.1%) and 1999 2004 (9.0%). CONCLUSIONS: Data suggests that T. gondii infections continue to decline in the United States, but the overall infection rate remains substantial at nearly 7%. Despite the limitations in the Continuous NHANES cross-sectional survey, the association between well water use and T. gondii infection warrants further research. PMID- 25012251 TI - MYC amplification is associated with poor survival in small cell lung cancer: a chromogenic in situ hybridization study. AB - PURPOSE: Small cell lung cancer (SCLC) is a highly aggressive tumor, and few studies have examined the amplification status of the MYC gene in tumor samples using chromogenic in situ hybridization (CISH). Emerging target treatments associated with MYC status in SCLC necessitates the evaluation of MYC using current methodologies, such as CISH. In this study, we evaluated tissue samples from untreated patients to determine the relation between MYC amplification and clinical and pathological factors, including survival. METHODS: Formalin-fixed paraffin-embedded tumor samples were obtained from 77 patients with SCLC who underwent a diagnostic biopsy for SCLC. The samples were analyzed by CISH using a MYC probe (ZytoDot((r)) CISH probe). The relationship between cytogenetic analysis, pathologic characteristics and survival time was evaluated using the Chi-square test, Fisher's test and Mann-Whitney method. A regression model was constructed to exclude any confounding factors. RESULTS: Of 77 samples, 64.9 % were from bronchi biopsy and the remainder was from the mediastinal, cervical and supraclavicular lymph nodes. The MYC oncogene was amplified in 20 % of the tumors. After the multivariate regression analysis, patients with MYC amplification had a significantly shorter survival time (4.67 weeks) versus patients without MYC amplification (26.15 weeks) (p = 0.02, CI 1.355-10.261). CONCLUSION: MYC amplification is a frequent event in SCLC and is related to a short survival time. MYC amplification may be an independent prognostic factor for SCLC. Further studies are required to support this finding and clarify the role of MYC in SCLC tumorigenesis. PMID- 25012252 TI - The association of menstrual and reproductive factors with thyroid nodules in Chinese women older than 40 years of age. AB - The purpose of the study was to explore the association of menstrual and reproductive factors with thyroid nodules in Chinese women older than 40 years of age. A questionnaire was completed by 6,571 women aged 40 years or older in a community-based epidemiological investigation of thyroid nodules conducted from June to November 2011 in Nanjing City. Thyroid nodules were measured by ultrasound. The Thyroid Imaging Reporting and Data System score was used to differentiate between benign and possibly malignant nodules. Menopausal age (>55 vs. <50 years: RR = 1.17, 95 % CI 1.00-1.34) and number of reproductive years (>40 vs. <35 years: RR = 1.12, 95 % CI 1.01-1.24) increased the risk of thyroid nodules, but were not associated with suspected malignant nodules. Women who experienced more pregnancies (>=5 vs. <=1: RR = 2.09, 95 % CI 1.79-2.40) and abortions (>=3 vs. 0: RR = 1.61, 95 % CI 1.41-1.81) were prone to development of thyroid nodules, and more likely to form suspected malignant nodules (pregnancies, RR = 3.59, 95 % CI 1.60-7.20; abortions, RR = 2.36, 95 % CI 1.31 4.06). Furthermore, higher risks of thyroid nodules (RR = 1.36, 95 % CI 1.14 1.59) and suspected malignant nodules (RR = 2.80, 95 % CI 1.08-6.53) were observed in women who had undergone artificial compared with natural abortion. Periods of elevated estrogen and progesterone levels in women, such as pregnancy, were the key occasions for occurrence of both benign and suspiciously malignant thyroid nodules, while longer lifetime length of exposure to female sex hormones might promote the growth of thyroid nodules. PMID- 25012253 TI - Acute effects of acylated ghrelin on salbutamol-induced metabolic actions in humans. AB - The aim of this study is to describe a potential modulatory effect of acute acylated ghrelin (AG) administration on the glucose, insulin, and free fatty acids (FFA) responses to salbutamol (SALBU). Six healthy young male volunteers underwent the following four testing sessions in random order at least 7 days apart: (a) acute AG administration (1.0 MUg/kg i.v. as bolus at 0'); (b) SALBU infusion (0.06 MUg/kg/min i.v. from -15' to +45'); (c) SALBU infusion+AG; and (d) isotonic saline infusion. Blood samples for glucose, insulin, and FFA levels were collected every 15 min. As expected, with respect to saline, SALBU infusion induced a remarkable increase in glucose (10.8+/-5.6 mmol/l*min; P<0.05), insulin (2436.8+/-556.9 pmol/l*min; P<0.05), and FFA (18.9+/-4.5 mmol/l*min; P<0.01) levels. A significant increase in glucose (7.4+/-3.9 mmol/l*min; P<0.05) and FFA levels (10.0+/-2.8 mmol/l*min; P<0.01) without significant variations in insulin levels were recorded after AG administration. Interestingly, the hyperglycemic effect of AG appeared to be significantly potentiated during SALBU infusion (26.7+/-4.8 mmol/l*min; P<0.05). On the other hand, the stimulatory effect of SALBU on insulin and FFA was not significantly modified by AG administration. The results of this study show that acute AG administration has a synergic effect with beta2-adrenergic receptor activation by SALBU on blood glucose increase, suggesting that their pharmacological hyperglycemic action takes place via different mechanisms. On the other hand, AG has a negligible influence on the other pharmacological metabolic effects of SALBU infusion. PMID- 25012254 TI - Assessment of FSHR, AMH, and AMHRII variants in women with polycystic ovary syndrome. PMID- 25012255 TI - Challenges and opportunities in the management of Clostridium difficile infection. AB - Clostridium difficile infection (CDI) is increasing in all regions of the world where sought. There is no gold standard for diagnosis of CDI, with available tests having limitations. Prevention of CDI will be seen with antibiotic stewardship, improved disinfection of hospitals and nursing homes, chemo- and immuno-prophylaxis and next generation probiotics. The important therapeutic agents are oral vancomycin and fidaxomicin with metronidazole being used only in mild cases or when oral therapy cannot be given. Current therapy of CDI for 10 days is associated with high rate of recurrence that may be prevented by prolonging initial therapy. Future treatment strategies will focus on drugs that inhibit C. difficile, reduce toxin activity and inflammation in the gut, and improve colonic flora diversity. PMID- 25012256 TI - The role of psychological maturity in direct and indirect aggressiveness in Spanish adolescents. AB - Understanding which factors are related to different kinds of aggressive behaviors in adolescents might help to improve violence-prevention programs for schools and families. Although some studies show that adolescents who are less psychologically mature tend to display more behavioral problems, few studies have been performed on the relationship between aggressive behavior and psychological maturity in adolescence, and no studies have focused specifically on indirect aggression. For this reason, the current research tests the role of psychological maturity in direct and indirect aggressiveness in a sample of 193 Spanish adolescents (49% boys and 51% girls) between 14 and 18 years old (M = 16.1, SD = 1.18). The results show that psychological maturity is related to both kinds of aggressiveness. In fact, less mature adolescents tend to show higher levels of direct aggression (r = -.22, p < .01) and indirect aggression (r = -.44, p < .01). More specifically, the dimensions of psychological maturity most related to aggressiveness are self-reliance and identity: self-reliance is the main predictor of indirect aggression (p < .01) and identity is the main predictor of direct aggression (p < .01). Moreover, overall psychological maturity is more related to indirect aggression in men than in women (p < .05), so the increase in psychological maturity implies a greater decrease of indirect aggression in men. PMID- 25012257 TI - Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. AB - Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which susceptible individuals are at risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene which inactivate the enzyme and alters the function of the tricarboxylic acid (Krebs) cycle. Issues surrounding surveillance and treatment for HLRCC-associated renal cell cancer were considered as part of a recent international symposium on HLRCC. The management protocol proposed in this article is based on a literature review and a consensus meeting. The lifetime renal cancer risk for FH mutation carriers is estimated to be 15 %. In view of the potential for early onset of RCC in HLRCC, periodic renal imaging and, when available, predictive testing for a FH mutation is recommended from 8 to 10 years of age. However, the small risk of renal cell cancer in the 10-20 years age range and the potential drawbacks of screening should be carefully discussed on an individual basis. Surveillance preferably consists of annual abdominal MRI. Treatment of renal tumours should be prompt and generally consist of wide-margin surgical excision and consideration of retroperitoneal lymph node dissection. The choice for systemic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts of families. PMID- 25012258 TI - Diphenyl diselenide modulates gene expression of antioxidant enzymes in the cerebral cortex, hippocampus and striatum of female hypothyroid rats. AB - INTRODUCTION: Cellular antioxidant signaling can be altered either by thyroid disturbances or by selenium status. AIMS: To investigate whether or not dietary diphenyl diselenide can modify the expression of genes of antioxidant enzymes and endpoint markers of oxidative stress under hypothyroid conditions. METHODS: Female rats were rendered hypothyroid by continuous exposure to methimazole (MTZ; 20 mg/100 ml in the drinking water) for 3 months. Concomitantly, MTZ-treated rats were either fed or not with a diet containing diphenyl diselenide (5 ppm). mRNA levels of antioxidant enzymes and antioxidant/oxidant status were determined in the cerebral cortex, hippocampus and striatum. RESULTS: Hypothyroidism caused a marked upregulation in mRNA expression of catalase, superoxide dismutase (SOD-1, SOD-3), glutathione peroxidase (GPx-1, GPx-4) and thioredoxin reductase (TrxR-1) in brain structures. SOD-2 was increased in the cortex and striatum, while TrxR-2 increased in the cerebral cortex. The increase in mRNA expression of antioxidant enzymes was positively correlated with the Nrf-2 transcription in the cortex and hippocampus. Hypothyroidism caused oxidative stress, namely an increase in lipid peroxidation and reactive oxygen species levels in the hippocampus and striatum, and a decrease in nonprotein thiols in the cerebral cortex. Diphenyl diselenide was effective in reducing brain oxidative stress and normalizing most of the changes observed in gene expression of antioxidant enzymes. CONCLUSION: The present work corroborates and extends that hypothyroidism disrupts antioxidant enzyme gene expression and causes oxidative stress in the brain. Furthermore, diphenyl diselenide may be considered a promising molecule to counteract these effects in a hypothyroidism state. PMID- 25012260 TI - Photodegradation of amyloid beta and reduction of its cytotoxicity to PC12 cells using porphyrin derivatives. AB - A purpose-designed porphyrin-peptide hybrid effectively degraded amyloid beta monomer and oligomers associated with Alzheimer's disease. Degradation was achieved using light irradiation in the absence of any additives and under neutral conditions. Moreover, the hybrid effectively neutralized the cytotoxicity of amyloid beta in PC12 cells upon photoirradiation. PMID- 25012259 TI - Enzymatic production of 5-aminovalerate from L-lysine using L-lysine monooxygenase and 5-aminovaleramide amidohydrolase. AB - 5-Aminovalerate is a potential C5 platform chemical for synthesis of valerolactam, 5-hydroxyvalerate, glutarate, and 1,5-pentanediol. It is a metabolite of l-lysine catabolism through the aminovalerate pathway in Pseudomonas putida. L-Lysine monooxygenase (DavB) and 5-aminovaleramide amidohydrolase (DavA) play key roles in the biotransformation of L-lysine into 5 aminovalerate. Here, DavB and DavA of P. putida KT2440 were expressed, purified, and coupled for the production of 5-aminovalerate from L-lysine. Under optimal conditions, 20.8 g/L 5-aminovalerate was produced from 30 g/L L-lysine in 12 h. Because L-lysine is an industrial fermentation product, the two-enzyme coupled system presents a promising alternative for the production of 5-aminovalerate. PMID- 25012261 TI - The impact of symptom burden on patient quality of life in chronic myeloid leukemia. AB - Patients with chronic myeloid leukemia (CML) in chronic phase are living longer on BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy, placing emphasis on issues related to symptom burden and quality of life (QoL). Furthermore, the potential for adverse events with longer-term therapy may result in dose adjustments, treatment discontinuation, or nonadherence, all of which may negatively affect treatment efficacy and QoL. However, instruments to specifically measure the impact of symptom burden and treatment on health-related QoL in patients with CML have not been widely available until recently. The FACT-Leu is a validated tool that measures leukemia-specific and more general QoL concerns. Other tools specific to CML, including the MDASI-CML and the EORTC QLQ-CML24, are undergoing validation. Here, we describe TKI therapy-related symptom burden and its effect on adherence and treatment response, outline instruments to measure symptom burden and QoL in CML, and summarize the available clinical data on QoL of patients on TKI therapy. QoL is an aspect of CML disease management that will continue to gain prominence in the coming years. We believe that the instruments developed now will have a role in informing treatment decisions in routine practice and allowing clinicians to proactively address issues related to symptom burden and QoL. PMID- 25012262 TI - Intradiploic dermoid cyst of the lateral frontotemporal skull: case report and review of the literature. AB - BACKGROUND: Intradiploic dermoid cysts represent 0.04-0.7% of cranial tumors. Fewer than 20 cases of dermoid cysts occurring in the lateral frontotemporal region with a sinus tract and bony involvement are described, only 7 with intracranial extension. We present the first report of such a lesion arising within the lateral coronal suture. As the literature on this topic grows, the matter of preoperative imaging for soft tissue and bony lesions of the lateral frontotemporal region is evolving, and this report offers a preliminary set of criteria for when imaging is a necessity. CASE REPORT: A 2-year-old male presented with a bony lesion in the right frontotemporal region. Since birth the lesion had grown commensurately with the patient. Examination revealed an immobile hard mass overlying the right coronal suture with no discernable abnormality. Computed tomography demonstrated a cystic lesion without evidence of intracranial extension. Intraoperatively, the exophytic lesion was fully enclosed by bony matrix, interrupting the coronal suture as it approached the pterion. Following resection, pathology revealed an intradiploic dermoid cyst. CONCLUSION: Intradiploic dermoid cysts occurring within patent cranial sutures away from the midline are rarely described lesions. Complete surgical resection with careful follow-up is the treatment of choice. PMID- 25012263 TI - Voluntary wheel running mitigates the stress-induced bone loss in ovariectomized rats. AB - In estrogen-deficient rodents with osteopenia, repetitive exposure to mild-to moderate stress, which mimics the chronic aversive stimuli (CAS) of the modern urban lifestyle in postmenopausal women, has been hypothesized to cause the bone microstructure to further deteriorate. Recently, we have provided evidence in rats that voluntary impact exercise, e.g., wheel running, is as effective as pharmacological treatments for stress-induced anxiety and depression. The present study, therefore, aims to investigate whether a 4-week CAS exposure aggravates trabecular bone loss in ovariectomized (Ovx) rats, and whether CAS-induced bone loss can be rescued by voluntary wheel running. CAS was found to elevate the serum levels of corticosterone, a stress hormone from the adrenal gland. Dual energy X-ray absorptiometry revealed a decrease in bone mineral content (BMC) in the tibiae of CAS-exposed Ovx rats as compared to the CAS-free Ovx rats (control), while having no detectable effect on bone mineral density (BMD). Bone histomorphometric analysis of the proximal tibial metaphysis showed that CAS decreased trabecular bone volume and increased trabecular separation, which were completely restored to the baseline values of Ovx rats by voluntary wheel running. This CAS-induced trabecular bone loss in Ovx rats was probably due to an enhancement of osteoclast-mediated bone resorption, as indicated by increases in osteoclast surface and active erosion surface. Moreover, wheel running as well as non-impact exercise (endurance swimming) effectively increased the tibial BMD and BMC of CAS-exposed Ovx rats. It can be concluded that exercise is an effective intervention in mitigating CAS-induced bone loss in estrogen-deficient rats. PMID- 25012264 TI - Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis. AB - BACKGROUND: Metaplastic breast cancer (MBC) is a rare histologic subtype needing further characterization. The aim of our study was to compare MBC to infiltrating ductal carcinoma (IDC) of the breast and to identify demographic, clinicopathologic, treatment, and survival differences. METHODS: MBC and IDC patients were identified using the Surveillance, Epidemiology, and End Results (SEER) public-use data set. Disease-specific survival (DSS) differences were compared using the Kaplan-Meier method and log-rank tests. Univariate and multivariate Cox proportional hazard models were used to assess factors prognostic for DSS. To control for hormone receptor status, a subsequent planned analysis was completed for receptor-negative MBC and IDC. Lastly, a matched case control analysis was conducted to minimize potential bias due to baseline demographic, clinical, and pathologic differences. RESULTS: The SEER data set included 1,011 MBC and 253,818 IDC patients diagnosed from 2001 to 2010. MBC patients had larger, higher grade tumors, had less frequent axillary nodal involvement, and were more likely to be treated with mastectomy. Five-year DSS rates were significantly worse for patients with MBC than for IDC patients (78 vs. 93 %, p < 0.0001) and for patients with receptor-negative MBC than receptor negative IDC (77 vs. 85 %, p < 0.0001). The findings were confirmed on matched analysis. Prognostic factors identified on multivariate analyses included age, MBC histology, tumor grade, T stage, and axillary lymph node involvement. CONCLUSIONS: MBC patients have shorter DSS than IDC patients. Improved clinical and biological understanding of MBC may result in more effective therapy and better cancer outcomes. PMID- 25012265 TI - Optimal prophylactic method of venous thromboembolism for gastrectomy in Korean patients: an interim analysis of prospective randomized trial. AB - BACKGROUND: Whereas routine prophylaxis for venous thromboembolism (VTE) is frequently utilized in the West, Asian physicians employ it much less often, based on its recorded rarity amongst their patients. This study was designed to examine the incidence of VTE and to determine the optimal method of thromboembolic prophylaxis following gastrectomy for cancer. METHODS: In this prospective, randomized trial, patients were assigned to either an intermittent pneumatic compression (IPC) only or an IPC plus enoxaparin. The primary end point of this study was to determine the VTE incidence rate within 30 days of surgery. A history with physical examinations for VTE and a serum d-dimer test was scheduled on postoperative days (POD) 0, 1, 4, and 7. Duplex ultrasonography (DUS) was performed as an objective test for deep vein thrombosis at POD 4. An interim analysis was performed to determine if it was ethical to continue the study. This clinical trial was registered at www.clinicaltrials.gov (NCT01448746). RESULTS: Among the 220 patients, 3 (all from the IPC group) were diagnosed with VTE; these cases were asymptomatic, having been detected only on DUS 4 days after surgery. Postoperative bleeding occurred in 12 cases, among which 11 patients were in the IPC plus enoxaparin group. CONCLUSIONS: This interim analysis showed a higher incidence of VTE in the IPC group but a higher bleeding rate in the IPC plus enoxaparin group. We expect that this study, once completed, will provide information key to the determination of the optimal method for preventing VTE in Korean gastric cancer patients. PMID- 25012266 TI - Clinical and pathological response to neoadjuvant chemotherapy based on primary tumor reduction is correlated to survival in hormone receptor-positive but not hormone receptor-negative locally advanced breast cancer. AB - PURPOSE: This study was designed to examine the relationship between different methodologies for response evaluation and long-term survival estimation in patients underwent neoadjuvant chemotherapy (NCT) for breast cancer. METHODS: We retrospectively analyzed 569 patients who were diagnosed with LABC and received NCT followed by breast and axilla surgery. The RECIST 1.1 criteria and Miller Payne (MP) grading scale were used to evaluate patient responses to NCT. Univariate and multivariate survival analyses were performed to investigate the correlation between treatment response and long-term patient survival. RESULTS: Clinical response (RFS [P < 0.001]; OS [P = 0.003]), pathological response evaluated by pCR (RFS [P < 0.001]; OS [P < 0.001]), and MP grade (RFS [P < 0.001]; OS [P < 0.001]) were significant predictors of risks of relapse and survival. However, in hormone receptor-positive (ER and/or PR+) subtypes, the clinical response (P = 0.004 for Luminal-A and P = 0.038 for Luminal-B) and MP grade (P = 0.002 for Luminal-A and P < 0.001 for Luminal-B) significantly predicted RFS independently according to multivariate Cox regression model. MP grade (P = 0.015 for Luminal-A and P = 0.009 for Luminal-B) also was an independent predictor of patients' OS. However, these two methods failed to predict patient survival in hormone receptor-negative (ER and PR-) subtypes. CONCLUSIONS: Our findings indicate that the value of response evaluation methods varies for different breast cancer subtypes. Conceiving of further prospective approaches for new individualized response-evaluation models are needed in the neoadjuvant setting. PMID- 25012267 TI - Platelet counts in the first seven days of life and patent ductus arteriosus in preterm very low-birth-weight infants. AB - BACKGROUND: Decreased platelet number and/or function are related to patent ductus arteriosus (PDA) in mice. Whether this is also the case in human infants remains controversial. OBJECTIVES: To investigate the association between platelet count nadir within the first 7 days of life and the rate of hemodynamically significant PDA (HSPDA), as well as the rate of response to the treatment with cyclooxygenase (COX) inhibitors. METHODS: This is a retrospective study of a cohort of 194 very low-birth-weight (VLBW) infants (<1,500 g) with gestational age <30 weeks. HSPDA was assessed by echocardiography on day 3 of life. RESULTS: HSPDA was present in 105 infants (54.1%). Of these, 101 were treated with COX inhibitors. The treatment failure rate was 21.8%. Median platelet count nadir and rate of thrombocytopenia - defined as platelet count <150 * 10(9)/l and graded as mild (100 to <150 * 10(9)/l), moderate (50 to <100 * 10(9)/l) or severe (<50 * 10(9)/l) - within the first 2 days of life were not significantly associated with the presence of HSPDA on day 3. Moreover, low platelet counts, either on days 1-2 or 3-7, were not significantly associated with the rate of response to treatment with COX inhibitors. CONCLUSIONS: Our data provide further evidence for the lack of association between platelet counts within the first days of life and either spontaneous or pharmacological closure of the ductus arteriosus in VLBW infants. PMID- 25012268 TI - Analysis of regional bone scan index measurements for the survival of patients with prostate cancer. AB - BACKGROUND: A bone scan is a common method for monitoring bone metastases in patients with advanced prostate cancer. The Bone Scan Index (BSI) measures the tumor burden on the skeleton, expressed as a percentage of the total skeletal mass. Previous studies have shown that BSI is associated with survival of prostate cancer patients. The objective in this study was to investigate to what extent regional BSI measurements, as obtained by an automated method, can improve the survival analysis for advanced prostate cancer. METHODS: The automated method for analyzing bone scan images computed BSI values for twelve skeletal regions, in a study population consisting of 1013 patients diagnosed with prostate cancer. In the survival analysis we used the standard Cox proportional hazards model and a more advanced non-linear method based on artificial neural networks. The concordance index (C-index) was used to measure the performance of the models. RESULTS: A Cox model with age and total BSI obtained a C-index of 70.4%. The best Cox model with regional measurements from Costae, Pelvis, Scapula and the Spine, together with age, got a similar C-index (70.5%). The overall best single skeletal localisation, as measured by the C-index, was Costae. The non-linear model performed equally well as the Cox model, ruling out any significant non linear interactions among the regional BSI measurements. CONCLUSION: The present study showed that the localisation of bone metastases obtained from the bone scans in prostate cancer patients does not improve the performance of the survival models compared to models using the total BSI. However a ranking procedure indicated that some regions are more important than others. PMID- 25012269 TI - Mental associations between law and competitiveness: a cross-cultural investigation. AB - Previous research suggests that individuals from countries that adopt an adversarial legal system, such as Canada or United Kingdom, mentally associate "law" more strongly with concepts related to competition than concepts related to cooperation. We examined whether people from a country with a non-adversarial legal system show similar mental associations. Participants from Spain and the UK completed a Single-Category Implicit Association Test. Spanish participants mentally associated the law with competition less strongly than participants from the UK (the average D-score was significantly greater than zero in the predicted direction, t(189) = 8.16, p < .001; d=1.18). Exploratory analysis also suggested that this difference between the countries was stronger among participants who believed that the method of legal practice in their own country was more adversarial. Moreover, perceiving the legal system as adversarial predicted automatic associations between law and competition for UK but not for Spanish participants. These findings suggest that legal system plays a relevant role in shaping not only individuals' actions, but their cognitive processes. PMID- 25012270 TI - Glycine selectively reduces intestinal injury during endotoxemia. AB - BACKGROUND: Glycine is well known to protect the intestine against ischemia reperfusion injury and during mechanical manipulation. Here, we studied whether glycine protects the small intestine during endotoxemia, even without being the site of the infection. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was infused at a rate of 1 mg/kg * h over a period of 7 h (subacute endotoxemia) in male Wistar rats. Glycine (single dose: 50 mg/kg * 15 min) was applied intravenously at 180 and 270 min after the beginning of the LPS infusion. Systemic parameters were periodically determined. The small intestine was analyzed for macroscopic (hemorrhages) and histopathologic changes (hematoxylin and eosin staining), and markers of inflammation (myeloperoxidase activity). RESULTS: Glycine neither decreased mortality nor beneficially affected vital parameters (e.g., mean arterial blood pressure and breathing rate), electrolytes, blood gases including pH and base excess, and plasma parameters of tissue injury such as lactate concentration, hemolysis, and aminotransferases activities during experimental endotoxemia. It, however, specifically diminished the LPS-induced small intestinal injury, as indicated by less intestinal accumulation of blood, less intestinal hemorrhages, and reduced intestinal hemoglobin content. CONCLUSIONS: The present results demonstrate that glycine selectively protects the small intestine during subacute endotoxemia, even after manifestation of a severe systemic impairment. Because glycine is non-toxic at low doses, an administration of a moderate glycine dose (50-100 mg/kg) may be suitable to protect from intestinal damage during sepsis. Its true clinical potential, however, needs to be verified in further experimental studies and clinical trials. PMID- 25012271 TI - Effect of Mailuoning injection on 8-iso-prostaglandin F2 alpha and superoxide dismutase in rabbits with extremity ischemia-reperfusion injury. AB - BACKGROUND: To date, there are no effective treatments for extremity ischemia reperfusion (IR) injury. The objective of the present study was to explore the protective effect of Mailuoning on IR injury by investigating the plasma levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF2alpha) and the activity of superoxide dismutase (SOD) in rabbits. MATERIALS AND METHODS: The experimental models of posterior limb IR injury were established in thirty rabbits that were divided into three groups: the sham, IR, and IR + Mailuoning groups. At the end of ischemia, Mailuoning was injected intravenously into the rabbits in the IR + Mailuoning group, and normal saline solution was administered to the rabbits in the sham and IR groups. Venous blood samples were collected to measure the levels of 8-iso-PGF2alpha and the activity of SOD in the plasma at the following time points: at the onset of ischemia, the end of ischemia, and 2, 4, 8, 12, and 24 h after reperfusion. The skeletal muscles were harvested to examine the ultrastructure. RESULTS: The levels of 8-iso-PGF2alpha increased significantly and SOD activity decreased in the IR group at every time point after reperfusion (P <0.01 or P <0.05). In contrast, the levels of 8-iso-PGF2alpha and SOD activity were not significantly different after reperfusion in the IR + Mailuoning group (P >0.05) but were significantly different compared with the IR group (P <0.01). Using electron microscopy, the skeletal muscle injury was shown to be milder in the IR+ Mailuoning group after reperfusion compared with the IR group. CONCLUSIONS: The Mailuoning is capable of decreasing the excessive production of 8-iso-PGF2alpha and protecting SOD activity, thereby exhibiting a protective effect on extremity IR injury. PMID- 25012272 TI - Reoperative parathyroidectomy: who is at risk and what is the risk? AB - BACKGROUND: Persistent and recurrent hyperparathyroidism necessitate reoperation, which is associated with increased procedure-specific complication rates. The effect of reoperative parathyroidectomy on more generalized outcomes is poorly understood. We sought to determine patient, provider, and perioperative characteristics associated with reoperation, as well as to determine the associated risks. METHODS: All patients receiving a parathyroidectomy in the American College of Surgeons National Surgical Quality Improvement Program database (2008-2011) were identified. Patients receiving initial parathyroidectomy were compared with those receiving reoperative parathyroidectomy. Descriptive statistics and univariate analyses were performed. Multivariate logistic regression models were developed for significant outcome measures. RESULTS: Of 9114 parathyroidectomies performed, 8738 (95.9%) were initial and 376 (4.1%) were reoperative. The annual rate of reoperation was 3.6% 4.8%. Patients undergoing reoperative parathyroidectomy were more likely to be obese (48.5 versus 40.0%, P = 0.009) and American Society of Anesthesiologist class 3 (40.7 versus 30.3%, P = 0.001) than patients undergoing initial parathyroidectomy. There was no difference in gender, age, or race. Reoperations had a longer median operative time (101 minimum, interquartile range [IQR] [74 146] versus 76 [55-105], P <0.001) and a longer postoperative length of stay (median days until discharge 1, IQR [1-1] versus 1, IQR [0-1], P <0.001). No difference was found in the rates of mortality and common postoperative morbidity as measured in NSQIP. Patients undergoing reoperation were more likely to be readmitted within 30 d (12.7 versus 2.6%, P <0.001). After adjusting for confounders, reoperation continued to be significantly associated with readmission (odds ratio 3.82, confidence interval: 1.63-8.97; P = 0.002). CONCLUSIONS: Obesity and an American Society of Anesthesiologist 3 classification are independently associated with reoperation. Readmission within 30 d is associated with reoperation and is a target for patient education and quality improvement after this procedure. PMID- 25012273 TI - Food consumption patterns of Balearic Islands' adolescents depending on their origin. AB - Over the last decade, the immigrant population of the Balearic Islands archipelago (Spain), in the Mediterranean, has risen to 22% of its total population. The aim of this study was to assess food consumption patterns among Balearic Islands' adolescents depending on their origin. A population-based cross sectional nutritional survey was carried out in the Balearic Islands (2007-2008; n = 1,231; 12-17 years old). Dietary assessment was based on a 145-item semi quantitative food-frequency questionnaire. Food consumption differences between the adolescents' point of origin and time of arrival were been studied, as well as average daily meals and snacks. The adolescents' origin and number of years living in the Balearic Islands were also assessed. Native adolescents and immigrants from other Mediterranean countries showed healthier food consumption patterns than their peers from non-Mediterranean countries. Immigrant adolescents adapted their eating patterns to native dietary patterns increasingly, the longer they lived in the Balearic Islands. PMID- 25012274 TI - Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study. AB - Previous evidences support that increased oxidative stress (OxS) may play an important role in metabolic syndrome (MetS) and both are closely linked to vascular dysfunction. This study determined whether there is a relationship between endothelial function and relative telomere length (RTL) in MetS subjects. In this cross-sectional study from the LIPGENE cohort, a total of 88 subjects (36 men and 52 women) were divided into four groups by quartiles of telomere length. We measured ischemic reactive hyperemia (IRH), total nitrite (NO) and protein carbonyl (PC) plasma levels, F2-isoprostanes urinary levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) plasma activities. IRH and NO plasma levels were higher in subjects with longer RTL (quartiles 3 and 4), while PC plasma levels, F2-isoprostanes urinary levels, and GPx and SOD plasma activities were lower in quartile 4 subjects (longest RTL). Additionally, MetS subjects with longer RTL had greater homeostatic model assessment-beta level and lower triglycerides plasma levels. Our results suggest that endothelial dysfunction, associated with high levels of OxS, could be entailed in an increment of telomere attrition. Thus, further support of the molecular and cellular mechanisms involved in vascular dysfunction may contribute to the development of strategies to decelerate vascular aging or prevent cardiovascular disease. PMID- 25012276 TI - Does bold emphasis facilitate the process of visual-word recognition? AB - The study of the effects of typographical factors on lexical access has been rather neglected in the literature on visual-word recognition. Indeed, current computational models of visual-word recognition employ an unrefined letter feature level in their coding schemes. In a letter recognition experiment, Pelli, Burns, Farell, and Moore-Page (2006), letters in Bookman boldface produced more efficiency (i.e., a higher ratio of thresholds of an ideal observer versus a human observer) than the letters in Bookman regular under visual noise. Here we examined whether the effect of bold emphasis can be generalized to a common visual-word recognition task (lexical decision: "is the item a word?") under standard viewing conditions. Each stimulus was presented either with or without bold emphasis (e.g., actor vs. actor). To help determine the locus of the effect of bold emphasis, word-frequency (low vs. high) was also manipulated. Results revealed that responses to words in boldface were faster than the responses to the words without emphasis -this advantage was restricted to low-frequency words. Thus, typographical features play a non-negligible role during visual-word recognition and, hence, the letter feature level of current models of visual-word recognition should be amended. PMID- 25012275 TI - Age-related changes in cardiovascular system, autonomic functions, and levels of BDNF of healthy active males: role of yogic practice. AB - Aging is associated with decline in cardiovascular, autonomic function, and brain derived neurotropic factor (BDNF). Reports are scanty regarding whether yoga can improve age-related degenerative changes in healthy active men. This study is designed to appraise the role of yoga in improving age-related degenerative changes in cardiometabolic risk profile, autonomic function, stress, and BDNF. Healthy active males of three age groups (20-29, 30-39, and 40-49 years) were randomly assigned to practice yoga daily 1 h for 3 months. Significantly higher values of heart rate (HR), blood pressure (BP), load in heart (DoP), myocardial oxygen consumption (RPP), and total cholesterol (TC) were noted in senior age group. HR, BP, DoP, RPP, and TC decreased significantly following yogic practice. High frequency (HF), total power (TP), all time domain variables of heart rate variability (HRV), and skin conductance (SC) were significantly decreased with advancement of age. HF, TP, and time domain parameters of HRV and SC increased significantly following yogic practice. Higher levels of catecholamines and low frequency (LF) power of HRV was noted with advancement of age. Levels of catecholamines and LF significantly decreased following yogic practice. Cortisol and adrenocorticotropic hormone (ACTH) level raised in senior age group. BDNF, serotonin, and dopamine were low in higher age group. Significant decrement of cortisol; ACTH; and increment in serotonin, dopamine, and BDNF was noted following yogic practice. This study revealed that yogic practices might help in the prevention of age-related degeneration by changing cardiometabolic risk factors, autonomic function, and BDNF in healthy male. PMID- 25012277 TI - A survey of children's perspectives on pain management in the emergency department. AB - BACKGROUND: Children's pain is frequently underrecognized and undertreated. This study focuses exclusively on children's perspectives of and satisfaction with their pain management in the emergency department (ED). OBJECTIVES: Specific study objectives were to 1) describe the pain and ED treatment experienced by children, 2) measure the child's satisfaction with pain treatment, and 3) determine factors associated with satisfaction. METHODS: This prospective, descriptive survey examined a convenience sample of 100 children, aged 7-17 years, who were treated for pain in the pediatric ED of a Canadian hospital. We measured children's pain scores, overall satisfaction with their pain management, and perceptions of health care provider communication. RESULTS: Of the 100 children studied, 53 were male, and the mean age was 12.6 years. The maximum mean pain score was reported as 79 mm (95% confidence interval [CI] 75-82) and the mean score at discharge was reported as 34 mm (95% CI 29-39), using a 100-mm modified visual analog scale. The majority of children (92%) were satisfied; three children (3%) were very unhappy and four (4%) were unhappy with their pain treatment. Satisfaction was correlated with pain resolution (p = 0.018), effective child-provider communication (p = 0.045), and the perception that the medicine worked quickly (p = 0.034). CONCLUSIONS: Despite continued pain upon discharge, most children were satisfied with their pain management. However, it is important that emergency physicians not interpret patient satisfaction as equivalent to adequate provision of analgesia. The relationship between children's pain management and self-reported satisfaction needs to be further explored. PMID- 25012278 TI - Female patient with abdominal pain. PMID- 25012279 TI - Practicing emergency physicians report performing well on most emergency medicine milestones. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education's Next Accreditation System endorsed specialty-specific milestones as the foundation of an outcomes-based resident evaluation process. These milestones represent five competency levels (entry level to expert), and graduating residents will be expected to meet Level 4 on all 23 milestones. Limited validation data on these milestones exist. It is unclear if higher levels represent true competencies of practicing emergency medicine (EM) attendings. OBJECTIVE: Our aim was to examine how practicing EM attendings in academic and community settings self-evaluate on the new EM milestones. METHODS: An electronic self-evaluation survey outlining 9 of the 23 EM milestones was sent to a sample of practicing EM attendings in academic and community settings. Attendings were asked to identify which level was appropriate for them. RESULTS: Seventy-nine attendings were surveyed, with an 89% response rate. Sixty-one percent were academic. Twenty-three percent (95% confidence interval [CI] 20%-27%) of all responses were Levels 1, 2, or 3; 38% (95% CI 34%-42%) were Level 4; and 39% (95% CI 35%-43%) were Level 5. Seventy seven percent of attendings found themselves to be Level 4 or 5 in eight of nine milestones. Only 47% found themselves to be Level 4 or 5 in ultrasound skills (p = 0.0001). CONCLUSIONS: Although a majority of EM attendings reported meeting Level 4 milestones, many felt they did not meet Level 4 criteria. Attendings report less perceived competence in ultrasound skills than other milestones. It is unclear if self-assessments reflect the true competency of practicing attendings. The study design can be useful to define the accuracy, precision, and validity of milestones for any medical field. PMID- 25012281 TI - [Welcome to phytotherapy]. PMID- 25012280 TI - Using community level strategies to reduce asthma attacks triggered by outdoor air pollution: a case crossover analysis. AB - BACKGROUND: Evidence indicates that asthma attacks can be triggered by exposure to ambient air pollutants, however, detailed pollution information is missing from asthma action plans. Asthma is commonly associated with four criteria pollutants with standards derived by the United States Environmental Protection Agency. Since multiple pollutants trigger attacks and risks depend upon city specific mixtures of pollutants, there is lack of specific guidance to reduce exposure. Until multi-pollutant statistical modeling fully addresses this gap, some guidance on pollutant attack risk is required. This study examines the risks from exposure to the asthma-related pollutants in a large metropolitan city and defines the city-specific association between attacks and pollutant mixtures. Our goal is that city-specific pollution risks be incorporated into individual asthma action plans as additional guidance to prevent attacks. METHODS: Case-crossover analysis and conditional logistic regression were used to measure the association between ozone, fine particulate matter, nitrogen dioxide, sulfur dioxide and carbon monoxide pollution and 11,754 emergency medical service ambulance treated asthma attacks in Houston, Texas from 2004-2011. Both single and multi-pollutant models are presented. RESULTS: In Houston, ozone and nitrogen dioxide are important triggers (RR = 1.05; 95% CI: 1.00, 1.09), (RR = 1.10; 95% CI: 1.05, 1.15) with 20 and 8 ppb increase in ozone and nitrogen dioxide, respectively, in a multi-pollutant model. Both pollutants are simultaneously high at certain times of the year. The risk attributed to these pollutants differs when they are considered together, especially as concentrations increase. Cumulative exposure for ozone (0-2 day lag) is of concern, whereas for nitrogen dioxide the concern is with single day exposure. Persons at highest risk are aged 46-66, African Americans, and males. CONCLUSIONS: Accounting for cumulative and concomitant outdoor pollutant exposure is important to effectively attribute risk for triggering of an asthma attack, especially as concentrations increase. Improved asthma action plans for Houston individuals should warn of these pollutants, their trends, correlation and cumulative effects. Our Houston based study identifies nitrogen dioxide levels and the three-day exposure to ozone to be of concern whereas current single pollutant based national standards do not. PMID- 25012282 TI - [Phytotherapy in geriatrics and gerontology]. PMID- 25012283 TI - [Efficacy in phytotherapy]. PMID- 25012284 TI - [Looking to the future of herbal medicines]. PMID- 25012285 TI - [Between empiricism and evidence - ( re ) activation of veterinary phytotherapy]. PMID- 25012287 TI - Incremental prognostic significance of the elevated levels of pentraxin 3 in patients with heart failure with normal left ventricular ejection fraction. AB - BACKGROUND: Pentraxin 3 (PTX3) is a novel inflammatory marker produced by various cell types including those of the vasculature and the heart. The relationship between inflammatory markers and prognosis of patients with heart failure with normal ejection fraction (HFNEF) remains unknown. We investigated whether plasma PTX3 levels can predict future cardiovascular events in patients with HFNEF. METHODS AND RESULTS: Plasma PTX3, high-sensitivity C-reactive protein, and B-type natriuretic peptide levels were measured prospectively in 360 stable patients with HFNEF. The subsequent incidence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction (MI), unstable angina pectoris, nonfatal ischemic stroke, hospitalization for heart failure decompensation, and coronary revascularization, was determined. During a mean 30 month follow-up, 106 patients experienced cardiovascular events. These events were more frequent in patients with high plasma PTX3 levels (>3.0 ng/mL) than low levels (<=3.0 ng/mL). Multivariable Cox hazard analysis showed that PTX3 (hazard ratio: 1.16; 95% CI: 1.05 to 1.27; P<0.01) and B-type natriuretic peptide (hazard ratio: 1.08; 95% CI: 1.03 to 1.14; P<0.001), but not high-sensitivity C-reactive protein levels, were significant predictors of future cardiovascular events. Multivariable Cox analysis with the forced inclusion model, including 5 previously identified prognostic factors, found that PTX3 was a significant predictor of cardiovascular events (hazard ratio: 1.16; 95% CI: 1.06 to 1.27; P<0.01). The C-statistics for cardiovascular events substantially increased from 0.617 to 0.683 when PTX3 was added to the 5 previously identified prognostic factors. CONCLUSIONS: High plasma PTX3 levels, but not other inflammatory markers, are correlated with future cardiovascular events in patients with HFNEF. PTX3 may be a useful biomarker for assessment of risk stratification in HFNEF. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp; Unique identifier: UMIN000002170. PMID- 25012288 TI - Reduction in overall occurrences of ischemic events with vorapaxar: results from TRACER. AB - BACKGROUND: Clinical trials traditionally use time-to-first-event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER. METHODS AND RESULTS: TRACER randomized 12 944 patients with non-ST-segment elevation acute coronary syndromes to placebo or to protease-activated receptor 1 antagonist vorapaxar with a median follow-up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001). CONCLUSIONS: Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events. CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov. Unique identifier: NCT00527943. PMID- 25012289 TI - Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers. AB - BACKGROUND: C-reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti-inflammatory effects in humans. METHODS AND RESULTS: A placebo controlled study was used to evaluate the effects of ISIS 329993 (ISIS-CRPR x) on the acute-phase response after endotoxin challenge in 30 evaluable subjects. Healthy adult males were randomly allocated to receive 6 injections over a 22-day period of placebo or active therapy with ISIS 329993 at 400- or 600-mg doses. Eligible subjects were subsequently challenged with a bolus of endotoxin (2 ng/kg). Inflammatory and hematological biomarkers were measured before and serially after the challenge. ISIS-CRPR x was well tolerated with no serious adverse events. Median CRP levels increased more than 50-fold from baseline 24 hours after endotoxin challenge in the placebo group. In contrast, the median increase in CRP levels was attenuated by 37% (400 mg) and 69% (600 mg) in subjects pretreated with ISIS-CRPR x (P<0.05 vs. placebo). All other aspects of the acute inflammatory response were similar between treatment groups. CONCLUSION: Pretreatment of subjects with ISIS-CRPR x selectively reduced the endotoxin-induced increase in CRP levels in a dose-dependent manner, without affecting other components of the acute-phase response. These data demonstrate the specificity of antisense oligonucleotides and provide an investigative tool to further define the role of CRP in human pathological conditions. PMID- 25012290 TI - Penile torsion repair in children following a ladder step: simpler steps are usually sufficient. AB - OBJECTIVE: To evaluate the correction of different degrees of penile torsion following a ladder step so that simpler steps are used whenever possible. This can avoid the morbidity and complications of complex procedures. PATIENTS AND METHODS: Cases of congenital and acquired penile torsion were repaired on a ladder step basis irrespective of the degree of torsion, starting with degloving and skin realignment, then a dorsal dartos flap and finally corporopexy. The torsion is checked with artificial erection after each step, and if corrected completely then the next step(s) is omitted. RESULTS: Twenty-five cases of penile torsion (30-180 degrees ) were repaired over a 4-year period. Three cases were corrected by degloving only, 12 by degloving and skin realignment, five by a dartos flap and four required a corporopexy. Postoperative complications included five cases of penile edema, one case of hematoma and one case of dorsal skin gangrene. Residual torsion of <15 degrees occurred in three cases. No cases required redo surgery. CONCLUSION: A ladder step approach is a good option for penile torsion repair, starting with simpler techniques until complete correction is achieved. There is no need to plan a complex procedure in advance. PMID- 25012291 TI - A structural model of the active ribosome-bound membrane protein insertase YidC. AB - The integration of most membrane proteins into the cytoplasmic membrane of bacteria occurs co-translationally. The universally conserved YidC protein mediates this process either individually as a membrane protein insertase, or in concert with the SecY complex. Here, we present a structural model of YidC based on evolutionary co-variation analysis, lipid-versus-protein-exposure and molecular dynamics simulations. The model suggests a distinctive arrangement of the conserved five transmembrane domains and a helical hairpin between transmembrane segment 2 (TM2) and TM3 on the cytoplasmic membrane surface. The model was used for docking into a cryo-electron microscopy reconstruction of a translating YidC-ribosome complex carrying the YidC substrate FOc. This structure reveals how a single copy of YidC interacts with the ribosome at the ribosomal tunnel exit and identifies a site for membrane protein insertion at the YidC protein-lipid interface. Together, these data suggest a mechanism for the co translational mode of YidC-mediated membrane protein insertion. PMID- 25012292 TI - The involvement of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in the regulation of inflammation following coronary microembolization. AB - BACKGROUND/AIMS: Growing evidence shows that phosphatase and tensin homolog deleted on chromosome ten (PTEN) is involved in regulating inflammation in different pathological conditions. Therefore, we hypothesized that the upregulation of PTEN correlates with the impairment of cardiac function in swine following coronary microembolization (CME). METHODS: To possibly disclose an anti inflammatory effect of PTEN, we induced swine CME by injecting inertia plastic microspheres (42 MUm in diameter) into the left anterior descending coronary artery and analyzed the myocardial tissue by immunochemistry, qRT-PCR and western blot analyses. In addition, we downregulated PTEN using siRNA. RESULTS: Following CME, PTEN mRNA and protein levels were elevated as early as 3 h, peaked at 12 h, and then continuously decreased at 24 h and 48 h but remained elevated. Through linear correlation analysis, the PTEN protein level positively correlated with cTnI and TNF-alpha but was negatively correlated with LVEF. Furthermore, PTEN siRNA reduced the microinfarct volume, improved cardiac function (LVEF), reduced the release of cTnI, and suppressed PTEN and TNF-alpha protein expression. CONCLUSION: This study demonstrated, for the first time, that PTEN is involved in CME-induced inflammatory injury. The data generated from this study provide a rationale for the development of PTEN-based anti-inflammatory strategies. PMID- 25012293 TI - The multifunctional Staufen proteins: conserved roles from neurogenesis to synaptic plasticity. AB - Staufen (Stau) proteins belong to a family of RNA-binding proteins (RBPs) that are important for RNA localisation in many organisms. In this review we discuss recent findings on the conserved role played by Stau during both the early differentiation of neurons and in the synaptic plasticity of mature neurons. Recent molecular data suggest mechanisms for how Stau2 regulates mRNA localisation, mRNA stability, translation, and ribonucleoprotein (RNP) assembly. We offer a perspective on how this multifunctional RBP has been adopted to regulate mRNA localisation under several different cellular and developmental conditions. PMID- 25012294 TI - Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. AB - Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA-target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers. PMID- 25012295 TI - EBV microRNA BART 18-5p targets MAP3K2 to facilitate persistence in vivo by inhibiting viral replication in B cells. AB - EBV is an oncogenic human herpesvirus that has the ability to infect and transform B cells latently in vitro. However, the virus also establishes a lifetime, benign, persistent latent infection in resting memory B cells in vivo, where the virus is quiescent (i.e., expresses none of the known latent proteins). The virus encodes ~40 micro-RNAs (miRNAs), most of which are transcribed from the BamH1 fragment A rightward transcript (BART) region of the virus. We have shown previously that a subset of these miRNAs is present at high copy numbers in latently infected memory B cells in vivo, suggesting a role in maintaining latency. Here, we describe the role of one of these miRNAs, BART 18-5p. We show that it targets the 3'UTR of the mRNA, encoding the important cellular signaling molecule MAP kinase kinase kinase 2 (MAP3K2), at exactly the same site as the oncogenic cellular miRNA mir-26a-5p. To our knowledge, this is the first report of a virus encoding a miRNA that suppresses a target in the MAP kinase signaling cascade, a central signal transduction pathway that governs a broad spectrum of biological processes. We further show that MAP3K2 is an intermediary in the signaling pathways that initiate lytic viral replication. Thus, 18-5p expression in latently infected B cells has the effect of blocking viral replication. We propose that the role of 18-5p is to maintain latency by reducing the risk of fortuitous reactivation of the virus in latently infected memory B cells. PMID- 25012296 TI - PKA tightly bound to human placental mitochondria participates in steroidogenesis and is not modified by cAMP. AB - INTRODUCTION: Protein phosphorylation plays an important role in the modulation of steroidogenesis and it depends on the activation of different signaling cascades. Previous data showed that PKA activity is related to steroidogenesis in mitochondria from syncytiotrophoblast of human placenta (HPM). PKA localization and contribution in progesterone synthesis and protein phosphorylation of HPM was assessed in this work. METHODS: Placental mitochondria and submitochondrial fractions were used. Catalytic and regulatory PKA subunits were identified by Western blot. PKA activity was determined by the incorporation of (32)P into proteins in the presence or absence of specific inhibitors. The effect of PKA activators and inhibitors on steroidogenesis and protein phosphorylation in HPM was tested by radioimmunoassay and autoradiography. RESULTS: The PKAalpha catalytic subunit was distributed in all the submitochondrial fractions whereas betaII regulatory subunit was the main isoform observed in both the outer and inner membranes of HPM. PKA located in the inner membrane showed the highest activity. Progesterone synthesis and mitochondrial protein phosphorylation are modified by inhibitors of PKA catalytic subunit but are neither sensitive to inhibitors of the regulatory subunit nor to activators of the holoenzyme. DISCUSSION: The lack of response in the presence of PKA activators and inhibitors of the regulatory subunit suggests that the activation of intramitochondrial PKA cannot be prevented or further activated. CONCLUSIONS: The phosphorylating activity of PKA inside HPM could be an important component of the steroidogenesis transduction cascade, probably exerting its effects by direct phosphorylation of its substrates or by modulating other kinases and phosphatases. PMID- 25012297 TI - Spatial and temporal changes of decorin, type I collagen and fibronectin expression in normal and clone bovine placenta. AB - INTRODUCTION: Alteration of expression of various genes including extracellular matrix components, have been suggested to play major role in the placental pathologies after somatic cloning in mammals. The objectives of the present study were to analyze pattern of expression (mRNA and protein) of the small leucine rich proteoglycan, Decorin in association with Type I Collagen and Fibronectin in bovine placental tissues from normal and clone pregnancies. METHODS: Genotyping and allelic expression of Decorin were determined by Sanger sequencing. The expression patterns of Decorin, Type I collagen and Fibronectin 1 were analyzed by quantitative RT-qPCR and combined in situ hybydization (ISH) and immunohistochemistry (IHC) in endometrial and placental tissues from D18 to term from artificially inseminated and somatic cloning pregnancies. RESULTS: The expression levels of DCN increased in the AI endometrial stroma and chorionic mesenchyme during implantation and declined during placentome growth until term. Combined ISH and IHC revealed an unexpected discrepancy mRNA and protein tissue distribution. Moreover, Decorin was maintained in the placentome tissues from SCNT pregnancies while both mRNA and protein were absent in AI derived placenta. DISCUSSION: In bovine, the pattern of expression of Decorin exhibits significant changes during placental formation. Downregulation of Decorin is associated with proliferation, remodeling and vascularization of placental tissues. These observations reinforces the putative role of Decorin in these processes. CONCLUSIONS: These observations suggest that Decorin is involved in placental growth and that dysregulation of its expression is associated with placental abnormalities in SCNT derived pregnancy. PMID- 25012299 TI - Precision markedly attenuates repetitive lift capacity. AB - This study investigated the effect of precision on time to task failure in a repetitive whole-body manual handling task. Twelve participants were required to repetitively lift a box weighing 65% of their single repetition maximum to shoulder height using either precise or unconstrained box placement. Muscle activity, forces exerted at the ground, 2D body kinematics, box acceleration and psychophysical measures of performance were recorded until task failure was reached. With precision, time to task failure for repetitive lifting was reduced by 72%, whereas the duration taken to complete a single lift and anterior deltoid muscle activation increased by 39% and 25%, respectively. Yet, no significant difference was observed in ratings of perceived exertion or heart rate at task failure. In conclusion, our results suggest that when accuracy is a characteristic of a repetitive manual handling task, physical work capacity will decline markedly. PRACTITIONER SUMMARY: The capacity to lift repetitively to shoulder height was reduced by 72% when increased accuracy was required to place a box upon a shelf. Lifting strategy and muscle activity were also modified, confirming practitioners should take into consideration movement precision when evaluating the demands of repetitive manual handling tasks. PMID- 25012298 TI - The epidemiology of silent brain infarction: a systematic review of population based cohorts. AB - BACKGROUND: Cerebral infarction is a commonly observed radiological finding in the absence of corresponding, clinical symptomatology, the so-called silent brain infarction (SBI). SBIs are a relatively new consideration as improved imaging has facilitated recognition of their occurrence. However, the true incidence, prevalence and risk factors associated with SBI remain controversial. METHODS: Systematic searches of the Medline and EMBASE databases from 1946 to December 2013 were performed to identify original studies of population-based adult cohorts derived from community surveys and routine health screening that reported the incidence and prevalence of magnetic resonance imaging (MRI)-determined SBI. RESULTS: The prevalence of SBI ranges from 5% to 62% with most studies reported in the 10% to 20% range. Longitudinal studies suggest an annual incidence of between 2% and 4%. A strong association was seen to exist between epidemiological estimates of SBI and age of the population assessed. Hypertension, carotid stenosis, chronic kidney disease and metabolic syndrome all showed a strong association with SBI. Heart failure, coronary artery disease, hyperhomocysteinemia and obstructive sleep apnea are also likely of significance. However, any association between SBI and gender, ethnicity, tobacco or alcohol consumption, obesity, dyslipidemia, atrial fibrillation and diabetes mellitus remains unclear. CONCLUSIONS: SBI is a remarkably common phenomenon and endemic among older people. This systematic review supports the association of a number of traditional vascular risk factors, but also highlights disparities between clinically apparent and silent strokes, potentially suggesting important differences in pathophysiology and warranting further investigation. PMID- 25012300 TI - Oral manifestations of hereditary nonpolyposis colorectal cancer syndrome: a family case series. AB - INTRODUCTION: Hereditary nonpolyposis colorectal cancer is a colorectal cancer syndrome characterized by the development of colorectal cancer and extracolonic tumors, and this syndrome has an autosomal dominant mode of inheritance. To our knowledge, our study was the first to find dento-osseous anomalies and the second to observe Fordyce granules in a family with individuals with hereditary nonpolyposis colorectal cancer. CASE PRESENTATIONS: Twenty members of one Brazilian family with individuals with hereditary nonpolyposis colorectal cancer were analyzed according to the presence of colorectal cancer and the occurrence of Fordyce granules and dento-osseous anomalies. Their average age was 29.6 (range 7 to 53 years) years. Medical examinations of this family with hereditary nonpolyposis colorectal cancer were performed at the Coloproctology Division of our hospital. Then, all individuals were referred to our Oral Care Center for Inherited Diseases for intraoral examinations to verify the presence of Fordyce granules. Dental panoramic radiographs were done in order to describe dento osseous anomalies on applying the Dental Panoramic Radiograph System. Of the 20 family members, four were diagnosed with hereditary nonpolyposis colorectal cancer and all four presented Fordyce granules in their upper lip, but only one of these four patients (Case 2) had a significant dento-osseous anomaly. CONCLUSIONS: Our familial study verified the presence of Fordyce granules in all individuals diagnosed with hereditary nonpolyposis colorectal cancer, and the presence of significant dento-osseous anomalies in one of these cases. However, the relationship between oral manifestations and hereditary nonpolyposis colorectal cancer should be further investigated. PMID- 25012301 TI - Strong enhancement of parity violation effects in chiral uranium compounds. AB - The effects of parity violation (PV) on the vibrational transitions of chiral uranium compounds of the type N=UXYZ and N=UHXY (X, Y, Z = F, Cl, Br, I) are analysed by means of exact two-component relativistic (X2C) Hartree-Fock and density functional calculations using NUFClI and NUHFI as representative examples. The PV contributions to the vibrational transitions were found to be in the Hz range, larger than for any of the earlier proposed chiral molecules. Thus, these systems are very promising candidates for future experimental PV measurements. A detailed comparison of the N=UHFI and the N=WHFI homologues reveals that subtle electronic structure effects, rather than exclusively a simple Z(5) scaling law, are the cause of the strong enhancement in PV contributions of the chiral uranium molecules. PMID- 25012302 TI - Landfill mining in Austria: foundations for an integrated ecological and economic assessment. AB - For the first time, basic technical and economic studies for landfill mining are being carried out in Austria on the basis of a pilot project. An important goal of these studies is the collection of elementary data as the basis for an integrated ecological and economic assessment of landfill mining projects with regard to their feasibility. For this purpose, economic, ecological, technical, organizational, as well as political and legal influencing factors are identified and extensively studied in the article. An important aspect is the mutual influence of the factors on each other, as this can significantly affect the development of an integrated assessment system. In addition to the influencing factors, the definition of the spatial and temporal system boundaries is crucial for further investigations. Among others, the quality and quantity of recovered waste materials, temporal fluctuations or developments in prices of secondary raw material and fuels attainable in the markets, and time and duration of dumping, play a crucial role. Based on the investigations, the spatial system boundary is defined in as much as all the necessary process steps, from landfill mining, preparing and sorting to providing a marketable material/product by the landfill operator, are taken into account. No general accepted definition can be made for the temporal system boundary because the different time-related influencing factors necessitate an individual project-specific determination and adaptation to the facts of the on-site landfill mining project. PMID- 25012303 TI - Calcium silicates synthesised from industrial residues with the ability for CO2 sequestration. AB - This work explored several synthesis routes to obtain calcium silicates from different calcium-rich and silica-rich industrial residues. Larnite, wollastonite and calcium silicate chloride were successfully synthesised with moderate heat treatments below standard temperatures. These procedures help to not only conserve natural resources, but also to reduce the energy requirements and CO2 emissions. In addition, these silicates have been successfully tested as carbon dioxide sequesters, to enhance the viability of CO2 mineral sequestration technologies using calcium-rich industrial by-products as sequestration agents. Two different carbon sequestration experiments were performed under ambient conditions. Static experiments revealed carbonation efficiencies close to 100% and real-time resolved experiments characterised the dynamic behaviour and ability of these samples to reduce the CO2 concentration within a mixture of gases. The CO2 concentration was reduced up to 70%, with a carbon fixation dynamic ratio of 3.2 mg CO2 per g of sequestration agent and minute. Our results confirm the suitability of the proposed synthesis routes to synthesise different calcium silicates recycling industrial residues, being therefore energetically more efficient and environmentally friendly procedures for the cement industry. PMID- 25012305 TI - It's make your mind up time. PMID- 25012304 TI - Auditory implicit semantic priming in Spanish-speaking children with and without specific language impairment. AB - We analyzed whether Spanish-speaking children with Specific Language Impairment (SLI) showed deficits in lexical-semantic processing/organization, and whether these lexical measures correlated with standardized measures of language abilities. Fourteen children with Typical Language Development (TLD) and 16 age matched children with SLI (8;0-9;11 years) participated. In a Lexical Decision (LD) task with implicit semantic priming, children judged whether a given speech pair contained two words (semantically related/unrelated) or a word-pseudoword. Children received a comprehensive language and reading test battery. Children with TLD exhibited significant semantic priming; they were faster for semantically related word pairs than for unrelated (p < .001) and than for word pseudoword pairs (p < .0002). The group with SLI did not exhibit significant semantic priming, despite showing more variability. Children with SLI made significantly slower LDs [F(1, 26) = 4.61, p < .05, partial eta2 = .15] and more errors [F(1, 26) = 4.16, p < .05, partial eta2 = .13] than children with TLD. Mean response time across all LD conditions and the receptive vocabulary (PPVT III) were significantly negativity correlated for children with SLI (r = -.71, p = .004). Children with SLI, especially those with the poorest language scores, showed a semantic-lexical deficit and a weakness in lexical-semantic association networks. Their performance on the LD task was significantly slower and poorer than for children with TLD. Increasing a child's vocabulary may benefit lexical access. PMID- 25012306 TI - Pharmacology: inflammatory definitions. PMID- 25012307 TI - Endangered Jaborandi. PMID- 25012308 TI - Sealant costs. PMID- 25012309 TI - Oral health: charcoal brushes. PMID- 25012310 TI - OMFS: work time restrictions. PMID- 25012311 TI - Short-term orthodontics: history puts it straight. PMID- 25012312 TI - 1914-2014: new cover series commemorates World War I. PMID- 25012316 TI - A dentist's life: how cool is that. PMID- 25012321 TI - Investigation: greening up the bottom line. PMID- 25012322 TI - Tim Elmer: 'in the armed forces we lose thousands of man hours each year to people leaving to have dental care delivered.'. AB - Tim Elmer talks to the BDJ about life in the Defence Dental Services, providing care on the frontline and the impact of dental disease on the Armed Forces. PMID- 25012323 TI - An overview of the prison population and the general health status of prisoners. AB - This article is the first in a series of four, which explore the oral and dental health of male prisoners in the United Kingdom. The series comprises: an overview of the general and oral health status of male prisoners, a discussion on how multi-disciplinary team working can be used to benefit the care of patients in prison environments and a description of the future planning of dental services for male prisoners. The oral health of prisoners is linked to their general health status, due in part to the presence of common risk factors such as smoking, drinking alcohol and in some cases use of recreational drugs, poor dietary and poor oral hygiene habits. Barriers to healthcare services can all have an effect on oral disease in this group. This paper highlights some of the common medical problems that oral healthcare providers face when treating prisoners in male UK prison establishments. PMID- 25012324 TI - General medicine and surgery for dental practitioners: part 3. Management of specific medical emergencies in dental practice. AB - In this paper, the actions needed to manage specific medical emergencies are discussed. Each emergency requires a correct diagnosis to be made for effective and safe management. Contemporary management in dental practice avoids the intravenous route when drugs are required to treat the emergency. PMID- 25012330 TI - Summary of: halitosis: a new definition and classification. PMID- 25012325 TI - Interventions for the prevention of dry socket: an evidence-based update. AB - This paper reviews the latest evidence for local and systemic interventions for the prevention of alveolar osteitis (dry socket). Dry socket is a painful and common post-operative complication following exodontia. Any interventions for the prevention of dry socket could reduce both its incidence and help avoid this painful complication. Prophylactic measures proposed in the literature are discussed. Furthermore, this article discusses both the clinical and histological stages of a normal healing socket. PMID- 25012331 TI - Summary of: acceptability of fissure sealants from the child's perspective. PMID- 25012332 TI - Experiences of clinical teaching for dental core trainees working in hospital. AB - There is recognition that the provision of excellence in education and training results in a skilled and competent workforce. However, the educational experiences of dental core trainees (DCT's) working in the hospital oral and maxillofacial surgery (OMFS) setting have not been previously investigated. In this paper, we examine DCT's learning experiences both 'formal' and 'non-formal' within the hospital setting of ward and clinic-based teaching. Are hospital dental core trainees receiving a meaningful educational experience? To conclude this paper, the authors recommend methods, based upon sound educational principles, to maximise the value of clinical sessions for teaching. PMID- 25012333 TI - Local anaesthesia through the action of cocaine, the oral mucosa and the Vienna group. AB - Local anaesthesia through the action of cocaine was introduced in Europe by the Vienna group, which includeed Freud, Koller and Konigstein. Before using the alkaloid in animal or human experimentation all these scientists tested it on their oral mucosa - so-called self-experimentation. Some of them with different pathologies (that is, in the case of Freud), eventually became addicted to the alkaloid. Here we attempt to describe the people forming the so-called 'Vienna group', their social milieu, their experiences and internal disputes within the setting of a revolutionary discovery of the times. PMID- 25012350 TI - Acceptability of fissure sealants from the child's perspective. AB - AIM: To seek children's opinions about the acceptability of resin fissure sealant placement. STUDY DESIGN: Service evaluation using a child-centred questionnaire issued to a prospective sample of consecutive hospital patients.Method Questionnaires were issued to children, aged 3 to 16 years, immediately after resin fissure sealant placement in the Paediatric Dentistry Department in Sheffield. Participants used a three-point faces scale for positive, neutral and negative responses, arranged as a Likert scale with minimal text, to rate their treatment experiences and satisfaction with the dental visit. RESULTS: Two hundred questionnaires were returned. Overall, 96% (n = 191) recorded a positive or neutral response for the ease at which they coped with the procedure, with most children positive about having fissure sealants placed again (66%; n = 132). Further analysis demonstrated that children who had fissure sealants on a previous occasion found them easier than those having them for the first time (p <0.05, chi-squared test). Almost half of all participants where ambivalent about the taste and feeling (46%; n = 92 and 55%; n = 110 respectively). The vast majority of children were satisfied with the explanations provided by their operator. CONCLUSION: Most participants found having resin fissure sealants placed an overall acceptable procedure, with patient acceptance improving with increased treatment experience. PMID- 25012351 TI - Real-time monitoring of immobilized single yeast cells through multifrequency electrical impedance spectroscopy. AB - We present a microfluidic device, which enables single cells to be reliably trapped and cultivated while simultaneously being monitored by means of multifrequency electrical impedance spectroscopy (EIS) in the frequency range of 10 kHz-10 MHz. Polystyrene beads were employed to characterize the EIS performance inside the microfluidic device. The results demonstrate that EIS yields a low coefficient of variation in measuring the diameters of captured beads (~0.13%). Budding yeast, Saccharomyces cerevisiae, was afterwards used as model organism. Single yeast cells were immobilized and measured by means of EIS. The bud growth was monitored through EIS at a temporal resolution of 1 min. The size increment of the bud, which is difficult to determine optically within a short time period, can be clearly detected through EIS signals. The impedance measurements also reflect the changes in position or motion of single yeast cells in the trap. By analyzing the multifrequency EIS data, cell motion could be qualitatively discerned from bud growth. The results demonstrate that single-cell EIS can be used to monitor cell growth, while also detecting potential cell motion in real-time and label-free approach, and that EIS constitutes a sensitive tool for dynamic single-cell analysis. PMID- 25012349 TI - Halitosis: a new definition and classification. AB - BACKGROUND: There is no universally accepted, precise definition, nor standardisation in terminology and classification of halitosis. OBJECTIVE: To propose a new definition, free from subjective descriptions (faecal, fish odour, etc), one-time sulphide detector readings and organoleptic estimation of odour levels, and excludes temporary exogenous odours (for example, from dietary sources). Some terms previously used in the literature are revised. RESULTS: A new aetiologic classification is proposed, dividing pathologic halitosis into Type 1 (oral), Type 2 (airway), Type 3 (gastroesophageal), Type 4 (blood-borne) and Type 5 (subjective). In reality, any halitosis complaint is potentially the sum of these types in any combination, superimposed on the Type 0 (physiologic odour) present in health. CONCLUSION: This system allows for multiple diagnoses in the same patient, reflecting the multifactorial nature of the complaint. It represents the most accurate model to understand halitosis and forms an efficient and logical basis for clinical management of the complaint. PMID- 25012352 TI - Characterization of hydromedusan Ca(2+)-regulated photoproteins as a tool for measurement of Ca(2+)concentration. AB - Calcium ion is a ubiquitous intracellular messenger, performing this function in many eukaryotic cells. To understand calcium regulation mechanisms and how disturbances of these mechanisms are associated with disease states, it is necessary to measure calcium inside cells. Ca(2+)-regulated photoproteins have been successfully used for this purpose for many years. Here we report the results of comparative studies on the properties of recombinant aequorin from Aequorea victoria, recombinant obelins from Obelia geniculata and Obelia longissima, recombinant mitrocomin from Mitrocoma cellularia, and recombinant clytin from Clytia gregaria as intracellular calcium indicators in a set of identical in vitro and in vivo experiments. Although photoproteins reveal a high degree of identity of amino acid sequences and spatial structures, and, apparently, have a common mechanism for the bioluminescence reaction, they were found to differ in the Ca(2+) concentration detection limit, the sensitivity of bioluminescence to Mg(2+), and the rates of the rise of the luminescence signal with a sudden change of Ca(2+) concentration. In addition, the bioluminescence activities of Chinese hamster ovary cells expressing wild-type photoproteins also differed. The light signals of cells expressing mitrocomin, for example, slightly exceeded the background, suggesting that mitrocomin may be hardly used to detect intracellular Ca(2+) without modifications improving its properties. On the basis of experiments on the activation of endogenous P2Y2 receptor in Chinese hamster ovary cells by ATP, we suggest that wild-type aequorin and obelin from O. longissima are more suitable for calcium detection in cytoplasm, whereas clytin and obelin from O. geniculata can be used for calcium measurement in cell compartments with high Ca(2+) concentration. PMID- 25012354 TI - Active learning materials for molecular and atomic spectroscopy. PMID- 25012353 TI - On chip preconcentration and fluorescence labeling of model proteins by use of monolithic columns: device fabrication, optimization, and automation. AB - Microfluidic systems with monolithic columns have been developed for preconcentration and on-chip labeling of model proteins. Monoliths were prepared in microchannels by photopolymerization, and their properties were optimized by varying the composition and concentration of the monomers to improve flow and extraction. On-chip labeling of proteins was achieved by driving solutions through the monolith by use of voltage then incubating fluorescent dye with protein retained on the monolith. Subsequently, the labeled proteins were eluted, by applying voltages to reservoirs on the microdevice, and then detected, by monitoring laser-induced fluorescence. Monoliths prepared from octyl methacrylate combine the best protein retention with the possibility of separate elution of unattached fluorescent label with 50% acetonitrile. Finally, automated on-chip extraction and fluorescence labeling of a model protein were successfully demonstrated. This method involves facile sample pretreatment, and therefore has potential for production of integrated bioanalysis microchips. PMID- 25012355 TI - Analytical bioluminescence and chemiluminescence. PMID- 25012356 TI - Very fast capillary electrophoresis with electrochemical detection for high throughput analysis using short, vertically aligned capillaries. AB - A method for conducting fast and efficient capillary electrophoresis (CE) based on short separation capillaries in vertical alignment was developed. The strategy enables for high-throughput analysis from small sample vials (low microliter to nanoliter range). The system consists of a lab-made miniaturized autosampling unit and an amperometric end-column detection (AD) cell. The device enables a throughput of up to 200 separations per hour. CE-AD separations of a dye model system in capillaries of only 4 to 7.5 cm length with inner diameters (ID) of 10 or 15 MUm were carried out under conditions of very high electric field strengths (up to 3.0 kV/cm) with high separation efficiency (half peak widths below 0.2 s) in less than 3.5 s migration time. A non-aqueous background electrolyte, consisting of 10 mM ammonium acetate and 1 M acetic acid in acetonitrile, was used. The practical suitability of the system was evaluated by applying it to the determination of dyes in overhead projector pens. PMID- 25012357 TI - Label-free in vitro visualization and characterization of caveolar bulbs during stimulated re-epithelialization. AB - Tip-enhanced Raman scattering (TERS) was paired with real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) to characterize lipid aggregates during stimulated re-epithelialization using an in vitro wound healing model. In this study, lipid fluctuations in the plasma membrane of epidermal keratinocytes were studied at multiple time points post-wounding. TERS measurements for the first time were also combined with sample analysis after initial wounding and 24 h of wound healing. This enabled simultaneous visualization and characterization of caveolar bulb distribution during wound healing stages, providing noninvasive insight into their associated lipid structure and coating protein, caveolin, in the nanometer range. The combination of Raman spectroscopy and scanning probe microscopy in TERS gives access to topographic and chemical structure information in a single experiment. It is the intrinsic specificity and sensitivity of TERS that enable this discrete detection of cell surface components on the nanometer scale. In contrast with competing biochemical methods, the applied technique does not interfere with the cellular composition, enabling lipid structure analysis without digestion or detergents, and displayed great potential for future biological in vivo studies. PMID- 25012358 TI - Rapid and simple electrochemical detection of morphine on graphene-palladium hybrid-modified glassy carbon electrode. AB - A hybrid of reduced graphene oxide-palladium (RGO-Pd) nano- to submicron-scale particles was simultaneously chemically prepared using microwave irradiation. The electrochemical investigation of the resulting hybrid was achieved using cyclic voltammetry and differential pulse voltammetry. RGO-Pd had a higher current response than unmodified RGO toward the oxidation of morphine. Several factors that can affect the electrochemical response were studied, including accumulation time and potential, Pd loading, scan rate, and pH of electrolyte. At the optimum conditions, the concentration of morphine was determined using differential pulse voltammetry in a linear range from 0.34 to 12 MUmol L(-1) and from 14 to 100 MUmol L(-1), with detection limits of 12.95 nmol L(-1) for the first range. The electrode had high sensitivity toward morphine oxidation in the presence of dopamine (DA) and of the interference compounds ascorbic acid (AA) and uric acid (UA). Electrochemical determination of morphine in a spiked urine sample was performed, and a low detection limit was obtained. Validation conditions including reproducibility, sensitivity, and recovery were evaluated successfully in the determination of morphine in diluted human urine. PMID- 25012359 TI - NMR-based metabolomics study of the biochemical relationship between sugarcane callus tissues and their respective nutrient culture media. AB - The culture of sugarcane leaf explant onto culture induction medium triggers the stimulation of cell metabolism into both embryogenic and non-embryogenic callus tissues. Previous analyses demonstrated that embryogenic and non-embryogenic callus tissues have distinct metabolic profiles. This study is the follow-up to understand the biochemical relationship between the nutrient media and callus tissues using one-dimensional (1D (1)H) and two-dimensional (2D (1)H-(13)C) NMR spectroscopy followed by principal component analysis (PCA). 1D (1)H spectral comparisons of fresh unspent media (FM), embryogenic callus media (ECM), non embryogenic callus media (NECM), embryogenic callus (EC), and non-embryogenic callus (NEC), showed different metabolic relationships between callus tissues and media. Based on metabolite fold change analysis, significantly changing sugar compounds such as glucose, fructose, sucrose, and maltose were maintained in large quantities by EC only. Significantly different amino acid compounds such as valine, leucine, alanine, threonine, asparagine, and glutamine and different organic acid derivatives such as lactate, 2-hydroxyisobutyrate, 4-aminobutyrate, malonate, and choline were present in EC, NEC, and NECM, which indicates that EC maintained these nutrients, while NEC either maintained or secreted the metabolites. These media and callus-specific results suggest that EC and NEC utilize and/or secrete media nutrients differently. PMID- 25012360 TI - Introducing enzyme selectivity: a quantitative parameter to describe enzymatic protein hydrolysis. AB - Enzyme selectivity is introduced as a quantitative parameter to describe the rate at which individual cleavage sites in a protein substrate are hydrolyzed relative to other cleavage sites. Whey protein isolate was hydrolyzed by Bacillus licheniformis protease, which is highly specific for Glu and Asp residues. The molar concentration of all peptides (58) from beta-lactoglobulin formed during hydrolysis was determined from the UV214 signal. The quality of identification and quantification of the peptides were described by newly defined parameters: the peptide sequence coverage (on average 94 %) and the molar sequence coverage (on average 75 %). The selectivity was calculated from the rate of hydrolysis of each cleavage site, and showed differences of up to a factor of 5,000. The ability to quantitatively discriminate the enzyme preference towards individual cleavage sites is considered essential to the understanding of enzymatic protein hydrolysis. PMID- 25012361 TI - Hydrodynamic simulations of self-phoretic microswimmers. AB - A mesoscopic hydrodynamic model to simulate synthetic self-propelled Janus particles which is thermophoretically or diffusiophoretically driven is here developed. We first propose a model for a passive colloidal sphere which reproduces the correct rotational dynamics together with strong phoretic effect. This colloid solution model employs a multiparticle collision dynamics description of the solvent, and combines stick boundary conditions with colloid solvent potential interactions. Asymmetric and specific colloidal surface is introduced to produce the properties of self-phoretic Janus particles. A comparative study of Janus and microdimer phoretic swimmers is performed in terms of their swimming velocities and induced flow behavior. Self-phoretic microdimers display long range hydrodynamic interactions with a decay of 1/r(2), which is similar to the decay of gradient fields generated by self-phoretic particle, and can be characterized as pullers or pushers. In contrast, Janus particles are characterized by short range hydrodynamic interactions with a decay of 1/r(3) and behave as neutral swimmers. PMID- 25012362 TI - Deletion of Cd151 reduces mammary tumorigenesis in the MMTV/PyMT mouse model. AB - BACKGROUND: Tetraspanins are transmembrane proteins that serve as scaffolds for multiprotein complexes containing, for example, integrins, growth factor receptors and matrix metalloproteases, and modify their functions in cell adhesion, migration and transmembrane signaling. CD151 is part of the tetraspanin family and it forms tight complexes with beta1 and beta4 integrins, both of which have been shown to be required for tumorigenesis and/or metastasis in transgenic mouse models of breast cancer. High levels of the tetraspanin CD151 have been linked to poor patient outcome in several human cancers including breast cancer. In addition, CD151 has been implicated as a promoter of tumor angiogenesis and metastasis in various model systems. METHODS: Here we investigated the effect of Cd151 deletion on mammary tumorigenesis by crossing Cd151-deficient mice with a spontaneously metastasising transgenic model of breast cancer induced by the polyoma middle T antigen (PyMT) driven by the murine mammary tumor virus promoter (MMTV). RESULTS: Cd151 deletion did not affect the normal development and differentiation of the mammary gland. While there was a trend towards delayed tumor onset in Cd151-/- PyMT mice compared to Cd151+/+ PyMT littermate controls, this result was only approaching significance (Log-rank test P-value =0.0536). Interestingly, Cd151 deletion resulted in significantly reduced numbers and size of primary tumors but did not appear to affect the number or size of metastases in the MMTV/PyMT mice. Intriguingly, no differences in the expression of markers of cell proliferation, apoptosis and blood vessel density was observed in the primary tumors. CONCLUSION: The findings from this study provide additional evidence that CD151 acts to enhance tumor formation initiated by a range of oncogenes and strongly support its relevance as a potential therapeutic target to delay breast cancer progression. PMID- 25012364 TI - What is the clinical relevance of in vitro epileptiform activity? AB - In vitro preparations provide an exceptionally rapid, flexible, and accessible approach to long-standing problems in epilepsy research including ictogenesis, epileptogenesis, and drug resistance. Acute slices suffer from a reduction in network connectivity that has traditionally been compensated through the application of acute convulsants. The utility and limitations of this approach have become clear over time and are discussed here. Other approaches such as organotypic slice preparations demonstrate the full spectrum of spontaneous epileptic activity and more closely mimic human responses to anticonvulsants, including the development of drug resistance. Newly developed transgenic and vector expression systems for fluorophores, optogenetics, and orphan receptors are being coupled with advances in imaging and image analysis. These developments have created the capacity to rapidly explore many new avenues of epilepsy research such as vascular, astrocytic and mitochondrial contributions to epileptogenesis. Rigorous study design as well as close collaboration with in vivo laboratories and clinical investigators will accelerate the translation of the exciting discoveries that will be revealed by these new techniques. PMID- 25012363 TI - How can we identify ictal and interictal abnormal activity? AB - The International League Against Epilepsy (ILAE) defined a seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain." This definition has been used since the era of Hughlings Jackson, and does not take into account subsequent advances made in epilepsy and neuroscience research. The clinical diagnosis of a seizure is empirical, based upon constellations of certain signs and symptoms, while simultaneously ruling out a list of potential imitators of seizures. Seizures should be delimited in time, but the borders of ictal (during a seizure), interictal (between seizures) and postictal (after a seizure) often are indistinct. EEG recording is potentially very helpful for confirmation, classification and localization. About a half-dozen common EEG patterns are encountered during seizures. Clinicians rely on researchers to answer such questions as why seizures start, spread and stop, whether seizures involve increased synchrony, the extent to which extra-cortical structures are involved, and how to identify the seizure network and at what points interventions are likely to be helpful. Basic scientists have different challenges in use of the word 'seizure,' such as distinguishing seizures from normal behavior, which would seem easy but can be very difficult because some rodents have EEG activity during normal behavior that resembles spike-wave discharge or bursts of rhythmic spiking. It is also important to define when a seizure begins and stops so that seizures can be quantified accurately for pre-clinical studies. When asking what causes seizures, the transition to a seizure and differentiating the pre-ictal, ictal and post-ictal state is also important because what occurs before a seizure could be causal and may warrant further investigation for that reason. These and other issues are discussed by three epilepsy researchers with clinical and basic science expertise. PMID- 25012366 TI - What is a seizure focus? AB - The seizure focus is the site in the brain from which the seizure originated and is most likely equivalent to the epileptogenic zone, defined as the area of cerebral cortex indispensable for the generation of clinical seizures. The boundaries of this region cannot be defined at present by any diagnostic test. Imaging and EEG recording can define regions of functional deficit during the interictal period, regions that generate interictal spikes, regions responsible for the ictal symptoms, regions from which the seizure is triggered, and regions of structural damage. However, these regions define the epileptogenic zone only when they are spatially concordant. The frequent discrepancies suggest the essential involvement of synaptically connected regions, that is a distributive focus, in the origination of most seizures. Here we review supporting evidence from animal studies and studies of persons undergoing surgical resection for medically-intractable epilepsy. We conclude that very few of the common seizures are truly local, but rather depend on nodal interactions that permit spontaneous network excitability and behavioral expression. Recognition of the distributive focus underlying most seizures has motivated many surgical programs to upgrade their intracranial studies to capture activity in as much of the network as possible. PMID- 25012365 TI - What is the importance of abnormal "background" activity in seizure generation? AB - Investigations of interictal epileptiform spikes and seizures have played a central role in the study of epilepsy. The background EEG activity, however, has received less attention. In this chapter we discuss the characteristic features of the background activity of the brain when individuals are at rest and awake (resting wake) and during sleep. The characteristic rhythms of the background EEG are presented, and the presence of 1/f (beta) behavior of the EEG power spectral density is discussed and its possible origin and functional significance. The interictal EEG findings of focal epilepsy and the impact of interictal epileptiform spikes on cognition are also discussed. PMID- 25012367 TI - What is a seizure network? Long-range network consequences of focal seizures. AB - What defines the spatial and temporal boundaries of seizure activity in brain networks? To fully answer this question a precise and quantitative definition of seizures is needed, which unfortunately remains elusive. Nevertheless, it is possible to ask under conditions where clearly divergent patterns of activity occur in large-scale brain networks whether certain activity patterns are part of the seizure while others are not. Here we examine brain network activity during focal limbic seizures, including diverse regions such as the hippocampus, subcortical arousal systems and fronto-parietal association cortex. Based on work from patients and from animal models we describe a characteristic pattern of intense increases in neuronal firing, cerebral blood flow, cerebral blood volume, blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) signals and cerebral metabolic rate of oxygen consumption in the hippocampus during focal limbic seizures. Similar increases are seen in certain closely linked subcortical structures such as the lateral septal nuclei and anterior hypothalamus, which contain inhibitory neurons. In marked contrast, decreases in all of these parameters are seen in the subcortical arousal systems of the upper brainstem and intralaminar thalamus, as well as in the fronto-parietal association cortex. We propose that the seizure proper can be defined as regions showing intense increases, while those areas showing opposite changes are inhibited by the seizure network and constitute long-range network consequences beyond the seizure itself. Importantly, the fronto-parietal cortex shows sleep like slow wave activity and depressed metabolism under these conditions, associated with impaired consciousness. Understanding which brain networks are directly involved in seizures versus which sustain secondary consequences can provide new insights into the mechanisms of brain dysfunction in epilepsy, hopefully leading to innovative treatment approaches. PMID- 25012368 TI - What is a seizure network? Very fast oscillations at the interface between normal and epileptic brain. AB - Although there is a great multiplicity of normal brain electrical activities, one can observe defined, relatively abrupt, transitions between apparently normal rhythms and clearly abnormal, higher amplitude, "epileptic" signals; transitions occur over tens of ms to many seconds. Transitional activity typically consists of low-amplitude very fast oscillations (VFO). Examination of this VFO provides insight into system parameters that differentiate the "normal" from the "epileptic." Remarkably, VFO in vitro is generated by principal neuron gap junctions, and occurs readily when chemical synapses are suppressed, tissue pH is elevated, and [Ca(2+)]o is low. Because VFO originates in principal cell axons that fire at high frequencies, excitatory synapses may experience short-term plasticity. If the latter takes the form of potentiation of recurrent synapses on principal cells, and depression of these on inhibitory interneurons, then the stage is set for synchronized bursting - if [Ca(2+)]o recovers sufficiently. Our hypothesis can be tested (in part) in patients, once it is possible to measure brain tissue parameters (pH, [Ca(2+)]o) simultaneously with ECoG. PMID- 25012369 TI - Is there such a thing as "generalized" epilepsy? AB - The distinction between generalized and partial epilepsies is probably one, if not the most, pregnant assertions in modern epileptology. Both absence and generalized tonic-clonic seizures, the prototypic seizures found in generalized epilepsies, are classically seen as the result of a rapid, synchronous recruitment of neuronal networks resulting in impairment of consciousness and/or convulsive semiology. The term generalized also refers to electroencephalographic presentation, with bilateral, synchronous activity, such as the classical 3 Hz spike and wave discharges of typical absence epilepsy. However, findings obtained from electrophysiological and functional imaging studies over the last few years, contradict this view, showing a rather focal onset for most of the so-called generalized seizure types. Therefore, we ask here the question whether "generalized epilepsy" does indeed exist. PMID- 25012370 TI - Are there really "epileptogenic" mechanisms or only corruptions of "normal" plasticity? AB - Plasticity in the nervous system, whether for establishing connections and networks during development, repairing networks after injury, or modifying connections based on experience, relies primarily on highly coordinated patterns of neural activity. Rhythmic, synchronized bursting of neuronal ensembles is a fundamental component of the activity-dependent plasticity responsible for the wiring and rewiring of neural circuits in the CNS. It is therefore not surprising that the architecture of the CNS supports the generation of highly synchronized bursts of neuronal activity in non-pathological conditions, even though the activity resembles the ictal and interictal events that are the hallmark symptoms of epilepsy. To prevent such natural epileptiform events from becoming pathological, multiple layers of homeostatic control operate on cellular and network levels. Many data on plastic changes that occur in different brain structures during the processes by which the epileptogenic aggregate is constituted have been accumulated but their role in counteracting or promoting such processes is still controversial. In this chapter we will review experimental and clinical evidence on the role of neural plasticity in the development of epilepsy. We will address questions such as: is epilepsy a progressive disorder? What do we know about mechanism(s) accounting for progression? Have we reliable biomarkers of epilepsy-related plastic processes? Do seizure-associated plastic changes protect against injury and aid in recovery? As a necessary premise we will consider the value of seizure-like activity in the context of normal neural development. PMID- 25012371 TI - When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? AB - The effect of seizures on neuronal death and the role of seizure-induced neuronal death in acquired epileptogenesis have been debated for decades. Isolated brief seizures probably do not kill neurons; however, severe and repetitive seizures (i.e., status epilepticus) certainly do. Because status epilepticus both kills neurons and also leads to chronic epilepsy, neuronal death has been proposed to be an integral part of acquired epileptogenesis. Several studies, particularly in the immature brain, have suggested that neuronal death is not necessary for acquired epileptogenesis; however, the lack of neuronal death is difficult if not impossible to prove, and more recent studies have challenged this concept. Novel mechanisms of cell death, beyond the traditional concepts of necrosis and apoptosis, include autophagy, phagoptosis, necroptosis, and pyroptosis. The traditional proposal for why neuronal death may be necessary for epileptogenesis is based on the recapitulation of development hypothesis, where a loss of synaptic input from the dying neurons is considered a critical signal to induce axonal sprouting and synaptic-circuit reorganization. We propose a second hypothesis - the neuronal death pathway hypothesis, which states that the biochemical pathways causing programmed neurodegeneration, rather than neuronal death per se, are responsible for or contribute to epileptogenesis. The reprogramming of neuronal death pathways - if true - is proposed to derive from necroptosis or pyroptosis. The proposed new hypothesis may inform on why neuronal death seems closely linked to epileptogenesis, but may not always be. PMID- 25012372 TI - How is homeostatic plasticity important in epilepsy? AB - Maintaining physiological variables within narrow operating limits by homeostatic mechanisms is a fundamental property of most if not all living cells and organisms. In recent years, research from many laboratories has shown that the activity of neurons and neural circuits are also homeostatically regulated. Here, we attempt to apply concepts of homeostasis in general, and more specifically synaptic homeostatic plasticity, to the study of epilepsy. We hypothesize that homeostatic mechanisms are actively engaged in the epileptic brain. These processes attempt to re-establish normal neuronal and network activity, but are opposed by the concurrent mechanisms underlying epileptogenesis. In forms of intractable epilepsy, seizures are so frequent and intense that homeostatic mechanisms are unable to restore normal levels of neuronal activity. In such cases, we contend that homeostatic plasticity mechanisms nevertheless remain active. However, their continuing attempts to reset neuronal activity become maladaptive and results in dyshomeostasis with neurobehavioral consequences. Using the developing hippocampus as a model system, we briefly review experimental results and present a series of arguments to propose that the cognitive neurobehavioral comorbidities of childhood epilepsy result, at least in part, from unchecked homeostatic mechanisms. PMID- 25012375 TI - Does mossy fiber sprouting give rise to the epileptic state? AB - Many patients with temporal lobe epilepsy display structural changes in the seizure initiating zone, which includes the hippocampus. Structural changes in the hippocampus include granule cell axon (mossy fiber) sprouting. The role of mossy fiber sprouting in epileptogenesis is controversial. A popular view of temporal lobe epileptogenesis contends that precipitating brain insults trigger transient cascades of molecular and cellular events that permanently enhance excitability of neuronal networks through mechanisms including mossy fiber sprouting. However, recent evidence suggests there is no critical period for mossy fiber sprouting after an epileptogenic brain injury. Instead, findings from stereological electron microscopy and rapamycin-delayed mossy fiber sprouting in rodent models of temporal lobe epilepsy suggest a persistent, homeostatic mechanism exists to maintain a set level of excitatory synaptic input to granule cells. If so, a target level of mossy fiber sprouting might be determined shortly after a brain injury and then remain constant. Despite the static appearance of synaptic reorganization after its development, work by other investigators suggests there might be continual turnover of sprouted mossy fibers in epileptic patients and animal models. If so, there may be opportunities to reverse established mossy fiber sprouting. However, reversal of mossy fiber sprouting is unlikely to be antiepileptogenic, because blocking its development does not reduce seizure frequency in pilocarpine-treated mice. The challenge remains to identify which, if any, of the many other structural changes in the hippocampus are epileptogenic. PMID- 25012374 TI - Do structural changes in GABA neurons give rise to the epileptic state? AB - Identifying the role of GABA neurons in the development of an epileptic state has been particularly difficult in acquired epilepsy, in part because of the multiple changes that occur in such conditions. Although once questioned, there is now considerable evidence for loss of GABA neurons in multiple brain regions in models of acquired epilepsy. This loss can affect several cell types, including both somatostatin- and parvalbumin-expressing interneurons, and the cell type that is most severely affected can vary among brain regions and models. Because of the diversity of GABA neurons in the hippocampus and cerebral cortex, resulting functional deficits are unlikely to be compensated fully by remaining GABA neurons of other subtypes. The fundamental importance of GABA neuron loss in epilepsy is supported by findings in genetic mouse models in which GABA neurons appear to be decreased relatively selectively, and increased seizure susceptibility and spontaneous seizures develop. Alterations in remaining GABA neurons also occur in acquired epilepsy. These include alterations in inputs or receptors that could impair function, as well as morphological reorganization of GABAergic axons and their synaptic connections. Such axonal sprouting could be compensatory if normal circuits are reestablished, but the creation of aberrant circuitry could contribute to an epileptic condition. The functional effects of GABA neuron alterations thus may include not only reductions in GABAergic inhibition but also excessive neuronal synchrony and, potentially, depolarizing GABAergic influences. The combination of GABA neuron loss and alterations in remaining GABA neurons provides likely, though still unproven, substrates for the epileptic state. PMID- 25012373 TI - Is plasticity of GABAergic mechanisms relevant to epileptogenesis? AB - Numerous changes in GABAergic neurons, receptors, and inhibitory mechanisms have been described in temporal lobe epilepsy (TLE), either in humans or in animal models. Nevertheless, there remains a common assumption that epilepsy can be explained by simply an insufficiency of GABAergic inhibition. Alternatively, investigators have suggested that there is hyperinhibition that masks an underlying hyperexcitability. Here we examine the status epilepticus (SE) models of TLE and focus on the dentate gyrus of the hippocampus, where a great deal of data have been collected. The types of GABAergic neurons and GABAA receptors are summarized under normal conditions and after SE. The role of GABA in development and in adult neurogenesis is discussed. We suggest that instead of "too little or too much" GABA there is a complexity of changes after SE that makes the emergence of chronic seizures (epileptogenesis) difficult to understand mechanistically, and difficult to treat. We also suggest that this complexity arises, at least in part, because of the remarkable plasticity of GABAergic neurons and GABAA receptors in response to insult or injury. PMID- 25012377 TI - Are changes in synaptic function that underlie hyperexcitability responsible for seizure activity? AB - The synaptic and intrinsic mechanisms responsible for epileptic seizures and briefer interictal epileptic discharges have been characterized in some detail. This chapter will outline some aspects of this work in the context of focal epilepsies, particularly in the temporal lobe, and will identify some of the major questions that remain. Early work, mainly using the actions of convulsant treatments on brain slices in vitro, revealed synaptic circuitry that could recruit populations of neurons into synchronous epileptic discharges. Subsequent investigations into cellular mechanisms of chronic experimental and clinical foci, again often in vitro, have revealed complex changes in synaptic properties, synaptic connectivity, intrinsic neuronal properties and selective losses of neurons: unraveling their roles in generating seizures, interictal discharges and interictal dysfunctions/comorbidities remains a significant challenge. In vivo recordings have revealed aspects of the pathophysiology of epileptic foci that have practical implications, for instance high-frequency oscillations, and potentially high-frequency hypersynchronous neuronal firing, which have been useful in localizing the epileptogenic zone for surgical resection. PMID- 25012378 TI - Does epilepsy cause a reversion to immature function? AB - Seizures have variable effects on brain. Numerous studies have examined the consequences of seizures, in light of the way that these may alter the susceptibility of the brain to seizures, promote epileptogenesis, or functionally alter brain leading to seizure-related comorbidities. In many -but not all- situations, seizures shift brain function towards a more immature state, promoting the birth of newborn neurons, altering the dendritic structure and neuronal connectivity, or changing neurotransmitter signaling towards more immature patterns. These effects depend upon many factors, including the seizure type, age of seizure occurrence, sex, and brain region studied. Here we discuss some of these findings proposing that these seizure-induced immature features do not simply represent rejuvenation of the brain but rather a de-synchronization of the homeostatic mechanisms that were in place to maintain normal physiology, which may contribute to epileptogenesis or the cognitive comorbidities. PMID- 25012379 TI - Are alterations in transmitter receptor and ion channel expression responsible for epilepsies? AB - Neuronal voltage-gated ion channels and ligand-gated synaptic receptors play a critical role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks in the brain. Changes in expression of voltage-gated ion channels, in particular sodium, hyperpolarization-activated cyclic nucleotide-gated (HCN) and calcium channels, and ligand-gated synaptic receptors, in particular GABA and glutamate receptors, have been reported in many types of both genetic and acquired epilepsies, in animal models and in humans. In this chapter we review these and discuss the potential pathogenic role they may play in the epilepsies. PMID- 25012376 TI - Does brain inflammation mediate pathological outcomes in epilepsy? AB - Inflammation in the central nervous system (CNS) is associated with epilepsy and is characterized by the increased levels of a complex set of soluble molecules and their receptors in epileptogenic foci with profound neuromodulatory effects. These molecules activate receptor-mediated pathways in glia and neurons that contribute to hyperexcitability in neural networks that underlie seizure generation. As a consequence, exciting new opportunities now exist for novel therapies targeting the various components of the immune system and the associated inflammatory mediators, especially the IL-1beta system. This review summarizes recent findings that increased our understanding of the role of inflammation in reducing seizure threshold, contributing to seizure generation, and participating in epileptogenesis. We will discuss preclinical studies supporting the hypothesis that pharmacological inhibition of specific proinflammatory signalings may be useful to treat drug-resistant seizures in human epilepsy, and possibly delay or arrest epileptogenesis. PMID- 25012380 TI - How do we make models that are useful in understanding partial epilepsies? AB - The goals of constructing epilepsy models are (1) to develop approaches to prophylaxis of epileptogenesis following cortical injury; (2) to devise selective treatments for established epilepsies based on underlying pathophysiological mechanisms; and (3) use of a disease (epilepsy) model to explore brain molecular, cellular and circuit properties. Modeling a particular epilepsy syndrome requires detailed knowledge of key clinical phenomenology and results of human experiments that can be addressed in critically designed laboratory protocols. Contributions to understanding mechanisms and treatment of neurological disorders has often come from research not focused on a specific disease-relevant issue. Much of the foundation for current research in epilepsy falls into this category. Too strict a definition of the relevance of an experimental model to progress in preventing or curing epilepsy may, in the long run, slow progress. Inadequate exploration of the experimental target and basic laboratory results in a given model can lead to a failed effort and false negative or positive results. Models should be chosen based on the specific issues to be addressed rather than on convenience of use. Multiple variables including maturational age, species and strain, lesion type, severity and location, latency from injury to experiment and genetic background will affect results. A number of key issues in clinical and basic research in partial epilepsies remain to be addressed including the mechanisms active during the latent period following injury, susceptibility factors that predispose to epileptogenesis, injury - induced adaptive versus maladaptive changes, mechanisms of pharmaco-resistance and strategies to deal with multiple pathophysiological processes occurring in parallel. PMID- 25012381 TI - Aligning animal models with clinical epilepsy: where to begin? AB - Treatment of the epilepsies have benefitted immensely from study of animal models, most notably in the development of diverse anti-seizure medications in current clinical use. However, available drugs provide only symptomatic relief from seizures and are often ineffective. As a result, a critical need remains for developing improved symptomatic or disease-modifying therapies - or ideally, preventive therapies. Animal models will undoubtedly play a central role in such efforts. To ensure success moving forward, a critical question arises, namely "How does one make laboratory models relevant to our clinical understanding and treatment?" Our answer to this question: It all begins with a detailed understanding of the clinical phenotype one seeks to model. To make our case, we point to two examples - Fragile X syndrome and status epilepticus-induced mesial temporal lobe epilepsy - and examine how development of animal models for these distinct syndromes is based upon observations by astute clinicians and systematic study of the disorder. We conclude that the continuous and effective interaction of skilled clinicians and bench scientists is critical to the optimal design and study of animal models to facilitate insight into the nature of human disorders and enhance likelihood of improved therapies. PMID- 25012383 TI - What epilepsy comorbidities are important to model in the laboratory? Clinical perspectives. AB - In recent years, there has been a focus on studies of comorbidity in epilepsy. The concept of epilepsy comorbidity is complex. This is partly because epilepsy is essentially a symptom for which there are many underlying causes, with multiple genetic and environmental influences. These causal conditions themselves carry comorbidities which vary from condition to condition. The fact that some psychiatric comorbidities are 'bidirectional' complicates this further. These issues reduce the usefulness of any unitary study of 'epilepsy comorbidity'. Epilepsy comorbidities can be divided into direct/indirect and somatic/psychiatric categories. Only some aspects are susceptible to experimental modeling. This chapter briefly reviews the clinical studies of cause, frequency, epidemiology and mortality of comorbidities, and their use as biomarkers for epilepsy. PMID- 25012384 TI - Epilepsy comorbidities: how can animal models help? AB - An epilepsy comorbidity is a condition or disorder that occurs at a frequency greater than chance in a person with epilepsy. Examples of common epilepsy comorbidities are depression, anxiety, and intellectual disability. Epilepsy comorbidities can be quite disabling, sometimes affecting a patient's quality of life to a greater extent than seizures. Animal models offer the opportunity to explore shared pathophysiological mechanisms, therapeutic options, and consequences of both the epilepsy syndrome and a given comorbidity. In this chapter, depression is used as an example of how animal models can inform translational questions about epilepsy comorbidities. PMID- 25012385 TI - What new modeling approaches will help us identify promising drug treatments? AB - Despite the development of numerous novel antiepileptic drugs (AEDs) in recent years, several unmet clinical needs remain, including resistance to AEDs in about 30 % of patients with epilepsy, adverse effects of AEDs that can reduce quality of life, and the lack of treatments that can prevent development of epilepsy in patients at risk. Animal models of seizures and epilepsy have been instrumental in the discovery and preclinical development of novel AEDs, but obviously the previously used models have failed to identify drugs that address unmet medical needs. Thus, we urgently need fresh ideas for improving preclinical AED development. In this review, a number of promising models will be described, including the use of simple vertebrates such as zebrafish (Danio rerio), large animal models such as the dog and newly characterized rodent models of pharmacoresistant epilepsy. While these strategies, like any animal model approach also have their limitations, they offer hope that new more effective AEDs will be identified in the coming years. PMID- 25012382 TI - What non-neuronal mechanisms should be studied to understand epileptic seizures? AB - While seizures ultimately result from aberrant firing of neuronal networks, several laboratories have embraced a non-neurocentric view of epilepsy to show that other cells in the brain also bear an etiologic impact in epilepsy. Astrocytes and brain endothelial cells are examples of controllers of neuronal homeostasis; failure of proper function of either cell type has been shown to have profound consequences on neurophysiology. Recently, an even more holistic view of the cellular and molecular mechanisms of epilepsy has emerged to include white blood cells, immunological synapses, the extracellular matrix and the neurovascular unit. This review will briefly summarize these findings and propose mechanisms and targets for future research efforts on non-neuronal features of neurological disorders including epilepsy. PMID- 25012386 TI - What are the arguments for and against rational therapy for epilepsy? AB - Although more than a dozen new anti-seizure drugs (ASDs) have entered the market since 1993, a substantial proportion of patients (~30 %) remain refractory to current treatments. Thus, a concerted effort to identify and develop new therapies that will help these patients continues. Until this effort succeeds, it is reasonable to re-assess the use of currently available therapies and to consider how these therapies might be utilized in a more efficacious manner. This applies to the selection of monotherapies in newly-diagnosed epilepsy, but perhaps, more importantly, to the choice of combination treatments in otherwise drug-refractory epilepsy. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action (MoAs) that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the MoA subclasses amongst available ASDs and an appreciation of the empirical evidence that supports the use of specific combinations. The majority of ASDs can be loosely categorized into those that target neurotransmission and network hyperexcitability, modulate intrinsic neuronal properties through ion channels, or possess broad-spectrum efficacy as a result of multiple mechanisms. Within each of these categories, there are discrete pharmacological profiles that differentiate individual ASDs. This chapter will consider how knowledge of MoA can help guide therapy in a rational manner, both in the selection of monotherapies for specific seizure types and syndromes, but also in the choice of drug combinations for patients whose epilepsy is not optimally controlled with a single ASD. PMID- 25012387 TI - How can advances in epilepsy genetics lead to better treatments and cures? AB - Advances in genetic analysis are fundamentally changing our understanding of the causes of epilepsy, and promise to add more precision to diagnosis and management of the clinical disorder. Single gene mutations that appear among more complex patterns of genomic variation can now be readily defined. As each mutation is identified, its predicted effects can now be validated in neurons derived from the patient's own stem cells, allowing a more precise understanding of the cellular defect. Parallel breakthroughs in genetic engineering now allow the creation of developmental experimental models bearing mutations identical to the human disorder. These models enable investigators to carry out detailed exploration of the downstream effects of the defective gene on the developing nervous system, and a framework for pursuing new therapeutic target discovery. Once these genetic strategies are combined with interdisciplinary technological advances in bioinformatics, imaging, and drug development, the promise of delivering clinical cures for some genetic epilepsies will be within our reach. PMID- 25012389 TI - Measurement invariance of the experiences in close relationships questionnaire across different populations. AB - The measurement invariance of the Experiences in Close Relationships (ECR) questionnaire was investigated across four samples of non-clinical subjects (N = 222), dermatological patients (N = 458), psychiatric inpatients (N = 156), and patients with drug-resistant epilepsy (N = 101). The results provided evidence of configural, metric, and scalar invariance across groups. Overall, our findings provide further support to the reliability and validity of the ECR. PMID- 25012388 TI - How might novel technologies such as optogenetics lead to better treatments in epilepsy? AB - Recent technological advances open exciting avenues for improving the understanding of mechanisms in a broad range of epilepsies. This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures. Optogenetics is a technique which, through cell-type selective expression of light-sensitive proteins called opsins, allows temporally precise control via light delivery of specific populations of neurons. Therefore, it is now possible not only to record interictal and ictal neuronal activity, but also to test causality and identify potential new therapeutic approaches. We first discuss the benefits and caveats to using optogenetic approaches and recent advances in optogenetics related tools. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research. PMID- 25012390 TI - Baicalein, an active component of Scutellaria baicalensis Georgi, prevents lysophosphatidylcholine-induced cardiac injury by reducing reactive oxygen species production, calcium overload and apoptosis via MAPK pathways. AB - BACKGROUND: Lysophosphatidylcholine (lysoPC), a metabolite from membrane phospholipids, accumulates in the ischemic myocardium and plays an important role in the development of myocardial dysfunction ventricular arrhythmia. In this study, we investigated if baicalein, a major component of Huang Qui, can protect against lysoPC-induced cytotoxicity in rat H9c2 embryonic cardiomyocytes. METHODS: Cell viability was detected by the MTT assay; ROS levels were assessed using DCFH-DA; and intracellular free calcium concentrations were assayed by spectrofluorophotometer. Cell apoptosis and necrosis were evaluated by the flow cytometry assay and Hoechst staining. Mitogen-Activated Protein Kinases (MAPKs), which included the ERK, JNK, and p38, and the apoptotic mechanisms including Bcl 2/Bax, caspase-3, caspase-9 and cytochrome c pathways were examined by Western blot analysis. The activation of MAPKs was examined by enzyme-linked immunosorbent assay. RESULTS: We found that lysoPC induced death and apoptosis of H9c2 cells in a dose-dependent manner. Baicalein could prevent lysoPC-induced cell death, production of reactive oxygen species (ROS), and increase of intracellular calcium concentration in H9c2 cardiomyoctes. In addition, baicalein also inhibited lysoPC-induced apoptosis, with associated decreased pro-apoptotic Bax protein, increased anti-apoptotic Bcl-2 protein, resulting in an increase in the Bcl-2/Bax ratio. Finally, baicalein attenuated lysoPC-induced the expression of cytochrome c, casapase-3, casapase-9, and the phosphorylations of ERK1/2, JNK, and p38. LysoPC-induced ERK1/2, JNK, and p38 activations were inhibited by baicalein. CONCLUSIONS: Baicalein protects cardiomyocytes from lysoPC-induced apoptosis by reducing ROS production, inhibition of calcium overload, and deactivations of MAPK signaling pathways. PMID- 25012391 TI - Nonpharmacological therapies for neurologic devices. PMID- 25012392 TI - Brain injury visible on early MRI after subarachnoid hemorrhage might predict neurological impairment and functional outcome. AB - BACKGROUND: In subarachnoid hemorrhage (SAH), brain injury visible within 48 h of onset may impact on admission neurological disability and 3-month functional outcome. With volumetric MRI, we measured the volume of brain injury visible after SAH, and assessed the association with admission clinical grade and 3-month functional outcome. METHODS: Retrospective cohort study conducted in the Neurocritical Care Division, Columbia University Medical Center, New York, USA. On brain MRI acquired within 48 h of SAH-onset and before aneurysm-securing (n = 27), two blinded readers measured DWI and FLAIR-lesion volumes using semi automated, computer segmentation software. RESULTS: Compared to post resuscitation Hunt-Hess grade 1-3 (70 %), high-grade patients (30 %) had higher lesion volumes on DWI (34 ml [IQR: 0-64] vs. 2 ml [IQR: 0.5-7], P = 0.02) and on FLAIR (81 ml [IQR: 24-127] vs. 3 ml [IQR: 0-27], P = 0.02). On DWI, each 10 ml increase in lesion volume was associated with a 101 %-increase in the odds of presenting with 1 grade more in the Hunt-Hess scale (aOR 2.01, 95 % CI 1.10-3.68, P = 0.02), but was not significantly associated with 3-month outcome. On FLAIR, each 10 ml increase in lesion volume was associated with 34 % higher odds of a 1 point increase on the Hunt-Hess scale (aOR 1.34, 95 % CI 1.06-1.68, P = 0.01) and 139 % higher odds of a 1-point increase on the 3-month mRS (aOR 2.39, 95 % CI 1.13-5.07, P = 0.02). CONCLUSION: The volume of brain injury visible on DWI and FLAIR within 48 h after SAH is proportional to neurological impairment on admission. Moreover, FLAIR-imaging implicates chronic brain injury-predating SAH as potentially relevant cause of poor functional outcome. PMID- 25012393 TI - Continuous microcarrier-based cell culture in a benchtop microfluidic bioreactor. AB - Microfluidic bioreactors are expected to impact cell therapy and biopharmaceutical production due to their ability to control cellular microenvironments. This work presents a novel approach for continuous cell culture in a microfluidic system. Microcarriers (i.e., microbeads) are used as growth support for anchorage-dependent mammalian cells. This approach eases the manipulation of cells within the system and enables harmless extraction of cells. Moreover, the microbioreactor uses a perfusion function based on the biocompatible integration of a porous membrane to continuously feed the cells. The perfusion rate is optimized through simulations to provide a stable biochemical environment. Thermal management is also addressed to ensure a homogeneous bioreactor temperature. Eventually, incubator-free cell cultures of Drosophila S2 and PC3 cells are achieved over the course of a week using this bioreactor. In future applications, a more efficient alternative to harvesting cells from microcarriers is also anticipated as suggested by our positive results from the microcarrier digestion experiments. PMID- 25012395 TI - Hydrothermal ablation complicated by acute peritonitis due to thermal injury to the intestines. PMID- 25012394 TI - Identification and characterization of long intergenic non-coding RNAs related to mouse liver development. AB - Long non-coding RNAs (lncRNAs) have been studied extensively over the last few years. Liver is an important organ that plays a crucial role in glucose metabolism and homeostasis; however, there are few reports of the identification and functional characterization of lncRNAs with important roles in liver development. Therefore, it is necessary to systematically identify lncRNAs that are involved in liver development. In this paper, we assembled the transcriptome using published RNA-seq data across three mouse liver developmental stages and identified 4,882 putative long intergenic non-coding RNAs (lincRNAs) expressed in at least one of the investigated stages. Combining these with Ensembl lincRNAs, we established a reference catalog of 6,602 transcribed lincRNAs in the mouse liver. We then analyzed all the lincRNAs in this reference catalog systematically and revealed that liver lincRNAs carry different genomic signatures from protein coding genes, while the putative lincRNAs are generally comparable with known Ensembl lincRNAs. In addition, putative lincRNAs are functionally associated with essential biological processes, including RNA splicing, protein localization and fatty acid metabolic process, implying that they may play an important role in regulating liver development. The validation of selected lincRNAs that are specifically expressed in developing liver tissues further suggested the effectiveness of our approach. Our study shows that lincRNAs that are differentially expressed during three liver developmental stages could have important regulatory roles in liver development. The identified putative lincRNAs are a valuable resource for further functional studies. PMID- 25012396 TI - Management and outcome of 25 heterotopic pregnancies in Zhejiang, China. AB - OBJECTIVE: To characterize general attributes of women with heterotopic pregnancy (HP) in order to establish an optimal management regimen. STUDY DESIGN: A retrospective analysis was conducted on 25 HPs recorded at the Women's Hospital of Zhejiang University between 2007 and 2011. Data on patients' symptoms, risk factors, diagnostic features, treatment and outcome were collected and analysed. RESULTS: All patients had conceived via assisted reproductive technology (ART), 72% had a history of pelvic inflammatory disease and 68% of patients were symptomatic. Fifty-six percent of patients were diagnosed with HP via routine transvaginal ultrasound examination at approximately 6-7 weeks of gestation. Eighty percent of patients underwent surgical treatment (35% laparoscopic salpingectomy, 65% laparotomy), and 20% of patients underwent medical treatment with local injection of methotrexate (MTX) or MTX in combination with potassium chloride (KCl) into ectopic sites such as the cervix or interstitium. Eighty eight percent of patients delivered live infants without congenital anomalies, and three patients (all of whom underwent surgical treatment) miscarried. CONCLUSIONS: Routine transvaginal ultrasound examination at approximately 6-7 weeks of gestation could facilitate the diagnosis of HP, although repeat ultrasound is necessary to avoid misdiagnosis. Prompt diagnosis and correct treatment, including local injection of MTX or MTX in combination with KCl into various ectopic sites, led to favourable prognoses. PMID- 25012397 TI - Age, trauma and the critical shoulder angle accurately predict supraspinatus tendon tears. AB - BACKGROUND: The pathogenesis of full-thickness tears of the rotator cuff remains unclear. Apart from age and trauma, distinct scapular morphologies have been found to be associated with rotator cuff disease. The purpose of the present study was to evaluate whether a score formed using these established risk factors was able to predict the presence of a rotator cuff tear reliably. METHODS: We retrospectively assessed a consecutive series of patients with a minimal age of 40 years old, who had true antero-posterior (AP) radiographs of their shoulders, as well as a magnetic resonance (MR) gadolinium-arthrography, between January and December 2011. In all of these patients, the critical shoulder angle (CSA) was determined, and MR images were assessed for the presence of rotator cuff tears. Additionally, the patients' charts were reviewed to obtain details of symptom onset. Based on these factors, the so-called rotator cuff tear (RCT) score was calculated. RESULTS: Patients with full-thickness RCTs were significantly older and had significantly larger CSAs than patients with intact rotator cuffs. Multiple logistic regression, using trauma, age and CSA as independent variables, revealed areas under the curve (AUCs) for trauma of 0.55, for age of 0.65 and for CSA of 0.86. The combination of all three factors was the most powerful predictor, with an AUC of 0.92. CONCLUSION: Age, trauma and the CSA can accurately predict the presence of a posterosuperior RCT. LEVEL OF EVIDENCE: Level IV. Case series with no comparison groups. PMID- 25012398 TI - Acetone utilization by sulfate-reducing bacteria: draft genome sequence of Desulfococcus biacutus and a proteomic survey of acetone-inducible proteins. AB - BACKGROUND: The sulfate-reducing bacterium Desulfococcus biacutus is able to utilize acetone for growth by an inducible degradation pathway that involves a novel activation reaction for acetone with CO as a co-substrate. The mechanism, enzyme(s) and gene(s) involved in this acetone activation reaction are of great interest because they represent a novel and yet undefined type of activation reaction under strictly anoxic conditions. RESULTS: In this study, a draft genome sequence of D. biacutus was established. Sequencing, assembly and annotation resulted in 159 contigs with 5,242,029 base pairs and 4773 predicted genes; 4708 were predicted protein-encoding genes, and 3520 of these had a functional prediction. Proteins and genes were identified that are specifically induced during growth with acetone. A thiamine diphosphate-requiring enzyme appeared to be highly induced during growth with acetone and is probably involved in the activation reaction. Moreover, a coenzyme B12- dependent enzyme and proteins that are involved in redox reactions were also induced during growth with acetone. CONCLUSIONS: We present for the first time the genome of a sulfate reducer that is able to grow with acetone. The genome information of this organism represents an important tool for the elucidation of a novel reaction mechanism that is employed by a sulfate reducer in acetone activation. PMID- 25012399 TI - Cognitive bias modification to prevent depression (COPE): study protocol for a randomised controlled trial. AB - BACKGROUND: Depression is a leading cause of disability worldwide and, although efficacious treatments are available, their efficacy is suboptimal and recurrence of symptoms is common. Effective preventive strategies could reduce disability and the long term social and health complications associated with the disorder, but current options are limited. Cognitive bias modification (CBM) is a novel, simple, and safe intervention that addresses attentional and interpretive biases associated with anxiety, dysphoria, and depression. The primary aim of this trial is to determine if CBM decreases the one-year onset of a major depressive episode among adults with subsyndromal depression. DESIGN AND METHODS: This randomised controlled trial will recruit 532 adults with subsyndromal symptoms of depression living in the Australian community (parallel design, 1:1 allocation ratio). Participants will be free of clinically significant symptoms of depression and of psychotic disorders, sensory and cognitive impairment, and risky alcohol use. The CBM intervention will target attentional and interpretive biases associated with depressive symptoms. The sessions will be delivered via the internet over a period of 52 weeks. The primary outcome of interest is the onset of a major depressive episode according the DSM-IV-TR criteria over a 12-month period. Secondary outcomes of interest include change in the severity of depressive symptoms as measured by the Patient Health Questionnaire (PHQ-9), use of antidepressants or benzodiazepines, and changes in attention and interpretive biases. The assessment of outcomes will take place 3, 6, 9, and 12 months after randomisation and will occur via the internet. DISCUSSION: We propose to test the efficacy of an innovative intervention that is well grounded in theory and for which increasing empirical evidence for an effect on mood is available. The intervention is simple, inexpensive, easy to access, and could be easily rolled out into practice if our findings confirm a role for CBM in the prevention of depression. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12613001334796. Date: 5th December 2013. PMID- 25012400 TI - Patient flow improvement for an ophthalmic specialist outpatient clinic with aid of discrete event simulation and design of experiment. AB - Continuous improvement in process efficiency for specialist outpatient clinic (SOC) systems is increasingly being demanded due to the growth of the patient population in Singapore. In this paper, we propose a discrete event simulation (DES) model to represent the patient and information flow in an ophthalmic SOC system in the Singapore National Eye Centre (SNEC). Different improvement strategies to reduce the turnaround time for patients in the SOC were proposed and evaluated with the aid of the DES model and the Design of Experiment (DOE). Two strategies for better patient appointment scheduling and one strategy for dilation-free examination are estimated to have a significant impact on turnaround time for patients. One of the improvement strategies has been implemented in the actual SOC system in the SNEC with promising improvement reported. PMID- 25012401 TI - The characteristics, implementation and effects of Aboriginal and Torres Strait Islander health promotion tools: a systematic literature search. AB - BACKGROUND: Health promotion by and with Aboriginal and Torres Strait Islander (hereafter Indigenous) Australians is critically important given a wide gap in health parity compared to other Australians. The development and implementation of step-by-step guides, instruments, packages, frameworks or resources has provided a feasible and low-resource strategy for strengthening evidence-informed health promotion practice. Yet there has been little assessment of where and how these tools are implemented or their effectiveness. This paper reviews the characteristics, implementation and effects of Indigenous health promotion tools. METHODS: Indigenous health promotion tools were identified through a systematic literature search including a prior scoping study, eight databases, references of other reviews and the authors' knowledge (n = 1494). Documents in the peer reviewed and grey literature were included if they described or evaluated tools designed, recommended or used for strengthening Indigenous Australian health promotion. Eligible publications were entered into an Excel spreadsheet and documented tools classified according to their characteristics, implementation and effects. Quality was appraised using the Dictionary for Effective Public Health Practice Project (EPHPP) and Critical Appraisal Skills Program (CASP) tools for quantitative and qualitative studies respectively. RESULTS: The review found that Indigenous health promotion tools were widely available. Of 74 publications that met inclusion criteria, sixty (81%) documented tools developed specifically for the Indigenous Australian population. All tools had been developed in reference to evidence; but only 22/74 (30%) publications specified intended or actual implementation, and only 11/74 (15%) publications evaluated impacts of the implemented tools. Impacts included health, environmental, community, organisational and health care improvements. The quality of impact evaluations was strong for only five (7%) studies. CONCLUSIONS: The small number and generally moderate quality of implementation and evaluation studies means that little is known about how tools work to strengthen Indigenous health promotion practice. The findings suggest that rather than continuing to invest in tool development, practitioners, policy makers and researchers could evaluate the implementation and effects of existing tools and publish the results. There is a need for long-term investment in research to review the current use of health promotion tools and the factors that are likely to enhance their implementation. PMID- 25012402 TI - Embryonal tumor with multilayered rosettes (ETMR): signed, sealed, delivered .... PMID- 25012403 TI - Posttraumatic stress disorder and suicide in 5.9 million individuals receiving care in the veterans health administration health system. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) confers risk for suicidal ideation and suicide attempts but a link with suicide is not yet established. Prior analyses of users of the Veterans health administration (VHA) Health System suggest that other mental disorders strongly influence the association between PTSD and suicide in this population. We examined the association between PTSD and suicide in VHA users, with a focus on the influence of other mental disorders. METHODS: Data were based on linkage of VA National Patient Care Database records and the Centers for Disease Control and Prevention's National Death Index, with data from fiscal year 2007-2008. Analyses were based on multivariate logistic regression and structural equation models. RESULTS: Among users of VHA services studied (N=5,913,648), 0.6% (N=3620) died by suicide, including 423 who had had been diagnosed with PTSD. In unadjusted analysis, PTSD was associated with increased risk for suicide, with odds ratio, OR (95% confidence interval, 95% CI)=1.34 (1.21, 1.48). Similar results were obtained after adjustment for demographic variables and veteran characteristics. After adjustment for multiple other mental disorder diagnoses, PTSD was associated with decreased risk for suicide, OR (95% CI)=0.77 (0.69, 0.86). Major depressive disorder (MDD) had the largest influence on the association between PTSD and suicide. LIMITATIONS: The analyses were cross-sectional. VHA users were studied, with unclear relevance to other populations. CONCLUSION: The findings suggest the importance of identifying and treating comorbid MDD and other mental disorders in VHA users diagnosed with PTSD in suicide prevention efforts. PMID- 25012404 TI - Fluoxetine-induced pancreatic beta cell dysfunction: New insight into the benefits of folic acid in the treatment of depression. AB - BACKGROUND: Major depressive disorder is a common psychiatric illness with reported prevalence rates of 12-16% in persons aged 12 and over. Depression is also associated with a high risk of new onset of type 2 diabetes (T2D). This relationship between depression and diabetes may be related to depression itself and/or drugs prescribed. Importantly, the use of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressants, increases the risk of developing T2D. However, the mechanism(s) underlying this association remains elusive. METHODS: Here we examine the effects of the SSRI fluoxetine (Prozac(r)) on beta cell function utilizing INS-1E cells, a rat beta cell line, to elucidate the underlying molecular mechanisms. RESULTS: Fluoxetine treatment significantly reduced glucose stimulated insulin secretion (GSIS). This decreased beta cell function was concomitant with an increased production of reactive oxygen species and oxidative damage which may contribute to decreased mitochondrial electron transport chain enzyme (ETC) activity. Importantly the fluoxetine-induced deficits in beta cell function were prevented by the addition of the antioxidant folic acid. LIMITATIONS: These studies were conducted in vitro; the in vivo relevance remains to be determined. CONCLUSIONS: These findings suggest that use of SSRI antidepressants may increase the risk of new onset T2D by causing oxidative stress in pancreatic beta cells. However, folic acid supplementation in patients taking SSRIs may reduce the risk of new onset diabetes via protection of normal beta cell function. PMID- 25012405 TI - Cognitive functions in euthymic Egyptian patients with bipolar disorder: are they different from healthy controls? AB - BACKGROUND: There is marked interest to research neurocognitive functions in bipolar disorder during euthymia. Consequently we aimed to study cognitive functions in euthymic bipolar patients and factors affecting them. METHODS: It is a cross sectional case-control study of 60 euthymic bipolar patients and 30 matched healthy controls. They were subjected to: Structured Clinical Interview for DSM-IV disorders, (SCID-I) to ascertain clinical diagnosis, Young Mania Rating Scale (YMRS), Hamilton Rating Scale for Depression (HRSD) to validate euthymia. Wechsler Adult Intelligence Scale (WAIS) for general intellectual abilities, Wechsler Memory Scale-Revised (WMS-R) for memory, Wisconsin Card Sorting Test (WCST) for executive functions, Continuous Performance Test (CPT) for attention and impulsivity, and an information sheet gathering patient data. RESULTS: Bipolar patients had statistically significant lower mean IQ scores in all WAIS subscales (p=0.000), significantly lower memory abilities especially digit span and visual memory, higher impulsivity and inattention (p=0.000) but no significant difference in response time by CPT. They displayed significantly lower executive performance on WCST. Patients' years of education correlated positively with IQ. Hospital admission, number, type of episodes and total number of episodes affected memory functions. Hospital admission and number of hypomanic episodes correlated with attention and impulsivity. Previous hospitalization correlated with executive functions. CONCLUSIONS: Euthymic bipolar patients exhibit cognitive deficits, which correlated with clinical variables as number, type of episodes and previous hospitalization, this knowledge could help minimize cognitive impairments for future patients. LIMITATIONS: The small sample size, cross sectional design and lack of premorbid cognitive assessment limit generalization of findings. PMID- 25012406 TI - Comorbidity between depression and asthma via immune-inflammatory pathways: a meta-analysis. AB - BACKGROUND: Depression is often present in patients with asthma and vice versa. In this review, we aimed to summarize reports on the comorbidity of depression and asthma, and to seek evidence that the biological mechanisms of allergy may have an important role linking asthma and depression. METHOD: To explore the relationship and pathway underpinning this comorbidity, we reviewed medical articles and undertook a meta-analysis of epidemiological studies on (i) incidence of asthma in patients with depression; (ii) morbidity of depression in patients with asthma; (iii) concentration of cytokines in depressed subjects. RESULTS: High level of comorbidity of asthma and depression was consistently demonstrated in 10 studies of patients with asthma and four studies of patients with depression. In search of biological connection of the two illnesses, thirty eight studies were included for Meta-analyses examining differences in allergy related cytokines between patients with depression and non-depressive subjects. In people with depression, concentration of monocytes related cytokines such as IL-1 (1.56ng/mL, 95% CI: 0.00-3.12, p=0.05) was significantly higher than that in non-depressive control subjects. At the same time, some other inflammatory factors including IL-4 (5.77pg/mL, 95% CI: 2.34-9.21, p=0.00010), IL-6 (1.44ng/mL, 95% CI: 1.05-1.82, p<0.00001) and TNF-alpha(3.01ng/mL, 95% CI: 1.76 4.26, p<0.00001) were extremely significantly higher in depressed people compared with the controls. There was no significant differences of the T cell related cytokine levels, IFN-gamma (-0.16ng/mL, 95% CI: -0.85-7.73, p=0.97), accompanied with IL-10 (0.67ng/mL, 95% CI: -0.84-2.18, p=0.38) between depressive and non depressive groups. CONCLUSIONS: The varying levels of certain cytokines play an important role in arousing and remitting asthma and depression. That suggests inflammatory response could be a common pathway adjusting both depression and asthma. PMID- 25012407 TI - Effects of clutter on information processing deficits in individuals with hoarding disorder. AB - BACKGROUND: Current cognitive behavioral models of hoarding view hoarding as a multifaceted problem stemming from various information processing deficits. However, there is also reason to suspect that the consequences of hoarding may in turn impact or modulate deficits in information processing. The current study sought to expand upon the existing literature by manipulating clutter to examine whether the presence of a cluttered environment affects information processing. METHODS: Participants included 34 individuals with hoarding disorder. Participants were randomized into a clutter or non-clutter condition and asked to complete various neuropsychological tasks of memory and attention. RESULTS: Results revealed that hoarding severity was associated with difficulties in sustained attention. However, individuals in the clutter condition relative to the non-clutter condition did not experience greater deficits in information processing. LIMITATIONS: Limitations include the cross-sectional design and small sample size. CONCLUSIONS: The current findings add considerably to a growing body of literature on the relationships between information processing deficits and hoarding behaviors. Research of this type is integral to understanding the etiology and maintenance of hoarding. PMID- 25012409 TI - Teasing apart low mindfulness: differentiating deficits in mindfulness and in psychological flexibility in predicting symptoms of generalized anxiety disorder and depression. AB - BACKGROUND: This research investigated the differential ability of three components of low mindfulness to uniquely predict symptoms of generalized anxiety disorder (GAD) and depression, while controlling for psychological inflexibility, a construct conceptually related to low mindfulness. Also examined was the meditational role of several mindfulness facets in the relationship between psychological inflexibility and symptoms of each disorder. METHODS: Using a clinical sample (n=153) containing mostly patients with GAD or depression diagnoses, we conducted hierarchical multiple regression analyses and mediation analyses to determine unique relationships. RESULTS: Whereas deficits in adopting a non-reactive perspective exhibited incremental validity beyond psychological inflexibility in predicting symptoms of GAD, deficits in acting with awareness did so in predicting symptoms of depression. Results of mediation analyses corroborated this pattern, as the relationships psychological inflexibility exhibited with symptoms of GAD and of depression were mediated by non-reactivity and acting with awareness, respectively. LIMITATIONS: The cross-sectional design of this study precludes causal interpretations of the mediation models. CONCLUSION: Findings corroborate the following conclusions: (i) the lack of present oriented awareness experienced by individuals with symptoms of depression is not completely accounted for by psychological inflexibility nor by symptoms of GAD; (ii) the reactive approach to automatic thoughts adopted by those with symptoms of GAD is not completely accounted for by psychological inflexibility nor by symptoms of depression. These conclusions suggest that it would be profitable for mindfulness-based therapies to concentrate on these specific mindfulness deficits to ameliorate the severity of GAD and depression. PMID- 25012408 TI - Persistence in the long term of the effects of a collaborative care programme for depression in primary care. AB - BACKGROUND: A collaborative care programme for depression in primary care has proven clinical effectiveness over a 12-months period. Because depression tends to relapse and to chronic course, our aim was to determine whether the effectiveness observed in the first year persists during 3 years of monitoring. METHODS: Randomised controlled trial with twenty primary care centres were allocated to intervention group or usual care group. The intervention consisted of a collaborative care programme with clinical, educational and organisational procedures. Outcomes were monitored by a blinded interviewer at baseline, 12 and 36 months. Clinical outcomes were response to treatment and remission rates, depression severity and health-related quality of life. TRIAL REGISTRATION: ISRCTN16384353. RESULTS: A total of 338 adult patients with major depression (DSM IV) were assessed at baseline. At 36 months, 137 patients in the intervention group and 97 in the control group were assessed (attrition 31%). The severity of depression (mean Patient Health Questionnaire-9 score) was 0.95 points lower in the intervention group [6.31 versus 7.25; p=0.324]. The treatment response rate was 5.6% higher in the intervention group than in the control group [66.4% versus 60.8%; p=0.379] and the remission rate was 9.2% higher [57.7% versus 48.5%; p=0.164]. No difference reached statistical significance. LIMITATIONS: The number of patients lost (31%) before follow-up may have introduced a bias. CONCLUSIONS: Clinical benefits shown in the first year were not maintained beyond: at 36 months the differences between the control group and the intervention group reduced in all the analysed variables. PMID- 25012410 TI - Efficacy and tolerability of antidepressants for sub-threshold depression and for mild major depressive disorder. AB - BACKGROUND: It is commonly assumed that robust evidence exists for the lack of efficacy of antidepressants at the milder end of the depression severity spectrum. In light of specific limitations of existing reviews, we assess if antidepressants are efficacious and tolerable for sub-threshold or mild major depressive disorder (MDD). METHOD: Systematic review and meta-analysis of randomised controlled trials of adults with sub-threshold depression or mild MDD (initial baseline symptom severity of HRSD<=20) comparing an antidepressant with placebo or treatment as usual (TAU) however defined. A pre-specified protocol was published (Prospero reference: CRD42013004505). RESULTS: 8 trials were included: 5 trials (453 participants) of sub-threshold depression and 3 trials (502 participants) of mild MDD. Trials of sub-threshold depression exhibited low risk of bias whereas those of mild MDD exhibited high risk. Two trials of sub threshold depression were pooled (n=102) to assess efficacy and favoured antidepressants over placebo statistically but the difference was small and unlikely to be clinically meaningful: mean difference -1.39 (-2.41, -0.36). Due to heterogeneity, no trials of mild MDD could be pooled for efficacy. There was no difference between antidepressant treatment and placebo for drop out due to adverse events. The maximum proportion in those receiving antidepressants dropping out due to adverse events was 17%, with indication of a dose effect. LIMITATIONS: Not all data from identified trials could be included in the meta analyses due to a lack of availability of relevant data. CONCLUSION: There is insufficient evidence to support or contest the efficacy of antidepressant medication for sub-threshold depression or mild MDD. More trials, with adequate follow up, are required to address this question. PMID- 25012411 TI - Somatic and cognitive symptoms as indicators of potential endophenotypes in bipolar spectrum disorders: an exploratory and proof-of-concept study comparing bipolar II disorder with recurrent brief depression and healthy controls. AB - BACKGROUND: We examined whether somatic symptoms reported by patients with bipolar spectrum disorder (BSD), in this study defined as bipolar II (BD-2) or recurrent brief depression with (RBD-H) or without (RBD-O) a history of hypomanic symptoms might point to the possible underlying disease markers (endophenotypes). We hypothesized that somatic symptoms that are possible indirect indicators of endophenotypes should be more prevalent among patients than among healthy controls; should not correlate with neuroticism; should not correlate with the severity of current mental status (e.g., anxiety, depression); and should not correlate with the use of psychotropic drugs including antiepileptics or be explained by co-morbid medical diseases. METHODS: Sixty-one patients (BD-2: n=21; RBD-H: n=19; RBD-O: n=21) were compared with 21 healthy controls. Assessments included a 123-item somatic symptom checklist; assessments for neuroticism, anxiety and depression. Candidate somatic symptoms were selected using a 4-step inclusion/exclusion procedure. RESULTS: Seven symptoms survived in all three groups: general (fatigue, feeling exhausted); sensory (leaden sensation in legs, pain in the body, impaired sense of smell); cognitive (loss of memory) and autonomic (excessive perspiration). In addition 15 symptoms survived in one or two groups (examples: impaired hearing, hypersensitivity to sound, inability to find words). LIMITATIONS: Possible selection bias and small sample size precludes firm conclusions with regards to specific symptoms. CONCLUSION: Our approach identified symptoms for which an association with BSDs has been suggested previously, as well as symptoms not commonly associated with BSDs. The findings support the feasibility and validity of using assessment of somatic symptoms as an approach to identify potential endophenotypes in BSDs. PMID- 25012412 TI - Profile of depressive symptoms in women in the perinatal and outside the perinatal period: similar or not? AB - PURPOSES: To analyze which Beck Depression Inventory-II (BDI-II) and Postpartum Depression Screening Scores (PDSS) total and dimensional scores, as well as symptomatic answers proportions significantly differ between women in the perinatal period (pregnant/postpartum) without major depression, with major depression and women outside the perinatal period. METHODS: 572 pregnant women in the third trimester completed Beck Depression Inventory-II and Postpartum Depression Screening Scale and were assessed with the Diagnostic Interview for Genetic Studies. 417 of these were also assessed (with the same instruments) at three months postpartum. Ninety non-pregnant women or that did not have a child in the last year (mean age=29.42+/-7.159 years) also filled in the questionnaires. RESULTS: Non-depressed pregnant women showed lower scores than depressed pregnant women and higher scores than women outside the perinatal period in the BDI-II total score and in its Somatic-Anxiety dimension. Non depressed postpartum women showed significantly higher scores than women outside the perinatal period only at Sleep/Eating Disturbances. Compared to women outside the perinatal period, pregnant women without depression presented higher scores only in the somatic items. Women with vs. without depression in the postpartum period did not significantly differ and both presented higher scores than women outside the perinatal period in the proportions of loss of energy and sleep changes. LIMITATIONS: Women outside the perinatal period were not diagnosed for the presence of a depressive disorder, but their BDI-II mean score was similar to the figures reported worldwide regarding women in childbearing age. CONCLUSION: In the perinatal period, most particularly at pregnancy, women experience significant somatic changes even if not clinically depressed. Cognitive-affective symptoms are more useful when assessing the presence of perinatal depression. PMID- 25012413 TI - Is the Psychotic Depression Assessment Scale a useful diagnostic tool? The CRESCEND study. AB - BACKGROUND: The Psychotic Depression Assessment Scale (PDAS) has been validated as a method of assessing the severity and treatment outcomes of psychotic depression (PD). We aimed to compare the results of the PDAS in PD and non psychotic depression (non-PD) patients and validate the PDAS as a diagnostic tool for PD. METHODS: We included 53 patients with PD and 441 with non-PD who participated in the Clinical Research Center for Depression study in South Korea. In addition to the PDAS, psychometric tools including the HAMD17, HAMA, BPRS, CGI S, SOFAS, SSI-Beck, WHOQOL-BREF, AUDIT, and FTND were used to assess, respectively, depression, anxiety, overall symptoms, global severity, social functioning, suicidal ideation, quality of life, alcohol use, and nicotine use. RESULTS: After adjusting for age and total HAMD17 score, PD patients had higher scores for depressive mood, hallucinations, unusual thought content, suspiciousness, blunted affect, and emotional withdrawal on the PDAS and higher total scores on the SSI-Beck than non-PD patients. Binary logistic regression identified hallucinatory behavior and emotional withdrawal as predictors of PD. Receiver operating characteristic analysis showed that emotional withdrawal could be used to differentiate psychotic from non-psychotic depression. LIMITATIONS: The inter-rater reliability for psychometric assessments was not evaluated. CONCLUSIONS: In addition to assessing the severity and treatment outcomes of PD, PDAS can help in the diagnosis of PD. PMID- 25012414 TI - The Brief Assessment of Cognition In Affective Disorders (BAC-A):performance of patients with bipolar depression and healthy controls. AB - BACKGROUND: Cognitive deficits in bipolar disorder are significant enough to impact everyday functioning. A key question for treatments aimed at cognition is which cognitive domains are most affected by bipolar disorder and which cognitive tests have the best psychometric characteristics for this population. METHOD: 432 patients assessed at study entry in a treatment study of bipolar depression were assessed with a version of a new cognitive measure - the Brief Assessment of Cognition in Affective Disorder (BAC-A), which assesses traditional cognitive constructs with six subtests measuring memory, processing speed, working memory, and reasoning and problem solving, and a new measure of affective processing. From the cohort of 432 patients, 309 were selected based upon their demographic similarities to a previously collected healthy control sample of 309 subjects. Patients and controls completed the traditional cognitive tests and the Affective Processing Test. Results. Patients with bipolar depression and healthy controls differed significantly on all cognitive measures (P<0.001). The two alternate forms of the Affective Processing Test were very similar in both groups. The most robust discriminator of the groups was a composite score that combined the six core cognitive subtests of the Brief Assessment of Cognition (BAC) with two of the measures from the Affective Processing Test. LIMITATIONS: Test-retest reliabilities of the individual Affective Processing Test measures were low. CONCLUSION: The BAC-A is sensitive to the cognitive impairments in bipolar disorder patients in traditional neuropsychological domains and in cognitive processes believed to be specifically impaired in affective disorders. PMID- 25012415 TI - Effect of specific psychotherapy for chronic depression on neural responses to emotional faces. AB - BACKGROUND: Neurofunctional deficits in chronic depression (CD) have been understudied. Specifically there is no known published study of the effects of a specialized psychotherapy for CD (CBASP) on neurofunctional deficits. METHODS: Ten patients with a DSM-IV diagnosis of CD received a 12 week specialised psychotherapy (CBASP). Controls were healthy matched volunteers. All subjects participated in a prospective study with functional magnetic resonance imaging (fMRI) at baseline and after 12 weeks. During the fMRI scans, subjects performed an implicit and explicit emotional processing task while watching dynamic displays of neutral, positive (happy) and negative (fearful and sad) facial expressions. Effects of treatment were analyzed in a repeated measures design. The analysis was restricted to two anatomically defined regions of interest (ROI): the amygdala and the cingulum. RESULTS: 60% of patients responded to treatment. Patients with CD reported increased arousal to negative emotional expressions. They also showed an increase in left amygdala reactivity during implicit processing of emotional expressions following psychotherapy. We found no significant effect for the cingulum. LIMITATIONS: The main limitation of our study is the small sample size. Due to the lack of a control group it is also unclear whether the demonstrated effect is specific to the psychotherapy used in this study. CONCLUSIONS: For the first time our study demonstrates an effect of CBASP on neural processing of facial emotions in CD. It therefore adds to the growing evidence supporting this treatment. PMID- 25012416 TI - Association of testosterone levels and future suicide attempts in females with bipolar disorder. AB - BACKGROUND: Considerable evidence suggests that testosterone may play a role in the pathophysiology of mood disorders in females. This is the first prospective study to examine whether blood testosterone levels predict suicide attempts in females with bipolar disorder. METHODS: Females with a DSM-IV diagnosis of a bipolar disorder in a depressive or mixed episode with at least one past suicide attempt were enrolled. Demographic and clinical parameters were assessed and recorded. Plasma testosterone was assayed using a double antibody radioimmunoassay procedure. Patients were followed up prospectively for up to 2.5 years. RESULTS: At baseline, testosterone levels positively correlated with the number of previous major depressive episodes and suicide attempts. Cox proportional hazards regression analysis found that higher baseline testosterone levels predicted suicide attempts during the follow-up period. LIMITATIONS: A limitation of the study is that the sample size is modest. Another limitation is that we did not have a bipolar nonattempter or healthy volunteer control group for comparison. CONCLUSION: Testosterone levels may predict suicidal behavior in women with bipolar disorder. PMID- 25012417 TI - No evidence of DISC1-associated morphological changes in the hippocampus, anterior cingulate cortex, or striatum in major depressive disorder cases and healthy controls. AB - BACKGROUND: DISC1 imaging genetics studies in healthy controls, schizophrenia, and bipolar disorder cases have revealed morphological changes in brain regions involved in the pathophysiology of psychiatric disease including the hippocampus, anterior cingulate cortex (ACC), and the striatum. However, many of these studies have yielded discordant findings so there is a need for replication. Furthermore, despite evidence from human genetic studies and animal models implicating DISC1 in major depressive disorder (MDD), a DISC1 imaging genetics study in MDD cases has yet to be published. Thus, using neuroimaging data from MDD cases and a large sample of healthy controls we aimed to identify morphological changes representing neurobiological mechanisms underlying the association between DISC1 and MDD. METHODS: We utilized structural magnetic resonance imaging (sMRI) data from 512 healthy controls and 171 current MDD (SCID interview) cases, each with genotype data for non-synonymous DISC1 SNPs rs3738401, rs6675281, and rs821616. RESULTS: Region of interest analyses failed to reveal DISC1-associated morphological changes in the hippocampus, ACC, or striatum in MDD patients and healthy controls. Whole brain exploratory analyses identified a nominally significant cluster mapping to the border of the precentral and postcentral gyri associated with rs821616 in healthy controls only (p(uncorrected)<0.001). LIMITATIONS: We focused our analyses exclusively on three, but previously heavily studied, SNPs in DISC1. CONCLUSIONS: Our findings suggest that morphological changes in the hippocampus, ACC, and/or striatum of MDD patients do not represent neurobiological mechanisms underlying the association between DISC1 and MDD. However, we urge replication in independent samples of MDD cases. PMID- 25012418 TI - Neurocognitive predictors of antidepressant clinical response. AB - BACKGROUND: Executive dysfunction and psychomotor slowing in depressed patients have been associated with poor antidepressant clinical response, but little is known about the value of neurocognitive tests for differential prediction of response. METHODS: This report presents new findings for 70 depressed patients tested on neurocogntive tests before receiving treatment with a SSRI (escitalopram or citalopram), NDRI (bupropion) or dual mechanism therapy including a serotonergic agent, and for 57 healthy controls. RESULTS: As predicted from previous research, patients who did not respond to a SSRI or dual therapy showed poorer word fluency than responders, whereas this was not seen for patients treated with bupropion alone. Longer choice reaction time (RT) was also found in nonresponders to a SSRI or dual therapy, but the opposite trend was seen for bupropion. Using a combined index of word fluency and RT (with normative performance as a cutoff) yielded differential predictions of response. Equal to or above normal performance predicted good response to a SSRI or dual therapy, with high positive predictive value (90%) and specificity (78%) but lower sensitivity (53%). In contrast, less than normal performance predicted good response to bupropion alone (positive predictive value=82%; specificity=67%; sensitivity=90%). LIMITATIONS: Relatively small sample size, no placebo control, and combining across SSRI alone and dual treatments. CONCLUSIONS: Although findings are preliminary due to small sample size, brief tests of word fluency and psychomotor speed may help identify depressed patients who are unresponsive to a serotonergic agent, but who may respond to bupropion alone. PMID- 25012419 TI - The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state? AB - BACKGROUND: An important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR polymorphism and recurrent MDD. METHODS: We compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73). RESULTS: First, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=-2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C components. CONCLUSIONS: Despite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population. PMID- 25012421 TI - Latent classes of PTSD symptoms in Iraq and Afghanistan female veterans. AB - BACKGROUND: Recent studies have used latent class analysis (LCA) to identify subgroups of individuals who share similar patterns of PTSD symptom endorsement; however, further study is needed among female veterans, whose PTSD symptom expression may vary from that of their male counterparts. The current study examined latent PTSD symptom classes in female veterans who returned from recent military service in Iraq and Afghanistan, and explored military and demographic variables associated with distinct PTSD symptom presentations. METHODS: A retrospective analysis was conducted using existing medical records from female Iraq and Afghanistan veterans who were new users of VA mental health outpatient (MHO) care, had received a PTSD diagnosis anytime during the post-deployment period, and completed the PTSD checklist within 30 days of their first MHO visit (N=2425). RESULTS: The LCA results identified four latent classes of PTSD symptom profiles in the sample: High Symptom, Intermediate Symptom, Intermediate Symptom with High Emotional Numbing (EN), and Low Symptom. Race/ethnicity, age, time since last deployment, and distance from a VA facility emerged as predictors of PTSD symptom presentation. LIMITATIONS: The current study was cross-sectional and utilized administrative data. The results may not be generalizable to female veterans from other service eras. CONCLUSIONS: Longer times between end of last deployment and initiation of MHO services were associated with more symptomatic classes. Exploration of PTSD symptom presentation may enhance our understanding of the service needs of female veterans with PTSD, and suggests potential benefits to engaging veterans in MHO soon after last deployment. PMID- 25012420 TI - Perinatal depression and omega-3 fatty acids: a Mendelian randomisation study. AB - BACKGROUND: There have been numerous studies investigating the association between omega-3 fatty acids (FAs) and depression, with mixed findings. We propose an approach which is largely free from issues such as confounding or reverse causality, to investigate this relationship using observational data from a pregnancy cohort. METHODS: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort collected information on FA levels from antenatal blood samples and depressive symptoms at several time points during pregnancy and the postnatal period. Conventional epidemiological analyses were used in addition to a Mendelian randomisation (MR) approach to investigate the association between levels of two omega-3 FAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and perinatal onset depression, antenatal depression (AND) and postnatal depression (PND). RESULTS: Weak evidence of a positive association with both EPA (OR=1.07; 95% CI: 0.99-1.15) and DHA (OR=1.08; 95% CI: 0.98-1.19) with perinatal onset depression was found using a multivariable logistic regression adjusting for social class and maternal age. However, the strength of association was found to attenuate when using an MR analysis to investigate DHA. LIMITATIONS: Pleiotropy is a potential limitation in MR analyses; we assume that the genetic variants included in the instrumental variable are associated only with our trait of interest (FAs) and thus cannot influence the outcome via any other pathway. CONCLUSIONS: We found weak evidence of a positive association between omega-3 FAs and perinatal onset depression. However, without confirmation from the MR analysis, we are unable to draw conclusions regarding causality. PMID- 25012423 TI - Outcomes, feasibility and acceptability of a group support psychotherapeutic intervention for depressed HIV-affected Ugandan adults: a pilot study. AB - BACKGROUND: Psychotherapy is the recommended first line treatment for mild to moderate depression. However, its availability in low resource settings is limited. We developed a manualized culturally sensitive group support psychotherapeutic intervention for depressed HIV affected Ugandan adults. In this study, we aimed to assess its feasibility, acceptability and impact on depression, functioning, social support and self-esteem. METHODS: A total of 77 depressed individuals were assigned to the group intervention (n=48) and a wait list control group (n=29), and assessed before, during and at the end of the intervention. The self-reporting questionnaire, a locally relevant function assessment instrument, the Rosenberg self-esteem scale, and the multiple dimensions perceived social support scale were administered to assess depression symptoms, functioning, self-esteem and social support at three assessment periods. Multivariate longitudinal regression models were used to determine change in outcomes over time between the two groups. Participants were asked to evaluate the intervention. RESULTS: Post -intervention assessments indicate that, in comparison to the wait-list control group, the intervention group had a faster reduction in depression symptom scores [OR=0.00,95% CI, 0.00-0.003] and faster increase in functioning scores [OR=4.82, 95% CI, 2.39 to 9.75], social support scores [OR=2.68, 95% CI, 1.50-4.78] and self-esteem [OR=1.90, 95% CI 1.48-2.44]. Sixty-three percent of participants strongly agreed that the intervention had reduced their depression and would recommend it to other depressed individuals. LIMITATIONS: Inadequate study power due to small sample sizes may result in imprecise confidence intervals even when there are significant differences. The use of non-random samples could have resulted in selection bias. CONCLUSIONS: This intervention appears feasible, acceptable and promising in treating depression and restoring function, enhancing social support and self-esteem. Larger and randomized evaluations are warranted. PMID- 25012422 TI - Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof of-concept randomized double-blind study. AB - BACKGROUND AND OBJECTIVE: Because increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal. METHOD: This was a randomized, double-blind, placebo-controlled study of 48 patients who met criteria for DSM IV((r)) Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of >=14. Half the participants received 0.25mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial. RESULTS: One week after stopping the medication, the HAMD ratings of the drug treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend. One week after the medication was stopped, the Clinical Global Index fell 1.64+/-0.18 units for the medication-treated patients, compared to 1.12+/-0.26 units for the placebo group (P=0.05). The regimen was well tolerated. CONCLUSIONS: Seven days of an ultra-low dose of 0.25mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidol-induced behavioural supersensitivity to dopamine. LIMITATIONS: The sample was small. More patients are needed in a future study. PMID- 25012424 TI - Dimorphic changes of some features of loving relationships during long-term use of antidepressants in depressed outpatients. AB - The present study aimed at investigating the possible changes of some features of loving relationships during long-term treatment of depression with both selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs), by means of a specifically designed test, the so-called "Sex, Attachment, Love" (SALT) questionnaire. The sample was composed by 192 outpatients (123 women and 69 men, mean age+/-SD: 41.2+/-10.2 years), suffering from mild or moderate depression, according to DSM-IV-TR criteria, that were selected if they were treated with one antidepressant only for at least six months and were involved in a loving relationship. The results showed that SSRIs had a significant impact on the feelings of love and attachment towards the partner especially in men, while women taking TCAs complained of more sexual side effects than men. These data were supported also by the detection of a significant interaction between drug and sex on the "Love" and "Sex" domains. The present findings, while demonstrating a dimorphic effect of antidepressants on some component of loving relationships, need to be deepened in future studies. PMID- 25012425 TI - Blunted exercise-induced mobilization of monocytes in somatization syndromes and major depression. AB - BACKGROUND: Previous research indicates that physical activity may alter the number of immune cells. We examined whether increasing or decreasing the level of physical activity affects circulating lymphocyte and monocyte counts in patients with somatization syndromes and patients with major depression. METHODS: Thirty eight participants with major depression, 26 participants with somatization syndromes and 47 healthy controls participated in the study. Using an experimental within-subject design, participants were involved in 1 week of increased physical activity (daily exercise sessions) and 1 week of reduced physical activity. Counts of total lymphocytes, lymphocyte subsets and monocytes were determined before and after each trial. Linear mixed models adjusted for sex, body mass index, age, fitness status and the order of trials were used for longitudinal data analysis. RESULTS: One week of exercise increases the number of monocytes in healthy controls (p<.05), but not in patients with somatization syndromes or patients with major depression. In addition, after 1 week of exercise, depressive symptoms were reduced in patients with major depression (p<.05) while somatoform symptoms were reduced (p<.05) in both clinical groups. Baseline comparisons and mixed models indicated reduced T helper cell counts in patients with somatization syndromes. LIMITATIONS: Relatively small sample size. The time of physical activity was relatively short and restricted to low-graded exercise. CONCLUSIONS: This study demonstrates a blunted mobilization of monocytes by exercise in both patients with somatization syndromes and patients with major depression. In addition, even one week of exercise reduces somatoform and depressive symptoms. PMID- 25012426 TI - Lifetime mood spectrum symptoms among bipolar patients and healthy controls: a cross sectional study with the Mood Spectrum Self-Report questionnaire. AB - BACKGROUND: The "spectrum" model has advantages for the conceptualization of mental disorders, representing a complementary approach to the currently available categorical systems. We carried out a study in order to assess lifetime mood symptoms among patients with bipolar disorder (BD) and healthy controls from a dimensional perspective. METHODS: The Mood Spectrum Self-Report instrument (MOODS-SR) was administered to 101 bipolar patients (52 BD I, 32 BD II, and 17 BD NOS, 36 males/65 females, mean age+SD=36.10+/-13.34 years) and 38 healthy controls (16 males/22females, mean age+SD=35.18+/-13.70 years). The scores of the different MOOD-SR scales and subscales among patients and controls were compared using non-parametric tests (Mann-Whitney and Kruskal-Wallis). RESULTS: Bipolar patients scored significantly higher than healthy controls on the total MOOD-SR scores (BD: mean+/-SD=98.65+/-22.17; HC: mean+/-SD=12.92+/-10.72; p<0.01) and all subdomains. Multiple comparisons revealed lower scores among controls when compared to each one of the subtypes of BD, also regarding the total scores and all subdomains (p<0.01). Comparisons across the different subtypes of BD revealed statistically significant higher scores among BD I patients when compared to BD II and BD NOS patients, only in regard to the total MOOD-SR scores (BD I: mean+/ SD=102.94+/-22.79; BD II: mean+/-SD=93.53+/-21.97; BD NOS: mean+/-SD= 94.88+/ 18.68; p=0.03) and two subdomains: mood mania and energy mania. CONCLUSIONS: These results, although preliminary, suggest that even though the MOODS-SR seems effective in distinguishing BD patients from HC, it is not as good in discriminating different subtypes of BD, especially in respect to lifetime depressive symptoms. LIMITATIONS: Our sample size was small, and comprised by outpatients. The MOOD-SR measures only lifetime symptoms and does not take into account the progression of mood symptoms or the current mood state of patients. PMID- 25012427 TI - Rapid clozapine titration in treatment-refractory bipolar disorder. AB - BACKGROUND: Clozapine is effective in treatment-refractory bipolar disorder (BD). Guidelines recommend slow titration to prevent seizures, hypotension and myocarditis, but this stance is not supported by comparative data. OBJECTIVE: To evaluate the safety and effectiveness of rapid clozapine titration in BD. METHODS: Analysis of a consecutive cohort of treatment-refractory BD patients with mixed/manic episode admitted on alternate days to one of two units of a psychiatric hospital. On one unit, clozapine was started at 25mg followed by 25 50mg as needed every 6h (maximum=100mg/day) on day 1, followed by increases of 25 100mg/day. On the other unit, clozapine was initiated with 25mg in day 1, followed by increases of 25-50mg/day. The primary outcome was the number of days from starting clozapine until readiness for discharge, adjusted in logistic regression for the number of antipsychotics tried during the hospitalization, psychotropic co-treatments and presence of psychotic features. RESULTS: Patients subject to rapid (N=44) and standard (N=23) titration were similar in age, gender, smoking status, body mass index, illness severity at baseline and discharge, and highest clozapine dose. Clozapine was discontinued due to hypotension (N=1) and pneumonia (N=1) during rapid titration, and for excessive sedation (N=1) in each titration group. The number of hospital days from starting clozapine until readiness for discharge was 3.8 days shorter in the rapid titration group (12.7+/-6.3 vs. 16.5+/-5.8, p=0.0077). CONCLUSION: Rapid clozapine titration appeared safe and effective for treatment-refractory BD. The potential for shorter hospital stays justifies prospective trials of this method. PMID- 25012428 TI - Depression and pain impair daily functioning and quality of life in patients with major depressive disorder. AB - BACKGROUND: Depression and pain frequently occur together. The objective of this study was to investigate the effects of depression and pain on the impairment of daily functioning and quality of life (QOL) of depressed patients. METHODS: We enrolled 131 acutely ill inpatients with major depressive disorder. Depression, pain, and daily functioning were assessed using the 17-item Hamilton Depression Rating Scale, the Short-Form 36 (SF-36) Body Pain Index, and the Work and Social Adjustment Scale. Health-related QOL was assessed using three primary domains of the SF-36: social functioning, vitality, and general health perceptions. Pearson's correlation and structural equation modeling were used to examine relationships among the study variables. Five models were proposed. RESULTS: In all, 129 patients completed all the measures. Model 5, both depression and pain impaired daily functioning and QOL, was the most fitted structural equation model (chi(2)=9.2, df=8, p=0.33, GFI=0.98, AGFI=0.94, TLI=0.99, CFI=0.99, RMSEA=0.03). The correlation between pain and depression was weak (r=-0.27, z=-2.95, p=0.003). LIMITATION: This was a cross-sectional study with a small sample size. CONCLUSION: Depression and pain exert a direct influence on the impairment of daily functioning and QOL of depressed patients; this impairment could be expected regardless of increased pain, depression, or both pain and depression. Pain had a somewhat separate entity from depression. PMID- 25012430 TI - Comparison of inflammatory cytokine levels among type I/type II and manic/hypomanic/euthymic/depressive states of bipolar disorder. AB - OBJECTIVE: Inflammatory cytokines have been suggested to be the trait or state markers of bipolar disorder, but with inconsistent results. This may be related to small sample sizes and poor control of some important confounding factors. METHODS: Gender/age-matched outpatients with bipolar disorder and normal controls were enrolled. The clinical symptoms were rated using the Montgomery Asberg Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1), soluble P-selectin receptor (sP-selectin), and monocyte chemotactic protein-1 (MCP-1), were assessed by enzyme-linked immunosorbent assays. RESULTS: In total, 130 patients with bipolar disorder and 130 normal subjects were enrolled. Among the patients with bipolar disorder, 77 (59.2%) had bipolar I disorder, 53 (40.8%) had bipolar II disorder; 75 (57.7%) were in a euthymic state, 14 (10.8%) were in a manic/hypomanic state, and 41 (31.5%) were in a depressive state. The 130 bipolar patients had significantly higher levels of all cytokines than the normal controls (all p<0.0001). Using multivariate regression analysis with controlling of age, gender, BMI, smoking, duration of illness, and medication grouping, the patients with bipolar II disorder had significantly lower levels of sTNF-R1 than the patients with bipolar I disorder (p=0.038); the patients in a depressive state had significantly lower levels of sTNF-R1 than the patients in manic/hypomanic and euthymic states (p=0.009). CONCLUSION: The study supported the association of bipolar disorder with inflammatory dysregulation, and sTNF-R1 may be a potential biomarker for staging bipolar disorder. PMID- 25012429 TI - Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. AB - BACKGROUND: Apathy is a prominent feature of geriatric depression that predicts poor clinical outcomes and hinders depression treatment. Yet little is known about the neurobiology and treatment of apathy in late-life depression. This study examined apathy prevalence in a clinical sample of depressed elderly, response of apathy to selective serotonin reuptake inhibitor (SSRI) treatment, and neuroanatomical correlates that distinguished responders from non-responders and healthy controls. METHODS: Participants included 45 non-demented, elderly with major depression and 43 elderly comparison individuals. After a 2-week single-blind placebo period, depressed participants received escitalopram 10mg daily for 12 weeks. The Apathy Evaluation Scale (AES) and 24-item Hamilton Depression Rating Scale (HDRS) were administered at baseline and 12 weeks. MRI scans were acquired at baseline for concurrent structural and diffusion tensor imaging of anterior cingulate gray matter and associated white matter tracts. RESULTS: 35.5% of depressed patients suffered from apathy. This declined to 15.6% (p<0.1) following treatment, but 43% of initial sufferers continued to report significant apathy. Improvement of apathy with SSRI was independent of change in depression but correlated with larger left posterior subgenual cingulate volumes and greater fractional anisotropy of left uncinate fasciculi. LIMITATIONS: Modest sample size, no placebo control, post-hoc secondary analysis, use of 1.5T MRI scanner CONCLUSIONS: While prevalent in geriatric depression, apathy is separable from depression with regards to medication response. Structural abnormalities of the posterior subgenual cingulate and uncinate fasciculus may perpetuate apathetic states by interfering with prefrontal cortical recruitment of limbic activity essential to motivated behavior. PMID- 25012431 TI - Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. METHOD: BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. RESULTS: Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. LIMITATIONS: Small sample size in different episodes and drug-free patients was the limitation of thestudy. CONCLUSION: Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia. PMID- 25012432 TI - Topiramate as an adjuvant treatment for obsessive compulsive symptoms in patients with bipolar disorder: a randomized double blind placebo controlled clinical trial. AB - BACKGROUND: It has not been examined trialed whether obsessive compulsive symptoms in patients with bipolar disorder respond to topiramate as an adjuvant treatment. METHODS: This 4-month double-blind placebo-controlled randomized clinical trial examined the efficacy and safety of augmentation with topiramat for treating the patients with bipolar disorder, manic phase type-I, and obsessive compulsive disorder symptoms. Both groups received lithium+olanzapine+clonazepam. However, one group received topiramate and the other group placebo as adjuvant medications. Yale Brown obsessive compulsive behavior scale was used to assess the outcome. Adverse effects were also recorded. RESULTS: A total of 32 patients completed this trial. The mean score decreased from 24.2(4.8) to 17.6(8.7) in the topiramate group (P<0.003) and from 20.9(2.9) to 9.6(3.5) in the placebo group during this trial (P<0.0001). Additionally, 9(52.9%) out of 17 patients in the topiramate group and 2(12.5%) out of 16 patients in the placebo group showed more than 34% decline in YBOC score (x2=6.0, df=1, P<0.01). No serious adverse effects were detected. LIMITATIONS: The limitations of the present study were its small sample size and the fact that it was conducted in a single center. CONCLUSIONS: The combination of lithium+olanzapine+clonazepam decreased the symptoms of obsessive compulsive disorder in the patients with bipolar disorder type I. However, topiramate had a more significant effect than placebo on improvement of the patients with bipolar disorder and obsessive compulsive symptoms. This combination seems to be without serious adverse effects. PMID- 25012433 TI - Feelings of worthlessness, traumatic experience, and their comorbidity in relation to lifetime suicide attempt in community adults with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) and traumatic experience are independent risk factors for lifetime suicide attempt (LSA). However, the relationships between trauma history and depressive symptomatology as they relate to LSA are not fully understood. METHODS: A total of 12,532 adults, randomly selected through one-person-per-household method, completed a face-to-face interview using the Korean version of Composite International Diagnostic Interview (K-CIDI) and a questionnaire for LSA (response rate 80.2%). RESULTS: Among 825 subjects with MDD, 141 subjects reported an LSA (17.1%). LSAs were significantly greater in those who had experienced any trauma than in those who had not (chi(2)=34.66, p<0.0001). Multivariate logistic regression showed that only feelings of worthlessness were significantly associated with LSA among 20 depression symptoms in individuals with MDD (AOR=3.08, 95% CI 1.70-5.60). Feelings of worthlessness was associated with LSA in those who had experienced serious trauma (AOR=5.02, 95% CI 3.35-7.52), but not in those who had not. Serious traumas associated with LSA included military combat, witnessing a violent crime, rape or sexual assault, a bad beating, being threatened by others, and learning about traumas to others. Serious trauma showed no significant association with LSA in those who did not have feelings of worthlessness. PTSD was a comorbidity that showed the highest odds ratio with LSA in individuals with MDD. CONCLUSIONS: Feelings of worthlessness are more strongly associated with LSA than other depression symptoms in individuals with MDD, and it is significantly associated with LSA in those who experienced serious trauma but not in those who did not. PMID- 25012434 TI - Prevalence, nature and determinants of postpartum mental health problems among women who have migrated from South Asian to high-income countries: a systematic review of the evidence. AB - BACKGROUND: Women of reproductive age constitute a significant proportion of immigrants from South Asia to high-income countries. Pregnancy, childbirth and the postpartum period place increased demands on women's psychological resources and relationships. The aim of this review was to evaluate the available evidence about the prevalence, nature and determinants of postpartum mental health problems among South Asian women who have migrated to high-income countries. METHODS: Using a systematic strategy, CINAHL, Medline, PsychInfo and Web of Science databases were searched. RESULTS: Fifteen studies conducted in different high-income countries met inclusion criteria. Prevalence estimates of clinically significant symptoms of postpartum depression (CSS-PPD) varied widely (1.9-52%): the most common estimates ranged from 5 to 20%. Five studies found approximately a two-fold increase in risk of CSS-PPD (Odds Ratios 1.8-2.5) among overseas born women with a South Asian subgroup. The most common determinants appeared to be social factors, including social isolation and quality of relationship with the partner. Barriers to accessing health care included lack of English language proficiency, unfamiliarity with local services and lack of attention to mental health and cultural factors by health care providers. LIMITATIONS: The settings, recruitment strategies, inclusion and exclusion criteria, representative adequacy of the samples and assessment measures used in these studies varied widely. Many of these studies did not use formally validated tools or undertake specific subgroup analyses. CONCLUSIONS: Reductions in postpartum depression could be achieved by increasing awareness of available services and ensuring health care professionals support the mental health of women from diverse cultural and linguistic backgrounds. PMID- 25012435 TI - Disability in anxiety disorders. AB - BACKGROUND: This study compares disability levels between different anxiety disorders and healthy controls. We further investigate the role of anxiety arousal and avoidance behaviour in disability, and whether differences in these symptom patterns contribute to disability differences between anxiety disorders. METHODS: Data were from 1826 subjects from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose anxiety disorders. The World Health Organization Disability Assessment Schedule II was used to measure disability in six domains (cognition, mobility, selfcare, social interaction, life activities, participation). Severity of anxiety arousal and avoidance behaviour symptoms was measured using the Beck Anxiety Inventory and the Fear Questionnaire. RESULTS: All anxiety disorders were associated with higher disability. Disability was generally highest in multiple anxiety disorder (e.g. mean disability in cognition=33.7) and social anxiety disorder (mean=32.7), followed by generalized anxiety disorder (mean=27.2) and panic disorder with agoraphobia (mean=26.3), and lowest in panic disorder without agoraphobia (mean=22.1). Anxiety arousal was more associated with disability in life activities (B=8.5, p<0.001) and participation (B=9.9, p<0.001) whereas avoidance behaviour was more associated with disability in cognition (B=7.4, p<0.001) and social interaction (B=8.6, p<0.001). Different disability patterns between anxiety disorders were not completely explained by anxiety arousal and avoidance behaviour. LIMITATIONS: The cross-sectional study design precludes any causal interpretations. In order to examine the full range of comorbidity among anxiety, a greater range of anxiety disorders would have been preferable. CONCLUSIONS: Disability is highest in social anxiety disorder and multiple anxiety disorder. Both anxiety arousal and avoidance behaviour are associated with higher disability levels but do not fully explain the differences across anxiety disorders. PMID- 25012436 TI - Mental imagery in bipolar affective disorder versus unipolar depression: investigating cognitions at times of 'positive' mood. AB - BACKGROUND: Compared to unipolar depression (UD), depressed mood in bipolar disorder (BD) has been associated with amplified negative mental imagery of the future ('flashforwards'). However, imagery characteristics during positive mood remain poorly explored. We hypothesise first, that unlike UD patients, the most significant positive images of BD patients will be 'flashforwards' (rather than past memories). Second, that BD patients will experience more frequent (and more 'powerful') positive imagery as compared to verbal thoughts and third, that behavioural activation scores will be predicted by imagery variables in the BD group. METHODS: BD (n=26) and UD (n=26) patients completed clinical and trait imagery measures followed by an Imagery Interview and a measure of behavioural activation. RESULTS: Compared to UD, BD patients reported more 'flashforwards' compared to past memories and rated their 'flashforwards' as more vivid, exciting and pleasurable. Only the BD group found positive imagery more 'powerful', (preoccupying, 'real' and compelling) as compared to verbal thoughts. Imagery associated pleasure predicted levels of drive and reward responsiveness in the BD group. LIMITATIONS: A limitation in the study was the retrospective design. Moreover pathological and non-pathological periods of "positive" mood were not distinguished in the BD sample. CONCLUSIONS: This study reveals BD patients experience positive 'flashforward' imagery in positive mood, with more intense qualities than UD patients. This could contribute to the amplification of emotional states and goal directed behaviour leading into mania, and differentiate BD from UD. PMID- 25012437 TI - Impact of comorbid anxiety disorders and obsessive-compulsive disorder on 24 month clinical outcomes of bipolar I disorder. AB - BACKGROUND: This study investigated the impact of comorbid obsessive-compulsive disorder (OCD) and four anxiety disorders [panic disorder (PD), agoraphobia, social anxiety disorder (SAD), and generalized anxiety disorder (GAD)] on the clinical outcomes of bipolar disorder. METHODS: This study analysed data of 174 patients with bipolar I disorder who participated in the prospective observational study. Participants were assessed every 3 months for 24 months. The primary outcome measure was the achievement of symptomatic remission, defined by a total score on the Young Mania Rating Scale (YMRS) of <=12 and a total score on the 21-item Hamilton Depression Rating Scale (HAMD-21) of <=8. RESULTS: Comorbidity was associated with decreased likelihood of remission. However, the impact of individual disorders on outcome differed according to clinical and treatment situations. Most comorbid anxiety disorders and OCD had a negative effect on remission during the first year of evaluation, as measured by the HAMD 21, and in patients taking a conventional mood stabilizer alone. However, the association with poorer outcome was observed only for a few specific comorbid disorders in the second year (GAD and OCD), as measured by YMRS-defined remission (OCD), and in patients with olanzapine therapy (GAD and OCD). LIMITATIONS: Follow up evaluation of comorbid disorders was lacking. CONCLUSIONS: Comorbid anxiety disorders and OCD negatively influenced the clinical course of bipolar disorder. Specifically, OCD had a consistently negative impact on the outcome of bipolar I disorder regardless of clinical situation. Effective strategies for the control of these comorbidities are required to achieve better treatment outcomes. PMID- 25012438 TI - Dietary zinc is associated with a lower incidence of depression: findings from two Australian cohorts. AB - BACKGROUND: Several animal and human studies have shown that zinc plays a role in reducing depression, but there have been no longitudinal studies in both men and women on this topic. The aim of this study was to investigate dietary zinc, and the zinc to iron ratio, as predictors of incident depression in two large longitudinal studies of mid-age and older Australians. METHODS: Data were self reported, as part of the Australian Longitudinal Study on Women's Health (women aged 50-61 years) and Hunter Community Study (men and women aged 55-85 years). Validated food frequency questionnaires were used to assess dietary intake. Energy-adjusted zinc was ranked using quintiles and predictors of incident depression were examined using multivariate logistic regression. RESULTS: Both studies showed an inverse association between dietary zinc intake and risk of depression, even after adjusting for potential confounders. Compared to those with the lowest zinc intake those with the highest zinc intake had significantly lower odds of developing depression with a reduction of about 30-50%. There was no association between the zinc to iron ratio and developing depression in either study. LIMITATIONS: Dietary assessment was carried out only at baseline and although adjustments were made for all known potential confounders, residual confounding cannot be entirely excluded. CONCLUSIONS: Low dietary zinc intake is associated with a greater incidence of depression in both men and women, as shown in two prospective cohorts. Further studies into the precise role of zinc compared to other important nutrients from the diet are needed. PMID- 25012439 TI - Treatment of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review. AB - BACKGROUND: More than 20% of patients with bipolar disorder (BD) show lifetime comorbidity for obsessive-compulsive disorder (OCD), but treatment of BD-OCD is a clinical challenge. Although serotonin reuptake inhibitors (SRIs) are the first line treatment for OCD, they can induce mood instability in BD. An optimal treatment approach remains to be defined. METHODS: We systematically reviewed MEDLINE, Embase, PsychINFO and the Cochrane Library and retrieved data on clinical management of comorbid BD-OCD patients. Pharmacologic, psychotherapeutic and others alternative approaches were included. RESULTS: Fourteen studies were selected. In all selected studies BD-OCD patients received mood stabilizers. In the largest study, 42.1% of comorbid patients required a combination of multiple mood stabilizers and 10.5% a combination of mood stabilizers with atypical antipsychotics. Addition of antidepressants to mood stabilizers led to clinical remission of both conditions in only one study. Some BD-OCD patients on mood stabilizer therapy benefitted from adjunctive psychotherapy. LIMITATIONS: Most studies are case reports or cross-sectional studies based on retrospective assessments. Enrollment of subjects mainly from outpatient specialty units might have introduced selection bias and limited community-wide generalizability. CONCLUSIONS: Keeping in mind scantiness and heterogeneity of the available literature, the best interpretation of the available evidence appears to be that mood stabilization should be the primary goal in treating BD-OCD patients. Addition of SRI agents seems unnecessary in most cases, although it may be needed in a minority of BD patients with refractory OCD. PMID- 25012440 TI - The effects of ethnic, social and cultural factors on axis I comorbidity of bipolar disorder: results from the clinical setting in Korea. AB - OBJECTIVE: Ethnic, social and cultural factors contribute to axis I comorbid conditions in bipolar disorder (BPD). Korea has strict laws against illicit drugs and a relatively permissive prevailing attitude toward alcohol. The present study aimed to explore the lifetime axis I comorbidity rate in patients with BPD in Korea. METHODS: Clinically stable patients with bipolar I (n=222) and bipolar II (n=194) disorders were recruited from four tertiary medical centers in Korea. The subjects' diagnoses and axis I comorbid conditions were evaluated using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and the Korean version of the Diagnostic Interview for Genetic Studies (K-DIGS). The lifetime prevalence of anxiety disorders, substance use disorders and eating disorders was explored. The prevalence of these axis I comorbid conditions was compared with data from prior studies in other countries and to data concerning the general Korean population. RESULTS: A total of 45.1% of all subjects had at least one axis I comorbid condition. Anxiety disorders (30.2%) were the most common comorbidity, followed by alcohol use disorders (16.8%). Males with BPD showed a higher rate of alcohol dependence compared to the general male population and females with BPD showed a greater risk of having alcohol use disorder compared to the general female population. The rate of drug use disorder was extremely low (1.7%), and only one subject had an illicit-drug-related problem. LIMITATION: Cross-sectional studies. CONCLUSION: Comorbid conditions of Korean patients with BPD showed a distinct pattern, which is associated with the ethnic, social and cultural characteristics in Korea. PMID- 25012441 TI - Negative affectivity as a transdiagnostic factor in patients with common mental disorders. AB - BACKGROUND: Screening and monitoring systems are increasingly used in psychotherapy, but it has been questioned whether outcome measurement using multiple questionnaires is warranted. Arguably, type and number of assessment instruments should be determined by empirical research. This study investigated the latent factor structure of a multi-dimensional outcome measurement strategy used in English services aligned to the Improving Access to Psychological Therapies (IAPT) programme. METHODS: Factor analyses and structural equation models were performed on 11,939 intake assessments of outpatients accessing an IAPT service between 2008 and 2010. We examined whether three routinely employed instruments (PHQ-9 for depression, GAD-7 for anxiety, WSAS for functional impairment) assess empirically different dimensions. RESULTS: The instruments were found to assess mainly one general dimension and only some items of the GAD 7 and WSAS assess unique variance beyond this general dimension. In a structural equation model the disorder-specific factor scores were predicted by patients' diagnostic categories. LIMITATIONS: Since a large naturalistic data base was used, missing data for diagnoses and scale items were encountered. Diagnoses were obtained with brief case-finding measures rather than structured diagnostic interviews. CONCLUSION: Although the items seem to address mostly one dimension, some variance is due to differences between individuals in anxiety and impairment. While this generally supports multi-dimensional assessment in a primary care population, the clinical upshot of the study is to concentrate attention on transdiagnostic factors as a target for treatment. PMID- 25012442 TI - The alterations in inter-hemispheric functional coordination of patients with panic disorder: the findings in the posterior sub-network of default mode network. AB - OBJECTIVE: Voxel-mirrored homotopic connectivity (VMHC) has been studied in several neuropsychiatric illnesses. The inter-hemispheric interactions probably could explain the important aspects for the pathophysiology of panic disorder (PD). Therefore, we initiated this study to estimate the differences in VMHC values between the PD patients and controls. METHODS: Thirty first-episode medication-naive patients with PD and 21 controls were enrolled with age and gender controlled. All the participants received the scanning of resting-state functional magnetic resonance imaging (R-FMRI). The R-FMRI images were preprocessed and analyzed to obtain the VMHC values. The two-sample t test of VMHC data between PD patients and controls was performed. We also explored the relationship between the VMHC values and clinical characteristics. RESULTS: The controls had significantly higher VMHC values than patients in the posterior cingulate cortex and precuneus (false discovery rate corrected p<0.005). The one sided results by the unilateral hemisphere mask also confirmed that the results were indeed found in the right hemisphere. The VMHC value in the posterior cingulate cortex was also negatively correlated with panic severity. CONCLUSION: The alterations of inter-hemispheric coordination in cingulate-precuneus may play a role in the pathophysiology of PD. PMID- 25012443 TI - Characterization of patients with mood disorders for their prevalent temperament and level of hopelessness. AB - BACKGROUND: Mood disorders (MD) are disabling conditions throughout the world associated with significant psychosocial impairment. Affective temperaments, as well as hopelessness, may play a significant role in the pathophysiology of MD. The present study was designed to characterize patients with MD for their prevalent affective temperament and level of hopelessness. METHODS: Five hundred fifty-nine (253 men and 306 women) consecutive adult inpatients were assessed using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire version (TEMPS-A), the Gotland Scale for Male Depression (GSMD), the Beck Hopelessness Scale (BHS) and the Mini International Neuropsychiatric Interview (MINI). RESULTS: Higher cyclothymia and irritable temperaments were found in bipolar disorder-I (BD-I) patients compared to those with other Axis I diagnoses. Major depressive disorder (MDD) patients had lower hyperthymia than BD-I and BD-II patients and higher anxiety than patients with other Axis I diagnoses. Severe "male" depression was more common in BD-II patients compared to BD-I and MDD patients. BD-I patients and those with other axis I diagnoses reported lower BHS >=9 scores than those with BD-II and MDD. LIMITATIONS: The study had the limitations of all naturalistic designs, that is, potentially relevant variables were not addressed. Furthermore, the cross sectional nature of the study did not allow conclusions about causation, and the use of self-report measures could be potentially biased by social desirability. CONCLUSION: MDD patients were more likely to have higher anxious temperament, higher hopelessness and lower hyperthymic temperament scores, while BD-I patients more often had cyclothymic and irritable temperaments than patients with other Axis I diagnoses. The implications of the present results were discussed. PMID- 25012444 TI - Gender differences on functioning in depressive patients. AB - BACKGROUND: Depression is one of the most common disorders in primary care and the fourth most disabling medical condition worldwide. Although gender differences in the prevalence of depression are well established, the little available data on gender-related differences in disabilities among depression patients gives controversial results. This study aims to analyse whether there are gender differences in the disabilities experienced by patients with depression. METHODS: A cross-sectional, multicentre, nationwide epidemiological study was conducted, with 1226 patients. A Case Report Form was used to collect sociodemographic data and the 12-item version of the World Health Organization Disability Assessment Schedule II (WHO-DAS-II) was used to assess functioning. Depression severity was assessed using the Quick Inventory of Depressive Symptomatology (QIDS). RESULTS: Non-statistically significant differences in functioning were found between males and females. An item-by-item analysis of the WHO-DAS-II shows significant differences between both sexes in specific areas. Women obtained higher scores than men for standing for long periods and walking a long distance. Males scored higher than women in dealing with people you did not know well and maintaining a friendship. LIMITATIONS: Given the descriptive and cross-sectional nature of the study, the results are limited, highlighting the need for further research. Also, other variables that might influence disability, such as medical illnesses, were not considered. CONCLUSIONS: The effect of depression on disability is similar for both sexes but not uniform in terms of the impact on different aspects of the quality of life. These findings could be an important factor in the assessment of functioning and management of depression. PMID- 25012445 TI - Neurocognitive impairments among youth with pediatric bipolar disorder: a systematic review of neuropsychological research. AB - BACKGROUND: Pediatric bipolar disorder (PBD) has emerged as a field of research in which neuropsychological studies are continuously providing new empirical findings. Despite this, a comprehensive framework for neurocognitive impairments is still lacking, and most of the evidence remains unconnected. We addressed this question through a systematic review of neuropsychological research, with the aim of elucidating the main issues concerning this topic. METHOD: A comprehensive search of databases (PubMed, PsycINFO) was performed. Published manuscripts between 1990 and January 2014 were identified. Overall, 124 studies fulfilled inclusion criteria. Methodological differences between studies required a descriptive review of findings. RESULTS: Evidence indicates that verbal/visual spatial memory, processing speed, working memory, and social cognition are neurocognitive domains impaired in PBD youth. Furthermore, these deficits are greater among those who suffer acute affective symptoms, PBD type I, and/or attention deficit hyperactivity disorder (ADHD) comorbidity. In addition, several neurocognitive deficits imply certain changes in prefrontal cortex activity and are somewhat associated with psychosocial and academic disabilities. Strikingly, these deficits are consistently similar to those encountered in ADHD as well as severe mood dysregulation (SMD). Besides, some neurocognitive impairments appear before the onset of the illness and tend to maintain stable across adolescence. Finally, any therapy has not yet demonstrated to be effective on diminishing these neurocognitive impairments. LIMITATIONS: More prolonged follow-up studies aimed at delineating the course of treatment and the response to it are warranted. CONCLUSIONS: Despite noteworthy research on the neurocognitive profile of PBD, our knowledge is still lagging behind evidence from adult counterparts. PMID- 25012446 TI - Improvements in quality of life with desvenlafaxine 50mg/d vs placebo in employed adults with major depressive disorder. AB - BACKGROUND: Diminished quality of life (QOL) is associated with major depressive disorder (MDD). METHODS: QOL was assessed in a post-hoc analysis of a double blind, placebo-controlled trial. Employed adult outpatients with MDD were randomly assigned to 12 weeks of treatment with desvenlafaxine 50mg/d or placebo. Changes from baseline in the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) item scores at week 12 were analyzed using analysis of covariance with treatment, region, and baseline in the model. Correlations between change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score and Q-LES-Q scores were computed. RESULTS: The intent-to-treat population included 427 patients. There were statistically significant improvements from baseline for desvenlafaxine vs placebo in 10 of 16 Q-LES-Q item scores (P values <=0.0441). The percentage of patients with severe QOL impairment (>=2 SD below community norm) at week 12 was significantly lower for desvenlafaxine (46%) vs placebo (62%; P=0.0024; baseline: 95% and 94%, respectively). Change in Q-LES-Q total score was highly correlated with change in HAM-D17 score at week 12, LOCF (P<0.0001), and improvement in HAM-D17 total score at week 2 predicted change in Q-LES-Q total score at week 12 for the desvenlafaxine group (F=24.89; P<0.0001) but not placebo. LIMITATIONS: This analysis excluded patients who were unemployed, had severe comorbidities, and those taking multiple, concomitant medications. CONCLUSION: Improvement in QOL and depressive symptoms was significantly greater for employed depressed patients treated with desvenlafaxine vs placebo. PMID- 25012448 TI - Thoughts of self-harm and depression as prognostic factors in palliative care patients. AB - BACKGROUND: This study explored whether scores indicating depression on Patient Health Questionnaire 9 and patient reports of thoughts of self-harm were prognostic factors for survival in advanced cancer. METHOD: Patients with advanced cancer were recruited into the study from palliative care day units and invited to complete measures for depression which included Patient Health Questionnaire 9, and Edinburgh Depression Scale at recruitment, and at 8, 16 and 24 weeks. RESULTS: 629 patients were recruited into the study; 139 (22%) died during 6 months follow up and 235 patients (37.4%) died during the study period. The age range of patients recruited was 21-94 years-mean age 66 years and 67% of patients recruited were female. The overall median survival of patients recruited was 37.1 weeks (95% CI 36.0, 39.9 weeks) (range 0-116 weeks). The estimated median survival time of patients whose baseline PHQ9>=9 was 36 weeks with 95% confidence interval of (31, 39) and for patients whose baseline PHQ9<9 was 39 weeks (95% CI 37, 45)-baseline PHQ9 alone was predictive of death. The median survival times were 37.9 weeks for patients who did not indicate thoughts of self harm and 34.7 weeks for patients who reported thoughts of self-harm at baseline suggesting that risk of death was 1.4 times higher among patients who reported thoughts of self-harm. LIMITATIONS: Patients were recruited only from within palliative day care units and assessments were made only by validated tools and not by clinical interviews. CONCLUSIONS: In this large longitudinal study, moderate to severe depression as measured by PHQ9 and patient reports of thoughts of self-harm were associated with earlier mortality. This paper supports the need for supporting patients psychologically at the end of life and specifically in treating depression in this patient group. PMID- 25012447 TI - Personality, coping, risky behavior, and mental disorders in the offspring of parents with bipolar disorder: a comprehensive psychosocial assessment. AB - OBJECTIVES: It has been proposed that the offspring of parents with bipolar disorder (OBD), through genetic mechanisms and early family interactions, develop a heightened sensitivity to stress, maladaptive coping, and dysregulated behavior, which ultimately increases the risk for affective disorders. The current study tested certain predictions of this model by assessing different psychosocial and health-related outcomes in the OBD, including personality, coping style, smoking, suicidality, high-risk sexual behaviors, criminality, and mental health. METHOD: The sample was composed of 74 OBD and 75 control offspring, who were between 14 and 27 years of age (mean: 19.38+/-3.56). Participants underwent a diagnostic interview and a structured interview to assess high-risk behavior and other maladaptive outcomes, and they completed the Revised NEO Personality Inventory and Coping in Stressful Situations questionnaire. RESULTS: The rates of affective (31.1%) and non-affective (56.8%) disorders were elevated in the OBD compared to controls (9.5% and 32.4%). Relative to controls, OBD endorsed fewer task-oriented and more distraction coping strategies [Wilk's lambda=.83, F(1, 136) =6.92, p<.01], and were more likely to report engaging in high-risk sexual behavior (OR=2.37; Wald=4.13, 1 df, p<05). Importantly, OBD reported elevated high-risk sexual behavior relative to controls, irrespective of affective disorder diagnosis. CONCLUSION: The results highlight a potential risk profile for the OBD, consisting of ineffective coping strategies and risky sexual behavior and are discussed in the context of current knowledge of stress and coping in this population. LIMITATIONS: The present findings were based on cross-sectional data and relied on offspring self-report. It would be useful to corroborate these findings with biobehavioural and longitudinal measures. PMID- 25012449 TI - Epigenetic modulation of BDNF gene: differences in DNA methylation between unipolar and bipolar patients. AB - BACKGROUND: The brain derived neurotrophic factor (BDNF) gene and its epigenetic regulation have been repeatedly implicated in the pathophysiology of mood disorders. Following previous investigation in the field, we further investigated differences in BDNF promoter gene methylation in patients with mood disorders, comparing unipolar and bipolar subjects, on the basis of illness phase, gender, age and psychotropic prescription. METHODS: 154 patients (43 MDD; 61 BD I; 50 BD II), on stable pharmacological treatment, and 44 age-matched, healthy controls were recruited. BDNF methylation levels from peripheral blood mononuclear cells (PBMCs) were compared by analysis of variance followed by Bonferroni's post-hoc test. RESULTS: Similar, higher levels of BDNF gene promoter methylation were found in BD II and MDD patients, compared to BD I subjects (P<0.01). When stratified on the basis of mood status, methylation levels of depressed patients were significantly higher, compared to the levels of manic/mixed patients (P<0.01). While gender and age did not seem to influence methylation levels of BDNF gene promoter, patients on lithium and valproate showed overall lower levels. LIMITATIONS: Cross-sectional analysis using PBMCs with further investigation with larger samples, including drug-naive patients, needed to replicate findings in neuronal cells. CONCLUSIONS: Present data confirm our previous results of higher methylation levels in BD II (compared to BD I) and MDD patients (compared to controls). A closer relationship between BD II and MDD, compared to BD I patients as well an association of lower methylation levels with the presence of mania/mixed state, compared to the depressive phase, was observed. PMID- 25012450 TI - Long-term symptomatic and functional outcome following an intensive inpatient multidisciplinary intervention for treatment-resistant affective disorders. AB - BACKGROUND: The natural history of treatment-resistant depression (TRD) is poor, with high rates of chronicity and recurrence. We describe longer-term symptomatic and functional outcome following multimodal intensive inpatient treatment for TRD. METHODS: Symptomatic and functional outcomes were assessed in 71 participants (unipolar, n=51; bipolar, n=20) with severe TRD previously treated at a specialist inpatient unit a median of 34 months (IQR 19-52) post discharge. We looked at outcomes in defined subgroups (unipolar, bipolar and psychotic) and at symptom clusters to see whether certain aspects of depression were more resistant to treatment than others. RESULTS: Symptomatic improvement during the admission was maintained at follow up: HDRS21 scores fell from admission (median 22; IQR 19-25) to discharge (median 12; IQR 7-16) and follow-up (median 10; IQR 4 18). Overall, two-thirds of patients were judged to have a good long-term outcome, while half remained in full remission at follow-up. Outcomes were more favourable in bipolar patients, patients without a history of psychosis and patients who were discharged in remission, although a minority of responders at discharge no longer met response criteria at follow up, and conversely some patients discharged as non-responders did subsequently respond. Non-remitting depression was characterised by three main factors; anxiety, cognitive difficulties and sleep disturbance. Those who remitted had better functional outcomes as did those who had experienced a more sustained response to treatment whilst inpatients. Quality of life was poor for those who did not respond to the treatment package. LIMITATIONS: Variable follow-up length. CONCLUSIONS: This difficult-to-treat population gained long-term benefits from multidisciplinary inpatient treatment. Treatment to remission was associated with more favourable outcomes. Non-responsive depression was characterised by specific symptom clusters that might be amenable to more targeted treatments. PMID- 25012451 TI - The duration of light treatment and therapy outcome in seasonal affective disorder. AB - BACKGROUND: Seasonal affective disorder (SAD) is characterized by recurrent episodes of major depression with a seasonal pattern, treated with light therapy (LT). Duration of light therapy differs. This study investigates retrospectively whether a single week of LT is as effective as two weeks, whether males and females respond differently, and whether there is an effect of expectations as assessed before treatment. METHODS: 83 women, and 25 men received either one-week (n=42) or two weeks (n=66) of LT were included in three studies. Before LT, patients' expectations on therapy response were assessed. RESULTS: Depression severity was similar in both groups before treatment (F(1,106)=0.19ns) and decreased significantly during treatment (main effect "time" F(2,105)=176.7, p<0.001). The speed of therapy response differs significantly in treatment duration, in favor of 1 week (F(2,105)=3.2, p=0.046). A significant positive correlation between expectations and therapy response was found in women (rho=0.243, p=0.027) and not in men (rho=-0.154,ns). When expectation was added as a covariate in the repeated-measures analysis it shows a positive effect of the level of expectation on the speed of therapy response (F(2,104)=4.1, p=0.018). LIMITATIONS: A limitation is the retrospective design. CONCLUSIONS: There is no difference between 1 and 2 weeks of LT in overall therapy outcome, but the speed of therapy response differed between 1 week LT and 2 weeks LT. Together with the significant correlation between expectations and therapy response in women, we hypothesize that expectations play a role in the speed of therapy response. PMID- 25012452 TI - Ultrafast colorimetric detection of nucleic acids based on the inhibition of the oxidase activity of cerium oxide nanoparticles. AB - A label-free colorimetric method to detect nucleic acids, which relies on target DNA induced shielding of the oxidase activity of CeO2 NPs, is developed. With this novel strategy, target nucleic acids can be identified within a few minutes and without the need for post-purification of PCR products. PMID- 25012453 TI - (11)C-hydroxyephedrine positron emission tomography in the postoperative management of pheochromocytoma and paraganglioma. AB - AIM: Accurate detection of recurrent disease and restaging are essential in the postoperative surveillance of many patients with pheochromocytomas (PHEOs) and paragangliomas (PGLs). In this study, the impact of positron emission tomography (PET) and PET/computed tomography (CT) with (11)C-hydroxyephedrine (HED) was evaluated for the postoperative surveillance and diagnosis of recurrent disease and for functional monitoring of locoregional and systemic therapy. METHODS: One hundred and eleven HED-PET and PET/CT examinations performed in 48 patients after surgical intervention for PHEO/PGL were analyzed retrospectively. In a subgroup of 16 patients who underwent systemic and locoregional therapies, the tracer uptake in tumors was also measured as the functional volume (FV), maximum standardized uptake value (SUVmax), mean SUV (SUVmean) and as the total catecholamine transporter tumor volume (TCTTV) calculated as TCTTV = FV * SUVmean. The PET imaging results were correlated with CT/magnetic resonance imaging findings and biochemical and clinical follow-up data. RESULTS: In the first postoperative examination, HED-PET was positive in 24/48 and negative in 24/48 patients with no false-positive results, yielding 92.3% sensitivity and 100% specificity. For the 16 patients, there was a significant correlation between FV and SUVmax and SUVmax and TCTTV. TCTTV correlated significantly with plasma and urinary catecholamines. In 11/16 patients, SUVmax and TCTTV increased/decreased in parallel but not in the remaining 5 patients. CONCLUSION: HED-PET and PET/CT were found to be valuable in the postoperative follow-up in detecting recurrent and metastatic disease. In a subgroup of patients, functional monitoring of systemic and locoregional therapies was feasible by assessing the changes of the TCTTV, and therefore warrants further prospective evaluation. PMID- 25012454 TI - Miocene shift of European atmospheric circulation from trade wind to westerlies. AB - The modern European climatic regime is peculiar, due to its unitary winter but diverse summer climates and a pronounced Mediterranean climate in the south. However, little is known on its evolution in the deep time. Here we reconstruct the European summer climate conditions in the Tortonian (11.62-7.246 Ma) using plant fossil assemblages from 75 well-dated sites across Europe. Our results clearly show that the Tortonian Europe mainly had humid to subhumid summers and no arid climate has been conclusively detected, indicating that the summer-dry Mediterranean-type climate has not yet been established along most of the Mediterranean coast at least by the Tortonian. More importantly, the reconstructed distribution pattern of summer precipitation reveals that the Tortonian European must have largely been controlled by westerlies, resulting in higher precipitation in the west and the lower in the east. The Tortonian westerly wind field appears to differ principally from the trade wind pattern of the preceding Serravallian (13.82-11.62 Ma), recently deduced from herpetofaunal fossils. Such a shift in atmospheric circulation, if ever occurred, might result from the development of ice caps and glaciers in the polar region during the Late Miocene global cooling, the then reorganization of oceanic circulation, and/or the Himalayan-Tibetan uplift. PMID- 25012455 TI - FOLFIRINOX bevacizumab is a promising therapy for chemorefractory metastatic colorectal cancer. AB - PURPOSE: Fluoropyrimidines, oxaliplatin, irinotecan and targeted therapies represent the standard treatment of metastatic colorectal cancer. After failure of all these treatments, few options are available. In such chemorefractory patients the effect of triplet chemotherapy with bevacizumab (FOLFIRINOX bevacizumab) has never been investigated. PATIENTS AND METHODS: 49 consecutive patients bearing unresectable metastatic colorectal cancer and who experienced failure to oxaliplatin- and irinotecan-based chemotherapy were treated with oxaliplatin (85 mg/m(2)), irinotecan (180 mg/m(2)), leucovorin (400 mg/m(2)), and fluorouracil (400 mg/m(2) bolus then 2,400 mg/m(2)) repeated every 2 weeks. RESULTS: Median age was 63 (range 36-82) years. After a median follow-up of 12 months, the median progression-free survival was 5.8 months (95% CI 3.4-6.8) and the median overall survival was 11.9 months (95% CI 8-18). The response rate after the cycle was evaluable for 36 patients, whereby we observed 18% (95% CI 8 35) partial or complete response, 45% (95% CI 28-68) stable disease of more than 2 months, and 37% (95% CI 21-58) progression. CONCLUSION: This study suggests that bevacizumab + FOLFIRINOX may be active in mCRC patients after failure of classical lines of chemotherapy. PMID- 25012456 TI - Aging and potential for self-renewal: hydra living in the age of aging - a mini review. AB - Hydra present an interesting deviation from typical life histories: they have an extensive capacity to regenerate and self-renew and seem to defy the aging process. Hydra have the ability to decouple the aging process from their life history and therefore provide us with a unique opportunity to gain insight into the aging process not only for basal hydrozoans but also for other species across the tree of life. We argue that under steady feeding and asexual reproduction Hydra species are able to escape aging as a result of high levels of cell proliferation and regenerative ability. We further highlight cellular processes for stem cell maintenance, such as the telomere dynamic, which prevent the accumulation of damage and protect against diseases and pathogens that mediate this condition. In addition, we discuss the causes of aging in other Hydra species. PMID- 25012457 TI - MIRD pamphlet No. 25: MIRDcell V2.0 software tool for dosimetric analysis of biologic response of multicellular populations. AB - Patients undergoing nuclear medicine procedures for cancer therapy are administered radiopharmaceuticals that emit various types of radiation. Because radiation has differential delivery to and uptake by cells in tissue, radiation exposures are often highly nonuniform. Some cell populations in a tissue may contain widely different amounts of radioactivity, whereas other cell populations in the same tissue may contain no radioactivity, referred to as labeled and unlabeled cells, respectively. Furthermore, the toxicity of the radiations emitted can depend on the location of the radioactive decay within the cell (e.g., nucleus vs. cytoplasm). Therefore, the response of a given cell depends on the absorbed dose received from radiations emitted by decays within the cell (self-dose) and emitted by decays in neighboring cells (cross-dose), among other factors. Taken together, these variables make it difficult to predict the response of cell populations to radiopharmaceuticals. Accordingly, to assist in designing treatment plans for therapeutic radiopharmaceuticals, an applet software application called MIRDcell was developed. This applet models the distribution of radiopharmaceuticals in tissues, calculates the distribution of radiation dose, models responses on a cell-by-cell basis, and predicts the surviving fraction of the labeled and unlabeled cell populations. MIRDcell can be accessed at http://mirdcell.njms.rutgers.edu/. PMID- 25012458 TI - Preclinical evaluation of 3-18F-fluoro-2,2-dimethylpropionic acid as an imaging agent for tumor detection. AB - Deregulated cellular metabolism is a hallmark of many cancers. In addition to increased glycolytic flux, exploited for cancer imaging with (18)F-FDG, tumor cells display aberrant lipid metabolism. Pivalic acid is a short-chain, branched carboxylic acid used to increase oral bioavailability of prodrugs. After prodrug hydrolysis, pivalic acid undergoes intracellular metabolism via the fatty acid oxidation pathway. We have designed a new probe, 3-(18)F-fluoro-2,2 dimethylpropionic acid, also called (18)F-fluoro-pivalic acid ((18)F-FPIA), for the imaging of aberrant lipid metabolism and cancer detection. METHODS: Cell intrinsic uptake of (18)F-FPIA was measured in murine EMT6 breast adenocarcinoma cells. In vivo dynamic imaging, time course biodistribution, and radiotracer stability testing were performed. (18)F-FPIA tumor retention was further compared in vivo to (18)F-FDG uptake in several xenograft models and inflammatory tissue. RESULTS: (18)F-FPIA rapidly accumulated in EMT6 breast cancer cells, with retention of intracellular radioactivity predicted to occur via a putative (18)F FPIA carnitine-ester. The radiotracer was metabolically stable to degradation in mice. In vivo imaging of implanted EMT6 murine and BT474 human breast adenocarcinoma cells by (18)F-FPIA PET showed rapid and extensive tumor localization, reaching 9.1% +/- 0.5% and 7.6% +/- 1.2% injected dose/g, respectively, at 60 min after injection. Substantial uptake in the cortex of the kidney was seen, with clearance primarily via urinary excretion. Regarding diagnostic utility, uptake of (18)F-FPIA was comparable to that of (18)F-FDG in EMT6 tumors but superior in the DU145 human prostate cancer model (54% higher uptake; P = 0.002). Furthermore, compared with (18)F-FDG, (18)F-FPIA had lower normal-brain uptake resulting in a superior tumor-to-brain ratio (2.5 vs. 1.3 in subcutaneously implanted U87 human glioma tumors; P = 0.001), predicting higher contrast for brain cancer imaging. Both radiotracers showed increased localization in inflammatory tissue. CONCLUSION: (18)F-FPIA shows promise as an imaging agent for cancer detection and warrants further investigation. PMID- 25012459 TI - The efficacy of hepatic 90Y resin radioembolization for metastatic neuroendocrine tumors: a meta-analysis. AB - (90)Y resin radioembolization is an emerging treatment in patients with liver dominant metastatic neuroendocrine tumors (mNETs), despite the absence of level I data. The aim of this study was to evaluate the efficacy of this modality in a meta-analysis of the published literature. METHODS: A comprehensive review protocol screened all reports in the literature. Strict selection criteria were applied to ensure consistency among the selected studies: human subjects, complete response data with time interval, resin microspheres, more than 5 patients, not a duplicate cohort, English language, and separate and complete data for resin-based (90)Y treatment of mNET if the study included multiple tumor and microsphere types. Selected studies were critically appraised on 50 study criteria, in accordance with the research reporting standards for radioembolization. Response data (Response Evaluation Criteria in Solid Tumors) were extracted and analyzed using both fixed and random-effects meta-analyses. RESULTS: One hundred fifty-six studies were screened; 12 were selected, totaling 435 procedures for response assessment. Funnel plots showed no evidence of publication bias (P = 0.841). Critical appraisal revealed a median of 75% of desired criteria included in selected studies. Very high between-study heterogeneity ruled out a fixed-effects model. The random-effects weighted average objective response rate (complete and partial responses, CR and PR, respectively) was 50% (95% confidence interval, 38%-62%), and weighted average disease control rate (CR, PR, and stable disease) was 86% (95% confidence interval, 78%-92%). The percentage of patients with pancreatic mNET was marginally associated with poorer response (P = 0.030), accounting for approximately 23% of the heterogeneity among studies. The percentage of CR and PR correlated with median survival (R = 0.85; P = 0.008). CONCLUSION: This meta analysis confirms radioembolization to be an effective treatment option for patients with hepatic mNET. The pooled data demonstrated a high response rate and improved survival for patients responding to therapy. PMID- 25012460 TI - The microscopic complexities of C3 in breast cytology. AB - BACKGROUND: Fine-needle aspiration (FNA) of difficult breast lesions often results in an atypical (C3) report. The assortment of outcomes generated by C3 reports varies widely, and this has given rise to different clinical management pathways. OBJECTIVE: To identify and objectively assess microscopic features associated with atypical/C3 breast FNA cases. MATERIALS AND METHODS: A total of 230 atypical breast FNAs were subjected to a blind microscopic rescreen using a range of robust qualitative and quantitative cytological criteria including cellularity, architectural qualities, cytomorphology and background features. A logistic regression with a receiver operating characteristic (ROC) curve and the resultant forward stepwise analysis were conducted to assess the results. This statistical testing was measured against malignant, benign proliferative and benign non-proliferative outcomes. RESULTS: The malignant and benign proliferative outcomes showed a mixture of opposing protective and predictive individual cytological criteria. The stepwise analysis produced models demonstrating the best combination of individual cytological criteria for malignancy, proliferative and benign non-proliferative entities. In the malignancy model, discohesion, nuclear crowding within sheets, diminished numbers of bare bipolar nuclei and myoepithelial cells, the presence of tubules or necrosis and the absence of a cystic background were important features. The benign proliferative model suggested the same criteria but with the opposite implication and with the addition of several others, such as the presence of apocrine metaplasia, retained polarity and a speckled or coarse chromatin pattern. Age was a significant factor in malignant and proliferative outcomes. The benign non-proliferative stepwise analysis produced a model with fewer criteria (complex sheets, bare bipolar nuclei and a cystic background) limiting clinical application. CONCLUSION: Atypical/C3 breast cytology remains a legitimate reporting category. However, it is associated with a number of different histological outcomes. The incidence of the C3 category can be significantly reduced by controlling extrinsic factors and understanding the associated microscopic features. PMID- 25012461 TI - The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives. AB - Attention-deficit/hyperactivity disorder (ADHD) is a persistent neuropsychiatric disorder which is associated with impairments on a variety of cognitive measures and abnormalities in structural and functional brain measures. Genetic factors are thought to play an important role in the etiology of ADHD. The NeuroIMAGE study is a follow-up of the Dutch part of the International Multicenter ADHD Genetics (IMAGE) project. It is a multi-site prospective cohort study designed to investigate the course of ADHD, its genetic and environmental determinants, its cognitive and neurobiological underpinnings, and its consequences in adolescence and adulthood. From the original 365 ADHD families and 148 control (CON) IMAGE families, consisting of 506 participants with an ADHD diagnosis, 350 unaffected siblings, and 283 healthy controls, 79 % participated in the NeuroIMAGE follow-up study. Combined with newly recruited participants the NeuroIMAGE study comprehends an assessment of 1,069 children (751 from ADHD families; 318 from CON families) and 848 parents (582 from ADHD families; 266 from CON families). For most families, data for more than one child (82 %) and both parents (82 %) were available. Collected data include a diagnostic interview, behavioural questionnaires, cognitive measures, structural and functional neuroimaging, and genome-wide genetic information. The NeuroIMAGE dataset allows examining the course of ADHD over adolescence into young adulthood, identifying phenotypic, cognitive, and neural mechanisms associated with the persistence versus remission of ADHD, and studying their genetic and environmental underpinnings. The inclusion of siblings of ADHD probands and controls allows modelling of shared familial influences on the ADHD phenotype. PMID- 25012462 TI - The role of DCDC2 genetic variants and low socioeconomic status in vulnerability to attention problems. AB - Both genetic and socio-demographic factors influence the risk for behavioral problems in the developmental age. Genetic studies indicate that shared genetic factors partially contribute to behavioral and learning problems, in particular reading disabilities (RD). For the first time, we explore the conjoint role of DCDC2 gene, an identified RD candidate gene, and socioeconomic status (SES) upon behavioral phenotypes in a general population of Italian children. Two of the most replicated DCDC2 markers [i.e., regulatory element associated with dyslexia 1 (READ1), rs793862] were genotyped in 631 children (boys = 314; girls = 317) aged 11-14 years belonging to a community-based sample. Main and interactive effects were tested by MANOVA for each combination of DCDC2 genotypes and socioeconomic status upon emotional and behavioral phenotypes, assessed by Child Behavior Check-List/6-18. The two-way MANOVA (Bonferroni corrected p value = 0.01) revealed a trend toward significance of READ1(4) effect (F = 2.39; p = 0.016), a significant main effect of SES (F = 3.01; p = 0.003) and interactive effect of READ1(4) * SES (F = 2.65; p = 0.007) upon behavioral measures, showing higher attention problems scores among subjects 'READ1(4+) and low SES' compared to all other groups (p values range 0.00003-0.0004). ANOVAs stratified by gender confirmed main and interactive effects among girls, but not boys. Among children exposed to low socioeconomic level, READ1 genetic variant targets the worst outcome in children's attention. PMID- 25012463 TI - Associations between overweight, peer problems, and mental health in 12-13-year old Norwegian children. AB - Overweight and mental health problems represent two major challenges related to child and adolescent health. More knowledge of a possible relationship between the two problems and the influence of peer problems on the mental health of overweight children is needed. It has previously been hypothesized that peer problems may be an underlying factor in the association between overweight and mental health problems. The purpose of the present study was to investigate the associations between overweight, peer problems, and indications of mental health problems in a sample of 12-13-year-old Norwegian schoolchildren. Children aged 12 13 years were recruited from the seventh grade of primary schools in Telemark County, Norway. Parents gave information about mental health and peer problems by completing the extended version of the Strength and Difficulties Questionnaire (SDQ). Height and weight were objectively measured. Complete data were obtained for 744 children. Fisher's exact probability test and multiple logistic regressions were used. Most children had normal good mental health. Multiple logistic regression analysis showed that overweight children were more likely to have indications of psychiatric disorders (adjusted OR: 1.8, CI: 1.0-3.2) and peer problems (adjusted OR: 2.6, CI: 1.6-4.2) than normal-weight children, when adjusted for relevant background variables. When adjusted for peer problems, the association between overweight and indications of any psychiatric disorder was no longer significant. The results support the hypothesis that peer problems may be an important underlying factor for mental health problems in overweight children. PMID- 25012464 TI - Investigation of the interfacial effects of small chemical-modified TiO2 nanotubes on 3T3 fibroblast responses. AB - In order to gain insight into how interfacial effects influence cell responses, chemically modified anodized TiO2 nanotubes (ATNs) were used to simultaneously investigate the effects of nanoscale substrate structure and angstrom-scale chemicals on cell morphological change and cell growth. Two small chemicals were used to modify the ATNs, namely, 3-aminopropyltrimethoxysilane (APTMS) and 3 mercaptopropyltrimethoxysilane (MPTMS), resulting in APTMS-modified ATNs (APTMS ATNs) and MPTMS-modified ATNs (MPTMS-ATNs), respectively. In our in vitro observation of NIH/3T3 fibroblasts, cells thrived on both unmodified and modified ATNs. Quantitative analyses of cell numbers exhibited that APTMS-ATNs effectively facilitated cell proliferation and directed cell orientation owing to full cell substrate contact caused by positively charged amino groups (-NH3(+)) on the surface. In addition, scanning electron microscopy and fluorescence images showed different cell morphologies on APTMS-ATNs and MPTMS-ATNs. APTMS-ATNs resulted in flat spreading of fibroblasts, while MPTMS-ATNs resulted in fibroblasts with a three-dimensional solid shape and clear contours. The results indicate that the synergistic effects of nanotube surface topology and small chemical modification and, to a lesser extent, surface hydrophilicity, alter the interfacial interactions between cells and substrates, significantly affecting cell morphology, attachment, and growth. Using ATNs with different interfacial effects from various small chemicals, orientation of cells into various patterns can be achieved and investigation of cell fates, such as proliferation or stem cell differentiation, can be performed for future advanced medical or biological applications. PMID- 25012465 TI - Performance assessment of a brain-computer interface driven hand orthosis. AB - Stroke survivors are typically affected by hand motor impairment. Despite intensive rehabilitation and spontaneous recovery, improvements typically plateau a year after a stroke. Therefore, novel approaches capable of restoring or augmenting lost motor behaviors are needed. Brain-computer interfaces (BCIs) may offer one such approach by using neurophysiological activity underlying hand movements to control an upper extremity orthosis. To test the performance of such a system, we developed an electroencephalogram-based BCI controlled electrically actuated hand orthosis. Six able-bodied participants voluntarily grasped/relaxed one hand to elicit BCI-mediated closing/opening of the orthosis mounted on the opposite hand. Following a short training/calibration procedure, participants demonstrated real-time, online control of the orthosis by following computer cues. Their performances resulted in an average of 1.15 (standard deviation: 0.85) false alarms and 0.22 (0.36) omissions per minute. Analysis of signals from electrogoniometers mounted on both hands revealed an average correlation between voluntary and BCI-mediated movements of 0.58 (0.13), with all but one online performance being statistically significant. This suggests that a BCI driven hand orthosis is feasible, and therefore should be tested in stroke individuals with hand weakness. If proven viable, this technology may provide a novel approach to the neuro-rehabilitation of hand function after stroke. PMID- 25012466 TI - Early detection of impending necrotizing enterocolitis with urinary intestinal fatty acid-binding protein. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is diagnosed after the development of feeding intolerance and characteristic physical and imaging findings. Earlier detection of a subclinical prodrome might allow for the institution of measures that could prevent or attenuate the severity of the disease. OBJECTIVES: We sought to determine whether urinary intestinal fatty acid-binding protein (iFABPu) might be elevated prior to the first clinical manifestations of NEC. METHODS: Urine was collected daily from 62 infants of a gestational age of 24-28 weeks. Based on clinical, imaging and operative findings, subjects were determined to have Bell stage 2 or 3 NEC. In all the subjects with NEC and in 21 age-matched controls, iFABPu was determined using an ELISA, and was expressed in terms of its ratio to urinary creatinine (Cr), i.e. iFABPu/Cru. Receiver operating characteristic (ROC) curves were constructed to define the predictive value of iFABPu/Cru for impending NEC in the days prior to the first clinical manifestations. RESULTS: Five subjects developed NEC (stage 2: n = 3 and stage 3: n = 2). The day before the first clinical manifestation of NEC, a ROC curve showed that an iFABPu/Cru >10.2 pg/nmol predicted impending NEC with a sensitivity of 100% and a specificity of 95.6%. iFABPu/Cru did not predict NEC 2 days prior to the first sign of disease. CONCLUSIONS: An elevated iFABPu was a sensitive and specific predictor of impending NEC 1 day prior to the first clinical manifestations. iFABPu screening might identify infants at a high risk and allow for the institution of measures that could ameliorate or prevent NEC. PMID- 25012467 TI - Pharmacological doses of niacin stimulate the expression of genes involved in carnitine uptake and biosynthesis and improve the carnitine status of obese Zucker rats. AB - BACKGROUND: Activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARdelta causes an elevation of tissue carnitine concentrations through induction of genes involved in carnitine uptake [novel organic cation transporter 2, (OCTN2)], and carnitine biosynthesis [gamma-butyrobetaine dioxygenase (BBD), 4 N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH)]. Recent studies showed that administration of the plasma lipid-lowering drug niacin causes activation of PPARalpha and/or PPARdelta in tissues of obese Zucker rats, which have a compromised carnitine status and an impaired fatty acid oxidation capacity. Thus, we hypothesized that niacin administration to obese Zucker rats is also able to improve the diminished carnitine status of obese Zucker rats through PPAR mediated stimulation of genes involved in carnitine uptake and biosynthesis. METHODS: To test this hypothesis, we used plasma, muscle and liver samples from a recent experiment with obese Zucker rats, which were fed either a niacin-adequate diet (30 mg niacin/kg diet) or a diet with a pharmacological niacin dose (780 mg niacin/kg diet), and determined concentrations of carnitine in tissues and mRNA and protein levels of genes critical for carnitine homeostasis (OCTN2, BBD, TMABA DH). Statistical data analysis of all data was done by one-way ANOVA, and Fisher's multiple range test. RESULTS: Rats of the obese niacin group had higher concentrations of total carnitine in plasma, skeletal muscle and liver, higher mRNA and protein levels of OCTN2, BBD, and TMABA-DH in the liver and higher mRNA and protein levels of OCTN2 in skeletal muscle than those of the obese control group (P < 0.05), whereas rats of the obese control group had lower concentrations of total carnitine in plasma and skeletal muscle than lean rats (P < 0.05). CONCLUSION: The results show for the first time that niacin administration stimulates the expression of genes involved in carnitine uptake and biosynthesis and improves the diminished carnitine status of obese Zucker rats. We assume that the induction of genes involved in carnitine uptake and biosynthesis by niacin administration is mediated by PPAR-activation. PMID- 25012468 TI - Central nervous system infection caused by vancomycin-intermediate Staphylococcus aureus (SCCmec type IV, ST8). AB - A 77-year-old Japanese man with a history of surgical treatment of chronic subdural hemorrhage was hospitalized for drainage of a subdural abscess and brain abscess in the right occipital area. Pus obtained from both the subdural abscess and brain abscess grew vancomycin-intermediate Staphylococcus aureus (VISA) (minimum inhibitory concentration = 4 MUg/mL), which was confirmed by population analysis. The SCCmec type and sequence type were subsequently identified as IV and ST8, respectively. The VISA strains were both sensitive to levofloxacin, clindamycin, minocycline, and linezolid. The patient was successfully treated with linezolid and discharged on day 51 after admission. We herein describe the first reported case of a brain abscess and subdural abscess caused by VISA in Japan. PMID- 25012469 TI - Clinical characteristics of Raoultella ornithinolytica bacteremia: a case series and literature review. AB - Raoultella ornithinolytica is a rare pathogen in human infection and bacteremic cases had been scarcely reported. For further comprehension of the rare infection, we summarized clinical characteristics of 6 cases that were detected at our medical facility and 5 cases from previous literature. The most common infectious focus was biliary infection and elderly patients with a history of any biliary intervention or malignancy were considered to be at a great risk for the infection. The prognosis of the patients was quite satisfactory. Bacterial identification in this report was performed on the basis of biochemical tests alone, and further investigations by molecular analysis are required to confirm our findings. PMID- 25012470 TI - The influence of culture of honor and emotional intelligence in the acculturation of Moroccan immigrant women. AB - Migration is a normal process of people seeking new opportunities, work, or leisure in societies. The way people adapt to a new country (acculturation) is a complex process in which immigrants' evaluations about the culture of origin and their perceptions of the host country interact. The combination of these two factors produces four types of acculturation: separation, assimilation, integration, and marginalization. Several variables, such as personality, attitudes, and emotional intelligence, have been studied to help explain this process. However, the impact of a culture of honor and its interaction with other variables remains an open question that may help to explain how migrants can better adjust to their host culture. In this study, we examine the influence of the culture of honor (social) and emotional intelligence (individual) on acculturation. In a sample of 129 Moroccan women (mean age = 29, SD = 9.40) immigrants in Spain (mean time in Spain = 6 years, SD = 3.60), we investigated the relations among the variables of interest. Our results show that no significant differences emerged in the scores given for culture of honor (CH) and the acculturation strategies of the Moroccan immigrant women F(3, 99) = .233; p = .87. However women who preferred the integration strategy scored highest on emotional intelligence (EI), whereas the assimilated immigrants showed the lowest scores for EI F(3, 92) = 4.63; p = .005. Additionally, only in the case of integration does EI mediate between CH and the value given to the immigrant's own and host cultures (p <.001). PMID- 25012471 TI - Transplantation of endothelial progenitor cells in treating rats with IgA nephropathy. AB - BACKGROUND: Therapeutic options in IgAN are still limited. The aim of this study is to explore the feasibility of using endothelial progenitor cell to treat IgAN in rat model. METHODS: Rat bone marrow mononuclear cells (BM-MNCs) obtained with density gradient centrifugation were cultured in vitro, and induced into endothelial progenitor cells (EPCs). EPCs were identified by surface marker CD34, CD133 and VEGFR2 (FLK-1) and by Dil-Ac-LDL/FITC-UEA-1 double staining. EPCs were labeled with PKH26 prior to transplantation. Rat model of IgAN was established by oral administration of bovine serum albumin together with lipopolysaccharide via the caudal vein and subcutaneous injection of CCL4. Kidney paraffin sections were stained by H&E and PAS. Immunofluorescence was used to assess IgA deposition in the glomeruli. Peritubular capillary (PTC) density was determined by CD31 staining. Monocyte chemoattrant protein-1 (MCP-1), hypoxia-inducible factor 1alpha (HIF-1alpha) and CD105 were also measured by immunohistochemistry, western blotting and real-time fluorescent quantitative PCR. RESULTS: The transplanted BM EPCs were successfully located in IgAN rat kidney. After transplantation, Urinary red blood cell, urine protein, BUN, Scr and IgA serum level were significantly decreased, so were the areas of glomerular extracellular matrix and the IgA deposition in the glomeruli. In addition, PTC density was elevated. And the expression levels of HIF-1alpha and MCP-1 were significantly down-regulated, while the expression of CD105 was up-regulated. All these changes were not observed in control groups. CONCLUSION: The BM-EPCs transplantation significantly decreases the expansion of glomerular extracellular matrix and the deposition of IgA in the glomeruli; lowers the expression of inflammatory factors; increases PTC density; improves ischemic-induced renal tissue hypoxia, all of which improves the renal function and slows the progress of IgA nephropathy. PMID- 25012472 TI - C-arm cone-beam computed tomography in interventional oncology: technical aspects and clinical applications. AB - C-arm cone-beam computed tomography (CBCT) is a new imaging technology integrated in modern angiographic systems. Due to its ability to obtain cross-sectional imaging and the possibility to use dedicated planning and navigation software, it provides an informed platform for interventional oncology procedures. In this paper, we highlight the technical aspects and clinical applications of CBCT imaging and navigation in the most common loco-regional oncological treatments. PMID- 25012473 TI - Radiopharmaceutical study on Iodine-131-labelled hypericin in a canine model of hepatic RFA-induced coagulative necrosis. AB - PURPOSE: Hypericin (HYP) has been found avid to necrosis in small animal studies. We sought to evaluate the tissue distribution of (131)I-HYP in a large animal model and to explore the theranostic utilities of (131)I-HYP after radiofrequency ablation (RFA). MATERIALS AND METHODS: This animal experiment was approved by the institutional ethics committee. Twenty-five male dogs were enrolled and subjected to transabdominal hepatic RFA. (131)I-HYP was prepared by an electrophilic substitution method and intravenously administered at 0.5 mCi/kg. Systemic and regional distributions of (131)I-HYP were monitored dynamically by single-photon emission computed tomography/computed tomography (SPECT-CT), gamma counting, autoradiography, and fluorescent and light microscopy at different time points up to 14 days. Experimental data were quantified and statistically analysed. RESULTS: Most of the tissues and organs retained (131)I-HYP only transiently. (131)I-HYP was mainly metabolised in the liver and excreted into the bile. (131)I HYP gradually accumulated in the RFA-induced necrosis with a peak concentration occurring within 2 days and lasting over 2 weeks as visualised by in vivo SPECT CT and ex vivo autoradiography and fluorescent microscopy, and quantified by radioactivity and fluorescence measurements. Accumulation of (131)I-HYP was low in both the necrosis centre and normal liver tissue. CONCLUSION: (131)I-HYP showed persistent high affinity to hepatic thermo-coagulative necrosis, but only a transient uptake by normal liver in dogs. Necrosis caused by RFA could be indicated by (131)I-HYP on nuclear imaging, which suggests a supplementary measure for tumour detection and therapy. PMID- 25012474 TI - Role of virtopsy in the post-mortem diagnosis of drowning. AB - PURPOSE: Due to admitted limits of autopsy-based studies in the diagnosis of drowning, virtopsy is considered the new imaging horizon in these post-mortem studies. The aim of our study was to evaluate the role of virtopsy performed through computed tomography (CT) in the forensic diagnosis of drowning. MATERIALS AND METHODS: We retrospectively examined the CT data of four cadavers recovered from sea water and suspected to have died by drowning. Each patient underwent a full-body post-mortem CT scan, and then a traditional autopsy. RESULTS: All the cadavers showed fluid in the airways and patchy ground-glass opacities in the lung. Only one patient had no fluid in the digestive tract; this patient had a left parietal bone fracture with a large gap and other multiple bone fractures (nose, clavicle, first rib and patella). One of the three patients who had fluid in the digestive tract had no fluid in the paranasal sinuses. This latter patient showed cerebral oedema with subarachnoid and intraventricular haemorrhage, multiple bone fractures (orbital floor, ribs, sacrum and acetabular edge) and air in the heart, in the aorta and in bowel loops. CONCLUSION: To date, there are no autopsy findings pathognomonic of drowning. This study proves that virtopsy is a useful tool in the diagnosis of drowning in that it allows us to understand if the victim was alive or dead when he entered the water and if the cause of death was drowning. PMID- 25012475 TI - Male-driven grooming bouts in mixed-sex dyads of Kinda baboons (Papio kindae). AB - The behavior of the Central African Kinda baboon (Papio kindae) is not well documented. Having previously noted distinctive grooming behavior in several Kinda baboon populations, we investigated the topic more systematically in the Kafue National Park, Zambia. We recorded the duration and details of male-female dyadic interactions (approaches, withdrawals and time spent grooming) in the early morning and late afternoon. Such interactions were more often initiated by the male and terminated by the female partner. The male groomed the female more often, and longer, than she groomed him, regardless of the female's reproductive state or the presence of an infant. The bias towards male grooming was stronger in morning than evening interactions. These behaviors, whose function is not immediately obvious, and which are unlike those previously reported in baboons, further exemplify the distinctiveness of the taxon. PMID- 25012476 TI - Impact of ensemble learning in the assessment of skeletal maturity. AB - The assessment of the bone age, or skeletal maturity, is an important task in pediatrics that measures the degree of maturation of children's bones. Nowadays, there is no standard clinical procedure for assessing bone age and the most widely used approaches are the Greulich and Pyle and the Tanner and Whitehouse methods. Computer methods have been proposed to automatize the process; however, there is a lack of exploration about how to combine the features of the different parts of the hand, and how to take advantage of ensemble techniques for this purpose. This paper presents a study where the use of ensemble techniques for improving bone age assessment is evaluated. A new computer method was developed that extracts descriptors for each joint of each finger, which are then combined using different ensemble schemes for obtaining a final bone age value. Three popular ensemble schemes are explored in this study: bagging, stacking and voting. Best results were achieved by bagging with a rule-based regression (M5P), scoring a mean absolute error of 10.16 months. Results show that ensemble techniques improve the prediction performance of most of the evaluated regression algorithms, always achieving best or comparable to best results. Therefore, the success of the ensemble methods allow us to conclude that their use may improve computer-based bone age assessment, offering a scalable option for utilizing multiple regions of interest and combining their output. PMID- 25012477 TI - Decision tree based diagnostic system for moderate to severe obstructive sleep apnea. AB - One of the major modern medical issues, obstructive sleep apnea (OSA), particularly at moderate to severe levels, may potentially cause cardiovascular morbidity and mortality. However, polysomnography (PSG), a gold standard tool in diagnosing OSA, is cumbersome, has limited availability, and is costly and time consuming. Clinical prediction models thus are absolutely necessary in screening patients with OSA. Furthermore, the performance of the published prediction formulas is not satisfactory for Chinese populations. The aim of this study was to develop and validate a simple and accurate prediction system for the diagnosis of moderate to severe OSA by integrating an expert-based feature extraction technique with decision tree algorithms which have automatic feature selection capability in screening the moderate to severe OSA cases in Taiwan. Moreover, the backward stepwise multivariable logistic regression model and four other decision tree algorithms were also employed for comparison. The results showed that the proposed best prediction formula, with an overall accuracy reaching to 96.9 % in sensitivity = 98.2 % and specificity = 93.2 %, could present a good tool for screening moderate and severe Taiwanese OSA patients who require further PSG evaluation and medical intervention. Results also indicate that the proposed best prediction formula is simple, accurate, and reliable, and outperforms all the other prediction formulae considered in the present study. The proposed clinical prediction formula derived from three non-invasive features (Sex, Age, and AveSBP) may help prioritize patients for PSG studies as well as avoid a diagnosis of PSG in subjects who have a low probability of having the disease. PMID- 25012478 TI - Pulmonary adenocarcinoma T1N0M0 and its classification. AB - Over the last decade, use of the term bronchioloalveolar carcinoma (BAC) has come under constant scrutiny as some consider it an anachronism or a term that provides incorrect information about this neoplasm. To that extent, it has recently been suggested to replace the term BAC with that of in situ adenocarcinoma (AIS) or minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure bronchioloalveolar growth (AIS) or predominant bronchioloalveolar growth and <=5-mm invasion (MIA). However, as of today, there is no comprehensive study of these tumors, and most of what has been published in this context is based on a review of the literature that focused on scattered short series of cases describing either small adenocarcinomas or BAC. More recently, a large series of cases of a more comprehensive nature that included all early-stage adenocarcinomas (T1N0M0) has cast some doubt regarding the need for the proposed change in nomenclature. At the same time, it was suggested that if indeed that notion is maintained, a more serious and comprehensive study of actual cases must be undertaken. The details of the issues surrounding this subject are presented in this review. PMID- 25012479 TI - Autonomic dysfunction in chronic persistent dizziness. AB - OBJECTIVE: To investigate the autonomic dysfunction in patients with chronic persistent dizziness using standardized autonomic function tests. METHODS: We prospectively recruited 18 patients with chronic persistent dizziness after excluding other causes with extensive investigations. A standardized battery of autonomic tests including the head up tilt (HUT) test, Valsalva maneuver (VM), and heart rate (HR) response to deep breathing was performed. RESULTS: Approximately eighty percent of the patients showed at least one abnormality in autonomic tests. Two patterns of autonomic abnormality were identified: sympathetic failure, including abnormal decrease in blood pressure (BP) during HUT test or abnormal sympathetic indices related with the BP recovery during late phase II and phase IV during VM, and sympathetic hyperactivity, including abnormal increase in HR response during HUT test or an exaggerated phase IV response manifesting increased beta-adrenergic tone during VM. CONCLUSIONS: Autonomic dysfunction is frequently found in patients with chronic persistent dizziness after excluding other causes with extensive investigations. Sympathetic failure or hyperactivity may be postulated as one of the possible causes of chronic persistent dizziness. Clinicians should be aware of the possibility of autonomic dysfunction in patients with chronic dizziness, even if the dizziness is not orthostatic but persistent. PMID- 25012480 TI - Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. AB - Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests. PMID- 25012481 TI - Association study of two steroid biosynthesis genes (COMT and CYP17) with Alzheimer's disease in the Italian population. AB - The greater predisposition of women to Alzheimer's disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case-control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity. PMID- 25012482 TI - Misconceptions surrounding the genetic susceptibility to ischemic stroke. PMID- 25012483 TI - Tracheostomy ventilation in ALS: a Japanese bias. PMID- 25012484 TI - Psychological inflexibility mediates the effects of self-efficacy and anxiety sensitivity on worry. AB - Recent research has found low levels of general self-efficacy (GSE: beliefs about the ability to appropriately handle a wide range of stressors) and high levels of anxiety sensitivity (AS: fear of the negative consequences of experiencing anxiety) to be relevant predictors of pathological worry. This study examined the role of psychological inflexibility (PI: the dominance of private experiences over chosen values and contingencies in guiding action), the central component of the acceptance and commitment therapy model of psychopathology, in the effect of GSE and AS on worry. A total of 132 nonclinical participants completed questionnaires assessing the constructs of interest. Partial correlations and regression analyses showed that both GSE and AS were independent predictors of pathological worry after controlling for each other. However, mediation analyses revealed that psychological inflexibility completely mediated the independent effects of both GSE and AS on pathological worry. Theoretical and treatment implications of the results are discussed. PMID- 25012485 TI - CIP2A and PP2A in human leptomeninges, arachnoid granulations and meningiomas. AB - Previously we have found that mitogens stimulate proliferation of meningioma cells of all grades, in part, by activation of the PI3K-PKB/Akt-PRAS40-mTOR pathway regulated to some degree by the tumor suppressor phosphatase PP2A. PP2A activity is inhibited by the oncoprotein cancerous inhibitor of PP2A (CIP2A), which has not been studied in meningiomas to our knowledge. Six fetal and one adult human leptomeningeal samples and 38 meningiomas were evaluated by western blot. Fifteen adult arachnoid granulations and 58 formalin-fixed meningiomas (36 World Health Organization grade I, 15 grade II and seven grade III) were evaluated by immunohistochemistry. The effects of the mitogens platelet derived growth factor-BB (PDGF-BB) and cerebrospinal fluid on CIP2A were also studied. By western blot, CIP2A and PP2A were found in the five fetal and one adult leptomeninges and all meningiomas. By immunohistochemistry, CIP2A was detected in the arachnoid granulations and all meningiomas. CIP2A tended to be higher in grade III tumors. Three fetal leptomeningeal (two grade I and one grade II) and meningioma cells treated with PDGF-BB and/or human cerebrospinal fluid resulted in a slight increase in CIP2A in the leptomeningeal cells but not meningioma cells. Considered the mechanism of action and seen in other neoplasms, these findings raise the possibility that CIP2A may participate in the biology of meningiomas. PMID- 25012486 TI - Sonoablation and application of MRI guided focused ultrasound in a preclinical model. AB - Stereotaxic sonoablative surgery by MRI guided high intensity focused ultrasound (FUS) holds great potential in disorders of the central nervous system (CNS). We previously described the ExAblate 2000 system (InSightec, Tirat Carmel, Israel), currently in use for various pathologies including uterine, liver, and, breast tumors, and referred to as the "body" system. Using a porcine model we have previously demonstrated, using the body system, the ablative capacity and thermal transfer in the cortex; developed a reproducible and translational model of craniectomy and post-operative recovery in FUS; and determined a grouping strategy based on thermal ablation and pathologic incremental changes in the cortex. Here we describe a novel ExAblate 4000 system that is designed specifically to treat CNS disorders ("head" system). Twenty-two swine underwent an improved wide craniectomy for positioning of the ExAblate 4000 containing 1024 elements arrayed with MRI guidance. Further neurologic and pathological analysis was performed 1 week post-operatively. Subjects underwent a wide craniectomy followed by high intensity MR guided focused ultrasound (MRgHIFU) sonoablation. Thermal ultrasonic ablative lesions were achieved in all subjects (n=22) ranging from 52-65 degrees C following ~70 consecutive sonications at 80 watts. These subjects were grouped based on thermal ablative lesions and post-operative staging (MRI, gross and microscopic pathology). Our results indicate the reproducibility of a porcine model for cerebral ablation, achieved across a dynamic temperature range, and well tolerated in this cohort. The ExAblate 4000 system is efficient through a wide craniectomy as well as a closed skull and demonstrates a high safety margin. Incremental hemorrhage and necrosis were minimal and energy dependent, indicating MRgHIFU can be used for the treatment of various cerebral pathologies and movement disorders. PMID- 25012488 TI - Surgical strategies for ossified ligamentum flavum associated with dural ossification in thoracic spinal stenosis. AB - We describe two surgical strategies for treating thoracic spinal stenosis (TSS) with ossification of the ligamentum flavum (OLF) and dural ossification (DO), and discuss their postoperative efficacy. From January 2004 to June 2008, 147 patients underwent TSS surgery. Thirty three of those with intraoperative evidence of OLF and DO were included in the present study. Based on the different intraoperative treatment of the dura, these 33 patients were divided into two groups: Group A, 17 patients who had their dura slit and the ossification excised, and Group B, 16 patients treated by floating the ossified dura by thinning it with a drill. All patients underwent outpatient follow-up. Pre- and postoperative Japanese Orthopaedic Association (JOA) scores and recovery rates were evaluated. The mean follow-up period was 42 months. The incidence of DO with OLF in TSS was 22%. At 1 year follow-up, the mean JOA score improved from 5.12 +/ 1.17 to 6.94 +/- 0.90 in Group A and from 5.25 +/- 1.34 to 7.13 +/- 1.41 in Group B. Additionally, the mean JOA score improved from 5.18 +/- 1.24 to 7.03 +/- 1.16 in TSS patients with DO and from 5.52 +/- 1.21 to 7.21 +/- 1.18 in TSS patients without DO. The increased cross-sectional area of the pre- and postoperative dural sac at the level of stenosis suggested that decompression was complete. Both decompression methods are feasible for curing TSS with OLF and DO. Moreover, slitting the dura for ossified dura and ligamentum flavum removal to relax the spinal cord is a safe and reliable method. Even though it increased the surgical difficulties and risks, DO did not affect postoperative neurological recovery. PMID- 25012487 TI - Neurologic disorders, in-hospital deaths, and years of potential life lost in the USA, 1988-2011. AB - Premature mortality is a public health concern that can be quantified as years of potential life lost (YPLL). Studying premature mortality can help guide hospital initiatives and resource allocation. We investigated the categories of neurologic and neurosurgical conditions associated with in-hospital deaths that account for the highest YPLL and their trends over time. Using the Nationwide Inpatient Sample (NIS), we calculated YPLL for patients hospitalized in the USA from 1988 to 2011. Hospitalizations were categorized by related neurologic principal diagnoses. An estimated 2,355,673 in-hospital deaths accounted for an estimated 25,598,566 YPLL. The traumatic brain injury (TBI) category accounted for the highest annual mean YPLL at 361,748 (33.9% of total neurologic YPLL). Intracerebral hemorrhage, cerebral ischemia, subarachnoid hemorrhage, and anoxic brain damage completed the group of five diagnoses with the highest YPLL. TBI accounted for 12.1% of all inflation adjusted neurologic hospital charges and 22.4% of inflation adjusted charges among neurologic deaths. The in-hospital mortality rate has been stable or decreasing for all of these diagnoses except TBI, which rose from 5.1% in 1988 to 7.8% in 2011. Using YPLL, we provide a framework to compare the burden of premature in-hospital mortality on patients with neurologic disorders, which may prove useful for informing decisions related to allocation of health resources or research funding. Considering premature mortality alone, increased efforts should be focused on TBI, particularly in and related to the hospital setting. PMID- 25012489 TI - Trafficking mechanisms and regulation of TRPC channels. AB - TRPC channels are Ca(2+)-permeable cation channels which are regulated downstream from receptor-coupled PIP2 hydrolysis. These channels contribute to a wide variety of cellular functions. Loss or gain of channel function has been associated with dysfunction and aberrant physiology. TRPC channel functions are influenced by their physical and functional interactions with numerous proteins that determine their regulation, scaffolding, trafficking, as well as their effects on the downstream cellular processes. Such interactions also compartmentalize the Ca(2+) signals arising from TRPC channels. A large number of studies demonstrate that trafficking is a critical mode by which plasma membrane localization and surface expression of TRPC channels are regulated. This review will provide an overview of intracellular trafficking pathways as well as discuss the current state of knowledge regarding the mechanisms and components involved in trafficking of the seven members of the TRPC family (TRPC1-TRPC7). PMID- 25012490 TI - MUC1 expression in papillary thyroid carcinoma is associated with BRAF mutation and lymph node metastasis; the latter is the most important risk factor of relapse. AB - BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has increased over the past 30 years in Western countries. PTC is usually associated with a good prognosis, but there is a wide range of aggressiveness, and some patients develop distant metastasis and/or resistance to standard treatment. Early identification of these high-risk tumors is a current challenge for appropriate patient management. MUC1 expression has been studied previously in thyroid cancer, but its prognostic value remains controversial. Here, we correlated MUC1 expression in PTC with clinical and pathological features and with the presence of the BRAF(V600E) mutation. METHODS: We performed a clinical and morphological analysis of 190 thyroid tumors (95 PTCs and 95 adenomas). MUC1 immunohistochemistry was carried out on a tissue microarray using different antibodies. The presence of the BRAF(V600E) mutation was investigated by pyrosequencing. MUC1 mRNA levels were assessed by quantitative reverse transcription polymerase chain reaction on a subset of PTC. RESULTS: MUC1 expression was observed in 49% of PTCs and was found to correlate with the presence of papillary architecture, a stromal lymphoid infiltrate, aggressive histological subtypes, extrathyroidal extension, lymph node metastasis, nuclear pseudoinclusions, lymphovascular invasion, and the presence of the BRAF(V600E) mutation (p<0.0001). MUC1 was abundant in nuclear pseudoinclusions. Multivariate analysis showed a strong association of MUC1 expression with the presence of the BRAF(V600E) mutation and lymph node metastasis (p<0.0001). Lymph node metastasis was the most important risk factor of relapse. CONCLUSIONS: Our study shows an association between MUC1 expression and the presence of the BRAF(V600E) mutation in PTC. Analysis of MUC1 expression could improve the risk stratification of PTCs. PMID- 25012491 TI - Improvement of L-phenylalanine production from glycerol by recombinant Escherichia coli strains: the role of extra copies of glpK, glpX, and tktA genes. AB - BACKGROUND: For the production of L-phenylalanine (L-Phe), two molecules of phosphoenolpyruvate (PEP) and one molecule erythrose-4-phosphate (E4P) are necessary. PEP stems from glycolysis whereas E4P is formed in the pentose phosphate pathway (PPP). Glucose, commonly used for L-Phe production with recombinant E. coli, is taken up via the PEP-dependent phosphotransferase system which delivers glucose-6-phosphate (G6P). G6P enters either glycolysis or the PPP. In contrast, glycerol is phosphorylated by an ATP-dependent glycerol kinase (GlpK) thus saving one PEP. However, two gluconeogenic reactions (fructose-1,6 bisphosphate aldolase, fructose-1,6-bisphosphatase, FBPase) are necessary for growth and provision of E4P. Glycerol has become an important carbon source for biotechnology and reports on production of L-Phe from glycerol are available. However, the influence of FBPase and transketolase reactions on L-Phe production has not been reported. RESULTS: L-Phe productivity of parent strain FUS4/pF81 (plasmid-encoded genes for aroF, aroB, aroL, pheA) was compared on glucose and glycerol as C sources. On glucose, a maximal carbon recovery of 0.19 mM C(Phe)/C(Glucose) and a maximal space-time-yield (STY) of 0.13 g l(-1) h(-1) was found. With glycerol, the maximal carbon recovery was nearly the same (0.18 mM C(Phe)/C(Glycerol)), but the maximal STY was higher (0.21 g l(-1) h(-1)). We raised the chromosomal gene copy number of the genes glpK (encoding glycerol kinase), tktA (encoding transketolase), and glpX (encoding fructose-1,6 bisphosphatase) individually. Overexpression of glpK (or its feedback-resistant variant, glpK(G232D)) had little effect on growth rate; L-Phe production was about 30% lower than in FUS4/pF81. Whereas the overexpression of either glpX or tktA had minor effects on productivity (0.20 mM C(Phe)/C(Glycerol); 0.25 g l(-1) h(-1) and 0.21 mM C(Phe)/C(Glycerol); 0.23 g l(-1) h(-1), respectively), the combination of extra genes of glpX and tktA together led to an increase in maximal STY of about 80% (0.37 g l(-1) h(-1)) and a carbon recovery of 0.26 mM C(Phe)/C(Glycerol). CONCLUSIONS: Enhancing the gene copy numbers for glpX and tktA increased L-Phe productivity from glycerol without affecting growth rate. Engineering of glycerol metabolism towards L-Phe production in E. coli has to balance the pathways of gluconeogenesis, glycolysis, and PPP to improve the supply of the precursors, PEP and E4P. PMID- 25012493 TI - Automated generation of radical species in crystalline carbohydrate using ab initio MD simulations. AB - As the chemical structures of radiation damaged molecules may differ greatly from their undamaged counterparts, investigation and description of radiation damaged structures is commonly biased by the researcher. Radical formation from ionizing radiation in crystalline alpha-l-rhamnose monohydrate has been investigated using a new method where the selection of radical structures is unbiased by the researcher. The method is based on using ab initio molecular dynamics (MD) studies to investigate how ionization damage can form, change and move. Diversity in the radical production is gained by using different points on the potential energy surface of the intact crystal as starting points for the ionizations and letting the initial velocities of the nuclei after ionization be generated randomly. 160 ab initio MD runs produced 12 unique radical structures for investigation. Out of these, 7 of the potential products have never previously been discussed, and 3 products are found to match with radicals previously observed by electron magnetic resonance experiments. PMID- 25012492 TI - Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats. AB - BACKGROUND: Endoplasmic reticulum (ER) stress-induced podocyte apoptosis plays a critical role in the development of diabetic nephropathy (DN). Here, we tested the hypothesis that suppression of PERK-ATF4-CHOP pathway by Astragaloside IV (AS IV) is associated with inhibition of ER stress-induced podocyte apoptosis in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetic rats were treated with AS-IV at 5 and 10 mg.kg-1.d-1, p.o., for 12 weeks. Albuminuria examination, hematoxylin & eosin staining and TUNEL analysis were performed. Immunohistochemistry, western blot, and real-time PCR were used to detect renal expression of ER chaperone GRP78 and ER-associated apoptosis proteins. RESULTS: Treatment with AS-IV ameliorated albuminuria and renal histopathology in diabetic rats. Diabetic rats had significant increment in podocyte apoptosis as well as phosphorylated PERK and eIF2alpha in the kidneys, which were attenuated by AS-IV treatment. Furthermore, diabetic rats were found to have increased protein and mRNA expressions of GRP78 and ER-associated apoptosis proteins, such as ATF4, CHOP and TRB3, which were also attenuated by AS-IV treatment. Increased Bax expression and decreased Bcl-2 expression were detected in diabetic rats, and these changes were partially restored by AS-IV treatment. CONCLUSION: The protective effect of AS-IV on ER stress-induced podocyte apoptosis is associated with inhibition of PERK-ATF4-CHOP pathway. Down-regulation of PERK- ATF4-CHOP pathway by AS-IV may be a novel strategy for the treatment of DN. PMID- 25012494 TI - Multimodality imaging for patient evaluation and guidance of catheter ablation for atrial fibrillation - current status and future perspective. AB - Left atrial catheter ablation is an established non-pharmacological therapy for the treatment of atrial fibrillation. The importance of a noninvasive multimodality imaging approach is emphasized by the current guidelines for the various phases of the ablation work-up e.g. patient identification, therapy guidance and procedural evaluation. Advances in the capabilities of imaging modalities and the increasing cost of healthcare warrant a review of the multimodality approach. This review discusses the application of cardiac imaging for pulmonary vein and left atrial ablation divided into stages: pre-procedural stage (assessment of left atrial dimensions, left atrial appendage thrombus and pulmonary vein anatomy), peri-procedural stage (integration of anatomical and electrical information) and post-procedural stage (evaluation of efficacy by assessment of tissue properties). Each section is dedicated to one of the subtopics of a stage, allowing a thorough comparison to be made between the strengths and weaknesses of the different imaging modalities and the identification of one that exhibits the potential for a single technique approach. PMID- 25012495 TI - Aortic surgery is one of the risk factors for enhancement of pressure wave reflection in adult patients with congenital heart disease. AB - BACKGROUND: Excessive aortic pressure wave reflection is one of the risk factors of cardiovascular diseases. In some clinical course of congenital heart diseases, the elevated pressure wave reflection has been reported. The purpose of this study is to elucidate the risk factors of the enhanced pressure wave reflection in adult patients with congenital heart disease. METHODS: We enrolled 99 adult (>=20 years) patients with congenital heart disease. We measured their radial pressure augmentation index and examined the relationship between it and various clinical variables. RESULTS: The radial pressure augmentation index was 77.1 +/- 19.1% and it had a significant correlation with the history of aorto-pulmonary shunt (t=4.194; p<0.0001), age (t=4.091; p<0.0001), height (t=-3.580; p=0.001) and the history of direct aortic surgery (t=2.253; p=0.027). Forty-four patients (44.4%) demonstrated high radial augmentation index (>1SD of age- and gender matched control) and the determinants of the elevated radial augmentation index were the history of aorto-pulmonary shunt (odds ratio, 21.32; 95% confidence interval, 5.47-83.14; p<0.0001) and the direct aortic surgery (4.18; 1.38-12.72; p=0.012). CONCLUSIONS: The history of aortic surgeries enhances aortic pressure wave reflection in adult patients with congenital heart disease. The enhanced aortic pressure wave reflection is one of the risk factors for cardiovascular diseases. Therefore, the adult patients with congenital heart disease after aortic surgeries should be carefully observed and tightly controlled concerning the risk factors for cardiovascular diseases. PMID- 25012496 TI - Transient variations of transthoracic impedance as a predictor of heart failure and death in patients with implanted defibrillators. AB - BACKGROUND: Transient variations in physiological parameters may forewarn of life threatening cardiac events, but are difficult to identify clinically. Implantable cardioverter defibrillators (ICD) designed to measure transthoracic impedance provide a surrogate marker for pulmonary congestion. OBJECTIVE: The aim of this study is to determine if the frequency of changes in transthoracic impedance (TTI) is associated with congestive heart failure (CHF) exacerbation and predicts mortality. METHODS: We followed 109 consecutive patients (pts) with ICDs (n=58) or CRT-ICDs (n=51) for a mean of 21.3 (+10.2) months. Using 80 ohm-days as a reference, we correlated the frequency of TTI changes above this index to CHF hospitalizations or death. RESULTS: There was at least one TTI threshold crossing in 79 (72%) pts over 23.3 months follow-up, with a mean of 1.8 +/- 3.4 per year. There were 18 pts with CHF hospitalizations who had a mean of 4.3 TTI threshold crossings/year (S.D.=+/-7.3; median=2.8), compared to 1.3 (S.D.=+/-1.5; median=0.8) among pts without CHF hospitalizations (p=0.0006). Among 20 patients who died during follow-up, there were 4.2 (S.D.=+/-7.0; median=2.9) TTI threshold crossings/year, compared with 1.3 (S.D.=+/-1.3; median=0.9) threshold crossings/year among survivors (p=0.0004). Using Cox Proportional Hazard modeling, after adjusting for age, baseline EF, and number of shocks, TTI threshold crossing was an independent predictor of death (HR 1.72, 95% CI 1.26 2.36, p=0.001). CONCLUSIONS: Increased frequency of TTI threshold crossings may be a useful predictor of transient risk for identifying a subgroup of ICD recipients at greater individual risk for death or CHF hospitalizations. PMID- 25012497 TI - Clinical outcomes of patients treated with Nobori biolimus-eluting stent: Meta analysis of randomized trials. AB - BACKGROUNDS: The Nobori is a new-generation, biodegradable-polymer coated, biolimus-eluting stent (BES) that has recently been investigated in several randomized trials with inconsistent results. The aim of this study was to assess the efficacy and safety of Nobori BES versus other drug-eluting stents (DES) in patients treated with percutaneous coronary intervention (PCI). METHODS: We undertook a meta-analysis of randomized trials investigating Nobori BES versus other DES. Primary efficacy and safety outcomes were target lesion revascularization (TLR) and definite/probable stent thrombosis (ST), respectively. Secondary outcomes were the composite of cardiac death/myocardial infarction (MI)/target vessel revascularization (TVR), MI and death. RESULTS: A total of 9114 PCI-patients randomly received Nobori BES (n=5080) or other DES (n=4034). This latter group comprised patients receiving everolimus- (n=2533), sirolimus- (n=1376) or paclitaxel-eluting stents (n=125). Median follow-up was 11 months [interquartile range 9-12]. The Nobori BES versus other DES showed comparable risk of TLR (odds ratio [95% confidence interval]=0.91 [0.57-1.46], p=0.71). There was significant heterogeneity across trials due to significant lower TLR risk with Nobori BES versus paclitaxel-eluting stent (0.32 [0.10-0.98], p=0.046; p for interaction=0.009). Nobori BES versus other DES showed comparable risk of definite/probable ST (1.40 [0.66-2.97], p=0.39), cardiac death/MI/TVR (1.05 [0.88-1.25], p=0.59), MI (1.13 [0.87-1.48], p=0.37) and death (1.09 [0.81 1.48], p=0.56). CONCLUSIONS: Nobori BES has comparable efficacy with other limus eluting stents at 1-year follow-up. There is no difference in terms of safety profile between these stent platforms. PMID- 25012498 TI - Renin-angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis. AB - BACKGROUND: Renin-angiotensin system inhibition (RASI) is frequently avoided in aortic stenosis (AS) patients because of fear of hypotension. We evaluated if RASI with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) increased mortality in patients with mild to moderate AS. METHODS: All patients (n=1873) from the Simvastatin and Ezetimibe in Aortic Stenosis study: asymptomatic patients with AS and preserved left ventricular (LV) ejection fraction were included. Risks of sudden cardiac death (SCD), cardiovascular death and all-cause mortality according to RASI treatment were analyzed by multivariable time-varying Cox models and propensity score matched analyses. RESULTS: 769 (41%) patients received RASI. During a median follow-up of 4.3 +/- 0.9 years, 678 patients were categorized as having severe AS, 545 underwent aortic valve replacement, 40 SCDs, 103 cardiovascular and 205 all-cause deaths occurred. RASI was not associated with SCD (HR: 1.19 [95%CI: 0.50-2.83], p=0.694), cardiovascular (HR: 1.05 [95%CI: 0.62-1.77], p=0.854) or all-cause mortality (HR: 0.81 [95%CI: 0.55-1.20], p=0.281). This was confirmed in propensity matched analysis (all p>0.05). In separate analyses, RASI was associated with larger reduction in systolic blood pressure (p=0.001) and less progression of LV mass (p=0.040). CONCLUSIONS: RASI was not associated with SCD, cardiovascular or all-cause mortality in asymptomatic AS patients. However, RASI was associated with a potentially beneficial decrease in blood pressure and reduced LV mass progression. PMID- 25012499 TI - Enhanced age-dependent cerebrovascular dysfunction is mediated by adaptor protein p66Shc. AB - BACKGROUND: Aging is an independent risk factor for cardiovascular and cerebrovascular disease. To date, little is known about the mechanisms of aging of cerebral arteries and whether the aging gene p66(Shc) is implicated in it. The present study was designed to assess age-induced vascular dysfunction in cerebral and systemic arteries of wild type (wt) and p66(Shc-/-) mice. METHODS: Basilar arteries and size matched second order femoral arteries of 3-month (3M), 6-month (6M) and 2-year old (2Y) mice were studied in wt and p66(Shc-/-) mice. To assess vascular function, arterial rings mounted in a myograph for isometric tension recordings were exposed to increasing concentrations of acetylcholine and sodium nitroprusside. Reactive oxygen species (ROS) generation was assessed in femoral and basilar arteries using the spin trap 1-hydroxy-3-methoxycarbonyl-2,2,5,5 tetramethyl-pyrrolidine. RESULTS: In wt mice, endothelial function of the femoral artery was not affected by age unlike in the basilar artery where an age dependent dysfunction was observed. In p66(Shc-/-) a similar response was observed in the femoral artery; however, age-dependent endothelial dysfunction of the basilar artery was blunted as compared to wt. Levels of ROS were comparable in the femoral arteries of 3M and 2Y of wt and p66(Shc-/-) mice. Differently, ROS levels in the basilar artery of wt mice were strongly increased by age unlike in p66(Shc-/-) mice where they remained comparable irrespective of age. CONCLUSIONS: Endothelial function in cerebral arteries, but not in size-matched systemic ones, is heavily impaired by aging. This process is paralleled by an increased ROS production and is mediated by the p66(Shc) gene. PMID- 25012500 TI - Flow dimensions on daily activities with the Spanish version of the Flow Scale (DFS). AB - A sample of 250 students of psychology with an average age of 20.37 years, answered the Flow Q questionnaire indicating their favorite flow activity, and the Spanish version of the Dispositional Flow Scale (DFS). A confirmatory factor analysis assessed the DFS construct validity of the flow model on daily activities. Both a hierarchical model of eight first order factors reflecting a second order global flow factor, and a model with eight formative first order flow dimensions, showed good fit and discriminant power. Most optimal activities were found to be individual and structured, such as studying, reading and certain forms of individual sports. Leisure activities turned out to be more rewarding than studying. Sports displayed more flow, clear goals, merging of action and awareness, and autotelic experience. Reading also showed more flow, balance of challenge and skills, feedback, merging of action and awareness, and loss of self consciousness. On the other hand, studying displayed less flow, merging of action and awareness, and autotelic experience. PMID- 25012502 TI - RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. AB - Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8alpha(+) DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8(+) T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity. PMID- 25012503 TI - DAPK2 is a novel modulator of TRAIL-induced apoptosis. AB - Targeting molecules involved in TRAIL-mediated signalling has been hailed by many as a potential magic bullet to kill cancer cells efficiently, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR)4 and DR5, are well tolerated by cancer patients. Despite efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, as observed with other cancer therapies, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death associated protein kinase 2 (DAPK2) is a modulator of TRAIL signalling. Genetic ablation of DAPK2 using RNA interference causes phosphorylation of NF-kappaB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-kappaB target genes, which include proapoptotic DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAIL-induced killing, in a p53-independent manner. As DAPK2 is a kinase, it is imminently druggable, and our data thus offer a novel avenue to overcome TRAIL resistance in the clinic. PMID- 25012501 TI - Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non adherent, Erk signaling-dependent cells. AB - Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescence associated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance. PMID- 25012504 TI - Tumor suppressor WWOX regulates glucose metabolism via HIF1alpha modulation. AB - The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1alpha (HIF1alpha) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1alpha and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1alpha levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism. PMID- 25012506 TI - A comparative study of dual-X-ray absorptiometry and quantitative ultrasonography for the evaluating bone status in subjects with Rett syndrome. AB - Rett syndrome, an X-linked neurodevelopmental disorder primarily affecting girls, is frequently characterized by a reduced bone mineral density (BMD) with an increased risk of fragility fractures. The aim of the study was to assess bone status by DXA technique and by quantitative ultrasound (QUS) in subjects with Rett syndrome and to evaluate which DXA or QUS parameters better correlate with clinical features. In 156 Rett subjects (mean age 13.6 +/- 8.2 years) and in 62 controls, we measured BMD at femoral neck (BMD-FN) and at total femur (BMD-TF). Apparent volumetric bone mineral density (vBMAD) was also calculated. In all subjects, QUS parameters at phalanges by Bone Profiler-IGEA (amplitude-dependent speed of sound: AD-SoS and bone transmission time: BTT) were evaluated. We found that both DXA parameters and QUS parameters were significantly lower in Rett subjects than in controls. All clinical characteristics were positively correlated to BMD-FN, BMD-TF, AD-SoS, and BTT (p < 0.001) but not with vBMAD-FN. All ultrasonographic parameters were significantly correlated to BMD-FN and BMD TF, whereas vBMAD-FN showed only positive significant correlation with densitometric parameters (p < 001). In Rett subjects BMD-FN was predicted primarily by weight and movement capacity, whereas vBMAD-FN was predicted by weight, height, and calcium intake. Moreover, AD-SoS was predicted by weight, height, and age, while BTT was predicted only by height. In conclusion, in our study the performance of QUS at phalanges was similar to those of BMD at femur, therefore, both areal BMD at femur and QUS at phalanges (AD-SoS and BTT) may be equally useful in the evaluation of skeletal status in Rett patients. PMID- 25012505 TI - Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice. AB - Loss of function mutations in the Prkar1a gene are the cause of most cases of Carney complex disorder. Defects in Prkar1a are thought to cause hyper-activation of PKA signalling, which drives neoplastic transformation, and Prkar1a is therefore considered to be a tumour suppressor. Here we show that loss of Prkar1a in genetically modified mice caused transcriptional activation of several proapoptotic Bcl-2 family members and thereby caused cell death. Interestingly, combined loss of Bim and Prkar1a increased colony formation of fibroblasts in culture and promoted their growth as tumours in immune-deficient mice. Apart from inducing apoptosis, systemic deletion of Prkar1a caused cachexia with muscle loss, macrophage activation and increased lipolysis as well as serum triglyceride levels. Loss of single allele of Prkar1a did not enhance tumour development in a skin cancer model, but surprisingly, when combined with the loss of Bim, caused a significant delay in tumorigenesis and this was associated with upregulation of other BH3-only proteins, PUMA and NOXA. These results show that loss of Prkar1a can only promote tumorigenesis when Prkar1a-mediated apoptosis is somehow countered. PMID- 25012507 TI - Parathyroid hormone (1-34) modulates odontoblast proliferation and apoptosis via PKA and PKC-dependent pathways. AB - Parathyroid hormone (PTH) plays a key role in the development and homeostasis of mineralized tissues such as bone and dentine. We have reported that PTH (1-34) administration can increase dentine formation in mice and that this hormone modulates in vitro mineralization of odontoblast-like cells. The purpose of the present study was to investigate whether PTH (1-34) participates in the proliferative and apoptotic signaling of odontoblast-like cells (MDPC23). MDPC23 cells were exposed to 50 ng/ml hPTH (1-34) or vehicle for 1 (P1), 24 (P24), or 48 (P48) hours, and the cell proliferation, apoptosis, and cell number were evaluated. To examine whether changes in the proliferative and apoptotic signaling in response to PTH involve protein kinases A (PKA) and/or C (PKC), MDPC23 cells were exposed to PTH with or without PKC or PKA signaling pathway inhibitors. Overall, the results showed that the PKA pathway acts in response to PTH exposure maintaining levels of cell proliferation, while the PKC pathway is mainly involved for longer exposure to PTH (24 or 48 h), leading to the reduction of cell proliferation and increase of apoptosis. The exposure to PTH reduced the cell number in relation to the control group in a time-dependent manner. In conclusion, PTH modulates odontoblast-like cell proliferative and apoptotic response in a time-dependent manner. Both PKC and PKA pathways participate in PTH induced modulation in an antagonist mode. PMID- 25012509 TI - Driving a planar model system into the 3(rd) dimension: generation and control of curved pore-spanning membrane arrays. AB - The generation of a regular array of micrometre-sized pore-spanning membranes that protrude from the underlying surface as a function of osmotic pressure is reported. Giant unilamellar vesicles are spread onto non-functionalized Si/SiO(2) substrates containing a highly ordered array of cavities with pore diameters of 850 nm, an interpore distance of 4 MUm and a pore depth of 10 MUm. The shape of the resulting pore-spanning membranes is controlled by applying an osmotic pressure difference between the bulk solution and the femtoliter-sized cavity underneath each membrane. By applying Young-Laplace's law assuming moderate lateral membrane tensions, the response of the membranes to the osmotic pressure difference can be theoretically well described. Protruded pore-spanning membranes containing the receptor lipid PIP(2) specifically bind the ENTH domain of epsin resulting in an enlargement of the protrusions and disappearance as a result of ENTH-domain induced defects in the membranes. These results are discussed in the context of an ENTH-domain induced reduction of lateral membrane tension and formation of defects as a result of helix insertion of the protein in the bilayer. PMID- 25012508 TI - Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis. AB - BACKGROUND: Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC). METHODS: Patients with advanced CRC who had failed conventional treatment, or for whom no therapy of proven efficacy existed, were treated with nintedanib ranging from 50-450 mg once-daily (n = 14) or 150-250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further courses were permitted in the absence of progression or undue toxicity. The primary objective was the effect on the tumour vasculature using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and expressed as the initial area under the DCE-MRI contrast agent concentration-time curve after 60 seconds (iAUC60) or the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans). RESULTS: Patients received a median of 4.0 courses (range: 1-13). Among 21 evaluable patients, 14 (67%) had a >=40% reduction from baseline in Ktrans and 13 (62%) had a >=40% decrease from baseline in iAUC60, representing clinically relevant effects on tumour blood flow and permeability, respectively. A >=40% reduction from baseline in Ktrans was positively associated with non-progressive tumour status (Fisher's exact: p = 0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 (80%) achieved stable disease lasting >=8 weeks. Time to tumour progression (TTP) at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 65-114). Common drug related adverse events (AEs) included nausea (67%), vomiting (53%) and diarrhoea (40%); three patients experienced drug-related AEs >= grade 3. Four patients treated with nintedanib once-daily had an alanine aminotransferase and/or aspartate aminotransferase increase >= grade 3. No increases > grade 2 were seen in the twice-daily group. CONCLUSIONS: Nintedanib modulates tumour blood flow and permeability in patients with advanced, refractory CRC, while achieving antitumour activity and maintaining an acceptable safety profile. PMID- 25012510 TI - Acute and chronic pain in children. AB - Pain in neonates and children differs to that in adults. One of the many challenges associated with the diagnosis and management of pain in early life is that neonates are non-verbal and therefore incapable of communicating their pain effectively to their caregivers. Early life pain is characterised by lowered thermal and mechanical thresholds, and exaggerated and often inappropriate behavioural reactions to pain. These differing behavioural reactions are underpinned by increased excitability/decreased inhibition within the spinal dorsal horn. This itself is the result of immaturity in the anatomical expression of key neurotransmitters and neuromodulators within spinal pain circuits, as well as decreased inhibitory input to these circuits from brainstem centres, and an immature relationship between neuronal and non-neuronal cells which affects pain response. These differences between early and adult pain impact upon not just acute reactions to pain, but also the incidence, severity and duration of chronic pain. In this chapter, chronic pain in childhood is discussed, as are the structural and functional differences that underpin differences in acute pain processing between adults and children. The ability of pain that occurs in early life to alter life-long pain responding is also addressed. PMID- 25012511 TI - Preclinical assessment of pain: improving models in discovery research. AB - To date, animal models have not sufficiently "filtered" targets for new analgesics, increasing the failure rate and cost of drug development. Preclinical assessment of "pain" has historically relied on measures of evoked behavioral responses to sensory stimuli in animals. Such measures can often be observed in decerebrated animals and therefore may not sufficiently capture affective and motivational aspects of pain, potentially diminishing translation from preclinical studies to the clinical setting. Further, evidence indicates that there are important mechanistic differences between evoked behavioral responses of hypersensitivity and ongoing pain, limiting evaluation of mechanisms that could mediate aspects of clinically relevant pain. The mechanisms underlying ongoing pain in preclinical models are currently being explored and may serve to inform decisions towards the transition from drug discovery to drug development for a given target. PMID- 25012512 TI - Organizational citizenship behavior in schools: validation of a questionnaire. AB - The present study examines the psychometric properties (including factorial validity) of an organizational citizenship behavior (OCB) scale in a school context. A total of 321 middle and high school teachers from 59 schools in urban and rural areas of central Portugal completed the OCB scale at their schools. The confirmatory factor analysis validated a hierarchical model with four latent factors on the first level (altruism, conscientiousness, civic participation and courtesy) and a second order factor (OCB). The revised model fit with the data, chi 2 /gl = 1.97; CFI = .962; GFI = .952, RMSEA = .05. The proposed scale (comportamentos de cidadania organizacional em escolas- Revista CCOE-R)- is a valid instrument to assess teacher's perceptions of OCB in their schools, allowing investigation at the organizational level of analysis. PMID- 25012513 TI - Determination of internal energy distributions of laser electrospray mass spectrometry using thermometer ions and other biomolecules. AB - The internal energy distributions for dried and liquid samples that were vaporized with femtosecond duration laser pulses centered at 800 nm and postionized by electrospray ionization-mass spectrometry (LEMS) were measured and compared with conventional electrospray ionization mass spectrometry (ESI-MS). The internal energies of the mass spectral techniques were determined by plotting the ratio of the intact parent molecular features to all integrated ion intensities of the fragments as a function of collisional energy using benzylpyridinium salts and peptides. Measurements of dried p-substituted benzylpyridinium salts using LEMS resulted in a greater extent of fragmentation in addition to the benzyl cation. The mean relative internal energies, were determined to be 1.62 +/- 0.06, 2.0 +/- 0.5, and 1.6 +/- 0.3 eV for ESI-MS, dried LEMS, and liquid LEMS studies, respectively. Two-photon resonances with the laser pulses likely caused lower survival yields in LEMS analyses of dried samples but not liquid samples. In studies with larger biomolecules, LEMS analyses of dried samples from glass showed a decrease in survival yield compared with conventional ESI-MS for leucine enkephalin and bradykinin of ~15% and 11%, respectively. The survival yields for liquid LEMS analyses were comparable to or better than ESI-MS for benzylpyridinium salts and large biomolecules. PMID- 25012514 TI - Direct oral anticoagulants: integration into clinical practice. AB - The introduction of direct oral anticoagulants (OACs) for the treatment and prevention of thromboembolic disease represents a shift from the traditional vitamin K antagonist-based therapies, which have been the mainstay of treatment for almost 60 years. A challenge for hospital formularies will be to manage the use of direct OACs from hospital to outpatient settings. Three direct OACs apixaban, dabigatran and rivaroxaban-are widely approved across different indications, with rivaroxaban approved across the widest breadth of indications. A fourth direct OAC, edoxaban, has also completed phase III trials. Implementation of these agents by physicians will require an understanding of the efficacy and safety profile of these drugs, as well as an awareness of renal function, comedication use, patient adherence and compliance. Optimal implementation of direct OACs in the hospital setting will provide improved patient outcomes when compared with traditional anticoagulants and will simplify the treatment and prevention of thromboembolic diseases. PMID- 25012515 TI - Use of band-pass filter analysis to evaluate outcomes in an antidepressant trial for treatment resistant patients. AB - Band-pass filtering is a novel statistical methodology that proposes that filtering out data from trial sites generating non-plausible high or low levels of placebo response can yield a more accurate effect size and greater separation of active drug (when efficacious) from placebo. We applied band-pass filters to re-analyze data from a negative antidepressant trial (NCT00739908) evaluating CX157 (a reversible and selective monoamine oxidase inhibitor-A) versus placebo. 360 patients from 29 trial sites were randomized to either CX157 treatment (n=182) or placebo (n=178). We applied two filters of<3 or>7 points (filter #1) or<3 and>9 points (filter #2) mean change of the total MADRS placebo scores for each site. Trial sites that had mean placebo MADRS score changes exceeding the boundaries of these band-pass filter thresholds were considered non-informative and all of the data from these sites were excluded from the post-hoc re-analysis. The two band-pass filters reduced the sample of informative patients from 353 patients in the mITT population to 62 in filter #1 and 152 in the filter #2 group. The placebo response was reduced from 31.1% in the mITT population to 9.4% with filter #1 and 20.8% with filter #2. MMRM analysis revealed a non statistically significant trend of p=0.13 and 0.16 for the two filters in contrast to the mITT population (p= 0.58). Our findings support the band-pass filter hypothesis and highlight issues related to site-based scoring variability and inappropriate subject selection that may contribute to trial failure. PMID- 25012516 TI - "Tissue is the issue": circulating tumor cells in pancreatic cancer. PMID- 25012517 TI - Neutropenia and relative dose intensity on adjuvant FOLFOX chemotherapy are not associated with survival for resected colon cancer. AB - PURPOSE: Adjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy for resected high-risk colon cancer is associated with a low risk of febrile neutropenia (FN). Neutropenia, however, is a common cause of dose modification or delay with unknown consequences on outcomes. We examined the effect of neutropenia-related and other dose-limiting toxicities and relative dose intensity of oxaliplatin and 5-FU, on relapse-free and overall survival in patients treated with FOLFOX chemotherapy for resected high-risk colon cancer. METHODS: A chart review was conducted on patients treated at the British Columbia Cancer Agency receiving >=1 cycle of mFOLFOX6 chemotherapy for resected stage II or III colon cancer between January 1, 2006, and December 31, 2007. Relapse-free survival (RFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. RESULTS: One hundred fourteen patients (median age 59 years, 44 % male, 98 % stage III, median follow-up 5.2 years) were included. Ninety percent of the patients experienced any dose-limiting toxicity (DLT), while 58 % of the patients had a neutropenia-related DLT. There were no documented episodes of FN. Granulocyte colony-stimulating factor (GCSF) was used in 10 % of the patients. Median relative dose intensity (RDI) was 81 and 85 % for oxaliplatin and 5-FU, respectively. Oxaliplatin and 5-FU RDI were not associated with RFS or OS when analyzed as continuous variables or categorically. Grade II or grade III/IV neutropenia compared to no neutropenia was not associated with RFS or OS. CONCLUSIONS: DLTs affect the majority of patients on adjuvant FOLFOX for high risk colon cancer, but RFS and OS do not appear to be affected by the associated lower RDI of oxaliplatin and 5-FU. PMID- 25012518 TI - ERK5 signaling gets XIAPed: a role for ubiquitin in the disassembly of a MAPK cascade. PMID- 25012519 TI - An ethyl acetate fraction derived from Houttuynia cordata extract inhibits the production of inflammatory markers by suppressing NF-kB and MAPK activation in lipopolysaccharide-stimulated RAW 264.7 macrophages. AB - BACKGROUND: Houttuynia cordata Thunb. (Saururaceae) has been used in traditional medicine for treatment of inflammatory diseases. This study evaluated the anti inflammatory effects of an ethyl acetate fraction derived from a Houttuynia cordata extract (HCE-EA) on the production of inflammatory mediators and the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. METHODS: To measure the effects of HCE-EA on pro-inflammatory cytokine and inflammatory mediator's expression in RAW 264.7 cells, we used the following methods: cell viability assay, Griess reagent assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting analysis. RESULTS: HCE-EA downregulated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL-6) production in the cells, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Furthermore, HCE-EA suppressed nuclear translocation of the NF-kappaB p65 subunit, which correlated with an inhibitory effect on IkappaBalpha (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation. HCE-EA also attenuated the activation of MAPKs (p38 and JNK). CONCLUSIONS: Our results suggest that the anti-inflammatory properties of HCE-EA may stem from the inhibition of pro-inflammatory mediators via suppression of NF-kappaB and MAPK signaling pathways. PMID- 25012521 TI - In vitro characterization of scaffold-free three-dimensional mesenchymal stem cell aggregates. AB - Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation along multiple cell lineages and have potential applications in a wide range of therapies. These cells are commonly cultured as monolayers on tissue culture plastic but possibly lose their cell-specific properties with time in vitro. There is growing interest in culturing adherent cells via three-dimensional (3D) techniques in order to recapitulate 3D in vivo conditions. We describe a novel method for generating and culturing rabbit MSCs as scaffold-free 3D cell aggregates by using micropatterned wells via a forced aggregation technique. The viability and proliferative capability of MSC aggregates were assessed via Live/Dead staining and 5-ethynyl-2'-deoxyuridine (EdU) incorporation. Enzyme linked immunosorbent assay and antibody-based multiplex protein assays were used to quantify released growth factors and chemokines. The gene expression profile of MSCs as 3D aggregates relative to MSCs grown as monolayers was evaluated via quantitative real-time polymerase chain reaction. The rabbit MSCs were able to form compact cell aggregates and remained viable in 3D culture for up to 7 days. We also demonstrated enhanced gene and protein expression related to angiogenesis and wound healing in MSCs cultured under 3D conditions. In vitro tube formation and scratch assay revealed superior neovessel formation and greater cell recovery and migration in response to 3D conditioned media after wounding. Our data further suggest that adipose-derived stem cell aggregates have greater potential than dermal fibroblasts or bone-marrow-derived MSCs in accelerating wound healing and reducing scarring. PMID- 25012520 TI - NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse. AB - During the formation of dental enamel, maturation-stage ameloblasts express ion transporting transmembrane proteins. The SLC4 family of ion-transporters regulates intra- and extracellular pH in eukaryotic cells by cotransporting HCO3 (-) with Na(+). Mutation in SLC4A4 (coding for the sodium-bicarbonate cotransporter NBCe1) induces developmental defects in human and murine enamel. We have hypothesized that NBCe1 in dental epithelium is engaged in neutralizing protons released during crystal formation in the enamel space. We immunolocalized NBCe1 protein in wild-type dental epithelium and examined the effect of the NBCe1 null mutation on enamel formation in mice. Ameloblasts expressed gene transcripts for NBCe1 isoforms B/D/C/E. In wild-type mice, weak to moderate immunostaining for NBCe1 with antibodies that recognized isoforms A/B/D/E and isoform C was seen in ameloblasts at the secretory stage, with no or low staining in the early maturation stage but moderate to high staining in the late maturation stage. The papillary layer showed the opposite pattern being immunostained prominently at the early maturation stage but with gradually less staining at the mid- and late maturation stages. In NBCe1 (-/-) mice, the ameloblasts were disorganized, the enamel being thin and severely hypomineralized. Enamel organs of CFTR (-/-) and AE2a,b (-/-) mice (CFTR and AE2 are believed to be pH regulators in ameloblasts) contained higher levels of NBCe1 protein than wild-type mice. Thus, the expression of NBCe1 in ameloblasts and the papillary layer cell depends on the developmental stage and possibly responds to pH changes. PMID- 25012522 TI - Neuronal calcium signaling in chronic pain. AB - Acute physiological pain, the unpleasant sensory response to a noxious stimulus, is essential for animals and humans to avoid potential injury. Pathological pain that persists after the original insult or injury has subsided, however, not only results in individual suffering but also imposes a significant cost on society. Improving treatments for long-lasting pathological pain requires a comprehensive understanding of the biological mechanisms underlying pain perception and the development of pain chronicity. In this review, we aim to highlight some of the major findings related to the involvement of neuronal calcium signaling in the processes that mediate chronic pain. PMID- 25012523 TI - Prevalence of inflammation and benign prostatic hyperplasia on autopsy in Asian and Caucasian men. AB - Inflammation has been suggested to be involved in the pathogenesis of benign prostatic hyperplasia (BPH). We studied the prevalence of inflammation and BPH in Asian and Caucasian men on prostate glands (n=320) obtained during autopsy in Moscow, Russia (Caucasian men, n=220), and Tokyo, Japan (Asian men, n=100). We correlated the presence and grade of acute inflammation (AI) or chronic inflammation (CI) and BPH. AI, CI, and histologic BPH were analyzed in a blinded fashion using a grading system (0-3). We used the Cochran-Armitage test for associations between the degree of BPH and clinical variables and proportional odds logistic regression models in multivariable analysis. Histologic BPH was observed in a similar proportion of Asian and Caucasian men (p=0.94). CI was found in>70% of men in both the Asian and Caucasian groups (p>0.05). Higher BPH scores were associated with more CI (p<0.001). In multivariate analyses, individuals with CI were 6.8 times more likely to have a higher BPH score than individuals without (p<0.0001). Men included in this study presented at the hospital and their symptomatic status was not known. The prevalence of CI and BPH on autopsy is similar in Asian and Caucasian men despite very different diet and lifestyle. CI is strongly associated in both groups with BPH. PATIENT SUMMARY: In this study, we looked at the prevalence of inflammation and benign prostatic hyperplasia (BPH) on autopsy in Asian and Caucasian men. We found chronic inflammation in>70% of men on autopsy. More chronic inflammation was associated with more BPH. PMID- 25012524 TI - Re: Nader Al Nakouzi, Sylvestre Le Moulec, Laurence Albiges, et al. Cabazitaxel remains active in patients progressing after docetaxel followed by novel androgen receptor pathway targeted therapies. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.04.015. PMID- 25012525 TI - Phenotypic and genotypic characteristics associated with biofilm formation in clinical isolates of atypical enteropathogenic Escherichia coli (aEPEC) strains. AB - BACKGROUND: Biofilm formation by enteropathogenic Escherichia coli (EPEC) have been recently described in the prototype typical EPEC E2348/69 strain and in an atypical EPEC O55:H7 strain. In this study, we sought to evaluate biofilm formation in a collection of 126 atypical EPEC strains isolated from 92 diarrheic and 34 nondiarrheic children, belonging to different serotypes. The association of biofilm formation and adhesin-related genes were also investigated. RESULTS: Biofilm formation occurred in 37 (29%) strains of different serotypes, when the assays were performed at 26 degrees C and 37 degrees C for 24 h. Among these, four strains (A79, A87, A88, and A111) formed a stronger biofilm than did the others. The frequency of biofilm producers was higher among isolates from patients compared with isolates from controls (34.8% vs 14.7%; P = 0.029). An association was found between biofilm formation and expression of type 1 fimbriae and curli (P < 0.05). Unlike the previously described aEPEC O55:H7, one aEPEC O119:HND strain (A111) formed a strong biofilm and pellicle at the air-liquid interface, but did not express curli. Transposon mutagenesis was used to identify biofilm-deficient mutants. Transposon insertion sequences of six mutants revealed similarity with type 1 fimbriae (fimC, fimD, and fimH), diguanylate cyclase, ATP synthase F1, beta subunit (atpD), and the uncharacterized YjiC protein. All these mutants were deficient in biofilm formation ability. CONCLUSION: This study showed that the ability to adhere to abiotic surfaces and form biofilm is present in an array of aEPEC strains. Moreover, it seems that the ability to form biofilms is associated with the presence of type 1 fimbriae and diguanylate cyclase. Characterization of additional biofilm formation mutants may reveal other mechanisms involved in biofilm formation and bring new insights into aEPEC adhesion and pathogenesis. PMID- 25012526 TI - Accumulation of connective tissue growth factor+ cells during the early phase of rat traumatic brain injury. AB - BACKGROUND: Glial scar formation is a common histopathological feature of traumatic brain injury (TBI). Astrogliosis and expression of transforming growth factor beta (TGF-beta) are key components of scar formation and blood-brain barrier modulation. Connective tissue growth factor (CTGF) is considered a cytokine mediating the effects of TGF-beta. METHODS: Here, we studied the CTGF expression in an open-skull weight-drop-induced TBI, with a focus on the early phase, most amenable to therapy. RESULTS: In normal rat brains of our study, CTGF+ cells were rarely observed. Significant parenchymal accumulation of CTGF+ non-neuron cells was observed 72 h post-TBI and increased continuously during the investigating time. We also observed that the accumulated CTGF+ non-neuron cells were mainly distributed in the perilesional areas and showed activated astrocyte phenotypes with typical stellate morphologic characteristics. CONCLUSION: Our observations demonstrated the time-dependent and lesion-associated accumulation of cellular CTGF expression in TBI, suggesting a pathological role of CTGF in TBI. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3963462091241165. PMID- 25012527 TI - Case-only designs for exploring the interaction between FCRL4 gene and suspected environmental factors in patients with ankylosing spondylitis. AB - The aim of this study was to explore the interaction between FCRL4 gene and environmental factors in patients with ankylosing spondylitis. Two hundred ninety seven ankylosing spondylitis (AS) Han Chinese patients were selected who were diagnosed at the Department of Rheumatology, First Affiliated Hospital, Anhui Medical University, in accordance with the modified New York criteria. The single nucleotide polymorphism (SNP) was genotyped by multiplex SNaPshot technique. The interaction between FCRL4 gene and ten environmental factors in AS patients was assessed by using a case-only study. The interaction between FCRL4 gene (rs2777963) and environmental factors was analyzed by chi-square test and logistic models. p values, odds ratio, and 95 % confidence intervals (CIs) were used for estimating the effects of interaction. Odds ratio (OR) for the interaction of gene * environment (G * E) between drinking group and non-drinking group was 2.61 [95 % CI (1.30, 5.23), p=0.007], with statistical significance. Within the cooking oil group, there also may be an interaction of G * E between main animal oil and main plant oil [OR=10.55, 95 % CI (5.55, 20.04), p<0.001]. However, there was no interaction between FCRL4 gene and the other eight environmental factors in patients with AS. The observed significant gene environment interaction suggests that drinking and cooking oil with FCRL4 gene has a significant interaction. Drinking and cooking oil may be risk exposure factors to take a combined action with predisposing genes in patients with AS. A larger sample case-control study is needed to illustrate the interaction mechanism in the further study. PMID- 25012528 TI - Comparing lumbo-pelvic kinematics in people with and without back pain: a systematic review and meta-analysis. AB - BACKGROUND: Clinicians commonly examine posture and movement in people with the belief that correcting dysfunctional movement may reduce pain. If dysfunctional movement is to be accurately identified, clinicians should know what constitutes normal movement and how this differs in people with low back pain (LBP). This systematic review examined studies that compared biomechanical aspects of lumbo pelvic movement in people with and without LBP. METHODS: MEDLINE, Cochrane Central, EMBASE, AMI, CINAHL, Scopus, AMED, ISI Web of Science were searched from inception until January 2014 for relevant studies. Studies had to compare adults with and without LBP using skin surface measurement techniques to measure lumbo pelvic posture or movement. Two reviewers independently applied inclusion and exclusion criteria, and identified and extracted data. Standardised mean differences and 95% confidence intervals were estimated for group differences between people with and without LBP, and where possible, meta-analyses were performed. Within-group variability in all measurements was also compared. RESULTS: The search identified 43 eligible studies. Compared to people without LBP, on average, people with LBP display: (i) no difference in lordosis angle (8 studies), (ii) reduced lumbar ROM (19 studies), (iii) no difference in lumbar relative to hip contribution to end-range flexion (4 studies), (iv) no difference in standing pelvic tilt angle (3 studies), (v) slower movement (8 studies), and (vi) reduced proprioception (17 studies). Movement variability appeared greater for people with LBP for flexion, lateral flexion and rotation ROM, and movement speed, but not for other movement characteristics. Considerable heterogeneity exists between studies, including a lack of detail or standardization between studies on the criteria used to define participants as people with LBP (cases) or without LBP (controls). CONCLUSIONS: On average, people with LBP have reduced lumbar ROM and proprioception, and move more slowly compared to people without LBP. Whether these deficits exist prior to LBP onset is unknown. PMID- 25012529 TI - Profiling patient attitudes to phosphate binding medication: a route to personalising treatment and adherence support. AB - OBJECTIVE: Nonadherence to phosphate binding medication (PBM) compromises the efficacy of treatment for chronic kidney disease, but its causes are poorly understood. This study sought to explore patient attitudes towards PBM and to evaluate the utility of the necessity-concerns framework for understanding adherence to PBM. DESIGN: A sample of 221 dialysis patients currently prescribed PBM were surveyed from eight UK renal units. MAIN OUTCOME MEASURES: Demographic data and clinical information, alongside the Beliefs about Medicines Questionnaire and the medication adherence report scale were reported. RESULTS: Low adherence to PBM was predicted by reduced beliefs in personal need for PBM (OR = .34; 95% CI: .14-.83; p < .05), and increased concerns about PBM (OR = 3.17; 95% CI: 1.87-5.37; p < .001). Patients were categorised into attitudinal groups based on their beliefs about PBM and being 'skeptical' of PBM (low necessity beliefs and high concerns) was most associated with low adherence. CONCLUSION: Strategies to improve adherence to PBM should aim to elicit and address patients' beliefs about their personal need for PBM and their concerns about this medication. PMID- 25012530 TI - Analysis of agreement between the German translation of the American Foot and Ankle Society's Ankle and Hindfoot Scale (AOFAS-AHS) and the Foot Function Index in its validated German translation by Naal et al. (FFI-D). AB - BACKGROUND: Despite its wide use in clinical outcome measurement, there is yet no validated German language version of the AOFAS-AHS available. After finishing cross-cultural adaption of the AOFAS-AHS according to the AAOS guidelines, an analysis of agreement was carried out. METHODS: This was done by means of the 18 item Foot Function Index in its validated German translation by Naal et al. (FFI D). The results of 91 orthopedic patients as well as healthy persons in both scores were then compared intraindividually. The cohort consisted of 46 individuals with hindfoot disorders and 45 persons without any hindfoot complaints. The FFI-D-Score was linearly transformed in the range 0-100 points of the AOFAS. RESULTS: Encouraging correlation was then found for the patients with hindfoot disorders (Spearman's correlation 0.73 (95% CI 0.52-0.85); a median deviation of -2 points (interquartile range -13 points; +13 points) in patients with hindfoot disorders implied good median intraindividual score concordance. However, with 30 of these 46 patients showing score deviations beyond or below a pre-specified +/-10 points range of clinically tolerable deviations, the scores cannot be considered exchangeable. CONCLUSION: Although the agreement analysis was performed for the German translation of the two questionnaires, analogous results can be expected also for other languages. It should be noted that the results do not allow for judging which of the scores is better suited to give a valid statement on patient outcome in treatment of hindfoot disorders. To verify which of these two scores is better suited to represent hindfoot-dysfunction a subsequent study using instrumental gait analysis and surface EMG is being carried out. PMID- 25012531 TI - Effect of a telephonic alert system (Healthy outlook) for patients with chronic obstructive pulmonary disease: a cohort study with matched controls. AB - BACKGROUND: Healthy Outlook was a telephonic alert system for patients with chronic obstructive pulmonary disease (COPD) in the UK. It used routine meteorological and communicable disease reports to identify times of increased risk to health. We tested its effect on hospital use and mortality. METHODS: Enrolees with a history of hospital admissions were linked to hospital administrative data. They were compared with control patients from local general practices, matched for demographic characteristics, health conditions, previous hospital use and predictive risk scores. We compared unplanned hospital admissions, admissions for COPD, outpatient attendances, planned admissions and mortality, over 12 months following enrolment. RESULTS: Intervention and matched control groups appeared similar at baseline (n = 1413 in each group). Over the 12 months following enrolment, Healthy Outlook enrolees experienced more COPD admissions than matched controls (adjusted rate ratio 1.26, 95% confidence interval (CI), 1.05-1.52) and more outpatient attendances (adjusted rate ratio 1.08, 95% CI, 1.03-1.12). Enrolees also had lower mortality rates over 12 months (adjusted odds ratio 0.61, 95% CI, 0.45-0.84). CONCLUSION: Healthy Outlook did not reduce admission rates, though mortality rates were lower. Findings for hospital utilization were unlikely to have been affected by confounding. PMID- 25012532 TI - Radiographic diagnosis of osteochondritis dissecans of the temporomandibular joint: two cases. AB - OBJECTIVE: To present two cases of osteochondritis dissecans (OCD) in temporomandibular joints (TMJs) evaluated by panoramic radiography and cone-beam computed tomography (CBCT). CLINICAL PRESENTATION AND INTERVENTION: Two patients were referred to the Oral and Maxillofacial Radiology Clinic with pain, preauricular tenderness on the TMJ region and limitation of mandibular movements. An earlier panoramic radiograph revealed radiopaque lesions adjacent to the condyles. CBCT images were obtained from patients to assess the radiopacities. The CBCT scan detected irregular-type radiopaque lesions on anterior and superior aspects of the right condyle as well as degenerative osseous changes on both TMJs. CONCLUSION: The CBCT images revealed degenerative osseous changes and loose bodies on TMJs. The lesions were diagnosed as OCD with the help of trauma history, as well as clinical and radiographic findings. PMID- 25012533 TI - On the origin of 'guttae'. PMID- 25012534 TI - Activation of the GPR30 receptor promotes lordosis in female mice. AB - BACKGROUND/AIMS: Estrogens are important effectors of reproduction and are critical for upregulating female reproductive behavior or lordosis in females. In addition to the importance of transcriptional regulation of genes by 17beta estradiol-bound estrogen receptors (ER), extranuclear signal transduction cascades such as protein kinase A (PKA) are also important in regulating female sexual receptivity. GPR30 (G-protein coupled receptor 30), also known as GPER1, a putative membrane ER (mER), is a G protein-coupled receptor that binds 17beta estradiol with an affinity that is similar to that possessed by the classical nuclear ER and activates both PKA and extracellular-regulated kinase signaling pathways. The high expression of GPR30 in the ventromedial hypothalamus, a region important for lordosis behavior as well as kinase cascades activated by this receptor, led us to hypothesize that GPR30 may regulate lordosis behavior in female rodents. METHOD: In this study, we investigated the ability of G-1, a selective agonist of GPR30, to regulate lordosis in the female mouse by administering this agent prior to progesterone in an estradiol-progesterone priming paradigm prior to testing with stud males. RESULTS: As expected, 17beta estradiol benzoate (EB), but not sesame oil, increased lordosis behavior in female mice. G-1 also increased lordosis behavior in female mice and decreased the number of rejective responses towards male mice, similar to the effect of EB. The selective GPR30 antagonist G-15 blocked these effects. CONCLUSION: This study demonstrates that activation of the mER GPR30 stimulates social behavior in a rodent model in a manner similar to EB. PMID- 25012535 TI - 18O depletion in monsoon rain relates to large scale organized convection rather than the amount of rainfall. AB - Oxygen isotopic variations in rainfall proxies such as tree rings and cave calcites from South and East Asia have been used to reconstruct past monsoon variability, mainly through the amount effect: the observed (18)O depletion of rain with increasing amount, manifested as a negative correlation of the monthly amount of tropical rain with its delta(18)O, both measured at the same station. This relation exhibits a significant spatial variability, and at some sites (especially North-East and peninsular India), the rainfall proxies are not interpretable by this effect. We show here that relatively higher (18)O-depletion in monsoon rain is not related necessarily to its amount, but rather, to large scale organized convection. Presenting delta(18)O analyses of ~654 samples of daily rain collected during summer 2012 across 9 stations in Kerala, southern India, we demonstrate that although the cross correlations between the amounts of rainfall in different stations is insignificant, the delta(18)O values of rain exhibit highly coherent variations (significant at P = 0.05). Significantly more (18)O-depletion in the rain is caused by clouds only during events with a large spatial extent of clouds observable over in the south eastern Arabian Sea. PMID- 25012536 TI - beta-catenin (CTNNB1) mutations are not associated with prognosis in advanced hepatocellular carcinoma. AB - OBJECTIVES: Mutation of the exon 3 of CTNNB1, the coding gene of beta-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/beta catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear. METHODS: Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed. RESULTS: A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features. CONCLUSION: In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC. PMID- 25012540 TI - Educating neonatal nurses in Brazil: a before-and-after study with interrupted time series analysis. AB - BACKGROUND: Preterm birth contributes significantly to infant mortality and morbidity, including blindness from retinopathy of prematurity (ROP). Access to intensive neonatal care is expanding in many countries, but care is not always optimal, one factor being that nursing is often by inadequately trained nurse assistants. OBJECTIVE: The aim of this study was to evaluate whether an educational package for nurses improves a range of outcomes including survival rates and severe ROP in 5 neonatal units in Rio de Janeiro, Brazil. METHODS: The study design included an uncontrolled before-and-after study in 5 units, with interrupted time series analysis. Participatory approaches were used to develop a self-administered educational package for control of pain, oxygenation, infection, nutrition, and temperature and to improve supportive care ('POINTS of Care'). Educational materials and DVD clips were developed and training skills of nurse tutors were enhanced. There were two 1-year periods of data collection before and after a 3-month period of self-administration of the education package. RESULTS: Overall, 74% of 401 nurses and nurse assistants were trained. A total of 679 and 563 infants were included in the pre- and post-training periods, respectively. Despite improvement in knowledge and nursing practices, such as the delivery and monitoring of oxygen, there was no change in survival (pre-training 80%, post-training 78.2%), severe ROP (1.6 vs. 2.8%), sepsis (11.3 vs. 12.3 cases per 1,000 infant days) or other outcomes. Outcomes worsened over the pre intervention period but the change to an improvement after the intervention was not statistically significant. During the study period many trained staff left the units, but few were replaced. CONCLUSIONS: Future studies need to focus on barriers to implementation, team building, leadership and governance, as well as the acquisition of knowledge and skills. PMID- 25012541 TI - Long-term outcome of an intravitreal dexamethasone implant for the treatment of noninfectious uveitic macular edema. AB - PURPOSE: To report the long-term outcome of an intravitreal dexamethasone drug delivery system (DEX-DDS) injection for noninfectious uveitic macular edema. METHODS: This was a retrospective study of 8 eyes (7 patients). RESULTS: The mean follow-up time was 17.3 months. Macular edema resolved in all eyes at 3.9 weeks (range 1-6.9) postinjection. The central point thickness improved from 612 +/- 143 to 250 +/- 55 um (p < 0.05). The mean best corrected visual acuity improved by 0.25 logMAR (p < 0.05) at 3.9 weeks (range 1-6.9) postinjection. In 5 eyes, macular edema did not recur after a mean follow-up of 14.5 months. In 3 eyes, macular edema relapsed after 4.7 months (range 3.6-6.3) and resolved again following further injections. Two eyes developed intraocular pressure elevation, which was well controlled with topical treatment. CONCLUSIONS: Intravitreal DEX DDS injections resulted in resolution of macular edema and visual acuity improvement. Some eyes required repeated injections, but most eyes achieved long term resolution. No significant complications were noticed. PMID- 25012542 TI - Health care provider perception of chronic kidney disease: knowledge and behavior among African American patients. AB - BACKGROUND: Chronic Kidney disease (CKD) is prevalent in the population, but also disproportionately affects African Americans. Disparities in care of chronic kidney disease and transplant for African Americans have also been reported. The purpose of this study is to determine the knowledge and reactions of chronic kidney disease patients regarding their disease, as perceived by nephrologists and clinic nurses in South Carolina. METHODS: Using a qualitative approach, key informant interviews were conducted with nephrologists, and three focus groups were held with nurses who specialize in chronic kidney disease. The results were recorded, transcribed, and analyzed using Qualrus software and the Grounded Theory Method. RESULTS: Dominant themes in the interviews and focus groups include: reaction to chronic kidney disease, differences in race, patient thoughts on dialysis, patient knowledge of types of treatment available, information availability, compliance to treatment, information source, and thoughts on kidney transplantation. The study found that the majority of clinicians agreed that there is typically a wide range of reactions in patients with chronic kidney disease. CONCLUSIONS: The majority of chronic kidney disease patients remain in denial of their diagnosis and do not want to agree to the necessary treatment to improve their condition. In addition, the clinicians reported that the incidence of chronic kidney disease is highest in the African American population and this population of patients typically gets their information on the disease from peers, others they have known that have had renal failure. We find clinicians report that patients typically do not remain compliant to recommended treatment regimens due to lack of knowledge and feelings of denial and fear, and frequently use religiosity as a coping mechanism. Silent progression and complexity of chronic kidney disease frequently result in many patients lacking essential knowledge and developing poor coping mechanisms to seek appropriate follow-up care and prevent progression and optimize outcome. Health care providers are aware of the barriers but may lack the tools and resources to overcome them. PMID- 25012543 TI - Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy. AB - BACKGROUND: Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. METHODS: We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. RESULTS: The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. CONCLUSIONS: This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy. PMID- 25012545 TI - Evolution of graphene molecules: structural and functional complexity as driving forces behind nanoscience. AB - The evolution of nanoscience is based on the ability of the fields of chemistry and physics to share competencies through mutually beneficial collaborations. With this in mind, in this Perspective, I describe three classes of compounds: rylene dyes, polyphenylene dendrimers, as well as nanographene molecules and graphene nanoribbons, which have provided a superb platform to nurture these relationships. The synthesis of these complex structures is demanding but also rewarding because they stimulate unique investigations at the single-molecule level by scanning tunneling microscopy and single-molecule spectroscopy. There are close functional and structural relationships between the molecules chosen. In particular, rylenes and nanographenes can be regarded as honeycomb-type, discoid species composed of fused benzene rings. The benzene ring can thus be regarded as a universal modular building block. Polyphenylene dendrimers serve, first, as a scaffold for dyes en route to multichromophoric systems and, second, as chemical precursors for graphene synthesis. Through chemical design, it is possible to tune the properties of these systems at the single-molecule level and to achieve nanoscale control over their self-assembly to form multifunctional (nano)materials. PMID- 25012544 TI - Functional imaging with diffusion-weighted MRI for lung biopsy planning: initial experience. AB - BACKGROUND: The purpose of this study was to evaluate the usefulness of diffusion weighted magnetic resonance imaging (DW-MRI) and positron emission tomography/computed tomography (PET/CT) in planning transthoracic CT-guided biopsies of lung lesions. METHODS: Thirteen patients with lung lesions suspicious for malignancy underwent CT-guided biopsy. Chest DW-MRI and apparent diffusion coefficient (ADC) calculation were performed to aid biopsy planning with fused images. MRI was indicated due to large heterogeneous masses, association with lung atelectasis/consolidation/necrosis, and/or divergent results of other biopsy type and histopathology versus clinical/radiological suspicion. Eight patients underwent PET/CT to identify appropriate areas for biopsy. RESULTS: Mean patient (n = 9 males) age was 59 (range, 30 to 78) years. Based on DW-MRI results, biopsies targeted the most suspicious areas within lesions. All biopsied areas showed higher DW signal intensity and lower ADCs (mean, 0.79 (range, 0.54 to 1.2) * 10(-3) mm2/s), suggesting high cellularity. In patients who underwent PET/CT, areas with higher 18-fluorodeoxyglucose concentrations (standard uptake value mean, 7.7 (range, 3.6 to 13.7)) corresponded to areas of higher DW signal intensity and lower ADCs. All biopsies yielded adequate material for histopathological diagnosis. CONCLUSIONS: Functional imaging is useful for lung biopsy planning. DW-MRI and PET/CT increase overall performance and enable the collection of adequate material for specific diagnosis. PMID- 25012546 TI - Targeting nuclear receptors with lentivirus-delivered small RNAs in primary human hepatocytes. AB - BACKGROUND: RNA interference (RNAi) has tremendous potential for investigating gene function and for developing new therapies. Primary human hepatocytes (PHH) are the "gold standard" for studying the regulation of hepatic metabolism in vitro. However, application of RNAi in PHH has some technical hurdles. The objective of this study was to develop effective and robust protocol for transduction of PHH with lentiviral vectors. METHODS: We used lentiviral vectors to transduce PHH for introduction of short hairpin RNAs (shRNAs) targeting constitutive androstane receptor (CAR), peroxisome proliferator activated receptor alpha (PPARalpha), and microRNA, miR-143. Infection efficiency was quantitatively analyzed by flow cytometry and microscopy. Target gene expression was assessed using quantitative real-time (qRT-PCR) method. RESULTS: Lentiviral vector transduction resulted in >=95% of infected cells at low multiplicity of infection (MOI) of 3, which did not impair cellular viability. We demonstrated the feasibility of this technique in studies on targeting nuclear receptors, PPARalpha and CAR, with shRNAs as well as in lentivirus-mediated overexpression and knock-down of miRNA-143 experiments. CONCLUSIONS: We developed an efficient and robust protocol with standardized procedures for virus production, method of titer determination, and infection procedure for RNAi in primary human hepatocytes based on delivery of shRNAs, microRNAs or anti-microRNAs in different laboratory settings. This approach should be useful to study not only the regulation via nuclear receptors but also other biological, pharmacological, and toxicological aspects of drug metabolism. PMID- 25012547 TI - A confirmatory approach to understanding the four-factor structure of the Adolescent Drinking Index: evidence for a brief version. AB - The purpose of this study was to examine the psychometric properties of the original version of the Adolescent Drinking Index (ADI), and to examine the fit of a series of confirmatory factor analysis models to arrive at an abbreviated version that can be easily administered in settings with limited time for assessment. These aims were examined in a sample of 740 adolescents (Mage=15.26; 58.5% males) who completed the ADI during an emergency department visit. Results suggested that the four-domain design did not fit the data adequately. Results, however, demonstrated good fit for an 8-item adapted version with a four-factor structure: interpersonal, social, psychological, and physical indicators. This abbreviated version was also associated with outcomes such as hangover, alcohol withdrawal, and substance use. Findings from this study provide support for the use of an abbreviated version of the ADI for screening adolescents and referring them to appropriate interventions. PMID- 25012549 TI - Evidence-based treatment for opioid disorders: a 23-year national study of methadone dose levels. AB - Effective treatment for patients with opioid use problems is as critical as ever given the upsurge in heroin and prescription opioid abuse. Yet, results from prior studies show that the majority of methadone maintenance treatment (MMT) programs in the US have not provided dose levels that meet evidence-based standards. Thus, this paper examines the extent to which US MMT programs have made changes in the past 23 years to provide adequate methadone doses; we also identify factors associated with variation in program performance. Program directors and clinical supervisors of nationally-representative methadone treatment programs were surveyed in 1988 (n=172), 1990 (n=140), 1995 (n=116), 2000 (n=150), 2005 (n=146), and 2011 (n=140). Results show that the proportion of patients who received doses below 60 mg/day-the minimum recommended-declined from 79.5 to 22.8% in a 23-year span. Results from random effects models show that programs that serve a higher proportion of African-American or Hispanic patients were more likely to report low-dose care. Programs with Joint Commission accreditation were more likely to provide higher doses, as were a program that serves a higher proportion of unemployed and older patients. Efforts to improve methadone treatment practices have made substantial progress, but 23% of patients across the nation are still receiving doses that are too low to be effective. PMID- 25012550 TI - Co-occurring risk factors for arrest among persons with opioid abuse and dependence: implications for developing interventions to limit criminal justice involvement. AB - Persons who abuse or are dependent on opioids are at elevated risk for arrest. Co occurring behavioral health problems may exacerbate that risk, although the extent of any such increase has not been described. This study examines such risk factors among 40,238 individuals with a diagnosis of opioid abuse or dependence who were enrolled in the Massachusetts Medicaid program in 2010. Medicaid data were merged with statewide arrest data to assess the effects of co-existing mental illness, substance abuse, and previous arrests on arrest during 2010. Persons with serious mental illnesses (psychotic and bipolar disorders) and those with two or more pre-2010 arrests had significantly increased greater odds of arrest. We believe this to be the first study examining effects of co-occurring risk factors on arrest in a large population with opioid dependency/abuse. These findings identify predictors of arrest that could be used to design interventions targeting specific co-occurring risk factors. PMID- 25012548 TI - Distal and proximal factors associated with aggression towards partners and non partners among patients in substance abuse treatment. AB - Studies of violence in substance use disorder (SUD) treatment settings typically focus on partner aggression (PA) although non-partner aggression (NPA) is also a common problem. This study examines potentially distinct paths of distal and proximal risk factors related to aggression towards non-partners (NPA) and partners (PA) among a SUD treatment sample. The sample included 176 adults reporting past-year violence. Bivariate analyses indicated several distal and proximal factors were associated with NPA and PA. According to multivariate, multiple mediation analyses youth aggression history was a factor for both NPA and PA. Alcohol and cocaine use and psychological distress were associated with NPA; marijuana use was associated with PA. There also was evidence of indirect effects of distal factors on NPA and PA. The results suggest that there may be substantially different dynamics associated with NPA and PA, and have implications for developing screening, assessment and treatment protocols targeting violence among individuals in SUD treatment. PMID- 25012551 TI - Psychometric properties of the Spanish version of the Cocaine Selective Severity Assessment to evaluate cocaine withdrawal in treatment-seeking individuals. AB - Reliable and valid assessment of cocaine withdrawal is relevant for treating cocaine-dependent patients. This study examined the psychometric properties of the Spanish version of the Cocaine Selective Severity Assessment (CSSA), an instrument that measures cocaine withdrawal. Participants were 170 cocaine dependent inpatients receiving detoxification treatment. Principal component analysis revealed a 4-factor structure for CSSA that included the following components: 'Cocaine Craving and Psychological Distress', 'Lethargy', 'Carbohydrate Craving and Irritability', and 'Somatic Depressive Symptoms'. These 4 components accounted for 56.0% of total variance. Internal reliability for these components ranged from unacceptable to good (Chronbach's alpha: 0.87, 0.65, 0.55, and 0.22, respectively). All components except Somatic Depressive Symptoms presented concurrent validity with cocaine use. In summary, while some properties of the Spanish version of the CSSA are satisfactory, such as interpretability of factor structure and test-retest reliability, other properties, such as internal reliability and concurrent validity of some factors, are inadequate. PMID- 25012552 TI - The relationship between recovery and health-related quality of life. AB - Building upon recommendations to broaden the conceptualization of recovery and to assess its relationship with health-related quality of life (HRQoL), this study addressed three primary aims. These included: 1) testing the model fit of a hypothesized latent measure of recovery, 2) examining the extent to which this multidimensional measure of recovery was associated with concurrently measured HRQoL, and 3) examining the extent to which this multidimensional measure of recovery predicted changes in HRQoL during the subsequent year. Data were from 1,008 adults who completed follow-up assessments at 15 and 16 years post-intake. Confirmatory factor analysis indicated a good fit for a hypothesized recovery measure (CFI=.98; RMSEA=.06). Additionally, structural equation modeling suggested that this recovery measure was not only concurrently associated with HRQoL (beta=.78, p<.001), but was also a significant predictor of changes in HRQoL during the subsequent year (beta=.25, p<.001). PMID- 25012553 TI - Nonmedical prescription stimulant use among youth in the emergency department: prevalence, severity and correlates. AB - This study examined the prevalence, severity and correlates of nonmedical prescription stimulant use (NPSU) among youth in the emergency department (ED). Participants 14-20 years old presenting to the ED completed a survey. A multinomial logistic regression was used to compare those without NPSU, with mild NPSU and with moderate/severe NPSU on demographics, risk factors and ED utilization. There were 4389 participants; 8.3% reported past-year NPSU and 44% of those with past 3-month NPSU reported at least monthly use. After controlling for demographics, participants with mild NPSU or moderate/severe NPSU had higher odds of all substance use risk factors compared to those with no NPSU. Also, those with moderate/severe NPSU were more likely to report dating violence and nonmedical use of opioids or sedatives and less likely to use marijuana compared to those with mild NPSU. Healthcare setting screening and intervention efforts should consider NPSU concomitant with other substance use and explore the association of dating violence with NPSU. PMID- 25012554 TI - Providing smoking cessation programs to homeless youth: the perspective of service providers. AB - There is almost no information available on cigarette smoking among homeless youth, whether they are currently receiving services for smoking cessation, and how to best help them quit. This paper presents data collected from a series of semi-structured telephone interviews with service providers from 23 shelters and drop-in centers serving homeless youth in Los Angeles County about their current smoking cessation programming, interest in providing smoking cessation services to their clients, potential barriers to providing this service, and ways to overcome these barriers. Results indicated that 84% of facilities did not offer smoking cessation services, although nearly all (91%) were interested in doing so. Barriers to implementing formal smoking cessation programs on site included lack of resources (e.g., money, personnel) to support the programs, staff training, and concern that smoking cessation may not be a high priority for homeless youth themselves. Overall, service providers seemed to prefer a less intensive smoking cessation program that could be delivered at their site by existing staff. Data from this formative needs assessment will be useful for developing and evaluating a smoking cessation treatment that could be integrated into the busy, complex environment that characterizes agencies that serve homeless youth. PMID- 25012556 TI - Consumer perceptions of trauma assessment and intervention in substance abuse treatment. AB - Substance abuse treatment programs are increasing their use of integrated interventions for trauma and substance abuse. While positive behavioral outcomes have been associated with this model, the purpose of this study was to determine consumers' satisfaction with it. Participants were 51 men and 102 women who received trauma assessments and interventions through a drug treatment court. Satisfaction with treatment was measured through the Consumer Perception of Care (CPC). Participants were generally satisfied with the trauma assessments and interventions they received. Number of traumatic experiences, measured by the Adverse Childhood Experiences (ACE) scale, and level of distress, as assessed on the Trauma Symptom Inventory (TSI), were significantly associated with assessment and treatment satisfaction. Gender differences were noted, with men reporting fewer traumatic experiences and trauma-symptoms and less satisfaction with trauma assessment. Implications for the integration of trauma and substance abuse interventions in drug treatment courts and other programs are discussed. PMID- 25012555 TI - A pilot trial of a videogame-based exercise program for methadone maintained patients. AB - Few studies have examined exercise as a substance use disorder treatment. This pilot study investigated the feasibility and acceptability of an exercise intervention comprising the Wii Fit PlusTM and of a time-and-attention sedentary control comprising WiiTM videogames. We also explored their impact on physical activity levels, substance use, and psychological wellness. Twenty-nine methadone maintained patients enrolled in an 8-week trial were randomly assigned to either Active Game Play (Wii Fit PlusTM videogames involving physical exertion) or Sedentary Game Play (WiiTM videogames played while sitting). Participants had high satisfaction and study completion rates. Active Game Play participants reported greater physical activity outside the intervention than Sedentary Game Play participants despite no such differences at baseline. Substance use decreased and stress and optimism improved in both conditions. Active Game Play is a feasible and acceptable exercise intervention, and Sedentary Game Play is a promising time-and-attention control. Further investigations of these interventions are warranted. PMID- 25012557 TI - Divergence between adolescent and parental perceptions of conflict in relationship to adolescent empathy development. AB - Adolescents' developing empathy may be associated with the frequency of conflict with parents, as well as the level of agreement between adolescent and parental perceptions of the frequency of such conflicts. This 6-year longitudinal study investigated the link between adolescent empathy development and perceptions of the frequency of parent-child conflict, as reported by 467 adolescents (43% female, from age 13) and both parents. First, we investigated heterogeneity in empathy development by identifying classes of individuals with similar developmental trajectories. Adolescents were categorized into high-, average-, and low-empathy classes. Initial differences between these classes further increased from age 13 to 16, particularly for cognitive empathy. To assess the association between empathy and the frequency of conflict, we compared these empathy classes in terms of initial levels and over-time changes in the frequency of adolescent- and parent-reported conflict. Compared to the average- and high empathy classes, the low-empathy class evidenced elevated conflict throughout adolescence. Furthermore, the low- and average-empathy classes demonstrated temporary divergence between adolescent- and parent-reported conflict from early- to mid-adolescence, with adolescents underreporting conflict compared to both parents. Adolescents' agreement with parents was moderated by empathy class, while parents were always in agreement with one another. This may suggest that these discrepancies are related to distortions in adolescents' perceptions, as opposed to biased parental reports. These findings highlight the potential importance of early detection and intervention in empathy deficiencies, and suggest that lower adolescent empathy may indicate elevated family conflict, even if a failure to consider parents' perspective leads adolescents to underreport it. PMID- 25012558 TI - Technologies for monitoring the quality of endoscope reprocessing. PMID- 25012559 TI - The fate and reliability of endoscopy research presented at digestive disease week. PMID- 25012560 TI - Underwater endoscopic mucosal resection for recurrences after previous piecemeal resection of colorectal polyps (with video). AB - BACKGROUND: Conventional endoscopic treatment of a recurrent adenoma after piecemeal EMR (PEMR) of a colorectal laterally spreading tumor (LST) is technically difficult with low en bloc resection rates because of the inability to snare fibrotic residual. OBJECTIVE: To assess the feasibility of salvage underwater EMR (UEMR) for the treatment of recurrent adenoma after PEMR of a colorectal LST. DESIGN: Retrospective, cross-sectional study. SETTING: Single, tertiary-care referral center. PATIENTS: Patients who have recurrent adenoma after PEMR of colorectal LST (>=2 cm). INTERVENTIONS: UEMR versus EMR. MAIN OUTCOME MEASUREMENT: En bloc resection rate, endoscopic complete removal rate, recurrence rate on follow-up colonoscopy, adjunctive ablation rate with argon plasma coagulation (APC) during salvage procedure, and independent predictive factors for successful en bloc resection and endoscopic complete removal. RESULTS: Eighty salvage procedures (36 UEMRs vs 44 EMRs) were analyzed. En bloc resection rate (47.2% vs 15.9%, P = .002) and endoscopic complete removal rate (88.9% vs 31.8%, P < .001) were higher in the UEMR group than in the EMR group. APC ablation of visible residual during salvage procedure was lower in UEMR group than EMR group (11.1% vs 65.9%, P < .001). Recurrence rate on follow-up colonoscopy was significantly lower in the UEMR group than the EMR group (10% vs 39.4%, P = .02). UEMR was an independent predictor of successful en bloc resection and endoscopic complete removal. LIMITATIONS: Retrospective, single center study. CONCLUSIONS: UEMR can be a useful and feasible technique as a salvage procedure for recurrent colorectal adenoma after PEMR. PMID- 25012561 TI - Small-bowel capsule endoscopy in patients with unexplained chronic abdominal pain: a systematic review. AB - BACKGROUND: Patients frequently consult primary care physicians and gastroenterologists when experiencing chronic abdominal pain. Although its diagnostic efficacy in these settings is uncertain, small-bowel capsule endoscopy (SBCE) has been used to evaluate the unexplained reasons for abdominal pain. OBJECTIVE: To evaluate the diagnostic yield of SBCE in patients with unexplained chronic abdominal pain. DESIGN: We performed a retrospective review of publications reporting the diagnostic yield of SBCE in patients with unexplained chronic abdominal pain and calculated the overall diagnostic yield. SETTING: Two investigators independently searched studies from databases and analyzed the results. PATIENTS: A total of 1520 patients from 21 studies were included. INTERVENTIONS: Small-bowel capsule endoscopy. MAIN OUTCOME MEASUREMENTS: Per patient diagnostic yield, with 95% confidence intervals (CI), was evaluated by a random-effect model. Clear categorical analysis also was performed. RESULTS: The pooled diagnostic yield of SBCE in patients with unexplained chronic abdominal pain was 20.9% (95% CI, 15.9%-25.9%), with high heterogeneity (I(2) = 80.0%; P < .001). Inflammatory lesions were the most common (78.3%) positive findings, followed by tumors (9.0%). LIMITATIONS: Heterogeneity among studies, retrospective design, variable chronicity of abdominal pain, and different previous examinations before SBCE. CONCLUSION: SBCE provides a noninvasive diagnostic tool for patients with unexplained chronic abdominal pain, but the diagnostic yield is limited (20.9%). Among patients with positive findings, inflammatory lesions are the most common. PMID- 25012562 TI - Urinary metabolic profiles in early pregnancy are associated with preterm birth and fetal growth restriction in the Rhea mother-child cohort study. AB - BACKGROUND: Preterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother-child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers. METHODS: Our study was a case-control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints. RESULTS: We observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N acetyl resonance (IOR = 5.84 CI 1.44 to 39.50). This resonance was positively correlated with body mass index, and stratified analysis confirmed that N-acetyl glycoprotein and IPB were significantly associated in overweight and obese women only. Spontaneous PB cases were associated with elevated urinary lysine (IOR = 2.79 CI 1.20 to 6.98) and lower formate levels (IOR = 0.42 CI 0.19 to 0.94). CONCLUSIONS: Urinary metabolites measured at the end of the first trimester are associated with increased risk of negative birth outcomes, and provide novel information about the possible mechanisms leading to adverse pregnancies in the Rhea cohort. This study emphasizes the potential of metabolic profiling of urine as a means to identify novel non-invasive biomarkers of PB and FGR risk. PMID- 25012563 TI - Ultrasound-assisted extraction of polyphenols from native plants in the Mexican desert. AB - Several plants that are rich in polyphenolic compounds and exhibit biological properties are grown in the desert region of Mexico under extreme climate conditions. These compounds have been recovered by classic methodologies in these plants using organic solvents. However, little information is available regarding the use of alternative extraction technologies, such as ultrasound. In this paper, ultrasound-assisted extraction (UAE) parameters, such as the liquid:solid ratio, solvent concentration and extraction time, were studied using response surface methodology (RSM) for the extraction of polyphenols from desert plants including Jatrophadioica,Flourensiacernua, Turneradiffusa and Eucalyptuscamaldulensis. Key process variables (i.e., liquid:solid ratio and ethanol concentration) exert the greatest influence on the extraction of all of the phenolic compounds (TPC) in the studied plants. The best conditions for the extraction of TPC involved an extraction time of 40min, an ethanol concentration of 35% and a liquid:solid ratio ranging from 8 to 12mlg(-1) depending on the plant. The highest antioxidant activity was obtained in the E. camaldulensis extracts. The results indicated the ability of UAE to obtain polyphenolic antioxidant preparations from desert plants. PMID- 25012564 TI - Establishment and characterization of a rare atypical chronic myeloid leukemia cell line NT-1. AB - Human leukemia cell lines are of great value in leukemia research. In this study, we established and described the biological characteristics of a rare atypical chronic myeloid (aCML) leukemia cell line (NT-1). Mononuclear cells were isolated from the bone marrow of a patient with atypical chronic myeloid leukemia (Ph( )/bcr(-)/abl(-)), and were passaged by liquid culture. Cells were maintained without any cytokines for over 1 year, and named NT-1. This cell line was extensively characterized using morphological assays, flow cytometry, cytogenetic analysis, clonogenic culture, quantitative fluorescent PCR, short tandem repeating sequence PCR (STR-PCR) and array-CGH. Its tumorigenic capacity was also examined in nude mice. The NT-1 cell line had morphological features of chronic myeloid leukemia and major myeloid markers (CD13, CD33, CD11b). Additionally, NT 1 expressed progenitor cells and natural killer cell-related antigens such as CD34, CD117, CD56. Cytogenetic analysis initially demonstrated two abnormalities: 47, xx, +8 and 47, xx, +8 accompanied by t(5;12)(q31;p13) translocation. The one year passage process did not alter the karyotype. NT-1 cells maintained the same morphology, immunophenotyping and cytogenetic features as primary leukemia cells, which was strongly supported by STR-PCR results. Neither Epstein-Barr virus nor mycoplasma was detected in the NT-1 line. In addition, NT-1 cells showed high tumorigenic capacity in nude mice. NT-1 is a new atypical chronic myeloid leukemia cell line with the +8 and t(5,12) translocation, and exhibits high tumorigenicity in nude mice. This new cell line provides a useful tool for the study of leukemogenesis. PMID- 25012565 TI - Granulocyte-macrophage colony stimulating factor (GM-CSF) enhances the clinical responses to interferon-alpha (IFN) in newly diagnosed chronic myeloid leukemia (CML). AB - The majority of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) remain with residual disease. In contrast to TKIs, interferon (IFN) is directly toxic to CML progenitor cells, and myeloid growth factors such as GM-CSF may enhance IFN's cytotoxicity. We performed a phase 2 study of IFN+GM-CSF in 58 newly diagnosed CML patients before imatinib approval. Short-term clinical responses included: 60% major cytogenetic response, 28% complete cytogenetic response and 19% complete molecular response. Six patients remain off all therapy for CML (range: 15 months-12 years) after IFN+GM-CSF treatment. IFN+GM-CSF shows promise as an adjunctive therapy for CML. PMID- 25012566 TI - The alpha subunit of Go modulates cell proliferation and differentiation through interactions with Necdin. AB - BACKGROUND: Heterotrimeric GTP-binding proteins (G-proteins) play an important role in mediating signal transduction generated by neurotransmitters or hormones. Go, a member of the Gi/Go subfamily, is the most abundant G-protein found in the brain. Recently, the alpha subunit of Go (Galphao) was characterized as an inducer of neuronal differentiation. However, its underlying molecular mechanisms have remained unclear to date, since the downstream effectors of Galphao are ambiguous. RESULTS: A neurally differentiated embryonal carcinoma-derived protein (Necdin) was isolated as an interacting partner for Galphao from a mouse brain cDNA library using yeast two-hybrid screening. Interactions between the proteins were confirmed with several affinity binding assays, both in vitro and in vivo. Necdin interacted directly and preferentially with activated Galphao, compared to wild-type protein. Interestingly, Galphao did not interact with Galphai, despite high sequence homology between the two proteins. We subsequently analyzed whether Galphao modulates the cellular activities of Necdin. Notably, expression of Galphao significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oalpha-coupled receptor, augmented cell growth suppression, which was mediated by Galphao and Necdin in U87MG cells containing CB1R, Galphao, and Necdin as normal components. CONCLUSIONS: These results collectively suggest that Necdin is a candidate downstream effector for Galphao. Our findings provide novel insights into the cellular roles of Galphao and its coupled receptor. PMID- 25012567 TI - Bradykinin antagonists and thiazolidinone derivatives as new potential anti cancer compounds. AB - Glioblastoma (GB), the most aggressive brain tumour, and mantle cell lymphoma (MCL), a rare but very aggressive type of lymphoma, are highly resistant to chemotherapy. GB and MCL chemotherapy gives very modest results, the vast majority of patients experience recurrent disease. To find out the new treatment modality for drug-resistant GB and MCL cells, combining of bradykinin (BK) antagonists with conventional temozolomide (TMZ) treatment, and screening of thiazolidinones derivatives were the main objectives of this work. As it was revealed here, BKM-570 was the lead compound among BK antagonists under investigation (IC50 was 3.3 MUM) in human GB cells. It strongly suppressed extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation. BK antagonists did not decrease the viability of MCL cells, thus showing the cell-specific mode, while thiazolidinone derivatives, a novel group of promising anti-tumour compounds inhibited proliferation of MCL cells: IC50 of ID 4526 and ID 4527 compounds were 0.27 MUM and 0.16 MUM, correspondingly. However, single agents are often not effective in clinic due to activation of collateral pathways in tumour cells. We demonstrated a strong synergistic effect after combinatorial treatment by BKM-570 together with TMZ that drastically increased cytotoxic action of this drug in rat and human glioma cells. Small proportion of cells was still viable after such treatment that could be explained by presence of TMZ-resistant cells in the population. It is possible to expect that the combined therapy aimed simultaneously at different elements of tumourigenesis will be more effective with lower drug concentrations than the first-line drug temozolomide used alone in clinics. PMID- 25012568 TI - Synthesis and biological evaluation of 2-anilino-4-substituted-7H pyrrolopyrimidines as PDK1 inhibitors. AB - PDK1, a biological target that has attracted a large amount of attention recently, is responsible for the positive regulation of the PI3K/Akt pathway that is often activated in a large number of human cancers. A series of second generation 2-anilino-4-substituted-7H-pyrrolopyrimidines were synthesised by installation of various functions at the 4-position of the 7H-pyrrolopyrimidine scaffold. All compounds were screened against the isolated PDK1 enzyme and dose response analysis was obtained on the best compounds of the series. PMID- 25012569 TI - The development of new molecular tools containing a chemically synthesized carbohydrate ligand for the elucidation of carbohydrate roles via photoaffinity labeling: carbohydrate-protein interactions are affected by the structures of the glycosidic bonds and the reducing-end sugar. AB - Photoaffinity labeling technology is a highly efficient method for cloning carbohydrate-binding proteins. When the carbohydrate probes are synthesized according to conventional methods, however, the reducing terminus of the sugar is opened to provide an acyclic structure. Our continued efforts to solve this problem led to the development of new molecular tools with an oligosaccharide structure that contains a phenyldiazirine group for the elucidation of carbohydrate-protein interactions. We investigated whether carbohydrate-lectin interactions are affected by differences in the glycosidic formation and synthesized three types of molecular tools containing Galp-GlcpNAc disaccharide ligands and a photoreactive group (1, 2, 3). Photoaffinity labeling validated the recognition of the new ligand by different glycosidic bonds. Photoaffinity labeling also demonstrated that both the reducing end sugar and non-reducing end sugar recognized the Erythrina cristagalli agglutinin. PMID- 25012570 TI - Measuring affect at work based on the valence and arousal circumplex model. AB - Affective states have become a central topic of interest in research on organizational behavior. Recently, scholars have been paying more attention to the proposals of the Circumplex Model (Russell, 1980) in order to gain a finer grained understanding of job-related affect. However, the limited availability of well-validated measures to test this model in work settings, particularly in non English-speaking populations, is still a major drawback. Using three samples of English-speaking and Spanish-speaking workers, this article offers the cross validation of the Multi-Affect Indicator (Warr, 2007) between the original English version and its corresponding translation into Spanish. Multi-group Structural Equation Modeling supported the instrument's structure and its invariance between the two languages (English: chi2 = 65.56, df = 48, p = .05; RMSEA = .06; CFI = .97; Spanish: chi2 = 68.68, df = 48, p = .03; RMSEA = .05; CFI = .97). Furthermore, Circular Stochastic Modeling supported the theoretically proposed circumplex representation (chi2 = 139.85, df = 51, p < .01; chi2/df = 2.74, RMSEA = .06). Thus, this study offers an instrument that provides a more accurate approximation to affect at work, both in English and in another of the major language communities in the world, the Spanish-speaking population. PMID- 25012571 TI - Service climate as a mediator of organizational empowerment in customer-service employees. AB - The aim of this study is to examine the mediating role of the service climate between organizational empowerment (i.e., dynamic structural framework, control of workplace decisions, fluidity in information sharing) and service quality (functional and relational). 428 contact employees from 46 hotels participated in the survey. Correlations demonstrated that dynamic structural framework, control decisions, and fluidity in information sharing are related to both functional and relational service quality. Regression analyses and Sobel tests revealed that service climate totally mediated the relationship between all three dimensions of organizational empowerment and relational service quality. Implications for practice and future research are discussed. PMID- 25012572 TI - Improving the photocatalytic activity and anti-photocorrosion of semiconductor ZnO by coupling with versatile carbon. AB - Coupling ZnO with carbon materials using a suitable integration method to form ZnO-carbon composites has been established as a promising strategy to ameliorate the photocatalytic performance of semiconductor ZnO. In this perspective article, we describe the recent advances and current status of enhancing the photocatalytic activity and anti-photocorrosion of semiconductor ZnO by coupling with versatile carbon materials, e.g., C60, carbon nanotube, graphene and other carbon materials. The primary roles of carbon materials in boosting the photoactivity and photostability of ZnO have been outlined and illustrated with some selected typical examples. In particular, the three main kinds of mechanisms with regard to anti-photocorrosion of ZnO by coupling with carbon have been demonstrated. Finally, we give a concise perspective on this important research area and specifically propose further research opportunities in optimizing the photocatalytic performance of ZnO-carbon composites and widening the scope of their potential photocatalytic applications. PMID- 25012573 TI - Light emitting diodes (LEDs) applied to microalgal production. AB - Light-emitting diodes (LEDs) will become one of the world's most important light sources and their integration in microalgal production systems (photobioreactors) needs to be considered. LEDs can improve the quality and quantity of microalgal biomass when applied during specific growth phases. However, microalgae need a balanced mix of wavelengths for normal growth, and respond to light differently according to the pigments acquired or lost during their evolutionary history. This review highlights recently published results on the effect of LEDs on microalgal physiology and biochemistry and how this knowledge can be applied in selecting different LEDs with specific technical properties for regulating biomass production by microalgae belonging to diverse taxonomic groups. PMID- 25012574 TI - Evidence for validity of the brief resilient coping scale in a young Spanish sample. AB - The aim of the present study was to provide evidence of validity of the Brief Resilient Coping Scale for use in Spanish young population. A total of 365 university students responded to the Spanish version of the BRCS as well as to other tools for measuring personal perceived competence, life satisfaction, depression, anxiety, negative and positive affect, and coping strategies. Confirmatory factor analysis confirmed the unidimensional structure of the scale. Internal consistency reliability and temporal stability through Cronbach's alpha and test-retest correlations, respectively, were comparable to those found in the initial validation of the tool. The BRCS showed positive and significant correlations with personal perceived competence, optimism, life satisfaction, positive affect (p < .01), and some coping strategies (p < .05). Significant negative correlations were observed with depression, anxiety and negative affect. (p < .01). Multiple regression analysis with stepwise method showed that positive affect, negative affect, optimism and problem solving explained 41.8% of the variance of the BRCS (p < .001). The Spanish adaptation of the BRCS in a young population is satisfactory and comparable to those of the original version and with the Spanish version adapted in an elderly population. This supports its validity as a tool for the assessment of resilient coping tendencies in young people who speak Spanish and offers researchers and professionals interested in this area of study a simple tool for assessing it. PMID- 25012575 TI - CDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation. AB - Mitochondrial functions are essential for the survival and function of neurons. Recently, it has been demonstrated that mitochondrial functions are highly associated with mitochondrial morphology, which is dynamically changed by the balance between fusion and fission. Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin related protein 1 (Drp1), which promotes mitochondrial fission. Drp1 activity is regulated by several post-translational modifications, thereby modifying mitochondrial morphology. Here, we found that phosphorylation of Drp1 at serine 616 (S616) is mediated by cyclin-dependent kinase 5 (CDK5) in post-mitotic rat neurons. Perturbation of CDK5 activity modified the level of Drp1S616 phosphorylation and mitochondrial morphology in neurons. In addition, phosphorylated Drp1S616 preferentially localized as a cytosolic monomer compared with total Drp1. Furthermore, roscovitine, a chemical inhibitor of CDKs, increased oligomerization and mitochondrial translocation of Drp1, suggesting that CDK5-dependent phosphorylation of Drp1 serves to reduce Drp1's fission promoting activity. Taken together, we propose that CDK5 has a significant role in the regulation of mitochondrial morphology via inhibitory phosphorylation of Drp1S616 in post-mitotic neurons. PMID- 25012576 TI - Maternal satisfaction with a novel filtered-sunlight phototherapy for newborn jaundice in Southwest Nigeria. AB - BACKGROUND: In many resource-limited settings, the availability of effective phototherapy for jaundiced infants is frequently hampered by lack of, or inadequate resources to acquire and maintain conventional electric-powered phototherapy devices. This study set out to ascertain maternal experience and satisfaction with a novel treatment of infants with significant hyperbilirubinemia using filtered sunlight phototherapy (FSPT) in a tropical setting with irregular access to effective conventional phototherapy. METHODS: A cross-sectional satisfaction survey was conducted among mothers of jaundiced infants treated with FSPT in an inner-city maternity hospital in Lagos, Nigeria from November 2013 to March 2014. Mothers' experience during treatment was elicited with a pretested questionnaire consisting of closed and open-ended items. Satisfaction was rated on a five-point Likert scale. Correlates of overall maternal satisfaction were explored with descriptive and inferential non parametric statistics. RESULTS: A total of 191 mothers were surveyed, 77 (40%) of whom had no prior knowledge of neonatal jaundice. Maternal satisfaction was highest for quality of nursing care received (mean: 4.72 +/- 0.55, median: 5[IQR: 5-5]) and lowest for physical state of the test environment (mean: 3.85 +/- 0.74, median: 4[IQR: 3-4]). The overall rating (mean: 4.17 +/- 0.58, median: 4[IQR: 4 5]) and the observed effect of FSPT on the babies (mean: 4.34 +/- 0.58, 4[IQR: 4 5]) were quite satisfactory. FSPT experience was significantly correlated with the adequacy of information received (p < 0.0005), test environment (p = 0.002) and the observed effect of FSPT on the child (p < 0.0005). Almost all mothers (98.4%) indicated willingness to use FSPT in future or recommend it to others, although some (30 or 15.7%) disliked the idea of exposing newborns to sunlight. CONCLUSIONS: Mothers of jaundiced newborns in this population are likely to be satisfied with FSPT where it is inevitable as an alternative to conventional electric-powered phototherapy. Adequate information, good test environment and friendly nursing care must be ensured for satisfactory maternal experience. PMID- 25012578 TI - Atropinic burden of prescription forms in France: a study in community pharmacies in 2013. PMID- 25012577 TI - Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study. AB - AIMS: The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. METHOD AND RESULTS: In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6+/-48.4% versus +0.8+/-53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %+/-24.8% vs. -72.9%+/ 32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. CONCLUSION: The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg. PMID- 25012579 TI - Birth Prevalence of Fatty Acid beta-Oxidation Disorders in Iberia. AB - Mitochondrial fatty acid beta-oxidation disorders (FAOD) are main targets for newborn screening (NBS) programs, which are excellent data sources for accurate estimations of disease birth prevalence. Epidemiological data is of key importance for the understanding of the natural history of the disorders as well as to define more effective public health strategies. In order to estimate FAOD birth prevalence in Iberia, the authors collected data from six NBS programs from Portugal and Spain, encompassing the screening of more than 1.6 million newborns by tandem mass spectrometry (MS/MS), and compared it with available data from other populations. The participating NBS programs are responsible for the screening of about 46% of all Iberian newborns. Data reveals that Iberia has one of the highest FAOD prevalence in Europe (1:7,914) and that Portugal has the highest birth prevalence of FAOD reported so far (1:6,351), strongly influenced by the high prevalence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD; 1:8,380), one of the highest ever reported. This is justified by the fact that more than 90% of Portuguese MCADD patients are of Gypsy origin, a community characterized by a high degree of consanguinity. From the comparative analysis of various populations with comparable data other differences emerge, which points to the existence of significant variations in FAOD prevalences among different populations, but without any clear European variation pattern. Considering that FAOD are one of the justifications for MS/MS NBS, the now estimated birth prevalences stress the need to screen all Iberian newborns for this group of inherited metabolic disorders. PMID- 25012580 TI - NMR-Based Screening for Inborn Errors of Metabolism: Initial Results from a Study on Turkish Neonates. AB - Approximately 1 in 400 neonates in Turkey is affected by inherited metabolic diseases. This high prevalence is at least in part due to consanguineous marriages. Standard screening in Turkey now covers only three metabolic diseases (phenylketonuria, congenital hypothyroidism, and biotinidase deficiency). Once symptoms have developed, tandem-MS can be used, although this currently covers only up to 40 metabolites. NMR potentially offers a rapid and versatile alternative.We conducted a multi-center clinical study in 14 clinical centers in Turkey. Urine samples from 989 neonates were collected and investigated by using NMR spectroscopy in two different laboratories. The primary objective of the present study was to explore the range of variation of concentration and chemical shifts of specific metabolites without clinically relevant findings that can be detected in the urine of Turkish neonates. The secondary objective was the integration of the results from a healthy reference population of neonates into an NMR database, for routine and completely automatic screening of congenital metabolic diseases.Both targeted and untargeted analyses were performed on the data. Targeted analysis was aimed at 65 metabolites. Limits of detection and quantitation were determined by generating urine spectra, in which known concentrations of the analytes were added electronically as well as by real spiking. Untargeted analysis involved analysis of the whole spectrum for abnormal features, using statistical procedures, including principal component analysis. Outliers were eliminated by model building. Untargeted analysis was used to detect known and unknown compounds and jaundice, proteinuria, and acidemia. The results will be used to establish a database to detect pathological concentration ranges and for routine screening. PMID- 25012581 TI - A cluster analysis on students' perceived motivational climate. Implications on psycho-social variables. AB - The aim of this study was to examine how students' perceptions of the class climate influence their basic psychological needs, motivational regulations, social goals and outcomes such as boredom, enjoyment, effort, and pressure/tension. 507 (267 males, 240 females) secondary education students agreed to participate. They completed a questionnaire that included the Spanish validated versions of Perceived Motivational Climate in Sport Questionnaire (PMCSQ-2), Basic Psychological Needs in Exercise (BPNES), Perceived Locus of Causality (PLOC), Social Goal Scale-Physical Education (SGS-PE), and several subscales of the IMI. A hierarchical cluster analysis uncovered four independent class climate profiles that were confirmed by a K-Means cluster analysis: "high ego", "low ego-task", "high ego-medium task", and "high task". Several MANOVAs were performed using these clusters as independent variables and the different outcomes as dependent variables (p < .01). Results linked high mastery class climates to positive consequences such as higher students' autonomy, competence, relatedness, intrinsic motivation, effort, enjoyment, responsibility and relationship, as well as low levels of amotivation, boredom and pressure/tension. Students' perceptions of a performance class climate made the positive scores decrease significantly. Cluster 3 revealed that a mastery oriented class structure undermines the negative behavioral and psychological effects of a performance class climate. This finding supports the buffering hypothesis of the achievement goal theory. PMID- 25012582 TI - Platelet count and function in paediatric cardiac surgery: a prospective observational study. AB - BACKGROUND: Platelet deficiency, impaired platelet function, or both increase the risk of bleeding complications. We assessed platelet count and function during and after paediatric cardiac surgery. Secondary aims included the effect of modified ultrafiltration, identification of factors associated with platelet dysfunction, and to assess associations between platelet function and transfusion requirements. METHODS: Fifty-seven patients were included in a prospective observational study. Platelet count and platelet function (multiple-electrode impedance aggregometry) were analysed before and during cardiopulmonary bypass (CPB), after modified ultrafiltration, on arrival at the intensive care unit, and on the first postoperative day. Intraoperative transfusions of blood products were registered. RESULTS: Both platelet count and platelet aggregation were markedly reduced during surgery with the greatest reduction at the end of CPB. On postoperative day 1, platelet count was still reduced by 50%, while platelet aggregation had returned to-or above-preoperative levels. There were only moderate correlations between platelet count and platelet aggregation. Modified ultrafiltration had no significant influence on platelet count or aggregation. Young age, low weight, and long operation time were associated with poor platelet aggregation during surgery, while young age, low weight, high preoperative haemoglobin levels, and low preoperative platelet count were associated with poor aggregation after operation. Patients with impaired platelet function during CPB had markedly increased intraoperative transfusion requirements. CONCLUSIONS: Platelet count and platelet aggregation are markedly reduced during and immediately after paediatric cardiac surgery, especially in neonates. The recovery in aggregation is faster than that in platelet count. Intraoperative platelet dysfunction is associated with increased transfusion requirements. PMID- 25012583 TI - Gas chromatograph-surface acoustic wave for quick real-time assessment of blood/exhaled gas ratio of propofol in humans. AB - BACKGROUND: Although pilot studies have reported that exhaled propofol concentrations can reflect intraoperative plasma propofol concentrations in an individual, the blood/exhaled partial pressure ratio RBE varies between patients, and the relevant factors have not yet been clearly addressed. No efficient method has been reported for the quick evaluation of RBE and its association with inter individual variables. METHODS: We proposed a novel method that uses a surface acoustic wave (SAW) sensor combined with a fast gas chromatograph (GC) to simultaneously detect propofol concentrations in blood and exhaled gas in 28 patients who were receiving propofol i.v. A two-compartment pharmacokinetic (PK) model was established to simulate propofol concentrations in exhaled gas and blood after a bolus injection. Simulated propofol concentrations for exhaled gas and blood were used in a linear regression model to evaluate RBE. RESULTS: The fast GC-SAW system showed reliability and efficiency for simultaneous quantitative determination of propofol in blood (correlation coefficient R(2)=0.994, P<0.01) and exhaled gas (R(2)=0.991, P<0.01). The evaluation of RBE takes <50 min for a patient. The distribution of RBE in 28 patients showed inter individual differences in RBE (median 1.27; inter-quartile range 1.07-1.59). CONCLUSIONS: Fast GC-SAW, which analyses samples in seconds, can perform both rapid monitoring of exhaled propofol concentrations and fast analysis of blood propofol concentrations. The proposed method allows early determination of the coefficient RBE in individuals. Further studies are required to quantify the distribution of RBE in a larger cohort and assess the effect of other potential factors. CLINICAL TRIAL REGISTRATION: ChiCTR-ONC-13003291. PMID- 25012585 TI - Error modelling in anaesthesia: slices of Swiss cheese or shavings of Parmesan. PMID- 25012584 TI - Methadone is a local anaesthetic-like inhibitor of neuronal Na+ channels and blocks excitability of mouse peripheral nerves. AB - BACKGROUND: Opioids enhance and prolong analgesia when applied as adjuvants to local anaesthetics (LAs). A possible molecular mechanism for this property is a direct inhibition of voltage-gated Na(+) channels which was reported for some opioids. Methadone is an effective adjuvant to LA and was recently reported to inhibit cardiac Na(+) channels. Here, we explore and compare LA properties of methadone and bupivacaine on neuronal Na(+) channels, excitability of peripheral nerves, and cell viability. METHODS: Effects of methadone were explored on compound action potentials (CAP) of isolated mouse saphenous nerves. Patch clamp recordings were performed on Na(+) channels in ND7/23 cells, the alpha-subunits Nav1.2, Nav1.3, Nav1.7, and Nav1.8, and the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2). Cytotoxicity was determined using flow cytometry. RESULTS: Methadone (IC50 86-119 uM) is a state-dependent and unselective blocker on Nav1.2, Nav1.3, Nav1.7, and Nav1.8 with a potency comparable with that of bupivacaine (IC50 177 uM). Both bupivacaine and methadone also inhibit C- and A-fibre CAPs in saphenous nerves in a concentration-dependent manner. Tonic block of Nav1.7 revealed a discrete stereo-selectivity with a higher potency for levomethadone than for dextromethadone. Methadone is also a weak blocker of HCN2 channels. Both methadone and bupivacaine induce a pronounced cytotoxicity at concentrations required for LA effects. CONCLUSIONS: Methadone induces typical LA effects by inhibiting Na(+) channels with a potency similar to that of bupivacaine. This hitherto unknown property of methadone might contribute to its high efficacy when applied as an adjuvant to LA. PMID- 25012587 TI - Chronic kidney disease: a gateway for perioperative medicine. PMID- 25012586 TI - Survival after postoperative morbidity: a longitudinal observational cohort study. AB - BACKGROUND: Previous studies have suggested that there may be long-term harm associated with postoperative complications. Uncertainty exists however, because of the need for risk adjustment and inconsistent definitions of postoperative morbidity. METHODS: We did a longitudinal observational cohort study of patients undergoing major surgery. Case-mix adjustment was applied and morbidity was recorded using a validated outcome measure. Cox proportional hazards modelling using time-dependent covariates was used to measure the independent relationship between prolonged postoperative morbidity and longer term survival. RESULTS: Data were analysed for 1362 patients. The median length of stay was 9 days and the median follow-up time was 6.5 yr. Independent of perioperative risk, postoperative neurological morbidity (prevalence 2.9%) was associated with a relative hazard for long-term mortality of 2.00 [P=0.001; 95% confidence interval (CI) 1.32-3.04]. Prolonged postoperative morbidity (prevalence 15.6%) conferred a relative hazard for death in the first 12 months after surgery of 3.51 (P<0.001; 95% CI 2.28-5.42) and for the next 2 yr of 2.44 (P<0.001; 95% CI 1.62-3.65), returning to baseline thereafter. CONCLUSIONS: Prolonged morbidity after surgery is associated with a risk of premature death for a longer duration than perhaps is commonly thought; however, this risk falls with time. We suggest that prolonged postoperative morbidity measured in this way may be a valid indicator of the quality of surgical healthcare. Our findings reinforce the importance of research and quality improvement initiatives aimed at reducing the duration and severity of postoperative complications. PMID- 25012588 TI - Evaluation of direct antiviral activity of the Deva-5 herb formulation and extracts of five Asian plants against influenza A virus H3N8. AB - BACKGROUND: The herb formulation Deva-5 is used in traditional medicine to treat acute infectious diseases. Deva-5 is composed of five herbs: Gentiana decumbens L., Momordica cochinchinensis L., Hypecoum erectum L., Polygonum bistorta L., and Terminalia chebula Retz. Deva-5 and its five components were investigated for in vitro antiviral activity against avian influenza A virus subtype H3N8. METHODS: The water extracts of the herbal parts of G. decumbens, H. erectum and P. bistorta, the seeds of T. chebula and M. cochinchinensis and Deva-5 were prepared by boiling and clarified by low-speed centrifugation and filtration. To assess the antiviral properties, avian influenza virus isolate A/Teal/Tunka/7/2010(H3N8) was incubated at 37 degrees C for 30 min in the presence and absence of the extracts of five plants and DEVA-5 in various concentrations. Subsequently, the concentration of infectious virus in each sample was determined by plaque assays. Neutralisation indexes and 90% plaque reduction concentrations were estimated for each extract, and the significance of the data was evaluated using statistical methods. RESULTS: The extracts of G. decumbens, H. erectum, P. bistorta and Deva 5 demonstrated no significant toxicity at concentrations up to 2%, whereas extracts of T. chebula and M. cochinchinensis were well-tolerated by Madin-Darby canine kidney cells at concentrations up to 1%. The extracts of H. erectum, M. cochinchinensis and T. chebula reduced the titre of A/Teal/Tunka/7/2010 (H3N8) by approximately five-fold (p <= 0.05). The other three extracts did not significantly reduce the infectivity of the virus. The plaque reduction neutralisation tests revealed that none of the extracts tested were able to inhibit formation of plaques by 90%. However, three extracts, H. erectum, T. chebula and M. cochinchinensis, were able to inhibit formation of plaques by more than 50% at low dilutions from 1:3 to 1:14. The T. chebula extract had a concentration-dependent inhibitory effect. CONCLUSIONS: For the first time, the consistent direct antiviral action of the extracts of H. erectum, T. chebula and M. cochinchinensis was detected. These extracts significantly reduced the infectivity of influenza A virus H3N8 in vitro when used at high concentrations (0.5-1%). However, Deva-5 itself and the remainder of its components did not exhibit significant antiviral action. The results suggest that H. erectum, T. chebula and M. cochinchinensis plants contain substances with direct antiviral activity and could be promising sources of new antiviral drugs. PMID- 25012589 TI - The impact of global budgeting on treatment intensity and outcomes. AB - This paper investigates the effects of global budgets on the amount of resources devoted to cardio-cerebrovascular disease patients by hospitals of different ownership types and these patients' outcomes. Theoretical models predict that hospitals have financial incentives to increase the quantity of treatments applied to patients. This is especially true for for-profit hospitals. If that's the case, it is important to examine whether the increase in treatment quantity is translated into better treatment outcomes. Our analyses take advantage of the National Health Insurance of Taiwan's implementation of global budgets for hospitals in 2002. Our data come from the National Health Insurance's claim records, covering the universe of hospitalized patients suffering acute myocardial infarction, ischemic heart disease, hemorrhagic stroke, and ischemic stroke. Regression analyses are carried out separately for government, private not-for-profit and for-profit hospitals. We find that for-profit hospitals and private not-for-profit hospitals did increase their treatment intensity for cardio-cerebrovascular disease patients after the 2002 implementation of global budgets. However, this was not accompanied by an improvement in these patients' mortality rates. This reveals a waste of medical resources and implies that aggregate expenditure caps should be supplemented by other designs to prevent resources misallocation. PMID- 25012590 TI - NF-kappaB signaling and vesicle transport are correlated with the reactivation of the memory trace of morphine dependence. AB - BACKGROUND: Morphine has been widely used as a clinical anesthetic and analgesic. However, abuse of morphine might result in psychological and physiological dependence. Previous studies have indicated that memory mechanisms play critical roles in morphine dependence. METHODS: Morphine dependence was established in mice utilizing place preference conditioning (CPP). We observed changes in the methylome and transcriptome of the nucleus accumbens during the reactivation of the memory trace. We also monitored for changes in the methylome and transcriptome of mice that were acutely exposed to morphine. RESULTS: We detected 165 and 18 differentially expressed genes (DEGs) and 6 and 24 significant methyl sensitive cut counting (MSCC) windows in the acute morphine treatment and the CPP model, respectively. The changes in the methylome and transcriptome during the acute treatment were mainly caused by a response to the morphine stimulus; most of the DEGs were correlated with hormone or transcription factor activity regulation. The expression levels of Lcn2 and Hspb1, which participate in the activation of NF-kappaB, were significantly decreased in the CPP morphine treatment model. Besides, the alternative splicing of the curtailed isoform of Caps1 was significantly increased in the CPP morphine-treated group, and the methylation levels of Arf4, Vapa, and Gga3 were decreased. These genes play critical roles in the regulation of the Golgi network. CONCLUSIONS: The current study indicates that NF-kappaB signaling and vesicular transport are correlated with the reactivation of the memory trace in morphine-dependent mice. The results obtained in our study agree with previous observations and identify additional candidate genes for further research. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1196707364133126. PMID- 25012591 TI - Comparison of theoretical fixation stability of three devices employed in medial opening wedge high tibial osteotomy: a finite element analysis. AB - BACKGROUND: Medial open wedge high tibial osteotomy is a well-established procedure for the treatment of unicompartmental osteoarthritis and symptomatic varus malalignment. We hypothesized that different fixation devices generate different fixation stability profiles for the various wedge sizes in a finite element (FE) analysis. METHODS: Four types of fixation were compared: 1) first and 2) second generation Puddu plates, and 3) TomoFix plate with and 4) without bone graft. Cortical and cancellous bone was modelled and five different opening wedge sizes were studied for each model. Outcome measures included: 1) stresses in bone, 2) relative displacement of the proximal and distal tibial fragments, 3) stresses in the plates, 4) stresses on the upper and lower screw surfaces in the screw channels. RESULTS: The highest load for all fixation types occurred in the plate axis. For the vast majority of the wedge sizes and fixation types the shear stress (von Mises stress) was dominating in the bone independent of fixation type. The relative displacements of the tibial fragments were low (in MUm range). With an increasing wedge size this displacement tended to increase for both Puddu plates and the TomoFix plate with bone graft. For the TomoFix plate without bone graft a rather opposite trend was observed.For all fixation types the occurring stresses at the screw-bone contact areas pulled at the screws and exceeded the allowable threshold of 1.2 MPa for at least one screw surface. Of the six screw surfaces that were studied, the TomoFix plate with bone graft showed a stress excess of one out of twelve and without bone graft, five out of twelve. With the Puddu plates, an excess stress occurred in the majority of screw surfaces. CONCLUSIONS: The different fixation devices generate different fixation stability profiles for different opening wedge sizes. Based on the computational simulations, none of the studied osteosynthesis fixation types warranted an intransigent full weight bearing per se. The highest fixation stability was observed for the TomoFix plates and the lowest for the first generation Puddu plate. These findings were revealed in theoretical models and need to be validated in controlled clinical settings. PMID- 25012592 TI - A bioorthogonal (68)Ga-labelling strategy for rapid in vivo imaging. AB - Herein, we describe a fast and robust method for achieving (68)Ga-labelling of the EGFR-selective monoclonal antibody (mAb) Cetuximab using the bioorthogonal Inverse-electron-Demand Diels-Alder (IeDDA) reaction. The in vivo imaging of EGFR is demonstrated, as well as the translation of the method within a two-step pretargeting strategy. PMID- 25012594 TI - Isoflurane protects against injury caused by deprivation of oxygen and glucose in microglia through regulation of the Toll-like receptor 4 pathway. AB - Oxygen and glucose deprivation (OGD) are the most important factors related to tissue damage resulting from stroke. Microglial cells have been found to be very vulnerable to ischemia and OGD. It has been reported that isoflurane exposure can protect the mammalian brain from insults such as ischemic stroke; however, the effects of isoflurane on OGD-induced injury in microglia are as yet unknown. In this study, we investigated the effects of isoflurane on OGD-induced injury in microglia. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) revealed that OGD did indeed induce cell death in microglia. However, isoflurane preconditioning attenuated OGD-induced cell death. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated that isoflurane treatment alleviated OGD-induced apoptosis. Toll-like receptor 4 (TLR4) plays a considerable role in the induction of innate immune and inflammatory responses. Our results indicate that isoflurane preconditioning inhibits the upregulation of TLR4 as well as the activation of its downstream molecules, such as c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB), in BV-2 microglia exposed to OGD. Importantly, we also found that isoflurane pretreatment significantly reduces the production of proinflammatory factors such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-beta, and nitric oxide (NO). The results indicate that TLR4 and its downstream NF-kappaB-dependent signaling pathway contribute to the neuroprotection of microglia exposed to OGD/reoxygenation by administration of isoflurane. PMID- 25012593 TI - Inhibition of neuronal p38alpha, but not p38beta MAPK, provides neuroprotection against three different neurotoxic insults. AB - The p38 mitogen-activated protein kinase (MAPK) pathway plays a key role in pathological glial activation and neuroinflammatory responses. Our previous studies demonstrated that microglial p38alpha and not the p38beta isoform is an important contributor to stressor-induced proinflammatory cytokine upregulation and glia-dependent neurotoxicity. However, the contribution of neuronal p38alpha and p38beta isoforms in responses to neurotoxic agents is less well understood. In the current study, we used cortical neurons from wild-type or p38beta knockout mice, and wild-type neurons treated with two highly selective inhibitors of p38alpha MAPK. Neurons were treated with one of three neurotoxic insults (L glutamate, sodium nitroprusside, and oxygen-glucose deprivation), and neurotoxicity was assessed. All three stimuli led to neuronal death and neurite degeneration, and the degree of neurotoxicity induced in wild-type and p38beta knockout neurons was not significantly different. In contrast, selective inhibition of neuronal p38alpha was neuroprotective. Our results show that neuronal p38beta is not required for neurotoxicity induced by multiple toxic insults, but that p38alpha in the neuron contributes quantitatively to the neuronal dysfunction responses. These data are consistent with our previous findings of the critical importance of microglia p38alpha compared to p38beta, and continue to support selective targeting of the p38alpha isoform as a potential therapeutic strategy. PMID- 25012595 TI - Gonadotrophin-independent precocious puberty associated with later diagnosis of testicular embryonal carcinoma. AB - BACKGROUND: Testicular tumours are very rare in children. Germ cell tumours (GCTs) account for the majority of testicular tumours in young people, and embryonal carcinomas are a common component of GCTs in adolescents. CASE PRESENTATION: A 9.8-year-old boy presented with the development of pubic and facial hair over a period of 2 years. He had a growth spurt and examination revealed pubertal staging of G4 P4 A2 with a 6-mls testis on the right and a 4 mls testis on the left. Investigations revealed suppressed gonadotrophins, a testosterone concentration of 10.3 nmol/l and normal 17-hydroxyprogesterone and adrenal androgen levels. Tumour markers were negative. Following treatment with anastrazole, his height velocity slowed down. At the age of 13.7 years, his treatment was stopped. At the age of 14.8 years, he presented with a grossly enlarged right testis and elevated beta human chorionic gonadotrophin (>1,400 IU/l). He underwent right orchidectomy and histology revealed an embryonal carcinoma with no vascular invasion. Analysis of luteinizing hormone/choriogonadotrophin receptor revealed no mutation. CONCLUSION: We present a case of testicular embryonal carcinoma in a boy who had presented 5 years before with features suggestive of gonadotrophin-independent precocious puberty. PMID- 25012596 TI - Carbon monoxide and respiratory symptoms in young adult passive smokers: a pilot study comparing waterpipe to cigarette. AB - OBJECTIVES: Studies have correlated second hand smoke (SHS) with many diseases, especially respiratory effects. The goal of this study was to measure the impact of SHS on the respiratory symptoms and exhaled carbon monoxide. MATERIAL AND METHODS: The study population consisted of 50 young workers in restaurants serving waterpipes, 48 university students who sit frequently in the university cafeteria where cigarette smoking is allowed and 49 university students spending time in places where smoking is not allowed. Subjects completed questionnaires on socio-demographic characteristics, respiratory symptoms and exposure to SHS. Exhaled carbon monoxide levels were measured. ANOVA and Chi-square tests were used when applicable as well as linear and logistic regression analysis. RESULTS: Exposure to cigarette smoke in university (adjusted odds ratio (ORa) = 6.06) and occupational exposure to waterpipe smoke (ORa = 7.08) were predictors of chronic cough. Being married (ORa = 6.40), living near a heavy traffic road (ORa = 9.49) or near a local power generator (ORa = 7.54) appeared responsible for chronic sputum production. Moreover, predictors of chronic allergies were: being male (ORa = 7.81), living near a local power generator (ORa = 5.52) and having a family history of chronic respiratory diseases (ORa = 17.01). Carbon monoxide levels were augmented by the number of weekly hours of occupational exposure to waterpipe smoke (beta = 1.46) and the number of daily hours of exposure to cigarette smoke (beta = 1.14). CONCLUSIONS: In summary, young non-smoker subjects demonstrated more chronic cough and elevated carbon monoxide levels when exposed to SHS while the effect of waterpipe was even more evident. PMID- 25012597 TI - Thermal tolerance affects mutualist attendance in an ant-plant protection mutualism. AB - Mutualism is an often complex interaction among multiple species, each of which may respond differently to abiotic conditions. The effects of temperature on the formation, dissolution, and success of these and other species interactions remain poorly understood. We studied the thermal ecology of the mutualism between the cactus Ferocactus wislizeni and its ant defenders (Forelius pruinosus, Crematogaster opuntiae, Solenopsis aurea, and Solenopsis xyloni) in the Sonoran Desert, USA. The ants are attracted to extrafloral nectar produced by the plants and, in exchange, protect the plants from herbivores; there is a hierarchy of mutualist effectiveness based on aggression toward herbivores. We determined the relationship between temperature and ant activity on plants, the thermal tolerance of each ant species, and ant activity in relation to the thermal environment of plants. Temperature played a role in determining which species interact as mutualists. Three of the four ant species abandoned the plants during the hottest part of the day (up to 40 degrees C), returning when surface temperature began to decrease in the afternoon. The least effective ant mutualist, F. pruinosus, had a significantly higher critical thermal maximum than the other three species, was active across the entire range of plant surface temperatures observed (13.8-57.0 degrees C), and visited plants that reached the highest temperatures. F. pruinosus occupied some plants full-time and invaded plants occupied by more dominant species when those species were thermally excluded. Combining data on thermal tolerance and mutualist effectiveness provides a potentially powerful tool for predicting the effects of temperature on mutualisms and mutualistic species. PMID- 25012598 TI - Northward range expansion requires synchronization of both overwintering behaviour and physiology with photoperiod in the invasive Colorado potato beetle (Leptinotarsa decemlineata). AB - Photoperiodic phenological adaptations are prevalent in many organisms living in seasonal environments. As both photoperiod and growth season length change with latitude, species undergoing latitudinal range expansion often need to synchronize their life cycle with a changing photoperiod and growth season length. Since adaptive synchronization often involves a large number of time consuming genetic changes, behavioural plasticity might be a faster way to adjust to novel conditions. We compared behavioural and physiological traits in overwintering (diapause) preparation in three latitudinally different European Colorado potato beetle (Leptinotarsa decemlineata) populations reared under two photoperiods. Our aim was to study whether behavioural plasticity could play a role in rapid range expansion into seasonal environments. Our results show that while burrowing into the soil occurred in the southernmost studied population also under a non-diapause-inducing long photoperiod, the storage lipid content of these beetles was very low compared to the northern populations. However, similar behavioural plasticity was not found in the northern populations. Furthermore, the strongest suppression of energy metabolism was seen in pre-diapause beetles from the northernmost population. These results could indicate accelerated diapause preparation and possibly energetic adjustments due to temporal constraints imposed by a shorter, northern, growth season. Our results indicate that behavioural plasticity in burrowing may have facilitated initial range expansion of L. decemlineata in Europe. However, long-term persistence at high latitudes has required synchronization of burrowing behaviour with physiological traits. The results underline that eco-physiological life-history traits of insects, such as diapause, should be included in studies on range expansion. PMID- 25012599 TI - Limits of predictability in commuting flows in the absence of data for calibration. AB - The estimation of commuting flows at different spatial scales is a fundamental problem for different areas of study. Many current methods rely on parameters requiring calibration from empirical trip volumes. Their values are often not generalizable to cases without calibration data. To solve this problem we develop a statistical expression to calculate commuting trips with a quantitative functional form to estimate the model parameter when empirical trip data is not available. We calculate commuting trip volumes at scales from within a city to an entire country, introducing a scaling parameter alpha to the recently proposed parameter free radiation model. The model requires only widely available population and facility density distributions. The parameter can be interpreted as the influence of the region scale and the degree of heterogeneity in the facility distribution. We explore in detail the scaling limitations of this problem, namely under which conditions the proposed model can be applied without trip data for calibration. On the other hand, when empirical trip data is available, we show that the proposed model's estimation accuracy is as good as other existing models. We validated the model in different regions in the U.S., then successfully applied it in three different countries. PMID- 25012600 TI - Characterization and regulation of the resistance-nodulation-cell division-type multidrug efflux pumps MdtABC and MdtUVW from the fire blight pathogen Erwinia amylovora. AB - BACKGROUND: The Gram-negative bacterium Erwinia amylovora is the causal agent of the devastating disease fire blight in rosaceous plants such as apple, pear, quince, raspberry, and cotoneaster. In order to survive and multiply in a host, microbes must be able to circumvent the toxic effects of antimicrobial plant compounds, such as flavonoids and tannins. E. amylovora uses multidrug efflux transporters that recognize and actively export toxic compounds out of the cells. Here, two heterotrimeric resistance-nodulation-cell division (RND)-type multidrug efflux pumps, MdtABC and MdtUVW, from E. amylovora were identified. These RND systems are unusual in that they contain two different RND proteins forming a functional pump. RESULTS: To find the substrate specificities of the two efflux systems, we overexpressed the transporters in a hypersensitive mutant lacking the major RND pump AcrB. Both transporters mediated resistance to several flavonoids, fusidic acid and novobiocin. Additionally, MdtABC mediated resistance towards josamycin, bile salts and silver nitrate, and MdtUVW towards clotrimazole. The ability of the mdtABC- and mdtUVW-deficient mutants to multiply in apple rootstock was reduced. Quantitative RT-PCR analyses revealed that the expression of the transporter genes was induced during infection of apple rootstock. The polyphenolic plant compound tannin, as well as the heavy metal salt tungstate was found to induce the expression of mdtABC. Finally, the expression of the mdtABC genes was shown to be regulated by BaeR, the response regulator of the two component system BaeSR, a cell envelope stress response system that controls the adaptive responses to changes in the environment. CONCLUSIONS: The expression of MdtABC and MdtUVW is induced during growth of E. amylovora in planta. We identified the plant polyphenol tannin as inducer of mdtABC expression. The reduced ability of the mdtABC- and mdtUVW-deficient mutants to multiply in apple rootstock suggests that the efflux pumps are involved in resistance to plant antimicrobials, maybe including flavonoids, which were identified as substrates of both pumps. Furthermore, we found that the mdtABC operon belongs to the regulon of the two-component regulator BaeR suggesting a role of this RND transporter in the cell envelope stress response of E. amylovora. PMID- 25012601 TI - Identification of prognostic different subgroups in triple negative breast cancer by Her2-neu protein expression. AB - PURPOSE: Many patients with triple negative breast cancer (TNBC) have a poor outcome, but not all of them. This study has the aim to analyse the prognostic impact of tumour size, nodal status, grading, Her2-neu (human epithelial growth factor receptor 2) score and Ki-67 index. The main goal of this analysis is to find out if there are any differences in survival between patients with TNBC and a Her2-neu score 0 versus 1+2. EXPERIMENTAL DESIGN: Retrospectively, we studied a cohort of 121 patients with TNBC, diagnosed at the Saarland University Medical Center between December 2004 and June 2013. We compared the disease-free survival (DFS) and overall survival (OS) in those women on the basis of the different Her2 neu scores (0 versus 1 or 2 with negative FISH). RESULTS: One hundred and twenty one patients were included in this study. 58.68 % of them had a T2-4 tumour. 39.67 % were nodal positive and 67.77 % had high-grade tumours. The Her2-neu score was determined in 119 patients. 54.62 % of them had a score 0. In the 103 patients with a Ki-67 determination, the mean index was 44.5 %. We found that tumour size, nodal status and Her2-neu score are important prognostic factors. Patients with a Her2-neu score 0 had a significantly poorer outcome regarding DFS and OS. In contrast, the expression level of Ki-67 and the grading do not seem to have any prognostic value in TNBC. CONCLUSION: Besides tumour stage, grading and nodal status, the Her2-neu score 0 is able to function as a prognostic factor in patients with TNBC. PMID- 25012602 TI - "Win not by numbers, but by skill": Tchartchian G, Hackethal A, Herrmann A, Bojahr B, Wallwiener C, Ohlinger R, Ebert AD, De Wilde RL. Evaluation of SprayShieldTM adhesion barrier in a single center: randomized controlled study in 15 women undergoing reconstructive surgery after laparoscopic myomectomy. Arch Gynecol Obstet. 2014 Apr 30. [Epub ahead of print] PMID: 24781718. PMID- 25012603 TI - Message from the Editor-in-Chief. PMID- 25012604 TI - Supracervical hysterectomy by laparoendoscopic single site surgery. AB - OBJECTIVE: To evaluate the feasibility of laparoscopic supracervical hysterectomy (LSH) by single port access (SPA) with transcervical morcellation. STUDY DESIGN: Observational study conducted between September 2010 and March 2012 in two departments of Gynaecology. Forty women who required hysterectomy underwent LSH by SPA with transcervical morcellation. RESULTS: LSH by SPA with transcervical morcellation was completed successfully in 37/40 (93.5 %) patients. Mean operating time was 128 (+/-55) min and mean hospital stay was 3.5 (+/-1) days. The mean of uterus weight was 310 (+/-214) g. The mean estimated blood loss was 250 (+/-110) ml. Four women (10 %) required a second surgical intervention including two cases of endocervical bleeding. CONCLUSION: LSH by SPA with transcervical morcellation is a feasible procedure. PMID- 25012605 TI - Medical students' perception of objective structured clinical examination: a feedback for process improvement. AB - BACKGROUND: Medical educators have always been desirous of the best methods for formative and summative evaluation of trainees. The Objective Structured Clinical Examination (OSCE) is an approach for student assessment in which aspects of clinical competence are evaluated in a comprehensive, consistent, and structured manner with close attention to the objectivity of the process. Though popular in most medical schools globally, its use in Nigeria medical schools appears limited. OBJECTIVES: This study was conceived to explore students' perception about the acceptability of OSCE process and to provide feedback to be used to improve the assessment technique. DESIGN: A cross-sectional survey was conducted on final-year medical students, who participated in the final MBBS surgery examination in June 2011. A 19-item self-administered structured questionnaire was employed to obtain relevant data on demographics of respondents and questions evaluating the OSCE stations in terms of the quality of instructions and organization, learning opportunities, authenticity and transparency of the process, and usefulness of the OSCE as an assessment instrument compared with other formats. Students' responses were based on a 5-point Likert scales ranging from strongly disagree to strongly agree. The data were analyzed using SPSS, version 15 (SPSS, Inc, Chicago, IL). SETTING: The study took place at the University of Ilorin, College of Health Science. PARTICIPANTS: A total of 187 final-year medical students were enrolled in to the survey. RESULTS: Of 187 eligible students, 151 completed the self-administered questionnaire representing 80.7% response rate. A total of 61 (40.4%) students felt that it was easy to understand written instructions at the OSCE stations. In total, 106 (70.2%) students felt that the time allocated to each station was adequate. A total of 89 (58.9%) students agreed that the OSCE accurately measured their knowledge and skill, and 85 (56.3%) reported that OSCE enhanced their communication skill. Of the respondents, 80 (53%) felt that OSCE caused them to be nervous, and 73 (48.3%) expressed their concern about the interevaluator variability at manned stations. OSCE was perceived to be the second most fair test format by 53 (35.1%) respondents, and 56 (37.1%) also suggested that OSCE needs to be used much more than the other assessment formats. CONCLUSION: The findings in this survey appear reassuring regarding students' perception about the validity, objectivity, comprehensiveness, and overall organization of OSCE in the department of surgery. The need to introduce OSCE early in the surgical curriculum is also underscored. The overall feedback was very useful and will facilitate a critical review of the process. PMID- 25012606 TI - Are there gender differences in the emotional intelligence of resident physicians? AB - BACKGROUND: Because academic literature indicates that emotional intelligence (EI) is tied to work performance, job satisfaction, burnout, and client satisfaction, there is great interest in understanding physician EI. OBJECTIVE: To determine whether gender differences in resident EI profiles mirror EI gender differences in the general population. STUDY DESIGN (INCLUDE PARTICIPANTS AND SETTING): A total of 325 residents in 3 types of residency programs (pathology, pediatrics, and general surgery) at 3 large academic institutions were invited electronically to complete the validated Trait Emotional Intelligence Questionnaire (TEIQue), a tool consisting of 153 items that cluster to 15 independent facets, 4 composite factors, and 1 global EI score. RESULTS: The response rate was 42.8% (n = 139, women = 84). Global EI was not significantly different between men and women resident physicians (p = 0.74). Women scored higher than men in the TEIQue facets impulse control (p = 0.004) and relationships (p = 0.004). Men scored higher than women in 2 facets, stress management (p = 0.008) and emotion management (p = 0.023). Within surgery (n = 85, women = 46), women scored higher than men in impulse control (p = 0.006), whereas men scored higher in stress management (p = 0.008). CONCLUSIONS: Men and women residents across 3 specialties demonstrated near-identical global EI scores. However, gender differences in specific TEIQue facets suggest that similar to the general population, men and women residents may benefit from specific training of different EI domains to enhance well-rounded development. The lack of significant gender differences within surgery may indicate that surgery attracts individuals with particular EI profiles regardless of gender. Future research should focus on the functional relationship between educational interventions that promote targeted EI development and enhanced clinical performance. PMID- 25012607 TI - Ethics skills laboratory experience for surgery interns. AB - INTRODUCTION AND PURPOSE: Ethics curricula are nearly universal in residency training programs, but the content and delivery methods are not well described, and there is still a relative paucity of literature evaluating the effect of ethics curricula. Several commentators have called for more ethics curriculum development at the postgraduate level, and specifically in surgery training. We detail our development and implementation of a clinical ethics curriculum for surgery interns. METHODS: We developed curricula and simulated patient cases for 2 core clinical ethics skills--breaking bad news and obtaining informed consent. Educational sessions for each topic included (1) framework development (discussion of interns' current experience, development of a consensus framework for ethical practice, and comparison with established frameworks) and (2) practice with simulated patient followed by peer and faculty feedback. At the beginning and end of each session, we administered a test of confidence and knowledge about the topics to assess the effect of the sessions. RESULTS: A total of 98 surgical interns participated in the ethics skills laboratory from Spring 2008 to Spring 2011. We identified significant improvement in confidence regarding the appropriate content of informed consent (<0.001) and capacity to break bad news (<0.001). We also identified significant improvement in overall knowledge regarding informed consent (<0.01), capacity assessment (<0.05), and breaking bad news (0.001). Regarding specific components of informed consent, capacity assessment, and breaking bad news, significant improvement was shown in some areas, while we failed to improve knowledge in others. CONCLUSIONS: Through faculty-facilitated small group discussion, surgery interns were able to develop frameworks for ethical practice that paralleled established frameworks. Skills based training in clinical ethics resulted in an increase in knowledge scores and self-reported confidence. Evaluation of 4 annual cohorts of surgery interns demonstrates significant successes and some areas for improvement in this educational intervention. PMID- 25012608 TI - Metastatic renal cell carcinoma to the jaws: report of cases. AB - Renal cell carcinoma (RCC) is one of the most frequent urological malignancies in adults. RCC often metastasizes to other organs, but rarely to the oromaxillofacial region. Metastatic tumors to the jaws are also unusual. In this report, we present two cases of RCC metastasis to the jaws. Metastatic RCC is resistant to radiotherapy and chemotherapy, so surgery is the primary therapeutic choice. This report describes the diagnostic procedures utilized and the therapeutic process in the two cases. The differential diagnosis and treatment methods are discussed. PMID- 25012609 TI - Test-retest reliability of auditory brainstem responses to chirp stimuli in newborns. AB - OBJECTIVE: The purpose of this study was to examine the test-retest reliability of auditory brainstem responses (ABRs) to air- and bone-conducted chirp stimuli in newborns as a function of intensity. DESIGN: A repeated measures quasi experimental design was employed. STUDY SAMPLE: Thirty healthy newborns participated. ABRs were evoked using 60, 45, and 30 dB nHL air-conducted CE Chirps and 45, 30, and 15 dB nHL bone-conducted CE-Chirps at a rate of 57.7/s. Measures were repeated by a second tester. RESULTS: Statistically significant correlations (p <.0001) and predictive linear relations (p <.0001) were found between testers for wave V latencies and amplitudes to air- and bone-conducted CE Chirps. There were also no statistically significant differences between testers with wave V latencies and amplitudes to air- and bone-conducted CE-Chirps (p >.05). As expected, significant differences in wave V latencies and amplitudes were seen as a function of stimulus intensity for air- and bone-conducted CE Chirps (p <.0001). CONCLUSIONS: These results suggest that ABRs to air- and bone conducted CE-Chirps can be reliably repeated in newborns with different testers. The CE-Chirp may be valuable for both screening and diagnostic audiologic assessments of newborns. PMID- 25012610 TI - A novel mutation in the CSF1R gene causes a variable leukoencephalopathy with spheroids. AB - Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids is a neurodegenerative disease associated with mutations in the colony-stimulating factor 1 receptor gene (CSF1R). A 44-year-old woman with a 7-year history of depression presented with neurological signs and a recent cognitive decline. The diagnosis of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids was suspected based on the findings of a predominant frontal leukoencephalopathy and neuroaxonal spheroids on brain biopsy. She shares with her mother a novel CSF1R exon 18 missense mutation (c.2350G > A; p.V784M). The mother has a long standing bipolar disorder and mild multifocal white matter abnormalities in her 70s. This is the first report of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids due to this novel CSF1R missense mutation. Our report suggests that either marked intrafamilial variability or incomplete penetrance can be associated with CSF1R mutations. The observation of a small bone cyst in our patient supports the hypothesis that hereditary diffuse leukoencephalopathy with neuroaxonal spheroids and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy may belong to a spectrum of overlapping phenotypes. PMID- 25012611 TI - Coexistence of perineural invasion and lymph node metastases is a poor prognostic factor in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by radical resection and adjuvant chemotherapy. AB - OBJECTIVE: To determine the role of lymph node metastases (ypN) and perineural invasion (PNI) in patients with locally advanced rectal cancer (LARC). SUBJECTS AND METHODS: Eighty-eight LARC patients receiving preoperative chemoradiotherapy from April 2006 to November 2011 were enrolled in this study. Univariate and multivariate analyses were conducted to determine the association between clinicopathologic features and clinical outcome. RESULTS: The presence of ypN (p = 0.011) and PNI (p = 0.032) was a significant adverse prognostic factor for disease-free survival (DFS). High histologic grade (p = 0.015), PNI+ (p = 0.043) and ypN+ (p = 0.041) were adverse prognostic factors for overall survival (OS). Positive PNI was significantly associated with a higher risk of distant failure (odds ratio = 6.09; 95% CI: 1.57-27.05; p = 0.008). Moreover, patients with a coexistence of ypN+ and PNI+ had the significantly worst DFS (p < 0.001) and OS rates (p < 0.001) compared with other phenotypes. CONCLUSIONS: The presence of either PNI or ypN was a significant prognostic factor for predicting poor survival rates in LARC patients, especially those with a coexistence of both factors. Accordingly, we recommend an intensive follow-up and therapeutic programs for LARC patients with simultaneous PNI+ and ypN+. PMID- 25012612 TI - Effect of vitamin D replacement on hemoglobin concentration in subjects with concurrent iron-deficiency anemia and vitamin D deficiency: a randomized, single blinded, placebo-controlled trial. AB - BACKGROUND: The effect of vitamin D replacement on hemoglobin (Hb) concentration in subjects with concurrent deficiencies of vitamin D and iron is not known. METHODS: We report on an investigator-initiated, randomized, single-blinded, placebo-controlled, 12-week interventional trial. Thirty subjects with iron deficiency anemia (serum ferritin <15 ug/l) were randomized to an intervention arm (cholecalciferol, i.e. vitamin D3, 0.6 million units i.m. once) or placebo. In all subjects, iron deficiency was corrected with parental iron. Other causes of anemia were excluded with appropriate investigation. The primary end point was a rise in Hb concentration. RESULTS: Baseline parameters of age, BMI, hemogram values and levels of serum ferritin, 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) were similar in the 2 arms. Twelve weeks after vitamin D replacement, there was a significant increase in 25 (OH)D levels (57.7 +/- 20.5 vs. 14.1 +/- 6.2 ng/ml, p < 0.0001) and a decrease in PTH levels (32.4 +/- 16.4 vs. 52.9 +/- 18.4 pg/ml, p = 0.003) in subjects in the intervention arm when compared to the placebo arm. However, the increments in serum ferritin and Hb concentration in the intervention and placebo arm did not differ. CONCLUSION: Vitamin D replacement in subjects with iron-deficiency anemia after iron correction does not improve Hb concentration further. PMID- 25012613 TI - Incidence of cold-induced peripheral neuropathy and dose modification of adjuvant oxaliplatin-based chemotherapy for patients with colorectal cancer. AB - BACKGROUND: The CAPOX regimen is used for adjuvant treatment of colorectal cancer. A well-known side effect of oxaliplatin, which often leads to dose modification (DM), is acute neuropathy (AN). AN is provoked by cold, and it could therefore be expected that the degree of AN and thereby DM is more pronounced in the winter period compared to the summer period. METHOD: Patients with colorectal cancer who received adjuvant CAPOX from January 2005 to August 2011 were reviewed. Out of 108 patients who received adjuvant CAPOX, the oxaliplatin dose was reduced in 92 (85%) patients due to AN. Seventeen out of 31 (55%) patients already had a DM of oxaliplatin in the second cycle during the winter period (December to February; mean temperature 0.1-1.8 degrees C), while in the summer period (June to August; mean temperature 15.1-16.3 degrees C), only 4 (13%) patients needed DM (OR = 2.5, p = 0.022). CONCLUSION: In this study, we found that the risk of DM and discontinuation of oxaliplatin is highest in the winter period compared to the other seasons. This study draws attention to the importance of training in the proper handling of the acute neurotoxicity of oxaliplatin. PMID- 25012614 TI - Hyponatremia is a surrogate marker of poor outcome in peritoneal dialysis-related peritonitis. AB - BACKGROUND: Hyponatremia is known to be a marker of poor prognosis in many clinical conditions. The association between hyponatremia and clinical outcomes in peritoneal dialysis-related peritonitis (PDRP) has not been studied. We evaluated the association between hyponatremia and clinical parameters of patients with PDRP. METHODS: We conducted a retrospective analysis of medical records of patients with PDRP admitted to a medical center in the period 2004 2011. Patients with serum Na+ <130 mEq/L and >= 130 mEq/L at admission were divided into hyponatremic and normonatremic groups, respectively. The demographic and laboratory characteristics, pathogens of peritonitis, length of hospital stay and mortality rate were analyzed. RESULTS: Hyponatremia occurred in 27% (27/99) patients with PDRP. Gram-negative bacilli were the major pathogen responsible for 78% (21/27) PDRP in hyponatremic group while gram-positive cocci were found in 75% (41/55) PDRP in normonatremic groups. There was no significant difference in age, duration of dialysis, PD catheter removal rate and technique failure between two groups. Hyponatremic group had significantly higher serum CRP (p <0.001), lower serum albumin (p < 0.001) and phosphate (p < 0.05). Of note, serum Na+ level was positively correlated with serum albumin (p < 0.001), phosphate (p < 0.04) levels, and subjective global assessment (SGA) score (p < 0.001). Moreover, the length of hospital stay was longer and in-hospital mortality rate was higher in hyponatremic group (p < 0.001). Using a multivariable logistic regression, we showed that hyponatremia at admission is an independent predictor of in-hospital mortality (OR 76.89 95% CI 3.39-1741.67, p < 0.05) and long hospital stay (OR 5.37, 95% CI 1.58- 18.19, p < 0.05). CONCLUSIONS: In uremic patients with PDRP, hyponatremia at admission associated with a high frequency of gram negative bacilli infection, low serum albumin and phosphate levels, low SGA score, and poor prognosis with long hospital stay and high mortality rate. PMID- 25012615 TI - Alpha7 neuronal nicotinic receptor: a pluripotent target for diseases of the central nervous system. AB - Twenty years ago the alpha7 nicotinic acetylcholine receptor (nAChR) was thought to be vestigial with little biological relevance, but in recent years it has emerged as a functional target with ubiquitous localization and biological roles. In the last decade more than two thousand manuscripts have been published unraveling the multi-dimensional complexity of this target, the heterogeneity of its genetic variants, the spectrum of transducing signals, and the critical roles it plays in pivotal biological functions in the protection and maturation of neurons and stems cells, immune and inflammatory responses, sensory gating, mnemonic and attentional processes. In addition research and development of novel drugs has also promoted an intense debate on the role of activation, desensitization, beta -amyloid oligomers, glutamate, and alpha7 nAChR, in cognition, neuronal survival, and neurodegeneration. The initial alpha7 nAChRs transducing enzyme, aptly named after Janus the two-faced roman deity for crossroads and gateways, reflects the dichotomy of reports on alpha7 nAChRs in promoting neuronal survival and cognitive processes, or as the target of beta- amyloid oligomers to destabilize neuronal homeostasis leading to an irreversible neurochemical demise and dementia. It is therefore important to understand the functional neural bases of alpha7 nAChRs-mediated improvement of biological functions. The promise of alpha7 nAChR-directed drugs has already recently translated into proof-of-concept in controlled clinical trials but the full promise of this target(s) will be fully unraveled when its impact on neuronal health and survival is tested in controlled long-term clinical trials of disease progression. PMID- 25012617 TI - The small heat shock protein HspB8: role in nervous system physiology and pathology. AB - The accumulation and aggregation of misfolded proteins can be highly cytotoxic and may underlie several human degenerative diseases characterized by neuronal inclusions such as Alzheimer's, Parkinson's, prion-like and polyglutamine repeat diseases. In this context small heat shock proteins, molecular chaperones known to be induced by cell stress, play a fundamental role by facilitating folding of nascent polypeptides, preventing aggregation of misfolded proteins and enhancing their degradation. A recently identified member of the small heat shock protein family, HspB8, is of particular interest in the field of neurological diseases since mutations in its sequence correlate with development of distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. HspB8 expression has been detected in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington disease and spinocerebellar ataxia type 3. In the latter, HspB8 appears to be involved in protecting the cell from accumulation of insoluble aggregates either by preventing aggregation or by promoting degradation of improperly folded proteins. These data propose that HspB8 may be a major player in the neuroprotective response and a promising target for the development of therapeutic strategies. PMID- 25012618 TI - A novel prion protein-tyrosine hydroxylase interaction. AB - The prion protein (PrP) is currently one of the most studied molecules in the neurosciences. It is the main cause of a group of neurological diseases collectively called transmissible spongiform encephalopathies that severely affect both humans and a variety of mammals. Much effort has been directed to understanding the molecular basis of PrP activity, both in physiological and pathological terms. In this context, identification of neuronally-relevant interactors of PrP may play a crucial role. We recently discovered a specific, high-affinity (nanomolar KD) interaction with tyrosine hydroxylase (TH), a enzyme catalyzing the rate-limiting step in the synthesis of the neurotransmitter dopamine. Using molecular biological, biochemical and biophysical techniques we identified the C-terminal structured domain of PrP and the Nterminal regulatory domain of TH as interacting domains between these two proteins. This interaction does not affect TH activity in vitro, although co-expression experiments in HeLa and Chinese hamster ovary cells revealed that PrP is able to internalize TH. Moreover, TH modulated the level of expression of PrP and its localization at the plasma membrane. This novel interaction between two proteins of central importance in nervous system function may shed new light on our understanding of PrP in neurological diseases. PMID- 25012619 TI - Targeting of peripherally expressed pain-related molecules in injury- induced chronic neuropathic pain. AB - Neuropathic pain is a chronic disability associated with a dysfunction of the nervous system, initiated by a primary lesion or disease. Even after resolution of the initiating pathology, neuropathic pain often persists, leading to a significantly diminished quality of life. A vast literature has documented alterations in the expression and distribution of various pain-related proteins in the peripheral nervous system following injury or disease. The current review examines pain-related molecules in the pathogenesis of peripheral nerve injury induced pain and discusses potentially useful therapeutic targets on the basis of preclinical findings in rodent neuropathic pain models. There are indeed a number of cellular processes that are involved in maintaining the neuropathic pain state, but the current review will focus on transmembrane proteins, particularly the voltage-gated and ligand-gated ion channels, which modulate peripheral nerve function. Given the complexity of the process involved in peripheral nerves, clinical efficacy could be greatly enhanced if several of these targets are engaged at once. A key advantage of therapy directed peripherally is that penetration of the therapeutic into the CNS is not entirely necessary, thereby reducing the risk of adverse psychomotor effects. While a number of fascinating targets have been identified in preclinical rodent models, there is a need to confirm that they are in fact relevant to clinical neuropathic pain. Thus, the current review will also discuss the extent to which clinical data confirms the findings of preclinical studies. PMID- 25012616 TI - Therapeutic perspectives of drugs targeting Toll-like receptors based on immune physiopathology theory of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease associated with the development of dementia. It has been established that the pathological hallmarks of neurofibrillary tau protein tangles and senile beta-amyloid protein plaques lead to degeneration of neurons via inflammatory pathways. The progressive death of neurons, primarily cholinergic, results in a gradual and fatal decline of cognitive abilities and memory. By targeting these pathological hallmarks and their associated pathways, AD drug therapy can potentially attenuate the disease state. In this review article, we focus on newly proposed and experimental AD drug treatment. We discuss three characteristic areas of AD treatment: prevention of neurotoxic beta-amyloid protein plaque formation, stability of neuronal tau proteins, and increase in neuronal growth and function. The primary drug therapy methods and patents discussed include the use of neurotrophic factors and targeting of the amyloid precursor protein cleavage pathway as prevention of beta amyloid formation and tau aggregation. PMID- 25012620 TI - Local melatonin regulates inflammation resolution: a common factor in neurodegenerative, psychiatric and systemic inflammatory disorders. AB - In many psychiatric, neurodegenerative and systemic inflammatory disorders circadian melatonin is decreased whilst melatonin enzymes and melatonin receptors are genetic susceptibility factors. Treatment with melatonin is useful in a diverse range of medical conditions, including bipolar disorder, Alzheimer's disease, depression and fibromyalgia. Decreased melatonin effects are classically attributed to lost pineal production. However, melatonin, along with its immediate precursor N-acetylserotonin (NAS), is produced by many, if not all, mitochondrial containing cells, including immune cells and central glia. Here we review the data on local melatonin and NAS production and propose that astrocyte melatonin and NAS efflux is crucial to local central inflammation regulation at the glia-neuronal interface. Melatonin and NAS provide antioxidant and anti inflammatory effects, as well as increasing mitochondrial oxidative phosphorylation and functioning. Consequently, their decreased production at sites of local inflammation is proposed to underlie melatonin's genetic association with a diverse range of medical conditions. Similarly the benefits of serotonin boosting medications, including antidepressants, across a wide range of conditions are partly mediated by increasing serotonin availability for astrocytic local NAS and melatonin production. Such a conceptualization incorporates a plethora of data across different disorders, especially the commonalities in oxidative and nitrosative stress, anti-oxidants, tryptophan catabolites and mitochondrial dysregulation evident in a diverse array of medical conditions. Glia melatonin and NAS regulation are important treatment targets in psychiatric disorders, neurodegenerative disorders and glioma. PMID- 25012621 TI - Mechanisms of developing post-traumatic stress disorder: new targets for drug development and other potential interventions. AB - The post-traumatic stress disorder (PTSD) is defined as a severe anxiety disorder that develops after exposure to an event with actual, threatened, or perceived death or serious injury, or a threat to the physical integrity of oneself or others that results in significant psychological trauma. Moreover, the ability of people to handle acute severe stress experiences varies among individuals. Depending on the underlying personality and resiliency, therefore, PTSD can occur in individuals exposed to exceedingly stressful incidences or those who have encountered seemingly less overwhelming stressors. In addition to severe stressful exposure, multiple other factors including genetic susceptibility; past experiences; cultural, spiritual, and personal beliefs; bullying and harassments; and lack of support at the workplace, social, and home environement may contribute to the development of PTSD. Author investigated multiple potential mechanisms for the development and sustenance of PTSD based on the recent literature and his own experiences and insight. Based on this search, author indicates that among other pathological and biochemical abnormalities, hormonal aberrations are most likely key mechanisms initiating and the maintenance of the PTSD. These pathophysiological neuro-hormonal changes instigate maladaptive learning processes caused by sustained high levels of anxiety and fear, through a hypo-responsive hypothalamic-pituitary axis and hyper-responsive catecholamine system (persistently elevated blood norepinephrine levels and lower than appropriate glucocorticoid levels). In addition to having inappropriately low serum cortisol levels and high epinephrine and norepinephrine levels, patients with PTSD also have mitochondrial dysfunctions and other hormonal abnormalities. Based on these data, author concluded that these pathological, biochemical and sustained neurohormonal abnormalities are likely to influence the structural brain changes, particularly in the amygdala and hippocampus, which are characteristics of patients with PTSD. Considering these abnormalities, neuroendocrine system needs to be considered as a key target for new drug development for prevention and treatment of PTSD. PMID- 25012622 TI - Kv1.3 lymphocyte potassium channel inhibition as a potential novel therapeutic target in acute ischemic stroke. AB - Stroke-induced immunosuppression (SIIS) leads to severe complications in stroke patients, including an increased risk of infections. However, functional alterations of T lymphocytes during SIIS are poorly described in acute ischemic stroke (AIS). We aimed to characterize Ca(2+) influx kinetics in major lymphocyte subsets (CD4, Th1, Th2, CD8) in AIS patients without infection 6 hours and one week after the CNS insult. We also assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 lymphocyte K(+) channels. We took peripheral blood samples from 12 non-stroke individuals and 12 AIS patients. We used an innovative flow cytometry approach to determine Ca(2+) influx kinetics and the surface expression of Kv1.3 channels. Our results indicate that Ca(2+) influx kinetics is altered in the Th2 and CD8 subsets in AIS which may play a role in the development of SIIS. Specific inhibition of Kv1.3 channels selectively decreased Ca(2+) influx in the CD8 and Th2 subsets of AIS patients. The surface expression of Kv1.3 channels is also altered compared to non-stroke individuals. Kv1.3 channel inhibition might have beneficial therapeutic consequences in AIS, selectively targeting two distinct T cell subsets at two different time points following the CNS insult. Within hours after the insult, it might prevent excessive tissue injury through the inhibition of CD8 cells, while at one week after the insult, it may improve the inflammatory response through the inhibition of Th2 cells, thus reducing the unwanted clinical consequences of SIIS. PMID- 25012623 TI - Zolpidem abuse and dependency in an elderly patient with major depressive disorder: a case report. AB - OBJECTIVE: Zolpidem is a non-benzodiazepine hypnotic drug for treatment of insomnia. It has been introduced as a lower potential agent for dependency and abusive effects. CASE SUMMARY: In this study, the reported case was a 62 years old female patient suffering simultaneously with Major Depressive Disorder and Opium Dependency. After abrupt discontinuation of zolpidem, 570 mg per day, she exhibited severe withdrawal symptoms, led her to be admitted to emergency department. CONCLUSIONS: Zolpidem has a potency to be abused with high risk of dependency and withdrawal syndromes particularly among elderly patients with comorbid anxiety/depressive symptoms/disorders. PMID- 25012625 TI - Printing organs cell-by-cell: 3-D printing is growing in popularity, but how should we regulate the application of this new technology to health care? PMID- 25012624 TI - High-intensity cannabis use and adherence to antiretroviral therapy among people who use illicit drugs in a Canadian setting. AB - Cannabis is increasingly prescribed clinically and utilized by people living with HIV/AIDS (PLWHA) to address symptoms of HIV disease and to manage side effects of antiretroviral therapy (ART). In light of concerns about the possibly deleterious effect of psychoactive drug use on adherence to ART, we sought to determine the relationship between high-intensity cannabis use and adherence to ART among a community-recruited cohort of HIV-positive illicit drug users. We used data from the ACCESS study, an ongoing prospective cohort study of HIV-seropositive illicit drug users linked to comprehensive ART dispensation records in a setting of universal no-cost HIV care. We estimated the relationship between at least daily cannabis use in the last 6 months, measured longitudinally, and the likelihood of optimal adherence to ART during the same period, using a multivariate linear mixed-effects model accounting for relevant socio-demographic, behavioral, clinical and structural factors. From May 2005 to May 2012, 523 HIV-positive illicit drug users were recruited and contributed 2,430 interviews. At baseline, 121 (23.1 %) participants reported at least daily cannabis use. In bivariate and multivariate analyses we did not observe an association between using cannabis at least daily and optimal adherence to prescribed HAART (Adjusted Odds Ratio = 1.12, 95 % Confidence Interval [95 % CI]: 0.76-1.64, p value = 0.555.) High intensity cannabis use was not associated with adherence to ART. These findings suggest cannabis may be utilized by PLWHA for medicinal and recreational purposes without compromising effective adherence to ART. PMID- 25012626 TI - Hypoxic/ischemic and infectious events have cumulative effects on the risk of cerebral palsy in very-low-birth-weight preterm infants. AB - BACKGROUND: Hypoxia/ischemia and inflammation are two major mechanisms for cerebral palsy (CP) in preterm infants. OBJECTIVE: To investigate whether hypoxia/ischemia- and infection-related events in the perinatal and neonatal periods had cumulative effects on CP risk in very-low-birth-weight (VLBW) premature infants. METHODS: From 1995 to 2005, 5,807 VLBW preterm infants admitted to Taiwan hospitals were enrolled. The cumulative effects of hypoxic/ischemic and infectious events during the perinatal and neonatal periods on CP risk at corrected age 24 months were analyzed. RESULTS: Of the 4,355 infants with 24-month follow-up, 457 (10.5%) had CP. The CP group had significantly higher incidences of hypoxia/ischemia-related events in the perinatal and neonatal periods, and sepsis in the neonatal period than the normal group. Three hypoxic/ischemic events, including birth cardiopulmonary resuscitation (OR 2.25; 95% CI 1.81-2.82), patent ductus arteriosus (PDA) ligation (2.94; 1.35-5.75) and chronic lung disease (3.14; 2.61-3.85) had the most significant contribution to CP. Relative to CP risk for infants with neither the three hypoxic/ischemic events nor sepsis, the CP odds increased 1.98-, 2.26- and 2.15-fold for infants with birth cardiopulmonary resuscitation, PDA ligation and chronic lung disease, respectively; while the combination with sepsis further increased the odds to 3.18-, 3.83- and 3.25-fold, respectively. Using the three hypoxic/ischemic events plus sepsis, CP rates were 10.0, 16.7, 26.7, 40.0 and 54.7% for infants with none, one, two, three and four events, respectively. CONCLUSIONS: Hypoxic/ischemic and infectious events across the perinatal and neonatal periods exerted cumulative effects on CP risk in VLBW premature infants. PMID- 25012627 TI - Developmental age strengthens barriers to ethanol accumulation in zebrafish. AB - Fetal Alcohol Spectrum Disorders (FASD) describes a wide range of phenotypic defects affecting facial and neurological development associated with ethanol teratogenicity. It affects approximately 1 in 100 children born in the United States each year. Genetic predisposition along with timing and dosage of ethanol exposure are critical in understanding the prevalence and variability of FASD. The zebrafish attributes of external fertilization, genetic tractability, and high fecundity make it a powerful tool for FASD studies. However, a lack of consensus of ethanol treatment paradigms has limited the interpretation of these various studies. Here we address this concern by examining ethanol tissue concentrations across timing and genetic background. We utilize headspace gas chromatography to determine ethanol concentration in the AB, fli1:EGFP, and Tu backgrounds. In addition, we treated these embryos with ethanol over two different developmental time windows, 6-24 h post fertilization (hpf) and 24-48 hpf. Our analysis demonstrates that embryos rapidly equilibrate to a sub-media level of ethanol. Embryos then maintain this level of ethanol for the duration of exposure. The ethanol tissue concentration level is independent of genetic background, but is timing-dependent. Embryos exposed from 6 to 24 hpf were 2.7 4.2-fold lower than media levels, while embryos were 5.7-6.2-fold lower at 48 hpf. This suggests that embryos strengthen one or more barriers to ethanol as they develop. In addition, both the embryo and, to a lesser extent, the chorion, surrounding the embryo are barriers to ethanol. Overall, this work will help tighten ethanol treatment regimens and strengthen zebrafish as a model of FASD. PMID- 25012629 TI - Improvements in transfemoral catheterization access techniques. PMID- 25012628 TI - Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline. AB - BACKGROUND: Acute liver failure leads to systemic complications with one of the most dangerous being a decline in neurological function, termed hepatic encephalopathy. Neurological dysfunction is exacerbated by an increase of toxic metabolites in the brain that lead to neuroinflammation. Following various liver diseases, hepatic and circulating chemokines, such as chemokine ligand 2 (CCL2), are elevated, though their effects on the brain following acute liver injury and subsequent hepatic encephalopathy are unknown. CCL2 is known to activate microglia in other neuropathies, leading to a proinflammatory response. However, the effects of CCL2 on microglia activation and the pathogenesis of hepatic encephalopathy following acute liver injury remain to be determined. METHODS: Hepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) in the presence or absence of INCB 3284 dimesylate (INCB), a chemokine receptor 2 inhibitor, or C 021 dihydrochloride (C021), a chemokine receptor 4 inhibitor. Mice were monitored for neurological decline and time to coma (loss of all reflexes) was recorded. Tissue was collected at coma and used for real-time PCR, immunoblots, ELISA, or immunostaining analyses to assess the activation of microglia and consequences on pro-inflammatory cytokine expression. RESULTS: Following AOM administration, microglia activation was significantly increased in AOM-treated mice compared to controls. Concentrations of CCL2 in the liver, serum, and cortex were significantly elevated in AOM-treated mice compared to controls. Systemic administration of INCB or C021 reduced liver damage as assessed by serum liver enzyme biochemistry. Administration of INCB or C021 significantly improved the neurological outcomes of AOM-treated mice, reduced microglia activation, reduced phosphorylation of ERK1/2, and alleviated AOM induced cytokine upregulation. CONCLUSIONS: These findings suggest that CCL2 is elevated systemically following acute liver injury and that CCL2 is involved in both the microglia activation and neurological decline associated with hepatic encephalopathy. Methods used to modulate CCL2 levels and/or reduce CCR2/CCR4 activity may be potential therapeutic targets for the management of hepatic encephalopathy due to acute liver injury. PMID- 25012630 TI - Inhibitory effect of potassium alum on smooth muscle contraction of rabbit and its mechanism. AB - OBJECTIVE: To investigate the effects of potassium alum (Alunite) on smooth muscle contraction and phosphorylation of myosin light chain by myosin light chain kinase (MLCK) and to try to find out the clue of its mechanism. METHODS: An isolated rabbit duodenum smooth muscle strip was selected to study the effects of potassium alum on its contractile activity under the condition of Krebs' solution using HW-400S constant temperature smooth muscle trough. The myosin and MLCK were purified from chicken gizzard smooth muscle. Myosin light chain phosphorylation was determined by glycerol-polyacrylamide gel electrophoresis; myosin Mg2+-ATPase activity was measured by inorganic phosphate liberation method. RESULTS: Potassium alum (2.5-20 mmol/L) inhibited the contraction on duodenum in a dose related and a time-dependent manner; potassium alum could also inhibit the extent of phosphorylation of myosin light chain in a dose-related and a time-dependent manner; and potassium alum inhibited the extent of Mg2+-ATPase activity in a dose related manner. CONCLUSIONS: Potassium alum inhibited smooth muscle contraction in a way of inhibiting phosphorylation of myosin light chain and Mg2+-ATPase activity. This has revealed the molecular mechanism of treatment of gastrointestinal spastic disorders by potassium alum. PMID- 25012631 TI - Kidney tubular-cell secretion of osteoblast growth factor is increased by kaempferol: a scientific basis for "the kidney controlling the bone" theory of Chinese medicine. AB - OBJECTIVE: To study, at the cytological level, the basic concept of Chinese medicine that "the Kidney (Shen) controls the bone". METHODS: Kaempferol was isolated form Rhizoma Drynariae (Gu Sui Bu, GSB) and at several concentrations was incubated with opossum kidney (OK) cells, osteoblasts (MC3T3 E1) and human fibroblasts (HF) at cell concentrations of 2*10(4)/mL. Opossum kidney cell conditioned culture media with kaempferol at 70 nmol/L (70kaeOKM) and without kaempferol (0OKM) were used to stimulate MC3T3 E1 and HF proliferation. The bone morphological protein receptors I and II (BMPR I and II) in OK cells were identified by immune-fluorescence staining and Western blot analysis. RESULTS: Kaempferol was found to increase OK cell growth (P<0.05), but alone did not promote MC3T3 E1 or HF cell proliferation. However, although OKM by itself increased MC3T3 E1 growth by 198% (P<0.01), the 70kaeOKM further increased the growth of these cells by an additional 127% (P<0.01). It indicates that the kidney cell generates a previously unknown osteoblast growth factor (OGF) and kaempferol increases kidney cell secretion of OGF. Neither of these media had any significant effect on HF growth. Kaempferol also was found to increase the level of the BMPR II in OK cells. CONCLUSIONS: This lends strong support to the original idea that the Kidney has a significant influence over bone-formation, as suggested by some long-standing Chinese medical beliefs, kaempferol may also serve to stimulate kidney repair and indirectly stimulate bone formation. PMID- 25012633 TI - Heart & Lung special issue: Care of the critically ill adults and their family caregivers--Guest Editor comments. PMID- 25012632 TI - Chinese medicines and bioactive compounds for treatment of stroke. AB - Stroke is an important cause of mortality and morbidity worldwide but effective therapeutic strategy for the prevention of brain injury in patients with cerebral ischemia is lacking. Although tissue plasminogen activator has been used to treat stroke patients, this therapeutic strategy is confronted with ill side effects and is limited to patients within 3 h of a stroke. Due to the complexity of the events and the disappointing results from single agent trials, the combination of thrombolytic therapy and effective neural protection therapy may be an alternative strategy for patients with cerebral ischemia. Chinese medicine (CM) is the most widely practiced form of herbalism worldwide, as it is a sophisticated system of medical theory and practice that is specifically different from Western medicine. Most traditional therapeutic formulations consist of a combination of several drugs. The combination of multiple drugs is thought to maximize therapeutic efficacy by facilitating synergistic actions and preventing possible adverse effects while at the same time marking at multiple targets. CM has been labeled in ancient medicine systems as a treatment for various diseases associated with stroke. This review summarizes various CMs, bioactive compounds and their effects on cerebral ischemia. PMID- 25012634 TI - Methods for knowledge synthesis: an overview. AB - OBJECTIVES: To highlight recent advances in knowledge synthesis methods and reporting guidelines. BACKGROUND: Knowledge synthesis is critical to advancing practice, research, and policy, but synthesizing knowledge from an often heterogeneous body of literature is challenging. METHODS: A review of knowledge synthesis methods and reporting guidelines for health sciences research was completed using Google Scholar, Medline, CINAHL, and PsycInfo. Relevant information was critiqued and summarized for applicability to health science and practice. RESULTS: Recent advances and guidelines pertaining to systematic reviews, meta-analysis, qualitative synthesis, mixed studies reviews, integrative reviews, scoping reviews, RE-AIM reviews, and umbrella reviews are discussed and examples of the application of each method to cardiopulmonary research are provided. Methods of quality appraisal are also presented. CONCLUSIONS: Advancements in knowledge synthesis and reporting guidelines enhance the quality, scope, and applicability of results; thus improving health science and clinical practice, and advancing health policy. PMID- 25012636 TI - Surviving sudden cardiac death secondary to anomalous left coronary artery from the pulmonary artery: a case report and literature review. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is an uncommon type of congenital coronary anomaly. In adults, the clinical picture of ALCAPA varies widely between being asymptomatic, presenting similarly to other heart diseases, or as malignant arrhythmias. Patients who have cardiac arrest are usually young and do not exhibit prior warning symptoms. In this article we describe a case of a 22-year-old healthy male, who experienced cardiac arrest during exertion. He was then diagnosed with ALCAPA, which was surgically corrected. PMID- 25012635 TI - Patients' annual income adequacy, insurance premiums and out-of-pocket expenses related to heart failure care. AB - OBJECTIVES: To (1) identify the amount patients spend for insurance premiums, co payments, deductibles, and other out-of-pocket costs related to HF and chronic health care services and estimate their annual non-reimbursed and out-of-pocket costs; and (2) identify patients' concerns about nonreimbursed and out-of-pocket expenses. BACKGROUND: HF is one of the most expensive illnesses for our society with multiple health services and financial burdens for families. METHODS: Mixed methods with quantitative questionnaires and qualitative interviews. RESULTS: Patients (N = 149) reported annual averages for non-reimbursed health services co payments and out-of-pocket costs ranging from $3913 to $5829 depending on insurance coverage. Thirty one patients (21%) reported inadequate health coverage related to their non-reimbursed costs. CONCLUSIONS: Non-reimbursed costs related to HF care are substantial and vary depending on their insurance, health services use, and out-of-pocket costs. Patient referral to social services to assist with expenses could provide some relief from the burden of high HF-related costs. PMID- 25012637 TI - Beliefs about children's adjustment in same-sex families: Spanish and Chilean university students. AB - The main purpose of our study is to compare the beliefs of Spanish and Chilean university students about the effects that same-sex parents might have on their children. A total of 491 participants completed the study (208 Spaniards and 283 Chileans). The results indicate a kind of modern and subtle rejection based on hetero-normativity. Furthermore, the results indicated the effects of sex (men have a greater degree of rejection), traditional and sexist opinions linked to a greater rejection of same-sex parents, and the contact variable which inversely correlates with this rejection. The results show that the etiology of homosexual orientation also correlates with rejection of same-sex parents when it is believed that homosexuality is learned or can be changed. PMID- 25012638 TI - Patterns of ocular injury from paintball trauma. PMID- 25012639 TI - Chk1 activity is required for BAK multimerization in association with PUMA during mitochondrial apoptosis. AB - BACKGROUND: The Bcl-2 protein BAK is a key player in mitochondrial apoptosis and responds to a myriad of different death signals. Activation of BAK is a multistep process that involves a number of conformational changes mediated by BH3-only proteins or p53 which leads to BAK multimerization and pore formation in the mitochondrial outer membrane. We previously reported that BAK activation is dependent upon dephosphorylation of both tyrosine and serine residues. Further, recent reports demonstrated that PP2A activity is required for BAK multimerization. Since Chk1, a checkpoint kinase involved in the activation of G2 checkpoint, is regulated by PP2A, we therefore hypothesized that Chk1 is involved in BAK multimerization during cell cycle arrest upon severe DNA damage. FINDINGS: We now show that treatment of HCT116-WT BAK cells with a Chk1 inhibitor impaired BAK dimerization and mutimerization when treated with the DNA damaging agents UV or etoposide. As a result there is a concomitant decrease of cytochrome c release from isolated mitochondria challenged with tBid protein and failure in the activation of caspase3. Interestingly, co-immunoprecipitation studies suggest that Chk1 is required for recruitment of BH3- only protein PUMA to BAK. We also showed that Chk1 is associated with BAK upon DNA damage. CONCLUSION: These findings novelly demonstrate the involvement of a checkpoint kinase Chk1 is required for BAK activation and underscores the importance of involvement of Chk1 in mitochondrial apoptosis upon severe DNA damage. PMID- 25012640 TI - An MRI compatible loading device for the reconstruction of clinically relevant plantar pressure distributions and loading scenarios of the forefoot. AB - The purpose of this study is to demonstrate a new MRI compatible loading device capable of reconstructing realistic loading scenarios of the human foot for research in the field of foot biomechanics. This device has two different configurations: one used to compress the forefoot and one to bend the metatarsophalangeal joints. Required plantar pressure distribution under the metatarsal heads can be achieved by modifying the distribution of the dorsally applied forces. To validate the device, subject-specific plantar pressures were measured and then reconstructed using the device. For quiet stance the peak pressure reconstruction error was 3% while for mid-stance phase of gait it was 8%. The device was also used to measure the passive bending stiffness of the metatarsophalangeal joints of one subject with low intra-subject variability. A series of preliminary MRI scans confirmed that the loading device can be used to produce static weight-bearing images of the foot (voxel size: 0.23 mm * 0.23 mm * 1.00 mm). The results indicate that the device presented here can accurately reconstruct subject specific plantar pressure distributions and measure the foot's metatarsophalangeal passive stiffness. Possible future applications include the validation of finite element models, the investigation of the relationship between plantar pressure and internal stresses/strains and the study of the foot's inter-segmental passive stiffness. PMID- 25012641 TI - Rasch-Master's Partial Credit Model in the assessment of children's creativity in drawings. AB - The purpose of the present study was to use the Partial Credit Model to study the factors of the Test of Creativity in Children and identify which characteristics of the creative person would be more effective to differentiate subjects according to their ability level. A sample of 1426 students from first to eighth grades answered the instrument. The Partial Credits model was used to estimate the ability of the subjects and item difficulties on a common scale for each of the four factors, indicating which items required a higher level of creativity to be scored and will differentiate the more creative individuals. The results demonstrated that the greater part of the characteristics showed good fit indices, with values between 0.80 and 1.30 both infit and outfit, indicating a response pattern consistent with the model. The characteristics of Unusual Perspective, Expression of Emotion and Originality have been identified as better predictors of creative performance because requires greater ability level (usually above two standard deviation). These results may be used in the future development of an instrument's reduced form or simplification of the current correction model. PMID- 25012642 TI - Automated delineation of brain structures in patients undergoing radiotherapy for primary brain tumors: from atlas to dose-volume histograms. AB - PURPOSE: To implement and evaluate a magnetic resonance imaging atlas-based automated segmentation (MRI-ABAS) procedure for cortical and sub-cortical grey matter areas definition, suitable for dose-distribution analyses in brain tumor patients undergoing radiotherapy (RT). PATIENTS AND METHODS: 3T-MRI scans performed before RT in ten brain tumor patients were used. The MRI-ABAS procedure consists of grey matter classification and atlas-based regions of interest definition. The Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm was applied to structures manually delineated by four experts to generate the standard reference. Performance was assessed comparing multiple geometrical metrics (including Dice Similarity Coefficient - DSC). Dosimetric parameters from dose-volume-histograms were also generated and compared. RESULTS: Compared with manual delineation, MRI-ABAS showed excellent reproducibility [median DSCABAS=1 (95% CI, 0.97-1.0) vs. DSCMANUAL=0.90 (0.73-0.98)], acceptable accuracy [DSCABAS=0.81 (0.68-0.94) vs. DSCMANUAL=0.90 (0.76-0.98)], and an overall 90% reduction in delineation time. Dosimetric parameters obtained using MRI-ABAS were comparable with those obtained by manual contouring. CONCLUSIONS: The speed, reproducibility, and robustness of the process make MRI-ABAS a valuable tool for investigating radiation dose-volume effects in non-target brain structures providing additional standardized data without additional time consuming procedures. PMID- 25012643 TI - The origins of radiotherapy: discovery of biological effects of X-rays by Freund in 1897, Kienbock's crucial experiments in 1900, and still it is the dose. AB - The discovery of X-rays by Wilhelm Conrad Rontgen (1845-1923) was triggered by pursuing an anomalous phenomenon: arousal of fluorescence at a distance from tubes in which cathode rays were elicited, a phenomenon which suggested the existence of a new kind of ray other than cathode rays. The discovery of biological effects of these X-rays by Leopold Freund (1868-1943) was triggered by pursuit of the purportedly useless phenomenon of epilation and dermatitis ensuing from X-ray-diagnostic experiments that others had reported. The crucial experiments performed by Robert Kienbock (1871-1953) entailed the proof that X ray-dose, not electric phenomena, was the active agent of biological effects ensuing when illuminating the skin using Rontgen tubes. For both the discovery of X-rays and the discovery of their biological effectiveness, priority did not matter, but understanding the physical and medico-biological significance of phenomena that others had ignored as a nuisance. Present discussions about the clinical relevance of improving the dose distribution including protons and other charged particles resemble those around 1900 to a certain degree. PMID- 25012644 TI - Assessment of improved organ at risk sparing for meningioma: light ion beam therapy as boost versus sole treatment option. AB - PURPOSE: To compare photons, protons and carbon ions and their combinations for treatment of atypical and anaplastical skull base meningioma. MATERIAL AND METHODS: Two planning target volumes (PTVinitial/PTVboost) were delineated for 10 patients (prescribed doses 50 Gy(RBE) and 10 Gy(RBE)). Plans for intensity modulated photon (IMXT), proton (IMPT) and carbon ion therapy ((12)C) were generated assuming a non-gantry scenario for particles. The following combinations were compared: IMXT+IMXT/IMPT/(12)C; IMPT+IMPT/(12)C; and (12)C+(12)C. Plan quality was evaluated by target conformity and homogeneity (CI, HI), V95%, D2% and D50% and dose-volume-histogram (DVH) parameters for organs-at risk (OAR). If dose escalation was possible, it was performed until OAR tolerance levels were reached. RESULTS: CI was worst for IMXT. HI<0.05+/-0.01 for (12)C was significantly better than for IMXT. For all treatment options dose escalation above 60 Gy(RBE) was possible for four patients, but impossible for six patients. Compared to IMXT+IMXT, ion beam therapy showed an improved sparing for most OARs, e.g. using protons and carbon ions D50% was reduced by more than 50% for the ipsilateral eye and the brainstem. CONCLUSION: Highly conformal IMPT and (12)C plans could be generated with a non-gantry scenario. Improved OAR sparing favors both sole (12)C and/or IMPT plans. PMID- 25012645 TI - The effect of resistance training during radiotherapy on spinal bone metastases in cancer patients - a randomized trial. AB - PURPOSE: To compare the effects of resistance training versus passive physical therapy on bone density in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases. Secondly, to quantify pathological fractures after combined treatment. MATERIAL AND METHODS: In this randomized trial, 60 patients were allocated from September 2011 until March 2013 into one of the two groups: resistance training (group A) or passive physical therapy (group B) with thirty patients in each group during RT. Bone density in metastatic and non-metastatic vertebral bone was assessed at baseline, 3 and 6 months after RT. RESULTS: Bone density in all metastases increased significantly by 28.3% (IQR 11.4-139.0) and 80.3% (IQR 32.6-250.6) after 3 and 6 months in group A (both p < 0.01). The bone density in group A was significantly increased compared to control group after 3 and 6months (both p < 0.01, median 59.7; IQR 21.1-98.3 and median 62.9; IQR -9.7 to 161.7). The bone density data in group B showed no significant increase over the course of time (p = 0.289, median 5.5, IQR 0.0-62.2 and p = 0.057, median 52.1, IQR 0.0-162.7). 23.3% of the patients in group A and 30.0% of the patients in group B had pathological fractures, no fracture was assigned to intervention, and no difference between groups after 3 and 6 months was observed (p = 0.592 and p = 0.604). CONCLUSIONS: Our trial demonstrated that resistance training concomitant to RT can improve bone density in spinal bone metastases. This combined treatment is effective, practicable, and without side effects for patients. Importantly, the pathological fracture rate in the intervention group was not increased. The results offer a rationale for future large controlled investigations to confirm these findings. TRIAL REGISTRATION: Clinical trial identifier NCT01409720. PMID- 25012646 TI - Isolated keratinized gingiva incision in alveolar cleft bone grafts improves qualitative outcomes: a single surgeon's 23 year experience. AB - BACKGROUND: Few publications have described the flap design of the secondary cleft alveoloplasty. In this article we describe a modified technique of the classical flap design with the purpose of minimizing injury to the dental papillae and periodontium of the involved dentition. We report our long-term experience, specifically with regards to oronasal fistulae recurrence, wound healing and graft exposure and loss. METHODS: All the patients were operated on using the same technique by a single surgeon. A total of 148 clefts have been operated with this approach, involving 117 patients with complete cleft lip and palate with a follow-up between 12 and 240 months. RESULTS: The most important finding in this study is the excellent wound healing observed in almost all patients. Only three patients (2%) suffered a dehiscence with oronasal fistulae recurrence and bone loss. Another patient lost the graft without fistula recurrence. Minor dehiscence with partial bone loss occurred in 4 patients (2.7%). These patients did not need surgical closure and only superficial exposed bone particles were lost without compromising the clinical outcome. CONCLUSIONS: Our modification presents a flap design that is easy to elevate and mobilize, without disturbing the buccal sulcus or the gingival inter-dental papillae. PMID- 25012647 TI - Changes of the retrolingual pharynx during the Muller manoeuvre and during sleep in sleep apnoea. AB - OBJECTIVE: To determine whether the retrolingual pharynx shows the same morphometric modifications during the Muller manoeuvre and during drug-induced sleep endoscopy (DISE) with propofol in patients submitted for maxillomandibular advancement surgery. SUBJECTS AND METHODS: Eighteen patients submitted for maxillomandibular advancement surgery (MMAS) were evaluated endoscopically before and 6 month after surgery in the region of the retrolingual pharynx while seated and lying in dorsal decubitus (supine) while performing the Muller manoeuvre and during DISE with propofol, to verify and measure if the same morphometric changes occur in the retrolingual pharynx during the Muller manoeuvre and during DISE with propofol. The area, anteroposterior, and laterolateral retrolingual pharynx images were acquired using the Sony Vegas 8.0 software and recorded on a DVD. The Image J software was used to measure and compare these images. RESULTS: An increase in the pharyngeal aperture was observed in all measurements after surgery, specifically in area retrolingual pharynx images. When the Muller manoeuvre was performed, a greater gain (113%) in area retrolingual pharynx measurement was observed when the patient was awake and seated. With the patient was in dorsal decubitus during DISE with propofol there was a greater gain in area retrolingual pharynx measurement (201.33%) in the smaller aperture. CONCLUSION: The Muller manoeuvre after MMAS does not simulate the dimensions of the pharynx that occur during sleep. PMID- 25012648 TI - The Sudanese female face: normative craniofacial measurements and comparison with African-American and North American White females. AB - BACKGROUND: Ethnic differences in craniofacial dimensions and proportional relationships means that ethnicity-specific data is required for both diagnosis and treatment planning. This investigation establishes normative craniofacial anthropometric values for the Sudanese female (SF) population, compares with North American White (NAW) and African-American females (AA), and analyses the occurrence of neoclassical norms within the study sample. METHODS: Standardized frontal and profile facial photographs were taken of 100 female participants. Five vertical and five horizontal anthropometric measurements were determined. RESULTS: Significant differences were found between the 3 populations. The sample showed very poor compliance with the neoclassical norms. The upper face height of the SF was ~ 20-mm taller than the AA faces (p < 0.001). Midface, nasal and lower face heights were also significantly taller, by 15-mm, 10-mm and 10-mm respectively (p < 0.001). SF showed significant reduction in bizygomatic width (~ 30-mm), compared to NAW and AA (p < 0.001). Eye width was ~ 5-mm less than the AA sample and 3-mm less than the NAW sample (p < 0.001). Mouth width was ~ 5-mm less in SF than the other two groups (p < 0.001). The SF exhibited a reduced interalar width compared with AA (p < 0.001), but wider than the NAW (p < 0.001). CONCLUSIONS: The average SF face is significantly taller and narrower than the AA or NAW female face. The neoclassical proportional norms appear to be unreliable guides in relation to the SF face, and should not be used in comparative diagnosis and treatment planning. Use of the normative anthropometric data presented in this article, both linear and proportional values, should be considered in the diagnosis and treatment planning of young adult female patients of Sudanese descent. PMID- 25012649 TI - Characterizing occupational risk perception: the case of biological, ergonomic and organizational hazards in Spanish healthcare workers. AB - Understanding how risk is perceived by workers is necessary for effective risk communication and risk management. This study adapts key elements of the psychometric perspective to characterize occupational risk perception at a worker level. A total of 313 Spanish healthcare workers evaluated relevant hazards in their workplaces related to biological, ergonomic and organizational factors. A questionnaire elicited workers' ratings of 3 occupational hazards on 9 risk attributes along with perceived risk. Factor and regression analyses reveal regularities in how different risks are perceived, while, at the same time, the procedure helps to summarize specificities in the perception of each hazard. The main regularity is the weight of feeling of dread/severity in order to characterize the risk perceived (beta ranges from .22 to .41; p < .001). Data also suggest an underestimation of expert knowledge in relation to the personal knowledge of risk. Thus, participants consider their knowledge of the risk related to biological, ergonomic, and organizational hazards to be higher than the knowledge attributed to the occupational experts (mean differences 95% CIs [.10, .30], [.54, .94], and [0.52, 1.05]). We demonstrate the application of a feasible and systematic procedure to capture how workers perceive hazards in their immediate work environment. PMID- 25012650 TI - The diabetes drug target MitoNEET governs a novel trafficking pathway to rebuild an Fe-S cluster into cytosolic aconitase/iron regulatory protein 1. AB - In eukaryotes, mitochondrial iron-sulfur cluster (ISC), export and cytosolic iron sulfur cluster assembly (CIA) machineries carry out biogenesis of iron-sulfur (Fe S) clusters, which are critical for multiple essential cellular pathways. However, little is known about their export out of mitochondria. Here we show that Fe-S assembly of mitoNEET, the first identified Fe-S protein anchored in the mitochondrial outer membrane, strictly depends on ISC machineries and not on the CIA or CIAPIN1. We identify a dedicated ISC/export pathway in which augmenter of liver regeneration, a mitochondrial Mia40-dependent protein, is specific to mitoNEET maturation. When inserted, the Fe-S cluster confers mitoNEET folding and stability in vitro and in vivo. The holo-form of mitoNEET is resistant to NO and H2O2 and is capable of repairing oxidatively damaged Fe-S of iron regulatory protein 1 (IRP1), a master regulator of cellular iron that has recently been involved in the mitochondrial iron supply. Therefore, our findings point to IRP1 as the missing link to explain the function of mitoNEET in the control of mitochondrial iron homeostasis. PMID- 25012651 TI - Ki67 antigen contributes to the timely accumulation of protein phosphatase 1gamma on anaphase chromosomes. AB - Ki67 is a protein widely used as cell-proliferation marker, with its cellular functions being hardly unveiled. In this paper, we present the direct interaction between Ki67 and PP1gamma, a protein phosphatase showing characteristic accumulation on anaphase chromosomes via the canonical PP1-binding motif within Ki67. In cells depleted of Ki67, PP1gamma is targeted to anaphase chromosomes less efficiently. Additionally, overexpression of Ki67, but not a mutant form without the ability to bind PP1gamma, induced ectopic localization of PP1gamma omicronn metaphase chromosomes. These observations demonstrate that Ki67 is one factor that defines the cellular behavior of PP1gamma in anaphase. To explore the specific roles of the subset of PP1gamma recruited on chromosome via its interaction with Ki67 (PP1gamma-Ki67), endogenous Ki67 was replaced with a Ki67 mutant deficient in its ability to interact with PP1gamma. Although no obvious defects in the progression of mitosis were observed, the timing of dephosphorylation of the mutant Ki67 in anaphase was delayed, indicating that Ki67 itself is one of the substrates of PP1gamma-Ki67. PMID- 25012652 TI - Identification and functional characterization of nuclear mortalin in human carcinogenesis. AB - The Hsp70 family protein mortalin is an essential chaperone that is frequently enriched in cancer cells and exists in various subcellular sites, including the mitochondrion, plasma membrane, endoplasmic reticulum, and cytosol. Although the molecular mechanisms underlying its multiple subcellular localizations are not yet clear, their functional significance has been revealed by several studies. In this study, we examined the nuclear fractions of human cells and found that the malignantly transformed cells have more mortalin than the normal cells. We then generated a mortalin mutant that lacked a mitochondrial targeting signal peptide. It was largely localized in the nucleus, and, hence, is called nuclear mortalin (mot-N). Functional characterization of mot-N revealed that it efficiently protects cancer cells against endogenous and exogenous oxidative stress. Furthermore, compared with the full-length mortalin overexpressing cancer cells, mot-N derivatives showed increased malignant properties, including higher proliferation rate, colony forming efficacy, motility, and tumor forming capacity both in in vitro and in vivo assays. We demonstrate that mot-N promotes carcinogenesis and cancer cell metastasis by inactivation of tumor suppressor protein p53 functions and by interaction and functional activation of telomerase and heterogeneous ribonucleoprotein K (hnRNP-K) proteins. PMID- 25012653 TI - GABA(A) receptor pi (GABRP) stimulates basal-like breast cancer cell migration through activation of extracellular-regulated kinase 1/2 (ERK1/2). AB - Breast cancer is a heterogeneous disease comprised of distinct subtypes predictive of patient outcome. Tumors of the basal-like subtype have a poor prognosis due to inherent aggressiveness and the lack of targeted therapeutics. Basal-like tumors typically lack estrogen receptor-alpha, progesterone receptor and HER2/ERBB2, or in other words they are triple negative (TN). Continued evaluation of basal-like breast cancer (BLBC) biology is essential to identify novel therapeutic targets. Expression of the pi subunit of the GABA(A) receptor (GABRP) is associated with the BLBC/TN subtype, and herein, we reveal its expression also correlates with metastases to the brain and poorer patient outcome. GABRP expression in breast cancer cell lines also demonstrates a significant correlation with the basal-like subtype suggesting that GABRP functions in the initiation and/or progression of basal-like tumors. To address this postulate, we stably silenced GABRP in two BLBC cell lines, HCC1187 and HCC70 cells. Decreased GABRP reduces in vitro tumorigenic potential and migration concurrent with alterations in the cytoskeleton, specifically diminished cellular protrusions and expression of the BLBC-associated cytokeratins, KRT5, KRT6B, KRT14, and KRT17. Silencing GABRP also decreases phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) in both cell lines and selective inhibition of ERK1/2 similarly decreases the basal-like cytokeratins as well as migration. Combined, these data reveal a GABRP-ERK1/2-cytokeratin axis that maintains the migratory phenotype of basal-like breast cancer. GABRP is a component of a cell surface receptor, thus, these findings suggest that targeting this new signaling axis may have therapeutic potential in BLBC. PMID- 25012654 TI - Human pluripotent stem cells have a novel mismatch repair-dependent damage response. AB - Human pluripotent stem cells (PSCs) are presumed to have robust DNA repair pathways to ensure genome stability. PSCs likely need to protect against mutations that would otherwise be propagated throughout all tissues of the developing embryo. How these cells respond to genotoxic stress has only recently begun to be investigated. Although PSCs appear to respond to certain forms of damage more efficiently than somatic cells, some DNA damage response pathways such as the replication stress response may be lacking. Not all DNA repair pathways, including the DNA mismatch repair (MMR) pathway, have been well characterized in PSCs to date. MMR maintains genomic stability by repairing DNA polymerase errors. MMR is also involved in the induction of cell cycle arrest and apoptosis in response to certain exogenous DNA-damaging agents. Here, we examined MMR function in PSCs. We have demonstrated that PSCs contain a robust MMR pathway and are highly sensitive to DNA alkylation damage in an MMR-dependent manner. Interestingly, the nature of this alkylation response differs from that previously reported in somatic cell types. In somatic cells, a permanent G2/M cell cycle arrest is induced in the second cell cycle after DNA damage. The PSCs, however, directly undergo apoptosis in the first cell cycle. This response reveals that PSCs rely on apoptotic cell death as an important defense to avoid mutation accumulation. Our results also suggest an alternative molecular mechanism by which the MMR pathway can induce a response to DNA damage that may have implications for tumorigenesis. PMID- 25012655 TI - A conserved motif mediates both multimer formation and allosteric activation of phosphoglycerate mutase 5. AB - Phosphoglycerate mutase 5 (PGAM5) is an atypical mitochondrial Ser/Thr phosphatase that modulates mitochondrial dynamics and participates in both apoptotic and necrotic cell death. The mechanisms that regulate the phosphatase activity of PGAM5 are poorly understood. The C-terminal phosphoglycerate mutase domain of PGAM5 shares homology with the catalytic domains found in other members of the phosphoglycerate mutase family, including a conserved histidine that is absolutely required for catalytic activity. However, this conserved domain is not sufficient for maximal phosphatase activity. We have identified a highly conserved amino acid motif, WDXNWD, located within the unique N-terminal region, which is required for assembly of PGAM5 into large multimeric complexes. Alanine substitutions within the WDXNWD motif abolish the formation of multimeric complexes and markedly reduce phosphatase activity of PGAM5. A peptide containing the WDXNWD motif dissociates the multimeric complex and reduces but does not fully abolish phosphatase activity. Addition of the WDXNWD-containing peptide in trans to a mutant PGAM5 protein lacking the WDXNWD motif markedly increases phosphatase activity of the mutant protein. Our results are consistent with an intermolecular allosteric regulation mechanism for the phosphatase activity of PGAM5, in which the assembly of PGAM5 into multimeric complexes, mediated by the WDXNWD motif, results in maximal activation of phosphatase activity. Our results suggest the possibility of identifying small molecules that function as allosteric regulators of the phosphatase activity of PGAM5. PMID- 25012656 TI - Phototransformation of the red light sensor cyanobacterial phytochrome 2 from Synechocystis species depends on its tongue motifs. AB - Phytochromes are photoreceptors using a bilin tetrapyrrole as chromophore, which switch in canonical phytochromes between red (Pr) and far red (Pfr) light absorbing states. Cph2 from Synechocystis sp., a noncanonical phytochrome, harbors besides a cyanobacteriochrome domain a second photosensory module, a Pr/Pfr-interconverting GAF-GAF bidomain (SynCph2(1-2)). As in the canonical phytochromes, a unique motif of the second GAF domain, the tongue region, seals the bilin-binding site in the GAF1 domain from solvent access. Time-resolved spectroscopy of the SynCph2(1-2) module shows four intermediates during Pr -> Pfr phototransformation and three intermediates during Pfr -> Pr back-conversion. A mutation in the tongue's conserved PRXSF motif, S385A, affects the formation of late intermediate R3 and of a Pfr-like state but not the back-conversion to Pr via a lumi-F-like state. In contrast, a mutation in the likewise conserved WXE motif, W389A, changes the photocycle at intermediate R2 and causes an alternative red light-adapted state. Here, back-conversion to Pr proceeds via intermediates differing from SynCph2(1-2). Replacement of this tryptophan that is ~15 A distant from the chromophore by another aromatic amino acid, W389F, restores native Pr -> Pfr phototransformation. These results indicate large scale conformational changes within the tongue region of GAF2 during the final processes of phototransformation. We propose that in early intermediates only the chromophore and its nearest surroundings are altered, whereas late changes during R2 formation depend on the distant WXE motifs of the tongue region. Ser-385 within the PRXSF motif affects only late intermediate R3, when refolding of the tongue and docking to the GAF1 domain are almost completed. PMID- 25012657 TI - Structural and spectroscopic insights into BolA-glutaredoxin complexes. AB - BolA proteins are defined as stress-responsive transcriptional regulators, but they also participate in iron metabolism. Although they can form [2Fe-2S] containing complexes with monothiol glutaredoxins (Grx), structural details are lacking. Three Arabidopsis thaliana BolA structures were solved. They differ primarily by the size of a loop referred to as the variable [H/C] loop, which contains an important cysteine (BolA_C group) or histidine (BolA_H group) residue. From three-dimensional modeling and spectroscopic analyses of A. thaliana GrxS14-BolA1 holo-heterodimer (BolA_H), we provide evidence for the coordination of a Rieske-type [2Fe-2S] cluster. For BolA_C members, the cysteine could replace the histidine as a ligand. NMR interaction experiments using apoproteins indicate that a completely different heterodimer was formed involving the nucleic acid binding site of BolA and the C-terminal tail of Grx. The possible biological importance of these complexes is discussed considering the physiological functions previously assigned to BolA and to Grx-BolA or Grx-Grx complexes. PMID- 25012658 TI - Oleoyl coenzyme A regulates interaction of transcriptional regulator RaaS (Rv1219c) with DNA in mycobacteria. AB - We have recently shown that RaaS (regulator of antimicrobial-assisted survival), encoded by Rv1219c in Mycobacterium tuberculosis and by bcg_1279c in Mycobacterium bovis bacillus Calmette-Guerin, plays an important role in mycobacterial survival in prolonged stationary phase and during murine infection. Here, we demonstrate that long chain acyl-CoA derivatives (oleoyl-CoA and, to lesser extent, palmitoyl-CoA) modulate RaaS binding to DNA and expression of the downstream genes that encode ATP-dependent efflux pumps. Moreover, exogenously added oleic acid influences RaaS-mediated mycobacterial improvement of survival and expression of the RaaS regulon. Our data suggest that long chain acyl-CoA derivatives serve as biological indicators of the bacterial metabolic state. Dysregulation of efflux pumps can be used to eliminate non-growing mycobacteria. PMID- 25012659 TI - PrkC-mediated phosphorylation of overexpressed YvcK protein regulates PBP1 protein localization in Bacillus subtilis mreB mutant cells. AB - The YvcK protein has been shown to be necessary for growth under gluconeogenic conditions in Bacillus subtilis. Amazingly, its overproduction rescues growth and morphology defects of the actin-like protein MreB deletion mutant by restoration of PBP1 localization. In this work, we observed that YvcK was phosphorylated at Thr-304 by the protein kinase PrkC and that phosphorylated YvcK was dephosphorylated by the cognate phosphatase PrpC. We show that neither substitution of this threonine with a constitutively phosphorylated mimicking glutamic acid residue or a phosphorylation-dead mimicking alanine residue nor deletion of prkC or prpC altered the ability of B. subtilis to grow under gluconeogenic conditions. However, we observed that a prpC mutant and a yvcK mutant were more sensitive to bacitracin compared with the WT strain. In addition, the bacitracin sensitivity of strains in which YvcK Thr-304 was replaced with either an alanine or a glutamic acid residue was also affected. We also analyzed rescue of the mreB mutant strain by overproduction of YvcK in which the phosphorylation site was substituted. We show that YvcK T304A overproduction did not rescue the mreB mutant aberrant morphology due to PBP1 mislocalization. The same observation was made in an mreB prkC double mutant overproducing YvcK. Altogether, these data show that YvcK may have two distinct functions: 1) in carbon source utilization independent of its phosphorylation level and 2) in cell wall biosynthesis and morphogenesis through its phosphorylation state. PMID- 25012660 TI - beta-Arrestin 2 negatively regulates Toll-like receptor 4 (TLR4)-triggered inflammatory signaling via targeting p38 MAPK and interleukin 10. AB - The control of IL-10 production in Toll-like receptor (TLR) signals remains to be elucidated. Here, we report that beta-arrestin 2 positively regulates TLR triggered IL-10 production in a p38 mitogen-activated protein kinase (MAPK) dependent mechanism. In vitro studies with cells including peritoneal macrophages and HEK293/TLR4 cells have demonstrated that beta-arrestin 2 forms complexes with p38 and facilitates p38 activation after lipopolysaccharide (LPS) stimulation. Deficiency of beta-arrestin 2 and inhibition of p38 MAPK activity both ameliorate TLR4-stimulated IL-10 response. Additionally, in vivo experiments show that mice lacking beta-arrestin 2 produce less amount of IL-10, and are more susceptible to LPS-induced septic shock which is further enhanced by blocking IL-10 signal. These results reveal a novel mechanism by which beta-arrestin 2 negatively regulates TLR4-mediated inflammatory reactions. PMID- 25012661 TI - Class I and IIa histone deacetylases have opposite effects on sclerostin gene regulation. AB - Adult bone mass is controlled by the bone formation repressor sclerostin (SOST). Previously, we have shown that intermittent parathyroid hormone (PTH) bone anabolic therapy involves SOST expression reduction by inhibiting myocyte enhancer factor 2 (MEF2), which activates a distant bone enhancer. Here, we extended our SOST gene regulation studies by analyzing a role of class I and IIa histone deacetylases (HDACs), which are known regulators of MEF2s. Expression analysis using quantitative PCR (qPCR) showed high expression of HDACs 1 and 2, lower amounts of HDACs 3, 5, and 7, low amounts of HDAC4, and no expression of HDACs 8 and 9 in constitutively SOST-expressing UMR106 osteocytic cells. PTH induced Sost suppression was associated with specific rapid nuclear accumulation of HDAC5 and co-localization with MEF2s in nuclear speckles requiring serine residues 259 and 498, whose phosphorylations control nucleocytoplasmic shuttling. Increasing nuclear levels of HDAC5 in UMR106 by blocking nuclear export with leptomycin B (LepB) or overexpression in transient transfection assays inhibited endogenous Sost transcription and reporter gene expression, respectively. This repressor effect of HDAC5 did not require catalytic activity using specific HDAC inhibitors. In contrast, inhibition of class I HDAC activities and expression using RNA interference suppressed constitutive Sost expression in UMR106 cells. An unbiased comprehensive search for involved HDAC targets using an acetylome analysis revealed several non-histone proteins as candidates. These findings suggest that PTH-mediated Sost repression involves nuclear accumulation of HDAC inhibiting the MEF2-dependent Sost bone enhancer, and class I HDACs are required for constitutive Sost expression in osteocytes. PMID- 25012662 TI - The molecular mechanism of eukaryotic elongation factor 2 kinase activation. AB - Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF 2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to appropriately regulate protein translation rates. Here, an allosteric mechanism comprising two sequential conformations is described for eEF 2K activation. First, Ca(2+)/CaM binds eEF-2K with high affinity (Kd(CaM)(app) = 24 +/- 5 nm) to enhance its ability to autophosphorylate Thr-348 in the regulatory loop (R-loop) by > 10(4)-fold (k(auto) = 2.6 +/- 0.3 s(-1)). Subsequent binding of phospho-Thr-348 to a conserved basic pocket in the kinase domain potentially drives a conformational transition of the R-loop, which is essential for efficient substrate phosphorylation. Ca(2+)/CaM binding activates autophosphorylated eEF-2K by allosterically enhancing k(cat)(app) for peptide substrate phosphorylation by 10(3)-fold. Thr-348 autophosphorylation results in a 25-fold increase in the specificity constant (k(cat)(app)/K(m)(Pep-S) (app)), with equal contributions from k(cat)(app) and K(m)(Pep-S)(app), suggesting that peptide substrate binding is partly impeded in the unphosphorylated enzyme. In cells, Thr-348 autophosphorylation appears to control the catalytic output of active eEF-2K, contributing more than 5-fold to its ability to promote eEF-2 phosphorylation. Fundamentally, eEF-2K activation appears to be analogous to an amplifier, where output volume may be controlled by either toggling the power switch (switching on the kinase) or altering the volume control (modulating stability of the active R-loop conformation). Because upstream signaling events have the potential to modulate either allosteric step, this mechanism allows for exquisite control of eEF-2K output. PMID- 25012663 TI - Biased signaling favoring gi over beta-arrestin promoted by an apelin fragment lacking the C-terminal phenylalanine. AB - Apelin plays a prominent role in body fluid and cardiovascular homeostasis. We previously showed that the C-terminal Phe of apelin 17 (K17F) is crucial for triggering apelin receptor internalization and decreasing blood pressure (BP) but is not required for apelin binding or Gi protein coupling. Based on these findings, we hypothesized that the important role of the C-terminal Phe in BP decrease may be as a Gi-independent but beta-arrestin-dependent signaling pathway that could involve MAPKs. For this purpose, we have used apelin fragments K17F and K16P (K17F with the C-terminal Phe deleted), which exhibit opposite profiles on apelin receptor internalization and BP. Using BRET-based biosensors, we showed that whereas K17F activates Gi and promotes beta-arrestin recruitment to the receptor, K16P had a much reduced ability to promote beta-arrestin recruitment while maintaining its Gi activating property, revealing the biased agonist character of K16P. We further show that both beta-arrestin recruitment and apelin receptor internalization contribute to the K17F-stimulated ERK1/2 activity, whereas the K16P-promoted ERK1/2 activity is entirely Gi-dependent. In addition to providing new insights on the structural basis underlying the functional selectivity of apelin peptides, our study indicates that the beta-arrestin dependent ERK1/2 activation and not the Gi-dependent signaling may participate in K17F-induced BP decrease. PMID- 25012664 TI - Egr1 protein acts downstream of estrogen-leukemia inhibitory factor (LIF)-STAT3 pathway and plays a role during implantation through targeting Wnt4. AB - Embryo implantation is a highly synchronized process between an activated blastocyst and a receptive uterus. Successful implantation relies on the dynamic interplay of estrogen and progesterone, but the key mediators underlying embryo implantation are not fully understood. Here we show that transcription factor early growth response 1 (Egr1) is regulated by estrogen as a downstream target through leukemia inhibitory factor (LIF) signal transducer and activator of transcription 3 (STAT3) pathway in mouse uterus. Egr1 is localized in the subluminal stromal cells surrounding the implanting embryo on day 5 of pregnancy. Estrogen rapidly, markedly, and transiently enhances Egr1 expression in uterine stromal cells, which fails in estrogen receptor alpha knock-out mouse uteri. STAT3 is phosphorylated by LIF and subsequently recruited on Egr1 promoter to induce its expression. Our results of Egr1 expression under induced decidualization in vivo and in vitro show that Egr1 is rapidly induced after deciduogenic stimulus. Egr1 knockdown can inhibit in vitro decidualization of cultured uterine stromal cells. Chromatin immunoprecipitation data show that Egr1 is recruited to the promoter of wingless-related murine mammary tumor virus integration site 4 (Wnt4). Collectively, our study presents for the first time that estrogen regulates Egr1 expression through LIF-STAT3 signaling pathway in mouse uterus, and Egr1 functions as a critical mediator of stromal cell decidualization by regulating Wnt4. PMID- 25012665 TI - Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein. AB - The mitotic checkpoint (or spindle assembly checkpoint) is a fail-safe mechanism to prevent chromosome missegregation by delaying anaphase onset in the presence of defective kinetochore-microtubule attachment. The target of the checkpoint is the E3 ubiquitin ligase anaphase-promoting complex/cyclosome. Once all chromosomes are properly attached and bioriented at the metaphase plate, the checkpoint needs to be silenced. Previously, we and others have reported that TRIP13 AAA-ATPase binds to the mitotic checkpoint-silencing protein p31(comet). Here we show that endogenous TRIP13 localizes to kinetochores. TRIP13 knockdown delays metaphase-to-anaphase transition. The delay is caused by prolonged presence of the effector for the checkpoint, the mitotic checkpoint complex, and its association and inhibition of the anaphase-promoting complex/cyclosome. These results suggest that TRIP13 is a novel mitotic checkpoint-silencing protein. The ATPase activity of TRIP13 is essential for its checkpoint function, and interference with TRIP13 abolished p31(comet)-mediated mitotic checkpoint silencing. TRIP13 overexpression is a hallmark of cancer cells showing chromosomal instability, particularly in certain breast cancers with poor prognosis. We suggest that premature mitotic checkpoint silencing triggered by TRIP13 overexpression may promote cancer development. PMID- 25012667 TI - Inhibition of cardiomyocyte hypertrophy by protein arginine methyltransferase 5. AB - Protein arginine methyltransferase 5 (PRMT5), a protein arginine methyltransferase that catalyzes the symmetrical dimethylation of arginine residues within target proteins, has been implicated in many essential cellular processes ranging from the regulation of gene expression to cell proliferation and differentiation. PRMT5 is highly expressed in the heart; the functional role of PRMT5 in the heart, however, remains largely elusive. In the present study, we show that PRMT5 specifically interacts with GATA4 in both co-transfected HEK293T cells and neonatal rat cardiomyocytes by co-immunoprecipitation. Importantly, this interaction leads to the arginine methylation of GATA4 at positions of 229, 265, and 317, which leads to an inhibition of the GATA4 transcriptional activity, predominantly through blocking the p300-mediated acetylation of GATA4 in cardiomyocytes. Moreover, overexpression of PRMT5 substantially inhibited the acetylation of GATA4 and cardiac hypertrophic responses in phenylephrine stimulated cardiomyocytes, whereas knockdown of PRMT5 induced GATA4 activation and cardiomyocyte hypertrophy. Furthermore, in response to phenylephrine stimulation, PRMT5 translocates into the cytoplasm, thus relieving its repression on GATA4 activity in the nucleus and leading to hypertrophic gene expression in cardiomyocytes. These findings indicate that PRMT5 is an essential regulator of myocardial hypertrophic signaling and suggest that strategies aimed at activating PRMT5 in the heart may represent a potential therapeutic approach for the prevention of cardiac hypertrophy and heart failure. PMID- 25012669 TI - Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus. AB - BACKGROUND AND PURPOSE: MR imaging is used in the diagnostic evaluation of patients with idiopathic normal pressure hydrocephalus. The aim of this study was to describe the prevalence of several imaging features and their prognostic use in the selection of shunt candidates with idiopathic normal pressure hydrocephalus. MATERIALS AND METHODS: Preoperative MR imaging scans of the brain were retrospectively evaluated in 108 patients with idiopathic normal pressure hydrocephalus who had undergone a standardized, clinical evaluation before and 12 months after shunt surgery. The MR imaging features investigated were the Evans index, callosal angle, narrow sulci at the high convexity, dilation of the Sylvian fissure, diameters of the third ventricle and temporal horns, disproportionately enlarged subarachnoid space hydrocephalus, flow void through the aqueduct, focal bulging of the roof of the lateral ventricles, deep white matter hyperintensities, periventricular hyperintensities, and focal widening of sulci and aqueductal stenosis. RESULTS: In logistic regression models, with shunt outcome as a dependent variable, the ORs for the independent variables, callosal angle, disproportionately enlarged subarachnoid space hydrocephalus, and temporal horns, were significant (P < .05), both in univariate analyses and when adjusted for age, sex, and previous stroke. CONCLUSIONS: A small callosal angle, wide temporal horns, and occurrence of disproportionately enlarged subarachnoid space hydrocephalus are common in patients with idiopathic normal pressure hydrocephalus and were significant predictors of a positive shunt outcome. These noninvasive and easily assessed radiologic markers could aid in the selection of candidates for shunt surgery. PMID- 25012666 TI - Interferon-alpha acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line. AB - Interferon-alpha (IFN-alpha) is used clinically to treat hepatocellular carcinoma (HCC), although the detailed therapeutic mechanisms remain elusive. In particular, IFN-alpha has long been implicated in control of the cell cycle, but its actual point of action has not been clarified. Here, using time lapse imaging analyses of the human HCC cell line HuH7 carrying a fluorescence ubiquitination based cell cycle indicator (Fucci), we found that IFN-alpha induced cell cycle arrest in the G0/G1 phases, leading to apoptosis through an IFN-alpha type-2 receptor (IFNAR2)-dependent signaling pathway. Detailed analyses by time lapse imaging and biochemical assays demonstrated that the IFN-alpha/IFNAR2 axis sensitizes cells to apoptosis in the S/G2/M phases in preparation for cell death in the G0/G1 phases. In summary, this study is the first to demonstrate the detailed mechanism of IFN-alpha as an anticancer drug, using Fucci-based time lapse imaging, which will be informative for treating HCC with IFN-alpha in clinical practice. PMID- 25012668 TI - Increased risk of major depression subsequent to a first-attack and non-infection caused urticaria in adolescence: a nationwide population-based study. AB - BACKGROUND: Non-infection caused urticaria is a common ailment in adolescents. Its symptoms (e.g., unusual rash appearance, limitation of daily activities, and recurrent itching) may contribute to the development of depressive stress in adolescents; the potential link has not been well studied. This study aimed to investigate the risk of major depression after a first-attack and non-infection caused urticaria. METHODS: This study used the Taiwan Longitudinal Health Insurance Database. A total of 5,755 adolescents hospitalized for a first-attack and non-infection caused urticaria from 2005 to 2009 were recruited as the study group, together with 17,265 matched non-urticarial enrollees who comprised the control group. Patients who had any history of urticaria or depression prior to the evaluation period were excluded. Each patient was followed for one year to identify the occurrence of depression. Cox proportional hazards models were generated to compute the risk of major depression, adjusting for the subjects' sociodemographic characteristics. Depression-free survival curves were also analyzed. RESULTS: Thirty-four (0.6%) adolescents with non-infection caused urticaria and 59 (0.3%) non-urticarial control subjects suffered a new-onset episode of major depression during the study period. The stratified Cox proportional analysis showed that the crude hazard ratio (HR) of depression among adolescents with urticaria was 1.73 times (95% CI, 1.13-2.64) than that of the control subjects without urticaria. Moreover, the HR were higher in physical (HR: 3.39, 95% CI 2.77-11.52) and allergy chronic urticaria (HR: 2.43, 95% CI 3.18 9.78). CONCLUSION: Individuals who have a non-infection caused urticaria during adolescence are at a higher risk of developing major depression. PMID- 25012670 TI - Susceptibility-diffusion mismatch predicts thrombolytic outcomes: a retrospective cohort study. AB - BACKGROUND AND PURPOSE: Asymmetric hypointensity of cerebral veins on susceptibility-weighted imaging has been shown to indirectly reflect tissue hypoxia after cerebral ischemia. We therefore investigated whether patients with prominent asymmetry of the cerebral veins on SWI and a relatively small diffusion weighted imaging lesion (SWI-DWI mismatch), representing the presence of salvageable tissue, were more likely to benefit from thrombolytic therapy. MATERIALS AND METHODS: We conducted a retrospective study of the anterior circulation of patients with ischemic stroke with SWI/DWI acquired before thrombolysis. The asymmetry index was defined as the ratio of cerebral vein voxel count between the ischemic and normal hemisphere on the SWI phase map. We defined SWI-DWI mismatch as an asymmetry index score of >=1.75 with a DWI lesion volume of <=25 mL. Favorable outcome was defined as modified Rankin Scale 0-2 at 3 months. Univariate and multivariate logistic regression analyses were used to examine the association between the mismatch profile and favorable outcome. RESULTS: Fifty-four patients undergoing thrombolytic treatment were enrolled in this study. The rate of favorable outcome was significantly higher among patients with baseline SWI-DWI mismatch compared with those without (78% versus 44%; adjusted odds ratio, 6.317; 95% CI, 1.12-35.80; P = .037). Patients with SWI-DWI mismatch were also more likely to have a favorable outcome from reperfusion (91% versus 43%, P = .033) or recanalization (100% versus 40%, P = .013). The accuracy of SWI-DWI mismatch for predicting favorable outcome was higher than that of perfusion-diffusion mismatch (63% versus 48.1%). CONCLUSIONS: The presence of SWI DWI mismatch may identify patients with ischemia who would benefit from early reperfusion therapy. PMID- 25012671 TI - Racial and health insurance disparities of inpatient spine augmentation for osteoporotic vertebral fractures from 2005 to 2010. AB - BACKGROUND AND PURPOSE: Vertebroplasty and kyphoplasty are frequently utilized in the treatment of symptomatic vertebral body fractures. While prior studies have demonstrated disparities in the treatment of back pain and care for osteoporotic patients, disparities in spine augmentation have not been investigated. We investigated racial and health insurance status differences in the use of spine augmentation for the treatment of osteoporotic vertebral fractures in the United States. MATERIALS AND METHODS: Using the Nationwide Inpatient Sample from 2005 to 2010, we selected all discharges with a primary diagnosis of vertebral fracture (International Classification of Diseases-9 code 733.13). Patients who received spine augmentation were identified by using International Classification of Diseases-9 procedure code 81.65 for vertebroplasty and 81.66 for kyphoplasty. Patients with a diagnosis of cancer were excluded. We compared usage rates of spine augmentation by race/ethnicity (white, black, Hispanic, and Asian/Pacific Islander) and insurance status (Medicare, Medicaid, self-pay, and private). Comparisons among groups were made by using chi(2) tests. A multivariate logistic regression analysis was fit to determine variables associated with spine augmentation use. RESULTS: A total of 228,329 patients were included in this analysis, of whom 129,206 (56.6%) received spine augmentation. Among patients with spine augmentation, 97,022 (75%) received kyphoplasty and 32,184 (25%) received vertebroplasty; 57.5% (92,779/161,281) of white patients received spine augmentation compared with 38.7% (1405/3631) of black patients (P < .001). Hispanic patients had significantly lower spine augmentation rates compared with white patients (52.3%, 3777/7222, P < .001) as did Asian/Pacific Islander patients (53.1%, 1784/3361, P < .001). The spine augmentation usage rate was 57.2% (114,768/200,662) among patients with Medicare, significantly higher than that of those with Medicaid (43.9%, 1907/4341, P < .001) and those who self-pay (40.2%, 488/1214, P < .001). CONCLUSIONS: Our findings demonstrate substantial racial and health insurance-based disparities in the inpatient use of spinal augmentation for the treatment of osteoporotic vertebral fracture. PMID- 25012672 TI - Current and emerging MR imaging techniques for the diagnosis and management of CSF flow disorders: a review of phase-contrast and time-spatial labeling inversion pulse. AB - This article provides an overview of phase-contrast and time-spatial labeling inversion pulse MR imaging techniques to assess CSF movement in the CNS under normal and pathophysiologic situations. Phase-contrast can quantitatively measure stroke volume in selected regions, notably the aqueduct of Sylvius, synchronized to the heartbeat. Judicious fine-tuning of the technique is needed to achieve maximal temporal resolution, and it has limited visualization of CSF motion in many CNS regions. Phase-contrast is frequently used to evaluate those patients with suspected normal pressure hydrocephalus and a Chiari I malformation. Correlation with successful treatment outcome has been problematic. Time-spatial labeling inversion pulse, with a high signal-to-noise ratio, assesses linear and turbulent motion of CSF anywhere in the CNS. Time-spatial labeling inversion pulse can qualitatively visualize whether CSF flows between 2 compartments and determine whether there is flow through the aqueduct of Sylvius or a new surgically created stoma. Cine images reveal CSF linear and turbulent flow patterns. PMID- 25012673 TI - Gadolinium enhancement of atherosclerotic plaque in the middle cerebral artery: relation to symptoms and degree of stenosis. AB - BACKGROUND AND PURPOSE: High-resolution MR imaging can depict intracranial arterial atherosclerotic plaques. Our aim was to evaluate the relationship between the degree of enhancement of MCA plaques on contrast-enhanced high resolution MR imaging and ischemic stroke and stenosis severity. MATERIALS AND METHODS: This study enrolled 36 patients diagnosed with moderate-to-severe atherosclerotic MCA stenosis. A contrast-enhanced T1-weighted volume isotropic turbo spin-echo acquisition sequence was acquired for assessing plaque enhancement. Plaque-to-CSF contrast ratio was calculated after the signal intensity of plaques at the stenotic segment was measured. Univariate comparison and multivariate logistic regression analyses were performed for symptomatic and asymptomatic groups to assess the relationship between symptomatic stenosis and independent variables, including plaque-to-CSF contrast ratio, degree of stenosis, and clinical risk factors. Plaque-to-CSF contrast ratio was compared between the moderate and severe stenosis groups. RESULTS: Twenty-one patients had symptomatic MCA stenosis, and 15 had asymptomatic stenosis. The plaque-to-CSF contrast ratio was significantly higher in the symptomatic group than in the asymptomatic group (63.6 +/- 10.6% versus 54.1 +/- 13.5%, respectively; P < .05). The degree of stenosis also differed significantly between the 2 groups (P < .05). Multivariate analysis revealed that the degree of stenosis was the only independent predictor of ischemic stroke symptoms. The plaque-to-CSF contrast ratio of severe stenosis was significantly higher than that of moderate stenosis (66.8 +/- 8.7% versus 55.9 +/- 12.8%, respectively; P < .05). CONCLUSIONS: Plaque enhancement was significantly higher in patients with symptomatic plaques and may have been affected by the degree of stenosis. A difference in plaque enhancement according to the degree of stenosis has implications for understanding the development of intracranial atherosclerotic plaques. PMID- 25012674 TI - Spinal fluid biomechanics and imaging: an update for neuroradiologists. AB - Flow imaging with cardiac-gated phase-contrast MR has applications in the management of neurologic disorders. Together with computational fluid dynamics, phase-contrast MR has advanced our understanding of spinal CSF flow. Phase contrast MR is used to evaluate patients with Chiari I malformation who are candidates for surgical treatment. In theory, abnormal CSF flow resulting from the abnormal tonsil position causes syringomyelia and other neurologic signs and symptoms in patients with Chiari I. CSF flow imaging also has research applications in syringomyelia and spinal stenosis. To optimize MR acquisition and interpretation, neuroradiologists must have familiarity with healthy and pathologic patterns of CSF flow. The purpose of this review is to update concepts of CSF flow that are important for the practice of flow imaging in the spine. PMID- 25012675 TI - Safety and effectiveness of sacroplasty: a large single-center experience. AB - BACKGROUND AND PURPOSE: Sacral insufficiency fractures are a common cause of severe low back pain and immobilization in patients with osteoporosis or cancer. Current practice guideline recommendations range from analgesia and physical therapy to resection with surgical fixation. We sought to assess the safety and effectiveness of sacroplasty, an emerging minimally invasive treatment. MATERIALS AND METHODS: We performed a retrospective review of institutional databases for percutaneous sacroplasty performed between January 2004 and September 2013. Demographic and procedural data and pre- and posttreatment Visual Analog Scale, Functional Mobility Scale, and Analgesic Scale scores were reviewed. Overall response was rated by using a 4-point scale (1, complete resolution of pain; 2, improvement of pain; 3, no change; 4, worsened pain) assessed at short-term follow-up. RESULTS: Fifty-three patients were included; most (83%) were female. Fracture etiology was cancer-related (55%), osteoporotic insufficiency (30%), and minor trauma (15%). No major complication or procedure-related morbidity occurred. There were statistically significant decreases in the Visual Analog Scale (P < .001), Functional Mobility Scale (P < .001), and Analgesic Scale scores (P < .01) in 27 patients with recorded data: pretreatment Visual Analog Scale (median [interquartile range], 9.0 [8.0-10.0]); Functional Mobility Scale, 3.0 (2.0-3.0); and Analgesic Scale scores, 3.0 (3.0-4.0) were reduced to 3.0 (0.0 5.8), 1.0 (0.25-2.8), and 3.0 (2.0-3.8) posttreatment. When we used the overall 4 point score at a mean of 27 days, 93% (n = 45) reported complete resolution or improvement in overall pain. CONCLUSIONS: In this single-center cohort, sacroplasty was a safe and effective procedure. There were significant short-term gains in pain relief, increased mobility, and decreased dependence on pain medication. PMID- 25012679 TI - The impact of neuromyelitis optica on the recognition of emotional facial expressions: a preliminary report. AB - Although neuromyelitis optica (NMO) is classically recognized as an affectation of optic nerves and spinal cord, recent reports have shown brain atrophy and cognitive dysfunction in this condition. Importantly, emotion-related brain regions appear to be impaired in NMO. However, no studies of NMO' emotional processing have been published. The goal of the current study was to investigate facial emotion recognition in 10 patients with NMO and 10 healthy controls by controlling for relevant cognitive factors. Consistent with previous reports, NMO patients performed poorly across cognitive domains (divided attention, working memory, and information-processing speed). Our findings further evidence the relative inability of NMO patients to recognize negative emotions (disgust, anger, and fear), in comparison to controls, with these deficits not explained by other cognitive impairments. Results provide the first evidence that NMO may impair the ability to recognize negative emotions. These impairments appear to be related to possible damage in brain regions underling emotional networks, including the anterior cingulate cortex, amygdala, and medial prefrontal cortex. Findings increased both our understanding of NMO's cognitive impairment, and the neural networks underlying negative emotions. PMID- 25012680 TI - Edge state modulation of bilayer Bi nanoribbons by atom adsorption. AB - We investigated the behavior of edge states in two-dimensional bilayered Bi nanoribbons by atom adsorption based on the density functional method. We found that for a clean Bi zigzag ribbon the penetration depth of well-localized edge states is a function of the momentum-space width of the edge-state dispersion. Depending on the density of adsorbed H, Br and I atoms, respectively, the edge state can be changed from localized within a very narrow region to delocalized over the whole region in real space. Changes in atomic and electronic structures and topological insulator properties associated with the atomic adsorption on the edges of zigzag bilayer nanoribbon (ZBNR) are discussed. Our work suggests that ZBNR could be a possible candidate for nanoelectronic devices under some special conditions. PMID- 25012681 TI - Starting lithium prophylaxis early v. late in bipolar disorder. AB - BACKGROUND: No study has investigated when preventive treatment with lithium should be initiated in bipolar disorder. AIMS: To compare response rates among patients with bipolar disorder starting treatment with lithium early v. late. METHOD: Nationwide registers were used to identify all patients with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed lithium during the period 1995-2012 in Denmark (n = 4714). Lithium responders were defined as patients who, following a stabilisation lithium start-up period of 6 months, continued lithium monotherapy without being admitted to hospital. Early v. late intervention was defined in two ways: (a) start of lithium following first contact; and (b) start of lithium following a diagnosis of a single manic/mixed episode. RESULTS: Regardless of the definition used, patients who started lithium early had significantly decreased rates of non-response to lithium compared with the rate for patients starting lithium later (adjusted analyses: first v. later contact: P<0.0001; hazard ratio (HR) = 0.87, 95% CI 0.76 0.91; single manic/mixed episode v. bipolar disorder: P<0.0001; HR = 0.75, 95% CI 0.67-0.84). CONCLUSIONS: Starting lithium treatment early following first psychiatric contact or a single manic/mixed episode is associated with increased probability of lithium response. PMID- 25012682 TI - Suspicious young minds: paranoia and mistrust in 8- to 14-year-olds in the U.K. and Hong Kong. AB - BACKGROUND: Research on paranoia in adults suggests a spectrum of severity, but this dimensional approach has yet to be applied to children or to groups from different countries. AIMS: To investigate the structure, prevalence and correlates of mistrust in children living in the U.K. and Hong Kong. METHOD: Children aged 8-14 years from the U.K. (n = 1086) and Hong Kong (n = 1412) completed a newly developed mistrust questionnaire as well as standard questionnaire measures of anxiety, self-esteem, aggression and callous unemotional traits. RESULTS: Confirmatory factor analysis of the U.K. data supported a three-factor mode--mistrust at home, mistrust at school and eneral mistrust - with a clear positive skew in the data: just 3.4%, 8.5% and 4.1% of the children endorsed at least half of the mistrust items for home, school and general subscales respectively. These findings were replicated in Hong Kong. Moreover, compared with their peers, 'mistrustful' children (in both countries) reported elevated rates of anxiety, low self-esteem, aggression and callous unemotional traits. CONCLUSIONS: Mistrust may exist as a quantitative trait in children, which, as in adults, is associated with elevated risks of internalising and externalising problems. PMID- 25012683 TI - Functional connectivity and grey matter volume of the striatum in schizophrenia. AB - BACKGROUND: Alterations in the dopaminergic reward system, predominantly the striatum, constitute core characteristics of schizophrenia. AIMS: Functional connectivity of the dorsal striatum during reward-related trial-and-error learning was investigated in 17 people with schizophrenia and 18 healthy volunteers and related to striatal grey matter volume and psychopathology. METHOD: We used voxel-based morphometry and psychophysiological interaction to examine striatal volume and connectivity. RESULTS: A reduced functional connectivity between left striatum and temporo-occipital areas, precuneus and insula could be detected in the schizophrenia group. The positive correlation between grey matter volume and functional connectivity of the left striatum yielded significant results in a very similar network. Connectivity of the left striatum was negatively correlated with negative symptoms. CONCLUSIONS: Present results suggest a disruption in striatal functional connectivity that is closely linked to grey matter morphometry of the striatum. Decreased connectivity between the striatum and psychopathologically relevant networks may explain the emergence of negative symptoms. PMID- 25012684 TI - Discharges to prison from medium secure psychiatric units in England and Wales. AB - BACKGROUND: Early findings from a national study of discharges from 32 National Health Service medium secure units revealed that nearly twice as many patients than expected were discharged back to prison. AIMS: To compare the characteristics of those discharged back to prison with those discharged to the community, and consider the implications for ongoing care and risk. METHOD: Prospective cohort follow-up design. All forensic patients discharged from 32 medium secure units across England and Wales over a 12-month period were identified. Those discharged to prison were compared with those who were discharged to the community. RESULTS: Nearly half of the individuals discharged to prison were diagnosed with a serious mental illness and over a third with schizophrenia. They were a higher risk, more likely to have a personality disorder, more symptomatic and less motivated than those discharged to the community. CONCLUSIONS: Findings suggest that alternative models of prison mental healthcare should be considered to reduce risks to the patient and the public. PMID- 25012685 TI - Prognostic value of mammographic breast density in patients with metastatic breast cancer. AB - Breast density is a modifiable trait linked with breast cancer predisposition. However, the relation between mammographic breast density and survival outcome is not yet clarified. The present study aims to study the prognostic value of mammographic density in patients diagnosed with metastatic breast cancer. In this observational study, breast cancer patients with metastatic disease at diagnosis were enrolled. Two-view mammograms were performed at diagnosis, and breast density was quantitatively assessed. Progression-free survival (PFS) was correlated with breast density and other prognostic variables in univariate and multivariate analyses. PFS, stratified by different prognostic factors, was assessed in low compared to high density patients to check for possible differential survival outcome in patients' subgroups. Among the sixty enrolled patients, median PFS in low density patients was significantly better than those with high density (18.4 months, 95 % CI 14.88-22.15 vs. 9.3 months, 95 % CI 8.51 13.60, respectively, p = 0.002). Significant correlation of breast density with PFS persisted after adjustment by body mass index (p = 0.003) and after multivariate analysis incorporating other prognostic variables (HR 6.16, 95 % CI (2.17-17.48), p = 0.001). PFS was better in low density patients older than 40 years at diagnosis (p = 0.001), with HER2-negative disease (p = 0.015), hormonal receptor-positive phenotype (p = 0.020), patients with single site of metastasis (p = 0.006), and patients with bone-only metastases (p = 0.042). Breast density assessed at the time of diagnosis was significantly correlated with PFS of metastatic breast cancer patients. Survival outcome is improved in certain patients' subgroups with low breast density. PMID- 25012686 TI - Bacteriophages and medical oncology: targeted gene therapy of cancer. AB - Targeted gene therapy of cancer is of paramount importance in medical oncology. Bacteriophages, viruses that specifically infect bacterial cells, offer a variety of potential applications in biomedicine. Their genetic flexibility to go under a variety of surface modifications serves as a basis for phage display methodology. These surface manipulations allow bacteriophages to be exploited for targeted delivery of therapeutic genes. Moreover, the excellent safety profile of these viruses paves the way for their potential use as cancer gene therapy platforms. The merge of phage display and combinatorial technology has led to the emergence of phage libraries turning phage display into a high throughput technology. Random peptide libraries, as one of the most frequently used phage libraries, provide a rich source of clinically useful peptide ligands. Peptides are known as a promising category of pharmaceutical agents in medical oncology that present advantages such as inexpensive synthesis, efficient tissue penetration and the lack of immunogenicity. Phage peptide libraries can be screened, through biopanning, against various targets including cancer cells and tissues that results in obtaining cancer-homing ligands. Cancer-specific peptides isolated from phage libraries show huge promise to be utilized for targeting of various gene therapy vectors towards malignant cells. Beyond doubt, bacteriophages will play a more impressive role in the future of medical oncology. PMID- 25012687 TI - F-subunit reinforces torque generation in V-ATPase. AB - Vacuolar-type H(+)-pumping ATPases (V-ATPases) perform remarkably diverse functions in eukaryotic organisms. They are present in the membranes of many organelles and regulate the pH of several intracellular compartments. A family of V-ATPases is also present in the plasma membranes of some bacteria. Such V ATPases function as ATP-synthases. Each V-ATPase is composed of a water-soluble domain (V1) and a membrane-embedded domain (Vo). The ATP-driven rotary unit, V[Formula: see text], is composed of A, B, D, and F subunits. The rotary shaft (the DF subcomplex) rotates in the central cavity of the A3B3-ring (the catalytic hexamer ring). The D-subunit, which has a coiled-coil domain, penetrates into the ring, while the F-subunit is a globular-shaped domain protruding from the ring. The minimal ATP-driven rotary unit of V[Formula: see text] is comprised of the A3B3D subunits, and we therefore investigated how the absence of the globular shaped F-subunit affects the rotary torque generation of V[Formula: see text]. Using a single-molecule technique, we observed the motion of the rotary motors. To obtain the torque values, we then analyzed the measured motion trajectories based on the fluctuation theorem, which states that the law of entropy production in non-equilibrium conditions and has been suggested as a novel and effective method for measuring torque. The measured torque of A3B3D was half that of the wild-type V1, and full torque was recovered in the mutant V1, in which the F subunit was genetically fused with the D-subunit, indicating that the globular shaped F-subunit reinforces torque generation in V1. PMID- 25012688 TI - Solar ultraviolet radiation is necessary to enhance grapevine fruit ripening transcriptional and phenolic responses. AB - BACKGROUND: Ultraviolet (UV) radiation modulates secondary metabolism in the skin of Vitis vinifera L. berries, which affects the final composition of both grapes and wines. The expression of several phenylpropanoid biosynthesis-related genes is regulated by UV radiation in grape berries. However, the complete portion of transcriptome and ripening processes influenced by solar UV radiation in grapes remains unknown. RESULTS: Whole genome arrays were used to identify the berry skin transcriptome modulated by the UV radiation received naturally in a mid altitude Tempranillo vineyard. UV radiation-blocking and transmitting filters were used to generate the experimental conditions. The expression of 121 genes was significantly altered by solar UV radiation. Functional enrichment analysis of altered transcripts mainly pointed out that secondary metabolism-related transcripts were induced by UV radiation including VvFLS1, VvGT5 and VvGT6 flavonol biosynthetic genes and monoterpenoid biosynthetic genes. Berry skin phenolic composition was also analysed to search for correlation with gene expression changes and UV-increased flavonols accumulation was the most evident impact. Among regulatory genes, novel UV radiation-responsive transcription factors including VvMYB24 and three bHLH, together with known grapevine UV responsive genes such as VvMYBF1, were identified. A transcriptomic meta-analysis revealed that genes up-regulated by UV radiation in the berry skin were also enriched in homologs of Arabidopsis UVR8 UV-B photoreceptor-dependent UV-B responsive genes. Indeed, a search of the grapevine reference genomic sequence identified UV-B signalling pathway homologs and among them, VvHY5-1, VvHY5-2 and VvRUP were up-regulated by UV radiation in the berry skin. CONCLUSIONS: Results suggest that the UV-B radiation-specific signalling pathway is activated in the skin of grapes grown at mid-altitudes. The biosynthesis and accumulation of secondary metabolites, which are appreciated in winemaking and potentially confer cross-tolerance, were almost specifically triggered. This draws attention to viticultural practices that increase solar UV radiation on vineyards as they may improve grape features. PMID- 25012689 TI - Yeasts found on an ephemeral reproductive caste of the leaf-cutting ant Atta sexdens rubropilosa. AB - Winged males of leaf-cutting ants are considered an ephemeral reproductive caste only produced before the mating flight season. Although much is known about the yeast diversity found in fungus gardens of attine ants, no study has focused on the yeasts associated with males of leaf-cutting ants. Here, we surveyed the yeasts on the integuments of males of Atta sexdens rubropilosa and assessed their potential role in the attine ant-microbe symbiosis. Using culture-dependent techniques, we found yeasts to be abundant on the integuments of males (54.5 %, n = 200 alates). A total of 242 yeast strains were obtained representing six orders, ten genera and 25 species. Strains of Aureobasidium, Cryptococcus, Hannaella and Rhodotorula were prevalent on the integuments and likely originated from the fungus garden of the parental nest or from the soil. The majority of strains (87.1 %) produced at least one of the evaluated enzymes: pectinase, polygalacturonase, cellulase, xylanase, ligninases and lipase. Aureobasidium pullulans accounted for the highest number of strains that produced all enzymes. In addition, yeasts showed the ability to assimilate the resulting oligosaccharides, supporting observations of other studies that yeasts may be involved in the plant biomass metabolism in the fungus gardens. Because winged males harbor several yeasts with putative functional roles, these fungi may take part and be beneficial in the microbial consortia of the new incipient nest. PMID- 25012690 TI - Multiple nonsteroidal anti-inflammatory drug-induced cutaneous disease: relevance, natural evolution and relationship with atopy. PMID- 25012691 TI - Prediction of stress in mothers of children with autism spectrum disorders. AB - Raising a child with autism spectrum disorders presents families with exceptional caregiving challenges. Consequently, parents, particularly mothers, evidence unusually high stress levels. Previous research has identified relevant variables that help explain maternal stress: the child's behavior problems, social support and the sense of coherence (SOC) as a perception of problem. However, there are few longitudinal studies demonstrating how these variables correlate over time. We present a longitudinal study of 21 Spanish mothers of children with autism spectrum disorders (ASD) at two measurement time points over an interval of 4.5 years. Our aims are to examine the predictive relationships of these variables (behavior problems, social support and SOC) to stress and to analyse their changes over time. Data were collected through questionnaires. The results of the regression analysis (multiple adjusted R 2= .45, f2 = .82) highlight the predictive values of SOC (adjusted R 2 = .31) and the initial stress levels (Delta adjusted R 2 = .14) for stress levels 4.5-years later. Our study used t tests to compare measurements at the two time points; results demonstrate the permanence of stress levels and behavior problems and the effects of reduced social support and increased SOC levels (t(20) = 2.48, p = .02, Cohen's d = .63; t(20) = -4.22, p < .001, Cohen' d = .58). Implications for interventions are discussed. PMID- 25012692 TI - INECO frontal screening: an instrument to assess executive dysfunction in schizophrenia. AB - Although several brief sensitive screening tools are available to detect executive dysfunction, few have been developed to quickly assess executive functioning. The INECO Frontal Screening (IFS) is a brief tool which has proved be useful for the assessment of the executive functions in patients with dementia. The aim of this study was to explore whether the IFS is as sensitive and specific as the BADS, a battery designed to assess the dysexecutive syndrome, in schizophrenia. Our sample comprised a group of 34 schizophrenic patients (Mean age = 39.59, DP = 10.697) and 31 healthy controls (Mean age = 35.52, DP = 10.211). To all groups were administered the BADS, Wisconsin Card Sorting Test and IFS. The results suggest that schizophrenic patients performed significantly worse than the control group in all tests (p < .05). The IFS total score was 13.29 for the experimental group and 26.21 for the control group (p < .001). Considering a cut-off of 14 points, the IFS sensitivity was 100% and specificity 56% in detection of executive dysfunction in schizophrenia, compared with the BADS, that if we consider a cut-off of 11 points, was a sensitivity of 100% and a specificity of 50%. Thus, IFS is a brief, sensitive and specific tool for the detection of executive dysfunction in schizophrenia. PMID- 25012693 TI - Supramolecular self-assembly of morphology-dependent luminescent Ag nanoclusters. AB - Self-assembled thiolated Ag nanoclusters (NCs) were facilely synthesized through one-pot microwave-assisted reaction. By the mechanism of aggregation induced emission, the quantum yield of the AgNCs is as high as 25.6%. The as-prepared AgNCs give access to intriguing photophysical features and multicolour emission, which are found to be related to their fascinating supramolecular structures. PMID- 25012694 TI - Monogenic human skin disorders. AB - Human genodermatoses represent a broad and partly confusing spectrum of countless rare diseases with confluent and overlapping phenotypes often impeding a precise diagnosis in an affected individual. High-throughput sequencing techniques have expedited the identification of novel genes and have dramatically simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a skin disorder is crucial for the appropriate counselling of patients and their relatives regarding the course of the disease, prognosis and recurrence risks. Understanding the underlying pathophysiology is a prerequisite to understanding the disease and developing specific, targeted or individualized therapeutic approaches. We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We hope this may represent a useful tool in guiding dermatologists towards genetic diagnoses, providing patients with individual knowledge on the respective disorder and applying novel research findings to clinical practice. PMID- 25012695 TI - Development and validation of a new screening questionnaire for dysphagia in early stages of Parkinson's disease. AB - BACKGROUND: Dysphagia in patients with Parkinson's disease (PD) significantly reduces quality of life and predicted lifetime. Current screening procedures are insufficiently evaluated. We aimed to develop and validate a patient-reported outcome questionnaire for early diagnosis of dysphagia in patients with PD. METHODS: The two-phased project comprised the questionnaire, diagnostic scales construction (N = 105), and a validation study (N = 82). Data for the project were gathered from PD patients at a German Movement Disorder Center. For validation purposes, a clinical evaluation focusing on swallowing tests, tests of sensory reflexes, and fiberoptic endoscopic evaluation of swallowing (FEES) was performed that yielded a criteria sum score against which the results of the questionnaire were compared. Specificity and sensitivity were evaluated for the detection of noticeable dysphagia and for the risk of aspiration. RESULTS: The Munich Dysphagia Test - Parkinson's disease (MDT-PD) consists of 26 items that show high internal consistency (alpha = 0.91). For the validation study, 82 patients, aged 70.9 +/- 8.7 (mean +/- SD), with a median Hoehn & Yahr stage of 3, were assessed. 73% of patients had dysphagia with noticeable oropharyngeal symptoms (44%) or with penetration/aspiration (29%). The criteria sum score correlated positively with the screening result (r = 0.70, p < 0.001). The MDT-PD sum score classified not noticeable dysphagia vs. risk of aspiration (noticeable dysphagia) with a sensitivity of 90% (82%) and a specificity of 86% (71%), and yielded similar results in cross-validation, respectively. CONCLUSIONS: MDT-PD is a valid screening tool for early diagnosis of swallowing problems and aspiration risk, as well as initial graduation of dysphagia severity in PD patients. PMID- 25012696 TI - Deep brain stimulation for severe secondary stereotypies. PMID- 25012697 TI - Protective effect and the therapeutic index of indralin in juvenile rhesus monkeys. AB - The radioprotective effect of indralin in rhesus monkeys was examined over 60 d following gamma irradiation. Male and female rhesus macaques (Macaca mulatta) 2-3 years-old and weighing 2.1-3.5 kg were used. Animals were exposed to total-body gamma irradiation from (60)Co at a dose of 6.8 Gy (lethal dose, 100% lethality over 30 days). Indralin (40-120 mg kg(-1)) was administered intramuscularly 5 min prior to radiation exposure. Indralin taken at a dose of 120 mg kg(-1) protected five out of six monkeys (compared with the radiation control group, in which all 10 animals died). The average effective dose of indralin in the monkeys exposed to gamma irradiation for 30 min was equal to 77.3 (63.3-94.3) mg kg(-1), and the maximum tolerated dose of indralin administered to monkeys was 800 mg kg(-1). Indralin reduced radiation-induced injuries in macaques, thus resulting in a less severe course of acute radiation syndrome. Delayed and less pronounced manifestation of the haemorrhagic syndrome of the disease, and milder forms of both leukopenia and anaemia were also noted. The therapeutic index for indralin, expressed as the ratio of the maximum tolerated dose to the average effective dose, was equal to 10. Therefore, indralin has a significant radioprotective effect against radiation and has a high therapeutic index in rhesus monkeys. PMID- 25012698 TI - Cell-free expression and in meso crystallisation of an integral membrane kinase for structure determination. AB - Membrane proteins are key elements in cell physiology and drug targeting, but getting a high-resolution structure by crystallographic means is still enormously challenging. Novel strategies are in big demand to facilitate the structure determination process that will ultimately hasten the day when sequence information alone can provide a three-dimensional model. Cell-free or in vitro expression enables rapid access to large quantities of high-quality membrane proteins suitable for an array of applications. Despite its impressive efficiency, to date only two membrane proteins produced by the in vitro approach have yielded crystal structures. Here, we have analysed synergies of cell-free expression and crystallisation in lipid mesophases for generating an X-ray structure of the integral membrane enzyme diacylglycerol kinase to 2.28-A resolution. The quality of cellular and cell-free-expressed kinase samples has been evaluated systematically by comparing (1) spectroscopic properties, (2) purity and oligomer formation, (3) lipid content and (4) functionality. DgkA is the first membrane enzyme crystallised based on cell-free expression. The study provides a basic standard for the crystallisation of cell-free-expressed membrane proteins and the methods detailed here should prove generally useful and contribute to accelerating the pace at which membrane protein structures are solved. PMID- 25012700 TI - Chin tuck for prevention of aspiration: effectiveness and appropriate posture. AB - Chin tuck has been has been widely used to prevent aspiration in the patients with dysphagia. This study was performed to investigate the effectiveness and the degree of optimal neck flexion of chin tuck. Ninety-seven patients who showed aspiration in the videofluoroscopic swallow study (VFSS). Participants were grouped into the effective (patients who showed effect with chin tuck) and ineffective group (those who did not show effect with chin tuck). VFSS was performed in neutral and chin tuck position and findings were compared between the groups. Severity of aspiration was assessed by the point penetration aspiration scale. Duration of dysphagic symptoms, history of tracheostomy, and other possible contributing factors were also compared. Neck flexion angle was measured to find appropriate posture in which aspiration was prevented with chin tuck. Aspiration was reduced or eliminated in only 19 patients (19.6 %) with chin tuck. Oral transit time, pharyngeal delayed time and pharyngeal transit time were significantly shortened in both groups (p < 0.05), but the difference between the groups was not significant. Female sex and absence of residue in pyriform sinus favored the effect of chin tuck (p < 0.05). At least 17.5 degrees of neck flexion was required to achieve an effect with chin tuck. The effectiveness of chin tuck was less than anticipated. Patients without residue in pyriform sinus were more likely to benefit from chin tuck. Sufficient neck flexion was important in chin tuck to prevent aspiration. PMID- 25012701 TI - GJB2 c.-23+1G>A mutation is second most common mutation among Iranian individuals with autosomal recessive hearing loss. AB - GJB2 mutation analysis is used routinely as a first step in genetic testing for autosomal recessive non-syndromic sensorineural hearing loss. Although most GJB2 mutations can be detected by sequencing of the exon 2 of this gene, a prevalent splice mutation, c.-23+1G>A (IVS1+1G>A), is not usually included in the analyzed region. In this study, we have developed an ARMS-PCR strategy for detection of this mutation among Iranian deaf individuals. A total of 418 Iranian individuals with hearing loss consistent with autosomal recessive non-syndromic sensorineural hearing loss based on audiological test result, medical history, physical examination and pedigree of the family, were included in this study. c.35delG and c.-23+1G>A mutations were detected by using ARMS-PCR. Direct sequencing of the exon 2 of the GJB2 gene was performed for mutation analysis of the coding region of this gene. Among 418 investigated cases, a total of 81 patients (~19.4 %) with biallelic pathogenic mutations in the GJB2 gene and 13 cases with only one pathogenic mutant allele were identified. The total allele frequencies of the two most frequent mutations, c.35delG and c.-23+1G>A, among mutated alleles were found to be around 59 and 15.7 %, respectively. High frequency of the c.35delG and c.-23+1G>A mutations among Iranian deaf individuals shows the importance of developing rapid and cost-effective methods for primary mutation screening methods before performing direct sequencing. PMID- 25012702 TI - Variable extent of nasoantral window for resection of antrochoanal polyp: selection of the optimum endoscopic approach. AB - The aim of this study is to evaluate the long-term results of endoscopic sinus surgery in the treatment of antrochoanal polyps and the role of extending the middle meatal antrostomy on the expense of the inferior meatus in providing wide exposure and accessibility within the maxillary sinus to ensure complete removal of its antral portion. Thirty-six patients were reviewed. Two groups were identified: Group A including patients with antrochoanal polyps that were resected endoscopically through a classical wide middle meatal antrostomy and Group B which included those who underwent endoscopic removal via an extension of the antrostomy inferiorly through submucosal resection of the lateral bony skeleton of the inferior meatus. There were 13 female and 23 male patients with a mean age of 28 +/- 9.4 years. The mean follow-up period was 20.4 +/- 6.7 months. Six patients were recurrent after previous endoscopic surgery. Group A included 17 patients and the remaining 19 patients were assigned to Group B. Two patients from Group A developed symptomatic recurrence and were cured with revision extended antrostomy. Three patients showed endoscopic evidence of a developing cystic lesion within the maxillary sinus that was punctured through the wide antrostomy. Endoscopic resection is considered the main treatment modality of antrochoanal polyps. Modification of the technique through removal of the lateral bony skeleton of the inferior meatus with downward displacement of the inferior turbinate provided accessibility to the inferior and prelacrimal recesses of the maxillary sinus. PMID- 25012699 TI - Expanding the roles of chromatin insulators in nuclear architecture, chromatin organization and genome function. AB - Of the numerous classes of elements involved in modulating eukaryotic chromosome structure and function, chromatin insulators arguably remain the most poorly understood in their contribution to these processes in vivo. Indeed, our view of chromatin insulators has evolved dramatically since their chromatin boundary and enhancer blocking properties were elucidated roughly a quarter of a century ago as a result of recent genome-wide, high-throughput methods better suited to probing the role of these elements in their native genomic contexts. The overall theme that has emerged from these studies is that chromatin insulators function as general facilitators of higher-order chromatin loop structures that exert both physical and functional constraints on the genome. In this review, we summarize the result of recent work that supports this idea as well as a number of other studies linking these elements to a diverse array of nuclear processes, suggesting that chromatin insulators exert master control over genome organization and behavior. PMID- 25012703 TI - Pattern of hearing loss following cochlear implantation. AB - Cochlear implantation is associated with deterioration in hearing. Despite the fact that the damage is presumed to be of sensory origin, residual hearing is usually assessed by air-conduction thresholds alone. This study sought to determine if surgery may cause changes in air- and bone-conduction thresholds producing a mixed-type hearing loss. The sample included 18 patients (mean age 37 years) with an air-bone gap of 10 dB over three consecutive frequencies and measurable masked and reliable bone-conduction thresholds of operated and non operated ears who underwent cochlear implant surgery. All underwent comprehensive audiologic and otologic assessment and imaging before and after surgery. The air bone gap in the treated ears was 17-41 dB preoperatively and 13-59 dB postoperatively over 250-4,000 Hz. Air-conduction thresholds in the treated ears significantly deteriorated after surgery, by a mean of 10-21 dB. Bone-conduction levels deteriorated nonsignificantly by 0.8-7.5 dB. The findings indicate that the increase in air-conduction threshold after cochlear implantation accounts for most of the postoperative increase in the air-bone gap. Changes in the mechanics of the inner ear may play an important role. Further studies in larger samples including objective measures of inner ear mechanics may add information on the source of the air-bone gap. PMID- 25012704 TI - Association between the methylenetetrahydrofolate reductase gene C677T polymorphism and sudden sensorineural hearing loss: a meta-analysis. AB - A variety of epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and sudden sensorineural hearing loss (SSNHL), but the results were inconsistent. The aim of this meta-analysis was to clarify more accurately the association of this polymorphism with SSNHL. A systematic literature search of the associated studies up to May 1, 2014, was conducted using the following electronic databases: PubMed, Embase, Medline, and the China National Knowledge Infrastructure. Statistical analyses were performed by STATA12.0 software, with odds ratios (ORs) and their 95 % confidence intervals (CIs). Six eligible studies including covering 1,271 objects were identified. A pooled analysis of these studies showed no significant association between C677T polymorphism and risk of SSNHL: T vs. C (OR = 1.334, POR = 0.105); TT vs. CC (OR = 1.580, POR = 0.231); CT vs. CC (OR = 1.500, POR = 0.123); TT vs. CC + CT (OR = 1.326, POR = 0.293); and TT + CT vs. CC (OR = 1.540, POR = 0.102). But in subgroup analysis, a significant association was found in European populations (T vs. C, OR = 1.542, 95 % CI 1.008-2.359, P = 0.046; TT vs. CT + CC, OR = 1.856, 95 % CI 1.245-2.767, P = 0.002). There was no significant association in any model in the Asian populations. The present meta analysis suggests that MTHFR gene C677T polymorphism is significantly associated with increased risk of SSNHL disease in European populations, but no statistically significant association was found between the MTHFR C677T gene mutation and SSNHL in Asian. Further large and well-designed studies are needed to confirm this association. PMID- 25012706 TI - Motivational profiles and achievement goal dominance in physical education. AB - The main goal was to compare idiographic profiles of achievement goal dominance (AGD) and motivational profiles based on 2x2 achievement goals to improve our understanding of how the four achievement goals work in conjunction with one another, and to discern which profiles are most adaptive in the Physical Education context. A total of 351 students (203 males; 148 females) (M = 14.26 +/ 1.37 years) from 3 different secondary schools agreed to participate. 86.6% (N = 303) showed AGD, mostly mastery-approach dominance (62.9%).We examined the four AGD groups' idiographic profiles and how they relate to certain positive (autonomous motivation and positive affect) and negative variables (controlled motivation and amotivation). The results supported the hypotheses of AGD theory (MANOVA one-way, Wilks' lambda = .609, F(24, 298) = 7.96, p < .001, eta2 = .15). Subsequently, k-means cluster analysis was performed, yielding 4 distinct achievement goal profiles. The most adaptive was named "mastery goals", while "high achievement goals" were the second most adaptive. AGD participants'distribution across the different motivational clusters was also ascertained (MANOVA one-way, Wilks' lambda = .678, F(12, 910) = 12.01, p < .001, eta2 = .12). PMID- 25012705 TI - Fundamental frequency, sound pressure level and vocal dose of a vocal loading test in comparison to a real teaching situation. AB - Vocal loading capacity is an important aspect of vocal health, especially for people in vocally demanding occupations such as teaching. To analyze vocal loading, vocal loading tests (VLTs) or portable voice devices such as accelerometers have been used. However, it remains unclear how much a VLT in a clinical setup reflects the vocal effort of a real situation, in particular for teachers in a given classroom lesson. In this study of vocally healthy 101 student teachers, we analyzed different vocal doses for a 10-min VLT (80 dB at a distance of 30 cm) and a real 45-min teaching lesson. The phonation time, fundamental frequency, sound pressure level, and noise level were recorded using the VoxLog accelerometer/microphone system for both conditions. From these measurements the time dose, cycle dose, distance dose, energy dissipation dose, and radiated energy dose were calculated. The VLT was associated with a higher fundamental frequency, a higher sound pressure level, and higher relative phonation time compared to the real teaching lesson. Nevertheless, most vocal doses did not differ significantly between the conditions. A VLT of 10 min with >80 dB at 30 cm distance shows only small differences of vocal doses in comparison to a real teaching situation of 45 min. Thus, for clinical vocal assessment the vocal load of a VLT can be related to an approximately 45-min teaching situation. PMID- 25012707 TI - Femoral micropuncture or routine introducer study (FEMORIS). AB - OBJECTIVES: The Micropuncture(r) 21-gauge needle may reduce complications related to vessel trauma from inadvertent venous or posterior arterial wall puncture. METHODS: This was a single-center, multiple-user trial. Four hundred and two patients undergoing possible or definite percutaneous coronary intervention (PCI) were randomized 1:1 to an 18-gauge versus a 21-gauge needle. Patients and personnel pulling the sheaths and performing the follow-up were blinded. The primary end point was a composite of access bleeding. Events were tabulated following sheath removal, <= 24 h after the procedure and at the follow-up (at 1 2 weeks). End points were blindly adjudicated. RESULTS: The event rate overall was 12.4% and did not differ significantly between groups, although the 21-gauge needle was found to reduce events by more than one third. An exploratory subgroup analysis of prespecified variables indicated that: patients who did not undergo PCI or elective procedures, female patients and those with a final sheath size of <= 6 Fr all had a significant or near-significant reduction of complications with Micropuncture. CONCLUSIONS: Although no significant differences between the use of the 18- and 21-gauge needles were observed, there was a 50-75% reduction with Micropuncture in several subgroups. The study was terminated prematurely. Access site complications may be reduced by the use of the 21-gauge needle, particularly when the risk of bleeding is not high. Further multicenter data will be required to confirm these hypothesis-generating observations. PMID- 25012708 TI - A neuropsychoanalytical approach to the hard problem of consciousness. AB - A neuropsychoanalytical approach to the hard problem of consciousness revolves around the distinction between the subject of consciousness and objects of consciousness. In contrast to the mainstream of cognitive science, neuropsychoanalysis prioritizes the subject. The subject of consciousness is the indispensable page upon which consciousness of objects is inscribed. This has implications for our conception of the mental. The subjective being of consciousness is not registered in the classical exteroceptive modalities; it is not merely a cognitive representation, not only a memory trace. Rather, the exteroceptive modalities are registered in the subjective being. Cognitive representations are mental solids embedded within subjectivity, the tangible and visible (etc) properties of which are projected onto reality. It is important to recognize that mental solids (e.g., the body-as-object) are no more real than the subjective being they are inscribed in (the body-as-subject). Moreover, pure subjectivity is not without content or quality. This aspect of consciousness is conventionally described quantitatively as the level of consciousness, or wakefulness. But it feels like something to be awake. The primary modality of this aspect of consciousness is affect. Affect supplies the subjectivity that underpins all consciousness. Some implications of this approach are discussed here, in broad brush strokes. PMID- 25012709 TI - Co-evolution of human consciousness and language (revisited). AB - This article discusses the view that human consciousness may share aspects of "animal awareness" with other species, but has its unique form because humans possess language. Two ingredients of a theory of the evolution of human consciousness are offered: the view that a precis of intended activity is necessarily formed in the brain of a human that communicates in a human way; and the notion that such a precis underwrites the uniquely human aspect of consciousness. PMID- 25012710 TI - Triple-aspect monism: physiological, mental unconscious and conscious aspects of brain activity. AB - Brain activity contains three fundamental aspects: (a) The physiological aspect, covering all kinds of processes that involve matter and/or energy; (b) the mental unconscious aspect, consisting of dynamical patterns (i.e., frequency, amplitude and phase-modulated waves) embodied in neural activity. These patterns are variously operated (transmitted, stored, combined, matched, amplified, erased, etc), forming cognitive and emotional unconscious processes and (c) the mental conscious aspect, consisting of feelings experienced in the first-person perspective and cognitive functions grounded in feelings, as memory formation, selection of the focus of attention, voluntary behavior, aesthetical appraisal and ethical judgment. Triple-aspect monism (TAM) is a philosophical theory that provides a model of the relation of the three aspects. Spatially distributed neuronal dendritic potentials generate amplitude-modulated waveforms transmitted to the extracellular medium and adjacent astrocytes, prompting the formation of large waves in the astrocyte network, which are claimed to both integrate distributed information and instantiate feelings. According to the valence of the feeling, the large wave feeds back on neuronal synapses, modulating (reinforcing or depressing) cognitive and behavioral functions. PMID- 25012711 TI - Quantum effects in the understanding of consciousness. AB - This paper presents a historical perspective on the development and application of quantum physics methodology beyond physics, especially in biology and in the area of consciousness studies. Quantum physics provides a conceptual framework for the structural aspects of biological systems and processes via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically analyzed using quantum methods building conceptual foundations for quantum biology. Since consciousness is attributed to human (and possibly animal) mind, quantum underpinnings of cognitive processes are a logical extension. Several proposals, especially the Orch OR hypothesis, have been put forth in an effort to introduce a scientific basis to the theory of consciousness. At the center of these approaches are microtubules as the substrate on which conscious processes in terms of quantum coherence and entanglement can be built. Additionally, Quantum Metabolism, quantum processes in ion channels and quantum effects in sensory stimulation are discussed in this connection. We discuss the challenges and merits related to quantum consciousness approaches as well as their potential extensions. PMID- 25012712 TI - Genomic instantiation of consciousness in neurons through a biophoton field theory. AB - A theoretical framework is developed based on the premise that brains evolved into sufficiently complex adaptive systems capable of instantiating genomic consciousness through self-awareness and complex interactions that recognize qualitatively the controlling factors of biological processes. Furthermore, our hypothesis assumes that the collective interactions in neurons yield macroergic effects, which can produce sufficiently strong electric energy fields for electronic excitations to take place on the surface of endogenous structures via alpha-helical integral proteins as electro-solitons. Specifically the process of radiative relaxation of the electro-solitons allows for the transfer of energy via interactions with deoxyribonucleic acid (DNA) molecules to induce conformational changes in DNA molecules producing an ultra weak non-thermal spontaneous emission of coherent biophotons through a quantum effect. The instantiation of coherent biophotons confined in spaces of DNA molecules guides the biophoton field to be instantaneously conducted along the axonal and neuronal arbors and in-between neurons and throughout the cerebral cortex (cortico thalamic system) and subcortical areas (e.g., midbrain and hindbrain). Thus providing an informational character of the electric coherence of the brain - referred to as quantum coherence. The biophoton field is realized as a conscious field upon the re-absorption of biophotons by exciplex states of DNA molecules. Such quantum phenomenon brings about self-awareness and enables objectivity to have access to subjectivity in the unconscious. As such, subjective experiences can be recalled to consciousness as subjective conscious experiences or qualia through co-operative interactions between exciplex states of DNA molecules and biophotons leading to metabolic activity and energy transfer across proteins as a result of protein-ligand binding during protein-protein communication. The biophoton field as a conscious field is attributable to the resultant effect of specifying qualia from the metabolic energy field that is transported in macromolecular proteins throughout specific networks of neurons that are constantly transforming into more stable associable representations as molecular solitons. The metastability of subjective experiences based on resonant dynamics occurs when bottom-up patterns of neocortical excitatory activity are matched with top-down expectations as adaptive dynamic pressures. These dynamics of on going activity patterns influenced by the environment and selected as the preferred subjective experience in terms of a functional field through functional interactions and biological laws are realized as subjectivity and actualized through functional integration as qualia. It is concluded that interactionism and not information processing is the key in understanding how consciousness bridges the explanatory gap between subjective experiences and their neural correlates in the transcendental brain. PMID- 25012713 TI - Keeping time: could quantum beating in microtubules be the basis for the neural synchrony related to consciousness? AB - This paper discusses the possibility of quantum coherent oscillations playing a role in neuronal signaling. Consciousness correlates strongly with coherent neural oscillations, however the mechanisms by which neurons synchronize are not fully elucidated. Recent experimental evidence of quantum beats in light harvesting complexes of plants (LHCII) and bacteria provided a stimulus for seeking similar effects in important structures found in animal cells, especially in neurons. We argue that microtubules (MTs), which play critical roles in all eukaryotic cells, possess structural and functional characteristics that are consistent with quantum coherent excitations in the aromatic groups of their tryptophan residues. Furthermore we outline the consequences of these findings on neuronal processes including the emergence of consciousness. PMID- 25012714 TI - The origins of the brain's endogenous electromagnetic field and its relationship to provision of consciousness. AB - As a potential source of consciousness, the brain's endogenous electromagnetic (EM) field has much to commend it. Difficulties connecting EM phenomena and consciousness have been exacerbated by the lack of a specific conclusive biophysically realistic mechanism originating the EM field, its form and dynamics. This work explores a potential mechanism: the spatial and temporal coherent action of transmembrane ion channel currents which simultaneously produce electric and magnetic fields that dominate all other field sources. Ion channels, as tiny current filaments, express, at a distance, the electric and magnetic fields akin to those of a short (transmembrane) copper wire. Following assembly of appropriate formalisms from EM field theory, the paper computationally explores the scalar electric potential produced by the current filaments responsible for an action potential (AP) in a realistic hippocampus CA1 pyramidal neuron. It reveals that AP signaling can impress a highly structured, focused and directed "sweeping-lighthouse beam" that "illuminates" neighbors at mm scales. Ion channel currents thereby provide a possible explanation for both EEG/MEG origins and recently confirmed functional EM coupling effects. Finally, a physically plausible EM field decomposition is posited. It reveals objective and subjective perspectives intrinsic to the membrane-centric field dynamics. Perceptual "fields" can be seen to operate as the collective action of virtual EM boson composites (called qualeons) visible only by "being" the fields, yet objectively appear as the familiar EM field activity. This explains the problematic evidence presentation and offers a physically plausible route to a solution to the "hard problem". PMID- 25012715 TI - Afference copy as a quantitative neurophysiological model for consciousness. AB - Consciousness is a topic of considerable human curiosity with a long history of philosophical analysis and debate. We consider there is nothing particularly complicated about consciousness when viewed as a necessary process of the vertebrate nervous system. Here, we propose a physiological "explanatory gap" is created during each present moment by the temporal requirements of neuronal activity. The gap extends from the time exteroceptive and proprioceptive stimuli activate the nervous system until they emerge into consciousness. During this "moment", it is impossible for an organism to have any conscious knowledge of the ongoing evolution of its environment. In our schematic model, a mechanism of "afference copy" is employed to bridge the explanatory gap with consciously experienced percepts. These percepts are fabricated from the conjunction of the cumulative memory of previous relevant experience and the given stimuli. They are structured to provide the best possible prediction of the expected content of subjective conscious experience likely to occur during the period of the gap. The model is based on the proposition that the neural circuitry necessary to support consciousness is a product of sub/preconscious reflexive learning and recall processes. Based on a review of various psychological and neurophysiological findings, we develop a framework which contextualizes the model and briefly discuss further implications. PMID- 25012716 TI - Physical integration: a causal account for consciousness. AB - The issue of integration in neural networks is intimately connected with that of consciousness. In this paper, integration as an effective level of physical organization is contrasted with a methodological integrative approach. Understanding how consciousness arises out of neural processes requires a model of integration in just causal physical terms. Based on a set of feasible criteria (physical grounding, causal efficacy, no circularity and scaling), a causal account of physical integration for consciousness centered on joint causation is outlined. PMID- 25012718 TI - Editorial. PMID- 25012719 TI - Introduction: addressing the hard problem. PMID- 25012720 TI - A systematic review of studies using pedometers as an intervention for musculoskeletal diseases. AB - BACKGROUND: Physical activity (PA) plays an important role in the prevention and management of a number of chronic conditions. AIM: to investigate the evidence for effectiveness of pedometer-driven walking programs to promote physical activity among patients with musculoskeletal disorders (MSDs). METHOD: A comprehensive systematic review was performed using 11 electronic databases up to 20 February 2014. Keywords and MeSH terms included "musculoskeletal disorders", "walking", and "pedometer". Randomized controlled trials, published in English, that examined the effects of a pedometer-based walking intervention to increase physical activity levels and improve physical function and pain in patients with musculoskeletal disorders were included. RESULT: Of the 1996 articles retrieved, seven studies ranging in date of publication from 1998 to 2013 met the inclusion criteria, allowing data extraction on 484 participants with an age range of 40 to 82 years. Interventions lasted from 4 weeks to 12 months and the results across studies showed significant increases in step count (p < 0.05) following the intervention. Across these studies, there was a mean increase in PA of 1950 steps per day relative to baseline. Four studies reported improved scores for pain and/or physical function at the intervention completion point relative to controls. CONCLUSION: This study provides strong evidence for the effectiveness of pedometer walking interventions in increasing PA levels for patients with MSDs. Our findings suggest that a combination of interventions is likely to be the most effective strategy to maximize health benefits in the short term. Further research should include larger sample sizes, and longer intervention durations are required to support the role of pedometer walking interventions as a long term intervention for management of musculoskeletal disorders. PMID- 25012721 TI - Hyperhomocysteinemia is one of the risk factors associated with cerebrovascular stiffness in hypertensive patients, especially elderly males. AB - Hyperhomocystemia has been reported to be associated with cardiovascular disease, especially stroke. The resistive index (RI) estimated by carotid ultrasound is an established variable for estimating the risk of cerebral infarction. The aim of this study was to evaluate the relationship between homocysteine concentration and carotid RI, a marker of cerebral vascular resistance in essential hypertensive patients. We measured serum total homocysteine and carotid RI in 261 patients. Multiple linear regression analysis was used to determine the association of homocysteine with carotid RI and intima media thickness (IMT). Age, sex, BMI, systolic blood pressure (SBP), homocysteine, total cholesterol, high density lipoprotein-cholesterol (HDL-C), uric acid, CRP, HbA1c, estimated glomerular filtration rate, and use of antihypertensive agents were included as independent variables. Age, sex, use of antihypertensive agents, HDL-C and homocysteine levels were shown to be significant predictors of carotid RI, but not IMT. Multiple regression analysis in men older than 65 years showed homocysteine and SBP were associated significantly with carotid RI. In elderly male patients, homocysteine was the strongest predictor of carotid RI (B = 0.0068, CI = 0.0017-0.0120, P = 0.011) in the multivariate model. In conclusion, hyperhomocysteinemia is associated with carotid RI, a surrogate marker of cerebral vascular resistance, especially in elderly men. PMID- 25012722 TI - MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4. AB - BACKGROUND: Overexpression of microRNA-182 (miR-182) is found in various human cancers, including non-small cell lung cancer (NSCLC). Our aim is to investigate the association of miR-182 expression with the sensitivity of NSCLC to cisplatin. METHODS: TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-182 and programmed cell death 4 (PDCD4) protein. miR-182 and (or) PDCD4 depleted cell lines were generated using miR-182 inhibitor and (or) siRNA. The viabilities of treated cells were analyzed using MTT assay. RESULTS: The expression level of miR-182 in A549 cell line was significantly higher than that in NHBE cell line (p < 0.01). Transfection of miR-182 inhibitor induced sensitivity of A549 cells to cisplatin. A549 cells transfected with PDCD4 siRNA became more resistant to cisplatin therapy. We found an increase PDCD4 protein level following the transfection of miR-182 inhibitor using Western blot analysis. In addition, the enhanced growth-inhibitory effect by miR-182 inhibitor was weakened after the addition of PDCD4 siRNA. CONCLUSIONS: The results of the present study demonstrated that overexpression of miR-182 may involve in chemoresistance of NSCLC cells to cisplatin by down-regulating PDCD4. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793467320130186. PMID- 25012723 TI - Phospho-Cdc25 correlates with activating G2/M checkpoint in mouse zygotes fertilized with hydrogen peroxide-treated mouse sperm. AB - The presence of oxidative stress in sperm cryopreservation induces sperm DNA damage. Our previous study has discovered that gammaH2AX, the DNA-damaged marker, was activated in the early mouse embryos fertilized with hydrogen peroxide (H2O2) treated sperm. Furthermore, we found that checkpoint proteins ATM and Chk1 were phosphorylated and activated in the early mouse embryos. On the basis of previous researches, we examined the effects of sperm DNA damage on cell cycle arrest in mouse zygotes fertilized with H2O2-treated sperm. Development of fertilized eggs arrested at the PN disappearance stage. At 19 and 24 hours post-insemination (hpi), the percentage of zygotes at the PN disappearance stage was higher in H2O2 treated group compared to the control group. Immunofluorescence staining revealed Phospho-Cdc25C (Ser216) and Phospho-Cdc25B (Ser323) in or surrounding a single pronucleus, following insemination with H2O2-treated sperm. Our study suggests that fertilization with DNA-damaged sperm results in cell cycle arrest mediated by G2/M checkpoint activation in one of the pronuclei in mouse zygotes fertilized with H2O2-treated sperm; Phospho-Cdc25C and Phospho-Cdc25B correlate with activating G2/M checkpoint in zygotes fertilized with H2O2-treated sperm. PMID- 25012724 TI - Predictors of progression to chronic dialysis in survivors of severe acute kidney injury: a competing risk study. AB - BACKGROUND: Survivors of acute kidney injury are at an increased risk of developing irreversible deterioration in kidney function and in some cases, the need for chronic dialysis. We aimed to determine predictors of chronic dialysis and death among survivors of dialysis-requiring acute kidney injury. METHODS: We used linked administrative databases in Ontario, Canada, to identify patients who were discharged from hospital after an episode of acute kidney injury requiring dialysis and remained free of further dialysis for at least 90 days after discharge between 1996 and 2009. Follow-up extended until March 31, 2011. The primary outcome was progression to chronic dialysis. Predictors for this outcome were evaluated using cause-specific Cox proportional hazards models, and a competing risk approach was used to calculate absolute risk. RESULTS: We identified 4 383 patients with acute kidney injury requiring temporary in hospital dialysis who survived to discharge. After a mean follow-up of 2.4 years, 356 (8%) patients initiated chronic dialysis and 1475 (34%) died. The cumulative risk of chronic dialysis was 13.5% by the Kaplan-Meier method, and 10.3% using a competing risk approach. After accounting for the competing risk of death, previous nephrology consultation (subdistribution hazard ratio (sHR) 2.03; 95% confidence interval (CI) 1.61-2.58), a history of chronic kidney disease (sHR3.86; 95% CI 2.99-4.98), a higher Charlson comorbidity index score (sHR 1.10; 95% CI 1.05-1.15/per unit) and pre-existing hypertension (sHR 1.82; 95% CI 1.28 2.58) were significantly associated with an increased risk of progression to chronic dialysis. CONCLUSIONS: Among survivors of dialysis-requiring acute kidney injury who initially become dialysis independent, the subsequent need for chronic dialysis is predicted by pre-existing kidney disease, hypertension and global comorbidity. This information can identify patients at high risk of progressive kidney disease who may benefit from closer surveillance after cessation of the acute phase of illness. PMID- 25012725 TI - Khz-cp (crude polysaccharide extract obtained from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia) induces apoptosis by increasing intracellular calcium levels and activating P38 and NADPH oxidase-dependent generation of reactive oxygen species in SNU-1 cells. AB - BACKGROUND: Khz-cp is a crude polysaccharide extract that is obtained after nuclear fusion in Ganoderma lucidum and Polyporus umbellatus mycelia (Khz). It inhibits the growth of cancer cells. METHODS: Khz-cp was extracted by solvent extraction. The anti-proliferative activity of Khz-cp was confirmed by using Annexin-V/PI-flow cytometry analysis. Intracellular calcium increase and measurement of intracellular reactive oxygen species (ROS) were performed by using flow cytometry and inverted microscope. SNU-1 cells were treated with p38, Bcl-2 and Nox family siRNA. siRNA transfected cells was employed to investigate the expression of apoptotic, growth and survival genes in SNU-1 cells. Western blot analysis was performed to confirm the expression of the genes. RESULTS: In the present study, Khz-cp induced apoptosis preferentially in transformed cells and had only minimal effects on non-transformed cells. Furthermore, Khz-cp was found to induce apoptosis by increasing the intracellular Ca2+ concentration ([Ca2+]i) and activating P38 to generate reactive oxygen species (ROS) via NADPH oxidase and the mitochondria. Khz-cp-induced apoptosis was caspase dependent and occurred via a mitochondrial pathway. ROS generation by NADPH oxidase was critical for Khz-cp-induced apoptosis, and although mitochondrial ROS production was also required, it appeared to occur secondary to ROS generation by NADPH oxidase. Activation of NADPH oxidase was shown by the translocation of the regulatory subunits p47phox and p67phox to the cell membrane and was necessary for ROS generation by Khz-cp. Khz-cp triggered a rapid and sustained increase in [Ca2+]i that activated P38. P38 was considered to play a key role in the activation of NADPH oxidase because inhibition of its expression or activity abrogated membrane translocation of the p47phox and p67phox subunits and ROS generation. CONCLUSIONS: In summary, these data indicate that Khz-cp preferentially induces apoptosis in cancer cells and that the signaling mechanisms involve an increase in [Ca2+]i, P38 activation, and ROS generation via NADPH oxidase and mitochondria. PMID- 25012726 TI - Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting. AB - PURPOSE: Resistance to the antiemetic ondansetron is still a major problem resulting in discomfort and poor compliance with chemotherapy in acute myeloid leukemia (AML) patients. Based on our hypothesis that this clinical resistance to ondansetron is associated with ABCB1 genetic polymorphisms, we investigated whether ABCB1 gene variations affect the efficacy of ondansetron in chemotherapy induced nausea and vomiting. METHODS: AML patients (n = 215) treated for 3 days with high-dose cytarabine were enrolled in this study. Thirty minutes before the beginning of chemotherapy, 8 mg ondansetron was administered intravenously, followed by 24 mg by continuous infusion and 8 mg intravenously, once per day, until 2 days after chemotherapy. Chemotherapy-induced nausea and vomiting occurrence in the acute and delayed phases was calculated. ABCB1 and CYP2D6 polymorphisms were analyzed by allele-specific matrix-assisted laser desorption. Basic clinical characteristics of the AML patients were collected from medical records. FINDINGS: No differences in genotype distribution frequencies of ABCB1 polymorphisms and haplotypes were observed in patients with different CYP2D6 predicted phenotypes. During the acute phase, patients with the CG haplotype (C3435T and G2677T) were associated with a high risk of grade 3/4 nausea and vomiting (P = 0.003 and P = 0.026, respectively). After adjustment for age, sex, smoking status, alcohol drinking status, body surface area, body mass index, and Eastern Cooperative Oncology Group-Performance Status, multivariate survival analysis implicated the CG haplotype as a predictive marker of the risk of grade 3/4 chemotherapy-induced nausea and vomiting in AML patients (P = 0.003 and P = 0.039, respectively). In addition, a significant association between the 3435CC genotype and grade 3/4 vomiting in AML patients was observed (P = 0.016). However, no association between these ABCB1 gene polymorphisms and ondansetron efficacy was found in the delayed phase. IMPLICATIONS: These findings suggest that ABCB1 gene polymorphisms are associated with antiemetic efficacy of ondansetron in the acute phase after high-dose cytarabine chemotherapy in AML patients. PMID- 25012727 TI - Pharmacokinetics and safety of subcutaneous pasireotide and intramuscular pasireotide long-acting release in Chinese male healthy volunteers: a phase I, single-center, open-label, randomized study. AB - PURPOSE: The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies). METHODS: In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 MUg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated. FINDINGS: Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR. IMPLICATIONS: The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR. PMID- 25012728 TI - The limits of evidence in drug approval and availability: a case study of cilostazol and naftidrofuryl for the treatment of intermittent claudication. AB - PURPOSE: Despite numerous efforts to develop effective medications for the treatment of intermittent claudication (IC) over the past 4 decades, a gold standard medical management option has yet to be defined. Although not life threatening, IC interferes with mobility and activities of daily living, significantly impairing quality of life and potentially causing depression. Cilostazol, the leading pharmacologic agent for IC in the United States, was approved by the US Food and Drug Administration (FDA) in 1999 based on controversial data. Meanwhile, naftidrofuryl, the first-line pharmacologic agent for IC in the United Kingdom and Europe, has never been approved by the FDA and therefore is not available in the United States. The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect impossible. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted, because the manufacturers of these agents have much to lose and little to gain from such a study. OBJECTIVE: This article provides an overview of the pharmacology of cilostazol and naftidrofuryl, and the clinical studies leading to their approval and clinical acceptance. It further explores the possible sources of bias in analyzing these clinical trials, some of which have been brought to light by the National Institute for Health and Clinical Excellence (NICE) of the United Kingdom in its technology appraisal guidance. It also speculates the ways in which economic incentives may affect drug-marketing decisions. METHODS: A literature review of pharmacology and clinical trials for cilostazol and naftidrofuryl was performed in PubMed. The majority of included clinical trials were initially identified through the most recent Cochrane review articles as well as the FDA's approval packet for cilostazol. The technology appraisal guidance of the National Institute for Health and Care Excellence of the United Kingdom and the manufacturer's response to this guidance document were located via an online search engine. FINDINGS: The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect difficult. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted. IMPLICATIONS: The history of the evaluation, approval, and marketing of these drugs illustrates the limitations of data in the regulatory approval and marketing of agents whose benefit is subjective and difficult to quantify. Implementation of a standardized protocol with strict eligibility criteria, objective quantifiable measurement of drug effect, and validated endpoints will eventually allow development of an ideal pharmacotherapy for IC. PMID- 25012729 TI - Estimating effectiveness and cost of biologics for rheumatoid arthritis: application of a validated algorithm to commercial insurance claims. AB - PURPOSE: The aim of this analysis was to implement a claims-based algorithm to estimate biologic cost per effectively treated patient for biologics approved for moderate to severe rheumatoid arthritis (RA). METHODS: This retrospective analysis included commercially insured adults (aged 18-63 years) with RA in a commercial database, who initiated biologic treatment with abatacept, adalimumab, etanercept, golimumab, or infliximab between 2007 and 2010. The algorithm defined effectiveness as having all of the following: high adherence, no biologic dose increase, no biologic switching, no new nonbiologic disease-modifying antirheumatic drug, no increased or new oral glucocorticoid use, and no more than 1 glucocorticoid injection. For each biologic, cost per effectively treated patient was defined as total drug and administration costs (from allowed amounts on claims), divided by the number of patients categorized as effectively treated. FINDINGS: Of 15,351 patients, 12,018 (78.3%) were women, and the mean (SD) age was 49.7 (9.6) years. The algorithm categorized treatment as effective in the first year for 30% (1899/6374) of etanercept, 30% (1396/4661) of adalimumab, 20% (560/2765) of infliximab, 27% (361/1338) of abatacept, and 29% (62/213) of golimumab treated patients. The 1-year biologic cost per effectively treated patient, as defined by the algorithm, was nominally lower for subcutaneously injected biologics than for infused biologics. The 1-year biologic cost per effectively treated patient, as defined by the algorithm, was lowest for etanercept ($49,952), followed by golimumab ($50,189), adalimumab ($52,858), abatacept ($71,866), and infliximab ($104,333). IMPLICATIONS: Algorithm-defined effectiveness was similar for biologics other than infliximab. The 1-year biologic cost per effectively treated patient, as defined by the algorithm, was nominally lower for subcutaneously injected biologics than for infused biologics. PMID- 25012730 TI - Clinical and economic burden in patients with diagnosis of peripheral arterial disease in a claims database in Japan. AB - PURPOSE: The effect of peripheral arterial disease (PAD) among young and middle aged adults can be significant, but no previous study has examined the prognosis and the associated health care cost of the disease in this population. We evaluated the clinical and economic burden of PAD in patients from a large claims database to clarify the effect of the disease on a relatively young working Japanese population. METHODS: Patients aged >=45 and <=64 years with first PAD diagnosis between 2005 and 2011 comprised the PAD cohort (n = 362); an age- and sex-matched non-PAD comparison cohort (n = 362) was also identified. Rates of cardiovascular events/interventions, health care utilization, and costs were compared. FINDINGS: The mean (SD) age of the cohort was 52.8 (5.6) years and 40.8% were women. Baseline Charlson comorbidity index was significantly higher in the PAD cohort than in the non-PAD cohort (1.90 [2.19] vs 1.16 [1.99]; P < 0.001). The PAD cohort had significantly higher first-year event rates than did the non-PAD cohort for myocardial infarction (2.2% vs 0.2%; P = 0.019) and ischemic stroke (4.1% vs 0.5%; P = 0.001). Health care utilization was significantly greater for the PAD cohort for all parameters assessed (number of hospitalization, inpatient days, and outpatient visits) in the first year (all, P < 0.001). Total annual costs for health care were significantly higher in the PAD cohort than in the non-PAD cohort in the first year (P < 0.001). Among patients with diabetes, patients with PAD (n = 98) had significantly greater first-year event rates (myocardial infarction, ischemic stroke, coronary artery bypass surgery, peripheral arterial revascularization, percutaneous coronary intervention, and limb amputation; all, P < 0.001), significantly greater number of clinic visits (P = 0.023), and total cost burden than did patients without PAD (n = 63). IMPLICATIONS: Even in a relatively young working Japanese population, PAD is associated with substantial clinical and economic burden. PMID- 25012731 TI - Matrix production and remodeling as therapeutic targets for uterine leiomyoma. AB - Uterine leiomyoma, commonly known as fibroids, is a benign neoplasm of smooth muscle in women. The incidence of clinically symptomatic fibroids in reproductive age women is approximately 20 %, with nearly 80 % of black women suffering from this condition. Symptoms include severe pain and hemorrhage; fibroids are also a major cause of infertility or sub-fertility in women. Uterine leiomyoma consist of hyperplastic smooth muscle cells and an excess deposition of extracellular matrix, specifically collagen, fibronectin, and sulfated proteoglycans. Extracellular matrix components interact and signal through integrin-beta1 on the surface of uterine leiomyoma smooth muscle cells, provide growth factor storage, and act as co-receptors for growth factor-receptor binding. ECM and growth factor signaling through integrin-beta1 and growth factor receptors significantly increases cell proliferation and ECM deposition in uterine leiomyoma. Growth factors TGF-beta, IGF, PDGF, FGF and EGF are all shown to promote uterine leiomyoma progression and signal through multiple pathways to increase the expression of genes encoding matrix or matrix-modifying proteins. Decreasing integrin expression, reducing growth factor action and inhibiting ECM action on uterine leiomyoma smooth muscle cells are important opportunities to treat uterine leiomyoma without use of the current surgical procedures. Both natural compounds and chemicals are shown to decrease fibrosis and uterine leiomyoma progression, but further analysis is needed to make inroads in treating this common women's health issue. PMID- 25012733 TI - Amniotic membrane transplant for articular cartilage repair: an experimental study in sheep. AB - PURPOSE: The aim of the present study was to compare the potential for cartilage repair of fresh amniotic membrane (AM), cryopreserved AM and cryopreserved AM previously cultured with bone marrow mesenchymal stem cells (BM-MSCs) in an in vivo sheep animal model. METHODS: A full-thickness cartilage defect was surgically produced in 12 adult sheep, in the bearing region of the lateral femoral condyle. The animals were randomized into 4 groups (n=3): no treatment of the defect (G1); filling with fresh AM (G2); with cryopreserved AM previously cultivated with BM-MSCs (G3); with cryopreserved AM alone (G4). Postoperatively, the full load was possible. At two months, the animals were euthanized. The quality of the new synthesized tissue was evaluated with the macroscopic, by using International Cartilage Repair Society (ICRS) scale, and histological analyses, by using O'Driscoll scale. RESULTS: The control samples showed an ICRS grade III (abnormal); while the samples of Groups 2, 3 and 4 reported a grade II (similar to healthy cartilage). The mean value of O'Driscoll scale in the control group (3.3) was significantly lower compared to the treatment groups (G2: 10.7; G3: 8; G4: 11.3) (P <0.05). No significant differences were found between the experimental groups. CONCLUSION: AM could be a suitable material for the management of articular cartilage defects. Stem cells within AM demonstrated to be able to differentiate in chondrocytes in vivo. Fresh AM, cryopreserved AM and cryopreserved AM previously cultivated with BM-MSCs showed similar regenerative properties. PMID- 25012732 TI - Signet ring cell adenocarcinomas: different clinical-pathological characteristics of oesophageal and gastric locations. AB - AIMS: The incidence of oesogastric (OG) signet ring cell adenocarcinoma (SRC) is increasing in Western countries. The differential characteristics between oesophageal and gastric SRC tumours are unknown. We aimed to investigate the role of tumour location on prognosis in OG SRC. METHODS: Among 924 OG SRC resected in 21 centres from 1997 to 2010, consecutive patients who had oesophageal tumours (group OESO, n = 136) were matched to randomly selected patients who had gastric tumours (group GASTRIC, n = 363). Matching variables were gender, age, American Society of Anaesthesiologists score, malnutrition, pretherapeutic clinical TNM stage and neoadjuvant treatment. Patients and tumour characteristics were compared between groups and prognostic factors were identified. RESULTS: The two groups were well matched. Tumours in group GASTRIC were more advanced at surgical exploration, with higher rates of linitis plastica (P < 0.001), peritoneal carcinomatosis (P = 0.001), and advanced pTNM stages (P = 0.034). Radicality of resection and recurrence rates were similar (P > 0.480). Recurrences were more frequently distant (P < 0.001) and peritoneal (P < 0.001) in group GASTRIC. After adjustment on confounding variables, gastric location (P = 0.034) was independently associated with a better prognosis than oesophageal location. CONCLUSION: Gastric and oesophageal SRC tumours are distinct diseases. Despite similar pretherapeutic factors, gastric tumours were more advanced with a greater propensity for the peritoneal surface at the diagnosis and recurrence and associated with a better prognosis. PMID- 25012734 TI - VEGF, BMP-7, Matrigel(TM), hyaluronic acid, in vitro cultured chondrocytes and trephination for healing of the avascular portion of the meniscus. An experimental study in sheep. AB - OBJECTIVE: To evaluate the effects of VEGF, BMP-7, Matrigel(TM), hyaluronic acid, in vitro cultured chondrocytes and trephination to promote and enhance the healing process of avascular meniscal tears in an animal model. METHODS: A longitudinal tear was produced in the inner avascular part of the meniscus of 24 sheeps. Each tear was treated with trephination technique and suture. The animals were divided into 6 groups to receive a different treatment: control (I); VEGF, BMP-7, Matrigel(TM), hyaluronic acid, in vitro cultured chondrocytes. At 8 weeks from surgery, meniscal samples were explanted and analyzed by histology, immunohistochemistry, and histomorphometry. RESULTS: At the histological examination, Group IV and VI showed a partial closure of the meniscal lesion, whereas Group I, II, III, and V did not show any evidence of healing. In the group IV, the healed tissue represented the 22.95% of the lesion area. In the group VI, the healed tissue represented the 43.75% of the lesion area. CONCLUSIONS: Autologous chondrocytes and BMP-7 associated with trephination and suture techniques enhanced healing process of meniscal tears in the avascular inner third of the meniscus in ovine model. PMID- 25012735 TI - Fibronectin expression in the intervertebral disc of monkey. AB - BACKGROUND: Fibronectin, a large dimeric plasma glycoprotein found only in vertebrates, is a core component of several extracellular matrices. Integrin receptors regulate different cell activities. Fibronectin expression patterns in intervertebral disc have not been extensively studied. The aim of this study was to evaluate the distribution of fibronectin in the different regions of the intervertebral disc, and in intervertebral discs of different levels of monkeys. METHODS: Spines of nine 3-4 year-old cynomolgus monkeys (Macaca fascicularis) were studied. From every spine, 5 vertebral motion segments were sectioned (C5 C6, T3-T4, T9-T10, L2-L3, L4-L5) producing forty-five vertebral motion segments. These were bisected in the sagittal plane. Immunohistochemical studies were performed using specific antibodies to detect fibronectin. RESULTS: A positive immunoreaction for fibronectin was found in the endplates, in the peripheral annulus fibrosus, and in the longitudinal ligaments. There was no fibronectin immunoreactivity in the nucleus pulposus and in the central annular region close to the nucleus pulposus. There were no differences in immunoreactivity to fibronectin among discs of different levels and discs of different monkeys. CONCLUSIONS: Fibronectin may exert a role in the organization of the extracellular matrix of the intervertebral discs. Identifying the structural features of the intervertebral disc extracellular matrix may help to understand the mechanisms of intervertebral disc pathology. PMID- 25012736 TI - Unravelling the genetic susceptibility to develop ligament and tendon injuries. AB - PURPOSE: In the last decades, new evidences supported the relationship polymorphisms and the susceptibility to develop ligament and tendon injuries. We performed a review of the genetic factors involved in tendon and ligament injuries. METHODS: A review of the literature has been performed in a systematic fashion by using the terms "sports", "ligaments", "injuries", "tendon" and "genetics". PubMed, Embase, CINAHL, Cochrane, Medline and Google Scholar databases were screened over the years 1984-2014. RESULTS: The genes currently associated with tendon and ligament injuries include gene encoding for collagen, tenascin, matrix metallopeptidase, and growth factors. CONCLUSIONS: Tendon and ligament injuries do not have a single genetic cause. Predictive genomics DNA profiling for athletic performance and sport injuries allows to understand what genetic advantages have to be exploited, and which genetic barriers have to be overcome. Although these findings could explain why an individual is able to excel in one sport discipline rather than in a different one, and why an individual develops more injuries than another one, many other factors should be taken into account. Indeed, environment and lifestyle play a critical role in combination with gene profile in determing tendon and ligament injuries. PMID- 25012737 TI - Histopathological scores for tissue-engineered, repaired and degenerated tendon: a systematic review of the literature. AB - PURPOSE: This systematic review analyzes histological scoring systems for degenerative tendon-enthesis changes, ex vivo tendon-enthesis repair and tissue engineered tendon-enthesis repair. A secondary aim is to establish the validity and applicability of these scores to find a comprehensive and validated histological scoring system for the evaluation of tendon-enthesis tissue. METHODS: We performed a systematic review of the literature by analyzing the following databases: PubMed, Embase, Medline, CINAHL, and Cochrane. The methodology of the study was developed according to the PRISMA guidelines. RESULTS: Twenty-seven articles, describing a total of 9 scores for tendinopathy, 6 scores for tendon ruptures, and 12 scores for tendon regeneration were included. For enthesis changes, 4 studies describe a total of 3 scores for enthesopathy and 1 scores for enthesis regeneration. The Movin score and its modifications seem be the more comprehensive to assess the degenerative changes; the Soslowsky score, the Watkins score, the Novel scoring system and the Burssens score seem be the more comprehensive to assess tendon repair process. Only the Matthys score assesses the histological changes in enthesopathies, and the modified Watkins score has been well applied to assess enthesis repair. CONCLUSION: The assessment of tendon-enthesis structure can be performed with several histological scoring systems previously published in literature. However, no studies have been performed to validate these score in research settings. Further experimental and clinical studies should be developed to provide a comprehensive and validated scoring system for the histological assessment of tendon-enthesis repair. PMID- 25012738 TI - Bone marrow derived stem cells in trauma and orthopaedics: a review of the current trend. AB - Bone tissue engineering is a promising therapeutic option to enhance tissue regeneration and repair. The development of bone tissue engineering is directly related to changes in materials technology. While the inclusion of material requirements is standard in the design process of engineered bone substitutes, it is critical to incorporate clinical requirements in order to engineer a clinically relevant device. This review focuses on the potentials of bone marrow derived mesenchymal stem cells (BM-MSCs) in trauma and orthopaedics and presents the need for bone tissue-engineered alternatives. PMID- 25012739 TI - The role of tissue engineering in achilles tendon repair: a review. AB - Achilles tendon injuries are common but complex in nature. Healing occurs via scar tissue formation leading to poor patient outcomes. Currently surgical and non-surgical treatment leads to suboptimal tendon healing and has complications. Tissue engineering is an advancing field that can either augment surgical repair or provide an alternative method for Achilles tendon repair. This article will explore the principles behind tissue engineering in Achilles tendon repair. Furthermore it will describe the current literature regarding the different types of stem cells used in Achilles tendon repair, how different growth factors augment tendon repair, as well as the role of biomaterials in tissue engineering. PMID- 25012740 TI - Sources of adult mesenchymal stem cells for ligament and tendon tissue engineering. AB - Tendon and ligament injuries are common, and repair slowly with reduced biomechanical properties. With increasing financial demands on the health service and patients to recover from tendon and ligament injuries faster, and with less morbidity, health professionals are exploring new treatment options. Tissue engineering may provide the answer, with its unlimited source of natural cells that in the correct environment may improve repair and regeneration of tendon and ligament tissue. Mesenchymal stem cells have demonstrated the ability to self renew and have multilineage differentiation potential. The use of bone marrow derived mesenchymal stem cells has been reported, however significant in vitro culture expansion is required due to the low yield of cells, which has financial implications. Harvesting of bone marrow cells also has associated morbidity. Several studies have looked at alternative sources for mesenchymal stem cells. Reports in literature from animal studies have been encouraging, however further work is required. This review assesses the potential sources of mesenchymal stem cells for tissue engineering in tendons and ligaments. PMID- 25012741 TI - Growth factors and platelet rich plasma in anterior cruciate ligament reconstruction. AB - Platelet Rich Plasma (PRP) and growth factors have had encouraging results in several surgical specialties. Their use in orthopaedics is increasing and has been trialed in fracture management, spinal fusion and tendon and ligament healing. Anterior cruciate ligament (ACL) injuries are a significant economic burden and often require surgical reconstruction. This review article used laboratory and clinical studies to evaluate the effectiveness of PRP and growth factors as an adjunct to ACL reconstruction. Overall, the results of studies to date have been disappointing especially given the success in other specialties. PRP has been relatively successful in improving vascularization within the tibial tunnel but less so in the femoral tunnels. The targeting of specific growth factors seems to show more promise than generic PRP injections with vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) showing the most significant results in graft healing. Further trials are still required before a definitive conclusion can be reached. PMID- 25012742 TI - Systematic review of preclinical and clinical studies on scaffold use in knee ligament regeneration. AB - BACKGROUND: The management and treatment of ligamentous injuries within an orthopaedic population has continued to evolve throughout the last several decades. Limitations with autograft, allograft and synthetics have led to research into tissue engineering using scaffolds and mesenchymal stem cells. OBJECTIVES: This systematic review aims to examine and summarise the pre clinical in-vivo studies and limited clinical studies on the use of scaffolds in the treatment of ligamentous injuries Data sources: DATABASES: PubMed, CINAHL, Web of science, Medline, Cochrane library and Embase. The following key words and search terms were used: scaffolds, ligament, mesenchymal stem cells, tissue engineering, clinical, and preclinical. METHODS: A total of 118 articles were reviewed. 19 articles were identified as relevant for the purpose of this systematic literature review. An additional 2 articles were sourced from the reference list of reviewed articles. RESULTS: Three tables of studies were constructed: pre clinical biological scaffolds, pre clinical synthetic scaffolds and clinical scaffolds. CONCLUSIONS: There is a large body of pre clinical evidence that the use of scaffolds combined with mesenchymal stem cells can be a viable option in the regeneration of ligamentous structures with biological and mechanical properties suitable for function. There is, however, limited clinical evidence supporting the use of recently developed scaffolds and historical evidence of synthetic scaffolds failing in the management of anterior cruciate ligament repairs. There appears to be no consensus in the literature as to the nature of the scaffold material that is most suitable for clinical trials. No randomised control trials have yet been conducted. PMID- 25012743 TI - Use of stem cells and growth factors in rotator cuff tendon repair. AB - In this review, we analysed the role of stem cell and growth factor therapy on rotator cuff tendon repair. The injury to the rotator cuff tendons can be sustained in numerous ways and generally causes significant pain and disability to the affected individual. Following surgical repair of ruptured rotator cuff tendons re-rupture rates can be as high as 20-60%. In order to augment this repair process and to decrease the re-rupture rates tissue engineering methods can be used. These include the use of stem cells and growth factors. Mesenchymal stem cells are stem cells which can differentiate into a variety of connective tissue cell types and can therefore be utilised in repairing tendons. So far there has only been one human study using stem cells in rotator cuff tendon repair. This study has produced a positive result but consisted of only 14 patients and lacks a control group for comparison. Similar work has also been done using growth factors. Both individual and combination growth factor therapy have been used to improve rotator cuff tendon repair. However, the results so far have been disappointing with growth factors. For the purpose of future studies better techniques should be explored with regards to the delivery of stem cells and growth factors as well as the possibility of combining growth factor and stem cell therapy to improve repair rates. PMID- 25012744 TI - VEGF-A: the inductive angiogenic factor for development, regeneration and function of pancreatic beta cells. AB - The heart is the first organ to form during development in vertebrates, and many organs start to develop adjacent to the cardiovascular system. Endothelial cells (ECs) form the inner cell lining of blood vessels and represent the major cell type that interacts with developing organs including the pancreas. ECs receive signals from the developing pancreas to grow and, at the same time, release signals to determine cell-fate specification, morphogenesis and function of the pancreas. In addition to promoting survival of pancreatic islets, in this review, we discuss the role of the vascular niche and angiogenic factors, particularly VEGFA, during pancreatic beta cell development, regeneration and pathophysiological progression of diabetes. Nevertheless, unraveling the molecular signals involved in pancreatic beta cell development and regeneration may shed light into novel drug development to treat diabetes. PMID- 25012745 TI - Endothelial cells facilitate cell-based cardiac repair: progress and challenge. AB - About 1 billion cardiomyocytes are lost in heart disease such as myocardial infarction; the regeneration capacity of cardiomyocytes is extremely low and the heart is unable to fix this damage naturally. In the past 20 years, multiple cells, such as skeletal myoblasts, bone marrow-derived cells, cardiac progenitor cells and pluripotent stem cells have been utilized to test the efficacy on heart repair, but these cells show different kinds of drawbacks. Recent studies have revealed that concomitant transplantation of endothelial cells and stem cells can significantly improve the efficacy of cell based heart repair. In this review, we describe the progress on these studies with an emphasis on endothelial cell facilitated stem cell therapy. We also summarize the beneficial mechanisms of endothelial cells in cardiac repair and point out the potential challenges for endothelial cell-facilitated-cell therapy to be adopted for clinical application. PMID- 25012746 TI - Changes in lipid metabolism and extension of venous thromboembolism. AB - BACKGROUND/AIMS: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common diseases with a vast number of acquired and congenital risk factors. Disorders of the lipid metabolism are not established risk factors for venous thromboembolism (VTE) so far. However, in recent literature, associations between VTE and the metabolic syndrome, especially with elevated lipid parameters, have been described. The aim of our study was to investigate the association between the extension of VTE and changes in the lipid profile. METHODS: We included 178 VTE patients in our study; 59 patients had isolated PE, 39 patients had isolated DVT of the leg and 80 patients had both (DVT and PE). Concerning PE, we distinguished between massive and submassive PE. We evaluated plasma lipids and lipoproteins in PE and DVT patients as well as in massive and submassive PE patients. RESULTS: PE patients had higher levels of plasma triglycerides [median (interquartile range): 162 (109-254) vs. 136.5 (96.5-162) mg/dl, p = 0.047] and lower levels of high-density lipoprotein cholesterol (HDL-C; 52.1 +/- 17.2 vs. 63.9 +/- 22.7 mg/dl, p = 0.004) than DVT patients. Furthermore, PE patients were significantly older than DVT patients (59.6 +/- 16.9 vs. 52.2 +/- 15.5 years, p = 0.02). We were not able to find differences in lipid parameters in patients with massive PE compared to those with submassive PE. However, patients with massive PE were more obese than patients with submassive PE (body mass index 29.1 +/- 4.6 vs. 26.9 +/- 4.9, p = 0.012). CONCLUSIONS: Lipid parameters and lipoproteins differ between DVT and PE patients. PE patients had higher triglyceride and lower HDL-C levels compared with DVT patients. PMID- 25012747 TI - D-dimer and D-dimer/fibrinogen ratio in predicting pulmonary embolism in patients evaluated in a hospital emergency department. AB - OBJECTIVES: The D-dimer level, fibrinogen level, and D-dimer/fibrinogen ratio are used in the diagnosis of pulmonary embolism, but results vary. We evaluated these parameters in the diagnosis of pulmonary embolism in emergency clinic patients. METHODS: In this prospective study, 200 patients (pulmonary embolism, 100 patients; no pulmonary embolism, 100 patients) had D-dimer and fibrinogen levels measured before intervention. Pulmonary embolism was diagnosed with computed tomography angiography or ventilation-perfusion scintigraphy. RESULTS: Compared with patients who did not have pulmonary embolism, patients who had pulmonary embolism had significantly greater mean D-dimer level (pulmonary embolism, 6+/-7 MUg/ml; no pulmonary embolism, 1+/-1 MUg/ml; P?0.001) and D-dimer/fibrinogen ratio (pulmonary embolism, 3+/-3; no pulmonary embolism, 0.4+/-0.4; P?0.001), but similar mean fibrinogen levels (pulmonary embolism, 337+/-184 mg/dl; no pulmonary embolism, 384+/-200 mg/dl; not significant). In patients who had pulmonary embolism, mean D-dimer level and D-dimer/fibrinogen ratio were greater in high risk than non-high-risk patients. With D-dimer cutoff 0.35 MUg/ml, sensitivity was high (100%) and specificity was low (27%) for pulmonary embolism. With D dimer/fibrinogen ratio cutoff 0.13, sensitivity was high (100%) and specificity was low (37%) for pulmonary embolism. CONCLUSION: A D-dimer level <0.35 MUg/ml may exclude the diagnosis of pulmonary embolism. At a D-dimer cutoff 0.5 MUg/ml and D-dimer/fibrinogen ratio cutoff 1.0, the D-dimer/fibrinogen ratio may have better specificity than D-dimer level in the diagnosis of pulmonary embolism, but the D-dimer/fibrinogen ratio may lack sufficient specificity in screening. PMID- 25012748 TI - Serum angiostatin levels in patients with Behcet's disease: does angiogenesis play a role in the pathogenesis of Behcet's disease? AB - Angiogenesis plays an important role in the pathogenesis of inflammatory diseases, but the possible role of angiogenesis in Behcet's disease (BD) has not yet been studied. The aim of this study was to determine angiostatin levels in patients with BD and the role of angiogenesis in the pathogenesis of the disease. Thirty-seven patients with BD (mean age: 28.6+/-5.4 years, mean disease duration: 9.3+/-3.7 years) and 18 healthy controls were enrolled to the study. Twenty-four patients were in active and 13 patients were in inactive stage of the disease. The mean serum angiostatin level of patients with BD was 113.9+/-53.2 and 60.7+/ 20.1 ng/ml in healthy controls. The mean serum angiostatin level was 142.7+/-43.1 ng/ml in active and 86.9+/-15.5 ng/ml in inactive patients with BD. Serum angiostatin levels were significantly high in patients with BD compared with healthy controls (P<0.001) and it was significantly high in active patients compared with inactive patients with BD (P<0.001). In inactive patients with BD, serum angiostatin concentrations were found to be higher compared with healthy controls (P<0.01). In active BD patients, the mean serum angiostatin level was correlated with the deep vein thrombosis (r = 0.482, P = 0.05), uveitis (r = 0.582, P = 0.01), and arthritis (r = 0.492, P = 0.05). According to these results; elevated serum angiostatin levels in patients with BD suggest the possible role of angiogenesis in the pathogenesis of the disease and its high levels in inactive Behcet's patients is related with the continuous activation of the disease even in the subclinical period. PMID- 25012749 TI - Stressful life events and type 2 diabetes. AB - OBJECTIVES: The purpose of this study is to compare cases with type 2 diabetes and their controls for the frequency of stressful life events and social support before the occurrence of the disease. METHODS: The study of cases and their controls was undertaken in Belgrade. A case group comprised 179 subjects in whom type 2 diabetes was for the first time diagnosed in the 'Savski Venac' Medical Center during the period 2005-2007 year. The diagnosis was made by a specialist of internal medicine according to criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. For each case two controls were chosen among patients with trauma (fracture, reposition, internal/external fixation) who were treated at the 'Banjica' Institute for Orthopedic-Surgical Diseases during the same period. Cases and controls were matched by sex, age (+/ 2 years) and place of residence (Belgrade). Data were collected on demographic characteristics, habits, personal history, stressful life events, social support and family medical history. RESULTS: According to multivariate analysis low social support in personal history, such as relatives/friends help and financial assistance in solving problems, and bad management of monthly income were significantly positively related to type 2 diabetes. However, significantly more controls than cases had no financial insurance in case of urgent need CONCLUSION: Examine psychosocial factors play a role in the development of type 2 diabetes. PMID- 25012750 TI - Pulmonary embolism with Hampton's hump. PMID- 25012751 TI - Charcot spinal arthropathy in a diabetic patient. AB - We report a case of Charcot spinal arthropathy in a diabetic patient and emphasize the clinical reasoning leading to the diagnosis, discuss the differential diagnosis, and insist on the crucial role of the radiologist and pathologist which allows the distinction between Charcot spinal arthropathy and infectious or tumoural disorders of the spine. PMID- 25012752 TI - The "graying" of infertility services: an impending revolution nobody is ready for. AB - BACKGROUND: As demand for infertility services by older women continues to grow, because achievable in vitro fertilization (IVF) outcomes are widely underestimated, most fertility centers do not offer maximal treatment options with use of autologous oocytes. Limited data suggest that clinical IVF outcomes in excess of what the American Society for Reproductive Medicine (ASRM) considers "futile" can, likely, be achieved up to at least age 45 years. METHODS: In an attempt to point out an evolving demographic trend in IVF, we here report our center's IVF data for 2010-2012 and national U.S. data for 1997-2010. Though our center's data are representative of only one IVF center's patients, they, likely, are unique since they probably represent the most adversely selected IVF patient population ever reported and, thus, are predictive of future demographic trends. In addition we performed a systematic review of the literature on the subject based on PubMed, Medline and Google Scholar searches till year-end 2013. The literature search was performed using key words and phrases relevant to fertility treatments in older women. RESULTS: As demonstrated by our center's patient demographics and national U.S. data, IVF centers are destined to treat increasingly adversely selected patients. Despite our center's already extremely adversely selected patient population, age-specific IVF cycle outcomes in women above age 40 years, nevertheless, exceeded criteria for "futility" by the ASRM and widely quoted outcome expectations in the literature for patient ages. Age 43 discriminates between better and poorer clinical pregnancy and live birth rates. CONCLUSIONS: "Graying" of the infertility populations in the developed world, a problem with potentially far-reaching medical and societal consequences, has so far been only insufficiently addressed in the literature. As women's postmenopausal life spans already exceed postmenarcheal life spans at the start of the 20th century, the "graying" of infertility services can be expected to further accelerate, no longer as in recent decades bringing only women in their 40s into maternity wards but also women in their 50s and 60s. Medicine and society better get ready for this revolution. PMID- 25012754 TI - The responsiveness of TrkB to exogenous BDNF in frontal cortex during antibiotic treatment of Streptococcus pneumoniae meningitis. AB - Our previous studies suggested that the expression of TrkB and BDNF decreased concomitantly in brain during Streptococcus pneumoniae meningitis after antibiotic treatment, and that adjuvant administration of exogenous BDNF could rescue neurons from S. pneumoniae meningitis. In this study, we investigated the responsiveness of TrkB to exogenous BDNF treatment in frontal cortex during antibiotic treatment of S. pneumoniae meningitis. We found that adjuvant administration of exogenous BDNF led to increased number of survived neurons, improved the conduction of central auditory pathway and neurological disfunction, and up-regulated TrkB expression at the mRNA level in the frontal cortex of rats under S. pneumonia meningitis (P < 0.01). When treated with placebo, on the contrary, neurons in the frontal cortex of control rats were seriously damaged and the TrkB expression was remarkably decreased. These findings indicated that exogenous BDNF could up-regulate TrkB expression and thus played a neuroprotective role in frontal cortex injury from S. pneumoniae meningitis. They further confirmed our previous report that the decrease of intrinsic BDNF and TrkB expression is involved in the pathogenesis of neurological brain damage during S. pneumoniae meningitis after antibiotic treatment. PMID- 25012753 TI - Evolutionary and sequence-based relationships in bacterial AdoMet-dependent non coding RNA methyltransferases. AB - BACKGROUND: RNA post-transcriptional modification is an exciting field of research that has evidenced this editing process as a sophisticated epigenetic mechanism to fine tune the ribosome function and to control gene expression. Although tRNA modifications seem to be more relevant for the ribosome function and cell physiology as a whole, some rRNA modifications have also been seen to play pivotal roles, essentially those located in central ribosome regions. RNA methylation at nucleobases and ribose moieties of nucleotides appear to frequently modulate its chemistry and structure. RNA methyltransferases comprise a superfamily of highly specialized enzymes that accomplish a wide variety of modifications. These enzymes exhibit a poor degree of sequence similarity in spite of using a common reaction cofactor and modifying the same substrate type. RESULTS: Relationships and lineages of RNA methyltransferases have been extensively discussed, but no consensus has been reached. To shed light on this topic, we performed amino acid and codon-based sequence analyses to determine phylogenetic relationships and molecular evolution. We found that most Class I RNA MTases are evolutionarily related to protein and cofactor/vitamin biosynthesis methyltransferases. Additionally, we found that at least nine lineages explain the diversity of RNA MTases. We evidenced that RNA methyltransferases have high content of polar and positively charged amino acid, which coincides with the electrochemistry of their substrates. CONCLUSIONS: After studying almost 12,000 bacterial genomes and 2,000 patho-pangenomes, we revealed that molecular evolution of Class I methyltransferases matches the different rates of synonymous and non-synonymous substitutions along the coding region. Consequently, evolution on Class I methyltransferases selects against amino acid changes affecting the structure conformation. PMID- 25012755 TI - A pilot psychometric study of aberrant salience state in patients with Parkinson's disease and its association with dopamine replacement therapy. AB - An overactive striatal dopaminergic neurotransmission is described in psychosis and may be associated with a state of aberrant salience attribution. This pilot psychometric study investigated if features suggestive of an aberrant salience state, a condition of psychosis proneness, are associated with dopamine replacement therapy in patients with early Parkinson's disease (PD). 77 participants (50 medicated PD patients, 12 newly diagnosed drug-naive PD patients and 15 healthy controls) were enrolled and assessed with the Aberrant Salience Inventory (ASI). Differences between groups were found for ASI scores, and ASI scores correlated with the dopaminergic therapy, in particular levodopa. These findings preliminary suggested that the presence and the degree of an aberrant salience state may be associated with features of the dopaminergic therapy; further studies are needed to investigate which neuropsychiatric complications more common in PD patients may be characterized by an underlying aberrant salience state. PMID- 25012756 TI - Gender differences on motor and non-motor symptoms of de novo patients with early Parkinson's disease. AB - The affect of gender differences on clinical presentation of Parkinson's disease (PD) remains controversial. De novo PD subjects were recruited from a trial-based multicenter cohort in clinical sites of Chinese Parkinson Study Group. Demographic information, motor and non-motor symptom measurements were performed by face-to-face interview using specific scales. Scores and frequencies of symptoms were compared between male and female patients, and regression models were used to control the effects of age and disease duration. Totally 428 PD patients were enrolled in this study, and 60.3 % of them were male. Total UPDRS scores were not significantly different between male and female (25.02 +/- 12.84 vs. 25.24 +/- 13.22, adjusted p = 0.984). No significant gender differences were found on scores for four cardinal motor signs, neither on motor subtypes (PIGD 19.0 vs. 15.9 %, adjusted p = 0.303). Female patients more likely had depressive symptoms (38.8 vs. 27.5 %, adjusted p = 0.023; CES-D score 13.78 +/- 10.91 vs. 11.23 +/- 9.42, adjusted p = 0.015). Male patients had significantly higher scores for MMSE (28.26 +/- 2.21 vs. 27.00 +/- 3.38, adjusted p = 0.0001), and lower scores for identification (1.39 +/- 1.63 vs. 2.01 +/- 2.63, adjusted p = 0.002) in ADAS-cog. No significant differences were found for other non-motor symptoms including motivation problems (male 29.8 % vs. female 30.6 %, adjusted p = 0.760), fatigue (62.6 vs. 70.5 %, adjusted p = 0.140), constipation (37.2 vs. 30.1 %, adjusted p = 0.243), and sleep quality (57.6 vs. 61.3 %, adjusted p = 0.357; PSQI score: 5.62 +/- 3.31 vs. 6.10 +/- 3.53, adjusted p = 0.133). Female might be more depressed and have worse performance on cognition in early untreated PD patients, but gender differences are not apparent on motor and other non-motor symptoms. PMID- 25012757 TI - Pharmacokinetics of dexamethasone and nefopam administered alone or in combination using a newly developed prefilled multi-drug injector in rats. AB - BACKGROUND/AIM: It is significant for patients with traumatic brain injury (TBI) to receive prehospital emergency treatment as early as possible to reduce mortality. Therefore, a new prefilled multi-drug injector was developed to improve the treatment of TBI. Here, we studied the pharmacokinetics of dexamethasone (DXM) and nefopam using the injector to investigate the significance of drug interactions and the necessity of dose adjustment. METHODS: Rats were administered DXM and nefopam intramuscularly alone or in combination using the injector. The concentrations of DXM and nefopam were measured by means of HPLC. The noncompartmental approach was used to calculate pharmacokinetic parameters. RESULTS: All animals appeared to tolerate the injection very well. The maximum concentration 90% confidence interval (CI) of nefopam was in the bioequivalence range when nefopam was co-administered with DXM. However, the AUC 90% CI of nefopam was out of the range. A statistically significant alteration was also observed in the clearance of nefopam. The co-administration exhibited no significant influence on the pharmacokinetic parameters of DXM. CONCLUSIONS: These results indicate that the co-administration of DXM and nefopam using the prefilled multi-drug injector significantly alters some pharmacokinetic parameters of nefopam and has a minor effect on DXM pharmacokinetics. PMID- 25012759 TI - Associations of physical activity and inactivity with body tissue composition among healthy Polish women and women after mastectomy. AB - The aim of the study is to determine the relationship between physical activity and body composition among healthy women and women who have had mastectomy. This is in order to establish whether physical activity of women after breast cancer treatment improves composition and distribution of body mass components to a degree which will allow to achieve the body composition of healthy women. Research material consists of anthropometric measurements (body height, weight) of women and bioelectric impedance analysis (BIA) of body composition (using Akern - BIA 101 composition analyzer). Intensity of activity was assessed using the Physical Activity International Questionnaire. The sample consisted of 76 healthy women (active 44.74%, inactive 55.26%) and 70 females after mastectomy (54.29% and 45.71%, respectively). Mean chronological age of women after mastectomy was 53.40 years, SD=7.55, and of the healthy ones 52.38 years SD=11.01). A significant difference in body composition was noted among active and inactive women after mastectomy; namely the active females had lower weight (by approximately 12 kg), body mass index (BMI), level of fat mass (by approximately 8%) and (by approximately 5%) total body water. The active healthy women had 6% less fat mass, almost 4% more body water and 6% more fat free mass. Programmed physical activity undertaken by women after mastectomy is recommended and produces good results in the form of reduction of excessive body fat tissue. Through physical activity these women are able to achieve the same level of fat mass as healthy women. PMID- 25012758 TI - miRNAs affect the development of hepatocellular carcinoma via dysregulation of their biogenesis and expression. AB - The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non coding RNAs, which regulate the expression of various genes post transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes. PMID- 25012761 TI - Metabolic changes associated with selenium deficiency in mice. AB - Selenium (Se), which is a central component for the biosynthesis and functionality of selenoproteins, plays an important role in the anti-oxidative response, reproduction, thyroid hormone metabolism and the protection from infection and inflammation. However, dietary Se effects have not well been established to date and the available studies often present contradictory results. To obtain a better understanding of Se intake and its influence on the metabolism of living systems, we have utilized a metabolomics approach to gain insight into the specific metabolic alterations caused by Se deficiency in mice. Serum samples were collected from two groups of C57BL/6 mice: an experimental group which was fed a Se-deficient diet and controls consuming normal chow. The samples were analyzed by (1)H nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry. The resulting metabolite data were examined separately for both analytical methods and in a combined manner. By applying multivariate statistical analysis we were able to distinguish the two groups and detect a metabolite pattern associated with Se deficiency. We found that the concentrations of 15 metabolites significantly changed in serum samples collected from Se-deficient mice when compared to the controls. Many of the perturbed biological pathways pointed towards compensatory mechanisms during Se deficiency and were associated with amino acid metabolism. Our findings show that a metabolomics approach may be applied to identify the metabolic impact of Se and reveal the most impaired biological pathways as well as induced regulatory mechanisms during Se deficiency. PMID- 25012762 TI - Ultrafast shock compression of an oxygen-balanced mixture of nitromethane and hydrogen peroxide. AB - We apply ultrafast optical interferometry to measure the Hugoniot of an oxygen balanced mixture of nitromethane and hydrogen peroxide (NM/HP) and compare with Hugoniot data for pure nitromethane (NM) and a 90% hydrogen peroxide/water mixture (HP), as well as theoretical predictions. We observe a 2.1% percent mean pairwise difference between the measured shockwave speed (at the measured piston speed) in unreacted NM/HP and the corresponding "universal" liquid Hugoniot, which is larger than the average standard deviation of our data, 1.4%. Unlike the Hugoniots of both HP and NM, in which measured shock speeds deviate to values greater than the unreacted Hugoniot for piston speeds larger than the respective reaction thresholds, in the NM/HP mixture we observe shock speed deviations to values lower than the unreacted Hugoniot well below the von Neumann pressure (~28 GPa). Although the trend should reverse for high enough piston speeds, the initial behavior is unexpected. Possible explanations range from mixing effects to a complex index of refraction in the reacted solution. If this is indeed a signature of chemical initiation, it would suggest that the process may not be kinetically limited (on a ~100 ps time scale) between the initiation threshold and the von Neumann pressure. PMID- 25012760 TI - Zinc and autophagy. AB - Autophagy is a highly conserved degradative process through which cells overcome stressful conditions. Inasmuch as faulty autophagy has been associated with aging, neuronal degeneration disorders, diabetes, and fatty liver, autophagy is regarded as a potential therapeutic target. This review summarizes the present state of knowledge concerning the role of zinc in the regulation of autophagy, the role of autophagy in zinc metabolism, and the potential role of autophagy as a mediator of the protective effects of zinc. Data from in vitro studies consistently support the notion that zinc is critical for early and late autophagy. Studies have shown inhibition of early and late autophagy in cells cultured in medium treated with zinc chelators. Conversely, excess zinc added to the medium has shown to potentiate the stimulation of autophagy by tamoxifen, H2O2, ethanol and dopamine. The potential role of autophagy in zinc homeostasis has just begun to be investigated. Increasing evidence indicates that autophagy dysregulation causes significant changes in cellular zinc homeostasis. Autophagy may mediate the protective effect of zinc against lipid accumulation, apoptosis and inflammation by promoting degradation of lipid droplets, inflammasomes, p62/SQSTM1 and damaged mitochondria. Studies with humans and animal models are necessary to determine whether autophagy is influenced by zinc intake. PMID- 25012763 TI - Antecedents of moral pride: the harder the action, the greater the pride? AB - The study's aim was to analyze if some specific types of action generate higher levels of moral pride. Three variables were analyzed: whether the actions involved going against the group majority, whether they involved a personal cost of a different kind and whether they were the result of a prior intention. Participants were 160 adolescents aged between 14 and 16. Sixteen scenarios were designed (two for each combination of the three variables) in which someone needed help. Half of the participants were presented with 8 of these scenarios, and half with the other 8. In each scenario, participants were asked to state what they would feel and do and how much pride they would feel if they helped. Curiously enough, both prosocial behaviors which involved going against the majority, F(1, 140) = 60.36, p = .001, eta2 = .301 and those which involved a personal cost of a different kind, F(1, 140) = 10.17, p = .002, eta2 = .068 generated less moral pride. PMID- 25012764 TI - Comparison of an interactive CD-based and traditional instructor-led Basic Life Support skills training for nurses. AB - BACKGROUND: Basic Life Support (BLS) is a life-saving and fundamental skill in resuscitation. However, studies have reported limitations in BLS training outcomes for both health professional and lay populations, and noted the resource and time-intensive nature of traditional training approaches. PURPOSE: This exploratory study evaluated the effectiveness of an interactive CD-based BLS training programme that included unsupervised manikin practice compared with a traditional instructor-led BLS training programme involving demonstration and supervised practice. METHODS: A quasi-experimental post-test with follow-up design was used. The sample was comprised of two cohorts: Novice second-year undergraduate Nursing students (n=187) and Practising Nurses (n=107) in their first year of hospital employment. BLS skill outcomes were assessed at one week and again at eight weeks post training. FINDINGS: No statistically significant differences were found between the CD and traditional instructor-led BLS training methods in BLS skills of Novice and Practising Nurses at one week and eight weeks post training. However, there was a decrement in skill between one week and eight weeks post-training across both groups and an overall low level of competence. CONCLUSION: The failure to find a difference between the CD-based BLS programme with unsupervised manikin practice and a resource-intensive traditional instructor-led BLS training programme may indicate equivalence of the programmes or, even study design limitations. It is concerning that competence displayed by trainees from both groups was less than optimal and suggests the need for renewed efforts to develop and evaluate BLS training programmes which can achieve high rates of competence with acceptable skill retention over time. PMID- 25012765 TI - Raloxifene adjunctive therapy for postmenopausal women suffering from chronic schizophrenia: a randomized double-blind and placebo controlled trial. AB - BACKGROUND: Cumulative evidence from epidemiological, preclinical and clinical studies suggests estrogens may have psychoprotective effects in schizophrenic patients. Selective Estrogen Receptor Modulators could have therapeutic benefits in schizophrenia for both sexes without being hazardous to gynecological tissues or having feminizing effects. Few studies have been conducted regarding the effects of raloxifene on postmenopausal women suffering from schizophrenia. We conducted this placebo-controlled trial to compare the add-on effect of raloxifene to risperidone versus risperidone with placebo. METHODS: This was an 8 week, parallel-group, placebo-controlled trial undertaken at two universities affiliated psychiatric Hospitals in Iran. Forty-six postmenopausal women with the definite diagnosis of schizophrenia were enrolled in the study. Patients received risperidone (6 mg/day in 3 divided doses) combined with either placebo (N = 23) or 120 mg/day of raloxifene (N = 23) for 8 weeks. Patients were assessed by a psychiatrist at baseline and at 2 and 8 weeks after the start of medical therapy. Efficacy was defined as the change from baseline to endpoint in score on Positive and Negative Syndrome Scale (PANSS). RESULTS: For PANSS scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.77, p = 0.18]. For positive subscale scores, there was marginal significant interaction between intervention type and time [F (2, 47) = 2.93, p = 0.06] and there was substantial main effect for time [F (2, 47) = 24.39, p = 0.001] within both groups showing reduction in positive subscale scores across the three time periods. In addition, the main effect comparing two types of intervention was significant [F (1, 48) = 3.78, p = 0.02]. On the other hand, for negative subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.43, p = 0.23]. For general subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 0.03, p = 0.86]. CONCLUSIONS: According to our findings, raloxifene as an adjunctive treatment to risperidone was only superior in improvement of positive symptoms and it was not effective in treating negative and general psychopathology symptoms. TRIAL REGISTRATION: The trial was registered at the Iranian registry of clinical trials: IRCT201205131556N42. PMID- 25012766 TI - A state-based, proportional myoelectric control method: online validation and comparison with the clinical state-of-the-art. AB - BACKGROUND: Current clinical myoelectric systems provide unnatural prosthesis control, with limited functionality. In this study, we propose a proportional state-based control method, which allows switching between functions in a more natural and intuitive way than the traditional co-contraction switch method. METHODS: We validated the ability of the proposed system to provide precise control in both position and velocity modes. Two tests were performed with online visual feedback, involving target reaching and direct force control in grasping. The performance of the system was evaluated both on a subject with limb deficiency and in 9 intact-limbed subjects, controlling two degrees of freedom (DoF) of the hand and wrist. RESULTS: The system allowed completion of the tasks involving 1-DoF with task completion rate >96% and of those involving 2-DoF with completion rate >91%. When compared with the clinical/industrial state-of-the-art approach and with a classic pattern recognition approach, the proposed method significantly improved the performance in the 2-DoF tasks. The completion rate in grasping force control was >97% on average. CONCLUSIONS: These results indicate that, using the proposed system, subjects were successfully able to operate two DoFs, and to achieve precise force control in grasping. Thus, the proposed state based method could be a suitable alternative for commercial myoelectric devices, providing reliable and intuitive control of two DoFs. PMID- 25012767 TI - Characteristics of symptom presentation and risk factors in patients with erosive esophagitis and nonerosive reflux disease. AB - OBJECTIVE: The aim of this study was to investigate the effect of gender on symptom presentation and quality of life of patients with erosive esophagitis (EE) and nonerosive reflux disorder (NERD). SUBJECTS AND METHODS: Medical records from patients with gastroesophageal reflux disease (GERD) between January and December 2009 were reviewed. The patients were assigned to either the EE or the NERD group. The general demographic data, the modified Chinese GERDQ scores and the Short Form (SF)-36 life quality questionnaire scores of the two groups of patients were compared. RESULTS: Of the 261 patients, 87 (33.3%), 86 (33.0%) and 88 (33.7%) patients were classified into the EE, the NERD and the control groups, respectively. The patients in the EE group were significantly older (48.94 +/- 17.38 vs. 43.34 +/- 12.67 years), were predominately male (58.6 vs. 39.5%), had more frequently hiatal hernia (34.5 vs 17.4%), had a higher body weight (67.57 +/ 15.13 vs. 61.06 +/- 11.08 kg) and a higher body mass index (24.09 +/- 4.61 vs. 22.68 +/- 3.12) than those in the NERD group. The GERD-specific symptom scores and the general life quality scores of the EE and the NERD groups were similar, and both groups had lower life quality scores than the control group did. The female patients with NERD had a higher frequency of GERD symptoms and lower quality of life scores. Gender had no effect on symptom scores or life quality scores in the EE group. CONCLUSION: The GERD-specific symptom severity and general quality of life scores of the EE and the NERD patients were similar. Gender had a great influence on symptom presentation and quality of life in patients with NERD, but not in those with EE. PMID- 25012768 TI - Single incision transumbilical laparoscopic Roux-en-Y gastric bypass-our technique. AB - Laparoscopic Roux-en-Y gastric bypass (LRYGB) is considered the gold standard procedure in bariatric surgery but requires 4-7 ports. We have reported the first single incision transumbilical Roux-en-Y gastric bypass (SITU-RYGB) in 2009 (Huang et al. Obes Surg 19:1711-1715, 2009). Over the years, we have standardized our procedure and this video highlights the same by showing both inside and outside views. This video was shot from outside as well to give better understanding of the procedure. A 4.5-cm incision was made according to the contour of umbilicus and space was created over the sheath to give more range of movement to the instruments. The procedure was carried out using conventional laparoscopic instruments and replicating all the steps of the procedure under adequate visualization. Picture-in-picture effect has been used at important steps. Findings were recorded. The procedure took 96 min without any intraoperative complication. Blood loss was 20 cc. The incision was hardly noticeable at the end of the procedure. We have previously compared our results of SITU-RYGB with that of our multiport RYGB where operative time was longer for SITU-RYGB versus multiport technique (101.1 vs. 81.1 min, P = 0.001) (Huang et al. Surg Obes Relat Dis 8:201-207, 2012). No difference in complications was observed. The SITU-LRYGB patients reported greater satisfaction related to scarring than those who had undergone five-port surgery (P = 0.005). Difference in analgesia requirement was not statistically significant. There was no mortality. Compared with conventional LRYGB, SITU-RYGB resulted in acceptable complications, the same recovery, comparative weight loss, and better patient satisfaction related to scarring. PMID- 25012769 TI - Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy for the treatment of morbid obesity. a prospective study with 5 years of follow-up. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most widely used bariatric procedures today, and laparoscopic sleeve gastrectomy (LSG) is becoming increasingly popular. The aim of this study was to compare mid-term results of both procedures. METHODS: From January 2008 to December 2008, 117 obese patients were assigned by patient choice after informed consent to either a LRYGB procedure (n=75) or a LSG procedure (n=42). We determined operative time, length of stay, morbidity, comorbidity outcomes, failures, and excess weight loss at 5 years. RESULTS: Both groups were comparable in demographic characteristics and comorbidities at baseline. No significant statistical differences were found in length of stay and early major morbidity, but mean operative time was shorter in LSG group, p<0.05. Follow-up was achieved in 74 patients (63.2 %) at 5 years, and major complications (early and late) were 10 (21.2 %) for the LRYGB group and 3 (11.1 %) for the LSG group, p>0.05. Five years after surgery, the percentage of excess weight loss was similar in both groups (69.8 % for LRYGB and 67.3 % for LSG, p>0.05). Failures were more common for LSG group, 22.2 versus 12.7 % for LRYGB group, but this difference was not significant, p>0.05. CONCLUSIONS: Both techniques are comparable regarding safety and effectiveness after 5 years of follow-up, so not one procedure is clearly superior to the other. PMID- 25012770 TI - Association between cardiorespiratory fitness and accelerometer-derived physical activity and sedentary time in the general population. AB - OBJECTIVE: To determine the association between cardiorespiratory fitness and sedentary behavior, independent of exercise activity. PATIENTS AND METHODS: We included 2223 participants (aged 12-49 years; 1053 females [47%]) without known heart disease who had both cardiovascular fitness testing and at least 1 day of accelerometer data from the National Health and Nutrition Examination Survey 2003 2004. From accelerometer data, we quantified bouts of exercise as mean minutes per day for each participant. Sedentary time was defined as less than 100 counts per minute in mean minutes per day. Cardiorespiratory fitness was derived from a submaximal exercise treadmill test. Multivariable-adjusted linear regression analyses were performed with fitness as the dependent variable. Models were stratified by sex, adjusted for age, body mass index, and wear time, and included sedentary and exercise time. RESULTS: An additional hour of daily exercise activity time was associated with a 0.88 (0.37-1.39; P<.001) metabolic equivalent of task (MET) higher fitness for men and a 1.37 (0.43-2.31; P=.004) MET higher fitness for women. An additional hour of sedentary time was associated with a 0.12 (-0.02 to -0.22; P=.03) and a -0.24 (-0.10 to -0.38; P<.001) MET difference in fitness for men and women, respectively. CONCLUSION: After adjustment for exercise activity, sedentary behavior appears to have an inverse association with fitness. These findings suggest that the risk related to sedentary behavior might be mediated, in part, through lower fitness levels. PMID- 25012771 TI - A novel deletion in the thyrotropin Beta-subunit gene identified by array comparative genomic hybridization analysis causes central congenital hypothyroidism in a boy originating from Turkey. AB - BACKGROUND: Isolated central congenital hypothyroidism (ICCH) is rare but important. Most ICCH patients are diagnosed later, which results in severe growth failure and intellectual disability. OBJECTIVE: We describe a boy with ICCH due to a large homozygous TSHbeta gene deletion. RESULTS: A 51-day-old male Turkish infant, whose parents were first cousins, was admitted for evaluation of prolonged jaundice. His clinical appearance was compatible with hypothyroidism. Venous thyrotropin (TSH) was undetectably low, with a subsequent low free T4 and a low free T3, suggestive of central hypothyroidism. Using different PCR protocols, we could not amplify both coding exons of the boy's TSHbeta gene, which suggested a deletion. An array comparative genomic hybridization (aCGH) using specific probes around the TSHbeta gene locus showed him to be homozygous for a 6-kb deletion spanning all exons and parts of the 5' untranslated region of the gene. CONCLUSIONS: Infants who are clinically suspected of having hypothyroidism should be evaluated thoroughly, even if their TSH-based screening result is normal. In cases with ICCH and undetectably low TSH serum concentrations, a TSHbeta gene deletion should be considered; aCGH should be performed when gene deletions are suspected. In such cases, PCR-based sequencing techniques give negative results. PMID- 25012773 TI - Citation classics: top 50 cited articles in bariatric and metabolic surgery. AB - BACKGROUND: The number of times an article has been cited reflects its influence in a specific field. The aim of this study was to identify and characterize the most highly cited articles published on bariatric and metabolic surgery. METHODS: The 50 most frequently cited articles in bariatric and metabolic surgery were identified from the Scopus database in December 2013. RESULTS: The median number of citations was 383.5 (range 275-2482). Most of the articles were published from 2000-2012 (n = 35), followed by 1990-1999 (n = 12), then before 1990 (n = 3). These citation classics came from 8 countries, with the majority originating from the United States (n = 34), followed by Sweden (n = 4) and Australia (n = 4). The 50 articles were published in 20 journals, led by New England Journal of Medicine (n = 9) and Annals of Surgery (n = 9). Only 10 of the articles were published in obesity-specific journals. The level of evidence of the 49 clinical publications and 1 animal study consisted of level I (n = 5), II (n = 11), III (n = 9), IV (n = 19), and V (n = 6). Meta-analyses were 16% of the total citations. Metabolic (n = 12) and survival (n = 6) effects of surgery were among the most common fields of study. CONCLUSION: Extending from the early 1950s through the voluminous growth period of the early 2000s, the field of bariatric and metabolic surgery led to the emergence of many top-cited scientific articles. These articles have provided the scientific basis for the only currently effective treatment for severe obesity. Articles published in high-impact journals, innovative observational studies, meta-analyses, survival analyses, and research on postoperative metabolic changes are most likely to be cited in the field of bariatric surgery. PMID- 25012772 TI - Infant antibiotic exposure and the development of childhood overweight and central adiposity. AB - BACKGROUND: Obesity has been associated with disruption of the gut microbiota, which is established during infancy and vulnerable to disruption by antibiotics. OBJECTIVES: To investigate the association between early-life antibiotic exposure and subsequent development of overweight and central adiposity. METHODS: Provincial health-care records were linked to clinical and survey data from a Canadian longitudinal birth cohort study. Antibiotic exposure during the first year of life was documented from prescription records. Overweight and central adiposity were determined from anthropometric measurements at ages 9 (n=616) and 12 (n=431). Associations were determined by multiple logistic regression. RESULTS: Infants receiving antibiotics in the first year of life were more likely to be overweight later in childhood compared with those who were unexposed (32.4 versus 18.2% at age 12, P=0.002). Following adjustment for birth weight, breastfeeding, maternal overweight and other potential confounders, this association persisted in boys (aOR 5.35, 95% confidence interval (CI) 1.94-14.72) but not in girls (aOR 1.13, CI 0.46-2.81). Similar gender-specific associations were found for overweight at age 9 (aOR 2.19, CI 1.06-4.54 for boys; aOR 1.20, CI 0.53-2.70 for girls) and for high central adiposity at age 12 (aOR 2.85, CI 1.24 6.51 for boys; aOR 1.59, CI 0.68-3.68 for girls). CONCLUSIONS: Among boys, antibiotic exposure during the first year of life was associated with an increased risk of overweight and central adiposity in preadolescence, indicating that antibiotic stewardship is particularly important during infancy. Given the current epidemic of childhood obesity and the high prevalence of infant antibiotic exposure, further studies are necessary to determine the mechanisms underlying this association, to identify the long-term health consequences, and to develop strategies for mitigating these effects when antibiotic exposure cannot be avoided. PMID- 25012774 TI - Comment on: Risk prediction of complications of metabolic syndrome before and 6 years after gastric bypass. PMID- 25012775 TI - Gastric bypass surgery as treatment of recalcitrant gastroparesis. AB - BACKGROUND: Few treatments for idiopathic and diabetic gastroparesis exist beyond symptom management, and no study has described gastric surgery for gastroparesis in obese and morbidly obese patients. The objective of this study was to describe treatment of recalcitrant gastroparesis in obese adults with Roux-en-Y gastric bypass (RYGB) surgery. METHODS: A retrospective review was conducted of adult patients who underwent laparoscopic RYGB. Clinical data pre- and postsurgery and at a follow-up of up to 2 years were reviewed. Total symptom scores for gastroparetic symptom severity and frequency were compared presurgery and at follow-up using paired t tests. RESULTS: Seven obese and morbidly obese patients (body mass index [BMI] = 39.5, range = 33-54; 6 women) with idiopathic or diabetic gastroparesis reported marked symptom improvement, and total symptom scores significantly decreased after RYGB. All 4 patients who were taking prokinetics preoperatively no longer required their medication after surgery. Three patients required prolonged treatment with antinausea medications in the postoperative period. Mean BMI change was 9.1 units and mean percent excess weight lost was 71.6 lbs. No perioperative complications were experienced. Two required readmissions due to various concerns (dysphagia, nausea, anastomotic ulcer). CONCLUSIONS: In our cohort, no patients required the use of prokinetics after surgery and everyone experienced significant improvement in symptoms. Importantly, we found that RYGB is a safe surgical treatment for gastroparesis in obese patients. Our results indicate that gastroparesis, primarily believed to result in being underweight, can present in morbid obesity and can be markedly improved with RYGB. PMID- 25012776 TI - Comment on: Single incision laparoscopic bariatric surgery: a systematic review. PMID- 25012777 TI - A double challenge transplant-horseshoe kidney meets obesity. First case of horseshoe kidney transplantation after laparoscopic sleeve gastrectomy. PMID- 25012778 TI - Cyclooxygenase inhibitors inhibit antibody response through interference with MAPK/ERK pathways and BLIMP-1 inhibition. AB - Fever is a common symptom of illness in children, and although not harmful in itself, fever and its associated symptoms are often treated with antipyretic drugs. A number of national and other guidelines now recommend against their routine use; a conclusion that was initially supported by a study showing that the prophylactic use of paracetamol might reduce antibody response to some vaccine antigens, although data from booster vaccinations are more equivocal. Although in vivo data on the cause of this inhibition are scarce, in vitro data suggests that the cause may be due to inhibition of the mitogen activated protein kinase/extracellular regulated protein kinase pathways, and a subsequent reduction in the process of plasma cell differentiation at the beginning of the antibody response. This suggests that in high-risk patients these drugs could be avoided in the early part of an infection when plasma-cell differentiation is occurring. More data are needed to define this period; until then existing data support the recommendation against the routine use of these drugs. PMID- 25012779 TI - Letter to the editor: reply to Legare et al. PMID- 25012780 TI - Effect of clozapine on white matter integrity in patients with schizophrenia: a diffusion tensor imaging study. AB - Several diffusion tensor imaging (DTI) studies have reported disturbed white matter integrity in various brain regions in patients with schizophrenia, whereas only a few studied the effect of antipsychotics on DTI measures. The aim of this study was to investigate the effect of 12 weeks of clozapine treatment on DTI findings in patients with schizophrenia, and to compare the findings with those in unaffected controls. The study included 16 patients with schizophrenia who were assessed with the Positive and Negative Syndrome Scale, a neurocognitive test battery, and DTI at baseline and 12 weeks after the initiation of clozapine treatment. Eight unaffected controls were assessed once with the neurocognitive test battery and DTI. Voxel-wise analysis of DTI data was performed via tract based spatial statistics (TBSS). Compared with the control group, the patient group exhibited lower fractional anisotropy (FA) in 16 brain regions, including the bilateral superior longitudinal fasciculi, inferior fronto-occipital fasciculi, superior and inferior parietal lobules, cingulate bundles, cerebellum, middle cerebellar peduncles, and left inferior longitudinal fasciculus, whereas the patients had higher FA in six regions, including the right parahippocampus, left anterior thalamic radiation, and right posterior limb of the internal capsule before clozapine treatment. After 12 weeks of treatment with clozapine, white matter FA was increased in widespread brain regions. In two of the regions where FA had initially been lower in patients compared with controls (left inferior fronto-occipital fasciculus and superior parietal lobule), clozapine appeared to increase FA. An improvement in semantic fluency was correlated with the increase in FA value in the left inferior fronto-occipital fasciculus. An increase in FA following 12 weeks of treatment with clozapine suggests that this treatment alters white matter microstructural integrity in patients with schizophrenia previously treated with typical and/or atypical antipsychotics and, in some locations, reverses a previous deficit. PMID- 25012781 TI - Relationship between self-focused attention and mindfulness in people with and without hallucination proneness. AB - The purpose of this work was to study the relationship between self-focused attention and mindfulness in participants prone to hallucinations and others who were not. A sample of 318 healthy participants, students at the universities of Sevilla and Almeria, was given the Launay-Slade Hallucinations Scale-revised (LSHS-R, Bentall & Slade, 1985). Based on this sample, two groups were formed: participants with high (n = 55) and low proneness (n = 28) to hallucinations. Participants with a score higher than a standard deviation from the mean in the LSHS-R were included in the high proneness group, participants with a score lower than a standard deviation from the mean in the LSHR-R were included in the second one. All participants were also given the Self-Absorption Scale (SAS, McKenzie & Hoyle, 2008) and the Southampton Mindfulness Questionnaire (SMQ, Chadwick et al., 2008). The results showed that participants with high hallucination proneness had significantly higher levels of public (t(80) = 6.81, p < .001) and private (t(77) = 7.39, p < .001) self-focused attention and lower levels of mindfulness (t(81) = -4.56, p < .001) than participants in the group with low hallucination proneness. A correlational analysis showed a negative association between self-focused attention (private and public) and mindfulness (r = -0.23, p < .001; r = -0.38, p < .001 respectively). Finally, mindfulness was found to partly mediate between self-focused attention and hallucination proneness. The importance of self focused attention and mindfulness in understanding the etiology of hallucinations discussed and suggest some approaches to their treatment. PMID- 25012782 TI - A recycling model of the biokinetics of systemic tellurium. AB - PURPOSE: To develop a compartmental model of the systemic biokinetics of tellurium required for calculating the internal dose and interpreting bioassay measurements after incorporation of radioactive tellurium. MATERIALS AND METHODS: The compartmental model for tellurium was developed with the software SAAM II v. 2.0 ((c)The Epsilon Group, Charlottesville, Virginia, USA). Model parameters were determined on the basis of published retention and excretion data in humans and animals. RESULTS: The model consists of two blood compartments, one compartment each for liver, kidneys, thyroid, four compartments for bone tissues and a generic compartment for the soft tissues. The model predicts a rapid urinary excretion of systemic tellurium: 45% in the first 24 h and 84% after 50 d. Faecal excretion amounts to 0.4% after 3 d and 9% after 50 d. Whole body retention is 55% after one day, and 2.8% after 100 d. These values as well as the retained fractions in the single organs are reasonably consistent with the available human and animal data (studies with swine and guinea pigs). CONCLUSIONS: The proposed model gives a realistic description of the available biokinetic data for tellurium and will be adopted by the International Commission on Radiological Protection for applications in internal dosimetry. PMID- 25012783 TI - Screening for depression and anxiety disorders from pregnancy to postpartum with the EPDS and STAI. AB - The Edinburgh Postnatal Depression Scale (EPDS) and the State Anxiety Inventory (STAI-S) are widely used self-report measures that still need to be further validated for the perinatal period. The aim of this study was to examine the screening performance of the EPDS and the STAI-S in detecting depressive and anxiety disorders at pregnancy and postpartum. Women screening positive on EPDS (EPDS >= 9) or STAI-S (STAI-S >= 45) during pregnancy (n = 90), as well as matched controls (n = 58) were selected from a larger study. At 3 months postpartum, 99 of these women were reassessed. At a second stage, women were administered a clinical interview to establish a DSM-IV-TR diagnosis. Receiver operator characteristics (ROC) analysis yielded areas under the curve higher than .80 and .70 for EPDS and STAI-S, respectively. EPDS and STAI-S optimal cut-offs were found to be lower at postpartum (EDPS = 7; STAI-S = 34) than during pregnancy (EPDS = 9; STAI-S = 40). EPDS and STAI-S are reasonably valid screening tools during pregnancy and the postpartum. PMID- 25012784 TI - Microbial community composition and dynamics in high-temperature biogas reactors using industrial bioethanol waste as substrate. AB - Stillage, which is generated during bioethanol production, constitutes a promising substrate for biogas production within the scope of an integrated biorefinery concept. In this study, a microbial community was grown on thin stillage as mono-substrate in a continuous stirred tank reactor (CSTR) at a constant temperature of 55 degrees C, at an organic loading rate of 1.5 goTS/L*d and a retention time of 25 days. Using an amplicon-based dataset of 17,400 high quality sequences of 16S rRNA gene fragments (V2-V3 regions), predominance of Bacteria assigned to the families Thermotogaceae and Elusimicrobiaceae was detected. Dominant members of methane-producing Euryarchaeota within the CSTR belonged to obligate acetoclastic Methanosaetaceae and hydrogenotrophic Methanobacteriaceae. In order to investigate population dynamics during reactor acidification, the organic loading rate was increased abruptly, which resulted in an elevated concentration of volatile fatty acids. Acidification led to a decrease in relative abundance of Bacteria accompanied with stable numbers of Archaea. Nevertheless, the abundance of Methanosaetaceae increased while that of Methanobacteriales decreased successively. These findings demonstrate that a profound intervention to the biogas process may result in persistent community changes and reveals uncommon bacterial families as process-relevant microorganisms. PMID- 25012785 TI - A contribution of hydrogenotrophic methanogenesis to the biogenic coal bed methane reserves of Southern Qinshui Basin, China. AB - The activity of methanogens and related bacteria which inhabit the coal beds is essential for stimulating new biogenic coal bed methane (CBM) production from the coal matrix. In this study, the microbial community structure and methanogenesis were investigated in Southern Qinshui Basin in China, and the composition and stable isotopic ratios of CBM were also determined. Although geochemical analysis suggested a mainly thermogenic origin for CBM, the microbial community structure and activities strongly implied the presence of methanogens in situ. 454 pyrosequencing analysis combined with methyl coenzyme-M reductase (mcrA) gene clone library analysis revealed that the archaeal communities in the water samples from both coal seams were similar, with the dominance of hydrogenotrophic methanogen Methanobacterium. The activity and potential of these populations to produce methane were confirmed by the observation of methane production in enrichments supplemented with H2 + CO2 and formate, and the only archaea successfully propagated in the tested water samples was from the genus Methanobacterium. 454 pyrosequencing analysis also recovered the diverse bacterial communities in the water samples, which have the potential to play a role in the coal biodegradation fueling methanogens. These results suggest that the biogenic CBM was generated by coal degradation via the hydrogenotrophic methanogens and related bacteria, which also contribute to the huge CBM reserves in Southern Qinshui Basin, China. PMID- 25012786 TI - Novel and tightly regulated resorcinol and cumate-inducible expression systems for Streptomyces and other actinobacteria. AB - Inducible expression is a versatile genetic tool for controlling gene transcription, determining gene functions and other uses. Herein, we describe our attempts to create several inducible systems based on a cumate or a resorcinol switch, a hammerhead ribozyme, the LacI repressor, and isopropyl beta-d thiogalactopyranoside (IPTG). We successfully developed a new cumate (p isopropylbenzoic acid)-inducible gene switch in actinobacteria that is based on the CymR regulator, the operator sequence (cmt) from the Pseudomonas putida cumate degradation operon and P21 synthetic promoter. Resorcinol-inducible expression system is also functional and is composed of the RolR regulator and the PA3 promoter fused with the operator (rolO) from the Corynebacterium glutamicum resorcinol catabolic operon. Using the gusA (beta-glucuronidase) gene as a reporter, we showed that the newly generated expression systems are tightly regulated and hyper-inducible. The activity of the uninduced promoters is negligible in both cases. Whereas the induction factor reaches 45 for Streptomyces albus in the case of cumate switch and 33 in the case of resorcinol toggle. The systems are also dose-dependent, which allows the modulation of gene expression even from a single promoter. In addition, the cumate system is versatile, given that it is functional in different actinomycetes. Finally, these systems are nontoxic and inexpensive, as these are characteristics of cumate and resorcinol, and they are easy to use because inducers are water-soluble and easily penetrate cells. Therefore, the P21-cmt-CymR and PA3-rolO-RolR systems are powerful tools for engineering actinobacteria. PMID- 25012787 TI - Antifungal effect and mechanism of garlic oil on Penicillium funiculosum. AB - Garlic oil is a kind of fungicide, but little is known about its antifungal effects and mechanism. In this study, the chemical constituents, antifungal activity, and effects of garlic oil were studied with Penicillium funiculosum as a model strain. Results showed that the minimum fungicidal concentrations (MFCs, v/v) were 0.125 and 0.0313 % in agar medium and broth medium, respectively, suggesting that the garlic oil had a strong antifungal activity. The main ingredients of garlic oil were identified as sulfides, mainly including disulfides (36 %), trisulfides (32 %) and monosulfides (29 %) by gas chromatograph-mass spectrometer (GC/MS), which were estimated as the dominant antifungal factors. The observation results by transmission electron microscope (TEM) and scanning electron microscope (SEM) indicated that garlic oil could firstly penetrate into hyphae cells and even their organelles, and then destroy the cellular structure, finally leading to the leakage of both cytoplasm and macromolecules. Further proteomic analysis displayed garlic oil was able to induce a stimulated or weakened expression of some key proteins for physiological metabolism. Therefore, our study proved that garlic oil can work multiple sites of the hyphae of P. funiculosum to cause their death. The high antifungal effects of garlic oil makes it a broad application prospect in antifungal industries. PMID- 25012788 TI - Marital disruption and health insurance. AB - Despite the high levels of marital disruption in the United States and the fact that a significant portion of health insurance coverage for those less than age 65 is based on family membership, surprisingly little research is available on the consequences of marital disruption for the health insurance coverage of men, women, and children. We address this shortfall by examining patterns of coverage surrounding marital disruption for men, women, and children, further subset by educational level. Using the 1996, 2001, and 2004 panels of the Survey of Income and Program Participation (SIPP), we find large differences in health insurance coverage across marital status groups in the cross-section. In longitudinal analyses that focus on within-person change, we find small overall coverage changes but large changes in type of coverage following marital disruption. Both men and women show increases in private coverage in their own names, but offsetting decreases in dependent coverage tend to be larger. One surprising result is that dependent coverage for children also declines after marital dissolution, even though children are still likely to be eligible for that coverage. Children and (to a lesser extent) women show increases in public coverage around the time of divorce or separation. We also find that these patterns differ by education. The most vulnerable group appears to be lower educated women with children because the increases in private, own-name, and public insurance are not large enough to offset the large decrease in dependent coverage. As the United States implements federal health reform, it is critical that we understand the ways in which life course events-specifically, marital disruption-shape the dynamic patterns of coverage. PMID- 25012789 TI - Reply to the letter 'multiple nonsteroidal anti-inflammatory drug-induced cutaneous disease: relevance, natural evolution and relationship with atopy' by blanca-lopez et Al. PMID- 25012791 TI - Low-flow oxygen for positive pressure ventilation of preterm infants in the delivery room. AB - BACKGROUND: The recent newborn resuscitation guidelines have recommended that a pulse oximeter and oxygen blender be used to keep oxygen saturation (SpO2) within the target range. However, an oxygen blender and compressed air are not generally available in delivery rooms. OBJECTIVES: To determine whether using low-flow oxygen at 0.5-1 liters/min for positive pressure ventilation (PPV) via a self inflating bag (SIB) without a reservoir is effective and able to maintain SpO2 within the target range. METHODS: Infants with a gestational age (GA) <=32 weeks who initially required PPV after birth were enrolled. PPV was performed with low flow oxygen at 0.5-1 liters/min via an SIB without a reservoir, and the flow was adjusted in a stepwise manner (from 0.5 to 0.8 to 1 liters/min) to keep SpO2 in the target range. If the heart rate was still <100/min or SpO2 was <70% at 3 min or chest compression was needed, then 100% oxygen was provided. RESULTS: Forty seven infants were enrolled in the study with a median (interquartile range) GA and birth weight of 28 (27-30) weeks and 1,060 (770-1,360) g, respectively. Twelve infants were initially intubated and switched to 100% oxygen (n = 12) due to ineffective ventilation, which occurred predominately in lower GA infants with intrapartum fetal distress. Thirty infants were successfully resuscitated with low-flow oxygen PPV (success rate 85.7%, 30/35), and >80% of their SpO2 distribution during PPV was between the 3rd and 97th percentiles of the reference range. CONCLUSION: Low-flow oxygen for PPV via an SIB used in this study should be sufficient for providing oxygen in resuscitation of preterm infants as long as adequate ventilation is evident. This technique is simple and could be useful in a resource-limited setting. PMID- 25012790 TI - Risk assessment for Thai population: benchmark dose of urinary and blood cadmium levels for renal effects by hybrid approach of inhabitants living in polluted and non-polluted areas in Thailand. AB - BACKGROUND: The aim of the present study was to estimate the benchmark doses (BMD) for renal effects for health risk assessment of residents living in Cd polluted and non-polluted areas in a Thai population. METHODS: The study participants consisted of inhabitants aged 40 years or older who lived in a non polluted area (40 men and 41 women) and in the environmentally polluted Mae Sot District (230 men and 370 women) located in northwestern Thailand. We measured urinary and blood cadmium (Cd) as markers of long-term exposure and urinary beta2 microglobulin (beta2-MG) and N-acetyl-beta-D-glucosaminidase (NAG) as renal tubular effect markers. An updated hybrid approach was applied to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) of urinary and blood Cd for Cd-induced renal effects in these subjects. BMD and BMDL corresponding to an additional risk (BMR) of 5% were calculated with the background risk at zero exposure set to 5% after adjusting for age and smoking status. RESULTS: The estimated BMDLs of urinary Cd for renal effect markers were 6.9 for urinary beta2-MG and 4.4 for NAG in men and 8.1 for beta2-MG and 6.1 for NAG MUg/g creatinine (Creat) in women. These BMDLs of urinary Cd (MUg/g Creat) for NAG were less than the geometric mean urinary Cd in the polluted area (6.5 in men and 7.1 in women). The estimated BMDLs of blood Cd (MUg/L) were 6.2 for urinary beta2-MG and 5.0 for NAG in men and 5.9 for beta2-MG and 5.8 for NAG in women. The calculated BMDLs were similar or less compared with the geometric mean blood Cd (MUg/L) in the polluted Thai area (6.9 in men and 5.2 in women). CONCLUSION: The BMDLs of urinary and blood Cd for renal effects were estimated to be 4.4-8.1 MUg/g Creat and 4.4-6.2 MUg/L in the Thai population aged >= 40 years old, suggesting that more than 40% of the residents were at risk of adverse renal effects induced by Cd exposure in Thailand. PMID- 25012792 TI - Palladium/sulfoxide-phosphine-catalyzed highly enantioselective allylic etherification and amination. AB - The Pd/sulfoxide-phosphine-catalyzed highly enantioselective allylic etherification and amination with a wide range of O- and N-nucleophiles have been developed (up to 97% yield, 98.5% ee). The products can also be conveniently transformed into biologically active chiral heterocycles. PMID- 25012793 TI - Further advances in knowledge on the role of the private sector in health systems. PMID- 25012794 TI - Expansion in the private sector provision of institutional delivery services and horizontal equity: evidence from Nepal and Bangladesh. AB - Wealth-related inequity in the use of maternal healthcare services continues to be a substantial problem in most low- and middle-income countries. One strategic approach to increase the use of appropriate maternal healthcare services is to encourage the expansion of the role of the private sector. However, critics of such an approach argue that increasing the role of the private sector will lead to increased inequity in the use of maternal healthcare services. This article explores this issue in two South Asian countries that have traditionally had high rates of maternal mortality-Nepal and Bangladesh. The study is based on multiple rounds of nationally representative household survey data collected in Nepal and Bangladesh from 1996 to 2011. The methodology involves estimating a concentration index for each survey to assess changes in wealth-related inequity in the use of institutional delivery assistance over time. The results of the study suggest that the expansion of private sector supply of institutional-based delivery services in Nepal and Bangladesh has not led to increased horizontal inequity. In fact, in both countries, inequity was shown to have decreased over the study period. The study findings also suggest that the provision of government delivery services to the poor protects against increased wealth-related inequity in service use. PMID- 25012795 TI - Informal rural healthcare providers in North and South India. AB - Rural households in India rely extensively on informal biomedical providers, who lack valid medical qualifications. Their numbers far exceed those of formal providers. Our study reports on the education, knowledge, practices and relationships of informal providers (IPs) in two very different districts: Tehri Garhwal in Uttarakhand (north) and Guntur in Andhra Pradesh (south). We mapped and interviewed IPs in all nine blocks of Tehri and in nine out of 57 blocks in Guntur, and then interviewed a smaller sample in depth (90 IPs in Tehri, 100 in Guntur) about market practices, relationships with the formal sector, and their knowledge of protocol-based management of fever, diarrhoea and respiratory conditions. We evaluated IPs' performance by observing their interactions with three patients per condition; nine patients per provider. IPs in the two districts had very different educational backgrounds-more years of schooling followed by various informal diplomas in Tehri and more apprenticeships in Guntur, yet their knowledge of management of the three conditions was similar and reasonably high (71% Tehri and 73% Guntur). IPs in Tehri were mostly clinic-based and dispensed a blend of allopathic and indigenous drugs. IPs in Guntur mostly provided door-to-door services and prescribed and dispensed mainly allopathic drugs. In Guntur, formal private doctors were important referral providers (with commissions) and source of new knowledge for IPs. At both sites, IPs prescribed inappropriate drugs, but the use of injections and antibiotics was higher in Guntur. Guntur IPs were well organized in state and block level associations that had successfully lobbied for a state government registration and training for themselves. We find that IPs are firmly established in rural India but their role has grown and evolved differently in different market settings. Interventions need to be tailored differently keeping in view these unique features. PMID- 25012796 TI - Unravelling the quality of HIV counselling and testing services in the private and public sectors in Zambia. AB - BACKGROUND: Despite the substantial investment for providing HIV counselling and testing (VCT) services in Zambia, there has been little effort to systematically evaluate the quality of VCT services provided by various types of health providers. This study, conducted in 2009, examines VCT in the public and private sectors including private for-profit and NGO/faith-based sectors in Copperbelt and Luapula. METHODS: The study used five primary data collection methods to gauge quality of VCT services: closed-ended client interviews with clients exiting VCT sites; open-ended client interviews; interviews with facility managers; review of service statistics; and an observation of the physical environment for VCT by site. Over 400 clients and 87 facility managers were interviewed from almost 90 facilities. Sites were randomly selected and results are generalizable at the provincial level. RESULTS: The study shows concerning levels of underperformance in VCT services across the sectors. It reveals serious underperformance in counselling about key risk-reduction methods. Less than one third of clients received counselling on reducing number of sexual partners and only approximately 5% of clients received counselling about disclosing test results to partners. In terms of client profiles, the NGO sector attracts the most educated clients and less educated Zambians seek VCT services at very low rates (7%). The private for-profit performs equally or sometimes better than other sectors even though this sector is not adequately integrated into the Zambian national response to HIV. CONCLUSION: The private for-profit sector provides VCT services on par in quality with the other sectors. Most clients did not receive counselling on partner reduction or disclosure of HIV test results to partners. In a generalized HIV epidemic where multiple concurrent sexual partners are a significant problem for transmitting the disease, risk-reduction methods and discussion should be a main focus of pre-test and post-test counselling. PMID- 25012797 TI - Who gives birth in private facilities in Asia? A look at six countries. AB - Over the past two decades, multilateral organizations have encouraged increased engagement with private healthcare providers in developing countries. As these efforts progress, there are concerns regarding how private delivery care may effect maternal health outcomes. Currently available data do not allow for an in depth study of the direct effect of increasing private sector use on maternal health across countries. As a first step, however, we use demographic and health surveys (DHS) data to (1) examine trends in growth of delivery care provided by private facilities and (2) describe who is using the private sector within the healthcare system. As Asia has shown strong increases in institutional coverage of delivery care in the last decade, we will examine trends in six Asian countries. We hypothesize that if the private sector competes for clients based on perceived quality, their clientele will be wealthier, more educated and live in an area where there are enough health facilities to allow for competition. We test this hypothesis by examining factors of socio-demographic, economic and physical access and actual/perceived need related to a mother's choice to deliver in a health facility and then, among women delivering in a facility, their use of a private provider. Results show a significant trend towards greater use of private sector delivery care over the last decade. Wealth and education are related to private sector delivery care in about half of our countries, but are not as universally related to use as we would expect. A previous private facility birth predicted repeat private facility use across nearly all countries. In two countries (Cambodia and India), primiparity also predicted private facility use. More in-depth work is needed to truly understand the behaviour of the private sector in these countries; these results warn against making generalizations about private sector delivery care. PMID- 25012798 TI - Water, sanitation, hygiene, and nutrition: successes, challenges, and implications for integration. AB - OBJECTIVES: This study explores the integration of water, sanitation, and hygiene (WASH) and nutrition programming for improved child health outcomes and aims to identify barriers to and necessary steps for successful integration. METHODS: Sixteen semi-structured in-depth interviews were conducted with key stakeholders from both the WASH and nutrition sectors, exploring barriers to integration and potential steps to more effectively integrate programs. RESULTS: Key barriers included insufficient and siloed funding, staff capacity and interest, knowledge of the two sectors, coordination, and limited evidence on the impact of integrated programs. To achieve more effective integration, respondents highlighted the need for more holistic strategies that consider both sectors, improved coordination, donor support and funding, a stronger evidence base for integration, and leadership at all levels. CONCLUSIONS: Organizations desiring to integrate programs can use these results to prepare for challenges and to know what conditions are necessary for successfully integrated programs. Donors should encourage integration and fund operational research to improve the efficiency of integration efforts. Knowledge among sectors should be shared and incentives should be designed to facilitate better coordination, especially where both sectors are working toward common goals. PMID- 25012799 TI - Demand-based web surveillance of sexually transmitted infections in Russia. AB - OBJECTIVES: To investigate the possibility of using HIV- and syphilis-related web queries to predict incident diagnosis rates of sexually transmitted infections in Russia. METHODS: The regional volume of HIV/syphilis queries, normalized to the total number of queries submitted to the most popular search engine, was used to predict the notification rates of HIV/syphilis in each region by applying both global non-spatial and spatial statistics. RESULTS: Nationwide, both search volumes and regional HIV/syphilis diagnosis rates were positively spatially auto correlated, indicating a clustered pattern of spatial distribution. A high positive correlation between notification rates and search volume was observed. Compared with linear models, spatially explicit geographically weighted models adjusted for broadband Internet diffusion proved superior in predicting the regional level of the HIV/syphilis epidemic on the basis of their search volume. CONCLUSIONS: Timeliness, easy availability, low cost, and transparency make HIV- and syphilis-related web queries a promising addition to traditional methods of disease surveillance in Russia. Geographically weighted regression provides useful insights, as it is able to capture the spatial heterogeneity of the relationship between search volume and disease incidence. PMID- 25012801 TI - Addressing health-related interventions to immigrants: migrant-specific or diversity-sensitive? PMID- 25012800 TI - When to see a doctor for common health problems: distribution patterns of functional health literacy across migrant populations in Switzerland. AB - BACKGROUND: Knowing when to seek professional help for health problems is considered an important aspect of health literacy. However, little is known about the distribution of help-seeking knowledge in the general population or specific subpopulations. METHODS: We analysed data from the "Health Monitoring of the Swiss Migrant Population 2010" and used a short survey tool to study the distribution of help-seeking knowledge. We sampled members of four migrant groups (from Portugal, Turkey, Serbia and Kosovo; n = 2,614). Our tool contained 12 items that addressed common physical and psychological health problems. A total sum score measured help-seeking knowledge. Two sub-scores analysed knowledge related to potential overuse (minor symptoms) or potential underuse (major symptoms). We applied linear regression to show variations in help-seeking knowledge by age, sex, region of origin and length of stay. RESULTS: Controlling for self-rated health, we found that region of origin, higher education, female gender and younger age were significantly associated with higher knowledge scores. CONCLUSIONS: We present empirical evidence of unequal distribution of help-seeking knowledge across four migrant populations in Switzerland. Our findings contribute to current conceptual developments in health literacy, and provide starting points for future research. PMID- 25012802 TI - Relationship of serum gamma-glutamyltransferase levels with pulmonary function and chronic obstructive pulmonary disease. AB - BACKGROUND: Gamma-glutamyltransferase (GGT) levels within the normal reference range, possibly a biomarker of oxidative stress and/or exposure to various environmental chemicals, are associated with pulmonary function. However, it is unclear whether it is totally independent of cigarette smoking. Also, the potential interaction between serum GGT and cigarette smoking has not ever been evaluated. Therefore, this study investigated (1) whether serum GGT levels are associated with pulmonary function and chronic obstructive pulmonary disease (COPD), independent of cigarette smoking, and (2) whether there is any interaction between serum GGT and cigarette smoking status on pulmonary function. METHODS: The study subjects were 4,583 participants aged >= 40 in the 2010-2011 Korean National Health and Nutrition Examination Survey. The outcomes were pulmonary function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]) and spirometrically defined COPD. RESULTS: After adjusting for potential confounders, including cigarette smoking, serum GGT levels were inversely associated with FEV1 and FVC in both genders and positively associated with the risk of COPD in men (all P values < 0.01). In men, adjusted odds ratios of COPD were 1.0, 1.69, 1.97, and 2.02 across the quartiles of GGT level (P trend = 0.002). However, the associations between serum GGT and pulmonary function seemed to differ depending on the smoking status; inverse associations of GGT with FEV1 % and FVC % were clearly observed only among non-current smokers. CONCLUSIONS: In conclusion, in non-smokers serum GGT levels can be used to detect individuals at high risk of decreased pulmonary function and/or COPD. PMID- 25012804 TI - A comparative trial of laparoscopic magnetic sphincter augmentation and Nissen fundoplication. AB - BACKGROUND: Laparoscopic magnetic sphincter augmentation (MSA) with the LINX device is a promising new therapy for the treatment of gastroesophageal reflux disease (GERD). Initial studies have demonstrated MSA to be safe and effective. However, no direct comparison between MSA and laparoscopic Nissen fundoplication (LNF), the gold standard surgical therapy for GERD, has been performed. METHODS: A single institution, case-control study was conducted of MSA performed from 2012 to 2013 and a cohort of LNF matched for age, gender, and hiatal hernia size. RESULTS: MSA and LNF were both effective treatments for reflux with 75 and 83 % of patients, respectively, reporting resolution of GERD at short-term follow-up. Dysphagia was common following both MSA and LNF, but severe dysphagia requiring endoscopic dilation was more frequent after MSA (50 vs. 0 %, p = 0.01). Need for dilation did not correlate with size of the LINX device or any other examined patient factors. A trend toward decreased adverse GI symptoms of bloating, flatulence, and diarrhea was seen after MSA compared to LNF (0 vs. 33 %). MSA had a shorter operative time (64 vs. 90 min, p < 0.01) but other peri-operative outcomes, including pain, morbidity, and re-admissions were equivalent to LNF. MSA patients were more likely to be self-referred (58 vs. 0 %, p < 0.001). CONCLUSIONS: MSA and LNF are both effective and safe treatments for GERD; however, severe dysphagia requiring endoscopic intervention is more common with MSA. Other adverse GI side effects may be less frequent after MSA. Consideration should be paid to these distinct post-operative symptom profiles when selecting a surgical therapy for reflux disease. PMID- 25012805 TI - Can we identify risk factors during pregnancy for thrombo-embolic events during the puerperium and later in life? AB - OBJECTIVES: To investigate parturients at risk to develop venous thrombo-embolic events (VTE) in the puerperium or later in life, during a follow-up of more than a decade and compare risk factors for VTE during the puerperium with VTE later in life. METHODS: A nested case-control study was conducted to profile parturients at risk for VTE and a secondary analysis to compare risk factors for VTE during or after puerperium. We used a cohort of 95 257 women who gave birth between the years 1988 and 1998. RESULTS: Independent risk factors to develop VTE were peripartum hysterectomy, stillbirth, cesarean delivery (CD), obesity, pregnancy related hypertension, grandmultiparity and advanced maternal age. Women undergoing CD and those receiving blood transfusion were more likely to develop early versus late VTE (OR = 2.0, 95% CI = 1.15-3.5 and OR = 11.0, 95% CI = 2.25 55.5; respectively). Patients that encountered VTE during the puerperium had more pulmonary emboli and less deep vein thrombosis, compared with the late VTE group (p < 0.001). CONCLUSIONS: Maternal age, grandmultiparity, pregnancy-related hypertension, CD, obesity, stillbirth and peripartum hysterectomy are independent risk factors for the development of VTE. CD and blood transfusion were predictive of early versus late VTE. PMID- 25012806 TI - Predictors of cesarean delivery in women undergoing labor induction with a Foley balloon. AB - OBJECTIVE: To examine predictive characteristics for cesarean delivery (CD) in women undergoing labor induction with a Foley balloon (FB). METHODS: A secondary analysis of a randomized, double-blind, control trial examining labor induction with a transcervical 30 mL or 60 mL FB. One-hundred ninety-nine women with term, vertex, singleton pregnancies and Bishop score < 5 were randomized to receive a transcervical 30 mL or 60 mL FB. Mode of delivery, labor complications and neonatal outcomes were recorded. A multivariable model was performed to determine predictive characteristics for CD. RESULTS: Increasing maternal age (p = 0.04), nulliparity (p =0.002) and chorioamnionitis (p < 0.001) were significantly associated with an elevated risk for CD. Nulliparity was associated in an almost 4-fold increased CD risk (relative risk [RR]: 3.88; 95% confidence interval [CI]: 1.22-12.3). Women aged >= 40 years, had an almost 3-fold increased risk of CD as compared to women aged 20-29 (RR: 2.91; 95% CI: 1.36-6.19) years. Chorioamnionitis was associated with nearly a 2-fold increased risk for CD (RR: 1.87; 95% CI: 1.06-3.32). A gestational age of >= 41 weeks, prostaglandin use during induction and induction indication did not affect mode of delivery. CONCLUSION: In patients undergoing labor induction with a FB, increasing maternal age, nulliparity and chorioamnionitis are associated with an elevated risk for CD. PMID- 25012807 TI - Genetic causes of maturity onset diabetes of the young may be less prevalent in American pregnant women recently diagnosed with diabetes mellitus than in previously studied European populations. AB - CONTEXT: There are many causes of impaired glucose tolerance in pregnant women. It is unclear whether genetic etiologies are a source of impaired glucose tolerance in pregnant women. OBJECTIVE: To prospectively determine the prevalence of maturity onset diabetes of the young (MODY) due to glucokinase (GCK) mutations in an American population of women with recent onset diabetes mellitus and gestational diabetes. We hypothesized that based on America's higher prevalence of gestational diabetes mellitus (GDM) and Type 2 diabetes, there may be an increased prevalence of GK mutations in our population than in previously reported studies from European studies. DESIGN: Over a three-year period, 72 pregnant women with recently diagnosed diabetes mellitus were prospectively assessed for presence of the most common pathogenic GCK mutations. SETTING: This study was performed in a gestational diabetes clinic in Urban America and a high risk pregnancy clinic that served the military and their families on an American military base in Germany. PATIENTS: Seventy-two women; 65 with diagnosis of diabetes mellitus in this pregnancy (GDM/overt diabetes) and 7 with diagnosis in the last nine years prior to pregnancy were recruited during pregnancy and blood samples were obtained. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Each study participant's blood sample was analyzed with restriction fragment length polymorphism to assess for mutations in the GCK gene. RESULTS: There were 38 female and 34 male neonates born at 38 weeks gestation +/- 1.2 weeks. Mean birth weight was 3351 g +/- 450 g. There were no patients with GCK mutations found in our population 0/72. This prevalence is not greater than that seen in previous a similar study in European women with gestational diabetes, but in fact significantly less (p = 0.03). CONCLUSION: American women with recently diagnosed diabetes mellitus likely have no higher prevalence of MODY than in previously studied European women with diabetes mellitus and may have a lower prevalence. PMID- 25012809 TI - Lessons from the matricellular factor periostin. PMID- 25012808 TI - Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway. AB - The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ERalpha) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ERalpha (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ERalpha beta-lactamase cell line), in a quantitative high throughput screening (qHTS) format. The ability of the two assays to correctly identify ERalpha agonists and antagonists was evaluated using a set of 39 reference compounds with known ERalpha activity. Although both assays demonstrated adequate (i.e. >80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ERalpha binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERalpha active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERalpha signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals. PMID- 25012811 TI - Working together versus working autonomously: a new power-dependence perspective on the individual-level of analysis. AB - Recent studies have indicated that it is important to investigate the interaction between task interdependence and task autonomy because this interaction can affect team effectiveness. However, only a limited number of studies have been conducted and those studies focused solely on the team level of analysis. Moreover, there has also been a dearth of theoretical development. Therefore, this study develops and tests an alternative theoretical perspective in an attempt to understand if, and if so why, this interaction is important at the individual level of analysis. Based on interdependence theory and power dependence theory, we expected that highly task-interdependent individuals who reported high task autonomy would be more powerful and better performers. In contrast, we expected that similarly high task-interdependent individuals who reported less task autonomy would be less powerful and would be weaker performers. These expectations were supported by multi-level and bootstrapping analyses performed on a multi-source dataset (self-, peer-, manager-ratings) comprised of 182 employees drawn from 37 teams. More specifically, the interaction between task interdependence and task autonomy was gamma =.128, p <.05 for power and gamma =.166, p <.05 for individual performance. The 95% bootstrap interval ranged from .0038 to .0686. PMID- 25012810 TI - Characterization of a novel periodontal ligament-specific periostin isoform. AB - Periostin is a mesenchymal cell marker predominantly expressed in collagen-rich fibrous connective tissues, including heart valves, tendons, perichondrium, periosteum, and periodontal ligament (PDL). Knockdown of periostin expression in mice results in early-onset periodontitis and failure of cardiac healing after acute myocardial infarction, suggesting that periostin is essential for connective tissue homeostasis and regeneration. However, its role(s) in periodontal tissues has not yet been fully defined. In this study, we describe a novel human isoform of periostin (PDL-POSTN). Isoform-specific analysis by reverse-transcription polymerase chain-reaction (RT-PCR) revealed that PDL-POSTN was predominantly expressed in the PDL, with much lower expression in other tissues and organs. A PDL cell line transfected with PDL-POSTN showed enhanced alkaline phosphatase (ALPase) activity and calcified nodule formation, compared with cells transfected with the full-length periostin isoform. A neutralizing antibody against integrin-alphav inhibited both ALPase activity and calcified nodule formation in cells transfected with PDL-POSTN. Furthermore, co immunoprecipitation assays revealed that PDL-POSTN bound to integrin alphavbeta3 more strongly than the common isoform of periostin, resulting in strong activation of the integrin alphavbeta3-focal adhesion kinase (FAK) signaling pathway. These results suggest that PDL-POSTN positively regulates cytodifferentiation and mineralization in PDL cells through integrin alphavbeta3. PMID- 25012812 TI - Ethnotaxonomy of birds by the inhabitants of Pedra Branca Village, Santa Teresinha municipality, Bahia state, Brazil. AB - BACKGROUND: Studies on popular names of birds help to understand the relationship between human beings and birds and it also contributes to the field of ornithology. METHODS: This study aims to register the ethnotaxonomy of birds in the village of Pedra Branca, Santa Teresinha municipality, Bahia State, Brazil, by cataloguing and identifying their popular names, besides understanding the ethnoclassification system of local bird species. The ethno-ornithological data were obtained by means of semi-structured open interviews, and projective tests. RESULTS: We interviewed 48 residents and, in order to identify species, we chose five informants with a more detailed knowledge on local avifauna. We registered 139 common names, distributed into 108 ethnospecies and 33 synonyms, referring to 117 species. Nomenclatural criteria more frequently used were vocalization and coloring patterns. Following Berlin's principles of ethnobiological classification, three hierarchical levels were registered: life form, generic and specific, with three types of correspondence between Linnaean and folk classification systems. The bird life form ("passaro" in Portuguese) was associated only to wild species. CONCLUSIONS: The ethno-ornithological research in Pedra Branca Village has contributed with new information on popular nomenclature of birds and their etymology, showing that folk knowledge on birds is conveyed within the community. PMID- 25012813 TI - Rationale, design and methods of the Study of Work and Pain (SWAP): a cluster randomised controlled trial testing the addition of a vocational advice service to best current primary care for patients with musculoskeletal pain (ISRCTN 52269669). AB - BACKGROUND: Musculoskeletal pain is a major contributor to short and long term work absence. Patients seek care from their general practitioner (GP) and yet GPs often feel ill-equipped to deal with work issues. Providing a vocational case management service in primary care, to support patients with musculoskeletal problems to remain at or return to work, is one potential solution but requires robust evaluation to test clinical and cost-effectiveness. METHODS/DESIGN: This protocol describes a cluster randomised controlled trial, with linked qualitative interviews, to investigate the effect of introducing a vocational advice service into general practice, to provide a structured approach to managing work related issues in primary care patients with musculoskeletal pain who are absent from work or struggling to remain in work. General practices (n = 6) will be randomised to offer best current care or best current care plus a vocational advice service. Adults of working age who are absent from or struggling to remain in work due to a musculoskeletal pain problem will be invited to participate and 330 participants will be recruited. Data collection will be through patient completed questionnaires at baseline, 4 and 12 months. The primary outcome is self-reported work absence at 4 months. Incremental cost-utility analysis will be undertaken to calculate the cost per additional QALY gained and incremental net benefits. A linked interview study will explore the experiences of the vocational advice service from the perspectives of GPs, nurse practitioners (NPs), patients and vocational advisors. DISCUSSION: This paper presents the rationale, design, and methods of the Study of Work And Pain (SWAP) trial. The results of this trial will provide evidence to inform primary care practice and guide the development of services to provide support for musculoskeletal pain patients with work related issues. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52269669. PMID- 25012815 TI - Dissolution of cellulose in ionic liquids: an ab initio molecular dynamics simulation study. AB - Interactions determining the dissolution of a monomer of beta-cellulose, i.e., cellobiose in a room temperature ionic liquid, [Emim][OAc], have been studied using ab initio molecular dynamics simulations. Although anions are the predominant species in the first coordination shell of cellobiose, cations too are present to a minor extent around it. The presence of low concentration of water in the solution does not significantly alter the nature of the coordination environment of cellobiose. All intra-molecular hydrogen bonds of anti-syn cellobiose are replaced by inter-molecular hydrogen bonds formed with the anions, whereas the anti-anti conformer retains an intramolecular hydrogen bond. PMID- 25012814 TI - Microwave-assisted one-pot multi-component reaction: synthesis of novel and highly functionalized 3-(pyranyl)- and 3-(dihydropyridinyl)indole derivatives. AB - One-pot multi-component reaction of 3-cyanoacetyl indole, aromatic aldehydes and ethyl acetoacetate in the presence of InCl(3)/NH(4)OAc under microwave irradiation for 2-7 min afforded novel and highly functionalized 3-(pyranyl)- and 3-(dihydropyridinyl)indole derivatives, respectively, in good yield. PMID- 25012816 TI - Analysis of recanalization after endovascular treatment of intracranial aneurysm (ARETA trial): presentation of a prospective multicenter study. AB - PURPOSE: Aneurysm recanalization is a main concern after endovascular treatment of intracranial aneurysms. But to date, no systematic analysis of the risk factors affecting its occurrence has been conducted in a large series of patients. Analysis of Recanalization after Endovascular Treatment of intracranial Aneurysm (ARETA) is a multicenter, prospective trial whose aim is to collect a large series of patients treated endovascularly to analyze factors affecting aneurysm recanalization. STUDY DESIGN: Patients with ruptured or unruptured aneurysms treated endovascularly will be enrolled from December 2013 to December 2014 in 19 participating centers in France. Patient and aneurysm characteristics will be recorded as well as the type of endovascular treatment and the occurrence of procedural or post-procedural complications. Post-procedural and follow-up imaging after one year will be analyzed independently by two readers using a 3 grade scale (complete occlusion, neck remnant, or aneurysm remnant). The progression of aneurysm occlusion will also be evaluated (improved, stable, or worsened). Aneurysm occlusion at one year and progression of aneurysm occlusion will be analyzed in light of patient, aneurysm, and treatment factors. CONCLUSION: ARETA is a large, prospective, multicenter trial designed to assess predictive factors of aneurysm recanalization after endovascular treatment of intracranial aneurysms. PMID- 25012817 TI - Unintended pregnancy and subsequent use of modern contraceptive among slum and non-slum women in Nairobi, Kenya. AB - BACKGROUND: In spite of major gains in contraceptive prevalence over the last few decades, many women in most parts of the developing world who would like to delay or avoid pregnancy do not use any method of contraception. This paper seeks to: a) examine whether experiencing an unintended pregnancy is associated with future use of contraception controlling for a number factors including poverty at the household and community levels; and b) investigate the mechanisms through which experiencing an unintended pregnancy leads to uptake of contraception. METHODS: Quantitative and qualitative data from a cross-sectional research project conducted in 2009/10 in two slum settlements and two non-slum settings of Nairobi, Kenya are used. The quantitative component of the project was based on a random sample of 1,259 women aged 15-49 years. Logistic regression models were used to assess the effect of unintended pregnancy on future contraceptive use. The qualitative component of the project successfully interviewed a total of 80 women randomly selected from survey participants who had reported having at least one unintended pregnancy. RESULTS: Women whose last pregnancy was unintended were more likely to be using a modern method of contraception, compared to their peers whose last pregnancy was intended, especially among the wealthier group as shown in the interaction model. Among poor women, unintended pregnancy was not associated with subsequent use of contraception. The qualitative investigation with women who had an unplanned pregnancy reveals that experiencing an unintended pregnancy seems to have served as a "wake-up call", resulting in greater attention to personal risks, including increased interest in pregnancy prevention. For some women, unintended pregnancy was a consequence of strong opposition by their partners to family planning, while others reported they started using contraceptives following their unintended pregnancy, but discontinued after experiencing side effects. CONCLUSION: This study provides quantitative and qualitative evidence that women who have had an unintended pregnancy are "ready for change". Family planning programs may use the contacts with antenatal, delivery and post-delivery care system as an opportunity to identify women whose pregnancy is unplanned, and target them with information and services. PMID- 25012818 TI - Identification of 14,20-dihydroxy-docosahexaenoic acid as a novel anti inflammatory metabolite. AB - Docosahexaenoic acid (DHA) exhibits anti-inflammatory activity related to some of its oxygenated metabolites, such as D-series resolvins, protectin and maresin. Here, we analysed the lipids in inflammatory exudates using liquid chromatography tandem mass spectrometry and identified a novel DHA metabolite, 14,20-dihydroxy DHA (14,20-diHDHA) and showed that it is biosynthesized by eosinophils through the 12/15-lipoxygenase pathway. The chemical structure of the dominant 14,20 diHDHA isomer, which is endogenously biosynthesized by eosinophils, was identified as 14S,20R-diHDHA using chemically synthesized stereoisomers. Nanogram doses of 14,20-diHDHA displayed a potent anti-inflammatory action by limiting neutrophil infiltration in zymosan-induced peritonitis. The in vivo formation and potent anti-inflammatory action of 14,20-diHDHA may contribute to the protective effects of DHA. PMID- 25012819 TI - Dissecting tumour heterogeneity in flies: genetic basis of interclonal oncogenic cooperation. AB - Cancers develop through sequential acquisition of oncogenic mutations, indicating a crucial role of genetic alterations in tumour progression. However, accumulating evidence suggests that cancers also progress towards malignancy through cell-cell interactions within heterogeneous tumour tissue. Recent studies have indicated that tumour heterogeneity not only contributes to drug resistance and tumour recurrence but also plays an active role in promoting tumour progression. Especially, genetic studies in Drosophila have discovered novel types of tumour progression through cell-cell interactions and have dissected the underlying mechanisms. This review focuses on describing recent findings obtained from Drosophila genetics that provide genetic basis of interclonal oncogenic cooperation in heterogeneous tumour tissue. PMID- 25012820 TI - DNA-PKcs-interacting protein KIP binding to TRF2 is required for the maintenance of functional telomeres. AB - Human telomeres associate with shelterin, a six-protein complex that protects chromosome ends from being recognized as sites of DNA damage. The shelterin subunit TRF2 (telomeric repeat-binding factor 2) protects telomeres by facilitating their organization into the protective capping structure. We have reported previously that the DNA-PKcs (DNA-dependent protein kinase catalytic subunit)-interacting protein KIP associates with telomerase through an interaction with hTERT (human telomerase reverse transcriptase). In the present study, we identify KIP as a novel interacting partner of TRF2. KIP is able to interact with both TRF2 and DNA-PKcs at telomeres. Because KIP is required for the association between TRF2 and DNA-PKcs, the interplay of these three proteins may provide a mechanism for the recruitment of DNA-PKcs to telomeres. We also show that KIP binding to TRF2 enhances the telomere-binding activity of TRF2, suggesting that KIP acts as a positive regulator of TRF2 function. Furthermore, depletion of KIP induces DNA-damage response foci at telomeres, thereby leading to induction of growth arrest, cellular senescence and altered cell cycle distribution. Collectively, our findings suggest that KIP, in addition to its association with catalytically active telomerase, plays important roles in the maintenance of functional telomeres and the regulation of telomere-associated DNA damage response. Thus KIP represents a new pathway for modulating telomerase and telomere function in cancer. PMID- 25012821 TI - Species distribution and in vitro antifungal susceptibility profiles of yeast isolates from invasive infections during a Portuguese multicenter survey. AB - This is the first Portuguese multicenter observational and descriptive study that provides insights on the species distribution and susceptibility profiles of yeast isolates from fungemia episodes. Ten district hospitals across Portugal contributed by collecting yeast isolates from blood cultures and answering questionnaires concerning patients' data during a 12-month period. Molecular identification of cryptic species of Candida parapsilosis and C. glabrata complex was performed. The susceptibility profile of each isolate, considering eight of the most often used antifungals, was determined. Both Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) protocols were applied. The incidence of 240 episodes of fungemia was 0.88/1,000 admissions. Fifteen different species were found, with C. albicans (40 %) being the most prevalent, followed by C. parapsilosis (23 %) and C. glabrata (13 %). Most isolates were recovered from patients admitted to surgical wards or intensive care units, with 57 % being males and 32 % aged between 41 and 60 years. For both the CLSI and EUCAST protocols, the overall susceptibility rates ranged from 74 to 97 % for echinocandins and from 84 to 98 % for azoles. Important resistance rate discrepancies between protocols were observed in C. albicans and C. glabrata for echinocandins and in C. parapsilosis and C. tropicalis for azoles. Death associated with fungemia occurred in 25 % of the cases, with more than half of C. glabrata infections being fatal. The great number of Candida non-albicans is noteworthy despite a relatively low antifungal resistance rate. Studies like this are essential in order to improve empirical treatment guidelines. PMID- 25012822 TI - Mutant phenotype analysis suggests potential roles for C-type natriuretic peptide receptor (NPR-B) in male mouse fertility. AB - BACKGROUND: C-type natriuretic peptide (CNP) signaling through its receptor natriuretic peptide receptor B (NPR-B) is a key molecule for mammalian reproduction, and known to play important roles in female fertility. However, the function of these peptides in mouse male reproduction remains largely unknown. To determine the role of CNP/NPR-B signaling in male reproduction we investigated phenotype of Npr2-deficient short-limbed-dwarfism (Npr2(slw/slw)) mice, which have been shown to have gastrointestinal (GI) abnormalities. FINDINGS: In homozygous Npr2(slw/slw) mice, spermatogenesis is developmentally delayed at both 2 and 4 weeks of age, with vacuolation and degenerating apoptotic germ cells being observed at 3 weeks age. However, the adult Npr2(slw/slw) mice exhibited apparently normal spermatogenesis, albeit with some aberrant spermatids, suggesting that developmental delay was overcome. In addition, the adult Npr2(slw/slw) mice showed abnormal penile morphology (paraphimosis). CONCLUSIONS: The potential role of CNP signaling via the NPR-B receptor in male fertility appears to be mediated not through germ-cell development, but may be through maintenance of normal penile function. PMID- 25012823 TI - The effect of progesterone level prior to oocyte retrieval on the numbers of oocytes retrieved and embryo quality in IVF treatment cycles: an analysis of 2,978 cycles. AB - PURPOSE: The study was designed to evaluate the relationship between serum progesterone (P4) response after hCG administration and the number of oocytes retrieved and the embryo quality in fresh IVF cycles. METHODS: We conducted a retrospective cohort study of women aged 24-43 years who underwent first fresh IVF cycle from 2011 to 2013 at a single practice. We compared the post-hCG serum P4 level with values on the day of hCG trigger. Patients were analyzed in long and short protocols independently. In addition, patients were stratified by post hCG P4 response. Number of oocytes retrieved and embryo quality were the primary outcomes of interest. Ordinary least square regression models and logistic regression analysis models were created to identify predictive factors associated with embryological outcomes while adjusting for potential confounders. RESULTS: Among the 2,978 IVF cycles, 2,484 patients were in long protocols, and 494 patients were in short protocols. After adjusting for patient age, rFSH duration, and basal FSH levels, the associations between P4 response after hCG administration and number of oocytes retrieved (P < 0.001) remained statistically significant in both long and short protocols. Additionally, mature oocyte rate, fertilization rate, good quality embryo rate, pregnancy rate and implantation rate were not significantly associated with the P4 increase when adjusting for the same factors. However, pregnancy rate and implantation rate from frozen thawed cycles increased gradually across the seven groups. CONCLUSIONS: Post-hCG P4 levels were positively associated with the number of oocytes retrieved, but did not affect oocyte or embryo quality. Our study suggests that the change in the post-hCG P4 level is another parameter that can be used by clinicians to assess the number of oocytes retrieved, and may further to estimate the pregnancy rate and live birth rate indirectly. PMID- 25012824 TI - Spontaneous closure of post-intervention left anterior descending coronary pseudoaneurysm. AB - Coronary pseudoaneurysms are an unusual finding during coronary angiography and there are very little data on their prognosis in the literature. We report the case of a 62-year-old man admitted with an anterior myocardial infarction who developed a pseudoaneurysm in the mid left anterior descending artery some days after a type I coronary perforation during coronary angioplasty. Spontaneous closure of the pseudoaneurysm was observed during hospital follow-up. Spontaneous closure of coronary pseudoaneurysms may be more common in clinical practice than previously thought, but few cases have been reported. As the natural history of post-intervention coronary pseudoaneurysms has been little investigated, reports of their occurrence may help to clarify their evolution. PMID- 25012826 TI - Practical Radiation Oncology (PRO). PMID- 25012827 TI - Quality standards in radiation medicine. AB - PURPOSE: Identifying and conducting "best practice" medicine is arguably the ubiquitous goal of practitioners. However, to distill the many available quality standards, guidelines, recommendations, and indicators down to a best practice set requires a logical schema to group standards addressing similar quality issues and, from manageable lists of related standards, to extract the essential dimensions of quality. The purpose of this study was to explore a method of collating publicly available quality standards, in this case in radiation therapy, using a 2-step decision tree approach with statistical analysis. Successful grouping into manageable lists, addressing related quality issues, informs the ongoing development of quality indicators that are one expression of "best practice." METHODS AND MATERIALS: A comprehensive literature search was used to identify quality standards currently in use and publicly available. Using 2 decision trees, 5 evaluators assigned each standard to Donabedian's structure, process, or outcome and also to the target of the standard: patients, staff, equipment or clinical process, or organization for a total of 3 * 4 = 12 primary categories. RESULTS: A total of 454 radiation medicine program quality standards spread across 8 national and international documents was identified. Agreement between the 5 evaluators, using the free marginal kappa statistic, ranged from fair to almost perfect. In all but 2% of 5 * 454 evaluations were the evaluators able to assign a statement to categories in the decision trees suggesting that these trees are appropriate to the task. In only 3/454 was a majority (>= 3/5) decision not reached on the assignment to structure, process, or outcome. Sixty four percent of the standards were identified with structure, 26% with process and 10% with outcome. CONCLUSIONS: Donabedian's model constitutes a reliable method of managing quality standards. The 2-step decision tree framework can be applied to inform the further development of national and international quality standards. PMID- 25012825 TI - The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells. AB - BACKGROUND: It has been reported that direct activation of the cannabinoid CB1 receptor in epidermal growth factor (EGR)-stimulated PC-3 prostate cancer cells results in an anti-proliferative effect accompanied by a down-regulation of EGF receptors (EGFR). In the present study, we investigated whether similar effects are seen following inhibition of the endocannabinoid hydrolytic enzyme monoacylglycerol lipase (MGL). RESULTS: CB1 receptor expression levels were found to differ greatly between two experimental series conducted using PC-3 cells. The monoacylglycerol lipase inhibitor JZL184 increased levels of 2 arachidonoylglycerol in the PC-3 cells without producing changes in the levels of anandamide and related N-acylethanolamines. In the first series of experiments, JZL184 produced a small mitogenic effect for cells that had not been treated with EGF, whereas an anti-proliferative effect was seen for EGF-treated cells. An anti proliferative effect for the EGF-treated cells was also seen with the CB receptor agonist CP55,940. In the second batch of cells, there was an interaction between JZL184 and CB1 receptor expression densities in linear regression analyses with EGFR expression as the dependent variable. CONCLUSIONS: Inhibition of MGL by JZL184 can affect EGFR expression. However, the use in our hands of PC-3 cells as a model to investigate the therapeutic potential of MGL inhibitors and related compounds is compromised by their variability of CB1 receptor expression. PMID- 25012828 TI - The safety hazard. PMID- 25012830 TI - Clinical utility of integrated positron emission tomography/computed tomography imaging in the clinical management and radiation treatment planning of locally advanced rectal cancer. AB - PURPOSE: The role of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in the staging and radiation treatment planning of locally advanced rectal cancer is ill defined. We studied the role of integrated PET/CT in the staging, radiation treatment planning, and use as an imaging biomarker in rectal cancer patients undergoing multimodality treatment. METHODS AND MATERIALS: Thirty-four consecutive patients with T3-4N0-2M0-1 rectal adenocarcinoma underwent FDG-PET/CT scanning for staging and radiation treatment planning. Planned clinical management was compared before and after the addition of PET/CT information. Three radiation oncologists independently delineated CT based gross tumor volumes (GTVCT) using clinical information and CT imaging data, as well as gradient autosegmented PET/CT-based GTVs (GTVPETCT). The mean GTV, interobserver concordance index (CCI), and proximal and distal margins were compared. The maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), and dual-time point PET parameters were correlated with clinicopathologic endpoints. RESULTS: Clinical management was altered by PET/CT in 18% (n = 6) of patients with clinical upstaging in 6 patients and radiation treatment planning altered in 5 patients. Of the 30 evaluable preoperative patients, the mean GTVPETCT was significantly smaller than the mean GTVCT volumes: 88.1 versus 102.8 cc (P = .03). PET/CT significantly increased interobserver CCI in contouring GTV compared with CT only-based contouring: 0.56 versus 0.38 (P < .001). The proximal and distal margins were altered by a mean of 0.4 +/- 0.24 cm and -0.25 +/- 0.18 cm, respectively. MTV was inversely associated with 2-year progression-free survival (PFS) and overall survival (OS): smaller MTVs (<33 cc) had superior 2 year PFS (86% vs 60%, P = .04) and OS (100% vs 45%, P < .01) compared with larger MTVs (>33 cc). SUVmax and dual-time point PET parameters did not correlate with any endpoints. CONCLUSIONS: FDG-PET/CT imaging impacts overall clinical management and is useful in the radiation treatment planning of rectal cancer patients by decreasing interobserver variability in contouring target boost volumes. Pretreatment MTV may provide useful prognostic information and requires further study. PMID- 25012829 TI - Evaluation of threshold and gradient based (18)F-fluoro-deoxy-2-glucose hybrid positron emission tomographic image segmentation methods for liver tumor delineation. AB - PURPOSE: Image segmentation methods were studied to delineate liver lesions in (18)F-fluoro-2-deoxy-glucose positron emission tomographic (FDG-PET) images. The goal of this study was to identify a clinically practical, semiautomated FDG-PET avid volume segmentation method to improve the accuracy of liver tumor contouring for treatment planning in stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Pretreatment PET-CT image sets for 26 patients who received SBRT to 28 liver lesions were delineated using the following 3 methods: (1) Percent threshold with respect to background corrected maximum standard uptake values (SUV; threshold values varied from 10% to 50% with 10% increments); (2) threshold 3 standard deviations above mean background SUV (3sigma); and (3) a gradient based method that detects the edge of the FDG-PET avid lesion (edge). For each lesion, semiautomatically generated contours were evaluated with respect to reference contours manually drawn by 3 radiation oncologists. Two similarity metrics, Dice coefficient, and mean minimal distance (MMD), were employed to assess the volumetric overlap and the mean Euclidian distance between semiautomatically and observer-drawn contours. RESULTS: Mean Dice and MMD values for 10%, 20%, 30% threshold, 3sigma, and edge varied from 0.69 to 0.73, and from 3.44 mm to 3.94 mm, respectively (ideal Dice and MMD values are 1 and 0 mm, respectively). A statistically significant difference was not observed among 10%, 20%, 30% threshold, 3sigma, and edge methods, whereas 40% and 50% methods had inferior Dice and MMD values. CONCLUSIONS: Three PET segmentation methods were identified above as potential tools to accelerate liver lesion delineation. The edge method appears to be the most practical for clinical implementation as it does not require calculation of SUV statistics. However, the performance of all segmentation methods showed large lesion-to-lesion fluctuations. Therefore, such methods may be suitable for generating initial estimates of FDG-PET avid volumes rather than being surrogates for manual volume delineation. PMID- 25012831 TI - Orbital radiation therapy for Graves' ophthalmopathy: measuring clinical efficacy and impact. AB - PURPOSE: Graves' ophthalmopathy (GO) is an autoimmune condition primarily managed with prolonged courses of glucocorticoids, which can be associated with significant side effects. Orbital radiation therapy (RT) is an alternative treatment that has shown variable efficacy in improving orbital and visual symptoms. In this study, the therapeutic benefit of RT was evaluated in terms of patient's ability to taper their corticosteroid requirements, which may better reflect the proposed mechanism of RT and provide a clinically relevant response endpoint. METHODS AND MATERIALS: This is a retrospective review of consecutive patients treated with orbital RT for GO between 2000 and 2010 at a single tertiary hospital with a dedicated ocular radiation therapy clinic. The primary measure of treatment response was defined as the ability to taper glucocorticoids following RT without any further exacerbation of orbitopathy symptoms. Additional endpoints including ocular symptoms (diplopia, proptosis, visual acuity, extraocular movement) and need for surgical intervention were reported. RESULTS: Of 86 eligible patients, with a mean follow-up of 9.3 months, 81 (94%) patients responded to RT. Of patients taking corticosteroids at baseline, 91% were able to taper off corticosteroids completely and the remaining patients had decreased their doses by 83%. Diplopia, visual acuity, and extraocular movements improved in 29%, 81%, and 58% of patients, respectively. The median reduction in proptosis was 2.5 mm and 2 mm in the left and right eyes, respectively (range, -18 mm to 23 mm). CONCLUSIONS: Orbital RT is a generally well-tolerated treatment that helps minimize the dose and duration of corticosteroid therapy for patients with GO while improving ocular symptoms, including proptosis and diplopia. Prospective research should consider using corticosteroid requirement as a measure of response to orbital RT for GO. PMID- 25012832 TI - Does early posttreatment surveillance imaging affect subsequent management following stereotactic body radiation therapy for early-stage non-small cell lung cancer? AB - PURPOSE: Uncertainty exists regarding the optimal surveillance imaging strategy following stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC), particularly with respect to timing. We sought to determine how routine use of early (<6 months) posttreatment imaging affects subsequent management. METHODS AND MATERIALS: The records of all patients treated with SBRT between January 2007 and January 2013 for early-stage NSCLC were reviewed. Eligible patients underwent >= 1 early (defined as within 6 months following SBRT) surveillance imaging study. Radiographic findings and subsequent diagnostic or therapeutic interventions were identified. Proportions and exact 95% confidence intervals (CI) with early posttreatment surveillance findings and altered treatment were calculated, and cases were examined descriptively. RESULTS: Sixty-two patients with 67 lung tumors underwent 92 early surveillance imaging studies (86 computed tomographic [CT] and 6 positron emission/CT) at a median of 2.1 months (range, 0.1-5.9 months). New lung nodules were identified in 8 patients (13%), leading to a diagnosis of metastatic disease treated with systemic therapy in 2 patients and biopsy proven solitary lung recurrence in 2 patients, both treated successfully with local therapy. Tumor growth meeting Response Evaluation Criteria in Solid Tumors (RECIST) criteria was identified in 1 patient, who was followed with subsequent radiographic regression. In aggregate, the treatment of 4 patients (6.5%, 95% CI 1.7%-15.2%) was altered by early imaging; 2 (3.2%, 95% CI 0.4%-10.8%) with a potentially curative intervention. No predictors for utility of early surveillance were identified. CONCLUSIONS: Imaging within 6 months following SBRT for early-stage NSCLC resulted in a definitive intervention in approximately 3% of patients. In the era of cost-effective health care, a first scan at 6 months posttreatment may be adequate for most patients. Larger scale prospective studies are needed to address the optimal surveillance regimen following SBRT and to identify patients who may benefit from more aggressive surveillance regimens. PMID- 25012833 TI - Supportive and palliative radiation oncology service: impact of a dedicated service on palliative cancer care. AB - PURPOSE: The American Society of Clinical Oncology has recommended tailoring palliative cancer care (PCC) to the distinct and complex needs of advanced cancer patients. The Supportive and Palliative Radiation Oncology (SPRO) service was initiated July 2011 to provide dedicated palliative radiation oncology (RO) care to cancer patients. We used care providers' ratings to assess SPRO's impact on the quality of PCC and compared perceptions of PCC delivery among physicians practicing with and without a dedicated palliative RO service. METHODS AND MATERIALS: An online survey was sent to 117 RO care providers working at 4 Boston area academic centers. Physicians and nurses at the SPRO-affiliated center rated the impact of the SPRO service on 8 PCC quality measures (7-point scale, "very unfavorably" to "very favorably"). Physicians at all sites rated their department's performance on 10 measures of PCC (7-point scale, "very poorly" to "very well"). RESULTS: Among 102 RO care providers who responded (response rate, 89% for physicians; 83% for nurses), large majorities believed that SPRO improved the following PCC quality measures: overall quality of care (physician/nurse, 98%/92%); communication with patients and families (95%/96%); staff experience (93%/84%); time spent on technical aspects of PCC (eg, reviewing imaging) (88%/56%); appropriateness of treatment recommendations (85%/84%); appropriateness of dose/fractionation (78%/60%); and patient follow-up (64%/68%). Compared with physicians practicing in departments without a dedicated palliative RO service, physicians at the SPRO-affiliated department rated the overall quality of their department's PCC more highly (P = .02). CONCLUSIONS: Clinicians indicated that SPRO improved the quality of PCC. Physicians practicing within this dedicated service rated their department's overall PCC quality higher than physicians practicing at academic centers without a dedicated service. These findings point to dedicated palliative RO services as a promising means of improving PCC quality. PMID- 25012834 TI - Feasibility of prostate robotic radiation therapy on conventional C-arm linacs. AB - PURPOSE: Significant dosimetric improvement for radiation therapy using optimized noncoplanar fields has been previously demonstrated. The purpose here is to study the feasibility of optimized robotic noncoplanar radiation therapy, termed 4pi therapy, for prostate cancer treatments on a conventional C-arm linac. METHODS AND MATERIALS: Twelve low-risk prostate cancer patients previously treated by 2 arc volumetric modulated arc therapy (VMAT) were selected. Forty gray in 5 fractions were prescribed to cover 95% of the prostate planning target volume (PTV). To replan by 4pi therapy, a column generation method was used to optimize beam orientations and fluence. A total of 30 beams were selected for each patient. RESULTS: Both planning methods provided adequate PTV coverage. Compared against VMAT plans, the 4pi plan reduced the rectum V50%, V80%, V90%, D1cc, and the penile bulb maximum doses by 50%, 28%, 19% 11%, and 9% (P < .005), respectively, and the mean body dose was reduced from 2.07 Gy to 1.75 Gy (P = .0001). The bladder dose was only slightly reduced. CONCLUSIONS: By optimizing beam angles and fluences in the noncoplanar solution space, superior prostate treatment plan quality was achieved compared against state of the art VMAT plans. The dosimetric potential for 4pi therapy is established on an existing C-arm linac platform. PMID- 25012835 TI - Analysis of setup uncertainties for extremity sarcoma patients using surface imaging. AB - PURPOSE: Proper positioning of patients with extremity sarcoma tumors can be challenging. A surface imaging technique was utilized to quantify the setup uncertainties for sarcoma patients and to assess whether surface imaging could improve the accuracy of patient positioning. METHODS AND MATERIALS: Pretreatment and posttreatment 3-dimensional (3D) surface images were obtained for 16 patients and 236 treatments. Offline surface registration was performed to quantify interfraction and intrafraction setup errors, and the required planning target volume (PTV) margins were calculated. Setup differences were also assessed using root mean square (RMS) error analysis. RESULTS: For intrafraction variation, the mean 3D vector shift was 2.1 mm, and the systematic and random errors were 1.3 mm or less. When using a reference surface from the first fraction, the mean interfraction setup variation (3D vector shift) was 7.6 mm. Systematic and random errors were 3-4 mm in each direction. When using a computed tomographic based reference surface, the mean 3D vector shift was 9.5 mm. Systematic and random errors ranged from 3.1 to 7.9 mm. The required PTV margins were 1.0 cm, 1.2 cm, and 1.3 cm in the anterior-posterior, superior-inferior, and lateral directions, respectively. The mean (standard deviation) RMS errors for the uncorrected position were 4.7 mm (1.9 mm) and were reduced to 2.2 mm (0.8 mm) and 1.7 mm (0.8 mm), for 4 degree of freedom (DOF) and 6 DOF surface alignment, respectively. CONCLUSIONS: Intrafraction motion is small. Interfraction motion can exceed typical PTV margins and daily imaging should be utilized to reduce setup variations. Surface imaging may reduce setup errors and is a feasible technique for daily image guidance. PMID- 25012836 TI - Dorsal vagal complex of the brainstem: conformal avoidance to reduce nausea. AB - PURPOSE: To investigate the role of dose to the dorsal vagal complex (DVC) as an emetic stimulus in head-and-neck cancer patients treated with intensity modulated radiation therapy but without chemotherapy. METHODS AND MATERIALS: Seventy consecutively treated patients were analyzed for factors associated with nausea. The DVC was contoured on treatment planning scans using a previously published template and mean dose to the structure was analyzed for dose response. RESULTS: Nausea occurred in 26 of 70 patients (37%). Two patients (3%) experienced grade 2 nausea, with the remainder having grade 1 nausea. On univariate analysis, dose to the DVC, age, and T-stage were the only significant predictors of nausea. The highest quartile of dose to the DVC (>3000 cGy) was associated with an incidence of nausea of 67% compared with less than 30% in each of the other 3 quartiles (P = .0255). CONCLUSIONS: Dose to the DVC of the brainstem appears to correlate with radiation-induced nausea and vomiting. Attentive treatment planning efforts can reduce dose to this critical structure and hopefully minimize the risk of nausea. PMID- 25012837 TI - Vagal and recurrent laryngeal neuropathy following stereotactic ablative radiation therapy in the chest. AB - PURPOSE: To identify clinical and dosimetric factors associated with vagus nerve (VN) and recurrent laryngeal nerve (RecLN) injury following stereotactic ablative radiation therapy (SABR) in the chest. METHODS AND MATERIALS: We examined the clinical courses and SABR plans of 67 patients treated for T1 or T2 non-small cell lung cancer of the upper right or left lung, including 2 who developed vocal cord paresis (VCP) following treatment. After developing a contouring atlas for the VN and RecLN in the thorax, dose to those structures was retrospectively determined for each patient, and we identified 12 patients whose treatment imparted significant dose to either nerve and who were assessable for more than 12 months follow-up. Biologically effective doses using linear-quadratic (LQ) and linear quadratic-linear (LQ-L) modeling were correlated with VN and RecLN toxicity. RESULTS: Of 12 patients, 2 developed VCP. The first underwent repeat SABR and received a cumulative single fraction equivalent dose (alpha/beta = 3; SFED3) of 37.4 or 64.5 Gy to the VN and 13.7 or 15.3 Gy to the RecLN (by LQ or LQ L modeling, respectively). This was the highest VN dose and fifth highest RecLN dose in the cohort. The second had rheumatoid arthritis and connective tissue disease and received a SFED3 of 16 Gy to the VN and 19.5 Gy to the RecLN (by both LQ and LQ-L modeling). This was in the upper tertile of VN and RecLN doses for the cohort. CONCLUSIONS: Following SABR for non-small cell lung cancer, VCP was associated with high cumulative dose to the VN in 1 patient and a moderately high dose to the VN and RecLN in another patient with rheumatoid arthritis and connective tissue disease. Particularly in the setting of reirradiation or connective tissue disease, potential toxicity to the VN or RecLN should be considered. PMID- 25012838 TI - Improving patient safety in the radiation oncology setting through crew resource management. AB - PURPOSE: This paper demonstrates how the communication patterns and protocol rigors of a methodology called crew resource management (CRM) can be adapted to a radiation oncology environment to create a culture of patient safety. CRM training was introduced to our comprehensive radiation oncology department in the autumn of 2009. With 34 full-time equivalent staff, we see 100-125 patients daily on 2 hospital campuses. We were assisted by a consulting group with considerable experience in helping hospitals incorporate CRM principles and practices. Implementation steps included developing change initiative skills for key leaders, providing training in teamwork and communications, creating site specific tools for safety and efficiency, and collecting data to document results. METHODS AND MATERIALS: Our goals were to improve patient safety, teamwork, communication, and efficiency through the use of tools we developed that emphasized teamwork and communication, cross-checking, and routinizing specific protocols. Our CRM plan relies on the following 4 pillars: patient identification methods; "pause for the cause"; enabling all staff to halt treatment and question decisions; and daily morning meetings. We discuss some of the hurdles to change we encountered. RESULTS: Our safety record has improved. Our near-miss rate before CRM implementation averaged 11 per month; our near-miss rate currently averages 1.2 per month. In the 5 years prior to CRM implementation, we experienced 1 treatment deviation per year, although none rose to the level of "mis-administration." Since implementing CRM, our current patient treatment setup and delivery process has eliminated all treatment deviations. Our practices have identified situations where ambiguity or conflicting documentation could have resulted in inappropriate treatment or treatment inefficiencies. Our staff members have developed an extraordinary sense of teamwork combined with a high degree of personal responsibility to assure patient safety and have spoken up when they considered something potentially unsafe. We have increased our efficiency (and profitability); in 2012, our units of service were up 11.3% over 2009 levels with the same staffing level. CONCLUSIONS: The rigor and standardization introduced into our practice, combined with the increase in communication and teamwork have improved both safety and efficiency while improving both staff and patient satisfaction. CRM principles are highly adaptable and applicable to the radiation oncology setting. PMID- 25012839 TI - Disease control and toxicity outcomes using ruthenium eye plaque brachytherapy in the treatment of uveal melanoma. AB - PURPOSE: Ruthenium-106 ((106)Ru) eye plaques have the potential to achieve excellent tumor control with acceptable radiation toxicity. We evaluated our experience in the management of uveal melanoma treated with (106)Ru brachytherapy. METHODS AND MATERIALS: The records of 40 patients with uveal melanoma treated with brachytherapy using (106)Ru plaques from 2003 to 2007 at University of Texas MD Anderson Cancer Center were reviewed. Endpoints assessed included tumor control and toxicity. RESULTS: Median ophthalmologic follow-up was 67 months. Actuarial 5-year rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were 97%, 94%, and 92%. There were 3 deaths, 2 related to melanoma. Fifteen patients experienced clinically significant visual loss; no patients were diagnosed with neovascular glaucoma, and 1 patient developed a clinically significant radiation-associated cataract. No patient required enucleation. CONCLUSIONS: We report the largest published US cohort of patients treated with (106)Ru plaque brachytherapy for uveal melanoma. Tumor control was excellent, and toxicity was acceptably low. These data support the reintroduction of (106)Ru into clinical practice for ocular melanoma. PMID- 25012840 TI - Resting energy expenditure and the clearance of therapeutic proteins in pediatric subjects. AB - The effect of age on the clearance (CL) of therapeutic proteins has not been explored extensively in pediatric subjects. Recently, resting energy expenditure (REE) has been proposed to link age-dependent CL with developmental changes. Allometric relationship was explored to assess the impact of REE on the CL of therapeutic proteins in pediatric subjects. The CL of a therapeutic protein estimated from allometric scaling using REE was approximately 2-fold higher than that using body weight (BW) in younger children. For some monoclonal antibodies, REE was a better predictor than BW to estimate CL in pediatric subjects. Overall results suggest that the relationship of CL with REE and its clinical importance in therapeutic proteins need to be investigated further for pediatric subjects. PMID- 25012841 TI - Inferior vena cava injuries: a case series and review of the South African experience. AB - INTRODUCTION: Penetrating injury may involve the major vessels in the abdomen. Injury to the abdominal inferior vena cava (IVC) is uncommon and is usually caused by gunshot wounds. Mortality from IVC injuries is high and has changed little over time. AIM: The aim of the study was to report a series of IVC injuries from an urban trauma unit and to compare this with reports from similar institutions. METHOD: A retrospective review of penetrating abdominal injuries at Kalafong Hospital from 1993 to 2010 was performed. All cases of injury to the IVC were retrieved and the following data recorded: patient demographics, incident history, origin of referral, description of the IVC injury, associated injuries, operative management, hospital stay and outcome. The results were compared to those from similar institutions. RESULTS: Twenty-seven patients with IVC injuries were treated. All were caused by gunshot wounds, and all had associated intra abdominal injuries. The majority (56%) of injuries were infrarenal. The injury was managed most commonly by venorrhaphy and, when successful, all the patients survived. A third of patients with infrarenal injuries died, some after exploration of a stable peri-caval haematoma. Ten of the patients died (37%), half of them during surgery. These results are similar to those from similar institutions from earlier time periods. CONCLUSIONS: This report concurs with other studies. IVC injury carries a high mortality rate and that this has not improved over several decades. Less aggressive management of some stable patients or stable injuries is proposed by the authors for possible improvement of the mortality rate. PMID- 25012843 TI - A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract. AB - Intrinsic sensory neurons (ISNs) of the enteric nervous system respond to stimuli such as muscle tension, muscle length, distortion of the mucosa, and the chemical content in the lumen. ISNs form recurrent networks that probably drive many intestinal motor patterns and reflexes. ISNs express a large number of voltage- and calcium-gated ion channels, some of which are modified by inflammation or repeated physiological stimuli, but how interactions between different ionic currents in ISNs produce both normal and pathological behaviors in the intestine remains unclear. We constructed a model of ISNs including voltage-gated sodium and potassium channels, N-type calcium channels, big conductance calcium dependent potassium (BK) channels, calcium-dependent nonspecific cation channels (NSCa), intermediate conductance calcium-dependent potassium (IK) channels, hyperpolarization-activated cation (Ih) channels, and internal calcium dynamics. The model was based on data from the literature and our electrophysiological studies. The model reproduced responses to short or long depolarizing current pulses and responses to long hyperpolarizing current pulses. Sensitivity analysis showed that Ih, IK, NSCa, and BK have the largest influence on the number of action potentials observed during prolonged depolarizations. The model also predicts that changes to the voltage of activation for Ih have a large influence on excitability, but changes to the time constant of activation for Ih have a minor effect. Our model identifies how interactions between different iconic currents influence the excitability of ISNs and highlights an important role for Ih in enteric neuroplasticity resulting from disease. PMID- 25012842 TI - Genetic variation in GPBAR1 predisposes to quantitative changes in colonic transit and bile acid excretion. AB - The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7alpha-hydroxy-4 cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism (KLB rs17618244 and FGFR4 rs351855), BA receptor (GPBAR1 rs11554825), serotonin (5-HT) reuptake (SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation (TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h (r = 0.43; P < 0.001) and IP (r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 (P = 0.003) and total fecal BA [P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations (P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies. PMID- 25012844 TI - Comparison of manual and semiautomated techniques for analyzing gastric volumes with MRI in humans. AB - Gastric emptying, accommodation, and motility can be quantified with magnetic resonance imaging (MRI). The first step in image analysis entails segmenting the stomach from surrounding structures, usually by a time-consuming manual process. We have developed a semiautomated process to segment and measure gastric volumes with MRI. Gastric images were acquired with a three-dimensional gradient echo MRI sequence at 5, 10, 20, and 30 min after ingestion of a liquid nutrient (Ensure, 296 ml) labeled with gadolinium in 20 healthy volunteers and 29 patients with dyspeptic symptoms. The agreement between gastric volumes measured by manual segmentation and our new semiautomated algorithm was assessed with Lin's concordance correlation coefficient (CCC) and the Bland Altman test. At 5 min after a meal, food volumes measured by manual (352 +/- 4 ml) and semiautomated (346 +/- 4 ml) techniques were correlated {CCC[95% confidence interval (CI)] 0.70 (0.52, 0.81)}; air volumes measured by manual (88 +/- 6 ml) and semiautomated (84 +/- 6 ml) techniques were also correlated [CCC (95% CI) 0.89 (0.82, 0.94)]. Findings were similar at subsequent time points. The Bland Altman test was not significant. The time required for semiautomated segmentation ranged from an average of 204 s for the 5-min images to 233 s for the 20-min images. These times were appreciably smaller than the typical times of many tens of minutes, even hours, required for manual segmentation. To conclude, a semiautomated process can measure gastric food and air volume using MRI with comparable accuracy and far better efficiency than a manual process. PMID- 25012846 TI - Birth, meaningful viability and abortion. AB - What role does birth play in the debate about elective abortion? Does the wrongness of infanticide imply the wrongness of late-term abortion? In this paper, I argue that the same or similar factors that make birth morally significant with regard to abortion make meaningful viability morally significant due to the relatively arbitrary time of birth. I do this by considering the positions of Mary Anne Warren and Jose Luis Bermudez who argue that birth is significant enough that the wrongness of infanticide does not imply the wrongness of late-term abortion. On the basis of the relatively arbitrary timing of birth, I argue that meaningful viability is the point at which elective abortion is prima facie morally wrong. PMID- 25012847 TI - Ancestor embryos: embryonic gametes and genetic parenthood. AB - The proposal for reproducing human generations in vitro raises the question to what extent parenthood is possible in embryos and to what extent human rights and interests are dependent on conscious awareness. This paper argues that the interest in not being made a parent non-consensually for the benefit of others persists throughout the lifespan of the individual human organism. We do not become genetic parents by learning that we are parents; rather, we discover (or fail to discover) an existing genetic relationship between our offspring and ourselves. The claim to genetic parenthood of an embryo used for reproduction in vitro is, if anything, clearer than the claim of the adult for whom gametes are derived via ips cells, in that an embryo's cells, unlike an adult's somatic cells, are already functionally geared to producing gametes (among other types of cell). An embryo used to make gametes that are used in reproduction is immediately and non-consensually made a genetic parent and to that extent is wronged whether or not the parent embryo survives-as some could survive-the harvesting of cells. All human individuals carry objective interests in benefits appropriate to the kind of being they are; these include the stake in not being made a parent without one's consent, whether posthumously or otherwise. PMID- 25012845 TI - The ryanodine receptor is expressed in human pancreatic acinar cells and contributes to acinar cell injury. AB - Physiological calcium (Ca(2+)) signals within the pancreatic acinar cell regulate enzyme secretion, whereas aberrant Ca(2+) signals are associated with acinar cell injury. We have previously identified the ryanodine receptor (RyR), a Ca(2+) release channel on the endoplasmic reticulum, as a modulator of these pathological signals. In the present study, we establish that the RyR is expressed in human acinar cells and mediates acinar cell injury. We obtained pancreatic tissue from cadaveric donors and identified isoforms of RyR1 and RyR2 by qPCR. Immunofluorescence staining of the pancreas showed that the RyR is localized to the basal region of the acinar cell. Furthermore, the presence of RyR was confirmed from isolated human acinar cells by tritiated ryanodine binding. To determine whether the RyR is functionally active, mouse or human acinar cells were loaded with the high-affinity Ca(2+) dye (Fluo-4 AM) and stimulated with taurolithocholic acid 3-sulfate (TLCS) (500 MUM) or carbachol (1 mM). Ryanodine (100 MUM) pretreatment reduced the magnitude of the Ca(2+) signal and the area under the curve. To determine the effect of RyR blockade on injury, human acinar cells were stimulated with pathological stimuli, the bile acid TLCS (500 MUM) or the muscarinic agonist carbachol (1 mM) in the presence or absence of the RyR inhibitor ryanodine. Ryanodine (100 MUM) caused an 81% and 47% reduction in acinar cell injury, respectively, as measured by lactate dehydrogenase leakage (P < 0.05). Taken together, these data establish that the RyR is expressed in human acinar cells and that it modulates acinar Ca(2+) signals and cell injury. PMID- 25012848 TI - Detection, differentiation, and VP1 sequencing of duck hepatitis A virus type 1 and type 3 by a 1-step duplex reverse-transcription PCR assay. AB - Duck hepatitis A virus (DHAV) is an infectious pathogen causing fatal duck viral hepatitis in ducklings. Although both the inactivated vaccines and live attenuated vaccines have been used to protect ducklings, DHAV-1 and DHAV-3 still cause significant serious damage to the duck industry in China and South Korea. For rapid detection, differentiation, and epidemic investigation of DHAV in China, a genotype-specific 1-step duplex reverse-transcription (RT) PCR assay was established in this study. The sensitivity and specificity of the developed RT PCR assay was evaluated with nucleic acids extracted from 2 DHAV reference strains, and 9 other infectious viruses and bacteria. The genotype-specific primers amplified different size DNA fragments encompassing the complete VP1 gene of the DHAV-1 or DHAV-3. The assay detected the liver samples collected from experimentally infected ducklings and dead ducklings collected from different regions of China. Sequence analysis of these DNA fragments indicated that VP1 sequences of DHAV-1 can be used to distinguish wild type and vaccine strains. The phylogenetic analysis of VP1 sequences indicated that the developed RT-PCR assay can be used for epidemic investigation of DHAV-1 and DHAV-3. The developed RT-PCR assay can be used as a specific molecular tool for simultaneous detection, differentiation, and sequencing the VP1 gene of DHAV-1 and DHAV-3, which can be used for understanding the epidemiology and evolution of DHAV. PMID- 25012849 TI - Formulating poultry diets based on their indigestible components. AB - Since it started as an organized economic activity, poultry production has been undergoing an evolution toward the optimization of its feed formulation features. Notably, advances in the knowledge of birds' nutrient requirements have allowed recommendations that are increasingly closer to the needs of the birds. Over time, availability of nutrients and energy has been incorporated into those recommendations, especially to compensate for the variability in the digestibility of nutrients originating from variable feed ingredient sources. Instead of using the total energy and nutrient content, current tables of nutrient recommendations provide an estimate of the digestible fractions of the nutrients in ingredients. For instance, nonphytate P is preferred instead of total P to account for the unavailable phytate P, and digestible amino acids to account for the differences in digestibility of amino acids in different ingredients, whereas energy is usually expressed as a proportion that has been digested and metabolized (AME). With the increasing interest in the use of exogenous enzymes in poultry feeds, special attention is directed to the feed substrates such that an added enzyme can match it, forming an enzyme-substrate complex that will be followed by a chemical reaction within the gastrointestinal tract. As a consequence of a degradation reaction, nutrients released can be absorbed and metabolized. In general, nutritional data banks used in linear feed formulation software have limited data on the proportions of fractions of ingredients that are indigestible. Therefore, estimations of the presence of many substrates in the feeds, and therefore the benefits of adding exogenous enzymes, are frequently limited because of the scarcity of adequate information. The objective of this review paper is to provide insights into the use of expanded nutrient databanks to include all the molecules considered potentially indigestible for poultry such that the inclusion of exogenous enzymes allows the estimation of the values of the product originated by their hydrolysis. PMID- 25012850 TI - Combination of muscle tension and crust-freeze-air-chilling improved efficacy of air chilling and quality of broiler fillets. AB - The objective of this study was to evaluate the effects of water immersion chilling (WIC), air chilling (AC), and crust-freeze-air-chilling (CFAC) on the efficacy of broiler chilling and quality of breast fillets with and without muscle tension (MT), restraining both wings behind the carcass. In each of 3 replications, 66 birds were purchased locally and processed at the Michigan State University meat laboratory. After evisceration, one-half of the birds were subjected to MT and the remaining birds received no MT. Twenty-two birds (11 with and 11 without MT) per chilling were randomly assigned to WIC (ice/water slurry at 0.2 degrees C), AC (air at 1 degrees C/1.5 m/s), or CFAC (air at -12 degrees C/1.5 m/s). After chilling and aging for 3 h postmortem (PM), all breast fillets were deboned, one-half of which were immediately quick-frozen or cooked, whereas the remaining half were further aged on ice for 24 h PM. All left fillets were used for pH, R-value, and sarcomere measurements, whereas all right fillets were used for shear force. During chilling, breast temperature was reduced from 40 to 4 degrees C in an average of 62, 68, and 140 min for WIC, CFAC, and AC, respectively. The birds at 3 h PM had higher pH and shear force than those of birds at 24 h PM except the CFAC with no MT (P < 0.05). Breast fillets with MT showed lower shear force than the fillets without MT at 24 h PM (P < 0.05) in AC and CFAC. Based on these findings, the combination of CFAC and MT appears to improve both air chilling efficacy and breast fillet quality. PMID- 25012851 TI - Why is it important to understand substrates if we are to optimize exogenous enzyme efficacy? AB - The use of exogenous enzymes in feeds for poultry has increased dramatically between 1990 and 2013. Today, the use of enzymes is broad, going beyond phytases and beta-glucanases and xylanases to include other carbohydrases and proteases as well as lipases. The number of scientific articles and publications related to enzymes in feed clearly shows that this has been an area of intense and broad interest for scientists and nutritionists. However, knowledge of the different substrates available in the feed and how these substrates change depending on feed ingredient selection has not received the same level of attention. Understanding substrates is key to better developing and implementing exogenous enzymes. Of importance today is to potentiate endogenous digestive capabilities and use exogenous enzymes to optimize nutrient digestion and use. Our aim with this symposium was to call attention to the importance of having a more in-depth knowledge about substrates and to fill the large gaps in our current understanding of the digestive processes in poultry. PMID- 25012852 TI - Muscle hypertrophy in heavy weight Japanese quail line: delayed muscle maturation and continued muscle growth with prolonged upregulation of myogenic regulatory factors. AB - The objective of this study was to compare the temporal expression of myosin heavy chain (MyHC) isoforms, Pax7, and myogenic regulatory factors (MRF) between heavy weight (HW) and random bred control (RBC) Japanese quail lines during muscle development to better understand the mechanisms leading to increased skeletal muscle mass in the HW quail line selected for a greater BW at 4 wk of age separated from RBC quail. Expression of neonatal MyHC isoform began at 3 and 7 d posthatch in RBC and HW quail lines, respectively. In the RBC quail line, adult MyHC isoform, as a marker for muscle maturation, was expressed at 28 d posthatch with sustained expression through 75 d posthatch, whereas this protein was detected only at 75 d posthatch in the HW quail line. Moreover, Pax7 expression continued from embryonic ages to 14 d posthatch in the HW quail line and to 7 d posthatch in the RBC quail line. These expression patterns of MyHC isoforms and Pax7 in the HW quail line were accompanied by delayed muscle maturation and prolonged growth compared with the RBC quail line. Temporal expressions of the primary MRF showed that higher expression levels of MyoD and Myf-5 were observed at 9 and 11 d embryo in the HW quail line compared with the RBC quail line (P < 0.05). The HW quail line exhibited approximately 2 times greater average levels of myogenin expression from 7 to 75 d posthatch (P < 0.05) than the RBC quail line. Prolonged upregulation of these primary and secondary MRF during muscle development is associated with delayed maturation and continued muscle growth, which consequently would permit muscle hypertrophic potentials in the HW quail line compared with the RBC quail line. PMID- 25012853 TI - Starch digestion capacity of poultry. AB - Starch is quantitatively the most important nutrient in poultry diets and will to a large extent be present as intact starch granules due to very limited extent of gelatinization during pelleting. Although native starch is difficult to digest due to a semi-crystalline structure, even fast-growing broiler chickens appears to be able to digest this starch more or less completely during passage through the jejunum. However, reduced starch digestibility has been observed, particularly in pelleted diets containing large quantities of wheat. Although properties of the starch granule such as size and components on the granule surface may affect digestibility, the entrapment of starch granules in cell walls and a protein matrix may be even more important factors impeding starch digestion. In that case, this and the fact that amylase secretion is normally very high in poultry may explain the lack of convincing effects of exogenous alpha-amylase added to the diet. However, few well-designed experiments assessing mechanisms of starch digestion and the effect of alpha-amylase supplementation have been carried out, and thus more research is needed in this important area. PMID- 25012854 TI - Cold-batter mincing of hot-boned and crust-frozen air-chilled turkey breast allows for reduced sodium content in protein gels. AB - The purpose of this research was to evaluate sodium reduction in the protein gels that were prepared with turkey breasts after hot boning (HB), quarter (1/4) sectioning, crust-frozen air-chilling (CFAC), and cold temperature mincing. For each of 4 replications, 36 turkeys were slaughtered and eviscerated. One-half of the carcasses were randomly assigned to water immersion chilling for chill boning (CB), whereas the remaining carcasses were immediately HB and quarter sectioned/crust-frozen air-chilled (HB-1/4CFAC) in a freezing room (-12 degrees C, 1.0 m/s). After deboning, CB fillets were conventionally minced, whereas HB 1/4CFAC fillets were cold minced up to 27 min with 1 or 2% salt. From the beginning of mincing, the batter temperatures of HB-1/4CFAC were lower (P < 0.05) than those of CB batters up to 12 and 21 min for 2 and 1% salts, respectively. Upon mincing, the batter pH of the HB-1/4CFAC (P < 0.05) rapidly decreased and was not different (P > 0.05) from the pH of CB batters, except for the 1% salt HB 1/4CFAC batter after 15 min of mincing. The pattern of pH was not changed when the batters were stored overnight. The protein of 2% salt HB-1/4CFAC fillets was more extractable (P < 0.05) than that of CB fillets at 9, 12, 18, and 24 min. Similarly, the protein of 1% salt HB-1/4CFAC fillets was more extractable (P < 0.05) than that of CB fillets from 12 min. Stress values of 2% salt HB-1/4CFAC gels were higher (P < 0.05) than those of 1 and 2% salt CB gels, with intermediate values for 1% salt HB-1/4CFAC gels. In the scanning electron microscope image, prerigor batter appears to have more open space, less protein aggregation, and more protein-coated fat particles than those of postrigor batters. Based on these results, the combination of HB-1/4CFAC and cold-batter mincing technologies appear to improve protein functionality and sodium reduction capacity. PMID- 25012855 TI - Fiber and nonstarch polysaccharide content and variation in common crops used in broiler diets. AB - The current paper reviews content and variation in fiber and nonstarch polysaccharides (NSP) of common crops used in broiler diets. The cereal grain is a complex structure, and its cell walls (CW) differ in their composition and hence properties. Arabinoxylan (AX), mixed linkage (1->3; 1->4)-beta-glucan (beta glucan), cellulose, and the noncarbohydrate component lignin are the predominant polymers in cereals. They occur in different proportions depending on the species and tissue type. Rye, triticale, wheat, corn, and sorghum are all rich in AX, whereas barley and oats contain a high level of beta-glucan. The AX from rye, wheat, and triticale and beta-glucan from barley and oats are to a large extent soluble, whereas the solubility of AX found in corn and sorghum is lower than the other cereals. The ratio of arabinose to xylose gives a crude indication of the AX structure, which varies between the endosperm, the aleurone and the outer grain layers as well as between the same tissues from different grains. Varietal differences in AX structure of the endosperm are also identified. From the analysis of the released oligomers after hydrolysis with a specific (1->3,1->4) beta-d-glucan hydrolase, it is found that the ratio of trisaccharides (degree of polymerization 3) and tetrasaccharides (degree of polymerization 4) varies depending on the source, being higher in barley than in oats but lower than in wheat. The molecular weight of beta-glucan is higher than that of AX, and both polymers contribute to the viscosity of the extract. However, because AX molecules are more resistant to degradation than beta-glucan, the use of AX rich grains in broiler diets is usually more problematic than those containing high concentrations of beta-glucan. The cereal coproducts (brans and hulls) are concentrated sources of cellulose, lignin, and insoluble AX, but beta-glucan can also be present mainly in rye and wheat brans. The CW composition of seeds and grains of protein crops and feedstuffs are different from that of cereals. The main CW polymers are pectic substances (homogalacturonan, rhamnogalacturonan type I and II, xylogalacturonan, and arabinogalactans type I and II), xyloglucans, and cellulose, but there are significant differences in the composition of the parenchymatous (cotyledon) tissues and that of the hulls. In the hulls, cellulose is the predominant polysaccharide, followed by acidic xylans and pectic substances. The implications of the heterogeneous CW for the action of exogenous enzymes are discussed. PMID- 25012856 TI - Applications of a bis-urea phenylethynylene self-assembled nanoreactor for [2 + 2] photodimerizations. AB - Confined environments can be used to alter the selectivity of a reaction by influencing the organization of the reactants, altering the mobility of trapped molecules, facilitating one reaction pathway or selectively stabilizing the products. This manuscript utilizes a series of potentially photoreactive guests to interrogate the utility of the one-dimensional nanochannels of a porous host to absorb and facilitate the reaction of encapsulated guests. The host is a columnar self-assembled phenylethynylene bis-urea macrocycle, which absorbs guests, including coumarin, 6-methyl coumarin, 7-methyl coumarin, 7-methoxy coumarin, acenaphthylene, cis-stilbene, trans-stilbene, and trans-beta methylstyrene to afford crystalline inclusion complexes. We examine the structure of the host:guest complexes using powder X-ray diffraction, which suggests that they are well-ordered highly crystalline materials. Investigations using solid state cross-polarized magic angle spinning (13)C{(1)H}CP-MAS NMR spectroscopy indicate that the guests are mobile relative to the host. Upon UV-irradiation, we observed selective photodimerization reactions for coumarin, 6-methyl coumarin, 7 methyl coumarin, and acenaphthylene, while the other substrates were unreactive even under prolonged UV-irradiation. Grand Canonical Monte Carlo simulations suggest that the reactive guests were close paired and preorganized in configurations that facilitate the photodimerization with high selectivity while the unreactive guests did not exhibit similar close pairing. A greater understanding of the factors that control diffusion and reaction in confinement could lead to the development of better catalysts. PMID- 25012857 TI - Cost-effectiveness analysis of everolimus plus exemestane versus exemestane alone for treatment of hormone receptor positive metastatic breast cancer. AB - Everolimus in combination with exemestane significantly improved progression-free survival compared to exemestane alone in patients previously treated with non steroidal aromatase inhibitors in the BOLERO-2 trial. As a result, this combination has been approved by the food and drug administration to treat postmenopausal women with hormone receptor positive and HER2 negative metastatic breast cancer. A cost-effectiveness analysis was conducted to determine whether everolimus represents good value for money, utilizing data from BOLERO-2. A decision-analytic model was used to estimate the incremental cost-effectiveness ratio between treatment arms of the BOLERO-2 trial. Costs were obtained from the Center for Medicare Services drug payment table and physician fee schedule. Benefits were expressed as quality-adjusted progression-free survival weeks (QAPFW) and quality-adjusted progression-free years (QAPFY), with utilities/disutilities derived from the literature. Deterministic and probabilistic sensitivity analyses were performed. A willingness to pay threshold of 1-3 times the per capita gross domestic product was adopted, as per the definition of the World Health Organization. The U.S. per capita gross domestic product in 2013 was $49,965; thus, a threshold varying between $49,965 and $149,895 was considered. Everolimus/exemestane had an incremental benefit of 11.88 QAPFW (0.22 QAPFY) compared to exemestane and an incremental cost of $60,574. This translated into an ICER of $265,498.5/QAPFY. Univariate sensitivity analyses showed important variations of the ICER, ranging between $189,836.4 and $530,947/QAPFY. A tornado analysis suggested that the key drivers of our model, by order of importance, included health utility value for stable disease, everolimus acquisition costs, and transition probabilities from the stable to the progression states. The Monte-Carlo simulation showed results that were similar to the base-case analysis. This cost-effectiveness analysis showed that everolimus plus exemestane is not cost-effective compared to exemestane alone. Further research is needed to investigate the cost-effectiveness of the drug combination within sub-groups of the population studied in BOLERO-2. PMID- 25012858 TI - Impacts and limitations of recycling. PMID- 25012859 TI - Activated carbon from pyrolysis of brewer's spent grain: Production and adsorption properties. AB - Brewer's spent grain is a low cost residue generated by the brewing industry. Its chemical composition (high nitrogen content 4.35 wt.%, fibres, etc.) makes it very useful for the production of added value in situ nitrogenised activated carbon. The composition of brewer's spent grain revealed high amounts of cellulose (20.8 wt.%), hemicellulose (48.78 wt.%) and lignin (11.3 wt.%). The fat, ethanol extractives and ash accounted for 8.17 wt.%, 4.7 wt.% and 3.2 wt.%, respectively. Different activated carbons were produced in a lab-scale pyrolysis/activation reactor by applying several heat and steam activation profiles on brewer's spent grain. Activated carbon yields from 16.1 to 23.6 wt.% with high N-contents (> 2 wt.%) were obtained. The efficiency of the prepared activated carbons for phenol adsorption was studied as a function of different parameters: pH, contact time and carbon dosage relative to two commercial activated carbons. The equilibrium isotherms were described by the non-linear Langmuir and Freundlich models, and the kinetic results were fitted using the pseudo-first-order model and the pseudo-second-order model. The feasibility of an activated carbon production facility (onsite and offsite) that processes brewer's spent grain for different input feeds is evaluated based on a techno-economic model for estimating the net present value. Even though the model assumptions start from a rather pessimistic scenario, encouraging results for a profitable production of activated carbon using brewer's spent grain are obtained. PMID- 25012860 TI - Catalytic pyrolysis of waste furniture sawdust for bio-oil production. AB - In this study, the catalytic pyrolysis of waste furniture sawdust in the presence of ZSM-5, H-Y and MCM-41 (10 wt % of the biomass sample) was carried out in order to increase the quality of the liquid product at the various pyrolysis temperatures of 400, 450, 500 and 550(o)C. In the non-catalytic work, the maximum oil yield was obtained as 42% at 500(o)C in a fixed-bed reactor system. In the catalytic work, the maximum oil yield was decreased to 37.48, 30.04 and 29.23% in the presence of ZSM-5, H-Y and MCM-41, respectively. The obtained pyrolysis oils were analyzed by various spectroscopic and chromatographic techniques. It was determined that the use of a catalyst decreased acids and increased valuable organics found in the bio-oil. The removal of oxygen from bio-oil was confirmed with the results of the elemental analysis and gas chromatography-mass spectrometry. PMID- 25012861 TI - By-products from the biodiesel chain as a substrate to citric acid production by solid-state fermentation. AB - In this study, we propose the use of tung cake for the production of organic acids, with an emphasis on citric acid by solid-state fermentation. We evaluated the conditions of production and the by-products from the biodiesel chain as raw materials involved in this bioprocess. First, we standardized the conditions of solid-state fermentation in tung cake with and without residual fat and with different concentrations of glycerine using the fungus Aspergillus niger The solid-state fermentation process was monitored for 7 days considering the biomass growth and pH level. Citric acid production was determined by high-performance liquid chromatography. Fungal development was better in the crude tung cake, consisting of 20% glycerine. The highest citric acid yield was 350 g kg(-1) of biomass. Therefore, the solid-state fermentation of the tung cake with glycerine led to citric acid production using the Aspergillus niger fungus. PMID- 25012862 TI - Novel role of the antimicrobial peptide LL-37 in the protection of neutrophil extracellular traps against degradation by bacterial nucleases. AB - Neutrophil extracellular traps (NETs) have been described as a fundamental innate immune defence mechanism. They consist of a nuclear DNA backbone associated with different antimicrobial peptides (AMPs) which are able to engulf and kill pathogens. The AMP LL-37, a member of the cathelicidin family, is highly present in NETs. However, the function of LL-37 within NETs is still unknown because it loses its antimicrobial activity when bound to DNA in the NETs. Using immunofluorescence microscopy, we demonstrate that NETs treated with LL-37 are distinctly more resistant to S. aureus nuclease degradation than nontreated NETs. Biochemical assays utilising a random LL-37-fragment library indicated that the blocking effect of LL-37 on nuclease activity is based on the cationic character of the AMP, which facilitates the binding to neutrophil DNA, thus protecting it from degradation by the nuclease. In good correlation to these data, the cationic AMPs human beta defensin-3 and human neutrophil peptide-1 showed similar protection of neutrophil-derived DNA against nuclease degradation. In conclusion, this study demonstrates a novel role of AMPs in host immune defence: beside its direct antimicrobial activity against various pathogens, cationic AMPs can stabilise neutrophil-derived DNA or NETs against bacterial nuclease degradation. PMID- 25012863 TI - Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. AB - The hypothalamic-pituitary-gonadal (HPG) axis is active in the midgestational foetus but silenced towards term because of the negative feedback effects mediated by the placental hormones. This restraint is removed at birth, leading to reactivation of the axis and an increase in gonadotrophin levels. Gonadotrophin levels are high during the first 3 months of life but decrease towards the age of 6 months except for FSH levels in girls that remain elevated until 3-4 years of age. After this, the HPG axis remains quiescent until puberty. The postnatal gonadotrophin surge results in gonadal activation in both sexes. In boys, testosterone levels rise to a peak at 1-3 months of age and then decline following LH levels. Postnatal HPG axis activation is associated with penile and testicular growth and therefore considered important for the development of male genitalia. In girls, elevated gonadotrophin levels result in the maturation of ovarian follicles and in an increase in oestradiol levels. Biological significance and possible long-term consequences of this minipuberty remain elusive, as do the mechanisms that silence the HPG axis until puberty. However, the first months of life provide a 'window of opportunity' for functional studies of the HPG axis prior to pubertal development. PMID- 25012865 TI - Efficacy of antibiotics and non-steroidal anti-inflammatory drugs in non complicated acute bronchitis. PMID- 25012864 TI - Training modalities in robot-mediated upper limb rehabilitation in stroke: a framework for classification based on a systematic review. AB - Robot-mediated post-stroke therapy for the upper-extremity dates back to the 1990s. Since then, a number of robotic devices have become commercially available. There is clear evidence that robotic interventions improve upper limb motor scores and strength, but these improvements are often not transferred to performance of activities of daily living. We wish to better understand why. Our systematic review of 74 papers focuses on the targeted stage of recovery, the part of the limb trained, the different modalities used, and the effectiveness of each. The review shows that most of the studies so far focus on training of the proximal arm for chronic stroke patients. About the training modalities, studies typically refer to active, active-assisted and passive interaction. Robot-therapy in active assisted mode was associated with consistent improvements in arm function. More specifically, the use of HRI features stressing active contribution by the patient, such as EMG-modulated forces or a pushing force in combination with spring-damper guidance, may be beneficial.Our work also highlights that current literature frequently lacks information regarding the mechanism about the physical human-robot interaction (HRI). It is often unclear how the different modalities are implemented by different research groups (using different robots and platforms). In order to have a better and more reliable evidence of usefulness for these technologies, it is recommended that the HRI is better described and documented so that work of various teams can be considered in the same group and categories, allowing to infer for more suitable approaches. We propose a framework for categorisation of HRI modalities and features that will allow comparing their therapeutic benefits. PMID- 25012866 TI - Endothelin system mRNA variation in the heart of Zucker rats: evaluation of a possible balance with natriuretic peptides. AB - BACKGROUND AND AIMS: The deregulation of neurohormonal systems, including the natriuretic peptide (NP) and endothelin (ET) systems, may increase the possibility of developing obesity-related risk. The aim of our paper was to evaluate ET system mRNA variation in heart of the Zucker rat model together with the simultaneous evaluation of the NP system transcriptomic profile. In order to analyze the link between the ET-1 system and the inflammatory process, the cardiac expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha was also measured. METHODS AND RESULTS: Zucker rats of 11-13 weeks were subdivided into obese rats (O, n = 20) and controls (CO, n = 20): half of them were studied under fasting conditions (CO(fc)-O(fc)) and the remainder after the induction of acute hyperglycemia (CO(AH)-O(AH)). Cardiac mRNA expression of TNF alpha, IL-6, and NP/ET-1 systems was evaluated by Real-Time polymerase chain reaction. No significant difference for pre-proET-1, ET-A, and ET-B mRNA expression was detected between O and CO, whereas significantly lower mRNA levels of the ECE-1 were observed in O (p = 0.02). Regarding NPs, only BNP mRNA expression decreased significantly in O with respect to CO (p = 0.01). A down regulation of NPR-B and NPR-C and an up-regulation of NPR-A were observed in O. No significant difference for IL-6 and TNF-alpha mRNA was revealed. Subdividing into fasting and hyperglycemic rats, many of the genes studied maintained their mRNA expression pattern almost unchanged. CONCLUSIONS: The modulation of ET-1/NP systems in obesity could be a useful starting point for future studies aimed at identifying new therapeutic strategies for the treatment of cardiometabolic syndrome. PMID- 25012868 TI - Sphere-forming-like cells (squamospheres) with cancer stem-like cell traits from VX2 rabbit buccal squamous cell carcinoma. AB - Previous studies have demonstrated that spheroid type cells grown under suspension culture conditions have cancer stem cell (CSC) traits in a number of cancers, but this phenomenon has not yet been reported in the VX2 rabbit oral cancer model. Hence, this study aimed to study the spheroid cells from VX2 rabbit buccal squamous cell carcinomas (SCCs) and assess their CSC characteristics. Five adult male New Zealand white outbred rabbits were used to generate VX2 rabbit buccal SCC. Sphere-forming cell culture was performed for the VX2 rabbit buccal SCC specimens. The self-renewal capability; cluster of designation (CD) 44, CD133, acetaldehyde dehydrogenase 1 (ALDH1), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), Nestin, octamer-binding transcription factor 4 (Oct4) and reduced expression protein-1 (Rex-1) expression with reverse transcription-polymerase chain reaction (RT-PCR); chemoresistance to cisplatin and 5-fluorouracil; and in vivo tumorigenicity of spheroid cell transplantation in nude mice were evaluated to determine the CSC characteristics of the resulting spheroid cells. We successfully obtained spheroid cells from the VX2 rabbit OSCC tissues. The spheroid cells exhibited CSC traits, including the expression of CSC and stem cell markers (CD44, Bmi-1, Nestin, Oct4 and Rex-1), capacity to generate new spheroid colonies within 1 week of reseeding from single-dissociated spheroid cells, chemoresistance capacity and generation of tumour xenografts (with histological features resembling those of the original VX2 rabbit buccal SCC) from the transplantation of 10(3) undifferentiated spheroid cells into nude mice. In summary, we demonstrated that spheroid cells with CSC cell traits can be derived from VX2 rabbit buccal SCCs, indicating that this animal cancer model is applicable for studying CSCs in human oral cancers. PMID- 25012867 TI - Plasma proteins predict conversion to dementia from prodromal disease. AB - BACKGROUND: The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. METHODS: Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. RESULTS: Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). CONCLUSIONS: We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints. PMID- 25012871 TI - Lexical effects in word naming in spanish children. AB - Reading strategies depend on the consistency of the orthographic system. Recently the use of lexical strategies at early stages of reading acquisition has been shown even in transparent orthographies. The aim of this study was to know how different lexical and sublexical variables affect the reaction times (RTs) and articulation times (ATs) in word reading in Spanish children. A group of 46 children of typical reading level in the second and fourth grades of primary school were asked to read aloud 100 words presented on a computer screen. The stimuli were morphologically simple nouns with different ranges of length, frequency, imageability, orthographic neighbors and age of acquisition (AoA). Reading and articulation time were measured. Differences between means of the second and the fourth grade were seen in RTs (p < .001; Cohens' d = 1.41) and ATs (p < 001;Cohen's d = 1.41) in a t-test. Analyses of mixed-effects revealed that word length, a sublexical variable, and frequency and AoA, lexical variables, affected both grades, mainly on the RTs. The presence of lexical variables reducing RTs and ATs in second grade suggests that lexical reading is present from very early stages in Spanish children. PMID- 25012869 TI - Bacterial entombment by intratubular mineralization following orthograde mineral trioxide aggregate obturation: a scanning electron microscopy study. AB - The time domain entombment of bacteria by intratubular mineralization following orthograde canal obturation with mineral trioxide aggregate (MTA) was studied by scanning electron microscopy (SEM). Single-rooted human premolars (n=60) were instrumented to an apical size #50/0.06 using ProFile and treated as follows: Group 1 (n=10) was filled with phosphate buffered saline (PBS); Group 2 (n=10) was incubated with Enterococcus faecalis for 3 weeks, and then filled with PBS; Group 3 (n=20) was obturated orthograde with a paste of OrthoMTA (BioMTA, Seoul, Korea) and PBS; and Group 4 (n=20) was incubated with E. faecalis for 3 weeks and then obturated with OrthoMTA-PBS paste. Following their treatments, the coronal openings were sealed with PBS-soaked cotton and intermediate restorative material (IRM), and the roots were then stored in PBS for 1, 2, 4, 8 or 16 weeks. After each incubation period, the roots were split and their dentin/MTA interfaces examined in both longitudinal and horizontal directions by SEM. There appeared to be an increase in intratubular mineralization over time in the OrthoMTA-filled roots (Groups 3 and 4). Furthermore, there was a gradual entombment of bacteria within the dentinal tubules in the E. faecalis inoculated MTA-filled roots (Group 4). Therefore, the orthograde obturation of root canals with OrthoMTA mixed with PBS may create a favorable environment for bacterial entombment by intratubular mineralization. PMID- 25012872 TI - Evaluation of response to immunotherapy: new challenges and opportunities for PET imaging. PMID- 25012870 TI - Expression of cyclin-dependent kinase inhibitor 2A 16, tumour protein 53 and epidermal growth factor receptor in salivary gland carcinomas is not associated with oncogenic virus infection. AB - It is known that human papillomavirus (HPV) infection can cause squamous cell neoplasms at several sites, such as cervix uteri carcinoma and oral squamous carcinoma. There is little information on the expression of HPV and its predictive markers in tumours of the major and minor salivary glands of the head and neck. We therefore assessed oral salivary gland neoplasms to identify associations between HPV and infection-related epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitor 2A (CDKN2A/p16) and tumour protein p53 (TP53). Formalin-fixed, paraffin-embedded tissue samples from oral salivary gland carcinomas (n=51) and benign tumours (n=26) were analysed by polymerase chain reaction (PCR) analysis for several HPV species, including high-risk types 16 and 18. Evaluation of EGFR, CDKN2A, TP53 and cytomegalovirus (CMV) was performed by immunohistochemistry. Epstein-Barr virus (EBV) was evaluated by EBV-encoded RNA in situ hybridisation. We demonstrated that salivary gland tumours are not associated with HPV infection. The expression of EGFR, CDKN2A and TP53 may be associated with tumour pathology but is not induced by HPV. CMV and EBV were not detectable. In contrast to oral squamous cell carcinomas, HPV, CMV and EBV infections are not associated with malignant or benign neoplastic lesions of the salivary glands. PMID- 25012873 TI - Very high residual volumes should not prevent transurethral resection of the prostate being offered to men presenting with urinary retention. AB - OBJECTIVE: The aim of this study was to identify factors at presentation that can help to predict outcomes and guide subsequent management decisions in patients with acute on chronic retention. MATERIAL AND METHODS: The medical notes of 187 consecutive patients presenting with urinary retention at two teaching hospitals between 2008 and 2009 were reviewed. All patients were followed up for a minimum of 3 years. All patients were catheterized at presentation. The majority then underwent one or more of trial without catheter (TWOC), transurethral resection of the prostate (TURP) (both considered successful if the patient voided with a subsequent postvoid residual volume of <200 ml on three successive occasions) or long-term catheterization. Patient factors such as age, associated acute kidney injury (AKI), performance status, residual volume, prior lower urinary tract symptoms (LUTS), treatment of LUTS, diagnosis of diabetes and neuropathy were recorded. RESULTS: Increasing age (p = 0.002) and increasing residual volume (p = 0.046) were associated with a significant increase in the failure of TWOC. The rate of AKI increased significantly with residual volume (p < 0.0001). As residual volume increased so did the likelihood that a patient would undergo TURP (p = 0.0009). Age did not appear to influence the outcome of TURP (p = 0.17). Increasing residual volume did not significantly reduce the likelihood of successful TURP (p = 0.068). CONCLUSIONS: High residual volumes should not preclude TURP. There is a clear correlation between AKI and residual volume. Increasing age and residual volume both reduce the likelihood of successful TWOC. PMID- 25012874 TI - Explosion of the urinary bladder during transurethral resection of the prostate. AB - Transurethral resection of the prostate (TURP) remains the gold standard for the surgical treatment of benign prostatic hyperplasia. Complications during the procedure are rare. An extremely rare complication is a rupture of the urinary bladder. This article reports a case where an explosion occurred during TURP, resulting in a large intraperitoneal rupture of the urinary bladder. The patient underwent emergency laparotomy to repair the bladder. PMID- 25012875 TI - Seasonal changes in symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome: a seasonal follow-up study. AB - OBJECTIVE: The aim of this study was to evaluate whether seasonal changes aggravate the symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), by serial administration of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire for an extended period. MATERIAL AND METHODS: Seventy-seven men with CP/CPPS were serially evaluated with the Korean version of the NIH-CPSI questionnaire every 2-3 months from October 2008 to October 2012. The mean duration of follow-up was 27.11 +/- 10.00 months and the mean number of visits per patient was 14.68 +/- 5.33 times during the study. RESULTS: The number of patients complaining of breakthrough pain during the study was 31 in spring and autumn, nine in summer and 18 in winter. However, there were no significant differences in the mean NIH-CPSI scores across the seasons. In spring, summer and autumn, only urination symptoms correlated with quality of life (QoL) (r(2) = 0.277, p < 0.001). In winter, both pain items and urination symptoms correlated with QoL (pain: r(2) = 0.522, p < 0.001; urination symptoms: r(2) = 0.250, p < 0.001). CONCLUSION: Although fewer severe pain attacks occurred in summer, the mean NIH-CPSI scores did not differ across seasons. The pain from CP/CPPS had a greater impact on QoL during winter than it did in the other seasons. In addition, pain was a more significant determinant of QoL than urination symptoms during winter. PMID- 25012876 TI - Processing of situational information in story problem texts. An analysis from on line measures. AB - In three experiments, we investigated the extent to which readers process information related to the construction of a situation model when they are confronted with solving word problems. Considering that generation of inferences to match actions with particular goals is part of constructing of the situation model, we constructed "rich story problems", that is, word problems included in the context of a story, in which the characters propose goals, and then these goals are followed by actions to achieve it. In Experiments 1 and 2 the story problems were designed so that the character's goal was related to the activation of a problem schema, either explicitly (Experiment 1) or implicitly (Experiment 2). In Experiment 3 the problem schema activation was clearly separated from the goal information. In all three experiments, goal information availability was assessed by on-line measures. The results showed that participants processed situational information by keeping track of characters' goals. These results fit nicely with those studies that emphasize the role of situation model construction in word problem solving. PMID- 25012877 TI - Clostridium difficile 027 increasing detection in a teaching hospital in Rome, Italy. PMID- 25012878 TI - [True segmental neurofibromatosis]. PMID- 25012879 TI - Detection of cancer cells using triplex DNA molecular beacons based on expression of enhanced green fluorescent protein (eGFP). AB - A novel strategy was proposed for Ramos cell detection by combining the expression of enhanced green fluorescent protein (eGFP) with the cell aptamer recognition and the triplex molecular beacons. This system was successfully applied to cancer cell detection with high sensitivity and specificity. PMID- 25012880 TI - The quality of general movements after treatment with low-dose dexamethasone in preterm infants at risk of bronchopulmonary dysplasia. AB - BACKGROUND: High-dose dexamethasone (DXM) treatment of preterms at risk of bronchopulmonary dysplasia leads to a deterioration in quality of their general movements (GMs). It is unknown whether low-dose DXM affects GM quality similarly. OBJECTIVES: To assess the effect of low-dose DXM treatment on the quality of GMs and fidgety GMs (FMs). METHODS: A prospective study of preterms admitted to our NICU between 2010 and 2012, and treated with DXM (starting dose 0.25 mg/kg/day). We assessed GM/FM quality and calculated their motor optimality score (MOS) before, during, and after treatment up to 3 months postterm. Neurological follow up was performed between 12 and 36 months. We related risk factors with infants' GM trajectories and MOSs. At 3 months we compared the MOSs of low-dose DXM infants and a historical cohort of infants treated with high-dose DXM or hydrocortisone. RESULTS: 17 infants were included. GM/FM quality improved in 9 out of 13 initially abnormal infants (p = 0.004). Shorter periods of mechanical ventilation and higher birth weights were associated with better GM trajectories (p = 0.032 and p = 0.042, respectively). Infants starting treatment later had higher MOSs on day 7 (p = 0.047). Low-dose DXM infants had higher MOSs than high dose DXM infants (beta = -0.535; 95% CI -0.594 to -0.132; p = 0.003). Out of 17 infants, 2 died, 14 developed normally, and 1 developed with mild neurodevelopmental impairments. Infants whose GMs/FMs remained normal or improved had better outcomes than infants whose GMs/FMs remained abnormal (p = 0.019). CONCLUSIONS: Out of the 17 infants treated with low-dose DXM, 2 died. Of the surviving infants, neurological functioning improved with the majority having normal neurodevelopment at the age of 12-36 months. PMID- 25012881 TI - Physical activity and awareness in breast screening attendees in Black Country, UK. AB - This study aimed to determine the physical activity levels and awareness of the influence of physical activity and overweight/obesity on breast cancer risk among NHS breast screening programme (NHSBSP) attendees. One hundred and eighty-eight (white British = 95%; post-menopausal = 80%) attendees completed a demographic and anthropometric data questionnaire, International Physical Activity Questionnaire (IPAQ) and awareness of breast cancer risk factors questionnaire. IPAQ data were reported as continuous measures (MET-min . week(-1)) and as categorical variables (low, moderate and high activities). The highest median physical activity levels were reported in the domestic physical activity domain (756 MET-min . week(-1)). Most participants were categorized as 'moderately active' (45%), while 30% were classified in the 'high activity' and 25% as 'low activity' categories. Almost a third of participants (30%) reported no leisure time physical activity and 83% reported no vigorous physical activity. There was high awareness of the effects of physical activity (75%) and obesity (80%) on breast cancer risk. No significant differences were found between physical activity categories and awareness that physical activity can reduce breast cancer risk (p > 0.05). However, compared with moderate and high activity categories, participants in the 'low activity' category were significantly more likely to respond that they thought they achieved recommended physical activity levels (p < 0.05). Participants who are unaware of their inadequate physical activity levels may have a less positive intention to increase physical activity levels. Practical strategies aimed to increase knowledge of the recommended physical activity guidelines and facilitate the achievement of these guidelines may be required for NHSBSP attendees. PMID- 25012882 TI - Hepatosplenic T-cell lymphoma: a rare cause of hepatosplenomegaly. AB - We report a case of a man presenting with an unexplained fever, pancytopenia and hepatosplenomegaly without lymphadenopathy. Bone marrow flow cytometry strongly suggested hepatosplenic gammadelta T-cell lymphoma and infiltration of bone marrow samples by pathological T-lymphocytes confirmed the diagnosis. Despite chemotherapy the patient died 1 year after diagnosis. This is a rare disease that should be considered in the differential diagnosis of hepatosplenomegaly especially when it presents with B-symptoms and no lymph node enlargement. There is no standard therapy and the prognosis is poor. PMID- 25012883 TI - Bilateral transient osteoporosis of the hip in a 20-year-old man. AB - Transient osteoporosis is a rare musculoskeletal condition that has been reported in pregnant women and middle-aged men. We present a bilateral case in a young man. A 20-year-old man presented with spontaneous onset left hip pain. Investigations excluded other differential diagnoses such as infection or fracture. The pain resolved completely; 6 months later the patient presented with a similar episode of pain in the contralateral hip. This also resolved spontaneously. Doctors need to be aware of the possibility of spontaneous onset musculoskeletal pain due to transient osteoporosis occurring in young men. The typical presentation is of spontaneous onset progressive pain, often affecting the hip. Other pathology must be excluded. The investigation of choice is MRI, and the treatment is simple analgesia. PMID- 25012884 TI - Paradoxical air embolism and neurological insult during removal of a pulmonary artery catheter introducer. AB - A 54-year-old man was admitted to the intensive care unit following cardiac surgery. On day 6 postoperatively, approximately 2-3 min following the removal of the pulmonary artery (PA) catheter introducer sited in the right internal jugular vein, the patient became agitated, confused and then unresponsive. He was urgently moved onto the bed, laid supine, sedated with a propofol infusion, intubated and mechanically ventilated. A bedside transthoracic echocardiogram revealed extensive multiple air emboli in all cardiac chambers and review of the patient's intraoperative imaging confirmed the presence of patent foramen ovale (PFO). The following morning, sedation was discontinued and the trachea extubated. The patient was later transferred to the ward and then discharged home with no evidence of neurological deficit. This case reminds us of the importance of strict adherence to safety protocols when manipulating centrally positioned catheters and the high prevalence of undiagnosed PFO. PMID- 25012885 TI - Anastomotic leak after primary repair of tracheoesophageal fistula: a dreadful condition. PMID- 25012886 TI - Use of i-gel for caesarean section with kyphoscoliosis. AB - We describe the anaesthetic management using i-gel for airway maintenance in a patient with kyphoscoliosis presenting for emergency caesarean section due to fetal distress and scar tenderness. The patient had a history of previous caesarean section under general anaesthesia, and presently her cardiorespiratory status is stable. We used i-gel, the new supraglottic airway device, for maintaining the airway under intravenous anaesthesia using propofol. PMID- 25012887 TI - Ichthyosis with confetti: a rare diagnosis and treatment plan. AB - Congenital ichthyosis includes a group of rare skin disorders known for tiles of hyperkeratotic skin resembling fish scales. With age, the hyperkeratosis generally becomes more concentrated around joints which increases impairment. Ichthyosis with confetti, also known as ichthyosis variegata or congenital reticular ichthyosiform erythroderma, is an extremely rare form of ichthyosis. It usually begins as non-bullous congenital ichthyosiform erythroderma with the expected scaling. However, with time patients develop widespread 'confetti-like' patches of healthy skin. The healthy skin reflects clonal expansion of 'normal' or reverted cells. Cell reversion has potential for future therapies using revertant stem cells. Controlling symptoms with emollients is the goal of treatment for ichthyosis since it has no cure. PMID- 25012888 TI - Unexpected foreign body in the leg of an 8-month-old child. AB - Accidents and injuries associated with foreign bodies are important causes of childhood mortality. Diagnosis can be facilitated by obtaining a detailed history, performing a physical examination and utilising simple imaging methods. We report a case involving a fragmented sewing needle in the left leg of an 8 month-old male infant. He was admitted to our clinic with diffuse pain in the left leg, limitation of leg movements and an inability to stand. The patient was successfully treated with open surgery under fluoroscopy. Soft tissue foreign bodies and potential child physical abuse should be considered in children with ambiguous symptoms and unusual skin lesions. Parents should be educated on prevention of household accidents involving children. Penetration of sewing needles into the body has been rarely reported in the literature. We thus report this case to draw attention to the complications and morbidity associated with a delayed diagnosis in such cases. PMID- 25012889 TI - Bilateral dermoid ovarian cyst in an adolescent girl. AB - A 19-year-old unmarried woman with regular menstrual cycles presented with symptoms of vague abdominal pain of 1 month duration. General condition fair. Per abdomen-a firm, non-tender mass corresponding to 26 weeks of gestation with smooth surface, upper and lateral borders well defined, lower border not palpable was observed. Ultrasonography: left ovarian tumour 28*19 cm with mixed echogenicity was seen in the pelvis extending superiorly into the abdominal cavity with fat, fluid contents, multiple septations. Right ovary measures 6*4 cm with 3.7 cm focal hyperechoic lesion. Uterus anteverted, normal size. No free fluid seen. CT confirmed the ultrasonography findings. Cancer antigen (CA) 125 was 52 IU/mL. Exploratory laparotomy followed by left ovariotomy and salpingectomy and right ovarian cystectomy was performed, leaving behind a significant amount of normal ovarian tissue. Cut section of the gross specimen of the left ovarian tumour-dermoid cyst-plenty of sebaceous fluid and a large tuft of hair. The right ovarian cystectomy revealed a dermoid cyst with hair and pellets of sebum. Histopathology showed bilateral dermoid ovarian cyst. PMID- 25012890 TI - A bloody painful knee: delayed presentation of haemophilic arthropathy. PMID- 25012893 TI - Obsessive compulsive symptoms are related to lower quality of life in patients with Schizophrenia. AB - BACKGROUND: The aim of this study is to investigate the effects of obsessive compulsive symptoms (OCS) on quality of life (QoL) and to identify the OCS with a particular effect on QoL, and whether there are any such symptoms for patients with schizophrenia. METHODS: We studied three groups of patients with schizophrenia. One group of patients (n = 45) without OCS or obsessive-compulsive disorder (OCD), one group with OCS, not fulfilling the diagnostic criteria for OCD (n = 31), and one group with OCD as a comorbid condition (n = 24). Severity of clinical symptoms was evaluated with the Positive and Negative Symptom Scale and OCS was examined using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Symptom Checklist. We also administered the Y-BOCS. The patients' QoL was assessed using the Quality of Life Scale (QLS). RESULTS: QLS interpersonal relationships subscale scores of those with OCS were lower than those without OCS. There was no difference among OCS, non-OCS, and OCD groups in terms of QoL. There was no relationship between QLS scores and symmetry, contamination and causing harm obsessions, but those with cleaning and repeating compulsions had lower QoL. CONCLUSIONS: Questioning of comorbid OCS and treatment with specific medication in schizophrenia patients may increase QoL. PMID- 25012891 TI - Neutrophil gelatinase-associated lipocalin: ready for routine clinical use? An international perspective. AB - Acute kidney injury (AKI) remains a challenge in terms of diagnosis and classification, its morbidity and mortality remaining high in the face of improving clinical protocols. Current clinical criteria use serum creatinine (sCr) and urine output to classify patients. Ongoing research has identified novel biomarkers that may improve the speed and accuracy of patient evaluation and prognostication, yet the route from basic science to clinical practice remains poorly paved. International evidence supporting the use of plasma neutrophil gelatinase-associated lipocalin (NGAL) as a valuable biomarker of AKI and chronic kidney disease (CKD) for a number of clinical scenarios was presented at the 31st International Vicenza Course on Critical Care Nephrology, and these data are detailed in this review. NGAL was shown to be highly useful alongside sCr, urinary output, and other biomarkers in assessing kidney injury; in patient stratification and continuous renal replacement therapy (CRRT) selection in paediatric AKI; in assessing kidney injury in conjunction with sCr in sepsis; in guiding resuscitation protocols in conjunction with brain natriuretic peptide in burn patients; as an early biomarker of delayed graft function and calcineurin inhibitor nephrotoxicity in kidney transplantation from extended criteria donors; as a biomarker of cardiovascular disease and heart failure, and in guiding CRRT selection in the intensive care unit and emergency department. While some applications require further clarification by way of larger randomised controlled trials, NGAL nevertheless demonstrates promise as an independent biological marker with the potential to improve earlier diagnosis and better assessment of risk groups in AKI and CKD. This is a critical element in formulating quick and accurate decisions for individual patients, both in acute scenarios and in long term care, in order to improve patient prognostics and outcomes. PMID- 25012894 TI - Relations between patients in psychiatric and psychotherapeutic inpatient care: a literature review and conclusions for clinical practice and research. AB - OBJECTIVE: In psychiatric inpatient units patients live closely together, which facilitates mutual interactions. Patient relations are part of the therapeutic milieu, which is an important factor in helping patients to recover. Types of patient relations are nonbinding superficial encounters, working alliances, personal relations like close partner relationships, or sexual contacts. Intimate relations between patients are scientifically and in clinical practice, a rather, neglected topic. METHODS: A data search was conducted using the PubMed/MEDLINE databases with the key terms "patient relations" or "intimate relations between patients". RESULTS: Depending on the type of relation and inpatient unit, prevalence rates of 1.5-30% for intimate relations between patients in psychiatric hospitals are reported. Such relations can have beneficial effects, like the feelings of bonding or being liked, but also negative consequences, like burdening, worsening of the illness, treatment complications, or direct harm to the patient. CONCLUSION: Only a few units have development guidelines. It is the responsibility of the therapeutic staff and the hospital management to support a helpful therapeutic milieu, including positive patient interactions, and to protect as far as it is possible patients from negative encounters. PMID- 25012895 TI - Innovative alcohol use: assessing the prevalence of alcohol without liquid and other non-oral routes of alcohol administration. AB - BACKGROUND: Though case studies, media reports, and anecdotal evidence point to creative forms of alcohol use such as "eyeballing," inhalation through vaporizers and other "alcohol without liquid" (AWOL) devices, and "slimming" as a growing trend, no empirical study has assessed the veracity of these claims. The present study attempts to debunk, confirm, or alter the popular perception that young adults are administering alcohol in novel ways. METHODS: A self-report paper survey was administered to 2349 young adults selected for inclusion using a stratified random sampling technique. Respondents were asked to indicate all of the ways in which they had administered alcohol and presented options ranging from traditional oral consumption from a cup, can, or bottle to innovative techniques referenced by medical reports and news outlets. The prevalence of each form of innovative use was reported and explored. RESULTS: Innovative alcohol use was very rare in the sample. Only 25 of 2349 participants (1.1%) had engaged in one or more of the creative methods of alcohol consumption. Among these individuals, most reported either using an AWOL device and/or administering alcohol anally. Vaginal administration and "eyeballing" were only reported by three and one respondents, respectively. CONCLUSIONS: It appears that innovative alcohol use is more than an urban legend but that innovative use, even among a population with high rates of alcohol and drug use, is rare. Regardless, physicians and emergency medical personnel need to be aware of and prepared for dealing with innovative alcohol use. PMID- 25012896 TI - Enhanced striatal responses during expectancy coding in alcohol dependence. AB - BACKGROUND: Individuals with alcohol dependence are known to make disadvantageous decisions, possibly caused by alterations in either reward or punishment sensitivity, which lead to persistent alcohol use despite its adverse consequences. Previous studies in alcohol dependence have mainly focused on reward anticipation processing and results from these studies are mixed. To clarify the nature of the motivational deficit that underlies disadvantageous choice in alcohol dependence, the current study sought to characterize the neural representation of expected value in individuals with alcohol dependence, separating expectancy-related processing of gains and losses, as a function of outcome magnitude and outcome probability. METHOD: Functional MRI was used to examine brain responses during the expectation of gains and losses in patients with alcohol dependence (n=19) and healthy controls (n=19). The task manipulated outcome magnitude (?1 and ?5) and outcome probability (30% and 70%). RESULTS: Compared to healthy controls, patients with alcohol dependence were more responsive to the expectancy of large wins, in the caudate and putamen. This effect was driven by a higher caudate activity in the contrast comparing ?5 vs. ?1 trials in patients with alcohol dependence. There were no group differences in the responses to the expectancy for loss. The patient group reported lower expectancies of winning in the trial-by-trial ratings. CONCLUSIONS: Patients with alcohol dependence showed caudate hyperactivity when expecting wins. The result contrasts with past work using the monetary incentive delay task, showing caudate hypoactivity; the passive nature of our task contrasts with an active response requirement in the MIDT studies. PMID- 25012897 TI - Does early socio-economic disadvantage predict comorbid alcohol and mental health disorders? AB - BACKGROUND: Alcohol and mental health disorders are highly prevalent in the general population, with co-occurrence recognised as a major public health issue. Socio-economic factors are frequently associated with both disorders but their temporal association is unclear. This paper examines the association between prenatal socio-economic disadvantage and comorbid alcohol and mental health disorders at young adulthood. METHODS: An unselected cohort of women was enrolled during early pregnancy in the large longitudinal Mater-University of Queensland Study of Pregnancy (MUSP), at the Mater Misericordiae Public Hospital in Brisbane, Australia. The mothers and their offspring were followed over a 21 year period. Offspring from the MUSP birth cohort who provided full psychiatric information at age 21 and whose mothers provided socioeconomic information at baseline were included (n=2399). Participants were grouped into no-disorder, mental health disorder only, alcohol disorder only or comorbid alcohol and mental health disorders according to DSM-IV diagnoses at age 21 as assessed by the Composite International Diagnostic Interview. We used multivariate logistic regression analysis to compare associations of disorder group with single measures of prenatal socio-economic disadvantage including family income, parental education and employment, and then created a cumulative scale of socioeconomic disadvantage. RESULTS: Greater socio-economic disadvantage was more strongly associated with comorbidity (OR 3.36; CI95 1.37, 8.24) than with single disorders. This relationship was not fully accounted for by maternal mental health, smoking and drinking during pregnancy. CONCLUSION: Multiple domains of socio-economic disadvantage in early life are associated with comorbid alcohol and mental health disorders. PMID- 25012898 TI - New insights into iron acquisition by cyanobacteria: an essential role for ExbB ExbD complex in inorganic iron uptake. AB - Cyanobacteria are globally important primary producers that have an exceptionally large iron requirement for photosynthesis. In many aquatic ecosystems, the levels of dissolved iron are so low and some of the chemical species so unreactive that growth of cyanobacteria is impaired. Pathways of iron uptake through cyanobacterial membranes are now being elucidated, but the molecular details are still largely unknown. Here we report that the non-siderophore-producing cyanobacterium Synechocystis sp. PCC 6803 contains three exbB-exbD gene clusters that are obligatorily required for growth and are involved in iron acquisition. The three exbB-exbDs are redundant, but single and double mutants have reduced rates of iron uptake compared with wild-type cells, and the triple mutant appeared to be lethal. Short-term measurements in chemically well-defined medium show that iron uptake by Synechocystis depends on inorganic iron (Fe') concentration and ExbB-ExbD complexes are essentially required for the Fe' transport process. Although transport of iron bound to a model siderophore, ferrioxamine B, is also reduced in the exbB-exbD mutants, the rate of uptake at similar total [Fe] is about 800-fold slower than Fe', suggesting that hydroxamate siderophore iron uptake may be less ecologically relevant than free iron. These results provide the first evidence that ExbB-ExbD is involved in inorganic iron uptake and is an essential part of the iron acquisition pathway in cyanobacteria. The involvement of an ExbB-ExbD system for inorganic iron uptake may allow cyanobacteria to more tightly maintain iron homeostasis, particularly in variable environments where iron concentrations range from limiting to sufficient. PMID- 25012899 TI - Microbial dormancy improves development and experimental validation of ecosystem model. AB - Climate feedbacks from soils can result from environmental change followed by response of plant and microbial communities, and/or associated changes in nutrient cycling. Explicit consideration of microbial life-history traits and functions may be necessary to predict climate feedbacks owing to changes in the physiology and community composition of microbes and their associated effect on carbon cycling. Here we developed the microbial enzyme-mediated decomposition (MEND) model by incorporating microbial dormancy and the ability to track multiple isotopes of carbon. We tested two versions of MEND, that is, MEND with dormancy (MEND) and MEND without dormancy (MEND_wod), against long-term (270 days) carbon decomposition data from laboratory incubations of four soils with isotopically labeled substrates. MEND_wod adequately fitted multiple observations (total C-CO2 and (14)C-CO2 respiration, and dissolved organic carbon), but at the cost of significantly underestimating the total microbial biomass. MEND improved estimates of microbial biomass by 20-71% over MEND_wod. We also quantified uncertainties in parameters and model simulations using the Critical Objective Function Index method, which is based on a global stochastic optimization algorithm, as well as model complexity and observational data availability. Together our model extrapolations of the incubation study show that long-term soil incubations with experimental data for multiple carbon pools are conducive to estimate both decomposition and microbial parameters. These efforts should provide essential support to future field- and global-scale simulations, and enable more confident predictions of feedbacks between environmental change and carbon cycling. PMID- 25012900 TI - Interpreting 16S metagenomic data without clustering to achieve sub-OTU resolution. AB - The standard approach to analyzing 16S tag sequence data, which relies on clustering reads by sequence similarity into Operational Taxonomic Units (OTUs), underexploits the accuracy of modern sequencing technology. We present a clustering-free approach to multi-sample Illumina data sets that can identify independent bacterial subpopulations regardless of the similarity of their 16S tag sequences. Using published data from a longitudinal time-series study of human tongue microbiota, we are able to resolve within standard 97% similarity OTUs up to 20 distinct subpopulations, all ecologically distinct but with 16S tags differing by as little as one nucleotide (99.2% similarity). A comparative analysis of oral communities of two cohabiting individuals reveals that most such subpopulations are shared between the two communities at 100% sequence identity, and that dynamical similarity between subpopulations in one host is strongly predictive of dynamical similarity between the same subpopulations in the other host. Our method can also be applied to samples collected in cross-sectional studies and can be used with the 454 sequencing platform. We discuss how the sub OTU resolution of our approach can provide new insight into factors shaping community assembly. PMID- 25012901 TI - The subgingival microbiome of clinically healthy current and never smokers. AB - Dysbiotic oral bacterial communities have a critical role in the etiology and progression of periodontal diseases. The goal of this study was to investigate the extent to which smoking increases risk for disease by influencing the composition of the subgingival microbiome in states of clinical health. Subgingival plaque samples were collected from 200 systemically and periodontally healthy smokers and nonsmokers. 16S pyrotag sequencing was preformed generating 1,623,713 classifiable sequences, which were compared with a curated version of the Greengenes database using the quantitative insights into microbial ecology pipeline. The subgingival microbial profiles of smokers and never-smokers were different at all taxonomic levels, and principal coordinate analysis revealed distinct clustering of the microbial communities based on smoking status. Smokers demonstrated a highly diverse, pathogen-rich, commensal-poor, anaerobic microbiome that is more closely aligned with a disease-associated community in clinically healthy individuals, suggesting that it creates an at-risk-for-harm environment that is primed for a future ecological catastrophe. PMID- 25012902 TI - Bacteria on leaves: a previously unrecognised source of N2O in grazed pastures. AB - Nitrous oxide (N2O) emissions from grazed pastures are a product of microbial transformations of nitrogen and the prevailing view is that these only occur in the soil. Here we show this is not the case. We have found ammonia-oxidising bacteria (AOB) are present on plant leaves where they produce N2O just as in soil. AOB (Nitrosospira sp. predominantly) on the pasture grass Lolium perenne converted 0.02-0.42% (mean 0.12%) of the oxidised ammonia to N2O. As we have found AOB to be ubiquitous on grasses sampled from urine patches, we propose a 'plant' source of N2O may be a feature of grazed grassland. PMID- 25012903 TI - Widespread expression of conserved small RNAs in small symbiont genomes. AB - Genome architecture of a microbe markedly changes when it transitions from a free living lifestyle to an obligate symbiotic association within eukaryotic cells. These symbiont genomes experience numerous rearrangements and massive gene loss, which is expected to radically alter gene regulatory networks compared with those of free-living relatives. As such, it remains unclear whether and how these small symbiont genomes regulate gene expression. Here, using a label-free mass-spec quantification approach we found that differential protein regulation occurs in Buchnera, a model symbiont with a reduced genome, when it transitions between two distinct life stages. However, differential mRNA expression could not be detected between Buchnera life stages, despite the presence of a small number of putative transcriptional regulators. Instead a comparative analysis of small RNA expression profiles among five divergent Buchnera lineages, spanning a variety of Buchnera life stages, reveals 140 novel intergenic and antisense small RNAs and 517 untranslated regions that were significantly expressed, some of which have been conserved for ~65 million years. In addition, the majority of these small RNAs exhibit both sequence covariation and thermodynamic stability, indicators of a potential structural RNA role. Together, these data suggest that gene regulation at the post-transcriptional level may be important in Buchnera. This is the first study to empirically identify Buchnera small RNAs, and we propose that these novel small RNAs may facilitate post-transcriptional regulation through translational inhibition/activation, and/or transcript stability. Ultimately, post-transcriptional regulation may shape metabolic complementation between Buchnera and its aphid host, thus impacting the animal's ecology and evolution. PMID- 25012904 TI - Life on the edge: functional genomic response of Ignicoccus hospitalis to the presence of Nanoarchaeum equitans. AB - The marine hyperthermophilic crenarchaeon Ignicoccus hospitalis supports the propagation on its surface of Nanoarchaeum equitans, an evolutionarily enigmatic archaeon that resembles highly derived parasitic and symbiotic bacteria. The cellular and molecular mechanisms that enable this interarchaea relationship and the intimate physiologic consequences to I. hospitalis are unknown. Here, we used concerted proteomic and transcriptomic analyses to probe into the functional genomic response of I. hospitalis as N. equitans multiplies on its surface. The expression of over 97% of the genes was detected at mRNA level and over 80% of the predicted proteins were identified and their relative abundance measured by proteomics. These indicate that little, if any, of the host genomic information is silenced during growth in the laboratory. The primary response to N. equitans was at the membrane level, with increases in relative abundance of most protein complexes involved in energy generation as well as that of several transporters and proteins involved in cellular membrane stabilization. Similar upregulation was observed for genes and proteins involved in key metabolic steps controlling nitrogen and carbon metabolism, although the overall biosynthetic pathways were marginally impacted. Proliferation of N. equitans resulted, however, in selective downregulation of genes coding for transcription factors and replication and cell cycle control proteins as I. hospitalis shifted its physiology from its own cellular growth to that of its ectosymbiont/parasite. The combination of these multiomic approaches provided an unprecedented level of detail regarding the dynamics of this interspecies interaction, which is especially pertinent as these organisms are not genetically tractable. PMID- 25012905 TI - Early colonizing Escherichia coli elicits remodeling of rat colonic epithelium shifting toward a new homeostatic state. AB - We investigated the effects of early colonizing bacteria on the colonic epithelium. We isolated dominant bacteria, Escherichia coli, Enterococcus faecalis, Lactobacillus intestinalis, Clostridium innocuum and a novel Fusobacterium spp., from the intestinal contents of conventional suckling rats and transferred them in different combinations into germfree (GF) adult rats. Animals were investigated after various times up to 21 days. Proliferative cell markers (Ki67, proliferating cell nuclear antigen, phospho-histone H3, cyclin A) were higher in rats monocolonized with E. coli than in GF at all time points, but not in rats monocolonized with E. faecalis. The mucin content of goblet cells declined shortly after E. coli administration whereas the mucus layer doubled in thickness. Fluorescence in situ hybridization analyses revealed that E. coli resides in this mucus layer. The epithelial mucin content progressively returned to baseline, following an increase in KLF4 and in the cell cycle arrest-related proteins p21(CIP1) and p27(KIP1). Markers of colonic differentiated cells involved in electrolyte (carbonic anhydrase II and slc26A3) and water (aquaglyceroporin3 (aqp3)) transport, and secretory responses to carbachol were modulated after E. coli inoculation suggesting that ion transport dynamics were also affected. The colonic responses to simplified microbiotas differed substantially according to whether or not E. coli was combined with the other four bacteria. Thus, proliferation markers increased substantially when E. coli was in the mix, but very much less when it was absent. This work demonstrates that a pioneer strain of E. coli elicits sequential epithelial remodeling affecting the structure, mucus layer and ionic movements and suggests this can result in a microbiota-compliant state. PMID- 25012906 TI - Uterine artery pseudoaneurysm manifesting as delayed postpartum hemorrhage after precipitous delivery: three case reports. AB - Precipitous delivery may lead to serious maternal and neonatal complications. Uterine artery pseudoaneurysm (UAP) is one of the causes of delayed postpartum hemorrhage. Here we describe 3 cases of UAP manifesting as delayed postpartum hemorrhage after precipitous delivery. The duration of the second stage of labor in cases 1, 2, and 3 was 15, 15, and 60 min, respectively. Excessive vaginal bleeding occurred 10, 9, and 31 days after delivery, respectively. Ultrasonogram and pelvic angiography revealed the UAP in each case and uterine artery embolization was performed. UAP may be a complication of precipitous delivery. PMID- 25012908 TI - Morphological effects of the nanostructured ceria support on the activity and stability of CuO/CeO2 catalysts for the water-gas shift reaction. AB - Three CuO/CeO2 catalyst with different morphologies of ceria, namely nanospheres, nanorods and nanocubes, were synthesized and used to catalyze the water-gas shift (WGS) reaction. The reactivity tests showed that the Cu supported on the ceria nanospheres exhibited both the highest activity and superior stability when compared with the nanocube and nanorod ceria catalysts. Operando X-ray diffraction (XRD), X-ray absorption fine structure (XAFS) and diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS) methods were used to characterize these catalysts in their working state. High resolution electron microscopy (HRTEM, STEM) was used to look at the local atomic structure and nano scale morphology. Our results show that the morphology of the ceria support, which can involve different crystal faces and concentrations of defects and imperfections, has a critical impact on the catalytic properties and influences: (1) the dispersion of CuO in the as-synthesized catalyst; (2) the particle size of metallic Cu upon reduction during the WGS reaction, (3) the stability of the metallic Cu upon variations of temperature, and (4) the dissociation of water on the ceria support. The nanosphere ceria catalyst showed an excellent water dissociation capability, the best dispersion of Cu and a strong Cu-Ce interaction, therefore delivering the best performance among the three WGS catalysts. The metallic Cu, which is the active species during the WGS reaction, was more stabilized on the nanospheres than on the nanorods and nanocubes and thus led to a better stability of the nanosphere catalyst than the other two architectures. Each catalyst exhibited a distinctive line-shape in the 800-1600 cm(-1) region of the DRIFTS spectra, pointing to the existence of different types of carbonate or carboxylate species as surface intermediates for the WGS. PMID- 25012907 TI - Updates in biological therapies for knee injuries: full thickness cartilage defect. AB - Full thickness cartilage defect might occur at different ages, but a focal defect is a major concern in the knee of young athletes. It causes impairment and does not heal by itself. Several techniques were described to treat symptomatic full thickness cartilage defect. Recently, several advances were described on the known techniques of microfracture, osteochondral allograft, cell therapy, and others. This article brings an update of current literature on these well described techniques for full thickness cartilage defect. PMID- 25012909 TI - Antidepressant- and anxiolytic-like activities of an oil extract of propolis in rats. AB - PURPOSE: Propolis biological effects are mainly attributed to its polyphenolic constituents such as flavonoids and phenolic acids that were recently described in the chemical composition of an extract of propolis obtained with edible vegetal oil (OEP) by our group. The aim of this study was to evaluate the effect of OEP on the behavior of rats. MATERIALS AND METHODS: An in vivo open field (OF), elevated Plus-maze (EPM), and forced swimming (FS) tests were performed to evaluate locomotor activity, anxiolytic- and antidepressant effects of the extract. Besides, oxidative stress levels were measured in rat blood samples after the behavioral assays by evaluation of the Trolox equivalent antioxidant capacity (TEAC) and nitric oxide levels. RESULTS: OEP increased locomotion in the OF test (50mg/kg) and central locomotion and open arm entries in the OF and EPM tests (10-50mg/kg) and decreased the immobility time in the FS test (10-50mg/kg). Moreover, OEP reduced nitric oxide levels in response to swim stress induced in rats. CONCLUSION: OEP exerted stimulant, anxiolytic and antidepressant effects on the Central Nervous System and antioxidant activity in rats, highlighting propolis as a potential therapeutic compound for behavior impairment of anxiety and depression. PMID- 25012910 TI - Serum levels of soluble receptor for advanced glycation end-products and metabolic syndrome: the Northern Manhattan Study. AB - OBJECTIVE: Recent studies have shown a strong link between serum soluble receptor for advanced glycation end-products (sRAGE) levels and cardiovascular risk factors and disease. What is less clear is the relationship between metabolic risk factors and sRAGE levels. Here, we tested the hypothesis that lower sRAGE levels may be associated with the metabolic syndrome (MetS) in an urban multi ethnic population. MATERIALS/METHODS: From the Northern Manhattan Study (NOMAS), we included 1101 stroke-free participants (mean age: 71 +/- 9 years, 60% women, 64% Hispanic, 18% black, 16% white). Serum sRAGE was measured by ELISA. Quantile regression analysis was performed to evaluate the association between sRAGE and MetS components and MetS, after adjusting for sociodemographics, smoking status and kidney function. RESULTS: The median (interquartile) sRAGE was 899 pg/ml (647 1248 pg/ml), 42% had metabolic syndrome. The prevalence of unfavorable metabolic factors was 50% for waist circumference (WC), 81% for blood pressure, 39% for fasting glucose, 35% for reduced high density lipoproteins (HDL), and 23% for triglycerides. After adjustment, the median sRAGE levels were at least 120 pg/ml lower in those who had elevated WC (p<0.0001), blood pressure (p=0.0014), and fasting glucose (p<0.0001), and those who had 2 or more unfavorable metabolic factors. No relationship was seen between sRAGE levels and elevated triglycerides or reduced HDL levels. Interaction and stratified analyses revealed that the association of sRAGE with MetS was more prominent in Hispanics compared to whites, and displaying no association with components of MetS in blacks. CONCLUSIONS: sRAGE levels were mainly associated with MetS factors related to obesity, diabetes and hypertension, and displayed variation with ethnicity in a multi-ethnic population. Further studies of sRAGE, MetS and their relationship to cardiovascular disease are warranted. PMID- 25012911 TI - Pharmacological characteristics of the inhibitory effects of docosahexaenoic acid on vascular contractions studied in rat mesenteric artery. AB - BACKGROUND/AIMS: Effects of docosahexaenoic acid (DHA) on blood vessel contractions to various constrictors were investigated in rat mesenteric artery and compared with those of eicosapentaenoic acid (EPA) and linoleic acid (LA). METHODS: Tension changes in mesenteric ring segments were isometrically recorded. RESULTS: On sustained contractions induced by a thromboxane A2 mimetic (U46619), DHA exerted a strong inhibitory effect. This inhibitory effect of DHA on U46619 appeared both in endothelium-intact and endothelium-denuded preparations. Although the inhibitory effect of DHA on prostaglandin F2alpha (PGF2alpha) induced contractions was also significant, contractions to phenylephrine (PE) and high-KCI were not affected by DHA. As well as DHA, EPA strongly diminished U46619 and PGF2alpha-induced contractions without showing a substantial inhibition of PE- and high-KCl-induced contractions. By contrast, LA did not show any significant inhibitory effects on any contractions. The DHA-induced inhibitory actions exerted on U46619 and PGF2alpha also emerged if ring preparations were pretreated with this omega-3 polyunsaturated fatty acid (PUFA). CONCLUSION: DHA and EPA are found to more pronouncedly inhibit prostanoid receptor-mediated contractions than other constrictor responses of the mesenteric artery via endothelium-independent mechanisms. These inhibitory effects of omega-3 PUFAs on prostanoid receptor-mediated contractions may partly underlie the mechanisms by which these omega-3 PUFAs elicit protective actions against circulatory disorders. PMID- 25012912 TI - Convergent transcription through microsatellite repeat tracts induces cell death. AB - Microsatellite sequences, composed of short tandem repeats and randomly distributed in human genome, can become unstable during various DNA metabolic processes. Expansions of CAG, GAA, CGG and CCTG repeats located in specific genes are responsible for several human disorders. It is known that a major percentage of human genes simultaneously express both sense and antisense transcripts. Recently, we reported that convergent transcription through a CAG95 tract in human cells leads to cell cycle arrest as well as robust apoptosis. In this study, we studied the effects of convergent transcription through other types of repeats, using cell lines that contain substrates with inducible sense and antisense transcription through CGG66, GAA102, or CCTG134 tracts. We found that convergent transcription through all these repeats inhibits cell growth and induces cell death, though more moderately than convergent transcription through a CAG tract. These results suggest that convergent transcription through various types of tandem repeats represent a novel type of stress to cells. PMID- 25012913 TI - Alternative splicing and immune response of Crassostrea gigas tumor necrosis factor receptor-associated factor 3. AB - Diverse alternative splicing isoforms play an important role in immune diversity and specificity. Their role in molluscan host-defense is however poorly understood. We characterized two alternative isoforms of tumor necrosis factor receptor-associated factor 3 (TRAF3) in the Pacific oyster, Crassostrea gigas, which were named CgTRAF3-S and CgTRAF3-L. An intron was retained in CgTRAF3-L, introducing a premature termination codon. Comparison and phylogenetic analysis revealed that CgTRAF3 shared a higher identity with other species, suggesting the conservation of the two gene transcripts. Quantitative real-time PCR was performed and the expression levels of CgTRAF3 isoforms were found to be significantly changed after Vibrio anguillarum and ostreid herpesvirus 1 challenges. These two isoforms represented contrary trends, indicating that CgTRAF3-L might function as a negative regulator of CgTRAF3-S. We also investigated the expression level of the transcripts of the two CgTRAF3 isoforms, following the silence of C. gigas mitochondrial anti-viral signaling protein like gene (CgMAVS-like). We concluded that CgTRAF3 might be involved in a MAVS mediated immune signaling pathway. This study suggests that CgTRAF3 may be a response to bacterial and viral stimulation and that the two isoforms may be involved in immune response pathways. It is also possible that the two alternative splicing isoforms could be inter-coordinated and may promote survival of these oysters under immune stress conditions. PMID- 25012914 TI - Evaluation of clinical and laboratory findings with JAK2 V617F mutation as an independent variable in essential thrombocytosis. AB - Essential thrombocythemia (ET) is an entity of classic Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), characterized by thrombocytosis with megakaryocytic hyperplasia and thrombocytes are increased with abnormal functions. Discovery of the protein tyrosine kinase JAK2 V617F allele contributed to better understanding of the pathogenetic mechanisms of MPNs. Acquired single point mutation in the JAK2 V617F was determined approximately 50-60 % of patients with ET. In this study we aimed to investigate the relationship between JAK2 V617F gene mutation, hematologic, biochemical markers and the complications in the ET patients. A total of 268 patients diagnosed with ET and 219 of those studied for JAK2 gene mutation were followed at the hematology clinics of three major hospitals between 2008 and 2013 were screened retrospectively. Laboratory, clinical and hematologic parameters were compared for JAK2 V617F positive and JAK2 V617F negative patients with ET. 102 (46 %) patients were positive with the JAK2 V617F mutation. The complications were observed in 61 (28 %) patients and 38 (62 %) of them had JAK2 V617F mutation. The levels of white blood cells, neutrophil, basophil, red blood cells, hemoglobin, hematocrit, mean platelet volume, thrombocytes, eosinophil; urea, creatinine were significantly different in patients with the JAK2 V617F mutation (P < 0.05). Presence of the JAK2 V617F mutation supports the diagnosis of ET. It would be useful to investigate the JAK2 V617F mutation and the hematologic and biochemical markers at diagnosis with respect to consider the risk of developing complications and to take the precautions against these complications. PMID- 25012915 TI - Association between the MMP-9-1562 C>T polymorphism and the risk of stroke: a meta-analysis. AB - Matrix metalloproteinase (MMP)-9 so far is identified as extremely large and complicated MMP family member. Recently, dozens of studies have explored the association between a promoter polymorphism (-1562 C>T) in MMP-9 and stroke susceptibility. However, the conclusions of these studies still remain equivocal. Therefore, our current meta-analysis was conducted to investigate whether or not the MMP-9 promoter polymorphism is related to the risk of stroke. Electronic databases (PubMed, EMBASE, Web of Science, Cochrane Library and the Chinese Biomedical Literature Database) were searched to obtain all the available studies investigating this polymorphism and stroke from inception to October 2013. Overall and subgroup analyses were rigorously conducted after data extraction. Pooled odds ratio (OR) corresponding to 95 % confidence interval (CI) were estimated. The statistical analysis was performed using Review Manager 5.2. Totally, seven studies involving 1,624 cases and 1,525 controls were identified. The overall results suggested that there was no association of the C-1562T variant on stroke risk under the T allele versus C allele [OR T vs. C 0.98, 95 % CI (0.84, 1.15), P = 0.84], the dominant model [OR TT+TC vs. CC 0.95, 95 % CI (0.81, 1.13), P = 0.59], the recessive model [OR TT vs. TC+CC 1.55, 95 % CI (0.86, 2.81), P = 0.15], the homozygote comparison [OR TT vs. CC 1.48, 95 % CI (0.82, 2.68), P = 0.20] and the heterozygote comparison [OR TC vs. CC 0.93, 95 % CI (0.78, 1.10), P = 0.38]. In the subgroup analyses by ethnicity, age, stroke type and source of controls, no significant relations were observed in any genetic models. Our results indicated that MMP-9-1562 C>T polymorphism was not a risk factor for stroke. Further studies should focus on gene-gene and gene environment interactions, and provide a more convincing explanation for this association. PMID- 25012916 TI - Toll-like receptor of mud crab, Scylla serrata: molecular characterisation, ontogeny and functional expression analysis following ligand exposure, and bacterial and viral infections. AB - Toll-like receptors are sentinels of innate immune system, which recognise pathogen-associated molecular patterns, and subsequently activate production of antimicrobial peptides to contain the infection. In the present study, we cloned and characterised a Toll gene from Scylla serrata (SsToll) encoding 1005 amino acids with typical Toll-like receptor domain topology. Phylogenetic analysis revealed that it belongs to insect-type invertebrate Toll family showing 100 % identity with Scylla paramamosain (SpToll). The expression pattern of mRNA in different tissues indicated that SsToll is constitutively expressed in all the tissues examined, with varying expression levels. The expression was also detected in all the life-stages (egg, zoea stages 1-5, megalopa and crab instar) with the highest level observed in zoea 2. In-vitro studies using crab haemocyte culture demonstrated that SsToll transcripts are distinctly modulated in response to ligands such as peptidoglycan and lipopolysaccharide at all time-points. A significant change in SsToll expression was also noticed in haemocytes exposed to poly I:C (3-9 h). On the contrary, the transcription level of SsToll in response to white spot syndrome virus (WSSV) challenge was noticeably different. The change in expression in vitro was not significant at early time-points until 3 h; the transcripts showed a significant up-regulation commencing from 6 h, but not beyond 12 h. However, in vivo expression was unaffected at early time-points of WSSV challenge (until 12 h) and a gradual up-regulation was detected at 24 h. In vivo challenge with Vibrio parahaemolyticus resulted in delayed up-regulation of the gene. The results obtained in the present study suggest that SsToll might be involved in the innate immunity of mud crab. PMID- 25012917 TI - Estimation of maternal and neonatal mortality at the subnational level in Liberia. AB - OBJECTIVE: To establish representative local-area baseline estimates of maternal and neonatal mortality using a novel adjusted sisterhood method. METHODS: The status of maternal and neonatal health in Bomi County, Liberia, was investigated in June 2013 using a population-based survey (n=1985). The standard direct sisterhood method was modified to account for place and time of maternal death to enable calculation of subnational estimates. RESULTS: The modified method of measuring maternal mortality successfully enabled the calculation of area specific estimates. Of 71 reported deaths of sisters, 18 (25.4%) were due to pregnancy-related causes and had occurred in the past 3 years in Bomi County. The estimated maternal mortality ratio was 890 maternal deaths for every 100 000 live births (95% CI, 497-1301]. The neonatal mortality rate was estimated to be 47 deaths for every 1000 live births (95% CI, 42-52). In total, 322 (16.9%) of 1900 women with accurate age data reported having had a stillbirth. CONCLUSION: The modified direct sisterhood method may be useful to other countries seeking a more regionally nuanced understanding of areas in which neonatal and maternal mortality levels still need to be reduced to meet Millennium Development Goals. PMID- 25012918 TI - Unnecessary magnetic resonance imaging of hips: an economic burden to patients and the healthcare system. AB - Patients referred to orthopedists for hip pain due to arthritis may already have MRI studies ordered by their referring physicians despite plain radiographs being sufficient in most cases. Hence, we prospectively evaluated every patient referred to our institution during a 36-month period to identify the number of new patients with hip osteoarthritis who had an unnecessary MRI, the additional costs of these MRIs, and the extrapolated cost to the United States healthcare system during the next 10years. Overall, 15.4% of the patients presented with unnecessary MRIs, approximately, 330 to 440.5 million dollars may be spent on unnecessary hip MRIs in this patient population in America. We believe that referring physicians should not simultaneously order a radiograph and an MRI to evaluate hip pain. PMID- 25012919 TI - Management of dry eye in UK pharmacies. AB - PURPOSE: To investigate the ability of pharmacy staff in the United Kingdom (UK) to diagnose and treat dry eye. METHODS: A mystery shopper technique to simulate a patient with presumed dry eye was used in 50 pharmacy practices in major towns and cities across the UK. Pharmacies were unaware of their involvement in the study. With the exception of a predetermined opening statement to initiate the consultation, no further information was volunteered. Questions asked, diagnoses given, management strategy advised and staff type was recorded immediately after the consultation. RESULTS: The mean number of questions was 4.5 (SD 1.7; range 1 10). The most common question was the duration of symptoms (56%) and the least common was whether the patient had a history of headaches (2%). All pharmacy staff gave a diagnosis, but the majority were incorrect (58%), with only 42% correctly identifying dry eye. Treatment was advised by 92% of pharmacy staff, with the remaining 8% advising referral directly to the patient's GP or optometrist. Dry eye treatments involved topical ocular lubrication via eye drops (90%) and lipid based sprays (10%). However, only 10% gave administration advice, 10% gave dosage advice, 9% asked about contact lens wear, and none offered follow up although 15% also advised GP or optometrist referral. CONCLUSIONS: There is a need for improved ophthalmological training amongst pharmacists and pharmacy staff and establishment of cross referral relationships between pharmacies and optometry practices. PMID- 25012921 TI - [Genetics of primary headache syndromes]. AB - Migraine has an important genetic component. The prototypic monogenic form of migraine is hemiplegic migraine, a rare subtype of migraine with aura, for which three causative genes have been identified. Studies of transgenic animal models have substantially improved our understanding of the molecular pathophysiology of this monogenic model disease as well as of migraine in general. Beyond this, there are other (rarer) monogenic forms of migraine, e.g., in the context of hereditary mostly vascular syndromes such as CADASIL. By contrast, the common types of migraine with and without aura are genetically complex. With the identification of the first robust genetic risk variants in large genome-wide association studies, our knowledge in this still dynamically expanding field has substantially increased. This review summarizes the current status of migraine genetics, with a special focus on hemiplegic migraine as well as the most recent findings in complex migraine genetics. In addition, the first preliminary findings on the genetics of other types of primary headache disorders (cluster headache, tension-type headache) are briefly reviewed. PMID- 25012920 TI - Green tea extract suppresses N-methyl-N-nitrosourea-induced photoreceptor apoptosis in Sprague-Dawley rats. AB - BACKGROUND: Retinitis pigmentosa (RP) is a group of inherited neurodegenerative human diseases characterized by the loss of photoreceptor cells by apoptosis and eventual blindness. A single intraperitoneal (ip) injection of N-methyl-N nitrosourea (MNU) causes photoreceptor cell apoptosis within 7 days in rats. Green tea extract (THEA-FLAN 90S; GTE) is a common herbal supplement with pluripotent properties including antioxidant activity. The purpose of the present study was to evaluate the efficacy of GTE against photoreceptor apoptosis in 7 week-old female Sprague-Dawley rats that received a single ip injection of 40 mg/kg MNU. METHODS: The oral administration of 250 mg/kg/day GTE was initiated 3 days prior to MNU injection and continued once daily throughout the experiment. Rats were sacrificed at 12, 24, and 72 h and 7 days after MNU injection, and the eyes were examined morphologically and morphometrically. The photoreceptor cell ratio, retinal damage ratio, and retinal preservation ratio were used to determine the structural and functional alterations. The number of apoptotic photoreceptor cells per mm(2) was determined in situ by TdT-mediated dUTP digoxigenin nick end labeling (TUNEL). Our results indicated that oral administration of GTE significantly suppressed the loss of photoreceptor cells morphometrically 7 days after MNU injection. The number of TUNEL-positive cells per mm(2) in MNU-exposed rat central retina with or without GTE administration was 981 vs. 2056 at 24 h after MNU injection. CONCLUSIONS: GTE structurally and functionally suppressed MNU-induced photoreceptor cell apoptosis. These findings indicate that GTE may help to ameliorate the onset and progression of human RP. PMID- 25012922 TI - Risk factors and epidemiological characteristics of new neonatal porcine diarrhoea syndrome in four Danish herds. AB - BACKGROUND: The epidemiology of New Neonatal Porcine Diarrhoea Syndrome (NNPDS) was studied in four selected herds. A total of 941 new born piglets in 86 litters were evaluated for five consecutive days. NNPDS is a newly emerged syndrome, characterized by diarrhoea within the first week of life, which is un-responsive to antibiotics and not associated with known pathogens. The aetiology behind the syndrome is unknown, and specific risk factors predisposing piglets to develop NNPDS also remain to be determined.The study evaluated sow and piglet-level risk factors for developing NNPDS and described the epidemiologic characteristics within four herds previously diagnosed with the syndrome. NNPDS was defined as diarrhoea at any time-point during the second to fifth day of life. RESULTS: NNPDS was observed in a total of 60% (range: 39%-89%) of first parity piglets and 36% (range: 19-65%) of piglets born by mature sows. In total of 26% of piglets had liquid faeces on the day of birth. Approximately half of these piglets developed NNPDS. In the majority of cases (50-70% of cases within herds) symptoms started on the second or third day of life. Piglets in Herd 1 had12.8 times higher probability of developing NNPDS than piglets in Herd 4. First parity piglets had a 4.1 higher probability of developing NNPDS than piglets born by mature sows. Birth weight and faecal consistency on the day of birth were minor risk factors, each significant within one herd. CONCLUSIONS: The most important factors associated with NNPDS were herd of origin and sow-parity. The reason for one of the herds experiencing a considerably more severe outbreak than the others was not explained by factors addressed in this study.The epidemiological pattern of diarrhoea varied a lot between herds; however, in all herds first parity piglets seemed predisposed. This association may be explained by an infectious background of the syndrome, but further studies are needed to explain this association. PMID- 25012923 TI - Electronic structure of two precursors for nanofabrication: [(CH3)3CN]2W[N(CH3)2]2 and Ti(NMe2)2(NEt2)2. AB - The electronic structures of bis(tert-butylimino)bis(dimethylamino) tungsten and bis(N-ethylethanaminato)bis(N-methylmethanaminato) titanium heteroleptic complexes, which are precursors for atomic layer deposition of metallic nitride on surfaces, have been investigated by HeI and HeII UV photoelectron spectroscopy and DFT/OVGF calculations. We discuss the electronic structures of these two and other related d(0)-type complexes in relation to the mechanism of adsorption and decomposition of metal alkylamide precursors on surfaces. PMID- 25012924 TI - Female residents experiencing medical errors in general internal medicine: a qualitative study. AB - BACKGROUND: Doctors, especially doctors-in-training such as residents, make errors. They have to face the consequences even though today's approach to errors emphasizes systemic factors. Doctors' individual characteristics play a role in how medical errors are experienced and dealt with. The role of gender has previously been examined in a few quantitative studies that have yielded conflicting results. In the present study, we sought to qualitatively explore the experience of female residents with respect to medical errors. In particular, we explored the coping mechanisms displayed after an error. This study took place in the internal medicine department of a Swiss university hospital. METHODS: Within a phenomenological framework, semi-structured interviews were conducted with eight female residents in general internal medicine. All interviews were audiotaped, fully transcribed, and thereafter analyzed. RESULTS: Seven main themes emerged from the interviews: (1) A perception that there is an insufficient culture of safety and error; (2) The perceived main causes of errors, which included fatigue, work overload, inadequate level of competences in relation to assigned tasks, and dysfunctional communication; (3) Negative feelings in response to errors, which included different forms of psychological distress; (4) Variable attitudes of the hierarchy toward residents involved in an error; (5) Talking about the error, as the core coping mechanism; (6) Defensive and constructive attitudes toward one's own errors; and (7) Gender-specific experiences in relation to errors. Such experiences consisted in (a) perceptions that male residents were more confident and therefore less affected by errors than their female counterparts and (b) perceptions that sexist attitudes among male supervisors can occur and worsen an already painful experience. CONCLUSIONS: This study offers an in-depth account of how female residents specifically experience and cope with medical errors. Our interviews with female residents convey the sense that gender possibly influences the experience with errors, including the kind of coping mechanisms displayed. However, we acknowledge that the lack of a direct comparison between female and male participants represents a limitation while aiming to explore the role of gender. PMID- 25012925 TI - Microscopic functional specificity can be predicted from fMRI signals in ventral visual areas. AB - Functional areas specialized for recognition can be activated by a non-preferred stimulus as well as a preferred stimulus. The functional magnetic resonance imaging signals detected in response to different stimuli in an area may have the same or different amplitudes. However, it is uncertain whether the responses originate from the same neuronal populations or heterogeneous ones. To address this concern, we propose a novel method that uses multi-echo echo-planar imaging sequences to evaluate changes in the transverse relaxation profile caused by stimulation. According to this method, the areas related with visual recognition, i.e. fusiform face area and parahippocampal place area, have different transverse relaxation profiles to preferred and non-preferred stimuli, which can be considered as reflecting a difference in neuronal population processing stimuli in those areas. The proposed method can be useful for probing the microscopic functional specificity of brain areas. PMID- 25012926 TI - EXTEND II: an open-label phase III multicentre study to evaluate efficacy and safety of ranibizumab in Chinese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy and safety of monthly ranibizumab 0.5 mg in Chinese patients with subfoveal choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration (nAMD). METHODS: A 12-month open label single-arm multicenter phase III study that included treatment-naive (study eye) patients with primary/recurrent subfoveal CNV secondary to AMD. Patients (N = 114) aged >=50 years with best-corrected visual acuity (BCVA) of 73-24 letters were treated with monthly ranibizumab for 12 months. Main outcomes were mean BCVA change from baseline to month 4 (primary endpoint) and over time to month 12, effects of ranibizumab treatment on retinal structure (months 4 and 12), and safety. RESULTS: Ranibizumab led to significant improvements in mean BCVA +/- standard error (SE) at both months 4 and 12 versus baseline (+9.5 +/- 1.10 letters, 95 % confidence interval [CI] 7.3-11.7, and +12.7 +/- 1.14 letters, 95 % CI 10.4-14.9, respectively, both P < 0.0001). Ranibizumab prevented loss of vision (>=0 letters BCVA gain) in 91.2 % of patients. Mean central retinal thickness +/- SE reduced from baseline to month 12 (-119.9 +/- 12.97 um, 95 % CI 145.59 to -94.20, P < 0.0001). No new safety findings were reported in this study. CONCLUSION: Ranibizumab administered monthly over 12 months was effective in improving BCVA and was well-tolerated in Chinese nAMD patients. PMID- 25012927 TI - Comparisons of three anterior cervical surgeries in treating cervical spondylotic myelopathy. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) was one of the preferred treatments for degenerative cervical spondylosis. However, the motion of adjacent segment was significantly increased after operation. So cervical disc arthroplasty have been suggested to keep the motion of adjacent segment. A new implant named dynamic cervical implant (DCI) has been developed to keep the motion of adjacent segment. METHODS: We retrospectively reviewed 91 patients treated for single level cervical spondylotic myelopathy with anterior cervical discectomy and fusion (ACDF), dynamic cervical implant (DCI) and cervical total disc replacement (CTDR) between sep 2009 and Mar 2011 in our hospital. They were divided into three groups by surgical methods: ACDF group (group A, 34 cases), DCI group (group B, 25 cases), CTDR group (group C, 32 cases). Operation time, intraoperative blood loss, preoperative and postoperative JOA score and JOA recovery rate were compared among the three groups. Pre-and postoperative hyperextension and hyperflexion radiograms were observed to measure range of motion (ROM) of C2-7, operative and adjacent levels. RESULTS: There was no statistical difference in operative time, intraoperative blood loss, and JOA recovery rate (P > 0.05) among three groups. But the differences of their postoperative JOA scores and preoperative JOA scores were of statistical significance (P < 0.05). Compared the pre-and postoperative ROM of C2-7, operative, upper and lower levels of each group respectively, the difference between preoperative ROM and postoperative ROM of group A were of statistically significant (P < 0.05), while was no statistically significant of group C (P > 0.05). There was no statistically significant difference between preoperative ROM and postoperative ROM of upper and lower levels in group B (P > 0.05), but had statistically significance of C2-7 and operative levels (P < 0.05). CONCLUSIONS: Three operations are effective therapies for single level cervical spondylotic myelopathy. But each group has respective advantages and disadvantages. PMID- 25012928 TI - Podosomes in muscle cells and their role in the remodeling of neuromuscular postsynaptic machinery. AB - Podosomes are adhesive, matrix remodeling organelles that have been described in numerous cell types, including all three vertebrate muscle cell lineages. Podosomes have been intensively studied in smooth muscle cells, but they have also been described in cardiac myocytes and skeletal muscle cells where they are proposed to play a role in developmental remodeling of neuromuscular junction postsynaptic machinery. In this review, we summarize the current state of knowledge of podosomes in muscle cells, with a focus on their potential function at the maturing synapse. PMID- 25012929 TI - Plasmodium yoelii vitamin B5 pantothenate transporter candidate is essential for parasite transmission to the mosquito. AB - In nearly all non-photosynthetic cells, pantothenate (vitamin B5) transport and utilization are prerequisites for the synthesis of the universal essential cofactor Coenzyme A (CoA). Early studies showed that human malaria parasites rely on the uptake of pantothenate across the parasite plasma membrane for survival within erythrocytes. Recently, a P. falciparum candidate pantothenate transporter (PAT) was characterized by functional complementation in yeast. These studies revealed that PfPAT mediated survival of yeast cells in low pantothenate concentrations and restored sensitivity of yeast cells lacking pantothenate uptake to fenpropimorph. In addition, PfPAT was refractory to deletion in P. falciparum in vitro, but nothing is known about the in vivo functions of PAT in Plasmodium life cycle stages. Herein, we used gene-targeting techniques to delete PAT in Plasmodium yoelii. Parasites lacking PAT displayed normal asexual and sexual blood stage development compared to wild-type (WT) and WT-like p230p(-) parasites. However, progression from the ookinete to the oocyst stage and sporozoite formation were completely abolished in pat(-) parasites. These studies provide the first evidence for an essential role of a candidate pantothenate transport in malaria transmission to Anopheles mosquitoes. This will set the stage for the development of PAT inhibitors against multiple parasite life cycle stages. PMID- 25012930 TI - Count on kappa. AB - In the 1960s, the kappa statistic was introduced for the estimation of chance agreement in inter- and intra-rater reliability studies. The kappa statistic was strongly pushed by the medical field where it could be successfully applied via analyzing diagnoses of identical patient groups. Kappa is well suited for classification tasks where ranking is not considered. The main advantage of kappa is its simplicity and the general applicability to multi-class problems which is the major difference to receiver operating characteristic area under the curve. In this manuscript, I will outline the usage of kappa for classification tasks, and I will evaluate the role and uses of kappa in specifically machine learning and cheminformatics. PMID- 25012931 TI - A multicenter prospective cohort study of quality of life and economic outcomes after cataract surgery in Vietnam: the VISIONARY study. AB - PURPOSE: To measure the change in quality of life and economic circumstances after cataract surgery and identify the predictors of an improvement in these outcomes. DESIGN: A multicenter, prospective, longitudinal cohort study. PARTICIPANTS: Participants aged 18 years were recruited to the study if the clinical assessment of their best uncorrected vision was <= 6/18 in the better eye because of cataract [Corrected]. METHODS: Cataract surgery. MAIN OUTCOME MEASURES: Data were collected on quality of life and a multidimensional assessment of household economic circumstances (work status, income, asset ownership, household economic hardship, and catastrophic health expenditure). RESULTS: At 12 months follow-up, 381 of 480 participants were re-interviewed, and all had undergone surgery. There was a significant improvement in quality of life. Household economic circumstances also improved (mean change paid work participation/month: 44.5 hours, P < 0.0001; mean change unpaid work participation/month: 89.5 hours, P < 0.0001; change in proportion with hardship: 17%, P < 0.0001; and change in proportion with catastrophic health expenditure: 7%, P = 0.02). Improvements were most likely in near-poor households and were related to the type of surgery and complications after surgery. CONCLUSIONS: This research showed that cataract surgery is associated with meaningful improvements in quality of life and household economic circumstances that are indicative of positive transitions out of poverty. Given the unmet need for cataract surgery in low- and middle-income countries where cataract impairment is substantial, this research demonstrates the potential of a relatively simple, low-cost health intervention to greatly improve household economic circumstances. PMID- 25012932 TI - Re: Coster et al.: a comparison of lamellar and penetrating keratoplasty outcomes: a registry study (Ophthalmology 2014;121:979-87). PMID- 25012933 TI - Time course of changes in aniseikonia and foveal microstructure after vitrectomy for epiretinal membrane. AB - PURPOSE: To quantify aniseikonia in patients undergoing vitrectomy for epiretinal membrane (ERM) and to investigate the relationship between the aniseikonia and the foveal microstructure by spectral-domain (SD) optical coherence tomography (OCT). DESIGN: Prospective, consecutive, interventional case series. SUBJECTS: This study included 44 eyes of 44 patients undergoing vitrectomy for idiopathic ERM. METHODS: We examined visual acuity and aniseikonia using the New Aniseikonia Test and SD-OCT before and 3 and 6 months after surgery. On the basis of the obtained OCT image, we divided the 1.0 * 1.0-mm area centered on the fovea into 9 sections at 0.25-mm intervals and quantified the following parameters using an image-processing program: central foveal thickness and mean thickness of the ganglion cell layer, inner nuclear layer (INL), and outer retinal layer (outer nuclear layer + outer plexiform layer). The status of the photoreceptor inner segment/outer segment junction, external limiting membrane, and cone outer segment tips also was evaluated. MAIN OUTCOME MEASURES: Amount of aniseikonia 6 months after surgery. RESULTS: Of 44 patients, 39 (89%) had macropsia, 1 (2%) had micropsia, and 4 (9%) had no aniseikonia preoperatively. Mean preoperative aniseikonia was 6.2% +/- 4.5%. Vitrectomy significantly improved visual acuity in patients with ERM but did not change the amount of aniseikonia. Multiple regression analysis revealed that preoperative aniseikonia at 6 months was significantly related to preoperative INL thickness, whereas postoperative aniseikonia at 6 months was associated with postoperative INL thickness at 6 months. Preoperative INL thickness was found to be of significant prognostic value for postoperative aniseikonia at 6 months. CONCLUSIONS: Most of the patients with ERM had macropsia. Aniseikonia was not reduced after surgery. The amount of aniseikonia was associated with INL thickness. PMID- 25012935 TI - Author reply: To PMID 24491643. PMID- 25012934 TI - Intravitreal aflibercept for diabetic macular edema. AB - PURPOSE: A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME). DESIGN: Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS: We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement. METHODS: Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained >= 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography. RESULTS: Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining >= 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 MUm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 MUm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups. CONCLUSIONS: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated. PMID- 25012936 TI - Feasibility of time-resolved MR angiography for detecting recanalization of pulmonary arteriovenous malformations treated with embolization with platinum coils. AB - PURPOSE: To assess the feasibility of time-resolved magnetic resonance (MR) angiography as a follow-up method after embolization for pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: Evaluation of 28 PAVMs in 10 patients previously treated with embolization with platinum coils was performed. The mean observation period after embolization was 49 months. All patients underwent unenhanced chest computed tomography (CT) and time-resolved MR angiography followed by transcatheter digital subtraction angiography within 5 weeks for a definite diagnosis. Two radiologists reviewed the CT and time resolved MR angiography findings using a blinded method. On CT, the draining veins of the PAVMs were measured before and after embolization, and shrinkage rates were calculated. On time-resolved MR angiography, recanalization was diagnosed when the draining vein or aneurysmal sac or both were enhanced in the pulmonary arterial phase. Correlations between recanalization, the shrinkage rate of the draining vein, and the diagnostic accuracies of CT and time-resolved MR angiography were assessed and compared with digital subtraction angiography. RESULTS: Five lesions could not be measured on CT because of metallic artifacts. The mean shrinkage rates of the draining vein for recanalized and occluded PAVMs were 23% +/- 19 (SD) for recanalized PAVMs and 47% +/- 21 for occluded PAVMs (P = .001). The sensitivity and specificity were 93% and 53%, respectively, when the shrinkage rate threshold was set to 50%. On time-resolved MR angiography, the sensitivity and specificity were 93% and 100%, respectively, for Reader 1 and 100% and 93%, respectively, for Reader 2. The kappa coefficient was 0.86. CONCLUSIONS: Time-resolved MR angiography appears to be a feasible method for PAVM follow-up examinations and to provide a more accurate diagnosis of recanalization compared with unenhanced CT. PMID- 25012937 TI - HDAC inhibition through valproic acid modulates the methylation profiles in human embryonic kidney cells. AB - Post-translational modifications on the tails of core and linker histones dictate transcription and have vital roles in disease and development. Acetylation and deacetylation events enabled by histone acetyl transferases and histone deacetylases (HDACs) on the chromatin milieu are intricately involved in gene regulation. Inhibition of HDACs is emerging as a powerful strategy in regenerative therapy, transplantation, development and in nuclear reprogramming events. Valproic acid (VPA), belonging to the short-chain fatty acid group of HDAC inhibitors, modulates the epigenome altering gene expression profiles across cell lines. This work attempts to explore the methylation profiles triggered by VPA treatment on human embryonic kidney cells (HEK 293) through a biochemical and computational approach. VPA treatment (for 48 h) has been observed to hypermethylate lysine 4 on the core histone H3 and confers a hypomethylation status of H3 lysine 27 in HEK 293 cells leaving the nuclear area and nuclear contour unaltered. Our structural docking and Binding Free Energy (BFE) calculations establish an active role for VPA in inhibiting the demethylase JARID1A (Jumonji, AT Rich Interactive Domain 1A) and the methyl-transferase EZH2 (Enhancer of Zeste Homologue 2). This work has also proven that VPA can inhibit the activity of proteins like GSK3beta and PKCbetaII involved in developmental disorders. This work establishes a dynamic correlation between histone methylation events and HDAC inhibition and may define newer epigenetic strategies for treating neurodevelopmental and oncological disorders. PMID- 25012938 TI - How medium osmolarity influences dielectrophoretically assisted on-chip electrofusion. AB - Cells submitted to an electric field gradient experience dielectrophoresis. Such a force is useful for pairing cells prior to electrofusion. The latter event is induced by the application of electric field pulses leading to membrane fusion while cells are in physical contact. Nevertheless, the efficiency of dielectrophoretic pairing and electrofusion of cells are highly dependent on medium properties (osmolarity and conductivity). In this paper, we examine the effect of medium osmolarity on volume, viability and electrical properties of cells. Then we characterize in real time the impact of electropermeabilization of cells on their dielectrophoretic response. To do so, a microfluidic device, inducing particular field topologies is used. These real time observations are correlated to numerical analysis of the Clausius-Mossotti factor. Taking into account the identified changes, an electrofusion protocol adequate to the optimal medium (100 mOsm, 0.03 S/m) is defined. Up to 75% simultaneous binuclear rapid electrofusions were achieved and monitored with average membrane fusion duration lower than 12s. PMID- 25012939 TI - Racial disparities and the use of technology for self-management in blacks with heart failure: a literature review. AB - Heart failure is a debilitating illness that requires patients to be actively engaged in self-management. Self-management practices, including maintenance and management of an evidence-based medication regimen, are associated with improved outcomes. Yet, sustained engagement with self-management practices remains a challenge. Both self-management practices and clinical outcomes differ by race, with the poorest self-management and clinical outcomes reported in Blacks. Contemporary interventions to address self-management and reverse current trends in outcomes have evaluated the use of technology. Technological innovations, such as text messaging, social networking, and online learning platforms may provide a more accessible means for self-management of heart failure, yet these innovations have been understudied in the population at greatest risk - Blacks with heart failure. We conducted a review and discovered only four studies evaluating use of technology for self-management in Blacks. More studies are needed to close the gap on racial disparities and use of technology for self-management. PMID- 25012940 TI - IKZF1 rs4132601 polymorphism and acute lymphoblastic leukemia susceptibility: a meta-analysis. AB - Several studies have been conducted to examine the association between IKZF1 rs4132601 polymorphism and acute lymphoblastic leukemia (ALL) risk. However, the conclusions remain controversial. We therefore performed a meta-analysis. PubMed, Embase, Web of Science, Weipu and Chinese Biomedical Literature (CBM) databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. A total of 15 case-control studies with 8333 cases and 36 036 controls were included in this meta-analysis. The results suggested that rs4132601 was associated with an increased ALL risk. Significant associations were found among Caucasians and Hispanics but not among Asians. In subgroup analysis by age group, both adults and children showed increased ALL risk. In subgroup analysis by subtype of ALL, significantly increased risks were observed in B-cell ALL and B hyperdiploid ALL, but not in T-cell ALL. This study suggests that IKZF1 rs4132601polymorphism is a risk factor for ALL. PMID- 25012941 TI - Classification of non-Hodgkin lymphoma in Algeria according to the World Health Organization classification. AB - The relative distribution of non-Hodgkin lymphoma (NHL) subtypes differs markedly around the world. The aim of this study was to report this distribution in Algeria. A panel of four hematopathologists classified 197 consecutive cases according to the World Health Organization classification, including 87.3% B-cell and 12.7% T- or natural killer (NK)-cell NHLs. This series was compared with similar cohorts from Western Europe (WEU) and North America (NA). Algeria had a significantly higher frequency of diffuse large B-cell lymphoma (DLBCL: 52.8%) and a lower frequency of follicular lymphoma (FL: 13.2%) compared with WEU (DLBCL: 32.2%; FL: 20.0%) and NA (DLBCL: 29.3%; FL: 33.6%). The frequency of mantle cell lymphoma was lower in Algeria (2.5%) compared with WEU (8.3%). Smaller differences were also found among the NK/T-cell lymphomas. In conclusion, we found important differences between Algeria and Western countries, and further epidemiologic studies are needed to explain these differences. PMID- 25012942 TI - Achievement of morphologic and cytogenetic remission with single-agent hydroxyurea in a patient with acute myeloid leukemia with inv(16). PMID- 25012943 TI - Imatinib mesylate lacks efficacy in relapsed/refractory peripheral T cell lymphoma. AB - Platelet derived growth factor-alpha (PDGFR-alpha) is expressed in peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). Imatinib mesylate demonstrated in vitro cytotoxicity against primary PTCL, NOS cells. We initiated a trial of imatinib in 12 patients with relapsed or refractory T-cell non-Hodgkin lymphoma (T-NHL). PDGFR-alpha expression by immunohistochemistry and fluorescence in situ hybridization (FISH) to assess for FIP1L1-PDGFR-alpha fusion and/or PDGFR alpha amplification were not required for study entry. We documented no objective responses. The median progression-free survival was 21.0 days (90% confidence interval [CI] 15.0, 28.0) and median overall survival was 154 days (90% CI 35, 242). Four patients had tissue available for analysis of PDGFR-alpha by immunohistochemistry and three of these patients' tumors expressed PDGFR-alpha. Imatinib was not effective for the treatment of peripheral T cell lymphoma in an unselected group of patients in which PDGFR-alpha expression was not required for study entry. PMID- 25012945 TI - BCR-ABL1 T315I mutation, a negative prognostic factor for the terminal phase of chronic myelogenous leukemia treated with first- and second-line tyrosine kinase inhibitors, might be an indicator of allogeneic stem cell transplant as the treatment of choice. PMID- 25012944 TI - Impact of race and ethnicity on outcomes and health care utilization after allogeneic hematopoietic cell transplantation. AB - Disparities in outcomes after hematopoietic cell transplant (HCT) are reported mostly by registry studies. We examined the association of self-reported race and ethnicity with outcomes and health care utilization after allogeneic HCT in a single center study. Clinical and socioeconomic data of 296 adult patients who underwent allogeneic HCT from November 2003 to October 2012 were analyzed. Survival was compared between non-Hispanic Whites (NHW) and minority patients using Cox proportional hazards regression. Some 73% of patients were NHW and 27% were racial/ethnic minority patients. More minority patients were younger and had lower socioeconomic status. Both unadjusted and adjusted overall and progression free survival were comparable between the two groups. High risk disease, poor performance score and Medicare/Tricare were significant predictors of mortality. Health care utilization was comparable between the two groups. Homogeneity of medical care for allogeneic HCT may help overcome racial/ethnic disparities, but not those due to patients' primary insurance. PMID- 25012946 TI - Expression and pro-survival function of phospholipase Cgamma2 in diffuse large B cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) can be cured in about 60% of cases with immuno-chemotherapy. However, a large subset of patients with DLBCL do not go into remission, or relapse after first-line therapy. Further therapy options are therefore needed. Phospholipase Cgamma2 (PLCgamma2) is one of the key regulators of the B cell receptor signaling pathway, which targets several pro-proliferative factors, such as nuclear factor kappaB (NFkappaB), Ras and Akt. Using immunohistochemistry, we found that PLCgamma2 was strongly expressed in 63% of cases of DLBCL. The PLC inhibitor U73122 had an inhibitory effect on cell proliferation and induced apoptosis and G0/G1 cell cycle arrest. Co-treatment with enzastaurin or the Src inhibitor pp2 together with U73122 had an additive effect on cell proliferation compared to U73122 alone. Unexpectedly, strong PLCgamma2 expression was associated with better overall survival. In conclusion, PLCgamma2 is strongly expressed in a significant number of DLBCLs and has prognostic implications. Inhibition of PLCgamma2 could be a new target for lymphoma treatment. PMID- 25012947 TI - Diagnostic caveats of immunoreactivity for Ki67 and chromogranin A in hyalinizing trabecular tumour of the thyroid. PMID- 25012949 TI - Breathing easier: addressing the challenges of aerosolizing medications to infants and preschoolers. AB - An increasing number of patients are dependent on aerosolized therapy to manage pulmonary diseases, including asthma, cystic fibrosis, and pulmonary arterial hypertension. An aerosol therapy is only useful if it can be appropriately and consistently delivered in the desired dose to the lower respiratory tract. Many factors affect this deposition in young children, including anatomical and physiologic differences between adults and children, patient-mask interface issues, the challenge of administering medication to uncooperative children, and behavioral adherence. Moreover, the techniques used to assess aerosol delivery to pediatric patients need to be carefully evaluated as new therapies and drug device combinations are tested. In this review, we will address some of the challenges of delivering aerosolized medications to pediatric patients. PMID- 25012950 TI - Cardiac magnetic resonance evaluation of left ventricular remodelling distribution in cardiac amyloidosis. AB - BACKGROUND: Cardiac amyloidosis (CA) is associated with typical morphological features on echocardiography, including concentric LV hypertrophy (LVH). Cardiac magnetic resonance (CMR) can accurately depict anatomy in different cardiomyopathies. Our aim was to describe the morphological features and remodelling patterns of CA with CMR, and establish their diagnostic accuracy, as well as the value of traditional diagnostic criteria derived from echocardiography and electrocardiography. METHODS: Consecutive patients referred for CMR for possible CA were retrospectively evaluated. The diagnosis of CA was established in the presence of a positive cardiac biopsy and/or a typical pattern of myocardial late gadolinium enhancement. Morphological parameters were obtained from standard cine sequences. The presence and distribution of LVH, relative wall thickness (RWT) and LV remodelling patterns were determined. RESULTS: 130 patients (92 males (70.8%), age 64+/-13 years) were included. CA was diagnosed in 51 (39.2%). Patients with CA had increased LV wall thickness and LV mass index. An LV remodelling pattern different from concentric LVH was found in 42% of patients with CA, and asymmetric LVH was noted in 68.6%. A model including RWT, asymmetric LVH, and LVMI showed diagnostic accuracy of 88%, sensitivity of 67% and specificity of 86% for CA detection. Traditional diagnostic criteria for CA showed high specificity but poor sensitivity. CONCLUSIONS: Asymmetric LVH and remodelling patterns different from concentric LVH are common in CA. Increased LV mass index, increased RWT, and asymmetric LVH are independently associated with the diagnosis. Traditional diagnostic criteria show poor sensitivity. PMID- 25012948 TI - Guidance for laboratories performing molecular pathology for cancer patients. AB - Molecular testing is becoming an important part of the diagnosis of any patient with cancer. The challenge to laboratories is to meet this need, using reliable methods and processes to ensure that patients receive a timely and accurate report on which their treatment will be based. The aim of this paper is to provide minimum requirements for the management of molecular pathology laboratories. This general guidance should be augmented by the specific guidance available for different tumour types and tests. Preanalytical considerations are important, and careful consideration of the way in which specimens are obtained and reach the laboratory is necessary. Sample receipt and handling follow standard operating procedures, but some alterations may be necessary if molecular testing is to be performed, for instance to control tissue fixation. DNA and RNA extraction can be standardised and should be checked for quality and quantity of output on a regular basis. The choice of analytical method(s) depends on clinical requirements, desired turnaround time, and expertise available. Internal quality control, regular internal audit of the whole testing process, laboratory accreditation, and continual participation in external quality assessment schemes are prerequisites for delivery of a reliable service. A molecular pathology report should accurately convey the information the clinician needs to treat the patient with sufficient information to allow for correct interpretation of the result. Molecular pathology is developing rapidly, and further detailed evidence based recommendations are required for many of the topics covered here. PMID- 25012951 TI - Measurement of metals using DGT: impact of ionic strength and kinetics of dissociation of complexes in the resin domain. AB - As the measurement of metals by DGT (diffusion gradients in thin films) in low salinity media has been controversial, a thorough study of the impact of ionic strength (I) is timely. DGT accumulations of Cd, Co, and Ni in the presence of NTA at pH 7.5 with I in the range from 10(-4) to 0.5 M were obtained. An observed decrease in the metal accumulation as the ionic strength of the system decreased is partially explained by the electrostatic repulsion between the negatively charged resin domain and the dominant negatively charged complex species M-NTA. This electrostatic effect reduces the complex penetration into the resin domain, especially for nonlabile complexes, which do not fully dissociate in the gel domain. Analytical expressions, based on the Donnan model, were able to quantify these electrostatic effects. Additionally, the data indicate that the kinetic dissociation constant of M-NTA complexes in the resin layer is higher than Eigen predictions, suggesting a ligand-assisted dissociation mechanism. As the ionic strength decreases, the rate of reaction in the resin layer decreases due to the repulsion between the negatively charged resin sites and the complex species. This decrease contributes to the decrease in metal accumulation. These novel, previously unconsidered, effects of ionic strength and the ligand-assisted dissociation mechanism in the resin domain will affect DGT measurements made in freshwaters and soils. PMID- 25012952 TI - Testing the woman abuse screening tool to identify intimate partner violence in Indonesia. AB - Intimate Partner Violence (IPV) is a global public health problem. IPV prevalence in Indonesia has been estimated to be less than 1%, based on reported cases. It is likely that IPV prevalence is underreported in Indonesia, as it is in many other countries. Screening for IPV has been found to increase IPV identification, but no screening tools are in use in Indonesia. The aim of this study was to test the translated Woman Abuse Screening Tool (WAST) for detecting IPV in Indonesia. The WAST was tested against a diagnostic interview by a trained psychologist on 240 women attending two Primary Health Centers in Jakarta. IPV prevalence and the reliability, sensitivity, and specificity of the WAST were estimated. Prevalence of IPV by diagnostic interview was 36.3%, much higher than published estimates. The most common forms of IPV identified were psychological (85%) and physical abuse (24%). Internal reliability of the WAST was high (alpha = .801). A WAST score of 13 (out of 24) is the recommended cutoff for identifying IPV, but only 17% of the Indonesian sample scored 13 or higher. Test sensitivity of the WAST with a cutoff score of 13 was only 41.9%, with a specificity of 96.8%. With a cutoff score of 10, the sensitivity improved to 84.9%, while the specificity decreased to 61.0%. Use of the WAST with a cutoff score of 10 provides good sensitivity and reasonable specificity and would provide a much-needed screening tool for use in Indonesia. Although a lower cutoff would yield a greater proportion of false positives, most of the true cases would be identified, increasing the possibility that women experiencing abuse would receive needed assistance. PMID- 25012953 TI - Childhood victimization experiences of young adults in St. Petersburg, Russia. AB - The purpose of this study was to assess the prevalence of childhood victimization experiences in a sample of young adults in St. Petersburg, Russia. The study sample included 743 students aged 19 to 25 from 15 universities in St. Petersburg, Russia. All of the study participants completed a reliable questionnaire assessing the following types of childhood victimization: conventional crime, child maltreatment, peer victimization, sexual victimization, and witnessing violence. Participation in the study was anonymous. High rates of victimization and exposure to violence were reported by the study participants. The majority of the sample experienced at least one type of victimization during childhood or adolescence, and poly-victimization was reported frequently. The most common type of victimization reported was peer or sibling assault (66.94%), followed by witnessing an assault without weapon (63.91%), personal theft (56.19%), vandalism (56.06%), and emotional bullying (49.99%). Sexual assault by a known adult was reported by 1.45% males and 5.16% of females. This study provides new information on the scope of childhood victimization experiences in Russia. Further research is warranted, including epidemiological research with representative data across the country and studies of the impact of trauma and victimization on mental health and well-being of Russian adults and children. PMID- 25012954 TI - The interplay of trait anger, childhood physical abuse, and alcohol consumption in predicting intimate partner aggression. AB - The current study examined three well-established risk factors for intimate partner aggression (IPA) within Finkel and Eckhardt's I(3) model, including two impellance factors-trait anger and childhood physical abuse history-and the disinhibiting factor of alcohol consumption. Participants were 236 male and female college students in a committed heterosexual dating relationship who completed a battery of self-report measures assessing childhood physical abuse, trait anger, alcohol consumption, and IPA perpetration. Results revealed a significant three-way interaction showing that as the disinhibition factor alcohol consumption increased, the interaction of the two impelling factors, trait anger and childhood physical abuse, became increasingly more positive. Individuals who had high levels of childhood physical abuse and alcohol consumption were at greater risk of IPA perpetration when trait anger was high. Consistent with the I(3) model, these findings suggest that trait anger and a history of childhood physical abuse may increase tendencies to aggress against one's partner, whereas alcohol consumption may reduce individuals' abilities to manage these aggressive tendencies. The importance of interplay among these risk factors in elevating IPA risk is discussed, as are the implications for clinicians working with male and female IPA perpetrators. PMID- 25012955 TI - Hypofractionated stereotactic reirradiation for recurrent glioblastoma. AB - Treatment choices for recurrent glioblastoma patients are sparse and the results are not satisfactory. In this retrospective analysis, we evaluated the results of re-irradiation of locally recurrent glioblastoma patients with an image-guided, fractionated, frameless stereotactic radiotherapy (SRT) technique. We treated 37 patients with the diagnosis of recurrent glioblastoma from September 2009 to December 2011. SRT was performed in a median five fractions (range, 1-5 fractions) with CyberKnife((r)) (Accuray Incorporated, Sunnyvale, CA, USA). The dose given ranged from 14 to 32 Gy (median, 30 Gy). The median volume of the GTV was 24 cc (range, 2-81 cc). Median follow-up was 9.3 months. Five patients had regression in their lesions, 14 had stable disease, progression was observed in eight patients, and seven patients had pseudoprogression. The median survival following SRT was 10.6 months (range, 1.1-20 months) and overall survival following initial treatment was 35.5 months. The time to progression following SRT was 7.9 months in median. Patients with pseudoprogression had significantly longer survival after the first magnetic resonance imaging (MRI) compared to those with regression, stable or progressive disease (p = 0.012). The median survival after SRT for patients with pseudoprogression was 20 months. Patients who had GTV <24 cc had significantly longer survival following SRT compared to those with lesions >=24 cc (p = 0.015). Patients who had chemotherapy after SRT had a median survival of 16.8 months. This was 9.7 months for patients who were not prescribed any chemotherapy (p = 0.062). PMID- 25012956 TI - A RAD52 genetic variant located in a miRNA binding site is associated with glioma risk in Han Chinese. AB - As a crucial homologous recombination repair gene, RAD52 participates in maintenance of genomic stability and prevention of tumorigenesis. Although several cancer susceptibility RAD52 single nucleotide polymorphisms (SNPs) have been identified previously, little was known on how the RAD52 SNPs are involved in glioma development in Han Chinese. Therefore, we examined the association between five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and glioma risk using a case-control design. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with glioma risk, with the odds of having the rs7963551 AC or CC genotype in patients was 0.49 (95 % CI 0.37-0.65, P = 9.2 * 10(-6)) or 0.39 (95 % CI 0.18-0.81, P = 0.012) compared with the AA genotype. These data are consistent with functional relevance of allelic regulation of RAD52 expression by the rs7963551 SNP and miRNA let-7 in cancer cells. Stratified analyses elucidated that statistically significant association between glioma and rs7963551 SNP only existed in either astrocytic tumors (P = 6.3 * 10(-6)) or oligoastrocytic tumors (P = 0.002). In conclusion, our results support the hypothesis that genetic variants influencing miRNA-mediated regulation of tumor suppressor genes or oncogenes may contribute glioma susceptibility. PMID- 25012957 TI - A nurse-delivered brief health education intervention to improve pneumococcal vaccination rate among older patients with chronic diseases: a cluster randomized controlled trial. AB - BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine is recommended for elders, especially those with chronic conditions. OBJECTIVE: The aim of this study was to determine if an additional multi-component health education intervention increases the uptake rate of the pneumococcal vaccination among older patients with chronic diseases. METHODS: A cluster randomized controlled trial was conducted from 3 December 2007 to 7 March 2008. The clusters were the individual weeks within five Hong Kong outpatient clinics over a 10-week period. A sample of 2517 patients aged 65 or above with chronic diseases was recruited. Intervention group received a 3-min brief telephone education intervention before and a 3-min face-to-face intervention during scheduled medical appointments at the respective clinics. All subjects received standard care including health education leaflets and/or a video show at the clinics. Pneumococcal vaccination rate and awareness of the vaccination at 3-month follow up were measured. RESULTS: The vaccination rate was higher in the intervention group compared to the control group (57% vs 48%; relative risk=1.20, 95% CI=1.06-1.37), but the two groups did not differ significantly in their awareness of the vaccination at 3 month follow up (65% vs 59%, relative risk=0.86, 95% CI=0.69-1.07). DISCUSSION: A nurse-delivered brief health education intervention was effective in increasing uptake of pneumococcal vaccination among older patients with chronic diseases. PMID- 25012958 TI - A systematic review of economic evaluations assessing interventions aimed at preventing or treating pressure ulcers. AB - BACKGROUND: Pressure ulcers have an adverse impact on patients and can also result in additional costs and workload for healthcare providers. Interventions to prevent pressure ulcers are focused on identifying at risk patients and using systems such as mattresses and turning to relieve pressure. Treatments for pressure ulcers are directed towards promoting wound healing and symptom relief. Both prevention and treatments have associated costs for healthcare providers. The aim of this study was to systematically review the economic evidence for prevention and treatment interventions for pressure ulcers. DESIGN: A systematic review of comparative clinical studies that evaluate interventions to either prevent or treat pressure ulcers. DATA SOURCES: Searches of the major electronic databases were conducted to identify citations that reported costs or economic analysis for interventions directed towards prevention or treatment of pressure ulcers. Only comparative clinical studies were included. Review articles, case series, non-randomised studies, and studies in a foreign language that did not have an abstract in English were excluded from the review. REVIEW METHODS: Decisions regarding inclusion or exclusion were based on a consensus of the authors after review of the title or abstract. Potential citations were obtained for more detailed review and assessed against the inclusion criteria. The studies identified for inclusion were assessed against the 24 key criteria contained in the CHEERS checklist. Costs were standardised to US dollars and adjusted for inflation to 2012 rates. RESULTS: The searches identified 105 potential studies. After review of the citations a total of 23 studies were included: 12 examined prevention interventions and 11 treatments. Review against the CHEERS criteria showed that the majority of included trials had poor reporting and a lack of detail regarding how costs were calculated. Few studies reported more than aggregate costs of treatments with only a small number reporting unit cost outcomes. CONCLUSIONS: Existing evidence was poor in regard to the economic evaluation of interventions for the prevention and treatment of pressure ulcers. Much of the published literature had poor reporting quality when compared to guidelines which provide key criteria for studies to adequately examine costs within an economic analysis. PMID- 25012959 TI - Transcutaneous oxygen tension monitoring in critically ill patients receiving packed red blood cells. AB - PURPOSE: Whether transfusions of packed red blood cells (PRBCs) affect tissue oxygenation in stable critically ill patients is still matter of discussion. The microvascular capacity for tissue oxygenation can be determined noninvasively by measuring transcutaneous oxygen tension (tcpO2). The aim of this study was to assess tissue oxygenation by measuring tcpO2 in stable critically ill patients receiving PRBC transfusions. METHODS: Nineteen stable critically ill patients, who received 2 units of PRBC, were prospectively included into this pilot study. Transcutaneous oxygen tension was measured continuously during PRBC transfusions using Clark's electrodes. In addition, whole blood viscosity and global hemodynamics were determined. RESULTS: Reliable measurement signals during continuous tcpO2 monitoring were observed in 17 of 19 included patients. Transcutaneous oxygen tension was related to the global oxygen consumption (r= 0.78; P=.003), the arterio-venous oxygen content difference (r=-0.65; P=.005), and the extraction rate (r=-0.71; P=.02). The transfusion-induced increase of the hemoglobin concentration was paralleled by an increase of the whole blood viscosity (P<.001). Microvascular tissue oxygenation by means of tcpO2 was not affected by PRBC transfusions (P=.46). Packed red blood cell transfusions resulted in an increase of global oxygen delivery (P=.02) and central venous oxygen saturation (P=.01), whereas oxygen consumption remained unchanged (P=.72). CONCLUSIONS: In stable critically ill patients, microvascular tissue oxygenation can be continuously monitored by Clark's tcpO2 electrodes. According to continuous tcpO2 measurements, the microvascular tissue oxygenation is not affected by PRBC transfusions. PMID- 25012960 TI - Adipose tissue lipolysis and circulating lipids in acute and subacute critical illness: effects of shock and treatment. AB - PURPOSE: The purpose of this study is to assess lipid metabolism at the tissue level in critically ill subjects. MATERIALS AND METHODS: We studied 182 patients with systemic inflammatory response syndrome/severe sepsis or shock during the acute (day 1) and subacute phase of critical illness (day 6). All subjects had a tissue microdialysis (MD) catheter placed in femoral adipose tissue upon admission to the intensive care unit (ICU). Plasma cholesterol, high-density lipoprotein, low-density lipoprotein, free fatty acids (FFAs), triglyceride, and MD glycerol (GLYC) were measured on days 1 and 6 in the ICU. RESULTS: On admission, 56% of the patients had increased levels (>200 MUmol/L) of MD GLYC. Patients with shock displayed more pronounced subcutaneous tissue lipolysis and more profound derangements of circulating lipids vs patients without shock (but no appreciable differences in FFA levels). Furthermore, in patients with shock during the acute period, there were positive, albeit weak, correlations of subcutaneous tissue lipolysis (MD GLYC), plasma FFAs (r=0.260; P=.01), and norepinephrine's dose (r=0.230; P=.01), whereas during the subacute phase, MD GLY levels were higher in patients receiving glucocorticoids (344.7+/-276.0 MUmol/L vs 252.2+/-158.4 MUmol/L; P=.03). CONCLUSIONS: Subcutaneous tissue lipolysis is only one of the many determinants of plasma FFAs. Routinely applied therapeutic modalities in the ICU interfere with adipose tissue metabolism. PMID- 25012962 TI - Sleep debt and obesity. AB - Short sleep duration has been shown to be associated with elevated body mass index (BMI) in many epidemiological studies. Several pathways could link sleep deprivation to weight gain and obesity, including increased food intake, decreased energy expenditure, and changes in levels of appetite-regulating hormones, such as leptin and ghrelin. A relatively new factor that is contributing to sleep deprivation is the use of multimedia (e.g. television viewing, computer, and internet), which may aggravate sedentary behavior and increase caloric intake. In addition, shift-work, long working hours, and increased time commuting to and from work have also been hypothesized to favor weight gain and obesity-related metabolic disorders, because of their strong link to shorter sleep times. This article reviews the epidemiological, biological, and behavioral evidence linking sleep debt and obesity. PMID- 25012961 TI - Glasgow Coma Scale score dominates the association between admission Sequential Organ Failure Assessment score and 30-day mortality in a mixed intensive care unit population. AB - OBJECTIVE: The Sequential Organ Failure Assessment (SOFA) score, a measure of multiple-organ dysfunction syndrome, is used to predict mortality in critically ill patients by assigning equally weighted scores across 6 different organ systems. We hypothesized that specific organ systems would have a greater association with mortality than others. DESIGN: We retrospectively studied patients admitted over a period of 4.2 years to a mixed-profile intensive care unit (ICU). We recorded age and comorbidities, and calculated SOFA organ scores. The primary outcome was 30-day all-cause mortality. We determined which organ subscores of the SOFA score were most associated with mortality using multiple analytic methods: random forests, conditional inference trees, distanced-based clustering techniques, and logistic regression. SETTING: A 24-bed mixed-profile adult ICU that cares for medical, surgical, and trauma (level 1) patients at an academic referral center. PATIENTS: All patients' first admission to the study ICU during the study period. MEASUREMENTS AND MAIN RESULTS: We identified 9120 first admissions during the study period. Overall 30-day mortality was 12%. Multiple analytical methods all demonstrated that the best initial prediction variables were age and the central nervous system SOFA subscore, which is determined solely by Glasgow Coma Scale score. CONCLUSIONS: In a mixed population of critically ill patients, the Glasgow Coma Scale score dominates the association between admission SOFA score and 30-day mortality. Future research into outcomes from multiple-organ dysfunction may benefit from new models for measuring organ dysfunction with special attention to neurologic dysfunction. PMID- 25012963 TI - Expression of monocyte subsets and angiogenic markers in relation to carotid plaque neovascularization in patients with pre-existing coronary artery disease and carotid stenosis. AB - AIM: To characterize blood monocyte subsets in patients with different degrees of carotid atherosclerosis and pathological carotid plaque neovascularization. METHODS: Assessment of carotid plaque neovascularization using contrast ultrasonography and flow cytometric quantification of monocyte subsets and their receptors involved in inflammation, angiogenesis, and tissue repair was done in 40 patients with carotid stenosis >= 50% and CAD (CS > 50), 40 patients with carotid stenosis < 50% and documented CAD (CS < 50), 40 hypercholesterolaemic controls (HC group), and 40 normocholesterolaemic controls (NC). RESULTS: CS > 50 and CS < 50 groups had increased counts of Mon1 ('classical' CD14++ CD16-CCR2 + cells) compared to HCs (P = 0.03, and P = 0.009). Mon3 ('non-classical' CD14 + CD16++ CCR2- cells) were only increased in CS < 50 compared with HCs (P < 0.01). Both CS>50 and CS < 50 groups showed increased expression of proinflammatory interleukin-6 receptor on Mon1 and Mon2 ('intermediate' CD14++ CD16 + CCR2+ cells); TLR4, proangiogenic Tie2 on all subsets (P < 0.01 for all). In multivariate regression analysis only high Mon1 count was a significant predictor of carotid stenosis (P = 0.04) and intima-media thickness (P = 0.02). In multivariate regression analysis only the Mon1 subset was significantly associated with severe, grade 2 neovascularization (P = 0.034). CONCLUSION: In this pilot study classical monocytes (Mon1) represent the only monocyte subset predictive of the severity of carotid and systemic atherosclerosis, such as carotid intima-media thickness, degree of carotid stenosis, and presence of carotid intraplaque neovascularization. PMID- 25012964 TI - Exercise-induced changes in inflammatory processes: Implications for thrombogenesis in cardiovascular disease. AB - Sedentary lifestyle is a risk factor and a strong predictor for chronic disease and premature death. Low-grade inflammation has been proved a key player in the pathogenesis of cardiovascular disease. Inflammatory processes have been also involved in maintaining the balance between coagulation and fibrinolysis. In addition, an inverse linear dose-response relation between physical activity and mortality risks has also been reported. However, the favorable effects of structured exercise programs and the independent contribution of physical activity to cardiovascular risk are still under investigation. In response to heavy exercise, interleukin-6 (IL-6) is secreted by contracting skeletal muscles, followed by an acute reactant release of C-reactive protein (CRP). Both CRP and IL-6 can stimulate monocyte tissue factor production, provoke platelet hyperreactivity, promote fibrinogen biosynthesis, and enhance microparticle formation and erythrocyte aggregability, thus triggering prothrombotic state. By contrast, regular exercise and physical activity are protective against all-cause mortality through suppressing pro-inflammatory cytokine production, enhancing anti-inflammatory mediators and antioxidant development, and promoting fibrinolytic activity. Low-load resistance exercise also plays an advantageous role in thrombogenesis by reducing inflammatory processes and potentiating fibrinolytic features. In the present review article, we provide an overview of the impact of different modes and intensities of physical activity on vascular inflammation and thrombogenesis. PMID- 25012965 TI - Editorial overview: Ecology and industrial microbiology. PMID- 25012966 TI - Canine epidermal lipid sampling by skin scrub revealed variations between different body sites and normal and atopic dogs. AB - BACKGROUND: Previously, we evaluated a minimally invasive epidermal lipid sampling method called skin scrub, which achieved reproducible and comparable results to skin scraping. The present study aimed at investigating regional variations in canine epidermal lipid composition using the skin scrub technique and its suitability for collecting skin lipids in dogs suffering from certain skin diseases. Eight different body sites (5 highly and 3 lowly predisposed for atopic lesions) were sampled by skin scrub in 8 control dogs with normal skin. Additionally, lesional and non-lesional skin was sampled from 12 atopic dogs and 4 dogs with other skin diseases by skin scrub. Lipid fractions were separated by high performance thin layer chromatography and analysed densitometrically. RESULTS: No significant differences in total lipid content were found among the body sites tested in the control dogs. However, the pinna, lip and caudal back contained significantly lower concentrations of ceramides, whereas the palmar metacarpus and the axillary region contained significantly higher amounts of ceramides and cholesterol than most other body sites. The amount of total lipids and ceramides including all ceramide classes were significantly lower in both lesional and non-lesional skin of atopic dogs compared to normal skin, with the reduction being more pronounced in lesional skin. The sampling by skin scrub was relatively painless and caused only slight erythema at the sampled areas but no oedema. Histological examinations of skin biopsies at 2 skin scrubbed areas revealed a potential lipid extraction from the transition zone between stratum corneum and granulosum. CONCLUSIONS: The present study revealed regional variations in the epidermal lipid and ceramide composition in dogs without skin abnormalities but no connection between lipid composition and predilection sites for canine atopic dermatitis lesions. The skin scrub technique proved to be a practicable sampling method for canine epidermal lipids, revealed satisfying results regarding alterations of skin lipid composition in canine atopic dermatitis and might be suitable for epidermal lipid investigations of further canine skin diseases. Although the ceramide composition should be unaffected by the deeper lipid sampling of skin scrub compared to other sampling methods, further studies are required to determine methodological differences. PMID- 25012967 TI - Production of acylated homoserine lactone by a novel marine strain of Proteus vulgaris and inhibition of its swarming by phytochemicals. AB - A marine strain of Proteus vulgaris capable of activating multiple acylated homoserine lactone (AHL)-based reporter cultures was isolated. The cognate signal molecule was characterized as octanoyl homoserine lactone (OHL) and its production was observed to be growth dependent, with maximum production (5.675 ug l(-1)) at 24 h growth. The strain exhibited swarming, but its motility was not affected upon addition of pure OHL or culture supernatant. Phytochemicals such as quercitin and berberine chloride inhibited OHL production and reduced swarming. FliA, the predominantly upregulated protein during swarming, was considered as a possible target for these inhibitors, and docking of the two most active and two least active inhibitors to this protein suggested preferential binding of the former set of compounds. Apart from adding new evidence to AHL production in Proteus vulgaris, active inhibitors shortlisted from this study could help in identifying lead compounds to act against this opportunistic pathogen of the respiratory and gastrointestinal tract. PMID- 25012968 TI - Plant-derived compatible solutes proline betaine and betonicine confer enhanced osmotic and temperature stress tolerance to Bacillus subtilis. AB - L-Proline is a widely used compatible solute and is employed by Bacillus subtilis, through both synthesis and uptake, as an osmostress protectant. Here, we assessed the stress-protective potential of the plant-derived L-proline derivatives N-methyl-L-proline, L-proline betaine (stachydrine), trans-4-L hydroxproline and trans-4-hydroxy-L-proline betaine (betonicine) for cells challenged by high salinity or extremes in growth temperature. l-Proline betaine and betonicine conferred salt stress protection, but trans-4-L-hydroxyproline and N-methyl-L-proline was unable to do so. Except for L-proline, none of these compounds served as a nutrient for B. subtilis. L-Proline betaine was a considerably better osmostress protectant than betonicine, and its import strongly reduced the l-proline pool produced by B. subtilis under osmotic stress conditions, whereas a supply of betonicine affected the L-proline pool only modestly. Both compounds downregulated the transcription of the osmotically inducible opuA operon, albeit to different extents. Mutant studies revealed that L-proline betaine was taken up via the ATP-binding cassette transporters OpuA and OpuC, and the betaine-choline-carnitine-transporter-type carrier OpuD; betonicine was imported only through OpuA and OpuC. L-Proline betaine and betonicine also served as temperature stress protectants. A striking difference between these chemically closely related compounds was observed: L-proline betaine was an excellent cold stress protectant, but did not provide heat stress protection, whereas the reverse was true for betonicine. Both compounds were primarily imported in temperature-challenged cells via the high-capacity OpuA transporter. We developed an in silico model for the OpuAC-betonicine complex based on the crystal structure of the OpuAC solute receptor complexed with L-proline betaine. PMID- 25012969 TI - Adherence to abiotic surface induces SOS response in Escherichia coli K-12 strains under aerobic and anaerobic conditions. AB - During the colonization of surfaces, Escherichia coli bacteria often encounter DNA-damaging agents and these agents can induce several defence mechanisms. Base excision repair (BER) is dedicated to the repair of oxidative DNA damage caused by reactive oxygen species (ROS) generated by chemical and physical agents or by metabolism. In this work, we have evaluated whether the interaction with an abiotic surface by mutants derived from E. coli K-12 deficient in some enzymes that are part of BER causes DNA damage and associated filamentation. Moreover, we studied the role of endonuclease V (nfi gene; 1506 mutant strain) in biofilm formation. Endonuclease V is an enzyme that is involved in DNA repair of nitrosative lesions. We verified that endonuclease V is involved in biofilm formation. Our results showed more filamentation in the xthA mutant (BW9091) and triple xthA nfo nth mutant (BW535) than in the wild-type strain (AB1157). By contrast, the mutant nfi did not present filamentation in biofilm, although its wild-type strain (1466) showed rare filaments in biofilm. The filamentation of bacterial cells attaching to a surface was a consequence of SOS induction measured by the SOS chromotest. However, biofilm formation depended on the ability of the bacteria to induce the SOS response since the mutant lexA Ind(-) did not induce the SOS response and did not form any biofilm. Oxygen tension was an important factor for the interaction of the BER mutants, since these mutants exhibited decreased quantitative adherence under anaerobic conditions. However, our results showed that the presence or absence of oxygen did not affect the viability of BW9091 and BW535 strains. The nfi mutant and its wild-type did not exhibit decreased biofilm formation under anaerobic conditions. Scanning electron microscopy was also performed on the E. coli K-12 strains that had adhered to the glass, and we observed the presence of a structure similar to an extracellular matrix that depended on the oxygen tension. In conclusion, it was proven that bacterial interaction with abiotic surfaces can lead to SOS induction and associated filamentation. Moreover, we verified that endonuclease V is involved in biofilm formation. PMID- 25012970 TI - Suboptimal decision making in borderline personality disorder: effect of potential losses. AB - This research explored the underlying processes mediating risky decisions for individuals with Borderline Personality Disorder (BPD). We tested whether BPD patients were more apt to take risks compared to a matched comparison group. We used two controlled tasks designed to assess risky decision-making, both to achieve gains and to avoid losses. Overall, BPD patients showed increased risk taking compared to the comparison group (p = .011, eta2 = .224), and were especially likely to be risk-seeking when the decision was framed as a potential loss (p < .0001, d = 1.77). When the outcome involved pure losses, BPD patients were insensitive to the relative expected value between choice options resulting in suboptimal decision making (p = .004, d = 1.24), but did not differ from the comparison group when taking risks to achieve gains (p = .603, d = 0.21). We discuss these results in the context of behavioral and neuropsychiatric research suggesting abnormalities BPD patients' ability to effectively regulate affect. PMID- 25012971 TI - Adenosine testing after second-generation balloon devices (cryothermal and laser) mediated pulmonary vein ablation for atrial fibrillation. AB - AIMS: Adenosine administration after pulmonary vein (PV) isolation using radiofrequency and cryoablation can cause acute recovery of conduction to the PVs and predicts atrial fibrillation (AF) recurrence. This study evaluated whether adenosine testing after second-generation balloon devices (cryothermal and laser) could reveal dormant PV reconduction and recurrence rate of AF. METHODS: Out of total 60 patients, 20 patients underwent PV isolation using laser balloon and for the remaining patients, the cryoballoon was used. Following PVI, waiting period of 30 min was obtained. Thereafter, a bolus 15-21 mg of adenosine was injected followed by rapid saline flush. The subsequent response was assessed for each vein using an in situ lasso catheter. Further ablation (if needed) using laser balloon and cryocatheter respectively was done, until no reconduction occurred after repeat adenosine. RESULTS: Acute PV isolation was achieved in all 80 PVs of 20 patients (100 %) using laser device and in 151 PVs (96.2 %) of 38 patients (95 %) using cryoballoon. However, in seven patients (35 %), 11 PVs (13.7 %) (4 LSPV, 2 LIPV, 4 RSPV, and 1 RIPV) showed dormant PV potentials after adenosine administration in laser group. Cryoballoon group showed dormant reconduction in four patients (10 %), four PVs (5 %) [one LSPV, one LIPV, and two RIPV]. The follow-up of 337 +/- 92.4 days for cryoballoon and 267 +/- 76.9 days for laser balloon group demonstrated similar success rates (85 %). CONCLUSION: Adenosine testing after PV isolation using second-generation balloon based energy devices (laser and cryothermal) reveals dormant conduction in initially isolated PVs with similar long-term success rate. PMID- 25012972 TI - Performance of the HAS-BLED high bleeding-risk category, compared to ATRIA and HEMORR2HAGES in patients with atrial fibrillation: a systematic review and meta analysis. AB - INTRODUCTION: Atrial fibrillation (AF) patients' major bleeding risk should be evaluated through risk scores such as HAS-BLED, HEMORR2HAGES or ATRIA. These scores were validated in independent studies with different methods. Therefore, we aimed to review and estimate the value added by ATRIA and HEMORR2HAGES compared to HAS-BLED. METHODS: Medline and Cochrane Library (July 2013) were searched, as well as reviews and references of obtained articles. We looked for studies reporting data for diagnostic accuracy of HAS-BLED with any of HEMORR2HAGES or ATRIA scores, concerning Major Bleeding events. We determined the sensitivity, specificity, and diagnostic odds ratio (DOR) of ATRIA and HEMORR2HAGES compared to HAS-BLED within the same studies. Random effects meta analysis was performed in order to derive diagnostic accuracy estimates. Heterogeneity was assessed through I (2) test. RESULTS: Six studies fulfilled inclusion criteria. Five studies evaluated simultaneously HAS-BLED and HEMORR2HAGES. Sensitivity, specificity, and DOR were respectively 0.53 (0.52 0.54), 0.65 (0.65-0.65) and 2.11 (1.91-2.35) for HAS-BLED, and 0.27 (0.26-0.27), 0.89 (0.89-0.89) and 2.90 (2.77-3.04) for HEMORR2HAGES. Four studies compared HAS BLED with ATRIA. Sensitivity, specificity, and DOR were respectively 0.41 (0.35 0.48), 0.78 (0.76-0.79) and 2.22 (1.08-4.55) for HAS-BLED, and 0.23 (0.17-0.29), 0.91 (0.90-0.91) and 1.98 (1.29-3.03) for ATRIA. CONCLUSIONS: The 'high-risk' categories of the evaluated major bleeding-risk scores are not sensitive. HAS BLED, due to its sensitivity (compared to other scores) and ease to apply, is recommended for the assessment of AF patients' major bleeding risk. PMID- 25012973 TI - [Proliferative vitreoretinopathy: prophylactic treatment]. AB - Proliferative vitreoretinopathy (PVR) is a complex process. It causes contractile fibrocellular membranes that may prevent retinal reattachment. PVR therefore remains one of the most severe complications of rhegmatogenous retinal detachment (RD), with an incidence of 5-11%, and is among the most frequent causes of surgical failure (50-75%). Its severity derives from the complexity of the surgery required to treat patients and from its uncertain anatomic and functional prognosis. The first step in preventing PVR is to identify patients at risk by means of clinical and/or biological factors such as the characteristics of retinal tears (large size, number) and detachment (preexisting PVR, extent), and the use of cryotherapy. Surgeons must therefore adapt their surgical approach to the risk of PVR. The study of animal models and the natural history of the condition in humans demonstrate the importance of early antiproliferative treatment in the early stage of the disease. Combining 5-fluoro-uracil and heparin in the vitrectomy infusion lowers the rate of postoperative PVR onset in patients with PVR risk factors. The evaluation of new molecules and new dosages will lead to a decisive step in the fight against PVR. PMID- 25012974 TI - [Scleromalacia in congenital erythropoietic porphyria: a case report]. PMID- 25012975 TI - Base excision repair in Archaea: back to the future in DNA repair. AB - Together with Bacteria and Eukarya, Archaea represents one of the three domain of life. In contrast with the morphological difference existing between Archaea and Eukarya, these two domains are closely related. Phylogenetic analyses confirm this evolutionary relationship showing that most of the proteins involved in DNA transcription and replication are highly conserved. On the contrary, information is scanty about DNA repair pathways and their mechanisms. In the present review the most important proteins involved in base excision repair, namely glycosylases, AP lyases, AP endonucleases, polymerases, sliding clamps, flap endonucleases, and ligases, will be discussed and compared with bacterial and eukaryotic ones. Finally, possible applications and future perspectives derived from studies on Archaea and their repair pathways, will be taken into account. PMID- 25012977 TI - Supplementing formula-fed piglets with a low molecular weight fraction of bovine colostrum whey results in an improved intestinal barrier. AB - To test the hypothesis that a low molecular weight fraction of colostral whey could affect the morphology and barrier function of the small intestine, 30 3-d old piglets (normal or low birth weight) were suckled (n = 5), artificially fed with milk formula (n = 5), or artificially fed with milk formula with a low molecular weight fraction of colostral whey (n = 5) until 10 d of age. The small intestine was sampled for histology (haematoxylin and eosin stain; anti-KI67 immunohistochemistry) and enzyme activities (aminopeptidase A, aminopeptidase N, dipeptidylpeptidase IV, lactase, maltase, and sucrase). In addition, intestinal permeability was evaluated via a dual sugar absorption test and via the measurement of occludin abundance. Artificially feeding of piglets reduced final BW (P < 0.001), villus height (P < 0.001), lactase (P < 0.001), and dipeptidylpeptidase IV activities (P < 0.07), whereas crypt depth (P < 0.001) was increased. No difference was observed with regard to the permeability measurements when comparing artificially fed with naturally suckling piglets. Supplementing piglets with the colostral whey fraction did not affect BW, enzyme activities, or the outcome of the dual sugar absorption test. On the contrary, the small intestines of supplemented piglets had even shorter villi (P = 0.001) than unsupplemented piglets and contained more occludin (P = 0.002). In conclusion, at 10 d of age, no differences regarding intestinal morphology and permeability measurements were observed between the 2 BW categories. In both weight categories, the colostral whey fraction affected the morphology of the small intestine but did not improve the growth performances or the in vivo permeability. These findings should be acknowledged when developing formulated milk for neonatal animals with the aim of improving the performance of low birth weight piglets. PMID- 25012978 TI - Monte Carlo loop refinement and virtual screening of the thyroid-stimulating hormone receptor transmembrane domain. AB - Metropolis Monte Carlo (MMC) loop refinement has been performed on the three extracellular loops (ECLs) of rhodopsin and opsin-based homology models of the thyroid-stimulating hormone receptor transmembrane domain, a class A type G protein-coupled receptor. The Monte Carlo sampling technique, employing torsion angles of amino acid side chains and local moves for the six consecutive backbone torsion angles, has previously reproduced the conformation of several loops with known crystal structures with accuracy consistently less than 2 A. A grid-based potential map, which includes van der Waals, electrostatics, hydrophobic as well as hydrogen-bond potentials for bulk protein environment and the solvation effect, has been used to significantly reduce the computational cost of energy evaluation. A modified sigmoidal distance-dependent dielectric function has been implemented in conjunction with the desolvation and hydrogen-bonding terms. A long high-temperature simulation with 2 kcal/mol repulsion potential resulted in extensive sampling of the conformational space. The slow annealing leading to the low-energy structures predicted secondary structure by the MMC technique. Molecular docking with the reported agonist reproduced the binding site within 1.5 A. Virtual screening performed on the three lowest structures showed that the ligand-binding mode in the inter-helical region is dependent on the ECL conformations. PMID- 25012979 TI - Donor evaluation in heart transplantation: The end of the beginning. AB - The evaluation of organ donors is of critical importance in all areas of solid organ transplantation. Donor characteristics have been shown to have robust effects on heart transplant recipient outcomes, and evaluation of the donor for suitability for heart transplantation is therefore very comprehensive. The donor evaluation process is composed of several steps, beginning with the identification of a potential organ donor and ending with the transplantation of a donor heart. The purpose of this review is to dissect the complex process of donor evaluation into its component steps and to highlight the diverse approaches used by transplant clinicians around the world to optimize outcomes at each step. We provide a summary of donor characteristics that have been associated with increased recipient mortality and discuss areas of uncertainty. Recent additions to the literature present novel insights and solutions to vexing problems in donor evaluation, such as how to make a more accurate assessment of allograft quality. Continued advancement in the evaluation of donors is essential to maintain heart transplantation as a viable therapy that provides excellent long term survival for patients with end-stage heart failure. PMID- 25012981 TI - The World Health Organization's MPOWER framework and international human rights treaties: an opportunity to promote global tobacco control. PMID- 25012980 TI - Invasive pulmonary aspergillosis in heart transplant recipients: two radiologic patterns with a different prognosis. AB - BACKGROUND: Computed tomography (CT) findings can be used to classify invasive pulmonary aspergillosis (IPA) in 2 patterns: airway-invasive (AIR) or angioinvasive (ANG). METHODS: AIR-IPA was considered when the CT revealed peribronchial consolidation or a tree-in-bud pattern and ANG-IPA when a nodule, cavity, halo sign, infarct-shaped, or mass-like consolidation was found. We evaluated the correlation among IPA patterns on CT and outcomes in heart transplant (HT) recipients. RESULTS: The study included 27 HT recipients with a CT scan performed at the time of IPA diagnosis. The study interval was from 1988 to 2011. Ten AIR-IPA patients (37.1%) were compared with 17 ANG-IPA patients (62.9%). During the post-transplantation period before IPA developed, AIR patients required hemodialysis more frequently (40% vs 5.9%, p = 0.04). AIR patients also had more intercurrent bacterial pneumonia (23.5% vs 70%, p < 0.001), and IPA was diagnosed later after onset of symptoms (2.7 vs 8.5 d, p = 0.09). After diagnosis, AIR-IPA patients required more mechanical ventilation (23.5% vs 90%, p < 0.01) and had a higher related mortality rate (23.5% vs 70%, p = 0.04). CONCLUSIONS: Our study shows that the AIR pattern represents 37% of IPA episodes in HT recipients and is associated with a more protracted clinical presentation, later diagnosis, and higher mortality rate. PMID- 25012982 TI - Acanthamoeba keratitis: a new normal. PMID- 25012983 TI - Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability. PMID- 25012984 TI - GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts. AB - Elevated insulin levels have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes characterized by a poor prognosis. Insulin stimulates the proliferation, migration, and invasiveness of cancer cells through diverse transduction pathways, including estrogen signaling. As G protein estrogen receptor 1 (GPER1) mediates rapid cell responses to estrogens, we evaluated the potential of insulin to regulate GPER1 expression and function in leiomyosarcoma cancer cells (SKUT-1) and breast cancer-associated fibroblasts (CAFs), which were used as a model system. We found that insulin transactivates the GPER1 promoter sequence and increases the mRNA and protein expression of GPER1 through the activation of the PRKCD/MAPK1/c-Fos/AP1 transduction pathway, as ascertained by means of specific pharmacological inhibitors and gene-silencing experiments. Moreover, cell migration triggered by insulin occurred through GPER1 and its main target gene CTGF, whereas the insulin induced expression of GPER1 boosted cell-cycle progression and the glucose uptake stimulated by estrogens. Notably, a positive correlation between insulin serum levels and GPER1 expression was found in cancer fibroblasts obtained from breast cancer patients. Altogether, our data indicate that GPER1 may be included among the complex network of transduction signaling triggered by insulin that drives cells toward cancer progression. PMID- 25012987 TI - New sedative/hypnotic dosing guidelines. PMID- 25012985 TI - Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. AB - Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and >=4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each cohort, one patient was randomly assigned to placebo and three patients to telotristat etiprate, at 150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was assigned to placebo and six patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated: 18 received telotristat etiprate and five received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate treated patients, 5/18 (28%) experienced a >=30% reduction in BM frequency for >=2 weeks, 9/16 (56%) experienced biochemical response (>=50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted. PMID- 25012988 TI - The Job Embeddedness instrument: an evaluation of validity and reliability. AB - A cross sectional correlational mailed survey was used to assess the validity and reliability of the Job Embeddedness (JE) instrument for predicting nurse retention. A regression model using the variables of JE and age were predictive of nurse retention in a sample of Registered Nurses (RNs) working in long term care (LTC) settings. This study supports the multi-dimensionality, validity and reliability of the underlying JE construct. However a different factor structure was suggested that better fit the data. Long term care organizations (LTC) may benefit from a strategy of increasing the embeddedness of their existing employees in order to increase nurse retention. Job embbededness could be used as a foundation to provide effective nurse retention strategies in LTC settings. PMID- 25012986 TI - Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression. AB - Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members, Bcl2a1 (Bcl2a1a) and Mcl1, and can be effectively targeted by Obatoclax, a small-molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model have uncovered a promising druggable feature of aggressive thyroid cancers. PMID- 25012989 TI - Venous thromboembolism knowledge among older post-hip fracture patients and their caregivers. AB - Patient education about venous thromboembolism (VTE) prevention is needed to prevent complications and costly re-hospitalization. Nurses are uniquely positioned to provide vital education as patients transition from the inpatient setting to after discharge. Still, little is known about patient knowledge deficits and those of their caregivers. The purpose of this study was to explore VTE prevention knowledge in a sample of older hip fracture patients and family caregivers. At the time of hospital discharge, surveys were completed by hip fracture surgery patients (>=65; n=30) and family caregivers (n=30). Participants reported needs for more prophylactic anticoagulation and side effects education. Mean education satisfaction was 3.49 out of 5 among patients and 3.83 among caregivers. Focused patient education regarding the wisdom of VTE prevention, potential risks involved, and patient and caregiver roles in advocating for better prevention measures is needed for these patients at risk for hospital readmission secondary to VTE. PMID- 25012990 TI - Equal improvement in glycaemia with lixisenatide given before breakfast or the main meal of the day. AB - AIMS: The aim of this study is to explore whether administration timing affects glycaemic control by lixisenatide once-daily in type 2 diabetes mellitus (T2DM). METHODS: A phase IIIb, open-label, 1:1 randomized, active-controlled, 24-week multicentre study of T2DM patients inadequately controlled on metformin was conducted. Patients were administered lixisenatide before breakfast or the main meal. The primary endpoint was change from baseline at week 24 in glycated haemoglobin (HbA1c). Other endpoints: changes in body weight, fasting plasma glucose (FPG), 7-point self-monitored plasma glucose (SMPG) and Diabetes Treatment Satisfaction Questionnaire status (DTSQs) score. Adverse events (AEs) were monitored. RESULTS: Mean change in HbA1c from baseline at week 24 was -0.65% (-7.1mmol/mol; main meal) and -0.74% (-8.1mmol/mol; breakfast). Mean changes in FPG, body weight and DTSQs score were comparable between groups. The mean change in body weight (kg) was -2.60 (main meal) and -2.80 (breakfast group). The 7 point SMPG profiles showed greatest reductions in postprandial glucose after the meal at which lixisenatide was administered, with a residual effect seen on the subsequent meal. AE rates were similar between groups, including gastrointestinal AEs. CONCLUSIONS: Lixisenatide before the main meal was noninferior to lixisenatide before breakfast in patients insufficiently controlled on metformin. Lixisenatide treatment allows flexibility in administration timing. PMID- 25012992 TI - Thoracic endovascular aortic repair: are we approaching total endovascular solutions for thoracic aortic disease? AB - Thoracic endovascular aortic repair (TEVAR) has become an attractive alternative treatment option for thoracic aortic disease. New devices and advanced image guided procedures are continuously expanding the indications. This article focuses on currently available endovascular solutions for thoracic aortic disease and future 'all endovascular' directions of TEVAR. Currently available endovascular solutions, such as hybrid operations, chimney stent grafting and transapical stent graft deployment, for ascending aortic pathologies are presented. Additionally, the impact of upcoming new technologies, such as endovascular treatment of Stanford Type A dissections of the ascending aorta, is elaborated. With improving device technology, diverse available stent grafts and imaging modalities, TEVAR has become safer and holds promising potential to expand treatment options, especially for the ascending aorta and the aortic arch. PMID- 25012991 TI - Influences of the neighbourhood food environment on adiposity of low-income preschool-aged children in Los Angeles County: a longitudinal study. AB - BACKGROUND: Few studies have examined the association between the food environment and adiposity in early childhood, a critical time for obesity prevention. The objective of this study was to examine the longitudinal association between neighbourhood food environment and adiposity among low-income preschool-aged children in a major metropolitan region in the USA. METHODS: The study sample was 32 172 low-income preschool-aged children in Los Angeles County who had repeated weight and height measurements collected between ages 2 and 5 years through a federal nutrition assistance programme. We conducted multilevel longitudinal analyses to examine how spatial densities of healthy and unhealthy retail food outlets in the children's neighbourhoods were related to adiposity, as measured by weight-for-height z-score (WHZ), while controlling for neighbourhood-level income and education, family income, maternal education, and child's gender and race/ethnicity. RESULTS: Density of healthy food outlets was associated with mean WHZ at age 3 in a non-linear fashion, with mean WHZ being lowest for those exposed to approximately 0.7 healthy food outlets per square mile and higher for lesser and greater densities. Density of unhealthy food outlets was not associated with child WHZ. CONCLUSIONS: We found a non-linear relationship between WHZ and density of healthy food outlets. Research aiming to understand the sociobehavioural mechanisms by which the retail food environment influences early childhood obesity development is complex and must consider contextual settings. PMID- 25012993 TI - Posaconazole prophylaxis in neutropenic patients with hematological malignancies: limits in clinical practice. AB - Posaconazole (PSZ) is being used for prophylaxis in hematological patients who are at high risk for invasive fungal disease (IFD), but absorption limitations have been reported. Our objective was to assess both the feasibility and the efficacy of PSZ prophylaxis in clinical practice. From March 2010 to September 2010, all patients admitted to our unit for chemotherapy for acute leukemia or hematopoietic stem cell transplantation received optimized PSZ prophylaxis 200 mg four times daily with cola soda. PSZ trough concentrations (Cmin) were monitored at days 5, 7, 14, and 21. The incidence of IFDs was determined and compared to that of a historical control group. Thirty-five consecutive patients were prospectively included. PSZ prophylaxis was interrupted for 29% of them at day 14 and 51% of them at day 21. The main limitations were impracticality of oral feeding (29%) and occurrence of suspected IFDs (23%). PSZ median Cmin were 0.47, 0.40, 0.24, 0.36 MUg/mL at days 5, 7, 14, and 21, respectively. Eighty percent of patient results were lower than the target Cmin of 0.5 MUg/ml on day 14, the higher-risk period associated with neutropenia. Four probable breakthrough IFDs (11%) were diagnosed in 2010; no clear association between PSZ Cmin and occurrence of infection was observed. The incidence of IFDs was unchanged (historical control group: 9.7%; P = 0.72). Implementation of systematic PSZ prophylaxis did not significantly decrease the incidence of IFDs at our center. PSZ interruptions related to mucositis and too low Cmin were the main limitations to its use. PMID- 25012994 TI - Known and novel sources of variability in the nicotine metabolite ratio in a large sample of treatment-seeking smokers. AB - BACKGROUND: The ratio of 3'hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates. METHODS: NMR as a predictive biomarker of cessation outcomes is being investigated (NCT01314001). In addition to strong CYP2A6 genetic influences on NMR, demographic and hormonal factors alter NMR. Here, we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial (N = 1,672). RESULTS: Participants (mean age = 45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians versus African Americans [0.41 (0.20) vs. 0.33 (0.21); P < 0.001], and in females versus males [0.41 (0.22) vs. 0.37 (0.20); P < 0.001]. Among females, birth control pill use (N = 17) and hormone replacement therapy (N = 14) were associated with 19.5% (P = 0.09) and 29.3% (P = 0.06) higher mean NMR, respectively, albeit nonsignificantly. BMI was negatively associated with NMR (Rho = -0.14; P < 0.001), whereas alcohol use (Rho = 0.11; P < 0.001) and cigarette consumption (Rho = 0.12; P < 0.001) were positively associated with NMR. NMR was 16% lower in mentholated cigarette users (P < 0.001). When analyzed together in a linear regression model, these predictors (each <=2%) accounted for <8% of total NMR variation. CONCLUSIONS: Although these factors significantly affected NMR, they contributed little (together <8%; each <=2%) to total NMR variation. IMPACT: Thus, when using NMR, for example, to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification. PMID- 25012995 TI - Automated measurement of volumetric mammographic density: a tool for widespread breast cancer risk assessment. AB - INTRODUCTION: Mammographic density is a strong risk factor for breast cancer and an important determinant of screening sensitivity, but its clinical utility is hampered due to the lack of objective and automated measures. We evaluated the performance of a fully automated volumetric method (Volpara). METHODS: A prospective cohort study included 41,102 women attending mammography screening, of whom 206 were diagnosed with breast cancer after a median follow-up of 15.2 months. Percent and absolute dense volumes were estimated from raw digital mammograms. Genotyping was performed in a subset of the cohort (N = 2,122). We examined the agreement by side and view and compared density distributions across different mammography systems. We also studied associations with established density determinants and breast cancer risk. RESULTS: The method showed good agreement by side and view, and distributions of percent and absolute dense volume were similar across mammography systems. Volumetric density was positively associated with nulliparity, age at first birth, hormone use, benign breast disease, and family history of breast cancer, and negatively with age and postmenopausal status. Associations were also observed with rs10995190 in the ZNF365 gene (P < 1.0 * 10(-6)) and breast cancer risk [HR for the highest vs. lowest quartile, 2.93; 95% confidence interval, 1.73-4.96 and 1.63 (1.10-2.42) for percent and absolute dense volume, respectively]. CONCLUSIONS: In a high throughput setting, Volpara performs well and in accordance with the behavior of established density measures. IMPACT: Automated measurement of volumetric mammographic density is a promising tool for widespread breast cancer risk assessment. PMID- 25012996 TI - Incidence of colorectal adenomas: birth cohort analysis among 4.3 million participants of screening colonoscopy. AB - BACKGROUND: Most colorectal cancers develop from adenomas. We aimed to estimate sex- and age-specific incidence rates of colorectal adenomas and to assess their potential implications for colorectal cancer screening strategies. METHODS: Sex- and age-specific incidence rates of colorectal adenomas were derived by a birth cohort analysis using data from 4,322,085 screening colonoscopies conducted in Germany and recorded in a national database in 2003-2012. In addition, cumulative risks of colorectal cancer among colonoscopically neoplasm-free men and women were estimated by combining adenoma incidence rates with previously derived adenoma-colorectal cancer transition rates. RESULTS: Estimated annual incidence in percentage (95% confidence interval) in age groups 55-59, 60-64, 65-69, 70-74, and 75-79 was 2.4 (2.2-2.6), 2.3 (2.1-2.6), 2.4 (2.1-2.6), 2.2 (1.8-2.5), and 1.8 (1.2-2.3) among men, and 1.4 (1.3-1.5), 1.5 (1.4-1.7), 1.6 (1.4-1.8), 1.6 (1.3 1.8), and 1.2 (0.8-1.6) among women. Estimated 10- and 15-year risks of clinically manifest colorectal cancer were 0.1% and 0.5% or lower, respectively, in all groups assessed. CONCLUSIONS: Annual incidence rates of colorectal adenomas are below 2.5% and 2% among men and women, respectively, and show little variation by age. IMPACT: Risk of clinically manifest colorectal cancer is expected to be very small within 10 years and beyond after negative colonoscopy for men and women at all ages. The use of rescreening after a negative screening colonoscopy above 60 years of age may be very limited. PMID- 25012998 TI - Androgen receptor polymorphism-dependent variation in prostate-specific antigen concentrations of European men. AB - BACKGROUND: Androgens acting via the androgen receptor (AR) stimulate production of PSA, which is a clinical marker of prostate cancer. Because genetic variants in the AR may have a significant impact on the risk of being diagnosed with prostate cancer, the aim was to investigate whether AR variants were associated with the risk of having PSA above clinically used cutoff thresholds of 3 or 4 ng/mL in men without prostate cancer. METHODS: Men without prostate cancer history (n = 1,744) were selected from the European Male Ageing Study cohort of 40 to 79-year-old men from eight different European centers. Using linear and logistic regression models, with age and center as covariates, we investigated whether AR variants (CAG repeat-length and/or SNP genotype) were associated with having serum PSA concentrations above 3 or 4 ng/mL, which often are set as cutoff concentrations for further investigation of prostate cancer. RESULTS: Carriers of the SNP rs1204038 A-allele (16% of the men) were more likely to have PSA>3 and 4 ng/mL (OR; 95% confidence intervals, 1.65; 1.13-2.40 and 1.87; 1.18-2.96, respectively) than G-allele carriers. They also had shorter CAG repeats (median 20 vs. 23, P < 0.0005), but CAG repeat length per se did not affect the PSA concentrations. CONCLUSION: The A-allele of the SNP rs1204038 gives a 65% higher risk of having PSA above 3 ng/mL than the G-allele in men without prostate cancer, and thereby an increased risk of being referred for further examination on suspicion of prostate cancer. IMPACT: Serum PSA as a clinical marker could be improved by adjustment for AR-genotype. PMID- 25012997 TI - Metabolic health reduces risk of obesity-related cancer in framingham study adults. AB - BACKGROUND: It is unknown whether the risk for obesity-related cancers differs between metabolically unhealthy and healthy overweight/obese adults. METHODS: Data on body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and random blood glucose in Framingham Heart Study adults (n = 3,763) ages 55 to 69 years were used to estimate risks of obesity-related cancers (n = 385), including postmenopausal breast, female reproductive, colon, liver, gallbladder, pancreas, and kidney cancers, as well as esophageal adenocarcinomas. Multivariable-adjusted Cox proportional hazards models were used to estimate risk for obesity-related cancers associated with body fat and metabolic health (as defined by glucose levels) among subjects in three risk groups (vs. referent group with normal weight/normal glucose): normal weight/elevated glucose, overweight/normal glucose, and overweight/elevated glucose. RESULTS: Overweight adults [BMI >= 25 or WHtR >= 0.51 (men) and >=0.57 (women)] with elevated glucose (>=125 mg/dL) had a statistically significant 2-fold increased risk of developing obesity-related cancer, whereas overweight adults with normal glucose had a 50% increased risk. Normal-weight adults with elevated glucose had no excess cancer risk. The effects of BMI and WHtR were independent of one another. Finally, overweight women with elevated blood glucose had a 2.6-fold increased risk [95% confidence interval (CI), 1.4-4.9] of female reproductive (cervical, endometrial, uterine cancers) and postmenopausal breast cancers, whereas overweight women with normal glucose levels had only a 70% increased risk (95% CI, 1.1-2.5). CONCLUSION: These results suggest that cancer risk may be lower among metabolically healthy overweight/obese older adults than among overweight/obese adults with metabolic dysfunction. IMPACT: Metabolic dysfunction and obesity act synergistically to increase cancer risk. PMID- 25013001 TI - 45th Mary McMillan lecture: If greatness is a goal.... PMID- 25013000 TI - Predicting response to motor control exercises and graded activity for patients with low back pain: preplanned secondary analysis of a randomized controlled trial. AB - BACKGROUND: Current treatments for low back pain have small effects. A research priority is to identify patient characteristics associated with larger effects for specific interventions. OBJECTIVE: The aim of this study was to identify simple clinical characteristics of patients with chronic low back pain who would benefit more from either motor control exercises or graded activity. DESIGN: This study was a secondary analysis of the results of a randomized controlled trial. METHODS: One hundred seventy-two patients with chronic low back pain were enrolled in the trial, which was conducted in Australian physical therapy clinics. The treatment consisted of 12 initial exercise sessions over an 8-week period and booster sessions at 4 and 10 months following randomization. The putative effect modifiers (psychosocial features, physical activity level, walking tolerance, and self-reported signs of clinical instability) were measured at baseline. Measures of pain and function (both measured on a 0-10 scale) were taken at baseline and at 2, 6, and 12 months by a blinded assessor. RESULTS: Self reported clinical instability was a statistically significant and clinically important modifier of treatment response for 12-month function (interaction: 2.72; 95% confidence interval=1.39 to 4.06). Participants with high scores on the clinical instability questionnaire (>=9) did 0.76 points better with motor control exercises, whereas those who had low scores (<9) did 1.93 points better with graded activity. Most other effect modifiers investigated did not appear to be useful in identifying preferential response to exercise type. LIMITATIONS: The psychometric properties of the instability questionnaire have not been fully tested. CONCLUSIONS: A simple 15-item questionnaire of features considered indicative of clinical instability can identify patients who respond best to either motor control exercises or graded activity. PMID- 25012999 TI - Task-specific training in Huntington disease: a randomized controlled feasibility trial. AB - BACKGROUND: Task-specific training may be a suitable intervention to address mobility limitations in people with Huntington disease (HD). OBJECTIVE: The aim of this study was to assess the feasibility and safety of goal-directed, task specific mobility training for individuals with mid-stage HD. DESIGN: This study was a randomized, blinded, feasibility trial; participants were randomly assigned to control (usual care) and intervention groups. SETTING: This multisite study was conducted in 6 sites in the United Kingdom. PATIENTS: Thirty individuals with mid-stage HD (13 men, 17 women; mean age=57.0 years, SD=10.1) were enrolled and randomly assigned to study groups. INTERVENTION: Task-specific training was conducted by physical therapists in participants' homes, focusing on walking, sit to-stand transfers, and standing, twice a week for 8 weeks. Goal attainment scaling was used to individualize the intervention and monitor achievement of personal goals. MEASUREMENTS: Adherence and adverse events were recorded. Adjusted between-group comparisons on standardized outcome measures were conducted at 8 and 16 weeks to determine effect sizes. RESULTS: Loss to follow-up was minimal (n=2); adherence in the intervention group was excellent (96.9%). Ninety-two percent of goals were achieved at the end of the intervention; 46% of the participants achieved much better than expected outcomes. Effect sizes on all measures were small. LIMITATIONS: Measurements of walking endurance were lacking. CONCLUSIONS: The safety of and excellent adherence to a home-based, task-specific training program, in which most participants exceeded goal expectations, are encouraging given the range of motivational, behavioral, and mobility issues in people with HD. The design of the intervention in terms of frequency (dose), intensity (aerobic versus anaerobic), and specificity (focused training on individual tasks) may not have been sufficient to elicit any systematic effects. Thus, a larger-scale trial of this specific intervention does not seem warranted. PMID- 25013002 TI - Electrophysiological Evidence for a Sensory Recruitment Model of Somatosensory Working Memory. AB - Sensory recruitment models of working memory assume that information storage is mediated by the same cortical areas that are responsible for the perceptual processing of sensory signals. To test this assumption, we measured somatosensory event-related brain potentials (ERPs) during a tactile delayed match-to-sample task. Participants memorized a tactile sample set at one task-relevant hand to compare it with a subsequent test set on the same hand. During the retention period, a sustained negativity (tactile contralateral delay activity, tCDA) was elicited over primary somatosensory cortex contralateral to the relevant hand. The amplitude of this component increased with memory load and was sensitive to individual limitations in memory capacity, suggesting that the tCDA reflects the maintenance of tactile information in somatosensory working memory. The tCDA was preceded by a transient negativity (N2cc component) with a similar contralateral scalp distribution, which is likely to reflect selection of task-relevant tactile stimuli at the encoding stage. The temporal sequence of N2cc and tCDA components mirrors previous observations from ERP studies of working memory in vision. The finding that the sustained somatosensory delay period activity varies as a function of memory load supports a sensory recruitment model for spatial working memory in touch. PMID- 25013004 TI - "A day in my life" photography project: the silent voice of pediatric bone marrow transplant patients. AB - A photovoice project was conducted with pediatric bone marrow transplant (BMT) patients to examine their coping skills and interpretation of their experience during a BMT, especially when hospitalized. We also wanted to determine how photovoice could be used within a pediatric BMT unit. Sixteen children (ages 4 14) and 2 young adults (ages 22 and 25) from a pediatric BMT unit participated in the project. Six BMT outpatients participated in the data analysis and evaluation phase. Fourteen clinical staff evaluated the impact of the project on their practice. Three primary themes emerged from the pre- and post-BMT photos, accompanying detailed notes, and BMT outpatient analysis of the photos: (a) BMT is "torture," (b) BMT is "time slipping away," and (c) BMT requires normalization, comfort, distraction, and support. BMT patients and staff concluded that photovoice helped express and release emotions regarding the challenges of BMT. BMT staff noted that the results of this project reminded them of the importance of being patient-centered and mindful of patient experience and the therapeutic relationship. PMID- 25013005 TI - Knowledge and risk perception of late effects among childhood cancer survivors and parents before and after visiting a childhood cancer survivor clinic. AB - Survivors of childhood cancer are at risk for a variety of treatment-related late effects and require lifelong individualized surveillance for early detection of late effects. This study assessed knowledge and perceptions of late effects risk before and after a survivor clinic visit. Young adult survivors (>= 16 years) and parents of child survivors (< 16 years) were recruited prior to initial visit to a cancer survivor program. Sixty-five participants completed a baseline survey and 50 completed both a baseline and follow-up survey. Participants were found to have a low perceived likelihood of developing a late effect of cancer therapy and many incorrect perceptions of risk for individual late effects. Low knowledge before clinic (odds ratio = 9.6; 95% confidence interval, 1.7-92.8; P = .02) and low perceived likelihood of developing a late effect (odds ratio = 18.7; 95% confidence interval, 2.7-242.3; P = .01) were found to predict low knowledge of late effect risk at follow-up. This suggests that perceived likelihood of developing a late effect is an important factor in the individuals' ability to learn about their risk and should be addressed before initiation of education. PMID- 25013006 TI - A nurse practitioner patient care team: implications for pediatric oncology. AB - The role of the pediatric advanced practice registered nurse continues to evolve within the ever-changing field of health care. In response to increased demand for health care services and because of a variety of changes in the health care delivery system, nurse practitioner patient care teams are an emerging trend in acute care settings. Care provided by nurse practitioner teams has been shown to be effective, efficient, and comprehensive. In addition to shorter hospital stays and reduced costs, nurse practitioner teams offer increased quality and continuity of care, and improved patient satisfaction. Nurse practitioner patient care teams are well suited to the field of pediatric oncology, as patients would benefit from care provided by specialized clinicians with a holistic focus. This article provides health care professionals with information about the use of nurse practitioner patient care teams and implications for use in pediatric oncology. PMID- 25013007 TI - Impact of a teen weekend on the social support needs of adolescents with cancer. AB - Adolescents are particularly vulnerable to the psychosocial stressors of a cancer diagnosis because of the unique expectations of their developmental stage. Their developing autonomy and self-image place them at increased risk for negative outcomes related to cancer diagnosis. One response to the developmental and supportive care needs of adolescents with cancer (AYA) was the development of a teen weekend, named Teenapalooza by participants, which was intended to provide a social outlet for AYA to spend time with other AYA. Teens engaged in activities together and spent the night at a centrally located venue supervised by trained medical and child life staff. It became apparent to staff that Teenapalooza was providing more than fun and an opportunity to spend time with other AYA to participants. However, the mechanisms of support were poorly understood. A convenience sample of 9 prior Teenapalooza participants, aged 14 to 17 years, participated in qualitative interviews to better understand these mechanisms so that future interventions could build on this supportive framework. PMID- 25013008 TI - Assessing distractors and teamwork during surgery: developing an event-based method for direct observation. AB - OBJECTIVE: To develop a behavioural observation method to simultaneously assess distractors and communication/teamwork during surgical procedures through direct, on-site observations; to establish the reliability of the method for long (>3 h) procedures. METHODS: Observational categories for an event-based coding system were developed based on expert interviews, observations and a literature review. Using Cohen's kappa and the intraclass correlation coefficient, interobserver agreement was assessed for 29 procedures. Agreement was calculated for the entire surgery, and for the 1st hour. In addition, interobserver agreement was assessed between two tired observers and between a tired and a non-tired observer after 3 h of surgery. RESULTS: The observational system has five codes for distractors (door openings, noise distractors, technical distractors, side conversations and interruptions), eight codes for communication/teamwork (case-relevant communication, teaching, leadership, problem solving, case-irrelevant communication, laughter, tension and communication with external visitors) and five contextual codes (incision, last stitch, personnel changes in the sterile team, location changes around the table and incidents). Based on 5-min intervals, Cohen's kappa was good to excellent for distractors (0.74-0.98) and for communication/teamwork (0.70-1). Based on frequency counts, intraclass correlation coefficient was excellent for distractors (0.86-0.99) and good to excellent for communication/teamwork (0.45-0.99). After 3 h of surgery, Cohen's kappa was 0.78-0.93 for distractors, and 0.79-1 for communication/teamwork. DISCUSSION: The observational method developed allows a single observer to simultaneously assess distractors and communication/teamwork. Even for long procedures, high interobserver agreement can be achieved. Data collected with this method allow for investigating separate or combined effects of distractions and communication/teamwork on surgical performance and patient outcomes. PMID- 25013009 TI - Speech-triggered atrial tachycardia originating from the superior vena cava. PMID- 25013010 TI - Stepwise delayed potential ablation using simultaneous three-dimensional delayed potential and voltage mapping in a patient with epicardial ventricular tachycardias from a left ventricular aneurysm. PMID- 25013011 TI - Atrial fibrillation in patients with ischaemic stroke in the Swedish national patient registers: how much do we miss? AB - AIMS: Data from national discharge registers are commonly used to estimate prevalence and incidence of atrial fibrillation (AF) in epidemiology studies. However, sensitivity and specificity of register-based AF diagnosis have not been evaluated. We sought to assess the validity of AF diagnosis in the Swedish Patient Register against electrocardiography (ECG) documentation of AF. METHODS AND RESULTS: The study sample comprised of 336 patients [median age 76 (interquartile range (IQR) 67-82 years, 136 female] with first-ever ischaemic stroke, enroled in the Lund Stroke Register from March 2001 to February 2002 and 1 : 1 age- and gender-matched control subjects without stroke from the population register. Data was exported from the patient register in October 2011 (the end of follow-up). Atrial fibrillation documentation by ECG was assessed using an electronic archive containing all ECGs taken in the hospital catchment area starting in 1988. A total of 7247 ECGs were reviewed, with the median number of ECGs per person being 7.5 (IQR 3-15). Atrial fibrillation was detected by ECG in 190 patients; and in 188 patients by linkage with patient register. In most patients, AF was documented first by ECG data, with median time to register diagnosis being 16 days (IQR 3-859). Specificity of AF diagnosis in the Swedish Patient Register was 93%, sensitivity was 80%. CONCLUSION: Despite the high specificity, AF diagnosis in the Swedish Patient Register assessed in the population of ischaemic stroke patients and age- and gender-matched control subjects has modest sensitivity, which may result in underestimating prevalent and incident AF cases if only register data are used for identification of subjects with AF in epidemiology studies. PMID- 25013012 TI - The atrial fibrillation epidemic: a validated diagnosis, or not? PMID- 25013013 TI - Radiofrequency ablation of accessory pathways in patients with the Wolff Parkinson-White syndrome: the long-term mortality and risk of atrial fibrillation. AB - AIMS: To assess the long-term mortality and occurrence of post-ablation atrial fibrillation in patients undergoing a radiofrequency ablation for the Wolff Parkinson-White (WPW) syndrome. METHODS AND RESULTS: A retrospective cohort study of patients (N = 362) subjected to radiofrequency ablation of the WPW syndrome at Aarhus University Hospital from 1990 to 2011. A comparison cohort (N = 3619) was generated from the Danish National Board of Health Central Population Registry. We found no significant difference in all-cause mortality when comparing the WPW group with the control group [hazard ratio (HR): 0.77 and confidence interval (CI): 0.47-1.25]. After radiofrequency ablation, the WPW group had a significantly higher risk of atrial fibrillation than the control group (HR: 4.77 and CI: 3.05-7.43). Atrial fibrillation prior to ablation (HR: 4.66 and CI: 2.09 10.41) and age over 50 years (HR: 9.79 and CI: 4.29-22.36) at the time of ablation were independent risk factors for post-ablation atrial fibrillation in the WPW group. CONCLUSION: Patients with radiofrequency ablation-treated WPW syndrome have a post-ablation mortality that is similar to the background population. The risk of atrial fibrillation remains high after radiofrequency ablation of the WPW syndrome. PMID- 25013015 TI - African elephants (Loxodonta africana) recognize visual attention from face and body orientation. AB - How do animals determine when others are able and disposed to receive their communicative signals? In particular, it is futile to make a silent gesture when the intended audience cannot see it. Some non-human primates use the head and body orientation of their audience to infer visual attentiveness when signalling, but whether species relying less on visual information use such cues when producing visual signals is unknown. Here, we test whether African elephants (Loxodonta africana) are sensitive to the visual perspective of a human experimenter. We examined whether the frequency of gestures of head and trunk, produced to request food, was influenced by indications of an experimenter's visual attention. Elephants signalled significantly more towards the experimenter when her face was oriented towards them, except when her body faced away from them. These results suggest that elephants understand the importance of visual attention for effective communication. PMID- 25013016 TI - Ischemic postconditioning relieves cerebral ischemia and reperfusion injury through activating T-LAK cell-originated protein kinase/protein kinase B pathway in rats. AB - BACKGROUND AND PURPOSE: Ischemic postconditioning (IPostC) protects against ischemic brain injury. To date, no study has examined the role of T-LAK-cell originated protein kinase (TOPK) in IPostC-afforded neuroprotection. We explored the molecular mechanism related with TOPK in antioxidant effect of IPostC against ischemia/reperfusion. METHODS: Focal ischemia was induced in rats by transient middle cerebral artery occlusion. Reactive oxygen species production in the peri infarct cortex was detected using dihydroethidium. Malondialdehyde, as a marker of lipid peroxidation, and 3-nitrotyrosine, as a marker of protein oxidation, were detected by ELISA. The expression or location of antioxidant proteins and signal molecules TOPK, phosphatase, and tensin homolog, and Akt was analyzed by Western blotting and immunofluorescence. RESULTS: Our results revealed that IPostC relieved transient middle cerebral artery occlusion-induced oxidative damage by reducing reactive oxygen species, malondialdehyde, and 3-nitrotyrosine accumulation in the peri-infarct cortex and raised levels of antioxidants perioxiredoxin-1, peroxiredoxin-2, and thioredoxin-1. In addition, IPostC increased p-AKT and p-TOPK levels, which colocalized in neural cells. In vitro TOPK knockdown by small interfering RNA decreased the levels of antioxidants peroxiredoxin-1, thioredoxin, and manganese superoxide dismutase activity in PC12 cells. In vivo intracerebroventricular injection of TOPK small interfering RNA reversed IPostC-induced neuroprotection by increasing infarct volume and nitric oxide content and reducing manganese superoxide dismutase activity. Moreover, IPostC-evoked Akt activation was blocked by TOPK small interfering RNA in vivo, but the decreased phosphorylated phosphatase and tensin homolog level in ischemia/reperfusion was not influenced by IPostC or by TOPK small interfering RNA treatment. CONCLUSIONS: Our results suggest that the antioxidative effects of TOPK/Akt might contribute to the neuroprotection of IPostC treatment against transient middle cerebral artery occlusion. PMID- 25013017 TI - Mammalian target of rapamycin cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke. AB - BACKGROUND AND PURPOSE: Whether the mammalian target of rapamycin (mTOR) pathway is protective against brain injury from stroke or is detrimental is controversial, and whether it is involved in the protective effects of ischemic postconditioning (IPC) against stroke is unreported. Our study focuses on the protective role of mTOR against neuronal injury after stroke with and without IPC. METHODS: We used both an in vitro oxygen-glucose deprivation model with a mixed neuronal culture and hypoxic postconditioning, as well as an in vivo stroke model with IPC. Rapamycin, a specific pharmacological inhibitor of mTOR, and mTOR short hairpin RNA lentiviral vectors were used to inhibit mTOR activity. A lentiviral vector expressing S6K1, a downstream molecule of mTOR, was used to confirm the protective effects of mTOR. Infarct sizes were measured and protein levels were examined by Western blot. RESULTS: We report that stroke resulted in reduced levels of phosphorylated proteins in the mTOR pathway, including S6K1, S6, and 4EBP1, and that IPC increased these proteins. mTOR inhibition, both by the mTOR inhibitor rapamycin and by mTOR short hairpin RNA, worsened ischemic outcomes in vitro and in vivo and abolished the protective effects of hypoxic postconditioning and IPC on neuronal death in vitro and brain injury size in vivo. Overexpression of S6K1 mediated by lentiviral vectors significantly attenuated brain infarction. CONCLUSIONS: mTOR plays a crucial protective role in brain damage after stroke and contributes to the protective effects of IPC. PMID- 25013019 TI - Return to work after stroke: a nursing state of the science. PMID- 25013018 TI - Chronic stress, depressive symptoms, anger, hostility, and risk of stroke and transient ischemic attack in the multi-ethnic study of atherosclerosis. AB - BACKGROUND AND PURPOSE: This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults. METHODS: Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years. RESULTS: One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all P for trend <=0.02) but not for trait anger (P>0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16-2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11-2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29-3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor-adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables. CONCLUSIONS: Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors. PMID- 25013020 TI - Standard-dose intravenous tissue-type plasminogen activator for stroke is better than low doses. AB - BACKGROUND AND PURPOSE: It remains uncertain whether lower dose intravenous tissue-type plasminogen activator (tPA) for stroke is as effective and safe as the standard dose. METHODS: We analyzed data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China). Patients who were treated within 4.5 hours after symptom onset were included. These patients were divided into 5 groups according to tPA doses given: <0.5, 0.5 to 0.7, 0.7 to 0.85, 0.85 to 0.95, and >=0.95 mg/kg. Symptomatic intracranial hemorrhage, mortality, and 90-day outcome assessed by modified Rankin scale were analyzed. RESULTS: A total of 919 patients were enrolled. Among them, 9 had <0.5 mg/kg, 75 had 0.5 to 0.7 mg/kg, 131 had 0.7 to 0.85 mg/kg, 678 had 0.85 to 0.95 mg/kg, and 26 had >=0.95 mg/kg. Because of sample sizes, only 0.5 to 0.7, 0.7 to 0.85, and 0.85 to 0.95 mg/kg groups were compared. Median tPA doses were 0.64, 0.79, and 0.90 mg, respectively. After adjustment for the baseline variables, there were no significant differences in mortality(5.41% versus 8.66% versus 7.36%; P=0.695) and symptomatic intracranial hemorrhage (0% versus 3.82% versus 1.46%; P=0.106). The 0.5 to 0.7 mg/kg group had less excellent recovery outcome (modified Rankin scale, 0-1) than 0.85 to 0.95 mg/kg group (41.89% versus 53.83%; odds ratio=0.58; P=0.031) at 90 days. The 0.70 to 0.85 mg/kg group had less functional independence outcome (modified Rankin scale, 0-2) than 0.85 to 0.95 mg/kg group (54.33% versus 64.51%; odds ratio=0.66; P=0.036) at 90 days. CONCLUSIONS: Our study suggests that standard-dose intravenous tPA for stroke had more favorable outcome without increasing the risk of symptomatic intracranial hemorrhage than low-dose tPA. For Asian people, 0.9 mg/kg should be the optimal dose of tPA to treat acute ischemic stroke. PMID- 25013021 TI - A new micro-computed tomography-based high-resolution blood-brain barrier imaging technique to study ischemic stroke. AB - BACKGROUND AND PURPOSE: Micro-computed tomography (mCT) offers high-resolution images, but it suffers from low contrast sensitivity and poor soft tissue contrast. We introduce a new mCT imaging technique with improved sensitivity for the dynamic spatial and temporal characterization of poststroke blood-brain barrier (BBB) dysfunction in small animals in vivo. METHODS: Transient middle cerebral artery occlusion was induced for 1 hour in 10- to 12-week-old C57BL/6 mice (n=35). At 4, 24, and 48 hours after ischemic stroke, serial in vivo mCT imaging was performed 5 minutes after intravenous infusion (n=3) or intracarotid infusion of iopromide (240 MUL) for 5 minutes (n=32). After intravenous injection of 2% Evans blue, we performed ex vivo near-infrared fluorescent imaging of parenchymal Evans blue leakage, visual assessment of poststroke parenchymal hematoma, triphenyltetrazolium chloride staining of the brain tissue, and quantitative mapping of stroke-related brain lesions. RESULTS: Infarct-related BBB dysfunction could be demonstrated with intra-arterial but not with intravenous infusion of iopromide. Iopromide leakage across the dysfunctional BBB showed a monophasic (not biphasic) course for 48 hours after ischemic insult in both the parenchymal hematoma (n=5) and the non-parenchymal hematoma (n=24) groups, with relatively severe leakiness and greater hemispheric midline shift in animals with hemorrhage. Parenchymal staining on in vivo mCT overlapped with ex vivo fluorescent staining because of Evans blue. Multivariable analyses showed that midline shift and the amount of iopromide leakage at each of the 3 time points predicted the final infarct size at 48 hours. CONCLUSIONS: The new mCT BBB imaging technique, based on the intra-arterial infusion of clinically available iopromide, allows serial quantitative visualization of poststroke BBB dysfunction in mice, with high resolution and in a sensitive manner. PMID- 25013022 TI - The value of resting-state functional magnetic resonance imaging in stroke. PMID- 25013023 TI - Malignant hemispheric infarction: diagnosis and management by hemicraniectomy. PMID- 25013024 TI - Response to letter regarding article, "Non-ST-segment-elevation myocardial infarction in patients undergoing carotid endarterectomy or carotid artery stent placement". PMID- 25013025 TI - A dark side of subcortical diffusion-weighted lesions? Characteristics, cause, and outcome in large subcortical infarction: the Bergen Norwegian stroke cooperation study. AB - BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) is highly accurate in identifying and locating ischemic stroke injury. Few studies using DWI have investigated large subcortical infarctions (LSIs). We aimed to study clinical characteristics, cause, and outcome in patients with ischemic stroke with LSI diagnosed on DWI and compare these with those who had lacunar DWI lesions or DWI lesions located elsewhere. METHODS: Patients with stroke admitted between February 2006 and July 2013 were prospectively registered in a stroke database and examined with DWI. Patients with DWI lesions classified as LSI (subcortical, >=15 mm) were compared with those with lacunar lesions (subcortical, <15 mm, lacunar infarction [LI]), cortical lesions (cortical infarction [CI]), or no LSI, which included LI, CI, mixed cortical-subcortical, cerebellar, brain stem, and combined lesion locations. RESULTS: A total of 1886 patients with ischemic stroke were included, of which 128 patients (6.8%) had LSI, 317 (16.8%) LI, and 544 (28.8%) CI. The no LSI group included 1758 patients. Occlusive pathology in the proximal middle cerebral artery was more frequent in patients with acute stroke with LSI. Lacunar syndrome was associated with LSI when compared with CI and no LSI. Unknown cause was frequent in the LSI group (60.4%) and independently associated with LSI in the LSI versus LI (P<0.001), LSI versus CI (P=0.002), and LSI versus no LSI population (P<0.001). LSI was independently associated with unfavorable outcome, whether compared with LI (P=0.002), CI (P<0.001), or no LSI (P=0.002). CONCLUSIONS: LSI is associated with distinct clinical characteristics, unknown cause, and unfavorable outcome, which separates this stroke entity from patients with lacunar subcortical DWI lesions or DWI lesions located elsewhere. PMID- 25013026 TI - alpha4 integrin is a regulator of leukocyte recruitment after experimental intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is swiftly followed by an inflammatory response. A key component of this response is the recruitment of leukocytes into the brain, which promotes neurological injury in rodent models. However, the mechanisms by which leukocytes transmigrate across the endothelium into the injured brain are unclear. The present study examines leukocyte adhesion molecules (alpha4 integrin, L-selectin, and alphaLbeta2 integrin) on 4 leukocyte subtypes to determine which are important for leukocyte recruitment after ICH. METHODS: We used the blood injection mouse model of ICH, whereby 25 MUL of blood was injected into the striatum. Flow cytometry was used to quantify leukocyte populations and adhesion molecule expression in brain and blood. An alpha4 integrin-blocking antibody was administered to evaluate the contribution of alpha4 integrin in leukocyte migration and neurological injury. RESULTS: alpha4 integrin was elevated on all leukocyte populations in brain after ICH, whereas L selectin was unchanged and alphaLbeta2 was increased only on T cells. Antagonism of alpha4 resulted in decreased leukocyte transmigration and lessened neurobehavioral disability. CONCLUSIONS: alpha4 integrin is an important cell adhesion molecule involved in neuroinflammation after ICH. PMID- 25013027 TI - Extraction and separation of polysaccharides from Laminaria japonica by size exclusion chromatography. AB - A large number of studies have suggested that polysaccharides, such as fucoidan and laminarin, in various seaweeds have significant biological properties. A different distribution of molecular weights is a prominent sign of many polysaccharides. Therefore, a simple, fast and reliable high-performance size exclusion chromatography (HPSEC) method was proposed to separate fucoidan and laminarin from Laminaria japonica. After evaluating the different separation conditions for HPSEC, such as the type of mobile phase and flow rate, an acid extraction method was established and optimized by a systematic investigation of the influencing factors. Under the optimal conditions, 169.2 and 383.8 mg g(-1) of fucoidan and laminarin, respectively, were extracted. This method is suitable for the extraction and separation of polysaccharides with good reproducibility of the retention time, acceptable linearity, small relative standard deviation and low detection limits. PMID- 25013028 TI - Studies on quantitative determination of total alkaloids and berberine in five origins of crude medicine "Sankezhen". AB - The roots of Berberis plants are widely used as a traditional Chinese medicine called "Sankezhen", having the activities of antibacterial and anti-inflammatory, and the ingredients are alkaloids. This work aims to study and compare the total alkaloids and individual alkaloid (berberine) contents in roots and stems from five origins of Berberis plants (Berberis soulieana Schneid., B. henryana Schneid., B. triacanthophora Fedde, B. gagnepainii Schneid. and B. bergmanniae Schneid.) and provides some references for resource and quality evaluation of the medicine. Acid dye colorimetry and high-performance liquid chromatography were used in the determination. The results showed that the contents for the total alkaloids in root and stem samples were in the range of 1.60-4.72% and 0.76 2.70%, while those of the berberine were 0.70-2.92% and 0.23-1.07%. With higher contents of the total alkaloids and berberine, the roots of B. soulieana, B. gagnepainii and B. bergmanniae were good sources of "Sankezhen". Meanwhile, the contents were also high in stems of the three plants, indicating that the stems were likely to be alternative sources of "Sankezhen" after further research. As the results of precision, stability and recovery tests shown, the methods were simple, rapid and reliable, and provided valuable basis for quality evaluation and new resource investigation of "Sankezhen". PMID- 25013029 TI - Development and validation of a stability-indicating micellar liquid chromatographic method for the determination of timolol maleate in the presence of its degradation products. AB - A stability-indicating micellar liquid chromatographic (MLC) method was developed and validated for the quantitative determination of timolol maleate (TM) in the presence of its degradation products resulting from accelerated degradation in a run time not more than 8 min. TM was subjected to stress conditions of hydrolysis (including alkaline, acidic and thermal hydrolysis) and oxidation. An isocratic, rapid and mobile phase saving the micellar LC method was developed with a BioBasic phenyl column (150 * 1.0 mm, 5 um particle size) and a micellar mobile phase composed of 0.1 M sodium dodecyl sulfate, 10% of 1-propanol and 0.1% of triethylamine in 0.035 M ortho-phosphoric acid. The flow rate of the mobile phase was 0.1 mL/min. UV detection was adjusted at 298 nm and performed at room temperature. The method has been validated according to the International Conference on Harmonisation guidelines. The method is successfully applied for the determination of TM in bulk powder and pharmaceutical dosage form. PMID- 25013030 TI - The role of worksite health screening: a policy statement from the American Heart Association. PMID- 25013031 TI - Comprehensive investigation of radon exposure in Austrian tourist mines and caves. AB - According to Austrian Law, dose assessments in workplaces with potentially enhanced radon exposures are mandatory since 2008, including tourist mines and caves. A pilot study was carried out to evaluate the situation to test the measurement methods and to specify the main parameters controlling the radon concentration in tourist mines and caves. Radon was measured in six mines and three caves for 1 y, along with determining thoron and equilibrium factors and taking into account climatic, geological and site-related effects. The radon concentrations have a seasonal dependence with maximum in summer and minimum in winter, related to natural ventilation. Radon concentrations in the karst caves were quite low, as it was in the salt mine, whereas radon concentrations in copper and silver mines were high. The dose assessment of the employees yielded doses above 6 mSv a(-1) only in the copper mine. PMID- 25013032 TI - A comparison study of radiation exposure to patients during EVAR and Dyna CT in an angiosuite vs. an operating theatre. AB - The aim of this study was to assess the patient dosimetric impact of endovascular abdominal aortic aneurysm repair (EVAR), both in an operating theatre (OR) and in an angiosuite (AS), with the facility of Dynamic CT (Dyna CT, Siemens AG, Berlin, Germany). One hundred and forty-six consecutive EVAR procedures dating from May 2011 to March 2013 were analysed. These were performed either in an OR (n = 97) using a mobile C-arm or in an AS (n = 49) equipped with a ceiling-mounted angiography system. Air kerma area product (P(KA)) and total air kerma at reference point (K(a,r)) values were reported for all procedures and Dyna CT. Radiation exposure during EVAR was quite low in the majority of patients but nearly 50 % higher if performed in AS vs. OR. Median Dyna CT K(a,r) was the same as an entire EVAR procedure in OR. The higher patient's radiation exposure recorded in the AS should be balanced with the technical advantages given to the EVAR procedure. PMID- 25013033 TI - Dosimetric investigations of Tb3+-doped strontium silicate phosphor. AB - Tb(3+)-doped SrSiO(3) phosphor synthesised by co-precipitation technique exhibits intense green emission due to cross-relaxation phenomena between Tb(3+) ions. Dosimetric properties of this phosphor have been investigated using thermoluminescence (TL) technique. A dosimetrically useful glow peak observed was at 581 K along with a linear dose response over the wide dose range (100 mGy-4 Gy). TL parameters such as trap depth (E), frequency factor (s) and the order of kinetics (b) are determined by different methods such as Chen's peak shape, initial rise, isothermal decay and variable heating rate methods. Results of these methods are compared and reported in this study. PMID- 25013034 TI - The Spanish indoor radon mapping strategy. AB - Indoor radon mapping still represents a valuable tool for drawing the picture of the exposure of general public due to radon and radon progeny inhalation in a residential context. The information provided by means of a map is useful not only as awareness and strategic element for authorities and policy-makers, but also as a scientific start-up point in the design of epidemiological and other specific studies on exposure to natural radiation. The requirements for a good mapping are related to harmonisation criteria coming from European recommendations, as well as to national/local characteristics and necessities. Around 12,000 indoor radon measurements have been made since the Spanish national radon programme began at the end of the 1980s. A significant proportion of them resulted from the last campaign performed from 2009 to 12. This campaign completed the first version of a map based on a grid 10 * 10 km(2). In this paper, the authors present the main results of a new map together with the criteria adopted to improve the number of measurements and the statistical significance of them. PMID- 25013035 TI - A focus on child development. PMID- 25013037 TI - Indigenous peoples. Uncontacted tribe in Brazil emerges from isolation. PMID- 25013039 TI - Europe. Conflict erupts over landmark E.U. neuroscience plan. PMID- 25013038 TI - Nuclear weapons. Medical isotopes confound nuclear test monitoring. PMID- 25013040 TI - Water. India plans the grandest of canal networks. PMID- 25013041 TI - Paleoanthropology. RIP for a key Homo species? PMID- 25013042 TI - Monkey fever unbound. PMID- 25013043 TI - Microbiology. Taking the pulse of ocean microbes. PMID- 25013044 TI - HIV/AIDS. A fitness bottleneck in HIV-1 transmission. PMID- 25013045 TI - Imaging techniques. Low-energy electron diffraction at ultrafast speeds. PMID- 25013046 TI - Physics. An optical twist for triplet superconductors. PMID- 25013047 TI - Microbiology. A flipping cell wall ferry. PMID- 25013048 TI - Medicine. Hepatitis C can be cured globally, but at what cost? PMID- 25013049 TI - Biochemistry. Fishing for peroxidase protons. PMID- 25013050 TI - HIV/AIDS. Persistence by proliferation? PMID- 25013051 TI - Oceans. Microplastics in the seas. PMID- 25013052 TI - Twitter: big data opportunities. PMID- 25013053 TI - Twitter: big data opportunities--response. PMID- 25013054 TI - Leadership void for "designer baby" ethics. PMID- 25013055 TI - Science communication. Comment on "Quantifying long-term scientific impact". AB - Wang et al. (Reports, 4 October 2013, p. 127) claimed high prediction power for their model of citation dynamics. We replicate their analysis but find discouraging results: 14.75% papers are estimated with unreasonably large MU (>5) and lambda (>10) and correspondingly enormous prediction errors. The prediction power is even worse than simply using short-term citations to approximate long term citations. PMID- 25013056 TI - Science communication. Response to Comment on "Quantifying long-term scientific impact". AB - Wang, Mei, and Hicks claim that they observed large mean prediction errors when using our model. We find that their claims are a simple consequence of overfitting, which can be avoided by standard regularization methods. Here, we show that our model provides an effective means to identify papers that may be subject to overfitting, and the model, with or without prior treatment, outperforms the proposed naive approach. PMID- 25013058 TI - Australia. First, do harm reduction. PMID- 25013057 TI - Strategies against HIV/AIDS. Australia shows its neighbors how to stem an epidemic. Introduction. PMID- 25013059 TI - The limits of success. PMID- 25013060 TI - Papua New Guinea. In PNG, the epidemic that wasn't. PMID- 25013061 TI - Prevention, Papua New Guinea style. PMID- 25013062 TI - The circumcision conundrum. PMID- 25013063 TI - Indonesia. A consummate insider pushes ideas from outside Indonesia. PMID- 25013064 TI - Malaysia. Malaysia tries to follow Australia's path. PMID- 25013065 TI - End of AIDS--hype versus hope. PMID- 25013066 TI - A critical question for HIV vaccine development: which antibodies to induce? AB - A vaccine against HIV-1 must prevent infection against genetically diverse virus strains. Two approaches are currently being pursued to elicit antibody-mediated protection: vaccines that induce potent and broadly reactive neutralizing antibodies (bnAbs) or vaccines that induce "conventional antibodies," which are less potent and broadly neutralizing in comparison. Although bnAbs may provide the greatest level of protection, their structural and genetic characteristics make their elicitation through vaccination a major challenge. In contrast, conventional HIV-1 antibodies have been induced by vaccination and correlated with reduced HIV-1 infection in a phase III vaccine trial. Here, I present evidence that both approaches should be pursued with equal vigor. PMID- 25013068 TI - Space weather. Ionospheric control of magnetotail reconnection. AB - Observed distributions of high-speed plasma flows at distances of 10 to 30 Earth radii (R(E)) in Earth's magnetotail neutral sheet are highly skewed toward the premidnight sector. The flows are a product of the magnetic reconnection process that converts magnetic energy stored in the magnetotail into plasma kinetic and thermal energy. We show, using global numerical simulations, that the electrodynamic interaction between Earth's magnetosphere and ionosphere produces an asymmetry consistent with observed distributions in nightside reconnection and plasmasheet flows and in accompanying ionospheric convection. The primary causal agent is the meridional gradient in the ionospheric Hall conductance which, through the Cowling effect, regulates the distribution of electrical currents flowing within and between the ionosphere and magnetotail. PMID- 25013069 TI - Superconductivity. Observation of broken time-reversal symmetry in the heavy fermion superconductor UPt3. AB - Models of superconductivity in unconventional materials can be experimentally differentiated by the predictions they make for the symmetries of the superconducting order parameter. In the case of the heavy-fermion superconductor UPt3, a key question is whether its multiple superconducting phases preserve or break time-reversal symmetry (TRS). We tested for asymmetry in the phase shift between left and right circularly polarized light reflected from a single crystal of UPt3 at normal incidence and found that this so-called polar Kerr effect appears only below the lower of the two zero-field superconducting transition temperatures. Our results provide evidence for broken TRS in the low-temperature superconducting phase of UPt3, implying a complex two-component order parameter for superconductivity in this system. PMID- 25013067 TI - Immunologic strategies for HIV-1 remission and eradication. AB - Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4(+) T cells and perhaps other long-lived cellular reservoirs. In this Review, we discuss the role of the immune system in the establishment and maintenance of the latent HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which may eventually contribute to a curative intervention. PMID- 25013070 TI - Heme enzymes. Neutron cryo-crystallography captures the protonation state of ferryl heme in a peroxidase. AB - Heme enzymes activate oxygen through formation of transient iron-oxo (ferryl) intermediates of the heme iron. A long-standing question has been the nature of the iron-oxygen bond and, in particular, the protonation state. We present neutron structures of the ferric derivative of cytochrome c peroxidase and its ferryl intermediate; these allow direct visualization of protonation states. We demonstrate that the ferryl heme is an Fe(IV)=O species and is not protonated. Comparison of the structures shows that the distal histidine becomes protonated on formation of the ferryl intermediate, which has implications for the understanding of O-O bond cleavage in heme enzymes. The structures highlight the advantages of neutron cryo-crystallography in probing reaction mechanisms and visualizing protonation states in enzyme intermediates. PMID- 25013071 TI - Catalysis. Assessing the reliability of calculated catalytic ammonia synthesis rates. AB - We introduce a general method for estimating the uncertainty in calculated materials properties based on density functional theory calculations. We illustrate the approach for a calculation of the catalytic rate of ammonia synthesis over a range of transition-metal catalysts. The correlation between errors in density functional theory calculations is shown to play an important role in reducing the predicted error on calculated rates. Uncertainties depend strongly on reaction conditions and catalyst material, and the relative rates between different catalysts are considerably better described than the absolute rates. We introduce an approach for incorporating uncertainty when searching for improved catalysts by evaluating the probability that a given catalyst is better than a known standard. PMID- 25013072 TI - Imaging techniques. Ultrafast low-energy electron diffraction in transmission resolves polymer/graphene superstructure dynamics. AB - Two-dimensional systems such as surfaces and molecular monolayers exhibit a multitude of intriguing phases and complex transitions. Ultrafast structural probing of such systems offers direct time-domain information on internal interactions and couplings to a substrate or bulk support. We have developed ultrafast low-energy electron diffraction and investigate in transmission the structural relaxation in a polymer/graphene bilayer system excited out of equilibrium. The laser-pump/electron-probe scheme resolves the ultrafast melting of a polymer superstructure consisting of folded-chain crystals registered to a free-standing graphene substrate. We extract the time scales of energy transfer across the bilayer interface, the loss of superstructure order, and the appearance of an amorphous phase with short-range correlations. The high surface sensitivity makes this experimental approach suitable for numerous problems in ultrafast surface science. PMID- 25013073 TI - Earthquake dynamics. Supershear rupture in a M(w) 6.7 aftershock of the 2013 Sea of Okhotsk earthquake. AB - Earthquake rupture speeds exceeding the shear-wave velocity have been reported for several shallow strike-slip events. Whether supershear rupture also can occur in deep earthquakes is unclear, because of their enigmatic faulting mechanism. Using empirical Green's functions in both regional and teleseismic waveforms, we observed supershear rupture during the 2013 moment magnitude (M(w)) 6.7 deep earthquake beneath the Sea of Okhotsk, an aftershock of the large deep earthquake (M(w) 8.3). The M(w) 6.7 event ruptured downward along a steeply dipping fault plane at an average speed of 8 kilometers per second, suggesting efficient seismic energy generation. Comparing it to the highly dissipative 1994 M(w) 8.3 Bolivia earthquake, the two events represent end members of deep earthquakes in terms of energy partitioning and imply that there is more than one rupture mechanism for deep earthquakes. PMID- 25013074 TI - Ocean microbes. Multispecies diel transcriptional oscillations in open ocean heterotrophic bacterial assemblages. AB - Oscillating diurnal rhythms of gene transcription, metabolic activity, and behavior are found in all three domains of life. However, diel cycles in naturally occurring heterotrophic bacteria and archaea have rarely been observed. Here, we report time-resolved whole-genome transcriptome profiles of multiple, naturally occurring oceanic bacterial populations sampled in situ over 3 days. As anticipated, the cyanobacterial transcriptome exhibited pronounced diel periodicity. Unexpectedly, several different heterotrophic bacterioplankton groups also displayed diel cycling in many of their gene transcripts. Furthermore, diel oscillations in different heterotrophic bacterial groups suggested population-specific timing of peak transcript expression in a variety of metabolic gene suites. These staggered multispecies waves of diel gene transcription may influence both the tempo and the mode of matter and energy transformation in the sea. PMID- 25013075 TI - Microeconomics. Harnessing naturally occurring data to measure the response of spending to income. AB - This paper presents a new data infrastructure for measuring economic activity. The infrastructure records transactions and account balances, yielding measurements with scope and accuracy that have little precedent in economics. The data are drawn from a diverse population that overrepresents males and younger adults but contains large numbers of underrepresented groups. The data infrastructure permits evaluation of a benchmark theory in economics that predicts that individuals should use a combination of cash management, saving, and borrowing to make the timing of income irrelevant for the timing of spending. As in previous studies and in contrast to the predictions of the theory, there is a response of spending to the arrival of anticipated income. The data also show, however, that this apparent excess sensitivity of spending results largely from the coincident timing of regular income and regular spending. The remaining excess sensitivity is concentrated among individuals with less liquidity. PMID- 25013076 TI - Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. AB - Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease. PMID- 25013078 TI - Genetic oscillations. A Doppler effect in embryonic pattern formation. AB - During embryonic development, temporal and spatial cues are coordinated to generate a segmented body axis. In sequentially segmenting animals, the rhythm of segmentation is reported to be controlled by the time scale of genetic oscillations that periodically trigger new segment formation. However, we present real-time measurements of genetic oscillations in zebrafish embryos showing that their time scale is not sufficient to explain the temporal period of segmentation. A second time scale, the rate of tissue shortening, contributes to the period of segmentation through a Doppler effect. This contribution is modulated by a gradual change in the oscillation profile across the tissue. We conclude that the rhythm of segmentation is an emergent property controlled by the time scale of genetic oscillations, the change of oscillation profile, and tissue shortening. PMID- 25013077 TI - Bacterial cell wall. MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis. AB - Peptidoglycan (PG) is a polysaccharide matrix that protects bacteria from osmotic lysis. Inhibition of its biogenesis is a proven strategy for killing bacteria with antibiotics. The assembly of PG requires disaccharide-pentapeptide building blocks attached to a polyisoprene lipid carrier called lipid II. Although the stages of lipid II synthesis are known, the identity of the essential flippase that translocates it across the cytoplasmic membrane for PG polymerization is unclear. We developed an assay for lipid II flippase activity and used a chemical genetic strategy to rapidly and specifically block flippase function. We combined these approaches to demonstrate that MurJ is the lipid II flippase in Escherichia coli. PMID- 25013079 TI - In praise of early independence. PMID- 25013081 TI - Nucleic acid amplification tests for the diagnosis of Neisseria gonorrhoeae in low-prevalence settings: a review of the evidence. AB - OBJECTIVES: In UK Microbiology laboratories there is widespread use of nucleic acid amplification tests (NAATs) which allow the simultaneous 'dual' detection of Neisseria gonorrhoeae and Chlamydia trachomatis, although the prevalence of gonorrhoea in most areas is low and this may lead to high numbers of false positive results. The aim of this study was to examine the evidence base for unselected testing for gonorrhoea in the community. METHODS: A literature search was performed to review the use of dual testing in low prevalence settings by searching PubMed for appropriate terms linked to gonorrhoea diagnosis up to 1 December 2013 but without restriction of publication date. All publications with a prevalence of <1% were defined as low prevalence and included in this review. RESULTS: The publication search found data in low prevalence settings from three sources; genitourinary medicine clinics, laboratories outside the UK and from the National Chlamydia Screening Programme. The evidence base to support widespread screening for gonorrhoea was found to be limited and of variable quality. CONCLUSIONS: We were unable to find an evidence base to support widespread screening for gonorrhoea in the community. However, the increasing availability of dual NAATs may lead to more testing but this should be tempered by the public health need. Pilot studies and development of robust testing algorithms should be encouraged. PMID- 25013082 TI - Biosynthesis of the essential respiratory cofactor ubiquinone from phenylalanine in plants. PMID- 25013083 TI - Forensic veterinary pathology, today's situation and perspectives. AB - To investigate the current status of forensic veterinary pathology, a survey was composed directed at pathology laboratories and institutes, mostly in Europe. The questions included number of and type of cases, resources available, level of special training of the investigating pathologists and the general view on the current status and future of the discipline. The surveys were sent to 134 laboratories and were returned by 72 respondents of which 93 per cent work on forensic pathology cases. The results indicate scarcity of training opportunities and special education, and insufficient veterinary-specific reference data and information on forensic analyses. More cooperation with human forensic pathology was desired by many respondents, as was more interaction across country borders. PMID- 25013084 TI - Histophilus somni is a potential threat to beef cattle feedlots in Brazil. PMID- 25013086 TI - Retrospective cohort study of gastrointestinal stasis in pet rabbits. PMID- 25013085 TI - Medical treatment of 145 cases of gastric dilatation in rabbits. AB - Gastric dilatation is an acute and life-threatening condition in pet rabbits commonly caused by an intestinal obstruction with pellets of compressed hair. Surgery is normally considered to be the treatment of choice to alleviate the obstruction. However, for various reasons such as restrictions by the owner, a high anaesthetic risk due to the critical condition of the patient or concurrent diseases, surgical treatment may be impossible. In a three-year period, 145 cases of gastric dilatation were treated medically with a combination of metoclopramide, metamizole, balanced fluid electrolyte solution with glucose and syringe feeding. No gender or breed predisposition could be noted. Four animals were euthanased, three of them directly after diagnosis. Eleven animals died, eight of them on the day of presentation. The medical treatment was successful in 130 cases (89 per cent) with a mean treatment time of three days. The animals were released from hospital when eating and defecating normally. Although the use of medical treatment of gastric dilatation has to be thoroughly considered, especially regarding the severity of obstruction, the painfulness and the animal's welfare, the good survival rate observed with these animals makes it a good option for all cases where surgical treatment is contraindicated. PMID- 25013087 TI - Evaluation of a culture-based pathogen identification kit for bacterial causes of bovine mastitis. AB - Accurate identification of mastitis-causing bacteria supports effective management and can be used to implement selective use of antimicrobials for treatment. The objectives of this study were to compare the results from a culture-based mastitis pathogen detection test kit ('VetoRapid', Vetoquinol) with standard laboratory culture and to evaluate the potential suitability of the test kit to inform a selective treatment programme. Overall 231 quarter milk samples from five UK dairy farms were collected. The sensitivity and specificity of the test kit for the identification of Escherichia coli, Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus uberis and Enterococcus spp. ranged from 17 per cent to 84 per cent and 92 per cent to 98 per cent, respectively. In total, 23 of 68 clinical samples were assigned as meeting the requirement for antimicrobial treatment (Gram-positive organism cultured) according to standard culture results, with the test kit results having sensitivity and specificity of 91 per cent and 78 per cent, respectively. Several occurrences of misidentification are reported, including S. aureus being misidentified as coagulase-negative staphylococci and vice versa. The test kit provides rapid preliminary identification of five common causes of bovine mastitis under UK field conditions and is likely to be suitable for informing selective treatment of clinical mastitis caused by Gram-positive organisms. PMID- 25013088 TI - Variation of betaine, N,N-dimethylglycine, choline, glycerophosphorylcholine, taurine and trimethylamine-N-oxide in the plasma and urine of overweight people with type 2 diabetes over a two-year period. AB - BACKGROUND: Plasma betaine concentrations and urinary betaine excretions have high test-retest reliability. Abnormal betaine excretion is common in diabetes. We aimed to confirm the individuality of plasma betaine and urinary betaine excretion in an overweight population with type 2 diabetes and compare this with the individuality of other osmolytes, one-carbon metabolites and trimethylamine-N oxide (TMAO), thus assessing their potential usefulness as disease markers. METHODS: Urine and plasma were collected from overweight subjects with type 2 diabetes at four time points over a two-year period. We measured the concentrations of the osmolytes: betaine, glycerophosphorylcholine (GPC) and taurine, as well as TMAO, and the one-carbon metabolites, N,N-dimethylglycine (DMG) and free choline. Samples were measured using tandem mass spectrometry (LC MS/MS). RESULTS: Betaine showed a high degree of individuality (or test-retest reliability) in the plasma (index of individuality = 0.52) and urine (index of individuality = 0.45). Betaine in the plasma had positive and negative log-normal reference change values (RCVs) of 54% and -35%, respectively. The other osmolytes, taurine and GPC were more variable in the plasma of individuals compared to the urine. DMG and choline showed high individuality in the plasma and urine. TMAO was highly variable in the plasma and urine (log-normal RCVs ranging from 403% to -80% in plasma). CONCLUSIONS: Betaine is highly individual in overweight people with diabetes. Betaine, its metabolite DMG, and precursor choline showed more reliability than the osmolytes, GPC and taurine. The low reliability of TMAO suggests that a single TMAO measurement has low diagnostic value. PMID- 25013089 TI - The impact of distal embolization and distal protection on long-term outcome in patients with ST elevation myocardial infarction randomized to primary percutaneous coronary intervention--results from a randomized study. AB - OBJECTIVES: The impact of angiographically visible distal embolization (DE) and distal protection occurring during primary percutaneous coronary intervention (PCI) on long-term outcome has not been studied in a contemporary ST-segment elevation myocardial infarction (STEMI) cohort. To evaluate the association between DE and long-term outcome in STEMI patients treated with primary PCI with or without distal protection. METHODS AND RESULTS: In this post-hoc analysis of a randomized study, 591 STEMI patients were randomized to conventional primary PCI or primary PCI with distal protection and followed for 5 years. There was no statistically significant difference in MACE rate between patients treated with or wthout distal protection (19% versus 25%; p=0.10). There seemed to be interaction between distal protection and DE in major adverse cardiac events (MACE) (p=0.08), mortality (p=0.02) and reinfarction (p=0.06), but not admission for heart failure (p=0.40). DE was related to increased risk of admission for heart failure independently of distal protection (12.0% versus 5.0; p=0.015). The MACE rate for patients treated with standard PCI with DE was 31.3% compared to 24.8% for patients without DE (p=0.30), and 44.4% for patients treated with distal protection with DE compared to 17.9% for patients without DE (p=0.005). DE was not related to mortality (p=0.52) or reinfarction (p=0.52) among patients treated with standard PCI, but was related to higher rates of mortality (p=0.012) and reinfarction (p=0.008) when distal protection was used. CONCLUSION: DE occurred in 11% of STEMI patients treated with conventional primary PCI, and was associated with increased risk of development of heart failure. Distal protection did not improve the 5-years MACE rate, and might even aggravate the prognosis following DE, but this should only be considered hypothesis-generating. PMID- 25013090 TI - Comment on: 'comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial' by Qian-wen et al. PMID- 25013092 TI - The NHS: Celebrated and damned. PMID- 25013091 TI - Assessment of multifocality and axillary nodal involvement in early-stage breast cancer patients using 18F-FDG PET/CT compared to contrast-enhanced and diffusion weighted magnetic resonance imaging and sentinel node biopsy. AB - BACKGROUND: Non-invasive evaluation of the extent of axillary nodal involvement in early-stage breast cancer (ESBC) patients and accurate assessment of multifocality are both challenging. Few reports have explored whether 18F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) might be more useful than other diagnostic methods in these contexts. PURPOSE: To prospectively evaluate the diagnostic utility of FDG PET/CT, contrast enhanced, and diffusion-weighted magnetic resonance imaging (DCE-MRI and DWI), and sentinel lymph node biopsy (SNB), in detection of axillary metastatic lymph nodes in ESBC patients; and to explore the utilities of FDG PET/CT and DCE-MRI for identification of multifocality. MATERIAL AND METHODS: Twenty-four female patients (mean age, 47 +/- 9.9 years; range, 24-68 years) with ESBC underwent whole-body FDG PET/CT and breast MRI prior to operation. SNB and axillary lymph node dissection (ALND) were performed on all patients, as was mastectomy or wide local tumor excision. Histopathological findings served as the gold standard when evaluating either multifocality or axillary nodal involvement. RESULTS: The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, of PET/CT and DCE-MRI, used to detect multifocality, were as follows: 67% versus 78%, 100% versus 53%, 100% versus 50%, 83% versus 80%, and 88% versus 63%. SNB afforded the highest sensitivity (93%) in terms of detection of axillary metastasis. The sensitivity, NPV, and accuracy of PET/CT were 67%, 62%, and 75% respectively, thus higher than the equivalent values of either DCE-MRI or DWI. CONCLUSION: For assessment of multifocality in ESBC patients, highly specific results of PET/CT should be taken into account along with DCE-MRI findings. For evaluation of axillary nodal involvement, PET/CT has higher sensitivity, NPV, and accuracy values than DCE-MRI and DWI and may guide a surgical decision to proceed or not to SNB or ALND. PMID- 25013080 TI - HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck. AB - Heterosexual transmission of HIV-1 typically results in one genetic variant establishing systemic infection. We compared, for 137 linked transmission pairs, the amino acid sequences encoded by non-envelope genes of viruses in both partners and demonstrate a selection bias for transmission of residues that are predicted to confer increased in vivo fitness on viruses in the newly infected, immunologically naive recipient. Although tempered by transmission risk factors, such as donor viral load, genital inflammation, and recipient gender, this selection bias provides an overall transmission advantage for viral quasispecies that are dominated by viruses with high in vivo fitness. Thus, preventative or therapeutic approaches that even marginally reduce viral fitness may lower the overall transmission rates and offer long-term benefits even upon successful transmission. PMID- 25013094 TI - Transparency as a condition for JRSM publication? PMID- 25013093 TI - Questionable research and marketing of a combination drug for smoker's lungs. PMID- 25013095 TI - Perspectives on clinical leadership: a qualitative study exploring the views of senior healthcare leaders in the UK. AB - INTRODUCTION: Clinicians are being asked to play a major role leading the NHS. While much is written on about clinical leadership, little research in the medical literature has examined perceptions of the term or mapped the perceived attributes required for success. OBJECTIVE: To capture the views of senior UK healthcare leaders regarding their perception of the term 'clinical leadership' and the cultural backdrop in which it is being espoused. SETTING: UK Healthcare sector PARTICIPANTS: Senior UK Healthcare leaders METHODS: Twenty senior healthcare leaders including a former Health Minister, NHS Executives, NHS Strategic Health Authority, PCT and Acute Trust chief executives and medical directors, Medical Deans and other key actors in the UK medical leadership arena were interviewed between 2010 and 2011 using a semi-structured interview technique. Using grounded theory, themes were identified and subsequently analysed in an attempt to answer the broad questions posed. MAIN OUTCOME MEASURES: Not applicable for a qualitative research project RESULTS: A number of themes emerged from this qualitative study. First, there was evidence of changing attitudes among doctors, particularly trainees, towards becoming involved in clinical leadership. However, there was unease over the ambiguity of the term 'clinical leadership' and the implications for the future. There was, however, broad agreement as to the perceived attributes and skills required for success in healthcare leadership. CONCLUSIONS: Clinical leadership is often perceived to be doctor centric and 'Healthcare Leadership' may be a more inclusive term. An understanding of the historical medico-political context of the leadership debate is required by all healthcare leaders to fully understand the challenges of changing healthcare culture. Whilst the broad attributes deemed essential for success as a healthcare leaders are not new, significant effort and investment, including a physical Healthcare Academy, are required to best utilise and harmonise the breadth of leadership talent in the NHS. PMID- 25013096 TI - Thomas MacLagan's 1876 demonstration of the dramatic effects of salicin in rheumatic fever. PMID- 25013100 TI - Correction: Incorrect Spelling of Author's Name. PMID- 25013101 TI - Manslaughter and the doctor - conviction and sentence. PMID- 25013102 TI - Spatial co-ordination of foot contacts in unrestrained climbing insects. AB - Animals that live in a spatially complex environment such as the canopy of a tree, constantly need to find reliable foothold in three-dimensional (3D) space. In multi-legged animals, spatial co-ordination among legs is thought to improve efficiency of finding foothold by avoiding searching-movements in trailing legs. In stick insects, a 'targeting mechanism' has been described that guides foot placement of hind- and middle legs according to the position of their leading ipsilateral leg. So far, this mechanism has been shown for standing and tethered walking animals on horizontal surfaces. Here, we investigate the efficiency of this mechanism in spatial limb co-ordination of unrestrained climbing animals. For this, we recorded whole-body kinematics of freely climbing stick insects and analysed foot placement in 3D space. We found that touch-down positions of adjacent legs were highly correlated in all three spatial dimensions, revealing 3D co-ordinate transfer among legs. Furthermore, targeting precision depended on the position of the leading leg. A second objective was to test the importance of sensory information transfer between legs. For this, we ablated a proprioceptive hair field signaling the levation of the leg. After ablation, the operated leg swung higher and performed unexpected searching movements. Furthermore, targeting of the ipsilateral trailing leg was less precise in anteroposterior and dorsoventral directions. Our results reveal that the targeting mechanism is used by unrestrained climbing stick insects in 3D space and that information from the trochanteral hair field is used in ipsilateral spatial co-ordination among legs. PMID- 25013103 TI - A context-dependent alarm signal in the ant Temnothorax rugatulus. AB - Because collective cognition emerges from local signaling among group members, deciphering communication systems is crucial to understanding the underlying mechanisms. Alarm signals are widespread in the social insects and can elicit a variety of behavioral responses to danger, but the functional plasticity of these signals has not been well studied. Here we report an alarm pheromone in the ant Temnothorax rugatulus that elicits two different behaviors depending on context. When an ant was tethered inside an unfamiliar nest site and unable to move freely, she released a pheromone from her mandibular gland that signaled other ants to reject this nest as a potential new home, presumably to avoid potential danger. When the same pheromone was presented near the ants' home nest, they were instead attracted to it, presumably to respond to a threat to the colony. We used coupled gas chromatography/mass spectrometry to identify candidate compounds from the mandibular gland and tested each one in a nest choice bioassay. We found that 2,5-dimethylpyrazine was sufficient to induce rejection of a marked new nest and also to attract ants when released at the home nest. This is the first detailed investigation of chemical communication in the leptothoracine ants. We discuss the possibility that this pheromone's deterrent function can improve an emigrating colony's nest site selection performance. PMID- 25013104 TI - Gaze characteristics of freely walking blowflies Calliphora vicina in a goal directed task. AB - In contrast to flying flies, walking flies experience relatively strong rotational gaze shifts, even during overall straight phases of locomotion. These gaze shifts are caused by the walking apparatus and modulated by the stride frequency. Accordingly, even during straight walking phases, the retinal image flow is composed of both translational and rotational optic flow, which might affect spatial vision, as well as fixation behavior. We addressed this issue for an orientation task where walking blowflies approached a black vertical bar. The visual stimulus was stationary, or either the bar or the background moved horizontally. The stride-coupled gaze shifts of flies walking toward the bar had similar amplitudes under all visual conditions tested. This finding indicates that these shifts are an inherent feature of walking, which are not even compensated during a visual goal fixation task. By contrast, approaching flies showed a frequent stop-and-go behavior that was affected by the stimulus conditions. As sustained image rotations may impair distance estimation during walking, we propose a hypothesis that explains how rotation-independent translatory image flow containing distance information can be determined. The algorithm proposed works without requiring differentiation at the behavioral level of the rotational and translational flow components. By contrast, disentangling both has been proposed to be necessary during flight. By comparing the retinal velocities of the edges of the goal, its rotational image motion component can be removed. Consequently, the expansion velocity of the goal and, thus, its proximity can be extracted, irrespective of distance-independent stride coupled rotational image shifts. PMID- 25013105 TI - Niche-specific cognitive strategies: object memory interferes with spatial memory in the predatory bat Myotis nattereri. AB - Related species with different diets are predicted to rely on different cognitive strategies: those best suited for locating available and appropriate foods. Here we tested two predictions of the niche-specific cognitive strategies hypothesis in bats, which suggests that predatory species should rely more on object memory than on spatial memory for finding food and that the opposite is true of frugivorous and nectivorous species. Specifically, we predicted that: (1) predatory bats would readily learn to associate shapes with palatable prey and (2) once bats had made such associations, these would interfere with their subsequent learning of a spatial memory task. We trained free-flying Myotis nattereri to approach palatable and unpalatable insect prey suspended below polystyrene objects. Experimentally naive bats learned to associate different objects with palatable and unpalatable prey but performed no better than chance in a subsequent spatial memory experiment. Because experimental sequence was predicted to be of consequence, we introduced a second group of bats first to the spatial memory experiment. These bats learned to associate prey position with palatability. Control trials indicated that bats made their decisions based on information acquired through echolocation. Previous studies have shown that bat species that eat mainly nectar and fruit rely heavily on spatial memory, reflecting the relative consistency of distribution of fruit and nectar compared with insects. Our results support the niche-specific cognitive strategies hypothesis and suggest that for gleaning and clutter-resistant aerial hawking bats, learning to associate shape with food interferes with subsequent spatial memory learning. PMID- 25013106 TI - Precocene-I inhibits juvenile hormone biosynthesis, ovarian activation, aggression and alters sterility signal production in bumble bee (Bombus terrestris) workers. AB - Juvenile hormone (JH) is an important regulator of development and physiology in insects. While in many insect species, including bumble bees, JH functions as gonadotropin in adults, in some highly eusocial insects its role has shifted to regulate social behavior including division of labor, dominance and aggression. Studying JH functions across social insect species is important for understanding the evolution of sociality; however, these studies have been limited because of the inability to reduce JH levels without surgically removing its glandular source, the corpora allata. Precocene is known to inhibit JH biosynthesis in several non-social insects, but has been poorly studied in social insects. Here, we tested whether precocene-I can effectively reduce JH levels in Bombus terrestris workers, and examined its effects on their physiology and behavior. Precocene-I treatment of three-worker groups decreased JH titer and ovarian activation, irrespective of the bees' dominance rank within the group, and was remedied by JH replacement therapy. Precocene-I also decreased aggressiveness and increased ester-sterility signal production; these changes were rank-dependent, and affected mainly the most reproductive and the least aggressive workers, respectively, and could not be remedied by JH replacement therapy. These results clearly confirm the role of JH as a gonadotropin and mediator of aggression in B. terrestris, and indicate that JH effects are associated with worker dominance rank. The ability to chemically reduce JH titer provides us with a non-intrusive method to probe the evolutionary changes associated with JH and the hormonal mechanisms that are associated with reproduction and behavior in social insects. PMID- 25013107 TI - Fine-tuned echolocation and capture-flight of Myotis capaccinii when facing different-sized insect and fish prey. AB - Formerly thought to be a strictly insectivorous trawling bat, recent studies have shown that Myotis capaccinii also preys on fish. To determine whether differences exist in bat flight behaviour, prey handling and echolocation characteristics when catching fish and insects of different size, we conducted a field experiment focused on the last stage of prey capture. We used synchronized video and ultrasound recordings to measure several flight and dip features as well as echolocation characteristics, focusing on terminal buzz phase I, characterized by a call rate exceeding 100 Hz, and buzz phase II, characterized by a drop in the fundamental well below 20 kHz and a repetition rate exceeding 150 Hz. When capturing insects, bats used both parts of the terminal phase to the same extent, and performed short and superficial drags on the water surface. In contrast, when preying on fish, buzz I was longer and buzz II shorter, and the bats made longer and deeper dips. These variations suggest that lengthening buzz I and shortening buzz II when fishing is beneficial, probably because buzz I gives better discrimination ability and the broader sonar beam provided by buzz II is useless when no evasive flight of the prey is expected. Additionally, bats continued emitting calls beyond the theoretical signal-overlap zone, suggesting that they might obtain information even when they have surpassed that threshold, at least initially. This study shows that M. capaccinii can regulate the temporal components of its feeding buzzes and modify prey capture technique according to the target. PMID- 25013109 TI - Use of a gyroscope/accelerometer data logger to identify alternative feeding behaviours in fish. AB - We examined whether we could identify the feeding behaviours of the trophic generalist fish Epinephelus ongus on different prey types (crabs and fish) using a data logger that incorporated a three-axis gyroscope and a three-axis accelerometer. Feeding behaviours and other burst behaviours, including escape responses, intraspecific interactions and routine movements, were recorded from six E. ongus individuals using data loggers sampling at 200 Hz, and were validated by simultaneously recorded video images. For each data-logger record, we extracted 5 s of data when any of the three-axis accelerations exceeded absolute 2.0 g, to capture all feeding behaviours and other burst behaviours. Each feeding behaviour was then identified using a combination of parameters that were derived from the extracted data. Using decision trees with the parameters, high true identification rates (87.5% for both feeding behaviours) with low false identification rates (5% for crab-eating and 6.3% for fish-eating) were achieved for both feeding behaviours. PMID- 25013108 TI - Social regulation of cortisol receptor gene expression. AB - In many social species, individuals influence the reproductive capacity of conspecifics. In a well-studied African cichlid fish species, Astatotilapia burtoni, males are either dominant (D) and reproductively competent or non dominant (ND) and reproductively suppressed as evidenced by reduced gonadotropin releasing hormone (GnRH1) release, regressed gonads, lower levels of androgens and elevated levels of cortisol. Here, we asked whether androgen and cortisol levels might regulate this reproductive suppression. Astatotilapia burtoni has four glucocorticoid receptors (GR1a, GR1b, GR2 and MR), encoded by three genes, and two androgen receptors (ARalpha and ARbeta), encoded by two genes. We previously showed that ARalpha and ARbeta are expressed in GnRH1 neurons in the preoptic area (POA), which regulates reproduction, and that the mRNA levels of these receptors are regulated by social status. Here, we show that GR1, GR2 and MR mRNAs are also expressed in GnRH1 neurons in the POA, revealing potential mechanisms for both androgens and cortisol to influence reproductive capacity. We measured AR, MR and GR mRNA expression levels in a microdissected region of the POA containing GnRH1 neurons, comparing D and ND males. Using quantitative PCR (qPCR), we found D males had higher mRNA levels of ARalpha, MR, total GR1a and GR2 in the POA compared with ND males. In contrast, ND males had significantly higher levels of GR1b mRNA, a receptor subtype with a reduced transcriptional response to cortisol. Through this novel regulation of receptor type, neurons in the POA of an ND male will be less affected by the higher levels of cortisol typical of low status, suggesting GR receptor type change as a potential adaptive mechanism to mediate high cortisol levels during social suppression. PMID- 25013110 TI - Patterns of fuel use during locomotion in mammals revisited: the importance of aerobic scope. AB - Fuel selection patterns during exercise are thought to be conserved among sea level native mammals when intensity is expressed relative to maximum aerobic capacity (V(O2,max)). However, this claim is based on data from only a few species larger than rats, and has never been tested statistically. Thus, we investigated fuel use in a small mammal (Mus musculus, CD-1 strain), and combined these data with published data on rats, dogs, goats and humans to evaluate the robustness of the mammalian fuel selection model. We found that mice rely less on carbohydrates to power moderate intensity exercise at the same % V(O2,max) than larger mammals. We suggest that this difference is due to a decline in aerobic scope (O2 available for exercise above resting metabolism) as body size decreases. We propose a redefined fuel use model that reflects changes in fractional aerobic scope with body size. Our results indicate that exercise defined as percent aerobic scope is a better predictor of fuel use across a wide range of quadruped species from mice to dogs and running humans. PMID- 25013111 TI - Female gray treefrogs, Hyla versicolor, are responsive to visual stimuli but unselective of stimulus characteristics. AB - The visual ecology of nocturnal anurans is poorly understood, but there is growing evidence that vision plays a role in important behaviors such as mate choice. While several recent studies have demonstrated that females are responsive to visual cues when selecting mates, the forces responsible for these preferences are unknown. We investigated the responsiveness of female gray treefrogs, Hyla versicolor, to video playbacks of calling conspecific males in which we varied attributes of the vocal sac, a conspicuous visual characteristic of calling males and a target of female choice in other species. Females responded surprisingly strongly to the video playbacks, but did so indiscriminately with respect to variation in vocal sac characteristics. We followed up on these results with a series of additional tests that examined female responses to abstract stimuli. Females continued to respond to such stimuli, leading us to conclude that their behavior was related to a generalized phototactic response. Because of this, we were unable to make conclusions regarding female preferences for vocal sac characteristics. Nonetheless, our results are significant in two respects. First, we illustrate that despite much effort into improving video playback methodologies, challenges remain, and we offer our experimental design as a method to ensure that appropriate conclusions can be drawn from such studies. Second, we argue that the female phototactic response has potentially significant behavioral implications and in general the consequences of anuran visual preferences deserve further investigation. PMID- 25013112 TI - K+ absorption by locust gut and inhibition of ileal K+ and water transport by FGLamide allatostatins. AB - The scanning ion-selective electrode technique (SIET) was utilized for the first time in Locusta migratoria to characterize K(+) transport along the digestive tract and to determine the effect of two locust FGLamide allatostatins (FGLa/ASTs) on K(+) transport: a previously sequenced FGLa/AST from Schistocerca gregaria (Scg-AST-6; ARPYSFGL-NH2) and a newly sequenced FGLa/AST from L. migratoria (Locmi-FGLa/AST-2; LPVYNFGL-NH2). Regional differences in K(+) fluxes along the gut were evident, where K(+) efflux in vitro (or absorption into the hemolymph in vivo) was greatest at the anterior ileum, and lowest at the colon. Ileal K(+) efflux was inhibited by both Scg-AST-6 and Locmi-FGLa/AST-2, with maximal inhibition at 10(-10) and 10(-11) mol l(-1), respectively. Both FGLa/ASTs also inhibited cAMP-stimulated K(+) efflux from the ileum. Locmi-FGLa/AST-2 also inhibited efflux of water across the ileum. Locusts are terrestrial insects living in dry climates, risking desiccation and making water conservation a necessity. The results suggest that FGLa/ASTs may be acting as diuretics by increasing K(+) excretion and therefore increasing water excretion. Thus it is likely that FGLa/ASTs are involved in the control of hemolymph water and ion levels during feeding and digestion, to help the locust deal with the excess K(+) load (and subsequently fluid) when the meal is processed. PMID- 25013113 TI - Physiological vagility and its relationship to dispersal and neutral genetic heterogeneity in vertebrates. AB - Vagility is the inherent power of movement by individuals. Vagility and the available duration of movement determine the dispersal distance individuals can move to interbreed, which affects the fine-scale genetic structure of vertebrate populations. Vagility and variation in population genetic structure are normally explained by geographic variation and not by the inherent power of movement by individuals. We present a new, quantitative definition for physiological vagility that incorporates aerobic capacity, body size, body temperature and the metabolic cost of transport, variables that are independent of the physical environment. Physiological vagility is the speed at which an animal can move sustainably based on these parameters. This meta-analysis tests whether this definition of physiological vagility correlates with empirical data for maximal dispersal distances and measured microsatellite genetic differentiation with distance {[F(ST)/[1-F(ST))]/ln distance} for amphibians, reptiles, birds and mammals utilizing three locomotor modes (running, flying, swimming). Maximal dispersal distance and physiological vagility increased with body mass for amphibians, reptiles and mammals utilizing terrestrial movement. The relative slopes of these relationships indicate that larger individuals require longer movement durations to achieve maximal dispersal distances. Both physiological vagility and maximal dispersal distance were independent of body mass for flying vertebrates. Genetic differentiation with distance was greatest for terrestrial locomotion, with amphibians showing the greatest mean and variance in differentiation. Flying birds, flying mammals and swimming marine mammals showed the least differentiation. Mean physiological vagility of different groups (class and locomotor mode) accounted for 98% of the mean variation in genetic differentiation with distance in each group. Genetic differentiation with distance was not related to body mass. The physiological capacity for movement (physiological vagility) quantitatively predicts genetic isolation by distance in the vertebrates examined. PMID- 25013114 TI - Is warmer better? Decreased oxidative damage in notothenioid fish after long-term acclimation to multiple stressors. AB - Antarctic fish of the suborder Notothenioidei have evolved several unique adaptations to deal with subzero temperatures. However, these adaptations may come with physiological trade-offs, such as an increased susceptibility to oxidative damage. As such, the expected environmental perturbations brought on by global climate change have the potential to significantly increase the level of oxidative stress and cellular damage in these endemic fish. Previous single stressor studies of the notothenioids have shown they possess the capacity to acclimate to increased temperatures, but the cellular-level effects remain largely unknown. Additionally, there is little information on the ability of Antarctic fish to respond to ecologically relevant environmental changes where multiple variables change concomitantly. We have examined the potential synergistic effects that increased temperature and P(CO2) have on the level of protein damage in Trematomus bernacchii, Pagothenia borchgrevinki and Trematomus newnesi, and combined these measurements with changes in total enzymatic activity of catalase (CAT) and superoxide dismutase (SOD) in order to gauge tissue specific changes in antioxidant capacity. Our findings indicate that total SOD and CAT activity levels displayed only small changes across treatments and tissues. Short-term acclimation to decreased seawater pH and increased temperature resulted in significant increases in oxidative damage. Surprisingly, despite no significant change in antioxidant capacity, cellular damage returned to near-basal levels, and significantly decreased in T. bernacchii, after long term acclimation. Overall, these data suggest that notothenioid fish currently maintain the antioxidant capacity necessary to offset predicted future ocean conditions, but it remains unclear whether this capacity comes with physiological trade-offs. PMID- 25013115 TI - Mechanical processing via passive dynamic properties of the cockroach antenna can facilitate control during rapid running. AB - The integration of information from dynamic sensory structures operating on a moving body is a challenge for locomoting animals and engineers seeking to design agile robots. As a tactile sensor is a physical linkage mediating mechanical interactions between body and environment, mechanical tuning of the sensor is critical for effective control. We determined the open-loop dynamics of a tactile sensor, specifically the antenna of the American cockroach, Periplaneta americana, an animal that escapes predators by using its antennae during rapid closed-loop tactilely mediated course control. Geometrical measurements and static bending experiments revealed an exponentially decreasing flexural stiffness (EI) from base to tip. Quasi-static experiments with a physical model support the hypothesis that a proximodistally decreasing EI can simplify control by increasing preview distance and allowing effective mapping to a putative control variable--body-to-wall distance--compared with an antenna with constant EI. We measured the free response at the tip of the antenna following step deflections and determined that the antenna rapidly damps large deflections: over 90% of the perturbation is rejected within the first cycle, corresponding to almost one stride period during high-speed running (~50 ms). An impulse-like perturbation near the tip revealed dynamics that were characteristic of an inelastic collision, keeping the antenna in contact with an object after impact. We contend that proximodistally decreasing stiffness, high damping and inelasticity simplify control during high-speed tactile tasks by increasing preview distance, providing a one-dimensional map between antennal bending and body-to-wall distance, and increasing the reliability of tactile information. PMID- 25013116 TI - Exercising for food: bringing the laboratory closer to nature. AB - Traditionally, exercise physiology experiments have borne little resemblance to how animals express physical activity in the wild. In this experiment, 15 adult male rats were divided into three equal-sized groups: exercise contingent (CON), non-exercise contingent (NON) and sedentary (SED). The CON group was placed in a cage with a running wheel, where the acquisition of food was contingent upon the distance required to run. Every 3 days the distance required to run to maintain food intake at free feeding levels was increased by 90% in comparison to the previous 3 days. The NON group was housed identically to the CON group, but food acquisition was not dependent upon running in the wheel. Finally, the SED group was kept in small cages with no opportunity to perform exercise. A two-way ANOVA with repeated measures was used to determine significant differences in responses between the experimental phases and treatment groups, and ANCOVA was used to analyse growth and tissue mass variables with body length and body mass used separately as covariates. A post hoc Tukey's test was used to indicate significant differences. A Pearson's correlation was used to test the relationship between the distance travelled by the animal and the distance/food ratio. The level of significance was set at P<0.05 for all tests. The CON group showed the hypothesized correlation between distance required to run to obtain food and the mean distance travelled (P<0.001), during 45 days in the contingency phase. This group showed a decrease in body mass, rather than an increase as shown by NON and SED groups. The CON group had a significantly lower body temperature (P<0.05) and adiposity (P<0.05) when compared with the other two groups for the same body size. The present experimental model based on animals choosing the characteristics of their physical exercise to acquire food (i.e. distance travelled, speed and duration) clearly induced physiological effects (body characteristics and internal temperature), which are useful for investigating relevant topics in exercise physiology such as the link between exercise, food and body mass. PMID- 25013117 TI - Clinical characterization of mild cognitive impairment as a prodrome to dementia with Lewy bodies. AB - Limited information regarding the specificity of mild cognitive impairment (MCI) as it relates to dementia with Lewy bodies (DLB) exists. Here, we summarize the clinical phenotype of MCI in clinically suspect DLB. Ten patients with a primary diagnosis of MCI and secondary diagnoses of DLB were identified. Patients underwent clinical neurological and neuropsychological evaluation that included application of McKeith criteria. We found parkinsonism and gait abnormality in 9 of the 10 patients; fluctuations in 8 of the 10; and hallucinations and dream enactment behavior in 5 of the 10. Of the 10 cases, 4 were classified as nonamnestic MCI and 6 were amnestic MCI. Of the 10 cases, 9 displayed executive and/or visuospatial dysfunction. Of the 10 cases, 6 have progressed to DLB. Progression of MCI to DLB is not dependent on memory impairment. The presence of core clinical features-parkinsonism and cognitive fluctuations-and predominant executive and visuospatial dysfunction +/- memory impairment is suggestive of a prodromal DLB presentation. PMID- 25013118 TI - Prolonged grief in caregivers of community-dwelling dementia patients. AB - OBJECTIVES: To estimate the frequency of prolonged grief disorder (PGD) in 90 primary caregivers of patients with dementia who live in the community dwelling in Milan and to identify the relationship between grief intensity (GI) and other caregiver variables; another aim was to clarify the role of the objective cognitive and functional impairment of the patients and the level of deterioration perceived by caregivers. DESIGN: Cross-sectional study. RESULTS: In all, 16.7% of caregivers had PGD. Caregiver variables increasing GI and the risk of developing PGD were burden, anxiety, and some sociodemographic features. The objective level of patient's deterioration was irrelevant for PGD probability/GI, while the deterioration level perceived by the caregiver increased PGD probability and GI. CONCLUSIONS: Caregivers of patients with dementia may experience grief symptoms that are associated with low educational level, high level of burden and anxiety, and high perceived deterioration of their demented relatives' cognitive and functional abilities. PMID- 25013121 TI - Predicting recidivism in sex offenders with the Psychological Inventory of Criminal Thinking Styles (PICTS). AB - The purpose of this study was to determine whether the Psychological Inventory of Criminal Thinking Styles (PICTS) was capable of predicting recidivism in 322 male sex offenders released from prison-based sex offender programs in a Midwestern state. The Static-99R and PICTS General Criminal Thinking (GCT), Reactive (R), and Entitlement (En) scores all correlated significantly with general recidivism, the Static-99R correlated significantly with violent recidivism, and the Static 99R score and PICTS GCT, Proactive (P), and En scores correlated significantly with failure to register as a sex offender (FTR) recidivism. Area under the curve effect size estimates varied from small to large, and Cox regression analyses revealed that the PICTS En score achieved incremental validity relative to the Static-99R in predicting general recidivism and the PICTS GCT, P, and En scores achieved incremental validity relative to the Static-99R in predicting FTR recidivism. It is speculated that the PICTS in general and the En scale in particular may have utility in risk management and treatment planning for sex offenders by virtue of their focus on antisocial thinking. PMID- 25013119 TI - The 2-C-methylerythritol 4-phosphate pathway in melon is regulated by specialized isoforms for the first and last steps. AB - The 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway provides the precursors for the biosynthesis of plastidial isoprenoids, which include the carotenoid pigments of many fruits. We have analysed the genes encoding the seven enzymes of the MEP pathway in melon (Cucumis melo L.) and determined that the first one, 1 deoxyxylulose 5-phosphate synthase (DXS), and the last one, 1-hydroxy-2-methyl-2 (E)-butenyl 4-diphosphate reductase (HDR), are represented in the genome as a small gene family and paralogous pair, respectively. In the case of DXS, three genes encode functional DXS activities which fall into previously established type I (CmDXS1) and II (CmDXS2a and CmDXS2b) categories, while a fourth DXS-like gene belonging to the type III group did not encode a protein with DXS activity. Their expression patterns and phylogenies suggest that CmDXS1 is functionally specialized for developmental and photosynthetic processes, while CmDXS2a and CmDXS2b are induced in flowers and ripening fruit of orange- (but not white-) fleshed varieties, coinciding with beta-carotene accumulation. This is the first instance connecting type II DXS genes to specialized isoprenoid biosynthesis in the fruit of an agronomically important species. Two HDR paralogues were shown to encode functional enzymes, although only CmHDR1 was highly expressed in the tissues and developmental stages tested. Phylogenetic analysis showed that in cucurbits such as melon, these HDR paralogues probably arose through individual gene duplications in a common angiosperm ancestor, mimicking a prior division in gymnosperms, while other flowering plants, including apple, soy, canola, and poplar, acquired HDR duplicates recently as homoeologues through large-scale genome duplications. We report the influence of gene duplication history on the regulation of the MEP pathway in melon and the role of specialized MEP-pathway isoforms in providing precursors for beta-carotene production in orange-fleshed melon varieties. PMID- 25013122 TI - Reading the Road Signs: The Utility of the MMPI-2 Restructured Form Validity Scales in Prediction of Premature Termination. AB - This study examined the utility of the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) Validity Scales in prediction of premature termination in a sample of 511 individuals seeking services from a university-based psychology clinic. Higher scores on True Response Inconsistency Revised and Infrequent Psychopathology Responses increased the risk of premature termination, whereas higher scores on Adjustment Validity lowered the risk of premature termination. Additionally, when compared with individuals who did not prematurely terminate, individuals who prematurely terminated treatment had lower Global Assessment of Functioning scores at both intake and termination and made fewer improvements. Implications of these findings for the use of the MMPI-2-RF Validity Scales in promoting treatment compliance are discussed. PMID- 25013120 TI - Targeting of a polytopic membrane protein to the inner envelope membrane of chloroplasts in vivo involves multiple transmembrane segments. AB - The inner envelope membrane (IEM) of the chloroplast plays crucial roles in forming an osmotic barrier and controlling metabolite exchange between the organelle and the cytosol. The IEM therefore harbours a number of membrane proteins and requires the import and integration of these nuclear-encoded proteins for its biogenesis. Recent studies have demonstrated that the transmembrane segment of single-spanning IEM proteins plays key roles in determining their IEM localization. However, few studies have focused on the molecular mechanisms by which polytopic membrane proteins are targeted to the IEM. In this study, we investigated the targeting mechanism of polytopic IEM proteins using the protein Cor413im1 as a model substrate. Cor413im1 does not utilize a soluble intermediate for its targeting to the IEM. Furthermore, we show that the putative fifth transmembrane segment of Cor413im1 is necessary for its targeting to the IEM. The C-terminal portion containing this transmembrane segment is also able to deliver Cor413im1 protein to the IEM. However, the fifth transmembrane segment of Cor413im1 itself is insufficient to target a fusion protein to the IEM. These data suggest that the targeting of polytopic membrane proteins to the chloroplast IEM in vivo involves multiple transmembrane segments and that chloroplasts have evolved a unique mechanism for the integration of polytopic proteins to the IEM. PMID- 25013124 TI - Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients. AB - PURPOSE: We conducted a phase I multicenter trial in naive metastatic castrate resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. EXPERIMENTAL DESIGN: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was >=30% PSA decline within 3 months. RESULTS: Eight dose levels (40-8,000 MUg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 MUg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 MUg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 MUg daily. Respectively, 85% and 76% of the patients had >=30% PSA decline within 3 months and >=50% PSA decline at any time during the study. Median time to PSA progression was 169 days. CONCLUSION: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (>=30% PSA response: 85%; >=50% PSA response: 76%). A randomized phase II study is planned. PMID- 25013125 TI - Noninvasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never-smokers: a proof-of-concept study from BioCAST/IFCT-1002. AB - PURPOSE: Tumor somatic mutation analysis is part of the standard management of metastatic lung cancer. However, physicians often have to deal with small biopsies and consequently with challenging mutation testing. Circulating free DNA (cfDNA) is a promising tool for accessing the tumor genome as a liquid biopsy. Here, we evaluated next-generation sequencing (NGS) on cfDNA samples obtained from a consecutive series of patients for the screening of a range of clinically relevant mutations. EXPERIMENTAL DESIGN: A total of 107 plasma samples were collected from the BioCAST/IFCT-1002 lung cancer study (never-smokers cohort). Matched tumor DNA (tDNA) was obtained for 68 cases. Multiplex PCR-based assays were designed to target specific coding regions in EGFR, KRAS, BRAF, ERBB2, and PI3KCA genes, and amplicon sequencing was performed at deep coverage on the cfDNA/tDNA pairs using the NGS IonTorrent Personal Genome Machine Platform. RESULTS: CfDNA concentration in plasma was significantly associated with both stage and number of metastatic sites. In tDNA, 50 mutations (36 EGFR, 5 ERBB2, 4 KRAS, 3 BRAF, and 2 PIK3CA) were identified, of which 26 were detected in cfDNA. Sensitivity of the test was 58% (95% confidence interval, 43%-71%) and the estimated specificity was 87% (62%-96%). CONCLUSION: These data demonstrate the feasibility and potential utility of mutation screening in cfDNA using IonTorrent NGS for the detection of a range of tumor biomarkers in patients with metastatic lung cancer. PMID- 25013127 TI - Assessment of the therapeutic alliance of youth and parents with team members in youth residential psychiatry. AB - Although therapeutic alliance is widely acknowledged as a key component for therapeutic change, its role is almost unknown in youth residential psychiatry. A likely reason for the lack of research is the absence of assessment tools and procedures for youth residential settings. This study assesses the psychometric properties of the Dutch version of the Family Engagement Questionnaire (FEQ), an alliance measure completed by team members. In addition, agreement among team members is explored. Eleven youth psychiatric day and inpatient units participated. Parent counsellors and case managers of 86 patients from 6 to 17 years old reported on the therapeutic alliance. Exploratory factor analysis of team members' reports resulted in meaningful structures, with child and parent alliance scales primarily corresponding to the conceptualization of the developers and earlier factor analysis. Internal reliability and validity were good for most of the subscales. The hypothesis that team members would show low levels of agreement in their reports of the therapeutic alliance was confirmed, demonstrating the need to include multiple team members in assessment procedures. Overall, this study underscores the psychometric properties of the Dutch version of the FEQ. Team members in residential youth psychiatric settings are encouraged to reflect regularly with their colleagues on the youth and parent therapeutic alliance. PMID- 25013128 TI - Two Human Challenge Studies Confirm High Infectivity of Norwalk Virus. PMID- 25013123 TI - Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts. AB - PURPOSE: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity. EXPERIMENTAL DESIGN: The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity. RESULTS: ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%). CONCLUSION: These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy. PMID- 25013126 TI - Excess of proximal microsatellite-stable colorectal cancer in African Americans from a multiethnic study. AB - PURPOSE: African Americans (AA) have the highest incidence of colorectal cancer compared with other U.S. populations and more proximal colorectal cancers. The objective is to elucidate the basis of these cancer disparities. EXPERIMENTAL DESIGN: Of note, 566 AA and 328 non-Hispanic White (NHW) colorectal cancers were ascertained in five Chicago hospitals. Clinical and exposure data were collected. Microsatellite instability (MSI) and BRAF (V600E) and KRAS mutations were tested. Statistical significance of categorical variables was tested by the Fisher exact test or logistic regression and age by the Mann-Whitney U test. RESULTS: Over a 10-year period, the median age at diagnosis significantly decreased for both AAs (68-61; P < 0.01) and NHWs (64.5- 62; P = 0.04); more AA patients were diagnosed before age 50 than NHWs (22% vs. 15%; P = 0.01). AAs had more proximal colorectal cancer than NHWs (49.5% vs. 33.7%; P < 0.01), but overall frequencies of MSI, BRAF and KRAS mutations were not different nor were they different by location in the colon. Proximal colorectal cancers often presented with lymphocytic infiltrate (P < 0.01) and were diagnosed at older ages (P = 0.02). Smoking, drinking, and obesity were less common in this group, but results were not statistically significant. CONCLUSIONS: Patients with colorectal cancer have gotten progressively younger. The excess of colorectal cancer in AAs predominantly consists of more proximal, microsatellite stable tumors, commonly presenting lymphocytic infiltrate and less often associated with toxic exposures or a higher BMI. Younger AAs had more distal colorectal cancers than older ones. These data suggest two different mechanisms driving younger age and proximal location of colorectal cancers in AAs. PMID- 25013130 TI - Complete Genome Sequences of Four Novel Lactococcus lactis Phages Distantly Related to the Rare 1706 Phage Species. AB - Lactoccocus lactis is a Gram-positive bacterium widely used in the dairy industry in the production of an array of cheeses and other fermented milk products. Here, we describe the sequencing and genome annotations of a set of four phages virulent to L. lactis and exhibiting similarities to phage 1706. PMID- 25013129 TI - Factors affecting health adaptation of Chinese adolescents with type 1 diabetes: A path model testing. AB - Glycemic control and quality of life (QoL) are both considered indicators of health adaptation among adolescents with type 1 diabetes (T1D). The purpose of this study was to construct a path model addressing the influences of individual characteristics, school support, resilience, and self-care behaviors on glycated hemoglobin (HbA1c) and QoL among adolescents with T1D in Taiwan. This was a cross sectional design study. A structured questionnaire was used to collect information on individual characteristics, school support, resilience, self-care behaviors, and QoL. The latest HbA1c was collected from medical records. Data from 238 adolescents with T1D were analyzed using structural equation modeling to test the hypothesized path model. The findings indicated that self-care behaviors and resilience both directly influenced HbA1c and QoL. School support directly influenced QoL but indirectly influenced HbA1c. We suggest that improving self care behaviors and resilience could be considered an appropriate intervention for enhancing the health adaptation of adolescents with T1D. Increasing school support might be a strategy to improve QoL among adolescents with T1D. PMID- 25013131 TI - Complete Genome Sequences of Two Porcine Circovirus Type 2 Field Isolates Bearing an Unusual Sequence Duplication in the rep Gene. AB - Porcine circovirus type 2 (PCV-2) is the etiologic agent of porcine circovirus associated disease (PCVAD). PCV-2 is classified into three genotypes. Here, we present the complete genomic sequences of two PCV-2 isolates (KM and H026) with an unusual sequence duplication in the rep gene coding for viral replicase proteins. PMID- 25013132 TI - Genome Analysis of a Tembusu Virus, GX2013H, Isolated from a Cheery Valley Duck in Guangxi, China. AB - We report here the complete genome sequence of a duck Tembusu virus (DTMUV) strain, GX2013H, isolated from a duck from Cheery Valley in the Guangxi Province of southern China in 2013. We obtained the strain GX2013H from a Cheery Valley duck with severely decreased egg production and neurological signs. The genome of GX2013H is 10,990 nucleotides (nt) in length and contains a single open reading frame encoding a putative polyprotein of 3,425 amino acids (aa). A comparison of the complete sequence and the deduced amino acid sequence of GX2013H with published sequences of 15 other chicken anemia viruses from China showed that the homologies of the nucleotides are approximately 96.5% to 97.5% and the homologies of the deduced amino acid sequences are approximately 98.9% to 99.3%. This report will help to understand the epidemiology and molecular characteristics of TMUV in Guangxi. PMID- 25013133 TI - Draft Whole-Genome Sequences of Nine Non-O157 Shiga Toxin-Producing Escherichia coli Strains. AB - Shiga toxin-producing Escherichia coli (STEC) is an important food-borne pathogen. Here, we report the draft whole-genome sequences of nine STEC strains isolated from clinical cases in the United States. This is the first report of such information for STEC of serotypes O69, H11, O145:H25, O118:H16, O91:H21, O146:H21, O45:H2, O128:H2, and O121:H19. PMID- 25013134 TI - First Whole-Genome Sequence of a Clinical Isolate of Multidrug-Resistant Mycobacterium bovis BCG. AB - The attenuated BCG strain of Mycobacterium bovis is widely used as a vaccine against tuberculosis. However, in rare cases, it can be pathogenic to humans. Here, we report the first draft of a whole-genome sequence of a multidrug resistant clinical isolate of M. bovis BCG. PMID- 25013135 TI - Draft Genome Sequence of Environmental Vibrio cholerae 2012EL-1759 with Similarities to the V. cholerae O1 Classical Biotype. AB - Vibrio cholerae 2012EL-1759 is an environmental isolate from Haiti that was recovered in 2012 during a cholera outbreak. The genomic backbone is similar to that of the prototypical V. cholerae O1 classical biotype strain O395, and it carries the Vibrio pathogenicity islands (VPI-1 and VPI-2) and a cholera toxin (CTX) prephage. PMID- 25013136 TI - Draft Genome Sequence of Rhodosporidium toruloides CECT1137, an Oleaginous Yeast of Biotechnological Interest. AB - We report the sequencing of the basidiomycetous yeast Rhodosporidium toruloides CECT1137. The current assembly comprises 62 scaffolds, for a total size of ca. 20.45 Mbp and a G+C content of ca. 61.9%. The genome annotation predicts 8,206 putative protein-coding genes. PMID- 25013137 TI - Complete Genome Sequence of the Streptococcus sp. Strain VT 162, Isolated from the Saliva of Pediatric Oncohematology Patients. AB - Streptococcus sp. strain VT 162 was isolated from the saliva of pediatric oncohematology patients. Its full genome is 2,045,418 bp. The availability of this genome will provide insights into the composition of microbial flora among pediatric oncohematology patients and the host interaction and pathogenicity of this species. PMID- 25013138 TI - Draft Genome Sequence of Marine-Derived Actinomycete Nocardiopsis sp. Strain TP A0876, a Producer of Polyketide Pyrones. AB - Here we report the draft genome sequence of Nocardiopsis sp. strain TP-A0876, isolated from marine sediment, which produces polyketide-derived pyrones called nocapyrones. The genome contains three polyketide synthase (PKS) gene clusters, one of which was proposed to be responsible for nocapyrone biosynthesis. This genome sequence will facilitate the study of the potential for secondary metabolism in Nocardiopsis strains. PMID- 25013139 TI - Draft Genome Sequence of Weissella oryzae SG25T, Isolated from Fermented Rice Grains. AB - Weissella oryzae was originally isolated from fermented rice grains. Here we report the draft genome sequence of the type strain of W. oryzae. This first report on the genomic sequence of this species may help identify the mechanisms underlying bacterial adaptation to the ecological niche of fermented rice grains. PMID- 25013141 TI - Draft Genome Sequence of the Bordetella bronchiseptica Swine Isolate KM22. AB - Bordetella bronchiseptica swine isolate KM22 has been used in experimental infections of swine as a model of clinical B. bronchiseptica infections within swine herds and to study host-to-host transmission. Here we report the draft genome sequence of KM22. PMID- 25013140 TI - Draft Genome Sequence of the Brazilian Cyanobium sp. Strain CACIAM 14. AB - Given the scarcity of data pertaining to whole-genome sequences of cyanobacterial strains isolated in Brazil, we hereby present the draft genome sequence of the Cyanobium sp. strain CACIAM 14, isolated in southeastern Amazonia. PMID- 25013143 TI - Complete Genome Sequence of Mycoplasma californicum Strain HAZ160_1 from Bovine Mastitic Milk in Japan. AB - Bovine mycoplasmal mastitis is spreading quickly among cows. It often leads to clinical mastitis outbreaks and often results in huge economic losses. Mycoplasma californicum is an important causal species of bovine mastitis. Presented here is the 799,088-bp complete genome sequence of M. californicum strain HAZ160_1, which was isolated in Japan. PMID- 25013142 TI - First Complete Genome Sequence of Staphylococcus xylosus, a Meat Starter Culture and a Host to Propagate Staphylococcus aureus Phages. AB - Staphylococcus xylosus is a bacterial species used in meat fermentation and a commensal microorganism found on animals. We present the first complete circular genome from this species. The genome is composed of 2,757,557 bp, with a G+C content of 32.9%, and contains 2,514 genes and 79 structural RNAs. PMID- 25013144 TI - Complete Genome Sequences of Two Central European Brucella suis bv. 2 Haplotype 2c Strains Isolated from Wild Boars. AB - The Brucella suis haplotype 2c is commonly isolated from wild boars and domestic pigs across Central Europe, though it is rarely described in the Iberian Peninsula. We report here the complete and annotated genome sequences of two haplotype 2c strains isolated from wild boars in the northeast region of Spain, above the Ebro River. PMID- 25013146 TI - Draft Genome Sequence of Polaromonas glacialis Strain R3-9, a Psychrotolerant Bacterium Isolated from Arctic Glacial Foreland. AB - Here we report the draft genome sequence of the psychrotolerant Polaromonas glacialis strain R3-9, isolated from Midtre Lovenbreen glacial foreland near Ny Alesund, Svalbard Archipelago, Norway. PMID- 25013145 TI - Draft Genomes of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Strain MM66 and MM66 Derivatives with Altered Vancomycin Resistance Levels. AB - The draft genomes of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) strain MM66 and MM66 isolates demonstrating altered vancomycin resistance levels were produced in an effort to provide information on mutations contributing to the vancomycin resistance levels observed in these strains. PMID- 25013147 TI - Draft Genome Sequence of Mycobacterium neoaurum Strain DSM 44074T. AB - We report the draft genome sequence of Mycobacterium neoaurum strain DSM 44074(T), a nontuberculosis species responsible for opportunistic infections in immunocompromised patients. The strain described here is composed of 5,536,033 bp, with a G+C content of 66.24%, and carries 5,274 protein-coding genes and 72 RNA genes. PMID- 25013148 TI - Complete Genome Sequence of Vibrio anguillarum Phage CHOED Successfully Used for Phage Therapy in Aquaculture. AB - Vibrio anguillarum phage CHOED was isolated from Chilean mussels. It is a virulent phage showing effective inhibition of V. anguillarum. CHOED has potential in phage therapy, because it can protect fish from vibriosis in fish farms. Here, we announce the completely sequenced genome of V. anguillarum phage CHOED. PMID- 25013149 TI - Reduced information processing speed as primum movens for cognitive decline in MS. AB - BACKGROUND: Cognitive impairment affects half of the multiple sclerosis (MS) patient population and is an important contributor to patients' daily activities. Most cognitive impairment studies in MS are, however, cross-sectional or/and focused on the early disease stages. OBJECTIVE: We aim to assess the time course of decline of different cognitive domains. METHODS: We collected neuropsychological data on 514 MS patients to construct Kaplan-Meier survival curves of the tests included in the Neuropsychological Screening Battery for MS (NSBMS) and the Symbol Digit Modalities Test (SDMT). Cox-proportional hazard models were constructed to examine the influence of MS onset type, age at onset, gender, depression and level of education on the time course, expressed as age or disease. RESULTS: Survival curves of tests focusing on information processing speed (IPS) declined significantly faster than tests with less specific demands of IPS. Median age for pathological decline was 56.2 years (95% CI: 54.4-58.2) on the SDMT and 63.9 years (95% CI: 60-66.9) on the CLTR, a memory task. CONCLUSION: In conclusion, IPS is the cognitive domain not only most widely affected by MS but it is also the first cognitive deficit to emerge in MS. PMID- 25013150 TI - Perivascular spaces in MS patients at 7 Tesla MRI: a marker of neurodegeneration? AB - BACKGROUND: Virchow-Robin spaces (VRS) are associated with vascular and neurodegenerative disease. In multiple sclerosis (MS), VRS have been associated with neuroinflammation. Ultra-high field imaging may be used to gain insight in these contradictory findings. OBJECTIVE: The objective of this paper is to analyze VRS in MS patients using high-resolution 7 Tesla (T) MRI. Additionally, we investigated whether the widening of VRS is related to inflammatory or neurodegenerative aspects of MS. METHODS: Thirty-four MS patients and 11 healthy controls were examined at 7T. Number and size of VRS were measured on three dimensional (3D) T1-weighted images, and 3D fluid-attenuated inversion recovery (FLAIR) images were used for MS lesion detection. Brain atrophy was quantified by computing supratentorial brain volume fraction (sBVF). VRS counts were correlated with clinical variables, lesion count and sBVF. RESULTS: MS patients displayed more VRS (median 11) than healthy controls (median four), p = 0.001. VRS size did not differ between both groups. VRS count in MS patients was associated with sBVF (rho = -0.40, p = 0.02), but not with lesion count (p = 0.22). CONCLUSIONS: The 7T MRI reveals increased numbers of VRS in MS. The finding that VRS are associated with supratentorial brain atrophy, but not with lesion count, suggests that VRS might rather serve as a neurodegenerative than an inflammatory marker in MS. PMID- 25013151 TI - Multiple sclerosis and psychiatric disorders: comorbidity and sibling risk in a nationwide Swedish cohort. AB - BACKGROUND: Psychiatric disorders are known to be prevalent in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to study comorbidity between MS and bipolar disorder, schizophrenia and depression in a nationwide cohort and to determine whether shared genetic liability underlies the putative association. METHODS: We identified ICD-diagnosed patients with MS (n = 16,467), bipolar disorder (n = 30,761), schizophrenia (n = 22,781) and depression (n = 172,479) in the Swedish National Patient Register and identified their siblings in the Multi Generation Register. The risk of MS was compared in psychiatric patients and in matched unexposed individuals. Shared familial risk between MS and psychiatric disorders was estimated by sibling comparison. RESULTS: The risk of MS was increased in patients with bipolar disorder (hazard ratio (HR) 1.8, 95% confidence interval (CI) 1.6-2.2, p < 0.0001) and depression (HR 1.9, 95% CI 1.7 2.0, p < 0.0001). MS risk in schizophrenia was decreased (HR 0.6, 95% CI 0.4-0.9, p = 0.005). The association between having a sibling with a psychiatric disorder and developing MS was not significant. CONCLUSION: We found a strong positive association between MS and bipolar disorder and depression that could not be explained by genetic liability. The unexpected negative association between MS and schizophrenia might be spurious or indicate possible protective mechanisms that warrant further exploration. PMID- 25013152 TI - Therapy-related acute leukaemia with mitoxantrone: four years on, what is the risk and can it be limited? AB - Therapy-related acute leukaemia (TRAL) is a significant concern, when considering treatment with mitoxantrone for multiple sclerosis (MS). We re-evaluated the literature, identifying all case reports and series of > 50 patients reporting TRAL cases in MS. TRAL was diagnosed in 0.73% of the 12,896 patients identified. Median onset was 22 months following treatment. We calculated a number needed to harm of 137.5 exposed patients, significantly higher than our 2008 analysis. We found that 82.8% of patients were exposed to > 60 mg/m(2) with a relative risk of 1.85 (p = 0.018) compared to < 60 mg/m(2), strongly suggesting a relationship to dose. MS treatment regimens which limit the mitoxantrone dose to < 60 mg/m(2) reduce the risk of TRAL. PMID- 25013153 TI - Detecting clinically-relevant changes in progressive multiple sclerosis. AB - OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS). METHODS: From a cohort of prospectively followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS. RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW. CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS. PMID- 25013154 TI - Anti-aquaporin-4 antibody-positive dorsal midbrain syndrome. AB - Neuromyelitis optica spectrum disorders (NMOSD) can cause various ocular motor disorders in addition to optic neuritis. Ocular motor findings associated with NMOSD include spontaneous vertical and gaze-evoked nystagmus, wall-eyed bilateral internuclear ophthalmoplegia, and trochlear nerve palsy. The association between dorsal midbrain syndrome and anti-aquaporin-4 antibody seropositivity has not been reported. Here, we report a patient displaying typical dorsal midbrain syndrome and anti-aquaporin-4 antibody seropositivity. PMID- 25013155 TI - The visual pathway as a model to understand brain damage in multiple sclerosis. AB - Patients with multiple sclerosis (MS) almost always experience effects in the visual pathway; and thus, visual dysfunction is not only common but also highly relevant. The visual pathway represents a model of acute focal central nervous system (CNS) damage, through acute optic neuritis and retinal periphlebitis, as well as a model of chronic, diffuse CNS damage through chronic retinopathy and optic neuropathy. The optic pathway can be accurately evaluated in detail, due to the availability of highly sensitive imaging techniques (e.g. magnetic resonance imaging or optical coherent tomography) or electrophysiological tests (multifocal visual evoked potentials or electroretinography). These techniques allow the interactions between the different processes at play to be evaluated, such as inflammation, demyelination, axonal damage and neurodegeneration. Moreover, these features mean that the visual pathway can be used as a model to test new neuroprotective or regenerative therapies. PMID- 25013156 TI - Variability explained by strength, body composition and gait impairment in activity and participation measures for children with cerebral palsy: a multicentre study. AB - OBJECTIVE: To determine the amount of variability in scores on activity and participation measures used to assess ambulatory individuals with cerebral palsy explained by strength, body composition, gait impairment and participant characteristics. DESIGN: Multicentre prospective cross-sectional study. SETTING: Seven paediatric-orthopaedic specialty hospitals. PARTICIPANTS: Three hundred and seventy-seven ambulatory individuals (241 males, 136 females) with cerebral palsy, Gross Motor Function Classification System (GMFCS) levels I-III (I = 148, II = 153, III = 76), ages 8-18 years (mean 12 years 9 months, SD 2 years 8 months). METHODS: Participants completed assessments of GMFCS level, patient history, lower extremity muscle strength, Gross Motor Function Measure (GMFM-66), Pediatric Outcomes Data Collection Instrument (PODCI), instrumented gait analysis, 1 minute walk test, Timed Up-and-Go and body composition. Multiple linear regression and bootstrap analyses were performed for each outcome measure, stratified by GMFCS level. RESULTS: The amount of variability in outcome measures explained by participant characteristics, strength, and gait impairment ranged from 11% to 50%. Gait impairment was the most common predictor variable and frequently explained the greatest variance across all outcome measures and GMFCS levels. As gait impairment increased, scores on outcome measures decreased. Strength findings were inconsistent and not a primary factor. Body composition contributed minimally (<4%) in explaining variability. Participant characteristics (cerebral palsy type, gestational age and age at walking onset), were significant predictor variables in several models. CONCLUSIONS: Variability in outcome measure scores is multifaceted and only partially explained by strength and gait impairment illustrating the challenges of attempting to explain variation within this heterogeneous population. Clinicians treating individuals with cerebral palsy should consider this when developing treatment paradigms. PMID- 25013157 TI - Using the glucometrics website to benchmark ICU glucose control before and after the NICE-SUGAR study. AB - Prior to 2009, intensive glycemic control was the standard in main intensive care units (ICUs). Glucose targets have been recalibrated after publication of the NICE-SUGAR study in that year, followed by updated guidelines that endorsed more moderated control. We sought to determine if the prevalence of hyperglycemia in US ICUs had increased after the NICE-SUGAR study's results were reported. We used data from hospitals submitted to the Yale GlucometricsTM website to assess mean blood glucose values, percentage of blood glucose within various ranges, and the prevalence of hypo- and hyperglycemic excursions, based on the patient-day method, comparing the pre- to post-NICE-SUGAR time period. Among more than a total of 2 million blood glucose determinations, comprising 408 790 patient-days, median patient-day blood glucose decreased from 144 mg/dL to 141 mg/dL (P < .001) in the pre- versus post-NICE-SUGAR time period. The percentage of patient days with a mean blood glucose of 110-179 mg/dl increased from 58.3 to 63.6%. The percentage of patient-days with either hypoglycemia (<70 mg/dl) or severe hyperglycemia (>=300 mg/dl) decreased during this time. Our results suggest that glycemic control in US ICUs has improved when comparing time periods before versus after publication of the NICE-SUGAR study. We found no evidence that fewer hypoglycemic events were achieved at the expense of more hyperglycemia. PMID- 25013158 TI - Case definition: postartemisinin delayed hemolysis. PMID- 25013159 TI - A microRNA involved in the germinal center reaction. PMID- 25013160 TI - Does TP53 guard ALL genomes? PMID- 25013161 TI - SDF-1 directs megakaryocyte relocation. PMID- 25013162 TI - Acute graft-versus-host disease: more than just alloreactivity. PMID- 25013163 TI - Exploring the applicability of equine blood to bloodstain pattern analysis. AB - Bloodstain pattern analysis (BPA) is the forensic application of the interpretation of distinct patterns which blood exhibits during a bloodletting incident, providing key evidence with its ability to map the sequence of events. Here, we explore the use of equine blood and investigate its suitability within the field of BPA. Blood is a complex fluid, and finding a suitable safe substitute to human blood that encompasses all of its characteristics has been the focus of many investigations. Animal blood has been concluded as the closest and therefore the most suitable alternate. However, it seems that currently only porcine blood is most prominently utilised.In this study, equine blood was investigated, using two different anti-clotting methods, where blood impacts were explored over a typical range of varying impact velocities upon a selection of commonly encountered surfaces. Key BPA parameters, such as the diameters of the resulting bloodstains, number of spines and area of origin were measured, which were subsequently applied into previously derived BPA equations.We find that defibrinated equine blood is a suitable alternative and offers the same conclusive outcomes to human blood. This gives bloodstain pattern investigators and researchers an additional choice of blood which can be of benefit when certain bloods are difficult to attain or when the activity involves the usage of a large quantity of blood. Additionally we explore the effect on BPA of aged blood, which revealed a significant decrease in stain diameter of up to 12.78 % when blood has been left for 57 days. A shelf life of no more than 12 days is recommended when blood is refrigerated at 4C. PMID- 25013164 TI - Protrusion of the tongue in bodies burned after death: Two cases of arson to cover homicide. AB - In the forensic assessment of burned bodies, the question of whether the victim was exposed to fire before or after death is of crucial importance. Many authors consider tongue protrusion in cases of burned bodies to be a post-mortem phenomenon. Deep-heating effects of fire are sufficient to cook muscle. The muscle becomes shortened by dehydration and protein denaturation. Exposure to heat causes flexion of the extremities on the contraction of muscles and tendons heat rigour. The flexors, being bulkier than the extensors, contract more and force the limbs into the position of general flexion. The genioglossus is the major muscle of the tongue and is responsible for protruding or sticking out the tongue: by means of its inferior fibres, it draws the root of the tongue forward and protrudes the apex from the mouth. Similar to the action of limb flexors exposed to heat and the appearance of post-mortem general flexion of a burned body due to heat rigour, perhaps the geniglossus could be shortened by heat, causing post-mortem tongue protrusion to appear as heat rigour of the tongue. In this paper, we present two such cases of protrusion of the tongue in bodies burned after death - cases of arson to cover homicide. PMID- 25013165 TI - Effects of hypercapnia on T cells in lung ischemia/reperfusion injury after lung transplantation. AB - T cells play a key role in lung ischemia/reperfusion injury (IRI). Hypercapnia has been indicated to decrease IRI and inhibit immunity. This study aimed to evaluate the effects of hypercapnia on T cells during lung IRI and to identify the underlying mechanism of these effects. In the in vivo study, rat recipients of lung transplants were randomized into a control group M and a hypercapnia group H. Peripheral blood T cells and cytokines were analyzed during reperfusion. In the in vitro study, we analyzed the T cells and cytokine levels in culture media from phytohemagglutinin-stimulated T cells from normal rats, stimulated under the normal (group C), hypercapnic (group H), or buffer hypercapnic (group BH) condition. In the in vivo study, the CD3(+)/CD4(+) T-cell ratio and interleukin (IL)-2, IL-8, interferon (IFN)-gamma, intracellular adhesion molecule (ICAM)-1, and P-selectin levels were decreased, but the IL-4 and IL-10 levels were increased, after reperfusion in group H compared to group M. In the in vitro study, groups H and BH exhibited a decreased CD2(+)/CD28(+) ratio and IL-2 and IFN-gamma levels, but elevated IL-4 and IL-10 levels, compared to group C. The CD2(+)/CD28(+) ratio was not different between groups BH and H; however, group H evidenced a lower IL-2 level and higher IL-4 and IL-10 levels compared to group BH. Hypercapnia decreased the CD3(+)/CD4(+) T-cell ratio and pro-inflammatory cytokine levels, but promoted anti-inflammatory factors in lung IRI. Hypercapnia inhibits CD2 and CD28 in T cells by CO2 and modulates T-cell cytokines via acidosis. PMID- 25013166 TI - Inadequate GP facilities are hampering patient care, BMA survey finds. PMID- 25013167 TI - Evidence of efficient stop codon readthrough in four mammalian genes. AB - Stop codon readthrough is used extensively by viruses to expand their gene expression. Until recent discoveries in Drosophila, only a very limited number of readthrough cases in chromosomal genes had been reported. Analysis of conserved protein coding signatures that extend beyond annotated stop codons identified potential stop codon readthrough of four mammalian genes. Here we use a modified targeted bioinformatic approach to identify a further three mammalian readthrough candidates. All seven genes were tested experimentally using reporter constructs transfected into HEK-293T cells. Four displayed efficient stop codon readthrough, and these have UGA immediately followed by CUAG. Comparative genomic analysis revealed that in the four readthrough candidates containing UGA-CUAG, this motif is conserved not only in mammals but throughout vertebrates with the first six of the seven nucleotides being universally conserved. The importance of the CUAG motif was confirmed using a systematic mutagenesis approach. One gene, OPRL1, encoding an opiate receptor, displayed extremely efficient levels of readthrough (~31%) in HEK-293T cells. Signals both 5' and 3' of the OPRL1 stop codon contribute to this high level of readthrough. The sequence UGA-CUA alone can support 1.5% readthrough, underlying its importance. PMID- 25013168 TI - Reverse gyrase--recent advances and current mechanistic understanding of positive DNA supercoiling. AB - Reverse gyrases are topoisomerases that introduce positive supercoils into DNA in an ATP-dependent reaction. They consist of a helicase domain and a topoisomerase domain that closely cooperate in catalysis. The mechanism of the functional cooperation of these domains has remained elusive. Recent studies have shown that the helicase domain is a nucleotide-regulated conformational switch that alternates between an open conformation with a low affinity for double-stranded DNA, and a closed state with a high double-stranded DNA affinity. The conformational cycle leads to transient separation of DNA duplexes by the helicase domain. Reverse gyrase-specific insertions in the helicase module are involved in binding to single-stranded DNA regions, DNA unwinding and supercoiling. Biochemical and structural data suggest that DNA processing by reverse gyrase is not based on sequential action of the helicase and topoisomerase domains, but rather the result of an intricate cooperation of both domains at all stages of the reaction. This review summarizes the recent advances of our understanding of the reverse gyrase mechanism. We put forward and discuss a refined, yet simple model in which reverse gyrase directs strand passage toward increasing linking numbers and positive supercoiling by controlling the conformation of a bound DNA bubble. PMID- 25013169 TI - A novel reannotation strategy for dissecting DNA methylation patterns of human long intergenic non-coding RNAs in cancers. AB - Despite growing consensus that long intergenic non-coding ribonucleic acids (lincRNAs) are modulators of cancer, the knowledge about the deoxyribonucleic acid (DNA) methylation patterns of lincRNAs in cancers remains limited. In this study, we constructed DNA methylation profiles for 4629 tumors and 705 normal tissue samples from 20 different types of human cancer by reannotating data of DNA methylation arrays. We found that lincRNAs had different promoter methylation patterns in cancers. We classified 2461 lincRNAs into two categories and three subcategories, according to their promoter methylation patterns in tumors. LincRNAs with resistant methylation patterns in tumors had conserved transcriptional regulation regions and were ubiquitously expressed across normal tissues. By integrating cancer subtype data and patient clinical information, we identified lincRNAs with promoter methylation patterns that were associated with cancer status, subtype or prognosis for several cancers. Network analysis of aberrantly methylated lincRNAs in cancers showed that lincRNAs with aberrant methylation patterns might be involved in cancer development and progression. The methylated and demethylated lincRNAs identified in this study provide novel insights for developing cancer biomarkers and potential therapeutic targets. PMID- 25013171 TI - MegaTevs: single-chain dual nucleases for efficient gene disruption. AB - Targeting gene disruptions in complex genomes relies on imprecise repair by the non-homologous end-joining DNA pathway, creating mutagenic insertions or deletions (indels) at the break point. DNA end-processing enzymes are often co expressed with genome-editing nucleases to enhance the frequency of indels, as the compatible cohesive ends generated by the nucleases can be precisely repaired, leading to a cycle of cleavage and non-mutagenic repair. Here, we present an alternative strategy to bias repair toward gene disruption by fusing two different nuclease active sites from I-TevI (a GIY-YIG enzyme) and I-OnuI E2 (an engineered meganuclease) into a single polypeptide chain. In vitro, the MegaTev enzyme generates two double-strand breaks to excise an intervening 30-bp fragment. In HEK 293 cells, we observe a high frequency of gene disruption without co-expression of DNA end-processing enzymes. Deep sequencing of disrupted target sites revealed minimal processing, consistent with the MegaTev sequestering the double-strand breaks from the DNA repair machinery. Off-target profiling revealed no detectable cleavage at sites where the I-TevI CNNNG cleavage motif is not appropriately spaced from the I-OnuI binding site. The MegaTev enzyme represents a small, programmable nuclease platform for extremely specific genome-engineering applications. PMID- 25013170 TI - Hypermethylated-capped selenoprotein mRNAs in mammals. AB - Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5'-end m(7)G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5'-end maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo. PMID- 25013172 TI - Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6. AB - Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that recognizes mRNAs with premature stop codons and targets them for rapid degradation. Evidence from previous studies has converged on UPF1 as the central NMD factor. In human cells, the SMG1 kinase phosphorylates UPF1 at the N-terminal and C-terminal tails, in turn allowing the recruitment of the NMD factors SMG5, SMG6 and SMG7. To understand the molecular mechanisms, we recapitulated these steps of NMD in vitro using purified components. We find that a short C-terminal segment of phosphorylated UPF1 containing the last two Ser-Gln motifs is recognized by the heterodimer of SMG5 and SMG7 14-3-3-like proteins. In contrast, the SMG6 14-3-3-like domain is a monomer. The crystal structure indicates that the phosphoserine binding site of the SMG6 14-3-3-like domain is similar to that of SMG5 and can mediate a weak phospho-dependent interaction with UPF1. The dominant SMG6-UPF1 interaction is mediated by a low-complexity region bordering the 14-3-3-like domain of SMG6 and by the helicase domain and C-terminal tail of UPF1. This interaction is phosphorylation independent. Our study demonstrates that SMG5-SMG7 and SMG6 exhibit different and non-overlapping modes of UPF1 recognition, thus pointing at distinguished roles in integrating the complex NMD interaction network. PMID- 25013173 TI - Free mRNA in excess upon polysome dissociation is a scaffold for protein multimerization to form stress granules. AB - The sequence of events leading to stress granule assembly in stressed cells remains elusive. We show here, using isotope labeling and ion microprobe, that proportionally more RNA than proteins are present in stress granules than in surrounding cytoplasm. We further demonstrate that the delivery of single strand polynucleotides, mRNA and ssDNA, to the cytoplasm can trigger stress granule assembly. On the other hand, increasing the cytoplasmic level of mRNA-binding proteins like YB-1 can directly prevent the aggregation of mRNA by forming isolated mRNPs, as evidenced by atomic force microscopy. Interestingly, we also discovered that enucleated cells do form stress granules, demonstrating that the translocation to the cytoplasm of nuclear prion-like RNA-binding proteins like TIA-1 is dispensable for stress granule assembly. The results lead to an alternative view on stress granule formation based on the following sequence of events: after the massive dissociation of polysomes during stress, mRNA stabilizing proteins like YB-1 are outnumbered by the burst of nonpolysomal mRNA. mRNA freed of ribosomes thus becomes accessible to mRNA-binding aggregation-prone proteins or misfolded proteins, which induces stress granule formation. Within the frame of this model, the shuttling of nuclear mRNA-stabilizing proteins to the cytoplasm could dissociate stress granules or prevent their assembly. PMID- 25013174 TI - A transient disruption of fibroblastic transcriptional regulatory network facilitates trans-differentiation. AB - Transcriptional Regulatory Networks (TRNs) coordinate multiple transcription factors (TFs) in concert to maintain tissue homeostasis and cellular function. The re-establishment of target cell TRNs has been previously implicated in direct trans-differentiation studies where the newly introduced TFs switch on a set of key regulatory factors to induce de novo expression and function. However, the extent to which TRNs in starting cell types, such as dermal fibroblasts, protect cells from undergoing cellular reprogramming remains largely unexplored. In order to identify TFs specific to maintaining the fibroblast state, we performed systematic knockdown of 18 fibroblast-enriched TFs and analyzed differential mRNA expression against the same 18 genes, building a Matrix-RNAi. The resulting expression matrix revealed seven highly interconnected TFs. Interestingly, suppressing four out of seven TFs generated lipid droplets and induced PPARG and CEBPA expression in the presence of adipocyte-inducing medium only, while negative control knockdown cells maintained fibroblastic character in the same induction regime. Global gene expression analyses further revealed that the knockdown-induced adipocytes expressed genes associated with lipid metabolism and significantly suppressed fibroblast genes. Overall, this study reveals the critical role of the TRN in protecting cells against aberrant reprogramming, and demonstrates the vulnerability of donor cell's TRNs, offering a novel strategy to induce transgene-free trans-differentiations. PMID- 25013176 TI - Phosphorothioate oligonucleotides can displace NEAT1 RNA and form nuclear paraspeckle-like structures. AB - Nuclear paraspeckles are built co-transcriptionally around a long non-coding RNA, NEAT1. Here we report that transfected 20-mer phosphorothioate-modified (PS) antisense oligonucleotides (ASOs) can recruit paraspeckle proteins to form morphologically normal and apparently functional paraspeckle-like structures containing no NEAT1 RNA. PS-ASOs can associate with paraspeckle proteins, including P54nrb, PSF, PSPC1 and hnRNPK. NEAT1 RNA can be displaced by transfected PS-ASO from paraspeckles and rapidly degraded. Co-localization of PS ASOs with P54nrb was observed in canonical NEAT1-containing paraspeckles, in perinucleolar caps upon transcriptional inhibition, and importantly, in paraspeckle-like or filament structures lacking NEAT1 RNA. The induced formation of paraspeckle-like and filament structures occurred in mouse embryonic stem cells expressing little or no NEAT1 RNA, suggesting that PS-ASOs can serve as seeding molecules to assemble paraspeckle-like foci in the absence of NEAT1 RNA. Moreover, CTN, an RNA reported to be functionally retained in paraspeckles, was also observed to localize to paraspeckle-like structures, implying that paraspeckle-like structures assembled on PS-ASOs are functional. Together, our results indicate that functional paraspeckles can form with short nucleic acids other than NEAT1 RNA. PMID- 25013177 TI - In vivo generation of DNA sequence diversity for cellular barcoding. AB - Heterogeneity is a ubiquitous feature of biological systems. A complete understanding of such systems requires a method for uniquely identifying and tracking individual components and their interactions with each other. We have developed a novel method of uniquely tagging individual cells in vivo with a genetic 'barcode' that can be recovered by DNA sequencing. Our method is a two component system comprised of a genetic barcode cassette whose fragments are shuffled by Rci, a site-specific DNA invertase. The system is highly scalable, with the potential to generate theoretical diversities in the billions. We demonstrate the feasibility of this technique in Escherichia coli. Currently, this method could be employed to track the dynamics of populations of microbes through various bottlenecks. Advances of this method should prove useful in tracking interactions of cells within a network, and/or heterogeneity within complex biological samples. PMID- 25013175 TI - The DEAD-box helicase Ded1 from yeast is an mRNP cap-associated protein that shuttles between the cytoplasm and nucleus. AB - The DEAD-box helicase Ded1 is an essential yeast protein that is closely related to mammalian DDX3 and to other DEAD-box proteins involved in developmental and cell cycle regulation. Ded1 is considered to be a translation-initiation factor that helps the 40S ribosome scan the mRNA from the 5' 7-methylguanosine cap to the AUG start codon. We used IgG pull-down experiments, mass spectrometry analyses, genetic experiments, sucrose gradients, in situ localizations and enzymatic assays to show that Ded1 is a cap-associated protein that actively shuttles between the cytoplasm and the nucleus. NanoLC-MS/MS analyses of purified complexes show that Ded1 is present in both nuclear and cytoplasmic mRNPs. Ded1 physically interacts with purified components of the nuclear CBC and the cytoplasmic eIF4F complexes, and its enzymatic activity is stimulated by these factors. In addition, we show that Ded1 is genetically linked to these factors. Ded1 comigrates with these proteins on sucrose gradients, but treatment with rapamycin does not appreciably alter the distribution of Ded1; thus, most of the Ded1 is in stable mRNP complexes. We conclude that Ded1 is an mRNP cofactor of the cap complex that may function to remodel the different mRNPs and thereby regulate the expression of the mRNAs. PMID- 25013179 TI - Dynamics and stability of polymorphic human telomeric G-quadruplex under tension. AB - As critical DNA structures capping the human chromosome ends, the stability and structural polymorphism of human telomeric G-quadruplex (G4) have drawn increasing attention in recent years. This work characterizes the equilibrium transitions of single-molecule telomeric G4 at physiological K(+) concentration. We report three folded states of telomeric G4 with markedly different lifetime and mechanical stability. Our results show that the kinetically favored folding pathway is through a short-lived intermediate state to a longer-lived state. By examining the force dependence of transition rates, the force-dependent transition free energy landscape for this pathway is determined. In addition, an ultra-long-lived form of telomeric G4 structure with a much stronger mechanical stability is identified. PMID- 25013178 TI - Structure, stability and behaviour of nucleic acids in ionic liquids. AB - Nucleic acids have become a powerful tool in nanotechnology because of their conformational polymorphism. However, lack of a medium in which nucleic acid structures exhibit long-term stability has been a bottleneck. Ionic liquids (ILs) are potential solvents in the nanotechnology field. Hydrated ILs, such as choline dihydrogen phosphate (choline dhp) and deep eutectic solvent (DES) prepared from choline chloride and urea, are 'green' solvents that ensure long-term stability of biomolecules. An understanding of the behaviour of nucleic acids in hydrated ILs is necessary for developing DNA materials. We here review current knowledge about the structures and stabilities of nucleic acids in choline dhp and DES. Interestingly, in choline dhp, A-T base pairs are more stable than G-C base pairs, the reverse of the situation in buffered NaCl solution. Moreover, DNA triplex formation is markedly stabilized in hydrated ILs compared with aqueous solution. In choline dhp, the stability of Hoogsteen base pairs is comparable to that of Watson-Crick base pairs. Moreover, the parallel form of the G-quadruplex is stabilized in DES compared with aqueous solution. The behaviours of various DNA molecules in ILs detailed here should be useful for designing oligonucleotides for the development of nanomaterials and nanodevices. PMID- 25013180 TI - Competitive binding-based optical DNA mapping for fast identification of bacteria -multi-ligand transfer matrix theory and experimental applications on Escherichia coli. AB - We demonstrate a single DNA molecule optical mapping assay able to resolve a specific Escherichia coli strain from other strains. The assay is based on competitive binding of the fluorescent dye YOYO-1 and the AT-specific antibiotic netropsin. The optical map is visualized by stretching the DNA molecules in nanofluidic channels. We optimize the experimental conditions to obtain reproducible barcodes containing as much information as possible. We implement a multi-ligand transfer matrix method for calculating theoretical barcodes from known DNA sequences. Our method extends previous theoretical approaches for competitive binding of two types of ligands to many types of ligands and introduces a recursive approach that allows long barcodes to be calculated with standard computer floating point formats. The identification of a specific E. coli strain (CCUG 10979) is based on mapping of 50-160 kilobasepair experimental DNA fragments onto the theoretical genome using the developed theory. Our identification protocol introduces two theoretical constructs: a P-value for a best experiment-theory match and an information score threshold. The developed methods provide a novel optical mapping toolbox for identification of bacterial species and strains. The protocol does not require cultivation of bacteria or DNA amplification, which allows for ultra-fast identification of bacterial pathogens. PMID- 25013181 TI - Co-transcriptional recruitment of Puf6 by She2 couples translational repression to mRNA localization. AB - Messenger RNA (mRNA) localization is coupled to the translational repression of transcripts during their transport. It is still unknown if this coupling depends on physical interactions between translational control and mRNA localization machineries, and how these interactions are established at the molecular level. In yeast, localization of transcripts like ASH1 to the bud depends on the RNA binding protein She2. During its transport, ASH1 mRNA translation is repressed by Puf6. Herein, we report that She2 recruits Puf6 on ASH1 co-transcriptionally. The recruitment of Puf6 depends on prior co-transcriptional loading of Loc1, an exclusively nuclear protein. These proteins form a ternary complex, in which Loc1 bridges Puf6 to She2, that binds the ASH1 3'UTR. Using a genome-wide ChIP-chip approach, we identified over 40 novel targets of Puf6, including several bud localized mRNAs. Interestingly, the co-transcriptional recruitment of Puf6 on genes coding for these bud-localized mRNAs is also She2- and Loc1-dependent. Our results suggest a coordinated assembly of localization and translational control machineries on localized mRNAs during transcription, and underline the importance of co-transcriptional events in establishing the cytoplasmic fate of mRNAs. PMID- 25013182 TI - HRAS is silenced by two neighboring G-quadruplexes and activated by MAZ, a zinc finger transcription factor with DNA unfolding property. AB - The HRAS promoter contains immediately upstream of the transcription start site two neighboring G-elements, each capable of folding into a G-quadruplex structure. We have previously found that these G-quadruplexes bind to the zinc finger transcription factors MAZ and Sp1. In the present study we have examined the interaction between the HRAS promoter and MAZ, demonstrating for the first time that the protein unfolds the G-quadruplex structures. We also demonstrate that MAZ-GST, in the presence of the complementary strands, promotes a rapid transformation of the two HRAS quadruplexes into duplexes. By a mutational analysis of the HRAS G-elements, we dissected the MAZ-binding sites from the quadruplex-forming motifs, finding that the two neighboring G-quadruplexes bring about a dramatic repression of transcription, in a synergistic manner. We also discovered that the two G-quadruplexes are strong targets for small anticancer molecules. We found that a cell-penetrating anthratiophenedione (ATPD-1), which binds tightly to the G-quadruplexes (DeltaT > 15 degrees C), promotes the total extinction of HRAS transcription. In contrast, when one of the two G-quadruplexes was abrogated by point mutations, ATPD-1 repressed transcription by only 50%. Our study provides relevant information for the rationale design of targeted therapy drugs specific for the HRAS oncogene. PMID- 25013184 TI - Reflex Epilepsy Triggered by Smell. AB - Reflex epilepsies can be provoked by various types of external stimuli, but triggered by smell is rare in the literature. In this case report, we present a patient whose reflex epilepsy is triggered by smell. Physical examination findings and electrophysiologic studies of the patient are discussed. PMID- 25013183 TI - Impact of next-generation sequencing error on analysis of barcoded plasmid libraries of known complexity and sequence. AB - Barcoded vectors are promising tools for investigating clonal diversity and dynamics in hematopoietic gene therapy. Analysis of clones marked with barcoded vectors requires accurate identification of potentially large numbers of individually rare barcodes, when the exact number, sequence identity and abundance are unknown. This is an inherently challenging application, and the feasibility of using contemporary next-generation sequencing technologies is unresolved. To explore this potential application empirically, without prior assumptions, we sequenced barcode libraries of known complexity. Libraries containing 1, 10 and 100 Sanger-sequenced barcodes were sequenced using an Illumina platform, with a 100-barcode library also sequenced using a SOLiD platform. Libraries containing 1 and 10 barcodes were distinguished from false barcodes generated by sequencing error by a several log-fold difference in abundance. In 100-barcode libraries, however, expected and false barcodes overlapped and could not be resolved by bioinformatic filtering and clustering strategies. In independent sequencing runs multiple false-positive barcodes appeared to be represented at higher abundance than known barcodes, despite their confirmed absence from the original library. Such errors, which potentially impact barcoding studies in an application-dependent manner, are consistent with the existence of both stochastic and systematic error, the mechanism of which is yet to be fully resolved. PMID- 25013185 TI - England's NHS faces a funding crisis, report says. PMID- 25013186 TI - Retroperitoneal fibrosis due to B-cell non-Hodgkin lymphoma: Responding to rituximab! AB - Retroperitoneal fibrosis is a rare disease manifesting as chronic soft tissue fibrosis in the retroperitoneum, with potential anatomic and/or functional compromise of adjacent organs. It can be primary (idiopathic) or secondary to other conditions such as cancers, autoimmune disorders, or drugs. We report herein a 66-year-old patient with symptomatic retroperitoneal fibrosis leading to bilateral hydronephrosis and renal failure, in whom, after a complex diagnostic work-up and protracted clinical course, a B-cell non-Hodgkin lymphoma in the retroperitoneal space and several vertebral bodies was identified. The patient was treated with radiation therapy and weekly rituximab infusions, with resolution of hydronephrosis and lower back pain. We include a thorough literature review on etiopathogenesis, diagnosis, therapy, and prognosis of retroperitoneal fibrosis. A meticulous search for malignancy is necessary in this rare condition that, if positive, may have significant therapeutic and prognostic implications. PMID- 25013187 TI - Posterior reversible encephalopathy syndrome due to targeted agents: vemurafinib among suspects! AB - Posterior reversible encephalopathy syndrome features reversible cortical neurologic dysfunction and characteristic findings on brain imaging studies. This syndrome can be caused by several agents including traditional chemotherapy and immunosuppressive drugs. Targeted therapies such as agents binding vascular endothelial growth factor/VEGFR, CD20 and cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) antigens are also among the culprits. Vemurafenib is a BRAF gene inhibitor that has not been previously linked with posterior reversible encephalopathy syndrome. We report herein the first such case and believe that further studies confirming this association are warranted. We further review the existing posterior reversible encephalopathy syndrome cases associated with targeted therapies in the scientific literature. PMID- 25013188 TI - Role of local practitioners highlighted at BVA Welsh dinner. PMID- 25013189 TI - FAWC reviews the evidence base for animal welfare. PMID- 25013190 TI - Companies agree insurance partnership. PMID- 25013191 TI - US industry engages with voluntary AMR initiative. PMID- 25013192 TI - Pilot badger culls: Badger Trust granted a judicial review. PMID- 25013193 TI - Welfare implications of equine breeding. PMID- 25013194 TI - Old PDP website to close. PMID- 25013195 TI - Animal welfare: what has changed in the past 50 years? AB - The 3(rd) CABI symposium on animal welfare and behaviour was held on June 11, and featured a range of talks on 'animals as machines'. The symposium marked the 50(th) anniversary of the publication of the book 'Animal Machines' by Ruth Harrison. The book decried the conditions experienced at that time by many animals kept in intensive farming systems, and the speakers at the symposium discussed how far animal welfare had come since its publication. Georgina Mills reports. PMID- 25013196 TI - Bovine abortions caused by Helcococcus ovis. PMID- 25013197 TI - Visceral leishmaniasis: a One Health approach. PMID- 25013198 TI - Concern over maedi visna breakdowns. PMID- 25013199 TI - International conference on M bovis. PMID- 25013200 TI - Transmission of bovine TB. PMID- 25013201 TI - Availability of adder antivenom. PMID- 25013202 TI - Non-stun slaughter. PMID- 25013203 TI - Alternatives to animal research in acute lung injury. PMID- 25013205 TI - The Meaning of Coping for Psychiatric Patients. AB - Contemporary psychiatric theory holds that a precipitant of major mental illness is the inability of some vulnerable individuals to cope with the difficulties of everyday life. Such mentally ill people are characterized as having deficient, dysfunctional, or absent coping skills. Recently, researchers have exerted considerable effort to distinguish between productive and nonproductive coping. In this article, we argue that not only are such conceptualizations reliant on reductive, circular logic, but they also miss the essentially rational, local, and individual nature of coping in psychiatric patients' lives. We used semistructured interviews and thematic analyses of psychiatric patients' descriptions of their coping. Patients reported that professional intervention reduced their ability to cope, that they distrusted the mental health system and its professionals, that coping mechanisms were misinterpreted, that situational crises modulated coping, and that sometimes coping was just "not coping." We argue for a more respectful, nuanced understanding of coping among mental health professionals. PMID- 25013204 TI - Acute hantavirus infection induces galectin-3-binding protein. AB - Hantaviruses are zoonotic viruses that cause life-threatening diseases when transmitted to humans. Severe hantavirus infection is manifested by impairment of renal function, pulmonary oedema and capillary leakage. Both innate and adaptive immune responses contribute to the pathogenesis, but the underlying mechanisms are not fully understood. Here, we showed that galectin-3-binding protein (Gal 3BP) was upregulated as a result of hantavirus infection both in vitro and in vivo. Gal-3BP is a secreted glycoprotein found in human serum, and increased Gal 3BP levels have been reported in chronic viral infections and in several types of cancer. Our in vitro experiments showed that, whilst Vero E6 cells (an African green monkey kidney cell line) constitutively expressed and secreted Gal-3BP, this protein was detected in primary human cells only as a result of hantavirus infection. Analysis of Gal-3BP levels in serum samples of cynomolgus macaques infected experimentally with hantavirus indicated that hantavirus infection induced Gal-3BP also in vivo. Finally, analysis of plasma samples collected from patients hospitalized because of acute hantavirus infection showed higher Gal-3BP levels during the acute than the convalescent phase. Furthermore, the Gal-3BP levels in patients with haemorrhagic fever with renal syndrome correlated with increased complement activation and with clinical variables reflecting the severity of acute hantavirus infection. PMID- 25013206 TI - Problem-Focused Coping: Skipped-Generation Caregivers Affected by HIV/AIDS in Vietnam. AB - In this article, we examine skipped-generation caregivers who foster their grandchildren orphaned by HIV/AIDS in Vietnam. We investigated the challenges facing this population and the ways in which grandparents handled their trials on behalf of their families. Specifically, how did caregivers make sense of their roles, and how did these meanings inform their coping strategies? We conducted in depth qualitative interviews with 21 older caregivers and 7 key informants and selected 5 caregivers from the sample to complete participant observations. The participants understood coping as problem-focused coping; for example, by considering a set of caregiving-related activities that included providing childcare, making money, borrowing money, cooking, and doing other daily chores. The voices of older caregivers must be a vital component to influence and inform service organizations and HIV sectors working in Vietnam. Based on a deeper understanding of the caregiving process, we outline implications for service development within the area of HIV caregiving. PMID- 25013207 TI - Age-related increase of VGF-expression in T lymphocytes. AB - VGF is a protein expressed by neurons and processed into several peptides. It plays a role in energy homeostasis and promotes growth and survival. Recently, VGF mRNA was detected in peripheral leukocytes. Since it is known that aging is associated with a decrease in the development and function of neuronal as well as immune cells, we addressed the question whether a peripheral expression of VGF by CD3+ T cells and CD56+ NK cells is correlated with age. Therefore, the frequency of VGF+CD3+ and VGF+CD56+ cells was determined in mentally healthy volunteers aged between 22 and 88. We found an age-dependent increase in the number of VGF+CD3+ T cells that correlated with HbA1c and the body mass index (BMI). VGF expression by NK cells was age-independent. Blockade of VGF reduced proliferation and secretion of cytokines such as IL-2, IL-17A, IL-1beta, IL-10 and TNF by CD3+ T cells and PBMCs. Rapamycin-mediated T cell blockade significantly reduced the frequency of VGF-expressing T cells. We conclude that VGF contributes to survival and function of peripheral T cells. The age-dependent increase in VGF-expression could serve as mechanism that counterregulates the decrease in functionality of T lymphocytes. PMID- 25013209 TI - Smallpox samples are found in FDA storage room in Maryland. PMID- 25013210 TI - Neuroscientists condemn European brain simulation project. PMID- 25013208 TI - Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing. AB - The role that mtDNA heteroplasmy plays in healthy aging, familial longevity and the heritability patterns of low levels heteroplasmy in the elderly are largely unknown. We analyzed the low levels of mtDNA heteroplasmy in blood in a cohort of centenarians, their offspring and a group of offspring of non long-lived parents, characterized by a less favorable health phenotype. The aims of this study are to: (i) investigate the transmission of low level heteroplasmies in the elderly; (ii) explore the association of heteroplasmy with age and longevity and (iii) investigate heteroplasmy patterns in these three groups. We sequenced a 853 bp mtDNA fragment in 88 individuals to an average coverage of 49334-fold, using quality control filtering and triplicate PCR analysis to reduce any methodological bias, and we detected 119 heteroplasmic positions with a minor allele frequency>=0.2%. The results indicate that low-level heteroplasmies are transmitted and maintained within families until extreme age. We did not find any heteroplasmic variant associated with longevity and healthy aging but we identified an unique heteroplasmy profile for each family, based on total level and positions. This familial profile suggests that heteroplasmy may contribute to familial longevity. PMID- 25013211 TI - Rapid uptake of new surgical technique associated with rise in harms, study finds. PMID- 25013212 TI - Attending cervical cancer screening, opportunities and obstacles: a qualitative study on midwives' experiences telephoning non-attendees in Sweden. AB - AIM: As part of a research project aimed at increasing participation in the cervical cancer screening program (CCS), we explored midwives' unique experiences of telephoning non-attendees and offering Pap smear appointments. METHODS: Twenty midwives, in four focus groups, discussed their experiences of a study investigating ways to increase participation in the CCS. The group discussions were tape-recorded and transcribed verbatim and underwent qualitative content analysis. RESULTS: Speaking with more than 1000 non-attendees provided the midwives with new perspective on the CCS and they realised that improving it might address a number of reasons for not participating. These reasons were often related to logistics, such as scheduling flexibility and appointment booking. The telephone conversations revealed that some women required more individual attention, while it was discovered that others did not require screening. The midwives considered the CCS to be life-saving; participating in this screening activity gave them a sense of satisfaction and pride. CONCLUSIONS: This study shows that midwives can improve access and prevent non-attendance at the cervical cancer screening program when they are aware of women's varying requirements for attending screening. PMID- 25013214 TI - The "Oscars of medicine" are coming to New Delhi: who will you nominate as a hero of Indian healthcare? PMID- 25013213 TI - Long-term sickness absence during pregnancy and the gender balance of workplaces. AB - AIMS: This study addresses how the gender composition of workplaces affects pregnant women's sickness absence. It also assesses whether an observed association may be explaine by differential selection to female- or male dominated workplaces. METHODS: The analyses are based on Norwegian registry data from 2003-2011. Using Poisson regressions with detailed control for occupational categories, I examine whether the number of absence days are associated with the proportion of females at the workplace. I address possible selection effects by Poisson regressions with fixed individual effects using only within-individual variation on women with two or more pregnancies during the time window. RESULTS: The analyses indicate a positive and significant relationship between the female proportion in workplaces and sickness absence rates during pregnancy. Analyses limited to within-individual variation also show positive and significant effects of similar strength, indicating that the observed relationship is not due to differential selection of absence-prone pregnant workers to female-dominated workplaces. CONCLUSIONS: The proportion of female individuals at workplaces is positively associated with sickness absence rates during pregnancy this association is not likely explained by occupational nor individual characteristics the results are consistent with absence culture theory and more lenient norms concerning sickness absence during pregnancy at female-dominated workplaces. PMID- 25013215 TI - Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. AB - BACKGROUND: Metformin is an effective oral anti-hyperglycaemic drug used as first line medical treatment for type 2 diabetes. It improves systemic hyperglycaemia by reducing hepatic glucose production and enhancing peripheral insulin sensitivity. It also stimulates fat oxidation and reduces fat synthesis and storage. The molecular mechanism of this drug is thought to be secondary to its actions on the mitochondrial respiratory chain. METHODS: This paper reviews the relevant literature (research articles up to October 2013) on the use of metformin in infertility, polycystic ovary syndrome (PCOS), pregnancy and gynaecological cancers. We present a comprehensive discussion of the evidence supporting the efficacy of metformin in these clinical conditions. RESULTS: Metformin is used clinically off-label in the management of hirsutism, acne and insulin resistance in PCOS, although the evidence for anti-androgenic effects is inconsistent. Metformin is also used to improve ovulation in women with PCOS both alone and in combination with clomiphene citrate. Trial findings are conflicting but metformin treatment in IVF/ICSI cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates. Metformin also appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight and obese women. Studies have shown that metformin is safe in pregnancy and women with GDM treated with metformin have less weight gain during pregnancy than those treated with insulin. One study with a 2-year follow-up demonstrated that babies born to women treated with metformin also developed less visceral fat, making them less prone to insulin resistance in later life. These findings have sparked interest in the use of metformin for pregnant, obese, non-diabetic women. On-going clinical trials are underway to determine if women treated prophylactically with metformin have a reduced incidence of GDM and demonstrate less weight gain during pregnancy. The hypothesis in these studies is that babies born to obese women on prophylactic metformin will also have better outcomes. Epidemiological studies have linked metformin exposure to a decreased risk of cancer. Pre-clinical experiments report that metformin has a growth-static effect on several cancers, including endometrial cancer, which may be partly due to the effect of metformin on the PI3K/AKT/mTOR signal transduction pathway. A number of on-going early phase clinical trials aim to explore the anti-cancer effects of metformin and investigate its potential as a chemopreventative or adjuvant treatment. CONCLUSIONS: Obesity is on the rise in developing countries and is strongly linked to several reproductive health problems, including PCOS, GDM and endometrial cancer. Traditional lifestyle measures aimed at weight reduction are challenging to implement and maintain. Metformin may be a valuable alternative to, or adjunct for, modifying the toxic effects of obesity in these populations. This review will appraise the evidence for the use of metformin for the prevention and treatment of adverse health outcomes in obstetrics and gynaecology. PMID- 25013216 TI - From gametogenesis and stem cells to cancer: common metabolic themes. AB - BACKGROUND: Both pluripotent stem cells (PSCs) and cancer cells have been described as having similar metabolic pathways, most notably a penchant for favoring glycolysis even under aerobiosis, suggesting common themes that might be explored for both stem cell differentiation and anti-oncogenic purposes. METHODS: A search of the scientific literature available in the PubMed/Medline was conducted for studies on metabolism and mitochondrial function related to gametogenesis, early development, stem cells and cancers in the reproductive system, notably breast, prostate, ovarian and testicular cancers. RESULTS: Both PSCs and some types of cancer cells, particularly reproductive cancers, were found to obtain energy mostly by glycolysis, often reducing mitochondrial activity and oxidative phosphorylation. This strategy links proliferating cells, allowing for the biosynthesis reactions necessary for cell division. Interventions that affect metabolic pathways, and force cells to change their preferences, can lead to shifts in cell status, increasing either pluripotency or differentiation of stem cells, and causing cancer cells to become more or less aggressive. Interestingly metabolic changes in many cases seemed to lead to cell transformation, not necessarily follow it, suggesting a direct role of metabolic choices in influencing the (epi)genetic program of different cell types. CONCLUSIONS: There are uncanny similarities between PSCs and cancer cells at the metabolic level. Furthermore, metabolism may also play a direct role in cell status and targeting metabolic pathways could therefore be a promising strategy for both the control of cancer cell proliferation and the regulation of stem cell physiology, in terms of manipulating stem cells toward relevant phenotypes that may be important for tissue engineering, or making cancer cells become less tumorigenic. PMID- 25013217 TI - Risk of thrombosis in women with malignancies undergoing ovarian stimulation for fertility preservation. AB - BACKGROUND: Compared with the general population, cancer patients have a higher risk of venous thromboembolism as well as arterial thrombotic events such as stroke, myocardial infarction and peripheral arterial embolism. Therefore a possible concern for women with malignancies undergoing ovarian stimulation for fertility preservation is the increased risk of venous or arterial thrombosis. METHODS: In this article, we revised current available literature on the risk of thrombosis in patients with cancer and in women undergoing ovarian stimulation, with the ultimate aim of drawing some indications for preventive measures. RESULTS: Unfortunately, there are no specific data on the risk of thrombosis in women with cancer undergoing ovarian stimulation for fertility preservation. However, the literature suggests that the cancer type and stage, surgery, and chemotherapy all influence the risk of venous and, possibly, arterial thrombosis. Reports of cases of ovarian stimulation in women without malignancies have shown that venous thrombosis rarely occurs unless a pregnancy is achieved, while arterial thrombosis can occur in the absence of pregnancy but is usually only associated with ovarian hyperstimulation syndrome (OHSS). OHSS increases the risk of thrombotic events, but only the early form of the syndrome is relevant for women undergoing fertility preservation. CONCLUSIONS: The available evidence on the risks of thrombosis for women undergoing ovarian stimulation for fertility preservation due to a malignancy is reassuring. However the avoidance of the early form of OHSS in women preserving oocytes/embryos due to malignancy is crucial. For these cycles, we advocate the use of a regimen of ovarian stimulation with gonadotrophin releasing hormone (GnRH) antagonists using GnRH agonists to trigger ovulation, an approach that has been shown to markedly reduce the risk of OHSS. Antithrombotic prophylaxis should be administered only to selected subgroups of women such as those with other risk factors or those who do develop early OHSS. PMID- 25013218 TI - Impact of ovarian stimulation with gonadotrophins on embryo aneuploidy. PMID- 25013220 TI - Should we screen heterosexuals for extra-genital chlamydial and gonococcal infections? AB - Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) are two of the most prevalent bacterial sexually transmitted infections in the UK. Although the high burden of extra-genital infections with GC and CT in men who have sex with men has been well established, a significant number of extra-genital site infections with CT and GC could similarly be present in heterosexual women. For this reason we started to routinely offer extra-genital site testing for GC and CT in all patients attending our sexual health clinic who reported having had receptive anal sex and/or giving oral sex. This followed a review of current evidence by the clinical team and a change in local testing policy. This study not only confirmed a large reservoir of extra-genital infection amongst men who have sex with men, but also demonstrates that a comparable reservoir of extra-genital infection is present amongst heterosexual women. Our study adds to the mounting evidence that extra-genital site testing in heterosexual women should occur when oral or anal sexual activity is reported. PMID- 25013221 TI - Lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome. AB - Human immunodeficiency virus-infected patients are at increased risk of drug reactions because of immune dysregulation and multiple drug intake. Lichenoid drug reactions to isoniazid have been reported previously in the literature. However, for lichenoid drug reaction to isoniazid to be so extensive to present as exfoliative dermatitis is rare. We report here a rare case of lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome. PMID- 25013222 TI - Endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymphadenopathy: effect of the learning curve. AB - This study aimed to evaluate the learning curve and efficacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the examination of mediastinal or hilar lymph nodes suspected of having cancer or of benign disease such as sarcoidosis. A success-adjusted cumulative sum model was used to evaluate the learning curve for diagnostic rates and operation time. A total of 99 patients (77 men and 22 women) who underwent EBUS-TBNA from April 2011 to March 2012 in a single centre were analysed retrospectively. The quantity of lymph node sampling was deemed to be appropriate for histopathological examination in 97 of 99 patients (97%). Twenty-three cases (23%) were clearly diagnosed with neoplastic disease, 60 (60%) with reactive hyperplasia, 11 (11%) with granulomatosis and 3 (3%) histopathologically suspicious for lymph node metastasis. The sensitivity, specificity, and positive and negative predictive values and diagnostic accuracy for EBUS-TBNA were 80, 100, 100, 87.1 and 91.5%, respectively. According to the learning curve analysis, the ability to perform EBUS required performing approximately 37 procedures for the trials. In conclusion, more successful results are obtained after a certain learning curve, as is the case for every other invasive procedure. PMID- 25013223 TI - alpha1 Antitrypsin deficiency: current best practice in testing and augmentation therapy. AB - alpha1 Antitrypsin deficiency (AATD) increases the risk of chronic obstructive pulmonary disease (COPD), liver disease and other conditions. Although it is not a rare disease, it is a condition rarely diagnosed because of unawareness by most healthcare providers who manage subjects at risk. Testing recommendations have been published and strongly suggest testing all subjects with confirmed COPD, cryptogenic liver cirrhosis, subjects with incompletely reversible airflow obstruction and siblings of affected individuals. Testing strategies usually imply a combination of measures of alpha1 antitrypsin (AAT) levels, phenotyping and genotyping, techniques that have been facilitated for in-office use by development of testing kits using dried blood spots. Early detection of subjects is crucial to apply effective preventive measures and early institution of therapy. The only specific Food and Drug Administration - approved therapy for this condition is lifelong weekly intravenous AAT replacement (augmentation therapy). Observational studies strongly suggest a beneficial effect of augmentation therapy in slowing lung function decline and randomized trials suggest a beneficial effect in slowing the progression of emphysema over time as measured by computed tomography. In addition, augmentation therapy has been shown to modulate systemic inflammatory responses and affect markers of elastin degradation. As new markers of disease progression are discovered, new doses of AAT replacement are tested and sub-phenotypes of disease are described, treatment recommendations are likely to change towards a more individualized therapeutic approach. PMID- 25013224 TI - Flavobacterium arsenatis sp. nov., a novel arsenic-resistant bacterium from high arsenic sediment. AB - A novel bacterial strain Z(T) was isolated from the high-arsenic sediment in Jianghan Plain, China. The strain was Gram-staining-negative, rod-shaped and formed yellow colonies. This bacterium is capable of tolerating arsenate and arsenite, with MICs of 40 mM and 20 mM, respectively. The strain also possesses catalase and does not produce oxidase. The nucleotide sequence of the 16S rRNA gene of the isolate showed the highest similarity (96.9%) to that of the type strain of Flavobacterium soli. On the basis of the 16S rRNA gene sequence analysis and the phenotypic properties of strain Z(T), it was assigned to the genus Flavobacterium. The major respiratory menaquinone was MK-6 and the predominant fatty acids were iso-C15:0, summed feature 3 (containing C16:1omega6c and/or C16:1omega7c) and iso-C15:1G. The major polar lipids were phosphatidylethanolamine, three uncharacterized aminophospholipids and four unidentified phospholipids. The DNA G+C content was 32.1 mol%. Based on the phenotypic and genotypic data presented in this article, it can be concluded that this isolate represents a novel species of the genus Flavobacterium, for which the name Flavobacterium arsenatis sp. nov. is proposed. The type strain is Z(T) ( = CCTCC AB 2013048(T) = KCTC 32397(T)). PMID- 25013225 TI - Description of Symbiobacterium ostreiconchae sp. nov., Symbiobacterium turbinis sp. nov. and Symbiobacterium terraclitae sp. nov., isolated from shellfish, emended description of the genus Symbiobacterium and proposal of Symbiobacteriaceae fam. nov. AB - Three novel moderately anaerobic, thermophilic, rod-shaped bacterial strains, KY38(T), KY46(T) and KA13(T), were isolated from shellfish collected on the Pacific coastline of Enoshima, Japan. Phylogenetic analysis of the 16S rRNA gene sequences indicated that these bacteria belong to the genus Symbiobacterium, sharing sequence similarities of 97.8% (KY38(T)), 96.4% (KY46(T)) and 93.3% (KA13(T)) with the type strain of Symbiobacterium thermophilum, the only species of the genus with a validly published name. These isolates reduced nitrate and grew optimally at 55-60 degrees C. Strains KY38(T) and KA13(T) formed endospore like structures in the terminal or subterminal part of their cells at low frequencies. Genomic DNA G+C contents were 68.8 (KY38(T)), 67.2 (KY46(T)) and 67.1 (KA13(T)) mol%. The isolates all presented the predominant menaquinone MK-6, major fatty acids iso-C15:0, C16:0 and iso-C17:0 and the major polar lipids phosphatidylglycerol, phosphatidylethanolamine and unknown glycol-containing phospholipids. On the basis of their morphological, physiological and phylogenetic properties, strains KY38(T), KY46(T) and KA13(T) represent three novel species, for which the names Symbiobacterium ostreiconchae sp. nov. (type strain KY38(T) = DSM 27624(T) = KCTC 4567(T) = JCM 15048(T)), Symbiobacterium turbinis sp. nov. (type strain KY46(T) = DSM 27625(T) = KCTC 4568(T) = JCM 15996(T)) and Symbiobacterium terraclitae sp. nov. (type strain KA13(T) = DSM 27138(T) = KCTC 4569(T) = JCM 15997(T)) are proposed. An emended description of the genus Symbiobacterium is also presented. The phylogenetic distinctiveness of the genus Symbiobacterium indicates its affiliation with a novel family, for which the name Symbiobacteriaceae fam. nov. is proposed. PMID- 25013226 TI - Oligoflexus tunisiensis gen. nov., sp. nov., a Gram-negative, aerobic, filamentous bacterium of a novel proteobacterial lineage, and description of Oligoflexaceae fam. nov., Oligoflexales ord. nov. and Oligoflexia classis nov. AB - A phylogenetically novel proteobacterium, strain Shr3(T), was isolated from sand gravels collected from the eastern margin of the Sahara Desert. The isolation strategy targeted bacteria filterable through 0.2-um-pore-size filters. Strain Shr3(T) was determined to be a Gram-negative, aerobic, non-motile, filamentous bacterium. Oxidase and catalase reactions were positive. Strain Shr3(T) showed growth on R2A medium, but poor or no growth on nutrient agar, trypticase soy agar and standard method agar. The major isoprenoid quinone was menaquinone-7. The dominant cellular fatty acids detected were C16:1omega5c and C16:0, and the primary hydroxy acid present was C12:0 3-OH. The DNA G+C content was 54.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain Shr3(T) was affiliated with an uncultivated lineage of the phylum Proteobacteria; the nearest known type strain, with 83% sequence similarity, was Desulfomicrobium orale DSM 12838(T) in the class Deltaproteobacteria. The isolate and closely related environmental clones formed a novel class-level clade in the phylum Proteobacteria with high bootstrap support (96-99%). Based on these results, the novel class Oligoflexia classis nov. in the phylum Proteobacteria and the novel genus and species Oligoflexus tunisiensis gen. nov., sp. nov. are proposed for strain Shr3(T), the first cultivated representative of the Oligoflexia. The type strain of Oligoflexus tunisiensis is Shr3(T) ( = JCM 16864(T) = NCIMB 14846(T)). We also propose the subordinate taxa Oligoflexales ord. nov. and Oligoflexaceae fam. nov. in the class Oligoflexia. PMID- 25013227 TI - Prauserella coralliicola sp. nov., isolated from the coral Galaxea fascicularis. AB - A novel Gram-stain-positive actinobacterium, designated strain SCSIO 11529(T), was isolated from tissues of the stony coral Galaxea fascicularis, and characterized by using a polyphasic approach. The temperature range for growth was 22-50 degrees C (optimum 28-45 degrees C), the pH range for growth was 6.0 8.0 (optimum pH 7.0), and the NaCl concentration range for growth was 0-7% (w/v) NaCl. The polar lipid profile contained diphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine and an unknown polar lipid. The predominant menaquinone was MK-9(H4). The major fatty acids (>10%) were iso-C16:0, iso-C17:1omega6c, iso C16:1 H and C16:1omega7c/iso-C15:0 2-OH. The DNA G+C content of strain SCSIO 11529(T) was 70.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain SCSIO 11529(T) belongs to the genus Prauserella, with the closest neighbours being Prauserella marina MS498(T) (97.0% 16S rRNA gene sequence similarity), Prauserella rugosa DSM 43194(T) (96.4%) and Prauserella flava YIM 90630(T) (95.9%). Based on the evidence of the present study, strain SCSIO 11529(T) is considered to represent a novel species of the genus Prauserella, for which the name Prauserella coralliicola sp. nov. is proposed. The type strain is SCSIO 11529(T) ( = DSM 45821(T) = NBRC 109418(T)). PMID- 25013228 TI - Arthrobacter pityocampae sp. nov., isolated from Thaumetopoea pityocampa (Lep., Thaumetopoeidae). AB - A bacterium (strain Tp2(T)) was isolated from a caterpillar of the pine processionary moth, Thaumetopoea pityocampa (Den. & Schiff.) (Lepidoptera: Thaumetopoeidae), a destructive pine forest pest. The bacterium is a Gram-stain positive, red-pigmented coccus, oxidase-negative, nitrate-reducing, non-motile and non-spore-forming. Strain Tp2(T) was subjected to a taxonomic study using polyphasic approach that included morphological and biochemical characterizations, 16S rRNA gene sequence analysis, DNA-DNA hybridization, DNA G+C content analysis, comparative fatty acid profiles, and analyses of quinones and polar lipids. The 16S rRNA gene sequence of strain Tp2(T) revealed that Arthrobacter agilis DSM 20550(T) was the closest known strain (98% 16S rRNA gene sequence similarity). DNA-DNA hybridization of A. agilis DSM 20550(T) and strain Tp2(T) resulted in a DNA-DNA relatedness value of 11.9% (20.2% reciprocal). The DNA base composition of strain Tp2(T) was 69.5 mol%, which is consistent with the other recognized members of Actinobacteria that have a high G+C content in their genome. The polar lipid pattern of strain Tp2(T) consisted of diphosphatidylglycerol (major), phosphatidylglycerol and phosphatidylinositol and unknown glycolipids. The cellular fatty acids were anteiso C15:0 and anteiso C17:0 and the major menaquinone was MK-9(II-H2). The peptidoglycan type was A3alpha with an L-Lys-L-Thr-L-Ala3 interpeptide bridge. The above-mentioned characterization qualifies strain Tp2(T) as genotypically and phenotypically distinct from closely related species of the genus Arthrobacter with validly published names. Strain Tp2(T) is therefore proposed to represent a novel species of the genus Arthrobacter, described as Arthrobacter pityocampae sp. nov. The type strain is Tp2(T) ( = DSM 21719(T) = NCCB 100254(T)). PMID- 25013229 TI - Bacillus mesonae sp. nov., isolated from the root of Mesona chinensis. AB - A Gram-stain-positive, short rod-shaped and motile, mildly halotolerant, endospore-forming bacterium, FJAT-13985(T), was isolated from the internal tissues of Mesona chinensis root. Strain FJAT-13985(T) grew at 20-45 degrees C (optimum 30 degrees C) and pH 5.7-9.0 (optimum pH 7.0) and in the presence of 0 2% (w/v) NaCl [optimum 1% (w/v)]. The strain was catalase-positive and oxidase negative. The cell wall of strain FJAT-13985(T) contained meso-diaminopimelic acid and the predominant isoprenoid quinone was MK-7 (97.4%). The major fatty acids of the strain were anteiso-C15:0 (23.3%) and iso-C15:0 (40.8%). The DNA G+C content was 41.64 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain FJAT-13985(T) is a member of the genus Bacillus and is most closely related to Bacillus drentensis DSM 15600(T) (98.4%), Bacillus vireti DSM 15602(T) (98.2%) and Bacillus novalis DSM 15603(T) (98.3%). DNA-DNA hybridization indicated that relatedness between strain FJAT-13985(T) and its closest relative, B. drentensis DSM 15600(T), was 36.63%. The phenotypic, chemotaxonomic and genotypic properties clearly indicate that strain FJAT-13985(T) represents a novel species of the genus Bacillus, for which the name Bacillus mesonae sp. nov. is proposed. The type strain is FJAT-13985(T) ( = DSM 25968(T) = CGMCC1.12238(T)). PMID- 25013230 TI - Pseudoxanthobacter liyangensis sp. nov., isolated from dichlorodiphenyltrichloroethane-contaminated soil. AB - An aerobic, Gram-stain negative, pale, rod-shaped, nitrogen-fixing bacterial strain, DDT-3(T), was isolated from dichlorodiphenyltrichloroethane-contaminated soil in Liyang, PR China. Strain DDT-3(T) grew at temperatures ranging from 20 to 40 degrees C (optimum 30-37 degrees C) and a pH of between 5.0 and 10.0 (optimum pH 7.0-8.0). The G+C content of the total DNA was 70.1 mol%. The 16S rRNA gene sequence of strain DDT-3(T) showed the highest similarity to that of Pseudoxanthobacter soli CC4(T) (99.6%), followed by Kaistia dalseonensis B6-8(T) (93.3%), Kaistia soli 5YN9-8(T) (93.0%) and Amorphus orientalis YIM D10(T) (93.0%). Strain DDT-3(T) showed less than 92.6 % similarity with other species of the family Xanthobacteraceae. The major cellular fatty acids of strain DDT-3(T) were C19:0 cyclo omega8c (42.6%), C16:0 (33.2%) and C18:1omega7c (10.0%). The only respiratory quinone was ubiquinone Q-10. The characteristic diamino acid of the peptidoglycan was meso-diaminopimelic acid. The major polar lipids were glycolipid, lipid, phosphatidylcholine, aminolipid, phosphatidylmethylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The polyamine profile consisted of major amounts of putrescine (92.9%) and minor amounts of spermidine (5.0%) and spermine (2.1%). These chemotaxonomic data support the affiliation of strain DDT-3(T) with the genus Pseudoxanthobacter. The DNA-DNA hybridization value between strain DDT-3(T) and strain CC4(T) was 47.8% (reciprocal 44.3%). DNA-DNA hybridization data as well as the biochemical and physiological characteristics strongly supported the genotypic and phenotypic differentiation of strain DDT-3(T) and strain CC4(T). Strain DDT-3(T), therefore, represents a novel species of the genus Pseudoxanthobacter, for which the name Pseudoxanthobacter liyangensis sp. nov. is proposed. The type strain is DDT-3(T) ( = KACC 16601(T) = CCTCC AB 2013167(T)). PMID- 25013231 TI - Bradyrhizobium ingae sp. nov., isolated from effective nodules of Inga laurina grown in Cerrado soil. AB - Root-nodule bacteria were isolated from Inga laurina (Sw.) Willd. growing in the Cerrado Amazon region, State of Roraima, Brazil. The 16S rRNA gene sequences of six strains (BR 10250(T), BR 10248, BR 10249, BR 10251, BR 10252 and BR 10253) showed low similarities with currently described species of the genus Bradyrhizobium. Phylogenetic analyses of sequences of five housekeeping genes (dnaK, glnII, gyrB, recA and rpoB) revealed Bradyrhizobium iriomotense EK05(T) to be the closest type strain (97.4% sequence similarity or less). Chemotaxonomic data, including fatty acid profiles [with the major components C16:0 and summed feature 8 (C18:1omega6c/C18:1omega7c)], the slow growth rate and carbon compound utilization patterns supported the assignment of our strains to the genus Bradyrhizobium. Results from DNA-DNA hybridizations and physiological traits differentiated our strains from the closest related species of the genus Bradyrhizobium with validly published names. Sequences of symbiosis-related genes for nodulation (nodC) and nitrogen fixation (nifH) grouped together with those of B. iriomotense EK05(T) and Bradyrhizobium sp. strains BR 6610 (used as a commercial inoculant for Inga marginata in Brazil) and TUXTLAS-10 (previously observed in Central America). Based on these data, the six strains represent a novel species, for which the name Bradyrhizobium ingae sp. nov. is proposed. The type strain is BR 10250(T) ( = HAMBI 3600(T)). PMID- 25013232 TI - omega-Azido fatty acids as probes to detect fatty acid biosynthesis, degradation, and modification. AB - FAs play a central role in the metabolism of almost all known cellular life forms. Although GC-MS is regarded as a standard method for FA analysis, other methods, such as HPLC/MS, are nowadays widespread but are rarely applied to FA analysis. Here we present azido-FAs as probes that can be used to study FA biosynthesis (elongation, desaturation) or degradation (beta-oxidation) upon their uptake, activation, and metabolic conversion. These azido-FAs are readily accessible by chemical synthesis and their metabolic products can be easily detected after click-chemistry based derivatization with high sensitivity by HPLC/MS, contributing a powerful tool to FA analysis, and hence, lipid analysis in general. PMID- 25013233 TI - Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor. AB - The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT(1) receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT(1) receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT(1) receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT(1) receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G protein independently through beta-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT(1) receptor. PMID- 25013234 TI - Graph Estimation with Joint Additive Models. AB - In recent years, there has been considerable interest in estimating conditional independence graphs in high dimensions. Most previous work has assumed that the variables are multivariate Gaussian, or that the conditional means of the variables are linear; in fact, these two assumptions are nearly equivalent. Unfortunately, if these assumptions are violated, the resulting conditional independence estimates can be inaccurate. We propose a semi-parametric method, graph estimation with joint additive models, which allows the conditional means of the features to take on an arbitrary additive form. We present an efficient algorithm for our estimator's computation, and prove that it is consistent. We extend our method to estimation of directed graphs with known causal ordering. Using simulated data, we show that our method performs better than existing methods when there are non-linear relationships among the features, and is comparable to methods that assume multivariate normality when the conditional means are linear. We illustrate our method on a cell-signaling data set. PMID- 25013235 TI - An Immersed Boundary Method for Two-fluid Mixtures. AB - We present an Immersed Boundary method for interactions between elastic boundaries and mixtures of two fluids. Each fluid has its own velocity field and volume-fraction. A penalty method is used to enforce the condition that both fluids' velocities agree with that of the elastic boundaries. The method is applied to several problems: Taylor's swimming sheet problem for a mixture of two viscous fluids, peristaltic pumping of a mixture of two viscous fluids, with and without immersed particles, and peristaltic pumping of a mixture of a viscous fluid and a viscoelastic fluid. The swimming sheet and peristalsis problems have received much attention recently in the context of a single viscoelastic fluid. Numerical results demonstrate that the method converges and show its capability to handle a number of flow problems of substantial current interest. They illustrate that for each of these problems, the relative motion between the two fluids changes the observed behaviors profoundly compared to the single fluid case. PMID- 25013236 TI - Cautious to a Fault: Self-Protection and the Trajectory of Marital Satisfaction. AB - A contextual model of self-protection is proposed to explain when adhering to cautious "if-then" rules in daily interaction erodes marital satisfaction. People can self-protect against partner non-responsiveness by distancing when a partner seems rejecting, promoting a partner's dependence when feeling unworthy, or by devaluing a partner in the face of costs. The model implies that being less trusting elicits self-protection, and that mismatches between self-protective practices and encountered risk accelerate declines in satisfaction. A longitudinal study of newlyweds revealed that the fit between self-protection practices and risk predicted declines in satisfaction over three years. When people self-protected more initially, satisfaction declined more in low-risk (i.e., low conflict, resilient partner) than high-risk relationships (i.e., high conflict, vulnerable partner). However, when people self-protected less initially, satisfaction declined more in high-risk than low-risk relationships. Process evidence was consistent with moderated mediation: In low-risk relationships only, being less trusting predicted higher levels of self protective caution that forecast later declines in satisfaction. PMID- 25013237 TI - Ego depletion decreases trust in economic decision making. AB - Three experiments tested the effects of ego depletion on economic decision making. Participants completed a task either requiring self-control or not. Then participants learned about the trust game, in which senders are given an initial allocation of $10 to split between themselves and another person, the receiver. The receiver receives triple the amount given and can send any, all, or none of the tripled money back to the sender. Participants were assigned the role of the sender and decided how to split the initial allocation. Giving less money, and therefore not trusting the receiver, is the safe, less risky response. Participants who had exerted self-control and were depleted gave the receiver less money than those in the non-depletion condition (Experiment 1). This effect was replicated and moderated in two additional experiments. Depletion again led to lower amounts given (less trust), but primarily among participants who were told they would never meet the receiver (Experiment 2) or who were given no information about how similar they were to the receiver (Experiment 3). Amounts given did not differ for depleted and non-depleted participants who either expected to meet the receiver (Experiment 2) or were led to believe that they were very similar to the receiver (Experiment 3). Decreased trust among depleted participants was strongest among neurotics. These results imply that self-control facilitates behavioral trust, especially when no other cues signal decreased social risk in trusting, such as if an actual or possible relationship with the receiver were suggested. PMID- 25013238 TI - Ambivalence Toward Adult Children: Differences Between Mothers and Fathers. AB - The authors examined how ambivalence toward adult children within the same family differs between mothers and fathers and whether patterns of maternal and paternal ambivalence can be explained by the same set of predictors. Using data collected in the Within-Family Differences Study, they compared older married mothers' and fathers' (N = 129) assessments of ambivalence toward each of their adult children (N = 444). Fathers reported higher levels of ambivalence overall. Both mothers and fathers reported lower ambivalence toward children who were married, better educated, and who they perceived to hold similar values; however, the effects of marital status and education were more pronounced for fathers, whereas the effect of children's value congruence was more pronounced for mothers. Fathers reported lower ambivalence toward daughters than sons, whereas mothers reported less ambivalence toward sons than daughters. PMID- 25013239 TI - A C-H oxidation approach for streamlining synthesis of chiral polyoxygenated motifs. AB - Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation state manipulations. Herein a strategy for synthesizing a readily diversifiable class of chiral building blocks, allylic alcohols, through sequential asymmetric C-H activation/resolution is evaluated against the state-of-the-art. The C-H oxidation routes' capacity to strategically introduce oxygen into a sequence and thereby minimize non productive manipulations is demonstrated to effect significant decreases in overall step-count and increases in yield and synthetic flexibility. PMID- 25013240 TI - A patterned microtexture to reduce friction and increase longevity of prosthetic hip joints. AB - More than 285,000 total hip replacement surgeries are performed in the US each year. Most prosthetic hip joints consist of a cobalt-chromium (CoCr) femoral head that articulates with a polyethylene acetabular component, lubricated with synovial fluid. The statistical survivorship of these metal-on-polyethylene prosthetic hip joints declines significantly after 10 to 15 years of use, primarily as a result of polyethylene wear and wear debris incited disease. The current engineering paradigm to increase the longevity of prosthetic hip joints is to improve the mechanical properties of the polyethylene component, and to manufacture ultra-smooth articulating surfaces. In contrast, we show that adding a patterned microtexture to the ultra-smooth CoCr femoral head reduces friction when articulating with the polyethylene acetabular liner. The microtexture increases the load-carrying capacity and the thickness of the joint lubricant film, which reduces contact between the articulating surfaces. As a result, friction and wear is reduced. We have used a lubrication model to design the geometry of the patterned microtexture, and experimentally demonstrate reduced friction for the microtextured compared to conventional smooth surrogate prosthetic hip joints. PMID- 25013241 TI - Course and Severity of Maternal Depression: Associations with Family Functioning and Child Adjustment. AB - Number of lifetime episodes, duration of current episode, and severity of maternal depression were investigated in relation to family functioning and child adjustment. Participants were the 151 mother-child pairs in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) child multi-site study. Mothers were diagnosed with Major Depressive Disorder; children (80 males and 71 females) ranged in age from 7 to 17 years. Measures of child adjustment included psychiatric diagnoses, internalizing and externalizing symptoms, and functional impairment. Measures of family functioning included family cohesion, expressiveness, conflict, organization, and household control; parenting measures assessed maternal acceptance and psychological control. Children of mothers with longer current depressive episodes were more likely to have internalizing and externalizing symptoms, with this association being moderated by child gender. Mothers with more lifetime depressive episodes were less likely to use appropriate control in their homes. PMID- 25013242 TI - Virus infection of Haptolina ericina and Phaeocystis pouchetii implicates evolutionary conservation of programmed cell death induction in marine haptophyte virus interactions. AB - The mechanisms by which phytoplankton cope with stressors in the marine environment are neither fully characterized nor understood. As viruses are the most abundant entities in the global ocean and represent a strong top-down regulator of phytoplankton abundance and diversity, we sought to characterize the cellular response of two marine haptophytes to virus infection in order to gain more knowledge about the nature and diversity of microalgal responses to this chronic biotic stressor. We infected laboratory cultures of the haptophytes Haptolina ericina and Phaeocystis pouchetii with CeV-01B or PpV-01B dsDNA viruses, respectively, and assessed the extent to which host cellular responses resemble programmed cell death (PCD) through the activation of diagnostic molecular and biochemical markers. Pronounced DNA fragmentation and activation of cysteine aspartate-specific proteases (caspases) were only detected in virus infected cultures of these phytoplankton. Inhibition of host caspase activity by addition of the pan-caspase inhibitor z-VAD-fmk did not impair virus production in either host-virus system, differentiating it from the Emiliania huxleyi Coccolithovirus model of haptophyte-virus interactions. Nonetheless, our findings point to a general conservation of PCD-like activation during virus infection in ecologically diverse haptophytes, with the subtle heterogeneity of cell death biochemical responses possibly exerting differential regulation on phytoplankton abundance and diversity. PMID- 25013243 TI - The Genetic Basis of Primate Behavior: Genetics and Genomics in Field-Based Primatology. PMID- 25013245 TI - Platinum-Catalyzed Reduction of DMF by 1,1,3,3-Tetramethyldisiloxane, HMeSi2OSiMe2H: New Intermediates HSiMe2OSiMe2OCH2NMe2 and HSiMe2(OSiMe2)3OCH2NMe2 and Their Further Chemical Reactivity. AB - The use of Karstedt's catalyst to study the reduction of Me2NCHO (DMF) by the popular "dual SiH"-containing tetramethyldisiloxane, HMe2SiOSiMe2H (1), has revealed that the first step in the process involves an initial single hydrosilylation to form HSiMe2OSiMe2OCH2NMe2 (3). This intermediate is readily isolated and purified via distillation. In the continued presence of the catalyst, 3 transforms to the transient tetrasiloxane HMe2SiOSiMe2OSiMe2OSiMe2OCH2NMe2 (4), along with the formation of Me3N. The tetrasiloxane 4 itself transforms to Me3N and (Me2SiO) n (n = 4-6). Despite the demonstrated reactivity of 3, it can also be used to perform the expected metal catalyzed hydrosilylation chemistry of the SiH group as well as reactions of the SiOCH2NMe2 functionality involving siloxane chain extension and is thus an important new reagent for siloxane chemistry. PMID- 25013244 TI - Factors associated with recruitment and retention of diverse children with asthma. AB - This study examines factors associated with recruitment and retention of Latino, Dominican (DR) and mainland Puerto Rican (PR), and non-Latino white (NLW) families into a pediatric asthma study. Over eleven hundred (n=1185) families were screened, and 489 (n= 174 NLW, n= 160 DR, n= 155 PR) were enrolled. Rates of recruitment by source of recruitment and rates of retention differed by ethnic group. Families whose caregiver had never married had lower odds of completing the study. The findings highlight the need for further study to examine the effectiveness of specific recruitment and retention strategies with Latino and non-Latino white families. PMID- 25013246 TI - Neonatal analgesia: A neglected issue in the tropics. AB - Pain control in newborns is poorly understood and often neglected in neonatal practice in many settings in our environment. Managing pain among newborns can be quite challenging and the effectiveness of various interventions used to ameliorate pain in this category of patients are either unknown or poorly understood by many a people engaged in the care of newborns in one way or the other. A search for published works on neonatal analgesia was performed using Google and PubMed. The Cochrane Database of Systematic Reviews was also searched. The areas of focus were definition, pathophysiology and management of pain in neonates. Relevant information was extracted and processed. Contrary to what is widely believed in many quarters, howbeit erroneously, there is compelling evidence that newborns do indeed feel pain. Supportive care, comprising of use of sucrose, glucose, breastfeeding, kangaroo mother care are worthwhile measures in ameliorating pain in the newborn. Novel therapies (such as sensorial saturation and swaddling) have been evaluated and proven useful. The use of sedation did not show any beneficial results. PMID- 25013247 TI - Ethics of clinical trials in Nigeria. AB - The conduct of clinical trials for the development and licensing of drugs is a very important aspect of healthcare. Drug research, development and promotion have grown to a multi-billion dollar global business. Like all areas of human endeavour involving generation and control of huge financial resources, it could be subject to deviant behaviour, sharp business practices and unethical practices. The main objective of this review is to highlight potential ethical challenges in the conduct of clinical trials in Nigeria and outline ways in which these can be avoided. Current international and national regulatory and ethical guidelines are reviewed to illustrate the requirements for ethical conduct of clinical trials. Past experiences of unethical conduct of clinical trials especially in developing countries along with the increasing globalisation of research makes it imperative that all players should be aware of the ethical challenges in clinical trials and the benchmarks for ethical conduct of clinical research in Nigeria. PMID- 25013248 TI - Acute abdominal pain in patients with lassa fever: Radiological assessment and diagnostic challenges. AB - BACKGROUND: To highlight the problems of diagnosis and management of acute abdomen in patients with lassa fever. And to also highlight the need for high index of suspicion of lassa fever in patients presenting with acute abdominal pain in order to avoid surgical intervention with unfavourable prognosis and nosocomial transmission of infections, especially in Lassa fever-endemic regions. MATERIALS AND METHODS: A review of experiences of the authors in the management of lassa fever over a 4-year period (2004-2008). Literature on lassa fever, available in the internet and other local sources, was studied in November 2010 and reviewed. RESULTS: Normal plain chest radiographic picture can change rapidly due to pulmonary oedema, pulmonary haemorrhage and acute respiratory distress syndrome. Plain abdominal radiograph may show dilated bowels with signs of paralytic ileus or dynamic intestinal obstruction due to bowel wall haemorrhage or inflamed and enlarged Peyer's patches. Ultrasound may show free intra peritoneal fluid due to peritonitis and intra-peritoneal haemorrhage. Bleeding into the gall bladder wall may erroneously suggest infective cholecystitis. Pericardial effusion with or without pericarditis causing abdominal pain may be seen using echocardiography. High index of suspicion, antibody testing for lassa fever and viral isolation in a reference laboratory are critical for accurate diagnosis. CONCLUSION: Patients from lassa fever-endemic regions may present with features that suggest acute abdomen. Radiological studies may show findings that suggest acute abdomen but these should be interpreted in the light of the general clinical condition of the patient. It is necessary to know that acute abdominal pain and vomiting in lassa fever-endemic areas could be caused by lassa fever, which is a medical condition. Surgical option should be undertaken with restraint as it increases the morbidity, may worsen the prognosis and increase the risk of nosocomial transmission. PMID- 25013249 TI - Quality assurance in blood culture: A retrospective study of blood culture contamination rate in a tertiary hospital in Nigeria. AB - BACKGROUND: Blood culture is a critical tool for diagnosing septicaemia. Quite frequently, contamination of blood sample poses a great challenge to accurate diagnosis. This study evaluated the rate of blood culture contamination in our hospital over a one-year period. MATERIALS AND METHODS: It was a retrospective study of 1032 blood cultures carried out in a clinical laboratory of a tertiary hospital in North Central part of Nigeria between 2010 and 2011. RESULTS: There were 730 blood cultures from paediatric and 302 adult patients. The overall yield was 22%; 107 out of the 730 were contaminated giving a contamination rate of 10.4%. Contamination rate was higher in children than in adult (11% vs 8%) specimen. These rates were much higher than the acceptable benchmark of 2-3%. The main contaminants were coagulase negative Staphylococcus, Bacillus species, Diphtheroids and Enterococcus species. CONCLUSION: Contamination rate is high, and mainly due to normal skin flora, suggesting aseptic collection challenges as the main cause. We recommend a review of the entire process of blood collection for culture and analysis with a view to instituting appropriate quality assurance measures to reduce the contamination rate. PMID- 25013250 TI - The impact of a HIV prevention of mother to child transmission program in a nigerian early infant diagnosis centre. AB - BACKGROUND: Mothers infected with human immunodeficiency virus (HIV) can transmit the virus to their babies in utero, intrapartum or postpartum through breastfeeding. Maternal to child transmission can be prevented through administration of antiretroviral drugs to mother and child, and through restriction of breastfeeding. This study evaluated the effectiveness of prevention of mother-to-child transmission (PMTCT) activities in reducing the incidence of HIV infection among exposed babies at the National Hospital Abuja, Nigeria. MATERIALS AND METHODS: Early infant diagnosis laboratory records of 515 exposed babies aged below 18 months who had polymerase chain reaction (PCR) test between January 1(st) 2011 and December 31(st) 2012 were reviewed. The details of antiretroviral (ARV) therapy commencement for mother and baby, infant feeding choices, mode of delivery and HIV test results were analysed. RESULTS: Of the 515 samples tested, 36 (7.0%) were found to be positive. The mean age of exposed children tested was 4 months. Highest prevalence was among children in the age group 6-18 months (16.1%). There was statistically significant association between HIV positive results and age. (P = 0.0000). If the mother and child pairs received ARVs, the prevalence was 1.3%, whereas if the mother only received ARV, then the prevalence was 4.6%, and when only the child received ARV the prevalence was 20.0%. When neither the mother nor the child received ARVs, the prevalence was 66.7%. CONCLUSION: There was a high prevalence of HIV among exposed children in our setting, especially if the mother and child pairs did not receive any form of antiretroviral prophylaxis. This further emphasises the usefulness of ARVs as the single most important intervention in PMTCT. Therefore, there is need to expand antiretroviral coverage, ensure access of the PMTCT program, and provide effective services to support infected children. PMID- 25013251 TI - Risk factors and 30-day case fatality of first-ever stroke in Basrah, Iraq. AB - BACKGROUND: The aim of this hospital-based study is to determine the types, the frequency of risk factors and the 30-day case fatality of first-ever stroke in Basrah, Iraq. MATERIALS AND METHODS: This was a hospital-based prospective study between January 2008 and July 2008 in Basrah, Iraq. Two hundred twenty-five (225) patients, who were admitted for first-ever stroke to the four major hospitals in Basrah, were interviewed and followed up for 30 days. Risk factors studied were smoking, history of diabetes mellitus, hypertension, atrial fibrillation, ischaemic heart diseases and transient ischaemic attack. RESULTS: The mean age of the studied subjects was 63.8 +/- 12.3 years. Males constituted 56% of cases. Clinical types of stroke were ischaemic stroke (83.6%), intracerebral haemorrhage (16%) and subarachnoid haemorrhage (0.4%). The prevalence of risk factors was; hypertension (66.2%), family history of stroke (31.6%), ischaemic heart diseases (28.9%), smoking (28.4%), diabetes mellitus (28%), transient ischaemic attack (10.2%), atrial fibrillation (9.8%) and heart failure (5.8%). The 30-day case fatality rate was 22.7%. CONCLUSIONS: Ischaemic stroke was the highly prevalent type. Hypertension, family history of stroke, ischaemic heart diseases, smoking and diabetes mellitus were the major risk factors of first ever stroke in Basrah. The 30-day case fatality rate of stroke in Basrah was nearly similar to that in western countries, but higher than that reported in the neighbouring Arab countries. Early detection of modifiable risk factors that can prevent stroke or at least minimise its complications is highly recommended. PMID- 25013252 TI - Assessment of dyslipidemia in pre-dialysis patients in south-west Nigeria. AB - BACKGROUND: Majority of chronic kidney disease (CKD) patients are more likely to die of cardiovascular complications before reaching end stage renal disease. The Kidney Disease Outcomes Quality Initiative (K/DOQI) recommends that all CKD patients should be evaluated for dyslipidemia and for treatment to reduce the risk of cardiovascular events. PATIENTS AND METHODS: A cross-sectional case control study to determine the frequency of occurrence of lipid abnormalities in patients with CKD and compare these abnormalities with that of normal controls. A total of 100 patients and 100 controls were recruited for the study. Demographic and clinical data were obtained using structured questionnaire. Weight, height and waist circumference, body mass index (BMI) and blood pressure were also obtained. Subjects had their fasting lipid profile and fasting plasma glucose assayed after overnight fast of 8-14 hours. Low-density lipoprotein (LDL) was obtained using Friedwald formula. RESULT: The study revealed that total cholesterol (TC) was elevated above normal levels in 44% of cases compared with 6% in controls (P < 0.001), with the mean (SD) value of 5.82 +/- 3.28 mmol/l for cases compared with 3.9 +/- 1.0 mmol/l (P < 0.001) in controls. Low density lipoprotein was elevated in 48% of cases compared with 14% in controls (P < 0.001), with the mean (SD) values of 4.15 +/- 2.74 mmol/l and 2.57 +/- 0.95 mmol/l for cases and controls, respectively, (P < 0.001). Triglyceride (TG) was elevated above normal level in 26% of cases compared with none in the controls (P < 0.001), with the mean (SD) values of 1.41 +/- 1.10 mmol/l and 0.64 +/- 0.24 mmol/l for cases and controls, respectively (P < 0.001). All Lipid fractions except HDL also correlated significantly with levels of proteinuria TC (r = 0.345, P = 0.001), TG (r = 0.268, P = 0.011) LDL (r = 0.366, P = 0.001). CONCLUSION: Dyslipidemia is common among patients with CKD. Regular evaluation of all CKD patients for dyslipidemia and treatment need be instituted. PMID- 25013253 TI - Surgeon's satisfaction on the use of invented needle magnet in reducing the risk of sharp injuries in the operating room. AB - BACKGROUND: Healthcare workers, especially operating room personnel, are at increased risk for sharps injury and transmission of blood-borne pathogens as a result of their occupation. Infection with these pathogens occurs mainly by percutaneous or mucocutaneous exposure to blood-borne pathogens. This study evaluated the effectiveness of using invented needle magnet in reducing the risk of sharp injuries in the operating room. MATERIALS AND METHODS: THE NEEDLE MAGNET DEVICE IS CONSISTED OF THREE PARTS: a cap, a magnet and a metal container. It was invented by the authors for the first time in Iran. The average weight of this device is 200 g and it can be easily placed near the surgery field or on the myostand. It has magnetic properties that attracts the sharp pointed particles during surgery and preserve them in a protected space. The device was used in surgical field by 33 surgeons during 90 surgical operations. Then, the satisfaction of participants and effectiveness of the device in protection against sharps injury was evaluated by a questionnaire. RESULTS: Thirty-one surgeons (94%) believed that needle magnet reduces dispersion of sharp instruments; 79% of the participants suggested that our device reduces sharps injury during operation; 29 surgeons (88%) intended to use this device during operation. Thus, the use of needle magnet within surgical field may reduce the chances of sharps injury during surgery. CONCLUSION: The use of needle magnet within surgical field reduces the chance of sharp injury during surgery and the surgeons were satisfied with its use. PMID- 25013254 TI - Perioperative findings and complications of non-vascularised iliac crest graft harvest: The experience of a Nigerian tertiary hospital. AB - BACKGROUND: The reconstruction of a mandibular defect remains a significant challenge to the reconstructive surgeon. In developing countries like Nigeria, the required facilities and expertise for vascularised graft surgery are not readily available, thus mandibular defects are commonly reconstructed with non vascularised bone grafts. The aim of this study is to describe the experience with the reconstruction of mandibular defects using non-vascularised iliac crest bone grafts (NVICBG) at a Nigerian tertiary hospital. PATIENTS AND METHODS: This was a descriptive longitudinal study in which data was prospectively collected from patients who had mandibular reconstruction secondary to benign lesions using NVICBG at the University College Hospital, Ibadan, over a 24-month period. Information recorded included demography, cause of mandibular defect, type of mandibular resection, span of defect, peri-operative data, recipient site complications and donor site complications. Patient satisfaction with facial aesthetic outcome was assessed with the use of visual analogue scale score. RESULTS: Twenty patients had mandibular resection and immediate reconstruction with NVICBG. The mean age was 31.61 (+/-11.05) years. Mean span of the defects was 10.65 (+/-2.88) cm. At the recipient site, two patients had extra-oral wound dehiscence and two patients had intra-oral wound dehiscence of which one patient had loss of the graft. Donor site complications noted were seromas and wound dehiscence. Eighteen patients had paraesthesia of the lateral femoral cutaneous nerve. All patients had temporary abnormal gait. The mean duration of abnormal gait was 2.11 weeks (SD +/-0.74). Majority of the patients were satisfied with the aesthetic outcome. CONCLUSION: NVICBG, though limited in its versatility has satisfactory aesthetic outcome with relatively few complications. It appears that this method of reconstruction can be used even for large mandibular defects contrary to perceptions of many reconstructive surgeons. PMID- 25013255 TI - Comparative effect of Citrus sinensis and carbimazole on serum T4, T3 and TSH levels. AB - BACKGROUND: There are previous independent reports on the anti-thyroid property of Citrus sinensis. This isoflavones and phenolic acid-rich natural agent is widely consumed as dietary supplement, thus the need to investigate its comparative effect with a standard anti-thyroid drug on T4, T3 and thyroid stimulating hormone (TSH) levels. OBJECTIVE: To compare the effect of Citrus sinensis and carbimazole (CARB) on blood levels of thyroid hormones (T4 and T3) and TSH. MATERIALS AND METHODS: Male wistar albino rats weighing 100-150 g were employed in this research. The rats were randomly assigned to four groups of seven rats per group. Group I served as control and were administered distilled water while groups II-IV were administered with 1500 mg/kg of Citrus sinensis (fresh orange juice; FOJ), 0.1 MUg/g of levothyroxine (LVT) and 0.01 mg/g of CARB, respectively, per oral once daily for 28 days. The animals were sacrificed under chloroform anaesthesia and blood sample collected by cardiac puncture and processed by standard method to obtain serum. TSH, T4 and T3 were assayed with the serum using ARIA II automated radioimmunoassay instrument. RESULTS: The results showed that TSH level was significantly (P < 0.05) decreased in LVT treated group compared with the FOJ group. T4 was significantly (P < 0.05) decreased in the FOJ and CARB groups compared with the control and LVT groups. LVT significantly increased T4 when compared with FOJ group. T3 was significantly (P < 0.05) decreased in the CARB group compared with the control. CONCLUSION: These findings suggest that FOJ alters thyroid hormones metabolism to reduce their serum levels with a compensatory elevations of TSH level in a direction similar to CARB. PMID- 25013256 TI - Adequacy of resources for provision of maternal health services at the primary health care level in Nnewi, Nigeria. AB - BACKGROUND: To determine the adequacy of resources (human and material) for provision of maternal health services at the primary health care (PHC) level in Nnewi, Nigeria. MATERIALS AND METHODS: A cross-sectional study of women utilising maternal health services in four public PHC facilities in Nnewi selected using multistage sampling technique was done. Data was collected using a mix of quantitative and qualitative methods. Quantitative data was analysed using statistical package for social sciences (SPSS) version 16, while qualitative data was reported verbatim, analysed thematically and necessary quotes presented. RESULTS: Two hundred and eighty women were studied. The mean age of respondents was 29.2 +/- 5.9 years, while 231 (82.5%) were married. Most of them (82.5%) and 184 (66.1%), had their blood pressure and body weight respectively measured, while 196 (70.0%) had tetanus toxoid vaccination. Less than half of the respondents (41.4%) had urine test for sugar, and protein, while 94 (33.8%) had blood test for anaemia. The four facilities studied had most of the equipment and drugs available but in insufficient quantities. In three out of the four facilities, the physical structures were mostly good. None of them is equipped to provide an essential obstetric care (EOC) services, while one medical doctor covered all the facilities studied. CONCLUSIONS: This study showed that none of the health facilities is equipped with the minimum equipment package, essential drugs nor staff complement required to enable them offer quality maternal health services. With advocacy, technical support and funding, strategies could be implemented to provide quality maternal health services. PMID- 25013257 TI - CD4+ T Lymphocytes count in sickle cell anaemia patients attending a tertiary hospital. AB - BACKGROUND: Sickle cell haemoglobin (HbS) is the commonest abnormal haemoglobin and it has a worldwide distribution. Reports have shown that patients with sickle cell anaemia (HbSS) have an increased susceptibility to infection leading to increased morbidity and mortality. Impaired leucocyte function and loss of both humoral and cell-mediated immunity are some of the mechanisms that have been reported to account for the immunocompromised state in patients with sickle cell disease. This study was carried out to determine the CD4+ T lymphocytes count in patients with sickle cell anaemia. MATERIALS AND METHODS: A comparative cross sectional study of 40 sickle cell anaemia patients in steady state (asymptomatic for at least 4 weeks) attending haematology clinic and 40 age and sex-matched healthy HbA control were recruited into the study. Both HbS patients and the controls were HIV negative. The blood samples obtained were analyzed for CD4+ T cell by Flow cytometry. RESULTS: The study found that there was no significant difference in the number of CD4+ T lymphocyte count between individuals with sickle cell anaemia and HbA (1016 +/- 513 cells/MUL vs 920 +/- 364cells/MUL). CONCLUSION: It is recommended that the functionality of CD4+ T lymphocyte should be considered rather than the number in further attempt to elucidate the cellular immune dysfunction in patients with sickle cell anaemia. PMID- 25013258 TI - Cyanide-induced hyperthyroidism in male Wistar rats. AB - BACKGROUND: Cyanide is one of the major environmental pollutants termed thyroid disruptor. Regardless of its origin, it is a primary toxic agent. This study was designed to understand the impact of prolonged low dose cyanide exposure on the structure and function of the thyroid gland. MATERIALS AND METHODS: Twelve F1 male Wistar rats were used for this study. They were divided into two groups of six animals each. The first group served as the control group and received 0.25M sucrose while the second group being the treated group received 2 mg/kg body weight (BW) potassium hexacyanoferrate III solution. The treatment duration was 56 days following which the animals were sacrificed by cervical dislocation. Blood samples were drawn to determine serum FT3, FT4 and thyroid stimulating hormone (TSH) levels. The thyroid gland was also excised and processed for light microscopic studies. RESULT: An increase in serum FT3 and FT4 with decrease serum TSH was obtained in the treated group. Application of one-way analysis of variance (ANOVA) statistical analysis showed that there were highly significant differences (P < 0.05) in the activities of FT3, FT4 and TSH when compared with those of the control group. Light microscopic examination of thyroid gland from the treated group revealed marked epithelial hyperplasia with cellular degeneration and scanty cytoplasm while the control group revealed normal thyroid architecture. CONCLUSION: Results obtained revealed that hyperthyroidism was induced by cyanide. PMID- 25013259 TI - Outcomes of asymptomatic malaria parasitaemia in neonates in a tertiary hospital, southeast Nigeria. AB - BACKGROUND: Malaria infestation during pregnancy is mostly asymptomatic and untreated especially in unbooked pregnancies. It presents with almost all the fetal complications of overt malaria in pregnancy. The aim of this study was to determine the effect of asymptomatic malaria parasitaemia on the neonates of unbooked parturients delivered at term at the Federal Teaching Hospital, Abakaliki. MATERIALS AND METHODS: This study was conducted in the labour ward complex of the Federal Teaching Hospital, Abakaliki from March to May 2012. Unbooked pregnant women who fulfilled the inclusion criteria and gave consent were consecutively recruited. Cord blood and placenta tissue were collected for haemoglobin concentration determination and histology, respectively. Birth weights were determined with an electronic weighing machine. Statistical Analysis was done with 2008 Epi InfoTM software and level of significant was set at P value <0.05. RESULTS: A total of 250 unbooked parturients were recruited, of which 194 (77.6%) had asymptomatic malaria parasitaemia while 227 (90.8%) had placental parasitisation. The prevalence of low birth weight in the study was 16.4%. There was significant relationship between asymptomatic malaria parasitemia and birth weight (X(2) = 43.70, P-value < 0.001). There were no low birth-weight deliveries among paturients without placental parasitemia. No neonate, however, had anaemia in the study. CONCLUSION: Asymptomatic malaria parasitemia and placental parasitisation by malaria parasites contribute to the outcome of the foetal birth weight. Asymptomatic malaria parasitaemia and placental parasitaemia did not result in a corresponding foetal anaemia on babies delivered. PMID- 25013260 TI - Sexual assault in Ile-Ife, Nigeria. AB - BACKGROUND: Sexual assault (SA) is a shattering malevolence against women. This study determined the burden, periodicity, presentation and management of SA in Ile-Ife, Nigeria. MATERIALS AND METHODS: Retrospective analysis of the hospital records of 76 SA survivors managed over a 5-year period (2007-2011) in Obafemi Awolowo University Teaching Hospitals complex (OAUTHC), Ile-Ife. RESULTS: Sexual assault accounted for 0.69% of all female and 5.2% of all gynaecological emergencies in OAUTHC, Ile-Ife. The survivors' ages ranged from 4 to 50 years (mean = 17.7 +/- 8.8years) and adolescents made up for 48%. The peak prevalence of SA was in February and December and among adults and under-16-year-old survivors, respectively. Daytime and weekday SA were significantly more common among the under-16-year-old survivors (P = 0.008). Majority of the survivors (62%) knew their assailant(s). Neighbours were the commonest perpetrators identified (28.2%) and the assailants' house was the commonest location (39.4%). Weapons were involved in 29.6% of cases and various injuries were identified in 28.2% of the survivors. Hospital presentation was within 24 hours in majority (76.1%) of the survivors, but rape kit examinations were not performed as the kits were not available. Although appropriate medical management was routinely commenced, only 12.7% of survivors returned for follow-up. CONCLUSIONS: Seasonal and diurnal patterns exist in the prevalence of SA in Ile-Ife and most survivors that reported in the hospital presented early. Rape kit examinations were, however, not executed, due to non-availability. Personnel training, protocol development, provision of rape kits and free treatment of SA survivors are, therefore, recommended. Public enlightenment on preventive strategies based on the observed periodicity and age patterns is also suggested. PMID- 25013261 TI - Is vaginal delivery safe after previous lower segment caesarean section in developing country? AB - BACKGROUND: To analyse the mode of delivery in trial of labour (TOL), incidence of successful vaginal deliveries and indications of repeat caesarean section (CS). MATERIALS AND METHODS: Prospective selective study. Study population consisted of 367 pregnant women with previous one lower segment caesarean section (LSCS) in reproductive age group. These were grouped in to three groups, Group 1 (n = 239): Women, who were elected for repeat CS without a TOL. Group 2 (n = 76): Women, who were given TOL and delivered vaginally. Group 3 (n = 52): Women, who were given a TOL but due to failed trial, had to be taken for emergency repeat section. The maternal and foetal outcome was studied in all the groups. STATISTICAL METHOD USED: The data was entered in the Microsoft excel worksheet, values expressed as mean +/- SD. Chi-square test was done to compare the categorical variables among the groups. ANOVA (one-way analysis of variance) was done to compare the baseline characteristics of patients and time to delivery among the groups. RESULTS: Out of 128 women who were given TOL, 76 (59.37%) vaginal birth after caesarean (VBAC) occurred, out of which 40 (52.63%) had spontaneous vaginal deliveries without augmentation of labour and 36 (47.36%) subjects had augmentation of labour with artificial rupture of membranes (ARMs) and oxytocin. A total of 52 women (40.62%) underwent emergency LSCS. CONCLUSION: Proper selection and counselling about clinically significant risks, women can be given TOL with careful monitoring and taken for emergency LSCS on minimal indication is the best answer to management of previous one CS in labour. PMID- 25013262 TI - Pattern and presentation of acute abdomen in a Nigerian teaching hospital. AB - BACKGROUND: Abdominal pain of sudden onset is the hallmark of most non-traumatic emergency surgical presentations. This presents a scenario of urgency to the young surgeon who has to determine which of a myriad of disease conditions the patient is presenting with. Such a physician has to rely on experience and a sound knowledge of the local aetiological spectrum in making a clinical diagnosis. OBJECTIVE: To determine the epidemiology and aetiological spectrum of diseases presenting as acute abdomen in the adult population at the hospital surgical emergency unit. PATIENTS AND METHODS: Two hundred and seventy-six patients presenting at the University of Ilorin Teaching Hospital emergency unit and managed by the general surgeons between 1(st) of May 2009 and 30(th) of April 2010 were recruited and followed-up throughout the period of admission. The biodata and clinical information inclusive of diagnosis, investigations, treatment modality and outcome were entered in a structured questioner. Standardised treatment was given to all patients and difficulties encountered in their management were also noted. The data collected was evaluated using SPSS16. RESULTS: Acute abdomen constituted 9.6% of total surgical emergency admissions with patients aged 16-45 years constituting 78.3%. The commonest cause of acute abdomen was appendicitis (30.3%) followed by intestinal obstruction (27.9%), perforated typhoid ileitis 14.9% and peptic ulcer disease (7.6%), respectively. CONCLUSION: The result from the study is similar to what has been reported in other tropical settings with inflammatory lesions being the major problem. There is also a rising incidence of post-operative adhesions and gradual decline in incidence of obstructed hernia. PMID- 25013263 TI - Herniated near-term pregnancy through an incisional hernia treated with polypropylene mesh: A case report. AB - The management of a large incisional hernia amidst gravid uterus in its sac is a very challenging obstetric entity. Because of the uncommonness of this entity, there has not been any evidence-based guideline regarding the optimal mode of treatment and so treatment is largely individualised. We present the case of a 32 year-old booked G7P6+0 Nigerian woman with two living children who was already booked for elective repeat lower segment Caesarean section (CS) and 'Caesarean' herniorrhaphy at 38 weeks of gestation but only to present at 36-weeks gestation with a 4-hour history of labour pains. She had an emergency lower segment CS 2 years earlier due to obstructed labour but the CS was complicated by wound infection. Examination revealed gravid uterus that herniated through the incisional hernia. She subsequently had emergency lower segment CS with the repair of the hernia with polypropylene mesh. She had uneventful post-operative recovery. Herniated uterus of near-term pregnancy through an incisional hernia has not been reported in our hospital. As in our case, triumphant management required brave but multidisciplinary approach and currently there are emerging management options such as the use of mesh and laparoscopic technique. PMID- 25013264 TI - Autosensitisation (Autoeczematisation) reactions in a case of diaper dermatitis candidiasis. AB - Diaper dermatitis is the most common cutaneous diagnosis in infants. Most cases are associated with the yeast colonisation of Candida or diaper dermatitis candidiasis (DDC). It is an irritating and inflammatory acute dermatitis in the perineal and perianal areas resulting from the occlusion and irritation caused by diapers. Autoeczematization to a distant focus of dermatophyte infection very rarely presents as DDC. We present a 1-month-old boy with lesion on diaper area (gluteal area, perineum, groin and genitalia) and with clusters of pustules and vesicles on a large erythematous base over the dorsal area of both hands. PMID- 25013265 TI - Superficial ulnar artery: Clinical recommendations to avoid iatrogenic complications due to variation in arterial system. AB - Superficial ulnar artery is an uncommon variation in which the ulnar artery is having its course superficial to the flexors of the forearm and may arise directly from axillary or brachial arteries. The proper understanding and knowledge of variation of arterial systems is helpful for judicious planning of various reconstructive procedures in oncological, orthopaedic and reconstructive surgeries. We present a case of variant course of ulnar artery which was noted during exploration of a right distal forearm wound. We suggest few clinical recommendations to avoid iatrogenic complications due to variation in arterial system. PMID- 25013266 TI - Signaling in multiple modalities in male rhesus macaques: sex skin coloration and barks in relation to androgen levels, social status, and mating behavior. AB - The past decade has seen an increasing shift in animal communication towards more studies that incorporate aspects of signaling in multiple modalities. Although nonhuman primates are an excellent group for studying the extent to which different aspects of condition may be signaled in different modalities, and how such information may be integrated during mate choice, very few studies of primate species have incorporated such analyses. Here, we present data from free ranging male rhesus macaques on sex skin coloration (modeled to receiver perception), bark vocal signals, androgen levels, morphometric variables, dominance status, and female mate choice. We show that, consistent with data on females, most intra- and interindividual variation in sex skin appearance occurs in luminance rather than color. Sex skin luminance was significantly correlated across different skin regions. Sex skin luminance did not correlate with the majority of bark parameters, suggesting the potential for the two signals to convey different information. Sex skin appearance was not related to androgen levels although we found some evidence for links between androgen levels and bark parameters, several of which were also related to morphometric variables. We found no evidence that either signal was related to male dominance rank or used in female mate choice, though more direct measures of female proceptive behavior are needed. Overall, the function of male sex skin coloration in this species remains unclear. Our study is among the first nonhuman primate studies to incorporate measurements of multiple signals in multiple modalities, and we encourage other authors to incorporate such analyses into their work. PMID- 25013267 TI - Young Adult Casual Sexual Behavior: Life Course Specific Motivations and Consequences. PMID- 25013268 TI - Processing gap-filler dependencies in Chinese: What does it tell us about semantic processing? PMID- 25013269 TI - Effects of Task-oriented Approach on Affected Arm Function in Children with Spastic Hemiplegia Due to Cerebral Palsy. AB - [Purpose] The purpose of the present study was to examine the effects of task oriented approach on motor function of the affected arm in children with spastic hemiplegia due to cerebral palsy. [Subjects] Twelve children were recruited by convenience sampling from 2 local rehabilitation centers. The present study utilized a one-group pretest-posttest design. All of children received task oriented training for 6 weeks (40 min/day, 5 days/week) and also underwent regular occupational therapy. Three clinical tests, Box and Block Test (BBT), Manual Ability Measure (MAM-16), and Wee Functional Independence Measure (WeeFIM) were performed 1 day before and after training to evaluate the effects of the training. [Results] Compared with the pretest scores, there was a significant increase in the BBT, MAM-16, and WeeFIM scores of the children after the 6-week practice period. [Conclusion] The results of this study suggest that a task oriented approach to treatment of the affected arm improves functional activities, such as manual dexterity and fine motor performance, as well as basic daily activities of patients with spastic hemiplegia due to cerebral palsy. PMID- 25013270 TI - Comparative analysis electroencephalographic of alpha, Beta and gamma bands of a healthy individual and one with hemiparesis. AB - [Purpose] The study analyzed the electroencephalographic (EEG) data of the central cortical areas, during execution of the motor gestures of feeding, activation of the system of mirror neurons, and imagery between a right hemiparetic volunteer (RHV) and a healthy volunteer (HV). [Subjects and Methods] The volunteers' EEG data were recorded with their eyes open for 4 minutes while they performed five experimental tasks. [Results] The alpha band, absolute power value of HV was lower than that of RHV. In the beta band, during the practice condition, there was an increase in the magnitude of the absolute power value of HV at T3, possibly because T3 is representative of secondary motor areas that work with cortical neurons related to planning and organizing sequence of movements performed by the hands. The gamma band is related to the state of preparation for movement and memory. The results of this study indicate that there was increased activation of the gamma frequency band of HV. [Conclusion] The findings of this study have revealed the changes in pattern characteristics of each band which may be associated with the brain injury of the hemiparetic patient. PMID- 25013271 TI - Scapulothoracic Muscle Activity during Use of a Wall Slide Device (WSD), a Comparison with the General Wall Push up Plus. AB - [Purpose] The purpose of this study was to evaluate the effect of the wall slide device on activation of the scapulothoracic musculature. [Subjects] We recruited 15 healthy male subjects. [Methods] The subjects performed the general wall push up plus (WPUP) and the wall slide with device (WSD) exercises. During the exercises, the muscle activities of the upper and lower trapezius (UT, LT), middle and lower serratus anterior (MSA, LSA), and pectoralis major (PM) were measured. [Results] The normalized muscle activity data of the WSD were significantly higher in UT, MSA and LSA than the WPUP. [Conclusion] Our results suggest that exercise using the WSD can more effectively activate the scapulothoracic musculature than the general WPUP. PMID- 25013272 TI - Contralateral sensory and motor effects of unilateral kaltenborn mobilization in patients with thumb carpometacarpal osteoarthritis: a secondary analysis. AB - [Purpose] The aim of this study was to determine changes in pressure sensitivity and pinch strength in patients with thumb carpometacarpal (CMC) osteoarthritis (OA) in the contralateral hand after unilateral Kaltenborn mobilization on the symptomatic hand. [Subjects and Methods] Twenty-nine females with dominant hand thumb CMC osteoarthritis participated (age 70-90), and were randomized into 2 groups. The experimental group received a Kaltenborn mobilization, and the placebo group received a nontherapeutic dose of intermittent ultrasound. Pressure pain thresholds (PPT) at the thumb CMC joint, scaphoid bone and hamate bone and tip and tripod pinch strength were assessed before and after the intervention and 1 week (1st follow-up) and 2 weeks (2nd follow-up) after the intervention. [Results] Significant increases in PPT in the experimental group at all follow-up periods as compared with baseline data were found. The post-intervention between group mean differences for PPT were 1.1 (95%CI 0.4-1.8) for the CMC joint, 1.1 (95%CI 0.2-2.1) for the scaphoid, and 1.5 (95%CI 0.5-2.8) for the hamate. The post-intervention between-group mean differences were 0.5 (95%CI 0.2-0.9) for the tip pinch and 0.3 (95%CI 0.1-0.6) for the tripod pinch. [Conclusion] The current secondary analysis found that Kaltenborn mobilization for the symptomatic hand reduces pressure pain sensitivity (PPT increases) and also produces motor changes in the contralateral non-treated hand compared with a placebo group. PMID- 25013273 TI - Eltgol acutelly improves airway clearance and reduces static pulmonary volumes in adult cystic fibrosis patients. AB - Chest physical therapy techniques are essential in order to reduce the frequency of recurrent pulmonary infections that progressively affect lung function in cystic fibrosis patients. Recently, ELTGOL (L'Expiration Lente Totale Glotte Ouverte en decubitus Lateral) emerged as an inexpensive and easy to perform therapeutic option. The aim of this study was to compare the acute effects of ELTGOL and the Flutter valve in stable adult patients with cystic fibrosis. [Subjects and Methods] This was a randomized, crossover study with a sample of cystic fibrosis outpatients. The subjects underwent two protocols (Flutter Valve and ELTGOL interventions, referred to as ELTGOL and FLUTTER) in a randomized order with a one-week washout interval between them. The main outcomes were pulmonary function variables and expectorated sputum dry weight. [Results] ELTGOL cleared 0.34 g more of secretions than FLUTTER (95% CI 0.11 to 0.57). When comparing the physiological effects of ELTGOL and FLUTTER, the first was superior in improving airway resistance (-0.51 cmH2O/L/s; 95% CI -0.88 to -0.14) and airway conductance (0.016 L/s/cmH2O; 95% CI 0.008 to 0.023). [Conclusion] ELTGOL promoted higher secretion removal and improvement in airway resistance and conductance than the Flutter valve. These techniques were equivalent in reducing the pulmonary hyperinflation and air trapping in cystic fibrosis patients. PMID- 25013274 TI - Comparative study of hamstring and quadriceps strengthening treatments in the management of knee osteoarthritis. AB - [Purpose] Osteoarthritis (OA) of the knee is the most common form of joint disease. It is one of the major causes of impaired function that reduces quality of life (QOL) worldwide. The purpose of this study was to compare exercise treatments for hamstring and quadriceps strength in the management of knee osteoarthritis. [Subjects and Methods] Forty patients with OA knee, aged 50-65 years were divided into 2 groups. The first group (57.65+/-4.78 years) received hot packs and performed strengthening exercises for the quadriceps and hamstring, and stretching exercises for the hamstring. The second group (58.15+/-5.11 years) received hot packs and performed strengthening exercises for only the quadriceps, and stretching exercise for the hamstring. Outcome measures were the WOMAC (Western Ontario and McMaster Universities OA index questionnaire), Visual Analogue Scale (VAS) assessment of pain, the Fifty-Foot Walk Test (FWS), and Handheld dynamometry. [Results] There was a significant difference between the groups. The first group showed a more significant result than the second group. [Conclusion] Strengthening of the hamstrings in addition to strengthening of the quadriceps was shown to be beneficial for improving subjective knee pain, range of motion and decreasing the limitation of functional performance of patients with knee osteoarthritis. PMID- 25013275 TI - The effects of running in place on healthy adults' lumbar stability. AB - [Purpose] The purpose of this study was to examine the effects of running in place while using the abdominal drawing-in method on healthy adults' lumbar stability. [Subjects] A total of 30 subjects were divided into a training group of 15 subjects and a control group of 15 subjects. [Methods] The training group ran in place using the abdominal drawing-in method for 30 minutes per session, three sessions per week, for a total of six weeks. For both the training group and the control group, static lumbar stability (SLS) and dynamic lumbar stability (DLS) were measured before and after the experiment using a pressure biofeedback unit. [Results] Pre- and post-intervention measurements were compared within the training group and the control group. According to the results, the training group showed statistically significant differences in DLS. [Conclusion] Running in place, which can be performed easily regardless of time and location, can be recommended as an exercise that will improve the dynamic lumbar stability of students or office workers. PMID- 25013276 TI - Tai chi improves oxidative stress response and DNA damage/repair in young sedentary females. AB - [Purpose] This study was to examine the effects of 12 weeks of Tai Chi (TC) exercise on antioxidant capacity, and DNA damage/repair in young females who did not perform regular physical exercise. [Subjects and Methods] Ten female students from a Chinese university voluntarily participated in this program. All of them practiced the 24-form simplified Tai Chi, 5 times weekly, for 12 weeks. Plasma levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), glutathione (GSH), hydroxyl radical inhibiting capacity (OH.-IC), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 8-oxoguanine DNA glycosylase (OGG1) were measured at 0, 8, and 12 weeks. Heart rate (HR) was monitored during the last set of the training session at 4, 8, and 12 weeks. [Results] Plasma SOD and OH.-IC levels were increased at 8 and 12 weeks compared to the baseline (0 weeks). Gpx and GSH levels did not change significantly throughout the study period. The plasma MDA level was decreased significantly at 8 weeks but not at 12 weeks compared to the baseline value. While the plasma 8-OHdG level did not change throughout the study period, the plasma OGG1 level was significantly increased at 8 and 12 weeks compared to the baseline value. [Conclusion] TC practice for 12 weeks efficiently improved the oxidative stress response in young females who did not perform regular physical exercise. The TC exercise also increased the DNA repairing capacity. PMID- 25013277 TI - Effects of Low-frequency Current Sacral Dermatome Stimulation on Idiopathic Slow Transit Constipation. AB - [Purpose] This study aimed to determine whether low-frequency current therapy can be used to reduce the symptoms of idiopathic slow transit constipation (ISTC). [Subjects] Fifteen patients (ten male and five female) with idiopathic slow transit constipation were enrolled in the present study. [Results] Bowel movements per day, bowel movements per week, and constipation assessment scale scores significantly improved after low-frequency current simulation of S2-S3. [Conclusion] Our results show that stimulation with low-frequency current of the sacral dermatomes may offer therapeutic benefits for a subject of patients with ISTC. PMID- 25013278 TI - Characteristics of postural muscle activation patterns induced by unexpected surface perturbations in elite ski jumpers. AB - [Purpose] This study investigated the characteristics of postural control following postural disturbance in elite athletes. [Subjects] Ten elite ski jumpers and ten control subjects participated in this study. [Methods] Subjects were required to maintain balance without stepping following unexpected horizontal surface perturbation in a forward or backward direction. [Results] A lower and reproducible peak magnitude of the center of mass velocity was shown in the athlete group compared to the control group. Cross-correlation analyses showed longer time lags at the moment of peak correlation coefficient between trunk flexor and extensor muscle activities, and shorter time lags and higher correlations between ankle flexor and extensor muscle activities were shown in the athlete group than in the control group. [Conclusion] The elite ski jumpers showed superior balance performance following surface perturbations, more reciprocal patterns in agonist-antagonist pairs of proximal postural muscles, and more co-contraction patterns in distal postural muscles during automatic postural responses than control individuals. This strategy may be useful in sports requiring effective balance recovery in environments with a dynamically changing surface, as well as in rehabilitation. PMID- 25013279 TI - Are Korean Adults Meeting the Recommendation for Physical Activity during Leisure Time? AB - [Purpose] The purpose of this study was to determine if Korean adults meet their physical activity recommendations during their leisure time to promote a healthy living. [Subjects and Methods] The sample included South Korean adults, aged over 20, who were currently residing in K City, South Korea. The author used a quota sampling technique to select 1,000 samples. Of the 1,000 questionnaires distributed, 845 questionnaires were used to conduct a chi(2) test. [Results] It was revealed by the questionnaire that there was a clear distinction in the categories of very high level activity (11.0%), high level activity (29.1%), acceptable level activity (12.9%), low level activity (9.7%), and inactive level of physical activity (38.3%) in Korean adults' leisure time. [Conclusions] The most interesting finding was that more than half of Korean adults do reach the recommendation of at least 30 minutes of moderate activity, on three or more days a week for at least three months. The other interesting finding was that the questionnaire is a useful instrument suitable for analyzing the recommendations of physical activity, comprising frequency, intensity, time, and overall duration. PMID- 25013280 TI - The effect of sacroiliac joint mobilization on pelvic deformation and the static balance ability of female university students with si joint dysfunction. AB - [Purpose] The present study aimed to determine the effect of an 8-week program of joint mobilization on changes in pelvic obliquity and pain level in seventeen female university students aged in their 20's with sacroiliac joint dysfunction by dividing them into two groups: a joint mobilization group (MWM) and a control group. [Subjects] Seventeen subjects were selected from female university students aged in their 20's attending N University in Cheon-An City, Korea, The subjects had sacroiliac joint syndrome, but experienced no problems with daily living and had no previous experience of joint mobilization exercise. The subjects were randomly assigned to a joint mobilization group of eight and a control group of nine who performed joint mobilization exercise. [Methods] Body fat and lean body mass were measured using InBody 7.0 (Biospace, Korea). The Direct Segmental Multi-frequency Bioelectrical Impedance Analysis Method (DSM BIA) was used for body composition measurement. A pressure footstool (Pedoscan, DIERS, Germany) and a trunk measurement system (Formetric 4D, DIERS, Germany), a 3D image processing apparatus with high resolution for vertebrae, were used to measure 3D trunk images of the vertebrae and pelvis obliquity, as well as static balance ability. [Result] The MWM group showed a significantly better Balance than the control group. In addition, the results of the left/right and the front/rear balance abilities were significantly better than those of the control group. [Conclusion] This study proved that a combination of mobilization with movement and functional training was effective in reducing pelvis malposition and pain, and improving static stability control. PMID- 25013281 TI - Correlation between Pediatric Balance Scale and Functional Test in Children with Cerebral Palsy. AB - [Purpose] To investigate the correlation of functional balance with the functional performance of children with cerebral palsy. [Subjects and Methods] This was a cross-sectional study of children with cerebral palsy with mild to moderate impairment. The children were divided into 3 groups based on motor impairment. The evaluation consisted of the administration of the Pediatric Balance Scale (PBS) and the Pediatric Evaluation Disability Inventory. Correlations between the instruments were determined by calculating Pearson's correlation coefficients. [Results] In Group 1, a strong positive correlation was found between the PBS and the mobility dimension of the Pediatric Evaluation Disability Inventory (r=0.82), and a moderate correlation was found between the PBS and self-care dimension of the Pediatric Evaluation Disability Inventory (r=0.51). In Group 2, moderate correlations were found between the PBS and both the self-care dimension (r=0.57) and mobility dimension (r=0.41) of the Pediatric Evaluation Disability Inventory. In Group 3, the PBS was weakly correlated with the self-care dimension (r=0.11) and moderately correlated with the mobility dimension (r=0.55). [Conclusion] The PBS proved to be a good auxiliary tool for the evaluation of functional performance with regard to mobility, but cannot be considered a predictor of function in children with cerebral palsy. PMID- 25013282 TI - Effects of Inclined Treadmill Walking on Pelvic Anterior Tilt Angle, Hamstring Muscle Length, and Trunk Muscle Endurance of Seated Workers with Flat-back Syndrome. AB - [Purpose] This study investigated the effects of inclined treadmill walking on pelvic anterior tilt angle, hamstring muscle length, and back muscle endurance of seated workers with flat-back syndrome. [Subjects] Eight seated workers with flat back syndrome who complained of low-back pain in the L3-5 region participated in this study. [Methods] The subjects performed a walking exercise on a 30 degrees inclined treadmill. We measured the pelvic anterior tilt angle, hamstring muscle length, and back muscle endurance before and after inclined treadmill walking. [Results] Anterior pelvic tilt angle and active knee extension angle significantly increased after inclined treadmill walking. Trunk extensor and flexor muscle endurance times were also significantly increased compared to the baseline. [Conclusion] Inclined treadmill walking may be an effective approach for the prevention or treatment of low-back pain in flat-back syndrome. PMID- 25013283 TI - The effect of trunk stabilization exercise using an unstable surface on the abdominal muscle structure and balance of stroke patients. AB - [Purpose] This study investigated the effect of unstable surface trunk stabilization exercise on the abdominal muscle structure and balance of stroke patients. [Subjects] The subjects were divided into two groups: an unstable surface trunk stabilization exercise group (n=13), and a stable surface trunk stabilization exercise group (n=11). [Methods] Both groups performed trunk stabilization exercise for 30 minutes, 3 days per week for 6 weeks. Abdominal muscle thickness and the Berg Balance Scale (BBS) were measured at the baseline and after 6 weeks. [Results] There was a significant improvement in the internal oblique muscle thickness, transversus abdominis thickness and balance ability of the unstable surface trunk stabilization exercise group. [Conclusion] The unstable surface trunk stabilization exercise improved the internal oblique and transversus abdominis muscles and balance ability. These results suggest that unstable surface trunk exercise is useful in the rehabilitation stroke patients. PMID- 25013285 TI - Experimental joint immobilization and remobilization in the rats. AB - [Purpose] The purpose of our study was to clarify temporal effects on restrictions to range of motion and the histopathological changes of joint components after joint immobilization in a rat knee-contracture model. [Subjects] Fifty-four male Wistar rats were randomly divided into two groups: a fixation group, and a control group. [Methods] In the fixation group, unilateral knee joints were immobilized at full flexion using a plaster cast for 4 weeks. At four weeks the animals were randomly divided into six subgroups, corresponding to the time of examination after cast removal: 0, 4, 8, 16, 24, and 32 weeks. For comparison, control group animals of corresponding age were also examined. [Results] Although movement restrictions of the knee joint had completely recovered 6 weeks after the cast removal, cartilage and synovial membrane structures did not completely recover. [Conclusion] These findings have not previously been reported, and as they form an addition to the fundamental scientific foundations of physical therapy, further research must examine these findings from a variety of perspectives. PMID- 25013284 TI - Changes in postural sway according to footwear types of hemiparetic stroke patients. AB - [Purpose] The purpose of the current study was to investigate the influence of footwear type on postural sway of hemiparetic stroke patients. [Subjects] Thirty two stroke patients who were undergoing a rehabilitation program were recruited on a voluntary basis from local rehabilitation unit. [Methods] This study had a single-group repeated-measures design. The Good Balance system was used to measure the postural sway velocity (anteroposterior and mediolateral) and velocity moment of the subjects under the eyes open and eyes closed conditions in the standing posture. Postural sway of the subjects in four types of footwear was measured, including barefoot, high heel-collar shoes, flat shoes, or slippers. [Results] The postural sway when wearing the flat shoes or slippers was significantly higher than that when barefoot or wearing high heel-collar shoes. In addition, postural sway velocity and velocity moment of all the footwear types were significantly higher under the eyes closed condition than under the eyes open condition. [Conclusion] Our results reveal that when the subjects wore flat shoes or slippers they had more difficulty than when they wore the high heel collar shoes in postural control when maintaining standing balance. We believe that this result provides basic information for improvements in postural control and may be useful in balance training to prevent falls after stroke. PMID- 25013286 TI - EMG Activity in the Abdominal Muscles and the Kinematics of the Lumbar Spine during Unilateral Upper-limb Resistance Exercises under Stable and Unstable Conditions. AB - [Purpose] We investigated the effects of unstable conditions on the electromyographic (EMG) activity of the rectus abdominis (RA) and the transverse abdominis-internal oblique (TrA-IO) muscles, and lumbar kinematics during unilateral upper-limb resistance exercises using elastic tubing bands. [Subjects] Twelve healthy males were recruited. [Methods] The subjects performed isometric left shoulder abduction using an elastic tubing band in a sitting position on a chair, and on a Swiss ball. During this exercise, EMG activities of the RA and TrA-IO were recorded using a wireless EMG system, and a three-dimensional motion analysis system monitored lumbar kinematics. Differences in EMG activities of the RA and TrA-IO, the ratio of TrA-IO to RA activity, and lumbar kinematics were compared between the stable and unstable conditions using the paired t-test. [Results] Under the unstable condition, the EMG activities of both muscles were significantly greater than that under the stable condition; however the ratio of TrA-IO to RA activity did not significantly differ between the conditions. The lumbar angle significantly differed only in the coronal plane. [Conclusions] These findings indicate that trunk posture should be considered when performing exercises under unstable conditions. PMID- 25013287 TI - Multi-directional Reach Test: An Investigation of the Limits of Stability of People Aged between 20-79 Years. AB - [Purpose] The multi-directional reach test (MDRT) is a simple, inexpensive, reliable and valid screening tool for assessing the limits of stability in the anterorposterior and mediolateral directions. The aim of this study was to quantify the limits of stability of people aged between 20 and 79 years using the MDRT. [Subjects] One hundred and eighty subjects were divided into the following 6 age groups: 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years (n=30 per group). [Methods] The MDRT was used to measure the limits of stability in four directions: forward, backward, leftward and rightward. Subjects performed maximal outstretched arm reach in each direction with their feet flat on the floor. [Results] All age groups performed the greatest values of the limit of stability in the forward direction. The 60-79 year group demonstrated significantly lower limits of stability in the forward, leftward and rightward directions compared to the 20-39 year group. [Conclusion] The limits of stability declined with age mainly in the forward, leftward and rightward directions. The MDRT appears to be a useful assessment tool for postural control and balance of those aged 60 years and over. PMID- 25013288 TI - The Influence of "wuqinxi" exercises on the Lumbosacral Multifidus. AB - [Purpose] To investigate the effect of the five animals (wuqinxi) exercises on the lumbosacral multifidus. [Subjects and Methods] This study enrolled two groups of volunteers, 15 volunteers who did the five animals exercises, the experimental group, and 15 volunteers who did aerobic exercise (walking), the control group. Both before and after the 1 year exercise intervention, the average surface electromyography (ASEMG) of the two groups in the process of flexion and extension was recorded and analyzed using DASYLab10.0 software, and the flexion extension ratio (FER) was calculated. [Results] The ASEMG in the process of flexion was lower than the ASEMG in the process of extension both before and after the 1 year exercise intervention on both sides of all volunteers. There was no significant difference in FER between the experimental group and control group before the 1 year exercise intervention; however, the FER of experimental group was lower than that of the control group after the 1 year exercise intervention. There was no significant difference between the two sides in any individual both before and after the 1 year exercise intervention in both groups. [Conclusion] The "wuqinxi" exercises improved the function of the lumbosacral multifidus, and might be an alternative method of reducing low back pain. PMID- 25013289 TI - The Postural Control Characteristics of Individuals with and without a History of Ankle Sprain during Single-leg Standing: Relationship between Center of Pressure and Acceleration of the Head and Foot Parameters. AB - [Purpose] This study aimed to investigate the postural control characteristics of individuals with and without a history of ankle sprain during single-leg standing by examining the relationship between various parameters of center of pressure (COP) and head and foot acceleration. [Subjects] Twenty subjects with and 23 subjects without a history of ankle sprain (sprain and control groups, respectively) participated. [Methods] Mean and maximum COP velocity and maximum COP range in the anteroposterior and mediolateral components of movement were calculated using a gravicorder. The anteroposterior and mediolateral maximum accelerations of the head and foot, as well as the root mean square (RMS) of each acceleration parameter, were measured using accelerometers. [Results] In the mediolateral component, a significant positive correlation was found between maximum acceleration of the foot and all COP parameters in the sprain group. [Conclusion] Our findings suggest that mediolateral momentary motion of the foot in individuals with a history of ankle sprain has relevance to various parameters of COP. PMID- 25013290 TI - The Effect of the Abdominal Drawing-in Manoeuvre during Forward Steps. AB - [Purpose] A decrease in hip extension has been reported to be a factor in short step width and slow walking speed. Hip motion is related to pelvic and spinal motion, and transversus abdominis (TrA) activation is important for stabilising the pelvis and spine. The abdominal drawing-in manoeuvre (ADIM) can be performed to activate the TrA. The purpose of this study was to examine the influence of the ADIM on forward steps as a gait exercise. [Subjects] The subjects were 20 healthy men (mean age, 20.8 +/- 2.4 years). [Methods] Thicknesses of the lateral abdominal muscles during forward step posture with and without ADIM were measured using ultrasound, and kinematics of the hip and pelvis were examined using a three-dimensional motion capture system. [Results] Thicknesses of the TrA and internal oblique increased during forward steps with ADIM. In addition, hip extension increased and pelvic rotation and oblique angles decreased during forward step with ADIM. [Conclusion] We believe that ADIM activates the so-called corset muscles, which consequently stabilise the pelvis and spine and increase hip extension. Our results suggest that an ADIM could increase hip extension during gait exercise. PMID- 25013291 TI - Differences in Muscle Activities of the Infraspinatus and Posterior Deltoid during Shoulder External Rotation in Open Kinetic Chain and Closed Kinetic Chain Exercises. AB - [Purpose] This study investigated the changes in electromyographic (EMG) activities of the infraspinatus and posterior deltoid muscles during shoulder external rotation under open kinetic chain (OKC) and closed kinetic chain (CKC) exercise conditions. [Subjects] In total, 15 healthy males participated in this study. [Methods] Subjects performed shoulder external rotations under CKC and OKC conditions while standing with and without weight support provided by a height adjustable table. Pressure biofeedback was used to ensure a constant amount of weight support. The activities of the infraspinatus and posterior deltoid muscles during shoulder external rotation were measured using a wireless surface EMG system. The paired t-test was used to compare the EMG activities of the infraspinatus and the posterior deltoid muscles and the ratio of the infraspinatus to the posterior deltoid during shoulder external rotation under OKC and CKC conditions. [Results] The EMG activity of the infraspinatus and the ratio of the infraspinatus to the posterior deltoid activities were significantly increased, whereas the posterior deltoid activity was significantly decreased under the CKC condition compared to the OKC condition. [Conclusion] Clinicians should consider the CKC shoulder external rotation exercise when they wish to selectively strengthen the infraspinatus. PMID- 25013292 TI - The effect of underwater gait training on balance ability of stroke patients. AB - [Purpose] The purpose of this study was to investigate the effects of underwater treadmill gait training on the balance ability of stroke patients. [Subjects] Twenty-two patients with stroke were randomly assigned to an underwater treadmill group (n =11) or a control group (n =11). [Methods] Both groups received general rehabilitation for 30 min per session, 5 times per week, over a 4-week period. The underwater treadmill group received additional underwater gait training for 30 min per session, 5 times per week, over the same 4-week period. Static and dynamic balances were evaluated before and after the intervention. [Results] The means of static and dynamic balance ability increased significantly in both groups, but there was no significant difference between the two groups. [Conclusion] Compared to the general rehabilitation program, underwater treadmill gait training was not more effective at improving the balance ability of stroke patients than land-based training. PMID- 25013294 TI - The Effects of Push-ups with the Trunk Flexed on the Shoulder and Trunk Muscles. AB - [Purpose] The purpose of this study was to compare the activity of the shoulder and trunk muscles in two push-up positions: standard push-ups and push-ups with the trunk flexed. [Subjects] Fifteen young adult males participated in the study. [Methods] This study measured the clavicular and sternocostal portions of the pectoralis major, the serratus anterior, and the rectus abdominis during push-ups under the two conditions. [Results] The activity of the sternocostal portion of the pectoralis major and that of the rectus abdominis were significantly greater under Condition 1 than under Condition 2. The activity of the clavicular portion of the pectoralis major and that of the serratus anterior were significantly greater under Condition 2 compared with Condition 1. [Conclusion] These results indicate that exercises can selectively activate muscle parts under different clinical situations. PMID- 25013293 TI - Effects of balance and gait training on the recovery of the motor function in an animal model of Parkinson's disease. AB - [Purpose] This study was conducted to investigate the effect of balance and gait training on the recovery of the motor function in a Parkinson's disease animal models. [Subjects and Methods] A total of 40 mice were randomly classified into four groups with 10 in each group: Group I-Normal; Group II-Parkinson's disease and no training; Group III-Parkinson's disease and balance training was performed; and Group IV-Parkinson's disease and gait training. Parkinson's disease was induced by administration of MPTP to animals in Groups II-IV. Groups III and IV did training once a day, five days a week, for four weeks. Neurobehavioral evaluation was performed through the pole and open-field tests. Immunological evaluation was performed via TH (tyrosine hydroxylase) protein expression, using western blot analysis. [Results] In the result of the pole test, Groups III and IV showed significantly greater motor function recovery than to Group II. The results of the open-field test also showed that Groups III and IV had significantly greater motor function recovery than to Group II, and Group IV showed significantly greater motor function recovery than to Group III. Using western blot analysis, we determined that the expression of TH protein in the corpus striatum was greatest in group I, followed by Groups III and IV, and that Group II had the lowest TH protein expression in the corpus striatum. [Conclusion] The results of this study showed that balance and gait training were effective at recovering the motor functions of a Parkinson's disease animal models induced by MPTP, and that gait training was more effective than balance training. PMID- 25013295 TI - Effect of a Dynamic Air Cushion on the Development of Leg Edema during Wheelchair Sitting. AB - [Purpose] To clarify how a novel dynamic cushion affects the leg edema evoked by wheelchair sitting, we measured the changes in leg volume induced during wheelchair sitting with the dynamic air cushion or a static cushion. [Subjects and Methods] Nine healthy male subjects participated in this study. Leg edema during wheelchair sitting was evaluated with strain gauge plethysmography (the gauge was placed around the middle portion of the lower thigh). Following a period of rest, each subject was asked to sit on a wheelchair containing the dynamic cushion for 15 min. Then, the protocol was repeated with a static cushion. The angles of the knee and ankle joints were set to 90 degrees, and no footrests were used. [Results] The change in leg volume observed during sitting on the dynamic cushion (0.00 +/- 0.03 mL/100 mL) was smaller than that observed during sitting on the static cushion (0.02 +/- 0.02 mL/100 mL). [Conclusion] These results suggested that the dynamic cushion relieved leg edema during wheelchair sitting. PMID- 25013296 TI - Intra-rater and Inter-rater Reliability of Mandibular Range of Motion Measures Considering a Neutral Craniocervical Position. AB - [Purpose] The aim of this study was to determine the inter-rater and intra-rater reliability of the mandibular range of motion (ROM) considering the neutral craniocervical position when performing the measurements. [Subjects and Methods] The sample consisted of 50 asymptomatic subjects. Two raters measured four mandibular ROMs (maximal mouth opening (MMO), laterals, and protrusion) using the craniomandibular scale. Subjects alternated between raters, receiving two complete trials per day, two days apart. Intra- and inter-rater reliability was determined using intra-class correlation coefficients (ICCs). Bland-Altman analysis was used to assess reliability, bias, and variability. Finally, the standard error of measurement (SEM) and minimal detectable change (MDC) were analyzed to measure responsiveness. [Results] Reliability was good for MMO (inter rater, ICC= 0.95-0.96; intra-rater, ICC= 0.95-0.96) and for protrusion (inter rater, ICC= 0.92-0.94; intra-rater, ICC= 0.93-0.96). Reliability was moderate for lateral excursions. The MMO and protrusion SEM ranged from 0.74 to 0.82 mm and from 0.29 to 0.49 mm, while the MDCs ranged from 1.73 to 1.91 mm and from 0.69 to 0.14 mm respectively. The analysis showed no random or systematic error, suggesting that effect learning did not affect reliability. [Conclusion] A standardized protocol for assessment of mandibular ROM in a neutral craniocervical position obtained good inter- and intra-rater reliability for MMO and protrusion and moderate inter- and intra-rater reliability for lateral excursions. PMID- 25013297 TI - Effects of kinesiology taping on repositioning error of the knee joint after quadriceps muscle fatigue. AB - [Purpose] The purpose of this study was to identify the effects of kinesiology taping on repositioning error of the knee joint after quadriceps muscle fatigue. [Subjects] Thirty healthy adults with no orthopaedic or neurological problems participated in this study. [Methods] The repositioning error of the knee joint was measured using a digital goniometer when the subjects extended their dominant side knee to a random target angle (30 degrees , 45 degrees , or 60 degrees ) with their eyes closed, before and after a quadriceps muscle fatigue protocol, and after application of kinesiology tape. [Results] We found that repositioning errors of the dominant-side knee joint increased after quadriceps fatigue compared with no-fatigue conditions. However, kinesiology taping of the quadriceps muscle and patella after quadriceps fatigue significantly decreased repositioning errors of the knee joint. [Conclusion] These results suggest that quadriceps fatigue increases the repositioning error of the knee joint, whereas application of kinesiology tape decreases fatigue-induced joint repositioning error. PMID- 25013298 TI - Factors affecting the musculoskeletal symptoms of korean police officers. AB - ] This study was conducted to investigate efficient, systematic management of the Korean police and to examine the status and prevention of musculoskeletal disorders in Korean police officers. [Subjects and Methods] A survey of police officers (353 subjects) who visited the National Police Hospital from March 2013 to May 2013 was conducted using a structured questionnaire. [Results] The incidence of pain was 44.2% in the shoulder, 41.4% in the waist, 31.2% in the neck, 26.1% in the legs/foot, 16.7% in the hand/wrist/finger, and 14.7% in the arm/elbow. The comparative risk of the relevant part factors was analyzed by multiple regression analysis. The shoulder had a 4.87 times higher risk in police lieutenants compared with those under the rank of corporal and a 1.78 times higher risk in people with chronic diseases than those without chronic diseases. The arm/elbow had a 2.37 times higher risk in people who exercised than those who did not exercise and a 1.78 times higher risk in people with a chronic disease than those without chronic diseases. Generally, people with a chronic disease showed a higher risk than those without chronic diseases. [Conclusion] The results of this study could be useful as basic data for improvement of police welfare, specialized treatment for the health safety of the police, and efficient management of police resources. PMID- 25013299 TI - The Relationship between Quadriceps Thickness, Radiological Staging, and Clinical Parameters in Knee Osteoarthritis. AB - [Purpose] The aim of this study was to investigate the relationship between clinical parameters, radiological staging and evaluated ultrasound results of quadriceps muscle thickness in knee osteoarthritis. [Subjects] The current study comprised 75 patients (51 female, 24 male) with a mean age of 57.9+/-5.2 years (range 40-65 years) and a diagnosis of osteoarthritis in both knees. [Methods] Knee radiographs were evaluated according to the Kellgren-Lawrence grading system. Clinical evaluation performed with the visual analog scale (VAS), Western Ontario and McMaster Osteoarthritis Index (WOMAC), the 50-meter walking test, and the 10-step stair test. The thickness of the muscle layer of the quadriceps femoris (M. vastus intermedius and M. rectus femoris) was measured with high resolution real-time ultrasonography. [Results] The results of this study showed a significant negative correlation between quadriceps thickness and age, duration of disease, stage of knee OA, and VAS, WOMAC, 50-m walking test, and 10-step stair test scores. [Conclusion] The evaluation of quadriceps muscle thickness with ultrasound can be considered a practical and economical method in the diagnosis and follow-up of knee osteoarthritis. PMID- 25013300 TI - Comparison of Upper Trapezius, Anterior Deltoid, and Serratus Anterior Muscle Activity during Push-up plus Exercise on Slings and a Stable Surface. AB - [Purpose] The purpose of this study was to identify effects of push-up plus exercise on different support surfaces on upper extremity muscular activity. [Subjects] The subjects were 28 students (10 males, 18 females) at B University. [Methods] The subjects performed push-up plus exercises either on slings or on a fixed support. [Results] Push-up plus exercises on slings showed significant increases in the muscle activity of the trapezius (upper fiber), deltoid (anterior fiber), and serratus anterior muscles compared with stabilization exercises on a fixed support. [Conclusion] Based on these results, it is considered that performance of the push-up plus exercise on slings will increase scapular muscle activity. PMID- 25013301 TI - Efficacy of kinesiology taping for recovery from occupational wrist disorders experienced by a physical therapist. AB - [Purpose] The aim of this paper was to report the efficacy of kinesiology taping for recovery from wrist pain and limited range of motion (ROM) in a physical therapist with repetitive strain injuries. [Subjects] A 32 year-old male physical therapist developed recurring severe pain in the dominant wrist and limited active ROM with extremely painful supination. [Methods] The kinesiology tape was applied to the lumbricals, musculi interossei dorsales, palmares, the wrist extensor and flexor muscles, and the wrist joint for 3 weeks for an average of 10 h/day. [Results] After application of the kinesiology tape, the Numeric Pain Rating Scale and Patient-rated Wrist Evaluation scores decreased, and the Patient Specific Functional Scale score increased in comparison with the initial score. [Conclusion] Repeated kinesiology taping of the wrist muscles and joint could be an effective method for recovery from occupational wrist disorders experienced by physical therapists. PMID- 25013302 TI - Transcranial Direct Current Stimulation Combined with Treadmill Gait Training in Delayed Neuro-psychomotor Development. AB - [Purpose] The aim of the present study was to describe the results of transcranial direct current stimulation combined with treadmill training in a child with delayed neuro-psychomotor development. [Subject and Methods] Transcranial direct current stimulation (intensity: 1 mA) was applied over the primary motor cortex for 20 minutes during simultaneous treadmill training (2.5 km/h) in ten sessions. [Results] Clinically significant improvement was found in motor development (fine motor subscale, 23 to 25; gross motor subscale, 32 to 41). Reductions in mean oscillation of the center of pressure were found in the anteroposterior (239.2 to 146.5 mm) and mediolateral (177.4 to 149.2 mm) directions. Increases occurred in cadence (106 to 123 steps/minute), step length (0.16 to 0.23 m), step width (0.09 to 0.14 m) and gait velocity with support (0.3 to 0.7 m/s). [Conclusion] After treatment, the child was able to initiate the standing position for the first time and walk without support. PMID- 25013303 TI - Effect of locomotor training on motor recovery and walking ability in patients with incomplete spinal cord injury: a case series. AB - [Purpose] The aim of this study was to describe the effect of locomotor training on a treadmill for three individuals who have an incomplete spinal cord injury (SCI). [Subjects and Methods] Three indivduals (2 males, 1 female) with incomplete paraplegia participated in this prospective case series. All subjects participated in locomotor training for a maximum of 20 minutes on a motorized treadmill without elevation at a comfortable walking speed three days a week for four weeks as an adjunct to a conventional physiotherapy program. The lower extremity strength and walking capabilities were used as the outcome measures of this study. Lower extremity strength was measured by lower extremity motor score (LEMS). Walking capability was assessed using the Walking Index for Spinal Cord Injury (WISCI II). [Results] An increase in lower extremity motor score and walking capabilities at the end of training program was found. [Conclusion] Gait training on a treadmill can enhance motor recovery and walking capabilities in subjects with incomplete SCI. Further research is needed to generalize these findings and to identify which patients might benefit from locomotor training. PMID- 25013304 TI - MEMS-BASED 3D CONFOCAL SCANNING MICROENDOSCOPE USING MEMS SCANNERS FOR BOTH LATERAL AND AXIAL SCAN. AB - A fiber-optic 3D confocal scanning microendoscope employing MEMS scanners for both lateral and axial scan was designed and constructed. The MEMS 3D scan engine achieved a lateral scan range of over +/- 26 degrees with a 2D MEMS scanning micromirror and a depth scan of over 400 MUm with a 1D MEMS tunable microlens. The lateral resolution and axial resolution of this system were experimentally measured as 1.0 MUm and 7.0 MUm, respectively. 2D and 3D confocal reflectance images of micro-patterns, micro-particles, onion skins and acute rat brain tissue were obtained by this MEMS-based 3D confocal scanning microendoscope. PMID- 25013306 TI - A novel microneedle array for the treatment of hydrocephalus. AB - We present a microfabricated 10 by 10 array of microneedles for the treatment of a neurological disease called communicating hydrocephalus. Together with the previously reported microvalve array, the current implantable microneedle array completes the microfabricated arachnoid granulations (MAGs) that mimic the function of normal arachnoid granulations (AGs). The microneedle array was designed to enable the fixation of the MAGs through dura mater membrane in the brain and thus provide a conduit for the flow of cerebrospinal fluid (CSF). Cone shaped microneedles with hollow channels were fabricated using a series of microfabrication techniques: SU-8 photolithography for tapered geometry, reactive ion etching for sharpening the microneedles, 248 nm deep UV excimer laser machining for creating through-hole inside the microneedles, and metal sputtering for improved rigidity. Puncture tests were conducted using porcine dura mater and the results showed that the fabricated microneedle array is strong enough to pierce the dura mater. The in-vitro biocompatibility test result showed that none of the 100 outlets of the microneedles exposed to the bloodstream were clogged significantly by blood cells. We believe that these test results demonstrate the potential use of the microneedle array as a new treatment of hydrocephalus. PMID- 25013305 TI - Towards an Automated MEMS-based Characterization of Benign and Cancerous Breast Tissue using Bioimpedance Measurements. AB - Micro-Electro-Mechanical-Systems (MEMS) are desirable for use within medical diagnostics because of their capacity to manipulate and analyze biological materials at the microscale. Biosensors can be incorporated into portable lab-on a-chip devices to quickly and reliably perform diagnostics procedure on laboratory and clinical samples. In this paper, electrical impedance-based measurements were used to distinguish between benign and cancerous breast tissues using microchips in a real-time and label-free manner. Two different microchips having inter-digited electrodes (10 um width with 10 um spacing and 10 um width with 30 um spacing) were used for measuring the impedance of breast tissues. The system employs Agilent E4980A precision impedance analyzer. The impedance magnitude and phase were collected over a frequency range of 100 Hz to 2 MHz. The benign group and cancer group showed clearly distinguishable impedance properties. At 200 kHz, the difference in impedance of benign and cancerous breast tissue was significantly higher (3110 Omega) in the case of microchips having 10 um spacing compared to microchip having 30 um spacing (568 Omega). PMID- 25013307 TI - Modelling of Binding Free Energy of Targeted Nanocarriers to Cell Surface. AB - We have developed a numerical model based on Metropolis Monte Carlo (MC) and the weighted histogram analysis method (WHAM) that enables the calculation of the absolute binding free energy between functionalized nanocarriers (NC) and endothelial cell (EC) surfaces. The binding affinities are calculated according to the free energy landscapes. The model predictions quantitatively agree with the analogous measurements of specific antibody coated NCs (100~nm in diameter) to intracellular adhesion molecule-1 (ICAM-1) expressing EC surface in in vitro cell culture experiments. The model also enables an investigation of the effects of a broad range of parameters that include antibody surface coverage of NC, glycocalyx in both in vivo and in vitro conditions, shear flow and NC size. Using our model we explore the effects of shear flow and reproduce the shear-enhanced binding observed in equilibrium measurements in collagen-coated tube. Furthermore, our results indicate that the bond stiffness, representing the specific antibody-antigen interaction, significantly impacts the binding affinities. The predictive success of our computational protocol represents a sound quantitative approach for model driven design and optimization of functionalized nanocarriers in targeted vascular drug delivery. PMID- 25013308 TI - Emotional intelligence and organizational effectiveness. PMID- 25013309 TI - Clinical management of alcohol withdrawal: A systematic review. AB - Alcohol withdrawal is commonly encountered in general hospital settings. It forms a major part of referrals received by a consultation-liaison psychiatrist. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on pharmacological management of alcohol withdrawal in humans with no limit on the date of publication. Articles not relevant to clinical management were excluded based on the titles and abstract available. Full-text articles were obtained from this list and the cross-references. There were four meta-analyses, 9 systematic reviews, 26 review articles and other type of publications like textbooks. Alcohol withdrawal syndrome is a clinical diagnosis. It may vary in severity. Complicated alcohol withdrawal presents with hallucinations, seizures or delirium tremens. Benzodiazepines have the best evidence base in the treatment of alcohol withdrawal, followed by anticonvulsants. Clinical institutes withdrawal assessment-alcohol revised is useful with pitfalls in patients with medical comorbidities. Evidence favors an approach of symptom-monitored loading for severe withdrawals where an initial dose is guided by risk factors for complicated withdrawals and further dosing may be guided by withdrawal severity. Supportive care and use of vitamins is also discussed. PMID- 25013310 TI - Internal consistency and factor structure of 12-item general health questionnaire in visually impaired students. AB - BACKGROUND: As there are no instruments to measure psychological wellness or distress in visually impaired students, we studied internal consistency and factor structure of GHQ-12 in visually impaired children. MATERIALS AND METHODS: Internal consistency analysis (Cronbach's alpha and item total correlation) and exploratory factor analysis (principal component analysis) were carried out to identify factor structure of 12-item general health questionnaire (GHQ-12). RESULTS: All items of GHQ-12 were significantly associated with each other and the Cronbach's alpha coefficient for the scale was 0.7. On analysis of principal component, three-factor solution was found that accounted for 47.92% of the total variance. The factors included, 'general well-being', 'depression' and 'cognitive', with Cronbach's alpha coefficients being 0.70, 0.59, and 0.34, respectively. CONCLUSION: Our study findings suggest GHQ-12 is a reliable with adequate internal consistency scale and multidimensional factor structure in visually impaired students. PMID- 25013311 TI - Nursing students' attitude toward suicide prevention. AB - BACKGROUND: Preventing suicide depends upon different health professionals' knowledge regarding suicide, attitude toward suicide attempters, skills to assess and manage suicidal risk. OBJECTIVES: This study was aimed to assess the attitude of nursing students toward suicide prevention. MATERIALS AND METHODS: 308 nursing students were recruited from the two institutions through total enumeration method. Attitude toward suicide prevention scale was administered. Study design was cross-sectional. RESULTS: Majority were single females, from urban locality, who were pursuing BSc Nursing with the mean age of 20 years. Only minority had previous exposure to suicide prevention programs or workshops. Nearly half of the subjects had positive attitude toward working with suicidal patients. Again half of the subjects considered unemployment and poverty as main causes of suicide and were quite hopeless about it and they also perceived that most of the suicidal people would not reveal their suicidal plans to others. CONCLUSIONS: Merely half of the students had positive attitude toward working with suicidal patients. Hence, there is strong need to organize more educational and training programs on suicide prevention so that these budding health professionals could be more equipped and trained to manage these suicidal patients. PMID- 25013312 TI - Racial differences in suicidal ideation among school going adolescents. AB - BACKGROUND: Young adults are at increased risk for suicidal behavior and there is growing concern about racial differences in suicidal ideation, especially in the younger population. AIM: The aim of this study is to assess suicidal ideation in school going tribal and nontribal adolescents and to study its relationships with psychological well-being, depression, and anxiety. MATERIALS AND METHODS: A total of 259 students of Classes X, XI, and XII of three Schools of Ranchi, who fulfilled inclusion and exclusion criteria, were screened for suicidal ideation by Suicidal Ideation Questionnaire (SIQ) and psychological well-being by General Health Questionnaire-12 (GHQ-12). The level of anxiety and depression was assessed by Hospital Anxiety Depression Scale (HADS). RESULTS: Overall 33.2% of the adolescents had suicidal ideation out of which 34.2% were tribal-students and 32.8% nontribal-students with no significant intergroup difference. Psychological discomfort (GHQ-12 Score >=3) was noticed in 59.1% of adolescents, but no racial difference was found. However, the mean HADS depression score was significantly higher in tribal adolescents, more so in tribal boys than nontribal adolescents or boys, respectively. There was a significant positive correlation of SIQ total score in all the adolescents with GHQ-12 total score, HADS total score, HADS anxiety score, and HADS depression score. CONCLUSION: There were no racial differences in suicidal ideation and psychological discomfort among tribal and nontribal adolescents. Tribal adolescents, and more specifically tribal boys, had more depression than their nontribal counterparts. Suicidal ideation was positively correlated with psychological discomfort, anxiety, and depression. PMID- 25013313 TI - Psychiatric morbidity in asymptomatic human immunodeficiency virus patients. AB - BACKGROUND: Psychiatric morbidity in human immunodeficiency virus (HIV) patients is being studied all over the world. There is paucity of Indian literature particularly in asymptomatic HIV individuals. AIM: The aim of the following study is to establish the prevalence and the determinants of psychiatric morbidity in asymptomatic HIV patients. MATERIALS AND METHODS: A cross-sectional study was undertaken to assess psychiatric morbidity as per ICD-10 dacryocystorhinostomy criteria in 100 consecutive asymptomatic seropositive HIV patients and an equal number of age, sex, education, economic and marital status matched HIV seronegative control. All subjects were assessed with the general health questionnaire (GHQ), mini mental status examination, hospital anxiety and depression scale (HADS) and sensation seeking scale (SSS) and the scores were analyzed statistically. RESULTS: Asymptomatic HIV positive patients had significantly higher GHQ caseness and depression but not anxiety on HADS as compared to HIV seronegative controls. On SSS asymptomatic HIV seropositive subjects showed significant higher scores in thrill and adventure seeking, experience seeking and boredom susceptibility as compared to controls. HIV seropositive patients had significantly higher incidence of total psychiatric morbidity. Among the individual disorders, alcohol dependence syndrome, sexual dysfunction and adjustment disorder were significantly increased compared with HIV seronegative controls. CONCLUSION: Psychiatric morbidity is higher in asymptomatic HIV patients when compared to HIV seronegative controls. Among the individual disorders, alcohol dependence syndrome, sexual dysfunction and adjustment disorder were significantly increased compared with HIV seronegative controls. High sensation seeking and substance abuse found in HIV seropositive patients may play a vital role in engaging in high-risk behavior resulting in this dreaded illness. PMID- 25013314 TI - Anxiety in school students: Role of parenting and gender. AB - BACKGROUND: The prevalence of anxiety is high in school going children; however pattern of parenting and gender of the child are important factors for the development of anxiety. Gender role and parenting patterns are important construct that vary across different sociocultural setting hence are important to be studied in Indian context. MATERIALS AND METHODS: In a cross sectional study all students of both sexes studying in class VIII, were assessed using the Spence anxiety scale (children version). RESULTS: The sample consisted of 146 (55% male and 45% female) with a mean age of 12.71 years. A total of 16 (11%) students scored above cutoff for high anxiety, the mean scores across gender shows that female students scored significantly higher in total and all sub types of anxiety. Most of the students perceived their parents 'Democratic' and other two authoritarian and permissive type of parenting were almost equal. There was significantly higher anxiety among the students who perceived their parents as authoritarian. CONCLUSIONS: The prevalence of high anxiety was 11% in class VIII students. High anxiety in students was significantly associated with female gender and authoritarian parenting pattern as perceived by the children. PMID- 25013315 TI - Family burden in injecting versus noninjecting opioid users. AB - BACKGROUND: A substance-dependent person in the family affects almost all aspects of family life that also impact the lives of the significant others and causes enormous burden. OBJECTIVES: This study was aimed to assess the pattern of burden borne by the family caregivers of patients with opioid-dependence-injecting drug users (IDU) and noninjecting drug users (NIDU). MATERIALS AND METHODS: A cross sectional study was conducted with ICD-10 diagnosed-opioid-dependent subjects (IDU and NIDU, N = 40 in each group) and their family caregivers attending a de addiction centre at a multispecialty teaching hospital in North India. Family Burden interview schedule was used to assess the pattern of burden borne by the family caregivers. RESULTS: The IDU group was characterized by older age, longer duration of substance dependence, greater subjective and objective family burden in all the areas compared to NIDU group, and single status and unemployment were associated with severe objective burden. The family burden was associated neither with age, education, or duration of dependence of the patients, nor with family size, type of caregiver or caregiver's education in either group. CONCLUSION: All caregivers reported a moderate or severe burden, which indicates the significance and need for further work in this area. PMID- 25013316 TI - Relationship of reasons and fears of treatment with outcome in substance using population attending a de-addiction centre. AB - BACKGROUND: Substance users approach a treatment facility for a variety of reasons as well as avoid or delay in help seeking due to perceived fears with treatment facilities. Sometimes these factors might be associated with treatment outcomes. OBJECTIVES: We studied the relationship of reasons and fears of treatment seeking with treatment outcome in substance users. MATERIALS AND METHODS: One hundred subjects, attending the Drug Deaddiction and Treatment Centre, PGIMER, were prospectively recruited by purposive sampling. A semistructured proforma was used to gather sociodemographic and clinical data. Reasons of help-seeking and fear questionnaire, social support scale, and PGI locus of control scale were then applied. Followup data were available for 69 patients, which were classified into good or poor outcome based on relapse status. RESULTS: At 6 months followup, 22 patients had relapsed, while 47 patients did not relapse. A higher degree of dysfunction due to substance at baseline was associated with relapsed status at followup. Parents or guardians coming to know about resuming substance and being unemployed for a long time were the reasons associated with relapsed status, while needing to consult a doctor immediately was significantly related to abstinent status at followup. Fear of not being able to meet substance using friends was associated with a poorer outcome in the form of relapse. CONCLUSIONS: Reasons for treatment seeking as well as fears related to treatment have significant implications on the clinical outcome of substance abusing patients. Addressing these could help in better patient outcomes. PMID- 25013317 TI - An open-label trial of memantine in treatment-resistant obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is often refractory to treatment. Glutamatergic neurotransmission modulating agents like memantine, an N-methyl-D aspartate receptor open channel blocker (antagonist), has been reported to be beneficial in OCD. MATERIALS AND METHODS: Twelve subjects of OCD who had been on various medications for over 5 years, but were poor responders, were enrolled for a 12-week open-label trial with fixed dose trial of memantine as an augmenting agent. The OCD symptoms and adverse effects of the drug were monitored. RESULTS: Out of 12 subjects, eight had clear benefit, with reduction of 25% or more on Yale-Brown Obsessive-Compulsive Scale, and there were no side-effects with the medication. CONCLUSION: Memantine may be beneficial for treatment-resistant OCD as an augmenting agent. PMID- 25013318 TI - Neuropsychiatric manifestations of Fahr's disease pathogenesis and potential for treatment. AB - Fahr's disease (FD) is a rare neuropsychiatric disease consisting of bilateral basal ganglia calcification with neurological, cognitive, and psychiatric manifestations. We report here a sporadic case of FDs with its neuropsychology. PMID- 25013319 TI - Juvenile obsessive-compulsive disorder: A case report. AB - Obsessive-compulsive disorder (OCD) is one of the more disabling and potentially chronic anxiety disorders that occurs in several medical settings. However, it is often under-recognized and under-treated. The condition is now known to be prevalent among children and adolescents. Obsessional images as a symptom occur less frequently than other types of obsessions. In this report, we describe a young boy who presented himself predominantly with obsessional images. The diagnostic and treatment challenges in juvenile OCD are discussed. PMID- 25013320 TI - Acute psychosis: A neuropsychiatric dilemma. AB - The acute onset of psychotic symptoms in elderly can be the presenting clinical feature for various Central Nervous System as well as other systemic illnesses. The diagnosis and treatment of such presentation require a cautious medical work up and high level of suspicion even if the patient is not showing any cardinal symptoms for organic pathology. PMID- 25013321 TI - Olanzapine-induced neuroleptic malignant syndrome in a patient with bipolar affective disorder: Does quetiapine holds the solution? AB - Neuroleptic Malignant Syndrome (NMS) is a rare, severe and life threatening condition induced by antipsychotic medications. It is commonly encountered with the use of first generation antipsychotics, however cases of NMS have been reported with the use of second generation antipsychotics like Olanzapine, Risperidone, Paliperidone, Aripiprazole, Ziprasidone, Amisulpride, Quetiapine and Clozapine, though the incidence of such reports is rare. Due to decreased use of first generation antipsychotics, NMS is reported less frequently now a days. In this case report- we highlight the management issues of a patient suffering from bipolar affective disorder, who had developed NMS following intramuscular injection of haloperidol, which was withdrawn and olanzapine was given later on. The patient had again developed NMS with olanzapine. Finally the patient was managed with modified electroconvulsive therapy and discharged on Lithium carbonate and Quetiapine. PMID- 25013322 TI - Assessment of prevalence of tobacco consumption among psychiatric inmates residing in Central Jail, Bhopal, Madhya Pradesh, India: A cross-sectional survey. AB - AIM: The aim of the current cross-sectional study was to assess the prevalence of tobacco consumption among psychiatric jail patients residing in Central Jail, Bhopal, Madhya Pradesh, India. MATERIALS AND METHODS: The study subjects consisted of prediagnosed psychiatric patients residing in Central Jail, Bhopal, Madhya Pradesh, India. A matched control consisting of cross-section of the population, that is, jail inmates residing in the same Central Jail locality was also assessed to compare the psychiatric subjects. An 18 item questionnaire was used to assess the prevalence of tobacco consumption among study subjects. RESULTS: The total number of subjects examined was 244, which comprised of 122 psychiatric inmates and 122 nonpsychiatric inmates. Among all psychiatric inmates, about 57.4% of inmates had a diagnosis of depression, 14.8% had psychotic disorders (such as schizophrenia), and 12.3% had anxiety disorder. A total of 77% study inmates, which comprised of 87.7% psychiatrics and 66.4% nonpsychiatrics had a habit of tobacco consumption (smokeless or smoking). CONCLUSION: The information presented in this study adds to our understanding of the common tobacco related practices among psychiatric inmate population. Efforts to increase patient awareness of the hazards of tobacco consumption and to eliminate the habit are needed to improve oral and general health of the prison population. PMID- 25013323 TI - Response to article: Stress and periodontal disease: The link and logic!! PMID- 25013324 TI - Enhanced recovery after surgery in laparoscopic gastric cancer surgery: Many questions, few answers. PMID- 25013325 TI - Single incision laparoscopic hepatectomy: A systematic review. AB - Single incision laparoscopic surgery is a rather innovative surgical technique. A systematic literature review was performed with the intention to evaluate the till now clinical evidence regarding the application of single incision technique on liver resections as a method of management in hepatic lesions. Twelve relative studies were found in the field including 30 patients with a age range from 29 to 90 years and a body mass index from 20.1 to 36.5 kg/m(2). Primary hepatic carcinoma (40%), metastatic nodules (26.7%), hepatic cysts (16.7%), hepatic haemangiomas (13.3%) and hepatic adenoma (3.3%) were the most common indications of the lesions resected. The types of hepatectomy performed included partial hepatectomy (43.3%), segmentectomy (30%) and lobectomy (26.7%). In the majority of the patients, left lateral segments (II-III-IV) (76.7%) were resected. The median operative time was 110 min (range: 55-235) while the median quantity of blood loss was 50 ml (range: 0-100). No conversion to open surgery and no transfusion were needed. The duration of hospital stay ranged between 2 and 11 days. No complications, no cases of disease recurrence or death of patients were reported. None of the studies included described data on the cosmesis of the application of single incision laparoscopic technique on hepatic resections. Moreover, the surgical technique, as well as the different type of ports used is also presented in this review. Single site port laparoscopic surgery is a promising minimally invasive procedure for liver resections. PMID- 25013326 TI - Spillage-free laparoscopic management of hepatic hydatid disease using the hydatid trocar canula. AB - INTRODUCTION: This study was undertaken to demonstrate the efficacy of the Hydatid Trocar Canula system for safe and effective treatment of hepatic hydatid cysts. MATERIALS AND METHODS: All cases presenting to our centre for treatment of hydatid cyst of the liver with certain exceptions were considered for laparoscopic management using the specifically designed Hydatid Trocar Canula system. The technique of surgery and the step wise sequence of deployment of the device are described. RESULTS: Since January 2007, 16 patients compromising six males and 10 females underwent this procedure at our centre. The average age of the patients was 37.6 years and all of them had a single cyst. The average duration of surgery was 86 minutes. None of the cases suffered intraoperative mishap like spillage or anaphylaxis. Till date, follow-up has been maintained in 81.3% of the patients and no recurrence has been detected. CONCLUSION: The correct use of the Hydatid Trocar Canula system allows for spillage-free and complete evacuation of hepatic hydatid cysts. PMID- 25013327 TI - The voice of Holland: Dutch public and patient's opinion favours single-port laparoscopy. AB - INTRODUCTION: Single-port laparoscopy is prospected as the future of minimal invasive surgery. It is hypothesised to cause less post operative pain, with a shorter hospitalisation period and improved cosmetic results. Population- and patient-based opinion is important for the adaptation of new techniques. This study aimed to assess the opinion and perception of a healthy population and a patient population on single-port laparoscopy compared with conventional laparoscopy. MATERIALS AND METHODS: An anonymous 33-item questionnaire, describing conventional and single-port laparoscopy, was given to 101 patients and 104 healthy volunteers. The survey participants (median age 44 years; range 17-82 years) were asked questions about their personal situation and their expectations and perceptions of the two different surgical techniques; conventional multi-port laparoscopy and single-port laparoscopy. RESULTS: A total of 72% of the participants had never heard of single-port laparoscopy before. The most important concern in both groups was the risk of surgical complications. When complication risks remain similar, 80% prefers single-port laparoscopy to conventional laparoscopy. When the risk of complications increases from 1% to 10%, 43% of all participants prefer single-port laparoscopy. A total of 70% of the participants are prepared to receive treatment in another hospital if single port surgery is not performed in their hometown hospital. The preference for single-port approach was higher in the female population. CONCLUSION: Although cure and safety remain the main concerns, the population and patients group have a favourable perception of single-port surgery. The impact of public opinion and patient perception towards innovative techniques is undeniable. If the safety of the two different procedures is similar, this study shows a positive attitude of both participant groups in favour of single-port laparoscopy. However, solid scientific proof for the safety and feasibility of this new surgical technique needs to be obtained before this procedure can be implemented into everyday practice. PMID- 25013328 TI - Laparoscopic necrosectomy in acute necrotizing pancreatitis: Our experience. AB - CONTEXT: Pancreatic necrosis is a local complication of acute pancreatitis. The development of secondary infection in pancreatic necrosis is associated with increased mortality. Pancreatic necrosectomy is the mainstay of invasive management. AIMS: Surgical approach has significantly changed in the last several years with the advent of enhanced imaging techniques and minimally invasive surgery. However, there have been only a few case series related to laparoscopic approach, reported in literature to date. Herein, we present our experience with laparoscopic management of pancreatic necrosis in 28 patients. MATERIALS AND METHODS: A retrospective study of 28 cases [20 men, 8 women] was carried out in our institution. The medical record of these patients including history, clinical examination, investigations, and operative notes were reviewed. The mean age was 47.8 years [range, 23-70 years]. Twenty-one patients were managed by transgastrocolic, four patients by transgastric, two patients by intra-cavitary, and one patient by transmesocolic approach. RESULTS: The mean operating time was 100.8 min [range, 60-120 min]. The duration of hospital stay after the procedure was 10-18 days. Two cases were converted to open (7.1%) because of extensive dense adhesions. Pancreatic fistula was the most common complication (n = 8; 28.6%) followed by recollection (n = 3; 10.7%) and wound infection (n = 3; 10.7%). One patient [3.6%] died in postoperative period. CONCLUSIONS: Laparoscopic pancreatic necrosectomy is a promising and safe approach with all the benefits of minimally invasive surgery and is found to have reduced incidence of major complications and mortality. PMID- 25013329 TI - Early rehabilitation after surgery program versus conventional care during perioperative period in patients undergoing laparoscopic assisted total gastrectomy. AB - OBJECTIVE: To evaluate the safety and efficacy of early rehabilitation after surgery program (ERAS) in patients undergoing laparoscopic assisted total gastrectomy. MATERIALS AND METHODS: This is a study where 47 patients who are undergoing lap assisted total gastrectomy are selected. Twenty-two (n = 22) patients received enhanced recovery programme (ERAS) management and rest twenty five (n = 25) conventional management during the perioperative period. The length of postoperative hospital stay, time to passage of first flatus, intraoperative and postoperative complications, readmission rate and 30 day mortality is compared. Serum levels of C-reactive protein pre-operatively and also on post-op day 1 and 3 are compared. RESULTS: Postoperative hospital stay is shorter in ERAS group (78 +/- 26 h) when compared to conventional group (140 +/- 28 h). ERAS group passed flatus earlier than conventional group (37 +/- 9 h vs. 74 +/- 16 h). There is no significant difference in complications between the two groups. Serum levels of CRP are significantly low in ERAS group in comparison to conventional group. [d1 (52.40 +/- 10.43) g/L vs. (73.07 +/- 19.32) g/L, d3 (126.10 +/- 18.62) g/L vs. (160.72 +/- 26.18) g/L)]. CONCLUSION: ERAS in lap-assisted total gastrectomy is safe, feasible and efficient and it can ameliorate post-operative stress and accelerate postoperative rehabilitation in patients with gastric cancer. Short term follow up results are encouraging but we need long term studies to know its long term benefits. PMID- 25013330 TI - Randomised study on single stage laparo-endoscopic rendezvous (intra-operative ERCP) procedure versus two stage approach (Pre-operative ERCP followed by laparoscopic cholecystectomy) for the management of cholelithiasis with choledocholithiasis. AB - INTRODUCTION: The 'Rendezvous' technique consists of laparoscopic cholecystectomy (LC) standards with intra-operative cholangiography followed by endoscopic sphincterotomy. The sphincterotome is driven across the papilla through a guidewire inserted by the transcystic route. In this study, we intended to compare the two methods in a prospective randomised trial. MATERIALS AND METHODS: From 2005 to 2012, we enrolled 83 patients with a diagnosis of cholecysto choledocolithiasis. They were randomised into two groups. In 'group-A',41 patients were treated with two stages management, first by pre-operative endoscopic retrograde cholangiopancreatography (ERCP) and common bile duct (CBD) clearance and second by LC. In 'group-B', 42 patients were treated with LC and intra-operative cholangiography; and when diagnosis of choledocholithiasis was confirmed, patients had undergone one stage management of by Laparo-endoscopic Rendezvous technique. RESULTS: In arm-A and arm-B groups, complete CBD clearance was achieved in 29 and 38 patients, respectively. Failure of the treatment in arm A was 29% and in arm-B was 9.5%. In arm-A, selective CBD cannulation was achieved in 33 cases (80.5%) and in arm-B in 39 cases (93%). In arm-Agroup, post-ERCP hyperamylasia was presented in nine patients (22%) and severe pancreatitis in five patients (12%) versus none of the patients (0%) in arm-B group, respectively. Mean post-operative hospital stay in arm-A and arm-B groups are 10.9 and 6.8 days, respectively. CONCLUSION: One stage laparo-endoscopic rendezvous approach increases selective cannulation of CBD, reduces post-ERCP pancreatitis, reduces days of hospital stay, increases patient's compliance and prevents unnecessary intervention to CBD. PMID- 25013331 TI - "Down-to-Up" transanal NOTES Total mesorectal excision for rectal cancer: Preliminary series of 9 patients. AB - BACKGROUND: Applications for natural orifice translumenal endoscopic surgery (NOTES) to access the abdominal cavity have increased in recent years. Despite potential advantages of transanal and transcolonic NOTES for colorectal pathology, it has not been widely applied in the clinical setting. This study describes a series of nine patients for whom we performed transanal retrograde ("Down-to-Up") total mesorectal excision for rectal cancer. MATERIALS AND METHODS: Under IRB approval, informed consent was obtained from each patient with rectal adenocarcinoma. Rectosigmoidectomy with total mesorectal excision was performed using low rectal translumenal access to the mesorectal fascia and subsequent dissection in a retrograde fashion. This was achieved using either a single port device or flexible colonoscope with endoscopic instrumentation and laparoscopic assistance. This was followed by transanal extraction of the specimen and hand-sewn anastomosis. RESULTS: Mean operative time was 311 min. Mean hospital stay was 7.56 days. Complications occurred in two patients, and consisted of one anastomotic leakage with reoperation and one intraoperative conversion to open surgery because of impossibility to dissect the specimen. TME specimen integrity was adequate in six patients. CONCLUSION: This series suggests that a retrograde mesorectal dissection via a NOTES technique is feasible in patients with rectal adenocarcinoma. This technique may act as a complimentary part of operative treatment for rectal cancer alongside other minimally invasive strategies. Long-term follow up will be needed to assess oncological results. PMID- 25013332 TI - Laparoscopic excision of large ciliated hepatic foregut cyst. AB - Ciliated hepatic foregut cysts (CHFCs) are rare congenital cysts of the liver that originate from the embryologic foregut. Despite an increase in incidence, they remain rare and several key characteristics remain poorly understood, including the range of presentation and the risk of malignant conversion. Large, symptomatic cysts and small asymptomatic, atypical cysts should be resected. We present a patient who recently underwent laparoscopic excision of a CHFC, review the literature and propose the rationale for attempting removal of these cysts through a laparoscopic approach. PMID- 25013333 TI - Complete laparoscopic removal of a gastric trichobezoar. AB - Trichobezoars are seen usually in adolescent girls and laparotomy is required to remove them, though recently laparoscopic assisted and laparoscopic removal have been reported in adults and older children. We report this 4-year-old boy who underwent complete laparoscopic removal of a gastric trichobezoar, both for its rarity in such young boys and also because he is the youngest reported patient to undergo complete laparoscopic removal of a gastric trichobezoar. PMID- 25013334 TI - Asymptomatic intraperitoneal ascariasis: Importance of diagnostic laparoscopy. AB - Migration of Ascaris from intestine into peritoneal cavity is rare and usually presents as acute abdomen. We report a case of 41-year-old male who was admitted for laparoscopic mesh rectopexy for rectal prolapse. During the initial laparoscopy, purulent fluid was seen in pelvis. A complete diagnostic laparoscopy was done. An omental nodule was found, which was excised and extracted in a bag. On histopathology, the omental nodule revealed gravid Ascaris lumbricoides. PMID- 25013335 TI - Meralgia paraesthetica: Laparoscopic surgery as a cause then and a cure now. AB - Meralgia Paraesthetica (MP) is a rare condition, in which the patient experiences a burning sensation along the distribution of the lateral femoral cutaneous nerve of the thigh, due to entrapment neuropathy at the lateral end of the inguinal ligament as it exits the pelvis. There are several causes of this condition including laparoscopic inguinal hernioplasty. Diagnosed clinically, intervention is indicated for failed conservative measures. We herewith report a patient with MP and symptomatic cholelithiasis, treated for both laparoscopically. This is the third reported case in the literature that has been treated laparoscopically. PMID- 25013336 TI - Primary laparoscopic cholecystectomy in patients with portal cavernoma and non obstructive portal biliopathy: Two case reports. AB - A laparoscopic cholecystectomy can be technically challenging with co-existing portal hypertension, as commonly seen with cirrhosis of the liver. Extra hepatic portal vein obstruction (EHPVO) although less common, is a significant cause of portal hypertension in India. EHPVO has a unique clinical profile, which differentiates it from portal hypertension associated with cirrhosis of the liver. This impacts therapy in EHPVO algorithmically and operatively. We report two cases of symptomatic gall stones with portal cavernoma. Further evaluation revealed non-obstructive portal biliopathy. Both underwent a successful laparoscopic cholecystectomy. We highlight the importance of careful operative strategy, diligent haemostasis and the feasibility of performing a laparoscopic cholecystectomy in patients with symptomatic gall stones associated with a portal cavernoma. PMID- 25013337 TI - Retention of an endoscopic capsule. AB - Capsule endoscopy is a highly advanced, newer technology to look for small bowel diseases. But it has certain contraindications such as bowel narrowing, strictures that have to be ruled out on Barium studies or with computed tomography. We present a rare case of retention of endoscopic capsule even after ruling out stricture or bowel thickening on radiological imaging. PMID- 25013338 TI - Laparoscopic repair of a small bowel herniation through a broad ligament defect. AB - A 44-year-old female presented with a diagnosis of intestinal obstruction from unknown origin. Laparoscopy revealed herniation of small bowel trough a defect in the left broad ligament. After reduction, the defect was corrected laparoscopically. The post operative recovery was uneventful. PMID- 25013339 TI - Wound healing: The presiding deity of surgery. PMID- 25013340 TI - Goel's classification of atlantoaxial "facetal" dislocation. PMID- 25013341 TI - Morphometric analysis of the cervical facets and the feasibility, safety, and effectiveness of Goel inter-facet spacer distraction technique. AB - AIM: Quantitative anatomy of the facets of the sub-axial cervical spine was performed. The purpose of the evaluation was to determine the feasibility of insertion of Goel inter-facetal articular spacers in the sub-axial cervical spine. Only few studies detailing the morphometry of the facets are available in the literature. MATERIALS AND METHODS: Ten cervical vertebrae from C3 to C7 with a total of 20 facets were evaluated by the author. The anatomic parameters studied were the height, width, thickness, shape, orientation, and inclination of each of the superior and inferior facets. The alterations in a number of intervertebral segmental distances were measured before and after spacer insertion. The distance of the inferior facet from the foramen tranversarium, spinal canal, and neural foramina was measured to assess safety of spacer insertion with respect to the vertebral artery and neural structures. RESULTS: The height, width and thickness of the superior facets from C3 to C7 ranged from 6 to 12 mm, 8 to 12 mm, and 2.5 to 6 mm, respectively. The inferior facets had an average height of 10.5 mm, average width of 11.2 mm and average thickness of 3.5 mm. The inclination of the superior facets with respect to the transverse plane ranged from 22 degrees to 45 degrees and that of the inferior facets ranged from 29 degrees to 53 degrees . The distance of the anterior margin of the inferior facet from the posterior border of the foramen transversium ranged from 5 to 7 mm. This distance was maximum at C3 level, then decreased at C4 and remained constant from C5 to C7. CONCLUSION: This anatomic evaluation aided in understanding the morphology of the cervical facets and the suitability of the cervical facetal articular cavity for insertion of spacers. PMID- 25013342 TI - Only fixation for lumbar canal stenosis: Report of an experience with seven cases. AB - STUDY DESIGN AND OBJECTIVE: The author reports experience with treatment of degenerative lumbar canal stenosis that involved fixation-arthrodesis of the affected spinal segment using "double insurance" transarticular screws for each joint. No direct bone, ligament or disc resection is done for decompression of the spinal dural tube or root canal. METHODS AND SUMMARY OF BACKGROUND DATA: During the period March 2011-September 2011, seven patients having lumbar canal stenosis were treated with a modification of transarticular method of screw fixation that involved insertion of two or "double insurance" screws at each articular joint. The operation involved section of the spinous process at its base, opening up of the facet joint, denuding of articular cartilage, insertion of intra-articular bone graft and insertion of two transarticular screws at each facet joint. The fixation was done in four levels in two patients, at three levels in four patients and at two levels in one patient. Oswestry disability index and visual analog scale were used to clinically assess the patients before and after the surgery and at follow-up. RESULTS: During the average period of follow-up of 26.9 months (range 24-30 months), there was varying degree of recovery of symptoms. The procedure resulted in firm stabilization and fixation of the spinal segment and provided a ground for arthrodesis. During the period of follow-up, one patient underwent re-exploration and decompressive laminectomy as she continued to have significant pain symptom. CONCLUSIONS: Vertical instability and telescoping, listhesis or overriding of the facets on physical activity seems to be the defining phenomenon in the pathogenesis of lumbar canal stenosis. The clinical outcome in our patients suggest that fixation of the spinal segment can be a rationale form of treatment. "Double insurance" transarticular method of treatment is a simple, safe, and effective method of spinal stabilization. PMID- 25013343 TI - Primary paraganglioma of the spine: A clinicopathological study of eight cases. AB - CONTEXT: Spinal paragangliomas are rare neuroendocrine tumors of the extra adrenal paraganglionic system. AIMS: This study describes the clinicopathological features of eight cases of spinal paraganglioma and highlights the significance of important morphological features and immunohistochemistry in the diagnosis of paraganglioma at this unusual site. MATERIAL AND METHODS: All the cases of primary spinal paragangliomas diagnosed during the last six years (2008-2013) in the Department of Pathology at our hospital were reviewed. RESULTS: There were six males and two females. The mean age at diagnosis was 50.4 years. All patients presented with low back pain. All tumors were located in the cauda equina or conus medullaris region. Magnetic Resonance Imaging and intraoperative appearance were that of a vascular, well-circumscribed intradural, extramedullary tumor suggestive of either schwannoma or ependymoma. All the patients underwent gross total resection of the tumor. Histopathology in five of the cases showed 'ependymoma-like histology' while only three cases had a predominant classic 'zellballen' pattern. Two cases had prominent 'gangliocytic differentiation'. In the five cases with 'ependymoma-like histology', the diagnosis was confirmed on Immunohistochemistry (IHC). CONCLUSIONS: Even though relatively rare, paraganglioma should be considered in the differential diagnosis of spinal tumors and due to their clinical, radiological and histopathological similarity to schwannoma and ependymoma, the diagnosis should be based on close examination of the clinical, radiological and pathological findings. PMID- 25013344 TI - Orthosis for thoracolumbar burst fractures without neurologic deficit: A systematic review of prospective randomized controlled trials. AB - BACKGROUND: Traditionally, conservative treatment of thoracolumbar (TL) burst fractures without neurologic deficit has encompassed the application of an extension brace. However, their effectiveness on maintaining the alignment, preventing posttraumatic deformities, and improving back pain, disability and quality of life is doubtful. OBJECTIVE: The objective was to identify and summarize the evidence from randomized controlled trials (RCTs) to determine whether bracing patients who suffer TL fractures adds benefices to the conservative manage without bracing. MATERIALS AND METHODS: Seven databases were searched for relevant RCTs that compared the clinical and radiological outcomes of orthosis versus no-orthosis for TL burst fractures managed conservatively. Primary outcomes were: (1) Loss of kyphotic angle; (2) failure of conservative management requiring subsequent surgery; and (3) disability and pain outcomes. Secondary outcomes were defined by health-related quality of life and in-hospital stay. RESULTS: Based on predefined inclusion criteria, only two eligible high quality RCTs with a total of 119 patients were included. No significant difference was identified between the two groups regarding loss of kyphotic angle, pain outcome, or in-hospital stay. The pooled data showed higher scores in physical and mental domains of the Short-Form Health Survey 36 in the group treated without orthosis. CONCLUSION AND RECOMMENDATION: The current evidence suggests that orthosis could not be necessary when TL burst fractures without neurologic deficit are treated conservatively. However, due to limitations related with number and size of the included studies, more RCTs with high quality are desirable for making recommendations with more certainty. PMID- 25013345 TI - Unilateral atlanto-axial fractures in near side impact collisions: An under recognized entity in cervical trauma. AB - OBJECTIVE: Nearside impact collisions presenting with lateral mass fractures of atlanto-axial vertebrae contralateral to the impact site represents a rare fracture pattern that does not correlate with previously described injury mechanism. We describe our clinical experience with such fractures and propose a novel description of biomechanical forces involved in this unique injury pattern. The findings serve to alert clinicians to potentially serious consequences of associated unrecognized and untreated vertebral artery injury. MATERIAL AND METHODS: In addition to describing our clinical experience with three of these fractures, a review of Crash Injury Research and Engineering Network (CIREN) database was conducted to further characterize such fractures. A descriptive analysis of three recent lateral mass fractures of the atlanto-axial segment is coupled with a review of the CIREN database. A total of 4047 collisions were screened for unilateral fractures of atlas or axis. Information was screened for side of impact and data regarding impact velocity, occupant injuries and use of restraints. RESULTS: Following screening of unilateral fractures of atlas and axis for direct side impacts, 41 fractures were identified. Cross referencing these cases for occurrence contralateral to side of impact identified four such fractures. Including our recent clinical experience, seven injuries were identified: Five C1 and two C2 fractures. Velocity ranged from 14 to 43 km/h. Two associated vertebral artery injuries were identified. CONCLUSIONS: Complexity of the atlanto-axial complex is responsible for a sequence of events that define load application in side impacts. This study demonstrates the vulnerability of vertebral artery to injury under unique translational forces and supports the use or routine screening for vascular injury. Diminished sensitivity of plain radiography in identifying these injuries suggests that computerized tomography should be used in all patients wherein a similar pattern of injury is suspected. PMID- 25013346 TI - The surgical management of the rheumatoid spine: Has the evolution of surgical intervention changed outcomes? AB - CONTEXT: Surgery for the rheumatoid cervical spine has been shown to stabilize the unstable spine; arrest/improve the progression of neurological deficit, help neck pain, and possibly decelerate the degenerative disease process. Operative intervention for the rheumatoid spine has significantly changed over the last 30 years. AIMS: The purpose of this study was to review all cases of cervical rheumatoid spine requiring surgical intervention in a single unit over the last 30 years. MATERIALS AND METHODS: A prospectively-maintained spine database was retrospectively searched for all cases of rheumatoid spine, leading to a review of indications, imaging, Ranawat and Myelopathy Disability Index measures, surgical morbidity, and survival curve analysis. RESULTS: A total of 224 cases were identified between 1981 and 2011. Dividing the data into three time-epochs, there has been a significant increase in the ratio of segment-saving Goel-Harms C1-C2: Occipitocervical fixation (OCF) surgery and survival has increased between 1981 and 2011 from 30% to 51%. Patients undergoing C1-C2 fixation were comparatively less myelopathic and in a better Ranawat class preoperatively, but postoperative outcome measures were well-preserved with favorable mortality rates over mean 39.6 months of follow-up. However, 11% of cases required OCF at mean 28 months post-C1-C2 fixation, largely due to instrumentation failure (80%). CONCLUSION: We present the largest series of surgically managed rheumatoid spines, revealing comparative data on OCF and C1-C2 fixation. Although survival has improved over the last 30 years, there have been changes in medical, surgical and perioperative management over that period of time too confounding the interpretation; however, the analysis presented suggests that rheumatoid patients presenting early in the disease process may benefit from C1 to C2 fixation, albeit with a proportion requiring OCF at a later time. PMID- 25013347 TI - (68)Ga-DOTATATE-positron emission tomography imaging in spinal meningioma. AB - Imaging with positron emission tomography (PET) and (68)Ga-DOTA peptides is a promising method in intracranial meningiomas. Especially in recurrent meningioma discrimination between scar tissue and recurrent tumor tissue in magnetic resonance imaging (MRI) is often difficult. We report the first case of (68)Ga DOTATATE-PET/computed tomography (PET/CT) imaging in recurrent spinal meningioma. A 64-year-old Caucasian female patient was referred to our department with the second recurrence of thoracic meningothelial meningioma. In MRI, it remained unclear if the multiple enhancements seen represented scar tissue or vital tumor. We offered (68)Ga-DOTATATE-PET/CT imaging in order to evaluate the best strategy. (68)Ga-DOTATATE-PET/CT imaging revealed strong tracer uptake in parts of the lesions. The pattern did distinctly differ from MRI enhancement. Multiple biopsies were performed in the PET-positive and PET-negative regions. Histological results confirmed the prediction of (68)Ga-DOTATATE-PET with vital tumor in PET-positive regions and scar tissue in PET-negative regions. Differentiating scar tissue from tumor can be challenging in recurrent spinal meningioma with MRI alone. In the presented case, (68)Ga-DOTATATE-PET imaging was able to differentiate noninvasively between tumor and scar. PMID- 25013348 TI - Syringomyelia and spinal arachnoiditis resulting from aneurysmal subarachnoid hemorrhage: Report of two cases and review of the literature. AB - Syringomyelia resulting from arachnoiditis secondary to aneurysmal subarachnoid hemorrhage (SAH) is an extremely rare clinical entity with few cases reported in the literature. The presentation, management, and pathogenesis of syringomyelia in this setting is poorly understood. We describe the presentation, radiology, management, and outcomes in two patients with syringomyelia resulting from arachnoiditis secondary to aneurysmal SAH and review the literature on this rare condition. Case number 1 was treated successfully with syrinx-subarachnoid shunt after extensive lysis of adhesions. Case number 2 was treated with syringoperitoneal shunt. Both patients had radiographic decreased syrinx size postoperatively. These patients add to the small literature on syringomyelia occurring secondary to SAH-associated arachnoiditis. The radiographic outcomes demonstrate that in the appropriately selected patient, syrinx-subarachnoid or syringoperitoneal shunting are viable options. PMID- 25013349 TI - Thyroid storm following anterior cervical spine surgery for Koch's spine. AB - The primary objective was to report this rare case and discuss the probable mechanism of thyroid storm following anterior cervical spine surgery for Kochs cervical spine. PMID- 25013350 TI - Assessment of long-term kyphosis following transthoracic corpectomy with single adjacent level posterior instrumentation. AB - Anterior thoracic spinal instrumentation has traditionally been supported by a posterior thoracic construct spanning from at least two levels above to two levels below; however, instrumentation at a single-level above and below may be adequate to support such a construct. We report two cases of transthoracic corpectomy with short-segment posterior fixation with success in long-term stabilization. Two patients with thoracic vertebral malignancy resulting in spinal deformity and spinal cord compression underwent transthoracic corpectomy with placement of an expandable cage proceeded by posterior fixation one level above and one level below. Using the Cobb angle, the degree of kyphosis was measured at 3, 6, and 12 months postoperatively. Long-term spinal stabilization was achieved in both patients. There was no significant increase in kyphosis and no evidence of hardware failure in either patient during the follow-up period. Transthoracic corpectomy with supplementary posterior fixation one level above and below may be adequate to stabilize the spine. PMID- 25013351 TI - Molecular determinants of ligand binding at the human histamine H1 receptor: Site directed mutagenesis results analyzed with ligand docking and molecular dynamics studies at H1 homology and crystal structure models. AB - The human histamine H1 G-protein coupled receptor (GPCR) is an important drug target for inflammatory, sleep, and other neuropsychiatric disorders. To delineate molecular determinants for ligand binding for drug discovery purposes, human H1 receptor models were built by homology to the crystal structure of the human beta2 adrenoceptor (beta2AR) and from the recently reported crystal structure of the human H1 receptor complex with doxepin at 3.1 A (PDB code 3RZE). Ligand affinity of histamine and the H1 antagonists mepyramine and (2S, 4R)-(-) trans-4-phenyl-2-N, N-dimethylaminotetralin (PAT) at wild type and point-mutated (D3.32A, Y3.33A, W4.56A, F5.47A, W6.48A, Y6.51A, F6.52A, F6.55A, Y7.43A) human H1 receptors were determined experimentally and results analyzed by ligand docking and molecular dynamic studies at WT and point-mutated H1 receptor models. Differences in ligand binding affinities correlated to differences in ligand binding modes at models built according to homology or crystal structure, indicating, both models are accurate templates for predicting ligand affinity for H1 drug design. PMID- 25013352 TI - Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer. AB - Inflammatory pathway plays an important role in tumor cell progression of colorectal cancers. Although colon cancer is considered as one of the leading causes of death worldwide, very few drugs are available for its effective treatment. Many studies have examined the effects of specific COX-2 and 5-LOX inhibitors on human colorectal cancer, but the role of isothiocyanates (ITSCs) as COX-LOX dual inhibitors engaged in hyaluronan-CD44 interaction has not been studied. In the present work, we report series of ITSC analogs incorporating bioisosteric thiosemicarbazone moiety. These inhibitors are effective against panel of human colon cancer cell lines including COX-2 positive HCA-7, HT-29 cells lines, and hyaluronan synthase-2 (Has2) enzyme over-expressing transformed intestinal epithelial Apc10.1Has2 cells. Specifically, our findings indicate that HA-CD44v6-mediated COX-2/5-LOX signaling mediate survivin production, which in turn, supports anti-apoptosis and chemo-resistance leading to colon cancer cell survival. The over-expression of CD44v6shRNA as well as ITSC treatment significantly decreases the survival of colon cancer cells. The present results thus offer an opportunity to evolve potent inhibitors of HA synthesis and CD44v6 pathway and thus underscoring the importance of the ITSC analogs as chemopreventive agents for targeting HA/CD44v6 pathway. PMID- 25013354 TI - Modeling Change in the Presence of Non-Randomly Missing Data: Evaluating A Shared Parameter Mixture Model. AB - In longitudinal research, interest often centers on individual trajectories of change over time. When there is missing data, a concern is whether data are systematically missing as a function of the individual trajectories. Such a missing data process, termed random coefficient-dependent missingness, is statistically non-ignorable and can bias parameter estimates obtained from conventional growth models that assume missing data are missing at random. This paper describes a shared-parameter mixture model (SPMM) for testing the sensitivity of growth model parameter estimates to a random coefficient-dependent missingness mechanism. Simulations show that the SPMM recovers trajectory estimates as well as or better than a standard growth model across a range of missing data conditions. The paper concludes with practical advice for longitudinal data analysts. PMID- 25013353 TI - Claudin Proteins And Neuronal Function. AB - The identification and characterization of the claudin family of tight junction (TJ) proteins in the late 1990s ushered in a new era for research into the molecular and cellular biology of intercellular junctions. Since that time, TJs have been studied in the contexts of many diseases including deafness, male infertility, cancer, bacterial invasion and liver and kidney disorders. In this review, we consider the role of claudins in the nervous system focusing on the mechanisms by which TJs in glial cells are involved in neuronal function. Electrophysiological evidence suggests that claudins may operate in the central nervous system (CNS) in a manner similar to polarized epithelia. We also evaluate hypotheses that TJs are the gatekeepers of an immune-privileged myelin compartment and that TJs emerged during evolution to form major adhesive forces within the myelin sheath. Finally, we consider the implications of CNS myelin TJs in the contexts of behavioral disorders (schizophrenia) and demyelinating/hypomyelinating diseases (multiple sclerosis and the leukodystrophies), and explore evidence of a possible mechanism governing affective disorder symptoms in patients with white matter abnormalities. PMID- 25013356 TI - An approach of estimating individual growth curves for young thoroughbred horses based on their birthdays. AB - We propose an approach of estimating individual growth curves based on the birthday information of Japanese Thoroughbred horses, with considerations of the seasonal compensatory growth that is a typical characteristic of seasonal breeding animals. The compensatory growth patterns appear during only the winter and spring seasons in the life of growing horses, and the meeting point between winter and spring depends on the birthday of each horse. We previously developed new growth curve equations for Japanese Thoroughbreds adjusting for compensatory growth. Based on the equations, a parameter denoting the birthday information was added for the modeling of the individual growth curves for each horse by shifting the meeting points in the compensatory growth periods. A total of 5,594 and 5,680 body weight and age measurements of Thoroughbred colts and fillies, respectively, and 3,770 withers height and age measurements of both sexes were used in the analyses. The results of predicted error difference and Akaike Information Criterion showed that the individual growth curves using birthday information better fit to the body weight and withers height data than not using them. The individual growth curve for each horse would be a useful tool for the feeding managements of young Japanese Thoroughbreds in compensatory growth periods. PMID- 25013355 TI - Oxidative response of neutrophils to platelet-activating factor is altered during acute ruminal acidosis induced by oligofructose in heifers. AB - Reactive oxygen species (ROS) production is one of the main mechanisms used to kill microbes during innate immune response. D-lactic acid, which is augmented during acute ruminal acidosis, reduces platelet activating factor (PAF)-induced ROS production and L-selectin shedding in bovine neutrophils in vitro. This study was conducted to investigate whether acute ruminal acidosis induced by acute oligofructose overload in heifers interferes with ROS production and L-selectin shedding in blood neutrophils. Blood neutrophils and plasma were obtained by jugular venipuncture, while ruminal samples were collected using rumenocentesis. Lactic acid from plasma and ruminal samples was measured by HPLC. PAF-induced ROS production and L-selectin shedding were measured in vitro in bovine neutrophils by a luminol chemiluminescence assay and flow cytometry, respectively. A significant increase in ruminal and plasma lactic acid was recorded in these animals. Specifically, a decrease in PAF-induced ROS production was observed 8 h after oligofructose overload, and this was sustained until 48 h post oligofructose overload. A reduction in PAF-induced L-selectin shedding was observed at 16 h and 32 h post oligofructose overload. Overall, the results indicated that neutrophil PAF responses were altered in heifers with ruminal acidosis, suggesting a potential dysfunction of the innate immune response. PMID- 25013357 TI - Anti-inflammatory and Intestinal Barrier-protective Activities of Commensal Lactobacilli and Bifidobacteria in Thoroughbreds: Role of Probiotics in Diarrhea Prevention in Neonatal Thoroughbreds. AB - We previously isolated the commensal bacteria lactobacilli and bifidobacteria from the Thoroughbred intestine and prepared the horse probiotics LacFi(TM), consisting of Lactobacillus ruminis KK14, L. equi KK 15, L. reuteri KK18, L. johnsonii KK21, and Bifidobacterium boum HU. Here, we found that the five LacFi(TM) constituent strains remarkably suppressed pro-inflammatory interleukin 17 production in mouse splenocytes stimulated with interleukin-6 and transforming growth factor-beta. The protective effects of the probiotic on impaired intestinal barrier function were evaluated in Caco-2 cells treated with tumor necrosis factor-alpha. Evaluation of transepithelial resistance showed that all the strains exhibited intestinal barrier protective activity, with significant suppression of barrier impairment by L. reuteri KK18. The LacFi(TM) constituent strains were detected in neonatal LacFi(TM)-administered Thoroughbred feces using polymerase chain reaction denaturing gradient gel electrophoresis and culture methods. These five strains were found to be the predominant lactobacilli and bifidobacteria in the intestinal microbiota of LacFi(TM)-administered Thoroughbreds. Administration of LacFi(TM) to neonatal Thoroughbreds decreased diarrhea incidence from 75.9% in the control group (n=29 neonatal Thoroughbreds) to 30.7% in the LacFi(TM)-administered group (n=101 neonatal Thoroughbreds) immediately after birth to 20 weeks after birth. LacFi(TM) treatment also prevented diarrhea especially at and around 4 weeks and from 10 to 16 weeks. The duration of diarrhea was also shorter in the probiotics-administered group (7.4 +/- 0.8 days) than in the control group (14.0 +/- 3.2 days). These results indicate that the LacFi(TM) probiotics regulates intestinal function and contributes to diarrhea prevention. PMID- 25013358 TI - Histopathological characteristics of endometrosis in thoroughbred mares in Japan: results from 50 necropsy cases. AB - Uteri from 50 necropsied nonpregnant Japanese Thoroughbred brood mares (1-30 years of age) were investigated to clarify the histopathological characteristics of endometrosis in Japanese Thoroughbred mares and the distribution pattern of endometrosis lesions in the uterus as a whole. Endometrosis was observed in all animals over 6 years of age and in all of the 21 mares aged over 12 years of age. The affected mares showed elastofibrosis of arteries, veins and lymphatic vessels in the uterine wall, atrophy of the uterine smooth muscle layers and hyperplasia of collagen fibers among the smooth muscle fascicles of the myometrium, in addition to pathomorphologic features of endometrosis such as stromal endometrial fibrosis accompanied by endometrial atrophy, periglandular fibrosis and reduction of uterine glands. The severity of the histopathological changes increased with advancing age. Lymphatic vessels with elastofibrosis showed marked lymph congestion, leading to lymphatic edema. With increasing age, the extent of the distribution of these lesions tended to expand from focal to diffuse involvement of the entire uterus. Based on these findings, we speculate that aging plays a role in the pathogenesis of endometrosis; circulatory disturbances due to intrauterine angiosis or angiopathy, particularly reduction of the arterial blood supply and disturbance of venous drainage, resulting in a reduction of lymphatic drainage (lymphatic edema), are closely related to the onset and progression of endometrial fibrosis and myometrial atrophy with fibroplasia may result in myometrial hypofunction during the peri-implantation or puerperal period. PMID- 25013359 TI - The Antiphagocytic Activity of SeM of Streptococcus equi Requires Capsule. AB - Resistance to phagocytosis is a crucial virulence property of Streptococcus equi (Streptococcus equi subsp. equi; Se), the cause of equine strangles. The contribution and interdependence of capsule and SeM to killing in equine blood and neutrophils were investigated in naturally occurring strains of Se. Strains CF32, SF463 were capsule and SeM positive, strains Lex90, Lex93 were capsule negative and SeM positive and strains Se19, Se1-8 were capsule positive and SeM deficient. Phagocytosis and killing of Se19, Se1-8, Lex90 and Lex93 in equine blood and by neutrophils suspended in serum were significantly (P <= 0.02) greater compared to CF32 and SF463. The results indicate capsule and SeM are both required for resistance to phagocytosis and killing and that the anti-phagocytic property of SeM is greatly reduced in the absence of capsule. PMID- 25013360 TI - Immigrant Sexual Citizenship: Intersectional Templates among Mexican Gay Immigrants to the United States. AB - Existing literature on sexual citizenship has emphasized the sexuality-related claims of de jure citizens of nation-states, generally ignoring immigrants. Conversely, the literature on immigration rarely attends to the salience of sexual issues in understanding the social incorporation of migrants. This article seeks to fill the gap by theorizing and analyzing immigrant sexual citizenship. While some scholars of sexual citizenship have focused on the rights and recognition granted formally by the nation-state and others have stressed more diffuse, cultural perceptions of community and local belonging, we argue that the lived experiences of immigrant sexual citizenship call for multiscalar scrutiny of templates and practices of citizenship that bridge national policies with local connections. Analysis of ethnographic data from a study of 76 Mexican gay and bisexual male immigrants to San Diego, California reveals the specific citizenship templates that these men encounter as they negotiate their intersecting social statuses as gay/bisexual and as immigrants (legal or undocumented); these include an "asylum" template, a "rights" template, and a "local attachments" template. However, the complications of their intersecting identities constrain their capacity to claim immigrant sexual citizenship. The study underscores the importance of both intersectional and multiscalar approaches in research on citizenship as social practice. PMID- 25013361 TI - Biofabrication of ZnS:Mn luminescent nanocrystals using histidine, hexahistidine, and His-tagged proteins: a comparison study. AB - The ubiquitous hexahistidine purification tag has been used to conjugate proteins to the shell of CdSe:ZnS quantum dots (QDs) due to its affinity for surface exposed Zn2+ ions but little attention has been paid to the potential of His tagged proteins for mineralizing luminescent ZnS nanocrystals. Here, we compare the ability of free histidine, a His tag peptide, His-tagged thioredoxin (TrxA, a monomeric protein), and N- and C-terminally His-tagged versions of Hsp31 (a homodimeric protein) to support the synthesis of Mn-doped ZnS nanocrystals from aqueous precursors under mild conditions of pH (8.2) and temperature (37 degrees C). We find that: (1) it is possible to produce poor quality QDs when histidine is used at high (8 mM) concentration; (2) an increase in local histidine concentration through repetition of the amino acid as a His tag decreases the amount of needed reagent ~10-fold and improves optical properties; (3) fusion of the same His tag to TrxA allows for ZnS:Mn QDs mineralization at micromolar concentrations; and (4) doubling the local hexahistidine concentration by exploiting Hsp31 dimerization further improves nanocrystal luminescence with the brightest particles obtained when His tags are spatially co-localized at the Hsp31 N-termini. Although hexahistidine tracts are not as efficient as combinatorially selected ZnS binding peptides at QD synthesis, it should be possible to use the large number of available His-tagged proteins and the synthesis approach described herein to produce luminescent nanoparticles whose protein shell carries a broad range of functions. PMID- 25013362 TI - Structured functional additive regression in reproducing kernel Hilbert spaces. AB - Functional additive models (FAMs) provide a flexible yet simple framework for regressions involving functional predictors. The utilization of data-driven basis in an additive rather than linear structure naturally extends the classical functional linear model. However, the critical issue of selecting nonlinear additive components has been less studied. In this work, we propose a new regularization framework for the structure estimation in the context of Reproducing Kernel Hilbert Spaces. The proposed approach takes advantage of the functional principal components which greatly facilitates the implementation and the theoretical analysis. The selection and estimation are achieved by penalized least squares using a penalty which encourages the sparse structure of the additive components. Theoretical properties such as the rate of convergence are investigated. The empirical performance is demonstrated through simulation studies and a real data application. PMID- 25013363 TI - Presence of antibodies against self human leukocyte antigen class II molecules in autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) can arise de novo after liver transplantation (LT) for non-autoimmune liver diseases. Considering the identical features of de novo AIH after LT and classical AIH, as well as the importance of anti-human leukocyte antigen (HLA) antibodies in graft rejection, we investigated the presence of circulating anti-HLA class II antibodies in the sera of 35 patients with AIH, 30 patients with primary biliary cirrhosis (PBC), and 30 healthy donors using fluorescent dye-impregnated beads bound to HLA molecules. We then investigated the allele specificity of the antibodies and identified the HLA alleles in each patient using DNA-based HLA typing. We also examined HLA class II expression in liver samples using immunohistochemistry. Anti-HLA class II antibodies were detected significantly more frequently in the patients with AIH (88.1%) than in the patients with PBC (33.3%) or in the healthy donors (13.3%) (both P <0.01). We confirmed that the anti-HLA class II antibodies in the AIH patients showed specificity for several HLA class II alleles, including self HLA class II alleles. Moreover, positive reactivity with anti-self HLA class II antibodies was associated with higher serum transaminase levels. In conclusion, we demonstrated, for the first time, that antibodies against self HLA class II alleles were detectable in patients with AIH. Our results suggest that an antibody-mediated immune response against HLA class II molecules on hepatocytes may be involved in the pathogenesis or acceleration of liver injury in AIH. PMID- 25013364 TI - How much colonic redundancy could be obtained by splenic flexure mobilization in laparoscopic anterior or low anterior resection? AB - BACKGROUND AND OBJECTIVES: Splenic flexure mobilization (SFM) is performed to ensure a tension free anastomosis with an adequate resection margin in laparoscopic anterior resection (AR) or low anterior resection (LAR). This retrospective study was performed to determine the amount of colonic redundancy that can be expected by SFM. METHODS: Retrospective review of medical record for a total of 203 patients who underwent SFM during laparoscopic AR or LAR for the treatment of sigmoid colon or rectal cancer was performed. RESULTS: The obtained redundancy of the colon by SFM was 27.81 +/- 7.29 cm from the sacral promontory. The redundancy of the colon by SFM with high ligation of the inferior mesenteric vein (IMV) (29.54 +/- 7.17 cm from the sacral promontory) was greater than that with low ligation of the IMV (24.94 +/- 6.07 cm from the sacral promontory, P < 0.0001). It took about 9.82% of the total operation time to perform SFM. There was no intraoperative complication during SFM. CONCLUSIONS: SFM during laparoscopic AR or LAR is a safe and feasible option. Based on the result of this study, one can gain about 27.81 cm redundancy of the colon by SFM. PMID- 25013365 TI - Risk factors for major adverse events of video-assisted thoracic surgery lobectomy for lung cancer. AB - AIMS: The purpose of this study was to identify the risk factors for major adverse events of VATS (Video-Assisted Thoracic Surgery) lobectomy for primary lung cancer. METHODS: 1806 Patients (1032 males, 57.1%) planned to undergo VATS lobectomy for stage IA-IIIA lung cancer from July 2007 to June 2012. The Thoracic Morbidity and Mortality Classification TM&M system was used to evaluate the presence and severity of complications. Postoperative complications were observed during a 30-day follow up. Univariate and multivariate analysis were used to analyze the independent risk factors for major adverse events. RESULTS: Successful rate of VATS lobectomy was 97.6% (1763/1806). Major complications occurred in 129 patients (7.3%), with a mortality of 0.3% (5/1763). Pulmonary complications contribute up to 90.7% of the major complications and 80% of mortality. Logistic regression indicated that comorbidities, elder age >=70y, operative time >=240min and hybrid VATS were predictors for major adverse events (P<0.05). Hybrid and converted VATS lobectomy result in higher major adverse events compared with complete VATS, 15.1%, 20.9% and 7.4% respectively (P=0.013). CONCLUSIONS: The overall complication rate and mortality of VATS lobectomy are low, while major complications sometimes occur. Pulmonary complications are the most common major complications and cause of mortality. Age >=70y, comorbidities, operative time >=240min and Hybrid VATS are predictors of major adverse events. PMID- 25013366 TI - Suppression of peritoneal tumorigenesis by placenta-derived mesenchymal stem cells expressing endostatin on colorectal cancer. AB - MSCs-based therapy for cancer is a relatively new but rapidly growing area of research. Human term placenta, an attractive source of MSCs (PMSCs), appears to have great advantage due to its easy access without invasive procedures, its lack of ethical issues and its high-throughput and young age. In the present study, we isolated MSCs from placenta and characterized their morphology and differentiation capacities. We next investigated the underlying antitumor effects and the potential mechanism of PMSCs to express endostatin using adenoviral transduction (Ad-Endo) in a colorectal peritoneal carcinomatosis (CRPC) mouse model. For in vitro experiments, the migratory potential of Ad-Endo-PMSCs towards tumor cells was demonstrated using a double-chamber assay, and the anti angiogenesis ability of endostatin from engineered PMSCs was evaluated using the tube formation assay. For the in vivo study, mice harboring CT26 colorectal cancer indicated a significant reduction in tumor nodules and a prolongation of survival following Ad-Endo-PMSCs therapy. These observations were associated with significantly decreased tumor cell proliferation and blood vessel counts as well as increased tumor cell apoptosis. These data suggested the potential of PMSCs based gene therapy for the targeted delivery of therapeutic proteins in cancer. PMID- 25013367 TI - Chuanhu anti-gout mixture versus colchicine for acute gouty arthritis: a randomized, double-blind, double-dummy, non-inferiority trial. AB - BACKGROUND: The Chuanhu anti-gout mixture has been used for many years in the treatment of gout in Chinese Traditional Medicine, and current methods for treatments for acute gouty arthritis have been either less effective or have had serious side effects. METHODS: In this 12-week, double-blind, double-dummy, non inferiority study, outpatient individuals with newly diagnosed acute gouty arthritis were randomly assigned to receive Chuanhu anti-gout mixture or colchicine. Both the study investigators and the participants were masked to the treatment assignments. The primary outcome was the recurrence rate of acute gouty arthritis, and the secondary outcomes were changes in white blood cells (WHC) and C-reactive protein (CRP). This trial is registered at ISRCTN.org as trial ISRCTN65219941. RESULTS: A total of 176 patients were randomly assigned to receive either the Chuanhu anti-gout mixture or Colchicine. The overall recurrence rates in the Chuanhu anti-gout mixture group (CH group) and the Colchicine group (Col group) were 12.50% vs 14.77% (difference -2.22%, 95% confidence interval (95% CI): -10.78%~6.23%), meeting the predefined non inferiority criterion of 15%, as did the data for WHC and CRP. The incidence of adverse events (mainly diarrhea) was less in the Col group than in the CH group (2.27% vs 28.41%, 95% CI 0.01~0.26). In addition, changes in blood uric acid, alanine aminotransferase, aspartate aminotransferase and creatinine in the CH group were significantly larger compared to those in the Col group (P<0.05). CONCLUSIONS: The Chuanhu anti-gout mixture was non-inferior to colchicine for the treatment of acute gouty arthritis. The study suggested that the Chuanhu anti gout mixture can be considered an alternative choice for the treatment of acute gouty arthritis because of its lower incidence of adverse events and its protection of kidney and renal function. PMID- 25013368 TI - Gestational hypoxia up-regulates protein kinase C and inhibits calcium-activated potassium channels in ovine uterine arteries. AB - OBJECTIVE: The present study tested the hypothesis that gestational hypoxia up regulates protein kinase C (PKC) and inhibits calcium-activated potassium channels (KCa)-mediated relaxations of uterine arteries in pregnancy. STUDY DESIGN: Uterine arteries were isolated from nonpregnant (NPUA) and pregnant (PUA) (~140 day gestation) sheep maintained at either sea level or high altitude (3,820 m for 110 days, PaO2: 60 mmHg). Contractions of uterine arteries were determined. KEY FINDINGS: In normoxic PUA, selective inhibition of large-conductance KCa (BK) channels significantly enhanced PKC activator phorbol 12, 13-dibutyrate (PDBu) induced contractions. This effect was abrogated by chronic hypoxia in gestation. Unlike BK channels, inhibition of small-conductance KCa (SK) channels had no significant effect on PDBu-mediated contractions. In normoxic PUA, activation of both BK with NS1619 or SK with NS309 produced concentration-dependent relaxations, which were not altered by the addition of PDBu. However, in uterine arteries treated with chronic hypoxia (10.5% O2 for 48 h), both NS1619- and NS309 induced relaxations were significantly attenuated by PDBu. In NPUAs, inhibition of BK channels significantly enhanced PDBu-induced contractions in both normoxic and hypoxic animals. CONCLUSION: The results suggest that in the normoxic condition BK inhibits PKC activity and uterine vascular contractility, which is selectively attenuated by chronic hypoxia during gestation. In addition, hypoxia induces PKC-mediated inhibition of BK and SK activities and relaxations of uterine arteries in pregnancy. PMID- 25013369 TI - Comparison of iodine-125 seed implantation and pancreaticoduodenectomy in the treatment of pancreatic cancer. AB - OBJECTIVE: This retrospective study compared the advantages and disadvantages of iodine-125 (125I) seed implantation and pancreaticoduodenectomy (PD) in the treatment of pancreatic cancer. METHODS: Patients with diagnosed pancreatic cancer who were treated with 125125I seed implantation (30 patients) or PD (30 patients) in our hospital were evaluated for operative time, bleeding, liver function, time to first bowel movement and normal diet, survival, and medical costs. RESULTS: Compared with patients who underwent PD, those given 125I seed implantation had significantly shorter operative time, less bleeding, higher albumin, shorter periods to bowel movement and normal diet, lower risk of complications, and lower medical costs (P < 0.001, each). The difference of bilirubin level, time to feeding, and median survival were not significant statistically between two treatment grouops. CONCLUSION: For pancreatic cancer patients for whom PD is not appropriate or who refuse PD, 125I seed implantation is a good option. PMID- 25013370 TI - Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in Renin-Angiotensin System (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) study. AB - OBJECTIVE: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). METHODS: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor treated patients with blood pressure (BP) readings of >= 130/80 mmHg and <= 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of >= 300 mg/g, and an estimated glomerular filtration rate (eGFR) of >= 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. RESULTS: Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). CONCLUSIONS: The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria. PMID- 25013371 TI - The basic social medical insurance is associated with clinical outcomes in the patients with ST-elevation myocardial infarction: a retrospective study from Shanghai, China. AB - OBJECTIVE: Several social economic factors play important roles in treatments of ST-elevation myocardial infarction (STEMI) and finally influence the clinical outcomes. The basic social medical insurance (BSMI) is an important economic factor in China's medical system. However, the impact of BSMI on clinical outcomes in STEMI patients has not been explored yet. The aim of this study is to investigate whether BSMI is a predictor of clinical outcomes in the patients with STEMI in Shanghai, China. MATERIAL AND METHODS: In this retrospective study, 681 STEMI patients from different areas in Shanghai were classified into four groups: new rural cooperative medical scheme (NCMS) group, urban resident basic medical insurance scheme (URBMI) group, urban employee basic medical insurance scheme (UEBMI) group and UNINSURED group, major adverse events (cardiac death, nonfatal reinfarction, clinically driven target lesion revascularization/target vessel revascularization, stroke, heart failure) were regarded as study endpoints to determine whether BSMI was a prognostic factor. RESULTS: During a mean follow-up of 36 months, the incidence of major adverse events was significantly higher in NCMS patients (64; 38.8%) compared with the other groups: URBMI (47; 24.6%); UEBMI (28; 15.6%); UNISURED (40; 27.6%). Similarly, cardiac mortality was also higher in NCMS group (19; 11.5%). A Kaplan-Meier survival analysis revealed significantly lower event-free survival rate for major adverse events (p < 0.001) and cardiac mortality (p = 0.01) in NCMS group. Multivariate Cox regression analysis revealed that BSMI was an important prognostic factor in STEMI patients. CONCLUSION: These results demonstrate that BSMI is closely associated with the major adverse events-free survival rate at 36-month follow-up in the STEMI patients under the current policies in Shanghai, China. PMID- 25013372 TI - Renal transplantation: relationship between hospital/surgeon volume and postoperative severe sepsis/graft-failure. a nationwide population-based study. AB - BACKGROUND AND OBJECTS: We explored the relationship between hospital/surgeon volume and postoperative severe sepsis/graft-failure (including death). METHODS: The Taiwan National Health Insurance Research Database claims data for all patients with end-stage renal disease patients who underwent kidney transplantation between January 1, 1999, and December 31, 2007, were reviewed. Surgeons and hospitals were categorized into two groups based on their patient volume. The two primary outcomes were severe sepsis and graft failure (including death). The logistical regressions were done to compute the Odds ratios (OR) of outcomes after adjusting for possible confounding factors. Kaplan-Meier analysis was used to calculate the cumulative survival rates of graft failure after kidney transplantation during follow-up (1999-2008). RESULTS: The risk of developing severe sepsis in a hospital in which surgeons do little renal transplantation was significant (odds ratio [OR]; p = 0.0115): 1.65 times (95% CI: 1.12-2.42) higher than for a hospital in which surgeons do many. The same trend was true for hospitals with a low volume of renal transplantations (OR = 2.39; 95% CI: 1.62 3.52; p < 0.0001). The likelihood of a graft failure (including death) within one year for the low-volume surgeon group was 3.1 times higher than for the high volume surgeon group (p < 0.0001); the trend was similar for hospital volume. Female patients had a lower risk than did male patients, and patients >= 55 years old and those with a higher Charlson comorbidity index score, had a higher risk of severe sepsis. CONCLUSIONS: We conclude that the risk of severe sepsis and graft failure (including death) is higher for patients treated in hospitals and by surgeons with a low volume of renal transplantations. Therefore, the health authorities should consider exporting best practices through educational outreach and regulation and then providing transparent information for public best interest. PMID- 25013374 TI - Cyclic phosphatidic acid inhibits alkyl-glycerophosphate-induced downregulation of histone deacetylase 2 expression and suppresses the inflammatory response in human coronary artery endothelial cells. AB - Activation of the endothelium by alkyl-glycerophosphate (AGP) has been implicated in the development of atherosclerosis. Our previous study suggested that cyclic phosphatidic acid (cPA) inhibits arterial wall remodeling in a rat model in vivo. However, the mechanisms through which specific target genes are regulated during this process remain unclear. Here, we examined whether cPA inhibited AGP-induced expression of class I histone deacetylases (HDACs, namely HDAC1, HDAC2, HDAC3, and HDAC8), which may affect subsequent transcriptional activity of target genes. Our experimental results showed that human coronary artery endothelial cells (HCAECs) expressed high levels of HDAC2 and low levels HDAC1, HDAC3, and HDAC8. Moreover, AGP treatment induced downregulation of HDAC2 expression in HCAECs. However, cotreatment with cPA inhibited this downregulation of HDAC2 expression. Interestingly, treatment with AGP increased the expression and secretion of endogenous interleukin (IL)-6 and IL-8; however, this effect was inhibited when HCAECs were cotreated with cPA or the synthetic peroxisome proliferator-activator receptor gamma (PPARgamma) antagonist T0070907. Thus, our data suggested that cPA may have beneficial effects in inflammation-related cardiovascular disease by controlling HDAC2 regulation. PMID- 25013373 TI - Alanine aminotransferase-old biomarker and new concept: a review. AB - Measurement of serum alanine aminotransferase (ALT) is a common, readily available, and inexpensive laboratory assay in clinical practice. ALT activity is not only measured to detect liver disease, but also to monitor overall health. ALT activity is influenced by various factors, including viral hepatitis, alcohol consumption, and medication. Recently, the impact of metabolic abnormalities on ALT variation has raised concern due to the worldwide obesity epidemic. The normal ranges for ALT have been updated and validated considering the metabolic covariates in the various ethnic districts. The interaction between metabolic and demographic factors on ALT variation has also been discussed in previous studies. In addition, an extremely low ALT value might reflect the process of aging, and frailty in older adults has been raised as another clinically significant feature of this enzyme, to be followed with additional epidemiologic investigation. Timely updated, comprehensive, and systematic introduction of ALT activity is necessary to aid clinicians make better use of this enzyme. PMID- 25013375 TI - Recent advances in drug repositioning for the discovery of new anticancer drugs. AB - Drug repositioning (also referred to as drug repurposing), the process of finding new uses of existing drugs, has been gaining popularity in recent years. The availability of several established clinical drug libraries and rapid advances in disease biology, genomics and bioinformatics has accelerated the pace of both activity-based and in silico drug repositioning. Drug repositioning has attracted particular attention from the communities engaged in anticancer drug discovery due to the combination of great demand for new anticancer drugs and the availability of a wide variety of cell- and target-based screening assays. With the successful clinical introduction of a number of non-cancer drugs for cancer treatment, drug repositioning now became a powerful alternative strategy to discover and develop novel anticancer drug candidates from the existing drug space. In this review, recent successful examples of drug repositioning for anticancer drug discovery from non-cancer drugs will be discussed. PMID- 25013376 TI - Long non-coding RNA URHC regulates cell proliferation and apoptosis via ZAK through the ERK/MAPK signaling pathway in hepatocellular carcinoma. AB - Long non-coding RNAs (lncRNAs) have previously been implicated in human disease states, especially cancer. Although the aberrant expression of lncRNAs has been observed in cancer, the biological functions and molecular mechanisms underlying aberrantly expressed lncRNAs in hepatocellular carcinoma (HCC) have not been widely established. In the present study, we investigated a novel lncRNA, termed URHC (up-regulated in hepatocellular carcinoma), and evaluated its role in the progression of HCC. Expression profiling using a lncRNA microarray revealed that URHC was highly expressed in 3 HCC cell lines compared to normal hepatocytes. Quantitative real-time polymerase chain reaction (qRT-PCR) analyses confirmed that URHC expression was increased in hepatoma cells and HCC tissues. Moreover, using qRT-PCR, we confirmed that URHC expression was up-regulated in 30 HCC cases (57.7%) and that its higher expression was correlated with poor overall survival. We further demonstrated that URHC inhibition reduced cell proliferation and promoted apoptosis. We hypothesize that URHC may function by regulating the sterile alpha motif and leucine zipper containing kinase AZK (ZAK) gene, which is located near URHC on the same chromosome. We found that ZAK mRNA levels were down regulated in HCC tissues and the expression levels of ZAK were negatively correlated with those of URHC in the above HCC tissues. Next, we confirmed that URHC down-regulated ZAK, which is involved in URHC-mediated cell proliferation and apoptosis. Furthermore, ERK/MAPK pathway inactivation partially accounted for URHC-ZAK-induced cell growth and apoptosis. Thus, we concluded that high URHC expression can promote cell proliferation and inhibit apoptosis by repressing ZAK expression through inactivation of the ERK/MAPK pathway. These findings may provide a novel mechanism and therapeutic targets for the treatment of HCC. PMID- 25013377 TI - Predicting disease-related proteins based on clique backbone in protein-protein interaction network. AB - Network biology integrates different kinds of data, including physical or functional networks and disease gene sets, to interpret human disease. A clique (maximal complete subgraph) in a protein-protein interaction network is a topological module and possesses inherently biological significance. A disease related clique possibly associates with complex diseases. Fully identifying disease components in a clique is conductive to uncovering disease mechanisms. This paper proposes an approach of predicting disease proteins based on cliques in a protein-protein interaction network. To tolerate false positive and negative interactions in protein networks, extending cliques and scoring predicted disease proteins with gene ontology terms are introduced to the clique-based method. Precisions of predicted disease proteins are verified by disease phenotypes and steadily keep to more than 95%. The predicted disease proteins associated with cliques can partly complement mapping between genotype and phenotype, and provide clues for understanding the pathogenesis of serious diseases. PMID- 25013378 TI - Amoebozoa possess lineage-specific globin gene repertoires gained by individual horizontal gene transfers. AB - The Amoebozoa represent a clade of unicellular amoeboid organisms that display a wide variety of lifestyles, including free-living and parasitic species. For example, the social amoeba Dictyostelium discoideum has the ability to aggregate into a multicellular fruiting body upon starvation, while the pathogenic amoeba Entamoeba histolytica is a parasite of humans. Globins are small heme proteins that are present in almost all extant organisms. Although several genomes of amoebozoan species have been sequenced, little is known about the phyletic distribution of globin genes within this phylum. Only two flavohemoglobins (FHbs) of D. discoideum have been reported and characterized previously while the genomes of Entamoeba species are apparently devoid of globin genes. We investigated eleven amoebozoan species for the presence of globin genes by genomic and phylogenetic in silico analyses. Additional FHb genes were identified in the genomes of four social amoebas and the true slime mold Physarum polycephalum. Moreover, a single-domain globin (SDFgb) of Hartmannella vermiformis, as well as two truncated hemoglobins (trHbs) of Acanthamoeba castellanii were identified. Phylogenetic evidence suggests that these globin genes were independently acquired via horizontal gene transfer from some ancestral bacteria. Furthermore, the phylogenetic tree of amoebozoan FHbs indicates that they do not share a common ancestry and that a transfer of FHbs from bacteria to amoeba occurred multiple times. PMID- 25013379 TI - Targeting the sheddase activity of ADAM17 by an anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation. AB - A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK) stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC. PMID- 25013380 TI - Type-IV antifreeze proteins are essential for epiboly and convergence in gastrulation of zebrafish embryos. AB - Many organisms in extremely cold environments such as the Antarctic Pole have evolved antifreeze molecules to prevent ice formation. There are four types of antifreeze proteins (AFPs). Type-IV antifreeze proteins (AFP4s) are present also in certain temperate and even tropical fish, which has raised a question as to whether these AFP4s have important functions in addition to antifreeze activity. Here we report the identification and functional analyses of AFP4s in cyprinid fish. Two genes, namely afp4a and afp4b coding for AFP4s, were identified in gibel carp (Carassius auratus gibelio) and zebrafish (Danio rerio). In both species, afp4a and afp4b display a head-to-tail tandem arrangement and share a common 4-exonic gene structure. In zebrafish, both afp4a and afp4b were found to express specifically in the yolk syncytial layer (YSL). Interestingly, afp4a expression continues in YSL and digestive system from early embryos to adults, whereas afp4b expression is restricted to embryogenesis. Importantly, we have shown by using afp4a-specific and afp4b-specifc morpholino knockdown and cell lineage tracing approaches that AFP4a participates in epiboly progression by stabilizing yolk cytoplasmic layer microtubules, and AFP4b is primarily related to convergence movement. Therefore, both AFP4 proteins are essential for gastrulation of zebrafish embryos. Our current results provide first evidence that AFP such as AFP4 has important roles in regulating developmental processes besides its well-known function as antifreeze factors. PMID- 25013381 TI - MicroRNA-135a inhibits cell proliferation by targeting Bmi1 in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal solid tumor due to the lack of reliable early detection markers and effective therapies. MicroRNAs (miRNAs), noncoding RNAs that regulate gene expression, are involved in tumorigenesis and have a remarkable potential for the diagnosis and treatment of malignancy. In this study, we investigated aberrantly expressed miRNAs involved in PDAC by comparing miRNA expression profiles in PDAC cell lines with a normal pancreas cell line and found that miR-135a was significantly down-regulated in the PDAC cell lines. The microarray results were validated by qRT-PCR in PDAC tissues, paired adjacent normal pancreatic tissues, PDAC cell lines, and a normal pancreas cell line. We then defined the tumor-suppressing significance and function of miR-135a by constructing a lentiviral vector to express miR-135a. The overexpression of miR-135a in PDAC cells decreased cell proliferation and clonogenicity and also induced G1 arrest and apoptosis. We predicted Bmi1 may be a target of miR-135a using bioinformatics tools and found that Bmi1 expression was markedly up-regulated in PDAC. Its expression was inversely correlated with miR-135a expression in PDAC. Furthermore, a luciferase activity assay revealed that miR-135a could directly target the 3'-untranslated region (3'-UTR) of Bmi1. Taken together, these results demonstrate that miR-135a targets Bmi1 in PDAC and functions as a tumor suppressor. miR-135a may offer a new perspective for the development of effective miRNA-based therapy for PDAC. PMID- 25013382 TI - Dimethyloxaloylglycine improves angiogenic activity of bone marrow stromal cells in the tissue-engineered bone. AB - One of the big challenges in tissue engineering for treating large bone defects is to promote the angiogenesis of the tissue-engineered bone. Hypoxia inducible factor-1alpha (HIF-1alpha) plays an important role in angiogenesis-osteogenesis coupling during bone regeneration, and can activate a broad array of angiogenic factors. Dimethyloxaloylglycine (DMOG) can activate HIF-1alpha expression in cells at normal oxygen tension. In this study, we explored the effect of DMOG on the angiogenic activity of bone mesenchymal stem cells (BMSCs) in the tissue engineered bone. The effect of different concentrations of DMOG on HIF-1a expression in BMSCs was detected with western blotting, and the mRNA expression and secretion of related angiogenic factors in DMOG-treated BMSCs were respectively analyzed using qRT-PCR and enzyme linked immunosorbent assay. The tissue-engineered bone constructed with beta-tricalcium phosphate (beta-TCP) and DMOG-treated BMSCs were implanted into the critical-sized calvarial defects to test the effectiveness of DMOG in improving the angiogenic activity of BMSCs in the tissue-engineered bone. The results showed DMOG significantly enhanced the mRNA expression and secretion of related angiogenic factors in BMSCs by activating the expression of HIF-1alpha. More newly formed blood vessels were observed in the group treated with beta-TCP and DMOG-treated BMSCs than in other groups. And there were also more bone regeneration in the group treated with beta TCP and DMOG-treated BMSCs. Therefore, we believed DMOG could enhance the angiogenic activity of BMSCs by activating the expression of HIF-1alpha, thereby improve the angiogenesis of the tissue-engineered bone and its bone healing capacity. PMID- 25013384 TI - Comparison of intraocular lens types for cataract surgery in eyes with uveitis. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: The aim of this systematic review is to summarize the effects of different IOLs after cataract surgery in uveitis patients. Alternative types of IOLs include PMMA, silicone, acrylic with or without heparin-surface modification. PMID- 25013387 TI - Letter from the editor. PMID- 25013385 TI - Towards an Understanding of Neuropsychiatric Manifestations in Fragile X Premutation Carriers. AB - Fragile X-associated disorders (FXD) are a group of disorders caused by expansion of non-coding CGG repeat elements in the fragile X (FMR1) gene. One of these disorders, fragile X syndrome (FXS), is the most common heritable cause of intellectual disability, and is caused by large CGG repeat expansions (>200) resulting in silencing of the FMR1 gene. An increasingly recognized number of neuropsychiatric FXD have recently been identified that are caused by 'premutation' range expansions (55-200). These disorders are characterized by a spectrum of neuropsychiatric manifestations ranging from an increased risk of neurodevelopmental, mood and anxiety disorders to neurodegenerative phenotypes such as the fragile X-associated tremor ataxia syndrome (FXTAS). Here, we review advances in the clinical understanding of neuropsychiatric disorders in premutation carriers across the lifespan and offer guidance for the detection of such disorders by practicing psychiatrists and neurologists. PMID- 25013383 TI - Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. AB - Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The primary purpose of this paper is to summarize recent studies of the links between HDACs and cancer, and further discuss the underlying mechanisms of anti-tumor activities of HDAC inhibitors and clinical implications. PMID- 25013386 TI - Growth of Diffraction-Quality Protein Crystals Using a Harvestable Microfluidic Device. AB - Protein crystallization is the major bottleneck in the entire process of protein crystallography, and obtaining diffraction-quality crystals can be unpredictable and sometimes exceptionally difficult, requiring many rounds of high-throughput screening. Recently, a more time- and cost-saving strategy to use the commercially available microfluidic devices called Crystal Formers has emerged. Herein we show the application of such a device using a protein from Legionella pneumophila called LidL that is predicted to be involved in the ability to efficiently manipulate host cell trafficking events once internalized by the host cell. After setting up just one 96-channel Crystal Former tray, we were able to obtain a diffraction-quality crystal that diffracted to 2.76 A. These results show that Crystal Formers can be used to screen and optimize crystals to directly produce crystals for structure determination. PMID- 25013388 TI - Immunizations in children with inflammatory bowel disease treated with immunosuppressive therapy. AB - The vast majority of patients with inflammatory bowel disease (IBD) will receive immunosuppressive therapy at some point for their disease, whether for the short term (such as a course of corticosteroids) or long term (such as maintenance therapy with immunomodulators or biologics). The systemic immunosuppression places patients at increased risk for infections. Therefore, it is important that patients are up-to-date with immunizations to minimize vaccine-preventable infections. However, the literature shows that the rate of immunization in patients with IBD is low. Ideally, the vaccination status is checked at diagnosis, and patients are immunized with the vaccines they need. Drawing titers is helpful in cases in which vaccination history is unclear or to confirm that titers are at an adequate level in cases in which patients have been vaccinated. Current guidelines recommend that patients with IBD follow the same routine immunization schedule as healthy children, but patients should not be administered live vaccines if they are receiving immunosuppressive therapy. Therefore, it is ideal to administer any necessary vaccinations as early as possible, prior to starting immunosuppressive therapy. Patients may receive inactivated vaccines regardless of immunosuppressive status. The IBD literature suggests that inactivated vaccines are safe and do not worsen disease activity. In general, patients with IBD mount an immune response to vaccines, but the response may be lower if patients are receiving immunosuppressive therapy, especially tumor necrosis factor inhibitors. PMID- 25013389 TI - Gastric intestinal metaplasia and early gastric cancer in the west: a changing paradigm. AB - Gastric cancer remains the fifth leading cancer diagnosis worldwide, and it is the third leading cause of cancer-related mortality. The incidence of gastric cancer within the United States, however, has remained substantially lower than elsewhere, which has led to a lack of screening and surveillance in clinical practice. Patients with known premalignant lesions, such as gastric intestinal metaplasia, which can increase the risk of gastric cancer by as much as 6-fold, might benefit from surveillance guidelines to detect gastric cancer at an earlier, potentially curative stage. Chro-moendoscopy with optical magnification, narrow-band imaging, and other image-enhanced endoscopic techniques are commercially available to assist in the diagnosis of premalignant gastric lesions and early gastric cancer. Furthermore, endoscopic mucosal resection and endoscopic submucosal dissection have become more widely available and offer potentially curative endoscopic resection for dysplastic lesions of the stomach and early gastric cancers, which is an alternative to traditional surgical resection. PMID- 25013390 TI - Functional heartburn. PMID- 25013391 TI - Advances in the management of hepatitis B virus infection. PMID- 25013392 TI - Endoscopic management of esophageal strictures. PMID- 25013393 TI - Risk assessment in Crohn's disease. PMID- 25013394 TI - Diverticular hemorrhage of the appendix. PMID- 25013395 TI - In the pipeline. PMID- 25013397 TI - Unraveling complexity of interconnected regulatory circuits in lipid metabolism. PMID- 25013396 TI - Assessing the effects of common variation in the FOXP2 gene on human brain structure. AB - The FOXP2 transcription factor is one of the most well-known genes to have been implicated in developmental speech and language disorders. Rare mutations disrupting the function of this gene have been described in different families and cases. In a large three-generation family carrying a missense mutation, neuroimaging studies revealed significant effects on brain structure and function, most notably in the inferior frontal gyrus, caudate nucleus, and cerebellum. After the identification of rare disruptive FOXP2 variants impacting on brain structure, several reports proposed that common variants at this locus may also have detectable effects on the brain, extending beyond disorder into normal phenotypic variation. These neuroimaging genetics studies used groups of between 14 and 96 participants. The current study assessed effects of common FOXP2 variants on neuroanatomy using voxel-based morphometry (VBM) and volumetric techniques in a sample of >1300 people from the general population. In a first targeted stage we analyzed single nucleotide polymorphisms (SNPs) claimed to have effects in prior smaller studies (rs2253478, rs12533005, rs2396753, rs6980093, rs7784315, rs17137124, rs10230558, rs7782412, rs1456031), beginning with regions proposed in the relevant papers, then assessing impact across the entire brain. In the second gene-wide stage, we tested all common FOXP2 variation, focusing on volumetry of those regions most strongly implicated from analyses of rare disruptive mutations. Despite using a sample that is more than 10 times that used for prior studies of common FOXP2 variation, we found no evidence for effects of SNPs on variability in neuroanatomy in the general population. Thus, the impact of this gene on brain structure may be largely limited to extreme cases of rare disruptive alleles. Alternatively, effects of common variants at this gene exist but are too subtle to be detected with standard volumetric techniques. PMID- 25013398 TI - Standardized training for resident doctors in China. PMID- 25013399 TI - Metabolic regulation by protein tyrosine phosphatases. AB - Obesity and the metabolic syndrome and their associated morbidities are major public health issues, whose prevalence will continue to increase in the foreseeable future. Aberrant signaling by the receptors for leptin and insulin plays a pivotal role in development of the metabolic syndrome. More complete molecular-level understanding of how both of these key signaling pathways are regulated is essential for full characterization of obesity, the metabolic syndrome, and type II diabetes, and for developing novel treatments for these diseases. Phosphorylation of proteins on tyrosine residues plays a key role in mediating the effects of leptin and insulin on their target cells. Here, we discuss the molecular methods by which protein tyrosine phosphatases, which are key physiological regulators of protein phosphorylation in vivo, affect signaling by the leptin and insulin receptors in their major target tissues. PMID- 25013400 TI - Rab proteins implicated in lipid storage and mobilization. AB - Abnormal intracellular accumulation or transport of lipids contributes greatly to the pathogenesis of human diseases. In the liver, excess accumulation of triacylglycerol (TG) leads to fatty liver disease encompassing steatosis, steatohepatitis and fibrosis. This places individuals at risk of developing cirrhosis, hepatocellular carcinoma or hepatic decompensation and also contributes to the emergence of insulin resistance and dyslipidemias affecting many other organs. Excessive accumulation of TG in adipose tissue contributes to insulin resistance as well as to the release of cytokines attracting leucocytes leading to a pro-inflammatory state. Pathological accumulation of cholesteryl ester (CE) in macrophages in the arterial wall is the progenitor of atherosclerotic plaques and heart disease. Overconsumption of dietary fat, cholesterol and carbohydrates explains why these diseases are on the increase yet offers few clues for how to prevent or treat individuals. Dietary regimes have proven futile and barring surgery, no realistic alternatives are at hand as effective drugs are few and not without side effects. Overweight and obesity related diseases are no longer restricted to the developed world and as such, constitute a global problem. Development of new drugs and treatment strategies are a priority yet requires as a first step, elucidation of the molecular pathophysiology underlying each associated disease state. The lipid droplet (LD), an up to now overlooked intracellular organelle, appears at the heart of each pathophysiology linking key regulatory and metabolic processes as well as constituting the site of storage of both TGs and CEs. As the molecular machinery and mechanisms of LDs of each cell type are being elucidated, regulatory proteins used to control various cellular processes are emerging. Of these and the subject of this review, small GTPases belonging to the Rab protein family appear as important molecular switches used in the regulation of the intracellular trafficking and storage of lipids. PMID- 25013402 TI - A genetic variant in pseudogene E2F3P1 contributes to prognosis of hepatocellular carcinoma. AB - Certain pseudogenes may regulate their protein-coding cousins by competing for miRNAs and play an active biological role in cancer. However, few studies have focused on the association of genetic variations in pseudogenes with cancer prognosis. We selected six potentially functional single nucleotide polymorphisms (SNPs) in cancer-related pseudogenes, and performed a case-only study to assess the association between those SNPs and the prognosis of hepatocellular carcinoma (HCC) in 331 HBV-positive HCC patients without surgical treatment. Log-rank test and Cox proportional hazard models were used for survival analysis. We found that the A allele of rs9909601 in E2F3P1 was significantly associated with a better prognosis compared with the G allele [adjusted hazard ratio (HR) = 0.69, 95% confidence interval (CI) = 0.56-0.86, P = 0.001]. Additionally, this protective effect was more predominant for patients without chemotherapy and transcatheter hepatic arterial chemoembolization (TACE) treatment. Interestingly, we also detected a statistically significant multiplicative interaction between genotypes of rs9909601 and chemotherapy or TACE status on HCC survival (P for multiplicative interaction < 0.001). These findings indicate that rs9909601 in the pseudogene E2F3P1 may be a genetic marker for HCC prognosis in Chinese. PMID- 25013403 TI - Expression of human hepatic lipase negatively impacts apolipoprotein A-I production in primary hepatocytes from Lipc-null mice. AB - This study aimed to examine whether expression of human hepatic lipase (hHL) exerted an intracellular effect on hepatic production of apolipoprotein (apo) A I. The levels of secreted and cell-associated apoA-I were contrasted between primary hepatocytes isolated from Lipc-null and C57BL/6 mice, and between Lipc null hepatocytes transfected with either hHL-encoding or control adenovirus. An HSPG-binding deficient hHL protein (hHLmt) was used to determine the impact of cell surface binding on HL action. Accumulation of apoA-I in conditioned media of primary hepatocytes isolated from Lipc-null mice was increased as compared to that from C57BL/6 mice. Metabolic labeling experiments showed that secretion of (35)S-apoA-I from Lipc-null cells was significantly higher than that from C57BL/6 cells. Expression of hHL in Lipc-null hepatocytes, through adenovirus-mediated gene transfer, resulted in decreased synthesis and secretion of (35)S-apoA-I, but not (35)S-apoE, as compared with cells transfected with control adenovirus. Expression of HSPG-binding deficient hHLmt in Lipc-null cells also exerted an inhibitory effect on apoA-I production, even though hHLmt displayed impaired exit from the endoplasmic reticulum as compared with hHL. Subcellular fractionation revealed that expression of hHL or hHLmt led to increased microsome-association of apoA-I relative to non-transfected control. Expression of hHL negatively impacts hepatic production of apoA-I. PMID- 25013401 TI - Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion. AB - Apolipoprotein B (apoB) is the main protein component of very low density lipoprotein (VLDL) and is necessary for the assembly and secretion of these triglyceride (TG)-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein (LDL) in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation (ERAD) by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regulated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autophagy and postprandial activation of the unfolded protein response (UPR) may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states. PMID- 25013405 TI - Correlation of obstructive sleep apnea hypopnea syndrome with metabolic syndrome in snorers. AB - Though obstructive sleep apnea hypopnea syndrome (OSAHS) and metabolic syndrome (MS) are correlated; the contributing factors for the occurrence of MS in Chinese snorers remain largely undefined. We aimed to investigate the associated pathogenesis of coexistence of OSAHS and MS in Chinese snorers. A total of 144 Chinese habitual snorers were divided into 3 groups, the control group (simple snorers) (n = 36), the mild OSAHS group (n = 52) and the moderate-to-severe OSAHS group (n = 56). The incidence of MS in the moderate-to-severe OSAHS group (26.8%) was significantly higher than that in the control group (8.3%), the mild OSAHS group (11.1%) and all the OSAHS patients (19.45%) (all P < 0.05). Homeostatic model assessment (HOMA) index and proinsulin (PI) were negatively correlated with nocturnal meanSpO2 and miniSpO2. Meanwhile, nocturnal SpO2 were negatively correlated with body mass index, waist and neck circumferences and diastolic blood pressure, but positively correlated with total cholesterol and high-density lipoprotein cholesterol. The study indicated that in Chinese snorers, moderate-to-severe OSAHS was closely associated with MS via nocturnal hypoxemia. PMID- 25013404 TI - Class A scavenger receptor activation inhibits endoplasmic reticulum stress induced autophagy in macrophage. AB - Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Involvement of autophagy in bulk degradation of cellular components has been recognized recently as an important mechanism for cell survival under endoplasmic reticulum (ER) stress. We previously found that the engagement of class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, pro-apoptotic mechanisms mediated by SR-A are not fully understood. Therefore, we sought to see if SR-A mediated apoptosis was associated with autophagy in macrophages. Here, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophagosomes under ER stress. The inhibition of LC3-II formation was paralleled by the activation of the mTOR pathway, and the inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Furthermore, apoptosis induced by fucoidan was prevented under ER stress by the mTOR inhibitor. We propose that fucoidan, a SR-A agonist, may contribute to macrophage apoptosis during ER stress by inhibiting autophagy. PMID- 25013406 TI - Position and complications of pedicle screw insertion with or without image navigation techniques in the thoracolumbar spine: a meta-analysis of comparative studies. AB - Computer-navigated pedicle screw insertion is applied to the thoracic and lumbar spine to attain high insertion accuracy and a low rate of screw-related complications. However, some in vivo and in vitro studies have shown that no advantages are gained with the use of navigation techniques compared to conventional techniques. Additionally, inconsistent conclusions have been drawn in various studies due to different population characteristics and methods used to assess the accuracy of screw placement. Moreover, it is not clear whether pedicle screw insertion with navigation techniques decreases the incidence of screw-related complications. Therefore, this study was sought to perform a meta analysis of all available prospective evidence regarding pedicle screw insertion with or without navigation techniques in human thoracic and lumbar spine. We considered in vivo comparative studies that assessed the results of pedicle screw placement with or without navigation techniques. PubMed, Ovid MEDLINE and EMBASE databases were searched. Three published randomized controlled trials (RCTs) and nine retrospective comparative studies met the inclusion criteria. These studies included a total of 732 patients in whom 4,953 screws were inserted. In conclusion, accuracy of the position of grade I, II, III and IV screws and complication rate related to pedicle screw placement were significantly increased when navigation techniques were used in comparison to conventional techniques. Future research in this area should include RCTs with well-planned methodology to limit bias and report on validated, patient-based outcome measures. PMID- 25013407 TI - Retraction. PMID- 25013408 TI - Drainage vs. non-drainage after cholecystectomy for acute cholecystitis: a retrospective study. AB - Many surgeons practice prophylactic drainage after cholecystectomy without reliable evidence. This study was conducted to answer the question whether to drain or not to drain after cholecystectomy for acute calculous cholecystitis. A retrospective review of all patients who had cholecystectomy for acute cholecystitis in Aseer Central Hospital, Abha, Saudi Arabia, was conducted from April 2010 to April 2012. Data were extracted from hospital case files. Preoperative data included clinical presentation, routine investigations and liver function tests. Operative data included excessive adhesions, bleeding, bile leak, and drain insertion. Complicated cases such as pericholecystic collections, mucocele and empyema were also reported. Patients who needed therapeutic drainage were excluded. Postoperative data included hospital stay, volume of drained fluid, time of drain removal, and drain site problems. The study included 103 patients allocated into two groups; group A (n = 38) for patients with operative drain insertion and group B (n = 65) for patients without drain insertion. The number of patients with preoperative diagnosis of acute non complicated cholecystitis was significantly greater in group B (80%) than group A (36.8%) (P < 0.001). Operative time was significantly longer in group A. All patients who were converted from laparoscopic to open cholecystectomy were in group A. Multivariate analysis revealed that hospital stay was significantly (P < 0.001) longer in patients with preoperative complications. There was no added benefit for prophylactic drain insertion after cholecystectomy for acute calculous cholecystitis in non-complicated or in complicated cases. PMID- 25013409 TI - Analytical characteristics of a qPCR-based molecular diagnostic assay - conceptual considerations for laboratory personnel. PMID- 25013410 TI - Diagnosis of arboviruses using indirect sandwich IgG ELISA in horses from the Brazilian Amazon. AB - BACKGROUND: The Amazon as a whole is the largest reservoir of arboviruses worldwide, while the Brazilian Amazon hosts the largest variety of arboviruses isolated to date. In this study, the results of an indirect sandwich IgG ELISA, standardized for 19 arbovirustypes circulating among horses in Brazilian Amazon, were compared to results of the hemagglutination inhibition test. A screening test assessed the conditional probability distribution and a Pearson linear correlation test determined the correlation strength among the absorbance values recorded for viruses from the same family. FINDINGS: Sensitivity varied between 40.85 and 100%; the specificity was low and ranged from 39.71 to 67.0%; and the accuracy varied between 41 and 65.2%. The test developed in this study yielded a large number of serological cross-reactions. CONCLUSIONS: The test can be employed to detect IgG antibodies within one arbovirus family; however, the hemagglutination test or other more specific techniques, such as the serum neutralization test in mice or the plaque-reduction neutralization test, are essential complementary methods for positive cases. PMID- 25013411 TI - Platelet rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw: personal experience and review of the literature. AB - Bisphosphonates (BPs) are a class of synthetic drugs commonly used to treat bone metastasis and various bone diseases that cause osseous fragility (such as osteoporosis). Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a common complication in patients who received BPs, especially intravenously. Recently, osteonecrosis of the jaw (ONJ) caused by chemotherapeutic not belonging to BPs drug class has been reported. For this reason, it has been proposed recently to rename BRONJ in antiresorptive agents related osteonecrosis of the jaw (ARONJ), to include a wider spectrum of drugs that may cause osteonecrosis of the jaw. The most debated topic about ARONJ/BRONJ is therapy. The most adequate procedure is far from being standardized and prevention seems to play a pivotal role. In our study, we considered 72 patients with BRONJ with nonsurgical therapy, surgical therapy, and surgical therapy with platelet rich plasma (PRP) gel to evaluate its therapeutic effect in promoting ONJ wounds healing. Good results showed by PRP in improving wound healing give away to case-control randomized studies that could give definitive evidence of its effectiveness. PMID- 25013412 TI - State of oral mucosa as an additional symptom in the course of primary amyloidosis and multiple myeloma disease. AB - Multiple myeloma (myeloma multiplex (MM)) is a malignant non-Hodgkin's lymphoma derived from B cell. Its essence is a malignant clone of plasma cells synthesizing growth of monoclonal immunoglobulin, which infiltrate the bone marrow, destroy the bone structure, and prevent the proper production of blood cells components. The paper presents a case of 62-year-old patient who developed symptoms in addition to neurological and haematological changes in the oral mucosa in the course of multiple myeloma. The treatment resulted in partial improvement. The authors wish to draw attention not only to nonspecificity and rarity of changes in the mouth which can meet the dentist but also to the complexity of the multidisciplinary therapy patients diagnosed with MM. PMID- 25013413 TI - Histoplasmosis presenting as granulomatous hepatitis: case report and review of the literature. AB - Background. Histoplasma capsulatum is the most common endemic mycosis in the United States and is a frequent cause of opportunistic infection in immunodeficient hosts. Histoplasmosis is most often self-limiting and goes unrecognized in the immunocompetent population but can progress to disseminated histoplasmosis in patients with an impaired immune system. Liver involvement as a part of disseminated histoplasmosis which usually originates in the lung is well known. However, extrapulmonary hepatic histoplasmosis as a primary manifestation is extremely rare. Case Presentation. We report a rare case of histoplasmosis that presented as persistent fever and abnormal liver function tests in a 66-year old female with rheumatoid arthritis, receiving infliximab. Conclusion. Emphasizing histoplasmosis as a major cause of acute granulomatous hepatitis and fever of unknown origin in cell mediated immunodeficient population, this case highlights the need for high index of suspicion and the importance of prompt diagnosis since any delay of treatment can be life threatening in this population. PMID- 25013414 TI - How adolescent subjective health and satisfaction with weight and body shape are related to participation in sports. AB - BACKGROUND: Physical exercise has positive effects on health. However, its associations with self-rated health and body image, which are important predictors for adolescents' wellbeing and later morbidity, are complex. METHODS: Cross-sectional survey among 2527 Norwegian adolescents. We examined the relations between self-reported gender, body size, amount and type of exercise and measures of self-rated health, drive for thinness, and desire to change body, with binary logistic regression analyses. RESULTS: Girls and overweight students reported to a greater extent than their peers impaired self-rated health, weight concerns, and desire to change their body. Increasing amount of time spent on sports was related to improved self-rated health in a dose-response manner. Both girls and boys who engaged in individual sports with an advantage of leanness, but only girls engaged in team sports, reported an increased desire to change the body. However, weight concern was not related to amount or type of sports. CONCLUSIONS: Physical exercise is positively related to self-reported health but has negative associations with body image for many adolescents. Health promotion efforts should consider this paradox and stimulate physical activity and sports along with body acceptance. PMID- 25013417 TI - Evaluation of Protein Expression in Housekeeping Genes across Multiple Tissues in Rats. AB - BACKGROUND: Housekeeping genes, which show constant protein expression patterns between different tissue types, are very important in molecular biological studies as an internal control for protein research. METHODS: The protein expression profiles of seven housekeeping genes (HPRT1, PPIA, GYS1, TBP, YWHAZ, GAPDH and ACTB) in various rat tissues (cerebrum, cerebellum, cardiac ventricle and atrium, psoas muscle, femoral muscle, liver, spleen, kidney, and aorta) were analyzed by Western blot and compared by coefficient of variation (CV). RESULTS: HPRT1 was stably expressed (CV<=10%) in six tissues (cerebrum, cerebellum, ventricle, femoral muscle, spleen, and kidney), PPIA was stably expressed in five tissues (cerebrum, cerebellum, ventricle, spleen and kidney), YWHAZ was stably expressed in three tissues (cerebrum, cerebellum, and kidney), and GAPDH was stably expressed in four tissues (cerebrum, ventricle, psoas muscle, and kidney). In comparison, GYS1, TBP, and ACTB were found to have CV values over 10% in all tissues. Of the seven genes examined, four (HPRT1, PPIA, YWHAZ, and GAPDH) were found to be stably expressed across multiple organs, with low CV values (<=10%). CONCLUSIONS: These results will provide fundamental information regarding internal controls for protein expression studies and can be used for analysis of postmortem protein degradation patterns in forensic medicine. PMID- 25013416 TI - Extrapulmonary lymphangioleiomyoma: clinicopathological analysis of 4 cases. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a slowly progressive neoplastic disease that predominantly affects females. Usually, LAM affects the lung; it can also affect extrapulmonary sites, such as the mediastinum, the retroperitoneum, or the lymph nodes, although these locations are rare. A localized form of LAM can manifest as extrapulmonary lesions; this form is referred to as extrapulmonary lymphangioleiomyoma (E-LAM). Due to the rare occurrence of E-LAM and its variable, atypical location, E-LAM is often difficult to diagnose. Herein, we report the clinicopathological information from four E-LAM cases, and also review previous articles investigating this disease. METHODS: Four patients with E-LAM were identified at the Samsung Medical Center (Seoul, Korea) from 1995 to 2012. All E-LAM lesions underwent surgical excision. RESULTS: All patients were females within the age range of 43 to 47 years. Two patients had para-aortic retroperitoneal masses, while the other two patients had pelvic lesions; two out of the four patients also had accompanying pulmonary LAM. In addition, no patient displayed any evidence of tuberous sclerosis. Histologically, two patients exhibited nuclear atypism with cytologic degeneration. CONCLUSIONS: E-LAM should be considered in the differential diagnosis of patients presenting with pelvic or para-aortic masses. We also conclude that further clinical and pathological evaluation is needed in patients with E-LAM and nuclear atypism. PMID- 25013415 TI - Current Concepts and Occurrence of Epithelial Odontogenic Tumors: II. Calcifying Epithelial Odontogenic Tumor Versus Ghost Cell Odontogenic Tumors Derived from Calcifying Odontogenic Cyst. AB - Calcifying epithelial odontogenic tumors (CEOTs) and ghost cell odontogenic tumors (GCOTs) are characteristic odontogenic origin epithelial tumors which produce calcifying materials from transformed epithelial tumor cells. CEOT is a benign odontogenic tumor composed of polygonal epithelial tumor cells that show retrogressive calcific changes, amyloid-like deposition, and clear cytoplasm. Differentially, GCOTs are a group of transient tumors characterized by ghost cell presence, which comprise calcifying cystic odontogenic tumor (CCOT), dentinogenic ghost cell tumor (DGCT), and ghost cell odontogenic carcinoma (GCOC), all derived from calcifying odontogenic cysts (COCs). There is considerable confusion about COCs and GCOTs terminology, but these lesions can be classified as COCs or GCOTs, based on their cystic or tumorous natures, respectively. GCOTs include ameloblastomatous tumors derived from dominant odontogenic cysts classified as CCOTs, ghost cell-rich tumors producing dentinoid materials as DGCTs, and the GCOT malignant counterpart, GCOCs. Many authors have reported CEOTs and GCOTs variably express keratins, beta-catenin, BCL-2, BSP, RANKL, OPG, Notch1, Jagged1, TGF-beta, SMADs, and other proteins. However, these heterogeneous lesions should be differentially diagnosed to allow for accurate tumor progression and prognosis prediction. PMID- 25013419 TI - Expression of CD99 in Multiple Myeloma: A Clinicopathologic and Immunohistochemical Study of 170 Cases. AB - BACKGROUND: Multiple myeloma (MM) is a heterogeneous and ultimately fatal disease. Risk stratification using prognostic biomarkers is crucial to individualize treatments. We sought to investigate the role of CD99, a transmembrane protein highly expressed in many hematopoietic cells including subpopulations of normal and neoplastic plasma cells, for MM risk stratification. METHODS: CD99 expression was measured in paraffin samples of bone marrow and extramedullary biopsies of 170 patients with MM. Patients were divided into those with high score (moderately and strongly positive) and low score (negative and weakly positive), with all staining being cytoplasmic and/or membranous. RESULTS: High anti-CD99 immunostaining was observed in 72 of 136 (52.9%) bone marrow biopsies and 24 of 87 (27.6%) extramedullary biopsies in MM. High CD99 expression of extramedullary specimens was associated with significantly longer overall survival (OS; p=.016). High CD99 expression of extramedullary specimens was also associated with better prognosis in the nonautologous stem cell transplantation group of MM patients (p=.044). In multivariate analysis, International Staging System stage was an independent prognostic factor, whereas CD99 expression was no longer statistically significant. CONCLUSIONS: Expression of CD99 in extramedullary specimens was correlated with longer OS, suggesting that CD99 may be a helpful immunohistochemical marker for risk stratification. PMID- 25013418 TI - Classic papillary thyroid carcinoma with tall cell features and tall cell variant have similar clinicopathologic features. AB - BACKGROUND: The tall cell variant of papillary thyroid carcinoma (TCVPTC) is more aggressive than classic papillary thyroid carcinoma (PTC), but the percentage of tall cells needed to diagnose TCVPTC remains controversial. In addition, little is known about the clinicopathologic features of classic PTC with tall cell features (TCF). METHODS: We retrospectively selected and reviewed the clinicopathologic features and presence of the BRAF mutation in 203 cases of classic PTC, 149 cases of classic PTC with TCF, and 95 cases of TCVPTCs, which were defined as PTCs having <10%, 10-50%, and >=50% tall cells, respectively. RESULTS: TCVPTCs and classic PTCs with TCF did not vary significantly in clinicopathologic characteristics such as pathologic (p) T stage, extrathyroidal extension, pN stage, lateral lymph node metastasis, or BRAF mutations; however, these features differed significantly in TCVPTCs and classic PTCs with TCF in comparison to classic PTCs. Similar results were obtained in a subanalysis of patients with microcarcinomas (<=1.0 cm in size). CONCLUSIONS: Classic PTCs with TCF showed a similar BRAF mutation rate and clinicopathologic features to TCVPTCs, but more aggressive characteristics than classic PTCs. PMID- 25013420 TI - Mesenchymal stromal cells promote tumor progression in fibrosarcoma and gastric cancer cells. AB - BACKGROUND: Extensive evidence has accumulated regarding the role of mesenchymal stromal cells (MSCs) in tumor progression, but the exact effects and mechanisms underlying this role remain unclear. We investigated the effects of MSC associated tumor progression in MSC-sarcoma models and a gastric cancer metastatic model. METHODS: We conducted an in vitro growth kinetics assay and an in vivo tumor progression assay for sarcoma cells and gastric cancer cells in the presence or absence of MSCs. RESULTS: MSC-cocultured human fibrosarcoma cells (HT1080) showed accelerated growth compared with HT1080 alone (79- vs 37-fold change, p<.050). For HT1080, human MSC-coinjected tumors showed significantly greater and highly infiltrative growth compared to those of HT1080 alone (p=.035). For mouse fibrosarcoma cells (WEHI164), mouse MSC-coinjected tumors had greater volume than those of WEHI164 alone (p=.141). For rat sarcoma cells (RR1022), rat MSC-coinjected tumors exhibited greater volume and infiltrative growth than those of RR1022 alone (p=.050). For human gastric cancer cells (5FU), tumors of 5FU alone were compact, nodular in shape, and expansile with good demarcation and no definite lung metastatic nodules, whereas tumors grown in the presence of human MSCs showed highly desmoplastic and infiltrative growth and multiple lung metastasis. CONCLUSIONS: We observed morphological evidence for MSC associated tumor progression of fibrosarcomas and gastric cancer cells. PMID- 25013421 TI - Well-differentiated papillary mesothelioma of the tunica vaginalis: a case study and review of the literature. AB - Well-differentiated papillary mesothelioma is an uncommon tumor of the testes that usually presents as a hydrocele. Here, we present the case of one patient who did not have a history of asbestos exposure. The tumor was localized in the tunica vaginalis and was composed of three pedunculated masses macroscopically. Microscopically, branching papillary structures with focal coagulative necrosis were present. In addition to immunohistochemistry, simian virus 40 DNA was also tested by polymerase chain reaction. This report presents one case of this rare entity, its clinical and macroscopic features, and follow-up results. PMID- 25013422 TI - Low-grade adenosquamous carcinoma of the breast with diverse expression patterns of myoepithelial cell markers on immunohistochemistry: a case study. AB - This paper reports a case of low-grade adenosquamous carcinoma (LGASC) arising in a 69-year-old woman, who presented with a 1-cm palpable mass on her right breast. Core needle biopsy diagnosed the mass as a fibroadenoma. After six months, the mass increased in size, and the patient received subsequent mammotome excision. On microscopic examination, bland-looking small glands were infiltrating into the fibrotic stroma with lymphocytic infiltrates at the periphery. Hematoxylin and eosin staining revealed relatively easily detectable myoepithelial cells along the outside in each of the glandular structures with variable degrees of squamous metaplasia. Based on histologic features, the patient was diagnosed with LGASC. LGASC is a rare variant of metaplastic carcinoma, which is characterized by a favorable prognosis. Due to the bland cytology and presence of myoepithelial cells, LGASC can be misdiagnosed as benign lesion. Additionally, inconsistent expression of myoepithelial markers could aid the diagnosis of LGASC. PMID- 25013423 TI - Anaplastic Transformation of Papillary Thyroid Carcinoma in a Young Man: A Case Study with Immunohistochemical and BRAF Analysis. AB - This study reports a case of anaplastic transformation from a well-differentiated thyroid carcinoma in a young patient. The first recurrent tissue contained poorly differentiated foci that revealed lower thyroglobulin, thyroid transcription factor 1 (TTF-1), and galectin-3 expression than the well-differentiated area. However there was no increased p53 or Ki-67 expression in the poorly differentiated foci, nor in the well-differentiated area. The tissue subsequently relapsed and revealed only anaplastic features, complete loss of thyroglobulin, TTF-1, and galectin-3 expression and revealed an increase in p53 and Ki-67 expression. The BRAF V600E and BRAF V600V mutation were found in the initially diagnosed papillary thyroid carcinoma and the poorly differentiated foci of the recurring papillary thyroid carcinoma; however, only the BRAF V600V mutation was found in the anaplastic carcinoma. These results suggest that overexpression of p53 and Ki-67 contributed to the anaplastic transformation. We also found that the BRAF type changed during the tumor relapse. PMID- 25013424 TI - A case of metastatic angiosarcoma diagnosed by liquid-based preparation: peculiar cytoplasmic changes. AB - Angiosarcoma with predominantly epithelioid features is a rare soft tissue neoplasm and the interpretation of its cytopathologic findings may be difficult. We report a case of metastatic angiosarcoma with predominantly epithelioid features diagnosed by liquid-based cytology. The cytopathologic findings in this case differed from those of the conventional preparation and we found a clean background, no hyperchromatic nuclei and several cytoplasmic changes, including intracytoplasmic vacuoles with peculiar shapes, juxtanuclear condensation and perinuclear clearing. Identification of these changes using liquid-based cytology supplemented with immunochemistry may be helpful in reaching a correct cytopathologic diagnosis. PMID- 25013425 TI - Bilateral stafne bone cavity in the anterior mandible with heterotopic salivary gland tissue: a case report. PMID- 25013426 TI - Dedifferentiated solitary fibrous tumor of thoracic cavity. PMID- 25013427 TI - Intracranial extracerebral glioneuronal heterotopia with adipose tissue and a glioependymal cyst: a case report and review of the literature. PMID- 25013428 TI - Primary gastric histiocytic sarcoma reminiscent of inflammatory pseudotumor: a case report with review of the literature. PMID- 25013429 TI - The basic facts of korean breast cancer in 2011: results of a nationwide survey and breast cancer registry database. AB - Breast cancer is the second most frequent malignancy in Korean women, with a continuously increasing incidence. The Korean Breast Cancer Society has constructed a nationwide breast cancer database through an online registration program. The aim of the present study was to report the fundamental facts on Korean breast cancer in 2011, and to analyze the changing patterns in clinical characteristics and breast cancer management in Korea over the last 10 years. Data on newly diagnosed breast cancer patients, including the total number of cases, age, stage, and type of surgery, for the year 2011 were collected from 84 hospitals and clinics nationwide using a questionnaire survey. Additional data relating to the changing patterns of breast cancer in Korea were collected from the online breast cancer registry database and analyzed. According to nationwide survey data, a total of 16,967 patients were newly diagnosed with breast cancer in 2011. The crude incidence of female breast cancer, including invasive cancer and in situ cancer, was 67 cases per 100,000 women. Analysis of the survey and registry data gave equivalent results in terms of age distribution, stage, and type of surgery. The median age at diagnosis was 50 years, and the proportion of postmenopausal women (51.3%) was higher than that of premenopausal women (48.7%) with breast cancer. The incidence of stage 0 and stage I breast cancer increased continuously over the last 10 years (56.3% in 2011), and breast conserving surgery (65.7%) was performed more frequently than total mastectomy (33.8%). The total number of breast reconstruction surgeries increased approximately 8-fold. We conclude that the clinical characteristics of breast cancer have changed over the past 10 years in Korea, and surgical management has changed accordingly. Analysis of nationwide registry data will contribute to a better understanding of the characteristics of breast cancer in Korea. PMID- 25013430 TI - The educational utility of simulations in teaching history and physical examination skills in diagnosing breast cancer: a review of the literature. AB - This paper is a review of the literature examining the use of medical simulations to teach our future healthcare providers how to diagnose breast cancer. MEDLINE and Embase databases were searched to identify the literature published between 1990 and 2014. In total, 113 articles were retrieved and evaluated for their relevance to the topic. Simulation methods, such as standardized patients and breast models were found to enhance students' abilities to perform patient histories and physical examinations to detect breast cancer. In addition, simulation can help trainees learn how to communicate bad news to patients effectively. There is an abundance of literature supporting the continued use of simulations in the curricula of medical schools. However, future studies based on sound theoretical frameworks are needed to evaluate the positive effects of simulation-based education on patient outcomes. PMID- 25013431 TI - Positive expression of insulin-like growth factor-1 receptor is associated with a positive hormone receptor status and a favorable prognosis in breast cancer. AB - PURPOSE: Insulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined. METHODS: IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive. RESULTS: Positive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031). CONCLUSION: Positive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status. PMID- 25013432 TI - Clinicopathologic characteristics of breast cancer stem cells identified on the basis of aldehyde dehydrogenase 1 expression. AB - PURPOSE: Breast cancer displays varying molecular and clinical features. The ability to form breast tumors has been shown by several studies with aldehyde dehydrogenase 1 (ALDH1) positive cells. The aim of this study is to investigate the association between ALDH1 expression and clinicopathologic characteristics of invasive ductal carcinoma. METHODS: We investigated breast cancer tissues for the prevalence of ALDH1(+) tumor cells and their prognostic value. The present study included paraffin-embedded tissues of 70 patients with or without recurrences. We applied immunohistochemical staining for the detection of ALDH1(+) cells. Analysis of the association of clinical outcomes and molecular subtype with marker status was conducted. RESULTS: ALDH1(+) and ALDH1(-) tumors were more frequent in triple-negative breast cancers and in luminal A breast cancers, respectively (p<0.01). ALDH1 expression was found to exert significant impact on disease free survival (DFS) (ALDH1(+) vs. ALDH1(-), 53.1+/-6.7 months vs. 79.2+/ 4.7 months; p=0.03) and overall survival (OS) (ALDH1(+) vs. ALDH1(-), 68.5+/-4.7 months vs. 95.3+/-1.1 months; p<0.01). In triple-negative breast cancer (TNBC) patients, DFS and OS showed no statistical differences according to ALDH1 expression (ALDH1(+) vs. ALDH1(-), 45.3+/-9.4 months vs. 81.3+/-7.4 months, p=0.52; 69.0+/-7.5 months vs. 91.3+/-6.3 months, p=0.67). However, non-TNBC patients showed significant OS difference between ALDH1(+) and ALDH1(-) tumors (ALDH1(+) vs. ALDH1(-), 77.6+/-3.6 months vs. 98.0+/-1.0 months; p=0.04) with no statistical difference of DFS (ALDH1(+) vs. ALDH1(-), 60.5+/-8.0 months vs. 81.8+/-4.6 months; p=0.27). CONCLUSION: Our findings suggest that the expression of ALDH1 in breast cancer may be associated with TNBC and poor clinical outcomes. On the basis of our findings, we propose that ALDH1 expression in breast cancer could be correlated with poor prognosis, and may contribute to a more aggressive cancer phenotype. PMID- 25013433 TI - Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry. AB - PURPOSE: Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations. METHODS: We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group). RESULTS: The patients of the BRCA1 group were diagnosed at a younger age (median age, 37 years) and had tumors of higher histological (61.3% with histological grade 3) and nuclear (37.5% with nuclear grade 3) grade than those of the registry group. In addition, the frequency of ductal carcinoma in situ in the BRCA1 group was lower (3.7%) than in the registry group, and the BRCA1 group were more likely to be triple-negative breast cancer (61.3%). Patients in the BRCA2 group were also younger at diagnosis (mean age, 41 years) and were more likely to have involvement of the axillary node than the registry group (45.5% vs. 33.5%, p=0.002). The BRCA1 and BRCA2 groups did not show a correlation between tumor size and axillary node involvement. CONCLUSION: We report the characteristics of BRCA mutation positive breast cancer patients in the Korean population through multicenter data and nation-wide breast cancer registry study. However, BRCA-mutated breast cancers appear highly complex, and further research on their molecular basis is needed in Korea. PMID- 25013434 TI - Fatty Acid Composition of Tissue Cultured Breast Carcinoma and the Effect of Stearoyl-CoA Desaturase 1 Inhibition. AB - PURPOSE: Stearoyl-CoA desaturase 1 (SCD1) is a novel therapeutic target in various malignancies, including breast cancer. The present study was designed to investigate the effect of the pharmacologic inhibition of SCD1 on fatty acid composition in tissue explant cultures of human breast cancer and to compare these effects with those in adjacent nonneoplastic breast tissue. METHODS: Paired samples of tumor and adjacent noncancerous tissue were isolated from 12 patients with infiltrating ductal breast cancer. Samples were explant cultured in vitro, exposed to the highly selective SCD1 inhibitor CAY10566, and examined for fatty acid composition by gas liquid chromatography. The cytotoxic and antigrowth effects were evaluated by quantification of lactate dehydrogenase release and by sulforhodamine B (SRB) measurement, respectively. RESULTS: Breast cancer tissue samples were found to have higher levels of monounsaturated fatty acids (MUFA) (p<0.001) and arachidonic acid (20:4n-6, p<0.001) and a lower level of linoleic acid (18:2n-6, p=0.02) than the normal-appearing breast tissues. While exhibiting no evident cytotoxicity, treatment with the SCD1 inhibitor, CAY10566 (0.1-1 uM), for 48 hours significantly increased 18:2n-6 levels in both the tumor and adjacent normal-appearing tissue (approximately 1.2 fold, p<0.05). However, the breast cancer tissue samples showed significant increases in the levels of MUFA and 20:4n-6 compared to the normal-appearing breast tissues (p<0.05). The SRB growth assay revealed a higher rate of inhibition with the SCD1 inhibitor in breast cancer tissues than in normal-appearing tissues (p<0.01, 41% vs. 29%). The SCD1 inhibitor also elevated saturated fatty acid (1.46-fold, p=0.001) levels only in the tumor tissue explant. CONCLUSION: The fatty acid composition and response to SCD1 inhibition differed between the explant cultures from breast cancer and the adjacent normal-appearing tissue. Altered fatty acid composition induced by SCD1 inhibition may also, in addition to Delta9 desaturation, modulate other reactions in de novo fatty acid synthesis and lipogenesis, and subsequently affect the overall survival and progression of breast cancer. PMID- 25013435 TI - miR-205 and miR-200c: Predictive Micro RNAs for Lymph Node Metastasis in Triple Negative Breast Cancer. AB - PURPOSE: We examined expression profiles of 16 micro RNAs (miRNAs) in triple negative breast cancers to identify their potential as biomarkers for lymph node metastasis. METHODS: The expression profiles of miR-9, miR-21, miR-30a, miR-30d, miR-31, miR-34a, miR-34c, miR-100, miR-122, miR-125b, miR-146a, miR-146b, miR 155, miR-181a, miR-200c, and miR-205 were examined by using real-time quantitative reverse transcription polymerase chain reaction in tumor samples and corresponding benign breast tissues. Their associations with histopathological features and prognostic parameters were assessed. RESULTS: When compared with the expression in benign breast tissues, seven of the miRNAs (miR-31, miR-205, miR 34a, miR-146a, miR-125b, miR-34c, and miR-181a) were downregulated more than 1.5 fold in tumor tissues, whereas, only miR-21 was found to be upregulated more than 1.5-fold in tumor tissues. Although miR-200c levels were decreased only 1.12-fold in tumor tissues, the reduced expressions of miR-200c and miR-205 were significantly associated with lymph node metastasis (p=0.021 and p=0.016, respectively). CONCLUSION: Our results demonstrate that miR-205 and miR-200c expression levels may be useful in predicting lymph node metastasis in triple negative breast cancer patients. PMID- 25013436 TI - The Catechol-O-Methyltransferase Val158Met Polymorphism Contributes to the Risk of Breast Cancer in the Chinese Population: An Updated Meta-Analysis. AB - PURPOSE: Catechol-O-methyltransferase (COMT) enzyme plays a central role in estrogen-induced carcinogenesis. Emerging evidence from association studies has revealed that the functional Val158Met polymorphism (rs4680 G>A) of the Catechol O-methyltransferase gene (COMT) has been implicated in susceptibility to breast cancer in the Chinese population, while results of individual published studies remain inconclusive and inconsistent. To assess this association in the Chinese population, a meta-analysis was performed. METHODS: Eligible studies were searched on MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, and the Chinese Biomedicine Database. Odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were pooled to assess the association between COMT polymorphisms and the risk of breast cancer using RevMan 5.2 and Stata 12.0 software. RESULTS: The meta-analysis included 14 eligible studies, with a total of 4,626 breast cancer cases and 5,637 controls. Overall, the COMT Val158Met polymorphism (rs4680 G>A) was significantly associated with an increased risk of breast cancer in several genetic models (A/A vs. G/G: OR, 1.59, 95% CI, 1.12-2.27; A/A vs. G/A+G/G: OR, 1.62, 95% CI, 1.14-2.29; A vs. G: OR, 1.15, 95% CI, 1.00-1.32), and a subgroup analysis according to menopausal status showed that this association was especially evident among premenopausal Chinese women (A/A vs. G/G: OR, 1.87, 95% CI, 0.99-3.54; A/A vs. G/A+G/G: OR, 1.94, 95% CI, 1.03-3.63). CONCLUSION: The results of this meta-analysis indicated that COMT Val158Met variants contribute to breast cancer susceptibility in the Chinese population, particularly among premenopausal women. PMID- 25013437 TI - Effects of geometrical uncertainties on whole breast radiotherapy: a comparison of four different techniques. AB - PURPOSE: The purpose of this study was to quantify the target coverage, homogeneity, and robustness of the dose distributions against geometrical uncertainties associated with four whole breast radiotherapy techniques. METHODS: The study was based on the planning-computed tomography-datasets of 20 patients who underwent whole breast radiotherapy. A total of four treatment plans (wedge, field-in-field [FIF], hybrid intensity-modulated radiotherapy [IMRT], and full IMRT) were created for each patient. The hybrid IMRT plans comprised two opposed tangential open beams plus two IMRT beams. Setup errors were simulated by moving the beam isocenters by 5 mm in the anterior or posterior direction. RESULTS: With the original plan, the wedge technique yielded a high volume receiving >=107% of the prescription dose (V107; 7.5%+/-4.2%), whereas the other three techniques yielded excellent target coverage and homogeneity. A 5 mm anterior displacement caused a large and significant increase in the V107 (+5.2%+/-4.1%, p<0.01) with the FIF plan, but not with the hybrid IMRT (+0.4%+/-1.2%, p=0.11) or full IMRT (+0.7%+/-1.8%, p=0.10) plan. A 5-mm posterior displacement caused a large decrease in the V95 with the hybrid IMRT (-2.5%+/-3.7%, p<0.01) and full IMRT ( 4.3%+/-5.1%, p<0.01) plans, but not with the FIF plan (+0.1%+/-0.7%, p=0.74). The decrease in V95 was significantly smaller with the hybrid IMRT plan than with the full IMRT plan (p<0.01). CONCLUSION: The FIF, hybrid IMRT, and full IMRT plans offered excellent target coverage and homogeneity. Hybrid IMRT provided better robustness against geometrical uncertainties than full IMRT, whereas FIF provided comparable robustness to that of hybrid IMRT. PMID- 25013438 TI - A pilot randomized clinical study of the additive treatment effect of photodynamic therapy in breast cancer patients with chest wall recurrence. AB - PURPOSE: This study investigated the additive effect of photodynamic therapy (PDT) plus traditional radiotherapy (RT) for patients with breast cancer and chest wall recurrence. METHODS: A total of 40 patients with recurrent breast cancer were prospectively randomized to receive RT alone (group A, n=20) or PDT and RT in combination (group B, n=20). Traditional RT at a dose of 50 Gy was delivered in 25 fractions with or without exposure to 5-aminolevulinic acid and red light as PDT. RESULTS: The response rates were not statistically different between the groups, but more patients achieved a complete response (CR) in group B (50%) than in group A (20%). The median time to CR in group B was significantly shorter than that in group A (109.6 days vs. 175.2 days, p=0.001). Adverse event profiles were not different between the groups. CONCLUSION: An additive antitumor effect is demonstrated with additional PDT to RT. This combination therapy might reduce the duration of exposure to RT, but further investigation is warranted. PMID- 25013439 TI - Low rates of additional cancer detection by magnetic resonance imaging in newly diagnosed breast cancer patients who undergo preoperative mammography and ultrasonography. AB - PURPOSE: We evaluated the efficacy of breast magnetic resonance imaging (MRI) for detecting additional malignancies in breast cancer patients newly diagnosed by breast ultrasonography and mammography. METHODS: We retrospectively reviewed the records of 1,038 breast cancer patients who underwent preoperative mammography, bilateral breast ultrasonography, and subsequent breast MRI between August 2007 and December 2010 at single institution in Korea. MRI-detected additional lesions were defined as those lesions detected by breast MRI that were previously undetected by mammography and ultrasonography and which would otherwise have not been identified. RESULTS: Among the 1,038 cases, 228 additional lesions (22.0%) and 30 additional malignancies (2.9%) were detected by breast MRI. Of these 228 lesions, 109 were suspected to be malignant (Breast Imaging-Reporting and Data System category 4 or 5) on breast MRI and second-look ultrasonography and 30 were pathologically confirmed to be malignant (13.2%). Of these 30 lesions, 21 were ipsilateral to the main lesion and nine were contralateral. Fourteen lesions were in situ carcinomas and 16 were invasive carcinomas. The positive predictive value of breast MRI was 27.5% (30/109). No clinicopathological factors were significantly associated with additional malignant foci. CONCLUSION: Breast MRI was useful in detecting additional malignancy in a small number of patients who underwent ultrasonography and mammography. PMID- 25013440 TI - Reliability of the percent density in digital mammography with a semi-automated thresholding method. AB - PURPOSE: The reliability of the quantitative measurement of breast density with a semi-automated thresholding method (CumulusTM) has mainly been investigated with film mammograms. This study aimed to evaluate the intrarater reproducibility of percent density (PD) by CumulusTM with digital mammograms. METHODS: This study included 1,496 craniocaudal digital mammograms from the unaffected breast of breast cancer patients. One rater reviewed each mammogram and estimated the PD using the CumulusTM method. All images were reassessed by the same rater 1 month later without reference to the previously assigned values. The repeatability of the PD was evaluated by an intraclass correlation coefficient (ICC). All patients were grouped based on their body mass index (BMI), age, family history of breast cancer, breastfeeding history and breast area (calculated with CumulusTM), and subgroup analysis for the ICC of each group was performed. All patients were categorized by their Breast Imaging Reporting and Data System (BI-RADS) density pattern, and the mean and standard deviation of the PD by each BI-RADS categories were compared. RESULTS: The ICC for the PD was 0.94, indicating excellent repeatability. The discrepancy between the paired PD values ranged from 0 to 23.93, with an average of 3.90 (standard deviation=3.39). The subgroup ICCs for the PD ranged from 0.88 to 0.96, indicating excellent reliability in all subgroups regardless of patient variables. The ICCs of the PD for the high-risk (BI-RADS 3 and 4) and low-risk (BI-RADS 1 and 2) groups were 0.90 and 0.88, respectively. CONCLUSION: This study suggests that PD calculated with digital mammograms has an acceptable reliability regardless of patient age, BMI, family history of breast cancer, breastfeeding history, breast size, and BI-RADS density pattern. PMID- 25013441 TI - Ductal Carcinoma In Situ Detected by Shear Wave Elastography within a Fibroadenoma. AB - Fibroadenoma is the most common breast tumor in women. Malignant transformation occurs rarely within fibroadenoma at older ages. Clinicians, radiologists, and pathologists need to be aware of malignant transformation within fibroadenomas. Radiologic studies play an important role in the diagnosis of fibroadenoma; however, radiologic findings are often nonspecific for malignancy and may appear completely benign. We detected an occult ductal carcinoma in situ that originated inside a fibroadenoma by using shear wave elastography. We report shear wave elastography findings of ductal carcinoma in situ within fibroadenoma and discuss the diagnostic role of this modality. PMID- 25013442 TI - Microdochectomy assisted by ultrasound-guided indigo carmine staining of intraductal lesions: a case report. AB - Spontaneous bloody nipple discharge from a single duct is a significant clinical problem. When performing preoperative marking of the discharging duct, it is sometimes difficult to identify the duct owing to intermittent discharge. Precise preoperative marking of the discharging duct and intraductal lesions is very important to avoid unnecessary wide excision of breast tissue or failure to remove the cause of nipple discharge. We herein present a case of preoperative ultrasound-guided indigo carmine staining in a patient with no discharge on the day of surgery. When a dilated duct is visualized on ultrasound, the targeted duct can be localized using indigo carmine staining, and it is possible to perform a precise minimal volume microdochectomy. PMID- 25013443 TI - Murine Models of Polycystic Kidney Disease. AB - Polycystic diseases affect approximately 1/1000 and are important causes of kidney failure. No therapies presently are in clinical practice that can prevent disease progression. Multiple mouse models have been produced for the genetic forms of the disease that most commonly affect humans. In this report, we review recent progress in the field and describe some of the outstanding challenges. PMID- 25013444 TI - Ethanol Extract of Alismatis rhizome Inhibits Adipocyte Differentiation of OP9 Cells. AB - The rhizome of Alisma orientale (Alismatis rhizome) has been used in Asia for promoting diuresis to eliminate dampness from the lower-jiao and to expel heat. In this study, an ethanol extract of the rhizome of Alisma orientale (AOE) was prepared and its effects on adipocyte differentiation of OP9 cells were investigated. Treatment with AOE in a differentiation medium for 5 days resulted in dose-dependent inhibition of lipid droplet formation in OP9 cells. Furthermore, AOE significantly inhibited adipocyte differentiation by downregulating the expression of the master transcription factor of adipogenesis, peroxisome proliferation-activity receptor gamma (PPAR gamma ), and related genes, including CCAAT/enhancer binding protein beta (C/EBP beta ), fatty acid binding protein (aP2), and fatty acid synthase (FAS). AOE exerted its inhibitory effects primarily during the early adipogenesis stage (days 1-2), at which time it also exerted dose-dependent inhibition of the expression of C/EBP beta , a protein related to the inhibition of mitotic clonal expansion. Additionally, AOE decreased the expression of autophagy-related proteins, including beclin 1, and the autophagy-related genes, (Atg) 7 and Atg12. Our results indicate that AOE's inhibitory effects on adipocyte differentiation of OP9 cells are mediated by reduced C/EBP beta expression, causing inhibition of mitotic clonal expansion and autophagy. PMID- 25013445 TI - Research on traditional medicine: what has been done, the difficulties, and possible solutions. AB - Traditional medicine (TM) is being used more frequently all over the world. However most often these are choices made by the patient. Integrating TM into mainstream health care would require research to understand the efficacy, safety, and mechanism of action of TM systems. This paper describes research done on TM and difficulties encountered in researching TM, especially when an attempt is made to conform to the model for conventional medicine. The research articles were PubMed searched and categorized as experimental, quasiexperimental, reviews, descriptive, historical, interviews, case histories, and abstract not available. The last part of the report provides suggestions to make research on TM more acceptable and useful, with the ultimate goal of integrating TM into mainstream healthcare with sufficient knowledge about the efficacy, safety, and mechanism of action of TM systems. PMID- 25013446 TI - Lingonberry (Vaccinium vitis-idaea L.) Exhibits Antidiabetic Activities in a Mouse Model of Diet-Induced Obesity. AB - Vaccinium vitis-idaea, commonly known as lingonberry, has been identified among species used by the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes. In a previous study, the ethanol extract of berries of V. vitis-idaea enhanced glucose uptake in C2C12 muscle cells via stimulation of AMP-activated protein kinase (AMPK) pathway. The purpose of this study was to examine the effect of plant extract in a dietary mouse model of mild type 2 diabetes. C57BL/6 mice fed a high-fat diet (HFD, ~35% lipids) for 8 weeks that become obese and insulin-resistant (diet-induced obesity, DIO) were used. Treatment began by adding V. vitis-idaea extract to HFD at 3 different concentrations (125, 250, and 500 mg/Kg) for a subsequent period of 8 weeks (total HFD, 16 weeks). The plant extract significantly decreased glycemia and strongly tended to decrease insulin levels in this model. This was correlated with a significant increase in GLUT4 content and activation of the AMPK and Akt pathways in skeletal muscle. V. vitis idaea treatment also improved hepatic steatosis by decreasing hepatic triglyceride levels and significantly activated liver AMPK and Akt pathways. The results of the present study confirm that V. vitis-idaea represents a culturally relevant treatment option for Cree diabetics and pave the way to clinical studies. PMID- 25013447 TI - Collaboration of Japanese kampo medicine and modern biomedicine. PMID- 25013448 TI - Preliminary study on pain reduction of monosodium iodoacetate-induced knee osteoarthritis in rats by carbon dioxide laser moxibustion. AB - In order to study the effects of CO2 laser moxibustion on the pain and inflammatory cytokine expression in the spinal dorsal horn of rats with monosodium iodoacetate- (MIA-) induced knee osteoarthritis (KOA), we designed an experiment by randomly assigning 8 SD rats into 3 groups, namely, a CO2 laser moxibustion group, a sham treatment group, and a blank control group. The treatment group received a laser moxibustion on acupoint Dubi (ST 35; 5 min/treatment, 1 treatment/day) for 8 days, and after treatment, the rats exhibited significantly increased interhindpaw differences compared with their preinduction values. Meanwhile, cytokine microarray analysis showed that one cytokine (TIMP-1) was significantly upregulated and two cytokines (Agrin and MMP 8) were significantly downregulated in treatment group. The present study suggested that CO2 laser moxibustion created certain pain reduction in the rats with MIA-induced KOA and significantly inhibited the expression of most inflammatory cytokines in the ipsilateral spinal dorsal horn. PMID- 25013449 TI - Selective Antibiofilm Effects of Lucilia sericata Larvae Secretions/Excretions against Wound Pathogens. AB - Background. Maggot debridement therapy (MDT), using Lucilia sericata larvae, represents efficient, simple, and low-cost therapy for the treatment of chronic wounds. Aim. The aim was to investigate the antibiofilm activity of maggot excretions/secretions (ES) against biofilm of wound isolates Staphylococcus aureus (S. aureus), Enterobacter cloacae (E. cloacae), and Proteus mirabilis (P. mirabilis). Methods. Quantification of biofilm formation, was carried out using a microtiter plate assay. Proteolytic activity of maggot ES was performed using skim milk agar plates. A solid phase extraction and reverse phase HPLC C18 chromatography were employed to the isolate of maggot ES antibiofilm compounds. Results. Maggot ES at 100 mg/mL concentration significantly reduced biofilm formation thus disrupting established biofilm of E. cloacae. Heat-treated ES did not show any antibiofilm activity towards E. cloacae. Similar results were obtained in the case of S. aureus; however, the heat-treatment of maggot ES did not affect its antibiofilm activity. Moreover, a compound with molecular weight of 25 kDa exhibiting antibiofilm activity was identified in maggot ES. On the other hand, maggot ES protected and even stimulated P. mirabilis biofilm formation. Conclusions. Our results suggest that maggot ES may act selectively against different bacterial strain. PMID- 25013450 TI - Rabdosia japonica var. glaucocalyx Flavonoids Fraction Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice. AB - Rabdosia japonica var. glaucocalyx (Maxim.) Hara, belonging to the Labiatae family, is widely used as an anti-inflammatory and antitumor drug for the treatment of different inflammations and cancers. Aim of the Study. To investigate therapeutic effects and possible mechanism of the flavonoids fraction of Rabdosia japonica var. glaucocalyx (Maxim.) Hara (RJFs) in acute lung injury (ALI) mice induced by lipopolysaccharide (LPS). Materials and Methods. Mice were orally administrated with RJFs (6.4, 12.8, and 25.6 mg/kg) per day for 7 days, consecutively, before LPS challenge. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analysis. The level of complement 3 (C3) in serum was quantified by a sandwich ELISA kit. Results. RJFs significantly attenuated LPS-induced ALI via reducing productions of the level of inflammatory mediators (TNF- alpha , IL-6, and IL-1 beta ), and significantly reduced complement deposition with decreasing the level of C3 in serum, which was exhibited together with the lowered myeloperoxidase (MPO) activity and nitric oxide (NO) and protein concentration in BALF. Conclusions. RJFs significantly attenuate LPS-induced ALI via reducing productions of proinflammatory mediators, decreasing the level of complement, and reducing radicals. PMID- 25013451 TI - The effects of opioids on HIV reactivation in latently-infected T-lymphoblasts. AB - BACKGROUND: Opioids may have effects on susceptibility to HIV-infection, viral replication and disease progression. Injecting drug users (IDU), as well as anyone receiving opioids for anesthesia and analgesia may suffer the clinical consequences of such interactions. There is conflicting data between in vitro experiments showing an enhancing effect of opioids on HIV replication and clinical data, mostly showing no such effect. For clarification we studied the effects of the opioids heroin and morphine on HIV replication in cultured CD4 positive T cells at several concentrations and we related the observed effects with the relevant reached plasma concentrations found in IDUs. METHODS: Latently infected ACH-2 T lymphoblasts were incubated with different concentrations of morphine and heroine. Reactivation of HIV was assessed by intracellular staining of viral Gag p24 protein and subsequent flow cytometric quantification of p24 positive cells. The influence of the opioid antagonist naloxone and the antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH) on HIV reactivation was determined. Cell viability was investigated by 7-AAD staining and flow cytometric quantification. RESULTS: Morphine and heroine triggered reactivation of HIV replication in ACH-2 cells in a dose-dependent manner at concentrations above 1 mM (EC50 morphine 2.82 mM; EC50 morphine 1.96 mM). Naloxone did not interfere with heroine-mediated HIV reactivation, even at high concentrations (1 mM). Opioids also triggered necrotic cell death at similar concentrations at which HIV reactivation was observed. Both opioid-mediated reactivation of HIV and opioid-triggered cell death could be inhibited by the antioxidants GSH and NAC. CONCLUSIONS: Opioids reactivate HIV in vitro but at concentrations that are far above the plasma levels of analgesic regimes or drug concentrations found in IDUs. HIV reactivation was mediated by effects unrelated to opioid-receptor activation and was tightly linked to the cytotoxic activity of the substances at millimolar concentrations, suggesting that opioid-mediated reactivation of HIV was due to accompanying effects of cellular necrosis such as activation of reactive oxygen species and NF-kappaB. PMID- 25013452 TI - Study on construction of a medical x-ray direct digital radiography system and hybrid preprocessing methods. AB - We construct a medical X-ray direct digital radiography (DDR) system based on a CCD (charge-coupled devices) camera. For the original images captured from X-ray exposure, computer first executes image flat-field correction and image gamma correction, and then carries out image contrast enhancement. A hybrid image contrast enhancement algorithm which is based on sharp frequency localization contourlet transform (SFL-CT) and contrast limited adaptive histogram equalization (CLAHE), is proposed and verified by the clinical DDR images. Experimental results show that, for the medical X-ray DDR images, the proposed comprehensive preprocessing algorithm can not only greatly enhance the contrast and detail information, but also improve the resolution capability of DDR system. PMID- 25013453 TI - Background-suppressed MR venography of the brain using magnitude data: a high pass filtering approach. AB - Conventional susceptibility-weighted imaging (SWI) uses both phase and magnitude data for the enhancement of venous vasculature and, thus, is subject to signal loss in regions with severe field inhomogeneity and in the peripheral regions of the brain in the minimum-intensity projection. The purpose of this study is to enhance the visibility of the venous vasculature and reduce the artifacts in the venography by suppressing the background signal in postprocessing. A high-pass filter with an inverted Hamming window or an inverted Fermi window was applied to the Fourier domain of the magnitude images to enhance the visibility of the venous vasculature in the brain after data acquisition. The high-pass filtering approach has the advantages of enhancing the visibility of small veins, diminishing the off-resonance artifact, reducing signal loss in the peripheral regions of the brain in projection, and nearly completely suppressing the background signal. The proposed postprocessing technique is effective for the visualization of small venous vasculature using the magnitude data alone. PMID- 25013454 TI - Solution of radiative transfer equation with a continuous and stochastic varying refractive index by legendre transform method. AB - The present paper gives a new computational framework within which radiative transfer in a varying refractive index biological tissue can be studied. In our previous works, Legendre transform was used as an innovative view to handle the angular derivative terms in the case of uniform refractive index spherical medium. In biomedical optics, our analysis can be considered as a forward problem solution in a diffuse optical tomography imaging scheme. We consider a rectangular biological tissue-like domain with spatially varying refractive index submitted to a near infrared continuous light source. Interaction of radiation with the biological material into the medium is handled by a radiative transfer model. In the studied situation, the model displays two angular redistribution terms that are treated with Legendre integral transform. The model is used to study a possible detection of abnormalities in a general biological tissue. The effect of the embedded nonhomogeneous objects on the transmitted signal is studied. Particularly, detection of targets of localized heterogeneous inclusions within the tissue is discussed. Results show that models accounting for variation of refractive index can yield useful predictions about the target and the location of abnormal inclusions within the tissue. PMID- 25013455 TI - Mathematical methods for assessing the prognostic of fixed partial dentures resulting from evaluating a group of dental patients in Romania. AB - Based on some mathematical and statistical approaches, our study leads to some conclusions concerning the procedures related to the orodental prosthetics. Occlusal equilibration in orodental prosthetics is a major issue because besides motivating patients for a regular daily oral hygiene, it could significantly increase the longevity of FPR. More dental hygiene information should be given after prosthetic treatment and patients should be motivated to attend recalls on a regular basis for professional teeth-cleaning. Interdental cleaning aids should be explained and the patients have to be motivated to use them at least once a day and the using technique should be individualized. Regarding the application of the deformable models theory, implemented in the context of an expert type software environment, it is known that the fact that modelling by advanced methods and techniques based on the deformable surfaces theory increases the efficiency of the dentofacial prosthetics procedures is a domain of great interest in the actual medical research. PMID- 25013456 TI - Emitters of N-photon bundles. AB - Controlling the ouput of a light emitter is one of the basic tasks of photonics, with landmarks such as the laser and single-photon sources. The development of quantum applications makes it increasingly important to diversify the available quantum sources. Here, we propose a cavity QED scheme to realize emitters that release their energy in groups, or "bundles" of N photons, for integer N. Close to 100% of two-photon emission and 90% of three-photon emission is shown to be within reach of state of the art samples. The emission can be tuned with system parameters so that the device behaves as a laser or as a N-photon gun. The theoretical formalism to characterize such emitters is developed, with the bundle statistics arising as an extension of the fundamental correlation functions of quantum optics. These emitters will be useful for quantum information processing and for medical applications. PMID- 25013457 TI - Diagnostic utility of novel combined arrays for genome-wide simultaneous detection of aneuploidy and uniparental isodisomy in losses of pregnancy. AB - BACKGROUND: This proof-of-principle study demonstrates the usefulness and robustness of a novel array based method for the elucidation of genetic causes underlying early pregnancy loss. A combined microarray utilizing comparative genomic hybridization and single nucleotide polymorphism detection (CGH + SNP) was used for parallel genome-wide identification of copy number and heterozygosity status of 70 products of conception. Results of samples with previously determined aneuploidies were juxtaposed to those of a second cohort appearing normal after routine genetic diagnostics. RESULTS: All chromosomal imbalances were confirmed, in one sample of the aneuploid panel additional monosomy X was discovered. Genome-wide uniparental disomy causing a complete hydatidiform mole was identified in another sample. No specimen featured microaberrations of obvious clinical relevance. Among cases with presumable euploidy, one microdeletion and a single region of homozygosity were assigned unclear clinical significance. CONCLUSIONS: The results prove the utility of combined imbalance and homozygosity mapping for routine workup of these challenging specimens. Moreover parallel screening at submicroscopic resolution facilitates the detection of novel genetic alterations underlying spontaneous abortion. PMID- 25013458 TI - Effect of glycemic variability on short term prognosis in acute myocardial infarction subjects undergoing primary percutaneous coronary interventions. AB - OBJECTIVE: Glycemic variability (GV) still remains unclear whether acute glycemic excursion has the important prognostic significance in ST-segment elevation myocardial infarction (STEMI) patients undergoing p-PCI. So our aim is to assess the prognostic value of GV in STEMI patients undergoing p-PCI. METHODS: We studied 237 STEMI patients undergoing p-PCI, whose clinical and laboratory data were collected. We used a continuous glucose monitoring system (CGMS) to measure the fluctuations of blood glucose. Participants were grouped into diabetes group and non-diabetes group, and grouped into tertiles of mean amplitude of glycemic excursions (MAGE). The major adverse cardiac events (MACE) of patients was documented during in-hospital and 30-day follow-up. The relationship of MAGE and the incidence of MACE were analyzed. RESULTS: Data from 237 subjects were incorporated into the statistical analysis, a higher MAGE level was associated with the higher peak CK-MB values (r = 0.374, P <0.01), and the higher peak cTnI values (r = 0.410, P <0.01). The rate of composite MACE by MAGE tertiles (<2.37 mmol/l, 2.37-3.65 mmol/l and >3.65 mmol/l) was 7.5% vs. 14.1% vs. 22.8%, respectively (P = 0.025); STEMI patients with a higher MAGE level had a significantly higher non-IRA revascularization compared with those with lower MAGE levels (32% vs. 15% vs. 21%, P = 0.037). Moreover, diabetic patients with higher MAGE level had significantly higher incidence of composite MACE and non IRA revascularization, non-diabetic subjects did not show the similar results. In multivariable logistic analysis, the independent predictors of MACE were: MBG, MAGE and LVEF in diabetic subjects and were MBG and MAGE in nondiabetic subjects. Other factors were not significantly associated with MACE. CONCLUSIONS: Greater GV is associated with composite MACE and non-IRA revascularization during in hospital and 30-day follow-up in unadjusted analyses, especially for diabetic subjects. After multivariable logistic analysis, GV remains an independent prognostic factor for composite MACE in STEMI patients undergoing p-PCI. PMID- 25013459 TI - Construction of a versatile and functional nanoparticle platform derived from a helical diblock copolypeptide-based biomimetic polymer. AB - Sequential polymerization of N-carboxyanhydrides accelerated by nitrogen flow is utilized to generate a novel well-defined diblock copolypeptide (PDI = 1.08), with incorporation of alkyne-functionalized side-chain groups allowing for rapid and efficient thiol-yne click-type modifications, followed by self-assembly into nanopure water to construct a helical polypeptide-based versatile and functional nanoparticle platform. PMID- 25013460 TI - Stromal fibroblast activation and their potential association with uterine fibroids (Review). AB - Uterine fibroids are the most common type of benign, gynecologic neoplasm and are the primary indication for performance of a hysterectomy, accounting for >200,000 hysterectomies annually in the USA. At present, females are younger and exhibit larger leiomyomas at the time of diagnosis. Cancer-associated fibroblasts in tumor microenvironments have emerged as an important target for cancer therapy. Repeated stimulation by infectious or non-infectious agents in the uterine tissues, including inflammation, mechanical forces or hypoxia, stimulate the resident fibroblasts to undergo specific activation and, thus, are significant in tumorigenesis. Furthermore, complex signaling pathways regulate the mechanisms of fibroblastic activation. The current review focuses on the molecular mechanisms of fibroblastic activation and the potential association with uterine leiomyoma pathogenesis, enabling an integrated pathogenic analysis for review of the therapeutic options. PMID- 25013461 TI - The paediatric story of human papillomavirus (Review). AB - Human papillomavirus (HPV) is composed of a particularly heterogeneous family of DNA viruses, which has gained much attention in recent years due to the discoveries of Professor Harald zur Hausen, who first identified a connection between HPV and cervical cancer. Professor Harald zur Hausen, the 'Father of HPV Virology', was the recipient of the 2008 Nobel Prize. HPV can be transmitted through physical contact via autoinoculation or fomites, sexual contact, as well as vertically from the HPV-positive mother to her newborn, causing subclinical or clinical infections. In infancy and childhood, HPV-associated clinical infections include skin warts, genital warts and juvenile recurrent respiratory papillomatosis, while cervical squamous intraepithelial lesions have also been reported among adolescent girls. To date, several research teams, worldwide, have extensively investigated HPV from the paediatric point of view. This primitive effort has been performed before the recent great expansion of paediatric HPV research due to the vaccination programmes against HPV, which were introduced into clinical practice in 2006. In this review article, we present a brief overview of paediatric HPV research after the first report in 1978 involving children in the research of HPV until the time point of this great expansion. In the future, it is expected that further unresolved issues will be addressed and clarified, as the paediatric story of HPV remains a challenging research target. PMID- 25013462 TI - Role of secreted type I collagen derived from stromal cells in two breast cancer cell lines. AB - Collagen is one of numerous components of the cellular microenvironment. To date, the association between the microenvironment and tumorigenesis of malignant breast cancer remains elusive. Therefore, the aim of the present study was to investigate the potential role of a secretory protein of stromal cells, type I collagen, in the development of the aggressive characteristics of breast cancer cells. MDA-MB231 and MCF7 breast cancer cell lines were maintained in cultured media of normal human dermal fibroblasts (HDFs) and type I collagen-containing media. The morphological changes, adhesion capacity and matrix metalloproteinase (MMP)-1, -2 and -9 mRNA levels were evaluated. The results revealed that cell sprouting and adhesion capacity were enhanced in the MCF7 and MDA-MB231 breast cancer cells in HDF-conditioned culture media as well as in response to type I collagen treatment. The expression of MMP-9 mRNA was high in breast cancer cells cultured with the media of normal HDFs, compared with that of the control media. These data indicate that type I collagen, which is secreted by stromal fibroblasts, may augment the aggressive characteristics of breast cancer cells through the induction of MMP-9 mRNA. PMID- 25013463 TI - Crucial role of treatment with palliative intent for a patient with advanced thymic carcinoma. AB - Thymic carcinoma is a rare cancer that is more aggressive and shows a poorer prognosis compared with thymoma. Molecular analysis has demonstrated that this entity is clearly distinct from thymoma. However, no definitive clinical management has been reported, and the roles of chemotherapy and radiotherapy for advanced thymic carcinoma remain unclear given the rarity of this clinicopathology. The current study reports the case of a 65-year-old male who presented with advanced thymic carcinoma with solitary brain and pulmonary metastases, but demonstrated long-term survival following multiple lines of chemotherapy and radiotherapy with palliative intent. Although the solitary brain metastasis was well controlled for several years using whole-brain irradiation, cognitive function gradually declined with cerebral atrophy. Thymic carcinoma is known to show a poor prognosis and aggressive clinical progress, however, it occasionally demonstrates a clinically indolent course. Modalities of treatment should thus be selected prudently to avoid toxicity, in consideration of the possibility of long-term survival. Stereotactic radiation therapy for brain metastases, including cyberknife or gamma-knife surgery, appears to represent the optimal local treatment for such patients with unexpectedly longer survival due to indolent thymic carcinoma. PMID- 25013464 TI - Expression and clinical significance of FXYD3 in endometrial cancer. AB - FXYD3 expression is upregulated in numerous cancer cell types. The present study compared the FXDY3 expression in normal endometrium, premalignant lesion and endometrial cancer tissue samples, and investigated the correlation between FXDY3 expression and clinicopathological features. FXYD3 expression was analyzed by streptavidin-peroxidase immunohistochemistry in 21 normal endometrial tissue samples, 18 atypical endometrial hyperplasia samples and 50 tissues obtained from patients diagnosed with endometrial cancer. The percentage of FXYD3-positive cell expression in the normal endometrium, atypical hyperplasia and endometrial cancer tissues samples was 0, 22, and 26%, respectively. The differences between the atypical hyperplasia and endometrial cancer groups were statistically significant when compared with the normal group (P=0.007 and P=0.037, respectively). There was no significant difference between the atypical hyperplasia and endometrial cancer groups. The percentage of FXYD3-positive cells correlated with the fertility frequency (P<0.05). In conclusion, FXYD3 is a potential biomarker for endometrial cancer, and its upregulation may be an early event in endometrial carcinoma progression. In addition, FXYD3 expression in endometrial carcinoma correlates with fertility frequency. PMID- 25013466 TI - Pathological characteristics of esophageal cancer. AB - The pathological characteristics of esophageal squamous cell carcinoma, which include regularly occurring multiple carcinogenic lesions (MLs), severe dysplasia (SD) and direct intramural infiltration (DI), were investigated using large pathological sections. A total of 52 esophageal cancer patients underwent surgical resection and were diagnosed with esophageal squamous cell carcinoma. Large sections of the surgical resection specimens were then made for pathological examination. The actual length of the carcinoma was calculated during surgery from the length determined microscopically. ML, SD and DI were identified during pathological examination of the large sections by microscope and were statistically analyzed. The lesion lengths obtained by the various inspection methods differed from each other. ML, SD and DI were identified in 15, 28 and 41 patients, respectively. Furthermore, a higher incidence of DI was observed in patients with lymphatic infiltration or those with a later stage of disease. ML, SD and DI were identified as characteristics of esophageal squamous cell carcinoma, and ML and DI were found to correlate with lymphatic infiltration. PMID- 25013465 TI - Gene expression analysis of potential genes and pathways involved in the pathogenic mechanisms of parvovirus B19 in human colorectal cancer. AB - In order to investigate the pathogenic mechanisms of parvovirus B19 in human colorectal cancer, plasmids containing the VP1 or VP2 viral capsid proteins or the NS1 non-structural proteins of parvovirus B19 were constructed and transfected into primary human colorectal epithelial cells and LoVo cells. Differential gene expression was detected using a human genome expression array. Functional gene annotation analyses were performed using Database for Annotation, Visualization and Integrated Discovery v6.7 software. Gene ontology (GO) analyses revealed that VP1-related functions included the immune response, immune system process, defense response and the response to stimulus, while NS1-associated functions were found to include organelle fission, nuclear division, mitosis, the M-phase of the mitotic cell cycle, the mitotic cell cycle, M-phase, cell cycle phase, cell cycle process and cell division. Pathway expression analysis revealed that VP1-associated pathways included cell adhesion molecules, antigen processing and presentation, cytokines and the inflammatory response. Moreover, NS1 associated pathways included the cell cycle, pathways in cancer, colorectal cancer, the wnt signaling pathway and focal adhesion. Among the differential genes detected in the present study, 12 genes were found to participate in general cancer pathways and six genes were observed to participate in colorectal cancer pathways. NS1 is a key molecule in the pathogenic mechanism of parvovirus B19 in colorectal cancer. Several GO categories, pathways and genes were selected and may be the key targets through which parvovirus B19 participates in colorectal cancer pathogenesis. PMID- 25013467 TI - Expression and significance of MMP2 and HIF-1alpha in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a serious threat to human health. HCC is a malignant tumor and its invasion and metastasis are the result of multigene interactions. Matrix metalloproteinase-2 (MMP-2) is capable of degrading the majority of components of the extracellular matrix and is regarded to closely correlate with tumor invasion and metastasis. Furthermore, the hypoxia-inducible factor 1alpha (HIF-1alpha) is an important transcription factor, which is closely associated with the process of tumor growth. The aim of the present study was to investigate the expression of MMP2 and HIF-1alpha) in HCC, and the relationship between MMP2/HIF-1alpha protein expression and the clinical/pathological characteristics of HCC. The mRNA levels of MMP2 and HIF-1alpha were detected in 32 cases of HCC and the corresponding normal adjacent tissues with fluorescence based quantitative polymerase chain reaction (qPCR). The protein expression of MMP2 and HIF-1alpha was assessed in 45 HCC cases and 33 cases of corresponding normal adjacent tissue, using immunohistochemical methods. The association between MMP2/HIF-1alpha and pathological features of HCC, and the correlation between MMP2 and HIF-1alpha were analyzed. The Kaplan-Meier method was used to assess the impact of MMP2 and HIF-1alpha expression on survival. The fluorescence based qPCR demonstrated that MMP2 and HIF-1alpha mRNA expression levels in the HCC tissues were 0.84+/-0.17 and 0.87+/-0.11, respectively, which were significantly higher than those in the adjacent normal tissues (0.70+/-0.13 and 0.68+/-0.13, respectively; P<0.05). Immunohistochemical analysis revealed that MMP2 and HIF-1alpha protein expression in the HCC tissues was 63.1 and 70.8%, respectively, which was also higher than that in the adjacent normal tissues (34.2 and 36.8%, respectively). There was no significant correlation between the expression of MMP2 or HIF-1alpha protein and the age or gender of patients with HCC (P>0.05). However, there was significant correlation between MMP2 or HIF 1alpha protein expression and tumor size, metastasis, presence of a capsule and clinical TNM staging of HCC. Their expression also had a significant effect on patient survival time. In conclusion, MMP2 and HIF-1alpha are overexpressed in HCC, and the MMP2 signaling pathway may promote the development of HCC together with HIF-1alpha. PMID- 25013468 TI - Combined effect of papuamine and doxorubicin in human breast cancer MCF-7 cells. AB - Our previous study reported that an extract of an Indonesian marine sponge, Haliclona sp., showed potent cytotoxicity and induced apoptosis. The major cytotoxic chemical compound was identified as papuamine, which caused reduction of cell survival through activation of c-Jun N-terminal kinase (JNK) in human breast cancer MCF-7 cells. Doxorubicin (DOX), a Streptomyces metabolite, is used in chemotherapy against a wide range of cancers, including breast cancer. The present study examined the combined effect of papuamine and DOX on MCF-7 cells. The effect of these reagents on cell growth was assessed by a colony formation assay. Incubation with either of the reagents alone resulted in concentration dependent decreases in the colony formation of the MCF-7 cells. Incubation with the reagents together at sub-cytotoxic concentrations resulted in significant decreases in colony formation. The phosphorylation of JNK, the activated form of the protein, was elevated in a concentration-dependent manner upon co-incubation with papuamine and DOX. Fluorescence intensity analysis demonstrated that papuamine caused a small, but non-significant, decrease in cellular accumulation of DOX. These results indicate that the combinatory effect of papuamine and DOX is not associated with changes in the cellular accumulation of DOX, and may instead reflect additive effects on JNK activation. This study indicates that papuamine may represent a novel type of modulator for DOX chemotherapy. PMID- 25013470 TI - Comparison of K-ras mutations in lung, colorectal and gastric cancer. AB - K-ras is involved in the EGFR pathway that regulates cell survival, motility and proliferation, as well as angiogenesis and metastasis. It is also essential for carcinogenesis. The K-ras mutation status can be used to predict the therapeutic efficacy of targeted drugs such as cetuximab. The aim of this study was to compare K-ras mutation in different types of cancer. Nested and COLD-PCR were used to detect K-ras mutations. The Chi-squared test was used for statistical analysis. In this study, the total K-ras mutation frequency was found to be 9.09, 18.61 and 6.67% in lung, colorectal and gastric cancer, respectively. Similar K ras mutation frequencies were detected among sample types and genders for lung and gastric cancer, with the exception of colorectal cancer. However, age had no impact on the K-ras mutation rates. PMID- 25013469 TI - Esophageal granular cell tumor: Clinical, endoscopic and histological features of 19 cases. AB - Esophageal granular cell tumors (GCTs) are rare and often misdiagnosed. To demonstrate their clinicopathological features, the present study reports 19 cases and reviews the literature. There were 11 female and eight male esophageal GCT patients with a median age of 42.0 years. All the tumors were solitary. The majority of patient indications for endoscopy (89.5%) were non-specific and endoscopic therapy was performed in 17 cases with a relapse in one case after a 12-month follow-up. The endoscopic appearance of esophageal GCT was variable and the majority of tumors (80.0%) were located in the middle and lower esophageal segments. The size of the tumors ranged from 0.4 to 2 cm in diameter and the surface was white-gray, pink or yellow. Nine patients underwent an endoscopic ultrasound exam, eight of which demonstrated hypoechoic echostructures with a smooth margin and intracavity growth features. One case was derived from the muscularis propria layer with an irregular margin and intra- and extra-cavity growth features. The histological features could mimic other tumors and immunohistochemical stains are usually positive for S-100, periodic acid-Schiff, neuron-specific enolase and nestin. Three cases indicated pleomorphism and Ki-67 was locally positive. Esophageal GCTs are rare and endoscopic ultrasound features are variable. Immunohistochemical staining may aid in the diagnosis. PMID- 25013471 TI - Differential levels of L-homocysteic acid and lysophosphatidylcholine (16:0) in sera of patients with ovarian cancer. AB - Ovarian cancer (OVC) is one of the most difficult types of cancer to detect in the early stages of its development. There have been numerous attempts to identify a biomarker for OVC; however, an accurate diagnostic marker has yet to be identified. The present study profiled OVC candidate metabolites from the serum to identify potential diagnostic markers for OVC. Data regarding low-mass ions (LMIs) in the serum were obtained using matrix-assisted laser desorption/ionization (MALDI)-time-of-flight analysis. MALDI-mass spectrometry (MS) analysis of each serum sample was repeated six times in order to reduce the likelihood of experimental errors. The intensity of the LMI mass peaks were normalized using total peak area sums. The normalized intensity of LMI was used in principal component analysis-discriminant analysis to differentiate between 142 patients with OVC and 100 healthy control participants. Liquid chromatography MS/MS was used to identify the selected LMIs. Extracted ion chromatogram analysis was used to measure the relative quantity of candidate metabolites from the LMI mass peak areas. The concentration of common metabolites in the serum was determined using ELISA. The top 20 LMI mass peaks with a weigh factor over 0.05 were selected to distinguish between the patients with OVC and the controls. Among the LMIs, two with 184.05 and 496.30 m/z were identified as L-homocysteic acid (HCA) and lysophosphatidylcholine (LPC) (16:0), respectively. The relative quantity of LPC (16:0) was found to be decreased in the OVC serum (P=0.05), while the quantity of HCA was observed to be significantly higher in the OVC serum (P<0.001). HCA was not detected in 59 cases out of the 63 control participants; however, the majority of the cases of OVC (16/25) exhibited significantly higher quantities of HCA. When the cutoff was 10 nmol/ml, the sensitivity and specificity of HCA were 64.0 and 96.9%, respectively. The level of LPC (16:0) was significantly correlated with tumor grade (P=0.045). HCA and LPC (16:0) showed correlation with stage and tumor histology, but the limited sample size resulted in a lack of statistical significance. The findings of the present study suggest that HCA may have potential to be a biomarker for OVC. The stratified screening including LPC (16:0) did not significantly increase the power for OVC screening; however, the present study showed that profiling LMIs in serum may be useful for identifying candidate metabolites for OVC screening. PMID- 25013472 TI - Relative influence of c-Kit expression and epidermal growth factor receptor gene amplification on survival in patients with non-small cell lung cancer. AB - c-Kit and epidermal growth factor receptor (EGFR) have critical roles in cell proliferation and differentiation in patients with non-small cell lung cancer (NSCLC). The present study aimed to investigate the prognostic impact of c-Kit and/or EGFR expression in tumor tissue samples from 146 patients with NSCLC. c Kit expression was analyzed using immunohistochemistry and the expression of EGFR was assessed using fluorescence in situ hybridization. Univariate and multivariate analyses identified that c-Kit is a significant negative prognostic factor. The expression of c-Kit was correlated with poor differentiation, pleura involvement and smoking history (P=0.043, 0.007 and 0.032, respectively). Furthermore, patients with c-Kit-positive expression were associated with a significantly lower overall survival compared with those exhibiting c-Kit negative expression (P=0.048). The median follow-up time was 19 months post surgery. EGFR gene amplification as a result of polysomy of chromosome 7 was found to be negatively correlated with poor differentiation and smoking history (P=0.023 and 0.044, respectively). The findings of the present study indicate that c-Kit and EGFR expression is a strong, independent, negative prognostic factor in NSCLC. PMID- 25013473 TI - Rapid onset lung squamous cell carcinoma with prominent peritoneal carcinomatosis and an eosinophilic leukemoid reaction, with coexistence of the BRAF V600E and oncogenic KRAS G12A mutations: A case report. AB - Peritoneal carcinomatosis from lung cancer is rare, particularly from lung squamous cell carcinoma (LSCC). Concurrent somatic BRAF and KRAS mutations within the same tumor specimen have not been reported. The present study describes the case of a treatment-naive LSCC patient with coexisting BRAF V600E and oncogenic KRAS G12A mutations in the primary lung lesion and the peritoneal metastases. The patient presented with prominent peritoneal carcinomatosis and an eosinophilic leukemoid reaction, but no respiratory symptoms. The patient succumbed 8 days after the onset of the condition due to rapid aggravation of the peritoneal carcinomatosis. To the best of our knowledge, this is the first study concerning the coexistence of BRAF and KRAS mutations in LSCC. Intensive activation of ERK was also observed in the primary lung lesion and the peritoneal metastases. Although the exact pathogenesis was unclear, the observations indicated that in the present study, the BRAF V600E and KRAS G12A mutations may have cooperate in inducing the malignant phenotype of LSCC. This case also highlighted the potential aggressive course and unusual pattern of spread of this specific dual mutated tumor. PMID- 25013474 TI - Expression and clinical significance of the phosphatidylinositol 3-kinase/protein kinase B signal transduction pathway in non-small cell lung carcinoma. AB - The overactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway has been examined in various carcinomas and is reported to be significantly correlated with prognosis. However, little is known with regard to the PI3K/Akt signal transduction pathway in advanced non-small cell lung carcinoma (NSCLC). The present study investigated the expression of PI3K and phosphorylated (p)-Akt protein and its clinical significance in NSCLC. The clinical records of 157 patients with NSCLC (70 stage I-IIIA and 87 stage IIIB-IV cases), consisting of 75 cases of squamous cell carcinoma and 82 cases of adenocarcinoma, together with 30 resected lung cancer tumor-adjacent tissue samples, were retrospectively evaluated. PI3K and p-Akt expression in the NSCLC and tumor-adjacent tissues were measured using an immunohistochemical method, and its correlation with the clinicopathological data and prognosis in advanced NSCLC was evaluated. PI3K and p-Akt expression was significantly higher in the cancer tissues (chi2=14.8455; P=0.001) than in the tumor-adjacent tissues (chi2=14.2615; P=0.001). The overexpression of p-Akt in stage I-IIIA NSCLC was associated with lymph node metastasis (chi2=6.1189; P=0.013) and tumor-node-metastasis (TNM) stage (chi2=8.9752; P=0.011), however, no correlation was observed with gender, age, pathological type and histological grade. The overexpression of p-Akt in stage IIIB-IV NSCLC was only associated with TNM stage (chi2=5.7501; P=0.016), and no correlation was observed with gender, age, pathological type, histological grade and Eastern Cooperative Oncology Group (ECOG) performance status (PS). The overexpression of PI3K was not found to correlate with the aforementioned clinicopathological variables in all patients. Survival was significantly improved in advanced NSCLC with PI3K- and p-Akt-negative expression compared with PI3K- and p-Akt-positive expression [P13K: 17.70 months (95% confidence interval (CI), 15.11-20.28 months) vs. 13.43 months (95% CI, 11.83-15.02 months); P=0.004; and p-Akt: 17.13 months (95% CI, 14.93-19.34 months) vs. 13.07 months (95% CI, 11.32-14.82 months); P=0.007]. Multivariate analysis showed that PI3K [hazard ratio (HR)=2.143; 95% CI, 1.211-3.790; P=0.009], p-Akt (HR=1.991; 95% CI, 1.009 3.927; P=0.047), TNM stage (HR=4.788; 95% CI, 2.591-8.848; P=0.001) and ECOG-PS (HR=3.272; 95% CI, 1.701-6.296; P=0.001) were independent predictors for survival in stage IIIB-IV NSCLC. These results indicated that p-Akt overexpression closely correlates with factors of an unfavorable prognosis in NSCLC. PI3K and p-Akt overexpression are independent markers of a poor prognosis in advanced NSCLC. PMID- 25013475 TI - Rare presentation of peripheral primitive neuroectodermal tumor in the maxilla and mandible: A report of two cases. AB - Peripheral primitive neuroectodermal tumor (pPNET) is a rare and highly malignant undifferentiated tumor, which presents in infants and young adults. pPNETs in the head and neck region are uncommon and have a varying incidence of occurrence. Peripheral PNETs of the maxilla and mandible are particularly rare. At present, only 16 cases of pPNET of the maxilla and 13 cases of pPNET of the mandible have been reported. The present study describes a case of pPNET of the maxilla in a 16 year-old male and a case of pPNET of the mandible in another 16-year-old male. The present study reports the radiological findings and the clinical courses of the two patients. PMID- 25013476 TI - Cluster of differentiation 45 activation is crucial in interleukin-10-dependent tumor-associated dendritic cell differentiation. AB - Tumor-associated dendritic cells (TADCs) are important in tumor immune surveillance, and it has been reported that the secretion of interleukin (IL)-10 by cancer cells is a major factor involved in the induction of TADCs in the tumor microenvironment. In the present study, IL-10 was found to activate cluster of differentiation (CD)45 protein tyrosine phosphatase (PTPase), inducing a TADC like phenomenon. The PTPase inhibitor, phenylarsine oxide, and a CD45 inhibitor reversed the IL-10-induced impaired differentiation of the DCs, and also reversed the induction of the TADCs by A549, MDA-MB-231 and SW480 conditioned media, which thus represents a novel therapy to reduce immune surveillance in the tumor microenvironment. The present study is the first to identify that CD45 is involved in IL-10-activated signaling in myeloid lineage cells. PMID- 25013477 TI - Comparison of hand-assisted laparoscopic surgery and conventional laparotomy for colorectal cancer: Interim results from a single institution. AB - The present study aimed to compare the results of hand-assisted laparoscopic surgery (HALS) and conventional laparotomy (CL) at a single institution in Japan. Of the 212 patients with stage I/II/III colorectal cancer who received a curative resection, 98 patients underwent HALS and 114 patients underwent CL. The clinical background and post-operative management did not differ between the two groups. There were no significant differences in the 3-year relapse-free and 3-year overall survival rates between the HALS and CL groups for the patients in any stage. Blood loss during surgery was 250.1 and 135.5 ml (mean and median; the same hereafter) in stage I patients receiving HALS versus 608.2 and 315.5 ml in stage I CL patients (P=0.006), while it was 277.6 and 146 ml in stage II patients receiving HALS versus 548.6 and 347 ml in stage II CL patients (P=0.004). Post operative hospital stay was recorded at 16.8 and 15 days in stage III patients receiving HALS versus 23.1 and 21 days in stage III CL patients (P=0.001). There were no significant differences in the operating time or complications between the two groups. These results indicate that the survival rate was comparable for HALS and CL, while HALS caused less surgical stress and achieved a better cosmetic outcome. The results of the final analysis of this cohort are awaited. PMID- 25013478 TI - Adult pancreatic hemangioma: A case report. AB - Vascular neoplasms of the pancreas are extremely rare and usually manifest as symptomatic, cystic lesions. This study presents a case that includes the clinicopathologic information used to discriminate pancreatic hemangioma from other types of cystic lesion of the pancreas. A 40-year-old female visited hospital with a chief complaint of abdominal pain. The serum CEA and CA19-9 levels of the patient were within the normal limits. An abdominal computed tomography scan and magnetic resonance imaging showed a 100-mm mass lesion in the body and tail of the pancreas, and the tumor extended toward the retroperitoneum and surrounded the splenic vein. The lesion was subsequently resected. Macroscopically, it was a multiloculated cyst with intracystic hemorrhage. Microscopically, the lesion was composed of numerous, heterogeneous cysts lined by a flattened single layer of cells without significant atypia. Notably, numerous neoplastic vessels extended into the interlobular septa of the pancreas and surrounded the main pancreatic duct. Immunohistochemical analysis showed that the lining cells expressed CD31 and CD34. The lesion was diagnosed as adult pancreatic hemangioma. Surgical treatment may be required when a direct contact between the lesion and the pancreatic tissue is demonstrated using imaging. PMID- 25013479 TI - Pregnenolone, a cholesterol metabolite, induces glioma cell apoptosis via activating extrinsic and intrinsic apoptotic pathways. AB - Gliomas are one of the most common types of malignant tumors worldwide, however, an effective therapeutic strategy not yet been fully determined. The present study aimed to investigate the anti-glioma activity and underlying mechanisms of pregnenolone, which originates from cholesterol and is metabolized into important steroid hormones in the body. The results demonstrated that 100 MUM pregnenolone induced a significant loss of cell viability in various malignant glioma cell lines. In the U-87 MG, LN-18 and C6 cell lines, the loss of cell viability resulted from cell apoptosis, which was evidenced by apoptotic nuclear morphology changes and caspase 3 activation. Moreover, the increased activities of caspase 8 and 9 strongly indicated that pregnenolone activated the extrinsic and intrinsic pathways of apoptosis. Additionally, glioma cell apoptosis was prevented by the general caspase inhibitor, Z-VAD-FMK. In the C6 cells, upregulation of Fas and Fas ligand triggered the activation of the extrinsic pathway, whereas knockdown of Fas significantly abrogated the cell apoptosis that was induced by pregnenolone. Furthermore, downregulation of the anti-apoptotic protein, B-cell lymphoma 2 and upregulation of pro-apoptotic proteins, such as Bax and Bak, activated the intrinsic pathway. In conclusion, pregnenolone induced glioma cell apoptosis in a caspase-dependent manner, which was mediated by activation of the extrinsic and intrinsic apoptotic pathways. PMID- 25013480 TI - Regulatory effects of miRNA on gastric cancer cells. AB - The present study aimed to screen the regulatory mechanism of microRNA (miR/miRNA) typing on gastric cancer cells in gastric cancer tissues. In total, 46 patients who underwent gastric resection in Xiangya Hospital of Central-South University (Changsha, Hunan, China) between January and December 2012 were selected. Gastric cancer cells were obtained for RNA extraction, and miRNAs were detected by quantitative polymerase chain reaction. Compared with the expression levels in the normal gastric mucosa, the expression levels of miR-9, miR-433, miR 19b and miR-370 were downregulated; the differences was statistically significant, except for miR-19b (P<0.05). miRNAs play a regulative role in the occurrence and development of gastric cancer, and changes in their expression provide a basis for the diagnosis of this disease. PMID- 25013481 TI - Effects of damage-regulated autophagy regulator gene on the SGC7901 human gastric cancer cell line. AB - The aim of this study was to investigate the effects of the adenoviral-mediated autophagy gene, damage-regulated autophagy regulator (DRAM), on the proliferation and autophagy of SGC7901 human gastric cancer cells in vitro. The recombinant adenovirus, AdMax-pDC315-DRAM-EGFP, working as a virus vector of DRAM was constructed and infected into the SGC7901 human gastric cancer cell line. The MTT assay was used to determine the growth rate of the SGC7901 cells. Activation of autophagy was monitored with monodansylcadaverin (MDC) staining following AdMax pDC315-DRAM-EGFP treatment. Immunofluorescent staining was used to examine the expression of microtubule-associated protein 1 light chain 3 (LC3), and western blotting was used to examine the expression of apoptosis- and autophagy associated proteins, including Beclin1, p53, p21 and B-cell lymphoma 2 (Bcl-2), in the culture supernatant. The viability of the SGC7901 cells was activated by AdMax-pDC315-DRAM-EGFP treatment. The AdMax-pDC315-DRAM-EGFP-treated cells exhibited positive LC3 expression detected by immunoreactivity and MDC staining. Inductions in the expression of the apoptosis-related proteins, p53 and p21, and the autophagic protein, Beclin1, were revealed by western blot analysis. By contrast, downregulation of the apoptosis-related protein, Bcl-2, following AdMax pDC315-DRAM-EGFP treatment was identified. In conclusion, the present study demonstrated that AdMax-pDC315-DRAM-EGFP treatment resulted in upregulation of the level of autophagy and induction of cell proliferation in the SGC7901 human gastric cancer cell line in vitro. PMID- 25013482 TI - Primary dedifferentiated liposarcoma of the femur presenting with malignant fibrous histiocytoma: A case report and review of the literature. AB - In the current report a case of a 26-year-old male with a primary dedifferentiated liposarcoma of the femur accompanied by malignant fibrous histiocytoma is presented. The patient complained of a dull intermittent pain, for three months, along the anterolateral aspect of the right knee and was referred to Southwest Hospital (Chongqing, China) in May 2013. All of the radiographic findings, including radiography, magnetic resonance image and emission computed tomography (CT) supported the diagnosis of a primary malignant bone tumor. CT-guided biopsy results demonstrated blood clots and a small quantity of heterogeneous cells. Thus, a limb-salvage procedure, involving a wide resection and total knee endoprosthesis replacement, was performed in May 2012. The final pathological diagnosis was of a primary dedifferentiated liposarcoma of the femur and the dedifferentiated tissue was identified as malignant fibrous histiocytoma. On review of the literature, it was identified that primary intraosseous liposarcoma are a rare and malignant tumor of the skeletal system, with only a small number of cases reported in the English literature since 1980. To the best of our knowledge, a case of dedifferentiated liposarcoma has not previously been reported. PMID- 25013484 TI - Role of PTCH1 gene methylation in gastric carcinogenesis. AB - The present study aimed to investigate the role of PTCH1 methylation in gastric carcinogenesis and the therapeutic effect of the methylation inhibitor, 5-aza-2' deoxycytidine (5-aza-dC), in the treatment of gastric cancer. Total RNA was extracted from 20 gastric cancer tissues, their corresponding adjacent normal tissues and a gastric cancer AGS cell line. PTCH1 mRNA expression was detected by quantitative PCR, and the PTCH1 methylation of the promoter was examined by methylation-specific PCR. The AGS cells were treated with 5-Aza-dC; apoptosis and the cell cycle were examined by flow cytometry, and the PTCH1 methylation level was observed. PTCH1 expression was negatively correlated with promoter methylation in the gastric cancer tissues, their corresponding adjacent normal tissues and the gastric cancer AGS cell line (r=-0.591, P=0.006). 5-Aza-dC treatment caused apoptosis and the G0/G1 phase arrest of the AGS cells, and also induced the demethylation and increased expression of PTCH1. In conclusion, the study found that the hypermethylation of the PTCH1 gene promoter region is one of the main causes of low PTCH1 expression in AGS cells. Demethylation agent 5-Aza dC can reverse the methylation status of PTCH1 and regulate the expression of PTCH1, indicating its potential role in gastric cancer treatment. PMID- 25013483 TI - LRIG2 expression and prognosis in non-small cell lung cancer. AB - The human leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) protein has been shown to be of prognostic value in several types of human cancer, however, the expression profiles of LRIG2 have not been described in non-small cell lung cancer (NSCLC). The present study evaluated the mRNA expression of LRIG2 in tumor specimens obtained from 39 NSCLC patients by SYBR Green quantitative polymerase chain reaction and the protein expression of LRIG2 in formalin-fixed paraffin sections obtained from 116 NSCLC patients by immunohistochemistry. The correlations between LRIG2 expression and clinicopathological data were analyzed. The patient survival data were collected retrospectively and the possible prognostic value of LRIG2 protein expression was investigated. The results showed that the mRNA expression of LRIG2 was decreased in NSCLC cancer tissues, which was associated with histological subtypes and tumor differentiation status. The protein expression of LRIG2 was only observed in the cytoplasm of the tumor tissue, which conformed to the mRNA expression results. Furthermore, the patients with high LRIG2 cytoplasmic expression showed poor survival times, and the five-year survival rate for patients with high LRIG2 expression was 27.8%, compared with 38.8% for patients with low expression (P=0.034), indicating that LRIG2 expression levels may have a potential role in the pathogenesis of NSCLC, and also a significant prognostic value. Further studies are required to fully elucidate the exact function of LRIG2 in NSCLC. PMID- 25013485 TI - High EphA2 protein expression in renal cell carcinoma is associated with a poor disease outcome. AB - The receptor tyrosine kinase, ephrin type-A receptor 2 (EphA2), is normally expressed at sites of cell-to-cell contact in adult epithelial tissues, however, recent studies have shown that it is also overexpressed in various types of epithelial carcinomas, with the greatest level of EphA2 expression observed in metastatic lesions. In the present study, the association between the expression of EphA2 and the outcome of RCC patients was assessed. The high expression level of EphA2 was identified by log-rank test for a statistically significant prediction of the RCC outcome. In an overall multivariate analysis, the high expression level of EphA2 was identified as an independent predictor of RCC outcome. The length of survival of the patients with high EphA2 expression was shorter than that of the patients with a low level of expression (relative risk, 2.304; 95% CI, 1.102-4.818; P=0.027). The analysis of the expression levels of EphA2 in tumor tissues may aid in the identification of the patient subgroup that are at a high risk of a poor disease outcome. PMID- 25013486 TI - Suppressive effects of simvastatin on the human acute promyelocytic leukemia NB4 cell line through the regulation of the nuclear factor-kappaB signaling pathway. AB - The present study examined the effects of simvastatin on the proliferation, apoptosis and gene expression levels involved in the nuclear factor-kappaB (NF kappaB) signaling pathway in the human acute promyelocytic leukemia NB4 cell line by methyl thiazolyl tetrazolium assay, flow cytometry and the Human NF-kappaB Signaling Pathway RT2 ProfilerTM PCR Array profiles. The results showed that simvastatin significantly inhibited proliferation and induced apoptosis of the NB4 cells in a time- and dose-dependent manner. Changes were noted in the expression levels of 56 genes involved in the NF-kappaB signaling pathways in the NB4 cells treated with 15 MUm simvastatin at 48 h post-incubation, among which, 47 genes were downregulated and 9 were upregulated. In conclusion, simvastatin potentially inhibits the proliferation and induces the apoptosis of NB4 cells through the regulation of the expression levels of genes involved in the NF kappaB signaling pathway. PMID- 25013487 TI - 5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9 dependent and mediated by activation of protein kinase C-delta AB - Elucidation of the molecular mechanisms by which 5-fluorouracil (5-FU) induces apoptosis is required in order to understand the resistance of colorectal cancer (CRC) cells to 5-FU. In the current study, 5-FU-induced apoptosis was assessed using the propidium iodide method. Involvement of protein kinase C (PKC) was assessed by evaluating the extent of their activation in CRC, following treatment with 5-FU, using biochemical inhibitors and western blot analysis. The results revealed that 5-FU induces varying degrees of apoptosis in CRC cells; HCT116 cells were identified to be the most sensitive cells and SW480 were the least sensitive. In addition, 5-FU-induced apoptosis was caspase-dependent as it appeared to be initiated by caspase-9. Furthermore, PKCE was marginally expressed in CRC cells and no changes were observed in the levels of cleavage or phosphorylation following treatment with 5-FU. The treatment of HCT116 cells with 5-FU increased the expression, phosphorylation and cleavage of PKCdelta. The inhibition of PKCdelta was found to significantly inhibit 5-FU-induced apoptosis. These results indicated that 5-FU induces apoptosis in CRC by the activation of PKCdelta and caspase-9. In addition, the levels of PKCdelta activation may determine the sensitivity of CRC to 5-FU. PMID- 25013488 TI - Cytological features of pure micropapillary carcinoma of various organs: A report of eight cases. AB - Micropapillary carcinoma (MPC) is a rare aggressive tumor, which generally accompanies the primary carcinoma of the organ of its origin, while the pure form is extremely uncommon. Angiolymphatic involvement is widespread and a considerable proportion of the cases present with metastases. The current study presents eight pure MPC cases arising from the breast (n=3), urinary bladder (n=3), parotid gland (n=1) and lung (n=1, presenting with pericardial effusion), with the cytological findings. The eight patients included three female and five male cases aged between 48 and 74 years. The most common cytological findings were three-dimensional aggregates, cell clusters with angulated or scalloped borders, single cells with a columnar configuration and eccentric nuclei, and high-grade nuclear features. Histopathological sections showed accompanying in situ ductal carcinoma in the cases of MPC arising in the parotid gland and breast (n=3), and one case in the bladder exhibited only in situ MPC. The average follow up period was 20 months (range, 6-54 months) and, during this period, three patients succumbed to the disease. At present, four patients are alive with disease and one patient is alive and disease-free. In conclusion, cytology is an important tool for the diagnosis and management of MPC. PMID- 25013489 TI - High-throughput sequencing to identify miRNA biomarkers in colorectal cancer patients. AB - The altered expression of microRNAs (miRNAs) is associated with a number of cancer types. The study of the association between the miRNA profile and cancer may be useful to identify potential biomarkers of certain types of cancer. In the present study, 19 miRNAs were identified by high-throughput sequencing in the serum of colorectal cancer (CRC) patients. A network analysis was performed based on a computational approach to identify associations between CRC and miRNAs. The present study may be useful to identify cancer-specific signatures and potentially useful biomarkers for the diagnosis of CRC. The network analysis of miRNA-target genes may aid in identifying altered miRNA regulatory networks that are involved in tumor pathogenesis. PMID- 25013490 TI - Evaluation of photodynamic therapy in adhesion protein expression. AB - Photodynamic therapy (PDT) is a treatment modality that has clinical applications in both non-neoplastic and neoplastic diseases. PDT involves a light-sensitive compound (photosensitizer), light and molecular oxygen. This procedure may lead to several different cellular responses, including cell death. Alterations in the attachment of cancer cells to the substratum and to each other are important consequences of photodynamic treatment. PDT may lead to changes in the expression of cellular adhesion structure and cytoskeleton integrity, which are key factors in decreasing tumor metastatic potential. HEp-2 cells were photosensitized with aluminum phthalocyanine tetrasulfonate and zinc phthalocyanine, and the proteins beta1-integrin and focal adhesion kinase (FAK) were assayed using fluorescence microscopy. The verification of expression changes in the genes for FAK and beta1 integrin were performed by reverse transcription-polymerase chain reaction (RT PCR). The results revealed that HEp-2 cells do not express beta-integrin or FAK 12 h following PDT. It was concluded that the PDT reduces the adhesive ability of HEp-2 cells, inhibiting their metastatic potential. The present study aimed to analyze the changes in the expression and organization of cellular adhesion elements and the subsequent metastatic potential of HEp-2 cells following PDT treatment. PMID- 25013491 TI - Adenoid cystic carcinoma of the cardia: Report of a rare case and review of the Chinese literature. AB - Adenoid cystic carcinoma (ACC) is a relatively common head and neck tumor, however, is rare in the digestive tracts. There have been <100 cases of esophageal ACC reported to date and no cases of gastric ACC. The present study reports the exceptional case of a 53-year-old male with a primary ACC of the cardia. The patient underwent a radical total gastrectomy with D2 lymphadenectomy and Roux-en-Y esophagojejunal reconstruction. Immunohistochemical analysis identified a case of primary ACC that exhibited a positive expression for cytokeratin, calponin, cluster of differentiation 117, p63 and smooth muscle actin, with typical cribriform foci. No signs of recurrence have been detected during the 30-month follow-up. Thus, a precise diagnosis of ACC is primarily based on the results of immunohistochemical analysis and radical resection is considered to be the best treatment option for ACC of the digestive tracts. The current study also reviewed 17 cases of ACC of the esophagus reported in China, with special reference to the criteria for histological diagnosis and therapeutic options. The prognosis of esophageal ACC is poor due to early metastasis, mainly relying on the resectability of the tumor. PMID- 25013492 TI - Effect of folylpolyglutamate synthase A22G polymorphism on the risk and survival of patients with acute lymphoblastic leukemia. AB - Folylpolyglutamate synthase (FPGS) is the key enzyme that converts the chemotherapeutic agent, methotrexate (MTX), into MTX polyglutamate. An A22G polymorphism has been found in the FPGS gene. This study aimed to evaluated whether the A22G polymorphism in the FPGS gene is associated with an increased risk of acute lymphoblastic leukemia (ALL) and whether it plays a role in increasing the survival of patients with ALL. In this study, a total of 70 patients with ALL and 100 healthy individuals were genotyped by polymerase chain reaction and sequencing methods. The homozygous variant, 22G/G [odds ratio (OR)=3.88; 95% confidence interval (CI): 2.50-6.03] and the heterozygous variant, 22A/G (OR=1.37; 95% CI: 1.26-48.95) were risk factors for ALL. Patients with the 22A/G genotype had an OR of 1.81 (95% CI: 1.57-5.74; P=0.049) and carriers of the 22G/G genotype had an OR of 2.44 (95% CI: 2.40-11.82; P=0.017) for relapse. A significant association between the A22G polymorphism and survival of patients with ALL was found (P<0.05); whereas, individuals with A/G or G/G genotypes had a decreased overall survival (log-rank test, P=0.044). Although preliminary, these data suggest that the genotypes of the A22G polymorphism may be risk factors for ALL and may play a role in the survival of patients with ALL. PMID- 25013493 TI - Primary choriocarcinoma of the posterior mediastinum in a male: A case report and review of the literature. AB - Primary choriocarcinoma of the posterior mediastinum is considered to be extremely rare, and the majority of these tumors occur in the gonads and uterus. The current study presents the case of a 40-year-old male who presented to the Department of Thoracic Surgery (Medical College of Yangzhou University, Yangzhou, China) with left chest pain for two months. Computed tomography of the chest showed a 4.9*5.2-cm mass in the posterior mediastinum and enlargement of the mediastinal lymph nodes. Resection of the tumor and upper lobe of the left lung was performed and the patient received combination chemotherapy with six courses of etoposide plus cisplatin. The patient recovered and was discharged. One year post surgery and chemotherapy, the patient was followed up and evidence of a recurrent tumor in the cerebrum was observed. PMID- 25013494 TI - Granuloma induced by sustained-release fluorouracil implants misdiagnosed as a hepatic tumor: A case report. AB - Sustained-release fluorouracil (FU) implants have been extensively used in peritoneal interstitial chemotherapy, and during surgery for gastrointestinal tumors, breast cancer and hepatic tumors. Currently, studies regarding the complications associated with sustained-release FU implants are rare. The present study describes the case of a 61-year-old male who presented with a space occupying lesion of the left lobe of the liver six months after undergoing a radical total gastrectomy. Thus, laparoscopic exploration was performed to remove the tumor. Postoperative histological examination demonstrated that the lesion in the left lobe comprised of necrotic tissue with granulation tissue hyperplasia. Based on the surgical and postoperative histological findings, the mass was proposed to be due to a high concentration of local sustained-release FU implants. Furthermore, the drug was partially surrounded and had been insufficiently metabolized over a long time period, which was proposed to have caused necrosis, proliferation and fibrillation, and induced granuloma. In conclusion, local high concentrations of sustained-release FU implants may be associated with granuloma and this finding may enable improved management of sustained-release FU implants during surgery. PMID- 25013495 TI - Peripheral primitive neuroectodermal tumor of the parotid gland in a child: A case report. AB - Primitive neuroectodermal tumor (PNET) is a term used to describe a group of highly malignant neoplasms of soft-tissue origin, with varying degrees of divergent differentiation. The occurrence of peripheral PNET in the head and neck region has been reported infrequently in the medical literature. This disease generally occurs in adolescents and young adults, and rarely occurs in children <3 years old. The current study presents an extremely rare case of pPNET of the parotid gland in a 2-year-old male, which had been previously misdiagnosed and treated as a mumps. The lesion showed the characteristic histological features of pleomorphic cellular infiltrate with hyperchromatic small cells scattered in the fibrovascular stroma, interposed by fibrous septa and Homer-Wright rosettes. Positive immunohistochemical staining for CD99 and vimentin was detected. The patient was treated with chemotherapy and radiotherapy following surgical removal, and has been under close observation since the treatment (approximately seven months), with no signs of recurrence. The clinical history and radiological and histopathological findings are presented, together with the immunoreactivity of this tumor. PMID- 25013496 TI - Clinicopathological and immunohistochemical analysis of spindle cell carcinoma of the larynx or hypopharynx: A report of three cases. AB - Spindle cell carcinoma (SpCC) is a rare and unusual biphasic malignant tumor, which involves sarcomatoid proliferation of pleomorphic spindle cells and squamous cell carcinoma. There are various reports on the clinical and pathological findings of SpCC in the head and neck; however, this type of tumor remains uncommon in the larynx and hypopharynx. The histogenesis of SpCC has been the subject of debate for many decades. Although it is generally accepted that SpCC is a monoclonal epithelial neoplasm, and the spindle cell element is derived from squamous epithelium with divergent mesenchymal differentiation, this type of tumor poses a significant diagnostic challenge to pathologists and clinicians with regard to the therapeutic approach. In the present report, three cases of SpCC of the larynx or hypopharynx were investigated. The histological and immunohistochemistry findings are presented to provide further data on this rare type of tumor. PMID- 25013497 TI - Treatment of nasopharyngeal carcinoma with pulmonary tuberculosis and gout: A case report. AB - In China, the incidence of nasopharyngeal carcinoma (NPC) and tuberculosis remains high. Additionally, there has been a marked increase in the prevalence of gout. In recent years, there has been an increase in the number of co-existing diseases. To the best of our knowledge, there have been no previous cases reported in the literature with regard to patients suffering from NPC complicated with pulmonary tuberculosis and gout. The present study describes the case of a 59-year-old male with this condition. The patient received a combination of anti tumor, anti-tuberculosis and anti-gout therapies, and experienced no severe adverse reactions during treatment. At present, the patient's Eastern Cooperative Oncology Group performance status is good, there has been no local recurrence or distant metastasis of the NPC, and the pulmonary tuberculosis and gout are well controlled. The aim of this study was to provide insight into the treatment of patients suffering from co-existing conditions. PMID- 25013498 TI - Pituitary adenoma with gangliocytoma: Report of two cases. AB - Worldwide, cases of pituitary adenoma with gangliocytoma are rarely reported. The current study reports the cases of two 47-year-old females who presented with masses in the sellar region following a general examination and radiological imaging. The two patients underwent sellar region tumor resection via the trans naso-sphenoid approach. The histopathological examination confirmed the diagnosis of a hormone-free pituitary adenoma with gangliocytoma. The two patients were in good condition and experienced no specific discomfort subsequent to the follow-up after surgery. Gangliocytoma is a slowly growing and non-metastasizing tumor. A biopsy is required to differentiate a gangliocytoma from a malignant neuroblastoma, and excision is usually curative. PMID- 25013499 TI - Deleted in liver cancer 1 expression and localization in hepatocellular carcinoma tissue sections. AB - The deleted in liver cancer (DLC) protein family is composed of proteins that are hypothesized to function predominantly by regulating the activity of the small GTPases. The aim of the present study was to determine the expression and exact localization of DLC1 in hepatocellular carcinoma (HCC) tissue sections. In two types of HCC tissues, typical and fibrolamellar, immunohistochemical and immunofluorescent analysis were performed to assess DLC1 immunoreactivity. Additionally, the DLC1 gene status was determined by the fluorescence in situ hybridization. According to the observations, DLC1 is often lost in cancer cells; however, it can remain within the stromal component of tumor sections. The DLC1 immunoreactivity was particularly noticeable within the capsules surrounding the tumor masses. It was found that the DLC1 gene was deleted in 52% of HCC cases. In addition, the hemizygous deletion was observed to be independent of the HCC subtype. The results indicate that although the loss of DLC1 is a common step during hepatocarcinogenesis, this protein may be present in the tumor microenvironment. PMID- 25013500 TI - Significant association between the Axin2 rs2240308 single nucleotide polymorphism and the incidence of prostate cancer. AB - The Wnt signaling pathway plays a crucial role in human cancer development, and axis inhibition protein 2 (Axin2) is a master scaffold protein involved in Wnt signaling. Axin2 negatively regulates Wnt signaling and acts as a tumor suppressor protein. The present study evaluated the association between the Axin2 single nucleotide polymorphism (SNP) rs2240308 [guanine (G)/adenine (A)] and the incidence of prostate cancer. In total, 103 patients with prostate cancer and 100 cancer-free control males were included in this case-control study, and were genotyped using the genomic DNA extracted from peripheral blood samples. The results revealed a higher incidence of prostate cancer in the subjects with the homozygous GG genotype and a reduced cancer incidence in the patients with the GA genotype of the rs2240308 SNP (G/A) in the Axin2 gene. The adjusted odds ratio for carriers with the GA genotype was 0.377 (95% CI, 0.206-0.688; P=0.001) and that for the AA genotype was 0.830 (95% CI, 0.309-2.232; P=0.712) compared with the GG genotype. Therefore, the GA genotype was found to exhibit a protective effect that decreased the risk of prostate cancer. To the best of our knowledge, this is the first study to demonstrate the significant association between this SNP (rs2240308, G/A) and the risk of prostate cancer. This association indicates the possibility that the variations in the Axin2 gene in this position may play a significant role in promoting the development of cancer in the prostate. We believe that the Axin2 SNP (rs2240308) could be a useful biomarker for the predisposition and early diagnosis of the disease. PMID- 25013501 TI - Drug resistance reversed by silencing LIM domain-containing protein 1 expression in colorectal carcinoma. AB - The role of LIM domain-containing protein 1 (LIMD1) in the multidrug resistance of colorectal carcinoma (CRC) has not yet been established. The aim of the current study was to investigate the chemosensitivity of CRC multidrug-resistant (MDR) cells following the silencing of LIMD1. The MDR phenotypic Colo205 and HCT 8 cell lines were examined, which were established by exposure to increasing doses of 5-fluorouracil (5-FU) over a period of one year. LIMD1 siRNA constructs were transfected into CRC MDR cells and the phenotypic effects were determined comprehensively. The Colo205 and HCT-8 cell lines were more resistant to 5-FU compared with their respective parental cell lines. In addition, the two MDR cell types expressed significantly more LIMD1 compared with their parental lines. The stably transfected cells showed various degrees of reversal of the MDR phenotype, and 5-FU-induced apoptosis was increased in the transfected cells compared with the controls. In conclusion, RNA interference targeting LIMD1 may present a novel therapeutic option for CRC. PMID- 25013503 TI - Investigation of the epidermal growth factor receptor mutation rate in non-small cell lung cancer patients and the analysis of associated risk factors using logistic regression. AB - The aim of the present study was to investigate the mutation rate of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients and to apply logistic regression analysis to investigate the factors associated with EGFR gene mutation to provide data for the treatment of NSCLC. Paraffin tissue, bronchoscopy or pleural effusion specimens were collected from 176 NSCLC patients following pathological diagnosis. The EGFR gene exon 19 delL747-S75linss and delL747-S752ins deletion mutations, and the exon 20 T790M and exon 21 L858R mutations were identified using amplification refractory mutation system analysis. The clinical data and laboratory results of the patients were collected, and the total mutation rate of the EGFR gene in exons 19, 20 and 21 in the 176 NSCLC patients was found to be 48.3% (85/176). In addition, the EGFR gene mutation rate in adenocarcinoma was found to be significantly higher than that in squamous cell and large cell carcinoma (chi2=12.454; P=0.002). Furthermore, the mutation rate was found to be significantly higher in females than in males (chi2=13.78; P=0.001). The rate of exon 19 mutation was 21.0% (37/176), whereas the rate of exon 20 T90M mutation was 1.7% (3/176) and that of exon 21 L858R mutation was 29.0% (51/176). The logistic regression analysis revealed that the female gender, adenocarcinoma, distant metastasis and chemotherapy are factors associated with EGFR gene mutation (P<0.05). The female gender resulted in an increased incidence (2.438 times that of males) of EGFR mutation. Similarly, adenocarcinoma, distant metastasis and chemotherapy exhibited an increase in EGFR mutation risk (by 2.571, 2.810 and 0.367 times, respectively). The rate of EGFR mutation was high in the NSCLC patients, predominantly in exons 21 and 19. Therefore, these factors (female gender, adenocarcinoma, distant metastasis and chemotherapy) may increase the probability of EGFR gene mutations. PMID- 25013502 TI - Correlation of clinical, cytological and histological findings in oral squamous cell carcinomas. AB - The present study aimed to investigate the efficiency of exfoliative cytology by correlating the clinical lesions of oral squamous cell carcinoma (OSCC) with exfoliative cytology and histopathological findings. Cases of OSCC diagnosed between 1984 and 2010 were analyzed. The inclusion criteria for the present study were the availability of detailed clinical findings and a diagnosis of the disease through exfoliative cytology and histopathology. The cases were assessed and assigned scores, which were then submitted to modal expression analysis, which considers the higher frequency scores, thus relating the variables. The cytological findings demonstrated that the majority of the cases had malignant potential. Exfoliative cytology should be used as a supplementary tool for the diagnosis of OSCC, as it enables the early detection of these lesions. However, cytology should not be used as a substitute for histopathological examination. PMID- 25013504 TI - A new phantom and empirical formula for apparent diffusion coefficient measurement by a 3 Tesla magnetic resonance imaging scanner. AB - The aim of this study was to create a new phantom for a 3 Tesla (3T) magnetic resonance imaging (MRI) device for the calculation of the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), and to mimic the ADC values of normal and tumor tissues at various temperatures, including the physiological body temperature of 37 degrees C. The phantom was produced using several concentrations of sucrose from 0 to 1.2 M, and the DWI was performed using various phantom temperatures. The accurate ADC values were calculated using the DWIs of the phantoms, and an empirical formula was developed to calculate the ADC values of the phantoms from an arbitrary sucrose concentration and arbitrary phantom temperature. The empirical formula was able to produce ADC values ranging between 0.33 and 3.02*10-3 mm2/sec, which covered the range of ADC values of the human body that have been measured clinically by 3T MRI in previous studies. The phantom and empirical formula developed in this study may be available to mimic the ADC values of the clinical human lesion by 3T MRI. PMID- 25013506 TI - Pinellia pedatisecta agglutinin-based lectin blot analysis distinguishes between glycosylation patterns in various cancer cell lines. AB - The analysis of altered glycosylation patterns may provide biomarkers for various types of cancer. The present study developed a Pinellia pedatisecta agglutinin (PPA)-based lectin blot analysis technique, which was used to analyze the glycosylation patterns in various types of cancer cells. Results showed that a typical band located between 47 and 85 kDa was obtained in the HL60 leukemia cells, whereas three typical bands located between 20 and 47 kDa were observed in the Kasumi-1 leukemia cells. For the PLC, BEL-7404, Huh7 and H1299 solid tumor cell lines, different band patterns were detected, with bands typically located between 55 and 100 kDa. The findings of the present study show that PPA-based lectin blot analysis is capable of distinguishing between glycosylation patterns in leukemia and solid tumor cell lines. The glycofiles detected using PPA-based lectin blot analysis may provide a 'glycosylation fingerprint' for a variety of cancer cells, which may be valuable for cancer prognosis and diagnosis. PMID- 25013505 TI - Utility of diffusion-weighted imaging to assess hepatocellular carcinoma viability following transarterial chemoembolization. AB - The purpose of the present study was to evaluate whether diffusion-weighted imaging (DWI) can be used to assess hepatocellular carcinoma (HCC) viability following transarterial chemoembolization (TACE). A total of 41 consecutive patients were treated according to chemoembolization protocols. The follow-up was performed between six and eight weeks post-chemoembolization by multidetector computed tomography [or enhanced magnetic resonance imaging (MRI)] and DW-MRI on the same day. The presence of any residual tumor and the extent of tumor necrosis were evaluated according to the European Association for the Study of the Liver. The apparent diffusion coefficient (ADC) values of the entire area of the treated mass and the vital and necrotic tumor tissues were recorded. Correlation coefficients were also calculated to compare the percentage of necrosis with ADC values. The mean ADC values of the necrotic and vital tumor tissues were 2.22+/ 0.31*10-3 mm2/sec and 1.42+/-0.25*10-3 mm2/sec, respectively (Mann-Whitney U test, P<0.001). The results from the receiver operating characteristic analysis showed that the threshold ADC value was 1.84*10-3 mm2/sec with 92.3% sensitivity and 100% specificity for identifying the necrotic tumor tissues. A significant linear regression correlation was identified between the ADC value of the entire area of the treated mass and the extent of tumor necrosis (r=0.58; P<0.001). In conclusion, DWI can be used to assess HCC viability following TACE. PMID- 25013507 TI - JAK2 V617F detected in two B-cell chronic lymphocytic leukemia patients without coexisting Philadelphia chromosome-negative myeloproliferative neoplasms: A report of two cases. AB - The JAK2 V617F mutation has been observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs), including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. This mutation has also been observed in a small number of other myeloid malignancies, such as acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome. The JAK2 V617F allele has rarely been evaluated in lymphoproliferative disorders. In total, 28 JAK2 V617F-positive B-cell lymphocytic leukemia (B-CLL) patients have previously been reported and all presented with Ph-MPN concomitantly. However, following investigation of the JAK2 V617F mutation in 63 B-CLL patients at the Shanghai First People's Hospital (Shanghai, China) between January 2008 and December 2012 via allele-specific polymerase chain reaction, two B-CLL patients without a history of Ph-MPN were identified to carry the JAK2 V617F allele. PMID- 25013508 TI - Bartholin gland carcinoma: A case report. AB - Bartholin gland carcinomas (BGCs) are extremely rare tumors accounting for <1% of all female genital malignancies. The current study presents a 49-year-old female with an eight-year history of BGC. A mass was identified in the vulva and the patient underwent an excisional biopsy, which revealed a left Bartholin adenoid cystic carcinoma. The patient subsequently received surgery, chemotherapy and biological therapy, and has survived. Therefore, the present case indicates that surgery is important for the treatment of BGC, however; multimodal therapy may be a more effective treatment strategy. PMID- 25013509 TI - DNA repair gene XRCC3 Thr241Met polymorphism and susceptibility to glioma: A case control study. AB - The DNA repair gene, X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism may be associated with a susceptibility to glioma. The present study aimed to investigate the association between the XRCC3 Thr241Met polymorphism and the potential susceptibility to gliomas. A hospital-based case-control study was conducted, which included a total of 886 patients with glioma and 886 healthy control subjects. Peripheral blood samples were extracted and the polymerase chain reaction-restriction fragment length polymorphism method was performed to analyze the genotypes. The glioma patients had a significantly higher frequency of the XRCC3 241 MetMet genotype [odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.09-2.41; P=0.02] compared with the control subjects. When stratified by the grade of the glioma, the patients with stage IV glioma (according to the World Health Organization classification) had a significantly higher frequency of the XRCC3 241 MetMet genotype (OR=1.61; 95% CI: 1.06-2.44; P=0.03). When stratified by the histology of the glioma, there was no significant difference in the distribution of each genotype. The findings of the present study indicate that the XRCC3 Thr241Met polymorphism is associated with a susceptibility to glioma. PMID- 25013510 TI - BRAF-activated long non-coding RNA contributes to colorectal cancer migration by inducing epithelial-mesenchymal transition. AB - Long non-coding RNAs (lncRNAs) are recently identified regulators in tumorigenesis and tumour progression. BRAF-activated lncRNA (BANCR) is overexpressed in melanoma and has a potential functional role in melanoma cell migration. However, little is known concerning the role of BANCR in the development of colorectal cancer (CRC). The current study examined BANCR expression in 60 pairs of CRC and matched adjacent normal tissues. The quantitative polymerase chain reaction results showed that BANCR was frequently overexpressed in cancer tissues and this overexpression was found to significantly correlate with lymph node metastasis and tumour stage. The ectopic expression of BANCR contributed to the migration of human CRC Caco-2 cells, whereas knockdown of BANCR inhibited the migration of the HCT116 cells in vitro. Further investigation into the underlying mechanisms responsible for the migratory effects revealed that BANCR induced the epithelial-mesenchymal transition (EMT) through an MEK/extracellular signal-regulated kinase-dependent mechanism as treatment with the MEK inhibitor, U0126 decreased migration and reversed the EMT in the BANCR-overexpressed HCT116 cells. These results revealed the significance of BANCR in the molecular etiology of CRC and implied the potential application of BANCR in the therapeutic treatment of CRC. PMID- 25013511 TI - Clinicopathological analysis and prognostic factors of 11 patients with primary non-Hodgkin lymphoma of the small intestine in a single institute. AB - The gastrointestinal (GI) tract is the most common extranodal site of involvement in non-Hodgkin lymphoma (NHL). Primary GI NHL is frequently discussed in survival analyses. Primary intestinal NHL is significantly different from primary gastric NHL with regard to its clinical features, pathological subtype, treatment and prognosis. The small intestine is involved in lymphoma less often than the large intestine. The present study aimed to analyze the clinical and pathological characteristics of primary NHL of the small intestine and its prognostic factors. A retrospective analysis was performed on clinical data from 313 cases of NHL that occurred between 1995 and 2008 in the Tri-Service General Hospital (National Defense Medical Center, Taipei, Taiwan). Among these cases, 11 cases of primary NHL of the small intestine were identified. A Cox model was used to perform the multivariate analysis. The Kaplan-Meier method was used for the survival analysis. From the 11 patients with primary NHL of the small intestine, seven patients were male (63.6%) and four patients were female (36.3%). Furthermore, nine patients (81.8%) were diagnosed with B-cell lymphoma, of which five (45.5%) were also diagnosed with diffuse large B-cell lymphoma (DLBL). Abdominal pain and/or distention were present in six (54.5%) of the patients and jejunum involvement was also observed in six (54.5%) of the 11 patients. The mean overall survival (OS) time of the 11 patients was 27.2 months and the four-year survival rate was 36.3%. The mean OS time in the patients with jejunum involvement was shorter than in those without jejunum involvement (16.9 vs. 39.6 months), although this difference was not significant (P=0.657). Surgical treatment was performed on four of the six patients with jejunum involvement due to an acute abdomen or perforation-related peritonitis. The results of the present study indicate that DLBL is the most common subtype of primary lymphoma of the small intestine, and that the site involved in NHL may affect the potential for surgery in patients with intestinal lymphoma. Furthermore, patients with primary lymphoma of the small intestine have been found to have a poor outcome compared with those with lymphoma in other regions of the GI tract. In the present study, a similar trend was observed, however, the sizes of the subgroups of primary lymphoma of the small intestine were too small for individual analysis. PMID- 25013512 TI - Prognostic significance of C-reactive protein in patients with intermediate-risk metastatic renal cell carcinoma treated with molecular targeted therapy. AB - The present study aimed to investigate the impact of pre-treatment C-reactive protein (CRP) levels on the prediction of prognosis in patients with metastatic renal cell carcinoma (mRCC), who were classified as intermediate-risk patients using the Memorial Sloan Kettering Cancer Center (MSKCC) risk classification and who received molecular targeted therapy. The oncological outcome of 140 patients with mRCC who underwent molecular targeted therapy was analyzed. Patients were divided into favorable-, intermediate- and poor-risk groups (groups F, I and P, respectively) based on the MSKCC risk classification. The patients in group I were then further classified into two groups based on pre-treatment serum CRP levels. The overall survival (OS) rates of the patients in these groups were then assessed. The OS rate of the patients in group I with normal pre-treatment CRP levels was found to be significantly increased compared with that of patients with high pre-treatment CRP levels (P<0.0001), while there was no significant difference in the OS rate in the patients with normal pre-treatment CRP levels in group I compared with those in group F. Multivariate analyses revealed that high pre-treatment CRP levels were an independent prognostic factor for OS in the patients in group I (P<0.0001; hazard ratio, 3.898). Thus, pre-treatment CRP levels may be a candidate predictor for OS in patients with intermediate-risk mRCC. PMID- 25013513 TI - Natural killer/T-cell lymphoma-associated hemophagocytic syndrome: A case report. AB - Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal disease with no optimal treatment. The present study reports the clinical features, diagnosis and treatment process of three patients with relapsed NK/T-cell lymphoma-associated HPS. All of the patients were classified as Ann Arbor stage IV and presented with a poor performance status. Two patients were successfully treated with a pegaspargase-containing combination regimen and one patient succumbed due to serious complications. These cases indicate that for patients with a history of lymphoma, the diagnosis of HPS should be considered when patients present with progressive high fever, pancytopenia and liver dysfunction. Early identification and effective treatments, including pegaspargase-based regimens are essential for an enhanced prognosis. PMID- 25013514 TI - Cutaneous metastatic adenocarcinoma complicated by spontaneous tumor lysis syndrome: A case report. AB - The present study reports the case of a 71-year-old female with metastatic adenocarcinoma of the skin who developed tumor lysis syndrome (TLS) upon admittance to the First Affiliated Hospital of Liaoning Medical University (Jinzhou, China). The patient presented to the hospital due to multiple subcutaneous nodules, lethargy and weakness, but succumbed without any cancer therapy. Metastases to the skin from solid carcinomas are uncommon, and several studies have reported patients with minimal primary symptoms despite extensive metastatic skin disease. However, few cases were accompanied with spontaneous TLS at the time of presentation. TLS may be a severe complication during the therapy for hematological and oncological diseases. Although spontaneous TLS in internal tumors has been reported, it is extremely rare. The present study highlights the fact that multiple subcutaneous metastases may occur with the symptoms of spontaneous TLS, and may be key for the early recognition of this syndrome. PMID- 25013515 TI - Simultaneous occurrence of two B-cell malignancies: A case report. AB - The present study describes the case of a 75-year-old male with coexisting multiple myeloma and diffuse large B-cell lymphoma. Although the two malignancies are mature B-cell neoplasms, their clinical manifestations are very different and the clinical approaches used to treat these two types of tumor vary. The patient in the present case was diagnosed with the simultaneous existence of two different B-cell tumors and was successfully treated using the DCEP regimen. The simultaneous presentation of two mature B-cell neoplasms, types of hematological malignancy, is very rare, thus the present case is considered to be interesting. PMID- 25013516 TI - Hepatocellular carcinoma metastasis to the lacrimal gland: A case report. AB - Hepatocellular carcinoma (HCC) is a globally common neoplasm, with regional metastasis associated with >50% of the tumors. Extrahepatic metastasis is also common, with the lungs, diaphragm, abdominal lymph nodes and bone being the most frequently affected regions. However, to the best of our knowledge, HCC metastasis to the lacrimal gland has not been reported in the literature. Only one case of metastasis to the lacrimal sac from a renal cell carcinoma has been reported. The current study presents the case of a 56-year-old male with ocular symptoms who was eventually diagnosed with HCC. The therapeutic alternatives for such cases are also discussed according to the reviewed literature. Clinicians should be watchful for the appearance of tumors in the lacrimal gland in patients with a history of malignancy. PMID- 25013517 TI - Ameloblastic carcinoma: An analysis of 12 cases with a review of the literature. AB - The diagnosis of ameloblastic carcinoma is often difficult and the optimal treatment methods remain controversial. The current study retrospectively investigated the optimal diagnosis and treatment methods of 12 ameloblastic carcinoma patients at the West China Hospital of Stomatology, Sichuan University (Chengdu, China), and 20 patients selected from the PubMed database, were reviewed. The clinical features, diagnosis and outcome of the different treatments were evaluated. Ameloblastic carcinoma occurred in 12 out of a total of 538 ameloblastoma patients; the majority were of the primary type. Of the 538 ameloblastoma patients, 294 were male, 244 were female with a male to female ratio of 1.2:1. The predilection age is 20-30 years, which accounts for 40% of the total. In total, 461 cases were in the mandible and 77 were located in the maxilla. The cure rate of the primary type and the recurrence rate of the secondary type tumors were higher in the patients from the West China Hospital of Stomatology compared with those reported in the literature. In particular, a case with a long-term survival of 30 years is presented, which is considered to be relatively rare. The evolution of the clinical course has experienced three stages: Ameloblastoma (1978) followed by metastatic ameloblastoma (2000) and finally ameloblastic carcinoma (2008). To avoid recurrence, wide local excision with postoperative radiation therapy is required. While novel therapeutic regimens should also be considered as appropriate, including carbon ion therapy and Gamma Knife stereotactic radiosurgery. However, controlled studies with larger groups of patients are required to increase the accuracy of results. PMID- 25013519 TI - Intradural schwannoma complicated by lumbar disc herniation at the same level: A case report and review of the literature. AB - Intradural tumours of the spine are usually benign and have a good prognosis, if they are diagnosed and removed early. Lumbar disc herniation is a common cause of chronic, acute, or recurrent lumbar radiculopathy. However, to date, there have been no reports of progressive neurological deficiencies due to the co-existence of two significant pathologies contributing to intradural and extradural compression. The current study reports the rare case of a patient with simultaneous extradural and intradural compression of the nerve root due to co existent intervertebral disc herniation and an intradural schwannoma at the same level. A 71-year-old female suffering from lower back pain and radiating pain of the right lower extremities was admitted to Busan Korea Hospital (Busan, Korea). Magnetic resonance imaging revealed lumbar disc herniation at L4-5 and a mass occupying the intradural space at the same level of the compressed dural sac. Using the posterior approach, surgical excision of the two pathologies was performed. Pathological diagnosis confirmed schwannoma and the symptoms markedly improved. PMID- 25013518 TI - JSI124 inhibits breast cancer cell growth by suppressing the function of B cells via the downregulation of signal transducer and activator of transcription 3. AB - JSI-124, also known as cucurbitacin I, is a selective inhibitor of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and in vitro and in vivo studies have found that it has anti-tumor and anti proliferative properties. However, the role of JSI124 in tumor-associated B cells has yet to be elucidated. The present study demonstrated that STAT3 is significantly activated in the B cells of patients with breast cancer. Furthermore, a 4T1 tumor-bearing mouse model revealed that JSI124 effectively inhibited tumor growth. Moreover, the STAT3 levels in the B cells of the JSI124 treated mice were found to be significantly decreased. B cells from normal Balb/c mice, the 4T1-bearing mice and the JSI124-treated 4T1 mice were purified and intravenously injected into the 4T1-bearing Balb/c mice. Tumor growth data showed that the 4T1 tumor mouse-derived B cells, which exhibited a higher level of STAT3, promoted tumor growth, while the JSI124-treated 4T1 mouse-derived B cells had a tumor suppressor function. Furthermore, the B cells from the normal Balb/c mice were treated with phosphate-buffered saline, JSI124 and 4T1 tumor cells, then the B cell STAT3 levels were analyzed. Following injection into the 4T1 mice, the 4T1 cell-treated B cells were observed to enhance tumor growth, while the JSI124-treated B cells were found to inhibit the growth of 4T1 tumors in vivo. These findings show a novel role of JSI124 in tumor suppression through the downregulation of the expression of STAT3 in tumor-associated B cells. PMID- 25013520 TI - High serum macrophage inflammatory protein-3alpha is associated with the early recurrence or metastasis of non-small cell lung cancer following primary pulmonary resection. AB - The present study sought to characterize the role of macrophage inflammatory protein-3alpha (MIP-3alpha) in non-small cell lung cancer (NSCLC) patients with early recurrence or metastasis after primary pulmonary resection. Follow-up examinations were conducted for 203 NSCLC patients with primary pulmonary resection for two years post-operatively, and data was also collected for 20 healthy subjects. Serum MIP-3alpha levels were determined prior to surgery and at post-operative days (PODs) 30, 90 and 180, and the relevant clinical and operative variables were collected. Serum MIP-3alpha was measured using a commercially available enzyme-linked immunosorbent assay. There were no significant differences in age, gender and histological type among all groups (P>0.05). Serum MIP-3alpha levels on POD 180 were significantly higher in the recurrence group than in the non-recurrence group and healthy subjects (P=0.001). There was no significant difference in the serum MIP-3alpha level at PODs 90 and 180 in the patients with or without adjuvant chemotherapy (P>0.05). The recurrence rate in the high serum MIP-3alpha level group was 41.67%, much higher than the 23.53% observed in the low level group (P=0.006). The patients with high serum levels of MIP-3alpha had a significantly shorter overall recurrence-free time compared with those with low levels (P=0.004). Multivariate Cox's regression analyses showed that only serum MIP-3alpha level was significant, with a hazard ratio of 1.061, a 95% confidence interval of 1.044-1.078 and a P-value of 0.001. The serum MIP-3alpha level in the patients with liver and bone metastases were remarkably higher than those with recurrence at other sites. The high post operative serum MIP-3alpha levels were associated with an increased risk of post operative early recurrence or metastasis in the lung cancer patients, specifically in those with bone or liver metastases. PMID- 25013521 TI - The current status and future perspectives of nuclear medicine in Korea. AB - Since the introduction of nuclear medicine in 1959, Korea accomplished a brilliant development in terms of both clinical practice and research activities, which was mainly due to the dedication of nuclear medicine specialists, consisting of physicians, technicians, and scientists, and strong support from the Korean Government. Now, Korea has 150 medical institutes, performing approximately 561,000 nuclear imaging procedures and 11.6 million in vitro studies in 2008, and ranked fourth in the number of presentations at the Annual Meeting of the Society of Nuclear Medicine (SNM) in 2008. The successful progress in this field has allowed Korea to focus on the international promotion of nuclear medicine, especially in the developing and underdeveloped countries. In consequence, the Asian Regional Cooperative Council for Nuclear Medicine (ARCCNM) was established in 2001, and Seoul hosted the 9th Congress of the World Federation of Nuclear Medicine and Biology (WFNMB) in 2006. In the future, Korea will strive to sustain its rate of advancement in the field and make every effort to share its progress and promote the exchange of scientific information at the international level. PMID- 25013522 TI - Postoperative Functional Outcome After Off-Pump Versus On-Pump Coronary Artery Bypass Grafting Using Gated Myocardial SPECT: A Comparison by Propensity Score Analysis. AB - PURPOSE: We evaluated the short-term and mid-term differences in perfusion and function after off-pump and on-pump coronary artery bypass grafting (CABG) using gated myocardial single photon emission computed tomography. MATERIALS AND METHODS: A total of 70 patients with coronary artery disease who underwent CABG were included based on the propensity score matching results from 165 patients. Thirty-five patients underwent off-pump and 35 patients on-pump CABG. Rest (201)Tl/dipyridamole stress (99 m)Tc-methoxyisobutylisonitrile gated single photon emission computed tomographies were performed preoperatively and postoperatively at short-term (103 +/- 23 days after surgery) and mid-term follow up (502 +/- 111 days after surgery). Changes in left ventricular ejection fraction, end systolic volume, stress and rest segmental perfusion, and segmental wall thickening were compared between the two groups. The segments with preoperative rest (201)Tl uptake under 60% of maximum uptake were included in the segmental analysis. RESULTS: Left ventricular ejection fraction (P = 0.001) and end systolic volume (P = 0.008) showed significant improvement in both groups. There were no significant short-term and mid-term differences between the two groups in terms of left ventricular ejection fraction (P = 0.309) and end systolic volume (P = 0.938). Likewise, segmental rest (P = 0.178) and stress perfusion (P = 0.071), and systolic wall thickening (P = 0.241) showed significant improvement in both groups with similar time courses. CONCLUSION: Off pump CABG resulted in significant improvements in left ventricular ejection fraction, end systolic volume, and regional myocardial perfusion and function that are comparable to on-pump CABG at short-term and mid-term. Gated myocardial SPECT successfully revealed that off-pump CABG is as good as on-pump CABG from the viewpoint of myocardial perfusion and function. PMID- 25013523 TI - Tc-99m Ciprofloxacin SPECT of Pulmonary Tuberculosis. AB - PURPOSE: Tc-99m ciprofloxacin is available for imaging infection. However, there has been no study on employing single photon emission computed tomography (SPECT) with using Tc-99m ciprofloxacin to image active pulmonary tuberculosis. Therefore, we conducted this study to assess the efficacy of Tc-99m ciprofloxacin SPECT for imaging active pulmonary tuberculosis. METHODS: Twenty-one participants were enrolled in this prospective study. They were divided into two groups according to the clinical and radiological assessment. Group one (Gr. 1) consisted of five normal volunteers and six patients with inactive pulmonary tuberculosis. Group two (Gr. 2) consisted of ten patients with active pulmonary tuberculosis. SPECT was performed 3 h after injecting 555 MBq (15 mCi) of Tc-99m ciprofloxacin. The findings of Tc-99m ciprofloxacin SPECT were interpreted by a nuclear medicine specialist and then the results were analyzed according to the patients' clinical and radiological classifications. RESULTS: The results of Tc 99m ciprofloxacin SPECT were as follows: eight true-positive cases, ten true negative cases, one false-positive case and two false-negative cases. The sensitivity and specificity was 80.0% and 90.9%, respectively. The positive predictive value was 88.9% and the negative predictive value was 83.3%. CONCLUSIONS: Tc-99m ciprofloxacin SPECT is feasible for imaging active pulmonary tuberculosis. It is a useful nuclear-imaging method for discriminating between the active and inactive tuberculosis states in patients with a past medical history of pulmonary tuberculosis. PMID- 25013524 TI - Isolated system towards a successful radiotherapy treatment. AB - PURPOSE: Establishment of the specifications and standards for successful radiotherapy treatments through identifying three objectives: administering the appropriate low-waste dose, developing dose-delivery skills and monitoring an earlier response to therapy. METHODS: The appropriate low-waste dose is administered via the work-energy principle, considering the interaction between the drug and the tumor as an isolated system. Then, chelated with any compound that could form a lipid-soluble complex with the radioactive metal ions, it is injected directly into the tumor via a multihole needle to improve the distribution of the injectate solution. This can be detected by monitoring the tumor response through newer imaging techniques that combine single photon emission computed tomography (SPECT) with computed tomography (CT), or positron emission tomography (PET) with CT, so that nonresponding tumors can be identified early to modify the administered dose. RESULTS: The accuracy of estimating the initial effective radioactive dose depends on the equivalence of the growth energy of the tumor estimated from the CT scan and the decay energy of the effective radioactive dose. Besides earlier or more accurate assessment of the tumor response by PET with the glucose analogue (18)F-fluoro-2-deoxyglucose ((18)F-FDG), this contributes to the most safe and low-cost successful treatment. This approach assessed the therapeutic significance of lipid-soluble compounds with the radioactive metal ions in protecting system isolation, which plays a major role in targeted tumor therapy. CONCLUSION: Treatment success shows that the three identified objectives are completely dependent objectives. It should also be taken into consideration that radionuclide decay-generated Auger electrons may be more effective in very small tumors to avoid a cross dose. PMID- 25013525 TI - Experience of Dual Time Point Brain F-18 FDG PET/CT Imaging in Patients with Infectious Disease. AB - Dual time point FDG PET imaging (DTPI) has been considered helpful for discrimination of benign and malignant disease, and staging lymph node status in patients with pulmonary malignancy. However, DTPI for benign disease has been rarely reported, and it may show a better description of metabolic status and extent of benign infectious disease than early imaging only. The authors report on the use F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging with additional delayed imaging on a 52 year-old man with sparganosis and a 70-year-old man with tuberculous meningitis. To the best of our knowledge, this is the first report on dual time point PET/CT imaging in patients with cerebral sparganosis and tuberculous meningitis. PMID- 25013526 TI - Pleomorphic adenoma mimicking malignant tumor in the parapharyngeal space in a patient with gastric carcinoma. AB - A 68-year-old man underwent total gastrectomy for stomach cancer. On the follow up FDG PET/CT image 18 months later, intense focal (18)F-fluorodeoxyglucose (FDG) uptake was noted in the right parapharyngeal space. This lesion showed intermediate signal intensity on T1-weighted image and heterogeneous high signal intensity on T2-weighted image. The mass was heterogenously enhanced by gadolinium enhancement. This lesion was pathologically confirmed as pleomorphic adenoma by excision. This case highlights the fact that both benign and malignant lesions in the parotid gland may exhibit intense FDG activity and the need for pathologic confirmation of parotid gland lesions for accurate disease staging. PMID- 25013527 TI - Diffuse Pulmonary Uptake of Tc-99m Methylene Diphosphonate in a Patient with Non tuberculosis Mycobacterial Infection. AB - Extra-osseous uptake of bone-seeking radiopharmaceuticals has been reported at various sites and it is known to be induced by various causes. Diffuse pulmonary infection, such as tuberculosis, can be a cause of lung uptake of bone-scan agent. Here we report on a patient with non-tuberculosis mycobacterial infection (NTM) who demonstrated diffuse pulmonary uptake on Tc-99m MDP bone scan. After medical treatment for NTM, the patient's lung lesions improved. Extraskeletal lung Tc-99m MDP uptake on bone scan may suggest lung parenchymal damage associated with disease activity. PMID- 25013528 TI - Bone Scintigraphy Findings of A Case with Maffucci's Syndrome. AB - Maffucci's syndrome is a sporadic rare congenital disease that is characterized by enchondromatosis and soft tissue hemangiomas. A systemic evaluation should be considered because this syndrome is related to generalized mesodermal dysplasia, which has a high likelihood of a malignant transformation. Whole-body bone scintigraphy might be helpful for detecting skeletal involvement. We present a case of Maffucci's syndrome using bone scintigraphy to evaluate the extent of the disease. PMID- 25013529 TI - Reverse Redistribution in Myocardial Perfusion Imaging: Revisited with 64-slice MDCT. AB - The authors report myocardial perfusion imaging of a patient showing reverse redistribution (RR) and a 64-slice multidetector-row computed tomography (MDCT) with corresponding findings. The patient had subendocardial myocardial infarction (MI) with positive electrocardiogram (EKG) findings and elevated levels of cardiac isoenzymes. Experiencing this case emphasizes the importance of complementary correlation of a new diagnostic modality that helps us to understand the nature of RR. PMID- 25013531 TI - Peritoneal Lymphomatosis Imaged by F-18 FDG PET/CT. AB - Peritoneal lymphomatosis is uncommon, but when encountered is associated with aggressive histological subtypes of high-grade lymphoma, such as small-cell, large-cell, mixed large and small cell, non-cleaved, lymphoblastic Burkitt-like, and diffuse large B cell lymphomas. The CT findings of peritoneal lymphomatosis are linear or nodular peritoneal thickening, retroperitoneal lymphadenopathy, omental and mesenteric involvement with streak-like infiltrations or a bulky mass, bowel wall thickening, hepatosplenomegaly, and ascites. The authors report the first FDG PET/CT images of diffuse large B-cell lymphoma of small bowel origin associated with peritoneal lymphomatosis in a 69-year-old man. The lesions demonstrated intense FDG uptake in PET/CT images. PMID- 25013530 TI - Is this Red Spot the Blue Spot (locus ceruleus)? AB - The authors report brain images of 18F-FDG-PET in a case of schizophrenia. The images showed strikingly increased bilateral uptake in the locus ceruleus. The locus ceruleus is called the blue spot and known to be a center of the norepinephrinergic system. PMID- 25013532 TI - Unusual case of occult Brucella osteomyelitis in the skull detected by bone scintigraphy. AB - Brucellosis is a worldwide infectious disease of animals that can be transmitted to humans. Osteoarticular involvement is the most common complication of brucellosis. A 47-year-old man, who was a stockbreeder, complained of myalgia with fever and chills for 2 weeks. The serology titers and blood cultures for brucellosis were positive. Bone scintigraphy demonstrated a focally increased uptake in the left supraorbital area. Plain radiographs showed an osteolytic lesion, and an MRI revealed signal abnormalities in the corresponding site. We present an unususal case of occult Brucella osteomyelitis in the frontal bone of the skull detected by bone scintigraphy. PMID- 25013533 TI - Estimating networks with jumps. AB - We study the problem of estimating a temporally varying coefficient and varying structure (VCVS) graphical model underlying data collected over a period of time, such as social states of interacting individuals or microarray expression profiles of gene networks, as opposed to i.i.d. data from an invariant model widely considered in current literature of structural estimation. In particular, we consider the scenario in which the model evolves in a piece-wise constant fashion. We propose a procedure that estimates the structure of a graphical model by minimizing the temporally smoothed L1 penalized regression, which allows jointly estimating the partition boundaries of the VCVS model and the coefficient of the sparse precision matrix on each block of the partition. A highly scalable proximal gradient method is proposed to solve the resultant convex optimization problem; and the conditions for sparsistent estimation and the convergence rate of both the partition boundaries and the network structure are established for the first time for such estimators. PMID- 25013534 TI - One grammar or two? Sign Languages and the Nature of Human Language. AB - Linguistic research has identified abstract properties that seem to be shared by all languages-such properties may be considered defining characteristics. In recent decades, the recognition that human language is found not only in the spoken modality but also in the form of sign languages has led to a reconsideration of some of these potential linguistic universals. In large part, the linguistic analysis of sign languages has led to the conclusion that universal characteristics of language can be stated at an abstract enough level to include languages in both spoken and signed modalities. For example, languages in both modalities display hierarchical structure at sub-lexical and phrasal level, and recursive rule application. However, this does not mean that modality based differences between signed and spoken languages are trivial. In this article, we consider several candidate domains for modality effects, in light of the overarching question: are signed and spoken languages subject to the same abstract grammatical constraints, or is a substantially different conception of grammar needed for the sign language case? We look at differences between language types based on the use of space, iconicity, and the possibility for simultaneity in linguistic expression. The inclusion of sign languages does support some broadening of the conception of human language-in ways that are applicable for spoken languages as well. Still, the overall conclusion is that one grammar applies for human language, no matter the modality of expression. WIREs Cogn Sci 2014, 5:387-401. doi: 10.1002/wcs.1297 This article is categorized under: Linguistics > Linguistic Theory. PMID- 25013537 TI - Neurotoxin waste from drawing product through the vial stopper. AB - Botulinum toxin injection is the most common cosmetic surgery procedure in the world. Current technique requires reconstitution that can produce product waste resulting in significant loss of profit as well as inaccuracy of actual units injected. By random sampling of "used empty" vials, it was shown that an average of 5 units are potentially wasted by the conventional methods of drawing up the product with a needle through the stopper of an inverted vial. Depending on the pricing and dilution of the product, this can result in a profit loss of $50 to $60 per vial, which can quickly add up to tens of thousands of dollars in a busy practice. Removing the stopper, tilting the vial, and aspirating the last residual with a small gauge needle can result in significant savings. Finally, this residual was calculated at a five-percent loss, which results in an inaccuracy of actual units delivered. PMID- 25013536 TI - Moisturizing different racial skin types. AB - The skin is a complex organ involved in thermoregulation, gas exchange, protection against pathogens, and barrier function to maintain proper hydration. When dry, the ability for skin to execute these tasks becomes impaired. Dry skin affects almost everyone as we age, but it is also dependent on external factors, such as dry climate, colder temperatures, and repeated washing. In addition, increasing evidence has shown racial variability in the physiological properties of skin, which directly impacts water content of the stratum corneum and sensitivity to exogenously applied agents. A multitude of products have been developed to treat dry skin, and as a group, moisturizers have been designed to either impart or restore hydration in the stratum corneum. Given the large number of moisturizers presently available, depending on individual components, several different mechanisms may be employed to promote skin hydration. As there exists dramatic racial variability in skin properties, certain moisturizers may thus be more effective in some and less effective in others to treat the common condition of dry skin. PMID- 25013535 TI - Diagnostic and prognostic biomarkers in melanoma. AB - Melanoma is a lethal melanocytic neoplasm. Unfortunately, the histological diagnosis can be difficult at times. Distinguishing ambiguous melanocytic neoplasms that are benign nevi from those that represent true melanoma is important both for treatment and prognosis. Diagnostic biomarkers currently used to assist in the diagnosis of melanoma are usually specific only for melanocytic neoplasms and not necessarily for their ability to metastasize. Traditional prognostic biomarkers include depth of invasion and mitotic count. Newer diagnostic and prognostic biomarkers utilize immunohistochemical staining as well as ribonucleic acid, micro-ribonucleic acid, and deoxyribonucleic acid assays and fluorescence in situ hybridization. Improved diagnostic and prognostic biomarkers are of increasing importance in the treatment of melanoma with the development of newer and more targeted therapies. Herein, the authors review many of the common as well as newer diagnostic and prognostic biomarkers used in melanoma. PMID- 25013538 TI - Neuromodulator threading: revisiting an approach to neurotoxin delivery. AB - Neuromodulator toxins are traditionally delivered to facial muscles via a depot technique using a 32g needle. This article revisits the threading technique, which was used more commonly in the 1990s and early 2000s prior to the introduction of the 32g x 1/2" gamma ray sterilized needle. A description of the threading technique, illustrated by diagrams and patient photos, is presented for the orbicularis oris and corrugator supercilii injection sites. In contrast to the depot technique in which the needle enters the skin at a 90-degree angle, the threading technique enters the skin at a 20- to 30-degree angle. Specifically, for the orbicularis oris, onabotulinum toxin A injections are performed 2 to 5mm beyond the "white roll" of the vermillion border. After the needle punctures the skin, the toxin is injected while withdrawing in a threading manner parallel to the vermillion border. This method is repeated along the entire length of the orbicularis oris muscle. For the corrugator supercilii muscles, the injection technique differs slightly. A depot injection is given at the most medial point of the muscle, targeting the body of the muscle. The tail of the corrugator supercilii is injected using the threading technique as described for the orbicularis oris, in which the needle inserts at a 20- to 30-degree angle. This paper revisits the threading injection technique for neurotoxin treatment of the orbicularis and corrugator supercilii sites. PMID- 25013539 TI - Fulminans in dermatology: a call to action: a recommendation for consideration of the term scleredema fulminans. AB - The term fulminans is used infrequently in dermatology, being reserved for those cases of rapid onset with potentially severe sequelae or those that are life threatening, thereby warranting urgent intervention. In this commentary, the authors propose that the term scleredema fulminans be utilized in severe, progressive cases of scleredema adultorum of Buschke presenting with rapid onset. PMID- 25013540 TI - Injection therapy for the management of superficial subcutaneous lipomas. AB - Superficial subcutaneous lipomas are common benign tumors of the subcutaneous adipose tissue. Removal of superficial subcutaneous lipomas is achieved with simple surgical excision for the purposes of improved cosmesis, removing painful lipomas, or for the removal of a lipoma affecting function through mass effect. As research in localized fat reduction has improved, therapies successful in this domain have been applied to the management of lipomas as a surgical alternative. In this review article, the authors review the basic science of injection therapies used in the management of lipomas as well as their potential efficacy and limitations. PMID- 25013542 TI - Role of antibiotics on surgical site infection in cases of open and laparoscopic cholecystectomy: a comparative observational study. AB - INTRODUCTION: Surgical site infection (SSI) comes as third most common healthcare related infection which produces morbidity and deaths at large. Still many authors believe that it is better not to use prophylactic antibiotics in simple and uncomplicated cases. Laparoscope, now-a-days is a much used instrument for abdominal surgeries. Even after new aseptic techniques SSI remains to be a major problem. AIMS AND OBJECTIVES: To study the effect of antibiotics on superficial SSI in the cases of open and laparoscopic cholecystectomy. OBSERVATION AND RESULTS: One hundred patients were enrolled for cholecystectomy. The patients were divided into two groups, A and B. Group A consisted of patients in whom laparoscopic cholecystectomy was done and group B in whom open cholecystectomy was done. The male female ratio was 1: 2.23. The mean age of patients in Group A was 46 years and in Group B was 44; Standard deviation (SD) for age was 14.8% and 13.8% in groups A and B respectively; t-value was 0.654 and P value was 0.515 and they were not significant. The number of males and females was 16 and 26 respectively in Group A and 11 and 31 in Group B. The Chi square X(2) = 1.36 and P value was 0.248 and both were insignificant. The rate of superficial surgical site infection was 2.63% in both the groups. CONCLUSION: Our study concludes that there is no difference in the outcome of patients in cases of open as well as laparoscopic cholecystectomy. There is no significant difference in the surgical site infection rate in cases of open as well as laparoscopic cholecystectomy. PMID- 25013543 TI - Single Stage Reconstruction of Type IIA Defect of the Ear Lobule: The Limberg flap Technique Revisited. AB - The ear lobule is an important reference point for symmetry of the face and its loss causes an obvious aesthetic abnormality. Type II A defects are characterized by loss of the ear lobule without presence of a nubbin of tissue attached to the cheek. Such defects are typically seen in individuals having an unattached ear lobule. The goal of surgery should be an aesthetically pleasing reconstruction that maintains symmetry with the opposite ear lobule. The Limberg-flap technique using a doubled-over skin flap allows a one stage reconstruction of the ear lobule. It is technically simple and may be performed under local anesthesia. The aesthetic results are generally well acceptable and there is a good color match between the neolobule and the surrounding skin. PMID- 25013541 TI - N-acetyl-serotonin protects HepG2 cells from oxidative stress injury induced by hydrogen peroxide. AB - Oxidative stress plays an important role in the pathogenesis of liver diseases. N Acetyl-serotonin (NAS) has been reported to protect against oxidative damage, though the mechanisms by which NAS protects hepatocytes from oxidative stress remain unknown. To determine whether pretreatment with NAS could reduce hydrogen peroxide- (H2O2-) induced oxidative stress in HepG2 cells by inhibiting the mitochondrial apoptosis pathway, we investigated the H2O2-induced oxidative damage to HepG2 cells with or without NAS using MTT, Hoechst 33342, rhodamine 123, Terminal dUTP Nick End Labeling Assay (TUNEL), dihydrodichlorofluorescein (H2DCF), Annexin V and propidium iodide (PI) double staining, immunocytochemistry, and western blot. H2O2 produced dramatic injuries in HepG2 cells, represented by classical morphological changes of apoptosis, increased levels of malondialdehyde (MDA) and intracellular reactive oxygen species (ROS), decreased activity of superoxide dismutase (SOD), and increased activities of caspase-9 and caspase-3, release of cytochrome c (Cyt-C) and apoptosis-inducing factor (AIF) from mitochondria, and loss of membrane potential (DeltaPsim). NAS significantly inhibited H2O2-induced changes, indicating that it protected against H2O2-induced oxidative damage by reducing MDA levels and increasing SOD activity and that it protected the HepG2 cells from apoptosis through regulating the mitochondrial apoptosis pathway, involving inhibition of mitochondrial hyperpolarization, release of mitochondrial apoptogenic factors, and caspase activity. PMID- 25013544 TI - Hollow mill for extraction of stripped titanium screws: an easy, quick, and safe technique. AB - Removal of jammed titanium screws can be difficult due to the problem of stripping of the hexagonal heads of the screws. We present a technique of extraction of stripped screws with the use of a standard 4.5 mm stainless steel hollow mill in a patient of peri-implant fracture of the radius fixed with a titanium locking plate 2 years back. The technique is quick, safe, and cost effective. PMID- 25013545 TI - Esthetic Management of Gingival Lesions in Anterior Maxilla: The Role of VIP-CT Flap, a Technical Note. AB - PURPOSE: Anterior maxilla is a high esthetic demand region. Reconstruction of the soft tissue loss after pathologic resection needs special techniques. MATERIALS AND METHODS: This article describes the novel use of vascularized interpositional periosteal connective tissue flap of palate (VIP-CT) for reconstruction after resection of long-lasting pyogenic granuloma in anterior maxilla with underlying bone resorption in interdental region. RESULTS: Good esthetic results both in labial gingiva and interdental region were obtained. CONCLUSION: VIP-CT flap is an ideal option for reconstruction of the pathologic lesions that affect the anterior maxilla and create pathologic space in interdental region. PMID- 25013546 TI - Bilateral paratesticular liposarcoma - a rare case report. AB - Paratesticular liposarcomas are rare tumors and are often reported as isolated cases. Patients usually present with a painless scrotal or inguinal mass, mimicking inguinal hernia. They refer to liposarcomas arising from the spermatic cord, testicular tunics, and epididymis. We report a case of bilateral scrotal swelling which was misdiagnosed as inguinal hernia. Intraoperative diagnosis of testicular tumor was made. High inguinal orchiectomy was done. Histopathological examination revealed it to be liposarcoma of the cord. To our knowledge, there is no reported case of bilateral paratesticular liposarcoma in English literature, hence we report this case. PMID- 25013547 TI - A case of esophagopericardial fistula as a complication of upper gastro intestinal endoscopy. AB - A case of suppurative pericarditis from an esophagopericardial fistula (EPF) following the upper gastrointestinal endoscopy (UGIE). A 38-year-old schizophrenic male patient with gastro-esophageal reflux disease (GORD) and previously dilated esophageal stricture was presented with acute retrosternal chest pain. The patient pulled out the endoscope during UGIE the previous day. A barium swallow (BS) post endoscopy was normal. The patient was initially hemodynamically stable and cardiac evaluation was normal. The patient subsequently developed features of cardiogenic shock. Echocardiography confirmed pericardial effusion and pericardial aspiration yielded pus. Surgical drainage with pericardial tube insertion was done. Pericardial biopsy revealed acute suppurative inflammation with food particles. The patient continued with antibiotics and pericardial drainage for 14 days and repeat BS and chest computerized tomography scan revealed no EPF. The patient was discharged 24 days after the presentation and remained well at follow-up. A rare, serious complication of UGIE which may be easily missed and is associated with a high mortality with delayed treatment. PMID- 25013548 TI - Desmoid fibromatosis of submandibular region. AB - Desmoid fibromatosis is a benign yet locally aggressive tumor with a tendency to recur. It causes considerable morbidity particularly when it arises in a small area in the head and neck region. This tumor is extremely rare in the submandibular region. We report a case of desmoid tumor in the submandibular region in a 32-year-old male who presented with right submandibular swelling postextraction of right lower wisdom tooth. Excision biopsy was carried out initially following inconclusive fine needle aspiration and discussion at multidisciplinary meeting. The tumor recurred 4 months following initial excisional biopsy necessitating a more radical secondary approach involving segmental mandibulectomy. Intraoperatively we also noted that the tumor was originating from the site of previous wisdom tooth extraction, raising the question of surgical trauma as precursor of desmoid tumor. We achieved a negative resection margin and a complete remission for 24 months. PMID- 25013549 TI - Anterior Roux-en-Y Pancreatico-jejunostomy for Pancreatic Trauma. AB - Isolated pancreatic laceration is a rare injury. The typical mechanism by which it occurs is overstretching of the pancreas across the vertebral column during blunt abdominal trauma. The management depends on the location and extent of the injury. Disruption of the pancreatic duct usually requires operative treatment. Operative options for pancreatic laceration at the neck include distal pancreatectomy or suturing of the cephalic remnant and Roux-en-Y pancreatico jejunostomy on the left remnant. We are reporting two cases of isolated pancreatic injury with disruption of the pancreatic duct but preserved posterior surface of the pancreas. These patients were managed by performing anterior Roux en-Y pancreatico-jejunostomy at the lacerated area. Both the patients had successful outcome with removal of drains by 6(th) postoperative day. Anterior Roux-en-Y pancreatico-jejunostomy in this particular scenario is easy, less time consuming, and has the advantage of preserving the pancreas and the spleen. PMID- 25013550 TI - Magnet-retained Prophylactic Appliance for Post-excisional Pressure Therapy and Custom-made Acrylic Therapeutic Pressure Appliance for Auricular Keloid: A Clinical Report. AB - Keloid is cutaneous lesion characterized by fibrous growth produced as a result of aberration in the healing process. Pressure therapy, in combination with other forms of therapy, is used for the management of keloids. Clips or stents are generally used for the therapy and prophylaxis. This report presents use of presurgical compression and prophylactic passive pressure therapy with acrylic appliances for auricular keloids in a patient. Spring and magnets were used in the design of custom-made appliances for compression and retention. PMID- 25013551 TI - Massive spontaneous hemothorax, giant intrathoracic meningocele, and kyphoscoliosis in neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF-1) is a heterogeneous autosomal dominant disease with an incidence ranging from 1 in 2500 to 1 in 3000. Rare intrathoracic vascular disorders resulting in massive spontaneous hemothorax with fatal consequences may occur in these patients, so also are various types of skeletal dysplasia which may result in dramatic presentations, posing management challenges to the attending physicians. We report the case of a 43-year-old woman with NF-1 who developed spontaneous massive hemothorax and was discovered to have a concurrent giant intrathoracic meningocele and thoracic kyphoscoliosis with severe vertebral dysplastic changes. Surgical treatment via a right thoracotomy with primary repair of the meningocele and spinal fusion with fibula graft resulted in good outcome. This case represents an extreme manifestation of this otherwise indolent disease in clinical practice. PMID- 25013552 TI - Construction of a jejunal pouch after total gastrectomy. AB - Total gastrectomy for cancer results in many digestive troubles leading to an impairement of the quality of life. Different types of reconstruction have been proposed to improve the postoperative digestive functions. According to several prospective randomized trials and a recent meta-analysis, the Roux-en-Y jejunal pouch construction appears to be the best technique for reconstruction concerning the postoperative quality of life. However, this safe reconstructive surgery is not still recognized as a gold standard. PMID- 25013553 TI - Treatment of pseudoarthrosis after minimally invasive hallux valgus correction. AB - OBJECTIVE: Treatment of mild and moderate hallux valgus deformities. DISCUSSION: Minimally invasive technique enables surgeons to treat mild and moderate hallux valgus deformities with excellent and good results in the majority of patients. Nonunion of first metatarsal, moreover, has only rarely been reported. SUMMARY: We describe the essential steps of a surgical technique for the treatment of nonunions after miniinvasive subcapital first metatarsal osteotomy reconstructed using a tricortical iliac crest bone graft. PMID- 25013554 TI - A practical tip to prevent intraoperative blockage of suction tubing. PMID- 25013555 TI - Conservative Treatment of Gall Bladder Perforation is Not the Standard. PMID- 25013556 TI - Dorsal slit-sleeve technique for male circumcision. PMID- 25013557 TI - IL-2 Receptor Antagonist (Basiliximab) Is Associated with Rapid Fibrosis Progression in Patients with Recurrent Hepatitis C after Liver Transplantation Using Serial Biopsy Specimens. AB - BACKGROUND: Recurrence of hepatitis C virus (HCV) infection following orthotopic liver transplantation (OLT) is universal. There is paucity of data on the safety and efficacy of interleukin (IL)-2 receptor antagonist (IL-2RA) when added to the standard immunosuppression regimen in OLT recipients with recurrent HCV infection. OBJECTIVES: To evaluate the efficacy of IL-2RA (Basiliximab) in preventing acute cellular rejection (ACR) in patients with recurrent HCV infection after OLT and to assess the impact of IL-2RA in promoting fibrosis progression in post-OLT recurrent HCV infection. METHODS: Using an electronic pathology database, we identified all OLT/HCV patients with at least 2 post-OLT liver biopsies (1998-2006). Standard immunosuppression consisted of steroids and calcineurin inhibitor with and without mycophenolate mofetil. All patients who were transplanted after May 2004 received IL-2RA induction therapy. The Ludwig Batts system was used to stage all biopsies (593 biopsies from 124 patients). The first biopsy that showed post-OLT fibrosis or the last follow-up biopsy was used for time-to-progression analysis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify factors associated with the progression of fibrosis. RESULTS: ACR was significantly (p<0.001) lower in patients who received IL-2RA (20 of 70, 29%) compared to those who did not (33 of 54, 61%). The median (25%ile, 75%ile) follow-up was 12.1 (6.1, 23.9) months during which 61% of patients had progression of fibrosis. Univariate analysis revealed that a higher HCV RNA load at 4 months post-OLT (p=0.002), cytomegalovirus (CMV) infection (p<0.001), use of steroid therapy for ACR (p=0.043), and use of IL-2RA (p<0.001) were associated with higher hazards for the progression of fibrosis. Viral load at 4 months post-OLT was significantly (p=0.025) higher in patients who had IL-2RA therapy (median [25%ile, 75%ile]: 2.9 [1.0, 5.0] *10(6) vs. 1.4 [1.0, 2.3] *10(6)). In multivariate analysis, patients who received IL-2RA therapy were 3.1 (95% CI: 1.8-5.3) times more likely to develop fibrosis than those who did not treated with IL-2RA. Steroid therapy for ACR remained significantly (Hazard Ratio=2.9, p=0.002) associated with the progression of fibrosis. CONCLUSION: IL-2RA (Basiliximab) decreases the rate of ACR. However, it may be associated with more rapid histological progression of the disease in post-OLT recurrent HCV. PMID- 25013558 TI - The concept of death and deceased organ donation. AB - An individual who has sustained either irreversible cessation of circulatory and respiratory functions, or irreversible cessation of all functions of the entire brain, including the brainstem is dead. A person is not dead unless his brain is dead. The time-honored criteria of stoppage of the heartbeat in circulation are indicative of death only when they persist long enough for the brain to die. Brain death does not require every brain cell to be nonviable but the criteria require an irreversible loss of neurologic function of a patient interminably supported by a mechanical respirator. For death to be diagnosed by an irreversible cessation of circulation and respiration an absence of circulation should be observed for at least two but no more than five minutes. Irreversibility is determined by a "permanent" loss of function meaning that the function will not be restored 1) because it will neither return spontaneously, nor 2) will it return as a result of medical intervention because physicians have decided not to attempt resuscitation. PMID- 25013559 TI - Cell-based regenerative therapy as an alternative to liver transplantation for end-stage liver disease: experience from iran. AB - Several types of cells including mature hepatocytes, adult liver progenitor cells and human embryonic stem cells, fetal liver progenitor cells, bone marrow derived hematopoietic or mesenchymal stem cells, and umbilical cord blood cells-both in rodents and humans-have been reported to be capable of self-replication, giving rise to daughter hepatocytes, both in vivo and in vitro. They have been shown to be able to repopulate liver in both animal models of liver injury and in patients with liver disease and to improve liver function. Human embryonic stem cell therapy seems to be a great promise for the treatment of liver cirrhosis, but there is no human clinical application due to ethical concerns or difficulties in harvesting or safely and efficiently expanding sufficient quantities. In contrast, adult bone marrow-derived hematopoietic or mesenchymal stem cells, which can be easily and safely harvested, have been used in clinical trials to treat several chronic diseases including chronic liver disease. Cell therapy offers exciting promise for future treatment of cirrhosis and metabolic liver diseases, but significant technical hurdles remain that will only be overcome through years of intensive research. There is also serious concern about the long term safety of stem cell therapy and the possibility of tumor development. Herein, we present our experience with cell therapy in treatment of chronic liver disease in Iran. PMID- 25013560 TI - Mini-incision living donors nephrectomy using anterior muscle-splitting approach with hybrid technique. AB - BACKGROUND: Significant morbidity is associated with standard open flank living donor nephrectomy. Laparoscopic donor nephrectomy is criticized for a steep learning curve and a tendency to avoid the right kidney. The anterior muscle splitting technique uses principles or advantages of an open extraperitoneal approach with minimal morbidity and the advantageous muscle-splitting (instead of cutting) procedure. OBJECTIVE: To compare mini-incision laparoscopic instrument assisted (MILIA) live donor nephrectomy using a muscle-splitting technique to the standard open-flank donor nephrectomy (ODN) approach for efficacy and safety. METHODS: MILIA living donor nephrectomies were performed in 119 donors and compared to a cohort of open-flank nephrectomy donors (n=38) from the same center. Both donor groups were matched for body mass index as well as other personal characteristics. RESULTS: The mean donor age was 35 (range: 18-60) years. The right kidney was procured in 28% of cases. The majority of donors were female (58%) and Caucasian (60%). No differences were observed between MILIA and ODN donors for the age, gender and ethnicity. However, MILIA donors experienced a longer mean+/-SD operative time (234+/-47 vs. 197+/-33 min, p<0.0001) but a shorter hospital stay (4+/-1 vs. 6+/-3 days for the ODN group, p<0.0001) and less intraoperative blood loss (215+/-180 vs. 331+/-397 mL, p<0.02). No difference was found in the number of units of blood transfused (0.13+/-0.6 vs. 0.34+/-1.0 units, p=0.13). Right-sided kidneys were almost equally harvested in both groups (29% of MILIA donors vs. 26% of ODN donors). Post-operatively, MILIA donors had a significantly lower mean pain scores at one week and one month after surgery (p<0.001). They showed significant better post-operative recovery-earlier stopping of pain medications and restoration of other preoperative activities. Moreover, they were better satisfied with their scar appearance. Scores on the short form-36 quality of life questionnaire were comparable for both groups. CONCLUSION: MILIA is a viable option as an alternative for pure laparoscopic donor nephrectomy. MILIA appears to be as safe as open donor nephrectomy and may provide advantages over ODN, such as smaller incision, shorter hospital stay, and less incisional pain. Patient recovery and satisfaction after MILIA are excellent. This technique avoids the possibility of adhesive intestinal obstruction and also improves handling of major complications (e.g., bleeding) of laparoscopic donor nephrectomy. Utilization of this hybrid technique is particularly feasible on smaller (BMI<24 kg/m(2)) and medium-sized (BMI<28 kg/m(2)) donors. We believe that this technique should be adopted by centers that have limited advanced laparoscopic surgical experience and also it could be used selectively for the right donor nephrectomies, even in centers performing hand assisted donor nephrectomies by including a small patch of inferior vena cava for a better quality of right donor kidney during transplantation. PMID- 25013561 TI - Current challenges of organ donation programs in syria. AB - BACKGROUND: Renal transplantation is the optimal treatment for the majority of patients with end-stage renal disease. OBJECTIVE: To examine the donor characteristics of kidney transplants in Syria and the impact of national Syrian legislation on the evolution of kidney transplantation activities in the private and public sectors. METHODS: Available data on all kidney transplants performed in Syria over the last 2 decades was retrospectively analyzed to assess the characteristics of kidney donors and recipients with a focus upon transplants since 2003. RESULTS: The kidney transplant rate has increased from 7 kidney transplants per million populations in 2002 to more than 17 in 2007. In the meantime, a substantial decline in the rate of kidney transplantation performed on Syrian nationals abroad was observed from 65% of all kidney transplantations in 1998 to less than 2% in 2007. Despite the prohibition to buy a kidney in Syria, vendors had found ways to sell their kidneys through disreputable brokers. Potential related donors were not inclined to donate kidneys to their relatives as long as kidneys could be bought from a non-related donor. By 2008, the percent of related donors in private sector represented only 8% of all donors, as compared to 50% in public hospitals. Consequently, in January 2008, the government of Syria issued a pronouncement restricting kidney transplantation to the public sector with a new national regulatory oversight of transplantation practices. Since this 2008 Administrative Order was promulgated, the kidney transplant rate in public hospitals has substantially increased by 55% with the establishment of new public transplant centers in the 3 largest cities in Syria. CONCLUSION: The recommendations of the Istanbul Declaration and the Revised Guiding Principles of the World Health Organization have yet to be implemented in Syria but the expansion of kidney transplants in the public sector is an important initial step for initiating a deceased organ donation program as an essential component of a comprehensive approach to the problem of the organ shortage. PMID- 25013562 TI - Donor kidney recovery methods and the incidence of lymphatic complications in kidney transplant recipients. AB - BACKGROUND: Lymphatic leak and lymphocele are well-known complications after kidney transplantation. OBJECTIVE: To determine the incidence of lymphatic complications in recipients of living donor kidneys. METHODS: Among 642 kidney transplants performed between 1999 and 2007, the incidence of lymphatic complications was retrospectively analyzed in recipients of living donor kidneys procured by laparoscopic nephrectomy (LP, n=218) or by open nephrectomy (OP, n=127) and deceased donor kidneys (DD, n=297). A Jackson-Pratt drain was placed in the retroperitoneal space in all recipients and was maintained until the output became less than 30 mL/day. RESULTS: Although the incidence of symptomatic lymphocele, which required therapeutic intervention, was comparable in all groups, the duration of mean+/-SD drain placement was significantly longer in the LP group-8.6+/-2.7 days compared to 5.6+/-1.2 days in the OP group and 5.4+/-0.7 days in the DD group (p<0.001). Higher output of lymphatic drainage in recipients of LP kidneys could lead to a higher incidence of lymphocele if wound drainage is not provided. CONCLUSION: More meticulous back table preparation may be required in LP kidneys to decrease lymphatic complications after kidney transplantation. These observations also support the suggestion that the major source of persistent lymphatic drainage following renal transplantation is severed lymphatics of the allograft rather than those of the recipient's iliac space. PMID- 25013564 TI - Emphysematous pyelonephritis in a transplant kidney. AB - Emphysematous pyelonephritis (EPN) is a severe necrotizing infection of the kidney and its surrounding tissues. It is characterized by the production of gas within the kidney and perinephric structures. EPN often affects diabetic women but can also occur in nondiabetic patients who have ureteral obstruction and in immunocompromised patients. Herein, we report EPN in a 23-year-old woman who had a renal transplantation. PMID- 25013565 TI - Editorial. PMID- 25013563 TI - Liver transplantation in the presence of old portal vein thrombosis. AB - BACKGROUND: Portal vein thrombosis (PVT) has been mentioned as a potential obstacle to liver transplantation (LTx). OBJECTIVE: To review the impact of PVT on orthotopic liver transplant (OLT) outcome. METHOD: Between January 2006 and April 2009, 440 OLT were performed in Shiraz Transplant Unit of whom, 35 (7.9%) cases had old PVT with recanalization. Data were retrospectively collected regarding the demographics, indication for OLT, Child-Turgot-Pugh classification, pre-transplant diagnosis of PVT, perioperative course and managements, relapse of PVT, early post-operative mortality and morbidity. All patients received liver from deceased donors, underwent thrombendvenectomy with end-to-end anastomosis without interposition graft and evaluated daily for 5 days and thereafter, biweekly by duplex sonography during the follow-up period for 2 months. They were treated by therapeutic doses of heparin followed by warfarin to maintain an INR of 2-2.5. RESULTS: The causes of end-stage liver disease were hepatitis B in 11, cryptogenic cirrhosis in 11, primary sclerosing cholangitis in 5 and other causes in 8 recipients. Extension of thrombosis was through confluence of superior mesenteric and splenic vein in 32 and to superior mesenteric vein in 3 patients. The mean+/-SD operation time was 7.2+/-1.5 hrs. The mean+/-SD transfusion requirement was 5.4+/-2.8 units of packed cells. The mean+/-SD duration of hospital stay in these patients was 17.7+/-10.9 days. Eight patients died; 1 developed early in-hospital PVT, 1 had hepatic vein thrombosis, and 1 died of in hospital ischemic cerebrovascular accident, despite a full anticoagulant therapy. The mean+/-SD follow-up period for those 28 patients discharged from hospital was 16.6+/-7.9 months; none of them developed relapse of PVT. The overall mortality and morbidity was 28% and 32%, respectively. There was no relapse of PVT in the other patients. CONCLUSION: The presence of PVT at the time of OLT is not a contraindication for the operation but those with PVT have a more difficult surgery, develop more postoperative complications, and experience a higher in hospital mortality. PMID- 25013566 TI - Living organ donation: an ethical evolution or evolution of ethics? AB - The disparity between available and needed organs is rapidly increasing, and the number of patients dying while still on the waiting list is growing exponentially. As a partial solution to this disparity, living unrelated transplantation is being performed more frequently, and some have proposed providing financial incentives to donors. The aim of this discussion is to illustrate that with an ever-increasing number of living unrelated transplantations, society and the transplant community should adopt a more active role in developing specific strategies to scrutinize the process. The current paper will also examine the viewpoint that medical ethics is not separable from the prevailing needs of society and involves a constant balancing of often opposing goods. Issues surrounding living unrelated donor transplantation illustrate ethics as a dynamically evolving field, which is often influenced by necessity and which evolves with progression of science and society. As part of this evolution, it is the collective responsibility of society and the transplant community to devise safeguards to guarantee adherence to basic principles of ethics and to avoid "situational ethics." PMID- 25013567 TI - Living kidney donation: the outcomes for donors. AB - During the past decade, the number of transplantation from living kidney donors has substantially increased worldwide. The rate of increase varies from one country to another. The risk of unilateral nephrectomy to the donor includes perioperative mortality and morbidity plus the long-term risk of living with a single kidney. The rate of perioperative mortality and morbidity is about 0.03% and 10%, respectively. More attention is required to prevent serious complications of laparoscopic donor nephrectomy. A grading system in recording perioperative complications is necessary for making it available to each potential donor. The number of studies on long-term outcome of living donors is very limited. The overall evidence suggests that the risk of end-stage kidney disease is not increased in donors, however, mild renal failure, hypertension and proteinuria are not uncommon in living donors. There is also concern that the incidence of cardiovascular disease may be higher in kidney donors. Establishing living donor registry and follow-up is extremely important. Only through these registries the long-term risk of kidney donation will become more apparent. Because of severe shortage of transplantable kidneys, some transplant centers are now using donors with comorbidities and few centers are involved in transplant tourism with inadequate donor screening and follow-up. Prevention of these unacceptable practices in living kidney donors was emphasized in Amsterdam Forum in 2004 and Istanbul Summit in 2008. PMID- 25013568 TI - Abdominal wall closure of renal transplant recipients: an undermined challenge. AB - Tension-free muscle closure is essential in kidney transplantation, both in adult and pediatric patients. Tight muscle closure may lead to renal transplant compartment syndrome either due to compression of the renal parenchyma or due to kinking of the renal vessels. It may also cause kinking of the transplant kidney ureter, wound dehiscence and incisional hernia. Many techniques have been proposed in an attempt to achieve tension-free closure. There is a wrong belief among some surgeons that using prosthetic mesh may increase the incidence of infection complications in these immunosuppressed patients. Also, there is fear that one is not able to monitor the renal graft by ultrasound and perform biopsy in the presence of a mesh. Other alternative techniques to mesh closure include subcutaneous placement and intraperitonealization of the kidney transplant. These techniques however, are valuable when mesh closure is unfavorable or contraindicated as in case of the presence of a potential source of infection like a stoma. Abdominal wall fasciotomy can be adjunctive to various techniques of muscle closure. PMID- 25013569 TI - Comparision of barry and barry-taguchi ureterovesical reimplantation techniques in kidney transplantations: a randomized clinical trial. AB - BACKGROUND: Renal transplantation is the treatment of choice for chronic renal failure. Using a suitable ureterovesical anastomosis technique can prevent most of risks for kidney graft. Extravesical ureteroneocystostomy is becoming popular in renal transplantation because of the low complication rate and technical ease. The decreased complication rate is due to limited bladder dissection and the need for a shorter ureteral segment from the donor. OBJECTIVE: In this study we assessed the effectiveness and complications of a new technique, Barry-Taguchi technique and compared it with Barry technique. METHODS: We recorded all urological complications developed in the recipient's kidney between September 2004 and March 2007 (mean follow-up 12 months) after performing extravesical Barry-Taguchi (new technique) and Barry ureteroneocystostomy. The urological complications studied included complicated hematuria, urinary fistula, and ureteral stenosis. RESULTS: A total 100 patients who underwent Barry-Taguchi technique and 98 patients who underwent Barry technique were studied. The incidence of urological complications in Barry-Taguchi and Barry re-implantation technique was 4% (n=4) and 5% (n=5%), respectively. These complications included 1 urinary leakage and 3 ureteral obstructions for Barry-Taguchi technique, and 4 obstructions and 1 leakage from Barry group. In both trial groups, no complicated hematuria has occurred. In addition, the recorded time taken for ureteral anastomosis ranged from 4 to 16 (mean 8.3) min for Barry-Taguchi technique and 5 to 20 (mean 9.9) min in Barry technique. CONCLUSION: The Barry-Taguchi extravesical ureteroneocystostomy technique is a rapid and rather simple technique. Without increasing the incidence of urological complication rate, it is a reliable method for performing ureteroneocystostomy. PMID- 25013570 TI - The effect of simvastatin on lowering panel reactive antibody titer in sensitized dialysis patients: a randomized placebo controlled clinical trial. AB - BACKGROUND: Patients with panel reactive antibodies (PRA) have many difficulties to find a crossmatch-negative kidney for transplantation and are at a higher risk of post-transplantation rejection. OBJECTIVE: To evaluate the effect of simvastatin on PRA and post-transplant outcome of these sensitized patients. METHODS: 82 patients with end-stage renal disease (ESRD) with a PRA >=25% were evaluated. In a one-year follow-up, the patients were treated with simvastatin. These patients were compared with 82 matched controls receiving placebo tablets. At the end of the second and 12(th) month, PRA was rechecked in all patients. Those patients who underwent transplantation continued to take simvastatin six months after transplantation. Serum creatinine levels were checked at monthly intervals post-operation. RESULTS: The mean+/-SD PRA level at the end of the second month was 36.63%+/-31.14% and 45.34%+/-24.36% in cases and controls, respectively (P=0.012). Seven patients in the case group and 10 in the control group were lost to follow-up. The remaining patients continued to take simvastatin for 12 month. The mean+/-SD PRA level at the end of the 12(th) month was 24.02%+/-31.04% in cases and 43.15%+/-26.56% in controls (P=0.001). 25 patients underwent renal transplantation and continued to receive simvastatin 6 months after transplantation. These patients were matched with 25 controls treating with placebo. The mean+/-SD creatinine level 6 months after kidney transplantation was 2.05+/-1.14 mg/dL and 3.15+/-1.09 mg/dL in cases and controls consecutively (P=0.02). CONCLUSION: Simvastatin can be safely used to lower PRA and improve post-transplantation outcomes. PMID- 25013571 TI - The impact of hepatitis B infection on outcome of kidney transplantation: a long term study. AB - BACKGROUND: With the success of kidney transplantation, liver disease has emerged as an important cause of morbidity and mortality in kidney recipients. OBJECTIVE: To determine the impact of hepatitis B virus (HBV) infection on patients and graft survival in both short- and long-terms. METHODS: 99 renal transplant patients infected with HBV on follow-up in two major transplant centers were included in a retrospective study. These patients were grafted between 1986 and 2005 and divided into two groups: (1) those only positive for hepatitis B surface antigen (HBsAg) and (2) those who were also positive for hepatitis C virus antibodies (HCV Ab). RESULTS: There were 88 patients with HBsAg(+) and 11 with both HBsAg(+) and HCV Ab(+). The mean+/-SD age of patients was 38.8+/-13.2 years, and the median follow-up after transplantation was 19 months. Although not significant, the allograft survival rate in the first group (HBV(+)) was better compared to that in the second group (HBV(+) and HCV(+)); 1, 5 and 10 years graft survival rates were 91, 77 and 62 in the first group and 70, 56 and 28 in the second group, respectively (P=0.07). The overall mortality was 5% (4 of 88) in the first and 27% (3 of 11) in the second group (P=0.02). CONCLUSION: Renal allograft recipients with HBV and HCV infections has a poor survival rate compared to patients with only HBV infection. However, there is no significant difference in terms of renal graft survival between the two groups. PMID- 25013572 TI - Death in the eyes of the beholder. AB - The US Uniform Determination of Death Act provides two alternatives for determining death-the circulatory criteria and the neurological criteria-yet history and the public's current understanding of death in the US may mean that only brain death criteria can be relied upon without raising public suspicion that the medical profession is sacrificing the well-being of one group of patients (i.e., those dying after traumatic injury) to save another group (i.e., those in need of organs). The problem is exacerbated by existing debate on the appropriate waiting time after which death is inevitable and when the brain should be actually considered dead through prolonged absence of autoresuscitation. Given the difficulty of definitive determination of the time when brain function has ceased, two solutions are proposed: abandon the Dead Donor Rule or redefine death. Implementing the former would mean convincing the public to accept organ harvesting before the dying patient is completely brain dead through the writing of advance directives to permit organ harvest when death is inevitable though not confirmed. For the latter, reeducation would be necessary to persuade the public to accept the circulatory criteria for death as an independent determinant for death or the medical community would need to reconsider if the cessation of higher brain function is enough to be the basis for determining death. In conclusion, organ retrieval policies, no matter how medically sound, should seek to avoid the possibility of a public backlash that could result in fewer organs available for transplant. PMID- 25013573 TI - Congenital hepatic fibrosis and need for liver transplantation. AB - Herein, we describe two patients who underwent liver transplantation with the clinical diagnosis of hepatic failure and cryptogenic cirrhosis; histopathology of the explanted hepatectomy specimen revealed congenital hepatic fibrosis. To the best of our knowledge, coexistence of hepatic failure and cirrhosis in congenital hepatic fibrosis, have not yet been reported in the English literature. PMID- 25013574 TI - Acute Appendicitis following Laparoscopic Live Donor Nephrectomy. AB - Acute abdominal pain following laparoscopic live donor nephrectomy (LLDN) might be a diagnostic dilemma, and prompt diagnosis and management is of paramount importance. Herein, we describe a case of acute appendicitis in a 62-year-old kidney donor who presented with acute abdominal pain 16 days following LLDN with features inconsistent with a diagnosis of acute appendicitis. An ultrasound scan suggested strangulated Spigelian hernia unrelated to the operative wound. Exploration of the wound and mini-laparotomy showed no evidence of wound dehiscence or a hernia, but revealed an inflamed appendix wrapped up with omentum. Appendectomy led to complete recovery of the patient. It is imperative to maintain a high index of suspicion for acute appendicitis in this situation to avoid septic complications that might adversely affect the residual renal function and cause negative impact on kidney donation. To the best of our knowledge, this is the first reported case of acute appendicitis following LLDN. PMID- 25013575 TI - Characteristics of oral abnormalities in liver transplant candidates. AB - BACKGROUND: Several oral mucosal abnormalities have been reported to occur more frequently in patients with liver disease. It has, however, not been determined if these conditions are related to the disease or are manifestations of extraneous factors not associated with the liver pathology. OBJECTIVE: To identify and quantify oral abnormalities in candidates for liver transplantation, and to determine whether these conditions were correlated with the type of liver disease or were the result of other patient variables. METHODS: Oral examinations were performed on 300 candidates for liver transplantation to assess their oral health and to record the presence and types of oral mucosal pathologies. Abnormalities most frequently encountered were analyzed for significant associations with classification of liver disease, hyposalivation, diuretic therapy, edentulism, or smoking. RESULTS: Among these subjects, 175 (58%) had one or more abnormalities. The anomalies most frequently found were fissured tongue (37%), atrophy of the papillae of the tongue (18%), angular cheilitis (4%) and manifestations of clinical candidiasis (2%). Clinical hyposalivation was found in 28.7% of all patients and 70% of those who were on diuretic therapy. Fissured tongue and atrophy of the tongue papillae were significantly associated with hyposalivation (p<0.001); hyposalivation was correlated to diuretic therapy (p=0.028). Pathologies suggestive of candidiasis were significantly associated with hyposalivation and total edentulism. CONCLUSION: Several oral mucosal abnormalities that have previously been linked with liver diseases were found to be primarily associated with diuretic-induced hyposalivation, smoking, and total edentulism. PMID- 25013576 TI - Post-reperfusion Syndrome and Outcome Variables after Orthotopic Liver Transplantation. AB - BACKGROUND: Post-reperfusion syndrome (PRS) is an important complication during liver transplantation. OBJECTIVE: We studied the occurrence and severity of PRS in patients who underwent orthotopic liver transplantation (OLT) to investigate how PRS was correlated to clinical variables and outcomes. METHODS: We retrospectively recorded intra- and peri-operative data for 184 adult patients who received cadaveric OLT during a 3-year period from 2005 to 2008. Patients were divided into two groups according to the severity of PRS: Group 1 (mild or no PRS) comprised 152 patients; and group 2 (significant PRS) consisted of 32 patients. RESULTS: There were no significant differences in demographic and pre operative data between groups. Group 2 had more total blood loss than group 1 (p=0.036), especially after reperfusion (p=0.023). Group 2 required more packed red cell transfusions (p=0.005), more fresh frozen plasma (p=0.003) and more platelets (p=0.043) than group 1. Fibrinolysis was more frequent in group 2 (p=0.004). Hospital stay in group 2 was significantly longer than in group 1 (p=0.034), but the frequencies of other outcomes including infection, retransplantation, dialysis, rejection and extended donor criteria did not differ significantly between groups. CONCLUSIONS: Bleeding, blood transfusion and fibrinolysis occurred more often in the group of severe PRS after reperfusion. Although postoperative complications like rejection, infection and the dialysis rate were not significantly different in the two groups, hospital stay was more prolonged in the group with severe PRS. PMID- 25013577 TI - Subcutaneous nephrovesical bypass in kidney transplanted patients. AB - BACKGROUND: Renal transplant ureteral stricture or obstruction is a rare but devastating complication after renal transplantation. OBJECTIVE: To determine the efficacy and complications of subcutaneous prosthetic ureters as a salvage procedure in transplanted kidneys with recurrent ureteral obstruction. METHODS: 5 subcutaneous prosthetic ureters were inserted in 5 kidney recipients who had recurrent ureteral stenosis and failed endoscopic and open reconstructive surgeries. The prosthetic ureter consisted of an internal silicone tube covered by a coiled PTFE tube. The proximal end of the tube was introduced in the transplanted kidney percutaneously, the tube was passed through a subcutaneous tunnel, and the distal end was inserted in the bladder through a small suprapubic incision. RESULTS: The mean follow-up of patients was 11.3 months. One of the patients re-operated two days after the procedure because of urinary leakage from the distal end of the prosthetic ureter. No infection or tube encrustation was encountered. CONCLUSION: Subcutaneous prosthetic ureter is a safe alternative for permanent percutaneous nephrostomy in transplanted kidneys with obstructed ureter and failed endoscopic and open procedures. PMID- 25013578 TI - Live donor partial hepatectomy for liver transplantation: is there a learning curve? AB - BACKGROUND: Donor safety is the first priority in living donor liver transplantation (LDLT). OBJECTIVE: To determine the characteristics and outcome of live liver donors who underwent donor hepatectomy from January, 1997 to May, 2007 at Massachusetts General Hospital. METHODS: 30 patients underwent LDLT between January, 1997 and May, 2007 at our institution. RESULTS: The type of graft was the right lobe (segments 5-8) in 14, left lobe (segments 2-4) in 4, and left lateral sector (segments 2 and 3) in 12 patients. The mean donor age was 36 (range: 26-57) years. The mean follow-up was 48 (range: 18-120) months. No deaths occurred. Overall, 8 (26.6%) patients experienced a total of 14 post-operative complications. Donor complications based on graft type were as follows: left lateral sector (16.7%), left lobe (25%), and right lobe (35.7%). The experience was divided into two periods 1997-2001 (n=15) and 2002-2007 (n=15). Overall complications during 2 periods were 40% and 13.3%, respectively (p<0.001). The incidence of grade III complication also significantly decreased; 66.7% vs 33.3% (p<0.01). CONCLUSION: Partial hepatectomy in living donors has a learning curve which appears to be approximately 15 cases. This learning curve is not restricted to the surgeons performing the procedure but involves all aspects of patient care. PMID- 25013579 TI - Should post kidney transplantation hyperlipidemia considered a risk factor for graft function? AB - BACKGROUND: Hyperlipidemia is a common problem after kidney transplantation. OBJECTIVE: To uncover the real impact of post kidney transplantation hyperlipidemia on graft function and survival, and to determine whether it is just a biochemical phenomenon after using immunosuppressant or a part of disease pathology. METHODS: 330 kidney transplants were managed in Sina Hospital Kidney Transplantation Unit affiliated to Tehran University of Medical Sciences, Tehran, Iran from September 1994 till February 2010. The demographic characteristics of the patients, causes of chronic kidney diseases, history of pretransplantation dialysis, pretransplantation comorbidities (e.g., hypertension, diabetes mellitus [DM], hyperlipidemia and coronary artery disease), rejection episodes, status of infection with cytomegalous virus [CMV], post-transplantation DM, hyperlipidemia, ischemic heart disease [IHD], and graft and patient survival were recorded. A serum creatinine level >2 mg/dL was considered as "graft deterioration," and return to dialysis as "graft loss." According to the presence or absence of post kidney transplantation hypercholesterolemia (>200 mg/dL) or hypertriglyceridemia (>200 mg/dL), the patients were classified into "hyperlipidemic" or "non hyperlipidemic." The presence of clinical or paraclinical coronary artery disease was also determined in both groups. RESULTS: The incidence of hyperlipidemia elevated from 8% to 50% before and after transplantation. 2.7% developed clinical IHD. 13% of hyperlipidemics and 22% of non-hyperlipidemics developed graft deterioration. Among hyperlipidemics with deteriorated grafts 40% had premorbid diseases, 68% had CMV infection and 82% had hypertension. Only 22% had previous acute rejection and 27% received deceased kidney transplant. CONCLUSIONS: post kidney transplantation hyperlipidemia is just an associated phenomenon secondary to the use of immunosuppressant medications, which have no obvious impact on renal graft function and can be easily controlled by instituting dietary modifications and use of modern antilipid medications. Post kidney transplantation CMV infection and hypertension are considered as the main threatening risk for renal graft-even more dangerous than acute or chronic rejections. PMID- 25013580 TI - Effect of Isoproterenol on LDL Susceptibility to Oxidation and Serum Total Antioxidant Capacity in Cyclosporine-Treated Rats. AB - BACKGROUND: Cyclosporine therapy is associated with a variety of adverse effects. Recent studies have suggested increased oxidative stress as a cause of these side effects. OBJECTIVE: Since, melatonin is one of the most powerful known antioxidants, and considering that isoproterenol is one of the drugs stimulating endogenous melatonin production, we tried to determine the effect of isoproterenol on LDL susceptibility to oxidation and serum total antioxidant capacity in cyclosporine-treated rats. METHODS: 32 male Wistar rats were divided into four groups: group A were controls that received placebo; group B received intraperitoneal isoproterenol (20 mg/kg/d) alone; group C received intravenous cyclosporine (15 mg/kg/d) alone; and group D received both drugs simultaneously at the same doses and durations-cyclosporine one week after administration of isoproterenol. Blood samples were drawn four times from rats in each group: before injections, during the treatment, end of the treatment, and one week after the last injections. RESULTS: There was a significant (p<0.05) increase in LDL susceptibility to oxidation, and a decrease in serum total antioxidant capacity (p<0.05) in group C rats. But, there were no significant changes in group B and D rats in terms of LDL susceptibility to oxidation and total antioxidant capacity. CONCLUSION: Isoproterenol may be capable of delaying adverse effects of cyclosporine by preventing the increase in LDL susceptibility to oxidation, and decrease in serum total antioxidant capacity. PMID- 25013582 TI - Histopathological Study of Chronic Hepatitis B: A Comparative Study of Ishak and METAVIR Scoring Systems. AB - BACKGROUND: Ishak and METAVIR scoring systems are among the most commonly used histopathological systems to evaluate chronic hepatitis. OBJECTIVE: To assess the level of agreement between these two scoring systems in patients with chronic hepatitis B. METHODS: Liver biopsy samples taken from 92 patients with chronic hepatitis B were considered as the training set; 57 more biopsy specimens were used as the validation set. In the training set, grade of necroinflammation and stage of fibrosis for each liver biopsy specimen were determined by two expert liver pathologists using both Ishak and METAVIR systems. Inter-observer variability between the two pathologists was evaluated. Biopsy specimens of the validation set were seen and scored by a third expert pathologist. In the training set, criteria were developed to categorize Ishak grading and staging systems separately to best fit with the METAVIR scoring system. The criteria found in the training set, was then tested in the validation set. The level of agreement between the two scoring systems was assessed by weighted kappa statistics. RESULTS: For the training set, agreement between the two pathologists was excellent. Using our proposed criteria in the training set, there was excellent level of agreement in grading (kappa = 0.89) and staging (kappa = 0.99) between Ishak and METAVIR systems. In the validation set, the criteria led to substantial correlation (kappa = 0.61) in grading, and excellent correlation (kappa = 0.94) in staging between the two systems. CONCLUSION: Using our proposed criteria, excellent or at least substantial concordance between Ishak and METAVIR scoring systems can be achieved for the degree of both necro-inflammatory changes and fibrosis. PMID- 25013581 TI - The applications of bone marrow-derived stem cells to induce tolerance and chimerism in organ transplantation. AB - Progress in understanding the cellular and molecular biology of the immune system, in the second half of the 20(th) century brings the transplantation of replacement organs and tissues in clinical reality to cure disease. Immunosuppressive agents that are part of nearly every transplantation procedure, are toxic to some extent and their chronic use predisposes the patient to the development of infection and cancer. Alternatives to immunosuppression include modulation of host immune system to reduce the immune response and the induction of a state of immunologic tolerance. Induction of hematopoietic mixed chimerism through donor bone marrow transplantation offers a promising approach for tolerance induction as a prelude to organ transplantation. Furthermore, mesenchymal stromal cells have important effects on the host immune system and possess immune modulation properties that make them attractive for potential use in organ transplantation as immunosuppressant. Both modalities might potentially provide novel therapeutic options for treatment/prevention of rejection and/or repair of organ allografts through their multifaceted properties. In this review, evidences for the tolerogenic properties and mechanisms of hematopoietic mixed chimerism as well as mesenchymal stromal cells effects on allograft surveillance are summarized. PMID- 25013583 TI - Comparison of Enterocystoplasty and Ureterocystoplasty before Kidney Transplantation. AB - BACKGROUND: Augmentation cystoplasty before or after renal transplantation is an option for patients with end-stage renal disease who are candidates for renal transplantation and have low capacity and poorly compliant bladders. OBJECTIVE: To compare two surgical methods of bladder augmentation-enterocystoplasty (EC) and ureterocystoplasty (UC)-before kidney transplantation, and their outcome with that in kidney recipients who had normal bladder function. METHODS: During a 20 year period (1988-2008), 1406 renal transplantation were performed in our center by our team. In 16 patients having a mean age of 18.8 years, EC (group A) and in 8 with mean age of 11.5 years, UC (group B) were performed before renal transplantation. These two groups were compared with a control group of 30 recipients with normal bladder (group C) with mean age of 15.6 years, for kidney function, graft and patient survival, and the frequency of urinary tract infection (UTI). RESULTS: There was normal graft function in 11 of group A, 7 of group B, and 24 of group C patients, during a mean follow-up of 73.1 months. The mean+/-SD serum creatinine in follow-up was 1.72+/-0.31, 1.37+/-0.13 and 1.33+/ 0.59 mg/dL in groups A, B and C, respectively. No statistically significant differences were observed among the 3 studied groups in terms of 1-, 5- and 10 year graft and patient survivals. Number of episodes of febrile UTI requiring hospitalization was 23, 6 and 2 in groups A, B and C, respectively. UTI and urosepsis were significantly more frequent in group A than groups B (p=0.025) and C (p=0.001); no significant difference was observed in the frequency between groups B and C (p=0.310). CONCLUSION: Both EC and UC are equally recommended before renal transplantation for reconstruction of the lower urinary tract; use of each method should be individualized depending on specific conditions of recipient. PMID- 25013584 TI - Concomitant cryptococcosis and burkholderia infection in an asymptomatic lung transplant patient with cystic fibrosis. AB - Concomitant pulmonary infections with Cryptococcus neoformans and Burkholderia cepacia in lung transplant recipients are very rare and create unique diagnostic and therapeutic dilemmas. Herein, we present a double lung transplant patient with cystic fibrosis who was found to have coinfection with these two rare organisms, though he was completely asymptomatic. PMID- 25013585 TI - The first modified multivisceral transplantation in the middle East: a major advance in transplantation surgery in shiraz transplant center. PMID- 25013586 TI - Pakistan abolishes kidney market and ushers in a new era of ethical transplantation. PMID- 25013587 TI - Organ Transplantation in Iran before and after Istanbul Declaration, 2008. PMID- 25013588 TI - World kidney day 2011: protect your kidneys, save your heart. PMID- 25013589 TI - Psychiatric aspects of organ transplantation. AB - Surgical transplantation of human organs from deceased as well as living donors to sick and dying patients began after the Second World War. Over the past 50 years the transplantation of human organs, tissues and cells has become a worldwide practice which has extended, and greatly enhanced the quality of hundreds of thousands of lives. The field of transplantation medicine provides an important chance for liaison between psychiatric professionals and other transplant physicians and surgeons. The discrepancy between the ever-increasing demand for organs but the decreasing supply makes it important to evaluate and prioritize individuals who are in dire need of the organ. However, this also gives rise to certain ethical questions. The following paper discusses various psychiatric aspects of organ transplantation in general. PMID- 25013590 TI - Evaluation of cytomegalovirus infection after six months of liver transplantation in children in shiraz, southern iran. AB - BACKGROUND: Liver transplantation (LT) is a life-saving treatment for end-stage liver diseases (ESLD). Cytomegalovirus (CMV) infection is one of the important causes of morbidity after LT. OBJECTIVE: To evaluate the incidence of late-onset (after 6 months of LT) CMV infection in pediatric recipients. METHODS: A retrospective analysis was conducted to evaluate 50 pediatric patients who underwent LT for 8 years at the LT Unit of Nemazee Hospital affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. We retrospectively investigated episodes of CMV infection after 6 months of LT proven by CMV antigenemia test. RESULTS: Three recipients (6%) developed late-onset CMV infection. These patients finally responded to ganciclovir. CONCLUSION: CMV infection is one of the most common post-LT viral infections that usually occurs in the first six months of LT. Our study shows that the incidence of late-onset CMV infection is relatively low, but it still remains a significant problem. Therefore, monitoring and management is crucial for improving the survival of children. PMID- 25013591 TI - Effect of cyclosporine-a on paraoxonase activity in wistar rats. AB - BACKGROUND: Many adverse effects have been reported on using cyclosporine (CSA) in organ transplantation. OBJECTIVE: To investigate the effects of CSA on paraoxonase (PON) activity and lipid peroxidation metabolites in early and late stage of peroxidation and also total antioxidant (TA). METHODS: Twenty 220-250 g adult male Wistar rats were included in the study. The animals were stored for one week in the animal room before the initial injection to habituate with temperature, humidity, and circadian rhythm of day (12 h) and night (12 h). The temperature was kept at 23 degrees C. Animals had access to food and water ad libitum. RESULTS: A significant (p=0.002) increase in the serum levels of conjugated diones was observed in the case compared to the control group. At the end of the study, malondialdehyde (MDA) levels in CSA group was significantly (p=0.01) higher than the control group. Serum PON1 activity was significantly (p=0.004) lower in the case than the control group. CONCLUSION: CSA administration could impair oxidant-antioxidant pathways and increase oxidative stress. Antioxidant therapy could be beneficial in patients treated with CSA. PMID- 25013593 TI - A feverish liver transplanted child. PMID- 25013592 TI - Liver transplantation and aortic valve replacement. AB - Surgical procedures involving heart and liver are rare and have been limited to either combined heart and liver transplantation or coronary artery bypass graft surgery (CABG) or aortic valve surgery and orthotopic liver transplantation (OLT). Aortic valve replacement (AVR) and pulmonary valve vegetectomy for bacterial endocarditis after OLT have also been reported. There are only five cases with aortic stenosis and cirrhosis reported to have combined AVR and liver transplantation. In the presence of cirrhosis, AVR has a significant risk for mortality because of bleeding from coagulopathy, renal failure, infection, and poor post-operative wound healing. Herein, we report on a case and management analysis of combined sequential AVR, and OLT in a 40-year-old cirrhotic man with Child and MELD score of C and 29, respectively. Echocardiography detected severe aortic insufficiency (AI) with enlarged left ventricle. Due to severe AI, the cardiologist recommended AVR prior to transplantation. The patient underwent metallic AVR. 4 months later, he received OLT. Both operations were successful and uneventful. Prioritizing AVR before OLT was successful in this patient. However, each patient must be evaluated individually and multiple factors should be assessed in pre-operation evaluation. PMID- 25013594 TI - Development of solid organ transplantation in syria. PMID- 25013595 TI - A Systematic Review and Meta-Analysis of Rituximab in Antibody-mediated Renal Allograft Rejection. AB - BACKGROUND: The standard treatment of antibody-mediated rejection (AMR) consists of antilymphocyte antibody, intravenous immunoglobulin, and plasmapheresis. This treatment is associated with a high rate of resistance and refractory AMR. Recent interest has focused on use of rituximab (RTX), a chimeric anti-CD20 monoclonal antibody. OBJECTIVE: We conducted a systematic review and meta-analysis of studies of RTX in AMR of the renal allograft. METHODS: Combining two comprehensive search themes (AMR and RTX), we searched electronic databases from 1969 through 2010, supplemented by a manual review of abstracts from nephrology and transplant meetings, and reference lists of review articles. All studies evaluating explicit response of patients with AMR to RTX were included. The outcome was pooled odds ratio (OR) of response to RTX. RESULTS: A total of 114 studies were identified, 94 of which were excluded on initial screening. Analysis of the 10 studies (249 patients) showed an OR of 3.16 (95% CI: 1.75-5.70) for response to RTX. Reported adverse effects included BK virus nephropathy, cytomegalovirus (CMV) viremia, pneumonia, herpes zoster, and septic shock. CONCLUSION: This study suggests that RTX is a reasonable therapeutic option in the treatment of AMR. Further randomized studies are necessary to establish its efficacy and safety. PMID- 25013596 TI - Recurrence of Disease Following Liver Transplantation: Nonalcoholic Steatohepatitis vs Hepatitis C Virus Infection. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an increasing indication for orthotopic liver transplantation (OLT) in the United States and other countries. However, the incidence of disease recurrence and natural course following OLT remains incompletely understood. OBJECTIVE: To estimate the incidence of recurrent disease, outcome and identify risk factors associated with disease recurrence in patients undergoing OLT for NASH as compared to those undergoing OLT for HCV cirrhosis. METHODS: We identified all patients with end-stage liver disease secondary to NASH (n=53) or HCV (n=95) cirrhosis who underwent OLT at our institution between 1998 and 2005. Protocol liver biopsies were performed (Day 7, Month 4 and yearly) after OLT, and as clinically indicated. Kaplan-Meier survival analysis was performed to assess the fibrosis progression and survival. Cox regression analysis was performed to identify factors associated with disease recurrence. RESULTS: Five-year survival was 90.5% in NASH vs 88.4% in HCV group (p=0.97). The median (25%ile, 75%ile) follow-up to last available biopsy was 12.7 (5.9, 26.3) months, during which 17 (32%) of NASH patients developed persistent fatty infiltration in their graft, 8 (15%) of whom had accompanying histologic features of recurrent NASH. There was no difference in the prevalence of post-OLT steatosis between HCV and NASH patients after adjusting for time of histologic follow-up (p=0.33). Patients with HCV infection were more likely to develop hepatic fibrosis post-OLT than those with NASH (62.1% vs 18.9%, p<0.001). Multivariate analysis identified post-OLT diabetes (HR=2.0, 95% CI: 1.2-3.2, p=0.007) as an independent risk factor for fibrosis development. Additionally, NASH subjects who received steroids had a significantly higher risk of developing hepatic fibrosis post-OLT than NASH patients who did not receive steroids and all HCV subjects (p<0.001). CONCLUSION: Recurrence of steatosis post-OLT is common. Corticosteroid use may contribute to fibrosis progression in this population. PMID- 25013597 TI - The role of ureteral stents for all ureteroneocystostomies in kidney transplants. AB - BACKGROUND: Despite significant advancements in renal transplantation, certain basic surgical practices such as the routine use of ureteral stents (US) remain controversial. A recent met-analysis of ureteral stenting concluded that the routine use of US resulted in improved outcomes. In contrast, the indiscriminate use of US can lead to adverse complications. OBJECTIVE: To better define this question, we reviewed our single center experience in which US were placed selectively. METHODS: 301 patients were eligible to be enrolled. 55 living donor and 246 deceased-donor charts were analyzed for donor and recipient clinical characteristics, immunosuppressive therapy and outcomes. RESULTS: 28 US were placed for either small bladder capacity (n=7), unhealthy appearing bladder tissue (n=8) or for an uncertain vascular supply to the ureter (n=13). Patients with US did not develop urinary leaks, 8 (28%) developed complications including obstruction, encrustation, and urinary tract infections. 12 (4.3%) non-stented patients developed a clinically significant urinary leak. Risk factors for urinary leaks included dual and en-bloc pediatric donor kidney transplants, extended criteria donors and the use of single U stitch technique for ureteral anastomoses. CONCLUSION: Our results demonstrate that the majority of patients can be successfully transplanted without the routine use of US. Selective use of US should be reserved for high-risk situations. PMID- 25013598 TI - Portal-endocrine and gastric-exocrine drainage technique in pancreatic transplantation. AB - BACKGROUND: Pancreas transplant (PTx) is an established treatment for patients with diabetes mellitus. Diagnosis of rejection has continued to be problematic. In 2007, a new technique of PTx with portal-endocrine and gastric exocrine (P-G) drainage was first performed at our institution. This technique facilitates access to pancreas allograft. OBJECTIVE: To report our experience with the first 30 patients who underwent PTx using P-G technique. METHODS: The first 30 patients who underwent PTx between 2007 and 2009 were studied. In these patients, arterial and venous anastomosis was similar to standard portal-enteric (P-E) technique, though contrary to other techniques of enteric drainage, the end of allograft jejunum was anastomosed to the anterior aspect of the stomach. RESULTS: Donor and recipient demographic data, number of antigen matches and immunosuppressant were collected. All patients achieved euglycemia. 3 patients underwent pancreatectomy: 2 due to vessel thrombosis and 1 due to chronic rejection. 3 patients died-2 with functioning pancreatic and renal allografts. 7 patients with CMV and 4 patients with rejection were diagnosed with endoscopy of allograft duodenum and treated. 1 year patient and graft survival was 94% and 85%, respectively. CONCLUSION: This novel technique of PTx has proven to be safe with good patient and allograft survival. Access to donor duodenum and pancreas allograft via endoscopy is unique to this technique and provides the added advantage of life-long easy access to allograft. PMID- 25013599 TI - Endothelial Nitric Oxide Synthase Gene T-786C Polymorphism in Renal Transplant Recipients. AB - BACKGROUND: Nitric oxide (NO) is a major mediator in vascular biology, regulating regional blood flow. NO and the enzymes required for its production contribute to ischemia-reperfusion injury. The T-786C functional polymorphism in the promoter region substantially reduces promoter activity of the endothelial nitric oxide synthase (eNOS) gene and compromises endothelial NO synthesis. OBJECTIVE: To examine the association between T-786C (rs 2070744) single nucleotide polymorphism (SNP) in eNOS gene and the development of acute rejection in renal transplant patients. METHODS: 60 renal transplant recipients (30 with episodes of acute rejection (ARs) and 30 without rejection (non-ARs)), between June 2008 and March 2010, were included in this study. The polymorphism was determined by PCR restriction fragment-length polymorphism analysis. RESULTS: The distribution of the genotypes were TT/TC/CC 60%, 33.4%, 6.6%, and 43%, 46.7%, 13.3% in ARs and non-ARs, respectively (p=0.28). The frequency of T-allele was 76.7% and 66.3%; and for C-allele was 66.6% and 33.3% in ARs and non-ARs, respectively (p=0.09). There were no significant associations between these polymorphisms and acute and chronic kidney allograft rejection. CONCLUSION: We could not detect any significant association between polymorphism in T-786C of eNOS gene and the development of acute rejection. PMID- 25013600 TI - Representation of organ transplantation in cinema and television. AB - Media whether print or visual such as films and television remains an important source of information and education for the general population even if it is not meant to be such. Films in particular have significant impact on the individual psyche. Films are meant for entertainment but it is inevitable that they will reflect the attitudes of society and in turn will influence the way societies and their members perceive conditions. In this paper we describe the use of films in making audiences aware of issues related to organ-donation. We review how films have dealt with the issue of organ transplantation over the years and suggest that a positive portrayal of organ transplantation in films and other media channels will allay negative attitudes in people and may act as catalysts of behavior change. This can motivate more people to donate organs posthumously. The portrayals of the act itself, its sequelae for the recipient and the donor's families will be discussed. PMID- 25013601 TI - Half-Saline versus Combined Normal Saline and 1/3-2/3 Intravenous Fluid Therapy in Kidney Transplantation. AB - BACKGROUND: Sufficient intravascular volume should be established for optimal graft function after renal transplantation. However, there is no recommendation for the type of fluid therapy post-operatively. We compared half-saline vs. normal saline and 1/3-2/3 intravenous fluid replacement after renal transplantation. METHODS: We enrolled all patients who underwent kidney transplantation between June 2008 and March 2010 in Golestan Hospital, Ahwaz, southwestern Iran. Patients were randomly divided into two groups using a blinded allocation technique. Group A patients (Case) received half saline, and group B patients (Control) received normal saline and 1/3-2/3 intravenous fluid. According to our protocol, we replaced as much as 100% of hourly urine output in the first day, followed by 90% and 70% of every 2-hour urine output in the 2nd and 3rd days, respectively. Blood pressure and pulse rate were recorded hourly. Serum sodium, potassium, creatinine and pH were assessed twice a day. RESULTS: There were 34 and 36 eligible patients in the case and control groups, respectively. The mean+/-SD 6-hour urine output in the first 5 days after surgery was 2586+/-725 mL in the control group and 2764+/-758 mL in the case group (p=0.31). The mean+/-SD serum creatinine level at the end of the 5th post operative day was 1.3+/-0.5 and 1.4+/-0.7 mg/dL in the case and control groups, respectively (p=0.56). Serum creatinine level did not reduce to 1.5 mg/dL or lower in 6 of 36 control subjects and in 4 of 34 cases at the end of the 5th day (p=0.558). The mean+/-SD time to creatinine level <1.5 mg/dL was 1.3+/-1 days in the control group and 1.7+/-0.8 days in the case group (p=0.635). Hyperkalemia occurred in 3 of 36 patients in the control group and in 2 of 34 patients in the case group (p=0.318). The incidence of hyponatremia in the control group was 11% (4 of 36 patients) vs no patients in the case group (p=0.115). CONCLUSION: Either half-saline or normal saline and 1/3-2/3 intravenous solution can be safely used as fluid replacement therapy after kidney transplantation. PMID- 25013602 TI - Evaluation of Candida infection after six months of transplantation in pediatric liver recipients in iran. AB - BACKGROUND: Liver transplantation (LT) is the standard treatment of end-stage liver diseases (ESLD). Invasive fungal infection is one of the important causes of morbidity and mortality after transplantation. OBJECTIVE: To determine the incidence of late-onset (after 6 months of LT) Candida infection in recipients. METHODS: A retrospective study was conducted to evaluate 50 pediatric patients after LT for 8 years at the LT Unit of Nemazee Hospital affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. We followed the patients until 6 months post-LT for episodes of Candida infection proven by culture. RESULTS: One recipient (2%) developed late-onset esophageal candidiasis with improvement after intravenous amphotricin therapy but finally expired with a diagnosis of post transplant lymphoproliferative disorder (PTLD). CONCLUSIONS: The incidence of late-onset Candida infection is not significant in pediatric liver recipient, but it still remains a significant problem. Control of Candida colonization would reduce the risk of invasive fungal infections and possibly more fatal complications. PMID- 25013603 TI - The molecular and antigenic tissue impact of viral infections on liver transplant patients with neonatal hepatitis. AB - BACKGROUND: Pathogenesis of neonatal hepatitis relates to various underlying causes including viral infections. Both hepatotropic and non-hepatotropic viruses may induce liver failures in infants before birth, during delivery, or shortly after birth. OBJECTIVES: The tissue impact of HCMV, HSV, HBV, HCV, and rotavirus and adenovirus infections was evaluated in studied infants with neonatal hepatitis. METHODS: The history of viral infections was analyzed in paraffin embedded biopsy and autopsy tissues of 22 infants with neonatal hepatitis between years 1996 and 2007, retrospectively. The tissue molecular presentation of HBV, HCV, HCMV, HSV, adenovirus, and rotavirus was evaluated by different qualitative simple and nested PCR and RT-PCR protocols. Immunohistochemistry (IHC) method was used for studying the antigenic prevalence of HSV-1, 2; HBV, HCMV and adenovirus infections. Also the laboratory liver indices of all patients with neonatal hepatitis were analyzed. RESULTS: The HBV and HSV genomes were detected in 3 (14%) of 22 infants. The rotavirus and HCV-RNA and also the HCMV-DNA were detected separately in 1 (4%) of 26 paraffin-embedded autopsy and biopsy tissues. The HBV and HSV-1 specific antigens were separately diagnosed in 1 (4%) of 26 neonatal samples by IHC protocols. Also the HSV-2 antigen was seen in 5 (23%) of 22 liver autopsy and biopsy specimens. Co-infections with HCMV, HSV, HBV, HCV, and rotavirus were detected in these infants with hepatitis. CONCLUSION: Diagnosis of single and mixed molecular and antigenic traces of HCMV, HSV, HBV, HCV and rotavirus underlines the etiologic role of these viruses in clinical pathogenesis of neonatal hepatitis. PMID- 25013604 TI - Quality of life and social life situation in islet transplanted patients: time for a change in outcome measures? AB - BACKGROUND: One of the overall goals in health care is to prolong life, increase patients' wellbeing and quality of life. Many of patients with severe insulin dependent diabetes mellitus experience fear of hypoglycemia (FoH), which forces them to change their lives both physically and socially to avoid episodes of hypoglycemia. OBJECTIVE: To investigate the quality of life and the social life situation, with special focus on the consequences of FoH in islet transplanted patients. METHODS: 11 patients (4 women and 7 men) were included; they have undergone islet transplantation at Uppsala University Hospital during the period 2001-2009. Short Form 36 (SF-36) and the Swedish version Hypoglycemia Fear Survey (Swe-HFS) were used to investigate quality of life, in relation to FoH. In addition, telephone interviews were conducted to investigate the patients social life situation in relation to FoH, after islet transplantation and were analyzed using a content analysis method. RESULTS: The mean value for quality of life was lower than that in the normal population. 3 out of 10 patients experienced FoH; one patient declined to answer the questionnaire. 3 predominant themes were revealed; one theme associated with pre-transplant, was "struggle for control of social life situation" and two themes associated with post-transplant, were "regain power and control of social life situation" and "at peace with the balance between the present and the future." CONCLUSION: The patients experienced improved control over social life situation while quality of life in relation to FoH may have improved following islet transplantation. PMID- 25013605 TI - Liver-kidney transplantation in primary hyperoxaluria type-1: case report and literature review. AB - Primary hyperoxaluria type-1 (PH1) is a rare inherited autosomal recessive disorder in which a deficiency of the hepatic enzyme alanine-glyoxylate aminotransferase leads to endogenous oxalate overproduction, renal failure, systemic oxalate deposition and death. As hemodialysis provides insufficient oxalate clearance, patients ultimately require both liver and kidney transplantation for correction of the metabolic abnormality and oxalate excretion. Herein, we describe a young adult male with end-stage renal disease and systemic oxalosis causing progressive disabling multi-organ dysfunction while awaiting transplantation. We review the literature regarding liver-kidney transplantation and suggest that for patients with PH1, a standardized assessment of organ dysfunction and functional impairment may improve identification of patients requiring urgent transplantation thereby reducing the morbidity and mortality that can occur with delayed transplantation. PMID- 25013606 TI - Incidental cyst in an explanted liver. PMID- 25013607 TI - Commemoration of 1000(th) liver transplantation in Shiraz Center. PMID- 25013608 TI - Outcomes of Late Corticosteroid Withdrawal after Renal Transplantation in Patients Exposed to Tacrolimus and/or Mycophenolate Mofetil: Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Corticosteroids are increasingly used in renal transplant patients to minimize organ rejection after transplantation. In attempts to reduce corticosteroids adverse effects, transplant professionals are customary attempted to taper off, and permanently stop corticosteroids after few months of administration with other immunosuppressants. OBJECTIVE: To evaluate clinical benefits and risks of late corticosteroid withdrawal in renal transplant patients treated with tacrolimus (TAC) or mycophenolate mofetil (MMF), or both. METHODS: A meta-analysis was performed of published randomized controlled trials that reported outcomes in kidney transplant patients who were randomized to corticosteroids maintenance or late withdrawal under concomitant immunosuppression by TAC, MMF or both. Outcomes included acute graft rejection; graft failure rate; all-cause mortality; incidence of post-transplant diabetes; change in serum creatinine and total cholesterol; and change in pediatric standardized height z-score. PubMed and Google Scholar were used in literature search between 1999 and April 1, 2010. Data were combined using unweighted random effects model. RESULTS: Nine studies randomized 1907 patients met the inclusion criteria: TAC (n=1); MMF (n=6); both (n=2). Compared to maintenance therapy, late corticosteroid withdrawal was associated with 34% increase in the risk of acute graft rejection (95% CI for OR: 0.47-3.82); 35% and 5% reductions in the risk of graft failure and patient's all-cause mortality (95% CI for OR: 0.26-1.60; 0.23 3.93, respectively); and 4% increase in post-transplant diabetes risk (95% CI for OR: 0.45-2.41). Late corticosteroid withdrawal was associated with substantial reduction in total cholesterol levels (mean difference: 18.1 mg/dL; 95% CI: 7.1 29.0 mg/dL), but did not reduce serum creatinine levels (0.00 mg/dL; 95% CI: 0.17 to 0.17). Stopping corticosteroids was associated with better pediatric growth outcomes. CONCLUSION: Late corticosteroid withdrawal under TAC and/or MMF-lead immunosuppression after kidney transplantation could provide benefits in terms of total cholesterol, patient and graft survival, and pediatric growth. This strategy, however did not reduce the risk of acute graft rejection, post transplant diabetes mellitus, and deterioration in serum creatinine levels. PMID- 25013609 TI - Induction with Rabbit Antithymocyte Globulin following Orthotopic Liver Transplantation for Hepatitis C. AB - BACKGROUND: Hepatitis C (HCV) is the most common indication for liver transplantation in the US. OBJECTIVE: Since steroids are the major stimulus of viral replication, we postulated that steroid-free immunosuppression might be a safer approach. METHODS: From January 1995 to October 2002, we used steroid plus calcineurin inhibitor (CNI) immunosuppression after liver transplantation for HCV (steroid group, n=81). From October 2002 to June 2007, rabbit antithymocyte globulin (RATG) induction, followed by CNI and azathioprine (RATG group, n=73) was utilized. RESULTS: There were no differences in 1- and 3-year patient/allograft survival rates. The incidence of acute rejection rate (19% vs. 28%), of biopsy-proven HCV recurrence (70% vs. 75%), and chronic rejection (6% vs. 9%) were comparable. The mean time to develop recurrent HCV was significantly longer in the RATG group (16.2 vs. 9.2 months, p=0.008). The incidence of severe portal fibrosis appears to be lower in RATG group compared to the steroid group; 14% vs. 4% (p=0.07). CONCLUSIONS: RATG induction is safe and effective after liver transplantation for HCV, but has no impact on the incidence of HCV recurrence and patient/allograft survival. However, a significant delay in time to HCV recurrence and a trend toward less rejection and portal fibrosis was observed. PMID- 25013610 TI - Cadaver transplantation in Recent Era: Is Cadaveric Graft Survival Similar to Living Kidney Transplantation? AB - BACKGROUND: Renal transplantation is the procedure of choice for most of patients with end-stage renal disease. The graft, however can be procured from either cadaver or living donors. OBJECTIVE: To compare graft and patient survival among patients who underwent kidney transplantation from cadaver donor vs. living donor. METHODS: From April 2002 to February 2010, we performed 138 cadaver kidney transplantations. We reviewed and compared one-year graft and patient survival with 138 living kidney transplantations. RESULTS: One-year graft and patient survivals in cadaveric groups were 93% and 96%, respectively, and in living groups were 92% and 97%, respectively. CONCLUSION: There was no significant difference in one-year graft and patient survival between living and cadaver donor kidney transplantation. PMID- 25013611 TI - Association of the Co-stimulatory Molecules Polymorphisms with CMV Infection in Liver Transplant Recipients. AB - BACKGROUND: Co-stimulatory molecules play a critical role in regulating T-cell function during CMV infection after liver transplantation. OBJECTIVE: To investigate the relationship between the polymorphisms of the co-stimulatory genes and the susceptibility to CMV infection after liver transplantation. METHODS: Single nucleotide polymorphisms (SNPs) in PD-1 gene (PD1.1 A/G, PD1.3 A/G, PD1.9 C/T) ICOS (-693 A/G, 1720 C/T), CTLA-4 gene (318 C/T, 1722 T/C, 1661 A/G, 49 A/G) and CD28 (+17 C/T) were analyzed by PCR-RFLP in 70 liver transplant patients. CMV infection was determined in these patients by antigenemia test. RESULTS: CTLA-4 49G showed significant association with CMV infection (p=0.03, OR=3.82, 95% CI: 0-3.5; p=0.01, OR=004, 95% CI: 0-1.3). G and T alleles in CTLA-4 gene (318 C/T and 1661 A/G) (p=0.03, OR=0, 95% CI: 0-3.5; p=0.01, OR=0.04, 95% CI: 0-1.3) were significantly higher in CMV-infected rejector group. CONCLUSION: CTLA-4 have significant role in CMV pathogenesis and rejection among CMV-positive liver transplant patients. PMID- 25013612 TI - Anxiety and Depression: A Comparison between Living and Cadaveric Renal Transplant Recipients. AB - BACKGROUND: Anxiety and depression are the most common psychological disorders in kidney transplant recipients that may affect disease process and graft survival. OBJECTIVE: Based on the types of kidney donation in our country, living vs. cadaveric donation, we conducted this study to compare psychological problems in renal recipients. METHODS: This cross-sectional study was conducted on kidney transplant recipients who were categorized according to their donors to "living" and "cadaveric" groups. Patients with stable condition were followed monthly in outpatient clinics. The psychological status of each patient was assessed by clinical interview and Spielberg State Trait Anxiety Inventory and the Beck Depression Inventory (BDI). The calculated Cronbach alpha for the reliability of the total scale was 0.95. RESULTS: We recruited 120 recipients (60 patients in each group of living and cadaveric donor transplantation) for the study. There was no significant difference in demographic data between two studied groups (p>0.05). The mean+/-SD anxiety score was significantly lower among living transplant recipients compared to cadaveric transplant recipients (80.2+/-15.2 vs. 86.9+/-18.8 p=0.03). We also found significant relation between depression score and kind of graft donation (11.6+/-5.7 in living vs. 16.4+/-9.4 in cadaveric groups; p<0.005). CONCLUSION: Psychological problems such as depression and anxiety are significantly higher in cadaveric than living renal recipients. Periodic psychological evaluations should be recommended for kidney transplant recipients, especially for the cadaveric group. PMID- 25013613 TI - Attitude and Willingness towards Tissue Donation in Iranian High School Students: Bone Marrow and Blood. AB - BACKGROUND: Tissue donation has been promising in prolonging the lives of people with life-threatening diseases. OBJECTIVE: To assess the attitude and willingness of high school students towards bone marrow (BM) and blood (as tissue) donation for maintaining a safe and adequate pool. METHODS: This cross-sectional study was conducted among the high school girls, aged 15-18 years, who studied in natural sciences, mathematics and humanities. All participants filled a questionnaire consisting of age, religion, education levels and study branch, attitude and willingness towards BM and blood donation according to a Likert scale. RESULTS: Out of 416 students, with the mean+/-SD age of 16.3+/-1.2 years, 31% studied in grade I, 27% in grade II (25% natural sciences, 27% mathematics, and 48% humanities), 26% in grade III (30% natural sciences, 34% mathematics, and 36% humanities), and 16% in pre-university level (college) (32% natural sciences, 42% mathematics, and 6% humanities). The students had highly positive attitudes toward BM and blood donation (mean+/-SD score of 4.2+/-0.54). The willingness for BM and blood donation was declared respectively, in 87% and 71% of respondents. Moreover, 16% of students wanted to donate only to their relatives and 84% to all persons in need of therapy. There was no significant correlation between the donation willingness and educational levels and study branch; however, these variables significantly correlated with attitude towards tissue donation (p=0.02, p=0.01, respectively). CONCLUSION: Despite positive attitude towards BM and blood donation, willingness for BM donation is lesser than blood which may be attributed to insufficient information about this type of tissue donation. An organized educational program for high school students in all aspects of tissue donation seems necessary. PMID- 25013614 TI - Physicians' Belief about Organ Donation. AB - BACKGROUND: Several studies have suggested that knowledge, attitudes and determinants concerning organ donation are influenced by many factors including gender, educational level, occupation, sociodemographic status, income level, culture and religion. OBJECTIVE: To highlight the awareness of cardiopulmonary and brain death (CD and BD) among the physicians and their belief about the organ donation. METHODS: In a cross-sectional study, 15% of 1700 physicians working under the auspices of Ministry of Health in Makkah region, were selected randomly from two hospitals of Makkah city, i.e., Alnoor Specialist Hospital and King Abdalaziz Hospital. A self-administered questionnaire with dichotomous answers was distributed to them. RESULTS: Out of 185 respondents, 174 (94.1%) identified the right definition of BD and CD and 155 (83.3%) agreed organ donation. The difference among physicians to differentiate CD from BD was not significant (p=0.2). CONCLUSION: Physicians had enough knowledge to differentiate CD from BD; most of them are highly positive regarding the concept of organ donation. PMID- 25013615 TI - Future perspectives for hand transplant in iran. AB - Hand transplant program is a communion of physicians and researchers during the current decade. 72 hands and digits were transplanted in 53 patients over the past 13 years. Unlike a solid organ transplant, hand transplantation involves various tissues, so it is called "composite tissue allotransplantation." This article discusses the plans for performing the first hand transplant in Iran. PMID- 25013616 TI - The first symposium on organ donation in collaboration with Spain. PMID- 25013617 TI - The global role of kidney transplantation for the world kidney day steering committee 2012. AB - World Kidney Day on March 8th, 2012, provides a chance to reflect on the success of kidney transplantation as a therapy for end-stage kidney disease that surpasses dialysis treatments, both for the quality and quantity of life, that it provides and for its cost effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end-stage kidney disease include the economic limitations which, in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation and vaccination. Even in high-income countries the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit. PMID- 25013618 TI - A Systematic Review and Meta-analysis of Prophylactic versus Pre-emptive Strategies for Preventing Cytomegalovirus Infection in Renal Transplant Recipients. AB - BACKGROUND: In kidney transplant (KT) recipients, CMV infection poses significant morbidity and mortality. Both prophylactic and pre-emptive approaches for preventing CMV infection have been utilized. OBJECTIVE: To compare the effectiveness of routine prophylaxis vs. pre-emptive treatment for preventing CMV disease after KT. METHODS: We conducted a systematic review and meta-analysis comparing the effectiveness of routine prophylaxis vs. pre-emptive treatment for preventing CMV disease after KT. Combining 4 comprehensive search terms (CMV, renal transplant, prophylaxis, pre-emptive); we searched PubMed, EMBASE, ISI Web of Science, and Cochrane Central Register from inception through January 2011. We also evaluated studies referenced in review articles and abstracts from meetings of major nephrology and transplant societies (2009-2011). Two authors independently extracted data and assessed methodological criteria. The primary outcome was the pooled estimate of the odds ratio (OR) of developing CMV infection. Secondary outcomes included OR of acute rejection, OR of graft loss and OR of death within first year of KT. Comprehensive Meta-analysis V2 software was used for data analysis. RESULTS: Analysis of 9 randomized controlled trials (991 patients; ganciclovir=5, valganciclovir=4) with CMV infection as an outcome revealed the OR of CMV infection to be 0.34 (95% CI: 0.25-0.46, p=0.008) for the prophylactic vs. the pre-emptive groups. The OR of acute rejection (7 studies; 1358 patients) was 0.52 (95% CI: 0.41-0.67, p=0.001) with prophylactic approach compared to pre-emptive treatment; graft loss (7 studies; OR 0.52 [95% CI: 0.34 1.12, p=0.32] and mortality (6 studies; OR 0.84 [95% CI: 0.62-1.23, p=0.23]) were similar between the two groups. CONCLUSIONS: Prophylactic approach is superior to pre-emptive approach in preventing CMV infection within the first year of kidney transplant. The risk of developing acute rejection is also lower with prophylactic approach in the first year of transplant but there is no significant difference in graft loss or mortality with either approach. PMID- 25013619 TI - Invasive fungal infections after renal transplantation. AB - BACKGROUND: Invasive fungal infection (IFI) is a leading cause of infection related mortality among kidney allograft recipients. OBJECTIVE: To estimate the incidence and etiology of systemic fungal infection in renal allograft recipients in Sydney transplant facility. METHODS: 471 kidney recipients, transplanted between 2000 and 2010 at the Westmead Hospital renal transplantation center, Sydney, Australia, were retrospectively surveyed. RESULTS: IFI developed in 10 (2.1%) of 471 patients. With a mean+/-SD new kidney transplants per year of 42.9+/-13, the mean+/-SD incidence of IFI was 0.9+/-0.6 for each year of transplantation. 4 patients had received kidneys from living donors and 7 from cadavers with a mean+/-SD age of 50.5+/-14 years. The mean time to IFI was 33 months after transplantation with majority within the first 2 years. Cryptococcus neoformans was responsible for 50% of episodes (n=5) followed by Aspergillus fumigatus (n=3), and Pseudallescheria boydii (n=3); there was a single case of mucurmycosis. Lungs (n=5) followed by meninges (n=4) and skin (n=3) were the most commonly involved sites. CONCLUSION: IFI remains a major concern in renal transplantation. A high index of suspicion is required for early diagnosis and treatment to reduce the mortality. In this regard, appropriate diagnostic tests are necessary, particularly for C. neoformans. PMID- 25013620 TI - Safety and adequacy of percutaneous biopsies in pediatric orthotopic kidney transplantation. AB - BACKGROUND: The gold standard for investigating the cause of renal graft dysfunction is renal biopsy. However, as this procedure is invasive and has inherent risks, its safety must be established. OBJECTIVE: To determine the safety of percutaneous renal biopsy in pediatric orthotopic renal transplantation. METHODS: Percutaneous renal biopsies performed on pediatric orthotopic renal transplants in a single center between 1987 and 2010 were studied. Biopsy specimen adequacy and post-procedure complications were reviewed by prospectively collected data. RESULTS: A total of 54 ultrasound "real-time" guided biopsies in 25 patients were performed. Minimum specimen adequacy was achieved in 98% of biopsy specimens. No major complications were identified; 6% of patients developed minor complications-e.g., grade 3 macroscopic hematuria that did not require intervention. CONCLUSION: Percutaneous renal biopsies using "real-time" ultrasound guidance on pediatric orthotopic kidney transplants is safe. PMID- 25013621 TI - Human Bone Marrow-derived Mesenchymal Stem Cell: A Source for Cell-Based Therapy. AB - BACKGROUND: The ability of mesenchymal stem cells (MSCs) to differentiate into many cell types, and modulate immune responses, makes them an attractive therapeutic tool for cell transplantation and tissue engineering. OBJECTIVE: This project was designed for isolation, culture, and characterization of human marrow derived MSCs based on the immunophenotypic markers and the differentiation potential. METHODS: Bone marrow of healthy donors was aspirated from the iliac crest. Mononuclear cells were layered over the Ficoll-Paque density-gradient and plated in tissue cultures dish. The adherent cells expanded rapidly and maintained with periodic passages until a relatively homogeneous population was established. The identification of adherent cells and the immune-surface markers was performed by flow cytometric analysis at the third passage. The in vitro differentiation of MSCs into osteoblast and adipocytes was also achieved. RESULTS: The MSCs were CD11b (CR3), CD45, CD34, CD31 (PCAM-1), CD40, CD80 (B7-1), and HLA-class II negative because antigen expression was less than 5%, while they showed a high expression of CD90, and CD73. The differentiation of osteoblasts, is determined by deposition of a mineralized extracellular matrix in the culture plates that can be detected with Alizarin Red. Adipocytes were easily identified by their morphology and staining with Oil Red. CONCLUSION: MSCs can be isolated and expanded from most healthy donors, providing for a source of cell-based therapy. PMID- 25013623 TI - Inclusion of IJOTM in Scopus and EMBASE. PMID- 25013622 TI - Serum vascular endothelial growth factor level in patients with hepatocellular carcinoma undergoing liver transplantation: experience of a single Western center. AB - BACKGROUND: The strongest predictor of tumor relapse after liver transplantation for hepatocellular carcinoma (HCC) is vascular invasion, appreciated only on explant analysis. High serum level of vascular endothelial growth factor (VEGF) is associated with worse outcomes after resection or locoregional therapies but its role in liver transplantation remains undefined. OBJECTIVE: We report the first western prospective study exploring serum VEGF in HCC liver transplant patients, correlating pre-operative serum VEGF with poor prognostic histologic features during explant analysis. METHODS: Between May 2008, and June 2010, 75 HCC patients underwent liver transplantation at our institution. Serum VEGF was measured every 3 months until liver transplantation and correlated with histopathologic findings on explant. RESULTS: There was no significant correlation between pre-transplant serum VEGF levels and tumor burden (median 31.0 pg/mL vs. 42.5 pg/mL, p=0.33, for tumors within and beyond the Milan criteria, respectively). Pre-transplant VEGF levels were higher in poorly differentiated tumors compared to well to moderately differentiated tumors, but not statistically significant (median 49.0 pg/mL vs. 31.0 pg/mL, p=0.26). Pre transplant VEGF did not correlate with vascular invasion (median 37.0 pg/mL vs. 31.0 pg/mL, p=0.35, in the presence and absence of vascular invasion, respectively). CONCLUSION: Pre-operative serum VEGF fails to predict unfavorable histologic HCC features in patients undergoing liver transplantation. Role of serum VEGF in liver transplant HCC patients remains unclear. PMID- 25013624 TI - Current status of pancreas and islet cell transplantation. AB - Pancreas transplantation has emerged as an effective treatment for patients with diabetes mellitus, especially those with established end-stage renal disease. Surgical and immunosuppressive advances have significantly improved allograft survival. The procedure reduces mortality compared with diabetic kidney transplant recipients and wait listed patients. Improvements in diabetic nephropathy and retinopathy have also been demonstrated. Pancreas transplantation can improve cardiovascular risk profiles, improve cardiac function and decrease cardiovascular events. Lastly, improvements in diabetic neuropathy and quality of life can result from pancreas transplantation. Pancreas transplantation remains the most effective method to establish durable euglycemia for patients with diabetes mellitus. PMID- 25013626 TI - Cytomegalovirus Infection following Kidney Transplantation: a Multicenter Study of 3065 Cases. AB - BACKGROUND: Cytomegalovirus (CMV) infection is a common complication following kidney transplantation. OBJECTIVE: To assess the incidence and risk factors of CMV infection among renal transplant recipients. METHODS: In a retrospective multicenter study, 3065 renal transplant recipients from 17 transplant centers of Iran were studied between April 2008 and January 2011. Kidney transplant patients were routinely monitored by sequential blood samples drawn for use in the CMV pp65 antigenemia assay, and for hematological and biochemistry tests. RESULTS: 63% of studied patients were males; the mean+/-SD age of participants was 38+/-15 years. The majority of cases (81%) received a kidney from a living unrelated donor (LURD), 9% from living related donor (LRD), and 10% from deceased donors. 671 patients experienced CMV viremia. The incidence of CMV infection was 21.9% (95% CI: 20.4%-23.4%). The rate was higher in the first 6 months after transplantation (p<0.001); in recipients with higher level of cyclosporine (p<0.001); in those with lower hemoglobin concentration (p=0.02); patients with elevated ALT (p<0.001); those with increased fasting blood sugar (p=0.005); recipients with dyslipidemia (p<0.05); deceased kidney recipients (p=0.006); and patients with kidney graft impairment (p=0.01). In multivariate regression analysis, time since kidney transplantation (p<0.001) and renal allograft failure (p<0.001) were the only risk factors associated with CMV infection. CONCLUSIONS: CMV infection was a common complication in the first 6 months of kidney transplantation, particularly among patients with kidney graft impairment. PMID- 25013625 TI - Pediatric renal transplantation. AB - Although the number of children with end-stage renal disease (ESRD) in need for renal transplantation is small compared with adults, the problem associated with renal transplant in children are numerous, varied, and often peculiar. Pre emptive transplantation has recently been growing in popularity as it avoids many of the associated long-term complications of ESRD and dialysis. Changes in immunosuppression to more potent agents over the years will have affected transplant outcome; there is also evidence that tacrolimus is more effective than cyclosporine. This review will discuss the short- and long-term complications such as acute and chronic rejection, hypertension, infections, and malignancies as well as factors related to long-term graft function. Chronic allograft nephropathy is the leading cause of renal allograft loss in pediatric renal transplant recipients. It is likely that it reflects a combination of both immune and nonimmune injury occurring cumulatively over time so that the ultimate solution will rely on several approaches. Transplant and patient survival have shown a steady increase over the years. The major causes of death after transplantation are cardiovascular disease, infection and malignancy. Transplantation in special circumstances such as children with abnormal urinary tracts and children with diseases that have the potential to recur after transplantation will also be discussed in this review. Non-compliance with therapeutic regimen is a difficult problem to deal with and affects patients and families at all ages, but particularly so at adolescence. Growth may be severely impaired in children with ESRD which may result in major consequences on quality of life and self-esteem; a better height attainment at transplantation is recognized as one of the most important factors in final height achievement. Although pediatric kidney transplantation is active in some parts of many developing countries, it is still inactive in many others and mostly relying on living donors. The lacking deceased programs in most of these countries is one of the main issues to be addressed to adequately respond to organ shortage. In conclusion, transplantation is currently the best option for children with ESRD. Although improvement in immunosuppression demonstrated excellent results and has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem. PMID- 25013627 TI - Relationship between Post-kidney Transplantation Antithymocyte Globulin Therapy and Wound Healing Complications. AB - BACKGROUND: Wound healing disorders are probably the most common post transplantation surgical complications. It is thought that wound healing disturbance occurs due to antiproliferative effects of immunosuppressive drugs. On the other hand, success of transplantation is dependent on immunosuppressive therapies. Antihuman thymocyte globulin (ATG) has been widely used as induction therapy but the impact of this treatment on wound healing is not fully understood. OBJECTIVE: To investigate wound healing complications after ATG therapy in renal transplant recipients. METHODS: The medical records of 333 kidney transplant recipients were assessed for wound healing disorders. Among these patients, 92 received ATG and 5 doses of 1.5 mg/kg ATG along with the standard protocol of drugs. RESULTS: The mean age of patients was 38.9 years. Of 333 recipients, 92 (23.7%) received ATG; 21 (6.3%) developed wound healing complications. There was a significant relationship between ATG therapy and wound complications (p=0.034). Also, women were more likely to develop wound healing disorders than men (p=0.002). No statistical difference was observed between age and wound healing complication (p=0.28). There was no significant difference between the mean duration of hospitalization between ATG and Non-ATG group (p=0.9). CONCLUSION: ATG increases the risk of overall wound complications. It is needed to pay more attention to the patients treated with this immunosuppressant to avoid the risk of re-interventions, lessen the duration of hospitalization and decrease the impairment of graft function. PMID- 25013628 TI - Liver Transplantation for Hepatocellular Carcinoma among African Americans in the United States. AB - BACKGROUND: There is increased prevalence of hepatocellular carcinoma (HCC) among African Americans (AA). Multicenter studies have shown advanced presentation, underutilization of treatment and decreased survival following liver transplantation (LT) among AA. However outcomes from single centers are not well reported. OBJECTIVE: To determine the outcome of AA undergoing LT for HCC at Cleveland Clinic, Cleveland, Ohio, between May 2007 and December 2009. METHODS: 245 consecutive patients undergoing evaluation and treatment for HCC within the mentioned time frame were studied, retrospectively. RESULTS: 80% of patients were male, 75.5% were Caucasian, 16.7% were AA and 7.8% were other ethnic groups. Compared to other ethnicities, AA subjects with HCC were more commonly female and were more likely to have hepatitis C virus (HCV) (83% vs. 51%, p<0.001). There were higher occurrence of HCV genotype 1 among AA compared to others among patients with this information (100% vs. 65%, p<0.001). In contrast to previous reports, there was no significant difference between the groups in terms of clinical presentation or management. 27% of AA underwent liver transplantation compared to 28% of the rest (p=0.88). Of the 68 patients who had LT, 9% died with no difference in post-LT survival between the two groups. CONCLUSIONS: HCV (and genotype 1) is a significant risk factor for HCC in the AA population. LT results in similar survival compared to other ethnicities. AA patients with HCC benefit equally from LT compared to other ethnicities. PMID- 25013629 TI - Exploring the needs and perceptions of Iranian families faced with brain death news and request to donate organ: a qualitative study. AB - BACKGROUND: Learning that one of your beloved ones is passing away and you have to decide on organ donation is a very stressful experience. OBJECTIVE: To explore the specific needs of families with a brain-dead patient during organ donation process. METHODS: A qualitative research using content analysis was used to obtain data from 26 purposely selected families in a transplantation center in Mashhad, northeastern Iran, regarding how they would face organ donation decisions. RESULTS: Data saturation was reached after 38 unstructured in-depth interviews and field notes, once data was transcribed and tabulated. Four major themes emerged as 1) family needs for emotional support, 2) empathy and compassion, 3) team efforts to assure family, and 4) shouldering grief. CONCLUSION: Study results highlighted the essential need for an expert team with specialized training to help families in despair deciding in favor or against organ donation. Moreover, discovering and explaining these specific needs help policy makers and administrators to plan interventions in relation to condition building to facilitate safe passing of the families through this difficult situation. PMID- 25013630 TI - Early Post-liver Transplantation Fever in a Child. PMID- 25013631 TI - Favorable Short-term Outcome in Deceased Kidney Donor Transplantation. PMID- 25013632 TI - Liver Transplantation in Patients with Portal Vein Thrombosis: Comparing Pre-MELD and MELD era. AB - BACKGROUND: Portal vein thrombosis (PVT) used to be a relative contraindication for liver transplantation (LT). This obstacle has been dealt with following the improvement of LT-related techniques. OBJECTIVE: To compare the outcome of adult patients with PVT who underwent LT before and after adopting MELD. METHODS: We retrospectively searched our database for deceased donor LT recipients who had PVT, were operated between 1990 and 2009, and were 18 years old or more. The outcome of patients operated in pre-MELD era (1990-2001) was then compared with that of those operated in MELD era (2002-2009). RESULTS: The incidence of patients undergoing LT with PVT has increased from 1.2% (491/40,730) in pre-MELD era to 6% (2540/42,601) in MELD era (p<0.01). Patients with PVT in MELD era were older (53.6 vs 50.5), had higher calculated MELD (21.3 vs 18.9), shorter length of hospital stay after LT (25 vs 21.7 days), more likely to develop HCC (14.8% vs 0), and more likely to receive DCD allograft (3.9% vs 0.8%). Donor risk indices were comparable in both groups (1.9 vs 1.9). The median waiting time before transplantation decreased during MELD era (71 vs 99 days). Allograft and patients survival was comparable between the two eras. However, allograft and patients survival rates were lower in patients with PVT compared to those without. In Cox regression analysis, PVT was associated with worse allograft (HR=1.3, 95% CI: 1.2 1.4, p<0.001) and patient survival (HR=1.3, 95% CI: 1.2-1.5, p<0.001) compared to non-PVT patients. CONCLUSIONS: The incidence of patients with PVT has increased in MELD era without improvement in outcomes. Donor and recipients characteristics changed in MELD era. PVT is still associated with poor outcomes compared to patients without PVT. PMID- 25013633 TI - En-bloc Transplantation: an Eligible Technique for Unilateral Dual Kidney Transplantation. AB - BACKGROUND: Kidney transplantation is the best available treatment for patients with end-stage renal disease. OBJECTIVE: To evaluate the en bloc anastomosis technique for unilateral dual kidney transplantation (DKT). METHODS: From May to October 2011, 5 patients (4 women and 1 man) with mean age of 31.8 years underwent unilateral DKT with this technique in which distal end of the aorta and proximal end of inferior vena cava (IVC) were closed with running sutures. Then, proximal end of the aorta and distal end of the IVC were anastomosed to internal (or external) iliac artery and external iliac vein, respectively. RESULTS: Post operative course was uneventful. No vascular and urologic complications developed; all patient had acceptable serum creatinine at discharge time and up of 2-6 months of post-operation follow up. CONCLUSION: Unilateral DKT is a safe method for performing DKT. The proposed en bloc anastomosis can improve the outcome of the graft by reducing the cold ischemia and the operation time. PMID- 25013634 TI - Incidence of BK Virus Nephropathy (BKVN) in Renal Transplant Recipients. AB - BACKGROUND: BK virus nephropathy (BKVN) is one of the complications of renal transplantation that causes graft loss in renal transplant recipients. OBJECTIVE: To determine the incidence of BKVN after renal transplantation in Hasheminejad Hospital, Tehran, Iran. METHODS: In this analytical cross-sectional study, we evaluated 31 consecutive kidney transplant recipients (21 men and 10 women) for BK and JC viral infections and BKVN during one year after transplantation, Urine of patients was tested for the presence of decoy cells and DNA of BK and JC virus by PCR. The serum load of BK and JC virus was assessed in patients 3, 6, 9, and 12 months after transplantation. Renal biopsy was performed in presence of allograft dysfunction or viral load >10(7) copies/mL. RESULTS: The prevalences of decoy cells and BK and JC viral DNA in urine of patients were 16%, 29%, and 23%, respectively. BK or JC virus was found in 45% of the urine samples. During one year follow-up, no cases of BKVN was observed. CONCLUSION: Despite a high rate of BK viral infection, no one with BKVN was observed in our kidney transplant recipients. Therefore, screening of all transplant recipients for BKVN is not recommended. PMID- 25013635 TI - Two-year experience of orthotopic liver transplantation in afzalipoor hospital, kerman, southeastern iran. AB - BACKGROUND: End-stage liver diseases are common in Iran. The only therapeutic option for these patients is liver transplantation. OBJECTIVE: To present our 2 year experience of liver transplantations in Afzalipoor Hospital, Kerman, southeastern Iran. METHODS: From November 2009 to September 2011, 12 patients underwent orthotopic liver transplantation in our center. Their data including demographics, indications for transplantation, MELD scores, post-operative complications and their management were collected. RESULTS: Patients (7 women and 5 men) aged between 14 and 55 years. Indications for the transplantation included HBV infection (n=5), cryptogenic cirrhosis (n=2), Wilson's disease, alcoholism (n=1), HCV infection (n=1), Budd-Chiari syndrome (n=1), and autoimmune hepatitis (n=1). MELD score of patients ranged from 16 to 30. All patients received tacrolimus, mycophenolate mofetile and corticosteroid, postoperatively. 2 patients died of pulmonary and intra-abdominal infections with resultant to multiple organ failure. Nonfunctioning of transplanted liver and ongoing bleeding resulted in death in another patients. 9 patients are well doing and have excellent liver functions. CONCLUSION: We had relatively successful results in our experience of orthotopic liver transplantation. Vicinity of our center to Shiraz Transplant Center would be an important factor in this success. PMID- 25013636 TI - Organ Procurement from Deceased Donors and its Impact on Organ Transplantation in Iran during the First Ten Years of Cadaveric Transplantation. AB - The Act of transplantation from deceased and dead-brain donors was ratified in the parliament in 2000. In the subsequent two years, few number of organs were procured from dead-brain patients and transplanted. Later on, a national network was established for organ procurement; units for recognizing brain death were established in Tehran and some other cities to provide the necessary infrastructure for organ transplantation from deceased and dead-brain donors. In this report, we described the outcome of organ procurement from deceased and dead brain donors after 10 years of its establishment in Iran. To do so, we collected data from some relevant published articles and also reports of the Ministry of Health released between 2001 and 2010. By the year 2010, 3673 organs were harvested from deceased donors and transplanted. The rate of liver transplantation has increased rapidly from 16 cases in 2001 to 280 cases in 2010 almost 18 times. There were 554 cadaveric kidney transplantation in 2010; it comprised 19% of total kidney transplantations that is almost 8 times that in 2001. Over the study period, organ procurement has increased by 6-fold. The rate of organ procurement from deceased and dead-brain donors has increased dramatically over the studied period. Considering the existing potentials for this scheme of organ procurement, it seems that improving the Iranian Network for Transplant Organ Procurement will lead to better results. PMID- 25013637 TI - Cochlear implantation after kidney transplantation. AB - Patients with chronic renal failure may develop sensorineural hearing loss. Cochlear implantation has rarely done after organ transplantation. Herein, we report on a 33-year-old kidney transplantation recipient who underwent cochlear implantation for her progressive sensorineural hearing loss in Khalili Hospital Cochlear Implant Center, affiliated to Shiraz University of Medical Sciences. The implantation was done successfully with no complications. Cochlear implantation may be an appropriate therapeutic option for sensorineural hearing loss caused by chronic renal failure. PMID- 25013638 TI - Facebook and organ transplantation. PMID- 25013639 TI - Invasive fungal infections following kidney transplantation. PMID- 25013640 TI - Changing pattern of organ donation and utilization in the USA. AB - BACKGROUND: Organ transplantation has proven highly effective in the treatment of various forms of end-stage organ failure. However, organ shortage is still the greatest challenge facing the field of organ transplantation. OBJECTIVE: To assess the pattern of organ donation and utilization during the past decade in the USA. METHODS: We studied OPTN/UNOS database for organ donation between January 2000 and December 2009. The retrieved records were then categorized into two time periods-from January 2000 to December 2004 (era 1), and from January 2005 to December 2009 (era 2). RESULTS: There were 65,802 living and 71,401 deceased donors in the US from 2000 to 2009, including 66,518 (93.2%) brain-dead donors and 4,883 (6.8%) donation after cardiac death. Comparing two periods-from January 2000 to December 2004 (era 1) and from January 2005 to December 2009 (era 2), the number of deceased donors increased by 25% from 31,692 to 39,709 and living donors decreased by 7.6%. Donation after cardiac death increased from 3.5% to 9.3%. The portion of donors older than 64 years increased from 6.9% in era 1 to 11.3% in era 2 (p=0.03). The number of donors with a body mass index of >35 kg/m(2) was also increased from 6.8% to 11.2%. A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was also noted from 38.1% in era 1 to 56.1% in era 2 (p<0.001), as was a corresponding decrease in the incidence of death due to head trauma (34.9% vs. 48.8%). The overall discard rate also increased by 41% from 13,411 in era 1 to 19,516 in era 2. This increase in discards was especially more prominent in donation after cardiac death group which rose by 374% from 440 in era 1 to 2,089 in era 2. The discard rate for livers and kidneys increased by 31% and 68%, respectively, comparing era 1 and era 2. We noted a 78% increase for discarded donation after cardiac death livers and 1,210% for discarded donation after cardiac death kidneys. CONCLUSION: We detected significant changes in the make-up of the donor pool over the past decade in the US. Over time, donor characteristics have changed with increased numbers of elderly donors and donors with comorbidities, especially donors who died of cardiovascular/cerebrovascular disease. The incidence of donation after cardiac death has increased significantly; brain-dead donors have only increased slightly and living donors have decreased. As the result, the discard rates have increased. The transplant community and policy makers should consider every precaution to safeguard the donor pool and prevent the decay of organ quality in favor of quantity. PMID- 25013641 TI - The incidence and risk factors of de novo skin cancer in the liver transplant recipients. AB - BACKGROUND: Liver transplantation (LT) increases the risk of de novo malignancies including skin cancers. However, risk factors for this type of cancers have not been well studied. OBJECTIVE: To determine the incidence of skin cancer in LT recipients, and to identify the risk factors of this type of cancer. METHODS: We identified all adult patients who underwent LT and developed de novo skin cancer post-LT at our institution between 1996 and 2009. We excluded the patients with history of skin cancer prior to LT. We also studied a control group of patients who underwent LT during the same period but did not develop skin cancer; the control group was matched (1:2) for age, gender and geographical place of residence. RESULTS: Over a median (IQR) follow-up of 41.5 (18.0, 98.6) months, 23 (2.3%) of 998 patients developed skin cancer post-LT, of whom 10 were identified with squamous cell carcinoma, 9 with basal cell carcinoma and 4 with melanoma. After adjusting the confounding variables, subjects who had combined liver/kidney transplant had 22 (95% CI: 5.1-99) times higher hazard of skin cancer compared to subjects with LT alone. Furthermore, patients who had non-skin cancer prior to LT had 23 (95% CI: 8.6-60) times higher hazard developing skin cancer after the transplant. Patients with history of alcohol consumption, as the underlying etiology of liver disease, had 4 (95% CI: 1.2-12.9) times higher hazard of developing skin cancer after transplantation. Type or duration of immunosuppression was not associated with increased risk of skin cancer post-LT. The post-LT survival outcome was not affected by the development of de novo skin cancer post-LT. CONCLUSION: Skin cancer is relatively common in LT recipients and should be monitored, particularly in patients with a history of pretransplant malignancy, recipients of combined liver and kidney transplant or having alcoholic cirrhosis as the underlying cause of liver disease. PMID- 25013642 TI - Electrolytes Disturbance and Cyclosporine Blood Levels among Kidney Transplant Recipients. AB - BACKGROUND: Kidney transplantation is associated with various biochemical abnormalities such as changes in serum blood level of sodium (Na), potassium (K), calcium (Ca), and phosphorous (P). Although cyclosporine (CsA) is used commonly, the prevalence of its side effects, including electrolytes disturbance, is not well understood. OBJECTIVE: To find the prevalence of electrolytes disturbance and its relation to CsA blood levels. METHODS: In a retrospective study, 3308 kidney transplant recipients transplanted between 2008 and 2011 were studied. We evaluated the relation between serum Ca, P, Na, K and CsA trough (C0) and 2-hour post-dose (C2) levels. RESULTS: The mean+/-SD age of recipients was 37+/-15 years; 63% of patients were male. Overall, C2 levels had correlation with Ca blood level (p=0.018; OR: 1.13, 95%CI: 1.02-1.25), C0 levels had also correlation with blood levels of P and Cr (p<0.001; OR: 1.83, 95% CI: 1.59-2.11). CONCLUSION: Electrolyte disturbances are prevalent. Higher serum levels of CsA can worsen the allograft function by disturbing the serum P and Ca levels. PMID- 25013643 TI - Comparison of Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) with Serum Creatinine in Prediction of Kidney Recovery after Renal Transplantation. AB - BACKGROUND: Because of some insult to kidney during transplantation, assessment of kidney function after the procedure is essential. It would be ideal to find a marker better than creatinine to early predict the acute kidney injury. OBJECTIVE: To compare with creatinine the predictive value of serum neutrophil gelatinase-associated lipocalin (NGAL) in detecting kidney recovery after renal transplantation. METHODS: We studied 33 patients who received kidney transplantation (deceased [n=20] and live [n=13]) during a 6-month period in 2010. Serum NGAL and creatinine, hemoglobin, and blood glucose were measured at 0, 12, 24, 48, and 72 hours after transplantation. The need for dialysis and kidney function in one week were studied. RESULTS: There were 16 men and 17 women with the mean+/-SD age of 36.3+/-12.2 (range: 14-58) years. Of the studied patients, 6 had delayed graft function (DGF; hemodialysis within the first week of transplant); 9 had slow graft function (SGF; serum creatinine reduction from transplantation to day 7 <70%), and 23 had immediate graft function (IGF; reduction in serum creatinine >=70%). At any time, serum NGAL, and creatinine levels were significantly higher among patients with DGF (p=0.024) and SGF (p=0.026) compared with those with IGF. However, in those who got IGF vs non-IGF, serum creatinine levels were not significantly different (p=0.59) but serum NGAL levels differed significantly(p=0.020). Receiver-operating characteristic (ROC) curve and area under curves (AUCs) of serum NGAL and serum creatinine levels on the first post-transplantation day had similar significance in predicting the patient's need to dialysis in the first week. However, using AUC of serum creatinine was not helpful in predicting non-IGF, compared to serum NGAL. The AUCs of the serum NGAL were 0.70 (95% CI: 0.52-0.89) and 0.76 (95% CI: 0.59-0.93) after 12 and 24 hours, respectively (p<0.05). The highest AUC (0.82) was attributed to serum NGAL of 24 hour (p=0.002). CONCLUSION: Serum NGAL level especially 24 hours post-transplantation, seems to be an early accurate predictor of both the need to dialysis and slow graft function within the first week of kidney transplantation. PMID- 25013644 TI - Differential expression pattern of the human endoderm-specific transcription factor sox17 in various tissues and cells. AB - BACKGROUND: Sox17 is a member of the Sry-related high mobility group (HMG) of transcription factors that is necessary for endodermal formation and liver development in multiple species. Sox17 gene expression is required for formation of definitive endoderm that gives rise to various tissues. OBJECTIVE: To examine the expression of Sox17 in various human tissues and cells. METHODS: Semiquantitative polymerase chain reaction (RT-PCR) was used to evaluate the expression of Sox17 in adult liver, small intestine, spleen, placenta, fetal liver as well as embryonic stem cells (ESCs), and human HepG2 hepatoma cell line. RESULTS: Low Sox17 gene expression was observed in ESCs. However, there was no expression of Sox17 in human placental tissue, small intestine, adult liver, spleen, and HepG2 cells. But its expression in human fetal liver was very high. CONCLUSION: The data presented in this study reflect the differential expression pattern of Sox17 in the fetal development during early mammalian endodermal formation which is temporal and tightly regulated. PMID- 25013645 TI - Liver transplantation for caroli disease. AB - Caroli disease is a rare congenital disorder characterized by multifocal, segmental dilatation of intrahepatic bile ducts. Patients with Caroli disease who have recurrent bouts of biliary infection, particularly those who also have complications related to portal hypertension may require liver transplantation. In liver transplant ward of Shiraz University of Medical Science we had 4 patients with Caroli disease who were transplanted. Herein, we describe the demographic characteristics and post-transplant course of the patients. These patients presented with liver failure, recurrent cholangitis and portal hypertension sequelae unresponsive to medical treatment. The mean age of patients was 24.5 (range: 18-36) years, the mean MELD score was 17.5 (range: 11-23), three patients were female; one was male. All of the patients had good post transplantation course except for one patient who developed post-operative biliary stricture for whom biliary reconstruction was done. PMID- 25013646 TI - Acute kidney injury: global health alert. AB - Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI. PMID- 25013647 TI - Association of Increased Plasma Interleukin-6 and TNF-alpha Levels in Donors with the Complication Rates in Liver Transplant Recipients. AB - BACKGROUND: Solid organ transplantation is the only definitive treatment available for patients with end-stage organ failure. Organs procured from brain death donors are the main source of transplants. Following brain death, a burst of inflammatory reaction develops; it is characterized by increased plasma levels of cytokines. This inflammatory reaction has been associated with increased early allograft dysfunction. OBJECTIVE: In this study, we test if the increased inflammatory response in brain-death donors is associated with more recipient complications. METHODS: We prospectively recruited 38 consecutive brain-death donors admitted to the intensive care units (ICUs) of Shiraz University of Medical Sciences. Following the declaration of brain death, the demographics data on donor and recipient characteristics and cause of brain death were recorded. The post-liver transplant complications in recipients were stratified according to the Clavien classification. Plasma levels of cytokines IL-6, IL-2, and TNF alpha were measured using enzyme linked immunosorbent assay (ELISA) kits, in all donors before organ procurement. RESULTS: The mean (range) age of donors was 44 (16-74) years. Trauma due to car accident was the most common cause of brain death (79%). The post-liver transplant complications occurred in 19 (50%) recipients. The mean+/-SD plasma TNF-alpha concentration was significantly (p<0.001) higher in recipients with grade 1-3 post-transplant complications (68.33+/-27.74 pg/mL) than those without complication (22.09+/-4.14 pg/mL). Recipients with complications had also a significantly (p=0.001) higher mean+/-SD donor plasma concentration of IL-6 (1009+/-375.5 pg/mL) compared to those without complications (779+/-202 pg/mL). No significant differences was observed between the two groups in respect to IL-2 concentration (0.295+/-0.333 vs 0.285+/-0.342 U/mL, p=0.207). Six recipients died of complications (grade5), in whom no correlation could be found with donor plasma cytokine concentrations. CONCLUSION: Higher plasma concentrations of IL-6 and TNF-alpha in donors before organ procurement, are associated with more post-operative complications in liver transplant recipients. PMID- 25013648 TI - Glutathione S-transferase Omega 2 Genetic Polymorphism and Risk of Hepatic Failure that Lead to Liver Transplantation in Iranian Population. AB - BACKGROUND: Liver transplantation is the treatment of choice for both acute and chronic hepatic failure. GSTs family is one of the most important genes in phase II detoxification interfering with the xenobiotics and free radical metabolism. GSTO2 (N142D) is a member of this family the polymorphism of which may influence the metabolism of active components and free radicals and may contribute to hepatic failure. OBJECTIVE: To investigate the association between GSTO2 genetic polymorphism and the susceptibility of hepatic failure that would lead to liver transplantation. METHODS: This case-control study included 330 healthy people and 302 patients with liver transplantation as a result of hepatic failure. To determine the variants of GSTO2, we used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: There was a significant association between D allele and hepatic failure, thus, people with DD genotype are more susceptible to develop heaptic failure leading to liver transplantation (OR=1.8, 95% CI: 1.10-2.95, p=0.02). We also observed that male sex increases the chance of hepatic failure (OR=2.69, 95% CI: 1.95-3.71, p=0.001). CONCLUSION: D allele may reduce the detoxification ability of liver so people with mutant D allele are more prone to develop hepatic failure. PMID- 25013649 TI - Reasons for Renal Donation among Living Unrelated Renal Donors in Khuzestan Province, Southwestern Iran. AB - BACKGROUND: The shortage of living-related and cadaveric donors lead to living unrelated kidney transplant in Iran. OBJECTIVE: We conducted this study to determine the motivations for unrelated-living kidney donation in Khuzestan province, southwestern Iran. METHODS: After obtaining an informed written consent, unrelated-living kidney donors were interviewed by the authors by means of a standardized questionnaire to assess their socioeconomic status and motivations for donation. RESULTS: 210 living kidney donors consisting of 167 men (79.5%) and 43 women (20.5%) with a mean+/-SD age of 28.4+/-5.6 years were studied. 117 (55.7%) donors were married. 6 (2.9%) of donors were university graduates; 39 (18.6%) high school graduates; 141 (67.1%) less than high school graduates; and 20 (9.5%) were illiterate. The motives for donation was mentioned mostly financial by 127 (60.5%) donors, mostly based on religious beliefs and altruism by 39 (18.6%), and a combination of financial, religious beliefs and altruism by 35 (16.7%) donors. CONCLUSION: Financial problems are the main motivation for living-unrelated kidney donation in Khuzestan province, southwestern Iran. PMID- 25013650 TI - Improving Outcomes of Liver Transplantation for Polycystic Disease in MELD Era. AB - BACKGROUND: Liver transplantation (LT) for polycystic liver disease (PLD) has evolved to be an option for treating these patients. Patients with PLD suffer from incapacitating symptoms because of very large liver volumes but liver function is preserved until a late stage. OBJECTIVE/METHODS: Herein, we reviewed the outcome of adult patients with PLD who underwent LT in the US comparing pre MELD (1990-2001) to MELD era (2002-2009). RESULTS: During this period, only 309 patients underwent LT for PLD. The number of LT for PLD is very low comparing the two eras. The percentage of patients who had combined liver and kidney transplantation (CLKT) for this disease has not changed during MELD era (42.8% vs 38.6%). The waiting time for LT (337 vs 272 days) and CLKT (289 vs 220) has increased in MELD era (p<0.001). In MELD era, 53.4% of LT and 31.2% of CLKT were done as MELD exceptional cases. The allograft and patent survival have significantly improved in MELD era. CONCLUSION: Patients with PLD had marked improvement of their outcomes after LT in MELD era. PMID- 25013651 TI - Very High Dose Epinephrine for the Treatment of Vasoplegic Syndrome during Liver Transplantation. AB - A 55-year-old man with hepatitis B and hepatocellular carcinoma was treated with liver transplantation without veno-venous bypass. During the procedure his arterial blood pressure remained at 55/30 mm Hg and did not respond to increasing doses of norepinephrine. Vasoplegia was managed aggressively with the intravenous infusion of high doses of epinephrine. PMID- 25013653 TI - International principles of deceased donor organ allocation. PMID- 25013652 TI - Liver transplantation from a donor with multiple biliary hamartomata. AB - Biliary hamartomata are rare benign lesions. Herein, we report on a 48-year-old man with a history of end-stage liver disease secondary to alcoholic liver disease. The patient received an orthotropic liver transplant from a brain-death woman. At the time of recovery, there were multiple lesions in the transplanted liver measuring 7-10 mm. Pathology revealed multiple biliary hamartomata. The postoperative course of the recipient was uncomplicated and he was discharged home 10 days after the transplantation. PMID- 25013655 TI - Pharmacovigilance Analysis of Serious Adverse Events Reported for Biologic Response Modifiers Used as Prophylaxis against Transplant Rejection: a Real-World Postmarketing Experience from the US FDA Adverse Event Reporting System (FAERS). AB - BACKGROUND: Immunosuppression by biologic response modifiers (BRM) is a crucial component for successful organ transplantation. In addition to their variable effectiveness in the prevention of organ rejection, these medications have safety concerns that complicate therapeutic outcomes in organ transplant patients. OBJECTIVE: This study aims at identifying and characterizing safety signals of serious adverse events associated with exposure to BRM among organ transplant patients in a real-world environment. METHODS: The FDA Adverse Event Reporting System was utilized to apply a pharmacovigilance disproportionality analysis to indentify serious adverse events. Associations between drugs and events were measured by empirical Bayes geometric mean (EBGM) and the corresponding 95% confidence intervals (EB05-EB95). Associations with EBGM>=2 were considered significant safety signals. RESULTS: From 1997 to 2012, a total of 12,151 serious adverse event reports for BRM were reported; 15.6% of them (n=1,711) met the safety signal threshold of EB05>1, and 11.6% of these signals (n=199) were significant (EBGM>=2). Sirolimus and mycophenolate accounted for the majority of all signals; antithymocyte immunoglobulin (ATI) and cyclosporine contributed to the majority of significant signals. The following significant signals were identified for ATI (reduced therapeutic response, pulmonary edema, hypotension, serum sickness, infusion-related reaction, and anaphylactic reaction); for azathioprine (alternaria infection, fungal skin infection, and lymphoproliferative disorder); for cyclosporine (neurotoxicity, graft vs. host disease, and thyroid cancer); for cyclophosphamide (disease progression); for daclizumab (cytomegalovirus infection); and for tacrolimus (coma and tremor). 33.6% of these events contributed to patient death (n=67); 6.5% were life threatening (n=13); 32.1% lead to hospitalization (n=64); and 27.6% resulted in other serious outcomes (n=55). CONCLUSION: Utilization of BRM for the prophylaxis against transplant rejection is associated with serious adverse events that could be fatal. PMID- 25013656 TI - Rate of family refusal of organ donation in dead-brain donors: the Iranian tissue bank experience. AB - BACKGROUND: The growing gap between organ supply and demand remains a worldwide serious problem. Losing dead-brain donor organs can be attributed to several reasons including un-recognition of potential donor by ICU staff, death before official declaration of brain death and high refusal rate of deceased donors' families. OBJECTIVE: To study the trend of dead-brain patients' relatives refusal of organ donation from 2007 to 2011. METHODS: This study was a retrospective review of all patients who had been introduced as brain death to the organ procurement unit (OPU) of Iranian Tissue Bank between April 2007 and April 2012 according to preliminary neurological exam performed in the hospital of origin. The refusal rate of dead-brain patients' families and its reasons was evaluated. RESULTS: A total of 874 ICU admitted patients with severe brain injury (Glasgow coma score <7) was introduced to our center and were visited by the coordinator team during April 2007 to April 2012. 412 (47%) patients were excluded from the study mainly due to unsuitability for donation according to the approved medical protocols (n=205) and not fulfilling the brain death criteria (n=66). The families of the remaining cases (n=462) had been interviewed 343 (74.2%) of whom permitted donation. The mean+/-SD age of donors was 29.8+/-13.2 years; the male/female ratio was almost 2. The most common reason of brain death was traffic collision (n=120; 56.3%) and cerebrovascular accidents (n=40; 18.8%). The refusal rate from 2007 to 2011 has decreased respectively, from 30.4% to 20% in Tehran, and from 57.1% to 51.6% in other cities. The overall refusal rate was 25.8%. CONCLUSION: Our study confirmed that more level of expertise of the coordinator team and continuous public education, would result in higher rate of consent to organ donation. PMID- 25013654 TI - Utilization of expanded criteria donors in liver transplantation. AB - Improvements in surgical techniques, immunosuppression, and post-transplantation patient care have led to the optimization of liver transplantation outcomes. However, the waiting list for liver transplantation is increasing at a greater pace. The large gap between the growing pool of patients waiting for liver transplantation and the scarcity of donor organs has fueled efforts to maximize existing donors and identify new sources. This article will be focused on the current state of liver transplantation using grafts from extended criteria donors (elderly donors, steatotic donors, donors with malignancies, donors with viral hepatitis) and from donation after cardiac death (DCD), as well as the use of partial grafts (split grafts and living-donor liver transplantation) and other suboptimal donors (donors with hypernatremia, infections, hypotension and inotropic support). Overall, broadened criteria for acceptable donor livers appear to lessen graft survival rates somewhat compared with rates for standard criteria organs. PMID- 25013657 TI - Dynamic Changes of IFN-gamma-producing Cells, TGF-beta and Their Preidctive Value in Early Outcomees of Renal Transplantation. AB - BACKGROUND: A growing body of evidence demonstrated an immune etiology as well as nonimmune mechanisms for episodes of clinical acute rejection and long-term allograft dysfunction. OBJECTIVE: To investigate the correlation of IFN-gamma producing cells and TGF-beta with incidence of clinical acute rejection in living related and unrelated kidney allogarft recipients during the first post transplant year. METHODS: This multi-center study was performed on 57 kidney allograft recipients from living-related (n=20) and unrelated (n=37) donors between April 2011 and September 2012 and who were followed prospectively for a mean period of one year. Peripheral blood samples were collected from all patients pre-transplantation and at days 14, 30 and 90 after transplantation; PBMCs were used as responding cells in enzyme-linked immunosorbent spot (ELISPOT) assay to measure the frequency of IFN-gamma-producing cells after stimulation with donor lymphocytes. Additionally, TGF-beta levels were measured in cell culture supernatants of ELISPOT assay. RESULTS: During the follow-up period, 45 (79%) patients were diagnosed with stable graft function (group A); 12 (21%) experienced clinical acute rejection episodes (group B). The frequency of IFN gamma-producing cells was significantly (p<0.001) higher in the rejection group in all three times after transplantation. Also, post-transplantation comparison for TGF-beta showed a significantly (p<0.001) higher contents in group A vs. group B. Comparing the post-transplantation levels of TGF-beta and mean numbers of IFN-gamma- producing cells between groups A and B demonstrated a continuous increment in TGF-beta and decreasing frequencies of IFN-gamma-producing cells in group A vs. group B. CONCLUSION: Serial post-transplantation monitoring of IFN gamma-producing donor reactive cells during the first months is a clinically feasible approach for identification of kidney allogarft recipients at risk for ongoing immune-mediated graft damage and later graft loss. PMID- 25013659 TI - Close collaboration of two transplantation research centers in iran. PMID- 25013658 TI - The molecular prevalence of viral infections in transplant candidates with bone marrow suppression, shiraz, southern iran, 2010. AB - BACKGROUND: Transient bone marrow suppression, characterized by acute inability of the bone marrow to produce circulating blood cells, may strongly relate to the pathogenesis of some viral infections. OBJECTIVE: To study the prevalence of some DNA and RNA viruses in patients with transient bone marrow suppression. METHODS: EDTA-treated blood samples were collected from 27 patients with clinically- and laboratory-confirmed transient bone marrow suppression. The genomic DNA of hepatitis B virus, adenovirus, polyomavirus BK, and parvovirus B19, and genomic RNA of hepatitis C and G viruses were extracted and amplified by sensitive and specific in-house simple and nested PCR and RT-PCR protocols, respectively. The risk factors that might be related to the studied viral infections were analyzed. RESULTS: Hepatitis B virus infection was diagnosed in 9 (33%) of 27 patients; adenovirus infection in 2 (7%); and parvovirus B19 infection in 7 (26%) of 27 patients. The genomic DNA of polyomovirus BK was not detected in any patients. Both hepatitis C and G viruses were found in 3 (11%) of 27 patients. CONCLUSION: Diagnosis of the high prevalence of hepatitis B virus, and parvovirus B19 in patients with transient bone marrow suppression, reflects the importance of these viral infections in introducing bone marrow suppression. This hypothesis should be confirmed in further studies. PMID- 25013660 TI - Human split-thickness skin allograft: skin substitute in the treatment of burn. AB - BACKGROUND: Human skin allograft has been used as wound coverage for a long time; it is one of the most successful and widely used dressings for burn wounds in the world. OBJECTIVE: To prepare a freeze-dried human split-thickness skin allograft and evaluate its cytotoxicity, the structure and physical properties after processing methods and clinical efficacy in burn patients. METHODS: After ensuring tissue safety, we lyophilized human cadaveric partial thickness skin and exposed it to gamma radiation. Histopathological and immunohistochemical properties, tensile strength and in vitro cytotoxicity were assayed for the skin samples. Then, we tested the samples in 11 patients with deep skin burn. RESULTS: On histological and histopathological examinations, we found a normal skin structure. The tensile strength of the rehydrated freeze-dried human skin allograft was not lesser than the fresh human skin. Cell viability in MTT testing was more than 95%. None of our patients showed any signs of immunological reactions or complications. CONCLUSION: Gamma-irradiated freeze-dried human split thickness skin is safe and non-toxic and can be used for the treatment of patients with deep skin burn. PMID- 25013661 TI - Serum Neutrophil Gelatinase-Associated Lipocalin versus Serum Creatinine for the Prediction of Acute Kidney Injury after Liver Transplantation. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation (LT), and considerably increases the morbidity and mortality of the procedure. The gold standard of measuring the kidney function, the serum creatinine level (sCr), has poor specificity and sensitivity for the early diagnosis of AKI. Novel biomarkers for the prediction or early diagnosis of AKI, would potentially increase the opportunities for therapeutic interventions. OBJECTIVE: To compare the diagnostic value of the standard renal marker, sCr and neutrophil gelatinase-associated lipocalin (NGAL) to predict AKI within 48 hours of LT. METHODS: During a 9-month period from 2010 to 2011, NGAL was measured two times in 90 patients who underwent LT from deceased donors-after induction of anesthesia (NGAL1) and 2 hours after reperfusion of the liver graft (NGAL2). Patients were grouped according to the presence of risk factors for developing AKI according to the Acute Kidney Injury Network criteria (increase of >=0.3 mg/dL in plasma creatinine above the baseline value within 48 hours). RESULTS: 60 men and 30 women with mean+/-SD age of 40.2+/-14.2 years were included in this study. The incidence of AKI was 34% (95% CI: 24%-44%). The difference between the NGAL1 and NGAL2 (DeltaNGAL) and the baseline NGAL concentration was predictive of AKI in all patients. Receiver operating characteristic (ROC) curve and area under curves (AUCs) of DeltaNGAL and sCr levels during the first 48 hours of LT were similar in predicting AKI. The AUCs of the DeltaNGAL to predict AKI was 0.64 (95% CI: 0.52-0.76). The development of AKI was significantly correlated with the number of units of fresh frozen plasma transfused intra-operatively (p=0.017) and cold ischemic time (p=0.042). CONCLUSION: Serum NGAL concentrations obtained during surgery is a predictor of AKI in patients undergoing LT. PMID- 25013662 TI - Isolation and Characterization of Human Mesenchymal Stem Cells Derived from Human Umbilical Cord Wharton's Jelly and Amniotic Membrane. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have a capacity for self-renewal and multi-potential differentiations. These cells are considered powerful sources for cell therapy in regenerative medicine and tissue engineering. The cells can be isolated from various tissues; however, harvesting from human umbilical cord and amniotic membrane is easy and accessible source. OBJECTIVE: To isolate and characterize the MSCs derived from human umbilical cord Wharton's jelly (WJ-MSC) and amniotic membrane (AM-MSC) with regard to their morphology, immunophenotype and mesodermal differentiation potential in order to obtain an alternative source of MSC for therapeutic clinical applications. METHODS: Fetal membranes and umbilical cords (n=3) were retrieved from healthy full-term women by elective cesarean delivery. Amniotic membrane and umbilical cord were separately minced and cultured in DMEM supplemented with 10% FBS. After reaching 80% of confluency, the umbilical cord WJ-MSC and AM-MSC were characterized by expression of cell surface markers with flowcytometry, stem cell gene expression with adipogenic/osteogenic potential. RESULTS: Both WJ-MSC and AM-MSC were spindle shaped cells, expressed MSC surface markers in flowcytometry and stem cell transcriptional factors (OCT4 and NANOG). After induction, the cells differentiated into adipogenic and osteogenic lineages. CONCLUSION: MSC were successfully generated from umbilical cord WJ-MSC and AM-MSC with similar mesenchymal markers and properties. PMID- 25013663 TI - Survival rate in lung, liver, heart and pancreas transplant recipients in iran: a registry-based study. AB - BACKGROUND: The main purpose of organ transplantation is to prolong and maintain a quality life for patients with organ dysfunction. OBJECTIVE: We tried to evaluate short-term survival rates in lung, liver, heart and pancreas recipients. METHODS: This longitudinal study was based on the data of national registry of recipients in Ministry of Health and Medical Education (MOHME), Iran. Survival rate after 1 year of transplantation, recipients' age, gender, ischemic time as well as the number of transplantation units, OP units and identification units were collected from the database for all transplantation done between 2010 and 2011. RESULTS: 407 (223 female, and 184 male) patients were enrolled in the study. 13 (3.2%) patients received lung, 299 (73.5%) liver, 85 (20.9%) heart and 10 (2.5%) received pancreas. Within 1 year of transplantation, 61.5% of lung recipients, 88.3% of liver recipients, 72.9% of heart recipients and 80% of pancreas recipients (overall 85.3%) were functioning. CONCLUSION: Given the short history of transplantation in Iran, we have achieved great success. PMID- 25013664 TI - Incidentally detected lymphatic filariasis in a renal allograft recipient. AB - Post-transplntation lymphocele is a well known complication, and lymphatic filariasis (LF) has occasionally been found to present as post-transplantation lymphocele. However, incidentally detected LF during transplantation surgery has not been reported. We present an incidentally detected LF presenting as enlarged lymph node in the right iliac fossa of a recipient during transplantation of donor kidney. He was subsequently treated after transplantation and had stable graft function without any complications after 8 months of follow-up. PMID- 25013665 TI - The first hand transplantation in iran. AB - Nowadays, hand transplantation is a very challenging procedure for surgeons and researchers worldwide. Despite many problems that may occur after this surgery, some centers continue to practice this highly sophisticated procedure. Herein, we report on a 38-year-old man who received hand transplant from a 24-year-old brain dead man. This patient had lost his right hand from the lower one-third of forearm six years before after a trauma from a mincing machine. Team members organized pre-operative research, cadaver dissection, legal consultation, religious permission and discussion to patient. This procedure was done by 15 Khordad Plastic Surgery Transplant team on February 27, 2013 for the first time in Iran. PMID- 25013666 TI - Living Donor Liver Transplantation for Hepatocellular Carcinoma: It Is All about Donors? AB - BACKGROUND: Live-donor liver transplantation (LDLT) is a valuable option for patients with hepatocellular carcinoma (HCC) as compared with deceased-donor liver transplantation (DDLT); the tumor could be eradicated early. METHODS: Herein, we reviewed the outcome of adult patients with HCC who underwent LDLT from 1990 to 2009 in the USA, as reported to United Network for Organ Sharing. RESULTS: Compared to DDLT (n=5858), patients who underwent LDLT for HCC (n=170) were more likely to be female (43.8% vs 23.8%), younger (mean age 48.6 vs 54.9 years) and have more tumors outside Milan criteria (30.7% vs 13.6%). However, the recipients of LDLT for HCC had a significantly shorter mean wait time before transplantation (173 vs 219 days; p=0.04). The overall allograft and patient survival were not different, though more patients in LDLT group were outside Milan criteria. Since implementation of the MELD exception for HCC, DDLT for HCC has increased form 337 (2.3%) cases in 2002 to 1142 (18.7%) in 2009 (p<0.001). However, LDLT for HCC has remained stable from 16 (5.7%) in 2002 to 14 (9.2%) in 2009 (p=0.1). Regions 1, 5 and 9 had the highest rate of LDLT for HCC compared to other regions. CONCLUSIONS: LDLT can achieve the same long-term outcomes compared to DDLT in patients with HCC. The current MELD prioritization for HCC reduces the necessity of LDLT for HCC except in areas with severe organ shortage. PMID- 25013667 TI - The effect of renal transplantation on ventricular repolarization in children with chronic renal failure. AB - BACKGROUND: Chronic renal failure and hemodialysis affect many ECG parameters which can affect cardiac repolarization. OBJECTIVE: To investigate the change in ventricular repolarization before and after kidney transplantation in children. METHODS: A total of 45 children with end-stage renal disease, 45 children at least 6 months after successful renal transplantation, and 45 normal age-matched subjects were enrolled into this study. A 12-lead ECG was recorded in the 3 groups. QT dispersion, QTc dispersion, and T peak to T end (TPE) dispersion were measured. RESULTS: In the patients before and after renal transplantation and the normal children, respectively, the mean+/-SD QT dispersion was 0.083+/-0.033, 0.056+/-0.029, and 0.033+/-0.016 (p<0.01); the mean+/-SD QTc dispersion was 0.104+/-0.038, 0.066+/-0.033, and 0.039+/-0.020 (p<0.01); the mean+/-SD TPE interval dispersion was 0.060+/-0.021, 0.045+/-0.021, and 0.034+/-0.019 (p<0.01). There was a significant correlation between left intra-ventricular diastolic diameter and QT dispersion, QTc dispersion, and TPE dispersion. The systolic velocity of the mitral valve also correlated with TPE dispersion (r=0.44, p=0.01). CONCLUSION: In children with chronic renal failure, indices of ventricular repolarization improve after transplantation, though they still remain longer than the normal values. PMID- 25013668 TI - Hemodynamic factors affecting the suitability of the donated heart and kidney for transplantation. AB - BACKGROUND: Due to the loss of autonomic nervous system, precise control of the hemodynamic status in dead brain potential donors presents a clinical dilemma. In these patients, due to head trauma and cerebral edema, fluids administration is restricted. Moreover, the decreased central venous pressure may put the viability of the organs at risk. OBJECTIVE: To investigate hemodynamic factors affecting the suitability of the donated heart and kidney for transplantation. METHODS: Data were retrospectively collected from the maintained databases of all dead brain donors (DBDs) admitted to our organ procurement unit (OPU) ICU between 1999 and 2008. In this study, laboratory variables in addition to demographic data were collected. The time between donor entrance to the DBD ICU and organ procurement, vital signs, hourly urine output, amount of IV fluid administered, and the dosage of vasopressor and desmopressin were recorded. The end-point of the study was organ suitability for organ retrieval. RESULTS: A total of 132 dead brain donors were studied. The mean+/-SD age of the donors was 26.3+/-12.2 years. The main cause of brain death was multiple trauma (53%). The organ retrieval rate was 82.6% for the kidney, 59.8% for the liver, and 53% for the heart. 83 (63%) and 106 (80.3%) donors had suitable hearts and kidneys, respectively. 66 cases did not receive desmopressin (50.4%) at all. The mean+/-SD dose of desmopressin the donors received was 7+/-1 ug. There was a significant association between the suitability of these two organs for transplantation and the dosage of the administered desmopressin and volume of IV solution the donors received. CONCLUSION: Fluid therapy and administration of desmopressin can improve the number and quality of retrieved organs from dead brain donors. PMID- 25013670 TI - Extensive ureteral stricture in renal transplant recipients: prevalence and impact on graft and patient survival. AB - Extensive ureteral stricture (EUS) after renal transplantation (RTx) is an important urological complication that adversely affects the longterm function of the allograft and therefore the morbidity and mortality of the recipients. We conducted this study to determine the prevalence of the EUS in RTx recipients and its impact on the patient and graft survival. We assessed retrospectively, 1450 patients who underwent renal transplantation by a fixed surgical team between December 1991 and December 2009 at Emam Reza Hospital, Mashhad University of Medical Science, Mashhad, Iran. EUS was diagnosed in 13 (1.1%) patients including 8 (61.5%) male. The mean+/-SD age of patients at the time of surgery was 33.6+/ 13.7 years; the length of follow-up was 77.9+/-63.5 months; and the ischemic time was 126.5+/-114.1 min. Mostly, EUS was noticed in recipients of transplants with more than one artery (p<0.05) and of cadaveric donors with more than 4 hour ischemic time (p<0.001). In follow-up, after ureteropyelostomy (7 cases), ipsilateral pyelopyloplasty (4 cases) and contralateral pyelopyeloplasty (2 cases), no evidence of ureteral stricture recurrence, graft loss or death was observed. We concluded that the incidence of EUS, as a urologic complication after RTx is very low. The advanced techniques of RTx that preserve the ureteric blood supply and the better procedures for ureteral reconstruction have improved the survival rate of patient and graft. PMID- 25013669 TI - The effect of stem cell transplantation on immunosuppression in living donor renal transplantation: a clinical trial. AB - BACKGROUND/OBJECTIVE: We designed a clinical trial on a group of live-donor renal transplantation (LDRT) patients subjected to pre-transplant stem cell transplantation (SCT) to minimize immunosuppression to low-dose steroid monotherapy. METHODS: LDRT patients subjected to pretransplant SCT who had stable graft function for >=2 years and serum creatinine (SCr) <2 mg/dL were recruited. Patients with diabetes, hepatitis C/B, rejections, or unwilling to participate, were excluded. They had been subjected to non-myeloablative conditioning of total lymphoid irradiation (TLI)/bortezomib and cyclophosphamide, rabbit-antithymocyte globulin (r-ATG) and rituximab with SCT. The maintenance immunosuppression consisted of calcineurin inhibitors (CNI) and/or anti-proliferative agents and prednisone. Donor-specific antibodies (DSA) and peripheral T-regulatory cells (CD127(low/-)/4(+)/25(high)) (p-Tregs) were studied before and after withdrawal of major immunosuppressants; graft biopsy was taken after 100 days of withdrawal in willing patients. Rejections were planned to be treated by anti-rejection therapy followed by rescue immunosuppression. RESULTS: All immunosuppression but prednisone, 5-10 mg/day has been successfully withdrawn for a mean of 2.2 years in 76 patients with a mean age of 31.4 years and a mean donor-recipient HLA match of 2.9. The mean SCr of 1.4 mg/dL and p-Tregs of 3.5% was remained stable after withdrawal; DSA status was negative in 35.5% and positive in 47.4% patients. Protocol biopsies in all 10 patients who gave the consent were unremarkable. CONCLUSION: Stable graft function in LDRT on low-dose steroid monotherapy using pre-transplant SCT under non-myeloablative conditioning with generation of p Tregs can be achieved successfully and safely. PMID- 25013671 TI - Cutaneous metastasis of cholangiocarcinoma: report of two cases. AB - Cutaneous metastasis of cholangiocarcinoma is extremely rare. It can be seen at distant locations or at the site of biliary drainage. To the best of our knowledge less than 30 cases have so far been reported in the English literature. This event should be considered in every skin lesion in a patient with cholangiocarcinoma and be treated promptly by resection and chemotherapy to increase the patient's survival. Herein, we report our experience with two patients with cholangiocarcinoma and cutaneous metastasis at the site of biliary drainage. PMID- 25013672 TI - Chronic kidney disease and the aging population. PMID- 25013673 TI - Differences in Medication Adherence between Living and Deceased Donor Kidney Transplant Patients. AB - BACKGROUND: Literature review suggests that adherence to immunosuppressive drugs may be lower in recipients of living than of deceased donor kidney grafts, possibly because of profile differences. OBJECTIVE: To compare the level of immunosuppressive adherence levels between patients with deceased and living ( related; -unrelated) donor grafts in Switzerland. METHODS: Using data from two similar cross-sectional studies at two transplant centers in Switzerland, the level of adherence between the two groups was compared. Medication adherence was assessed by self-report or electronic monitoring. Possible explanatory factors included age, beliefs regarding immunosuppressive drugs, depressive symptomatology, pre-emptive transplantation, and the number of transplants received, were also considered. Data were analyzed using logistic regression analysis. RESULTS: Unadjusted non-adherence odds were 2 to 3 times higher in living-related than deceased donor transplantation (ORs: 2.09-3.05; p<0.05). Adjustment for confounders showed that these differences were associated most with the younger age of living-related subjects and the belief that immunosuppressive drugs are less important for living-related donations. CONCLUSION: There is a lower immunosuppressive adherence in recipients of living related donor kidneys, possibly owing to differences in patient profile (ie, health beliefs regarding their immunosuppressive needs), knowledge of which may enhance adherence if addressed. PMID- 25013674 TI - Differential Expression of Insulin-Like Growth Factor-I Receptor on Human Bone Marrow-Derived Mesenchymal Stem Cells Induced by Tumor Necrosis Factor-alpha. AB - BACKGROUND: Cell-based therapy has been implicated in the treatment of liver diseases. Mesenchymal stem cells from various sources such as bone marrow are available. These cells are one of the major candidates in cell therapy. The production of insulin-like growth factor-I increases in the regenerating organ. The insulin-like growth factor-I in liver regeneration is effective after binding to insulin-like growth factor-I receptor. OBJECTIVE: To test our hypothesis that tumor necrosis factor-alpha can stimulate mesenchymal stem cells to express insulin-like growth factor-I receptor. METHODS: Bone marrow was aspirated from normal human donor after taking informed consent. Cells were isolated and cultured. Identification of cells was done by flowcytometry and functional tests. The fourth passage cells were treated with tumor necrosis factor-alpha at two doses of 1 and 10 ng/mL, and incubated for 2, 10, 24, and 48 hours. Insulin-like growth factor-I receptor gene expression was studied using real-time polymerase chain reaction. RESULTS: Flowcytometry showed that the human bone marrow mesenchymal stem cells were positive for CD90 and negative for CD45 and CD80. The insulin-like growth factor-I receptor gene expression was increased in tumor necrosis factor-alpha treated in comparison with untreated cells. CONCLUSION: Treatment of human bone marrow-derived mesenchymal stem cells with tumor necrosis factor-alpha increases gene expression of insulin-like growth factor-I receptor. This finding may be used for increasing the effectiveness of stem cell therapy in those with acute hepatic failure. PMID- 25013675 TI - Fabrication of a hard tissue replacement using natural hydroxyapatite derived from bovine bones by thermal decomposition method. AB - BACKGROUND: For the treatment of bone defects that exceed the critical size of the injury, several therapies have been investigated. Thermal decomposition method is suggested for extraction of natural hydroxyapatite bioceramic (HA). This technique in comparison with other methods of producing HA, has less complexity and greater economic efficiency. OBJECTIVE: In the present study, a thermal decomposition method is suggested for extraction of natural HA from bovine femur bones. METHODS: In this experiment, to extract the ceramic material, the bone samples were first de-fatted and ground to particles less than 420 MUm, and also 420-500 MUm, respectively. Prepared powders were heated at 170 degrees C for 24 h, and then divided into two groups for 6 h. The first group was heated at 750 degrees C; the second group was heated at 850 degrees C. The calcium phosphate compounds were obtained with complete elimination of the organic phase of the bone. These bioceramic compounds were characterized physiochemically by X ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR), energy dispersive X-ray (EDX), and scanning electron microscopy (SEM). RESULTS: We found that the powder heated at 750 degrees C in two dimensional scales was rich in carbonated hydroxyapatite, and therefore, eminently suitable for using in hard tissue replacements. However, increasing the temperature up to 850 degrees C reduced the Ca/P ratio to 1.5 in the powder sample sizes less than 420 MUm. Consequently, the obtained composition became rather similar to the chemical formula of tricalcium phosphate (TCP) that is appropriate in tissue engineering and drug delivery applications. CONCLUSION: The observations affirmed that by eliminating the collagen and other organic materials existing in the bovine bones, the mineral phase of the bone had the potential of transformation to nano particles. To investigate the repair of critical-size bone defects and bone augmentation, cylindrical blocks were fabricated by applying different pressures of 150, 160 and 170 MPa. The structure and compressive strength of the pressed samples after sintering at 1200 degrees C were characterized by SEM and compressive strength test. PMID- 25013676 TI - Shiraz guideline for the management of patients with brain death. PMID- 25013677 TI - Temporary Parenteral Tacrolimus Requirement due to Unexplained Low Through Levels in a Liver Transplant Patient with Short Bowel Syndrome. AB - An adequate level of tacrolimus in serum should be obtained to prevent acute rejection following liver transplantation. Because of good gastrointestinal absorption of oral tacrolimus, adequate trough levels can be achieved even in patients with short bowel syndrome. Rarely, adequate through levels cannot be obtained by oral administration of the drug for several reasons such as inadequate absorption, having a discordant patient, laboratory error, and/or interactions with other drugs and foods. Here, we described a 16-year-old patient who had undergone massive intestinal resection due to mesenteric torsion 5 years previously and required liver transplantation for cryptogenic cirrhosis. Her remnant small bowel length was 90 cm. After a successful living donor liver transplantation, oral tacrolimus administration resulted in inadequate through levels in some parts of the postoperative period. We checked up all the potential reasons but could not identify any cause. An intravenous tacrolimus including immunosuppressive regimen was temporarily required. She maintained adequate blood levels of tacrolimus by parenteral route for a while; thereafter, oral administration resulted in enough blood drug levels. She was discharged with oral tacrolimus therapy. We concluded that very rarely, adequate blood levels of tacrolimus cannot be achieved by oral administration for unexplained reasons. In such cases, temporary administration of parenteral tacrolimus can be life-saving. PMID- 25013678 TI - Outcomes of patients with portal vein thrombosis undergoing live donor liver transplantation. AB - BACKGROUND: Live donor liver transplantation (LDLT) for patients with portal vein thrombosis (PVT) creates several technical challenges due to severe pre-operative condition and extensive collaterals. Although deceased donor liver transplantation in patients with PVT is now routinely performed at most centers, the impact of PVT on LDLT outcomes is still controversial. OBJECTIVE: To determine the outcome of patients with PVT who underwent LDLT. METHODS: We reviewed the outcome of adult patients with PVT who underwent LDLT in the USA from 1998 to 2009. RESULTS: 68 (2.9%) of 2402 patients who underwent LDLT had PVT. Comparing patients with and without PVT who underwent LDLT, those with PVT were older (53 vs 50 yrs), more likely to be male, had longer length of stay (25 vs 18 days) and higher retransplantation rate (19% vs 10.7%). The allograft and patient survival was lower in patients with PVT. In Cox regression analysis, PVT was associated with worse allograft survival (HR=1.7, 95% CI: 1.1-2.5, p<0.001) and patient survival (HR=1.6, 95% CI: 1.2-2.4, p<0.001) than patients without PVT. CONCLUSIONS: Patients with PVT who underwent LDLT had a worse prognosis than those without PVT. PMID- 25013679 TI - Reducing stress and anxiety in caregivers of lung transplant patients: benefits of mindfulness meditation. AB - BACKGROUND: Caregivers are a vital resource in the care of transplant candidates or recipients. However, few strategies have been tested that attempt to decrease the stress and anxiety they commonly encounter. OBJECTIVE: To test the feasibility of using mindfulness-based stress reduction (MBSR) techniques to decrease stress and anxiety in caregivers of lung transplant candidates/recipients who required admission to an acute care facility. METHODS: 30 caregivers of lung transplant candidates/recipients were recruited during hospitalization of their significant other. Each completed the perceived stress scale (PSS) and state trait anxiety inventory (STAI) before and 4 weeks after receiving a DVD that demonstrated MBSR techniques. Participants were asked to practice MBSR techniques for 5-15 min a day for 4 weeks. RESULTS: The participants had a mean+/-SD age of 55.6+/-13.6 years; 77% of participants were female and 93% Caucasian. The mean PSS and STAI (trait and anxiety) scores of caregivers were higher than population norms pre- and post-intervention. Scores for caregivers who stated they watched the entire DVD and practiced MBSR techniques as requested (n=15) decreased significantly from pre- to post-testing for perceived stress (p=0.001), state anxiety (p=0.003) and trait anxiety (p=0.006). Scores for those who watched some or none of the DVD (n=15) did not change significantly. CONCLUSION: Caregivers can benefit from stress reduction techniques using MBSR. PMID- 25013680 TI - Multivisceral and small bowel transplantation at shiraz organ transplant center. AB - BACKGROUND: Multivisceral transplantations were initially done in animal models to understand the immunological effects. Later on, in human beings, it has been considered a salvage procedure for unresectable complex abdominal malignancies. With advancement in surgical techniques, availability of better immunosuppressive drugs, and development of better post-operative management protocols, outcomes have been improved after these complex surgical procedures. OBJECTIVE: To analyze and report results of multivisceral, modified multivisceral, and small bowel transplantations done at Shiraz Organ Transplant Center, Shiraz, southern Iran. METHODS: Medical records of all patients who underwent multivisceral, modified multivisceral, and small bowel transplants were retrospectively analyzed. RESULTS: There were 18 patients. The most common indications for the procedure in our series were unresectable carcinoma of pancreas followed by short bowel syndrome. 10 patients were alive after a median follow-up of 8.7 (range: 3-32) months. The remaining 8 patients died post-operatively, mostly from septicemia. CONCLUSION: Multivisceral and small bowel transplantations are promising treatments for complex abdominal pathologies. PMID- 25013681 TI - Knowledge and Attitude of Iranian Physicians towards Organ and Tissue Donation. AB - BACKGROUND: Nowadays, organ transplantation is the treatment of choice for end stage organ failure, which increases the importance of organ procurement. It seems that the attitude towards organ donation and transplantation affects people's satisfaction. Moreover, health care personnel, especially physicians, should be familiar with transplantation rules and standards. It seems that understanding the knowledge and attitude of this group can affect the transplantation center policies. OBJECTIVE: To assess knowledge and attitude of a group of Iranian physicians towards organ and tissue donation. METHODS: In a cross-sectional study, 560 Iranian physicians including nephrologists, urologists and internists were asked to fill out a validated questionnaire containing their demographics, knowledge and attitude towards organ and tissue donation and transplantation. RESULTS: Of 560 participants, 435 (78%) agreed with organ donation after death and 285 (51%) agreed with living kidney donation. The most common reason provided by those who agreed with donation was "helping people" whereas the most common cause of disagreement was "to honor the body." Only 32 (6%) physicians had no knowledge about transplantation rules. Complete awareness about theoretical basis and financial issues of transplantation was observed in 265 (47%) and 221 (40%) participants, respectively. CONCLUSION: Physicians had a good attitude towards organ and tissue transplantation although less than half of them had knowledge of transplantation rules and its theoretical basis and financial issues; therefore, additional awareness and education of physicians is needed in all areas of the organ donation process in Iran. PMID- 25013682 TI - Reliability of pre-transplant live donor renal biopsies in predicting the graft outcome. AB - BACKGROUND: Biopsy from deceased donors is of great value in predicting the efficacy and mid-term and long-term outcome of kidney transplantation. OBJECTIVE: To determine the prevalence of pathological changes in live donors' kidneys and their association with the graft outcome. METHODS: This cohort study was performed among a group of renal transplant recipients. Biopsy was taken from donor's kidney. The functionality of the grafted kidney was then evaluated by measuring serum creatinine, based on which, the patients were categorized into "successful" and "unsuccessful" groups. The results were compared based on biopsy results. RESULT: We studied 58 kidneys from live donors. The mean+/-SD urine volume on the first day after transplantation was 10,052+/-3286 mL. Absence of allograft dysfunction was seen in 55 (95%) patients during a month, 51 (88%) patients in 6 months, and 53 (91%) within a year. Glomerulosclerosis was seen in 20 (35%) patients, fibrosis in 9 (16%), tubular atrophy in 5 (9%), and intimal fibrosis in 3 (5%). The mean+/-SD serum creatinine in patients within 1-month survival was 1.15+/-0.19, within 3-month survival was 1.17+/-0.20, within 6-month survival was 1.21+/-0.20, within 9-month survival was 1.43+/-1.28, and within 1 year survival was 1.14+/-0.22. CONCLUSION: Kidney biopsy from live donors can show us a general status of kidney. Serum creatinine is the test of choice for evaluating the grafted kidney function. PMID- 25013683 TI - Mesenchymal hamartoma mimicking hepatoblastoma. AB - Mesenchymal hamartoma and hepatoblastoma are common causes of hepatic masses in pediatric population; they have similar radiologic and pathologic features. Herein, we present a case of mesenchymal hamartoma that was preoperatively diagnosed as hepatoblastoma. The mass was completely resected instead of being treated with preoperative chemotherapy. Postoperative pathological evaluation revealed mesenchymal hamartoma with free margins; the patient incidentally received the standard treatment. If we would have measured serum AFP in our patient, we could make the correct diagnosis preoperatively, because AFP increases largely in hepatoblastoma. When suspicious exists, serum AFP is a good guide in differentiating hepatoblastoma from mesenchymal hamartoma. PMID- 25013684 TI - Management of heparin-induced thrombocytopenia with fondaparinux in a patient with left ventricular assist device. AB - Heparin-induced thrombocytopenia is an immune-mediated serious adverse effect of heparin therapy. It is a relatively frequent complication among patients with mechanical circulatory support. Herein, we present a patient with severe heart failure and sepsis who developed heparin-induced thrombocytopenia shortly after implantation of left ventricular assist device as a bridge to transplantation and who was successfully treated with fondaparinux. PMID- 25013685 TI - A comparative study on tobacco cessation methods: a quantitative systematic review. AB - BACKGROUND: During recent years, there have been many advances in different types of pharmacological and non-pharmacological tobacco control treatments. In this study, we aimed to identify the most effective smoking cessation methods used in quit based upon a review of the literature. METHODS: We did a search of PubMed, limited to English publications from 2000 to 2012. Two trained reviewers independently assessed titles, abstracts and full texts of articles after a pilot inter-rater reliability assessment which was conducted by the author (GH). The total number of papers and their conclusions including recommendation of that method (positive) or not supporting (negative) was computed for each method. The number of negative papers was subtracted from the number of positive ones for each method. In cases of inconsistency between the two reviewers, these were adjudicated by author. RESULTS: Of the 932 articles that were critically assessed, 780 studies supported quit smoking methods. In 90 studies, the methods were not supported or rejected and in 62 cases the methods were not supported. Nicotine replacement therapy (NRT), Champix and Zyban with 352, 117 and 71 studies respectively were the most supported methods and e-cigarettes and non Nicotine medications with one case were the least supported methods. Finally, NRT with 39 and Champix and education with 36 scores were the most supported methods. CONCLUSIONS: Results of this review indicate that the scientific papers in the most recent decade recommend the use of NRT and Champix in combination with educational interventions. Additional research is needed to compare qualitative and quantitative studies for smoking cessation. PMID- 25013686 TI - A Qualitative Study of Community-based Health Programs in Iran: An Experience of Participation in I.R. Iran. AB - BACKGROUND: Community-based health programs (CBHPs) with participatory approaches has been recognized as an important tool in health promotion. The goal of this study was to understand the nature of participation practice in CBHP and to use the data to advocate for more participation-friendly policies in the community, academy and funding organizations. METHODS: In this qualitative study, 13 CBHPs, which were active for last 5 years have been assessed using semi-structural in depth interviews with programs principal and managers and focus group discussions with volunteers and service users. Data analysis was based on the deductive inductive content analysis considering the participatory approaches in these programs. RESULTS: The results show that, the main category of participation was divided to community participation and intersectional collaboration. The community participation level was very different from "main," "advisory" or "supporting" level. The process of recruitment of volunteers by the governmental organization was centralized and in non-governmental organizations was quite different. According to respondents opinion, financial and spiritual incentives especially tangible rewards, e.g., learning skills or capacity building were useful for engaging and maintaining volunteers' participation. For intersectional collaboration, strong and dedicated partners, supportive policy environment are critical. CONCLUSIONS: It seems that maintaining partnership in CBHP takes considerable time, financial support, knowledge development and capacity building. PMID- 25013687 TI - The Relationship between Intake of Dairy Products and Polycystic Ovary Syndrome in Women Who Referred to Isfahan University of Medical Science Clinics in 2013. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive women. Nearly 10% of young women in this period involved. Although factors such as Insulin Resistance, hyper insulinemia, obesity and dietary are suggested to be associated with PCOS, cause of PCOS is not completely understood. Dairy products (a key component of the usual diet) of participants can also affect the factors of this disease and may have beneficial effects on treatment of PCOS. However, research in this area is scarce. The purpose of this study was to evaluate the relationship between dairy products consumption and PCOS. METHODS: This descriptive cross-sectional study of 400 women was conducted in Shahid Beheshti Hospital of Isfahan University of Medical Science, Iran. Dietary intake was evaluated by validated food frequency questionnaire. Other variables such as ovarian disease, inherited predisposition, age at menarche, physical activity and history of other diseases were evaluated using questionnaire. Data analysis was performed by a logistic regression test using SPSS software version 15 Predictive analytics software and solutions. RESULTS: There were a significant association between PCOS and ovarian disease (P < 0.001), age (P < 0.001) and using medication (P = 0.001). Body mass index (BMI) was inversely associated with PCOS, but it was not significant (P = 0.068). There was a significant direct relationship between milk consumption and risk of PCOS after adjusting for confounding factors (P = 0.028). CONCLUSIONS: The findings of this study indicated that ovarian disease and medication use is directly linked to PCOS. Dairy consumption was not significantly correlated with PCOS. However, after adjustment for confounders, there was an direct relationship between milk consumption and risk of PCOS. PMID- 25013688 TI - World health organization-body mass index for age criteria as a tool for prediction of childhood and adolescent morbidity: a novel approach in southern karnataka, India. AB - BACKGROUND: Health status of children and adolescents is determined to a larger extent by their nutritional status. There are no published studies available on the influence of thinness on childhood morbidity using new World Health Organization-body mass index (WHO-BMI) for age criteria. METHODS: This cross sectional study was conducted in primary, high schools, pre-university and degree colleges at southern Karnataka for a period of 1 year. RESULTS: Majority 6924 (53.6%) were in the age group of 15-19 years with the mean age of 14.2 +/- 3.1 years. 6167 (47.7%) were males and 6749 (52.3%) were females. As per WHO growth standards for children between 5 and 19 years, taking BMI for age criteria into account, 9092 (70.4%) subjects were found to be normal, 3660 (28.3%) thin and 164 (1.3%) overweight/obesity. 8224 (63.7%) subjects were suffering from some sort of morbidities. Mean morbidities rank for subjects with thinness was found to be significantly higher compared with normal and overweight/obese subjects. Thinness was found to be the major predictor of morbidity age, sex and residing in rural areas. CONCLUSIONS: Magnitude of thinness among children and adolescents was 28.3%. BMI for age criteria was found to be a significant predictor of childhood and adolescent morbidity. PMID- 25013689 TI - Veterans and risk of heart disease in the United States: a cohort with 20 years of follow up. AB - BACKGROUND: THE AIM OF THE CURRENT STUDY WAS TWOFOLD: To investigate the effect of veteran status on risk of developing heart disease over a period of 20 years in the United States and to test if socio-economic characteristics, chronic conditions, health behaviors, body mass index (BMI) and depressive symptoms explain the association between veteran status and risk of heart disease. METHODS: Data came from the Health and Retirement Study, a 20 year national cohort from 1992 to 2012. The study enrolled a representative sample of Americans over the age of 50. We included 8,375 individuals who were older than 50 years at entry, did not have heart disease at baseline and provided data on heart disease over the next 20 years. Veteran status was considered to be the independent variable. Self-reported data on physician diagnosis of heart disease, which was measured on a biannual basis, was the outcome. Baseline socio-economic data (i.e. age, gender, race, marital status and education), chronic conditions (diabetes and hypertension), health behaviors (i.e. drinking, smoking, and exercise), BMI and depressive symptoms (modified Center for Epidemiologic Studies Depression Scale) were entered into logistic regressions. Logistic regression was used for data analysis. RESULTS: Veterans were at higher risk of having a new onset of heart disease (unadjusted relative risk [RR] = 1.996, 95% confidence interval [CI] =1.694-2.351), compared with non-veterans. Logistic regression confirmed the association between veteran status and heart disease (adjusted RR = 1.483, 95% CI = 1.176-1.871) after controlling for all covariates. CONCLUSIONS: Veterans may be at higher risk for heart disease over time and this link may be independent of baseline socio-economic characteristics, chronic medical conditions, health behaviors, BMI and depressive symptoms. Veterans may require more rigorous cardiovascular prevention programs. PMID- 25013690 TI - The effects of legumes on metabolic features, insulin resistance and hepatic function tests in women with central obesity: a randomized controlled trial. AB - BACKGROUND: The effect of high-legume hypocaloric diet on metabolic features in women is unclear. This study provided an opportunity to find effects of high legume diet on metabolic features in women who consumed high legumes at pre-study period. METHODS: In this randomized controlled trial after 2 weeks of a run-in period on an isocaloric diet, 42 premenopausal women with central obesity were randomly assigned into two groups: (1) Hypocaloric diet enriched in legumes (HDEL) and (2) hypocaloric diet without legumes (HDWL) for 6 weeks. The following variables were assessed before intervention and 3 and 6 weeks after its beginning: Waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting serum concentrations of triglyceride (TG), high density lipoprotein cholesterol, fasting blood sugar (FBS), insulin, homeostasis model of insulin resistance (HOMA-IR), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We used multifactor model of nested multivariate analysis of variance repeated measurements and t-test for statistical analysis. RESULTS: HDEL and HDWL significantly reduced the WC. HDEL significantly reduced the SBP and TG. Both HDEL and HDWL significantly increased fasting concentration of insulin and HOMA-IR after 3 weeks, but their significant effects on insulin disappeared after 6 weeks and HDEL returned HOMA-IR to basal levels in the subsequent 3 weeks. In HDEL group percent of decrease in AST and ALT between 3(rd) and 6(th) weeks was significant. In HDWL group percent of increase in SBP, DBP, FBS and TG between 3(rd) and 6(th) weeks was significant. CONCLUSIONS: The study indicated beneficial effects of hypocaloric legumes on metabolic features. PMID- 25013691 TI - Prophylactic Use of Oral Acetaminophen or IV Dexamethasone and Combination of them on Prevention Emergence Agitation in Pediatric after Adenotonsillectomy. AB - BACKGROUND: The present study was aimed to evaluate the efficacy of acetaminophen plus dexamethasone on post-operative emergence agitation in pediatric adenotonsillectomy. METHODS: A total of 128 patients were randomized and assigned among four groups as: Intravenous (IV) dexamethasone, oral acetaminophen, IV dexamethasone plus oral acetaminophen, placebo. Group 1 received 0.2 mg/kg dexamethasone plus 0.25 mg/kg strawberry syrup 2 h before surgery. Group 2 received 20 mg/kg oral acetaminophen (0.25 ml/kg) with 0.05 ml/kg IV normal saline. Group 3 received 20 mg/kg acetaminophen and 0.2 mg/kg dexamethasone intravenously. Group 4 received 0.25 ml/kg strawberry syrup and 0.05 ml/kg normal saline. Agitation was measured according to Richmond agitation sedation score in the post anesthetic care unit (PACU) after admission, 10, 20 and 30 min after extubation. Pain score was measured with FACE scale. Nurse satisfaction was measured with verbal analog scale. If agitation scale was 3 >= or pain scale was 4 >= meperidine was prescribed. If symptoms did not control wit in 15 min midazolam was prescribed. Patients were discharged from PACU according Modified Alderet Score. Data were analyzed with ANOVA, Chi-square, and Kruskal-Wallis among four groups. P < 0.05 was considered statistically significant. RESULTS: A total of 140 patients were recruited in the study, which 12 of them were excluded. Thus, 128 patients were randomized and assigned among four groups. The four treatment groups were generally matched at baseline data. Median of pain score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001, 0.003 respectively). Also median of agitation score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001). Incidence of pain and incidence of agitation after extubation were not statistically identical among groups (P < 0.001 and P = 0.002 respectively). Mean of recovery time, duration of agitation and 1(st) time to agitation appearance, meperidine and midazolam consumption, nurse satisfaction and complication frequency were not statistically identical among groups (P < 0.001). CONCLUSIONS: Acetaminophen, dexamethasone and combination of them are superior to placebo for prevention of agitation after adenotonsillectomy in children. Furthermore combinations of both drugs are superior to acetaminophen or dexamethasone separately. PMID- 25013692 TI - Supplementation of Eurycoma longifolia Jack Extract for 6 Weeks Does Not Affect Urinary Testosterone: Epitestosterone Ratio, Liver and Renal Functions in Male Recreational Athletes. AB - BACKGROUND: Eurycoma longifolia Jack (ElJ) has been shown to elevate serum testosterone and increased muscle strength in humans. This study investigated the effects of Physta((r)) a standardized water extract of ElJ (400 mg/day for 6 weeks) on testosterone: epitestosterone (T:E) ratio, liver and renal functions in male recreational athletes. METHODS: A total of 13 healthy male recreational athletes were recruited in this double blind, placebo-controlled, cross-over study. The participants were required to consume either 400 mg of ElJ or placebo daily for 6 weeks in the first supplementation regimen. Following a 3 week wash out period, the participants were requested to consume the other supplement for another 6 weeks. Mid-stream urine samples and blood samples were collected prior to and after 6 weeks of supplementation with either ElJ or placebo. The urine samples were subsequently analyzed for T:E ratio while the blood samples were analyzed for liver and renal functions. RESULTS: T:E ratio was not significantly different following 6 weeks supplementation of either ElJ or placebo compared with their respective baseline values. Similarly, there were no significant changes in both the liver and renal functions tests following the supplementation of ElJ. CONCLUSIONS: Supplementation of ElJ i.e. Physta((r)) at a dosage of 400 mg/day for 6 weeks did not affect the urinary T:E ratio and hence will not breach any doping policies of the International Olympic Committee for administration of exogenous testosterone or its precursor. In addition, the supplementation of ElJ at this dosage and duration was safe as it did adversely affect the liver and renal functions. PMID- 25013693 TI - Survey on air pollution and cardiopulmonary mortality in shiraz from 2011 to 2012: an analytical-descriptive study. AB - BACKGROUND: Expanding cities with rapid economic development has resulted in increased energy consumption leading to numerous environmental problems for their residents. The aim of this study was to investigate the correlation between air pollution and mortality rate due to cardiovascular and respiratory diseases in Shiraz. METHODS: This is an analytical cross-sectional study in which the correlation between major air pollutants (including carbon monoxide [CO], sulfur dioxide [SO2], nitrogen dioxide [NO2] and particle matter with a diameter of less than 10 MU [PM10]) and climatic parameters (temperature and relative humidity) with the number of those whom expired from cardiopulmonary disease in Shiraz from March 2011 to January 2012 was investigated. Data regarding the concentration of air pollutants were determined by Shiraz Environmental Organization. Information about climatic parameters was collected from the database of Iran's Meteorological Organization. The number of those expired from cardiopulmonary disease in Shiraz were provided by the Department of Health, Shiraz University of Medical Sciences. We used non-parametric correlation test to analyze the relationship between these parameters. RESULTS: The results demonstrated that in all the recorded data, the average monthly pollutants standard index (PSI) values of PM10 were higher than standard limits, while the average monthly PSI value of NO2 were lower than standard. There was no significant relationship between the number of those expired from cardiopulmonary disease and the air pollutant (P > 0.05). CONCLUSIONS: Air pollution can aggravate chronic cardiopulmonary disease. In the current study, one of the most important air pollutants in Shiraz was the PM10 component. Mechanical processes, such as wind blowing from neighboring countries, is the most important parameter increasing PM10 in Shiraz to alarming conditions. The average monthly variation in PSI values of air pollutants such as NO2, CO, and SO2 were lower than standard limits. Moreover, there was no significant correlation between the average monthly variation in PSI of NO2, CO, PM10, and SO2 and the number of those expired from cardiopulmonary disease in Shiraz. PMID- 25013694 TI - Trends in Weaning Practices among Infants and Toddlers in a Hilly Terrain of a Newly Formed State of India. AB - BACKGROUND: Weaning plays a major role in determining the nutritional status of a child. Poor weaning practices during infancy and early childhood, resulting in malnutrition, contribute to impairment of cognitive and social development, poor school performance and reduced productivity in later life. The objective of this study is to know weaning practices of mothers of difficult terrain. METHODS: Cross-sectional study was conducted in all villages under Rural Health Training Center, the field practice area of Department of Community Medicine. A total of 500 mothers with children within 3 years of age were included in the study. Pre tested pre-designed semi-structured questionnaire was used to collect information on weaning practices. RESULTS: Majority of children (51.57%) were weaned at >6 months and were observed to be more under nourished (79.34%) as compared with those between 4 months and 6 months (61.50%). Majority of boys were weaned earlier than girls irrespective of the age of the weaning. Malnutrition was found in majority of those children who were weaned inadequately in terms of both frequency and amount. CONCLUSIONS: The present study revealed suboptimal weaning practices among the mothers of hilly region. Thus, appropriate educational strategies should be directed particularly on counteracting various myths related to infant feeding Moreover, promotion of appropriate feeding should target not only on maternal caregivers, but also on other family members, particularly husbands and grandmothers, taking into account the social and cultural situation of the area. PMID- 25013695 TI - Cross-sectional Study to Acknowledge the Independent Association of the Socio demographic Determinants of Alcohol Use in an Urban Slum of North India. AB - BACKGROUND: To seek pleasure is man's innate nature. In his search for gratification, man has discovered a world of substances that intoxicated him. Those who fell within its trap, their life changed, their families aggrieved and they shrank from company. The addiction remained alone in the end. To many death was a relief. METHODS: A community based cross- sectional study was conducted in the Catchment area of UHTC (Urban Health and training Centre) where all males aged >=15 years residing in the study area were included. Data was collected by home visit using WHO questionnaire ( AUDIT: Alcohol use disorder identification test) Modified Kuppuswamy scale was used to assess the socio-economic status of the families. Data was analyzed by appropriate test using SPSS 20.0 version. Logistic regression was applied to the positively associated results. RESULTS: According to the AUDIT score, Hazardous, Dependent and harmful drinkers were 7.7%, 9.2% and 2.4% respectively. Age, marital status, education of the head of the family, occupation of the respondent, caste, family history of alcohol use had statistically significant association (P < 0.05, 95% confidence interval). Logistic regression was applied and marital status, family history of alcohol use and caste retained their statistical significance (P < 0.05, 95% confidence interval). CONCLUSIONS: It can be concluded that being young, being low educated, being married and having a family history of alcohol use are more at risk to it. This indicates the dire necessity to consider the above factors in order to combat with this evil of alcohol use. PMID- 25013696 TI - Follow-up Assessment of Under-nourished Children Under Integrated Child Development Services Scheme in Tapi District, India. AB - BACKGROUND: India shares the largest burden of under-nutrition in world. The aim of this study was to conduct follow-up assessment of under-nourished children attending anganwadi center (AWC). METHODS: This was a retrospective cohort study conducted in 50 AWC of Tapi district. Total 529 children aged 1-6 years diagnosed as under-nourished before 1 year were included. Pre-structured questionnaire was used for present day assessment of these children followed by Epi-info mediated analysis. RESULTS: Children of literate mothers had higher weight gain. Ninety percent of children attended anganwadi regularly, however 25% of children dropped out for more than 1 month. In 1 year, growth had faltered in 20% children and was stagnant in 63% of them. Children who were treated for under-nutrition; that completed course at Child Development and Nutrition Center; and whose parents were counseled about the under-nourished status of child had higher weight gain than their counterparts. CONCLUSIONS: Parents of under-nourished children must be counseled about the nutritional status of their child. In cases of under nourished child, referral to higher center must be ensured by health worker. Supplementary feeding as a long-term solution to country's under-nutrition problem should be studied in detail with the alternative solutions. PMID- 25013697 TI - In Vitro Impact of Hydro-alcoholic Extract of Rosa damascena Mill. on Rat Ileum Contractions and the Mechanisms Involved. AB - BACKGROUND: The petal's hydro-alcoholic extract of Rosa damascena Mill. on ileum contractions of Wistar rats and its possible mechanism were investigated. METHODS: Forty-eight male Wistar rats were divided into six groups. Ileum was placed adjacent to propranolol (1 MUM), naloxone (1 MUM) and L-NAME (100 MUM) and also under the influence of different doses (2-8 mM) of calcium chloride. RESULTS: Cumulative extract of R. damascena Mill. (100, 500, and 1000 mg/L) decreased ileum contractions induced by KCl (60 mM) in a dose-dependent manner (P < 0.0001). Propranolol and naloxone significantly decreased the inhibitory effect of the extract on contractions induced by KCl (P < 0.001), but L-NAME was ineffective. Furthermore, calcium led to the contraction of depolarized tissue through KCI and this contractile effect decreased significantly induced by the cumulative concentrations of the extract (P < 0.001). CONCLUSIONS: The results indicate that R. damascena Mill. dose-dependently (100, 500, and 1000 mg/L) decreases ileum movements of the rat probably through stimulating the beta adrenergic and opioid receptors and voltage-dependent calcium channels, and it may be used to treat digestive disorders. PMID- 25013698 TI - Pattern of Use of Earphone and Music Player Devices among Iranian Adolescents. AB - BACKGROUND: There is no information about the pattern of use of earphones and music players in Iranian adolescents. The aim of this study was to assess the prevalence and pattern of the use of earphone and music player devices as a main risk factor for hearing loss in adolescents of Tabriz city, northwest of Iran. METHODS: In this cross-sectional study in November 2011, 2,359 high school students were randomly selected and were asked to complete a 20-item questionnaire about the pattern of using earphones and music players. RESULTS: The results showed that 44.3% [confidence interval (CI) 95%: 38.3-50.3] of the respondents had a history of hearing problems that was significantly different between males and females (42.2% of males and 47% of females, p: 0.02). Notably, 36.8% of the participants stated that they listened to music without any rest or stop. Almost 49.6% (CI 95%: 44.4-54.4) of the students reported listening to 'somewhat loud' (gain setting at 50%) or 'very loud' (gain setting more than 50%) volume level of music. In terms of the kind of earphones, 17.1% of the participants used headphones, 34.8% used earbud-style headphones, 32.3% used supra-aural headphones, and 15.8% of them did not use any type of earphones. CONCLUSIONS: Students have risky patterns of using earphones and music-listening devices. Planning educational programs in this domain for adolescents especially in high schools is necessary. PMID- 25013699 TI - A Single-subject Study to Examine the Effects of Constrained-induced Aphasia Therapy on Naming Deficit. AB - Aphasia is prevalent in people following stroke, which can have a significant impact on the quality of life of the patients with stroke. One of the new methods for treatment of patients with aphasia is constraint-induced aphasia therapy (CIAT). The aim of this study was to investigate the efficacy of CIAT on naming deficits in individuals with chronic aphasia. This study had a prospective, single-subject study with A-B-A design. The CIAT was administered to two patients with chronic aphasia. Participants were a 57-year-old male and a 45-year-old female and had a stroke 60 and 36 months ago, respectively. In this study, the naming test was used as the outcome measure. The naming test was administered in three baseline sessions with 1 week interval between tests (phase A). Patients received CIAT for four consecutive weeks (3 days/week). Four measurements were taken during the treatment phase (phase B). In follow-up phase (phase A) two other measurements were performed. Visual analysis consisting of level, regression line, and variability were used to determine the effects of CIAT on naming. Both participants increased scores on naming test after phase A and B. The mean of the naming score improved from the baseline to the intervention phase in both participants. There was a positive trend in naming scores during the treatment phase compared with the trend in the baseline demonstrated by both participants. The results of this study showed that the CIAT can be effective in improving the naming deficit in patients with chronic post-stroke aphasia. PMID- 25013700 TI - Effect of yogic breathing techniques in new sputum positive pulmonary tuberculosis. AB - A 24-year-old, unmarried woman diagnosed of pulmonary tuberculosis (PTB) visited our hospital out-patient department in the month of August-2013. Patient came with the complaint of sever cough with expectoration; evening raise of temperature; gradual loss of appetite and weight since 2-weeks. We referred the patient to our hospital's Revised National Tuberculosis Program, direct observed treatment short-course center for sputum fluorescence microscopic examination (FME). FME report suggested the new smear positive, 2+ PTB. Our patient received yogic breathing techniques (YBT) for 45-min daily under the supervision for three alternate-days/week with anti-tuberculosis treatment (ATT) for the period of 8 weeks. After intervention our result showed better improvement in weight gain, body mass index, symptom scores, pulmonary function and health related quality of life with conversion of positive to negative FME for acid fast bacilli. It suggests YBT with ATT are effective in treating PTB and further studies required to warrant this effect. PMID- 25013701 TI - Breastfeeding reduces breast cancer risk: a case-control study in north India. AB - BACKGROUND: Worldwide, breast cancer is the most common cancer among women. In India and other developing countries, breast carcinoma ranks second only to cervical carcinoma among women. Although studies have been done globally, to find the association between breastfeeding and breast cancer, very few studies in India document such a benefit. METHODS: A case-control study was done from August 2009 to July 2010 in the wards of General Surgery and Oncosurgery at Pt. B. D. Sharma PGIMS, Rohtak, Haryana, India. A total of 128 histopathologically confirmed new cases of breast cancer during the study period were taken as cases. Equal numbers of controls were selected by simple random sampling. Controls were matched for age with a range of +/- 2 years. Subjects were interviewed using a pretested questionnaire after obtaining written informed consent. The categorical data were analyzed statistically using the Chi-square test and odds ratio with a 95% confidence interval. Continuous variables were analyzed using an independent t-test. All the analysis was done using SPSS, version 17. RESULTS: The age group of the cases was 25-78 years, while that of the controls was 24-79 years. The proportions of cases (56.3%) and controls (63.3%) living in rural areas were more than those living in urban areas. A significant association of breast cancer cases was found with caste, age at marriage, age at the first pregnancy, number of live births, and lifetime duration of breastfeeding. CONCLUSIONS: Breastfeeding has a significant role in reducing breast cancer, and so information, education, and communication activities for the promotion of breastfeeding and creating awareness about this fatal disease are the need of the hour. PMID- 25013702 TI - Prevalence of vitamin d deficiency and its related factors among university students in shiraz, iran. AB - BACKGROUNDS: Vitamin D deficiency is a public health concern even in sunny areas, so we decided to assess the prevalence of vitamin D deficiency and its related factors among university students in Shiraz. METHODS: This cross-sectional study was carried out on 254 (128 male and 126 female) university students. Demographic questionnaires and a questionnaire on exposure to sun light and sun protection were completed by the participants. Serum 25OH-vitamin D was measured using a radioimmunoassay kit. Data analysis was done using Statistical Package for Social Sciences (SPSS) software # 16. A P value less than 0.05 was considered as significant. RESULTS: Mean +/- standard deviation (SD) of serum 25OH-vitamin D was 49.29 +/- 12.87 (nmol/l) and 27.46 +/- 10.37 (nmol/l) among male and female students, respectively. 51.2% of female students were vitamin D insufficient and 44% of them had vitamin D deficiency. Prevalence of vitamin D insufficiency and marginal status among male students were 49.5 and 48%, respectively. Serum vitamin D of female students was significantly less than the males (P < 0.001). Serum vitamin D was negatively correlated to sun protection score (P < 0.001, r = 0.50), but there was no correlation between serum vitamin D and sun exposure. CONCLUSIONS: Vitamin D deficiency especially among female students is alarmingly prevalent. Increasing use of sunscreen lotion and clothing style could be the main factors inhibiting endogenous vitamin D synthesis which results in its deficiency. PMID- 25013703 TI - Re: "Protective Role of Silymarin and Deferoxamine against Iron Dextran-Induced Renal Iron Deposition in Male Rats," and "Co-Administration of Silymarin and Deferoxamine against Kidney, Liver and Heart Iron Deposition in Male Iron Overload Rat Model". PMID- 25013704 TI - Re-emergence of Wild Polio Virus in East Mediterranean Region: A Threat to World Polio Eradication Program Initiatives? PMID- 25013706 TI - Maternal Intensive Care': a systematic literature review. AB - OBJECTIVE: The objective of this systematic literature review is to review current scientific knowledge on the definition of and the indications for maternal/obstetric intensive care (MIC). METHODS: We conducted a extensive search in OVID MEDLINE, EMBASE, COCHRANE, CINHAL and CEBAM using the keywords: maternal/obstetric intensive care, subacute care, intermediate care, postacute care, critical care, sub intensive care, progressive patient care, postnatal care, perinatal care, obstetrical nursing, neonatology, pregnancy, maternal mortality/morbidity and pregnancy complication. A total of 180 articles and one guideline were identified and supplemented by a hand search. After title, abstract and full text evaluation, the articles and guideline were subjected to critical appraisal. RESULTS: Out of 180 potentially relevant articles, we identified 44 eligible articles of which 14 relevant MIC-articles of relatively good quality were selected. The concept 'maternal intensive care' was not found elsewhere, "high-dependency care" and "obstetrical intermediate care" appeared to be best comparable to what is understood as a MIC-service in Belgium. This thorough literature search resulted in a limited amount of scientific literature, with most studies retrospective observational tertiary centre based. No clear definition and admission criteria for maternal intensive care were found. CONCLUSION: This systematic literature review revealed that 1) there is no standard definition of maternal intensive care and 2) that admission criteria to a MIC unit differ widely. Further research is needed to create an evidence-based triage system to help clinicians attribute women to the appropriate level of care and thus stimulate an efficient utilization of maternal/obstetric intensive care services. PMID- 25013705 TI - Adhesion formation after laparoscopic surgery: what do we know about the role of the peritoneal environment? AB - In spite of the approaches that have been proposed to reduce postoperative peritoneal adhesions, they remain a major clinical problem because of the associated intestinal obstruction, chronic pelvic pain, female infertility and difficulties at the time of reoperation. The pathogenesis of the process have been focused almost exclusively on the local events induced by the surgical trauma, and the strategies for adhesion prevention thus focused on barriers to separate surgically denuded areas. The important role of the peritoneal cavity environment only recently became apparent and is not yet incorporated in adhesion reducing strategies. Recent data demonstrate that, in the presence of a direct surgical trauma, the entire peritoneal environment is quantitatively the most important factor in adhesion formation and hence adhesion prevention after both open and laparoscopic surgery. Indeed mesothelial hypoxia (CO2 pneumoperitoneum) or hyperoxia (open surgery), desiccation and surgical manipulation have been identified as factors cumulatively enhancing adhesions--. The clinical implication is especially relevant for laparoscopic surgery because the pneumoperitoneum, being a closed environment, can be easily conditioned. Although human studies are lacking, animal data indicate that peritoneal adhesions can be reduced by over 80% with a good surgical technique, with adequate pneumoperitoneum conditioning as adding 3-4% of oxygen to the CO2 pneumoperitoneum, prevention of desiccation and slight cooling. Adhesion prevention barriers remain additionally effective, although quantitatively less important. The relevance of all these strategies for adhesion prevention still have to be confirmed in humans, but since it seems that the peritoneal environment is quantitatively much more important than the surgical trauma, adhesion prevention research and strategies should be directed more to conditioning the peritoneal cavity than to the use of agents. PMID- 25013707 TI - Reproductive efficiency of human oocytes fertilized in vitro. PMID- 25013708 TI - Treatment of the menopause: the swinging pendulum. PMID- 25013709 TI - Infertility in public health: the case of Norway. AB - Infertility is a health issue that demonstrates how unequal access to health care is at a global level. In the poorer segments-- of the world, and in poor parts of wealthy societies, access is often minimal or non-existent. Public and lay attitudes to modern infertility treatment have been heavily debated alongside development of methods. I have looked at the changes in the public discourse in modern media, legislation, politics, and among professionals. The paper seeks to present and discuss some of these changes as they have evolved in one of the countries that have had one of the more strict laws regulating access to treatment, namely Norway. It is a country that nevertheless offers treatment in the public health system. The paper also tries to connect this discussion to the difficulties faced in every attempt to expand-- infertility services to the developing world. PMID- 25013710 TI - Exploring the functionality of the adult's venous compartment is of interest to the field of obstetrics. PMID- 25013713 TI - Editorial. PMID- 25013711 TI - Cervical length measured by transvaginal ultrasonography versus Bishop score to predict successful labour induction in term pregnancies. AB - OBJECTIVES: To compare the value of transvaginal ultrasonographic measurement of the cervical length versus the Bishop score, prior to induction of labour, in predicting the mode of delivery within four days. MATERIALS AND METHODS: This longitudinal study included 110 women (at term, singleton, vertex presentation) in whom induction of labour was performed at 37-42 weeks of gestation. Cervical length on transvaginal ultrasound and the Bishop score were assessed prior to induction according to standard protocol. Medical records were reviewed for relevant-- demographic and clinical data. Primary outcome criterion was successful vaginal delivery within 96 h. Univariate analyses and receiver operating characteristic (ROC) curves were used to examine differences between variables possibly predicting outcome. RESULTS: Of the 110 women 66 were nulliparous and 44 multiparous. Vaginal delivery within 96 h was successful in 48 (73%) nulliparous and in 40 (91%) multiparous women ( i.e. in 80% of the total population). The overall rate of caesarean delivery was 17%. THERE WAS A SIGNIFICANT DIFFERENCE BETWEEN NULLIPAROUS AND MULTIPAROUS WOMEN IN AGE, CERVICAL LENGTH (MEAN IN MM IN NULLIPAROUS WOMEN: 29.31, range: 5.00-56.00; in multiparous women: 37.04, range: 12.00-56.00), Bishop score and successful induction, but no significant difference between these subgroups in neonatal outcomes. Only the Bishop score in nulliparous women showed a significant relationship between this variable and predicting successful labour induction (area under the ROC curve 0.679; standard error 0.73; p < 0.05; 95% CI: 0.536-0.823). The best cut-off value for the Bishop score was 3, with a sensitivity of 56.3% and a specificity of 72.2%. CONCLUSION: In this study group significant independent prediction of vaginal delivery within 96 h is provided by the Bishop score but only in nulliparous women. Transvaginal ultrasonographic measurement of cervical length is not a significant independent predictor of vaginal delivery within 96 h. PMID- 25013715 TI - Prevalence of thrombophilic gene polymorphisms in an azari population of iran. AB - There is several evidence suggests that thrombophilic gene polymorphisms may influence susceptibility to thromboembolic events. The prevalence of these polymorphisms is different in various races and ethnics. Accordingly, we studied the prevalence of Factor V (G1691A and A4070G), prothrombin G20210A and PAI-1 4G/5G in healthy northwest population of Iran. In this prospective study, 500 healthy individuals, who had no history of both personal and family history of thromboembolic disorders, were selected as a sample of healthy population in northwestern Iran. Genotyping of these polymorphisms was performed using the amplification refractory mutation system-polymerase chain reaction method. No significant differences were detected between the expected and observed frequencies of FV G1691A and A4070G, prothrombin G20210A polymorphisms (P>0.05), while the expected frequency of 4G allele was significantly more than observed frequency in the studied population (P<0.01). These findings were compared with other reports from various populations. In conclusion, the allele frequency for FV G1691A and PAI-1 4G/5G polymorphisms showed relative consistency compared to those of previous studies, while the incidence pattern of FV A4070G polymorphism in Northwestern population of Iran showed conflicting results regarding other studied population. The prothrombin G20210A polymorphism was observed at a higher frequency than other studied populations. PMID- 25013712 TI - Biomedical infertility care in sub-Saharan Africa: a social science-- review of current practices, experiences and view points. AB - Some sort of infertility treatments, including the use of advanced reproductive technologies (ARTs), is nowadays provided at several places in sub-Saharan Africa. Yet, to date only a few studies have actually looked into the way these treatments are offered, used and experienced. In this review article the authors present and discuss empirical study findings that give insight into the way biomedical infertility care is provided, considered, experienced and/or used in sub-Saharan African countries. They concentrate on four themes that were often referred to in the reviewed studies and underline the importance of taking into account the local sociocultural context and notions when developing and implementing infertility care, namely: counselling, male involvement, acceptability of ARTs and the use of donor material (semen and embryos). In the conclusion the authors emphasize the importance of preventing infertility as part of integrated reproductive health programs and the need to improve the quality of (low tech) infertility care in the public health sector by means of standardized guidelines, training of health staff and improved counselling. In addition, from a reproductive rights perspective, they support initiatives to introduce low cost ARTs to treat tubal factor related infertility. They also point to potential unintended side effects of the introduction of ARTs and the use of donor material in the sub-Saharan African context, affecting gender inequity and inequity between citizens from different social classes, and argue that such effects should be acknowledged and avoided by all possible means. Finally, they present an agenda for future social science research on this topic in sub-Saharan Africa. PMID- 25013714 TI - Development of Myasthenia Gravis in a Patient with Chronic Myeloid Leukemia during Treatment with Nilotinib. AB - We report on a patient diagnosed with chronic myeloid leukemia (CML) who developed myasthenia gravis while on treatment with nilotinib. Autoimmune disease, including the development of myasthenia gravis, has been described in association with CML as well as the use of tyrosine kinase inhibitors. Second generation tyrosine kinase inhibitors are highly effective in the treatment of CML, although can result in adverse effects related to off-target kinase inhibition, and longer term reporting of adverse effects is required. PMID- 25013716 TI - Hemophagocytic lymphohistiocytosis and pelger-huet anomaly associated with colchicine intoxication. AB - Colchicine is frequently used in the treatment of familial Mediterranean fever (FMF). First symptoms of colchicine intoxication are gastrointestinal disturbances, such as abdominal cramps, diarrhea, pancytopenia and so on. Herein, we report a female FMF patient with pancytopenia and hemophagocytic lymphohitiocytosis (HLH), following colchicine intoxication for committing suicide. To our knowledge, this is the first reported case of a patient with HLH associated with colchicine intoxication. PMID- 25013717 TI - Multiparameter Flow Cytometry to Detect Hematogones and to Assess B-lymphocyte clonality in Bone Marrow Samples from Patients with Non-Hodgkin Lymphomas. AB - Hematogones are precursors of B-lymphocytes detected in small numbers in the bone marrow. Flow cytometry is the most useful tool to identify hematogones and, so far, 4-color methods have been published. In addition, flow cytometry is used in the diagnosis and follow-up of lymphomas. We developed a flow cytometric 7-color method to enumerate hematogones and to assess B-lymphocyte clonality for routine purposes. We evaluated 171 cases of B-cell non-Hodgkin lymphomas, either at diagnosis or in the course of follow-up. By our diagnostic method, which was carried out by the combination K/lambda/CD20/CD19/CD10/CD45/CD5, we were able to detect hematogones in 97.6% of samples and to distinguish normal B-lymphocytes, neoplastic lymphocytes and hematogones in a single step. The percentage of hematogones showed a significant inverse correlation with the degree of neoplastic infiltration and, when bone marrow samples not involved by disease were taken into consideration, resulted higher in patients during follow-up than in patients evaluated at diagnosis. PMID- 25013718 TI - Intensive serial biomarker profiling for the prediction of neutropenic Fever in patients with hematologic malignancies undergoing chemotherapy: a pilot study. AB - Neutropenic fever (NF) is a life-threatening complication of myelosuppressive chemotherapy in patients with hematologic malignancies and triggers the administration of broad-spectrum antimicrobials. The ability to accurately predict NF would permit initiation of antimicrobials earlier in the course of infection with the goal of decreasing morbid complications and progression to septic shock and death. Changes in the blood level of inflammatory biomarkers may precede the occurrence of NF. To identify potential biomarkers for the prediction of NF, we performed serial measurements of nine biomarkers [C-reactive protein (CRP), protein C, interleukin (IL)-6, IL-8, IL-10, IL-1beta, tumor necrosis factor-alpha, monocyte chemotactic protein-1, and intercellular adhesion molecule 1] using a multiplex ELISA array platform every 6-8 hours in patients undergoing myelosuppressive chemotherapy for hematologic malignancies. We found that the blood levels of IL-6 and CRP increased significantly 24 to 48 hours prior to the onset of fever. In addition, we showed that frequent biomarker monitoring is feasible using a bedside micro sample test device. The results of this pilot study suggest that serial monitoring of IL-6 and CRP levels using a bedside device may be useful in the prediction of NF. Prospective studies involving a larger cohort of patients to validate this observation are warranted. This trial is registered at ClinicalTrials.gov (NCT01144793). PMID- 25013719 TI - Ugi 4-CR Synthesis of gamma- and delta-Lactams providing new access to diverse enzyme interactions, a PDB analysis. AB - A three step synthesis of N-unsubstituted tetrazolo gamma- and delta-lactams involving a key Ugi-4CR is presented. The compounds, otherwise difficult to access, are conveniently synthesized in overall good yields by our route. PDB analysis of the N-unsubstituted gamma- and delta-lactam fragment reveals a strongly tri-directional hydrogen bond donor acceptor interaction with the amino acids of the binding sites. PMID- 25013720 TI - Essential medicines in Tanzania: does the new delivery system improve supply and accountability? AB - Objective: Assess whether reform in the Tanzanian medicines delivery system from a central 'push' kit system to a decentralized 'pull' Integrated Logistics System (ILS) has improved medicines accountability. Methods: Rufiji District in Tanzania was used as a case study. Data on medicines ordered and patients seen were compiled from routine information at six public health facilities in 1999 under the kit system and in 2009 under the ILS. Three medicines were included for comparison: an antimalarial, anthelmintic and oral rehydration salts (ORS). Results: The quality of the 2009 data was hampered by incorrect quantification calculations for orders, especially for antimalarials. Between the periods 1999 and 2009, the percent of unaccounted antimalarials fell from 60 to 18%, while the percent of unaccounted anthelmintic medicines went from 82 to 71%. Accounting for ORS, on the other hand, did not improve as the unaccounted amounts increased from 64 to 81% during the same period. Conclusions: The ILS has not adequately addressed accountability concerns seen under the kit system due to a combination of governance and system-design challenges. These quantification weaknesses are likely to have contributed to the frequent periods of antimalarial stock-out experienced in Tanzania since 2009. We propose regular reconciliation between the health information system and the medicines delivery system, thereby improving visibility and guiding interventions to increase the availability of essential medicines. PMID- 25013721 TI - Emergency planning and management in health care: priority research topics. AB - Many major incidents have significant impacts on people's health, placing additional demands on health-care organisations. The main aim of this paper is to suggest a prioritised agenda for organisational and management research on emergency planning and management relevant to U.K. health care, based on a scoping study. A secondary aim is to enhance knowledge and understanding of health-care emergency planning among the wider research community, by highlighting key issues and perspectives on the subject and presenting a conceptual model. The study findings have much in common with those of previous U.S.-focused scoping reviews, and with a recent U.K.-based review, confirming the relative paucity of U.K.-based research. No individual research topic scored highly on all of the key measures identified, with communities and organisations appearing to differ about which topics are the most important. Four broad research priorities are suggested: the affected public; inter- and intra organisational collaboration; preparing responders and their organisations; and prioritisation and decision making. PMID- 25013722 TI - Using systems thinking in state health policymaking: an educational initiative. AB - In response to limited examples of opportunities for state policymakers to learn about and productively discuss the difficult, adaptive challenges of our health system, the Georgia Health Policy Center developed an educational initiative that applies systems thinking to health policymaking. We created the Legislative Health Policy Certificate Program - an in-depth, multi-session series for lawmakers and their staff - concentrating on building systems thinking competencies and health content knowledge by applying a range of systems thinking tools: behavior over time graphs, stock and flow maps, and a system dynamics based learning lab (a simulatable model of childhood obesity). Legislators were taught to approach policy issues from the big picture, consider changing dynamics, and explore higher-leverage interventions to address Georgia's most intractable health challenges. Our aim was to determine how we could improve the policymaking process by providing a systems thinking-focused educational program for legislators. Over 3 years, the training program resulted in policymakers' who are able to think more broadly about difficult health issues. The program has yielded valuable insights into the design and delivery of policymaker education that could be applied to various disciplines outside the legislative process. PMID- 25013723 TI - Association between peripheral muscle strength, exercise performance, and physical activity in daily life in patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Resistance training of peripheral muscles has been recommended in order to increase muscle strength in patients with Chronic Obstructive Pulmonary Disease (COPD). However, whether peripheral muscle strength is associated with exercise performance (EP) and physical activity in daily life (PADL) in these patients needs to be investigated. The aim of this study is to evaluate whether strength of the quadriceps muscle (QS) is associated with EP and daily PADL in patients with COPD. METHODS: We studied patients with COPD (GOLD A-D) and measured maximal isometric strength of the left QS. PADL was measured for 7 days with a SenseWear-Pro(r) accelerometer. EP was quantified by the 6-minute walk distance (6MWD), the number of stands in the Sit-to-Stand Test (STST), and the handgrip-strength. Univariate and multivariate analyses were used to examine possible associations between QS, PADL and EP. RESULTS: In 27 patients with COPD with a mean (SD) FEV1 of 37.6 (17.6)% predicted, QS was associated with 6MWD, STST, and handgrip-strength but not with PADL. Multiple linear regression analyses showed that QS was independently associated with the 6MWD (beta = 0.42, 95% CI 0.09 to 0.84, p = 0.019), STST (beta = 0.50, 95% CI 0.11 to 0.86, p = 0.014) and with handgrip-strength (beta = 0.45, 95% CI 0.05 to 0.84, p = 0.038). CONCLUSIONS: Peripheral muscle strength may be associated with exercise performance but not with physical activity in daily life. This may be due to the fact that EP tests evaluate patients' true abilities while PADL accelerometers may not. PMID- 25013724 TI - Distribution of estrogenic steroids in municipal wastewater treatment plants in Tehran, Iran. AB - BACKGROUND: Estrogenic steroids such as estrone (E1), 17beta-estradiol (E2), estriol (E3), and 17alpha-ethinylestradiol (EE2) are among the most potent endocrine disrupting compounds (EDCs). Compared with North America, Europe and Japan there is no reliable information on the concentration of steroid hormones in wastewater treatment plants (WWTPs) influents and effluents in Iran. The aim of the present study was to determine the amounts of E1, E2, E3, and EE2 influents and effluents of 7 municipal WWTPs across Tehran, the capital city of Iran, in two seasons, summer and autumn, through solid-phase extraction (SPE) gas chromatography-mass spectrometry (GC-MS). RESULTS: The results showed that the concentrations of E1, E2, and EE2 in influents ranged from 6.54-18.76 ng/L, 1.02 8 ng/L and 4.18-11.76 ng/L, respectively. Also, the concentrations of E1, E2, and EE2 in effluents ranged from 1.04-4.99 ng/L, 0.5-2.20 ng/L and 0.5-2.58 ng/L, respectively. The levels of E3 were below the detection limit (0.5 ng/L). The percentage removal rate of E1, E2 and EE2 ranged between 61.76-87.25%, 50.98 82.63%, and 66.3-90.25%, respectively. Results indicated no significant correlation between hormone concentrations and seasons. CONCLUSIONS: The study showed that WWTP number 7 had significant differences in influent hormone concentrations compared with others. Results only showed a significant relationship between hormones and TSS removal rate, but there was no significant relationship between hormones and COD removal rate. The removal rate of hormone in WWTP number 4 and 7 were significantly different from the others. There was no significant correlation between hormone concentrations and seasons. PMID- 25013725 TI - Optimization of biomass and biokinetic constant in Mazut biodegradation by indigenous bacteria BBRC10061. AB - Optimization based on appropriate parameters can be applied to improve a process. Mazut degradation as a critical issue in environment requires optimization to be efficiently done. To provide biodegradation conditions, experiments were designed on the least interactions among levels of parameters consisting of pH, Tween 80, glucose, phosphorous source, nitrogen source, and time. Kinetic constants and biomass were calculated based on 16 assays, designed using Taguchi method, which constructed various mazut biodegradation conditions. Kinetics of mazut degradation by newly isolated bacteria Enterobacter cloacae closely followed second order kinetic model. Results of the 16 experiments showed that biomass was in the range of 0.019 OD600 to 2.75 OD600, and biokinetic constant was in the range of 0.2 * 10(-5) L/ (mg day) to 10(-4) L/ (mg day). Optimal level for each parameter was obtained through data analysis. For optimal biomass equal to 2.75 OD600, optimal pH, Tween80, glucose, phosphorous source, and time were 8.3, 4 g/L, 4 g/L, 9 g/L, and 10 days, respectively. For biokinetic constant equal to 1.2 * 10(-4) L/ (mg day), optimal pH, Tween80, glucose, phosphorous source, and nitrogen source were 8.3, 1 g/L, 4 g/L, 1 g/L, and 9 g/L, respectively. The optimum levels for biomass and biokinetic constant were the same except the levels of the Tween 80, and phosphorous source. Consequently, mazut may be more degraded with adjusting the conditions on the optimum condition. PMID- 25013726 TI - Study of Body Composition and Metabolic Parameters in HIV-1 Male Patients. AB - Background. HIV patients on highly active antiretroviral therapy (HAART) containing protease inhibitors (PIs) had been often associated with lipodystrophy. However, there are only few studies on association of nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTI and NNRTI) with lipodystrophy. Study Design. One hundred and one HIV male patients were categorised into ART naive (n = 22), zidovudine (n = 22), stavudine (n = 18), tenofovir (n = 15), and PIs (n = 24) based HAART. Their clinicoepidemiological data had been entered in preformed pro forma. The body composition, using TANITA machine and metabolic parameters like lipid profile, blood sugars was analysed. Results. Clinically, lipoatrophy of face was most prevalent in HIV patients on stavudine (15 patients, 83.3%) and PIs (20 patients, 83.3%) based HAART. The mean BMI among study population was in normal range. Excess visceral fat was most prevalent among patients on PIs, 4 patients (16.7%). The waist-hip ratio was significantly higher in PIs (P = 0.01) based HAART. There was no significant difference among different study populations in terms of BMI (P = 0.917), body water (P = 0.318), body fat (P = 0.172), bone mass (P = 0.200), and muscle mass (P = 0.070). Hypertriglyceridiemia was found in stavudine, tenofovir, and protease inhibitors regimens. Low levels of high density lipoprotein (HDL) was found zidovudine, stavudine, and PIs regimens. Fasting and postprandial hyperglycaemia was found PIs and impaired glucose tolerance in stavudine regimen. Conclusion. Patients on PIs were associated with truncal obesity and lipoatrophy of face, along with dyslipidemia and hyperglycaemia. Stavudine based regimen is associated with hypertriglyceridiemia and low HDL along with lipoatrophy of face. PMID- 25013727 TI - A comparison of the glasgow coma scale score with full outline of unresponsiveness scale to predict patients' traumatic brain injury outcomes in intensive care units. AB - Background. Neurological assessment is an essential element of early warning scores used to recognize critically ill patients. We compared the performance of the Glasgow Coma Scale (GCS) with Full Outline of Unresponsiveness (FOUR) scale as an alternative method in the identification of clinically relevant outcomes in traumatic brain injury. Objective. The purpose of this study was to compare the performance of GCS with FOUR scale. Methods. For this study 104 patients with brain injury were recruited from the ICU of Taleghani Hospital, a major teaching hospital in Kermanshah in the western part of Iran. Data was collected concurrently from the ICU admissions by three well-educated nurses and then checked for accuracy by the researcher. Patients were followed up until two weeks or hospital discharge to record their survival status. As a final point expected risk of mortality was calculated using the original formulas for each scale. Results. The mean age of 104 participants was 41.38 +/- 18.22 (rang 17 to 86 years) mostly (81 patients 77.9%) males. The FOUR scale has a better prediction for death than GCS. Conclusion. It appears that FOUR scale had better predictive power for mortality and may be a suitable alternative or complementary tool for GCS. PMID- 25013728 TI - Living with stigma: depressed elderly persons' experiences of physical health problems. AB - The aim of this paper is to deepen the understanding of depressed elderly persons' lived experiences of physical health problems. Individual in-depth interviews were conducted with 15 depressed elderly persons who suffer from physical health problems. A hermeneutic analysis was performed, yielding one main theme, living with stigma, and three themes: longing to be taken seriously, being uncertain about whether the pain is physical or mental, and a sense of living in a war zone. The second theme comprised two subthemes, feeling like a stranger and feeling dizzy, while the third had one subtheme: afraid of being helpless and dependent on others. Stigma deprives individuals of their dignity and reinforces destructive patterns of isolation and hopelessness. Nurses should provide information in a sensitive way and try to avoid diagnostic overshadowing. Effective training programmes and procedures need to be developed with more focus on how to handle depressive ill health and physical problems in older people. PMID- 25013729 TI - Pharmacovigilance and moroccan tuberculosis public program: current situation. AB - The objective of this work is to demonstrate the interest of integration of pharmacovigilance in Moroccan Tuberculosis Control Program (MTCP). Design and Data Collection. The integration of pharmacovigilance in MTCP was conducted in October 2012 with the Global Fund support. We compared the reports notified before and after this integration (period 1: January 2010-October 2012; period 2: October 2012-December 2013). The detection of signals was based on the Information Component available in VigiMine. We used the SPSS version 10.0 and MedCalc version 7.3 for data analysis. Results. The average number of spontaneous reports increased from 3.6 to 37.4 cases/month (P < 10(-3)). The average age was 40.7 +/- 17.5 years; the sex ratio was 0.8. Hepatic reactions (32.7%) predominated during the first period, while skin reactions (24.1%) were in the second period (P = 10(-4)), and 40.9% of cases in the first period were serious against 15.8% in second period (P = 0.003). Nine signals were generated (hepatic enzyme increase, cholestasis, jaundice, arthralgia, acne, lower limb edema, pruritus, skin rashes, and vomiting). Conclusion. The integration of pharmacovigilance in Moroccan Tuberculosis Control Program improved the management of ADRs and detected new signals of antituberculosis drugs. PMID- 25013731 TI - Gingival vitiligo: report of a case and review of the literature. AB - Rarely cases have been reported regarding depigmented lesions of the oral cavity. On reviewing the literature, only few cases of gingival vitiligo or similar lesions have been reported till date. These lesions pose a cosmetic challenge. We present here a case of vitiligo affecting gingiva. Vitiligo has been defined as an acquired, slowly progressive loss of cutaneous pigment which occurs as irregular, sharply defined patches which may or may not be surrounded by macroscopic hyperpigmentation. Differential diagnosis, detailed clinical history, histopathology, immunohistochemistry, and pathogenesis of this condition are discussed. PMID- 25013730 TI - Esthetic rehabilitation of anterior teeth with laminates composite veneers. AB - No- or minimal-preparation veneers associated with enamel preservation offer predictable results in esthetic dentistry; indirect additive anterior composite restorations represent a quick, minimally invasive, inexpensive, and repairable option for a smile enhancement treatment plan. Current laboratory techniques associated with a strict clinical protocol satisfy patients' restorative and esthetic needs. The case report presented describes minimal invasive treatment of four upper incisors with laminate nanohybrid resin composite veneers. A step-by step protocol is proposed for diagnostic evaluation, mock-up fabrication and trial, teeth preparation and impression, and adhesive cementation. The resolution of initial esthetic issues, patient satisfaction, and nice integration of indirect restorations confirmed the success of this anterior dentition rehabilitation. PMID- 25013732 TI - Delayed upper-airway injury after accidental alkaline ingestion. AB - A 62-year-old man presented to the emergency department one week after accidentally drinking an alkaline cleaning agent stored in unlabeled bottle. The day of the incident the patient presented to an outside hospital where he was admitted for an upper endoscopy of the esophagus which was found to be negative for acute injury. An initial chest X-ray taken the day of the incident was also found to be normal. After discharge the patient continued to have a sore throat and marked dysphagia which caused him to vomit repeatedly. Moreover, the patient began to develop chest pain with associated shortness of breath. We present a case of delayed airway injury and tracheal thickening and associated chest pain after alkaline ingestion and we discuss herein the pathophysiology and management of alkaline ingestions. PMID- 25013733 TI - Necrotizing myositis in a neutropenic patient: the use of ultrasound in the diagnosis of atypical presentations. AB - We report a case of fatal necrotizing soft tissue infection (NSTI) due to Clostridium perfringens (CP) in a neutropenic patient with diabetes mellitus. As in many cases, by the time a diagnosis was made, the condition had rapidly progressed to its late stages, resulting in a fatal outcome. The emergency physician should be aware of NSTI as a complication when patients present with pain out of proportion to physical findings and/or signs of soft tissue compromise. Negative prognostic factors for survival are diabetes mellitus, immunosuppression, age, and toxic shock syndrome. A bedside ultrasound scan allows for rapid evaluation in time-sensitive critically ill patients and can promote prompt treatment without the need to delay for further imaging studies. PMID- 25013734 TI - Carbon ion beam radiotherapy for sinonasal malignant tumors invading skull base. AB - Objective. To evaluate the treatment outcome and prognostic factors in patients with sinonasal malignant tumors invading skull base. Study Design and Setting. A retrospective clinical study at the Yamagata University School of Medicine. Subjects and Methods. Three patients with sinonasal malignant tumors invading skull base were presented in present study. All patients were treated with carbon ion beam radiotherapy. The prescribed dose to the center of the clinical target volume was 64.0 GyE/16 fractions over 4 weeks at 4.0 GyE/fraction per day. Results. All patients completed carbon ion beam radiotherapy without an interval. The mean observation period was 39.6 months (range: 11-54 months). There were no local or regional recurrences in all cases; however, one patient had a metastasis in distant organs. Regarding the complications, visual loss was observed in one eye of one patient whose optic nerve was entirely involved by the tumor and field of carbon ion beam radiotherapy. Radiation induced brain injury was observed in two patients; however, these patients do not complain about neurological abnormality and had no treatment for radiation induced brain necrosis. Conclusions. Carbon ion beam radiotherapy for sinonasal malignant tumors invading the skull base showed therapeutic effectiveness. PMID- 25013735 TI - A case of emphysematous osteomyelitis of the midfoot: imaging findings and review of the literature. AB - Emphysematous osteomyelitis is a rare but potentially fatal condition that must be considered whenever intraosseous gas is identified on imaging. The organisms implicated in most cases of emphysematous osteomyelitis are anaerobes or members of the Enterobacteriaceae family. Significant comorbidities, such as malignancy and diabetes mellitus, frequently predispose to this condition, and high mortality rates have been reported. The radiologist must be aware of the implications of identifying intraosseous gas in order to facilitate early diagnosis and expedite management. We report a unique case of a 58-year-old male with diabetes mellitus who presented with emphysematous osteomyelitis of the midfoot and necrotising fasciitis of the ipsilateral distal lower limb. Specimen cultures in this case revealed a pure growth of Group G Streptococcus. PMID- 25013736 TI - Marked multiple tendinitis at the onset of rheumatoid arthritis in a patient with heterozygous familial hypercholesterolemia: ultrasonographic observation. AB - A 59-year-old woman who had been diagnosed with heterozygous familial hypercholesterolemia developed rheumatoid arthritis (RA). She presented with marked tendinitis of the Achilles tendons, patellar tendons, and finger extensor tendons at the onset of RA. Ultrasonographic examination revealed that tendon lesions were predominantly tendinitis rather than paratenonitis, and that the tendinitis was of the noninsertional variety, rather than the insertional variety. Preexisting tendon xanthomas might have contributed to the unusually dominant noninsertional tendinitis of multiple tendons. PMID- 25013737 TI - Breast metastasis from esophagogastric junction cancer: a case report. AB - Metastasis to breast from nonmammary malignancy is only about 1.3-2.7%. A few cases of squamous cell carcinoma of esophagus and adenocarcinoma of stomach metastasizing to breast have been reported, but this is probably the first report of breast metastasis from esophagogastric junction (EGJ) cancer in the English literature. Herein we report a case of a 32-year-old patient diagnosed as adenocarcinoma of gastroesophageal junction, presenting with left breast metastasis two years after treatment. Given unusual site of metastasis in a follow-up case of EGJ cancer, not only it is challenging to differentiate it from primary carcinoma of breast but also it is important from treatment point of view. In our case, clinical data, radiology, histopathology, and immunohistochemistry (IHC) led us to reach the diagnosis. PMID- 25013738 TI - Pregnancy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei. AB - Pseudomyxoma peritonei is usually a benign tumor that is slightly more common in women. However, it requires aggressive surgical treatment and chemotherapy, often compromising future reproductive function. This report presents a case of pregnancy in a 35-year-old woman who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei. The tumor was diagnosed during a laparoscopic examination on a workup for infertility in 2008. Two months later, she underwent a peritonectomy followed by hyperthermic intraperitoneal chemotherapy and, regarding her will to conceive, ovaries and fallopian tubes were preserved. In March 2011, she went through an in vitro fertilization followed by an uneventful pregnancy and delivered a healthy child 39 weeks later. Ovaries are usually resected during the cytoreductive surgery, since they are common sites for neoplastic implants, and, even when not performed, little is known about the effects of local chemotherapy on female fertility. The largest international survey on this matter only describes seven similar cases. This particular report not only describes a rare condition but also adds to the upcoming discussion about whether ovaries can be preserved in specific situations, therefore keeping the prospect of conceiving after this treatment. PMID- 25013739 TI - Case of Acute Graft Failure during Suspected Humoral Rejection with Preserved Ejection Fraction, but Severely Reduced Longitudinal Deformation Detected by 2D Speckle Tracking. AB - This case displays limited utility of left ventricular ejection fraction to detect acute graft failure due to microvascular vasculopathy and suspected humoral rejection. Despite severe and progressive graft failure, clinically and by right heart catheterizations, left ventricular ejection fraction remained unchanged, indicating need of more reliable noninvasive methods for graft function surveillance. Global longitudinal strain relates to clinical heart failure, filling pressure, and cardiac index during suspected humoral rejection and microvascular dysfunction in this HTX patient. We suggest routine monitoring of graft function by global longitudinal strain as supplement to routine left ventricular ejection fraction and diastolic Doppler measurements. PMID- 25013740 TI - A case of recurrent renal aluminum hydroxide stone. AB - Renal stone disease is characterized by the differences depending on the age, gender, and the geographic location of the patients. Seventy-five percent of the renal stone components is the calcium (Ca). The most common type of the stones is the Ca oxalate stones, while Ca phosphate, uric acid, struvite, and sistine stones are more rarely reported. Other than these types, triamterene, adenosine, silica, indinavir, and ephedrine stones are also reported in the literature as case reports. However, to the best of our knowledge, aluminum hydroxide stones was not reported reported before. Herein we will report a 38-years-old woman with the history of recurrent renal colic disease whose renal stone was determined as aluminum hydroxide stone in type. Aluminum mineral may be considered in the formation of kidney stones as it is widely used in the field of healthcare and cosmetics. PMID- 25013741 TI - Pamidronate disodium for palliative therapy of feline bone-invasive tumors. AB - This study sought to quantify in vitro antiproliferative effects of pamidronate in feline cancer cells and assess feasibility of use of pamidronate in cats by assessing short-term toxicity and dosing schedule in cats with bone-invasive cancer. A retrospective pilot study included eight cats with bone invasive cancer treated with intravenous pamidronate. In vitro, pamidronate reduced proliferation in feline cancer cells (P < 0.05). One cat treated with pamidronate in combination with chemotherapy and two cats treated with pamidronate as a single agent after failing prior therapy had subjective clinically stable disease; median progression free interval in these cats from initial pamidronate treatment was 81 days. Three cats developed azotemia while undergoing various treatment modalities including nonsteroidal anti-inflammatory drugs and pamidronate. Median overall survival was 116.5 days for all cats and 170 days for cats with oral squamous cell carcinoma. Median progression free survival was 55 days for all cats and 71 days for cats with oral squamous cell carcinoma. Pamidronate therapy appears feasible for administration in cancer bearing cats with aggressive bone lesions in the dose range of 1-2 mg/kg every 21-28 days for multiple treatments. No acute or short-term toxicity was directly attributable to pamidronate. PMID- 25013743 TI - Phytoremediation of Explosives using Transgenic Plants. PMID- 25013744 TI - Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. AB - Metastasis is the main cause of death in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: (1) single cells and (2) multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Finally, although the two human tumors were derived from diverse genetic backgrounds, we found that their migratory tumor cells exhibited coordinated gene expression changes that led to the same end-phenotype of enhanced migration involving activating actin polymerization and myosin contraction. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor. PMID- 25013742 TI - Use of Nanotechnology to Develop Multi-Drug Inhibitors For Cancer Therapy. AB - Therapeutic agents that inhibit a single target often cannot combat a multifactorial disease such as cancer. Thus, multi-target inhibitors (MTIs) are needed to circumvent complications such as the development of resistance. There are two predominant types of MTIs, (a) single drug inhibitor (SDIs) that affect multiple pathways simultaneously, and (b) combinatorial agents or multi-drug inhibitors (MDIs) that inhibit multiple pathways. Single agent multi-target kinase inhibitors are amongst the most prominent class of compounds belonging to the former, whereas the latter includes many different classes of combinatorial agents that have been used to achieve synergistic efficacy against cancer. Safe delivery and accumulation at the tumor site is of paramount importance for MTIs because inhibition of multiple key signaling pathways has the potential to lead to systemic toxicity. For this reason, the development of drug delivery mechanisms using nanotechnology is preferable in order to ensure that the MDIs accumulate in the tumor vasculature, thereby increasing efficacy and minimizing off-target and systemic side effects. This review will discuss how nanotechnology can be used for the development of MTIs for cancer therapy and also it concludes with a discussion of the future of nanoparticle-based MTIs as well as the continuing obstacles being faced during the development of these unique agents.' PMID- 25013745 TI - Obstructive Sleep Apnea and Surgery: Quality Improvement Imperatives and Opportunities. AB - Obstructive sleep apnea (OSA) is more common in surgical candidates than in the general population and may increase susceptibility to perioperative complications that range from transient desaturation to catastrophic injuries. Understanding the potential impact of OSA on patients' surgical risk profile is of particular interest to otolaryngologists, who routinely perform airway procedures-including surgical procedures for treatment of OSA. Whereas the effects of OSA on long-term health outcomes are well documented, the relationship between OSA and surgical risk is not collinear, and clear consensus on the nature of the association is lacking. Better guidelines for optimization of pain control, perioperative monitoring, and surgical decision making are potential areas for quality improvement efforts. Many interventions have been suggested to mitigate the risk of adverse events in surgical patients with OSA, but wide variations in clinical practice remain. We review the current literature, emphasizing recent progress in understanding the complex pathophysiologic interactions noted in OSA patients undergoing surgery and outlining potential strategies to decrease perioperative risks. PMID- 25013746 TI - Seasonal variations of EPG Levels in gastro-intestinal parasitic infection in a southeast asian controlled locale: a statistical analysis. AB - We present a data based statistical study on the effects of seasonal variations in the growth rates of the gastro-intestinal (GI) parasitic infection in livestock. The alluded growth rate is estimated through the variation in the number of eggs per gram (EPG) of faeces in animals. In accordance with earlier studies, our analysis too shows that rainfall is the dominant variable in determining EPG infection rates compared to other macro-parameters like temperature and humidity. Our statistical analysis clearly indicates an oscillatory dependence of EPG levels on rainfall fluctuations. Monsoon recorded the highest infection with a comparative increase of at least 2.5 times compared to the next most infected period (summer). A least square fit of the EPG versus rainfall data indicates an approach towards a super diffusive (i. e. root mean square displacement growing faster than the square root of the elapsed time as obtained for simple diffusion) infection growth pattern regime for low rainfall regimes (technically defined as zeroth level dependence) that gets remarkably augmented for large rainfall zones. Our analysis further indicates that for low fluctuations in temperature (true on the bulk data), EPG level saturates beyond a critical value of the rainfall, a threshold that is expected to indicate the onset of the nonlinear regime. The probability density functions (PDFs) of the EPG data show oscillatory behavior in the large rainfall regime (greater than 500 mm), the frequency of oscillation, once again, being determined by the ambient wetness (rainfall, and humidity). Data recorded over three pilot projects spanning three measures of rainfall and humidity bear testimony to the universality of this statistical argument. PMID- 25013747 TI - Investigating the insecticidal potential of Geomyces (Myxotrichaceae: Helotiales) and Mortierella (Mortierellacea: Mortierellales) isolated from Antarctica. AB - Fungi isolated from environmentally challenging habitats can have adaptations of potential value when developed as insect pest-controls. Fungal isolates collected from Antarctica, Geomyces sp. I, Geomyces sp. II, Mortierella signyensis and M. alpina, were investigated for (i) growth characteristics at 0-35 degrees C, (ii) spore production at 10 and 20 degrees C, (iii) viability following exposure to freezing temperatures, and (iv) insecticidal activity against waxmoths (Galleria mellonella L.), houseflies (Musca domestica L.), mealworms (Tenebrio molitor L.) and black vine weevils (Otiorhynchus sulcatus Fabricius). All isolates showed growth between 5-20 degrees C, with some showing growth outside this range. Geomyces isolates sporulated over a wider range of conditions than the Mortierella isolates. Spore germination at 10 degrees C was higher for Geomyces sp. II when this isolate was produced at 10 compared to 20 degrees C (greatest difference 74.6 vs 32.7%). All isolates grew, with the exception of M. alpina, following exposure to -20 degrees C for 4 weeks. Insecticidal investigations showed M. alpina and M. signyensis caused significant mortality of waxmoth and housefly larvae via injection and soil inoculation, and M. alpina caused significant mortality of housefly larvae via baiting; the Geomyces isolates had little lethal effect. PMID- 25013748 TI - Scientometric analyses of studies on the role of innate variation in athletic performance. AB - Historical events have produced an ideologically charged atmosphere in the USA surrounding the potential influences of innate variation on athletic performance. We tested the hypothesis that scientific studies of the role of innate variation in athletic performance were less likely to have authors with USA addresses than addresses elsewhere because of this cultural milieu. Using scientometric data collected from 290 scientific papers published in peer-reviewed journals from 2000-2012, we compared the proportions of authors with USA addresses with those that listed addresses elsewhere that studied the relationships between athletic performance and (a) prenatal exposure to androgens, as indicated by the ratio between digits 2 and 4, and (b) the genotypes for angiotensin converting enzyme, alpha-actinin-3, and myostatin; traits often associated with athletic performance. Authors with USA addresses were disproportionately underrepresented on papers about the role of innate variation in athletic performance. We searched NIH and NSF databases for grant proposals solicited or funded from 2000-2012 to determine if the proportion of authors that listed USA addresses was associated with funding patterns. NIH did not solicit grant proposals designed to examine these factors in the context of athletic performance and neither NIH nor NSF funded grants designed to study these topics. We think the combined effects of a lack of government funding and the avoidance of studying controversial or non fundable topics by USA based scientists are responsible for the observation that authors with USA addresses were underrepresented on scientific papers examining the relationships between athletic performance and innate variation. PMID- 25013749 TI - Defining weaning age of camel calves in Eastern Ethiopia. AB - This experiment was conducted with the aim to define the weaning age of camel calves managed with pastoral farmers in eastern Ethiopia. Twenty camel calves (11 males and 9 females) were randomly assigned into five blocks based on their birth date. Calves within a block were further assigned to one of the four Treatments (T1, T2, T3, and T4). Calves in T1, T2, and T3 were weaned at 6, 8, and 10 months of age and supplemented with concentrate from weaning up to 12 months of age, respectively. They were supplemented with a mixture of noug seed (Guizotia abyssinica) cake and wheat bran at a ratio of 40% and 60%, respectively. Calves in T4 (control) were weaned at 12 months of age, hence were not supplemented with concentrate. Calves in all treatment groups browsed natural vegetation for 8 hours a day. Post weaning performance was evaluated for all calves at 14 months of age. The mean daily concentrate intake was significantly higher (P < 0.001) in the dry season compared to the wet season. Daily weight gain was significantly (P < 0.001) affected by treatment, sex of calves, and season of birth. Calves supplemented with concentrate gained relatively more weight (P < 0.001) than calves not supplemented. Calves born during the short rainy season gained more weight than those born during the short and long dry season. Three calves died, two from T3 and one from T4. From the study it was concluded that weaning calves at 8 months of age and supplementing with concentrate to the age of 12 months of age resulted in good post weaning growth rate and survivability of calves. PMID- 25013750 TI - Evaluation of antioxidant activities of extracts from 19 Chinese edible flowers. AB - Extracts of 19 selected edible flowers were investigated for their free radical scavenging activity (FRSA), polyphenolic contents and flavonoid contents in the paper. The results showed the extracts of Paeonia suffruticosa Andr., Paeonia lactiflora Pall., and Rosa rugosa Thunb. possessed obviously stronger DPPH FRSA (94.221 +/- 0.102; 93.739 +/- 0.424 and 94.244 +/- 0.163%, respectively), superoxide FRSA (55.818 +/- 1.518; 52.142 +/- 1.374 and 57.321 +/- 0.608%, respectively), hydroxyl FRSA (85.872 +/- 0.873; 89.307 +/- 0.803 and 88.560 +/- 0.277%, respectively) and polyphenolic contents (96.208 +/- 0.689; 87.938 +/- 1.187 and 92.164 +/- 0.799 mg CE/g, respectively) that were superior or comparable to black and green teas. Polyphenolic contents did correlate well with DPPH FRSA (r = 0.943, P < 0.01), superoxide FRSA (r = 0.833, P < 0.01), and hydroxyl FRSA (r = 0.500, P < 0.05). It indicated that this potent FRSA may be attributed to its phenolic compounds. These findings showed that the tested flowers could be considered as new sources of safe natural antioxidants and preservatives of food industry. PMID- 25013751 TI - Considering Cannabis: The Effects of Regular Cannabis Use on Neurocognition in Adolescents and Young Adults. AB - Thirty-six percent of high school seniors have used cannabis in the past year, and an alarming 6.5% smoked cannabis daily, up from 2.4% in 1993 (Johnston et al., 2013). Adolescents and emerging adults are undergoing significant neurodevelopment and animal studies suggest they may be particularly vulnerable to negative drug effects. In this review, we will provide a detailed overview of studies outlining the effects of regular (at least weekly) cannabis use on neurocognition, including studies outlining cognitive, structural and functional findings. We will also explore the public health impact of this research. PMID- 25013753 TI - Genome-wide analysis of HOXC9-induced neuronal differentiation of neuroblastoma cells. AB - Induction of differentiation is a therapeutic strategy in neuroblastoma, a common pediatric cancer of the sympathetic nervous system. The homeobox protein HOXC9 is a key regulator of neuroblastoma differentiation. To gain a molecular understanding of the function of HOXC9 in promoting differentiation of neuroblastoma cells, we conducted a genome-wide analysis of the HOXC9-induced differentiation program by microarray gene expression profiling and chromatin immunoprecipitation in combination with massively parallel sequencing (ChIP-seq). Here we describe in details the experimental system, methods, and quality control for the generation of the microarray and ChIP-seq data associated with our recent publication [1]. PMID- 25013752 TI - Arsenic Exposure and Subclinical Endpoints of Cardiovascular Diseases. AB - Mechanistic evidence suggests that arsenic exposure from drinking water increases the production of reactive oxygen species and influences inflammatory responses and endothelial nitric oxide homeostasis. These arsenic-induced events may lead to endothelial dysfunction that increases the risk of atherosclerosis and cardiovascular disease. We reviewed accumulating epidemiologic evidence that evaluated the association between arsenic exposure and intermediate markers and subclinical measures that predict future cardiovascular risk. Cross-sectional studies have indicated positive associations between high or low-to-moderate levels of arsenic exposure with indices of subclinical atherosclerosis, QT interval prolongation, and circulating markers of endothelial dysfunction. The evidence is limited for other intermediate endpoints such as markers of oxidative stress and inflammation, QT dispersion, and lipid profiles. Prospective studies are needed to enhance the causal inferences of arsenic's effects on subclinical endpoints of cardiovascular disease, especially at lower arsenic exposure levels. PMID- 25013754 TI - In vivo corneal neovascularization imaging by optical-resolution photoacoustic microscopy. AB - Corneal neovascularization leads to blurred vision, thus in vivo visualization is essential for pathological studies in animal models. Photoacoustic (PA) imaging can delineate microvasculature and hemodynamics noninvasively, which is suitable for investigating corneal neovascularization. In this study, we demonstrate in vivo imaging of corneal neovascularization in the mouse eye by optical-resolution photoacoustic microscopy (OR-PAM), where corneal neovascularization is induced by deliberate alkali burn injuries in C57BL6/J inbred mice corneas on the left eye. We used OR-PAM to image five mice with corneal alkali burn injuries; the uninjured eyes (right eye) in these mice are then used as the controls. Corneal images acquired by OR-PAM with and without alkali burn injury are compared, clear signs of corneal neovascularization are present in the OR-PAM images of injured eyes; the OR-PAM results are also confirmed by postmortem fluorescence-labeled confocal microscopy. PMID- 25013755 TI - Targeting the glutamatergic system to treat pathological gambling: current evidence and future perspectives. AB - Pathological gambling or gambling disorder has been defined by the DSM-5 as a behavioral addiction. To date, its pathophysiology is not completely understood and there is no FDA-approved treatment for gambling disorders. Glutamate is the principal excitatory neurotransmitter in the nervous system and it has been recently involved in the pathophysiology of addictive behaviors. In this paper, we review the current literature on a class of drugs that act as modulating glutamate system in PG. A total of 19 studies have been included, according to inclusion and exclusion criteria. Clinical trial and case series using glutamatergic drugs (N-acetylcysteine, memantine, amantadine, topiramate, acamprosate, baclofen, gabapentin, pregabalin, and modafinil) will be presented to elucidate the effectiveness on gambling behaviors and on the related clinical dimensions (craving, withdrawal, and cognitive symptoms) in PG patients. The results have been discussed to gain more insight in the pathophysiology and treatment of PG. In conclusion, manipulation of glutamatergic neurotransmission appears to be promising in developing improved therapeutic agents for the treatment of gambling disorders. Further studies are required. Finally, we propose future directions and challenges in this research area. PMID- 25013756 TI - Preconception screening for cytomegalovirus: an effective preventive approach. AB - Congenital cytomegalovirus (CMV) is the leading infectious cause of sensorineural hearing loss and delayed psychomotor development. Viral transmission to the fetus is far more likely to occur following a primary than a secondary maternal infection. Primary prevention seems to be the best means to reduce the burden of congenital CMV due to the lack of treatment options during pregnancy. We evaluated this approach on a cohort of 500 women planning pregnancy who attended our fertility clinic. Of the 444 who underwent CMV screening, 18 (4.1%) had positive IgM serology for CMV; of these, IgG avidity was high in 12 (remote infection) and low in 6 (recent infection). The latter were advised to delay pregnancy. All women who were seroimmune for CMV (366/444, 82.4%), including the 12 with remote infection, continued fertility treatment. The remaining patients (72/444, 16.2%), who were not immune to CMV at the initial screen, were advised to minimize CMV exposure by improving personal hygiene and to continue fertility treatment. None of the 69/72 (95.8%) women who were followed for one year were infected with CMV. Cytomegalovirus testing and counselling at preconception seemed effective in reducing CMV exposure in pregnancy. PMID- 25013757 TI - Outcome of corneal collagen crosslinking for progressive keratoconus in paediatric patients. AB - PURPOSE: To evaluate the efficacy of corneal collagen crosslinking for progressive keratoconus in paediatric patients. METHODS: This prospective study included 25 eyes of 18 patients (aged 18 years or younger) who underwent collagen crosslinking performed using riboflavin and ultraviolet-A irradiation (370 nm, 3 mW/cm2, 30 min). RESULTS: The mean patient age was 14.3+/-2.4 years (range 8-17) and mean followup duration was 20.1+/-14.25 months (range 6-48). Crosslinked eyes demonstrated a significant reduction of keratometry values. The mean baseline simulated keratometry values were 46.34 dioptres (D) in the flattest meridian and 50.06 D in the steepest meridian. At 20 months after crosslinking, the values were 45.67 D (P=0.03) and 49.34 D (P=0.005), respectively. The best spectacle corrected visual acuity (BSCVA) and topometric astigmatism improved after crosslinking. Mean logarithm of the minimum angle of resolution (logMAR) BSCVA decreased from 0.24 to 0.21 (P=0.89) and topometric astigmatism reduced from mean 3.50 D to 3.25 D (P=0.51). CONCLUSIONS: Collagen crosslinking using riboflavin and ultraviolet-A is an effective treatment option for progressive keratoconus in paediatric patients. Crosslinking stabilises the condition and, thus, reduces the need for corneal grafting in these young patients. PMID- 25013759 TI - Osthole attenuates doxorubicin-induced apoptosis in PC12 cells through inhibition of mitochondrial dysfunction and ROS production. AB - Doxorubicin (DOX) is a potent, broad-spectrum chemotherapeutic drug used for treatment of several types of cancers. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent prooxidant activity. It has been reported that DOX has toxic effects on normal tissues, including brain tissue. In the current study, we investigated the protective effect of osthole isolated from Prangos ferulacea (L.) Lindl. on oxidative stress and apoptosis induced by DOX in PC12 as a neuronal model cell line. PC12 cells were pretreated with osthole 2 h after treatment with different concentrations of DOX. 24 h later, the cell viability, mitochondrial membrane potential (MMP), the activity of caspase-3, the expression ratio of Bax/Bcl-2, and the generation of intracellular ROS were detected. We found that pretreatment with osthole on PC12 cells significantly reduced the loss of cell viability, the activity of caspase-3, the increase in Bax/Bcl-2 ratio, and the generation of intracellular ROS induced by DOX. Moreover, pretreatment with osthole led to an increase in MMP in PC12 cells. In conclusion, our results indicated that pretreatment with nontoxic concentrations of osthole protected PC12 cells from DOX-mediated apoptosis by inhibition of ROS production. PMID- 25013760 TI - Overexpression of D-xylose reductase (xyl1) gene and antisense inhibition of D xylulokinase (xyiH) gene increase xylitol production in Trichoderma reesei. AB - T. reesei is an efficient cellulase producer and biomass degrader. To improve xylitol production in Trichoderma reesei strains by genetic engineering, two approaches were used in this study. First, the presumptive D-xylulokinase gene in T. reesei (xyiH), which has high homology to known fungi D-xylulokinase genes, was silenced by transformation of T. reesei QM9414 strain with an antisense construct to create strain S6-2-2. The expression of the xyiH gene in the transformed strain S6-2-2 decreased at the mRNA level, and D-xylulokinase activity decreased after 48 h of incubation. This led to an increase in xylitol production from undetectable levels in wild-type T. reesei QM9414 to 8.6 mM in S6 2-2. The T. reesei Deltaxdh is a xylose dehydrogenase knockout strain with increased xylitol production compared to the wild-type T. reesei QM9414 (22.8 mM versus undetectable). The copy number of the xylose reductase gene (xyl1) in T. reesei Deltaxdh strain was increased by genetic engineering to create a new strain Delta9-5-1. The Delta9-5-1 strain showed a higher xyl1 expression and a higher yield of xylose reductase, and xylitol production was increased from 22.8 mM to 24.8 mM. Two novel strains S6-2-2 and Delta9-5-1 are capable of producing higher yields of xylitol. T. reesei has great potential in the industrial production of xylitol. PMID- 25013761 TI - p53 is a key regulator for osthole-triggered cancer pathogenesis. AB - Osthole has been reported to have antitumor activities via the induction of apoptosis and inhibition of cancer cell growth and metastasis. However, the detailed molecular mechanisms underlying the anticancer effects of osthole in human colon cancer remain unclear. In the present study, we have assessed osthole induced cell death in two different human colon cancer cell lines, HCT116 and SW480. Our results also showed that osthole activated proapoptotic signaling pathways in human colon cancer cells. By using cell culture insert system, osthole reduced cell motility in both human colon cancer cell lines. This study also provides evidence supporting the potential of osthole in p53 activation. Expression of p53, an apoptotic protein, was remarkably upregulated in cells treated with osthole. Importantly, the levels of phosphorylation of p53 on Ser15 (p-p53) and acetylation of p53 on Lys379 (acetyl-p53) were increased under osthole treatment. Our results also demonstrated that p53 was activated followed by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). Our study provides novel insights of p53-mediated responses under osthole treatment. Taken together, we concluded that osthole induces cancer cell death and inhibits migratory activity in a controlled manner and is a promising candidate for antitumor drug development. PMID- 25013762 TI - Translational research of telecare for the treatment of hepatitis C. AB - OBJECTIVE: Chronic hepatitis C virus (HCV) infection is a serious health problem in Taiwan. The high dropout rate due to side effects limits the efficacy of treatment. The objective of this study is to investigate the effectiveness of telecare for the treatment of chronic hepatitis. MATERIAL AND METHODS: Two hundred and ninety-eight patients randomly chose either of the two support programs. Group 1 was offered public health nurse consultation at outpatient clinic. Group 2 was offered telecare program with 24 hours of consultation services via a health communication center. All patients were treated with standard therapy and followed up for 72 weeks. RESULTS: Normalization of serum biochemistry was noted in both Group 1 (150 patients) and Group 2 (148 patients). The most common types of side effect in both groups were influenza-like symptoms. Patient compliance was 88% (Group 1) and 94.6% (Group 2). Total dropout cases were 18 (12%) in Group 1 and 8 (5.4%) in Group 2. The program costs were 232,632 USD (Group 1) and 112,500 USD (Group 2). CONCLUSION: Telecare system with health care communication center model is significant in reducing dropout rate and is more effective with easy access. PMID- 25013758 TI - Apoptosis and molecular targeting therapy in cancer. AB - Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID- 25013763 TI - Crude extracts from Lycium barbarum suppress SREBP-1c expression and prevent diet induced fatty liver through AMPK activation. AB - Lycium barbarum polysaccharide (LBP) is well known in traditional Chinese herbal medicine that, has beneficial effects. Previous study reported that LBP reduced blood glucose and serum lipids. However, the underlying LBP-regulating mechanisms remain largely unknown. The main purpose of this study was to investigate whether LBP prevented fatty liver through activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of sterol regulatory element-binding protein-1c (SREBP-1c). Male C57BL/6J mice were fed a low-fat diet, high-fat diet, or 100 mg/kg LBP-treatment diet for 24 weeks. HepG2 cells were treated with LBP in the presence of palmitic acid. In our study, LBP can improve body compositions and lipid metabolic profiles in high-fat diet-fed mice. Oil Red O staining in vivo and in vitro showed that LBP significantly reduced hepatic intracellular triacylglycerol accumulation. H&E staining also showed that LBP can attenuate liver steatosis. Hepatic genes expression profiles demonstrated that LBP can activate the phosphorylation of AMPK, suppress nuclear expression of SREBP-1c, and decrease protein and mRNA expression of lipogenic genes in vivo or in vitro. Moreover, LBP significantly elevated uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) expression of brown adipose tissue. In summary, LBP possesses a potential novel treatment in preventing diet-induced fatty liver. PMID- 25013764 TI - Immunological dysregulation in multiple myeloma microenvironment. AB - Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target. PMID- 25013765 TI - Investigation of potent lead for acquired immunodeficiency syndrome from traditional Chinese medicine. AB - Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), has become, because of the rapid spread of the disease, a serious global problem and cannot be treated. Recent studies indicate that VIF is a protein of HIV to prevent all of human immunity to attack HIV. Molecular compounds of traditional Chinese medicine (TCM) database filtered through molecular docking and molecular dynamics simulations to inhibit VIF can protect against HIV. Glutamic acid, plantagoguanidinic acid, and Aurantiamide acetate based docking score higher with other TCM compounds selected. Molecular dynamics are useful for analysis and detection ligand interactions. According to the docking position, hydrophobic interactions, hydrogen bonding changes, and structure variation, the study try to select the efficacy of traditional Chinese medicine compound Aurantiamide acetate is better than the other for protein-ligand interactions to maintain the protein composition, based on changes in the structure. PMID- 25013766 TI - Molecular phylogeny of the bamboo sharks (Chiloscyllium spp.). AB - Chiloscyllium, commonly called bamboo shark, can be found inhabiting the waters of the Indo-West Pacific around East Asian countries such as Malaysia, Myanmar, Thailand, Singapore, and Indonesia. The International Union for Conservation of Nature (IUCN) Red List has categorized them as nearly threatened sharks out of their declining population status due to overexploitation. A molecular study was carried out to portray the systematic relationships within Chiloscyllium species using 12S rRNA and cytochrome b gene sequences. Maximum parsimony and Bayesian were used to reconstruct their phylogeny trees. A total of 381 bp sequences' lengths were successfully aligned in the 12S rRNA region, with 41 bp sites being parsimony-informative. In the cytochrome b region, a total of 1120 bp sites were aligned, with 352 parsimony-informative characters. All analyses yield phylogeny trees on which C. indicum has close relationships with C. plagiosum. C. punctatum is sister taxon to both C. indicum and C. plagiosum while C. griseum and C. hasseltii formed their own clade as sister taxa. These Chiloscyllium classifications can be supported by some morphological characters (lateral dermal ridges on the body, coloring patterns, and appearance of hypobranchials and basibranchial plate) that can clearly be used to differentiate each species. PMID- 25013767 TI - ECM inspired coating of embroidered 3D scaffolds enhances calvaria bone regeneration. AB - Resorbable polymeric implants and surface coatings are an emerging technology to treat bone defects and increase bone formation. This approach is of special interest in anatomical regions like the calvaria since adults lose the capacity to heal large calvarial defects. The present study assesses the potential of extracellular matrix inspired, embroidered polycaprolactone-co-lactide (PCL) scaffolds for the treatment of 13 mm full thickness calvarial bone defects in rabbits. Moreover the influence of a collagen/chondroitin sulfate (coll I/cs) coating of PCL scaffolds was evaluated. Defect areas filled with autologous bone and empty defects served as reference. The healing process was monitored over 6 months by combining a novel ultrasonographic method, radiographic imaging, biomechanical testing, and histology. The PCL coll I/cs treated group reached 68% new bone volume compared to the autologous group (100%) and the biomechanical stability of the defect area was similar to that of the gold standard. Histological investigations revealed a significantly more homogenous bone distribution over the whole defect area in the PCL coll I/cs group compared to the noncoated group. The bioactive, coll I/cs coated, highly porous, 3 dimensional PCL scaffold acted as a guide rail for new skull bone formation along and into the implant. PMID- 25013768 TI - A new surgical technique of pancreaticoduodenectomy with splenic artery resection for ductal adenocarcinoma of the pancreatic head and/or body invading splenic artery: impact of the balance between surgical radicality and QOL to avoid total pancreatectomy. AB - For pancreatic ductal adenocarcinoma (PDAC) of the head and/or body invading the splenic artery (SA), we developed a new surgical technique of proximal subtotal pancreatectomy with splenic artery and vein resection, so-called pancreaticoduodenectomy with splenic artery resection (PD-SAR). We retrospectively reviewed a total of 84 patients with curative intent pancreaticoduodenectomy (PD) for PDAC of the head and/or body. These 84 patients were classified into the two groups: conventional PD (n=66) and PD-SAR (n=18). Most patients were treated by preoperative chemoradiotherapy (CRT). Postoperative MDCT clearly demonstrated enhancement of the remnant pancreas at 1 and 6 months in all patients examined. Overall survival rates were very similar between PD and PD-SAR (3-year OS: 23.7% versus 23.1%, P=0.538), despite the fact that the tumor size and the percentages of UICC-T4 determined before treatment were higher in PD SAR. Total daily insulin dose was significantly higher in PD-SAR than in PD at 1 month, while showing no significant differences between the two groups thereafter. PD-SAR with preoperative CRT seems to be promising surgical strategy for PDAC of head and/or body with invasion of the splenic artery, in regard to the balance between operative radicality and postoperative QOL. PMID- 25013769 TI - Discordant correlation between serological assays observed when measuring heterosubtypic responses against avian influenza H5 and H7 viruses in unexposed individuals. AB - The human population is constantly exposed to multiple influenza A subtypes due to zoonotic spillover and rapid viral evolution driven by intrinsic error-prone replication and immunological pressure. In this context, antibody responses directed against the HA protein are of importance since they have been shown to correlate with protective immunity. Serological techniques, detecting these responses, play a critical role for influenza surveillance, vaccine development, and assessment. As the recent human pandemics and avian influenza outbreaks have demonstrated, there is an urgent need to be better prepared to assess the contribution of the antibody response to protection against newly emerged viruses and to evaluate the extent of preexisting heterosubtypic immunity in populations. In this study, 68 serum samples collected from the Italian population between 1992 and 2007 were found to be positive for antibodies against H5N1 as determined by single radial hemolysis (SRH), but most were negative when evaluated using haemagglutination inhibition (HI) and microneutralisation (MN) assays. As a result of these discordant serological findings, the increased sensitivity of lentiviral pseudotypes was exploited in pseudotype-based neutralisation (pp-NT) assays and the results obtained provide further insight into the complex nature of humoral immunity against influenza A viruses. PMID- 25013770 TI - Influenza and other respiratory viruses involved in severe acute respiratory disease in northern Italy during the pandemic and postpandemic period (2009 2011). AB - Since 2009 pandemic, international health authorities recommended monitoring severe and complicated cases of respiratory disease, that is, severe acute respiratory infection (SARI) and acute respiratory distress syndrome (ARDS). We evaluated the proportion of SARI/ARDS cases and deaths due to influenza A(H1N1)pdm09 infection and the impact of other respiratory viruses during pandemic and postpandemic period (2009-2011) in northern Italy; additionally we searched for unknown viruses in those cases for which diagnosis remained negative. 206 respiratory samples were collected from SARI/ARDS cases and analyzed by real-time RT-PCR/PCR to investigate influenza viruses and other common respiratory pathogens; also, a virus discovery technique (VIDISCA-454) was applied on those samples tested negative to all pathogens. Influenza A(H1N1)pdm09 virus was detected in 58.3% of specimens, with a case fatality rate of 11.3%. The impact of other respiratory viruses was 19.4%, and the most commonly detected viruses were human rhinovirus/enterovirus and influenza A(H3N2). VIDISCA-454 enabled the identification of one previously undiagnosed measles infection. Nearly 22% of SARI/ARDS cases did not obtain a definite diagnosis. In clinical practice, great efforts should be dedicated to improving the diagnosis of severe respiratory disease; the introduction of innovative molecular technologies, as VIDISCA-454, will certainly help in reducing such "diagnostic gap." PMID- 25013771 TI - A bioinformatics pipeline for the analyses of viral escape dynamics and host immune responses during an infection. AB - Rapidly mutating viruses, such as hepatitis C virus (HCV) and HIV, have adopted evolutionary strategies that allow escape from the host immune response via genomic mutations. Recent advances in high-throughput sequencing are reshaping the field of immuno-virology of viral infections, as these allow fast and cheap generation of genomic data. However, due to the large volumes of data generated, a thorough understanding of the biological and immunological significance of such information is often difficult. This paper proposes a pipeline that allows visualization and statistical analysis of viral mutations that are associated with immune escape. Taking next generation sequencing data from longitudinal analysis of HCV viral genomes during a single HCV infection, along with antigen specific T-cell responses detected from the same subject, we demonstrate the applicability of these tools in the context of primary HCV infection. We provide a statistical and visual explanation of the relationship between cooccurring mutations on the viral genome and the parallel adaptive immune response against HCV. PMID- 25013772 TI - A large cross-sectional survey investigating the knowledge of cervical cancer risk aetiology and the predictors of the adherence to cervical cancer screening related to mass media campaign. AB - OBJECTIVES: The aims of this study were to compare the characteristics of women who got a Pap-test during the mass media campaign, carried out in an Italian region by broadcasts advertising, and two years later and to identify the determinants of knowledge of cervical cancer etiology and of the adherence to the mass media campaign. METHODS: A cross-sectional survey was carried out through a self-administered questionnaire. RESULTS: A total of 8570 randomly selected women were surveyed, 823 of these had a Pap-test during the mass media campaign period and 7747 two years later. Higher educational level, being not married, and living in urban areas were the main independent characteristics associated with a higher level of knowledge of cervical cancer etiology, although a previous treatment following a Pap smear abnormality was the strongest predictor (OR=2.88; 95% CI: 2.43-3.41). During the campaign period women had the Pap-test more frequently as a consequence of the mass media campaign (OR=8.28; 95% CI; 5.51-12.45). CONCLUSIONS: Mass media campaign is a useful tool to foster cervical screening compliance; however, its short-term effect suggests repeating it regularly. PMID- 25013773 TI - Lobe-specific heterogeneity in asymmetric dimethylarginine and matrix metalloproteinase levels in a rat model of obstructive cholestasis. AB - We investigated the effects of obstructive cholestasis in different hepatic lobes by evaluating asymmetric dimethylarginine (ADMA) (a nitric oxide synthase inhibitor), protein methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH) (enzymes involved, resp., in its synthesis and degradation), the cationic transporter (CAT), and metalloproteinase (MMP) activity. Sixteen male Wistar rats underwent a 3-day cholestasis by common bile duct ligation (BDL) or sham operation. Blood samples and hepatic biopsies from left lobe (LL), median lobe (ML), and right lobe (RL) were collected. Serum hepatic enzymes, tissue ADMA, DDAH activity, CAT-2 protein, mRNA expression of DDAH and PRMT, and MMP-2 and MMP-9 activity were monitored. Cholestasis was confirmed by altered serum hepatic enzymes. Higher levels of tissue ADMA were detected in RL and ML as compared with LL. PRMT mRNA expression and DDAH activity did not differ among the lobes after BDL. CAT-2 levels are higher in the RL and ML in the sham-operated group. Higher activity in MMP-2 and MMP-9 was found in RL. In conclusion, after cholestasis an increase in hepatic ADMA in RL and ML was detected as well as tissue MMP-2 and MMP-9 activation in RL, supporting the evidence of functional heterogeneity among the liver lobes also occurring in an obstructive cholestasis model. PMID- 25013774 TI - Influence of heating and cyclic tension on the induction of heat shock proteins and bone-related proteins by MC3T3-E1 cells. AB - Stress conditioning (e.g., thermal, shear, and tensile stress) of bone cells has been shown to enhance healing. However, prior studies have not investigated whether combined stress could synergistically promote bone regeneration. This study explored the impact of combined thermal and tensile stress on the induction of heat shock proteins (HSPs) and bone-related proteins by a murine preosteoblast cell line (MC3T3-E1). Cells were exposed to thermal stress using a water bath (44 degrees C for 4 or 8 minutes) with postheating incubation (37 degrees C for 4 hours) followed by exposure to cyclic strain (equibiaxial 3%, 0.2 Hz, cycle of 10 second tensile stress followed by 10-second rest). Combined thermal stress and tensile stress induced mRNA expression of HSP27 (1.41 relative fold induction (RFI) compared to sham-treated control), HSP70 (5.55 RFI), and osteopontin (1.44 RFI) but suppressed matrix metalloproteinase-9 (0.6 RFI) compared to the control. Combined thermal and tensile stress increased vascular endothelial growth factor (VEGF) secretion into the culture supernatant (1.54-fold increase compared to the control). Therefore, combined thermal and mechanical stress preconditioning can enhance HSP induction and influence protein expression important for bone tissue healing. PMID- 25013776 TI - Neutralizing effects of Mimosa tenuiflora extracts against inflammation caused by Tityus serrulatus scorpion venom. AB - Scorpion bite represents a significant and serious public health problem in certain regions of Brazil, as well as in other parts of the world. Inflammatory mediators are thought to be involved in the systemic and local immune response induced by Tityus serrulatus scorpion envenomation. The aim of this study was to evaluate the effect of extracts of Mimosa tenuiflora on model envenomation. In mice, the envenomation model is induced by Tityus serrulatus venom. Previous treatment of mice with fractions from M. tenuiflora was able to suppress the cell migration to the peritoneal cavity. The treatment of mice with M. tenuiflora extracts also decreased the levels of IL-6, IL-12, and IL-1beta. We concluded that the administration of the extract and fractions resulted in a reduction in cell migration and showed a reduction in the level of proinflammatory cytokines. This study demonstrates, for the first time, the anti-inflammatory effect of aqueous extract from the Mimosa tenuiflora plant on T. serrulatus venom. PMID- 25013775 TI - The ratio of estimated average glucose to fasting plasma glucose level is superior to glycated albumin, hemoglobin A1c, fructosamine, and GA/A1c ratio for assessing beta-cell function in childhood diabetes. AB - OBJECTIVE: This study investigated the use of the estimated average glucose to fasting plasma glucose ratio (eAG/fPG ratio) to screen for beta-cell function in pediatric diabetes. METHODS: Glycated hemoglobin (HbA1c), glycated albumin (GA), fructosamine, insulin, and C-peptide levels were measured. The ratio of GA to HbA1c (GA/A1c ratio) was calculated, and the homeostasis model assessment of beta cell function (HOMA-beta) was determined. RESULTS: Median values of C-peptide, insulin, and HOMA-beta levels were significantly higher in patients with an increased eAG/fPG ratio than in those with a decreased eAG/fPG ratio. C-peptide and HOMA-beta levels were more closely correlated with the eAG/fPG ratio than with GA, HbA1c, the GA/A1c ratio, and fructosamine. In contrast, body mass index was significantly associated with GA, GA/A1c ratio, and fructosamine, but not with the eAG/fPG ratio and HbA1c levels. To test the diagnostic accuracies of the eAG/fPG ratio for identifying HOMA-beta>30.0% in patients with type 2 diabetes, the area under the ROC curve of the eAG/fPG ratio was significantly larger than that of the GA/A1c ratio [0.877 (95% CI, 0.780-0.942) versus 0.775 (95% CI, 0.664 0.865), P=0.039]. CONCLUSIONS: A measurement of the eAG/fPG ratio may provide helpful information for assessing beta-cell function in pediatric patients with diabetes. PMID- 25013777 TI - The study of interactions between active compounds of coffee and willow (Salix sp.) bark water extract. AB - Coffee and willow are known as valuable sources of biologically active phytochemicals such as chlorogenic acid, caffeine, and salicin. The aim of the study was to determine the interactions between the active compounds contained in water extracts from coffee and bark of willow (Salix purpurea and Salix myrsinifolia). Raw materials and their mixtures were characterized by multidirectional antioxidant activities; however, bioactive constituents interacted with each other. Synergism was observed for ability of inhibition of lipid peroxidation and reducing power, whereas compounds able to scavenge ABTS radical cation acted antagonistically. Additionally, phytochemicals from willow bark possessed hydrophilic character and thermostability which justifies their potential use as an ingredient in coffee beverages. Proposed mixtures may be used in the prophylaxis or treatment of some civilization diseases linked with oxidative stress. Most importantly, strong synergism observed for phytochemicals able to prevent lipids against oxidation may suggest protective effect for cell membrane phospholipids. Obtained results indicate that extracts from bark tested Salix genotypes as an ingredient in coffee beverages can provide health promoting benefits to the consumers; however, this issue requires further study. PMID- 25013778 TI - Balloon dilatation of pediatric subglottic laryngeal stenosis during the artificial apneic pause: experience in 5 children. AB - INTRODUCTION: Balloon dilatation is a method of choice for treatment of laryngeal stenosis in children. The aim of procedure in apneic pause is to avoid new insertion of tracheostomy cannula. PATIENTS AND METHODS: The authors performed balloon dilatation of subglottic laryngeal strictures (SGS) in 5 children (3 girls and 2 boys) without tracheotomy. Two of them with traumatic and inflammatory SGS had a tracheal cannula removed in the past. The other 3 children with postintubation SGS had never had a tracheostomy before. The need for tracheostomy due to worsening stridor was imminent for all of them. RESULTS: The total of seven laryngeal dilatations by balloon esophagoplasty catheter in apneic pause was performed in the 5 children. The procedure averted the need for tracheostomy placement in 4 of them (80%). Failure of dilatation in girl with traumatic stenosis and concomitant severe obstructive lung disease led to repeated tracheostomy. CONCLUSION: Balloon dilatation of laryngeal stricture could be done in the absence of tracheostomy in apneic pause. Dilatation averted threatening tracheostomy in all except one case. Early complication after the procedure seems to be a negative prognostic factor for the outcome of balloon dilatation. PMID- 25013779 TI - An improved distance matrix computation algorithm for multicore clusters. AB - Distance matrix has diverse usage in different research areas. Its computation is typically an essential task in most bioinformatics applications, especially in multiple sequence alignment. The gigantic explosion of biological sequence databases leads to an urgent need for accelerating these computations. DistVect algorithm was introduced in the paper of Al-Neama et al. (in press) to present a recent approach for vectorizing distance matrix computing. It showed an efficient performance in both sequential and parallel computing. However, the multicore cluster systems, which are available now, with their scalability and performance/cost ratio, meet the need for more powerful and efficient performance. This paper proposes DistVect1 as highly efficient parallel vectorized algorithm with high performance for computing distance matrix, addressed to multicore clusters. It reformulates DistVect1 vectorized algorithm in terms of clusters primitives. It deduces an efficient approach of partitioning and scheduling computations, convenient to this type of architecture. Implementations employ potential of both MPI and OpenMP libraries. Experimental results show that the proposed method performs improvement of around 3-fold speedup upon SSE2. Further it also achieves speedups more than 9 orders of magnitude compared to the publicly available parallel implementation utilized in ClustalW-MPI. PMID- 25013780 TI - The influence of hypoxia during different pregnancy stages on cardiac collagen accumulation in the adult offspring. AB - We evaluated whether the timing of maternal hypoxia during pregnancy influenced cardiac extracellular matrix accumulation in the adult offspring. Rats in different periods of pregnancy were assigned to maternal hypoxia or control groups. Maternal hypoxia from day 3 to 21 of pregnancy or day 9 to 21 of pregnancy increased collagen I and collagen III expression in the left ventricle of adult offspring (both P<0.05). Maternal hypoxia from day 15 to 21 of pregnancy had no effect on adult collagen levels. Our results indicate that maternal hypoxia at critical windows of cardiovascular development can induce pathological cardiac remodeling in the adult rat offspring. PMID- 25013781 TI - Changes of costimulatory molecule CD28 on circulating CD8+ T cells correlate with disease pathogenesis of chronic hepatitis B. AB - Costimulatory signals are critical for antiviral immunity. The aim of this study was to evaluate the change of costimulatory molecule CD28 on circulating CD8+ T cells in chronic hepatitis B patients (CHB). Seventy CHB patients and fifty-six healthy controls were included, and forty-eight CHB patients were recruited for 52 weeks of longitudinal investigation. The proportions of circulating CD8+CD28+ and CD8+CD28- subpopulations were determined by flow cytometry, and the CD8+CD28+/CD8+CD28- T cells ratio was calculated. Compared with the subpopulation in healthy controls, high proportions of CD8+CD28- subpopulation were observed in CHB patients. Similarly, the CD8+CD28+/CD8+CD28- T cells ratio was significantly decreased in CHB patients compared with healthy controls and correlated significantly with hepatitis B virus (HBV) loads. High proportions of CD8+CD28- subpopulation and low CD8+CD28+/CD8+CD28- T cells ratio were observed in hepatitis B e antigen- (HBeAg-) positive individuals as compared with that in HBeAg-negative subjects. A significant decrease in CD8+CD28- subpopulation, increase in CD8+CD28+ subpopulation, and CD8+CD28+/CD8+CD28- T cells ratio were seen in those patients who received efficient antiviral therapy. Thus, aberrant CD28 expression on circulating CD8+ T cells and the CD8+CD28+/CD8+CD28- T cells ratio reflect the dysregulation of T cell activation and are related to the pathogenesis of chronic HBV infection. PMID- 25013782 TI - Evaluation of metabolic enzymes in response to Excel Mera 71, a glyphosate-based herbicide, and recovery pattern in freshwater teleostean fishes. AB - Metabolic enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated in Indian teleostean fishes, namely, Anabas testudineus (Bloch) and Heteropneustes fossilis (Bloch), for an exposure to 30 days of Excel Mera 71 (17.2 mg/L), a glyphosate formulation, and subsequent depuration under Liv.52, a plant extract at a dose of 187.5 mg/d/250 L for the same period in the same tissues under laboratory condition. ALT activity was significantly increased (P<0.05) in all the tissues and raised up to 229.19% in liver of A. testudineus (229.19%) and 128.61% in liver of H. fossilis. AST also increased significantly (P<0.05) and was maximum in liver of H. fossilis (526.19%) and minimum in gill of A. testudineus (124.38%). ALP activity was also raised highly in intestine of H. fossilis (490.61%) but was less in kidney of H. fossilis (149.48%). The results indicated that Excel Mera 71 caused alterations in the metabolic enzymatic activities in fish tissues and AST showed the highest alteration in both the fishes, while lowest in ALP and ALT in A. testudineus and H. fossilis, respectively. During depuration under Liv.52, all the enzyme activities came down towards the control condition which indicated the compensatory response by the fish against this herbicidal stress and it was in the following order: AST>ALT>ALP, in A. testudineus, while H. fossilis showed the following trend: ALT>AST>ALP. Therefore, these parameters could be used as indicators of herbicidal pollution in aquatic organisms and were recommended for environmental monitoring for investigating the mechanism involved in the recovery pattern. PMID- 25013783 TI - Lead screening for HIV-1 integrase (IN) inhibited by traditional Chinese medicine. AB - Human immunodeficiency virus causes the acquired immunodeficiency syndrome (AIDS) and becomes a serious world-wide problem because of this disease's rapid propagation and incurability. Integrase strand transfer inhibitors (INSTIs) supports HIV have rapid drug resistance for antitreatment. Screening the traditional Chinese medicine (TCM) database by simulating molecular docking and molecular dynamics may select molecular compounds to inhibit INSTIs against HIV drug resistance. (S)-cathinone and (1S,2S)-norpseudoephedrine are selected based on structure and ligand-based drugs are designed and then get higher bioactivity predicted score from SVM than Raltegravir and other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions and hydrogen bond variations define the main regions of important amino acids in integrase. In addition to the detection of TCM compound efficacy, we suggest (1S,2S)-norpseudoephedrine is better than the others based on the analysis of interaction and the effect on the structural variation. PMID- 25013784 TI - Intraoperative cerebral glioma characterization with contrast enhanced ultrasound. AB - BACKGROUND: Contrast enhanced ultrasound (CEUS) is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and a thorough characterization of cerebral glioma had never been performed before. AIM: To perform the first characterization of cerebral glioma using CEUS and to possibly achieve an intraoperative differentiation of different gliomas. METHODS: We performed CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An intraoperative qualitative analysis was performed comparing iCEUS with B-mode imaging. A postprocedural semiquantitative analysis was then performed for each case, according to EFSUMB criteria. Results were related to histopathology. RESULTS: We observed different CE patterns: LGG show a mild, dotted CE with diffuse appearance and slower, delayed arterial and venous phase. HGG have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns. CONCLUSION: Our study characterizes for the first time human brain glioma with CEUS, providing further insight regarding these tumors' biology. CEUS is a fast, safe, dynamic, real-time, and economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining surgical strategy. PMID- 25013786 TI - Chaotic analysis of the electroretinographic signal for diagnosis. AB - Electroretinogram (ERG) is a time-varying potential which arises from different layers of retina. To be specific, all the physiological signals may contain some useful information which is not visible to our naked eye. However this subtle information is difficult to monitor directly. Therefore the ERG signal features which are extracted and analyzed using computers are highly useful for diagnosis. This work discusses the chaotic aspect of the ERG signal for the controls, congenital stationary night blindness (CSNB), and cone-rod dystrophy (CRD) classes. In this work, nonlinear parameters like Hurst exponent (HE), the largest Lyapunov exponent (LLE), Higuchi's fractal dimension (HFD), and approximate entropy (ApEn) are analyzed for the three different classes. It is found that the measures like HE dimension and ApEn are higher for controls as compared to the other two classes. But LLE shows no distinguishable variation for the three cases. We have also analyzed the recurrence plots and phase-space plots which shows a drastic variation among the three groups. The results obtained show that the ERG signal is highly complex for the control groups and less complex for the abnormal classes with P value less than 0.05. PMID- 25013785 TI - Silicone oil: different physical proprieties and clinical applications. AB - Silicone oils are important tools in vitreoretinal surgery because they have the ability to displace aqueous humor from the retinal surface, maintaining the adhesion between retina and retinal pigment epithelium. To understand this capability, it is important to know the silicone oil characteristics. Herein, we report first on the main chemical-physical proprieties and then we review the clinical applications of the current silicone oil which is lighter than water with particular reference to their indications with small gauge vitrectomy. Finally, we describe the surgical techniques to inject and remove this type of silicone oil. In the summary of this paper, we explain why silicone oils are today increasingly used and why their introduction has improved the prognosis of several retinal diseases. In fact, having different types of silicone oils allows us to choose the appropriate endotamponade for every single case. PMID- 25013787 TI - Is Roux-Y binding pancreaticojejunal anastomosis feasible for patients undergoing left pancreatectomy? Results from a prospective randomized trial. AB - BACKGROUND: After pancreaticoduodenectomy, the Finnish binding pancreaticojejunal anastomosis (FBPJ) seems to reduce the risk for pancreatic fistula (POPF). Our aim was to investigate whether FBPJ is feasible and prevents the risk for POPF even after left pancreatectomy (LP). PATIENTS AND METHODS: 47 consecutive patients underwent LP. 27 patients were recruited on the basis of CT and, of these, 16 patients were randomized on the basis of findings during surgery (transection line must be left of portal vein, as 2-3 cm pancreatic mobilization is required for FBPJ) to receive either Roux-Y FBPJ or hand-sewn closure of the pancreatic remnant. RESULTS: Only 34% (16/47) of the patients met the randomization criteria. Clinically significant POPF rate was higher in FBPJ group (60%) compared to thand-sewn closure group (13%; P<0.05). POPF rate in FBPJ group was higher even when compared to all patients with hand-sewn closure (60% versus 37%; P<0.05). Overall, FBPJ was technically feasible for only 28% of patients. CONCLUSION: FBPJ cannot be recommended for the routine closure of the pancreatic remnant after LP, as it was not technically achievable in 72% of the cases. Moreover, the technique does not seem to reduce the risk for POPF compared to the hand-sewn closure. PMID- 25013788 TI - Endplates changes related to age and vertebral segment. AB - Endplate separations are defined as the presence of a space between the hyaline cartilage and the cortical bone of the adjacent vertebral body. This study evaluates endplate separations from the vertebral body and intervertebral discs and verifies if endplate separation is related to age and the spinal level. Groups were formed based on age (20-40 and 41-85 years old) and the vertebral segment (T7-T8 and L4-L5 segments). Histological analysis included assessment of the length of the vertebral endplates, the number and dimensions of the separations, and orientation of the collagen fibers, in the mid-sagittal slice. Two indexes were created: the separation index (number of separations/vertebral length) and separation extension index (sum of all separations/vertebral length). The results of the study demonstrated a direct relationship between the density of separations in the endplate and two variables: age and spinal level. PMID- 25013789 TI - A combined MPI-CUDA parallel solution of linear and nonlinear Poisson-Boltzmann equation. AB - The Poisson-Boltzmann equation models the electrostatic potential generated by fixed charges on a polarizable solute immersed in an ionic solution. This approach is often used in computational structural biology to estimate the electrostatic energetic component of the assembly of molecular biological systems. In the last decades, the amount of data concerning proteins and other biological macromolecules has remarkably increased. To fruitfully exploit these data, a huge computational power is needed as well as software tools capable of exploiting it. It is therefore necessary to move towards high performance computing and to develop proper parallel implementations of already existing and of novel algorithms. Nowadays, workstations can provide an amazing computational power: up to 10 TFLOPS on a single machine equipped with multiple CPUs and accelerators such as Intel Xeon Phi or GPU devices. The actual obstacle to the full exploitation of modern heterogeneous resources is efficient parallel coding and porting of software on such architectures. In this paper, we propose the implementation of a full Poisson-Boltzmann solver based on a finite-difference scheme using different and combined parallel schemes and in particular a mixed MPI-CUDA implementation. Results show great speedups when using the two schemes, achieving an 18.9x speedup using three GPUs. PMID- 25013790 TI - Evaluation of cardiac function index as measured by transpulmonary thermodilution as an indicator of left ventricular ejection fraction in cardiogenic shock. AB - INTRODUCTION: The PiCCO transpulmonary thermodilution technique provides two indices of cardiac systolic function, the cardiac function index (CFI) and the global ejection fraction (GEF). Both appear to be correlated with left ventricular ejection fraction (LVEF) measured by echocardiography in patients with circulatory failure, especially in septic shock. The aim of the present study was to test the reliability of CFI as an indicator of LVEF in patients with cardiogenic shock. METHODS: In thirty-five patients with cardiogenic shock, we performed (i) simultaneous measurements of echocardiography LVEF and cardiac function index assessed by transpulmonary thermodilution (n=72) and (ii) transpulmonary thermodilution before/after increasing inotropic agents (n=18). RESULTS: Mean LVEF was 31% (+/-11.7), CFI 3/min (+/-1), and GEF 14.2% (+/-6). CFI and GEF were both positively correlated with LVEF (P<0.0001, r2=0.27). CFI and GEF were significantly increased with inotropic infusion (resp., P=0.005, P=0.007). A cardiac function index<3.47/min predicted a left ventricular ejection fraction<=35% (sensitivity 81.1% and specificity 63%). In patients with right ventricular dysfunction, CFI was not correlated with LVEF. CONCLUSION: CFI is correlated with LVEF provided that patient does not present severe right ventricular dysfunction. Thus, the PiCCO transpulmonary thermodilution technique is useful for the monitoring of inotropic therapy during cardiogenic shock. PMID- 25013792 TI - Evaluation of correlation of cell cycle proteins and Ki-67 interaction in paranasal sinus inverted papilloma prognosis and squamous cell carcinoma transformation. AB - The recurrent sinonasal inverted papilloma (IP) could be transformed to sinonasal squamous cell carcinoma. We use protein expression patterns by immunohistochemical method to see whether the expression of p53, p16, p21, and p27 belongs to cell-cycle-regulators and PCNA (proliferating cell nuclear antigen) and Ki-67 the proliferation markers in sixty patients with sinonasal inverted papilloma, and 10 of them with squamous cell carcinoma transformation. Significantly elevated levels of Ki-67, p27, and PCNA in IP with squamous cell carcinoma transformation of sinonasal tract compared with inverted papilloma were revealed. No variation of p16, p21, PLUNC (palate, lung, and nasal epithelium clone protein) and p53 expression was correlated to sinonasal IP malignant transformation by multivariate survey. However, we found elevated PLUNC expression in IPs with multiple recurrences. Finally, we found that PCNA, p27 may interact with CDK1 which promote IP cell proliferation and correlate to sinonasal squamous cell carcinoma. Ki-67 could work throughout the cell cycles to cause malignant transformation. In conclusion, this is a first study showing the correlation of Ki-67, PCNA interacted with CDK1 might lead to malignant transformation. Elevated PLUNC expression in the sinonasal IPs was related to multiple recurrences in human. PMID- 25013793 TI - Correlation of choroidal thickness and volume measurements with axial length and age using swept source optical coherence tomography and optical low-coherence reflectometry. AB - PURPOSE: To report choroidal thickness and volume in healthy eyes using swept source optical coherence tomography (SS-OCT). METHODS: A prospective observational study of 122 patients examined with swept source OCT (DRI-OCT, Topcon, Japan). In each eye, we performed 256 horizontal scans, 12 mm in length and centered on the fovea. We calculated choroidal thickness manually with a built-in caliper and automatically using DRI-OCT mapping software. Choroidal volume was also automatically calculated. We measured axial length with optical low-coherence reflectometry (Lenstar LS 900, Haag-Streit, Switzerland). RESULTS: The choroid has focally increased thickness under the fovea. Choroid was thinnest in the outer nasal quadrant. In stepwise regression analysis, age was estimated as the most significant factor correlating with decreased choroidal thickness (F=23.146, P<0.001) followed by axial length (F=4.902, P=0.03). Refractive error was not statistically significant (F=1.16, P=0.28). CONCLUSIONS: SS-OCT is the first commercially available system that can automatically create choroidal thickness and volume maps. Choroidal thickness is increased at the fovea and is thinnest nasally. Age and axial length are critical for the estimation of choroidal thickness and volume. Choroidal measurements derived from SS-OCT images have potential value for objectively documenting disease-related choroidal thickness abnormalities and monitoring progressive changes over time. PMID- 25013791 TI - Emerging biomarkers and metabolomics for assessing toxic nephropathy and acute kidney injury (AKI) in neonatology. AB - Identification of novel drug-induced toxic nephropathy and acute kidney injury (AKI) biomarkers has been designated as a top priority by the American Society of Nephrology. Increasing knowledge in the science of biology and medicine is leading to the discovery of still more new biomarkers and of their roles in molecular pathways triggered by physiological and pathological conditions. Concomitantly, the development of the so-called "omics" allows the progressive clinical utilization of a multitude of information, from those related to the human genome (genomics) and proteome (proteomics), including the emerging epigenomics, to those related to metabolites (metabolomics). In preterm newborns, one of the most important factors causing the pathogenesis and the progression of AKI is the interaction between the individual genetic code, the environment, the gestational age, and the disease. By analyzing a small urine sample, metabolomics allows to identify instantly any change in phenotype, including changes due to genetic modifications. The role of liquid chromatography-mass spectrometry (LC MS), proton nuclear magnetic resonance (1H NMR), and other emerging technologies is strategic, contributing basically to the sudden development of new biochemical and molecular tests. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are closely correlated with the severity of kidney injury, representing noninvasive sensitive surrogate biomarkers for diagnosing, monitoring, and quantifying kidney damage. To become routine tests, uNGAL and KIM-1 should be carefully tested in multicenter clinical trials and should be measured in biological fluids by robust, standardized analytical methods. PMID- 25013794 TI - Missed opportunities: evolution of patients leaving without being seen or against medical advice during a six-year period in a Swiss tertiary hospital emergency department. AB - AIM: The study aimed at describing the evolution over a 6-year period of patients leaving the emergency department (ED) before being seen ("left without being seen" or LWBS) or against medical advice ("left against medical advice" or LAMA) and at describing their characteristics. METHODS: A retrospective database analysis of all adult patients who are admitted to the ED, between 2005 and 2010, and who left before being evaluated or against medical advice, in a tertiary university hospital. RESULTS: During the study period, among the 307,716 patients who were registered in the ED, 1,157 LWBS (0.4%) and 1,853 LAMA (0.9%) patients were identified. These proportions remained stable over the period. The patients had an average age of 38.5+/-15.9 years for LWBS and 41.9+/-17.4 years for LAMA. The median time spent in the ED before leaving was 102.4 minutes for the LWBS patients and 226 minutes for LAMA patients. The most frequent reason for LAMA was related to the excessive length of stay. CONCLUSION: The rates of LWBS and LAMA patients were low and remained stable. The patients shared similar characteristics and reasons for leaving were largely related to the length of stay or waiting time. PMID- 25013795 TI - Differential expression and immunolocalization of antioxidant enzymes in Entamoeba histolytica isolates during metronidazole stress. AB - Entamoeba histolytica infections are endemic in the Indian subcontinent. Five to eight percent of urban population residing under poor sanitary conditions suffers from Entamoeba infections. Metronidazole is the most widely prescribed drug used for amoebiasis. In order to understand the impact of metronidazole stress on the parasite, we evaluated the expression of two antioxidant enzymes, peroxiredoxin and FeSOD, in Entamoeba histolytica isolates during metronidazole stress. The results reveal that, under metronidazole stress, the mRNA expression levels of these enzymes did not undergo any significant change. Interestingly, immunolocalization studies with antibodies targeting peroxiredoxin indicate differential localization of the protein in the cell during metronidazole stress. In normal conditions, all the Entamoeba isolates exhibit presence of peroxiredoxin in the nucleus as well as in the membrane; however with metronidazole stress the protein localized mostly to the membrane. The change in the localization pattern was more pronounced when the cells were subjected to short term metronidazole stress compared to cells adapted to metronidazole. The protein localization to the cell membrane could be the stress response mechanism in these isolates. Colocalization pattern of peroxiredoxin with CaBp1, a cytosolic protein, revealed that the membrane and nuclear localization was specific to peroxiredoxin during metronidazole stress. PMID- 25013797 TI - Synthesis and antihypertensive screening of new derivatives of quinazolines linked with isoxazole. AB - A series of 7-substituted-3-(4-(3-(4-substitutedphenyl)-4,5-dihydroisoxazol-5 yl)phenyl)-2-substituted quinazolin-4(3H)-one (1-30) have been synthesized by the cyclization of (E)-3-(4-(3-substitutedphenyl)acrylolyl)phenyl)-2 (substitutedphenyl)-7-substituted quinazolin-4-(3H)-one with hydroxylamine hydrochloride. The synthesized compounds were examined for their in vivo antihypertensive activity using albino rats. All the titled compounds exhibited good to moderate antihypertensive activity. Compounds 7-Chloro-3-(4-(3-(4 chlorophenyl)-4,5- dihydroisoxazol-5-yl)phenyl)-2-p-tolylquinazolin-4(3H)-one (23) and 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-(4 methoxyphenyl)quinazolin-4(3H)-one (24) exhibited potent antihypertensive activity through their anticipated alpha 1-adrenergic receptor blocking property similar to its clinically used analogue, prazosin, without affecting heart rate with prolonged duration of action when tested in adrenaline induced hypertension in anaesthetized rats. PMID- 25013796 TI - Atrial natriuretic peptide and renal dopaminergic system: a positive friendly relationship? AB - Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways. PMID- 25013798 TI - Canine babesiosis in northwestern India: molecular detection and assessment of risk factors. AB - In the current study, a total of 214 blood samples from dogs in and around Ludhiana, Punjab (India), suspected for canine babesiosis were examined with conventional and molecular assays. Examination of Giemsa-stained peripheral thin blood smears revealed an overall prevalence of 7.47% (16/214) for canine babesiosis encompassing 0.93% (2/214) of large Babesia and 6.54% (14/214) of Babesia gibsoni. However, molecular diagnosis revealed 15.42% (33/214) samples positive for B. gibsoni infection as evident by the presence of 671 bp amplicon. The results of multivariate analysis showed that the prevalence of B. gibsoni was associated with various risk factors, namely, age (P<0.001; OR: 0.398; CI 95%: 0.080-1.799), sex (P=0.022; OR: 0.849; CI 95%: 0.403-1.791), breed of host (P=0.371; OR: 3.345; CI 95%: 1.045-10.710), and season (P=0.230; OR: 2.143; CI 95%: 0.788-5.830). The prevalence of B. gibsoni was higher in summer as compared to winter season and in younger dogs, while breed and sex of the host were not significantly associated with the occurrence of the disease. PMID- 25013800 TI - Renal transplantation in systemic lupus erythematosus: outcome and prognostic factors in 50 cases from a single centre. AB - BACKGROUND: End-stage renal disease (ESRD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). OBJECTIVES: To analyze the outcome and prognostic factors of renal transplantation in patients with ESRD due to SLE from January 1986 to December 2013 in a single center. RESULTS: Fifty renal transplantations were performed in 40 SLE patients (32 female (80%), mean age at transplantation 36+/-10.4 years). The most frequent lupus nephropathy was type IV (72.2%). Graft failure occurred in a total of 15 (30%) transplantations and the causes of graft failure were chronic allograft nephropathy (n=12), acute rejection (n=2), and chronic humoral rejection (1). The death-censored graft survival rates were 93.9% at 1 year, 81.5% at 5 years, and 67.6% at the end of study. The presence of deceased donor allograft (P=0.007) and positive anti-HCV antibodies (P=0.001) negatively influence the survival of the renal transplant. The patient survival rate was 91.4% at the end of the study. Recurrence of lupus nephritis in renal allograft was observed in one patient. CONCLUSION: Renal transplantation is a good alternative for renal replacement therapy in patients with SLE. In our cohort, the presence of anti-HCV antibodies and the type of donor source were related to the development of graft failure. PMID- 25013799 TI - Pulmonary arterial hypertension in adults: novel drugs and catheter ablation techniques show promise? Systematic review on pharmacotherapy and interventional strategies. AB - This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure. PMID- 25013801 TI - The increased type-1 and type-2 chemokine levels in children with acute RSV infection alter the development of adaptive immune responses. AB - Severe RSV infections and frequent recurrence could be related to the altered polarization of type-2/type-1 T cells. This increases the importance of determining distinctive chemokines and chemokine receptor profiles on memory T cells. We analyzed systemic adaptive T cell response in the acute (n=17) and convalescent phase (n=7) of RSV-infected children, in the acute (n=11) and convalescent phase (n=6) of children with other viral respiratory infections (adenovirus and influenza virus), and in healthy children (n=18). Expression of CCR4 and CXCR3 on effector-memory (TEM) and central-memory (TCM) T cells was compared between tested groups. Serum concentrations of specific chemokines were determined. High CXCL10 levels were detected in acutely infected children regardless of virus pathogen, whereas increased CCL17 production was RSV specific. Higher percentages of CCR4+ CD4 TEM cells in acute RSV infection were accompanied with higher percentages of CXCR3+ CD8 TEM cells, whereas the development of long-lived memory CXCR3+ CD4 and CD8 TCM cells seems to be compromised, as only children with other viral infections had higher percentages in the convalescent phase. Presence of type-2 and type-1 adaptive antiviral immune response, together with insufficient development of long-lived type-1 T cell memory, could play an important role in RSV pathogenesis and reinfection. PMID- 25013802 TI - Protective effects of Borago officinalis extract on amyloid beta-peptide(25-35) induced memory impairment in male rats: a behavioral study. AB - Alzheimer's disease (AD) is a neurodegenerative disorder and most common form of dementia that leads to memory impairment. In the present study we have examined the protective effects of Borago officinalis (borage) extract on Amyloid beta (A beta)-Induced memory impairment. Wistar male rats received intrahippocampal (IHP) injection of the A beta (25-35) and borage extract throughout gestation (100 mg/kg). Learning and memory functions in the rats were examined by the passive avoidance and the Morris water maze (MWM) tasks. Finally, the antioxidant capacity of hippocampus was measured using ferric ion reducing antioxidant power (FRAP) assay. The results showed that A beta (25-35) impaired step-through latency and time in dark compartment in passive avoidance task. In the MWM, A beta (25-35) significantly increased escape latency and traveled distance. Borage administration attenuated the A beta-induced memory impairment in both the passive avoidance and the MWM tasks. A beta induced a remarkable decrease in antioxidant power (FRAP value) of hippocampus and borage prevented the decrease of the hippocampal antioxidant status. This data suggests that borage could improve the learning impairment and oxidative damage in the hippocampal tissue following A beta treatment and that borage consumption may lead to an improvement of AD-induced cognitive dysfunction. PMID- 25013804 TI - Novel epoxy activated hydrogels for solving lactose intolerance. AB - "Lactose intolerance" is a medical problem for almost 70% of the world population. Milk and dairy products contain 5-10% w/v lactose. Hydrolysis of lactose by immobilized lactase is an industrial solution. In this work, we succeeded to increase the lactase loading capacity to more than 3-fold to 36.3 U/g gel using epoxy activated hydrogels compared to 11 U/g gel using aldehyde activated carrageenan. The hydrogel's mode of interaction was proven by FTIR, DSC, and TGA. The high activity of the epoxy group was regarded to its ability to attach to the enzyme's -SH, -NH, and -OH groups, whereas the aldehyde group could only bind to the enzyme's -NH2 group. The optimum conditions for immobilization such as epoxy chain length and enzyme concentration have been studied. Furthermore, the optimum enzyme conditions were also deliberated and showed better stability for the immobilized enzyme and the Michaelis constants, K m and V max, were doubled. Results revealed also that both free and immobilized enzymes reached their maximum rate of lactose conversion after 2 h, albeit, the aldehyde activated hydrogel could only reach 63% of the free enzyme. In brief, the epoxy activated hydrogels are more efficient in immobilizing more enzymes than the aldehyde activated hydrogel. PMID- 25013803 TI - Effect of the Zataria multiflora on systemic inflammation of experimental animals model of COPD. AB - The effects of Zataria multiflora (Z. multiflora) on systemic inflammation in guinea pigs model of COPD were examined. Control animals, COPD (induced by exposing animals to cigarette smoke), COPD+drinking water containing three concentrations of the extract of Z. multiflora, and COPD+dexamethasone were studied (n=6 for each group). Serum levels of IL-8 and malondialdehyde (MDA), total blood WBC (P<0.01 for all cases), and eosinophil counts (P<0.05) were higher and weight changes (P<0.05) were lower in the COPD group compared to controls. IL-8 level (P<0.001) and weight changes (P<0.01 to P<0.001) in all treated groups with Z. multiflora and total WBC number and MDA level in treated groups with two higher concentrations of the extract and lymphocytes percentage (P<0.05) in the highest concentration of Z. multiflora and dexamethasone (P<0.05 to P<0.001) were significantly improved compared to the COPD group. Results showed a preventive effect of hydroethanolic extract from Z. multiflora on all measured parameters in animals model of COPD which was comparable or even higher (in the highest concentration) compared to the effect of dexamethasone at the concentration used. PMID- 25013805 TI - Privacy preserving RBF kernel support vector machine. AB - Data sharing is challenging but important for healthcare research. Methods for privacy-preserving data dissemination based on the rigorous differential privacy standard have been developed but they did not consider the characteristics of biomedical data and make full use of the available information. This often results in too much noise in the final outputs. We hypothesized that this situation can be alleviated by leveraging a small portion of open-consented data to improve utility without sacrificing privacy. We developed a hybrid privacy preserving differentially private support vector machine (SVM) model that uses public data and private data together. Our model leverages the RBF kernel and can handle nonlinearly separable cases. Experiments showed that this approach outperforms two baselines: (1) SVMs that only use public data, and (2) differentially private SVMs that are built from private data. Our method demonstrated very close performance metrics compared to nonprivate SVMs trained on the private data. PMID- 25013806 TI - The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. AB - The ubiquitin-proteasome system and autophagy were long viewed as independent, parallel degradation systems with no point of intersection. By now we know that these degradation pathways share certain substrates and regulatory molecules and show coordinated and compensatory function. Two ubiquitin-like protein conjugation pathways were discovered that are required for autophagosome biogenesis: the Atg12-Atg5-Atg16 and Atg8 systems. Autophagy has been considered to be essentially a nonselective process, but it turned out to be at least partially selective. Selective substrates of autophagy include damaged mitochondria, intracellular pathogens, and even a subset of cytosolic proteins with the help of ubiquitin-binding autophagic adaptors, such as p62/SQSTM1, NBR1, NDP52, and Optineurin. These proteins selectively recognize autophagic cargo and mediate its engulfment into autophagosomes by binding to the small ubiquitin-like modifiers that belong to the Atg8/LC3 family. PMID- 25013807 TI - A RXR ligand 6-OH-11-O-hydroxyphenanthrene with antitumour properties enhances ( )-epigallocatechin-3-gallate activity in three human breast carcinoma cell lines. AB - (-)-Epigallocatechin-3-gallate (EGCG) and chemotherapeutic agents cotreatment can improve cytotoxicity against cancer cells. We showed that EGCG and the rexinoid 6 OH-11-O-hydroxyphenanthrene (IIF), given together, were cytotoxic toward MCF-7, MCF-7TAM, and MDA-MB-231, three breast carcinoma cell lines showing different molecular characteristics. Cell growth arrest and apoptosis were greater after EGCG and IIF cotreatment than after individual administration. Cytotoxicity was related to upregulation of 67-kDa laminin receptor (LR67), one of the principal molecular targets of EGCG, and activation of the nuclear retinoic X receptors (RXRs) pathway. Furthermore, the transcription factor Forkhead box O3 (Foxo3a), a protein able to trigger apoptosis through upregulation of genes necessary for cell death, was activated. EGCG and IIF cotreatment produced a significant nuclear import of Foxo3a from the cytoplasm in MCF-7, MCF-7TAM, and MDA-MB-231 cells. In MCF-7TAM cells only, Foxo3a nuclear localization was associated with p473AKT downregulation. For the first time we showed that when EGCG and IIF, two harmless molecules, were given together, they might increase cytotoxicity in three breast carcinoma cell lines, two of them being representative of poorly responsive breast carcinoma types. PMID- 25013809 TI - A mathematical model of skeletal muscle disease and immune response in the mdx mouse. AB - Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared. PMID- 25013808 TI - PET radiopharmaceuticals for imaging integrin expression: tracers in clinical studies and recent developments. AB - Noninvasive determination of integrin expression has become an interesting approach in nuclear medicine. Since the discovery of the first 18F-labeled cyclic RGD peptide as radiotracer for imaging integrin alphavbeta3 expression in vivo, there have been carried out enormous efforts to develop RGD peptides for PET imaging. Moreover, in recent years, additional integrins, including alpha5beta1 and alphavbeta6 came into the focus of pharmaceutical radiochemistry. This review will discuss the tracers already evaluated in clinical trials and summarize the preliminary outcome. It will also give an overview on recent developments to further optimize the first-generation compounds such as [18F]Galacto-RGD. This includes recently developed 18F-labeling strategies and also new approaches in 68Ga-complex chemistry. Furthermore, the approaches to develop radiopharmaceuticals targeting integrin alpha5beta1 and alphavbeta6 will be summarized and discussed. PMID- 25013810 TI - Simvastatin combined with antioxidant attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. AB - Traumatic brain injury (TBI) leads to important and deleterious neuroinflammation, as evidenced by indicators such as edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. After TBI, cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation. In our previous study, we proved that simvastatin could attenuate cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. This purpose of this study was to determine whether simvastatin combined with an antioxidant could produce the same effect or greater and to examine affected surrogate biomarkers for the neuroinflammation after traumatic brain injury in rat. In our study, cortical contusions were induced, and the effect of acute and continuous treatment of simvastatin and vitamin C on behavior and inflammation in adult rats following experimental TBI was evaluated. The results demonstrated that simvastatin combined with an antioxidant could provide neuroprotection and it may be attributed to a dampening of cerebral vascular endothelial inflammatory response. PMID- 25013811 TI - Effect of high-fat diet upon inflammatory markers and aortic stiffening in mice. AB - Changes in lifestyle such as increase in high-fat food consumption are an important cause for vascular diseases. The present study aimed to investigate the involvement of ACE and TGF- beta in the aorta stiffness induced by high-fat diet. C57BL/6 male mice were divided in two groups according to their diet for 8 weeks: standard diet (ST) and high-fat diet (HF). At the end of the protocol, body weight gain, adipose tissue content, serum lipids and glucose levels, and aorta morphometric and biochemical measurements were performed. Analysis of collagen fibers by picrosirius staining of aorta slices showed that HF diet promoted increase of thin (55%) and thick (100%) collagen fibers deposition and concomitant disorganization of these fibers orientations in the aorta vascular wall (50%). To unravel the mechanism involved, myeloperoxidase (MPO) and angiotensin I converting enzyme (ACE) were evaluated by protein expression and enzyme activity. HF diet increased MPO (90%) and ACE (28%) activities, as well as protein expression of ACE. TGF-beta was also increased in aorta tissue of HF diet mice after 8 weeks. Altogether, we have observed that the HF diet-induced aortic stiffening may be associated with increased oxidative stress damage and activation of the RAS in vascular tissue. PMID- 25013813 TI - EEG oscillatory phase-dependent markers of corticospinal excitability in the resting brain. AB - Functional meaning of oscillatory brain activity in various frequency bands in the human electroencephalogram (EEG) is increasingly researched. While most research focuses on event-related changes of brain activity in response to external events there is also increasing interest in internal brain states influencing information processing. Several studies suggest amplitude changes of EEG oscillatory activity selectively influencing cortical excitability, and more recently it was shown that phase of EEG activity (instantaneous phase) conveys additional meaning. Here we review this field with many conflicting findings and further investigate whether corticospinal excitability in the resting brain is dependent on a specific spontaneously occurring brain state reflected by amplitude and instantaneous phase of EEG oscillations. We applied single pulse transcranial magnetic stimulation (TMS) over the left sensorimotor cortex, while simultaneously recording ongoing oscillatory activity with EEG. Results indicate that brain oscillations reflect rapid, spontaneous fluctuations of cortical excitability. Instantaneous phase but not amplitude of oscillations at various frequency bands at stimulation site at the time of TMS-pulse is indicative for brain states associated with different levels of excitability (defined by size of the elicited motor evoked potential). These results are further evidence that ongoing brain oscillations directly influence neural excitability which puts further emphasis on their role in orchestrating neuronal firing in the brain. PMID- 25013812 TI - Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis? AB - The somatic mutation theory of carcinogenesis has eventually accumulated an impressive body of shortfalls and paradoxes, as admittedly claimed by its own supporters given that the cell-based approach can hardly explain the emergence of tissue-based processes, like cancer. However, experimental data and alternatives theories developed during the last decades may actually provide a new framework on which cancer research should be reframed. Such issue may be fulfilled embracing new theoretical perspectives, taking the cells-microenvironment interplay as the privileged level of observation and assuming radically different premises as well as new methodological frameworks. Within that perspective, the tumor microenvironment cannot be merely considered akin to new "factor" to be added to an already long list of "signaling factors"; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach. That endeavour entails three fundamental aspects: general biological premises, the level of observation (i.e., the systems to which we are looking for), and the principles of biological organization that would help in integrating and understanding experimental data. PMID- 25013814 TI - Directly-observed intermittent therapy versus unsupervised daily regimen during the intensive phase of antituberculosis therapy in HIV infected patients. AB - The World Health Organization strongly recommends using daily antituberculosis therapy (ATT) during the intensive phase for HIV infected patients. India has the highest burden of tuberculosis in the world, but HIV infected patients are still receiving intermittent ATT. In this study we compared the mortality in patients who received directly-observed intermittent ATT versus self-administered daily ATT with fixed dose combinations during the intensive phase in a context of freely available antiretroviral therapy. The study included 1460 patients, 343 in the intermittent ATT group and 1117 in the daily ATT group. Baseline covariates of the two groups were balanced using inverse probability of treatment weighting based on propensity score methods. In a sensitivity analysis, continuous variables (albumin, CD4 count, and age) were modelled using restricted cubic smoothing splines. Compared with patients who received daily ATT, patients who received intermittent ATT had a 40% higher risk of mortality (1.4 hazard ratio; 95% confidence interval, 1.14-1.7). We estimated that the use of daily ATT could achieve a 10% absolute reduction in mortality at 12 months. Self-administered daily ATT was not associated with an increased risk of default from treatment. These results support the immediate implementation of daily ATT for HIV infected patients during the intensive phase in India. PMID- 25013815 TI - Exposure of a 23F serotype strain of Streptococcus pneumoniae to cigarette smoke condensate is associated with selective upregulation of genes encoding the two component regulatory system 11 (TCS11). AB - Alterations in whole genome expression profiles following exposure of the pneumococcus (strain 172, serotype 23F) to cigarette smoke condensate (160 MUg/mL) for 15 and 60 min have been determined using the TIGR4 DNA microarray chip. Exposure to CSC resulted in the significant (P<0.014-0.0006) upregulation of the genes encoding the two-component regulatory system 11 (TCS11), consisting of the sensor kinase, hk11, and its cognate response regulator, rr11, in the setting of increased biofilm formation. These effects of cigarette smoke on the pneumococcus may contribute to colonization of the airways by this microbial pathogen. PMID- 25013817 TI - Parainfluenza virus type 1 induces epithelial IL-8 production via p38-MAPK signalling. AB - Human parainfluenza virus type 1 (HPIV-1) is the most common cause of croup in infants. The aim of this study was to describe molecular mechanisms associated with IL-8 production during HPIV-1 infection and the role of viral replication in MAPK synthesis and activation. An in vitro model of HPIV-1 infection in the HEp-2 and A549 cell lines was used; a kinetic-based ELISA for IL-8 detection was also used, phosphorylation of the mitogen-activated protein kinases (MAPKs) was identified by Western blot analysis, and specific inhibitors for each kinase were used to identify which MAPK was involved. Inactivated viruses were used to assess whether viral replication is required for IL-8 production. Results revealed a gradual increase in IL-8 production at different selected times, when phosphorylation of MAPK was detected. The secretion of IL-8 in the two cell lines infected with the HPIV-1 is related to the phosphorylation of the MAPK as well as viral replication. Inhibition of p38 suppressed the secretion of IL-8 in the HEp 2 cells. No kinase activation was observed when viruses were inactivated. PMID- 25013816 TI - MicroRNAs expression profiles in cardiovascular diseases. AB - The current search for new markers of cardiovascular diseases (CVDs) is explained by the high morbidity and mortality still observed in developed and developing countries due to cardiovascular events. Recently, microRNAs (miRNAs or miRs) have emerged as potential new biomarkers and are small sequences of RNAs that regulate gene expression at posttranscriptional level by inhibiting translation or inducing degradation of the target mRNAs. Circulating miRNAs are involved in the regulation of signaling pathways associated to aging and can be used as novel diagnostic markers for acute and chronic diseases such as cardiovascular pathologies. This review summarizes the biogenesis, maturation, and stability of miRNAs and their use as potential biomarkers for coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF). PMID- 25013819 TI - Use of telemedicine in disaster and remote places. AB - One of the methods, especially those living in remote areas or have crashed and does not have access to specialists is telemedicine. Telemedicine describes the use of medical information exchanged from one site to another via electronic communications to improve patients' health status and care. Travel and wait times between the initial consultations with the patient's own general practitioner and referral to specialist can be reduced and specialists have successfully provided remote triage and treatment consults of victims via the robot. The robot proved to be a useful means to extend resources and provide expert consulting if specialists were unable to physically be at the site. In fact, the telemedicine system is providing health care services for individuals who are not available because of geographical and environmental conditions. The aim of this study was to identify telemedicine applications in disaster, and proposed use of this technology in areas where the shortage of specialists in remote areas in disasters. This study was un-systematic (narrative) review. The literature was searched for using of telemedicine in disaster and remote places with the help of libraries, conference proceedings, data bank, and also search engines available at Google, Google scholar. In our searches, we employed the following keywords and their combinations: telemedicine, remote place, earthquake, disaster, war, and telecommunication in the searching areas of title, keyword, abstract, and full text. In this study, more than 85 articles and reports were collected and 26 of them were selected based on their relevancy. This literature review helps define the concept of "components and usages of the Telemedicine in disaster" as the new technology in the present age. PMID- 25013818 TI - Increased frequency of circulating follicular helper T cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection. AB - Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD) in children. The role of T follicular helper (TFH) cells in EV71-infected children remains unclear in regulating humoral immunity. The frequency of circulating ICOS(high)/PD-1(high)CXCR5(+)CD4(+) TFH cells in the children with mild and severe EV71 infection and healthy controls (HC) was detected by flow cytometry, respectively. IL-21 and IL-6 mRNA expression and their serum levels, Bcl-6 mRNA expression, and specific neutralizing antibodies against EV71 (NAb EV71) were measured. In the acute stage of patients with EV71 infection, increased frequencies of circulating TFH cells with ICOS(high) and PD-1(high) expression in the mild and severe patients were observed, and the positive correlations among the frequencies of circulating TFH cells and the serum levels of IL-21, IL-6, and NAb-EV71 titres were detected, respectively. Moreover, the expressions of IL-6 and IL-21 mRNA in PBMCs from patients were also significantly higher than those of HC. However, further analysis did not reveal any significant differences between mild and severe patients. These data indicate a role of TFH cells and associated cytokines in modulating the humoral response during the pathogenesis of EV71 infection. PMID- 25013820 TI - Experts' perceptions of the concept of induced demand in healthcare: A qualitative study in Isfahan, Iran. AB - CONTEXT: One of the most important subjects in health economics and healthcare management is the theory of induced demand. There are different views about the concept of induced demand. Extensive texts have been presented on induced demand, however a compatible concept has not necessarily been provided for this phenomenon and it has not been defined explicitly. AIMS: The main aim of this article is to understand the concept of induced demand with the use of experts' perceptions of Isfahan University of Medical Sciences. SETTINGS AND DESIGN: The research was done using a qualitative method. Semi-structured interview was used for data generation. Participants in this study were people who had been informed in this regard and had to be experienced and were known as experts. Purposive sampling was done for data saturation. MATERIALS AND METHODS: Seventeen people were interviewed and criteria such as "reliability of information" and "stability" of the data were considered. The anonymity of the interviewees was preserved. STATISTICAL ANALYSIS USED: The data are transcribed, categorized and then the thematic analysis was used. RESULTS: In this study, 21 sub-categories and three main categories were derived. Three main subjects were included: Induced demand definition, induced demand elements, and induced demand methods. Each of these issues contained some sub-subjects. CONCLUSION: The result of this study provides a framework for examining the concept of induced demand. The most notable findings include the definition of induced demand, induced demand elements, and method of induced demand. In induced demand definition, an important issue that is often overlooked is that inducing regarding to the effectiveness of clinical services and medical values can lead to better or worse outcomes for patients. These findings help the health policy makers study the phenomenon of induced demand with clear-sighted approach. PMID- 25013821 TI - Performance improvement through proactive risk assessment: Using failure modes and effects analysis. AB - INTRODUCTION: Cognizance of any error-prone professional activities has a great impact on the continuity of professional organizations in the competitive atmosphere, particularly in health care industry where every second has critical value in patients' life saving. Considering invaluable functions of medical record department - as legal document and continuity of health care - "failure mode and effects analysis (FMEA)" utilized to identify the ways a process can fail, and how it can be made safer. MATERIALS AND METHODS: The structured approach involved assembling a team of experts, employing a trained facilitator, introducing the rating scales and process during team orientation and collectively scoring failure modes. The probability of the failure-effect combination was related to the frequency of occurrence, potential severity, and likelihood of detection before causing any harm to the staff or patients. Frequency, severity and detectability were each given a score from 1 to 10. Risk priority numbers were calculated. RESULTS: In total 56 failure modes were identified and in subsets of Medical Record Department including admission unit dividing emergency, outpatient and inpatient classes, statististic, health data organizing and data processing and Medical Coding units. Although most failure modes were classified as a high risk group, limited resources were, as an impediment to implement recommended actions at the same time. CONCLUSION: Proactive risk assessment methods, such as FMEA enable health care administrators to identify where and what safeguards are needed to protect against a bad outcome even when an error does occur. PMID- 25013822 TI - Assessment of educational criteria in academic promotion: Perspectives of faculty members of medical sciences universities in Iran. AB - INTRODUCTION: One of the important criteria in the promotion of faculty members is in the scope of their educational roles and duties. The purpose of this study was the assessment of reasonability and attainability of educational criteria for scientific rank promotion from the perspective of the faculty members of Medical Sciences Universities in Iran. MATERIALS AND METHODS: This descriptive study was conducted in 2011 in 13 Universities of Medical Sciences in Iran. Through stratified sampling method, 350 faculty members were recruited. A questionnaire developed by the researchers was used to investigate the reasonability and attainability of educational criteria with scores from 1 to 5. The self administered questionnaire was distributed and collected at each university. The mean and standard deviation of reasonability and attainability scores were calculated and reported by using the SPSS software version 16. RESULTS: Faculty members considered many criteria of educational activities reasonable and available (with a mean score of more than 3). The highest reasonability and attainability have been obtained by the quantity and quality of teaching with the mean scores (3.93 +/- 1.15 and 3.82 +/- 1.17) and (3.9 +/- 1.22 and 4.13 +/- 1.06) out of five, respectively. The mean and standard deviation of total scores of reasonability of educational activities were 50.91 +/- 14.22 and its attainability was 60.3 +/- 13.72 from the total score of 90. DISCUSSION AND CONCLUSION: The faculty members of the Universities of Medical Sciences in Iran considered the educational criteria of promotion moderately reasonable and achievable. It is recommended to revise these criteria and adapt them according to the mission and special conditions of medical universities. Furthermore, providing feedback of evaluations, running educational researches, and implementing faculty development programs are suggested. PMID- 25013823 TI - Is there a digital divide among school students? an exploratory study from Puducherry. AB - BACKGROUND: The advent of internet has triggered a growth in provision of more interactive health promotion messages, which are likely to enhance the potential for behavior change especially among children. We intended to find out the determinants and prevalence of use of internet among school students of Puducherry. MATERIALS AND METHODS: An exploratory study was carried out among all the students belonging to the standards VI to IX (n = 421) in three schools from urban areas and two schools from rural areas of Puducherry. A pretested, self administered questionnaire which sought information on sociodemographic details (age, gender, standard of education, occupation of father, and type of school), use of internet, and place of accessing internet, hours of use, and reasons for use was utilized. The statistical significance between the categorical variables was done using chi-square test. All significance tests were two-tailed and statistical significance was defined as a value of P < 0.05. RESULTS: Majority (72.2%) were boys. Less than one-third (23.8%) of the students used internet. The use of internet was found to be significantly higher in mid-adolescents (Adjusted OR: 2.205); among boys (Adjusted OR: 3.835) and students from urban areas (Adjusted OR: 4.694). CONCLUSION: There is a geographical and gender divide observed among the school children in the use of internet. Taking the steps to bridging the digital divide will help utilize internet as a media for health promotion. PMID- 25013824 TI - Study the drug adherence and possible factor influencing drug adherence in HIV/AIDS patients in north eastern part of India. AB - BACKGROUND: Majority of HIV/AIDS patients who are on Highly Active Anti Retroviral Therapy (HAART), are not aware about drug adherence and its importance which is the most important factor for drug adherence. OBJECTIVES: To study the level of drug adherence in patients accessing antiretroviral therapy (ART) through the National program and factor influencing drug adherence. MATERIALS AND METHODS: In present study, we enrolled 102 newly diagnosed patients, among them in 79 patients, ART was started. To study the drug adherence a pretested, semistructured questionnaire was formed and patients were followed up for 6 months of the study. Pretest and posttest counseling was done to all such patients. RESULTS: A total of 28 patients missed the dose in 1(st) follow-up, nine patients missed in 2(nd) follow-up, eight patients missed in 3(rd) follow up. Three patients lost follow-up in 2(nd) follow-up, three patients further lost follow-up in 3(rd) follow-up. Running out of pills (40.0%), side effect (15.5%), and family problem (13.3%), poor transport facility for taking drug (8.9%) and forgetfulness (11.1%) are five major causes related to miss dose. In females patients, drug adherence (69%) was initially less than male patients (76%) but latter on female patients (96.3%) had better adherence than males (95.2%). CONCLUSION: This study suggest that drug adherence can be increased by proper counseling and close monitoring of the patients which may have a great role in preventing the drug resistance and ART response. PMID- 25013826 TI - The relationship between residents' interest to their specialty field and their level of anxiety. AB - INTRODUCTION: Studies showed that lack of interest in the field of study in the 1(st) year of residency could create stress and then causing psychological problems like anxiety. The purpose of this study was the evaluation of relationship between interest to the specialized field of study and the level of medical residents' anxiety in 2010. MATERIALS AND METHODS: This study was a cross sectional study. The statistical population of this study was the medical residents (1(st)-4(th) year) from the Universities of Medical Sciences of Isfahan, Gilan, Sanandaj and Kashan (370 residents). They were selected by stratified sampling method proportional to size and were included in this study. Data was collected by using the researcher-made questionnaire of demographic characteristics, the questionnaire about the field of study selection and Zung anxiety self-assessment standard questionnaire. The findings were analyzed by using the SPSS statistical software version 16, descriptive and analytical tests (t-test, one-way ANOVA and Pearson). The significance level was considered as P <= 0.05. RESULTS: The results showed that more than 92% of the surveyed residents did not have anxiety and were in the normal group. There was a significant correlation between the specialized field of interest and anxiety scores of the residents (P < 0.05). In particular, the following cases had a direct effect on interest rates and anxiety in residents: the amount of time for visiting and patient care, job stress, time for personal affairs, the ability to predict the agenda and job security. CONCLUSIONS: The relationship between various factors and anxiety level was corroborated that the residents' interest and success in studying was the result of their choices and management plans to eliminate barriers for the selection of the field and the favorite city by the officials and planners. PMID- 25013825 TI - Do Iranian tobacco growers support the World Health Organization framework convention on tobacco control? AB - CONTEXT: Studies on the World Health Organization Frame-work Convention on Tobacco Control (FCTC) are scarce in Iran and the Eastern Mediterranean region (EMR). AIM: This study was conducted in 2007-2008 in Iran to design a practical evaluation model of the implementation of FCTC with the potential to be adopted in the EMR. Given that, the findings of this evaluation can be useful in increasing political and public support for enforcing the implementation of legislations, testing their feasibility, and maintaining sustainability. The viewpoints of tobacco growers as part of stakeholders in this regardwould have an influential role. SETTINGS AND DESIGN: This study was a qualitative one to investigate the tobacco growers viewpoints about thestrengths/weaknesses of FCTC implementation in Iran. MATERIALS AND METHODS: In this study, we conducted semi structured in-depth individual interviews with 5 tobacco growers. All interviews were carried out with their permissionwere recorded and were assured that their interviews will be kept confidential. All questions were related to different FCTC articles, then written transcripts were prepared and the basic concepts were extrapolated. STATISTICAL ANALYSIS: After transcribing the recorded interviews, we extracted first level codes and main concepts from them. RESULTS: The findings suggested that although tobacco growers agreed with FCTC implementation, however, subjects like the necessity to support tobacco growers and obtaining insurance from the government, the necessity of the enforcement of national tobacco control law and planning to decrease access to tobacco by policy makers were the most key points that tobacco growers pointed to them. CONCLUSION: Our results showed that tobacco growers agreed with the implementation of FCTC but they worried about their job and the expenses of their daily life. Therefore, it seems that policy makers have to design a plan to support tobacco growers for changing tobacco with a safe cultivate. PMID- 25013827 TI - Comparison between student rating, faculty self-rating and evaluation of faculty members by heads of respective academic departments in the school of medicine in Birjand University of Medical Sciences in Iran. AB - INTRODUCTION: University teachers are one of the main pillars of university and the quality of their performance must continuously and systematically be evaluated. This evaluation can be carried out in various ways. The aim of the present study was to survey and to compare the evaluation of faculty members in the medical school in Birjand University of Medical Sciences by three different sources: Student rating, self-assessment, and evaluation by head of related department. MATERIALS AND METHODS: This descriptive analytical cross-sectional study was conducted in the academic year 2009-2010. Sampling was drawn from all students studying basic science and clinical training in the first and the second semesters. All heads of departments in basic science and clinical training and their faculty members took part in this study. Means of data collection were four different questionnaires designed in the education development center (EDC) and their validity and reliability had been verified by the center. These questionnaires were based on student rating, self-assessment, and evaluation of faculty members by heads of clinical and basic sciences academic departments. After the questionnaires were filled out, the obtained data was analyzed by Statistical Package for the Social Sciences (SPSS) software (version 13), independent t-test, and Pearson's correlation coefficient at the significant level of alpha = 0.05. RESULTS: In the present study, 2417 students completed the questionnaires regarding 63 faculty members, 87 faculty members completed the self-assessment form, and for 60 faculty members, 48 members in clinical and 12 members in basic science, the questionnaires were completed by heads of respective departments. Mean and standard deviation of student evaluation, self assessment, and teachers evaluation by heads of departments were 3.23 +/- 0.38, 3.51 +/- 0.33, and 3.60 +/- 0.32, respectively, and the difference between student rating and self-assessment was significant (P = 0.02). In comparing between managers scores with students evaluation, no significant difference was observed (P = 0.68). Comparison between self-assessment and teachers scores by managers showed a significant difference (P = 0.04). Mean scores of faculty members in clinical training and in basic science were 3.23 +/- 0.73 and 3.31 +/- 0.69 on the part of students, respectively; thus, the difference was significant (P = 0.004). CONCLUSION: Since, the present study was inconsistent with similar previously carried out investigations, the observed difference among the three procedures was statically significant; hence, it can be suggested that student's scores of teachers evaluation, previously used as the only one of evaluation source is not enough and other sources such as assessment by the respective department heads, dean of faculty, and self-assessment must also be taken into consideration. This collection can definitely yield a more favorable evaluation of faculty members and feedback can be more acceptable to them and it will be more effective in improving their education. PMID- 25013828 TI - Job satisfaction survey among health centers staff. AB - BACKGROUND: Due to the importance of health care organizations with significant responsibility for prevention and care, assessment of job satisfaction among health care staff is essential. Quality of health services will be decreased provided they are not satisfied. MATERIALS AND METHODS: This study was a cross sectional analysis of health care staff in Khomeinishahr (centers, buildings, and networks) If they had at least 6 months work experience, they could enter the study. Data included a two-part questionnaire with a standardized questionnaire, demographic variables, and Smith job descriptive index, which is a questionnaire with six domains. Reliability was obtained for each domain and its validity was reported 0.93. FINDINGS: The results showed an overall satisfaction score averages 43.55 +/- 12.8 (from 100). Job satisfaction score was not significantly different between the sexes. However, within the current attitude toward job satisfaction, men scores was better than women (P = 0.001). Highest score in job satisfaction was related to relationships with colleagues and lowest score was related to the income, benefits, and job promotion. The more the years of work, the less the job satisfaction was. The attitude toward the current job had a direct relationship with income (P = 0.01). There was a significant inverse relationship between educational level and job satisfaction in domains promotion, income, and benefits (P = 0.01). The staff with higher education levels was less satisfied with income and job promotion qualification. CONCLUSION: Managers should focus on job qualification to increase job satisfaction and improve the quality of work. PMID- 25013829 TI - The rate commitment to ISO 214 standard among the persian abstracts of approved research projects at school of health management and medical informatics, Isfahan University of Medical Sciences, Isfahan, Iran. AB - INTRODUCTION: Commitment to abstracting standards has a very significant role in information retrieval. The present research aimed to evaluate the rate of Commitment to ISO 214 Standard among the Persian abstracts of approved research projects at School of Health Management and Medical Informatics, Isfahan University of Medical Sciences, Isfahan, Iran. MATERIALS AND METHODS: This descriptive study used a researcher-made checklist to collect data, which was then analyzed through content analysis. The studied population consisted of 227 approved research projects in the School of Health Management and Medical Informatics, Isfahan University of Medical Sciences during 2001-2010. The validity of the checklist was measured by face and content validity. Data was collected through direct observations. Statistical analyzes including descriptive (frequency distribution and percent) and inferential statistics (Chi-square test) were performed in SPSS-16. RESULTS: The highest and lowest commitment rates to ISO 214 standard were in using third person pronouns (100%) and using active verbs (34/4%), respectively. In addition, the highest commitment rates to ISO 214 standard (100%) related to mentioning third person pronouns, starting the abstract with a sentence to explain the subject of the research, abstract placement, and including keyword in 2009. On the other hand, during 2001-2003, the lowest commitment rate was observed in reporting research findings (16/7%). Moreover, various educational groups differed significantly only in commitment to study goals, providing research findings, and abstaining from using abbreviations, signs, and acronyms. Furthermore, educational level of the corresponding author was significantly related with extracting the keywords from the text. Other factors of ISO 214 standard did not have significant relations with the educational level of the corresponding author. CONCLUSIONS: In general, a desirable rate of commitment to ISO 214 standard was observed among the Persian abstracts of approved research projects at the School of Health Management and Medical Informatics of Isfahan University of Medical Sciences. However, commitment rates differed between years. In addition, commitment to ISO 214 standard was not significantly related with educational group and level. PMID- 25013830 TI - Analyzing the level of knowledge and attitude of the mothers referring the urban health centers of Birjand about nutritional behaviors. AB - BACKGROUND: Achieving a balanced and proper nutrition is one of the most important health objectives in the early years of the child's life. The aim of this study is to determine the level of knowledge and attitude of the mothers covered by the urban health centers of Birjand about nutritional behaviors. MATERIALS AND METHODS: This descriptive-analytical study was conducted on the mothers with children less than five years referring the health centers of Birjand, in 1387. A questionnaire was prepared for data collection. Data were analyzed using SPSS software, Chi square, ANOVA, Tukey's post hoc and Pearson correlation coefficient statistical tests with a accuracy level of P < 0.05. RESULTS: Two hundred ninety four patients were studied. A meaningful difference was observed between the knowledge and attitude scores in terms of the mothers' education stand (P = 0.002). Eighty three point seven percent, 65.6%, 82.7% and 64.6% of mothers were aware about the importance of iron absorption, the onset of iron supplement drop, the minerals and vitamins in the body, and the effects of vitamin A deficiency, respectively. The mothers' knowledge and attitude about the nutritional behavior was evaluated at the average and good level, respectively. CONCLUSIONS: Considering the average level of the mothers' knowledge and attitude about children's nutritional behaviors, the retraining of family physicians and health centers staff about the importance of nutritional behaviors is recommended. PMID- 25013831 TI - Correlation of transrectal ultrasonographic findings with histo pathology in prostatic cancer. AB - OBJECTIVE: To estimate the incidence of hyperechoic, hypoechoic, isoechoic, prostatic cancer in TRUS (transrectal ultrasound guided) guided prostatic specimens. MATERIALS AND METHODS: Four hundred and ninety three patients with raised serum prostatic specific antigen (PSA) and abnormal DRE findings were subjected to TRUS-Guided prostate biopsy. Lateralized sextant biopsy plus prostatic cores from suspicious areas were obtained. RESULTS: Out of 493 patients who were enrolled in the study, 65 (13.18) patients showed hyperechoic lesions on TRUS and 211 (42.79) patients had hypoechoic lesions on TRUS. CONCLUSION: Our study has revealed that hyperechoic lesions on transrectal ultrasonography have more chances of prostatic cancer as reported in previous literature, so we suggest that we should take additional biopsy of hyperechoic lesions and perhaps it should be part of the standard protocol in patients suspected cancer prostate. PMID- 25013832 TI - Evaluation of pharmacy information system in teaching, private and social services Hospitals in 2011. AB - OBJECTIVE: Supporting a therapeutic approach and medication therapy management, the pharmacy information system (PIS) acts as one of the pillars of hospital information system. This ensures that medication therapy is being supported with an optimal level of safety and quality similar to other treatments and services. MATERIALS AND METHODS: The present study is an applied, cross-sectional study conducted on the PIS in use in selected hospitals. The research population included all users of PIS. The research sample is the same as the research population. The data collection instrument was the self-designed checklist developed from the guidelines of the American Society of Health System Pharmacists, Australia pharmaceutical Society and Therapeutic guidelines of the Drug Commission of the German Medical Association. The checklist validity was assessed by research supervisors and PIS users and pharmacists. FINDINGS: The findings of this study were revealed that regarding the degree of meeting the standards given in the guidelines issued by the Society of Pharmacists, the highest rank in observing input standards belonged to Social Services hospitals with a mean score of 32.75. Although teaching hospitals gained the highest score both in process standards with a mean score of 29.15 and output standards with a mean score of 43.95, the private hospitals had the lowest mean score of 23.32, 17.78, 24.25 in input, process and output standards, respectively. CONCLUSION: Based on the findings, it can be claimed that the studied hospitals had a minimal compliance with the input, output and processing standards related to the PIS. PMID- 25013833 TI - Influencing factors on health promoting behavior among the elderly living in the community. AB - INTRODUCTION: Health promotion behavior is one of the main criteria for determining health that is recognized as the basic factor in catching numerous diseases. Observing such behaviors by the elderly prevents affliction to various diseases and has potential effect in promoting health and increasing the elderly quality of life. This research was done for the aim of determining effective factors on health promotion behaviors and health status in the elderly of the Dena province. MATERIALS AND METHODS: One hundred twenty elderly of over 65 years of age were selected randomly to do this descriptive-analytical study (cross sectional type). The questionnaire regarding health promoting lifestyle profile 2 (HPLP2) was used for measuring the rate of health promotion behaviors. The data was collected by personal interviews and face to face method for completing the relevant questionnaire and was analyzed by SPSS software version 20 and also proper tests. RESULTS: The average score of the elderly health promotion behaviors in the Dena province (143.8) indicated the acceptable level of performing health promoting behaviors in this group, such that 85% of the elderly had intermediate health promoting behaviors and 15% had proper behaviors. Also, the results showed that the average score of the physical activity and nutrition sub-measuring conditions was lower than the average score of other sub measures of prevention had the highest average. Moreover, comparison of the correlation of health promotion behaviors with the sub-measures showed that apart from the healthy nutrition sub-measure, all the other sub-measures have significant correlation with health promotion behaviors. CONCLUSION: From the findings of this study, the authors recommend health providers to promote elderly health promotion behaviors in all communities by identifying health promotion behaviors in other parts of the country, and also designing suitable intervention programs based on effective factors on health promotion behaviors of the elderly people. PMID- 25013834 TI - Investigation of the age trends in patients with breast cancer and different sizes of tumors in Breast Cancer Research Center of Isfahan University of Medical Sciences in 2001-2010. AB - BACKGROUND: Breast cancer is the most common cause of death in women in the age range of 35-55 years. Each year, one or two cases of breast cancer per 1000 women are diagnosed as new cases. Despite the serious prognosis and high rate of morbidity, mortality, and pathogenicity, in the case of early diagnoses, the prognosis will be better. The aim of this study was to investigate the age trends in breast cancer patients with different sizes of tumors in Breast Cancer Research Center of Isfahan University of Medical Sciences in 2001-2010. MATERIALS AND METHODS: The information in radiotherapy and oncology of Isfahan University of Medical Sciences and Milad Hospital from 2001 to 2010 were coded and analyzed. Frequency of patients' age groups, tumor sizes and the year of cancer diagnosis were calculated. Correlation test was used for data analysis in statistical analysis in social science (SPSS) software version 18. FINDINGS: Among the 3722 patients with breast cancer, the highest relative frequency distribution, respectively was observed in the age of 40-49 years (34.4%), 50-59 years (26.6%), 30-39 years (17.7%), 60-69 years (13.2%), 20-29 years (2.5%), 70 years and older (5.2%) and less than 20 years. Relative frequency distribution of tumor sizes in a variety of 5 cm (T2) was with the frequency of 59.8%, and then 26% at 5 cm (T3), 10.5% at 2 cm (T1), 3.1% at T4 and 0.6 at In-situ, respectively. CONCLUSION: The investigation of age trends showed that diagnosis rate of breast cancer increased from 2001 to 2004. It reached its highest value in 2006 at the age range of 30-39 years. Then, the trend has been downward, and it has continued to decline until 2010, which could be the result of the equipping screening system and recording the malignant cases. 85.8% of the examined tumors in T2 and T3 group were visible and may be disturbing. Comparing the frequency distribution of the infected population showed that the highest incidence of breast cancer diagnosis were in the age range of 40-49 years. It seems that as long as the mass has not reached an obvious palpable state, it has not been diagnosed. PMID- 25013835 TI - Comparison of national and personal identity between person with internet addiction disorder and normal internet users. AB - BACKGROUNDS: The present study was carried out in order to compare national and personal identity and their subscales in internet addicts and nonaddicts. MATERIALS AND METHODS: This study was a descriptive-analytical research, and was carried out on 384 student internet users in different universities in the city of Isfahan who were selected using quota sampling. Subjects completed the questionnaires, then, subscales of personal and national identity questionnaires in internet addict and nonaddict were analyzed via SPSS16 software. RESULTS: Results indicated a significant difference between the scores of national identity and personal identity as well as all subscales in internet addicts and nonaddicts, except for national heritage and homeland defence factors. In addition, there was a negative and significant relationship between addiction to internet and personal and national identity, except for the fourth and fifth factors of national identity (viewpoints of others considering the national group and homeland defence). Moreover, after controlling for the sex variable, internet addiction had an effect on personal and national identity. CONCLUSION: The findings of this research indicate that an excess of internet use and overinvolvement in cyberspace and the addiction to them, could be associated with defects in some aspects of national and personal identity. PMID- 25013837 TI - Study skills and habits in Shiraz dental students; strengths and weaknesses. AB - INTRODUCTION: The dental students, the same as other students, during their academic courses are required to learn a wide range of scientific subjects. Obviously, choosing the inappropriate method of study leads to confuse and disenchantment of students and it causes wasting of their energy. The purpose of this study was to assess the existing strengths and weaknesses of the skills and study habits in Dental Students of Shiraz University of Medical Sciences in 2009 10. MATERIALS AND METHODS: In this cross-sectional study, all of the dental students (n = 274), who studied at the time of study at all levels in the academic year of 2009-10, were selected by the census. Data were collected by using the Huston University questionnaire consisted of two parts of demographic questions and 64 specific areas of study skills in eight domains of time management, concentration/memory, study aids/note taking, test strategies, information processing, motivation, self-assessment/reading, and writing skills. Following the retranslation of the questionnaire, the validity was confirmed by using the content validity method. The reliability was obtained by using the Cronbach's Alpha of 0.92. The data were analyzed with SPSS software version 17 and using analytical statistic tests. RESULTS: Students who have previously participated in the study skills workshops had stronger skills in comparison with the students who had not participated in these workshops. Time management skills (P = 0.04), motivation (P = 0.0001) and information processing (P = 0.03) in students with professional status were in a more favorable position and showed significant differences in terms of educational levels. The study skills mean score of the students living in student housings in comparison with the other students were significantly higher (P = 0.04). Marital status showed no significant differences in reading skills. CONCLUSION AND RECOMMENDATIONS: The review of study skills in the undergraduate and post-graduate dental students indicated that the residents had higher reading skills. By recognizing the existing strengths and weaknesses and holding programs through counseling centers can develop the study skills in the students. PMID- 25013836 TI - The effects of breast cancer educational intervention on knowledge and health beliefs of women 40 years and older, Isfahan, Iran. AB - INTRODUCTION: Breast cancer is an international health problem in the world over. Mammography screening behavior has critical role in early detection and decreasing of its mortality. Educational programs play an important role in promoting breast cancer screening behaviors and women health. Health belief models (HBM) is the most common models that have been applied in Mammography screening behaviors. The aim of this study was to determine the effect of breast cancer screening education using HBM on knowledge and health beliefs in 40 years women and older. MATERIALS AND METHODS: In this Population-based controlled trial, 290 women of 40 years and older were divided randomly into experimental and control groups. Health beliefs determined using the Persian version of Champion's health belief model scale (CHBMS). Questionnaires were completed before and 4 weeks after intervention. Four educational sessions were conducted each session lasting 90 min by lecturing, group discussion, showing slide and educational film based on HBM constructs. The obtained data were analyzed by SPSS (version 18) and statistical test at the significant level of alpha = 0.05. RESULTS: Mean scores of perceived susceptibility, perceived severity, perceived benefits, barriers and self-efficacy of mammography and health motivation in the experimental group had significant differences in comparison with the control group after educational intervention (P <= 0.001). CONCLUSION: The results of this study have confirmed the efficiency of educational intervention based on HBM in increasing of knowledge and health beliefs about breast cancer and mammography screening behavior. Hence, implementing appropriate educational programs with focus on benefits of Mammography in early detection of breast cancer and creating positive motivation for health among women, can increase their practice of having mammography screening. PMID- 25013838 TI - Yoga therapy for promoting emotional sensitivity in University students. AB - BACKGROUND: Students need emotional intelligence (EI) for their better academic excellence. There are three important psychological dimensions of EI: Emotional sensitivity (ES), emotional maturity (EM) and emotional competency (EC), which motivate students to recognize truthfully, interpret honestly and handle tactfully the dynamics of their behavioral pattern. OBJECTIVE: The study was designed to assess ES in the students undergoing yoga therapy program in the form of yoga instructor's course (YIC) module. MATERIALS AND METHODS: One hundred and eighty four YIC students with 25.77 +/- 4.85 years of mean age participated in this study of 21 days duration (a single group pre-post design). The ES data was collected before (pre) and after (post) YIC module using Emotional Quotient test developed by Dr Dalip Singh and Dr N K Chadha. STATISTICAL ANALYSIS: Means, standard deviations, Kolmogorov-Smirnov test, and Wilcoxon signed rank test were used for analyzing the data with the help of SPSS 16. RESULTS: The data analysis showed 3.63% significant increase (P < 0.01) in ES. CONCLUSION: The present study suggests that YIC module can result in improvement of ES among university students, thus paving the way for their academic success. Additional well designed studies are needed before a strong recommendation can be made. PMID- 25013839 TI - Making environmental health interesting for medical students-internet assisted facilitated collaborative learning approach. AB - BACKGROUND: Topics on environmental health are usually neglected by students and it is necessary for them to learn this area with a public health perspective as environment plays a vital role in multi-factorial causation of diseases. Hence there is a need for alternative teaching/learning methods to facilitate students in acquiring the required knowledge. OBJECTIVES: To increase the student interest and enhance their participation in acquiring knowledge in public health perspective of environmental health. Teaching Objectives/Learning Were: At the end of the session students should know the importance of air as an environmental factor in disease causation in special reference to public health hazards, the major sources of air pollution, major pollutants causing the health hazards, the way to measure pollutants and control them. MATERIALS AND METHODS: The whole class of students was divided into two batches and one session was planned for each batch. Each batch was divided into six small groups. The groups were given task of exploring the internet on the different topics mentioned in the learning objectives. All the students were asked to explore, compile information and collectively prepare a presentation and present their findings based on their reviews. Students' feedback was collected at the end of each session. RESULTS: Eighty five percent of them were clear about the learning objectives and interested about internet learning. Most of them gave a positive opinion about the newer teaching learning method. CONCLUSIONS: Internet assisted group study served as a valuable alternative, innovative, and interesting tool to teach and learn the environmental health as revealed by students' feedback. PMID- 25013840 TI - A questionnaire survey of awareness of physical activity among the faculties of medical college. AB - BACKGROUND: The physical activity in teaching faculties is an important aspect to maintain good health. This not only prevents the various non - communicable diseases but also has role in secondary prevention of diseases. It is also proven that the growing epidemic of obesity mostly in children is linked to recent decline in physical activity levels both in home, school and working places. Social class is thought to have a bearing on physical activity. On basis of this, the survey was done to assess the physical activity levels in higher social class population i.e. on teaching faculty of Melaka Manipal Medical College, Manipal, Karnataka, India. MATERIALS AND METHODS: Questionnaire study was implemented in 2010 as the design of this research without any manual intervention. No experiment was conducted in the research. Questions were specific and related to the physical activities in home and also in working environment. RESULTS: The study found that in medical college the lifestyle is restricted mostly to sedentary and moderate work. Most of faculties were using bike and cars to reach there working place and also we found the physical activities in the form of exercise and sports activity were lacking. DISCUSSION: In addition to the importance of a physical activity professional's potential influence on others as a model, engaging in a physically active lifestyle is very important for personal reasons. Achieving and maintaining a health-enhancing level of physical fitness is one of the basic standards for good teaching and maintaining good health. Physical activity in professionals leads to both personal health benefits, and improve job satisfaction. CONCLUSION: Infrastructure improvements such as sports activity in colleges among faculties, combined with regular exercise provide additional physical activity that would help reduce obesity and non-communicable diseases. PMID- 25013842 TI - A survey on rate of media literacy among Isfahan University of Medical Sciences' students using Iranian media literacy questionnaire. AB - INTRODUCTION: Media literacy is a 21(st) century approach to education. It provides a framework to access, analyze, evaluate, and create messages in a variety of forms - from print to video to the Internet. Also, it builds an understanding of the role of media in society as well as essential skills of inquiry and self-expression necessary for citizens of a democracy. The purpose of this research was to determine the rate of media literacy among Isfahan University of Medical Sciences' students using Iranian Media Literacy Questionnaire (IMLQ). MATERIALS AND METHODS: This is a survey research in which the data were collected by a researcher-made questionnaire. Its validity and reliability were confirmed by Library and Information Sciences specialists and Chronbach's alpha (r = 0.89), respectively. Statistical population consisted of all students in Isfahan University of Medical Sciences (7000 cases) and the samples were 364. Sampling method was random stratified sampling. Data were analyzed by descriptive (frequency distribution, mean) and inferential (T-test, ANOVA, and one-sample t-test) statistics through SPSS16 software. RESULTS: The findings showed that the mean level of media literacy among Isfahan University of Medical Sciences' students was 3.20 +/- 0.558 (higher than average). The highest mean was skill in avoiding confusion and focus on activates such as watching television, listening to radio, reading newspaper, and using internet; and the lowest mean was skill in membership and subscription in useful society networks. The mean of evaluation of media messages dimension was more than others. The lowest mean of dimensions was for selective and purposeful use of media with 2.99 +/- 0.761. Comparison between gender, married status, educational degree, and college type and the rate of media literacy among Isfahan University of Medical Sciences' students showed no significant difference. CONCLUSION: The results showed that the rate of media literacy among Isfahan University of Medical Sciences' students was higher than average. But students didn't have enough skill in membership and subscription in useful society networks and Skill in tracking news about your favorite artists and musicians. Generally, all students and education practitioners should pay special attention to factors affecting in improving media literacy as a basic capability in using media. PMID- 25013841 TI - Nutritional status and its relationship with bone mass density in postmenopausal women admitted in osteodensitometry center, Isfahan-Iran. AB - INTRODUCTION: Osteoporosis is a multifactorial disease and one of the most important modifiable factors in the development and maintenance of bone mass are nutrition nutritional status and its relationship with Bone Mass Density (BMD) in postmenopausal women admitted in osteodensitometry Center, Isfahan, Iran. MATERIALS AND METHODS: Seventy-two postmenopausal osteoporotic women were studied. BMD of the lumbar spine and total hip were measured using dual-energy X ray absorptiometry. Demographic and dietary intakes were collected by interview and using a validated food frequency questionnaires. T-scores, Pearson correlation and one way analysis of variance tests were conducted to analyze the data. RESULTS: Mean of age and duration of menopause was nearly 57.5 +/- 7.2 and 10.6 +/- 7.1 years, respectively. The mean t-scores for BMD of spine and hip were 0.877 +/- 0.179 and 0.997 +/- 0.21, respectively. The mean of calcium (Ca), phosphorous (P), fluoride (F), Vitamin D, K and Zn were less than DRI and Na more than it (all P value less than 0.0001). BMD of hip was significantly correlated with dietary Ca, animal protein, Zn (P < 0.05), but BMD of spine did not show any significant correlation with nutrients (P > 0.05). CONCLUSION: Most of the postmenopausal osteoporotic women in this study had a considerable deficiency in terms of micronutrients such as Ca, vitamin D and P, which can be deleterious for bone health. PMID- 25013843 TI - Simultaneous anatomical sketching as learning by doing method of teaching human anatomy. AB - OBJECTIVE: Learning by lecture is a passive experience. Many innovative techniques have been presented to stimulate students to assume a more active attitude toward learning. In this study, simultaneous sketch drawing, as an interactive learning technique was applied to teach anatomy to the medical students. MATERIALS AND METHODS: We reconstructed a fun interactive model of teaching anatomy as simultaneous anatomic sketching. To test the model's instruction effectiveness, we conducted a quasi- experimental study and then the students were asked to write their learning experiences in their portfolio, also their view was evaluated by a questionnaire. RESULTS: The results of portfolio evaluation revealed that students believed that this method leads to deep learning and understanding anatomical subjects better. Evaluation of the students' views on this teaching approach was showed that, more than 80% of the students were agreed or completely agreed with this statement that leaning anatomy concepts are easier and the class is less boring with this method. More than 60% of the students were agreed or completely agreed to sketch anatomical figures with professor simultaneously. They also found the sketching make anatomy more attractive and it reduced the time for learning anatomy. These number of students were agree or completely agree that the method help them learning anatomical concept in anatomy laboratory. More than 80% of the students found the simultaneous sketching is a good method for learning anatomy overall. CONCLUSION: Sketch drawing, as an interactive learning technique, is an attractive for students to learn anatomy. PMID- 25013844 TI - Bare-bones teaching-learning-based optimization. AB - Teaching-learning-based optimization (TLBO) algorithm which simulates the teaching-learning process of the class room is one of the recently proposed swarm intelligent (SI) algorithms. In this paper, a new TLBO variant called bare-bones teaching-learning-based optimization (BBTLBO) is presented to solve the global optimization problems. In this method, each learner of teacher phase employs an interactive learning strategy, which is the hybridization of the learning strategy of teacher phase in the standard TLBO and Gaussian sampling learning based on neighborhood search, and each learner of learner phase employs the learning strategy of learner phase in the standard TLBO or the new neighborhood search strategy. To verify the performance of our approaches, 20 benchmark functions and two real-world problems are utilized. Conducted experiments can been observed that the BBTLBO performs significantly better than, or at least comparable to, TLBO and some existing bare-bones algorithms. The results indicate that the proposed algorithm is competitive to some other optimization algorithms. PMID- 25013845 TI - A solution quality assessment method for swarm intelligence optimization algorithms. AB - Nowadays, swarm intelligence optimization has become an important optimization tool and wildly used in many fields of application. In contrast to many successful applications, the theoretical foundation is rather weak. Therefore, there are still many problems to be solved. One problem is how to quantify the performance of algorithm in finite time, that is, how to evaluate the solution quality got by algorithm for practical problems. It greatly limits the application in practical problems. A solution quality assessment method for intelligent optimization is proposed in this paper. It is an experimental analysis method based on the analysis of search space and characteristic of algorithm itself. Instead of "value performance," the "ordinal performance" is used as evaluation criteria in this method. The feasible solutions were clustered according to distance to divide solution samples into several parts. Then, solution space and "good enough" set can be decomposed based on the clustering results. Last, using relative knowledge of statistics, the evaluation result can be got. To validate the proposed method, some intelligent algorithms such as ant colony optimization (ACO), particle swarm optimization (PSO), and artificial fish swarm algorithm (AFS) were taken to solve traveling salesman problem. Computational results indicate the feasibility of proposed method. PMID- 25013846 TI - Fracture property of Y-shaped cracks of brittle materials under compression. AB - In order to investigate the properties of Y-shaped cracks of brittle materials under compression, compression tests by using square cement mortar specimens with Y-shaped crack were conducted. A true triaxial loading device was applied in the tests, and the major principle stresses or the critical stresses were measured. The results show that as the branch angle theta between the branch crack and the stem crack is 75 degrees , the cracked specimen has the lowest strength. In order to explain the test results, numerical models of Y-shaped cracks by using ABAQUS code were established, and the J-integral method was applied in calculating crack tip stress intensity factor (SIF). The results show that when the branch angle theta increases, the SIF K I of the branch crack increases from negative to positive and the absolute value K II of the branch crack first increases, and as theta is 50 degrees , it is the maximum, and then it decreases. Finally, in order to further investigate the stress distribution around Y-shaped cracks, photoelastic tests were conducted, and the test results generally agree with the compressive test results. PMID- 25013847 TI - Structural damage identification based on rough sets and artificial neural network. AB - This paper investigates potential applications of the rough sets (RS) theory and artificial neural network (ANN) method on structural damage detection. An information entropy based discretization algorithm in RS is applied for dimension reduction of the original damage database obtained from finite element analysis (FEA). The proposed approach is tested with a 14-bay steel truss model for structural damage detection. The experimental results show that the damage features can be extracted efficiently from the combined utilization of RS and ANN methods even the volume of measurement data is enormous and with uncertainties. PMID- 25013848 TI - An unbiased two-parameter estimation with prior information in linear regression model. AB - We introduce an unbiased two-parameter estimator based on prior information and two-parameter estimator proposed by Ozkale and Kaciranlar, 2007. Then we discuss its properties and our results show that the new estimator is better than the two parameter estimator, the ordinary least squares estimator, and explain the almost unbiased two-parameter estimator which is proposed by Wu and Yang, 2013. Finally, we give a simulation study to show the theoretical results. PMID- 25013849 TI - Theory, methods, and applications of fractional calculus. PMID- 25013850 TI - Domain adaptation for pedestrian detection based on prediction consistency. AB - Pedestrian detection is an active area of research in computer vision. It remains a quite challenging problem in many applications where many factors cause a mismatch between source dataset used to train the pedestrian detector and samples in the target scene. In this paper, we propose a novel domain adaptation model for merging plentiful source domain samples with scared target domain samples to create a scene-specific pedestrian detector that performs as well as rich target domain simples are present. Our approach combines the boosting-based learning algorithm with an entropy-based transferability, which is derived from the prediction consistency with the source classifications, to selectively choose the samples showing positive transferability in source domains to the target domain. Experimental results show that our approach can improve the detection rate, especially with the insufficient labeled data in target scene. PMID- 25013851 TI - In vitro cadmium-induced alterations in growth and oxidative metabolism of upland cotton (Gossypium hirsutum L.). AB - Cadmium (Cd) is a toxic pollutant, which cause both dose- and time-dependent physiological and biochemical alterations in plants. The present in vitro study was undertaken to explore Cd-induced physiological and biochemical changes in cotton callus culture at 0, 550, 700, 850, and 1000 MUM Cd for four different stress periods (7, 14, 21, and 28 days). At 1000 MUM Cd, mean growth values were lower than their respective control. The cell protein contents decreased only after 7-day and 14-day stress treatment. At 550 MUM Cd, malondialdehyde (MDA) contents decreased after various stress periods except 21-day period. Superoxide dismutase (SOD) activity at 1000 MUM Cd improved relative to its respective controls in the first three stress regimes. Almost a decreasing trend in the hydrogen peroxide (H2O2) and peroxidase (POD) activities at all Cd levels after different stress periods was noticed. Ascorbate peroxidase (APX) activity descended over its relevant controls in the first three stress regimes except at 700 MUM Cd after 14- and 21-day stress duration. Moreover, catalase (CAT) mean values significantly increased as a whole. From this experiment, it can be concluded that lipid peroxidation as well as reactive oxygen species (ROS) production was relatively higher as has been revealed by higher MDA contents and greater SOD, CAT activities. PMID- 25013853 TI - On the signless laplacian spectral radius of bicyclic graphs with perfect matchings. AB - The graph with the largest signless Laplacian spectral radius among all bicyclic graphs with perfect matchings is determined. PMID- 25013852 TI - Modelling and analysis on biomechanical dynamic characteristics of knee flexion movement under squatting. AB - The model of three-dimensional (3D) geometric knee was built, which included femoral-tibial, patellofemoral articulations and the bone and soft tissues. Dynamic finite element (FE) model of knee was developed to simulate both the kinematics and the internal stresses during knee flexion. The biomechanical experimental system of knee was built to simulate knee squatting using cadaver knees. The flexion motion and dynamic contact characteristics of knee were analyzed, and verified by comparing with the data from in vitro experiment. The results showed that the established dynamic FE models of knee are capable of predicting kinematics and the contact stresses during flexion, and could be an efficient tool for the analysis of total knee replacement (TKR) and knee prosthesis design. PMID- 25013854 TI - Power quality improvement by unified power quality conditioner based on CSC topology using synchronous reference frame theory. AB - This paper deals with the performance of unified power quality conditioner (UPQC) based on current source converter (CSC) topology. UPQC is used to mitigate the power quality problems like harmonics and sag. The shunt and series active filter performs the simultaneous elimination of current and voltage problems. The power fed is linked through common DC link and maintains constant real power exchange. The DC link is connected through the reactor. The real power supply is given by the photovoltaic system for the compensation of power quality problems. The reference current and voltage generation for shunt and series converter is based on phase locked loop and synchronous reference frame theory. The proposed UPQC CSC design has superior performance for mitigating the power quality problems. PMID- 25013855 TI - Photocatalytic degradation of methylene blue under UV light irradiation on prepared carbonaceous TiO2. AB - This study involves the investigation of altering the photocatalytic activity of TiO2 using composite materials. Three different forms of modified TiO2, namely, TiO2/activated carbon (AC), TiO2/carbon (C), and TiO2/PANi, were compared. The TiO2/carbon composite was obtained by pyrolysis of TiO2/PANi prepared by in situ polymerization method, while the TiO2/activated carbon (TiO2/AC) was obtained after treating TiO2/carbon with 1.0 M KOH solution, followed by calcination at a temperature of 450 degrees C. X-ray powder diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), thermogravimetric analysis (TG-DTA), Brunauer-Emmet-Teller (BET), and UV-Vis spectroscopy were used to characterize and evaluate the prepared samples. The specific surface area was determined to be in the following order: TiO2/AC > TiO2/C > TiO2/PANi > TiO2 (179 > 134 > 54 > 9 m(2) g(-1)). The evaluation of photocatalytic performance for the degradation of methylene blue under UV light irradiation was also of the same order, with 98 > 84.7 > 69% conversion rate, which is likely to be attributed to the porosity and synergistic effect in the prepared samples. PMID- 25013856 TI - In vitro study on the antioxidant potentials of the leaves and fruits of Nauclea latifolia. AB - This study was carried out to investigate the in vitro antioxidant potentials of the leaves and fruits of Nauclea latifolia, a straggling shrub or small tree, native to tropical Africa and Asia. Hot water extracts of the leaves and fruits of Nauclea latifolia were assessed for their total polyphenolic, flavanol, and flavonol contents as well as 1-diphenyl-2-picrylhydrazyl (DPPH) scavenging ability, ferric reducing antioxidant power (FRAP), Trolox equivalence antioxidant capacity (TEAC), and oxygen radical absorbance capacity (ORAC) assays. The aqueous extract of the leaves was found to contain higher level of total polyphenols (11.63 +/- 0.023 mg GAE/g), flavanol (1.45 +/- 0.10 mg CE/g), and flavonol (2.22 +/- 0.37 mg QE/g) than the extract of the fruits with values of 1.75 +/- 0.02 mg GAE/g (total polyphenol), 0.15 +/- 0.01 mg CE/g (flavanol), and 1.00 +/- 0.13 mg QE/g (flavonol). Similarly, the aqueous extract of the leaves also exhibited higher DPPH (IC50 20.64 mg/mL), FRAP (86.10 +/- 3.46 MUmol AAE/g), TEAC (94.83 +/- 3.57 MUmol TE/g), and ORAC (196.55 +/- 0.073 MUmol TE/g) than the extract of the fruits with DPPH (IC50 120.33 mg/mL), FRAP (12.23 +/- 0.40 MUmol AAE/g), TEAC (12.48 +/- 0.21 MUmol TE/g), and ORAC (58.88 +/- 0.073 MUmol TE/g). The present study showed that Nauclea latifolia has strong antioxidant potentials with the leaves demonstrating higher in vitro antioxidant activities than the fruits. PMID- 25013857 TI - Numerical simulation on slabs dislocation of Zipingpu concrete faced rockfill dam during the Wenchuan earthquake based on a generalized plasticity model. AB - After the Wenchuan earthquake in 2008, the Zipingpu concrete faced rockfill dam (CFRD) was found slabs dislocation between different stages slabs and the maximum value reached 17 cm. This is a new damage pattern and did not occur in previous seismic damage investigation. Slabs dislocation will affect the seepage control system of the CFRD gravely and even the safety of the dam. Therefore, investigations of the slabs dislocation's mechanism and development might be meaningful to the engineering design of the CFRD. In this study, based on the previous studies by the authors, the slabs dislocation phenomenon of the Zipingpu CFRD was investigated. The procedure and constitutive model of materials used for finite element analysis are consistent. The water elevation, the angel, and the strength of the construction joints were among major variables of investigation. The results indicated that the finite element procedure based on a modified generalized plasticity model and a perfect elastoplastic interface model can be used to evaluate the dislocation damage of face slabs of concrete faced rockfill dam during earthquake. The effects of the water elevation, the angel, and the strength of the construction joints are issues of major design concern under seismic loading. PMID- 25013858 TI - Exact multisoliton solutions of general nonlinear Schrodinger equation with derivative. AB - Multisoliton solutions are derived for a general nonlinear Schrodinger equation with derivative by using Hirota's approach. The dynamics of one-soliton solution and two-soliton interactions are also illustrated. The considered equation can reduce to nonlinear Schrodinger equation with derivative as well as the solutions. PMID- 25013859 TI - Water management practices affect arsenic and cadmium accumulation in rice grains. AB - Cadmium (Cd) and arsenic (As) accumulation in rice grains is a great threat to its productivity, grain quality, and thus human health. Pot and field studies were carried out to unravel the effect of different water management practices (aerobic, aerobic-flooded, and flooded) on Cd and As accumulation in rice grains of two different varieties. In pot experiment, Cd or As was also added into the soil as treatment. Pots without Cd or As addition were maintained as control. Results indicated that water management practices significantly influenced the Cd and As concentration in rice grains and aerobic cultivation of rice furnished less As concentration in its grains. Nonetheless, Cd concentration in this treatment was higher than the grains of flooded rice. Likewise, in field study, aerobic and flooded rice cultivation recorded higher Cd and As concentration, respectively. However, growing of rice in aerobic-flooded conditions decreased the Cd concentration by 9.38 times on average basis as compared to aerobic rice. Furthermore, this treatment showed 28% less As concentration than that recorded in flooded rice cultivation. The results suggested that aerobic-flooded cultivation may be a promising strategy to reduce the Cd and As accumulations in rice grains simultaneously. PMID- 25013860 TI - Life satisfaction and work-related satisfaction among anesthesiologists in Poland. AB - The aim of the study was to assess the level of life and job satisfaction of Polish anesthesiologists and to explore the impact of extrinsic-hygiene and intrinsic-motivating determinants. MATERIALS AND METHODS: A cross-sectional questionnaire study was conducted among consultant anesthesiologists in Lodz region. The questionnaire concerned patient care, burden, income, personal rewards, professional relations, job satisfaction in general, and life satisfaction. Respondents were asked to rate their level of satisfaction for each item on a seven-point Likert scale (1: extremely dissatisfied; 7: extremely satisfied). RESULTS: 86.03% of anesthesiologists were satisfied with their economic status, 77.94% found their health status satisfactory, and 52.21% viewed their personal future optimistically. In general, 71.32% of anesthesiologists were satisfied with their current job situation. Among the less satisfying job aspects were work-related stress (2.49; SD = 1.23), administrative burden (2.85; SD = 1.47), workload (3.63; SD = 1.56), and leisure time (3.09; SD = 1.44). CONCLUSIONS: Considerable work-related stress leads to job dissatisfaction among anesthesiologists. There is an association between job satisfaction and health status, social life, and economic status. Working for long hours by anesthesiologists results in a high risk of burnout. PMID- 25013861 TI - Genetic diversity analysis of Hypsizygus marmoreus with target region amplification polymorphism. AB - Hypsizygus marmoreus is an industrialized edible mushroom. In the present paper, the genetic diversity among 20 strains collected from different places of China was evaluated by target region amplification polymorphism (TRAP) analysis; the common fragment of TRAPs was sequenced and analyzed. Six fixed primers were designed based on the analysis of H. marmoreus sequences from GenBank database. The genomic DNA extracted from H. marmoreus was amplified with 28 TRAP primer combinations, which generated 287 bands. The average of amplified bands per primer was 10.27 (mean polymorphism is 69.73%). The polymorphism information content (PIC) value for TRAPs ranged from 0.32 to 0.50 (mean PIC value per TRAP primer combination is 0.48), which indicated a medium level of polymorphism among the strains. A total of 36 sequences were obtained from TRAP amplification. Half of these sequences could encode the known or unknown proteins. According to the phylogenetic analysis based on TRAP result, the 20 strains of H. marmoreus were classified into two main groups. PMID- 25013862 TI - Innovative product design based on comprehensive customer requirements of different cognitive levels. AB - To improve customer satisfaction in innovative product design, a topology structure of customer requirements is established and an innovative product approach is proposed. The topology structure provides designers with reasonable guidance to capture the customer requirements comprehensively. With the aid of analytic hierarchy process (AHP), the importance of the customer requirements is evaluated. Quality function deployment (QFD) is used to translate customer requirements into product and process design demands and pick out the technical requirements which need urgent improvement. In this way, the product is developed in a more targeted way to satisfy the customers. the theory of innovative problems solving (TRIZ) is used to help designers to produce innovative solutions. Finally, a case study of automobile steering system is used to illustrate the application of the proposed approach. PMID- 25013863 TI - Hydrological modeling of the Jiaoyi watershed (China) using HSPF model. AB - A watershed hydrological model, hydrological simulation program-Fortran (HSPF), was applied to simulate the spatial and temporal variation of hydrological processes in the Jiaoyi watershed of Huaihe River Basin, the heaviest shortage of water resources and polluted area in China. The model was calibrated using the years 2001-2004 and validated with data from 2005 to 2006. Calibration and validation results showed that the model generally simulated mean monthly and daily runoff precisely due to the close matching hydrographs between simulated and observed runoff, as well as the excellent evaluation indicators such as Nash Sutcliffe efficiency (NSE), coefficient of correlation (R (2)), and the relative error (RE). The similar simulation results between calibration and validation period showed that all the calibrated parameters had a certain representation in Jiaoyi watershed. Additionally, the simulation in rainy months was more accurate than the drought months. Another result in this paper was that HSPF was also capable of estimating the water balance components reasonably and realistically in space through the whole watershed. The calibrated model can be used to explore the effects of climate change scenarios and various watershed management practices on the water resources and water environment in the basin. PMID- 25013864 TI - Weak localization in graphene: theory, simulations, and experiments. AB - We provide a comprehensive picture of magnetotransport in graphene monolayers in the limit of nonquantizing magnetic fields. We discuss the effects of two-carrier transport, weak localization, weak antilocalization, and strong localization for graphene devices of various mobilities, through theory, experiments, and numerical simulations. In particular, we observe a minimum in the weak localization and strong localization length reminiscent of the minimum in the conductivity, which allows us to make the connection between weak and strong localization. This provides a unified framework for both localizations, which explains the observed experimental features. We compare these results to numerical simulation and find a remarkable agreement between theory, experiment, and numerics. Various graphene devices were used in this study, including graphene on different substrates, such as glass and silicon, as well as low and high mobility devices. PMID- 25013865 TI - Numerical simulation of monitoring corrosion in reinforced concrete based on ultrasonic guided waves. AB - Numerical simulation based on finite element method is conducted to predict the location of pitting corrosion in reinforced concrete. Simulation results show that it is feasible to predict corrosion monitoring based on ultrasonic guided wave in reinforced concrete, and wavelet analysis can be used for the extremely weak signal of guided waves due to energy leaking into concrete. The characteristic of time-frequency localization of wavelet transform is adopted in the corrosion monitoring of reinforced concrete. Guided waves can be successfully used to identify corrosion defects in reinforced concrete with the analysis of suitable wavelet-based function and its scale. PMID- 25013866 TI - Blocked autophagy by miR-101 enhances osteosarcoma cell chemosensitivity in vitro. AB - The adjuvant chemotherapy, such as cisplatin, doxorubicin, and methotrexate has significantly improved survival of osteosarcoma patients. However, the chemoresistance which arose with the chemotherapy blocks achieving favorable outcomes for some patients and finally led to relapse or metastatic disease. Studies have shown paradoxical functions of autophagy in tumor development, which has been demonstrated by microRNAs. In the present study, we determined the involvement of autophagy during the chemotherapy of osteosarcoma cell line, U-2 OS, and further determined the regulation of miR-101 on the autophagy in the U-2 OS cells. Results demonstrated that doxorubicin treatment of U-2 OS cells induced significantly high level of autophagy-characteristic acidic vesicular organelles (AVOs), and induced significant autophagy related protein expression in U-2 OS cells. While the miR-101 could significantly reduce the doxorubicin-induced AVOs and block the autophagy related protein expression in U-2 OS cells. Moreover, the autophagy blockage by miR-101 sensitized the U-2 OS cells to doxorubicin treatment. In summary, miR-101 blocks autophagy during the chemotherapy in osteosarcoma cells and enhances chemosensitivity in vitro. PMID- 25013867 TI - Minimization of temperature ranges between the top and bottom of an air flow controlling device through hybrid control in a plant factory. AB - To maintain the production timing, productivity, and product quality of plant factories, it is necessary to keep the growth environment uniform. A vertical multistage type of plant factory involves different levels of growing trays, which results in the problem of difference in temperature among vertically different locations. To address it, it is necessary to install air flow devices such as air flow fan and cooling/heating device at the proper locations in order to facilitate air circulation in the facility as well as develop a controlling technology for efficient operation. Accordingly, this study compares the temperature and air distribution within the space of a vertical multistage closed type plant factory by controlling cooling/heating devices and air flow fans harmoniously by means of the specially designed testbed. The experiment results indicate that in the hybrid control of cooling and heating devices and air flow fans, the difference in temperature decreased by as much as 78.9% compared to that when only cooling and heating devices were operated; the air distribution was improved by as much as 63.4%. PMID- 25013868 TI - Empirical analysis of retirement pension and IFRS adoption effects on accounting information: glance at IT industry. AB - This study reviews new pension accounting with K-IFRS and provides empirical changes in liability for retirement allowances with adoption of K-IFRS. It will help to understand the effect of pension accounting on individual firm's financial report and the importance of public announcement of actuarial assumptions. Firms that adopted K-IFRS had various changes in retirement liability compared to the previous financial report not based on K-IFRS. Their actuarial assumptions for pension accounting should be announced, but only few of them were published. Data analysis shows that the small differences of the actuarial assumption may result in a big change of retirement related liability. Firms within IT industry also have similar behaviors, which means that additional financial regulations for pension accounting are recommended. PMID- 25013869 TI - Research progress on expansive soil cracks under changing environment. AB - Engineering problems shunned previously rise to the surface gradually with the activities of reforming the natural world in depth, the problem of expansive soil crack under the changing environment becoming a control factor of expansive soil slope stability. The problem of expansive soil crack has gradually become a research hotspot, elaborates the occurrence and development of cracks from the basic properties of expansive soil, and points out the role of controlling the crack of expansive soil strength. We summarize the existing research methods and results of expansive soil crack characteristics. Improving crack measurement and calculation method and researching the crack depth measurement, statistical analysis method, crack depth and surface feature relationship will be the future direction. PMID- 25013870 TI - Experimental study on durability improvement of fly ash concrete with durability improving admixture. AB - In order to improve the durability of fly ash concrete, a series of experimental studies are carried out, where durability improving admixture is used to reduce drying shrinkage and improve freezing-thawing resistance. The effects of durability improving admixture, air content, water-binder ratio, and fly ash replacement ratio on the performance of fly ash concrete are discussed in this paper. The results show that by using durability improving admixture in nonair entraining fly ash concrete, the compressive strength of fly ash concrete can be improved by 10%-20%, and the drying shrinkage is reduced by 60%. Carbonation resistance of concrete is roughly proportional to water-cement ratio regardless of water-binder ratio and fly ash replacement ratio. For the specimens cured in air for 2 weeks, the freezing-thawing resistance is improved. In addition, by making use of durability improving admixture, it is easier to control the air content and make fly ash concrete into nonair-entraining one. The quality of fly ash concrete is thereby optimized. PMID- 25013871 TI - Hepatitis C worldwide and in Brazil: silent epidemic--data on disease including incidence, transmission, prevention, and treatment. AB - Hepatitis C virus (HCV) is endemic worldwide and according to the World Health Organization (WHO), there are about 150 million chronic carriers worldwide. The infection is a leading cause of liver diseases like cirrhosis and hepatocellular carcinoma (HCC); thus, HCV infection constitutes a critical public health problem. There are increasing efforts worldwide in order to reduce the global impact of hepatitis C through the implementation of programmatic actions that may increase the awareness of viral hepatitis and also improve surveillance, prevention, and treatment. In Brazil, about 1,5 million people have been chronically infected with HCV. The country has a vast territory with uneven population density, and hepatitis C incidence rates are variable with the majority of cases concentrated in the most populated areas. Currently, the main priorities of Brazilian Ministry of Health's strategies for viral hepatitis management include the prevention and early diagnosis of viral hepatitis infections; strengthening of the healthcare network and lines of treatment for sexually transmitted diseases, viral hepatitis, and AIDS; improvement and development of surveillance, information, and research; and promotion of universal access to medication. This review aims to summarize the available data on hepatitis C epidemiology and current status of efforts in prevention and infection control around the world and in Brazil. PMID- 25013872 TI - Parameter screening in microfluidics based hydrodynamic single-cell trapping. AB - Microfluidic cell-based arraying technology is widely used in the field of single cell analysis. However, among developed devices, there is a compromise between cellular loading efficiencies and trapped cell densities, which deserves further analysis and optimization. To address this issue, the cell trapping efficiency of a microfluidic device with two parallel micro channels interconnected with cellular trapping sites was studied in this paper. By regulating channel inlet and outlet status, the microfluidic trapping structure can mimic key functioning units of previously reported devices. Numerical simulations were used to model this cellular trapping structure, quantifying the effects of channel on/off status and trapping structure geometries on the cellular trapping efficiency. Furthermore, the microfluidic device was fabricated based on conventional microfabrication and the cellular trapping efficiency was quantified in experiments. Experimental results showed that, besides geometry parameters, cellular travelling velocities and sizes also affected the single-cell trapping efficiency. By fine tuning parameters, more than 95% of trapping sites were taken by individual cells. This study may lay foundation in further studies of single cell positioning in microfluidics and push forward the study of single-cell analysis. PMID- 25013873 TI - Effects of irrigation with treated wastewater on root and fruit mineral elements of Chemlali olive cultivar. AB - Twenty-year-old "Chemlali" olive trees trained to vase and rainfed were investigated in either "on" (2004) or "off" (2003) year. A randomized block design with three blocks and three treatments was used and each experimental plot consisted of nine olive trees. Three treatments were applied: (1) rainfed conditions (RF, used as control treatment); (2) irrigation with well water (WW); and (3) irrigation with treated wastewater (TWW). Irrigation with TWW led to a significant increase of root N, P, Ca, Zn, Mn, Na, and Cl concentrations, in particular in the on-year. Data showed significant differences, between the two years, for the concentration of the mineral elements in the roots, with general lower values in the on-year, probably as a consequence of nutrients movement upward in the tree. Fruit N, P, K, Zn, Mn, and Cl contents were significantly higher in TWW irrigated trees with respect to both RF and WW trees, whereas similar values for Ca, Mg, Na, and Cl contents were measured for WW and TWW irrigated trees. The irrigation with TWW allowed to reuse problematic waters and to save nutrients inputs in the olive orchard thus moving towards a more sustainable management of olive orchards in countries where water is the major limiting factor for agriculture. PMID- 25013874 TI - AudioSense: Enabling Real-time Evaluation of Hearing Aid Technology In-Situ. AB - AudioSense integrates mobile phones and web technology to measure hearing aid performance in real-time and in-situ. Measuring the performance of hearing aids in the real world poses significant challenges as it depends on the patient's listening context. AudioSense uses Ecological Momentary Assessment methods to evaluate both the perceived hearing aid performance as well as to characterize the listening environment using electronic surveys. AudioSense further characterizes a patient's listening context by recording their GPS location and sound samples. By creating a time-synchronized record of listening performance and listening contexts, AudioSense will allow researchers to understand the relationship between listening context and hearing aid performance. Performance evaluation shows that AudioSense is reliable, energy-efficient, and can estimate Signal-to-Noise Ratio (SNR) levels from captured audio samples. PMID- 25013875 TI - Outcomes of atrioesophageal fistula following catheter ablation of atrial fibrillation treated with surgical repair versus esophageal stenting. AB - INTRODUCTION: Atrioesophageal fistula (AEF) is a rare but devastating complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Surgical repair and esophageal stents are available treatment options for AEF. We report outcomes of these 2 management strategies. METHODS: Nine patients with AEF post-RFCA for AF were included in this study. AEF was diagnosed based on symptoms and chest CT imaging. Of the 9 patients, 5 received stents and 4 underwent surgical repair of fistula. RESULTS: AF ablation was performed under general anesthesia (n = 4) or conscious sedation (n = 5). During ablation, RF power was maintained between 25 and 35 Watts in areas close to the esophagus and energy delivery discontinued when esophageal temperature reached 38 degrees C. Seven patients underwent ablation with 3.5-mm open-irrigated catheter, 1 with 8 mm nonirrigated catheter, and 1 had surgical epicardial ablation. Seven patients received proton pump inhibitor and sucralfate before and after procedure. AEF symptoms developed within 2-6 weeks from ablation. Esophageal stenting was performed in 5 patients (median age 58 years, median time from RFCA 4 weeks) and 4 underwent surgical repair (median age 54 years, median time from RFCA 4 weeks) within 2-4 hours from diagnosis. All 5 patients receiving stents died within 1 week of the procedure due to cerebral embolism, septic shock, or respiratory failure. On the other hand, the 4 patients that received surgical repair were alive at median follow-up of 2.1 years (P = 0.005). CONCLUSIONS: Esophageal stenting should be discouraged and prompt surgical repair is crucial for survival in patients with atrioesophageal fistula. PMID- 25013876 TI - Plant diversity and overyielding: insights from belowground facilitation of intercropping in agriculture. AB - Despite increasing evidence that plant diversity in experimental systems may enhance ecosystem productivity, the mechanisms causing this overyielding remain debated. Here, we review studies of overyielding observed in agricultural intercropping systems, and show that a potentially important mechanism underlying such facilitation is the ability of some crop species to chemically mobilize otherwise-unavailable forms of one or more limiting soil nutrients such as phosphorus (P) and micronutrients (iron (Fe), zinc (Zn) and manganese (Mn)). Phosphorus-mobilizing crop species improve P nutrition for themselves and neighboring non-P-mobilizing species by releasing acid phosphatases, protons and/or carboxylates into the rhizosphere which increases the concentration of soluble inorganic P in soil. Similarly, on calcareous soils with a very low availability of Fe and Zn, Fe- and Zn-mobilizing species, such as graminaceous monocotyledonous and cluster-rooted species, benefit themselves, and also reduce Fe or Zn deficiency in neighboring species, by releasing chelating substances. Based on this review, we hypothesize that mobilization-based facilitative interactions may be an unsuspected, but potentially important mechanism enhancing productivity in both natural ecosystems and biodiversity experiments. We discuss cases in which nutrient mobilization might be occurring in natural ecosystems, and suggest that the nutrient mobilization hypothesis merits formal testing in natural ecosystems. PMID- 25013877 TI - Authors' comments in response. PMID- 25013878 TI - Non-communicable diseases: Healthy living needs global governance. PMID- 25013879 TI - History: Fifty years of EMBO. PMID- 25013880 TI - Brain fog. PMID- 25013881 TI - Barriers to trust. PMID- 25013882 TI - Be concerned. PMID- 25013883 TI - Crystal structure. Preface. PMID- 25013884 TI - Structure of the DNA double helix. Preface. PMID- 25013885 TI - Author response. PMID- 25013886 TI - Resurveying micrometastases in breast cancer: have we now turned the corner? PMID- 25013887 TI - Author response. PMID- 25013888 TI - Medicine in small doses. PMID- 25013889 TI - Maynard M. Cohen, MD, PhD (1920-2014). PMID- 25013890 TI - Employment: PhD overdrive. PMID- 25013891 TI - Reply: To PMID 24318981. PMID- 25013892 TI - Chest X-ray quiz. Interstitial pulmonary and alveolar oedema. PMID- 25013893 TI - TRPV4 channel inhibits TGF-beta1-induced proliferation of hepatic stellate cells. AB - TRPV4, one of the TRP channels, is implicated in diverse physiological and pathological processes including cell proliferation. However, the role of TRPV4 in liver fibrosis is largely unknown. Here, we characterized the role of TRPV4 in regulating HSC-T6 cell proliferation. TRPV4 mRNA and protein were measured by RT PCR and Western blot in patients and rat model of liver fibrosis in vivo and TGF beta1-activated HSC-T6 cells in vitro. Both mRNA and protein of TRPV4 were dramatically increased in liver fibrotic tissues of both patients and CCl4 treated rats. Stimulation of HSC-T6 cells with TGF-beta1 resulted in increase of TRPV4 mRNA and protein. However, TGF-beta1-induced HSC-T6 cell proliferation was inhibited by Ruthenium Red (Ru) or synthetic siRNA targeting TRPV4, and this was accompanied by downregulation of myofibroblast markers including alpha-SMA and Col1alpha1. Moreover, our study revealed that miR-203 was downregulated in liver fibrotic tissues and TGF-beta1-treated HSC-T6 cell. Bioinformatics analyses predict that TRPV4 is the potential target of miR-203. In addition, overexpression of miR-203 in TGF-beta1-induced HSC significantly reduced TRPV4 expression, indicating TRPV4, which was regulated by miR-203, may function as a novel regulator to modulate TGF-beta1-induced HSC-T6 proliferation. PMID- 25013894 TI - Quickly finding orthologs as reciprocal best hits with BLAT, LAST, and UBLAST: how much do we miss? AB - Reciprocal Best Hits (RBH) are a common proxy for orthology in comparative genomics. Essentially, a RBH is found when the proteins encoded by two genes, each in a different genome, find each other as the best scoring match in the other genome. NCBI's BLAST is the software most usually used for the sequence comparisons necessary to finding RBHs. Since sequence comparison can be time consuming, we decided to compare the number and quality of RBHs detected using algorithms that run in a fraction of the time as BLAST. We tested BLAT, LAST and UBLAST. All three programs ran in a hundredth to a 25th of the time required to run BLAST. A reduction in the number of homologs and RBHs found by the faster algorithms compared to BLAST becomes apparent as the genomes compared become more dissimilar, with BLAT, a program optimized for quickly finding very similar sequences, missing both the most homologs and the most RBHs. Though LAST produced the closest number of homologs and RBH to those produced with BLAST, UBLAST was very close, with either program producing between 0.6 and 0.8 of the RBHs as BLAST between dissimilar genomes, while in more similar genomes the differences were barely apparent. UBLAST ran faster than LAST, making it the best option among the programs tested. PMID- 25013895 TI - Streptococcus pneumoniae in saliva of Dutch primary school children. AB - While nasopharyngeal sampling is the gold standard for the detection of Streptococcus pneumoniae carriage, historically seen, saliva sampling also seems highly sensitive for pneumococcal detection. We investigated S. pneumoniae carriage in saliva from fifty schoolchildren by conventional and molecular methods. Saliva was first culture-enriched for pneumococci, after which, DNA was extracted from all bacterial growth and tested by quantitative-PCR (qPCR) for pneumococcus-specific genes lytA and piaA. Next, serotype composition of the samples was determined by serotype-specific qPCRs, conventional-PCRs (cPCR) and sequencing of cPCR amplicons. Although only 2 (4%) of 50 samples were positive by conventional diagnostic culture, 44 (88%) were positive for pneumococci by qPCR. In total, we detected the presence of at least 81 pneumococcal strains representing 20 serotypes in samples from 44 carriers with 23 carriers (52%) positive for multiple (up to 6) serotypes. The number of serotypes detected per sample correlated with pneumococcal abundance. This study shows that saliva could be used as a tool for future pneumococcal surveillance studies. Furthermore, high rates of pneumococcal carriage and co-carriage of multiple pneumococcal strains together with a large number of serotypes in circulation suggests a ubiquitous presence of S. pneumoniae in saliva of school-aged children. Our results also suggest that factors promoting pneumococcal carriage within individual hosts may weaken competitive interactions between S. pneumoniae strains. PMID- 25013896 TI - Modulation of glucose metabolism by balanced deep-sea water ameliorates hyperglycemia and pancreatic function in streptozotocin-induced diabetic mice. AB - The aim of this study was to determine the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in streptozotocin (STZ)-induced diabetic mice. BDSW was prepared by mixing DSW mineral extracts and desalinated water to yield a final hardness of 1000-4000 ppm. Male ICR mice were assigned to 6 groups; mice in each group were given tap water (normal and STZ diabetic groups) or STZ with BDSW of varying hardness (0, 1000, 2000, and 4000 ppm) for 4 weeks. The STZ with BDSW group exhibited lowered fasting plasma glucose levels than the STZ-induced diabetic group. Oral glucose tolerance tests showed that BDSW improves impaired glucose tolerance in STZ-induced diabetic mice. Histopathological evaluation of the pancreas showed that BDSW restores the morphology of the pancreatic islets of Langerhans and increases the secretion of insulin in STZ-induced diabetic mice. Quantitative real-time PCR assay revealed that the expression of hepatic genes involved in gluconeogenesis, glucose oxidation, and glycogenolysis was suppressed, while the expression of the genes involved in glucose uptake, beta-oxidation, and glucose oxidation in muscle were increased in the STZ with BDSW group. BDSW stimulated PI3-K, AMPK, and mTOR pathway-mediated glucose uptake in C2C12 myotubes. BDSW increased AMPK phosphorylation in C2C12 myotubes and improved impaired AMPK phosphorylation in the muscles of STZ-induced diabetic mice. Taken together, these results suggest that BDSW is a potential anti-diabetic agent, owing to its ability to suppress hyperglycemia and improve glucose intolerance by modulating glucose metabolism, recovering pancreatic islets of Langerhans and increasing glucose uptake. PMID- 25013897 TI - Neogenin as a receptor for early cell fate determination in preimplantation mouse embryos. AB - The first cell lineage determination in embryos takes place when two cell populations are set apart, each differentiating into the trophectoderm (TE) and inner cell mass (ICM), respectively. It is widely believed that position/polarity cues play a key role in triggering this differentiation, but it remains unclear how extracellular cues are transduced into cell fate determination. Here, we provide evidence that supports that neogenin is implicated in relaying extracellular cues into the first cell fate determination in preimplantation mouse embryos. A polarized and transient distribution of neogenin was manifested in early blastomeres. Neogenin up-regulation by its overexpression accelerated ICM development in the blastocyst concomitant with the activation of the ICM specific transcription factors Oct3/4, Sox2, and Nanog while its depletion by small hairpin RNAs (shRNAs) caused a developmental abnormality of poorly endowed ICM accompanied by the deactivation of Oct3/4, Sox2, and Nanog. Treatment with netrin-1 among neogenin ligands further impaired both embryonic development and ICM formation while repulsive guidance molecule c (RGMc) led to opposite consequences, enhancing ICM formation. From this study, we propose a model whereby neogenin interprets its own expression level to control the first cell fate determination in response to extracellular cues. PMID- 25013898 TI - Reliable quantification of protein expression and cellular localization in histological sections. AB - In targeted therapy, patient tumors are analyzed for aberrant activations of core cancer pathways, monitored based on biomarker expression, to ensure efficient treatment. Thus, diagnosis and therapeutic decisions are often based on the status of biomarkers determined by immunohistochemistry in combination with other clinical parameters. Standard evaluation of cancer specimen by immunohistochemistry is frequently impeded by its dependence on subjective interpretation, showing considerable intra- and inter-observer variability. To make treatment decisions more reliable, automated image analysis is an attractive possibility to reproducibly quantify biomarker expression in patient tissue samples. We tested whether image analysis could detect subtle differences in protein expression levels. Gene dosage effects generate well-graded expression patterns for most gene-products, which vary by a factor of two between wildtype and haploinsufficient cells lacking one allele. We used conditional mouse models with deletion of the transcription factors Stat5ab in the liver as well Junb deletion in a T-cell lymphoma model. We quantified the expression of total or activated STAT5AB or JUNB protein in normal (Stat5ab+/+ or JunB+/+), hemizygous (Stat5ab+/Delta or JunB+/Delta) or knockout (Stat5abDelta/Delta or JunBDelta/Delta) settings. Image analysis was able to accurately detect hemizygosity at the protein level. Moreover, nuclear signals were distinguished from cytoplasmic expression and translocation of the transcription factors from the cytoplasm to the nucleus was reliably detected and quantified using image analysis. We demonstrate that image analysis supported pathologists to score nuclear STAT5AB expression levels in immunohistologically stained human hepatocellular patient samples and decreased inter-observer variability. PMID- 25013899 TI - Liver fibrosis, host genetic and hepatitis C virus related parameters as predictive factors of response to therapy against hepatitis C virus in HIV/HCV coinfected patients. AB - OBJECTIVE: To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism). PATIENTS AND METHODS: A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, -238 TNF-alpha and -592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count. RESULTS: Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600,000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600,000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-alpha and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of -238 TNF-alpha genotype GG was detected in patients with significant liver fibrosis. CONCLUSIONS: In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a -238 TNF-alpha polymorphism in these patients. PMID- 25013900 TI - Discovery and comparative profiling of microRNAs in representative monopodial bamboo (Phyllostachys edulis) and sympodial bamboo (Dendrocalamus latiflorus). AB - BACKGROUND: According to the growth pattern of bamboo, sympodial bamboo and monopodial bamboo are considered as two mainly kinds of bamboo. They have different phenotypes and different characteristics in developmental stage. Much attention had been paid on the study of bamboo cultivation, processing, physiology, biochemistry and molecular biology, which had made great progresses in the last decade, especially for the highlighted achievement of the bamboo genomics. However, there is no information available on concerning comparative profiling of miRNAs between sympodial bamboo and monopodial bamboo, which might play important roles in the regulation of bamboo development. METHODOLOGY/PRINCIPAL FINDINGS: We identified the profiles of small RNAs using leaf tissues from one sympodial bamboo i.e. moso bamboo (Phyllostachys edulis) and another monopodial bamboo i.e. ma bamboo (Dendrocalamus latiflorus). The result showed that there were 19,295,759 and 11,513,888 raw sequence reads, in which 92 and 69 conserved miRNAs, as well as 95 and 62 novel miRNAs were identified in moso bamboo and ma bamboo, respectively. The ratio of high conserved miRNA families in ma bamboo is more than that in moso bamboo. In addition, a total of 49 and 106 potential targets were predicted in moso bamboo and ma bamboo, respectively, in which several targets for novel miRNAs are transcription factors that play important roles in plant development. More importantly, annotation of differentially expressed target genes was performed based on the analysis of pathway and gene ontology terms enrichment. CONCLUSIONS/SIGNIFICANCE: This study provides the first large-scale sight of discovery and comparative characterization of miRNAomes between two representative bamboos belonged to sympodial bamboo and monopodial bamboo, respectively. Although it will be necessary to validate the function of miRNAs through more experimental research in further, these results lay a foundation for unraveling the miRNA-mediated molecular processes in different kinds of bamboo. PMID- 25013901 TI - Early warning signs in social-ecological networks. AB - A number of social-ecological systems exhibit complex behaviour associated with nonlinearities, bifurcations, and interaction with stochastic drivers. These systems are often prone to abrupt and unexpected instabilities and state shifts that emerge as a discontinuous response to gradual changes in environmental drivers. Predicting such behaviours is crucial to the prevention of or preparation for unwanted regime shifts. Recent research in ecology has investigated early warning signs that anticipate the divergence of univariate ecosystem dynamics from a stable attractor. To date, leading indicators of instability in systems with multiple interacting components have remained poorly investigated. This is a major limitation in the understanding of the dynamics of complex social-ecological networks. Here, we develop a theoretical framework to demonstrate that rising variance--measured, for example, by the maximum element of the covariance matrix of the network--is an effective leading indicator of network instability. We show that its reliability and robustness depend more on the sign of the interactions within the network than the network structure or noise intensity. Mutualistic, scale free and small world networks are less stable than their antagonistic or random counterparts but their instability is more reliably predicted by this leading indicator. These results provide new advances in multidimensional early warning analysis and offer a framework to evaluate the resilience of social-ecological networks. PMID- 25013902 TI - Heritable genome editing with CRISPR/Cas9 in the silkworm, Bombyx mori. AB - We report the establishment of an efficient and heritable gene mutagenesis method in the silkworm Bombyx mori using modified type II clustered regularly interspaced short palindromic repeats (CRISPR) with an associated protein (Cas9) system. Using four loci Bm-ok, BmKMO, BmTH, and Bmtan as candidates, we proved that genome alterations at specific sites could be induced by direct microinjection of specific guide RNA and Cas9-mRNA into silkworm embryos. Mutation frequencies of 16.7-35.0% were observed in the injected generation, and DNA fragments deletions were also noted. Bm-ok mosaic mutants were used to test for mutant heritability due to the easily determined translucent epidermal phenotype of Bm-ok-disrupted cells. Two crossing strategies were used. In the first, injected Bm-ok moths were crossed with wild-type moths, and a 28.6% frequency of germline mutation transmission was observed. In the second strategy, two Bm-ok mosaic mutant moths were crossed with each other, and 93.6% of the offsprings appeared mutations in both alleles of Bm-ok gene (compound heterozygous). In summary, the CRISPR/Cas9 system can act as a highly specific and heritable gene-editing tool in Bombyx mori. PMID- 25013903 TI - The structure of the TFIIH p34 subunit reveals a von Willebrand factor A like fold. AB - RNA polymerase II dependent transcription and nucleotide excision repair are mediated by a multifaceted interplay of subunits within the general transcription factor II H (TFIIH). A better understanding of the molecular structure of TFIIH is the key to unravel the mechanism of action of this versatile protein complex within these vital cellular processes. The importance of this complex becomes further evident in the context of severe diseases like xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy, that arise from single point mutations in TFIIH subunits. Here we describe the structure of the p34 subunit of the TFIIH complex from the eukaryotic thermophilic fungus Chaetomium thermophilum. The structure revealed that p34 contains a von Willebrand Factor A (vWA) like domain, a fold which is generally known to be involved in protein protein interactions. Within TFIIH p34 strongly interacts with p44, a positive regulator of the helicase XPD. Putative protein-protein interfaces are analyzed and possible binding sites for the p34-p44 interaction suggested. PMID- 25013904 TI - Clinical characteristics and outcome of patients with neuroblastoma presenting genomic amplification of loci other than MYCN. AB - BACKGROUND: Somatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN. METHODS: Genomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected. RESULTS: In total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%+/ 11% vs 34.9%+/-7%, log-rank p<0.05). CONCLUSION: NBs harbouring regional amplification(s) without MNA are rare and seem to show atypical features in clinical presentation and genomic profile. Further high resolution genetic explorations are justified in this heterogeneous group, especially when considering these alterations as predictive markers for targeted therapy. PMID- 25013905 TI - Erectile dysfunction and risk of end stage renal disease requiring dialysis: a nationwide population-based study. AB - BACKGROUND: Previous studies have suggested that erectile dysfunction (ED) is an independent risk factor for macrovascular disease. Very few studies have evaluated the relationship between ED and risk of end stage renal disease (ESRD) requiring dialysis. METHODS: A random sample of 1,000,000 individuals from Taiwan's National Health Insurance database was collected. We selected the control group by matching the subjects and controls by age, diabetes, hypertension, coronary heart disease, hyperlipidemia, area of residence, monthly income and index date. We identified 3985 patients with newly-diagnosed ED between 2000 and 2008 and compared them with a matched cohort of 23910 patients without ED. All patients were tracked from the index date to identify which patients subsequently developed a need for dialysis. RESULTS: The incidence rates of dialysis in the ED cohort and comparison groups were 10.85 and 9.06 per 10000 person-years, respectively. Stratified by age, the incidence rate ratio for dialysis was greater in ED patients aged <50 years (3.16, 95% CI: 1.62-6.19, p = 0.0008) but not in aged 50-64 (0.94, 95% CI: 0.52-1.69, p = 0.8397) and those aged ? 65 (0.69, 95% CI: 0.32-1.52, p = 0.3594). After adjustment for patient characteristics and medial comorbidities, the adjusted HR for dialysis remained greater in ED patients aged <50 years (adjusted HR: 2.08, 95% CI: 1.05-4.11, p<0.05). The log-rank test revealed that ED patients <50-years-old had significantly higher cumulative incidence rates of dialysis than those without (p = 0.0004). CONCLUSION: Patients with ED, especially younger patients, are at an increased risk for ESRD requiring dialysis later in life. PMID- 25013906 TI - Spontaneous evolution in bilirubin levels predicts liver-related mortality in patients with alcoholic hepatitis. AB - The accurate prognostic stratification of alcoholic hepatitis (AH) is essential for individualized therapeutic decisions. The aim of this study was to develop a new prognostic model to predict liver-related mortality in Asian AH patients. We conducted a hospital-based, retrospective cohort study using 308 patients with AH between 1999 and 2011 (a derivation cohort) and 106 patients with AH between 2005 and 2012 (a validation cohort). The Cox proportional hazards model was constructed to select significant predictors of liver-related death from the derivation cohort. A new prognostic model was internally validated using a bootstrap sampling method. The discriminative performance of this new model was compared with those of other prognostic models using a concordance index in the validation cohort. Bilirubin, prothrombin time, creatinine, potassium at admission, and a spontaneous change in bilirubin levels from day 0 to day 7 (SCBL) were incorporated into a model for AH to grade the severity in an Asian patient cohort (MAGIC). For risk stratification, four risk groups were identified with cutoff scores of 29, 37, and 46 based on the different survival probabilities (P<0.001). In addition, MAGIC showed better discriminative performance for liver-related mortality than any other scoring system in the validation cohort. MAGIC can accurately predict liver-related mortality in Asian patients hospitalized for AH. Therefore, SCBL may help us decide whether patients with AH urgently require corticosteroid treatment. PMID- 25013907 TI - Association of toxicity of sorafenib and sunitinib for human keratinocytes with inhibition of signal transduction and activator of transcription 3 (STAT3). AB - Hand-foot skin reaction is a most common multi-kinase inhibitor-related adverse event. This study aimed to examine whether the toxicity of sorafenib and sunitinib for human keratinocytes was associated with inhibiting signal transduction and activator of transcription 3 (STAT3). We studied whether STAT3 activity affects sorafenib- and sunitinib-induced cell growth inhibition in HaCaT cells by WST-8 assay. Stattic enhanced the cell-growth inhibitory and apoptotic effects of sorafenib and sunitinib. HaCaT cells transfected with constitutively active STAT3 (STAT3C) were resistant to the sorafenib- and sunitinib-induced cell growth inhibition. STAT3 activity decreased after short-term treatment with sorafenib and sunitinib in a dose-dependent manner and recovered after long-term treatment with sorafenib and sunitinib at low doses. Moreover, the expression of survivin and bcl-2 decreased after treatment with sorafenib and sunitinib was concomitant with variations in STAT3 activity. Sorafenib-induced STAT3 inhibition was mediated by regulation via MAPK pathways in HaCaT cells, while sunitinib induced STAT3 inhibition was not. Thus, STAT3 activation mediating apoptosis suppressors may be a key factor in sorafenib and sunitinib-induced keratinocyte cytotoxicity. PMID- 25013908 TI - A water-soluble inclusion complex of pedunculoside with the polymer beta cyclodextrin: a novel anti-inflammation agent with low toxicity. AB - More than 50% of new drug candidates in drug discovery are lipophilic and exhibit poor aqueous solubility, which results in poor bioavailability and a lack of dose proportionality. Here, we improved the solubility of pedunculoside (PE) by generating a water-soluble inclusion complex composed of PE and the polymer beta cyclodextrin (CDP). We characterized this novel complex by 1H NMR, FT-IR, UV-vis spectroscopy, powder X-ray diffractometry and thermogravimetric analysis. The ratio of beta-cyclodextrin (beta-CD) units in CDP to PE was determined to be 2?1. The KD value of the inclusion complex was determined to be 4.29*10(-3) mol*L(-1). In contrast to the low solubility of PE, the water-solubility of the PE-CDP complex was greatly enhanced. A preclinical toxicological study indicated that PE CDP was well tolerated for a single administration. Importantly, the anti inflammation potency of the PE-CDP complex was higher than that of PE. As a result, the formation of inclusion complexes by water-soluble CDP opens up possible aqueous applications of insoluble drug candidates in drug delivery. PMID- 25013909 TI - Intraperitoneal administration of a tumor-associated antigen SART3, CD40L, and GM CSF gene-loaded polyplex micelle elicits a vaccine effect in mouse tumor models. AB - Polyplex micelles have demonstrated biocompatibility and achieve efficient gene transfection in vivo. Here, we investigated a polyplex micelle encapsulating genes encoding the tumor-associated antigen squamous cell carcinoma antigen recognized by T cells-3 (SART3), adjuvant CD40L, and granulocyte macrophage colony-stimulating factor (GM-CSF) as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC). Intraperitoneally administrated polyplex micelles were predominantly found in the lymph nodes, spleen, and liver. Compared with mock controls, the triple gene vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer cells, of which long-term surviving mice showed complete rejection when re-challenged with CT26 tumors. Moreover, the DNA vaccine inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung tumors in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+ DCs and CD4+/CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ T cells by neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine. In conclusion, a SART3/CD40L+GM-CSF gene-loaded polyplex micelle can be applied as a novel vaccine platform to elicit tumor rejection immunity regardless of the recipient MHC haplotype. PMID- 25013910 TI - Insecticide resistance status of United States populations of Aedes albopictus and mechanisms involved. AB - Aedes albopictus (Skuse) is an invasive mosquito that has become an important vector of chikungunya and dengue viruses. Immature Ae. albopictus thrive in backyard household containers that require treatment with larvicides and when adult populations reach pest levels or disease transmission is ongoing, adulticiding is often required. To assess the feasibility of control of USA populations, we tested the susceptibility of Ae. albopictus to chemicals representing the main insecticide classes with different modes of action: organochlorines, organophosphates, carbamates, pyrethroids, insect growth regulators (IGR), naturalytes, and biolarvicides. We characterized a susceptible reference strain of Ae. albopictus, ATM95, and tested the susceptibility of eight USA populations to five adulticides and six larvicides. We found that USA populations are broadly susceptible to currently available larvicides and adulticides. Unexpectedly, however, we found significant resistance to dichlorodiphenyltrichloroethane (DDT) in two Florida populations and in a New Jersey population. We also found resistance to malathion, an organophosphate, in Florida and New Jersey and reduced susceptibility to the IGRs pyriproxyfen and methoprene. All populations tested were fully susceptible to pyrethroids. Biochemical assays revealed a significant up-regulation of GSTs in DDT-resistant populations in both larval and adult stages. Also, beta-esterases were up regulated in the populations with suspected resistance to malathion. Of note, we identified a previously unknown amino acid polymorphism (Phe -> Leu) in domain III of the VGSC, in a location known to be associated with pyrethroid resistance in another container-inhabiting mosquito, Aedes aegypti L. The observed DDT resistance in populations from Florida may indicate multiple introductions of this species into the USA, possibly from tropical populations. In addition, the mechanisms underlying DDT resistance often result in pyrethroid resistance, which would undermine a remaining tool for the control of Ae. albopictus. Continued monitoring of the insecticide resistance status of this species is imperative. PMID- 25013912 TI - Emerging science of the human microbiome. AB - The human gastrointestinal tract hosts a large number of microbial cells which exceed their mammalian counterparts by approximately 3-fold. The genes expressed by these microorganisms constitute the gut microbiome and may participate in diverse functions that are essential to the host, including digestion, regulation of energy metabolism, and modulation of inflammation and immunity. The gut microbiome can be modulated by dietary changes, antibiotic use, or disease. Different ailments have distinct associated microbiomes in which certain species or genes are present in different relative quantities. Thus, identifying specific disease-associated signatures in the microbiome as well as the factors that alter microbial populations and gene expression will lead to the development of new products such as prebiotics, probiotics, antimicrobials, live biotherapeutic products, or more traditional drugs to treat these disorders. Gained knowledge on the microbiome may result in molecular lab tests that may serve as personalized tools to guide the use of the aforementioned products and monitor interventional progress. PMID- 25013911 TI - Effects of Aroclor 1254 on in vivo oocyte maturation in the mouse. AB - Polychlorinated biphenyls (PCBs) are stable, lipophilic compounds that accumulate in the environment and in the food chain. Though some studies provided evidence that PCBs had adverse effects on reproductive function, most of these results were from in vitro models. Therefore we investigated the effect of Aroclor 1254 (a commercial PCBs mixture) treatments on in vivo maturation and developmental potential of mouse oocytes. In the present study, female ICR mice were treated with different doses (12.5, 25 and 50 mg/kg) of Aroclor 1254 (a commercial PCB mixture) once every 72 hours by intraperitoneal injection for 9 days. After three treatments of Aroclor 1254, the mice were superovulated to collect oocytes one day after the last exposure. The effects of Aroclor 1254 on oocyte maturation, fertilization, and preimplantation embryonic development were investigated. Immunofluorescence-stained oocytes were observed under a confocal microscope to assess the effects of Aroclor 1254 on spindle morphology. Parthenogenic activation and the incidence of cumulus apoptosis in cumulus-oocyte complexes were observed as well. Oocytes exposed to different doses of Aroclor 1254 in vivo were associated with a significant decrease in outgrowth potential, abnormal spindle configurations, and the inhibition of parthenogenetic activation of ovulated oocytes. Furthermore, the incidence of apoptosis in cumulus cells was increased after exposed to Aroclor 1254. These results may provide reference for the treatment of reproductive diseases such as infertility or miscarriage caused by environmental contaminants. PMID- 25013913 TI - Modulation of dendritic cell immunobiology via inhibition of 3-hydroxy-3 methylglutaryl-CoA (HMG-CoA) reductase. AB - The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naive T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities. PMID- 25013914 TI - Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. AB - BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA 4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. METHODS: GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. RESULTS: Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. CONCLUSION: Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory. PMID- 25013915 TI - Water molecular system dynamics associated with amyloidogenic nucleation as revealed by real time near infrared spectroscopy and aquaphotomics. AB - The formation of amyloid fibrils proceeds via a nucleation-dependent mechanism in which nucleation phase is generally associated with a high free energy resulting in the rate-limiting step. On the basis of this kinetic feature, the nucleation is one of the most crucial phases controlling the pathogenesis of amyloidoses, but little is known about the details of how protein molecules and surrounding environment vary at this stage. Here, we applied near infrared (NIR) spectral monitoring of water structural changes in real time during the nucleation dependent fibrillation of insulin. Whilst multivariate spectral analysis in the 2050-2350 nm spectral region indicated cross-beta formation, characteristic transformations of water structure have been detected in the spectral region 1300 1600 nm corresponding to the first overtone of water OH stretching vibrations. Furthermore, specific water spectral patterns (aquagrams) related to different water molecular conformations have been found along the course of protein nucleation and aggregation. Right in the beginning, dissociation of hydrogen bonded network in bulk water and coinstantaneous protein and ion hydration were observed, followed by water hydrogen-bonded networks development, presumably forcing the nucleation. These specific transformations of water spectral pattern could be used further as a biomarker for early non-invasive diagnosis of amyloidoses prior to explosive amplification and deposits of amyloid fibrils. PMID- 25013916 TI - A clinical study of tracheobronchopathia osteochondroplastica: findings from a large Chinese cohort. AB - BACKGROUND AND STUDY AIMS: Tracheobronchopathia osteochondroplastica (TO) is an uncommon disease of the tracheobronchial system that leads to narrowing of the airway lumen from cartilaginous and/or osseous submucosal nodules. The aim of this study is to perform a detailed review of this rare disease in a large cohort of patients with TO proven by fiberoptic bronchoscopy from China. PATIENTS AND METHODS: Retrospective chart review was performed on 41,600 patients who underwent bronchoscopy in the Department of Respiratory Medicine of Changhai Hospital between January 2005 and December 2012. Cases of TO were identified based on characteristic features during bronchoscopic examination. RESULTS: 22 cases of bronchoscopic TO were identified. Among whom one-half were male and the mean age was 47.45+/-10.91 years old. The most frequent symptoms at presentation were chronic cough (n = 14) and increased sputum production (n = 10). Radiographic abnormalities were observed in 3/18 patients and findings on computed tomography consistent with TO such as beaded intraluminal calcifications and/or increased luminal thickenings were observed in 18/22 patients. Patients were classified into the following categories based on the severity of bronchoscopic findings: Stage I (n = 2), Stage II (n = 6) and Stage III (n = 14). The result that bronchoscopic improvement was observed in 2 patients administered with inhaled corticosteroids suggested that resolution of this disease is possible. CONCLUSIONS: TO is a benign disease with slow progression, which could be roughly divided into 3 stages on the basis of the characteristic endoscopic features and histopathologic findings. Chronic inflammation was thought to be more important than the other existing plausible hypotheses in the course of TO. Inhaled corticosteroids might have some impact on patients at Stage I/II. PMID- 25013917 TI - Evaluating the risks and benefits of participation in high-school football. PMID- 25013918 TI - A patient's request for steroids to enhance participation in wilderness sport and adventure. PMID- 25013920 TI - What we talk about when we talk about performance enhancement. PMID- 25013919 TI - Nonmaleficence in sports medicine. PMID- 25013921 TI - Drug testing in sport: hGH (human growth hormone). PMID- 25013922 TI - Concussion-related litigation against the National Football League. PMID- 25013923 TI - Addressing concussion in youth sports. PMID- 25013924 TI - Muscle as fashion: messages from the bodybuilding subculture. PMID- 25013925 TI - Physicians and the sports doping epidemic. PMID- 25013926 TI - Genetic analysis and prevalence studies of the brp exopolysaccharide locus of Vibrio vulnificus. AB - Phase variation in the Gram-negative human pathogen Vibrio vulnificus involves three colonial morphotypes- smooth opaque colonies due to production of capsular polysaccharide (CPS), smooth translucent colonies as the result of little or no CPS expression, and rugose colonies due to production of a separate extracellular polysaccharide (EPS), which greatly enhances biofilm formation. Previously, it was shown that the brp locus, which consists of nine genes arranged as an operon, is up-regulated in rugose strains in a c-di-GMP-dependent manner, and that plasmid insertions into the locus resulted in loss of rugosity and efficient biofilm production. Here, we have used non-polar mutagenesis to assess the involvement of individual brp genes in production of EPS and related phenotypes. Inactivation of genes predicted to be involved in various stages of EPS biosynthesis eliminated both the rugose colonial appearance and production of EPS, while knockout of a predicted flippase function involved in EPS transport resulted in a dry, lightly striated phenotype, which was associated with a reduction of brp-encoded EPS on the cell surface. All brp mutants retained the reduced motility characteristic of rugose strains. Lastly, we provide evidence that the brp locus is highly prevalent among strains of V. vulnificus. PMID- 25013927 TI - Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens. AB - Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB. PMID- 25013929 TI - Development of composite indices to measure the adoption of pro-environmental behaviours across Canadian provinces. AB - OBJECTIVE: The adoption of pro-environmental behaviours reduces anthropogenic environmental impacts and subsequent human health effects. This study developed composite indices measuring adoption of pro-environmental behaviours at the household level in Canada. METHODS: The 2007 Households and the Environment Survey conducted by Statistics Canada collected data on Canadian environmental behaviours at households' level. A subset of 55 retained questions from this survey was analyzed by Multiple Correspondence Analysis (MCA) to develop the index. Weights attributed by MCA were used to compute scores for each Canadian province as well as for socio-demographic strata. Scores were classified into four categories reflecting different levels of adoption of pro-environmental behaviours. RESULTS: Two indices were finally created: one based on 23 questions related to behaviours done inside the dwelling and a second based on 16 questions measuring behaviours done outside of the dwelling. British Columbia, Quebec, Prince-Edward-Island and Nova-Scotia appeared in one of the two top categories of adoption of pro-environmental behaviours for both indices. Alberta, Saskatchewan, Manitoba and Newfoundland-and-Labrador were classified in one of the two last categories of pro-environmental behaviours adoption for both indices. Households with a higher income, educational attainment, or greater number of persons adopted more indoor pro-environmental behaviours, while on the outdoor index, they adopted fewer such behaviours. Households with low-income fared better on the adoption of outdoors pro-environmental behaviours. CONCLUSION: MCA was successfully applied in creating Indoor and Outdoor composite Indices of pro environmental behaviours. The Indices cover a good range of environmental themes and the analysis could be applied to similar surveys worldwide (as baseline weights) enabling temporal trend comparison for recurring themes. Much more than voluntary measures, the study shows that existing regulations, dwelling type, households composition and income as well as climate are the major factors determining pro-environmental behaviours. PMID- 25013928 TI - Meis1 regulates epidermal stem cells and is required for skin tumorigenesis. AB - Previous studies have shown that Meis1 plays an important role in blood development and vascular homeostasis, and can induce blood cancers, such as leukemia. However, its role in epithelia remains largely unknown. Here, we uncover two roles for Meis1 in the epidermis: as a critical regulator of epidermal homeostasis in normal tissues and as a proto-oncogenic factor in neoplastic tissues. In normal epidermis, we show that Meis1 is predominantly expressed in the bulge region of the hair follicles where multipotent adult stem cells reside, and that the number of these stem cells is reduced when Meis1 is deleted in the epidermal tissue of mice. Mice with epidermal deletion of Meis1 developed significantly fewer DMBA/TPA-induced benign and malignant tumors compared with wild-type mice, suggesting that Meis1 plays a role in both tumor development and malignant progression. This is consistent with the observation that Meis1 expression increases as tumors progress from benign papillomas to malignant carcinomas. Interestingly, we found that Meis1 localization was altered to neoplasia development. Instead of being localized to the stem cell region, Meis1 is localized to more differentiated cells in tumor tissues. These findings suggest that, during the transformation from normal to neoplastic tissues, a functional switch occurs in Meis1. PMID- 25013930 TI - Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer. AB - Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int-/-) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC. PMID- 25013933 TI - Evaluation of the potential of 9 Nannochloropsis strains for biodiesel production. AB - Nannochloropsis have attracted sustained interest from algal biodiesel researchers due to their high biomass accumulation rate and high lipid content. There are six recognized species in the Nannochloropsis genus that are phylogenetically divided into Nannochloropsis gaditana, Nannochloropsis salina, Nannochloropsis granulata, Nannochloropsis limnetica, Nannochloropsis oceanica and Nannochloropsis oculata. In this study, the potential of 9 Nannochloropsis species from the 6 genus for biodiesel production was evaluated by determining their growth rate, biomass accumulation, lipid productivity, lipid composition, fatty acid profiles and biodiesel properties. The results showed that the best strain was N. oceanica IMET1, with lipid productivity of 158.76 +/- 13.83 mg L( 1)day(-1), TAG production of 1.67 +/- 0.20 g/L, favorable fatty acid profiles of C16-C18 (56.62 +/- 1.96%) as well as suitable biodiesel properties of higher cetane number (54.61 +/- 0.25), lower iodine number (104.85 +/- 2.80 g I2/100g) and relative low cloud point (3.45 +/- 0.50 degrees C). N. oceanica IMET1 could be consider as valuable feedstock for microalgal biodiesel production. PMID- 25013934 TI - Effects of a static magnetic field on phenol degradation effectiveness and Rhodococcus erythropolis growth and respiration in a fed-batch reactor. AB - The aim of this study was to evaluate the impact of short-term repeated exposure to a static magnetic field (induction 370 mT) on the Rhodococcus erythropolis cells. Specifically, it was ascertained the magnetic field's potential to influence degradation of a phenol substrate, cell growth and respiration activity (oxygen consumption) during substrate biodegradation. The experiment took place over 3 days, with R. erythropolis exposed to the magnetic field for the first day. During the experiment, different recirculation rates between the reactor and the magnetic contactor has been tested. Use of the magnetic field at higher recirculation rates (residence time in contactor was less than 7 min) stimulated substrate (phenol) oxidation by around 34%; which, in turn, promoted R. erythropolis growth by around 28% by shortening the lag- and exponential-phases and increasing bacterial respiration activity by around 10%. PMID- 25013931 TI - Health-related behaviors and effectiveness of trivalent inactivated versus live attenuated influenza vaccine in preventing influenza-like illness among young adults. AB - BACKGROUND: Vaccination is the preferred preventive strategy against influenza. Though health behaviors are known to affect immunity and vaccine delivery modes utilize different immune processes, data regarding the preferred influenza vaccine type among adults endorsing specific health-related behaviors (alcohol use, tobacco use, and exercise level) are limited. METHODS: The relative effectiveness of two currently available influenza vaccines were compared for prevention of influenza-like illness during 2 well-matched influenza seasons (2006/2007, 2008/2009) among US military personnel aged 18-49 years. Relative vaccine effectiveness was compared between those self-reporting and not reporting recent smoking history and potential alcohol problem, and by exercise level using Cox proportional hazard modeling adjusted for sociodemographic and military factors, geographic area, and other health behaviors. RESULTS: 28,929 vaccination events and 3936 influenza-like illness events over both influenza seasons were studied. Of subjects, 27.5% were smokers, 7.7% had a potential alcohol-related problem, 10.5% reported minimal exercise, and 4.4% reported high exercise levels. Overall, the risk of influenza-like illness did not significantly differ between live attenuated and trivalent inactivated influenza vaccine recipients (hazard ratio, 0.98; 95% confidence interval, 0.90-1.06). In the final adjusted model, the relative effectiveness of the 2 vaccine types did not differ by smoking status (p = 0.10), alcohol status (p = 0.21), or activity level (p = 0.11). CONCLUSIONS: Live attenuated and trivalent inactivated influenza vaccines were similarly effective in preventing influenza-like illness among young adults and did not differ by health-related behavior status. Influenza vaccine efforts should continue to focus simply on delivering vaccine. PMID- 25013935 TI - Synthesis and characterization of V(IV)O complexes of picolinate and pyrazine derivatives. Behavior in the solid state and aqueous solution and biotransformation in the presence of blood plasma proteins. AB - Oxidovanadium(IV) complexes with 5-cyanopyridine-2-carboxylic acid (HpicCN), 3,5 difluoropyridine-2-carboxylic acid (HpicFF), 3-hydroxypyridine-2-carboxylic acid (H2hypic), and pyrazine-2-carboxylic acid (Hprz) have been synthesized and characterized in the solid state and aqueous solution through elemental analysis, IR and EPR spectroscopy, potentiometric titrations, and DFT simulations. The crystal structures of the complexes (OC-6-23)-[VO(picCN)2(H2O)].2H2O (1.2H2O), (OC-6-24)-[VO(picCN)2(H2O)].4H2O (2.4H2O), (OC-6-24)-Na[VO(Hhypic)3].H2O (4), and two enantiomers of (OC-6-24)-[VO(prz)2(H2O)] (Lambda-5 and Delta-5) have been determined also by X-ray crystallography. 1 presents the first crystallographic evidence for the formation of a OC-6-23 isomer for bis(picolinato) V(IV)O complexes, whereas 2, 4, and 5 possess the more common OC-6-24 arrangement. The strength order of the ligands is H2hypic ? HpicCN > Hprz > HpicFF, and this results in a different behavior at pH 7.40. In organic and aqueous solution the three isomers OC-6-23, OC-6-24, and OC-6-42 are formed, and this is confirmed by DFT simulations. In all the systems with apo-transferrin (VO)2(apo-hTf) is the main species in solution, with the hydrolytic V(IV)O species becoming more important with lowering the strength of the ligand. In the systems with albumin, (VO)(x)HSA (x = 5, 6) coexists with VOL2(HSA) and VOL(HSA)(H2O) when L = picCN, prz, with [VO(Hhypic)(hypic)](-), [VO(hypic)2](2-), and [(VO)4(MU-hypic)4(H2O)4] when H2hypic is studied, and with the hydrolytic V(IV)O species when HpicFF is examined. Finally, the consequence of the hydrolysis on the binding of V(IV)O(2+) to the blood proteins, the possible uptake of V species by the cells, and the possible relationship with the insulin-enhancing activity are discussed. PMID- 25013936 TI - Effects of protease, phytase and a Bacillus sp. direct-fed microbial on nutrient and energy digestibility, ileal brush border digestive enzyme activity and cecal short-chain fatty acid concentration in broiler chickens. AB - Two experiments were conducted to determine the effects of protease and phytase (PP) and a Bacillus sp. direct-fed microbial (DFM) on dietary energy and nutrient utilization in broiler chickens. In the first experiment, Ross 308 broiler chicks were fed diets supplemented with PP and DFM in a 2*2 factorial arrangement. The 4 diets (control (CON), CON + PP, CON + DFM, and CON + PP + DFM) were fed from 15 21 days of age. In Experiment 1, significant interaction (P<=0.01) between PP and DFM on the apparent ileal digestibility coefficient for starch, crude protein, and amino acid indicated that both additives increased the digestibility. Both additives increased the nitrogen retention coefficient with a significant interaction (P<=0.01). Although no interaction was observed, significant main effects (P<=0.01) for nitrogen-corrected apparent ME (AMEn) for PP or DFM indicated an additive response. In a follow-up experiment, Ross 308 broiler chicks were fed the same experimental diets from 1-21 days of age. Activities of ileal brush border maltase, sucrase, and L-alanine aminopeptidase were increased (P<=0.01) by PP addition, while a trend (P = 0.07) for increased sucrase activity was observed in chickens fed DFM, in Experiment 2. The proportion of cecal butyrate was increased (P<=0.01) by DFM addition. Increased nutrient utilization and nitrogen retention appear to involve separate but complementary mechanisms for PP and DFM, however AMEn responses appear to have separate and additive mechanisms. PMID- 25013937 TI - Detecting memory and structure in human navigation patterns using Markov chain models of varying order. AB - One of the most frequently used models for understanding human navigation on the Web is the Markov chain model, where Web pages are represented as states and hyperlinks as probabilities of navigating from one page to another. Predominantly, human navigation on the Web has been thought to satisfy the memoryless Markov property stating that the next page a user visits only depends on her current page and not on previously visited ones. This idea has found its way in numerous applications such as Google's PageRank algorithm and others. Recently, new studies suggested that human navigation may better be modeled using higher order Markov chain models, i.e., the next page depends on a longer history of past clicks. Yet, this finding is preliminary and does not account for the higher complexity of higher order Markov chain models which is why the memoryless model is still widely used. In this work we thoroughly present a diverse array of advanced inference methods for determining the appropriate Markov chain order. We highlight strengths and weaknesses of each method and apply them for investigating memory and structure of human navigation on the Web. Our experiments reveal that the complexity of higher order models grows faster than their utility, and thus we confirm that the memoryless model represents a quite practical model for human navigation on a page level. However, when we expand our analysis to a topical level, where we abstract away from specific page transitions to transitions between topics, we find that the memoryless assumption is violated and specific regularities can be observed. We report results from experiments with two types of navigational datasets (goal-oriented vs. free form) and observe interesting structural differences that make a strong argument for more contextual studies of human navigation in future work. PMID- 25013938 TI - Four models of HIV counseling and testing: utilization and test results in South Africa. AB - BACKGROUND: HIV Counseling and Testing (HCT) is the point-of-entry for pathways of HIV care and prevention. However, HCT is not reaching many who are HIV infected and this may be related to the HCT provision model. We describe HCT utilization and HIV diagnosis using four models of HCT delivery: clinic-based, urban mobile, rural mobile, and stand-alone. METHODS: Using cross-sectional data from routine HCT provided in South Africa, we described client characteristics and HIV test results from information collected during service delivery between January 2009 and June 2012. RESULTS: 118,358 clients received services at clinic based units, 18,597; stand-alone, 28,937; urban mobile, 38,840; and rural mobile, 31,984. By unit, clients were similar in terms of median age (range 28-31), but differed in sex distribution, employment status, prior testing, and perceived HIV risk. Urban mobile units had the highest proportion of male clients (52%). Rural mobile units reached the highest proportion of clients with no prior HCT (61%) and reporting no perceived HIV risk (64%). Overall, 10,862 clients (9.3%) tested HIV-positive. CONCLUSIONS: Client characteristics varied by HCT model. Importantly, rural and urban mobile units reached more men, first-time testers, and clients who considered themselves to be at low risk for HIV. PMID- 25013939 TI - Helminth induced suppression of macrophage activation is correlated with inhibition of calcium channel activity. AB - Helminth parasites cause persistent infections in humans and yet many infected individuals are asymptomatic. Neurocysticercosis (NCC), a disease of the central nervous system (CNS) caused by the cestode Taenia solium, has a long asymptomatic phase correlated with an absence of brain inflammation. However, the mechanisms of immune suppression remain poorly understood. Here we report that murine NCC displays a lack of cell surface maturation markers in infiltrating myeloid cells. Furthermore, soluble parasite ligands (PL) failed to induce maturation of macrophages, and inhibited TLR-induced inflammatory cytokine production. Importantly, PL treatment abolished both LPS and thapsigargin-induced store operated Ca2+ entry (SOCE). Moreover, electrophysiological recordings demonstrated PL-mediated inhibition of LPS or Tg-induced currents that were TRPC1 dependent. Concomitantly STIM1-TRPC1 complex was also impaired that was essential for SOCE and sustained Ca2+ entry. Likewise loss of SOCE due to PL further inhibited NFkB activation. Overall, our results indicate that the negative regulation of agonist induced Ca2+ signaling pathway by parasite ligands may be a novel immune suppressive mechanism to block the initiation of the inflammatory response associated with helminth infections. PMID- 25013940 TI - Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours. AB - Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions. PMID- 25013941 TI - Time-dependent effect of orchidectomy on vascular nitric oxide and thromboxane A2 release. Functional implications to control cell proliferation through activation of the epidermal growth factor receptor. AB - This study analyzes whether the release of nitric oxide (NO) and thromboxane A2 (TXA2) depends on the time lapsed since gonadal function is lost, and their correlation with the proliferation of vascular smooth muscle cells (VSMC) mediated by the epidermal growth factor receptor (EGFR). For this purpose, aortic and mesenteric artery segments from control and 6-weeks or 5-months orchidectomized rats were used to measure NO and TXA2 release. The results showed that the basal and acetylcholine (ACh)-induced NO release were decreased 6 weeks post-orchidectomy both in aorta and mesenteric artery, but were recovered 5 months thereafter up to levels similar to those found in arteries from control rats. The basal and ACh-induced TXA2 release increased in aorta and mesenteric artery 6 weeks post-orchidectomy, and was maintained at high levels 5 months thereafter. Since we previously observed that orchidectomy, which decreased testosterone level, enlarged the muscular layer of mesenteric arteries, the effect of testosterone on VSMC proliferation was analyzed. The results showed that treatment of cultured VSMC with testosterone downregulated mitogenic signaling pathways initiated by the ligand-dependent activation of the EGFR. In contrast, the EGFR pathways were constitutively active in mesenteric arteries of long-term orchidectomized rats. Thus, the exposure of mesenteric arteries from control rats to epidermal growth factor (EGF) induced the activation of EGFR signaling pathways. However, the addition of EGF to arteries from orchidectomized rats failed to induce a further activation of these pathways. In conclusion, this study shows that the release of NO depends on the time lapsed since the gonadal function is lost, while the release of TXA2 is already increased after short periods post-orchidectomy. The alterations in these signaling molecules could contribute to the constitutive activation of the EGFR and its downstream signaling pathways after long period post-orchidectomy enhancing the proliferation of the vascular muscular layer. PMID- 25013942 TI - Embryonic miRNA profiles of normal and ectopic pregnancies. AB - Our objective was to investigate the miRNA profile of embryonic tissues in ectopic pregnancies (EPs) and controlled abortions (voluntary termination of pregnancy; VTOP). Twenty-three patients suffering from tubal EP and twenty-nine patients with a normal ongoing pregnancy scheduled for a VTOP were recruited. Embryonic tissue samples were analyzed by miRNA microarray and further validated by real time PCR. Microarray studies showed that four miRNAs were differentially downregulated (hsa-mir-196b, hsa-mir-30a, hsa-mir-873, and hsa-mir-337-3p) and three upregulated (hsa-mir-1288, hsa-mir-451, and hsa-mir-223) in EP compared to control tissue samples. Hsa-miR-196, hsa-miR-223, and hsa-miR-451 were further validated by real time PCR in a wider population of EP and control samples. We also performed a computational analysis to identify the gene targets and pathways which might be modulated by these three differentially expressed miRNAs. The most significant pathways found were the mucin type O-glycan biosynthesis and the ECM receptor-interaction pathways. We also checked that the dysregulation of these three miRNAs was able to alter the expression of the gene targets in the embryonic tissues included in these pathways such as GALNT13 and ITGA2 genes. In conclusion, analysis of miRNAs in ectopic and eutopic embryonic tissues shows different expression patterns that could modify pathways which are critical for correct implantation, providing new insights into the understanding of ectopic implantation in humans. PMID- 25013944 TI - The role of singing familiar songs in encouraging conversation among people with middle to late stage Alzheimer's disease. AB - BACKGROUND: Language deficits in people with Alzheimer's disease (AD) manifest, among other things, in a gradual deterioration of spontaneous speech. People with AD tend to speak less as the disease progresses and their speech becomes confused. However, the ability to sing old tunes sometimes remains intact throughout the disease. OBJECTIVE: The purpose of this study was to explore the role of singing familiar songs in encouraging conversation among people with middle to late stage AD. METHODS: Six participants attended group music therapy sessions over a one-month period. Using content analysis, we qualitatively examined transcriptions of verbal and sung content during 8 group sessions for the purpose of understanding the relationship between specific songs and conversations that occurred during and following group singing. RESULTS: Content analysis revealed that songs from the participants' past-elicited memories, especially songs related to their social and national identity. Analyses also indicated that conversation related to the singing was extensive and the act of group singing encouraged spontaneous responses. After singing, group members expressed positive feelings, a sense of accomplishment, and belonging. CONCLUSIONS: Carefully selecting music from the participants' past can encourage conversation. Considering the failure in spontaneous speech in people with middle to late stage AD, it is important to emphasize that group members' responses to each other occurred spontaneously without the researcher's encouragement. PMID- 25013945 TI - Construct validity and reliability of the Music Attentiveness Screening Assessment (MASA). AB - BACKGROUND: Music as alternate engagement (MAE) can be used effectively to distract children during painful or anxiety-provoking medical procedures. For such interventions to be successful, it would seem important to assess the degree to which a child can attend to musical stimuli. OBJECTIVE: The purposes of this study were as follows: (a) To establish construct validity by determining the extent to which the Music Attentiveness Screening Assessment (MASA) measures auditory attention; and (b) to gather evidence regarding MASA test-retest and inter-observer reliability. METHODS: The Auditory Attention (AA) subtest from the NEPSY-II (NEPSY, Second Edition) and the two items from MASA were administered to a nonclinical sample of children (N = 50) aged 5 to 9 years. RESULTS: There was a statistically significant proportion of AA score variance shared with MASA (both items), R (2) = .21, F(2, 47) = 6.34, p = .004. Test-retest reliability on the first MASA item was moderately high (Pearson r = .84) while on the second item it was lower (r = .63). Similarly, interobserver agreement was high for Item I (intraclass correlation coefficient [ICC] = .95) and lower for Item II (ICC = .71). CONCLUSIONS: Evidence suggests that MASA measures, at least in part, auditory attention. Despite this finding, a large proportion of unexplained variance remains. Furthermore, reliability estimates (test-retest and interobserver agreement) differ between both items. These findings are discussed with particular attention paid to the ways in which MASA should be revised and further study conducted. PMID- 25013946 TI - Effects of voice timbre and accompaniment on working memory as measured by sequential monosyllabic digit recall performance. AB - BACKGROUND: Information is often paired with music in an attempt to facilitate recall and enhance learning. However, there is a lack of basic research investigating how music carrying information might facilitate recall and subsequent learning. OBJECTIVE: The purpose of the current study was to determine the effects of voice timbre and accompaniment on working memory as measured by recall performance on a sequential digit recall task. Specific research questions were as follows: (a) How might female and male voice timbres affect serial recall? (b) How might piano, guitar, and no accompaniment affect serial recall? (c) Do music majors have enhanced recall accuracy when compared to nonmusic majors? METHODS: The recall of information paired with six different melodies was tested on 60 university students. Melodies were composed and recorded using female and male voices with three levels of accompaniment: guitar, piano, and no accompaniment. RESULTS: Participants had more accurate recall during the male voice and piano and no accompaniment conditions and least accurate recall during the female voice and guitar accompaniment conditions. CONCLUSIONS: As participants had most accurate recall during the male voice and with piano or no accompaniment, clinicians are encouraged to consider using no accompaniment or piano accompaniment when initially teaching social and academic information paired with music for later recall. When possible, vocal timbre (i.e., the potential benefit of male voicing) should also be considered. Implications for clinical practice, limitations of the study, and suggestions for future research are provided. PMID- 25013947 TI - Gatekeeping practices of music therapy academic programs and internships: a national survey. AB - BACKGROUND: Gatekeeping safeguards access to the practice of a profession to ensure the quality of clinical services. It involves selective admission, continuous evaluation, and timely and ethical decisions in response to trainees with severe professional competency problems (SPCP). To date, little information is available concerning gatekeeping practices in the field of music therapy. OBJECTIVE: This study investigated the extent and outcomes of gatekeeping practices across academic programs and National Roster internship sites approved by the American Music Therapy Association. Specifically, it examined the prevalence of trainees with SPCP, program-wide precautionary measures, common indicators of trainees with SPCP, remedial strategies, and supports and barriers to effective management. METHODS: Thirty-two academic program directors and 77 internship directors completed an online survey. Responses were compiled into aggregate form (frequencies & percentages) for analysis. Chi-square tests with Yates' correction were applied to compare the differences between academic programs and internships. RESULTS: A significantly higher percentage of academic programs (93.8%) reported having at least one trainee with SPCP over the past 5 years than did internships (66.2%). The most common indicators of competency problems included inadequate music skill development, emotional instability, limited communication skills, deficient interpersonal skills, defensiveness in supervision, and lack of insight. Typical remedial methods included referral to personal therapy, increased supervision, and repetition of practicum or extension of internship. CONCLUSIONS: Issues regarding trainees with SPCP are frequently addressed by academic and internship program directors. Improving clarity within professional guidelines and establishing more rigorous and consistent standards across training programs are recommended. PMID- 25013948 TI - Protein variants form a system of networks: microdiversity of IMP metallo-beta lactamases. AB - Genome and metagenome sequencing projects support the view that only a tiny portion of the total protein microdiversity in the biosphere has been sequenced yet, while the vast majority of existing protein variants is still unknown. By using a network approach, the microdiversity of 42 metallo-beta-lactamases of the IMP family was investigated. In the networks, the nodes are formed by the variants, while the edges correspond to single mutations between pairs of variants. The 42 variants were assigned to 7 separate networks. By analyzing the networks and their relationships, the structure of sequence space was studied and existing, but still unknown, functional variants were predicted. The largest network consists of 10 variants with IMP-1 in its center and includes two ubiquitous mutations, V67F and S262G. By relating the corresponding pairs of variants, the networks were integrated into a single system of networks. The largest network also included a quartet of variants: IMP-1, two single mutants, and the respective double mutant. The existence of quartets indicates that if two mutations resulted in functional enzymes, the double mutant may also be active and stable. Therefore, quartet construction from triplets was applied to predict 15 functional variants. Further functional mutants were predicted by applying the two ubiquitous mutations in all networks. In addition, since the networks are separated from each other by 10-15 mutations on average, it is expected that a subset of the theoretical intermediates are functional, and therefore are supposed to exist in the biosphere. Finally, the network analysis helps to distinguish between epistatic and additive effects of mutations; while the presence of correlated mutations indicates a strong interdependency between the respective positions, the mutations V67F and S262G are ubiquitous and therefore background independent. PMID- 25013949 TI - Peri-strut low-intensity areas in optical coherence tomography correlate with peri-strut inflammation and neointimal proliferation: an in-vivo correlation study in the familial hypercholesterolemic coronary swine model of in-stent restenosis. AB - BACKGROUND: Peri-strut low-intensity area (PLI) is a common imaging finding during the evaluation of in-stent neointima using optical coherence tomography (OCT). We aimed to determine the biological significance of PLI by comparing in vivo OCT images with the corresponding histological sections obtained from the familial hypercholesterolemic swine model of coronary stenosis. METHODS: A total of 26 coronary vessels of nine familial hypercholesterolemic swine were injured with 30% balloon overstretch and then immediately followed by everolimus eluting or bare metal stent placement at 20% overstretch. At 30 days, all stented vessels were subjected to in-vivo OCT analysis and were harvested for histological evaluation. For OCT analysis, stent cross-sections (three per stent) were categorized into presence (PLI+) or absence (PLI-) of PLI. In histology, inflammation and fibrin deposition were scored semiquantitatively from 0 (none) to 3 (severe). RESULTS: PLI was found in 64.9% of stent sections. Peri-strut inflammation was more frequently observed in OCT sections PLI (+) compared with PLI (-) (56.0 vs. 7.4%, P=0.01). In contrast, peri-strut fibrin deposits was similar in both groups (PLI+=58.0% vs. PLI-=59.3%, P=0.94). Histological neointimal thickness was significantly higher in PLI (+) sections (mean+/-SE: 0.68+/-0.06 vs. 0.34+/-0.02 mm; P<0.01), yielding a higher percent area stenosis compared with PLI (-) (mean+/-SE: 59.0+/-4.4 vs. 34.1+/-2.2%, P<0.01). The PLI diagnostic sensitivity and specificity for inflammation were 80 and 76.1%, respectively (>56% PLI, area under the curve=0.86, P<0.01), whereas for fibrin deposition, the sensitivity and specificity were 42.2 and 76.1%, respectively (area under the curve=0.56, P=NS). Area under the receiver operating characteristic curve was significantly higher for identifying inflammation than fibrin (0.86 vs. 0.56, P<0.01). The severity of PLI correlated with the neointimal thickness when assessed by OCT (R=0.79, P<0.001). CONCLUSION: The presence of PLI in OCT correlates with neointimal thickness and appears to have a diagnostic value in the recognition of peri-strut inflammation, therefore possibly serving as a surrogate for in-vivo assessment of stent efficacy. PMID- 25013950 TI - Identification of heat responsive genes in Brassica napus siliques at the seed filling stage through transcriptional profiling. AB - High temperature stress results in yield loss and alterations to seed composition during seed filling in oilseed rape (Brassica napus). However, the mechanism underlying this heat response is poorly understood. In this study, global transcription profiles of 20 d-old siliques of B. napus were analyzed after heat stress using a Brassica 95k EST microarray. The up-regulated genes included many HSF/HSP transcripts and other heat-related marker genes, such as ROF2, DREB2a, MBF1c and Hsa32, reflecting the conservation of key heat resistance factors among plants. Other up-regulated genes were preferentially expressed in heat-stressed silique walls or seeds, including some transcription factors and potential developmental regulators. In contrast, down-regulated genes differed between the silique wall and seeds and were largely tied to the biological functions of each tissue, such as glucosinolate metabolism in the silique wall and flavonoid synthesis in seeds. Additionally, a large proportion (one-third) of these differentially expressed genes had unknown functions. Based on these gene expression profiles, Arabidopsis mutants for eight heat-induced Brassica homologous genes were treated with different heat stress methods, and thermotolerance varied with each mutation, heat stress regimen and plant development stage. At least two of the eight mutants exhibited sensitivity to the heat treatments, suggesting the importance of the respective genes in responding to heat stress. In summary, this study elucidated the molecular bases of the heat responses in siliques during later reproductive stages and provides valuable information and gene resources for the genetic improvement of heat tolerance in oilseed rape breeding. PMID- 25013952 TI - Health-related quality of life in sarcoidosis. AB - PURPOSE OF REVIEW: The review presents an overview of the scientific publications in the field of health-related quality of life (HRQL) in sarcoidosis. RECENT FINDINGS: Literature on HRQL in sarcoidosis is limited. HRQL was mainly used as a primary or secondary endpoint in intervention studies. Moreover, most studies have measured HRQL in sarcoidosis by means of the generic questionnaire 36-Item Short-Form Health Survey. Sarcoidosis-specific questionnaires and computer adapted testing are innovative approaches to the field. SUMMARY: HRQL as a primary or secondary outcome in sarcoidosis studies is still scarce. In addition to the proper definition of the concept, the mode of measurement of HRQL remains a matter of debate. Because health-economical evaluations require data on gained quality of life, future studies on sarcoidosis should include HRQL as the study endpoint. PMID- 25013951 TI - Systemic treatment with erythropoietin protects the neurovascular unit in a rat model of retinal neurodegeneration. AB - Rats expressing a transgenic polycystic kidney disease (PKD) gene develop photoreceptor degeneration and subsequent vasoregression, as well as activation of retinal microglia and macroglia. To target the whole neuroglialvascular unit, neuro- and vasoprotective Erythropoietin (EPO) was intraperitoneally injected into four-week old male heterozygous PKD rats three times a week at a dose of 256 IU/kg body weight. For comparison EPO-like peptide, lacking unwanted side effects of EPO treatment, was given five times a week at a dose of 10 ug/kg body weight. Matched EPO treated Sprague Dawley and water-injected PKD rats were held as controls. After four weeks of treatment the animals were sacrificed and analysis of the neurovascular morphology, glial cell activity and pAkt localization was performed. The number of endothelial cells and pericytes did not change after treatment with EPO or EPO-like peptide. There was a nonsignificant reduction of migrating pericytes by 23% and 49%, respectively. Formation of acellular capillaries was significantly reduced by 49% (p<0.001) or 40% (p<0.05). EPO treatment protected against thinning of the central retina by 10% (p<0.05), a composite of an increase of the outer nuclear layer by 12% (p<0.01) and in the outer segments of photoreceptors by 26% (p<0.001). Quantification of cell nuclei revealed no difference. Microglial activity, shown by gene expression of CD74, decreased by 67% (p<0.01) after EPO and 36% (n.s.) after EPO-like peptide treatment. In conclusion, EPO safeguards the neuroglialvascular unit in a model of retinal neurodegeneration and secondary vasoregression. This finding strengthens EPO in its protective capability for the whole neuroglialvascular unit. PMID- 25013953 TI - The melatonin agonist ramelteon induces duration-dependent clock gene expression through cAMP signaling in pancreatic INS-1 beta-cells. AB - Prolonged exposure to melatonin improves glycemic control in animals. Although glucose metabolism is controlled by circadian clock genes, little is known about the role of melatonin signaling and its duration in the regulation of clock gene expression in pancreatic beta-cells. Activation of MT1 and MT2 melatonin receptors inhibits cAMP signaling, which mediates clock gene expression. Therefore, this study investigated exposure duration-dependent alterations in cAMP element-binding protein (CREB) phosphorylation and clock gene expression that occur during and after exposure to ramelteon, a selective melatonin agonist used to treat insomnia. In rat INS-1 cells, a pancreatic beta-cell line endogenously expressing melatonin receptors, ramelteon persistently decreased CREB phosphorylation during the treatment period (2-14 h), whereas the subsequent washout induced an enhancement of forskolin-stimulated CREB phosphorylation in a duration- and concentration-dependent manner. This augmentation was blocked by forskolin or the melatonin receptor antagonist luzindole. Similarly, gene expression analyses of 7 clock genes revealed the duration dependency of the effects of ramelteon on Rev-erbalpha and Bmal1 expression through melatonin receptor-mediated cAMP signaling; longer exposure times (14 h) resulted in greater increases in the expression and signaling of Rev-erbalpha, which is related to beta-cell functions. Interestingly, this led to amplified oscillatory Rev-erbalpha and Bmal1 expression after agonist washout and forskolin stimulation. These results provide new insights into the duration-dependent effects of ramelteon on clock gene expression in INS-1 cells and may improve the understanding of its effect in vivo. The applicability of these results to pancreatic islets awaits further investigation. PMID- 25013954 TI - Child mortality estimation 2013: an overview of updates in estimation methods by the United Nations Inter-agency Group for Child Mortality Estimation. AB - BACKGROUND: In September 2013, the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) published an update of the estimates of the under five mortality rate (U5MR) and under-five deaths for all countries. Compared to the UN IGME estimates published in 2012, updated data inputs and a new method for estimating the U5MR were used. METHODS: We summarize the new U5MR estimation method, which is a Bayesian B-spline Bias-reduction model, and highlight differences with the previously used method. Differences in UN IGME U5MR estimates as published in 2012 and those published in 2013 are presented and decomposed into differences due to the updated database and differences due to the new estimation method to explain and motivate changes in estimates. FINDINGS: Compared to the previously used method, the new UN IGME estimation method is based on a different trend fitting method that can track (recent) changes in U5MR more closely. The new method provides U5MR estimates that account for data quality issues. Resulting differences in U5MR point estimates between the UN IGME 2012 and 2013 publications are small for the majority of countries but greater than 10 deaths per 1,000 live births for 33 countries in 2011 and 19 countries in 1990. These differences can be explained by the updated database used, the curve fitting method as well as accounting for data quality issues. Changes in the number of deaths were less than 10% on the global level and for the majority of MDG regions. CONCLUSIONS: The 2013 UN IGME estimates provide the most recent assessment of levels and trends in U5MR based on all available data and an improved estimation method that allows for closer-to-real-time monitoring of changes in the U5MR and takes account of data quality issues. PMID- 25013955 TI - Improved identification of rapidly growing mycobacteria by a 16S-23S internal transcribed spacer region PCR and capillary gel electrophoresis. AB - The identification of rapidly growing mycobacteria (RGM) remains problematic because of evolving taxonomy, limitations of current phenotypic methods and absence of a universal gene target for reliable speciation. This study evaluated a novel method of identification of RGM by amplification of the mycobacterial 16S 23S rRNA internal transcribed spacer (ITS) followed by resolution of amplified fragments by capillary gel electrophoresis (CGE). Nineteen American Type Culture Collection (ATCC) Mycobacterium strains and 178 clinical isolates of RGM (12 species) were studied. All RGM ATCC strains generated unique electropherograms with no overlap with slowly growing mycobacteria species, including M. tuberculosis. A total of 47 electropherograms for the 178 clinical isolates were observed allowing the speciation of 175/178 (98.3%) isolates, including the differentiation of the closely related species, M. massiliense (M. abscessus subspecies bolletii) and M. abscessus (M. abscessus sensu stricto). ITS fragment size ranged from 332 to 534 bp and 33.7% of clinical isolates generated electropherograms with two distinct peaks, while the remainder where characterized with a single peak. Unique peaks (fragment lengths) were identified for 11/12 (92%) RGM species with only M. moriokaense having an indistinguishable electropherogram from a rarely encountered CGE subtype of M. fortuitum. We conclude that amplification of the 16S-23S ITS gene region followed by resolution of fragments by CGE is a simple, rapid, accurate and reproducible method for species identification and characterization of the RGM. PMID- 25013956 TI - Disruption of ion-trafficking system in the cochlear spiral ligament prior to permanent hearing loss induced by exposure to intense noise: possible involvement of 4-hydroxy-2-nonenal as a mediator of oxidative stress. AB - Noise-induced hearing loss is at least in part due to disruption of endocochlear potential, which is maintained by various K(+) transport apparatuses including Na(+), K(+)-ATPase and gap junction-mediated intercellular communication in the lateral wall structures. In this study, we examined the changes in the ion trafficking-related proteins in the spiral ligament fibrocytes (SLFs) following in vivo acoustic overstimulation or in vitro exposure of cultured SLFs to 4 hydroxy-2-nonenal, which is a mediator of oxidative stress. Connexin (Cx)26 and Cx30 were ubiquitously expressed throughout the spiral ligament, whereas Na(+), K(+)-ATPase alpha1 was predominantly detected in the stria vascularis and spiral prominence (type 2 SLFs). One-hour exposure of mice to 8 kHz octave band noise at a 110 dB sound pressure level produced an immediate and prolonged decrease in the Cx26 expression level and in Na+, K(+)-ATPase activity, as well as a delayed decrease in Cx30 expression in the SLFs. The noise-induced hearing loss and decrease in the Cx26 protein level and Na(+), K(+)-ATPase activity were abolished by a systemic treatment with a free radical-scavenging agent, 4-hydroxy-2,2,6,6 tetramethylpiperidine 1-oxyl, or with a nitric oxide synthase inhibitor, N(omega) nitro-L-arginine methyl ester hydrochloride. In vitro exposure of SLFs in primary culture to 4-hydroxy-2-nonenal produced a decrease in the protein levels of Cx26 and Na(+), K(+)-ATPase alpha1, as well as Na(+), K(+)-ATPase activity, and also resulted in dysfunction of the intercellular communication between the SLFs. Taken together, our data suggest that disruption of the ion-trafficking system in the cochlear SLFs is caused by the decrease in Cxs level and Na(+), K(+)-ATPase activity, and at least in part involved in permanent hearing loss induced by intense noise. Oxidative stress-mediated products might contribute to the decrease in Cxs content and Na(+), K(+)-ATPase activity in the cochlear lateral wall structures. PMID- 25013957 TI - Nanoemulsion gel-based topical delivery of an antifungal drug: in vitro activity and in vivo evaluation. AB - OBJECTIVE: In this study, attempt has been focused to prepare a nanoemulsion (NE) gel for topical delivery of amphotericin B (AmB) for enhanced as well as sustained skin permeation, in vitro antifungal activity and in vivo toxicity assessment. MATERIALS AND METHODS: A series of NE were prepared using sefsol-218 oil, Tween 80 and Transcutol-P by slow spontaneous titration method. Carbopol gel (0.5% w/w) was prepared containing 0.1% w/w AmB. Furthermore, NE gel (AmB-NE gel) was characterized for size, charge, pH, rheological behavior, drug release profile, skin permeability, hemolytic studies and ex vivo rat skin interaction with rat skin using differential scanning calorimeter. The drug permeability and skin irritation ability were examined with confocal laser scanning microscopy and Draize test, respectively. The in vitro antifungal activity was investigated against three fungal strains using the well agar diffusion method. Histopathological assessment was performed in rats to investigate their toxicological potential. RESULTS AND DISCUSSION: The AmB-NE gel (18.09 +/- 0.6 ug/cm(2)/h) and NE (15.74 +/- 0.4 ug/cm(2)/h) demonstrated the highest skin percutaneous permeation flux rate as compared to drug solution (4.59 +/- 0.01 ug/cm(2)/h) suggesting better alternative to painful and nephrotoxic intravenous administration. Hemolytic and histopathological results revealed safe delivery of the drug. Based on combined results, NE and AmB-NE gel could be considered as an efficient, stable and safe carrier for enhanced and sustained topical delivery for AmB in local skin fungal infection. CONCLUSION: Topical delivery of AmB is suitable delivery system in NE gel carrier for skin fungal infection. PMID- 25013959 TI - Surfactant-based drug delivery systems for treating drug-resistant lung cancer. AB - Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure-performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer-drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery. PMID- 25013958 TI - Formulation and characterization of acetaminophen nanoparticles in orally disintegrating films. AB - The purpose of this study was to prepare orally disintegrating films containing nanoparticles loaded with acetaminophen. Nanoparticles were prepared by the emulsion-solvent evaporation method where acetone phase containing acetaminophen and poly(lactide-co-glycolide acid) (PLGA) was added to water phase containing hydroxypropyl methyl cellulose, poly ethylene glycol, polyvinyl alcohol (PVA) and aspartame in a rate of 1.5 drop s(-1) and agitated at 1200 rpm. The size, polydispersity index (PI) and drug entrapment (DE) were measured. The emulsions were cast to form films, which were evaluated physico-mechanically. The effect of different degrees of hydrolization of PVA and polymerization of PLGA and the effect of different ratios of PVA to PLGA was studied. Films with acceptable physico-mechanical properties were further studied. The size and PI of the nanoparticles was dependent on PVA hydrolization, PLGA polymerization and the ratio of PVA to PLGA. All films disintegrated in less than one minute, but acetaminophen was not free in the dissolution media even after six days. These results may indicate that although the nanoparticles released from the films immediately when impressed in solution the drug is sustained in the nanoparticles for longer time, which is to be clarified in future work. PMID- 25013960 TI - Effects of hydration level and heat stress on thermoregulatory responses, hematological and blood rheological properties in growing pigs. AB - Heat stress is one of the major limiting factors of production efficiency in the swine industry. The aims of the present study were 1) to observe if hemorheological and hematological parameters could be associated to physiological acclimation during the first days of heat stress exposure and 2) to determine if water restriction could modulate the effect of thermal heat stress on physiological, hematological and hemorheological parameters. Twelve Large White male pigs were divided into an ad libitum and a water restricted group. All pigs were submitted to one week at 24 degrees C (D-7 to D-1). Then, at D0, temperature was progressively increased until 32 degrees C and maintained during one week (D1 to D7). We performed daily measurements of water and feed intake. Physiological (i.e., skin temperature, rectal temperature, respiratory rate), hematological and hemorheological parameters were measured on D-6, D-5, D0, D1, D2 and D7. Water restriction had no effect on physiological, hematological and hemorheological parameters. The first days of heat stress caused an increase in the three physiological parameters followed by a reduction of these parameters suggesting a successful acclimation of pigs to heat stress. We showed an increase in hematocrit, red blood cell aggregation and red blood cell aggregation strength during heat stress. Further, we observed an important release of reticulocytes, an increase of red blood cell deformability and a reduction of feed intake and blood viscosity under heat stress. This study suggests that physiological acute adaptation to heat stress is accompanied by large hematological and hemorheological changes. PMID- 25013961 TI - Vaccination with recombinant adenoviruses expressing the peste des petits ruminants virus F or H proteins overcomes viral immunosuppression and induces protective immunity against PPRV challenge in sheep. AB - Peste des petits ruminants (PPR) is a highly contagious disease of small ruminants caused by the Morbillivirus peste des petits ruminants virus (PPRV). Two recombinant replication-defective human adenoviruses serotype 5 (Ad5) expressing either the highly immunogenic fusion protein (F) or hemagglutinin protein (H) from PPRV were used to vaccinate sheep by intramuscular inoculation. Both recombinant adenovirus vaccines elicited PPRV-specific B- and T-cell responses. Thus, neutralizing antibodies were detected in sera from immunized sheep. In addition, we detected a significant antigen specific T-cell response in vaccinated sheep against two different PPRV strains, indicating that the vaccine induced heterologous T cell responses. Importantly, no clinical signs and undetectable virus shedding were observed after virulent PPRV challenge in vaccinated sheep. These vaccines also overcame the T cell immunosuppression induced by PPRV in control animals. The results indicate that these adenovirus constructs could be a promising alternative to current vaccine strategies for the development of PPRV DIVA vaccines. PMID- 25013963 TI - Value of perfusion-weighted MR imaging in the assessment of early cerebral alterations in neurologically asymptomatic HIV-1-positive and HCV-positive patients. AB - BACKGROUND AND PURPOSE: Asymptomatic central nervous system (CNS) involvement occurs in the early stage of the human immunodeficiency virus (HIV) infection. It has been documented that the hepatitis C virus (HCV) can replicate in the CNS. The aim of the study was to evaluate early disturbances in cerebral microcirculation using magnetic resonance (MR) perfusion-weighted imaging (PWI) in asymptomatic HIV-1-positive and HCV-positive patients, as well as to assess the correlation between PWI measurements and the clinical data. MATERIALS AND METHODS: Fifty-six patients: 17 HIV-1-positive non-treated, 18 HIV-1-positive treated with combination antiretroviral therapy (cART), 7 HIV-1/HCV-positive non treated, 14 HCV-positive before antiviral therapy and 18 control subjects were enrolled in the study. PWI was performed with a 1.5T MR unit using dynamic susceptibility contrast (DSC) method. Cerebral blood volume (CBV) measurements relative to cerebellum (rCBV) were evaluated in the posterior cingulated region (PCG), basal ganglia (BG), temporoparietal (TPC) and frontal cortices (FC), as well as in white matter of frontoparietal areas. Correlations of rCBV values with immunologic data and liver histology activity index (HAI) were analyzed. RESULTS: Significantly lower rCBV values were found in the right TPC and left FC as well as in PCG in HIV-1-positive naive (p = 0.009; p = 0.020; p = 0.012), HIV-1 cART treated (p = 0.007; p = 0.009; p = 0.033), HIV-1/HCV-positive (p = 0.007; p = 0.027; p = 0.045) and HCV-positive patients (p = 0.010; p = 0.005; p = 0.045) compared to controls. HIV-1-positive cART treated and HIV-1/HCV-positive patients demonstrated lower rCBV values in the right FC (p = 0.009; p = 0.032, respectively) and the left TPC (p = 0.036; p = 0.005, respectively), while HCV positive subjects revealed lower rCBV values in the left TPC region (p = 0.003). We found significantly elevated rCBV values in BG in HCV-positive patients (p = 0.0002; p<0.0001) compared to controls as well as to all HIV-1-positive subjects. There were no significant correlations of rCBV values and CD4 T cell count or HAI score. CONCLUSIONS: PWI examination enables the assessment of HIV-related as well as HCV-related early cerebral dysfunction in asymptomatic subjects. HCV-infected patients seem to reveal the most pronounced perfusion changes. PMID- 25013965 TI - Inflammasomes: Acting out. PMID- 25013964 TI - Validation of a LC-MS/MS method for quantifying urinary nicotine, six nicotine metabolites and the minor tobacco alkaloids--anatabine and anabasine--in smokers' urine. AB - Tobacco use is a major contributor to premature morbidity and mortality. The measurement of nicotine and its metabolites in urine is a valuable tool for evaluating nicotine exposure and for nicotine metabolic profiling--i.e., metabolite ratios. In addition, the minor tobacco alkaloids--anabasine and anatabine--can be useful for monitoring compliance in smoking cessation programs that use nicotine replacement therapy. Because of an increasing demand for the measurement of urinary nicotine metabolites, we developed a rapid, low-cost method that uses isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously quantifying nicotine, six nicotine metabolites, and two minor tobacco alkaloids in smokers' urine. This method enzymatically hydrolyzes conjugated nicotine (primarily glucuronides) and its metabolites. We then use acetone pretreatment to precipitate matrix components (endogenous proteins, salts, phospholipids, and exogenous enzyme) that may interfere with LC MS/MS analysis. Subsequently, analytes (nicotine, cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine N-oxide, nicotine 1'-N-oxide, anatabine, and anabasine) are chromatographically resolved within a cycle time of 13.5 minutes. The optimized assay produces linear responses across the analyte concentrations typically found in urine collected from daily smokers. Because matrix ion suppression may influence accuracy, we include a discussion of conventions employed in this procedure to minimize matrix interferences. Simplicity, low cost, low maintenance combined with high mean metabolite recovery (76-99%), specificity, accuracy (0-10% bias) and reproducibility (2-9% C.V.) make this method ideal for large high through-put studies. PMID- 25013966 TI - Innate immunity: Peroxisomes pack a distinct punch. PMID- 25013967 TI - Germination season and watering regime, but not seed morph, affect life history traits in a cold desert diaspore-heteromorphic annual. AB - Seed morph, abiotic conditions and time of germination can affect plant fitness, but few studies have tested their combined effects on plasticity of plant life history traits. Thus, we tested the hypothesis that seed morph, germination season and watering regime influence phenotypic expression of post-germination life history traits in the diaspore-heteromorphic cold desert winter annual/spring ephemeral Diptychocarpus strictus. The two seed morphs were sown in watered and non-watered plots in late summer, and plants derived from them were watered or not-watered throughout the study. Seed morph did not affect phenology, growth and morphology, survival, dry mass accumulation and allocation or silique and seed production. Seeds in watered plots germinated in autumn (AW) and spring (SW) but only in spring for non-watered plots (SNW). A high percentage of AW, SW and SNW plants survived and reproduced, but flowering date and flowering period of autumn- vs. spring-germinated plants differed. Dry mass also differed with germination season/watering regime (AW > SW > SNW). Number of siliques and seeds increased with plant size (AW > SW > SNW), whereas percent dry mass allocated to reproduction was higher in small plants: SNW > SW > AW. Thus, although seed morph did not affect the expression of life history traits, germination season and watering regime significantly affected phenology, plant size and accumulation and allocation of biomass to reproduction. Flexibility throughout the life cycle of D. strictus is an adaptation to the variation in timing and amount of rainfall in its cold desert habitat. PMID- 25013969 TI - Spatial relationships between gay stigma, poverty, and HIV infection among black and white men who have sex with men in Atlanta. PMID- 25013968 TI - Regulation of extracellular matrix organization by BMP signaling in Caenorhabditis elegans. AB - In mammals, Bone Morphogenetic Protein (BMP) pathway signaling is important for the growth and homeostasis of extracellular matrix, including basement membrane remodeling, scarring, and bone growth. A conserved BMP member in Caenorhabditis elegans, DBL-1, regulates body length in a dose-sensitive manner. Loss of DBL-1 pathway signaling also results in increased anesthetic sensitivity. However, the physiological basis of these pleiotropic phenotypes is largely unknown. We created a DBL-1 over-expressing strain and show that sensitivity to anesthetics is inversely related to the dose of DBL-1. Using pharmacological, genetic analyses, and a novel dye permeability assay for live, microwave-treated animals, we confirm that DBL-1 is required for the barrier function of the cuticle, a specialized extracellular matrix. We show that DBL-1 signaling is required to prevent animals from forming tail-entangled aggregates in liquid. Stripping lipids off the surface of wild-type animals recapitulates this phenotype. Finally, we find that DBL-1 signaling affects ultrastructure of the nematode cuticle in a dose-dependent manner, as surface lipid content and cuticular organization are disrupted in animals with genetically altered DBL-1 levels. We propose that the lipid layer coating the nematode cuticle normally prevents tail entanglement, and that reduction of this layer by loss of DBL-1 signaling promotes aggregation. This work provides a physiological mechanism that unites the DBL-1 signaling pathway roles of not only body size regulation and drug responsiveness, but also the novel Hoechst 33342 staining and aggregation phenotypes, through barrier function, content, and organization of the cuticle. PMID- 25013971 TI - Designing premarket observational comparative studies using existing data as controls: challenges and opportunities. AB - Due to the special nature of medical device clinical studies, observational (nonrandomized) comparative studies play important roles in the premarket safety/effectiveness evaluation of medical devices. While historical data collected in earlier investigational device exemption studies of a previously approved medical device have been used to form control groups in comparative studies, high-quality registry data are emerging to provide opportunities for the premarket evaluation of new devices. However, in such studies, various biases could be introduced in every stage and aspect of study and may compromise the objectivity of study design and validity of study results. In this article, challenges and opportunities in the design of such studies using propensity score methodology are discussed from regulatory perspectives. PMID- 25013970 TI - Phenotypic variation in infants, not adults, reflects genotypic variation among chimpanzees and bonobos. AB - Studies comparing phenotypic variation with neutral genetic variation in modern humans have shown that genetic drift is a main factor of evolutionary diversification among populations. The genetic population history of our closest living relatives, the chimpanzees and bonobos, is now equally well documented, but phenotypic variation among these taxa remains relatively unexplored, and phenotype-genotype correlations are not yet documented. Also, while the adult phenotype is typically used as a reference, it remains to be investigated how phenotype-genotye correlations change during development. Here we address these questions by analyzing phenotypic evolutionary and developmental diversification in the species and subspecies of the genus Pan. Our analyses focus on the morphology of the femoral diaphysis, which represents a functionally constrained element of the locomotor system. Results show that during infancy phenotypic distances between taxa are largely congruent with non-coding (neutral) genotypic distances. Later during ontogeny, however, phenotypic distances deviate from genotypic distances, mainly as an effect of heterochronic shifts between taxon specific developmental programs. Early phenotypic differences between Pan taxa are thus likely brought about by genetic drift while late differences reflect taxon-specific adaptations. PMID- 25013972 TI - Evaluation of an immunochromatographic point-of-care test for the simultaneous detection of nontreponemal and treponemal antibodies in patients with syphilis. AB - We described the evaluation of the Syphilis Screening & Confirm Assay for the simultaneous detection of nontreponemal and treponemal antibodies. A total of 248 samples were evaluated. The sensitivity of the tests was 98.8%, 99.5% and 98.9%, while specificity was 94.7%, 88.9% and 93.2%, respectively, as compared with the rapid plasma reagin, Treponema pallidum hemagglutination assay, and fluorescent treponemal antibody absorption tests. PMID- 25013973 TI - Scoring system avoids Chlamydia trachomatis overscreening in women seeking surgical abortions. AB - OBJECTIVE: To develop and validate a predictive score to avoid unnecessary screening and prophylactic antibiotic use in abortion clinics by identifying a group of women who are at very low risk for Chlamydia trachomatis (CT) infection. METHODS: This population-based retrospective study includes 1000 women who underwent surgical abortion between January and September 2010. The main outcome measure was the rate of CT infection among women seeking an induced abortion according to sociodemographic and clinical data. The score was developed by using two-thirds of the data set as the derivation sample to identify the strongest predictors of CT. A receiver operating characteristic curve established cutoffs and applied the score to the remaining one-third (validation sample). RESULTS: The rate of CT infection was 6.7%. Three criteria were independently associated with CT: gestation more than 10 weeks (adjusted odds ratio [aOR], 1.96; 95% confidence interval [95% CI], 1.06-3.64), not using contraception (aOR, 2.70; 95% CI, 1.41-5.16), and having 0 or 1 child (aOR, 3.46; 95% CI, 1.34-8.93). The CT score was based on these 3 criteria. The low-risk group was derived from values of the score (probability of CT, 1.3% [95% CI, 0-3.0]). Application of these criteria to the validation data set confirmed the diagnostic accuracy of the score (probability of CT, 0%). Sensitivity was 100% and specificity was 26.9% for the score in the validation data set. When applied to the validation data set, the score avoided 25.4% of CT tests and screened 100% of CT-infected women before surgical abortion. CONCLUSIONS: This easy-to-calculate score may prove useful for avoiding CT test in 25% of patients seeking surgical abortion. PMID- 25013974 TI - Understanding variability in adolescent women's sexually transmitted infection related perceptions and behaviors associated with main sex partners. AB - BACKGROUND: It is not well understood whether characteristics of adolescent main partnerships differ categorically from one relationship to the next or whether observed differences in sexually transmitted infection (STI)-related perceptions and sexual behaviors between main partnerships results from a failure to capture variability within adolescent main partnerships. The objective of this study was to examine the extent to which female adolescents' STI-related feelings, perceptions, and sexual behavior associated with main sex partners varied over the course of their relationship. METHODS: A cohort of adolescent women aged 16 to 19 years at baseline, recruited from health clinics or community venues, completed daily diaries on a Smartphone continuously for 18 months. Participants reported daily on their partner-specific feelings of closeness, trust, commitment, perceived risk for acquiring a sexually transmitted disease (PRSTD), perception of partner concurrency (PPC), and condom use for their main sexual partners. RESULTS: Relationships from 49 participants were used to examine variability over time in STI-related feelings, perceptions, and behavior. Overall, relationships were characterized by high levels of trust, closeness, and commitment and low levels of PPC, PRSTD, and condom use. However, for all but PRSTD, there was more variation (>50%) within than between relationships for each of these measures, although variability of PRSTD was high (47.1%). Residual variability for all perceptions and behaviors remained significant after controlling for trends over time. CONCLUSIONS: Diary data illustrate wide day-to day fluctuations in feelings of intimacy, PPCs, PRSTDs, and condom use indicating that these are dynamic attributes of adolescent romantic relationships. PMID- 25013975 TI - HIV/sexually transmitted infection prevalence and sexual behavior of men who have sex with men in 3 districts of Botswana: results from the 2012 biobehavioral survey. AB - BACKGROUND: Men who have sex with men (MSM) suffer significant stigma and discrimination; hence, they are reluctant to access health services. The Botswana Second National Strategic Framework for 2010-2016 stipulates the need to increase HIV prevention services for key populations as one of its prevention implementation strategies. We report here the prevalence of HIV and other sexually transmitted infections and risk factors for HIV infection among MSM in Botswana. METHODS: We conducted a cross-sectional survey using respondent driven sampling in 3 districts of Botswana: Gaborone, Francistown, and Kasane. RESULTS: Of the 454 participants recruited, most were Batswana (97.6%) with a mean age of 23.2 years (range, 18-53 years), with 74.9% aged between 20 and 29 years. The overall unadjusted HIV prevalence was 13.1% (95% confidence interval, 10.0-16.3), with 12.3%, 11.7%, and 25.9% in Gaborone, Francistown, and Kasane, respectively. Chlamydia trachomatis prevalence was higher than Neisseria gonorrhoeae in both urine and anal swabs, at 7.1% and 5.9%, respectively, versus 1.4% and 1.7%. Overall, 46.7% of respondents reported having sex with female partners. Men who have sex with men who thought they had a high chance of acquiring HIV had a significantly lower likelihood of using condom consistently than those who reported they had a lower chance of acquiring HIV (odds ratio = 0.4; 95% confidence interval, 0.2-0.7; P = 0.003). CONCLUSION: HIV prevalence of MSM was lower than what has been reported in other sub-Saharan African countries with generalized epidemics; however, their degree of participation in heterosexual sex signifies sexual networks beyond the MSM subpopulation. PMID- 25013976 TI - Sexual behaviors and other risk factors for oral human papillomavirus infections in young women. AB - BACKGROUND: Oral human papillomavirus (HPV) is associated with a rising incidence of certain head and neck cancers, and oral sex has been associated with oral HPV. This study sought to identify more specific patterns of oral sexual activity, including self-inoculation, that are associated with oral HPV infections in young women. METHODS: A total of 1010 women attending a large university completed a computer-based questionnaire and provided oral specimens that were tested for any oral HPV using a Linear Array assay that detects any HPV as well as 37 HPV genotypes. Twenty-seven women provided additional samples up to 12 months after enrollment. Bivariable and multivariable analyses were conducted to identify oral sexual patterns and other risk factors associated with prevalent oral HPV. RESULTS: Nineteen women had prevalent oral HPV (1.9%), with 10 women (1%) having a type-specific infection. Oral HPV was significantly associated with lifetime coital sex partnership numbers (P = 0.03), lifetime and yearly oral sex partnership numbers (P < 0.01), and hand and/or sex toy transfer from genitals to mouth (P < 0.001). Oral HPV was also associated with greater use of alcohol, cigarettes, marijuana, and sharing of smoking devices, lipstick, or toothbrushes (P < 0.05 for each), with an apparent dose-response for alcohol use and smoking behavior, stratified by number of sexual partners. Of 7 women with prevalent HPV who provided follow-up samples, none had evidence of a persistent type-specific infection. CONCLUSIONS: These data provide additional evidence of transmission of oral HPV from oral sexual activity and also suggest possible transmission from self-inoculation or sharing of oral products. PMID- 25013977 TI - Acquired macrolide-resistant Treponema pallidum after a human bite. AB - Syphilis is a systemic disease caused by the spirochete Treponema pallidum that is usually acquired through sexual exposure. PMID- 25013978 TI - Evaluation of a surveillance case definition for anogenital warts, Kaiser Permanente northwest. AB - BACKGROUND: Most studies of anogenital wart (AGW) epidemiology have used large clinical or administrative databases and unconfirmed case definitions based on combinations of diagnosis and procedure codes. METHODS: We developed and validated an AGW case definition using a combination of diagnosis codes and other information available in the electronic medical record (provider type, laboratory testing). We calculated the positive predictive value (PPV) of this case definition compared with manual medical record review in a random sample of 250 cases. Using this case definition, we calculated the annual age- and sex stratified prevalence of AGW among individuals 11 through 30 years of age from 2000 through 2005. RESULTS: We identified 2730 individuals who met the case definition. The PPV of the case definition was 82%, and the average annual prevalence was 4.16 per 1000. Prevalence of AGW was higher in females compared with males in every age group, with the exception of the 27- to 30-year-olds. Among females, prevalence peaked in the 19- to 22-year-olds, and among males, the peak was observed in 23- to 26-year-olds. CONCLUSIONS: The case definition developed in this study is the first to be validated with medical record review and has a good PPV for the detection of AGW. The prevalence rates observed in this study were higher than other published rates, but the age- and sex-specific patterns observed were consistent with previous reports. PMID- 25013979 TI - Surveillance of antimicrobial susceptibilities of Neisseria gonorrhoeae in Nanning, China, 2000 to 2012. AB - OBJECTIVES: To monitor the frequency of antibiotic resistance of Neisseria gonorrhoeae (NG) in Nanning, China, between 2000 and 2012. METHODS: The production of beta-lactamase by NG isolates was determined using the paper acidometric testing method. Antimicrobial susceptibility testing was performed for tetracycline, ciprofloxacin, spectinomycin, and ceftriaxone using the agar dilution method. The chi(2) test, t test, and univariate and multivariate analyses were used to analyze the statistical difference of the results. RESULTS: A total of 923 NG isolates were collected in Nanning between 2000 and 2012. Among these, 131 (14.2%) were penicillinase-producing NG, 520 (56.3%) isolates were tetracycline-resistant NG, and 857 (92.9%) isolates were ciprofloxacin-resistant strains. One spectinomycin-resistant strain was identified in 2000. There were 304 (32.9%) isolates with decreased susceptibility to ceftriaxone; the proportion of such isolates increased from 22.8% in 2000 to 2002 to 48.9% in 2006 to 2008 (P < 0.001), followed by a fall to 32.2% in 2009 to 2012 (P = 0.001). Patients' age of 16 to 25 years and isolate collection period of 2008 to 2012 (except 2011) were demonstrated to be risk factors for infection with isolates with decreased susceptibility to ceftriaxone. CONCLUSIONS: Antimicrobial susceptibility of NG isolates obtained from patients in Nanning from 2000 to 2012 was characterized by high occurrence of penicillinase-producing NG, tetracycline-resistant NG, and ciprofloxacin-resistant strains. Spectinomycin and ceftriaxone can be considered drugs of choice for empirical treatment of NG infection in Nanning. Moreover, we recommend a combination of 500 mg or higher dose of intramuscular ceftriaxone and 1 g oral azithromycin be used for the treatment of NG infection in Nanning and possibly in China. PMID- 25013980 TI - Syphilitic hepatitis treated with doxycycline in an HIV-infected patient and review of the literature. AB - An HIV-infected male patient who had sex with men and with a penicillin allergy presented with liver dysfunction due to secondary syphilis and was successfully treated with doxycycline. This case highlights that syphilitic hepatitis may be overlooked in this particular population, and health care providers should be attuned to this diagnosis. Doxycycline may be an acceptable alternative to penicillin for treatment of this clinical syndrome. PMID- 25013981 TI - Human papillomavirus vaccination and cervical cytology in young minority women. AB - BACKGROUND: Continued surveillance of human papillomavirus (HPV) vaccination is necessary to identify clinical benefits, particularly given the low rate of vaccine uptake and completion and vaccination of many young women after sexual debut. We studied the effect of catch-up HPV vaccination on cervical cytology and HPV infection in sexually active, low-income and minority young women. METHODS: We conducted a cross-sectional study of 235 women aged 21 to 30 years undergoing routine cervical cytology testing. Demographic and behavioral characteristics were self-reported. HPV vaccination status was determined by self-report and verified with electronic medical records. Liquid-based cytology samples were tested for HPV genotypes. Adjusted prevalence ratios between HPV vaccination and (1) abnormal cervical cytology result and (2) HPV genotype were estimated. FINDINGS: At the time of the study, 96 women (41%) had received at least 1 HPV vaccination, 54 of whom had completed the series; 97% of women were vaccinated after sexual debut. Twenty-four (10%) women had an abnormal cervical cytology result. The prevalence of abnormal cytology was 65% lower in women who received at least 1 HPV vaccination versus unvaccinated women (adjusted prevalence ratio, 0.35; 95% confidence interval, 0.14-0.89). Among 232 women with genotype results, 46 (20%; 95% confidence interval, 15%-26%) had HPV infection detected. HPV types 16, 18, 45, 53, and 66 were most prevalent. CONCLUSIONS: The prevalence of abnormal cytology was lower in vaccinated versus unvaccinated women, despite receipt of vaccination after sexual debut. Continued assessment of HPV vaccine effectiveness before and after sexual debut on HPV infection and cervical dysplasia is needed. PMID- 25013982 TI - Additional gonorrhea and Chlamydia infections found with rapid follow-up screening in men who have sex with men with an indication for HIV postexposure prophylaxis. AB - Sexually transmitted infection was found in 16.5% of the men who have sex with men with a postexposure prophylaxis indication. Chlamydia and gonorrhea screening was repeated after 14 days. Among those who were initially sexually transmitted infection negative, 4.1% had chlamydia or gonorrhea. In postexposure prophylaxis indicated men who have sex with men, repeat chlamydia and gonorrhea screening is advised to diagnose infections not apparent at baseline screening. PMID- 25013983 TI - In response to surveillance of HIV in the United States and England, Wales, and Northern Ireland: what have we learned and what do we do about it? PMID- 25013984 TI - Do epigenetic events take place in the vastus lateralis of patients with mild chronic obstructive pulmonary disease? AB - Muscle dysfunction is a major comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Several biological mechanisms including epigenetic events regulate muscle mass and function in models of muscle atrophy. Investigations conducted so far have focused on the elucidation of biological mechanisms involved in muscle dysfunction in advanced COPD. We assessed whether the epigenetic profile may be altered in the vastus lateralis of patients with mild COPD, normal body composition, and mildly impaired muscle function and exercise capacity. In vastus lateralis (VL) of mild COPD patients with well-preserved body composition and in healthy age-matched controls, expression of DNA methylation, muscle-enriched microRNAs, histone acetyltransferases (HTAs) and deacetylases (HDACs), protein acetylation, small ubiquitin-related modifier (SUMO) ligases, and muscle structure were explored. All subjects were clinically evaluated. Compared to healthy controls, in the VL of mild COPD patients, muscle function and exercise capacity were moderately reduced, DNA methylation levels did not differ, miR-1 expression levels were increased and positively correlated with both forced expiratory volume in one second (FEV1) and quadriceps force, HDAC4 protein levels were increased, and muscle fiber types and sizes were not different. Moderate skeletal muscle dysfunction is a relevant feature in patients with mild COPD and preserved body composition. Several epigenetic events are differentially expressed in the limb muscles of these patients, probably as an attempt to counterbalance the underlying mechanisms that alter muscle function and mass. The study of patients at early stages of their disease is of interest as they are a target for timely therapeutic interventions that may slow down the course of the disease and prevent the deleterious effects of major comorbidities. PMID- 25013986 TI - Applications of stable isotope analysis in mammalian ecology. AB - In this editorial, we provide a brief introduction and summarize the 10 research articles included in this Special Issue on Applications of stable isotope analysis in mammalian ecology. The first three articles report correction and discrimination factors that can be used to more accurately estimate the diets of extinct and extant mammals using stable isotope analysis. The remaining seven applied research articles use stable isotope analysis to address a variety of wildlife conservation and management questions from the oceans to the mountains. PMID- 25013985 TI - Hypoxia and exercise increase the transpulmonary passage of 99mTc-labeled albumin particles in humans. AB - Intrapulmonary arteriovenous anastomoses (IPAVs) are large diameter connections that allow blood to bypass the lung capillaries and may provide a route for right to-left embolus transmission. These anastomoses are recruited by exercise and catecholamines and hypoxia. Yet, whether IPAVs are recruited via direct, oxygen sensitive regulatory mechanisms or indirect effects secondary to redistribution pulmonary blood flow is unknown. Here, we hypothesized that the addition of exercise to hypoxic gas breathing, which increases cardiac output, would augment IPAVs recruitment in healthy humans. To test this hypothesis, we measured the transpulmonary passage of 99mTc-macroaggregated albumin particles (99mTc-MAA) in seven healthy volunteers, at rest and with exercise at 85% of volitional max, with normoxic (FIO2 = 0.21) and hypoxic (FIO2 = 0.10) gas breathing. We found increased 99mTc-MAA passage in both exercise conditions and resting hypoxia. However, contrary to our hypothesis, we found the greatest 99mTc-MAA passage with resting hypoxia. As an additional, secondary endpoint, we also noted that the transpulmonary passage of 99mTc-MAA was well-correlated with the alveolar arterial oxygen difference (A-aDO2) during exercise. While increased cardiac output has been proposed as an important modulator of IPAVs recruitment, we provide evidence that the modulation of blood flow through these pathways is more complex and that increasing cardiac output does not necessarily increase IPAVs recruitment. As we discuss, our data suggest that the resistance downstream of IPAVs is an important determinant of their perfusion. PMID- 25013987 TI - Development of a novel controlled-release nanocomposite based on poly(lactic acid) to increase the oxidative stability of soybean oil. AB - A poly(lactic acid) (PLA)-based nanocomposite active packaging was developed for the controlled release of tert-butylhydroquinone (TBHQ) antioxidant. The PLA based active films were loaded with only TBHQ (3% wt) or a mixture of modified cellulose nanofibre (MCNF) (8% wt) and TBHQ (3% wt) to obtain active and nanocomposite active films, respectively. Release studies indicated that the release rate of TBHQ in 95% ethanol simulant was significantly decreased by the addition of MCNF. Moreover, the presence of MCNF diminished the increasing effect of temperature on the release rate as when storage temperature increased from 4 degrees C to 40 degrees C. The diffusion coefficient (D) for PLA-TBHQ and PLA MCNF-TBHQ films increased from 6.75 and 4.34 * 10(-8) cm(2) s(-1) to 19.85 and 8.49 * 10(-8) cm(2) s(-1), respectively. Diffusion of TBHQ to soybean oil was enough to delay the induction of the oxidation of soybean oil stored for 6 months in contact with PLA-based films. Antioxidative activity of PLA-based active films considerably increased with increasing storage time as indicated by the increase in 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and the oxidative stability index (p < 0.05). This study demonstrates that effective controlled release antioxidant packaging could be obtained by using MCNF nanofiller, which leads to prolonged activity and an extended shelf-life in fatty foods. PMID- 25013988 TI - Preparation, characterization, in vitro bioactivity, and cellular responses to a polyetheretherketone bioactive composite containing nanocalcium silicate for bone repair. AB - In this study, a nanocalcium silicate (n-CS)/polyetheretherketone (PEEK) bioactive composite was prepared using a process of compounding and injection molding. The mechanical properties, hydrophilicity, and in vitro bioactivity of the composite, as well as the cellular responses of MC3T3-E1 cells (attachment, proliferation, spreading, and differentiation) to the composite, were investigated. The results showed that the mechanical properties and hydrophilicity of the composites were significantly improved by the addition of n CS to PEEK. In addition, an apatite-layer formed on the composite surface after immersion in simulated body fluid (SBF) for 7 days. In cell culture tests, the results revealed that the n-CS/PEEK composite significantly promoted cell attachment, proliferation, and spreading compared with PEEK or ultrahigh molecular weight polyethylene (UHMWPE). Moreover, cells grown on the composite exhibited higher alkaline phosphatase (ALP) activity, more calcium nodule formation, and higher expression levels of osteogenic differentiation-related genes than cells grown on PEEK or UHMWPE. These results indicated that the incorporation of n-CS to PEEK could greatly improve the bioactivity and biocompatibility of the composite. Thus, the n-CS/PEEK composite may be a promising bone repair material for use in orthopedic clinics. PMID- 25013989 TI - Real-time immuno-polymerase chain reaction in a 384-well format: detection of vascular endothelial growth factor and epidermal growth factor-like domain 7. AB - Immuno-polymerase chain reaction (immuno-PCR) combines the specificity of antibodies with the amplification power of PCR to detect low levels of proteins. Here, we describe the development of a 384-well immuno-PCR method that uses streptavidin coated on a PCR plate to capture complexes of biotinylated capture antibody, antigen, and DNA-labeled detection antibody. Unbound molecules are removed by a wash step using a standard plate washer. Antibody-DNA molecules in bound complexes are then detected directly on the plate using real-time PCR. Circulating human vascular endothelial growth factor concentrations measured by this method correlated with measurements obtained from enzyme-linked immunosorbent assay (ELISA). Using this method, we developed an assay for human epidermal growth factor-like domain 7 (EGFL7), an extracellular matrix-bound angiogenic factor. EGFL7 is expressed at a higher level in certain cancers, although endogenous EGFL7 concentrations have not been reported. Our 384-well EGFL7 immuno-PCR assay can detect 0.51pM EGFL7 in plasma, approximately 16-fold more sensitive than the ELISA, utilizing the same antibodies. This assay detected EGFL7 in lysates of non-small-cell lung cancer and hepatocellular carcinoma cell lines and also hepatocellular carcinoma, breast cancer, and ovarian cancer tissues. This 384-well immuno-PCR method can be used to develop high-throughput biomarker assays. PMID- 25013990 TI - Do territorial butterflies show a macroecological fighting pattern in response to environmental stability? AB - The territorial defense of mating sites by males should be favored when female monopolization is possible. Such monopolization should occur in species in which females emerge asynchronously, since males may have time to copulate with one female before the arrival of other. However, regions with smaller reproductive windows should promote higher synchronicity of female emergence, generating a predictable macroecological pattern associated to the rewards from territorial defense. In this study we evaluated the hypothesis that territorial male butterflies should invest more in fighting in species that occur in areas with stable climatic conditions that should present longer reproductive windows. We compiled studies reporting mean butterfly fighting times, mean trait differences among winners and losers and local Koppen climatic classification (a surrogate for climatic stability). We found that males from butterfly species located in areas with stable climatic conditions fight for longer times. However, although winners were stronger than intruders only in areas with intermediate climatic conditions, there was a marked variation among winner-loser comparisons in species in areas with stable climatic conditions. We conclude that males from butterfly species that occur in areas with stable climatic regimes invest more in fighting due to the higher payoffs accrued with territorial defense, but that such investment does not change the effect of trait asymmetries in settling territorial conflicts. This article is part of a Special Issue entitled: Special Issue:Neotropical Behaviour. PMID- 25013991 TI - The sub-chronic toxicity of regular White Spirit in rats. AB - Hydrocarbon solvents are mostly complex substances (UVCB) with carbon numbers in the range of approximately C5-C20. One of the most common types is a C9-C14 aliphatic solvent containing approximately 20% aromatics and commonly known as White Spirit in Europe and mineral spirits in the US. In previous repeated inhalation toxicity studies, White Spirit was reported to cause minimal systemic effects in most animal species with few effects other than male rat-specific kidney changes at levels up to approximately 2000mg/m(3). In the present study male and female rats were exposed to White Spirit vapors, 6h/day, 5days/week for 13weeks at levels of approximately 2000, 4000, or 8000mg/m(3) to assess the potential for effects at higher exposure levels. All of the rats survived the treatment period. In life observations were largely restricted to acute central nervous system (CNS) effects in the high exposure group. Terminal body weights of high exposure groups animals were significantly below control values. Statistically significant differences in the clinical and hematological observations were small and within normal physiological limits. Weights of some organs including liver, spleen and kidneys were elevated, but microscopic examination indicated that the only pathological effects were changes in the kidneys of the male rats, consistent with an alpha2u-globulin-mediated process, which is gender and species-specific and not relevant to humans. The overall no observed adverse effect level (NOAEC) was 4000mg/m(3). PMID- 25013992 TI - Conotoxins and their regulatory considerations. AB - Venom derived peptides from marine cone snails, conotoxins, have demonstrated unique pharmacological targeting properties that have been pivotal in advancing medical research. The awareness of their true toxic origins and potent pharmacological nature is emphasized by their 'select agent' classification by the US Centers for Disease Control and Prevention. We briefly introduce the biochemical and pharmacological aspects of conotoxins, highlighting current advancements into their biological engineering, and provide details to the present regulations that govern their use in research. PMID- 25013993 TI - Below-knee arterial calcification in type 2 diabetes: association with receptor activator of nuclear factor kappaB ligand, osteoprotegerin, and neuropathy. AB - CONTEXT: Calcification of the arterial wall in diabetes contributes to the arterial occlusive process occurring below the knee. The osteoprotegerin (OPG)/receptor activator of nuclear factor kappaB ligand (RANKL) system is suspected to be involved in the calcification process. OBJECTIVE: The aim of the study was to investigate whether there is a link between arterial calcification in type 2 diabetes and 1) conventional cardiovascular risk factors, 2) serum RANKL and OPG levels, and 3) neuropathy. PATIENTS AND METHODS: We objectively scored, in a cross-sectional study, infrapopliteal vascular calcification using computed tomography scanning in 198 patients with type 2 diabetes, a high cardiovascular risk, and a glomerular filtration rate >30 mL/min. Color duplex ultrasonography was performed to assess peripheral arterial occlusive disease, and mediacalcosis. Peripheral neuropathy was defined by a neuropathy disability score >6. RANKL and OPG were measured in the serum by routine chemistry. RESULTS: Below-knee arterial calcification was associated with arterial occlusive disease. In multivariate logistic regression analysis, the variables significantly and independently associated with the calcification score were age (odds ratio [OR] = 1.08; 95% confidence interval [CI] = 1.04-1.13; P < .0001), male gender (OR = 3.53; 95% CI = 1.54-8.08; P = .003), previous cardiovascular disease (OR = 2.78; 95% CI = 1.39-5.59; P = .005), and neuropathy disability score (per 1 point, OR = 1.21; 95% CI = 1.05-1.38; P = .006). The association with ln OPG, significantly associated with calcification score in univariate analysis (OR = 3.14; 95% CI = 1.05-9.40; P = .045), was no longer significant in multivariate analysis. RANKL and OPG/RANKL were not significantly associated with the calcification score. CONCLUSIONS: Below-knee arterial calcification severity is clearly correlated with peripheral neuropathy severity and with several usual cardiovascular risk factors, but not with serum RANKL level. PMID- 25013994 TI - Prevalence of low testosterone and predisposing risk factors in men with type 1 diabetes mellitus: findings from the DCCT/EDIC. AB - CONTEXT: Previous studies have demonstrated lower testosterone concentrations in men with type 2 diabetes mellitus. Data in men with type 1 diabetes mellitus (T1DM) are limited. OBJECTIVE: Our objective was to determine the prevalence of low testosterone in men with T1DM and identify predisposing factors. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of men with T1DM participating in UroEDIC (n = 641), an ancillary study of urologic complications in the Epidemiology of Diabetes Interventions and Complications (EDIC). MAIN OUTCOME MEASURES: Total serum testosterone levels were measured using mass spectrometry, and SHBG levels were measured using sandwich immunoassay on samples from EDIC year 17/18. Calculated free testosterone was determined using an algorithm incorporating binding constants for albumin and SHBG. Low testosterone was defined as total testosterone <300 mg/dL. Multivariate regression models were used to compare age, body mass index, factors related to diabetes treatment and control, and diabetic complications with testosterone levels. RESULTS: Mean age was 51 years. Sixty-one men (9.5%) had testosterone <300 mg/dL. Decreased testosterone was significantly associated with obesity (P < .01), older age (P < .01) and decreased SHBG (P < .001). Insulin dose was inversely associated with calculated free testosterone (P = .02). Hypertension retained a significant adjusted association with lower testosterone (P = .05). There was no observed significant relationship between lower testosterone and nephropathy, peripheral neuropathy, and autonomic neuropathy measures. CONCLUSION: The men with T1DM in the EDIC cohort do not appear to have a high prevalence of androgen deficiency. Risk factors associated with low testosterone levels in this population are similar to the general population. PMID- 25013995 TI - Clinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing's syndrome. AB - CONTEXT: Distinguishing between pituitary [Cushing's disease (CD)] and ectopic causes [ectopic ACTH syndrome (EAS)] of ACTH-dependent Cushing's syndrome can be challenging. Inferior petrosal sinus sampling (IPSS) best discriminates between CD and occult EAS but is a specialized procedure that is not widely available. Identifying adjunctive diagnostic tests may prove useful. In EAS, abnormal processing of the ACTH precursor proopiomelanocortin (POMC) and the accumulation of POMC-derived peptides might be expected and abnormal levels of other neuropeptides may be detected. OBJECTIVE: The objective of the study was to evaluate the diagnostic utility of POMC measurements for distinguishing between CD and occult EAS in patients referred for IPSS. Another objective of the study was to evaluate in parallel the diagnostic utility of another neuropeptide, agouti-related protein (AgRP), because we have observed a 10-fold elevation of AgRP in plasma in a patient with EAS from small-cell lung cancer. DESIGN AND PARTICIPANTS: Plasma POMC and AgRP were measured in 38 Cushing's syndrome patients presenting for IPSS, with either no pituitary lesion or a microadenoma on magnetic resonance imaging, and in 38 healthy controls. RESULTS: Twenty-seven of 38 patients had CD; 11 of 38 had EAS. The mean POMC was higher in EAS vs CD [54.5 +/- 13.0 (SEM) vs 17.2 +/- 1.5 fmol/mL; P < .05]. Mean AgRP was higher in EAS vs CD (280 +/- 76 vs 120 +/- 16 pg/mL; P = .01). Although there was an overlap in POMC and AgRP levels between the groups, the POMC levels greater than 36 fmol/mL (n = 7) and AgRP levels greater than 280 pg/mL (n = 3) were specific for EAS. When used together, POMC greater than 36 fmol/mL and/or AgRP greater than 280 pg/mL detected 9 of 11 cases of EAS, indicating that elevations in these peptides have a high positive predictive value for occult EAS. CONCLUSIONS: Expanding upon previous observations of high POMC in EAS, this study specifically demonstrates elevated POMC levels can identify occult ectopic tumors. Elevations in AgRP also favor the diagnosis of EAS, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker. PMID- 25013996 TI - Short-term, low-dose GH therapy improves insulin sensitivity without modifying cortisol metabolism and ectopic fat accumulation in adults with GH deficiency. AB - CONTEXT: Low-dose GH (LGH) therapy has been reported to improve insulin sensitivity in GH-deficient adults; however, the mechanism is unclear. HYPOTHESIS: Effects of LGH therapy on insulin sensitivity are mediated through changes in cortisol metabolism and ectopic fat accumulation. DESIGN AND SETTING: This was a double-blind, placebo-controlled, parallel, 3-month study. PARTICIPANTS AND INTERVENTION: Seventeen GH-deficient adults were randomized to receive either daily LGH or placebo injections. Fasting blood samples were collected at baseline, and months 1 and 3, whereas hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy scans, 24-hour cortisol production rates (CPRs), and sc abdominal fat biopsies were performed at baseline and month 3. MAIN OUTCOME MEASURES: Clamp glucose infusion rate, intramyocellular, extramyocellular, and intrahepatic lipid content, 24-hour CPRs, adipocyte size, and adipocyte 11beta-hydroxysteroid dehydrogenase activity in adults with GH deficiency were evaluated. RESULTS: At month 1, LGH did not alter fasting levels of glucose, insulin, C-peptide, free fatty acid, adiponectin, total IGF-1, IGF-1 bioactivity, IGF-2, IGF binding protein (IGFBP)-2, or IGF-1 to IGFBP-3 molar ratio. At month 3, LGH increased clamp glucose infusion rates (P < .01) and IGF-1 to IGFBP-3 molar ratio (P < .05), but fasting glucose, insulin, C-peptide, free fatty acid, adiponectin, IGF-1 bioactivity, IGF-2, IGFBP-2, 24-hour CPRs, adipocyte size, adipocyte 11beta-hydroxysteroid dehydrogenase activity, intrahepatic lipid, extramyocellular, or intramyocellular were unchanged. In the placebo group, all within-group parameters from months 1 and 3 compared with baseline were unchanged. CONCLUSIONS: Short-term LGH therapy improves insulin sensitivity without inducing basal lipolysis and had no effect on cortisol metabolism and ectopic fat accumulation in GH-deficient adults. This may reflect an LGH-induced increase in IGF-1 to IGFBP-3 molar ratio exerting insulin-like effects through the abundant muscle IGF-1 receptors, but this hypothesis requires confirmation with further studies. PMID- 25013997 TI - A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile. AB - CONTEXT: Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. OBJECTIVE: To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195 0092. SETTING AND DESIGN: Randomized, single-center, placebo-controlled, double blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. RESULTS: SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose <=0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non Asian subjects. CONCLUSIONS: SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment. PMID- 25013998 TI - Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. AB - CONTEXT: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood. OBJECTIVE: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients. DESIGN AND SETTING: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study. PATIENTS: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study. INTERVENTIONS: Mifepristone (300-1200 mg) was administered once daily. MAIN OUTCOME MEASURES: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment. RESULTS: A >=2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 +/- 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI. CONCLUSIONS: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable over time. Corticotroph tumor progression and regression may occur over time, but patients may have significant increases in ACTH levels without evidence of tumor growth. PMID- 25013999 TI - Cardiorespiratory fitness and visceral fat are key determinants of serum fibroblast growth factor 21 concentration in Japanese men. AB - CONTEXT: Fibroblast growth factor-21 (FGF21) is an important metabolic regulator suggested to improve glucose metabolism and prevent dyslipidemia. An FGF21 resistant state that increases circulating FGF21 has been reported in obese patients. Although regular exercise prevents metabolic disease, the relationship of the fitness level to serum FGF21 level and body fat distribution in humans remains poorly understood. OBJECTIVE: The objective of the study was to determine the relationship among the serum FGF21 concentration, cardiorespiratory fitness (CRF) level, and visceral fat area (VFA). DESIGN: Serum FGF21 was measured by an ELISA in 166 middle-aged and elderly Japanese men (aged 30-79 y) and 25 untrained and 21 endurance-trained young men (aged 19-29 y). CRF was assessed by measuring the peak oxygen uptake (VO2peak) and VFA by magnetic resonance imaging. RESULTS: In the middle-aged and elderly subjects, the serum FGF21 level correlated with the VO2peak (r = -0.355, P < .001) and VFA (r = 0.487, P < .001). Stepwise multiple regression analysis showed VFA to be most strongly associated with the serum FGF21 level (beta = .360, P < .001), and VO2peak was also an independent predictor of the serum FGF21 level (beta = -.174, P = .019). Furthermore, the proportion of subjects with an FGF21 level below the limit of detection was significantly higher among the endurance-trained than among the untrained young men (71.4% vs 24.0%, P = .001), and the VO2peak and VFA were independently associated with an undetectable FGF21 level (P < .05). CONCLUSIONS: CRF and VFA are key determinants of the circulating FGF21 concentration. PMID- 25014000 TI - Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. AB - CONTEXT: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations. OBJECTIVE: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations. DESIGN, SETTING, AND PATIENTS: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites. MAIN OUTCOME MEASURE: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations. RESULTS: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases. CONCLUSIONS: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk. PMID- 25014002 TI - Hormone secretion by pituitary adenomas is characterized by increased disorderliness and spikiness but more regular pulsing. AB - CONTEXT: Hormone secretion by functioning pituitary tumors is characterized by increased basal (nonpulsatile) secretion, enhanced pulse frequency, amplified pulse mass, and increased disorderliness. OBJECTIVE: The objective of the study was to quantify (subtle) abnormalities of hormone secretion by pituitary adenomas and the influence of selective pituitary surgery and suppressive medications on these parameters. METHODS: Approximate entropy (ApEn) was quantified with a refined algorithm, spikiness by a new method to evaluate sudden short-lived increases in hormone levels, and pulsing regularity, determined with a fully automated deconvolution program. These 3 distinct measures of secretory disruption were compared in untreated and treated patients with acromegaly, prolactinoma, and Cushing's disease together with matching profiles in healthy controls. RESULTS: ApEn and spikiness were markedly increased in all untreated patient groups and normalized after pituitary surgery in acromegaly and hypercortisolism. In contrast, hormone-suppressive medical treatment in acromegaly and prolactinoma did not normalize ApEn. Spikiness normalized in acromegalic patients but not in prolactinoma. GH and cortisol pulsing regularity was elevated in acromegaly and Cushing's disease, respectively, and normalized after surgery. Medical treatment caused normalization of pulsing regularity in acromegaly but not in prolactinoma patients. CONCLUSION: This study extends the understanding of disorganized hormone secretion by hyperfunctioning pituitary adenomas. The new findings are increased spikiness in all 3 tumor groups and increased pulsing regularity in GH- and ACTH-secreting adenomas. The mechanisms behind the marked pattern irregularity and the selective normalization by surgical and medical therapies are not established yet but may include diminished feedback signaling in addition to the anatomical and functional disorganization of intrapituitary cell networks. PMID- 25014001 TI - Effects of escitalopram on markers of bone turnover: a randomized clinical trial. AB - CONTEXT: Recent observational studies have suggested that the use of selective serotonin reuptake inhibitors is associated with an increased fracture risk and an accelerated bone loss, although conflicting results have been reported. Furthermore, because many of these studies have been performed in depressed women, confounding by indication may influence these findings. OBJECTIVE: The objective of the study was to determine whether selective serotonin reuptake inhibitors affect bone metabolism Design: This was a randomized controlled trial. SETTING: The study was conducted in four US clinical sites. PARTICIPANTS: Healthy peri- and postmenopausal women participated in the study. INTERVENTION: The intervention was escitalopram (10-20 mg/d) for the treatment of vasomotor symptoms. MAIN OUTCOME MEASURES: Serum carboxyterminal collagen crosslinks (CTX) and serum amino-terminal propeptide of type I collagen (P1NP) were measured. RESULTS: One hundred forty-one peri- or postmenopausal nondepressed women (mean age 53.7 y, SD 4.1) had baseline and 8-week follow-up samples available for analysis and were included in the study (69 escitalopram, 72 placebo). The groups were balanced across a broad range of baseline characteristics, including age, race, body mass index, smoking status, and mood symptoms. The between-group differences in the change in CTX and P1NP from baseline to week 8 were compared by a repeated-measures linear regression model adjusted for race, clinical center, and baseline measurement. Treatment with escitalopram reduced serum P1NP by 1.02 ng/mL on average [95% confidence interval (CI) -5.17, 3.12] compared with a reduction of 1.88 ng/mL (95% CI -4.82, 1.06) in the placebo group (P = .65). Similarly, serum CTX decreased 0.02 ng/mL on average (95% CI -0.05, 0.01) in the escitalopram group compared with 0.00 ng/mL (95% CI -0.02, 0.02) in the placebo group (P = .24). The results were similar when the analysis was restricted to those women whose adherence to study medication was 70% or greater. CONCLUSIONS: Although the study was limited to 8 weeks, these results suggest that escitalopram does not significantly alter bone metabolism in the short term. PMID- 25014003 TI - Pair bond formation is impaired by VPAC receptor antagonism in the socially monogamous zebra finch. AB - A variety of recent data demonstrate that vasoactive intestinal polypeptide (VIP) and VPAC receptors (which bind VIP, and to a lesser extent, pituitary adenylatecyclase activating peptide) are important for numerous social behaviors in songbirds, including grouping and aggression, although VIP relates to these behaviors in a site-specific manner. In order to determine the global effects of central VPAC receptor activation on social behavior, we here infused a VPAC receptor antagonist or vehicle twice daily into the lateral ventricle of colony housed male and female zebra finches and quantified a wide range of behaviors. Aggressive behaviors were not altered by ventricular infusions, consistent with known opposing, site-specific relationships of VIP innervation to aggression. Courtship and self-maintenance behaviors were likewise not altered. However, VPAC antagonism produced significant deficits in pair bonding. Antagonist subjects took longer to form a pair bond and were paired for significantly fewer observation sessions relative to control subjects (median 1.5 of 6 observation sessions for antagonist subjects versus 4 for control subjects). Antagonist subjects were also significantly less likely to be paired in the final observation session. Based on the known distribution of VPAC receptors in finches and other vertebrates, we propose that VPAC receptors may mediate pair bonding via a variety of brain areas that are known to be important for the establishment of partner preferences in voles, including the lateral septum, ventral tegmental area, nucleus accumbens and ventral pallidum. PMID- 25014004 TI - An enriched environment ameliorates memory impairments in PACAP-deficient mice. AB - We previously found that juvenile pituitary adenylate cyclase-activating polypeptide (PACAP)-knockout (PACAP(-/-)) mice reared in an enriched environment (EE) for 4 weeks showed attenuated hyperactivity, jumping behavior, impairments in social interaction, and depression-like behavior. The present study examined the effects of EE on memory function and memory-related protein levels in PACAP( /-) mice. Eight-week-old PACAP(-/-) mice displayed fear memory dysfunction in a contextual fear conditioning test and cognitive impairments in a novel object recognition test. Rearing of 4-week-old PACAP(-/-) mice in an EE for 4 weeks ameliorated these memory impairments. The beneficial effects of EE were also observed 2 weeks after a return to housing in a standard environment (SE). This suggests that the effects of EE on impaired memory are long-lasting. In both wild type and PACAP(-/-) mice, EE increased the protein levels of the NMDA receptor NR2B subunit, phospho-ERK, phospho-CaMKII, and brain-derived neurotrophic factor (BDNF) in the hippocampus, and decreased neurotrophin-3 levels, whereas it did not affect nerve growth factor and glial cell-derived neurotrophic factor levels. Increased levels of NR2B, phospho-ERK, phospho-CaMKII and BDNF were not observed 2 weeks after a return to housing in a SE. These findings suggest that living in an EE engenders long-lasting reductions in memory impairments in PACAP(-/-) mice. The present study also implies that increases in hippocampal memory-related protein and BDNF levels are responsible for the beneficial effects of an EE, but not for the maintenance of these effects. PMID- 25014005 TI - Inhomogeneous broadening induced long-lived integrated two-color coherence photon echo signal. AB - Recent observations of the long-lasting nonlinear signals in a variety of light harvesting complexes have initiated an active debate on the origin of long-lived coherence in the biological systems. In this work we show that disorder of site energy can induce a long-lived electronic coherence between two chromophores in a strongly coupled dimer system, in addition to the ensemble dephasing effect. This phenomenon is physically explained as the correlated fluctuation of excitons with the equal delocalization on two sites, when the site-energy distributions overlap to give resonance. Using the integrated two-color coherence photon echo signal as an example, we show that the coherence in such a system exhibits a biexponential decay with a slow component with a lifetime of hundreds of femtoseconds and a rapid component with a lifetime of tens of femtoseconds. The current result provides a possible microscopic basis for the electronic coherence to be the origin of the long-lived coherence signals to be considered along with other recently proposed mechanisms. PMID- 25014006 TI - Enhanced enzymatic reactivity for electrochemically driven drug metabolism by confining cytochrome P450 enzyme in TiO2 nanotube arrays. AB - Understanding the enzymatic reaction kinetics that occur within a confined space or interface is a significant challenge. Herein, a nanotube array enzymatic reactor (CYP2C9/Au/TNA) was constructed by electrostatically adsorbing enzyme on the inner wall of TiO2 nanotube arrays (TNAs). TNAs with different dimensions could be fabricated by the anodization of titanium foil through varying the anodization potential or time. The electrical conductivity of TNAs was improved by electrodepositing Au nanoparticles on the inner wall of TNAs. The cytochrome P450 2C9 enzyme (CYP2C9) was confined inside TNAs as a model. The enzymatic activity of CYP2C9 and tolbutamide metabolic yield could be effectively regulated by changing the nanotube diameter and length of TNAs. The enzymatic rate constant k(cat) and apparent Michaelis constant K(m)(app) were determined to be 9.89 s(-1) and 4.8 MUM at the tube inner diameter of about 64 nm and length of 1.08 MUm. The highest metabolic yield of tolbutamide reached 14.6%. Furthermore, the designed nanotube array enzymatic reactor could be also used in situ to monitor the tolbutamide concentration with sensitivity of 28.8 MUA mM(-1) and detection limit of 0.52 MUM. Therefore, the proposed nanotube array enzymatic reactor was a good vessel for studying enzyme biocatalysis and drug metabolism, and has potential applications including efficient biosensors and bioreactors for chemical synthesis. PMID- 25014007 TI - HELP LDL apheresis reduces plasma pentraxin 3 in familial hypercholesterolemia. AB - BACKGROUND: Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, is secreted by vascular cells in response to injury, possibly aiming at tuning arterial activation associated with vascular damage. Severe hypercholesterolemia as in familial hypercholesterolemia (FH) promotes vascular inflammation and atherosclerosis; low-density lipoprotein (LDL) apheresis is currently the treatment of choice to reduce plasma lipids in FH. HELP LDL apheresis affects pro- and antiinflammatory biomarkers, however its effects on PTX3 levels are unknown. We assessed the impact of FH and of LDL removal by HELP apheresis on PTX3. METHODS: Plasma lipids, PTX3, and CRP were measured in 19 patients with FH undergoing chronic HELP LDL apheresis before and after treatment and in 20 control subjects. In the patients assessment of inflammation and oxidative stress markers included also plasma TNFalpha, fibrinogen and TBARS. RESULTS: At baseline, FH patients had higher (p = 0.0002) plasma PTX3 than matched control subjects. In FH PTX3 correlated positively (p<=0.05) with age, gender and CRP and negatively (p = 0.01) with HELP LDL apheresis vintage. The latter association was confirmed after correction for age, gender and CRP. HELP LDL apheresis acutely reduced (p<=0.04) plasma PTX3, CRP, fibrinogen, TBARS and lipids, but not TNFalpha. No association was observed between mean decrease in PTX3 and in LDL cholesterol. PTX3 paralleled lipids, oxidative stress and inflammation markers in time-course study. CONCLUSION: FH is associated with increased plasma PTX3, which is acutely reduced by HELP LDL apheresis independently of LDL cholesterol, as reflected by the lack of association between change in PTX3 and in LDL levels. These results, together with the finding of a negative relationship between PTX3 and duration of treatment suggest that HELP LDL apheresis may influence both acutely and chronically cardiovascular outcomes in FH by modulating PTX3. PMID- 25014008 TI - Using the lives saved tool (LiST) to model mHealth impact on neonatal survival in resource-limited settings. AB - While the importance of mHealth scale-up has been broadly emphasized in the mHealth community, it is necessary to guide scale up efforts and investment in ways to help achieve the mortality reduction targets set by global calls to action such as the Millennium Development Goals, not merely to expand programs. We used the Lives Saved Tool (LiST)--an evidence-based modeling software--to identify priority areas for maternal and neonatal health services, by formulating six individual and combined interventions scenarios for two countries, Bangladesh and Uganda. Our findings show that skilled birth attendance and increased facility delivery as targets for mHealth strategies are likely to provide the biggest mortality impact relative to other intervention scenarios. Although further validation of this model is desirable, tools such as LiST can help us leverage the benefit of mHealth by articulating the most appropriate delivery points in the continuum of care to save lives. PMID- 25014009 TI - Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain. AB - Recent studies indicate that the release of high mobility group box 1 (HMGB1) following nerve injury may play a central role in the pathogenesis of neuropathic pain. HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End products (RAGE) and Toll-like receptors (TLRs). The degree to which HMGB1 activates a receptor is thought to be dependent upon the oxidative state of the ligand, resulting in the functional isoforms of all-thiol HMGB1 (at-HMGB1) acting through RAGE, and disufide HMGB1 (ds-HMGB1) interacting with TLR4. Though it is known that dorsal root ganglia (DRG) sensory neurons exposed to HMGB1 and TLR4 agonists can influence excitation, the degree to which at-HMGB1 signaling through neuronal RAGE contributes to neuropathic pain is unknown. Here we demonstrate that at-HMGB1 activation of nociceptive neurons is dependent on RAGE and not TLR4. To distinguish the possible role of RAGE on neuropathic pain, we characterized the changes in RAGE mRNA expression up to one month after tibial nerve injury (TNI). RAGE mRNA expression in lumbar dorsal root ganglion (DRG) is substantially increased by post-injury day (PID) 28 when compared with sham injured rodents. Protein expression at PID28 confirms this injury-induced event in the DRG. Moreover, a single exposure to monoclonal antibody to RAGE (RAGE Ab) failed to abrogate pain behavior at PID 7, 14 and 21. However, RAGE Ab administration produced reversal of mechanical hyperalgesia on PID28. Thus, at HMGB1 activation through RAGE may be responsible for sensory neuron sensitization and mechanical hyperalgesia associated with chronic neuropathic pain states. PMID- 25014010 TI - Influenza vaccination during early pregnancy contributes to neurogenesis and behavioral function in offspring. AB - Prenatal influenza virus infection has been associated with an increased risk of schizophrenia. Thus, inactivated flu vaccines are widely recommended for pregnant women. In a mouse model of pregnancy, immune activation via exposure to viruses or lipopolysaccharide (LPS) impaired brain development and behavioral function in offspring. The objective of our study was to determine if flu vaccination as an immune activation could affect postnatal neurogenesis and behavior. Female C57BL/6J mice were administered A(H1N1) influenza vaccine (AIV) or seasonal influenza vaccine (SIV) early in pregnancy. We found that the offspring of vaccinated mice, especially AIV group, presented superior performance in terms of exploratory behavior and spatial ability compared with controls at postnatal day 28 (P28), but at P56, there was no significance differences among these pups. Quantification of BrdU(+)/DCX(+) and BrdU(+)/NeuN(+) cells in the dentate gyrus (DG) indicated an increase in the hippocampal neurogenesis of the pups born to both vaccinated mothers. The cytokine levels in both the serum and hippocampus changed to varying degrees. Furthermore, administration of the A(H1N1) vaccine blocked LPS-induced cognitive impairment in the progeny. Altogether, the results suggest that maternal influenza vaccination promotes neurogenesis and behavioral function, as well as protection from LPS insults in the developing offspring. PMID- 25014011 TI - Increased tau phosphorylation and receptor for advanced glycation endproducts (RAGE) in the brain of mice infected with Leishmania amazonensis. AB - Leishmaniasis is a parasitosis caused by several species of the genus Leishmania, an obligate intramacrophagic parasite. Although neurologic symptoms have been observed in human cases of leishmaniasis, the manifestation of neurodegenerative processes is poorly studied. The aim of the present work was to investigate if peripheral infection of BALB/c mice with Leishmania amazonensis affects tau phosphorylation and RAGE protein content in the brain, which represent biochemical markers of neurodegenerative processes observed in diseases with a pro-inflammatory component, including Alzheimer's disease and Down syndrome. Four months after a single right hind footpad subcutaneous injection of L. amazonensis, the brain cortex of BALB/c mice was isolated. Western blot analysis indicated an increase in tau phosphorylation (Ser(396)) and RAGE immunocontent in infected animals. Brain tissue TNF-alpha, IL-1beta, and IL-6 levels were not different from control animals; however, increased protein carbonylation, decreased IFN-gamma levels and impairment in antioxidant defenses were detected. Systemic antioxidant treatment (NAC 20mg/kg, i.p.) inhibited tau phosphorylation and recovered IFN-gamma levels. These data, altogether, indicate an association between impaired redox state, tau phosphorylation and RAGE up-regulation in the brain cortex of animals infected with L. amazonensis. In this context, it is possible that neurologic symptoms associated to chronic leishmaniasis are associated to disruptions in the homeostasis of CNS proteins, such as tau and RAGE, as consequence of oxidative stress. This is the first demonstration of alterations in biochemical parameters of neurodegeneration in an experimental model of Leishmania infection. PMID- 25014012 TI - Assessing accuracy of genotype imputation in American Indians. AB - BACKGROUND: Genotype imputation is commonly used in genetic association studies to test untyped variants using information on linkage disequilibrium (LD) with typed markers. Imputing genotypes requires a suitable reference population in which the LD pattern is known, most often one selected from HapMap. However, some populations, such as American Indians, are not represented in HapMap. In the present study, we assessed accuracy of imputation using HapMap reference populations in a genome-wide association study in Pima Indians. RESULTS: Data from six randomly selected chromosomes were used. Genotypes in the study population were masked (either 1% or 20% of SNPs available for a given chromosome). The masked genotypes were then imputed using the software Markov Chain Haplotyping Algorithm. Using four HapMap reference populations, average genotype error rates ranged from 7.86% for Mexican Americans to 22.30% for Yoruba. In contrast, use of the original Pima Indian data as a reference resulted in an average error rate of 1.73%. CONCLUSIONS: Our results suggest that the use of HapMap reference populations results in substantial inaccuracy in the imputation of genotypes in American Indians. A possible solution would be to densely genotype or sequence a reference American Indian population. PMID- 25014013 TI - Relative myocardial blood flow by dynamic computed tomographic perfusion imaging predicts hemodynamic significance of coronary stenosis better than absolute blood flow. AB - OBJECTIVES: Quantitative myocardial perfusion imaging by computed tomography (CT) was recently introduced to calculate myocardial blood flow (MBF). Because absolute MBF thresholds may be affected by technique, methodology, and the microvasculature, we investigated whether a relative measure of MBF improves accuracy to identify hemodynamically significant coronary stenosis. MATERIALS AND METHODS: In this prospective study, 42 patients (mean [SD] age, 62.3[8.7] years; 8 women) with suspected or known coronary disease underwent dynamic CT myocardial perfusion imaging using adenosine vasodilation, before invasive angiography (coronary angiography) with fractional flow reserve (FFR). Within each myocardial territory MBF, the MBF relative to remote myocardium (MBFratio) was calculated and compared with coronary angiography and FFR. RESULTS: Of the 91 vessels interrogated by FFR (median, 0.81; interquartile range, 0.73-0.94), 45 vessels (49%) had an FFR value lower than 0.8 and were considered hemodynamically significant. Hyperemic MBF was lower in ischemic territories: 75.6 +/- 22.5 mL per 100 mL/min versus 98.3 +/- 23.1 mL per 100 mL/min (P < 0.0001). The MBFratio correlated better with FFR (P = 0.76) than the absolute MBF did (P = 0.52). Receiver operating curve analysis showed better discrimination by MBFratio: area under the curve of 0.85 versus 0.75 (P = 0.02). The MBF of remote myocardium varied between 60.7 and 167.2 mL per 100 mL/min and was lower in patients without heart rate acceleration (P = 0.0035). CONCLUSIONS: The MBFratio seems to better identify hemodynamically significant coronary artery disease than does the absolute MBF determined by dynamic CT perfusion imaging. This may be caused by microvascular status or related to the methodology. PMID- 25014015 TI - Effects of biochar and activated carbon amendment on maize growth and the uptake and measured availability of polycyclic aromatic hydrocarbons (PAHs) and potentially toxic elements (PTEs). AB - With the aim of investigating the effects of carbonaceous sorbent amendment on plant health and end point contaminant bioavailability, plant experiments were set up to grow maize (Zea mays) in soil contaminated with polycyclic aromatic hydrocarbons (PAHs) and metals. Maize and pine derived biochars, as well as a commercial grade activated carbon, were used as amendments. Plant growth characteristics, such as chlorophyll content and shoot to root biomass, improved with sorbent amendment to varying extents and contaminant uptake to shoots was consistently reduced in amended soils. By further defining the conditions in which sorbent amended soils successfully reduce contaminant bioavailability and improve plant growth, this work will inform field scale remediation efforts. PMID- 25014014 TI - Structural analysis and mutant growth properties reveal distinctive enzymatic and cellular roles for the three major L-alanine transaminases of Escherichia coli. AB - In order to maintain proper cellular function, the metabolism of the bacterial microbiota presents several mechanisms oriented to keep a correctly balanced amino acid pool. Central components of these mechanisms are enzymes with alanine transaminase activity, pyridoxal 5'-phosphate-dependent enzymes that interconvert alanine and pyruvate, thereby allowing the precise control of alanine and glutamate concentrations, two of the most abundant amino acids in the cellular amino acid pool. Here we report the 2.11-A crystal structure of full-length AlaA from the model organism Escherichia coli, a major bacterial alanine aminotransferase, and compare its overall structure and active site composition with detailed atomic models of two other bacterial enzymes capable of catalyzing this reaction in vivo, AlaC and valine-pyruvate aminotransferase (AvtA). Apart from a narrow entry channel to the active site, a feature of this new crystal structure is the role of an active site loop that closes in upon binding of substrate-mimicking molecules, and which has only been previously reported in a plant enzyme. Comparison of the available structures indicates that beyond superficial differences, alanine aminotransferases of diverse phylogenetic origins share a universal reaction mechanism that depends on an array of highly conserved amino acid residues and is similarly regulated by various unrelated motifs. Despite this unifying mechanism and regulation, growth competition experiments demonstrate that AlaA, AlaC and AvtA are not freely exchangeable in vivo, suggesting that their functional repertoire is not completely redundant thus providing an explanation for their independent evolutionary conservation. PMID- 25014016 TI - Decreasing effect and mechanism of FeSO4 seed particles on secondary organic aerosol in alpha-pinene photooxidation. AB - alpha-Pinene/NOx and alpha-pinene/HONO photooxidation experiments at varying humidity were conducted in smog chambers in the presence or absence of FeSO4 seed particles. FeSO4 seed particles decrease SOA mass as long as water was present on the seed particle surface, but FeSO4 seed particles have no decreasing effect on SOA under dryer conditions at 12% relative humidity (RH). The decreasing effect of FeSO4 seed particles on the SOA mass is proposed to be related to oxidation processes in the surface layer of water on the seed particles. Free radicals, including OH, can be formed from catalytic cycling of Fe(2+) and Fe(3+) in the aqueous phase. These radicals can react further with the organic products of alpha-pinene oxidation on the seed particles. The oxidation may lead to formation of smaller molecules which have higher saturation vapor pressures and favor repartitioning to the gas phase, and therefore, reduces SOA mass. PMID- 25014017 TI - Remobilisation of silver and silver sulphide nanoparticles in soils. AB - Manufactured nanoparticles (NPs) present in consumer products could enter soils through re-use of biosolids. Among these NPs are those based on silver (Ag), which are found sulphidised (e.g. silver sulphide, Ag2S) in biosolids. Herein, our aim was to examine the release of retained Ag(0) and Ag2S NPs in soils and biosolids as facilitated by environmentally and agriculturally relevant ligands. Under natural soil conditions, exemplified by potassium nitrate and humic acid experiments, release of Ag retained in soil was limited. The highest total Ag release was facilitated by ligands that simulated root exudates (citrate) or fertilisers (thiosulphate). Released Ag was predominantly present in the colloidal phase (>3 kDa-< 0.45 MUm); intact NPs only identified in Ag2S-NP extracts. For biosolids containing nanoparticulate-Ag-S, release was also enhanced by thiosulphate, though mostly as colloidal-Ag - not intact NPs. These results suggest that exposure to NPs as a result of its release from soils or biosolids will be low. PMID- 25014018 TI - Exposure to As(III) and As(V) changes the Ca2+-activation properties of the two major fibre types from the chelae of the freshwater crustacean Cherax destructor. AB - Arsenic is a known carcinogen found in the soil in gold mining regions at concentrations thousands of times greater than gold. Mining releases arsenic into the environment and surrounding water bodies. The main chemical forms of arsenic found in the environment are inorganic arsenite (As(III)) and arsenate (As(V)). Yabbies (Cherax destructor) accumulate arsenic at levels comparable to those in the sediment of their environment but the effect on their physiological function is not known. The effects of arsenic exposure (10 ppm sodium arsenite, AsNaO2 - 5.7 ppm As(III)) and 10 ppm arsenic acid, Na2HAsO4.7H2O - 2.6 ppm As(V)) for 40 days on the contractile function of the two major fibre types from the chelae were determined. After exposure, individual fibres were isolated from the chela, "skinned" (membrane removed) and attached to the force recording apparatus. Contraction was induced in solutions containing increasing [Ca(2+)] until a maximum Ca(2+)-activation was obtained. Submaximal force responses were plotted as a percentage of the maximum Ca(2+)-activated force. As(V) exposure resulted in lower levels of calcium required for activation than As(III) indicating an increased sensitivity to Ca(2+) after long term exposure to arsenate compared to arsenite. Myosin heavy chain and tropomyosin content in individual fibres was also decreased as a result of arsenic exposure. Single fibres exposed to As(V) produced significantly more force than muscle fibres from control animals. Long term exposure of yabbies to arsenic alters the contractile function of the two major fibre types in the chelae. PMID- 25014019 TI - Fruit over sunbed: carotenoid skin colouration is found more attractive than melanin colouration. AB - Skin colouration appears to play a pivotal part in facial attractiveness. Skin yellowness contributes to an attractive appearance and is influenced both by dietary carotenoids and by melanin. While both increased carotenoid colouration and increased melanin colouration enhance apparent health in Caucasian faces by increasing skin yellowness, it remains unclear, firstly, whether both pigments contribute to attractiveness judgements, secondly, whether one pigment is clearly preferred over the other, and thirdly, whether these effects depend on the sex of the face. Here, in three studies, we examine these questions using controlled facial stimuli transformed to be either high or low in (a) carotenoid colouration, or (b) melanin colouration. We show, firstly, that both increased carotenoid colouration and increased melanin colouration are found attractive compared to lower levels of these pigments. Secondly, we show that carotenoid colouration is consistently preferred over melanin colouration when levels of colouration are matched. In addition, we find an effect of the sex of stimuli with stronger preferences for carotenoids over melanin in female compared to male faces, irrespective of the sex of the observer. These results are interpreted as reflecting preferences for sex-typical skin colouration: men have darker skin than women and high melanization in male faces may further enhance this masculine trait, thus carotenoid colouration is not less desirable, but melanin colouration is relatively more desirable in males compared to females. Taken together, our findings provide further support for a carotenoid-linked health-signalling system that is highly important in mate choice. PMID- 25014020 TI - Novel coupling between TRPC-like and KNa channels modulates low threshold spike induced afterpotentials in rat thalamic midline neurons. AB - Neurons in thalamic midline and paraventricular nuclei (PVT) display a unique slow afterhyperpolarizing potential (sAHP) following the low threshold spike (LTS) generated by activation of their low voltage Ca(2+) channels. We evaluated the conductances underlying this sAHP using whole-cell patch-clamp recordings in rat brain slice preparations. Initial observations recorded in the presence of TTX revealed a marked dependency of the LTS-induced sAHP on extracellular Na(+): replacing Na(+) with TRIS(+) in the external medium eliminated the LTS-induced sAHP; substitution of Na(+) with either Li(+) or choline(+) in the external medium resulted in a gradual loss of the sAHP and its replacement with a prolonged slow afterdepolarizing potential (sADP). The LTS-induced sAHP was reduced by quinidine and potentiated by loxapine, suggesting involvement of KNa like channels. Canonical transient receptor potential (TRPC) channels were considered the source for Na(+) based on observations that the sAHP was suppressed by nonselective TRPC channel blockers (2-APB, flufenamic acid and ML204) but unchanged in the presence of TRPV1 channel blocker (SB-366791). In addition, after replacement of Na(+) with Li(+), the isolated LTS-induced sADP was significantly suppressed in the presence of 2-APB or ML204, after replacement of extracellular Ca(2+) with Sr(2+), and by intracellular Ca(2+) chelation with EGTA, data that collectively suggest involvement of Ca(2+)-activated TRPC-like conductances containing TRPC4/5 subunits. The isolated LTS-induced sADP also exhibited a strong voltage dependency, decreasing at hyperpolarizing potentials, further support for involvement of TRPC4/5 subunits. This sADP exhibited neurotransmitter receptor sensitivity, with suppression by 5-CT, a 5-HT7 receptor agonist, and enhancement by the neuropeptide orexin A. These data suggest that LTS-induced slow afterpotentials reflect a simultaneous interplay between KNa and TRPC-like conductances, novel for midline thalamic neurons. PMID- 25014021 TI - Interpersonal similarity between body movements in face-to-face communication in daily life. AB - Individuals are embedded in social networks in which they communicate with others in their daily lives. Because smooth face-to-face communication is the key to maintaining these networks, measuring the smoothness of such communication is an important issue. One indicator of smoothness is the similarity of the body movements of the two individuals concerned. A typical example noted in experimental environments is the interpersonal synchronization of body movements such as nods and gestures during smooth face-to-face communication. It should therefore be possible to estimate quantitatively the smoothness of face-to-face communication in social networks through measurement of the synchronization of body movements. However, this is difficult because social networks, which differ from disciplined experimental environments, are open environments for the face-to face communication between two individuals. In such open environments, their body movements become complicated by various external factors and may follow unstable and nonuniform patterns. Nevertheless, we consider there to be some interaction during face-to-face communication that leads to the interpersonal synchronization of body movements, which can be seen through the interpersonal similarity of body movements. The present study aims to clarify such interaction in terms of body movements during daily face-to-face communication in real organizations of more than 100 people. We analyzed data on the frequency of body movement for each individual during face-to-face communication, as measured by a wearable sensor, and evaluated the degree of interpersonal similarity of body movements between two individuals as their frequency difference. Furthermore, we generated uncorrelated data by resampling the data gathered and compared these two data sets statistically to distinguish the effects of actual face-to-face communication from those of the activities accompanying the communication. Our results confirm an interpersonal similarity of body movements between two individuals in face-to-face communication, for all the organizations studied, and suggest that some body interaction is behind this similarity. PMID- 25014022 TI - Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice. AB - Charcot--Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy characterized by progressive demyelination and distal muscle weakness. Abnormal expression of peripheral myelin protein 22 (PMP22) has been linked to CMT1A and is modeled by Trembler J (TrJ) mice, which carry the same leucine to proline substitution in PMP22 as affected pedigrees. Pharmacologic modulation of autophagy by rapamycin in neuron-Schwann cell explant cultures from neuropathic mice reduced PMP22 aggregate formation and improved myelination. Here we asked whether rapamycin administration by food supplementation, or intraperitoneal injection, could alleviate the neuropathic phenotype of affected mice and improve neuromuscular performance. Cohorts of male and female wild type (Wt) and TrJ mice were assigned to placebo or rapamycin treatment starting at 2 or 4months of age and tested monthly on the rotarod. While neither long-term feeding (8 or 10months) on rapamycin-enriched diet, or short-term injection (2months) of rapamycin improved locomotor performance of the neuropathic mice, both regimen benefited peripheral nerve myelination. Together, these results indicate that while treatment with rapamycin benefits the myelination capacity of neuropathic Schwann cells, this intervention does not improve neuromuscular function. The observed outcome might be the result of the differential response of nerve and skeletal muscle tissue to rapamycin. PMID- 25014023 TI - Altered selenium status in Huntington's disease: neuroprotection by selenite in the N171-82Q mouse model. AB - Disruption of redox homeostasis is a prominent feature in the pathogenesis of Huntington's disease (HD). Selenium an essential element nutrient that modulates redox pathways and has been reported to provide protection against both acute neurotoxicity (e.g. methamphetamine) and chronic neurodegeneration (e.g. tauopathy) in mice. The objective of our study was to investigate the effect of sodium selenite, an inorganic form of selenium, on behavioral, brain degeneration and biochemical outcomes in the N171-82Q Huntington's disease mouse model. HD mice, which were supplemented with sodium selenite from 6 to 14 weeks of age, demonstrated increased motor endurance, decreased loss of brain weight, decreased mutant huntingtin aggregate burden and decreased brain oxidized glutathione levels. Biochemical studies revealed that selenite treatment reverted HD associated changes in liver selenium and plasma glutathione in N171-82Q mice and had effects on brain selenoprotein transcript expression. Further, we found decreased brain selenium content in human autopsy brain. Taken together, we demonstrate a decreased selenium phenotype in human and mouse HD and additionally show some protective effects of selenite in N171-82Q HD mice. Modification of selenium metabolism results in beneficial effects in mouse HD and thus may represent a therapeutic strategy. PMID- 25014025 TI - Spliceozymes: ribozymes that remove introns from pre-mRNAs in trans. AB - Group I introns are pre-mRNA introns that do not require the spliceosome for their removal. Instead, they fold into complex three-dimensional structures and catalyze two transesterification reactions, thereby excising themselves and joining the flanking exons. These catalytic RNAs (ribozymes) have been modified previously to work in trans, whereby the ribozymes can recognize a splice site on a substrate RNA and replace the 5'- or 3'-portion of the substrate. Here we describe a new variant of the group I intron ribozyme from Tetrahymena that recognizes two splice sites on a substrate RNA, removes the intron sequences between the splice sites, and joins the flanking exons, analogous to the action of the spliceosome. This 'group I spliceozyme' functions in vitro and in vivo, and it is able to mediate a growth phenotype in E. coli cells. The intron sequences of the target pre-mRNAs are constrained near the splice sites but can carry a wide range of sequences in their interior. Because the splice site recognition sequences can be adjusted to different splice sites, the spliceozyme may have the potential for wide applications as tool in research and therapy. PMID- 25014026 TI - Antifungal activity of resveratrol derivatives against Candida species. AB - trans-Resveratrol (1a) is a phytoalexin produced by plants in response to infections by pathogens. Its potential activity against clinically relevant opportunistic fungal pathogens has previously been poorly investigated. Evaluated herein are the candidacidal activities of oligomers (2a, 3-5) of 1a purified from Vitis vinifera grape canes and several analogues (1b-1j) of 1a obtained through semisynthesis using methylation and acetylation. Moreover, trans-epsilon viniferin (2a), a dimer of 1a, was also subjected to methylation (2b) and acetylation (2c) under nonselective conditions. Neither the natural oligomers of 1a (2a, 3-5) nor the derivatives of 2a were active against Candida albicans SC5314. However, the dimethoxy resveratrol derivatives 1d and 1e exhibited antifungal activity against C. albicans with minimum inhibitory concentration (MIC) values of 29-37 MUg/mL and against 11 other Candida species. Compound 1e inhibited the yeast-to-hyphae morphogenetic transition of C. albicans at 14 MUg/mL. PMID- 25014028 TI - Frequent extreme cold exposure and brown fat and cold-induced thermogenesis: a study in a monozygotic twin. AB - INTRODUCTION: Mild cold acclimation is known to increase brown adipose tissue (BAT) activity and cold-induced thermogenesis (CIT) in humans. We here tested the effect of a lifestyle with frequent exposure to extreme cold on BAT and CIT in a Dutch man known as 'the Iceman', who has multiple world records in withstanding extreme cold challenges. Furthermore, his monozygotic twin brother who has a 'normal' sedentary lifestyle without extreme cold exposures was measured. METHODS: The Iceman (subject A) and his brother (subject B) were studied during mild cold (13 degrees C) and thermoneutral conditions (31 degrees C). Measurements included BAT activity and respiratory muscle activity by [18F]FDG PET/CT imaging and energy expenditure through indirect calorimetry. In addition, body temperatures, cardiovascular parameters, skin perfusion, and thermal sensation and comfort were measured. Finally, we determined polymorphisms for uncoupling protein-1 and beta3-adrenergic receptor. RESULTS: Subjects had comparable BAT activity (A: 1144 SUVtotal and B: 1325 SUVtotal), within the range previously observed in young adult men. They were genotyped with the polymorphism for uncoupling protein-1 (G/G). CIT was relatively high (A: 40.1% and B: 41.9%), but unlike during our previous cold exposure tests in young adult men, here both subjects practiced a g-Tummo like breathing technique, which involves vigorous respiratory muscle activity. This was confirmed by high [18F]FDG-uptake in respiratory muscle. CONCLUSION: No significant differences were found between the two subjects, indicating that a lifestyle with frequent exposures to extreme cold does not seem to affect BAT activity and CIT. In both subjects, BAT was not higher compared to earlier observations, whereas CIT was very high, suggesting that g-Tummo like breathing during cold exposure may cause additional heat production by vigorous isometric respiratory muscle contraction. The results must be interpreted with caution given the low subject number and the fact that both participants practised the g-Tummo like breathing technique. PMID- 25014027 TI - Collection and chemical composition of phloem sap from Citrus sinensis L. Osbeck (sweet orange). AB - Through utilizing the nutrient-rich phloem sap, sap feeding insects such as psyllids, leafhoppers, and aphids can transmit many phloem-restricted pathogens. On the other hand, multiplication of phloem-limited, uncultivated bacteria such as Candidatus Liberibacter asiaticus (CLas) inside the phloem of citrus indicates that the sap contains all the essential nutrients needed for the pathogen growth. The phloem sap composition of many plants has been studied; however, to our knowledge, there is no available data about citrus phloem sap. In this study, we identified and quantified the chemical components of phloem sap from pineapple sweet orange. Two approaches (EDTA enhanced exudation and centrifugation) were used to collect phloem sap. The collected sap was derivatized with methyl chloroformate (MCF), N-methyl-N- [tert-butyl dimethylsilyl]-trifluroacetamide (MTBSTFA), or trimethylsilyl (TMS) and analyzed with GC-MS revealing 20 amino acids and 8 sugars. Proline, the most abundant amino acid, composed more than 60% of the total amino acids. Tryptophan, tyrosine, leucine, isoleucine, and valine, which are considered essential for phloem sap-sucking insects, were also detected. Sucrose, glucose, fructose, and inositol were the most predominant sugars. In addition, seven organic acids including succinic, fumaric, malic, maleic, threonic, citric, and quinic were detected. All compounds detected in the EDTA-enhanced exudate were also detected in the pure phloem sap using centrifugation. The centrifugation technique allowed estimating the concentration of metabolites. This information expands our knowledge about the nutrition requirement for citrus phloem-limited bacterial pathogen and their vectors, and can help define suitable artificial media to culture them. PMID- 25014029 TI - Photoluminescent supramolecular hyperbranched polymer without conventional chromophores based on inclusion complexation. AB - A novel photoluminescent supramolecular hyperbranched polymer (SHP) without conventional chromophores was constructed for the first time by inclusion complexation between alpha-cyclodextrin and diethylenetriamine. The SHP showed wide-band fluorescence dependent upon the excitation wavelength. PMID- 25014030 TI - A high-density SNP Map of sunflower derived from RAD-sequencing facilitating fine mapping of the rust resistance gene R12. AB - A high-resolution genetic map of sunflower was constructed by integrating SNP data from three F2 mapping populations (HA 89/RHA 464, B-line/RHA 464, and CR 29/RHA 468). The consensus map spanned a total length of 1443.84 cM, and consisted of 5,019 SNP markers derived from RAD tag sequencing and 118 publicly available SSR markers distributed in 17 linkage groups, corresponding to the haploid chromosome number of sunflower. The maximum interval between markers in the consensus map is 12.37 cM and the average distance is 0.28 cM between adjacent markers. Despite a few short-distance inversions in marker order, the consensus map showed high levels of collinearity among individual maps with an average Spearman's rank correlation coefficient of 0.972 across the genome. The order of the SSR markers on the consensus map was also in agreement with the order of the individual map and with previously published sunflower maps. Three individual and one consensus maps revealed the uneven distribution of markers across the genome. Additionally, we performed fine mapping and marker validation of the rust resistance gene R12, providing closely linked SNP markers for marker assisted selection of this gene in sunflower breeding programs. This high resolution consensus map will serve as a valuable tool to the sunflower community for studying marker-trait association of important agronomic traits, marker assisted breeding, map-based gene cloning, and comparative mapping. PMID- 25014031 TI - Harnessing gene expression networks to prioritize candidate epileptic encephalopathy genes. AB - We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets. PMID- 25014032 TI - Dietary fat composition and cardiac events in patients with type 2 diabetes. AB - OBJECTIVE: To evaluate associations of dietary fat composition with the development of cardiac events in patients with type 2 diabetes, without ischemic heart disease who were followed for at least 12 months. METHODS: In this prospective cohort study the usual diet of patients was retrospectively assessed by a 3-day weighed diet record (WDR). Compliance with the WDR technique was assessed by comparing protein intake estimated from 3-day WDR and 24-h urinary nitrogen output. The following were considered cardiac events: myocardial infarction, myocardial revascularization procedures, congestive heart failure, new-onset angina pectoris, and sudden death. RESULTS: A total of 227 patients with type 2 diabetes (aged 59 +/- 10 years; 46.0% male), were followed during 4.6 years. In a multivariate Cox regression analysis, the intake of polyunsaturated fatty acids had a protective effect for cardiac events (HR = 0.31, 95% CI: 0.11 0.89; P = 0.03) adjusted for age, gender, duration of diabetes, smoking, compliance with WDR, using hypolipidemic agents, and the presence of hypertension and diabetic nephropathy. When the fat intake was divided into quartiles, the highest intake of alpha-linolenic acid (>1.25% of energy) was negatively associated with cardiac events (HR = 0.58, 95% CI: 0.39-0.85; P = 0.006), adjusted for the same covariates.. CONCLUSION: In patients with type 2 diabetes without ischemic heart disease, a high intake of polyunsaturated fatty acids, especially alpha linolenic acid, was protective for the development of cardiac events.. PMID- 25014033 TI - Association between periodontal disease and its treatment, flow-mediated dilatation and carotid intima-media thickness: a systematic review and meta analysis. AB - OBJECTIVE: This meta-analysis sought to investigate the association between carotid intima-media thickness (c-IMT), flow-mediated dilation (FMD) and periodontitis (PD) and to assess the effect of periodontal treatment on c-IMT and FMD. METHODS: Electronic database searching, hand searching of bibliographic references of included papers, related reviews, and journals in relation to oral, cardiovascular and ultrasound imaging field was carried out. Random effects meta analyses were performed to investigate the association of co-existence of increased c-IMT, impaired FMD and PD with potential changes in these variables following periodontal intervention. RESULTS: 2009 citations and 101 full text articles were screened, with 35 meeting the review inclusion criteria of which 22 suitable for quantitative analysis. Meta-analysis demonstrated that the diagnosis of PD was associated with a mean increase in c-IMT of 0.08 mm (95% C.I. = 0.07 0.09) and a mean difference in FMD of 5.1% compared to controls (95% C.I. = 2.08 8.11%). A meta-analysis of the effects of periodontal treatment on FMD showed a mean improvement of 6.64% between test and control (95% C.I. = 2.83-10.44%). CONCLUSIONS: This review demonstrated an association between increased c-IMT, impaired FMD and PD. Data from intervention studies suggested a beneficial effect of periodontal treatment on FMD indicating an improvement in endothelial function. The findings support investigation of periodontitis treatment on cardiovascular outcomes. PMID- 25014034 TI - Cardiovascular function in healthy Himalayan high-altitude dwellers. AB - BACKGROUND: Residents of the Himalayan valleys uniquely adapted to their hypoxic environment in terms of pulmonary vasculature, but their systemic vascular function is still largely unexplored. The aim of the study was to investigate vascular function and structure in rural Sherpa population, permanently living at high altitude in Nepal (HA), in comparison with control Caucasian subjects (C) living at sea level. METHODS AND RESULTS: 95 HA and 64 C were enrolled. Cardiac ultrasound, flow-mediated dilation (FMD) of the brachial artery, carotid geometry and stiffness, and aortic pulse wave velocity (PWV) were performed. The same protocol was repeated in 11 HA with reduced FMD, after 1-h 100% O2 administration. HA presented lower FMD (5.18 +/- 3.10 vs. 6.44 +/- 2.91%, p = 0.02) and hyperemic velocity than C (0.61 +/- 0.24 vs. 0.75 +/- 0.28 m/s, p = 0.008), while systolic pulmonary pressure was higher (29.4 +/- 5.5 vs. 23.6 +/- 4.8 mmHg, p < 0.0001). In multiple regression analysis performed in HA, hyperemic velocity remained an independent predictor of FMD, after adjustment for baseline brachial artery diameter, room temperature and pulse pressure, explaining 8.7% of its variance. On the contrary, in C brachial artery diameter remained the only independent predictor of FMD, after adjustment for confounders. HA presented also lower carotid IMT than C (0.509 +/- 0.121 vs. 0.576 +/- 0.122 mm, p < 0.0001), higher diameter (6.98 +/- 1.07 vs. 6.81 +/- 0.85 mm, p = 0.004 adjusted for body surface area) and circumferential wall stress (67.6 +/- 13.1 vs. 56.4 +/- 16.0 kPa, p < 0.0001), while PWV was similar. O2 administration did not modify vascular variables. CONCLUSIONS: HA exhibit reduced NO-mediated dilation in the brachial artery, which is associated to reduced hyperemic response, indicating microcirculatory dysfunction. A peculiar carotid phenotype, characterized by reduced IMT and enlarged diameter, was also found. PMID- 25014035 TI - Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. AB - BACKGROUNDS: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of function (g-o-f) mutations in PCSK9 (PCSK9 E32K). OBJECTIVES: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K. METHODS: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. RESULTS: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93 +/- 2.95 mmol/L, mean +/- SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06 +/- 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 +/- 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero FH cases with PCSK9 E32K (7.21 +/- 1.55 mmol/L) were significantly lower than those (8.94 +/- 1.53 mmol/L) in the hetero-FH by LDLR mutations. CONCLUSIONS: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations. PMID- 25014037 TI - Use of microarrays in the clinical practice of pediatric rheumatology: the future is now? AB - PURPOSE OF REVIEW: Systems immunology is an integrative approach that leverages high throughput technologies as well as mathematical and computational tools to investigate complex immunologic diseases by looking at the state of a system on a comprehensive scale. Gene expression profiling, also known as transcriptomics, measures the expression level of mRNAs (transcripts) in a given cell population at a specific time. Over the past decade, several major gene expression discoveries have been made in pediatric rheumatology, most notably the alpha interferon signature of systemic lupus erythematosus and the interleukin-1 signature in systemic onset juvenile idiopathic arthritis. This article reviews these discoveries, their clinical implications and the recent associated literature. RECENT FINDINGS: Interferon-alpha has been exploited as a therapeutic target in lupus. Interleukin-1 blockade has been utilized to treat systemic onset juvenile idiopathic arthritis and related autoinflammatory diseases. SUMMARY: Current gene expression studies extend our understanding of the disease pathogenesis of lupus and systemic onset juvenile idiopathic arthritis as well as related conditions. This knowledge has translated to the bedside with implications for clinical practice and direct therapeutic targeting. PMID- 25014036 TI - Haemostatic factors, lipoproteins and long-term mortality in a multi-ethnic population of Gujarati, African-Caribbean and European origin. AB - OBJECTIVES: To examine the relations between haemostatic factors and lipoproteins with mortality in British Europeans, African-Caribbeans (AfC) and Gujarati Indians. METHODS: A prospective cohort study of 331 subjects (40-79 years), followed-up over 26 years for mortality. Apolipoprotein-A1 (Apo-A1), apolipoprotein-B (Apo-B), factor VII coagulant activity (FVIIc), fibrinogen and von Willebrand Factor (vWF) were measured at baseline in 118 Europeans, 100 AfC and 113 Gujaratis. Aortic pulse wave velocity (aPWV) was measured in 174 participants. RESULTS: 147 (44.4%) subjects died during a median of 24 years follow-up with 69 cardiovascular deaths. Women at baseline had higher, and AfC males the lowest FVIIc and Apo-A1 levels. Baseline age-sex and ethnicity adjusted FVIIc levels were higher in those who died (131.0 vs. 117.4%; P = 0.048). In similarly adjusted partial correlations, Apo-A1 was inversely related to arterial stiffness (rho = -0.23, P = 0.04). Over the 26 years follow-up, participants below the median (i.e. with lower concentration) of FVIIc, Fibrinogen, Apo-B and vWF had better survival rates than those with higher concentrations; those with higher concentrations of Apo-A1 had better survival. In Cox multivariable regression analyses including sex, ethnicity and aPWV, independently increased risk of all-cause mortality came only from SBP (per 5 mmHg); P = 0.011), age (per year); P < 0.0001 and FVIIc at 7% (per 10-unit; HR 1.07 (1.02, 1.12); P = 0.008. Separately, Apo-A1 (HR 0.12 (0.02, 0.75; P = 0.029) was independently associated with a very significant 88% reduction in all-cause mortality. CONCLUSIONS: Despite a relatively small sample size, long-term follow-up suggests an independent effect of the prothrombotic state (via FVIIc) and apo-A1 (a constituent of HDL) on mortality. PMID- 25014038 TI - The intersection of immune deficiency and autoimmunity. AB - PURPOSE OF REVIEW: Immune deficiency and autoimmunity have been recognized as cotravelers for decades. This clinically oriented review brings together our evolving mechanistic understanding to highlight associations of particular relevance to rheumatologists. RECENT FINDINGS: Conceptually, all autoimmunity derives from a loss of tolerance. This distinguishes it from autoinflammation in which the innate immune system is dysregulated without necessarily affecting tolerance. Studies have demonstrated the profound effects of signaling defects, apoptotic pathways and the ramifications of homeostatic proliferation on tolerance. This foundation has translated into an improved understanding of the specific associations of autoimmune diseases with immune deficiencies. This important foundation paves the way for personalized treatment strategies. SUMMARY: This review identifies critical mechanisms important to conceptualize the association of primary immune deficiencies and autoimmunity. It highlights a growing appreciation of the hidden single gene defects affecting T-cells within the group of patients with early-onset pleomorphic autoimmunity. PMID- 25014040 TI - One-pot synthesis of Au@Pd core-shell nanocrystals with multiple high- and low index facets and their high electrocatalytic performance. AB - Bimetallic nanocrystals (NCs) enclosed by high-surface energy facets have been of enormous interest due to their pronounced catalytic performance in numerous chemical and electrochemical reactions. However, it remains a significant challenge to develop a facile method to synthesize bimetallic NCs with high surface energy facets in the form of finely tuned structures due to the difficulties in manipulating the nucleation and growth kinetics of NCs in the presence of multiple metal precursors. In the present work, a facile one-pot aqueous synthesis method is developed for the production of bimetallic Au@Pd core shell NCs with an unusual truncated hexoctahedral (THOH) shape without pre synthesized seeds. The THOH Au@Pd NCs are bound by multiple high- and low-index facets. The formation of this unique structure is realized through co-reduction of Au and Pd precursors under precisely controlled kinetic conditions. The prepared THOH NCs exhibit a prominent electrocatalytic performance for ethanol oxidation, which is attributed to their characteristic structural features. This study significantly expands the understanding of NC growth and will lead to fabricating novel nanomaterials with desired morphologies and functions. PMID- 25014039 TI - The pathogenesis, diagnosis and treatment of lupus nephritis. AB - PURPOSE OF REVIEW: Renal involvement is a major cause of morbidity and mortality in systemic lupus erythematosus. In this review, we provide an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis. RECENT FINDINGS: Localized long-lived plasma cells have been identified as playing an important role in lupus nephritis. In addition, the roles of aberrant expression of microRNAs and proinflammatory cytokines have been explored. Early diagnosis is important for effective treatment and multiple biomarkers have been identified; however, none has been yet validated for clinical use. Biomarker panels may turn out to be more accurate than each individual component. Biologic agents for the treatment of lupus nephritis are being studied, including belimumab which was recently approved for nonrenal systemic lupus erythematosus. Rituximab has not proven itself in large, placebo-controlled trials, although it is still being used in refractory cases of lupus nephritis. SUMMARY: Lupus nephritis is a potentially devastating complication of systemic lupus erythematosus. Immune cells, cytokines, and epigenetic factors have all been recently implicated in lupus nephritis pathogenesis. These recent discoveries may enable a paradigm shift in the treatment of this complex disease, allowing the tailoring of treatment to target specific pathogenic mediators at specific points in time in the progression of disease. VIDEO ABSTRACT: PMID- 25014041 TI - Residential greenness and birth outcomes: evaluating the influence of spatially correlated built-environment factors. AB - BACKGROUND: Half the world's population lives in urban areas. It is therefore important to identify characteristics of the built environment that are beneficial to human health. Urban greenness has been associated with improvements in a diverse range of health conditions, including birth outcomes; however, few studies have attempted to distinguish potential effects of greenness from those of other spatially correlated exposures related to the built environment. OBJECTIVES: We aimed to investigate associations between residential greenness and birth outcomes and evaluate the influence of spatially correlated built environment factors on these associations. METHODS: We examined associations between residential greenness [measured using satellite-derived Normalized Difference Vegetation Index (NDVI) within 100 m of study participants' homes] and birth outcomes in a cohort of 64,705 singleton births (from 1999-2002) in Vancouver, British Columbia, Canada. We also evaluated associations after adjusting for spatially correlated built environmental factors that may influence birth outcomes, including exposure to air pollution and noise, neighborhood walkability, and distance to the nearest park. RESULTS: An interquartile increase in greenness (0.1 in residential NDVI) was associated with higher term birth weight (20.6 g; 95% CI: 16.5, 24.7) and decreases in the likelihood of small for gestational age, very preterm (< 30 weeks), and moderately preterm (30-36 weeks) birth. Associations were robust to adjustment for air pollution and noise exposures, neighborhood walkability, and park proximity. CONCLUSIONS: Increased residential greenness was associated with beneficial birth outcomes in this population-based cohort. These associations did not change after adjusting for other spatially correlated built environment factors, suggesting that alternative pathways (e.g., psychosocial and psychological mechanisms) may underlie associations between residential greenness and birth outcomes. PMID- 25014042 TI - Cation type specific cell remodeling regulates attachment strength. AB - Single-molecule experiments indicate that integrin affinity is cation-type dependent, but in spread cells integrins are engaged in complex focal adhesions (FAs), which can also regulate affinity. To better understand cation-type dependent adhesion in fully spread cells, we investigated attachment strength by application of external shear. While cell attachment strength is indeed modulated by cations, the regulation of integrin-mediated adhesion is also exceedingly complex, cell specific, and niche dependent. In the presence of magnesium only, fibroblasts and fibrosarcoma cells remodel their cytoskeleton to align in the direction of applied shear in an alpha5-integrin/fibronectin-dependent manner, which allows them to withstand higher shear. In the presence of calcium or on collagen in modest shear, fibroblasts undergo piecewise detachment but fibrosarcoma cells exhibit increased attachment strength. These data augment the current understanding of force-mediated detachment by suggesting a dynamic interplay in situ between cell adhesion and integrins depending on local niche cation conditions. PMID- 25014043 TI - Magnetic stimulation of the cerebellum. Moving towards the clinic. PMID- 25014044 TI - Diabetes mellitus may induce cardiovascular disease by decreasing neuroplasticity. AB - Neuroplasticity has been defined "the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections". The nervous system monitors and coordinates internal organ function. Thus neuroplasticity may be associated with the pathogenesis of other diseases besides neuropsychiatric diseases. Decreased neuroplasticity is associated with cardiovascular disease (CVD) and a disease related to decreased neuroplasticity may confer a greater CVD risk. Diabetes mellitus (DM) is related to CVD and DM induces decreased neuroplasticity, which is manifested as depression, Alzheimer's disease and diabetic neuropathy. Therefore we conclude that DM may induce CVD by decreasing neuroplasticity. PMID- 25014045 TI - Arm weight support training improves functional motor outcome and movement smoothness after stroke. AB - The aim of this study was to compare the effectiveness in acute stroke patients of a rehabilitation program performed with or without an arm weight support device. Twenty-eight acute, first-ever unilateral stroke patients were enrolled in a single-blind, randomized controlled trial. Clinical evaluation included Fugl Mayer Assessment, Functional Independence Measure and kinematic analysis [maximum and mean hand velocity, maximum range of motion (Max RoM), normalized jerk (NJ)]. Patients received 12 daily 30-minute sessions (6/week) of additional upper limb therapy performed using an arm weight support device (study group) or additional traditional physiotherapy (control group). The patients were evaluated on admission and at the end of the rehabilitation intervention. The two groups were clinically comparable on admission (p>0.05). Both groups showed significant improvements in clinical scale scores and in Max RoM in flexionextension, while only the study group showed improvements in NJ and in Max RoM in adductionabduction. Rehabilitation training using an arm weight support device appears to be a useful method to supplement conventional therapy in acute stroke patients, increasing smoothness of movement and motor function. PMID- 25014046 TI - Liver cirrhosis in patients newly diagnosed with neurological phenotype of Wilson's disease. AB - Wilson's disease (WD) can manifest itself in different clinical forms, the neurological and hepatic ones being the most common. It is suggested that neurological signs and psychiatric symptoms develop secondary to liver involvement. The aim of this study was to characterize the liver disease in patients newly diagnosed with the neurological form of WD. Treatment-naive patients diagnosed with WD were classified into three phenotypic groups: hepatic, neurological and pre-symptomatic. Liver involvement was ascertained through surrogate markers: abdominal ultrasound and laboratory parameters. In addition, study participants were screened for esophageal varices. Of 53 consecutively diagnosed WD patients, 23 individuals (43.4%) had a predominantly neurological presentation. In this group, cirrhosis was diagnosed in 11 (47.8%) subjects. Esophageal varices were present in all of them. In every patient with neurological WD, there was at least one sign of hepatic disease on ultrasound examination, indicating universal presence of liver involvement. The prevalence of surrogate signs of cirrhosis was similar in patients with the neurological and in those with the hepatic phenotype. PMID- 25014047 TI - An observational retrospective/horizontal study to compare oxygen-ozone therapy and/or global postural re-education in complicated chronic low back pain. AB - Acute low back pain (LBP) is the fifth most common reason for physician visits and about nine out of ten adults experience back pain at some point in their life. In a large number of patients LBP is associated with disc herniation (DH). Recently, oxygen-ozone (O2O3) therapy has been used successfully in the treatment of LBP, reducing pain after the failure of other conservative treatments. The aim of this study was to assess the effects of O2O3 therapy in back pain rehabilitation, comparing three groups of patients suffering from chronic back pain associated with DH submitted to three different treatments: intramuscular O2O3 infiltrations, global postural An observational retrospective/horizontal study to compare oxygen-ozone therapy and/or global postural re-education in complicated chronic low back pain re-education (GPR), or a combination of the two (O2O3+GPR). The data show that pain severity before treatment was significantly lower in the patients treated with GPR alone (VAS score 7.4) than in the O2O3+GPR patients (VAS score 8.5) and the O2O3 patients (VAS score 8.6). At the end of treatment, pain severity was lower in the O2O3 patients than in the GPR-alone patients. After some years of follow-up only the difference between O2O3+GPR and GPR-alone remained significant. PMID- 25014048 TI - Cerebellar theta burst stimulation in stroke patients with ataxia. AB - Evidence for effective improvement of the symptoms of cerebellar stroke is still limited. Here, we investigated the effects of repetitive transcranial magnetic stimulation (rTMS) applied over the injured cerebellar hemisphere in six patients with posterior circulation stroke. We applied a two-week course of cerebellar intermittent theta burst stimulation (iTBS). Before and after the iTBS treatment, paired-pulse TMS methods were used to explore: i) the functional connectivity between the cerebellar hemisphere and the contralateral primary motor cortex (M1), by means of the cerebellar brain inhibition (CBI) protocol; and ii) the intracortical circuits in the contralateral M1, by means of the short intra cortical inhibition (SICI) and intra-cortical facilitation (ICF) protocols. Patients were also evaluated using the Modified International Cooperative Ataxia Rating Scale (MICARS). Cerebellar iTBS induced a decrease in CBI and an increase in ICF at an interstimulus interval of 15 msec. These neurophysiological changes were paralleled by a clinical improvement, shown by the MICARS posture and gait subscale scores. Cerebellar iTBS could be a promising tool to promote recovery of cerebellar stroke patients. PMID- 25014049 TI - How to assess abstract conceptual knowledge: construction, standardization and validation of a new battery of semantic memory tests. AB - The neuropsychological investigation of semantic memory has mainly focused on concrete concepts, while abstract concepts have been relatively neglected. We describe a new battery for assessing abstract concepts in brain-damaged patients. The battery includes three different tests: an association task, a multiplechoice naming-to-description task and a sentence completion task. The three tasks are based on the same 40 stimuli belonging to different categories of abstract concepts and they are tightly controlled for variables that can account for quantitative differences between abstract concepts (i.e. concreteness, imageability, context availability, familiarity, age of acquisition, mode of acquisition, emotional valence and arousal). The three tasks showed high reliability. Normative data were collected from 108 healthy Italian adults. To assess its sensitivity, the battery was administered to 13 patients with probable Alzheimer's disease who performed worse than matched controls. Significant correlations were also found between the tests and other semantic memory tests, supporting the validity of the battery. PMID- 25014050 TI - Elman neural network for the early identification of cognitive impairment in Alzheimer's disease. AB - Early detection of dementia can be useful to delay progression of the disease and to raise awareness of the condition. Alterations in temporal and spatial EEG markers have been found in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Herein, we propose an automatic recognition method of cognitive impairment evaluation based on EEG analysis using an artificial neural network (ANN) combined with a genetic algorithm (GA). The EEGs of 43 AD and MCI patients (aged between 62 and 88 years) were recorded, analyzed and correlated with their MMSE scores. Quantitative EEGs were calculated using discrete wavelet transform. The data obtained were analyzed by the means of the combined use of ANN and GA to determine the degree of cognitive impairment. The good recognition rate of ANN fed with these inputs suggests that the combined GA/ANN approach may be useful for early detection of AD and could be a valuable tool to support physicians in clinical practice. PMID- 25014051 TI - Hemifacial hyperhidrosis associated with ipsilateral/contralateral cervical disc herniation myelopathy. Functional considerations on how compression pattern determines the laterality. AB - Sweating is an important mechanism for ensuring constant thermoregulation, but hyperhidrosis may be disturbing. We present five cases of hemifacial hyperhidrosis as a compensatory response to an/hypohidrosis caused by cervical disc herniation. All the patients complained of hemifacial hyperhidrosis, without anisocoria or blepharoptosis. Sweat function testing and thermography confirmed hyperhidrosis of hemifacial and adjacent areas. Neck MRI showed cervical disc herniation. Three of the patients had lateral compression with welldemarcated hypohidrosis below the hyperhidrosis on the same side as the cervical lesion. The rest had paramedian compression with poorly demarcated hyperhidrosis and hypohidrosis on the contralateral side. Although MRI showed no intraspinal pathological signal intensity, lateral dural compression might influence the circulation to the sudomotor pathway, and paramedian compression might influence the ipsilateral sulcal artery, which perfuses the sympathetic descending pathway and the intermediolateral nucleus. Sweat function testing and thermography should be performed to determine the focus of the hemifacial hyperhidrosis, and the myelopathy should be investigated on both sides. PMID- 25014053 TI - Broadly tunable monolithic room-temperature terahertz quantum cascade laser sources. AB - Electrically pumped room-temperature semiconductor sources of tunable terahertz radiation in 1-5 THz spectral range are highly desired to enable compact instrumentation for THz sensing and spectroscopy. Quantum cascade lasers with intra-cavity difference-frequency generation are currently the only room temperature electrically pumped semiconductor sources that can operate in the entire 1-5 THz spectral range. Here we demonstrate that this technology is suitable to implementing monolithic room-temperature terahertz tuners with broadband electrical control of the emission frequency. Experimentally, we demonstrate ridge waveguide devices electrically tunable between 3.44 and 4.02 THz. PMID- 25014052 TI - Epilepsy and phenylketonuria: a case description and EEG-fMRI findings. AB - Phenylketonuria (PKU) is characterized by phenylalanine accumulation due to phenylalanine hydroxylase deficiency. Up to 50% of PKU patients experience seizures. We evaluated an adult PKU patient who suffered from absences and primarily generalized tonicclonic seizures, associated with generalized spikeand wave discharges (GSWs) on EEG. An analysis of blood oxygenation level-dependent (BOLD) signal changes during interictal epileptiform discharges showed early activation of the left perirolandic cortex followed by a BOLD signal decrease within cortical regions belonging to the default mode network and left frontoparietal cortex. Moreover, deactivation of the head of the right caudate nucleus and the left thalamus was observed. The fMRI pattern observed in our patient during GSWs is similar but not identical to that observed in idiopathic generalized epilepsy, suggesting different neurophysiological mechanisms. This is the first description of BOLD-fMRI patterns in a PKU patient with epilepsy. Similar studies in more patients might help to uncover the pathophysiology of seizures in this disease. PMID- 25014054 TI - Consumption of Bt rice pollen containing Cry1C or Cry2A protein poses a low to negligible risk to the silkworm Bombyx mori (Lepidoptera: Bombyxidae). AB - By consuming mulberry leaves covered with pollen from nearby genetically engineered, insect-resistant rice lines producing Cry proteins derived from Bacillus thuringiensis (Bt), larvae of the domestic silkworm, Bombyx mori (Linnaeus) (Lepidoptera: Bombyxidae), could be exposed to insecticidal proteins. Laboratory experiments were conducted to assess the potential effects of Cry1C- or Cry2A-producing transgenic rice (T1C-19, T2A-1) pollen on B. mori fitness. In a short-term assay, B. mori larvae were fed mulberry leaves covered with different densities of pollen from Bt rice lines or their corresponding near isoline (control) for the first 3 d and then were fed mulberry leaves without pollen. No effect was detected on any life table parameter, even at 1800 pollen grains/cm(2) leaf, which is much higher than the mean natural density of rice pollen on leaves of mulberry trees near paddy fields. In a long-term assay, the larvae were fed Bt and control pollen in the same way but for their entire larval stage (approximately 27 d). Bt pollen densities >= 150 grains/cm(2) leaf reduced 14-d larval weight, increased larval development time, and reduced adult eclosion rate. ELISA analyses showed that 72.6% of the Cry protein was still detected in the pollen grains excreted with the feces. The low exposure of silkworm larvae to Cry proteins when feeding Bt rice pollen may be the explanation for the relatively low toxicity detected in the current study. Although the results demonstrate that B. mori larvae are sensitive to Cry1C and Cry2A proteins, the exposure levels that harmed the larvae in the current study are far greater than natural exposure levels. We therefore conclude that consumption of Bt rice pollen will pose a low to negligible risk to B. mori. PMID- 25014055 TI - A co-adaptive brain-computer interface for end users with severe motor impairment. AB - Co-adaptive training paradigms for event-related desynchronization (ERD) based brain-computer interfaces (BCI) have proven effective for healthy users. As of yet, it is not clear whether co-adaptive training paradigms can also benefit users with severe motor impairment. The primary goal of our paper was to evaluate a novel cue-guided, co-adaptive BCI training paradigm with severely impaired volunteers. The co-adaptive BCI supports a non-control state, which is an important step toward intuitive, self-paced control. A secondary aim was to have the same participants operate a specifically designed self-paced BCI training paradigm based on the auto-calibrated classifier. The co-adaptive BCI analyzed the electroencephalogram from three bipolar derivations (C3, Cz, and C4) online, while the 22 end users alternately performed right hand movement imagery (MI), left hand MI and relax with eyes open (non-control state). After less than five minutes, the BCI auto-calibrated and proceeded to provide visual feedback for the MI task that could be classified better against the non-control state. The BCI continued to regularly recalibrate. In every calibration step, the system performed trial-based outlier rejection and trained a linear discriminant analysis classifier based on one auto-selected logarithmic band-power feature. In 24 minutes of training, the co-adaptive BCI worked significantly (p = 0.01) better than chance for 18 of 22 end users. The self-paced BCI training paradigm worked significantly (p = 0.01) better than chance in 11 of 20 end users. The presented co-adaptive BCI complements existing approaches in that it supports a non-control state, requires very little setup time, requires no BCI expert and works online based on only two electrodes. The preliminary results from the self paced BCI paradigm compare favorably to previous studies and the collected data will allow to further improve self-paced BCI systems for disabled users. PMID- 25014056 TI - Effect of pitavastatin on vascular reactivity in hypercholesterolemic rabbits. AB - BACKGROUND: Pitavastatin is the newest statin available in Brazil and likely the one with fewer side effects. Thus, pitavastatin was evaluated in hypercholesterolemic rabbits in relation to its action on vascular reactivity. OBJECTIVE: To assess the lowest dose of pitavastatin necessary to reduce plasma lipids, cholesterol and tissue lipid peroxidation, as well as endothelial function in hypercholesterolemic rabbits. METHODS: Thirty rabbits divided into six groups (n = 5): G1 - standard chow diet; G2 - hypercholesterolemic diet for 30 days; G3 - hypercholesterolemic diet and after the 16th day, diet supplemented with pitavastatin (0.1 mg); G4 - hypercholesterolemic diet supplemented with pitavastatin (0.25 mg); G5 - hypercholesterolemic diet supplemented with pitavastatin (0.5 mg); G6 - hypercholesterolemic diet supplemented with pitavastatin (1.0 mg). After 30 days, total cholesterol, HDL, triglycerides, glucose, creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) were measured and LDL was calculated. In-depth anesthesia was performed with sodium thiopental and aortic segments were removed to study endothelial function, cholesterol and tissue lipid peroxidation. The significance level for statistical tests was 5%. RESULTS: Total cholesterol and LDL were significantly elevated in relation to G1. HDL was significantly reduced in G4, G5 and G6 when compared to G2. Triglycerides, CK, AST, ALT, cholesterol and tissue lipid peroxidation showed no statistical difference between G2 and G3-G6. Significantly endothelial dysfunction reversion was observed in G5 and G6 when compared to G2. CONCLUSION: Pitavastatin starting at a 0.5 mg dose was effective in reverting endothelial dysfunction in hypercholesterolemic rabbits. PMID- 25014058 TI - Malaria and vascular endothelium. AB - Involvement of the cardiovascular system in patients with infectious and parasitic diseases can result from both intrinsic mechanisms of the disease and drug intervention. Malaria is an example, considering that the endothelial injury by Plasmodium-infected erythrocytes can cause circulatory disorders. This is a literature review aimed at discussing the relationship between malaria and endothelial impairment, especially its effects on the cardiovascular system. We discuss the implications of endothelial aggression and the interdisciplinarity that should guide the malaria patient care, whose acute infection can contribute to precipitate or aggravate a preexisting heart disease. PMID- 25014057 TI - Functional vascular study in hypertensive subjects with type 2 diabetes using losartan or amlodipine. AB - BACKGROUND: Antihypertensive drugs are used to control blood pressure (BP) and reduce macro- and microvascular complications in hypertensive patients with diabetes. OBJECTIVES: The present study aimed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan. METHODS: Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were randomly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine (5 mg/day) or losartan (100 mg/day). Patient evaluation included BP measurement, ambulatory BP monitoring, and assessment of vascular parameters using applanation tonometry, pulse wave velocity (PWV), and flow-mediated dilation (FMD) of the brachial artery. RESULTS: A total of 42 patients were evaluated (21 in each group), with a predominance of women (71%) in both groups. The mean age of the patients in both groups was similar (amlodipine group: 54.9 +/- 4.5 years; losartan group: 54.0 +/ 6.9 years), with no significant difference in the mean BP [amlodipine group: 145 +/- 14 mmHg (systolic) and 84 +/- 8 mmHg (diastolic); losartan group: 153 +/- 19 mmHg (systolic) and 90 +/- 9 mmHg (diastolic)]. The augmentation index (30% +/- 9% and 36% +/- 8%, p = 0.025) and augmentation pressure (16 +/- 6 mmHg and 20 +/- 8 mmHg, p = 0.045) were lower in the amlodipine group when compared with the losartan group. PWV and FMD were similar in both groups. CONCLUSIONS: Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan. However, the use of losartan may be associated with independent vascular reactivity to the pressor effect. PMID- 25014059 TI - Resistance training after myocardial infarction in rats: its role on cardiac and autonomic function. AB - BACKGROUND: Although resistance exercise training is part of cardiovascular rehabilitation programs, little is known about its role on the cardiac and autonomic function after myocardial infarction. OBJECTIVE: To evaluate the effects of resistance exercise training, started early after myocardial infarction, on cardiac function, hemodynamic profile, and autonomic modulation in rats. METHODS: Male Wistar rats were divided into four groups: sedentary control, trained control, sedentary infarcted and trained infarcted rats. Each group with n = 9 rats. The animals underwent maximum load test and echocardiography at the beginning and at the end of the resistance exercise training (in an adapted ladder, 40% to 60% of the maximum load test, 3 months, 5 days/week). At the end, hemodynamic, baroreflex sensitivity and autonomic modulation assessments were made. RESULTS: The maximum load test increased in groups trained control (+32%) and trained infarcted (+46%) in relation to groups sedentary control and sedentary infarcted. Although no change occurred regarding the myocardial infarction size and systolic function, the E/A ratio (-23%), myocardial performance index (-39%) and systolic blood pressure (+6%) improved with resistance exercise training in group trained infarcted. Concomitantly, the training provided additional benefits in the high frequency bands of the pulse interval (+45%), as well as in the low frequency band of systolic blood pressure (-46%) in rats from group trained infarcted in relation to group sedentary infarcted. CONCLUSION: Resistance exercise training alone may be an important and safe tool in the management of patients after myocardial infarction, considering that it does not lead to significant changes in the ventricular function, reduces the global cardiac stress, and significantly improves the vascular and cardiac autonomic modulation in infarcted rats. PMID- 25014060 TI - Validation of the Killip-Kimball classification and late mortality after acute myocardial infarction. AB - BACKGROUND: The classification or index of heart failure severity in patients with acute myocardial infarction (AMI) was proposed by Killip and Kimball aiming at assessing the risk of in-hospital death and the potential benefit of specific management of care provided in Coronary Care Units (CCU) during the decade of 60. OBJECTIVE: To validate the risk stratification of Killip classification in the long-term mortality and compare the prognostic value in patients with non-ST segment elevation MI (NSTEMI) relative to patients with ST-segment elevation MI (STEMI), in the era of reperfusion and modern antithrombotic therapies. METHODS: We evaluated 1906 patients with documented AMI and admitted to the CCU, from 1995 to 2011, with a mean follow-up of 05 years to assess total mortality. Kaplan Meier (KM) curves were developed for comparison between survival distributions according to Killip class and NSTEMI versus STEMI. Cox proportional regression models were developed to determine the independent association between Killip class and mortality, with sensitivity analyses based on type of AMI. RESULTS: The proportions of deaths and the KM survival distributions were significantly different across Killip class >1 (p <0.001) and with a similar pattern between patients with NSTEMI and STEMI. Cox models identified the Killip classification as a significant, sustained, consistent predictor and independent of relevant covariables (Wald chi2 16.5 [p = 0.001], NSTEMI) and (Wald chi2 11.9 [p = 0.008], STEMI). CONCLUSION: The Killip and Kimball classification performs relevant prognostic role in mortality at mean follow-up of 05 years post-AMI, with a similar pattern between NSTEMI and STEMI patients. PMID- 25014061 TI - Plasmonic micro lens for extraordinary transmission of broadband light. AB - Extraordinary transmittance and focusing of light in quasi far field region using miniaturized optical devices is a daunting task. A polarization independent, broadband, planar metallic transmissive micro aperture capable of achromatically focusing visible light in quasi far field region is proposed. The calculated enhancement factor of transmission efficiency was about ~2.2. The total transmission after the aperture is about 60%. This high throughput focusing device will open new avenues for focusing electromagnetic energy in the wide area of sensors and energy concentration. PMID- 25014062 TI - FeNO as a predictor of asthma control improvement after starting inhaled steroid treatment. AB - INTRODUCTION: The fraction of NO in exhaled air (FeNO) is a marker of inflammation in asthma. The aim of the present study was to assess, in a real world setting, whether only high (?50 ppb) FeNO levels predict improvement in asthma control when being treated with inhaled corticosteroids (ICS), as suggested by current guidelines on the clinical use of FeNO. METHODS: FeNO and asthma control were assessed in a retrospective observational study in 153 non smoking, steroid-naive, adult subjects with asthma with a mean age of 40 years both before and after 6 weeks (median follow-up time) of treatment with 500 MUg beclomethasone (median). RESULTS: Having at the initial visit intermediate FeNO (?25 and <50 ppb) and high FeNO (?50 ppb), compared to normal FeNO (<25 ppb), were associated with a larger proportion of subjects achieving an improvement of Asthma Control Questionnaire (ACQ) score with ?1 (78% and 67% vs 43%, p<0.05) or both ?1 improvement and asthma control at follow-up (31% and 37% vs 4%, p<0.05). These associations were consistent in multiple logistic regression models after adjustments for confounders. CONCLUSIONS: It is not only high but also intermediate FeNO levels that are associated with a significant improvement in asthma control after starting ICS treatment. This challenges current clinical guidelines stating that only high FeNO levels predict response to ICS treatment. PMID- 25014063 TI - Impact of presenting rhythm on short- and long-term neurologic outcome in comatose survivors of cardiac arrest treated with therapeutic hypothermia. AB - OBJECTIVES: To compare short- and long-term neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia presenting with nonshockable versus shockable initial rhythms. DESIGN: Retrospective cohort study. SETTING: Emergency department and ICU of an academic hospital. PATIENTS: One hundred twenty-three consecutive post-out-of hospital cardiac arrest adults (57 nonshockable rhythms, 66 shockable rhythms) treated with therapeutic hypothermia between 2006 and 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were collected from electronic health records. Neurologic outcomes were dichotomized by Cerebral Performance Category at discharge and 6- to 12-month follow-up and analyzed via multivariable logistic regressions. Groups were similar, except nonshockable rhythm patients were more likely to have a history of diabetes mellitus (p = 0.01), be dialysis dependent (p = 0.01), and not have bystander cardiopulmonary resuscitation (p = 0.05). At discharge, 3 of 57 patients (5%) with nonshockable rhythm versus 28 of 66 (42%) with shockable rhythm had a favorable outcome (unadjusted odds ratio, 0.08; 95% CI, 0.02-0.3; adjusted odds ratio, 0.1; 95% CI, 0.03-0.4). At follow-up, 4 of 55 patients (7%) versus 29 of 60 (48%) with nonshockable rhythm and shockable rhythm, respectively, had a favorable Cerebral Performance Category (odds ratio, 0.08; 95% CI, 0.03-0.3; adjusted odds ratio, 0.09; 95% CI, 0.09-0.3). Among those surviving hospitalization, favorable neurologic outcome was more likely at long term follow-up than at hospital discharge for both groups (odds ratio, 2.5; 95% CI, 1.3-4.7; adjusted odds ratio, 2.9; 95% CI, 1.4-6.2). No significant interaction between changes in neurologic status over time and presenting rhythm was seen (p = 0.93). CONCLUSIONS: These data indicate an association between initial nonshockable rhythm and significantly worse short- and long-term outcomes in patients treated with mild therapeutic hypothermia. Among survivors, neurologic status significantly improved over time for all patients and shockable rhythm patients and tended to improve over time for the small number of nonshockable rhythm patients who survived beyond hospitalization. No significant interaction between changes in neurologic status over time and presenting rhythm was seen. PMID- 25014064 TI - A multicenter study of the point prevalence of drug-induced hypotension in the ICU. AB - OBJECTIVE: To determine the point prevalence of drug-induced hypotension episodes in critically ill patients, to assess the episodes resulting from error, and to describe how episodes are treated. DESIGN: Multicenter observational, 24-hour snapshot study. SETTING: Forty-seven ICUs in 27 institutions located in the United States, Canada, and Singapore. PATIENTS: A total of 688 ICU patients were evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were included in the study if they had an episode of hypotension in the 24 hours prior to the clinical pharmacists' evaluation. The definition for a hypotensive episode is either a systolic blood pressure less than 90 mm Hg or a decrease in systolic blood pressure of 30 mm Hg over a 2-hour period. Each episode of unintentional hypotension was assessed for suspected drug-related causes. When a drug-related cause was suspected, an objective assessment tool, the modified Kramer, was used to determine causality. A score of at least "possible" was considered drug induced, referred to as a "drug-related hazardous condition." A drug-related hazardous condition is the temporal gap (intermediate stage) between the identification of an adverse drug reaction and the subsequent onset of drug induced injury, known as an "adverse drug event." Drug-induced episodes were evaluated for medication errors and treatment. One hundred fifty-eight patients experienced 204 hypotensive episodes that were considered unintentional and drug related. Common drugs implicated included propofol, fentanyl, metoprolol, lorazepam, hydralazine, and furosemide. A total of 54 episodes (26.5%) resulted from medication errors. Common error types were improper dose/quantity (46%) and prescribing (25%). A total of 56.9% episodes were treated. CONCLUSIONS: Many hypotensive episodes in the ICU are drug related and require treatment. A substantial portion of these episodes result from errors and are therefore preventable. This presents opportunities to improve prescribing including optimizing drug dosing to avoid possible patient harm from drug-induced hypotension. PMID- 25014066 TI - The morbidity and mortality conference in PICUs in the United States: a national survey. AB - OBJECTIVE: Determine how many morbidity and mortality conferences in PICUs across the United States conform to key elements of medical incident analysis. DESIGN: Web-based cross-sectional survey open from March to September 2013. SETTING: Seventy-five PICUs with regular morbidity and mortality conferences in the United States identified by cross-referencing publicly available databases. PARTICIPANTS: Multidisciplinary PICU staff who attend the PICU morbidity and mortality conference. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty four identified PICUs of 206 PICUs contacted had at least one respondent, with a 40.8% PICU-level response rate. The PICUs had a mean of three respondents (SD, 2.5; range, 1-13), with 45 of 84 (54%) having greater than one respondent. There were 305 total respondents to the survey, of which 220 of 300 (73%) self identified as attending physicians and 47 of 300 (16%) as fellows. Four PICUs with only one respondent were excluded due to poor question response rates. Forty nine of eighty-three PICUs (59%) had fellowship training programs. Five of eighty three PICUs (6%) had no regular morbidity and mortality conference. Among 75 PICUs with regular morbidity and mortality conferences, morbidity and mortality conference process and structure characteristics varied widely. Among PICUs with greater than one respondent, when asked about morbidity and mortality conference conformity to each of the three key elements of medical incident analysis, 62-68% had intra-PICU disagreement among respondents. Fifteen of thirty-seven PICUs with greater than one respondent (41%) had intra-PICU disagreement on all three key elements. CONCLUSIONS: Morbidity and mortality conferences varied widely in structure and process across PICUs in the United States. There was marked disagreement as to whether the morbidity and mortality conference conforms to key elements of medical incident analysis, which might itself be revealing a lack of morbidity and mortality conference structure and consistency. Future research is needed to identify barriers to the use of the morbidity and mortality conference as a patient safety improvement tool and to test strategies for effective implementation linked to improved patient outcomes. PMID- 25014065 TI - Substance P mediates reduced pneumonia rates after traumatic brain injury. AB - OBJECTIVES: Traumatic brain injury results in significant morbidity and mortality and is associated with infectious complications, particularly pneumonia. However, whether traumatic brain injury directly impacts the host response to pneumonia is unknown. The objective of this study was to determine the nature of the relationship between traumatic brain injury and the prevalence of pneumonia in trauma patients and investigate the mechanism of this relationship using a murine model of traumatic brain injury with pneumonia. DESIGN: Data from the National Trauma Data Bank and a murine model of traumatic brain injury with postinjury pneumonia. SETTING: Academic medical centers in Cincinnati, OH, and Boston, MA. PATIENTS/SUBJECTS: Trauma patients in the National Trauma Data Bank with a hospital length of stay greater than 2 days, age of at least 18 years at admission, and a blunt mechanism of injury. Subjects were female ICR mice 8-10 weeks old. INTERVENTIONS: Administration of a substance P receptor antagonist in mice. MEASUREMENTS AND MAIN RESULTS: Pneumonia rates were measured in trauma patients before and after risk adjustment using propensity scoring. In addition, survival and pulmonary inflammation were measured in mice undergoing traumatic brain injury with or without pneumonia. After risk adjustment, we found that traumatic brain injury patients had significantly lower rates of pneumonia compared to blunt trauma patients without traumatic brain injury. A murine model of traumatic brain injury reproduced these clinical findings with mice subjected to traumatic brain injury demonstrating increased bacterial clearance and survival after induction of pneumonia. To determine the mechanisms responsible for this improvement, the substance P receptor was blocked in mice after traumatic brain injury. This treatment abrogated the traumatic brain injury associated increases in bacterial clearance and survival. CONCLUSIONS: The data demonstrate that patients with traumatic brain injury have lower rates of pneumonia compared to non-head-injured trauma patients and suggest that the mechanism of this effect occurs through traumatic brain injury-induced release of substance P, which improves innate immunity to decrease pneumonia. PMID- 25014069 TI - Insights into the interactions of CO2 with amines: a DFT benchmark study. AB - The interaction between CO2 and 1,2-diaminoethane was computed using pure and hybrid density functionals. The CAM-B3LYP and wB97X-D functionals using a triple zeta basis set that includes diffuse and polarization functions are the best functionals for calculating the relative energies of the zwitterion intermediate compared to a coupled-cluster with a single, double and non-iterative triple excitation (CCSD(T)) approach extrapolated to a complete basis set limit. With the two functionals and the triple-zeta basis set, the zwitterion is 1.70 kcal mol(-1) less stable than the reactants, and close to 1.63 kcal mol(-1) computed using the CCSD(T) approach. The inclusion of vibrational and thermal corrections and of entropic effects increases the relative energy of the zwitterion to 14.7 kcal mol(-1). Bending of the CO2 geometry increases its acidity due to a 1.09 eV reduction in the LUMO energy. Calculation of the CO2 interaction energy with a set of amines revealed that the interaction energies show a high correlation with their basicities, with the stronger bases stabilizing the zwitterion. For the most basic amine computed (3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine), the Gibbs free energy of the zwitterion is 15.8 kcal mol(-1) lower than the reactants. Therefore, for this highly basic amine, the zwitterion may have a longer lifetime, in contrast to 2-aminoethanol (MEA), where it is only a transient species. PMID- 25014067 TI - Activation of hypoxia-inducible factor-1alpha in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion. AB - OBJECTIVE: Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1alpha is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1alpha plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion. DESIGN: Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia reporter mouse model and type 2 cell-specific hypoxia inducible factor-1alpha conditional knockout mice. The mice were killed at 5-, 24 , 48-, and 72-hour time points, and the extent of systemic and tissue hypoxia was assessed. In addition, injury and inflammation were assessed by measuring bronchoalveolar lavage cells (flow cytometry and cytospin), albumin (permeability injury), and cytokines (inflammation). Isolated type 2 cells from the hypoxia inducible factor-1alpha conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-kappaB and interleukin-1beta as intermediates in this interaction was studied. RESULTS: Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1alpha from lung samples was observed as early as 60 minutes, following the insult. The extent of lung injury following lung contusion was significantly reduced in conditional knockout mice at all the time points, when compared with the wild-type littermate mice. Release of proinflammatory cytokines, such as interleukin-1beta, interleukin-6, macrophage inflammatory protein-2, and keratinocyte chemoattractant, was significantly lower in conditional knockout mice. These actions are in part mediated through nuclear factor-kappaB. Hypoxia-inducible factor-1alpha in lung epithelial cells was shown to regulate interleukin-1beta promoter activity. CONCLUSION: Activation of hypoxia-inducible factor-1alpha in type 2 cell is a major driver of acute inflammation following lung contusion. PMID- 25014068 TI - Faster sound stream segmentation in musicians than in nonmusicians. AB - The musician's brain is considered as a good model of brain plasticity as musical training is known to modify auditory perception and related cortical organization. Here, we show that music-related modifications can also extend beyond motor and auditory processing and generalize (transfer) to speech processing. Previous studies have shown that adults and newborns can segment a continuous stream of linguistic and non-linguistic stimuli based only on probabilities of occurrence between adjacent syllables, tones or timbres. The paradigm classically used in these studies consists of a passive exposure phase followed by a testing phase. By using both behavioural and electrophysiological measures, we recently showed that adult musicians and musically trained children outperform nonmusicians in the test following brief exposure to an artificial sung language. However, the behavioural test does not allow for studying the learning process per se but rather the result of the learning. In the present study, we analyze the electrophysiological learning curves that are the ongoing brain dynamics recorded as the learning is taking place. While musicians show an inverted U shaped learning curve, nonmusicians show a linear learning curve. Analyses of Event-Related Potentials (ERPs) allow for a greater understanding of how and when musical training can improve speech segmentation. These results bring evidence of enhanced neural sensitivity to statistical regularities in musicians and support the hypothesis of positive transfer of training effect from music to sound stream segmentation in general. PMID- 25014070 TI - Association of body mass index with all-cause and cardiovascular disease mortality in the elderly. AB - OBJECTIVES: To evaluate the associations of body mass index (BMI) with all-cause, cardiovascular disease (CVD), and expanded CVD mortality in the elderly. DESIGN: Observational cohort study. SETTING: Annual physical examination program for the elderly from 2006 to 2010. PARTICIPANTS: We included 77,541 Taipei residents aged >= 65 years (39,365 men and 38,176 women). MEASUREMENTS: BMI was categorized as underweight (BMI<18.5), normal weight (18.5 <= BMI<25), overweight (25 <= BMI<30), grade 1 obesity (30 <= BMI<35), or grade 2-3 obesity (BMI >= 35). Mortality was ascertained by national death files. RESULTS: Underweight (hazard ratios [HRs] of all-cause, CVD, and expanded CVD mortality: 1.92, 1.74, and 1.77, respectively), grade 2-3 obesity (HRs: 1.59, 2.36, and 2.22, respectively), older age, male sex, smoking, and high fasting blood sugar were significant predictors of mortality. Meanwhile, being married/cohabitating, higher education, alcohol consumption, more regular exercise, and high total cholesterol were inversely associated with mortality. Multivariate stratified subgroup analyses verified smokers (HRs of all-cause, CVD, and expanded CVD mortality: 3.25, 10.71, and 7.86, respectively, for grade 2-3 obesity), the high triglyceride group (HRs: 5.82, 10.99, and 14.22, respectively for underweight), and patients with 3-4 factors related to metabolic syndrome (HRs: 4.86, 12.72, and 11.42, respectively, for underweight) were associated with mortality. CONCLUSION: The associations of BMI with all-cause, CVD, expanded CVD mortality in the elderly are represented by U-shaped curves, suggesting unilateral promotions or interventions in weight reduction in the elderly may be inappropriate. Heterogeneous effects of grades 1 and 2-3 obesity on mortality were observed and should be treated as different levels of obesity. PMID- 25014071 TI - Validation of suitable reference genes for expression normalization in Echinococcus spp. larval stages. AB - In recent years, a significant amount of sequence data (both genomic and transcriptomic) for Echinococcus spp. has been published, thereby facilitating the analysis of genes expressed during a specific stage or involved in parasite development. To perform a suitable gene expression quantification analysis, the use of validated reference genes is strongly recommended. Thus, the aim of this work was to identify suitable reference genes to allow reliable expression normalization for genes of interest in Echinococcus granulosus sensu stricto (s.s.) (G1) and Echinococcus ortleppi upon induction of the early pre-adult development. Untreated protoscoleces (PS) and pepsin-treated protoscoleces (PSP) from E. granulosus s.s. (G1) and E. ortleppi metacestode were used. The gene expression stability of eleven candidate reference genes (betaTUB, NDUFV2, RPL13, TBP, CYP-1, RPII, EF-1alpha, betaACT-1, GAPDH, ETIF4A-III and MAPK3) was assessed using geNorm, Normfinder, and RefFinder. Our qPCR data showed a good correlation with the recently published RNA-seq data. Regarding expression stability, EF 1alpha and TBP were the most stable genes for both species. Interestingly, betaACT-1 (the most commonly used reference gene), and GAPDH and ETIF4A-III (previously identified as housekeeping genes) did not behave stably in our assay conditions. We propose the use of EF-1alpha as a reference gene for studies involving gene expression analysis in both PS and PSP experimental conditions for E. granulosus s.s. and E. ortleppi. To demonstrate its applicability, EF-1alpha was used as a normalizer gene in the relative quantification of transcripts from genes coding for antigen B subunits. The same EF-1alpha reference gene may be used in studies with other Echinococcus sensu lato species. This report validates suitable reference genes for species of class Cestoda, phylum Platyhelminthes, thus providing a foundation for further validation in other epidemiologically important cestode species, such as those from the Taenia genus. PMID- 25014072 TI - Hemoglobin A1c for diagnosis of postpartum abnormal glucose tolerance among women with gestational diabetes mellitus: diagnostic meta-analysis. AB - OBJECTIVE: To evaluate the accuracy of glycosylated hemoglobin A1c (HbA1c) for the diagnosis of postpartum abnormal glucose tolerance among women with gestational diabetes mellitus (GDM). METHODS: After a systematic review of related studies, the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and other measures about the accuracy of HbA1c in the diagnosis of postpartum abnormal glucose tolerance were pooled using random-effects models. The summary receiver operating characteristic (SROC) curve was used to summarize the overall test performance. RESULTS: Six studies met our inclusion criteria. The pooled results on SEN, SPE, PLR, NLR, and DOR were 0.36 (95% CI 0.23-0.52), 0.85 (95% CI 0.73-0.92), 2.4 (95% CI 1.6-3.6), 0.75 (95% CI 0.63-0.88) and 3 (95% CI 2-5). The area under the summary receiver operating characteristic (SROC) curve was 0.67 with a Q value of 0.63. CONCLUSIONS: Measurement of HbA1c alone is not a sensitive test to detect abnormal glucose tolerance in women with prior GDM. PMID- 25014073 TI - Bright emission from a random Raman laser. AB - Random lasers are a developing class of light sources that utilize a highly disordered gain medium as opposed to a conventional optical cavity. Although traditional random lasers often have a relatively broad emission spectrum, a random laser that utilizes vibration transitions via Raman scattering allows for an extremely narrow bandwidth, on the order of 10 cm(-1). Here we demonstrate the first experimental evidence of lasing via a Raman interaction in a bulk three dimensional random medium, with conversion efficiencies on the order of a few percent. Furthermore, Monte Carlo simulations are used to study the complex spatial and temporal dynamics of nonlinear processes in turbid media. In addition to providing a large signal, characteristic of the Raman medium, the random Raman laser offers us an entirely new tool for studying the dynamics of gain in a turbid medium. PMID- 25014074 TI - Pharmacokinetics of concentration-controlled mycophenolate mofetil in proliferative lupus nephritis: an observational cohort study. AB - BACKGROUND: Mycophenolate mofetil (MMF) has variable pharmacokinetics. This study examines the pharmacokinetic and clinical correlations in proliferative lupus nephritis. METHODS: Thirty-four patients were started on MMF, and the area under the concentration-time curve (AUC) was measured by limited sampling strategies, and dosing was adjusted to achieve an AUC of 30-60 mg.h.L. Twenty-seven patients had at least 2 measurements, and renal response was assessed within 1 year. RESULTS: About 61.8% of patients had mycophenolic acid (MPA) AUC <30 mg.h.L with an empiric starting dose of 30 mg/kg. About 79.4% of patients achieved renal response by 1 year, and the median time to renal response was 111 days. MMF dose per body weight had a weak correlation with the AUC and did not correlate with trough concentrations. The median dose was 1.5 g/d at entry and 2 g/d after dose modification during the induction phase. Trough concentrations had a weak correlation with AUC. Patients with serum albumin >=35 g/L had a greater chance of having an AUC >=30 mg.h.L. The between-patient coefficient of variability for dose-normalized AUC was 37.9% at entry and 31% within 1 year, whereas repeated measurements over time in an individual had a good intraclass correlation of 0.78. Infections occurred in 11.8% and toxicities in 5.9%. MPA exposure was not significantly associated with adverse events. Patients with an AUC >=30 mg.h.L had greater renal response at 1 year. CONCLUSIONS: Lupus nephritis patients induced with concentration-controlled MMF had excellent renal response and fewer adverse events with lower than usual dosing. MPA exposure had high interpatient variability, requiring measurements for personalized dosing, and fewer adverse events. Long-term cost reduction is achievable with lower doses and good renal response in the majority of patients. PMID- 25014075 TI - Unexpected overestimation of methotrexate plasma concentrations: analysis of a single center pediatric population. AB - BACKGROUND: At this center, therapeutic drug monitoring of methotrexate (MTX) used to be performed by fluorescence polarization immunoassay (FPIA). We observed an increasing number of unusual high MTX concentrations at 48 and 72 hours during a couple of years. This study aimed to identify the causes of this variation. METHODS: A retrospective analysis was conducted on 272 patients hospitalized between January 2008 and October 2012. The whole MTX use system was analyzed using Ishikawa's method. The proportion of MTX concentrations <=0.2 MUmole/L at 48 (P48h) and 72 hours (P72h) was recorded and compared between both FPIA and EMITSiemens assays. A chi or a Fisher exact test was used (alpha = 0.05). RESULTS: Because of an announced withdrawal of the FPIA reagent, the method was switched in 2009 to an immunoenzymatic technique (EMITSiemens). Both P48h and P72h dropped significantly after 2009 (P48h: 45% versus 5% and P72h: 91% versus 47%; P < 0.0001). The replacement of the EMITSiemens reagent by the EMITARK Diagnostics reagent in 2012 led to an increase in both P48h and P72h. No significant difference was found in the proportions of MTX <=0.2 MUmole/L concentrations between FPIA and EMITARK Diagnostics at 48 (45% and 40%; P = 0.556) and 72 hours (91% and 100%; P = 0.231). Both internal and external quality control assessments gave regular satisfactory results during the study period. Furthermore, the interassay comparisons that were performed with internal quality controls and spiked serum samples showed similar results at the time of both shifts. The other changes observed in the MTX circuit were not associated with MTX concentration variations. CONCLUSIONS: The overestimation of the plasma concentration of MTX was concluded to be because of the assay reagent. A further study is consequently necessary to assess the impact of this analytical pitfall on the patients' survival. PMID- 25014076 TI - Therapeutic reference range for plasma concentrations of paroxetine in patients with major depressive disorders. AB - BACKGROUND: We investigated the relationship between plasma concentrations of paroxetine and the therapeutic effect of the drug, and we evaluated the therapeutic reference range for plasma concentration of paroxetine in patients with major depressive disorders (MDD). METHODS: In this study, 120 patients with MDD were treated with 10-40 mg/d of paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate the patients at 0, 1, 2, 4, and 6 weeks. At the 6-week treatment time point, the patients were divided into 7 groups according to their paroxetine plasma concentrations in increments of 20 ng/mL. We used an analysis of variance and a chi test to define the therapeutic reference range for plasma paroxetine concentrations. RESULTS: We used 50% as the cutoff values for the percentage of MADRS improvement to determine the responder rates, and we defined remitters as patients with MADRS scores <10 at the 6-week treatment time point. We analyzed the responder and remitter rates of the patients according to their plasma paroxetine concentrations: 20 ng/mL, 40 ng/mL, and 60 ng/mL using the chi test. According to the results of the chi test in the responder rates, the 20-60 ng/mL plasma paroxetine group showed the highest effect size. CONCLUSIONS: The results of this study suggested that a range of 20-60 ng/mL is the therapeutic reference range for concentrations of paroxetine in plasma in patients with MDD. PMID- 25014077 TI - Review: three synthesis methods of CdX (X = Se, S or Te) quantum dots. AB - Quantum dots (QDs) are one of the first nanotechnologies to be integrated with the biological sciences that used for imaging or tracking macromolecules/cells in cell/tissue. Because of QDs are important in biomedical and biological applications, identify a variety of synthesis methods to produce QDs with different characteristics also is particularly important. Hence, in this review the authors discussed three methods for synthesis of heavy metal chalcogenide based QDs for use in biomedical field: (i) Organometallic method for synthesis of QDs consists of three components: precursors, organic surfactants and solvents. The authors also discussed water-solubilisation strategies of synthesised QDs including encapsulation and ligand exchange. (ii) Aqueous synthesis technique using short-chain thiols as stabilising agents is a useful alternative to organometallic synthesis of CdSe, CdS and CdTe QDs. (iii) The third method discussed in this article for QDs synthesis involves the utilise of microorganisms to prepare QDs with controlled size, shape, chemical composition and functionality. The authors also discussed recently new methods for the synthesis of the appropriate QDs for use in biology. In addition, attachment of biomolecules such as antibodies, oligonucleotides on the surface of QDs for specific targeting and different opinions about toxicity of QD have been studied. PMID- 25014078 TI - Low electric field DNA separation and in-channel amperometric detection by microchip capillary electrophoresis. AB - Miniaturisation of microchip capillary electrophoresis (MCE) is becoming an increasingly important research topic, particularly in areas related to micro total analysis systems or lab on a chip. One of the important features associated with the miniaturised MCE system is the portable power supply unit. In this work, a very low electric field MCE utilising an amperometric detection scheme was designed for use in DNA separation. The device was fabricated from a glass/polydimethylsiloxane hybrid engraved microchannel with platinum electrodes sputtered onto a glass substrate. Measurement was based on a three-electrode arrangement, and separation was achieved using a very low electric field of 12 V/cm and sample volume of 1.5 ul. The device was tested using two commercial DNA markers of different base pair sizes. The results are in agreement with conventional electrophoresis, but with improved resolution. The sensitivity consistently higher than 100 nA, and the separation time approximately 45 min, making this microchip an ideal tool for DNA analysis. PMID- 25014079 TI - Electrospinning and electrospun nanofibres. AB - Fibres with diameters less than 1000 nm (or 1 um) are defined as nanofibres and they can be produced by several processing techniques, particularly by electrospinning (ES) technique. ES technique was invented by Formhals in 1934 that in this the electrical field imposes a uniaxial stretching of a viscoelastic jet derived from the polymer solution to continuously reduce the diameter and leads to formatting nanofibres. It is simple and cost-effectiveness technique for preparation of nanofibres. Electrospinning allows for fabricating polymer fibres with diameters varying from 3 nm to greater than 5 um and in the past decade due in large part to a higher interest in nanoscale properties and technologies. In synthesis process of nanofibres by ES technique, many factors affect on the synthetic nanofibres properties such as polymer properties, solvent properties, additives, polymer concentration, solution properties and so on. In this study, the authors reviewed basic electrospinning and introduces various polymers for preparation of nanofibres. PMID- 25014080 TI - One-pot synthesis and functionalisation of Fe2O3@C-NH2 nanoparticles for imaging and therapy. AB - The authors have prepared amine-modified Fe2O3@C nanoparticles with diameter of 20 nm by decomposing perchlorinated pyrene/Fe(NO3)3 mixture in the presence of ammonia in solvothermal conditions at 180 degrees C for 48 h by a one-step process. NH3 is not only a cocatalyst of Fe(NO3)3 for decomposition of perchlorinated pyrene, but also the source of surface functionalisation group. The effect of synthesis conditions on shape and size of nanoparticles and characterisation of their structure and functionalisation group are investigated in this research. The amino group in the surface of core-shell nanoparticles can be further functionalised with polyethylene glycol and folic acid to improve their solubility in aqueous solution and target cancer cells. The applications of functionalised core-shell nanoparticles in magnetic resonance imaging and cancer thermal therapy are also investigated in this research. PMID- 25014081 TI - Experimental investigation of magnetically actuated separation using tangential microfluidic channels and magnetic nanoparticles. AB - A novel continuous switching/separation scheme of magnetic nanoparticles (MNPs) in a sub-microlitre fluid volume surrounded by neodymium permanent magnet is studied in this work using tangential microfluidic channels. Polydimethylsiloxane tangential microchannels are fabricated using a novel micromoulding technique that can be done without a clean room and at much lower cost and time. Negligible switching of MNPs is seen in the absence of magnetic field, whereas 90% of switching is observed in the presence of magnetic field. The flow rate of MNPs solution had dramatic impact on separation performance. An optimum value of the flow rate is found that resulted in providing effective MNP separation at much faster rate. Separation performance is also investigated for a mixture containing non-magnetic polystyrene particles and MNPs. It is found that MNPs preferentially moved from lower microchannel to upper microchannel resulting in efficient separation. The proof-of-concept experiments performed in this work demonstrates that microfluidic bioseparation can be efficiently achieved using functionalised MNPs, together with tangential microchannels, appropriate magnetic field strength and optimum flow rates. This work verifies that a simple low-cost magnetic switching scheme can be potentially of great utility for the separation and detection of biomolecules in microfluidic lab-on-a-chip systems. PMID- 25014082 TI - Size-dependent antimicrobial response of zinc oxide nanoparticles. AB - Antibacterial and antifungal activities of zinc oxide nanoparticles (ZnO NPs) were investigated against infectious microorganisms. ZnO NPs were prepared by wet chemical precipitation method varying the pH values. Particle size and morphology of the as-prepared ZnO powders were characterised by X-ray diffraction, Fourier transform infrared spectroscopy and transmission electron microscope. The zone of inhibition by NPs ranged from 0 to 17 mm. The lowest minimum inhibitory concentration value of NPs is 25 ug.ml(-1) against Staphylococcus epidermidis. These studies demonstrate that ZnO NPs have wide range of antimicrobial activities towards various microorganisms. The results obtained in the authors' study indicate that the inhibitory efficacy of ZnO NPs is significantly dependent on its chosen concentration and size. Significant inhibition in antibacterial response was observed for S. epidermidis when compared with control antibiotic. PMID- 25014083 TI - Contactless dielectrophoretic manipulation of biological cells using pulsed magnetic fields. AB - Contactless method for manipulation of polar or polarisable micro and nanoscale particles based on the dielectrophoresis force exerted by the induced electric field in high pulsed magnetic field is presented in this study. Finite element method analysis of the magnetic and resulting induced electric fields is carried out. The structure of the magnetic field generator that was based on a controlled frequency spark gap, and the structure of the coil that was used as a load are described. Experimental data showing positive dielectrophoresis on the Jurkat T lymphoblasts is presented. The study discusses further developments of the technique, its limitations and possible applications. PMID- 25014084 TI - Tissue engineered poly(caprolactone)-chitosan-poly(vinyl alcohol) nanofibrous scaffolds for burn and cutting wound healing. AB - Natural-synthetic blend nanofibres have recently attracted more interest because of the ability of achieving desirable properties. Poly(epsilon-caprolactone) (PCL)-chitosan (Cs)-poly(vinyl alcohol) (PVA) blend nanofibrous scaffolds were electrospun in 2:1:1.33 mass ratio of PCL:Cs:PVA. The presence of PCL in the blend leads to improvement in web hydrophobicity and helped the web to retain its integrity in aqueous media. The scaffolds were used in two forms of acellular and with mesenchymal stem cells. They were applied on burn (n = 12) and excisional cutting (n = 12) wounds on dorsum skin of rats. Macroscopic investigations were carried out to measure the wounds areas. It was found that the area of wounds that were treated with cell-seeded nanofibrous scaffolds were smaller compared to other samples. Pathological results showed much better healing performance for cell-seeded scaffolds followed by acellular scaffolds compared with control samples. All these results indicate that PCL:Cs:PVA nanofibrous web would be a proper material for burn and cutting wound healing. PMID- 25014085 TI - Health in elite sports from a salutogenetic perspective: athletes' sense of coherence. AB - OBJECTIVE: Considering the high number of stressors encountered in the context of elite sports, a high sense of coherence (SOC) is crucial to allow athletes to maintain their health from both short- and long-term perspectives. The aim of this cross-sectional study was to investigate SOC in a population of elite athletes, focusing on identification of subsets of athletes with particularly high and low SOC scores, and any related predictors. The elite athletes' SOC scores were also evaluated for differences with those of the general population of Germany; whether a correlation between SOC and subjective health existed was additionally examined. METHOD: In total, 698 male and female elite athletes, drawn from Germany's highest-level national track and field squads, and first and second division handball teams, completed a survey that included the SOC-L9 Scale and measures of subjective health, sociodemographic information, and the number of injury lay-offs experienced during the athletes' careers to date. RESULTS: Classification tree analysis reveals six contrast groups with varying SOC scores. Several interacting factors determine the group to which an athlete belongs. Together with overuse injuries, additional factors are age, gender, and completed/not completed apprenticeship/degree. Female athletes aged between 19 and 25, who had already been subject to lay-offs due to overuse injuries, comprise the group with the lowest SOC scores. Overall, the SOC of elite athletes is slightly lower than in the general population. In accordance with other studies, a stronger SOC is also correlated significantly with better global subjective health. CONCLUSION: The identification of contrast groups with varying SOC scores contributes to the development of more targeted salutogenetic health promotion programs. Such programs would ideally include learning modules pertaining to coping with overuse injuries, as well as social support systems aiming to effectively combine education and elite sport. PMID- 25014087 TI - The clinical practice recommendations of the German Diabetes Association. PMID- 25014088 TI - Definition, classification and diagnosis of diabetes mellitus. PMID- 25014089 TI - Diabetic retinopathy and maculopathy. PMID- 25014090 TI - Diabetic kidney disesase. PMID- 25014092 TI - Diabetic neuropathy. PMID- 25014091 TI - Gestational diabetes mellitus (GDM) diagnosis, therapy and follow-up care: Practice Guideline of the German Diabetes Association(DDG) and the German Association for Gynaecologyand Obstetrics (DGGG). PMID- 25014093 TI - Diabetic foot syndrome. PMID- 25014095 TI - Clustering-based ensemble learning for activity recognition in smart homes. AB - Application of sensor-based technology within activity monitoring systems is becoming a popular technique within the smart environment paradigm. Nevertheless, the use of such an approach generates complex constructs of data, which subsequently requires the use of intricate activity recognition techniques to automatically infer the underlying activity. This paper explores a cluster-based ensemble method as a new solution for the purposes of activity recognition within smart environments. With this approach activities are modelled as collections of clusters built on different subsets of features. A classification process is performed by assigning a new instance to its closest cluster from each collection. Two different sensor data representations have been investigated, namely numeric and binary. Following the evaluation of the proposed methodology it has been demonstrated that the cluster-based ensemble method can be successfully applied as a viable option for activity recognition. Results following exposure to data collected from a range of activities indicated that the ensemble method had the ability to perform with accuracies of 94.2% and 97.5% for numeric and binary data, respectively. These results outperformed a range of single classifiers considered as benchmarks. PMID- 25014094 TI - Diagnosis, therapy and control of diabetes mellitus in children and adolescents. PMID- 25014096 TI - Infrared thermography for temperature measurement and non-destructive testing. AB - The intensity of the infrared radiation emitted by objects is mainly a function of their temperature. In infrared thermography, this feature is used for multiple purposes: as a health indicator in medical applications, as a sign of malfunction in mechanical and electrical maintenance or as an indicator of heat loss in buildings. This paper presents a review of infrared thermography especially focused on two applications: temperature measurement and non-destructive testing, two of the main fields where infrared thermography-based sensors are used. A general introduction to infrared thermography and the common procedures for temperature measurement and non-destructive testing are presented. Furthermore, developments in these fields and recent advances are reviewed. PMID- 25014097 TI - A locomotion intent prediction system based on multi-sensor fusion. AB - Locomotion intent prediction is essential for the control of powered lower-limb prostheses to realize smooth locomotion transitions. In this research, we develop a multi-sensor fusion based locomotion intent prediction system, which can recognize current locomotion mode and detect locomotion transitions in advance. Seven able-bodied subjects were recruited for this research. Signals from two foot pressure insoles and three inertial measurement units (one on the thigh, one on the shank and the other on the foot) are measured. A two-level recognition strategy is used for the recognition with linear discriminate classifier. Six kinds of locomotion modes and ten kinds of locomotion transitions are tested in this study. Recognition accuracy during steady locomotion periods (i.e., no locomotion transitions) is 99.71% +/- 0.05% for seven able-bodied subjects. During locomotion transition periods, all the transitions are correctly detected and most of them can be detected before transiting to new locomotion modes. No significant deterioration in recognition performance is observed in the following five hours after the system is trained, and small number of experiment trials are required to train reliable classifiers. PMID- 25014098 TI - Developing barbed microtip-based electrode arrays for biopotential measurement. AB - This study involved fabricating barbed microtip-based electrode arrays by using silicon wet etching. KOH anisotropic wet etching was employed to form a standard pyramidal microtip array and HF/HNO3 isotropic etching was used to fabricate barbs on these microtips. To improve the electrical conductance between the tip array on the front side of the wafer and the electrical contact on the back side, a through-silicon via was created during the wet etching process. The experimental results show that the forces required to detach the barbed microtip arrays from human skin, a polydimethylsiloxane (PDMS) polymer, and a polyvinylchloride (PVC) film were larger compared with those required to detach microtip arrays that lacked barbs. The impedances of the skin-electrode interface were measured and the performance levels of the proposed dry electrode were characterized. Electrode prototypes that employed the proposed tip arrays were implemented. Electroencephalogram (EEG) and electrocardiography (ECG) recordings using these electrode prototypes were also demonstrated. PMID- 25014099 TI - Embedded strain gauges for condition monitoring of silicone gaskets. AB - A miniaturized strain gauge with a thickness of 5 um is molded into a silicone O ring. This is a first step toward embedding sensors in gaskets for structural health monitoring. The signal of the integrated sensor exhibits a linear correlation with the contact pressure of the O-ring. This affords the opportunity to monitor the gasket condition during installation. Thus, damages caused by faulty assembly can be detected instantly, and early failures, with their associated consequences, can be prevented. Through the embedded strain gauge, the contact pressure applied to the gasket can be directly measured. Excessive pressure and incorrect positioning of the gasket can cause structural damage to the material of the gasket, which can lead to an early outage. A platinum strain gauge is fabricated on a thin polyimide layer and is contacted through gold connections. The measured resistance pressure response exhibits hysteresis for the first few strain cycles, followed by a linear behavior. The short-term impact of the embedded sensor on the stability of the gasket is investigated. Pull-tests with O-rings and test specimens have indicated that the integration of the miniaturized sensors has no negative impact on the stability in the short term. PMID- 25014100 TI - Wireless displacement sensing of micromachined spiral-coil actuator using resonant frequency tracking. AB - This paper reports a method that enables real-time displacement monitoring and control of micromachined resonant-type actuators using wireless radiofrequency (RF). The method is applied to an out-of-plane, spiral-coil microactuator based on shape-memory-alloy (SMA). The SMA spiral coil forms an inductor-capacitor resonant circuit that is excited using external RF magnetic fields to thermally actuate the coil. The actuation causes a shift in the circuit's resonance as the coil is displaced vertically, which is wirelessly monitored through an external antenna to track the displacements. Controlled actuation and displacement monitoring using the developed method is demonstrated with the microfabricated device. The device exhibits a frequency sensitivity to displacement of 10 kHz/um or more for a full out-of-plane travel range of 466 um and an average actuation velocity of up to 155 um/s. The method described permits the actuator to have a self-sensing function that is passively operated, thereby eliminating the need for separate sensors and batteries on the device, thus realizing precise control while attaining a high level of miniaturization in the device. PMID- 25014102 TI - Synchronous motor with hybrid permanent magnets on the rotor. AB - Powder metallurgy allows designers of electric motors to implement new magnetic circuit structures. A relatively new concept is the use of a magnet system consisting of various types of magnets on one rotor, for example sintered and bonded magnets. This concept has been applied to the design and manufacture of the four-pole rotor of a synchronous motor with 400 W power and a rotational speed of 1500 rpm. In this motor, the stator of an asynchronous motor type Sh 71 4B is applied. The application of the new construction of the rotor resulted in an increase in motor efficiency and power factor compared to an asynchronous motor with the same volume. PMID- 25014101 TI - A real-time fatigue monitoring and analysis system for lower extremity muscles with cycling movement. AB - A real-time muscle fatigue monitoring system was developed to quantitatively detect the muscle fatigue of subjects during cycling movement, where a fatigue progression measure (FPM) was built-in. During the cycling movement, the electromyogram (EMG) signals of the vastus lateralis and gastrocnemius muscles in one leg as well as cycling speed are synchronously measured in a real-time fashion. In addition, the heart rate (HR) and the Borg rating of perceived exertion scale value are recorded per minute. Using the EMG signals, the electrical activity and median frequency (MF) are calculated per cycle. Moreover, the updated FPM, based on the percentage of reduced MF counts during cycling movement, is calculated to measure the onset time and the progressive process of muscle fatigue. To demonstrate the performance of our system, five young healthy subjects were recruited. Each subject was asked to maintain a fixed speed of 60 RPM, as best he/she could, under a constant load during the pedaling. When the speed reached 20 RPM or the HR reached the maximal training HR, the experiment was then terminated immediately. The experimental results show that the proposed system may provide an on-line fatigue monitoring and analysis for the lower extremity muscles during cycling movement. PMID- 25014103 TI - Clinical significance of immunoglobulin deposition in leukocytoclastic vasculitis: a 5-year retrospective study of 88 patients at cleveland clinic. AB - OBJECTIVE: To study the diagnostic utility and clinical associations of immunoglobulin deposition, determined by direct immunofluorescence (DIF) in cutaneous leukocytoclastic vasculitis (LCV). METHODS: We performed a retrospective study of all biopsy-proven LCV cases seen at Cleveland Clinic between 2007 and 2012. All LCV cases in which DIF was performed were included. RESULTS: Of the 218 LCV cases, 106 cases had DIF performed and data from 88 cases were available: median (SD) age 53.3 (19.4), 52% male, 64.1% white, duration of rash 5.5 (20.8) months; follow-up 14 (19.7) months. DIF results showed any immunoglobulin and/or complement and/or fibrinogen in 70.5%, immunoglobulin A (IgA) in 36.4%, immunoglobulin M (IgM) in 21.6%, immunoglobulin G (IgG) in 11.4%. Patients with IgA deposition by DIF, compared with those without IgA, were younger, 44 (19) versus 56 (17) (P = 0.006), more likely to be white (P = 0.025) and had more organs affected by vasculitis (P = 0.002), higher incidence of gastrointestinal tract involvement (P = 0.0001) and renal disease (P = 0.006). No differences between rates of infection or malignancy were seen between DIF IgA, IgM, or IgG-positive versus negative patients. CONCLUSIONS: In patients with cutaneous LCV, IgA is the most common immunoglobulin found by DIF. IgA deposition, but not IgM or IgG, is predictive of associated renal and gastrointestinal organ involvement by vasculitis. No association between the type of immunoglobulin and preexisting infection or malignancy was found. DIF results add information that is clinically relevant to the diagnosis and management of LCV. PMID- 25014104 TI - Capacity of dermatologists to diagnose oral and perioral lesions compared with orthodontists, primary care physicians, and pediatricians. AB - Oral pathology is an interdisciplinary field of unclear boundaries. Only a few studies have been previously published comparing the diagnostic capacity among different specialists taking care of the disorders involving oral mucosa and perioral skin. The goal of this study was to assess the capacity for diagnosing dermatologic conditions involving the oral mucosa and perioral skin in children and adults among orthodontists, dermatologists, and primary care physicians. Samples of orthodontists (n = 118), dermatologists (n = 100), pediatricians (n = 75), and family doctors (n = 68) were selected for the study. Two tests of 30 color clinical photographs each were prepared, one containing oral lesions in children and other one in adults. Statistical and comparative analyses of correct and incorrect answers were performed in each group and subgroup of participants. Dermatologists were clearly better trained than other specialists in oral and perioral pathology. This advantage over their counterparts in other specialties was seen in both residents and board-certified dermatologists. Though by small margin, orthodontists showed better performance than pediatricians and family doctors. Dermatologists showed higher capacity to achieve the right diagnosis in common oral and perioral disorders than orthodontists, pediatricians, and family doctors. PMID- 25014105 TI - Nevus lipomatosus cutaneous superficialis with focal lipocytic pagetoid epidermal spread and secondary calcinosis cutis: a case report. AB - A case of nevus lipomatosus cutaneous superficialis is presented, wherein the lesion occurred as a gluteal swelling in a 6-year-old boy. On histopathology examination, it consisted of typical superficial expanses of mature adipose tissue in the papillary dermis of the polypoidal lesion. It was accompanied by 2 unusual findings, which consisted of the focal presence of lipocytes at the epidermal-dermal junction in the pagetoid manner and the prominent deposition of calcium resulting in calcinosis cutis-like lesions. Calcinosis cutis in the present case occurred as dystrophic calcification in focal fat necrosis changes of the lesion, whereas the focal pagetoid spread of fat cells is likely related to the same hamartomatous adipose tissue growth that ultimately results in the nevus lipomatosus. PMID- 25014106 TI - Specific skin infiltration as first sign of localized stage Hodgkin's lymphoma involving an epitrochlear node. AB - Cutaneous manifestation as the first sign of Hodgkin lymphoma (HL) is very rare and diagnostically challenging; especially, because the clinical presentation of specific skin involvement by HL is polymorphous. We present a 44-year-old man with erythematous indurate papules and plaques in the right forearm and arm where skin biopsy showed an HL. He also has an enlarged epitrochlear node, and later histopathologic study confirmed the diagnosis of HL subtype-mixed cellularity. Immunohistochemical stains in both biopsies showed that the atypical cells were positive for CD30 and CD15, and negative for CD20 and CD3. PAX5 stained the nuclei of the atypical large lymphoid cells weakly and Oct-2 staining was negative in the atypical cells. EBER and LMP1 protein were negative in both biopsies. Epitrochlear involvement in HL, like in our case, is a rare event (<1%). We reviewed data about prognosis, clinical appearance, and treatment of all the cases of HL specific skin involvement published after Sioutos et al, emphasizing the cases where HL specific skin involvement was the first sign of the disease as in our patient. PMID- 25014107 TI - Primary cutaneous endocrine mucin-producing sweat gland carcinoma co-occurring simultaneously with low-grade ductal mucinous breast cancer: a clinicopathologic conundrum. PMID- 25014108 TI - In vivo antileishmanial efficacy of miltefosine against Leishmania (Leishmania) amazonensis. AB - Leishmaniasis, a disease caused by parasites of the Leishmania genus, constitutes a significant health and social problem in many countries and is increasing worldwide. The conventional treatment, meglumine antimoniate (MA), presents numerous disadvantages, including invasiveness, toxicity, and frequent therapeutic failure, justifying the attempts at finding alternatives to the first line therapy. We have studied the comparative long-term efficacy of MA against miltefosine (MF) in Leishmania infection in experimental mice. The criteria for efficacy evaluation were footpad lesion size, anti-Leishmania antibodies level, histopathology of the site of inoculation (right footpad, RFP), splenic index (SI), and the presence of parasites in RFP, spleen, and liver, determined by polymerase chain reaction (PCR). Swiss mice, infected with Leishmania (Leishmania) amazonensis were treated, at different time points (5 and 40 days after infection) with either MA or MF. The efficacy of MF was better than that of MA for inhibiting lesions and for reducing tissue damage and presence/load of amastigotes in spleen and liver. Moreover, early administration of MF produced a clear reduction in splenomegaly and was equal in reducing antibody titles in comparison with MA. Our results demonstrated that MF is an effective and safe therapeutic alternative for leishmaniasis by L. (L.) amazonensis and is more efficacious than MA. PMID- 25014109 TI - Inhibition of angiotensin II-induced cardiac hypertrophy and associated ventricular arrhythmias by a p21 activated kinase 1 bioactive peptide. AB - Cardiac hypertrophy increases the risk of morbidity and mortality of cardiovascular disease and thus inhibiting such hypertrophy is beneficial. In the present study, we explored the effect of a bioactive peptide (PAP) on angiotensin II (Ang II)-induced hypertrophy and associated ventricular arrhythmias in in vitro and in vivo models. PAP enhances p21 activated kinase 1 (Pak1) activity by increasing the level of phosphorylated Pak1 in cultured neonatal rat ventricular myocytes (NRVMs). Such PAP-induced Pak1 activation is associated with a significant reduction of Ang II-induced hypertrophy in NRVMs and C57BL/6 mice, in vitro and in vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Thus our results suggest that Pak1 activation achieved by specific bioactive peptide represents a potential novel therapeutic strategy for cardiac hypertrophy and associated ventricular arrhythmias. PMID- 25014111 TI - Occurrence of free-living amoebae in streams of the Mexico Basin. AB - Free-living amoebae (FLA) are protozoa that are widely distributed in nature. They are important in the cycling of nutrients in aquatic food chains, but their distribution in natural aquatic environments is not well known. We conducted a survey to determine the presence and distribution of FLA and their relation to some physicochemical parameters in streams of the Mexico Basin in Central Mexico. Thirty-two sites from 18 streams were sampled. Samples were centrifuged and cultured onto NNA-media to isolate amoebae. Identifications were based on morphology. The pathogenicity of Acanthamoeba isolates was tested. Oxygen saturation, temperature, pH, specific conductance, water flow, dissolved reactive phosphorus, nitrites, nitrates, ammonia, dissolved inorganic nitrogen and coliforms were determined. One hundred-and-twenty FLA representing 18 genera were identified. The most frequent genera were Vannella, Rosculus and Acanthamoeba. The frequency of potentially pathogenic FLA was low and only 3 Acanthamoeba isolates were invasive in mice. The highest species richness of FLA was found in streams located into agriculture activity areas and those close to small villages that discharge wastewater into them. Water temperatures were always below 17 degrees C. Oxygen saturation and pH were within the limits for the growth of most FLA. The presence of Acanthamoeba and Naegleria was low; nevertheless, they include potentially pathogenic species and can act as vectors and reservoirs for microbial pathogens and can produce human infections. PMID- 25014110 TI - Combined NADPH oxidase 1 and interleukin 10 deficiency induces chronic endoplasmic reticulum stress and causes ulcerative colitis-like disease in mice. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the rectum which progressively extents. Its etiology remains unknown and the number of treatments available is limited. Studies of UC patients have identified an unbalanced endoplasmic reticulum (ER) stress in the non-inflamed colonic mucosa. Animal models with impaired ER stress are sensitive to intestinal inflammation, suggesting that an unbalanced ER stress could cause inflammation. However, there are no ER stress-regulating strategies proposed in the management of UC partly because of the lack of relevant preclinical model mimicking the disease. Here we generated the IL10/Nox1dKO mouse model which combines immune dysfunction (IL-10 deficiency) and abnormal epithelium (NADPH oxidase 1 (Nox1) deficiency) and spontaneously develops a UC-like phenotype with similar complications (colorectal cancer) than UC. Our data identified an unanticipated combined role of IL10 and Nox1 in the fine-tuning of ER stress responses in goblet cells. As in humans, the ER stress was unbalanced in mice with decreased eIF2alpha phosphorylation preceding inflammation. In IL10/Nox1dKO mice, salubrinal preserved eIF2alpha phosphorylation through inhibition of the regulatory subunit of the protein phosphatase 1 PP1R15A/GADD34 and prevented colitis. Thus, this new experimental model highlighted the central role of epithelial ER stress abnormalities in the development of colitis and defined the defective eIF2alpha pathway as a key pathophysiological target for UC. Therefore, specific regulators able to restore the defective eIF2alpha pathway could lead to the molecular remission needed to treat UC. PMID- 25014112 TI - Selective synthesis and redox sequence of a heterobimetallic nickel/copper complex of the noninnocent Siamese-twin porphyrin. AB - The Siamese-twin porphyrin (1H4) is a redox noninnocent pyrazole-expanded porphyrin with two equivalent dibasic {N4} binding sites. It is now shown that its selective monometalation can be achieved to give the nickel(II) complex 1H2Ni with the second {N4} site devoid of a metal ion. This intermediate is then cleanly converted to 1Ni2 and to the first heterobimetallic Siamese-twin porphyrin 1CuNi. Structural characterization of 1H2Ni shows that it has the same helical structure previously seen for 1Cu2, 1Ni2, and free base 1H6(2+). Titration experiments suggest that the metal-devoid pocket of 1H2Ni can accommodate two additional protons, giving [1H4Ni](2+). Both bimetallic complexes 1Ni2 and 1CuNi feature rich redox chemistry, similar to the recently reported 1Cu2, including two chemically reversible oxidations at moderate potentials between -0.3 and +0.5 V (vs Cp2Fe/Cp2Fe(+)). The locus of these oxidations, in singly oxidized [1Ni2](+) and [1CuNi](+) as well as twice oxidized [1CuNi](2+), has been experimentally derived from comparison of the electrochemical properties of the complete series of complexes 1Cu2, 1Ni2, and 1CuNi, and from electron paramagnetic resonance (EPR) spectroscopy and X-ray absorption spectroscopy (XAS) (Ni and Cu K edges). All redox events are largely ligand-based, and in heterobimetallic 1CuNi, the first oxidation takes place within its Cu-subunit, while the second oxidation then occurs in its Ni-subunit. Adding pyridine to solutions of [1Ni2](+) and [1CuNi](2+) cleanly converts them to metal-oxidized redox isomers with axial EPR spectra typical for Ni(III) having significant dz(2)(1) character, reflecting close similarity with nickel complexes of common porphyrins. The possibility of selectively synthesizing heterobimetallic complexes 1MNi from a symmetric binucleating ligand scaffold, with the unusual situation of three distinct contiguous redox sites (M, Ni, and the porphyrin-like ligand), further expands the Siamese-twin porphyrin's potential to serve as an adjustable platform for multielectron redox processes in chemical catalysis and in electronic applications. PMID- 25014113 TI - Epitaxially aligned cuprous oxide nanowires for all-oxide, single-wire solar cells. AB - As a p-type semiconducting oxide that can absorb visible light, cuprous oxide (Cu2O) is an attractive material for solar energy conversion. This work introduces a high-temperature, vapor-phase synthesis that produces faceted Cu2O nanowires that grow epitaxially along the surface of a lattice-matched, single crystal MgO substrate. Individual wires were then fabricated into single-wire, all-oxide diodes and solar cells using low-temperature atomic layer deposition (ALD) of TiO2 and ZnO films to form the heterojunction. The performance of devices made from pristine Cu2O wires and chlorine-exposed Cu2O wires was investigated under one-sun and laser illumination. These faceted wires allow the fabrication of well-controlled heterojunctions that can be used to investigate the interfacial properties of all-oxide solar cells. PMID- 25014114 TI - Vogt-Koyanagi-Harada disease. PMID- 25014115 TI - Sarcoid uveitis. PMID- 25014116 TI - Enhancing molecular recognition in electron donor-acceptor hybrids via cooperativity. AB - Herein, we report the synthesis of guanidinium bis-porphyrin tweezers 1 and fullerene carboxylate 3, their assembly into a novel supramolecular 1@3 electron donor-acceptor hybrid, and its characterization. In solution, the binding constant affording 1@3 is exceptionally high. 1@3, which features a highly confined topography, builds up from a combination of guanidinium-carboxylate hydrogen bonding and pi-pi stacking/charge-transfer motifs. The latter is governed by interactions between the electron-donating porphyrin and the electron accepting fullerene. Importantly, positive cooperativity between the applied binding motifs is corroborated by a number of experimental techniques, such as NMR, absorption, fluorescence, etc. In addition, transient absorption experiments shed light onto electron-transfer processes taking place in the ground state and upon photoexcitation. In fact, porphyrin excitation powers an electron transfer to the fullerene yielding charge separated state lifetimes in the nanosecond regime. PMID- 25014117 TI - From bacteria to piscivorous fish: estimates of whole-lake and component-specific metabolism with an ecosystem approach. AB - The influence of functional group specific production and respiration patterns on a lake's metabolic balance remains poorly investigated to date compared to whole system estimates of metabolism. We employed a summed component ecosystem approach for assessing lake-wide and functional group-specific metabolism (gross primary production (GPP) and respiration (R)) in shallow and eutrophic Lake Vortsjarv in central Estonia during three years. Eleven functional groups were considered: piscivorous and benthivorous fish; phyto-, bacterio-, proto- and metazooplankton; benthic macroinvertebrates, bacteria and ciliates; macrophytes and their associated epiphytes. Metabolism of these groups was assessed by allometric equations coupled with daily records of temperature and hydrology of the lake and measurements of food web functional groups biomass. Results revealed that heterotrophy dominated most of the year, with a short autotrophic period observed in late spring. Most of the metabolism of the lake could be attributed to planktonic functional groups, with phytoplankton contributing the highest share (90% of GPP and 43% of R). A surge of protozooplankton and bacterioplankton populations forming the microbial loop caused the shift from auto- to heterotrophy in midsummer. Conversely, the benthic functional groups had overall a very small contribution to lake metabolism. We validated our ecosystem approach by comparing the GPP and R with those calculated from O2 measurements in the lake. Our findings are also in line with earlier productivity studies made with 14C or chlorophyll a (chl-a) based equations. Ideally, the ecosystem approach should be combined with diel O2 approach for investigating critical periods of metabolism shifts caused by dynamics in food-web processes. PMID- 25014118 TI - Guest editors' note: Special issue associated with the 2013 ASA Biopharmaceutical FDA/Industry Statistics Workshop. PMID- 25014119 TI - Exploiting differential electrochemical stripping behaviors of Fe3O4 nanocrystals toward heavy metal ions by crystal cutting. AB - This study attempts to understand the intrinsic impact of different morphologies of nanocrystals on their electrochemical stripping behaviors toward heavy metal ions. Two differently shaped Fe3O4 nanocrystals, i.e., (100)-bound cubic and (111)-bound octahedral, have been synthesized for the experiments. Electrochemical results indicate that Fe3O4 nanocrystals with different shapes show different stripping behaviors toward heavy metal ions. Octahedral Fe3O4 nanocrystals show better electrochemical sensing performances toward the investigated heavy metal ions such as Zn(II), Cd(II), Pb(II), Cu(II), and Hg(II), in comparison with cubic ones. Specifically, Pb(II) is found to have the best stripping performance on both the (100) and (111) facets. To clarify these phenomena, adsorption abilities of as-prepared Fe3O4 nanocrystals have been investigated toward heavy metal ions. Most importantly, combined with theoretical calculations, their different electrochemical stripping behaviors in view of facet effects have been further studied and enclosed at the level of molecular/atom. Finally, as a trial to find a disposable platform completely free from noble metals, the potential application of the Fe3O4 nanocrystals for electrochemical detection of As(III) in drinking water is demonstrated. PMID- 25014120 TI - Loop interactions during catalysis by dihydrofolate reductase from Moritella profunda. AB - Dihydrofolate reductase (DHFR) is often used as a model system to study the relation between protein dynamics and catalysis. We have studied a number of variants of the cold-adapted DHFR from Moritella profunda (MpDHFR), in which the catalytically important M20 and FG loops have been altered, and present a comparison with the corresponding variants of the well-studied DHFR from Escherichia coli (EcDHFR). Mutations in the M20 loop do not affect the actual chemical step of transfer of hydride from reduced nicotinamide adenine dinucleotide phosphate to the substrate 7,8-dihydrofolate in the catalytic cycle in either enzyme; they affect the steady state turnover rate in EcDHFR but not in MpDHFR. Mutations in the FG loop also have different effects on catalysis by the two DHFRs. Despite the two enzymes most likely sharing a common catalytic cycle at pH 7, motions of these loops, known to be important for progression through the catalytic cycle in EcDHFR, appear not to play a significant role in MpDHFR. PMID- 25014125 TI - Computational predictions of glass-forming ability and crystallization tendency of drug molecules. AB - Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Huckel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds. PMID- 25014121 TI - Stable isotopes confirm a coastal diet for critically endangered Mediterranean monk seals. AB - Understanding the ecology and behaviour of endangered species is essential for developing effective management and conservation strategies. We used stable isotope analysis to investigate the foraging behaviour of critically endangered Mediterranean monk seals (Monachus monachus) in Greece. We measured carbon and nitrogen isotope ratios (expressed as delta(13)C and delta(15)N values, respectively) derived from the hair of deceased adult and juvenile seals and the muscle of their known prey to quantify their diets. We tested the hypothesis that monk seals primarily foraged for prey that occupy coastal habitats in Greece. We compared isotope values from seal hair to their coastal and pelagic prey (after correcting all prey for isotopic discrimination) and used these isotopic data and a stable isotope mixing model to estimate the proportion of coastal and pelagic resources consumed by seals. As predicted, we found that seals had similar delta(13)C values as many coastal prey species and higher delta(13)C values than pelagic species; these results, in conjunction with mean dietary estimates (coastal=61 % vs. pelagic=39 %), suggest that seals have a diverse diet comprising prey from multiple trophic levels that primarily occupy the coast. Marine resource managers should consider using the results from this study to inform the future management of coastal habitats in Greece to protect Mediterranean monk seals. PMID- 25014126 TI - Conformational isomerism influence on the properties of piperazinium bis(trifluoromethylsulfonyl)imide. AB - Investigation of conformational isomerism of ring compounds can help us get a clear comprehension of the ring structure and reveal significant structure activity relationship. In this study, conformational isomerism of the cationic moiety of ionic liquid 1-ethyl-1,4-dimethylpiperazinium bis(trifluoromethylsulfonyl)imide ([C2C1C1(4)pi][NTf2]) has been investigated by means of (1)H nuclear magnetic resonance spectra. The energy levels for different conformations of the cationic moiety [C2C1C1(4)pi](+) are obtained via density functional theory calculations. The predominant cis-conformer in [C2C1C1(4)pi][NTf2] at its liquid state is observed under ambient conditions, where the ethyl group locates at the equatorial position of quaternary nitrogen atom, consistent with the calculated results. The trans-conformer minorities in the IL convert to the cis-conformers when [C2C1C1(4)pi][NTf2] is well crystallized. Besides, the addition of polar solvents, such as ethanol, leads to a convenient and complete transformation from the trans-form to the recognizable cis-form. The phase-transition behaviors have been measured by means of differential scanning microcalorimetry (DSC), and the DSC results can be highly affected by the initial state of the IL. Density and viscosity measurements for mixtures of [C2C1C1(4)pi][NTf2] with ethanol or 1-propanol at different temperatures T = (293.15 to 323.15) K are performed. Conformational isomerism affects the excess molar volumes of [C2C1C1(4)pi][NTf2] + alcohol systems more significantly than the viscometric property. The behaviors, as comparison, for the mixtures of 1-n-pentyl-1,4-dimethyl-piperazinium bis(trifluoromethylsulfonyl)imide ([C5C1C1(4)pi][NTf2]) with ethanol are observed with the same phenomena as the common binary systems. On the basis of the experimental and calculated results of the ILs, it can be concluded that conformational isomerism in the cation of [C2C1C1(4)pi][NTf2] is quite significant, and it should be taken into account when sensitive properties are evaluated. PMID- 25014127 TI - An ecological approach to understanding barriers to employment for youth with disabilities compared to their typically developing peers: views of youth, employers, and job counselors. AB - PURPOSE: The purpose of this study is to explore the extent to which youth with physical disabilities encounter different barriers to finding employment compared to their typically developing peers. METHODS: This study draws on 50 qualitative in-depth interviews with a purposive sample of 31 youth (16 typically developing and 15 with a disability), and youth employers and job counselors knowledgeable about employment readiness among adolescents (n = 19). We utilize Bronfrebrenner's ecological framework to reveal the complex web of factors shaping youth's labor market outcomes. RESULTS: Only half of youth with a disability were working or looking for work compared to their peers. The findings show this was a result of different expectations of, and attitudes toward, youth with disabilities. For many youth with a disability, their peers, family and social networks often acted as a barrier to getting a job. Many youth also lacked independence and life skills that are needed to get a job (i.e. self-care and navigating public transportation) compared to their peers. Job counselors focused on linking youth to employers and mediating parental concerns. Employers appeared to have weaker links to youth with disabilities. System level barriers included lack of funding and policies to enhance disability awareness among employers. CONCLUSIONS: Youth with physical disabilities encounter some similar barriers to finding employment compared to their typically developing peers but in a stronger way. Barriers to employment exist at several levels including individual, sociostructural and environmental. The results highlight that although there are several barriers to employment for young people at the microsystem level, they are linked with larger social and environmental barriers. IMPLICATIONS FOR REHABILITATION: Clinicians working with youth should promote the development of skills that can lead to improved self-confidence and communication skills for youth. Encourage the development of extracurricular activities and social networking to build these skills and to make contacts for finding employment. Clinicians should support youth with disabilities and their parents in practicing independence skills (such as self-care, self-advocacy and navigating public transportation) they need prior to seeking employment. Vocational rehabilitation professionals should educate youth on how to disclose their condition to a potential employer, how to ask for ask for accommodations and how to market their abilities. Clinicians should help to link youth with disabilities to volunteer opportunities and to employers. Advocate for disability awareness training for employers regarding how to accommodate people with disabilities and the potential they offer in the workplace. PMID- 25014128 TI - Metal mesh device sensor immobilized with a trimethoxysilane-containing glycopolymer for label-free detection of proteins and bacteria. AB - Biosensors for the detection of proteins and bacteria have been developed using glycopolymer-immobilized metal mesh devices. The trimethoxysilane-containing glycopolymer was immobilized onto a metal mesh device using the silane coupling reaction. The surface shape and transmittance properties of the original metal mesh device were maintained following the immobilization of the glycopolymer. The mannose-binding protein (concanavalin A) could be detected at concentrations in the range of 10(-9) to 10(-6) mol L(-1) using the glycopolymer-immobilized metal mesh device sensor, whereas another protein (bovine serum albumin) was not detected. A detection limit of 1 ng mm(-2) was achieved for the amount of adsorbed concanavalin A. The glycopolymer-immobilized metal mesh device sensor could also detect bacteria as well as protein. The mannose-binding strain of Escherichia coli was specifically detected by the glycopolymer-immobilized metal mesh device sensor. The glycopolymer-immobilized metal mesh device could therefore be used as a label-free biosensor showing high levels of selectivity and sensitivity toward proteins and bacteria. PMID- 25014129 TI - Population-based cost-offset estimation for the treatment of borderline personality disorder: projected costs in a currently running, ideal health system. AB - Borderline personality disorder (BPD) is considered one of the most expensive mental disorders in terms of direct and indirect costs. The aim of this study was to carry out a cost-offset estimation of disorder-specific psychotherapy for BPD at the population level. The study investigated whether the possible financial benefits of dialectical behavior therapy outweigh the therapy costs, assuming a currently running, ideal health system, and whether the estimated cost-benefit relationships change depending upon the number of patients willing to be treated. A formula was elaborated that allows the user to calculate cost-benefit relationships for various conservative or progressive scenarios, with different stages of individuals' willingness to be treated (10%-90%). The possible costs and benefits of BPD-related treatment were evaluated using a 12-month, prevalence based approach. The annual costs for untreated BPD were 8.69 billion EUR annually. The cost-benefit relationship for the treatment remained constant at 1.52 for all scenarios, implying that for each EUR invested, 1.52 EUR can be gained within one year, independent of the willingness to be treated. Additional intangible benefits were calculated with the aid of Quality-Adjusted Life Years. Findings suggest that BPD-related treatment might well be efficient at the population level. PMID- 25014131 TI - Masked translation priming asymmetry in Chinese-English bilinguals: making sense of the Sense Model. AB - Masked translation priming asymmetry is the robust finding that priming from a bilingual's first language (L1) to their second language (L2) is stronger than priming from L2 to L1. This asymmetry has been claimed to be task dependent. The Sense Model proposed by Finkbeiner, Forster, Nicol, and Nakamura (2004) claims that the asymmetry is reduced in semantic categorization relative to lexical decision due to a category filtering mechanism that limits the features considered in categorization decisions to dominant, category-relevant features. This paper reports two pairs of semantic categorization and lexical decision tasks designed to test the Sense Model's predictions. The experiments replicated the finding of Finkbeiner et al. that L2-L1 priming is somewhat stronger in semantic categorization than lexical decision, selectively for exemplars of the category. However, the direct comparison of L2-L1 and L1-L2 translation priming across tasks failed to confirm the Sense Model's central prediction that translation priming asymmetry is significantly reduced in semantic categorization. The data therefore fail to support the category filtering account of translation priming asymmetry. Rather, they suggest that pre-activation of conceptual features of the target category provides feedback to lexical forms that compensates for the weak connections between the lexical and conceptual representations of L2 words. PMID- 25014130 TI - Population size, HIV, and behavior among MSM in Luanda, Angola: challenges and findings in the first ever HIV and syphilis biological and behavioral survey. AB - OBJECTIVES: To conduct the first population size estimation and biological and behavioral surveillance survey among men who have sex with men (MSM) in Angola. DESIGN: Population size estimation with multiplier method and a cross-sectional study using respondent-driven sampling. SETTING: Luanda Province, Angola. Study was conducted in a large hospital. PARTICIPANTS: Seven hundred ninety-two self identified MSM accepted a unique object for population size estimation. Three hundred fifty-one MSM were recruited with respondent-driven sampling for biological and behavioral surveillance survey. METHODS: Interviews and testing for HIV and syphilis were conducted on-site. Analysis used Respondent-Driven Sampling Analysis Tool and STATA 11.0. Univariate, bivariate, and multivariate analyses examined factors associated with HIV and unprotected sex. Six imputation strategies were used for missing data for those refusing to test for HIV. MAIN OUTCOME: A population size of 6236 MSM was estimated. Twenty-seven of 351 individuals were tested positive. Adjusted HIV prevalence was 3.7% (8.7% crude). With imputation, HIV seroprevalence was estimated between 3.8% [95% confidence interval (CI): 1.6 to 6.5] and 10.5% (95% CI: 5.6 to 15.3). Being older than 25 (odds ratio = 10.8, 95% CI: 3.5 to 32.8) and having suffered episodes of homophobia (odds ratio = 12.7, 95% CI: 3.2 to 49.6) significantly increased the chance of HIV seropositivity. CONCLUSIONS: Risk behaviors are widely reported, but HIV seroprevalence is lower than expected. The difference between crude and adjusted values was mostly due to treatment of missing values in Respondent Driven Sampling Analysis Tool. Solutions are proposed in this article. Although concerns were raised about feasibility and adverse outcomes for MSM, the study was successfully and rapidly completed with no adverse effects. PMID- 25014133 TI - Stent placement for treatment of long-segment (>=40 mm) carotid atherosclerotic stenosis: results and long-term follow-up in a single-center experience. AB - BACKGROUND: Treatment of long segment carotid stenosis (>=40 mm) with carotid artery stenting (CAS) has rarely been reported. In randomized trials, use of longer stents (>40 mm) has been associated with adverse clinical events. Here, we report our preliminary experience on the stent length and outcome in treating long segment carotid arterial stenosis. METHODS AND RESULTS: Between August 2003 and February 2013, 22 patients with long segment stenosis of the carotid artery were treated by CAS. The mean stent length was 58.5 mm (50-60 mm). The procedures were successful in all patients, and all reported remarkable relief of symptoms immediately after stent placement. Complications included 1 case of cerebral hemorrhage and one death from myocardial infarction at 10 months. The mean follow up was 27.3 months (10-60 months). One follow-up was lost. 2 patients had late stent thrombosis at 22 and 36 months by CTA follow-up. 18 patients had persistent relief, and angiography/CTA showed normal carotid flow. CONCLUSIONS: Our study showed that stenting for long carotid stenosis (>=40 mm) can be beneficial. Large scale clinical trial is needed to further evaluate its efficacy and safety. PMID- 25014132 TI - Dynamic conduction and repolarisation changes in early arrhythmogenic right ventricular cardiomyopathy versus benign outflow tract ectopy demonstrated by high density mapping & paced surface ECG analysis. AB - AIMS: The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy. METHODS: 22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol. RESULTS: Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43 +/- 20 ms) more than RVOT ectopy patients (36 +/- 14 ms, p = 0.03) or Normals (25 +/- 16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18 +/- 20 ms; RVOT ectopy: 5 +/- 14, Normal: 1 +/- 18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls. CONCLUSIONS: Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters. PMID- 25014134 TI - Retinoic acid regulates several genes in bile acid and lipid metabolism via upregulation of small heterodimer partner in hepatocytes. AB - Retinoic acid (RA) affects multiple aspects of development, embryogenesis and cell differentiation processes. The liver is a major organ that stores RA suggesting that retinoids play an important role in the function of hepatocytes. In our previous studies, we have demonstrated the involvement of small heterodimer partner (SHP) in RA-induced signaling in a non-transformed hepatic cell line AML 12. In the present study, we have identified several critical genes in lipid homeostasis (Apoa1, Apoa2 and ApoF) that are repressed by RA-treatment in a SHP dependent manner, in vitro and also in vivo with the use of the SHP null mice. In a similar manner, RA also represses several critical genes involved in bile acid metabolism (Cyp7a1, Cyp8b1, Mdr2, Bsep, Baat and Ntcp) via upregulation of SHP. Collectively our data suggest that SHP plays a major role in RA-induced potential changes in pathophysiology of metabolic disorders in the liver. PMID- 25014135 TI - The role of miR-326 and miR-26a in MS disease activity. PMID- 25014136 TI - The RNA expression signature of the HepG2 cell line as determined by the integrated analysis of miRNA and mRNA expression profiles. AB - Understanding miRNAs' regulatory networks and target genes could facilitate the development of therapies for human diseases such as cancer. Although much useful gene expression profiling data for tumor cell lines is available, microarray data for miRNAs and mRNAs in the human HepG2 cell line have only been compared with that of other cell lines separately. The relationship between miRNAs and mRNAs in integrated expression profiles for HepG2 cells is still unknown. To explore the miRNA-mRNA correlations in hepatocellular carcinoma (HCC) cells, we performed miRNA and mRNA expression profiling in HepG2 cells and normal liver HL-7702 cells at the genome scale using next-generation sequencing technology. We identified 193 miRNAs that are differentially expressed in these two cell lines. Of these, 89 miRNAs were down-regulated in HepG2 cells compared with HL-7702 cells, while 104 miRNAs were up-regulated. We also observed 3035 mRNAs that are significantly dys-regulated in HepG2 cells. We then performed an integrated analysis of the expression data for differentially expressed miRNAs and mRNAs and found several miRNA-mRNA pairs that are significantly correlated in HepG2 cells. Further analysis suggested that these differentially expressed genes were enriched in four tumorigenesis-related signaling pathways, namely, ErbB, JAK-STAT, mTOR, and WNT, which until now had not been fully reported. Our results could be helpful in understanding the mechanisms of HCC occurrence and development. PMID- 25014138 TI - A further rec(X)dup p and compilation of 23 cases. Comment on "molecular genetic and cytogenetic characterization of a partial Xp duplication and Xq deletion in a patient with premature ovarian failure" by Kim et al. Gene, 2014. http://dx.doi.org/10.1016/j.gene.2013.10.026. PMID- 25014137 TI - Bioinformatics analysis of plant orthologous introns: identification of an intronic tRNA-like sequence. AB - Orthologous introns have identical positions relative to the coding sequence in orthologous genes of different species. By analyzing the complete genomes of five plants we generated a database of 40,512 orthologous intron groups of dicotyledonous plants, 28,519 orthologous intron groups of angiosperms, and 15,726 of land plants (moss and angiosperms). Multiple sequence alignments of each orthologous intron group were obtained using the Mafft algorithm. The number of conserved regions in plant introns appeared to be hundreds of times fewer than that in mammals or vertebrates. Approximately three quarters of conserved intronic regions among angiosperms and dicots, in particular, correspond to alternatively-spliced exonic sequences. We registered only a handful of conserved intronic ncRNAs of flowering plants. However, the most evolutionarily conserved intronic region, which is ubiquitous for all plants examined in this study, including moss, possessed multiple structural features of tRNAs, which caused us to classify it as a putative tRNA-like ncRNA. Intronic sequences encoding tRNA like structures are not unique to plants. Bioinformatics examination of the presence of tRNA inside introns revealed an unusually long-term association of four glycine tRNAs inside the Vac14 gene of fish, amniotes, and mammals. PMID- 25014139 TI - Analysis of connection networks among miRNAs differentially expressed in early gastric cancer for disclosing some biological features of disease development. AB - This paper first identified differentially expressed miRNAs associated with early gastric cancer and then respectively constructed relevant connection networks among the identified differentially expressed miRNAs that corresponded to early gastric cancer and control tissues. Twenty-three differentially expressed miRNAs were identified, 18 of which were different with the related results on the same data, and they provide great discriminatory power between patients and controls. There are not only conserved unchangeable sub-networks but also different sub networks between the two connection networks. From the consistency and differences between two connection networks, we disclosed several new biological features that promote early gastric cancer development. This study shows 23 miRNAs that are early gastric cancer-specific and are worthy to do further experimental studies. The revealed biological features for early gastric cancer will provide new insights into improved understanding of the molecular mechanisms of this disease. PMID- 25014140 TI - Association between the IRS1 and FTO genes regulates body weight in rabbits. AB - Insulin receptor substrate (IRS) proteins play key roles in signal transduction in insulin and insulin-like growth factor signaling to control postnatal growth. The fat mass and obesity-associated (FTO) protein also play an essential role in postnatal growth. The aim of this study was to investigate the association between the IRS1 and FTO genes and the regulation of growth traits in rabbits. A total of nine synonymous SNPs were detected in the IRS1 coding sequence using direct sequencing, and the c.189G>T and c.2574G>A SNPs from two linkage disequilibrium blocks were further genotyped for association analysis in 216 New Zealand rabbits. The association results revealed that the TT genotype of c.189G>T and the AA genotype of c.2574G>A were significantly associated with higher body weight at 70 (BW70) and 84 (BW84) days of age and with higher average daily gain (P<0.05). Linear-regression analysis revealed that the two-gene combination model of FTO c.499G>A and IRS1 c.2574G>A was associated with BW70 and BW84. The combination model of the GA genotype of FTO c.499G>A with the AA genotype of IRS1 c.2574G>A was associated with preferred values for BW70 and BW84. The performance values for the FTO c.499G>A genotypes after stratification with regard to the IRS1 c.189G>T genotypes revealed that the TT genotype of IRS1 c.189G>T reduced the FTO c.499G>A significance associated with BW70 and BW84. Together, our data indicated that the IRS1 gene was associated with growth traits in rabbits. The IRS1 and FTO combination model may be exploited to assist breeders in selecting rabbits with preferred body weight. PMID- 25014141 TI - Mitomycin-C for mucous membrane overgrowth in OOKP eyes. AB - PURPOSE: The aim of this study was to report the use of mitomycin-C (MMC) in the treatment of mucous membrane overgrowth in eyes with osteo-odonto keratoprosthesis (OOKP). METHODS: Records of 4 cases with mucous membrane overgrowth after stage 2 OOKP surgery were reviewed. RESULTS: All the patients had undergone a mucous membrane trimming procedure followed by MMC application. None of the patients had any episode of recurrence of the mucous membrane overgrowth after a single application of MMC in the follow-up period that ranged from 1 to 11 years. CONCLUSIONS: MMC can successfully arrest mucous membrane overgrowth in OOKP-implanted eyes including refractory cases. PMID- 25014142 TI - Use of topical colistin in multiple drug-resistant Pseudomonas aeruginosa bacterial keratitis. AB - PURPOSE: The aim of this study was to report the utility of topical colistin in multi-drug resistant Pseudomonas aeruginosa bacterial keratitis. METHODS: Retrospective interventional case series included 8 patients with culture-proven multi-drug resistant P. aeruginosa (MDR-PA) bacterial keratitis who presented from June 2011 to January 2012 and were treated with colistin 0.19% as monodrug therapy. Clinical/microbiological data were collected from medical records. All patients underwent microbiological corneal scraping. Intensive half-hourly therapy with broad-spectrum antibiotics was changed to colistin 0.19% when antibiotic sensitivity reports were available. The outcome was a "complete success" if resolution of infection occurred with scar formation without any subsequent recurrence up to 2 weeks and "partial success" if it also required a cyanacrylate glue application. The outcome was a "failure" if the patient required a therapeutic graft or if the infection could not be controlled and the eye needed evisceration. RESULTS: The mean age was 45 +/- 16 years; the M:F ratio was 1:1. Seven patients had a history of ocular surgery. The mean size of the infiltrate was 15.41 +/- 22.2 mm and was full thickness in 5 patients. Success was achieved in 7 out of 8 patients, and the infiltrate gradually decreased with resolution of infection in a mean duration of 30.5 +/- 16 days. Complete and partial success were noted in 4 and 3 patients, respectively. The final visual acuity was 20/60 or better in 4 patients. One patient required a sclerocorneal patch graft. No complications of topical colistin were noticed. CONCLUSIONS: The early use of topical colistin 0.19% was found to be a safe and effective alternative in the management of multi-drug resistant P. aeruginosa bacterial keratitis. PMID- 25014143 TI - Long-term safety and efficacy of high-fluence collagen crosslinking of the vehicle cornea in Boston keratoprosthesis type 1. AB - PURPOSE: The aim of this study was to evaluate the safety and efficacy of very high-fluence collagen crosslinking (CXL) as a means of achieving increased corneal rigidity and reduced enzymatic digestion in the vehicle cornea of Boston keratoprosthesis (KPro) type 1. METHODS: Eleven consecutive patients fitted with a KPro (5 with a previous repeat cornea graft failure, 4 with ocular cicatricial pemphigoid, and 2 with chemical burn) underwent donor vehicle cornea pretreatment with very high-fluence prophylactic CXL in a 2-step procedure. First, the donor cornea was crosslinked with an intrastromal riboflavin instillation through a femtosecond laser-created pocket. This was followed up with a superficial CXL treatment. On the completion of the CXL pretreatment, the cornea center was trephined with the femtosecond laser, and the KPro was fitted onto the crosslinked donor cornea. Visual acuity, corneal surface, and donor vehicle cornea stability were evaluated. Follow-up evaluations were conducted over the next 9 years with a mean of 7.5 years. RESULTS: Mean uncorrected visual acuity improved from light perception to 20/60. One patient required a follow-up surgery, because of significant melt in the host cornea. None of the eyes developed melts and/or infection, especially on the vehicle cornea on which the KPro was fitted. CONCLUSIONS: Pretreatment with intrastromal and superficial very high-fluence CXL in conjunction with Boston type 1 KPro seems to be a safe and effective adjunctive treatment for achieving increased vehicle donor cornea rigidity. Additionally, there is an increased resistance to enzymatic degradation. This application may serve to enhance the biomechanical stability and external disease resistance of the donor vehicle cornea in patients with advanced external disease. PMID- 25014144 TI - Toxicity of intrastromal voriconazole injection on corneal endothelium in rabbits. AB - PURPOSE: The aim of this study was to evaluate the toxicity of intrastromally injected voriconazole on corneal endothelial cells in rabbits. METHODS: In total, 32 eyes of 16 rabbits (8 eyes for each group) were divided into 4 groups according to the concentration of voriconazole [group A: 50 MUg/0.1 mL (0.05%), group B: 100 MUg/0.1 mL (0.1%), group C: 250 MUg/0.1 mL (0.25%), or group D: 500 MUg/0.1 mL (0.5%)]. Right eyes were injected intrastromally with voriconazole at concentrations of 50 MUg/0.1 mL, 100 MUg/0.1 mL, 250 MUg/0.1 mL, or 500 MUg/0.1 mL. Left eyes were injected intrastromally with isotonic saline as controls. Central corneal thickness and endothelial cell counts were measured before and at 6 hours, 1 day, and 1 week after the injection was given. Corneas were then harvested for transmission electron microscopy. RESULTS: Only the 0.5% group did not significantly recover from corneal edema 1 week after the injection (P = 0.167, P = 0.051, P = 0.086, P = 0.001 in groups A-D, respectively). There were significant differences in endothelial cell counts for the 0.1% and 0.25% groups (P = 0.077, P = 0.019, P = 0.008 in groups A-C, respectively). Transmission electron microscopy evaluation revealed definite necrotic changes in endothelial cells at concentrations of 0.1%, 0.25%, and 0.5%, but only microstructural changes at a concentration of 0.05%. CONCLUSIONS: Our results suggest that voriconazole could be injected safely into the intrastromal layer at a concentration of 0.05% with low endothelial cell toxicity. However, injections should be administered with caution because of the risk of microstructural damage. PMID- 25014145 TI - Novel method to avoid the open-sky condition in penetrating keratoplasty: covered cornea technique. AB - PURPOSE: The aim of this study was to present a novel technique to avoid the open sky condition in pediatric and adult penetrating keratoplasty (PK). METHODS: Seventy-two eyes of 65 infants and children and 44 eyes of 44 adult patients were operated on using this technique. After trephining the recipient cornea up to a depth of 50% to 70%, the anterior chamber was entered at 1 point. Then, only a 2 clock hour segment of the recipient button was incised, and this segment was sutured to the recipient rim with a single tight suture. The procedure was repeated until the entire recipient button was excised and resutured. The donor corneal button was sutured to the recipient corneal rim. The sutures between the recipient button and the rim were then cut off, and the recipient button was drawn out. RESULTS: None of the patients operated on with this technique developed complications related to the open-sky condition. Visual acuities, graft failure rates, and endothelial cell loss were comparable with the findings of studies performed for conventional PK. CONCLUSIONS: The technique described avoids the open-sky condition during the entire PK procedure. Endothelial cell loss rates are acceptable. PMID- 25014146 TI - Screening of refractive surgery candidates for LASIK and PRK. AB - PURPOSE: The aim of this study was to evaluate exclusion criteria in screening patients for refractive surgery. METHODS: Patients screened for initial refractive surgery by a single surgeon at the Cole Eye Institute (Cleveland Clinic) between 2007 and 2012 were reviewed. Exclusion criteria for patients who were not offered refractive surgery based on history and/or examination parameters were analyzed. RESULTS: A total of 1067 refractive candidates were enrolled in the study. Five hundred nineteen (48.6%) were male and 548 (51.4%) were female with a mean age of 39 +/- 12 (range, 17-78) years. Refractive surgery was performed in 657 (61.6%) patients, and photorefractive keratectomy was considered the best option for 106 (9.9%) patients. Four hundred ten (38.4%) of all screened patients did not have refractive surgery, and 134 of these patients (12.6%) were considered to have contraindications for laser in situ keratomileusis and photorefractive keratectomy. Among the excluded patients, 69 (51.5%) were male and 65 (48.5%) were female with a mean age of 40 +/- 14 (range, 18-78) years. Abnormal corneal topography (34.3%) and low or insufficient corneal thickness (23.1%) were the most common reasons for exclusion. High myopia (10.5%) and (insipient or definite) cataract (9.7%) were also common reasons for exclusion. Other common factors for exclusion were high hyperopia (3.7%), need to wear reading glasses after surgery (3.7%), and severe dry eye unresponsive to treatment (3.7%). CONCLUSIONS: Abnormal corneal topography and low, or insufficient, corneal thickness remain the most common exclusion factors for corneal refractive surgery. Factors such as cataract, too high of correction, and severe dry eye are also common reasons for exclusion of patients. PMID- 25014147 TI - Low-dose pulsed intravenous cyclophosphamide for severe ocular cicatricial pemphigoid in elderly patients. AB - PURPOSE: Ocular cicatricial pemphigoid (OCP) is a relatively rare autoimmune disease affecting elderly patients and causing severe symptoms that may culminate in blindness. Treatment is based on immunosuppression, but optimal regimens have not been established. METHODS: A prospective unmasked case series of all patients with severe OCP who gave consent and completed treatment and >=6 months of follow up in the cornea and immunomodulation outpatient clinics of an academic hospital. Monthly pulses of intravenous cyclophosphamide (IVC; 500 mg) were administered with ondansetron and adjusted according to response. RESULTS: Over 14 years, 13 patients (median age 77 years) met inclusion criteria. All had bilateral OCP (2 eyes were previously blind), but extraocular involvement was rare (1/13). Three to 28 pulses were given, and the patients were followed up for a median of 32 (range, 6-167) months. Remission of inflammation in both eyes was achieved in 12 patients (92%). Vision improved in 5 of 13 patients, stabilized in another 5 (combined, 77%), and worsened in only 3 patients. One patient's condition flared up during treatment that responded to steroids and increasing IVC frequency. In 4 patients and 6 eyes (25%), cicatrization progressed (usually, Foster stages 1-3). Two late relapses occurred and responded to retreatment. IVC was generally well tolerated, although nausea led to modification in 2 patients. One patient developed candida keratitis. CONCLUSIONS: Compared with other treatment modalities, low-dose monthly pulse IVC is found to be a relatively safe, simple, and usually effective alternative immunosuppressive treatment in severe OCP. PMID- 25014148 TI - Microkeratome-assisted two-stage technique of superficial anterior lamellar keratoplasty for Reis-Bucklers corneal dystrophy. AB - PURPOSE: The aim of this study was to describe a microkeratome-assisted 2-stage technique of superficial anterior lamellar keratoplasty (SALK) to manage Reis Bucklers corneal dystrophy (RBCD). METHODS: A microkeratome was used to create a 9-mm, 140-MUm-thick corneal flap in the first stage. Four weeks later, in the second stage, a Hessberg-Baron suction trephine was used to perform a 7.0-mm central trephination up to a depth of 150 MUm, within the corneal flap. Donor lamellar tissue was prepared using a microkeratome system, after which a vacuum punch was used to trephine a 7.0-mm lamellar button. This donor button was used to replace the central corneal flap in the recipient cornea without using any sutures. A bandage contact lens was applied for 2 weeks. RESULTS: This modified technique of staged sutureless SALK was used in 4 eyes of 2 patients with RBCD. Postoperatively, all eyes experienced an improvement in both uncorrected and best spectacle-corrected visual acuities. The average best spectacle-corrected visual acuity was 20/30 at the last follow-up (19 months, range 16-22 months). The cornea remained clear in all eyes until the last follow-up without any evidence of recurrence of RBCD. CONCLUSIONS: The staged technique of microkeratome assisted SALK allows the replacement of superficial corneal stroma without the necessity for any sutures and seems to be a safe and effective method for the treatment of RBCD. PMID- 25014149 TI - Influence of age and gender on corneal biomechanical properties in a healthy Italian population. AB - PURPOSE: The aim of this study was to assess corneal hysteresis (CH) and corneal resistance factor (CRF) in healthy subjects, to evaluate the relationship with age, and to investigate possible associations with other ocular factors. METHODS: Four hundred Italian subjects (male-to-female ratio, 168:232; mean age, 58.8 +/- 17.2 years) were included and divided into 5 subgroups based on age. CH, CRF, and central corneal thickness (CCT) were measured by using the Ocular Response Analyzer and the integrated handheld pachymeter, and their relationship with gender, age, and ocular factors was evaluated. RESULTS: The mean CH, CRF, and CCT values were 10 +/- 1.6 mm Hg, 10.5 +/- 1.7 mm Hg, and 532.2 MUm, respectively. Women had a lower mean CH (9.9 vs. 10.2 mm Hg; P = 0.04) and CRF (10.3 vs. 10.8 mm Hg; P = 0.03) than did men. The youngest subjects had the highest CH (11.2 +/- 1.5 mm Hg), whereas the oldest patients had the lowest CH values (9 +/- 1.1 mm Hg). No significant differences in CRF were observed between age groups. CH and CRF showed a positive correlation (r = 0.58; P < 0.001), and both had a positive association with CCT (r = 0.27; P < 0.001 and r = 0.57; P < 0.001, respectively). The strongest correlations were observed between Goldmann-correlated intraocular pressure (IOP) and corneal-compensated IOP (r = 0.68; P < 0.001) and between Goldmann-correlated IOP and Goldmann applanation tonometry (r = 0.88; P < 0.001). CONCLUSIONS: Gender and advancing age may influence corneal biomechanical properties. In our population, CH decreased with aging, and men demonstrated a higher CH and CRF than women did. Further, CH, CRF, and CCT were significantly related. PMID- 25014150 TI - Use of topical bevacizumab for conjunctival intraepithelial neoplasia. AB - PURPOSE: To report our experience in the treatment of intraepithelial neoplasia of the conjunctiva using topical bevacizumab. METHODS: Ten eyes of 10 patients with conjunctival neoplasia received 25 mg/mL bevacizumab topically. Changes in the lesions were documented weekly using digital photography. After topical treatment, excisional biopsy was performed. RESULTS: The mean age of the patients was 60.5 +/- 12 (33-77) years. The mean duration of topical treatment was 7.8 +/- 1.3 (5-14) weeks. The size and vascularity of the tumors reduced weekly. All patients underwent excisional biopsy, cryotherapy, and amnion membrane transplantation. The histopathologic diagnosis of the lesions was carcinoma in situ. No recurrence was observed during the follow-up of patients for 6 months. CONCLUSIONS: Topical bevacizumab is an effective treatment to reduce the tumor size before surgery and may be a good alternative for adjuvant therapy of conjunctival neoplasms. PMID- 25014152 TI - Sub-tenon triamcinolone acetonide injections for topical medication intolerance in chronic blepharokeratoconjunctivitis. AB - PURPOSE: To report the efficacy of sub-Tenon triamcinolone acetonide (TA) injections for chronic blepharokeratoconjunctivitis (BKC) in 2 patients who were intolerant to topical therapies. METHODS: In this retrospective observational case series, the records of 2 patients with chronic BKC who received sub-Tenon TA injections were reviewed. RESULTS: Both patients, a 4-year-old girl and a 21-year old developmentally delayed man, were managed successfully with sub-Tenon TA injections. The treatment resulted in resolution of symptoms, diminished corneal haze, reduced conjunctival injection, and improved visual acuity without complications. CONCLUSIONS: This case series illustrates the potential benefit of using sub-Tenon TA injections for chronic BKC in patients who are intolerant to topical corticosteroid therapy. Therefore, sub-Tenon TA injections may be considered for patients with vision-threatening BKC and nonadherence to topical therapies. PMID- 25014151 TI - UV cross-linking of donor corneas confers resistance to keratolysis. AB - PURPOSE: The aim of this study was to develop a modified ex vivo corneal cross linking method that increases stromal resistance to enzymatic degradation for use as a carrier for the Boston keratoprosthesis. METHODS: Ex vivo cross-linking of human corneas was performed using Barron artificial anterior chambers. The corneas were deepithelialized, pretreated with riboflavin solution (0.1% riboflavin/20% dextran), and irradiated with ultraviolet A (UV-A) light (lambda = 370 nm, irradiance = 3 mW/cm) for various durations. The combined effect of UV-A and gamma (gamma) irradiation was also assessed using the commercially available gamma-irradiated corneal donors. The corneas were then trephined and incubated at 37 degrees C with 0.3% collagenase A solution. The time to dissolution of each cornea was compared across treatments. RESULTS: Deepithelialized corneas (no UV light, no riboflavin) dissolved in 5.8 +/- 0.6 hours. Cross-linked corneas demonstrated increased resistance to dissolution, with a time to dissolution of 17.8 +/- 2.6 hours (P < 0.0001). The corneal tissues' resistance to collagenase increased with longer UV-A exposure, reaching a plateau at 30 minutes. Cross linking both the anterior and posterior corneas did not provide added resistance when compared with cross-linking the anterior corneas only (P > 0.05). gamma irradiated corneas dissolved as readily as deepithelialized controls regardless of whether they were further cross-linked (5.6 +/- 1.2 hours) or not (6.1 +/- 0.6 hours) (P = 0.43). CONCLUSIONS: Collagen cross-linking of the deepithelialized anterior corneal surface for 30 minutes conferred optimal resistance to in vitro keratolysis by collagenase A. PMID- 25014153 TI - Bilateral adult epibulbar xanthogranulomas suspicious for Erdheim-Chester disease. AB - PURPOSE: The aim of this study was to report the clinical, imaging, and histopathological findings of bilateral, conjunctival adult-onset xanthogranulomas that raised the prospect of a mild form of Erdheim-Chester disease. METHODS: This is a case report. RESULTS: A 35-year-old white male complaining of ocular irritation, presented with bilateral, nasal and temporal, yellow, elevated conjunctival lumps first noticed 1.5 years back, which were not associated with other ocular findings. The lesions were firm, attached to the underlying episclera, and measured 1.1 * 0.9, 1.1 * 0.8, 1.2 * 0.5, and 0.5 * 0.5 cm in the temporal and nasal right and left eyes, respectively. Each mass was fleshy with vascularity at the peripheral margin. Histopathologic evaluation after excisional biopsy revealed lipidized xanthoma cells, multiple Touton giant cells, and lymphocytes. Immunohistochemical staining was positive for adipophilin (lipid), CD68, CD163 histiocytes, CD3 T cells (with CD8 cytotoxic T cells > CD4 T helper cells), and virtually no CD20 B cells or IgG4 plasma cells. The patient later acquired similar xanthogranulomatous subcutaneous lesions on the extremities. Positron emission tomography scans showed sclerosis in the medullary cavities of the tibia and the radius of both legs and arms, and an absence of retroperitoneal lesions. A normal serum immunoelectrophoresis and the absence of a BRAF gene mutation were demonstrated. CONCLUSIONS: Adult-onset xanthogranuloma can present as a solitary conjunctival mass without periocular or orbital involvement. The clinical, histopathologic, and radiologic findings in this case are suggestive of Erdheim-Chester disease without displaying any life-threatening lesions to date. Histopathologic and imaging studies can help in obtaining a diagnosis. Ophthalmologists should be aware that xanthogranulomatous conditions may have potential systemic implications, and a thorough systemic evaluation is recommended for lesions that initially seemed to be isolated in nature. PMID- 25014155 TI - OCT imaging of a traumatic endothelial ring. AB - PURPOSE: To report a case of a traumatic corneal endothelial ring sustained from a nonblast injury and its resolution with corneal optical coherence tomography (OCT) imaging. METHODS: The authors present a report of the clinical case with imaging of the lesion using corneal OCT. RESULTS: A 59-year-old man presented 1 day after sustaining a nonpenetrating foreign body injury to his cornea. Slit lamp examination showed an endothelial annular lesion of 3.3 mm in diameter, which was grey-white in color. No other signs of traumatic injury were present. Stromal edema and endothelial disruption were demonstrated on corneal OCT. This resolved completely on review. CONCLUSIONS: We describe a concussive injury that specifically disrupts endothelial cells in an annulus on the perimeter of the impact zone. This results in transient stromal edema immediately anterior to the injured endothelial cells. These OCT findings corroborate previous animal studies on the mechanism and sequelae of injury. PMID- 25014154 TI - Isotonic riboflavin and HPMC with accelerated cross-linking protocol. AB - PURPOSE: The aim of this study was to monitor corneal pachymetry changes during accelerated collagen cross-linking (CXL) for keratoconus while using isotonic riboflavin with HPMC. METHODS: All consecutive patients who underwent CXL for progressive keratoconus, using accelerated protocol and isotonic riboflavin with HPMC, from December 2012 to September 2013 were included in the study. The corneal pachymetry measurements were obtained at different time points: after epithelial removal, after riboflavin application for 20 minutes, and after ultraviolet A irradiation for 10 minutes at 9 mW/cm. RESULTS: A total of 14 eyes of 14 consecutive patients were included in this study. The mean age of the patients was 19 +/- 8 years. There were 8 left eyes and 6 right eyes. After epithelial debridement, the thinnest pachymetric readings were between 324 and 452 MUm (average, 401.4 +/- 40.7 MUm). No significant difference (P = 0.80) was found between the deepithelialized corneal thickness and after 20 minutes of isotonic riboflavin with HPMC (pachymetric average, 405.3 +/- 37.5 MUm). Pachymetric average after ultraviolet A irradiation was 419.29 +/- 20.60 MUm. There was no statistical significant change in the corneal thickness after the irradiation (P = 0.24). CONCLUSIONS: During corneal CXL using isotonic riboflavin and HPMC with accelerated cross-linking protocol, no significant decline in the corneal thickness was demonstrated. PMID- 25014156 TI - Reproducibility of grayscale and radiofrequency IVUS data acquisition in stented coronary arteries. AB - OBJECTIVES: Variability in data acquisition from intervened coronary arteries could represent a source of error that has implications for the design of serial stent studies. We assessed inter-pullback reproducibility of volumetric grayscale and radiofrequency intravascular ultrasound (IVUS) data in stented coronary arteries. DESIGN: Fifteen patients with coronary artery lesions treated with stent implantation were included and examined with two separate pullbacks using the Eagle Eye Gold-phased array 20 MHz IVUS catheter (Volcano). The arteries were divided into five segments, giving a total of 150 sub-segments for analyses. Matching of frames was performed using landmarks that were clearly visible in coronary angiography and intravascular pullbacks. Data were analyzed off-line at an independent Corelab. RESULTS: The inter-pullback reproducibility of geometrical data was very good for non-stented segments with relative differences less than 5% between pullbacks for lumen-, vessel-, and plaque volumes. For stented segments reproducibility was poorer with relative differences between pullbacks in the range of 5-10%. The inter-pullback reproducibility of compositional data demonstrated large standard deviations of relative differences, indicating a weaker agreement. CONCLUSIONS: Agreements between pullbacks were weaker in stented than those in non-stented segments. Based on our data, future longitudinal IVUS studies in intervened vessels should account for a variability of 5-10% attributed to the acquisition of images. PMID- 25014157 TI - Binding site preorganization and ligand discrimination in the purine riboswitch. AB - The progress of RNA research has suggested a wide variety of RNA molecules as possible targets for pharmaceutical drug molecules. Structure-based computational methods for predicting binding modes and affinities are now important tools in drug discovery, but these methods have mainly been focused on protein targets. Here we employ molecular dynamics free-energy perturbation calculations and the linear interaction energy method to analyze the energetics of ligand binding to purine riboswitches. Calculations are carried out for 14 different purine complexes with the guanine and adenine riboswitches in order to examine their ligand recognition principles. The simulations yield binding affinities in good agreement with experimental data and rationalize the selectivity of the riboswitches for different ligands. In particular, it is found that these receptors have an unusually high degree of electrostatic preorganization for their cognate ligands, and this effect is further quantified by explicit free energy calculations, which show that the standard electrostatic linear interaction energy parametrization is suboptimal in this case. The adenine riboswitch specifically uses the electrostatic preorganization to discriminate against guanine by preventing the formation of a G-U wobble base pair. PMID- 25014158 TI - Cytoplasmic and nuclear toxicity of 3,5-dimethylaminophenol and potential protection by selenocompounds. AB - Most common alkylanilines in the environment are 2,6-dimethylaniline (2,6-DMA), 3,5-dimethylaniline (3,5-DMA), and 3-ethylaniline (3-EA). 3,5-Dimethylaminophenol (3,5-DMAP), a metabolite of 3,5-DMA, is of particular interest, as it is potentially genotoxic. Supplementation with organic or inorganic forms of selenium (Se) may reduce toxicity following exposure to a wide variety of environmental chemicals. This study was designed to evaluate the protective effects of sodium selenite (SS) and selenomethionine (SM) at varying time points of supplementation (24 h and 72 h) against the cytotoxicity, reactive oxygen species (ROS) production, and genotoxicity of 3,5-DMAP in CHO AS52 cells. 3,5 DMAP caused dose-dependent increase of cytotoxicity, ROS production and genotoxicity, and generated free radicals in the nuclei. Thioredoxin reductase (TrxR), catalase and glutathione reductase activities, and glutathione levels were significantly lower while lipid peroxidation and protein oxidation levels were higher after 3,5-DMAP treatment in both cytoplasm and the nucleus vs. control. After 24 h, both SS and SM provided protection in antioxidant/oxidant status of the 3,5-DMAP-treated cells; however other than supplying higher glutathione peroxidase and TrxR activities, 72 h supplementation did not provide advanced improvement. Selenocompounds may be beneficial against cytotoxic and genotoxic potential of 3,5-DMAP and might protect both nucleus and cytoplasm following exposure to alkylanilines. PMID- 25014159 TI - Assessment of dietary exposure to bisphenol A in the French population with a special focus on risk characterisation for pregnant French women. AB - Bisphenol A (BPA) is used in a wide variety of products and objects for consumers use (digital media such as CD's and DVD's, sport equipment, food and beverage containers, medical equipment). Here, we demonstrate the ubiquitous presence of this contaminant in foods with a background level of contamination of less than 5 MUg/kg in 85% of the 1498 analysed samples. High levels of contamination (up to 400 MUg/kg) were found in some foods of animal origin. We used a probabilistic approach to calculate dietary exposure from French individual consumption data for infants under 36 months, children and adolescents from 3 to 17 years, adults over 18 years and pregnant women. The estimated average dietary exposure ranged from 0.12 to 0.14 MUg/kg body weight per day (bw/d) for infants, from 0.05 to 0.06 MUg/kg bw/d for children and adolescents, from 0.038 to 0.040 MUg/kg bw/d for adults and from 0.05 to 0.06 MUg/kg bw/d for pregnant women. The main sources of exposure were canned foods (50% of the total exposure), products of animal origin (20%) and 30% as a background level. Based on the toxicological values set by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) for pregnant women, the risk was non negligible. Thus, we simulated scenarios to study the influence of cans and/or food of animal origin on the BPA related risk for this specific population. PMID- 25014160 TI - Ubiquitin signaling: extreme conservation as a source of diversity. AB - Around 2 * 103-2.5 * 103 million years ago, a unicellular organism with radically novel features, ancestor of all eukaryotes, dwelt the earth. This organism, commonly referred as the last eukaryotic common ancestor, contained in its proteome the same functionally capable ubiquitin molecule that all eukaryotic species contain today. The fact that ubiquitin protein has virtually not changed during all eukaryotic evolution contrasts with the high expansion of the ubiquitin system, constituted by hundreds of enzymes, ubiquitin-interacting proteins, protein complexes, and cofactors. Interestingly, the simplest genetic arrangement encoding a fully-equipped ubiquitin signaling system is constituted by five genes organized in an operon-like cluster, and is found in archaea. How did ubiquitin achieve the status of central element in eukaryotic physiology? We analyze here the features of the ubiquitin molecule and the network that it conforms, and propose notions to explain the complexity of the ubiquitin signaling system in eukaryotic cells. PMID- 25014161 TI - MicroRNAs Control Macrophage Formation and Activation: The Inflammatory Link between Obesity and Cardiovascular Diseases. AB - Activation and recruitment of resident macrophages in tissues in response to physiological stress are crucial regulatory processes in promoting the development of obesity-associated metabolic disorders and cardiovascular diseases. Recent studies have provided compelling evidence that microRNAs play important roles in modulating monocyte formation, macrophage maturation, infiltration into tissues and activation. Macrophage-dependent systemic physiological and tissue-specific responses also involve cell-cell interactions between macrophages and host tissue niche cell components, including other tissue resident immune cell lineages, adipocytes, vascular smooth muscle and others. In this review, we highlight the roles of microRNAs in regulating the development and function of macrophages in the context of obesity, which could provide insights into the pathogenesis of obesity-related metabolic syndrome and cardiovascular diseases. PMID- 25014162 TI - Separating pairing from quantum phase coherence dynamics above the superconducting transition by femtosecond spectroscopy. AB - In classical superconductors an energy gap and phase coherence appear simultaneously with pairing at the transition to the superconducting state. In high-temperature superconductors, the possibility that pairing and phase coherence are distinct and independent processes has led to intense experimental search of their separate manifestations. Using femtosecond spectroscopy methods we now show that it is possible to clearly separate fluctuation dynamics of the superconducting pairing amplitude from the phase relaxation above the critical transition temperature. Empirically establishing a close correspondence between the superfluid density measured by THz spectroscopy and superconducting optical pump-probe response over a wide region of temperature, we find that in differently doped Bi(2)Sr(2)CaCu(2)O(8+delta) crystals the pairing gap amplitude monotonically extends well beyond Tc, while the phase coherence shows a pronounced power-law divergence as T -> T(c), thus showing that phase coherence and gap formation are distinct processes which occur on different timescales. PMID- 25014163 TI - Why do we laugh at misfortunes? An electrophysiological exploration of comic situation processing. AB - The goal of the present study was to shed some light on a particular kind of humour, called slapstick, by measuring brain bioelectrical activity during the perception of funny vs. non-funny pictures involving misfortunate circumstances. According to our hypothesis, the element mostly providing a comic feature in a misfortunate situation is the facial expression of the victims: the observer's reaction will usually be laughing only if the victims will show a funny bewilderment face and not a painful or anger expression. Several coloured photographs depicting people involved in misfortunate situations were presented to 30 Italian healthy volunteers, while their EEG was recorded. Three different situations were considered: people showing a painful or an angry expression (Affective); people showing a bewilderment expression and, so, a comic look (Comic); people engaged in similar misfortunate situations but with no face visible (No Face). Results showed that the mean amplitude of both the posterior N170 and anterior N220 components was much larger in amplitude to comic pictures, than the other stimuli. This early response could be considered the first identification of a comic element and evidence of the compelling and automatic response that usually characterizes people amused reaction during a misfortune. In addition, we observed a larger P300 amplitude in response to comic than affective pictures, probably reflecting a more conscious processing of the comic element. Finally, no face pictures elicited an anteriorly distributed N400, which might reflect the effort to comprehend the nature of the situation displayed without any affective facial information, and a late positivity, possibly indexing a re-analysis processing of the unintelligible misfortunate situation (comic or unhappy) depicted in the No Face stimuli. These data support the hypothesis that the facial expression of the victims acts as a specific trigger for the amused feeling that observers usually experience when someone falls down. Overall, the data indicate the existence of a neural circuit that is capable of recognize and appreciate the comic element of a misfortunate situation in a group of young adults. PMID- 25014164 TI - Lysine methyltransferase Smyd2 suppresses p53-dependent cardiomyocyte apoptosis. AB - Apoptosis, or programmed cell death, is an essential physiological process for proper embryogenesis as well as for homeostasis during aging. In addition, apoptosis is one of the major mechanisms causing cell loss in pathophysiological conditions such as heart failure. Thus, inhibition of apoptosis is an important approach for preventive and therapeutic strategies. Here we show that the histone 3 lysine 4- and lysine 36-specific methyltransferase Smyd2 acts as an endogenous antagonistic player of p53-dependent cardiomyocyte apoptosis. Smyd2 protein levels were significantly decreased in cardiomyocytes upon cobalt chloride induced apoptosis or myocardial infarction, while p53 expression was enhanced. siRNA-mediated knockdown of Smyd2 in cultured cardiomyocytes further enhanced cobalt chloride-induced cardiomyocyte apoptosis. In contrast, Smyd2 overexpression resulted in marked methylation of p53 and prevented its accumulation as well as apoptotic cell death in an Hsp90-independent manner. Moreover, overexpression, of Smyd2, but not Smyd2Y240F lacking a methyl transferase activity, significantly rescued CoCl2-induced apoptosis in H9c2 cardioblasts. Finally, Smyd2 cardiomyocyte-specific deletion in vivo promoted apoptotic cell death upon myocardial infarction, which correlated with enhanced expression of p53 and pro-apoptotic Bax. Collectively, our data indicate Smyd2 as a cardioprotective protein by methylating p53. PMID- 25014165 TI - Binding of the extreme carboxyl-terminus of PAK-interacting exchange factor beta (betaPIX) to myosin 18A (MYO18A) is required for epithelial cell migration. AB - The PAK2/betaPIX/GIT1 (p21-activated kinase 2/PAK-interacting exchange factor beta/G protein-coupled receptor kinase-interactor 1) complex has been shown to distribute to both membrane ruffles and focal adhesions of cells, where it plays an important role in regulating focal adhesion turnover. However, the detailed mechanism underlying this regulation is largely unknown. We previously reported that MYO18Aalpha interacts via its carboxyl terminus with the PAK2/betaPIX/GIT1 complex through direct binding to betaPIX, and that knockdown of MYO18Aalpha in epithelial cells causes accumulation of the complex in focal adhesions and decreased cell migration ability (Hsu et al., 2010). The current study characterized the detailed MYO18Aalpha-betaPIX interaction mechanism and the biological significance of this interaction. We found that deletion of the carboxyl-terminal globular domain of MYO18Aalpha profoundly altered the cellular localization of betaPIX and inhibited cell migration. betaPIX interacts through its most carboxyl-terminus, PAWDETNL (639-646), with MYO18Aalpha and partially colocalized with MYO18Aalpha in membrane ruffles of cells, whereas betaPIX(1 638), a mutant with deletion of PAWDETNL, accumulated in focal adhesions. Both focal adhesion numbers and area in betaPIX(1-638)-expressing cells were greater than those in cells expressing wild-type betaPIX(FL). Further experiments using deletion mutants of MYO18A and betaPIX showed that disruption of MYO18A-betaPIX interaction not only impaired cell motility but also decreased Rac1 activity. Collectively, our data unravel the interaction regions between MYO18A and betaPIX and provide evidence for the critical role of this interaction in regulating cellular localization of betaPIX, Rac1 activity, and adhesion and migration in epithelial cells. PMID- 25014166 TI - Phosphorylation of RSK2 at Tyr529 by FGFR2-p38 enhances human mammary epithelial cells migration. AB - The members of p90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases are downstream effectors of MAPK/ERK pathway that regulate diverse cellular processes including cell growth, proliferation and survival. In carcinogenesis, RSKs are thought to modulate cell motility, invasion and metastasis. Herein, we have studied an involvement of RSKs in FGF2/FGFR2-driven behaviours of mammary epithelial and breast cancer cells. We found that both silencing and inhibiting of FGFR2 attenuated phosphorylation of RSKs, whereas FGFR2 overexpression and/or its stimulation with FGF2 enhanced RSKs activity. Moreover, treatment with ERK, Src and p38 inhibitors revealed that p38 kinase acts as an upstream RSK2 regulator. We demonstrate for the first time that in FGF2/FGFR2 signalling, p38 but not MEK/ERK, indirectly activated RSK2 at Tyr529, which facilitated phosphorylation of its other residues (Thr359/Ser363, Thr573 and Ser380). In contrast to FGF2-triggered signalling, inhibition of p38 in the EGF pathway affected only RSK2-Tyr529, without any impact on the remaining RSK phosphorylation sites. p38-mediated phosphorylation of RSK2-Tyr529 was crucial for the transactivation of residues located at kinase C-terminal domain and linker-region, specifically, in the FGF2/FGFR2 signalling pathway. Furthermore, we show that FGF2 promoted anchorage-independent cell proliferation, formation of focal adhesions and cell migration, which was effectively abolished by treatment with RSKs inhibitor (FMK). These indicate that RSK2 activity is indispensable for FGF2/FGFR2-mediated cellular effects. Our findings identified a new FGF2/FGFR2 p38-RSK2 pathway, which may play a significant role in the pathogenesis and progression of breast cancer and, hence, may present a novel therapeutic target in the treatment of FGFR2-expressing tumours. PMID- 25014167 TI - Impedimetric and amperometric bifunctional glucose biosensor based on hybrid organic-inorganic thin films. AB - A novel glucose biosensor with an immobilized mediator was studied using electrochemical impedance spectroscopy (EIS) and amperometry measurements. The biosensor has a characteristic ultrathin form and is composed of a self-assembled monolayer anchoring glucose oxidase (GOx) covered with Langmuir-Blodgett (LB) films of Prussian blue (PB). The immobilized PB in the LB films acts as a mediator and enables the biosensor to work under a low potential (0.0V vs. Ag/AgCl). In the EIS measurements, a dramatic decrease in charge transfer resistance (Rct) was observed with sequential addition of glucose, which can be attributed to enzymatic activity. The linearity of the biosensor response was observed by the variation of the sensor response (1/Rct) as a function of glucose concentration in the range 0 to 25mM. The sensor also showed linear amperometric response below 130mM glucose. The organic-inorganic system of GOx and PB nanoclusters demonstrated bifunctional sensing action, both amperometry and EIS modes, as well as long sensing stability for 4 days. PMID- 25014168 TI - Acid-catalyzed autohydrolysis of wheat straw to improve sugar recovery. AB - A comparison study of autohydrolysis and acid-catalyzed autohydrolysis of wheat straw was performed to understand the impact of acid addition on overall sugar recovery. Autohydrolysis combined with refining is capable of achieving sugar recoveries in the mid 70s. If the addition of a small amount of acid is capable of increasing the sugar recovery even higher it may be economically attractive. Acetic, sulfuric, hydrochloric and sulfurous acids were selected for acid catalyzed autohydrolysis pretreatments. Autohydrolysis with no acid at 190 degrees C showed the highest total sugar in the prehydrolyzate. Enzymatic hydrolysis was performed for all the post-treated solids with and without refining at enzyme loadings of 4 and 10 FPU/g for 96 h. Acid-catalyzed autohydrolysis at 190 degrees C with sulfurous acid showed the highest total sugar recovery of 81.2% at 4 FPU/g enzyme charge compared with 64.3% at 190 degrees C autohydrolysis without acid. PMID- 25014169 TI - Uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis: presentation and management. PMID- 25014170 TI - Water confinement in faujasite cages: a deuteron NMR investigation in a wide temperature range. 1. Low temperature spectra. AB - Deuteron NMR spectra were measured for D2O confined in NaX, NaY, and DY faujasites with various D2O loadings at temperatures ranging from T = 70 K to T = 200 K with the aim to study the molecular mobility of confined water as a function of Si/Al ratio and loading. The recorded spectra were fitted with linear combinations of representative spectral components. At low loading, with the number of water molecules per unit cell close to the abundance of sodium cations, a component related to pi-jumps of water deuterons about the 2-fold symmetry axis dominated. For loadings at levels 3 times and 5 times higher than the initial loading level, Pake dublets due to rigid water deuterons dominated the recorded spectra. A set of the quadrupole coupling constant values of localized water deuterons was derived from the analysis of the Pake dublets. Their values were attributed to deuteron positions corresponding to the locations at oxygen atoms in the faujasite framework and locations within hydrogen-bonded water clusters inside faujasite cages. The contributions of the different spectral components were observed to change with increasing temperature according to the Arrhenius law with a characteristic dynamic crossover point at T = 165 K. Below T = 165 K a spectral component was observed whose contribution changed with temperature, yielding the activation energy of about 2 kJ/mol, characteristic for jumps between inversion-related water positions in clusters. PMID- 25014171 TI - Synthesis of poly(N-isopropylacrylamide)-co-poly(phenylboronate ester) acrylate and study on their glucose-responsive behavior. AB - We introduced thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) into the polymer structure of poly(ethylene glycol)-block-poly(phenylboronate ester) acrylate (MPEG-block-PPBDEMA) by block and random polymerization pathways in order to investigate the effect of polymer architecture on the glucose responsiveness and enhance their insulin release controllability. By following the structure, the continuous PNIPAM shell of the triblock polymer MPEG-block PNIPAM-block-PPBDEMA collapsing on the glucose-responsive PPBDEMA core formed the polymeric micelles with a core-shell-corona structure, and MPEG-block-(PNIPAM rand-PPBDEMA) exhibited core-corona micelles in which the hydrophobic core consisted of PNIPAM and PPBDEMA segments when the environmental temperature was increased above low critical solution temperature (LCST) of PNIPAM. The micellar morphologies can be precisely controlled by temperature change between 15 and 37 degrees C. As a result, the introduction of PNIPAM greatly enhanced the overall stability of insulin encapsulated in the polymeric micelles in the absence of glucose over incubation 80 h at 37 degrees C. Comparing to MPEG-block-PNIPAM block-PPBDEMA, the nanocarriers from MPEG-block-(PNIPAM-rand-PPBDEMA) showed great insulin release behavior which is zero insulin release without glucose, low release at normal blood glucose concentration (1.0 mg/mL). Therefore, these nanocarriers may be served as promising self-regulated insulin delivery system for diabetes treatment. PMID- 25014172 TI - Self-assembly of nanoparticles employing polymerization-induced phase separation. AB - Nanoparticles (NPs) may be homogeneously dispersed in the precursors of a polymer (reactive solvent) by an adequate selection of their stabilizing ligands. However, the dispersion can become metastable or unstable in the course of polymerization. If this happens, NP-rich domains can be segregated by a process called polymerization-induced phase separation (PIPS). This occurs mainly due to the decrease in the entropic contribution of the reactive solvent to the free energy of mixing (increase in its average size) and, for a reactive solvent generating a cross-linked polymer, the additional contribution of the elastic energy in the post-gel stage. The extent of PIPS will depend on the competition between phase separation and polymerization rates. It can be completely avoided, limited to a local scale or conveyed to generate different types of NPs' aggregates such as crystalline platelets, self-assembled structures with a hierarchical order and partitioning at the interface, and bidimensional patterns of NPs at the film surface. The use of a third component in the initial formulation such as a linear polymer or a block copolymer, provides the possibility of generating an internal template for the preferential location and self-assembly of phase-separated NPs. Some illustrative examples of morphologies generated by PIPS in solutions of NPs in reactive solvents, are analyzed in this feature article. PMID- 25014174 TI - Metabolic engineering of Escherichia coli for efficient free fatty acid production from glycerol. AB - Crude glycerol, generated as waste by-product in biodiesel production process, has been considered as an important carbon source for converting to value-added bioproducts recently. Free fatty acids (FFAs) can be used as precursors for the production of biofuels or biochemicals. Microbial biosynthesis of FFAs can be achieved by introducing an acyl-acyl carrier protein thioesterase into Escherichia coli. In this study, the effect of metabolic manipulation of FFAs synthesis cycle, host genetic background and cofactor engineering on FFAs production using glycerol as feed stocks was investigated. The highest concentration of FFAs produced by the engineered stain reached 4.82g/L with the yield of 29.55% (g FFAs/g glycerol), about 83% of the maximum theoretical pathway value by the type II fatty acid synthesis pathway. In addition, crude glycerol from biodiesel plant was also used as feedstock in this study. The FFA production was 3.53g/L with a yield of 24.13%. The yield dropped slightly when crude glycerol was used as a carbon source instead of pure glycerol, while it still can reach about 68% of the maximum theoretical pathway yield. PMID- 25014173 TI - MSCs inhibit bone marrow-derived DC maturation and function through the release of TSG-6. AB - Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that are characterized by the ability to take up and process antigens and prime T cell responses. Mesenchymal stem cells (MSCs) are multipotent cells that have been shown to have immunomodulatory abilities, including inhibition of DC maturation and function in vivo and in vitro; however, the underlying mechanism is far from clear. In this study we found that MSCs can inhibit the maturation and function of bone marrow-derived DCs by releasing TSG-6. In the presence of MSCs, lower expression of mature DC surface phenotype (CD80, CD86, MHC-II, and CD11c) was observed. In addition, typical DC functions, such as the production of IL-12 and the ability to prime T cells, were decreased when co-cultured with MSCs. In contrast, knockdown of TSG-6 reduced the inhibitory effect of MSCs on DC. Moreover, we found that TSG-6 can suppress the activation of MAPKs, and NF-kappaB signaling pathways within DCs during Lipopolysaccharides (LPS) stimulation. In conclusion, we suggest that TSG-6 plays an important role in MSCs-mediated immunosuppressive effect on DC. PMID- 25014175 TI - The impact of anti-apoptotic gene Bcl-2? expression on CHO central metabolism. AB - Anti-apoptosis engineering is an established technique to prolong the viability of mammalian cell cultures used for industrial production of recombinant proteins. However, the effect of overexpressing anti-apoptotic proteins on central carbon metabolism has not been systematically studied. We transfected CHO S cells to express Bcl-2?, an engineered anti-apoptotic gene, and selected clones that differed in their Bcl-2? expression and caspase activity. (13)C metabolic flux analysis (MFA) was then applied to elucidate the metabolic alterations induced by Bcl-2?. Expression of Bcl-2Delta reduced lactate accumulation by redirecting the fate of intracellular pyruvate toward mitochondrial oxidation during the lactate-producing phase, and it significantly increased lactate re uptake during the lactate-consuming phase. This flux redistribution was associated with significant increases in biomass yield, peak viable cell density (VCD), and integrated VCD. Additionally, Bcl-2? expression was associated with significant increases in isocitrate dehydrogenase and NADH oxidase activities, both rate-controlling mitochondrial enzymes. This is the first comprehensive (13)C MFA study to demonstrate that expression of anti-apoptotic genes has a significant impact on intracellular metabolic fluxes, especially in controlling the fate of pyruvate carbon, which has important biotechnology applications for reducing lactate accumulation and enhancing productivity in mammalian cell cultures. PMID- 25014176 TI - Changes in cardiac aldosterone and its synthase in rats with chronic heart failure: an intervention study of long-term treatment with recombinant human brain natriuretic peptide. AB - The physiological mechanisms involved in isoproterenol (ISO)-induced chronic heart failure (CHF) are not fully understood. In this study, we investigated local changes in cardiac aldosterone and its synthase in rats with ISO-induced CHF, and evaluated the effects of treatment with recombinant human brain natriuretic peptide (rhBNP). Sprague-Dawley rats were divided into 4 different groups. Fifty rats received subcutaneous ISO injections to induce CHF and the control group (n=10) received equal volumes of saline. After establishing the rat model, 9 CHF rats received no further treatment, rats in the low-dose group (n=8) received 22.5 MUg/kg rhBNP and those in the high-dose group (n=8) received 45 MUg/kg rhBNP daily for 1 month. Cardiac function was assessed by echocardiographic and hemodynamic analysis. Collagen volume fraction (CVF) was determined. Plasma and myocardial aldosterone concentrations were determined using radioimmunoassay. Myocardial aldosterone synthase (CYP11B2) was detected by quantitative real-time PCR. Cardiac function was significantly lower in the CHF group than in the control group (P<0.01), whereas CVF, plasma and myocardial aldosterone, and CYP11B2 transcription were significantly higher than in the control group (P<0.05). Low and high doses of rhBNP significantly improved hemodynamics (P<0.01) and cardiac function (P<0.05) and reduced CVF, plasma and myocardial aldosterone, and CYP11B2 transcription (P<0.05). There were no significant differences between the rhBNP dose groups (P>0.05). Elevated cardiac aldosterone and upregulation of aldosterone synthase expression were detected in rats with ISO-induced CHF. Administration of rhBNP improved hemodynamics and ventricular remodeling and reduced myocardial fibrosis, possibly by downregulating CYP11B2 transcription and reducing myocardial aldosterone synthesis. PMID- 25014178 TI - Clinical outcomes of warfarin anticoagulation after balloon dilation alone for the treatment of Budd-Chiari syndrome complicated by old inferior vena cava thrombosis. AB - BACKGROUND: To evaluate the safety and clinical efficacy of warfarin anticoagulation after balloon dilation alone for the treatment of Budd-Chiari syndrome (BCS) complicated by old inferior vena cava (IVC) thrombosis. METHODS: From January 2008 to November 2013, 19 BCS patients complicated with old IVC thrombosis were treated with balloon dilation followed by oral administration of anticoagulant warfarin. Follow-up was performed at 1 week, then 1, 2, 3, 6, and 12 months after balloon dilation, and then annually thereafter. IVC patency and morphologic changes of the old thrombus were examined by ultrasound, and clinical symptoms and signs were determined by clinical examinations during follow-up. RESULTS: Successful IVC balloon dilation was achieved in the 19 patients (100%). Inferior vena cavography demonstrated the patency of IVC lumen, and the size of the old thrombus was not altered. The mean pressure gradient between IVC and the right atrium was reduced from 27.5 +/- 3.0 cm H2O (range, 22-35) before treatment to 5.4 +/- 1.3 cm H2O (range: 2-7) after treatment (t = 41.6, P < 0.05; 1 cm H2O = 0.098 kPa). Patients were followed up as outpatients for an average of 15.9 +/- 14.4 months (range, 3-66). Anticoagulation with warfarin was well tolerated in all patients after balloon dilation alone. Of the 19 patients, complete resolution of the old thrombus was achieved in 12 patients and partial resolution was achieved in 7 patients. Color Doppler ultrasound showed that 17 patients had IVC lumen patency, and 2 patients had IVC reocclusion. None of the patients had recurrence of thrombosis, symptomatic pulmonary embolism, and bleeding complications throughout the follow-up period. CONCLUSIONS: Our results indicate that warfarin anticoagulation after balloon dilation alone is a safe and effective therapy for BCS patients with old IVC thrombosis. PMID- 25014177 TI - Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression. AB - The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Here we use a transgenic approach to compare the direct influence of normal with diminished AC reactivity on neuronal integrity and synapse recovery following extracranial facial nerve transection in mice. Our model allows straightforward interpretations of AC-neuron signalling by reducing confounding effects imposed by inflammatory cells. We show direct evidence that perineuronal reactive ACs play a major role in maintaining neuronal circuitry following distant axotomy. We reveal a novel function of astrocytic signal transducer and activator of transcription-3 (STAT3). STAT3 regulates perineuronal astrocytic process formation and re-expression of a synaptogenic molecule, thrombospondin-1 (TSP-1), apart from supporting neuronal integrity. We demonstrate that, through this new pathway, TSP-1 is responsible for the remote AC-mediated recovery of excitatory synapses onto axotomized motor neurons in adult mice. These data provide new targets for neuroprotective therapies via optimizing AC-driven plasticity. PMID- 25014179 TI - Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells. AB - BACKGROUND: Although the global use of the endocrine-disrupting chemical DDT has decreased, its persistence in the environment has resulted in continued human exposure. Accumulating evidence suggests that DDT exposure has long-term adverse effects on development, yet the impact on growth and differentiation of adult stem cells remains unclear. OBJECTIVES: Human mesenchymal stem cells (MSCs) exposed to DDT were used to evaluate the impact on stem cell biology. METHODS: We assessed DDT-treated MSCs for self-renewal, proliferation, and differentiation potential. Whole genome RNA sequencing was performed to assess gene expression in DDT-treated MSCs. RESULTS: MSCs exposed to DDT formed fewer colonies, suggesting a reduction in self-renewal potential. DDT enhanced both adipogenic and osteogenic differentiation, which was confirmed by increased mRNA expression of glucose transporter type 4 (GLUT4), lipoprotein lipase (LpL), peroxisome proliferator-activated receptor gamma (PPARgamma), leptin, osteonectin, core binding factor 1 (CBFA1), and FBJ murine osteosarcoma viral oncogene homolog (c Fos). Expression of factors in DDT-treated cells was similar to that in estrogen treated MSCs, suggesting that DDT may function via the estrogen receptor (ER) mediated pathway. The coadministration of ICI 182,780 blocked the effects of DDT. RNA sequencing revealed 121 genes and noncoding RNAs to be differentially expressed in DDT-treated MSCs compared with controls cells. CONCLUSION: Human MSCs provide a powerful biological system to investigate and identify the molecular mechanisms underlying the effects of environmental agents on stem cells and human health. MSCs exposed to DDT demonstrated profound alterations in self renewal, proliferation, differentiation, and gene expression, which may partially explain the homeostatic imbalance and increased cancer incidence among those exposed to long-term EDCs. PMID- 25014180 TI - Efficacy and safety of, and patient satisfaction with, colonoscopic-administered fecal microbiota transplantation in relapsing and refractory community- and hospital-acquired Clostridium difficile infection. AB - OBJECTIVE: To report the efficacy and safety of, and patient satisfaction with, colonoscopic fecal microbiota transplantation (FMT) for community- and hospital acquired Clostridium difficile infection (CDI). METHODS: A retrospective medical records review of patients who underwent FMT between July 1, 2012 and August 31, 2013 was conducted. A total of 22 FMTs were performed on 20 patients via colonoscopy. The patients were divided into 'community-acquired' and 'hospital acquired' CDI. Telephone surveys were conducted to determine procedure outcome and patient satisfaction. Primary cure rate was defined as resolution of diarrhea without recurrence within three months of FMT, whereas secondary cure rate described patients who experienced resolution of diarrhea and return of normal bowel function after a second course of FMT. RESULTS: Nine patients met the criteria for community-acquired CDI whereas 11 were categorized as hospital acquired CDI. A female predominance in the community-acquired group (88.89% [eight of nine]) was found (P=0.048). The primary cure rate was 100% (nine of nine) and 81.8% (nine of 11 patients) in community- and hospital-acquired CDI groups, respectively (P=0.189). Two patients in the hospital-acquired group had to undergo a repeat FMT for persistent symptomatic infection; the secondary cure rate was 100%. During the six-month follow-up, all patients were extremely satisfied with the procedure and no complications or adverse events were reported. CONCLUSION: FMT was a highly successful and very acceptable treatment modality for treating both community- and hospital-acquired CDI. PMID- 25014181 TI - Surveillance patterns after curative-intent colorectal cancer surgery in Ontario. AB - BACKGROUND: Postoperative surveillance following curative-intent resection of colorectal cancer (CRC) is variably performed due to existing guideline differences and to the limited data supporting different strategies. OBJECTIVES: To examine population-based rates of surveillance imaging and endoscopy in patients in Ontario following curative-intent resection of CRC with no evidence of recurrence, as well as patient or disease factors that may predispose certain groups to more frequent versus less frequent surveillance; to provide insight to the care patients receive in the presence of conflicting guidelines, in efforts to help improve care of CRC survivors by identifying any potential underuse or overuse of particular surveillance modalities, or inequalities in access to surveillance. METHOD: A retrospective cohort study was conducted using data from the Ontario Cancer Registry and several linked databases. Ontario patients undergoing curative-intent CRC resection from 2003 to 2007 were identified, excluding patients with probable disease relapse. In the five-year period following surgery, the number of imaging and endoscopic examinations was determined. RESULTS: There were 4960 patients included in the study. Over the five-year postoperative period, the highest proportion of patients who underwent postoperative surveillance received the following number of tests for each modality examined: one to three abdominopelvic computed tomography (CT) scans (n=2073 [41.8%]); one to three abdominal ultrasounds (n=2443 [49.3%]); no chest CTs, one to three chest x-rays (n=2385 [48.1%]); and two endoscopies (n=1845 [37.2%]). Odds of not receiving any abdominopelvic imaging (CT or abdominal ultrasound) were higher in those who did not receive adjuvant chemotherapy (OR 6.99 [95% CI 5.26 to 9.35]) or those living in certain geographical areas, but were independent of age, sex and income. Nearly all patients (n=4473 [90.2%]) underwent >=1 endoscopy at some point during the follow-up period. CONCLUSION: In contrast to findings from similar studies in other jurisdictions, most Ontario CRC survivors receive postoperative surveillance with imaging and endoscopy, and care is equitable across sociodemographic groups, although unexplained geographical variation in practice exists and warrants further investigation. PMID- 25014182 TI - Fecal occult blood testing as a diagnostic test in symptomatic patients is not useful: a retrospective chart review. AB - BACKGROUND: The fecal occult blood test (FOBT) is a screening tool designed for the early detection of colorectal cancer in primary care. Although not validated for use in hospitalized patients, it is often used by hospital physicians for reasons other than asymptomatic screening. OBJECTIVE: To profile the in-hospital use of the FOBT and assess its impact on patient care. METHODS: Patient charts were retrospectively reviewed for all FOBTs conducted over a three-month period in 2011 by the central laboratory supporting the three acute care campuses of Hamilton Health Sciences (Hamilton, Ontario). RESULTS: A total of 229 patients underwent 351 tests; 52% were female and the mean age was 49 years (range one to 104 years). A total of 80 (34.9%) patients had at least one positive test. The most common indications for testing were anemia (51.0%) and overt gastrointestinal bleeding (19.2%). Only one patient had testing performed for asymptomatic colorectal cancer screening. In only 20 (8.7%) cases medications were modified before testing and diet was modified in only 21 (9.2%) cases. Most patients (85.2%) were taking one or more medications that could result in a false positive result. Only 18 (7.9%) patients had a digital rectal examinations documented, of which seven were positive. All patients with a positive digital rectal examination underwent endoscopic procedures that revealed a source of bleeding. Among 44 patients with overt gastrointestinal bleeding, 12 (27.3%) had endoscopic investigations delayed to await results of the FOBT. Four patients were referred despite a negative FOBT due to a high degree of suspicion of gastrointestinal bleeding. CONCLUSIONS: The FOBT is often used inappropriately in the hospital setting. Confounding factors, such as diet and medication use, which may lead to false positives, are often ignored. Use of the FOBT in-hospital may lead to inappropriate management of patients, increased length of stay and increased direct medical costs. Use of the FOBT should be limited to validated indications only. PMID- 25014183 TI - Functional and biochemical interaction between PPARalpha receptors and TRPV1 channels: Potential role in PPARalpha agonists-mediated analgesia. AB - Transient receptor potential vanilloid type-1 (TRPV1) channels expressed in primary afferent neurons play a critical role in nociception triggered by endogenous and exogenous compounds. In the present study, the functional and biochemical interaction between TRPV1 channels and type-alpha peroxisome proliferator-activated receptors (PPARalpha) has been investigated. In TRPV1 expressing CHO cells, patch-clamp studies revealed that acute application of the PPARalpha agonists clofibrate (CLO; 0.1-100 MUM), WY14643 (1-300 MUM), or GW7647 (0.1-100 nM) activated TRPV1 currents in a concentration-dependent manner, with EC50s of 5.3 +/- 0.8 MUM, 13.0 +/- 1.2 MUM, and 12.7 +/- 0.3 nM, respectively. The role of PPARalpha in these pharmacological responses was confirmed by the ability of the PPARalpha antagonist GW6471 (10 MUM) to block CLO-, WY14643- and GW7647-induced TRPV1 activation, and by the observation that modulation of PPARalpha levels via siRNA-mediated suppression or PPARalpha over-expression affected TRPV1 channel activation by PPARalpha agonists accordingly. In cells cotransfected with PPARalpha and TRPV1, PPARalpha receptors were detected in TRPV1-immunoprecipitated fractions. When compared to capsaicin (CAP), TRPV1 currents activated by PPARalpha agonists showed a higher degree of acute desensitization and tachyphylaxis; moreover, GW7647, when pre-incubated at a concentration (1nM) unable to activate TRPV1 currents per se, desensitized CAP induced TRPV1 currents. Finally, a sub-effective concentration of each PPARalpha agonist inhibited TRPV1-dependent bradykinin-induced [Ca(2+)]i transients in sensory neurons. Collectively, these results provide evidence for a PPARalpha mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARalpha agonists in vivo. PMID- 25014184 TI - Novel immunological strategies for islet transplantation. AB - Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications. PMID- 25014185 TI - Risk management tools and the case study Brassica napus: evaluating possible effects of genetically modified plants on soil microbial diversity. AB - The cultivation of GMPs in Europe raises many questions about the environmental risks, in particular about their ecological impact on non-target organisms and on soil properties. The aim of a multidisciplinary group engaged in a LIFE+project (MAN-GMP-ITA) was to validate and improve an existing environmental risk assessment (ERA) methodology on GMPs within the European legislative framework on GMOs. Given the impossibility of evaluating GMO impact directly, as GMPs are banned in Italy, GMPs have not been used at any stage of the project. The project thus specifically focused on the conditions for the implementation of ERA in different areas of Italy, with an emphasis on some sensitive and protected areas located in the North, Centre, and South of the country, in order to lay the necessary baseline for evaluating the possible effects of a GMP on soil communities. Our sub-group carried out soil analyses in order to obtain soil health and fertility indicators to be used as baselines in the ERA model. Using various methods of chemical, biochemical, functional and genetic analysis, our study assessed the changes in diversity and functionality of bacterial populations, and arbuscular mycorrhizal fungi. The results show that plant identity and growth, soil characteristics, and field site climatic parameters are key factors in contributing to variation in microbial community structure and diversity, thus validating our methodological approach. Our project has come to the conclusion that the uneven composition and biological-agronomical quality of soils need to be taken into consideration in a risk analysis within the framework of ERA for the release of genetically modified plants. PMID- 25014186 TI - Chelant-enhanced heavy metal uptake by Eucalyptus trees under controlled deficit irrigation. AB - We tested the hypothesis that controlled deficit irrigation (CDI) of the fast growing, salinity resistant Eucalyptus camaldulensis tree with timely EDTA application can enhance sediment clean-up while minimizing leaching of metal complexes. 220-L lysimeters containing a sand-metal-polluted sludge mixture. Established saplings were irrigated with tap or desalinized (RO) water with/without 4-times daily addition of EDTA, EDDS and citric acid. In the 2nd season (2008/9) the chelates were added at 2 mM for ~ 70 summer days. Diagnostic leaves and soil solution compositions were regularly monitored, the latter by applying prescribed leaching at an overall leaching percentage of ~ 0.4%. While the three chelants solubilized sludge metals in batch extraction, EDDS often being the more efficient chelant, EDTA only was effective in the soil system. Leachate and leaves peak average concentrations in EDTA treatment vs. the control treatments were: Cd: 200 mg L(-1) vs. 1.0 and 67 vs. 21 mg kg(-1); Cu: 90 vs. 1.5 mg L(-1) and 17 vs. 3.0 mg kg(-1); Ni: 60 mg L(-1) vs. 14 and 20 vs. 6.0 mg kg( 1); Pb: >44 vs. 0.1 mg L(-1) and 9.0 vs. 1.0 mg kg(-1); and Zn: 650 vs. 4.0 mg L( 1) and 200 vs. 70 mg kg(-1), all respectively. Peak average leachate EDTA concentration was >60 mM, yet acclimating soil microflora gradually degraded most all the EDTA. In incubation study, EDDS and EDTA half-lives in acclimated lysimeter media were 5-11 days and >= 27 days, respectively. It suggests that sustainable phytoextraction of heavy metals is feasible under careful CDI with EDTA (yet not with biodegradable chelants) augmentation at low doses. Despite that the eucalypt was highly salinity (and EDTA) resistant, CDI using RO water further reduces soil solution salinity, thus increasing the usefulness of this remediation technique. PMID- 25014188 TI - Mechanical gate control for atom-by-atom cluster assembly with scanning probe microscopy. AB - Nanoclusters supported on substrates are of great importance in physics and chemistry as well as in technical applications, such as single-electron transistors and nanocatalysts. The properties of nanoclusters differ significantly from those of either the constituent atoms or the bulk solid, and are highly sensitive to size and chemical composition. Here we propose a novel atom gating technique to assemble various atom clusters composed of a defined number of atoms at room temperature. The present gating operation is based on the transfer of single diffusing atoms among nanospaces governed by gates, which can be opened in response to the chemical interaction force with a scanning probe microscope tip. This method provides an alternative way to create pre-designed atom clusters with different chemical compositions and to evaluate their chemical stabilities, thus enabling investigation into the influence that a single dopant atom incorporated into the host clusters has on a given cluster stability. PMID- 25014189 TI - A socio-technical critique of tiered services: implications for interprofessional care. AB - In the health and social care sector, tiered services have become an increasingly influential way of organising professional expertise to address the needs of vulnerable people. Drawing on its application to UK child welfare services, this paper discusses the merits of the tiered model from a socio-technical perspective - an approach that has emerged from the fields of accident analysis and systems design. The main elements of a socio-technical critique are outlined and used to explore how tiered services provide support to families and prevent harm to children. Attention is drawn to the distribution of expertise and resources in a tiered system, and to the role of referral and gate-keeping procedures in dispersing accountability for outcomes. An argument is made for designing systems "against demand", and the paper concludes by discussing some alternative models of multi-agency provision. PMID- 25014187 TI - Maternal health care utilization in Nairobi and Ouagadougou: evidence from HDSS. AB - BACKGROUND: Maternal mortality is higher and skilled attendance at delivery is lower in the slums of Nairobi (Kenya) compared to Ouagadougou (Burkina Faso). Lower numbers of public health facilities, greater distance to facilities, and higher costs of maternal health services in Nairobi could explain these differences. OBJECTIVE: By comparing the use of maternal health care services among women with similar characteristics in the two cities, we will produce a more nuanced picture of the contextual factors at play. DESIGN: We use birth statistics collected between 2009 and 2011 in all households living in several poor neighborhoods followed by the Nairobi and the Ouagadougou Health and Demographic Surveillances Systems (n=3,346 and 4,239 births). We compare the socioeconomic characteristics associated with antenatal care (ANC) use and deliveries at health facilities, controlling for demographic variables. RESULTS: ANC use is greater in Nairobi than in Ouagadougou for every category of women. In Ouagadougou, there are few differentials in having at least one ANC visit and in delivering at a health facility; however, differences are observed for completing all four ANC visits. In Nairobi, less-educated, poorer, non-Kikuyu women, and women living in the neighborhood farther from public health services have poorer ANC and deliver more often outside of a health facility. CONCLUSIONS: These results suggest that women are more aware of the importance of ANC utilization in Nairobi compared to Ouagadougou. The presence of numerous for-profit health facilities within slums in Nairobi may also help women have all four ANC visits, although the services received may be of substandard quality. In Ouagadougou, the lack of socioeconomic differentials in having at least one ANC visit and in delivering at a health facility suggests that these practices stem from the application of well-enforced maternal health regulations; however, these regulations do not cover the entire set of four ANC visits. PMID- 25014190 TI - Experimental infection of Mongolian gerbils with Baylisascaris potosis. AB - The present study evaluated the pathogenicity of Baylisascaris potosis, a newly described ascarid nematode, in Mongolian gerbils. Gerbils were infected with varying doses of either B. potosis or Baylisascaris transfuga embryonated eggs (100, 1,000, and 4,000) for 30 days postinfection (pi). Baylisascaris potosis infected gerbils showed no clinical signs of disease; however, gerbils exposed to 1,000 and 4,000 B. transfuga eggs showed severe neurologic signs at 22-29 days and 14-15 days pi, respectively. Histopathologic examination revealed larvae and lesions in the intestine, lung, liver, and muscles of B. potosis-infected gerbils, but not in the brain, whereas B. transfuga larvae were found only in the brain and muscle. These results indicate that B. potosis larvae migrate through numerous organs and are associated with visceral larva migrans in gerbils, but less frequently migrate to the nervous system in gerbils than does B. transfuga . PMID- 25014191 TI - Heat shock protein 90 inhibitor mycoepoxydiene modulates kinase signaling in cervical cancer cells and inhibits in-vivo tumor growth. AB - Heat shock protein 90 (Hsp90) functions within multiple signaling pathways on the basis of its ability to serve as a chaperone for more than 100 client proteins. Thus, inhibition of Hsp90 alone can trigger numerous pathways. Mycoepoxydiene (MED) can inhibit Hsp90 function and induce apoptosis in cervical cancer cells. However, the antitumor efficacy of MED in vivo is still not clear. We examined the efficacy of MED in a mouse xenograft model to further elucidate HeLa cell fate and also assessed the mechanism of altered protein signaling in response to this compound in vitro. Our data showed that Hsp90 inhibition simultaneously triggers signaling that regulates both cell death and cell proliferation, and that HeLa cell death may be a result of the disequilibrium of these signals. MED induces cell death as a result of the destabilization of Akt and IKK, which may promote cell death through a reduction in the activation of Bad and nuclear factor-kappaB. However, MED also induces the MEK/ERK pathway, which is classically considered to promote cell survival. MEK/ERK activation leads to an increase in p21, a cyclin-dependent kinase inhibitor, and is independent of Raf, but is shown to be mediated by p53. MED also leads to a decrease in several additional G2/M regulatory proteins independent of the MEK/ERK pathway. These results indicate an interesting mechanism of cross-talk between the inhibition of Akt phosphorylation and the activation of the MEK pathway by MED and provide in vivo evidence for the potential of inhibiting Hsp90 as a candidate anticancer treatment. PMID- 25014192 TI - Mapping of single-site magnetic anisotropy tensors in weakly coupled spin clusters by torque magnetometry. AB - Single-crystal torque magnetometry performed on weakly-coupled polynuclear systems provides access to a complete description of single-site anisotropy tensors. Variable-temperature, variable-field torque magnetometry was used to investigate triiron(III) complex [Fe3La(tea)2(dpm)6] (Fe3La), a lanthanum(III) centred variant of tetrairon(III) single molecule magnets (Fe4) (H3tea = triethanolamine, Hdpm = dipivaloylmethane). Due to the presence of the diamagnetic lanthanoid, magnetic interactions among iron(III) ions (si = 5/2) are very weak (<0.1 cm(-1)) and the magnetic response of Fe3La is predominantly determined by single-site anisotropies. The local anisotropy tensors were found to have Di > 0 and to be quasi-axial with |Ei/Di| ~ 0.05. Their hard axes form an angle of approximately 70 degrees with the threefold molecular axis, which therefore corresponds to an easy magnetic direction for the molecule. The resulting picture was supported by a High Frequency EPR investigation and by DFT calculations. Our study confirms that the array of peripheral iron(III) centres provides substantially noncollinear anisotropy contributions to the ground state of Fe4 complexes, which are of current interest in molecular magnetism and spintronics. PMID- 25014193 TI - Inkjet printing of flexible high-performance carbon nanotube transparent conductive films by "coffee ring effect". AB - Transparent and flexible conductors are a major component in many modern optoelectronic devices, such as touch screens for smart phones, displays, and solar cells. Carbon nanotubes (CNTs) offer a good alternative to commonly used conductive materials, such as metal oxides (e.g. ITO) for flexible electronics. The production of transparent conductive patterns, and arrays composed of connected CNT "coffee rings" on a flexible substrate poly(ethylene terephthalate), has been reported. Direct patterning is achieved by inkjet printing of an aqueous dispersion of CNTs, which self-assemble at the rim of evaporating droplets. After post-printing treatment with hot nitric acid, the obtained TCFs are characterized by a sheet resistance of 156 Omega sq(-1) and transparency of 81% (at 600 nm), which are the best reported values obtained by inkjet printing of conductive CNTs. This makes such films very promising as transparent conductors for various electronic devices, as demonstrated by using an electroluminescent device. PMID- 25014194 TI - The efficacy of bamboo charcoal in comparison with smectite to reduce the detrimental effect of aflatoxin B1 on in vitro rumen fermentation of a hay-rich feed mixture. AB - Two commercial materials, a bamboo charcoal (BC) and a smectite clay (SC), were assessed in vitro with aflatoxin B1 (AFB1) in an equilibrium adsorption test. The adsorption capacity and proportion adsorbed (0.381 MUg/mg, 0.955) for BC were greater than for SC (0.372 MUg/mg, 0.931). The effects of in vitro ruminal fermentation of hay-rich feed incubated with 1.0 MUg/mL AFB1 for 0-10 g/L doses of BC and SC were measured at 39 degrees C for 72 h. The BC and SC binders increased AFB1 loss at dosages >=1.0 g/L (p < 0.0001). Average AFB1 loss (p < 0.0001) was greater for SC (0.904) than BC (0.881). Both SC and SC addition increased in vitro dry matter loss, and the average dry matter losses were similar. Asymptotic gas volume and volatile fatty acid production were greater for BC than for SC (p < 0.0001). Thus, BC may be as effective as SC in removing aflatoxin B1's detrimental effects on rumen degradability and fermentation under the occurrence of microbial aflatoxin degradation. PMID- 25014195 TI - Identification and characterization of the insecticidal toxin "makes caterpillars floppy" in Photorhabdus temperata M1021 using a cosmid library. AB - Photorhabdus temperata is an entomopathogenic enterobacterium; it is a nematode symbiont that possesses pathogenicity islands involved in insect virulence. Herein, we constructed a P. temperata M1021 cosmid library in Escherichia coli XL1-Blue MRF' and obtained 7.14 * 105 clones. However, only 1020 physiologically active clones were screened for insect virulence factors by injection of each E. coli cosmid clone into Galleria mellonella and Tenebrio molitor larvae. A single cosmid clone, PtC1015, was consequently selected due to its characteristic virulent properties, e.g., loss of body turgor followed by death of larvae when the clone was injected into the hemocoel. The sequence alignment against the available sequences in Swiss-Prot and NCBI databases, confirmed the presence of the mcf gene homolog in the genome of P. temperata M1021 showing 85% homology and 98% query coverage with the P. luminescens counterpart. Furthermore, a 2932 amino acid long Mcf protein revealed limited similarity with three protein domains. The N-terminus of the Mcf encompassed consensus sequence for a BH3 domain, the central region revealed similarity to toxin B, and the C-terminus of Mcf revealed similarity to the bacterial export domain of ApxIVA, an RTX-like toxin. In short, the Mcf toxin is likely to play a role in the elimination of insect pests, making it a promising model for use in the agricultural field. PMID- 25014197 TI - Prenatal exposure to low doses of atrazine affects mating behaviors in male guppies. AB - Performing appropriate mating behaviors is crucial to male reproductive success, especially in species where mating is predominantly via female mate choice. Mating behaviors are hormonally regulated and may be sexually selected traits: courtship displays are selected via mate choice, while forced copulations and aggressive behaviors are selected for via intrasexual competition. Endocrine disrupting compounds interfere with proper hormonal functioning in exposed animals. Exposures during developmentally crucial life stages can have irreversible effects lasting through adulthood. I tested the effects of prenatal exposure to environmentally relevant doses of a commonly used herbicide, atrazine (1 and 13.5MUg/L) on mating behaviors in male guppies. Guppies were used as a model organism to test the effects of atrazine exposure on wildlife reproductive health. Adult female guppies were mated and exposed to the treatments throughout the gestation period, and offspring born to them were raised without further treatment. At adulthood, the males were tested for the effects of prenatal exposure on their mating behaviors such as courtship displays, gonopodium swings, forced copulatory attempts, and competitive and aggressive behaviors towards rivals who were not exposed to atrazine. I also tested female preference for treated males compared to control males. Atrazine-exposed males were less likely to perform the mating behaviors, and performed them less frequently, than control males. Atrazine exposure also made males less aggressive towards rivals. Females preferred untreated males over atrazine-treated males. In all cases, a non monotonic pattern was seen, highlighting the significance of low-dose exposures. PMID- 25014196 TI - Elimination of Kalrn expression in POMC cells reduces anxiety-like behavior and contextual fear learning. AB - Kalirin, a Rho GDP/GTP exchange factor for Rac1 and RhoG, is known to play an essential role in the formation and maintenance of excitatory synapses and in the secretion of neuropeptides. Mice unable to express any of the isoforms of Kalrn in cells that produce POMC at any time during development (POMC cells) exhibited reduced anxiety-like behavior and reduced acquisition of passive avoidance behavior, along with sex-specific alteration in the corticosterone response to restraint stress. Strikingly, lack of Kalrn expression in POMC cells closely mimicked the effects of global Kalrn knockout on anxiety-like behavior and passive avoidance conditioning without causing the other deficits noted in Kalrn knockout mice. Our data suggest that deficits in excitatory inputs onto POMC neurons are responsible for the behavioral phenotypes observed. PMID- 25014198 TI - Sensitivity to differences in the motor origin of drawings: from human to robot. AB - This study explores the idea that an observer is sensitive to differences in the static traces of drawings that are due to differences in motor origin. In particular, our aim was to test if an observer is able to discriminate between drawings made by a robot and by a human in the case where the drawings contain salient kinematic cues for discrimination and in the case where the drawings only contain more subtle kinematic cues. We hypothesized that participants would be able to correctly attribute the drawing to a human or a robot origin when salient kinematic cues are present. In addition, our study shows that observers are also able to detect the producer behind the drawings in the absence of these salient kinematic cues. The design was such that in the absence of salient kinematic cues, the drawings are visually very similar, i.e. only differing in subtle kinematic differences. Observers thus had to rely on these subtle kinematic differences in the line trajectories between drawings. However, not only motor origin (human versus robot) but also motor style (natural versus mechanic) plays a role in attributing a drawing to the correct producer, because participants scored less high when the human hand draws in a relatively mechanical way. Overall, this study suggests that observers are sensitive to subtle kinematic differences between visually similar marks in drawings that have a different motor origin. We offer some possible interpretations inspired by the idea of "motor resonance". PMID- 25014199 TI - [Clinical neuropsychology: at the crossroads or beyond?]. PMID- 25014200 TI - [Multiple sclerosis, neuromyelitis optica and spasticity: control of specific symptoms and quality of life]. AB - Spastic movement disorders show a high lifetime prevalence among patients suffering from multiple sclerosis and neuromyelitis optica. Due to the high number of factors interacting with the individual manifestations of spasticity, its symptomatic treatment affords continuous and careful balancing of therapeutic measures. A trend observed over the past few years is to base symptomatic treatment of MS on subjective assessments of functional disorders rather than on specific individual pathological signs and symptoms. This has led to a more generous and more patient-oriented perspective. Therefore, a detailed analysis, characterisation and evaluation of the individual clinical course of the disease is not only indispensable, but is actually gaining even more importance in avoiding uncontrolled polypharmacy with correspondingly increased risks for side effects. PMID- 25014201 TI - [Executive task performance under deep brain stimulation of the subthalamic nucleus in Parkinson's disease revisited: the modulating influence of apathy, depression and mood]. AB - We investigated the moderating influence of apathy, depression and transient mood changes on executive functions under best medical treatment and under postoperative stimulation-on and -off conditions in a sample of 33 patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN), 33 PD patients with pharmacological treatment only and 34 healthy controls. In comparison to clinical and healthy control groups, DBS patients showed worse executive task performance and also more severe symptoms of depression and apathy. Apathy accounted for differences in stroop interference between groups. The effects of DBS on stroop interference were explained by increased state anxiety in the -off, so that DBS STN had no significant influence on test performance. Consideration of neuropsychiatric symptoms and acute mood changes is an important aspect when evaluating neuropsychological deficits in DBS patients. PMID- 25014202 TI - [Indicators of patient care in Psychiatric and Psychosomatic Facilities (VIPP project)--a database project]. AB - INTRODUCTION: In Germany a new and unique remuneration system for psychiatric and psychosomatic stationary treatments (PEPP system) was introduced in 2013 on an optional basis. From 2015 it will be mandatory for psychiatric and psychosomatic facilities. The introduction of the PEPP system brings up different questions regarding the possible incentives of the new remuneration system and its effects on the supply of psychiatric and psychosomatic treatments. To conduct these necessary analyses a reliable database is needed. MATERIAL AND METHODS: The goal of the project "Indicators of patient care in Psychiatric and Psychosomatic Facilities" (VIPP project) is to gather a representative database which reflects the situation of day-to-day patient care performed by German psychiatric and psychosomatic facilities. The S 21 data set represents the basis of this database which will be complemented by other data sources (i. e., financial statements and other economic data). A number of more than 100 ,000 cases per year has already been exceeded. These case data were provided by a wide range of psychiatric hospitals, departments and universities that participate in this project. The dataset is anonymised and by pooling the data it is not possible to identify the cases of a specific clinic. Participants receive a web-based access and have the possibility to analyse the data independently. RESULTS: Using the examples of coding accuracy and rehospitalisation rates the variety as well as the enormous potential of this database can be demonstrated. DISCUSSION: On the base of the VIPP database valid patient care indicators can be identified and cross-sectional analyses can be conducted. From such results key data on health economic strategies can be derived and the incentives, strengths and limitations of this constantly changing system can be identified. PMID- 25014203 TI - [The "Erlangen System" of open care: a tribute to Gustav Kolb (1870-1938)]. AB - BACKGROUND: This year marks the 80th anniversary of the forced retirement (1st March 1934) of Gustav Kolb (1870 - 1938). He is considered the founder of the "Erlangen System" of open care. The following article pays tribute to Gustav Kolb's "life's work", by delineating the formation, active period and the fall of his "Erlangen system" in its historical context. METHOD: Relevant archive materials and secondary literature were assessed. RESULTS: Beginning in 1914, Gustav Kolb, as Director of the Mental Asylum in Erlangen (1911 - 1934) introduced the care of the emotionally ill in their own families. In 1930, 4200 of the 770 000 residents in a catchment area covering about 3200 square kilometers were being treated in open care. The "Erlangen system" was the largest organisation of its kind in Germany. Although Gustav Kolb was inspired by eugenic ideas, he opposed the national-socialist health politics. Kolb withdrew professionally in 1933 and died five years later. DISCUSSION: The situation in the tense area of open care between helping institutions for and controlling bodies over emotionally ill people was relatively balanced in the Weimar Republic. Later, Gustav Kolb's organisational thoroughness, with its creation of a central register of people under open care in the Erlangen system, provided considerable biogenetic information. Tragically, this was abused as an important source in carrying out the national-socialist law for prevention of genetically impaired offspring (14.7.1933). Several aspects contributed to the misfortune that Kolb's liberal system could be distorted to a recording instrument by the National Socialists. Final Comment: Individual efforts to reestablish open care facilities after 1945 were not implemented. It was not until during the socio psychiatric movement of the 1960 s that Kolb's concept could achieve a renaissance, although it was unnamed and unrecognised at the time. PMID- 25014204 TI - [Mortality and sudden unexpected death in epilepsy (SUDEP)]. PMID- 25014205 TI - Mechanosynthesis of imine, beta-ketoenamine, and hydrogen-bonded imine-linked covalent organic frameworks using liquid-assisted grinding. AB - A variety of aromatic amines/hydrazides and aldehydes have been utilized for the construction of crystalline COFs at a faster rate and in high yield, irrespective of their reactivity and solubility using the Liquid-Assisted Grinding (LAG) method. PMID- 25014208 TI - Solvent-induced syntheses, crystal structures, magnetic properties, and single crystal-to-single-crystal transformation of azido-Cu(II) coordination polymers with 2-naphthoic acid as co-ligand. AB - Based on the solvent-induced effect, three new azido-copper coordination polymers -[Cu(2-na)(N3)] (1), [Cu(2-na)(N3)] (2), and [Cu(2-na)(N3)(C2H5OH)] (3) (where 2 na = 2-naphthoic acid)--have been successfully prepared. Structure analysis shows that the Cu(II) cations in compounds 1-3 present tetra-, penta-, and hexa coordination geometries, respectively. Compound 1 is a well-isolated one dimensional (1D) chain with the EO-azido group, while 2 is an isomer of 1 and exhibits a two-dimensional (2D) layer involving the EE-azido group. Thermodynamically, density functional theory (DFT) calculation reveals that 2 occupies the stable state and 1 locates in the metastable state. Compound 3 consists of a 1D chain with triple bridging mode, which is derived from 1, and undergoes a single-crystal-to-single-crystal transformation by soaking in ethanol solvent; the powdery product of 1, namely 1b, could be yielded after the dealcoholization of compound 3. Magnetic measurements indicate that compounds 1-3 perform strong intrachain ferromagnetic interactions, experiencing long-range magnetic ordering and slow magnetic relaxation. Compound 1 features the metamagnetic behavior with a transition temperature of 15 K, while 2 and 3 display spin glass behavior with the phase transition temperatures of 15 and 12 K, respectively. Magneto-structure relationships are investigated as well. PMID- 25014209 TI - The N-terminal region of amyloid beta controls the aggregation rate and fibril stability at low pH through a gain of function mechanism. AB - Alzheimer's disease is linked to a pathological polymerization of the endogenous amyloid beta-peptide (Abeta) that ultimately forms amyloid plaques within the human brain. We used surface plasmon resonance (SPR) to measure the kinetic properties of Abeta fibril formation under different conditions during the polymerization process. For all polymerization processes, a critical concentration of free monomers, as defined by the dissociation equilibrium constant (K(D)), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the K(D), polymerization cannot occur. However, the K(D) for Abeta has previously been shown to be several orders of magnitude higher than the concentrations found in the cerebrospinal and interstitial fluids of the human brain, and the mechanism by which Abeta amyloid forms in vivo has been a matter of debate. Using SPR, we found that the K(D) of Abeta dramatically decreases as a result of lowering the pH. Importantly, this effect enables Abeta to polymerize within a picomolar concentration range that is close to the physiological Abeta concentration within the human brain. The stabilizing effect is dynamic, fully reversible, and notably pronounced within the pH range found within the endosomal and lysosomal pathways. Through sequential truncation, we show that the N-terminal region of Abeta contributes to the enhanced fibrillar stability due to a gain of function mechanism at low pH. Our results present a possible route for amyloid formation at very low Abeta concentrations and raise the question of whether amyloid formation in vivo is restricted to a low pH environment. These results have general implications for the development of therapeutic interventions. PMID- 25014210 TI - Vision screening in children: why and how? PMID- 25014207 TI - Liposome reconstitution and modulation of recombinant prenylated human Rac1 by GEFs, GDI1 and Pak1. AB - Small Rho GTPases are well known to regulate a variety of cellular processes by acting as molecular switches. The regulatory function of Rho GTPases is critically dependent on their posttranslational modification at the carboxyl terminus by isoprenylation and association with proper cellular membranes. Despite numerous studies, the mechanisms of recycling and functional integration of Rho GTPases at the biological membranes are largely unclear. In this study, prenylated human Rac1, a prominent member of the Rho family, was purified in large amount from baculovirus-infected Spodoptera frugiperda insect cells using a systematic detergent screening. In contrast to non-prenylated human Rac1 purified from Escherichia coli, prenylated Rac1 from insect cells was able to associate with synthetic liposomes and to bind Rho-specific guanine nucleotide dissociation inhibitor 1 (GDI1). Subsequent liposome reconstitution experiments revealed that GDI1 efficiently extracts Rac1 from liposomes preferentially in the inactive GDP bound state. The extraction was prevented when Rac1 was activated to its GTP bound state by Rac-specific guanine nucleotide exchange factors (GEFs), such as Vav2, Dbl, Tiam1, P-Rex1 and TrioN, and bound by the downstream effector Pak1. We found that dissociation of Rac1-GDP from its complex with GDI1 strongly correlated with two distinct activities of especially Dbl and Tiam1, including liposome association and the GDP/GTP exchange. Taken together, our results provided first detailed insights into the advantages of the in vitro liposome based reconstitution system to study both the integration of the signal transducing protein complexes and the mechanisms of regulation and signaling of small GTPases at biological membranes. PMID- 25014211 TI - Wide field super-resolution surface imaging through plasmonic structured illumination microscopy. AB - We experimentally demonstrate a wide field surface plasmon (SP) assisted super resolution imaging technique, plasmonic structured illumination microscopy (PSIM), by combining tunable SP interference (SPI) with structured illumination microscopy (SIM). By replacing the laser interference fringes in conventional SIM with SPI patterns, PSIM exhibits greatly enhanced resolving power thanks to the unique properties of SP waves. This PSIM technique is a wide field, surface super resolution imaging technique with potential applications in the field of high speed biomedical imaging. PMID- 25014212 TI - Superhydrophilic polystyrene nanofiber materials generating O2((1)Delta(g)): postprocessing surface modifications toward efficient antibacterial effect. AB - The surfaces of electrospun polystyrene (PS) nanofiber materials with encapsulated 1% w/w 5,10,15,20-tetraphenylporphyrin (TPP) photosensitizer were modified through sulfonation, radio frequency (RF) oxygen plasma treatment, and polydopamine coating. The nanofiber materials exhibited efficient photogeneration of singlet oxygen. The postprocessing modifications strongly increased the wettability of the pristine hydrophobic PS nanofibers without causing damage to the nanofibers, leakage of the photosensitizer, or any substantial change in the oxygen permeability of the inner bulk of the polymer nanofiber. The increase in the surface wettability yielded a significant increase in the photo-oxidation of external polar substrates and in the antibacterial activity of the nanofibers in aqueous surroundings. The results reveal the crucial role played by surface hydrophilicity/wettability in achieving the efficient photo-oxidation of a chemical substrate/biological target at the surface of a material generating O2((1)Deltag) with a short diffusion length. PMID- 25014213 TI - Extracellular matrix biomarker, fibulin-1, is closely related to NT-proBNP and soluble urokinase plasminogen activator receptor in patients with aortic valve stenosis (the SEAS study). AB - BACKGROUND: Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS). METHODS: In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo. RESULTS: During treatment, fibulin-1 became more closely associated with NT-proBNP (betayear0 = 0.10, p = 0.08, betayear1 = 0.16, p = 0.005, betayear4 = 0.22, p<0.001) and suPAR (betayear0 = 0.05, p = 0.34, betayear1 = 0.16, p = 0.006, betayear4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (betayear0 = -0.14, p = 0.005, betayear1 = -0.08, p = 0.11, betayear4 = -0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.Ryear02 = 0.19, Adj.Ryear12 = 0.22, Adj.Ryear42 = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm2/m2 (median value), fibulin-1 was more closely associated to NT-proBNP (betayear0 = 0.25, betayear1 = 0.21, betayear4 = 0.22, all p<0.01), and suPAR (betayear0 = 0.09, p = 0.26, betayear1 = 0.23, betayear4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation. CONCLUSIONS: Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load. PMID- 25014214 TI - Subtle mutation detection of SMN1 gene in Chinese spinal muscular atrophy patients: implication of molecular diagnostic procedure for SMN1 gene mutations. AB - Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. Approximately 90-95% of SMA patients have a homozygous deletion of SMN1, and 5 10% of patients are believed to have subtle mutations. The molecular diagnosis of SMN1 subtle mutations is hampered by a highly homologous SMN2 gene. It is important to establish a rational molecular diagnostic procedure for SMN1 subtle mutations. We analyzed the SMN1 mutations in nine nonhomozygous patients by the following procedures: multiplex ligation-dependent probe amplification, genomic sequencing, T-A cloning on cDNA or genomic level, and/or real-time quantitative analysis. By the above molecular diagnostic procedure, six SMN1 subtle mutations, including c.5C>G(p.Ala2Gly), c.22_23 insA (p.Ser8LysfsX23), c.40G>T(p.Glu14X), c.43C>T(p.Gln15X), c.683T>A(p.Leu228X), and c.56delT(p.Val19GlyfsX21), were identified in nine Chinese patients. p.Glu14X has not been reported previously. Compared with the level of full-length SMN1 transcripts in the healthy carriers (14.1+/-4.5), the patient with p.Ala2Gly had no significant reduction (13.9+/ 3.64, p=0.955). However, the levels in the patients carrying other mutations were significantly reduced (0.27+/-0.139 to 13.9+/-3.64, p=0.000-0.004). We present a reliable and rational diagnostic procedure for SMN1 subtle mutations, which would be helpful in molecular diagnosis of SMA compound heterozygotes. Our work extends the SMN1 mutation spectrum. PMID- 25014215 TI - Structured cyclic peptides that bind the EH domain of EHD1. AB - EHD1 mediates long-loop recycling of many receptors by forming signaling complexes using its EH domain. We report the design and optimization of cyclic peptides as ligands for the EH domain of EHD1. We demonstrate that the improved affinity from cyclization allows fluorescence-based screening applications for EH domain inhibitors. The cyclic peptide is also unusually well-structured in aqueous solution, as demonstrated using nuclear magnetic resonance-based structural models. Because few EH domain inhibitors have been described, these more potent inhibitors will improve our understanding of the roles of EHD1 in the context of cancer invasion and metastasis. PMID- 25014216 TI - PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3beta and several PKC isoforms. AB - Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK) 3beta(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3beta(Ser9), FKHR(Ser256), and PKC epsilon(Ser729) and the level of Hsp90 were increased, while the activity of PKC alpha/betaII(Thr638/641), zeta/lambda(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling. PMID- 25014217 TI - Post-transcriptional regulation of BCL2 mRNA by the RNA-binding protein ZFP36L1 in malignant B cells. AB - The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the 'maximum information coefficient' (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3' untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3' untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells. PMID- 25014218 TI - Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic beta-cells. AB - INTRODUCTION: In a recent study, we confirmed good chemical and physical compatibility of microencapsulated pancreatic beta-cells using a novel formulation of low viscosity sodium alginate (LVSA), Poly-L-Ornithine (PLO), and the tertiary bile acid, ursodeoxycholic acid (UDCA). This study aimed to investigate the effect of UDCA on the morphology, swelling, stability, and size of these new microcapsules. It also aimed to evaluate cell viability in the microcapsules following UDCA addition. MATERIALS AND METHODS: Microencapsulation was carried out using a Buchi-based system. Two (LVSA-PLO, control and LVSA-PLO UDCA, test) pancreatic beta-cells microcapsules were prepared at a constant ratio of 10:1:3, respectively. The microcapsules' morphology, cell viability, swelling characteristics, stability, mechanical strength, Zeta potential, and size analysis were examined. The cell contents in each microcapsule and the microencapsulation efficiency were also examined. RESULTS: The addition of UDCA did not affect the microcapsules' morphology, stability, size, or the microencapsulation efficiency. However, UDCA enhanced cell viability in the microcapsules 24 h after microencapsulation (p < 0.01), reduced swelling (p < 0.05), reduced Zeta potential (- 73 +/- 2 to - 54 +/- 2 mV, p < 0.01), and increased mechanical strength of the microcapsules (p < 0.05) at the end of the 24-h experimental period. DISCUSSION AND CONCLUSION: UDCA increased beta-cell viability in the microcapsules without affecting the microcapsules' size, morphology, or stability. It also increased the microcapsules' resistance to swelling and optimized their mechanical strength. Our findings suggest potential benefits of the bile acid UDCA in beta-cell microencapsulation. PMID- 25014220 TI - Cytokine expression in the cervical stroma of HIV-positive and HIV-negative women with cervical intraepithelial neoplasia. AB - Cervical intraepithelial neoplasias (CINs) are a major public health issue. The prevalence of CINs is higher in women with the human immunodeficiency virus (HIV). The objective of this study was to determine whether there are differences in the immune responses in the cervical stroma of HIV-infected and -uninfected women with CIN. The responses were assessed according to the immunohistochemical expression of cytokines interleukin (IL)-4, IL-12, interferon gamma (IFN-gamma), and tumor growth factor beta (TGF-beta). In addition, we determined whether there were differences in the local immune responses between patients with CIN1 and CIN 2/3. A cross-sectional study was performed using material collected by cervical conization in HIV-infected and -uninfected women with CIN. The conization was performed using loop electrical excision procedure (LEEP) from January 1999 to May 2004. The evaluation of cytokines in the cervical stroma was based on immunohistochemistry. No differences were found between the two groups of women regarding HIV status. However, the associations between IL-12 expression and CIN 2/3 (p=0.016) in HIV-infected women and between IL-4 expression and CIN 1 (p=0.0456) in HIV-infected women were significant when the interaction between HIV infection and lesion grade was assessed. Additionally, a significant association between TGF-beta expression and CIN 2/3 in both groups was observed regardless of HIV infection (p=0.000). An interaction between HIV infection and CIN grade was detected because IL-12 and IL-4 expression increased in the presence of HIV infection. Regarding the CIN grade, there was a high prevalence of TGF-beta in CIN 2/3 lesions, which reflected the predominance of an immunoregulatory environment. PMID- 25014221 TI - Editorial: part 1: network biology in translational bioinformatics and systems biology. PMID- 25014222 TI - Comprehensive study of tumour single nucleotide polymorphism array data reveals significant driver aberrations and disrupted signalling pathways in human hepatocellular cancer. AB - The authors describe an integrated method for analysing cancer driver aberrations and disrupted pathways by using tumour single nucleotide polymorphism (SNP) arrays. The authors new method adopts a novel statistical model to explicitly quantify the SNP signals, and therefore infers the genomic aberrations, including copy number alteration and loss of heterozygosity. Examination on the dilution series dataset shows that this method can correctly identify the genomic aberrations even with the existence of severe normal cell contamination in tumour sample. Furthermore, with the results of the aberration identification obtained from multiple tumour samples, a permutation-based approach is proposed for identifying the statistically significant driver aberrations, which are further incorporated with the known signalling pathways for pathway enrichment analysis. By applying the approach to 286 hepatocellular tumour samples, they successfully uncover numerous driver aberration regions across the cancer genome, for example, chromosomes 4p and 5q, which harbour many known hepatocellular cancer related genes such as alpha-fetoprotein (AFP) and ectodermal-neural cortex (ENC1). In addition, they identify nine disrupted pathways that are highly enriched by the driver aberrations, including the systemic lupus erythematosus pathway, the vascular endothelial growth factor (VEGF) signalling pathway and so on. These results support the feasibility and the utility of the proposed method on the characterisation of the cancer genome and the downstream analysis of the driver aberrations and the disrupted signalling pathways. PMID- 25014219 TI - Hepatitis C virus hypervariable region 1 variants presented on hepatitis B virus capsid-like particles induce cross-neutralizing antibodies. AB - Hepatitis C virus (HCV) infection is still a serious global health burden. Despite improved therapeutic options, a preventative vaccine would be desirable especially in undeveloped countries. Traditionally, highly conserved epitopes are targets for antibody-based prophylactic vaccines. In HCV-infected patients, however, neutralizing antibodies are primarily directed against hypervariable region I (HVRI) in the envelope protein E2. HVRI is the most variable region of HCV, and this heterogeneity contributes to viral persistence and has thus far prevented the development of an effective HVRI-based vaccine. The primary goal of an antibody-based HCV vaccine should therefore be the induction of cross-reactive HVRI antibodies. In this study we approached this problem by presenting selected cross-reactive HVRI variants in a highly symmetric repeated array on capsid-like particles (CLPs). SplitCore CLPs, a novel particulate antigen presentation system derived from the HBV core protein, were used to deliberately manipulate the orientation of HVRI and therefore enable the presentation of conserved parts of HVRI. These HVRI-CLPs induced high titers of cross-reactive antibodies, including neutralizing antibodies. The combination of only four HVRI CLPs was sufficient to induce antibodies cross-reactive with 81 of 326 (24.8%) naturally occurring HVRI peptides. Most importantly, HVRI CLPs with AS03 as an adjuvant induced antibodies with a 10-fold increase in neutralizing capability. These antibodies were able to neutralize infectious HCVcc isolates and 4 of 19 (21%) patient-derived HCVpp isolates. Taken together, these results demonstrate that the induction of at least partially cross-neutralizing antibodies is possible. This approach might be useful for the development of a prophylactic HCV vaccine and should also be adaptable to other highly variable viruses. PMID- 25014223 TI - Inferring non-synonymous single-nucleotide polymorphisms-disease associations via integration of multiple similarity networks. AB - Detecting associations between human genetic variants and their phenotypic effects is a significant problem in understanding genetic bases of human inherited diseases. The focus is on a typical type of genetic variants called non synonymous single nucleotide polymorphisms (nsSNPs), whose occurrence may potentially alter the structures of proteins, affecting functions of proteins, and thereby causing diseases. Most of the existing methods predict associations between nsSNPs and diseases based on features derived from only protein sequence and/or structure information, and give no information about which specific disease an nsSNP is associated with. To cope with these problems, the identification of nsSNPs that are associated with a specific disease from a set of candidate nsSNPs as a binary classification problem has been formulated. A new approach has been adopted for predicting associations between nsSNPs and diseases based on multiple nsSNP similarity networks and disease phenotype similarity networks. With a series of comprehensive validation experiments, it has been demonstrated that the proposed method is effective in both recovering the nsSNP disease associations and inferring suspect disease-associated nsSNPs for both diseases with known genetic bases and diseases of unknown genetic bases. PMID- 25014224 TI - Degree-adjusted algorithm for prioritisation of candidate disease genes from gene expression and protein interactome. AB - Computational methods play an important role in the disease genes prioritisation by integrating many kinds of data sources such as gene expression, functional annotations and protein-protein interactions. However, the existing methods usually perform well in predicting highly linked genes, whereas they work quite poorly for loosely linked genes. Motivated by this observation, a degree-adjusted strategy is applied to improve the algorithm that was proposed earlier for the prediction of disease genes from gene expression and protein interactions. The authors also showed that the modified method is good at identifying loosely linked disease genes and the overall performance gets enhanced accordingly. This study suggests the importance of statistically adjusting the degree distribution bias in the background network for network-based modelling of complex diseases. PMID- 25014225 TI - Discovery of significant pathways in breast cancer metastasis via module extraction and comparison. AB - Discovering significant pathways rather than single genes or small gene sets involved in metastasis is becoming more and more important in the study of breast cancer. Many researches have shed light on this problem. However, most of the existing works are relying on some priori biological information, which may bring bias to the models. The authors propose a new method that detects metastasis related pathways by identifying and comparing modules in metastasis and non metastasis gene co-expression networks. The gene co-expression networks are built by Pearson correlation coefficients, and then the modules inferred in these two networks are compared. In metastasis and non-metastasis networks, 36 and 41 significant modules are identified. Also, 27.8% (metastasis) and 29.3% (non metastasis) of the modules are enriched significantly for one or several pathways with p-value <0.05. Many breast cancer genes including RB1, CCND1 and TP53 are included in these identified pathways. Five significant pathways are discovered only in metastasis network: glycolysis pathway, cell adhesion molecules, focal adhesion, stathmin and breast cancer resistance to antimicrotubule agents, and cytosolic DNA-sensing pathway. The first three pathways have been proved to be closely associated with metastasis. The rest two can be taken as a guide for future research in breast cancer metastasis. PMID- 25014227 TI - MPGraph: multi-view penalised graph clustering for predicting drug-target interactions. AB - Identifying drug-target interactions has been a key step for drug repositioning, drug discovery and drug design. Since it is expensive to determine the interactions experimentally, computational methods are needed for predicting interactions. In this work, the authors first propose a single-view penalised graph (SPGraph) clustering approach to integrate drug structure and protein sequence data in a structural view. The SPGraph model does clustering on drugs and targets simultaneously such that the known drug-target interactions are best preserved in the clustering results. They then apply the SPGraph to a chemical view with drug response data and gene expression data in NCI-60 cell lines. They further generalise the SPGraph to a multi-view penalised graph (MPGraph) version, which can integrate the structural view and chemical view of the data. In the authors' experiments, they compare their approach with some comparison partners, and the results show that the SPGraph could improve the prediction accuracy in a small scale, and the MPGraph can achieve around 10% improvements for the prediction accuracy. They finally give some new targets for 22 Food and Drug Administration approved drugs for drug repositioning, and some can be supported by other references. PMID- 25014226 TI - In silico identification of potential targets and drugs for non-small cell lung cancer. AB - Lung cancer is one of the leading causes of death in both the USA and Taiwan, and it is thought that the cause of cancer could be because of the gain of function of an oncoprotein or the loss of function of a tumour suppressor protein. Consequently, these proteins are potential targets for drugs. In this study, differentially expressed genes are identified, via an expression dataset generated from lung adenocarcinoma tumour and adjacent non-tumour tissues. This study has integrated many complementary resources, that is, microarray, protein protein interaction and protein complex. After constructing the lung cancer protein-protein interaction network (PPIN), the authors performed graph theory analysis of PPIN. Highly dense modules are identified, which are potential cancer associated protein complexes. Up- and down-regulated communities were used as queries to perform functional enrichment analysis. Enriched biological processes and pathways are determined. These sets of up- and down-regulated genes were submitted to the Connectivity Map web resource to identify potential drugs. The authors' findings suggested that eight drugs from DrugBank and three drugs from NCBI can potentially reverse certain up- and down-regulated genes' expression. In conclusion, this study provides a systematic strategy to discover potential drugs and target genes for lung cancer. PMID- 25014229 TI - Prediction and determination of the stereochemistry of the 1,3,5-trimethyl substituted alkyl chain in verucopeptin, a microbial metabolite. AB - For the prediction of the relative stereochemistry of 1,3-dimethyl substitution in alkyl chains, a simple approach based on (1)H NMR data was recently proposed; Deltadelta values of methylene protons located between methyl-substituted methine carbons can be diagnostic for predicting it. Here we applied this empirical "geminal proton rule" to verucopeptin, a lipopeptide from Streptomyces sp. To determine the absolute stereochemistry of the 1,3,5-trimethyl-substituted alkyl chain in verucopeptin, we converted the corresponding alkyl chain to a carboxylic acid by oxidative cleavage. The geminal proton rule clearly predicted the relative stereochemistry as 31S*,33S*,35R*. This prediction was definitely confirmed by synthesizing four possible diastereomers and comparing their NMR spectra. Furthermore, we reinvestigated the geminal proton rule using reported compounds and our synthesized compounds. Our result strongly suggests that the rule was solid, at least for predicting the stereochemistry of 2,4-dimethylated and 2,4,6-trimethylated fatty acids. PMID- 25014228 TI - Increased expression of flotillin-2 protein as a novel biomarker for lymph node metastasis in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot 2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC. PMID- 25014230 TI - Myeloid derived suppressor cells (MDSCs) are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs) in chronic myeloid leukemia patients. AB - Tumor immune tolerance can derive from the recruitment of suppressor cell population, including myeloid derived suppressor cells (MDSCs), able to inhibit T cells activity. We identified a significantly expanded MDSCs population in chronic myeloid leukemia (CML) patients at diagnosis that decreased to normal levels after imatinib therapy. In addition, expression of arginase 1 (Arg1) that depletes microenvironment of arginine, an essential aminoacid for T cell function, resulted in an increase in patients at diagnosis. Purified CML CD11b+CD33+CD14-HLADR- cells markedly suppressed normal donor T cell proliferation in vitro. Comparing CML Gr-MDSCs to autologous polymorphonuclear leukocytes (PMNs) we observed a higher Arg1 expression and activity in PMNs, together with an inhibitory effect on T cells in vitro. Our data indicate that CML cells create an immuno-tolerant environment associated to MDSCs expansion with immunosuppressive capacity mediated by Arg1. In addition, we demonstrated for the first time also an immunosuppressive activity of CML PMNs, suggesting a strong potential immune escape mechanism created by CML cells, which control the anti-tumor reactive T cells. MDSCs should be monitored in imatinib discontinuation trials to understand their importance in relapsing patients. PMID- 25014231 TI - Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation. AB - INTRODUCTION: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma. AREAS COVERED: This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib. EXPERT OPINION: Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions. PMID- 25014233 TI - Chronic hepatitis B treatment eligibility and actual treatment rates in patients in community gastroenterology and primary care settings. AB - GOALS: This study aims to compare the eligibility and treatment rates of patients evaluated by gastroenterology [gastrointestinal (GI)] specialists for chronic hepatitis B (CHB) and patients followed by their primary care physicians (PCPs) only. BACKGROUND: Guidelines have been devised to direct the care of patients with CHB but data on the application of these guidelines, especially in primary care settings, has been limited to date. STUDY: Consecutive CHB patients were enrolled retrospectively from several community clinics in the San Francisco Bay Area: 2 GI referral clinics, 3 primary care clinics, and a multispecialty medical center. Patients were classified as group 1 if they saw a gastroenterologist for CHB within 6 months of presentation or as group 2 if they only saw PCPs. Eligibility according to AASLD 2009 and US Panel 2008 guidelines was determined using clinical and laboratory data available within 6 months of presentation. RESULTS: Patients in group 2 had lower eligibility rates according to both US Panel 2008 (32% vs. 51%, P < 0.001) and AASLD 2009 (8% vs. 24%, P < 0.001) guidelines. GI specialists treated US Panel-eligible patients more readily than PCPs (45% vs. 25%, P < 0.001), and treatment rates in AASLD-eligible patients suggested a similar trend (68% vs. 50%, P = 0.080). CONCLUSIONS: GI specialists were more likely than PCPs to see patients who were treatment eligible, and also more likely to initiate antiviral therapy. However, there are still a considerable number of patients from both settings who did not receive treatment despite being eligible. PMID- 25014232 TI - Does translational symmetry matter on the micro scale? Fibroblastic and osteoblastic interactions with the topographically distinct poly(epsilon caprolactone)/hydroxyapatite thin films. AB - Material composition and topography of the cell-contacting material interface are important considerations in the design of biomaterials at the nano and micro scales. This study is one of the first to have assessed the osteoblastic response to micropatterned polymer-ceramic composite surfaces. In particular, the effect of topographic variations of composite poly(epsilon-caprolactone)/hydroxyapatite (PCL/HAp) films on viability, proliferation, migration and osteogenesis of fibroblastic and osteoblastic MC3T3-E1 cells was evaluated. To that end, three different micropatterned PCL/HAp films were compared: flat and textured, the latter of which included films comprising periodically arranged and randomly distributed oval topographic features 10 MUm in diameter, 20 MUm in separation and 10 MUm in height, comparable to the dimensions of MC3T3-E1 cells. PCL/HAp films were fabricated by the combination of a bottom-up, soft chemical synthesis of the ceramic, nanoparticulate phase and a top-down, photolithographic technique for imprinting fine, microscale features on them. X-ray diffraction analysis indicated an isotropic orientation of both the polymeric chains and HAp crystallites in the composite samples. Biocompatibility tests indicated no significant decrease in their viability when grown on PCL/HAp films. Fibroblast proliferation and migration onto PCL/HAp films proceeded slower than on the control borosilicate glass, with the flat composite film fostering more cell migration activity than the films containing topographic features. The gene expression of seven analyzed osteogenic markers, including procollagen type I, osteocalcin, osteopontin, alkaline phosphatase, and the transcription factors Runx2 and TGFbeta-1, was, however, consistently upregulated in cells grown on PCL/HAp films comprising periodically ordered topographic features, suggesting that the higher levels of symmetry of the topographic ordering impose a moderate mechanochemical stress on the adherent cells and thus promote a more favorable osteogenic response. The obtained results suggest that topography can be a more important determinant of the cell/surface interaction than the surface chemistry and/or stiffness as well as that the regularity of the distribution of topographic features can be a more important variable than the topographic features per se. PMID- 25014234 TI - Residual amount of HBV DNA in serum is related to relapse in chronic hepatitis B patients after cessation of nucleos(t)ide analogs. AB - OBJECTIVE: To investigate the relationship between relapse and the levels of the residual amount of HBV DNA in serum at cessation in chronic hepatitis B patients meeting 2008 Asian Pacific Association for the Study of the Liver (APASL) nucleos(t)ide analogs (NAs) cessation criteria. METHODS: A total of 72 chronic hepatitis B patients who took NAs and had reached 2008 APASL cessation criteria entered the study. Patients were followed up for 6 months or longer after antiviral therapy was stopped. Serum HBV DNA level at cessation was detected by a highly sensitive polymerase chain reaction assay with detection limitation of 2 IU/mL. RESULTS: Of all the 72 patients, 42 patients (65.3%) relapsed after NA cessation. The detectable rate of the trace amount of HBV DNA at cessation was 41.7% by highly sensitive polymerase chain reaction reagents. The detectable rate of patients with consolidation treatment duration of <18 months was higher than that with consolidation duration of >=18 months (47.5% vs. 15.4%, P=0.034), and the detectable rate of patients with HBeAg seroconversion within 6 months of treatment was lower than that of >=6 months (25.0% vs. 61.5%, P=0.036). The residual amount of HBV DNA and detectable rate at cessation showed significant differences between relapsed and nonrelapsed patients (130.4+/-420.90 vs 44.6+/ 155.16 IU/mL, P=0.004; 55.3% vs. 16.0%, P=0.001). The cutoff value predicting relapse was 2.24 IU/mL, with a sensitivity of 0.553 and specificity of 0.840. CONCLUSIONS: Residual amount of HBV DNA in serum at NA cessation is associated with HBV relapse. The cutoff value predicting relapse was 2.24 IU/mL, with a sensitivity of 0.553 and specificity of 0.840. PMID- 25014235 TI - Current and emerging treatment options for fecal incontinence. AB - Fecal incontinence (FI) is a multifactorial disorder that imposes considerable social and economic burdens. The aim of this article is to provide an overview of current and emerging treatment options for FI. A MEDLINE search was conducted for English-language articles related to FI prevalence, etiology, diagnosis, and treatment published from January 1, 1990 through June 1, 2013. The search was extended to unpublished trials on ClinicalTrials.gov and relevant publications cited in included articles. Conservative approaches, including dietary modifications, medications, muscle-strengthening exercises, and biofeedback, have been shown to provide short-term benefits. Transcutaneous electrical stimulation was considered ineffective in a randomized clinical trial. Unlike initial studies, sacral nerve stimulation has shown reasonable short-term effectiveness and some complications. Dynamic graciloplasty and artificial sphincter and bowel devices lack randomized controlled trials and have shown inconsistent results and high rates of explantation. Of injectable bulking agents, dextranomer microspheres in non-animal stabilized hyaluronic acid (NASHA Dx) has shown significant improvement in incontinence scores and frequency of incontinence episodes, with generally mild adverse effects. For the treatment of FI, conservative measures and biofeedback therapy are modestly effective. When conservative therapies are ineffective, invasive procedures, including sacral nerve stimulation, may be considered, but they are associated with complications and lack randomized, controlled trials. Bulking agents may be an appropriate alternative therapy to consider before more aggressive therapies in patients who fail conservative therapies. PMID- 25014236 TI - Digestive Symptoms in Healthy People and Subjects With Irritable Bowel Syndrome: Validation of Symptom Frequency Questionnaire. AB - GOALS: The aim of this study was to validate the ability of symptom frequency questionnaire to differentiate between irritable bowel syndrome (IBS) patients and healthy subjects. BACKGROUND: A digestive symptom frequency questionnaire (DSFQ) was previously used in a food efficacy trial in a non-IBS population with mild gastrointestinal symptoms. STUDY: We compared 2 well-defined populations: 100 IBS patients fulfilling Rome III criteria (mean age 32 y; range, 18 to 59 y), and 100 sex-matched and age-matched healthy subjects. Frequency of individual digestive symptoms (abdominal pain/discomfort, bloating, flatulence, borborygmi) was assessed using a 5-point Likert scale (from none to everyday of the week) and the IBS severity with the IBS-SSS questionnaire. Health-Related Quality of life (HRQoL) was assessed with the Food and Benefits Assessment (FBA) and Functional Digestive Disorders Quality of Life (FDDQL) questionnaires. The digestive (dis)comfort dimension of these questionnaires was considered as the main dimension for HRQoL. RESULTS: The DSFQ discriminated IBS from healthy subjects with a significant difference (P<0.001) between groups (estimated mean difference=5.58; 95% CI, 4.91-6.28). On the basis of the ROC curve (AUC=0.9479), a cutoff value of 5 gives a sensitivity of 92% and a specificity of 84%, with a positive likelihood ratio of 5.75. Composite score of symptoms correlated strongly (P<0.0001) with digestive discomfort measured by FDDQL (-0.816), digestive comfort measured by FBA (-0.789), and the IBS-SSS score (0.762). CONCLUSIONS: Measurement of digestive symptom frequency by means of the DSFQ can differentiate IBS from healthy subjects, and shows a good correlation with other validated questionnaires (clinical trial #NCT01457378). PMID- 25014237 TI - Biography of Theodore M. Bayless, MD. PMID- 25014238 TI - Outcomes of patients with acute upper gastrointestinal nonvariceal hemorrhage referred to interventional radiology for potential embolotherapy. AB - PURPOSE: To report the outcomes following catheter angiography with or without embolization in patients with acute upper gastrointestinal nonvariceal hemorrhage (UGINH). MATERIALS AND METHODS: A review of electronic medical records was performed to identify all potential patients for this study between 2001 and 2011. Patients with first-time UGINH who required angiographic localization and endovascular treatment were included. Patients with variceal bleeding and prior surgical or endovascular intervention for the gastrointestinal system were excluded. Society of Interventional Radiology guidelines and American College of Radiology "appropriateness criteria" reporting standards were followed. RESULTS: We identified 74 patients (men/women=46/28) with a mean age of 60 years. Thirty four patients were found to have active bleeding on angiography. One patient from this group did not undergo embolization because of an angiographic diagnosis of aortoenteric fistula. Technical failure was encountered in 2/34 patients; therefore, the technical success of embolization was 94%. Forty of 74 patients showed no angiographic evidence of active bleeding; 18 patients underwent prophylactic embolization using endoscopically placed clips as targets; and 22 patients had no embolotherapy. Thus, we grouped the patients into 3 groups: (1) therapeutic embolization; (2) prophylactic/empiric embolization; and (3) no embolotherapy groups. The clinical success of embolization was 67% to 68% in the therapeutic embolization group and 67% in the prophylactic embolization group. Early rebleeding rates were 33.8%, 51.6%, 33.3%, and 12% among all the patients, the therapeutic embolization group, the prophylactic embolization group, and the no endovascular treatment group, respectively. Mortality was significantly high in patients with advanced age (P=0.001), cerebrovascular disorders (P=0.037), and positive angiography (P=0.026), even when clinical success was achieved. CONCLUSIONS: Acute UGINH remains a clinical challenge with increased mortality rates, even with high technical success rates. Patients with negative findings on angiography have lower early rebleeding rates than patients with active bleeding during angiography or endoscopy-guided prophylactic/empiric embolization. PMID- 25014239 TI - Predictive scores in primary biliary cirrhosis: a retrospective single center analysis of 204 patients. AB - GOALS: The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany. BACKGROUND: PBC is a chronic autoimmune liver disease with a female gender predominance and a peak incidence in the fifth decade of life. PBC is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts in liver histology and the presence of antimitochondrial antibodies in the serum of nearly 95% of patients. In 5% to 20% of patients an overlap syndrome with autoimmune hepatitis (AIH) is diagnosed. Ursodeoxycholic acid is widely accepted as the standard medical treatment. STUDY: A total of 204 patients with PBC or PBC/AIH were retrospectively analyzed with regard to their clinical, biochemical, serological, and histologic features. PBC was diagnosed on the basis of the American Association for the Study of Liver Diseases criteria. Specific PBC scores, such as the MRS, the European and the Yale model, as well as nonspecific scores such as the Child-Pugh, the Model for End-stage Liver Disease, and Aspartate Aminotransferase to Platelet Ratio Index score were analyzed for their utility to predict the clinical outcome of patients. RESULTS: One hundred eighty-four patients with PBC alone and 20 with primary biliary cirrhosis/autoimmune hepatitis overlap were followed up for an average of 7.0 (range, 0.5 to 33.2) years. Importantly, baseline values of serum bilirubin, alkaline phosphatase, immunoglobulin M (IgM) and IgG, as well as antimitochondrial antibodies titers did not allow in properly predicting patient's outcome. The MRS proved clinical applicability. Patients with an R value <6 did not develop liver-related complications. The Aspartate Aminotransferase to Platelet Ratio Index score had a significant correlation with the histologic degree of liver fibrosis, with limited value of scores between 1.0 and 1.5. Patients with a Model for End-stage Liver Disease score >=8 (n=17) had a significantly higher risk to undergo liver transplantation or liver-related death. Outcome was less favorable than predicted by the European model. All scores showed low positive predictive values, limiting their applicability in clinical practice. CONCLUSIONS: Herein, we demonstrate that clinical risk scores in PBC should be interpreted with care. The MRS proved to be helpful to predict a favorable outcome. Novel approaches to predict outcome are needed to identify patients who may benefit from alternative, intensified treatment regimens. PMID- 25014240 TI - Predictors for Celiac Disease in Adult Cases of Duodenal Intraepithelial Lymphocytosis. AB - BACKGROUND: Duodenal intraepithelial lymphocytosis (D-IEL) is an early marker for celiac disease (CD). However, the majority of cases are due to non-CD-related conditions. GOALS: To identify the predictors of CD when presented with D-IEL. METHODS: A total of 215 adult patients with D-IEL had undergone prospective and systematic evaluation for CD and other recognized associations.The gold-standard diagnosis of CD was based upon the presence of HLA-DQ2 and/or DQ8, persistence or progression of D-IEL following a gluten challenge, followed by symptomatic improvement on a gluten-free diet.Binary logistic regression models, adjusting for age and sex, were subsequently performed to compare presenting variables between CD and non-CD cases, and to determine their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: CD was diagnosed in 48 cases (22%) and non-CD in 167 cases (78%). There was no statistical difference in baseline demographics, clinical symptoms (ie, diarrhea, weight loss, abdominal pain), anemia, or hematinics between the CD and non-CD group.Patients with CD, in comparison with non-CD, were significantly more likely to have a positive family history of CD (21% vs. 3.6%, OR 6.73; PPV 62.5%, NPV 81%, specificity 96.4%), positive HLA-DQ status (100% vs. 49.1%; PPV 36.4%, NPV 100%, specificity 50.9%), and presence of endomysial antibody (EMA) (48% vs. 0%; PPV 100%, NPV 87%, specificity 100%); all P<=0.001.A normal tissue transglutaminase antibody (TTG) level was seen in 29.2% CD and 83.2% non-CD cases (OR 0.084, P<0.001; PPV 9.2%). There was no difference in the prevalence of TTG levels 1 to 2*upper limit of normal (ULN) between the groups (29.2% CD vs. 14.4% non-CD; PPV 33% to 38%). However, TTG levels between 3 and 20*ULN were significantly more prevalent in the CD group (33.3% vs. 2.4%, PPV 66.6% to 89%), whereas a TTG>20*ULN was exclusive to CD (8.3%, P<0.001, PPV 100%). CONCLUSIONS: In the setting of D-IEL, only the presence of a positive EMA or TTG>20*ULN at the outset can be used to make an immediate diagnosis of CD. Gastrointestinal symptoms, family history, anemia, or other celiac serology results do not reliably distinguish CD from non-CD without further investigations. PMID- 25014241 TI - Insulin resistance correlated with the severity of liver histology in Japanese NAFLD patients: a multicenter retrospective study. PMID- 25014242 TI - The CD133+ cell as advanced medicinal product for myocardial and limb ischemia. AB - Ischemic diseases are the major cause of death and morbidity in Western countries. In the last decade, cell therapy has been suggested to be a promising treatment both in acute/chronic myocardial and peripheral ischemia. Different cell lineages have been tested, including endothelial progenitor cells. A subpopulation of bone marrow-derived immature ECPs, expressing the highly conserved stem cell glycoprotein antigen prominin-1 or CD133 marker, was shown to possess pro-angiogenic and antiapoptotic effects on ischemic tissues. The mechanisms implicated in CD133+ cells ability to contribute to neovascularization processes have been attributed to their ability to directly differentiate into newly forming vessels and to indirectly activate pro-angiogenic signaling by paracrine mechanisms. A large body of in vivo experimental evidences has demonstrated the potential of CD133+ cells to reverse ischemia. Moreover, several clinical trials have reported promising beneficial effects after infusion of autologous CD133+ into ischemic heart and limbs exploiting various delivery strategies. These trials have contributed to characterize the CD133+ manufacturing process as an advanced cell product (AMP). The aim of this review is to summarize available experimental and clinical data on CD133+ cells in the context of myocardial and peripheral ischemia, and to focus on the development of the CD133+ cell as an anti-ischemic AMP. PMID- 25014243 TI - Comparison of occupational radiation exposure from myocardial perfusion imaging with Rb-82 PET and Tc-99m SPECT. AB - OBJECTIVE: Rubidium-82 (Rb-82) PET myocardial perfusion imaging (MPI) has superior diagnostic accuracy, at least similar prognostic value, and lower patient radiation exposure when compared with technetium-99m single-photon emission computed tomography (Tc-99m SPECT) MPI. The aim of this study was to compare occupational radiation exposure from the two modalities and show that improvements for the patient do not come at a cost to staff. MATERIALS AND METHODS: Electronic personal dosimeters were worn by staff involved in the administration and imaging of routine clinical Tc-99m SPECT and Rb-82 PET MPI, and during tracer production and QC. To estimate dose to the staff in the event of a medical emergency, a survey meter was placed in close contact with the patient during Rb-82 infusion and imaging, and immediately after administration for Tc-99m SPECT. RESULTS: Mean (SD) whole-body effective dose to staff during a single MPI procedure was 0.4 (0.4) MUSv for Rb-82 PET (1110 MBq) and 3.3 (1.7) MUSv for Tc-99m SPECT (350 MBq). Staff effective dose during tracer production and QC was low (<0.2 MUSv/patient) and comparable between tracers. An additional effective dose was measured at close contact to the patient during, and immediately after, tracer administration, although this will not pose a significant radiation risk to staff with either technique as long as this is not routine practice. CONCLUSION: There is a significant reduction in effective dose during Rb-82 PET when compared with Tc-99m SPECT MPI because of the short half life of Rb-82 and reduced patient contact. PMID- 25014244 TI - SUMO-specific protease 1 modulates cadmium-augmented transcriptional activity of androgen receptor (AR) by reversing AR SUMOylation. AB - Cadmium is a potential prostate carcinogen and can mimic the effects of androgen by a mechanism that involves the hormone-binding domain of the androgen receptor (AR), which is a key transcriptional factor in prostate carcinogenesis. We focused on transcriptional activity of AR to investigate the toxicity of cadmium exposure on human prostate cell lines. Cadmium increased the proliferative index of LNCaP and the proliferative effect was obstructed significantly by AR blocking agent. In luciferase assay, cadmium activated the transcriptional activity of AR in 293T cells co-transfected with wild-type AR and an ARE (AR response elements) luciferase reporter gene. Cadmium also increased expression of PSA, a downstream gene of AR, whereas the metal had no significant effect on AR amount. AR is regulated by multiple posttranslational modifications including SUMOylation. SUMOylated AR shows a lower transcriptional activity. SUMO-specific protease 1 (SENP1) decreases AR SUMOylation by deconjugating AR-SUMO covalent bond. We detected that cadmium increased the amount of SENP1 in a dose and time dependent manner. Knocking down of SENP1 by RNAi led to decrease of PSA expression and transcriptional activity of AR in luciferase assay. Furthermore, co immunoprecipitation (Co-IP) results showed that SUMOylation level of AR was decreased after cadmium treatment. In conclusion, our results indicated that cadmium-induced SENP1 enhanced AR transcriptional activity by decreasing AR SUMOylation. PMID- 25014246 TI - Charging and uncharging a neutral polymer in solution: a small-angle neutron scattering investigation. AB - Aqueous formulations containing polymers and surfactants find several applications in pharmaceutics, coatings, inks, and home products. The association between polymers and surfactants contributes greatly to the function of these complex fluids, however, the effects of polar organic solvents, ubiquitous in formulations, remain mostly unexplored. We have analyzed small angle neutron scattering (SANS) data to determine the conformation of a "model" nonionic polymer, poly(ethylene oxide) (PEO), in aqueous solutions as affected by the presence of an ionic surfactant, sodium dodecyl sulfate (SDS), and subsequent addition of short-chain alcohol (ethanol or 2-propanol). PEO chains (MW = 90,000) are Gaussian in dilute aqueous solutions, but become polyelectrolyte-like upon the addition of 30 mM SDS, with about 6 SDS micelles bound to each PEO chain. Micelles associated with polymer are similar in structure and interactions to micelles that form in aqueous solutions in the absence of polymer. Addition of alcohol alters both the polymer and micelle structure and interactions, leads to detachment of micelles from the polymer, and the PEO chains regain their Gaussian conformation. 2-Propanol is more effective than ethanol in influencing the polymer conformation and the properties of SDS micelles in aqueous solutions, either in the presence or in the absence of PEO. This study contributes fundamental insights on polymer and surfactant organization in solution, as well as new, quantitative information on systems that are widely used in practice. PMID- 25014245 TI - Nephron-sparing surgery for multifocal and hereditary renal tumors. AB - PURPOSE OF REVIEW: Despite the controversy surrounding the benefits of nephron sparing surgery, multiple absolute indications for nephron-sparing surgery still exist, including the classic indications of hereditary and bilateral kidney tumors. RECENT FINDINGS: Multiple genetic mutations have been identified which lead to hereditary kidney cancer conditions. These are briefly reviewed because the surgical management of hereditary kidney tumors depends on the genetic and histologic subtypes involved. Clear understanding of these hereditary conditions is crucial for proper surgical management of these tumors. SUMMARY: Complex partial nephrectomy for multiple renal tumors, or multiplex partial nephrectomy, requires not only exceptional surgical skills but expertise of numerous nonsurgical methodologies, such as hands-on intraoperative ultrasonography and interpretation of multiple imaging modalities. In addition, multidisciplinary management is crucial for optimal outcomes in patient care. This review evaluates the most advanced surgical techniques and perioperative management required to successfully care for these challenging cases. PMID- 25014247 TI - Sphingolipids and ceramides of mouse aqueous humor: Comparative profiles from normotensive and hypertensive DBA/2J mice. AB - PURPOSE: To identify the sphingolipid and ceramide species and their quantitative differences between normotensive and hypertensive intraocular pressure states in DBA/2J mouse aqueous humor (AH). METHODS: Normotensive and hypertensive AH was sampled from mice by paracentesis. Lipid extraction was performed using modifications of the Bligh and Dyer method. Protein concentration was estimated using the Bradford colorimetric assay. Sphingolipids and ceramides were identified and subjected to ratiometric quantification using appropriate class specific lipid standards on a TSQ Quantum Access Max triple quadrupole mass spectrometer. RESULTS: The comparative profiles of normotensive and hypertensive DBA/2J mouse AH showed several species of sphingomyelin, sphingoid base, sphingoid base-1-phosphate (S1P) and ceramides common between them. A number of unique lipids in each of the above lipid classes were also identified in normotensive AH that were absent in hypertensive AH and vice versa. CONCLUSION: A number of sphingolipid and ceramide species were found to be uniquely present in normotensive, but absent in hypertensive AH and vice versa. Further pursuit of these findings is likely to contribute towards expanding our understanding of the molecular changes associated with increased intraocular pressure (IOP) and glaucoma. PMID- 25014249 TI - First year growth in relation to prenatal exposure to endocrine disruptors - a Dutch prospective cohort study. AB - Growth in the first year of life may already be predictive of obesity later in childhood. The objective was to assess the association between prenatal exposure to various endocrine disrupting chemicals (EDCs) and child growth during the first year. Dichloro-diphenyldichloroethylene (DDE), mono(2-ethyl-5 carboxypentyl)phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP), mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), polychlorinated biphenyl-153, perfluorooctanesulfonic acid, and perfluoro-octanoic acid were measured in cord plasma or breast milk. Data on weight, length, and head circumference (HC) until 11 months after birth was obtained from 89 mother-child pairs. Mixed models were composed for each health outcome and exposure in quartiles. For MEOHP, boys in quartile 1 had a higher BMI than higher exposed boys (p = 0.029). High DDE exposure was associated with low BMI over time in boys (0.8 kg/m2 difference at 11 m). Boys with high MECPP exposure had a greater HC (1.0 cm difference at 11 m) than other boys (p = 0.047), as did girls in the second quartile of MEHHP (p = 0.018) and DDE (p < 0.001) exposure. In conclusion, exposure to phthalates and DDE was associated with BMI as well as with HC during the first year after birth. These results should be interpreted with caution though, due to the limited sample size. PMID- 25014248 TI - Anaerobes and bacterial vaginosis in pregnancy: virulence factors contributing to vaginal colonisation. AB - The aetiology and pathogenesis of bacterial vaginosis (BV) is unclear but it appears to be associated with factors that disrupt the normal acidity of the vagina thus altering the equilibrium between the normal vaginal microbiota. BV has serious implications for female morbidity, including reports of pelvic inflammatory disease, adverse pregnancy outcomes, increased susceptibility to sexually transmitted infections and infertility. This paper reviewed new available information regarding possible factors contributing to the establishment of the BV vaginal biofilm, examined the proposed role of anaerobic microbial species recently detected by new culture-independent methods and discusses developments related to the effects of BV on human pregnancy. The literature search included Pubmed (NLM), LISTA (EBSCO), and Web of Science. Because of the complexity and diversity of population groups, diagnosis and methodology used, no meta-analysis was performed. Several anaerobic microbial species previously missed in the laboratory diagnosis of BV have been revealed while taking cognisance of newly proposed theories of infection, thereby improving our understanding and knowledge of the complex aetiology and pathogenesis of BV and its perceived role in adverse pregnancy outcomes. PMID- 25014251 TI - Effects of wink glass on blink rate, nibut and ocular surface symptoms during visual display unit use. AB - PURPOSE/AIM: Wink glass (WG), an invention to stimulate blinking at interval of 5 s was designed to reduce dry eye symptoms during visual display unit (VDU) use. The objective of this study is to investigate the effect of WG on visual functions that include blink rate, ocular surface symptoms (OSS) and tear stability during VDU use. MATERIALS AND METHODS: A total of 26 young and asymptomatic subjects were instructed to read articles in Malay language with a computer for 20 min with WG whereby their blink rate, pre- and post-task tear break-up time, and OSS were recorded. The results were compared to another reading session of the subjects wearing a transparent plastic sheet as a control. RESULTS: Non-invasive tear break-up time was reduced after reading session with transparent plastic sheet (pre-task = 5.97 s, post-task = 5.14 s, z = -2.426, p = 0.015, Wilcoxon), but remained stable (pre-task = 5.62 s, post-task = 5.35 s, z = -0.67, p = 0.501) during the reading session with WG. The blink rate recorded during reading session with plastic sheet was 9 blinks/min (median) and this increased to 15 blinks/min (z = -3.315, p = 0.001) with WG. The reading task caused OSS (maximum scores = 20) with median score of 1 (0-8) reduced to median score of 0 (0-3) after wearing WG (z = -2.417, p = 0.016). CONCLUSION: WG was found to increase post-task tear stability, increased blinking rate and reduced OSS during video display unit use among young and healthy adults. Although it may be considered as an option to improve dry eye symptoms among VDU users, further studies are warranted to establish its stability and its effect on subjects with dry eyes. PMID- 25014250 TI - Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments. AB - The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific C(T) values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with C(T) values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC C(T) > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7-16) versus 22 (18-33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF C(T) is a poor surrogate of load in extrapulmonary specimens. PMID- 25014252 TI - Microbial transformation of nandrolone with Cunninghamella echinulata and Cunninghamella blakesleeana and evaluation of leishmaniacidal activity of transformed products. AB - Therapeutic potential of nandrolone and its derivatives against leishmaniasis has been studied. A number of derivatives of nandrolone (1) were synthesized through biotransformation. Microbial transformation of nandrolone (1) with Cunninghamella echinulata and Cunninghamella blakesleeana yielded three new metabolites, 10beta,12beta,17beta-trihydroxy-19-nor-4-androsten-3-one (2), 10beta,16alpha,17beta-trihydroxy-19-nor-4-androsten-3-one (3), and 6beta,10beta,17beta-trihydroxy-19-nor-4-androsten-3-one (4), along with four known metabolites, 10beta,17beta-dihydroxy-19-nor-4-androsten-3-one (5), 6beta,17beta-dihydroxy-19-nor-4-androsten-3-one (6) 10beta-hydroxy-19-nor-4 androsten-3,17-dione (7) and 16beta,17beta-dihydroxy-19-nor-4-androsten-3-one (8). Compounds 1-8 were evaluated for their anti-leishmanial activity. Compounds 1 and 8 showed a significant activity in vitro against Leishmania major. The leishmanicidal potential of compounds 1-8 (IC50=32.0+/-0.5, >100, 77.39+/-5.52, 70.90+/-1.16, 54.94+/-1.01, 80.23+/-3.39, 61.12+/-1.39 and 29.55+/-1.14 MUM, respectively) can form the basis for the development of effective therapies against the protozoal tropical disease leishmaniasis. PMID- 25014253 TI - Comparison of Biolog GEN III MicroStation semi-automated bacterial identification system with matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S ribosomal RNA gene sequencing for the identification of bacteria of veterinary interest. AB - Recent advances in phenotypic and chemotaxonomic methods have improved the ability of systems to resolve bacterial identities at the species level. Key to the effective use of these systems is the ability to draw upon databases which can be augmented with new data gleaned from atypical or novel isolates. In this study we compared the performance of the Biolog GEN III identification system (hereafter, GEN III) with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing in the identification of isolates of veterinary interest. The use of strains that had proven more difficult to identify by routine methods was designed to test the systems' abilities at the extremes of their performance range. Over an 18month period, 100 strains were analysed by all three methods. To highlight the importance of identification to species level, a weighted scoring system was devised to differentiate the capacity to identify at genus and species levels. The overall relative weighted scores were 0.869:0.781:0.769, achieved by 16S rRNA gene sequencing, GEN III and MALDI-TOF MS respectively, when compared to the 'gold standard'. Performance to the genus level was significantly better using 16S rRNA gene sequencing; however, performance to the species level was similar for all three systems. PMID- 25014254 TI - Labels direct infants' attention to commonalities during novel category learning. AB - Recent studies have provided evidence that labeling can influence the outcome of infants' visual categorization. However, what exactly happens during learning remains unclear. Using eye-tracking, we examined infants' attention to object parts during learning. Our analysis of looking behaviors during learning provide insights going beyond merely observing the learning outcome. Both labeling and non-labeling phrases facilitated category formation in 12-month-olds but not 8 month-olds (Experiment 1). Non-linguistic sounds did not produce this effect (Experiment 2). Detailed analyses of infants' looking patterns during learning revealed that only infants who heard labels exhibited a rapid focus on the object part successive exemplars had in common. Although other linguistic stimuli may also be beneficial for learning, it is therefore concluded that labels have a unique impact on categorization. PMID- 25014255 TI - Anesthesia management for endovascular treatment. AB - PURPOSE OF REVIEW: The review highlights recent data regarding the safety and efficacy of endovascular treatment of cerebrovascular disease and concerns in anesthesia management. RECENT FINDINGS: Ongoing trials, including the Barrow Ruptured Aneurysm Trial and the International Subarachnoid Aneurysm Trial II, are aimed at improving understanding of the applicability of the International Subarachnoid Aneurysm Trial data and the roles of surgical clipping and endovascular treatment in the broad general patient population of ruptured aneurysms. Two recent studies in unruptured brain arteriovenous malformation management - ARUBA (a multicenter, randomized clinical trial) and the Scottish population-based cohort study - concluded that conservative medical management is superior to interventional therapy (including endovascular embolization) in preventing death or stroke. Three randomized clinical trials failed to prove the superiority of endovascular therapy to standard care for acute ischemic stroke, but pointed out to the need and direction of future trials. Studies of anesthesia for acute ischemic stroke suggested that inadequate brain perfusion may contribute to poorer outcome. SUMMARY: Recent data further support the role of endovascular coiling for ruptured aneurysm in broader patient populations. Further studies are needed to investigate the proper management of unruptured arteriovenous malformations, and the key factors in endovascular therapy and anesthesia management associated with stroke outcome. PMID- 25014256 TI - Colonization of olive trees (Olea europaea L.) with the arbuscular mycorrhizal fungus Glomus sp. modified the glycolipids biosynthesis and resulted in accumulation of unsaturated fatty acids. AB - The influence of arbuscular mycorrhizal (AM) fungi colonization on photosynthesis, mineral nutrition, the amount of phospholipids and glycolipids in the leaves of olive (Olea europaea L.) trees was investigated. After six months of growth, the rate of photosynthesis, carboxylation efficiency, transpiration and stomatal conductance in mycorrhizal (M) plants was significantly higher than that of non-mycorrhizal (NM) plants. The inoculation treatment increased the foliar P and Mg but not N. The amount of glycolipids in the leaves of M plants was significantly higher than that of NM plants. However, the amount of phospholipids in the leaves of M plants was not significantly different to that in the leaves of NM plants. Also, we observed a significant increase in the level of alpha-linolenic acid (C18:3omega3) in glycolipids of M plants. This work supports the view that increased glycolipids level in the leaves of M plants could be involved, at least in part, in the beneficial effects of mycorrhizal colonization on photosynthesis performance of olive trees. To our knowledge, this is the first report on the effect of AM fungi on the amount of glycolipids in the leaves of mycorrhizal plants. PMID- 25014257 TI - Assessment of the physiological responses to drought in different sugar beet genotypes in connection with their genetic distance. AB - Drought affects many physiological processes, which influences plant productivity. The aim of this study was to evaluate the degree of genotypic diversity in drought tolerance of sugar beet genotypes (Beta vulgaris L.) in connection with their genetic distance. Three hybrid genotypes produced by crossing double haploid genotype (P-pollinator) with cytoplasmic male-sterile female part (MS), as well as with two parent lines, were examined. Drought conditions were imposed by the cessation of watering at the 3-4 leaf stage for about three months, after which irrigation was resumed. Control plants were optimally irrigated throughout the entire vegetation period. Long-term drought significantly increased the wilting of leaves (Wilt.), specific leaf weight (SLW), the succulence index (Suc.I), leaf senescence and membrane damage (El-l). Simultaneously, the osmotic potential (psis), leaf area index (LAI), absorption of photosynthetic active radiation (PAR) and the efficiency of the photosynthetic apparatus (Phi PSII) declined under water deficit conditions. The examined genotypes demonstrated a clear diversity in their physiological response to drought. Based on these findings, we suggest that traits that are strongly correlated with root and sugar yield, e.g. Phi PSII, LAI, PAR absorption and psis, could be used as potential selection criteria in physiological-associated breeding strategies to improve drought tolerance in sugar beet. There was not a significant correlation between the genetic distance separating different sugar beet genotypes and the observed heterotic effect of root or sugar yields, with the exception of heterosis of root yield under optimal conditions, where the correlation was negative. PMID- 25014258 TI - Functional characterization of xanthoxin dehydrogenase in rice. AB - Abscisic acid (ABA) is a phytohormone that plays a key role in biotic and abiotic stress responses. ABA metabolic genes are promising targets for molecular breeding work to improve stress tolerance in crops. The accumulation of ABA does not always improve stress tolerance since stress-induced accumulation of ABA in pollen inhibits the normal course of gametogenesis, affecting grain yields in cereals. This effect highlights the importance of manipulating the ABA levels according to the type of tissues. The aim of this study was to assign an ABA biosynthetic enzyme, xanthoxin dehydrogenase (XanDH), as a functional marker to modulate ABA levels in rice. XanDH is a member of the short-chain dehydrogenase/reductase family that catalyzes the conversion of xanthoxin to abscisyl aldehyde (ABAld). Previously, this enzyme had only been identified in Arabidopsis, as AtABA2. In this study, a XanDH named OsABA2 was identified in rice. Phylogenetic analysis indicated that a single gene encodes for OsABA2 in the rice genome. Its amino acid sequence contains two motifs that are essential for cofactor binding and catalytic activity. Expression analysis of OsABA2 mRNA showed that the transcript level did not change in response to treatment with ABA or dehydration. Recombinant OsABA2 protein expressed in Escherichia coli converted xanthoxin to ABAld in an NAD-dependent manner. Moreover, expression of OsABA2 in an Arabidopsis aba2 mutant rescued the aba2 mutant phenotypes, characterized by reduced growth, increased water loss, and germination in the presence of paclobutrazol, a gibberellin biosynthesis inhibitor or high concentration of glucose. These results indicate that OsABA2 is a rice XanDH that functions in ABA biosynthesis. PMID- 25014259 TI - Hyperpolization-activated Ca(2+) channels in guard cell plasma membrane are involved in extracellular ATP-promoted stomatal opening in Vicia faba. AB - Extracellular ATP (eATP) plays essential roles in plant growth, development, and stress tolerance. Extracellular ATP-regulated stomatal movement of Arabidopsis thaliana has been reported. Here, ATP was found to promote stomatal opening of Vicia faba in a dose-dependent manner. Three weakly hydrolysable ATP analogs (adenosine 5'-O-(3-thio) triphosphate (ATPgammaS), 3'-O-(4-benzoyl) benzoyl adenosine 5'-triphosphate (Bz-ATP) and 2-methylthio-adenosine 5'-triphosphate (2meATP)) showed similar effects, indicating that ATP acts as a signal molecule rather than an energy charger. ADP promoted stomatal opening, while AMP and adenosine did not affect stomatal movement. An ATP-promoted stomatal opening was blocked by the NADPH oxidase inhibitor diphenylene iodonium (DPI), the reductant dithiothreitol (DTT) or the Ca(2+) channel blockers GdCl3 and LaCl3. A hyperpolarization-activated Ca(2+) channel was detected in plasma membrane of guard cell protoplast. Extracellular ATP and weakly hydrolyzable ATP analogs activated this Ca(2+) channel significantly. Extracellular ATP-promoted Ca(2+) channel activation was markedly inhibited by DPI or DTT. These results indicated that eATP may promote stomatal opening via reactive oxygen species that regulate guard cell plasma membrane Ca(2+) channels. PMID- 25014260 TI - Plasticity in stomatal size and density of potato leaves under different irrigation and phosphorus regimes. AB - The morphological features of stomata including their size and density could be modulated by environmental cues; however, the underlying mechanisms remain largely elusive. Here, the effect of different irrigation and phosphorus (P) regimes on stomatal size (SS) and stomatal density (SD) of potato leaves was investigated. The plants were grown in split-root pots under two P fertilization rates (viz., 0 and 100mgkg(-1) soil, denoted as P0 and P1, respectively) and subjected to full (FI), deficit (DI), and partial root-zone drying (PRD) irrigation regimes. Results showed that SS and SD were unresponsive to P but significantly affected by the irrigation treatment. FI plants had the largest SS, followed by DI, and PRD the smallest; and the reverse was the case for SD. Compared to FI and DI, PRD plants had significantly lower values of specific leaf area (SLA) and leaf carbon isotope discrimination (Delta(13)C) under P0. Midday leaf water potential (Psileaf) and stomatal conductance (gs) was similar for DI and PRD, which was significantly lower than that of FI. Leaf contents of C, N, K, Ca and Mg were higher in PRD than in DI plants, particularly under P0. When analyzed across the three irrigation regimes, it was found that the P1 plants had significantly higher leaf contents of P and Mg, but significantly lower leaf K content compared to the P0 plants. Linear correlation analyses revealed that SS was positively correlated with Psileaf and Delta(13)C; whereas SD was negatively correlated with Psileaf, Delta(13)C and SLA, and positively correlated with leaf C, N and Ca contents. And gs was positively correlated with SS but negatively correlated with SD. Collectively, under low P level, the smaller and denser stomata in PRD plants may bring about a more efficient stomatal control over gas exchange, hereby potentially enhance water-use efficiency as exemplified by the lowered leaf Delta(13)C under fluctuating soil moisture conditions. PMID- 25014261 TI - A morpho-physiological approach differentiates bread wheat cultivars of contrasting tolerance under cyclic water stress. AB - Leaf micromorphological traits and some physiological parameters with potential relevance to drought tolerance mechanisms were investigated in four selected winter wheat varieties. Plants were subjected to two cycles of drought treatment at anthesis. Yield components confirmed contrasting drought-sensitive and tolerant behavior of the genotypes. Drought tolerance was associated with small flag leaf surfaces and less frequent occurrence of stomata. Substantial variation of leaf cuticular thickness was found among the cultivars. Thin cuticle coincided with drought sensitivity and correlated with a high rate of dark-adapted water loss from leaves. Unlike in Arabidopsis, thickening of the cuticular matrix in response to water deprivation did not occur. Water stress induced epicuticular wax crystal depositions preferentially on the abaxial leaf surfaces. According to microscopy and electrolyte leakage measurements from leaf tissues, membrane integrity was lost earlier or to a higher extent in sensitive than in tolerant genotypes. Cellular damage and a decline of relative water content of leaves in sensitive cultivars became distinctive during the second cycle of water deprivation. Our results indicate strong variation of traits with potential contribution to the complex phenotype of drought tolerance in wheat genotypes. The maintained membrane integrity and relative water content values during repeated water limited periods were found to correlate with drought tolerance in the selection of cultivars investigated. PMID- 25014262 TI - Endogenous isoflavone methylation correlates with the in vitro rooting phases of Spartium junceum L. (Leguminosae). AB - Spartium junceum L. (Leguminosae) is a perennial shrub, native to the Mediterranean region in southern Europe, widespread in all the Italian regions and, as a leguminous species, it has a high isoflavone content. An in vitro culture protocol was developed for this species starting from stem nodal sections of in vivo plants, and isoflavone components of the in vitro cultured tissues were studied by means of High Performance Liquid Chromatography (HPLC) analytical techniques. Two main isoflavones were detected in the S. junceum tissues during the in vitro propagation phases: Genistein (4',5,7-Trihydroxyisoflavone), already reported in this species, and its methylated form 4',5,7-Trimethoxyisoflavone, detected for the first time in this plant species (0.750 +/- 0.02 mg g(-1) dry tissue). The presence of both of these compounds in S. junceum tissues was consistently detected during the in vitro multiplication phase. The absence of the methylated form within plant tissues in the early phases of the in vitro adventitious root formation was correlated with its negative effect displayed on root induction and initiation phases, while its presence in the final "root manifestation" phase influenced positively the rooting process. The unmethylated form, although detectable in tissues in the precocious rooting phases, was no longer present in the final rooting phase. Its effect on rooting, however, proved always to be beneficial. PMID- 25014263 TI - Genome-wide expression analysis of rice ABC transporter family across spatio temporal samples and in response to abiotic stresses. AB - Although the super family of ATP-binding cassette (ABC) proteins plays key roles in the physiology and development of plants, the functions of members of this interesting family mostly remain to be clarified, especially in crop plants. Thus, systematic analysis of this family in rice (Oryza sativa), a major model crop plant, will be helpful in the design of effective strategies for functional analysis. Phylogenomic analysis that integrates anatomy and stress meta-profiling data based on a large collection of rice Affymetrix array data into the phylogenic context provides useful clues into the functions for each of the ABC transporter family members in rice. Using anatomy data, we identified 17 root preferred and 16-shoot preferred genes at the vegetative stage, and 3 pollen, 2 embryo, 2 ovary, 2 endosperm, and 1 anther-preferred gene at the reproductive stage. The stress data revealed significant up-regulation or down-regulation of 47 genes under heavy metal treatment, 16 genes under nutrient deficient conditions, and 51 genes under abiotic stress conditions. Of these, we confirmed the differential expression patterns of 14 genes in root samples exposed to drought stress using quantitative real-time PCR. Network analysis using RiceNet suggests a functional gene network involving nine rice ABC transporters that are differentially regulated by drought stress in root, further enhancing the prediction of biological function. Our analysis provides a molecular basis for the study of diverse biological phenomena mediated by the ABC family in rice and will contribute to the enhancement of crop yield and stress tolerance. PMID- 25014265 TI - Nitric-oxide inhibits nyctinastic closure through cGMP in Albizia lophantha leaflets. AB - Nitric oxide (NO) is a highly reactive radical that acts as a direct or indirect cellular signalling molecule in plant growth, development and environmental responses. Here we studied the contribution of NO to the control of leaflet movements during nyctinastic closure. For this purpose, we tested the effect of NO donors and an NO scavenger, all supplied in light, on Albizia lophantha leaflet closure after transferral to darkness. Exogenous NO, applied as four donors [sodium nitroprusside (SNP), diethylammonium (Z)-1-(N,N-diethylamino) diazen-1-ium-1,2-diolate (DEA-NONOate), S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GS-NO)], inhibited nyctinastic leaflet closure while the application of an NO scavenger [2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (cPTIO)] plus SNP cancelled the effect of the latter. The inclusion of Nomega-nitro-l-arginine methyl ester (l-NAME) or sodium tungstate in the incubation media enhanced nyctinastic closure and also resulted in a decrease in the nitrate plus nitrite released by leaflets into the incubation solution. These results support the notion that NO is involved in regulating the nyctinastic closure of A. lophantha leaflets. Cellular perception of NO did not appear to be mediated by calcium. Pharmacological application of inhibitors of soluble guanylate cyclase (sGC) [1H-[1,2,4]-oxadiazole-[4,3-a] quinoxalin-1-one (ODQ) and 6-anilino-5,8-quinolinequinone (Ly83583)], phosphodiesterase type 5 (PDE5) (Sildenafil) and the cyclic guanosine monophosphate (cGMP) analogue 8-bromoguanosine-3',5'-cyclomonophosphate sodium salt (8-Br-cGMP) indicated that cGMP was downstream of the NO signalling cascade during nyctinastic closure. PMID- 25014264 TI - Physiology and transcriptomics of water-deficit stress responses in wheat cultivars TAM 111 and TAM 112. AB - Hard red winter wheat crops on the U.S. Southern Great Plains often experience moderate to severe drought stress, especially during the grain filling stage, resulting in significant yield losses. Cultivars TAM 111 and TAM 112 are widely cultivated in the region, share parentage and showed superior but distinct adaption mechanisms under water-deficit (WD) conditions. Nevertheless, the physiological and molecular basis of their adaptation remains unknown. A greenhouse study was conducted to understand the differences in the physiological and transcriptomic responses of TAM 111 and TAM 112 to WD stress. Whole-plant data indicated that TAM 112 used more water, produced more biomass and grain yield under WD compared to TAM 111. Leaf-level data at the grain filling stage indicated that TAM 112 had elevated abscisic acid (ABA) content and reduced stomatal conductance and photosynthesis as compared to TAM 111. Sustained WD during the grain filling stage also resulted in greater flag leaf transcriptome changes in TAM 112 than TAM 111. Transcripts associated with photosynthesis, carbohydrate metabolism, phytohormone metabolism, and other dehydration responses were uniquely regulated between cultivars. These results suggested a differential role for ABA in regulating physiological and transcriptomic changes associated with WD stress and potential involvement in the superior adaptation and yield of TAM 112. PMID- 25014266 TI - Dehydration induces expression of GALACTINOL SYNTHASE and RAFFINOSE SYNTHASE in seedlings of pea (Pisum sativum L.). AB - The exposition of 7-day-old pea seedlings to dehydration induced sudden changes in the concentration of monosaccharides and sucrose in epicotyl and roots tissues. During 24h of dehydration, the concentration of glucose and, to a lesser extent, fructose in seedling tissues decreased. The accumulation of sucrose was observed in roots after 4h and in epicotyls after 8h of stress. Epicotyls and roots also began to accumulate galactinol and raffinose after 8h of stress, when small changes in the water content of tissues occurred. The accumulation of galactinol and raffinose progressed parallel to water withdrawal from tissues, but after seedling rehydration both galactosides disappeared. The synthesis of galactinol and raffinose by an early induction (during the first hour of treatment) of galactinol synthase (PsGolS) and raffinose synthase (PsRS) gene expression as well as a later increase in the activity of both enzymes was noted. Signals possibly triggering the induction of PsGolS and PsRS gene expression and accumulation of galactinol and raffinose in seedlings are discussed. PMID- 25014267 TI - An empirical analysis of White privilege, social position and health. AB - Accumulated evidence has demonstrated that social position matters for health. Those with greater socioeconomic resources and greater perceived standing in the social hierarchy have better health than those with fewer resources and lower perceived standing. Race is another salient axis by which health is stratified in the U.S., but few studies have examined the benefit of White privilege. In this paper, we investigated how perceptions of inequality and subjective and objective social status affected the health and well-being of N = 630 White residents in three Boston neighborhoods lying on a social gradient differentiated by race, ethnicity, income and prestige. Outcomes were self-rated health, dental health, and happiness. Results suggested that: neighborhood residence was not associated with health after controlling for individual level factors (e.g., positive ratings of the neighborhood, education level); objective measures of socioeconomic status were associated with better self-reported and dental health, but subjective assessments of social position were more strongly associated; and White residents living in the two wealthiest neighborhoods, and who perceived Black families as welcome in their neighborhoods enjoyed better health than those who believed them to be less welcome. However, those who lived in the least wealthy and most diverse neighborhood fared worse when reporting Black families to be welcome. These results suggest that White privilege and relative social position interact to shape health outcomes. PMID- 25014268 TI - Investigating the influence of African American and African Caribbean race on primary care doctors' decision making about depression. AB - This paper explores differences in how primary care doctors process the clinical presentation of depression by African American and African-Caribbean patients compared with white patients in the US and the UK. The aim is to gain a better understanding of possible pathways by which racial disparities arise in depression care. One hundred and eight doctors described their thought processes after viewing video recorded simulated patients presenting with identical symptoms strongly suggestive of depression. These descriptions were analysed using the CliniClass system, which captures information about micro-components of clinical decision making and permits a systematic, structured and detailed analysis of how doctors arrive at diagnostic, intervention and management decisions. Video recordings of actors portraying black (both African American and African-Caribbean) and white (both White American and White British) male and female patients (aged 55 years and 75 years) were presented to doctors randomly selected from the Massachusetts Medical Society list and from Surrey/South West London and West Midlands National Health Service lists, stratified by country (US v.UK), gender, and years of clinical experience (less v. very experienced). Findings demonstrated little evidence of bias affecting doctors' decision making processes, with the exception of less attention being paid to the potential outcomes associated with different treatment options for African American compared with White American patients in the US. Instead, findings suggest greater clinical uncertainty in diagnosing depression amongst black compared with white patients, particularly in the UK. This was evident in more potential diagnoses. There was also a tendency for doctors in both countries to focus more on black patients' physical rather than psychological symptoms and to identify endocrine problems, most often diabetes, as a presenting complaint for them. This suggests that doctors in both countries have a less well developed mental model of depression for black compared with white patients. PMID- 25014269 TI - Association of PvuII and XbaI polymorphisms in estrogen receptor alpha gene with the risk of hepatitis B virus infection in the Guangxi Zhuang population. AB - BACKGROUND AND OBJECTIVE: Available evidence has suggested that estrogen receptor alpha (ESR1) is implicated in the pathogenic process of hepatitis B infection. Therefore, we evaluated the association of PvuII (rs2234693) and XbaI (rs9340799) in ESR1 and HBV infection in Guangxi Zhuang populations. METHODS: A total of 389 subjects were divided into four groups: 112 patients with chronic hepatitis B (CHB), 65 patients with hepatitis B virus (HBV)-related liver cirrhosis (LC), 107 patients with HBV-related hepatocellular carcinoma (HCC), and 105 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect ESR1 gene PvuII and XbaI polymorphisms. RESULTS: Compared with healthy controls, binary logistic regression analyses show that the CC genotype of PvuII was associated with a significantly increased susceptibility to CHB compared with the TT genotype (OR=1.760, 95% CI 1.316-2.831; p=0.044). The PvuII CC genotype was also associated with significantly increased risk of HBV related LC (OR=1.921, 95% CI 1.342-2.478; p=0.043). Similarly, the subjects bearing the homozygous CC genotype of PvuII polymorphism also had more than a 1.7 fold increased risk for development of HCC (OR=1.748, 95% CI 1.313-2.787; p=0.010) compared with those bearing the TT genotype. Furthermore, the AC haplotype was associated with a significantly increased risk of HCC with an OR of 1.456 (p=0.003). In contrast, there were no significant differences in the genotype and allele of XbaI polymorphisms in the ESR1 gene between the groups of patients and healthy controls. In addition, ESR1 polymorphisms were not significantly associated with susceptibility to HBV-related HCC when using CHB and LC patients as references. CONCLUSION: We conclude that the CC genotype of PvuII in ESR1 is associated with an increased risk of CHB, HBV-related LC and HCC in Guangxi Zhuang populations. PMID- 25014270 TI - Induction of naming after observing visual stimuli and their names in children with autism. AB - A novel procedure to induce pairing naming, considered the emergence of tacts and selection of pictures after observing names and its corresponding pictures without specific consequences, was probed in 4 persons with autism who lacked this capability with a multiple probe design across participants. Five pictures were selected per set. The participants observed the pictures on a computer screen while the experimenter said the name of the picture. Then, the emission of untaught uninstructed tacts of the pictures was tested without reinforcement. The cycle was repeated until a criterion of 90% correct responses was achieved. Thereafter, in probes without reinforcement, the participants tacted the pictures without specific instructions and also when asked to name them, and selected the correct picture upon hearing their names. The procedure was repeated with two additional stimulus sets and the probed relations emerged always. Two children showed the emergence with fewer trials across sets, which indicate emergence induction. Thus, the procedure served to test whether the pairing naming capability was missing and induced the capability. The results may have important utility in teaching persons diagnosed with autism and other learning difficulties and for accelerating learning in all children. PMID- 25014271 TI - Determinants of gross motor skill performance in children with visual impairments. AB - Children with visual impairments (CWVI) generally perform poorer in gross motor skills when compared with their sighted peers. This study examined the influence of age, sex, and severity of visual impairment upon locomotor and object control skills in CWVI. Participants included 100 CWVI from across the United States who completed the Test of Gross Motor Development II (TGMD-II). The TGMD-II consists of 12 gross motor skills including 6 object control skills (catching, kicking, striking, dribbling, throwing, and rolling) and 6 locomotor skills (running, sliding, galloping, leaping, jumping, and hopping). The full range of visual impairments according to United States Association for Blind Athletes (USABA; B3=20/200-20/599, legally blind; B2=20/600 and up, travel vision; B1=totally blind) were assessed. The B1 group performed significantly worse than the B2 (0.000 <= p <= 0.049) or B3 groups (0.000 <= p <= 0.005); however, there were no significant differences between B2 and B3 except for the run (p=0.006), catch (p=0.000), and throw (p=0.012). Age and sex did not play an important role in most of the skills, with the exception of boys outperforming girls striking (p=0.009), dribbling (p=0.013), and throwing (p=0.000), and older children outperforming younger children in dribbling (p=0.002). The significant impact of the severity of visual impairment is likely due to decreased experiences and opportunities for children with more severe visual impairments. In addition, it is likely that these reduced experiences explain the lack of age-related differences in the CWVI. The large disparities in performance between children who are blind and their partially sighted peers give direction for instruction and future research. In addition, there is a critical need for intentional and specific instruction on motor skills at a younger age to enable CWVI to develop their gross motor skills. PMID- 25014272 TI - Exploring tool innovation: a comparison of Western and Bushman children. AB - A capacity for constructing new tools, or using old tools in new ways, to solve novel problems is a core feature of what it means to be human. Yet current evidence suggests that young children are surprisingly poor at innovating tools. However, all studies of tool innovation to date have been conducted with children from comparatively privileged Western backgrounds. This raises questions as to whether or not previously documented tool innovation failure is culturally and economically specific. In the current study, thus, we explored the innovation capacities of children from Westernized urban backgrounds and from remote communities of South African Bushmen. Consistent with past research, we found tool innovation to occur at extremely low rates and that cultural background had no bearing on this. The current study is the first to empirically test tool innovation in children from non-Western backgrounds, with our data being consistent with the view that despite its key role in human evolution, a capacity for innovation in tool making remains remarkably undeveloped during early childhood. PMID- 25014273 TI - Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis. AB - AIMS/HYPOTHESES: To examine hepatic expression of cholesterol-trafficking proteins, mitochondrial StarD1 and endosomal StarD3, and their relationship with dyslipidaemia and steatosis in Zucker (fa/fa) genetically obese rats, and to explore their functional role in lipid metabolism in rat McArdle RH-7777 hepatoma cells. METHODS: Expression of StarD1 and StarD3 in rat liver and hepatoma samples were determined by Q-PCR and/or immunoblotting; lipid mass by colorimetric assays; radiolabelled precursors were utilised to measure lipid synthesis and secretion, and lipidation of exogenous apolipoprotein A-I. RESULTS: Hepatic expression of StarD3 protein was repressed by genetic obesity in (fa/fa) Zucker rats, compared with lean (Fa/?) controls, suggesting a link with storage or export of lipids from the liver. Overexpression of StarD1 and StarD3, and knockdown of StarD3, in rat hepatoma cells, revealed differential effects on lipid metabolism. Overexpression of StarD1 increased utilisation of exogenous (preformed) fatty acids for triacylglycerol synthesis and secretion, but impacted minimally on cholesterol homeostasis. By contrast, overexpression of StarD3 increased lipidation of exogenous apoA-I, and facilitated de novo biosynthetic pathways for neutral lipids, potentiating triacylglycerol accumulation but possibly offering protection against lipotoxicity. Finally, StarD3 overexpression altered expression of genes which impact variously on hepatic insulin resistance, inducing Ppargcla, Cyp2e1, Nr1h4, G6pc and Irs1, and repressing expression of Scl2a1, Igfbp1, Casp3 and Serpine 1. CONCLUSIONS/INTERPRETATION: Targeting StarD3 may increase circulating levels of HDL and protect the liver against lipotoxicity; loss of hepatic expression of this protein, induced by genetic obesity, may contribute to the pathogenesis of dyslipidaemia and steatosis. PMID- 25014274 TI - Identification of a phospholipase B encoded by the LPL1 gene in Saccharomyces cerevisiae. AB - Phospholipids also play a major role in maintaining the lipid droplet (LD) morphology. In our current study, deletion of LPL1 resulted in altered morphology of LDs and was confirmed by microscopic analysis. LPL1/YOR059c contains lipase specific motif GXSXG and acetate labeling in the LPL1 overexpressed strains depicted a decrease in glycerophospholipids and an increase in free fatty acids. The purified Lpl1p showed phospholipase activity with broader substrate specificity, acting on all glycerophospholipids primarily at sn-2 position and later at sn-1 position. Localization studies precisely revealed that Lpl1 is exclusively localized in the LD at the stationary phase. Site directed mutagenesis experiments clearly demonstrated that the lipase motif is vital for the phospholipase activity. In summary, our results demonstrate that yeast Lpl1 exerts phospholipase activity, plays a vital role in LD morphology, and its absence results in altered LD size. Based on the localization and enzyme activity we renamed YOR059c as LPL1 (LD phospholipase 1). PMID- 25014275 TI - Prostaglandin modulates TLR3-induced cytokine expression in human astroglioma cells. AB - Cyclooxygenase (COX) products and pattern recognition receptors are important modulators of neuroinflammation; however, the role of prostaglandins and toll like receptor (TLR) signaling and the functional crosstalk between COX modulators remains unclear, especially in astrocytes that closely modulate neuronal functions. Here, we studied the effect of prostaglandins on toll-like receptor 3 (TLR3)-induced cytokine expression in human astroglioma CRT-MG cells. Prostaglandin E2 (PGE2) was shown to increase cytosolic cAMP levels in an EP2 receptor dependent manner. Interestingly, the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) mediated phosphorylation of NF-kappaB and extracellular stress-related kinase 1/2 (ERK1/2), which significantly decreased following PGE2 treatment. In addition, PGE2 increased the phosphorylation and inactivation of glycogen synthesis kinase-3beta (GSK-3beta), whereas poly(I:C) decreased it. We observed that PGE2 decreased tumor necrosis factor-alpha (TNF-alpha) production evoked by poly(I:C), whereas PGE2 potentiated poly(I:C)-triggered interleukin-8 (IL-8) production. These results suggest that prostaglandin modulates the TLR3-mediated cytokine profile in astrocytes via EP2 receptors and regulates the NF-kappaB, ERK1/2 and GSK-3beta signaling pathways. PMID- 25014276 TI - Ingrid Toft (June 2, 1959-April 26, 2014). PMID- 25014277 TI - Late preterm births: an "almost" overlooked group of newborns. PMID- 25014278 TI - [Intention to breastfeed and complementary feeding of postpartum women in a teaching hospital in southern Brazil]. AB - This article seeks to analyze the intention of mothers to breastfeed and the prospects for introduction of complementary food in the first year of life. A cross-sectional study was conducted from September to December 2010 at the Teaching Hospital of the Federal University of Pelotas in the state of Rio Grande do Sul, Brazil. Data were obtained through a standardized questionnaire, containing questions about socioeconomic conditions, breastfeeding and complementary feeding. 170 mothers were enlisted, with a mean age of 26.5 +/- 5.8 years old. Among them, 99% had received prenatal medical care and only 49% recalled having received information about breastfeeding and/or supplementary feeding during the care. All of the mothers intended to breastfeed exclusively for a mean time of 5.5 +/- 1.6 months. Years of schooling, mothers who do not work outside the home, lower maternal age and receiving information about breastfeeding during prenatal care were associated with longer duration of exclusive breastfeeding. Regarding complementary food, bean soup was the food most intended for the child's first year of life, with an acceptance of 99.41%, while tea was the one with the earliest intention. The duration of breastfeeding was below the WHO guidelines, and complementary food was considered to be misguided. PMID- 25014279 TI - [Inequalities in prenatal care in a southeastern city in Brazil]. AB - The scope of this article is to evaluate the association between adequate prenatal care and sociodemographic variables in Niteroi in the state of Rio de Janeiro. It involved a cross-sectional study conducted between 2000 and 2009 evaluating 62,449 live births using data from the Brazilian Live Birth Information System (SINASC). Multivariate analysis by logistic regression was performed considering quantitatively adequate prenatal care - seven or more visits - as the dependent variable, and maternal age, educational level and skin color as independent variables. The time trends of mother's age, educational level and prenatal visits were also analyzed. The significance level was 5%. There was an improvement in educational level, reduction in adolescent pregnancy and an increase in mothers aged over 35 in Niteroi. Women who attended seven or more prenatal visits remained above 80%, though with differences according to age, education and skin color. Adult women (OR = 1.4; IC95% 1.39-1.56). women with eight or more years of schooling (OR = 2.5; IC95% 2.45-2.70) and white women (OR = 2.4; IC95% 2.30-2.53) had more chances of adequate prenatal care. Health inequalities in maternal health care on offer in Niteroi were identified, despite improvements in social and demographic indicators in the city. PMID- 25014280 TI - [Adaptation of the process of prenatal care in accordance with criteria established by the Humanization of Prenatal and Birth Program and the World Health Organization]. AB - The scope of this article is to assess the adequacy of the process of prenatal care provided to users of the Unified Health System in the city of Vitoria, in accordance with criteria established by the Humanization of Prenatal and Birth Program (PHPN) and the World Health Organization (WHO). The information on the prenatal care records of 360 pregnant women interned in public hospitals in the city at the time of delivery were assessed. The information was collected, processed and submitted to descriptive statistical analysis for calculations of absolute and relative frequencies and confidence intervals. None of the pregnant women were given entirely appropriate prenatal care in accordance with WHO criteria, and only 5% of pregnant women received prenatal care in line with PHPN. 44.7% of the women did not begin prenatal care until the 4th month. With respect to conducting technical procedures in the appointments, the main emphasis was on checking maternal weight (95.0%) and blood pressure (95.6%). The results indicate the need for a review of the number of prenatal appointments in the municipality and the adoption of strategies to meet the minimum criteria that need to be performed during prenatal care in public health services. PMID- 25014281 TI - [Evaluation of the quality of data in the Live Birth Information System and the Information System on Mortality during the neonatal period in the state of Espirito Santo, Brazil, between 2007 and 2009]. AB - Health information systems make it possible to be aware of health problems and often represent the sole source of information, thereby making it essential to assess their quality. The scope of this paper was to evaluate the quality of data about live births and deaths in the neonatal period in the Live Births Information System (SINASC) and Mortality Information System (SIM) in the state of Espirito Santo during the period from 2007 to 2009. Descriptive methodology with secondary data obtained from the electronic address of the Informatics Department of the Unified Health System was used to analyze the dimensions of quality of information, namely accessibility, timeliness and completeness. The results indicate that the information is accessible and timely, with a lag of three years compared to the beginning of the study. The completeness of the variables analyzed in SINASC was predominantly classified as excellent. SIM revealed a high percentage of missing data on the number of the Live Birth Declaration, mother's education, age and reproductive history. The conclusion reached is that SINASC is an excellent source of information about births, though SIM reveals a marked need for improvements in the completeness of its information. PMID- 25014282 TI - [Breastfeeding in children from 0 to 59 months in the state of Pernambuco, Brazil, in accordance with weight at birth]. AB - The scope of this paper was to describe and analyze the practice of breastfeeding in children under five years of age in the state of Pernambuco, in 2006 in accordance with birth weight. It involved a cross-sectional study with a sample of 1,595 children. The chi square test was used to examine bivariate associations and Poisson regression was applied for multivariate adjustment of conditioning factors to exclusive breastfeeding > 4 months, according to birth weight. It was found that the practice of prenatal care and number of visits benefited children born weighing > 2,500 gram, compared to those with birth weight < 2,500 g (low birth weight - LBW). There was no statistical difference in the ratings of breastfeeding, according to birth weight. The years of formal study and type of delivery variables were linked to the group associated with LBW, while for children weighing > 2,500 g associations with the per capita income, geographical area, guidance on breastfeeding during prenatal care and sex of the children variables were detected. The group of LBW children did not benefit from recommendations regarding breastfeeding and also the results from the relations of the variables that remained in the two groups were different, representing the final models of the multivariate analyses. PMID- 25014283 TI - [Primary health care and its attributes: the situation of children under two years of age according to their caregivers]. AB - The scope of this study was to evaluate the attributes of primary health care for children and establish associated factors. A cross-sectional, observational and analytical study was conducted. Data were collected from interviews with caregivers of children enrolled in primary health care services, using a sociodemographic and health protocol, an instrument of economic classification and the Brazilian version of the Project Complexity Assessment Tool questionnaire for children. Models were developed using Poisson regression to search for associations. Only the longitudinality attribute was well evaluated. All the other mean scores were considered low. More than 80% of respondents rated the special and general scores of primary health care with low values. Children who had no brothers, were of the female sex, with socioeconomic classification A or B, and who had male caregivers with no partner were significantly associated with the low scores. Primary health care was thus poorly rated. PMID- 25014284 TI - [Spatial analysis of infant mortality and the adequacy of vital information: a proposal for defining priority areas]. AB - This is an ecological study that sought to assess the relationship between the spatial clustering of infant mortality and the adequacy of vital information. The adequacy of information from the Brazilian Live Birth Database (SINASC) and Mortality Database (SIM) were examined using a validated method that uses five indicators calculated by municipality and population size. Municipalities were classified as either having consolidated data, data currently being consolidated, or not having consolidated data. Voronoi polygons were generated for spatial analysis in order to minimize any proximity issues among municipalities. The local Moran index was applied to identify spatial clustering of infant mortality. It was established that 76.2% of all municipalities had consolidated vital data. Infant mortality clustering was seen in 34 municipalities comprising three spatial clusters. An association was also found between the adequacy of vital information and the spatial clustering of infant mortality. Geostatistical techniques proved to have predictive power to identify spatial clustering with consolidated vital information. The approach will contribute to the improvement of data quality and can be used for planning actions seeking to reduce infant mortality. PMID- 25014285 TI - [Impact variables on the decline in infant mortality in the state of Sao Paulo, Brazil: 1998-2008]. AB - This is an ecological, analytical and retrospective study comprising the 645 municipalities in the State of Sao Paulo, the scope of which was to determine the relationship between socioeconomic, demographic variables and the model of care in relation to infant mortality rates in the period from 1998 to 2008. The ratio of average annual change for each indicator per stratum coverage was calculated. Infant mortality was analyzed according to the model for repeated measures over time, adjusted for the following correction variables: the city's population, proportion of Family Health Programs (PSFs) deployed, proportion of Growth Acceleration Programs (PACs) deployed, per capita GDP and SPSRI (Sao Paulo social responsibility index). The analysis was performed by generalized linear models, considering the gamma distribution. Multiple comparisons were performed with the likelihood ratio with chi-square approximate distribution, considering a significance level of 5%. There was a decrease in infant mortality over the years (p < 0.05), with no significant difference from 2004 to 2008 (p > 0.05). The proportion of PSFs deployed (p < 0.0001) and per capita GDP (p < 0.0001) were significant in the model. The decline of infant mortality in this period was influenced by the growth of per capita GDP and PSFs. PMID- 25014286 TI - [Birth weight and factors associated with the prenatal period: a cross-sectional study in a maternity hospital of reference]. AB - This study examined factors related to birth weight in a maternity hospital in the city of Rio de Janeiro. It is a descriptive, sectional study conducted in the Herculano Pinheiro Maternity Hospital (HMHP) in Rio de Janeiro between December 2008 and February 2009, with postpartum mothers between 20 and 34 years of age. The chi-square test, the Student's t test and the logistical regression model were applied. 14.6% of the infants had low birth weight (less than 2500 g). There was a negative correlation between birth weight and smoking habits of the mother. The pre-pregnancy weight, maternal pre-pregnancy body mass index and number of pre-natal visit variables were positively associated with birth weight. Multiple regression analysis indicated maternal age as being a risk factor for low birth weight. The conclusion reached is that the marital status situation, where this was perceived as an important variable, as well as the number of prenatal visits, which in group analysis showed no statistical significance, deserve further investigation together with other studies. PMID- 25014287 TI - [Children's attitudes regarding health care and perception of pain: the mediating role of medical fears]. AB - This study sought to contribute to a better understanding of children's attitudes and opinions regarding health care, mainly in terms of medical procedures, institutions and the efficacy of health professionals. The sample included 381 children, recruited from different schools in Lisbon. The more negative attitudes were attributed to institutions, while positive attitudes were related to the efficacy of health professionals. Medical procedures were considered less painful compared to potential day-to-day accidents. Higher levels of pain were reported by children of the female sex and by children during the primary education phase. Medical fears mediated the relationship between the perception of pain and children's attitudes with respect to health care. Higher levels of pain perception were seen to be related to more negative attitudes regarding health care. However, this relationship was diminished when children's fears about medical issues were contemplated. In conclusion, a translated instrument to assess children's attitudes regarding health care is needed, as it may even contribute to the development of intervention programs within the scope of the promotion of attitudes towards health care. PMID- 25014288 TI - [Chronic diseases in children and adolescents: a review of the literature]. AB - The scope of this article is to analyze papers published between 2003 and 2011 that focus on discussions regarding chronic conditions or chronic diseases in children and adolescents. It combines a methodological review of the literature and thematic analysis of content in order to identify the elements that characterize chronic diseases in children and adolescents and the specificities generated by these chronic conditions. The review of the literature resulted in a description of the series of articles identified by year of publication, country of origin, type of study, population and the chronic condition addressed. Thematic content analysis generated two core themes: Definition of chronic disease and Ways of handling chronic disease in children and teenagers. The main conclusion reached is that the age transitions when a disease is diagnosed and treated since childhood involve transformations that include changes in health facilities, discharge processes, decision making and networking that include family, hospital, school and institutions that guarantee the child's rights. PMID- 25014289 TI - [Use of the linkage method to identify the risk factors associated with infant mortality: an integrative review of the literature]. AB - Global concern in relation to child mortality gained visibility with the release of the Millennium Development Goals in 2000 in which the reduction of child mortality is included under goal number four, which proposes to reduce the mortality rate of children under five years by two thirds between 1990 and 2015. Reducing child mortality has been a major priority of social health policies of the Brazilian government. The identification of risk factors associated with infant mortality can assist in the planning of actions to restructure and improve care for pregnant women and newborns in order to reduce child mortality. With this in mind, this study sets out to analyze the use of the linkage method to identify risk factors associated with infant mortality. An integrative review of the literature was conducted for this purpose and eight complete articles published between 2008 and 2013 were analyzed using the following key words: infant mortality, risk factors and information systems. The use of the linkage method proved to be very useful, enabling adequate investigation of the factors most strongly related to child mortality, showing its relevance to the study of public health problems. PMID- 25014290 TI - [The challenges of nanotechnology for the sanitary vigilance of medication]. AB - The development of effective and safe nanotechnology medication with a high cost benefit ratio is a strategic imperative for public health in Brazil. The lack of information demands sanitary regulation geared to protecting health and the environment. This study seeks to assess the current stage of development, the regulatory framework and the challenges facing nanotechnology medication in Brazil, emphasizing sanitary surveillance. Document analysis was conducted in national and international regulatory agency sites. Despite the incipient regulation for this type of medication, 7 registered nanotechnology products were found in Brazil, without clear identification on leaflets or packaging regarding their nanotechnology composition, as well as 4 similar products. Risk assessment and regulation of such medication requires specialized personnel and equipment, as well as the participation of society in the formulation and implementation of regulatory policies. The suggestion proposed is that the regulatory framework should follow the precautionary principle, whereby products are registered as new medication with clear information on the labeling and controlled usage, until further results on the assessment of risk are obtained. PMID- 25014291 TI - [Implementation of multi-strategy programs: a proposal for an evaluation matrix]. AB - The programs that seek to achieve comprehensive changes involve the relationship between different public policies, understanding the diversity of social demands in each context and enhancing a participative dynamic. Due to the complexity of these experiences, it is important to review the traditional perspectives and discuss alternatives. Based on the analytical framework of the so-called theory driven evaluation, the core focus of which is the analysis of the validity of the concepts that link processes and results and the exploratory case study of the qualitative character of the federal Bolsa Familia cash transfer program, the paper proposes a methodological matrix as its main result to support the evaluation of interventions related to health promotion, food security and poverty reduction. PMID- 25014292 TI - [Seroprevalence and factors associated with human immunodeficiency virus (HIV) and syphilis in inmates in the state of Pernambuco, Brazil]. AB - Prison inmates are more vulnerable to HIV and other Sexually Transmitted Infections (STIs) due to risk factors such as needle sharing and unprotected sex with homosexuals. The aim of this work was to determine the seroprevalence and risk factors associated with the human immunodeficiency virus (HIV-1/2) and syphilis among male inmates in Caruaru, State of Pernambuco, Brazil. A cross sectional study was performed between May and July 2011, when 1,097 inmates at a prison in Caruaru were assessed by means of interviews and blood sample collection for performing the respective tests. The prevalence was 1.19% for HIV infection and 3.92% for syphilis. HIV infection showed a statistically significant association (p <0.05), with injected drug use, homosexuality and blood transfusions. With respect to HIV status and syphilis, factors related to sex life were statistically significant (p <0.05). The prison population is a high risk group for the diseases investigated. The prevalence rates identified indicate the need to implement prevention programs, helping to contain such diseases in this particular population group. PMID- 25014293 TI - [The experience of a public institution in the training of health professionals to work in primary care]. AB - This scope of this paper is to analyze the training of nurses and physicians to work in primary care at a public institution in the municipality of Marilia, duly identifying the concepts of professors, coordinators and graduates in relation to the formation of health professionals. It is a qualitative, exploratory study with interviews conducted with 21 individuals. The results revealed that according to the individuals interviewed, both courses prepare professionals to work in primary care, albeit with limitations in relation to actions in management collective and care. The interviewees believe that the use of active methodologies has been important in the teaching and learning process. Also, the fact that from the first year of undergraduate studies the students participate in primary health care broadens their knowledge of this reality. The study highlights the need to enhance the teaching-service partnership and strategies to improve the training physicians to work in primary health care. PMID- 25014294 TI - [Professional Master's in Public Health: from legal precepts to experience in a research and education institution]. AB - This study is about the discourses that prevailed over the course of time in Brazilian legislation for the Master's Course in Public Health, and how a Brazilian research and education institution in the area of Public Health appropriated these discourses in the creation of its course proposals. Discourse analysis techniques were applied to legal documents and to sixteen master's programs developed in the institution under scrutiny. The results revealed that with respect to legislation, analysis of the historical timeline makes it possible to say that the initial lack of definition progressively gave rise to the understanding that the identity of such post-graduate education presupposes pedagogical practices that promote the strengthening of ties between academia and the workplace. And, in relation to the master's course proposals for public health in the institutions under scrutiny, they still operate with traditionally consolidated training schemes and tend to standardize their proposals with those of the academic model. It was assumed in this study that the series of proposals would clearly mirror the intentions and, above all, the vision of the training institutions in the area of public health on this stricto sensu model, the identity of which also appears poorly defined. PMID- 25014295 TI - [Disposal of drugs: an analysis of the practices in the family health program]. AB - The scope of this article is to discuss the perception of health workers in relation to the disposal of drugs and analyze how this practice occurs in family health units in a city in the state of Bahia. It involved a qualitative and exploratory study together with nurses, nursing assistants, community health workers and pharmacists of Pharmaceutical Care and Health Surveillance. Semi structured interviews were conducted with systematic observation and use of previously-drafted scripts and the content analysis method was used for data analysis. The results showed poor understanding regarding proper disposal among the workers, dissonant practices in the implementation of the regulations and a lack of communication between health surveillance and other health services. The creation of effective strategies must involve the whole process from management to the prescription and use of drugs and requires further political, economic and social participation. PMID- 25014296 TI - [A study of the overall burden of oral disease in the state of Minas Gerais, Brazil: 2004-2006]. AB - Oral disease is a major public health problem due to its prevalence in practically all age groups. This is a study of the overall burden of dental caries, edentulism and periodontal disease. The Disability-Adjusted Life Year (DALY) indicator was used as it simultaneously measures the impact of mortality and of health problems that affect the quality of life. The overall burden of oral diseases was analyzed in absolute terms and in rates per 1000 inhabitants. The number of Years Lived with Disability (YLD) due to dental caries was 4,489. An estimated 33,888 YLD were lost due to edentulism, with a rate of 1.8/1000 (2.2/1000 among women). An estimated 3217 YLD were lost due to periodontal disease, with a rate of 0.2/1000 for both sexes. Edentulism was the condition that contributed most to the overall burden of oral diseases and is more frequent among women. Higher rates of edentulism and periodontal disease were found in persons aged 45-69 years, while dental caries was more frequent from 15-49 years. The overall burden of oral disease studies represent an important aspect of health diagnosis, integrating both fatal and non-fatal outcomes. Furthermore, these studies provide highly relevant information for preventive and therapeutic policy making. PMID- 25014297 TI - [Principles of universality, comprehensiveness and equity in a hearing health care service]. AB - This article analyzed whether the practices of hearing health care were consistent with the principles of universality, comprehensiveness and equity from the standpoint of professionals. It involved qualitative research conducted at a Medium Complexity Hearing Health Care Center. A social worker, three speech therapists, a physician and a psychologist constituted the study subjects. Interviews were conducted as well as observation registered in a field diary. The thematic analysis technique was used in the analysis of the material. The analysis of interviews resulted in the construction of the following themes: Universality and access to hearing health, Comprehensive Hearing Health Care and Hearing Health and Equity. The study identified issues that interfere with the quality of service and run counter to the principles of Brazilian Unified Health System. The conclusion reached was that a relatively simple investment in training and professional qualification can bring about significant changes in order to promote a more universal, comprehensive and equitable health service. PMID- 25014298 TI - [Qualitative research into the scientific production in the field of bioethics]. AB - This article discusses the character and use of qualitative research methods in the field of bioethics. A systematic review of articles published in Latin American countries and selected from the SciELO database was conducted, with special emphasis on articles that employed qualitative research methodology. The set of articles reveals a field of bioethics composed of three distinct vectors. The first refers to the dual characterization of bioethics that can be defined as a social movement or as a discipline; the second differentiates bioethics from other fields of ethics, especially from predominantly deontology-based professional ethics; and the third is related to ethical approaches adopted in the analyses conducted in the research. A relatively insignificant part of these texts result from qualitative research and they can be divided into four categories according to their themes and guidelines: bioethics as a field and/or discourse; training in health; ethics, care, and clinical practice; formulation of health policy. The production shows, on the one hand, a relatively timid approach of social science researchers to the field of bioethics and, on the other hand, little use of qualitative methodologies in research in the field and, in some cases, a certain lack of precision regarding use of the methods. PMID- 25014299 TI - [Social capital in rural areas: adaptation to Spanish and factor validation of a scale]. AB - Social capital is considered a structural determinant of social development and wellbeing. Its cognitive component assesses the degree of confidence of the population in their systems for social organization, as well as community interactions to coordinate social responses to social problems. There are few available scales for measuring this construct. This work presents the adaptation to Spanish and psychometric validation of a scale for measuring social capital in a rural setting. The Wang Social Cognitive Scale was also adapted to Spanish. 1200 questionnaires were applied to adults in 12 villages of the municipality of Tierra Alta, (Colombia) recruited by random sampling. Factor analysis of the scale was performed based on a polychoric correlation matrix. Exploratory factor analysis suggests the existence of two principal factors distributed as follows: 7 items for factor 1, trust (eigenvalue 3.23) and 2 items, for factor 2, distrust (eigenvalue 1.40). As observed by Wang, Q9 and Q10 could be ambiguous questions which do not contribute enough to either of the factors. The first factor validation to Spanish language of the Wang Social Capital Scale is presented in the social context of rural Colombia. PMID- 25014300 TI - [Cross-cultural adaptation of the KIDSCREEN questionnaire to measure health related quality of life in the 8 to18 year-old Mexican population]. AB - The scope of this study was to develop the culturally-adapted version of the KIDSCREEN-52 questionnaire for Mexican adolescents aged 8 to 18, and to analyze its reliability and validity. A translation and back translation was carried out from English to Spanish and vice versa. Cognitive interviews were conducted and confirmatory factor analysis (CFA) was used to verify the content validity of the questionnaire. Based on previous studies (i.e. the Argentinian version) mean scores of dimensions were compared to assess construct validity. Reliability was also analyzed. The results showed that the content validity of the version retained the original concepts, duly adapted to the Mexican culture and language. The AFC confirmed the structure of the 10 original dimensions. Two scales achieved the ceiling effect. The instrument's internal consistency was acceptable (ranged from 0.5 to 0.86), and reproducibility obtained low coefficients in 5 dimensions (0.22 to 0.78). The Mexican KIDSCREEN-52 version is equivalent to the original in terms of content, structure, and construct validity. The conclusion was that theKIDSCREEN -52 tool is suitable for application in the Mexican population aged 8 to 18. Further studies are needed to explore its application in clinical settings. PMID- 25014301 TI - [Suicide and work in Brazilian metropolises: an ecological study]. AB - The scope of this study was to correlate suicide mortality with health indicators and work in six Brazilian metropolises: Porto Alegre, Recife, Salvador, Belo Horizonte, Rio de Janeiro and Sao Paulo. It was an ecological study, the outcome of which is the death rate from suicide in the historical series from 2002 to 2010, and the independent variables are the indicators of occupational activity and mental suffering. Statistical association using the Pearson Correlation test was conducted and the variables associated with suicide (p < 0.05) were included in a multivariate linear regression model. The suicide mortality was higher in Porto Alegre, followed by Sao Paulo, and the trend of the phenomenon was in the ascendant (p = 0.03). It was observed that the economically active and gainfully employed population remained in the final regression model in the city of Sao Paulo. The association between suicide mortality and occupational variables suggests that work in the context of insecurity worsens the quality of life of the working population, causing physical and mental suffering and increasing the risk of self-harm. PMID- 25014302 TI - [Evaluation of the accessibility to the Specialized Dental Care Center within the scope of the macro region of Sobral, in the state of Ceara, Brazil]. AB - The Specialized Dental Care Center for the region of Sobral in the state of Ceara (CEO-R) has characteristics that render it unique, as it has regional coverage and is managed by a Local Health Consortium (which comprises 24 cities). It also works in conjunction with the School of Dentistry of the Federal University of Ceara - Sobral Campus, combining care and academic study in the same location. The scope of this article was to evaluate the accessibility to specialized care in this region with the implementation of this CEO-R. A descriptive-exploratory study with a quantitative approach was conducted by means of the collection and analysis of secondary data regarding the availability and usage of this service in addition to the application of semi-structured interviews with Oral Health Coordinators of the 24 municipalities in the consortium. The results showed that the CEO-R is equipped to meet the demand. However, geographic, financial and organizational barriers were detected, which explains the low rates of appointments scheduled and use of the services and the high rate of missed appointments, causing a significant financial impact on the cities included in the consortium. PMID- 25014303 TI - [Between caring and monitoring: ambiguities and contradictions in the discourse of a female penitentiary officer]. AB - The scope of this paper was to establish how the discourse of a female penitentiary officer working in a prison for women reflects, in different ways, the inherent contradiction of prisons, namely their double mission of punishing and resocializing criminals. The data collected in a female prison in Rio Grande do Sul were evaluated using Critical Discourse Analysis, which seeks to understand how discursive productions reflect social power relations. The analyses show that this officer's practice is based simultaneously on punitive and resocializing ideologies, expressed in contradictory feelings of anger and affection towards incarcerated women. Results point to the centrality of gender in the relationship established between officers and interns. Thus, the fact of being a female officer caring and monitoring other women makes this daily relationship even more complex. This complexity extrapolates the limits imposed by prisons. PMID- 25014304 TI - [Prevalence and factors associated with violence suffered by incarcerated women for drug trafficking in the state of Pernambuco, Brazil: a cross-sectional study]. AB - The scope of this study was to estimate the prevalence and factors associated with the violence suffered by women accused of drug trafficking in the 24 months prior to incarceration in the Women's Penal Colony in the State of Pernambuco. A cross-sectional study including 290 women aged 18 and above, with up to twelve months imprisonment, was performed for the data collection period. A questionnaire was applied to research the socioeconomic and demographic variables and the characteristics of violence and drug trafficking. All of the participants signed a consent form. The association between variables and intensity of exposure and response were determined by the chi-square test and the values (p < 0.05) were considered statistically significant. The study revealed that 71.4% of women were young; 78.9% non white, 85.8% unmarried with children, 83.3% had low education and 72.6% had income below the minimum wage. Furthermore, 56.9% were users of illicit drugs and 67.5% participated by performing some role in drug trafficking. A high prevalence of some form of violence suffered were observed in the population studied and the partner was the most frequent perpetrator (44.1%), calling for the authorities to pay greater attention in the actions of prevention of such violence. PMID- 25014305 TI - [The practical applicability of empowerment in health promotion strategies]. AB - The scope of this study is to identify what empowerment strategies were addressed for the promotion of health in health research, characterizing them from a socio critical and post-structuralist standpoint. It involved an Integrative Review conducted in May 2011 of the Medline, Lilacs and SciELO databases. The inclusion criteria were complete research articles, case reports or experience reports, published between 2002 and 2011 in Portuguese, Spanish and English. The research criteria included the key words "empowerment" and "health promotion" (DeCS/BIREME). Twenty articles, which presented strategies of individual and/or social empowerment that were characterized by a socio-critical perspective, were selected. It is considered that some activities, mainly those that included thematic discussion groups, represented a mobilization and empowerment strategy. These included theater, culture circles, community therapy, therapeutic learning workshops, home visits, university extension and social action projects. It is considered that all empowerment strategies are inherently health promotion strategies, but not all health promotion strategies effectively result in empowerment. PMID- 25014306 TI - [Therapeutic itineraries of transvestites from the central region of the state of Rio Grande do Sul, Brazil]. AB - The scope of this paper is to shed light on the therapeutic itineraries of transvestites from Santa Maria in the central region of the state of Rio Grande do Sul in southern Brazil. The study sought to follow the complex trajectories followed by transvestites in their quest for health care. Field research was conducted between January and November 2012 with transvestites from different cities in the state who were living in Santa Maria at the time. It involved qualitative methodology using ethnographic research. The results showed that the interviewees avoid institutionalized health services, opting for other forms of health care. In this respect, it is noteworthy that of the group of 49 transvestites who were included in this study, 48 sought health care in "African religion groups" or "batuque" ("drumming"), as they refer to them. The transvestites stated that they opted for "African religion groups" as they saw them as places that were able to afford forms of care and protection, without questioning bodily changes and sexual orientation. This article may help to shed light on some of the unusual trajectories of transvestites in their quest for health care. PMID- 25014307 TI - [Preference for behavior conducive to physical activity and physical activity levels of children from a southern Brazil city]. AB - This article aims to describe preferences for behavior conducive to physical activity (PA) and to evaluate the influence of these preferences on physical activity of children from Pelotas in the state of Rio Grande do Sul. It involved a cross-sectional study with children aged 4 to 11. Behavior conducive to PA was evaluated using the Netherlands Physical Activity Questionnaire (NPAQ). Time spent in moderate-to-vigorous physical activity (MVPA) was measured by accelerometry. Variance analysis and linear regression were performed to evaluate associations between questions from the NPAQ and independent variables and between each form of behavior and time spent in MVPA, respectively. Children in the higher economic bracket liked to draw more and preferred less vigorous games and playing outside than poorer children. Older children were less extrovert and liked to draw less than younger children. Enjoying sports, disliking drawing and liking to play outside were positively associated with daily time spent in MVPA. Some characteristics studied were associated with behavior conducive to PA, and economic status proved to be the most important influence. Preferences like enjoying sports positively influenced the time spent in MVPA. PMID- 25014310 TI - Reconstructing propagation networks with natural diversity and identifying hidden sources. AB - Our ability to uncover complex network structure and dynamics from data is fundamental to understanding and controlling collective dynamics in complex systems. Despite recent progress in this area, reconstructing networks with stochastic dynamical processes from limited time series remains to be an outstanding problem. Here we develop a framework based on compressed sensing to reconstruct complex networks on which stochastic spreading dynamics take place. We apply the methodology to a large number of model and real networks, finding that a full reconstruction of inhomogeneous interactions can be achieved from small amounts of polarized (binary) data, a virtue of compressed sensing. Further, we demonstrate that a hidden source that triggers the spreading process but is externally inaccessible can be ascertained and located with high confidence in the absence of direct routes of propagation from it. Our approach thus establishes a paradigm for tracing and controlling epidemic invasion and information diffusion in complex networked systems. PMID- 25014309 TI - Reactivation of latent HIV-1 by new semi-synthetic ingenol esters. AB - The ability of HIV to establish long-lived latent infection is mainly due to transcriptional silencing of viral genome in resting memory T lymphocytes. Here, we show that new semi-synthetic ingenol esters reactivate latent HIV reservoirs. Amongst the tested compounds, 3-caproyl-ingenol (ING B) was more potent in reactivating latent HIV than known activators such as SAHA, ingenol 3,20 dibenzoate, TNF-alpha, PMA and HMBA. ING B activated PKC isoforms followed by NF kappaB nuclear translocation. As virus reactivation is dependent on intact NF kappaB binding sites in the LTR promoter region ING B, we have shown that. ING B was able to reactivate virus transcription in primary HIV-infected resting cells up to 12 fold and up to 25 fold in combination with SAHA. Additionally, ING B promoted up-regulation of P-TEFb subunits CDK9/Cyclin T1. The role of ING B on promoting both transcription initiation and elongation makes this compound a strong candidate for an anti-HIV latency drug combined with suppressive HAART. PMID- 25014311 TI - The use of social media by state tobacco control programs to promote smoking cessation: a cross-sectional study. AB - BACKGROUND: The promotion of evidence-based cessation services through social media sites may increase their utilization by smokers. Data on social media adoption and use within tobacco control programs (TCPs) have not been reported. OBJECTIVE: This study examines TCP use of and activity levels on social media, the reach of TCP sites, and the level of engagement with the content on sites. METHODS: A cross-sectional descriptive study of state TCP social media sites and their content was conducted. RESULTS: In 2013, 60% (30/50) of TCPs were using social media. Approximately one-quarter (26%, 13/50) of all TCPs used 3 or more social media sites, 24% (12/50) used 2, and 10% (5/50) used 1 site. Overall, 60% (30/50) had a Facebook page, 36% (18/50) had a Twitter page, and 40% (20/50) had a YouTube channel. The reach of social media was different across each site and varied widely by state. Among TCPs with a Facebook page, 73% (22/30) had less than 100 likes per 100,000 adults in the state, and 13% (4/30) had more than 400 likes per 100,000 adults. Among TCPs with a Twitter page, 61% (11/18) had less than 10 followers per 100,000 adults, and just 1 state had more than 100 followers per 100,000 adults. Seven states (23%, 7/30) updated their social media sites daily. The most frequent social media activities focused on the dissemination of information rather than interaction with site users. Social media resources from a national cessation media campaign were promoted infrequently. CONCLUSIONS: The current reach of state TCP social media sites is low and most TCPs are not promoting existing cessation services or capitalizing on social media's interactive potential. TCPs should create an online environment that increases participation and 2-way communication with smokers to promote free cessation services. PMID- 25014312 TI - Synthesis of ZnO nanorods and their application in the construction of a nanostructure-based electrochemical sensor for determination of levodopa in the presence of carbidopa. AB - A novel carbon paste electrode modified with ZnO nanorods and 5-(4'-amino-3' hydroxy-biphenyl-4-yl)-acrylic acid (3,4'-AAZCPE) was fabricated. The electrochemical study of the modified electrode, as well as its efficiency for the electrocatalytic oxidation of levodopa, is described. The electrode was employed to study the electrocatalytic oxidation of levodopa, using cyclic voltammetry (CV), chronoamperometry (CHA), and square-wave voltammetry (SWV) as diagnostic techniques. It has been found that the oxidation of levodopa at the surface of the modified electrode occurs at a potential of about 370 mV less positive than that of an unmodified carbon paste electrode. The SWV results exhibit a linear dynamic range from 1.0 * 10(-7) M to 7.0 * 10(-5) M and a detection limit of 3.5 * 10(-8) M for levodopa. In addition, this modified electrode was used for the simultaneous determination of levodopa and carbidopa. Finally, the modified electrode was used for the determination of levodopa and carbidopa in some real samples. PMID- 25014313 TI - Dietary administration of microalgae alone or supplemented with Lactobacillus sakei affects immune response and intestinal morphology of Pacific red snapper (Lutjanus peru). AB - The aim of this study was to evaluate the effect of dietary microalgae Navicula sp single or in combination with Lactobacillus sakei on growth performance, humoral immune parameters and intestinal morphology in Pacific red snapper, Lutjanus peru. The experimental fish were grouped into four treatment diets which were a control diet (commercial diet, Control), silage microalgae Navicula sp plus L. sakei (10(6) CFU g(-1), Navicula + L. sakei), lyophilized microalgae (Navicula) and L. sakei (10(6) CFU g(-1), L. sakei). The blood and intestine samples were collected on week 4 and 8. The weight gain showed an additive effect of Navicula + L. sakei at 8 weeks of treatment compared with fish fed control diet. Overall, physiological parameters such as total protein and hemoglobin were increased in fish fed with Navicula and L. sakei diets at 4 and 8 weeks of feeding assay, respectively. There was a significant improvement in immune parameters, principally in myeloperoxidase, lysozyme, total antiproteases activities and IgM in fish fed with Navicula + L. sakei and L. sakei diets at 4 or 8 weeks of treatments. Serum antioxidant capabilities revealed significant increase in phosphatase alkaline, esterase, protease, superoxide dismutase and catalase in groups which received diet supplemented with Navicula + L. sakei and L. sakei diets. Finally, light microscopy observations revealed no effect of experimental diets on microvilli height. Curiously, the presence of vacuoles inside the enterocytes was significant higher in the intestine of L. sakei group after four or six weeks of feeding. Elevated intraepithelial leucocyte levels and melanomacrophages centers were observed in fish fed Navicula or control diets at any time of the experiment. To conclude, the results of the present study demonstrate that the fish that were fed with Navicula + L. sakei or L. sakei diets yielded significantly better immune status and antioxidant capabilities. PMID- 25014314 TI - The impaired intestinal mucosal immune system by valine deficiency for young grass carp (Ctenopharyngodon idella) is associated with decreasing immune status and regulating tight junction proteins transcript abundance in the intestine. AB - This study investigated the effects of dietary valine on the growth, intestinal immune response, tight junction proteins transcript abundance and gene expression of immune-related signaling molecules in the intestine of young grass carp (Ctenopharyngodon idella). Six iso-nitrogenous diets containing graded levels of valine (4.3-19.1 g kg(-)(1) diet) were fed to the fish for 8 weeks. The results showed that percentage weight gain (PWG), feed intake and feed efficiency of fish were the lowest in fish fed the valine-deficient diet (P < 0.05). In addition, valine deficiency decreased lysozyme, acid phosphatase activities and complement 3 content in the intestine (P < 0.05), down-regulated mRNA levels of interleukin 10, transforming growth factor beta1, IkappaBalpha and target of rapamycin (TOR) (P < 0.05), and up-regulated tumor necrosis factor alpha, interleukin 8 and nuclear factor kappaB P65 (NF-kappaB P65) gene expression (P < 0.05). Additionally, valine deficiency significantly decreased transcript of Occludin, Claudin b, Claudin c, Claudin 3, and ZO-1 (P < 0.05), and improved Claudin 15 expression in the fish intestine (P < 0.05). However, valine did not have a significant effect on expression of Claudin 12 in the intestine of grass carp (P > 0.05). In conclusion, valine deficiency decreased fish growth and intestinal immune status, as well as regulated gene expression of tight junction proteins, NF-kappaB P65, IkappaBalpha and TOR in the fish intestine. Based on the quadratic regression analysis of lysozyme activity or PWG, the dietary valine requirement of young grass carp (268-679 g) were established to be 14.47 g kg(-1) diet (4.82 g 100 g(-1) CP) or 14.00 g kg(-1) diet (4.77 g 100 g(-1) CP), respectively. PMID- 25014315 TI - Proteome dynamics in neutrophils of adult zebrafish upon chemically-induced inflammation. AB - Neutrophils are the most abundant polymorphonuclear leukocytes, presenting the first line of defence against infection or tissue damage. To characterize the molecular changes on the protein level in neutrophils during sterile inflammation we established the chemically-induced inflammation (ChIn) assay in adult zebrafish and investigated the proteome dynamics within neutrophils of adult zebrafish upon inflammation. Through label-free proteomics we identified 48 proteins that were differentially regulated during inflammation. Gene ontology analysis revealed that these proteins were associated with cell cycle, nitric oxide signalling, regulation of cytoskeleton rearrangement and intermediate filaments as well as immune-related processes such as antigen presentation, leucocyte chemotaxis and IL-6 signalling. Comparison of protein expression dynamics with transcript expression dynamics suggests the existence of regulatory mechanisms confined to the protein level for some genes. This is the first proteome analysis of adult zebrafish neutrophils upon chemically-induced inflammation providing a valuable reference for future studies using zebrafish inflammation models. PMID- 25014316 TI - Pubertal maturation and cortisol level in response to a novel social environment among female adolescents. AB - Research indicates changes in HPA-axis activity across puberty. The current study extends existing work by evaluating pubertal status and cortisol level in a novel social environment (research laboratory) while controlling for several important biological, behavioral, and psychological variables. Participants were 30 girls (ages 9-16 years) from the United States. Pubertal status was assessed via the Pubertal Development Scale. Salivary samples were collected at laboratory introduction and a matched at-home period; laboratory-introduction levels were regressed on basal cortisol levels to create standardized residual scores. After controlling for covariates, pubertal status was positively associated with residualized cortisol values. Findings indicate more advanced puberty related to greater cortisol response to the laboratory; data are discussed in terms of future research and building biopsychosocial models of the puberty psychopathology linkage. PMID- 25014317 TI - Direct observation of two-electron Ag(I)/Ag(III) redox cycles in coupling catalysis. AB - Silver is extensively used in homogeneous catalysis for organic synthesis owing to its Lewis acidity, and as a powerful one-electron oxidant. However, two electron redox catalytic cycles, which are most common in noble metal organometallic reactivity, have never been considered. Here we show that a Ag(I)/Ag(III) catalytic cycle is operative in model C-O and C-C cross-coupling reactions. An aryl-Ag(III) species is unequivocally identified as an intermediate in the catalytic cycle and we provide direct evidence of aryl halide oxidative addition and C-N, C-O, C-S, C-C and C-halide bond-forming reductive elimination steps at monometallic silver centres. We anticipate our study as the starting point for expanding Ag(I)/Ag(III) redox chemistry into new methodologies for organic synthesis, resembling well-known copper or palladium cross-coupling catalysis. Furthermore, findings described herein provide unique fundamental mechanistic understanding on Ag-catalysed cross-coupling reactions and dismiss the generally accepted conception that silver redox chemistry can only arise from one-electron processes. PMID- 25014318 TI - Neonatal herpes infections in The Netherlands in the period 2006-2011. AB - OBJECTIVE: To monitor the incidence of neonatal herpes in The Netherlands between 2006 and 2011, as well as the adherence to the rather conservative Dutch prevention policy. METHODS: Questionnaires were sent to all virology laboratories (n = 44), gynaecology and paediatrics departments of all hospitals in The Netherlands (n = 89). Questionnaires for the laboratories pertained to rates of proven cases of neonatal herpes; for the gynaecologists and paediatricians it pertained to rates of genital herpes during pregnancy and neonatal herpes, and their policy. For gynaecologists this concerned the risk of herpes simplex virus transmission in case of primary genital herpes during pregnancy or labour; for paediatricians it concerned the diagnostic policy in a neonate suspected of neonatal herpes. RESULTS: For the period 2006-2011 38 cases of neonatal herpes were reported, yielding an incidence of 4.7 per 100,000 births. The estimated annual number of pregnant women with primary or recurrent genital herpes was 278. Of the responding gynaecologists and paediatricians, only 59% and up to 39%, respectively, reported a policy in accordance with the national guideline. CONCLUSIONS: The incidence of neonatal herpes in The Netherlands seems to have increased in the period 2006-2011. Combined with suboptimal guideline adherence this warrants strategies to improve awareness and subsequent adherence. PMID- 25014320 TI - Effect of dopamine infusion on thyroid hormone tests and prolactin levels in very low birth weight infants. AB - OBJECTIVE: To evaluate the effect of dopamine on thyroid hormone tests and prolactin (PRL) and to assess requirement for L-thyroxin (LT4). METHODS: The infants (n = 102) were divided into three groups (Group 1; received no dopamine, Group 2 received <=25 mg/kg cumulative dose and Group 3; received >25 mg/kg cumulative dose). Blood samples were taken at 6-8 days (timepoint 1), 13-15 days (timepoint 2), and 4-6 weeks of life (timepoint 3). RESULTS: Respiratory distress syndrome was higher in group 2 and 3. Patnet ductus arteriosus was higher in group 3 than in groups 1 and 2. Duration and cumulative dose in group 3 were higher than group 2. There was no difference between thyroid hormones that were taken after stopping infusion at timepoint 3 among all groups. No therapy with LT4 was needed. PRL levels were higher at timepoint 1 in group 1 than compared to group 2 and 3 (p < 0.05), and no difference between group 2 and 3 (p > 0.05). This difference was disappeared at following timepoints. CONCLUSIONS: The release of TSH, FT3, FT4 and PRL were not inhibited and prophylactic thyroid hormone treatment was not required in VLBW infants receiving dopamine infusions. PMID- 25014319 TI - Candidate gene study for smoking, alcohol use, and body weight in a sample of pregnant women. AB - OBJECTIVE: Prenatal smoking, alcohol use, and obesity have significant effects on maternal and fetal health. However, not much is known about the genetic contributions to these risk factors among pregnant women. We evaluate the associations between several candidate genes and smoking, alcohol use, pre pregnancy body weight, and weight gain during pregnancy in a sample of pregnant women. METHODS: The study analyzes a sample of about 1900 mothers from the Danish National Birth Cohort. We test the association between 1450 SNPs in/near 117 genes/loci and various risk factor measures. RESULTS: Only a few SNPs in FTO were significantly associated with pre-pregnancy obesity and body mass index (4 and 2 SNPs, respectively) after SNP-level correction for multiple testing. A few loci were significantly related to various smoking measures (any smoking, quitting and cigarette number) with gene/locus-level correction for multiple testing, but not after SNP-level correction. Similarly, some loci were significant for the alcohol measures at the gene/locus-level but not at SNP-level correction. CONCLUSION: The study suggests that the majority of the evaluated candidate genes may not play an important role in influencing these risk factors among pregnant women, highlighting the importance of other genetic factors and non-genetic contributors to their etiology. PMID- 25014321 TI - Punitive policing and associated substance use risks among HIV-positive people in Russia who inject drugs. AB - INTRODUCTION: Drug law enforcement is part of the HIV risk environment among people who inject drugs (PWID). Punitive policing practices such as extrajudicial arrests for needle possession and police planting of drugs have been described anecdotally in Russia, but these experiences and their associations with risky drug behaviours have not been quantified. This study aims to quantify the burden of extrajudicial police arrests among a cohort of HIV-positive PWID in Russia and to explore its links to drug-related health outcomes. METHODS: In a cross sectional study of 582 HIV-positive people with lifetime injection drug use (IDU) in St. Petersburg, Russia, we estimated the prevalence of self-reported extrajudicial police arrests. We used multiple logistic regression to evaluate associations between arrests and the following outcomes: overdose, recent IDU and receptive needle sharing. FINDINGS: This cohort's mean age was 29.8 years, 60.8% were male; 75.3% reported non-fatal drug overdose, 50.3% recent IDU and 47.3% receptive needle sharing. Extrajudicial arrests were reported by more than half (60.5%, 95% confidence interval [CI]: 56.5-64.5) and were associated with higher odds of non-fatal drug overdose (AOR 1.52, 95% CI: 1.02-2.25) but not with recent IDU (AOR 1.17, arrests were associated with receptive needle sharing (AOR 1.84, 95% CI: 1.09-3.09). CONCLUSIONS: Extrajudicial police arrests were common among this cohort of Russian HIV-positive PWID and associated with non-fatal overdose and, among those with recent IDU, receptive needle sharing. As a part of the HIV risk environment of PWIDs, these practices might contribute to HIV transmission and overdose mortality. Further research is needed to relate these findings to the operational environment of law enforcement and to better understand how police interventions among PWIDs can improve the HIV risk environment. PMID- 25014322 TI - Utility of surveillance imaging after minor blunt head trauma. AB - OBJECT: Nonoperative blunt head trauma is a common reason for admission in a pediatric hospital. Adverse events, such as growing skull fracture, are rare, and the incidence of such morbidity is not known. As a result, optimal follow-up care is not clear. METHODS: Patients admitted after minor blunt head trauma between May 1, 2009, and April 30, 2013, were identified at a single institution. Demographic, socioeconomic, and clinical characteristics were retrieved from administrative and outpatient databases. Clinical events within the 180-day period following discharge were reviewed and analyzed. These events included emergency department (ED) visits, need for surgical procedures, clinic visits, and surveillance imaging utilization. Associations among these clinical events and potential contributing factors were analyzed using appropriate statistical methods. RESULTS: There were 937 admissions for minor blunt head trauma in the 4 year period. Patients who required surgical interventions during the index admission were excluded. The average age of the admitted patients was 5.53 years, and the average length of stay was 1.7 days; 15.7% of patients were admitted for concussion symptoms with negative imaging findings, and 26.4% of patients suffered a skull fracture without intracranial injury. Patients presented with subdural, subarachnoid, or intraventricular hemorrhage in 11.6%, 9.19%, and 0.53% of cases, respectively. After discharge, 672 patients returned for at least 1 follow-up clinic visit (71.7%), and surveillance imaging was obtained at the time of the visit in 343 instances. The number of adverse events was small and consisted of 34 ED visits and 3 surgeries. Some of the ED visits could have been prevented with better discharge instructions, but none of the surgery was preventable. Furthermore, the pattern of postinjury surveillance imaging utilization correlated with physician identity but not with injury severity. Because the number of adverse events was small, surveillance imaging could not be shown to positively influence outcomes. CONCLUSIONS: Adverse events after nonoperative mild traumatic injury are rare. The routine use of postinjury surveillance imaging remains controversial, but these data suggest that such imaging does not effectively identify those who require operative intervention. PMID- 25014323 TI - Magnetoencephalography helps delineate the extent of the epileptogenic zone for surgical planning in children with intractable epilepsy due to porencephalic cyst/encephalomalacia. AB - OBJECT: Porencephalic cyst/encephalomalacia (PC/E) is a brain lesion caused by ischemic insult or hemorrhage. The authors evaluated magnetoencephalography (MEG) spike sources (MEGSS) to localize the epileptogenic zone in children with intractable epilepsy secondary to PC/E. METHODS: The authors retrospectively studied 13 children with intractable epilepsy secondary to PC/E (5 girls and 8 boys, age range 1.8-15 years), who underwent prolonged scalp video electroencephalography (EEG), MRI, and MEG. Interictal MEGSS locations were compared with the ictal and interictal zones as determined from scalp video-EEG. RESULTS: Magnetic resonance imaging showed PC/E in extratemporal lobes in 3 patients, within the temporal lobe in 2 patients, and in both temporal and extratemporal lobes in 8 patients. Magnetoencephalographic spike sources were asymmetrically clustered at the margin of PC/E in all 13 patients. One cluster of MEGSS was observed in 11 patients, 2 clusters in 1 patient, and 3 clusters in 1 patient. Ictal EEG discharges were lateralized and concordant with MEGSS in 8 patients (62%). Interictal EEG discharges were lateralized and concordant with MEGSS hemisphere in 9 patients (69%). Seven patients underwent lesionectomy in addition to MEGSS clusterectomy with (2 patients) and without (5 patients) intracranial video-EEG. Temporal lobectomy was performed in 1 patient and hemispherectomy in another. Eight of 9 patients achieved seizure freedom following surgery. CONCLUSIONS: Magnetoencephalography delineated the extent of the epileptogenic zone adjacent to PC/E in patients with intractable epilepsy. Complete resection of the MEGSS cluster along with PC/E can provide favorable seizure outcomes. PMID- 25014324 TI - High-dose methotrexate monotherapy followed by radiation for CD30-positive, anaplastic lymphoma kinase-1-positive anaplastic large-cell lymphoma in the brain of a child. AB - The authors report the case of an 11-year-old immunocompetent boy with primary CNS CD30-positive anaplastic large-cell lymphoma (ALCL) that was also positive for anaplastic lymphoma kinase-1. His initial clinical manifestation was acute meningitis of unknown etiology. Findings on CT scanning were normal. Although he received empirical treatment against infection, his systemic and neurological status deteriorated. Subsequent MRI revealed newly emerged enhanced lesions and concomitant edema in the left parietal lobe. Diagnosis was confirmed following a brain biopsy and immunohistochemical staining. Three courses of systemic high dose methotrexate (HD-MTX) treatment with 2-week intervals was started, followed by whole-brain radiation. His clinical course improved, and he has remained disease-free for more than 8 years without any additional treatment. Because ALCL originating in the brain is extremely rare and difficult to diagnose, no standard treatment has been established. This report suggests that systemic HD-MTX monotherapy can be an effective and worthwhile tailored therapeutic option for pediatric primary CNS ALCL. PMID- 25014325 TI - Aquaporin-4 autoimmunity masquerading as a brainstem tumor. AB - Brainstem glioma is a highly devastating disease, and any mass-like lesion in the brainstem can raise suspicion of this diagnosis. However, other inflammatory, demyelinating, or degenerative diseases can mimic brainstem glioma in clinical presentation and imaging features. Therefore, diagnosis based solely on imaging is often insufficient for brainstem lesions and may lead to incorrect diagnosis and treatment. This case report is the first description of central nervous system aquaporin-4 (AQP4) autoimmunity confined mainly to the brainstem. It demonstrates the wide spectrum of neuroinflammatory diseases in children and highlights the utility of surgical biopsy for suspicious brainstem lesions with atypical imaging features for glioma. PMID- 25014326 TI - Ertl below-knee amputation using a vascularized fibular strut in a nontrauma elderly population: a case series. AB - BACKGROUND: Tibiofibular bone bridging (Ertl) during a below-knee amputation (BKA) is used to create a stable bony platform, granting the patient improved rotary stability, higher end bearing potential, and ultimately, more functional ambulatory ability. However, limited data are available in the literature on actual patient outcomes, despite numerous reports of the technique. The purpose of this study was to report our experience with distal tibiofibular bone bridging using a vascularized fibular bone graft in an elderly nontrauma population. METHODS: We performed an institutional review board-approved, retrospective review of BKAs performed by the senior author between 2004 and 2011. Surgical indications, complications, and outcomes were recorded. A subgroup analysis and comparison was performed among patients that had received vascularized bone bridging and those that had not. RESULTS: A total of 294 BKAs were performed on 270 nontrauma patients. Of these, 30 (11%) were done on 29 patients with tibiofibular bone bridging. The mean clinical follow-up among the Ertl subgroup was 11 months (range, 1-42 months), and 17 months (range, 23 days-78 months) in the non-Ertl subgroup. The ambulation rate was 100% (29/29) in the Ertl group, and 78% (161/207) in the control group (P = 0.004). The overall rate of operative revision due to any etiology among groups did not differ significantly (P = 0.255). CONCLUSIONS: Tibiofibular bone bridging with vascularized fibula leads to a significantly higher rate of ambulation without a significantly higher rate of complications in a nontrauma population. Although this technique has been widely described in trauma patients, clinical data are lacking for the nontrauma population. This is the largest reported series of Ertl amputations in nontraumatic population to date and our results demonstrate a significant benefit of the Ertl technique in this population. LEVEL OF EVIDENCE: Level IV. PMID- 25014327 TI - Is it necrotizing fasciitis or necrotizing cellulitis after varicella zoster infection? Two case reports. AB - Necrotizing fasciitis and necrotizing cellulitis are serious cutaneous complications in varicella patients. Differentiation of necrotizing cellulitis from necrotizing fasciitis can initially be challenging because of indistinct clinical course at the onset of infection and the lack of definitive diagnostic criteria. This paper reports 2 children with necrotizing cellulitis that developed after varicella infection to draw the attention of health care providers to necrotizing cellulitis that showed slower clinical course than necrotizing fasciitis and recovered with conservative treatment approaches without aggressive surgical intervention. PMID- 25014328 TI - Recent progress in design, synthesis, and applications of one-dimensional TiO2 nanostructured surface heterostructures: a review. AB - One-dimensional TiO2 nanostructured surface heterostructures (1D TiO2NSHs) have been comprehensively studied during the past two decades because of the possible practical applications in various fields, including photocatalysis, dye sensitized solar cells, sensors, lithium batteries, biomedicine, catalysis, and supercapacitors. Combining extensive advancements in materials science and nanotechnology, a 1D TiO2NSH material with well-controlled size, morphology, and composition has been designed and synthesized. More importantly, its superior properties, including a high aspect ratio structure, chemical stability, large specific surface area, excellent electronic or ionic charge transfer, and a specific interface effect, have attracted a great deal of interest in improving current performance and exploring new applications. In this tutorial review, we introduce the characteristics of 1D TiO2 nanostructures, the design principles for the fabrication of 1D TiO2NSHs, and we also summarize the recent progress in developing synthesis methods and applications of 1D TiO2NSHs in different fields. The relationship between the secondary phase and the 1D TiO2 nanostructure and between the performance in applications and the excellent physical properties of 1D TiO2NSHs are also discussed. PMID- 25014329 TI - Coffee-ring effect-based simultaneous SERS substrate fabrication and analyte enrichment for trace analysis. AB - Based on the "coffee-ring effect", we developed a highly efficient SERS platform which integrates the fabrication of SERS-active substrates and the preconcentration of analytes into one step. The high sensitivity, robustness, reproducibility and simplicity make this platform ideal for on-site analysis of small volume samples at low concentrations in complex matrices. PMID- 25014330 TI - Bilateral spontaneous pneumothorax in a patient with longstanding ankylosing spondylitis. PMID- 25014331 TI - Distribution, diversity and drivers of blood-borne parasite co-infections in Alaskan bird populations. AB - Avian species are commonly infected by multiple parasites, however few studies have investigated the environmental determinants of the prevalence of co infection over a large scale. Here we believe that we report the first, detailed ecological study of the prevalence, diversity and co-infections of four avian blood-borne parasite genera: Plasmodium spp., Haemoproteus spp., Leucocytozoon spp. and Trypanosoma spp. We collected blood samples from 47 resident and migratory bird species across a latitudinal gradient in Alaska. From the patterns observed at collection sites, random forest models were used to provide evidence of associations between bioclimatic conditions and the prevalence of parasite co infection distribution. Molecular screening revealed a higher prevalence of haematozoa (53%) in Alaska than previously reported. Leucocytozoons had the highest diversity, prevalence and prevalence of co-infection. Leucocytozoon prevalence (35%) positively correlated with Trypanosoma prevalence (11%), negatively correlated with Haemoproteus prevalence (14%) and had no correlation with Plasmodium prevalence (7%). We found temperature, precipitation and tree cover to be the primary environmental drivers that show a relationship with the prevalence of co-infection. The results provide insight into the impacts of bioclimatic drivers on parasite ecology and intra-host interactions, and have implications for the study of infectious diseases in rapidly changing environments. PMID- 25014332 TI - Genetics and the clinical approach to paragangliomas. AB - This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56.4% in mutation (+) and 3.2% in mutation (-) patients (RR 8.7, p < 0.0001). E-PGL were found in 33.6% of mut+ and 17.3% of mut- (RR 1.7, p < 0.0001). In mutation (+) patients PGLs malignancy varied with location, adrenal (6.4%) thoraco-abdominal E-PGL (38%), H & N E-PGL (10%). Malignancy rates were 8.2% in mutation (-) and lower in mutation (+) PGLs except for SDHB 36.5% and SDHC 8.3%. Exclusion of a mutation lowered the probability of malignancy significantly in E-PGL (RR 0.03 (95% CI 0.1-0.6); p < 0.001). Mutation analysis provides valuable preoperative information to assess the risk of malignancy in A-PG and E-PGLs and should be considered in the work up of all E-PGL lesions. PMID- 25014333 TI - Block copolymer self-assembly controlled by the "green" gas stimulus of carbon dioxide. AB - Stimuli-responsive macromolecules have inspired much interest in polymer science. Inputting an external stimulus to these polymers can modulate their chain structures and self-assembled architectures for functional outputs. This appealing feature has made this class of polymer materials promising for many emerging applications. In order to apply these polymer systems in organisms and further make them adaptive to physiological environments, it is important to explore new stimulation modes. In this Feature Article, we review the recent development of using carbon dioxide (CO2) as a stimulus for tuning or controlling block copolymer (BCP) self-assembly. We show that a series of CO2-responsive functionalities can easily be incorporated into BCP structures, and that rationally designed BCPs can have their self-assembled structures undergo drastic changes in size, shape, morphology and function, controlled by the amount of CO2 in aqueous solution. This gas stimulus has some distinct advantages over other conventional stimuli: it is truly "green" for the environment of the target polymer system without any chemical contaminations; the stimulating strength or magnitude can be precisely adjusted with the continuous gas flow; and, being a key metabolite in cells, it provides a convenient physiological signal to allow synthetic polymer systems to mimic certain properties of organelles and act as intelligent macromolecular machines and devices. PMID- 25014334 TI - Complete mitochondrial genome of the hydrothermal vent tubeworm, Ridgeia piscesae (Polychaeta, Siboglinidae). AB - The complete mitochondrial genome of Ridgeia piscesae (Polychaeta, Siboglinidae), one of the dominant taxa in deep-sea hydrothermal vents, is reported here for the first time. The R. piscesae mitogenome is 15,002 bp in total length and includes 13 protein-coding gene sequences, small and large rRNA sequences and 22 tRNA sequences. All genes are encoded on the heavy strand. The mitochondrial genomes of R. piscesae and other six polychaete species have a conserved gene order. PMID- 25014335 TI - Sensitizing Tb(III) and Eu(III) emission with triarylboron functionalized 1,3 diketonato ligands. AB - Four BMes2Ar (Mes = mesityl, Ar = phenyl or duryl) functionalized 1,3-diketonato ligands have been investigated for use in selective sensitization of Tb(III) and Eu(III) emission. These ligands have the general formula of [R1C(O)CR2C(O)R3](-) (R1 = Ph, R2 = H, R3 = p-Ph-BMes2, L1; R1 = R3 = p-Ph-BMes2, R2 = H, L2; R1 = R3 = Me, R2 = p-Ph-BMes2, L3; R1 = R3 = Me, R2 = p-duryl-BMes2, L4) and belong to class I (L1 and L2) and class II (L3 and L4), respectively. In class I, the boron unit is conjugated with the phenyl linker and the diketone backbone, while in class II, the boron unit, the linker unit, and the diketone unit are nonconjugated with a mutually orthogonal arrangement. To understand the impact of the location of the BMes2Ar unit on the electronic properties of the 1,3-diketone molecules and their ability in activating lanthanide emission, the difluoroboron chelate compounds (1-BF2 to 4-BF2) of ligands L1-L4 were synthesized and examined. The class I ligands were effective in activating Eu(III) emission, while the class II ligands were effective in activating Tb(III) emission. Four Ln(III) complexes, 1Eu, 2Eu, 3Tb, and 4Tb, based on the L1-L4 ligands, respectively, were prepared and examined. The emission quantum efficiency of 1Eu and 2Eu is low (Phi(Eu) <= 0.01 in THF, 0.07-0.13 in the solid state), but can be greatly enhanced by the addition of fluoride ions. In contrast, the complex 4Tb has a moderate emission efficiency (Phi(Tb) = 0.14 in THF, 0.47 in the solid state) and experiences a distinct emission quenching upon the addition of fluoride. The selective sensitization of Eu(III) and Tb(III) by L1-L4 and the distinct luminescent response of their Ln(III) complexes toward fluoride ions are caused by the distinct intraligand charge transfer transitions of the two different classes of ligands involving the BMes2 unit. PMID- 25014336 TI - Toward understanding the growth mechanism: tracing all stable intermediate species from reduction of Au(I)-thiolate complexes to evolution of Au25 nanoclusters. AB - Despite 20 years of progress in synthesizing thiolated gold nanoclusters (Au NCs), the knowledge of their growth mechanism still lags behind. Herein the detailed process from reduction of Au(I)-thiolate complex precursors to the eventual evolution of and focusing to the atomically precise Au25 NCs was revealed for the first time by monitoring the time evolution of Au(I) precursor and Au NC intermediate species with ESI-MS. A two-stage, bottom-up formation and growth process was proposed: a fast stage of reduction-growth mechanism, followed by a slow stage of intercluster conversion and focusing. Balanced reactions of formation for each identified NC were suggested, backed by theoretical calculations of the thermodynamic driving force. This work advances one step further toward understanding the mechanism of formation and growth of thiolated Au NCs. PMID- 25014337 TI - High-temperature stability and saturation magnetization of superparamagnetic nickel nanoparticles in microporous polysilazane-derived ceramics and their gas permeation properties. AB - Superparamagnetic Ni nanoparticles with diameters of about 3 nm are formed in situ at room temperature in a polysilazane matrix, forming Ni/polysilazane nanocomposite, in the reaction between a polysilazane and trans-bis(aceto kO)bis(2-aminoethanol-k(2)N,O)nickel(II). The thermolysis of the Ni/polysilazane nanocomposite at 700 degrees C in an argon atmosphere results in a microporous superparamagnetic Ni/silicon oxycarbonitride (Ni/SiCNO) ceramic nanocomposite. The growth of Ni nanoparticles in Ni/SiCNO ceramic nanocomposite is totally suppressed even after thermolysis at 700 degrees C, as confirmed by HRTEM and SQUID characterizations. The analysis of saturation magnetization of Ni nanoparticles in Ni/polysilazane and Ni/SiCNO nanocomposites indicates that the saturation magnetization of Ni nanoparticles is higher than expected values and infers that the surfaces of Ni nanoparticles are not oxidized. The microporous superparamagnetic Ni/SiCNO nanocomposite is shaped as a free-standing monolith and foam. In addition, Ni/SiCNO membranes are fabricated by the dip-coating of a tubular alumina substrate in a dispersion of Ni/polysilazane in THF followed by a thermolysis at 700 degrees C under an argon atmosphere. The gas separation performance of Ni/SiCNO membranes at 25 and 300 degrees C is assessed by the single gas permeance (pressure rise technique) using He, H2, CO2, N2, CH4, n propene, n-propane, n-butene, n-butane, and SF6 as probe molecules. After hydrothermal treatment, the higher increase in the hydrogen permeance compared to the permeance of other gases as a function of temperature indicates that the hydrogen affinity of Ni nanoparticles influences the transport of hydrogen in the Ni/SiCNO membrane and Ni nanoparticles stabilize the structure against hydrothermal corrosion. PMID- 25014338 TI - Five principles: returning genetic testing results to research participants. PMID- 25014340 TI - Biologically inspired nanofibers for use in translational bioanalytical systems. AB - Electrospun nanofiber mats are characterized by large surface-area-to-volume ratios, high porosities, and a diverse range of chemical functionalities. Although electrospun nanofibers have been used successfully to increase the immobilization efficiency of biorecognition elements and improve the sensitivity of biosensors, the full potential of nanofiber-based biosensing has not yet been realized. Therefore, this review presents novel electrospun nanofiber chemistries developed in fields such as tissue engineering and drug delivery that have direct application within the field of biosensing. Specifically, this review focuses on fibers that directly encapsulate biological additives that serve as immobilization matrices for biological species and that are used to create biomimetic scaffolds. Biosensors that incorporate these nanofibers are presented, along with potential future biosensing applications such as the development of cell culture and in vivo sensors. PMID- 25014341 TI - Analytical approaches for size and mass analysis of large protein assemblies. AB - Analysis of the size and mass of nanoparticles, whether they are natural biomacromolecular or synthetic supramolecular assemblies, is an important step in the characterization of such molecular species. In recent years, electrospray ionization (ESI) has emerged as a technology through which particles with masses up to 100 MDa can be ionized and transferred into the gas phase, preparing them for accurate mass analysis. Here we review currently used methodologies, with a clear focus on native mass spectrometry (MS). Additional complementary methodologies are also covered, including ion-mobility analysis, nanomechanical mass sensors, and charge-detection MS. The literature discussed clearly demonstrates the great potential of ESI-based methodologies for the size and mass analysis of nanoparticles, including very large naturally occurring protein assemblies. The analytical approaches discussed are powerful tools in not only structural biology, but also nanotechnology. PMID- 25014339 TI - Plasma membrane Ca2+-ATPase isoforms composition regulates cellular pH homeostasis in differentiating PC12 cells in a manner dependent on cytosolic Ca2+ elevations. AB - Plasma membrane Ca(2+)-ATPase (PMCA) by extruding Ca(2+) outside the cell, actively participates in the regulation of intracellular Ca(2+) concentration. Acting as Ca(2+)/H(+) counter-transporter, PMCA transports large quantities of protons which may affect organellar pH homeostasis. PMCA exists in four isoforms (PMCA1-4) but only PMCA2 and PMCA3, due to their unique localization and features, perform more specialized function. Using differentiated PC12 cells we assessed the role of PMCA2 and PMCA3 in the regulation of intracellular pH in steady-state conditions and during Ca(2+) overload evoked by 59 mM KCl. We observed that manipulation in PMCA expression elevated pHmito and pHcyto but only in PMCA2-downregulated cells higher mitochondrial pH gradient (DeltapH) was found in steady-state conditions. Our data also demonstrated that PMCA2 or PMCA3 knock down delayed Ca(2+) clearance and partially attenuated cellular acidification during KCl-stimulated Ca(2+) influx. Because SERCA and NCX modulated cellular pH response in neglectable manner, and all conditions used to inhibit PMCA prevented KCl-induced pH drop, we considered PMCA2 and PMCA3 as mainly responsible for transport of protons to intracellular milieu. In steady-state conditions, higher TMRE uptake in PMCA2-knockdown line was driven by plasma membrane potential (Psip). Nonetheless, mitochondrial membrane potential (Psim) in this line was dissipated during Ca(2+) overload. Cyclosporin and bongkrekic acid prevented Psim loss suggesting the involvement of Ca(2+)-driven opening of mitochondrial permeability transition pore as putative underlying mechanism. The findings presented here demonstrate a crucial role of PMCA2 and PMCA3 in regulation of cellular pH and indicate PMCA membrane composition important for preservation of electrochemical gradient. PMID- 25014343 TI - Ambient femtosecond laser vaporization and nanosecond laser desorption electrospray ionization mass spectrometry. AB - Recent investigations of ambient laser-based transfer of molecules into the gas phase for subsequent mass spectral analysis have undergone a renaissance resulting from the separation of vaporization and ionization events. Here, we seek to provide a snapshot of recent femtosecond (fs) duration laser vaporization and nanosecond (ns) duration laser desorption electrospray ionization mass spectrometry experiments. The former employs pulse durations of <100 fs to enable matrix-free laser vaporization with little or no fragmentation. When coupled to electrospray ionization, femtosecond laser vaporization provides a universal, rapid mass spectral analysis method requiring no sample workup. Remarkably, laser pulses with intensities exceeding 10(13) W cm(-2) desorb intact macromolecules, such as proteins, and even preserve the condensed phase of folded or unfolded protein structures according to the mass spectral charge state distribution, as demonstrated for cytochrome c and lysozyme. Because of the ability to vaporize and ionize multiple components from complex mixtures for subsequent analysis, near perfect classification of explosive formulations, plant tissue phenotypes, and even the identity of the manufacturer of smokeless powders can be determined by multivariate statistics. We also review the more mature field of nanosecond laser desorption for ambient mass spectrometry, covering the wide range of systems analyzed, the need for resonant absorption, and the spatial imaging of complex systems like tissue samples. PMID- 25014344 TI - Point-of-care platforms. AB - Point-of-care applications are gaining increasing interest in clinical diagnostics and emergency applications. Biosensors are used to monitor the biomolecular interaction process between a disease biomarker and a recognition element such as a reagent. Essential are the quality and selectivity of the recognition elements and assay types used to improve sensitivity and to avoid nonspecific interactions. In addition, quality measures are influenced by the detection principle and the evaluation strategies. For these reasons, this review provides a survey and validation of recognition elements, assays, and various types of detection methods for point-of-care testing (POCT) platforms. Common applications of clinical parameters are discussed and considered. In this ever changing field, a snapshot of current applications is needed. We provide such a snapshot by way of a table including literature citations and also discuss these applications in more detail throughout. PMID- 25014342 TI - Ultrafast 2D NMR: an emerging tool in analytical spectroscopy. AB - Two-dimensional nuclear magnetic resonance (2D NMR) spectroscopy is widely used in chemical and biochemical analyses. Multidimensional NMR is also witnessing increased use in quantitative and metabolic screening applications. Conventional 2D NMR experiments, however, are affected by inherently long acquisition durations, arising from their need to sample the frequencies involved along their indirect domains in an incremented, scan-by-scan nature. A decade ago, a so called ultrafast (UF) approach was proposed, capable of delivering arbitrary 2D NMR spectra involving any kind of homo- or heteronuclear correlation, in a single scan. During the intervening years, the performance of this subsecond 2D NMR methodology has been greatly improved, and UF 2D NMR is rapidly becoming a powerful analytical tool experiencing an expanded scope of applications. This review summarizes the principles and main developments that have contributed to the success of this approach and focuses on applications that have been recently demonstrated in various areas of analytical chemistry--from the real-time monitoring of chemical and biochemical processes, to extensions in hyphenated techniques and in quantitative applications. PMID- 25014345 TI - Resonance-enhanced multiphoton ionization mass spectrometry (REMPI-MS): applications for process analysis. AB - Process analysis is an emerging discipline in analytical sciences that poses special requirements on analytical techniques, especially when conducted in an online manner. Mass spectrometric methods seem exceedingly suitable for this task, particularly if a soft ionization method is applied. Resonance-enhanced multiphoton ionization (REMPI) in combination with time-of-flight mass spectrometry (TOFMS) provides a selective and sensitive means for monitoring (poly)aromatic compounds in process flows. The properties of REMPI and various variations of the ionization process are presented. The potential of REMPI for process analysis is highlighted with several examples, and drawbacks of the method are also noted. Applications of REMPI-TOFMS for the detection and monitoring of aromatic species in a large variety of combustion processes comprising flames, vehicle exhaust, and incinerators are discussed. New trends in technical development and combination with other analytical methods are brought forward. PMID- 25014346 TI - High-throughput proteomics. AB - Mass spectrometry (MS)-based high-throughput proteomics is the core technique for large-scale protein characterization. Due to the extreme complexity of proteomes, sophisticated separation techniques and advanced MS instrumentation have been developed to extend coverage and enhance dynamic range and sensitivity. In this review, we discuss the separation and prefractionation techniques applied for large-scale analysis in both bottom-up (i.e., peptide-level) and top-down (i.e., protein-level) proteomics. Different approaches for quantifying peptides or intact proteins, including label-free and stable-isotope-labeling strategies, are also discussed. In addition, we present a brief overview of different types of mass analyzers and fragmentation techniques as well as selected emerging techniques. PMID- 25014347 TI - Analysis of exhaled breath for disease detection. AB - Breath analysis is a young field of research with great clinical potential. As a result of this interest, researchers have developed new analytical techniques that permit real-time analysis of exhaled breath with breath-to-breath resolution in addition to the conventional central laboratory methods using gas chromatography-mass spectrometry. Breath tests are based on endogenously produced volatiles, metabolites of ingested precursors, metabolites produced by bacteria in the gut or the airways, or volatiles appearing after environmental exposure. The composition of exhaled breath may contain valuable information for patients presenting with asthma, renal and liver diseases, lung cancer, chronic obstructive pulmonary disease, inflammatory lung disease, or metabolic disorders. In addition, oxidative stress status may be monitored via volatile products of lipid peroxidation. Measurement of enzyme activity provides phenotypic information important in personalized medicine, whereas breath measurements provide insight into perturbations of the human exposome and can be interpreted as preclinical signals of adverse outcome pathways. PMID- 25014348 TI - Ionophore-based optical sensors. AB - This review provides an overview of the key aspects of designing ionophore-based optical sensors (IBOS). Exact response functions are developed and compared with a simplified, generalized equation. We also provide a brief introduction into less established but promising working principles, namely dynamic response and exhaustive exchange. Absorbance and fluorescence are the main optical readout strategies used in the evaluation of a sensor response, but they usually require a robust referencing technique for real-world applications. Established referencing schemes using IBOS as well as those from other optical sensors are also discussed. Finally, the power of recently developed photoresponsive ion extraction/release systems is outlined and discussed in view of dynamically switchable IBOS or regenerative exhaustive exchange IBOS. PMID- 25014349 TI - Concerted proton-electron transfers: fundamentals and recent developments. AB - Proton-coupled electron transfers (PCET) are ubiquitous in natural and synthetic processes. This review focuses on reactions where the two events are concerted. Semiclassical models of such reactions allow their kinetic characterization through activation versus driving force relationships, estimates of reorganization energies, effects of the nature of the proton acceptor, and H/D kinetic isotope effect as well as their discrimination from stepwise pathways. Several homogeneous reactions (through stopped-flow and laser flash-quench techniques) and electrochemical processes are discussed in this framework. Once the way has been rid of the improper notion of pH-dependent driving force, water appears as a remarkable proton acceptor in terms of reorganization energy and pre exponential factor, thanks to its H-bonded and H-bonding properties, similarly to purposely synthesized "H-bond train" molecules. The most recent developments are in modeling and description of emblematic concerted proton-electron transfer (CPET) reactions associated with the breaking of a heavy-atom bond in an all concerted process. PMID- 25014350 TI - Immune response to Fc tagged GP5 glycoproteins of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) glycoprotein 5 (GP5) is the most abundant envelope glycoprotein and a key target for neutralizing antibodies. Previous studies have demonstrated that the native GP5 glycoprotein is poorly immunogenic and not able to induce robust protective responses, probably due to the presence of a non-neutralizing decoy epitope and shielding N linked glycans close to its neutralizing epitope. In the present report, two Fc tagged GP5 proteins (GP5-Fc containing a truncated GP5 with the deletion of its signal peptide and transmembrane regions, and GP5N-Fc containing only the ectodomain of GP5) were designed based on the sequences of a highly pathogenic PRRSV strain and produced using a baculovirus/insect cell expression system. Immunization studies showed that both GP5-Fc and GP5N-Fc elicited strong serum responses in the absence of adjuvant to the native GP5 present on the surface of purified PRRSV virons. Although GP5N-Fc failed in inducing significant titer of neutralizing antibodies in mice, GP5-Fc was shown as an effective inducer of neutralizing antibodies specific to PRRSV. Our results suggest that the modified GP5 glycoprotein with Fc tag has the potential to be a candidate for the future development of new generation vaccine against PRRSV infection. PMID- 25014351 TI - The impact of resources for clinical surveillance on the control of a hypothetical foot-and-mouth disease epidemic in Denmark. AB - The objectives of this study were to assess whether current surveillance capacity is sufficient to fulfill EU and Danish regulations to control a hypothetical foot and-mouth disease (FMD) epidemic in Denmark, and whether enlarging the protection and/or surveillance zones could minimize economic losses. The stochastic spatial simulation model DTU-DADS was further developed to simulate clinical surveillance of herds within the protection and surveillance zones and used to model spread of FMD between herds. A queuing system was included in the model, and based on daily surveillance capacity, which was 450 herds per day, it was decided whether herds appointed for surveillance would be surveyed on the current day or added to the queue. The model was run with a basic scenario representing the EU and Danish regulations, which includes a 3 km protection and 10 km surveillance zone around detected herds. In alternative scenarios, the protection zone was enlarged to 5 km, the surveillance zone was enlarged to 15 or 20 km, or a combined enlargement of the protection and surveillance zones was modelled. Sensitivity analysis included changing surveillance capacity to 200, 350 or 600 herds per day, frequency of repeated visits for herds in overlapping surveillance zones from every 14 days to every 7, 21 and 30 days, and the size of the zones combined with a surveillance capacity increased to 600 herds per day. The results showed that the default surveillance capacity is sufficient to survey herds on time. Extra resources for surveillance did not improve the situation, but fewer resources could result in larger epidemics and costs. Enlarging the protection zone was a better strategy than the basic scenario. Despite that enlarging the surveillance zone might result in shorter epidemic duration, and lower number of affected herds, it resulted frequently in larger economic losses. PMID- 25014352 TI - Quartz knapping strategies in the Howiesons Poort at Sibudu (KwaZulu-Natal, South Africa). AB - The variability associated with Sibudu's Howiesons Poort Industry highlights the unpredictable trajectory of technology in the Middle Stone Age. We reach this conclusion through a study of the technology on quartz from one of the Howiesons Poort layers (Grey Sand) from Sibudu rock shelter. Quartz bifacial technology has previously been described at the site, but this new in-depth study of the quartz technology reveals other strategies. First is the recurring employment of bipolar knapping, formerly considered as a defining feature of the Later Stone Age. Secondly, we highlight a laminar technology with emphasis on small quartz bladelets. Bipolar cores are most common, followed by prismatic cores. The knapping strategies in Grey Sand seem to involve systematic recycling and the deliberate production of microliths. PMID- 25014353 TI - Analyzing the first drafts of the human proteome. AB - This letter analyzes two large-scale proteomics studies published in the same issue of Nature. At the time of the release, both studies were portrayed as draft maps of the human proteome and great advances in the field. As with the initial publication of the human genome, these papers have broad appeal and will no doubt lead to a great deal of further analysis by the scientific community. However, we were intrigued by the number of protein-coding genes detected by the two studies, numbers that far exceeded what has been reported for the multinational Human Proteome Project effort. We carried out a simple quality test on the data using the olfactory receptor family. A high-quality proteomics experiment that does not specifically analyze nasal tissues should not expect to detect many peptides for olfactory receptors. Neither of the studies carried out experiments on nasal tissues, yet we found peptide evidence for more than 100 olfactory receptors in the two studies. These results suggest that the two studies are substantially overestimating the number of protein coding genes they identify. We conclude that the experimental data from these two studies should be used with caution. PMID- 25014354 TI - Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: I. Discovery in female atlantic croaker and evidence ZIP9 mediates testosterone-induced apoptosis of ovarian follicle cells. AB - Rapid, cell surface-initiated, pregenomic androgen actions have been described in various vertebrate cells, but the receptors mediating these actions remain unidentified. We report here the cloning and expression of a cDNA from Atlantic croaker (Micropogonias undulatus) ovaries encoding a 33-kDa, seven-transmembrane protein with binding and signaling characteristics of a membrane androgen receptor that is unrelated to any previously described steroid receptor. Instead, croaker membrane androgen receptor has 81-93% amino acid sequence identity with zinc transporter ZIP9 (SLC39A9) subfamily members, indicating it is a ZIP9 protein. Croaker ZIP9 is expressed in gonadal tissues and in brain and is up regulated in the ovary by reproductive hormones. Croaker ZIP9 protein is localized to plasma membranes of croaker granulosa cells and human breast cancer (SKBR-3) cells stably transfected with ZIP9. Recombinant croaker ZIP9 has a high affinity (dissociation constant, Kd, 12.7 nM), limited capacity (maximal binding capacity 2.8 nM/mg protein), displaceable, single binding site-specific for androgens, characteristic of steroid receptors. Testosterone activates a stimulatory G protein coupled to ZIP9, resulting in increased cAMP production. Testosterone promotes serum starvation-induced cell death and apoptosis in transfected cells and in croaker ovarian follicle cells that is associated with rapid increases in intracellular free zinc concentrations, suggesting an involvement of zinc in this nonclassical androgen action to promote apoptosis. These responses to testosterone are abrogated by treatment with ZIP9 small interfering RNA. The results provide the first evidence that zinc transporter proteins can function as specific steroid membrane receptors and indicate a previously unrecognized signaling pathway mediated by steroid receptors involving alterations in intracellular zinc. PMID- 25014355 TI - Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: II. Role of human ZIP9 in testosterone-induced prostate and breast cancer cell apoptosis. AB - Recently, we discovered a cDNA in teleost ovarian follicle cells belonging to the zinc transporter ZIP9 subfamily (SLC39A9) encoding a protein with characteristics of a membrane androgen receptor (mAR). Here, we demonstrate that human ZIP9 expressed in MDA-MB-468 breast cancer cells and stably overexpressed in human prostate cancer PC-3 cells (PC-3-ZIP9) also displays the ligand binding and signaling characteristics of a specific, high-affinity mAR. Testosterone treatment of MDA-MB-468 and PC-3-ZIP9 cells caused activation of G proteins and second messenger pathways as well as increases in intracellular free zinc concentrations that were accompanied by induction of apoptosis. [1,2,6,7-(3)H] testosterone binding and these responses were abrogated in MDA-MB-468 cells after ZIP9 small interfering RNA (siRNA) treatment and absent in PC-3 cells transfected with empty vector, confirming that ZIP9 functions as an mAR. Testosterone treatment caused up-regulation of proapoptotic genes Bax (Bcl-2-associated X protein), p53 (tumor protein p53), and JNK (c-Jun N-terminal kinases) in both cell lines and increased expression of Bax, Caspase 3, and cytochrome C proteins. Treatment with a zinc chelator or a MAPK inhibitor blocked testosterone-induced increases in Bax, p53, and JNK mRNA expression. The results suggest that both androgen signaling and zinc transporter functions of ZIP9 mediate testosterone promotion of apoptosis. ZIP9 is widely expressed in human tissues and up regulated in malignant breast and prostate tissues, suggesting that it is a potential therapeutic target for treating breast and prostate cancers. These results provide the first evidence for a mechanism mediated by a single protein through which steroid and zinc signaling pathways interact to regulate physiological functions in mammalian cells. PMID- 25014357 TI - A new, high energy Sn-C/Li[Li(0.2)Ni(0.4)/3Co(0.4)/3Mn(1.6/3)]O2 lithium-ion battery. AB - In this paper we report a new, high performance lithium-ion battery comprising a nanostructured Sn-C anode and Li[Li0.2Ni0.4/3Co0.4/3Mn1.6/3]O2 (lithium-rich) cathode. This battery shows highly promising long-term cycling stability for up to 500 cycles, excellent rate capability, and a practical energy density, which is expected to be as high as 220 Wh kg(-1) at the packaged cell level. Considering the overall performance of this new chemistry basically related to the optimized structure, morphology, and composition of the utilized active materials as demonstrated by XRD, TEM, and SEM, respectively, the system studied herein is proposed as a suitable candidate for application in the lithium-ion battery field. PMID- 25014356 TI - E-cadherin can replace N-cadherin during secretory-stage enamel development. AB - BACKGROUND: N-cadherin is a cell-cell adhesion molecule and deletion of N cadherin in mice is embryonic lethal. During the secretory stage of enamel development, E-cadherin is down-regulated and N-cadherin is specifically up regulated in ameloblasts when groups of ameloblasts slide by one another to form the rodent decussating enamel rod pattern. Since N-cadherin promotes cell migration, we asked if N-cadherin is essential for ameloblast cell movement during enamel development. METHODOLOGY/PRINCIPAL FINDINGS: The enamel organ, including its ameloblasts, is an epithelial tissue and for this study a mouse strain with N-cadherin ablated from epithelium was generated. Enamel from wild type (WT) and N-cadherin conditional knockout (cKO) mice was analyzed. MUCT and scanning electron microscopy showed that thickness, surface structure, and prism pattern of the cKO enamel looked identical to WT. No significant difference in hardness was observed between WT and cKO enamel. Interestingly, immunohistochemistry revealed the WT and N-cadherin cKO secretory stage ameloblasts expressed approximately equal amounts of total cadherins. Strikingly, E-cadherin was not normally down-regulated during the secretory stage in the cKO mice suggesting that E-cadherin can compensate for the loss of N-cadherin. Previously it was demonstrated that bone morphogenetic protein-2 (BMP2) induces E and N-cadherin expression in human calvaria osteoblasts and we show that the N cadherin cKO enamel organ expressed significantly more BMP2 and significantly less of the BMP antagonist Noggin than did WT enamel organ. CONCLUSIONS/SIGNIFICANCE: The E- to N-cadherin switch at the secretory stage is not essential for enamel development or for forming the decussating enamel rod pattern. E-cadherin can substitute for N-cadherin during these developmental processes. Bmp2 expression may compensate for the loss of N-cadherin by inducing or maintaining E-cadherin expression when E-cadherin is normally down-regulated. Notably, this is the first demonstration of a natural endogenous increase in E cadherin expression due to N-cadherin ablation in a healthy developing tissue. PMID- 25014360 TI - Eye contact elicits bodily self-awareness in human adults. AB - Eye contact is a typical human behaviour known to impact concurrent or subsequent cognitive processing. In particular, it has been suggested that eye contact induces self-awareness, though this has never been formally proven. Here, we show that the perception of a face with a direct gaze (that establishes eye contact), as compared to either a face with averted gaze or a mere fixation cross, led adult participants to rate more accurately the intensity of their physiological reactions induced by emotional pictures. Our data support the view that bodily self-awareness becomes more acute when one is subjected to another's gaze. Importantly, this effect was not related to a particular arousal state induced by eye contact perception. Rejecting the arousal hypothesis, we suggest that eye contact elicits a self-awareness process by enhancing self-focused attention in humans. We further discuss the implications of this proposal. PMID- 25014359 TI - Lantibiotic immunity: inhibition of nisin mediated pore formation by NisI. AB - Nisin, a 3.4 kDa antimicrobial peptide produced by some Lactococcus lactis strains is the most prominent member of the lantibiotic family. Nisin can inhibit cell growth and penetrates the target Gram-positive bacterial membrane by binding to Lipid II, an essential cell wall synthesis precursor. The assembled nisin Lipid II complex forms pores in the target membrane. To gain immunity against its own-produced nisin, Lactococcus lactis is expressing two immunity protein systems, NisI and NisFEG. Here, we show that the NisI expressing strain displays an IC50 of 73 +/- 10 nM, an 8-10-fold increase when compared to the non expressing sensitive strain. When the nisin concentration is raised above 70 nM, the cells expressing full-length NisI stop growing rather than being killed. NisI is inhibiting nisin mediated pore formation, even at nisin concentrations up to 1 uM. This effect is induced by the C-terminus of NisI that protects Lipid II. Its deletion showed pore formation again. The expression of NisI in combination with externally added nisin mediates an elongation of the chain length of the Lactococcus lactis cocci. While the sensitive strain cell-chains consist mainly of two cells, the NisI expressing cells display a length of up to 20 cells. Both results shed light on the immunity of lantibiotic producer strains, and their survival in high levels of their own lantibiotic in the habitat. PMID- 25014361 TI - Human transgene-free amniotic-fluid-derived induced pluripotent stem cells for autologous cell therapy. AB - The establishment of a reliable prenatal source of autologous, transgene-free progenitor cells has enormous potential in the development of regenerative medicine-based therapies for infants born with devastating birth defects. Here, we show that a largely CD117-negative population of human amniotic fluid mesenchymal stromal cells (AF-MSCs) obtained from fetuses with or without prenatally diagnosed anomalies are readily abundant and have limited baseline differentiation potential when compared with bone-marrow-derived MSCs and other somatic cell types. Nonetheless, the AF-MSCs could be easily reprogrammed into induced pluripotent stem cells (iPSCs) using nonintegrating Sendai viral vectors encoding for OCT4, SOX2, KLF4, and cMYC. The iPSCs were virtually indistinguishable from human embryonic stem cells in multiple assays and could be used to generate a relatively homogeneous population of neural progenitors, expressing PAX6, SOX2, SOX3, Musashi-1, and PSA-NCAM, for potential use in neurologic diseases. Further, these neural progenitors showed engraftment potential in vivo and were capable of differentiating into mature neurons and astrocytes in vitro. This study demonstrates the usefulness of AF-MSCs as an excellent source for the generation of human transgene-free iPSCs ideally suited for autologous perinatal regenerative medicine applications. PMID- 25014362 TI - Reference Standard Test and the Diagnostic Ability of Spectral Domain Optical Coherence Tomography in Glaucoma. AB - PURPOSE: To evaluate the relationship between the reference standard used to diagnose glaucoma and the diagnostic ability of spectral domain optical coherence tomograph (SDOCT). METHODS: In a cross-sectional study, 280 eyes of 175 consecutive subjects, referred to a tertiary eye care center for glaucoma evaluation, underwent optic disc photography, visual field (VF) examination, and SDOCT examination. The cohort was divided into glaucoma and control groups based on 3 reference standards for glaucoma diagnosis: first based on the optic disc classification (179 glaucoma and 101 control eyes), second on VF classification (glaucoma hemifield test outside normal limits and pattern SD with P-value of <5%, 130 glaucoma and 150 control eyes), and third on the presence of both glaucomatous optic disc and glaucomatous VF (125 glaucoma and 155 control eyes). Relationship between the reference standards and the diagnostic parameters of SDOCT were evaluated using areas under the receiver operating characteristic curve, sensitivity, and specificity. RESULTS: Areas under the receiver operating characteristic curve and sensitivities of most of the SDOCT parameters obtained with the 3 reference standards (ranging from 0.74 to 0.88 and 72% to 88%, respectively) were comparable (P>0.05). However, specificities of SDOCT parameters were significantly greater (P<0.05) with optic disc classification as reference standard (74% to 88%) compared with VF classification as reference standard (57% to 74%). CONCLUSIONS: Diagnostic parameters of SDOCT that was significantly affected by reference standard was the specificity, which was greater with optic disc classification as the reference standard. This has to be considered when comparing the diagnostic ability of SDOCT across studies. PMID- 25014363 TI - Social category formation is induced by cues of sharing knowledge in young children. AB - Previous research has shown that human infants and young children are sensitive to the boundaries of certain social groups, which supports the idea that the capacity to represent social categories constitutes a fundamental characteristic of the human cognitive system. However, the function this capacity serves is still debated. We propose that during social categorization the human mind aims at mapping out social groups defined by a certain set of shared knowledge. An eye tracking paradigm was designed to test whether two-year-old children differentially associate conventional versus non-conventional tool use with language-use, reflecting an organization of information that is induced by cues of shared knowledge. Children first watched videos depicting a male model perform goal-directed actions either in a conventional or in a non-conventional way. In the test phase children were presented with photographs taken of the model and of a similarly aged unfamiliar person while listening to a foreign (Experiment 1) or a native language (Experiment 2) text. Upon hearing the foreign utterance children looked at the model first if he had been seen to act in an unconventional way during familiarization. In contrast, children looked at the other person if the model had performed conventional tool use actions. No such differences were found in case of the native language. The results suggest that children take the conventionality of behavior into account in forming representations about a person, and they generalize to other qualities of the person based on this information. PMID- 25014364 TI - The effect of central vision loss on perception of mutual gaze. AB - PURPOSE: To evaluate the effects of central vision loss (CVL) on mutual gaze perception (knowing whether somebody else is looking at you), an important nonverbal visual cue in social interactions. METHODS: Twenty-three persons with CVL (visual acuity 20/50 to 20/200), 16 with a bilateral central scotoma and 7 without, and 23 age-matched control subjects completed a gaze perception task and a brief questionnaire. They adjusted the eyes of a life-size virtual head on a monitor at a 1-m distance until they either appeared to be looking straight at them or were at the extreme left/right or up/down positions at which the eyes still appeared to be looking toward them (defining the range of mutual gaze in the horizontal and vertical planes). RESULTS: The nonscotoma group did not differ from the control subjects in any gaze task measure. However, the gaze direction judgments of the scotoma group had significantly greater variability than those of the nonscotoma and control groups (p < 0.001). In addition, their mutual gaze range tended to be wider (p = 0.15), suggesting a more liberal judgment criterion. Contrast sensitivity was the strongest predictor of variability in gaze direction judgments followed by self-reported difficulties. CONCLUSIONS: Our results suggest that mutual gaze perception is relatively robust to CVL. However, a follow-up study that simulates less-than-optimal viewing conditions of everyday social interactions is needed. The gaze perception task holds promise as a research tool for investigating the effects of vision impairment on mutual gaze judgments. Self-reported difficulty and contrast sensitivity were both independent predictors of gaze perception performance, suggesting that the task captured higher-order as well as low-level visual abilities. PMID- 25014365 TI - Cone structure in subjects with known genetic relative risk for AMD. AB - PURPOSE: Utilize high-resolution imaging to examine retinal anatomy in patients with known genetic relative risk (RR) for developing age-related macular degeneration (AMD). METHODS: Forty asymptomatic subjects were recruited (9 men, 31 women; age range, 51 to 69 years; mean age, 61.4 years). Comprehensive eye examination, fundus photography, and high-resolution retinal imaging using spectral domain optical coherence tomography and adaptive optics were performed on each patient. Genetic RR scores were developed using an age-independent algorithm. Adaptive optics scanning light ophthalmoscope images were acquired in the macula extending to 10 degrees temporal and superior from fixation and were used to calculate cone density in up to 35 locations for each subject. RESULTS: Relative risk was not significantly predictive of fundus grade (p = 0.98). Only patients with a high RR displayed drusen on Cirrus or Bioptigen OCT. Compared to an eye with a grade of 0, an eye with a fundus grade equal to or greater than 1 had a 12% decrease in density (p < 0.0001) and a 5% increase in spacing (p = 0.0014). No association between genetic RR and either cone density (p = 0.435) or spacing (p = 0.538) was found. Three distinct adaptive optics scanning light ophthalmoscope phenotypical variations of photoreceptor appearance were noted in patients with grade 1 to 3 fundi. These included variable reflectivity of photoreceptors, decreased waveguiding, and altered photoreceptor mosaic overlying drusen. CONCLUSIONS: Our data demonstrate the potential of multimodal assessment in the understanding of early anatomical changes associated with AMD. Adaptive optics scanning light ophthalmoscope imaging reveals a decrease in photoreceptor density and increased spacing in patients with grade 1 to 3 fundi, as well as a spectrum of photoreceptor changes, ranging from variability in reflectivity to decreased density. Future longitudinal studies are needed in genetically characterized subjects to assess the significance of these findings with respect to the development and progression of AMD. PMID- 25014366 TI - Interactive effects of ocean acidification, elevated temperature, and reduced salinity on early-life stages of the pacific oyster. AB - Ocean acidification (OA) effects on larvae are partially attributed for the rapidly declining oyster production in the Pacific Northwest region of the United States. This OA effect is a serious concern in SE Asia, which produces >80% of the world's oysters. Because climate-related stressors rarely act alone, we need to consider OA effects on oysters in combination with warming and reduced salinity. Here, the interactive effects of these three climate-related stressors on the larval growth of the Pacific oyster, Crassostrea gigas, were examined. Larvae were cultured in combinations of temperature (24 and 30 degrees C), pH (8.1 and 7.4), and salinity (15 psu and 25 psu) for 58 days to the early juvenile stage. Decreased pH (pH 7.4), elevated temperature (30 degrees C), and reduced salinity (15 psu) significantly delayed pre- and post-settlement growth. Elevated temperature lowered the larval lipid index, a proxy for physiological quality, and negated the negative effects of decreased pH on attachment and metamorphosis only in a salinity of 25 psu. The negative effects of multiple stressors on larval metamorphosis were not due to reduced size or depleted lipid reserves at the time of metamorphosis. Our results supported the hypothesis that the C. gigas larvae are vulnerable to the interactions of OA with reduced salinity and warming in Yellow Sea coastal waters now and in the future. PMID- 25014367 TI - Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations. AB - This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation. PMID- 25014368 TI - Application of a continuous intrinsic dissolution-permeation system for relative bioavailability estimation of polymorphic drugs. AB - A new continuous dissolution-permeation system, consisting of an intrinsic dissolution apparatus and an Ussing chamber, was developed for screening and identification of high-bioavailability polymorphisms at pre-formulation stages. Three different solid forms of two model drugs (agomelatine and carbamazepine) were used to confirm the system's predictive ability. Ranks for cumulative permeation of the three solids were: Form III>Form I>Form II for agomelatine, and Form III>Form I>the dihydrate form for carbamazepine. Regression analysis of these parameters and published pharmacokinetics confirmed linear IVIVCs (most correlation coefficients >0.9). To confirm dissolution-absorption relationships, permeability coefficients were calculated. Relatively constant values among various polymorphisms for each drug supported a linear dependency between polymorphism-increased dissolution and polymorphism-enhanced permeation. A combined analysis of intrinsic dissolution rates and permeability coefficients revealed that both drugs are of the BCS II class and have dissolution-limited absorption. In conclusion, our new system was valuable not only for high bioavailability polymorphism screening, but also for drug classification within the BCS system. PMID- 25014369 TI - pH-sensitive nanoparticles for colonic delivery of curcumin in inflammatory bowel disease. AB - Nano-scaled particles have been found to preferentially accumulate in inflamed regions. Local delivery of anti-inflammatory drugs loaded in nanoparticles to the inflamed colonic site is of great interest for inflammatory bowel disease (IBD) treatment. Curcumin (CC) is an anti-inflammatory local agent, which presents poor ADME properties. Hence, we evaluated, both in vitro and in vivo, the local delivery of CC using pH-sensitive polymeric nanoparticles (NPs) combining both poly(lactide-co-glycolide) acid (PLGA) and a polymethacrylate polymer (Eudragit((r)) S100). CC-NPs significantly enhanced CC permeation across Caco-2 cell monolayers when compared to CC in suspension. CC-NPs significantly reduced TNF-alpha secretion by LPS-activated macrophages (J774 cells). In vivo, CC-NPs significantly decreased neutrophil infiltration and TNF-alpha secretion while maintaining the colonic structure similar to the control group in a murine DSS induced colitis model. Our results support the use of nanoparticles made of PLGA and Eudragit((r)) S100 combination for CC delivery in IBD treatment. PMID- 25014370 TI - Improving oral bioavailability of metformin hydrochloride using water-in-oil microemulsions and analysis of phase behavior after dilution. AB - Microemulsions show significant promise for enhancing the oral bioavailability of biopharmaceutics classification system (BCS) class II drugs, but how about class III drugs remains unclear. Here we employed metformin hydrochloride (MET) as the model drug and prepared drug-loaded water-in-oil (W/O) microemulsions selecting different hydrophile-lipophile balance (HLB) surfactant systems, using HLB 8 as a cut-off. We examined the phase behaviors of microemulsions after dilution and attempted to correlate these behaviors to drug oral bioavailability. ME-A, including a lower content of surfactants (35%), underwent a transition of W/O emulsion and then became a stable O/W emulsion in a light milky appearance; ME-B, in contrast, introducing a higher content of surfactants (45%), still remained transparent or semitransparent upon dilution. Unexpectedly, ME-A showed significantly higher oral bioavailability, which can be reduced by blocking the lymphatic absorption pathway. Comparatively, the AUC of ME-B is lower, close to MET solution. Both microemulsions behaved similarly in intestinal perfusion test because of the dilution before perfusion, lacking of the important phase transition of W/O emulsion. These findings suggest that W/O microemulsions improve oral bioavailability of BCS class III drug by promoting lymphatic absorption. Analyzing the phase behavior of microemulsions after dilution may help predict the drug oral bioavailability and optimize formulations. PMID- 25014371 TI - Target selective micelles for bombesin receptors incorporating Au(III) dithiocarbamato complexes. AB - Pure sterically stabilized micelles (SSM) of DSPE-PEG2000, and sterically stabilized mixed micelles (SSMM) containing PC or DOPC phospholipids (5, 10 or 20% mol/mol with respect to DSPE-PEG2000) are developed as delivery systems for the gold based cytotoxic drug Au(III)-dithiocarbamato complex AuL12. In particular, SSMM containing 5% of PC at 5mM of lipid concentration encapsulates 61.0 MUg of AuL12 with a DL% of 1.13. The gold complex remains stable up to 72 h when incorporated in the aggregate, as indicated by UV-vis measurements. Incorporation in micelle composition of a low amount of the peptide derivative MonY-BN-AA1, containing a bombesin peptide analogue does not influence structural parameters of the micelles (diameter around 20 nm) neither the AuL12 loading parameters. Target selective properties of the peptide containing full aggregate on PC-3 cells overexpressing the GRP/bombesin receptors are observed by in vitro cytotoxic studies: a decrease of cell viability, ~ 50%, is obtained in cells treated with AuL12-targeted micelles at 10 MUM drug concentration for 48 h with respect to untargeted micelles. PMID- 25014372 TI - Optimization of madecassoside liposomes using response surface methodology and evaluation of its stability. AB - Polar compounds with large molecular weight have poor membrane permeability, liposomes can promote drugs to penetrate epidermis and remain or release at dermis. Madecassoside (MA) exhibits powerful potency in treatment of skin disorders such as wound healing, scar management, and psoriasis, but it is not easy to penetrate epidermis for its hydrophilic nature. The aim of this work is to get the optimum process conditions and evaluate physicochemical properties and physical stability of MA liposomes. In order to avoid this disadvantage and maintain long term drug storage, MA Liposomes were designed to achieve optimum preparation conditions using response surface methodology (RSM) in our experiment. The process and formulation variables were optimized by achieving maximum drug encapsulation efficiency. The optimum conditions were 0.4424 g of madecassoside, 8.174 of ratio of egg yolk lecithin to cholesterol, 65 s of ultrasonic time. The results of particle size, zeta potential and encapsulation efficiency of madecassoside liposomes were 293 nm, -35.6 mV, and 40.90%, respectively, on the basis of the above optimum conditions. According to the morphology of liposomes and encapsulation efficiency of triplicate experiments conducted at optimum conditions, MA liposomes obtained by this optimized formulation had characters of favorable repeatability and proper particle size. The physical stability tests of MA liposomes indicated that its suitable storage temperature was at 4 degrees C with higher encapsulation efficiency. PMID- 25014373 TI - Editorial: part 2: network construction and mining for systems biology. PMID- 25014374 TI - Construction and analysis of microRNA-transcription factor regulation network in Arabidopsis. AB - Transcription factors (TFs) and microRNAs (miRNAs) are two major types of regulators of gene expression, at transcriptional and post-transcriptional levels, respectively. By gathering their gene regulatory relationships, gene regulatory networks (GRNs) could be formed. A network motif is a type of connection pattern among a set of nodes which appears significantly more frequently than in random networks. Investigations of the network motifs often yield biological insights into the nature of the network. The previous study on miRNA-TF regulation networks concentrated on animals, and relied heavily on computational predictions. The authors collected data concerning miRNA regulation and transcriptional regulation relationships in Arabidopsis from publicly available databases, and further incorporated them with the protein-protein interaction data. All the data in the author's collection are supported by experiments. They screened the network motifs, whose size ranges between 1 and 4. The biological implications of the motifs were further analysed, and a flower development related network was constructed as an example. In this example, they illustrated the relevance of the network with the given process, and proposed the association of several genes with flowers by a network cluster identification. In this study, they analysed the properties of the GRN in Arabidopsis, and discussed their biological implications, as well as their potential applications. PMID- 25014375 TI - Using graphical adaptive lasso approach to construct transcription factor and microRNA's combinatorial regulatory network in breast cancer. AB - Discovering the regulation of cancer-related gene is of great importance in cancer biology. Transcription factors and microRNAs are two kinds of crucial regulators in gene expression, and they compose a combinatorial regulatory network with their target genes. Revealing the structure of this network could improve the authors' understanding of gene regulation, and further explore the molecular pathway in cancer. In this article, the authors propose a novel approach graphical adaptive lasso (GALASSO) to construct the regulatory network in breast cancer. GALASSO use a Gaussian graphical model with adaptive lasso penalties to integrate the sequence information as well as gene expression profiles. The simulation study and the experimental profiles verify the accuracy of the authors' approach. The authors further reveal the structure of the regulatory network, and explore the role of feedforward loops in gene regulation. In addition, the authors discuss the combinatorial regulatory effect between transcription factors and microRNAs, and select miR-155 for detailed analysis of microRNA's role in cancer. The proposed GALASSO approach is an efficient method to construct the combinatorial regulatory network. It also provides a new way to integrate different data sources and could find more applications in meta analysis problem. PMID- 25014376 TI - Construction and investigation of breast-cancer-specific ceRNA network based on the mRNA and miRNA expression data. AB - It has been proved and widely acknowledged that messenger RNAs can talk to each other by competing for a limited pool of miRNAs. The competing endogenous RNAs are called as ceRNAs. Although some researchers have recently used ceRNAs to do biological function annotations, few of them have investigated the ceRNA network on specific disease systematically. In this work, using both miRNA expression data and mRNA expression data of breast cancer patient as well as the miRNA target relations, the authors proposed a computational method to construct a breast-cancer-specific ceRNA network by checking whether the shared miRNA sponges between the gene pairs are significant. The ceRNA network is shown to be scale free, thus the topological characters such as hub nodes and communities may provide important clues for the biological mechanism. Through investigation on the communities (the dense clusters) in the network, it was found that they are related to cancer hallmarks. In addition, through function annotation of the hub genes in the network, it was found that they are related to breast cancer. Moreover, classifiers based on the discriminative hubs can significantly distinguish breast cancer patients' risks of distant metastasis in all the three independent data sets. PMID- 25014377 TI - Modelling epigenetic regulation of gene expression in 12 human cell types reveals combinatorial patterns of cell-type-specific genes. AB - The maintenance of the diverse cell types in a multicellular organism is one of the fundamental mysteries of biology. Modelling the dynamic regulatory relationships between the histone modifications and the gene expression across the diverse cell types is essential for the authors to understand the mechanisms of the epigenetic regulation. Here, the authors thoroughly assessed the histone modification enrichment profiles at the promoters and constructed quantitative models between the histone modification abundances and the gene expression in 12 human cell types. The author's results showed that the histone modifications at the promoters exhibited remarkably cell-type-dependent variability in the cell type-specific (CTS) genes. They demonstrated that the variable profiles of the modifications are highly predictive for the dynamic changes of the gene expression across all the cell types. Their findings revealed the close relationship between the combinatorial patterns of the histone modifications and the CTS gene expression. They anticipate that the findings and the methods they used in this study could provide useful information for the future studies of the regulatory roles of the histone modifications in the CTS genes. PMID- 25014378 TI - Anti-triangle centrality-based community detection in complex networks. AB - Community detection has been extensively studied in the past decades largely because of the fact that community exists in various networks such as technological, social and biological networks. Most of the available algorithms, however, only focus on the properties of the vertices, ignoring the roles of the edges. To explore the roles of the edges in the networks for community discovery, the authors introduce the novel edge centrality based on its antitriangle property. To investigate how the edge centrality characterises the community structure, they develop an approach based on the edge antitriangle centrality with the isolated vertex handling strategy (EACH) for community detection. EACH first calculates the edge antitriangle centrality scores for all the edges of a given network and removes the edge with the highest score per iteration until the scores of the remaining edges are all zero. Furthermore, EACH is characterised by being free of the parameters and independent of any additional measures to determine the community structure. To demonstrate the effectiveness of EACH, they compare it with the state-of-the art algorithms on both the synthetic networks and the real world networks. The experimental results show that EACH is more accurate and has lower complexity in terms of community discovery and especially it can gain quite inherent and consistent communities with a maximal diameter of four jumps. PMID- 25014379 TI - ACSM clinician profile. Anthony C. Luke. PMID- 25014380 TI - The salt paradox for athletes. PMID- 25014382 TI - Is rest the best intervention for concussion? Lessons learned from the whiplash model. PMID- 25014383 TI - Why obesity should be treated as a disease. PMID- 25014384 TI - Exercise prescription: who is the pharm D? PMID- 25014385 TI - To screen or not to screen: commentary and review on screening laboratory tests in elite athletes. PMID- 25014386 TI - Eating disorders in female athletes: use of screening tools. AB - Screening female athletes for eating disorders is not performed commonly even though the American College of Sports Medicine, National Athletic Trainer Association, and International Olympic Committee have guidelines recommending screening. Eating disorders are more prevalent in the female athlete population than in the general population and carry short-term and long-term consequences that can affect sport performance. There are several screening tools available that have been studied in the general population and fewer tools that were validated specifically in female athletes. Female athletes with eating disorder pathology often have different factors and environmental pressures contributing to their pathology that can be identified best with an athlete-specific screening tool. We will discuss various screening tools available and the evidence for each one. Screening for eating disorders in all female athletes is an important part of the preparticipation examination and should be done using a tool specifically validated for the female athlete. PMID- 25014387 TI - 2014 female athlete triad coalition consensus statement on treatment and return to play of the female athlete triad. AB - The female athlete triad is a medical condition often observed in physically active girls and women and involves three components: (1) low energy availability with or without disordered eating, (2) menstrual dysfunction, and (3) low bone mineral density. Female athletes often present with one or more of the three triad components, and early intervention is essential to prevent its progression to serious end points that include clinical eating disorders, amenorrhea, and osteoporosis. This consensus statement presents a set of recommendations developed following the first (San Francisco, CA) and second (Indianapolis, IN) International Symposia on the Female Athlete Triad. This consensus statement was intended to provide clinical guidelines for physicians, athletic trainers, and other health care providers for the screening, diagnosis, and treatment of the female athlete triad and to provide clear recommendations for return to play. The expert panel has proposed a risk stratification point system that takes into account magnitude of risk to assist the physician in decision making regarding sport participation, clearance, and return to play. Guidelines are offered for clearance categories, management by a multidisciplinary team, and implementation of treatment contracts. PMID- 25014388 TI - Promoting exercise as medicine for prediabetes and prehypertension. AB - Prediabetes and prehypertension are conditions that reflect higher-than-normal blood glucose level and elevated blood pressure. The use of the term "pre" helps highlight the potentially slippery slope toward fully realized diabetes or hypertension. In both situations, recommended lifestyle modifications include a focus on regular exercise, including cardiorespiratory (aerobic) activity and resistance training. In spite of strong evidence related to the benefits of exercise, the number of American adults meeting even minimal targets is low. Therefore medical and health professionals should utilize strategies (including goal setting, problem solving, and relapse prevention, feedback, self-monitoring, and modeling) to encourage behavior change. PMID- 25014389 TI - Obesity and prognosis in chronic diseases--impact of cardiorespiratory fitness in the obesity paradox. AB - The effects of overweight and obesity on chronic diseases, particularly on cardiovascular disease (CVD), and its impact on increasing CVD risk factors and total CVD are reviewed. However despite the adverse effects of obesity on CVD risk factors and CVD, obesity has a surprising association with prognosis in patients with established diseases, often showing an "obesity paradox," [corrected] where overweight (body mass index (BMI), 25 to 29.9 kg.m(-2)) and obese patients (BMI, >=30 kg.m(-2)) with established CVD frequently have a better prognosis than that of their leaner counterparts (BMI, <25 kg.m(-2)) with the same diseases. Fitness-versus-fatness debate is summarized also, including the critical role that fitness plays to alter the relationship between adiposity and subsequent prognosis. PMID- 25014390 TI - The role of exercise in cancer treatment: bridging the gap. AB - In recent years, there has been a burgeoning amount of evidence-based scientific data demonstrating the benefit of exercise during and following cancer treatment. This compelling evidence has resulted in major stakeholders in cancer management, including the American College of Sports Medicine, American Society of Clinical Oncology, National Comprehensive Cancer Network, American Cancer Society, Oncology Nursing Society, and the Commission on Cancer, advocating exercise as an integral component of cancer care. Despite the acknowledgment of exercise as an essential component, it remains virtually absent in routine cancer treatment. This article discusses the role of exercise in cancer treatment utilizing a community-based program. The rationale presented is that a scalable and replicable standard of care model is a plausible avenue to assimilate exercise into routine oncology practice. PMID- 25014391 TI - The effects of exercise training on the traditional lipid profile and beyond. AB - The purpose of this review is to provide up-to-date information regarding the effects of aerobic and resistance exercise training on the traditional blood lipid and lipoprotein profile. In addition, emerging coronary artery disease (CAD) risk factors, such as postprandial lipemia (PPL) and metabolic syndrome (MetS), are reviewed. Numerous studies report that aerobic exercise combined with weight loss significantly reduces blood cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG) while improving high-density lipoprotein cholesterol (HDL-C). Both aerobic and resistance training demonstrated a reduction in non-HDL-C independent of changes in body weight. Transient beneficial effects of a single session of aerobic exercise are observed for PPL. Nonetheless further research is needed to provide a better understanding of the potential mechanisms for reducing PPL. Exercise as an intervention for patients with MetS leads to improved CAD risk factors including atherogenic dyslipidemia, blood pressure, body composition, insulin sensitivity, and fat metabolism. PMID- 25014392 TI - A systematic review of the aerobic exercise program variables for people with schizophrenia. AB - A number of studies demonstrate the positive benefits of exercise for people with schizophrenia and schizoaffective disorders; however the exercise program variables resulting in these positive effects have not been evaluated. Therefore the aim of this systematic review was to describe the aerobic exercise program variables used in randomized controlled trials reporting the positive effect of exercise in the treatment of schizophrenia or schizoaffective disorder. Studies were analyzed for exercise frequency, intensity, session duration, exercise type, intervention duration, delivery of exercise, and level and quality of supervision and adherence. Study quality was assessed using the Physiotherapy Evidence Database scale. Three studies met the inclusion criteria. In general, exercise intervention variables are reported poorly. We find that aerobic exercise including treadmill walking and cycle exercise undertaken as a supervised group intervention lasting 30 to 40 min per session and undertaken 3 times weekly at moderate intensity appears to be valuable for people with schizophrenia or schizoaffective disorder. Interventions ranged from 10 to 16 wk. No adverse events were reported in the included studies. Evidence suggests that aerobic exercise is safe and beneficial for people with schizophrenia or schizoaffective disorder. PMID- 25014393 TI - Community fitness center-based physical activity interventions: a brief review. AB - Sedentary lifestyle is associated with cardiovascular and metabolic diseases. A compelling body of evidence demonstrates the amelioration and prevention of such conditions with increased levels of physical activity (PA). Despite this evidence, many public health initiatives aimed at increasing PA have failed to demonstrate clinically relevant effects on public health. It has been hypothesized that the highly controlled environments in which PA and health research is conducted limits its replicability in real-world community settings. This review aimed to evaluate the effectiveness of community fitness center-based interventions on inactivity-related diseases in adults. Data from 11 investigations highlighted 3 factors: (1) a lack of community-based PA studies, (2) a lack of clinically relevant data, and 3) further reliance on self-report and rudimentary measurements. It is concluded that the current laboratory-based evidence for PA and health is to be replicated yet in real-world settings and that rigorous and clinically relevant naturalistic research is required. PMID- 25014395 TI - Self-association behavior of a novel nonproteinogenic beta-strand-mimic in an organic solvent. AB - The self-association behavior of a newly characterized beta-strand-mimic, presented by an achiral nonproteinogenic model system Boc-gamma-Abz-NHMe (1: Boc = tert-butyloxycarbonyl; gamma-Abz = gamma-aminobenzoic acid; NHMe = N methylamide), have been investigated using (1)H NMR and FT-IR absorption spectroscopy, in combination with computational ab initio calculations. The concentration dependence of (1)H NMR chemical shifts of the amide-NHs in CDCl3 exhibited noncooperative behavior of self-association, whereas the variable temperature (1)H NMR chemical shifts data of the amide-NHs, i.e., temperature coefficient (Deltadelta/DeltaT) values, could be accounted for by significant enhancement of self-association, i.e., aggregates higher than dimers. In the absence of N-H...O intramolecular H-bond in 1, the intense FT-IR absorption bands in informative amide-A region, i.e., N-H stretches at ~3465 and 3438 cm(-1) in chloroform solution, could be interpreted in terms of intermolecular H-bonding. The ab initio quantum mechanical calculations performed on two discrete isolated antiparallel H-bonded duplexes with a face-to-face and an edge-to-edge aromatic aromatic interaction provided strong support for their relative importance to stabilize favorable dimeric structures. The thermodynamic parameters deduced from van't Hoff plots, constructed from variable temperature (1)H NMR data of the amide-NHs in CDCl3, also substantiated the effectiveness of aromatic-aromatic interactions for dimer formation and higher-order self-association. In view of the enormous structural importance of beta-strand-like building blocks in peptide design, we highlight intrinsic self-associating potentials of the readily available gamma-Abz moiety, besides the fact that such planar secondary structural mimics are presumed to offer greater prospective for constructing peptidomimetics and therapeutically relevant small molecules. PMID- 25014394 TI - Setting standards for medically-based running analysis. AB - Setting standards for medically based running analyses is necessary to ensure that runners receive a high-quality service from practitioners. Medical and training history, physical and functional tests, and motion analysis of running at self-selected and faster speeds are key features of a comprehensive analysis. Self-reported history and movement symmetry are critical factors that require follow-up therapy or long-term management. Pain or injury is typically the result of a functional deficit above or below the site along the kinematic chain. PMID- 25014396 TI - Pre-hospital resuscitation exposure--when is enough, enough? PMID- 25014397 TI - Association of STAT3 common variations with obesity and hypertriglyceridemia: protective and contributive effects. AB - Signal transducer and activator of transcription 3 (STAT3) plays an important role in energy metabolism. Here we explore whether STAT3 common variations influence risks of obesity and other metabolic disorders in a Chinese Han population. Two tagging single nucleotide polymorphisms (tagSNPs), rs1053005 and rs957970, were used to capture the common variations of STAT3. Relationships between genotypes and obesity, body mass index, plasma triglyceride and other metabolic diseases related parameters were analyzed for association study in 1742 subjects. Generalized linear model and logistic regression model were used for quantitative data analysis and case-control study, respectively. rs1053005 was significantly associated with body mass index and waist circumference (p=0.013 and p=0.02, respectively). rs957970 was significantly associated with plasma level of triglyceride (p=0.007). GG genotype at rs1053005 had lower risks of both general obesity and central obesity (OR=0.40, p=0.034; OR=0.42, p=0.007, respectively) compared with AA genotype. CT genotype at rs957970 had a higher risk of hypertriglyceridemia (OR=1.43, p=0.015) compared with TT genotype. Neither of the two SNPs was associated with othermetabolic diseases related parameters. Our observations indicated that common variations of STAT3 could significantly affect the risk of obesity and hypertriglyceridemia in Chinese Han population. PMID- 25014398 TI - Chrysin suppressed inflammatory responses and the inducible nitric oxide synthase pathway after spinal cord injury in rats. AB - Chrysin (CH), a natural plant flavonoid, has shown a variety of beneficial effects. Our present study was conducted to evaluate the therapeutic potential of CH three days after spinal cord injury (SCI) in rats and to probe the underlying neuroprotective mechanisms. SCI was induced using the modified weight-drop method in Wistar rats. Then, they were treated with saline or CH by doses of 30 and 100 mg/kg for 26 days. Neuronal function was assessed with the Basso Beattle Bresnahan locomotor rating scale (BBB). The water content of spinal cord was determined after traumatic SCI. The NF-kappaB p65 unit, TNF-alpha, IL-1beta and IL-6 in serums, as well as the apoptotic marker, caspase-3, of spinal cord tissues were measured using commercial kits. The protein level and activity of inducible nitric oxide synthase (iNOS) were detected by western blot and a commercial kit, respectively. NO (nitric oxide) production was evaluated by the determination of nitrite concentration. The rats with SCI showed marked reductions in BBB scores, coupled with increases in the water content of spinal cord, the NF-kappaB p65 unit, TNF-alpha, IL-1beta, IL-6, iNOS, NO production and caspase-3. However, a CH supplement dramatically promoted the recovery of neuronal function and suppressed the inflammatory factors, as well as the iNOS pathway in rats with SCI. Our findings disclose that CH improved neural function after SCI in rats, which might be linked with suppressing inflammation and the iNOS pathway. PMID- 25014399 TI - Functional characterization and molecular identification of vitamin C transporter (SVCT2) in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells. AB - PURPOSE: The main goal of this study is to investigate the existence of sodium dependent vitamin C transport system (SVCT2) and to define time-dependent uptake mechanism and intracellular regulation of ascorbic acid (AA) in human corneal epithelial (HCEC) and human retinal pigment epithelial (D407) cells. METHODS: Uptake of [(14)C] AA was studied in HCEC and D407 cells. Functional aspects of [(14)C] AA uptake were studied in the presence of different concentrations of unlabeled AA, pH, temperature, metabolic inhibitors, substrates and structural analogs. Molecular identification of SVCT2 was examined with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Uptake of [(14)C] AA was observed to be sodium, chloride, temperature, pH and energy-dependent in both cell lines. [(14)C] AA uptake was found to be saturable, with Km values of 46.14 +/- 6.03 and 47.26 +/- 3.24 MUM and Vmax values of 17.34 +/- 0.58 and 31.86 +/- 0.56 pmol/min/mg protein, across HCEC and D407 cells, respectively. The process is inhibited by structural analogs (L-AA and D-Iso AA) but not by structurally unrelated substrates (glucose and PAHA). Ca(++)/calmodulin and protein kinase pathways play an important role in modulating uptake of AA. A 626 bp band corresponding to a vitamin C transporter (SVCT2) has been identified by RT-PCR analysis in both the cell lines. CONCLUSION: This research article reports regarding the ascorbic acid uptake mechanism, kinetics and regulation by sodium dependent vitamin C transporter (SVCT2) in HCEC and D407 cells. Also, SVCT2 can be utilized for targeted delivery in enhancing ocular permeation and bioavailability of highly potent ophthalmic drugs. PMID- 25014400 TI - Size or spacing: which limits letter recognition in people with age-related macular degeneration? AB - Recent evidence suggests a double dissociation of size and spacing limit on letter recognition-it is limited by size in the fovea and critical spacing in the normal periphery. Here, we evaluated whether size or spacing limits letter recognition in people with age-related macular degeneration (AMD) who must use their peripheral vision. We measured the size threshold for recognizing lowercase letters presented alone, or flanked by two letters at various center-to-center nominal letter spacings (multiples of letter size) for 11 observers with AMD. For comparison, similar measurements were obtained at 5 degrees and 10 degrees eccentricity in the nasal and lower visual fields in three older adults with normal vision. Single-letter size thresholds were worse for observers with AMD than at comparable retinal locations in the normal periphery. For flanked letters, size threshold improved with larger nominal spacing up to the critical spacing, beyond which size threshold was unaffected by the flankers. Seven AMD observers had a nominal critical spacing between 1.25* and 1.80*, values close to those in the normal fovea, suggesting that their letter recognition is size limited; two had a nominal critical spacing of 3-4*, values close to those in the normal periphery, implying that their letter recognition is limited by spacing; and another two had a nominal critical spacing of ~2.3*, implying that their letter recognition is limited by both size and spacing. The wide range of nominal critical spacings observed in our AMD observers may reflect the degree of completeness of their adaptation process to vision loss. PMID- 25014401 TI - A perspective on multisensory integration and rapid perturbation responses. AB - In order to perform accurate movements, the nervous system must transform sensory feedback into motor commands that compensate for errors caused by motor variability and external disturbances. Recent studies focusing on the importance of sensory feedback in motor control have illustrated that the brain generates highly flexible responses to visual perturbations (hand-cursor or target jumps), or following mechanical loads applied to the limb. These parallel approaches have emphasized sophisticated, goal-directed feedback control, but also reveal that flexible perturbation responses are expressed at different latencies depending on what sensory system is engaged by the perturbation. Across studies, goal-directed visuomotor responses consistently emerge in muscle activity ~100ms after a perturbation, while mechanical perturbations evoke goal-directed muscle responses in as little as ~60ms (long-latency responses). We discuss the limitation of current models of multisensory integration in light of these asynchronous processing delays, and suggest that understanding how the brain performs real time multisensory integration is an open question for future studies. PMID- 25014402 TI - Effects of nutrient levels and average culture pH on the glycosylation pattern of camelid-humanized monoclonal antibody. AB - The impact of operating conditions on the glycosylation pattern of humanized camelid monoclonal antibody, EG2-hFc produced by Chinese hamster ovary (CHO) cells has been evaluated by a combination of experiments and modeling. Cells were cultivated under different levels of glucose and glutamine concentrations with the goal of investigating the effect of nutrient depletion levels and ammonia build up on the cell growth and the glycoprofiles of the monoclonal antibody (Mab). The effect of average pH reduction on glycosylation level during the entire culture time or during a specific time span was also investigated. The relative abundance of glycan structures was quantified by hydrophilic interaction liquid chromatography (HILIC) and the galactosylation index (GI) and the sialylation index (SI) were determined. Lower initial concentrations of glutamine resulted in lower glucose consumption and lower cell yield but increased GI and SI levels when compared to cultures started with higher initial glutamine levels. Similarly, reducing the average pH of culture resulted in lower growth but higher SI and GI levels. These findings indicate that there is a tradeoff between cell growth, resulting Mab productivity and the achievement of desirable higher glycosylation levels. A dynamic model, based on a metabolic flux analysis (MFA), is proposed to describe the metabolism of nutrients, cell growth and Mab productivity. Finally, existing software (GLYCOVIS) that describes the glycosylation pathways was used to illustrate the impact of extracellular species on the glycoprofiles. PMID- 25014403 TI - Improvement and simplification of fed-batch bioprocesses with a highly soluble phosphotyrosine sodium salt. AB - Fed-batch culture bioprocesses are currently used predominantly for the production of recombinant proteins, especially monoclonal antibodies. In these cultures, concentrated feeds are added during cultivation to prevent nutrient depletion, thus extending the cellular growth phase and increasing product concentrations. One limitation in these bioprocesses arises from the low solubility or stability of some compounds at high concentrations, in particular amino acids. This study describes the synthesis and evaluation of a phosphotyrosine disodium salt as a tyrosine source in fed-batch processes. This molecule is highly soluble in concentrated feeds at neutral pH. Mechanistic studies demonstrated that the molecule is cleaved in the cell culture supernatant after processing by released phosphatases, leading to phosphate and free L tyrosine which can be taken up by the cells. No intact phosphotyrosine was detected intracellularly or incorporated into the sequence of the monoclonal antibody. The use of this new molecule allows the simplification of fed-batch processes in large scale manufacturing via the implementation of neutral pH, highly concentrated feeds. PMID- 25014404 TI - Spatial variation of management of childhood diarrhea in Malawi. AB - This study reports the spatial variability in household management of diarrhea among under-fives in Malawi. Using data from 2010 Malawi Demographic and Health Survey, we examined oral rehydration and feeding practices of mothers and caregivers of 3105 children with an episode of diarrhea by mapping district effect residual in geo-additive probit model and analyzing residual spatial effects in a Bayesian approach. The findings suggest that although diarrhea is relatively less prevalent in the Northern Region, this region lags behind in terms of adoption of appropriate practices for home-based management of diarrhea in children compared to the Central Regions and Southern Regions. A cluster of five predominantly rural districts in the eastern part of the Southern Region showed remarkably high level of household care for childhood diarrhea relative to the rest of the country. The fixed effects show the importance of breastfeeding, paternal education, wealth index, and ethnicity on oral rehydration, while paternal education, marital status, and ethnicity show significant influence on feeding for children with a diarrhea episode. The paper discusses the apparent inverse relationship between regional prevalence of diarrhea episodes and care seeking practices for childhood diarrhea in Malawi, and makes relevant recommendations for policy. PMID- 25014405 TI - Electron energy loss spectrum of graphane from first-principles calculations. AB - In this study, the energy loss near edge structure (ELNES) of carbon atoms in chair and tricycle conformers of hydrogenated graphene, namely 'graphane', has been calculated in the density functional theory using FP-LAPW method, and then, it has been compared with that of graphite and graphene. Using ELNES from chair conformer, the carbon K-edge was found to have a few main features including electron transition from 1s orbital of carbon atom to pi*, sigma*, and a hybridization of these two states. The first feature in tricycle conformer, however, has contributions of both pi* and sigma* states. The comparison of ELNES and the unoccupied density of states in each structure also justifies this. The energy difference between pi* and sigma* features of graphane conformers was decreased relative to it in graphite and graphene. Since the inclusion of core holes and super-cells is essential for accurate reproduction of features in graphite and graphene, it may be essential as well for the ELNES spectra of graphane conformers. PMID- 25014406 TI - Use of a two-way non-rebreathing valve to simplify the measurement of twitch mouth pressure using an inspiratory pressure trigger and the establishment of an optimal trigger threshold for healthy subjects and COPD patients. AB - OBJECTIVE: Controlled twitch mouth pressure (Tw Pmo) via the use of a two-way non rebreathing valve is a new method to assess diaphragm contractility. The optimal trigger threshold was confirmed. DESIGN: We sought to determine the optimal trigger threshold for 17 healthy subjects (29+/-4 years) and 17 COPD patients (64+/-10 years). The Tw Pmo, twitch oesophageal pressure (Tw Pes) and twitch transdiaphragmatic pressure (Tw Pdi) in response to phrenic nerve stimulation were measured using an inspiratory pressure trigger at -1, -2, -3, -4, -5 and -6 cmH2O. RESULTS: The lung volume did not change during triggering at different trigger thresholds using a two-way non-rebreathing valve. The highest correlation between Tw Pmo and Tw Pes in healthy subjects and COPD patients occurred for a -2 cmH2O trigger threshold (r=0.939 and r=0.869, P<0.0001). The narrowest limits of agreement for Tw Pmo and Tw Pes both occurred at -2 cmH2O in healthy subjects, with a bias (range) of -0.4 cmH2O (-1.85 to 1.41), and in COPD patients, with a bias (range) of 0.1 6cmH2O (-1.36-1.67). CONCLUSIONS: We conclude that the measurement of Tw Pmo using a two-way non-rebreathing valve is of clinical value to investigate the suspected diaphragm contractility. The highest trigger threshold for clinical applications was -2 cmH2O. PMID- 25014407 TI - Regional and inter-regional theta oscillation during episodic novelty processing. AB - Recent event-related potential (ERP) and functional magnetic resonance imaging (fMRI) studies suggest that novelty processing may be involved in processes that recognize the meaning of a novel sound, during which widespread cortical regions including the right prefrontal cortex are engaged. However, it remains unclear how those cortical regions are functionally integrated during novelty processing. Because theta oscillation has been assumed to have a crucial role in memory operations, we examined local and inter-regional neural synchrony of theta band activity during novelty processing. Fifteen right-handed healthy university students participated in this study. Subjects performed an auditory novelty oddball task that consisted of the random sequence of three types of stimuli such as a target (1000Hz pure tone), novel (familiar environmental sounds such as dog bark, buzz, car crashing sound and so on), and standard sounds (950Hz pure tone). Event-related spectra perturbation (ERSP) and the phase-locking value (PLV) were measured from human scalp EEG during task. Non-parametric statistical tests were applied to test for significant differences between stimulus novelty and stimulus targets in ERSP and PLV. The novelty P3 showed significant higher amplitude and shorter latency compared with target P3 in frontocentral regions. Overall, theta activity was significantly higher in the novel stimuli compared with the target stimuli. Specifically, the difference in theta power between novel and target stimuli was most significant in the right frontal region. This right frontal theta activity was accompanied by phase synchronization with the left temporal region. Our results imply that theta phase synchronization between right frontal and left temporal regions underlie the retrieval of memory traces for unexpected but familiar sounds from long term memory in addition to working memory retrieval or novelty encoding. PMID- 25014408 TI - Frontal and parietal EEG asymmetries interact to predict attentional bias to threat. AB - Frontal and parietal electroencephalographic (EEG) asymmetries mark vulnerability to depression and anxiety. Drawing on cognitive theories of vulnerability, we hypothesise that cortical asymmetries predict attention to threat. Participants completed a dot-probe task in which bilateral face displays were followed by lateralised targets at either short (300ms) or long (1050ms) SOA. We also measured N2pc to face onset as an index of early attentional capture. At long SOA only, frontal and parietal asymmetry interacted to predict attentional bias to angry faces. Those with leftward frontal asymmetry showed no attentional bias. Among those with rightward frontal asymmetry those with low right parietal activity showed vigilance for threat, and those with high right parietal activity showed avoidance. Asymmetry was not related to the N2pc or to attentional bias at the short SOA. Findings suggest that trait asymmetries reflect function in a fronto-parietal network that controls attention to threat. PMID- 25014409 TI - Disturbances of spontaneous empathic processing relate with the severity of the negative symptoms in patients with schizophrenia: a behavioural pilot-study using virtual reality technology. AB - Behavioural and neuroimaging data have recently pointed out that empathy (feeling into someone else) is associated with mental imagery and transformation related to one's and other's visuo-spatial perspectives. Impairments of both empathic and visuo-spatial abilities have been observed in patients with schizophrenia. Especially, it has been suggested that schizophrenics are altered in spontaneously simulating another individual's first-person experience. However, there is so far only little evidence regarding the relationship between deficits in empathy and disturbances in spontaneous heterocentered coding in schizophrenia. In the present pilot-study, we tested with schizophrenic patients our behavioural paradigm that enables to measure from the bodily postures and movements whether individuals in ecologically more valid conditions are interacting with another individual by using egocentered - as in sympathy (feeling with someone else) - or heterocentered - as in empathy - visuo-spatial mechanisms. For that, ten patients and ten controls, standing and moving, interacted with a virtual tightrope walker, displayed life-sized, standing and moving as well. We show that patients with higher negative symptoms had, in most cases, deficits in spontaneously using heterocentered visuo-spatial mechanisms and employed preferentially an egocentered referencing to interact with the avatar. In contrast, preserved spontaneous heterocentered visuo-spatial strategies were not linked to a prevailing negative or positive symptomatology. Our data suggest that the severity of the negative symptoms in schizophrenia relates with disturbances of spontaneous ("on-line") empathic processing in association with lower scoring self-reported trait cognitive empathy. PMID- 25014410 TI - Reasoning from transitive premises: an EEG study. AB - Neuroimaging studies have contributed to a major advance in understanding the neural and cognitive mechanisms underpinning deductive reasoning. However, the dynamics of cognitive events associated with inference making have been largely neglected. Using electroencephalography, the present study aims at describing the rapid sequence of processes involved in performing transitive inference (A B; B C therefore "A C"; with AB meaning "A is to the left of B"). The results indicate that when the second premise can be integrated into the first one (e.g. A B; B C) its processing elicits a P3b component. In contrast, when the second premise cannot be integrated into the first premise (e.g. A B; D C), a P600-like components is elicited. These ERP components are discussed with respect to cognitive expectations. PMID- 25014411 TI - Cortical functional connectivity is associated with the valence of affective states. AB - The study investigates the relationships between the valence of affective states and the cortical patterns of functional connectivity. The information flow rate and direction were estimated by means of Directed Transfer Function (DTF), a multivariate method based on Granger causality. It was calculated on EEG activity recorded during mental imagery tasks. As a result, three regions were revealed as main network hubs, where the information outflow changed specifically with valence: the anterior orbitofrontal cortex, and the right posterior and right temporal area. The role of these structures in synchronizing the cortical affective network as well as in mediating different aspects of emotional state is discussed. PMID- 25014413 TI - Ultrastructure of the spermatozoa of Psammotettix striatus (Linnaeus) and Exitianus nanus (Distant) (Hemiptera: Auchenorrhyncha: Cicadellidae: Deltocephalinae). AB - Previous studies of insect spermatozoa indicate that these specialized cells have undergone significant morphological evolution and exhibit traits useful for reconstructing phylogenetic relationships. Although leafhoppers (Cicadellidae) are among the largest and most economically important insect families, few comparative studies of their spermatozoa have been published. Here, the ultrastructure of mature spermatozoa of two leafhoppers Psammotettix striatus (Linnaeus) and Exitianus nanus (Distant), representing two different tribes of the largest leafhopper subfamily, Deltocephalinae, was examined by light and transmission electron microscopy. The shape and ultrastructure of spermatozoa of the two species are very similar to those of other Cicadellidae as well as other Auchenorrhyncha, comprising a conical acrosome invaginated to form a subacrosomal space, a filiform homogeneously condensed nucleus, a lamellate centriolar adjunct connecting the nucleus with the mid-piece/flagellum, a long flagellum with a 9 + 9 + 2 axoneme pattern and two symmetrical mitochondrial derivatives with an orderly array of peripheral cristae, and two drop-shaped accessory bodies. They may be distinguished by the size of the sperm, and the shape of the nucleus, accessory bodies, and paracrystalline region of mitochondrial derivatives. The fine morphology and ultrastructure of spermatozoon in P. striatus and E. nanus are illustrated, along with a brief discussion of the implications for classification and phylogenetic analyses of the subfamily. PMID- 25014412 TI - Ceftriaxone preserves glutamate transporters and prevents intermittent hypoxia induced vulnerability to brain excitotoxic injury. AB - Hypoxia alters cellular metabolism and although the effects of sustained hypoxia (SH) have been extensively studied, less is known about chronic intermittent hypoxia (IH), commonly associated with cardiovascular morbidity and stroke. We hypothesize that impaired glutamate homeostasis after chronic IH may underlie vulnerability to stroke-induced excitotoxicity. P16 organotypic hippocampal slices, cultured for 7 days were exposed for 7 days to IH (alternating 2 min 5% O2-15 min 21% O2), SH (5% O2) or RA (21% O2), then 3 glutamate challenges. The first and last exposures were intended as a metabolic stimulus (200 uM glutamate, 15 min); the second emulated excitotoxicity (10 mM glutamate, 10 min). GFAP, MAP2, and EAAT1, EAAT2 glutamate transporters expression were assessed after exposure to each hypoxic protocol. Additionally, cell viability was determined at baseline and after each glutamate challenge, in presence or absence of ceftriaxone that increases glutamate transporter expression. GFAP and MAP2 decreased after 7 days IH and SH. Long-term IH but not SH decreased EAAT1 and EAAT2. Excitotoxic glutamate challenge decreased cell viability and the following 200 uM exposure further increased cell death, particularly in IH-exposed slices. Ceftriaxone prevented glutamate transporter decrease and improved cell viability after IH and excitotoxicity. We conclude that IH is more detrimental to cell survival and glutamate homeostasis than SH. These findings suggest that impaired regulation of extracellular glutamate levels is implicated in the increased brain susceptibility to excitotoxic insult after long-term IH. PMID- 25014414 TI - The antitumor effect of formosanin C on HepG2 cell as revealed by 1H-NMR based metabolic profiling. AB - Formosanin C (FC) is a pure compound isolated from Rhizoma Paridis. In the past years, antitumor effects of FC have been observed in several cultural cells and animal systems. However, there was no research particular on liver cancer. In this experiment, 3-(4, 5-dimethylthiazol diphenyltetrazolium bromide (MTT) dye reduction assay was used to evaluate cell viability of HepG2 cells with FC treatment. 4', 6-diamidino-2-phenylindole (DAPI) staining, Annexin V-FITC/PI assay and DNA fragment assay were applied to observe FC-induced apoptosis. Cell cycle analysis and NMR metabolic profiles were used to identify molecular mechanisms of FC in HepG2 cells. As a result, FC inhibited the growth of HepG2 cells through inducing apoptosis and S phase arrest. Cells cultured in the presence or absence of FC was different in metabolic profiles. The treatment decreased acetate, ethanol, choline and betaine, and increased butyrate, fatty acids, leucine and valine in HepG2 cells. In conclusion, metabolomic analysis of the exometabolome of FC-treated HepG2 cells, together with traditional methods such as apoptosis test and cell cycle analysis provided a holistic method for elucidating mechanisms of potential anti-cancer drug, FC. PMID- 25014415 TI - Ultra-performance liquid chromatography-mass spectrometry as a sensitive and powerful technology in lipidomic applications. AB - Lipidomics, the comprehensive illumination of lipid-based information in biology systems, involves in identifying lipids and profiling lipids and lipid-derived mediators. The development of lipidomics enables the characterization of lipid species and detailed lipid profiling in body fluid, tissue or cell, and allows for a wider understanding of the biological roles of lipid networks. Lipidomic research has been greatly facilitated by recent advances in ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and involved in lipid extraction, lipid identification and data analysis supporting applications from qualitative and quantitative assessment of multiple lipid species. UPLC technique, different mass spectrometry technique, lipid extraction and data analysis in lipidomics are reviewed. Afterwards, examples are provided on the use of UPLC-MS for finding lipid biomarkers in disease, drug, food, nutrition and plant fields. We also discuss the UPLC-MS-based lipidomics for the future perspectives and their potential problems. PMID- 25014416 TI - Exploration of the binding modes of buffalo PGRP1 receptor complexed with meso diaminopimelic acid and lysine-type peptidoglycans by molecular dynamics simulation and free energy calculation. AB - The peptidoglycan recognition proteins (PGRPs) are the key components of innate immunity, and are highly specific for the recognition of bacterial peptidoglycans (PGN). Among different mammalian PGRPs, the PGRP1 binds to murein PGN of Gram positive bacteria (lysine-type) and also have bactericidal activity towards Gram negative bacteria (diaminopimelic acid or Dap-type). Buffaloes are the major sources of milk and meat in Asian sub-continents and are highly exposed to bacterial infections. The PGRP activates the innate-immune signaling, but their studies has been confined to limited species due to lack of structural and functional information. So, to understand the structural constituents, 3D model of buffalo PGRP1 (bfPGRP1) was constructed and conformational and dynamics properties of bfPGRP1 was studied. The bfPGRP1 model highly resembled human and camel PGRP structure, and shared a highly flexible N-terminus and centrally placed L-shaped cleft. Docking simulation of muramyl-tripeptide, tetrapeptide, pentapeptide-Dap-(MTP-Dap, MTrP-Dap and MPP-Dap) and lysine-type (MTP-Lys, MTrP Lys and MPP-Lys) in AutoDock 4.2 and ArgusLab 4.0.1 anticipated beta1, alpha2, alpha4, beta4, and loops connecting beta1-alpha2, alpha2-beta2, beta3-beta4 and alpha4-alpha5 as the key interacting domains. The bfPGRP1-ligand complex molecular dynamics simulation followed by free binding energy (BE) computation conceded BE values of -18.30, -35.53, -41.80, -25.03, -24.62 and -22.30 kJ mol( 1) for MTP-Dap, MTrP-Dap, MPP-Dap, MTP-Lys, MTrP-Lys and MPP-Lys, respectively. The groove-surface and key binding residues involved in PGN-Dap and Lys-type interaction intended by the molecular docking, and were also accompanied by significant BE values directed their importance in pharmacogenomics, and warrants further in vivo studies for drug targeting and immune signaling pathways exploration. PMID- 25014417 TI - Identification of coregulators influenced by estrogen receptor subtype specific binding of the ER antagonists 4-hydroxytamoxifen and fulvestrant. AB - The aim of the present study was to investigate modulation of the interaction of ERalpha and ERbeta with coregulators in the ligand dependent responses induced by the ER antagonistic compounds 4OHT and fulvestrant. Comparison with the modulation index (MI) profiles for the ER agonist estradiol (E2) will elucidate whether differences in the (ant)agonist dependent interaction of ERalpha and ERbeta with coregulators expressed in MI profiles contribute to the differences in (ant)agonist responses. To this end, the selected ER antagonistic compounds were first characterized for intrinsic relative potency and efficacy towards ERalpha and ERbeta using ER selective U2OS reporter gene assays, and subsequently tested for ligand dependent modulation of the interaction of ERalpha and ERbeta with coregulators using the MARCoNI assay. Results obtained indicate a preference of 4OHT to antagonize ERbeta and find fulvestrant to be less ER specific. MARCoNI assay responses reveal that ERalpha and ERbeta mediated interaction with coregulators expressed in MI profiles are similar for 4OHT and fulvestrant and generally opposite to the MI profile of the ER agonist E2. Hierarchical clustering based on the MI profiles appeared able to clearly discriminate the two compounds with ER antagonistic properties from the ER agonist E2. Taken together the data reveal that modulation of the interaction of ERs with coregulators discriminates ER agonists from antagonists but does not discriminate between the less specific ER antagonist fulvestrant and the preferential ERbeta antagonistic compound 4OHT. It is concluded that differences in modulation of the interaction of ERalpha and ERbeta with coregulators contribute to the differences in ligand dependent responses induced by ER agonists and ER antagonists but the importance of the subtle differences in modulation of the interaction of ERs with coregulators between the ER antagonistic compounds 4OHT and fulvestrant for the ultimate biological effect remains to be established. PMID- 25014418 TI - A novel toxicity mechanism of CdSe nanoparticles to Saccharomyces cerevisiae: enhancement of vacuolar membrane permeabilization (VMP). AB - Cadmium selenide (CdSe) nanoparticles are implemented in a wide range of applications, but their potential risk to the ecosystem, especially to the organisms essential for the maintenance of ecosystem homeostasis, such as fungal populations, plants and bacteria, remains to be elucidated. In this study, we investigated their toxicity to one of the most important fungal model organisms, Saccharomyces cerevisiae. Growth inhibition assays revealed that the synthesized CdSe nanoparticles with the sizes of 20-30 nm had strong inhibitory effect on yeast growth (IC50=80 ppm). This toxicity was not attributed to mitochondrial dysfunction and autophagy, but was dependent on End3-mediated endocytosis, and was associated with reactive oxygen species (ROS) accumulation and an enhancement of vacuolar membrane permeabilization (VMP). These results reveal a key role of the vacuole during the interaction between CdSe nanoparticles and yeast cells. PMID- 25014420 TI - [In process citation]. PMID- 25014419 TI - Dynamic connectivity at rest predicts attention task performance. AB - Consistent spatial patterns of coherent activity, representing large-scale networks, have been reliably identified in multiple populations. Most often, these studies have examined "stationary" connectivity. However, there is a growing recognition that there is a wealth of information in the time-varying dynamics of networks which has neural underpinnings, which changes with age and disease and that supports behavior. Using factor analysis of overlapping sliding windows across 25 participants with Parkinson disease (PD) and 21 controls (ages 41-86), we identify factors describing the covarying correlations of regions (dynamic connectivity) within attention networks and the default mode network, during two baseline resting-state and task runs. Cortical regions that support attention networks are affected early in PD, motivating the potential utility of dynamic connectivity as a sensitive way to characterize physiological disruption to these networks. We show that measures of dynamic connectivity are more reliable than comparable measures of stationary connectivity. Factors in the dorsal attention network (DAN) and fronto-parietal task control network, obtained at rest, are consistently related to the alerting and orienting reaction time effects in the subsequent Attention Network Task. In addition, the same relationship between the same DAN factor and the alerting effect was present during tasks. Although reliable, dynamic connectivity was not invariant, and changes between factor scores across sessions were related to changes in accuracy. In summary, patterns of time-varying correlations among nodes in an intrinsic network have a stability that has functional relevance. PMID- 25014421 TI - Anthropometric parameters' cut-off points and predictive value for metabolic syndrome in women from Cartagena, Colombia. AB - Objective. To estimate anthropometric parameters' (APs) cut-off points and association for metabolic syndrome (MetS). Materials and methods. A cross sectional study was carried out with a total of 434 adult women from Cartagena de Indias, Colombia, in 2012. APs measured were waist circumference (WC), body mass index (BMI), body adiposity index (BAI), waist-hip ratio (WHR) and waist-height ratio (WHtR). Cut-off points were estimated by a receiver operating characteristic curve (ROC). Logistic regression was applied to estimate possible associations. Results. Cut-off points for WC, BMI, BAI, WHR and WHtR were 85 cm, 28 kg/m(2), 39%, 0.80 and 56, respectively. Only WHtR was associated to MetS (OR=1.11, CI95% [1.07-1.15]). Conclusion. WC cut-off point was higher than those proposed for Latin-American women by the Joint Interim Statement (JIS). WHtR had a low predictive value for MetS. PMID- 25014422 TI - [Food availability according to food security-insecurity among Mexican households]. AB - OBJECTIVE: To know the differences in food availability according to food insecurity level among the Mexican households. MATERIALS AND METHODS: We analyzed the database of the National Survey of Household's Incomes and Expenditures (n=27 445 households). Households were classified according to the Latin American and Caribbean Inventory of Food Security. The availability of each food group was estimated as grams per day per equivalent adult. RESULTS: 50.0% of Mexican households experienced some degree of food insecurity. Among households with food insecurity there was high availability of corn, wheat, egg, and sugars; but there was low availability of fresh fruits and vegetables, lean meat, poultry, seafood, milk, cheeses, and sweetened beverages. CONCLUSION: Although in households with food insecurity there is lower availability of most food groups (both with high nutrient density and with high energy density); they have higher availability of cheap foods, which in some cases are only source of energy but do not provide nutrients. PMID- 25014423 TI - [Validity of Pro Children Project questionnaire for assessing psychosocial factors of fruit and vegetable intake in Mexico]. AB - OBJECTIVE: To determine content and construct validity for the Mexican version of Pro Children Project questionnaire for assessing psychosocial factors, related to fruit and vegetable intake in samples of 10-12 year-old schoolchildren. MATERIALS AND METHODS: The questionnaire consisted of 87 items. It was administered to 2084 children in an instrumental study conducted in 2011 in Ciudad Juarez, Chihuahua, Mexico. RESULTS: Kappa statistic resulted in good agreement between experts (kappa=0.69), very good agreement in children (kappa=0.93). Seven factors were obtained that explained 37.87% of the variance in fruit and 48.18% of the variance in vegetable. Cronbach's alpha values were low to moderate (range 0.55 to 0.83). An internal structure of seven first order factors was confirmed in fruits and six linked to vegetables. CONCLUSION: The questionnaire provides sufficient validity for assessing psychosocial factors related to fruit and vegetable intake in 10-12 year old schoolchildren. Finally, implications of the findings in the test adaptation process for assessing psychosocial factors of fruit and vegetable intake and for future research in this instrument are discussed. PMID- 25014424 TI - [Between contradictions and risks: Mexican male adolescents' views about teenage pregnancy and its association with sexual behavior]. AB - OBJECTIVE: To explore the opinions of Mexican male adolescents regarding teenage pregnancy and analyze its association with sexual behavior. MATERIALS AND METHODS: This is a cross-sectional study using a self-administered questionnaire among a conventional sample of male students (15-19 years old) in eight public schools in Morelos and Mexico City. Analyses include multivariate models to identify the association between opinions and sexual behaviors. RESULTS: Overall, 68% agree that a teenage pregnancy is a negative event. In a hypothetical case, if a girlfriend got pregnant in this moment 56% would continue in the school whereas 18% would definitely abandon it. Those who affirm that a teenage pregnancy is something very bad have greater odds of using condoms (OR=1.8; p<0.05). CONCLUSIONS: Male adolescents' views about teenage pregnancy are associated with some sexual behaviors; however their opinions reflect several contradictions. The design of surveys directed exclusively to explore male adolescents' opinions about reproductive health is urgent. PMID- 25014425 TI - Clinical and epidemiological features of extrapulmonary tuberculosis in a high incidence region. AB - OBJECTIVE: To describe the clinical features of extrapulmonary tuberculosis (EXPTB) and to evaluate epidemiological data to search for potential explanations for its high frequency in the state of Aguascalientes, Mexico. MATERIALS AND METHODS: Clinical records of all patients with tuberculosis seen in Aguascalientes in 2008 were reviewed, and official databases were analyzed. RESULTS: EXPTB comprised 60.5% of the 86 cases evaluated, being lymph nodes the main site affected. Patients with EXPTB were younger and more obese than subjects with pulmonary tuberculosis (PTB). One third of cases in either group had diabetes, a frequency much higher than expected. Epidemiological analysis showed that PTB incidence, but not EXPTB incidence, decreases as geographical altitude increases, and had a descendent trend from 1997 to 2011. CONCLUSIONS: The lower frequency of PTB (due to its inverse relationship with altitude and its descendent trend in last years) might explain the high frequency of EXPTB. Obesity appeared to protect against developing pulmonary involvement, and diabetes was more frequent than expected among PTB and EXPTB cases. PMID- 25014426 TI - Risk factors for cardiovascular disease among Mexican-American adults in the United States and Mexico: a comparative study. AB - OBJECTIVE: To compare cardiovascular disease (CVD) risk factors in a cohort of Mexican health workers with representative samples of US-born and Mexico-born Mexican-Americans living in the US. MATERIALS AND METHODS: Data were obtained from the Mexican Health Worker Cohort Study (MHWCS) in Mexico and the National Health and Nutrition Examination Survey (NHANES) IV 1999-2006 in the US. Regression analyses were used to investigate CVD risk factors. RESULTS: In adjusted analyses, NHANES participants were more likely than MHWCS participants to have hypertension, high total cholesterol, diabetes, obesity, and abdominal obesity, and were less likely to have low HDL cholesterol and smoke. Less educated men and women were more likely to have low HDL cholesterol, obesity, and abdominal obesity. CONCLUSIONS: In this binational study, men and women enrolled in the MHWCS appear to have fewer CVD risk factors than US-born and Mexico-born Mexican-American men and women living in the US. PMID- 25014427 TI - ATM polymorphisms IVS24-9delT, IVS38-8T>C, and 5557G>A in Mexican women with familial and/or early-onset breast cancer. AB - OBJECTIVE: To assess whether in Mexican population the frequencies of ATM polymorphisms IVS24-9delT, IVS38-8-T>C, and 5557G>A in breast cancer (BC) cases and healthy controls were different from those found in other countries. MATERIALS AND METHODS: Frequencies of polymorphisms conferring BC risk IVS24 9delT, IVS38-8T>C, and 5557G>A were analyzed by PCR-RFLP in 94 patients with familial and/or early onset BC, and 97 healthy controls randomly selected. Allele frequencies analysis was done using chi(2) and Hardy-Weinberg test. RESULTS: Frequencies of heterozygous were: for 5557G>A, 13% cases, 0%controls (p=0.0009); for IVS24-9delT, 21% cases, 8% controls (p=0.0122); for IVS38-8T>C, only one case. 5557G>A and IVS24-9delT were more frequent in cases than in controls. The allelic frequencies found in 5557G>A are similar to those described by Gonzalez Hormazabal in Chile. CONCLUSION: The similarity of results in this polymorphism between Chilean and Mexican populations may be due to both being crossbred with an Amerindian-Spanish component, while differences may be due to fact that Chilean population has a greater European component than Mexican's. PMID- 25014428 TI - Household risk factors associated to infestation of Triatoma dimidiata, the Chagas disease vector in Central Region of Veracruz, Mexico. AB - OBJECTIVE: To evaluate risk factors facilitating the colonization of dwellings by Triatoma dimidiata in the central region of the state of Veracruz. MATERIALS AND METHODS: We applied socioeconomic questionnaires and entomologic surveys in three localities (Chavarrillo, Soyacuautla and Arroyo Agrio) in central Veracruz involving 115 households. RESULTS: We found that the main risk factors were the predominance of unplastered walls and particularly those made of light weight aggregate concrete blocks and wood. At Chavarrillo, houses usually have unplastered walls, whereas in Soyocuautla walls are commonly manufactured with wood. In Arroyo Agrio, the phenomenon was seasonal, and bugs were commonly found in the dry season, particularly in relatively new houses, less than 20 years old. CONCLUSIONS: These results help to improve the surveillance capacity for this vector and the control strategies to reduce the transmission of Chagas disease in the state of Veracruz and other sites where this species is present. PMID- 25014429 TI - [Reflections on public-private participation in healthcare]. AB - Health care is one of the major issues in social policy, affected by multiple factors, such as the increase in health costs, crisis, and the degree of private participation in the financing of services. In this essay we reflect on this participation of the private sector in health care, with Brazil as a reference country and taking into account member states of the Union of South American Nations. Based on a qualitative study using data from national and international organizations, we found significant private participation in health care of countries in various continents, with an increase of public and private spending between 2000 and 2010. Regardless of the adopted health system, there was an increase of private spending in most countries analyzed, which emphasizes the need to further evaluate the performance of public and private sectors, as well as the regulatory frameworks for their participation in health care, thus enabling policies that promote quality improvement and the expansion of coverage. PMID- 25014432 TI - Momentum-resolved hidden-order gap reveals symmetry breaking and origin of entropy loss in URu2Si2. AB - Spontaneous symmetry breaking in physical systems leads to salient phenomena at all scales, from the Higgs mechanism and the emergence of the mass of the elementary particles, to superconductivity and magnetism in solids. The hidden order state arising below 17.5 K in URu2Si2 is a puzzling example of one of such phase transitions: its associated broken symmetry and gap structure have remained longstanding riddles. Here we directly image how, across the hidden-order transition, the electronic structure of URu2Si2 abruptly reconstructs. We observe an energy gap of 7 meV opening over 70% of a large diamond-like heavy-fermion Fermi surface, resulting in the formation of four small Fermi petals, and a change in the electronic periodicity from body-centred tetragonal to simple tetragonal. Our results explain the large entropy loss in the hidden-order phase, and the similarity between this phase and the high-pressure antiferromagnetic phase found in quantum-oscillation experiments. PMID- 25014431 TI - Incorporation of copper nanoparticles into paper for point-of-use water purification. AB - As a cost-effective alternative to silver nanoparticles, we have investigated the use of copper nanoparticles in paper filters for point-of-use water purification. This work reports an environmentally benign method for the direct in situ preparation of copper nanoparticles (CuNPs) in paper by reducing sorbed copper ions with ascorbic acid. Copper nanoparticles were quickly formed in less than 10 min and were well distributed on the paper fiber surfaces. Paper sheets were characterized by x-ray diffraction, scanning electron microscopy, energy dispersive x-ray spectroscopy, and atomic absorption spectroscopy. Antibacterial activity of the CuNP sheets was assessed for by passing Escherichia coli bacteria suspensions through the papers. The effluent was analyzed for viable bacteria and copper release. The CuNP papers with higher copper content showed a high bacteria reduction of log 8.8 for E. coli. The paper sheets containing copper nanoparticles were effective in inactivating the test bacteria as they passed through the paper. The copper levels released in the effluent water were below the recommended limit for copper in drinking water (1 ppm). PMID- 25014433 TI - Expression and colocalization patterns of calbindin-D28k, calretinin and parvalbumin in the rat hypothalamic arcuate nucleus. AB - Calcium binding proteins (CaBPs) form a diverse group of molecules that function as signal transducers or as intracellular buffers of Ca(2+) concentration. They have been extensively used to histochemically categorize cell types throughout the brain. One region which has not yet been characterized with regard to CaBP expression is the hypothalamic arcuate nucleus, which plays a vital role in neuroendocrine control and the central regulation of energy metabolism. Using in situ hybridization and immunofluorescence, we have investigated the cellular distribution of the three CaBPs, calbindin-D28k (CB), calretinin (CR) and parvalbumin (PV) in the rat arcuate nucleus. Both mRNA and immunoreactivity was detected in the arcuate nucleus for CB - located in the medial aspects - and CR - located ventrolaterally. No PV mRNA was detected in the arcuate nucleus. Immunofluorescence results for PV were ambiguous; while one antibody detected a group of cell somata, a different antibody failed to visualize any arcuate nucleus cell profiles. Using double-labeling, neither of the examined CaBPs were observed in cells immunoreactive for the signaling molecules agouti gene-related protein, tyrosine hydroxylase, neurotensin, growth hormone-releasing hormone, somatostatin, enkephalin, dynorphin or galanin. We did, however, observe CB- and CR-immunoreactivity, in two distinct populations of neurons immunoreactive for the melanocortin peptide alpha-melanocyte-stimulating hormone. These data identify distinct subpopulations of arcuate neurons defined by their expression of CaBPs and provide further support for differentiation between subpopulations of anorexigenic melanocortin neurons. PMID- 25014434 TI - Biodegradable large compound vesicles with controlled size prepared via the self assembly of branched polymers in nanodroplet templates. AB - Generally, it is very difficult to control the size of large compound vesicles. Here, we introduce a novel method for the preparation of biodegradable large compound vesicles with controlled size and narrow size distribution by using aqueous nanodroplets as templates. PMID- 25014435 TI - Multiple sparse volumetric priors for distributed EEG source reconstruction. AB - We revisit the multiple sparse priors (MSP) algorithm implemented in the statistical parametric mapping software (SPM) for distributed EEG source reconstruction (Friston et al., 2008). In the present implementation, multiple cortical patches are introduced as source priors based on a dipole source space restricted to a cortical surface mesh. In this note, we present a technique to construct volumetric cortical regions to introduce as source priors by restricting the dipole source space to a segmented gray matter layer and using a region growing approach. This extension allows to reconstruct brain structures besides the cortical surface and facilitates the use of more realistic volumetric head models including more layers, such as cerebrospinal fluid (CSF), compared to the standard 3-layered scalp-skull-brain head models. We illustrated the technique with ERP data and anatomical MR images in 12 subjects. Based on the segmented gray matter for each of the subjects, cortical regions were created and introduced as source priors for MSP-inversion assuming two types of head models. The standard 3-layered scalp-skull-brain head models and extended 4-layered head models including CSF. We compared these models with the current implementation by assessing the free energy corresponding with each of the reconstructions using Bayesian model selection for group studies. Strong evidence was found in favor of the volumetric MSP approach compared to the MSP approach based on cortical patches for both types of head models. Overall, the strongest evidence was found in favor of the volumetric MSP reconstructions based on the extended head models including CSF. These results were verified by comparing the reconstructed activity. The use of volumetric cortical regions as source priors is a useful complement to the present implementation as it allows to introduce more complex head models and volumetric source priors in future studies. PMID- 25014436 TI - The key role of vibrational entropy in the phase transitions of dithiazolyl-based bistable magnetic materials. AB - The neutral radical 1,3,5-trithia-2,4,6-triazapentalenyl (TTTA) is a prototype of molecule-based bistable materials. TTTA crystals undergo a first-order phase transition between their low-temperature diamagnetic and high-temperature paramagnetic phases, with a large hysteresis loop that encompasses room temperature. Here, based on ab initio molecular dynamics simulations and new X ray measurements, we uncover that the regular stacking motif of the high temperature polymorph is the result of a fast intra-stack pair-exchange dynamics, whereby TTTA radicals continually exchange the adjacent TTTA neighbour (upper or lower) with which they form an eclipsed dimer. Such unique dynamics, observed in the paramagnetic phase within the whole hysteresis loop, is the origin of a significant vibrational entropic gain in the low-temperature to high-temperature transition and thereby it plays a key role in driving the phase transition. This finding provides a new key concept that needs to be explored for the rational design of novel molecule-based bistable magnetic materials. PMID- 25014437 TI - Aggressive transsphenoidal resection of tumors invading the cavernous sinus in patients with acromegaly: predictive factors, strategies, and outcomes. AB - OBJECT: Cavernous sinus (CS) invasion is the most important preoperative predictor of remission in the surgical treatment of growth hormone-producing pituitary adenomas. The purpose of this study was to evaluate the effectiveness of an aggressive technique for removal of tumors invading the CS in patients with acromegaly. METHODS: The authors retrospectively reviewed the cases of 150 consecutive patients with acromegaly who underwent primary transsphenoidal surgery in 2010 and 2011. The authors reviewed preoperative Knosp grade, intraoperative findings, histology of the medial wall of the CS, and surgical outcome according to the current consensus criteria for acromegaly. RESULTS: Cavernous sinus invasion was identified in 55 patients (36.7%): definite CS involvement by the tumor was observed under direct vision in 41 patients (74.5%), while invasion was histologically verified in 39 patients (70.9%). Invasion increased in frequency with the higher Knosp grade but was observed in 14.4% (13 of 90) of Grade 0 and 1 tumors. Overall, the remission rate fulfilling stringent criteria was 84.7% (127 of 150). Although CS invasion was significantly associated with an unfavorable outcome (p < 0.0001), remission was achieved in 69.1% (38 of 55) of patients with invasion. No major complications occurred in this series. CONCLUSIONS: Cavernous sinus invasion is the most significant, independent predictor of unfavorable outcome. Confirmation of invasion requires direct observation within the CS regardless of the microscope or endoscope used. Particularly in cases in which only the medial wall is involved, histological verification is always necessary to detect the occult invasion. Direct removal of the invading tumor, by sharp excision of the medial wall of the CS, is effective and safe and increases the chance of remission. PMID- 25014438 TI - Trigeminal neuralgia caused by a trigeminocerebellar artery. AB - This 31-year-old woman presented with typical right trigeminal neuralgia caused by a trigeminocerebellar artery, manifesting as pain uncontrollable with medical treatment. Preoperative neuroimaging studies demonstrated that the offending artery had almost encircled the right trigeminal nerve. This finding was confirmed intraoperatively, and decompression was completed. The neuralgia resolved after the surgery; the patient had slight transient hypesthesia, which fully resolved within the 1st month after surgery. The neuroimaging and intraoperative findings showed that the offending artery directly branched from the upper part of the basilar artery and, after encircling and supplying tiny branches to the nerve root, maintained its diameter and coursed toward the rostral direction of the cerebellum, which indicated that the artery supplied both the trigeminal nerve and the cerebellum. The offending artery was identified as the trigeminocerebellar artery. This case of trigeminal neuralgia caused by a trigeminocerebellar artery indicates that this variant is important for a better understanding of the vasculature of the trigeminal nerve root. PMID- 25014439 TI - Editorial: management of invasion by pituitary adenomas. PMID- 25014441 TI - Value-based neurosurgery: measuring and reducing the cost of microvascular decompression surgery. AB - OBJECT: Care providers have put significant effort into optimizing patient safety and quality of care. Value, defined as meaningful outcomes achieved per dollar spent, is emerging as a promising framework to redesign health care. Scarce data exist regarding cost measurement and containment for episodes of neurosurgical care. The authors assessed how cost measurement and strategic containment could be used to optimize the value of delivered care after the implementation and maturation of quality improvement initiatives. METHODS: A retrospective study of consecutive patients undergoing microvascular decompression was performed. Group 1 comprised patients treated prior to the implementation of quality improvement interventions, and Group 2 consisted of those treated after the implementation and maturation of quality improvement processes. A third group, Group 3, represented a contemporary group studied after the implementation of cost containment interventions targeting the three most expensive activities: pre incision time in the operating room (OR) and total OR time, intraoperative neuromonitoring (IOM), and bed assignment (and overall length of stay [LOS]). The value of care was assessed for all three groups. RESULTS: Forty-four patients were included in the study. Average preparation time pre-incision decreased from 73 to 65 to 45 minutes in Groups 1, 2, and 3, respectively. The average total OR time and OR cost were 434 minutes and $8513 in Group 1; 348 minutes and $7592 in Group 2; and 407 minutes and $8333 in Group 3. The average cost for IOM, excluding electrode needles, was $1557, $1585, and $1263, respectively, in Groups 1, 2, and 3. Average total cost for bed assignment was $5747, $5198, and $4535, respectively, in Groups 1, 2, and 3. The average total LOS decreased from 3.16 days in Group 1 to 2.14 days in Group 3. Complete relief of or a significant decrease in preoperative symptomatology was achieved in 42 of the 44 patients, respectively. Overall, the average cost of a surgical care episode (index hospitalization + readmission/reoperation) decreased 25% from Group 1 to 3. CONCLUSIONS: Linking cost-containment and cost-reduction strategies to ongoing outcome improvement measures is an important step toward the optimization of value-based delivery of care. PMID- 25014440 TI - Bleeding propensity of cavernous malformations: impact of tight junction alterations on the occurrence of overt hematoma. AB - OBJECT: Endothelial tight junction (TJ) expression is mostly absent in cerebral cavernous malformations (CMs), which causes increased perilesional erythrocyte and fluid oozing. However, in a subset of CM lesions, foci of preserved TJ staining are observed along endothelial cell contacts. The clinical relevance of this finding is unclear. This study investigates the relevance of the focal TJ protein expression and its association with CM bleeding propensity. METHODS: Immunohistochemical staining for the TJ proteins claudin-5, occludin, and ZO-1 was performed on 32 CM specimens that were resected during 2008-2010. The patients were allocated to 2 groups according to TJ protein expression, and the clinical and radiological parameters of aggressiveness were analyzed and compared. RESULTS Complete absence of TJ expression was identified in 20 specimens, and focal TJ protein expression in 12. CMs without TJ immunoreactivity were significantly larger (p = 0.022) and had a significantly greater propensity for development of frank hematomas (p = 0.028) and perilesional edema (p = 0.013). Symptom severity, multiplicity, developmental venous anomaly (DVA) presence, and CM location did not show a significant difference depending on TJ expression. CONCLUSIONS: In a univariate analysis the authors observed significantly less propensity for frank hematomas and perilesional edema as well as smaller size in CM lesions with focal TJ expression compared with CMs without TJ expression. The observed difference in TJ protein expression might be the reason for differences in bleeding propensity of the CM lesions. Although this finding cannot be used in predictive manner at this time, it is a basis for further multivariate analyses of possible CM biological predictors. PMID- 25014442 TI - [Role of distance learning in the education and the training of the investigator]. PMID- 25014443 TI - [Role of Angptl4 in nephrotic syndrome: a two-faced protein]. PMID- 25014444 TI - [Protection of vascular integrity in reperfusion during stroke]. PMID- 25014445 TI - [HIV-2 reveals an antiviral mechanism of detection by innate immunity]. PMID- 25014446 TI - [Alzheimer disease and endosomal traffic in neurons]. PMID- 25014447 TI - [TTC7A, a critical effector for the intestinal and immune system homeostasis]. PMID- 25014449 TI - [Decreasing dynamin 2 to rescue myotubular myopathy]. PMID- 25014448 TI - [TET-OGT interaction potentiates transcription by regulating histone H3 methylation]. PMID- 25014450 TI - [Tanycytes gate leptin transport into the hypothalamus]. PMID- 25014451 TI - [Plasticity of the blood-hypothalamus barrier: a role in energy homeostasis]. PMID- 25014452 TI - [V-ATPase is a pH sensor controlling vesicular membrane fusion]. PMID- 25014453 TI - [Endothelial junctions: exploiting their instability in the development of biomarkers for vascular remodelling]. PMID- 25014454 TI - [Superior colliculus as a subcortical center for visual selection]. AB - Our visual system has limited resources, which need to be allocated in priority to the most relevant elements of the environment. The brain centers of this allocation mechanism, called visual attention, have been studied primarily in cortex. In this review, we describe the role of the superior colliculus, a structure of the brainstem, in attention control. This nucleus exerts its influence on visual selection independently of cortical attentional mechanisms. The exact nature of the subcortical circuits involved remains unknown but it can be hypothesized that the loop connecting the superior colliculus to the basal ganglia are a central actor of this subcortical selection process. PMID- 25014455 TI - [Embryo implantation: role of interleukin 1 family members]. AB - Endometrial receptivity to embryo implantation is one of the fundamental features of reproduction. Success of natural or assisted embryo implantation is low (20 25%). Implantation remains the result of a successful collaboration, tightly regulated and closely coordinated, between maternal and embryonic tissues located at the crossroads of endocrinology and immunology. In scientific terms, this collaboration is a mystery of human reproduction. The implanted blastocyst within the endometrium is dependent on a fine-tuned synchronization. Therefore, an accurate dialogue between the mother and the embryo is timely required to orchestrate mutual and well-synchronized changes in the developing embryo and maternal responsiveness in order to achieve a successful implantation. Maternal derived mediators, such as steroid hormones, matrix-degrading enzymes, integrins, cytokines, chemokines, and many embryonic growth factors could be involved in the feto-maternal dialogue. Therefore, what is the maternal molecular signature compatible with embryo implantation? PMID- 25014456 TI - [What the study of seminal fluid proteins in Drosophila tells us about the evolution of reproduction]. AB - Decrease in male fertility observed in the past decades have involved sperm quantity and quality disorders. However, decrease in quality or quantity of seminal fluid may also trigger drastic reduction of female and also male fertility. The present paper documents on the composition of seminal fluid, the consequences on sperm cells and on the physiological and behavioral effects towards females. The work evidences the crucial role of seminal fluid in the postcopulatory interactions between the sexes and illustrates the selective effects in the male-female coevolution. PMID- 25014457 TI - [Retrotransposons: selfish DNA or active epigenetic players in somatic cells?]. AB - Transposable elements (TE) represent around 40% of the human genome. They are endogenous mobile DNA sequences able to jump and duplicate in the host genome. TE have long been considered as "junk" DNA but are now believed to be important regulators of gene expression by participating to the establishment of the DNA methylation profile. Recent advances in genome sequencing reveals a higher transposition frequency and TE driven gene expression in somatic cells than previously thought. As TE propagation is deleterious and may be involved in oncogenic mechanisms, host cells have developed silencing mechanisms mainly described in germinal and embryonic cells. However, somatic cells are also proned to TE transposition and use specific mechanisms involving tumor suppressor proteins including p53, Rb and PLZF. These transcription factors specifically target genomic retrotransposon sequences, histone deacetylase and DNA methylase activities, inducing epigenetic modifications related to gene silencing. Thus, these transcription factors negatively regulate TE expression by the formation of DNA methylation profil in somatic cells possibly associated with oncogenic mechanisms. PMID- 25014458 TI - [Immunological synapse is a dynamic signaling platform for T cell activation]. AB - Adaptive immune responses are initiated by the recognition of antigens by T lymphocytes. Antigen recognition triggers the generation of immunological synapses. These are dynamic and finely organized cell-cell contacts formed between T lymphocytes and antigen presenting cells. Immunological synapse formation results from a major T cell reorganization process, involving the polarization of the actin cytoskeleton, the microtubule network and the intracellular vesicle traffic. These processes facilitate the generation, the dynamics and the regulation of molecular complexes at the synapse that are responsible for T cell activation. The human immunodeficiency virus (HIV) targets in various manners immunological synapse generation and function, thus modifying the capacity of infected T cells to respond to further antigen stimulation. PMID- 25014459 TI - [A first outbreak of Ebola virus in West Africa]. PMID- 25014460 TI - [Cancer research: a privileged field of investigation on chance, reductionism and holism]. AB - The debate between reductionism and anti-reductionism, dealing with the ultimate constituents of the world, is one of the fundamental issues in the philosophy of science. However, in biology, reductionism is less of an ontological and more of an epistemological question: it argues that the explanation of biological processes resides in deciphering the genetic code of living entities. This position is still prevalent in cancer biology, which has long been defined as a cellular process where genetic alterations are responsible for aberrant proliferation. While the hypothesis of somatic mutations remains the central theoretical model, a bundle of experimental data reveals how important the disturbances of tissue organisation are in cancer development, leading to a renewal of holistic and organicist approaches. This latter perspective in particular attempts to contextualise and rethink the centrality of the genetic level by proposing a new conception of cancerogenesis as a tissue disease. PMID- 25014461 TI - [Hypotheses for the genesis of cancer: a historical perspective]. AB - The explanation of cancer has always been tightly related to the state of knowledge in biology, and its transformations. The present situation is not different. New techniques, such as deep sequencing, are rapidly moving our vision of cancer in an impredictable way. Systems biology, epigenetics, and the study of stem cells are generating new hypotheses on cancer and its evolution. New roles for aleatory events in the genesis of cancer have been proposed. In the traditional opposition between holism and reductionism, organisms and molecules, an intermediary level, the cancer cell, seems to be the most appropriate to study oncogenesis. PMID- 25014462 TI - [A reductionnist approach of cancer]. AB - According to a reductionnist view, a malignant tumour emerges and evolves as a consequence of genetic damages that accumulate in a cell. These damages generate a major clone and a number of sub-clones. A dynamic equilibrium emerges between these sub-clones in a given environment. Upon a multiform selective pressure, a great heterogeneity can appear in the primary tumour, between the primary tumour and its metastases, and between metastases in diverse tissues. The ability to identify this heterogeneity in installed tumours, and the detection of tumour cells before the appearance of this intra-tumour complexity, are major challenges in current oncology. PMID- 25014463 TI - [Cancer and the elusive cancer genes]. AB - For almost a century, the somatic mutation theory (SMT) has been the prevalent theory to explain carcinogenesis. The SMT posits that the accumulation of mutations in the genome of a single normal cell is responsible for the transformation of such cell into a neoplasm. Implicitly, this theory claims that the default state of cells in metazoan is quiescence and that cancer is a cell based, genetic and molecular disease. From lessons learned while performing our own research on control of cell proliferation and while adopting an organicist perspective, in 1999, we proposed a competing theory, the tissue organization field theory (TOFT). In contraposition to the SMT, (1) the TOFT posits that cancer is a tissue-based disease whereby carcinogens (directly) and mutations in the germ-line (indirectly) may alter normal interactions between the stroma and their adjacent epithelium. And (2) the TOFT explicitly acknowledges that the default state of all cells is proliferation and motility, a premise that is relevant to and compatible with evolutionary theory. Theoretical arguments and experimental evidence are presented to compare the merits of the original SMT and its variants and those of the TOFT in organizing principles, construct objectivity, and ultimately explain carcinogenesis. PMID- 25014464 TI - [Stochastic phenomena and the tumoral process]. AB - In the reductionist perspective, genetic modifications are considered to initiate cancer. Their appearance is a stochastic phenomenon, but there are some biases linked to DNA sequence or exposure to mutagenic agents for instance. Cancer genome sequencing has shown a high inter- and intra-tumoral heterogeneity, sometimes questioning the genetic origin of cancer. Other stochastic processes are also studied in cancer, especially epigenetic modifications. They have a major role in diversifying phenotypes among cancer cells in the progression steps, but might also provide an alternative to genetic theories of cancer initiation. Nevertheless, the reductionist framework remains dominant here. Finally, stochastic cell-to-cell variations in gene expression constitute a third class of stochastic phenomena that can be considered as causal factors in cancer. Highlighting the role of high gene expression variability due to disruption of cellular interactions and communications allows avoiding reductionism by considering the interplay between genetic and tissue levels at every step of the disease. No organization level is privileged in this alternative theory. PMID- 25014465 TI - [How does the fate intervene in the debate between holism and reductionism? conclusion of the file cancer/Haredhol]. PMID- 25014466 TI - [Monshot projects in biology]. AB - Three recent and very large projects aim to integrate several "omics" approaches in order to promote pro-active medicine and to create a "Wellness industry". PMID- 25014467 TI - [Symmetric or asymmetric division: sonic Hedgehog controls the fate of neural stem cells]. PMID- 25014468 TI - The necessity for increased attention to pulsed low-level laser therapy. PMID- 25014469 TI - Views on death with regard to end-of-life care preferences among cancer patients at a Japanese university hospital. AB - OBJECTIVE: This study investigates the views on death among cancer patients in Japan and examines how these views are related to age, sex, and physical condition. We also investigate how these views are related to where patients would like to spend their final days and whether or not they would like to be told how long they have left to live. METHOD: We targeted 450 cancer patients receiving outpatient treatment in the radiology department at the University of Tokyo Hospital. We used the Death Attitudes Inventory (DAI) developed by Hirai to measure attitudes about death. RESULTS: Of the 450 patients approached, we received responses from 310 (69% collection rate). The results of the t test and one-way ANOVA showed that, in terms of "death anxiety/fear," the under-65 group (17.73 +/- 6.69) scored significantly higher than the 65-and-over group (15.43 +/ 7.69, t = 2.685, df = 280, p < 0.01); the group with KPS scores 70 or above (16.88 +/- 7.21) scored higher than the group with KPS scores below 70 (12.73 +/- 7.09, t = 2.168, df = 280, p = 0.03); and no significant difference was found for sex, metastasis, or treatment stage. SIGNIFICANCE OF RESULTS: Our results demonstrate that, although views on death among cancer patients may differ according to sex, age, and physical condition, taking these factors into account when understanding such views can be useful in predicting where patients may wish to spend their final days. PMID- 25014470 TI - Reducing the inversion degree of MnFe2O4 nanoparticles through synthesis to enhance magnetization: evaluation of their (1)H NMR relaxation and heating efficiency. AB - Manganese ferrite (MnFe2O4) nanoparticles of identical size (9 nm) and with different inversion degrees were synthesized under solvothermal conditions as a candidate theranostic system. In this facile approach, a long-chain amine, oleylamine, was utilized as a reducing and surface-functionalizing agent. The synthesized nanoparticles were shown to have a cubic-spinel structure as characterized by TEM and XRD patterns. Control over their inversion degree was achieved by a simple change of manganese precursor from Mn(acac)2 to Mn(acac)3. The variation in the inversion degree is ascribed to the partial oxidation of Mn(2+) to Mn(3+), as was evidenced by X-ray absorption near edge structure spectroscopy and extended X-ray absorption fine structure spectroscopy at both the Fe and Mn K-edges. The reduction of the inversion degree from 0.42 to 0.22 is close to the corresponding bulk value of 0.20 and led to elevated magnetization (65.7 emu g(-1)), in contrast to the Neel temperature, which was decreased owing to the weaker superexchange interactions between the tetrahedral and octahedral sites within the spinel structure. In order to evaluate the performance of these nanoprobes as a possible bifunctional targeting system, the (1)H NMR relaxation of the samples was tested together with their specific loss power under an alternating magnetic field as a function of concentration. The hydrophobic as prepared MnFe2O4 nanoparticles converted to hydrophilic nanoparticles with cetyltrimethylammonium bromide (CTAB). The MnFe2O4 nanoparticles, well-dispersed in aqueous media, were shown to have r2 relaxivity of up to 345.5 mM(-1) s(-1) and heat release of up to 286 W g(-1), demonstrating their potential use for bioapplications. PMID- 25014471 TI - Enantioselective synthesis of gamma-tetrasubstituted nitrosulfonyl carboxylates and amides via L-tert-leucine-derived-squaramide catalyzed conjugate addition of nitrosulfones to acrylates and acrylamides. AB - Michael addition of alpha-nitrosulfones to aryl- and alkyl acrylates and acrylamides proceeds in the presence of 5-10 mol% of an amino acid derived new organocatalyst to provide gamma-tetrasubstituted gamma-nitro-gamma-sulfonyl carboxylates and amides in excellent yields and enantioselectivities. Scale-up of the reaction to multi-grams, convenient recovery of the catalyst and its recyclability without any drop in yield and selectivity are attractive features of this methodology. PMID- 25014472 TI - Tumor growth in complex, evolving microenvironmental geometries: a diffuse domain approach. AB - We develop a mathematical model of tumor growth in complex, dynamic microenvironments with active, deformable membranes. Using a diffuse domain approach, the complex domain is captured implicitly using an auxiliary function and the governing equations are appropriately modified, extended and solved in a larger, regular domain. The diffuse domain method enables us to develop an efficient numerical implementation that does not depend on the space dimension or the microenvironmental geometry. We model homotypic cell-cell adhesion and heterotypic cell-basement membrane (BM) adhesion with the latter being implemented via a membrane energy that models cell-BM interactions. We incorporate simple models of elastic forces and the degradation of the BM and ECM by tumor-secreted matrix degrading enzymes. We investigate tumor progression and BM response as a function of cell-BM adhesion and the stiffness of the BM. We find tumor sizes tend to be positively correlated with cell-BM adhesion since increasing cell-BM adhesion results in thinner, more elongated tumors. Prior to invasion of the tumor into the stroma, we find a negative correlation between tumor size and BM stiffness as the elastic restoring forces tend to inhibit tumor growth. In order to model tumor invasion of the stroma, we find it necessary to downregulate cell-BM adhesiveness, which is consistent with experimental observations. A stiff BM promotes invasiveness because at early stages the opening in the BM created by MDE degradation from tumor cells tends to be narrower when the BM is stiffer. This requires invading cells to squeeze through the narrow opening and thus promotes fragmentation that then leads to enhanced growth and invasion. In three dimensions, the opening in the BM was found to increase in size even when the BM is stiff because of pressure induced by growing tumor clusters. A larger opening in the BM can increase the potential for further invasiveness by increasing the possibility that additional tumor cells could invade the stroma. PMID- 25014473 TI - Punishment does not promote cooperation under exploration dynamics when anti social punishment is possible. AB - It has been argued that punishment promotes the evolution of cooperation when mutation rates are high (i.e. when agents engage in 'exploration dynamics'). Mutations maintain a steady supply of agents that punish free-riders, and thus free-riders are at a disadvantage. Recent experiments, however, have demonstrated that free-riders sometimes also pay to punish cooperators. Inspired by these empirical results, theoretical work has explored evolutionary dynamics where mutants are rare, and found that punishment does not promote the evolution of cooperation when this 'anti-social punishment' is allowed. Here we extend previous theory by studying the effect of anti-social punishment on the evolution of cooperation across higher mutation rates, and by studying voluntary as well as compulsory Public Goods Games. We find that for intermediate and high mutation rates, adding punishment does not promote cooperation in either compulsory or voluntary public goods games if anti-social punishment is possible. This is because mutations generate agents that punish cooperators just as frequently as agents that punish defectors, and these two effects cancel each other out. These results raise questions about the effectiveness of punishment for promoting cooperation when mutations are common, and highlight how decisions about which strategies to include in the strategy set can have profound effects on the resulting dynamics. PMID- 25014474 TI - A study of spermatozoan swimming stability near a surface. AB - The swimming stability of spermatozoa with a specified planar beat pattern in the presence of a no-slip flat surface is explored in a modelling study exploiting direct numerical computation via the boundary element method and dynamical systems theory. Parameter sweeps varying the sperm head morphology and flagellar beat pattern wavenumber are conducted and reveal that stable surface swimming is a robust hydrodynamical phenomenon across extensive parameter values, emphasising that diverse sperm will readily swim adjacent to a surface without detailed feedback. There is little sensitivity to the details of the sperm head morphologies considered and, in particular, cells with human sperm head geometries are well approximated by those with prolate ellipsoid heads. However, surface accumulation is predicted to be inhibited by changes associated with mammalian sperm hyperactivation and quantitative aspects, such as the accumulation height associated with surface swimming, are sensitive to the flagellar beat pattern wavenumber and even to the asymptotically small modelling approximations of slender body theory. In particular, the predicted sensitivity of the accumulation height of swimming sperm to the beat pattern wavenumber is sufficient to suggest the possibility that the limited focal depth of typical microscopy studies analysing flagellar patterns with a fixed focal plane may inadvertently bias the wavenumber of the sperm that are observed. PMID- 25014475 TI - Multiclass classification of sarcomas using pathway based feature selection method. AB - Feature selection is an important research topic in bioinformatics, to date a large number of methods have been developed. Recently several pathway based feature selection protocols, such as the condition-responsive genes method, have been proposed for better classification performance. However, these conventional pathway based methods may lead to the selection of relevant but redundant genes in a given pathway while missing the other useful genes. Also these methods were limited to binary classification, while in many clinical problems a multiclass protocol is preferred such as the classification of sarcomas. Here, we propose a new pathway based feature selection method named Redundancy Removable Pathway based feature selection method (RRP) for the binary and multiclass classification problems. Three classifiers were implemented to compare the performance and gene functions of gene-based, conventional pathway based, and our RRP method. The validation results suggest that the RRP method is a feasible and robust feature selection method for multi-class prediction problems. PMID- 25014476 TI - Effect of water table fluctuations on phreatophytic root distribution. AB - The vertical root distribution of riparian vegetation plays a relevant role in soil water balance, in the partition of water fluxes into evaporation and transpiration, in the biogeochemistry of hyporheic corridors, in river morphodynamics evolution, and in bioengineering applications. The aim of this work is to assess the effect of the stochastic variability of the river level on the root distribution of phreatophytic plants. A function describing the vertical root profile has been analytically obtained by coupling a white shot noise representation of the river level variability to a description of the dynamics of root growth and decay. The root profile depends on easily determined parameters, linked to stream dynamics, vegetation and soil characteristics. The riparian vegetation of a river characterized by a high variability turns out to have a rooting system spread over larger depths, but with shallower mean root depths. In contrast, a lower river variability determines root profiles with higher mean root depths. PMID- 25014477 TI - Sequence-based predictor of ATP-binding residues using random forest and mRMR-IFS feature selection. AB - We develop a computational and statistical approach (ATPBR) for predicting ATP binding residues in proteins from amino acid sequences by using random forests with a novel hybrid feature. The hybrid feature incorporates a new feature called PSSMPP, the predicted secondary structure and orthogonal binary vectors. The mRMR IFS feature selection method is utilized to construct the best prediction model. At last, ATPBR achieves significantly improved performance over existing methods, with 87.53% accuracy and a Matthew's correlation coefficient of 0.554. In addition, our further analysis demonstrates that PSSMPP distinguishes more effectively between ATP-binding and non-binding residues. Besides, the optimal features selected by the mRMR-IFS method improve the prediction performance and may provide useful insights for revealing the mechanisms of ATP and proteins interactions. PMID- 25014478 TI - Sonographic Weight Estimation in Small-for-Gestational-Age Fetuses. AB - PURPOSE: To determine the accuracy of sonographic weight estimation (WE) for small-for-gestational-age (SGA) fetuses, and to further differentiate the evaluation between symmetric and asymmetric SGA fetuses. MATERIALS AND METHODS: The accuracy of WE in SGA fetuses (n = 898) was evaluated using 14 sonographic models and was further differentiated between symmetric (n = 750) and asymmetric (n = 148) SGA fetuses. SGA fetuses were considered to be asymmetric with a head circumference to abdominal circumference ratio above the 95th percentile. The accuracy of the different formulas was compared using means of percentage errors (MPE), medians of absolute percentage errors (MAPE), and proportions of estimates within 10 % of actual birth weight. RESULTS: RESULTS for the subgroup of asymmetric SGA fetuses differed significantly from the subgroup of symmetric SGA fetuses. MPE values were closer to zero with most of the formulas in the asymmetric SGA group. Apart from the Siemer, Shepard, Merz and Warsof equations, all formulas showed an underestimation of fetal weight in asymmetric SGA fetuses. In contrast, in the symmetric SGA group, all of the formulas commonly used for fetuses in a normal weight range showed a systematic overestimation of fetal weight. Overall the best accuracy was achieved by using the Sabbagha equation (MPE 1.7 %; SD 9.0 %; MAPE: 6.0). CONCLUSION: An accurate WE in SGA fetuses is feasible using the Sabbagha formula. However, one has to be aware of the significant differences in WE between symmetric and asymmetric SGA fetuses. PMID- 25014479 TI - Bedside ultrasound of the neck confirms endotracheal tube position in emergency intubations. AB - PURPOSE: In controlled environments such as the operating room, bedside ultrasound (BUS) of the neck has shown high accuracy for distinguishing endotracheal (ETI) from esophageal intubations. We sought to determine the accuracy of BUS for endotracheal tube (ETT) position in the emergency department (ED) setting. MATERIALS AND METHODS: We assessed the utility of BUS in a single center observational study in an ED setting. BUS was performed either simultaneously with ED intubation (S/ED), within < 3 minutes of ED intubation (A/ED), or in < 3 minutes of patient's ED arrival after pre-hospital intubation (A/EMS). Trained ED providers performed BUS; intubators were blinded to ultrasound findings. We used Cormack and Lehane categories (CL) to classify intubation attempts as "easy" (CL-I/II), "moderate" (CL-III) and "difficult" (CL IV). Additional data included the diagnostic accuracy of the sonographer and intubator compared to the clinical outcome, anatomy identified by sonography and time to diagnosis. RESULTS: During a 10-month period, 89 subjects with 115 intubation attempts were included in the study, and 86 patients/101 attempts with complete data were used in the study (63-easy, 19-moderate, 19-difficult). The sonographers achieved 100 % accuracy with respect to determining the correct ETT position utilizing an anterior neck approach, while the intubators' accuracy in assessing correct tube location was 97 % compared to the clinical outcome. A blinded review of sonography findings confirmed all BUS anatomical findings. A sonographically empty esophagus was 100 % specific for endotracheal intubation, and a "double trachea sign" was 100 % sensitive and 91 % specific for esophageal intubation. The sonographic time to diagnosis was significantly faster than the intubator time to diagnosis ("easy" p < 0.001; n = 47; "moderate" p = 0.001; n = 15; "difficult" p < 0.001; n = 19); Wilcoxon test; A/EMS cases excluded). CONCLUSION: In this emergency setting, ultrasound determined ETT locations rapidly with 100 % accuracy and independently of the CL-category. PMID- 25014480 TI - Importance of transvaginal ultrasound applying elastography for identifying deep infiltrating endometriosis - a feasibility study. AB - PURPOSE: To evaluate the presence of a lesion indicative of endometriosis with transvaginal elastography. MATERIALS AND METHODS: Transvaginal ultrasound and clinical examination were carried out in 48 women with clinical symptoms indicative of endometriosis. In 31 cases strain values were measured at two regions of interest (ROIs) in the Douglas's cul-de-sac during a cycle of compression and decompression with a vaginal probe. RESULTS: A significant difference was found for the ratio of the ROI measuring points in the Douglas' cul-de-sacs of women with a palpable nodule in examination compared to women without a palpable nodule (p = 0.002). CONCLUSION: The ratio of strain values between two ROIs in the Douglas' s cul-de-sac is associated with the presence of an endometriotic lesion. In the future, these findings could allow for a more detailed pre-surgical evaluation and possibly serve as a novel diagnostic tool for predicting deep infiltrating endometriosis. PMID- 25014481 TI - Prediction of hemodynamic reactivity during total intravenous anesthesia for suspension laryngoscopy using Analgesia/Nociception Index (ANI): a prospective observational study. AB - BACKGROUND: The Analgesia/Nociception Index (ANI), a 0-100 non-invasive index calculated from heart rate variability, reflects the analgesia/nociception balance during general anesthesia. The principal objective of this study was to evaluate the performance of ANI to predict hemodynamic reactivity during suspension laryngoscopy. The secondary objectives were to investigate the performances of ANI and bispectral index (BIS) to assess sedation and of BIS to predict hemodynamic reactivity during the procedure. METHODS: Fifty patients undergoing suspension laryngoscopy with total intravenous anesthesia using propofol and remifentanil were analysed in this prospective observational study. The ANI, BIS and Observer's Assessment of Alertness/Sedation (OAA/S) scale were measured at predefined time-points during the procedure. Receiver-operating characteristic (ROC) curves were built to evaluate the performance of ANI and BIS to predict hemodynamic reactivity (increase by more than 20% of heart rate and/or systolic blood pressure within 5 min) and assess sedation (OAA/S <= 2) during the procedure. RESULTS: For the prediction of hemodynamic reactivity, better performance was observed with ANI in comparison to BIS (ROC curve AUC [95% CI] = 0.88 [0.83-0.92] vs. 0.73 [0.66-0.79], P < 0.05). The sensitivity and specificity of ANI <= 55 to predict hemodynamic reactivity within 5 min were 88% and 83%, respectively. For the assessment of sedation, a better performance was observed with BIS in comparison to ANI (ROC curve AUC [95% CI] = 0.91 [0.86-0.94] vs. 0.68 [0.61-0.74], respectively, P < 0.05). CONCLUSION: ANI exhibits good performance for the prediction of hemodynamic reactivity and BIS exhibits good performance for the assessment of sedation during suspension laryngoscopy with propofol/remifentanil total intravenous anesthesia. PMID- 25014482 TI - Evaluation and treatment of preoperative anxiety in children: are we doing what we should do? PMID- 25014483 TI - Programmed stereoselective assembly of DNA-binding helical metallopeptides. AB - A flexible and versatile synthetic approach for the construction of water-stable DNA-binding chiral peptide helicates based on the solid phase peptide synthesis (SPPS) methodology is reported. PMID- 25014484 TI - Occurrence of diverse mutations in isoniazid- and rifampicin-resistant Mycobacterium tuberculosis isolates from autochthonous and immigrant populations of Saudi Arabia. AB - For the first time in Saudi Arabia, the impact of a patient's ethnic background on mutations conferring resistance to rifampicin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis isolates was analyzed on a nationwide sample collection. Four hundred fifteen isolates were subjected to drug susceptibility testing, mutation analysis, spoligotyping, and 24 loci-based Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat typing, respectively. Phenotypically, 41 (9.9%) isolates were resistant to RIF, 239 (57.6%) to INH, and 135 (32.5%) to both RIF and INH, respectively. Forty (9.6%), 236 (56.8%), and 133 (32%) isolates were determined as resistant to RIF, INH, and to both by molecular assay. Codon 531 (S531L) mutations (69.4%) in the rpoB gene and codon 315 (S315T) mutations (67.2%) in the katG gene were the most prominent among RIF- and INH resistant isolates, respectively. The autochthonous population showed a predominance of rpoB codon 516 and 526 mutations, while the inhA promoter position -15 and -8 mutations were prominent among immigrants. A strain cluster ratio of 32% (30 clusters) was observed and 24 clusters displayed identical mutations. Overall, Euro-American lineages were predominant. However, Beijing (56.7%) and EAI (42.7%) were noticed with the highest cluster rate. In Saudi Arabia, the occurrence of mutations responsible for INH and RIF resistance was significantly associated with the ethnic origin of the patient. PMID- 25014485 TI - A simple self-calibrating method to measure the height of fluorescent molecules and beads at nanoscale resolution. AB - We describe a simple self-calibrating technique, incident-beam interference sweeping, for measuring the height of fluorescent labels. Using a tilted back reflecting mirror and a scanning laser beam, a modulated fluorescence emission allows height determination of a label from a surface with a resolution of ~ 3 nm. In addition, we show that the absolute distance of a label from the top mounted mirror can be determined with a resolution of a few tens of nanometers over a micrometer range. PMID- 25014487 TI - Thrombosis following ovarian hyperstimulation syndrome. AB - The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67-75%) involving upper limbs and neck, then arterial (25-33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation. PMID- 25014488 TI - Reactive oxygen species in follicular fluid may serve as biochemical markers to determine ovarian aging and follicular metabolic age. AB - INTRODUCTION: The aim of this study was to evaluate the role of oxidative stress in the process of ovarian aging. METHODS: Follicular fluid (FF) from two randomly selected sibling follicles was collected from women undergoing in-vitro fertilization and tested for hydrogen peroxide (H(2)O(2)) levels. RESULTS: Group A consists of seven women with whom each of the two sibling separate follicle yielded an oocyte that was later discordantly developed to a low- and top-quality embryo. Group B consists of 13 patients in whom one of the sibling follicle yielded an oocyte while the other did not (empty follicle). High-quality embryos were derived from follicles with lower H(2)O(2) levels compared to follicles from which poor-quality embryos developed (1.004 units +/- 0.260 versus 1.145 units +/ 0.236, p < 0.02). H(2)O(2) levels were significantly higher (0.951 units +/- 0.233 versus 0.623 units +/- 0.309, p < 0.001) in sibling follicles containing oocyte compared to empty follicles. CONCLUSION: During the process of ovarian ageing, there might be a gradual increase in H(2)O(2) level in the follicle. Finally, when the follicle ages and becomes empty of oocyte H(2)O(2) levels drops significantly. Therefore, H(2)O(2) levels in FF may serve as a possible marker to determine ovarian aging and follicular metabolic age. PMID- 25014486 TI - Current advances in polymer-based nanotheranostics for cancer treatment and diagnosis. AB - Nanotheranostics is a relatively new, fast-growing field that combines the advantages of treatment and diagnosis via a single nanoscale carrier. The ability to bundle both therapeutic and diagnostic capabilities into one package offers exciting prospects for the development of novel nanomedicine. Nanotheranostics can deliver treatment while simultaneously monitoring therapy response in real time, thereby decreasing the potential of over- or under-dosing patients. Polymer based nanomaterials, in particular, have been used extensively as carriers for both therapeutic and bioimaging agents and thus hold great promise for the construction of multifunctional theranostic formulations. Herein, we review recent advances in polymer-based systems for nanotheranostics, with a particular focus on their applications in cancer research. We summarize the use of polymer nanomaterials for drug delivery, gene delivery, and photodynamic therapy, combined with imaging agents for magnetic resonance imaging, radionuclide imaging, and fluorescence imaging. PMID- 25014489 TI - Gas-phase ions produced by freezing water or methanol for analysis using mass spectrometry. AB - Introducing water or methanol containing a low concentration of volatile or nonvolatile analyte into an inlet tube cooled with dry ice linking atmospheric pressure and the first vacuum stage of a mass spectrometer produces gas-phase ions even of small proteins that can be detected by mass spectrometry. Collision induced dissociation experiments conducted in the first vacuum region of the mass spectrometer suggest analyte ions being protected by a solvent cage. The charges may be produced by processes similar to those proposed for charge separation under freezing conditions in thunderclouds. By this process, the surface of an ice pellet is charged positive and the interior negative so that removal of surface results in charge separation. A reversal of surface charge is expected for a heated droplet surface, and this is observed by heating rather than cooling the inlet tube. These observations are consistent with charged supercooled droplets or ice particles as intermediates in the production of analyte ions under freezing conditions. PMID- 25014490 TI - Language ability of children with and without a history of stuttering: a longitudinal cohort study. AB - PURPOSE: This study aims to determine whether the communication and language skills of children who have a history of stuttering are different from children who do not have a history of stuttering at ages 2-5 years. METHOD: This study utilizes data from the Early Language in Victoria Study (ELVS), a longitudinal study with a community sample of 1910 children recruited in Melbourne, Australia, as well as a concurrent study examining the onset and progression of stuttering. Participants with a history of stuttering (n = 181) and a control group without a history of stuttering (n = 1438) were identified according to the established protocol of these two existing studies. RESULT: The stuttering group scored higher than the non-stuttering group on all of the communication and language outcomes measured. The group differences were statistically significant on four of the seven measures and these findings were maintained when potentially confounding factors were controlled for. CONCLUSION: Importantly, the children with a history of stuttering, as a group, and the control group without a history of stuttering demonstrated developmentally-appropriate early communication and language skills. PMID- 25014491 TI - The development of a feeding, swallowing and oral care program using the PRECEDE PROCEED model in an orphanage-hospital in Guatemala. AB - PURPOSE: The purpose of this study was to evaluate a long-term on-going international academic service-learning (I-ASL) intervention. Its goal was to improve swallowing, feeding and oral care technique of medical staff in an orphanage in Guatemala to children who are medically complex and have special needs. METHOD: The PRECEDE-PROCEED model was used as the conceptual framework of the program. Five major target areas were identified during the diagnosis, assessment, implementation and evaluation phases of the model: knowledge and skills, feeding equipment, feeding and oral care technique, positioning and communication. Verbal instruction, modelling and small group training was provided by the research team across all visits. A five-day intervention designed to increase feeders' knowledge of feeding and oral care technique, signs and symptoms and complications of dysphagia and to improve their feeding, positioning and oral care technique was implemented and evaluated. RESULT: Statistical analyses showed significant increases in knowledge and appropriate feeding, positioning and oral care technique. CONCLUSION: As a consequence of the intervention, a trusting and mutually supportive relationship was built between the I-ASL team and the host organization. PMID- 25014492 TI - Toll-like receptor 4 and hepatitis B infection: molecular mechanisms and pathogenesis. AB - Hepatitis B virus (HBV) infection mainly causes liver disease, including inflammation, cirrhosis, and hepatocellular carcinoma (HCC). It has been documented that prolonged hepatitis B-infected patients are unable to clear HBV from hepatocytes completely. Previous investigations have suggested that various genetic and immunologic parameters may be responsible for the induction of prolonged infection forms. Toll-like receptors (TLRs), as members of pathogen recognition receptors (PRRs), play critical roles in the recognition of viruses and the induction of appropriate immune responses. Thus, TLRs may be considered as essential sensors for the recognition of HBV and the induction of immune responses against this virus. It has been documented that TLR4 plays key roles in the detection of several microbial pathogen-associated molecular pattern molecules, including bacterial lipopolysaccharide (LPS), as well as endogenous ligands (damage-associated molecular pattern molecules) and subsequently activates pro-inflammatory transcription factors in either MYD88 or TRIF dependent pathways. Previous investigations have proposed that TLR4 might be involved in appropriate immune responses against HBV. Therefore, the aim of this review is to present the recent data regarding the important roles of TLR4 in HBV recognition and regulation of immune responses against this virus, and also its roles in the pathogenesis of cirrhosis and HCC as complications of prolonged hepatitis B infections. PMID- 25014493 TI - The enigmatic marine reptile nanchangosaurus from the lower triassic of Hubei, China and the phylogenetic affinities of Hupehsuchia. AB - The study of the holotype and of a new specimen of Nanchangosaurus suni (Reptilia; Diapsida; Hupehsuchia) revealed a suite of hitherto unrecognized characters. For example, Nanchangosaurus has bipartite neural spines and its vertebral count is nearly identical to that of Hupehsuchus. It differs from the latter in having poorly developed forelimbs despite the advanced ossification in the rest of the skeleton. Other differences all pertain to hupehsuchian plesiomorphies retained in Nanchangosaurus, such as low neural spines. The relationship of Hupehsuchia within Diapsida was analyzed based on a data matrix containing 41 taxa coded for 213 characters, of which 18 were identified as aquatic adaptations from functional inferences. These aquatic adaptations may be vulnerable to the argumentation of character homology because expectation for homoplasy is high. There is an apparent incongruence between phylogenetic signals from aquatic adaptations and the rest of the data, with aquatic adaptations favoring all marine reptiles but Helveticosaurus to form a super-clade. However, this super-clade does not obtain when aquatic adaptations were deleted, whereas individual marine reptile clades are all derived without them. We examined all possible combinations of the 18 aquatic adaptations (n = 262143) and found that four lineages of marine reptiles are recognized almost regardless of which of these features were included in the analysis: Hupehsuchia-Ichthyopterygia clade, Sauropterygia-Saurosphargidae clade, Thalattosauria, and Helveticosaurus. The interrelationships among these four depended on the combination of aquatic adaptations to be included, i.e., assumed to be homologous a priori by bypassing character argumentation. Hupehsuchia always appeared as the sister taxon of Ichthyopterygia. PMID- 25014494 TI - Genomics and Proteomics Provide New Insight into the Commensal and Pathogenic Lifestyles of Bovine- and Human-Associated Staphylococcus epidermidis Strains. AB - The present study reports comparative genomics and proteomics of Staphylococcus epidermidis (SE) strains isolated from bovine intramammary infection (PM221) and human hosts (ATCC12228 and RP62A). Genome-level profiling and protein expression analyses revealed that the bovine strain and the mildly infectious ATCC12228 strain are highly similar. Their genomes share high sequence identity and synteny, and both were predicted to encode the commensal-associated fdr marker gene. In contrast, PM221 was judged to differ from the sepsis-associated virulent human RP62A strain on the basis of distinct protein expression patterns and overall lack of genome synteny. The 2D DIGE and phenotypic analyses suggest that PM221 and ATCC12228 coordinate the TCA cycle activity and the formation of small colony variants in a way that could result in increased viability. Pilot experimental infection studies indicated that although ATCC12228 was able to infect a bovine host, the PM221 strain caused more severe clinical signs. Further investigation revealed strain- and condition-specific differences among surface bound proteins with likely roles in adhesion, biofilm formation, and immunomodulatory functions. Thus, our findings revealed a close link between the bovine and commensal-type human strains and suggest that humans could act as a reservoir of bovine mastitis-causing SE strains. PMID- 25014495 TI - Acute stroke in patients on new direct oral anticoagulants: how to manage, how to treat? AB - INTRODUCTION: For a long time, vitamin K antagonists (VKA) were the only available oral anticoagulants for clinical use. It is conceivable that the number of patients treated with novel direct oral anticoagulants (NOAC) will increase, due to the easy handling and the favorable risk-benefit profile compared with VKA. It is, therefore, expected that clinicians will be increasingly confronted with the question on how to treat acute ischemic stroke (AIS) if there is an indication for thrombolysis or how to manage intracranial bleedings. AREAS COVERED: In this review, we discuss controversies on thrombolysis in patients anticoagulated with NOAC, the dilemma of when to restart anticoagulation after AIS, and whether (and when) to re-institute oral anticoagulation after a brain hemorrhage. We provide suggestions for the management of these situations. EXPERT OPINION: Thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic International normalized ratio values (<= 1.7) may be considered according to guideline. Thrombolysis is contraindicated if intake of NOAC is reported in a patient, but no other information is available on-time of last intake of NOAC. Prothrombin complex concentrate have been proposed as a plausible, but unproven therapy to reverse the anticoagulant effects of NOACs. PMID- 25014497 TI - New method for geometric calibration and distortion correction of conventional C arm. AB - Image distortion correction and geometric calibration are critical operations for using C-arm DSA (Digital Subtraction Angiography) images to digitally navigate vascular interventional surgery. In traditional ways, C-arm images are corrected with global or local correction methods where a supposed virtual ideal image is needed, and then the corrected images are utilized to calibrate the C-arm with a pin-hole model. In this paper, we propose a new method to calibrate the C-arm with a nonlinear model and to improve navigation performance. We first calibrate the C-arm with a nonlinear model and then the distortion correction is accomplished without virtual ideal image. In this paper, the nonlinear model of C arm imaging system is addressed at first, and then the C-arm is calibrated with a two-stage method. In the first stage, the C-arm is calibrated with the markers in image center by RAC (radial alignment constraint) method, and in the second stage the calibration parameters are optimized with Levenberg-Marquadt algorithm by minimizing the sum of the square of difference between all markers' real distorted positions and their theoretical distorted positions in the phantom image. Based on the calibration result, the image distortion can be corrected. To verify our method, experiments were conducted with a conventional DSA C-arm machine in hospital. The errors in distortion correction and 3D (three dimensional) reconstruction were quantitatively compared with the global polynomial correction method and visual model method, and the results showed that the proposed method had better performance in distortion correction and 3D reconstruction. PMID- 25014496 TI - mTOR inhibition by everolimus in childhood acute lymphoblastic leukemia induces caspase-independent cell death. AB - Increasingly, anti-cancer medications are being reported to induce cell death mechanisms other than apoptosis. Activating alternate death mechanisms introduces the potential to kill cells that have defects in their apoptotic machinery, as is commonly observed in cancer cells, including in hematological malignancies. We, and others, have previously reported that the mTOR inhibitor everolimus has pre clinical efficacy and induces caspase-independent cell death in acute lymphoblastic leukemia cells. Furthermore, everolimus is currently in clinical trial for acute lymphoblastic leukemia. Here we characterize the death mechanism activated by everolimus in acute lymphoblastic leukemia cells. We find that cell death is caspase-independent and lacks the morphology associated with apoptosis. Although mitochondrial depolarization is an early event, permeabilization of the outer mitochondrial membrane only occurs after cell death has occurred. While morphological and biochemical evidence shows that autophagy is clearly present it is not responsible for the observed cell death. There are a number of features consistent with paraptosis including morphology, caspase-independence, and the requirement for new protein synthesis. However in contrast to some reports of paraptosis, the activation of JNK signaling was not required for everolimus induced cell death. Overall in acute lymphoblastic leukemia cells everolimus induces a cell death that resembles paraptosis. PMID- 25014498 TI - Biomechanical evaluation of the impact of various facet joint lesions on the primary stability of anterior plate fixation in cervical dislocation injuries: a cadaver study: Laboratory investigation. AB - OBJECT: Injuries of the subaxial cervical spine including facet joints and posterior ligaments are common. Potential surgical treatments consist of anterior, posterior, or anterior-posterior fixation. Because each approach has its advantages and disadvantages, the best treatment is debated. This biomechanical cadaver study compared the effect of different facet joint injuries on primary stability following anterior plate fixation. METHODS: Fractures and plate fixation were performed on 15 fresh-frozen intact cervical spines (C3-T1). To simulate a translation-rotation injury in all groups, complete ligament rupture and facet dislocation were simulated by dissecting the entire posterior and anterior ligament complex between C-4 and C-5. In the first group, the facet joints were left intact. In the second group, one facet joint between C-4 and C-5 was removed and the other side was left intact. In the third group, both facet joints between C-4 and C-5 were removed. The authors next performed single-level anterior discectomy and interbody grafting using bone material from the respective thoracic vertebral bodies. An anterior cervical locking plate was used for fixation. Continuous loading was performed using a servohydraulic test bench at 2 N/sec. The mean load failure was measured when the implant failed. RESULTS: In the group in which both facet joints were intact, the mean load failure was 174.6 +/- 46.93 N. The mean load failure in the second group where only one facet joint was removed was 127.8 +/- 22.83 N. In the group in which both facet joints were removed, the mean load failure was 73.42 +/- 32.51 N. There was a significant difference between the first group (both facet joints intact) and the third group (both facet joints removed) (p < 0.05, Kruskal-Wallis test). CONCLUSIONS: In this cadaver study, primary stability of anterior plate fixation for dislocation injuries of the subaxial cervical spine was dependent on the presence of the facet joints. If the bone in one or both facet joints is damaged in the clinical setting, anterior plate fixation in combination with bone grafting might not provide sufficient stabilization; additional posterior stabilization may be needed. PMID- 25014499 TI - The effects of smoking on perioperative outcomes and pseudarthrosis following anterior cervical corpectomy: Clinical article. AB - OBJECT: Smoking is one of the leading causes of preventable morbidity and death in the U.S. and has been associated with perioperative complications. In this study, the authors examined the effects of smoking on perioperative outcomes and pseudarthrosis rates following anterior cervical corpectomy. METHODS: All adult patients from 2006 to 2011 who underwent anterior cervical corpectomy were identified. Patients were categorized into 3 groups: patients who never smoked (nonsmokers), patients who quit for at least 1 year (quitters), and patients who continue to smoke (current smokers). Demographic, medical, and surgical covariates were collected. Multivariate analysis was used to define the relationship between smoking and blood loss, 30-day complications, length of hospital stay, and pseudarthrosis. RESULTS: A total of 160 patients were included in the study. Of the 160 patients, 49.4% were nonsmokers, 25.6% were quitters, and 25.0% were current smokers. The overall 30-day complication rate was 20.0%, and pseudarthrosis occurred in 7.6% of patients. Mean blood loss was 368.3 ml and mean length of stay was 6.5 days. Current smoking status was significantly associated with higher complication rates (p < 0.001) and longer lengths of stay (p < 0.001); current smoking status remained an independent risk factor for both outcomes after multivariate logistic regression analysis. The complications that were experienced in current smokers were mostly infections (76.5%), and this proportion was significantly greater than in nonsmokers and quitters (p = 0.013). Current smoking status was also an independent risk factor for pseudarthrosis at 1-year follow-up (p = 0.012). CONCLUSIONS: Smoking is independently associated with higher perioperative complications (especially infectious complications), longer lengths of stay, and higher rates of pseudarthrosis in patients undergoing anterior cervical corpectomy. PMID- 25014500 TI - A retrospective study of iliac crest bone grafting techniques with allograft reconstruction: do patients even know which iliac crest was harvested? Clinical article. AB - OBJECT: Considerable biological research has been performed to aid bone healing in conjunction with lumbar fusion surgery. Iliac crest autograft is often considered the gold standard because it has the vital properties of being osteoconductive, osteoinductive, and osteogenic. However, graft site pain has been widely reported as the most common donor site morbidity. Autograft site pain has led many companies to develop an abundance of bone graft extenders, which have limited proof of efficacy. During the surgical consent process, many patients ask surgeons to avoid harvesting autograft because of the reported pain complications. The authors sought to study postoperative graft site pain by simply asking patients whether they knew which iliac crest was grafted when a single skin incision was made for the fusion operation. METHODS: Twenty-five patients underwent iliac crest autografting with allograft reconstruction during instrumented lumbar fusion surgery. In all patients the autograft was harvested through the same skin incision but with a separate fascial incision. At various points postoperatively, the patients were asked if they could tell which iliac crest had been harvested, and if so, how much pain did it cause (10-point Numeric Rating Scale). RESULTS: Most patients (64%) could not correctly determine which iliac crest had been harvested. Of the 9 patients who correctly identified the side of the autograft, 7 were only able to guess. The 2 patients who confidently identified the side of grafting had no pain at rest and mild pain with activity. One patient who incorrectly guessed the side of autografting did have significant sacroiliac joint degenerative pain bilaterally. CONCLUSIONS: Results of this study indicate the inability of patients to clearly define their graft site after iliac crest autograft harvest with allograft reconstruction of the bony defect unless they have a separate skin incision. This simple, easily reproducible pilot study can be expanded into a larger, multiinstitutional investigation to provide more definitive answers regarding the ideal, safe, and cost-effective bone graft material to be used in spinal fusions. PMID- 25014501 TI - The evolution of T2-weighted intramedullary signal changes following ventral decompressive surgery for cervical spondylotic myelopathy: Clinical article. AB - OBJECT: T2-weighted intramedullary increased signal intensity (ISI) on MRI in patients with cervical spondylotic myelopathy (CSM) appears to represent a wide spectrum of pathological changes that determine reversibility of cord damage. Although sharp T2-weighted ISI on preoperative imaging may correlate with poorer surgical outcomes, there are limited data on how these changes progress following surgery. In this study, the authors characterized pre-and postoperative ISI changes in patients undergoing surgery for CSM and studied their postoperative evolution in an attempt to quantify their clinical significance. METHODS: The preoperative and postoperative MR images obtained in 56 patients who underwent oblique cervical corpectomy for CSM were reviewed, and the ISI was classified into 4 subtypes based on margins and intensity: Type 0 (none), Type 1 ("fuzzy"), Type 2 ("sharp"), and Type 3 ("mixed"). The locations of the ISI were further classified as focal if they represented single discrete lesions, multifocal if there were multiple lesions with intervening normal cord, and multisegmental if the lesions were continuous over more than 1 segment. The maximum craniocaudal length of the ISI was measured on each midsagittal MR image. The Nurick grade and Japanese Orthopaedic Association (JOA) score were used to assess clinical status. The mean duration of follow-up was 28 months. RESULTS: T2-weighted ISI changes were noted preoperatively in 54 patients (96%). Most preoperative ISI changes were Type 1 (41%) or Type 3 (34%), with a significant trend toward Type 2 (71%) changes at follow-up. Multi-segmental and Type 3 lesions tended to regress significantly after surgery (p = 0.000), reducing to Type 2 changes at follow-up. Clinical outcomes did not correlate with ISI subtype; however, there was a statistically significant trend toward improvement in postoperative Nurick Grade in patients with a > 50% regression in ISI size. In addition, patients with more than 18 months of follow-up showed significant regression in ISI size compared with patients imaged earlier. On logistic regression analysis, preoperative Nurick grade and duration of follow-up were the only significant predictors of postoperative improvement in functional status (OR 4.136, p = 0.003, 95% CI 1.623 10.539 and OR 6.402, p = 0.033, 95% CI 1.165-35.176, respectively). CONCLUSIONS: There is a distinct group of patients with multisegmental Type 3 intramedullary changes who show remarkable radiological regression after surgery but demonstrate a residual sharp focal ISI at follow-up. A regression of the ISI by > 50% predicts better functional outcomes. Patients with a good preoperative functional status remain the most likely to show improvement, and the improvement continues to occur even at remote follow-up. The clinical relevance of the quality of the T2-weighted ISI changes in patients with CSM remains uncertain; however, postoperative regression of the ISI change is possibly a more important correlate of patient outcome than the quality of the ISI change alone. PMID- 25014502 TI - Migration of fragments into the spinal canal after intervertebral polyethylene glycol implantation: an extremely rare adverse effect: Case report. AB - Percutaneous intervertebral hydrogel (polyethylene glycol) implantation is a current treatment procedure that aims to restore hydration of a degenerated disc. There have been a few studies that claim that polyethylene glycol is successful for pain relief as the intervertebral space restores its hydration and elasticity. This procedure is reported to be indicated for discogenic low-back pain and mild radicular pain as it contributes to disc restoration. In this report, the authors describe the case of a 43-year-old woman who was admitted with low-back and right leg pain. Muscle strength in dorsiflexion of the right ankle and right toe was 3/5. The patient had undergone hydrogel implantation for L4-5 intervertebral disc restoration 2 days prior to presentation. There was a significant increase in the patient's complaints after hydrogel implantation, and acute weakness in the right ankle and toe had developed. Magnetic resonance imaging of the lumbar vertebrae, which was performed before the hydrogel implantation, showed a significant narrowing of the L4-5 disc space height, and a disc herniation that extended to the right neural foramen and caused compression of the dural sac. The patient underwent surgery immediately. The sequestered disc fragment that caused a prominent stenosis in the spinal canal, as well as hydrogel fragments, was removed. There was an improvement in the patient's complaints and motor deficit postoperatively. In this paper, a very rare complication is reported. In patients who have increased pain after intervertebral hydrogel implantation and who develop a neurological deficit, the migration of the applied material into the spinal canal should be considered. PMID- 25014503 TI - Cervical osteophyte resulting in compression of the jugular foramen: Case report. AB - Jugular foramen syndrome is a condition characterized by unilateral paresis of cranial nerves IX, X, and XI in the setting of extrinsic compression. Here, the authors describe the case of a giant cervical osteophyte resulting in compression of the jugular foramen. A 74-year-old man who presented with progressive dysphagia and dysarthria was found to have right-sided tongue deviation, left palatal droop, and hypophonia. His dysphagia had progressed to the point that he had lost 25 kg over a 4-month period, necessitating a gastrostomy to maintain adequate nutrition. He underwent extensive workup for his dysphagia with several normal radiographic studies. Ultimately, CT scanning and postcontrast MRI revealed a posterior osteophyte arising from the C1-2 joint space and projecting into the right jugular foramen. This resulted in a jugular foramen syndrome in addition to delayed filling of the patient's right internal jugular vein distal to the osteophyte. Although rare, a posterior cervical osteophyte should be considered in cases of jugular foramen syndrome. PMID- 25014504 TI - Metastatic renal cell carcinoma, with a radiographically occult primary tumor, presenting in the operative site of a thoracic meningioma: long-term follow-up: Case report. AB - Lesions metastatic to the site of a meningioma resection from a different primary tumor are rare. Metastasis of a tumor without a known primary tumor is also rare. Metastasis of a renal cell carcinoma, without an identifiable primary tumor, to the bed of a meningioma resection has not been previously reported. The authors describe the case of a 54-year-old man who presented with decreased sensory and motor function in the lower extremities. He underwent T3-5 laminectomies and gross-total removal of an intradural, extramedullary meningioma. The postoperative course was uneventful, and the patient regained full neurological function. After a 3-year period, he developed progressive upper thoracic pain and lower-extremity paresthesias. Imaging studies showed an epidural mass at the T2-4 levels and what appeared to be blastic involvement of the T2-4 vertebrae. A metastatic workup was negative. Emergency revision laminectomies yielded a fibrous, nonvascular mass. Neuropathology was consistent with metastatic renal cell carcinoma. After 6 months, the patient's symptoms of pain and paresthesias recurred. Repeat excision, with decompression of the spinal cord, revealed tumor cells morphologically and immunophenotypically similar to those obtained from the prior surgery. Cytogenetic analysis confirmed the presence of metastatic renal cell carcinoma. A novel case of an epidural metastatic renal cell carcinoma, of unknown primary origin, in the same operative bed of a previously resected intradural, extramedullary meningioma of the thoracic spine is reported. PMID- 25014505 TI - Low midlife blood pressure, survival, comorbidity, and health-related quality of life in old age: the Helsinki Businessmen Study. AB - OBJECTIVE: The aim of the present study was to examine the long-term impact of midlife blood pressure (BP) on mortality, comorbidity, and health-related quality of life (HRQoL) in old age. METHODS: These are longitudinal analyses of the Helsinki Businessmen Study, a cohort of business executives, born in 1919-1934, whose BP was measured between 1964 and 1973 (n = 3267). Comorbidity and HRQoL with RAND-36 [Short Form (SF)-36] were assessed from questionnaires in 2000; mortality up to 31 July 2012 was ascertained from national registers. Baseline BP was categorized as normal, less than 120 mmHg systolic and less than 80 mmHg diastolic (n = 121); prehypertension, 120-139 mmHg systolic or 80-89 mmHg diastolic (n = 2131); stage 1 hypertension, 140-159 mmHg systolic or 90-99 mmHg diastolic (n = 757); and stage 2 hypertension, more than 160 mmHg systolic or more than 100 mmHg diastolic (n = 258). Main outcome measures were long-term mortality, comorbidity, and HRQoL in old age. RESULTS: During the 48-year follow up, 2013 men (61.6%) died. There was a graded relationship between BP and total mortality (P < 0.001). The men with normal BP had the lowest mortality; the age adjusted difference in mean survival was 7.5 years between the normal and stage 2 baseline BP groups, and 11.2 months between normal and prehypertension groups. Lower BP in midlife was associated with better scores in the physical functioning (P-linear trend <0.001) and general health (P = 0.01) scales of RAND-36 in old age. RAND-36 scales associated with mental health were not affected by midlife BP. CONCLUSION: Lower BP in midlife is associated with longer life and better physical HRQoL in old age. PMID- 25014506 TI - Genetic variance in ABCB1 and CYP3A5 does not contribute toward the development of chronic kidney disease after liver transplantation. AB - INTRODUCTION: Chronic kidney disease (CKD) after liver transplantation (LT) is a major clinical problem that appears to be associated with nongenetic as well as genetic determinants. Calcineurin inhibitor (CNI) use is considered to play a major role in the development of CKD after LT. We studied the influence of single nucleotide polymorphisms (SNPs) in the genes of the donor and recipient CNI metabolizing enzyme CYP3A5 and the CNI-transporting ABCB1 on the development of CKD after LT. MATERIALS AND METHODS: Tacrolimus (Tac) predose concentrations at different time-points after transplantation and the CYP3A5 6986A>G and ABCB1 3435C>T SNPs were determined in 125 LT recipients and their respective donors to study the influence of Tac predose levels and genetics on the development of CKD. RESULTS: After a median follow-up of 5.7+/-2.9 years, CKD developed in 47 patients (36%). The Tac predose levels were not correlated with the development of CKD. Neither did we find a correlation between the investigated SNPs in either donor or recipient ABCB1 and CYP3A5 genes (or combinations thereof) and the development of CKD. These genetic variations did not relate to Tac predose blood concentrations in our study. CONCLUSION: An individual's risk of developing CKD after LT is not associated with genetic variation in either recipient or donor CYP3A5 or ABCB1 genotype status. PMID- 25014507 TI - Reduction of U(VI) by Fe(II) during the Fe(II)-accelerated transformation of ferrihydrite. AB - X-ray absorption spectroscopy has been used to study the reduction of adsorbed U(VI) during the Fe(II)-accelerated transformation of ferrihydrite to goethite. The fate of U(VI) was examined across a variety of pH values and Fe(II) concentrations, with results suggesting that, in all cases, it was reduced over the course of the Fe(III) phase transformation to a U(V) species incorporated in goethite. A positive correlation between U(VI) reduction and ferrihydrite transformation rate constants implies that U(VI) reduction was driven by the production of goethite under the conditions used in these studies. This interpretation was supported by additional experimental evidence that demonstrated the (fast) reduction of U(VI) to U(V) by Fe(II) in the presence of goethite only. Theoretical redox potential calculations clearly indicate that the reduction of U(VI) by Fe(II) in the presence of goethite is thermodynamically favorable. In contrast, reduction of U(VI) by Fe(II) in the presence of ferrihydrite is largely thermodynamically unfavorable within the range of conditions examined in this study. PMID- 25014508 TI - Terminalia arjuna in coronary artery disease: ethnopharmacology, pre-clinical, clinical & safety evaluation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia arjuna (Roxb.) Wight & Arn. is one of the most popular and beneficial medicinal plants in indigenous system of medicine for the treatment of cardiovascular diseases. This comprehensive review provides latest updates on traditional use, phytochemistry, pharmacological and toxicological data, clinical efficacy and safety of Terminalia arjuna as well as outlined strategies for future research and development to scientifically validate the therapeutic potential of this plant. MATERIALS AND METHODS: Information about Terminalia arjuna was collected via a systematic electronic and library search of various indexed and non-indexed journals, some local books and varied articles published on ethnopharmacology, phytochemistry and traditional uses. Various pre-clinical (2000-2014) and clinical studies (1990-2014) have also been considered regarding efficacy and safety profile of Terminalia arjuna. RESULTS: Evidence from various in vitro, in vivo and clinical trials reveal the pleiotropic effects of Terminalia arjuna such as anti-atherogenic, hypotensive, inotropic, anti-inflammatory, anti-thrombotic and antioxidant actions for treatment of various cardiovascular disorders. It is clearly documented that this plant has a good safety profile when used in conjunction with other conventional drugs. However, there is a paucity of data regarding the exact molecular mechanism of its action, appropriate form of drug administration, whether whole crude drug or aqueous or alcoholic extract should be used, toxicological studies and its interaction with other drugs. CONCLUSIONS: In conclusion, this review highlights the importance as well as pleiotropic actions and functional aspects of Terminalia arjuna especially in cardiovascular diseases. Though, various pharmacological studies and clinical trials support its benefit in the CVD as per traditional use, new clinical trials using more rigorous state of the art technology and in a larger population setup are warranted to assess the traditional putative efficacy of Terminalia arjuna. PMID- 25014509 TI - Ethnomedicinal practices in the highlands of central Nepal: a case study of Syaphru and Langtang village in Rasuwa district. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The present paper documents the utilization of medicinal plants for the treatment of various human ailments in two village development committees in the Rasuwa district of central Nepal. It also evaluates the ethnopharmacological significance of the documented reports and identifies species of high indigenous priority in local therapeutics. MATERIALS AND METHODS: The ethnobotanical information was collected by interviews and group discussions using standard ethnobotanical procedures. The homogeneity of informant's knowledge was validated by Informant consensus factor (F(IC)) and the relative importance of a plant species used as medicine in the study area was calculated with the help of use value (UV). RESULTS: The present study identified a total of 46 medicinal plants belonging to 26 families used for the treatment of 38 human ailments. Besides medicinal uses, the study has also documented the culinary and cultural use of 13 species of medicinal plants. The most commonly used part was root constituting about 42% of the total utilized plants. The most commonly used form of preparation was paste (31.91%). We found new usage reports for 9 medicinal plants. The F(IC) value in the present study ranged from 0.66 to 1 with 84.6% values greater than 0.8 indicating high consensus among the informants. The most preferred species was Neopicrorhiza scrophulariflora (UV=0.96) and the lowest used value was found for Lyonia ovalifolia (UV=0.32). CONCLUSIONS: People of Rasuwa possess rich traditional knowledge in medicinal plants utilization with strong consensus among local people on the utilization of species evident by higher F(IC) values in different ailment categories. Strong pharmacological evidence for a majority of species being currently used as medicines shows that the plants used in local therapeutics are likely to be more effective in treating different medical ailments. The bioactive compounds extracted from these medicinal plants could subsequently be used in the creation of novel drugs to treat life threatening human diseases. The species with high use values are the ones likely to be more vulnerable because of high demand and high collection pressure. Therefore, it is imperative to prioritize such species for cultivation and sustainable management in order to ensure their long term availability. PMID- 25014510 TI - Gender differences in survival and the use of primary care prior to diagnosis of three cancers: an analysis of routinely collected UK general practice data. AB - OBJECTIVE: To explore whether there are gender differences in the number of GP recorded cases, the probability of survival and consulting pattern prior to diagnosis amongst patients with three non-sex-specific cancers. DESIGN: Cross sectional study. SETTING: UK primary care. SUBJECTS: 12,189 patients aged 16 years or over diagnosed with colorectal cancer (CRC), 11,081 patients with lung cancer and 4,352 patients with malignant melanoma, with first record of cancer diagnosis during 1997-2006. MAIN OUTCOME MEASURES: Cancer cases recorded in primary care; probability of survival following diagnosis; and number of GP contacts within the 24 months preceding diagnosis. RESULTS: From 1997-2006, overall rates of GP recorded CRC and lung cancer cases recorded were higher in men than in women, but rates of malignant melanoma were higher in women than in men. Gender differences in survival were small; 49% of men and 53% of women survived at least 5 years following CRC diagnosis; 9% of men and 12% of women with lung cancer, and 77% of men and 86% of women with malignant melanoma. The adjusted male to female relative hazard ratio of death in all patients was 1.20 (95%CI 1.13-1.30), 1.24 (95%CI 1.16-1.33) and 1.73 (95%CI 1.51-2.00) for CRC, lung cancer and malignant melanoma respectively. However, gender differences in the relative risk were much smaller amongst those who died during follow-up. For each cancer, there was little evidence of gender difference in the percentage who consulted and the number of GP contacts made within 24 months prior to diagnosis. CONCLUSIONS: This study found that patterns of consulting prior to cancer diagnosis differed little between two genders, providing no support for the hypothesis that gender differences in survival are explained by gender differences in consultation for more serious illness, and suggests the need for a more critical view of gender and consultation. PMID- 25014511 TI - Doppler renal resistive index for early detection of acute kidney injury after major orthopaedic surgery: a prospective observational study. AB - BACKGROUND: Postoperative acute kidney injury (AKI) is a cause of morbidity and mortality. Its diagnosis requires better markers than variations in diuresis or postoperative serum creatinine. OBJECTIVES: The aim of this study was to evaluate the accuracy of Doppler renal resistive index for early detection of AKI after hip or knee arthroplasty. DESIGN: A prospective observational study. SETTING: A single-centre study in a university hospital. PATIENTS: Fifty men and women older than 65 years, requiring hip or knee replacement with at least two perioperative AKI risk factors, including diabetes, arteritis, chronic heart or renal dysfunction, and prescription of angiotensin-converting enzyme (ACE) inhibitors. Exclusion criteria were poor abdominal echogenicity, arrhythmia, respiratory failure or agitation. INTERVENTION: Renal resistive index was measured preoperatively and in the postanaesthesia care unit. RESULTS: Sixteen patients presented with AKI in the postoperative period. Resistive index was increased in this group in both the preoperative [0.72 (0.69 to 0.73) vs. 0.66 (0.58 to 0.71); P = 0.01] and postoperative periods [0.75 (0.71 to 0.75) vs. 0.67 (0.62 to 0.72); P = 0.0001]. Resistive index evaluated by ROC curves and AUC to detect AKI was 0.862 [95% confidence interval (95% CI) 0.735 to 0.943]. The most accurate cut off value was a postoperative resistive index of 0.705 (sensitivity = 94%, specificity = 71%, LR+ = 3.19 and LR- = 0.09). The grey area between 0.705 and 0.73, corresponding to the inconclusive zone, included 26% (13/50) of all the patients. CONCLUSION: Postoperative resistive index appears to be effective for early detection of AKI after major orthopaedic surgery. Resistive index can be measured in the postoperative care unit in patients at risk of AKI. TRIAL REGISTRATION NUMBER: 29-0512. PMID- 25014512 TI - Antenatal testing in uncomplicated pregnancies: should testing be initiated after 40 or 41 weeks? AB - OBJECTIVE: This study aims to compare outcomes of antenatal testing in women who received testing between 40 weeks and 40+6 weeks versus those who received testing at >=41 weeks. MATERIALS AND METHODS: This retrospective study included women without maternal comorbidities, who were referred for outpatient antenatal testing for gestational age >=40 weeks. We compared women who received antenatal testing between 40 and 40+6 weeks (Group 1), to those who were only tested at >=41 weeks (Group 2). RESULTS: A total of 827 Group 1 and 244 Group 2 pregnancies were evaluated. One-hundred and eighty-nine (18%) were sent to labor and delivery (L&D) for further evaluation. There were no significant differences between groups in terms of being sent or admitted to labor and delivery, the reason for which women were sent, induction of labor, mode of delivery, neonatal length of stay, or admission to intensive care. CONCLUSION: Pregnancies tested at 40 weeks were identified as abnormal and sent to L&D at the same rate as those tested at 41 weeks. Therefore, it may be reasonable to initiate fetal surveillance at the estimated date of delivery. PMID- 25014513 TI - Placental gene expression of inflammatory markers and growth factors--a case control study of obese and normal weight women. AB - OBJECTIVE: To survey the placental gene expression of inflammatory markers and growth factors in non-smoking obese women with an uncomplicated pregnancy without associated morbidity and delivery at term compared with normal weight women. METHODS: Placental tissue samples from 32 obese women (body mass index, BMI>=35.0 kg/m2) were compared with samples from 94 normal weight women (BMI 18.5-25.0 kg/m2) matched for age (+/-1 year), gestational age (+/-3 days), parity and mode of delivery. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to analyse toll receptor-2 and -4, interleukin-6 and -8, tumour necrosis factor-alpha, leptin, adiponectin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor. RESULTS: There was no significant difference in gene expression in placental tissue samples from obese and normal weight women. CONCLUSION: We found no difference in the occurrence of inflammatory marker and growth factor mRNA levels in placental tissue samples from a large group of obese women without associated morbidity and with healthy infants compared to a closely matched control group of healthy normal weight women. Compared with the previous studies, this anomalous finding may be explained by the absence of associated morbidity in the obese women in our study. PMID- 25014514 TI - The value of lipopolysaccharide binding protein for diagnosis of late-onset neonatal sepsis in very low birth weight infants. AB - OBJECTIVE: To assess the accuracy of lipopolysaccharide binding protein (LBP) for diagnosing late-onset neonatal sepsis (LONS) in very low birth weight (VLBW) infants. STUDY DESIGN: Observational, prospective study. We assessed the diagnostic performance of LBP in 26 suspected LONS episodes among 54 patients. Proven and probable LONS episodes were recorded according to established criteria. Receiver operating characteristic curve analysis was performed to evaluate LBP's ability to predict LONS. RESULTS: LONS was diagnosed in 17 of 26 episodes. LBP levels were significantly higher in confirmed LONS episodes (P<0.001). The area under the curve of LBP was 0.89. A cut-off of 17.5 MUg/mL had a sensitivity of 94.1%, a specificity of 77.8%, a positive predictive value of 88.9% and a negative predictive value of 87.5%. CONCLUSIONS: Serum LBP measurement may be useful as an additional tool in the evaluation of suspected LONS in VLBW infants. PMID- 25014515 TI - Study of the relationship in pregnant women between hepatitis B markers and a placenta positive for hepatitis B surface antigen. AB - AIMS: A placenta with hepatitis B virus (HBV) is one of the main reasons for transplacental transmission during pregnancy. This study aims to explore the factors influencing the presence of hepatitis B surface antigen (HBsAg) in the placenta and the synergistic effect of these factors. METHODS: A total of 155 placentae and blood specimens were collected from HBsAg-positive mothers and their newborns. HBsAg in placenta was detected using the immunohistochemistry method. HBV serum markers were detected using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods. RESULTS: The results showed that hepatitis B e antigen (HBeAg) positive, or HBV DNA positive status, is significantly associated with an HBsAg-positive placenta. A synergistic effect was present. The hazard ratio for a HBsAg-positive placenta in mothers with HBeAg and HBV DNA was 1.97 times higher than the sum of the independent relative risk of each separate effect (synergy index, S=1.97). There was a statistically significant association between HBsAg in newborns and HBsAg in placenta, and the risk of newborns with HBsAg was greater (odds ratio values 3.33 and 5.31, respectively) when placental cells close to the fetal side were HBsAg positive. CONCLUSIONS: Being positive for HBeAg and/or HBV DNA are significant risk factors for HBsAg in the placenta. HBsAg can pass through the placenta via cellular transfer, possibly contributing to transplacental transmission. PMID- 25014516 TI - Haemorrhagic and thrombotic complications in pregnant women with acquired and congenital cardiac disease. AB - BACKGROUND: Pregnant patients with cardiac disease have significantly higher predicted maternal morbidity and mortality compared to the general obstetric population. Published guidelines on optimal management of these patients recommend multidisciplinary care provision. There are few published data on the incidence of haematological complications in pregnant women with cardiac disease, although the data that does exist suggests a relatively high rate of bleeding and thrombotic events. AIMS: To determine the outcomes in terms of haematological morbidity occurring within a cohort of pregnant women with cardiac disease in the setting of multidisciplinary care provision. METHODS: Patients were identified from a database compiled by the obstetric cardiology service listing all cardiac patients managed in the Rotunda maternity hospital during the period from 2004 to 2011. Data were obtained from the medical and obstetric case notes relating to details of perinatal care and the occurrence of antenatal and postnatal complications. RESULTS: During the 8-year review period, 451 women with cardiac disease were assessed. Fifty-nine were determined to have moderate to high-risk disease. Each received consultant-delivered multidisciplinary care, where written management strategies were agreed by collaborating senior colleagues either preconceptually or in early pregnancy. No venous thromboembolic events occurred and a modest rate of post-partum haemorrhage (approximately 5%) was recorded. There were no maternal deaths. CONCLUSION: The relatively favourable outcomes observed within our institution highlight the importance of a multidisciplinary approach to the management of pregnant women with cardiac disease, particularly in scenarios where limited published evidence exists to guide management. PMID- 25014517 TI - Associated anomalies in congenital diaphragmatic hernia: perinatal characteristics and impact on postnatal survival. AB - OBJECTIVE: We aimed to investigate the clinical characteristics and postnatal outcomes of fetuses with congenital diaphragmatic hernia (CDH) and additional anomalies. MATERIALS AND METHODS: We reviewed the charts of fetuses with CDH managed between 2005 and 2013. Patients were divided into complex and isolated groups based on the presence of additional anomalies. We analyzed the respective polyhydramnios, liver herniation, stomach position, lung to thorax transverse area ratio (LTR), and prognoses of the two groups. The survival rates of both groups were assessed based on the LTR as well as on stomach and liver positions. RESULTS: CDH was diagnosed in 65 fetuses, and additional anomalies were found in 23. The incidences of liver herniation, polyhydramnios, and death were significantly higher, and LTR was significantly lower, in the complex group. The mortality rate of fetuses with a LTR <0.08 was lower than that of fetuses with a LTR of >=0.08 in the complex group. Further, the survival rate of fetuses with intrathoracic liver was lower than those without liver herniation. CONCLUSIONS: The prognosis of complex CDH is poor. This may result from both the associated anomalies and the severity of CDH itself. Even in complex CDHs, intrathoracic liver and LTR values are useful in estimating postnatal outcome. PMID- 25014518 TI - Novel application of three-dimensional HDlive imaging in prenatal diagnosis from the first trimester. AB - Recent development of three-dimensional (3D) high definition (HD) ultrasound has resulted in remarkable progress in visualization of early embryos and fetuses in sonoembryology. The new technology of HDlive assesses both structural and functional developments in the first trimester with greater reliably than two dimensional (2D) ultrasound. The ability to visualize not only fetal face, hands, fingers, feet, and toes, but also amniotic membranes, is better with volumetric ultrasound than 2D ultrasound. In this article, detailed and comprehensive structures of normal and abnormal fetuses depicted by 3D HDlive are presented, including various faces of Down's syndrome and holoprosencephaly, as well as low set ear and finger/toe abnormalities from the first trimester. Three-dimensional HDlive further "humanizes" the fetus, enables detailed observation of the fetal face in the first trimester as shown in this article, and reveals that a small fetus is not more a fetus but a "person" from the first trimester. There has been an immense acceleration in understanding of early human development. The anatomy and physiology of embryonic development is a field where medicine exerts greatest impact on early pregnancy at present, and it opens fascinating aspects of embryonic differentiation. Clinical assessment of those stages of growth relies heavily on 3D/four-dimensional (4D) HDlive, one of the most promising forms of noninvasive diagnostics and embryological phenomena, once matters for textbooks are now routinely recorded with outstanding clarity. New advances deserve the adjective "breathtaking", including 4D parallel study of the structural and functional early human development. PMID- 25014519 TI - Reply to: a cerclage is not a modified Total Cervical Occlusion! PMID- 25014520 TI - Long-term biological variability of galectin-3 after heart transplantation. AB - BACKGROUND: Galectin-3 is an emerging biomarker of heart failure and of myocardial fibrosis risk. Monitoring of galectin-3 is essential during treatment with galectin-3 inhibitors. The aim of our study was to assess long-term biological variability in a specific group of unhealthy subjects. METHODS: The biological variability of galectin-3 was measured in a group of 44 patients after heart transplantation (HTx). Six samples were taken from each patient during a 12 month period. Galectin-3 was measured with an Abbott Architect automated immunoassay. RESULTS: Intraindividual (CVi) and interindividual (CVg) variabilities were calculated together with the reference change value (RCV), the log-normal RCV for increase (RCV+), and the log-normal RCV for decrease (RCV-). The CVi, CVg, RCV, RCV+, and RCV- were 28.2%, 35.6%, 78.6%, 116%, and -53.7%, respectively. The index of individuality was 0.79. CONCLUSIONS: The concentrations of galectin-3 in patients followed 12 months after HTx fluctuated around the homeostatic point, with CVi of approximately 28%. RCVs of +116% (log normal increase) and -54% (log-normal decrease) mean that the concentration of galectin-3 would need to approximately double or decrease by half to indicate a new process. PMID- 25014521 TI - Role of leptin in female reproduction. AB - Reproductive function is dependent on energy resources. The role of weight, body composition, fat distribution and the effect of diet have been largely investigated in experimental female animals as well as in women. Any alteration in diet and/or weight may induce abnormalities in timing of sexual maturation and fertility. However, the cellular mechanisms involved in the fine coordination of energy balance and reproduction are largely unknown. The brain and hypothalamic structures receive endocrine and/or metabolic signals providing information on the nutritional status and the degree of fat stores. Adipose tissue acts both as a store of energy and as an active endocrine organ, secreting a large number of biologically important molecules termed adipokines. Adipokines have been shown to be involved in regulation of the reproductive functions. The first adipokine described was leptin. Extensive research over the last 10 years has shown that leptin is not only an adipose tissue-derived messenger of the amount of energy stores to the brain, but also a crucial hormone/cytokine for a number of diverse physiological processes, such as inflammation, angiogenesis, hematopoiesis, immune function, and most importantly, reproduction. Leptin plays an integral role in the normal physiology of the reproductive system with complex interactions at all levels of the hypothalamic-pituitary gonadal (HPG) axis. In addition, leptin is also produced by placenta, where it plays an important autocrine function. Observational studies have demonstrated that states of leptin excess, deficiency, or resistance can be associated with abnormal reproductive function. This review focuses on the leptin action in female reproduction. PMID- 25014523 TI - Copeptin in critical illness. PMID- 25014524 TI - Association of retrospective markers of glycemia and the use of continuous glucose monitoring in white adults with type 2 diabetes mellitus--a preliminary report. PMID- 25014522 TI - Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia. AB - BACKGROUND: The added value of biomarkers, such as procalcitonin (PCT), C reactive protein (CRP), and white blood cells (WBC), as adjuncts to clinical risk scores for predicting the outcome of patients with community-acquired pneumonia (CAP) is in question. We investigated the prognostic accuracy of initial and follow-up levels of inflammatory biomarkers in predicting death and adverse clinical outcomes in a large and well-defined cohort of CAP patients. METHODS: We measured PCT, CRP and WBC on days 1, 3, 5, and 7 and followed the patients over 30 days. We applied multivariate regression models and area under the curve (AUC) to investigate associations between these biomarkers, the clinical risk score CURB-65, and clinical outcomes [i.e., death and intensive care unit (ICU) admission]. RESULTS: Of 925 patients with CAP, 50 patients died and 118 patients had an adverse clinical outcome. None of the initial biomarker levels significantly improved the CURB-65 score for mortality prediction. Follow-up biomarker levels showed significant independent association with mortality at days 3, 5, and 7 and with improvements in AUC. Initial PCT and CRP levels were independent prognostic predictors of adverse clinical outcome, and levels of all biomarkers during the course of disease provided additional prognostic information. CONCLUSIONS: This study provides robust insights into the added prognostic value of inflammatory markers in CAP. Procalcitonin, CRP, and to a lesser degree WBC provided some prognostic information on CAP outcomes, particularly when considering their kinetics at days 5 and 7 and when looking at adverse clinical outcomes instead of mortality alone. PMID- 25014525 TI - Editorial comment. PMID- 25014527 TI - A close look at brain dynamics: cells and vessels seen by in vivo two-photon microscopy. AB - The cerebral vasculature has a unique role in providing a constant supply of oxygen and nutrients to ensure normal brain functions. Blood vessels that feed the brain are far from being simply channels for passive transportation of fluids. They form complex structures made up of different cell types. These structures regulate blood supply, local concentrations of O2 and CO2, transport of small molecules, trafficking of plasma cells and fine cerebral functions in normal and diseased brains. Until few years ago, analysis of these functions has been typically based on post mortem techniques, whose interpretation is limited by the need for tissue processing at specific times. For a reliable and effective picture of the dynamic processes in the central nervous system, real-time information in vivo is required. There are now few in vivo systems, among which two-photon microscopy (2-PM) is a truly innovative tool for studying the brain. 2 PM has been used to dissect specific aspects of vascular and immune cell dynamics in the context of neurological diseases, providing exciting results that could not have been obtained with conventional methods. This review summarizes the latest findings on vascular and immune system action in the brain, with particular focus on the dynamic responses after ischemic brain injury. 2-PM has helped define the hierarchical architecture of the brain vasculature, the dynamic interaction between the vasculature and immune cells recruited to lesion sites, the effects of blood flow on neuronal and microglial activity and the ability of cells of the neurovascular unit to regulate blood flow. PMID- 25014526 TI - Greater physiological and behavioral effects of interrupted stress pattern compared to daily restraint stress in rats. AB - Repeated stress can trigger a range of psychiatric disorders, including anxiety. The propensity to develop abnormal behaviors after repeated stress is related to the severity, frequency and number of stressors. However, the pattern of stress exposure may contribute to the impact of stress. In addition, the anxiogenic nature of repeated stress exposure can be moderated by the degree of coping that occurs, and can be reflected in homotypic habituation to the repeated stress. However, expectations are not clear when a pattern of stress presentation is utilized that diminishes habituation. The purpose of these experiments is to test whether interrupted stress exposure decreases homotypic habituation and leads to greater effects on anxiety-like behavior in adult male rats. We found that repeated interrupted restraint stress resulted in less overall homotypic habituation compared to repeated daily restraint stress. This was demonstrated by greater production of fecal boli and greater corticosterone response to restraint. Furthermore, interrupted restraint stress resulted in a lower body weight and greater adrenal gland weight than daily restraint stress, and greater anxiety-like behavior in the elevated plus maze. Control experiments demonstrated that these effects of the interrupted pattern could not be explained by differences in the total number of stress exposures, differences in the total number of days that the stress periods encompased, nor could it be explained as a result of only the stress exposures after an interruption from stress. These experiments demonstrate that the pattern of stress exposure is a significant determinant of the effects of repeated stress, and that interrupted stress exposure that decreases habituation can have larger effects than a greater number of daily stress exposures. Differences in the pattern of stress exposure are therefore an important factor to consider when predicting the severity of the effects of repeated stress on psychiatric disorders. PMID- 25014528 TI - Functional brain connectivity from EEG in epilepsy: seizure prediction and epileptogenic focus localization. AB - Today, neuroimaging techniques are frequently used to investigate the integration of functionally specialized brain regions in a network. Functional connectivity, which quantifies the statistical dependencies among the dynamics of simultaneously recorded signals, allows to infer the dynamical interactions of segregated brain regions. In this review we discuss how the functional connectivity patterns obtained from intracranial and scalp electroencephalographic (EEG) recordings reveal information about the dynamics of the epileptic brain and can be used to predict upcoming seizures and to localize the seizure onset zone. The added value of extracting information that is not visibly identifiable in the EEG data using functional connectivity analysis is stressed. Despite the fact that many studies have showed promising results, we must conclude that functional connectivity analysis has not made its way into clinical practice yet. PMID- 25014530 TI - Lycodine-type alkaloids from Lycopodiastrum casuarinoides and their acetylcholinesterase inhibitory activity. AB - Four new lycodine-type alkaloids, namely 16-hydroxyhuperzine B (1), N-methyl-11 acetoxyhuperzine B (2), 8,15-dihydrolycoparin A (3) and (7S,12S,13R)-huperzine D 16-O-beta-d-glucopyranoside (4), along with ten known analogues 5-14, were isolated from the whole plant of Lycopodiastrum casuarinoides. The structures of the new compounds were elucidated by means of spectroscopic techniques (IR, MS, NMR, and CD) and chemical methods. Compounds 1 and 2 possessed four connected six membered rings, while compounds 3 and 4 were piperidine ring cleavage products. In particular, compound 4 was a lycopodium alkaloidal glycoside which is reported for the first time. Among the isolated compounds N-demethylhuperzinine (7), huperzine C (8), huperzine B (9) and lycoparin C (13) possessed significant inhibitory activity against acetylcholinesterase, and the new compound 1 showed moderate inhibitory activity. The structure activity relationships were discussed. PMID- 25014531 TI - Plumbagin modulates leukemia cell redox status. AB - Plumbagin is a plant naphtoquinone exerting anti-cancer properties including apoptotic cell death induction and generation of reactive oxygen species (ROS). The aim of this study was to elucidate parameters explaining the differential leukemia cell sensitivity towards this compound. Among several leukemia cell lines, U937 monocytic leukemia cells appeared more sensitive to plumbagin treatment in terms of cytotoxicity and level of apoptotic cell death compared to more resistant Raji Burkitt lymphoma cells. Moreover, U937 cells exhibited a ten fold higher ROS production compared to Raji. Neither differential incorporation, nor efflux of plumbagin was detected. Pre-treatment with thiol-containing antioxidants prevented ROS production and subsequent induction of cell death by apoptosis whereas non-thiol-containing antioxidants remained ineffective in both cellular models. We conclude that the anticancer potential of plumbagin is driven by pro-oxidant activities related to the cellular thiolstat. PMID- 25014532 TI - Facile, regio- and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities. AB - A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E) arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 MUM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-alpha-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines. PMID- 25014533 TI - Polyphenolic content, antioxidant and antimicrobial activities of Lycium barbarum L. and Lycium chinense Mill. leaves. AB - This study was performed to evaluate the in vitro antioxidant and antimicrobial activities and the polyphenolic content of Lycium barbarum L. and L. chinense Mill. leaves. The different leave extracts contain important amounts of flavonoids (43.73 +/- 1.43 and 61.65 +/- 0.95 mg/g, respectively) and showed relevant antioxidant activity, as witnessed by the quoted methods. Qualitative and quantitative analyses of target phenolic compounds were achieved using a HPLC UV-MS method. Rutin was the dominant flavonoid in both analysed species, the highest amount being registered for L. chinense. An important amount of chlorogenic acid was determined in L. chinense and L. barbarum extracts, being more than twice as high in L. chinense than in L. barbarum. Gentisic and caffeic acids were identified only in L. barbarum, whereas kaempferol was only detected in L. chinense. The antioxidant activity was evaluated by DPPH, TEAC, hemoglobin ascorbate peroxidase activity inhibition (HAPX) and inhibition of lipid peroxidation catalyzed by cytochrome c assays revealing a better antioxidant activity for the L. chinense extract. Results obtained in the antimicrobial tests revealed that L. chinense extract was more active than L. barbarum against both Gram-positive and Gram-negative bacterial strains. The results suggest that these species are valuable sources of flavonoids with relevant antioxidant and antimicrobial activities. PMID- 25014534 TI - Molecular and chemical regulation of the Keap1-Nrf2 signaling pathway. AB - Extracellular and intracellular oxidants or electrophiles are key contributors to the damages in cellular macromolecules, such as DNA, proteins and lipids. Nrf2 is a master transcription factor that modulates a cellular antioxidant response program and plays an important role in the protection against oxidants and electrophiles. Keap1 is a regulator of Nrf2 by serving as a substrate adaptor for Cullin3-dependent E3 ubiquitin ligase. While Nrf2 activation is a feasible strategy for treatment of age-related diseases, aberrant Nrf2 activation also confers a selective growth advantage of tumor cells during chemotherapy or radiotherapy. In the present review, we provide an overview of the Keap1-Nrf2-ARE system, the domain organization of Nrf2 and Keap1, and the regulatory mechanisms of Nrf2 proteolysis by Keap1. We also discuss how Nrf2 prevents tumor promotion, hampers the sensitivity of selected tumors against chemotherapy or radiotherapy, and reprograms the metabolism to facilitate the tumor proliferation. Finally, we illustrate the current status in the development of Nrf2 chemical activators and inhibitors for the use of potential chemopreventive agents and chemotherapeutic adjuvants, respectively. PMID- 25014535 TI - Synthesis of a 2"-deoxy-beta-GalCer. AB - Structural studies of ternary complexes of CD1d/glycosyl ceramides/iNKT cells and CD1d/sulfatide/sulfatide reactive Type II NKT cells have shown how the polar moieties on the glycolipids interact with both the antigen presenting protein (CD1d) and the T cell receptors. However, these structures alone do not reveal the relative importance of these interactions. This study focuses on the synthesis of the previously unknown 2"-deoxy-beta-galactosyl ceramide 2. This glycolipid is also evaluated for its ability to stimulate iNKT cells and sulfatide-reactive Type II NKT cells. PMID- 25014536 TI - Capsaicin: a potent inhibitor of carbonic anhydrase isoenzymes. AB - Carbonic anhydrase (CA, EC 4.2.1.1) is a zinc containing metalloenzyme that catalyzes the rapid and reversible conversion of carbon dioxide (CO2) and water (H2O) into a proton (H+) and bicarbonate (HCO3-) ion. On the other hand, capsaicin is the main component in hot chili peppers and is used extensively used in spices, food additives and drugs; it is responsible for their spicy flavor and pungent taste. There are sixteen known CA isoforms in humans. Human CA isoenzymes I, and II (hCA I and hCA II) are ubiquitous cytosolic isoforms. In this study, the inhibition properties of capsaicin against the slow cytosolic isoform hCA I, and the ubiquitous and dominant rapid cytosolic isozymes hCA II were studied. Both CA isozymes were inhibited by capsaicin in the micromolar range. This naturally bioactive compound has a Ki of 696.15 uM against hCA I, and of 208.37 uM against hCA II. PMID- 25014538 TI - The toxic effect of air on primary human retinal pigment epithelium cells. AB - PURPOSE: To investigate the toxic effect of air on primary human retinal pigment epithelium cells (RPE) over time. METHODS: RPE cultures were retrieved from six donor eyes and cultivated at 37 degrees C in 5% CO(2) and 95% humidified air. The RPE were divided in six groups with each group containing four samples. Six groups of RPE cultures were set up and four samples were enclosed in each group: group 1 consisted of samples in which RPE were exposed to air for 1 hour. Group 2 consisted of RPE exposed to air for 3 hours, group 3 for 6 hours group 4 for 12 hours group 5 for 24 hours and group 6 for 36 hours respectively. RESULTS: Six hours after exposure, the morphology of the cells was still intact. At 12 hours few cells appeared enlarged. 24 hours after exposure to air the cells started losing their typical morphology and appeared deformed. Viability was higher than 95% in groups 1-3 while for groups 4-6 was 75.5%, 15.5% and 7.3%, respectively. CONCLUSION: The toxic effect of air for the studied in vitro model of RPE is not significant for the first 6 hours. The morphology of the cells progressively changed after 12 hours of exposure and almost all cells appeared apoptotic at 36 hours. PMID- 25014537 TI - ESEEM analysis of multi-histidine Cu(II)-coordination in model complexes, peptides, and amyloid-beta. AB - We validate the use of ESEEM to predict the number of (14)N nuclei coupled to a Cu(II) ion by the use of model complexes and two small peptides with well-known Cu(II) coordination. We apply this method to gain new insight into less explored aspects of Cu(II) coordination in amyloid-beta (Abeta). Abeta has two coordination modes of Cu(II) at physiological pH. A controversy has existed regarding the number of histidine residues coordinated to the Cu(II) ion in component II, which is dominant at high pH (~8.7) values. Importantly, with an excess amount of Zn(II) ions, as is the case in brain tissues affected by Alzheimer's disease, component II becomes the dominant coordination mode, as Zn(II) selectively substitutes component I bound to Cu(II). We confirm that component II only contains single histidine coordination, using ESEEM and set of model complexes. The ESEEM experiments carried out on systematically (15)N labeled peptides reveal that, in component II, His 13 and His 14 are more favored as equatorial ligands compared to His 6. Revealing molecular level details of subcomponents in metal ion coordination is critical in understanding the role of metal ions in Alzheimer's disease etiology. PMID- 25014539 TI - A large scale population-based cohort study on the risk of ovarian neoplasm in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To investigate whether the risk of developing ovarian cancer is elevated in women with diabetes mellitus. METHODS: The study is a population based cohort study. Women with type 2 diabetes (n=319,310) and age-matched controls (n=319,308) were selected from the ambulatory care claims and beneficiary registry in 2000, respectively. Selected patients were linked to the in-patient claims (2000-2008) to identify admissions due to ovarian (ICD-9-CM: 183.xx) cancer. The person-year approach with Poisson assumption was used to estimate the incidence density rate. The age-specific hazard ratios (HRs) of ovarian cancer in relation to diabetes were calculated using multivariate Cox proportional hazard regression model. RESULTS: The overall incidence density rate of ovarian cancer was estimated at 1.87 (95% confidence interval (CI) 1.70-2.05) per 10,000 patient-years for patients with diabetes. The corresponding figures for controls were slightly lower at 1.79 per 10,000 patient-years. The incidence density of ovarian cancer was increased with age in diabetes but not in controls. The covariate-adjusted HR for ovarian cancer was statistically compared with null (adjusted HR=1.06, 95% CI=0.92-1.22) in women with diabetes. Moderately elevated HR was noted in women with diabetes aged <50 (adjusted HR=1.17, 95% CI=0.82-1.65) and in women with diabetes aged >65 (adjusted HR=1.10, 95% CI=0.92-1.42). The null association between diabetes and ovarian cancer remains true regardless of the disease duration of diabetes. CONCLUSION: This large-scale cohort study provides little support on the putative association between type 2 diabetes and the risk of ovarian cancer. PMID- 25014540 TI - Overall survival after pelvic exenteration for gynecologic malignancy. AB - BACKGROUND: Five-Year survival after pelvic exenteration for gynecologic malignancies has been reported as high as 60%. The objective of this study was to determine overall survival (OS) after pelvic exenteration and evaluate factors impacting outcome. METHODS: A retrospective review of all women who underwent pelvic exenteration at our institution between February 1993 and December 2010 was performed. OS was defined as time from exenteration to date of death or last contact. Survival analysis was performed using the Kaplan Meyer method. Multivariate analysis was performed to determine the impact of clinical and pathologic factors on survival outcomes. RESULTS: One hundred sixty patients with gynecologic malignancy underwent pelvic exenteration. Five-year recurrence free survival (RFS) was 33% (95%CI 0.25-0.40). Factors which negatively impacted RFS included shorter treatment-free interval (p=.050), vulvar primary (p=.032), positive margins (p<.001), lymphovascular space invasion (LVSI, p<.001), positive lymph nodes (p<.001) and perineural invasion (p=0.030). In multivariate analysis, positive margins (p=.040), positive nodes (p<.001) and lymphovascular space invasion (LVSI, p=.003) retained a significant impact on RFS. Five-year OS was 40% (95% CI 0.32-0.48). Factors which negatively impacted OS included vulvar primary (p=.04), positive margins (p<.001), LVSI (p<.001), positive lymph nodes (p<.001) and perineural invasion (p=.008). In multivariate analysis, positive nodes (p=.001) and LVSI (p=.001) retained a significant impact on OS. CONCLUSION: Five-year OS after pelvic exenteration was 40%. Survival outcomes have not significantly improved despite improvements in technique and patient selection. Multiple non-modifiable factors at the time of exenteration are associated with poor survival. PMID- 25014542 TI - Adnexal masses requiring surgical intervention in women with advanced cervical cancer. AB - OBJECTIVE: Surgical evaluation of adnexal masses in patients with cervical cancer can be considered in order to optimize treatment outcomes and rule out a second pathologic process. Our objective was to review treatment patterns and outcomes in women with advanced cervical cancer (ACC) and an adnexal mass. METHODS: A retrospective review was performed with IRB approval of patients treated for advanced cervical cancer at our institution between 1990 and 2011. Patients were identified using institutional databases and tumor registries. Descriptive statistics were performed using Microsoft Excel 2011 and Instat was used to perform Fisher's exact test and student T-tests. RESULTS: Two hundred twenty eight patients with stage IIB-IVB cervical cancer were identified, 50 (22%) of whom had an adnexal mass on initial imaging studies (31 stage IIB, 15 stage IIIB, 3 stage IVA, 3 stage IVB). The mean follow up time of patients with adnexal masses was 22 months (range 3-128 months). Thirteen of 50 (26%) patients underwent surgical evaluation of the adnexal mass. Six were found to have cervical cancer metastatic to the adnexae, while seven had benign adnexal lesions. Thirty-seven of 50 (74%) patients were conservatively managed. All 37 women had cystic masses <8 cm or complex masses <5 cm in size. Thirty-four of the 37 (92%) patients had resolution of their adnexal mass and 3 were deemed stable on follow up imaging. Twenty three percent of surgically managed patients and 57% of conservatively managed patients had disease recurrence (p=0.05). There were no recurrences in the adnexa. CONCLUSION: Twelve percent of women with ACC and an adnexal mass have ovarian metastases. Patients with cystic masses less than 8 cm and complex masses less than 5 cm in size can be expectantly managed. PMID- 25014541 TI - Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma. AB - OBJECTIVE: The renin-angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is the main effector of RAS, and AGTR2 antagonizes AGTR1. Accumulating evidence supports the role of RAS in the paracrine regulation of tumorigenesis in several cancer types. Although treatment with AGTR1 antagonist (losartan) or AGTR2 agonist (CGP42112A) inhibits tumor progression in several cancer cells, their combined treatment has not been reported. METHODS: In this study, we estimated the expression of AGTR1 and AGTR2 in epithelial ovarian cancer cells and tissues. Then, we evaluated the anti cancer effects of combined treatment with losartan and/or CGP42112A in ovarian cancer cells and human umbilical vein endothelial cells (HUVEC). RESULTS: AGTR1 protein was detected in 86% of ovarian cancer tissues, while AGTR2 was not detected in immunohistochemistry. The mRNA expression of AGTR1 obtained from the cancer genome atlas (TCGA) dataset showed that AGTR1 overexpression was correlated with poor survival. Treatment with either losartan or CGP42112A reduced the angiotensin II (Ang II)-mediated cell survival in both ovarian cancer cells and HUVEC. Combined treatment with losartan and CGP42112A synergistically decreased cell survival. As a downstream pathway, phosphorylation of phospholipase C beta3 (PLC beta3) and expression of vascular endothelial growth factor (VEGF) decreased synergistically in combined treatment. CONCLUSION: The results suggest that dual regulation of AGTR1 and AGTR2 may be a novel therapeutic strategy for epithelial ovarian carcinoma through inhibition of cancer cell survival as well as anti-angiogenesis. TRANSLATIONAL RELEVANCE: This study investigated the expressions of AGTR1 and AGTR2 in epithelial ovarian carcinoma and the therapeutic potential of AGTR modulation with specific antagonist and/or agonist in epithelial ovarian cancer cells. Treatment of AGTR1 antagonist, losartan and/or AGTR2 agonist, CGP42112A synergistically mediated anti-cancer effects including the decrease of cell survival and down-regulation of VEGF. PMID- 25014543 TI - Validation of the modes of transmission model as a tool to prioritize HIV prevention targets: a comparative modelling analysis. AB - BACKGROUND: The static Modes of Transmission (MOT) model predicts the annual fraction of new HIV infections acquired across subgroups (MOT metric), and is used to focus HIV prevention. Using synthetic epidemics via a dynamical model, we assessed the validity of the MOT metric for identifying epidemic drivers (behaviours or subgroups that are sufficient and necessary for HIV to establish and persist), and the potential consequence of MOT-guided policies. METHODS AND FINDINGS: To generate benchmark MOT metrics for comparison, we simulated three synthetic epidemics (concentrated, mixed, and generalized) with different epidemic drivers using a dynamical model of heterosexual HIV transmission. MOT metrics from generic and complex MOT models were compared against the benchmark, and to the contribution of epidemic drivers to overall HIV transmission (cumulative population attributable fraction over t years, PAFt). The complex MOT metric was similar to the benchmark, but the generic MOT underestimated the fraction of infections in epidemic drivers. The benchmark MOT metric identified epidemic drivers early in the epidemics. Over time, the MOT metric did not identify epidemic drivers. This was not due to simplified MOT models or biased parameters but occurred because the MOT metric (irrespective of the model used to generate it) underestimates the contribution of epidemic drivers to HIV transmission over time (PAF5-30). MOT-directed policies that fail to reach epidemic drivers could undermine long-term impact on HIV incidence, and achieve a similar impact as random allocation of additional resources. CONCLUSIONS: Irrespective of how it is obtained, the MOT metric is not a valid stand-alone tool to identify epidemic drivers, and has limited additional value in guiding the prioritization of HIV prevention targets. Policy-makers should use the MOT model judiciously, in combination with other approaches, to identify epidemic drivers. PMID- 25014544 TI - A versatile complementation assay for cell-to-cell and long distance movements by cucumber mosaic virus based agro-infiltration. AB - Microinjection, bombardment or tobamovirus and potexvirus based assay has been developed to identify the putative movement protein (MP) or to characterize plasmodesma-mediated macromolecular transport. In this study, we developed a versatile complementation assay for the cell-to-cell and long distance movements of macromolecules by agro-infiltration based on the infectious clones of cucumber mosaic virus (CMV). The movement-deficient CMV reporter was constructed by replacing the MP on RNA 3 with ER targeted GFP. The ectopic expression of CMV MP was able to efficiently move the RNA3-MP::erGFP reporter from the original cell to neighboring cells, whereas CMV MP-M5 mutant was unable to initiate the movement. Importantly, the presence of CMV RNA1 and RNA2 can dramatically amplify the movement signals once the RNA3-MP::erGFP reporter moves out of the original cell. The appropriate observation time for this movement complementation assay was at 48-72 hours post infiltration (hpi), whereas the optimal incubation temperature was between 25 and 28 degrees C. The ectopic co-expression of MPs from other virus genera, NSm from tomato spotted wilt tospovirus (TSWV) or NSvc4 from rice stripe tenuivirus (RSV), could also facilitate the movement of the RNA3::erGFP reporter from the original cell into other cells. The chimeric mutant virus created by substituting the MP of CMV RNA3 with NSm from TSWV or NSvc4 from RSV move systemically in Nicotiana benthamiana plants by agro-infiltration. This agro-infiltration complementation assay is simple, efficient and reliable. Our approach provides an alternative and powerful tool with great potentials in identifying putative movement protein and characterizing macromolecular trafficking. PMID- 25014545 TI - Effects of density functionals and dispersion interactions on geometries, bond energies and harmonic frequencies of EUX3 (E=N, P, CH; X=H, F, Cl). AB - Quantum-chemical calculations have been performed to evaluate the geometries, bonding nature and harmonic frequencies of the compounds [EUX3] at DFT, DFT-D3, DFT-D3(BJ) and DFT-dDSc levels using different density functionals BP86, BLYP, PBE, revPBE, PW91, TPSS and M06-L. The stretching frequency of UN bond in [NUF3] calculated with DFT/BLYP closely resembles with the experimental value. The performance of different density functionals for accurate UN vibrational frequencies follows the order BLYP>revPBE>BP86>PW91>TPSS>PBE>M06-L. The BLYP functional gives accurate value of the UE bond distances. The uranium atom in the studied compounds [EUX3] is positively charged. Upon going from [EUF3] to [EUCl3], the partial Hirshfeld charge on uranium atom decreases because of the lower electronegativity of chlorine compared to flourine. The Gopinathan-Jug bond order for UE bonds ranges from 2.90 to 3.29. The UE bond dissociation energies vary with different density functionals as M06-L0.05) was observed in the CA yield for given doses except 4 and 5Gy, between the laboratories, among the scorers and also staining methods adapted suggest the reliability and validates the inter-lab comparisons exercise for triage applications. PMID- 25014549 TI - Complete inhibition of the renin-angiotensin-aldosterone system; where do we stand? AB - PURPOSE OF REVIEW: This review presents the role of combination therapy of renin angiotensin-aldosterone system blockade on cardiovascular and kidney disease. RECENT FINDINGS: Three large randomized controlled trials comparing combination therapy of renin-angiotensin-aldosterone system blockade to monotherapy in individuals with increased cardiovascular risk, chronic kidney disease, or diabetic nephropathy have been reported. These trials - ONTARGET, ALTITUDE, and VA NEPHRON-D - demonstrated an excess risk of adverse effects [especially acute kidney injury (AKI) and hyperkalemia] with combination therapy, without significant benefit in reducing cardiovascular and renal morbidity. SUMMARY: Current evidence supports avoiding dual renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. Subsequent studies of dual renin-angiotensin-aldosterone system blockade should examine adverse event risks and renal progression endpoints. PMID- 25014550 TI - Synchronous gist, colon and breast adenocarcinoma with double colonic polyp metastases. AB - INTRODUCTION: Long term survivors of breast cancer are at risk of developing distant metastasis years after the initial treatment. We report a case of breast adenocarcinoma with colonic polyp metastases, as well as synchronous primary colonic adenocarcinoma and a gastric GIST. PRESENTATION OF CASE: An 83 year old female underwent colonoscopy for rectal bleeding. This showed a primary colonic adenocarcinoma, a pedunculated polyp in the ascending colon and two polyps in the sigmoid colon. A staging CT scan did not show distant metastasis, but revealed a small gastric GIST which was managed conservatively. A right hemicolectomy showed a T3N0 colonic adenocarcinoma and a polyp contained metastatic adenocarcinoma from a breast primary. The patient had undergone surgery 30 years ago for an invasive lobular carcinoma. Further clinical assessment demonstrated an impalpable grade II Invasive ductal carcinoma in the contralateral breast. She was started on hormonal treatment and at 18 months follow-up, she was well with stable disease. DISCUSSION: Invasive lobular cancer is the most common histological type of breast cancer that metastasizes to the colon. There is no consensus on the management of breast cancer metastasis to the gastrointestinal tract. Co-existence of a GIST and an adenocarcinoma at two separate locations is uncommon. These are two different cancer entities and it is unclear whether these two are related by as causal relationship. CONCLUSION: This is a rare case of three distinct tumours; association between them is unlikely. However, the case highlights the importance of a multidisciplinary approach to cancer treatment. PMID- 25014551 TI - Dynamics of the microbiota in response to host infection. AB - Longitudinal studies of the microbiota are important for discovering changes in microbial communities that affect the host. The complexity of these ecosystems requires rigorous integrated experimental and computational methods to identify temporal signatures that promote physiologic or pathophysiologic responses in vivo. Employing a murine model of infectious colitis with the pathogen Citrobacter rodentium, we generated a 2-month time-series of 16S rDNA gene profiles, and quantitatively cultured commensals, from multiple intestinal sites in infected and uninfected mice. We developed a computational framework to discover time-varying signatures for individual taxa, and to automatically group signatures to identify microbial sub-communities within the larger gut ecosystem that demonstrate common behaviors. Application of this model to the 16S rDNA dataset revealed dynamic alterations in the microbiota at multiple levels of resolution, from effects on systems-level metrics to changes across anatomic sites for individual taxa and species. These analyses revealed unique, time dependent microbial signatures associated with host responses at different stages of colitis. Signatures included a Mucispirillum OTU associated with early disruption of the colonic surface mucus layer, prior to the onset of symptomatic colitis, and members of the Clostridiales and Lactobacillales that increased with successful resolution of inflammation, after clearance of the pathogen. Quantitative culture data validated findings for predominant species, further refining and strengthening model predictions. These findings provide new insights into the complex behaviors found within host ecosystems, and define several time dependent microbial signatures that may be leveraged in studies of other infectious or inflammatory conditions. PMID- 25014553 TI - Picking up the threads: extracellular matrix signals in epithelial morphogenesis. AB - Basal adhesion signals are the main driver of epithelial polarization and differentiation. Recent advances are starting to expose a novel and remarkable complexity in extracellular matrix control of epithelial morphogenesis. Mechanical properties such as matrix stiffness and cell confinement are emerging as key regulators of epithelial behavior, modulating cytoskeletal dynamics, which transduce into nuclear signals that regulate differentiation. Moreover, coherent cell migration behaviors, such as organ rotation, control basement membrane secretion and reorganization, and matrix degradation and remodeling are now proposed to be required for proper polarity maintenance and acquisition of organ shape. Furthermore, planar cell polarity components orient all these activities, thus, providing a reasonable explanation for the generation of morphogenetic axes during morphogenesis. PMID- 25014554 TI - Optically controlled molecular switching of an indolobenzoxazine-type photochromic compound. AB - Photochromic forward (oxazine ring-opening) and backward (oxazine ring-closing) switching dynamics of an indolobenzoxazine compound were studied by femtosecond pump-repump-probe technique. A UV pulse was used to excite the ring-closed form of the photochromic compound, causing a C-O bond cleavage and the formation of a spectrally red-shifted isomer within a time scale of ca. 100 ps. A successive, temporally delayed near-IR pulse, resonant to the red-most absorption maximum of the ring-opened form, was used to reexcite the molecular system, causing a fast photoinduced oxazine ring closure, thereby "short-circuiting" the normally nanosecond lasting photocycle and returning ~6% of the molecules to the main molecular ground state. Two possible models, involving the S1 excited state of the terminal photoproduct and its hot ground state, are introduced to explain the pre- and post-reexcitation spectral development and the photoinduced switching back mechanics. PMID- 25014552 TI - Localized micro- and nano-scale remodelling in the diabetic aorta. AB - Diabetes is strongly associated with cardiovascular disease, but the mechanisms, structural and biomechanical consequences of aberrant blood vessel remodelling remain poorly defined. Using an experimental (streptozotocin, STZ) rat model of diabetes, we hypothesized that diabetes enhances extracellular protease activity in the aorta and induces morphological, compositional and localized micromechanical tissue remodelling. We found that the medial aortic layer underwent significant thickening in diabetic animals but without significant changes in collagen or elastin (abundance). Scanning acoustic microscopy demonstrated that such tissue remodelling was associated with a significant decrease in acoustic wave speed (an indicator of reduced material stiffness) in the inter-lamellar spaces of the vessel wall. This index of decreased stiffness was also linked to increased extracellular protease activity (assessed by semi quantitative in situ gelatin zymography). Such a proteolytically active environment may affect the macromolecular structure of long-lived extracellular matrix molecules. To test this hypothesis, we also characterized the effects of diabetes on the ultrastructure of an important elastic fibre component: the fibrillin microfibril. Using size exclusion chromatography and atomic force microscopy, we isolated and imaged microfibrils from both healthy and diabetic aortas. Microfibrils derived from diabetic tissues were fragmented, morphologically disrupted and weakened (as assessed following molecular combing). These structural and functional abnormalities were not replicated by in vitro glycation. Our data suggest that proteolysis may be a key driver of localized mechanical change in the inter-lamellar space of diabetic rat aortas and that structural proteins (such as fibrillin microfbrils) may be biomarkers of diabetes induced damage. PMID- 25014555 TI - Two karate kids with pediatric idiopathic intervertebral disc calcification. PMID- 25014557 TI - Bilateral facet dislocation of the C2-C3 cervical spine with double level spinal cord transection. PMID- 25014558 TI - Heterotopic ossification after transforaminal lumbar interbody fusion without bone morphogenetic protein use. PMID- 25014556 TI - Is multimodal care effective for the management of patients with whiplash associated disorders or neck pain and associated disorders? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - BACKGROUND CONTEXT: Little is known about the effectiveness of multimodal care for individuals with whiplash-associated disorders (WAD) and neck pain and associated disorders (NAD). PURPOSE: To update findings of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders and evaluate the effectiveness of multimodal care for the management of patients with WAD or NAD. STUDY DESIGN/SETTING: Systematic review and best-evidence synthesis. PATIENT SAMPLE: We included randomized controlled trials (RCTs), cohort studies, and case-control studies. OUTCOME MEASURES: Self-rated recovery, functional recovery (eg, disability, return to activities, work, or school), pain intensity, health-related quality of life, psychological outcomes (eg, depression, fear), or adverse events. METHODS: We systematically searched five electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Central Register of Controlled Trials) from 2000 to 2013. RCTs, cohort, and case-control studies meeting our selection criteria were eligible for critical appraisal. Random pairs of independent reviewers critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network criteria. Scientifically admissible studies were summarized using evidence tables and synthesized following best-evidence synthesis principles. RESULTS: We retrieved 2,187 articles, and 23 articles were eligible for critical appraisal. Of those, 18 articles from 14 different RCTs were scientifically admissible. There were a total of 31 treatment arms, including 27 unique multimodal programs of care. Overall, the evidence suggests that multimodal care that includes manual therapy, education, and exercise may benefit patients with grades I and II WAD and NAD. General practitioner care that includes reassurance, advice to stay active, and resumption of regular activities may be an option for the early management of WAD grades I and II. Our synthesis suggests that patients receiving high-intensity health care tend to experience poorer outcomes than those who receive fewer treatments for WAD and NAD. CONCLUSIONS: Multimodal care can benefit patients with WAD and NAD with early or persistent symptoms. The evidence does not indicate that one multimodal care package is superior to another. Clinicians should avoid high utilization of care for patients with WAD and NAD. PMID- 25014559 TI - Spinal cord infarct as the primary presentation of aortic dissection. PMID- 25014560 TI - Evaluation of matrix effects using a spike recovery approach in a dilute-and inject liquid chromatography-tandem mass spectrometry opioid monitoring assay. AB - BACKGROUND: Liquid chromatography-tandem mass spectrometry has become the gold standard for quantitative analysis of compounds in human matrices. Introduction of these assays into clinical practice, where false positive and false negative results have substantial implications, requires careful attention to matrix effects. We describe an evaluation of matrix effects in human urine from a dilute and-inject liquid chromatography-tandem mass spectrometric assay for the quantitative analysis of opioids and metabolites. METHODS: A spike-recovery approach was employed for each analyte in each sample. We examined the impact of spike-recovery for the 6 glucuronides measured in this assay and compared the analytes for which conventional stable isotope-labeled internal standards were used with the analytes for which analog internal standards were used. RESULTS: For analytes that had analog internal standards, up to 1.5% of negative samples failed our requirement of recovering at least 80% of the expected spiked concentration while passing all other quality control parameters. CONCLUSIONS: Using spike-recovery as a quality control parameter decreases the rate of false negatives for compounds using analog internal standards, but does not have benefit for compounds with conventional stable isotope-labeled internal standards. PMID- 25014562 TI - The ACA's contraceptive mandate: religious freedom, women's health, and corporate personhood. PMID- 25014561 TI - Structure, integrity, and function of the hypoplastic corpus callosum in spina bifida myelomeningocele. AB - Although there are many studies of people with complete or partial hypogenesis of the corpus callosum (CC), little is understood about the hypoplastic CC in which all structures are present but thinned. Spina bifida myelomeningocele (SBM) is a model organism for such studies because many have either a hypogenetic or hypoplastic CC. We used diffusion tensor tractography (DTT) to evaluate the hypoplastic CC in SBM and its relation to interhemispheric functions and intelligence quotient (IQ). Participants were individuals with SBM and an intact or hypoplastic CC (n=28), who were compared to a typically developing comparison group (n=32). Total and regional DTT volume and integrity measures (fractional anisotropy, axial diffusivity, and radial diffusivity) of the CC were related to measures of intelligence (IQ), bimanual motor functioning, and dichotic auditory performance. As predicted, DTT showed variations in volume and integrity that were maximized in the entire CC and the posterior CC. IQ correlated with entire CC volume, anterior and posterior regional CC volumes, and also with measures of integrity. Bimanual motor functioning correlated with the anterior and posterior volumes of the CC but not with any integrity measures. Axial diffusivity in the posterior CC was negatively correlated with right ear dichotic listening performance. The hypoplastic CC is not macrostructurally or microstructurally intact in SBM, even when it appears radiologically intact. Both volume and integrity of the posterior regions were related to reductions in IQ and to interhemispheric processing. These findings may transfer to other disorders characterized by a hypoplastic CC. PMID- 25014563 TI - A critical analysis of calcium carbonate mesocrystals. AB - The term mesocrystal has been widely used to describe crystals that form by oriented assembly, and that exhibit nanoparticle substructures. Using calcite crystals co-precipitated with polymers as a suitable test case, this article looks critically at the concept of mesocrystals. Here we demonstrate that the data commonly used to assign mesocrystal structure may be frequently misinterpreted, and that these calcite/polymer crystals do not have nanoparticle substructures. Although morphologies suggest the presence of nanoparticles, these are only present on the crystal surface. High surface areas are only recorded for crystals freshly removed from solution and are again attributed to a thin shell of nanoparticles on a solid calcite core. Line broadening in powder X-ray diffraction spectra is due to lattice strain only, precluding the existence of a nanoparticle sub-structure. Finally, study of the formation mechanism provides no evidence for crystalline precursor particles. A re-evaluation of existing literature on some mesocrystals may therefore be required. PMID- 25014564 TI - Fouling of enhanced biological phosphorus removal-membrane bioreactors by humic like substances. AB - Fouling by free extracellular polymeric substances was studied in an enhanced biological phosphorus removal-membrane bioreactor. It was demonstrated that the free extracellular polymeric substances, primarily consisting of humic-like substances, were adsorbed to the membrane used in the enhanced biological phosphorus removal-membrane bioreactor plant. Infrared analyses indicated the presence of the humic-like substances on the membrane's active surface after filtration of the free extracellular polymeric substances suspension. Scanning electron microscopy showed the presence of a gel layer on the membrane surface after filtration of the free extracellular polymeric substances suspension. The gel layer caused a significant decline in water flux. This layer was not entirely removed by a backwashing, and the membrane's water flux could not be re established. The membrane used in the enhanced biological phosphorus removal membrane bioreactor plant showed infrared spectra similar to that fouled by the free extracellular polymeric substances suspension in the laboratory. Thus, the results of this study show the importance of humic-like substances in irreversible fouling of enhanced biological phosphorus removal-membrane bioreactor systems. PMID- 25014565 TI - Integration of microbial fuel cell techniques into activated sludge wastewater treatment processes to improve nitrogen removal and reduce sludge production. AB - Bioelectrochemical systems are emerging for wastewater treatment, yet little is known about how well they can be integrated with current wastewater treatment processes. In this bench-scale study, the microbial fuel cell (MFC) technique was incorporated into the Modified Ludzack-Ettinger (MLE) process (phase I) and later with the membrane bioreactor (MBR) process (phase II) to evaluate the performance of MFC assisted wastewater treatment systems (i.e., MLE-MFC and MBR-MFC). There was no significant difference in the effluent NH4(+)-N concentration between the systems integrating MFC and the open circuit controls. The average effluent COD concentration was significantly lower in the MLE-MFC, but it did not change much in the MBR-MFC because of the already low COD concentrations in MBR operation. The MLE-MFC and MBR-MFC systems increased the NO3(-)-N removal efficiencies by 31% (+/-12%) and 20% (+/-12%), respectively, and reduced sludge production by 11% and 6%, respectively, while generating an average voltage of 0.13 (+/-0.03) V in both systems. Analysis of the bacterial specific oxygen uptake rate, the sludge volume index, and ammonia-oxidizing bacterial population (dominated by Nitrosomonas through terminal restriction fragment length polymorphism analysis) indicated that there was no significant difference in sludge activity, settling property, and nitrifying community structure between the MFC assisted systems and the open circuit controls. The results suggest that the wastewater treatment systems could achieve higher effluent water quality and lower sludge production if it is integrated well with MFC techniques. PMID- 25014566 TI - Nepsilon-carboxymethyllysine-mediated endoplasmic reticulum stress promotes endothelial cell injury through Nox4/MKP-3 interaction. AB - N(epsilon)-carboxymethyllysine (CML) is an important driver of diabetic vascular complications and endothelial cell dysfunction. However, how CML dictates specific cellular responses and the roles of protein tyrosine phosphatases and ERK phosphorylation remain unclear. We examined whether endoplasmic reticulum (ER) localization of MAPK phosphatase-3 (MKP-3) is critical in regulating ERK inactivation and promoting NADPH oxidase-4 (Nox4) activation in CML-induced endothelial cell injury. We demonstrated that serum CML levels were significantly increased in type 2 diabetes patients and diabetic animals. CML induced ER stress and apoptosis, reduced ERK activation, and increased MKP-3 protein activity in HUVECs and SVECs. MKP-3 siRNA transfection, but not that of MKP-1 or MKP-2, abolished the effects of CML on HUVECs. Nox4-mediated activation of MKP-3 regulated the switch to ERK dephosphorylation. CML also increased the integration of MKP-3 with ERK, which was blocked by silencing MKP-3. Exposure of antioxidants abolished CML-increased MKP-3 activity and protein expression. Furthermore, immunohistochemical staining of both MKP-3 and CML was increased, but phospho-ERK staining was decreased in the aortic endothelium of streptozotocin-induced and high-fat diet-induced diabetic mice. Our results indicate that an MKP-3 pathway might regulate ERK dephosphorylation through Nox4 during CML-triggered endothelial cell dysfunction/injury, suggesting that therapeutic strategies targeting the Nox4/MKP-3 interaction or MKP-3 activation may have clinical implications for diabetic vascular complications. PMID- 25014567 TI - Dynamic changes in the distribution and time course of blood-brain barrier permeative nitroxides in the mouse head with EPR imaging: visualization of blood flow in a mouse model of ischemia. AB - Electron paramagnetic resonance (EPR) imaging using nitroxides as redox-sensitive probes is a powerful, noninvasive method that can be used under various physiological conditions to visualize changes in redox status that result from oxidative damage. Two blood-brain barrier-permeative nitroxides, 3-hydroxymethyl 2,2,5,5-tetramethylpyrrolidine-1-oxyl (HMP) and 3-methoxycarbonyl-2,2,5,5 tetramethylpyrrolidine-1-yloxy (MCP), have been widely used as redox-sensitive probes in the brains of small animals, but their in vivo distribution and properties have not yet been analyzed in detail. In this study, a custom-made continuous-wave three-dimensional (3D) EPR imager was used to obtain 3D EPR images of mouse heads using MCP or HMP. This EPR imager made it possible to take 3D EPR images reconstructed from data from 181 projections acquired every 60s. Using this improved EPR imager and magnetic resonance imaging, the distribution and reduction time courses of HMP and MCP were examined in mouse heads. EPR images of living mice revealed that HMP and MCP have different distributions and different time courses for entering the brain. Based on the pharmacokinetics of the reduction reactions of HMP and MCP in the mouse head, the half-lives of HMP and MCP were clearly and accurately mapped pixel by pixel. An ischemic mouse model was prepared, and the half-life of MCP was mapped in the mouse head. Compared to the half-life in control mice, the half-life of MCP in the ischemic model mouse brain was significantly increased, suggesting a shift in the redox balance. This in vivo EPR imaging method using BBB-permeative MCP is a useful noninvasive method for assessing changes in the redox status in mouse brains under oxidative stress. PMID- 25014568 TI - Next generation phylogeography of cave and surface Astyanax mexicanus. AB - The loss of traits is a commonly observed evolutionary pattern in cave organisms, but due to extensive morphological convergence, inferring relationships between cave and surface populations can be difficult. For instance, Astyanax mexicanus (the blind Mexican cavefish) is thought to have repeatedly lost its eyes following colonization of cave environments, but the number of evolutionarily independent invasions of this species into caves remains unclear. Because of these repeated losses, it has become a model organism for studying the genetic basis of phenotypic trait loss. Here we reconstruct a high-resolution phylogeography for A. mexicanus inferred from both mitochondrial DNA and several thousand single nucleotide polymorphisms. We provide novel insight into the origin of cave populations from the Sabinos and Rio Subterraneo caves and present evidence that the Sabinos cave population is part of a unique cave lineage unrelated to other A. mexicanus cave populations. Our results indicate A. mexicanus cave populations have at least four independent origins. PMID- 25014569 TI - Phylogeny and taxonomy of sculpins, sandfishes, and snailfishes (Perciformes: Cottoidei) with comments on the phylogenetic significance of their early-life history specializations. AB - Despite recent progress on the higher-level relationships of the Cottoidei and its familial components, phylogenetic conflict and uncertainty remain within the Cottoidea. We analyzed a dataset composed of 4518 molecular (mitochondrial 12S, tRNA-Val, 16S, and cytochrome b and nuclear TMO-4c4, Histone H3, and 28S) and 72 morphological characters for 69 terminals to address cottoid intrarelationships. The resulting well-resolved phylogeny was used to produce a revised taxonomy that is consistent with the available molecular and morphological data and recognizes six families: Agonidae, Cottidae, Jordaniidae, Psychrolutidae, Rhamphocottidae, and Scorpaenichthyidae. The traditional Agonidae was expanded to include traditional hemitripterids and Hemilepidotus. The traditional Cottidae was restricted to Leptocottus, Trachidermus, and the riverine, lacustrine, and Lake Baikal freshwater cottoids. Jordaniidae (Jordania and Paricelinus) was separated from the traditional cottids; Psychrolutidae was expanded from the traditional grouping to include nearly all traditional marine cottids and the single species of bathylutichthyid. Rhamphocottidae was expanded to include the traditional ereuniids, and Scorpaenichthyidae separated Scorpaenichthys from the traditional cottids. The importance of early-life-history characters to the resulting phylogeny and taxonomy were highlighted. PMID- 25014570 TI - Synergistic roles for lipids and proteins in the permanent adhesive of barnacle larvae. AB - Thoracian barnacles rely heavily upon their ability to adhere to surfaces and are environmentally and economically important as biofouling pests. Their adhesives have unique attributes that define them as targets for bio-inspired adhesive development. With the aid of multi-photon and broadband coherent anti-Stokes Raman scattering microscopies, we report that the larval adhesive of barnacle cyprids is a bi-phasic system containing lipids and phosphoproteins, working synergistically to maximize adhesion to diverse surfaces under hostile conditions. Lipids, secreted first, possibly displace water from the surface interface creating a conducive environment for introduction of phosphoproteins while simultaneously modulating the spreading of the protein phase and protecting the nascent adhesive plaque from bacterial biodegradation. The two distinct phases are contained within two different granules in the cyprid cement glands, implying far greater complexity than previously recognized. Knowledge of the lipidic contribution will hopefully inspire development of novel synthetic bioadhesives and environmentally benign antifouling coatings. PMID- 25014571 TI - Structure elucidation and immunomodulatory activity of a beta glucan from the fruiting bodies of Ganoderma sinense. AB - A polysaccharide named GSP-2 with a molecular size of 32 kDa was isolated from the fruiting bodies of Ganoderma sinense. Its structure was well elucidated, by a combined utilization of chemical and spectroscopic techniques, to be a beta glucan with a backbone of (1->4)- and (1->6)-Glcp, bearing terminal- and (1->3) Glcp side-chains at O-3 position of (1->6)-Glcp. Immunological assay exhibited that GSP-2 significantly induced the proliferation of BALB/c mice splenocytes with target on only B cells, and enhanced the production of several cytokines in human peripheral blood mononuclear cells and derived dendritic cells. Besides, the fluorescent labeled GSP-2 was phagocytosed by the RAW 264.7 cells and induced the nitric oxide secretion from the cells. PMID- 25014572 TI - Feasibility of a palliative care intervention for cancer patients in Phase I clinical trials. AB - BACKGROUND: Cancer patients with advanced disease who have exhausted most treatment options are often offered participation in Phase I clinical trials. To date, studies that assess the benefits of palliative care provided concurrently in Phase I clinical trial settings are lacking. The overall purpose of this study was to test the feasibility of a palliative care intervention administered concurrently to cancer patients receiving treatment in a Phase I clinical trial. METHODS: Cancer patients enrolling in a Phase I clinical trial were invited to participate in this study. Patients completed baseline questionnaires prior to treatment initiation that assessed quality of life (QOL), symptom distress, psychological distress, and satisfaction with care. Patients then received the palliative care intervention (PCI), which consisted of comprehensive QOL assessment, care planning for the patient during an interdisciplinary team meeting, and two patient education sessions. Patients were surveyed again at 1 and 2 months following treatment initiation. RESULTS: A total of 14 patients were accrued to the pilot over a 3-month time period, representing 70% of eligible patients. Patient retention was high at 1 month (75%), and had declined at 2 months (50%). Patient outcome measure scores, including symptom distress, psychological distress, and satisfaction with care, were relatively stable over time, except for overall QOL, which declined over time. CONCLUSIONS: Concurrent palliative care is feasible for cancer patients treated in Phase I clinical trial settings. A large, multisite randomized controlled trial based on this pilot will be launched to test the efficacy of the intervention in this understudied cancer population. PMID- 25014573 TI - Gingiva laser welding: preliminary study on an ex vivo porcine model. AB - OBJECTIVE: The use of lasers to fuse different tissues has been studied for 50 years. As none of these experiments concerned the oral soft tissues, our objective was to assess the feasibility of laser gingiva welding. MATERIALS AND METHODS: Porcine full-thickness gingival flaps served to prepare calibrated samples in the middle of which a 2 cm long incision was closed, either by conventional suture or by laser tissue welding (LTW). To determine the irradiation conditions yielding the best tensile strength, 13 output power values, from 0.5 to 5 W, delivered either at 10 Hz or in continuous wave mode, were tested on six indocyanine green (ICG) concentrations, from 8% to 13% (588 samples). Then, some samples served to compare the tensile strength between the laser welded and the sutured gingiva; the other samples were histologically processed in order to evaluate the thermal damage extent. The temperature rise during the LTW was measured by thermocouples. Another group of 12 samples was used to measure the temperature elevation by thermal camera. RESULTS: In the laser welding groups, the best tensile strength (p<0.05) was yielded by the 9% ICG saline solution (117 mM) at 4.5 W, 10 Hz, and a fluence of 31.3 kJ/cm(2). The apposition strength revealed no statistically significant difference (p<0.05) between the sutured and the laser welded gingiva at 4.5 W, 10 Hz, and 9% ICG solution. The mean temperature was 74+/-5.4 degrees C at the upper surface and 42+/-8.9 degrees C at the lower surface. The damaged zone averaged 333 MUm at the upper surface. CONCLUSIONS: The 808 nm diode laser associated with ICG can achieve oral mucosa LTW, which is conceivable as a promising technique of gingival repair. PMID- 25014574 TI - Synthesis and characterization of mononuclear Zn(II), Co(II) and Ni(II) complexes containing a sterically demanding silanethiolate ligand derived from tris(2,6 diisopropylphenoxy)silanethiol. AB - Four heteroleptic complexes of nickel(ii), cobalt(ii) and zinc(ii), containing a monodentate silanethiolate ligand derived from tris(2,6 diisopropylphenoxy)silanethiol (TDST), were prepared and characterized. Nickel(ii) and cobalt(ii) complexes of the formula M(NH3)2(TDST)2 (M = Ni(ii) complex , M = Co(ii) complex ) were obtained from the respective chlorides. Zinc complexes of the general formula Zn(acac)(TDST)(L), where L = EtOH (complex ) or H2O (complex ), were obtained from zinc acetylacetonate. A single-crystal X-ray structural analysis revealed that all crystalline products are solvent adducts. The geometries of ligands in the complexes are typical: distorted tetrahedral in zinc and cobalt(ii) complexes and square planar in nickel(ii) compounds. Magnetic studies performed for Ni(ii) and Co(ii) compounds confirmed the diamagnetic character of the first complex and high-spin paramagnetic configuration of the latter. Nickel(ii) and cobalt(ii) complexes were additionally characterized by UV Vis and IR spectroscopy. IR bands for ligands in the complexes were assigned with the help of the DFT vibrational frequency calculations. PMID- 25014575 TI - Fluorescence enhancement of a fluorescein derivative upon adsorption on cellulose. AB - 9-[1-(2-Methyl-4-methoxyphenyl)]-6-hydroxy-3H-xanthen-3-one (2-Me-4-OMe TG) is a fluorescein derivative dye whose photophysical properties show a remarkable pH dependence. In aqueous solution the fluorescence quantum yield (Phif) of its anionic species is nearly a hundred times higher than that of its neutral species. Such a large difference in Phif makes 2-Me-4-OMe TG useful as an "on off" pH indicator. Here we report that adsorption on the surface of microcrystalline cellulose exerts a profound effect upon the photophysical properties of 2-Me-4-OMe TG. On the solid only the dye neutral species is observed and its Phif is 0.31 +/- 0.10, which is approximately thirty times higher than the value found for the neutral species in aqueous solution (Phif = 0.01). 2-Me-4-OMe TG and Dabcyl (DB) were co-adsorbed on the surface of microcrystalline cellulose to study the transfer of excitation energy from the former to the latter. In the absence of the dye, the formation of DB aggregates is observed at concentrations greater than 0.34 MUmol per gram of cellulose, while in the presence of 2-Me-4-OMe TG the formation of DB aggregates is thoroughly inhibited. The quenching of fluorescence of 2-Me-4-OMe TG by DB reaches efficiencies as high as 90% for the most concentrated samples. PMID- 25014576 TI - A prospective, multi-institutional study of flexible ureteroscopy for proximal ureteral stones smaller than 2 cm. AB - PURPOSE: Flexible ureteroscopy is rapidly becoming a first line therapy for many patients with renal and ureteral stones. However, current understanding of treatment outcomes in patients with isolated proximal ureteral stones is limited. Therefore, we performed a prospective, multi-institutional study of ureteroscopic management of proximal ureteral stones smaller than 2 cm to better define clinical outcomes associated with this approach. MATERIALS AND METHODS: Adult patients with proximal ureteral calculi smaller than 2 cm were prospectively identified. Patients with concomitant ipsilateral renal calculi or prior ureteral stenting were excluded from study. Flexible ureteroscopy, holmium laser lithotripsy and ureteral stent placement was performed. Ureteral access sheath use, laser settings and other details of perioperative and postoperative management were based on individual surgeon preference. Stone clearance was determined by the results of renal ultrasound and plain x-ray of the kidneys, ureters and bladder 4 to 6 weeks postoperatively. RESULTS: Of 71 patients 44 (62%) were male and 27 (38%) were female. Mean age was 48.2 years. ASA((r)) score was 1 in 12 cases (16%), 2 in 41 (58%), 3 in 16 (23%) and 4 in 2 (3%). Mean body mass index was 31.8 kg/m(2), mean stone size was 7.4 mm (range 5 to 15) and mean operative time was 60.3 minutes (range 15 to 148). Intraoperative complications occurred in 2 patients (2.8%), including mild ureteral trauma. Postoperative complications developed in 6 patients (8.7%), including urinary tract infection in 3, urinary retention in 2 and flash pulmonary edema in 1. The stone-free rate was 95% and for stones smaller than 1 cm it was 100%. CONCLUSIONS: Flexible ureteroscopy is associated with excellent clinical outcomes and acceptable morbidity when applied to patients with proximal ureteral stones smaller than 2 cm. PMID- 25014577 TI - Artificial urinary sphincter placement in compromised urethras and survival: a comparison of virgin, radiated and reoperative cases. AB - PURPOSE: Although long-term outcomes after initial placement of artificial urinary sphincters are established, limited data exist comparing sphincter survival in patients with compromised urethras (prior radiation, artificial urinary sphincter placement or urethroplasty). We evaluated artificial urinary sphincter failure in patients with compromised and noncompromised urethras. MATERIALS AND METHODS: We performed a retrospective analysis of 86 sphincters placed at a single institution between December 1997 and September 2012. We assessed patient demographic, comorbid disease and surgical characteristics. All nonfunctioning, eroded or infected devices were considered failures. RESULTS: Of the 86 patients reviewed 67 (78%) had compromised urethras and had higher failure rates than the noncompromised group (34% vs 21%, p=0.02). Compared to the noncompromised group, cases of prior radiation therapy (HR 4.78; 95% CI 1.27, 18.04), urethroplasty (HR 8.61; 95% CI 1.27, 58.51) and previous artificial urinary sphincter placement (HR 8.14; 95% CI 1.71, 38.82) had a significantly increased risk of failure. The risk of artificial urinary sphincter failure increased with more prior procedures. An increased risk of failure was observed after 3.5 cm cuff placement (HR 8.62; 95% CI 2.82, 26.36) but not transcorporal placement (HR 1.21; 95% CI 0.49, 2.99). CONCLUSIONS: Artificial urinary sphincter placement in patients with compromised urethras from prior artificial urinary sphincter placement, radiation or urethroplasty had a statistically significant higher risk of failure than placement in patients with noncompromised urethras. Urethral mobilization and transection performed during posterior urethroplasty surgeries likely compromise urethral blood supply, predisposing patients to failure. Patients with severely compromised urethras from multiple prior procedures may have improved outcomes with transcorporal cuff placement rather than a 3.5 cm cuff. PMID- 25014579 TI - Microcirculatory effects of selective endothelin-A receptor antagonism in testicular torsion. AB - PURPOSE: Testicular torsion without timely intervention causes incurable damage to the testis. We examined the causative role of microcirculatory injury in torsion induced testicular damage with particular regard to endothelin-A receptor activation. MATERIALS AND METHODS: The microcirculatory consequences of testicular torsion were assessed in the presence or absence of endothelin-A receptor antagonism in rats. Microcirculatory perfusion changes (red blood cell velocity and pulsatile flow pattern alterations) were examined by an orthogonal polarization spectral imaging technique. Microcirculatory inflammatory alterations were assessed by fluorescence intravital video microscopy after 60 minute torsion followed by 240-minute reperfusion. As a specific endothelin-A receptor inhibitor, the antisense homology box derived peptide ETR-p1/fl was applied 10 minutes before reperfusion. Tissue accumulation of leukocytes was estimated by myeloperoxidase activity in tissue biopsies taken at the end of the 4-hour reperfusion period. In further experiments testicular weight as a marker of permanent damage was evaluated 45 days after torsion. RESULTS: The physiological pulsatile flow pattern ceased in the initial phase of reperfusion while leukocyte-endothelial interactions increased throughout the examined reperfusion period. Endothelin-A receptor antagonism caused earlier return of pulsatile flow and recovery of red blood cell velocity, and alleviated microcirculatory inflammatory reactions and atrophy. CONCLUSIONS: Results suggest a pathophysiological role of endothelin-A receptor activation in the pathogenesis of testicular torsion. This effect is related to deterioration in testicular perfusion and activation of microcirculatory inflammatory reactions. PMID- 25014578 TI - Improved split renal function after percutaneous nephrostomy in young adults with severe hydronephrosis due to ureteropelvic junction obstruction. AB - PURPOSE: We evaluated percutaneous nephrostomy for adult kidneys with severe hydronephrosis due to ureteropelvic junction obstruction and less than 10% split renal function. MATERIALS AND METHODS: In this retrospective analysis we included patients who underwent percutaneous nephrostomy for unilateral ureteropelvic junction obstruction of the kidneys with hydronephrosis and less than 10% split renal function at our hospital between May 2009 and January 2012. Adults (age 18 years or greater) were divided into those 35 years or younger (young adults) and older than 35 years (older adults). The percutaneous nephrostomy remained in situ a mean +/- SD of 6.62 +/- 2.55 weeks and patients underwent repeat renography before pyeloplasty. When there was no significant improvement in split renal function (10% or greater) and drainage (greater than 400 ml per day), nephrectomy was performed. Otherwise pyeloplasty was performed. Patients were followed by renography, ultrasound and contrast computerized tomography at 3 and 6 months, at 1 year and annually thereafter. RESULTS: Of 53 patients 30 (56.6%) showed improvement after percutaneous nephrostomy drainage and urine output greater than 400 ml per day with percutaneous nephrostomy. Pyeloplasty was then performed. Of 29 young adults 24 (82.8%) showed improved split renal function vs 6 of 24 older adults (25%). Nephrectomy of the other 23 kidneys was performed. At a mean followup of 19.27 +/- 7.82 months (range 12 to 36), no patient showed hypertension or urinary tract infection. CONCLUSIONS: Split renal function detected by renography may not accurately predict recovered, poorly functioning kidneys, especially in young adults. First observing the recoverability of hydronephrotic kidneys by percutaneous nephrostomy drainage and then preserving select kidneys may be an effective method to manage poorly functioning kidneys due to ureteropelvic junction obstruction. PMID- 25014580 TI - Expression of the tumor suppressive miRNA-23b/27b cluster is a good prognostic marker in clear cell renal cell carcinoma. AB - PURPOSE: We observed abnormal expression of the microRNA-23b/27b (miR-23b/27b) cluster in our previous study of miRNA expression signatures. However, the relationship between aberrant miRNA expression and clear cell renal cell carcinoma is not well established. We investigated the functional significance of the miR-23b/27b cluster in clear cell renal cell carcinoma cells and evaluated these miRNAs as biomarkers to predict the risk of clear cell renal cell carcinoma. MATERIALS AND METHODS: Expression levels of miR-23b and miR-27b were determined by quantitative real-time reverse transcriptase-polymerase chain reaction. The association between miRNA expression and overall survival was estimated by the Kaplan-Meier method. Gain of function assays were performed using mature miR-23b and miR-27b in the 786-O and A498 renal cell carcinoma cell lines. Targets regulated by these miRNAs were predicted by in silico analysis. RESULTS: Expression of the miR-23b/27b cluster was significantly decreased in clear cell renal cell carcinoma tissue specimens and associated with pathological grade and stage. Significantly shorter overall survival was observed in patients with lower expression of the miR-23b/27b cluster. Restoration of miR-23b and miR 27b significantly inhibited cancer cell proliferation, migration and invasion. CONCLUSIONS: Expression of the miR-23b/27b cluster was frequently decreased in clear cell renal cell carcinoma tissue. Reduced expression of these miRNAs increased the risk of disease progression and predicted poor survival. Thus, miR 23b and miR-27b function as tumor suppressors, targeting several oncogenic genes in clear cell renal cell carcinoma cells. PMID- 25014581 TI - Polymeric supra-amphiphiles based on terminal group electrostatic interactions: fabrication of micelles with modifiable surfaces. AB - On the basis of terminal group electrostatic interactions (TGEI), a supra amphiphile is formed between a homopolymer of polylactic acid with carboxyl group at one end (PLA-COOH) and hepta-6-hydrazyl-beta-cyclodextrin (HH-CD). The amphiphile can self-assemble into a micellar structure in aqueous solution. The outer surface of the micelle, which is composed of cyclodextrins, can be further modified via host-guest interactions. Considering the biocompatibility of the building blocks, the application of the micelles in a nanocarrier of anticancer drugs is further explored. PMID- 25014582 TI - Rowell syndrome. PMID- 25014583 TI - Unusual widespread cutaneous eruption due to nilotinib therapy for chronic myeloid leukemia. PMID- 25014584 TI - Eruptive xanthomas after extensive tattooing: a case report and literature review. PMID- 25014585 TI - Malignant melanoma in Ferrara, Northern Italy: epidemiologic survey focusing on tumor thickness. AB - AIM: Estimates of malignant melanoma (MM) incidence and prognosis vary widely. The present study was performed to analyze epidemiologic and prognostic aspects of primary MM mainly in relation to tumor thickness. METHODS: We conducted a retrospective study on a cohort of 435 patients with diagnosis of primary MM between 1997 and 2011. RESULTS: In the period 2009-2011, among the MM diagnosed 50.00% were thin, 32.43% in situ and 17.57% thicker while in 1997-1999 MM>1 mm accounted for 51.61% of diagnoses. Mean age of patients affected with thin MM was significantly lower than that of patients with MM>1 mm, and mean thickness resulted significantly lower in female patients than in males. Mean thickness of MM located on easily self-evaluable body areas was significantly lower than in those not accessible for skin self-examination. The commonest histogenetic type was superficially spreading melanoma. Mitotic rate, ulceration and vertical growth phase all resulted related to MM thickness. Out of 61 patients with thin MM who underwent SLNB, 3 resulted positive (4.92%): neither thickness >0.75 mm, nor ulceration, mitotic rate or Clark level were found to be associated with SLNB positivity. Five-year survival rate was 98.3% for thin MM patients and 76.4% for thick MM patients. CONCLUSION: Our trend analysis evidences a continuing increase of thinner primary MM throughout the study period, potentially enhancing patient prognosis. Regular skin self-examination could contribute to earlier recognition of MM. Identification of more powerful predictors of thin MM prognosis is necessary. PMID- 25014586 TI - Successful management of angiolymphoid hyperplasia with eosinophilia in a split face trial of topical tacrolimus and timolol solution. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon, benign condition characterized by multiple benign angiomatous nodules or plaques. Cutaneous lesions can be painful, pruritic, pulsatile, or potentially disfiguring resulting in significant morbidity. ALHE is a pathologic diagnosis featuring proliferations of capillary-sized vessels with epithelioid endothelial cells surrounded by larger, thick-walled vessels and accompanying eosinophils and lymphocytes. Surgery is generally required, however the skin lesions often recur after excision. ALHE is notoriously difficult to treat and many physicians would prefer a non-invasive treatment of choice. We report a case of ALHE that was successfully treated with the novel use of topical tacrolimus in a split-face trial with topical timolol solution. PMID- 25014587 TI - Cutaneous signs of classical dermatomyositis. AB - Idiopathic immune myopathies (IIM) are an heterogeneous group of autoimmune muscle disorders characterized by progressive muscle involvement. Dermatomyositis (DM) is the most common form of IIM. It is a multisystem disorder characterized by symmetric proximal, extensor, inflammatory myopathy, vascular involvement and a characteristic cutaneous eruption. Six types of DM have been identified: idiopathic, juvenile (JDM), cancer-related other autoimmune diseases-related, iatrogenic DM and amyopathic DM. Cutaneous manifestations of DM are the most important aspect of this disease and can precede from several months to years muscle or systemic involvement. Three groups of signs have been described: pathognomonic, highly characteristic and compatible. Although differences exist among the different clinical presentation of skin lesions, they share common histological findings including the presence of interface dermatitis with epidermal atrophy, basement membrane degeneration, vacuolar alteration of basal keratinocytes, and dermal changes consisting of interstitial mucin deposition and a sparse lymphocytic infiltrate. DM is a serious disease; the correct evaluation of any skin lesion suggesting an early diagnosis is of utmost importance. Skin signs may, also, represent a marker of treatment efficacy even though systemic symptoms worsening may not always be followed by more severe skin lesions. PMID- 25014589 TI - The dopamine-Mo(VI) complexation-assisted large-scale aqueous synthesis of a single-layer MoS2/carbon sandwich structure for ultrafast, long-life lithium-ion batteries. AB - Single-layer MoS2-carbon nanocomposites (SLMoS2/C) are facilely prepared via a dopamine (DOPA)-Mo(VI) complexation-assisted approach. The large interlayer spacing, sandwich structure and crumpled nanosheet morphology of SLMoS2/C render it excellent electrochemical performances as a lithium-ion battery anode, showing a reversible capacity of 500 mA h g(-1) at a discharge rate of 5 A g(-1). PMID- 25014588 TI - Substrate- and cofactor-independent inhibition of histone demethylase KDM4C. AB - Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging, as the active sites of KDM1A-B and KDM4A-D histone demethylases are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and 4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation, and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family. PMID- 25014590 TI - OsNAC111, a blast disease-responsive transcription factor in rice, positively regulates the expression of defense-related genes. AB - Plants respond to pathogen attack by transcriptionally regulating defense-related genes via various types of transcription factors. We identified a transcription factor in rice, OsNAC111, belonging to the TERN subgroup of the NAC family that was transcriptionally upregulated after rice blast fungus (Magnaporthe oryzae) inoculation. OsNAC111 was localized in the nucleus of rice cells and had transcriptional activation activity in yeast and rice cells. Transgenic rice plants overexpressing OsNAC111 showed increased resistance to the rice blast fungus. In OsNAC111-overexpressing plants, the expression of several defense related genes, including pathogenesis-related (PR) genes, was constitutively high compared with the control. These genes all showed blast disease-responsive expression in leaves. Among them, two chitinase genes and one beta-1,3-glucanase gene showed reduced expression in transgenic rice plants in which OsNAC111 function was suppressed by a chimeric repressor (OsNAC111-SRDX). OsNAC111 activated transcription from the promoters of the chitinase and beta-1,3 glucanase genes in rice cells. In addition, brown pigmentation at the infection sites, a defense response of rice cells to the blast fungus, was lowered in OsNAC111-SRDX plants at the early infection stage. These results indicate that OsNAC111 positively regulates the expression of a specific set of PR genes in the disease response and contributes to disease resistance. PMID- 25014591 TI - Bioguided isolation, characterization, and biotransformation by Fusarium verticillioides of maize kernel compounds that inhibit fumonisin production. AB - Fusarium verticillioides infects maize ears, causing ear rot disease and contamination of grain with fumonisin mycotoxins. This contamination can be reduced by the presence of bioactive compounds in kernels that are able to inhibit fumonisin biosynthesis. To identify such compounds, we used kernels from a maize genotype with moderate susceptibility to F. verticillioides, harvested at the milk-dough stage (i.e., when fumonisin production initiates in planta), and applied a bioguided fractionation approach. Chlorogenic acid was the most abundant compound in the purified active fraction and its contribution to fumonisin inhibitory activity was up to 70%. Moreover, using a set of maize genotypes with different levels of susceptibility, chlorogenic acid was shown to be significantly higher in immature kernels of the moderately susceptible group. Altogether, our data indicate that chlorogenic acid may considerably contribute to either maize resistance to Fusarium ear rot, fumonisin accumulation, or both. We further investigated the mechanisms involved in the inhibition of fumonisin production by chlorogenic acid and one of its hydrolyzed products, caffeic acid, by following their metabolic fate in supplemented F. verticillioides broths. Our data indicate that F. verticillioides was able to biotransform these phenolic compounds and that the resulting products can contribute to their inhibitory activity. PMID- 25014592 TI - Transgenic tomato plants overexpressing tyramine N-hydroxycinnamoyltransferase exhibit elevated hydroxycinnamic acid amide levels and enhanced resistance to Pseudomonas syringae. AB - Hydroxycinnamic acid amides (HCAA) are secondary metabolites involved in plant development and defense that have been widely reported throughout the plant kingdom. These phenolics show antioxidant, antiviral, antibacterial, and antifungal activities. Hydroxycinnamoyl-CoA:tyramine N-hydroxycinnamoyl transferase (THT) is the key enzyme in HCAA synthesis and is induced in response to pathogen infection, wounding, or elicitor treatments, preceding HCAA accumulation. We have engineered transgenic tomato plants overexpressing tomato THT. These plants displayed an enhanced THT gene expression in leaves as compared with wild type (WT) plants. Consequently, leaves of THT-overexpressing plants showed a higher constitutive accumulation of the amide coumaroyltyramine (CT). Similar results were found in flowers and fruits. Moreover, feruloyltyramine (FT) also accumulated in these tissues, being present at higher levels in transgenic plants. Accumulation of CT, FT and octopamine, and noradrenaline HCAA in response to Pseudomonas syringae pv. tomato infection was higher in transgenic plants than in the WT plants. Transgenic plants showed an enhanced resistance to the bacterial infection. In addition, this HCAA accumulation was accompanied by an increase in salicylic acid levels and pathogenesis-related gene induction. Taken together, these results suggest that HCAA may play an important role in the defense of tomato plants against P. syringae infection. PMID- 25014594 TI - White light spectral interferometry as a spectrometer calibration tool. AB - For this paper, we used a white light interferometer in combination with spectral lamps to perform the wavelength calibration of a dispersive spectrometer. Illuminating the spectrometer with suitable spectral lamps gives the wavelength pixel number relationship at discrete positions of the spectrometer detector array, and the wavelength-dependent phase difference at the output of the white light interferometer allows for a complete spectral calibration at any point on the detector (i.e., for every wavelength in the spectral range of the spectrometer). The details of this new calibration procedure are discussed, and two practical examples exhibiting the robustness of the method are presented. In addition, certain issues relating to minimizing the number of spectral lines used in the calibration procedure are examined. PMID- 25014593 TI - Ultraviolet absorption spectroscopy in optically dense fireballs using broadband second-harmonic generation of a pulsed modeless dye laser. AB - Broadband frequency doubling of a modeless dye laser pulse is used to enable single-shot absorption spectroscopy in the ultraviolet for optically dense, energetic-materials fireball applications. Band widths of approximately 1-3 nm are generated in the 226 and 268 nm regions using a doubling crystal. Strong focusing of the fundamental beam onto the crystal is found to be sufficient to achieve 1-5% conversion efficiency with a pulse intensity sufficient to saturate the array detector even after 75% attenuation through the fireball. The technique is demonstrated with nitric oxide (NO) absorption in a gas cell and is then used to perform the first detection and temperature fitting of aluminum monofluoride (AlF) and magnesium monofluoride (MgF) in a fireball environment. PMID- 25014595 TI - A modified infrared spectrometer with high time resolution and its application for investigating fast conformational changes of the GTPase Ras. AB - Time-resolved infrared spectroscopy is a valuable tool for the investigation of proteins and protein interactions. The investigation of many biological processes is possible by means of caged compounds, which set free biologically active substances upon light activation. Some caged compounds could provide sub nanosecond time resolution, e.g., para-hydroxyphenacyl-guanosine 5'-triphosphate (GTP) forms GTP in picoseconds. However, the time resolution in single shot experiments with rapid-scan Fourier transform infrared (FT-IR) spectrometers is limited to about 10 ms. Here we use an infrared diode laser instead of the conventional globar and achieve a time resolution of 100 ns. This allows for the time-resolved measurement of the fast Ras(off) to Ras(on) conformational change at room temperature. We quantified the activation parameters for this reaction and found that the free energy of activation for this reaction is mainly enthalpic. Investigation of the same reaction in the presence of the Ras binding domain of the effector Raf (RafRBD) reveals a four orders of magnitude faster reaction, indicating that Ras.RafRBD complex formation directly induces the conformational change. Recent developments of broadly tunable quantum cascade lasers will further improve time resolution and usability of the setup. The reported 100 ns time resolution is the best achieved for a non-repetitive experiment so far. PMID- 25014596 TI - Pressure and temperature dependence of the Raman peak intensity ratio of asymmetric stretching vibration (nu3) and asymmetric bending overtone (2nu2) of methane. AB - Raman peaks of the asymmetric stretching vibration (nu3) and the asymmetric bending overtone (2nu2) of methane were studied at elevated pressures and temperatures, from 3 to 51 MPa and from 298.15 to 473.15 K. The peak intensity ratios of nu3 and 2nu2 were calculated, and the relationship among peak intensity ratio, temperature, and pressure/density were derived using equations. Such relationships allow geologists to determine the pressure and density of methane fluid inclusions using Raman spectroscopic measurements of the peak intensity ratios of nu3 and 2nu2. PMID- 25014597 TI - Insights into the mechanism of polymer coating self-healing using Raman spectroscopy. AB - Self-healing polymer coatings are an emerging class of smart materials. Upon mechanical damage the material properties may be restored by self-healing, which can be triggered externally, e.g., by an increased temperature. An alternative approach relies on embedding capsules with repair agents into the polymers, the rupture of which is induced by the mechanical damage, and the release of the repair agents triggers the self-repair reaction. The work at hand presents in situ Raman spectroscopic investigations on the reaction dynamics in such self healing polymer coatings. Analysis of the Raman spectra allows one to assign specific Raman bands characteristic for the progress of the self-healing reaction. PMID- 25014598 TI - Raman spectroscopy and scanning electron microscopy characterizations of fission track method datable zircon grains. AB - Spectroscopic and morphological studies, designed to improve our understanding of the physicochemical phenomena that occur during zircon crystallization, are presented. The zircon fission track method (ZFTM) is used routinely in various laboratories around the world; however, there are some methodological difficulties needing attention. Depending on the surface fission track density observed under an optical microscope, the zircon grain surfaces are classified as homogeneous, heterogeneous, hybrid, or anomalous. In this study, zircon grain surfaces are characterized using complementary techniques such as optical microscopy (OM), micro-Raman spectroscopy, and scanning electron microscopy (SEM), both before and after chemical etching. Our results suggest that anomalous grains have subfamilies and that etching anisotropy related to heterogeneous grains is due to different crystallographic faces within the same polished surface that cannot be observed under an optical microscope. The improved methodology was used to determine the zircon fission track ages of samples collected from the Bauru Group located in the north of Parana Basin, Brazil. A total of 514 zircon grains were analyzed, consisting of 10% homogeneous, about 10% heterogeneous, about 20% hybrid, and 60% anomalous grains. These results show that the age distributions obtained for homogeneous, heterogeneous, and hybrid grains are both statistically and geologically compatible. PMID- 25014599 TI - Determination of the botanical origin of honey by front-face synchronous fluorescence spectroscopy. AB - Front-face synchronous fluorescence spectroscopy combined with chemometrics is used to classify honey samples according to their botanical origin. Synchronous fluorescence spectra of three monofloral (linden, sunflower, and acacia), polyfloral (meadow mix), and fake (fake acacia and linden) honey types (109 samples) were collected in an excitation range of 240-500 nm for synchronous wavelength intervals of 30-300 nm. Chemometric analysis of the gathered data included principal component analysis and partial least squares discriminant analysis. Mean cross-validated classification errors of 0.2 and 4.8% were found for a model that accounts only for monofloral samples and for a model that includes both the monofloral and polyfloral groups, respectively. The results demonstrate that single synchronous fluorescence spectra of different honeys differ significantly because of their distinct physical and chemical characteristics and provide sufficient data for the clear differentiation among honey groups. The spectra of fake honey samples showed pronounced differences from those of genuine honey, and these samples are easily recognized on the basis of their synchronous fluorescence spectra. The study demonstrated that this method is a valuable and promising technique for honey authentication. PMID- 25014600 TI - Localization of human hair structural lipids using nanoscale infrared spectroscopy and imaging. AB - Atomic force microscopy (AFM) and infrared (IR) spectroscopy have been combined in a single instrument (AFM-IR) capable of producing IR spectra and absorption images at a sub-micrometer spatial resolution. This new device enables human hair to be spectroscopically characterized at levels not previously possible. In particular, it was possible to determine the location of structural lipids in the cuticle and cortex of hair. Samples of human hair were embedded, cross-sectioned, and mounted on ZnSe prisms. A tunable IR laser generating pulses of the order of 10 ns was used to excite sample films. Short duration thermomechanical waves, due to infrared absorption and resulting thermal expansion, were studied by monitoring the resulting excitation of the contact resonance modes of the AFM cantilever. Differences are observed in the IR absorbance intensity of long-chain methylene-containing functional groups between the outer cuticle, middle cortex, and inner medulla of the hair. An accumulation of structural lipids is clearly observed at the individual cuticle layer boundaries. This method should prove useful in the future for understanding the penetration mechanism of substances into hair as well as elucidating the chemical nature of alteration or possible damage according to depth and hair morphology. PMID- 25014601 TI - Chemical structure and interlayer distance correlation of graphite oxide in the heating process as revealed by in situ Fourier transform infrared spectroscopy and wide-angle X-ray diffraction techniques. AB - The thermal reduction behavior of graphite oxide (GO) film in an air atmosphere during a continuous heating process was monitored in situ using temperature dependent infrared (IR) spectroscopy and synchrotron radiation wide-angle X-ray diffraction (WAXD) techniques. The results show that most of the water adsorbed by the GO sheets is removed by heating them to 130 degrees C. The dehydration process leads to a slight decrease of the interplane distance of the GO sheets. The IR data suggest that the thermal reduction occurs starting at 160 degrees C. The synchronous change of the of hydroxyl and carbonyl stretching mode (nu(-OH) and nu(C=C)) bands of GO between 160 and 210 degrees C suggest that the recovery of conjugated structure is mainly due to the reduction of -OH groups in this temperature region, in which the d spacing has not been affected. When the temperature reaches 210 degrees C, the rapid reduction of C=O groups together with the removal of the residual -OH and ether (C-O-C) groups leads to the sudden collapse of the GO sheets. Based on these findings, we present a schematic of the thermal stability of GO film in a continuous heating process, in which the thermal-induced chemical and crystallographic structural changes of the GO film have been correlated. PMID- 25014602 TI - Instrument response standard in time-resolved fluorescence spectroscopy at visible wavelength: quenched fluorescein sodium. AB - Time-resolved fluorescence properties of quenched fluorescein sodium, including self-quenching and collisional quenching by iodide, have been studied by using a picosecond time-correlated single-photon counting (TCSPC) apparatus, together with an upconversion spectrophotofluorometer with a time resolution better than 300 fs. The steady-state fluorescence intensity of fluorescein sodium reached the maximum when its concentration was 510 MUM with pH > 9. Both the fluorescence intensity and lifetime decreased with increasing concentrations of NaI quencher. When the NaI concentration was 12.2 M, a monoexponential decay with a lifetime as short as 17 ps was exactly determined for the first time using the femtosecond resolved upconversion system. Picosecond time-resolved fluorescence measurements of circular permuted green and yellow fluorescent proteins (cpGFP and cpYFP) were reported, demonstrating that the fluorescence decay of quenched fluorescein sodium is a better approximation of the instrument response function (IRF) needed for the accurate deconvolution of fluorescence lifetime data, particularly for detectors used in the visible spectral region. We believe that this picosecond lifetime standard will find wide applications in fluorescence lifetime imaging microscopy (FLIM). PMID- 25014603 TI - Spectroscopic investigations on thin adhesive layers in multi-material laminates. AB - Three different spectroscopic approaches, Raman linescans, Raman imaging, and attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) imaging were evaluated for the visualization of the thin adhesive layers (3-6 MUm) present in polymeric photovoltaic backsheets. The cross-sections of the multilayer laminates in the original, weathered, and artificially aged samples were investigated spectroscopically in order to describe the impact of the environmental factors on the evenness and thickness of the adhesive layers. All three methods were found to be suitable tools to detect and visualize these thin layers within the original and aged polymeric laminates. However, as the adhesive layer is not very uniform in thickness and partly disintegrates upon weathering and/or artificial aging, Raman linescans yield only qualitative information and do not allow for an estimation of the layer thickness. Upon increasing the measuring area by moving from one-dimensional linescans to two-dimensional Raman images, a much better result could be achieved. Even though a longer measuring time has to be taken into account, the information on the uniformity and evenness of the adhesive layer obtainable using the imaging technique is much more comprehensive. Although Raman spectroscopy is known to have the superior lateral resolution as compared with ATR FT-IR spectroscopy, the adhesive layers of the samples used within this study (layer thickness 3-6 MUm) could also be detected and visualized by applying the ATR FT-IR spectroscopic imaging method. However, the analysis of the images was quite a demanding task, as the thickness of the adhesive layer was in the region of the resolution limit of this method. The information obtained for the impact of artificial aging and weathering on the adhesive layer obtained using Raman imaging and ATR FT-IR imaging was in good accordance. PMID- 25014604 TI - Infrared spectroscopic analysis of sub-monolayer perfluoropolyether Z-Tetraol films used in boundary lubrication. AB - Infrared specular reflection spectra of Z-Tetraol on a gold substrate was simulated and studied experimentally. The simulated spectra were obtained using a classical dispersion analysis coupled with solutions of Maxwell's equations for transmission and reflection of electromagnetic radiation. The simulated spectra, which are based on a randomly oriented sample, provide excellent fits for Z Tetraol over a wide film thickness range. Spectroscopic data are provided for the Z-Tetraol -(CF2O)p-(CF2CF2O)q- main chain. The differences in the transverse and longitudinal optical infrared spectra are discussed for off-normal reflection spectra in the thin film limit. Corrections to the infrared reflection spectra for sub-monolayer coverage using effective medium theory are also discussed. PMID- 25014605 TI - Variable-temperature Fourier transform near-infrared imaging spectroscopy of the deuterium/hydrogen exchange in liquid D2O. AB - In the present publication, the deuterium/hydrogen (D/H) exchange of liquid D2O exposed to water vapor of the surrounding atmosphere has been studied by variable temperature Fourier transform near-infrared (FT-NIR) imaging spectroscopy. Apart from the visualization of the exchange process in the time-resolved FT-NIR images, kinetic parameters and the activation energy for this D/H exchange reaction have been derived from the Arrhenius plot of the variable-temperature spectroscopic data. PMID- 25014606 TI - Simulation of attenuated total reflection infrared absorbance spectra: applications to automotive clear coat forensic analysis. AB - Attenuated total reflection (ATR) is a widely used sampling technique in infrared (IR) spectroscopy because minimal sample preparation is required. Since the penetration depth of the ATR analysis beam is quite shallow, the outer layers of a laminate or multilayered paint sample can be preferentially analyzed with the entire sample intact. For this reason, forensic laboratories are taking advantage of ATR to collect IR spectra of automotive paint systems that may consist of three or more layers. However, the IR spectrum of a paint sample obtained by ATR will exhibit distortions, e.g., band broadening and lower relative intensities at higher wavenumbers, compared with its transmission counterpart. This hinders library searching because most library spectra are measured in transmission mode. Furthermore, the angle of incidence for the internal reflection element, the refractive index of the clear coat, and surface contamination due to inorganic contaminants can profoundly influence the quality of the ATR spectrum obtained for automotive paints. A correction algorithm to allow ATR spectra to be searched using IR transmission spectra of the paint data query (PDQ) automotive database is presented. The proposed correction algorithm to convert transmission spectra from the PDQ library to ATR spectra is able to address distortion issues such as the relative intensities and broadening of the bands, and the introduction of wavelength shifts at lower frequencies, which prevent library searching of ATR spectra using archived IR transmission data. PMID- 25014607 TI - Defect-free, size-tunable graphene for high-performance lithium ion battery. AB - The scalable preparation of graphene in control of its structure would significantly improve its commercial viability. Despite intense research in this area, the size control of defect-free graphene (df-G) without any trace of oxidation or structural damage remains a key challenge. Here, we propose a new scalable route for generating df-G with a controllable size of submicron to micron through sequential insertion of potassium and pyridine at low temperature. Structural and chemical analyses confirm that the df-G perfectly preserves the intrinsic properties of graphene. The Co3O4 (<50 nm) wrapped by ~ 10.5 MUm(2) df G has unprecedented capacity, rate capability, and cycling stability with capacities as high as 1050 mAh g(-1) at 500 mA g(-1) and 900 mAh g(-1) at 1000 mA g(-1) even after 200 cycles, which suggests enticing potential for the use in high performance lithium ion batteries. PMID- 25014608 TI - Poly(3-hexylthiophene) nanotubes with tunable aspect ratios and charge transport properties. AB - Regioregular poly(3-hexylthiophene) (RR-P3HT) nanotubes (200 nm in diameter) with tunable aspect ratios from 25 to 300 were prepared using a polymer melt wetting technique. Aspect-ratio tunability was achieved by controlling the wetting behavior of RR-P3HT melts in a template. The crystallinity and chain orientation of RR-P3HT were studied by grazing incidence X-ray diffraction, wide-angle X-ray diffraction, and polarized photoluminescence spectroscopy. Results suggest that RR-P3HT chains in the lamellar structure prefer to be perpendicular to the axis of the RR-P3HT nanotubes, forming a face-on conformation in the RR-P3HT nanotubes that leads to increased carrier mobility of RR-P3HT. Field-effect transistors were fabricated based on a single RR-P3HT nanotube and showed a carrier mobility of 0.14 +/- 0.02 cm(2)/V.s. PMID- 25014609 TI - Betahistine metabolites, aminoethylpyridine, and hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo. AB - OBJECTIVE: Betahistine is a histamine-like drug that is used in the treatment of Meniere's disease. It is commonly believed that betahistine increases cochlear blood flow and thus decreases the endolymphatic hydrops that is the cause of Meniere's. Despite common clinical use, there is little understanding of the kinetics or effects of its metabolites. This study investigated the effect of the betahistine metabolites aminoethylpyridine, hydroxyethylpyridine, and pyridylacetic acid on cochlear microcirculation. DESIGN: Guinea pigs were randomly assigned to one of the groups: placebo, betahistine, or equimolar amounts of aminoethylpyridine, hydroxyethylpyridine, or pyridylacetic acid. Cochlear blood flow and mean arterial pressure were recorded for three minutes before and 15 minutes after treatment. STUDY SAMPLE: Thirty Dunkin-Hartley guinea pigs assigned to one of five groups with six guinea pigs per group. RESULTS: Betahistine, aminoethylpyridine, and hydroxyethylpyridine caused a significant increase in cochlear blood flow in comparison to placebo. The effect seen under aminoethylpyridin was greatest. The group treated with pyridylacetic acid showed no significant effect on cochlear blood flow. CONCLUSION: Aminoethylpyridine and hydroxyethylpyridine are, like betahistine, able to increase cochlear blood flow significantly. The effect of aminoethylpyridine was greatest. Pyridylacetic acid had no effect on cochlear microcirculation. PMID- 25014610 TI - Multiresponsive rolling circle amplification for DNA logic gates mediated by endonuclease. AB - Rolling circle amplification (RCA), an efficient isothermal amplification method allowing the polymerase-mediated generation of long single-stranded DNA molecules made of tandem repeats, has been widely used in biomedical and nanotechnology fields due to structural and compositional versatility of its components. In this work, we confer multiresponsiveness to RCA reactions by designing dumbbell-shaped DNA templates and hairpin probes containing different endonuclease cleavage sites. Endonucleases trigger the release of RCA primers or the cleavage of DNA templates, which controls subsequent RCA reactions. A set of one-input and two input DNA logic gates, which use endonucleases or hairpin probes as inputs, including YES, NOT, AND, OR, NOR, and INHIBIT, are constructed on the basis of our proposed multiresponsive RCA reactions. We demonstrate flexibility and scalability of these logic gates by integrating them to fabricate more complex three-input logic circuits (AND-OR and NOR-AND circuits). Moreover, our strategy is used to construct an assay system for endonuclease activity. Our proposed method might be applicable in the multichannel detection of endonucleases, nucleic acids, and other biomolecules. PMID- 25014612 TI - Carbon nanotube deformation and collapse under metal contacts. AB - In carbon nanotube transistors, typically part of the nanotube is covered by a metal contact. This covered region plays an important role due to the significant electron transfer length. Here we predict that capillary and van der Waals forces cause the nanotube to deform or even collapse under the metal. Nanotubes are known to collapse when their diameters are above some critical value around 4 nm. Under the metal, we find that spontaneous collapse occurs for diameters down to ~ 1.5-1.6 nm, close to the range used in high-performance transistors. Even at smaller diameters, we find surprisingly large deformations that could significantly affect the electronic structure. PMID- 25014611 TI - Astrobiological stoichiometry. AB - Chemical composition affects virtually all aspects of astrobiology, from stellar astrophysics to molecular biology. We present a synopsis of the research results presented at the "Stellar Stoichiometry" Workshop Without Walls hosted at Arizona State University April 11-12, 2013, under the auspices of the NASA Astrobiology Institute. The results focus on the measurement of chemical abundances and the effects of composition on processes from stellar to planetary scales. Of particular interest were the scientific connections between processes in these normally disparate fields. Measuring the abundances of elements in stars and giant and terrestrial planets poses substantial difficulties in technique and interpretation. One of the motivations for this conference was the fact that determinations of the abundance of a given element in a single star by different groups can differ by more than their quoted errors. The problems affecting the reliability of abundance estimations and their inherent limitations are discussed. When these problems are taken into consideration, self-consistent surveys of stellar abundances show that there is still substantial variation (factors of ~ 2) in the ratios of common elements (e.g., C, O, Na, Al, Mg, Si, Ca) important in rock-forming minerals, atmospheres, and biology. We consider how abundance variations arise through injection of supernova nucleosynthesis products into star-forming material and through photoevaporation of protoplanetary disks. The effects of composition on stellar evolution are substantial, and coupled with planetary atmosphere models can result in predicted habitable zone extents that vary by many tens of percent. Variations in the bulk composition of planets can affect rates of radiogenic heating and substantially change the mineralogy of planetary interiors, affecting properties such as convection and energy transport. PMID- 25014613 TI - Molecular dynamics simulations of self-emulsifying drug-delivery systems (SEDDS): influence of excipients on droplet nanostructure and drug localization. AB - In this study, molecular dynamics (MD) simulations were applied to model the lipidic nanoscale droplets that form when self-emulsifying drug-delivery systems (SEDDS) disperse into microemulsions in the gastrointestinal (GI) tract. The influence of the excipient composition on the droplet nanostructure and on the localization of drug molecules was monitored by the drug immersion depth and the molecular association bias between hydrophilic and hydrophobic moieties. A SEDDS standard system consisting of capric (C10) fatty acid chain length triglycerides and drug molecule cyclosporin A (CyA) was compared to systematic excipient variations. Investigating the drug-loading capacity of droplets yielded a negligible influence of drug molecules on the droplet nanostructure; increasing the drug load merely resulted in increased drug exposure to the aqueous environment. The variation of triglyceride fatty acid chain lengths yielded clearly distinguishable droplet association patterns (random, lamellar-like, and vesicle-like), which could prove beneficial for predicting and engineering drug solubilization in SEDDS. The addition of surfactant poly(ethylene glycol) (PEG-6) revealed the formation of an encapsulating surfactant shell with a negligible impact on the droplet interior triglyceride nanostructure, which could potentially be utilized to protect drug molecules from digestion. Mono- and diglyceride molecules displayed an increased tendency to accumulate at the droplet surface as well, in accordance with their capacity to act as surfactants, while also significantly interfering with the interior droplet nanostructure. The addition of monoglyceride molecules in particular caused the CyA molecule to be solubilized in a hydrophilic droplet core region consisting of polar triglyceride moieties. This mode of drug localization was in stark contrast to that of other systems, where CyA was predominantly found in the interfacial region of the aqueous environment. PMID- 25014614 TI - Age-related changes in functional network connectivity associated with high levels of verbal fluency performance. AB - The relative preservation of receptive language abilities in older adults has been associated with adaptive changes in cerebral activation patterns, which have been suggested to be task-load dependent. However, the effects of aging and task demands on the functional integration of neural networks contributing to speech production abilities remain largely unexplored. In the present functional neuroimaging study, data-driven spatial independent component analysis and hierarchical measures of integration were used to explore age-related changes in functional connectivity among cortical areas contributing to semantic, orthographic, and automated word fluency tasks in healthy young and older adults, as well as to assess the effect of age and task demands on the functional integration of a verbal fluency network. The results showed that the functional integration of speech production networks decreases with age, while at the same time this has a marginal effect on behavioral outcomes in high-performing older adults. Moreover, a significant task demand/age interaction was found in functional connectivity within the anterior and posterior subnetworks of the verbal fluency network. These results suggest that local changes in functional integration among cortical areas supporting lexical speech production are modulated by age and task demands. PMID- 25014616 TI - A commentary about the AMPHORA study: selected caveats, comments, and considerations about its conditions of diversity, uncertainty, and unpredictability. AB - This point-of-view commentary explores a selected range of issues relevant to alcoholic beverage drinking and nondrinking patterns documented by the AMPHORA European study which, with hind-sight, limits its generalizability, with fore sight are generally inadequately considered and documented and, with ordinary insight, are not likely to affect the ongoing and future behaviors of policy making and sustaining stakeholders whatever their sources of influence and whatever the levels and quality of evidence-informed data, information, and derived knowledge. PMID- 25014615 TI - Characteristics of a treatment-seeking population in outpatient addiction treatment centers in Mexico. AB - BACKGROUND: Baseline patients' characteristics are critical for treatment planning, as these can be moderators of treatment effects. In Mexico, information on treatment seekers with substance use disorders is scarce and limited to demographic characteristics. OBJECTIVE: This paper presents and analyses demographic characteristics, substance use related problems, clinical features, and addiction severity in a sample of treatment seekers from the first multi-site randomized clinical trial implemented in the Mexican Clinical Trials Network on Addiction and Mental Health. METHODS: A total of 120 participants were assessed prior randomization. Chi square or F-tests were used to compare sites across variables. Spearman correlation was used to associate negative consequences of substance use and motivation to change. RESULTS: The majority of participants were men, and the most prevalent substances reported were alcohol, marijuana, and cocaine. Participants were predominantly on the contemplation or action stage of change, and this was correlated with the perception of the negative consequences associated with substance use. Participants reported a high prevalence of substance use related problems. CONCLUSIONS: Substance use related problems, clinical features, and addiction severity reported by treatment seekers are important characteristics to take into account when planning treatment as they facilitate tailoring treatment to meet patients' needs. PMID- 25014617 TI - TPH2 genotype is associated with PTSD's avoidance symptoms in Chinese female earthquake survivors. AB - Genetic factors are important in the development of post-traumatic stress disorder (PTSD) following exposure to traumatic events. However, the molecular genetic underpinnings of this disorder have not been definitive. This study examined the association between tryptophan hydroxylase 2 (TPH2) rs11178997 genotype, a single-nucleotide polymorphism (SNP) located in the transcriptional control region, and PTSD symptoms. A total of 326 Chinese adults who suffered from the deadly 2008 Wenchuan earthquake and lost their children during the disaster participated in this study. PTSD symptoms were measured with PTSD checklist, and the SNP was successfully genotyped by the MassARRAY system. The results indicated that, although the rs11178997 genotype was not associated with total PTSD symptoms, it could significantly predict severity of PTSD's avoidance symptoms in women. These findings support that TPH2 may play an important functional role in the development of PTSD and contribute to the limited literature regarding the genetic basis and the sex-specific expression of PTSD's symptoms. PMID- 25014618 TI - Genetic association analysis of CNR1 and CNR2 polymorphisms with schizophrenia in a Korean population. AB - Located on 6q15 and 1p36.11, cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) genes are considered to be a positional and functional candidate gene for the development of mental disorders such as schizophrenia because CNR1 is known as a regulator of dopamine signaling in the hippocampus and the cerebral cortex. However, few genetic studies have been carried out to investigate an association of CNR1 and CNR2 polymorphisms and the risk of schizophrenia. In this study, although the result indicates that CNR1 and CNR2 variations are unlikely to influence schizophrenia susceptibility in a Korean population, the findings would provide meaningful information for further genetic studies. PMID- 25014619 TI - Sensory and Thermal Quantitative Testing in Children With Sickle Cell Disease. AB - Very little is known about pain processing in sickle cell disease (SCD). We examined the mechanical and thermal sensory patterns in children with SCD. Children ages 10 to 17 years (n = 48; mean 13.7 +/- 2.0 y; 22 females) participated in quantitative sensory testing (QST) procedures and completed a quality of life (PedsQL) and anxiety and depression scale (RCADS). Thirteen children showed evidence of abnormal pain processing, indicated by decreased sensitivity to heat or cold sensations (hypoesthesia), and pain experienced with nonpainful stimuli (allodynia). Pain ratings associated with cold and warm sensations were significantly higher in the subgroup with abnormal QST compared with the 35 SCD children with normal QST (P = 0.01 and P < 0.0001, respectively). The presence of hypoesthesia and allodynia in children with SCD may represent abnormal changes in the peripheral and central nervous system. Clinicians need to be aware that sickle cell pain may not only be inflammatory or ischemic secondary to vasoocclusion and hypoxia, but may also be neuropathic secondary to nerve injury or nerve dysfunction. Neuropathic pain in SCD may be the result of tissue damage after vaso-occlusion in neural tissues, whether peripherally or centrally. Future studies are needed to determine the presence of neuropathic pain in children with SCD. PMID- 25014620 TI - Novel insights into Fukushima nuclear accident from isotopic evidence of plutonium spread along coastal rivers. AB - The Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident led to important releases of radionuclides into the environment, and trace levels of plutonium (Pu) were detected in northeastern Japan. However, measurements of Pu isotopic atom and activity ratios are required to differentiate between the contributions of global nuclear test fallout and FDNPP emissions. In this study, we used a double-focusing sector field ICP-MS to measure Pu atom and activity ratios in recently deposited sediment along rivers draining the most contaminated part of the inland radioactive plume. Results showed that plutonium isotopes (i.e., (239)Pu, (240)Pu, (241)Pu, and (242)Pu) were detected in all samples, although in extremely low concentrations. The (241)Pu/(239)Pu atom ratios measured in sediment deposits (0.0017-0.0884) were significantly higher than the corresponding values attributed to the global fallout (0.00113 +/- 0.00008 on average for the Northern Hemisphere between 31 degrees -71 degrees N: Kelley, J. M.; Bond, L. A.; Beasley, T. M. Global distribution of Pu isotopes and (237)Np. Sci. Total. Env. 1999, 237/238, 483-500). The results indicated the presence of Pu from FDNPP, in slight excess compared to the Pu background from global fallout that represented up to ca. 60% of Pu in the analyzed samples. These results demonstrate that this radionuclide has been transported relatively long distances (~45 km) from FDNPP and been deposited in rivers representing a potential source of Pu to the ocean. In future, the high (241)Pu/(239)Pu atom ratio of the Fukushima accident sourced-Pu should be measured to quantify the supply of continental-originating material from Fukushima Prefecture to the Pacific Ocean. PMID- 25014621 TI - High-speed resistance training is more effective than low-speed resistance training to increase functional capacity and muscle performance in older women. AB - OBJECTIVE: To examine the effects of 12 weeks of high-speed resistance training (RT) versus low-speed RT on muscle strength [one repetition of maximum leg-press (1RMLP) and bench-press (1RMBP), plus dominant (HGd) and non-dominant maximum isometric handgrip], power [counter-movement jump (CMJ), ball throwing (BT) and 10-m walking sprint (S10)], functional performance [8-foot up-and-go test (UG) and sit-to-stand test (STS)], and perceived quality of life in older women. METHODS: 45 older women were divided into a high-speed RT group [EG, n=15, age=66.3+/-3.7y], a low-speed RT group [SG, n=15, age=68.7+/-6.4y] and a control group [CG, n=15, age=66.7+/-4.9y]. The SG and EG were submitted to a similar 12 week RT program [3 sets of 8 reps at 40-75% of the one-repetition maximum (10.05). Sixty-six patients had persistently high tPSA levels and 64 of them underwent prostate biopsy. Prostate cancer was detected in 8 of them (12.5%). CONCLUSIONS: A seven-day course of antibiotherapy is enough to normalize PSA levels in gray-zone patients. If recurrence of PSA increase is seen during follow-up, antibiotherapy can be useful again in those patients who previously benefited from it, while it will prove unnecessary in those who did not have their tPSA level normalized by it. PMID- 25014680 TI - Spore Dispersal by Dothistroma septosporum in Northwest British Columbia. AB - We studied spore dispersal by Dothistroma septosporum, causal agent of a serious outbreak of red band needle blight in lodgepole pine plantations in northwest British Columbia. Spore abundance was assessed at different distances and heights from inoculum sources and microclimatic factors were recorded during two consecutive years. Conidia were observed on spore traps from June to September during periods of rainfall. It was rare to detect spores more than 2 m away from inoculum sources. The timing and number of conidia dispersed were strongly tied to the climatic variables, particularly rainfall and leaf wetness. Should the trend toward increased spring and summer precipitation in the study area continue, the results suggest that disease spread and intensification will also increase. Increasing the planting distances between lodgepole pine trees through mixed species plantations and overall reduction in use of lodgepole pine for regeneration in wet areas are the best strategies to reduce the spread of the disease and enhance future productivity of plantations in the study area. PMID- 25014681 TI - Leaf Gas Exchange and Chlorophyll a Fluorescence in Maize Leaves Infected with Stenocarpella macrospora. AB - This study investigated the effect of macrospora leaf spot (MLS), caused by Stenocarpella macrospora, on photosynthetic gas exchange parameters and chlorophyll a fluorescence parameters determined in leaves of plants from two maize cultivars ('ECVSCS155' and 'HIB 32R48H') susceptible and highly susceptible, respectively, to S. macrospora. MLS severity was significantly lower in the leaves of plants from ECVSCS155 relative to the leaves of plants from HIB 32R48H. In both cultivars, net CO2 assimilation rate, stomatal conductance, and transpiration rate significantly decreased, while the internal to ambient CO2 concentration ratio increased in inoculated plants relative to noninoculated plants. The initial fluorescence and nonphotochemical quenching significantly increased in inoculated plants of ECVSCS155 and HIB 32R48H, respectively, relative to noninoculated plants. The maximum fluorescence, maximum PSII quantum efficiency, coefficient for photochemical quenching, and electron transport rate significantly decreased in inoculated plants relative to noninoculated plants. For both cultivars, concentrations of total chlorophyll (Chl) (a+b) and carotenoids and the Chl a/b ratio significantly decreased in inoculated plants relative to noninoculated plants. In conclusion, the results from the present study demonstrate, for the first time, that photosynthesis in the leaves of maize plants is dramatically affected during the infection process of S. macrospora, and impacts are primarily associated with limitations of a diffusive and biochemical nature. PMID- 25014679 TI - Nanoparticle-cell interactions: molecular structure of the protein corona and cellular outcomes. AB - The use of nanoparticles (NPs) in biology and medicine requires a molecular-level understanding of how NPs interact with cells in a physiological environment. A critical difference between well-controlled in vitro experiments and in vivo applications is the presence of a complex mixture of extracellular proteins. It has been established that extracellular serum proteins present in blood will adsorb onto the surface of NPs, forming a "protein corona". Our goal was to understand how this protein layer affected cellular-level events, including NP binding, internalization, and transport. A combination of microscopy, which provides spatial resolution, and spectroscopy, which provides molecular information, is necessary to probe protein-NP-cell interactions. Initial experiments used a model system composed of polystyrene NPs functionalized with either amine or carboxylate groups to provide a cationic or anionic surface, respectively. Serum proteins adsorb onto the surface of both cationic and anionic NPs, forming a net anionic protein-NP complex. Although these protein-NP complexes have similar diameters and effective surface charges, they show the exact opposite behavior in terms of cellular binding. In the presence of bovine serum albumin (BSA), the cellular binding of BSA-NP complexes formed from cationic NPs is enhanced, whereas the cellular binding of BSA-NP complexes formed from anionic NPs is inhibited. These trends are independent of NP diameter or cell type. Similar results were obtained for anionic quantum dots and colloidal gold nanospheres. Using competition assays, we determined that BSA-NP complexes formed from anionic NPs bind to albumin receptors on the cell surface. BSA-NP complexes formed from cationic NPs are redirected to scavenger receptors. The observation that similar NPs with identical protein corona compositions bind to different cellular receptors suggested that a difference in the structure of the adsorbed protein may be responsible for the differences in cellular binding of the protein-NP complexes. Circular dichroism spectroscopy, isothermal titration calorimetry, and fluorescence spectroscopy show that the structure of BSA is altered following incubation with cationic NPs, but not anionic NPs. Single particle-tracking fluorescence microscopy was used to follow the cellular internalization and transport of protein-NP complexes. The single particle tracking experiments show that the protein corona remains bound to the NP throughout endocytic uptake and transport. The interaction of protein-NP complexes with cells is a challenging question, as the adsorbed protein corona controls the interaction of the NP with the cell; however, the NP itself alters the structure of the adsorbed protein. A combination of microscopy and spectroscopy is necessary to understand this complex interaction, enabling the rational design of NPs for biological and medical applications. PMID- 25014682 TI - Sterics level the rates of proton transfer to [Ni(XPh){PhP(CH2CH2PPh2)2}]+ (X = O, S or Se). AB - Rates of proton transfers between lutH(+) (lut = 2,6-dimethylpyridine) and [Ni(XPh)(PhP{CH2CH2PPh2}2)](+) (X = O, S or Se) are slow and show little variation (k(O) : k(S) : k(Se) = 1 : 12 : 9). This unusual behaviour is a consequence of sterics affecting the optimal interaction between the reactants prior to proton transfer. PMID- 25014683 TI - Toward more comprehensive food labeling. PMID- 25014684 TI - Nutrient-content claims--guidance or cause for confusion? PMID- 25014685 TI - Culturally and Linguistically Appropriate Services--advancing health with CLAS. PMID- 25014687 TI - Lanreotide in metastatic enteropancreatic neuroendocrine tumors. AB - BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.). PMID- 25014689 TI - Single-pill combination regimens for treatment of HIV-1 infection. PMID- 25014690 TI - Images in clinical medicine. Intermittent facial flushing and diarrhea. PMID- 25014691 TI - Case records of the Massachusetts General Hospital. Case 22-2014. A 40-year-old woman with postpartum dyspnea and hypoxemia. PMID- 25014692 TI - Niacin and HDL cholesterol--time to face facts. PMID- 25014693 TI - Changes in the treatment landscape for chronic lymphoid leukemia. PMID- 25014694 TI - High versus low blood-pressure target in septic shock. PMID- 25014688 TI - Assessment of second-line antiretroviral regimens for HIV therapy in Africa. AB - BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (<=4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). CONCLUSIONS: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.). PMID- 25014695 TI - High versus low blood-pressure target in septic shock. PMID- 25014696 TI - High versus low blood-pressure target in septic shock. PMID- 25014697 TI - High versus low blood-pressure target in septic shock. PMID- 25014698 TI - Changes in diabetes-related complications in the United States. PMID- 25014699 TI - Changes in diabetes-related complications in the United States. PMID- 25014700 TI - Changes in diabetes-related complications in the United States. PMID- 25014701 TI - Changes in diabetes-related complications in the United States. PMID- 25014702 TI - Changes in diabetes-related complications in the United States. PMID- 25014703 TI - ICU-acquired weakness and recovery from critical illness. PMID- 25014704 TI - ICU-acquired weakness and recovery from critical illness. PMID- 25014705 TI - ICU-acquired weakness and recovery from critical illness. PMID- 25014706 TI - Safety profile of extended-release niacin in the AIM-HIGH trial. PMID- 25014707 TI - Treating our "situations" with science, not shame. PMID- 25014708 TI - Treating our "situations" with science, not shame. PMID- 25014709 TI - Images in clinical medicine. Video photomicroscopy. PMID- 25014710 TI - Highly functionalized tertiary-carbinols and carbinamines from the asymmetric gamma-alkoxyallylboration of ketones and ketimines with the borabicyclodecanes. AB - The first asymmetric gamma-alkoxyallylboration of representative ketones provides beta-alkoxy tert-homoallylic alcohols 10 whose diastereoselectivities range from 99% syn (acetophenone) to 99% anti (pinacolone) both with high ee (>95%). This distribution is attributable to the c/t isomerization of the BBD reagents and the greater reactivity of 7 vs 1 and of aromatic vs alkyl ketones. A ketone-based direct synthesis of a fostriecin intermediate and the tert-amine 26 are reported, each with high selectivities. PMID- 25014711 TI - DNA-length-dependent quenching of fluorescently labeled iron oxide nanoparticles with gold, graphene oxide and MoS2 nanostructures. AB - We controlled the fluorescence emission of a fluorescently labeled iron oxide nanoparticle using three different nanomaterials with ultraefficient quenching capabilities. The control over the fluorescence emission was investigated via spacing introduced by the surface-functionalized single-stranded DNA molecules. DNA molecules were conjugated on different templates, either on the surface of the fluorescently labeled iron oxide nanoparticles or gold and nanographene oxide. The efficiency of the quenching was determined and compared with various fluorescently labeled iron oxide nanoparticle and nanoquencher combinations using DNA molecules with three different lengths. We have found that the template for DNA conjugation plays significant role on quenching the fluorescence emission of the fluorescently labeled iron oxide nanoparticles. We have observed that the size of the DNA controls the quenching efficiency when conjugated only on the fluorescently labeled iron oxide nanoparticles by setting a spacer between the surfaces and resulting change in the hydrodynamic size. The quenching efficiency with 12mer, 23mer and 36mer oligonucleotides decreased to 56%, 54% and 53% with gold nanoparticles, 58%, 38% and 32% with nanographene oxide, 46%, 38% and 35% with MoS2, respectively. On the other hand, the presence, not the size, of the DNA molecules on the other surfaces quenched the fluorescence significantly with different degrees. To understand the effect of the mobility of the DNA molecules on the nanoparticle surface, DNA molecules were attached to the surface with two different approaches. Covalently immobilized oligonucleotides decreased the quenching efficiency of nanographene oxide and gold nanoparticles to ~22% and ~21%, respectively, whereas noncovalently adsorbed oligonucleotides decreased it to ~25% and ~55%, respectively. As a result, we have found that each nanoquencher has a powerful quenching capability against a fluorescent nanoparticle, which can be tuned with surface functionalized DNA molecules. PMID- 25014712 TI - Recent approaches to chemical discovery and development against malaria and the neglected tropical diseases human African trypanosomiasis and schistosomiasis. PMID- 25014713 TI - Rapid discrimination of bacteria by paper spray mass spectrometry. AB - Paper spray mass spectrometry ambient ionization is utilized for rapid discrimination of bacteria without sample preparation. Bacterial colonies were smeared onto filter paper precut to a sharp point, then wetted with solvent and held at a high potential. Charged droplets released by field emission were sucked into the mass spectrometer inlet and mass spectra were recorded. Sixteen different species representing eight different genera from Gram-positive and Gram negative bacteria were investigated. Phospholipids were the predominant species observed in the mass spectra in both the negative and positive ion modes. Multivariate data analysis based on principal component analysis, followed by linear discriminant analysis, allowed bacterial discrimination. The lipid information in the negative ion mass spectra proved useful for species level differentiation of the investigated Gram-positive bacteria. Gram-negative bacteria were differentiated at the species level by using a numerical data fusion strategy of positive and negative ion mass spectra. PMID- 25014714 TI - Sex differences in dynamic closed kinetic chain upper quarter function in collegiate swimmers. AB - CONTEXT: Upper quarter injuries have a higher incidence in female swimmers; however, to date, there are few ways to assess the basic functional ability of this region. The upper quarter Y balance test (YBT-UQ) may assist in this process because it was developed to provide a fundamental assessment of dynamic upper quarter ability at the limit of stability. OBJECTIVE: To examine how sex affects performance on the YBT-UQ in swimmers. DESIGN: Cohort study. PATIENTS OR OTHER PARTICIPANTS: Forty-three male and 54 female National Collegiate Athletic Association Division I college swimmers were recruited preseason. MAIN OUTCOME MEASURE(S): We measured YBT-UQ performance for the left and right limbs in the medial, inferolateral, and superolateral directions. The maximum score for each direction was normalized to upper extremity length. The average of the greatest normalized reach scores in each reach direction was used to develop a composite score (average distance in 3 directions/limb length [LL] * 100). To examine reach symmetry between sexes, the difference in centimeters between the left and right sides was calculated for each reach direction prior to normalization. Statistical analysis was conducted using an independent-samples t test (P < .05). RESULTS: Average scores in the medial (women: 92.5 +/- 7.4%LL, men: 100.0 +/- 8.7%LL; P < .01) and inferolateral (women: 85.6 +/- 10.3%LL, men: 89.8 +/- 10.8%LL; P = .05) directions and composite score (women: 83.4 +/- 8.3%LL, men: 88.3 +/- 8.9%LL; P < .01) were higher in men than in women. No differences were observed for reach symmetry in any direction. CONCLUSIONS: Performance on several YBT-UQ indices was worse for female than male collegiate swimmers. These results may have implications for the use of preseason and return-to-sport testing in swimmers as a measurement of upper quarter function and symmetry. PMID- 25014716 TI - Surface-enhanced Raman scattering-based detection of cancerous renal cells. AB - Surface-enhanced Raman scattering (SERS) is used for the differentiation of human kidney adenocarcinoma, human kidney carcinoma, and non-cancerous human kidney embryonic cells. Silver nanoparticles (AgNPs) are used as substrate in the experiments. A volume of colloidal suspension containing AgNPs is added onto the cultured cells on a CaF(2) slide, and the slide is dried at the overturned position. A number of SERS spectra acquired from the three different cell lines are statistically analyzed to differentiate the cells. Principal component analysis (PCA) combined with linear discriminate analysis (LDA) was performed to differentiate the three kidney cell types. The LDA, based on PCA, provided for classification among the three cell lines with 88% sensitivity and 84% specificity. This study demonstrates that SERS can be used to identify renal cancers by combining this new sampling method and LDA algorithms. PMID- 25014715 TI - Salvage of the thiamin pyrimidine moiety by plant TenA proteins lacking an active site cysteine. AB - The TenA protein family occurs in prokaryotes, plants and fungi; it has two subfamilies, one (TenA_C) having an active-site cysteine, the other (TenA_E) not. TenA_C proteins participate in thiamin salvage by hydrolysing the thiamin breakdown product amino-HMP (4-amino-5-aminomethyl-2-methylpyrimidine) to HMP (4 amino-5-hydroxymethyl-2-methylpyrimidine); the function of TenA_E proteins is unknown. Comparative analysis of prokaryote and plant genomes predicted that (i) TenA_E has a salvage role similar to, but not identical with, that of TenA_C and (ii) that TenA_E and TenA_C also have non-salvage roles since they occur in organisms that cannot make thiamin. Recombinant Arabidopsis and maize TenA_E proteins (At3g16990, GRMZM2G080501) hydrolysed amino-HMP to HMP and, far more actively, hydrolysed the N-formyl derivative of amino-HMP to amino-HMP. Ablating the At3g16990 gene in a line with a null mutation in the HMP biosynthesis gene ThiC prevented its rescue by amino-HMP. Ablating At3g16990 in the wild-type increased sensitivity to paraquat-induced oxidative stress; HMP overcame this increased sensitivity. Furthermore, the expression of TenA_E and ThiC genes in Arabidopsis and maize was inversely correlated. These results indicate that TenA_E proteins mediate amidohydrolase and aminohydrolase steps in the salvage of thiamin breakdown products. As such products can be toxic, TenA_E proteins may also pre-empt toxicity. PMID- 25014718 TI - Confocal Raman microscopy for investigating synthesis and characterization of individual optically trapped vinyl-polymerized surfactant particles. AB - Small polymeric particles are increasingly employed as adsorbent materials, as molecular carriers, as delivery vehicles, and in preconcentration applications. The rational development of these materials requires in situ methods of analysis to characterize their synthesis, structure, and applications. Optical-trapping confocal Raman microscopy is a spectroscopic method capable of acquiring information at several stages of the development of such dispersed particulate materials. In the present study, an example material is developed and tested using confocal Raman microscopy for characterization at each stage of the process. Specifically, the method is used to investigate the synthesis, structure, and applications of individual polymeric surfactant particles produced by the vinyl polymerization of sodium 11-acrylamidoundecanoate (SAAU). The kinetics of polymerization can be monitored over time by measuring the loss of the acrylamide C=C functional groups using confocal Raman microscopy of particles optically trapped by the excitation laser, where, within the limits of detecting the vinyl functional group, the complete polymerization of the SAAU monomer was achieved. The polymerized SAAU particles are spherical, and they exhibit uniform access to water throughout their structure, as tested by the penetration of heavy water (D2O) and collection of spatially resolved Raman spectra from the interior of the particle. These porous particles contain hydrophobic domains that can be used to accumulate molecules for adsorption or carrier applications. This property was tested by using confocal Raman microscopy to measure the accumulation equilibria and kinetics of a model compound, dioxybenzone. The partitioning of this compound into the polymer surfactant could be determined on a quantitative basis using relative scattering cross sections of the SAAU monomer and the adsorbate. The study points out the utility of optical-trapping confocal Raman microscopy for investigating the synthesis, structure, and potential carrier applications of polymeric particle materials. PMID- 25014719 TI - Fast determination of thiacloprid by photoinduced chemiluminescence. AB - A new and sensitive application of chemiluminescence detection has been developed for the determination of the pesticide thiacloprid in water. It was based on the on-line photoreaction of thiacloprid in a basic medium, with quinine acting as the sensitizer of the chemiluminescent response; cerium (IV) in sulfuric acid medium was used as the oxidant. High degrees of automation and reproducibility were achieved using a flow-injection analysis (FIA) manifold. The validation of the method was performed in terms of selectivity, linearity, limit of detection (LOD), precision, and accuracy. Liquid chromatography with ultraviolet (UV) detection was used as reference for mineral, tap, ground, and spring water samples. The proposed method is fast (with a throughput of 130 h(-1)), sensitive (LOD of 0.8 ng mL(-1) without preconcentration steps and of 0.08 ng mL(-1) with solid-phase extraction [SPE]), low cost, and possible to couple with separation methods for the simultaneous determination of other pesticides. The enhanced chemiluminescence intensity was linear with the thiacloprid concentration above the 2-80 and 80-800 ng mL(-1) ranges. A possible reaction mechanism is also discussed. PMID- 25014717 TI - An effect of cellulose crystallinity on the moisture absorbability of a pharmaceutical tablet studied by near-infrared spectroscopy. AB - In this study, we investigated molecular-level variation of tablets caused by grinding and its effect on their actual moisture absorbability. Model tablets contained acetaminophen as an active pharmaceutical ingredient and microcrystalline cellulose (MCC) as an excipient. Different levels of grinding were applied during the tablet formulation to intentionally cause the structural variation of the MCC. The moisture absorbability of tablets showed obvious variation depending on the grinding time, and the corresponding change in near infrared spectra was readily captured. The detailed analysis of the variation of the band frequencies (i.e., wavenumber) revealed that the grinding process substantially disintegrates the crystalline and generates a glassy amorphous structure of MCC, which is a requirement to absorb water molecules. Consequently, it is very likely that the change of the moisture absorbability of the tablets is closely related to the development of the amorphous structure. These results indicate that the pharmaceutical product performances can be influenced by the physical properties of the excipient, which in turn can be controlled by the grinding process. PMID- 25014720 TI - An investigation of micro-hollow cathode glow discharge generated optical emission spectroscopy for hydrocarbon detection and differentiation. AB - The analytical utility of a micro-hollow cathode glow discharge plasma for detection of varied hydrocarbons was tested using acetone, ethanol, heptane, nitrobenzene, and toluene. Differences in fragmentation pathways, reflecting parent compound molecular structure, led to differences in optical emission patterns that can then potentially serve as signatures for the species of interest. Spectral simulations were performed emphasizing the CH (A(2)Delta X(2)Pi), CH (C(2)Sigma-X(2)Pi), and OH (A(2)Sigma(+)-X(2)Pi) electronic systems. The analytical utility of selected emission lines is demonstrated by a linear relationship between optical emission spectroscopy and parent compound concentration over a wide range, with detection limits extending down to parts per billion (ppb) levels. PMID- 25014721 TI - Two-dimensional fourier transform infrared (FT-IR) correlation spectroscopy study of the imidization reaction from polyamic acid to polyimide. AB - The mechanism of the thermal imidization of solid-state polyamic acid was studied using Fourier transform infrared (FT-IR) spectroscopy using the two-dimensional correlation spectroscopy method. It is assumed that two isomers exist in a polyamic acid segment: one is called the para-segment, which favors imidization reaction, the other is the meta-segment, which is not in favor for imidization unless the temperature is high enough. The results show that the imidization process differs for the two states of polyamic acid segments. The para-segment is more sensitive to the heat environment for the formation of imide ring, and it will take several intermediate steps to complete the ring closure at the aid of the solvent. As for the meta-segment, the ring will be closed before the imide formation due to the powerful energy provided in the high-temperature environment, and the ever-increasing chain rigidity and the loss of solvent during the heating process make this path the only option to continue the imidization process. PMID- 25014722 TI - Benign odontogenic tumors versus histochemically related tissues: preliminary results from mid-infrared and solid-state nuclear magnetic resonance spectroscopy. AB - Three types of human odontogenic tumors histologically classified as compound composite odontoma, ossifying fibroma, and Pindborg tumor were characterized using mid-infrared spectroscopy (mid-IR) and solid-state nuclear magnetic resonance (ssNMR). For comparison, human jawbone and dental mineralized tissues such as dentin, enamel, and dental cement were also characterized. The studies focused on the structural properties and chemical composition of pathological tissues versus histochemically related tissues. All analyzed tumors were composed of organic and mineral parts and water. Apatite was found to be the main constituent of the mineral part. Various components (water, structural hydroxyl groups, carbonate ions (CO(3)(2-)), and hydrogen phosphate ions (HPO(4)(2-))) and physicochemical parameters (index of apatite maturity and crystallinity) were examined. The highest organic/mineral ratio was observed in fibrocementoma, a finding that can be explained by the fibrous character of the tumor. The lowest relative HPO(4)(2-) content was found in odontoma. This tumor is characterized by the highest mineral crystallinity index and content of structural hydroxyl groups. The Pindborg tumor mineral portion was found to be poorly crystalline and rich in HPO(4)(2-). The relative CO(3)(2-) content was similar in all samples studied. The results of spectroscopic studies of odontogenic tumors were consistent with the standard histochemical analysis. It was shown that the various techniques of ssNMR and elaborate analysis of the mid-IR spectra, applied together, provide valuable information about calcified benign odontogenic tumors. PMID- 25014723 TI - Experimental study of laser-induced breakdown spectroscopy (LIBS) for direct analysis of coal particle flow. AB - Laser-induced breakdown spectroscopy (LIBS) was employed to directly analyze coal particles in the form of descending flow. Coal-particle ablation was performed using a 1064 nm neodymium-doped yttrium aluminum garnet (Nd : YAG) laser at atmospheric conditions. Spectral identification schemes were used to acquire spectra containing all the emission lines of the important elements in coal. These acquired spectra were classified as representative spectra. The background of the line emission plus three times the standard deviation of the background of the representative spectra was chosen as the threshold value. A method using a single line and a method using combined multiple lines (C, 247.8 nm; N, 746.8 nm; Si, 288.2 nm; and Ca, 396.8 nm) were compared to obtain the best results for the spectral identification of coal particle flow. The feasibility of rejecting the partial breakdown spectra was verified using quantitative analysis of fixed carbon in coal. PMID- 25014724 TI - White light photothermal lens spectrophotometer for the determination of absorption in scattering samples. AB - We developed a pump-probe photothermal lens spectrophotometer that uses a broadband arc-lamp and a set of interference filters to provide tunable, nearly monochromatic radiation between 370 and 730 nm as the pump light source. This light is focused onto an absorbing sample, generating a photothermal lens of millimeter dimensions. A highly collimated monochromatic probe light from a low power He-Ne laser interrogates the generated lens, yielding a photothermal signal proportional to the absorption of light. We measure the absorption spectra of scattering dye solutions using the device. We show that the spectra are not affected by the presence of scattering, confirming that the method only measures the absorption of light that results in generation of heat. By comparing the photothermal spectra with the usual absorption spectra determined using commercial transmission spectrophotometers, we estimate the quantum yield of scattering of the sample. We discuss applications of the device for spectroscopic characterization of samples such as blood and gold nanoparticles that exhibit a complex behavior upon interaction with light. PMID- 25014725 TI - Subsurface Raman analysis of thin painted layers. AB - Here we present, for the first time, an extension of spatially offset Raman spectroscopy to thin (tens of micrometers thick), highly turbid stratified media such as those encountered in paintings. The method permits the non-destructive interrogation of painted layers in situations where conventional Raman microscopy is not applicable due to high turbidity of the top layer(s). The concept is demonstrated by recovering the pure Raman spectra of paint sub-layers that are completely obscured by paint over-layers. Potential application areas include the analysis of paintings in art preservation and restoration avoiding the cross sectional analysis used currently with this type of samples. The technique also holds promise for the development as a non-destructive subsurface tool for in situ analysis using portable instruments. PMID- 25014726 TI - A line-scan hyperspectral system for high-throughput Raman chemical imaging. AB - A line-scan hyperspectral system was developed to enable Raman chemical imaging for large sample areas. A custom-designed 785 nm line laser based on a scanning mirror serves as an excitation source. A 45 degrees dichroic beam splitter reflects the laser light to form a 24 cm * 1 mm excitation line normally incident on the sample surface. Raman signals along the laser line are collected by a detection module consisting of a dispersive imaging spectrograph and a CCD camera. A hypercube is accumulated line by line as a motorized table moves the samples transversely through the laser line. The system covers a Raman shift range of -648.7 to 2889.0 cm(-1) and a 23 cm wide area. An example application for authenticating milk powder is presented to demonstrate the system performance. In 4 min the system acquired a 512 * 110 * 1024 hypercube (56 320 spectra) from four, 47 mm diameter Petri dishes containing four powder samples. Chemical images were created for detecting two adulterants (melamine and dicyandiamide) that had been mixed into the milk powder. PMID- 25014727 TI - Microemulsions with the ionic liquid ethylammonium nitrate: phase behavior, composition, and microstructure. AB - In this study, we investigate properties of microemulsions which consist of the ionic liquid (IL) ethylammonium nitrate (EAN), the nonionic surfactant C12E3 and an n-alkane, namely n-dodecane or n-octane. The compositions of the coexisting phases are calculated from the densities and volumes of the respective phases. Since the interfacial tension between the water-rich and the oil-rich phase in traditional microemulsions (containing water and oil) relates to the microstructure, spinning drop tensiometry is used to measure the interfacial tension sigmaab and to estimate the domain sizes. Finally, measuring the self diffusion coefficients of all components via the Fourier Transform Pulsed Gradient Spin Echo (FTPGSE) NMR technique allowed distinguishing between continuous and discrete structures. Our results indicate that the general principles underlying water-n-alkane-CiEj microemulsions can indeed be transferred to oil-in-EAN droplet and the respective bicontinuous microemulsions, while differences are observed for EAN-in-oil droplet microemulsions. PMID- 25014728 TI - Antibodies specific for nucleic acids and applications in genomic detection and clinical diagnostics. AB - Detection of nucleic acids using antibodies is uncommon. This is in part because nucleic acids are poor immunogens and it is difficult to elicit antibodies having high affinity to each type of nucleic acid while lacking cross-reactivity to others. We describe the origins and applications of a variety of anti-nucleic acid antibodies, including ones reacting with modified nucleosides and nucleotides, single-stranded DNA, double-stranded DNA, RNA, DNA:RNA hybrids, locked-nucleic acids or peptide nucleic acid:nucleic acid hybrids. Carefully selected antibodies can be excellent reagents for detecting bacteria, viruses, small RNAs, microRNAs, R-loops, cancer cells, stem cells, apoptotic cells and so on. The detection may be sensitive, simple, rapid, specific, reproducible, quantitative and cost-effective. Current microarray and diagnostic methods that depend on cDNA or cRNA can be replaced by using antibody detection of nucleic acids. Therefore, development should be encouraged to explore new utilities and create a robust arsenal of new anti-nucleic acid antibodies. PMID- 25014729 TI - Structural analysis of the homodimeric reaction center complex from the photosynthetic green sulfur bacterium Chlorobaculum tepidum. AB - The reaction center (RC) complex of the green sulfur bacterium Chlorobaculum tepidum is composed of the Fenna-Matthews-Olson antenna protein (FMO) and the reaction center core (RCC) complex. The RCC complex has four subunits: PscA, PscB, PscC, and PscD. We studied the FMO/RCC complex by chemically cross-linking the purified sample followed by biochemical and spectroscopic analysis. Blue native gels showed that there were two types of FMO/RCC complexes, which are consistent with complexes with one copy of FMO per RCC and two copies of FMO per RCC. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the samples after cross-linking showed that all five subunits of the RC can be linked by three different cross-linkers: bissulfosuccinimidyl suberate, disuccinimidyl suberate, and 3,3-dithiobis-sulfosuccinimidyl propionate. The interaction sites of the cross-linked complex were also studied using liquid chromatography coupled to tandem mass spectrometry. The results indicated that FMO, PscB, PscD, and part of PscA are exposed on the cytoplasmic side of the membrane. PscD helps stabilize FMO to the reaction center and may facilitate transfer of the electron from the RC to ferredoxin. The soluble domain of the heme-containing cytochrome subunit PscC and part of the core subunit PscA are located on the periplasmic side of the membrane. There is a close relationship between the periplasmic portions of PscA and PscC, which is needed for the efficient transfer of the electron between PscC and P840. PMID- 25014730 TI - Immunohistochemistry with the anti-BRAF V600E (VE1) antibody: impact of pre analytical conditions and concordance with DNA sequencing in colorectal and papillary thyroid carcinoma. AB - The most common of all activating BRAF mutations (T1799A) leads to a substitution of valine (V) to glutamic acid (E) at the position 600 of the amino acid sequence. The major goal of this study was to compare detection of the BRAF V600E mutation by DNA sequencing with immunohistochemistry (IHC) using the anti-BRAF V600E (VE1) antibody. Archival formalin fixed, paraffin embedded tissues from 352 patients with colon adenocarcinoma (n = 279) and papillary thyroid carcinoma (n = 73) were evaluated for the BRAF V600E mutation by sequencing and IHC. The discordant cases were re-evaluated by repeat IHC, SNaPshot and next-generation sequencing (NGS). Furthermore, the effect of pre-analytical variables on the utility of this antibody was evaluated in two xenograft mouse models.After resolving 15 initially discordant cases, 212 cases were negative for the BRAF V600E mutation by IHC. Of these, 210 cases (99.1%) were also negative by sequencing and two cases (0.9%) remained discordant. Of the 140 cases that were IHC positive for BRAF V600E, 138 cases were confirmed by sequencing (98.6%) and two cases remained discordant (1.4%). Overall, the negative predictive value was 99.1%, positive predictive value 98.6%, sensitivity 98.6%, specificity 99.1% and overall percentage agreement 98.9% (348/352 cases). Tissue fixation studies indicated that tissues should be fixed for 12-24 h within 2 h of tissue collection with 10% neutral buffered formalin. PMID- 25014731 TI - Considerations for protein intake in managing weight loss in athletes. AB - A large body of evidence now shows that higher protein intakes (2-3 times the protein Recommended Dietary Allowance (RDA) of 0.8 g/kg/d) during periods of energy restriction can enhance fat-free mass (FFM) preservation, particularly when combined with exercise. The mechanisms underpinning the FFM-sparing effect of higher protein diets remain to be fully elucidated but may relate to the maintenance of the anabolic sensitivity of skeletal muscle to protein ingestion. From a practical point of view, athletes aiming to reduce fat mass and preserve FFM should be advised to consume protein intakes in the range of ~1.8-2.7 g kg( 1) d(-1) (or ~2.3-3.1 g kg(-1) FFM) in combination with a moderate energy deficit (-500 kcal) and the performance of some form of resistance exercise. The target level of protein intake within this recommended range requires consideration of a number of case-specific factors including the athlete's body composition, habitual protein intake and broader nutrition goals. Athletes should focus on consuming high-quality protein sources, aiming to consume protein feedings evenly spaced throughout the day. Post-exercise consumption of 0.25-0.3 g protein meal( 1) from protein sources with high leucine content and rapid digestion kinetics (i.e. whey protein) is recommended to optimise exercise-induced muscle protein synthesis. When protein is consumed as part of a mixed macronutrient meal and/or before bed slightly higher protein doses may be optimal. PMID- 25014732 TI - Geochemical and microbiological responses to oxidant introduction into reduced subsurface sediment from the Hanford 300 Area, Washington. AB - Pliocene-aged reduced lacustrine sediment from below a subsurface redox transition zone at the 300 Area of the Hanford site (southeastern Washington) was used in a study of the geochemical response to introduction of oxygen or nitrate in the presence or absence of microbial activity. The sediments contained large quantities of reduced Fe in the form of Fe(II)-bearing phyllosilicates, together with smaller quantities of siderite and pyrite. A loss of ca. 50% of 0.5 M HCl extractable Fe(II) [5-10 mmol Fe(II) L(-1)] and detectable generation of sulfate (ca. 0.2 mM, equivalent to 10% of the reduced inorganic sulfur pool) occurred in sterile aerobic reactors. In contrast, no systematic loss of Fe(II) or production of sulfate was observed in any of the other oxidant-amended sediment suspensions. Detectable Fe(II) accumulation and sulfate consumption occurred in non-sterile oxidant-free reactors. Together, these results indicate the potential for heterotrophic carbon metabolism in the reduced sediments, consistent with the proliferation of known heterotrophic taxa (e.g., Pseudomonadaceae, Burkholderiaceae, and Clostridiaceae) inferred from 16S rRNA gene pyrosequencing. Microbial carbon oxidation by heterotrophic communities is likely to play an important role in maintaining the redox boundary in situ, i.e., by modulating the impact of downward oxidant transport on Fe/S redox speciation. Diffusion-reaction simulations of oxygen and nitrate consumption coupled to solid-phase organic carbon oxidation indicate that heterotrophic consumption of oxidants could maintain the redox boundary at its current position over millennial time scales. PMID- 25014733 TI - Comparison of trends in US health-related quality of life over the 2000s using the SF-6D, HALex, EQ-5D, and EQ-5D visual analog scale versus a broader set of symptoms and impairments. AB - BACKGROUND: A number of instruments have been developed to measure health-related quality of life (HRQoL), differing in the health domains covered and their scoring. Although few such measures have been consistently included in US national health surveys over time, the surveys have included data on a broad range of symptoms and impairments, which enables the tracking of population health trends. OBJECTIVES: To compare trends in HRQoL as measured using existing instruments versus using a broader range of symptoms and impairments collected in multiple years of nationally representative data. DATA AND MEASURES: Data were from the 2000-2010 Medical Expenditure Panel Survey, which is nationally representative of the noninstitutionalized US population. Level of and trends in HRQoL derived from a broad range of survey symptoms and impairments (SSI) was compared with HRQoL from the SF-6D, the HALex, and, between 2000 and 2003, the EuroQol-5D (EQ-5D) and EQ-5D Visual Analog Scale. RESULTS: Trends in HRQoL were similar using different measures. The SSI scores correlated 0.66-0.80 with scores from other measures and mean SSI scores were between those of other measures. Scores from all HRQoL measures declined similarly with increasing age and with the presence of comorbid conditions. CONCLUSIONS: Measuring HRQoL using a broader range of symptoms and impairments than those in a single instrument yields population health trends similar to those from other measures while making maximum use of existing data and providing rich detail on the factors underlying change. PMID- 25014734 TI - Factors associated with having a usual source of care in an ethnically diverse sample of Asian American adults. AB - BACKGROUND: Despite significant population increases, how Asian Americans ethnic subgroups vary in having a usual source of care (USC) is poorly understood. OBJECTIVES: To examine how having a USC varies among Asian American ethnic subgroups (Chinese, Filipinos, Japanese, Koreans, Vietnamese, and South Asians), and the potential factors influencing variation in having a USC. RESEARCH DESIGN: Data were from 2005 and 2009 California Health Interview Survey. Logistic regressions and pair-wise comparisons were used to compare odds of having a USC among Asian ethnic adults (18-64 y) and to examine ethnicity-specific associations with immigration-related factors (English proficiency, length of residence, and living in an ethnically concordant neighborhood) and key enabling (employment, income, insurance), predisposing (education), and need (health status) factors. Models also adjusted for other sociodemographic factors. RESULTS: Significant differences in the magnitude of the variation and factors influencing having a USC were found across Asian subgroups. Korean and Japanese adults had 52%-69% lower adjusted odds of having a USC compared with Chinese. Among all Asian subgroups, uninsured adults had 85%-94% lower adjusted odds of having a USC. Patterns of associations with USC and key factors varied by specific Asian subgroup. CONCLUSIONS: Patterns of associations for USC varied by Asian subgroup, although uninsurance persisted significantly across all subgroups. Persistent variation and heterogenous associations suggest that targeted, ethnicity-specific policies and outreach are needed to improve having a USC for Asian American ethnic adults. PMID- 25014686 TI - Effects of extended-release niacin with laropiprant in high-risk patients. AB - BACKGROUND: Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain. METHODS: After a prerandomization run in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). RESULTS: During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001). CONCLUSIONS: Among participants with atherosclerotic vascular disease, the addition of extended-release niacin laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.). PMID- 25014735 TI - Inflammatory risk factors and pathologies promoting Alzheimer's disease progression: is RAGE the key? AB - Epidemiological studies reveal growing evidence that most cases of Alzheimer's Disease (AD) likely involve a combination of genetic and environmental risk factors. Identifying and validating these risk factors remains one of the most critical scientific challenges. Several diseases appear to have strong implications for neurodegeneration leading to dementia. This risk encompasses different forms of cardiovascular disease, carotid atherosclerosis, history of hypertension or high cholesterol, Type II diabetes, stroke or transient ischemic attack and brain trauma. However, the molecular pathways that are common and central in the progression of these diseases and AD are not yet elucidated. Unveiling these critical mechanisms at the molecular level is necessary for the development of therapeutic strategies aimed at preventing AD progression. The Receptor for Advanced Glycation Endproducts (RAGE) plays a key role in all the diseases that represent a risk for AD. RAGE-mediated signaling also contributes to neurodegeneration in AD, suggesting that it may mediate the effect of risk factors in promoting AD. We will summarize the current knowledge on the role of RAGE in pathologies promoting AD and in AD progression. We will also provide evidence showing the relevance of RAGE-induced inflammation as a risk pathway that is implicated in AD pathophysiology. PMID- 25014736 TI - Methods for the discovery of emerging pathogens. AB - Recently, there has been a steady increase in the number of recognized pathogenic microorganisms, specifically bacteria. The development of genetic technologies, MALDI-TOF mass spectrometry and new culturing techniques has significantly widened the repertoire of known microorganisms and therefore pathogenic microorganisms. The repertoire of infectious agents has been studied in various environments including water, soil, pets, livestock, wildlife and arthropods. Using different methods, many known pathogens can be identified in these samples; therefore, the impact of emergent pathogens on humans can be examined and novel pathogens can be identified. In this special issue, we discuss the identification of emerging pathogens in the environment and animals. PMID- 25014737 TI - From transplantation to transgenics: mouse models of developmental hematopoiesis. AB - The mouse is integral to our understanding of hematopoietic biology. Serving as a mammalian model system, the mouse has allowed for the discovery of self-renewing multipotent stem cells, provided functional assays to establish hematopoietic stem cell identity and function, and has become a tool for understanding the differentiation capacity of early hematopoietic progenitors. The advent of genetic technology has strengthened the use of mouse models for identifying critical pathways in hematopoiesis. Full genetic knockout models, tissue-specific gene deletion, and genetic overexpression models create a system for the dissection and identification of critical cellular and genetic processes underlying hematopoiesis. However, the murine model has also introduced perplexity in understanding developmental hematopoiesis. Requisite in utero development paired with circulation has historically made defining sites of origin and expansion in the murine hematopoietic system challenging. However, the genetic accessibility of the mouse as a mammalian system has identified key regulators of hematopoietic development. Technological advances continue to generate extremely powerful tools that when translated to the murine system provide refined in vivo spatial and temporal control of genetic deletion or overexpression. Future advancements may add the ability of reversible genetic manipulation. In this review, we describe the major contributions of the murine model to our understanding of hematopoiesis. PMID- 25014739 TI - Nucleophilic reactions of bromocyclopentane in the structure-H methane + bromocyclopentane mixed hydrate system at high pressures. AB - Thermodynamic stability boundary in the structure-H methane + bromocyclopentane mixed hydrate system was measured at pressures from 20 to 100 MPa. The thermodynamic stability boundary of the methane + bromocyclopentane mixed hydrate exhibits anomalous behavior under conditions at high pressures and high temperatures. This phenomenon is due to the elimination and substitution reactions of bromocyclopentane to cyclopentene and cyclopentanol, respectively. The nucleophilic reactions of bromocyclopentane are mainly advanced in the liquid bromocyclopentane-rich phases, while it is restrained when bromocyclopentane is enclathrated in hydrate cage. PMID- 25014740 TI - Looking for results in non-small-cell lung cancer: is bio-chemotherapy the right answer? PMID- 25014741 TI - The aging bone marrow and its impact on immune responses in old age. AB - With aging the immune system undergoes significant age-related changes. These age dependent changes are referred to as immunosenescence and are partially responsible for the poor immune response to infections and the low efficacy of vaccination in elderly persons. Immunosenescence is characterized by a decrease in innate and adaptive cell-mediated immune function in the peripheral blood and the bone marrow. The aging of bone marrow cells and in particular, of adaptive immune cells in the bone marrow has been addressed relatively rarely. It is therefore the goal of this review to summarize what is known about the effect of age on bone marrow immune cells and their precursors in mice and humans. PMID- 25014743 TI - The influence of maternal infant feeding practices and beliefs on the expression of food neophobia in toddlers. AB - Food neophobia is a highly heritable trait characterized by the rejection of foods that are novel or unknown and potentially limits dietary variety, with lower intake and preference particularly for fruits and vegetables. Understanding non-genetic (environmental) factors that may influence the expression of food neophobia is essential to improving children's consumption of fruits and vegetables and encouraging the adoption of healthier diets. The aim of this study was to examine whether maternal infant feeding beliefs (at 4 months) were associated with the expression of food neophobia in toddlers and whether controlling feeding practices mediated this relationship. Participants were 244 first-time mothers (M=30.4, SD=5.1 years) allocated to the control group of the NOURISH randomized controlled trial. The relationships between infant feeding beliefs (Infant Feeding Questionnaire) at 4 months and controlling child feeding practices (Child Feeding Questionnaire) and food neophobia (Child Food Neophobia Scale) at 24 months were tested using correlational and multiple linear regression models (adjusted for significant covariates). Higher maternal Concern about infant under-eating and becoming underweight at 4 months was associated with higher child food neophobia at 2 years. Similarly, lower Awareness of infant hunger and satiety cues was associated with higher child food neophobia. Both associations were significantly mediated by mothers' use of Pressure to eat. Intervening early to promote positive feeding practices to mothers may help reduce the use of controlling practices as children develop. Further research that can further elucidate the bi-directional nature of the mother-child feeding relationship is still required. PMID- 25014742 TI - Better quality of mother-child interaction at 4 years of age decreases emotional overeating in IUGR girls. AB - BACKGROUND/OBJECTIVES: While most "fetal programming" area focused on metabolic disease, intrauterine growth restriction (IUGR) is also associated with a preference for less healthy food. Post-natal factors such as strained maternal child interactions are equally related to obesogenic eating behaviors. We investigated if IUGR and the quality of the mother/child relationship affect emotional overeating in children. SUBJECTS/METHODS: Participants were 196 children from a prospective birth cohort (the MAVAN project). As part of the protocol at 4 years of age, mothers completed the Children Eating Behavior Questionnaire (CEBQ) and mother-child interactions were scored during a structured task. A GLM adjusted for BMI examined the interaction between the "Atmosphere" score (ATM) task, sex and IUGR on the emotional over-eating domain of the CEBQ. RESULTS: There was a significant interaction of BWR vs. sex vs. ATM (P = .02), with no effects of IUGR, sex or ATM. The model was significant for girls with low ATM scores (B = -2.035, P = .014), but not for girls with high (P = 0.94) or boys with high (P = .27) or low (P = .19) ATM scores. Only in IUGR girls, 48 months emotional over-eating correlated with BMI at that age (r = 0.560, P = 0.013) and predicted BMI in the subsequent years (r = 0.654, P = 0.006 at 60 months and r = 0.750, P = 0.005 at 72 months). CONCLUSIONS: IUGR and exposure to a negative emotional atmosphere during maternal-child interactions predicted emotional overeating in girls but not in boys. The quality of mother infant interaction may be an important target for interventions to prevent emotional overeating and overweight in early development, particularly in girls with a history of IUGR. PMID- 25014744 TI - Eating practices and habitus in mothers. A Brazilian population-based survey. AB - A population-based cross-sectional study was conducted with mothers living in the city of Santos, Brazil, in order to investigate their eating practices, and the interface between those practices and the concept of habitus. From a cluster analysis of the scores for dietary pattern and for food preparation and consumption, the mothers were categorised into five clusters of eating practices: practical mothers (19.8%), symbiotic mothers (3.2%), health-conscious hedonists (17.3%), traditionalists (34.6%), and family cooks (25.1%). To access the habitus of the eating-practice clusters, the following variables were compared: location of residence, profession, socioeconomic status, weight-loss practices, risk behaviours for eating disorders, disordered eating attitudes, body dissatisfaction, and cultural and technological consumption. For all the groups, the observed eating practices were permeated by responsibility for the family's diet, but with different manifestations. For symbiotic mothers, practical mothers, and family cooks, the primary function of their relation with food was to nourish their families, with little expression of their own tastes and preferences. The traditionalists and the health-conscious hedonists, on the other hand, manifested their role as mothers by providing food considered 'nutritionally proper' to their family members. Furthermore, aspects of contemporary lifestyles, such as little time for food, individualisation of meals, and consumption of processed foods, were found to coexist with the valorisation and maintenance of the traditional meals within some groups. The variety of eating practices could not be understood as a linear association between economic and cultural capitals; however, eating practices seemed to interact with those capitals, composing a habitus. PMID- 25014738 TI - Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives. AB - Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal associated lymphoid tissues (NALT). Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV) etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents. PMID- 25014745 TI - Synthesis and antiviral activity of new phenylimidazopyridines and N benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolines. AB - Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5 g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive sense (ssRNA(+)) or negative-sense (ssRNA(-)), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 MUM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5 c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 MUM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2'-C-methyl-guanosine. Moreover, several N benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 MUM. PMID- 25014746 TI - Interaction of ferrocene appended Ru(II), Rh(III) and Ir(III) dipyrrinato complexes with DNA/protein, molecular docking and antitumor activity. AB - Efficacy of the ferrocene appended piano-stool dipyrrinato complexes [(eta(6) C6H6)RuCl(fcdpm)] (1), [(eta(6)-C10H14)RuCl(fcdpm)] (2), [(eta(6) C12H18)RuCl(fcdpm)] (3) [(eta(5)-C5Me5)RhCl(fcdpm)] (4) and [(eta(5) C5Me5)IrCl(fcdpm)] (5) [fcdpm = 5-ferrocenyldipyrromethene] toward anticancer activity have been described. Binding of the complexes with calf thymus DNA (CT DNA) and BSA (bovine serum albumin) have been thoroughly investigated by UV-Vis and fluorescence spectroscopy. Binding constants for 1-5 (range, 10(4)-10(5) M( 1)) validated their efficient binding with CT-DNA. Molecular docking studies revealed interaction through minor groove of the DNA, on the other hand these also interact through hydrophobic residues of the protein, particularly cavity in the subdomain IIA. In vitro anticancer activity have been scrutinized by MTT assay, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA ladder (fragmentation) assay against Dalton's Lymphoma (DL) cells. Present study revealed that rhodium complex (4) is more effective relative to ruthenium (1-3) and iridium (5) complexes. PMID- 25014747 TI - Synthesis and effects on cell viability of flavonols and 3-methyl ether derivatives on human leukemia cells. AB - Flavonoids are polyphenolic compounds which display an array of biological activities and are considered potential antitumor agents. Here we evaluated the antiproliferative activity of selected synthetic flavonoids against human leukemia cell lines. We found that 4'-bromoflavonol (flavonol 3) was the most potent. This compound inhibited proliferation in a concentration-dependent manner, induced apoptosis and blocked cell cycle progression at the S phase. Cell death was found to be associated with the cleavage and activation of multiple caspases, the activation of the mitogen-activated protein kinase pathway and the up-regulation of two death receptors (death receptor 4 and death receptor 5) for tumor necrosis factor-related apoptosis-inducing ligand. Moreover, combined treatments using 4'-bromoflavonol and TRAIL led to an increased cytotoxicity compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer. PMID- 25014748 TI - Design and synthesis of new of 3-(benzo[d]isoxazol-3-yl)-1-substituted pyrrolidine-2, 5-dione derivatives as anticonvulsants. AB - A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a 7d, 8a-8d, 9a-9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3 (benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol 3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs. PMID- 25014749 TI - Reliability and variability of diffusion tensor imaging (DTI) tractography in pediatric epilepsy. AB - BACKGROUND: Diffusion tensor imaging (DTI) tractography is useful for isolating white matter (WM) trajectories and exploring microstructural integrity. Tractography can be performed on atypical brain anatomy when landmarks are malformed or displaced but has been criticized for its subjectivity even when investigators have advanced anatomical knowledge. Also, little is known about the variability and reliability of tractography as a tool for assessing white matter damage in clinical populations such as children with pediatric epilepsy. METHODS: Children diagnosed with epilepsy [N=43, mean age=11.7 years, standard deviation=3.7 years, 53% male] underwent a DTI sequence (6 directions, 2*2*3 mm voxels). Tractography for six white matter tracts (anterior forceps, fornices, bilateral arcuate fasciculi, and bilateral anterior cingula) was conducted twice by two experienced tractographers. Percent coefficient of variation (CV; for measuring variability) and intraclass correlation coefficients (ICCs; for measuring reliability) were calculated for tract volume and diffusion variables (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]). RESULTS: Diffusion variables showed low variability (CV=2.7-8.8%) and very high reliability (ICC=.97-.99) except for limbic tracts [fornix (ICC=.75-.94); cingulum (ICC=.71-.98)]. Tract volume measurements showed high variability (CV=21.9-62.0%) and moderate reliability (ICC=.54-.99). Overall, tract volume measurements were much more variable and less reliable than diffusion characteristics. Limbic structures showed more variability compared with others. CONCLUSIONS: This suggests that DTI tractography and resulting diffusivity variables can reliably inform on the integrity of WM structures in a clinical sample with pediatric epilepsy and highlights the importance of reporting reliability information in studies that aim to answer clinical questions about WM integrity. PMID- 25014750 TI - Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. AB - PURPOSE OF REVIEW: The management of retinoblastoma is complex and involves strategically chosen methods of enucleation, radiotherapy, chemotherapy, laser photocoagulation, thermotherapy, and cryotherapy. Chemotherapy has become the most common eye-sparing modality. There are four routes of delivery of chemotherapy for retinoblastoma, including intravenous, intra-arterial, periocular, and intravitreal techniques. The purpose of this review is to discuss the current rationale for each method and the anticipated outcomes. RECENT FINDINGS: The diagnosis of retinoblastoma should be clinically established prior to embarking on a chemotherapy protocol. There are over 25 conditions that can closely simulate retinoblastoma in a young child. In addition, enucleation is an acceptable method for management, particularly with advanced retinoblastoma. Intravenous chemotherapy is generally used for germline mutation (bilateral, familial) retinoblastoma with excellent tumor control for groups A, B, and C and intermediate control for group D eyes. Intra-arterial chemotherapy is used as primary therapy in selected cases for nongermline mutation (unilateral) retinoblastoma with excellent control, and also used as secondary therapy for recurrent solid retinoblastoma, subretinal seeds, and vitreous seeds. Periocular chemotherapy is employed to boost local chemotherapy dose in advanced bilateral groups D and E eyes or for localized recurrences. Intravitreal chemotherapy is used for recurrent vitreous seeds from retinoblastoma. Patients at high risk for metastases should receive intravenous chemotherapy. SUMMARY: Chemotherapy is effective for retinoblastoma and the targeted treatment route depends on the clinical features and anticipated outcomes. PMID- 25014751 TI - Genome-wide association study success in ophthalmology. AB - PURPOSE OF REVIEW: Much progress in our understanding of the genetic profile of many ophthalmic diseases has been made over the last decade. Identification of novel gene associations allows insight into the mechanisms of disease and potentially enables the identification of individuals at increased risk, as well as facilitating the development of new treatments. We highlight key recent discoveries using the genome-wide association study design. RECENT FINDINGS: Over the last 2 years, we have seen major international collaborations successfully conduct genome-wide association study to identify genetic pathways associated with eye diseases, such as myopia, age-related macular degeneration and glaucoma. Similarly other studies have identified and confirmed genes associated with ocular biometry or disease-specific endophenotypes. SUMMARY: Our understanding of the genetic architecture of common eye diseases, such as myopia, age-related macular degeneration and glaucoma, is rapidly expanding. With reducing costs of next-generation sequencing, we expect a transition to large-scale interrogation at the whole exome and genome level, which will enable the identification of rare variants which confer a level of sensitivity and specificity to predict risk that will allow us to further understand, predict and intervene in genetic-based eye diseases. PMID- 25014752 TI - Is stereotactic radiosurgery the best treatment option for patients with a radiosurgery-based arteriovenous malformation score <= 1? AB - OBJECTIVE: The best management of patients with brain arteriovenous malformations (BAVM) is controversial. The radiosurgery-based arteriovenous malformation (AVM) score (RBAS) was developed to predict outcomes for patients with BAVM having stereotactic radiosurgery (SRS). METHODS: The RBAS is calculated for patients with BAVM having SRS at our center as part of our prospectively maintained SRS database (RBAS = [0.1] [AVM volume; cm(3)] + [0.02] [patient age; years] + [0.5] [AVM location; 0 = cerebral/cerebellar hemispheres/corpus callosum, 1 = basal ganglia/thalamus/brainstem]). Review of the SRS database from 1990 to 2009 identified 80 patients with a RBAS <=1 and at least 1 year of follow-up. The primary end point of the study was a decline in modified Rankin Score. The mean follow-up after SRS was 68 months (range, 12-133). RESULTS: The mean patient age was 25.2 years (range, 7-44). Seventy-six patients (95%) had superficially located BAVMs; the mean BAVM volume was 2.3 cm(3) (range, 0.1-8.0). The mean RBAS was 0.76 (range, 0.21-1.00). The patients' MRS before SRS was 0 (n = 52, 65%), 1 (n = 24, 30%), 2 (n = 3, 4%), and 3 (n = 1, 1%). BAVM obliteration was confirmed in 92% of patients with follow-up beyond 3 years (70/76; 95% confidence interval 84%-97%). No patient had a hemorrhage or a radiation-related complication after SRS. The observed rate of modified Rankin Score decrease after SRS was 0% (0/80; 95% confidence interval 0%-6%). CONCLUSIONS: SRS provided a high rate of obliteration at very low risk for patients with BVAM with a RBAS <=1. Patient outcomes after SRS are likely equivalent to resection for younger patients with small-volume BAVM who do not require a craniotomy for clot removal. PMID- 25014753 TI - Metrics to assess ecological condition, change, and impacts in sandy beach ecosystems. AB - Complexity is increasingly the hallmark in environmental management practices of sandy shorelines. This arises primarily from meeting growing public demands (e.g., real estate, recreation) whilst reconciling economic demands with expectations of coastal users who have modern conservation ethics. Ideally, shoreline management is underpinned by empirical data, but selecting ecologically meaningful metrics to accurately measure the condition of systems, and the ecological effects of human activities, is a complex task. Here we construct a framework for metric selection, considering six categories of issues that authorities commonly address: erosion; habitat loss; recreation; fishing; pollution (litter and chemical contaminants); and wildlife conservation. Possible metrics were scored in terms of their ability to reflect environmental change, and against criteria that are widely used for judging the performance of ecological indicators (i.e., sensitivity, practicability, costs, and public appeal). From this analysis, four types of broadly applicable metrics that also performed very well against the indicator criteria emerged: 1.) traits of bird populations and assemblages (e.g., abundance, diversity, distributions, habitat use); 2.) breeding/reproductive performance sensu lato (especially relevant for birds and turtles nesting on beaches and in dunes, but equally applicable to invertebrates and plants); 3.) population parameters and distributions of vertebrates associated primarily with dunes and the supralittoral beach zone (traditionally focused on birds and turtles, but expandable to mammals); 4.) compound measurements of the abundance/cover/biomass of biota (plants, invertebrates, vertebrates) at both the population and assemblage level. Local constraints (i.e., the absence of birds in highly degraded urban settings or lack of dunes on bluff-backed beaches) and particular issues may require alternatives. Metrics - if selected and applied correctly - provide empirical evidence of environmental condition and change, but often do not reflect deeper environmental values per se. Yet, values remain poorly articulated for many beach systems; this calls for a comprehensive identification of environmental values and the development of targeted programs to conserve these values on sandy shorelines globally. PMID- 25014754 TI - Micromolar biosensing of nitric oxide using myoglobin immobilized in a synthetic silk film. AB - In this work we investigate the use of coiled-coil silk proteins, produced in recombinant Escherichia coli, as a new material for immobilizing biosensors. Myoglobin was embedded in transparent honeybee silk protein films. Immobilized myoglobin maintained a high affinity for nitric oxide (KD NO=52 uM) and good sensitivity with a limit of detection of 5 uM. The immobilized myoglobin-silk protein film was stable and could be stored as a dry film at room temperature for at least 60 days. The effect of immobilization on the structure of myoglobin was fully investigated using UV/visible, Fourier Transform Infrared and Raman spectroscopy, which indicated a weakening in the strength of the iron-histidine bond. This study demonstrates that recombinant coiled-coil silk proteins provide a safe and environmentally friendly alternative to sol-gels for stabilizing heme proteins for use as optical biosensors. PMID- 25014755 TI - The development of associate learning in school age children. AB - Associate learning is fundamental to the acquisition of knowledge and plays a critical role in the everyday functioning of the developing child, though the developmental course is still unclear. This study investigated the development of visual associate learning in 125 school age children using the Continuous Paired Associate Learning task. As hypothesized, younger children made more errors than older children across all memory loads and evidenced decreased learning efficiency as memory load increased. Results suggest that age-related differences in performance largely reflect continued development of executive function in the context of relatively developed memory processes. PMID- 25014756 TI - Coronary sinus biomarker sampling compared to peripheral venous blood for predicting outcomes in patients with severe heart failure undergoing cardiac resynchronization therapy: the BIOCRT study. AB - BACKGROUND: A significant minority of patients receiving cardiac resynchronization therapy (CRT) remain nonresponsive to this intervention. OBJECTIVE: This study aimed to determine whether coronary sinus (CS) or baseline peripheral venous (PV) levels of established and emerging heart failure (HF) biomarkers are predictive of CRT outcomes. METHODS: In 73 patients (aged 68 +/- 12 years; 83% men; ejection fraction 27% +/- 7%) with CS and PV blood samples drawn simultaneously at the time of CRT device implantation, we measured amino terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (gal-3), and soluble ST2 (sST2) levels. NT-proBNP concentrations >2000 pg/mL, gal-3 concentrations >25.9 ng/mL, and sST2 concentrations >35 ng/mL were considered positive on the basis of established PV cut points for identifying "high-risk" individuals with HF. CRT response was adjudicated by the HF Clinical Composite Score. A major adverse cardiovascular event (MACE) was defined as the composite end point of death, cardiac transplant, left ventricular assist device, and HF hospitalization at 2 years. RESULTS: NT-proBNP concentrations were 20% higher in the CS than in the periphery, while gal-3 and sST2 concentrations were 10% higher in the periphery than in the CS (all P < .001). There were 45% CRT nonresponders at 6 months and 16 (22%) patients with MACE. Triple-positive CS values yielded the highest specificity of 95% for predicting CRT nonresponse. Consistently, CS strategies identified patients at higher risk of developing MACE, with >11-fold adjusted increase for triple-positive CS patients compared to triple-negative patients (all P <= .04). PV strategies were not predictive of MACE. CONCLUSION: Our findings suggest that CS sampling of HF biomarkers may be better than PV sampling for predicting CRT outcomes. Larger studies are needed to confirm our findings. PMID- 25014757 TI - Involvement of beta-adrenoceptors in the differentiation of human induced pluripotent stem cells into mesodermal progenitor cells. AB - Previous studies suggest that beta-adrenoceptor stimulation may enhance the cardiac differentiation of mouse embryonic stem (ES) cells. It remains unclear whether the differentiations of ES cells and induced pluripotent stem (iPS) cells rely on similar molecular mechanisms. In addition, no previous studies have shown that human iPS cells express beta-adrenoceptors. Therefore, in the present study, we determined the involvement of beta-adrenoceptors in the differentiation of human iPS cells into mesodermal progenitor cells. The induction of differentiation of human iPS cells into kinase insert domain receptor (KDR) positive mesodermal progenitor cells was performed on feeder cells in a differentiation medium with basic fibroblast growth factor (bFGF), bone morphogenetic protein-4 (BMP-4), and activin A. When the iPS cells that were exposed to bFGF, BMP-4, and activin A were treated with L-isoproterenol (a beta adrenoceptor agonist) for 4 days, the expression of KDR was significantly increased compared to that in the cells that were not treated with L isoproterenol. Pretreatment of the cells with either atenolol (a beta1 adrenoceptor antagonist) or ICI-118551 (a beta2-adrenoceptor antagonist) significantly inhibited the L-isoproterenol-induced increase in KDR expression. In addition, pretreatment with both H89 (a protein kinase A inhibitor) and SB203580 (a p38 MAPK inhibitor) significantly inhibited the L-isoproterenol induced increase in KDR expression. Treatment with L-isoproterenol enhanced the phosphorylation of p38 MAPK in human iPS cells exposed to bFGF, BMP-4, and activin A. These results suggest that beta-adrenoceptor stimulation in human iPS cells may enhance their differentiation into mesodermal progenitor cells via the activation of either protein kinase A or p38 MAPK. PMID- 25014758 TI - Equine digital veins are more sensitive to superoxide anions than digital arteries. AB - This work was designed to investigate (i) the effect of superoxide dismutase (SOD) inhibition on endothelial function and (ii) the free radical-induced endothelial dysfunction in equine digital veins (EDVs) and equine digital arteries (EDAs) isolated from healthy horses. EDV and EDA rings were suspended in a 5 ml organ bath containing Krebs solution. After a 60 min equilibration period, EDV and EDA rings were contracted with phenylephrine. Then, cumulative concentration-response curves (CCRCs) to acetylcholine were performed. In both EDVs and EDAs, acetylcholine (1 nM to 10 uM) produced concentration-dependent relaxation. We investigated the influence of SOD inhibition by diethyldithiocarbamate (DETC; 100 uM), a CuZnSOD inhibitor, on EDAs and EDVs relaxant responses to acetylcholine. Acetylcholine -mediated relaxation was impaired by DETC only in EDVs. SOD activity assayed by a xanthine-xanthine oxidase method was higher in EDAs compared with EDVs (P<0.05). CCRCs to acetylcholine established in the presence of pyrogallol (30 uM) or homocysteine (20 uM), two superoxide anions generating systems showed that in both EDVs and EDAs, the acetylcholine-mediated relaxation was significantly impaired by pyrogallol and homocysteine. This impairment was more pronounced in EDVs than in EDAs. Moreover, the pyrogallol-induced impairment of acetylcholine-mediated relaxation was potentiated by DETC to a greater extent in EDVs. We concluded that due to the lower activity of SOD, EDVs are more sensitive to superoxide anions than EDAs. So, any alteration of superoxide anions metabolism is likely to have a more important impact on venous rather than arterial relaxation. PMID- 25014759 TI - A national study examining closed points of dispensing (PODs): existence, preparedness, exercise participation, and training provided. AB - The Centers for Disease Control and Prevention recommends using open points of dispensing (PODs) and alternative modalities, such as closed PODs, for mass dispensing of medical countermeasures. However, closed POD existence has not been assessed. In 2013 we sent an online questionnaire to US Cities Readiness Initiative (CRI) and non-CRI public health disaster planners. Chi-square tests were used to determine differences between CRIs and non-CRIs when comparing having at least 1 closed POD, and to compare having a closed POD and perceived mass dispensing preparedness. A total of 301 disaster planners participated. Almost all (89.3%, n=218) jurisdictions have considered establishing a closed POD, and three-quarters (74.2%, n=181) currently have at least one. CRIs were more likely than non-CRIs to have a closed POD (85.0% vs 58.5%, X(2)=21.3, p<.001). Those with 1 or more closed PODs were more likely to believe their jurisdiction could distribute medical countermeasures within 48 hours compared to those without a closed POD (78.5% vs 21.5%; X(2)=10.8, p=.001). Half had a written plan and/or written standing orders (59.1% and 52.5%, respectively). Almost half (42%, n=72) have done no preevent training for POD staff in the past 2 years; almost 20% (18%, n=32) do not plan to offer any just-in-time training. Nearly 40% (n=70) have conducted no exercises in the past year. Closed PODs contribute to community preparedness; their establishment should be followed by development of written plans, worker training, and exercises. PMID- 25014761 TI - Effects of corticosterone on contextual fear consolidation in intact and ovariectomized female rats. AB - Previous studies have shown that post-training administration of glucocorticoids enhances memory consolidation in male rats, but theirs effects on female rats are not known. Thus, this study was conducted to examine the effects of corticosterone (CORT) on contextual fear memory consolidation in intact and ovariectomized (OVX) female rats. In Experiment 1, post-training administration of CORT (0.3, 3, and 10 mg/kg) to OVX female rats impaired memory consolidation at a 0.3 mg dose of CORT. In Experiment 2, post-training injection of CORT (0.3 mg/kg) to female rats in proestrus stage (when the levels of estrogens are highest) enhances and in the estrus stage (when the levels of estrogens are lowest) impaired memory retention. In Experiment 3, OVX female rats injected with CORT (0.3 mg/kg) and one of the three doses of 17beta-estradiol (1, 10 or 100 MUg/kg) following training. 48-h memory retention test indicated that CORT enhanced memory retention in OVX female rats that received concurrent injection of 10 or 100 MUg doses of 17beta-estradiol. These findings indicate that cognitive effects of CORT in female rats can be modulated with the plasma levels of estrogens: when the levels of estrogens are low, corticosterone has a negative effect, while when the levels of estrogens are high; the corticosterone has a positive enhancing effect. PMID- 25014760 TI - A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a. AB - beta-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1-S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, a concept that will be valuable for the design of insect-selective insecticides. PMID- 25014762 TI - Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men. AB - Sex-limited selection can moderate the elimination of deleterious mutations from the population and contribute to the high prevalence of common human diseases. Accordingly, deleterious mutations in autosomal genes that are exclusively expressed in only one of the sexes undergo sex-limited selection and can reach higher frequencies than mutations similarly selected in both sexes. Here we show that the number of deleterious SNPs in genes exclusively expressed in men is twofold higher than in genes that are selected in both sexes. Additional analyses suggest that the increased number of damaging mutations we found in male-specific genes is due to reduced selection in females. These results are noteworthy since many of these male-specific genes are known to be crucial for male reproduction, and are thus likely to be under strong purifying selection. We suggest that inheritance of male-infertility-causative mutations through unaffected female lineages contributes to the high incidence of male infertility. PMID- 25014763 TI - Polymeric nanoparticles-embedded organogel for roxithromycin delivery to hair follicles. AB - Drug delivery into hair follicles with the use of nanoparticles (NPs) is gaining more importance as drug-loaded NPs may accumulate in hair follicle openings. The aim was to develop and evaluate a pluronic lecithin organogel (PLO) with roxithromycin (ROX)-loaded NPs for follicular targeting. Polymeric NPs were evaluated in terms of particle shape, size, zeta potential, suspension stability, encapsulation efficiency and in vitro drug release. Lyophilized NPs were incorporated into the PLO and rheological measurements of the nanoparticles embedded organogels were done. The fate of the NPs in the skin was traced by incorporation of a fluorescent dye into the NPs. As a result, ROX was efficiently incorporated into polymeric NPs characterized by the appropriate size (approximately 300 nm) allowing drug delivery to hair follicles. In ex vivo human skin penetration studies, horizontal skin sections revealed fluorescence deep in the hair follicles. Although the organogel has higher affinity to the lipidic follicular area than an aqueous suspension of NPs, it did not seem to improve penetration of the NPs along the hair shaft. The results proved that it was possible to achieve preferential targeting to the pilosebaceous unit using polymeric NPs formulated either into the aqueous suspension or semisolid topical formulation. PMID- 25014764 TI - Screening biological traits and fluoride contents of native vegetations in arid environments to select efficiently fluoride-tolerant native plant species for in situ phytoremediation. AB - High fluoride pollution has been detected in the surrounding soils of the coastal superphosphate industries in the Gulf of Gabes (Southeast of Tunisia). A study was conducted in vicinity of factories analysing plant functional traits combined with plant fluoride accumulation and soil metal concentrations aiming to screen more efficiently native plant species tolerant to this pollution. Aerial parts of 18 plant species out of the 10 most abundant species per site were harvested on two polluted sites of Gabes and Skhira at the vicinity of the factories and on the less polluted site of Smara. Native plant species accumulated fluoride following the gradient of soil pollution. Fluoride contents of plant aerial parts ranged from 37 mg kg(-1) to 360 mg kg(-1) and five plant species were only found in the most polluted site. However these latter had low biomass and soil cover. Crossing biological traits and fluoride contents, a selection grid for potentially restorative plant species enabled the selection of three native perennials i.e. Rhanterium suaveolens, Atractylis serratuloides and, Erodium glaucophyllum as potential candidates for an in-situ phytoremediation program on arid fluoride-polluted sites. This approach may be used in other fluoride polluted Mediterranean environments. PMID- 25014765 TI - Avoiding death on rounds. PMID- 25014766 TI - Quality of the blood pressure phenotype in the GEnotipo, Fenotipo y Ambiente de la hipertension arterial en UruguaY (GEFA-HT-UY) study. AB - BACKGROUND: In the ongoing GEnotipo, Fenotipo y Ambiente de la HiperTension Arterial en UruguaY (GEFA-HT-UY) study, we applied standardized epidemiological methods to determine complex phenotypes including blood pressure (BP). In this report, we present the quality control of the conventionally measured BP. METHODS: Three trained observers measured BP five times consecutively in the seated position at each of two home visits and one clinic visit according to the guidelines of the European Society of Hypertension. On 1 December 2013, 4379 single BP readings in 170 participants were available for analysis. RESULTS: Fewer BP readings than the five planned per contact occurred only at one home visit. Among observers, the frequency of identical consecutive readings for systolic or diastolic BP varied from 0 to 4.2%. The occurrence of odd readings ranged from 0.1 to 0.6%. Only 21.6% of the systolic and diastolic BP readings ended on zero (expected 20%). At home visits, there was a progressive decline in BP from the first to the fifth reading. The average of the five BP readings also decreased from the first to the second home visit (-5.63/-2.34 mmHg). CONCLUSIONS: Our study highlighted the necessity to implement a stringent quality control of the conventionally measured BP. The procedures set up in the GEFA-HT UY study are resulting in a well-defined BP phenotype, which is consistent with that in other population studies. PMID- 25014767 TI - Immunomodulatory properties of pancreatic islet-derived stem cells co-cultured with T cells: Does it contribute to the pathogenesis of type 1 diabetes? AB - BACKGROUND: Previously, we isolated stem cells from rat pancreatic islets (rPI SCs) with similar characteristics of bone-marrow derived-mesenchymal stem cells (MSCs). We aimed to investigate the immunomodulatory effects of them on stimulated T-cells. METHODS: Following in vitro co-culturing directly and indirectly, the response of T-cells stimulated by concanavalin-A and immunosuppressive activity of rPI-SCs were evaluated by analysing in terms of cell viability, proliferation and apoptosis, cell cycle, differentiation of Treg, cytokines and some regulatory factors produced from T and SCs. RESULTS: Our results have firstly demonstrated that rPI-SCs like MSCs could regulate stimulated T-cell responses by altering their cell-cycle and cytokine profile, inhibiting the cell proliferation, and inducing the apoptosis and differentiation of Treg. Direct and indirect in vitro co-cultures of rPI-SCs with stimulated T cells showed immunosuppressive effects. CONCLUSION: Therefore, we are introducing a novel type of stem cell with immunomodulatory properties. On the other hand, it is questionable why PI-SCs cannot protect the insulin producing cells from attacks of autoreactive T-cells in the developing of type1 diabetes. For this purpose, further molecular researches in vitro and in vivo are needed to clarify why PI-SCs may not suppress attacks of autoreactive-immune-cells towards PIs. PI SCs from diseased people should be compared with pancreas of healthy ones at both genomic and proteomic levels. PMID- 25014768 TI - Vitreous proteomic analysis of idiopathic epiretinal membranes. AB - To understand the molecular mechanisms of idiopathic epiretinal membranes (iERMs), the vitreous proteomes of patients with iERMs were investigated. The vitreous proteome in patients with iERMs (n = 8) and donor samples (n = 8) was analysed using reversed phase high-performance liquid chromatography (RP-HPLC) coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) and GeneGo MetacoreTM. This research followed the tenets of the Declaration of Helsinki for the use of human subjects. In this current study, 226 significant changes in protein abundance (abundance ratio >2, p < 0.01) were identified in the vitreous proteome of iERM patients compared to normal control vitreous, including 122 proteins that were present at lower levels and 104 proteins that were present at higher levels. In the iERM vitreous samples, complement components, inflammation-related proteins and matrix metalloproteinase were present at higher levels, while normal cytoskeleton proteins were present at lower levels. The top GeneGo pathway was "immune response", the top process network was "inflammation", and the top KEGG pathway was "coagulation cascades". The essential 2-node proteins of the network were estrogen receptor 1 (ESR1) and p300. Among those found at higher levels, ubiquitin-conjugating enzyme E2O (UBE2O) and complement C4A (C4A) were the most abundant proteins, and could be detected in each of the iERM vitreous samples. It can be concluded that iERMs are a complicated pathological process involving inflammation, immune response, and cytoskeleton remolding. UBE2O and C4A may be candidate biomarkers for iERMs. PMID- 25014771 TI - A decade of modelling drug release from arterial stents. AB - Drug-eluting stents have revolutionised the treatment of coronary artery disease. These small medical devices have attracted much interest over the past decade from biologists, clinicians, engineers and mathematicians alike. This article provides a comprehensive review of the modelling of drug release from arterial stents and the subsequent drug transport through arterial tissue, and acts as a useful reference equally for those who are already involved in drug-eluting stents research and for those who are starting out in the field. Assembled in this review are the main models of drug release and arterial drug transport that have been published in the literature to date. Many of the models presented in this paper have evolved from drug transport models in other applications. Furthermore, the ideas presented in this review may also be extended to other drug-delivery applications, such as drug coated balloons, transdermal patches and therapeutic contact lenses. PMID- 25014769 TI - Drosophila polypyrimidine tract-binding protein (DmPTB) regulates dorso-ventral patterning genes in embryos. AB - The Drosophila polypyrimidine tract-binding protein (dmPTB or hephaestus) plays an important role during embryogenesis. A loss of function mutation, heph(03429), results in varied defects in embryonic developmental processes, leading to embryonic lethality. However, the suite of molecular functions that are disrupted in the mutant remains unknown. We have used an unbiased high throughput sequencing approach to identify transcripts that are misregulated in this mutant. Misregulated transcripts show evidence of significantly altered patterns of splicing (exon skipping, 5' and 3' splice site switching), alternative 5' ends, and mRNA level changes (up and down regulation). These findings are independently supported by reverse-transcription-polymerase chain reaction (RT-PCR) analysis and in situ hybridization. We show that a group of genes, such as Zerknullt, z600 and screw are among the most upregulated in the mutant and have been functionally linked to dorso-ventral patterning and/or dorsal closure processes. Thus, loss of dmPTB function results in specific misregulated transcripts, including those that provide the missing link between the loss of dmPTB function and observed developmental defects in embryogenesis. This study provides the first comprehensive repertoire of genes affected in vivo in the heph mutant in Drosophila and offers insight into the role of dmPTB during embryonic development. PMID- 25014770 TI - Multiscale modelling of saliva secretion. AB - We review a multiscale model of saliva secretion, describing in brief how the model is constructed and what we have so far learned from it. The model begins at the level of inositol trisphosphate receptors (IPR), and proceeds through the cellular level (with a model of acinar cell calcium dynamics) to the multicellular level (with a model of the acinus), finally to a model of a saliva production unit that includes an acinus and associated duct. The model at the level of the entire salivary gland is not yet completed. Particular results from the model so far include (i) the importance of modal behaviour of IPR, (ii) the relative unimportance of Ca(2+) oscillation frequency as a controller of saliva secretion, (iii) the need for the periodic Ca(2+) waves to be as fast as possible in order to maximise water transport, (iv) the presence of functional K(+) channels in the apical membrane increases saliva secretion, (v) the relative unimportance of acinar spatial structure for isotonic water transport, (vi) the prediction that duct cells are highly depolarised, (vii) the prediction that the secondary saliva takes at least 1mm (from the acinus) to reach ionic equilibrium. We end with a brief discussion of future directions for the model, both in construction and in the study of scientific questions. PMID- 25014772 TI - Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia. PMID- 25014773 TI - Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group. AB - CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk stratified therapy. PMID- 25014775 TI - Effect of CAL-101, a PI3Kdelta inhibitor, on ribosomal rna synthesis and cell proliferation in acute myeloid leukemia cells. PMID- 25014774 TI - Human HMGA2 protein overexpressed in mice induces precursor T-cell lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes. HMGA2 (high-mobility group AT-hook 2) gene expression is extremely low in normal adult tissues, but it is overexpressed in many tumors. To identify the biological function of HMGA2, we generated transgenic mice carrying the human HMGA2 gene under control of the VH promoter/EMU enhancer. Approximately 90% of EMU-HMGA2 transgenic mice became visibly sick between 4 and 8 months due to the onset and progression of a T-ALL-like disease. Characteristic features included severe alopecia (30% of mice); enlarged lymph nodes and spleen; and profound immunological abnormalities (altered cytokine levels, hypoimmunoglobulinemia) leading to reduced immune responsiveness. Immunophenotyping showed accumulation of CD5+CD4+, CD5+CD8+ or CD5+CD8+CD4+ T-cell populations in the spleens and bone marrow of sick animals. These findings show that HMGA2-driven leukemia in mice closely resembles spontaneous human T-ALL, indicating that HMGA2 transgenic mice should serve as an important model for investigating basic mechanisms and potential new therapies of relevance to human T-ALL. PMID- 25014776 TI - Members of the Meloidogyne avirulence protein family contain multiple plant ligand-like motifs. AB - Sedentary plant-parasitic nematodes engage in complex interactions with their host plants by secreting effector proteins. Some effectors of both root-knot nematodes (Meloidogyne spp.) and cyst nematodes (Heterodera and Globodera spp.) mimic plant ligand proteins. Most prominently, cyst nematodes secrete effectors that mimic plant CLAVATA3/ESR-related (CLE) ligand proteins. However, only cyst nematodes have been shown to secrete such effectors and to utilize CLE ligand mimicry in their interactions with host plants. Here, we document the presence of ligand-like motifs in bona fide root-knot nematode effectors that are most similar to CLE peptides from plants and cyst nematodes. We have identified multiple tandem CLE-like motifs conserved within the previously identified Meloidogyne avirulence protein (MAP) family that are secreted from root-knot nematodes and have been shown to function in planta. By searching all 12 MAP family members from multiple Meloidogyne spp., we identified 43 repetitive CLE like motifs composing 14 unique variants. At least one CLE-like motif was conserved in each MAP family member. Furthermore, we documented the presence of other conserved sequences that resemble the variable domains described in Heterodera and Globodera CLE effectors. These findings document that root-knot nematodes appear to use CLE ligand mimicry and point toward a common host node targeted by two evolutionarily diverse groups of nematodes. As a consequence, it is likely that CLE signaling pathways are important in other phytonematode pathosystems as well. PMID- 25014777 TI - Palladium-catalyzed asymmetric hydrogenation of 3-phthalimido substituted quinolines. AB - Homogeneous Pd-catalyzed asymmetric hydrogenation of 3-phthalimido substituted quinolines was successfully developed, providing facile access to chiral substituted tetrahydroquinolines bearing two contiguous stereogenic centers with up to 90% ee. PMID- 25014778 TI - Bioactivation potential of thiophene-containing drugs. AB - Thiophene is a five-membered, sulfur-containing heteroaromatic ring commonly used as a building block in drugs. It is considered to be a structural alert, as its metabolism can lead to the formation of reactive metabolites. Thiophene S-oxides and thiophene epoxides are highly reactive electrophilic thiophene metabolites whose formation is cytochrome P450-dependent. These reactive thiophene-based metabolites are quite often responsible for drug-induced hepatotoxicity. Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis. However, inclusion of the thiophene moiety in drugs does not necessarily result in toxic effects. The presence of other, less toxic metabolic pathways, as well as an effective detoxification system in our body, protects us from the bioactivation potential of the thiophene ring. Thus, the presence of a structural alert itself is insufficient to predict a compound's toxicity. The question therefore arises as to which factors significantly influence the toxicity of thiophene-containing drugs. There is no easy way to answer this question. However, the findings presented here indicate that, for a number of reasons, daily dose and alternative metabolic pathways are important factors when predicting toxicity and will therefore be discussed together with examples. PMID- 25014779 TI - Facile in situ synthesis of BiOCl nanoplates stacked to highly porous TiO2: a synergistic combination for environmental remediation. AB - A novel nanocomposite material made of two-dimensional BiOCl nanoplates assembled into highly porous titania has been successfully prepared following a facile sol gel reaction. Both the TiO2 (anatase) and BiOCl components are crystalline as demonstrated by X-ray diffraction and transmission electron microscopy analyses. TiO2 exhibits a highly porous network and possesses a small crystallite size, whereas BiOCl forms micrometer-sized plates with nanometer thicknesses. Aqueous photocatalytic activity tests with this novel material have been performed on photodegradation of Rhodamine B under ultraviolet-visible light irradiation. Interestingly, the attachment of the BiOCl nanoplates to the TiO2 network significantly enhances the photocatalytic activity of the material compared to that of pure TiO2 due to the formation of BiOCl/TiO2 heterojunctions. Thus, this pertinent synergistic combination of TiO2 and BiOCl proves to be a promising strategy for the large-scale production of a new generation of photocatalysts with excellent properties for the degradation of organic pollutants. PMID- 25014780 TI - Moderating effect of gender on the prospective relation of physical activity with psychosocial outcomes and asthma control in adolescents: a longitudinal study. AB - OBJECTIVE: Adolescents with asthma experience more psychosocial and physiological problems compared to their healthy peers. Physical activity (PA) might decrease these problems. This study was the first observational longitudinal study to examine whether habitual PA could predict changes in psychosocial outcomes (i.e., symptoms of anxiety and depression, quality of life [QOL] and stress) and asthma control over time in adolescents with asthma and whether gender moderated these relationships. METHODS: Adolescents with asthma (N = 253; aged 10-14 years at baseline) were visited at home in the spring/summer of 2012 and 2013. They completed questionnaires assessing their habitual PA, symptoms of anxiety and depression, QOL, perceived stress and asthma control. Path analyses using Mplus were conducted to examine longitudinal relationships among habitual PA, psychosocial outcomes and asthma control (controlled for body mass index, age and gender). Using multi-group analyses, we examined whether gender moderated these relationships. RESULTS: Path analyses in the total group showed that habitual PA did not predict changes in psychosocial outcomes or asthma control over time. Multi-group analyses showed that gender moderated the relation of habitual PA with anxiety and depression. Habitual PA only significantly predicted a decrease in anxiety and depression over time for girls but not for boys. CONCLUSIONS: Increasing habitual PA in girls with asthma might decrease their symptoms of anxiety and depression. PMID- 25014781 TI - Method for the evaluation of structure-activity relationship information associated with coordinated activity cliffs. AB - Activity cliffs are generally defined as pairs of active compounds having a large difference in potency. Although this definition of activity cliffs focuses on compound pairs, the vast majority of cliffs are formed in a coordinated manner. This means that multiple highly and weakly potent compounds form series of activity cliffs, which often overlap. In activity cliff networks, coordinated cliffs emerge as disjoint activity cliff clusters. Recently, we have identified all cliff clusters from current bioactive compounds and analyzed their topologies. For structure-activity relationship (SAR) analysis, activity cliff clusters are of high interest, since they contain more SAR information than cliffs that are individually considered. For medicinal chemistry applications, a key question becomes how to best extract SAR information from activity cliff clusters. This represents a challenging problem, given the complexity of many activity cliff configurations. Herein we introduce a generally applicable methodology to organize activity cliff clusters on the basis of structural relationships, prioritize clusters, and systematically extract SAR information from them. PMID- 25014782 TI - Manipulating dispersion and distribution of graphene in PLA through novel interface engineering for improved conductive properties. AB - This study aimed to enhance the conductive properties of PLA nanocomposite by controlling the dispersion and distribution of graphene within the minor phase of the polymer blend. Functionalized graphene (f-GO) was achieved by reacting graphene oxide (GO) with various silanes under the aid of an ionic liquid. Ethylene/n-butyl acrylate/glycidyl methacrylate terpolymer elastomer (EBA-GMA) was introduced as the minor phase to tailor the interface of matrix/graphene through reactive compatibilization. GO particles were predominantly dispersed in PLA in a self-agglomerating pattern, while f-GO was preferentially located in the introduced rubber phase or at the PLA/EBA-GMA interfaces through the formation of the three-dimensional percolated structures, especially for these functionalized graphene with reactive groups. The selective localization of the f-GO also played a crucial role in stabilizing and improving the phase morphology of the PLA blend through reducing the interfacial tension between two phases. The establishment of the percolated network structures in the ternary system was responsible for the improved AC conductivity and better dielectric properties of the resulting nanocomposites. PMID- 25014783 TI - Cost analysis of a nucleic acid amplification test in the diagnosis of pulmonary tuberculosis at an urban hospital with a high prevalence of TB/HIV. AB - INTRODUCTION: The Centers for Disease Control and Prevention has recommended using a nucleic acid amplification test (NAAT) for diagnosing pulmonary tuberculosis (TB) but there is a lack of data on NAAT cost-effectiveness. METHODS: We conducted a prospective cohort study that included all patients with an AFB smear-positive respiratory specimen at Grady Memorial Hospital in Atlanta, GA, USA between January 2002 and June 2008. We determined the sensitivity, specificity, and positive and negative predictive value of a commercially available and FDA-approved NAAT (amplified MTD, Gen-Probe) compared to the gold standard of culture. A cost analysis was performed and included costs related to laboratory tests, hospital charges, anti-TB medications, and contact investigations. Average cost per patient was calculated under two conditions: (1) using a NAAT on all AFB smear-postive respiratory specimens and (2) not using a NAAT. One-way sensitivity analyses were conducted to determine sensitivity of cost difference to reasonable ranges of model inputs. RESULTS: During a 6 1/2 year study period, there were 1,009 patients with an AFB smear-positive respiratory specimen at our public urban hospital. We found the NAAT to be highly sensitive (99.6%) and specific (99.1%) on AFB smear-positive specimens compared to culture. Overall, the positive predictive value (PPV) of an AFB smear-positive respiratory specimen for culture-confirmed TB was 27%. The PPV of an AFB smear positive respiratory specimen for culture-confirmed TB was significantly higher for HIV-uninfected persons compared to those who were HIV-seropositive (152/271 [56%] vs. 85/445 [19%]; RR = 2.94, 95% CI 2.36-3.65, p<0.001). The cost savings of using the NAAT was $2,003 per AFB smear-positive case. CONCLUSIONS: Routine use of the NAAT on AFB smear-positive respiratory specimens was highly cost saving in our setting at a U.S. urban public hospital with a high prevalence of TB and HIV because of the low PPV of an AFB smear for culture-confirmed TB. PMID- 25014784 TI - Simultaneous mass quantification of nanoparticles of different composition in a mixture by microdroplet generator-ICPTOFMS. AB - This work investigated the potential of a high temporal resolution inductively coupled plasma time-of-flight mass spectrometer (ICPTOFMS) in combination with a microdroplet generator (MDG) for simultaneous mass quantification of different nanoparticles (NPs) in a mixture. For this purpose, a test system containing certified Au NPs, well characterized Ag NPs, and core-shell NPs composed of an Au core and an Ag shell was employed. Thanks to the full spectra coverage and rapid simultaneous detection of the TOFMS, the element composition of individual particles can be determined. The pure Ag NPs and the core-shell NPs could be differentiated despite the same mass of Ag they contain. Calibration with monodisperse droplets consisting of standard solutions allowed for the mass quantification of NPs without the use of NP certified materials. On the basis of this mass quantification, the sizes of NPs originating from the same aqueous suspension were simultaneously determined with an accuracy of 7-12%. The size equivalent limits of detection estimated with the 3*sigma criterion were 13 nm for Au and 16 nm for Ag. Estimation of the LODs using Poisson statistics resulted in 19 and 27 nm, respectively. In addition, the 30 MUs temporal resolution of the ICPTOFMS allowed studying interactions of NPs with the ICP based on their transient MS signals. The results demonstrated a difference in vaporization behavior of the core-shell NPs and solutions and indicated that vaporization of the Ag shell takes place prior to the Au core. PMID- 25014787 TI - Electrical stimuli in the central nervous system microenvironment. AB - Electrical stimulation to manipulate the central nervous system (CNS) has been applied as early as the 1750s to produce visual sensations of light. Deep brain stimulation (DBS), cochlear implants, visual prosthetics, and functional electrical stimulation (FES) are being applied in the clinic to treat a wide array of neurological diseases, disorders, and injuries. This review describes the history of electrical stimulation of the CNS microenvironment; recent advances in electrical stimulation of the CNS, including DBS to treat essential tremor, Parkinson's disease, and depression; FES for the treatment of spinal cord injuries; and alternative electrical devices to restore vision and hearing via neuroprosthetics (retinal and cochlear implants). It also discusses the role of electrical cues during development and following injury and, importantly, manipulation of these endogenous cues to support regeneration of neural tissue. PMID- 25014788 TI - Advances in computed tomography imaging technology. AB - Computed tomography (CT) is an essential tool in diagnostic imaging for evaluating many clinical conditions. In recent years, there have been several notable advances in CT technology that already have had or are expected to have a significant clinical impact, including extreme multidetector CT, iterative reconstruction algorithms, dual-energy CT, cone-beam CT, portable CT, and phase contrast CT. These techniques and their clinical applications are reviewed and illustrated in this article. In addition, emerging technologies that address deficiencies in these modalities are discussed. PMID- 25014785 TI - Optical neural interfaces. AB - Genetically encoded optical actuators and indicators have changed the landscape of neuroscience, enabling targetable control and readout of specific components of intact neural circuits in behaving animals. Here, we review the development of optical neural interfaces, focusing on hardware designed for optical control of neural activity, integrated optical control and electrical readout, and optical readout of population and single-cell neural activity in freely moving mammals. PMID- 25014789 TI - Shaping magnetic fields to direct therapy to ears and eyes. AB - Magnetic fields have the potential to noninvasively direct and focus therapy to disease targets. External magnets can apply forces on drug-coated magnetic nanoparticles, or on living cells that contain particles, and can be used to manipulate them in vivo. Significant progress has been made in developing and testing safe and therapeutic magnetic constructs that can be manipulated by magnetic fields. However, we do not yet have the magnet systems that can then direct those constructs to the right places, in vivo, over human patient distances. We do not yet know where to put the external magnets, how to shape them, or when to turn them on and off to direct particles or magnetized cells-in blood, through tissue, and across barriers-to disease locations. In this article, we consider ear and eye disease targets. Ear and eye targets are too deep and complex to be targeted by a single external magnet, but they are shallow enough that a combination of magnets may be able to direct therapy to them. We focus on how magnetic fields should be shaped (in space and time) to direct magnetic constructs to ear and eye targets. PMID- 25014786 TI - The role of mechanical forces in tumor growth and therapy. AB - Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase cells' invasive and metastatic potential. Tumor vessels-while nourishing the tumor-are usually leaky and tortuous, which further decreases perfusion. Hypoperfusion and hypoxia contribute to immune evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression causes a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nanotherapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers. PMID- 25014790 TI - Electrical control of epilepsy. AB - Epilepsy afflicts approximately 1-2% of the world's population. The mainstay therapy for treating the chronic recurrent seizures that are emblematic of epilepsy are drugs that manipulate levels of neuronal excitability in the brain. However, approximately one-third of all epilepsy patients get little to no clinical relief from this therapeutic regimen. The use of electrical stimulation in many forms to treat drug-refractory epilepsy has grown markedly over the past few decades, with some devices and protocols being increasingly used as standard clinical treatment. This article seeks to review the fundamental modes of applying electrical stimulation-from the noninvasive to the nominally invasive to deep brain stimulation-for the control of seizures in epileptic patients. Therapeutic practices from the commonly deployed clinically to the experimental are discussed to provide an overview of the innovative neural engineering approaches being explored to treat this difficult disease. PMID- 25014791 TI - Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans. AB - The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 * 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population. PMID- 25014792 TI - Adoptive transfer of heme oxygenase-1 (HO-1)-modified macrophages rescues the nuclear factor erythroid 2-related factor (Nrf2) antiinflammatory phenotype in liver ischemia/reperfusion injury. AB - Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-beta-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2 deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage. PMID- 25014794 TI - Manipulation of p-wave scattering of cold atoms in low dimensions using the magnetic field vector. AB - It is well known that the magnetic Feshbach resonances of cold atoms are sensitive to the magnitude of the external magnetic field. Much less attention has been paid to the direction of such a field. In this work we calculate the scattering properties of spin polarized fermionic atoms in reduced dimensions, near a p-wave Feshbach resonance. Because of the spatial anisotropy of the p-wave interaction, the scattering has a nontrivial dependence on both the magnitude and the direction of the magnetic field. In addition, we identify an inelastic scattering process which is impossible in the isotropic-interaction model; the rate of this process depends considerably on the direction of the magnetic field. Significantly, an Einstein-Podolsky-Rosen entangled pair of identical fermions may be produced during this inelastic collision. This work opens a new method to manipulate resonant cold atomic interactions. PMID- 25014793 TI - Activation of poly(ADP-ribose) polymerase-1 delays wound healing by regulating keratinocyte migration and production of inflammatory mediators. AB - Poly(ADP-ribosyl)ation (PARylation) is a protein modification reaction regulating various diverse cellular functions ranging from metabolism, DNA repair and transcription to cell death. We set out to investigate the role of PARylation in wound healing, a highly complex process involving various cellular and humoral factors. We found that topically applied poly[ADP-ribose] polymerase (PARP) inhibitors 3-aminobenzamide and PJ-34 accelerated wound closure in a mouse model of excision wounding. Moreover, wounds also closed faster in PARP-1 knockout mice as compared with wild-type littermates. Immunofluorescent staining for poly(ADP ribose) (PAR) indicated increased PAR synthesis in scattered cells of the wound bed. Expression of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase and matrix metalloproteinase-9 was lower in the wounds of PARP-1 knockout mice as compared with control, and expression of IL 1beta, cyclooxygenase-2, TIMP-1 and -2 also were affected. The level of nitrotyrosine (a marker of nitrating stress) was lower in the wounds of PARP-1 knockout animals as compared with controls. In vitro scratch assays revealed significantly faster migration of keratinocytes treated with 3-aminobenzamide or PJ34 as compared with control cells. These data suggest that PARylation by PARP-1 slows down the wound healing process by increasing the production of inflammatory mediators and nitrating stress and by slowing the migration of keratinocytes. PMID- 25014795 TI - Absolute absorption cross sections from photon recoil in a matter-wave interferometer. AB - We measure the absolute absorption cross section of molecules using a matter-wave interferometer. A nanostructured density distribution is imprinted onto a dilute molecular beam through quantum interference. As the beam crosses the light field of a probe laser some molecules will absorb a single photon. These absorption events impart a momentum recoil which shifts the position of the molecule relative to the unperturbed beam. Averaging over the shifted and unshifted components within the beam leads to a reduction of the fringe visibility, enabling the absolute absorption cross section to be extracted with high accuracy. This technique is independent of the molecular density, it is minimally invasive and successfully eliminates many problems related to photon cycling, state mixing, photobleaching, photoinduced heating, fragmentation, and ionization. It can therefore be extended to a wide variety of neutral molecules, clusters, and nanoparticles. PMID- 25014796 TI - No psi-epistemic model can fully explain the indistinguishability of quantum states. AB - According to a recent no-go theorem [M. Pusey, J. Barrett and T. Rudolph, Nat. Phys. 8, 475 (2012)], models in which quantum states correspond to probability distributions over the values of some underlying physical variables must have the following feature: the distributions corresponding to distinct quantum states do not overlap. In such a model, it cannot coherently be maintained that the quantum state merely encodes information about underlying physical variables. The theorem, however, considers only models in which the physical variables corresponding to independently prepared systems are independent, and this has been used to challenge the conclusions of that work. Here we consider models that are defined for a single quantum system of dimension d, such that the independence condition does not arise, and derive an upper bound on the extent to which the probability distributions can overlap. In particular, models in which the quantum overlap between pure states is equal to the classical overlap between the corresponding probability distributions cannot reproduce the quantum predictions in any dimension d >= 3. Thus any ontological model for quantum theory must postulate some extra principle, such as a limitation on the measurability of physical variables, to explain the indistinguishability of quantum states. Moreover, we show that as d->infinity, the ratio of classical and quantum overlaps goes to zero for a class of states. The result is noise tolerant, and an experiment is motivated to distinguish the class of models ruled out from quantum theory. PMID- 25014797 TI - Observation of Efimov resonances in a mixture with extreme mass imbalance. AB - We observe two consecutive heteronuclear Efimov resonances in an ultracold Li-Cs mixture by measuring three-body loss coefficients as a function of magnetic field near a Feshbach resonance. The first resonance is detected at a scattering length of a_((0))=-320(10)a_((0)), corresponding to ~7(~3) times the Li-Cs (Cs-Cs) van der Waals range. The second resonance appears at 5.8(1.0)a_((0)), close to the unitarity-limited regime at the sample temperature of 450 nK. Indication of a third resonance is found in the atom loss spectra. The scaling of the resonance positions is close to the predicted universal scaling value of 4.9 for zero temperature. Deviations from universality might be caused by finite-range and temperature effects, as well as magnetic field-dependent Cs-Cs interactions. PMID- 25014798 TI - Ultrafast and fault-tolerant quantum communication across long distances. AB - Quantum repeaters (QRs) provide a way of enabling long distance quantum communication by establishing entangled qubits between remote locations. In this Letter, we investigate a new approach to QRs in which quantum information can be faithfully transmitted via a noisy channel without the use of long distance teleportation, thus eliminating the need to establish remote entangled links. Our approach makes use of small encoding blocks to fault-tolerantly correct both operational and photon loss errors. We describe a way to optimize the resource requirement for these QRs with the aim of the generation of a secure key. Numerical calculations indicate that the number of quantum memory bits at each repeater station required for the generation of one secure key has favorable polylogarithmic scaling with the distance across which the communication is desired. PMID- 25014799 TI - Fast quantum gate via Feshbach-Pauli blocking in a nanoplasmonic trap. AB - We propose a simple idea for realizing a quantum gate with two fermions in a double well trap via external optical pulses without addressing the atoms individually. The key components of the scheme are Feshbach resonance and Pauli blocking, which decouple unwanted states from the dynamics. As a physical example we study atoms in the presence of a magnetic Feshbach resonance in a nanoplasmonic trap and discuss the constraints on the operation times for realistic parameters, reaching a fidelity above 99.9% within 42 MUs, much shorter than existing atomic gate schemes. PMID- 25014800 TI - Measuring the spin of black holes in binary systems using gravitational waves. AB - Compact binary coalescences are the most promising sources of gravitational waves (GWs) for ground-based detectors. Binary systems containing one or two spinning black holes are particularly interesting due to spin-orbit (and eventual spin spin) interactions and the opportunity of measuring spins directly through GW observations. In this Letter, we analyze simulated signals emitted by spinning binaries with several values of masses, spins, orientations, and signal-to-noise ratios, as detected by an advanced LIGO-Virgo network. We find that for moderate or high signal-to-noise ratio the spin magnitudes can be estimated with errors of a few percent (5%-30%) for neutron star-black hole (black hole-black hole) systems. Spins' tilt angle can be estimated with errors of 0.04 rad in the best cases, but typical values will be above 0.1 rad. Errors will be larger for signals barely above the threshold for detection. The difference in the azimuth angles of the spins, which may be used to check if spins are locked into resonant configurations, cannot be constrained. We observe that the best performances are obtained when the line of sight is perpendicular to the system's total angular momentum and that a sudden change of behavior occurs when a system is observed from angles such that the plane of the orbit can be seen both from above and below during the time the signal is in band. This study suggests that direct measurement of black hole spin by means of GWs can be as precise as what can be obtained from x-ray binaries. PMID- 25014801 TI - Black hole hair in generalized scalar-tensor gravity. AB - The most general action for a scalar field coupled to gravity that leads to second-order field equations for both the metric and the scalar--Horndeski's theory--is considered, with the extra assumption that the scalar satisfies shift symmetry. We show that in such theories, the scalar field is forced to have a nontrivial configuration in black hole spacetimes, unless one carefully tunes away a linear coupling with the Gauss-Bonnet invariant. Hence, black holes for generic theories in this class will have hair. This contradicts a recent no-hair theorem which seems to have overlooked the presence of this coupling. PMID- 25014802 TI - Evidence for bouncing evolution before inflation after BICEP2. AB - The BICEP2 Collaboration reports a detection of primordial cosmic microwave background (CMB) B mode with a tensor-to-scalar ratio r = 0.20(-0.05)(+0.07) (68% C.L.). However, this result disagrees with the recent Planck limit r < 0.11 (95% C.L.) on constraining inflation models. In this Letter we consider an inflationary cosmology with a preceding nonsingular bounce, which gives rise to observable signatures on primordial perturbations. One interesting phenomenon is that both the primordial scalar and tensor modes can have a step feature on their power spectra, which nicely cancels the tensor excess power on the CMB temperature power spectrum. By performing a global analysis, we obtain the 68% C.L. constraints on the parameters of the model from the Planck+WP and BICEP2 data together: the jump scale log(10)(k(B)/Mpc(-1)) = -2.4 +/- 0.2 and the spectrum amplitude ratio of bounce to inflation r(B) = P(m)/A(s) = 0.71 +/- 0.09. Our result reveals that the bounce inflation scenario can simultaneously explain the Planck and BICEP2 observations better than the standard cold dark matter model with a cosmological constant, and can be verified by future CMB polarization measurements. PMID- 25014803 TI - Universal density profile for cosmic voids. AB - We present a simple empirical function for the average density profile of cosmic voids, identified via the watershed technique in LambdaCDM N-body simulations. This function is universal across void size and redshift, accurately describing a large radial range of scales around void centers with only two free parameters. In analogy to halo density profiles, these parameters describe the scale radius and the central density of voids. While we initially start with a more general four-parameter model, we find two of its parameters to be redundant, as they follow linear trends with the scale radius in two distinct regimes of the void sample, separated by its compensation scale. Assuming linear theory, we derive an analytic formula for the velocity profile of voids and find an excellent agreement with the numerical data as well. In our companion paper [Sutter et al., arXiv:1309.5087 [Mon. Not. R. Astron. Soc. (to be published)]], the presented density profile is shown to be universal even across tracer type, properly describing voids defined in halo and galaxy distributions of varying sparsity, allowing us to relate various void populations by simple rescalings. This provides a powerful framework to match theory and simulations with observational data, opening up promising perspectives to constrain competing models of cosmology and gravity. PMID- 25014806 TI - beta+ Gamow-Teller transition strengths from 46Ti and stellar electron-capture rates. AB - The Gamow-Teller strength in the beta(+) direction to (46)Sc was extracted via the (46)Ti(t,(3)He + gamma) reaction at 115 MeV/u. The gamma-ray coincidences served to precisely measure the very weak Gamow-Teller transition to a final state at 991 keV. Although this transition is weak, it is crucial for accurately estimating electron-capture rates in astrophysical scenarios with relatively low stellar densities and temperatures, such as presupernova stellar evolution. Shell model calculations with different effective interactions in the pf shell-model space do not reproduce the experimental Gamow-Teller strengths, which is likely due to sd-shell admixtures. Calculations in the quasiparticle random phase approximation that are often used in astrophysical simulations also fail to reproduce the experimental Gamow-Teller strength distribution, leading to strongly overestimated electron-capture rates. Because reliable theoretical predictions of Gamow-Teller strengths are important for providing astrophysical electron-capture reaction rates for a broad set of nuclei in the lower pf shell, we conclude that further theoretical improvements are required to match astrophysical needs. PMID- 25014807 TI - Alignment dependent enhancement of the photoelectron cutoff for multiphoton ionization of molecules. AB - The multiphoton ionization rate of molecules depends on the alignment of the molecular axis with respect to the ionizing laser polarization. By studying molecular frame photoelectron angular distributions from N(2), O(2), and benzene, we illustrate how the angle-dependent ionization rate affects the photoelectron cutoff energy. We find alignment can enhance the high energy cutoff of the photoelectron spectrum when probing along a nodal plane or when ionization is otherwise suppressed. This is supported by calculations using a tunneling model with a single ion state. PMID- 25014808 TI - High-precision spectroscopy of the forbidden 2 3s1->2 1p1 transition in quantum degenerate metastable helium. AB - We have measured the forbidden 2 (3)S(1)->2 (1)P(1) transition at 887 nm in a quantum degenerate gas of metastable (4)He atoms confined in an optical dipole trap. The determined transition frequency is 338 133 594.4 (0.5) MHz, from which we obtain an ionization energy of the 2 (1)P(1) state of 814 709 148.6 (0.5) MHz. This ionization energy is in disagreement by >3sigma with the most accurate quantum electrodynamics calculations available. Our measurements also provide a new determination of the lifetime of the 2 (1)P(1) state of 0.551 (0.004)(stat) ((-0.000)(+0.013))(syst) ns, which is the most accurate determination to date and in excellent agreement with theory. PMID- 25014809 TI - Interval prediction of molecular properties in parametrized quantum chemistry. AB - The accurate evaluation of molecular properties lies at the core of predictive physical models. Most reliable quantum-chemical calculations are limited to smaller molecular systems while purely empirical approaches are limited in accuracy and reliability. A promising approach is to employ a quantum-mechanical formalism with simplifications and to compensate for the latter with parametrization. We propose a strategy of directly predicting the uncertainty interval for a property of interest, based on training-data uncertainties, which sidesteps the need for an optimum set of parameters. PMID- 25014810 TI - Many-electron QED corrections to the g factor of lithiumlike ions. AB - A rigorous QED evaluation of the two-photon exchange corrections to the g factor of lithiumlike ions is presented. The screened self-energy corrections are calculated for the intermediate-Z region, and its accuracy for the high-Z region is essentially improved in comparison with that of previous calculations. As a result, the theoretical accuracy of the g factor of lithiumlike ions is significantly increased. The theoretical prediction obtained for the g factor of (28)Si(11+) g(th) = 2.000 889 892(8) is in an excellent agreement with the corresponding experimental value g(exp) = 2.000 889 889 9(21) [A. Wagner et al., Phys. Rev. Lett. 110, 033003 (2013). PMID- 25014811 TI - Two-photon rotational action spectroscopy of cold OH- at 1 ppb accuracy. AB - The fundamental rotational transition J = 1<-0 of the anion OH(-) has been measured by cooling mass-selected OH(-) ions to 10 K in a 22-pole ion trap and applying a novel rotational-rovibrational two-photon scheme. A transition frequency of (1 123 101.0410 +/- 0.0014) MHz was obtained with so far unprecedented accuracy. The general application of the presented action spectroscopy scheme to other anions and cations is discussed. PMID- 25014812 TI - Optical response of gas-phase atoms at less than lambda/80 from a dielectric surface. AB - We present experimental observations of atom-light interactions within tens of nanometers (down to 11 nm) of a sapphire surface. Using photon counting we detect the fluorescence from of order one thousand Rb or Cs atoms, confined in a vapor with thickness much less than the optical excitation wavelength. The asymmetry in the spectral line shape provides a direct readout of the atom-surface potential. A numerical fit indicates a power law -C(alpha)/r(alpha) with alpha = 3.02 +/- 0.06 confirming that the van der Waals interaction dominates over other effects. The extreme sensitivity of our photon-counting technique may allow the search for atom-surface bound states. PMID- 25014813 TI - Tracing electron-ion recombination in nanoplasmas produced by extreme-ultraviolet irradiation of rare-gas clusters. AB - We investigate electron-ion recombination in nanoplasmas produced by the ionization of rare-gas clusters with intense femtosecond extreme-ultraviolet (XUV) pulses. The relaxation dynamics following XUV irradiation is studied using time-delayed 790-nm pulses, revealing the generation of a large number of excited atoms resulting from electron-ion recombination. In medium-sized Ar-Xe clusters, these atoms are preferentially created in the Xe core within 10 ps after the cluster ionization. The ionization of excited atoms serves as a sensitive probe for monitoring the cluster expansion dynamics up to the ns time scale. PMID- 25014814 TI - Quantum emitters near a metal nanoparticle: strong coupling and quenching. AB - We investigate the interplay between quenching and strong coupling in systems that include a collection of quantum emitters interacting with a metal nanoparticle. By using detailed numerical simulations and analytical modeling, we demonstrate that quantum emitters can exhibit strong coupling with the particle dipole resonance at distances at which the quenching to nonradiative channels is expected to dominate the dynamics. These results can be accounted for in terms of the pseudomode character of the higher multipole modes of the nanoparticle and the corresponding reduction of the induced loss rate. These findings expand the current understanding of light-matter interaction in plasmonic systems and could contribute to the development of novel quantum plasmonic platforms. PMID- 25014815 TI - Simultaneous measurement of complementary observables with compressive sensing. AB - The more information a measurement provides about a quantum system's position statistics, the less information a subsequent measurement can provide about the system's momentum statistics. This information trade-off is embodied in the entropic formulation of the uncertainty principle. Traditionally, uncertainly relations correspond to resolution limits; increasing a detector's position sensitivity decreases its momentum sensitivity and vice versa. However, this is not required in general; for example, position information can instead be extracted at the cost of noise in momentum. Using random, partial projections in position followed by strong measurements in momentum, we efficiently determine the transverse-position and transverse-momentum distributions of an unknown optical field with a single set of measurements. The momentum distribution is directly imaged, while the position distribution is recovered using compressive sensing. At no point do we violate uncertainty relations; rather, we economize the use of information we obtain. PMID- 25014816 TI - Long-distance transfer and routing of static magnetic fields. AB - We show how the static magnetic field of a finite source can be transferred and routed to arbitrary long distances. This is achieved by using transformation optics, which results in a device made of a material with a highly anisotropic magnetic permeability. We show that a simplified version of the device, made by a superconducting-ferromagnet hybrid, also leads to an excellent transfer of the magnetic field. The latter is demonstrated with a proof-of-principle experiment where a ferromagnet tube coated with a superconductor improves the transfer of static magnetic fields with respect to conventional methods by a 400% factor over distances of 14 cm. PMID- 25014817 TI - Reconfigurable directional lasing modes in cavities with generalized PT symmetry. AB - We introduce a new family of generalized PT-symmetric cavities that involve gyrotropic elements and support reconfigurable unidirectional lasing modes. We derive conditions for which these modes exist and investigate a simple electronic circuit that experimentally demonstrates their feasibility in the radio-frequency domain. PMID- 25014818 TI - Speckle-based x-ray phase-contrast and dark-field imaging with a laboratory source. AB - We report on the observation and application of near-field speckles with a laboratory x-ray source. The detection of speckles is possible thanks to the enhanced brilliance properties of the used liquid-metal-jet source, and opens the way to a range of new applications in laboratory-based coherent x-ray imaging. Here, we use the speckle pattern for multimodal imaging of demonstrator objects. Moreover, we introduce algorithms for phase and dark-field imaging using speckle tracking, and we show that they yield superior results with respect to existing methods. PMID- 25014819 TI - Phase transitions and edge scaling of number variance in Gaussian random matrices. AB - We consider N * N Gaussian random matrices, whose average density of eigenvalues has the Wigner semicircle form over [-?2],?2]. For such matrices, using a Coulomb gas technique, we compute the large N behavior of the probability P(N,L)(N(L)) that N(L) eigenvalues lie within the box [-L,L]. This probability scales as P(N,L)(N(L) = kappa(L)N) ~ exp(-betaN(2)psi(L)(kappa(L))), where beta is the Dyson index of the ensemble and psi(L)(kappa(L)) is a beta-independent rate function that we compute exactly. We identify three regimes as L is varied: (i) N(-1)?L < ?2 (bulk), (ii) L~?2 on a scale of O(N(-2/3)) (edge), and (iii) L > sqrt[2] (tail). We find a dramatic nonmonotonic behavior of the number variance V(N)(L) as a function of L: after a logarithmic growth ?ln(NL) in the bulk (when L~O(1/N)), V(N)(L) decreases abruptly as L approaches the edge of the semicircle before it decays as a stretched exponential for L > sqrt[2]. This "dropoff" of V(N)(L) at the edge is described by a scaling function V(beta) that smoothly interpolates between the bulk (i) and the tail (iii). For beta = 2 we compute V(2) explicitly in terms of the Airy kernel. These analytical results, verified by numerical simulations, directly provide for beta = 2 the full statistics of particle-number fluctuations at zero temperature of 1D spinless fermions in a harmonic trap. PMID- 25014804 TI - Observation of eta'->pi+ pi pi+ pi- and eta'->pi+pi- pi0 pi0. AB - Using a sample of 1.3 * 10(9) J/psi events collected with the BESIII detector, we report the first observation of eta(')->pi(+)pi(-)pi(+)pi(-) and eta(') >pi(+)pi(-)pi(0)pi(0). The measured branching fractions are B(eta(')->pi(+)pi( )pi(+)pi(-)) = [8.53 +/- 0.69(stat.) +/- 0.64(syst.)]*10(-5) and B(eta(') >pi(+)pi(-)pi(0) pi(0)) = [1.82 +/- 0.35(stat.) +/- 0.18(syst.)] * 10(-4), which are consistent with theoretical predictions based on a combination of chiral perturbation theory and vector-meson dominance. PMID- 25014820 TI - Experimental realization of a new type of crystalline undulator. AB - A new scheme of making crystalline undulators was recently proposed and investigated theoretically by Andriy Kostyuk, concluding that a new type of crystalline undulator would be not only viable, but better than the previous scheme. This article describes the first experimental measurement of such a crystalline undulator, produced by using Si(1-x)Ge(x)-graded composition and measured at the Mainzer Microtron facility at beam energies of 600 and 855 MeV. We also present theoretical models developed to compare with the experimental data. PMID- 25014821 TI - Role of quantum fluctuations in the hexatic phase of cold polar molecules. AB - Two-dimensional crystals melt via an intermediate hexatic phase, which is characterized by an anomalous scaling of spatial and orientational correlation functions and the absence of an attraction between dislocations. We propose a protocol to study the effect of quantum fluctuations on the nature of this phase with a model system of strongly correlated ultracold polar molecules. Dislocations can be located in experiment from local energy differences which induce internal stark shifts in the molecules. We present a criterion to identify the hexatic phase from the statistics of the end points of topological defect strings and find a hexatic phase, which is dominated by quantum fluctuations, between the crystal and superfluid phases. PMID- 25014822 TI - Growth modes of quasicrystals. AB - The growth of quasicrystals, i.e., aperiodic structures with long-range order, seeded from the melt is investigated using a dynamical phase field crystal model. Depending on the thermodynamic conditions, two different growth modes are detected, namely defect-free growth of the stable quasicrystal and a mode dominated by phasonic flips which are incorporated as local defects into the grown structure such that random tilinglike ordering emerges. The latter growth mode is unique to quasicrystals and can be verified in experiments on one component mesoscopic systems. PMID- 25014823 TI - Investigating amorphous order in stable glasses by random pinning. AB - We investigate stable glassy states that are found when glass-forming liquids are biased to lower than average dynamical activity. By pinning the positions of randomly chosen particles, we show that many-body correlations in these states are relatively strong and long ranged compared to equilibrium reference states. The presence of strong many-body correlations in these apparently disordered systems supports the idea that stable glassy states exhibit a kind of "amorphous order," which helps to explain their stability. PMID- 25014824 TI - Single-electron dynamics of an atomic silicon quantum dot on the H-Si(100)-(2*1) surface. AB - Here we report the direct observation of single electron charging of a single atomic dangling bond (DB) on the H-Si(100)-2*1 surface. The tip of a scanning tunneling microscope is placed adjacent to the DB to serve as a single-electron sensitive charge detector. Three distinct charge states of the dangling bond- positive, neutral, and negative--are discerned. Charge state probabilities are extracted from the data, and analysis of current traces reveals the characteristic single-electron charging dynamics. Filling rates are found to decay exponentially with increasing tip-DB separation, but are not a function of sample bias, while emptying rates show a very weak dependence on tip position, but a strong dependence on sample bias, consistent with the notion of an atomic quantum dot tunnel coupled to the tip on one side and the bulk silicon on the other. PMID- 25014825 TI - Origin of spectral purity and tuning sensitivity in a spin transfer vortex nano oscillator. AB - We investigate the microwave characteristics of a spin transfer nano-oscillator (STNO) based on coupled vortices as a function of the perpendicular magnetic field H(?). Interestingly, we find that our vortex-based oscillator is quasi isochronous independently of H(?) and for a dc current ranging between 18 and 25 mA. It means that the severe nonlinear broadening usually observed in STNOs can be suppressed on a broad range of bias. Still, the generation linewidth displays strong variations on H(?) (from 40 kHz to 1 MHz), while the frequency tunability in current remains almost constant (7 MHz/mA). This demonstrates that isochronicity does not necessarily imply a loss of frequency tunability, which is here governed by the current induced Oersted field. It is not sufficient either to achieve the highest spectral purity in the full range of H(?). We show that the observed linewidth broadenings are due to the excited mode interacting with a lower energy overdamped mode, which occurs at the successive crossings between harmonics of these two modes. These findings open new possibilities for the design of STNOs and the optimization of their performance. PMID- 25014805 TI - Cold-nuclear-matter effects on heavy-quark production at forward and backward rapidity in d + Au collisions at ?sNN = 200 GeV. AB - The PHENIX experiment has measured open heavy-flavor production via semileptonic decay over the transverse momentum range 1 < p(T) < 6 GeV/c at forward and backward rapidity (1.4 < |y| < 2.0) in d+Au and p + p collisions at ?sNN = 200 GeV. In central d+Au collisions, relative to the yield in p + p collisions scaled by the number of binary nucleon-nucleon collisions, a suppression is observed at forward rapidity (in the d-going direction) and an enhancement at backward rapidity (in the Au-going direction). Predictions using nuclear-modified-parton distribution functions, even with additional nuclear-p(T) broadening, cannot simultaneously reproduce the data at both rapidity ranges, which implies that these models are incomplete and suggests the possible importance of final-state interactions in the asymmetric d + Au collision system. These results can be used to probe cold-nuclear-matter effects, which may significantly affect heavy-quark production, in addition to helping constrain the magnitude of charmonia-breakup effects in nuclear matter. PMID- 25014826 TI - S matrix from matrix product states. AB - We use the matrix product state formalism to construct stationary scattering states of elementary excitations in generic one-dimensional quantum lattice systems. Our method is applied to the spin-1 Heisenberg antiferromagnet, for which we calculate the full magnon-magnon S matrix for arbitrary momenta and spin, the two-particle contribution to the spectral function, and higher order corrections to the magnetization curve. As our method provides an accurate microscopic representation of the interaction between elementary excitations, we envisage the description of low-energy dynamics of one-dimensional spin chains in terms of these particlelike excitations. PMID- 25014827 TI - Curvature effects in thin magnetic shells. AB - A magnetic energy functional is derived for an arbitrary curved thin shell on the assumption that the magnetostatic effects can be reduced to an effective easy surface anisotropy; it can be used for solving both static and dynamic problems. General static solutions are obtained in the limit of a strong anisotropy of both signs (easy-surface and easy-normal cases). It is shown that the effect of the curvature can be treated as the appearance of an effective magnetic field, which is aligned along the surface normal for the case of easy-surface anisotropy and is tangential to the surface for the case of easy-normal anisotropy. In general, the existence of such a field excludes the solutions that are strictly tangential or strictly normal to the surface. As an example, we consider static equilibrium solutions for a cone surface magnetization. PMID- 25014828 TI - Quench dynamics of the anisotropic Heisenberg model. AB - We develop an analytical approach for the study of the quench dynamics of the anisotropic Heisenberg model (XXZ model) on the infinite line. We present the exact time-dependent wave functions after a quench in an integral form for any initial state and for any anisotropy Delta by means of a generalized Yudson contour representation. We calculate the evolution of several observables from two particular initial states: starting from a local Neel state we calculate the time evolution of the antiferromagnetic order parameter-staggered magnetization; starting from a state with consecutive flipped spins (1) we calculate the evolution of the local magnetization and express it in terms of the propagation of magnons and bound state excitations, and (2) we predict the evolution of the induced spin currents. These predictions can be confronted with experiments in ultracold gases in optical lattices. We also show how the "string" solutions of Bethe ansatz equations emerge naturally from the contour approach. PMID- 25014829 TI - Ultrafast dynamics of massive dirac fermions in bilayer graphene. AB - Bilayer graphene is a highly promising material for electronic and optoelectronic applications since it is supporting massive Dirac fermions with a tunable band gap. However, no consistent picture of the gap's effect on the optical and transport behavior has emerged so far, and it has been proposed that the insulating nature of the gap could be compromised by unavoidable structural defects, by topological in-gap states, or that the electronic structure could be altogether changed by many-body effects. Here, we directly follow the excited carriers in bilayer graphene on a femtosecond time scale, using ultrafast time- and angle-resolved photoemission. We find a behavior consistent with a single particle band gap. Compared to monolayer graphene, the existence of this band gap leads to an increased carrier lifetime in the minimum of the lowest conduction band. This is in sharp contrast to the second substate of the conduction band, in which the excited electrons decay through fast, phonon-assisted interband transitions. PMID- 25014830 TI - ab initio study of hot carriers in the first picosecond after sunlight absorption in silicon. AB - Hot carrier thermalization is a major source of efficiency loss in solar cells. Because of the subpicosecond time scale and complex physics involved, a microscopic characterization of hot carriers is challenging even for the simplest materials. We develop and apply an ab initio approach based on density functional theory and many-body perturbation theory to investigate hot carriers in semiconductors. Our calculations include electron-electron and electron-phonon interactions, and require no experimental input other than the structure of the material. We apply our approach to study the relaxation time and mean free path of hot carriers in Si, and map the band and k dependence of these quantities. We demonstrate that a hot carrier distribution characteristic of Si under solar illumination thermalizes within 350 fs, in excellent agreement with pump-probe experiments. Our work sheds light on the subpicosecond time scale after sunlight absorption in Si, and constitutes a first step towards ab initio quantification of hot carrier dynamics in materials. PMID- 25014831 TI - Activating membranes. AB - We present a general dynamical theory of a membrane coupled to an actin cortex containing polymerizing filaments with active stresses and currents, and demonstrate that active membrane dynamics [S. Ramaswamy et al., Phys. Rev. Lett. 84, 3494 (2000)] and spontaneous shape oscillations emerge from this description. We also consider membrane instabilities and patterns induced by the presence of filaments with polar orientational correlations in the tangent plane of the membrane. The dynamical features we predict should be seen in a variety of cellular contexts involving the dynamics of the membrane-cytoskeleton composite and cytoskeletal extracts coupled to synthetic vesicles. PMID- 25014832 TI - Infrared-activated proton transfer in aqueous nafion proton-exchange-membrane nanochannels. AB - We report on the observation of a strong reorganization of the proton hydration structure in hydrated Nafion membranes following single-quantum excitation of a proton vibration with ~4 MUm light pulses. The reorganization takes place with a time constant of 170 +/- 20 fs and leads to a strong red shift of the excited proton vibration and the rise of new waterlike O-H stretch absorption bands. These observations can be explained from a vibrational-excitation-induced change of the proton-hydration structure that involves transfer of the proton charge. The results are consistent with recent quantum molecular dynamics simulations of proton transfer in Nafion membranes. PMID- 25014833 TI - Role of the occluded conformation in bacterial dihydrofolate reductases. AB - Dihydrofolate reductase (DHFR) from Escherichia coli (EcDHFR) adopts two major conformations, closed and occluded, and movement between these two conformations is important for progression through the catalytic cycle. DHFR from the cold adapted organism Moritella profunda (MpDHFR) on the other hand is unable to form the two hydrogen bonds that stabilize the occluded conformation in EcDHFR and so remains in a closed conformation during catalysis. EcDHFR-S148P and MpDHFR-P150S were examined to explore the influence of the occluded conformation on catalysis by DHFR. Destabilization of the occluded conformation did not affect hydride transfer but altered the affinity for the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP(+)) and changed the rate-determining step of the catalytic cycle for EcDHFR-S148P. Even in the absence of an occluded conformation, MpDHFR follows a kinetic pathway similar to that of EcDHFR with product release being the rate-limiting step in the steady state at pH 7, suggesting that MpDHFR uses a different strategy to modify its affinity for NADP(+). DHFRs from many organisms lack a hydrogen bond donor in the appropriate position and hence most likely do not form an occluded conformation. The link between conformational cycling between closed and occluded forms and progression through the catalytic cycle is specific to EcDHFR and not a general characteristic of prokaryotic DHFR catalysis. PMID- 25014836 TI - Resolution of fluorophore mixtures in biological media using fluorescence spectroscopy and Monte Carlo simulation. AB - In excitation-emission fluorescence spectroscopy, the simultaneous quantitative prediction and qualitative resolution of mixtures of fluorophores using chemometrics is a major challenge because of the scattering and reabsorption effects (turbidity) presented mainly in biomaterials. The measured fluorescence spectra are distorted by multiple scattering and reabsorption events in the surrounding medium, thereby diminishing the performance of the commonly used three-way resolution methods such as parallel factor (PARAFAC) analysis or multivariate curve resolution-alternating least squares (MCR-ALS). In this work we show that spectral loadings and concentration profiles from model mixtures provided using PARAFAC and MCR-ALS are severely distorted by reabsorption and scattering phenomena, although both models fit rather well the experimental data in terms of percentage of the explained variance. The method to correct the fluorescence excitation-emission matrix (EEM) consisted in measuring the optical properties (absorption parameter MUa , scattering parameter MUs, and anisotropy factor g) of samples and calculating the corresponding transfer function by means of the Monte Carlo simulation method. By applying this transfer function to the measured EEM, it was possible to compensate for reabsorption and scattering effects and to restore the ideal EEM, i.e., the EEM that is due only to fluorophores, without distortions from the absorbers and scatterers that are present. The PARAFAC and MCR-ALS decomposition of the resulting ideal EEMs provided spectral loadings and concentration profiles that matched the true profiles. PMID- 25014837 TI - Estimating soil organic carbon content with visible-near-infrared (vis-NIR) spectroscopy. AB - The selection of a calibration method is one of the main factors influencing measurement accuracy with visible-near-infrared (Vis-NIR, 350-2500 nm) spectroscopy. This study, based on both air-dried unground (DU) and air-dried ground (DG) soil samples, used nine spectral preprocessing methods and their combinations, with the aim to compare the commonly used partial least squares regression (PLSR) method with the new machine learning method of support vector machine regression (SVMR) to find a robust method for soil organic carbon (SOC) content estimation, and to further explore an effective Vis-NIR spectral preprocessing strategy. In total, 100 heterogeneous soil samples collected from Southeast China were used as the dataset for the model calibration and independent validation. The determination coefficient (R(2)), root mean square error (RMSE), residual prediction deviation (RPD), and ratio of performance to interquartile range were used for the model evaluation. The results of this study show that both the PLSR and SVMR models were significantly improved by the absorbance transformation (LOG), standard normal variate with wavelet detrending (SW), first derivative (FD), and mean centering (MC) spectral preprocessing methods and their combinations. SVMR obtained optimal models for both the DU and DG soil, with R(2), RMSE, and RPD values of 0.72, 2.48 g/kg, and 1.83 for DU soil and 0.86, 1.84 g/kg, and 2.60 for DG soil, respectively. Among all the PLSR and SVMR models, SVMR showed a more stable performance than PLSR, and it also outperformed PLSR, with a smaller mean RMSE of 0.69 g/kg for DU soil and 0.50 g/kg for DG soil. This study concludes that PLSR is an effective linear algorithm, but it might not be sufficient when dealing with a nonlinear relationship, and SVMR turned out to be a more suitable nonlinear regression method for SOC estimation. Effective SOC estimation was obtained based on the DG soil samples, but the accurate estimation of SOC with DU soil samples needs to be further explored. In addition, LOG, SW, FD, and MC are valuable spectral preprocessing methods for Vis-NIR optimization, and choosing two of them (except for FD + SW and LOG + FD) in a simple combination is a good way to get acceptable results. PMID- 25014838 TI - Gas-phase plume from laser-irradiated fiberglass-reinforced polymers via imaging fourier transform spectroscopy. AB - Emissive plumes from laser-irradiated fiberglass-reinforced polymers (FRP) were investigated using a mid-infrared imaging Fourier transform spectrometer, operating at fast framing rates (50 kHz imagery and 2.5 Hz hyperspectral imagery) with adequate spatial (0.81 mm(2) per pixel) and spectral resolution (2 cm(-1)). Fiberglass-reinforced polymer targets were irradiated with a 1064 nm continuous wave neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for 60 s at 100 W in air. Strong emissions from H(2)O, CO, CO(2), and hydrocarbons were observed between 1800 and 5000 cm(-1). A single-layer radiative transfer model was developed for the spectral region from 2000 to 2400 cm(-1) to estimate spatial maps of temperature and column densities of CO and CO(2) from the hyperspectral imagery. The spectral model was used to compute the absorption cross sections of CO and CO(2) using spectral line parameters from the high-temperature extension of the HITRAN. The analysis of pre-combustion spectra yields effective temperatures rising from ambient to 1200 K and suddenly increasing to 1515 K upon combustion. The peak signal-to-noise ratio for a single spectrum exceeds 60:1, enabling temperature and column density determinations with low statistical error. For example, the spectral analysis for a single pixel within a single frame yields an effective temperature of 1019 +/- 6 K, and CO and CO(2) column densities of 1.14 +/- 0.05 and 1.11 +/- 0.03 * 10(18) molec/cm(2), respectively. Systematic errors associated with the radiative transfer model dominate, yielding effective temperatures with uncertainties of >100 K and column densities to within a factor of 2-3. Hydrocarbon emission at 2800 to 3200 cm(-1) is well correlated with CO column density. PMID- 25014839 TI - A method to obtain the absorption coefficient spectrum of single grain coal in the aliphatic C-H stretching region using infrared transflection microspectroscopy. AB - A method was developed to obtain the absorption coefficient spectrum of a grain of coal (as small as 10(-7)) in the region of aliphatic and aromatic C-H stretching bands (2700-3200 cm(-1)) using infrared transflection microspectroscopy. In this method, the complex refractive index n - ik was determined using an optimization algorithm with the Kramers-Kronig transform so that the calculated transflection spectrum from the Fresnel equation corresponded to the measured one. The obtained absorption coefficients were compared with the bulk values determined from the potassium bromide (KBr) pellet measurement method. PMID- 25014840 TI - Darkfield reflection visible microspectroscopy equipped with a color mapping system of a brown altered granite. AB - Visible darkfield reflectance spectroscopy equipped with a color mapping system has been developed and applied to a brown-colored Rokko granite sample. Sample reflectance spectra converted to Kubelka-Munk (KM) spectra show similar features to goethite and lepidocrocite. Raman microspectroscopy on the granite sample surface confirms the presence of these minerals. Here, L*a*b* color values (second Commission Internationale d'Eclairage [CIELab] 1976 color space) were determined from the sample reflection spectra. Grey, yellow, and brown zones of the granite show different L*, a*, and b* values. In the a*-b* diagram, a* and b* values in the grey and brown zones are on the lepidocrocite/ferrihydrite trends, but their values in the brown zone are larger than those in the grey zone. The yellow zone shows data points close to the goethite trend. Iron (hydr)oxide-rich areas can be visualized by means of large a* and b* values in the L*, a*, and b* maps. Although the present method has some problems and limitations, the visible darkfield reflectance spectroscopy can be a useful method for colored-material characterization. PMID- 25014841 TI - Structural characterization of hydrogen peroxide-oxidized anthracites by X-ray diffraction, fourier transform infrared spectroscopy, and Raman spectra. AB - The structural characteristics of raw coal and hydrogen peroxide (H(2)O(2)) oxidized coals were investigated using scanning electron microscopy, X-ray diffraction (XRD), Raman spectra, and Fourier transform infrared (FT-IR) spectroscopy. The results indicate that the derivative coals oxidized by H(2)O(2) are improved noticeably in aromaticity and show an increase first and then a decrease up to the highest aromaticity at 24 h. The stacking layer number of crystalline carbon decreases and the aspect ratio (width versus stacking height) increases with an increase in oxidation time. The content of crystalline carbon shows the same change tendency as the aromaticity measured by XRD. The hydroxyl bands of oxidized coals become much stronger due to an increase in soluble fatty acids and alcohols as a result of the oxidation of the aromatic and aliphatic C-H bonds. In addition, the derivative coals display a decrease first and then an increase in the intensity of aliphatic C-H bond and present a diametrically opposite tendency in the aromatic C-H bonds with an increase in oxidation time. There is good agreement with the changes of aromaticity and crystalline carbon content as measured by XRD and Raman spectra. The particle size of oxidized coals (<200 nm in width) shows a significant decrease compared with that of raw coal (1 MUm). This study reveals that the optimal oxidation time is ~24 h for improving the aromaticity and crystalline carbon content of H(2)O(2)-oxidized coals. This process can help us obtain superfine crystalline carbon materials similar to graphite in structure. PMID- 25014842 TI - Polymorph characterization of active pharmaceutical ingredients (APIs) using low frequency Raman spectroscopy. AB - Polymorph detection, identification, and quantitation in crystalline materials are of great importance to the pharmaceutical industry. Vibrational spectroscopic techniques used for this purpose include Fourier transform mid-infrared (FT-MIR) spectroscopy, Fourier transform near-infrared (FT-NIR) spectroscopy, Raman spectroscopy, and terahertz (THz) and far-infrared (FIR) spectroscopy. Typically, the fundamental molecular vibrations accessed using high-frequency Raman and MIR spectroscopy or the overtone and combination of bands in the NIR spectra are used to monitor the solid-state forms of active pharmaceutical ingredients (APIs). The local environmental sensitivity of the fundamental molecular vibrations provides an indirect probe of the long-range order in molecular crystals. However, low frequency vibrational spectroscopy provides access to the lattice vibrations of molecular crystals and, hence, has the potential to more directly probe intermolecular interactions in the solid state. Recent advances in filter technology enable high-quality, low-frequency Raman spectra to be acquired using a single-stage spectrograph. This innovation enables the cost-effective collection of high-quality Raman spectra in the 200-10 cm(-1) region. In this study, we demonstrate the potential of low-frequency Raman spectroscopy for the polymorphic characterization of APIs. This approach provides several benefits over existing techniques, including ease of sampling and more intense, information-rich band structures that can potentially discriminate among crystalline forms. An improved understanding of the relationship between the crystalline structure and the low-frequency vibrational spectrum is needed for the more widespread use of the technique. PMID- 25014843 TI - Combined photothermal lens and photothermal mirror characterization of polymers. AB - We propose a combined thermal lens and thermal mirror method as concurrent photothermal techniques for the physical characterization of polymers. This combined method is used to investigate polymers as a function of temperature from room temperature up to 170 degrees C. The method permits a direct determination of thermal diffusivity and thermal conductivity. Additional measurements of specific heat, linear thermal expansion, and temperature-dependent optical path change are also performed. A complete set of thermal, optical, and mechanical properties of polycarbonate and poly (methyl methacrylate) samples are obtained. Methods presented here can be useful for in situ characterization of semitransparent materials, where fast and non-contacting measurements are required. PMID- 25014844 TI - Sensitive surface-enhanced Raman scattering (SERS) detection of nitroaromatic pollutants in water. AB - The increasing and urgent demand for clean water requires new approaches for identifying possible contaminants. In the present study, polymer substrates with embedded silver nanoparticles are employed to reveal the presence of traces of nitroaromatic compounds in water on the basis of the surface-enhanced Raman scattering (SERS) effect. These platforms provide an easy and sensitive method of detecting of low concentrations of these organic pollutants in contaminated water. PMID- 25014845 TI - An assessment of the potential of laser-induced breakdown spectroscopy (LIBS) for the analysis of cesium in liquid samples of biological origin. AB - The present study describes the development of an analytical method for the determination of cesium in biological fluid samples (human urine and blood samples) by laser-induced breakdown spectroscopy (LIBS). The developed method is based on sample presentation by liquid-to-solid conversion, enhancing the emission signal by drying the liquid into small "pockets" created in a metal support (zinc plate), and allows the analysis to be carried out on as little as 1 MUL of sample volume, in a closed sample cell. Absolute detection limits on the Cs I 852.1 nm spectral line were calculated by the IUPAC 3sigma method to be 6 ng in the urine sample and 27 ng in the blood serum sample. It is estimated that LIBS may be used to detect highly elevated concentration levels of Cs in fluid samples taken from people potentially exposed to surges of Cs from non-natural sources. PMID- 25014846 TI - Structural deformation of longitudinal arches during running in soccer players with medial tibial stress syndrome. AB - The purpose of this study was to compare angular change and translational motion from the medial longitudinal arch (MLA) and lateral longitudinal arch (LLA) during running between medial tibial stress syndrome (MTSS) and non-MTSS subjects. A total of 10 subjects volunteered, comprising 5 subjects with MTSS and 5 subjects without injury (non-MTSS) as the control group. All subjects performed the test movement that simulated running. Fluoroscopic imaging was used to investigate bone movement during landing in running. Sagittal motion was defined as the angular change and translational motion of the arch. A Mann-Whitney U-test was performed to determine the differences in the measured values between the MTSS and non-MTSS groups. The magnitude of angular change for the MLA and LLA was significantly greater for subjects with MTSS than for control subjects. Translational motion of the MLA and LLA of the MTSS group was also significantly greater than that of the non-MTSS group (all p < 0.05). Soccer players with MTSS have an abnormal structural deformation of foot during support (or stance) phase of running, with a large decrease in both the MLA and LLA. This abnormal motion could be a risk factor for the development of MTSS in these subjects. PMID- 25014847 TI - Enhanced depth imaging optical coherence tomography of intraocular tumors: from placid to seasick to rock and rolling topography--the 2013 Francesco Orzalesi Lecture. AB - PURPOSE: To review enhanced depth imaging optical coherence tomography of intraocular tumors. METHODS: Review of tumor surface topography and internal characteristics based on published reports and personal experience. RESULTS: Using enhanced depth imaging optical coherence tomography, choroidal nevus showed smooth moderate dome-shape and with overlying retinal pigment epithelial alterations, subretinal cleft, and photoreceptor loss. Choroidal melanoma was smooth, moderately dome-shaped, and with overlying "shaggy" photoreceptors. Choroidal metastasis showed "lumpy, bumpy" irregular surface topography, subretinal fluid, and shaggy photoreceptors. Choroidal hemangioma was smooth, acutely dome-shaped and with subretinal fluid and/or cystoid retinal edema. Choroidal lymphoma showed "placid, rippled, or seasick" surface, correlating with increasing tumor thickness. Choroidal osteoma displayed smooth undulating surface with intralesional lamellar lines and tubules, representing bone lamellae or vessels. Choroidal melanocytosis produced flat but uniformly thickened choroid with increased stromal density. Choroidal hemorrhage displayed slightly "scalloped" surface in the outer choroid. All choroidal tumors showed inward compression of the choroidal vasculature, except for hemangioma in which the vessels were expanded. Sclerochoroidal calcification arose within the sclera as a "rocky" or "rolling" topography and solitary idiopathic choroiditis appeared as a domed or "volcanic" focal scleral thickening, each causing intense choroidal compression. Retinal tumors such as small retinoblastoma, astrocytic hamartoma, and hemangioblastoma arose abruptly adjacent to normal retina. Exophytic retinoblastoma and retinal hemangioblastoma depicted a full-thickness disorganized retinal mass with normal retina draped over the margins. Flat astrocytic hamartoma arose within the nerve fiber layer, and thicker tumors involved full-thickness retina with "moth-eaten" or cavitary appearance. Retinal pigment epithelial lesions such as congenital hypertrophy of retinal pigment epithelial showed flat topography with transmission of light through lacunae, occasional subretinal cleft and uniform photoreceptor loss, whereas combined hamartoma of retina/retinal pigment epithelial showed "sawtooth" pattern of vitreoretinal traction leading to mini-peak or maxi-peak retinal folds. CONCLUSIONS: Enhanced depth imaging optical coherence tomography shows characteristic topographical and intralesional patterns that appear to be suggestive for selected intraocular tumors. PMID- 25014848 TI - Accuracy and reliability of naevus self-counts. AB - A high number of melanocytic naevi is one of the major risk factors for cutaneous melanoma. Therefore, counting the number of acquired naevi could be a useful strategy to identify individuals at an increased risk for targeted skin cancer screening. The aim of this study was to assess agreement between naevus self counts and counts of trained examiners as well as to analyse potential determinants of the magnitude of agreement. In a large cross-sectional survey (n=1772), university students counted their naevi on both arms and were additionally examined by specifically trained examiners in a mutually blinded manner. Further data on other melanoma risk factors such as skin phototype, hair colour or freckling were collected by a questionnaire. The relative difference between the two naevus counts and the ratio of the counts were calculated to quantify agreement. Regression modelling was performed to identify independent determinants of agreement. The overall agreement was moderate, with participants counting on average 14% more naevi than the examiners. In terms of the potential determinants associated with agreement, skin type and medical education showed a strong effect. The difference in naevus counts was significantly larger for individuals with lighter skin types compared with those with a dark skin (Fitzpatrick type IV), and medical students yielded a naevus count more similar to the examiner's count than nonmedical students. Naevus self-counts can only provide a rough estimate of the number of naevi, but may not be accurate enough to reliably identify a high-risk group for melanoma screening, especially in individuals with light skin types. PMID- 25014849 TI - Knowledge, Attitude and Behaviour for Choosing Oral Hygiene Aids among Students of Management Institutes, Ghaziabad, India. AB - OBJECTIVE: There is a lot of information available about various oral hygiene aids used for the maintenance of oral hygiene and the prevention of oral diseases but the reason why people choose a particular product is under-reported. This study sought to assess the knowledge, attitudes and behaviour of choosing oral hygiene aids among students of management institutes in Ghaziabad, India. METHOD: A cross-sectional survey was conducted in five management institutes selected by simple random sampling and data were collected from 1224 students by self administered structured validated questionnaire. RESULTS: The study showed that toothbrush (96.8%) and toothpaste (95.2%) were the main products used for the maintenance of oral hygiene. The most commonly used brand dentifrices were Colgate and Close-Up (47%, 23.3%) and in toothbrush, Oral B and Colgate (48.4%, 30.9%), respectively. A particular brand of toothpaste was preferred by 66.4% of the subjects because of childhood and parental use, which was the most influential factor (56.9%). Bristle design was the main criterion for choosing a toothbrush (44.9%), followed by bristle consistency (33.1%). The most commonly used toothbrushes were of soft bristle consistency (51.2%) and 10.9% of the subjects did not know the type of bristle consistency present in their toothbrush. CONCLUSION: Selection of oral hygiene products was based more on parental influence and there seems to be a lack of knowledge and awareness about how to choose a dentifrice and toothbrush. PMID- 25014850 TI - HPV and HPV Vaccine Awareness: Where Are We? PMID- 25014851 TI - Evaluation of the Hypoglycaemic Activity of Petiveria alliacea (Guinea Hen Weed) Extracts in Normoglycaemic and Diabetic Rat Models. AB - OBJECTIVE: Petiveria alliacea (P alliacea) has ethno-traditional use as a hypoglycaemic agent in Jamaica and is yet to be scientifically validated as such. Therefore, extracts of aerial parts of the plant were evaluated for hypoglycaemic activity in normoglycaemic and diabetic rats. METHOD: Aqueous and hexane extracts prepared from leaves of P alliacea were tested for hypoglycaemic activity. An acute administration of the extracts (200 and 400 mg/kg body weight) was evaluated in normoglycaemic rats. Additionally, the hypoglycaemic effect of sub chronic administration was assessed in streptozotocin-induced diabetic rats. Blood glucose was recorded using a glucometer and test strips. Data were analysed using Student's t-test (p <= 0.05). RESULTS: The aqueous and hexane extracts demonstrated no significant reduction of fasting blood glucose (FBG) and no significant improvement of glucose tolerance in normal rats. The aqueous extract (400 mg/kg body weight) increased FBG from 4.75 +/- 0.28 mmol/L to 5.88 +/- 0.46 when compared to control (p <= 0.001). In diabetic rats, the hexane extract (400 mg/kg body weight) caused reduction of FBG after two weeks of treatment (p <= 0.010), but this was not sustained. The aqueous extract showed no reduction of FBG in diabetic rats. CONCLUSION: The aqueous extract of P alliacea demonstrated a hyperglycaemic effect in normoglycaemic rats and showed no hypoglycaemic activity in diabetic rats. The hexane extract caused no hypoglycaemic action in normal rats and failed to sustain an initial hypoglycaemic action in diabetic rats. This study presents evidence that does not support significant hypoglycaemic activity of P alliacea; this could hold significant implications for its use in ethno-traditional medicine. PMID- 25014852 TI - The application of chromosome abnormality chip detection in male infertility. AB - OBJECTIVE: To discuss the application of microarray technology in the diagnosis of male infertility. METHODS: Sixteen loci, including a sex-determining region on the Y chromosome, were investigated by polymerase chain reaction (PCR) in infertile male patients. Chromosome abnormality chip with 180 000 probes was used to detect small deletion, small amplification and loss of heterozygosity. RESULTS: By PCR, nine of 103 infertile patients were found to have sequence tagged site microdeletions. Microdeletions were not observed in control samples. The deletions detected by PCR were present in six azoospermic men (6/44, 13.6%) and in three oligoasthenoteratozoospermic (OATS) men (3/59, 5%).The overall frequency of microdeletions in infertile men was 8.7% (9/103). Chromosome abnormality chip detection 500+ detected more amplification or deletion in 51 infertile patients and the overall frequency of microdeletions in infertile men was 49.5% (51/103). CONCLUSION: Chromosome abnormality chip detection system provides a sensitive, economic and high-throughput method for detecting the deletion or amplification of genomic DNA sequences of infertile patients. Not only can it identify Yq deletions, but it can also find other chromosome abnormalities and facilitate the understanding of male infertility. PMID- 25014853 TI - Autophagy facilitates the sorafenib resistance of hepatocellular carcinoma cells. AB - Liver cancer is the second most frequent cause of cancer death in men and the sixth leading cause of cancer death in women. Hepatocellular carcinoma (HCC) represents the major subtype in liver cancer and its five-year survival rate remains very poor. Sorafenib, a molecular targeted therapeutic agent, was the first drug approved for the treatment of patients with HCC. However, the clinical response of sorafenib was seriously limited by drug resistance. Autophagy is an evolutionarily conserved mechanism among all eukaryotes. Recently, many studies have indicated that autophagy can be activated as a cellular protective mechanism in many tumour cells. Thus, we hypothesized that autophagy may play an important role in hepatocellular carcinoma's resistance to sorafenib. Although the exact role of autophagy in the sorafenib resistance of HCC is still complex and further studies are needed to be proven, at least it suggests that autophagy may be a new therapeutic target for the sorafenib resistance of HCC. PMID- 25014854 TI - Immunoglobulin Heavy Chain Gene Rearrangement in Non B-cell Haematological Malignancies. AB - OBJECTIVE: Clonality detection through amplifying immunoglobulin heavy chain (IGH) gene rearrangements by polymerase chain reaction (PCR) is a useful tool in diagnosis of various B-lymphoid malignancies. Immunoglobulin heavy chain gene rearrangement can be an optimal target for clonality detection in B-lymphoid malignancies. In the present study, we evaluated the presence of IGH gene rearrangement in non B-cell haemato-oncology patients including T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloblastic leukaemia (AML) and biphenotypic leukaemia. MEHTODS: We studied 18 cases of haematological malignancies which comprised five patients with T-ALL, 12 patients with AML and one with biphenotypic leukaemia. RESULTS: We found that the incidence of IGH gene rearrangement in T-ALL and AML were three (60%) and two (16.7%), respectively. The patient with biphenotypic leukaemia was negative for IGH gene rearrangement. CONCLUSION: Immunoglobulin gene rearrangement, which occurs in almost all haematological malignancies of B-cell lineage, also presents in a very small proportion of T-cell or myeloid malignancies. PMID- 25014855 TI - Association between Obesity and Impaired Glucose Tolerance in New Providence Adolescents as Demonstrated by the HbA1c Test. AB - OBJECTIVE: To explore the association between obesity and the development of impaired glucose tolerance (IGT) in Bahamian adolescents. METHODS: Eight hundred and seventy-three adolescents were randomly selected from five high schools in New Providence. Each student's weight, height, and waist and hip circumferences were recorded to determine body mass index (BMI). Individuals with BMIs above the 84th and 95th percentiles were classified as overweight and obese, respectively. Venous blood samples were collected from each subject and haemoglobin A1c (HbA1c) levels were measured using a direct immunoassay method. The criterion established by the International Expert Committee for the diagnosis of IGT (HbA1c concentration of 6.0-6.4%) was used. An analysis of covariance was performed to evaluate the relationship between obesity and IGT, and a logistic regression analysis predicted the risk of IGT based on BMI classification. RESULTS: Of the 861 adolescents who completed the study, 15.0% were classified as overweight, 15.2% as obese and 7.9% as severely obese. The overall cumulative prevalence of IGT based on HbA1c levels was 16 100 cases per 100 000 adolescents and was greater in males than in females. Higher percentages of overweight and obese students were identified as having IGT compared with their normal-weight counterparts. An analysis of covariance with post hoc analyses revealed that severely obese males and females, respectively were almost 26 (OR = 25.54, 95% CI 9.92, 65.77) or 23 (OR = 22.96,95% CI 9.81, 53.73) times more likely to develop IGT than their normal-weight counterparts (p < 0.05). CONCLUSION: The data show a strong positive association between IGT and obesity among Bahamian adolescents. PMID- 25014856 TI - Diagnostic Value of p16 Methylation for Malignant Pleural Effusions: A Meta analysis. AB - OBJECTIVE: To evaluate the overall diagnostic performance of the p16 methylation for diagnosing malignant pleural effusion (MPE). METHODS: All published literature in English and Chinese were reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled by using random effects model or fixed-effects model. Summary receiver operating characteristic (SROC) curve was used to evaluate the overall diagnostic value. RESULTS: Six studies were included with a total of 378 cases. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of p16 methylation in the diagnosis of MPE were 0.41 [95% confidence interval (CI) 0.35, 0.48], 0.97 [95% CI 0.93, 0.99], 9.57 [95% CI 4.53, 20.20], 0.61 [95% CI 0.45, 0.82] and 19.82 [95% CI 8.35, 47.04], respectively. The area under the curve (AUC) was 0.864. CONCLUSION: Pleural p16 methylation test plays a useful role in the diagnosis of MPE. PMID- 25014857 TI - Differences of Ventricular Late Potential between Acute STEMI and NSTEMI Patients. AB - OBJECTIVE: To discuss the positive rate of ventricular late potential (VLP) between patients with acute ST-segment elevation myocardial infarction (STEMI) and patients with acute non NSTEMI. METHODS: One hundred and sixty-three cases of acute myocardial infarction (90 patients with STEMI and 73 with NSTEMI), admitted to the First Hospital of China Medical University between June 2011 and August 2011, underwent VLP examination. RESULTS: The VLP positive rate of the STEMI group was 54.4%, while that of the NSTEMI group was 38.4%, and the differences have statistical meaning (chi2 = 4.186, p < 0.05). The occurrence rate of ventricular arrhythmia in VLP positive patients was 11.7%, while in VLP negative patients it was 3.5% (chi2 = 4.005, p < 0.05). CONCLUSION: The VLP positive rate of the STEMI group is higher than that of the NSTEMI group. PMID- 25014858 TI - Is Timely and Appropriate Antifungal Drug Enough for Survival of Adult Cases with Candidaemia? Five-year Experience. AB - OBJECTIVE: Candidaemia is the fourth most common cause of nosocomial bloodstream infections. The objective of this paper was to evaluate the risk factors associated with mortality in patients with candidaemia with respect to Candida species and their susceptibilities, retrospectively. METHODS: All consecutive patients who developed candidaemia at an 800-bed training and research hospital were enrolled in this retrospective, observational, single centre study during the period June 2006 to December 2011. RESULTS: A total of 97 candidaemia episodes were identified in 97 patients during the study period with an overall incidence of four episodes/10 000 admissions in adults. Crude 30-day mortality rates among patients with candidaemia were 56% (55 of 97 cases). Urinary catheterization, immunosuppressive therapy, acute physiology and chronic health evaluation (APACHE) II score (>= 16) and hypoalbuminaemia were found to be independent risk factors for fatal candidaemia. CONCLUSIONS: Adult cases with candidaemia who have risk factors associated with mortality are more likely to have poor prognosis despite appropriate and timely initiated antifungal drug treatment. Empiric antifungal drug should be tailored according to the severity of the patients' conditions and local antifungal susceptibility. PMID- 25014859 TI - Knowledge and Attitudes toward HPV and the HPV Vaccines in The Bahamas. AB - OBJECTIVE: High-risk types of human papillomavirus (HPV) are a necessary, albeit not sufficient, cause for cervical cancer development. In The Bahamas, cervical cancer is one of the leading causes of cancer despite screening and educational efforts. As a vaccine programme is being considered, awareness of HPV-related conditions and its vaccine needs to be measured. METHODS: This study design was cross-sectional and carried out at three clinical sites and one community in Nassau, Bahamas. All participants were over the age of 18 years and were invited to answer a (self-administered) questionnaire regarding knowledge and attitudes toward HPV and its vaccines. RESULTS: Of 399 participants, 75% were female and 23% male. About 41% had a high school education and 55.4% had some tertiary college education. Forty-six per cent had heard of HPV and 35% heard of the vaccine. The mean number of correct answers about HPV was 2.93 +/- 3.17 of 10 questions, while for the vaccine, it was 1.37 +/- 1.58 of five questions. Multivariable logistic regression indicated that some college education was associated with more HPV and HPV vaccine knowledge. Seventy-three per cent needed reassurance of the vaccine's safety and efficacy. Sixty-five per cent would vaccinate their daughters and 68% would vaccinate their sons if the vaccine was safe and effective. CONCLUSION: More public education is needed to increase awareness of cervical cancer and HPV-related diseases. Reassurance with respect to vaccine safety and efficacy also needs to be addressed. Since the majority would vaccinate their children, there is the potential for a national vaccination programme to succeed. PMID- 25014860 TI - Length of Stay and Outcome of Hospitalized Chronic Obstructive Pulmonary Disease Patients, Differences between General Medical Ward and Intensive Care Unit: A Cohort Study. AB - BACKGROUND: Exacerbations of Chronic Obstructive Pulmonary Disease (ECOPD) are a major problem worldwide and usually a leading cause for hospitalizations and in some cases, indication for invasive mechanical ventilation (IMV). OBJECTIVE: The aim of this study was to determine the length of stay in hospital and outcome of ECOPD patients. We compared the length of hospital stay in the medical ward, intensive care unit (ICU) departments and discharges during a period of six months. METHODS: This was an observational, longitudinal prospective study of 242 COPD patients that were admitted with COPD exacerbation. In each patient, acute physiology and chronic health evaluation (APACHE) II score and serial arterial blood gases (ABG) were measured upon and during admission. RESULTS: Eighty per cent (194) of 242 COPD patients were admitted to the medical department and most of them were discharged within five days. Forty-eight needed IMV and stayed in hospital more than ten days; overall mortality rate was about 5%. CONCLUSION: Most of the hospitalized patients with COPD exacerbation (60%) were discharged within five days, 20% needed IMV and stayed in hospital more than ten days. PMID- 25014861 TI - Incidences and Clinical Implications of Communications between Musculocutaneous Nerve and Median Nerve in the Arm - A Cadaveric Study. AB - OBJECTIVES: Variations such as communications between median nerve and musculocutaneous nerve or in their abnormal branching pattern constitute a major concern in clinical and surgical field. Knowledge of these variations not only provides the clinician with a proper interpretation of the case, but also minimizes the complication in surgical approaches in this region. METHOD: We examined 50 isolated upper limbs to investigate the possible incidences of various types of communications between these two neighbouring peripheral nerves. RESULT: Twenty-eight per cent of limbs were found to have communication between these two nerves. When categorized according to Venieratos and Anagnostopoulou's classification method, 11 out of 14 cases (79%) showed type I communications, two out of 14 (14%) showed type II and the remaining one (7%) showed type III communication pattern. CONCLUSION: Prior knowledge of communications between these two neighbouring nerves, both in terms of their incidences and pattern of communications, may be of considerable significance to neurologists and orthopaedic surgeons in dealing with nerve entrapment syndromes in the upper limb of patients. PMID- 25014862 TI - Stabilizing Effects of a Particulate Demineralized Bone Matrix in the L4 Interbody Space with and without PEEK Cage - A Literature Review and Preliminary Results of a Cadaveric Biomechanical Study. AB - We reviewed the biological elements supporting the usefulness of a specifically designed particulate form of demineralized bone matrix (DBM) with spinal fusion, and report some limitations of its use described in the medical literature and in the interbody space using a cadaveric biomechanical model. A literature review and description of the techniques used to augment spinal fusion are presented, including a more thorough review of recent findings of cadaveric biomechanical flexibility studies using DBM alone at different percentage fills of the existing disc space and DBM with a polyetheretherketone (PEEK) interbody cage. The need for DBM was established by reviewing limitations of autografts and allografts in spinal fusion. Demineralized bone matrix used alone did not increase stability post discectomy at L4-L5, but was demonstrated to exhibit satisfactory stability when used with a PEEK interbody cage. There may be a future role for DBM that hardens and fills disc space more rigidly, overcoming this limitation to its use. PMID- 25014863 TI - Microwave hyperthermia in conjunction with radiotherapy in superficial tumours: correlation of thermal parameters with tumour regression. AB - OBJECTIVE: The aim of the present study is to evaluate the correlation between the thermal parameters of hyperthermia and the clinical outcome in patients with superficial tumours. METHODS: In this study, 20 patients were included with either submandibular lymph nodes from head and neck cancer, or breast cancer relapses post-mastectomy. They were treated with radiation in combination with one session of 433 MHz microwave hyperthermia (1 hour, 42.5 degrees C-46 degrees C). The dose of irradiation ranged from 54 to 60 Gy. The thermal parameters calculated were the minimum volume temperature, the maximum volume temperature and the time interval where the volume temperature was greater than 44 degrees C. RESULTS: All patients responded positively to the combined treatment and 60% of the patients showed a complete response. Of the three parameters tested, the only parameter that was found to correlate with the reduction of the tumour diameter was the time with volume temperatures greater than 44 degrees C (p < 0.001, Spearman rho). No moderate toxicity was observed. CONCLUSION: Microwave heating should be over 44 degrees C for favourable treatment response, when combined with radiotherapy. More patients are needed to confirm the above results. PMID- 25014864 TI - A vision for oral and maxillofacial pathology in Jamaica. AB - Oral and maxillofacial pathology is an important bridging specialty between dentistry and medicine. This branch of dentistry is gaining special interest as a result of increasing number of oral cancer and microbial diseases. The advancements of medicine and basic medical sciences may help in directing the research in dentistry and oral and maxillofacial pathology. This paper highlights the new area and scope for oral and maxillofacial pathology in Jamaica. PMID- 25014865 TI - Sleep: A 'Wake-up' Call. AB - This report aims to attract attention toward the importance of sleep in medical students and young resident doctors. With growing stress levels among students, sleep problems have become a common affair. Concepts like sleep disorders, chronotypes, indicators of sleep deprivation are worth knowing. As found in a questionnaire-based review, significant gaps in sleep education exist today among medical students. There are many health hazards of sleep deprivation like anxiety, depression, hypertension, obesity, diabetes, increased error rate at work, breast malignancy, decreased dexterity and adverse impact on academic performance that are dealt with in this article. These issues are not covered well in the conventional didactic lectures on 'sleep' in the medical curriculum. The medical profession demands health caregivers to stay up all night and keep working. Hence, the current medical education curriculum should lay special emphasis on sleep education. PMID- 25014866 TI - 'Fishy' Make-up on the Hook for Mercury Exposure: A Case Series. AB - OBJECTIVE: This report examines the source and outcome of four Barbadian women with extremely high hair mercury concentrations (361-5617 ug/g inorganic mercury) due to topical application of mercury containing skin-lightening cosmetics. METHODS: Inorganic hair and urine mercury analysis was done at the toxicological centre laboratory of the Institut National de Sante Publique du Quebec (Standard Council of Canada accredited). The clinical examinations were performed on location at the Queen Elizabeth Hospital of Barbados. RESULTS: Urine samples [7 135 ug/L, normal < 2 ug/L] revealed elevated mercury concentrations signifying systemic exposure. Reported symptoms during the clinical examination were consistent but nonspecific to chronic mercury exposure. CONCLUSION: Evidently, cosmetics containing dangerous levels of mercury are still available for purchase in Barbados and should be entirely banned. PMID- 25014867 TI - Critical illness in energy metabolism genetic disorder: rhabdomyolysis, acute kidney injury, respiratory arrest. AB - In very long-chain acylCoA dehydrogenase deficiency (VLCAD), the activity of this enzyme is either reduced or absent with the inability to use long-chain fatty acids as energy substrates. A 25-year old male with VLCAD was admitted to the Emergency Department of Policlinico Teaching Hospital (Modena, Italy)for generalized weakness and oliguria, after a period of physical and mental stress and inadequate compliance to a long-chain fatty acid free diet. Laboratory tests were compatible with acute kidney injury. Seventy-two hours after admission, the subject had an episode of chest pain with elevated markers of myocardial necrosis. The rapid deterioration of muscular strength and the subsequent worsening respiratory failure necessitated ventilator support within the local Medical Intensive Care Unit. There, the patient showed a prompt normalization of respiratory parameters and a steady improvement of renal function. An inadequate compliance to lifestyle and dietary restriction in VLCAD may trigger severe and potentially lethal crisis. The in-hospital management of these patients calls for early intensive care admission as their conditions may deteriorate without warning. PMID- 25014868 TI - A rare cause of rhabdomyolysis from Brucella: a case report. AB - Rhabdomyolysis is caused by myocyte necrosis, which results in the release of muscular cell contents into the circulation and extracellular fluid. We present a case of rhabdomyolysis due to brucella infection without any complications. Following the treatment for brucella, creatinine kinase level was significantly reduced. Rhabdomyolysis associated with brucella is rare in children. PMID- 25014869 TI - A case report: primary melanoma of the nasal cavity. AB - We report a rare case of sinonasal mucosal malignant melanoma in the nasal cavity. The patient had respiratory difficulty, continuous epistaxis and nasal pain. We identified a malignant tumour which is a rare pathology with detailed physical examination, anterior rhinoscopy, computed tomography (CT) scan, magnetic resonance imaging (MRI) and histopathologic examination. The patient did not accept surgical procedures and was referred for chemotherapy orimmunotherapy. Continued follow-up of this is necessary. PMID- 25014870 TI - Can hashimoto thyroiditis cause massive pericardial effusion? PMID- 25014871 TI - Widespread idiopathic calcinosis cutis: a case report. PMID- 25014872 TI - Colorectal anastomotic leakage at the university hospital of the west indies: an analysis of risk factors. AB - BACKGROUND: Anastomotic leakage remains a concern in general surgical practice. The significance lies in the resultant abdominal sepsis, related morbidity and mortality, risk of anastomotic loss, permanent stoma creation and the effect on local recurrence and overall patient survival in colorectal cancer cases. OBJECTIVES: This study serves to determine the leak rates and the mortality thereof related to colonic and rectal anastomoses at the University Hospital of the West Indies (UHWI) in Kingston, Jamaica. Independent factors contributing to anastomotic leaks in these patients will also be assessed and correlations determined. METHODS: A review of the medical records of one hundred and thirty three cases of colonic and rectal anastomoses identified retrospectively over a three-year period provided relevant information for analysis. RESULTS: Anastomotic leaks were identified in twelve patients, providing a leak rate of 9.0%. No 30-day mortality related to anastomotic leakage was noted. Based on a multivariate analysis, male gender was identified as the sole independent factor related to anastomotic leakage. CONCLUSION: Colorectal anastomotic leak rates at UHWI fell at the upper limit of leak rates typically quoted in the literature. No modifiable risk factor appeared to contribute to this leak rate. Early identification and intervention is critical in limiting mortality associated with colorectal anastomotic leakage. PMID- 25014873 TI - Different effects of two cyclic chalcone analogues on redox status of Jurkat T cells. AB - Chalcones are intermediary compounds of the biosynthetic pathway of the naturally flavonoids. Previous studies have demonstrated that chalcones and their conformationally rigid cyclic analogues have tumour cell cytotoxic and chemopreventive effects. It has been shown that equitoxic doses of the two cyclic chalcone analogues (E)-2-(4'-methoxybenzylidene)-(2) and (E)-2-(4' methylbenzylidene)-1-benzosuberone (3) have different effect on cell cycle progress of the investigated Jurkat cells. It was also found that the compounds affect the cellular thiol status of the treated cells and show intrinsic (non enzyme-catalyzed) reactivity towards GSH under cell-free conditions. In order to gain new insights into the cytotoxic mechanism of the compounds, effects on the redox status and glutathione level of Jurkat cells were investigated. Detection of intracellular ROS level in Jurkat cells exposed to 2 and 3 was performed using the dichlorofluorescein-assay. Compound 2 did not influence ROS activity either on 1 or 4h exposure; in contrast, chalcone 3 showed to reduce ROS level at both timepoints. The two compounds had different effects on cellular glutathione status as well. Compound 2 significantly increased the oxidized glutathione (GSSG) level showing an interference with the cellular antioxidant defence. On the contrary, chalcone 3 enhanced the reduced glutathione level, indicating enhanced cellular antioxidant activity. To investigate the chalcone-GSH conjugation reactions under cellular conditions, a combination of a RP-HPLC method with electrospray ionization mass spectrometry (ESI-MS) was performed. Chalcone-GSH adducts could not be observed either in the cell supernatant or the cell sediment after deproteinization. The investigations provide further details of dual - cytotoxic and chemopreventive - effects of the cyclic chalcone analogues. PMID- 25014874 TI - Precision cut intestinal slices are an appropriate ex vivo model to study NSAID induced intestinal toxicity in rats. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used therapeutic agents, however, they are associated with a high prevalence of intestinal side effects. In this investigation, rat precision cut intestinal slices (PCIS) were evaluated as an ex vivo model to study NSAID-induced intestinal toxicity. Firstly, PCIS were incubated with 0-200 MUM diclofenac (DCF), one of the most intensively studied NSAIDs, to investigate whether they could correctly reflect the toxic mechanisms. DCF induced intestinal toxicity in PCIS was shown by morphological damage and ATP depletion. DCF induced endoplasmic-reticulum (ER) stress, mitochondrial injury and oxidative stress were reflected by up-regulated HSP-70 (heat shock protein 70) and BiP (binding immunoglobulin protein) gene expression, caspase 9 activation, GSH (glutathione) depletion and HO-1 (heme oxygenase 1) gene up-regulation respectively. Furthermore, DCF intestinal metabolites, which gave rise to protein adduct but not toxicity, were detected in PCIS. Secondly, PCIS were incubated with various concentrations of five NSAIDs. Typical NSAID-induced morphological changes were observed in PCIS. The ex vivo toxicity ranking (diflunisal> diclofenac = indomethacin > naproxen ? aspirin) showed good correlation with published in vitro and in vivo data, with diflunisal being the only exception. In conclusion, PCIS correctly reflect the various mechanisms of DCF-induced intestinal toxicity, and can serve as an ex vivo model for the prediction of NSAID-induced intestinal toxicity. PMID- 25014875 TI - Application of mass balance models and the chemical activity concept to facilitate the use of in vitro toxicity data for risk assessment. AB - Practical, financial, and ethical considerations related to conducting extensive animal testing have resulted in various initiatives to promote and expand the use of in vitro testing data for chemical evaluations. Nominal concentrations in the aqueous phase corresponding to an effect (or biological activity) are commonly reported and used to characterize toxicity (or biological response). However, the true concentration in the aqueous phase can be substantially different from the nominal. To support in vitro test design and aid the interpretation of in vitro toxicity data, we developed a mass balance model that can be parametrized and applied to represent typical in vitro test systems. The model calculates the mass distribution, freely dissolved concentrations, and cell/tissue concentrations corresponding to the initial nominal concentration and experimental conditions specified by the user. Chemical activity, a metric which can be used to assess the potential for baseline toxicity to occur, is also calculated. The model is first applied to a set of hypothetical chemicals to illustrate the degree to which test conditions (e.g., presence or absence of serum) influence the distribution of the chemical in the test system. The model is then applied to set of 1194 real substances (predominantly from the ToxCast chemical database) to calculate the potential range of concentrations and chemical activities under assumed test conditions. The model demonstrates how both concentrations and chemical activities can vary by orders of magnitude for the same nominal concentration. PMID- 25014876 TI - Tegaserod, a small compound mimetic of polysialic acid, promotes functional recovery after spinal cord injury in mice. AB - In a previous study, we have shown that the small organic compound tegaserod, a drug approved for clinical application in an unrelated condition, is a mimic of the regeneration-beneficial glycan polysialic acid (PSA) in a mouse model of femoral nerve injury. Several independent observations have shown positive effects of PSA and its mimetic peptides in different paradigms of injury of the central and peripheral mammalian nervous systems. Since small organic compounds generally have advantages over metabolically rapidly degraded glycans and the proteolytically vulnerable mimetic peptides, a screen for a small PSA mimetic compound was successfully carried out, and the identified molecule proved to be beneficial in neurite outgrowth in vitro, independent of its originally described function as a 5-HT4 receptor agonist. In the present study, a mouse spinal cord compression device was used to elicit severe compression injury. We show that tegaserod promotes hindlimb motor function at 6 weeks after spinal cord injury compared to the control group receiving vehicle only. Immunohistology of the spinal cord rostral and caudal to the lesion site showed increased numbers of neurons, and a reduced area and intensity of glial fibrillary acidic protein immunoreactivity. Quantification of regrowth/sprouting of axons immunoreactive for tyrosine hydroxylase and serotonin showed increased axonal density rostral and caudal to the injury site in the ventral horns of mice treated with tegaserod. The combined observations suggest that tegaserod has the potential for treatment of spinal cord injuries in higher vertebrates. PMID- 25014877 TI - Interplay between intra- and interhemispheric remodeling of neural networks as a substrate of functional recovery after stroke: adaptive versus maladaptive reorganization. AB - Brain injuries such as focal stroke initiate a myriad of neural events leading to local and remote alterations in cerebral networks. The neurochemical and neurophysiological mechanisms underlying these postlesion changes raise the question of their beneficial or adverse effects on functional recovery. In this review, we aim to reconcile findings from animal and patients studies using a "from cellular-to network-levels" perspective to gain further insights into the neuroplasticity mechanisms underlying recovery of sensorimotor functions. Ultimately, an integrative view of the multiple facets of poststroke changes should give an impetus to novel neurorehabilitation strategies by providing evidence of how neuroscience findings can be translated and operationalized within the context of restorative stroke. PMID- 25014879 TI - Re-entrant phase behavior in confined two-patch colloidal particles. AB - We present a version of density functional approach for the system of patchy colloidal particles confined in slitlike pores with hard walls. Each particle possesses two off-center sites of the types A and B, and in addition to single A A and B-B bonds, formation of the double A-B-A and B-A-B bonds is allowed. The proposed approach is based on the fundamental measure theory and the second order perturbation theory of Wertheim. For the model in question, a re-entrant phase behavior in a bulk system has been found [Kalyuzhnyi Y. V.; Cummings, P. T., J. Chem. Phys. 2013, 139, 104905] . Our calculations revealed that the re-entrant phase diagrams are also observed in confined systems. The upper critical temperature decreases with the pore width, while the lower critical temperature increases very slightly. PMID- 25014878 TI - Diagnostic efficiency of hemoglobin A1c for newly diagnosed diabetes and prediabetes in community-based Chinese adults aged 40 years or older. AB - BACKGROUND: Europeans and Americans are gradually accepting the hemoglobin A1c (HbA1c) threshold of 6.5% for diagnosing diabetes proposed by the American Diabetes Association, but the cutoff of HbA1c for the Chinese population is unclear. We evaluated the diagnostic efficiency of HbA1c for diagnosing newly diagnosed diabetes and prediabetes in community-based Chinese adults 40 years of age or older. SUBJECTS AND METHODS: In this study 8,239 subjects (5,496 women) 40 90 years of age underwent HbA1c and oral glucose tolerance test measurement after an overnight fast. Diabetes and prediabetes were defined by the World Health Organization criteria. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic efficiency of HbA1c, and the optimal cutoff was defined as the point on the receiver operating characteristic curve with the largest Youden index. Spearman correlation was used for correlation analysis. RESULTS: The prevalence of newly diagnosed diabetes and prediabetes was 10.7% (880/8,239) and 19.0% (1,564/8,239), respectively. Fasting plasma glucose and postprandial plasma glucose were positively correlated with HbA1c level (r=0.725 and r=0.673, both P<0.001, respectively). For diagnosing diabetes, the AUC was 0.857 (95% confidence interval, 0.841-0.873), and the optimal cutoff for HbA1c was 6.3%, with the largest Youden index being 0.581. For diagnosing prediabetes, the AUC was 0.681 (95% confidence interval, 0.666-0.697), and the optimal cutoff for HbA1c was 5.9%, with the largest Youden index being 0.280. CONCLUSIONS: An HbA1c threshold of 6.3% was highly valuable for diagnosing newly diagnosed diabetes, and a value of 5.9% was weakly valuable for diagnosing prediabetes in community-based Chinese adults 40 years of age or older. PMID- 25014880 TI - Analysis of the transcriptome and immune function of monocytes during IFNalpha based therapy in chronic HCV revealed induction of TLR7 responsiveness. AB - Although in vitro studies have been performed to dissect the mechanism of action of IFNalpha, detailed in vivo studies on the long-term effects of IFNalpha on monocytes have not been performed. Here we examined peripheral blood from 14 chronic HCV patients at baseline and 12 weeks after start of IFNalpha-based therapy. Monocytes were phenotyped by flow-cytometry and their function evaluated upon TLR stimulation and assessed by multiplex cytokine assays. During therapy of HCV patients, monocytes displayed a hyperactive state as evidenced by increased TLR-induced pro-inflammatory cytokine levels, as well as enhanced CD69 and CD83 mRNA and protein expression. Moreover, monocytes from 8 patients at baseline and 12 weeks after start of IFNalpha-based therapy were transcriptomically profiled by high throughput RNA-sequencing. Detailed RNA-seq analysis of monocytes showed significant ISG mRNA induction during therapy. Importantly, IFNalpha-based therapy activated TLR7 signaling pathways, as demonstrated by up-regulated expression of TLR7, MyD88, and IRF7 mRNA, whereas other TLR family members as well as CD1c, CLEC4C, and CLEC9A were not induced. The induction of TLR7 responsiveness of monocytes by IFNalpha in vivo in HCV patients is relevant for the development of TLR7 agonists that are currently under development as a promising immunotherapeutic compounds to treat chronic viral hepatitis. PMID- 25014881 TI - Probing the active conformation of FGLamide allatostatin analogs with N-terminal modifications using NMR spectroscopy and molecular modeling. AB - The FGLamide allatostatins (ASTs) can inhibit the production of juvenile hormone in vitro, and they therefore are regarded as possible insect growth regulator candidates for pest control. To understand the structural features of the ASTs that cause the differences in their activity the pentapeptide and four N-terminal modifications of AST analogs (H17, K9, K10 and K23) were selected to investigate their conformations. From NMR spectroscopy and molecular modeling, it is clear that K23 and K9 have a type IV beta-turn and a gamma turn in DMSO, respectively. The pentapeptide, H17 and K10 form a flexible conformation. Our study indicates that this flexible conformation could be an important and indispensable structural element for activity, whereas the turn structure may not be especially significant for biological activity. PMID- 25014882 TI - Radioactive characterization of leachates and efflorescences in the neighbouring areas of a phosphogypsum disposal site as a preliminary step before its restoration. AB - After the recent closure of certain phosphoric acid plants located in the South West of Spain, it has been decided to restore a big extension (more than six hundred hectares) of salt-marshes, where some million tonnes of phosphogypsum (PG), the main by-product generated by these plants, had been disposed of. This PG is characterized by its content of high activity concentrations of several radionuclides from the uranium series, mainly (226)Ra, (210)Pb, and (210)Po and, to a lesser extent, U-isotopes. The PG disposal area can be considered as a potential source of radionuclides into their nearby environment, through the waters which percolate from them and through the efflorescences formed in their surroundings. For this reason, a detailed radioactive characterization of the mentioned waters and efflorescences has been considered essential for a proper planning of the restoration tasks to be applied in the near future in the zone. To this end, U-isotopes, (234)Th, (230)Th, (226)Ra, (210)Pb and (210)Po activity concentrations have been determined by applying both alpha-particle and gamma-ray spectrometric techniques to selected water and efflorescence aliquots collected in the area. The analysis of the obtained results has enabled to obtain information about the geochemical behaviour in the area of the different radionuclides analyzed; and the conclusion to be drawn that, in the restoration plan under preparation, both the prohibition of outflowing waters from the disposal area to the neighbouring salt-marshes, and the removal of all the efflorescences now disseminated in their surroundings are essential. PMID- 25014883 TI - When the dust settles: stable xenon isotope constraints on the formation of nuclear fallout. AB - Nuclear weapons represent one of the most immediate threats of mass destruction. In the event that a procured or developed nuclear weapon is detonated in a populated metropolitan area, timely and accurate nuclear forensic analysis and fallout modeling would be needed to support attribution efforts and hazard assessments. Here we demonstrate that fissiogenic xenon isotopes retained in radioactive fallout generated by a nuclear explosion provide unique constraints on (1) the timescale of fallout formation, (2) chemical fractionation that occurs when fission products and nuclear fuel are incorporated into fallout, and (3) the speciation of fission products in the fireball. Our data suggest that, in near surface nuclear tests, the presence of a significant quantity of metal in a device assembly, combined with a short time allowed for mixing with the ambient atmosphere (seconds), may prevent complete oxidation of fission products prior to their incorporation into fallout. Xenon isotopes thus provide a window into the chemical composition of the fireball in the seconds that follow a nuclear explosion, thereby improving our understanding of the physical and thermo chemical conditions under which fallout forms. PMID- 25014885 TI - Multiple loading conditions analysis can improve the association between finite element bone strength estimates and proximal femur fractures: a preliminary study in elderly women. AB - This is a preliminary case-control study on osteopenic/osteoporotic elderly women, testing the association of proximal femur fracture with minimum femoral strength, as derived from finite element (FE) analysis in multiple loading conditions. Fracture cases (n=22) in acute conditions were enrolled among low trauma fractures admitted in various hospitals in the Emilia Romagna Region, Italy. Women with no history of low-trauma fractures were enrolled as controls (n=33). Patients were imaged with DXA to obtain aBMD, and with a bilateral full femur CT scan. FE-strength was derived in stance and fall configurations: (i) as the minimum strength among those obtained for multiple loading conditions spanning a domain of plausible force directions, and (ii) as the strength associated to the most commonly used single loading conditions. The association of FE-strength and aBMD with fractures was tested with logistic regression models, deriving odds ratios (ORs) and area under the receiver operating characteristic curve (AUC). FE-strength from multiple loading conditions better classified fracture cases from controls (OR per SD change=9.6, 95% CI=3.0-31.3, AUC=0.87 in stance; OR=9.5, 95% CI=2.9-31.2, AUC=0.88 in fall) compared to aBMD (OR=3.6, 95% CI=1.6-8.2, AUC=0.79 for total femur aBMD), while FE-strength results from the most commonly used single loading conditions were similar to aBMD. Only FE-strength from multiple loading conditions remained significant in age- and aBMD-adjusted models (OR=10.5, 95% CI=1.8-61.3, AUC=0.95). In summary, we highlighted the importance of considering different loading conditions to identify bone weakness, and confirmed that femoral FE-strength estimates may add value to aBMD predictions in elderly osteopenic/osteoporotic women. PMID- 25014884 TI - Tissue-nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the Alpl(-/-) mouse model of infantile hypophosphatasia. AB - Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. OBJECTIVES: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl(-/-) mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. METHODS: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. RESULTS: Alpl(-/-) mice feature craniofacial shape abnormalities suggestive of limited anterior posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl(-/-) mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. CONCLUSIONS: These findings demonstrate that Alpl(-/-) mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base. PMID- 25014886 TI - Total phosphorus reference condition for subalpine lakes: a comparison among traditional methods and a new process-based watershed approach. AB - Different methods for estimating the total phosphorus (TP) reference conditions of lakes have rarely been compared. This work tests the uncertainty and accuracy of the most frequently used approaches (Morpho-edaphic index -MEI-, export coefficient, diatoms and pigment-inferred TP models) for 35 subalpine lakes. Furthermore, we propose a new process-based watershed approach that was tested on a subalpine environment and consists of combining a space for time substitution with a space for space substitution. The possible presence of uncontaminated or less contaminated environments inside or next to the watershed can be exploited by training a hydrological transport watershed model according to the uncontaminated conditions and then applying the calibration to the entire watershed, which reconstructs a natural or semi-natural TP load scenario. We found that the root mean square error (RMSE) for the MEI is 4 MUg L(-1). However, its application is limited for lakes that present with an alkalinity <=1 meq L( 1). For lakes with a higher alkalinity, we observed a loss of predictive capability that results from the lower solubility of phosphorus under conditions of high calcium content. The export coefficient model was applied with a mean export coefficient and presents similar prediction capabilities as the MEI. The chlorophyll-inferred TP model shows a higher uncertainty (RMSE = 8 MUg L(-1)); however, it produced fewer underestimations and overestimations. With regards to the diatom-inferred TP model, we are only able to evaluate an uncertainty of 5 MUg L(-1) at the European level. Finally, the proposed process-based watershed approach adequately predicted the reference condition of the selected lake and had an uncertainty lower than the other methods (2 MUg L(-1)). We conclude by revealing the potential and limitations of this approach in the field of ecological lake modelling more and more attracted by TP pristine load inputs in studies on the effects of climate change and eutrophication of lakes. PMID- 25014887 TI - Fundamental aspects related to batch and fixed-bed sulfate sorption by the macroporous type 1 strong base ion exchange resin Purolite A500. AB - Acid mine drainage is a natural process occurring when sulfide minerals such as pyrite are exposed to water and oxygen. The bacterially catalyzed oxidation of pyrite is particularly common in coal mining operations and usually results in a low-pH water polluted with toxic metals and sulfate. Although high sulfate concentrations can be reduced by gypsum precipitation, removing lower concentrations (below 1200 mg/L) remains a challenge. Therefore, this work sought to investigate the application of ion exchange resins for sulfate sorption. The macroporous type 1 strong base IX resin Purolite A500 was selected for bath and fixed-bed sorption experiments using synthetic sulfate solutions. Equilibrium experiments showed that sulfate loading on the resin can be described by the Langmuir isotherm with a maximum uptake of 59 mg mL-resin(-1). The enthalpy of sorption was determined as +2.83 kJ mol(-1), implying an endothermic physisorption process that occurred with decreasing entropy (-15.5 J mol(-1).K( 1)). Fixed-bed experiments were performed at different bed depths, flow rates, and initial sulfate concentrations. The Miura and Hashimoto model predicted a maximum bed loading of 25-30 g L-bed(-1) and indicated that both film diffusion (3.2 * 10(-3) cm s(-1) to 22.6 * 10(-3) cm s(-1)) and surface diffusion (1.46 * 10(-7) cm(2) s(-1) to 5.64 * 10(-7) cm(2) s(-1)) resistances control the sorption process. It was shown that IX resins are an alternative for the removal of sulfate from mine waters; they ensure very low residual concentrations, particularly in effluents where the sulfate concentration is below the gypsum solubility threshold. PMID- 25014888 TI - Developing and validating a practical decision support tool (DST) for biomass selection on marginal land. AB - Marginal, often contaminated, sites exist in large areas across the world as a result of historic activities such as industry, transportation and mineral extraction. Remediation, or other improvements, of these sites is typically only considered for sites with high exploitation pressure and those posing the highest risks to human health or the environment. At the same time there is increasing competition for land resources for different needs such as biofuel production. Potentially some of this land requirement could be met by production of biomass on brownfield or other marginal land, thereby improving the land while applying the crop cultivation as part of an integrated management strategy. The design and decision making for such a strategy will be site specific. A decision support framework, the Rejuvenate DST (decision support tool) has been developed with the aim of supporting such site specific decision making. This tool is presented here, and has been tested by applying it to a number of case study sites. The consequent SWOT (strength, weakness, opportunities and threats) analysis is discussed and evaluated. The DST was found to be systematic, transparent, and applicable for diverse sites in France, Romania and Sweden, in addition to the sites to which it was applied through its development. The DST is regarded as especially useful if applied as a checklist in an iterative way throughout the decision process, from identifying potential crops to identifying knowledge gaps, working/non-working management strategies and potential risks. The DST also provides a structure promoting effective stakeholder engagement. PMID- 25014889 TI - Advancing biopharmaceutical process science through transcriptome analysis. AB - Global survey of transcriptome dynamics can provide molecular insights into cell physiology. In the past few years, DNA microarray for transcriptome analysis has been augmented by high-throughput sequencing methods; extending the reach of transcriptome analysis to the rodent species of biotechnological importance, for which the development of genomic tools has been lagging. The rapid accumulation of sequencing data for these species highlighted the need for more evidence-based annotation. Recent findings in the epigenetic regulation in human and mouse will inspire similar research in CHO and BHK cells. Transcriptome studies in these recombinant cells will likely lay the foundation for a systems-based genome engineering which can be used to develop superior producing cell lines. Herein, we summarized the recent findings and advances in transcriptome studies of cell culture bioprocesses. The potential impact of transcriptomics on biopharmaceutical process technology is also discussed. PMID- 25014890 TI - Biopharmaceutical discovery and production in yeast. AB - The selection of an expression platform for recombinant biopharmaceuticals is often centered upon suitable product titers and critical quality attributes, including post-translational modifications. Although notable differences between microbial, yeast, plant, and mammalian host systems exist, recent advances have greatly mitigated any inherent liabilities of yeasts. Yeast expression platforms are important to both the supply of marketed biopharmaceuticals and the pipelines of novel therapeutics. In this review, recent advances in yeast-based expression of biopharmaceuticals will be discussed. The advantages of using glycoengineered yeast as a production host and in the discovery space will be illustrated. These advancements, in turn, are transforming yeast platforms from simple production systems to key technological assets in the discovery and selection of biopharmaceutical lead candidates. PMID- 25014891 TI - Prophylactic and therapeutic vaccination with a nanoparticle-based peptide vaccine induces efficient protective immunity during acute and chronic retroviral infection. AB - Retroviral infections e.g. HIV still represent a unique burden in the field of vaccine research. A common challenge in vaccine design is to find formulations that create appropriate immune responses to protect against and/or control the given pathogen. Nanoparticles have been considered to be ideal vaccination vehicles that mimic invading pathogens. In this study, we present biodegradable calcium phosphate (CaP) nanoparticles, functionalized with CpG and retroviral T cell epitopes of Friend virus (FV) as excellent vaccine delivery system. CaP nanoparticles strongly increased antigen delivery to antigen-presenting cells to elicit a highly efficient T cell-mediated immune response against retroviral FV infection. Moreover, single-shot immunization of chronically FV-infected mice with functionalized CaP nanoparticles efficiently reactivated effector T cells which led to a significant decrease in viral loads. Thus, our findings clearly indicate that a nanoparticle-based peptide immunization is a promising approach to improve antiretroviral vaccination. FROM THE CLINICAL EDITOR: In this study, biodegradable calcium phosphate nanoparticles were used as a vaccine delivery system after functionalization with CpG and Friend virus-derived T-cell epitopes. This vaccination strategy resulted in increased T-cell mediated immune response even in chronically infected mice, providing a promising approach to the development of clinically useful antiretroviral vaccination strategies. PMID- 25014892 TI - Effect of lipidated gonadotropin-releasing hormone peptides on receptor mediated binding and uptake into prostate cancer cells in vitro. AB - Gonadotropin-releasing hormone (GnRH) receptors are overexpressed on many cancer cells but not on primary cell lines. This study was designed to investigate the targeting ability and uptake of dendritic lipidated [Gln(1)]-GnRH peptide analogues on receptor-positive prostate cancer PC-3 cells relative to receptor negative ovarian carcinoma SKOV-3 cells for potential application in drug delivery. Direct antiproliferative effect of these was investigated on three GnRH receptor positive cancer cells, PC-3, LNCaP and DU145. A significant dose dependent growth inhibitory effect was produced in DU145 cells by 5 dendrimers giving an IC50 value of 22-35 MUM. All compounds were non-toxic to the normal peripheral blood mononuclear cells. FROM THE CLINICAL EDITOR: This study demonstrates the use of specific dendritic lapidated GnRH analogues in growth inhibition of GnRH receptor positive prostate cancer cell lines, suggesting potential future clinical use of this or similar strategies to address GnRH receptor positive cancer cells. PMID- 25014894 TI - Public health emergency planning for children in chemical, biological, radiological, and nuclear (CBRN) disasters. AB - Children represent nearly a quarter of the US population, but their unique needs in chemical, biological, radiological, and nuclear (CBRN) emergencies may not be well understood by public health and emergency management personnel or even clinicians. Children are different from adults physically, developmentally, and socially. These characteristics have implications for providing care in CBRN disasters, making resulting illness in children challenging to prevent, identify, and treat. This article discusses these distinct physical, developmental, and social traits and characteristics of children in the context of the science behind exposure to, health effects from, and treatment for the threat agents potentially present in CBRN incidents. PMID- 25014893 TI - Transcriptional network control of normal and leukaemic haematopoiesis. AB - Transcription factors (TFs) play a key role in determining the gene expression profiles of stem/progenitor cells, and defining their potential to differentiate into mature cell lineages. TF interactions within gene-regulatory networks are vital to these processes, and dysregulation of these networks by TF overexpression, deletion or abnormal gene fusions have been shown to cause malignancy. While investigation of these processes remains a challenge, advances in genome-wide technologies and growing interactions between laboratory and computational science are starting to produce increasingly accurate network models. The haematopoietic system provides an attractive experimental system to elucidate gene regulatory mechanisms, and allows experimental investigation of both normal and dysregulated networks. In this review we examine the principles of TF-controlled gene regulatory networks and the key experimental techniques used to investigate them. We look in detail at examples of how these approaches can be used to dissect out the regulatory mechanisms controlling normal haematopoiesis, as well as the dysregulated networks associated with haematological malignancies. PMID- 25014895 TI - Photo-enhanced antinodal conductivity in the pseudogap state of high-Tc cuprates. AB - A major challenge in understanding the cuprate superconductors is to clarify the nature of the fundamental electronic correlations that lead to the pseudogap phenomenon. Here we use ultrashort light pulses to prepare a non-thermal distribution of excitations and capture novel properties that are hidden at equilibrium. Using a broadband (0.5-2 eV) probe, we are able to track the dynamics of the dielectric function and unveil an anomalous decrease in the scattering rate of the charge carriers in a pseudogap-like region of the temperature (T) and hole-doping (p) phase diagram. In this region, delimited by a well-defined T*neq(p) line, the photoexcitation process triggers the evolution of antinodal excitations from gapped (localized) to delocalized quasiparticles characterized by a longer lifetime. The novel concept of photo-enhanced antinodal conductivity is naturally explained within the single-band Hubbard model, in which the short-range Coulomb repulsion leads to a k-space differentiation between nodal quasiparticles and antinodal excitations. PMID- 25014896 TI - Photo-convertible tagging for localization and dynamic analyses of low-expression proteins in filamentous fungi. AB - Photo-convertible fluorescent proteins (PCFPs) undergo a dramatic change in their excitation and emission spectra upon irradiation at specific wavelengths, thus rendering a different color. Dendra2 is a commercially available PCFP used to track the redistribution of proteins within cellular compartments, their life time or interactions. Before photo-conversion Dendra2 exhibits green fluorescence, which becomes red after irradiation with either UV or blue lights. Multiple studies including Dendra2 as a molecular tool have been described in eukaryotes but not in filamentous fungi. Here we present a method to tag low expression proteins from the filamentous fungus Aspergillus nidulans with Dendra2 and track their cellular dynamics. The regulator of asexual development FlbB was selected as control, a transcription factor that is expressed at low levels and can be used as a marker for the tip and nuclei of vegetative hyphae. This control provided us with a visual way to confirm the functionality of our genomic and plasmid constructs, since a non-functional FlbB protein renders a block in development and a characteristic aconidial phenotype. Our protocol combines standardized cloning and transformation procedures with the use of a mercury lamp microscope to convert and follow Dendra2 within cells. Hence, we present a rapid, simple and inexpensive method that makes tracking analysis of proteins that present technical difficulties to be followed feasible in filamentous fungi. PMID- 25014899 TI - Distinct expression profiles of stress defense and DNA repair genes in Daphnia pulex exposed to cadmium, zinc, and quantum dots. AB - The ever-increasing production and use of nanocrystaline semiconductors (Quantum dots; QDs) will inevitably result in increased appearance of these nanomaterials in the aquatic environment. However, the behavior and potential toxicity of heavy metal constituted nanoparticulates in aquatic invertebrates is largely unknown, especially with regard to molecular responses. The freshwater crustacean Daphnia pulex is a well-suited toxicological and ecological model to study molecular responses to environmental stressors. In this study, D. pulex were exposed for 48 h to sublethal doses of QDs (25% and 50% of LC50) with differing spectral properties (CdTe and CdSe/ZnS QDs) and Cd and Zn salts. Our data suggest that acute exposure to both CdSO4 and Cd-based QDs leads to Cd uptake in vivo, which was biologically supported by the observation of increased expression of metallothionein (MT-1). Furthermore, Cd, Zn, and CdSe/ZnS QDs induced different patterns of gene expression regarding stress defense and DNA repair, which furthers our knowledge regarding which response pathways are affected by nanoparticulate forms of metals versus ionic forms in aquatic crustaceans. PMID- 25014898 TI - Functions of Armigeres subalbatus C-type lectins in innate immunity. AB - C-type lectins (CTLs) are a superfamily of calcium-dependent carbohydrate binding proteins containing at least one carbohydrate-recognition domain (CRD) and they are present in almost all metazoans. Insect CTLs may function as pattern recognition receptors and play important roles in innate immunity. In this study, we selected five AsCTLs from the mosquito Armigeres subalbatus, a natural vector of filarial nematodes, and performed both in vitro and in vivo studies to elucidate their functions in innate immunity. AsCTLMA15, AsCTLGA5 and AsCTL15 were mainly expressed in hemocytes, AsCTL16 was expressed in fat body, while AsCTLMA11 was expressed in both hemocytes and fat body, and only AsCTLMA11 and AsCTL16 were expressed at high levels in adult females. In vitro binding assays showed that all five recombinant AsCTLs could bind to different microbial cell wall components, including lipopolysaccharide (LPS), lipid A, peptidoglycan (PG), lipoteichoic acid (LTA), zymosan and laminarin (beta-1,3-glucan). Recombinant AsCTLs also bound to several Gram-negative and Gram-positive bacteria, and could agglutinate bacterial cells. Injection of double-stranded RNAs (dsRNAs) could significantly reduce expression of the five AsCTL mRNAs, and the survival of mosquitoes treated with dsRNA to AsCTLGA5 was significantly decreased after Escherichia coli infection, but did not change significantly after Micrococcus luteus infection compared to the control groups, suggesting that Ar. subalbatus AsCTLGA5 may participate in innate immunity against E. coli. PMID- 25014900 TI - Occurrence of Pseudomonas aeruginosa in Kuwait soil. AB - Environmentally ubiquitous bacteria such as Pseudomonas aeruginosa evolved mechanisms to adapt and prevail under diverse conditions. In the current investigation, strains of P. aeruginosa demonstrating high rates of crude oil utilization and tolerance to high concentrations of heavy metals were found in both crude oil-contaminated and uncontaminated sites in Kuwait, and were dominant in the contaminated sites. The incidence of P. aeruginosa in tested soils implies the definitive pattern of crude oil contamination in the selection of the bacterial population in petroleum-contaminated sites in Kuwait. Surprisingly, the unculturable P. aeruginosa in different soil samples showed significant high similarity coefficients based on 16S-RFLP analyses, implying that the unculturable fraction of existing bacterial population in environmental samples is more stable and, hence, reliable for phylogenetic studies compared to the culturable bacteria. PMID- 25014901 TI - Determining the effects of a mixture of an endocrine disrupting compound, 17alpha ethinylestradiol, and ammonia on fathead minnow (Pimephales promelas) reproduction. AB - Aquatic organisms are exposed to a multitude of contaminants and to fully understand the impact of multiple stressors on fish populations, we must first understand the mechanism of action for each toxicant and how the combined effects manifest at the level of the individual. 17alpha-ethinylestradiol (EE2) has been known to cause adverse reproductive effects including reduced fecundity and fertility, intersex and skewed sex ratios in fish by mimicking naturally produced estrogen at low concentrations. Ammonia can cause adverse reproductive and mortality effects in individual fish through effects or damage to the central nervous system. Both EE2 and ammonia are found in most municipal effluents in various concentrations. A flow-through diluter system was used to test the individual effects of these two contaminants at their respective no observable adverse effect concentration (NOAEC) as well as their combined effects on fathead minnow, (Pimephales promelas) reproduction in a mixture exposure. While neither contaminant nor their mixture altered reproduction in terms of fecundity, their mixture resulted in significant fathead minnow mortality during a 21 d exposure. This study demonstrated the need to consider mixture effects when assessing risk for toxicity testing with multiple stressors. PMID- 25014902 TI - Microcystin-LR impairs zebrafish reproduction by affecting oogenesis and endocrine system. AB - Previous studies have shown that microcystins (MCs) are able to exert negative effects on the reproductive system of fish. However, few data are actually available on the effects of MC-LR on the reproductive system of female fish. In the present study, female zebrafish were exposed to 2, 10, and 50 MUg L(-1) of MC LR for 21 d, and its effects on oogenesis, sex hormones, transcription of genes on the hypothalamic-pituitary-gonad (HPG) axis, and reproduction were investigated for the first time. It was observed that egg production significantly declined at ? 10 MUg L(-1) MC-LR. MC-LR exposure to zebrafish increased the concentrations of 17beta-estradiol (E2) and vitellogenin (VTG) at 10 MUg L(-1) level, whereas concentrations of E2, VTG and testosterone declined at 50 MUg L(-1) MC-LR. The transcriptions of steroidogenic pathway gene (cyp19a, cyp19b, 17betahsd, cyp17 and hmgra) changed as well after the exposure and corresponded well with the alterations of hormone levels. A number of intra- and extra-ovarian factors, such as gnrh3, gnrhr1, fshbeta, fshr, lhr, bmp15, mrpbeta, ptgs2 and vtg1 which regulate oogenesis, were significantly changed with a different dose-related effect. Moreover, MC-LR exposure to female zebrafish resulted in decreased fertilization and hatching rates, and may suggest the possibility of trans-generational effects of MC-LR exposure. The results demonstrate that MC-LR could modulate endocrine function and oogenesis, eventually leading to disruption of reproductive performance in female zebrafish. These data suggest there is a risk for aquatic population living in MC polluted areas. PMID- 25014903 TI - Mercury, APOE, and child behavior. AB - Methylmercury (MeHg) is a neurotoxicant and may have an adverse impact on child behavior. However, this impact was found to be inconsistent in fish-eating populations. Although the positive effects of the nutrients provided by a fish diet may overcome the effect of MeHg, the possibility of genetic variants influencing an individual's response to MeHg has also been discussed. The role of the Apolipoprotein E (APOE) epsilon 4 allele (epsilon4) on MeHg related neurotoxicity is still unclear. In the present study, we investigated the role of APOE variants in the relationship between cord blood mercury (Hg) and child behavior. A total of 166 subjects were recruited at delivery, and their cord blood was collected for laboratory analyses of Hg and the APOE genotype. The Child Behavior Checklist (CBCL) was administered to the subjects when they reached the age of two years. An increase in cord blood Hg concentrations in APOE epsilon4 carriers was consistently associated with an increased score for all CBCL syndromes. After controlling for potential confounding factors, the group of epsilon4 carriers with an elevated cord blood Hg concentration had significantly higher scores in the syndrome categories of general internalizing, emotionally reactive, and anxiety/depression as well as CBCL total scores. Furthermore, general externalizing and aggressive syndromes were borderline significantly higher in this group. In conclusion, we suggest that APOE may modify the toxicity of MeHg. APOE epsilon4 carriers may be more vulnerable to the effects of MeHg on child behavior at the age of two years. PMID- 25014904 TI - Four CISH paralogues are present in rainbow trout Oncorhynchus mykiss: differential expression and modulation during immune responses and development. AB - Suppressor of cytokine signalling (SOCS) family members are crucial in the control and attenuation of cytokine induced responses via activation of the JAK/STAT, TLR and NF-kB signalling pathways. SOCS proteins orchestrate the termination of many types of immune responses and are often the targets of microbial pathogens exploiting SOCS mechanisms to evade the host's immune response. Through whole and lineage specific genome duplication events, the teleost cytokine/SOCS network is complex. Not only are the orthologues of all mammalian SOCS members present, namely cytokine inducible Src homology 2 (SH2) containing protein (CISH) and SOCS-1 to -7, but multiple gene copies exist that may potentially become functionally divergent. In this paper we focus on the CISH genes in rainbow trout (Oncorhynchus mykiss), and have cloned two further paralogues, CISHa2 and CISHb2, additional to the known CISHa1 and CISHb1 genes. We present for the first time a comparative expression analysis of these four paralogues, to establish whether subfunctionalisation is apparent. In vivo examination of gene expression revealed a higher constitutive expression level of CISHa paralogues compared to CISHb expression in adult trout tissues. All CISHs were relatively highly abundant in immune tissues but CISHa2 and CISHb2 had highest expression in the heart and muscle. An inverse picture of CISH abundance during trout ontogeny was seen, and further hints at differential roles of the four genes in immune regulation and development. Stimulation of head kidney (HK) leukocytes with trout recombinant interleukin (rIL)-15 and rIL-21 had a major effect on CISHa2 and to a lesser extent CISHa1 expression. In HK macrophages rIL 1beta, phytohemagglutinin, and phorbol 12-myristate 13-acetate also had a strong impact on CISHa2 expression. Yersinia ruckeri infection caused a temporally and spatially differential onset of CISH expression that may be viewed in the context of pathogen evasion strategies. These data, against the backdrop of fish specific whole genome duplication events and functional divergence, provide the first evidence for differential roles of the four trout CISH genes in immune control and development. PMID- 25014905 TI - Prevalence of antibodies to Toxoplasma gondii in South Korean wild boar (Sus scrofa coreanus). AB - Abstract Toxoplasma gondii is an obligate intracellular protozoan parasite and a commonly encountered pathogen in humans and animals. The wild boar (Sus scrofa coreanus) is considered a good indicator when monitoring environmental contamination by T. gondii. We surveyed the prevalence of antibodies against T. gondii in wild boars from South Korea. Blood samples were collected from 426 wild boars captured in eight provinces of South Korea during the hunting seasons in 2008-12. Antibodies against T. gondii were detected using an indirect enzyme linked immunosorbent assay in samples from 152 of boars, indicating an overall antibody prevalence of 36% (95% confidence interval=31-40%). PMID- 25014906 TI - Chemical immobilization and anesthesia of free-living aardvarks (Orycteropus afer) with ketamine-medetomidine-midazolam and isoflurane. AB - Abstract We evaluated the effectiveness of a ketamine-medetomidine-midazolam drug combination administered intramuscularly by remote injection followed by isoflurane anesthesia in free-living aardvarks (Orycteropus afer). Seven aardvarks weighing 33-45 kg were immobilized to perform surgical implantation of temperature loggers using 3.8 mg/kg ketamine, 0.1 mg/kg medetomidine, and 0.25 mg/kg midazolam. Immobilized aardvarks were transported to a surgical theater and received 0.5-1% isoflurane in oxygen after tracheal intubation. After surgery, medetomidine was antagonized with 0.5 mg/kg atipamezole, and aardvarks were released at the site of capture. We recorded induction and recovery times, clinical and physiologic parameters, and conducted blood gas analyses before and during isoflurane administration. Aardvarks showed initial effects within 3 min and reached lateral recumbency within 7 min after drug administration. Heart rate (50-67 beats/min), respiratory rate (10-15 breaths/min), oxygen hemoglobin saturation (SaO2; 90-97%), and rectal temperature (34.0-37.5 C) were within acceptable physiologic ranges. Mean arterial blood pressure was initially high (146 +/- 12 mmHg), but the hypertension resolved over time. Rectal temperature dropped significantly during anesthesia. Four animals had to be treated to relieve apnea. Blood gas analyses revealed mild to moderate hypercapnia but no hypoxaemia. The ketamine-medetomidine-midazolam combination provided effective immobilization. Combined with a low concentration of isoflurane, it can be used for prolonged surgical procedures in wild aardvarks. However, caution is needed, and monitoring of clinical parameters is required. PMID- 25014907 TI - Use of acepromazine and medetomidine in combination for sedation and handling of Rocky Mountain elk (Cervus elaphus nelsoni) and black bears (Ursus americanus). AB - We opportunistically evaluated a combination of acepromazine maleate and medetomidine HCl for use in sedating Rocky Mountain elk (Cervus elaphus nelsoni) and black bears (Ursus americanus) as an alternative to scheduled drug combinations. This combination was safe and effective with limitations inherent in its sedative rather than anesthetic properties. PMID- 25014909 TI - GPCRserver: an accurate and novel G protein-coupled receptor predictor. AB - G protein coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, pass through the cellular membrane seven times and play diverse biological roles in the cells such as signaling, transporting of molecules and cell-cell communication. In this work, we develop a web server, namely the GPCRserver, which is capable of identifying GPCRs from genomic sequences, and locating their transmembrane regions. The GPCRserver contains three modules: (1) the Trans-GPCR for the transmembrane region prediction by using sequence evolutionary profiles with the assistance of neural network training, (2) the SSEA-GPCR for identifying GPCRs from genomic data by using secondary structure element alignment, and (3) the PPA-GPCR for identifying GPCRs by using profile-to profile alignment. Our predictor was strictly benchmarked and showed its favorable performance in the real application. The web server and stand-alone programs are publicly available at . PMID- 25014908 TI - Surveillance for Baylisascaris procyonis in raccoons (Procyon lotor) from Wyoming, USA. AB - Baylisascaris procyonis is a common roundworm of raccoons that causes severe clinical disease in many vertebrates, including humans. The distribution of B. procyonis in the US is poorly documented in portions of its range and has not been reported from Wyoming. Our objectives were to determine the statewide distribution and prevalence of this parasite in raccoons in Wyoming, using intestinal and fecal examinations. We examined 363 raccoons from 23 Wyoming counties in 2009-11, testing the reliability of two methods (intestinal extrusion and incision) to determine worm burdens. We found 163 raccoons (45%) positive for B. procyonis. The two methods of examination did not differ, although extrusion missed some infections. Neither age nor sex affected apparent prevalence or worm burdens. Prevalence did not differ with land use, yet burden was highest among rural raccoons. Fecal examination revealed that juvenile raccoons had a higher proportion of patent infections than adults, but neither sex nor location were indicators of prevalence. Egg density (eggs per gram of feces) did not differ by sex or age; however, rural raccoons had higher egg densities than urban/suburban animals. Understanding the distribution and prevalence of B. procyonis in Wyoming, especially in and around highly populated areas, is an important step in educating the general public and medical community on the potential risks of raccoon roundworm infection. PMID- 25014910 TI - Cerebral microvasculature resistance to acute endothelin-1-induced functional down-regulation in rat. PMID- 25014911 TI - Hemorheology, ankle brachial pressure index (ABPI) and toe brachial pressure index (TBPI) in metabolic syndrome. AB - INTRODUCTION: Microvascular dysfunction is associated with metabolic syndrome (MetS) and its components. The objective of our study was to assess macro and microvascular abnormalities in MetS and compare the strength of association of the ankle brachial pressure index (ABPI), toe brachial pressure index (TBPI) and hemorheological parameters with MetS. MATERIALS AND METHODS: 100 participants were recruited from a rural Australian town. Anthropometric measurements were taken along with blood pressures (BP) at the arm, the ankle and the big toe for calculating ABPI and TBPI. Whole blood viscosity (WBV), erythrocyte aggregation, erythrocyte deformability, lipid profile and blood sugar level were analyzed. Recruited participants were classified into MetS and non-MetS following National Cholesterol Education Program Adult Treatment Panel III definition. Data were analyzed by IBM SPSS 20 software. RESULTS: WBV and erythrocyte aggregation were higher whereas erythrocyte deformability was lower in participants with MetS when compared to participants without MetS. Age, sex and diabetes mellitus adjusted odds ratio for predicting MetS was not significant for ABPI and TBPI whereas it was significant for hemorheological parameters. Receiver Operating Characteristics curve showed that TBPI better classified MetS than ABPI but association of hemorheological parameters was superior to that of ABPI and TBPI with MetS. CONCLUSIONS: Both microcirculation defects and macrovascular circulation defects were present in MetS. The concurrences of the components of MetS could have an additive effect in enhancing alterations in hemorheological parameters which may give rise to severe microvasculopathy. The association of hemorheological parameters was stronger than the association of TBPI and ABPI with MetS. PMID- 25014912 TI - Turning a band insulator into an exotic superconductor. AB - Understanding exotic, non-s-wave-like states of Cooper pairs is important and may lead to new superconductors with higher critical temperatures and novel properties. Their existence is known to be possible but has always been thought to be associated with non-traditional mechanisms of superconductivity where electronic correlations play an important role. Here we use a first principles linear response calculation to show that in doped Bi2Se3 an unconventional p-wave like state can be favoured via a conventional phonon-mediated mechanism, as driven by an unusual, almost singular behaviour of the electron-phonon interaction at long wavelengths. This may provide a new platform for our understanding of superconductivity phenomena in doped band insulators. PMID- 25014913 TI - Pyrazine-derived disulfide-reducing agent for chemical biology. AB - For fifty years, dithiothreitol (DTT) has been the preferred reagent for the reduction of disulfide bonds in proteins and other biomolecules. Herein we report on the synthesis and characterization of 2,3-bis(mercaptomethyl)pyrazine (BMMP), a readily accessible disulfide-reducing agent with reactivity under biological conditions that is markedly superior to DTT and other known reagents. PMID- 25014914 TI - Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. AB - In the current study, we aimed to investigate the transcriptomic responses and identify specific molecular signatures of low-molecular-weight saturated aliphatic aldehydes (LSAAs). To evaluate the change in gene expression levels, A549 human alveolar epithelial cells were exposed to six LSAAs (propanal, butanal, pentanal, hexanal, heptanal, and octanal) for 48 h. Clustering analysis of gene expression data show that the low carbon number group (LCG; propanal, butanal, and pentanal) was distinguished from the high carbon number group (HCG; hexanal, heptanal, and octanal). Also, transcriptomic profiling indicates that the LCG exposure group was more sensitive in gene alterations than the HCG group. Supervised analysis revealed 703 LCG specific genes and 55 HCG specific genes. After gene ontology (GO) analysis on LCG specific genes, we determined several key pathways which are known as being related to increase pulmonary toxicity such as cytokine-cytokine receptor interaction and chemokine signaling pathway. However, we did not find pulmonary toxicity-related pathways through GO analysis on HCG specific genes. Genes that are expressed in only the low carbon LSAA exposure group were regarded as biomarkers of aldehyde-induced pulmonary toxicity. In conclusion, this study describes changes in gene expression profiles in the in vitro respiratory system in response to exposure to 6 LSAAs with different carbon numbers and relates these gene alterations to pulmonary toxicity related pathways. Moreover, novel carbon number-specific genes and pathways can be more widely implemented in combination with the traditional technique for assessment and prediction of exposure to environmental toxicants. PMID- 25014915 TI - Do the changes in temperature and light affect the functional response of the benthic mud snail Heleobia australis (Mollusca: Gastropoda)? AB - The aim of this study was to determine the influence of temperature increase combined to conditions of light incidence on functional response of Heleobia australis. Experiments were conducted using nine to ten food concentrations for each treatment: 20 degrees C without light; 30 degrees C without light and, 30 degrees C under low light intensity. For each experiment, the functional response type III (sigmoidal) was fitted and equation parameters were determined. Results suggest that, if the sediment temperature increases, H. australis will not have its ingestion rates affected negatively, whilst its feeding behavior seems to be negatively affected by light. Ingestion rates estimated for organic content in the Guanabara Bay were: 0.34 ugC ind-1h-1 at 20 degrees C without light, 1.44 ugC ind-1h-1 at 30 degrees C without light and 0.64 ugC ind-1h-1 at 30 degrees C under light incidence. Higher ingestion rates were estimated at the high temperature, even under light incidence, and temperature seems to have outweighed the light effect. In contrast, if higher carbon content is considered, despite high temperature, the experiment conducted with light incidence showed lower ingestion rates than those from the experiment at 20 degrees C without light. This study provides the first quantification of H. australis ingestion rates and the effects that changes in temperature and light have on its feeding behavior. PMID- 25014916 TI - Phytochemical profile and antimicrobial properties of Lotus spp. (Fabaceae). AB - The phytochemical profile and antimicrobial activity of cultivar (cv.) extracts of Lotus uliginosus (cvs. Trojan and Serrano), L. tenuis (cv. Larranaga) and L. corniculatus (cv. Sao Gabriel) were investigated. The phytochemical analysis revealed tannins, coumarins and flavonoids in all extracts, with variations among cultivars, showing genotypic variability. By High Performance Liquid Chromatographic method, the cvs. Larranaga and Sao Gabriel showed the highest percentage of catechin and epicatechin, respectively, and presented rutin, which was not detected in the other ones. These genotypes showed antifungal activity but not antibacterial one. The cv. Larranaga inhibited the mycelia growth of Alternaria sp. and Fusarium graminearum while the cv. Sao Gabriel was active only against Alternaria sp. The cultivars showed the greatest amounts of secondary metabolites and demonstrated significant activity against filamentous fungi. The results provide a direction for further research about pharmacological use of Lotus spp. PMID- 25014917 TI - Morphometric differences of Microgramma squamulosa (Kaulf.) de la Sota (Polypodiaceae) leaves in environments with distinct atmospheric air quality. AB - Plants growing in environments with different atmospheric conditions may present changes in the morphometric parameters of their leaves. Microgramma squamulosa (Kaulf.) de la Sota is a neotropical epiphytic fern found in impacted environments. The aims of this study were to quantitatively compare structural characteristics of leaves in areas with different air quality conditions, and to identify morphometric parameters that are potential indicators of the effects of pollution on these plants. Fertile and sterile leaves growing on isolated trees were collected from an urban (Estancia Velha) and a rural (Novo Hamburgo) environment, in Rio Grande do Sul, Brazil. For each leaf type, macroscopic and microscopic analyses were performed on 192 samples collected in each environment. The sterile and fertile leaves showed significantly greater thickness of the midrib and greater vascular bundle and leaf blade areas in the rural environment, which is characterized by less air pollution. The thickness of the hypodermis and the stomatal density of the fertile leaves were greater in the urban area, which is characterized by more air pollution. Based on the fact that significant changes were found in the parameters of both types of leaves, which could possibly be related to air pollutants, M. squamulosa may be a potential bioindicator. PMID- 25014918 TI - First record of an anomalously colored franciscana dolphin, Pontoporia blainvillei. AB - On October 2011, a newborn franciscana dolphin with an anomalously coloration was sighted in Babitonga Bay, southern Brazil. The calf was totally white. Besides the potential mother and newborn, the group also had the presence of another adult, who always was swimming behind the pair. Both adults had the typical coloration of the species, with the back in grayish brown. The group, composed by the white franciscana calf, his pontential mother and one more adult, was reported in five occasions. The group was always in the same area where it was first recorded and showed the same position during swimming. Between first and last sighting of the white calf (113 days) the color has not changed. This is the first case of a white franciscana dolphin. This coloration has never been reported despite the high number of dead franciscanas recovered each year along the distribution of the species, resulting from accidental capture in fishing nets. This fact leads us to believe that this is a very rare characteristic for this species. We considered the possibility that this franciscana could be an albino dolphin. PMID- 25014920 TI - Acceptance of cravings: how smoking cessation experiences affect craving beliefs. AB - Metacognitive models theorize that more negative appraisals of craving-related thoughts and feelings, and greater efforts to avoid or control these experiences, exacerbate suffering and increase chances the person will use substances to obtain relief. Thus far, little research has examined how attempts to quit smoking influence the way people perceive and respond to cravings. As part of a larger study, 176 adult smokers interested in quitting participated in two lab sessions, four days apart. Half the sample began a quit attempt the day after the first session; craving-related beliefs, metacognitive strategies, and negative affect were assessed at the second session. Participants who failed to abstain from smoking more strongly endorsed appraisals of craving-related thoughts as negative and personally relevant. Negative appraisals correlated strongly with distress and withdrawal symptoms. Attempting to quit smoking increased use of distraction, thought suppression and re-appraisal techniques, with no difference between successful and unsuccessful quitters. Negative beliefs about cravings and rumination predicted less change in smoking one month later. Results suggest that smoking cessation outcomes and metacognitive beliefs likely have a bidirectional relationship that is strongly related to negative affect. Greater consideration of the impact of cessation experiences on mood and craving beliefs is warranted. PMID- 25014919 TI - Cell-free urinary microRNA-99a and microRNA-125b are diagnostic markers for the non-invasive screening of bladder cancer. AB - BACKGROUND: Evidence implicated the diagnostic significance of microRNAs in whole urine/urine sediments in urothelial carcinoma of the bladder (UCB). However, the contaminated blood cells in patients with haematouria significantly altered the expression profiles of urinary microRNA, influencing the test accuracy. METHODS: MicroRNA profiles of the urine supernatants of UCB patients and controls without any malignancy and profiles of malignant and corresponding normal mucosa tissues from the patients were determined by microRNA microarray and compared to identify differentially expressed microRNAs. The differential expression was verified in the tissues of an independent patient cohort by RT-qPCR. The diagnostic significance of selected microRNAs as biomarkers in the urine supernatant was investigated in the expanded cohorts. RESULTS: MicroRNA-99a and microRNA-125b were down-regulated in the urine supernatants of UCB patients. The degree of down regulation was associated with the tumor grade. A diagnostic model was developed using a combined index of the levels of microRNA-99a and microRNA-125b in the urine supernatant with a sensitivity of 86.7%, a specificity of 81.1% and a positive predicted value (PPV) of 91.8%. Discriminating between high- and low grade UCB, the model using the level of microRNA-125b alone exhibited a sensitivity of 81.4%, a specificity of 87.0% and a PPV of 93.4%. CONCLUSIONS: The results revealed a unique microRNA expression signature in the urine supernatants of UCB patients for the development of molecular diagnostic tests. An effective cell-free urinary microRNA-based model was developed using a combined index of the levels of microRNA-99a and microRNA-125b to detect UCB with good discriminating power, high sensitivity and high specificity. PMID- 25014921 TI - Journal of Music Therapy: advancing the science and practice of music therapy. PMID- 25014922 TI - The systematic review as a research process in music therapy. AB - BACKGROUND: Music therapists are challenged to present evidence on the efficacy of music therapy treatment and incorporate the best available research evidence to make informed healthcare and treatment decisions. Higher standards of evidence can come from a variety of sources including systematic reviews. OBJECTIVE: To define and describe a range of research review methods using examples from music therapy and related literature, with emphasis on the systematic review. In addition, the authors provide a detailed overview of methodological processes for conducting and reporting systematic reviews in music therapy. METHODS: The systematic review process is described in five steps. Step 1 identifies the research plan and operationalized research question(s). Step 2 illustrates the identification and organization of the existing literature related to the question(s). Step 3 details coding of data extracted from the literature. Step 4 explains the synthesis of coded findings and analysis to answer the research question(s). Step 5 describes the strength of evidence evaluation and results presentation for practice recommendations. RESULTS: Music therapists are encouraged to develop and conduct systematic reviews. This methodology contributes to review outcome credibility and can determine how information is interpreted and used by clinicians, clients or patients, and policy makers. CONCLUSIONS: A systematic review is a methodologically rigorous research method used to organize and evaluate extant literature related to a clinical problem. Systematic reviews can assist music therapists in managing the ever-increasing literature, making well-informed evidence based practice and research decisions, and translating existing music-based and nonmusic based literature to clinical practice and research development. PMID- 25014923 TI - Percussion use and training: a survey of music therapy clinicians. AB - BACKGROUND: Percussion instruments are commonly used in music therapy practice; however, the body of published literature regarding music therapy-related percussion training and practice is limited. OBJECTIVE: The purpose of our survey study was to describe: (a) clinician perspectives of their academic percussion training; (b) use of percussion testing during academic training; (c) clinician perspectives on relevance, adequacy, and importance of academic percussion training; (d) clinician perspectives of their nonacademic percussion training; and (e) current use of percussion in clinical practice. Through comparisons of these parameters, we sought to provide information that may inform future percussion use and training. METHODS: Participants were selected using an email list from the Certification Board for Music Therapists. Board-certified music therapists (MT-BC) were provided with a researcher-created survey about academic percussion training, nonacademic percussion training, and use of percussion in clinical practice. RESULTS: Survey response rate was 14.4% (611/4234). We used demographic data to address potential nonresponse error and ensure population representation for region of residence and region of academic training. Results revealed concerns about perceived adequacy of percussion training received during music therapy education (14.6% reported receiving no academic percussion training; 40.6% reported training was not adequate), and absence of percussion specific proficiency exams. Of the training received, 62.8% indicated that training was relevant; however, a majority (76.5%) recommended current music therapy students receive more percussion training on instruments and skills most relevant to clinical practice. CONCLUSIONS: Comparisons between academic training, perceived needs in academic training, and clinical usage may inform future training and clinical competency. We provide suggestions for developing future training, as well as for furthering clinical implementation and research. PMID- 25014924 TI - The types and characteristics of clients' perceptions of the Bonny method of Guided Imagery and Music. AB - BACKGROUND: Developed by Helen Bonny, Guided Imagery and Music (BMGIM) has mainly been used to assist people with mental health issues. In order to provide clients with the most effective therapy, we need to examine the BMGIM process from the clients' perspective, rather than the therapists.' Understanding the types and characteristics of clients' experiences within the BMGIM process would be helpful to therapists. In order to assess clients' experiences more objectively, a different research methodology is needed to measure and compare the perspectives of clients in the BMGIM process. OBJECTIVE: The purpose of this study was to identify the types and characteristics of perceptions in clients with mental health problems of the BMGIM experience. METHODS: Q methodology was used to characterize client BMGIM perceptions. Scores from Q samples were coded into Q sample scores in order to calculate Q sort collected from a P sample of 20 participants. Participants were involved in the Q sorting as Q sorters and P sample. Q factor analysis was conducted using the QUANL program. RESULTS: The types and characteristics of the participants' perceptions were analyzed for three segments of the BMGIM session. From a factor analysis, (a) two factors were identified in the before music experience segment, (b) three factors in the during music experience segment, and (c) three factors in the after music experience segment. CONCLUSIONS: Factors that intervened in the therapeutic process of BMGIM were obtained from participants' direct GIM experiences. The knowledge of the types and characteristics of participants' perceptions of the GIM process will help therapists deliver more effective therapeutic interventions. Q methodology may also contribute to gaining a better understanding of BMGIM process. PMID- 25014925 TI - Effects of group music therapy on quality of life, affect, and participation in people with varying levels of dementia. AB - BACKGROUND: There is substantive literature reporting the importance and benefits of music and music therapy programs for older adults, and more specifically for those with dementia. However, few studies have focused on how these programs may contribute to quality of life. OBJECTIVES: Objectives for this exploratory study were: (a) to evaluate the potential effect of group music therapy program participation on the quality of life of older people with mild, moderate, and severe dementia living in a nursing home; (b) to identify and analyze changes in affect and participation that take place during music therapy sessions; and (c) to suggest recommendations and strategies for the design of future music therapy studies with people in various stages of dementias. METHODS: Sixteen participants (15 women; 1 man), with varying level of dementia participated in 12 weekly music therapy sessions. Based on Global Deterioration Scale (GDS) scores, phases of cognitive function were as follows: mild (n = 9; GDS 3-4), moderate (n = 5; GDS 5), and severe (n = 2; GDS 6-7). Data were collected using the GENCAT scale on Quality of Life. Sessions 1, 6, and 12 were also video recorded for post-hoc analysis of facial affect and participation behaviors. RESULTS: There was no significant difference in quality of life scores from pre to posttest (z = 0.824; p =0.410). However, there was a significant improvement in median subscale scores for Emotional Well-being (z = -2.176, p = 0.030), and significant worsening in median subscale scores for Interpersonal Relations (z =-2.074; p = 0.038) from pre to posttest. With regard to affect and participation, a sustained high level of participation was observed throughout the intervention program. Expressions of emotion remained low. CONCLUSIONS: Authors discuss implications of study findings to inform and improve future research in the areas of music therapy, quality of life, and individuals with dementia. PMID- 25014927 TI - Online decoding of hidden Markov models for gait event detection using foot mounted gyroscopes. AB - In this paper, we present an approach to the online implementation of a gait event detector based on machine learning algorithms. Gait events were detected using a uniaxial gyro that measured the foot instep angular velocity in the sagittal plane to feed a four-state left-right hidden Markov model (HMM). The short-time Viterbi algorithm was used to overcome the limitation of the standard Viterbi algorithm, which does not allow the online decoding of hidden state sequences. Supervised learning of the HMM structure and validation with the leave one-subject-out validation method were performed using treadmill gait reference data from an optical motion capture system. The four gait events were foot strike, flat foot (FF), heel off (HO), and toe off. The accuracy ranged, on average, from 45 ms (early detection, FF) to 35 ms (late detection, HO); the latency of detection was less than 100 ms for all gait events but the HO, where the probability that it was greater than 100 ms was 25%. Overground walking tests of the HMM-based gait event detector were also successfully performed. PMID- 25014928 TI - Drift-free position estimation for periodic movements using inertial units. AB - Latest advances in microelectromechanical systems have made inertial units (IUs) a powerful tool for human motion analysis. However, difficulties in handling their output signals must be overcome. The purpose of this study was to develop the novel "PB-algorithm" based on polynomial data fitting, splines interpolation, and the wavelet transform, one after the other, to cancel drift disturbances in position estimation for periodic movements. High-accuracy position measurements from an optical system (Vicon Nexus 1.0) were used to validate the proposed method and comparison with another drift-correction algorithm was provided. Results indicate the accuracy with respect to the Vicon's reference signal (euclidean error lower than 54.62 * 10(-3) m and correlation coefficient higher than 0.968). A reduction of the root-mean-square error of 68.74% was obtained when the proposed two-step method was compared with a modified-band limited Fourier linear combiner. All methods were applied to data from the 30-s chair stand test, which is one of the most used clinical tests dealing with lower body strength assessment, falls prediction, and gait disorders in older adults. The relevance of this study is that after cancelling drift disturbances, and obtaining an accurate Z-position estimation, it is possible to evaluate the sit to-stand and stand-to-sit transitions from the whole test. PMID- 25014929 TI - Efficient heart sound segmentation and extraction using ensemble empirical mode decomposition and kurtosis features. AB - An efficient heart sound segmentation (HSS) method that automatically detects the location of first ( S1) and second ( S2) heart sound and extracts them from heart auscultatory raw data is presented here. The heart phonocardiogram is analyzed by employing ensemble empirical mode decomposition (EEMD) combined with kurtosis features to locate the presence of S1, S2, and extract them from the recorded data, forming the proposed HSS scheme, namely HSS-EEMD/K. Its performance is evaluated on an experimental dataset of 43 heart sound recordings performed in a real clinical environment, drawn from 11 normal subjects, 16 patients with aortic stenosis, and 16 ones with mitral regurgitation of different degrees of severity, producing 2608 S1 and S2 sequences without and with murmurs, respectively. Experimental results have shown that, overall, the HSS-EEMD/K approach determines the heart sound locations in a percentage of 94.56% and segments heart cycles correctly for the 83.05% of the cases. Moreover, results from a noise stress test with additive Gaussian noise and respiratory noises justify the noise robustness of the HSS-EEMD/K. When compared with four other efficient methods that mainly employ wavelet transform, energy, simplicity, and frequency measures, respectively, using the same experimental database, the HSS-EEMD/K scheme exhibits increased accuracy and prediction power over all others at the level of 7-19% and 4-9%, respectively, both in controls and pathological cases. The promising performance of the HSS-EEMD/K paves the way for further exploitation of the diagnostic value of heart sounds in everyday clinical practice. PMID- 25014930 TI - A machine learning approach to improve contactless heart rate monitoring using a webcam. AB - Unobtrusive, contactless recordings of physiological signals are very important for many health and human-computer interaction applications. Most current systems require sensors which intrusively touch the user's skin. Recent advances in contact-free physiological signals open the door to many new types of applications. This technology promises to measure heart rate (HR) and respiration using video only. The effectiveness of this technology, its limitations, and ways of overcoming them deserves particular attention. In this paper, we evaluate this technique for measuring HR in a controlled situation, in a naturalistic computer interaction session, and in an exercise situation. For comparison, HR was measured simultaneously using an electrocardiography device during all sessions. The results replicated the published results in controlled situations, but show that they cannot yet be considered as a valid measure of HR in naturalistic human computer interaction. We propose a machine learning approach to improve the accuracy of HR detection in naturalistic measurements. The results demonstrate that the root mean squared error is reduced from 43.76 to 3.64 beats/min using the proposed method. PMID- 25014931 TI - Robustness, specificity, and reliability of an in-ear pulse oximetric sensor in surgical patients. AB - For many years, pulse oximetry has been widely used in the clinical environment for a reliable monitoring of oxygen saturation ( SpO2) and heart rate. But since common sensors are mainly placed to peripheral body parts as finger or earlobe, it is still highly susceptible to reduced peripheral perfusion, e.g., due to centralization. Therefore, a novel in-ear pulse oximetric sensor (placed against the tragus) was presented in a prior work which is deemed to be independent from perfusion fluctuations due to its proximity to the trunk. Having demonstrated the feasibility of in-ear SpO2 measurement with reliable specificity in a laboratory setting, we now report results from a study on in-ear SpO2 in a clinical setting. For this, trials were performed on 29 adult patients undergoing surgery. In-ear SpO2 data are compared with SaO2 data obtained by blood gas analysis, and with three reference pulse oximeters applied to the finger, ear lobe, and forehead. In addition, we derived an SpO2-independent perfusion index by means of the wavelengths used. The feasibility and robustness of in-ear SpO2 measurement is demonstrated under challenging clinical conditions. SpO2 shows good accordance with SaO2, a high level of comparability with the reference pulse oximeters, and was significantly improved by introducing a new algorithm for artifact reduction. The perfusion index also shows a good correlation with the reference data. PMID- 25014932 TI - Investigation of galvanic-coupled intrabody communication using the human body circuit model. AB - Intrabody Communication (IBC) is a technique that uses the human body as a transmission medium for electrical signals to connect wearable electronic sensors and devices. Understanding the human body as the transmission medium in IBC paves way for practical implementation of IBC in body sensor networks. In this study, we propose a model for galvanic coupling-type IBC based on a simplified equivalent circuit representation of the human upper arm. We propose a new way to calculate the electrode-skin contact impedance. Based on the model and human experimental results, we discuss important characteristics of galvanic coupling type IBC, namely, the effect of tissues, anthropometry of subjects, and electrode configuration on signal propagation. We found that the dielectric properties of the muscle primarily characterize the received signal when receiver electrodes are located close to transmitter electrodes. When receiver and transmitter electrodes are far apart, the skin dielectric property affects the received signal. PMID- 25014933 TI - Hierarchical approaches to estimate energy expenditure using phone-based accelerometers. AB - Physical inactivity is linked with increase in risk of cancer, heart disease, stroke, and diabetes. Walking is an easily available activity to reduce sedentary time. Objective methods to accurately assess energy expenditure from walking that is normalized to an individual would allow tailored interventions. Current techniques rely on normalization by weight scaling or fitting a polynomial function of weight and speed. Using the example of steady-state treadmill walking, we present a set of algorithms that extend previous work to include an arbitrary number of anthropometric descriptors. We specifically focus on predicting energy expenditure using movement measured by mobile phone-based accelerometers. The models tested include nearest neighbor models, weight-scaled models, a set of hierarchical linear models, multivariate models, and speed-based approaches. These are compared for prediction accuracy as measured by normalized average root mean-squared error across all participants. Nearest neighbor models showed highest errors. Feature combinations corresponding to sedentary energy expenditure, sedentary heart rate, and sex alone resulted in errors that were higher than speed-based models and nearest-neighbor models. Size-based features such as BMI, weight, and height produced lower errors. Hierarchical models performed better than multivariate models when size-based features were used. We used the hierarchical linear model to determine the best individual feature to describe a person. Weight was the best individual descriptor followed by height. We also test models for their ability to predict energy expenditure with limited training data. Hierarchical models outperformed personal models when a low amount of training data were available. Speed-based models showed poor interpolation capability, whereas hierarchical models showed uniform interpolation capabilities across speeds. PMID- 25014934 TI - A food recognition system for diabetic patients based on an optimized bag-of features model. AB - Computer vision-based food recognition could be used to estimate a meal's carbohydrate content for diabetic patients. This study proposes a methodology for automatic food recognition, based on the bag-of-features (BoF) model. An extensive technical investigation was conducted for the identification and optimization of the best performing components involved in the BoF architecture, as well as the estimation of the corresponding parameters. For the design and evaluation of the prototype system, a visual dataset with nearly 5000 food images was created and organized into 11 classes. The optimized system computes dense local features, using the scale-invariant feature transform on the HSV color space, builds a visual dictionary of 10000 visual words by using the hierarchical k-means clustering and finally classifies the food images with a linear support vector machine classifier. The system achieved classification accuracy of the order of 78%, thus proving the feasibility of the proposed approach in a very challenging image dataset. PMID- 25014935 TI - An online sleep apnea detection method based on recurrence quantification analysis. AB - This paper introduces an online sleep apnea detection method based on heart rate complexity as measured by recurrence quantification analysis (RQA) statistics of heart rate variability (HRV) data. RQA statistics can capture nonlinear dynamics of a complex cardiorespiratory system during obstructive sleep apnea. In order to obtain a more robust measurement of the nonstationarity of the cardiorespiratory system, we use different fixed amount of neighbor thresholdings for recurrence plot calculation. We integrate a feature selection algorithm based on conditional mutual information to select the most informative RQA features for classification, and hence, to speed up the real-time classification process without degrading the performance of the system. Two types of binary classifiers, i.e., support vector machine and neural network, are used to differentiate apnea from normal sleep. A soft decision fusion rule is developed to combine the results of these classifiers in order to improve the classification performance of the whole system. Experimental results show that our proposed method achieves better classification results compared with the previous recurrence analysis based approach. We also show that our method is flexible and a strong candidate for a real efficient sleep apnea detection system. PMID- 25014936 TI - A comparative study of different level interpolations for improving spatial resolution in diffusion tensor imaging. AB - This paper studies and evaluates the feasibility and the performance of different level interpolations for improving spatial resolution of diffusion tensor magnetic resonance imaging (DT-MRI or DTI). In particular, the following techniques are investigated: anisotropic interpolation operating on scalar gray level images, log-Euclidean interpolation method, and the quaternion interpolation method, which operate on diffusion tensor fields. The performance is evaluated both qualitatively and quantitatively using criteria such as tensor determinant, fractional anisotropy (FA), mean diffusivity (MD), fiber length, etc. We conclude that tensor field interpolations allow avoiding undesirable swelling effect in DTI, which is not the case with scalar gray-level interpolation, and that scalar gray-level image interpolation and log-Euclidean tensor field interpolation suffer from decrease in FA and MD, which may mislead the interpretation of the clinical parameters FA and MD. In contrast, the quaternion tensor field interpolation avoids such FA and MD decrease, which suggests its use for clinical applications. PMID- 25014937 TI - A multiscale optimization approach to detect exudates in the macula. AB - Pathologies that occur on or near the fovea, such as clinically significant macular edema (CSME), represent high risk for vision loss. The presence of exudates, lipid residues of serous leakage from damaged capillaries, has been associated with CSME, in particular if they are located one optic disc-diameter away from the fovea. In this paper, we present an automatic system to detect exudates in the macula. Our approach uses optimal thresholding of instantaneous amplitude (IA) components that are extracted from multiple frequency scales to generate candidate exudate regions. For each candidate region, we extract color, shape, and texture features that are used for classification. Classification is performed using partial least squares (PLS). We tested the performance of the system on two different databases of 652 and 400 images. The system achieved an area under the receiver operator characteristic curve (AUC) of 0.96 for the combination of both databases and an AUC of 0.97 for each of them when they were evaluated independently. PMID- 25014938 TI - Shape analysis of the human brain: a brief survey. AB - The survey outlines and compares popular computational techniques for quantitative description of shapes of major structural parts of the human brain, including medial axis and skeletal analysis, geodesic distances, Procrustes analysis, deformable models, spherical harmonics, and deformation morphometry, as well as other less widely used techniques. Their advantages, drawbacks, and emerging trends, as well as results of applications, in particular, for computer aided diagnostics, are discussed. PMID- 25014939 TI - Semantic description of liver CT images: an ontological approach. AB - Radiologists inspect CT scans and record their observations in reports to communicate with physicians. These reports may suffer from ambiguous language and inconsistencies resulting from subjective reporting styles, which present challenges in interpretation. Standardization efforts, such as the lexicon RadLex for radiology terms, aim to address this issue by developing standard vocabularies. While such vocabularies handle consistent annotation, they fall short in sufficiently processing reports for intelligent applications. To support such applications, the semantics of the concepts as well as their relationships must be modeled, for which, ontologies are effective. They enable the software to make inferences beyond what is present in the reports. This paper presents the open-source ontology onlira (Ontology of the Liver for Radiology), which is developed to support such intelligent applications, such as identifying and ranking similar liver patient cases. onlira is introduced in terms of its concepts, properties, and relations. Examples of real liver patient cases are provided for illustration purposes. The ontology is evaluated in terms of its ability to express real liver patient cases and address semantic queries. PMID- 25014940 TI - MRI-based segmentation of pubic bone for evaluation of pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is a major women's health problem. Its diagnosis through magnetic resonance imaging (MRI) has become popular due to current inaccuracies of clinical examination. The diagnosis of POP on MRI consists of identifying reference points on pelvic bone structures for measurement and evaluation. However, it is currently performed manually, making it a time consuming and subjective procedure. We present a new segmentation approach for automating pelvic bone point identification on MRI. It consists of a multistage mechanism based on texture-based block classification, leak detection, and prior shape information. Texture-based block classification and clustering analysis using K-means algorithm are integrated to generate the initial bone segmentation and to identify leak areas. Prior shape information is incorporated to obtain the final bone segmentation. Then, the reference points are identified using morphological skeleton operation. Results demonstrate that the proposed method achieves higher bone segmentation accuracy compared to other segmentation methods. The proposed method can also automatically identify reference points faster and with more consistency compared with the manually identified point process by experts. This research aims to enable faster and consistent pelvic measurements on MRI to facilitate and improve the diagnosis of female POP. PMID- 25014941 TI - XDS-I outsourcing proxy: ensuring confidentiality while preserving interoperability. AB - The interoperability of services and the sharing of health data have been a continuous goal for health professionals, patients, institutions, and policy makers. However, several issues have been hindering this goal, such as incompatible implementations of standards (e.g., HL7, DICOM), multiple ontologies, and security constraints. Cross-enterprise document sharing (XDS) workflows were proposed by Integrating the Healthcare Enterprise (IHE) to address current limitations in exchanging clinical data among organizations. To ensure data protection, XDS actors must be placed in trustworthy domains, which are normally inside such institutions. However, due to rapidly growing IT requirements, the outsourcing of resources in the Cloud is becoming very appealing. This paper presents a software proxy that enables the outsourcing of XDS architectural parts while preserving the interoperability, confidentiality, and searchability of clinical information. A key component in our architecture is a new searchable encryption (SE) scheme-Posterior Playfair Searchable Encryption (PPSE)-which, besides keeping the same confidentiality levels of the stored data, hides the search patterns to the adversary, bringing improvements when compared to the remaining practical state-of-the-art SE schemes. PMID- 25014942 TI - Manual stage acquisition and interactive display of digital slides in histopathology. AB - More powerful PC architectures, high-resolution cameras working at increasing frame rates, and more and more accurate motorized microscopes have boosted new applications in the field of biomedicine and medical imaging. In histopathology, the use of digital slides (DSs) imaging through dedicated hardware for digital pathology is increasing for several reasons: digital annotation of suspicious lesions, recorded clinical history, and telepathology as a collaborative environment. In this paper, we propose the first method known in the literature for real-time whole slide acquisition and displaying conceived for conventional nonautomated microscopes. Differently from DS scanner, our software enables biologists and histopathologists to build and view the DS in real time while inspecting the sample, as they are accustomed to. In addition, since our approach is compliant with existing common microscope positions, provided with camera and PC, this could contribute to disseminate the whole slide technology in the majority of small labs not endowed with DS hardware facilities. Experiments performed with different histologic specimens (referring to tumor tissues of different body parts as well as to tumor cells), acquired under different setup conditions and devices, prove the effectiveness of our approach both in terms of quality and speed performances. PMID- 25014943 TI - A review on the state-of-the-art privacy-preserving approaches in the e-health clouds. AB - Cloud computing is emerging as a new computing paradigm in the healthcare sector besides other business domains. Large numbers of health organizations have started shifting the electronic health information to the cloud environment. Introducing the cloud services in the health sector not only facilitates the exchange of electronic medical records among the hospitals and clinics, but also enables the cloud to act as a medical record storage center. Moreover, shifting to the cloud environment relieves the healthcare organizations of the tedious tasks of infrastructure management and also minimizes development and maintenance costs. Nonetheless, storing the patient health data in the third-party servers also entails serious threats to data privacy. Because of probable disclosure of medical records stored and exchanged in the cloud, the patients' privacy concerns should essentially be considered when designing the security and privacy mechanisms. Various approaches have been used to preserve the privacy of the health information in the cloud environment. This survey aims to encompass the state-of-the-art privacy-preserving approaches employed in the e-Health clouds. Moreover, the privacy-preserving approaches are classified into cryptographic and noncryptographic approaches and taxonomy of the approaches is also presented. Furthermore, the strengths and weaknesses of the presented approaches are reported and some open issues are highlighted. PMID- 25014944 TI - Assessing executive function using a computer game: computational modeling of cognitive processes. AB - Early and reliable detection of cognitive decline is one of the most important challenges of current healthcare. In this project, we developed an approach whereby a frequently played computer game can be used to assess a variety of cognitive processes and estimate the results of the pen-and-paper trail making test (TMT)--known to measure executive function, as well as visual pattern recognition, speed of processing, working memory, and set-switching ability. We developed a computational model of the TMT based on a decomposition of the test into several independent processes, each characterized by a set of parameters that can be estimated from play of a computer game designed to resemble the TMT. An empirical evaluation of the model suggests that it is possible to use the game data to estimate the parameters of the underlying cognitive processes and using the values of the parameters to estimate the TMT performance. Cognitive measures and trends in these measures can be used to identify individuals for further assessment, to provide a mechanism for improving the early detection of neurological problems, and to provide feedback and monitoring for cognitive interventions in the home. PMID- 25014945 TI - A methodology for improving tear film lipid layer classification. AB - Dry eye is a symptomatic disease which affects a wide range of population and has a negative impact on their daily activities. Its diagnosis can be achieved by analyzing the interference patterns of the tear film lipid layer and by classifying them into one of the Guillon categories. The manual process done by experts is not only affected by subjective factors but is also very time consuming. In this paper we propose a general methodology to the automatic classification of tear film lipid layer, using color and texture information to characterize the image and feature selection methods to reduce the processing time. The adequacy of the proposed methodology was demonstrated since it achieves classification rates over 97% while maintaining robustness and provides unbiased results. Also, it can be applied in real time, and so allows important time savings for the experts. PMID- 25014946 TI - Spatial normalization of human back images for dermatological studies. AB - A large number of pigmented skin lesions (PSLs) are a strong predictor of malignant melanoma. Many dermatologists advocate total body photography for high risk patients because detecting new-appearing, disappearing, and changing PSL is important for early detection of the disease. However, manual inspection and matching of PSL is a subjective, tedious, and error-prone task. A computer program for tracking the corresponding PSL will greatly improve the matching process. In this paper, we describe the construction of the first human back template (atlas), which is used to facilitate spatial normalization of the PSL during the matching process. Four pairs of anatomically meaningful landmarks (neck, shoulder, armpit, and hip points) are used as reference points on the back image. Using the landmarks, a grid with longitudes and latitudes is constructed and overlaid on each subject-specific back image. To perform spatial normalization, the grid is registered into the back template, a unit-square rectilinear grid. To demonstrate the benefits of using the back template, we apply several state-of-the-art point-matching algorithms on 56 pairs of real dermatological images and show that utilizing spatially normalized coordinates improves the PSL matching accuracies. PMID- 25014947 TI - Comparison of cephalic and extracephalic montages for transcranial direct current stimulation--a numerical study. AB - While studies have shown that the application of transcranial direct current stimulation (tDCS) has been beneficial in the stimulation of cortical activity and treatment of neurological disorders in humans, open questions remain regarding the placement of electrodes for optimal targeting of currents for a given functional area. Given the difficulty of obtaining in vivo measurements of current density, modeling of conventional and alternative electrode montages via the finite element method has been utilized to provide insight into tDCS montage performance. It has been shown that extracephalic montages might create larger total current densities in deeper brain regions, specifically in white matter as compared to an equivalent cephalic montage. Extracephalic montages might also create larger average vertical current densities in the primary motor cortex and in the somatosensory cortex.At the same time, the horizontal current density either remains approximately the same or decreases. The metrics used in this paper include either the total local current density through the entire brain volume or the average vertical current density as well as the average horizontal current density for every individual lobe/cortex. PMID- 25014948 TI - 3-D ultrasound-guided robotic needle steering in biological tissue. AB - Robotic needle steering systems have the potential to greatly improve medical interventions, but they require new methods for medical image guidance. Three dimensional (3-D) ultrasound is a widely available, low-cost imaging modality that may be used to provide real-time feedback to needle steering robots. Unfortunately, the poor visibility of steerable needles in standard grayscale ultrasound makes automatic segmentation of the needles impractical. A new imaging approach is proposed, in which high-frequency vibration of a steerable needle makes it visible in ultrasound Doppler images. Experiments demonstrate that segmentation from this Doppler data is accurate to within 1-2 mm. An image-guided control algorithm that incorporates the segmentation data as feedback is also described. In experimental tests in ex vivo bovine liver tissue, a robotic needle steering system implementing this control scheme was able to consistently steer a needle tip to a simulated target with an average error of 1.57 mm. Implementation of 3-D ultrasound-guided needle steering in biological tissue represents a significant step toward the clinical application of robotic needle steering. PMID- 25014949 TI - A noncontact capacitive sensing system for recognizing locomotion modes of transtibial amputees. AB - This paper presents a noncontact capacitive sensing system (C-Sens) for locomotion mode recognition of transtibial amputees. C-Sens detects changes in physical distance between the residual limb and the prosthesis. The sensing front ends are built into the prosthetic socket without contacting the skin. This novel signal source improves the usability of locomotion mode recognition systems based on electromyography (EMG) signals and systems based on capacitance signals obtained from skin contact. To evaluate the performance of C-Sens, we carried out experiments among six transtibial amputees with varying levels of amputation when they engaged in six common locomotive activities. The capacitance signals were consistent and stereotypical for different locomotion modes. Importantly, we were able to obtain sufficiently informative signals even for amputees with severe muscle atrophy (i.e., amputees lacking of quality EMG from shank muscles for mode classification). With phase-dependent quadratic classifier and selected feature set, the proposed system was capable of making continuous judgments about locomotion modes with an average accuracy of 96.3% and 94.8% for swing phase and stance phase, respectively (Experiment 1). Furthermore, the system was able to achieve satisfactory recognition performance after the subjects redonned the socket (Experiment 2). We also validated that C-Sens was robust to load bearing changes when amputees carried 5-kg weights during activities (Experiment 3). These results suggest that noncontact capacitive sensing is capable of circumventing practical problems of EMG systems without sacrificing performance and it is, thus, promising for automatic recognition of human motion intent for controlling powered prostheses. PMID- 25014950 TI - A powered prosthetic intervention for bilateral transfemoral amputees. AB - This paper presents the design and validation of a control system for a pair of powered knee and ankle prostheses to be used as a prosthetic intervention for bilateral transfemoral amputees. The control system leverages communication between the prostheses for enhanced awareness and stability, along with power generation at the knee and ankle joints to better restore biomechanical functionality in level ground walking. The control methodology employed is a combination of an impedance-based framework for weight-bearing portions of gait and a trajectory-based approach for the nonweight-bearing portions. The control system was implemented on a pair of self-contained powered knee and ankle prostheses, and the ability of the prostheses and control approach to provide walking functionality was assessed in a set of experimental trials with a bilateral transfemoral amputee subject. Specifically, experimental data from these trials indicate that the powered prostheses and bilateral control architecture provide gait kinematics that reproduce healthy gait kinematics to a greater extent than the subject's daily-use passive prostheses. PMID- 25014951 TI - Impedance Changes Indicate Proximal Ventriculoperitoneal Shunt Obstruction In Vitro. AB - Extracranial cerebrospinal fluid (CSF) shunt obstruction is one of the most important problems in hydrocephalus patient management. Despite ongoing research into better shunt design, robust and reliable detection of shunt malfunction remains elusive. The authors present a novel method of correlating degree of tissue ingrowth into ventricular CSF drainage catheters with internal electrical impedance. The impedance based sensor is able to continuously monitor shunt patency using intraluminal electrodes. Prototype obstruction sensors were fabricated for in-vitro analysis of cellular ingrowth into a shunt under static and dynamic flow conditions. Primary astrocyte cell lines and C6 glioma cells were allowed to proliferate up to 7 days within a shunt catheter and the impedance waveform was observed. During cell ingrowth a significant change in the peak-to-peak voltage signal as well as the root-mean-square voltage level was observed, allowing the impedance sensor to potentially anticipate shunt malfunction long before it affects fluid drainage. Finite element modeling was employed to demonstrate that the electrical signal used to monitor tissue ingrowth is contained inside the catheter lumen and does not endanger tissue surrounding the shunt. These results may herald the development of "next generation" shunt technology that allows prediction of malfunction before it affects patient outcome. PMID- 25014952 TI - Using ultrasound backscattering signals and Nakagami statistical distribution to assess regional cataract hardness. AB - This study aims to analyze the protein aggregates spatial distribution for different cataract degrees, and correlate this information with the lens acoustical parameters and by this way, assess the cataract regional hardness. Different cataract degrees were induced ex vivo in porcine lenses. A 25 MHz ultrasonic transducer was used to obtain the acoustical parameters (velocity, attenuation, and backscattering signals). B-scan and Nakagami images were constructed. Also, lenses with different cataract degrees were sliced in two regions (nucleus and cortex), for fibers and collagen detection. A significant increase with cataract formation was found for the velocity, attenuation, and brightness intensity of the B-scan images and Nakagami m parameter ( ). The acoustical parameters showed a good to moderate correlation with the m parameter for the different stages of cataract formation. A strong correlation was found between the protein aggregates in the cortex and the m parameter. Lenses without cataract are characterized using a classification and regression tree, by a mean brightness intensity <=0.351, a variance of the B-scan brightness intensity <=0.070, a velocity <=1625 m/s, and an attenuation <=0.415 dB/mm.MHz (sensitivity: 100% and specificity: 72.6%). To characterize different cataract degrees, the m parameter should be considered. Initial stages of cataract are characterized by a mean brightness intensity >0.351 and a variance of the m parameter >0.110. Advanced stages of cataract are characterized by a mean brightness intensity >0.351, a variance of the m parameter <=0.110, and a mean m parameter >0.374. For initial and advanced stages of cataract, a sensitivity of 78.4% and a specificity of 86.5% are obtained. PMID- 25014953 TI - A method to study precision grip control in viscoelastic force fields using a robotic gripper. AB - Instrumented objects and multipurpose haptic displays have commonly been used to investigate sensorimotor control of grasping and manipulation. A major limitation of these devices, however, is the extent to which the experimenter can vary the interaction dynamics to fully probe sensorimotor control mechanisms. We propose a novel method to study precision grip control using a grounded robotic gripper with two moving, mechanically coupled finger pads instrumented with force sensors. The device is capable of stably rendering virtual mechanical properties with a wide dynamic range of achievable impedances. Eight viscoelastic force fields with different combinations of stiffness and damping parameters were implemented, and tested on eight healthy subjects performing 30 consecutive repetitions of a grasp, hold, and release task with time and position constraints. Rates of thumb and finger force were found to be highly correlated (r>0.9) during grasping, revealing that, despite the mechanical coupling of the two finger pads, subjects performed grasping movements in a physiological fashion. Subjects quickly adapted to the virtual dynamics (within seven trials), but, depending on the presented force field condition, used different control strategies to correctly perform the task. The proof of principle presented in this paper underscores the potential of such a one-degree-of-freedom robotic gripper to study neural control of grasping, and to provide novel insights on sensorimotor control mechanisms. PMID- 25014954 TI - An image reconstruction algorithm for 3-D electrical impedance mammography. AB - The Sussex MK4 electrical impedance mammography system is especially designed for 3-D breast screening. It aims to diagnose breast cancer at an early stage when it is most treatable. Planar electrodes are employed in this system. The challenge with planar electrodes is the inaccuracy and poor sensitivity in the vertical direction for 3-D imaging. An enhanced image reconstruction algorithm using a duo mesh method is proposed to improve the vertical accuracy and sensitivity. The novel part of the enhanced image reconstruction algorithm is the correction term. To evaluate the new algorithm, an image processing based error analysis method is presented, which not only can precisely assess the error of the reconstructed image but also locate the center and outline the center and outline the shape of the objects of interest. Although the enhanced image reconstruction algorithm and the image processing based error analysis method are designed for the Sussex MK4 system, they are applicable to all electrical impedance tomography systems, regardless of the hardware design. To validate the enhanced algorithm, performance results from simulations, phantoms and patients are presented. PMID- 25014955 TI - Characterization of the immediate effect of a training session on a manual wheelchair simulator with haptic biofeedback: towards more effective propulsion. AB - Eighteen manual wheelchair users (MWUs) with spinal cord injury participated in a training session on a new manual wheelchair simulator with haptic biofeedback (HB). The training aimed to modify participants' mechanical effective force (MEF) along the push phase to achieve a target MEF pattern slightly more effective than their pre-training pattern. More HB was provided if the participants' achieved MEF pattern deviated from the target. Otherwise, less HB was provided. The deviation between the participants' achieved MEF and the target, as well as the mean achieved MEF, were computed before, during and after the training session. During the training, participants generally exceeded the target pattern at the beginning of the push cycle and achieved it towards the end. On average, participants also increased their mean MEF by up to 15.7% on the right side and 12.4% on the left side between the pre-training and training periods. Finally, eight participants could modify their MEF pattern towards the target in post training. The simulator tested in this study represents a valuable tool for developing new wheelchair propulsion training programs. Haptic biofeedback also provides interesting potential for training MWUs to improve propulsion effectiveness. PMID- 25014956 TI - Using the electromyogram to anticipate torques about the elbow. AB - Processed (i.e., rectified, smoothed) electromyogram (EMG) activity from skeletal muscles precedes mechanical tension by 50-100 ms. This property can be exploited to anticipate muscle mechanical activity. Thus, we investigated the ability of surface EMG to estimate joint torque at future times, up to 750 ms. EMG recorded from the biceps and triceps muscles of 54 subjects during constant-posture, force varying contractions was related to elbow torque. Higher-order FIR models, combined with advanced EMG processing (whitening; four EMG channels per muscle), provided a nearly identical minimum error of 5.48 +/-2.21% MVC(F) (flexion maximum voluntary contraction) over the time advance range of 0-60 ms. Error grew for larger time advances. The more common method of filtering EMG amplitude with a Butterworth filter (second-order, 1.5 Hz cutoff frequency) produced a statistically inferior minimum torque error of 6.90 +/-2.39% MVC(F), with an error nadir at a time advance of 60 ms. Error was progressively poorer at all other time advances. Lower-order FIR models mimicked the poorer performance of the Butterworth models. The more advanced models provide lower estimation error, require no selection of an electromechanical delay term and maintain their lowest error over a substantial range of advance times. PMID- 25014957 TI - Kinematic parameters to evaluate functional performance of sit-to-stand and stand to-sit transitions using motion sensor devices: a systematic review. AB - Clinicians commonly use questionnaires and tests based on daily life activities to evaluate physical function. However, the outcomes are usually more qualitative than quantitative and subtle differences are not detectable. In this review, we aim to assess the role of body motion sensors in physical performance evaluation, especially for the sit-to-stand and stand-to-sit transitions. In total, 53 full papers and conference abstracts on related topics were included and 16 different parameters related to transition performance were identified as potentially meaningful to explain certain disabilities and impairments. Transition duration is the most used to evaluate chair-related tests in real clinical settings. High fall-risk fallers and frail subjects presented longer and more variable transition duration. Other kinematic parameters have also been highlighted in the literature as potential means to detect age-related impairments. In particular, vertical linear velocity and trunk tilt range were able to differentiate between different frailty levels. Frequency domain measures such as spectral edge frequency were also higher for elderly fallers. Lastly, approximate entropy values were larger for subjects with Parkinson's disease and were significantly reduced after treatment. This information could help clinicians in their evaluations as well as in prescribing a physical fitness program to correct a specific deficit. PMID- 25014958 TI - Motor imagery learning induced changes in functional connectivity of the default mode network. AB - Numerous studies provide evidences that motor skill learning changes the activity of some brain regions during task as well as some resting networks during rest. However, it is still unclear how motor learning affects the resting-state default mode network (DMN). Using functional magnetic resonance imaging, this study investigated the alteration of the DMN after motor skill learning with mental imagery practice. Fourteen participants in the experimental group learned to imagine a sequential finger movement over a two-week period while twelve control participants did not undergo motor imagery learning. For the experimental group, interregional connectivity, estimated by the graph theory method, between the medial temporal lobe, lateral temporal, and lateral parietal cortex within the DMN was increased after learning, whereas activity of the DMN network, estimated by the independent component analysis method, remained stable. Moreover, the experimental group showed significant improvement in motor performance after learning and a negative correlation between the alteration of the execution rate and changes in activity in the lateral parietal cortex. These results indicate that the DMN could be sculpted by motor learning in a manner of altering interregional connectivity and may imply that the DMN plays a role in improving behavioral performance. PMID- 25014959 TI - EEG gamma band oscillations differentiate the planning of spatially directed movements of the arm versus eye: multivariate empirical mode decomposition analysis. AB - The neural dynamics underlying the coordination of spatially-directed limb and eye movements in humans is not well understood. Part of the difficulty has been a lack of signal processing tools suitable for the analysis of nonstationary electroencephalographic (EEG) signals. Here, we use multivariate empirical mode decomposition (MEMD), a data-driven approach that does not employ predefined basis functions. High-density EEG, and arm and eye movements were synchronously recorded in 10 subjects performing time-constrained reaching and/or eye movements. Subjects were allowed to move both the hand and the eyes, only the hand, or only the eyes following a 500-700 ms delay interval where the hand and gaze remained on a central fixation cross. An additional condition involved a nonspatially-directed "lift" movement of the hand. The neural activity during a 500 ms delay interval was decomposed into intrinsic mode functions (IMFs) using MEMD. Classification analysis revealed that gamma band (30 Hz) IMFs produced more classifiable features differentiating the EEG according to the different upcoming movements. A benchmark test using conventional algorithms demonstrated that MEMD was the best algorithm for extracting oscillatory bands from EEG, yielding the best classification of the different movement conditions. The gamma rhythm decomposed using MEMD showed a higher correlation with the eventual movement accuracy than any other band rhythm and than any other algorithm. PMID- 25014960 TI - WIMAGINE: wireless 64-channel ECoG recording implant for long term clinical applications. AB - A wireless 64-channel ElectroCorticoGram (ECoG) recording implant named WIMAGINE has been designed for various clinical applications. The device is aimed at interfacing a cortical electrode array to an external computer for neural recording and control applications. This active implantable medical device is able to record neural activity on 64 electrodes with selectable gain and sampling frequency, with less than 1 MUV(RMS) input referred noise in the [0.5 Hz - 300 Hz] band. It is powered remotely through an inductive link at 13.56 MHz which provides up to 100 mW. The digitized data is transmitted wirelessly to a custom designed base station connected to a PC. The hermetic housing and the antennae have been designed and optimized to ease the surgery. The design of this implant takes into account all the requirements of a clinical trial, in particular safety, reliability, and compliance with the regulations applicable to class III AIMD. The main features of this WIMAGINE implantable device and its architecture are presented, as well as its functional performances and long-term biocompatibility results. PMID- 25014961 TI - c-erbB-2 as a possible target for the use of magnetic nanoparticles in breast cancer cells. AB - Breast cancer (BC) is the most frequent malignancy among women worldwide and has been associated with high mortality because of the late treatment of the disease. Our group has proposed a selective ablation of breast cancer cells by the use of magnetic fields assisted by magnetic nanoparticles. The principle is to increase the conductivity of tumoral tissue by the use of a bioconjugated "nanoparticle antibody" that recognizes specific antigens on the surface of the cancer cells. The aim of this study was to evaluate the c-erbB-2 antigen in breast cancer cells of type BT-474, MCF-7, and MDA-MB-231 as a possible target for the use of magnetic nanoparticles coupled to a specific Monoclonal Antibody (Mab). Quantitative real-time polymerase chain reaction and flow cytometry were used to estimate the relative expressions of the c-erbB-2 gene and the c-erbB-2 antigen in the cell lines, respectively. A covalent union of magnetic nanoparticles to anti c-erbB-2 Mab was used to develop the bioconjugate. Fluorescence microscopy was used to determine the cells that were tagged by the bioconjugate. The results show a well-differentiated relative expression of c-erbB-2 in the studied cell lines and are qualitatively in agreement with the fluorescent marking by the magnetic nanoparticles. The selected breast cancer cells appear to be suitable for experimental evaluation of selective targeting by magnetic nanoparticles. PMID- 25014962 TI - Microarray data classification using the spectral-feature-based TLS ensemble algorithm. AB - The reliable and accurate identification of cancer categories is crucial to a successful diagnosis and a proper treatment of the disease. In most existing work, samples of gene expression data are treated as one-dimensional signals, and are analyzed by means of some statistical signal processing techniques or intelligent computation algorithms. In this paper, from an image-processing viewpoint, a spectral-feature-based Tikhonov-regularized least-squares (TLS) ensemble algorithm is proposed for cancer classification using gene expression data. In the TLS model, a test sample is represented as a linear combination of the atoms of a dictionary. Two types of dictionaries, namely singular value decomposition (SVD)-based eigenassays and independent component analysis (ICA) based eigenassays, are proposed for the TLS model, and both are extracted via a two-stage approach. The proposed algorithm is inspired by our finding that, among these eigenassays, the categories of some of the testing samples can be assigned correctly by using the TLS models formed from some of the spectral features, but not for those formed from the original samples only. In order to retain the positive characteristics of these spectral features in making correct category assignments, a strategy of classifier committee learning (CCL) is designed to combine the results obtained from the different spectral features. Experimental results on standard databases demonstrate the feasibility and effectiveness of the proposed method. PMID- 25014963 TI - A communication theoretical analysis of FRET-based mobile ad hoc molecular nanonetworks. AB - Nanonetworks refer to a group of nanosized machines with very basic operational capabilities communicating to each other in order to accomplish more complex tasks such as in-body drug delivery, or chemical defense. Realizing reliable and high-rate communication between these nanomachines is a fundamental problem for the practicality of these nanonetworks. Recently, we have proposed a molecular communication method based on Forster Resonance Energy Transfer (FRET) which is a nonradiative excited state energy transfer phenomenon observed among fluorescent molecules, i.e., fluorophores. We have modeled the FRET-based communication channel considering the fluorophores as single-molecular immobile nanomachines, and shown its reliability at high rates, and practicality at the current stage of nanotechnology. In this study, for the first time in the literature, we investigate the network of mobile nanomachines communicating through FRET. We introduce two novel mobile molecular nanonetworks: FRET-based mobile molecular sensor/actor nanonetwork (FRET-MSAN) which is a distributed system of mobile fluorophores acting as sensor or actor node; and FRET-based mobile ad hoc molecular nanonetwork (FRET-MAMNET) which consists of fluorophore-based nanotransmitter, nanoreceivers and nanorelays. We model the single message propagation based on birth-death processes with continuous time Markov chains. We evaluate the performance of FRET-MSAN and FRET-MAMNET in terms of successful transmission probability and mean extinction time of the messages, system throughput, channel capacity and achievable communication rates. PMID- 25014964 TI - Adaptive pulse width control and sampling for low power pulse oximetry. AB - Remote sensing of physiological parameters could be a cost effective approach to improving health care, and low-power sensors are essential for remote sensing because these sensors are often energy constrained. This paper presents a power optimized photoplethysmographic sensor interface to sense arterial oxygen saturation, a technique to dynamically trade off SNR for power during sensor operation, and a simple algorithm to choose when to acquire samples in photoplethysmography. A prototype of the proposed pulse oximeter built using commercial-off-the-shelf (COTS) components is tested on 10 adults. The dynamic adaptation techniques described reduce power consumption considerably compared to our reference implementation, and our approach is competitive to state-of-the-art implementations. The techniques presented in this paper may be applied to low power sensor interface designs where acquiring samples is expensive in terms of power as epitomized by pulse oximetry. PMID- 25014966 TI - Nonsmooth ICA contrast minimization using a Riemannian Nelder-Mead method. AB - This brief concerns the design and application of a Riemannian Nelder-Mead algorithm to minimize a Hartley-entropybased contrast function to reliably estimate the sources from their mixtures. Despite its nondifferentiability, the contrast function is endowed with attractive properties such as discriminacy, and hence warrants an effort to be effectively handled by a derivative-free optimizer. Aside from tailoring the Nelder-Mead technique to the constraint set, namely, oblique manifold, the source separation results attained in an empirical study with quasi-correlated synthetic signals and digital images are presented, which favor the proposed method on a comparative basis. PMID- 25014967 TI - Evolutionary fuzzy ARTMAP neural networks for classification of semiconductor defects. AB - Wafer defect detection using an intelligent system is an approach of quality improvement in semiconductor manufacturing that aims to enhance its process stability, increase production capacity, and improve yields. Occasionally, only few records that indicate defective units are available and they are classified as a minority group in a large database. Such a situation leads to an imbalanced data set problem, wherein it engenders a great challenge to deal with by applying machine-learning techniques for obtaining effective solution. In addition, the database may comprise overlapping samples of different classes. This paper introduces two models of evolutionary fuzzy ARTMAP (FAM) neural networks to deal with the imbalanced data set problems in a semiconductor manufacturing operations. In particular, both the FAM models and hybrid genetic algorithms are integrated in the proposed evolutionary artificial neural networks (EANNs) to classify an imbalanced data set. In addition, one of the proposed EANNs incorporates a facility to learn overlapping samples of different classes from the imbalanced data environment. The classification results of the proposed evolutionary FAM neural networks are presented, compared, and analyzed using several classification metrics. The outcomes positively indicate the effectiveness of the proposed networks in handling classification problems with imbalanced data sets. PMID- 25014968 TI - An efficient topological distance-based tree kernel. AB - Tree kernels proposed in the literature rarely use information about the relative location of the substructures within a tree. As this type of information is orthogonal to the one commonly exploited by tree kernels, the two can be combined to enhance state-of-the-art accuracy of tree kernels. In this brief, our attention is focused on subtree kernels. We describe an efficient algorithm for injecting positional information into a tree kernel and present ways to enlarge its feature space without affecting its worst case complexity. The experimental results on several benchmark datasets are presented showing that our method is able to reach state-of-the-art performances, obtaining in some cases better performance than computationally more demanding tree kernels. PMID- 25014969 TI - GrDHP: a general utility function representation for dual heuristic dynamic programming. AB - A general utility function representation is proposed to provide the required derivable and adjustable utility function for the dual heuristic dynamic programming (DHP) design. Goal representation DHP (GrDHP) is presented with a goal network being on top of the traditional DHP design. This goal network provides a general mapping between the system states and the derivatives of the utility function. With this proposed architecture, we can obtain the required derivatives of the utility function directly from the goal network. In addition, instead of a fixed predefined utility function in literature, we conduct an online learning process for the goal network so that the derivatives of the utility function can be adaptively tuned over time. We provide the control performance of both the proposed GrDHP and the traditional DHP approaches under the same environment and parameter settings. The statistical simulation results and the snapshot of the system variables are presented to demonstrate the improved learning and controlling performance. We also apply both approaches to a power system example to further demonstrate the control capabilities of the GrDHP approach. PMID- 25014970 TI - Transfer learning for visual categorization: a survey. AB - Regular machine learning and data mining techniques study the training data for future inferences under a major assumption that the future data are within the same feature space or have the same distribution as the training data. However, due to the limited availability of human labeled training data, training data that stay in the same feature space or have the same distribution as the future data cannot be guaranteed to be sufficient enough to avoid the over-fitting problem. In real-world applications, apart from data in the target domain, related data in a different domain can also be included to expand the availability of our prior knowledge about the target future data. Transfer learning addresses such cross-domain learning problems by extracting useful information from data in a related domain and transferring them for being used in target tasks. In recent years, with transfer learning being applied to visual categorization, some typical problems, e.g., view divergence in action recognition tasks and concept drifting in image classification tasks, can be efficiently solved. In this paper, we survey state-of-the-art transfer learning algorithms in visual categorization applications, such as object recognition, image classification, and human action recognition. PMID- 25014971 TI - A Novel Classification Method for Prediction of Rectal Bleeding in Prostate Cancer Radiotherapy Based on a Semi-Nonnegative ICA of 3D Planned Dose Distributions. AB - The understanding of dose/side-effects relationships in prostate cancer radiotherapy is crucial to define appropriate individual's constraints for the therapy planning. Most of the existing methods to predict side-effects do not fully exploit the rich spatial information conveyed by the three-dimensional planned dose distributions. We propose a new classification method for three dimensional individuals' doses, based on a new semi-nonnegative ICA algorithm to identify patients at risk of presenting rectal bleeding from a population treated for prostate cancer. The method first determines two bases of vectors from the population data: the two bases span vector subspaces, which characterize patients with and without rectal bleeding, respectively. The classification is then achieved by calculating the distance of a given patient to the two subspaces. The results, obtained on a cohort of 87 patients (at two year follow-up) treated with radiotherapy, showed high performance in terms of sensitivity and specificity. PMID- 25014972 TI - Evaluation of healthy EEG responses for spelling through listener-assisted scanning. AB - We investigated whether listener-assisted scanning, an alternative communication method for persons with severe motor and visual impairments but preserved cognitive skills, could be used for spelling with EEG. To that end spoken letters were presented sequentially, and the participants made selections by performing motor execution/imagery or a cognitive task. The motor task was a brisk dorsiflexion of both feet, and the cognitive task was related to working memory and perception of human voice. The motor imagery task yielded the most promising results with respect to letter selection accuracy, albeit with a large variation in individual performance. The cognitive task yielded significant ( p = 0.05) albeit moderate results. Closer inspection of grand average ERPs for the cognitive task revealed task-related modulation of a late negative component, which is novel in the auditory BCI literature. Guidelines for further development are presented. PMID- 25014974 TI - The manumeter: a wearable device for monitoring daily use of the wrist and fingers. AB - Nonobtrusive options for monitoring the wrist and hand movement are needed for stroke rehabilitation and other applications. This paper describes the "manumeter," a device that logs total angular distance travelled by wrist and finger joints using a magnetic ring worn on the index finger and two triaxial magnetometers mounted in a watch-like unit. We describe an approach to estimate the wrist and finger joint angles using a radial basis function network that maps differential magnetometer readings to joint angles. We tested this approach by comparing manumeter estimates of total angular excursion with those from a passive goniometric exoskeleton worn simultaneously as seven participants completed a set of 12 manual tasks at low-, medium-, and high-intensity conditions on a first testing day, 1-2 days later, and 6-8 days later, using only the original calibration from the first testing day. Manumeter estimates scaled proportionally to the intensity of hand activity. Estimates of angular excursion made with the manumeter were 92.5% +/- 28.4 (SD), 98.3% +/- 23.3, and 94.7% +/- 19.3 of the goniometric exoskeleton across the three testing days, respectively. Magnetic sensing of wrist and finger movement is nonobtrusive and can quantify the amount of use of the hand across days. PMID- 25014973 TI - On the use of coupled shape priors for segmentation of magnetic resonance images of the knee. AB - Active contour techniques have been widely employed for medical image segmentation. Significant effort has been focused on the use of training data to build prior statistical models applicable specifically to problems where the objects of interest are embedded in cluttered background. Usually, the training data consist of whole shapes of certain organs or structures obtained manually by clinical experts. The resulting prior models enforce segmentation accuracy uniformly over the entire structure or structures to be identified. In this paper, we consider a new coupled prior shape model which is demonstrated to provide high accuracy, specifically in the region of the interest where precision is most needed for the application of the segmentation of the femur and tibia in magnetic resonance (MR) images. Experimental results for the segmentation of MR images of human knees demonstrate that the combination of the new coupled prior shape and a directional edge force provides the improved segmentation performance. Moreover, the new approach allows for equivalent accurate identification of bone marrow lesions, a promising biomarker related to osteoarthritis, to the current state of the art but requires significantly less manual interaction. PMID- 25014975 TI - Invariant Surface EMG Feature Against Varying Contraction Level for Myoelectric Control Based on Muscle Coordination. AB - Variations in muscle contraction effort have a substantial impact on performance of pattern recognition based myoelectric control. Though incorporating changes into training phase could decrease the effect, the training time would be increased and the clinical viability would be limited. The modulation of force relies on the coordination of multiple muscles, which provides a possibility to classify motions with different forces without adding extra training samples. This study explores the property of muscle coordination in the frequency domain and found that the orientation of muscle activation pattern vector of the frequency band is similar for the same motion with different force levels. Two novel features based on discrete Fourier transform and muscle coordination were proposed subsequently, and the classification accuracy was increased by around 11% compared to the traditional time domain feature sets when classifying nine classes of motions with three different force levels. Further analysis found that both features decreased the difference among different forces of the same motion ) and maintained the distance among different motions p > 0.1). This study also provided a potential way for simultaneous classification of hand motions and forces without training at all force levels. PMID- 25014976 TI - A physiological time series dynamics-based approach to patient monitoring and outcome prediction. AB - Cardiovascular variables such as heart rate (HR) and blood pressure (BP) are regulated by an underlying control system, and therefore, the time series of these vital signs exhibit rich dynamical patterns of interaction in response to external perturbations (e.g., drug administration), as well as pathological states (e.g., onset of sepsis and hypotension). A question of interest is whether "similar" dynamical patterns can be identified across a heterogeneous patient cohort, and be used for prognosis of patients' health and progress. In this paper, we used a switching vector autoregressive framework to systematically learn and identify a collection of vital sign time series dynamics, which are possibly recurrent within the same patient and may be shared across the entire cohort. We show that these dynamical behaviors can be used to characterize the physiological "state" of a patient. We validate our technique using simulated time series of the cardiovascular system, and human recordings of HR and BP time series from an orthostatic stress study with known postural states. Using the HR and BP dynamics of an intensive care unit (ICU) cohort of over 450 patients from the MIMIC II database, we demonstrate that the discovered cardiovascular dynamics are significantly associated with hospital mortality (dynamic modes 3 and 9, p=0.001, p=0.006 from logistic regression after adjusting for the APACHE scores). Combining the dynamics of BP time series and SAPS-I or APACHE-III provided a more accurate assessment of patient survival/mortality in the hospital than using SAPS I and APACHE-III alone (p=0.005 and p=0.045). Our results suggest that the discovered dynamics of vital sign time series may contain additional prognostic value beyond that of the baseline acuity measures, and can potentially be used as an independent predictor of outcomes in the ICU. PMID- 25014977 TI - A distributed approach to alarm management in chronic kidney disease. AB - This paper presents the feasibility study of using a distributed approach for the management of alarms from chronic kidney disease patients. In a first place, the key issues regarding alarm definition, classification, and prioritization according to available normalization efforts are analyzed for the main scenarios addressed in hemodialysis. Then, the middleware proposed for alarm management is described, which follows the publish/subscribe pattern, and supports the Object Management Group data distribution service (DDS) standard. This standard facilitates the real-time monitoring of the exchanged information, as well as the scalability and interoperability of the solution developed regarding the different stakeholders and resources involved. Finally, the results section shows, through the proof of concept studied, the viability of DDS for the activation of emergency protocols in terms of alarm prioritization and personalization, as well as some remarks about security, privacy, and real-time communication performance. PMID- 25014978 TI - A standardized SOA for clinical data interchange in a cardiac telemonitoring environment. AB - Care of chronic cardiac patients requires information interchange between patients' homes, clinical environments, and the electronic health record. Standards are emerging to support clinical information collection, exchange and management and to overcome information fragmentation and actors delocalization. Heterogeneity of information sources at patients' homes calls for open solutions to collect and accommodate multidomain information, including environmental data. Based on the experience gained in a European Research Program, this paper presents an integrated and open approach for clinical data interchange in cardiac telemonitoring applications. This interchange is supported by the use of standards following the indications provided by the national authorities of the countries involved. Taking into account the requirements provided by the medical staff involved in the project, the authors designed and implemented a prototypal middleware, based on a service-oriented architecture approach, to give a structured and robust tool to congestive heart failure patients for their personalized telemonitoring. The middleware is represented by a health record management service, whose interface is compliant to the healthcare services specification project Retrieve, Locate and Update Service standard (Level 0), which allows communication between the agents involved through the exchange of Clinical Document Architecture Release 2 documents. Three performance tests were carried out and showed that the prototype completely fulfilled all requirements indicated by the medical staff; however, certain aspects, such as authentication, security and scalability, should be deeply analyzed within a future engineering phase. PMID- 25014979 TI - Sparsity-inspired nonparametric probability characterization for radio propagation in body area networks. AB - Parametric probability models are common references for channel characterization. However, the limited number of samples and uncertainty of the propagation scenario affect the characterization accuracy of parametric models for body area networks. In this paper, we propose a sparse nonparametric probability model for body area wireless channel characterization. The path loss and root-mean-square delay, which are significant wireless channel parameters, can be learned from this nonparametric model. A comparison with available parametric models shows that the proposed model is very feasible for the body area propagation environment and can be seen as a significant supplement to parametric approaches. PMID- 25014980 TI - Blood Vessel Segmentation of Fundus Images by Major Vessel Extraction and Subimage Classification. AB - This paper presents a novel three-stage blood vessel segmentation algorithm using fundus photographs. In the first stage, the green plane of a fundus image is preprocessed to extract a binary image after high-pass filtering, and another binary image from the morphologically reconstructed enhanced image for the vessel regions. Next, the regions common to both the binary images are extracted as the major vessels. In the second stage, all remaining pixels in the two binary images are classified using a Gaussian mixture model (GMM) classifier using a set of eight features that are extracted based on pixel neighborhood and first and second-order gradient images. In the third postprocessing stage, the major portions of the blood vessels are combined with the classified vessel pixels. The proposed algorithm is less dependent on training data, requires less segmentation time and achieves consistent vessel segmentation accuracy on normal images as well as images with pathology when compared to existing supervised segmentation methods. The proposed algorithm achieves a vessel segmentation accuracy of 95.2%, 95.15%, and 95.3% in an average of 3.1, 6.7, and 11.7 s on three public datasets DRIVE, STARE, and CHASE_DB1, respectively. PMID- 25014981 TI - Development of a wireless oral-feeding monitoring system for preterm infants. AB - Oral-feeding disorder is common in preterm infants. It not only shows the adverse effect for growth and neurodevelopment in clinical but also becomes one of the important indicators of high-risk group for neurodevelopment delay in preterm infants. Preterm infants must coordinate the motor patterns of sucking, swallowing, and respiration skillfully to avoid choking, aspiration, oxygen desaturation, bradycardia, or apnea episodes. However, up to now, the judgment and classification severity in preterm infants are mostly subjective and phasic evaluations. Directly monitoring the coordination of sucking-swallowing-breathing during oral feeding simultaneously is difficult for preterm infants. In this study, we proposed a wireless oral-feeding monitoring system for preterm infants to quantitatively monitor the sucking pressure via a designed sucking pressure sensing device, swallowing activity via a microphone to detect swallowing sound, and diaphragmatic breathing movement via surface electromyogram. Moreover, a sucking-swallowing-breathing detection algorithm is also proposed to evaluate the events of sucking-swallowing-breathing activities. Furthermore, verification of the accuracy and rationality of oral-feeding parameters with clinical findings including sucking, swallowing, and breathing in term and preterm infants had proved the practicality and value of the proposed system. PMID- 25014982 TI - Novel neural networks-based fault tolerant control scheme with fault alarm. AB - In this paper, the problem of adaptive active fault-tolerant control for a class of nonlinear systems with unknown actuator fault is investigated. The actuator fault is assumed to have no traditional affine appearance of the system state variables and control input. The useful property of the basis function of the radial basis function neural network (NN), which will be used in the design of the fault tolerant controller, is explored. Based on the analysis of the design of normal and passive fault tolerant controllers, by using the implicit function theorem, a novel NN-based active fault-tolerant control scheme with fault alarm is proposed. Comparing with results in the literature, the fault-tolerant control scheme can minimize the time delay between fault occurrence and accommodation that is called the time delay due to fault diagnosis, and reduce the adverse effect on system performance. In addition, the FTC scheme has the advantages of a passive fault-tolerant control scheme as well as the traditional active fault tolerant control scheme's properties. Furthermore, the fault-tolerant control scheme requires no additional fault detection and isolation model which is necessary in the traditional active fault-tolerant control scheme. Finally, simulation results are presented to demonstrate the efficiency of the developed techniques. PMID- 25014983 TI - Direct solution to the minimal generalized pose. AB - Pose estimation is a relevant problem for imaging systems whose applications range from augmented reality to robotics. In this paper we propose a novel solution for the minimal pose problem, within the framework of generalized camera models and using a planar homography. Within this framework and considering only the geometric elements of the generalized camera models, an imaging system can be modeled by a set of mappings associating image pixels to 3-D straight lines. This mapping is defined in a 3-D world coordinate system. Pose estimation performs the computation of the rigid transformation between the original 3-D world coordinate system and the one in which the camera was calibrated. Using synthetic data, we compare the proposed minimal-based method with the state-of-the-art methods in terms of numerical errors, number of solutions and processing time. From the experiments, we conclude that the proposed method performs better, especially because there is a smaller variation in numerical errors, while results are similar in terms of number of solutions and computation time. To further evaluate the proposed approach we tested our method with real data. One of the relevant contributions of this paper is theoretical. When compared to the state-of-the-art approaches, we propose a completely new parametrization of the problem that can be solved in four simple steps. In addition, our approach does not require any predefined transformation of the dataset, which yields a simpler solution for the problem. PMID- 25014984 TI - Boosting for multi-graph classification. AB - In this paper, we formulate a novel graph-based learning problem, multi-graph classification (MGC), which aims to learn a classifier from a set of labeled bags each containing a number of graphs inside the bag. A bag is labeled positive, if at least one graph in the bag is positive, and negative otherwise. Such a multi graph representation can be used for many real-world applications, such as webpage classification, where a webpage can be regarded as a bag with texts and images inside the webpage being represented as graphs. This problem is a generalization of multi-instance learning (MIL) but with vital differences, mainly because instances in MIL share a common feature space whereas no feature is available to represent graphs in a multi-graph bag. To solve the problem, we propose a boosting based multi-graph classification framework (bMGC). Given a set of labeled multi-graph bags, bMGC employs dynamic weight adjustment at both bag- and graph-levels to select one subgraph in each iteration as a weak classifier. In each iteration, bag and graph weights are adjusted such that an incorrectly classified bag will receive a higher weight because its predicted bag label conflicts to the genuine label, whereas an incorrectly classified graph will receive a lower weight value if the graph is in a positive bag (or a higher weight if the graph is in a negative bag). Accordingly, bMGC is able to differentiate graphs in positive and negative bags to derive effective classifiers to form a boosting model for MGC. Experiments and comparisons on real world multi-graph learning tasks demonstrate the algorithm performance. PMID- 25014985 TI - Semi-flocking algorithm for motion control of mobile sensors in large-scale surveillance systems. AB - The ability of sensors to self-organize is an important asset in surveillance sensor networks. Self-organize implies self-control at the sensor level and coordination at the network level. Biologically inspired approaches have recently gained significant attention as a tool to address the issue of sensor control and coordination in sensor networks. These approaches are exemplified by the two well known algorithms, namely, the Flocking algorithm and the Anti-Flocking algorithm. Generally speaking, although these two biologically inspired algorithms have demonstrated promising performance, they expose deficiencies when it comes to their ability to maintain simultaneous robust dynamic area coverage and target coverage. These two coverage performance objectives are inherently conflicting. This paper presents Semi-Flocking, a biologically inspired algorithm that benefits from key characteristics of both the Flocking and Anti-Flocking algorithms. The Semi-Flocking algorithm approaches the problem by assigning a small flock of sensors to each target, while at the same time leaving some sensors free to explore the environment. This allows the algorithm to strike balance between robust area coverage and target coverage. Such balance is facilitated via flock-sensor coordination. The performance of the proposed Semi Flocking algorithm is examined and compared with other two flocking-based algorithms once using randomly moving targets and once using a standard walking pedestrian dataset. The results of both experiments show that the Semi-Flocking algorithm outperforms both the Flocking algorithm and the Anti-Flocking algorithm with respect to the area of coverage and the target coverage objectives. Furthermore, the results show that the proposed algorithm demonstrates shorter target detection time and fewer undetected targets than the other two flocking based algorithms. PMID- 25014986 TI - Graph-based sensor fusion for classification of transient acoustic signals. AB - Advances in acoustic sensing have enabled the simultaneous acquisition of multiple measurements of the same physical event via co-located acoustic sensors. We exploit the inherent correlation among such multiple measurements for acoustic signal classification, to identify the launch/impact of munition (i.e., rockets, mortars). Specifically, we propose a probabilistic graphical model framework that can explicitly learn the class conditional correlations between the cepstral features extracted from these different measurements. Additionally, we employ symbolic dynamic filtering-based features, which offer improvements over the traditional cepstral features in terms of robustness to signal distortions. Experiments on real acoustic data sets show that our proposed algorithm outperforms conventional classifiers as well as the recently proposed joint sparsity models for multisensor acoustic classification. Additionally our proposed algorithm is less sensitive to insufficiency in training samples compared to competing approaches. PMID- 25014987 TI - Adaptive memetic computing for evolutionary multiobjective optimization. AB - Inspired by biological evolution, a plethora of algorithms with evolutionary features have been proposed. These algorithms have strengths in certain aspects, thus yielding better optimization performance in a particular problem. However, in a wide range of problems, none of them are superior to one another. Synergetic combination of these algorithms is one of the potential ways to ameliorate their search ability. Based on this idea, this paper proposes an adaptive memetic computing as the synergy of a genetic algorithm, differential evolution, and estimation of distribution algorithm. The ratio of the number of fitter solutions produced by the algorithms in a generation defines their adaptability features in the next generation. Subsequently, a subset of solutions undergoes local search using the evolutionary gradient search algorithm. This memetic technique is then implemented in two prominent frameworks of multiobjective optimization: the domination- and decomposition-based frameworks. The performance of the adaptive memetic algorithms is validated in a wide range of test problems with different characteristics and difficulties. PMID- 25014988 TI - SEG-SSC: a framework based on synthetic examples generation for self-labeled semi supervised classification. AB - Self-labeled techniques are semi-supervised classification methods that address the shortage of labeled examples via a self-learning process based on supervised models. They progressively classify unlabeled data and use them to modify the hypothesis learned from labeled samples. Most relevant proposals are currently inspired by boosting schemes to iteratively enlarge the labeled set. Despite their effectiveness, these methods are constrained by the number of labeled examples and their distribution, which in many cases is sparse and scattered. The aim of this paper is to design a framework, named synthetic examples generation for self-labeled semi-supervised classification, to improve the classification performance of any given self-labeled method by using synthetic labeled data. These are generated via an oversampling technique and a positioning adjustment model that use both labeled and unlabeled examples as reference. Next, these examples are incorporated in the main stages of the self-labeling process. The principal aspects of the proposed framework are: 1) introducing diversity to the multiple classifiers used by using more (new) labeled data; 2) fulfilling labeled data distribution with the aid of unlabeled data; and 3) being applicable to any kind of self-labeled method. In our empirical studies, we have applied this scheme to four recent self-labeled methods, testing their capabilities with a large number of data sets. We show that this framework significantly improves the classification capabilities of self-labeled techniques. PMID- 25014989 TI - A new incomplete pattern classification method based on evidential reasoning. AB - The classification of incomplete patterns is a very challenging task because the object (incomplete pattern) with different possible estimations of missing values may yield distinct classification results. The uncertainty (ambiguity) of classification is mainly caused by the lack of information of the missing data. A new prototype-based credal classification (PCC) method is proposed to deal with incomplete patterns thanks to the belief function framework used classically in evidential reasoning approach. The class prototypes obtained by training samples are respectively used to estimate the missing values. Typically, in a c -class problem, one has to deal with c prototypes, which yield c estimations of the missing values. The different edited patterns based on each possible estimation are then classified by a standard classifier and we can get at most c distinct classification results for an incomplete pattern. Because all these distinct classification results are potentially admissible, we propose to combine them all together to obtain the final classification of the incomplete pattern. A new credal combination method is introduced for solving the classification problem, and it is able to characterize the inherent uncertainty due to the possible conflicting results delivered by different estimations of the missing values. The incomplete patterns that are very difficult to classify in a specific class will be reasonably and automatically committed to some proper meta-classes by PCC method in order to reduce errors. The effectiveness of PCC method has been tested through four experiments with artificial and real data sets. PMID- 25014990 TI - Multiagent reinforcement learning with unshared value functions. AB - One important approach of multiagent reinforcement learning (MARL) is equilibrium based MARL, which is a combination of reinforcement learning and game theory. Most existing algorithms involve computationally expensive calculation of mixed strategy equilibria and require agents to replicate the other agents' value functions for equilibrium computing in each state. This is unrealistic since agents may not be willing to share such information due to privacy or safety concerns. This paper aims to develop novel and efficient MARL algorithms without the need for agents to share value functions. First, we adopt pure strategy equilibrium solution concepts instead of mixed strategy equilibria given that a mixed strategy equilibrium is often computationally expensive. In this paper, three types of pure strategy profiles are utilized as equilibrium solution concepts: pure strategy Nash equilibrium, equilibrium-dominating strategy profile, and nonstrict equilibrium-dominating strategy profile. The latter two solution concepts are strategy profiles from which agents can gain higher payoffs than one or more pure strategy Nash equilibria. Theoretical analysis shows that these strategy profiles are symmetric meta equilibria. Second, we propose a multistep negotiation process for finding pure strategy equilibria since value functions are not shared among agents. By putting these together, we propose a novel MARL algorithm called negotiation-based Q-learning (NegoQ). Experiments are first conducted in grid-world games, which are widely used to evaluate MARL algorithms. In these games, NegoQ learns equilibrium policies and runs significantly faster than existing MARL algorithms (correlated Q-learning and Nash Q-learning). Surprisingly, we find that NegoQ also performs well in team Markov games such as pursuit games, as compared with team-task-oriented MARL algorithms (such as friend Q-learning and distributed Q-learning). PMID- 25014991 TI - IMP3 signatures of fallopian tube: a risk for pelvic serous cancers. AB - BACKGROUND: Recent advances suggest fallopian tube as the main cellular source for women's pelvic serous carcinoma (PSC). In addition to TP53 mutations, many other genetic changes are involved in pelvic serous carcinogenesis. IMP3 is an oncofetal protein which has recently been observed to be overexpressed in benign looking tubal epithelia. Such findings prompted us to examine the relationship between IMP3 over-expression, patient age and the likelihood of development of PSC. METHODS: Fallopian tubes from three groups (low-risk, high-risk, and PSC) of patients with matched ages were studied. Age was recorded in 10 years intervals ranging from age 20 to older than 80. The number of IMP3 signatures (defined by 10 or more tubal secretory cells stained positively and continuously in benign appearing tubal mucosa) from both tubal fimbria and ampulla segments was measured. The data was analyzed by standard contingency table and Poisson distribution methods after age adjustment. IMP3 overexpression was also examined in serous tubal intraepithelial carcinoma and PSC. RESULTS: The positive IMP3 stained cells are mainly tubal secretory cells. The absolute number of tubal IMP3 signatures increased significantly within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. IMP3 signatures were more frequent in the patients of both high-risk and PSC groups. The presence of IMP3 signatures in tubal mucosa was significantly associated with tubal or pelvic serous carcinogenesis (p < 0.001). CONCLUSIONS: The findings suggest that tubal secretory cells with IMP3 signatures showing growth advantage could potentially serve as a latent precancer biomarker for tubal or pelvic serous carcinomas in women. PMID- 25014992 TI - Correction of a severe facial asymmetry with computerized planning and with the use of a rapid prototyped surgical template: a case report/technique article. AB - Management of significant facial asymmetry presents a challenge due to the geometric complexity of the bony and other facial structures. Manual model surgery is an essential part of treatment planning but it can be complicated, time-consuming and may contain potential errors. Computer-aided surgery has revolutionized the correction of maxillofacial deformities. The aim of this study was to report a case of facial asymmetry when computerised simulation surgery was performed instead of manual model surgery and a virtually planned wafer splint was fabricated. A 26-year-old male was presented with a severe right-sided hemimandibular elongation. Following presurgical orthodontics high-resolution computer tomography scan was performed. The stack images were reformatted into a three-dimensional structure. Virtual Le Fort-I osteotomy was performed and the symmetry of the maxilla was corrected with the help of a three-dimensional planning software. A virtual intermediate surgical wafer was designed and produced with three-dimensional rapid prototyping technology. The mandible was rotated into the correct position following virtual bilateral sagittal split osteotomy to visualize the movements of the osteotomised mandibular segments. The two-jaw procedure was performed according to the virtual plan. The facial symmetry was improved significantly and stable occlusion was achieved. This complex case shows the advantages of computer-aided surgical planning and three dimensional rapid prototyping for the correction of facial asymmetries. PMID- 25014993 TI - Health effects of occupational exposure to uranium: do physicochemical properties matter? AB - PURPOSE: Physicochemical properties of uranium, including isotopic composition and solubility, are determinants of its toxicity. We reviewed epidemiological studies in civilian and military workers known to be exposed to uranium with different physicochemical properties to investigate its long-term effects, such as cancerous and circulatory diseases. MATERIALS AND METHODS: We systematically searched the Pubmed and the Scopus databases to identify studies of uranium- processing workers (published between 1980 and 2013) and veterans of the wars in the Persian Gulf and the Balkans (published between 1991 and 2013) in which defined outcomes, such as lung, lymphohematopoietic, kidney cancers, and circulatory diseases were examined. RESULTS from these studies in terms of risk of each health outcome (mortality or incidence) and analyses of dose-response relationship were examined to present the impact of uranium physicochemical properties on the observed results. RESULTS: Twenty-seven articles were reviewed. There is some evidence for increased lung cancer risk among uranium-processing workers. The evidence is less strong for lymphohematopoietic cancer. We found that most of the studies insufficiently assessed the physicochemical properties of uranium and some of them used proxies for the exposure assessment and risk estimation analyses. Studies of veterans of the wars in the Persian Gulf and the Balkans are uninformative in respect to internal uranium exposure. CONCLUSIONS: Existing epidemiological data on the physicochemical properties of uranium and associated health outcomes are inconclusive. Further studies among certain groups of uranium-processing workers (uranium-enrichment and fuel-fabrication workers) could contribute to our knowledge of the health effects of uranium with respect to its physicochemical properties. PMID- 25014994 TI - Multiresistant extended-spectrum beta-lactamase-producing Enterobacteriaceae from humans, companion animals and horses in central Hesse, Germany. AB - BACKGROUND: Multiresistant Gram-negative bacteria producing extended-spectrum beta-lactamases (ESBLs) are an emerging problem in human and veterinary medicine. This study focused on comparative molecular characterization of beta-lactamase and ESBL-producing Enterobacteriaceae isolates from central Hesse in Germany. Isolates originated from humans, companion animals (dogs and cats) and horses. RESULTS: In this study 153 (83.6%) of the human isolates (n = 183) and 163 (91.6%) of the animal isolates (n = 178) were confirmed as ESBL producers by PCR and subsequent sequencing of the PCR amplicons. Predominant ESBL subtypes in human and animal samples were CTX-M-15 (49.3%) and CTX-M-1 (25.8%) respectively. Subtype blaCTX-M-2 was found almost exclusively in equine and was absent from human isolates. The carbapenemase OXA-48 was detected in 19 ertapenem-resistant companion animal isolates in this study. The Plasmid-encoded quinolone resistance (PMQR) gene aac('6)-Ib-cr was the most frequently detected antibiotic- resistance gene present in 27.9% of the human and 36.9% of the animal ciprofloxacin resistant isolates. Combinations of two or up to six different resistance genes (penicillinases, ESBLs and PMQR) were detected in 70% of all isolates investigated. The most frequent species in this study was Escherichia coli (74%), followed by Klebsiella pneumoniae (17.5%), and Enterobacter cloacae (4.2%). Investigation of Escherichia coli phylogenetic groups revealed underrepresentation of group B2 within the animal isolates. CONCLUSIONS: Isolates from human, companion animals and horses shared several characteristics regarding presence of ESBL, PMQR and combination of different resistance genes. The results indicate active transmission and dissemination of multi-resistant Enterobacteriaceae among human and animal populations. PMID- 25014995 TI - The electronic self report assessment and intervention for cancer: promoting patient verbal reporting of symptom and quality of life issues in a randomized controlled trial. AB - BACKGROUND: The electronic self report assessment - cancer (ESRA-C), has been shown to reduce symptom distress during cancer therapy The purpose of this analysis was to evaluate aspects of how the ESRA-C intervention may have resulted in lower symptom distress (SD). METHODS: Patients at two cancer centers were randomized to ESRA-C assessment only (control) or the Web-based ESRA-C intervention delivered to patients' homes or to a tablet in clinic. The intervention allowed patients to self-monitor symptom and quality of life (SxQOL) between visits, receive self-care education and coaching to report SxQOL to clinicians. Summaries of assessments were delivered to clinicians in both groups. Audio-recordings of clinic visits made 6 weeks after treatment initiation were coded for discussions of 26 SxQOL issues, focusing on patients'/caregivers' coached verbal reports of SxQOL severity, pattern, alleviating/aggravating factors and requests for help. Among issues identified as problematic, two measures were defined for each patient: the percent SxQOL reported that included a coached statement, and an index of verbalized coached statements per SxQOL. The Wilcoxon rank test was used to compare measures between groups. Clinician responses to problematic SxQOL were compared. A mediation analysis was conducted, exploring the effect of verbal reports on SD outcomes. RESULTS: 517 (256 intervention) clinic visits were audio-recorded. General discussion of problematic SxQOL was similar in both groups. Control group patients reported a median 75% of problematic SxQOL using any specific coached statement compared to a median 85% in the intervention group (p = .0009). The median report index of coached statements was 0.25 for the control group and 0.31 for the intervention group (p = 0.008). Fatigue, pain and physical function issues were reported significantly more often in the intervention group (all p < .05). Clinicians' verbalized responses did not differ between groups. Patients' verbal reports did not mediate final SD outcomes (p = .41). CONCLUSIONS: Adding electronically delivered, self-care instructions and communication coaching to ESRA-C promoted specific patient descriptions of problematic SxQOL issues compared with ESRA-C assessment alone. However, clinician verbal responses were no different and subsequent symptom distress group differences were not mediated by the patients' reports. TRIAL REGISTRATION: NCT00852852; 26 Feb 2009. PMID- 25014996 TI - Xuan Bai Cheng Qi formula as an adjuvant treatment of acute exacerbation of chronic obstructive pulmonary disease of the syndrome type phlegm-heat obstructing the lungs: a multicenter, randomized, double-blind, placebo controlled clinical trial. AB - BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause of morbidity and mortality. Traditional Chinese medicine (TCM) is used to treat AECOPD as adjunctive therapy. This study aimed to evaluate the efficacy and safety of the TCM formula Xuan Bai Cheng Qi as an adjuvant therapy for AECOPD patients with the syndrome type of phlegm-heat obstructing the lungs. METHODS: A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted. A total of 244 patients were divided into the intervention group (n = 122, treated with conventional medicine and Xuan Bai Cheng Qi) and the control group (n = 122, treated with conventional medicine and placebo). Total symptom scores (cough, phlegm, wheezing, chest congestion) before treatment and at 3, 5, 7, 10 days post-treatment were recorded. Lung function, arterial blood gas, serum inflammatory cytokines, oxidation/anti-oxidation index were observed before treatment and at the end of the 10-day treatment. RESULTS: A total of 242 patients completed the study. The full analysis set (FAS) population was 244 and the per-protocol analysis set (PPS) population was 229. After the 10-day treatment, symptom scores of the Xuan Bai Cheng Qi group were significantly lower over time compared with the control group (FAS: mean difference -1.84, 95% CI 2.66 to -1.03, P < .001; PPS: mean difference -1.87, 95% CI -2.71 to -1.03, P < .001). FEV1, FVC, and FEV1%pred were significantly higher over time in the Xuan Bai Cheng Qi group compared with those in the control group (day 10, FAS and PPS: P < .05). PaO2 and PaCO2 were significantly improved in the Xuan Bai Cheng Qi group (day 10, FAS and PPS: P < .05). Xuan Bai Cheng Qi was also found to ameliorate cytokine levels and oxidation/antioxidant index compared with placebo. There were no differences in safety variables and adverse events between the two groups. CONCLUSIONS: Xuan Bai Cheng Qi formula appears to be a safe and beneficial treatment for AECOPD of phlegm-heat obstructing the lungs syndrome type. PMID- 25014997 TI - Ingested hyaluronan moisturizes dry skin. AB - Hyaluronan (HA) is present in many tissues of the body and is essential to maintain moistness in the skin tissues, which contain approximately half the body's HA mass. Due to its viscosity and moisturizing effect, HA is widely distributed as a medicine, cosmetic, food, and, recently marketed in Japan as a popular dietary supplement to promote skin moisture. In a randomized, double blind, placebo-controlled clinical study it was found that ingested HA increased skin moisture and improved treatment outcomes for patients with dry skin. HA is also reported to be absorbed by the body distributed, in part, to the skin. Ingested HA contributes to the increased synthesis of HA and promotes cell proliferation in fibroblasts. These effects show that ingestion of HA moisturizes the skin and is expected to improve the quality of life for people who suffer from dry skin. This review examines the moisturizing effects of dry skin by ingested HA and summarizes the series of mechanisms from absorption to pharmacological action. PMID- 25014998 TI - The presence of tumor-infiltrating IL-17-producing cells in juvenile nasopharyngeal angiofibroma tumor microenvironment is a poor prognostic factor. AB - BACKGROUND: Although juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor histologically, it demonstrates aggressive propensity of locally destructive growth causing bone erosion. The patients with JNA remain high recurrence rate after surgical excision. Th17 cells secrete the proinflammatory cytokine interleukin-17 (IL-17), and play an important role in carcinogenesis and tumor progression. So far, no studies have focused on the significance of IL-17 producing cells in the JNA tumor microenvironment. The current study was designed to investigate the localization and level of tumor-infiltrating IL-17-producing cells in JNA microenvironment. The presence and number of IL-17-producing cells were further analyzed for a possible association with clinicopathological features and disease outcome. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of IL-17 in a tissue microarray from 70 patients with JNA and 10 control subjects. Correlations between the levels of IL-17 expression and clinicopathologic variables, as well as tumor recurrence, were assessed. RESULTS: In vessels, the IL-17-producing cells were identified in pericytes and irregular smooth muscle cells, but the matured vascular endothelial cells showed no IL-17 reactivity. The expression of IL-17 in stromal cells was concentrated in the less differentiated and plump cells that contained a central hypochromatic nucleus and single small nucleolus. Chi-square test showed that tumor stage (p=0.09), operation history (p=0.828), operation approach (p=0.159), and volume of intraoperative hemorrhage (p=0.352) were not associated with the expression of IL-17 in JNA patients. However, intratumoral IL-17-producing cells were negatively associated with patient's age (p=0.004). Furthermore, we found that patients with extensive infiltration of IL-17-producing cells had significantly higher recurrence rates than those with less infiltration of IL-17 producing cells (p=0.028). Log rank analysis showed that JNA patients with high levels of IL-17 had significantly shorter disease free survival (DFS) than those with low levels of IL-17 (p=0.004). Univariate Cox regression analysis suggested that IL-17 and patient's age were significantly associated with DFS. Multivariate analysis indicated that high infiltration with IL-17-producing cells was associated with poor DFS. Of all clinicopathological features, IL-17 level was an independent factor predicting the patient's prognosis. CONCLUSION: In JNA patients, a high level of IL-17-producing cells was negatively associated with patient's age. Patients with extensive infiltration of IL-17-producing cells had significantly higher tumor recurrence rates. High infiltration of IL-17-producing cells in JNA microenvironment is an independent poor prognostic factor for shorter disease-free survival. Future studies further focusing on the role of IL 17 may provide more promising therapeutic methods for extensive JNA tumors. PMID- 25014999 TI - Pixel based focusing for photoacoustic and ultrasound dual-modality imaging. AB - It is desired that the same imaging functional modules such as beamformation, envelope detection, and digital scan conversion (DSC) are employed for the efficient development of a cross-sectional photoacoustic (PA) and ultrasound (US) dual-modality imaging system. The beamformation can be implemented using either delay-and-sum beamforming (DAS-BF) or adaptive beamforming methods, each with their own advantages and disadvantages for the dual-modality imaging. However, the DSC is always problematic because it causes blurring the fine details of an image, e.g., edges. This paper demonstrates that the pixel based focusing method is suitable for the dual-modality imaging; beamformation is directly conducted on each display pixel and thus DSC is not necessary. As a result, the artifacts by DSC are no longer a problem, so that the proposed method is capable of providing the maximum spatial resolution achievable by DAS-BF. The performance of the proposed method was evaluated through simulation and ex vivo experiments with a microcalcification-contained breast specimen, and the results were compared with those from DAS-BF and adaptive beamforming methods with DSC. The comparison demonstrated that the proposed method effectively overcomes the disadvantages of each beamforming method. PMID- 25015000 TI - Periodic shock-emission from acoustically driven cavitation clouds: a source of the subharmonic signal. AB - Single clouds of cavitation bubbles, driven by 254kHz focused ultrasound at pressure amplitudes in the range of 0.48-1.22MPa, have been observed via high speed shadowgraphic imaging at 1*10(6) frames per second. Clouds underwent repetitive growth, oscillation and collapse (GOC) cycles, with shock-waves emitted periodically at the instant of collapse during each cycle. The frequency of cloud collapse, and coincident shock-emission, was primarily dependent on the intensity of the focused ultrasound driving the activity. The lowest peak-to-peak pressure amplitude of 0.48MPa generated shock-waves with an average period of 7.9+/-0.5MUs, corresponding to a frequency of f0/2, half-harmonic to the fundamental driving. Increasing the intensity gave rise to GOC cycles and shock emission periods of 11.8+/-0.3, 15.8+/-0.3, 19.8+/-0.2MUs, at pressure amplitudes of 0.64, 0.92 and 1.22MPa, corresponding to the higher-order subharmonics of f0/3, f0/4 and f0/5, respectively. Parallel passive acoustic detection, filtered for the fundamental driving, revealed features that correlated temporally to the shock-emissions observed via high-speed imaging, p(two-tailed) < 0.01 (r=0.996, taken over all data). Subtracting the isolated acoustic shock profiles from the raw signal collected from the detector, demonstrated the removal of subharmonic spectral peaks, in the frequency domain. The larger cavitation clouds (>200MUm diameter, at maximum inflation), that developed under insonations of peak-to-peak pressure amplitudes >1.0MPa, emitted shock-waves with two or more fronts suggesting non-uniform collapse of the cloud. The observations indicate that periodic shock-emissions from acoustically driven cavitation clouds provide a source for the cavitation subharmonic signal, and that shock structure may be used to study intra-cloud dynamics at sub-microsecond timescales. PMID- 25015001 TI - Transcriptome analysis of the differences in gene expression between testis and ovary in green mud crab (Scylla paramamosain). AB - BACKGROUND: The green mud crab (Scylla paramamosain) is the most prevalent crustacean on the southeast coast of China. The molecular regulatory mechanism of sex determination and gonadal differentiation in this species has received considerable attention in recent years because of the huge differences--both biological and economic--between male and female crabs. In this study, next generation sequencing technology was used to develop deep-coverage transcriptomic sequencing data for the testis and ovary of S. paramamosain. RESULTS: A total of 365,116 reads (testis 171,962, ovary 193,154) with an average sequence length of 285 bp were produced from testis and ovary cDNA libraries. After filtering out contaminating reads, the clean reads were assembled, producing a total of 21,791 isotigs and leaving 22,814 reads as singlets. Using the BLASTX program, 3,471 unique sequences (2,275 isotigs and 1,196 singletons) were annotated with known protein sequences from the NCBI non-redundant (Nr) protein sequence database. The Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses allowed the 224 unique sequences that were annotated with enzyme code (EC) numbers to be mapped into 174 KEGG pathways. After comparing the ovary and testis libraries, 4,021 gonad-differentially, 10,522 ovary-specifically, and 19,013 testis specifically expressed genes were identified. Moreover, 33 ovary-specific, 14 testis-specific, and 34 gonad-differential transcripts were confirmed by semi quantitative PCR and quantitative real-time PCR. In addition, 8,610 putative simple sequence repeats (SSRs) and 23,879 potential single nucleotide polymorphisms (SNPs) were identified. CONCLUSION: This is the first large-scale RNA sequencing of S. paramamosain to be reported. We have identified many important functional genes and made a preliminary attempt to construct the regulatory network involved in the gonadal development of crustaceans. The annotated transcriptome data will provide fundamental support for future research into the reproduction biology of S. paramamosain. A large number of candidate SSRs and SNPs were detected, which could be used as genetic markers for population genetics and functional genomics in this species. PMID- 25015002 TI - Cytokine secretion from brain macrophages infected with human immunodeficiency virus in vitro and treated with raltegravir. AB - BACKGROUND: Integrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection. During HIV infection, macrophages can extravasate from the blood to the brain, while producing chemotaxic proteins and cytokines, which have detrimental effects on central nervous system cells. The main goal of this study was to understand the effects of raltegravir (RAL) on human brain macrophage production of immune-mediators when infected with HIV, but did not compare with other antiretroviral agents. METHODS: Pro-inflammatory cytokines, IFN-gamma, IL-10, IL-12-p70, IL-1, IL-8, TNF alpha, and IL-6 were measured simultaneously in tissue culture supernatants from primary brain derived macrophages, microglia. We tested the effects of RAL on markers of astrocytosis and neurite integrity in primary human neuroglial cultures. RESULTS: RAL administered at 20 nM effectively suppressed HIV infection in microglia over 9 days. Only IL-8, IL-10, and TNF-alpha were above the detection limit in the majority of samples and RAL significantly suppressed the rate of cytokine production in HIV-infected microglia. During RAL-alone, the rate of IL-8 secretion was higher. CONCLUSIONS: RAL did not affect neurite area but inhibited astrocyte growth in the neuroglial cultures. Exploring the effects of RAL on pro-inflammatory molecule production in brain macrophages may contribute to designing ARV neuroprotective strategies in chronic HIV infection. PMID- 25015003 TI - Ultrafast structural dynamics of Cu(I)-bicinchoninic acid and their implications for solar energy applications. AB - In this study, ultrafast optical transient absorption and X-ray transient absorption (XTA) spectroscopy are used to probe the excited-state dynamics and structural evolution of copper(I) bicinchoninic acid ([Cu(I)(BCA)2](+)), which has similar but less frequently studied biquinoline-based ligands compared to phenanthroline-based complexes. The optical transient absorption measurements performed on the complex in a series of polar protic solvents demonstrate a strong solvent dependency for the excited lifetime, which ranges from approximately 40 ps in water to over 300 ps in 2-methoxyethanol. The XTA experiments showed a reduction of the prominent 1s -> 4pz edge peak in the excited-state X-ray absorption near-edge structure (XANES) spectrum, which is indicative of an interaction with a fifth ligand, most likely the solvent. Analysis of the extended X-ray absorption fine structure (EXAFS) spectrum shows a shortening of the metal-ligand bond in the excited state and an increase in the coordination number for the Cu(II) metal center. A flattened structure is supported by DFT calculations that show that the system relaxes into a flattened geometry with a lowest-energy triplet state that has a dipole-forbidden transition to the ground state. While the short excited-state lifetime relative to previously studied Cu(I) diimine complexes could be attributed to this dark triplet state, the strong solvent dependency and the reduction of the 1s -> 4pz peak in the XTA data suggest that solvent interaction could also play a role. This detailed study of the dynamics in different solvents provides guidance for modulating excited-state pathways and lifetimes through structural factors such as solvent accessibility to fulfill the excited-state property requirements for efficient light harvesting and electron injection. PMID- 25015006 TI - Clonidine in the sedation of mechanically ventilated children: a pilot randomized trial. AB - PURPOSE: Clonidine is often used as a sedative in critically ill children, but its effectiveness has not been evaluated in a large, rigorous randomized controlled trial. Our objectives in this pilot trial were to assess the feasibility of a larger trial with respect to (1) effective screening, (2) recruitment, (3) timely drug administration, and (4) protocol adherence. MATERIALS AND METHODS: This is a randomized, blinded, placebo-controlled pilot trial. Mechanically ventilated children received enteral clonidine 5 MUg/kg or placebo every 6 hours; additional sedatives were at the discretion of attending physicians. RESULTS: We enrolled 50 children. The median interquartile range (IQR) age was 2.5 (0.7-5.2) years, and Pediatric Risk of Mortality score on pediatric intensive care unit admission was 12 (8-15). In terms of feasibility outcomes, 90 (87%) of 104 eligible patients were approached for consent, and on average, 1.7 children were enrolled per month. Thirty-five (70%) were enrolled within 1 day of becoming eligible (mean, 1.2 days). Thereafter, 94% of doses were administered by protocol. Clinical outcomes and adverse effects were not significantly different between the groups. CONCLUSIONS: This pilot trial demonstrated feasibility of a larger randomized controlled trial. Some important challenges emerged, allowing refinement of the study protocol and enrolment estimates. We recommend that future trials capitalize on the experience gained and use these results to design a larger trial focusing on clinically important outcomes. PMID- 25015005 TI - Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice. AB - INTRODUCTION: Syndecans are heparan sulphate proteoglycans expressed by endothelial cells. Syndecan-3 is expressed by synovial endothelial cells of rheumatoid arthritis (RA) patients where it binds chemokines, suggesting a role in leukocyte trafficking. The objective of the current study was to examine the function of syndecan-3 in joint inflammation by genetic deletion in mice and compare with other tissues. METHODS: Chemokine C-X-C ligand 1 (CXCL1) was injected in the joints of syndecan-3-/-and wild-type mice and antigen-induced arthritis performed. For comparison chemokine was administered in the skin and cremaster muscle. Intravital microscopy was performed in the cremaster muscle. RESULTS: Administration of CXCL1 in knee joints of syndecan-3-/-mice resulted in reduced neutrophil accumulation compared to wild type. This was associated with diminished presence of CXCL1 at the luminal surface of synovial endothelial cells where this chemokine clustered and bound to heparan sulphate. Furthermore, in the arthritis model syndecan-3 deletion led to reduced joint swelling, leukocyte accumulation, cartilage degradation and overall disease severity. Conversely, CXCL1 administration in the skin of syndecan-3 null mice provoked increased neutrophil recruitment and was associated with elevated luminal expression of E selectin by dermal endothelial cells. Similarly in the cremaster, intravital microscopy showed increased numbers of leukocytes adhering and rolling in venules in syndecan-3-/-mice in response to CXCL1 or tumour necrosis factor alpha. CONCLUSIONS: This study shows a novel role for syndecan-3 in inflammation. In the joint it is selectively pro-inflammatory, functioning in endothelial chemokine presentation and leukocyte recruitment and cartilage damage in an RA model. Conversely, in skin and cremaster it is anti-inflammatory. PMID- 25015004 TI - A review of the vector management methods to prevent and control outbreaks of West Nile virus infection and the challenge for Europe. AB - West Nile virus infection is a growing concern in Europe. Vector management is often the primary option to prevent and control outbreaks of the disease. Its implementation is, however, complex and needs to be supported by integrated multidisciplinary surveillance systems and to be organized within the framework of predefined response plans. The impact of the vector control measures depends on multiple factors and the identification of the best combination of vector control methods is therefore not always straightforward. Therefore, this contribution aims at critically reviewing the existing vector control methods to prevent and control outbreaks of West Nile virus infection and to present the challenges for Europe.Most West Nile virus vector control experiences have been recently developed in the US, where ecological conditions are different from the EU and vector control is organized under a different regulatory frame. The extrapolation of information produced in North America to Europe might be limited because of the seemingly different epidemiology in the European region. Therefore, there is an urgent need to analyse the European experiences of the prevention and control of outbreaks of West Nile virus infection and to perform robust cost-benefit analysis that can guide the implementation of the appropriate control measures. Furthermore, to be effective, vector control programs require a strong organisational backbone relying on a previously defined plan, skilled technicians and operators, appropriate equipment, and sufficient financial resources. A decision making guide scheme is proposed which may assist in the process of implementation of vector control measures tailored on specific areas and considering the available information and possible scenarios. PMID- 25015007 TI - Cardiac index monitoring by femoral arterial thermodilution after cardiac surgery in children. AB - PURPOSE: The aim of this study is to determine whether the maintenance of cardiac index (CI) measured by femoral arterial thermodilution during the postoperative period after heart surgery in children is related to short-term outcome. MATERIALS AND METHODS: A prospective observational study in a pediatric intensive care unit at a referral hospital for congenital heart disease was conducted. Thirty-five children after open heart surgery were monitored in 5 planned times with PiCCO (Pulsion Medical System AG, Munich, Germany) during the first 24 hours after admission. Normal CI was defined as 3 L min(-1) m(-2) or greater. RESULTS: Eighteen patients hold CI at every measurement point. In this group, the median stay in the pediatric intensive care unit was 3 days (range, 2-7 days) compared with the median of 6 days (range, 2-34 days) obtained by the rest (P<.005). Duration of mechanical ventilation was 12 hours (range, 3-48 hours), and overall stay in the hospital was 6 days (range, 2-15 days) compared with 25 hours (range 6-432 hours) and 16 days (range, 4-50 days) obtained by the second group (P<.05). No complications were attributed to the use of the device. CONCLUSIONS: Monitoring by femoral arterial thermodilution has been feasible in our experience. Maintenance of a CI of 3 L min(-1) m(-2) or greater is related to a better patient's early outcome. PMID- 25015008 TI - The chiropractic scope of practice in the United States: a cross-sectional survey. AB - OBJECTIVE: The purpose of this study was to assess the current status of chiropractic practice laws in the United States. This survey is an update and expansion of 3 original surveys conducted in 1987, 1992, and 1998. METHODS: A cross-sectional survey of licensure officials from the Federation of Chiropractic Licensing Boards e-mail list was conducted in 2011 requesting information about chiropractic practice laws and 97 diagnostic, evaluation, and management procedures. To evaluate content validity, the survey was distributed in draft form at the fall 2010 Federation of Chiropractic Licensing Boards regional meeting to regulatory board members and feedback was requested. Comments were reviewed and incorporated into the final survey. A duplicate question was imbedded in the survey to test reliability. RESULTS: Partial or complete responses were received from 96% (n = 51) of the jurisdictions in the United States. The states with the highest number of services that could be performed were Missouri (n = 92), New Mexico (n = 91), Kansas (n = 89), Utah (n = 89), Oklahoma (n = 88), Illinois (n = 87), and Alabama (n = 86). The states with the highest number of services that cannot be performed are New Hampshire (n = 49), Hawaii (n = 47), Michigan (n = 42), New Jersey (n = 39), Mississippi (n = 39), and Texas (n = 30). CONCLUSION: The scope of chiropractic practice in the United States has a high degree of variability. Scope of practice is dynamic, and gray areas are subject to interpretation by ever-changing board members. Although statutes may not address specific procedures, upon challenge, there may be a possibility of sanctions depending on interpretation. PMID- 25015009 TI - Balance control impairment induced after OKS in patients with vestibular migraine: an intercritical marker. AB - The aim of the study was to assess the effects of optokinetic stimulation (OKS) on vestibular postural control in migraine patients with recurrent vertigo. 15 patients with vestibular migraine (VM) were enrolled in a posturographic study in eyes open (OE) and eyes closed (CE) condition. The tests were performed between attacks of headache and vertigo at three different time: before, during, and 60 min after OKS. Data of patients with VM were compared with those obtained from two control groups matched for sex and age (15 for each group): (a) normal subjects not suffering from migraine without history of recurrent vertigo (N group); (b) subjects suffering from migraine with no history of recurrent vertigo (M group). Mean sway path velocity and sway area were analyzed. OKS increased the instability in all groups during the stimulus, and both the velocity and area values were higher in M and VM group. However, there was not significant difference between these two groups when stability was examined in OE condition before, during and after OKS stimulation. Conversely, in CE condition a significant greater instability was induced after OKS stimulation only in VM. In particular, post-stimulus values were significantly higher than the pre-stimulus one only in this group, while no significant difference was observed in other groups. A spatial analysis of the sway area evidenced that the instability induced by the OKS in VM group occurred along the direction of OKS. We suggest that this enhanced instability observed after OKS during the intercritical period may be considered an useful marker to support the diagnostic definition of VM in the absence of other vestibular signs. PMID- 25015010 TI - The effect of width of facial canal in patients with idiopathic peripheral facial paralysis on the development of paralysis. AB - The aim of this prospective study is to investigate whether the possible stenosis due to anatomic variations of labyrinthine segment (LS), tympanic segment (TS) and mastoid segment (MS) of the facial canal in the temporal bone is a predisposing factor in the development of paralysis. 22 patients with idiopathic peripheral facial paralysis (IPFP) were included in the study. Multi-slice computed tomography (MSCT) with 64 detectors was used for temporal bone imaging of the patients. Reconstruction images in axial, coronal and sagittal planes were created in workstation computers from the captured images. The diameters and lengths of LS, TS and MS of the facial canal were measured. The mean values of LD, ND and SL of LS were 1.31 +/- 0.39, 0.91 +/- 0.27, 4.17 +/- 0.48 in patient group and 1.26 +/- 0.29, 0.95 +/- 0.21, 4.60 +/- 1.36 in control group, respectively. The mean values of LD, ND and SL of TS were 1.11 +/- 0.22, 0.90 +/- 0.14, 12.63 +/- 1.47 in patient group and 1.17 +/- 0.23, 0.85 +/- 0.24, 12.10 +/- 1.79 in control group, respectively. The mean values of LD, ND and SL of MS were 1.80 +/- 0.30, 1.44 +/- 0.29 vs. 14.3 +/- 1.90 in patient group 1.74 +/- 0.38, 1.40 +/- 0.29, 14.15 +/- 2.16 in control group, respectively. The measurements of the parameters of all three segments in patient group and control group were similar. Similar results between patient and control group were obtained in this study investigating the effect of stenosis in facial canal in the development of IPFP. PMID- 25015011 TI - The comparison of the viability of crushed, morselized and diced cartilage grafts: a confocal microscopic study. AB - To compare the cellular viability of diced, crushed, and morselized cartilage used in nasal surgeries. In this study, cartilage was extracted from the ears of seven New Zealand rabbits and was subsequently either diced, crushed or morselized to an amorphous state, or left unmodified. The four types of grafts were then implanted in the back regions of the rabbits. After 3 months, the cellular viability from four groups was compared to a control group using confocal microscopy. Analysis of the data obtained from the enumeration of live cells showed no statistically significant difference between the unmodified graft group and the control group. The diced, crushed, and morselized cartilage groups did show a statistically significant difference in terms of live cell count with the highest number of live cells in diced cartilage group. A statistically significant decrease in live cell count was detected in crushed cartilage group. Our study shows that the viability of cells in diced cartilage grafts is greater than those in crushed or morselized cartilage grafts. PMID- 25015013 TI - The use of a low cost 3D scanning and printing tool in the manufacture of custom made foot orthoses: a preliminary study. AB - BACKGROUND: Custom foot orthoses are currently recognized as the gold standard for treatment of foot and lower limb pathology. While foam and plaster casting methods are most widely used in clinical practice, technology has emerged, permitting the use of 3D scanning, computer aided design (CAD) and computer aided manufacturing (CAM) for fabrication of foot molds and custom foot orthotic components. Adoption of 3D printing, as a form of CAM, requires further investigation for use as a clinical tool.This study provides a preliminary description of a new method to manufacture foot orthoses using a novel 3D scanner and printer and compare gait kinematic outputs from shod and traditional plaster casted orthotics. FINDINGS: One participant (male, 25 years) was included with no lower extremity injuries. Foot molds were created from both plaster casting and 3D scanning/printing methods. Custom foot orthoses were then fabricated from each mold. Lower body plug-in-gait with the Oxford Foot Model on the right foot was collected for both orthotic and control (shod) conditions. The medial longitudinal arch was measured using arch height index (AHI) where a decrease in AHI represented a drop in arch height. The lowest AHI was 21.2 mm in the running shoes, followed by 21.4 mm wearing the orthoses made using 3D scanning and printing, with the highest AHI of 22.0 mm while the participant wore the plaster casted orthoses. CONCLUSION: This preliminary study demonstrated a small increase in AHI with the 3D printing orthotic compared to the shod condition. A larger sample size may demonstrate significant patterns for the tested conditions. PMID- 25015014 TI - Circulating leptin, resistin, adiponectin, visfatin, adipsin and ghrelin levels and insulin resistance in postmenopausal women with and without the metabolic syndrome. AB - OBJECTIVE: To measure serum levels of adipsin, leptin, resistin, adiponectin, visfatin, ghrelin and insulin in postmenopausal women screened for the metabolic syndrome (METS). METHODS: Serum of 100 postmenopausal women was analyzed using multiplex technology for the mentioned analytes. In addition, values for the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Comparisons were performed in accordance to the presence or not of the METS and each of its components. Criteria of the American Heart Association were used to define the METS. RESULTS: Age and time since menopause onset were similar in women with the METS (n=57) as compared to those without the syndrome (n=43). METS women displayed significantly higher levels of adipsin, leptin, resistin, insulin and HOMA-IR values and lower adiponectin levels. These differences were mainly observed among women with abdominal obesity, independent of fulfilling METS criteria or not. In this same sense, lower adiponectin levels significantly related to low HDL-C and high triglyceride levels; and higher insulin and HOMA-IR values related to high triglyceride and glucose levels, respectively. CONCLUSION: In this sample, postmenopausal women with the METS displayed higher insulin and adipokine levels. These were mainly related to abdominal obesity and metabolic and lipid abnormalities. More research is warranted in this regard. PMID- 25015015 TI - Compositions and constituents of freshwater dissolved organic matter isolated by reverse osmosis. AB - Dissolved organic matter (DOM) from riverine and lacustrine water was isolated using a reverse osmosis (RO) system. Solid-state (13)C nuclear magnetic resonance ((13)C NMR) was used to quantitatively evaluate the compositions and constituents of DOM, which are compared with previous investigations on marine DOM. Results indicated that concentration factor (CF) was a key metric controlling yield and sorption of DOM on the RO system. The sorption was likely non-selective, based on the (13)C NMR and delta(13)C analyses. Carbohydrates and lipids accounted for 25.0-41.5% and 30.2-46.3% of the identifiable DOM, followed by proteins (18.2 19.8%) and lignin (7.17-12.8%). The freshwater DOM contained much higher alkyl and aromatic C but lower alkoxyl and carboxyl C than marine DOM. The structural difference was not completely accounted for by using structure of high molecular weight (HMW) DOM, suggesting a size change involved in transformations of DOM during the transport from rivers to oceans. PMID- 25015016 TI - Coastal exposure to oil spill impacts from the Finisterre Traffic Separation Scheme. AB - This study analyzes the coastal exposure to potential oil spills coming from the various corridors that constitute the Finisterre Traffic Separation Scheme (NW Iberia). A Lagrangian model was executed with results from a realistic configuration of an ocean model during 2012, validated here against High Frequency (HF) radar-derived surface currents. Virtual particles were released each hour and followed during the next 4 days. A series of maps summarize which regions would be impacted and when. We have learnt, for example, that Cape Finisterre is the most affected area under a wide range of scenarios and that a sensitive area such as the National Park of the Atlantic Islands would require protective actions in less than 24 h if oil spills from the south eventually occurred. A complete analysis by corridor and during specific wind events is available through a web tool, which could be useful for decision makers in case of contingency. PMID- 25015017 TI - Polar organic micropollutants in the coastal environment of different marine systems. AB - Polar anthropogenic organic micropollutants are frequently detected in freshwater and discharged on large scale into marine systems. In this work the results of 153 samples collected from the shorelines of the Baltic Sea (Germany), Northern Adriatic Sea (Italy), Aegean Sea and Dardanelles (Greece & Turkey), San Francisco Bay (USA), Pacific Ocean (USA), Mediterranean Sea (Israel), and Balearic Sea (Spain) are presented. The samples were analyzed for various classes of micropollutants such as pharmaceuticals, corrosion inhibitors, biocides, and stimulants. Caffeine, paraxanthine, theobromine, tolyltriazole, 1H-benzotriazole, and atrazine were detected in>50% of all samples. The detection frequencies of carbamazepine, iopamidol, diuron, sulfamethoxazole, paracetamol, theophylline, and atenolol were between 20% and 32%. As caffeine is linked to untreated wastewater, the widespread occurrence of raw sewage in marine environments and thus potentially elevated nutrient concentrations and risk for the presence of wastewater-related pathogens is remarkable. PMID- 25015018 TI - Evaluation of CO2 solubility-trapping and mineral-trapping in microbial-mediated CO2-brine-sandstone interaction. AB - Evaluation of CO2 solubility-trapping and mineral-trapping by microbial-mediated process was investigated by lab experiments in this study. The results verified that microbes could adapt and keep relatively high activity under extreme subsurface environment (pH<5, temperature>50 degrees C, salinity>1.0 mol/L). When microbes mediated in the CO2-brine-sandstone interaction, the CO2 solubility trapping was enhanced. The more biomass of microbe added, the more amount of CO2 dissolved and trapped into the water. Consequently, the corrosion of feldspars and clay minerals such as chlorite was improved in relative short-term CO2-brine sandstone interaction, providing a favorable condition for CO2 mineral-trapping. Through SEM images and EDS analyses, secondary minerals such as transition-state calcite and crystal siderite were observed, further indicating that the microbes played a positive role in CO2 mineral trapping. As such, bioaugmentation of indigenous microbes would be a promising technology to enhance the CO2 capture and storage in such deep saline aquifer like Erdos, China. PMID- 25015019 TI - Optical diagnostic techniques for use in lesions of the head and neck: review of the latest developments. AB - Optical biopsy systems are a potential adjunct to the histopathological assessment of tissue specimens; they are not invasive and can give an immediate result. We review the most common optical biopsy techniques used to detect lesions of the head and neck: elastic scattering spectroscopy, microendoscopy, narrow band imaging, fluorescence, and optical coherence tomography, and discuss their clinical use. PMID- 25015020 TI - Split-mouth comparison of physics forceps and extraction forceps in orthodontic extraction of upper premolars. AB - We compared outcome variables (operative complications, inflammatory complications, and operating time) in patients being treated by orthodontic extraction of upper premolars with the Physics forceps or the universal extraction forceps. We organised a single blind, split-mouth clinical trial to compare the outcomes of the 2 groups (n=54 premolars). The Physics forceps group had lower mean (SD) visual analogue scores (VAS) for pain (0.59 (0.57)) on the first postoperative day than the other group (1.04 (0.85)) (p=0.03). There were no other significant differences between the 2 groups in any other variable studied. PMID- 25015021 TI - Age-dependent HLA profiles of the Israeli population: impact on hematopoietic cell donor recruitment and availability. AB - Approximately three million people have immigrated to the state of Israel since it was founded. Consequently, the immunogenetic profile of the younger generation may consist of a genetic mixture of formerly distinct population groups. We aimed to investigate whether HLA profiles in the Israeli population are age dependent and how this influences representation of various age groups in local donor registries. We determined HLA-A*, HLA-B*, and HLA-DRB1* low-resolution phenotypes of three age groups (n = 4,169 in each): (1) cord blood units collected between 2009 and 2013 (BABIES) and adult registry donors (2) aged 18-28 years (YOUNG) and (3) aged 49-60 years (OLD). We compared the results with virtual groups that simulate the offspring of the actual study groups. None of the three actual age groups were in Hardy-Weinberg equilibrium. The YOUNG presented four HLA-B alleles that were absent in the OLD and BABIES. A significantly higher percentage among the OLD and BABIES had a "matched" individual within their group in comparison to the YOUNG. In the YOUNG, the 10 most common haplotypes account for 16.7 % of the population, in comparison to 18.2 % in the OLD or 19.8 % in the BABIES group. The BABIES group was genetically remote from all other groups. Further disparities were found between the actual and the corresponding virtual groups. We conclude that discrete age groups in Israel present distinct immunogenetic profiles, where the younger generation is more heterogeneous. The population dynamics of the age dependent HLA profile is multifactorial: gradual intersubgroup admixture, nonrandom mating, and entry of new alleles. PMID- 25015022 TI - Mortality rates are going down in clinical use of inotropics. Temporal trends for prognosis in acute decompensated heart failure (1992/1999-2005/ 2006). PMID- 25015023 TI - Predictive value of brachial-ankle pulse wave velocity for long-term clinical outcomes after percutaneous coronary intervention in a Korean cohort. AB - OBJECTIVE: The aim of this study was to determine the associations of brachial ankle pulse wave velocity (baPWV), high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) with the development of adverse outcomes after percutaneous coronary intervention (PCI). METHODS: The baPWV, hs-cTnT and NT-proBNP were analyzed in 372 patients who underwent PCI. The primary endpoint was cardiac death. RESULTS: There were 21 events of cardiac death during a mean of 25.8 months of follow-up. When the baPWV cut-off level was set to 1672 cm/s using the receiver operating characteristic curve, the sensitivity was 85.7% and the specificity was 60.1% for differentiating between the group with cardiac death and the group without cardiac death. Kaplan-Meier analysis revealed that the higher baPWV group (>=1672 cm/s) had a significantly higher cardiac death rate than the lower baPWV group (<1672 cm/s) (11.4% vs. 1.4%, log-rank: P<0.0001). This value was more useful in patients with myocardial injury (hs-cTnT>=0.1 ng/mL) or heart failure (NT-proBNP>=450 pg/mL). CONCLUSIONS: The results of this study show that high baPWV is a predictive marker for cardiac death after PCI. PMID- 25015024 TI - Long-term mortality risk in patients with an implantable cardioverter defibrillator: Influence of heart rate and QRS duration. AB - BACKGROUND: A paucity of studies has investigated the role of autonomic cardiac regulation as well as cardiac conduction in relation to prognosis in implantable cardioverter-defibrillator (ICD) patients. Therefore, we examined the association of heart rate and QRS duration with long-term mortality risk in first-time ICD patients, adjusting also for measures of emotional distress. METHODS: Resting heart rate and QRS duration were assessed prior to ICD implantation in 448 patients. Primary study endpoint was all-cause mortality (up to 6.0 year follow up, median follow-up of 5.6 years (IQR: 1.9)). The impact of heart rate and QRS duration on time to all-cause mortality was separately assessed with Cox proportional hazard regression analysis, adjusting for clinical factors and symptoms of depression and anxiety. RESULTS: Mean (SD) heart rate was 68.0 +/- 13.3 bpm and mean QRS duration was 130.9 +/- 36.9 ms. Heart rate of >=80 bpm was associated with increased risk of mortality (HR=1.86; 95% CI=1.15-3.00; p=.011) in unadjusted analysis. In adjusted analyses, this relationship remained significant both with depression (HR=1.86, 95% CI=1.12-3.09; p=.017) and anxiety (HR=1.82, 95% CI=1.10-3.03; p=.021) and clinical measures as covariates. QRS duration of >=120 ms was associated with impaired prognosis in unadjusted analysis (HR=2.00, 95% CI=1.27-3.14; p=.003), but was reduced to non-significance in adjusted analysis when medical comorbidities were included (HR=1.15, 95% CI=0.70-1.89; p=.60). CONCLUSIONS: This study shows that increased heart rate is associated with impaired prognosis. Since heart rate is a relatively easy measurable parameter of autonomic functioning, heart rate should be included as a measure for risk stratification in daily clinical practice. PMID- 25015025 TI - Misleading Bias-Driven Expectations in Referential Processing and the Facilitative Role of Contrastive Accent. AB - Probabilistic preferences are often facilitative in language processing and may assist in discourse prediction. However, occasionally these sources of information may lead to inaccurate expectations. The current study investigated a test case of this scenario. An eye-tracking experiment examined the interpretation of ambiguous personal pronouns in the context of implicit causality biases. We tested whether reference resolution may be facilitated online by contrastive accent in cases of a bias-inconsistent referent. Implicit causality biases directed looks to the biased noun phrase; however, when the name of the bias-inconsistent antecedent was accented (e.g., JOHN envied Bill because he ...), this tendency was modulated. Contrastive accent seems to dampen the occasionally confusing prediction of implicit causality biases in referential processing. This demonstrates one way in which the spoken language comprehension system copes with occasional misguidance of otherwise helpful probabilistic information. PMID- 25015026 TI - Meaning Inhibition and Sentence Processing in Chinese. AB - The present study examined the inhibitory processes of spoken word recognition of Chinese homophones during sentence processing, using a standard cross-modal naming experiment with an innovative design and materials construction. Results confirmed that (1) preceding sentence context has exerted an early effect on disambiguating among different alternative meanings of the homophones; (2) the contextually inappropriate meanings of the ambiguous word were inhibited rapidly during sentence processing; and (3) the present results also demonstrated that the inhibitory mechanism could be sustained to a longer duration following the occurrence of the ambiguous word (homophone). Finally, all these results clearly revealed the dynamics of interaction of context effects and spoken word recognition processes. PMID- 25015027 TI - Open-label dose optimization of methylphenidate modified release long acting (MPH LA): a post hoc analysis of real-life titration from a 40-week randomized trial. AB - BACKGROUND AND OBJECTIVES: In the management of attention-deficit hyperactivity disorder (ADHD) in adults it is important to recognize that individual patients respond to a wide range of methylphenidate doses. Studies with methylphenidate modified release long acting (MPH-LA) in children have reported the need for treatment optimization for improved outcomes. We report the results from a post hoc analysis of a 5-week dose optimization phase from a large randomized, placebo controlled, multicenter 40-week study (9-week double-blind dose confirmation phase, 5-week open-label dose optimization phase, and 26-week double-blind maintenance of effect phase). METHODS: Patients entering the open-label dose optimization phase initiated treatment with MPH-LA 20 mg/day; up/down titrated to their optimal dose (at which there was balance between control of symptoms and side effects) of 40, 60, or 80 mg/day in increments of 20 mg/week by week 12 or 13. Safety was assessed by monitoring the adverse events (AEs) and serious AEs. Efficacy was assessed by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Attention-Deficit Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores. RESULTS: At the end of the dose confirmation phase, similar numbers of patients were treated optimally with each of the 40, 60, and 80 mg/day doses (152, 177, and 160, respectively) for MPH-LA. Mean improvement from baseline in the dose confirmation phase in total scores of DSM-IV ADHD RS and SDS were 23.5 +/- 9.90 and 9.7 +/- 7.36, respectively. CONCLUSIONS: Dose optimization with MPH-LA (40, 60, or 80 mg/day) improved treatment outcomes and was well-tolerated in adult ADHD patients. PMID- 25015028 TI - Predicting psychosis in a general adolescent psychiatric sample. AB - INTRODUCTION: Current psychosis risk criteria have often been studied on a pre selected population at specialized clinics. We investigated whether the Structured Interview for Prodromal Syndromes (SIPS) is a useful tool for psychosis risk screening among adolescents in general psychiatric care. METHODS: 161 adolescents aged 15-18 with first admission to adolescent psychiatric services in Helsinki were interviewed with the SIPS to ascertain Clinical High Risk (CHR) state. The participants were followed via the national hospital discharge register, patient files, and follow-up interviews. DSM-IV Axis I diagnoses were made at baseline and 12 months. Register follow-up spanned 2.8-8.9 years, and hospital care for a primary psychotic disorder and any psychiatric disorder were used as outcomes. RESULTS: CHR criteria were met by 54 (33.5%) of the adolescents. Three conversions of psychosis as defined by SIPS emerged during follow-up, two of whom belonged to the CHR group. The positive predictive value of the CHR status was weak (1.9%) but its negative predictive value was 98.0%. Using the DSM-IV definition of psychosis, there were five conversions, three of which were in the CHR group. In regression analyses, hospital admissions for primary psychotic disorder were predicted by positive symptom intensity in the baseline SIPS. In addition, CHR status and SIPS positive and general symptoms predicted hospitalization for psychiatric disorder. DISCUSSION: Psychosis incidence was low in our unselected sample of adolescent psychiatric patients. CHR status failed to predict SIPS or DSM-IV psychoses significantly at 12 months. However, in a longer follow-up, CHR did predict psychiatric hospitalization. PMID- 25015029 TI - Test-retest reliability of N400 event-related brain potential measures in a word pair semantic priming paradigm in patients with schizophrenia. AB - The N400 event-related brain potential (ERP), a negative voltage deflection occurring approximately 400ms after onset of any meaningful stimulus, is reduced in amplitude when the stimulus is preceded by related context. Previous work has found this N400 semantic priming effect to be decreased in schizophrenia, suggesting impairment in using meaningful context to activate related concepts in semantic memory. Thus, N400 amplitude may be a useful biomarker of abnormal semantic processing and its response to treatment in schizophrenia. To help assess the validity of N400 amplitude as a longitudinal measure in schizophrenia, we evaluated its test-retest reliability. ERPs were recorded in sixteen schizophrenia patients who viewed prime words, each followed at 300- or 750-ms stimulus-onset asynchrony (SOA) by a target that was either a related or unrelated word, or nonword. Participants' task was to indicate whether or not the target was a real word. They were retested on the same procedure one week later. Test-retest reliability was assessed by calculating Pearson's r and intraclass correlation coefficients (ICCs) across timepoints for N400 amplitudes for related and unrelated targets, at each SOA. Consistent with previous results, there were no significant differences between patients' N400 amplitudes for related and unrelated targets, at any SOA/timepoint combination. Pearson's r and ICCs for N400 amplitudes at Fz across timepoints were significant for both target types at each SOA (ranges: r 0.52-0.64, ICC 0.52-0.63; all p<.04). The results suggest potential utility of N400 amplitude as a longitudinal neurophysiological biomarker of semantic processing abnormalities in schizophrenia. PMID- 25015030 TI - The role of laparoscopy-assisted renal autotransplantation in the treatment of primary ureteral tumor. AB - BACKGROUND: To evaluate the effect and safety of laparoscopy-assisted renal autotransplantation treatment for primary ureteral cancer (PUC). METHODS: Medical records of patients undergoing hand-assisted retroperitoneoscopic nephroureterectomy-extracorporeal total ureterectomy-renal autotransplantation pyelocystostomy (Lap AutoTx) were analyzed. Demographic, intraoperative, and postoperative data were assessed. RESULTS: Fifteen patients diagnosed with PUC underwent this novel approach. Three kidneys were abandoned owing to the detection of residual cancer on the renal pelvic junction, surgeon's judgment on three severe atherosclerotic arteries, and palpable pelvic lymph nodes proven to be evidence of metastatic disease by frozen section analysis. Twelve patients (mean +/- SD age 67.5 +/- 7.5 years) were treated with Lap AutoTx for PUC successfully. No perioperative mortality occurred. One patient with solitary kidney experienced delayed graft function that required short-term hemodialysis. Three recurrent superficial diseases in three patients were treated with transurethral resection. The mean +/- SD follow-up duration was 12.1 +/- 6.7 months (range 3-24 months). The renal pelvicaliceal system was easily examined by flexible cystoscopy. CONCLUSIONS: Lap AutoTx is less invasive compared with the traditional two-incisional manner and can be performed safely even among elderly patients. Compared with other currently used therapies, this novel treatment can be used to successfully treat PUC with the added advantages of total resection of the ureteral lesion, preservation of the renal function, and simplification of follow-up procedures.Primary ureteral cancer (PUC) is an aggressive disease and has a poor prognosis.1 Studies have shown high prevalence and invasiveness of PUC in Taiwan.2,3 Nephroureterectomy with excision of the bladder cuff is still believed to be the gold standard treatment for PUC.4 Most PUC occurs among individuals aged more than 60 years, and most of these patients are also at high risk of chronic kidney disease (CKD).5,6 Nephroureterectomy not only results in excessive loss of renal function, but also puts the patient at risk of CKD, which contributes to the progression of end-stage renal disease requiring dialysis. In addition, diminished renal function after nephroureterectomy compromises the possible use of adjuvant chemotherapy for advanced disease.Endoscopic surgery (ES) and segmental resection (SR) can be used for renal preservation in PUC cases, but there still are limitations to these approaches, and indefinite invasive ureteroscopy is required during follow-up. Only a few studies have focused on renal autotransplantation (AutoTx) after extracorporeal total ureterectomy (ETU) for PUC. This type of treatment possesses advantages of total resection of malignant ureteral lesions, preservation of renal function, and simplification of follow-up protocols. In two reported case series, all cases involved surgery performed with the traditional 2-incision approach, and only a few cases involved pure PUC.7,8 We have reported that hand-assisted retroperitoneoscopic nephroureterectomy (HARNU) for the treatment of PUC is less invasive and results in better functional outcomes with fewer complications and comparable oncologic control compared with open nephroureterectomy.9 In this study, we report our experience of this treatment combined with ETU and AutoTx for pure PUC. PMID- 25015031 TI - Scoring systems of severity in patients with multiple trauma. AB - Trauma is a major cause of morbidity and mortality; hence severity scales are important adjuncts to trauma care in order to characterize the nature and extent of injury. Trauma scoring models can assist with triage and help in evaluation and prediction of prognosis in order to organise and improve trauma systems. Given the wide variety of scoring instruments available to assess the injured patient, it is imperative that the choice of the severity score accurately match the application. Even though trauma scores are not the key elements of trauma treatment, they are however, an essential part of improvement in triage decisions and in identifying patients with unexpected outcomes. This article provides the reader with a compendium of trauma severity scales along with their predicted death rate calculation, which can be adopted in order to improve decision making, trauma care, research and in comparative analyses in quality assessment. PMID- 25015032 TI - Cytotoxicity comparison of quercetin and its metabolites from in vitro fermentation of several gut bacteria. AB - Part of quercetin is coerced into the colon after ingestion and interacts with the gut microbiota. The interaction between quercetin and gut microbiota will influence human health. The cytotoxicity of quercetin and its metabolites from human gut bacteria in vitro fermentation was investigated in this study. The 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) (MTT) and agar diffusion disc methods were individually applied in vitro to examine their inhibitory effect on three cultured human cancer cells and five pathogenic bacteria species. The results showed that the metabolites from Clostridium perfringens and Bacteroides fragilis exerted a strong inhibitory effect (P < 0.05) on HCT-116 cells and that of Weissella confusa was stronger (P < 0.01) on both A549 cells and HeLa cells than on the others. Most metabolites have similar or decreased inhibitory ability on human cancer cells compared to quercetin itself. This inhibitory effect had not been detected in quercetin and its metabolites in five common pathogenic bacteria species. Quercetin is a potential chemopreventive agent. However, this study reported that some gut bacteria can improve their function of inhibiting cancer cells after fermenting quercetin. PMID- 25015033 TI - Efficacy of swim-up versus density gradient centrifugation in improving sperm deformity rate and DNA fragmentation index in semen samples from teratozoospermic patients. AB - PURPOSE: To compare the efficacy of swim-up and DGC in improving sperm deformity and DNA fragmentation and to determine which method is better in teratozoospermic patients requiring artificial reproduction. METHODS: The present study compared the effects of swim-up and density gradient centrifugation (DGC), the two most commonly used semen preparation methods, on sperm deformity rate and DNA fragmentation index (DFI) in semen samples from teratozoospermic patients. RESULTS: The results demonstrated that both swim-up and DGC yielded a significantly lower sperm deformity rate and DFI in comparison to unprocessed whole semen, with DGC having more favorable results. Sperm deformity rate in unprocessed whole semen samples was significantly lower in the 20-29 age group than in the 40-49 age group, but no significant difference was observed in DFI between different age groups. There was no significant correlation between sperm deformity rate and DFI. CONCLUSIONS: Our findings suggest that enrichment of sperm with normal morphology and intact DNA in teratozoospermic patients could be achieved by both DGC and swim-up procedures, and that DGC is a better method. PMID- 25015034 TI - Serum antimullerian hormone measurements with second generation assay at two distinct menstrual cycle phases for prediction of cycle cancellation, pregnancy and live birth after in vitro fertilization. AB - PURPOSE: This study investigated the usefulness of serum antimullerian hormone (AMH) measurements at two distinct menstrual cycle phases to predict in vitro fertilization (IVF) outcomes. METHODS: This was a prospective observational study enrolling 135 consecutive patients referred for conventional IVF or ICSI in a university hospital. Blood samples were obtained for serum AMH measurements on days 3 and 18-20, while transvaginal ultrasound was performed for antral follicle count (AFC) at day 3 of the menstrual cycle immediately before treatment. AMH was measured with the new Beckman Coulter Generation II (GenII) assay. The main outcome measures were cycle cancellation due to poor ovarian response, clinical pregnancy, and live birth. RESULTS: There was a strong correlation between AMH levels measured at day 3 and day 18-20 of the menstrual cycle (r = 0.837; P < 0.0001). Day 18-20 serum AMH was comparable to day 3 serum AMH and AFC for the prediction of cycle cancellation (areas under the ROC curve were 0.84 for day 3 AMH, 0.89 for day 18-20 AMH, and 0.80 for AFC). Day 18-20 AMH had a modest predictive value for pregnancy or live birth (area under ROC curve 0.71 for both), which was comparable to that of day 3 AMH; however, AFC had no predictive value for these outcomes. CONCLUSIONS: Day 18-20 AMH was comparable to day 3 AMH for the prediction of cycle cancellation, clinical pregnancy, and live birth after IVF. Both AMH measurements were accurate for the prediction of cancellation but were significantly less useful for the prediction of pregnancy or live birth. PMID- 25015036 TI - Correlated analysis of semi-quantitative immunohistochemical features of E cadherin, VEGF and CD105 in assessing malignant potentiality of oral submucous fibrosis. AB - Oral submucous fibrosis, a potentially premalignant condition for oral squamous cell carcinoma, manifests both non-dysplastic and dysplastic grades. Early and specific identification of its malignant potentiality suffers from diagnostic limitations that may be addressed by correlated molecular pathology attributes having histopathological backdrop. Present study correlates expressional alteration in prime epithelial marker E-cadherin, with neo-angiogenic molecules viz. VEGF and CD105 for elucidation of malignant potentiality in different stages of oral submucous fibrosis. Sixty-eight incision biopsies from normal oral mucosa (n = 10), non-dysplastic (n = 18) and different dysplastic grades (n = 40) of oral submucous fibrosis were semi-quantitatively analyzed for immunohistochemical expressions of E-cadherin (membranous and cytoplasmic), VEGF and CD105 which were further statistically correlated. The loss of membranous E-cadherin with increase in cytoplasmic accumulation in differentiative layers of epithelium through the progression of dysplasia was noted along with up-regulation in VEGF expressions. The number of CD105(+) blood vessels and their major axis also showed significant increase from non-dysplasia toward higher grades of dysplasia. The positive correlation between deregulated expression of epithelial cell-cell adhesion molecule and increase in neo-angiogenic attributes of oral submucous fibrosis with increase in dysplastic grades indicated elucidatory potential of molecular expression features in assessment of malignant potentiality in oral submucous fibrosis. PMID- 25015035 TI - Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): an oncoprotein with many hands. AB - Oncoprotein CIP2A a Cancerous Inhibitor of PP2A forms an "oncogenic nexus" by virtue of its control on PP2A and MYC stabilization in cancer cells. The expression and prognostic function of CIP2A in different solid tumors including colorectal carcinoma, head and neck cancers, gastric cancers, lung carcinoma, cholangiocarcinoma, esophageal cancers, pancreatic carcinoma, brain cancers, breast carcinoma, bladder cancers, ovarian carcinoma, renal cell carcinomas, tongue cancers, cervical carcinoma, prostate cancers, and oral carcinoma as well as a number of hematological malignancies are just beginning to emerge. Herein, we reviewed the recent progress in our understanding of (1) how an "oncogenic nexus" of CIP2A participates in the tumorigenic transformation of cells and (2) how we can prospect/view the clinical relevance of CIP2A in the context of cancer therapy. The review will try to understand the role of CIP2A (a) as a biomarker in cancers and evaluate the prognostic value of CIP2A in different cancers (b) as a therapeutic target in cancers and (c) in drug response and developing chemo resistance in cancers. PMID- 25015037 TI - Use of the National Health and Nutrition Examination Survey to calculate the impact of obesity and diabetes on cost and prevalence of urolithiasis in 2030. AB - BACKGROUND: The prevalence of urolithiasis and its risk factors such as obesity and diabetes have increased over time. OBJECTIVE: Determine the future cost and prevalence of kidney stones using current and projected estimates for stones, obesity, diabetes, and population rates. DESIGN, SETTING, AND PARTICIPANTS: The stone prevalence in 2000 was estimated from the National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 2007-2010. The cost per percentage prevalence of stones in 2000, calculated using Urologic Diseases in America Project data, was used to estimate the annual cost of stones in 2030, adjusting for inflation and increases in population, stone prevalence, obesity and diabetes rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was prevalence and cost of stones in 2030. The secondary outcomes were the impact of obesity and diabetes on these values, calculated using odds ratios for stones by body mass index and diabetes status. RESULTS AND LIMITATIONS: The annual cost of stone disease in 2000, adjusted for inflation to 2014 US dollars, was approximately $2.81 billion. After accounting for increases in population and stone prevalence from 2000, the estimated cost of stones in 2007 in 2014 US dollars was $3.79 billion. Future population growth alone would increase the cost of stone disease by $780 million in 2030. Based on projected estimates for 2030, obesity will independently increase stone prevalence by 0.36%, with an annual cost increase of $157 million. Diabetes will independently increase stone prevalence by 0.72%, associated with a cost increase of $308 million annually by 2030. NHANES data, however, capture patient self-assessment rather than medical diagnosis, which is a potential bias. CONCLUSIONS: The rising prevalence of obesity and diabetes, together with population growth, is projected to contribute to dramatic increases in the cost of urolithiasis, with an additional $1.24 billion/yr estimated by 2030. PATIENT SUMMARY: Obesity, diabetes, and population rates will contribute to an estimated $1.24 billion/yr increase in the cost of kidney stones by 2030. PMID- 25015039 TI - Derivation of Chondrogenic Cells from Human Embryonic Stem Cells for Cartilage Tissue Engineering. AB - Human embryonic stem cells (hESCs) have the ability to self-renew and differentiate into any cell lineage of the three germ layers, therefore holding great promise for regenerative applications in dentistry and medicine. We previously described a micromass culture system as a model system to induce and study the chondrogenic commitment of hESCs. Using this system, chondrogenic cells can be further isolated and expanded under specific growth factor conditions. When encapsulated in hyaluronic acid (HA)-based hydrogels and cultured under appropriate growth factor and medium conditions, these chondrogenic cells synthesized and deposited extracellular matrix (ECM) characteristic of neocartilage. Here, we describe the micromass culture of hESCs, the isolation and expansion of hESC-derived chondrogenic cells, and the three-dimensional (3-D) culture of the chondrogenic cells in hydrogels for cartilage tissue engineering. We will also describe the various tools and techniques used for characterizing the tissue-engineered cartilage. PMID- 25015038 TI - TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. AB - Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes-such as transmembrane protease, serine 2 (TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11,152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2-ERG fusions with increasing patient age is limited to low-grade cancers (Gleason <=3+4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non-androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients. PMID- 25015041 TI - Exploring the potential of large vertebrates as early warning sentinels of threats to marine ecosystems, human health and wellbeing. PMID- 25015040 TI - Cannabinoid receptor-2 and HIV-associated neurocognitive disorders. AB - Despite the wide spread use of highly active antiretroviral therapy (HAART), mild forms of HIV-associated neuro cognitive disorders (HAND) remain commonplace. HAART treated patients now show low levels of viremia and more subtle yet biologically important signs of brain macrophage and microglial activation. Adjunctive therapeutic strategies are required to eliminate HIV-1 infection and suppress immune activation and its associated neuroinflammation. In this regard, cannabinoid receptor-2(CB2) activation is a promising means to attenuate HAND by inhibiting HIV replication, down regulating inflammation, and suppressing chemokine-like activity of viral neurotoxic proteins (for example, Tat and HIV 1gp120), and thereby prevent neuronal and synaptic loss. Inhibiting even low level HIV replication can attenuate neuronal injury by decreasing the production of neurotoxins. Down regulation of inflammation by CB2 activation is mediated through blunted activation of peri vascular macrophages and microglia; decreased production of tumor necrosis factor-alpha, chemokines and virotoxins. Down regulated neuroinflammation can decrease blood brain barrier permeability and leukocyte infiltration resulting in reduced neuronal injury. It is suggested that CB2 agonists may further attenuate HAND in HIVinfected patients on HAART. In addition, CB2 activation may also blunt brain injury by attenuating drug addiction. PMID- 25015042 TI - Dual-color bioluminescence imaging assay using green- and red-emitting beetle luciferases at subcellular resolution. AB - Bioluminescence imaging is widely used to monitor cellular events, including gene expression in vivo and in vitro. Moreover, recent advances in luciferase technology have made possible imaging at the single-cell level. To improve the bioluminescence imaging system, we have developed a dual-color imaging system in which the green-emitting luciferase from a Brazilian click beetle (Emerald Luc, ELuc) and the red-emitting luciferase from a railroad worm (Stable Luciferase Red, SLR) were used as reporters, which were localized to the peroxisome and the nucleus, respectively. We clearly captured simultaneously the subcellular localization of ELuc in the peroxisome and SLR in the nucleus of a single cell using a high-magnification objective lens with 3-min exposure time without binning using a combination of optical filters. Furthermore, to apply this system to quantitative time-lapse imaging, the activation of nuclear factor triggered by tumor necrosis factor alpha was measured using nuclear-targeted SLR and peroxisome-targeted ELuc as the test and internal control reporters, respectively. We successfully quantified the kinetics of activation of nuclear factor kappaB using nuclear-targeted SLR and the transcriptional change of the internal control promoter using peroxisome-targeted ELuc simultaneously in a single cell, and showed that the activation kinetics, including activation rate and amplitude, differed among cells. The results demonstrated that this imaging system can visualize the subcellular localization of reporters and track the expressions of two genes simultaneously at subcellular resolution. PMID- 25015043 TI - Analytical pyrolysis-based study on intra-skeletal organic matrices from Mediterranean corals. AB - Off-line analytical pyrolysis combined with gas chromatography-mass spectroscopy (GC-MS), directly or after trimethylsilylation, along with infrared spectroscopy and amino acid analysis was applied for the first time to the characterization of the intra-skeletal organic matrix (OM) extracted from four Mediterranean hard corals. They were diverse in growth form and trophic strategy namely Balanophyllia europaea and Leptopsammia pruvoti-solitary corals, only the first having zooxanthelle-and Cladocora caespitosa and Astroides calycularis-colonial corals, only the first with zooxanthelle. Pyrolysis products evolved from OM could be assigned to lipid (e.g. fatty acids, fatty alcohols, monoacylglicerols), protein (e.g. 2,5-diketopiperazines, DKPs) and polysaccharide (e.g. anhydrosugars) precursors. Their quantitative distribution showed for all the species a low protein content with respect to lipids and polysaccharides. A chemometric approach using principal component analysis (PCA) and clustering analysis was applied on OM mean amino acidic compositions. The small compositional diversity across coral species was tentatively related with coral growth form. The presence of N-acetyl glucosamine markers suggested a functional link with other calcified tissues containing chitin. The protein fraction was further investigated using novel DKP markers tentatively identified from analytical pyrolysis of model polar linear dipeptides. Again, no correlation was observed in relation to coral ecology. These analytical results revealed that the bulk structure and composition of OMs among studied corals are similar, as it is the textural organization of the skeleton mineralized units. Therefore, they suggest that coral's biomineralization is governed by similar macromolecules, and probably mechanisms, independently from their ecology. PMID- 25015044 TI - Two-dimensional heart-cut LC-LC improves accuracy of exact-matching double isotope dilution mass spectrometry measurements of aflatoxin B1 in cereal-based baby food, maize, and maize-based feed. AB - Aflatoxins, mycotoxins of fungi of the Aspergillus sp., pose a risk to consumer health and are, therefore, regulated by more than 100 countries. To facilitate method development and validation as well as assessment of measurement capabilities, availability of certified reference materials and proficiency testing schemes is important. For these purposes, highly accurate determinations of the aflatoxin content in the materials used are necessary. We describe here the use of two-dimensional heart-cut LC-LC in combination with exact-matching double isotope dilution mass spectrometry to determine the content of aflatoxin B1 in three materials used in a proficiency testing scheme. The serious reduction in ionization suppression afforded by the two-dimensional heart-cut LC-LC had a positive effect on the precision of the measured isotope ratios of the exact matching double isotope dilution mass spectrometry. This is evidenced by the expanded measurement uncertainty (k=2) of 0.017 MUg/kg or 8.9 % relative to a mass fraction of aflatoxin B1 in a cereal-based baby food of 0.197 MUg/kg. This value is in perfect agreement with the consensus value of this material from a proficiency test (PT) scheme for National Reference Laboratories executed by the European Reference Laboratory for Mycotoxins. The effort necessary to perform the described methodology precludes its frequent use but for specific applications we see it as a valuable tool. PMID- 25015045 TI - Quantitative bioimaging of p-boronophenylalanine in thin liver tissue sections as a tool for treatment planning in boron neutron capture therapy. AB - An analytical method using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was developed and applied to assess enrichment of 10B containing p-boronophenylalanine-fructose (BPA-f) and its pharmacokinetic distribution in human tissues after application for boron neutron capture therapy (BNCT). High spatial resolution (50 MUm) and limits of detection in the low parts per-billion range were achieved using a Nd:YAG laser of 213 nm wavelength. External calibration by means of 10B-enriched standards based on whole blood proved to yield precise quantification results. Using this calibration method, quantification of 10B in cancerous and healthy tissue was carried out. Additionally, the distribution of 11B was investigated, providing 10B enrichment in the investigated tissues. Quantitative imaging of 10B by means of LA-ICP-MS was demonstrated as a new option to characterise the efficacy of boron compounds for BNCT. PMID- 25015046 TI - Caffeine and its rapidly expanding role in the pathogenesis of malignancies. PMID- 25015047 TI - Structure-function relationships of inhibition of mosquito cytochrome P450 enzymes by flavonoids of Andrographis paniculata. AB - The cytochrome P450 monooxygenases are known to play a major role in pyrethroid resistance, by means of increased rate of insecticide detoxification as a result of their overexpression. Inhibition of detoxification enzymes may help disrupting insect detoxifying defense system. The Anopheles minimus CYP6AA3 and CYP6P7 have shown pyrethroid degradation activity and been implicated in pyrethroid resistance. In this study inhibition of the extracts and constituents of Andrographis paniculata Nees. leaves and roots was examined against benzyloxyresorufin O-debenzylation (BROD) of CYP6AA3 and CYP6P7. Four purified flavones (5,7,4'-trihydroxyflavone, 5-hydroxy-7,8-dimethoxyflavone, 5-hydroxy 7,8,2',3'-tetramethoxyflavone, and 5,4'-dihydroxy-7,8,2',3'-tetramethoxyflavone), one flavanone (5-hydroxy-7,8-dimethoxyflavanone) and a diterpenoid (14-deoxy 11,12-didehydroandrographolide) containing inhibitory effects toward both enzymes were isolated from A. paniculata. Structure-function relationships were observed for modes and kinetics of inhibition among flavones, while diterpenoid and flavanone were inferior to flavones. Docking of flavones onto enzyme homology models reinforced relationships on flavone structures and inhibition modes. Cell based inhibition assays employing 3-(4,5-dimethylthiazol-2-y-l)-2,5 diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that these flavonoids efficiently increased susceptibility of CYP6AA3- and CYP6P7-expressing Spodoptera frugiperda (Sf9) cells to cypermethrin toxicity, due to inhibition effects on mosquito enzymes. Thus synergistic effects on cypermethrin toxicity of A. paniculata compounds as a result of enzyme inhibition could be useful for mosquito vector control and insecticide resistance management in the future. PMID- 25015048 TI - Anti-parasitic activities of specific bacterial extracellular products of Streptomyces griseus SDX-4 against Ichthyophthirius multifiliis. AB - The ciliate Ichthyophthirius multifiliis is one of the most pathogenic parasites of fish maintained in captivity. In this study, effects of bacterial extracellular products of Streptomyces griseus SDX-4 against I. multifiliis were determined. The fermentation liquor of S. griseus was extracted successively in a separating funnel with petroleum ether, ethyl acetate, and n-butanol. In vitro assays revealed that the n-butanol extracts (NBu-E) and ethyl acetate extracts (Eto-E) of S. griseus were observed to be more effective against theronts than the other extracts with median effective concentration (EC50) values of 0.86 and 12.5 mg L(-1), respectively, and significantly reduced the survival of the tomonts and the total number of theronts released by the tomonts (P<0.05). All encysted tomonts were killed when the concentration of NBu-E was 30.0 mg L(-1). Results of in vivo test demonstrated that the number of I. multifiliis trophonts on the grass carp treated with NBu-E was markedly lower compared to the control group at 11 days after exposed to theronts (P<0.05). In the control group, 100% mortality was observed owing to heavy I. multifiliis infection at 11 days after the exposure. On the other hand, only 9.5% mortality owing to parasite infection was recorded in the groups treated with the NBu-E (30 mg L(-1)). The median lethal dose (LD50) of NBu-E for grass carp was 152.4 mg L(-1). Our results indicate that n-butanol extract of S. griseus will be useful in aquaculture for controlling I. multifiliis infections. PMID- 25015049 TI - Natural light influences cercarial emergence of Calicophoron daubneyi but not that of Haplometra cylindracea from temperature-challenged Galba truncatula. AB - Laboratory investigations on Galba truncatula experimentally infected with Calicophoron daubneyi were carried out to study the influence of natural light and sky nebulosity on cercarial emergence in snails subjected every week outdoors to a thermal shock (a mean of 12 degrees C for 3 h) during the patent period. The same study was also performed in G. truncatula naturally infected with Haplometra cylindracea according to the same protocol. Compared to infected controls always reared indoors at 20 degrees C, the number of cercariae emerging from snails subjected outdoors to a thermal shock was significantly greater, whatever parasite species. Natural light had an effect on snails releasing C. daubneyi cercariae after the thermal shock because their numbers were significantly higher between 601 and 1,200 lx and for the highest nebulosity values (7-8 octas). In contrast, the type of light used during thermal shock did not influence cercarial emergence of H. cylindracea because the numbers of cercariae per shedding snail noted under natural light or a 3,000-lx artificial light did not significantly differ from each other. Most snails releasing H. cylindracea cercariae were significantly more numerous for light levels higher than 3,000 lx. As for Fasciola hepatica cercariae, natural light had a significant influence on cercarial emergence of C. daubneyi, and this behavioural particularity for cercariae of both digeneans might be due to the fact that both species develop in the same ruminants and the same snail host. PMID- 25015050 TI - Fumigant activity of eleven essential oil compounds and their selected binary mixtures against Culex pipiens pallens (Diptera: Culicidae). AB - To seek natural products for the development of environment friendly mosquito control agents, fumigant activity of eleven essential oil compounds and the joint action of the active compounds were evaluated against Culex pipiens pallens adults. Fumigant bioassay demonstrated that carvacrol exhibited the highest fumigant activity followed by thymol and l-perillaldehyde, with LC50 values of 0.26, 0.28, and 0.34 mg/L air, respectively. Among the binary mixtures of four compounds with preferable performance, only the binary mixture of carvacrol and thymol (1:1, w/w) displayed a synergistic effect with the co-toxicity coefficient (CTC) value of 174.1 and LC50 value of 0.16 mg/L air. Furthermore, the actual efficacy of the binary mixture at 300 mg/mat (KT50 = 7.9, 15.8, and 22.0 min after 0, 2, and 4 h of preliminary heating, respectively) was comparable with that of d-allethrin at 30 mg/mat (KT50 = 8.7, 17.9, and 21.2 min after 0, 2, and 4 h of preliminary heating, respectively) tested in vaporizing mats by the glass chamber method (70 * 70 * 70 cm). These results revealed that carvacrol, thymol, and their binary mixture have potential for the development of natural fumigants for adult mosquito control. PMID- 25015051 TI - The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies. AB - Numbers of observational studies suggest that the JAK2 46/1 (GGCC) haplotype may increase the risk of myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT), but the results remain controversial. We aimed to examine the association between the JAK2 46/1 haplotype and risk of MPNs and SVT by conducting a meta-analysis. PubMed, EMBASE, Cochrane Library, CBM, and CNKI databases were searched to identify eligible studies without restrictions and by reviewing reference lists of obtained articles. Both fixed and random-effects models were used to calculate the summary risk estimates. We identified 26 observational studies of the JAK2 46/1 haplotype and risk of MPNs and SVT involving 8,561 cases and 7,434 participants. In the overall analysis, it was found that the JAK2 46/1 haplotype significantly elevated the risk of MPNs (rs10974944: C vs T: odds ratio (OR) = 2.19, 95 % confidence interval (CI) = 1.86 2.57, P < 0.0001; CC vs TT: OR = 4.63, 95 % CI = 3.32-6.47, P < 0.0001; CT vs TT: OR = 2.49, 95 % CI = 2.11-2.95, P < 0.0001; (CC + CT) vs TT: OR = 2.92, 95 % CI = 2.51-3.39, P < 0.0001; rs12343867: C vs T: OR = 1.88, 95 % CI = 1.59-2.22, P < 0.0001; CC vs TT: OR = 3.16, 95 %CI = 2.14-4.65, P < 0.0001; CT vs TT: OR = 2.04, 95 % CI = 1.51-2.74, P < 0.0001; (CC + CT) vs TT: OR = 2.25, 95 % CI = 1.73-2.95, P < 0.0001) and SVT (C vs T: OR = 1.27, 95 % CI = 1.06-1.52, P = 0.011; CC vs TT: OR = 2.33, 95 % CI = 1.42-3.81, P = 0.001; (CC + CT) vs TT: OR = 1.25, 95 % CI = 1.02-1.53, P = 0.034). There was no evidence of a significant association between the rs12343867 and the risk of SVT in the genetic model (CT vs TT: OR = 1.01, 95 % CI = 0.80-1.29, P = 0.906). This meta-analysis provides new evidence supporting the conclusion that the JAK2 46/1 haplotype enrichment is significantly associated with the development of MPNs and SVT in these patients. PMID- 25015052 TI - Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia. AB - Calreticulin (CALR) mutations were recently identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) devoid of JAK2 and MPL mutations. We evaluated the clinical, laboratory, and molecular features of a Taiwanese population of patients with ET. Among 147 ET patients, CALR mutations were detected in 33 (22.5 %), JAK2V617F in 94 (63.9 %), and MPL mutations in 4 (2.7 %). Sixteen (10.9 %) patients were negative for all three mutations (CALR, JAK2V617F, and MPL; triple negative). Interestingly, one patient with the type 2 CALR mutation also harbored a low allele burden (0.025 %) of JAK2V617F mutation. Furthermore, we found a novel CALR mutation, with the resultant protein sharing an identical amino acid sequence to the type 6 CALR mutant. Compared to those with JAK2 mutation, CALR-mutated ET patients were characterized by younger age, lower leukocyte count, higher platelet count, and decreased risk of thrombosis. CALR mutations had a favorable impact on thrombosis-free survival (TFS) for ET patients, whereas the respective TFS outcomes were similarly poorer in JAK2 mutated ET and PV patients. Multivariate analysis confirmed that younger age (<60 years), presence of CALR mutations, and a lower platelet count (<1,000 * 10(9)/L) were independently associated with a longer TFS in ET patients. The current study demonstrates that CALR mutations characterize a special group of ET patients with unique phenotypes that are not discrepant from those seen in Western countries. PMID- 25015053 TI - HFE-related hemochromatosis risk mutations in Latvian population. PMID- 25015054 TI - The hepcidin gene promoter nc.-1010C > T; -582A > G haplotype modulates serum ferritin in individuals carrying the common H63D mutation in HFE gene. AB - Hereditary hemochromatosis is an autosomal recessive disorder characterized by severe iron overload. It is usually associated with homozygosity for the HFE gene mutation c.845G > A; p.C282Y. However, in some cases, another HFE mutation (c.187C > G; p.H63D) seems to be associated with the disease. Its penetrance is very low, suggesting the possibility of other iron genetic modulators being involved. In this work, we have screened for HAMP promoter polymorphisms in 409 individuals presenting normal or increased serum ferritin levels together with normal or H63D-mutated HFE genotypes. Our results show that the hepcidin gene promoter TG haplotype, originated by linkage of the nc.-1010C > T and nc.-582A > G polymorphisms, is more frequent in the HFE_H63D individuals presenting serum ferritin levels higher than 300 MUg/L than in those presenting the HFE_H63D mutation but with normal serum ferritin levels or in the normal control group.Moreover, it was observed that the TG haplotype was associated to increased serum ferritin levels in the overall pool of HFE_H63D individuals. Thus, our data suggest that screening for these polymorphisms could be of interest in order to explain the phenotype. However, this genetic condition seems to have no clinical significance. PMID- 25015055 TI - Chronic hepatitis E virus infection following allogeneic hematopoietic stem cell transplantation: an important differential diagnosis for graft versus host disease. PMID- 25015056 TI - CD40 promotes the development of early diabetic retinopathy in mice. AB - AIMS/HYPOTHESIS: Microangiopathy is a leading complication of diabetes that commonly affects the retina. Degenerate capillaries are a central feature of diabetic retinopathy. An inflammatory process has been linked to the development of diabetic retinopathy but its regulation is incompletely understood. Cluster of differentiation (CD) 40 is a member of the TNF receptor superfamily that promotes the development of certain inflammatory disorders. The role of CD40 in diabetic microangiopathy is unknown. METHODS: B6 and Cd40-/- mice were administered streptozotocin to induce diabetes. Leucostasis was assessed using fluorescein isothiocyanate-conjugated concanavalin A. Retinal Icam1 and Cd40 mRNA levels were examined using real-time PCR. Protein nitration was assessed by immunohistochemistry. Histopathology was examined in the retinal vasculature. CD40 expression was assessed by flow cytometry and immunohistochemistry. Intercellular adhesion molecule 1 (ICAM-1) and nitric oxide synthase 2 (NOS2) were examined by immunoblot and/or flow cytometry. Nitric oxide production was examined by immunoblot and Griess reaction. RESULTS: In mouse models of diabetes, Cd40-/- mice exhibited reduced retinal leucostasis and did not develop capillary degeneration in comparison with B6 mice. Diabetic Cd40-/- mice had diminished ICAM-1 upregulation and decreased protein nitration. Cd40 mRNA levels were increased in the retinas of diabetic B6 mice compared with non-diabetic controls. CD40 expression increased in retinal Muller cells, endothelial cells and microglia of diabetic animals. CD40 stimulation upregulated ICAM-1 in retinal endothelial cells and Muller cells. CD40 ligation upregulated NOS2 and nitric oxide production by Muller cells. CONCLUSIONS/INTERPRETATION: CD40-deficient mice were protected fromthe development of diabetic retinopathy. These mice exhibited diminished inflammatory responses linked to diabetic retinopathy. CD40 stimulation of retinal cells triggered these pro-inflammatory responses. PMID- 25015057 TI - Professional educational needs for chemotherapy-induced nausea and vomiting (CINV): multinational survey results from 2388 health care providers. AB - PURPOSE: Because as many as 30% of cancer patients who receive chemotherapy of moderate or high emetogenic potential suffer from chemotherapy-induced nausea and vomiting (CINV), we undertook a multinational survey to identify health care providers' perceived knowledge gaps, barriers,and educational interests relevant to CINV. METHODS: An Internet-based survey was developed and was electronically disseminated to members of Medscape, an international Internet-based continuing medical education provider. RESULTS: A total of 2388 health care providers responded to the survey. Although breakthrough nausea and vomiting was the most common CINV-related issue they managed in the preceding year, managing delayed nausea was the most problematic in that time period. Thirty-two percent of health care providers delayed or discontinued a patient's chemotherapy because of CINV. Cost of antiemetics, patients' poor adherence to antiemetic regimens, and health care providers' underestimation of risk for CINV were all barriers to effective management. Health care providers expressed a wide range of educational interests, including managing breakthrough CINV, keeping up with novel antiemetic agents, and learning about emerging approaches for CINV prevention/management. CONCLUSIONS: This survey of health care providers uncovered key barriers and educational needs relevant to the management of CINV. The findings from this survey can be used to develop educational initiatives focused on improving the care of cancer patients at risk for or suffering from CINV. PMID- 25015058 TI - Comparison of the EORTC QLQ-BN20 and the FACT-Br quality of life questionnaires for patients with primary brain cancers: a literature review. AB - PURPOSE: This review compares and contrasts the development, validity, and characteristics of two quality of life (QOL) assessment tools used in patients with primary brain cancers: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Brain Cancer Module (EORTC QLQ-BN20) and the Functional Assessment of Cancer Therapy-Brain (FACT-Br). METHODS: A literature search was conducted using the Cochrane Central Register of Controlled Trials (June 2013), Ovid EMBASE (1947 to 2013, week 27), and Ovid MEDLINE (1946 to July 2013, week 1) to identify studies that discussed the development, characteristics, validity, and reliability of the EORTC QLQ-BN20 or the FACT-Br. RESULTS: The EORTC QLQ-BN20 consists of 20 items that assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. Items are presented as questions on a scale ranging from 1 = "not at all" to 4 = "very much." Reliability and validity testing of the QLQ-BN20 revealed a Cronbach's alpha coefficient that ranged from 0.71 to 0.90. The FACT-Br consists of 23 items that assess general well-being and brain cancer-specific concerns that include concentration, memory, seizures, eyesight, hearing, speech, personality, expression of thoughts, weakness, coordination, and headaches. These items are presented as statements on a scale ranging from 0 = "not applicable" to 4 = "extremely relevant." The FACT-Br underwent validity as well as test-retest reliability testing with 101 and 46 patients, respectively. Validity testing found low to moderate correlation with the FACT-G questionnaire, while reliability testing for the brain subscale revealed an acceptable correlation coefficient (r = 0.66; p < 0.001). CONCLUSIONS: The QLQ-BN20 and the FACT-Br are both valid and reliable tools that have been used extensively in the primary brain cancer population. Choice between the two tools should consider each instrument's individual strengths and weaknesses. PMID- 25015059 TI - Recombinant activated factor VII in clinical practice: a 2014 update. AB - Recombinant activated factor VII (rFVIIa) was initially developed to treat bleeding episodes in patients with congenital hemophilia and inhibitors. Due to the initial success in this clinical setting, its use has been extended to other coagulopathies characterized by impaired thrombin generation, i.e. acquired hemophilia, inherited factor VII deficiency and Glanzmann's thrombasthenia, for which it is currently licensed. Extensive research in the last decade has increased our knowledge of the mechanisms utilized by rFVIIa to restore normal hemostasis. This paper reviews current understanding of the mechanisms of action of rFVIIa before summarizing the clinical experience, in terms of safety and efficacy, to date in its licensed indications. PMID- 25015061 TI - Elevated levels of serum sCXCL16 in systemic lupus erythematosus; potential involvement in cutaneous and renal manifestations. AB - The aim of this study was to investigate the levels and clinical significance of serum soluble chemokine (C-X-C motif) ligand 16 (sCXCL16) in patients with systemic lupus erythematosus (SLE), as well as the sCXCL16 molecule's associations with disease activity and organ damage. Thirty-five patients with SLE, 16 patients with rheumatoid arthritis (RA), and 15 healthy controls were included in this study. The demographic and clinical features of the patients were recorded. The serum levels of sCXCL16 were determined. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI), and organ damage was evaluated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI). The serum levels of sCXCL16 in the patients with SLE were higher than those in the patients with RA (P = 0.002) or healthy controls (P < 0.0001). The levels in the patients with active SLE were higher than those in the disease inactive patients (P = 0.008). Positive correlations were identified between serum sCXCL16 concentrations and both SLEDAI (r = 0.564; P < 0.0001) and SDI scores (r = 0.396; P = 0.018). Both SLEDAI (P = 0.021) and serum levels of CXCL16 (P = 0.023) decreased after conventional treatment in 12 initial onset cases of SLE patients. Elevated serum sCXCL16 levels were discovered in the SLE patients with cutaneous (P = 0.006) and renal involvement (P = 0.032). Soluble CXCL16 may become a useful serological marker of disease activity and skin and renal involvement in SLE patients; thus, it may be used for evaluation of therapeutic interventions. PMID- 25015063 TI - Clustering of surface NMDA receptors is mainly mediated by the C-terminus of GluN2A in cultured rat hippocampal neurons. AB - N-methyl-D-aspartate receptors (NMDARs) containing different GluN2 subunits play distinct roles in synaptic plasticity. Such differences may not only be determined by the channel properties, but also by differential surface distribution and synaptic localization.In the present study, using a Cy3 conjugated Fab fragment of the GFP antibody to label surface-located GluN2 subunits tagged with GFP at the N-terminus,we observed the membrane distribution patterns of GluN2A- or GluN2B-containing NMDARs in cultured rat hippocampal neurons. We found that surface NMDARs containing GluN2A, but not those containing GluN2B,were inclined to cluster at DIV7. Swapping the carboxyl termini of the GluN2 subunits completely reversed these distribution patterns. In addition, surface NMDARs containing GluN2A were preferentially associated with PSD-95. Taken together, the results of our study suggest that the clustering distribution of GluN2A containing NMDARs is determined by the GluN2AC-terminus, and its interaction with PSD-95 plays animportant role in this process. PMID- 25015062 TI - Glial cells in neuronal development: recent advances and insights from Drosophila melanogaster. AB - Glia outnumber neurons and are the most abundant cell type in the nervous system. Whereas neurons are the major carriers, transducers, and processors of information, glial cells, once considered mainly to play a passive supporting role, are now recognized for their active contributions to almost every aspect of nervous system development. Recently, insights from the invertebrate organism Drosophila melanogaster have advanced our knowledge of glial cell biology. In particular, findings on neuron-glia interactions via intrinsic and extrinsic mechanisms have shed light on the importance of glia during different stages of neuronal development. Here, we summarize recent advances in understanding the functions of Drosophila glia, which resemble their mammalian counterparts in morphology and function, neural stem-cell conversion, synapse formation, and developmental axon pruning. These discoveries reinforce the idea that glia are substantial players in the developing nervous system and further advance the understanding of mechanisms leading to neurodegeneration. PMID- 25015064 TI - Uric acid as a predictor of in-hospital mortality in acute myocardial infarction: a meta-analysis. AB - Uric acid (UA) is generalized as a byproduct the terminal steps of purine catabolism, which are catalyzed by xanthine oxidoreductase. Xanthine oxidase activity and uric acid synthesis are reported to be increased under tissue ischemia. Therefore, elevated uric acid may act as a prognostic marker of acute myocardial infarction (AMI). A few studies have showed that UA is associated with therapeutic outcomes in patients with acute myocardial infarction. The purpose of this meta-analysis is to evaluate the prognostic significance of the UA as a predictor of in-hospital mortality. We performed a systematic review and included studies that used both UA and in-hospital mortality from Embase and PubMed. Six studies have been included in this review with totally 5,686 patients. During the follow-up, high UA level was found to be associated with an increased risk of in hospital mortality [risk ratios (RR) 2.10 (1.03-4.26), number needed to harm (NNH) 37], MACE [RR 3.44 (2.33-5.08), NNH 17]. High UA level has the potential to be an important prognostic marker for in-hospital mortality in individuals with AMI. PMID- 25015065 TI - Obtusifolin treatment improves hyperlipidemia and hyperglycemia: possible mechanism involving oxidative stress. AB - Clinical research has confirmed the efficacy of several plant extracts in the modulation of oxidative stress associated with hyperlipidemia and hyperglycemia induced by obesity and diabetes. Findings indicate that obtusifolin has antioxidant properties. The aim of this study was to evaluate the possible protective effects of obtusifolin against oxidative damage in diabetic hyperlipidemia and hyperglycemia. In this study, the rats were divided into the following groups with eight animals in each: control, untreated diabetic, three obtusifolin (10, 30, and 90 mg/kg/day)-treated diabetic groups. Diabetes was induced by streptozotocin (STZ) in rats. STZ was injected intraperitoneally at a single dose of 60 mg/kg for diabetes induction. Obtusifolin (intraperitoneal injection) was administered 3 days after STZ administration; these injections were continued to the end of the study (4 weeks). At the end of the 4-week period, blood was drawn for biochemical assays. In order to determine the changes of cellular antioxidant defense systems, antioxidant enzymes including glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were measured in serum. Moreover, we also measured serum nitric oxide (NO) and serum malondialdehyde (MDA) levels, markers of lipid peroxidation. STZ induced diabetes caused an elevation (P < 0.001) of blood glucose, MDA, NO, total lipids, triglycerides and cholesterol, with reduction of GSH level and CAT and SOD activities. The results indicated that the significant elevation in the blood glucose, MDA, NO, total lipids, triglycerides and cholesterol; also the reduction of glutathione level and CAT and SOD activity were ameliorated in the obtusifolin treated diabetic groups compared with the untreated groups, in a dose-dependent manner (P < 0.05, P < 0.01, P < 0.001). These results suggest that obtusifolin has antioxidant properties and improves chemically induced diabetes and its complications by modulation of oxidative stress. PMID- 25015066 TI - Late remote ischemic preconditioning provides benefit to patients undergoing elective percutaneous coronary intervention. AB - To assess whether late remote ischemic preconditioning (L-RIPC) is effective in myocardial protection in patients with ischemic heart disease undergoing elective percutaneous coronary intervention (PCI). L-RIPC is exerted by newly synthesized cardioprotective proteins. The cardioprotective effects of L-RIPC are more durable. 200 consecutive patients undergoing elective PCI were randomized to receive L-RIPC (induced by three 5-minute inflations of a blood pressure cuff to 200 mmHg around the upper arm, followed by 5-min intervals of reperfusion) or control (an uninflated cuff around the arm) at 18 h before PCI. Creatine phosphokinase (CK), its cardiac isoenzyme (CK-MB), troponin I (TNI), and high sensitivity C-reactive protein (hs-CRP) levels were measured at 24 h after PCI. Adverse events' rates at 6 months were assessed. Compared with the control group, patients in L-RIPC group were observed with significantly lower incidences in Chest pain score >1 and ECG ST deviation >1 mm (P < 0.05). The median TNI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.009 vs. 0.036 ng/mL, 123 vs. 186 IU/L, 15 vs. 27 IU/L; P < 0.05). There was no statistical difference in hs-CRP between two groups. At 6 months, the adverse events' rate was lower in the L-RIPC group (P = 0.036). L-RIPC is effective in myocardial protection in patients undergoing elective PCI and reduces adverse events' rate at 6 months. PMID- 25015067 TI - The partial code blue. PMID- 25015068 TI - Late and very late drug-eluting stent thrombosis in the immediate postoperative period after antiplatelet withdrawal: a retrospective study. AB - BACKGROUND: Late (31-360 days after deployment) and very late (>360 days after deployment) stent thrombosis is a feared complication after drug-eluting stent (DES) deployment. The American College of Cardiology/American Heart Association guidelines recommend dual antiplatelet therapy for 12 months due to the lack of protection beyond this period in randomized trials. The perioperative period is a unique state of generalized hypercoagulability which can predispose people to DES thrombosis when combined with the rebound hypercoagulable effect of antiplatelet withdrawal. METHODS: A retrospective chart review was performed to detect incidences of late and very late postoperative DES thrombosis after elective noncardiac surgery. Only definite and probable cases of stent thrombosis were included. All cases were analyzed for patient demographics, comorbidities, type of surgery, intervention history, preoperative antiplatelets management, postoperative course and outcome. RESULTS: A total of six patients with prior DES deployment (10-42 months earlier, average 30 months) developed DES thrombosis (five very late and one late) in the immediate postoperative period. All patients had stable coronary artery disease and were cleared for surgery (intermediate cardiac risk surgery) by their cardiologist. In all patients, antiplatelets were discontinued 4-7 days (average 5.6 days) prior to surgery to minimize operative bleeding. Five of six patients developed ST-segment elevation myocardial infarction. Half of the patients had simultaneous two-vessel DES thrombosis and two cases had single vessel thrombosis. Three patients developed ventricular fibrillation and cardiac arrest. One-third of the patients died during the index hospitalization. Coronary thrombectomy and angioplasty was successful in the remaining four cases. The incidence of postoperative late and very late DES thrombosis among all patients undergoing noncardiac surgery who were older than 40 years was 0.006%. CONCLUSION: Caution should be exercised when attempting to withdraw antiplatelets preoperatively in patients with DES even when the recommended 12-month period of dual antiplatelet therapy (DAPT) has elapsed. The significant morbidity and mortality of this complication warrants further research to study the ideal perioperative management of antiplatelets in patients with prior DES deployment over 1 year who are still receiving DAPT. PMID- 25015069 TI - Humidity-regulated dormancy onset in the Fabaceae: a conceptual model and its ecological implications for the Australian wattle Acacia saligna. AB - BACKGROUND AND AIMS: Seed dormancy enhances fitness by preventing seeds from germinating when the probability of seedling survival and recruitment is low. The onset of physical dormancy is sensitive to humidity during ripening; however, the implications of this mechanism for seed bank dynamics have not been quantified. This study proposes a model that describes how humidity-regulated dormancy onset may control the accumulation of a dormant seed bank, and seed experiments are conducted to calibrate the model for an Australian Fabaceae, Acacia saligna. The model is used to investigate the impact of climate on seed dormancy and to forecast the ecological implications of human-induced climate change. METHODS: The relationship between relative humidity and dormancy onset was quantified under laboratory conditions by exposing freshly matured non-dormant seeds to constant humidity levels for fixed durations. The model was field-calibrated by measuring the response of seeds exposed to naturally fluctuating humidity. The model was applied to 3-hourly records of humidity spanning the period 1972-2007 in order to estimate both temporal variability in dormancy and spatial variability attributable to climatic differences among populations. Climate change models were used to project future changes in dormancy onset. KEY RESULTS: A sigmoidal relationship exists between dormancy and humidity under both laboratory and field conditions. Seeds ripened under field conditions became dormant following very short exposure to low humidity (<20 %). Prolonged exposure at higher humidity did not increase dormancy significantly. It is predicted that populations growing in a temperate climate produce 33-55 % fewer dormant seeds than those in a Mediterranean climate; however, dormancy in temperate populations is predicted to increase as a result of climate change. CONCLUSIONS: Humidity regulated dormancy onset may explain observed variation in physical dormancy. The model offers a systematic approach to modelling this variation in population studies. Forecast changes in climate have the potential to alter the seed bank dynamics of species with physical dormancy regulated by this mechanism, with implications for their capacity to delay germination and exploit windows for recruitment. PMID- 25015071 TI - Invasive ductal carcinoma of the breast with clear cell and pseudo-lactating changes. AB - Invasive ductal carcinoma of the breast with clear cell changes is a very rare pathological entity. There are <150 cases of this breast cancer subtype reported in the literature. Clear cell carcinoma could be easily missed or under-diagnosed in a breast core biopsy specimen due to the fact that this subtype tends to show a papillary pattern with clear cell and pseudo-lactating changes, especially in young female patients. Normal breast tissue may possess clear cells as a consequence of the physiological changes of pregnancy, the clearing of the cytoplasm within myoepithelial cells, or the clearing of the cytoplasm in apocrine metaplasia. Owing to its aggressive clinical course, clear cell carcinoma must be differentiated from other subtypes of breast carcinoma. Special attention given to this rare subtype by pathologists and clinicians could avoid misdiagnosis and delay of treatment. PMID- 25015070 TI - Gains of chromosomes 7 and 17 in tubulocystic carcinoma of kidney: two cases with fluorescence in situ hybridisation analysis. AB - Tubulocystic carcinoma (TCC) is a very rare renal tumour with unique gross and microscopic features, alternatively considered as low-grade collecting duct carcinoma. Recent studies favoured distinction of TCC from collecting duct carcinoma, and some cases of TCC synchronously coexisting with other renal cell tumour subtypes were described. We report here two new cases of pure (case 1) or mixed (case 2) TCC with fluorescence in situ hybridisation (FISH) analysis, which showed gains of chromosomes 7 and 17 in the pure TCC of case 1, as well as in the TCC and the papillary renal cell carcinoma (PRCC) components in case 2. These data may further support the notion that TCC is more closely related to PRCC. PMID- 25015072 TI - Single surgeon coelioscopic orchiectomy of desert tortoises (Gopherus agassizii) for population management. AB - Orchiectomy in chelonians is a challenging procedure, especially in large species with deep and elongated testes and extensive mesorchial attachments. Single surgeon coelioscopic orchiectomy was performed in seven adult desert tortoises (Gopherus agassizii), maintained at the Desert Tortoise Conservation Center (DTCC) in Las Vegas, for population management. Surgery was successfully conducted through a bilateral prefemoral approach via sequential vascular clip ligation and radiosurgery (monopolar/bipolar). Bipolar endoscopic forceps were considered indispensable due to the extensive mesorchial attachments and their close association with the kidney. A mechanical arm was effectively used to permit orchiectomy to be completed by a single surgeon. Six of seven animals recovered from anaesthesia. Necropsy demonstrated that the death of the other was unrelated to surgical complications. One animal experienced surgically significant haemorrhage, but still made a clinical recovery. The six tortoises were returned to the DTCC and, six months postoperatively, remain healthy. This small study suggests this minimally invasive technique is an effective method for bilateral orchiectomy in desert tortoises and might be preferable in large chelonians with elongated testes. PMID- 25015073 TI - Autologous fat grafting for painful finger scars. PMID- 25015074 TI - Police advise GPs to take steps against telephone fraud. PMID- 25015076 TI - In-hospital worsening heart failure and associations with mortality, readmission, and healthcare utilization. AB - BACKGROUND: A subset of patients hospitalized with acute heart failure experiences worsening clinical status and requires escalation of therapy. Worsening heart failure is an end point in many clinical trials, but little is known about its prevalence in clinical practice and its associated outcomes. METHODS AND RESULTS: We analyzed inpatient data from the Acute Decompensated Heart Failure National Registry linked to Medicare claims to examine the prevalence and outcomes of patients with worsening heart failure, defined as the need for escalation of therapy at least 12 hours after hospital presentation. We compared patients with worsening heart failure to patients with an uncomplicated hospital course and patients with a complicated presentation. Of 63 727 patients hospitalized with acute heart failure, 11% developed worsening heart failure. These patients had the highest observed rates of mortality, all-cause readmission, and Medicare payments at 30 days and 1 year after hospitalization (P < 0.001 for all comparisons). The adjusted hazards of 30-day mortality were 2.56 (99% CI, 2.34 to 2.80) compared with an uncomplicated course and 1.29 (99% CI, 1.17 to 1.42) compared with a complicated presentation. The adjusted cost ratios for postdischarge Medicare payments at 30 days were 1.35 (99% CI, 1.24 to 1.46) compared with an uncomplicated course and 1.11 (99% CI, 1.02 to 1.22) compared with a complicated presentation. CONCLUSIONS: In-hospital worsening heart failure was common and was associated with higher rates of mortality, all-cause readmission, and postdischarge Medicare payments. Prevention and treatment of in hospital worsening heart failure represents an important goal for patients hospitalized with acute heart failure. PMID- 25015075 TI - Reducing endoglin activity limits calcineurin and TRPC-6 expression and improves survival in a mouse model of right ventricular pressure overload. AB - BACKGROUND: Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-beta1). TGF-beta1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-beta1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO. METHODS AND RESULTS: We first demonstrate that endoglin is required for TGF-beta1-mediated calcineurin/TRPC-6 expression and up-regulation of alpha-smooth muscle antigen (alpha-SMA), a marker of myofibroblast transformation, in human RV fibroblasts. Using endoglin haploinsufficient mice (Eng(+/-)) we show that reduced endoglin activity preserves RV function, limits RV fibrosis, and attenuates activation of the calcineurin/TRPC-6/alpha-SMA pathway in a model of angio-obliterative pulmonary hypertension. Next, using Eng(+/-) mice or a neutralizing antibody (Ab) against endoglin (N-Eng) in wild-type mice, we show that reduced endoglin activity improves survival and attenuates RV fibrosis in models of RVPO induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of RV fibrosis and calcineurin levels in wild-type mice treated with a N-Eng Ab, compared to an immunoglobulin G control. CONCLUSION: These data establish endoglin as a regulator of TGF-beta1 signaling by calcineurin and TRPC-6 in the RV and identify it as a potential therapeutic target to limit RV fibrosis and improve survival in RVPO, a common cause of death in cardiac and pulmonary disease. PMID- 25015077 TI - Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform. AB - RATIONALE: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. However, human cardiac tissues are difficult to procure in sufficient enough quantities for studying the mechanisms of cardiac-specific viral infection. OBJECTIVE: This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus induced viral myocarditis and to screen antiviral therapeutics for efficacy. METHODS AND RESULTS: hiPSC-CMs were infected with a luciferase-expressing coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs for alterations in cellular morphology and calcium handling. Viral proliferation in hiPSC-CMs was quantified using bioluminescence imaging. Antiviral compounds including interferonbeta1, ribavirin, pyrrolidine dithiocarbamate, and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of these compounds to reduce CVB3-Luc proliferation in hiPSC CMs was consistent with reported drug effects in previous studies. Mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways after interferonbeta1 treatment. CONCLUSIONS: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to predict antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that can screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion. PMID- 25015078 TI - Small heterodimer partner blocks cardiac hypertrophy by interfering with GATA6 signaling. AB - RATIONALE: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated. OBJECTIVE: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. METHODS AND RESULTS: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP-null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and, by direct physical interaction with Gata6, interfered with the binding of Gata6 to GATA-binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an antidiabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin induced antihypertrophic effect was attenuated either by SHP small interfering RNA in cardiomyocytes or in SHP-null mice. CONCLUSIONS: These results establish SHP as a novel antihypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced antihypertrophic response. PMID- 25015079 TI - A large number of nuclear genes in the human parasite blastocystis require mRNA polyadenylation to create functional termination codons. AB - Termination codons in mRNA molecules are typically specified directly by the sequence of the corresponding gene. However, in mitochondria of a few eukaryotic groups, some mRNAs contain the termination codon UAA deriving one or both adenosines from transcript polyadenylation. Here, we show that a similar phenomenon occurs for a substantial number of nuclear genes in Blastocystis spp., divergent unicellular eukaryote gut parasites. Our analyses of published genomic data from Blastocystis sp. subtype 7 revealed that polyadenylation-mediated creation of termination codons occurs in approximately 15% of all nuclear genes. As this phenomenon has not been noticed before, the procedure previously employed to annotate the Blastocystis nuclear genome sequence failed to correctly define the structure of the 3'-ends of hundreds of genes. From sequence data we have obtained from the distantly related Blastocystis sp. subtype 1 strain, we show that this phenomenon is widespread within the Blastocystis genus. Polyadenylation in Blastocystis appears to be directed by a conserved GU-rich element located four nucleotides downstream of the polyadenylation site. Thus, the highly precise positioning of the polyadenylation in Blastocystis has allowed reduction of the 3'-untranslated regions to the point that, in many genes, only one or two nucleotides of the termination codon are left. PMID- 25015081 TI - Ten-Year Publication Trajectories of Health Services Research Career Development Award Recipients: Collaboration, Awardee Characteristics, and Productivity Correlates. AB - This study's purpose was to identify distinct publishing trajectories among 442 participants in three prominent mentored health services research career development programs (Veterans Affairs, National Institutes of Health, and Agency for Healthcare Research & Quality) in the 10 years after award receipt and to examine awardee characteristics associated with different trajectories. Curricula vitae (CVs) of researchers receiving awards between 1991 and 2010 were coded for publications, grants, and awardee characteristics. We found that awardees published at constant or increasing rates despite flat or decreasing rates of first-author publications. Senior-author publications rose concurrently with rates of overall publications. Higher overall publication trajectories were associated with receiving more grants, more citations as measured by the h-index, and more authors per article. Lower trajectory groups were older and had a greater proportion of female awardees. Career development awards supported researchers who generally published successfully, but trajectories varied across individual researchers. Researchers' collaborative efforts produced an increasing number of articles, whereas first author articles were written at a more consistent rate. Career development awards in health services research supported the careers of researchers who published at a high rate; future research should further examine reasons for variation in publishing among early career researchers. PMID- 25015082 TI - Perceptions about community applications of RE-AIM in the promotion of evidence based programs for older adults. AB - Despite the growing literature about the RE-AIM framework as a planning, implementation, and evaluation tool, little is known about practitioners' adoption of the framework, confidence to utilize framework elements, or perceptions of its usefulness. To assess how RE-AIM was implemented by state aging service providers and public health partners, data were collected using an Internet-delivered, cross-sectional survey from 40 stakeholders in 27 funded states in an evidence-based disease prevention initiative for older adults. Most participants agreed the framework was useful for planning, implementation, and evaluation and relevant for evaluators, providers, community leaders, and policy makers. Yet nearly half felt monitoring RE-AIM requirements requires special expertise, and one third felt the different RE-AIM elements were difficult to measure. Findings indicate the RE-AIM's appropriateness and utility for planning and evaluating the dissemination of evidence-based programs to older adults; however, additional trainings, resources, and technical assistance are warranted to enhance uptake in community-wide intervention efforts. PMID- 25015084 TI - Quantum nonlocality does not exist. AB - Quantum nonlocality is shown to be an artifact of the Copenhagen interpretation, in which each observed quantity has exactly one value at any instant. In reality, all physical systems obey quantum mechanics, which obeys no such rule. Locality is restored if observed and observer are both assumed to obey quantum mechanics, as in the many-worlds interpretation (MWI). Using the MWI, I show that the quantum side of Bell's inequality, generally believed nonlocal, is really due to a series of three measurements (not two as in the standard, oversimplified analysis), all three of which have only local effects. Thus, experiments confirming "nonlocality" are actually confirming the MWI. The mistaken interpretation of nonlocality experiments depends crucially on a question-begging version of the Born interpretation, which makes sense only in "collapse" versions of quantum theory, about the meaning of the modulus of the wave function, so I use the interpretation based on the MWI, namely that the wave function is a world density amplitude, not a probability amplitude. This view allows the Born interpretation to be derived directly from the Schrodinger equation, by applying the Schrodinger equation to both the observed and the observer. PMID- 25015083 TI - Minimal detectable change for mobility and patient-reported tools in people with osteoarthritis awaiting arthroplasty. AB - BACKGROUND: Thoughtful use of assessment tools to monitor disease requires an understanding of clinimetric properties. These properties are often under reported and, thus, potentially overlooked in the clinic. This study aimed to determine the minimal detectable change (MDC) and coefficient of variation per cent (CV%) for tools commonly used to assess the symptomatic and functional severity of knee and hip osteoarthritis. METHODS: We performed a test-retest study on 136 people awaiting knee or hip arthroplasty at one of two hospitals. The MDC95 (the range over which the difference [change] for 95% of patients is expected to lie) and the coefficient of variation per cent (CV%) for the visual analogue scale (VAS) for joint pain, the six-minute walk test (6MWT), the timed up-and-go (TUG) test, the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Hip Disability and Osteoarthritis Outcome Score (HOOS) subscales were calculated. RESULTS: Knee cohort (n = 75) - The MDC95 and CV% values were as follows: VAS 2.8 cm, 15%; 6MWT 79 m, 8%; TUG +/-36.7%, 13%; KOOS pain 20.2, 19%; KOOS symptoms 24.1, 22%; KOOS activities of daily living 20.8, 17%; KOOS quality of life 26.6, 44. Hip cohort (n = 61) - The MDC95 and CV% values were as follows: VAS 3.3 cm, 17%; 6MWT 81.5 m, 9%; TUG +/-44.6%, 16%; HOOS pain 21.6, 22%; HOOS symptoms 22.7, 19%; HOOS activities of daily living 17.7, 17%; HOOS quality of life 24.4, 43%. CONCLUSIONS: Distinguishing real change from error is difficult in people with severe osteoarthritis. The 6MWT demonstrates the smallest measurement error amongst a range of tools commonly used to assess disease severity, thus, has the capacity to detect the smallest real change above measurement error in everyday clinical practice. PMID- 25015085 TI - Structural basis for the binding and incorporation of nucleotide analogs with L stereochemistry by human DNA polymerase lambda. AB - Although lamivudine and emtricitabine, two L-deoxycytidine analogs, have been widely used as antiviral drugs for years, a structural basis for D stereoselectivity against L-dNTPs, enantiomers of natural nucleotides (D-dNTPs), by any DNA polymerase or reverse transcriptase has not been established due to lack of a ternary structure of a polymerase, DNA, and an incoming L-dNTP. Here, we report 2.10-2.25 A ternary crystal structures of human DNA polymerase lambda, DNA, and L-deoxycytidine 5'-triphosphate (L-dCTP), or the triphosphates of lamivudine ((-)3TC-TP) and emtricitabine ((-)FTC-TP) with four ternary complexes per asymmetric unit. The structures of these 12 ternary complexes reveal that relative to D-deoxycytidine 5'-triphosphate (D-dCTP) in the canonical ternary structure of Pollambda-DNA-D-dCTP, L-dCTP, (-)3TC-TP, and (-)FTC-TP all have their ribose rotated by 180 degrees . Among the four ternary complexes with a specific L-nucleotide, two are similar and show that the L-nucleotide forms three Watson-Crick hydrogen bonds with the templating nucleotide dG and adopts a chair like triphosphate conformation. In the remaining two similar ternary complexes, the L-nucleotide surprisingly interacts with the side chain of a conserved active site residue R517 through one or two hydrogen bonds, whereas the templating dG is anchored by a hydrogen bond with the side chain of a semiconserved residue Y505. Furthermore, the triphosphate of the L-nucleotide adopts an unprecedented N shaped conformation. Our mutagenic and kinetic studies further demonstrate that the side chain of R517 is critical for the formation of the abovementioned four complexes along proposed catalytic pathways for L-nucleotide incorporation and provide the structural basis for the D-stereoselectivity of a DNA polymerase. PMID- 25015088 TI - Whither whole brain radiotherapy for primary CNS lymphoma? PMID- 25015087 TI - Regulation of the pentose phosphate pathway in cancer. AB - Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway. PMID- 25015089 TI - Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. AB - BACKGROUND: Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy. METHODS: Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry. RESULTS: Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5 fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 uM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio. CONCLUSIONS: This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678. PMID- 25015091 TI - A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCdelta and E cadherin. AB - Accumulation of genetic and epigenetic changes contributes to cancer development and progression. Compared with gene mutations or deletions, epigenetic changes are reversible, which alter the chromatin structure remodeling instead of changes in DNA sequence, and therefore become a promising strategy for chemotherapy. Histone deacetylases (HDACs) are a class of enzymes that responsible for the epigenetic regulation of gene expression. MPT0G030 is a potent and selective class I HDAC inhibitor which showed broad-spectrum cytotoxicity against various human cancer cell lines. in vitro fluorometric HDAC activity assay showed that MPT0G030 effectively inhibited Class I HDACs (HDAC1~3), which were overexpressed in many malignant neoplasms. Interestingly, MPT0G030 not only induced histone acetylation and tumor suppressor p21 transcription, but also redistributed E cadherin and activated Protein Kinase C delta (PKCdelta), which was linked to cell apoptosis and differentiation. Further, activation of PKCdelta was demonstrated to be modulated through HDAC1. The in vivo anticancer activity of MPT0G030 and the importance of PKCdelta were confirmed in the HT-29 tumor xenograft models. Taken together, those results indicate that MPT0G030, a class I HDAC inhibitor, has great potential as a new drug candidate for cancer therapy. PMID- 25015090 TI - Functional analysis of a novel glioma antigen, EFTUD1. AB - BACKGROUND: A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas. METHODS: EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed. RESULTS: EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone. CONCLUSION: These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas. PMID- 25015092 TI - Anti-mosquito plants as an alternative or incremental method for malaria vector control among rural communities of Bagamoyo District, Tanzania. AB - BACKGROUND: Plants represent one of the most accessible resources available for mosquito control by communities in Tanzania. However, no documented statistics exist for their contribution in the management of mosquitoes and other insects except through verbal and some publications. This study aimed at assessing communities' knowledge, attitudes and practices of using plants as an alternative method for mosquito control among selected communities in a malaria-prone area in Tanzania. METHODS: Questionnaires were administered to 202 respondents from four villages of Bagamoyo District, Pwani Region, in Tanzania followed by participatory rural appraisal with village health workers. Secondary data collection for plants mentioned by the communities was undertaken using different search engines such as googlescholar, PubMED and NAPRALERT. RESULTS: Results showed about 40.3% of respondents used plants to manage insects, including mosquitoes. A broad profile of plants are used, including "mwarobaini" (Azadirachta indica) (22.5%), "mtopetope" (Annona spp) (20.8%), "mchungwa/mlimau" (Citrus spp) (8.3%), "mvumbashi/uvumbati" (Ocimum spp) (7.4%), "mkorosho" (Anacadium occidentale) (7.1%), "mwembe" (5.4%) (Mangifera indica), "mpera" (4.1%) (Psidium spp) and "maganda ya nazi" (4.1%) (Cocos nucifera). Majority of respondents collected these plants from the wild (54.2%), farms (28.9%) and/or home gardens (6%). The roles played by these plants in fighting mosquitoes is reflected by the majority that deploy them with or without bed-nets (p > 0.55) or insecticidal sprays (p >0.22). Most respondents were aware that mosquitoes transmit malaria (90.6%) while few respondents associated elephantiasis/hydrocele (46.5%) and yellow fever (24.3%) with mosquitoes. Most of the ethnobotanical uses mentioned by the communities were consistent with scientific information gathered from the literature, except for Psidium guajava, which is reported for the first time in insect control. CONCLUSION: This survey has indicated some knowledge gap among community members in managing mosquito vectors using plant. The communities need a basic health education and sensitization for effective exploitation of this valuable tool for reducing mosquitoes and associated disease burdens. On the other hand, the government of Tanzania should strengthen advocacy of botanical pesticides development, registration and regulation for public health benefits because they are source of pest control tools people rely on them. PMID- 25015093 TI - Signaling pathways involved in osteogenesis and their application for bone regenerative medicine. AB - Bone regeneration is a well organized but complex physiological process, in which different cell types and their activated signaling pathways are involved. In bone regeneration and remodeling processes, mesenchymal stem cells (MSCs) have a crucial role, and their differentiation during these processes is regulated by specific signaling molecules (growth factors/cytokines and hormones) and their activated intracellular networks. Especially the utilization of the molecular machinery seems crucial to consider prior to developing bone implants, bone substitute materials, and cell-based constructs for bone regeneration. The aim of this review is to provide an overview of the signaling mechanisms involved in bone regeneration and remodeling and the osteogenic potential of MSCs to become a key cellular resource for such regeneration and remodeling processes. Additionally, an overview of possibilities to beneficially exploit cell signaling processes to optimize bone regeneration is provided. PMID- 25015094 TI - Perceived outcomes of spiritual healing and explanations--a qualitative study on the perspectives of German healers and their clients. AB - BACKGROUND: Limited research has been conducted on contemporary spiritual healing in European countries. The aim of this article is to report how German healers and their clients experienced and perceived the outcomes of spiritual healing and which explanations they use to describe the perceived effects. METHODS: Semistructured interviews and participatory observation was used to collect data from spiritual healers and their clients. Analyses were based on the methodological concept of directed qualitative content analysis. Data was analyzed using MAXQDA software, discussed and reviewed by a multidisciplinary research team consisting of medical anthropologists, medical doctors and a religious studies scholar. RESULTS: In total 15 healers and 16 clients participated in this study, 24 interviews with healers, 20 interviews with clients and 8 participatory observations were analyzed. Healers and clients reported outcomes as positively perceived body sensations, increased well-being, positive emotions and symptomatic relief of medical complaints. Clients often described changes in their self-concepts and adapted life values. Explanations for perceived effects included connecting with transcendent sources, construction of meaning, as a result of the client-healer relationship, and as empowerment to make changes. Because the interviewed clients were recruited by the healers, a selection bias towards positive healing experiences is possible. CONCLUSION: We hypothesize that concepts of meaning construction, resource activation and the utilization of the clients' expectations help to explain the data. Grounded in the emic perspective, we propose to use the following outcomes for further prospective studies: positive body sensations, changes of self-concepts and values, changes of medical symptoms and complaints. From the etic perspective, physical, emotional, social and spiritual wellbeing, sense of coherence, meaningfulness of life, empowerment, resource activation, change and symptom control should be further explored as potential outcomes. PMID- 25015095 TI - Diagnosis of immediate food allergy. PMID- 25015096 TI - Patients with long term conditions can hold health and social care budgets from 2015. PMID- 25015097 TI - Number of animals used in science increased slightly in 2013, Home Office reports. PMID- 25015098 TI - NICE draft guidance recommends lowering body mass threshold for weight loss surgery. PMID- 25015099 TI - TCF7L2 is a master regulator of insulin production and processing. AB - Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D. PMID- 25015101 TI - Inventory of the cichlid olfactory receptor gene repertoires: identification of olfactory genes with more than one coding exon. AB - BACKGROUND: To help understand the molecular mechanisms underlying the remarkable phenotypic diversity displayed by cichlids, the genome sequences of O. niloticus, P. nyererei, H. burtoni, N. brichardi and M. zebra were recently determined. Here, we present the contents of the olfactory receptor (OR) repertoires in the genomes of these five fishes. RESULTS: We performed an exhaustive TBLASTN search of the five cichlid genomes to identify their OR repertoires as completely as possible. We used as bait a set of ORs described in the literature. The cichlid repertoires thereby extracted contained large numbers of complete genes (O. niloticus 158; H. burtoni 90; M. zebra 102; N. brichardi 69; P. nyererei 88), a small numbers of pseudogenes and many "edge genes" corresponding to incomplete genes located at the ends of contigs. A phylogenetic tree was constructed and showed these repertoires include a large number of families and subfamilies. It also allowed the identification of a large number of OR analogues between cichlids with very high amino-acid identity (>= 99%). Nearly 9% of the full length cichlid OR genes are composed of several coding exons. This is very unusual for vertebrate OR genes. Nevertheless, the evidence is strong, and includes the donor and acceptor splice junction sequences; also, the positions of these genes in the phylogenetic tree indicate that they constitute subfamilies well apart from non-OR G protein-coupled receptor families. CONCLUSIONS: Cichlid OR repertoires are made up of a larger number of genes and fewer pseudogenes than those in other teleosts except zebrafish. These ORs share all identified properties common to all fish ORs; however, the large number of families and subfamilies, each containing few ORs implies that they have evolved more rapidly. This high level of OR diversity is consistent with the substantial phenotypic diversity that characterizes cichlids. PMID- 25015100 TI - Phenotypic severity of homozygous GCK mutations causing neonatal or childhood onset diabetes is primarily mediated through effects on protein stability. AB - Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI <= 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity. PMID- 25015102 TI - Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function. AB - INTRODUCTION: Speckle tracking echocardiography (STE) is a relatively novel and sensitive method for assessing ventricular function and may unmask myocardial dysfunction not appreciated with conventional echocardiography. The association of ventricular dysfunction and prognosis in sepsis is unclear. We sought to evaluate frequency and prognostic value of biventricular function, assessed by STE in patients with severe sepsis or septic shock. METHODS: Over an eighteen month period, sixty patients were prospectively imaged by transthoracic echocardiography within 24 hours of meeting severe sepsis criteria. Myocardial function assessment included conventional measures and STE. Association with mortality was assessed over 12 months. RESULTS: Mortality was 33% at 30 days (n = 20) and 48% at 6 months (n = 29). 32% of patients had right ventricle (RV) dysfunction based on conventional assessment compared to 72% assessed with STE. 33% of patients had left ventricle (LV) dysfunction based on ejection fraction compared to 69% assessed with STE. RV free wall longitudinal strain was moderately associated with six-month mortality (OR 1.1, 95% confidence interval, CI, 1.02-1.26, p = 0.02, area under the curve, AUC, 0.68). No other conventional echocardiography or STE method was associated with survival. After adjustment (for example, for mechanical ventilation) severe RV free wall longitudinal strain impairment remained associated with six-month mortality. CONCLUSION: STE may unmask systolic dysfunction not seen with conventional echocardiography. RV dysfunction unmasked by STE, especially when severe, was associated with high mortality in patients with severe sepsis or septic shock. LV dysfunction was not associated with survival outcomes. PMID- 25015104 TI - Evidence of an 'invitation' effect in feeding sylvatic Stegomyia albopicta from Cambodia. AB - BACKGROUND: Orientation of haematophagous insects towards a potential host is largely mediated by kairomones that, in some groups or species may include chemicals produced during feeding by the insects themselves, the so called 'invitation' effect. METHODS: The 'invitation' effect in blood-feeding diurnally active Stegomyia albopicta was investigated over 33 days in secondary forest in Mondolkiri Province, Cambodia. Two human volunteers sitting inside a shelter collected mosquitoes and noted where and when they landed. A 10% emanator of a synthetic pyrethroid with high vapour action was in use on alternate days. RESULTS: Overall, 2726 mosquitoes were collected, 1654 of which had the landing site recorded. The heads of the volunteers were the locations with the highest density of landings per surface area whilst the knees and elbows accounted for most of the landings received on the arms and legs. Landings recorded within three minutes of each other on a collector were about 2.5 times more likely to be on the same body part than on a random body part, weighted for landing site preference. This preference did not vary with collector or pyrethroid. CONCLUSIONS: The 'invitation' effect may be due to a semio-chemical produced early in the feeding process. Incorporation of such a chemical into traps designed to control this important vector of dengue and chikungunya viruses might potentially improve their attractiveness. PMID- 25015103 TI - Human area MT+ shows load-dependent activation during working memory maintenance with continuously morphing stimulation. AB - BACKGROUND: Initially, human area MT+ was considered a visual area solely processing motion information but further research has shown that it is also involved in various different cognitive operations, such as working memory tasks requiring motion-related information to be maintained or cognitive tasks with implied or expected motion.In the present fMRI study in humans, we focused on MT+ modulation during working memory maintenance using a dynamic shape-tracking working memory task with no motion-related working memory content. Working memory load was systematically varied using complex and simple stimulus material and parametrically increasing retention periods. Activation patterns for the difference between retention of complex and simple memorized stimuli were examined in order to preclude that the reported effects are caused by differences in retrieval. RESULTS: Conjunction analysis over all delay durations for the maintenance of complex versus simple stimuli demonstrated a wide-spread activation pattern. Percent signal change (PSC) in area MT+ revealed a pattern with higher values for the maintenance of complex shapes compared to the retention of a simple circle and with higher values for increasing delay durations. CONCLUSIONS: The present data extend previous knowledge by demonstrating that visual area MT+ presents a brain activity pattern usually found in brain regions that are actively involved in working memory maintenance. PMID- 25015105 TI - Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells. AB - BACKGROUND: Recent findings indicate that exosomes released from cancer cells contain microRNAs (miRNAs) that may be delivered to cells of tumor microenvironment. RESULTS: To elucidate whether miRNAs secreted from chronic myelogenous leukemia cells (CML) are shuttled into endothelial cells thus affecting their phenotype, we first analysed miRNAs content in LAMA84 exosomes. Among the 124 miRNAs identified in LAMA84 exosomes, we focused our attention on miR-126 which was found to be over-overexpressed in exosomes compared with producing parental cells. Transfection of LAMA84 with Cy3-labelled miR-126 and co culture of leukemia cells with endothelial cells (EC) confirmed that miR-126 is shuttled into HUVECs. The treatment of HUVECs with LAMA84 exosomes for 24 hours reduced CXCL12 and VCAM1 expression, both at the mRNA and protein level, and negatively modulated LAMA84 motility and cells adhesion. Transfection in HUVECs of miR-126 inhibitor reversed the decrease of CXCL12 and restored the motility and adhesion of LAMA84 cells while the over-expression of miR-126, showed opposite effects. CONCLUSION: Our results show that the miR-126 shuttled by exosomes is biologically active in the target cells, and support the hypothesis that exosomal miRNAs have an important role in tumor-endothelial crosstalk occurring in the bone marrow microenvironment, potentially affecting disease progression. PMID- 25015106 TI - Molecular modeling and molecular dynamics simulations based structural analysis of the SG2NA protein variants. AB - BACKGROUND: SG2NA is a member of the striatin sub-family of WD-40 repeat proteins. Striatin family members have been associated with diverse physiological functions. SG2NA has also been shown to have roles in cell cycle progression, signal transduction etc. They have been known to interact with a number of proteins including Caveolin and Calmodulin and also propagate the formation of a multimeric protein unit called striatin-interacting phosphatase and kinase. As a pre-requisite for such interaction ability, these proteins are known to be unstable and primarily disordered in their arrangement. Earlier we had identified that it has multiple isoforms (namely 35, 78, 87 kDa based on its molecular weight) which are generated by alternative splicing. However, detailed structural information of SG2NA is still eluding the researchers. RESULTS: This study was aimed towards three-dimensional molecular modeling and characterization of SG2NA protein and its isoforms. One structure out of five was selected for each variant having the least value for C score. Out of these, m35 kDa with a C score value of -3.21 was the most poorly determined structure in comparison to m78 kDa and m87 kDa variants with C scores of -1.16 and -1.97 respectively. Further evaluation resulted in about 61.6% residues of m35 kDa, 76.6% residues of m78 kDa and 72.1% residues of m87 kDa falling in the favorable regions of Ramchandran Plot. Molecular dynamics simulations were also carried out to obtain biologically relevant structural models and compared with previous atomic coordinates. N terminal region of all variants was found to be highly disordered. CONCLUSION: This study provides first-hand detailed information to understand the structural conformation of SG2NA protein variants (m35 kDa, m78 kDa and m87 kDa). The WD-40 repeat domain was found to constitute antiparallel strands of beta-sheets arranged circularly. This study elucidates the crucial structural features of SG2NA proteins which are involved in various protein-protein interactions and also reveals the extent of disorder present in the SG2NA structure crucial for excessive interaction and multimeric protein complexes. The study also potentiates the role of computational approaches for preliminary examination of unknown proteins in the absence of experimental information. PMID- 25015107 TI - TFF1 activates p53 through down-regulation of miR-504 in gastric cancer. AB - The expression of TFF1 is frequently down-regulated in human gastric cancer whereas its knockout leads to the development of gastric adenomas and carcinomas in mouse models. The molecular mechanisms underlying the TFF1 tumor suppressor functions remain unclear. In this study, we demonstrate, using colony formation assay and Annexin V staining, that reconstitution of TFF1 expression in gastric cancer cell models suppresses cell growth and promotes cell death. Furthermore, using a tumor xenograft mouse model of gastric cancer, we demonstrated that reconstitution of TFF1 suppresses tumor growth in vivo. The results from PG13 luciferase reporter assay and Western blot analysis indicated that TFF1 promotes the expression and transcription activity of p53 protein. Further analysis using cycloheximide-based protein assay and quantitative real-time PCR data suggested that TFF1 does not interfere with p53 mRNA levels or protein stability. Alternatively, we found that the reconstitution of TFF1 down-regulates miR-504, a negative regulator of p53. Western blot analysis data demonstrated that miR-504 abrogates TFF1-induced p53 protein expression and activity. In conclusion, the in vitro and in vivo data demonstrate, for the first time, a novel mechanism by which the tumor suppressor functions of TFF1 involve activation of p53 through down-regulation of miR-504. PMID- 25015108 TI - The risk factors for tuberculosis in liver or kidney transplant recipients. AB - BACKGROUND: Liver or kidney transplant recipients are at a higher risk of developing tuberculosis (TB) than general population. We aimed to clarify the incidence density of and risk factors for TB in liver or kidney transplant recipients in the present study. METHODS: All patients with TB following liver or kidney transplantation were investigated retrospectively at the Third Xiangya Hospital, Central South University, Changsha, China. The incidence density of TB was calculated. We performed a nested case-control study (1:1) to investigate by univariate and multivariate logistic regression analysis the potential risk factors for TB. RESULTS: From January 2000 to August 2013, 1748 kidney and 166 liver transplant recipients were performed at a university teaching hospital. Among the 1914 recipients, 45 cases (2.4%) of TB were reported. The incidence density was 506 cases per 105 patient-years in kidney or liver transplant recipients, which was 7 times higher than in the general Chinese population (around 70 cases per 105 person-years). The median time to develop TB was 20.0 months (interquartile ratio: 5.0-70.0). The receipt of a graft from a cadaveric donor (odds ratio [OR] = 3.7; 95% confidence interval [CI] = 1.4-10.0; P = 0.010) and the preoperative evidence of latent TB (OR = 6.8; 95% CI = 2.0-22.7; P = 0.002) were identified as two risk factors for developing TB in liver or kidney transplant recipients. CONCLUSIONS: The incidence density of TB among liver or kidney transplant recipients was much higher than in the general Chinese population. Recipients receiving a graft from a cadaveric donor and the preoperative evidence of latent TB were two major risk factors for developing TB in liver or kidney transplant recipients. PMID- 25015109 TI - A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis. AB - Nucleolin overexpression and DNA hypermethylation have been implicated in cancer pathogenesis, but whether and how these aberrations cooperate in controlling leukemia cell fate remains elusive. Here, we provide the first mechanistic insights into the role of nucleolin in leukemogenesis through creating a DNA hypermethylation profile in leukemia cells. We found that, in leukemia patients, nucleolin levels are significantly elevated and nucleolin overexpression strongly associates with DNMT upregulation and shorter survival. Enforced nucleolin expression augmented leukemia cell proliferation, whereas nucleolin dysfunction by RNA interference and inhibitory molecule AS1411 blocked leukemia cell clonogenic potential in vitro and impaired tumorigenesis in vivo. Mechanistic investigations showed that nucleolin directly activates NFkappaB signaling, and NFkappaB activates its downstream effector, DNA methylation machinery. Indeed, nucleolin overexpression increased NFkappaB phosphorylation and upregulated DNMT1 that is followed by DNA demethylation; by contrast, nucleolin dysfunction dephosphorylated NFkappaB and abrogated DNMT1 expression, which resulted in decreased global DNA methylation, restored p15INK4B expression and DNA hypomethylation on p15INK4B promoter. Notably, NFkappaB inactivation diminished, whereas NFkappaB overexpression enhanced DNMT1 promoter activity and endogenous DNMT1 expression. Collectively, our studies identify nucleolin as an unconventional epigenetic regulator in leukemia cells and demonstrate nucleolin NFkappaB-DNMT1 axis as a new molecular pathway underlying AML leukemogenesis. PMID- 25015111 TI - Medicaid Expansion and the Victims of Partisanship. PMID- 25015110 TI - A case of fungal keratitis and onychomycosis simultaneously infected by Trichophyton species. AB - BACKGROUND: Fungal keratitis is difficult to treat that can result in corneal blindness requiring penetrating keratoplasty and in fungal endothalmitis. We report a case of fungal keratitis and onychomycosis simultaneously infected by Trichophyton. CASE PRESENTATION: A 77-year old male presented with ocular pain, conjunctival injection, and severe loss of vision in his left eye. His best corrected visual acuity was hand movements in the left eye, and slit-lamp examination showed a corneal ulcer with feathery margin and hypopyon. Bacterial and fungal smear/culture showed no organism, and there was no improvement in spite of treatment with topical fortified 5% cefazolin and 2% tobramycin. Trichophyton species was identified by repeated cultures. We found onychomycosis on the patient's foot, where the same fungal species were identified. Regimen was changed to topical itraconazole and systemic intravenous itraconazole. No clinical improvement was observed, so therapeutic penetrating keratoplasty and cryotherapy was done with continuation of antifungal therapy. The graft was clear at postoperative 1 month and no evidence of recurrence was found. CONCLUSION: It is important to identify the pathogen of keratitis because early identification of pathogen causing keratitis provides the appropriate treatment in early phase of keratitis. It is necessary to search for other fungal skin infections such as onychomycosis and athelete's foot considering the fungal keratitis following skin infection. In addition, fungal skin infection including onychomycosis should be treated for prevention of fungal keratitis as soon as possible. PMID- 25015112 TI - Comparison of clinical outcome variables in patients with and without etomidate facilitated anesthesia induction ahead of major cardiac surgery: a retrospective analysis. AB - INTRODUCTION: It is well known that etomidate may cause adrenal insufficiency. However, the clinical relevance of adrenal suppression after a single dose of etomidate remains vague. The aim of this study was to investigate the association between the administration of a single dose of etomidate or an alternative induction regime ahead of major cardiac surgery and clinical outcome parameters associated with adrenal suppression and onset of sepsis. METHODS: The anesthesia and intensive care unit (ICU) records from patients undergoing cardiac surgery over five consecutive years (2008 to 2012) were retrospectively analyzed. The focus of the analysis was on clinical parameters like mortality, ventilation hours, renal failure, and sepsis-linked serum parameters. Multivariate analysis and Cox regression were applied to derive the results. RESULTS: In total, 3,054 patient records were analyzed. A group of 1,775 (58%) patients received a single dose of etomidate; 1,279 (42%) patients did not receive etomidate at any time. There was no difference in distribution of age, American Society of Anesthesiologists physical score, duration of surgery, and Acute Physiology and Chronic Health Evaluation II score. Postoperative data showed no significant differences between the two groups in regard to mortality (6.8% versus 6.4%), mean of mechanical ventilation hours (21.2 versus 19.7), days in the ICU (2.6 versus 2.5), hospital days (18.7 versus 17.4), sepsis-associated parameters, Sequential Organ Failure Assessment score, and incidence of renal failure. Administration of etomidate showed no significant influence (P = 0.6) on hospital mortality in the multivariate Cox analysis. CONCLUSIONS: This study found no evidence for differences in key clinical outcome parameters based on anesthesia induction with or without administration of a single dose of etomidate. In consequence, etomidate might remain an acceptable option for single-dose anesthesia induction. PMID- 25015113 TI - Complete endovascular debranching of the aortic arch: A report of two cases. AB - Patients suffering from aortic arch aneurysms continue to encounter few treatment options. Because of co-morbidities, most are deemed to not be open surgical candidates. The two cases presented here demonstrate a novel endovascular approach in the care of an arch aneurysm complicated by dissection. Even though final graft configurations differed slightly between the two cases, all three great vessels were successfully de-branched through the combination of standard endovascular aneurysm repair techniques and modifications to off-the-shelf devices. Aortic flow was compartmentalized in the ascending aorta at or near the level of the sinotubular junction. This was done with a physician-assembled endografts. One of these lumens was dedicated to the descending aorta, while the other was further divided into three channels used to stent the great vessels. Completion angiography demonstrated patency in the arch, great vessels, and descending aorta. No endoleaks have been reported. Although data is limited, this approach appears promising. PMID- 25015115 TI - NHS reforms have made complaining more confusing for patients. PMID- 25015114 TI - Racial and insurance based disparities in the treatment of carotid artery stenosis: a study of the Nationwide Inpatient Sample. AB - BACKGROUND AND PURPOSE: Minorities and uninsured/underinsured patients have poorer access to healthcare system resources, especially preventative treatments. We sought to determine whether racial and insurance based disparities existed in the treatment of carotid artery stenosis. METHODS: Using the Nationwide Inpatient Sample, hospitalizations for carotid artery stenting and carotid endarterectomy for symptomatic and asymptomatic carotid artery stenosis from 2005 to 2011 were identified. We calculated chi(2) tests, and bivariate and multivariable logistic regression models were fit to assess differences in the characteristics of patients receiving carotid revascularization for asymptomatic compared with symptomatic carotid artery stenosis. Demographic characteristics studied included race/ethnicity (white, black, Hispanic, Asian/Pacific Islander) and primary payer status (Medicare, Medicaid, private insurance, self-pay and no charge). RESULTS: Between 2005 and 2011, 890 680 patients underwent carotid revascularization for the treatment of carotid artery stenosis (92.1% asymptomatic and 7.9% symptomatic). Multivariate logistic regression analysis demonstrated that Medicaid (OR=0.87, 95% CI 0.83 to 0.92, p<0.0001) and self-pay patients (OR=0.48, 95% CI 0.45 to 0.51, p<0.0001) had a lower odds of being revascularized for asymptomatic carotid artery stenosis compared with private insurance patients. Black (OR=0.81, 95% CI -0.77 to 0.84, p<0.0001) and Hispanic (OR=0.86, 95% CI 0.83 to 0.90, p<0.0001) patients had significantly lower odds of revascularization for asymptomatic carotid artery stenosis compared with white patients. CONCLUSIONS: Minorities and self-pay/Medicaid patients were less likely to receive carotid revascularization when asymptomatic-rather they were more likely to have treatment only after symptoms had developed. These findings suggest possible disparities in the degree of morbidity related to carotid artery stenosis, the likelihood of early detection, and/or the likelihood of treatment conditional on indication. PMID- 25015116 TI - Deafening silence? Time to reconsider whether organisations are silent or deaf when things go wrong. AB - Several public inquiries into healthcare failings in the UK have noted that employees of failing organizations attempt to raise concerns about shortcomings in care, often over a prolonged period of time, only for those concerns to be ignored. However, healthcare literature has largely focused on how organizations and their employees are silent in the face of such failings, positioning employees as daring not to speak in response to serious workplace problems or issues. We argue that only focussing on organizational silence is a critical mistake which misrepresents actual events and overly-simplifies the complexities of workplace culture. The disregard shown by academics, practitioners and policy makers to employee voice strategies, which do not amount to whistle-blowing, but equally cannot either be defined as "silence", results in signals being ignored that can be effective in preventing and ending wrongdoing by others. In addition to understanding silence we suggest therefore that better understanding of why organizations are deaf to, or disregard, employee concerns are needed. We propose that a virtuous cycle is possible, whereby the introduction of systems that result in better listening and valuing of employee concerns reinforces a culture of speaking up and, in turn, organizational learning. Similarly, organizations that disregard employees concerns are destined not to learn, ultimately falling silent and failing. PMID- 25015117 TI - Different associations between obesity and impaired fasting glucose depending on serum gamma-glutamyltransferase levels within normal range: a cross-sectional study. AB - BACKGROUND: Despite the consistent relationship between serum gamma glutamyltransferase (GGT) and type 2 diabetes (T2D), one unsolved issue is the role of serum GGT in the well-known association between obesity and T2D. This study was performed to investigate whether the association between body mass index (BMI) and impaired fasting glucose (IFG) differed depending on serum GGT levels within the normal range. METHODS: Study subjects were 2,424 men and 3,652 women aged >= 40, participating in the Fifth Korean National Health and Nutrition Examination Survey. Serum GGT levels within the normal range were classified into gender-specific tertiles. RESULTS: Among men and women belonging to the lowest tertile of serum GGT, BMI showed statistically non-significant weak associations with the risk of IFG. However, among persons in the highest tertile of serum GGT, the risk of IFG was 3 - 4 times higher among persons with BMI >= 25 kg/m2 than those with BMI < 23 kg/m2 (Pinteraction = 0.032 in men and 0.059 in women). CONCLUSIONS: The well-known strong association between BMI and IFG was observed mainly among persons with elevation of serum GGT to certain physiological levels, suggesting a critical role of serum GGT in the pathogenesis of IFG. This finding has an important clinical implication because serum GGT can be used to detect high-risk obese persons. PMID- 25015118 TI - Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin. AB - Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces cell-cycle arrest and apoptosis in mammalian cells. Recent studies have demonstrated that prostate cancer (PCa) cells can acquire radio-resistance when DOC-2/DAB2 interactive protein (DAB2IP) is downregulated. In this study, we showed that CDT could induce cell death in DAB2IP-deficient PCa cells. A combination of CDT and radiotherapy significantly elicited cell death in DAB2IP deficient PCa cells by inhibiting the repair of ionizing radiation (IR)-induced DNA double-strand break (DSB) during G2/M arrest, which is triggered by ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses. We also found that CDT administration significantly increased the efficacy of radiotherapy in a xenograft mouse model. These results indicate that CDT can be a potent therapeutic agent for radio-resistant PCa. PMID- 25015119 TI - Testing the risk of predation hypothesis: the influence of recolonizing wolves on habitat use by moose. AB - Considered as absent throughout Scandinavia for >100 years, wolves (Canis lupus) have recently naturally recolonized south-central Sweden. This recolonization has provided an opportunity to study behavioral responses of moose (Alces alces) to wolves. We used satellite telemetry locations from collared moose and wolves to determine whether moose habitat use was affected by predation risk based on wolf use distributions. Moose habitat use was influenced by reproductive status and time of day and showed a different selection pattern between winter and summer, but there was weak evidence that moose habitat use depended on predation risk. The seemingly weak response may have several underlying explanations that are not mutually exclusive from the long term absence of non-human predation pressure: intensive harvest by humans during the last century is more important than wolf predation as an influence on moose behavior; moose have not adapted to recolonizing wolves; and responses may include other behavioral adaptations or occur at finer temporal and spatial levels than investigated. PMID- 25015120 TI - Observations and models of emissions of volatile terpenoid compounds from needles of ponderosa pine trees growing in situ: control by light, temperature and stomatal conductance. AB - Terpenoid emissions from ponderosa pine (Pinus ponderosa subsp. scopulorum) were measured in Colorado, USA over two growing seasons to evaluate the role of incident light, needle temperature, and stomatal conductance in controlling emissions of 2-methyl-3-buten-2-ol (MBO) and several monoterpenes. MBO was the dominant daylight terpenoid emission, comprising on average 87% of the total flux, and diurnal variations were largely determined by light and temperature. During daytime, oxygenated monoterpenes (especially linalool) comprised up to 75% of the total monoterpenoid flux from needles. A significant fraction of monoterpenoid emissions was dependent on light and 13CO2 labeling studies confirmed de novo production. Thus, modeling of monoterpenoid emissions required a hybrid model in which a significant fraction of emissions was dependent on both light and temperature, while the remainder was dependent on temperature alone. Experiments in which stomata were forced to close using abscisic acid demonstrated that MBO and a large fraction of the monoterpene flux, presumably linalool, could be limited at the scale of seconds to minutes by stomatal conductance. Using a previously published model of terpenoid emissions, which explicitly accounts for the physicochemical properties of emitted compounds, we were able to simulate these observed stomatal effects, whether induced experimentally or arising under naturally fluctuation conditions of temperature and light. This study shows unequivocally that, under naturally occurring field conditions, de novo light-dependent monoterpenes comprise a significant fraction of emissions in ponderosa pine. Differences between the monoterpene composition of ambient air and needle emissions imply a significant non-needle emission source enriched in Delta-3-carene. PMID- 25015121 TI - Habitat fragmentation, tree diversity, and plant invasion interact to structure forest caterpillar communities. AB - Habitat fragmentation and invasive species are two of the most prominent threats to terrestrial ecosystems. Few studies have examined how these factors interact to influence the diversity of natural communities, particularly primary consumers. Here, we examined the effects of forest fragmentation and invasion of exotic honeysuckle (Lonicera maackii, Caprifoliaceae) on the abundance and diversity of the dominant forest herbivores: woody plant-feeding Lepidoptera. We systematically surveyed understory caterpillars along transects in 19 forest fragments over multiple years in southwestern Ohio and evaluated how fragment area, isolation, tree diversity, invasion by honeysuckle and interactions among these factors influence species richness, diversity and abundance. We found strong seasonal variation in caterpillar communities, which responded differently to fragmentation and invasion. Abundance and richness increased with fragment area, but these effects were mitigated by high levels of honeysuckle, tree diversity, landscape forest cover, and large recent changes in area. Honeysuckle infestation was generally associated with decreased caterpillar abundance and diversity, but these effects were strongly dependent on other fragment traits. Effects of honeysuckle on abundance were moderated when fragment area, landscape forest cover and tree diversity were high. In contrast, negative effects of honeysuckle invasion on caterpillar diversity were most pronounced in fragments with high tree diversity and large recent increases in area. Our results illustrate the complex interdependencies of habitat fragmentation, plant diversity and plant invasion in their effects on primary consumers and emphasize the need to consider these processes in concert to understand the consequences of anthropogenic habitat change for biodiversity. PMID- 25015122 TI - Development, survival, and phenotypic plasticity in anthropogenic landscapes: trade-offs between offspring quantity and quality in the nettle-feeding peacock butterfly. AB - Habitats selected for development may have important fitness consequences. This is relevant within the framework of niche shifts in human-dominated landscapes. Currently, the peacock butterfly (Aglais io) occurs ubiquitously, covering many habitat types, whereas its distribution used to be much more restricted. Indeed, its host plant (stinging nettle Urtica dioica) was limited to natural forest gaps on relatively nitrogen-rich soil, but due to land use changes and eutrophication, host plants are now quasi-omnipresent in Western Europe. In order to assess the impact of specific anthropogenic habitat types on host plant quality and environmental conditions for phenotypic trait values, an experiment was conducted in woodlands, field margins, and urban gardens. Larval development was studied in field enclosures, and adult traits were analyzed to test predicted effects of warmer and more nitrogen-rich conditions in field margins compared to woodlands and urban gardens. Survival to the adult stage was highest in woodlands and lowest in field margins, and whilst development time did not differ amongst habitat types, butterflies that developed in field margins were larger and had higher lipid content and wing loadings than conspecifics from woodlands and urban gardens. Nettles in field margins provided warmer microclimates. However, and contrary to predictions, the nitrogen level within host plant leaves was highest in woodlands. Hence, anthropogenic landscapes may pose a conflict for choosing what is ultimately the best breeding habitat, as survival was highest in woodlands (followed by urban gardens), but adults with highest fitness predictions were produced in field margins (and secondarily urban gardens). PMID- 25015123 TI - Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. AB - Recent findings indicate an isoform-specific role for apolipoprotein E (apoE) in the elimination of beta-amyloid (Abeta) from the brain. ApoE is closely associated with various lipoprotein receptors, which contribute to Abeta brain removal via metabolic clearance or transit across the blood-brain barrier (BBB). These receptors are subject to ectodomain shedding at the cell surface, which alters endocytic transport and mitigates Abeta elimination. To further understand the manner in which apoE influences Abeta brain clearance, these studies investigated the effect of apoE on lipoprotein receptor shedding. Consistent with prior reports, we observed an increased shedding of the low-density lipoprotein receptor (LDLR) and the LDLR-related protein 1 (LRP1) following Abeta exposure in human brain endothelial cells. When Abeta was co-treated with each apoE isoform, there was a reduction in Abeta-induced shedding with apoE2 and apoE3, while lipoprotein receptor shedding in the presence of apoE4 remained increased. Likewise, intracranial administration of Abeta to apoE-targeted replacement mice (expressing the human apoE isoforms) resulted in an isoform-dependent effect on lipoprotein receptor shedding in the brain (apoE4 > apoE3 > apoE2). Moreover, these results show a strong inverse correlation with our prior work in apoE transgenic mice in which apoE4 animals showed reduced Abeta clearance across the BBB compared to apoE3 animals. Based on these results, apoE4 appears less efficient than other apoE isoforms in regulating lipoprotein receptor shedding, which may explain the differential effects of these isoforms in removing Abeta from the brain. PMID- 25015124 TI - Progress in pediatrics in 2013: choices in allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses. AB - This review will provide new information related to pathophysiology and management of specific diseases that have been addressed by selected articles published in the Italian Journal of Pediatrics in 2013, focusing on allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses in children. Recommendations for interpretation of skin prick test to foods in atopic eczema, management of allergic conjunctivitis, hypertension and breastfeeding in women treated with antiepileptic drugs and healthy breakfast have been reported. Epidemiological studies have given emphasis to high incidence of autoimmune disorders in patients with Turner syndrome, increasing prevalence of celiac disease, frequency of hypertension in adolescents, incidence and risk factor for retinopathy of prematurity. Advances in prevention include elucidation of the role of probiotics in reducing occurrence of allergies and feeding intolerance, and events of foetal life that influence later onset of diseases. Mechanistic studies suggested a role for vitamin D deficiency in asthma and type 1 diabetes and for reactivation of Varicella-Zoster virus in aseptic meningitis. Regarding diagnosis, a new mean for the diagnosis of hyperbilirubinaemia in newborns, a score for recognition of impaired nutritional status and growth and criteria for early Dyke-Davidoff Masson Syndrome have been suggested. New therapeutic approaches consist of use of etanercept for reducing insulin dose in type 1 diabetes, probiotics in atopic eczema, and melatonin in viral infections. PMID- 25015125 TI - Detection and linkage to mobile genetic elements of tetracycline resistance gene tet(M) in Escherichia coli isolates from pigs. AB - BACKGROUND: In Escherichia coli the genes involved in the acquisition of tetracycline resistance are mainly tet(A) and tet(B). In addition, tet(M) is the most common tetracycline resistance determinant in enterococci and it is associated with conjugative transposons and plasmids. Although tet(M) has been identified in E. coli, to our knowledge, there are no previous reports studying the linkage of the tet(M) gene in E. coli to different mobile genetic elements. The aim of this study was to determine the occurrence of tet(A), tet(B), and tet(M) genes in doxycycline-resistant E. coli isolates from pigs, as well as the detection of mobile genetic elements linked to tet(M) in E. coli and its possible transfer from enterococci. RESULTS: tet(A) was the most frequently detected gene (87.9%) in doxycycline-resistant isolates. tet(M) was found in 13.1% E. coli isolates. The tet(M) gene was detected in relation with conjugative transposons in 10 out of 36 enterococci isolates analyzed but not in any of E. coli isolates positive for tet(M). Southern blot showed that in E. coli and in most of the enterococci isolates the tet(M) gene was carried on a plasmid. According to the phylogenetic analysis, E. coli contained a new tet(M) allele grouping separately. Mating experiments revealed that tet(M) was carried on a mobile element successfully transferred between enterococci and between enterococci and E. coli. CONCLUSIONS: The detection of tet(M) in E. coli isolates from pigs was higher than expected. In our study, tet(M) detected in E. coli seems not to have been transferred from enterococci, although it can not be ruled out that the horizontal transfer of this gene occurred from other intestinal tract bacteria. PMID- 25015127 TI - Empowerment, Leadership, and Sustainability in a Faith-Based Partnership to Improve Health. AB - Community-based participatory research is a noted approach for improving community health and reducing health disparities. Community partnerships can serve as a catalyst for change in public health efforts. This article will apply empowerment theory and sustainability principles to an existing faith-based partnership. BRANCH Out is a partnership among 13 African American churches, the City of Milwaukee Health Department-Community Nutrition, and the Medical College of Wisconsin. The partnership goal was to change inaccurate perceptions, knowledge and negative attitudes, and behaviors about chronic disease and promote healthy youth leadership. Faith-based empowerment can occur at the individual, organizational, and community level. BRANCH Out demonstrates how partnerships can be sustained in multiple ways. The partnership also highlights the unique contributions of churches to community health outcomes. PMID- 25015126 TI - Toll free mobile communication: overcoming barriers in maternal and neonatal emergencies in Rural Bangladesh. AB - BACKGROUND: Toll free mobile telephone intervention to support mothers in pregnancy and delivery period was tested in one sub district of Bangladesh. Qualitative research was conducted to measure the changes of mobile phone use in increasing communication for maternal and neonatal complications. METHODS: In depth interviews were conducted among twelve Community Skilled Birth Attendants and fourteen mothers along with their husbands prior to intervention. At intervention end, six Community Skilled Birth Attendants were purposively selected for in-depth interview. Semi structured interviews were conducted among all 27 Community Skilled Birth Attendants engaged in the intervention. One Focus Group Discussion was conducted with 10 recently delivered mothers. Thematic analysis and triangulation of different responses were conducted. RESULTS: Prior to intervention, Community Skilled Birth Attendants reported that mobile communication was not a norm. It was also revealed that poor mothers had poor accessibility to mobile services. Mothers, who communicated through mobile phone with providers noted irritability from Community Skilled Birth Attendants and sometimes found phones switched off. At the end of the project, 85% of mothers who had attended orientation sessions of the intervention communicated with Community Skilled Birth Attendants through mobile phones during maternal health complications. Once a complication is reported or anticipated over phone, Community Skilled Birth Attendants either made a prompt visit to mothers or advised for direct referral. More than 80% Community Skilled Birth Attendants communicated with Solution Linked Group for guidance on maternal health management. Prior to intervention, Solution Linked Group was not used to receive phone call from Community Skilled Birth Attendants. Community Skilled Birth Attendants were valued by the mothers. Mothers viewed that Community Skilled Birth Attendants are becoming confident in managing complication due to communication with Solution Linked Group. CONCLUSIONS: The use of mobile technology in this intervention took a leap from simply rendering information to providing more rapid services. Active participation of service providers along with mothers' accessibility motivated both the service providers and mothers to communicate through mobile phone for maternal health issues. These altogether made the shift towards adoption of an innovation. PMID- 25015128 TI - Review and evaluation of faith-based weight management interventions that target African American women. AB - This integrative review was conducted to present results of the use of recommended criteria to evaluate faith-based weight management interventions (WMIs) that target African American women. This group experiences the highest prevalence of adult obesity in the US when compared to other ethnic groups. "Best practice" WMIs can help to alleviate obesity. Faith-based interventions hold promise for helping to address the problem of obesity in African American women since a significant portion of these persons views the church as a trusted entity that advocates for their well-being. No systematic evaluation of faith-based WMIs has been reported even though there is an ongoing plea for the need for better evaluation of health interventions that prioritizes comprehensive description of their attributes (e.g., linkage to theory, interventionists' background, and dosage) to enable replication and a broader assessment of their validity to include appropriateness and feasibility). Critique criteria were applied to faith based WMIs (n = 5) that target African American women. Findings highlighted the need for increased disclosure about the (1) interventionists' background, (2) intervention's location within the church setting, and (3) nature of any "pre intervention"' treatment. The review also indicated the need for interventions that are (1) designed from robust research methodologies (effectiveness) that include randomization of both church setting and participants, (2) deemed appropriate from the perspective of African American women targeted, and (3) are financially feasible-without steep participant incentives/implementation costs that compromise internal validity and any positive outcomes generated. PMID- 25015129 TI - Autophagy and microRNA dysregulation in liver diseases. AB - Autophagy is a catabolic process through which organelles and cellular components are sequestered into autophagosomes and degraded via fusion with lysosomes. Autophagy plays a role in many physiological processes, including stress responses, energy homeostasis, elimination of cellular organelles, and tissue remodeling. In addition, autophagy capacity changes in various disease states. A series of studies have shown that autophagy is strictly controlled to maintain homeostatic balance of energy metabolism and cellular organelle and protein turnover. These studies have also shown that this process is post transcriptionally controlled by small noncoding microRNAs that regulate gene expression through complementary base pairing with mRNAs. Conversely, autophagy regulates the expression of microRNAs. Therefore, dysregulation of the link between autophagy and microRNA expression exacerbates the pathogenesis of various diseases. In this review, we summarize the roles of autophagy and microRNA dysregulation in the course of liver diseases, with the aim of understanding how microRNAs modify key autophagic effector molecules, and we discuss how this dysregulation affects both physiological and pathological conditions. This article may advance our understanding of the cellular and molecular bases of liver disease progression and promote the development of strategies for pharmacological intervention. PMID- 25015130 TI - Determination of mechanical properties of spatially heterogeneous breast tissue specimens using contact mode atomic force microscopy (AFM). AB - This paper outlines a comprehensive parametric approach for quantifying mechanical properties of spatially heterogeneous thin biological specimens such as human breast tissue using contact-mode Atomic Force Microscopy. Using inverse finite element (FE) analysis of spherical nanoindentation, the force response from hyperelastic material models is compared with the predicted force response from existing analytical contact models, and a sensitivity study is carried out to assess uniqueness of the inverse FE solution. Furthermore, an automation strategy is proposed to analyze AFM force curves with varying levels of material nonlinearity with minimal user intervention. Implementation of our approach on an elastic map acquired from raster AFM indentation of breast tissue specimens indicates that a judicious combination of analytical and numerical techniques allow more accurate interpretation of AFM indentation data compared to relying on purely analytical contact models, while keeping the computational cost associated an inverse FE solution with reasonable limits. The results reported in this study have several implications in performing unsupervised data analysis on AFM indentation measurements on a wide variety of heterogeneous biomaterials. PMID- 25015131 TI - Design modifications and computational fluid dynamic analysis of an outflow cannula for cardiopulmonary bypass. AB - Cardiopulmonary bypass is a well-established technique during open heart surgeries. However, neurological complications due to insufficient cerebral oxygen supply occur and the severe consequences must not be neglected. Recent computational fluid dynamics (CFD) studies showed that during axillary cannulation the cerebral perfusion is strongly affected by the distance between the cannula tip and the vertebral artery branch. In this study we use two modifications of the cannula design to analyze the flow characteristics by means of CFD and experimental validation with particle image velocimetry (PIV). One approach applies a spin to the blood stream with a helical surface in the cannula cross section. Another approach uses radial bores in a constricted cannula tip to split the outflow jet. The additional helicity improves the perfusion of the cerebral vessels and suppresses the blood suction in the right vertebral artery observed with a standard cannula. The cannula with a helix throughout the entire length changes the blood flow from 2124 to 32 mL/min in comparison with an unmodified design and has the lowest prediction of blood damage. Separating the blood stream does not deliver satisfying results. The PIV measurements validate the simulations and correspond with the velocity distribution as well as vortex locations. PMID- 25015132 TI - A novel coaptation plate device for functional mitral regurgitation: an in vitro study. AB - A novel mitral valve repair device, coaptation plate (CP), was proposed to treat functional mitral regurgitation. The objective of this study was to test efficacy of the CP in an in vitro model of functional mitral regurgitation. Ten fresh porcine mitral valves were mounted in a left heart simulator, Mitral regurgitation was emulated by means of annular dilatation, and the asymmetrical or symmetrical papillary muscles (PM) displacement. A rigid and an elastic CPs were fabricated and mounted in the orifice of regurgitant mitral valves. Steady flow leakage in a hydrostatic condition and regurgitant volume in a pulsatile flow were measured before and after implantation of the CPs. The rigid and elastic CPs reduced mitral valve regurgitant volume fraction from 60.5 +/- 11.4 to 35 +/- 11.6 and 36.5 +/- 9.9%, respectively, in the asymmetric PM displacement. Mitral regurgitation was much lower in the symmetric PM displacement than in the asymmetric PM displacement, and was not significantly reduced after implantation of either CP. In conclusion, both the rigid and elastic CPs are effective and have no difference in reduction of functional mitral regurgitation. The CP does not aggravate mitral valve coaptation and may be used as a preventive way. PMID- 25015133 TI - Testing problem solving in turkey vultures (Cathartes aura) using the string pulling test. AB - To examine problem solving in turkey vultures (Cathartes aura), six captive vultures were presented with a string-pulling task, which involved drawing a string up to access food. This test has been used to assess cognition in many bird species. A small piece of meat suspended by a string was attached to a perch. Two birds solved the problem without apparent trial-and-error learning; a third bird solved the problem after observing a successful bird, suggesting that this individual learned from the other vulture. The remaining birds failed to complete the task. The successful birds significantly reduced the time needed to solve the task from early trials compared to late trials, suggesting that they had learned to solve the problem and improved their technique. The successful vultures solved the problem in a novel way: they pulled the string through their beak with their tongue, and may have gathered the string in their crop until the food was in reach. In contrast, ravens, parrots and finches use a stepwise process; they pull the string up, tuck it under foot, and reach down to pull up another length. As scavengers, turkey vultures use their beak for tearing and ripping at carcasses, but possess large, flat, webbed feet that are ill-suited to pulling or grasping. The ability to solve this problem and the novel approach used by the turkey vultures in this study may be a result of the unique evolutionary pressures imposed on this scavenging species. PMID- 25015134 TI - Reward expectation modulates variability in path choice in rats. AB - The relationship between behavioral variability and reward expectation has been examined in recent years. This relationship is predictive: when an animal has a low expectation of reinforcement for a particular behavioral set, they engage in high levels of variability in their actions. We conducted two experiments to further investigate this relationship using a novel measure of behavioral variability. In Experiment 1, two groups of rats were trained to travel through a column maze, with many possible reinforced pathways, to receive either their maintenance diet (i.e., chow) or a highly palatable sugary reward (cereal). We hypothesized that animals trained with a maintenance-diet food source (chow) would demonstrate more variation in the pathways taken to the goal location than those animals trained with the highly palatable alternative. In Experiment 2, all rats were trained to travel through the maze to receive alternating outcomes of chow or cereal in a within-subjects design. Results from both experiments indicated that rats emitted greater variability in paths taken to the goal when the reinforcer was the maintenance chow. These results corroborate the relationship between reward and behavioral variability in a new behavioral measure. PMID- 25015135 TI - Artificial grammar learning in zebra finches and human adults: XYX versus XXY. AB - Abstracting syntactic rules is critical to human language learning. It is debated whether this ability, already present in young infants, is human- and language specific or can also be found in non-human animals, indicating it may arise from more general cognitive mechanisms. Current studies are often ambiguous and few have directly compared rule learning by humans and non-human animals. In a series of discrimination experiments, we presented zebra finches and human adults with comparable training and tests with the same artificial stimuli consisting of XYX and XXY structures, in which X and Y were zebra finch song elements. Zebra finches readily discriminated the training stimuli. Some birds also discriminated novel stimuli when these were composed of familiar element types, but none of the birds generalized the discrimination to novel element types. We conclude that zebra finches show evidence of simple rule abstraction related to positional learning, suggesting stimulus-bound generalization, but found no evidence for a more abstract rule generalization. This differed from the human adults, who categorized novel stimuli consisting of novel element types into different groups according to their structure. The limited abilities for rule abstraction in zebra finches may indicate what the precursors of more complex abstraction as found in humans may have been like. PMID- 25015136 TI - The accuracy and utility of contrast-enhanced MR angiography for localization of spinal dural arteriovenous fistulas: the Toronto experience. AB - OBJECTIVES: The purpose of this study was to determine the accuracy and utility of contrast-enhanced MR angiography (CE-MRA) in spinal dural arteriovenous fistulas (SDAVF). METHODS: A retrospective analysis from 1999-2012 identified 70 patients clinically suspected of harboring a SDAVF. Each patient underwent consecutive conventional MR-imaging, CE-MRA, and digital subtraction angiography (DSA). The presence or absence of serpentine flow voids, T2-weighted hyperintensity, and cord enhancement were evaluated, as well as location of the fistula as predicted by CE-MRA. DSA was used as the reference standard. RESULTS: Of the 70 cases, 53 were determined to be a SDAVF, 10 cases were shown to be other forms of vascular malformation, and 7 were DSA-negative. On MRI, all reported cases of SDAVF showed serpentine flow voids (100 %). T2-weighted hyperintensity was seen in 48 of 50 cases (96 %), extending to the conus in 41 of 48 cases (85 %). Cord enhancement was seen in 38 of 41 cases (93 %). CE-MRA correctly localized the SDAVF in 43 of the 53 cases (81 %). CONCLUSIONS: CE-MRA is a useful non-invasive examination for the detection and localization of SDAVF. CE-MRA facilitates but does not replace DSA as confirmation of location, fistula type, and arterial detail, which are required before treatment. KEY POINTS: * CE MRA correctly localized the site of the SDAVF in over 80 % of cases. * CE-MRA facilitates diagnostic DSA and expedites the diagnostic process. * CE-MRA does not replace diagnostic DSA in SDAVF cases as confirmative test. * CE-MRA provides better understanding of missed or mislocalized SDAVF cases. PMID- 25015137 TI - Safety of pertussis vaccination in pregnant women in UK: observational study. AB - OBJECTIVE: To examine the safety of pertussis vaccination in pregnancy. DESIGN: Observational cohort study. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: 20,074 pregnant women with a median age of 30 who received the pertussis vaccine and a matched historical unvaccinated control group. MAIN OUTCOME MEASURE: Adverse events identified from clinical diagnoses during pregnancy, with additional data from the matched child record identified through mother-child linkage. The primary event of interest was stillbirth (intrauterine death after 24 weeks' gestation). RESULTS: There was no evidence of an increased risk of stillbirth in the 14 days immediately after vaccination (incidence rate ratio 0.69, 95% confidence interval 0.23 to 1.62) or later in pregnancy (0.85, 0.44 to 1.61) compared with historical national rates. Compared with a matched historical cohort of unvaccinated pregnant women, there was no evidence that vaccination accelerated the time to delivery (hazard ratio 1.00, 0.97 to 1.02). Furthermore, there was no evidence of an increased risk of stillbirth, maternal or neonatal death, pre-eclampsia or eclampsia, haemorrhage, fetal distress, uterine rupture, placenta or vasa praevia, caesarean delivery, low birth weight, or neonatal renal failure, all serious events that can occur naturally in pregnancy. CONCLUSION: In women given pertussis vaccination in the third trimester, there is no evidence of an increased risk of any of an extensive predefined list of adverse events related to pregnancy. In particular, there was no evidence of an increased risk of stillbirth. Given the recent increases in the rate of pertussis infection and morbidity and mortality in neonates, these early data provide initial evidence for evaluating the safety of the vaccine in pregnancy for health professionals and the public and can help to inform vaccination policy making. PMID- 25015139 TI - Gross examination. AB - The examination of organs and tissues macroscopically in order to establish a diagnosis and to select relevant portions for subsequent microscopic examination and special studies is fundamental to the practice of pathology. In the autopsy room, in the surgical pathology laboratory and, very often, in the operating room, gross pathology is the essential, underlying basis of morphologic diagnosis. Diagnoses on the basis of gross examination can be accurately made in as many as 90 % of specimens (Grossman IW, A primer of gross pathology, Charles C Thomas, 1972). In the remaining 10 % the skilled pathologist can be close to the diagnosis or can, at least, construct an accurate differential diagnosis that can provide guidance for subsequent studies. Sadly the numbers of pathologists with skills in macroscopic ("gross") pathology is rapidly declining, with concomitant loss in the quality of gross examinations, lower accuracy and elegance of specimen descriptions, and lack of precision in sample selection for special studies. This clearly impacts the quality of surgical pathology practice and, inevitably, the quality of patient care. The decline of gross pathology is a result of a number of factors, including a marked decrease in the numbers of autopsies which means that there are fewer opportunities for pathologists to hone gross pathology skills and to gain proficiency in handling tissues for appropriate further study. This is compounded by an increasing reliance on pathologists' assistants (PAs) for the handling, description and sampling of gross specimens, by the expanded utilization of biopsies rather than resections prior to initiating therapy and by the reliance on highly sophisticated immunopathology, molecular and genomic methods for diagnosis and even for determination of therapy. Despite these and other changes in medical and pathology practice, careful examination of the gross specimen is still the sine qua non of surgical and autopsy pathology practice. PMID- 25015138 TI - Genome-wide analysis of trans-splicing in the nematode Pristionchus pacificus unravels conserved gene functions for germline and dauer development in divergent operons. AB - Discovery of trans-splicing in multiple metazoan lineages led to the identification of operon-like gene organization in diverse organisms, including trypanosomes, tunicates, and nematodes, but the functional significance of such operons is not completely understood. To see whether the content or organization of operons serves similar roles across species, we experimentally defined operons in the nematode model Pristionchus pacificus. We performed affinity capture experiments on mRNA pools to specifically enrich for transcripts that are trans spliced to either the SL1- or SL2-spliced leader, using spliced leader-specific probes. We obtained distinct trans-splicing patterns from the analysis of three mRNA pools (total mRNA, SL1 and SL2 fraction) by RNA-seq. This information was combined with a genome-wide analysis of gene orientation and spacing. We could confirm 2219 operons by RNA-seq data out of 6709 candidate operons, which were predicted by sequence information alone. Our gene order comparison of the Caenorhabditis elegans and P. pacificus genomes shows major changes in operon organization in the two species. Notably, only 128 out of 1288 operons in C. elegans are conserved in P. pacificus. However, analysis of gene-expression profiles identified conserved functions such as an enrichment of germline expressed genes and higher expression levels of operonic genes during recovery from dauer arrest in both species. These results provide support for the model that a necessity for increased transcriptional efficiency in the context of certain developmental processes could be a selective constraint for operon evolution in metazoans. Our method is generally applicable to other metazoans to see if similar functional constraints regulate gene organization into operons. PMID- 25015140 TI - The pathologist's guide to fixatives. AB - Proper tissue fixation is essential to ensure the highest level of specimen evaluation. Pathologists and laboratory staff are frequently consulted by clinical counterparts regarding what fixative should be used for different tissues or to enable a diagnosis of a specific condition. It is vital for the patient that the pathologist provides accurate information to ensure proper fixation. Frequently, once a tissue has been fixed inadequately or inappropriately, remedial changes may no longer be possible. Most often formalin is an adequate choice, if not the optimal one; however, there are certain situations when placing the tissue in formalin may limit the ability to reach a definitive diagnosis. It is imperative for pathologists to have the knowledge to communicate which fixative is optimal. Furthermore, as we move into a world of personalized medicine, where ancillary testing has both diagnostic and specific therapeutic implications, knowledge about how different fixatives affect immunohistochemistry, cytogenetics, and molecular studies becomes even more significant. This chapter provides practical information regarding common fixatives, their mechanism of action and optimal uses. PMID- 25015141 TI - Tissue processing and hematoxylin and eosin staining. AB - The hematoxylin and eosin (H&E) stained tissue section is the cornerstone of anatomical pathology diagnosis. The H&E procedure stains the nucleus and cytoplasm contrasting colors to readily differentiate cellular components. However, staining results are dependent on proper specimen processing, which involves tissue preservation, dehydration, clearing, and paraffin infiltration. While improvements in instrumentation for both tissue processing and staining have been beneficial, limitations in the chemical reagents used must always be considered. PMID- 25015142 TI - Light microscope alignment methods. AB - Instructions for proper alignment for each of the most common wide field light microscopy contrast techniques are presented: bright field, polarization, dark field, phase contrast, differential interference contrast, and fluorescence. These are then followed by methods on photomicrography, measurement, and cleaning. An extensive set of Notes provides practical tips for each of these methods. PMID- 25015143 TI - Immunohistochemistry in surgical pathology: principles and practice. AB - The extent to which data from immunohistochemical (IHC) staining are useful is critically dependent not only upon the proper performance and control of the method but also upon appropriate interpretation. A decade ago an individual pathologist may have nurtured a reasonable expectation of achieving a comprehensive understanding of the IHC literature across the whole field of pathology. Today such an expectation is clearly unreasonable with a simple Medline search of the IHC literature postdating the general adoption of antigen retrieval (arbitrarily 1996), yielding more than 100,000 "relevant" articles. The problem is compounded by enormous variability in sample preparation, by the literally thousands of antibodies that are available in catalogs, by the complexity of the tissue section environment, exactly which cells stain, or which do not, and by the subjective assessment of the presence and intensity of specific staining.This chapter describes attempts being made to address these issues. It also outlines the practical steps that may be taken to maximize effectiveness and reproducibility of IHC results within a lab. Adopting a "total test" mindset with attention to every phase of the process is the key initial step.The rapid growth of predictive markers, companion diagnostics, or advanced personalized diagnostics merely serves to underline the inadequacies of IHC and to reinforce the necessity for improved standardization, consistent interpretation, and precise quantification that almost certainly will involve the introduction of new internal and external reference standards, plus digital assistance in interpretation and quantification. PMID- 25015144 TI - Optimizing direct immunofluorescence. AB - Immunofluorescence is a laboratory technique that utilizes a fluorophore-labeled antibody to detect immune complexes in tissue. Most of the labeled antibodies used in a clinical laboratory bind the conserved domains within each class of human antibodies, allowing them to detect a wide range of autoimmune complexes. Drawbacks to this technique mostly relate to proper handling of the specimen and the fluorophore-labeled antibodies. Therefore, having a basic understanding of fluorophores and antibodies is important for processing a specimen that yields a high signal-to-background ratio as well as troubleshooting problems, should they arise. PMID- 25015145 TI - Electron microscopy: a brief history and review of current clinical application. AB - This chapter describes the historic development of techniques that has made it possible to use electron microscopy, principally transmission electron microscopy, for diagnostic purposes. It was described how the standard techniques for preparing tissue for light microscopy had been modified to make it possible to view the ultrastructural components of a cell, tissue, or organ that cannot be resolved with a light microscope. There is a discussion of the types of tissues and cells that were and are currently observed by electron microscopy for diagnostic purposes. All of the materials that are used in tissue preparation and the general protocols for processing the tissues are also included. There are also notes which describe steps that can be changed or modified and why depending on conditions and anticipated outcome. PMID- 25015146 TI - A practical approach to clinical and research biobanking. AB - Powerful technologies critical to personalized medicine and targeted therapeutics require the analysis of carefully validated, procured, stored, and managed biospecimens. Reflecting advancements in biospecimen science, the National Cancer Institute and the International Society for Biological and Environmental Repositories are periodically publishing best practices that can guide the biobanker. The modern biobank will operate more like a clinical laboratory with formal accreditation, standard operating procedures, and quality assurance protocols. This chapter highlights practical issues of consent, procurement, storage, quality assurance, disbursement, funding, and space. Common topics of concern are discussed including the differences between clinical and research biospecimens, stabilization of biospecimens during procurement, optimal storage temperatures, and technical validation of biospecimen content and quality. With quickly expanding biospecimen needs and limited healthcare budgets, biobanks may need to be selective as to what is stored. Furthermore, a shift to room temperature storage modalities where possible can reduce long-term space and fiscal requirements. PMID- 25015147 TI - Hospital autopsy performance and reporting. AB - Postmortem examinations have been performed for centuries (King and Meehan, Am J Pathol 73(2): 514-541, 1973; Burton, The history of the autopsy. Hodder Arnold, Hachette UK, London, pp 1-10, 2010) and have a long and venerable tradition, one which is sadly on the decline worldwide (Underwood, The future of the autopsy. Hodder Arnold, Hachette UK, London, pp 11-17, 2010; Nemetz et al., Mayo Clin Proc 64:1065-2076, 1989; Kaplan, Hum Pathol 9(2):127-129, 1978; Roberts, N Engl J Med 299:332-337, 1978; Haber, Arch Pathol Lab Med 120:714-717, 1996; AMA Council on Scientific Affairs, Arch Pathol Lab Med 120:721-726, 1996; Sanner, Arch Pathol Lab Med 118:878-883, 1994; Robinson, Hum Pathol 14(7):566-568, 1983). One of the reasons cited for the decline in postmortem examinations is new imaging techniques such as computerized tomography and magnetic resonance imaging. The advent of these new diagnostic procedures has not resulted in obsolescence of the relatively low-cost, high-yield autopsy examination (Goldman et al., N Engl J Med 308:1000-1005, 1983). The procedure for performance of an autopsy, using the Zenker method (Volmar, History of autopsy technique. College of American Pathologists, Northfield, IL, pp 18-19, 2003), is described, in addition to the content and format of the written report. PMID- 25015148 TI - Characterization of HER2 status by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). AB - The use of human epidermal growth factor receptor type 2 (HER2) gene amplification and overexpression as a molecular predictive marker has become critically important for proper selection of breast cancer patients for treatment with targeted therapeutic agents such as trastuzumab, lapatinib, pertuzumab, and T-DM1. A high level of sensitivity and specificity of molecular tests for this alteration is desirable. The American Society of Clinical Oncology and College of American Pathology have jointly established consensus guidelines to standardize characterization of this alteration in breast cancers. This chapter provides a brief overview of pre-analytic and analytical processing of breast specimens as well as subsequent molecular evaluation for HER2 status. PMID- 25015149 TI - Intraoperative frozen section consultation in gynecologic pathology. AB - Intraoperative consultation (IOC) in gynecologic pathology is aimed at providing or confirming the diagnosis at the time of surgery and evaluating the extent of disease in order to assist the surgeon in determining the surgical procedure being performed. This chapter discusses the main indications for IOC in gynecologic pathology and describes how to submit and process these specimens in order to obtain optimal material. In addition, diagnostic pitfalls and ancillary testing related to IOC in gynecologic pathology are summarized. PMID- 25015150 TI - Processing dermatological biopsies. AB - Dermatological biopsies can be obtained from many anatomic areas and fulfill a variety of diagnostic roles. Due to this variety, the handling and processing of dermatological specimens pose unique challenges. The small size, disparate shapes, and anatomic variation seen on skin biopsies require specialized techniques to enable sufficient sampling, proper orientation, and accurate diagnoses. This chapter addresses issues related specifically to the processing of small specimens, evaluation for biopsies for alopecia, nail specimens, frozen sections, and specimens requiring direct immunofluorescence. PMID- 25015151 TI - Human papillomavirus testing in head and neck squamous cell carcinoma: best practice for diagnosis. AB - Human papillomavirus (HPV)-associated oropharyngeal carcinoma is now recognized as a clinically distinct subtype of head and neck cancer with important prognostic implications. HPV testing is recommended as the standard of care for all patients diagnosed with oropharyngeal squamous cell carcinoma. Here, we describe a practical approach to HPV testing within the setting of the diagnostic histopathology laboratory. PMID- 25015152 TI - Peripheral blood smears, bone marrow aspiration, trephine and clot biopsies: methods and protocols. AB - Maximum diagnostic information is obtained when peripheral blood smears, bone marrow aspiration smears, trephine biopsy imprints, trephine and clot biopsy sections are simultaneously examined. Peripheral blood smears reflect end organ function and provide clues to underlying hematolymphoid pathology that may prompt additional studies including bone marrow examination. Bone marrow aspiration alone has diagnostic utility in the evaluation of a limited number of primary hematological conditions including: megaloblastic anemias, hyporegenerative anemias, certain hemolytic anemias, normochromic normocytic anemias, neutropenias, thrombocytopenias, immunoglobulin disorders, storage diseases, and leukemias (Bain, J Clin Pathol 54:657-663, 2001). Bone marrow trephine biopsy is indicated in those situations where marrow aspiration is unsuccessful; in evaluation of cytopenias, myelofibrosis, suspicion of lymphoma, metastatic tumor, granulomatous disease, evaluation of myeloproliferative neoplasms, and for the examination of trabecular bone in metabolic diseases (Bain, J Clin Pathol 54:737 742, 2001). Many of the indications for marrow aspiration overlap with those for trephine biopsy. Because it is not possible to predict which patients will have diagnostic aspiration biopsies and which will have diagnostic trephine biopsies, both procedures are routinely performed together (Brynes et al., Am J Clin Pathol 70:753-759, 1978; Cotelingam, Adv Anat Pathol 10:8-26, 2003; Lee et al., Int J Lab Hematol 30:349-364, 2008; Peterson et al., Arch Pathol Lab Med 126:1050-1056, 2002). PMID- 25015153 TI - Processing the lymph node biopsy. AB - The testing modalities available and necessary to precisely diagnose lymphadenopathies, lymphadenitides, and lymphomas are numerous. However, to much chagrin, the tissue samples submitted for evaluation are frequently limited in size. Consequently, the triage of each individual lymph node sample with judicious apportionment of tissue for diagnostic testing has become of paramount importance. We describe a practical approach to processing the lymph node specimen to maximize the diagnostic utility of the sample provided. PMID- 25015154 TI - Handling and interpretation of heart transplant biopsies. AB - The biopsy material that is available for evaluation of the transplant heart is retrieved from an invasive biopsy procedure that is often small or suboptimal for evaluation. It is essential that the tissue is handled optimally from the time it is removed from the body to the time it is placed on the microscope stage to facilitate the best opportunity for an adequate diagnosis and to prevent the necessity for repeat costly and invasive procedures. Furthermore, the diagnostic information may be time sensitive for the treating clinician and mishandling the tissue or requiring a repeat biopsy will delay the start of treatment if the biopsy discloses actionable information. Herein we describe an optimized protocol for handling and interpreting heart transplant biopsies. PMID- 25015155 TI - Handling and interpretation of lung transplant biopsies. AB - The transbronchial biopsy is the gold standard for evaluation of rejection in the lung allograft. The biopsy is an invasive procedure that produces small quantities of tissue that is prone to crush artifact and is often suboptimal for evaluation. Furthermore, the biopsies should contain both alveolar tissue and airway wall to be considered adequate. Therefore, it is essential that the tissue is carefully handled at all stages of tissue processing and evaluation to ensure the best evaluation in a time sensitive and cost effective manner. Herein we describe an optimized protocol for handling and interpreting lung transplant biopsies. PMID- 25015156 TI - Liver: tissue handling and evaluation. AB - Liver diseases remain among the most important causes of morbidity and mortality worldwide. Although the diagnostic tools (e.g., blood studies, imaging, genetic and molecular tests) available to clinicians have greatly expanded in number and increased in sensitivity, the examination of liver tissue by a pathologist skilled and experienced in hepatopathology remains vitally important in the evaluation and care of the patient with liver abnormalities. In some disorders, such as autoimmune hepatitis, liver biopsy is considered mandatory. The indications for performing liver biopsies have changed over the years (e.g., large duct obstruction was a common diagnostic problem 50 years ago and is only uncommonly so currently). Liver samples come to the pathologist as aspiration biopsies for cytologic examination, tissue biopsies (fine needle, core, transjugular, and wedge), resections, and explants. Each demands slightly different approaches for optimal handling and evaluation. PMID- 25015157 TI - Handling and interpretation of the medical renal biopsy. AB - Renal biopsy is the gold standard for diagnosis of kidney disease; indeed, it allows for determination of the type, extent, site, and nature of renal involvement in medical diseases, and it alters the clinical diagnosis in as many as 25-50 % of cases. At the same time, it is a relatively safe procedure with life-threatening complications occurring in less than 0.1 % of biopsies. The diagnosis of renal biopsies is complex, requiring correlation of the findings in three modalities: light, immunofluorescence, and electron microscopy. For that reason, appropriate division and fixation of the renal biopsy is required, and protocols for these processes are provided. PMID- 25015158 TI - Optimizing prostate specimen handling for diagnosis and prognosis. AB - Optimal processing, handling, and sampling of prostatic biopsies, transurethral resections, and radical prostatectomy specimens ensure accurate diagnosis and staging. Prognostic factors derived from careful examination of tissue samples are critical for patient management, including cancer volume, extraprostatic extension, surgical margins, vascular/lymphatic invasion, and perineural invasion. This chapter addresses these important issues, including recent recommendations of a consensus panel of the International Society of Urologic Pathologists. PMID- 25015159 TI - Optimal handling of bone tumor specimens. AB - The diagnosis of bone tumors is challenging and depends on optimal processing of specimens as well as integration of radiographic and clinical information. The correct diagnosis will often require ancillary techniques such as immunohistochemistry, flow cytometry and molecular or cytogenetic analysis. From a pathologist's standpoint, optimal processing of specimens is paramount and often requires some foreknowledge of anticipated diagnosis in order to triage a specimen properly. The type of specimen, small vs. large, will often dictate the type of information that should be reported by the pathologist. Small specimens, including core biopsies and small incisional biopsies, are often obtained for primary diagnosis and as such, require a different approach to management. In addition to assuring the adequacy of the specimen for diagnosis, the pathologist will often need to triage these materials for appropriate ancillary studies. Large specimens, including amputations and large resections, pose a different set of technical problems for handling and processing. In this setting, information such as grading, staging, and marginal status become more crucial and the subsequent processing of the specimen should be handled in a very standardized manner to facilitate optimal pathologic reporting. This chapter offers a concise but detailed review for handling both types of bone tumor specimens. PMID- 25015160 TI - CNS intraoperative consultation: a survival guide for non-neuropathologists. AB - Intraoperative consultations for central nervous system disease may be challenging due to limitations of sample size, lack of familiarity with neurosurgical procedures, or poor access to neuroimaging studies. Despite these challenges, the surgical pathologist is charged with determining if the tissue sample is representative of the pathologic process while ensuring that enough diagnostic tissue has been retained for routine histology, immunohistochemistry, fluorescence in situ hybridization, molecular testing, and in some cases, tissue banking. Here, we present basic methods and a practical approach for CNS intraoperative consultation including critical pre-analytic considerations that promote optimal tissue management. PMID- 25015161 TI - Examining and processing eye specimens. AB - This chapter provides basic and useful information about handling and processing eye specimens as well as diagnosing common diseases encountered by ophthalmic pathologists. Each section is devoted to a specific part of the eye (cornea, conjunctiva, iris and cilliary body, choroid, retina, vitreous, and the optic nerve), providing useful pearls about the basic anatomy, disease processes, special staining, and tissue processing. PMID- 25015162 TI - Optimizing the skeletal muscle biopsy. AB - Knowledge of disorders of skeletal muscle remains of importance for the practicing pathologist. While genetic testing has proved useful in the diagnosis of many patients, especially those with the more common forms of muscular dystrophy, less common genetic myopathies, congenital myopathies, and toxic myopathies, often related to commonly used therapeutic agents such as statins, still require pathological analysis for diagnostic purposes. A contemporary pathologist may expect to be consulted about unusual familial neuromuscular disorders, autoimmune disorders, and drug-induced myopathies, often in the context of patients with multiple medical conditions that complicate the clinical and pathological analysis. A working knowledge of skeletal muscle biopsy and its clinical utility as well as its limitations is therefore important for all pathologists. Each pathologist must decide if they wish to process the biopsy in their own laboratory, or if the specimen should be sent to a reference laboratory for analysis. PMID- 25015163 TI - Acute hepatitis after starting pinaverium bromide in a patient taking mirtazapine. AB - A 56-year-old man presented with chronic abdominal pain. He had been evaluated extensively in the recent past undergoing upper gastrointestinal endoscopy, colonoscopy and CT scan of the abdomen with normal results. The provisional diagnosis of irritable bowel syndrome was performed and pinaverium bromide was started. The patient had pre-existing hypertension, a major depressive disorder and gastro-oesophageal reflux disease. He had been taking nebivolol and pantoprazole for several years and mirtazapine for the last 1 year. The patient developed nausea, vomiting and anorexia after 5 days of starting pinaverium bromide. Investigations revealed marked elevation of liver enzymes and bilirubin. He was negative for HIV, HBSAg, anti-hepatitis C virus, IgM for hepatitis A virus, hepatitis E virus, antinuclear antibody and antimitochondrial antibody. An ultrasound showed mild hepatomegaly with hypoechoic echo texture; the rest of scan was normal. Pinaverium and mirtazapine were stopped immediately. The patient was treated symptomatically and his liver profile returned to normal after 4 weeks. PMID- 25015164 TI - Left main stem/LCA arising from right coronary sinus with an interarterial course. AB - A 67-year-old woman presented to the accident and emergency department with central chest pain for the past 4 months. She described the pain as severe, retrosternal, intermittent, indigestion/burning type, with radiations to the left arm. She had used antacids with no relief. Her medical history included hypertension, chronic obstructive pulmonary disease, pulmonary fibrosis, left mastectomy for breast cancer, hypercholesterolaemia and osteoarthritis. Her medications included anastrazole, indapamide, perindopril, aspirin, clopidogrel, atorvastatin, salbutamol and atrovent inhalers. She was a non-smoker and vegetarian. Two brothers each had a myocardial infarction when in their early 40s. PMID- 25015165 TI - A rare presentation of Hodgkin's lymphoma in a very young child, with involvement of the appendix. AB - Hodgkin's lymphoma involving the appendix in young children is an exceptionally rare disease. We report a case of a child less than 3 years who presented to us with gradual weight loss, progressive pallor and diffuse abdominal pain. The symptoms were preceded by a history of varicella infection about 6 months ago. The clinical progression was marked by intermittent episodes of acute abdominal pain and fever, mimicking acute intra-abdominal inflammatory process such as appendicitis. Investigations revealed that the child had direct Coomb's test positive haemolytic anaemia, raised platelet counts, lymphopenia and hypergammaglobulinaemia. The CT of the abdomen showed the presence of significant lymph nodes. Abdominal laparoscopy and biopsy of the lymph nodes showed mixed cellularity Hodgkin's lymphoma that also involved the appendix. Subsequent staging detected an advanced stage IV disease. The child was referred immediately to a specialised oncology centre for further management. Unfortunately he was lost in follow-up. PMID- 25015166 TI - Adenocarcinoma of the pigmented ciliary epithelium. AB - Adenocarcinoma of the pigmented ciliary epithelium is an exceptionally rare eye tumour, with only a few cases reported to date. We encountered such a case in a 50-year-old woman who reported seeing floaters in her right eye. Fundus examination and MRI revealed an elevated lesion located in the ciliary body compressing the lens. The ciliary body was resected under the diagnosis of ciliary adenoma. On histological examination, the tumour exhibited epithelial features with glandular formation and moderate nuclear pleomorphism. The tumour invaded the subepithelial stroma of the ciliary body. Immunohistochemical findings were positive for cytokeratin OSCAR, AE1/AE3, CK7, EMA, S100, Melan A, HMB45, and microphthalmia-associated transcription factor. PMID- 25015167 TI - HIV in India: the Jogini culture. AB - Jogini is the name for a female sexually exploited temple attendant and is used interchangeably with Devadasi in the state of Andhra Pradesh, India. Jogini are twice more likely than other women who are used for sexual intercourse in India to be HIV positive, and their rate of mortality from HIV is 10 times the total mortality rate for all women in India. The four states in India with the most Jogini also have the highest prevalence of HIV. The following case is unfortunately typical of the Jogini and sheds light on a potentially disastrous public health problem in rural South India. PMID- 25015168 TI - Intestinal pseudo-obstruction as a presenting symptom of Guillain-Barre syndrome. PMID- 25015170 TI - A rare cause of rash in elderly: diagnostic dilemma. PMID- 25015169 TI - Traumatic subchondral fracture of the femoral head in a healed trochanteric fracture. AB - An 82-year-old woman sustained a trochanteric fracture of the left femur after a fall. Fracture fixation was performed using proximal femoral nail antirotation (PFNA) II, and she was able to walk with a T-cane after 3 months. Eleven months following the operation, the patient presented with left hip pain after a fall. Radiographs showed a subchondral collapse of the femoral head located above the blade tip. The authors removed the PFNA-II and subsequently performed cemented bipolar hemiarthroplasty. Histological evaluation of the femoral head showed osteoporosis with no evidence of osteonecrosis. Repair tissue, granulation tissue and callus formation were seen at the collapsed subchondral area. Based on these findings, a traumatic subchondral fracture of the femoral head in a healed trochanteric fracture was diagnosed. A traumatic subchondral fracture of the femoral head may need to be considered as a possible diagnosis after internal fixation of the trochanteric fracture. PMID- 25015171 TI - Peptide regulation of gene expression and protein synthesis in bronchial epithelium. AB - INTRODUCTION: Some studies have shown that peptides have high treatment potential due to their biological activity, harmlessness, and tissue-specific action. Tetrapeptide Ala-Asp-Glu-Leu (ADEL) was effective on models of acute bacterial lung inflammation, fibrosis, and toxic lung damage in several studies. METHODS: We measured Ki67, Mcl-1, p53, CD79, and NOS-3 protein levels in the 1st, 7th, and 14th passages of bronchoepithelial human embryonic cell cultures. Gene expression of NKX2-1, SCGB1A1, SCGB3A2, FOXA1, FOXA2, MUC4, MUC5AC, and SFTPA1 was measured by real-time polymerase chain reaction. Using the methods of spectrophotometry, viscometry, and circular dichroism, we studied the ADEL-DNA interaction in vitro. RESULTS: Peptide ADEL regulates the levels of Ki67, Mcl-1, p53, CD79, and NOS-3 proteins in cell cultures of human bronchial epithelium in various passages. The strongest activating effect of peptide ADEL on bronchial epithelial cell proliferation through Ki67 and Mcl-1 was observed in "old" cell cultures. ADEL regulates the expression of genes involved in bronchial epithelium differentiation: NKX2-1, SCGB1A1, SCGB3A2, FOXA1, and FOXA2. ADEL also activates several genes, which reduced expression correlated with pathological lung development: MUC4, MUC5AC, and SFTPA1. Spectrophotometry, viscometry, and circular dichroism showed ADEL-DNA interaction, with a binding region in the major groove (N7 guanine). CONCLUSIONS: ADEL can bind to specific DNA regions and regulate gene expression and synthesis of proteins involved in the differentiation and maintenance of functional activity of the bronchial epithelium. Through activation of some specific gene expression, peptide ADEL may protect the bronchial epithelium from pulmonary pathology. ADEL also may have a geroprotective effect on bronchial tissue. PMID- 25015172 TI - Palliative interventional pulmonology procedures in the incarcerated population with cancer: a case series. AB - RATIONALE: Cancer is the second most common cause of death in incarcerated population and lung cancer is the most common cause of cancer death in this group. Inmates are excluded from most published surveys and research,thus the effectiveness of lung cancer palliation in this population is not known. OBJECTIVE: To report the feasibility and safety of palliative interventional pulmonary procedures in inmates with cancer. STUDY DESIGN: Retrospective review of registry data from a single center. MATERIALS AND METHODS: Inmate data on prospectively enrolled data registry (2009-2012) from the interventional pulmonology procedural registry at Virginia Commonwealth University was extracted and analyzed for safety and efficacy. Inmates with lung cancer and advanced malignancies with pleural or airway metastasis requiring airway debulking (mechanical/thermal), airway stenting, and tunneled pleural catheter (TPC) placement were included in the analysis. RESULTS: A total of 16 procedures were performed in 12 incarcerated patients. These included six TPC placements in six patients. Ten procedures were performed in seven patients with airway obstruction. These procedures included rigid and flexible bronchoscopy with mechanical (rigid and balloon dilation) and thermal (laser, argon plasma coagulation, and cautery) tumor debulking and dilation,airway stenting, and tracheostomy in one case. All six TPCpatients had immediate symptomatic relief and improved lung aeration on chest radiograph. Three of six patients had successful auto-pleurodesis. In the seven patients with airway obstruction, three patients reported symptomatic relief and one had resolution of post-obstructive pneumonia. No immediate- or long-term procedure-related complications were reported. CONCLUSION: Incarcerated patients with advanced malignancy may benefit from interventional pulmonology procedures with low complications. Palliative interventional pulmonology procedures in inmates should not be withheld solely on their incarceration status. PMID- 25015173 TI - Physical properties and biological/odontogenic effects of an experimentally developed fast-setting alpha-tricalcium phosphate-based pulp capping material. AB - BACKGROUND: Recently, fast-setting alpha-tricalcium-phosphate (TCP) cement was developed for use in the pulp capping process. The aim of this study was to investigate the physical properties and biological effects of alpha-TCP cement in comparison with mineral trioxide aggregate (MTA). METHODS: We measured the setting time, pH values, compressive strength, and solubility of the two materials. We evaluated biocompatibility on the basis of cell morphology and a viability test using human dental pulp cells (hDPCs). Chemical composition of each material was analyzed by energy dispersive x-ray spectroscopic (EDS) analysis. The expression of odontogenic-related genes was evaluated by Western blotting and immunofluorescence. The calcified nodule formation was measured by Alizarin red staining. We performed the pulp capping procedure on rat teeth for histological investigation. The data were analyzed by an independent t-test for physical properties, one-way ANOVA for biological effects, and the Mann-Whitney U test for tertiary dentin formation. A P value of less than 0.05 was considered statistically significant for all tests. RESULTS: The setting time, pH values, and compressive strength of alpha-TCP was lower than that of MTA (P < 0.05); however, the solubility of alpha-TCP was higher than that of MTA (P < 0.05). The resultant cell viability observed with the two materials was similar (P > 0.05). Scanning electron microscopy (SEM) revealed that cells attached to both materials were flat and had cytoplasmic extensions. The expression of odontogenic-related markers and mineralized nodule formation were higher in the two experimental groups compared to the control group (P < 0.05). Continuous tertiary dentin was formed underneath the capping materials in all samples of the tested groups. CONCLUSIONS: Our study demonstrated that the alpha-TCP exhibited biocompatibility and odontogenicity comparable to MTA, whereas it had a quicker setting time. PMID- 25015174 TI - A population pharmacokinetic and pharmacodynamic modelling approach to support the clinical development of RBP-6000, a new, subcutaneously injectable, long acting, sustained-release formulation of buprenorphine, for the treatment of opioid dependence. AB - BACKGROUND AND OBJECTIVES: This study implemented pharmacokinetic/pharmacodynamic modelling to support the clinical development of RBP-6000, a new, long-acting, sustained-release formulation of buprenorphine for the treatment of opioid dependence. Such a formulation could offer advantages over existing buprenorphine pharmacotherapy by improving patient compliance and reducing the diversion of the product. METHODS: A population pharmacokinetic model was developed using 36 opioid-dependent subjects who received single subcutaneous doses of RBP-6000. Another pharmacokinetic/pharmacodynamic model was developed using MU-opioid receptor occupancy (uORO) data to predict efficacy of RBP-6000 after repeated doses. It was also assessed how buprenorphine plasma concentrations were correlated with opioid withdrawal symptoms and hydromorphone agonist blockade data from 15 heroin-dependent subjects. RESULTS: The resulting pharmacokinetic model accurately described buprenorphine and norbuprenorphine plasma concentrations. A saturable maximum effect (E max) model with 0.67 ng/mL effective concentration at 50 % of maximum (EC50) and 91 % E max best described uORO versus buprenorphine plasma concentrations. Linear relationships were found among uORO, withdrawal symptoms and blockade of agonist effects. CONCLUSION: Previously published findings have demonstrated uORO >=70 % is needed to achieve withdrawal suppression and blockade of opioid agonist subjective effects. Model simulations indicated that a 200 mg RBP-6000 dose should achieve 2-3 ng/mL buprenorphine average concentrations and desired efficacy. PMID- 25015175 TI - Circulating levels of maternal plasma cell-free pregnancy-associated placenta specific microRNAs are associated with placental weight. AB - The aim of this study was to investigate the relationship between plasma concentration of cell-free pregnancy-associated placenta-specific microRNAs and clinical variables (placental weight, maternal body mass index, and neonatal birth weight). Circulating levels of cell-free pregnancy-associated placenta specific microRNAs (miR-515-3p, miR-517a, miR-517c and miR-518b) in maternal plasma were measured by quantitative real-time RT-PCR in sixty-two pregnant women. The levels of cell-free pregnancy-associated placenta-specific microRNAs were significantly associated with placental weight, but not associated with body mass index or birth weight. Therefore, the measurement of cell-free pregnancy associated placenta-specific miRNAs levels in maternal plasma may reflect the pregnancy status related to placenta volume. PMID- 25015176 TI - Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the combination of UMEC with the long-acting beta2-agonist (LABA) vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD) in the US and EU. They are not indicated for the treatment of asthma. METHODS: In this 52-week, double-blind, placebo-controlled, parallel group safety study (GSK study DB2113359; NCT01316887), patients were randomized 2:2:1 to UMEC/VI 125/25 mcg, UMEC 125 mcg, or placebo. Study endpoints included adverse events (AEs), clinical chemistry and hematology parameters, vital signs, 12-lead, and 24-hour Holter electrocardiograms. COPD exacerbations and rescue medication use were assessed as safety parameters; lung function was also evaluated. RESULTS: The incidence of on-treatment AEs, serious AEs (SAEs), and drug-related AEs was similar between treatment groups (AEs: 52-58%; SAEs: 6-7%; drug-related AEs: 12-13%). Headache was the most common AE in each treatment group (8-11%). AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups. No clinically meaningful effects on vital signs or laboratory assessments were reported for active treatments versus placebo. The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo; for UMEC 125 mcg, the incidences of ectopic supraventricular beats, sustained supraventricular tachycardia, and ectopic supraventricular rhythm were >=2% greater than placebo. With active treatments, COPD exacerbations were fewer (13-15% of patients reporting >=1 exacerbation) and on average less rescue medication was required (1.6-2.2 puffs/day) versus placebo (24% reporting >=1 exacerbation, 2.6 puffs/day). Both active treatments improved lung function versus placebo. CONCLUSION: UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD. PMID- 25015178 TI - Answer to the Letter to the Editor of R.E.E. Omana et al. concerning "Anterior pedicle screw fixation of C2: an anatomic analysis of axis morphology and simulated surgical fixation" by Zeng-Hui Wu et al. Eur Spine J (2014) 23:356-361. PMID- 25015177 TI - Atherogenic subfractions of lipoproteins in the treatment of metabolic syndrome by physical activity and diet - the RESOLVE trial. AB - BACKGROUND: We aimed to comprehensively evaluate lipoprotein profile including lipid particle size following a lifestyle intervention in metabolic syndrome (MetS) volunteers and to assess the associations between lipoprotein subfractions and carotid-intima-media-thickness (CIMT) - a surrogate indicator of atherogenesis. METHODS: 100 participants (50-70 years) from the RESOLVE trial, underwent a one-year follow-up beginning with a three-week residential program combining high exercise volume (15-20 h/week), restrictive diet (-500 kcal/day), and education. For baseline references, 40 aged-matched healthy controls were recruited. Independent associations between subfractions of lipoproteins and CIMT were evaluated using a generalized estimating equations model accounting for variation in correlations between repeated measures. The lipoprotein subfractions profile was assessed using Lipoprint(r) electrophoresis allowing to separate: the very low-density lipoprotein (VLDL) fraction, then the intermediate-density lipoprotein (IDL) C, B and A, the low-density lipoprotein (LDL) with subfractions 1 and 2 as large LDL and subfractions 3 to 7 as small dense LDL (sdLDL), and the high density lipoprotein (HDL) subfractions categorized into large, intermediate, and small HDL. Apolipoproteins A1 and B were also measured. RESULTS: 78 participants completed the program. At baseline, apolipoproteins B/A1, VLDL, sdLDL and small HDL were higher in MetS than in healthy controls; IDL, LDL size, large and intermediate HDL were lower. Despite time-related regains during the follow-up, lipoprotein subfractions traditionally involved in cardiovascular risk, such as sdLDL, improved immediately after the residential program with values closest to those of healthy controls. CIMT improved throughout the lifestyle intervention. Using a generalized estimating equations model, none of the subfractions of lipoproteins nor apolipoproteins were linked to CIMT. CONCLUSIONS: Lipoprotein subfractions traditionally involved in CVR, decreased after the 3-week residential program. During a 12 month follow-up, the time related regains remained closer to the values of healthy controls than they were at baseline. CIMT improved throughout the lifestyle intervention. However, we failed to demonstrate a link between some lipoprotein subfractions and the atherogenicity directly measured from the wall thickness of arteries (CIMT). Further investigations are required to explore the atherogenicity of lipoprotein subfractions. TRIAL REGISTRATION: NCT00917917. PMID- 25015180 TI - Comparison of fusion rates following transforaminal lumbar interbody fusion using polyetheretherketone cages or titanium cages with transpedicular instrumentation. AB - PURPOSE: Compared to titanium cage, polyetheretherketone (PEEK) cage with pedicle screw fixation has been increasingly used in transforaminal lumbar interbody fusion (TLIF). However, there is insufficient evidence supporting the superiority of PEEK cages over titanium cages as optimal TLIF spacers. The aim of this study was to compare the clinical and radiographic outcomes of patients at a 2-year follow-up after undergoing instrumented TLIF in which either a PEEK cage or a titanium cage was implanted. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected 48 patients who underwent single-level TLIF in which the first 23 patients received a titanium cage and the 25 patients received a PEEK cage. Patient demographics, clinical outcomes, and radiographic imaging were studied. RESULTS: Improvement of clinical outcomes was comparable between the two groups. Based on the criteria using computed tomography, 96 % in the Titanium group and 64 % in the PEEK group showed fusion at 12 months. At 24 months, fusion rate in the Titanium group was increased to 100 %, while PEEK group showed 76 % of fusion rate. In the PEEK group, vertebral osteolysis was noted in 60 % of the cases with nonunion. This abnormal finding was not observed in the Titanium group. Vertebral osteolysis was significantly associated with nonunion. CONCLUSIONS: The superiority of PEEK cages over titanium cages for bony fusion was not demonstrated. Additionally, we found unfavorable radiographic findings in the cases with a PEEK cage, which may lead to nonunion. Improvement in biocompatibility of a PEEK cage will be needed to increase the fusion rate. PMID- 25015181 TI - Malignant peripheral nerve sheath tumors presenting as spinal dumbbell tumors: clinical outcomes and characteristic imaging features. AB - PURPOSE: To investigate the clinical outcomes and imaging features of malignant peripheral nerve sheath tumors (MPNSTs) presenting as spinal dumbbell tumors. METHODS: We retrospectively reviewed the clinical outcomes and imaging features of consecutive cases of spinal dumbbell MPNSTs (n=8) and schwannomas (n=15). RESULTS: A maximal diameter>5 cm was more frequently seen in MPNSTs (88%) than in schwannomas (14%). Irregularly lobulated margins occurred frequently in MPNSTs (75%), but not in schwannomas (21%). Indistinguishable boundaries were observed in 63% of MPNSTs, but only 7% of schwannomas. Osteolytic bone destruction was found exclusively in MPNSTs (50% of MPNSTs vs. 0% of schwannomas). CONCLUSIONS: There is little clinical information relating to spinal dumbbell MPNSTs. We propose that the following imaging features are suggestive of spinal dumbbell MPNSTs: maximal diameter>5 cm, irregularly lobulated shape, boundary indistinguishable from surrounding tissues, and osteolytic bone destruction. PMID- 25015182 TI - Herd-of-origin effect on the post-weaning performance of centrally tested Nellore beef cattle. AB - The objective of a performance test station is to evaluate the performance of potential breeding bulls earlier in order to decrease the generation interval and increase genetic gain as well. This study evaluates the herd-of-origin influence on end-of-test weight (ETW), average daily weight gain during testing (ADG), average daily weight gain during the adjustment period (ADGadj), rib eye area (REA), marbling (MARB), subcutaneous fat thickness (SFT), conformation (C), early finishing (EF), muscling (M), navel (N) and temperament (T) scores, and scrotal circumference (SC) of Nellore cattle that underwent a performance test. We evaluated 664 animals that participated in the performance tests conducted at the Center for Performance CRV Lagoa between 2007 and 2012. Components of variance for each trait were estimated by an animal model (model 1), using the restricted maximum likelihood method. An alternative animal model (model 2) included, in addition to the fixed effects present in S1, the non-correlated random effect of herd-year (HY). A significant HY effect was observed on ETW, REA, SFT, ADGadj, C, and Cw (p < 0.05). The estimated heritability of all traits decreased when the HY effect was included in the model; also, the bull rank, in deciles, changed significantly for traits ETW, REA, SFT, and C. The adjustment period did not completely remove the environmental effect of herd of origin on ETW, REA, SFT, and C. It is recommended that the herd-of-origin effect should be included in the statistical models used to predict the breeding values of the participants of these performance tests. PMID- 25015183 TI - A comparative study of production performance and animal health practices in organic and conventional dairy systems. AB - Health and production management strategies influence environmental impacts of dairies. The objective of this paper was to measure risk factors on health and production parameters on six organic and conventional bovine, caprine, and ovine dairy herds in southeastern Brazil over six consecutive years (2006-2011). The organic operations had lower milk production per animal (P <= 0.05), lower calf mortality (P <= 0.05), less incidence of mastitis (P <= 0.05), fewer rates of spontaneous abortions (P <= 0.05), and reduced ectoparasite loads (P <= 0.05) compared to conventional herds and flocks. Organic herds, however, had greater prevalence of internal parasitism (P <= 0.05) than conventional herds. In all management systems, calves, kids, and lambs had greater oocyte counts than adults. However, calves in the organic group showed lower prevalence of coccidiosis. In addition, animals in the organic system exhibited lower parasitic resistance to anthelmintics. Herd genetic potential, nutritive value of forage, feed intake, and pasture parasite loads, however, may have influenced productive and health parameters. Thus, although conventional herds showed greater milk production and less disease prevalence, future research might quantify the potential implications of these unreported factors. PMID- 25015184 TI - One-step synthesis of large-scale graphene film doped with gold nanoparticles at liquid-air interface for electrochemistry and Raman detection applications. AB - We demonstrated a facile one-step synthesis strategy for the preparation of a large-scale reduced graphene oxide multilayered film doped with gold nanoparticles (RGO/AuNP film) and applied this film as functional nanomaterials for electrochemistry and Raman detection applications. The related applications of the fabricated RGO/AuNP film in electrochemical nonenzymatic H2O2 biosensor, electrochemical oxygen reduction reaction (ORR), and surface-enhanced Raman scattering (SERS) detection were investigated. Electrochemical data indicate that the H2O2 biosensor fabricated by RGO/AuNP film shows a wide linear range, low limitation of detection, high selectivity, and long-term stability. In addition, it was proved that the created RGO/AuNP film also exhibits excellent ORR electrochemical catalysis performance. The created RGO/AuNP film, when serving as SERS biodetection platform, presents outstanding performances in detecting 4 aminothiophenol with an enhancement factor of approximately 5.6 * 10(5) as well as 2-thiouracil sensing with a low concentration to 1 MUM. It is expected that this facile strategy for fabricating large-scale graphene film doped with metallic nanoparticles will spark inspirations in preparing functional nanomaterials and further extend their applications in drug delivery, wastewater purification, and bioenergy. PMID- 25015186 TI - A simple control for sediment-toxicity exposures using the amphipod, Hyalella azteca. AB - Sediment-toxicity exposures comparing survival and growth of the freshwater amphipod, Hyalella azteca, are often components of aquatic-habitat assessments. Standardized exposure methods have been established and require evaluations for quality assurance. Test acceptability using performance-based criteria can be determined from exposures to control sediments, which are collected from the environment or formulated from commercially available components. Amending sand with leached alfalfa solids provided a simple formulated sediment that elicited consistently acceptable survival and growth in 28-day exposures with and without a daily feeding regime. A procedure is described for preparing the sediment along with results from comparisons among sand, amended sand, and field-collected sediments that incorporated three feeding regimes. PMID- 25015185 TI - Micro-RNAs in regenerating lungs: an integrative systems biology analysis of murine influenza pneumonia. AB - BACKGROUND: Tissue regeneration in the lungs is gaining increasing interest as a potential influenza management strategy. In this study, we explored the role of microRNAs, short non-coding RNAs involved in post-transcriptional regulation, during pulmonary regeneration after influenza infection. RESULTS: We profiled miRNA and mRNA expression levels following lung injury and tissue regeneration using a murine influenza pneumonia model. BALB/c mice were infected with a sub lethal dose of influenza A/PR/8(H1N1) virus, and their lungs were harvested at 7 and 15 days post-infection to evaluate the expression of ~300 miRNAs along with ~36,000 genes using microarrays. A global network was constructed between differentially expressed miRNAs and their potential target genes with particular focus on the pulmonary repair and regeneration processes to elucidate the regulatory role of miRNAs in the lung repair pathways. The miRNA arrays revealed a global down-regulation of miRNAs. TargetScan analyses also revealed specific miRNAs highly involved in targeting relevant gene functions in repair such as miR 290 and miR-505 at 7 dpi; and let-7, miR-21 and miR-30 at 15 dpi. CONCLUSION: The significantly differentially regulated miRNAs are implicated in the activation or suppression of cellular proliferation and stem cell maintenance, which are required during the repair of the damaged lungs. These findings provide opportunities in the development of novel repair strategies in influenza-induced pulmonary injury. PMID- 25015187 TI - Characterization of heavy metal contamination in the habitat of red-crowned crane (Grus japonensis) in Zhalong Wetland, northeastern China. AB - Heavy metal enrichment in the prey of red-crowned cranes in Zhalong Wetland, northeastern China was researched. Lead and Cd were the most abundant elements in the sediments; their concentrations ranged from 9.85 to 127 ppm and from 1.23 to 10.6 ppm, respectively. Six aquatic animal taxa contained detectable levels of heavy metals, in the decreasing order of Cyprinidae > Cobitidae > Dytiscidae > Odontobutidae > Viviparidae > Aeshnidae. Metal concentrations in these taxa followed the order: Zn > Cu > Cr > Pb > Hg > Cd. Metals in tissues of the red crowned crane varied in the following order: Zn > Cr > Cu > Pb > Cd > Hg in feathers, and Zn > Cu > Hg > Cr > Pb > Cd in eggshells. Cadmium concentrations in the feathers of the red-crowned crane exceeded a level considered to be potentially toxic in birds (i.e., 0.22 ppm), ranging from 1.42 to 3.06 ppm. PMID- 25015188 TI - Anticancer bioactive peptide (ACBP) inhibits gastric cancer cells by upregulating growth arrest and DNA damage-inducible gene 45A (GADD45A). AB - Recently, we reported that anticancer bioactive peptide (ACBP), purified from goat spleens immunized with human gastric cancer extracts, significantly inhibited gastric cancer cells in vitro and gastric tumors in vivo via repressing cell growth and promoting apoptosis, making it a promising potential biological anticancer drug. However, it is not known what genes are functionally required for the ACBP effects. Here, we first found that two tumor suppressor genes, cyclin-dependent kinase inhibitor 2B (CDKN2B) and growth arrest and DNA damage inducible alpha (GADD45A), were upregulated significantly in the cells with ACBP treatment by microarray screening and the findings were validated by real-time RT PCR. Next, GADD45A mRNA and protein expressions were downregulated in the gastric cancer cells by lentivirus-mediated RNAi; then, cell viability, cell cycle, and apoptosis were assayed by MTT and flow cytometry. Interestingly, our results indicated that cell viability was not dependent on GADD45A without ACBP treatment; however, cell sensitivity to ACBP was significantly decreased in ACBP treated gastric cancer cells with GADD45A downregulation. Therefore, we demonstrate that GADD45A was functionally required for ACBP to inhibit gastric cancer cells, suggesting that GADD45A may become a biomarker for ACBP sensitivity. Our findings have significant implications on the molecular mechanism understanding, biomarker development, and anticancer drug development of ACBP. PMID- 25015189 TI - Abnormal MGMT promoter methylation may contribute to the risk of esophageal cancer: a meta-analysis of cohort studies. AB - This meta-analysis was conducted aiming to evaluate the relationship between abnormal O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and the risk of esophageal cancer (EC). A range of electronic databases was searched: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) without language restrictions. Meta-analysis was performed with the use of the STATA 12.0 software. In the present meta-analysis, 9 clinical cohort studies with a total of 861 EC patients were included. The pooled results revealed that the frequency of MGMT promoter methylation in cancer tissues was significantly higher than in adjacent and normal tissues (cancer tissues vs adjacent tissues, odds ratio (OR) = 6.73, 95 % confidence intervals (95 % CI) 4.75 ~ 9.55, P < 0.001; cancer tissues vs normal tissues, OR = 13.68, 95 % CI 9.47 ~ 19.75, P < 0.001, respectively). Subgroup analyses by pathological type, ethnicity, and sample size suggested that abnormal MGMT promoter methylation also exhibited a higher frequency in all these subgroups (all P < 0.05). Our findings provide empirical evidence that abnormal MGMT promoter methylation may contribute to the risk of EC. Thus, detection of MGMT promoter methylation may be utilized as a valuable diagnostic marker for EC. PMID- 25015190 TI - Enhancement of silencing DNA polymerase beta on the radiotherapeutic sensitivity of human esophageal carcinoma cell lines. AB - Human DNA polymerase beta (DNA polymerasebeta (polbeta)) is a small monomeric protein which is essential for short-patch base excision repair (BER). It plays an important role in regulating the radiation sensitivity of tumor cells in the course of tumor radiation therapy. In this study, qRT-PCR and Western blot assays were used to quantify polbeta expression levels in esophageal carcinoma (EC) cells that were transfected with polbeta small interfering RNA (siRNA). Cell counting Kit-8 (CCK-8), flow cytometry, and Hoechst/PI stain assays were conducted to evaluate the effects of silencing polbeta on the radiotherapeutic sensitivity of EC cells. We found that the expression levels of polbeta in EC cells were significantly decreased after transfection with polbeta siRNA. Then, we found that polbeta silencing increased the sensitivity of EC cells to radiation therapy. In conclusion, our study paves the way for a better understanding of the mechanism of the polbeta gene in DNA repair, and we propose that RNA interference technology will have important applications in gene therapy of EC and other cancers in the future. PMID- 25015191 TI - Expression of RKIP in chronic myelogenous leukemia K562 cell and inhibits cell proliferation by regulating the ERK/MAPK pathway. AB - RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen activated protein kinase/extracellular signal-regulated kinase signaling cascade. We investigated the expression of RKIP in chronic myelogenous leukemia (CML) K562 cells and the effects of RKIP on the characteristics of K562 cells. The recombinant plasmid pcDNA3.1-RKIP was established and transfected into K562 cells with the help of Lipofectamine 2000. At the same time, the RKIP-siRNA was transfected into K562 cells in another group. The expressions of RKIP in all groups were assayed by Western blot after 48 h. MTT (3-(4, 5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide) assay was used to analyze the cell viability. Flow cytometry (FCM) was used to examine the cell cycle and cell apoptosis. Colony forming unit (CFU) assay was used to analyze the effect of RKIP on the clonogenic growth of CML cells. Western blot or luciferase reporter assay was used to detect the effect of RKIP on the level of phospho-ERK1/2 or the transcriptional activity of NF-kappaB. Western blot analysis showed that the plasmid pcDNA3.1-RKIP or RKIP-siRNA significantly enhanced or decreased RKIP expression (p < 0.01), respectively. In addition, MTT, FCM, and CFU assay indicated that the overexpression of RKIP significantly lowered the cell viability, cell proliferation and the clonogenic growth (p < 0.05), but improved cell apoptosis (p < 0.01). Western blot analysis or luciferase reporter assay showed that the level of phospho-ERK1/2 or the transcriptional activity of NF kappaB was strongly inhibited by overexpression of RKIP. All these results could bring us a new perspective for biological therapy in myelogenous leukemia in the future. PMID- 25015192 TI - Hsa-miR-1 downregulates long non-coding RNA urothelial cancer associated 1 in bladder cancer. AB - MicroRNAs (miRNAs) are known to mainly target protein-coding genes at post transcriptional level, resulting in mRNA destabilization and/or translational repression. Long non-coding RNAs (lncRNAs) are emerging as a novel set of targets for miRNAs. Here, we report that downregulated hsa-miR-1 and upregulated lncRNA urothelial cancer associated 1 (UCA1) were inversely expressed in bladder cancer. Hsa-miR-1 decreased the expression of UCA1 in bladder cancer cells in an Ago2 slicer-dependent manner. The binding site between UCA1 and hsa-miR-1 was confirmed. Overexpression of hsa-miR-1 inhibited bladder cancer cell growth, induced apoptosis, and decreased cell motility. Knockdown of UCA1 expression phenocopied the effects of upregulation of hsa-miR-1. Transfection of UCA1 expression vector partly reversed the changes caused by transfection of pre-miR-1 plasmids. This study provides evidence for hsa-miR-1 to play tumor suppressive roles via downregulating lncRNA UCA1 in bladder cancer, which may have potential therapeutic significance. PMID- 25015193 TI - Early defects identified by computed tomography angiography are associated with left ventricular dysfunction and exercise intolerance following acute myocardial infarction. AB - PURPOSE: We evaluated the influence of early defects (EDs) in the infarcted myocardium after reperfusion, detected by computed tomography angiography (CTA), on cardiac function and exercise capacity in the chronic phase. MATERIALS AND METHODS: We retrospectively analyzed 48 acute myocardial infarction (AMI) patients who underwent both CTA using 64-slice multidetector CT within 14 +/- 6 days and cardiopulmonary exercise testing within 3 months after AMI onset between 2005 and 2007. The patients were divided into 2 groups: the EDs <75 % or EDs >=75 % group. Brain natriuretic peptide (BNP) levels and ejection fraction (EF) were measured 6 months after AMI onset. RESULTS: The minute ventilation-carbon dioxide production slope was significantly higher in the EDs >=75 % group (28.7 +/- 4.9) than in the EDs <75 % group (25.1 +/- 3.1, P = 0.048). EF at 6 months was significantly lower in the EDs >=75 % group (48.1 +/- 12.0 %) than in the EDs <75 % group (56.8 +/- 10.0 %, P = 0.01). Log of BNP levels was higher in the EDs >=75 % group than in the EDs <75 % group (P < 0.001). CONCLUSION: EDs detected by CTA in the acute phase of AMI influenced myocardial dysfunction and exercise intolerance in the chronic phase. PMID- 25015194 TI - Small interfering RNA (siRNA)-mediated knockdown of macrophage migration inhibitory factor (MIF) suppressed cyclin D1 expression and hepatocellular carcinoma cell proliferation. AB - Macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory chemokine, plays important roles in cancer-related biological processes. However, few studies have focused on the clinical relevance of MIF and cyclin D1 expression in hepatocellular carcinoma cells (HCCs). In this study, MIF and cyclin D1 expression levels in HCC tissues and cell lines were significantly upregulated compared with adjacent normal tissues or a normal liver cell line. In HCC specimens, MIF expression positively correlated with cyclin D1 expression. Additionally, MIF and cyclin D1 expression positively correlated with tumor size. MIF knockdown inhibited the proliferation of PLC and HepG2 cells and promoted apoptosis. However, small interfering RNA (siRNA) against MIF did not influence the cell cycle in these cells. In an in vivo xenograft model, MIF knockdown reduced the tumor growth rate. The expression levels of Bcl-2, p-caspase-3, BIM and Bax were upregulated, while the expression levels of cyclin D1, p-Akt and p ERK were downregulated in MIF-knockdown cells. These findings indicate that MIF siRNA reduces proliferation and increases apoptosis in HCC cells. MIF knockdown inhibits the expression of growth-related proteins and induces the expression of apoptosis-related proteins, supporting a role for MIF as a novel therapeutic target for HCC. PMID- 25015196 TI - The eye jerking trick, no need to panic. PMID- 25015195 TI - Engineering the Pseudomonas aeruginosa II lectin: designing mutants with changed affinity and specificity. AB - This article focuses on designing mutations of the PA-IIL lectin from Pseudomonas aeruginosa that lead to change in specificity. Following the previous results revealing the importance of the amino acid triad 22-23-24 (so-called specificity binding loop), saturation in silico mutagenesis was performed, with the intent of finding mutations that increase the lectin's affinity and modify its specificity. For that purpose, a combination of docking, molecular dynamics and binding free energy calculation was used. The combination of methods revealed mutations that changed the performance of the wild-type lectin and its mutants to their preferred partners. The mutation at position 22 resulted in 85% in inactivation of the binding site, and the mutation at 23 did not have strong effects thanks to the side chain being pointed away from the binding site. Molecular dynamics simulations followed by binding free energy calculation were performed on mutants with promising results from docking, and also at those where the amino acid at position 24 was replaced for bulkier or longer polar chain. The key mutants were also prepared in vitro and their binding properties determined by isothermal titration calorimetry. Combination of the used methods proved to be able to predict changes in the lectin performance and helped in explaining the data observed experimentally. PMID- 25015197 TI - Planning evaluation of C-arm cone beam CT angiography for target delineation in stereotactic radiation surgery of brain arteriovenous malformations. AB - PURPOSE: Stereotactic radiation surgery (SRS) is one of the therapeutic modalities currently available to treat cerebral arteriovenous malformations (AVM). Conventionally, magnetic resonance imaging (MRI) and MR angiography (MRA) and digital subtraction angiography (DSA) are used in combination to identify the target volume for SRS treatment. The purpose of this study was to evaluate the use of C-arm cone beam computed tomography (CBCT) in the treatment planning of SRS for cerebral AVMs. METHODS AND MATERIALS: Sixteen consecutive patients treated for brain AVMs at our institution were included in this retrospective study. Prior to treatment, all patients underwent MRA, DSA, and C-arm CBCT. All images were coregistered using the GammaPlan planning system. AVM regions were delineated independently by 2 physicians using either C-arm CBCT or MRA, resulting in 2 volumes: a CBCT volume (VCBCT) and an MRA volume (VMRA). SRS plans were generated based on the delineated regions. RESULTS: The average volume of treatment targets delineated using C-arm CBCT and MRA were similar, 6.40 cm(3) and 6.98 cm(3), respectively (P=.82). However, significant regions of nonoverlap existed. On average, the overlap of the MRA with the C-arm CBCT was only 52.8% of the total volume. In most cases, radiation plans based on VMRA did not provide adequate dose to the region identified on C-arm CBCT; the mean minimum dose to VCBCT was 29.5%, whereas the intended goal was 45% (P<.001). The mean volume of normal brain receiving 12 Gy or more in C-arm CBCT-based plans was not greater than in the MRA-based plans. CONCLUSIONS: Use of C-arm CBCT images significantly alters the delineated regions of AVMs for SRS planning, compared to that of MRA/MRI images. CT-based planning can be accomplished without increasing the dose to normal brain and may represent a more accurate definition of the nidus, increasing the chances for successful obliteration. PMID- 25015198 TI - 30 Gy or 34 Gy? Comparing 2 single-fraction SBRT dose schedules for stage I medically inoperable non-small cell lung cancer. AB - PURPOSE: To review outcomes of 2 single-fraction lung stereotactic body radiation therapy (SBRT) schedules used for medically inoperable early stage lung cancer. METHODS AND MATERIALS: Patients in our institution have been treated on and off protocols using single-fraction SBRT (30 Gy and 34 Gy, respectively). All patients had node-negative lung cancer measuring <=5 cm and lying >=2 cm beyond the trachea-bronchial tree and were treated on a Novalis/BrainLAB system with the ExactTrac positioning system for daily image guidance. RESULTS: For the interval from 2009 to 2012, 80 patients with 82 lesions were treated with single-fraction lung SBRT. Fifty-five patients (69%) and 25 patients (31%) received 30 Gy and 34 Gy, respectively. In a comparison of 30 Gy and 34 Gy cohorts, patient and tumor characteristics were balanced and median follow-up in months was 18.7 and 17.8, respectively. The average heterogeneity-corrected mean doses to the target were 33.75 Gy and 37.94 Gy for the 30-Gy and 34-Gy prescriptions, respectively. Comparing 30-Gy and 34-Gy cohorts, 92.7% and 84.0% of patients, respectively, experienced no toxicity (P was not significant), and had neither grade 3 nor higher toxicities. For the 30-Gy and 34-Gy patients, rates of 1-year local failure, overall survival, and lung cancer-specific mortality were 2.0% versus 13.8%, 75.0% versus 64.0%, and 2. 1% versus 16.0%, respectively (P values for differences were not significant). CONCLUSIONS: This is the largest single fraction lung SBRT series yet reported. and it confirms the safety, efficacy, and minimal toxicity of this schedule for inoperable early stage lung cancer. PMID- 25015199 TI - Feasibility of multimodal deformable registration for head and neck tumor treatment planning. AB - PURPOSE: To investigate the feasibility of using deformable registration in clinical practice to fuse MR and CT images of the head and neck for treatment planning. METHOD AND MATERIALS: A state-of-the-art deformable registration algorithm was optimized, evaluated, and compared with rigid registration. The evaluation was based on manually annotated anatomic landmarks and regions of interest in both modalities. We also developed a multiparametric registration approach, which simultaneously aligns T1- and T2-weighted MR sequences to CT. This was evaluated and compared with single-parametric approaches. RESULTS: Our results show that deformable registration yielded a better accuracy than rigid registration, without introducing unrealistic deformations. For deformable registration, an average landmark alignment of approximatively 1.7 mm was obtained. For all the regions of interest excluding the cerebellum and the parotids, deformable registration provided a median modified Hausdorff distance of approximatively 1 mm. Similar accuracies were obtained for the single parameter and multiparameter approaches. CONCLUSIONS: This study demonstrates that deformable registration of head-and-neck CT and MR images is feasible, with overall a significanlty higher accuracy than for rigid registration. PMID- 25015200 TI - Dosimetrically triggered adaptive intensity modulated radiation therapy for cervical cancer. AB - PURPOSE: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. METHODS AND MATERIALS: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). RESULTS: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. CONCLUSIONS: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost. PMID- 25015201 TI - Determination of internal target volume for radiation treatment planning of esophageal cancer by using 4-dimensional computed tomography (4DCT). AB - PURPOSE: To determine an efficient strategy for the generation of the internal target volume (ITV) for radiation treatment planning for esophageal cancer using 4-dimensional computed tomography (4DCT). METHODS AND MATERIALS: 4DCT sets acquired for 20 patients with esophageal carcinoma were analyzed. Each of the 4DCT sets was binned into 10 respiratory phases. For each patient, the gross tumor volume (GTV) was delineated on the 4DCT set at each phase. Various strategies to derive ITV were explored, including the volume from the maximum intensity projection (MIP; ITV_MIP), unions of the GTVs from selected multiple phases ITV2 (0% and 50% phases), ITV3 (ITV2 plus 80%), and ITV4 (ITV3 plus 60%), as well as the volumes expanded from ITV2 and ITV3 with a uniform margin. These ITVs were compared to ITV10 (the union of the GTVs for all 10 phases) and the differences were measured with the overlap ratio (OR) and relative volume ratio (RVR) relative to ITV10 (ITVx/ITV10). RESULTS: For all patients studied, the average GTV from a single phase was 84.9% of ITV10. The average ORs were 91.2%, 91.3%, 94.5%, and 96.4% for ITV_MIP, ITV2, ITV3, and ITV4, respectively. Low ORs were associated with irregular breathing patterns. ITV3s plus 1 mm uniform margins (ITV3+1) led to an average OR of 98.1% and an average RVR of 106.4%. CONCLUSIONS: The ITV generated directly from MIP underestimates the range of the respiration motion for esophageal cancer. The ITV generated from 3 phases (ITV3) may be used for regular breathers, whereas the ITV generated from 4 phases (ITV4) or ITV3 plus a 1-mm uniform margin may be applied for irregular breathers. PMID- 25015202 TI - A phase 2 trial of radiation therapy with concurrent paclitaxel chemotherapy after surgery in patients with high-risk endometrial cancer: a Korean Gynecologic Oncologic Group study. AB - PURPOSE: A phase 2 study was completed by the Korean Gynecologic Oncologic Group to evaluate the efficacy and toxicity of concurrent chemoradiation with weekly paclitaxel in patients with high-risk endometrial cancer. METHODS AND MATERIALS: Pathologic requirements included endometrial endometrioid adenocarcinoma stages III and IV. Radiation therapy consisted of a total dose of 4500 to 5040 cGy in 5 fractions per week for 6 weeks. Paclitaxel 60 mg/m(2) was administered once weekly for 5 weeks during radiation therapy. RESULTS: Fifty-seven patients were enrolled between January 2006 and March 2008. The median follow-up time was 60.0 months (95% confidence interval [CI], 51.0-58.2). All grade 3/4 toxicities were hematologic and usually self-limited. There was no life-threatening toxicity. The cumulative incidence of intrapelvic recurrence sites was 1.9% (1/52), and the cumulative incidence of extrapelvic recurrence sites was 34.6% (18/52). The estimated 5-year disease-free and overall survival rates were 63.5% (95% CI, 50.4 76.5) and 82.7% (95% CI, 72.4-92.9), respectively. CONCLUSIONS: Concurrent chemoradiation with weekly paclitaxel is well tolerated and seems to be effective for high-risk endometrioid endometrial cancers. This approach appears reasonable to be tested for efficacy in a prospective, randomized controlled study. PMID- 25015204 TI - Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: risk factors for late toxicity. AB - PURPOSE: To identify factors associated with grade >=3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. RESULTS: The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9 55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. CONCLUSIONS: Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus. PMID- 25015203 TI - Long-term results of a randomized trial in locally advanced rectal cancer: no benefit from adding a brachytherapy boost. AB - PURPOSE/OBJECTIVE(S): Mature data on tumor control and survival are presented from a randomized trial of the addition of a brachytherapy boost to long-course neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer. METHODS AND MATERIALS: Between March 2005 and November 2008, 248 patients with T3 4N0-2M0 rectal cancer were prospectively randomized to either long-course preoperative CRT (50.4 Gy in 28 fractions, per oral tegafur-uracil and L leucovorin) alone or the same CRT schedule plus a brachytherapy boost (10 Gy in 2 fractions). The primary trial endpoint was pathologic complete response (pCR) at the time of surgery; secondary endpoints included overall survival (OS), progression-free survival (PFS), and freedom from locoregional failure. RESULTS: Results for the primary endpoint have previously been reported. This analysis presents survival data for the 224 patients in the Danish part of the trial. In all, 221 patients (111 control arm, 110 brachytherapy boost arm) had data available for analysis, with a median follow-up time of 5.4 years. Despite a significant increase in tumor response at the time of surgery, no differences in 5-year OS (70.6% vs 63.6%, hazard ratio [HR] = 1.24, P=.34) and PFS (63.9% vs 52.0%, HR=1.22, P=.32) were observed. Freedom from locoregional failure at 5 years were 93.9% and 85.7% (HR=2.60, P=.06) in the standard and in the brachytherapy arms, respectively. There was no difference in the prevalence of stoma. Explorative analysis based on stratification for tumor regression grade and resection margin status indicated the presence of response migration. CONCLUSIONS: Despite increased pathologic tumor regression at the time of surgery, we observed no benefit on late outcome. Improved tumor regression does not necessarily lead to a relevant clinical benefit when the neoadjuvant treatment is followed by high-quality surgery. PMID- 25015205 TI - Lung volume reduction after stereotactic ablative radiation therapy of lung tumors: potential application to emphysema. AB - PURPOSE: Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. METHODS AND MATERIALS: We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and >=6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, alpha/beta = 3). RESULTS: 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade >=3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED >=60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001). CONCLUSIONS: We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS. PMID- 25015206 TI - Clinical usefulness of 18F-fluorodeoxyglucose-positron emission tomography in patients with locally advanced pancreatic cancer planned to undergo concurrent chemoradiation therapy. AB - PURPOSE: To assess the role of coregistered (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in detecting radiographically occult distant metastasis (DM) at staging in patients with locally advanced pancreatic cancer (LAPC) and to study whether FDG-PET parameters can predict relatively long-term survival in patients who are more likely to benefit from chemoradiation therapy (CRT). METHODS AND MATERIALS: From our institutional database, we identified 388 LAPC patients with M0 on conventional computed tomography (CT) who were planned to undergo CRT. Coregistered FDG-PET staging was offered to all patients, and follow-up FDG-PET was used at the clinical discretion of the physician. RESULTS: FDG-PET detected unsuspected CT-occult DM in 33% of all 388 patients and allowed them to receive systemic therapy immediately. The remaining 260 patients (PET-M0) underwent CRT selectively as an initial treatment. Early DM arose in 13.1% of 260 patients, and the 1-year estimated locoregional recurrence rate was 5.4%. Median overall survival (OS) and progression-free survival (PFS) were 14.6 and 9.3 months, respectively, at a median follow-up time of 32.3 months (range, 10-99.1 months). Patients with a baseline standardized uptake value (SUV) <3.5 and/or SUV decline >=60% had significantly better OS and PFS than those having none, even after adjustment for all potential confounding variables (all P<.001). CONCLUSIONS: FDG-PET can detect radiographically occult DM at staging in one third of patients and spare them from the potentially toxic therapy. Additionally, FDG-PET parameters including baseline SUV and SUV changes may serve as useful clinical markers for predicting the prognosis in LAPC patients. PMID- 25015207 TI - Fat composition changes in bone marrow during chemotherapy and radiation therapy. AB - PURPOSE: To quantify changes in bone marrow fat fraction and determine associations with peripheral blood cell counts. METHODS AND MATERIALS: In this prospective study, 19 patients received either highly myelotoxic treatment (radiation therapy plus cisplatin, 5-fluorouracil mitomycin C [FU/MMC], or cisplatin/5-FU/cetuximab) or less myelotoxic treatment (capecitabine-radiation therapy or no concurrent chemotherapy). Patients underwent MR imaging and venipuncture at baseline, midtreatment, and posttreatment visits. We performed mixed effects modeling of the mean proton density fat fraction (PDFF[%]) by linear time, treatment, and vertebral column region (lumbar [L]4-sacral [S]2 vs thoracic [T]10-L3 vs cervical[C]3-T9), while controlling for cumulative mean dose and other confounders. Spearman rank correlations were performed by white blood cell (WBC) counts versus the differences in PDFF(%) before and after treatment. RESULTS: Cumulative mean dose was associated with a 0.43% per Gy (P=.004) increase in PDFF(%). In the highly myelotoxic group, we observed significant changes in PDFF(%) per visit within L4-S2 (10.1%, P<.001) and within T10-L3 (3.93%, P=.01), relative to the reference C3-T9. In the less myelotoxic group, we did not observe significant changes in PDFF(%) per visit according to region. Within L4-S2, we observed a significant difference between treatment groups in the change in PDFF(%) per visit (5.36%, P=.04). Rank correlations of the inverse log differences in WBC versus the differences in PDFF(%) overall and within T10 S2 ranged from 0.69 to 0.78 (P<.05). Rank correlations of the inverse log differences in absolute neutrophil counts versus the differences in PDFF(%) overall and within L4-S2 ranged from 0.79 to 0.81 (P<.05). CONCLUSIONS: Magnetic resonance imaging fat quantification is sensitive to marrow composition changes that result from chemoradiation therapy. These changes are associated with peripheral blood cell counts. This study supports a rationale for bone marrow sparing treatment planning to reduce the risk of hematologic toxicity. PMID- 25015208 TI - Sodium L-ascorbate enhances elastic fibers deposition by fibroblasts from normal and pathologic human skin. AB - BACKGROUND: Vitamin C (L-ascorbic acid), a known enhancer of collagen deposition, has also been identified as an inhibitor of elastogenesis. OBJECTIVE: Present studies explored whether and how the L-ascorbic acid derivative (+) sodium L ascorbate (SA) would affect production of collagen and elastic fibers in cultures of fibroblasts derived from normal human skin and dermal fat, as well as in explants of normal human skin, stretch-marked skin and keloids. METHODS: Effects of SA on the extracellular matrix production were assessed quantitatively by PCR analyses, western blots, biochemical assay of insoluble elastin and by immuno histochemistry. We also evaluated effects of SA on production of the reactive oxygen species (ROS) and phosphorylation of IGF-I and insulin receptors. RESULTS: SA, applied in 50-200 MUM concentrations, stimulates production of both collagen and elastic fibers in all tested cultures. Moreover, combination of SA with a proline hydroxylase inhibitor induces a beneficial remodelling in explants of dermal scars, resulting in the inhibition of collagen deposition and induction of new elastogenesis. Importantly, we revealed that SA stimulates elastogenesis only after intracellular influx of non-oxidized ascorbate anions (facilitated by the sodium-dependent ascorbate transporter), that causes reduction of intracellular ROS, activation of c-Src tyrosine kinase and the enhancement of IGF-1-induced phosphorylation of the IGF-1 receptor that ultimately triggers elastogenic signalling pathway. CONCLUSION: Our results endorse the use of this potent stimulator of collagen and elastin production in the treatment of wrinkled and stretch-marked skin. They also encourage inclusion of SA into therapeutic combinations with collagenogenesis inhibitors to prevent formation of dermal scars and keloids. PMID- 25015209 TI - Latent class bivariate model for the meta-analysis of diagnostic test accuracy studies. AB - BACKGROUND: Several types of statistical methods are currently available for the meta-analysis of studies on diagnostic test accuracy. One of these methods is the Bivariate Model which involves a simultaneous analysis of the sensitivity and specificity from a set of studies. In this paper, we review the characteristics of the Bivariate Model and demonstrate how it can be extended with a discrete latent variable. The resulting clustering of studies yields additional insight into the accuracy of the test of interest. METHODS: A Latent Class Bivariate Model is proposed. This model captures the between-study variability in sensitivity and specificity by assuming that studies belong to one of a small number of latent classes. This yields both an easier to interpret and a more precise description of the heterogeneity between studies. Latent classes may not only differ with respect to the average sensitivity and specificity, but also with respect to the correlation between sensitivity and specificity. RESULTS: The Latent Class Bivariate Model identifies clusters of studies with their own estimates of sensitivity and specificity. Our simulation study demonstrated excellent parameter recovery and good performance of the model selection statistics typically used in latent class analysis. Application in a real data example on coronary artery disease showed that the inclusion of latent classes yields interesting additional information. CONCLUSIONS: Our proposed new meta analysis method can lead to a better fit of the data set of interest, less biased estimates and more reliable confidence intervals for sensitivities and specificities. But even more important, it may serve as an exploratory tool for subsequent sub-group meta-analyses. PMID- 25015210 TI - Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. AB - Colorectal cancer (CRC) is a common tumor type with a high mortality rate, in part due to intrinsic drug resistance. Although bevacizumab, a VEGF-directed neutralizing antibody, is particularly active in this pathology, some patients never respond for reasons not well understood. We here wish to clarify the role of autocrine VEGF signaling in the response of CRC cells to angiogenesis inhibition. Our results show that CRC cells with intrinsic bevacizumab-resistance displayed pronounced upregulation of autocrine HIF-VEGF-VEGFR signaling in response to prolonged bevacizumab exposure whereas the same signaling pathway was downregulated in bevacizumab-sensitive xenografts. Importantly, both bevacizumab sensitive and -resistant CRC xenografts were sensitive to nintedanib, a small molecule angiokinase inhibitor, which was associated with inhibition of mTORC1. In vitro studies revealed that bevacizumab-resistant cells displayed intrinsically higher HIF-VEGF signaling intensity and hypoxia tolerance compared to their bevacizumab-sensitive counterparts. Interestingly, although nintedanib showed comparable activity toward bevacizumab-sensitive cells under normoxia and hypoxia, the drug was three-fold more toxic to the resistant cells under hypoxia, suggesting that nintedanib attenuated the survival signaling that usually protects these cells from hypoxia-mediated cell death. In conclusion, our findings support a role for autocrine VEGF signaling in the survival of CRC cells to hypoxia and thus to angiogenesis inhibition. We further show that nintedanib, a small molecule angiokinase inhibitor, is active toward CRC models with intrinsic bevacizumab resistance supporting clinical trials of nintedanib in patients that do not respond to bevacizumab, alone or in combination with bevacizumab to increase angiogenesis inhibition. PMID- 25015212 TI - Networking between community health programs: a team-work approach to improving health service provision. AB - BACKGROUND: Networking between non-government organisations in the health sector is recognised as an effective method of improving service delivery. The Uttarakhand Cluster was established in 2008 as a collaboration of community health programs in rural north India with the aim of building capacity, increasing visibility and improving linkages with the government. This qualitative research, conducted between 2011-2012, examined the factors contributing to formation and sustainability of this clustering approach. METHODS: Annual focus group discussions, indicator surveys and participant observation were used to document and observe the factors involved in the formation and sustainability of an NGO network in North India. RESULTS: The analysis demonstrated that relationships were central to the formation and sustainability of the cluster. The elements of small group relationships: forming, storming, norming and performing emerged as a helpful way to describe the phases which have contributed to the functioning of this network with common values, strong leadership, resource sharing and visible progress encouraging the ongoing commitment of programs to the network goals. CONCLUSIONS: In conclusion, this case study demonstrates an example of a successful and effective network of community health programs. The development of relationships was seen to be to be an important part of promoting effective resource sharing, training opportunities, government networking and resource mobilisation and will be important for other health networks to consider. PMID- 25015213 TI - Re: Arora et al.: Role of corneal collagen cross-linking in pseudophakic bullous keratopathy: a clinicopathological study (Ophthalmology 2013;120:2413-8). PMID- 25015214 TI - Vision-related quality of life before and after keratoplasty for Fuchs' endothelial dystrophy. AB - PURPOSE: To assess vision-related quality of life in Fuchs' dystrophy and changes in vision-related quality of life after 3 types of keratoplasty (penetrating keratoplasty [PK], deep lamellar endothelial keratoplasty [DLEK], and Descemet stripping endothelial keratoplasty [DSEK]). DESIGN: Prospective, observational case series. PARTICIPANTS: Sixty-three subjects with Fuchs' endothelial dystrophy: 12 subjects (12 eyes) received PK, 11 subjects (11 eyes) received DLEK, and 40 subjects (40 eyes) received DSEK. METHODS: Subjects were examined before keratoplasty and at regular intervals through 3 years after keratoplasty. At each examination, vision-related quality of life was assessed using the 25 item National Eye Institute Visual Functioning Questionnaire; best spectacle corrected and uncorrected visual acuities were measured by using the electronic Early Treatment of Diabetic Retinopathy Study protocol; keratometric cylinder was measured by a manual keratometer. Disability glare was measured with a straylight meter. MAIN OUTCOME MEASURES: Vision-related quality of life composite score. RESULTS: Vision-related quality of life composite score for all eyes with Fuchs' dystrophy before keratoplasty was 72 +/- 11 (n = 63) and did not differ between groups (P = 0.88). Vision-related quality of life improved by 6 months (PK, P = 0.008; DLEK, P = 0.03; DSEK, P < 0.001), with continued improvement between 6 months and 3 years after PK (P = 0.01) and DSEK (P = 0.004). At 6 months, the composite score was higher after DSEK than after PK (P = 0.006). At 3 years, there were no differences in composite scores between the 3 treatments (P = 0.33; mean minimum detectable difference, 8 [alpha = 0.05; beta = 0.20]). After keratoplasty, quality of life was correlated with uncorrected visual acuity at 1 year (r = -0.38; P = 0.001) and at 3 years (r = -0.36; P = 0.02), with disability glare at 3 years (r = -0.41; P = 0.02), and with best-corrected visual acuity at 6 months (r = -0.34; P = 0.03), but not thereafter. CONCLUSIONS: Vision-related quality of life in patients with Fuchs' endothelial dystrophy is significantly impaired but improves after keratoplasty, irrespective of the technique. The improvement is faster after DSEK than after PK, and this might be explained in part by rapid improvement in uncorrected visual acuity after DSEK. This study affirms an advantage of endothelial keratoplasty over PK with respect to patient reported outcomes. PMID- 25015215 TI - Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. AB - OBJECTIVE: To evaluate the 24-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or as needed (pro re nata [PRN]) in patients with neovascular age-related macular degeneration (wet AMD). DESIGN: Twenty-four-month, multicenter, randomized, double-masked, active treatment-controlled phase 3 trial. PARTICIPANTS: Patients (n = 1098) >= 50 years of age with treatment-naive subfoveal wet AMD. METHODS: Patients were randomized to receive intravitreal injections of ranibizumab 0.5 mg or 2.0 mg monthly or PRN after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change in best-corrected visual acuity (BCVA) from baseline at month 12. Key secondary end points included mean change in BCVA from baseline at month 24, proportion of patients who gained >= 15 letters in BCVA, mean number of ranibizumab injections, and mean change in central foveal thickness from baseline over time by spectral-domain optical coherence tomography. Ocular and systemic safety events also were evaluated through month 24. RESULTS: At month 24, the mean change from baseline in BCVA was (letters) +9.1 (0.5 mg monthly), +7.9 (0.5 mg PRN), +8.0 (2.0 mg monthly), and +7.6 (2.0 mg PRN). The change in mean BCVA from month 12 to 24 was (letters) -1.0, -0.3, -1.2, and -1.0, respectively. The proportion of patients who gained >= 15 letters from baseline in BCVA at month 24 was 34.5%, 33.1%, 37.6%, and 34.8%, respectively. The mean number of ranibizumab injections through month 24 was 21.4, 13.3, 21.6, and 11.2, respectively; 5.6 and 4.3 mean injections were required in year 2 in the 0.5 mg and 2.0 mg PRN groups, respectively. The average treatment interval in the 0.5 mg PRN group was 9.9 weeks after 3 monthly loading doses, and 93% of these patients did not require monthly dosing. Ocular and systemic safety profiles over 2 years were similar among all 4 treatment groups and were consistent with previous ranibizumab trials in AMD. CONCLUSIONS: At month 24, mean BCVA improvements were clinically meaningful and similar among all 4 ranibizumab treatment groups. The 0.5 mg PRN group achieved a mean gain of 7.9 letters at month 24 with an average of 13.3 injections (5.6 injections in year 2). No new safety events were identified over 24 months. PMID- 25015216 TI - Author reply: To PMID 23953101. PMID- 25015218 TI - Mechanism of action of the tri-hybrid antimicrobial peptide LHP7 from lactoferricin, HP and plectasin on Staphylococcus aureus. AB - The tri-hybrid peptide-LHP7 has the potent activity against Gram-positive and Gram-negative as well as fungi, but its mechanism of action has remained elusive. The effluences of LHP7 on the Staphylococcus aureus cell membrane and targets of intracellular action were investigated. LHP7 exhibited an inhibitory effect on the S. aureus growth, similar to those achieved by plectasin, vancomycin and gramicidin. The membrane integrity studies confirmed that LHP7 disrupted the cell membrane, indicating a membrane permeabilizing killing action. A marginal decline in the intensity fluorescence indicated no significant depolarization of the membrane potential following LHP7 treatment. Furthermore, electron microscopy showed that cell shrinkage, cell wall thickening, cellular content leakage, and cell disruption were observed in the cells treated with LHP7. A gel retardation assay showed that LHP7 bound to the genomic DNA of S. aureus or plasmid DNA at a mass ratio of 2.5-10 (peptide/DNA). Circular dichroism indicated that LHP7 inserted into the groove of DNA. The cell cycle analysis showed that after the treatment with LHP7 for 30 and 60 min, the proportion of cells in I-phase increased from 8.71 to 12.09 % and from 8.71 to 15.68 %, indicating that LHP7 induced arrest of cells in the I-phase. These results would conduce to elucidate its underlying antibacterial mechanism. PMID- 25015217 TI - Author reply: To PMID 24359625. PMID- 25015219 TI - Interaction of U(VI) with Schizophyllum commune studied by microscopic and spectroscopic methods. AB - Biosorption of actinides like uranium by fungal cells can play an important role in the mobilization or immobilization of these elements in nature. Sorption experiments of U(VI) with Schizophyllum commune at different initial uranium concentrations and varying metal speciation showed high uranium sorption capacities in the pH range of 4-7. A combination of high angle annular dark-field and scanning transmission electron microscopy analysis (HAADF-STEM) showed that living mycelium cells accumulate uranium at the cell wall and intracellular. For the first time the fluorescence properties of uranium accumulates were investigated by means of time-resolved laser-induced fluorescence spectroscopy (TRLFS) beside the determination of corresponding structural parameters using X ray absorption fine structure spectroscopy (EXAFS). While the oxidation state of uranium remained unchanged during sorption, uranium speciation changed significantly. Extra and intracellular phosphate groups are mainly responsible for uranium binding. TRLFS spectra clearly show differences between the emission properties of dissolved species in the initial mineral medium and of uranium species on fungi. The latter were proved to be organic and inorganic uranyl phosphates formed depending on the uranyl initial concentration and in some cases on pH. PMID- 25015220 TI - Detection of underdiagnosed concurrent branch retinal artery occlusion in a patient with central retinal vein occlusion using spectral domain optical coherence tomography. AB - BACKGROUND: Combined branch retinal artery and central retinal vein occlusion is a rare condition that has been infrequently reported. This case report, aside from reporting the above-mentioned condition, highlights the importance of performing spectral domain optical coherence tomography in establishing a complete diagnosis, especially in uncertain and complicated cases. We also present spectral domain optical coherence tomography findings of a case of combined unilateral simultaneous central retinal vein and branch retinal artery occlusion. CASE PRESENTATION: We present a single case of an initially missed, unilateral branch retinal artery occlusion combined with central retinal vein occlusion in a 51-year-old female Chinese patient without a significant past medical history, who experienced sudden, painless vision diminution in her right eye eleven days prior to presentation. She eventually recovered visual acuity to 0.60, despite having presented with poor vision. CONCLUSION: Combined unilateral central retinal vein and branch retinal artery occlusion may occur in patients with no medical history of arterial hypertension and diabetes mellitus and can achieve a relatively good visual outcome. This case reaffirms the significance of performing a spectral domain optical coherence tomography examination in patients suffering from central retinal vein occlusion with suspicion of unilateral simultaneous branch retinal artery occlusion to identify the affected pathological areas. PMID- 25015221 TI - Fidelity to the healing relationship: a medical student's challenge to contemporary bioethics and prescription for medical practice. AB - As a medical student, I observed that different physicians had strikingly different attitudes and approaches when caring for patients. The care of one patient in particular continues to challenge my understanding of illness and moral responsibility in the practice of medicine. In this paper, I illustrate the care of this patient in order to evaluate the dominant ethics I was taught in medical school, in theory and in practice, and argue neither principlism nor the ethics of care fully captures the moral responsibility of physicians. Emphasising fidelity to the healing relationship, a core principle derived from Pellegrino's virtue theory, I conclude that this approach to clinical ethics fully explains physician responsibility. Pellegrino deconstructs the practice of medicine to clarify the moral event within the clinical encounter and offers a sufficiently useful and justified approach to patient care. PMID- 25015222 TI - Philosophising outside of the academy. PMID- 25015223 TI - Genetic diversity of Brucella ovis isolates from Rio Grande do Sul, Brazil, by MLVA16. AB - BACKGROUND: Ovine epididymitis is predominantly associated with Brucella ovis infection. Molecular characterization of Brucella spp. achieved by multi-locus variable number of tandem repeats (VNTR) analyses (MLVA) have proved to be a powerful tool for epidemiological trace-back studies. Thus, the aim of this study was to evaluate the genetic diversity of Brucella ovis isolates from Rio Grande do Sul State, Brazil, by MLVA16. FINDINGS: MLVA16 genotyping identified thirteen distinct genotypes and a Hunter-Gaston diversity index of 0.989 among the fourteen B. ovis genotyped strains. All B. ovis MLVA16 genotypes observed in the present study represented non-previously described profiles. Analyses of the eight conserved loci included in panel 1 (MLVA8) showed three different genotypes, two new and one already described for B. ovis isolates. Among ten B. ovis isolates from same herd only two strains had identical pattern, whereas the four isolates with no epidemiologic information exhibited a single MLVA16 pattern each. Analysis of minimal spanning tree, constructed using the fourteen B. ovis strains typed in this study together with all nineteen B. ovis MLVA16 genotypes available in the MLVAbank 2014, revealed the existence of two clearly distinct major clonal complexes. CONCLUSIONS: In conclusion, the results of the present study showed a high genetic diversity among B. ovis field isolates from Rio Grande do Sul State, Brazil, by MLVA16. PMID- 25015225 TI - Bioaccumulation characteristics of perfluoroalkyl acids (PFAAs) in coastal organisms from the west coast of South Korea. AB - Year-round monitoring for perfluoroalkyl acids (PFAAs) along the west coast of South Korea targeting long-term changes in water and coastal organisms has been conducted since 2008. In this study, we present the most recent 5-years of accumulated data and scrutinize the relationship between concentrations in water and biota highlighting bioaccumulation characteristics. Twelve individual PFAAs in samples of water (n=43) and biota (n=59) were quantified by use of HPLC-MS/MS after solid phase extraction. In recent years, concentrations of PFAAs in water have been generally decreasing, but profiles of relative concentrations of individual PFAAs vary among location and year. Bioaccumulation of PFAAs in various organisms including fishes, bivalves, crabs, gastropods, shrimps, starfish, and polychaetes varied among species. However, overall bioaccumulation of PFAAs was dependent on corresponding concentrations of PFAAs in water within an area. In organ-specific distributions of PFAAs, greater concentrations of PFAAs were found in intestine of fish (green eel goby). This result suggests that PFAAs are mainly accumulated via dietary exposure, while greater concentrations were found in gill and intestine of bivalve (oyster) which suggests both waterborne and dietary exposures to these organisms. Concentrations of PFAAs in biota did not decrease over time (2008-2010), indicating that continuing bioaccumulation followed by slow degradation or excretion of PFAAs accumulated in biota. Overall, spatio-temporal distributions of PFAAs in water and bioaccumulation characteristics seemed to be associated with recent restrictions of PFOS-based products and uses of PFBS-based substitutes. PMID- 25015224 TI - Determining the validity and reliability of the Chinese version of the Kidney Disease Quality of Life Questionnaire (KDQOL-36TM). AB - BACKGROUND: Health-related quality of life is a crucial outcome for the chronic kidney disease population, the Kidney Disease Quality of Life (KDQOL) questionnaire is commonly used as an integral part of clinical evaluations. The abbreviated version of the KDQOL-36TM has been translated into Mandarin Chinese, but has not been tested for use in the Chinese patients. The aim of the study was to evaluate the validity and reliability of the KDQOL-36TM with a sample of Chinese patients. METHODS: The Mandarin Chinese version of the KDQOL-36TM has been translated by Amgen, Inc. and the MAPI Institution following the instrument translation specifications provided by the RAND health. The translated instrument was further reviewed by a Chinese expert panel for content validity and translational equivalence. The KDQOL-36TM along with Beck depression Inventory-II were administrated to 103 chronic renal disease patients recruited through convenience sampling procedure from the renal wards and an outpatient dialysis clinic. The convergent validity was determined through investigating the correlational evidence of the KDQOL-36TM with the Beck depression Inventory-II and the overall health rating. Known-group validity was supported by the evidence that the instrument could differentiate subgroups of patients. The internal consistency was estimated using Cronbach's alpha and test-retest reliability was examined using an intraclass correlation coefficient. RESULTS: For the convergent validity, there were positive correlations between the overall health rating and most of the KDQOL-36TM subscales, and the Beck depression inventory score was inversely correlated with the mental component summary score and disease-specific scores of the scale. Significant correlations were noted between disease-targeted and generic dimensions of the KDQOL-36TM. The results of the known-group comparisons indicated females, the unemployed, and patients had a longer dialysis history reported a worse quality of life. With regard to the reliability, the Cronbach's alpha ranged from 0.69 to 0.78, and the intraclass correlation test retest was higher than 0.70. CONCLUSIONS: The Mandarin Chinese version of the KDQOL-36TM is a brief, valid, and reliable instrument for use in examining the quality of life of chronic kidney disease patients in China. PMID- 25015226 TI - Efficient decomposition of a new fluorochemical surfactant: perfluoroalkane disulfonate to fluoride ions in subcritical and supercritical water. AB - Decomposition of (-)O3SC3F6SO3(-) in subcritical and supercritical water was investigated, and the results were compared with the results for C3F7SO3(-). This is the first report on the decomposition of perfluoroalkane disulfonates, which are being introduced in electronics industry as greener alternatives to environmentally persistent and bioaccumulative perfluoroalkyl surfactants. Addition of zerovalent iron to the reaction system dramatically increased the yield of F(-) in the reaction solution: when the reaction of (-)O3SC3F6SO3(-) was carried out in subcritical water at 350 degrees C for 6h, the F(-) yield was 70%, which was 23times the yield without zerovalent iron. Prolonged reaction increased the F(-) formation: after 18h, the F(-) yield from the reaction of (-)O3SC3F6SO3( ) reached 81%, which was 2.1times the F(-) yield from the reaction of C3F7SO3(-). Although the reactivity of FeO toward these substrates was lower than zerovalent iron in subcritical water, the reactivity was enhanced when the reaction temperature was elevated to supercritical state, at which temperature FeO underwent in situ disproportionation to form zerovalent iron, which acted as the reducing agent. When the reaction of (-)O3SC3F6SO3(-) was carried out in the presence of FeO in supercritical water at 380 degrees C for 18h, the F(-) yield reached 92%, which was the highest yield among tested. PMID- 25015227 TI - The evaluation of national time trends, quality of care, and factors affecting the use of minimally invasive breast biopsy and open biopsy for diagnosis of breast lesions. AB - BACKGROUND: Minimally invasive breast biopsy is a recommended biopsy method for suspicious lesions. This study examines national trends and factors associated with the use of open breast biopsy (OBB). METHODS: The national inpatient sample database was used to examine trends and factors associated with the use of OBB. Factors associated with OBB were evaluated using chi-square test for univariate analysis and logistic regression for multivariate analysis. RESULTS: OBB rate was 34%. Patients below 50 years of age had OBB rates of 47%, while those above 50 had OBB rates of 29.1% (P < .001). Higher OBB rates were observed in Asian (39.8%) and Hispanic (40.6%) women compared with white women (34.1%, P < .001). Private insurance patients were more likely to have OBB compared with Medicaid/Medicare patients (40.9% vs 30.6%, P < .001). About 1.2% of women who underwent OBB required multiple biopsies for diagnosis compared with .5% for minimally invasive breast biopsy (P < .001). CONCLUSIONS: OBB is still performed in one third of women despite higher morbidity and less accuracy. Factors associated with higher OBB rate included younger age; Asian ethnicity; private insurance; small, rural, and nonteaching hospitals. PMID- 25015228 TI - Protective effect of quercetin against in vitro erythrocyte rheology alterations produced by arsenic. AB - Humans are exposed to heavy metals such as arsenic (As), through contaminated food and drinking water. The effect of As on RBC membrane is one of the most important biological effects. In a previous work, we have studied the AsVin vitro effect on erythrocytes biophysical properties discovering alterations regarding aggregability deformability, cell morphology, membrane fluidity and osmotic response. We have also observed that the presence of the metal produces an oxidative stress in RBCs that might be the origin of rheological impairment. In the present work we analyzed RBCs rheological properties associated with membrane fluidity and lipid peroxidation in presence of As and quercetin (Qc). From our results we can conclude that RBCs treatment with Qc is efficient to prevent the impairment of the mechanical properties of the cell membrane produced by the As, through oxygen reactive agents in the membrane structure, mainly on the lipids. This protective effect is observed in the preservation of the erythrocytes rheological properties and consequently in the maintenance of an appropriate blood flow, specially in the small vessels in the peripheral circulation. PMID- 25015229 TI - Combined use of ursodeoxycholic acid and bosentan prevents liver toxicity caused by endothelin receptor antagonist bosentan monotherapy: two case reports. AB - INTRODUCTION: Pulmonary arterial hypertension is a fatal disease characterized by progressive remodeling of the pulmonary arteries and an increase in pulmonary vascular resistance. Up to 50% of patients with systemic sclerosis have pulmonary arterial hypertension, which significantly affects the prognosis. The endothelin receptor antagonist bosentan is used for the treatment of pulmonary arterial hypertension and shows a great beneficial effect. However, the most frequent side effect of bosentan is liver toxicity, which often requires dose reduction and discontinuation. CASE PRESENTATION: We report two cases (a 64-year-old Japanese woman and a 69-year old Japanese woman) of systemic sclerosis, both with severe Raynaud's phenomenon and pulmonary arterial hypertension. Both patients had initially received bosentan monotherapy, which caused liver toxicity as indicated by increased levels of alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. After dose reduction or discontinuation of bosentan, these liver function abnormalities were normalized and the patients subsequently received retreatment with a combination of bosentan and ursodeoxycholic acid. The results of liver function tests did not show any abnormalities after this combination therapy. CONCLUSIONS: These reports suggest the usefulness of ursodeoxycholic acid for preventing liver toxicity caused by bosentan. Thus, the addition of ursodeoxycholic acid to the treatment protocol is expected to be useful when liver toxicity emerges as a side effect of bosentan. PMID- 25015230 TI - Development of a cell permeable competitive antagonist of RhoA and CRMP4 binding, TAT-C4RIP, to promote neurite outgrowth. AB - Neurons fail to re-extend their processes within the central nervous system environment in vivo, and this is partly because of inhibitory proteins expressed within myelin debris and reactive astrocytes that actively signal to the injured nerve cells to limit their growth. The ability of the trans-acting activator of transcription (TAT) protein transduction domain (PTD) to transport macromolecules across biological membranes raises the possibility of developing it as a therapeutic delivery tool for nerve regeneration. Most studies have produced TAT PTD fusion protein in bacteria, which can result in problems such as protein solubility, the formation of inclusion bodies and the lack of eukaryotic posttranslational modifications. While some groups have investigated the production of TAT PTD fusion protein in mammalian cells, these strategies are focused on generating TAT PTD fusions that are targeted to the secretory pathway, where furin protease as well as other proteases can cleave the TAT PTD. As an alternative to mutating the furin cleavage site in the TAT PTD, we describe a novel method to generate cytosolic TAT PTD fusion proteins and purify them from cell lysates. Here, we use this method to generate TAT-C4RIP, a cell permeable competitive antagonist of binding between the small GTPase RhoA and the cytosolic phosphoprotein Collapsin response mediator protein 4 (CRMP4). We demonstrate that TAT-C4RIP transduces cells in vitro and in vivo and retains its biological activity to attenuate myelin inhibition in an in vitro neurite outgrowth assay. PMID- 25015231 TI - Cell surface protein C23 affects EGF-EGFR induced activation of ERK and PI3K-AKT pathways. AB - The epidermal growth factor (EGF) pathway has been reported as canonical causes in cancer development. Meanwhile, the involvement of C23 in multiple signaling pathways has been also investigated (Lv et al., 2014). However, the effect of C23 on EGF pathway in glioblastoma is not fully characterized. In the present study, C23 and the epidermal growth factor receptor (EGFR) of U251 cell line were inhibited by C23 and EGFR antibodies, respectively; and then C23 and EGFR siRNAs were used to knock down endogenous C23 and EGFR, respectively. In addition, soft agar and MTT assay were also introduced. Compared with control, either C23 or EGFR antibodies efficiently repressed the phosphorylation levels of ERK1/2 (p<0.000) and AKT (p<0.000). Similarly, either C23 or EGFR siRNAs indeed resulted in C23 and EGFR knockdown, and further suppressed the expression of p-ERK1/2 and p-AKT. Most importantly, immunoprecipitation revealed C23 interacted with EGFR once U251 was exposed to EGF treatment. In addition, the MTT and soft-agar assay also identified that C23 or EGFR siRNAs could obviously affected cell growth (p=0.004) and invasiveness, as cell viability and colony formation decreased markedly. Our results suggest that C23 plays a crucial role in activation of EGF induced ERK and PI3K-AKT pathways via interacting with EGFR; furthermore, C23 could be indicative of an important factor in glioblastoma development and a useful target for glioblastoma treatment. PMID- 25015232 TI - Prevalence and predictors of female sexual dysfunction: a protocol for a systematic review. AB - BACKGROUND: Sexual function is an essential component of life. For this reason, sexual dysfunction can have a negative impact on the wellbeing of men and women alike. Since the turn of the 21st century, research on female sexual dysfunction (FSD) has gained momentum. While FSD is often assessed in people with ill health, sexual dysfunction is an illness of its own entity and is also prevalent in non patient populations. A critical review of current literature on female sexual dysfunction in general populations will shed light on possible determinants as well as at-risk groups. Thus, the aim of this systematic review is to assess the prevalence and the predictors of female sexual dysfunction in general populations. METHODS/DESIGN: A systematic review of current literature on FSD will be performed. Studies will be considered for review if they report quantitative data on the prevalence of female sexual dysfunction. Outcome measures will include the prevalence of FSD, the time period assessed, and significant predictors for each domain of FSD. The scientific databases MEDLINE, EMBASE, PsycINFO, and Web of Science will be systematically searched in cooperation with a medical research librarian. Hand searches for further relevant publications will also be undertaken. Screening of search results and extraction of data from included studies will be conducted cooperatively by two authors. The quality of the studies will be appraised and documented. Results will be compiled and presented in evidence tables. DISCUSSION: In the past decade, population based studies on female sexual dysfunction have increased in number and grown more varied in their cultural settings. This review aims to provide a current overview of the prevalence of female sexual dysfunction in populations from various countries, cultures, and age groups in order to provide a better understanding of its effect on women's lives today. PMID- 25015235 TI - A phage tail-derived element with wide distribution among both prokaryotic domains: a comparative genomic and phylogenetic study. AB - Prophage sequences became an integral part of bacterial genomes as a consequence of coevolution, encoding fitness or virulence factors. Such roles have been attributed to phage-derived elements identified in several Gram-negative species: The type VI secretion system (T6SS), the R- and F-type pyocins, and the newly discovered Serratia entomophila antifeeding prophage (Afp), and the Photorhabdus luminescens virulence cassette (PVC). In this study, we provide evidence that remarkably conserved gene clusters, homologous to Afp/PVC, are not restricted to Gram-negative bacteria but are widespread throughout all prokaryotes including the Archaea. Even though they are phylogenetically closer to pyocins, they share key characteristics in common with the T6SS, such as the use of a chaperon-type AAA+ ATPase and the lack of a host cell lysis mechanism. We thus suggest that Afp/PVC-like elements could be classified as phage-like-protein-translocation structures (PLTSs) rather than as pyocins. The reconstruction of phylogeny and the conserved gene content suggest that the diversification of prophage sequences to PLTS occurred in bacteria early in evolution and only once, but PLTS clusters have been horizontally transferred to some of the bacterial lineages and to the Archaea. The adaptation of this element in such a wide host range is suggestive of its versatile use in prokaryotes. PMID- 25015236 TI - Exploring mental health consequences of childhood abuse and the relevance of religiosity. AB - Although childhood abuse is an established risk factor for mental health problems in adulthood, there is relatively little empirical evidence concerning intervening factors that may mitigate the risk. One potentially protective factor is religiosity. A unique opportunity to explore religiosity's relevance exists with a community-based sample of adult Jewish women that includes sizable subsamples of both rigorously devout ultra-Orthodox (Haredi) and nonreligious Secular Jews. A global measure of any childhood abuse (ACA) includes sexual, physical, and/or emotional abuse. Mental health is assessed with the Brief Symptom Inventory (BSI distress) and a single item reflecting unresolved anger about the past. Predictors of distress severity are examined with separate hierarchical regressions for each religious observance (RO) group. Despite being located at opposite ends of the religiosity spectrum, several surprising similarities emerge including no significant RO group differences in distress among abuse survivors. Moreover, ACA emerges as the strongest predictor of BSI distress within both groups and regressions explain similar amounts of variance. In contrast, two important differences emerge regarding unresolved anger and any recent abuse (ARA). Anger makes a strong contribution to explaining Haredi distress severity, less so for Secular respondents (6.1% vs. 2.9% respectively) while ARA is significant only for Haredi respondents. These initial findings suggest that abusive traumas in childhood may seriously compromise religiosity's potentially protective role. Broadening the research agenda to focus on resilient survivors would expand our understanding of healing resources-both within and outside of a religious framework. Moreover, a better understanding of unresolved anger would likely enhance interventions with greater potential for mitigating the suffering of those abused in childhood. PMID- 25015237 TI - Athletic coaches as violence prevention advocates. AB - Adolescent relationship abuse (ARA) is a significant public health problem. Coaching Boys Into Men (CBIM) is an evidence-based ARA prevention program that trains coaches to deliver violence prevention messages to male athletes. Assessing acceptability and impact of CBIM on coaches may inform prevention efforts that involve these important adults in health promotion among youth. As part of a two-armed cluster-randomized controlled trial of CBIM in 16 high schools in Northern California, coaches completed baseline and postseason surveys (n = 176) to assess their attitudes and confidence delivering the program. Coaches in the intervention arm also participated in interviews (n = 36) that explored program acceptability, feasibility, and impact. Relative to controls, intervention coaches showed increases in confidence intervening when witnessing abusive behaviors among their athletes, greater bystander intervention, and greater frequency of violence-related discussions with athletes and other coaches. Coaches reported the program was easy to implement and valuable for their athletes. Findings illustrate the value of exploring attitudinal and behavioral changes among ARA prevention implementers, and suggest that coaches can gain confidence and enact behaviors to discourage ARA among male athletes. Coaches found the program to be feasible and valuable, which suggests potential for long-term uptake and sustainability. PMID- 25015238 TI - Forgiveness as a mediator of the intergenerational transmission of violence. AB - Bowen Family Systems Theory and Social Learning Theory served as a framework for examining the potential role of offspring maternal forgiveness in the intergenerational transmission (IGT) of violence. Using 285 emerging adults, we tested the hypotheses that higher accounts of witnessed interpersonal violence perpetrated by either parent would relate to increased reports of dating violence, and that offspring's capacity to forgive mothers for current transgressions would mediate this relationship. Witnessing interpersonal violence perpetrated by either parent significantly related to offspring dating violence perpetration and victimization. In addition, witnessing violence perpetrated by either parent significantly related to offspring dating violence perpetration, via offspring's capacity to forgive. Contrary to expectation, offspring's capacity to forgive mothers did not mediate the link between father-perpetrated violence and dating violence victimization; however, it did serve as mediator in the association between mother-perpetrated violence and offspring dating violence victimization. Overall, the findings suggest that witnessing violence perpetrated by either parent explains a portion of the variance in offspring dating violence indirectly through offspring's capacity to forgive mothers for current transgressions. The present study contributes to previous research on the IGT of violence by identifying forgiveness as a mechanism in which intimate partner violence is transmitted generationally. Implications and future directions are discussed for researchers and clinicians. PMID- 25015239 TI - Delivery of genes into the CF airway. AB - Gene therapy was suggested as a potential treatment for cystic fibrosis (CF), even before the identification of the CFTR gene. Initial enthusiasm has been tempered as it became apparent that reintroduction of the CFTR gene into the cells of the lung is more difficult than anticipated. Here, we review the major gene delivery vectors evaluated clinically, and suggest that advances in either plasmid DNA design and/or hybrid lentivirus biology may finally facilitate lung gene transfer with efficiencies sufficient for CF gene therapy to offer clinical benefit. PMID- 25015240 TI - Statins as adjunct therapy in COPD: how do we cope after STATCOPE? PMID- 25015241 TI - Unfolding and aggregation of a glycosylated monoclonal antibody on a cation exchange column. Part I. Chromatographic elution and batch adsorption behavior. AB - A glycosylated IgG2 monoclonal antibody exhibits a two-peak elution behavior when loaded on a strong cation exchange column and eluted with either a linear salt gradient or two salt steps at increasing salt concentrations. The two-peak behavior is more pronounced for conditions where the initial antibody binding is stronger, i.e. at lower pH and buffer concentration, where the hold time prior to elution is longer, where the protein mass load is lower, and where the load flow rate is higher. The effect is also dependent on the resin type, being prominent for the polymer-functionalized resin Fractogel EMD SO3(-) and virtually absent for a macroporous resin with similar backbone but no grafted polymers. Size exclusion chromatography and dynamic light scattering show that the early eluting peak consists exclusively of the native monomeric species while the late eluting peak is a mixture of monomeric and aggregated species. Batch adsorption/desorption experiments show that the bound protein can be desorbed in two steps, with a fraction desorbed in 0.33 M NaCl, corresponding to native monomer, and a second fraction desorbed in 1M NaCl. The latter fraction decreases with protein mass load and becomes almost negligible when the resin is initially completely saturated with protein. Confocal laser scanning microscopy showed that the two-peak elution/desorption behavior is related to the unique kinetics of protein binding in the Fractogel resin. Following partial loading of the resin, the bound protein migrates toward the center of the particles during a hold step and is redistributed across the particle volume attaining low local bound protein concentrations. For these conditions the protein is apparently destabilized forming a strongly-bound unfolded intermediate that, in turn, generates aggregates upon elution in high salt. PMID- 25015234 TI - Maternal vaccination: moving the science forward. AB - BACKGROUND: Infections remain one of the leading causes of morbidity in pregnant women and newborns, with vaccine-preventable infections contributing significantly to the burden of disease. In the past decade, maternal vaccination has emerged as a promising public health strategy to prevent and combat maternal, fetal and neonatal infections. Despite a number of universally recommended maternal vaccines, the development and evaluation of safe and effective maternal vaccines and their wide acceptance are hampered by the lack of thorough understanding of the efficacy and safety in the pregnant women and the offspring. METHODS: An outline was synthesized based on the current status and major gaps in the knowledge of maternal vaccination. A systematic literature search in PUBMED was undertaken using the key words in each section title of the outline to retrieve articles relevant to pregnancy. Articles cited were selected based on relevance and quality. On the basis of the reviewed information, a perspective on the future directions of maternal vaccination research was formulated. RESULTS: Maternal vaccination can generate active immune protection in the mother and elicit systemic immunoglobulin G (IgG) and mucosal IgG, IgA and IgM responses to confer neonatal protection. The maternal immune system undergoes significant modulation during pregnancy, which influences responsiveness to vaccines. Significant gaps exist in our knowledge of the efficacy and safety of maternal vaccines, and no maternal vaccines against a large number of old and emerging pathogens are available. Public acceptance of maternal vaccination has been low. CONCLUSIONS: To tackle the scientific challenges of maternal vaccination and to provide the public with informed vaccination choices, scientists and clinicians in different disciplines must work closely and have a mechanistic understanding of the systemic, reproductive and mammary mucosal immune responses to vaccines. The use of animal models should be coupled with human studies in an iterative manner for maternal vaccine experimentation, evaluation and optimization. Systems biology approaches should be adopted to improve the speed, accuracy and safety of maternal vaccine targeting. PMID- 25015242 TI - High-performance thin-layer chromatography screening of multi class antibiotics in animal food by bioluminescent bioautography and electrospray ionization mass spectrometry. AB - The world-wide usage and partly abuse of veterinary antibiotics resulted in a pressing need to control residues in animal-derived foods. Large-scale screening for residues of antibiotics is typically performed by microbial agar diffusion tests. This work employing high-performance thin-layer chromatography (HPTLC) combined with bioautography and electrospray ionization mass spectrometry introduces a rapid and efficient method for a multi-class screening of antibiotic residues. The viability of the bioluminescent bacterium Aliivibrio fischeri to the studied antibiotics (16 species of 5 groups) was optimized on amino plates, enabling detection sensitivity down to the strictest maximum residue limits. The HPTLC method was developed not to separate the individual antibiotics, but for cleanup of sample extracts. The studied antibiotics either remained at the start zones (tetracyclines, aminoglycosides, fluoroquinolones, and macrolides) or migrated into the front (amphenicols), while interfering co-extracted matrix compounds were dispersed at hRf 20-80. Only after a few hours, the multi-sample plate image clearly revealed the presence or absence of antibiotic residues. Moreover, molecular information as to the suspected findings was rapidly achieved by HPTLC-mass spectrometry. Showing remarkable sensitivity and matrix-tolerance, the established method was successfully applied to milk and kidney samples. PMID- 25015243 TI - Novel supports in chiral stationary phase development for liquid chromatography. Preparation, characterization and application of ordered mesoporous silica particles. AB - Recent advances in the development of new materials are having a major impact on analytical chemistry. For example, the unique properties of ordered mesoporous silicas (OMSs) have been shown to enhance the analytical performance of many existing techniques or allow new, exciting ones to be developed. Likewise, the introduction of organo-functional groups makes OMSs highly versatile and enables them to perform specialized tasks, such as the separation of chiral compounds. This review provides an overview with the most relevant achievements in the preparation of OMS particles functionalized with chiral selectors. In addition, some examples from the last fifteen years regarding the analytical applications of functionalized OMS for chiral separations by high-performance liquid chromatography, ultra-high pressure high-performance liquid chromatography and capillary electrochromatography have been reviewed. PMID- 25015244 TI - A gated atmospheric pressure drift tube ion mobility spectrometer-time-of-flight mass spectrometer. AB - Identifying the compounds of an unknown gas mixture by using an ion mobility spectrometer (IMS) is a difficult task, because several ion species can be generated in the ionization process. One method to analyze the occurring peaks in an IMS spectrum is coupling an IMS to a mass spectrometer (MS). In our setup we coupled a (3)H drift tube IMS to a Bruker micrOTOF II. Therefore, the detector plate of the IMS is pierced and a transfer capillary is inserted. The ions are transferred via gas flow and electric fields into the MS. The transmission of the ions through the transfer capillary can be shuttered very precisely by increasing the electric potential of the detector generating a repulsive electric field. Thus, it is possible to transfer single ion clouds of generated IMS spectra into the mass spectrometer where a corresponding mass spectrum is generated. In this work we analyze the positive and negative IMS spectra of single analytes as well as gas mixtures and characterize the occurring ion species. PMID- 25015245 TI - [Role of omalizumab in the management of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis]. PMID- 25015246 TI - [Reply]. PMID- 25015247 TI - [Hermansky-Pudlak syndrome: a case report]. PMID- 25015248 TI - [Pulmonary thromboembolism and multiple cerebral infarctions in a 36-year-old woman]. PMID- 25015249 TI - [Myocardial stunning, stress cardiomyopathies and takotsubo syndrome]. PMID- 25015250 TI - [Imperfect osteogenesis]. PMID- 25015251 TI - [Incidence of haematological neoplasms in Castilla y Leon, Spain]. AB - BACKGROUND AND OBJECTIVE: We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y Leon (2,5 million inhabitants) and its distribution by age, gender and histological type. PATIENTS AND METHOD: The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10 years period was analyzed, compared with other studies. RESULTS: The overall age adjusted incidence was 29.4 cases/10(5) inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th 7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). CONCLUSIONS: A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated. PMID- 25015252 TI - [Knowledge, expectancies and preferences in regard to the patient self determination act among primary care patients]. PMID- 25015253 TI - [Stroke in very old patients and ethics in clinical research]. PMID- 25015254 TI - [Limitations of the utilization of cardiovascular risk tables and statins]. PMID- 25015255 TI - [Non celiac villous atrophy: more confusion or a new syndrome?]. PMID- 25015257 TI - The basic reproduction number for cellular SIR networks. AB - The basic reproduction number R0 is the average number of new infections produced by a typical infective individual in the early stage of an infectious disease, following the introduction of few infective individuals in a completely susceptible population. If R0 <1, then the disease dies, whereas for R0 >1 the infection can invade the host population and persist. This threshold quantity is well studied for SIR compartmental or mean field models based on ordinary differential equations, and a general method for its computation has been proposed by van den Driessche and Watmough. We concentrate here on SIR epidemiological models that take into account the contact network N underlying the transmission of the disease. In this context, it is generally admitted that R0 can be approximated by the average number R2,3 of infective individuals of generation three produced by an infective of generation two. We give here a simple analytic formula of R2,3 for SIR cellular networks. Simulations on two dimensional cellular networks with von Neumann and Moore neighborhoods show that R2;3 can be used to capture a threshold phenomenon related the dynamics of SIR cellular network and confirm the good quality of the simple approach proposed recently by Aparicio and Pascual for the particular case of Moore neighborhood. PMID- 25015256 TI - Reactive astrogliosis in response to hemorrhagic fever virus: microarray profile of Junin virus-infected human astrocytes. AB - BACKGROUND: Arenavirus Junin is the causative agent of Argentine hemorrhagic fever. Limited information is available concerning the pathogenesis of this human disease, especially the pathogenesis of acute and late neurological symptoms. METHODS: In our study we present for the first time cDNA microarray profile of human astrocytes infected with the virulent strain of Junin virus. Transcriptional profiling was confirmed by quantitative real-time RT-PCR and cytokine/chemokine/growth factor assay. RESULTS: We demonstrated the impact of virus infection on immune/inflammatory response/interferon signaling and apoptosis. Pro-apoptotic response and amplification with time of pro-inflammatory cascade of human astrocytes suggested neurodegenerative dysfunctional reactive astrogliosis in response to Junin virus infection. CONCLUSION: Our results suggest potential pathogenic role of astroglial cells in the development of neurological symptoms and late neurological syndrome during Argentine hemorrhagic fever. PMID- 25015259 TI - Assessing Knowledge Sharing Among Academics: A Validation of the Knowledge Sharing Behavior Scale (KSBS). AB - BACKGROUND: There is a belief that academics tend to hold on tightly to their knowledge and intellectual resources. However, not much effort has been put into the creation of a valid and reliable instrument to measure knowledge sharing behavior among the academics. OBJECTIVES: To apply and validate the Knowledge Sharing Behavior Scale (KSBS) as a measure of knowledge sharing behavior within the academic community. SUBJECTS: Respondents (N = 447) were academics from arts and science streams in 10 local, public universities in Malaysia. MEASURES: Data were collected using the 28-item KSBS that assessed four dimensions of knowledge sharing behavior namely written contributions, organizational communications, personal interactions, and communities of practice. RESULTS: The exploratory factor analysis showed that the items loaded on the dimension constructs that they were supposed to represent, thus proving construct validity. A within-factor analysis revealed that each set of items representing their intended dimension loaded on only one construct, therefore establishing convergent validity. All four dimensions were not perfectly correlated with each other or organizational citizenship behavior, thereby proving discriminant validity. However, all four dimensions correlated with organizational commitment, thus confirming predictive validity. Furthermore, all four factors correlated with both tacit and explicit sharing, which confirmed their concurrent validity. All measures also possessed sufficient reliability (alpha > .70). CONCLUSION: The KSBS is a valid and reliable instrument that can be used to formally assess the types of knowledge artifacts residing among academics and the degree of knowledge sharing in relation to those artifacts. PMID- 25015258 TI - Association of ACE gene I/D polymorphism and ACE levels with hemorrhagic stroke: comparison with ischemic stroke. AB - In the present study, we investigated the association of insertion/deletion polymorphism of ACE gene with genetic predisposition to hemorrhagic stroke and also determined the mean ACE activity levels in ischemic and hemorrhagic stroke patients. Two hundred hemorrhagic stroke, 200 ischemic stroke patients and 200 gender and age matched controls were recruited for the study. We found statistically significant difference in the genotypic distribution between hemorrhagic patients and controls for dominant, co-dominant and recessive models. Significant difference was observed in the allelic frequencies between hemorrhagic patients and controls. Multiple logistic regression analysis confirmed these findings [adjusted OR for DD genotype was 2.46 (95 % CI 1.43 4.21) and p = 0.001] and [adjusted OR for ID genotype was 5.45 (95 % CI 2.6-10.4) and p = 0.001]. We have already established the association of this polymorphism in ischemic stroke patients. Comparing hemorrhagic with ischemic stroke, we found a significant difference in genotypic distribution between the two [for II vs. DD, chi (2) = 4.75; p = 0.03, OR = 0.5 (95 % CI 0.27-0.93) and for DD vs. ID, chi (2) = 5.1; p = 0.02, OR = 1.8 (95 % CI 1.1-3.3)]. Our results indicate that DD genotype and D allele are important risk factors for the development of stroke. Individuals harboring DD genotype of ACE I/D polymorphism are more predisposed to hemorrhagic stroke than ischemic stroke. Further, the mean ACE activity level was found to be significantly higher in hemorrhagic and ischemic stroke in comparison with controls, but there was no significant difference in the levels found between the two types of stroke. PMID- 25015260 TI - A method for analyzing changing prison populations: explaining the growth of the elderly in prison. AB - BACKGROUND: For the past several decades, the U.S. prison system has witnessed a steady and persistent increase in the ages of prison populations. Given the additional costs and burdens placed on prisons as they house older inmates, this aging trend has generated intense interest among policy makers and academics who seek to understand why prison populations are getting older. OBJECTIVE: This article presents a method for evaluating drivers influencing the change in age distributions among prisoners. METHOD: We define a methodological approach and demonstrate its application using prison data from four states reporting to the Bureau of Justice Statistics' National Corrections Reporting Program. RESULTS: We find that since 2000, the primary driver of overall growth in the elderly populations in prison (defined as inmates over 50) is the increasing admission age of offenders entering prison. Moreover, changes in offense mix and sentence length/time served over the last decade have had significantly less influence on the age composition of prison populations. We also find that the impact of explanatory factors varies across states and offense types. For example, prison admission and exit rates explain much of the change in elderly drug offenders in New York, but not elderly violent offenders, where admission age plays a much stronger explanatory role. CONCLUSION: Our analysis offers an effective demonstration that supports the use of this method as an important and informative first step toward understanding components of change that affect the problem of prison aging. PMID- 25015261 TI - Pairwise cluster randomization: an exposition. AB - BACKGROUND: Cluster randomization (CR) is often used for program evaluation when simple random assignment is inappropriate or infeasible. Pairwise cluster random (PCR) assignment is a more efficient alternative, but evaluators seemed to be deterred from PCR because of bias and identification problems. This article explains the problems, argues that they can be mitigated through design choices, and demonstrates that the suitability of PCR can be tested using Monte Carlo procedures. RESEARCH DESIGN: The article presents simple formulas showing how the PCR estimator is biased and explains why its standard error is not identified. Formal derivations appear in a longer companion article. Using those formulas, this article discusses how good design can mitigate the problems with bias and identification. Using Monte Carol simulation, this article also shows how to choose between CR and PCR at the design stage. CONCLUSIONS: This article advocates for wider use of the PCR design. PCR loses its appeal when the investigator lacks baseline data for matching the clusters. Its use is less compelling when there are a large number of clusters. But when the evaluator is working with a fairly small number of clusters-26 in the running example used in this article-PCR is an attractive alternative to CR. PMID- 25015262 TI - Novel physico-chemical diagnostic tools for high throughput identification of bovine mastitis associated gram-positive, catalase-negative cocci. AB - BACKGROUND: The routine diagnosis of Streptococcus spp. and other mastitis associated gram-positive, catalase-negative cocci is still based upon biochemical tests and serological methods, which frequently provide ambiguous identification results. We therefore aimed to establish an accurate identification system for differential diagnosis of mastitis associated Streptococcus spp. and related species using biophysical techniques such as Fourier-transform infrared (FTIR) spectroscopy and MALDI - TOF/MS. RESULTS: Based on a panel of 210 isolates from cases of bovine mastitis, an unsupervised FTIR spectral reference library was established and an artificial neural network (ANN) - assisted identification system was developed. All bacterial isolates were previously identified by species-specific PCR and/or 16S rRNA gene sequence analysis. An overall identification rate of 100% at species level for 173 strains unknown to the ANN and the library was achieved by combining ANN and the spectral database, thus demonstrating the suitability of our FTIR identification system for routine diagnosis. In addition, we investigated the potential of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of mastitis associated Streptococcus spp. and related bacteria. Using the Microflex LT System, MALDI Biotyper softwareTM (V3.3) we achieved an accuracy rate of 95.2%. A blind study, including 21 clinical samples from dairy cows, revealed a 100% correct species identification rate for FTIR and 90.5% for MALDI-TOF MS, indicating that these techniques are valuable tools for diagnosis. CONCLUSIONS: This study clearly demonstrates that FTIR spectroscopy as well as MALDI-TOF MS can significantly improve and facilitate the identification and differentiation of mastitis associated Streptococcus spp. and related species. Although the FTIR identification system turned out being slightly superior to MALDI-TOF MS in terms of identification on species level, both methods offer interesting alternatives to conventional methods currently used in mastitis diagnosis as both of them provide high accuracy at low operating costs once the instrument is acquired. PMID- 25015263 TI - Risk modulation of GSTM1-GSTT1 interactions to head and neck cancer in tobacco users. AB - Tobacco use and environmental air pollution are the established etiological factors in head and neck cancer (HNC) progression. Nevertheless, not all the inhabitants with high usage of tobacco from the same polluted locality are suffering with HNC and this is due to the existence of factors like inter individual genetic polymorphisms, life time exposure to tobacco and the rate of xenobiotic metabolism enzyme (XME) activity. The present study investigates the polymorphic genotypes of the most important XME, glutathione-S-transferase Mu 1 (GST M1) and Theta 1 (GST T1) as the risk modulator to HNC among tobacco habituated inhabitants of Saurashtra in Gujarat, a region in western India. A population based case-control study was done in 252 HNC patients and 504 healthy controls. Blood samples were collected from the subjects and investigated for polymorphic genotypes of GST M1 and GST T1. Estimation of the odds of risks was done by logistic regressions. Among the subjects with high usage of tobacco, M1 not null-T1 null genotypes presence was found as risk reducing factor to HNC with 0.334 folds (95 % CI; 0.170-0.659). The presence of M1 null-T1 not null genotypes was found with susceptibility to HNC among the subjects with no habit of tobacco chewing, adjusted odds ratio (AOR) 3.170 (1.128-8.913) and no habit of smoking, AOR of 2.544 (1.094-5.963). The present study reveals the finding of significantly increased risk to HNC by interactions of GST M1 null-GST T1 not null polymorphic genotypes among the subjects with nil or less tobacco usage shed some light for the insights of biomarker application in early detection of HNC. PMID- 25015264 TI - Expression pattern of hTERT telomerase subunit gene in different stages of chronic myeloid leukemia. AB - Telomerase is activated in chronic myeloid leukemia (CML); however, it is not known whether the catalytic telomerase reverse transcriptase subunit (hTERT) is vital in the progression of this disease. This study involved patients with CML in the chronic phase (pretreatment and after treatment), accelerated and blastic phase. Expression of the hTERT gene differed significantly among the four major groups (p < 0.05). We also compared hTERT expression according to demographic parameter such as age and sex, and found no significant differences (p > 0.05). Taken together, our findings suggest the importance of hTERT as a valuable molecular marker in the follow-up of patients with CML, which may have clinical implications for the prognosis. PMID- 25015265 TI - Alterations in the Sp1 binding and Fmr-1 gene expression in the cortex of the brain during maturation and aging of mouse. AB - Fragile X mental retardation protein (FMRP) has been implicated in learning, memory and cognition, therefore, information on alterations in FMRP expression during maturation and aging may provide a clue towards understanding mechanisms of age-dependent cognitive changes in the brain. In the present paper, we have studied Fmr-1 gene expression and its correlation with interaction of a tans acting factor Sp1with Fmr-1 promoter in the cerebral cortex of female mice at post natal period during maturation and aging. Our data reveal that level of Fmr 1 transcript in the cerebral cortex is significantly up regulated at day 7 after birth compared to day 0 (the day of birth) and is gradually down regulated from day 15 onward to old age. The pattern of Fmr-1 transcript levels corresponds with the level of FMRP, however, its level is significantly up regulated in old age compared to adult mice. Our EMSA data revealed the formation of a single complex as a result of binding of Sp1with Fmr-1 promoter sequence. Its intensity gradually decreased from the day 0 (day of birth) till day 15, remained unaltered in young, significantly decreased in adult and significantly increased in old age. Our data suggests that age-dependent alteration in the Fmr-1 gene expression is associated with Sp1 interaction with Fmr-1 promoter which in turn might be related with cognitive development during brain maturation and aging. PMID- 25015266 TI - Purification and mass spectrometry based characterization of a pediocin produced by Pediococcus acidilactici 13. AB - Bacteriocins are antimicrobial peptides produced by several bacterial species. Among the bacteriocins pediocin-like bacteriocins have a significant inhibitory activity on the foodborne pathogens especially on Listeria monocytogenes. This study aims to select a simple and usable purification method to purify/concentrate the antimicrobial peptide and characterization of the bacteriocin produced by Pediococcus acidilactici 13 by using proteomic approaches which is a recent omic technology. For purification dialysis, ultrafiltration method was used, and as a result of this study the bacteriocin activity reached 819,200 AU/mL from 102,400 AU/mL initially. Two dimensional gel electrophoresis and then matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF MS) analysis were carried out to identify the current bacteriocin and related proteins. Obtained data revealed similarity to pediocin PA-1 transport/processing ATP-binding protein PedD (accession number: P36497), pediocin operon PedC (accession number: Q68GC4) and bacteriocin pediocin PA-1 (accession number: P29430) from UniProtKB/Swiss-Prot databank, thus the bacteriocin produced by P. acidilactici 13 is considered similar to pediocin PA 1. PMID- 25015267 TI - Head fat is a novel method of measuring metabolic disorder in Chinese obese patients. AB - BACKGROUND: Body adiposity, especially ectopic fat accumulation, has a range of metabolic and cardiovascular effects. The aim of this study was to investigate the association between head fat and metabolic values in Chinese obese patients. METHODS: Data of this cross-sectional study from 66 obese patients were collected. Fat distribution was measured by dual-energy X-ray absorptiometry, and data of body weight, body mass index (BMI), neck circumference (NC), waist circumference (WC), hip circumference (HC), visceral index, basal metabolism (BM), glucose metabolism, lipid levels, uric acid (UA) had been collected. RESULTS: 1) Head fat was significantly associated with BMI, WC, HC, visceral index, BM, total fat and total fat excluding head fat in both males and females (p<0.05). Head fat was positively correlated with upper limb fat, trunk fat, weight, fasting plasma C peptide, fasting plasma insulin and UA in women(p<0.05), and the association was not statistically significant in male (p>0.05). Head fat was positively corrected with NC in males (p<0.05) but not females (p>0.05). There was no significant correlation between head fat and fasting plasma glucose, total choleslerolemia, triglyceridemia, high-density lipoprotein cholesterol, low density lipoprotein cholesterol and free fat acid in either gender (p>0.05). 2) Receiver operating characteristic analysis showed that a head fat of 1925.6 g and a head fat of 1567.85 g were the best cut-off values to determine subjects with low high-density lipoprotein cholesterol and hyperuricemia respectively. CONCLUSIONS: Head fat accumulation was closely associated with increased body fat, hyperinsulinemia, hyperuricemia, and impared lipid profile, suggesting it might be used as an indicator for dyslipidemia and hyperuricemia. PMID- 25015268 TI - Stories from Lake Volta: the lived experiences of trafficked children in Ghana. AB - Child trafficking is one of the worst forms of child maltreatment and is often difficult to recognize when it happens intra-country. This paper presents the narratives of children on their experiences as victims of trafficking in fishing communities along the Volta Lake in the Volta region of Ghana. The narratives were co-constructed with the children through child-friendly participatory approaches which involved drawings, writing, and in-depth interviews. The stories reflect the magnitude of maltreatment trafficked children suffer, which ranges from physical to psychological and emotional. The authors recommend commitment by the government to the implementation of the Human Trafficking Act to deter child traffickers. Further studies on the living conditions of rescued children and the need to implement strategies to prevent re-trafficking are suggested. PMID- 25015269 TI - Purification and immunophenotypic characterization of murine MZ and T2-MZP cells. AB - B cells are generated every day in the bone marrow, but only a small fraction integrates the peripheral B-cell pool. In the murine spleen, we can find several B-cell subsets representing various maturation stages and/or cell functions. The spleen is a complex lymphoid organ organized in two main structures with different functions: the red and white pulp. The red pulp is flowed with blood while the white pulp is organized in primary follicles, with a B-cell area composed of follicular B cells and a T-cell area surrounding a periarterial lymphatic sheath. The frontier between the red and white pulp is defined as the marginal zone and contains the marginal zone B cells. Because B cells, localized in different areas, are characterized by distinct expression levels of B-cell receptor (BCR) and other surface markers, splenic B-cell subsets can be easily identified and purified by flow cytometry analyses and cell sorting (FACS).Here, we will focus on marginal zone B cells and their precursors giving some experimental hints to identify, generate, and isolate these cells. We will combine the use of FACS analysis and confocal microscopy to visualize marginal zone B cells in cell suspension and tissue sections, respectively. PMID- 25015270 TI - Purification and immune phenotyping of B-1 cells from body cavities of mice. AB - B-1 cells are innate-like lymphocytes that generate natural, polyreactive antibodies with important functions in tissue homeostasis and immune defense. While B-1-cell frequencies in secondary lymphoid tissues are low, relative high frequencies are found within peritoneal and pleural cavities of mice, including both CD5(+) B-1a and CD5(-) B-1b cells. They represent reservoirs of B-1 cells that can be activated for migration to lymphoid tissues to secrete antibodies and/or cytokines. Here, we outline efficient methods for the extraction and magnetic isolation of B-1a cells from the peritoneal and pleural cavities and the separation and phenotypic characterization of B-1a and B1-b cells by flow cytometry. PMID- 25015271 TI - Purification and immunophenotypic characterization of murine B10 B cells. AB - Regulatory B10 cells represent a rare CD1d(hi)CD5(+) IL-10-secreting B cell subset in mice which is induced to produce IL-10 after 5 h of in vitro stimulation with a combination of B cell mitogen and chemical stimulants. Although B10 cells only constitute 1-2 % of splenic CD19(+) B cells, they play important roles in controlling T cell-mediated immune responses in an antigen specific and IL-10-dependent manner. The regulatory effects of B10 cells have been demonstrated in multiple mouse models of inflammatory and autoimmune diseases. Herein, we described current methods for identification and purification of CD1d(hi)CD5(+) B10 cells. PMID- 25015272 TI - Purification and immunophenotypic characterization of human B cells with regulatory functions. AB - The analysis of human B cell populations of the blood relies on the expression of surface markers, mainly CD19, CD24, CD38, and CD27. According to these surface markers, three main B cell subsets can be identified in the blood: immature transitional B cells (CD19(+)CD24(high)CD38(high)), naive B cells (CD19(+)CD24(int)CD38(int)) that have not encountered an antigen, and memory B cells (CD19(+)CD27(+)). To date, human B cells with regulatory functions have been essentially described within the CD24(high)CD38(high) transitional B cell subset. CD24(high)CD38(high) transitional B cells are able to produce interleukin 10 (IL-10) and to regulate in vitro Th1 and Th17 CD4(+) T cell activation. Here, we provide the methods to analyze and purify the CD24(high)CD38(high) transitional B cell subset for further in vitro experiments. We also provide a reliable method to detect B cell IL-10 production using intracellular cytokine staining. PMID- 25015273 TI - IL-10 detection in murine B cells: pros and cons of the different techniques. AB - With the recently increased understanding of the roles of B cells in immune response and autoimmune pathogenesis, various techniques have been used for the detection of IL-10 production in B cells. In this chapter, we describe several commonly used methods for the effective detection of IL-10 in B cells at both mRNA and protein levels, including quantitative PCR analysis, intracellular staining of IL-10 by flow cytometry, ELISA assay for secreted IL-10 detection, and ELISPOT assay of enumerating IL-10-producing B cells. Moreover, we provide a detailed protocol for the detection of IL-10-producing B cells in situ by immunofluorescence microscopy. Together, the application of these described methods for the detection of IL-10 will facilitate the characterization of B cell subsets with regulatory functions and enhance our current understanding on the critical roles of B cells in immune response and autoimmune development. PMID- 25015275 TI - Characterization and activity of Fas ligand producing CD5+ B cells. AB - B lymphocytes make several contributions to immune regulation including production of antibodies with regulatory properties, release of immune suppressive cytokines, and expression of death-inducing ligands. A role for Fas ligand (FasL)-expressing "killer" B cells in regulating T helper cell survival and chronic inflammation has been demonstrated in animal models of schistosome worm infection, asthma, and autoimmune arthritis. Interestingly, a population of CD5(+) B cells found in the spleen and lungs of naive mice constitutively expresses FasL and has potent killer function against T helper cells that is antigen-specific and FasL-dependent. Killer B cells therefore represent a novel target for immune modulation in many disease settings. Our laboratory has recently published methods of characterizing FasL(+) B cells and inducing their proliferation in vitro. This chapter will describe detailed methods of identifying and expanding killer B cells from mice, detecting FasL expression in B cells, and performing functional killing assays against antigen-specific TH cells. PMID- 25015274 TI - TGF-beta detection and measurement in murine B cells: pros and cons of the different techniques. AB - Recent studies have demonstrated the importance of regulatory B cells in autoimmune, allergic, and inflammatory diseases. These B cells have an ability to suppress excessive immune reactions by multiple mechanisms. Most studies have focused on IL-10-producing B cells, but we have previously reported that transforming growth factor (TGF)-beta1 secretion by B cells also plays an important role in intestinal homeostasis and mucosal inflammation. B cell secreted TGF-beta may be involved in the regulation of T cell immunity (differentiation, proliferation, and apoptosis) that is relevant to the pathogenesis of autoimmune or inflammatory disease. Here, we provide detailed instruction for detecting and measuring TGF-beta produced by B cells. PMID- 25015276 TI - Utilization of a lentiviral system for the generation of B cells with regulatory properties. AB - B cells are classically considered for their unique capacity to produce antibodies. Besides this, B cells can also present antigen, costimulate T cells, and secrete cytokines. Recent studies have demonstrated that activated B cells could regulate immunity by the secretion of anti-inflammatory cytokines. Because of their capacity to inhibit immune responses, B cells became of interest as a potential vehicle for the treatment of autoimmune disorders via cell-based therapy. Different approaches have been developed to empower B cells with regulatory properties. An attractive strategy involves their genetic engineering to enforce their expression of suppressive genes. This can be achieved using retroviral vectors. However, most retroviral vectors require prior activation of the B cells for transduction, and the administration of activated B cells may lead to unpredictable outcomes in recipients, including to an enhancement of immune responses. In contrast, resting B cells are poorly immunogenic and therefore safer for the suppression of undesired immune responses in adoptive cell therapy. In this chapter, we describe an approach to generate genetically modified resting B cells with lentiviral vectors using a protocol that is rapid, simple, and neither requires nor induces activation of B cells. PMID- 25015277 TI - Ex vivo generation of murine IL-10-producing B cells by fusokines. AB - Naive B cells are crucial components of adaptive immunity. In addition to their capacity to produce immunoglobulins, a minor subset termed regulatory B cells or Bregs has been proven to modulate inflammation through the secretion of soluble mediators. The two main technical difficulties with their clinical use lie in their relatively low abundance in vivo and the scarcity of known methods for their ex vivo expansion. While studying the pharmacological properties of a novel bifunctional granulocyte macrophage-colony-stimulating factor (GM-CSF) and IL-15 fusion transgene (GIFT15) on unfractionated splenocytes in vitro, we observed that the GIFT15 fusokine had a remarkable and unprecedented effect on naive B cells by converting them into suppressor cells of B-cell ontogeny (hereafter referred to as GIFT15 inducible (i)Bregs). Moreover, GIFT15 promoted iBreg proliferation. We present in this report a detailed protocol using the GIFT15 fusokine as a tool for the ex vivo generation of murine iBregs, which may serve as an immediate remedy to their abundance challenge in the clinic. PMID- 25015278 TI - Toll-like receptor ligation for the induction of regulatory B cells. AB - Toll-like receptors (TLRs) are key components for the recognition of microorganisms, for the initiation of innate immunity, and for promoting adaptive immune responses. TLR signaling in B cells, in addition to B cell receptor or CD40 ligation, plays an important role in B cell differentiation and activation. In contrast, various infectious agents and/or TLR ligands can also prime B cells to induce tolerance and downregulate inflammatory reactions; those B cells are called regulatory B (Breg) cells and are characterized by a dominant IL-10 production. Several studies have suggested that Breg cells are impaired in patients with autoimmune diseases and allergic asthma. However, the role for TLR ligands in the induction of Breg cells as a potential therapy for some of these inflammatory diseases has not yet been investigated. Here, we provide detailed instructions on how to analyze and validate cytokine production in human and mouse B cells in response to various TLR ligands. Furthermore, we describe an assay to investigate the suppressive properties of TLR-induced B cells to confirm their regulatory B cell status. PMID- 25015279 TI - The generation of regulatory B cells by helminth parasites. AB - The activation of B cells by pathogens to elicit antibody production is a central facet of immunity. Pathogens also evoke the expansion of B cells that can function in the regulation of immunity. Different pathogens have been described with the capacity to drive such regulatory B (Breg) cells. One group of pathogens, parasitic helminths, has been used experimentally to identify and explore immunological mechanisms of Breg cells. Several species of helminths have demonstrated the capacity to expand Breg cell populations in mice, while the presence of Breg cells in humans infected with certain helminths has also been identified. Herein, we outline how the helminth Schistosoma mansoni can expand Breg cellular responses in vitro. We describe the establishment of a laboratory based S. mansoni life cycle and methodology for detecting Breg cells via flow cytometry. PMID- 25015280 TI - Use of cocultures for the study of cellular interactions influencing B cell regulatory functions. AB - Many immunological processes are contextually controlled by complex interactions among different cell types. Several studies have shown that B cells produce the immune regulatory cytokine IL-10 in response to different external stimuli but also to immune-mediated signals. Endogenous signals that derive from the cross talk between B lymphocytes and other cells of the immune system can affect IL-10 production by B cells in both physiological and pathological conditions. With the aim to provide a guide for the study of how partner cells can induce IL-10 producing B cells, here we describe the protocols to investigate IL-10 production at a single cell level in a dendritic cell-B cell coculture in vitro system. These methods are a proof of concept that can be easily extrapolated and adapted to the study of the interaction between B cells and other immune cell types. PMID- 25015281 TI - Regulatory B cells in experimental mouse models of arthritis. AB - Regulatory B cells (Bregs) have been shown to play a role in the suppression of a wide variety of immune responses. For the study of autoimmune inflammation, experimental models of arthritis have acted as a valuable tool in understanding the function of Bregs in maintaining immune homeostasis. In this chapter, we will focus on the study of transitional-2 marginal zone precursor Bregs (T2-MZPs) in the context of two experimental arthritis models: antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA). We will specifically focus on how to induce arthritis as well as methods for the isolation and functional study of Bregs both in vitro and in vivo. PMID- 25015282 TI - Regulatory B cells in mouse models of systemic lupus erythematosus (SLE). AB - Regulatory B cells are now recognized as an essential component of the immune system. The function of regulatory B cells is dependent on IL-10. The cell surface phenotype of murine IL-10-producing regulatory B cells is reported to be CD1d(hi)CD5(+) B cell or CD21(hi)CD23(hi) T2 marginal zone precursor B cells. B cells play several critical roles in the pathogenesis of systemic lupus erythematosus (SLE). It is now apparent that regulatory B cells are important for disease suppression in SLE. Regulatory B cells inhibit disease onset of NZB/W F1 mice, a spontaneous SLE mouse model. Furthermore, the potential therapeutic effect of regulatory B cells in NZB/W F1 mice is highlighted by the adoptive transfer of splenic CD1d(hi)CD5(+) B cells. Regulatory B cells also suppress the disease manifestation in MRL-Fas(lpr) mice, a SLE mouse model. Thus, regulatory B cells have protective role and therapeutic effects in mouse modes of SLE. Herein, the methods for evaluating SLE mouse model, B-cell depletion, and regulatory B cell analysis are provided. These methods should facilitate the study of regulatory B cells in SLE. PMID- 25015283 TI - Regulatory B cells in allergic airways disease and asthma. AB - B cells have long been known to participate in both innate and adaptive immune responses by contributing to antigen presentation and by producing antigen specific antibodies. Recent evidence shows that certain B-cell subsets can also inhibit T-cell immune responses. Like regulatory T cells (Treg), these regulatory B cells (Breg) appear to comprise several subpopulations. How Breg cells are generated and how they control immune responses in vivo are just beginning to be elucidated. Here, we provide detailed instructions for the identification, isolation, and functional characterization of Breg cells in a murine model of allergic airway disease. PMID- 25015284 TI - Regulatory B cells in mouse models of intestinal inflammation. AB - Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition with increasing incidence and prevalence around the world. Although B cells had generally been believed to play a pathogenic role in IBD due to the production of autoantibodies, a growing body of evidence from mouse models suggests the coexistence of pathogenic B cells and regulatory B cells, termed Breg, in this disorder. Since some unique techniques are required to closely study the Breg in gut-associated lymphoid tissues (GALT), we herein describe how to induce colitis in mice and how to analyze the phenotype and function of GALT-specific Breg. PMID- 25015285 TI - Regulatory B cells in experimental autoimmune encephalomyelitis (EAE). AB - B cells are thought to play a pathogenic role in multiple sclerosis (MS), an autoimmune disease affecting the central nervous system (CNS). This idea is supported by the reduction of disease in MS patients undergoing antibody-mediated B cell depletion therapy. In contrast, in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, B cells have been shown to play a regulatory role. This is suggestive of a dual role for B cells in CNS autoimmunity. It is possible that a critical balance between the pathogenic and regulatory populations of B cells might be involved in the manifestation of the disease. Although in mice, different B cell subsets have been shown to exert immunoregulation through varied mechanisms, the phenotype of regulatory B cells in humans and factors affecting their function are not well known. Also, the origin and development of regulatory B cells is not known. It is important to thoroughly identify the different populations of B cells that might be involved in suppressing CNS autoimmunity, their mode of function and factors that regulate their immunosuppressive properties for using regulatory B cells as a therapy for MS. Here we present methods to study the phenotype and mechanisms of immune suppression by B cells in different mouse models of EAE. PMID- 25015286 TI - Regulatory B cells, helminths, and multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Autoimmunity appears to play a key role in both susceptibility to MS and development of disease, and pathogenesis has been linked to defects in distinct regulatory cell subsets. B cells are known for their capacity to produce antibodies. Recent advances in B cell biology, however, have demonstrated that regulatory B cells, a functional subset of B cells, contribute to tolerance development. Regulatory B cells were originally described in mouse autoimmunity and inflammation models where they dampen inflammation, but have also been found in several helminth infection models. We recently demonstrated that helminth-infected MS patients show a significantly lower clinical and radiological disease activity. Parasite-driven protection was associated with regulatory T cell induction and secretion of suppressive cytokines such as IL-10 and TGF-beta. In addition, helminth infections in MS patients induced regulatory B cell populations producing high levels of IL-10, dampening harmful immune responses through a mechanism mediated, at least in part, by the ICOS-B/RP-1 pathway. More importantly, production of IL-10 by B cells in this study was restricted to helminth-infected individuals exclusively.The first part of this chapter will detail the criteria used in this study for selection of helminth infected MS patients, MS patients without infection, and patients infected with Trypanosoma cruzi. Methods for isolation of peripheral blood CD19(+) cells and in particular for their stimulation with heat-inactivated Staphylococcus aureus Cowan strain, CDw32L cells, and CD40 antibody will also be described in detail. Finally, we will illustrate the procedures used to analyze phenotypic surface markers on these cells and characterize them in terms of IL-4, IL-6, IL-10, TNF alpha, lymphotoxin, and TGF-beta secretion. PMID- 25015287 TI - Generation and identification of tumor-evoked regulatory B cells. AB - The involvement of Bregs in cancer remains poorly understood despite their well documented regulation of responses to the self and protection from harmful autoimmunity. We recently discovered a unique regulatory B cell subset evoked by breast cancer to mediate protection of metastasizing cancer cells. These results together with the wealth of findings of the last 40 years on B cells in tumorigenesis suggest the existence of additional cancer Bregs modulating anticancer responses. To facilitate the search for them, here we provide our detailed protocol for the characterization and generation of tumor-evoked regulatory B cells. Wherever applicable, we also discuss nuances and uniqueness of a Breg study in cancer to warn potential pitfalls. PMID- 25015289 TI - Proteomic analysis reveals a FANCA-modulated neddylation pathway involved in CXCR5 membrane targeting and cell mobility. AB - The aim of this study was to identify novel substrates of the FANCcore complex, the inactivation of which leads to the genetic disorder Fanconi anemia, which is associated with bone marrow failure, developmental abnormalities and a predisposition to cancer. Eight FANC proteins participate in the nuclear FANCcore complex, which functions as an E3 ubiquitin-ligase that monoubiquitylates FANCD2 and FANCI in response to replicative stress. Here, we use mass spectrometry to compare proteins from FANCcore-complex-deficient cells to those of rescued control cells after treatment with hydroxyurea, an inducer of FANCD2 monoubiquitylation. FANCD2 and FANCI appear to be the only targets of the FANCcore complex. We identify other proteins that are post-translationally modified in a FANCA- or FANCC-dependent manner. The majority of these potential targets localize to the cell membrane. Finally, we demonstrate that (a) the chemokine receptor CXCR5 is neddylated; (b) FANCA but not FANCC appears to modulate CXCR5 neddylation through an unknown mechanism; (c) CXCR5 neddylation is involved in targeting the receptor to the cell membrane; and (d) CXCR5 neddylation stimulates cell migration and motility. Our work has uncovered a pathway involving FANCA in neddylation and cell motility. PMID- 25015288 TI - E(y)1/TAF9 mediates the transcriptional output of Notch signaling in Drosophila. AB - Transcriptional activation of Notch signaling targets requires the formation of a ternary complex that involves the intracellular domain of the Notch receptor (NICD), DNA-binding protein Suppressor of Hairless [Su(H), RPBJ in mammals] and coactivator Mastermind (Mam). Here, we report that E(y)1/TAF9, a component of the transcription factor TFIID complex, interacts specifically with the NICD-Su(H) Mam complex to facilitate the transcriptional output of Notch signaling. We identified E(y)1/TAF9 in a large-scale in vivo RNA interference (RNAi) screen for genes that are involved in a Notch-dependent mitotic-to-endocycle transition in Drosophila follicle cells. Knockdown of e(y)1/TAF9 displayed Notch-mutant-like phenotypes and defects in target gene and activity reporter expression in both the follicle cells and wing imaginal discs. Epistatic analyses in these two tissues indicated that E(y)1/TAF9 functions downstream of Notch cleavage. Biochemical studies in S2 cells demonstrated that E(y)1/TAF9 physically interacts with the transcriptional effectors of Notch signaling Su(H) and NICD. Taken together, our data suggest that the association of the NICD-Su(H)-Mastermind complex with E(y)1/TAF9 in response to Notch activation recruits the transcription initiation complex to induce Notch target genes, coupling Notch signaling with the transcription machinery. PMID- 25015290 TI - CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer. AB - Chloride intracellular channel 3 (CLIC3) drives invasiveness of pancreatic and ovarian cancer by acting in concert with Rab25 to regulate the recycling of alpha5beta1 integrin from late endosomes to the plasma membrane. Here, we show that in two estrogen receptor (ER)-negative breast cancer cell lines, CLIC3 has little influence on integrin recycling, but controls trafficking of the pro invasive matrix metalloproteinase MT1-MMP (also known as MMP14). In MDA-MB-231 cells, MT1-MMP and CLIC3 are localized primarily to late endosomal/lysosomal compartments located above the plane of adhesion and near the nucleus. MT1-MMP is transferred from these late endosomes to sites of cell-matrix adhesion in a CLIC3 dependent fashion. Correspondingly, CLIC3-knockdown opposes MT1-MMP-dependent invasive processes. These include the disruption of the basement membrane as acini formed from MCF10DCIS.com cells acquire invasive characteristics in 3D culture, and the invasion of MDA-MB-231 cells into Matrigel or organotypic plugs of type I collagen. Consistent with this, expression of CLIC3 predicts poor prognosis in ER-negative breast cancer. The identification of MT1-MMP as a cargo of a CLIC3-regulated pathway that drives invasion highlights the importance of late endosomal sorting and trafficking in breast cancer. PMID- 25015292 TI - Chk1 protects against chromatin bridges by constitutively phosphorylating BLM serine 502 to inhibit BLM degradation. AB - Chromatin bridges represent incompletely segregated chromosomal DNA connecting the anaphase poles and can result in chromosome breakage. The Bloom's syndrome protein helicase (BLM, also known as BLMH) suppresses formation of chromatin bridges. Here, we show that cells deficient in checkpoint kinase 1 (Chk1, also known as CHEK1) exhibit higher frequency of chromatin bridges and reduced BLM protein levels compared to controls. Chk1 inhibition leads to BLM ubiquitylation and proteasomal degradation during interphase. Furthermore, Chk1 constitutively phosphorylates human BLM at serine 502 (S502) and phosphorylated BLM localises to chromatin bridges. Mutation of S502 to a non-phosphorylatable alanine residue (BLM-S502A) reduces the stability of BLM, whereas expression of a phospho mimicking BLM-S502D, in which S502 is mutated to aspartic acid, stabilises BLM and prevents chromatin bridges in Chk1-deficient cells. In addition, wild-type but not BLM-S502D associates with cullin 3, and cullin 3 depletion rescues BLM accumulation and localisation to chromatin bridges after Chk1 inhibition. We propose that Chk1 phosphorylates BLM-S502 to inhibit cullin-3-mediated BLM degradation during interphase. These results suggest that Chk1 prevents deleterious anaphase bridges by stabilising BLM. PMID- 25015291 TI - Interaction of SQSTM1 with the motor protein dynein--SQSTM1 is required for normal dynein function and trafficking. AB - The dynein motor protein complex is required for retrograde transport of vesicular cargo and for transport of aggregated proteins along microtubules for processing and degradation at perinuclear aggresomes. Disruption of this process leads to dysfunctional endosome accumulation and increased protein aggregation in the cell cytoplasm, both pathological features of neurodegenerative diseases. However, the exact mechanism of dynein functionality in these pathways is still being elucidated. Here, we show that the scaffolding protein SQSTM1 directly interacts with dynein through a previously unidentified dynein-binding site. This interaction is independent of HDAC6, a known interacting protein of both SQSTM1 and dynein. However, knockdown of HDAC6 increases the interaction of SQSTM1 with dynein, indicating a possible competitive interaction. Using different dynein cargoes, we show that SQSTM1 is required for proper dynein motility and trafficking along microtubules. Based on our results, we propose a new model of competitive interaction between SQSTM1 and HDAC6 with dynein. In this model, SQSTM1 would not only affect the association of polyubiquitylated protein aggregates and endosomes with dynein, but would also be required for normal dynein function. PMID- 25015293 TI - Septin ring assembly is regulated by Spt20, a structural subunit of the SAGA complex. AB - Accurate cell division requires the proper assembly of high-order septin structures. In fission yeast (Schizosaccharomyces pombe), Spn1-Spn4 are assembled into a primary septin ring at the division site, and the subsequent recruitment of Mid2 to the structure results in a stable septin ring. However, not much is known about the regulation of this key process. Here, we found that deletion of Spt20, a structural subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional activation complex, caused a severe cell separation defect. The defect was mainly due to impaired septin ring assembly, as 80% of spt20Delta cells lost septin rings at the division sites. Spt20 regulates septin ring assembly partially through the transcriptional activation of mid2(+). Spt20 also interacted with Spn2 and Mid2 in vitro and was associated with other components of the ring in vivo. Spt20 colocalized with the septin ring, but did not separate when the septin ring split. Importantly, Spt20 regulated the stability of the septin ring and was required for the recruitment of Mid2. The transcription dependent and -independent roles of Spt20 in septin ring assembly highlight a multifaceted regulation of one process by a SAGA subunit. PMID- 25015294 TI - Divergent and convergent roles for kinases and phosphatases in neurofilament dynamics. AB - C-terminal neurofilament phosphorylation mediates cation-dependent self association leading to neurofilament incorporation into the stationary axonal cytoskeleton. Multiple kinases phosphorylate the C-terminal domains of the heavy neurofilament subunit (NF-H), including cyclin-dependent protein kinase 5 (CDK5), mitogen-activated protein kinases (MAPKs), casein kinase 1 and 2 (CK1 and CK2) and glycogen synthase kinase 3beta (GSK3beta). The respective contributions of these kinases have been confounded because they phosphorylate multiple substrates in addition to neurofilaments and display extensive interaction. Herein, differentiated NB2a/d1 cells were transfected with constructs expressing GFP tagged NF-H, isolated NF-H sidearms and NF-H lacking the distal-most 187 amino acids. Cultures were treated with roscovitine, PD98059, Li(+), D4476, tetrabromobenzotriazole and calyculin, which are active against CDK5, MKK1 (also known as MAP2K1), GSK3beta, CK1, CK2 and protein phosphatase 1 (PP1), respectively. Sequential phosphorylation by CDK5 and GSK3beta mediated the neurofilament-neurofilament associations. The MAPK pathway (i.e. MKK1 to ERK1/2) was found to downregulate GSK3beta, and CK1 activated PP1, both of which promoted axonal transport and restricted neurofilament-neurofilament associations to axonal neurites. The MAPK pathway and CDK5, but not CK1 and GSK3beta, inhibited neurofilament proteolysis. These findings indicate that phosphorylation of neurofilaments by the proline-directed MAPK pathway and CDK5 counterbalance the impact of phosphorylation of neurofilaments by the non-proline-directed CK1 and GSK3beta. PMID- 25015295 TI - Rho/ROCK pathway inhibition by the CDK inhibitor p27(kip1) participates in the onset of macrophage 3D-mesenchymal migration. AB - Infiltration of macrophages into tissue can promote tumour development. Depending on the extracellular matrix architecture, macrophages can adopt two migration modes: amoeboid migration--common to all leukocytes, and mesenchymal migration- restricted to macrophages and certain tumour cells. Here, we investigate the initiating mechanisms involved in macrophage mesenchymal migration. We show that a single macrophage is able to use both migration modes. Macrophage mesenchymal migration is correlated with decreased activity of Rho/Rho-associated protein kinase (ROCK) and is potentiated when ROCK is inhibited, suggesting that amoeboid inhibition participates in mechanisms that initiate mesenchymal migration. We identify the cyclin-dependent kinase (CDK) inhibitor p27(kip1) (also known as CDKN1B) as a new effector of macrophage 3D-migration. By using p27(kip1) mutant mice and small interfering RNA targeting p27(kip1), we show that p27(kip1) promotes mesenchymal migration and hinders amoeboid migration upstream of the Rho/ROCK pathway, a process associated with a relocation of the protein from the nucleus to the cytoplasm. Finally, we observe that cytoplasmic p27(kip1) is required for in vivo infiltration of macrophages within induced tumours in mice. This study provides the first evidence that silencing of amoeboid migration through inhibition of the Rho/ROCK pathway by p27(kip1) participates in the onset of macrophage mesenchymal migration. PMID- 25015297 TI - Why do green rods of frog and toad retinas look green? AB - Amphibian "green" rods express a blue-sensitive cone visual pigment, and should look yellow. However,when observing them axially under microscope one sees them as green. We used single-cell microspectrophotometry (MSP) to reveal the basis of the perceived color of these photoreceptors. Conventional side-on MSP recording of the proximal cell segments reveals no selective longwave absorbing pigment explaining the green color. End-on MSP recording shows, in addition to the green rod visual pigment, an extra 2- to 4-fold attenuation being almost flat throughout the visible spectrum. This attenuation is absent in red (rhodopsin) rods, and vanishes in green rods when the retina is bathed in high-refractive media, and at wide illumination aperture. The same treatments change the color from green to yellow. It seems that the non-visual pigment attenuation is a result of slender green rod myoids operating as non-selective light guides. We hypothesize that narrow myoids, combined with photomechanical movements of melanin granules, allow a wide range of sensitivity regulation supporting the operation of green rods as blue receptors at mesopic-to low-photopic illumination levels.End-on transmittance spectrum of green rods looks similar to the reflectance spectrum of khaki military uniforms. So their greenness is the combined result of optics and human color vision. PMID- 25015296 TI - TRIM15 is a focal adhesion protein that regulates focal adhesion disassembly. AB - Focal adhesions are macromolecular complexes that connect the actin cytoskeleton to the extracellular matrix. Dynamic turnover of focal adhesions is crucial for cell migration. Paxillin is a multi-adaptor protein that plays an important role in regulating focal adhesion dynamics. Here, we identify TRIM15, a member of the tripartite motif protein family, as a paxillin-interacting factor and a component of focal adhesions. TRIM15 localizes to focal contacts in a myosin-II-independent manner by an interaction between its coiled-coil domain and the LD2 motif of paxillin. Unlike other focal adhesion proteins, TRIM15 is a stable focal adhesion component with restricted mobility due to its ability to form oligomers. TRIM15 depleted cells display impaired cell migration and reduced focal adhesion disassembly rates, in addition to enlarged focal adhesions. Thus, our studies demonstrate a cellular function for TRIM15 as a regulatory component of focal adhesion turnover and cell migration. PMID- 25015299 TI - The Dendritic Differentiation of Purkinje Neurons: Unsolved Mystery in Formation of Unique Dendrites. PMID- 25015298 TI - Quantification of biological network perturbations for mechanistic insight and diagnostics using two-layer causal models. AB - BACKGROUND: High-throughput measurement technologies such as microarrays provide complex datasets reflecting mechanisms perturbed in an experiment, typically a treatment vs. control design. Analysis of these information rich data can be guided based on a priori knowledge, such as networks or set of related proteins or genes. Among those, cause-and-effect network models are becoming increasingly popular and more than eighty such models, describing processes involved in cell proliferation, cell fate, cell stress, and inflammation have already been published. A meaningful systems toxicology approach to study the response of a cell system, or organism, exposed to bio-active substances requires a quantitative measure of dose-response at network level, to go beyond the differential expression of single genes. RESULTS: We developed a method that quantifies network response in an interpretable manner. It fully exploits the (signed graph) structure of cause-and-effect networks models to integrate and mine transcriptomics measurements. The presented approach also enables the extraction of network-based signatures for predicting a phenotype of interest. The obtained signatures are coherent with the underlying network perturbation and can lead to more robust predictions across independent studies. The value of the various components of our mathematically coherent approach is substantiated using several in vivo and in vitro transcriptomics datasets. As a proof-of-principle, our methodology was applied to unravel mechanisms related to the efficacy of a specific anti-inflammatory drug in patients suffering from ulcerative colitis. A plausible mechanistic explanation of the unequal efficacy of the drug is provided. Moreover, by utilizing the underlying mechanisms, an accurate and robust network-based diagnosis was built to predict the response to the treatment. CONCLUSION: The presented framework efficiently integrates transcriptomics data and "cause and effect" network models to enable a mathematically coherent framework from quantitative impact assessment and data interpretation to patient stratification for diagnosis purposes. PMID- 25015300 TI - Association between polymorphism of TGFA Taq I and cleft lip and/or palate: a meta-analysis. AB - BACKGROUND: Cleft lip and palate (CL/P) is one of the most common malformations in humans. Transforming growth factor alpha (TGFA) is a well characterized mammalian growth factor which might contribute to the development of CL/P. This meta-analysis aimed to summarize the association between the TGFA Taq I polymorphisms and CL/P. METHODS: We retrieved the relevant articles from PubMed, EMBASE, ISI Web of Science and SCOPUS databases. Studies were selected using specific inclusion and exclusion criteria. The odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated to assess the association between TGFA Taq I polymorphism and CL/P risk. Meta-analyses were performed on the total data set and separately for the major ethnic groups, disease type and source of control. All analyses were performed using the Stata software. RESULTS: Twenty articles were included in the present analysis. There is a significant association between the TGFA Taq I polymorphism and CL/P (C1C2 vs C1C1: OR = 1.67, 95% CI = 1.23-2.25, C2C2 + C1C2 vs C1C1C1: OR = 1.52, 95% CI = 1.15-2.01; C2 vs C1:OR = 1.41, 95% CI = 1.12-1.78). Stratified analyses suggested that the TGFA Taq I polymorphism was significantly associated with CL/P in Caucasians (C1C2 vs C1C1: OR = 1.95, 95% CI = 1.34-2.86; C2C2 + C1C2 vs C1C1: OR = 1.68, 95% CI = 1.18-2.38; C2 vs V1: OR = 1.52, 95% CI = 1.14 -2.02). CONCLUSION: TGFA Taq I polymorphism may be associated with the risk of CL/P. PMID- 25015302 TI - Intravenous versus Subcutaneous Drug Administration. Which Do Patients Prefer? A Systematic Review. AB - BACKGROUND: Intravenous (IV) drug delivery is commonly used for its rapid administration and immediate drug effect. Most studies compare IV to subcutaneous (SC) delivery in terms of safety and efficacy, but little is known about what patients prefer. METHODS: A systematic review was conducted by searching seven electronic databases for articles published up to February 2014. Included studies were randomized controlled trials (RCTs) and/or crossover designs investigating patient preference for SC versus IV administration. The risk of bias in the RCTs was determined using the Cochrane Collaboration tool. Reviewers independently extracted data and assessed the risk of bias. Any discrepancies were resolved by consensus. RESULTS: The search identified 115 publications, but few (6/115) met the inclusion criteria. Patient populations and drugs investigated were diverse. Four of six studies demonstrated a clear patient preference for SC administration. Main factors associated with SC preference were time saving and the ability to have treatment at home. Only three studies used study-specific instruments to measure preference. CONCLUSIONS: Results suggest that patients prefer SC over IV delivery. Patient preference has clearly been neglected in clinical research, but it is important in medical decision making when choosing treatment methods as it has implications for adherence and quality of life. If the safety and efficacy of both administration routes are equivalent, then the most important factor should be patient preference as this will ensure optimal treatment adherence and ultimately improve patient experience or satisfaction. Future drug efficacy and safety studies should include contemporaneous, actual patient preference where possible, utilizing appropriate measures. PMID- 25015301 TI - Management of refractory OAB in the non-neurogenic patient. AB - Overactive bladder (OAB) is one of the most common bothersome urological diseases. It also has a negative economic impact. Pathophysiology entails changes in neurogenic and myogenic factors, as well as urinary biomarkers such as nerve growth factor (NGF) and prostaglandins (PGs). With symptoms from OAB-Dry to OAB Wet, the urodynamic pattern of OAB bladder is often characterized by idiopathic detrusor overactivity with lower threshold of sensation, diminished compliance and capacity. Treatment ranges from a combination of behavioral modifications (BM)/ pelvic floor muscle training (PFMT) to combinations of antimuscarinics, Botox injection, nerve stimulation and augmentation cystoplasty. Herein, a contemporary review on the different aspects of management of refractory OAB in patients without neuropathic disorders is presented. PMID- 25015303 TI - The severity of attention deficit hyperactivity symptoms and its relationship with lifetime substance use and psychological variables among 10th grade students in Istanbul. AB - AIM: The aim of this study was to determine the severity of attention deficit hyperactivity symptoms (ADHS) and related psychological and behavioral variables among 10th grade students in Istanbul/Turkey. METHODS: Cross-sectional online self-report survey conducted in 45 schools in 15 districts Istanbul. The questionnaire included sections about demographic data and use of substances including tobacco, alcohol and drugs. Also ADHS, depression, anxiety, anger and sensation seeking subscales of Psychological Screening Test for Adolescents (PSTA) were used. The analyses were conducted based on the 4938 subjects. RESULTS: Mean ADHS score was higher in females and among those with a lifetime use of tobacco, alcohol and drug, and having self-harming behavior and suicidal thoughts. ADHS score was correlated with depression, anxiety, anger and sensation seeking scores. In univariate covariance analysis (ANCOVA); depression, anxiety, anger, sensation seeking, lifetime alcohol use and suicidal thoughts predicted the severity of ADHS. CONCLUSIONS: The findings suggest that, since ADHS is associated with depression, anxiety, anger, sensation seeking, lifetime alcohol use and suicidal thoughts among 10th grade students, clinicians should screen suicidality and comorbid psychiatric symptoms routinely in adolescents with ADHS. PMID- 25015304 TI - The association of Internet addiction symptoms with anxiety, depression and self esteem among adolescents with attention-deficit/hyperactivity disorder. AB - BACKGROUND: The aims of this study were to examine the associations of the severity of Internet addiction symptoms with various dimensions of anxiety (physical anxiety symptoms, harm avoidance, social anxiety, and separation/panic) and depression symptoms (depressed affect, somatic symptoms, interpersonal problems, and positive affect) and self-esteem among adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD) in Taiwan. METHOD: A total of 287 adolescents aged between 11 and 18 years who had been diagnosed with ADHD participated in this study. Their severity of Internet addiction symptoms was assessed using the Chen Internet Addiction Scale. Anxiety and depression symptoms and self-esteem were assessed using the Taiwanese version of the Multidimensional Anxiety Scale for Children (MASC-T), the Center for Epidemiological Studies Depression Scale (CES-D), and the Rosenberg Self-Esteem Scale (RSES), respectively. The association between the severity of Internet addiction symptoms and anxiety and depression symptoms and self-esteem were examined using multiple regression analyses. RESULTS: The results indicated that higher physical symptoms and lower harm avoidance scores on the MASC-T, higher somatic discomfort/retarded activity scores on the CES-D, and lower self-esteem scores on the RSES were significantly associated with more severe Internet addiction symptoms. CONCLUSIONS: Prevention and intervention programs for Internet addiction in adolescents with ADHD should take anxiety, depression, and self-esteem into consideration. PMID- 25015305 TI - Anomalous union of the pancreaticobiliary duct without choledochal cyst: is cholecystectomy alone sufficient? AB - PURPOSE: Anomalous union of the pancreaticobiliary duct (AUPBD) is frequently associated with choledochal cyst and biliary tract cancers. Management of AUPBD with choledochal cyst consists of extrahepatic bile duct excision and cholecystectomy. In cases of AUPBD without choledochal cyst, cholecystectomy alone is usually recommended.This study aimed to evaluate the occurrence of biliary tract cancer in AUPBD patients in order to assess the validity of the currently recommended operative management. METHODS: Of a total of 10,255 endoscopic retrograde cholangiopancreatography cases performed at two Korea University hospitals from 2001 to 2010, 55 (0.54 %) cases of AUPBD were identified. Patients with AUPBD were divided according to its subtype (P-C union and C-P union) and the presence of choledochal cyst for analysis. The occurrence of benign and malignant disease was evaluated and compared between the groups. RESULTS: Gallbladder stones were more frequently found in AUPBD patients without choledochal cyst (p=0.032). Biliary tract cancer occurred more frequently in P-C union (p=0.050),especially the common bile duct cancer (p=0.023). When analyzed according to the presence of choledochal cyst, biliary tract cancer occurred more frequently in AUPBD patients without choledochal cyst (p=0.005), with bile duct cancer being significantly more common (p=0.015). However, there was no difference in the presence of gallbladder cancer between the two groups (p=0.318). CONCLUSIONS: Since cancers of the biliary tract occur more frequently in the AUPBD group without choledochal cyst,cholecystectomy alone may not be protective of the future occurrence of bile duct cancers, and thus, vigilant surveillance is necessary in this population group. PMID- 25015306 TI - [A parotid abscess caused by Salmonella typhimurium]. PMID- 25015307 TI - Compliance to recommendations for the management of curative treatment of Plasmodium vivax/ovale infections. AB - OBJECTIVES: We assessed the compliance to recommendations for the routine management of Plasmodium vivax/ovale malaria, and analyzed the impact of discrepancies on the quality of care. PATIENTS AND METHODS: We reviewed the cases of P. ovale and P. vivax malaria treated at the Besancon University Hospital, France (2008-2013). RESULTS: Chloroquine was prescribed in 44% of the 18 cases (4 due to P. ovale, 14 to P. vivax). Radical cure with primaquine was prescribed after the first bout of malaria for 6 patients. The primaquine dose prescribed was inferior to the recommended one for 4 patients. The mean delay between schizonticide treatment and primaquine cure was 43 days. CONCLUSIONS: The delay before access to primaquine radical cure was the only parameter, likely to alter treatment effectiveness, but also difficult to shorten. Future national guidelines should take into account that not all patients have access to primaquine treatment immediately after schizonticide treatment. PMID- 25015308 TI - Gastritis due to Helicobacter pylori, an unusual cause of chronic diarrhoea in HIV infected patients. PMID- 25015309 TI - Comparison of hospital databases on antibiotic consumption in France, for a single management tool. AB - CONTEXT: The surveillance of antibiotic use in hospitals and of data on resistance is an essential measure for antibiotic stewardship. There are 3 national systems in France to collect data on antibiotic use: DREES, ICATB, and ATB RAISIN. We compared these databases and drafted recommendations for the creation of an optimized database of information on antibiotic use, available to all concerned personnel: healthcare authorities, healthcare facilities, and healthcare professionals. METHODOLOGY: We processed and analyzed the 3 databases (2008 data), and surveyed users. RESULTS: The qualitative analysis demonstrated major discrepancies in terms of objectives, healthcare facilities, participation rate, units of consumption, conditions for collection, consolidation, and control of data, and delay before availability of results. The quantitative analysis revealed that the consumption data for a given healthcare facility differed from one database to another, challenging the reliability of data collection. We specified user expectations: to compare consumption and resistance data, to carry out benchmarking, to obtain data on the prescribing habits in healthcare units, or to help understand results. CONCLUSIONS: The study results demonstrated the need for a reliable, single, and automated tool to manage data on antibiotic consumption compared with resistance data on several levels (national, regional, healthcare facility, healthcare units), providing rapid local feedback and educational benchmarking. PMID- 25015310 TI - A case of Whipple's disease evolving over 30 years. PMID- 25015311 TI - Flow-preserved coil embolization using a side-holed indwelling catheter for common hepatic artery pseudoaneurysm: report of three cases. AB - We report three cases of hepatic artery pseudoaneurysm, which were all treated successfully using a combination of coil embolization and a side-holed 5F indwelling catheter for maintaining minimal hepatic artery blood flow with exclusion of the pseudoaneurysm. The tip of an infusion catheter was placed in the right hepatic artery and a side hole was positioned at the celiac axis. Coil embolization was then performed from the proper to the common hepatic artery using detachable coils. Hemostasis was achieved in all patients, with a final angiogram showing the hepatic arteries through the indwelling catheter. One major hepatic infarction and one focal liver abscess caused by reflux cholangitis manifested on postoperative days (PODs) 11 and 87, respectively. All patients survived and the indwelling catheter was removed on POD 136-382 without complication. PMID- 25015312 TI - Confronting the Cultural Challenge of the Whiteness of Nursing: Aboriginal Registered Nurses' Perspectives. AB - Abstract This paper presents the findings of a study that that interviewed Aboriginal nurses to explore their experiences of the whiteness of nursing. Despite concerted efforts to improve the health of Aboriginal Australians, it still remains equivalent to third world countries. One strategy to address this that has been identified is to increase the participation rates of Aboriginal registered nurses within the Australian healthcare workforce. Presently Aboriginal nurses account for only a small percentage of the nursing workforce. While there has been research into the recruitment and retention strategies dedicated to improving the numbers of Aboriginal registered nurses, this paper focus on the experiences of Aboriginal registered nurses within Australia's mainstream healthcare system, where they are exposed and subjected on a daily basis to the 'whiteness of nursing'. PMID- 25015313 TI - Asymptomatic adults should not be screened for carotid artery stenosis, US panel concludes. PMID- 25015314 TI - UTP is not a biased agonist at human P2Y(11) receptors. AB - Biased agonism describes a multistate model of G protein-coupled receptor activation in which each ligand induces a unique structural conformation of the receptor, such that the receptor couples differentially to G proteins and other intracellular proteins. P2Y receptors are G protein-coupled receptors that are activated by endogenous nucleotides, such as adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP). A previous report suggested that UTP may be a biased agonist at the human P2Y11 receptor, as it increased cytosolic [Ca2+], but did not induce accumulation of inositol phosphates, whereas ATP did both. The mechanism of action of UTP was unclear, so the aim of this study was to characterise the interaction of UTP with the P2Y11 receptor in greater detail. Intracellular Ca2+ was monitored in 1321N1 cells stably expressing human P2Y11 receptors using the Ca2+-sensitive fluorescent indicator, fluo-4. ATP evoked a rapid, concentration-dependent rise in intracellular Ca2+, but surprisingly, even high concentrations of UTP were ineffective. In contrast, UTP was slightly, but significantly more potent than ATP in evoking a rise in intracellular Ca2+ in 1321N1 cells stably expressing the human P2Y2 receptor, with no difference in the maximum response. Thus, the lack of response to UTP at hP2Y11 receptors was not due to a problem with the UTP solution. Furthermore, coapplying a high concentration of UTP with ATP did not inhibit the response to ATP. Thus, contrary to a previous report, we find no evidence for an agonist action of UTP at the human P2Y11 receptor, nor does UTP act as an antagonist. PMID- 25015315 TI - Clostridium difficile infection in diabetes. AB - Diabetes-related hospitalization and hospital utilization is a serious challenge to the health care system, a situation which may be further aggravated by nosocomial Clostridium difficile (C. difficile) infection (CDI). Studies have demonstrated that diabetes increases the risk of recurrent CDI with OR (95% CI) 2.99 (1.88, 4.76). C. difficile is a gram-positive, spore-forming anaerobic bacterium which is widely distributed in the environment. Up to 7% of healthy adults and up to 45% of infants may have asymptomatic intestinal carriage of C. difficile. A large number of strains of C. difficile have been identified. A number of PCR or sequence-based molecular typing methods are available for typing C. difficile isolates. C. difficile virulence evolved independently in the highly epidemic lineages, associated with the expression of toxin genes and other virulence factors. This article briefly reviews recent progresses in the bateriology of C. difficile and highlights the limited knowledge of potential mechanisms for the increased risk of CDI in diabetes which warrants further research. PMID- 25015316 TI - Effect of glycemic control on intact parathyroid hormone level in end stage renal disease patients on maintenance hemodialysis. AB - AIMS: We evaluated the relationship between iPTH levels and glycemic control in patients with diabetes and end stage renal disease (ESRD) on maintenance hemodialysis (MHD). METHODS: The study included 98 subjects with ESRD and type 2 diabetes aged 30-75 years who were on MHD. These were divided into two groups- patients with HbA1c >7.0 (53 mmol/mol) (poor glycemic control group) and patients with HbA1c <7.0 (53 mmol/mol) (good glycemic control group). All patients had been on regular bicarbonate haemodialysis for more than 6 months using polysulfone membrane dialyzer; 4 h per episode 3 times/week, with a dialysis fluid of 3.0 mEq/L of calcium concentration. 1-alpha-(OH)D3 and calcium carbonate were used routinely in all patients. The contribution of each relevant biological parameter to serum iPTH level was assessed using multiple regression test. RESULTS: Poor glycemic control was associated with reduced serum iPTH level and good glycemic control with higher serum iPTH. The serum HbA1c level was significantly correlated with the serum iPTH level (p=0.0003). CONCLUSIONS: Glycemic control is a significant determinant of iPTH level in diabetic ESRD patients on MHD. PMID- 25015317 TI - Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses. AB - AIMS: In search of add-on treatments to metformin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors are potential candidates. This meta-analysis examines the potential use of SGLT-2 inhibitors in combination with metformin as a therapeutic option for type 2 diabetes management in patients with inadequate control with metformin. METHODS: A literature search was made in several databases for randomized controlled trials (RCTs) utilizing metformin therapy combined with SGLT-2 inhibitors or placebo. Heterogeneity was estimated with I(2) statistics and random effect model was chosen for the meta-analyses of mean differences in changes from baseline in both SGLT-2 inhibitor treated and control groups. RESULTS: Seven RCTs were selected for the meta-analysis. In comparison with placebo-MET, the SGLT-2 inhibitor-MET combination therapy resulted in significant HbA1c decline in 12-24 week duration, to less extent after 1 year (-0.37 [-0.77, 0.03]; P=0.07) but not by 2 year (-0.41 [-1.09, 0.28]; P=0.24) duration. SGLT-2 inhibitor-MET significantly lowered FPG and body weight after 24 weeks, 1 year, and 2 years. Systolic and diastolic blood pressure declined only in the short term (12-24 weeks). After 2 years, neither systolic (-1.80 [-6.18, 2.58]; P=0.42) nor diastolic blood pressure (-0.20 [-2.94, 2.54]; P=0.89) declined significantly more than control. Incidence of suspected genital infections was slightly more in SGLT-2 inhibitor-MET group. CONCLUSION: SGLT-2 inhibition in combination with metformin is a potential therapeutic option based on its effects on glycemic control, body weight, and blood pressure, but further trials are required to refine this evidence. PMID- 25015318 TI - A comparative study between open and laparoscopic approach in radical cystectomy with orthotopic ileal neobladder. AB - OBJECTIVE: Probably, laparoscopic radical cystectomy with ileal neobladder and neovesicourethral anastomosis is one of the most complex procedures in minimally invasive surgery. MATERIAL AND METHODS: Prospective study carried out in 72 patients surgically treated for invasive bladder neoplasia between January 2008 and October 2013. Patients were undergone to radical cystectomy with ileal neobladder (open approach in 33 patients and laparoscopic approach in 39). The study assessed comparatively surgical outcomes, continence rate and postoperative complications. RESULTS: Mean age was 63.5+/-9 years (64.3 open vs. 62.7 laparoscopic, P=.46) mean surgery time 323.6+/-78.7 minutes (321.3 vs. 326.5, P=.77), average hospital stay 14.8 days+/-8,1 (16.2 vs. 13.6, P=.2), transfusion rate 40.3% (66.7% vs. 17.9%, P<.0001) and complications rate 47.2% (63.6% vs. 33.3%, P=.01). Major complications were reported in 29.1% of cases (39.4% open vs. 20,5% laparoscopic, P=.07). With a mean follow-up rate of 42.5+/-19.2 months (range 15-70), 50 (69.4%) patients remain alive and free of disease. Continence was evaluated in these patients: total continence rate was 38% (50% vs. 27%, P=.09) and diurnal continence rate 58% (70.8% vs. 46.1%, P=.07). Self catheterization rate was 8% (4.2% vs. 11.5%, P=.67). Total incontinence rate was 34% (25% vs. 42.3%, P=.19). CONCLUSION: According to our experience, transfusion rate, number and severity of complications are lower in laparoscopic cystectomy with ileal neobladder. No statistically significant impact on operative time and on hospital stay was observed. In patients undergone to laparoscopic approach, continence rate is lower but not statistically significant. PMID- 25015319 TI - De novo sequencing and comparative analysis of holy and sweet basil transcriptomes. AB - BACKGROUND: Ocimum L. of family Lamiaceae is a well known genus for its ethnobotanical, medicinal and aromatic properties, which are attributed to innumerable phenylpropanoid and terpenoid compounds produced by the plant. To enrich genomic resources for understanding various pathways, de novo transcriptome sequencing of two important species, O. sanctum and O. basilicum, was carried out by Illumina paired-end sequencing. RESULTS: The sequence assembly resulted in 69117 and 130043 transcripts with an average length of 1646 +/- 1210.1 bp and 1363 +/- 1139.3 bp for O. sanctum and O. basilicum, respectively. Out of the total transcripts, 59648 (86.30%) and 105470 (81.10%) from O. sanctum and O. basilicum, and respectively were annotated by uniprot blastx against Arabidopsis, rice and lamiaceae. KEGG analysis identified 501 and 952 transcripts from O. sanctum and O. basilicum, respectively, related to secondary metabolism with higher percentage of transcripts for biosynthesis of terpenoids in O. sanctum and phenylpropanoids in O. basilicum. Higher digital gene expression in O. basilicum was validated through qPCR and correlated to higher essential oil content and chromosome number (O. sanctum, 2n = 16; and O. basilicum, 2n = 48). Several CYP450 (26) and TF (40) families were identified having probable roles in primary and secondary metabolism. Also SSR and SNP markers were identified in the transcriptomes of both species with many SSRs linked to phenylpropanoid and terpenoid pathway genes. CONCLUSION: This is the first report of a comparative transcriptome analysis of Ocimum species and can be utilized to characterize genes related to secondary metabolism, their regulation, and breeding special chemotypes with unique essential oil composition in Ocimum. PMID- 25015320 TI - E3-ligase Skp2 predicts poor prognosis and maintains cancer stem cell pool in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is one of the severe head and neck carcinomas, which is rare in west countries but has high incidence in Southern Asia especially South China. Although NPC is relatively sensitive to radiotherapy, the prognosis of patients is poor due to the advanced stage at the time of diagnosis. Therefore, it is important to understand the mechanisms involved in tumorigenesis and develop early diagnostic techniques. S-phase kinase associated protein 2 (Skp2) is overexpressed in several human cancers and associates with poor prognosis. However, its function in NPC has not been fully addressed. In this study we found Skp2 was highly expressed in NPC specimen and correlated with poor prognosis. We generated Skp2 knockdown cells to further delineate its role in NPC development. Knockdown of Skp2 partially reduced cell proliferation, promoted cellular senescence, and decreased the population of stem cell like aldehyde dehydrogenase1 positive cells as well as their self-renewal ability. Our study not only interprets the predictive role of Skp2 in the poor prognosis of NPC patients, but also reveals that Skp2 regulates the NPC cancer stem cell maintenance, which shed lights on the target therapy and early diagnosis of NPC in clinical application. PMID- 25015321 TI - Successful removal of strangulating metal penile ring using a dental handpiece. AB - BACKGROUND: Under emergency conditions, the dental handpiece can be a useful tool for removing a strangulating penile ring. OBJECTIVE: To report the successful use of a dental handpiece (dental drill) to remove a strangulating penile ring in an emergency. METHOD: A case report of a strangulating metal penile ring in a psychiatric patient who presented at the accident and emergency unit of Delta State University Teaching Hospital. RESULT: The metal ring was removed using a diamond bur in a dental handpiece. CONCLUSIONS: In case of emergency, the dental handpiece is a useful tool for removing a strangulating penile ring. PMID- 25015322 TI - Longevity, aging and rapamycin. AB - The federal drug administration (FDA)-approved compound rapamycin was the first pharmacological agent shown to extend maximal lifespan in both genders in a mammalian species. A major question then is whether the drug slows mammalian aging or if it has isolated effects on longevity by suppressing cancers, the main cause of death in many mouse strains. Here, we review what is currently known about the effects that pharmacological or genetic mammalian target of rapamycin (mTOR) inhibition have on mammalian aging and longevity. Currently available evidence seems to best fit a model, wherein rapamycin extends lifespan by suppressing cancers. In addition the drug has symptomatic effects on some aging traits, such as age-related cognitive impairments. PMID- 25015323 TI - Spinal stimulation for movement disorders. AB - Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson's disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders. PMID- 25015325 TI - How do gait frequency and serum-replacement interval affect polyethylene wear in knee-wear simulator tests? AB - Polyethylene wear (PE) is known to be a limiting factor in total joint replacements. However, a standardized wear test (e.g. ISO standard) can only replicate the complex in vivo loading condition in a simplified form. In this study, two different parameters were analyzed: (a) Bovine serum, as a substitute for synovial fluid, is typically replaced every 500,000 cycles. However, a continuous regeneration takes place in vivo. How does serum-replacement interval affect the wear rate of total knee replacements? (b) Patients with an artificial joint show reduced gait frequencies compared to standardized testing. What is the influence of a reduced frequency? Three knee wear tests were run: (a) reference test (ISO), (b) testing with a shortened lubricant replacement interval, (c) testing with reduced frequency. The wear behavior was determined based on gravimetric measurements and wear particle analysis. The results showed that the reduced test frequency only had a small effect on wear behavior. Testing with 1 Hz frequency is therefore a valid method for wear testing. However, testing with a shortened replacement interval nearly doubled the wear rate. Wear particle analysis revealed only small differences in wear particle size between the different tests. Wear particles were not linearly released within one replacement interval. The ISO standard should be revised to address the marked effects of lubricant replacement interval on wear rate. PMID- 25015326 TI - Percutaneous thrombin injection treatment of a gluteal pseudoaneurysm following radiofrequency ablation of a hip osteoid osteoma in a 6-year-old boy. AB - Osteoid osteomas are benign bone lesions that present with bone pain in children and young adults. Over the last 2 decades, radiofrequency ablation has become the mainstay of treatment and is now preferred over surgical resection. Major complications of the procedure are very rare, consisting mostly of local skin burns. We present a case of a child presenting with a gluteal pseudoaneursym following CT-guided radiofrequency ablation of an acetabular osteoid osteoma, which was then treated successfully with percutaneous thrombin injection. PMID- 25015327 TI - [Be careful with intrauterine balloon placement in the management of secondary post partum hemorrhage]. PMID- 25015328 TI - Therapeutic effect of intensive granulocyte and monocyte adsorption apheresis combined with thiopurines for steroid- and biologics-naive Japanese patients with early-diagnosed Crohn's disease. AB - BACKGROUND: Early induction with biologics can reduce complications in patients with Crohn's disease (CD) and improve their quality of life. The safety of biologics, however, is uncertain. Granulocyte and monocyte adsorptive apheresis (GMAA) is a natural biologic therapy that selectively removes granulocytes and monocytes/macrophages and has few severe adverse effects. The effects of GMAA on patients with early-diagnosed CD are unclear. We investigated the effects of GMAA combined with thiopurines on patients with early-diagnosed CD. METHODS: Twenty two corticosteroid- and biologic-naive patients with active early-diagnosed CD were treated with intensive GMAA (twice per week) combined with thiopurines administration. Active early-diagnosed CD was defined as follows: (i) within 2years after diagnosis of CD, (ii) with no history of both surgical treatment and endoscopic dilation therapy, and (iii) Crohn's Disease Activity Index (CDAI) was higher than 200. We investigated the ratios of clinical remission defined as CDAI was less than or equal to 150 at 2, 4, 6 and 52weeks and mucosal healing defined as a Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) as 0 at 6 and 52weeks. Adverse events were recorded at each visit. RESULTS: The ratios of clinical remission at 2, 4, and 6 weeks were 6 of 22 (27.2%), 12 of 22 (54.5%), and 17 of 22 (77.2%), respectively. At 52 weeks, 18 of 21 patients (81.8%) were in clinical remission. The ratios of mucosal healing at 6 and 52 weeks were 5 of 22 (22.7%) and 11 of 22 (50%), respectively. The difference in the mucosal healing ratio was significant between 6 and 52 weeks (p = 0.044). No serious adverse effects were observed during this study. CONCLUSIONS: Combination therapy with intensive GMAA and thiopurines administration rapidly induced high remission in patients with active early-diagnosed CD without serious adverse effect. Mucosal healing was observed in 50.0% of enrolled patients. This combination therapy might be a rational option for patients with early-diagnosed CD. PMID- 25015329 TI - Identification of kit(M541L) somatic mutation in chronic eosinophilic leukemia, not otherwise specified and its implication in low-dose imatinib response. AB - Activating mutations of KIT receptor tyrosine kinase have been reported in different neoplasms. The M541L KIT substitution (KIT(M541L)) has been described to be associated with pediatric mastocytosis, to enhance growth rate of the affected cells and to confer higher sensitivity to imatinib therapy. We investigated the presence of KIT(M541L) in five males with chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), all negative for Platelet-derived growth factor-alpha (PDGFR) or PDGFRbeta abnormalities, which responded to imatinib therapy. To assess whether the mutation was constitutive or somatic in nature, we evaluated its presence analyzing either the neoplastic or normal cell population (epidermal cells or CD3-positive T lymphocytes). KIT(M541L) substitution was found in 4 out of 5 patients and in all it was somatic in nature. All patients were treated with low dose imatinib (100 mg daily orally), achieving complete and persistent clinical and hematological remission (median follow-up 74 months). One patient relapsed after 50 months. Our study strongly suggests to search for the KIT(M541L) in patients with CEL, NOS, negative for PDGFRalpha and PDGFRbeta abnormalities, to identify a subgroup of cases who may benefit from low dose imatinib therapy. PMID- 25015331 TI - Overall survival benefit from surgical resection in treatment of recurrent glioblastoma. PMID- 25015330 TI - Multiple myeloma dell-derived microvesicles are enriched in CD147 expression and enhance tumor cell proliferation. AB - Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells within the bone marrow. There is a growing literature that tumor cells release biologically active microvesicles (MVs) that modify both local and distant microenvironments. In this study, our goals were to determine if MM cells release MVs, and if so, begin to characterize their biologic activity. Herein we present clear evidence that not only do both patient MM cells and human MM cell lines (HMCLs) release MVs, but that these MVs stimulate MM cell growth. Of interest, MM-derived MVs were enriched with the biologically active form of CD147, a transmembrane molecule previously shown by us to be crucial for MM cell proliferation. Using MVs isolated from HMCLs stably transfected with a CD147-GFP fusion construct (CD147GFP), we observed binding and internalization of MV derived CD147 with HMCLs. Cells with greater CD147GFP internalization proliferated at a higher rate than did cells with less CD147GFP association. Lastly, MVs obtained from CD147 downregulated HMCLs were attenuated in their ability to stimulate HMCL proliferation. In summary, this study demonstrates the significance of MV shedding and MV-mediated intercellular communication on malignant plasma cell proliferation, and identifies the role of MV-enriched CD147 in this process. PMID- 25015332 TI - Still a long way to go to achieve multidisciplinarity for the benefit of patients: commentary on the ESMO position paper (Annals of Oncology 25(1): 9-15, 2014). PMID- 25015333 TI - Prognostic significance of miR-34a in Ewing sarcoma is associated with cyclin D1 and ki-67 expression. AB - BACKGROUND: At diagnosis, identification of reliable biological indicators of prognosis to allow stratification of patients according to different risks is an important but still unresolved aspect in the treatment of Ewing sarcoma (EWS) patients. This study aimed to explore the role of miR-34A expression on prognosis of EWS patients. PATIENTS AND METHODS: Specimens from 109 patients with non metastatic EWS treated at the Rizzoli Institute with neoadjuvant chemotherapy (protocols ISG/SSGIII, EW-1, EW-2, EW-REN2, EW-REN3, EW-PILOT) and 17 metastases were studied. Sixty-eight patients (62%) remained disease-free and 41 (38%) relapsed (median follow-up: 67 months, range 9-241 months). Expression of miR-34a and of some of its targets (cyclin D1, bcl-2, SIRT1 and YY1) was evaluated by qRT PCR using TaqMan MicroRNA Assays and/or by immunohistochemistry on tissue microarrays from the same patients. RESULTS: High expression of miR-34a in localized tumors was significantly related to better event-free and overall survival (P = 0.004). Relevance of miR-34a was confirmed by using different calibrators (normal mesenchymal stem cells and different normal tissues). By multivariate Cox regression analysis, low miR-34a expression as well as nontotal necrosis and high levels of lactate dehydrogenase were all confirmed as independent risk factors associated with poor outcome. Expression of miR-34a was lower in metastases than in primary tumors. It inversely correlated with expression of cyclin D1 and Ki-67. CONCLUSIONS: By demonstrating its relationship with clinical outcome, we propose evaluation of miR-34a at diagnosis of EWS patients to allow early risk stratification. Validation of these results would nonetheless ultimately need a prospective assessment. PMID- 25015334 TI - Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in Europe and worldwide, with the peak incidence in patients >70 years of age. However, as the treatment algorithms for the treatment of patients with CRC become ever more complex, it is clear that a significant percentage of older CRC patients (>70 years) are being less than optimally treated. This document provides a summary of an International Society of Geriatric Oncology (SIOG) task force meeting convened in Paris in 2013 to update the existing expert recommendations for the treatment of older (geriatric) CRC patients published in 2009 and includes overviews of the recent data on epidemiology, geriatric assessment as it relates to surgery and oncology, and the ability of older CRC patients to tolerate surgery, adjuvant chemotherapy, treatment of their metastatic disease including palliative chemotherapy with and without the use of the biologics, and finally the use of adjuvant and palliative radiotherapy in the treatment of older rectal cancer patients. An overview of each area was presented by one of the task force experts and comments invited from other task force members. PMID- 25015336 TI - Sexual kindred spirits: actual and overperceived similarity, complementarity, and partner accuracy in heterosexual couples. AB - We examined whether sexual similarity, complementarity, and perceptual accuracy exist within a large sample of heterosexual couples. Partners exhibited similarity and complementarity of sexual preferences, and they perceived each other's preferences with a considerable degree of accuracy; these effects were greater than found in randomly assigned pseudocouples. In addition, people overperceived sexual similarity and complementarity, and they overperceived the accuracy with which their partner knew their preferences. We suggest these three forms of overperception are the result of motivated cognitive processes in service of sexual relationship maintenance. Using actor-partner interdependence modeling (Kenny, Kashy, & Cook, 2006), overperception predicted sexual satisfaction, as did complementarity, but similarity and accuracy did not. These findings indicate that motivated cognition may foster sexual satisfaction, as theories of motivated relationship cognitions suggest. PMID- 25015335 TI - Birth weight and adult cancer incidence: large prospective study and meta analysis. AB - BACKGROUND: Most evidence about associations between birth weight and adult cancer risk comes from studies linking birth records to cancer registration data, where information on known risk factors for cancer is generally lacking. Here, we report on associations between birth weight and cause-specific cancer risk in a large cohort of UK women, and investigate how observed associations are affected by other factors. METHODS: A total of 453 023 women, born in the 1930s and 1940s, reported their birth weight, maternal smoking, parental heights, age at menarche, adult height, adult smoking, and many other personal characteristics. They were followed for incident cancer. Using Cox regression, relative risks by birth weight were estimated for cancers with more than 1500 incident cases, adjusting for 17 potential confounding factors, individually and simultaneously. RESULTS: Birth weight reported in adulthood was strongly correlated with that recorded at birth (correlation coefficient = 0.78, P < 0.0001). Reported birth weight was associated with most of the potential confounding factors examined, the strongest association being with adult height. After 9.2 years follow-up per woman, 39 060 incident cancers were registered (4414 colorectal, 3175 lung, 1795 malignant melanoma, 14 542 breast, 2623 endometrial, 2009 ovarian, 1565 non-Hodgkin lymphoma, and 8937 other cancers). Associations with birth weight were null or weak and reduced after adjustment by adult height (P[trend] > 0.01 for every cancer, after adjustment). In contrast, adult height was strongly related to the risk of every cancer except lung cancer, after adjusting for birth weight and other factors (P[trend] < 0.0001 for most cancers). For lung cancer, adjusting for smoking reduced the association with birth weight. Meta-analyses were dominated by our findings. CONCLUSION: Birth weight and adult height are correlated and likely to be markers of some aspect of growth that affects cancer risk in adulthood. However, birth weight adds little, if any, additional information to adult height as a predictor of cancer incidence in women. PMID- 25015337 TI - Stereotypes as stumbling-blocks: how coping with stereotype threat affects life outcomes for people with physical disabilities. AB - Stereotype threat, the concern about being judged in light of negative stereotypes, causes underperformance in evaluative situations. However, less is known about how coping with stereotypes can aggravate underperformance over time. We propose a model in which ongoing stereotype threat experiences threaten a person's sense of self-integrity, which in turn prompts defensive avoidance of stereotype-relevant situations, impeding growth, achievement, and well-being. We test this model in an important but understudied population: the physically disabled. In Study 1, blind adults reporting higher levels of stereotype threat reported lower self-integrity and well-being and were more likely to be unemployed and to report avoiding stereotype-threatening situations. In Study 2's field experiment, blind students in a compensatory skill-training program made more progress if they had completed a values-affirmation, an exercise that bolsters self-integrity. The findings suggest that stereotype threat poses a chronic threat to self-integrity and undermines life outcomes for people with disabilities. PMID- 25015338 TI - Red and romantic rivalry: viewing another woman in red increases perceptions of sexual receptivity, derogation, and intentions to mate-guard. AB - Research has shown that men perceive women wearing red, relative to other colors, as more attractive and more sexually receptive; women's perceptions of other women wearing red have scarcely been investigated. We hypothesized that women would also interpret female red as a sexual receptivity cue, and that this perception would be accompanied by rival derogation and intentions to mate-guard. Experiment 1 demonstrated that women perceive another woman in a red, relative to white, dress as sexually receptive. Experiment 2 demonstrated that women are more likely to derogate the sexual fidelity of a woman in red, relative to white. Experiment 3 revealed that women are more likely to intend to guard their romantic partner from a woman wearing a red, relative to a green, shirt. These results suggest that some color signals are interpreted similarly across sex, albeit with associated reactions that are sex-specific. PMID- 25015339 TI - LDL cholesterol as a predictor of mortality, and beyond: to fast or not to fast, that is the question? PMID- 25015340 TI - Prognostic value of fasting versus nonfasting low-density lipoprotein cholesterol levels on long-term mortality: insight from the National Health and Nutrition Examination Survey III (NHANES-III). AB - BACKGROUND: National and international guidelines recommend fasting lipid panel measurement for risk stratification of patients for prevention of cardiovascular events. However, the prognostic value of fasting versus nonfasting low-density lipoprotein cholesterol (LDL-C) is uncertain. METHODS AND RESULTS: Patients enrolled in the National Health and Nutrition Examination Survey III (NHANES III), a nationally representative cross-sectional survey performed from 1988 to 1994, were stratified on the basis of fasting status (>=8 or <8 hours) and followed for a mean of 14.0 (+/-0.22) years. Propensity score matching was used to assemble fasting and nonfasting cohorts with similar baseline characteristics. The risk of outcomes as a function of LDL-C and fasting status was assessed with the use of receiver operating characteristic curves and bootstrapping methods. The interaction between fasting status and LDL-C was assessed with Cox proportional hazards modeling. Primary outcome was all-cause mortality. Secondary outcome was cardiovascular mortality. One-to-one matching based on propensity score yielded 4299 pairs of fasting and nonfasting individuals. For the primary outcome, fasting LDL-C yielded prognostic value similar to that for nonfasting LDL-C (C statistic=0.59 [95% confidence interval, 0.57-0.61] versus 0.58 [95% confidence interval, 0.56-0.60]; P=0.73), and LDL-C by fasting status interaction term in the Cox proportional hazards model was not significant (Pinteraction=0.11). Similar results were seen for the secondary outcome (fasting versus nonfasting C statistic=0.62 [95% confidence interval, 0.60-0.66] versus 0.62 [95% confidence interval, 0.60-0.66]; P=0.96; Pinteraction=0.34). CONCLUSIONS: Nonfasting LDL-C has prognostic value similar to that of fasting LDL C. National and international agencies should consider reevaluating the recommendation that patients fast before obtaining a lipid panel. PMID- 25015341 TI - Coronary computed tomographic angiography and incidental pulmonary nodules. PMID- 25015342 TI - Cost-effectiveness of follow-up of pulmonary nodules incidentally detected on cardiac computed tomographic angiography in patients with suspected coronary artery disease. AB - BACKGROUND: Pulmonary nodules (PNs) are often detected incidentally during coronary computed tomographic (CT) angiography, which is increasingly being used to evaluate patients with chest pain symptoms. However, the efficiency of following up on incidentally detected PN is unknown. METHODS AND RESULTS: We determined demographic and clinical characteristics of stable symptomatic patients referred for coronary CT angiography in whom incidentally detected PNs warranted follow-up. A validated lung cancer simulation model was populated with data from these patients, and clinical and economic consequences of follow-up per Fleischner guidelines versus no follow-up were simulated. Of the 3665 patients referred for coronary CT angiography, 591 (16%) had PNs requiring follow-up. The mean age of patients with PNs was 59+/-10 years; 66% were male; 67% had ever smoked; and 21% had obstructive coronary artery disease. The projected overall lung cancer incidence was 5.8% in these patients, but the majority died of coronary artery disease (38%) and other causes (57%). Follow-up of PNs was associated with a 4.6% relative reduction in cumulative lung cancer mortality (absolute mortality: follow-up, 4.33% versus non-follow-up, 4.54%), more downstream testing (follow-up, 2.34 CTs per patient versus non-follow-up, 1.01 CTs per patient), and an average increase in quality-adjusted life of 7 days. Costs per quality-adjusted life-year gained were $154 700 to follow up the entire cohort and $129 800 per quality-adjusted life-year when only smokers were included. CONCLUSIONS: Follow-up of PNs incidentally detected in patients undergoing coronary CT angiography for chest pain evaluation is associated with a small reduction in lung cancer mortality. However, significant downstream testing contributes to limited efficiency, as demonstrated by a high cost per quality adjusted life-year, especially in nonsmokers. PMID- 25015343 TI - Vitamin D promotes vascular regeneration. AB - BACKGROUND: Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone 1,25-dihydroxycholecalciferol (1,25-dihydroxy-vitamin D3; 1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D3 deficiency, however, has been linked to cardiovascular disease because the hormone has anti inflammatory properties. We therefore hypothesized that 1,25-VitD3 promotes regeneration after vascular injury. METHODS AND RESULTS: In healthy volunteers, supplementation of vitamin D3 (4000 IU cholecalciferol per day) increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells, which are thought to promote vascular regeneration. Similarly, in mice, 1,25-VitD3 (100 ng/kg per day) increased the number of angiogenic myeloid cells and promoted reendothelialization in the carotid artery injury model. In streptozotocin induced diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the impaired angiogenesis in the femoral artery ligation model. Angiogenic myeloid cells home through the stromal cell-derived factor 1 (SDF1) receptor CXCR4. Inhibition of CXCR4 blocked 1,25-VitD3-stimulated healing, pointing to a role of SDF1. The combination of injury and 1,25-VitD3 increased SDF1 in vessels. Conditioned medium from injured, 1,25-VitD3-treated arteries elicited a chemotactic effect on angiogenic myeloid cells, which was blocked by SDF1 neutralizing antibodies. Conditional knockout of the vitamin D receptor in myeloid cells but not the endothelium or smooth muscle cells blocked the effects of 1,25-VitD3 on healing and prevented SDF1 formation. Mechanistically, 1,25 VitD3 increased hypoxia-inducible factor 1-alpha through binding to its promoter. Increased hypoxia-inducible factor signaling subsequently promoted SDF1 expression, as revealed by reporter assays and knockout and inhibitory strategies of hypoxia-inducible factor 1-alpha. CONCLUSIONS: By inducing SDF1, vitamin D3 is a novel approach to promote vascular repair. PMID- 25015344 TI - Evaluation of spatial and temporal variations in marine sediments quality using multivariate statistical techniques. AB - Spatial and temporal variations of sediment quality in Matanzas Bay (Cuba) were studied by determining a total of 12 variables (Zn, Cu, Pb, As, Ni, Co, Al, Fe, Mn, V, CO32-, and total hydrocarbons (THC). Surface sediments were collected, annually, at eight stations during 2005-2008. Multivariate statistical techniques, such as principal component (PCA), cluster (CA), and lineal discriminant (LDA) analyses were applied for identification of the most significant variables influencing the environmental quality of sediments. Heavy metals (Zn, Cu, Pb, V, and As) and THC were the most significant species contributing to sediment quality variations during the sampling period. Concentrations of V and As were determined in sediments of this ecosystem for the first time. The variation of sediment environmental quality with the sampling period and the differentiation of samples in three groups along the bay were obtained. The usefulness of the multivariate statistical techniques employed for the environmental interpretation of a limited dataset was confirmed. PMID- 25015345 TI - Metals in horseshoe crab eggs from Delaware Bay, USA: temporal patterns from 1993 to 2012. AB - The health of horseshoe crab (Limulus polyphemus) eggs is important not only to maintain horseshoe crab populations, but because they are a resource for higher trophic levels, such as fish and shorebirds. We examined the concentrations of arsenic, cadmium, chromium, lead, manganese, mercury, and selenium in the eggs of horseshoe crabs from Delaware Bay (between New Jersey and Delaware, USA) in 1993, 1994, 1995, 1999, 2000, and 2012 to determine if there were significant temporal changes and if levels appear to pose a health risk to the crabs themselves, or to predators that consume them. All metal levels declined in horseshoe crab eggs between 1994 and 2012, although the declines were much less consistent for lead and chromium than that for mercury and cadmium. Levels of contaminants found in these eggs are well below those known to cause adverse effects in the crabs themselves or to organisms that consume them, such as migrating shorebirds. PMID- 25015346 TI - Environmental monitoring and assessment of the water bodies of a pre-construction urban wetland. AB - It is planned that the Dayanghan Wetland in China will be transformed into a national park but little is known about its current water quality and pollution status. Thus, we monitored the physical and chemical characteristics of the Dayanghan Wetland, which showed that the water quality was generally good. However, the chemical oxygen demand was more than double the reference value, which may be attributable to previous tillage for vegetable crops and other farmlands. In addition, nickel and chromium caused low-level pollution in the water bodies of the Dayanghan Wetland. The mean trophic level index and nutrient quality index were 39.1 and 2.69, respectively. Both indices suggest that the water bodies of the Dayanghan Wetland are in a mesotrophic state and that no eutrophication has occurred. The study would provide a precise report on the status of environmental quality of the water bodies of a typical pre-construction wetland for the administration and decision of the local government and the planning agent. PMID- 25015347 TI - Bioavailability assessment of phosphorus and metals in soils and sediments: a review of diffusive gradients in thin films (DGT). AB - This paper provides an overview of the principle and latest development of the diffusive gradients in thin films (DGT) technology and its applications in environmental studies with a focus on bioavailability assessment of phosphorus and metals in sediments and soils. Compared with conventional methods, DGT, as a passive sampling method, has significant advantages: in situ measurement, time averaged concentrations and high spatial resolution. The in situ measurement avoids artificial influences including contamination of samples and sample treatment which may change the forms of chemicals. The time averaged concentration reflects representative measurement over a period of time. The high resolution information captures the biogeochemical heterogeneity of elements of interest distributed in microenvironments, such as in the rhizosphere and the vicinity of the sediment-water interface. Moreover, DGT is a dynamic technique which simultaneously considers the diffusion of solutes and their kinetic resupply from the solid phases. All the advantages of DGT significantly promote the collection of "true" information of the bioavailable or labile forms of chemicals in the environment. DGT provides potential for applications in agriculture, environmental monitoring and the mining industry. However, the applications are still at the early testing stage. Further studies are needed to properly interpret the DGT-measured results under complex environmental conditions, and standard procedures and guideline values based on DGT are required to pave the way for its routine applications in environmental monitoring. PMID- 25015349 TI - Taxonomic affinity of the Pliocene hominin fossils from Fejej, Ethiopia. PMID- 25015348 TI - Red blood cell (RBC) transfusion rates among US chronic dialysis patients during changes to Medicare end-stage renal disease (ESRD) reimbursement systems and erythropoiesis stimulating agent (ESA) labels. AB - BACKGROUND: Several major ESRD-related regulatory and reimbursement changes were introduced in the United States in 2011. In several large, national datasets, these changes have been associated with decreases in erythropoiesis stimulating agent (ESA) utilization and hemoglobin concentrations in the ESRD population, as well as an increase in the use of red blood cell (RBC) transfusions in this population. Our objective was to examine the use of RBC transfusion before and after the regulatory and reimbursement changes implemented in 2011 in a prevalent population of chronic dialysis patients in a large national claims database. METHODS: Patients in the Truven Health MarketScan Commercial and Medicare Databases with evidence of chronic dialysis were selected for the study. The proportion of chronic dialysis patients who received any RBC transfusion and RBC transfusion event rates per 100 patient-months were calculated in each month from January 1, 2007 to March 31, 2012. The results were analyzed overall and stratified by primary health insurance payer (commercial payer or Medicare). RESULTS: Overall, the percent of chronic dialysis patients with RBC transfusion and RBC transfusion event rates per 100 patient-months increased between January 2007 and March 2012. When stratified by primary health insurance payer, it appears that the increase was driven by the primary Medicare insurance population. While the percent of patients with RBC transfusion and RBC transfusion event rates did not increase in the commercially insured population between 2007 and 2012 they did increase in the primary Medicare insurance population; the majority of the increase occurred in 2011 during the same time frame as the ESRD-related regulatory and reimbursement changes. CONCLUSIONS: The regulatory and reimbursement changes implemented in 2011 may have contributed to an increase in the use of RBC transfusions in chronic dialysis patients in the MarketScan dataset who were covered by Medicare plus Medicare supplemental insurance. PMID- 25015350 TI - Accounting for standard errors of vision-specific latent trait in regression models. AB - PURPOSE: To demonstrate the effectiveness of Hierarchical Bayesian (HB) approach in a modeling framework for association effects that accounts for SEs of vision specific latent traits assessed using Rasch analysis. METHODS: A systematic literature review was conducted in four major ophthalmic journals to evaluate Rasch analysis performed on vision-specific instruments. The HB approach was used to synthesize the Rasch model and multiple linear regression model for the assessment of the association effects related to vision-specific latent traits. The effectiveness of this novel HB one-stage "joint-analysis" approach allows all model parameters to be estimated simultaneously and was compared with the frequently used two-stage "separate-analysis" approach in our simulation study (Rasch analysis followed by traditional statistical analyses without adjustment for SE of latent trait). RESULTS: Sixty-six reviewed articles performed evaluation and validation of vision-specific instruments using Rasch analysis, and 86.4% (n = 57) performed further statistical analyses on the Rasch-scaled data using traditional statistical methods; none took into consideration SEs of the estimated Rasch-scaled scores. The two models on real data differed for effect size estimations and the identification of "independent risk factors." Simulation results showed that our proposed HB one-stage "joint-analysis" approach produces greater accuracy (average of 5-fold decrease in bias) with comparable power and precision in estimation of associations when compared with the frequently used two-stage "separate-analysis" procedure despite accounting for greater uncertainty due to the latent trait. CONCLUSIONS: Patient-reported data, using Rasch analysis techniques, do not take into account the SE of latent trait in association analyses. The HB one-stage "joint-analysis" is a better approach, producing accurate effect size estimations and information about the independent association of exposure variables with vision-specific latent traits. PMID- 25015351 TI - The detection of macular analysis by SD-OCT for optic chiasmal compression neuropathy and nasotemporal overlap. AB - PURPOSE: To assess the diagnostic performance of the macular parameters detected by spectral-domain optical coherence tomography (SD-OCT) in band atrophy (BA) eyes. METHODS: Forty-nine BA eyes with permanent temporal hemianopia and 89 normal eyes were enrolled. Any patients who had nasal visual field loss were excluded. Each participant was imaged by three-dimensional (3D) OCT-2000, and 10 * 10 grids in the macula were automatically allocated. The thickness of the macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL)+ (GCL+inner plexiform layer [IPL]), and GCL++ (RNFL+GCL+IPL) in both nasal and temporal hemiretina was calculated and compared between the BA and normal eyes. The areas under the receiver operating characteristic curves (AUCs) in these parameters were compared between the nasal hemiretina and the temporal hemiretina. RESULTS: All the parameters in the BA eyes were significantly thinner than those in the normal eyes. The AUCs for the mRNFL, GCL+, and GCL++ thickness in the nasal hemiretina were 0.890, 0.988, and 0.981, respectively. The parameters in the nasal hemiretina showed significantly higher AUCs than those parameters in the temporal hemiretina. In the temporal hemiretina, the damaged grids in the mRNFL were located in the arcuate areas in each hemifield. CONCLUSIONS: The inner macular parameters in the nasal hemiretina exhibited high diagnostic abilities to detect BA. The GCL+ was more affected than mRNFL. The characteristic pattern of mRNFL and GCL+ thinning was implicated in the anatomical architecture regarding the nasotemporal overlap of the crossed and uncrossed fibers around the fovea. (www.umin.ac.jp/ctr number, UMIN000006900.). PMID- 25015352 TI - Evidence for the Involvement of MMP14 in MMP2 Processing and Recruitment in Exosomes of Corneal Fibroblasts. AB - PURPOSE: Matrix metalloproteinase (MMP) 14 has been shown to promote angiogenesis, but the underlying mechanisms are poorly understood. In this study, we investigated exosomal transport of MMP14 and its target, MMP2, from corneal fibroblasts to vascular endothelial cells as a possible mechanism governing MMP14 activity in corneal angiogenesis. METHODS: We isolated MMP14-containing exosomes from corneal fibroblasts by sucrose density gradient and evaluated exosome content and purity by Western blot analysis. We then investigated exosome transport in vitro from corneal fibroblasts to two populations of vascular endothelial cells, human umbilical vein endothelial cells (HUVECs) and calf pulmonary artery endothelial cells (CPAECs). Western blot analysis and gelatin zymography were used to determine levels of MMP14 and MMP2, respectively, in exosomal fractions derived from cultured wild-type, MMP14 enzymatic domain deficient (MMP14Deltaexon4), and MMP14-null corneal fibroblasts. RESULTS: Matrix metalloproteinase 14-containing exosomes isolated from corneal fibroblasts were readily taken up in vitro by HUVECs and CPAECs. We found that MMP14 was enriched in exosomal fractions of cultured corneal fibroblasts. Moreover, loss of the MMP14 enzymatic domain resulted in accumulation of pro-MMP2 protein in exosomes, whereas MMP2 was nearly undetectable in exosomes of MMP14-null fibroblasts. CONCLUSIONS: Our results indicate that exosomes secreted by corneal fibroblasts can transport proteins, including MMP14, to vascular endothelial cells. In addition, recruitment of MMP2 into corneal fibroblast exosomes is an active process that depends, at least in part, on the presence of MMP14. The role of exosomal MMP14 transport in corneal angiogenesis has important implications for therapeutic applications targeting angiogenic processes in the cornea. PMID- 25015353 TI - Retinal oxygen metabolism during normoxia and hyperoxia in healthy subjects. AB - PURPOSE: To characterize retinal metabolism during normoxia and hyperoxia in healthy subjects. METHODS: Forty-six healthy subjects were included in the present study, and data of 41 subjects could be evaluated. Retinal vessel diameters, as well as oxygen saturation in arteries and veins, were measured using the Dynamic Vessel Analyzer. In addition, retinal venous blood velocity was measured using bidirectional laser Doppler velocimetry, retinal blood flow was calculated, and oxygen and carbon dioxide partial pressures were measured from arterialized capillary blood from the earlobe. Measurements were done during normoxia and during 100% oxygen breathing. RESULTS: Systemic hyperoxia caused a significant decrease in retinal venous diameter (-13.0% +/- 4.5%) and arterial diameter (-12.1% +/- 4.0%), in retinal blood velocity (-43.4% +/- 7.7%), and in retinal blood flow (-57.0% +/- 5.7%) (P < 0.001 for all). Oxygen saturation increased in retinal arteries (+4.4% +/- 2.3%) and in retinal veins (+19.6% +/- 6.2%), but the arteriovenous oxygen content difference significantly decreased ( 29.4% +/- 19.5%) (P < 0.001 for all). Blood oxygen tension in arterialized blood showed a pronounced increase from 90.2 +/- 7.7 to 371.3 +/- 92.7 mm Hg (P < 0.001). Calculated oxygen extraction in the eye decreased by as much as 62.5% +/- 9.5% (P < 0.001). CONCLUSIONS: Our data are compatible with the hypothesis that during 100% oxygen breathing a large amount of oxygen, consumed by the inner retina, comes from the choroid, which is supported by previous animal data. Interpretation of oxygen saturation data in retinal arteries and veins without quantifying blood flow is difficult. (ClinicalTrials.gov number, NCT01692821.). PMID- 25015354 TI - Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4 year DHAX trial. AB - PURPOSE: Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks. METHODS: Males (n = 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA = 33; placebo = 27) adhered to the protocol >= 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment emergent adverse events including blood chemistry metabolites were recorded. RESULTS: By year 4, supplementation elevated plasma and red blood cell-DHA 4.4- and 3.6-fold, respectively, compared with the placebo group (P < 0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P > 0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort. CONCLUSIONS: Long-term, high-dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances. (ClinicalTrials.gov number, NCT00100230.). PMID- 25015355 TI - The role of thrombin in proliferative vitreoretinopathy. AB - PURPOSE: To determine the role of thrombin in the development of proliferative vitreoretinopathy (PVR). METHODS: Vitreous was collected from patients undergoing a vitrectomy (macular holes and puckers, n = 11 [controls]; retinal detachment without PVR development following vitrectomy, n = 15 [RRD1]; retinal detachment with PVR development within 6 months after vitrectomy, n = 11 [RRD2]; and established PVR, n = 14 [PVR]). Thrombin activity in vitreous was determined using a thrombin-specific chromogenic substrate. ARPE-19 cells were stimulated with 8* diluted vitreous samples in the presence and absence of hirudin. The samples were analyzed at t = 0 and t = 24 hours for the presence of 27 cytokines/chemokines and growth factors using a multiplex approach. In comparable studies, ARPE-19 cells were stimulated for 2 hours, and mRNA expression levels for CCL2, CXCL8, GMCSF, IL6, and PDGFB were determined by real-time quantitative (RQ)-PCR. RESULTS: Thrombin activity was significantly (P < 0.05) higher in vitreous of the PVR group compared to the other groups. Proliferative vitreoretinopathy vitreous stimulated the production of chemokine (C-C motif) ligand (CCL)2, chemokine (C-X-C motif) ligand (CXCL)8, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and platelet-derived growth factor (PDGF)-BB by ARPE-19 to significantly (P < 0.05) higher levels than vitreous from the RRD1 and RRD2 groups. These effects of PVR vitreous were significantly (P < 0.05) reduced by hirudin. These data were confirmed by mRNA studies. CONCLUSIONS: Thrombin activity is increased in vitreous of patients with established PVR and is involved in the activation of proinflammatory and profibrotic pathways in RPE cells. Inhibition of thrombin activity may therefore represent a potential treatment option for proliferative vitreoretinopathy. PMID- 25015356 TI - Set-based joint test of interaction between SNPs in the VEGF pathway and exogenous estrogen finds association with age-related macular degeneration. AB - Purpose:Age-Related Macular Degeneration (AMD) is the leading cause of irreversible visual loss in developed countries. Its etiology includes genetic and environmental factors. Although VEGFA variants are associated with AMD, the joint action of variants within the VEGF pathway and their interaction with non genetic factors has not been investigated. Methods:Affymetrix 6.0 chipsets were used to genotype 668,238 SNPs in 1,207 AMD cases and 686 controls. Environmental exposures were collected by questionnaire. A set-based test was conducted using the chi-square statistic at each SNP derived from Kraft's 2df joint test. Pathway and gene-based test statistics were calculated as the mean of all independent SNP statistics. Phenotype labels were permuted 10,000 times to generate an empirical p-value. Results: While a main effect of the VEGF pathway was not identified, the pathway was associated with neovascular AMD in women when accounting for birth control pill (BCP) use (P= 0.017). Analysis of VEGF's subpathways found that SNPs in the Proliferation subpathway were associated with neovascular AMD (P=0.029) when accounting for BCP use. Nominally significant genes within this subpathway were also observed. Stratification by BCP use revealed novel significant genetic effects in women who had taken BCPs. Conclusions: These results illustrate that some AMD genetic risk factors may only be revealed when considering complex relationships among risk factors. This shows the utility of exploring pathways of previously associated genes to find novel effects. It also demonstrates the importance of incorporating environmental exposures in tests of genetic association at the SNP, gene, or pathway level. PMID- 25015357 TI - Fundus autofluorescence and photoreceptor cell rosettes in mouse models. AB - PURPOSE: This study was conducted to study correlations among fundus autofluorescence (AF), RPE lipofuscin accumulation, and photoreceptor cell degeneration and to investigate the structural basis of fundus AF spots. METHODS: Fundus AF images (55 degrees lens; 488-nm excitation) and spectral-domain optical coherence tomography (SD-OCT) scans were acquired in pigmented Rdh8(-/ )/Abca4(-/-) mice (ages 1-9 months) with a confocal scanning laser ophthalmoscope (cSLO). For quantitative fundus AF (qAF), gray levels (GLs) were calibrated to an internal fluorescence reference. Retinal bisretinoids were measured by quantitative HPLC. Histometric analysis of outer nuclear layer (ONL) thicknesses was performed, and cryostat sections of retina were examined by fluorescence microscopy. RESULTS: Quantified A2E and qAF intensities increased until age 4 months in the Rdh8(-/-)/Abca4(-/-) mice. The A2E levels declined after 4 months of age, but qAF intensity values continued to rise. The decline in A2E levels in the Rdh8(-/-)/Abca4(-/-) mice paralleled reduced photoreceptor cell viability as reflected in ONL thinning. Hyperautofluorescent puncta in fundus AF images corresponded to photoreceptor cell rosettes in SD-OCT images and histological sections stained with hematoxylin and eosin. The inner segment/outer segment containing core of the rosette emitted an autofluorescence detected by fluorescence microscopy. CONCLUSIONS: When neural retina is disordered, AF from photoreceptor cells can contribute to noninvasive fundus AF images. Hyperautofluorescent puncta in fundus AF images are attributable, in at least some cases, to photoreceptor cell rosettes. PMID- 25015358 TI - Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis. AB - PURPOSE: To rescue visual loss and optic neuropathy in experimental autoimmune encephalomyelitis (EAE). METHODS: Encephalomyelitis was induced in mice that received intravitreal injections of AAV2-mtHSP70Flag or AAV2-Cox8-mCherry. Additional mice were injected with AAV2-Cox8-mCherry, but not sensitized for EAE. Visual function was assessed by pattern electroretinograms (PERG) at 1, 3, and 6 months post injection (MPI). Optical coherence tomography (OCT) evaluated the thickness of the inner plexiform layer + nerve fiber layers at 1, 3, and 6 MPI. Retinas and optic nerves (ONs) of mice euthanized 6 MPI were processed for light and electron microscopy. Expression of mtHSP70Flag in the retina and ONs was evaluated by RT-PCR, immunofluorescence, and Western blotting. The activities of respiratory complexes I and III, as well as mitochondrial protein import were quantitated. RESULTS: Expression: immunofluorescence revealed punctate and perinuclear expression of mtHSP70Flag that colocalized with mitochondrial porin in thy1.2 labeled retinal ganglion cells (RGCs). Immunoblotting and RT-PCR confirmed mtHSP70Flag expression in the retina and ON. Rescue: treatment with mtHSP70Flag resulted in a 44% increase in PERG amplitude and less delays in latency relative to the EAE-mCherry group that also showed progressive inner retinal thinning. At 6 MPI, the almost 50% loss of RGCs and optic nerve axons in EAE mice was suppressed by mtHSP70Flag. In addition, retinas of EAE-mtHSP70Flag mice showed nearly complete rescue of complex I and III activities that was reduced by one-third in the EAE-mCherry retinas. Lastly, reductions in import of COX8-mCherry into mitochondria of mice sensitized for EAE improved by 30% with mtHSP70Flag gene therapy. CONCLUSIONS: Mitochondrial HSP70 ameliorates mitochondrial dysfunction that culminates in irreversible visual loss and atrophy of the optic nerve in EAE suggesting that it may be useful to prevent irreversible disability in patients with optic neuritis and multiple sclerosis (MS). PMID- 25015360 TI - Inverse relationship between high blood 25-hydroxyvitamin D and late stage of age related macular degeneration in a representative Korean population. AB - PURPOSE: To investigate the association of 25-hydroxyvitamin D with AMD. METHODS: A population-based, cross-sectional study using a nationwide, systemic stratified, multistage-clustered sampling method involved a total of 17,045 subjects older than 40 years who participated in the Korean National Health and Nutrition Examination Survey 2008 to 2012. All participants underwent standardized interviews, evaluation of blood 25-hydroxyvitamin D levels, and comprehensive ophthalmic examinations. A 45 degrees digital fundus photograph of both eyes was taken under physiologic mydriasis. All fundus photographs were graded using the international classification and grading system. RESULTS: Blood 25-hydroxyvitamin D levels were 17.5 ng/mL in women and 20.0 ng/mL in men. After adjusting for potential confounders including age, sex, smoking status, hypertension, heart problems, stroke, and sunlight-exposure time, the odds ratio (OR) for late AMD significantly decreased in the highest blood 25-hydroxyvitamin D quintile (OR, 0.32; 95% confidence interval [CI], 0.12-0.81; P for trend = 0.018) compared with the lowest quintile in men, but not in women. Early AMD was not associated with blood 25-hydroxyvitamin D levels in either sex. CONCLUSIONS: High level of blood 25-hydroxyvitamin D was inversely associated with late AMD in men but not women. Considering antiangiogenic and antifibrotic action of vitamin D, association between two variables warrants further studies. PMID- 25015359 TI - Notch signaling functions in retinal pericyte survival. AB - PURPOSE: Pericytes, the vascular cells that constitute the outer layer of capillaries, have been shown to have a crucial role in vascular development and stability. Loss of pericytes precedes endothelial cell dysfunction and vascular degeneration in small-vessel diseases, including diabetic retinopathy. Despite their clinical relevance, the cellular pathways controlling survival of retinal pericytes remain largely uncharacterized. Therefore, we investigated the role of Notch signaling, a master regulator of cell fate decisions, in retinal pericyte survival. METHODS: A coculture system of ligand-dependent Notch signaling was developed using primary cultured retinal pericytes and a mesenchymal cell line derived from an inducible mouse model expressing the Delta-like 1 Notch ligand. This model was used to examine the effect of Notch activity on pericyte survival using quantitative PCR (qPCR) and a light-induced cell death assay. The effect of Notch gain- and loss-of-function was analyzed in monocultures of retinal pericytes using antibody arrays to interrogate the expression of apoptosis related proteins. RESULTS: Primary cultured retinal pericytes differentially expressed key molecules of the Notch pathway and displayed strong expression of canonical Notch/RBPJK (recombination signal-binding protein 1 for J-kappa) downstream targets. A gene expression screen using gain- and loss-of-function approaches identified genes relevant to cell survival as downstream targets of Notch activity in retinal pericytes. Ligand-mediated Notch activity protected retinal pericytes from light-induced cell death. CONCLUSIONS: Our results have identified signature genes downstream of Notch activity in retinal pericytes and suggest that tight regulation of Notch signaling is crucial for pericyte survival. PMID- 25015361 TI - Ganglion cell-inner plexiform layer thickness of high definition optical coherence tomography in perimetric and preperimetric glaucoma. AB - PURPOSE: We determined the diagnostic performance of ganglion cell-inner plexiform layer (GCIPL) parameters of high definition optical coherence tomography (HD-OCT) in perimetric and preperimetric glaucoma, and compared it to optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) parameters. METHODS: In a cross-sectional study, 53 eyes of normal subjects and 83 eyes of glaucoma patients (62 perimetric and 21 preperimetric) from the Longitudinal Glaucoma Evaluation Study (LOGES) underwent HD-OCT imaging with Optic Disc and Macular Cube protocols. Diagnostic abilities of GCIPL, ONH, and RNFL parameters were determined using area under receiver operating characteristic curves (AUC) and likelihood ratios (LR). RESULTS: The AUCs of GCIPL parameters to diagnose perimetric glaucoma ranged from 0.84 to 0.90. The same of ONH and RNFL parameters ranged from 0.88 to 0.97 and 0.56 to 0.94, respectively. The AUCs of GCIPL, ONH, and RNFL parameters to diagnose preperimetric glaucoma ranged from 0.55 to 0.63, 0.77 to 0.92, and 0.39 to 0.80, respectively. For diagnosing preperimetric glaucoma, AUCs of all GCIPL parameters were significantly lower (P < 0.05) than those of the global ONH (vertical cup-to disc ratio [CDR]; AUC, 0.92) and RNFL (average RNFL; AUC, 0.79) parameters. Outside normal limits category of GCIPL parameters also were associated with significantly smaller effects on the posttest probability of perimetric and preperimetric glaucoma. CONCLUSIONS: The diagnostic ability of GCIPL parameters was similar to that of ONH and peripapillary RNFL parameters in perimetric glaucoma. However, in preperimetric glaucoma, the diagnostic ability of GCIPL parameters was significantly lower than that of ONH and RNFL parameters. PMID- 25015362 TI - The lack of OmpF, but not OmpC, contributes to increased antibiotic resistance in Serratia marcescens. AB - The environmental organism Serratia marcescens is one of the primary causes of numerous nosocomial outbreaks and opportunistic infections. Multi-drug resistance is now a common feature among S. marcescens clinical isolates, complicating the efficacy of treatment. Recent reports have attributed antibiotic resistance to altered porin expression as well as perturbation of the intrinsic AmpC beta lactamase production pathway. In this study, we aimed to genetically correlate the absence of OmpF and OmpC classical porins with increased antibiotic resistance. In generating isogenic porin mutant strains, we avoided incorporating additional resistance through the use of antibiotic cassettes in gene replacement and adopted an alternative strategy in creating clean unmarked mutant strains. We found that lack of OmpF, but not OmpC, significantly increased antibiotic MIC values to the beta-lactam drugs such as ampicillin and cefoxitin as well as to nitrofurantoin. Furthermore, we found that cefoxitin did not induce intrinsic AmpC beta-lactamase production, indicating that the increased MIC values were a result of reduced permeability of cefoxitin due to the lack of OmpF. Genetic deletion of both ompF and ompC did not compromise the integrity of the bacterial cell envelope in optimal growth conditions, suggesting that other outer-membrane porins may function in a compensatory role to facilitate nutrient uptake and cell envelope integrity. Taken together, to our knowledge this is the first study that genetically correlates increased antibiotic resistance with altered porin expression in S. marcescens. PMID- 25015364 TI - Multiple or mixed cerebral microbleeds and dementia in patients with vascular risk factors. AB - OBJECTIVE: To investigate whether cerebral microbleeds (CMBs) are independently associated with incident dementia in patients with vascular risk factors. METHODS: Using data from a Japanese cohort of participants with vascular risk factors in an observational study from 2001, we evaluated the association between CMBs at baseline and incident dementia. Baseline brain MRI was used to determine small-vessel disease (CMBs, lacunar infarcts, and white matter hyperintensities) and brain atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE epsilon4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings. RESULTS: Of the 524 subjects (mean age 68 +/- 8.3 years, 57.6% male, 12.8 +/- 2.6 years of schooling, 21.6% CMBs), 44 patients with incident dementia (20 Alzheimer disease, 18 vascular dementia, 3 mixed-type, and 3 other) were diagnosed during the median 7.5-year follow-up. In multivariate analysis, the presence of overall CMBs was not associated with an increased risk of incident all-cause dementia (p = 0.15). However, multiple CMBs (>= 2) or mixed (lobar and deep) CMBs were associated with the increased risk of all-cause dementia, whereas strictly lobar CMBs showed no association with any dementia. CONCLUSIONS: Multiple CMBs or mixed CMBs independently showed higher risk of all-cause dementia. Our results reinforce the hypothesis that CMBs exert deleterious effects on dementia incidence, suggesting that this association may be mediated by vascular burden. PMID- 25015363 TI - Preventing visual field deficits from neurosurgery. AB - OBJECTIVE: We assessed whether display of optic radiation tractography during anterior temporal lobe resection (ATLR) for refractory temporal lobe epilepsy (TLE) can reduce the severity of postoperative visual field deficits (VFD) and increase the proportion of patients who can drive and whether correction for brain shift using intraoperative MRI (iMRI) is beneficial. METHODS: A cohort of 21 patients underwent ATLR in an iMRI suite. Preoperative tractography of the optic radiation was displayed on the navigation and operating microscope displays either without (9 patients) or with (12 patients) correction for brain shift. VFD were quantified using Goldmann perimetry and eligibility to drive was assessed by binocular Esterman perimetry 3 months after surgery. Secondary outcomes included seizure freedom and extent of hippocampal resection. The comparator was a cohort of 44 patients who underwent ATLR without iMRI. RESULTS: The VFD in the contralateral superior quadrant were significantly less (p = 0.043) with iMRI guidance (0%-49.2%, median 14.5%) than without (0%-90.9%, median 24.0%). No patient in the iMRI cohort developed a VFD that precluded driving whereas 13% of the non-iMRI cohort failed to meet UK driving criteria. Outcome did not differ between iMRI guidance with and without brain shift correction. Seizure outcome and degree of hippocampal resection were unchanged. CONCLUSIONS: Display of the optic radiation with image guidance reduces the severity of VFD and did not affect seizure outcome or hippocampal resection. Correction for brain shift is possible but did not further improve outcome. Future work to incorporate tractography into conventional neuronavigation systems will make the work more widely applicable. PMID- 25015365 TI - Visual field mapping to prevent visual field deficits in epilepsy surgery: Seeing the problem. PMID- 25015367 TI - School nurses' familiarity and perceptions of academic accommodations for student athletes following sport-related concussion. AB - The purpose of this study was to evaluate school nurses' familiarity and perceptions regarding academic accommodations for student-athletes following sport-related concussion. School nurses (N = 1,246) accessed the survey School Nurses' Beliefs, Attitudes and Knowledge of Pediatric Athletes with Concussions (BAKPAC-SN). The BAKPAC-SN contained several questions pertaining to concussion management and academic accommodations. There were significant differences regarding personal experience as well as familiarity of academic accommodations (p < .001) between school nurses who work at a school that employs an athletic trainer and school nurses who work at a school that does not employ an athletic trainer. There were significant weak positive relationships between years of experience and familiarity with academic accommodations (r = .210, p < .001), 504 plans (r = .243, p < .001), and individualized education plans (r = .205, p < .001). School nurses employed at a single school were significantly more familiar with academic accommodations (p = .027) and 504 plans (p = .001) than school nurses employed at multiple schools. Health care professionals should collaborate to effectively manage a concussed patient and should consider academic accommodations to ensure whole-person health care. PMID- 25015366 TI - Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. AB - OBJECTIVE: To identify risk factors for intracranial hemorrhage in the natural history course of brain arteriovenous malformations (AVMs) using individual patient data meta-analysis of 4 existing cohorts. METHODS: We harmonized data from Kaiser Permanente of Northern California (n = 856), University of California San Francisco (n = 787), Columbia University (n = 672), and the Scottish Intracranial Vascular Malformation Study (n = 210). We censored patients at first treatment, death, last visit, or 10-year follow-up, and performed stratified Cox regression analysis of time-to-hemorrhage after evaluating hemorrhagic presentation, sex, age at diagnosis, deep venous drainage, and AVM size as predictors. Multiple imputation was performed to assess impact of missing data. RESULTS: A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation. Hemorrhagic presentation (hazard ratio 3.86, 95% CI 2.42-6.14) and increasing age (1.34 per decade, 1.17-1.53) independently predicted hemorrhage and remained significant predictors in the imputed dataset. Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60, 0.95-2.68, p = 0.02 in imputed dataset) may be additional predictors. AVM size was not associated with intracerebral hemorrhage in multivariable models (p > 0.5). CONCLUSION: This large, individual patient data meta-analysis identified hemorrhagic presentation and increasing age as independent predictors of hemorrhage during follow-up. Additional AVM cohort data may further improve precision of estimates, identify new risk factors, and allow validation of prediction models. PMID- 25015369 TI - Understanding P values. PMID- 25015368 TI - A randomised controlled trial of acceptance and commitment therapy (ACT) for psychosis: study protocol. AB - BACKGROUND: Cognitive behavior therapy for psychosis has been a prominent intervention in the psychological treatment of psychosis. It is, however, a challenging therapy to deliver and, in the context of increasingly rigorous trials, recent reviews have tempered initial enthusiasm about its effectiveness in improving clinical outcomes. Acceptance and commitment therapy shows promise as a briefer, more easily implemented therapy but has not yet been rigorously evaluated in the context of psychosis. The purpose of this trial is to evaluate whether Acceptance and Commitment Therapy could reduce the distress and disability associated with psychotic symptoms in a sample of community-residing patients with chronic medication-resistant symptoms. METHODS/DESIGN: This is a single (rater)-blind multi-centre randomised controlled trial comparing Acceptance and Commitment Therapy with an active comparison condition, Befriending. Eligible participants have current residual hallucinations or delusions with associated distress or disability which have been present continuously over the past six months despite therapeutic doses of antipsychotic medication. Following baseline assessment, participants are randomly allocated to treatment condition with blinded, post-treatment assessments conducted at the end of treatment and at 6 months follow-up. The primary outcome is overall mental state as measured using the Positive and Negative Syndrome Scale. Secondary outcomes include preoccupation, conviction, distress and disruption to life associated with symptoms as measured by the Psychotic Symptom Rating Scales, as well as social functioning and service utilisation. The main analyses will be by intention-to-treat using mixed-model repeated measures with non-parametric methods employed if required. The model of change underpinning ACT will be tested using mediation analyses. DISCUSSION: This protocol describes the first randomised controlled trial of Acceptance and commitment therapy in chronic medication-resistant psychosis with an active comparison condition. The rigor of the design will provide an important test of its action and efficacy in this population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12608000210370. Date registered: 18 April 2008. PMID- 25015370 TI - Socioeconomic disparities in secondhand smoke exposure among US never-smoking adults: the National Health and Nutrition Examination Survey 1988-2010. AB - BACKGROUND: Secondhand smoke (SHS) is a leading preventable cause of illness, disability and mortality. There is a lack of quantitative analyses on socioeconomic disparities in SHS; especially, it is not known how socioeconomic disparities have changed in the past two decades in the USA. OBJECTIVES: To examine socioeconomic disparities and long-term temporal trends in SHS exposure among US never-smoking adults aged >=20 years. METHODS: 15 376 participants from the National Health and Nutrition Examination Survey (NHANES) 1999-2010 were included in the analysis of socioeconomic disparities; additional 8195 participants from NHANES III 1988-1994 were included in the temporal trend analysis. SHS exposure was assessed using self-reported exposure in the home and workplace as well as using serum cotinine concentrations >=0.05 ng/mL. Individual socioeconomic status (SES) was assessed using poverty-to-income ratio. RESULTS: During the period 1999-2010, 6% and 14% of participants reported SHS exposure in the home and workplace, respectively; 40% had serum cotinine-indicated SHS exposure. Individual SES was strongly associated with SHS exposure in a dose response fashion; participants in the lowest SES group were 2-3 times more likely to be exposed to SHS compared with those in the highest SES group. During the period 1988-2010, the prevalence declined over 60% for the three types of SHS exposure. However, for cotinine-indicated exposure, the magnitudes of the declines were smaller for lower SES groups compared with higher SES groups, leading to widening socioeconomic disparities in SHS exposure. CONCLUSIONS: SHS exposure is still widespread among US never-smoking adults, and socioeconomic disparities for cotinine-indicated exposure have substantially increased in the past two decades. PMID- 25015371 TI - A novel approach for monitoring tobacco use in local communities by wastewater analysis. AB - OBJECTIVE: We propose a novel approach for measuring tobacco use in a community through the chemical analysis of nicotine metabolites in urban wastewater. It offers frequent monitoring and 'real-time', 'evidence-based' estimates of tobacco consumption which may complement epidemiological surveillance systems normally repeated only every few years. METHODS: Two urinary metabolites of nicotine, namely cotinine and trans-3'-hydroxycotinine, were selected as biomarkers of tobacco consumption in urban wastewater. During smoking, a known amount of nicotine is absorbed and after metabolism excreted as metabolites in urine, ending up in the wastewater; quantitative analysis of the metabolites in the wastewater allows back-calculation of the nicotine collectively absorbed by the population producing the sewage and, indirectly, their tobacco use. Representative samples of wastewater were collected from sewage treatment plants in eight Italian cities and analysed by mass spectrometry. Mass loads of the metabolites were used to estimate nicotine consumption. RESULTS: Wastewater analysis in the cities under study was used to estimate the number of cigarettes smoked, in order to compare the results of this study with those obtained from population surveys. The number of cigarettes calculated with the two methods were closely comparable and wastewater analysis was sufficiently sensitive to confirm the differences in tobacco consumption between northern and southern Italy, previously described in population surveys. CONCLUSIONS: The described approach can serve as a supplementary indicator of tobacco consumption in local communities. This approach can provide objective and updated information, which are useful to assess the efficacy of tobacco-control interventions, with the aim of designing and implementing effective tobacco control plans. PMID- 25015372 TI - Sociodemographic correlates of self-reported exposure to e-cigarette communications and its association with public support for smoke-free and vape free policies: results from a national survey of US adults. AB - BACKGROUND: Exposure to e-cigarette communications (eg, advertisements, news and entertainment media, and interpersonal discussion) may influence support for smoke-free or vape-free policies. This study examined the sociodemographic correlates of self-reported exposure to e-cigarette communications and their relationships with support for restricting vaping and smoking in public venues. METHOD: Online survey data was collected from a representative sample of US adults (n=1449) between October and December 2013 (mean age=50 years, 51% female, 8% African-American, 10% Hispanic, 6% other races) and weighted to match the US adult population. We fitted multiple regression models, adjusting for demographic variables, to examine associations between support for policies to restrict vaping and smoking in public venues and self-reported frequency of exposure to e cigarette communications in the preceding month. We fitted separate models to assess associations between policy support and frequency of exposures weighted by whether each category of e-cigarette communications was perceived as positive or negative. RESULTS: Higher self-reported exposure to advertising (B=-0.022, p=0.006), other media (B=-0.022, p=0.043) and interpersonal discussion (B=-0.071, p<0.0005) perceived as positive were associated with lower support for vaping restrictions, adjusting for covariates. Exposure to e-cigarette communications was associated with lower support for smoking restrictions in bivariate analyses but was not significant after adjusting for covariates. CONCLUSIONS: Further research is needed to assess whether messages portraying e-cigarettes as a way to circumvent smoking restrictions from advertisements and other media are influencing public support for vape-free policies. These findings provide empirical evidence to inform the policy debate over regulating specific e cigarette advertising claims. PMID- 25015374 TI - Delayed primary closure of contaminated abdominal wall defects with non crosslinked porcine acellular dermal matrix compared with conventional staged repair: a retrospective study. AB - INTRODUCTION: Synthetic mesh has been used traditionally to repair abdominal wall defects, but its use is limited in the case of bacterial contamination. New biological materials are now being used successfully for delayed primary closure of contaminated abdominal wall defects. The costs of biological materials may prevent surgeons from using them. We compared the conventional staged repair of contaminated abdominal wall defects with a single-stage procedure using a non crosslinked porcine acellular dermal matrix. METHODS: A total of 14 cases with Grade 3 contaminated abdominal wall defects underwent delayed primary closure of the abdomen using a non-crosslinked porcine acellular dermal matrix (StratticeTM Reconstructive Tissue Matrix, LifeCell Corp., Branchburg, NJ, USA). The results were compared with a group of 14 patients who had received conventional treatment for the repair of contaminated abdominal wall defects comprising a staged repair during two separate hospital admissions employing synthetic mesh. Treatment modalities, outcomes, and costs were compared. RESULTS: In all cases treated with delayed primary closure employing non-crosslinked porcine acellular dermal matrix, there were no complications related to its use. Two patients died due to unrelated events. Although treatment costs were estimated to be similar in the two groups, the patients treated with porcine acellular dermal matrix spent less time as an inpatient than those receiving conventional two-stage repair. CONCLUSIONS: Delayed primary closure of contaminated abdominal wall defects using a non-crosslinked porcine acellular dermal matrix may be a suitable alternative to conventional staged repair. In our patients, it resulted in early restoration of abdominal wall function and shorter hospitalization. The costs for treating contaminated abdominal wall defects using porcine acellular dermal matrix during a single hospital admission were not higher than costs for conventional two-stage repair. Further randomized studies are needed to expand upon these findings. PMID- 25015373 TI - Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury. AB - OBJECTIVE: The mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence of fatty acids, adipokines, and body weight on OA following joint injury in an obese mouse model. METHODS: Mice were fed high-fat diets rich in various fatty acids (FA) including saturated FAs (SFAs), omega-6 polyunsaturated FAs (PUFAs), and omega-3 PUFAs. OA was induced by destabilising the medial meniscus. Wound healing was evaluated using an ear punch. OA, synovitis and wound healing were determined histologically, while bone changes were measured using microCT. Activity levels and serum cytokines were measured at various time-points. Multivariate models were performed to elucidate the associations of dietary, metabolic and mechanical factors with OA and wound healing. RESULTS: Using weight-matched mice and multivariate models, we found that OA was significantly associated with dietary fatty acid content and serum adipokine levels, but not with body weight. Furthermore, spontaneous activity of the mice was independent of OA development. Small amounts of omega-3 PUFAs (8% by kcal) in a high-fat diet were sufficient to mitigate injury-induced OA, decreasing leptin and resistin levels. omega-3 PUFAs significantly enhanced wound repair, SFAs or omega-6 PUFAs independently increased OA severity, heterotopic ossification and scar tissue formation. CONCLUSIONS: Our results indicate that with obesity, dietary FA content regulates wound healing and OA severity following joint injury, independent of body weight, supporting the need for further studies of dietary FA supplements as a potential therapeutic approach for OA. PMID- 25015376 TI - Separation of small molecules on novel monolithic poly(vinylphosphonic acid/ethylene dimethacrylate) columns. AB - In HPLC, monolithic organic stationary phases are usually restricted to the separation of high-molecular-weight compounds such as proteins or oligonucleotides. The aim of this study was to enlarge the applicability of monolithic stationary phases to the micro-liquid chromatography separation of smaller molecules. For this, a new monolithic stationary phase was synthesized by radical polymerization of vinylphosphonic acid (VPA) and ethylene dimethacrylate (EDMA) using azobisisobutyronitrile as radical initiator. In situ reactions at two different temperatures and reaction times resulted in poly(VPA/EDMA) capillaries and allowed fast separations for small molecules, especially parabens and alkylbenzenes. The capillaries showed high mechanical stability, low-swelling properties, high permeability and lower surface area as expected. Polymerization at 75 degrees C for 20 min exhibited efficient separation of parabens within 1.5 min with short half-peak widths and satisfactory resolutions. Apart from attenuated total reflectance Fourier transform infrared (ATR-IR) measurements, the pH-dependent separation of alkylbenzenes confirmed the incorporation of phosphonate groups into the polymeric network, resulting into deprotonation of the stationary phase at pH >4. Moreover, methylparaben and propylparaben were quantitatively determined in human saliva after treatment with paraben-containing tooth paste. PMID- 25015375 TI - ERCC1-positive circulating tumor cells in the blood of ovarian cancer patients as a predictive biomarker for platinum resistance. AB - BACKGROUND: Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance. METHODS: The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1. RESULTS: At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1(+)CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1(+)CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis. CONCLUSIONS: The presence of ERCC1(+)CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer. PMID- 25015377 TI - Simultaneous quantification of three pyranocoumarins of Peucedanum praeruptorum in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetic study. AB - A simple, rapid and robust liquid chromatography-tandem mass spectrometry was established and validated for simultaneous quantifications of three pyranocoumarins (praeruptorin A-C) in rat plasma. Following a single-step liquid liquid extraction, the analytes were separated on a reversed-phase C18 column with a mobile phase consisting of methanol and 10 mM ammonium acetate solution (70 : 30, v/v) at a constant flow rate of 0.3 mL/min. The linear calibration curves were obtained over the concentration ranges 2.93-1470 ng/mL for praeruptorin A, 1.47-734 ng/mL for praeruptorin B and 2.00-1000 ng/mL for praeruptorin C. The within-batch accuracy was -8.6 to 7.5% for praeruptorin A, 9.5 to 12.0% for praeruptorin B and -10.5 to 12.5% for praeruptorin C, respectively. The between-batch accuracy was -3.5 to 1.4% for praeruptorin A, 8.7 to 3.4% for praeruptorin B and -6.0 to 4.3% for praeruptorin C, respectively. The within-batch and between-batch precisions were <=13.1 and <=8.2%, respectively. This method is suitable to simultaneously determine the three pyranocoumarins in plasma and thus to investigate the pharmacokinetics of the pyranocoumarins of Peucedanum praeruptorum in rats. PMID- 25015378 TI - Less invasive implantation of HeartWare left ventricular assist device. AB - Mechanical support by means of ventricular assist devices is at present the most promising alternative of efforts aimed at increasing the supply of donor organs. The support of the left dysfunctional ventricle enables appropriate haemodynamic stabilization and recovery of secondary organ failure, often present in these severely ill patients. The current results of left ventricular assist device (LVAD) therapy for bridge to transplantation are excellent when compared with the outcome without the availability of this therapy. Additionally, a rapid extubation of these patients has demonstrated to be efficient in cardiac surgery for faster recovery and rehabilitation. Consequently, in recent years, surgical objectives have become much more clearly defined, and the concept of less invasive cardiac surgery can be applied to make this operation less complicated, anatomically focused with a greater clinical impact. We describe an LVAD implantation technique, applying the concept of less invasive cardiac surgery, consisting in the association of reduced surgical approaches, off-pump implantation and reduced administration of heparin dose, in order to achieve rapid extubation and rehabilitation of the patient, preserving low morbidity, and still meeting all the goals of the standard procedure. PMID- 25015379 TI - Characterization of the complete mitochondrial genomes of Nematodirus oiratianus and Nematodirus spathiger of small ruminants. AB - BACKGROUND: Nematodirus spp. are among the most common nematodes of ruminants worldwide. N. oiratianus and N. spathiger are distributed worldwide as highly prevalent gastrointestinal nematodes, which cause emerging health problems and economic losses. Accurate identification of Nematodirus species is essential to develop effective control strategies for Nematodirus infection in ruminants. Mitochondrial DNA (mtDNA) could provide powerful genetic markers for identifying these closely related species and resolving phylogenetic relationships at different taxonomic levels. METHODS: In the present study, the complete mitochondrial (mt) genomes of N. oiratianus and N. spathiger from small ruminants in China were obtained using Long-range PCR and sequencing. RESULTS: The complete mt genomes of N. oiratianus and N. spathiger were 13,765 bp and 13,519 bp in length, respectively. Both mt genomes were circular and consisted of 36 genes, including 12 genes encoding proteins, 2 genes encoding rRNA, and 22 genes encoding tRNA. Phylogenetic analyses based on the concatenated amino acid sequence data of all 12 protein-coding genes by Bayesian inference (BI), Maximum likelihood (ML) and Maximum parsimony (MP) showed that the two Nematodirus species (Molineidae) were closely related to Dictyocaulidae. CONCLUSIONS: The availability of the complete mtDNA sequences of N. oiratianus and N. spathiger not only provides new mtDNA sources for a better understanding of nematode mt genomics and phylogeny, but also provides novel and useful genetic markers for studying diagnosis, population genetics and molecular epidemiology of Nematodirus spp. in small ruminants. PMID- 25015380 TI - High resolution mapping of modified DNA nucleobases using excision repair enzymes. AB - The incorporation and creation of modified nucleobases in DNA have profound effects on genome function. We describe methods for mapping positions and local content of modified DNA nucleobases in genomic DNA. We combined in vitro nucleobase excision with massively parallel DNA sequencing (Excision-seq) to determine the locations of modified nucleobases in genomic DNA. We applied the Excision-seq method to map uracil in E. coli and budding yeast and discovered significant variation in uracil content, wherein uracil is excluded from the earliest and latest replicating regions of the genome, possibly driven by changes in nucleotide pool composition. We also used Excision-seq to identify sites of pyrimidine dimer formation induced by UV light exposure, where the method could distinguish between sites of cyclobutane and 6-4 photoproduct formation. These UV mapping data enabled analysis of local sequence bias around pyrimidine dimers and suggested a preference for an adenosine downstream from 6-4 photoproducts. The Excision-seq method is broadly applicable for high precision, genome-wide mapping of modified nucleobases with cognate repair enzymes. PMID- 25015381 TI - RSC-dependent constructive and destructive interference between opposing arrays of phased nucleosomes in yeast. AB - RSC and SWI/SNF are related ATP-dependent chromatin remodeling machines that move nucleosomes, regulating access to DNA. We addressed their roles in nucleosome phasing relative to transcription start sites in yeast. SWI/SNF has no effect on phasing at the global level. In contrast, RSC depletion results in global nucleosome repositioning: Both upstream and downstream nucleosomal arrays shift toward the nucleosome-depleted region (NDR), with no change in spacing, resulting in a narrower and partly filled NDR. The global picture of RSC-depleted chromatin represents the average of a range of chromatin structures, with most genes showing a shift of the +1 or the -1 nucleosome into the NDR. Using RSC ChIP data reported by others, we show that RSC occupancy is highest on the coding regions of heavily transcribed genes, though not at their NDRs. We propose that RSC has a role in restoring chromatin structure after transcription. Analysis of gene pairs in different orientations demonstrates that phasing patterns reflect competition between phasing signals emanating from neighboring NDRs. These signals may be in phase, resulting in constructive interference and a regular array, or out of phase, resulting in destructive interference and fuzzy positioning. We propose a modified barrier model, in which a stable complex located at the NDR acts as a bidirectional phasing barrier. In RSC-depleted cells, this barrier has a smaller footprint, resulting in narrower NDRs. Thus, RSC plays a critical role in organizing yeast chromatin. PMID- 25015383 TI - Gene length and expression level shape genomic novelties. AB - Gene duplication and alternative splicing are important mechanisms in the production of genomic novelties. Previous work has shown that a gene's family size and the number of splice variants it produces are inversely related, although the underlying reason is not well understood. Here, we report that gene length and expression level together explain this relationship. We found that gene lengths correlate with both gene duplication and alternative splicing: Longer genes are less likely to produce duplicates and more likely to exhibit alternative splicing. We show that gene length is a dynamic property, increasing with evolutionary time--due in part to the insertions of transposable elements- and decreasing following partial gene duplications. However, gene length alone does not account for the relationship between alternative splicing and gene duplication. A gene's expression level appears both to impose a strong constraint on its length and to restrict gene duplications. Furthermore, high gene expression promotes alternative splicing, in particular for long genes, and alternatively, short genes with low expression levels have large gene families. Our analysis of the human and mouse genomes shows that gene length and expression level are primary genic properties that together account for the relationship between gene duplication and alternative splicing and bias the origin of novelties in the genome. PMID- 25015384 TI - More must be done for head and neck cancer patients, audit shows. PMID- 25015382 TI - Genomic analysis of the causative agents of coccidiosis in domestic chickens. AB - Global production of chickens has trebled in the past two decades and they are now the most important source of dietary animal protein worldwide. Chickens are subject to many infectious diseases that reduce their performance and productivity. Coccidiosis, caused by apicomplexan protozoa of the genus Eimeria, is one of the most important poultry diseases. Understanding the biology of Eimeria parasites underpins development of new drugs and vaccines needed to improve global food security. We have produced annotated genome sequences of all seven species of Eimeria that infect domestic chickens, which reveal the full extent of previously described repeat-rich and repeat-poor regions and show that these parasites possess the most repeat-rich proteomes ever described. Furthermore, while no other apicomplexan has been found to possess retrotransposons, Eimeria is home to a family of chromoviruses. Analysis of Eimeria genes involved in basic biology and host-parasite interaction highlights adaptations to a relatively simple developmental life cycle and a complex array of co-expressed surface proteins involved in host cell binding. PMID- 25015385 TI - Seek and you shall remember: scene semantics interact with visual search to build better memories. AB - Memorizing critical objects and their locations is an essential part of everyday life. In the present study, incidental encoding of objects in naturalistic scenes during search was compared to explicit memorization of those scenes. To investigate if prior knowledge of scene structure influences these two types of encoding differently, we used meaningless arrays of objects as well as objects in real-world, semantically meaningful images. Surprisingly, when participants were asked to recall scenes, their memory performance was markedly better for searched objects than for objects they had explicitly tried to memorize, even though participants in the search condition were not explicitly asked to memorize objects. This finding held true even when objects were observed for an equal amount of time in both conditions. Critically, the recall benefit for searched over memorized objects in scenes was eliminated when objects were presented on uniform, non-scene backgrounds rather than in a full scene context. Thus, scene semantics not only help us search for objects in naturalistic scenes, but appear to produce a representation that supports our memory for those objects beyond intentional memorization. PMID- 25015386 TI - Potentially avoidable hospitalisation for constipation in Victoria, Australia in 2010-11. AB - BACKGROUND: When primary care of constipation fails, the patient may need emergency hospitalisation for disimpaction. This study aimed to provide population-based data on the number of unplanned admissions and the cost to the healthcare system for constipation in Victoria, Australia in financial year 2010 11. METHODS: The Victorian Admitted Episodes Dataset was examined to find the number of emergency hospital separations coded as constipation (ICD-10-AM Code K390). An estimate of costs was determined from the number of weighted inlier equivalent separations (WIES) multiplied by the WEIS price, used by the Victorian Government for funding purposes. RESULTS: There were 3978 emergency separations for constipation in Victoria in 2010-2011, 92% in public hospitals. Fifty-five percent were female and 38% > 75 years old. One third stayed overnight and 1/3 more than 1 day. The emergency bed day rate was 7.1 per 10,000 of population. The estimate of cost, based on WEIS, was approximately $8.3 million. Potential savings could be made by reducing the number of separations in 6 Local Government Areas (LGAs). CONCLUSIONS: This study shows that the burden (in number of admissions, emergency bed days and overall direct costs) in managing emergency admissions for constipation in Victoria, Australia, is very significant and likely to be similar in other developed countries. Improved primary healthcare and alternative ways to achieve faecal disimpaction without emergency admission could save the public health system a proportion of this $8.3 million. PMID- 25015387 TI - In vivo evaluation of inflammatory bowel disease with the aid of MUPET and the translocator protein 18 kDa radioligand [18F]DPA-714. AB - PURPOSE: The purpose of the study was to validate [18F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, as a probe to non-invasively quantify the inflammatory state in inflammatory bowel disease (IBD) animal models. PROCEDURES: Quantitative positron emission tomography (PET) imaging of intestinal inflammation was conducted with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) a glucose metabolism surrogate marker and [18F]DPA-714 a ligand of the 18 kDa TSPO, on two IBD models. The first model was induced using dextran sodium sulfate (DSS), creating global inflammation in the colon. The second model was induced by rectally administering trinitrobenzenesulfonic acid (TNBS), creating local and acute inflammation. RESULTS: The level of inflammation was analyzed using PET imaging on days 7 and 8. The analysis obtained with [18F]DPA-714, yielded a significant difference between the DSS treated (0.50 +/- 0.17%ID/cc) and non treated rats (0.35 +/- 0.15%ID/cc). [18F]FDG on the other hand did not yield a significant difference. We did observe a mean glucose consumption in the colon increase from 0.40 +/- 0.11 %ID/cc to 0.54 +/- 0.17 %ID/cc. In the TNBS model, the uptake level of [18 F]DPA-714 increased significantly from 0.46 +/- 0.23%ID/cc for the non-treated group, to 1.30 +/- 0.62%ID/cc for those treated. PET signal was correlated with increased TSPO expression at cellular level. CONCLUSIONS: Results indicate that [18F]DPA-714 is suitable for studying inflammation in IBD models. [18F]DPA-714 could be a good molecular probe to non invasively evaluate the level and localization of inflammation. Moreover, in vivo imaging using this TSPO ligand is potentially a powerful tool to stage and certainly to follow the evolution and therapeutic efficiency at molecular level within this disease family. PMID- 25015388 TI - Nerve repair: toward a sutureless approach. AB - Peripheral nerve repair for complete section injuries employ reconstructive techniques that invariably require sutures in their application. Sutures are unable to seal the nerve, thus incapable of preventing leakage of important intraneural fluids from the regenerating nerve. Furthermore, sutures are technically demanding to apply for direct repairs and often induce detrimental scarring that impedes healing and functional recovery. To overcome these limitations, biocompatible and biodegradable glues have been used to seal and repair peripheral nerves. Although creating a sufficient seal, they can lack flexibility and present infection risks or cytotoxicity. Other adhesive biomaterials have recently emerged into practice that are usually based on proteins such as albumin and collagen or polysaccharides like chitosan. These adhesives form their union to nerve tissue by either photothermal (tissue welding) or photochemical (tissue bonding) activation with laser light. These biomaterial adhesives offer significant advantages over sutures, such as their capacity to unite and seal the epineurium, ease of application, reduced invasiveness and add the potential for drug delivery in situ to facilitate regeneration. This paper reviews a number of different peripheral nerve repair (or reconstructive) techniques currently used clinically and in experimental procedures for nerve injuries with or without tissue deficit. PMID- 25015389 TI - Intraoperative continuous monitoring of facial motor evoked potentials in acoustic neuroma surgery. AB - The preservation of facial nerve function is one of the primary objectives in acoustic neuroma surgery. We detail our method of continuous intraoperative facial motor evoked potential (MEP) monitoring and present criteria for the preservation of facial nerve function to avoid postoperative facial nerve palsy. Our study population was comprised of 15 patients who did not (group 1), and 20 who did (group 2) undergo facial MEP monitoring during surgery to remove acoustic neuromas. In group 2, we continuously stimulated the facial motor cortex at 5- or 10-s intervals throughout surgery. Electromyograms (EMGs) were recorded from the contralateral orbicularis oculi- and orbicularis oris muscles. Optimal anode and cathode placement was at the facial motor cortex and the vertex, respectively. Postoperative facial palsy occurred in 8 of the 15 group 1 patients; in 2 it improved to grade II at 6 months after the operation. Of the 20 group 2 patients, 7 suffered postoperative facial palsy. At 6 months after the operation, their facial nerve function was normal. At the end of the operation, the ratio of the amplitude of the supramaximal EMG to the amplitude at the dural opening was 39.6 % in patients with- and 94.3 % in patients without transient postoperative facial palsy. Continuous facial MEP monitoring not only alerts to surgical invasion of the facial nerves but also helps to predict postoperative facial nerve function. To preserve a minimum amplitude ratio of 50 %, even transient postoperative facial palsy must be avoided. MEP monitoring is an additional useful modality for facial nerve monitoring during acoustic neuroma surgery. PMID- 25015390 TI - Comparison of the Self-reported Foot and Ankle Score (SEFAS) and the American Orthopedic Foot and Ankle Society Score (AOFAS). AB - BACKGROUND: The Self-reported Foot and Ankle Score (SEFAS) is a patient-reported outcome measure, while the American Orthopedic Foot and Ankle Society Score (AOFAS) is a clinician-based score, both used for evaluation of foot and ankle disorders. The purpose of this study was to compare the psychometric properties of these 2 scoring systems. METHODS: A total of 95 patients with great toe disorders and 111 patients with ankle or hindfoot disorders completed the 2 scores before and after surgery. We evaluated time to complete the scores in seconds, correlations between scores with Spearman's correlation coefficient (r s), floor and ceiling effects by proportion of individuals who reached the minimum or maximum values, test-retest reliability and interobserver reliability by intraclass correlation coefficient (ICC), internal consistency by Cronbach's coefficient alpha (CA), and responsiveness by effect size (ES). Data are provided as correlation coefficients, means, and standard deviations. RESULTS: SEFAS was completed 3 times faster than AOFAS. The scores correlated with an r s of .49 for great toe disorders and .67 for ankle/hindfoot disorders (both P < .001). None of the scores had any floor or ceiling effect. SEFAS test-retest ICC values measured 1 week apart were .89 for great toe and .92 for ankle/hindfoot disorders, while the corresponding ICC values for AOFAS were .57 and .75. AOFAS interobserver reliability ICC values were .70 for great toe and .81 for ankle/hindfoot disorders. SEFAS CA values were .85 for great toe and .86 for ankle/hindfoot disorders, while the corresponding CA values for AOFAS were .15 and .42. SEFAS ES values were 1.15 for great toe and 1.39 for ankle/hindfoot disorders, while the corresponding ES values for AOFAS were 1.05 and 1.73. CONCLUSION: As SEFAS showed similar or better outcome in our tests and was completed 3 times faster than AOFAS, we recommend SEFAS for evaluation of patients with foot and ankle disorders. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 25015391 TI - Percutaneous lateral ankle ligament reconstruction using a split peroneus longus tendon free graft: technical tip. PMID- 25015392 TI - Outcomes Following Microfracture in Grade 3 and 4 Articular Cartilage Lesions of the Ankle. AB - BACKGROUND: The purpose of this study was to document outcomes following microfracture of articular cartilage lesions of the ankle. Our hypothesis was that patients who underwent ankle microfracture would have good to excellent outcomes. METHODS: This study was institutional review board approved. Patients older than 18 years who underwent ankle microfracture surgery for Outerbridge grade 3 or 4 articular cartilage lesions, by a single surgeon, were included. Detailed intraoperative findings were documented at surgery. Patients completed a questionnaire with Foot and Ankle Disability Index (FADI), Lysholm, Tegner, and patient satisfaction with outcome. All data were collected prospectively and stored in a data registry and retrospectively reviewed. Forty patients (21 males, 19 females, mean age = 42 years [range, 19-65 years]) were included in this study. Thirteen (33%) had previous ankle surgery. Follow-up was obtained for 94% of patients (n = 34). Mean follow-up time was 26 months (range, 12-48 months). RESULTS: Mean talar defect size was 70 mm2 (range, 4-300 mm2). Mean tibia defect size was 31 mm2 (range, 8-54 mm2). Four patients (10.5%) required subsequent surgery following microfracture surgery. Mean time to second surgery was 17 months (range, 4-32 months). Mean Lysholm score was 74 (range, 31-96). Mean FADI Activities of Daily Living (ADL) was 81 (range, 33-99), FADI Sport was 62 (range, 13-100), and FADI total score was 77 (range, 28-98). Median Tegner was 4 (range, 0-10). Median patient satisfaction was 8 (range, 3-10). Patients who had previous ankle surgery had significantly lower outcome scores versus patients who did not have previous ankle surgery for FADI ADL (70 vs 81, P = .029) and FADI Total (51 vs 77, P = .028). Days from injury to surgery were correlated with age at surgery (r = .323, P = .042) and negatively correlated with FADI ADL (r = -.431, P = .014), FADI Sport (r = -.490, P = .004), FADI Total (r = -.429, P = .014), and Tegner (r = -.402, P = .023). CONCLUSION: Patients who underwent microfracture for grade 3 or 4 ankle articular cartilage lesions had high patient satisfaction. Patients who had previous ankle surgery had lower postoperative ankle function; however, patient satisfaction remained high. This study supports microfracture for treatment of grade 3 and 4 ankle articular cartilage lesions. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25015393 TI - Subtalar joint configuration on weightbearing CT scan. AB - BACKGROUND: Standard values that describe the morphology of the subtalar (ST) joint have previously been obtained from cadaveric studies or by using conventional unloaded radiographs. It is known that these parameters differ significantly from those measured in vivo and in loaded images, limiting the diagnostic value of the previously published morphological parameters in the literature. However, the morphology of the ST joint clearly affects its function. The objective of this study was to determine the morphology of the posterior facet of the ST joint using loaded computed tomography (CT) images and to describe the different configurations found in asymptomatic patients. METHODS: A weightbearing CT scan was performed on 59 patients without any history of hindfoot and ankle pathology. The shape of the posterior facet and the subtalar vertical angle (SVA) were measured in 3 different coronal planes of the ST joint. RESULTS: The posterior facet was concave in 88% and flat in 12%. The posterior facet was oriented in valgus in 90% and varus in 10% when measured in the middle coronal plane. However, the SVA changed depending on which coronal plane it was measured in. CONCLUSION: We believe it is important to get a better insight into the morphological parameters of the ST joint. CLINICAL RELEVANCE: Knowledge of subtalar joint morphology could help clarify why certain failures have occurred in reconstructive hindfoot surgery and thus might help plan the surgical procedure to reduce these failures in the future. PMID- 25015394 TI - Prognostic value of the microRNA-29 family in patients with primary osteosarcomas. AB - The aim of this study was to facilitate and deepen the understanding of the associations of the microRNA-29 (miR-29) family with tumor progression and patients' prognosis of primary osteosarcoma. We examined expression levels of miR 29a, miR-29b, and miR-29c in tumor tissues and patients' sera of 80 cases of primary osteosarcomas by quantitative real-time reverse transcriptase-polymerase chain reaction. The correlations of their serum levels with clinicopathological characteristics and patient prognosis were also analyzed. The expression levels of miR-29a, miR-29b, and miR-29c in osteosarcoma tissues and patients' sera were all significantly higher than those in normal controls (all P < 0.05). The serum levels of miR-29a and miR-29b in the patients with higher tumor grade (both P = 0.01), positive metastasis (both P = 0.006), and positive recurrence (both P = 0.006) were both markedly higher than those with lower tumor grade, negative metastasis, and negative recurrence. According to the survival analysis of 80 osteosarcoma patients, cases in the miR-29a-high and miR-29b-high-expression groups both showed shorter overall survival (OS, both P < 0.001) and disease-free survival (DFS, both P < 0.001). Furthermore, the serum levels of miR-29a and miR 29b were both independent prognostic factors for OS and DFS of osteosarcoma patients. However, high miR-29c level was not related to any clinicopathological characteristics and patient prognosis of osteosarcomas (P > 0.05). The findings from the present study reveal that the miR-29 family may play crucial roles in the development and progression of human osteosarcoma. In particular, the serum levels of miR-29a and miR-29b may well estimate the prognosis of patients with this malignancy. PMID- 25015395 TI - Increased MMP-21 expression in esophageal squamous cell carcinoma is associated with progression and prognosis. AB - Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy, requiring effective biomarkers for prognosis and therapeutic responsiveness. In this retrospective study of banked pathology material, we investigated the protein expression of MMP-21 in ESCC and its association with clinical significance. MMP-21 protein expression was investigated in 311 cases of ESCC by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of MMP-21 expression with clinicopathological characteristics and overall survival of patients with ESCC. Results showed that MMP-21 expression was significantly increased in ESCC (P < 0.001). It was also found that MMP-21 expression in ESCC was associated with tumor invasion (P < 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001) and TNM stage (P < 0.001). Kaplan-Meier analysis showed MMP-21 expression was associated with overall survival of patients with ESCC for patients with tumors of positive MMP-21 staining tend to have worse overall survival (P < 0.001). Multivariate analysis proved that MMP-21 was an independent prognostic factor for overall survival for patients with ESCC (P < 0.001). These results suggested the potential role of MMP 21 in tumor progression and prognosis predication of human ESCC. It might also be a novel molecular target for therapeutic intervention. PMID- 25015396 TI - Thyroid carcinoma after treatment for malignancies in childhood and adolescence: from diagnosis through follow-up. AB - With improvements in the survival rates after childhood cancer, many clinicians have turned their attention to reporting on late effects, and how they might be prevented or treated. In childhood the thyroid gland is especially vulnerable to the carcinogenic action of ionizing radiation. This retrospective study focused on secondary thyroid cancers seen at our institution over more than 30 years (between 1980 and 2012) in patients treated for other malignancies in pediatric age. 36 patients were identified. In most cases, the primary cancer had been Hodgkin disease, and all the patients had been administered radiotherapy for their first malignancy. The secondary thyroid cancers were treated with total thyroidectomy in 27 cases (six with lymphadenectomy), and hemithyroidectomy in nine (one with lymphadenectomy). 12 Patients were also given radiometabolic therapy. All but two had TSH suppression therapy. The histological diagnoses were: 31 papillary and five follicular carcinomas. At 5 and 10 years, the OS was 100 and 95 %, respectively, and the PFS was 96 and 83 %. None of the patients died of their thyroid disease. Nodal involvement at onset was the only factor correlating with recurrence. Surgical sequelae only occurred in patients who underwent total thyroidectomy. Survival in these patients did not depend on the extent of surgery on the thyroid parenchyma. Our data confirm a good prognosis for secondary thyroid cancer, prompting us to encourage a minimalist approach to the treatment of these particular patients wherever possible. PMID- 25015399 TI - Gastroduodenal ulcers on CT: forgotten, but not gone. AB - OBJECTIVE: To estimate the incidence of missed gastroduodenal ulcers on routine abdominal computed tomography (CT) and identify findings and methods to improve sensitivity of CT interpretation for peptic ulcers. MATERIALS AND METHODS: This is a retrospective chart and imaging review. Two blinded readers independently reviewed CTs performed within 7 days prior to endoscopy of 114 subjects; this included 57 consecutive subjects with proven gastroduodenal ulcers intermixed with 57 subjects with endoscopically normal examinations. Presence, location and size of ulcer crater, and ancillary findings (mural edema, asymmetric wall thickening, focal fat stranding, regional lymph nodes, and extraluminal gas) were recorded before and after review of multiplanar reformatted images. Radiology reports were then reviewed to determine if an ulcer was identified prospectively. RESULTS: Thirty-one ulcers (54%) were radiographically occult, missed by both readers. Thirteen ulcers were correctly and independently identified by both readers (sensitivity/specificity = 30%/100%). With review of multiplanar reformats, sensitivity and accuracy increased for both readers. When two or more ancillary findings were identified, the odds ratio of a true ulcer being present was greater than 5.6 (P = 0.0001). Both size and location of ulcer were important for detection; readers were more likely to identify gastric ulcers compared to duodenal or marginal ulcers (P = 0.02). Only 3/13 definitely visible ulcers were correctly identified during initial CT interpretation. CONCLUSIONS: Although CT has low sensitivity for peptic ulcer disease, the miss rate for visible peptic ulcers is high. Increased awareness, multiplanar imaging review, and identification of ancillary findings may improve sensitivity for gastroduodenal ulcers. PMID- 25015398 TI - Cross-sectional and longitudinal evaluation of liver volume and total liver fat burden in adults with nonalcoholic steatohepatitis. AB - PURPOSE: To explore the cross-sectional and longitudinal relationships between fractional liver fat content, liver volume, and total liver fat burden. METHODS: In 43 adults with non-alcoholic steatohepatitis participating in a clinical trial, liver volume was estimated by segmentation of magnitude-based low-flip angle multiecho GRE images. The liver mean proton density fat fraction (PDFF) was calculated. The total liver fat index (TLFI) was estimated as the product of liver mean PDFF and liver volume. Linear regression analyses were performed. RESULTS: Cross-sectional analyses revealed statistically significant relationships between TLFI and liver mean PDFF (R 2 = 0.740 baseline/0.791 follow up, P < 0.001 baseline/P < 0.001 follow-up), and between TLFI and liver volume (R 2 = 0.352/0.452, P < 0.001/< 0.001). Longitudinal analyses revealed statistically significant relationships between liver volume change and liver mean PDFF change (R 2 = 0.556, P < 0.001), between TLFI change and liver mean PDFF change (R 2 = 0.920, P < 0.001), and between TLFI change and liver volume change (R 2 = 0.735, P < 0.001). CONCLUSION: Liver segmentation in combination with MRI-based PDFF estimation may be used to monitor liver volume, liver mean PDFF, and TLFI in a clinical trial. PMID- 25015397 TI - Analysis of gamma-aminobutyric acid (GABA) type A receptor subtypes using isosteric and allosteric ligands. AB - The GABAA receptors (GABAARs) play an important role in inhibitory transmission in the brain. The GABAARs could be identified using a medicinal chemistry approach to characterize with a series of chemical structural analogues, some identified in nature, some synthesized, to control the structural conformational rigidity/flexibility so as to define the 'receptor-specific' GABA agonist ligand structure. In addition to the isosteric site ligands, these ligand-gated chloride ion channel proteins exhibited modulation by several chemotypes of allosteric ligands, that help define structure and function. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABAARs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Also in the trans-membrane domain are allosteric modulatory ligand sites, mostly positive, for diverse chemotypes with general anesthetic efficacy, namely, the volatile and intravenous agents: barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are apparent endogenous positive allosteric modulators of GABAARs. These binding sites depend on the GABAAR heteropentameric subunit composition, i.e., subtypes. Two classes of pharmacologically very important allosteric modulatory ligand binding site reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site, and the low-dose ethanol site. The benzodiazepine site is specific for certain subunit combination subtypes, mainly synaptically localized. In contrast, the low dose (high affinity) ethanol site(s) is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. PMID- 25015400 TI - Visceral fat quantification in asymptomatic adults using abdominal CT: is it predictive of future cardiac events? AB - PURPOSE: The purpose of this study was to determine if quantifying visceral adipose tissue (VAT) at CT in asymptomatic adults can predict the likelihood of future cardiac events. METHODS: Subcutaneous and visceral fat volumes were obtained from abdominal CT utilizing a validated semi-automated software tool in 663 asymptomatic adults (mean age 57.3 years, 379F/284M) undergoing colorectal screening. Patients were followed for subsequent cardiac events, defined as myocardial infarction or coronary intervention for a mean follow-up interval of 7.0 +/- 1.4 years. Relevant clinical data including Framingham risk score (FRS) were also collected. Statistical analysis included logistic regression, Pearson correlation coefficients, and Welch and Wilcoxon rank sum tests. RESULTS: Cardiac events were documented in 32 subjects (4.8%) an average 3.0 years after index CT. FRS was predictive of future cardiac events, signified by a higher score (mean score 11.9 vs. 7.4; p < 0.001). HDL levels were significantly lower in the cardiac event cohort (mean 52.2 vs. 61.0; p < 0.01). None of the other clinical variables were predictive and none of the CT-based fat measurements (visceral, subcutaneous, and total adipose tissue; visceral fat %) correlated with future cardiac events (p = 0.561-0.886). Mean visceral fat % in the cardiac event cohort was 38.1% vs. 39.1% for the non-event group. CONCLUSION: Quantification of VAT at abdominal CT was not predictive of future cardiac events in this asymptomatic cohort, whereas HDL levels and FRSs correlated well with risk. PMID- 25015401 TI - 18F-FDG-PET/CT is of limited value in primary staging of early stage cervical cancer. AB - PURPOSE: To assess the clinical benefit of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) in evaluating pelvic lymph nodes in patients with early stage cervical cancer (FIGO stage 1a-1b1), who have magnetic resonance imaging (MRI)-defined lymph node negative disease, with histopathologic results as the reference standard. MATERIALS AND METHODS: We assessed one hundred and seventy nine sequential 18F-FDG-PET/CT scans in women with newly diagnosed cervical carcinoma between January 2009 and September 2011. 47 of these patients had early stage disease (FIGO stage 1a-1b1) with no suspicious lymph nodes on MRI. 18F-FDG-PET/CT images were analyzed and histopathological findings (pelvic lymph node resection) served as the reference standard. RESULTS: The median age of patients was 48 (range 22-86) years. 66 % had squamous histotype. Median number of nodes dissected per patient was 21 (range 8-47), 2 of 47 patients had nodal metastases (4.25 %). All patients in this group had no suspicious lymph nodes on 18F-FDG-PET/CT. Overall patient based sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG-PET/CT for detection of nodal disease were 0 %, 100 %, 0 %, 96 %, and 96 % respectively. CONCLUSION: Pathologic validation of 18F-FDG PET/CT imaging demonstrates little value for 18F-FDG-PET/CT in patients with early stage (FIGO stage 1a-1b1) MRI-defined lymph node negative cervical carcinoma. Since the likelihood of metastatic nodal disease is very low in women with stage 1a-1b1 cervical cancer, we believe that 18F-FDG-PET/CT should not have a role in the routine pre-treatment evaluation of these women. PMID- 25015402 TI - Development of replication-competent adenovirus for bladder cancer by controlling adenovirus E1a and E4 gene expression with the survivin promoter. AB - Survivin is a member of the inhibitors of apoptosis protein family. Here, we examined survivin expression and confirmed abundant survivin expression in bladder cancer cells. This expression pattern indicated that the transcriptional regulatory elements that control survivin expression could be utilized to discriminate cancer from normal cells. We therefore generated a novel adenovirus termed Ad5/35E1apsurvivinE4 with the following characteristics: 1) E1A and E4 protein expression was dependent on survivin promoter activity; 2) the green fluorescence protein gene was inserted into the genome under the control of the CMV promoter; 3) most of the E3 sequences were deleted, but the construct was still capable of expressing the adenovirus death protein with potent cytotoxic effects; and 4) the fiber knob was from serotype 35 adenovirus. As expected from the abundant survivin expression observed in bladder cancer cells, Ad5/35E1apsurvivinE4 replicated better in cancer cells than in normal cells by a factor of 106 to 102. Likewise, Ad5/35E1apsurvivinE4 exerted greater cytotoxic effects on all bladder cancer cell lines tested. Importantly, Ad5/35E1apsurvivinE4 inhibited the growth of Ku7-Luc orthotopic xenografts in nude mice. Taken together, Ad5/35E1apsurvivinE4 indicates that the survivin promoter may be utilized for the development of a replication-competent adenovirus to target bladder cancers. PMID- 25015403 TI - The national alcohol helpline in Sweden: an evaluation of its first year. AB - BACKGROUND: Telephone helplines are easily available and can offer anonymity. Alcohol helplines may be a potential gateway to a more advanced support protocol, and they may function as a primary support option for some. However, although telephone helplines (quitlines) make up an established evidence-based support arena for smoking cessation, few studies have described such telephone-based alcohol counseling. METHODS: This study describes the basic characteristics of callers (n = 480) to the Swedish Alcohol Helpline during its first year of operation, and assesses aspects of change in alcohol behavior in a selected cohort of clients (n = 40) willing to abstain from anonymity and enter a proactive support protocol. RESULTS: During the study period, 50% of callers called for consultation regarding their own alcohol use (clients), a third called about relatives with alcohol problems, and the others called for information. The clients' average age was 49 years, and half were females. The clients' average AUDIT score at baseline was 21 (std. dev. =7.2). Approximately a quarter had scores indicating hazardous alcohol use at baseline, while the others had higher scores. In a follow-up pilot study, the average AUDIT score had decreased from 21 to 14. While clients reporting more severe alcohol use showed a significant decrease at follow-up, hazardous users exhibited no change during the study period. CONCLUSION: The study indicates that telephone helplines addressing the general public can be a primary-care option to reduce risky alcohol use. A randomized controlled study is needed to control for the effect of spontaneous recovery. PMID- 25015404 TI - Nurse scientists overcoming challenges to lead transdisciplinary research teams. AB - Increasingly, scientific funding agencies are requiring that researchers move toward an integrated, transdisciplinary team science paradigm. Although the barriers to and rewards of conducting this type of research have been discussed in the literature, examples of how nurse investigators have led these teams to reconcile the differences in theoretical, methodological, and/or analytic perspectives that inevitably exist are lacking. In this article, we describe these developmental trajectory challenges through a case study of one transdisciplinary team, focusing on team member characteristics and the leadership tasks associated with successful transdisciplinary science teams in the literature. Specifically, we describe how overcoming these challenges has been essential to examining the complex and potentially cumulative effects that key intersections between legal, social welfare, and labor market systems may have on the health of disadvantaged women. Finally, we discuss this difficult but rewarding work within the context of lessons learned and transdisciplinary team research in relation to the future of nursing science. PMID- 25015405 TI - The 2014 National Nursing Research Roundtable: The science of caregiving. AB - The National Nursing Research Roundtable (NNRR) meets annually to provide an opportunity for the leaders of nursing organizations with a research mission to discuss and disseminate research findings to improve health outcomes. In 2014, the NNRR addressed the science of caregiving, a topic of increasing importance given that more people are living with chronic conditions and that managing chronic illness is shifting from providers to individuals, their families, and the communities where they live. The NNRR consisted of scientific presentations in which leading researchers discussed the latest advances in caregiving science across the life span and breakout sessions where specific questions were discussed. The questions focused on the policy and practice implications of caregiving science and provided an opportunity for nursing leaders to discuss ways to advance caregiving science. The nursing community is ideally positioned to design and test caregiver health interventions and to implement these interventions in clinical and community settings. PMID- 25015407 TI - 2013 Special Topics Conference: Peaks and pitfalls in longitudinal studies of symptom outcome data. AB - Symptom science is inherent in nursing care, with symptoms being guideposts for practice. The occurrence of symptoms has the potential to impact multiple health outcomes. In order to identify the natural history of a symptom, longitudinal data related to the occurrence and severity of symptoms over the disease/treatment epoch are essential and should include the collection of potential biologic correlates. One of the primary limitations with longitudinal studies is the problem of data missingness. This can then impact the analysis and interpretation of findings. Additionally, there are a variety of approaches to the analysis of the data. As part of the American Academy of Nursing Special Topics Conference this year, issues related to the planning and analysis of longitudinal data analysis were discussed. This article provides a summary of the presented content at that meeting. PMID- 25015406 TI - Social welfare utilization and needs of older adults in Taiwan: survey research. AB - BACKGROUND: The demand for long-term care for older adults has escalated sharply. A good policy dedicated to the welfare of older adults has improved their quality of life. The purpose of this study was to explore the social welfare utilization and needs of older adults and compare their differences among age groups, genders, and functional dependency levels. METHODS: Three hundred eighty-four stratified, random-sampled Taiwanese community-dwelling older adults were recruited for this survey research. Participants rated their utilization of and needs for the 30 social welfare services provided by the government on a Likert type scale. RESULTS: The most widely used and needed social welfare services by the older adults were senior monetary stipend and a subsidy for the national health insurance premium. Young-old, male, and functionally independent older adults had more knowledge of the social welfare services than their counterparts. CONCLUSIONS: While designing a comprehensive social welfare system, differing needs of different age groups, genders, and functional dependency levels should be taken into consideration. PMID- 25015408 TI - Frontline registered nurse job satisfaction and predictors over three decades: a meta-analysis from 1980 to 2009. AB - BACKGROUND: Frontline registered nurses' job satisfaction is important because it is tied to retention, organizational commitment, workforce safety, patient safety, and cost savings. The purpose of this study was to comprehensively, quantitatively examine the largest, moderate, and smallest predictors of frontline registered nurse job satisfaction from 1980 to 2009. METHODS: A non-a priori meta-analysis was used to analyze studies that met inclusion. RESULTS: Sixty-two studies and 27 job satisfaction predictors met inclusion for analysis. The largest effect sizes were found for task requirements (r = .61), empowerment (r = .55), and control (r = .52), and moderate effect sizes were found for 10 predictors. Fail-safe N indicates high reliability. Heterogeneity between studies was present in all of the 27 predictor analyses. CONCLUSIONS: The largest predictors of job satisfaction for the frontline registered nurse may be different than previously thought. Supporting past research, autonomy and stress were found to be moderate predictors of satisfaction. Heterogeneity indicates study differences or moderator influence in studies. PMID- 25015409 TI - Patient-Reported Outcomes Measurement Information System (PROMIS): efficient, standardized tools to measure self-reported health and quality of life. AB - All nurses are interested in the effects of diseases and treatments on individuals. Patient-reported outcome (PRO) measures are used to obtain self reported information about symptoms, function, perceptions, and experiences. However, there are challenges to their use, including multiple measures of the same concept, widely varying quality, excessive length and complexity, and difficulty comparing findings across studies and conditions. To address these challenges, the National Institutes of Health funded the Patient-Reported Outcomes Measurement Information System (PROMIS), a web-based repository of valid and reliable PRO measures of health concepts relevant to clinician and researchers. Through the PROMIS Assessment Center, clinicians and researchers can access PRO measures, administer computerized adaptive tests, collect self-report data, and report instant health assessments. The purpose of this article was to summarize the development and validation of the PROMIS measures and to describe its current functionality as it relates to nursing science. PMID- 25015410 TI - Scholarly productivity for nursing clinical track faculty. AB - Recent years have yielded substantial advancement by clinical track faculty in cohort expansion and collective contributions to the discipline of nursing. As a result, standards for progression and promotion for clinical faculty need to be more fully developed, articulated, and disseminated. Our school formed a task force to examine benchmarks for the progression and promotion of clinical faculty across schools of nursing, with the goal of guiding faculty, reviewers, and decision makers about what constitutes excellence in scholarly productivity. Results from analyses of curriculum vitae of clinical professors or associate professors at six universities with high research activity revealed a variety of productivity among clinical track members, which included notable diversity in the types of scholarly products. Findings from this project help quantify types of scholarship for clinical faculty at the time of promotion. This work provides a springboard for greater understanding of the contributions of clinical track faculty to nursing practice. PMID- 25015411 TI - Segregation of striated and smooth muscle lineages by a Notch-dependent regulatory network. AB - BACKGROUND: Lineage segregation from multipotent epithelia is a central theme in development and in adult stem cell plasticity. Previously, we demonstrated that striated and smooth muscle cells share a common progenitor within their epithelium of origin, the lateral domain of the somite-derived dermomyotome. However, what controls the segregation of these muscle subtypes remains unknown. We use this in vivo bifurcation of fates as an experimental model to uncover the underlying mechanisms of lineage diversification from bipotent progenitors. RESULTS: Using the strength of spatio-temporally controlled gene missexpression in avian embryos, we report that Notch harbors distinct pro-smooth muscle activities depending on the duration of the signal; short periods prevent striated muscle development and extended periods, through Snail1, promote cell emigration from the dermomyotome towards a smooth muscle fate. Furthermore, we define a Muscle Regulatory Network, consisting of Id2, Id3, FoxC2 and Snail1, which acts in concert to promote smooth muscle by antagonizing the pro-myogenic activities of Myf5 and Pax7, which induce striated muscle fate. Notch and BMP closely regulate the network and reciprocally reinforce each other?s signal. In turn, components of the network strengthen Notch signaling, while Pax7 silences this signaling. These feedbacks augment the robustness and flexibility of the network regulating muscle subtype segregation. CONCLUSIONS: Our results demarcate the details of the Muscle Regulatory Network, underlying the segregation of muscle sublineages from the lateral dermomyotome, and exhibit how factors within the network promote the smooth muscle at the expense of the striated muscle fate. This network acts as an exemplar demonstrating how lineage segregation occurs within epithelial primordia by integrating inputs from competing factors. PMID- 25015412 TI - Nocardia vulneris sp. nov., isolated from wounds of human patients in North America. AB - Nocardia species are ubiquitous in the environment with an increasing number of species isolated from clinical sources. From 2005 to 2009, eight isolates (W9042, W9247, W9290, W9319, W9846, W9851T, W9865, and W9908) were obtained from eight patients from three states in the United States and Canada; all were from males ranging in age from 47 to 81 years old; and all were obtained from finger (n = 5) or leg (n = 3) wounds. Isolates were characterized by polyphasic analysis using molecular, phenotypic, morphologic and chemotaxonomic methods. Sequence analysis of 16S rRNA gene sequences showed the eight isolates are 100 % identical to each other and belong in the genus Nocardia. The nearest phylogenetically related neighbours were found to be the type strains for Nocardia altamirensis (99.33 % sequence similarity), Nocardia brasiliensis (99.37 %), Nocardia iowensis (98.95 %) and Nocardia tenerifensis (98.44 %). The G+C content of isolate W9851T was determined to be 68.4 mol %. The DNA-DNA relatedness between strain W9851T and the N. brasiliensis type strain was 72.8 % and 65.8 % when measured in the laboratory and in silico from genome sequences, respectively, and 95.6 % ANI. Whole-cell peptidoglycan was found to contain meso-diaminopimelic acid; MK-8 (H4)omega-cyc was identified as the major menaquinone; the major fatty acids were identified as C16:0, 10 Me C18:0, and C18:1 w9c, the predominant phospholipids were found to include diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannosides; whole-cell sugars detected were arabinose and galactose; and mycolic acids ranging from 38 to 60 carbon atoms were found to be present. These chemotaxonomic analyses are consistent with assignment of the isolates to the genus Nocardia. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectra of the clinical isolates showed genus and species level profiles that were different from other Nocardia species. All isolates were resistant to ciprofloxacin, clarithromycin and imipenem but were susceptible to amikacin, amoxicillin/clavulanate, linezolid and trimethoprim/sulfamethoxazole. The results of our polyphasic analysis suggest the new isolates obtained from wound infections represent a novel species within the genus Nocardia, for which the name Nocardia vulneris sp. nov. is proposed, with strain W9851T (= DSM 45737T = CCUG 62683T = NBRC 108936T) as the type strain. PMID- 25015413 TI - The Belgian Diabetes in Pregnancy Study (BEDIP-N), a multi-centric prospective cohort study on screening for diabetes in pregnancy and gestational diabetes: methodology and design. AB - BACKGROUND: The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends universal screening with a 75 g oral glucose tolerance test (OGTT) using stricter criteria for gestational diabetes (GDM). This may lead to important increases in the prevalence of GDM and associated costs, whereas the gain in health is unclear. The goal of 'The Belgian Diabetes in Pregnancy Study' (BEDIP-N) is to evaluate the best screening strategy for pregestational diabetes in early pregnancy and GDM in an ethnically diverse western European population. The IADPSG screening strategy will be followed, but in addition risk questionnaires and a 50 g glucose challenge test (GCT) will be performed, in order to define the most practical and most cost effective screening strategy in this population. METHODS: BEDIP-N is a prospective observational cohort study in 6 centers in Belgium. The aim is to enroll 2563 pregnant women in the first trimester with a singleton pregnancy, aged 18-45 years, without known diabetes and without history of bariatric surgery. Women are universally screened for overt diabetes and GDM in the first trimester with a fasting plasma glucose and for GDM between 24-28 weeks using the 50 g GCT and independently of the result of the GCT, all women will receive a 75 g OGTT using the IADPSG criteria. Diabetes and GDM will be treated according to a standardized routine care protocol. Women with GDM, will be reevaluated three months postpartum with a 75 g OGTT. At each visit blood samples are collected, anthropometric measurements are obtained and self-administered questionnaires are completed. Recruitment began in April 2014. DISCUSSION: This is the first large, prospective cohort study rigorously assessing the prevalence of diabetes in early pregnancy and comparing the impact of different screening strategies with the IADPSG criteria on the detection of GDM later in pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02036619. Registered 14-1-2014. PMID- 25015414 TI - Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. METHODS: A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. RESULTS: It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (<1% versus Dogon 7.9%). The Betica-Selma 968C/376G (~11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. CONCLUSIONS: The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency. PMID- 25015415 TI - Bile acids inhibit Na+/H+ exchanger and Cl-/HCO3- exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts. AB - Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl-/HCO3- exchanger (CBE) activities in cholecystectomised/ileum resected patients suffering from diarrhoea, compared to control patients. Acute treatment of colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca2+ elevation. We also showed that chenodeoxycholate induced Ca2+ release from the endoplasmic reticulum and extracellular Ca2+ influx contributing to the Ca2+ elevation. Importantly, our results suggest that the chenodeoxycholate-induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca2+ elevation. We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote the development of diarrhea. PMID- 25015416 TI - Abdominal CT: an intra-individual comparison between virtual monochromatic spectral and polychromatic 120-kVp images obtained during the same examination. AB - OBJECTIVES: To compare quantitative and subjective image quality between virtual monochromatic spectral (VMS) and conventional polychromatic 120-kVp imaging performed during the same abdominal computed tomography (CT) examination. MATERIALS AND METHODS: Our institutional review board approved this prospective study; each participant provided written informed consent. 51 patients underwent sequential fast kVp-switching dual-energy (80/140 kVp, volume CT dose index: 12.7 mGy) and single-energy (120-kVp, 12.7 mGy) abdominal enhanced CT over an 8 cm scan length with a random acquisition order and a 4.3-s interval. VMS images with filtered back projection (VMS-FBP) and adaptive statistical iterative reconstruction (so-called hybrid IR) (VMS-ASIR) (at 70 keV), as well as 120-kVp images with FBP (120-kVp-FBP) and ASIR (120-kVp-ASIR), were generated from dual energy and single-energy CT data, respectively. The objective image noises, signal-to-noise ratios and contrast-to-noise ratios of the liver, kidney, pancreas, spleen, portal vein and aorta, and the lesion-to-liver and lesion-to kidney contrast-to-noise ratios were measured. Two radiologists independently and blindly assessed the subjective image quality. The results were analyzed using the paired t-test, Wilcoxon signed rank sum test and mixed-effects model with Bonferroni correction. RESULTS: VMS-ASIR images were superior to 120-kVp-FBP, 120 kVp-ASIR and VMS-FBP images for all the quantitative assessments and the subjective overall image quality (all P<0.001), while VMS-FBP images were superior to 120-kVp-FBP and 120-kVp-ASIR images (all P<0.004). CONCLUSIONS: VMS images at 70 keV have a higher image quality than 120-kVp images, regardless of the application of hybrid IR. Hybrid IR can further improve the image quality of VMS imaging. PMID- 25015417 TI - Spine epidural and sacroiliac joints injections--when and how to perform. AB - OBJECTIVES: To review the state-of-the-art of image-guided techniques used to treat painful syndromes of the lower back, their indications, how they should be performed, their related risks and the expected results. METHODS: We describe the actual standards about image-guided infiltrative therapies both on spine and on sacroiliac joints. RESULTS: Both spinal epidural and sacroiliac injections appear useful in a large percentage of treated patients to get control of the perceived pain. Performing these therapies under CT or fluoroscopic guidance is the best and safest way to obtain satisfactory results because it is possible to target the use of drugs directly to the involved painful structures. CONCLUSIONS: Image guided injections of the epidural space and of the sacroiliac joints are effective techniques for the treatment of pain; their effectiveness is sometimes not lasting for long periods of time but considering the low associated risk when performed by trained personnel, they can be easily repeated. PMID- 25015418 TI - Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133. AB - Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive treatment. We have previously identified a CSC population derived from HCC that is characterized by CD133. Despite our growing knowledge of the importance of this subset of cells in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. Here, we report the epigenetic regulation of CD133 by miR-142-3p. The interaction between CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in HCC clinical samples as well as in cell lines. Importantly, lower miR-142-3p expression in HCC was significantly associated with worst survival. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce angiogenesis and resist chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these features. Thus, miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC. PMID- 25015420 TI - Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. PMID- 25015419 TI - Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells. AB - Mechanisms underlying therapy resistance of tumor cells include protein kinase Akt. Putative Akt targets include store-operated Ca(2+)-entry (SOCE) accomplished by pore forming ion channel unit Orai1 and its regulator STIM1. We explored whether therapy resistant (A2780cis) differ from therapy sensitive (A2780) ovary carcinoma cells in Akt, Orai1, and STIM1 expression, Ca(2+)-signaling and cell survival following cisplatin (100 uM) treatment. Transcript levels were quantified with RT-PCR, protein abundance with Western blotting, cytosolic Ca(2+) activity ([Ca(2+)]i) with Fura-2-fluorescence, SOCE from increase of [Ca(2+)]i following Ca(2+)-readdition after Ca(2+)-store depletion, and apoptosis utilizing flow cytometry. Transcript levels of Orai1 and STIM1, protein expression of Orai1, STIM1, and phosphorylated Akt, as well as SOCE were significantly higher in A2780cis than A2780 cells. SOCE was decreased by Akt inhibitor III (SH-6, 10 uM) in A2780cis but not A2780 cells and decreased in both cell lines by Orai1 inhibitor 2-aminoethoxydiphenyl borate (2-ABP, 50 uM). Phosphatidylserine exposure and late apoptosis following cisplatin treatment were significantly lower in A2780cis than A2780 cells, a difference virtually abolished by SH-6 or 2 ABP. In conclusion, Orai1/STIM1 expression and function are increased in therapy resistant ovary carcinoma cells, a property at least in part due to enhanced Akt activity and contributing to therapy resistance in those cells. PMID- 25015422 TI - Sir William Richard Gowers (1845-1915) and his eponym. PMID- 25015421 TI - Cross-situational statistical word learning in young children. AB - Recent empirical work has highlighted the potential role of cross-situational statistical word learning in children's early vocabulary development. In the current study, we tested 5- to 7-year-old children's cross-situational learning by presenting children with a series of ambiguous naming events containing multiple words and multiple referents. Children rapidly learned word-to-object mappings by attending to the co-occurrence regularities across these ambiguous naming events. The current study begins to address the mechanisms underlying children's learning by demonstrating that the diversity of learning contexts affects performance. The implications of the current findings for the role of cross-situational word learning at different points in development are discussed along with the methodological implications of employing school-aged children to test hypotheses regarding the mechanisms supporting early word learning. PMID- 25015423 TI - Supra-interthalamic adhesion approach: a modified surgical approach for neuroendoscopic biopsy of pineal tumors. PMID- 25015424 TI - Brain core temperature of patients with mild traumatic brain injury as assessed by DWI-thermometry. AB - INTRODUCTION: The aim of this study was to assess the brain core temperature of patients with mild traumatic brain injury (mTBI) using a noninvasive temperature measurement technique based on the diffusion coefficient of the cerebrospinal fluid. METHODS: This retrospective study used the data collected from April 2008 to June 2011. The patient group comprised 20 patients with a Glasgow Coma Scale score of 14 or 15 who underwent magnetic resonance imaging within 30 days after head trauma. The normal control group comprised 14 subjects who volunteered for a brain checkup (known in Japan as "brain dock"). We compared lateral ventricular (LV) temperature between patient and control groups. Follow-up studies were performed for four patients. RESULTS: LV temperature measurements were successfully performed for both patients and controls. Mean (+/-standard deviation) measured LV temperature was 36.9 +/- 1.5 degrees C in patients, 38.7 +/- 1.8 degrees C in follow-ups, and 37.9 +/- 1.2 degrees C in controls, showing a significant difference between patients and controls (P = 0.017). However, no significant difference was evident between patients and follow-ups (P = 0.595) or between follow-ups and controls (P = 0.465). CONCLUSIONS: A reduction in brain core temperature was observed in patients with mTBI, possibly due to a global decrease in metabolism. PMID- 25015425 TI - Temperature simulations in hyperthermia treatment planning of the head and neck region: rigorous optimization of tissue properties. AB - BACKGROUND AND PURPOSE: Hyperthermia treatment planning (HTP) is used in the head and neck region (H&N) for pretreatment optimization, decision making, and real time HTP-guided adaptive application of hyperthermia. In current clinical practice, HTP is based on power-absorption predictions, but thermal dose-effect relationships advocate its extension to temperature predictions. Exploitation of temperature simulations requires region- and temperature-specific thermal tissue properties due to the strong thermoregulatory response of H&N tissues. The purpose of our work was to develop a technique for patient group-specific optimization of thermal tissue properties based on invasively measured temperatures, and to evaluate the accuracy achievable. PATIENTS AND METHODS: Data from 17 treated patients were used to optimize the perfusion and thermal conductivity values for the Pennes bioheat equation-based thermal model. A leave one-out approach was applied to accurately assess the difference between measured and simulated temperature (?T). The improvement in ?T for optimized thermal property values was assessed by comparison with the ?T for values from the literature, i.e., baseline and under thermal stress. RESULTS: The optimized perfusion and conductivity values of tumor, muscle, and fat led to an improvement in simulation accuracy (?T: 2.1 +/- 1.2 degrees C) compared with the accuracy for baseline (?T: 12.7 +/- 11.1 degrees C) or thermal stress (?T: 4.4 +/- 3.5 degrees C) property values. CONCLUSION: The presented technique leads to patient group-specific temperature property values that effectively improve simulation accuracy for the challenging H&N region, thereby making simulations an elegant addition to invasive measurements. The rigorous leave-one-out assessment indicates that improvements in accuracy are required to rely only on temperature based HTP in the clinic. PMID- 25015426 TI - Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU: more than 20 years' experience at a single institution. AB - PURPOSE: The purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution. METHODS: We retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988-2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988-2006 with 39.6-40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003-2010 with 44-45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10-50 % residual tumor), and grade 3 (> 50 % residual tumor). RESULTS: Median follow-up time from the start of N-RCT was 100 months (range 2-213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 +/- 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 +/- 7 %, 35 +/- 6, and 36 +/- 7 % for group 1 and 55 +/- 7, 49 +/- 7, and 53 +/- 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality. CONCLUSION: Higher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens. PMID- 25015427 TI - Structure-revealing data fusion. AB - BACKGROUND: Analysis of data from multiple sources has the potential to enhance knowledge discovery by capturing underlying structures, which are, otherwise, difficult to extract. Fusing data from multiple sources has already proved useful in many applications in social network analysis, signal processing and bioinformatics. However, data fusion is challenging since data from multiple sources are often (i) heterogeneous (i.e., in the form of higher-order tensors and matrices), (ii) incomplete, and (iii) have both shared and unshared components. In order to address these challenges, in this paper, we introduce a novel unsupervised data fusion model based on joint factorization of matrices and higher-order tensors. RESULTS: While the traditional formulation of coupled matrix and tensor factorizations modeling only shared factors fails to capture the underlying structures in the presence of both shared and unshared factors, the proposed data fusion model has the potential to automatically reveal shared and unshared components through modeling constraints. Using numerical experiments, we demonstrate the effectiveness of the proposed approach in terms of identifying shared and unshared components. Furthermore, we measure a set of mixtures with known chemical composition using both LC-MS (Liquid Chromatography Mass Spectrometry) and NMR (Nuclear Magnetic Resonance) and demonstrate that the structure-revealing data fusion model can (i) successfully capture the chemicals in the mixtures and extract the relative concentrations of the chemicals accurately, (ii) provide promising results in terms of identifying shared and unshared chemicals, and (iii) reveal the relevant patterns in LC-MS by coupling with the diffusion NMR data. CONCLUSIONS: We have proposed a structure-revealing data fusion model that can jointly analyze heterogeneous, incomplete data sets with shared and unshared components and demonstrated its promising performance as well as potential limitations on both simulated and real data. PMID- 25015428 TI - [Treatment of severe ulcerative colitis flares]. AB - The treatment of severe ulcerative colitis remains a challenge for gastroenterologists. A not inconsiderable number of patients will experience severe flares throughout their lives and will require hospitalization. Mortality in severe ulcerative colitis is still high and consequently treatment must be aggressive, avoiding delays in rescue therapies or even surgery. The aim of this review was to describe the medical treatment of severe ulcerative colitis, highlighting recent therapeutic advances. PMID- 25015430 TI - Hospital discharge instructions: comprehension and compliance among older adults. AB - BACKGROUND: Little is known regarding the prevalence or risk factors for non comprehension and non-compliance with discharge instructions among older adults. OBJECTIVE: To quantify the prevalence of non-comprehension and non-compliance with discharge instructions and to identify associated patient characteristics. RESEARCH DESIGN: Prospective cohort study. SUBJECTS: Four hundred and fifty adults aged >= 65 admitted to medical and surgical units of a tertiary care facility and meeting inclusion criteria. MEASURES: We collected information on demographics, psycho-social factors, discharge diagnoses, and medications using surveys and patient medical records. Domains within discharge instructions included medications, follow-up appointments, diet, and exercise. At 5 days post discharge, we assessed comprehension by asking patients about their discharge instructions, and compared responses to written instructions from medical charts. We assessed compliance among patients who understood their instructions. RESULTS: Prevalence of non-comprehension was 5 % for follow-up appointments, 27 % for medications, 48 % for exercise and 50 % for diet recommendations. Age was associated with non-comprehension of medication [odds ratio (OR) 1.07; 95 % confidence interval (CI) 1.04, 1.12] and follow-up appointment (OR 1.08; 95 % CI 1.00, 1.17) instructions. Male sex was associated with non-comprehension of diet instructions (OR 1.91; 95 % CI 1.10, 3.31). Social isolation was associated with non-comprehension of exercise instructions (OR 9.42; 95 % CI 1.50, 59.11) Depression was associated with non-compliance with medication (OR 2.29; 95 % CI 1.02, 5.10) and diet instructions (OR 3.30; 95 % CI 1.24, 8.83). CONCLUSIONS: Non comprehension of discharge instructions among older adults is prevalent, multi factorial, and varies by domain. PMID- 25015431 TI - Capsule commentary on Ackerman et al., when to repatriate? Clinicians' perspectives on the transfer of patient management from specialty to primary care. PMID- 25015432 TI - Recurrent outbreaks of Serratia marcescens among neonates and infants at a pediatric department: an outbreak analysis. AB - PURPOSE: Serratia marcescens is a known cause of bloodstream infections (BSIs) and outbreaks in neonates receiving intensive care. Our aim was to analyze clinical and epidemiological characteristics of two outbreaks detected in our unit to prevent and control further epidemic infections. METHODS: Two episodes of BSI outbreaks in neonates have been investigated in a 20-month period at a pediatric department of a medical university in Hungary. We collected all S. marcescens strains that were isolated in the study period, and two strains that were isolated before the outbreaks. Strains were analyzed by pulsed-field gel electrophoresis (PFGE). Clinical data were collected for the BSIs during and between the outbreaks (n = 14). RESULTS: Out of the 28 S. marcescens isolates investigated by PFGE, 16 were blood isolates. All isolates represented four PFGE types. Pathogenic strains that caused epidemic BSIs were related to a single PFGE type (SM009). Strains with the same pulsotype could be detected before, between, and after the outbreak periods from surveillance cultures of neonates, and a water tap in the infant care unit despite intensive infection control measures. Case fatality rate of BSIs was 29%. Rate of complications in central nervous system was high: 3/14 neonates developed meningitis. CONCLUSIONS: Rapid spread and high mortality rate of S. marcescens infections necessitate a high suspicion when isolating this species in neonatal intensive care. Early identification of outbreaks is essential, that can be facilitated by determination of clonal relatedness using molecular methods, and with regular surveillance cultures of patients and environment. PMID- 25015434 TI - Lactobacillus reuteri is an effective option for the prevention of diarrhoea in preschool children but may not be cost-effective in all settings. PMID- 25015433 TI - Gastrointestinal pathogens detected by multiplex nucleic acid amplification testing in stools of pediatric patients and patients returning from the tropics. AB - BACKGROUND: Gastrointestinal infections are caused by a broad spectrum of pathogens. Conventional diagnostic procedures are resource and time consuming due to single pathogen testing, often in different laboratories. METHOD: We analyzed 312 consecutive stool samples from pediatric patients (n = 127) with gastroenteritis or from adult travelers returning from the tropics with suspected parasite infestation (n = 185) using commercial multiplex nucleic acid amplification testing (NAT) (xTAG gastrointestinal pathogen panel, Luminex) covering 15 diarrhea-causing pathogens. The results of the positive samples and a representative number of negative samples were compared to standard methods, including NAT, direct antigen detection (DAD), bacterial culture and microscopy. RESULTS: Of the 185 samples from adult travelers, 21 (11 %) were multiplexNAT positive, with enterotoxigenic Escherichia coli (4 %) being the predominant pathogen. Microscopic examination revealed Blastocystis hominis in 23 % not covered by the panel. MultiplexNAT scored positive in 66 pediatric samples (52 %), with rotavirus (27 %) being the most prevalent. All adenovirus-, rotavirus-, Clostridium difficile- and Cryptosporidium-positive samples were confirmed in external laboratories, but only 40 % of norovirus- and 29 % of Giardia-positive samples. Analysis of frozen specimens by bacterial culture showed the highest discrepancies with the multiplexNAT. CONCLUSION: Our study demonstrates broad detection of relevant gastroenteritis pathogens by multiplexNAT with a short turnaround time. This is important for diagnosis, infection control and empiric management of gastroenteritis patients, but may be selectively complemented by bacterial culture and resistance testing. PMID- 25015435 TI - A common haplotype of KIAA0319 contributes to the phonological awareness skill in Chinese children. AB - BACKGROUND: Previous studies have shown that KIAA0319 is a candidate gene for dyslexia in western populations. In view of the different languages used in Caucasian and Chinese populations, the aim of the present study was to investigate whether there is also an association of KIAA0319 in Chinese children with dyslexia and/or to the language-related cognitive skills. METHOD AND RESULTS: A total of twenty six single nucleotide polymorphisms (SNPs) were genotyped from three hundred and ninety three individuals from 131 Chinese families. Four of the SNPs have been reported in the literature and twenty two being tag SNPs at KIAA0319. Analysis for allelic and haplotypic associations was performed with the UNPHASED program and multiple testing was corrected using permutation. Results indicate that KIAA0319 is not associated with Chinese children with dyslexia but a haplotype consisting of rs2760157 and rs807507 SNPs were significantly associated with an onset detection test, a measure of phonological awareness (pnominal = 6.85 10-5 and pcorrected = 0.0029). CONCLUSION: In conclusion, our findings suggest that KIAA0319 is associated with a reading-related cognitive skill. PMID- 25015436 TI - Formulation and bioequivalence of two Valsartan/Amlodipine immediate release tablets after a single oral administration. AB - The aim of this study was to formulate a film-coated Valsartan/Amlodipine (VS/AM) immediate release tablets and to evaluate their in vivo release profile. VS/AM core tablets were manufactured using dry granulation method. Opadry aqueous coating dispersion was used as film coating material. Dissolution of the film coated tablets was tested in 900 ml of 0.5% SLS media, bioequivalence of tablets was tested by comparisons against the reference brand product. The ICH guidelines were used to evaluate the stability of the obtained tablets. The coated tablets were subjected to gastric pH, and drug release was analyzed using HPLC system to evaluate the efficiency of the film coat. The coated tablets had no defects. VS/AM release met the FDA guidelines for bioequivalence studies. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between test and reference. These findings suggest that aqueous film coating with Opadry system is an easy and economical approach for preparing stable film coated VS/AM tablets without compromising their in vivo drugs release. PMID- 25015437 TI - Development and formulation of metformin (Antidiabetic) effervescent Granules: to increase patient compliance and its stability study. AB - Convenience of administration and patient compliance are gaining importance in the formulation of dosage forms. Many patients, like elderly people and person with dysphagia find difficulty to swallow the tablets and thus do not comply with prescriptions. So the present study was conducted to develop and formulate metformin effervescent granules. The stability study was carried out for 24 weeks (168 days) at temperatures of 4 degrees C, Room temperature, 40 degrees C & 60 degrees C and at the end, the %age of drug remaining in the formulation was determined. The results showed that the formulation of metformin effervescent granules were remained best stable at 4 degrees C in refrigerator, as the %age of drug remaining is not decreased more than 5% and the formulation stored at room temperature, was also found to be very close to the standard at the end of 24 weeks. It is concluded from the study that granules may be another dosage form to use as antidiabetic pharmaceutical product. PMID- 25015438 TI - Effect of renin inhibition on adipokines in diabetic rats. AB - Insulin resistance predicts development of type 2 diabetes mellitus (DM). Adipocytes release tumor Necrosis factor-alpha (TNF-alpha), and adiponectin. They modulate whole-body insulin sensitivity . The disturbance in the relationship between good and bad adipokines may cause insulin resistance. The renin angiotensin aldosteron system (RAAS) plays a role in DM and the consequence of cardiovascular complications development. It is considered as a target for therapy. The present objective examined the relationship between renin angiotensin system and DM. There were, Group (1): Normal non obese rats, Group (2): Obese diabetic rats, Group (3): Obese diabetic rats with telmisartan, Group (4): Obese diabetic rats with enalapril, Group (5): Obese diabetic rats with aliskiren. There was a significant increase in serum glucose, lipid profile [triglycerides (TGs), low-density lipoprotein cholesterol (LDL), total serum cholesterol (TC)], tumor Necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA) and a significant decrease in adiponectin associated with minor changes in superoxide dismutase (SOD) activity in the obese diabetic rats. Administration of telmisartan, enalapril and or aliskiren caused a significant improvement in serum lipid profile and adiponectin, a minor improvement in SOD activity, a decrease in TNF-alpha and or MDA. Renin angiotensin blockers significantly improve the metabolism and oxidative dysfunctions in Type 2 DM and aliskiren may show a promising powerful therapy. PMID- 25015439 TI - Prolonged oral cyanide effects on feed intake, growth rate and blood parameters in rabbits. AB - Twelve adult rabbits bred locally were divided into two equal groups of 6; experimental and control groups. Rabbits in the experimental group were orally dosed with KCN at 3mg/kg body weight for 40 consecutive days. Members in control group were given placebo (distilled water) for the same period. Animals in both groups were offered feed at 90gm/kg/day while ample drinking water was available ad lib. Feed consumption and body weight of rabbits in both the groups were recorded. Blood samples were also drawn to determine various hematological parameters. Statistical analysis revealed a non-significant difference of total and daily feed intakes in rabbits of experimental and control groups. Whereas the feed efficiency of rabbits in the experimental group were significantly reduced (P<0.05) compared to controls. Likewise a significant decrease in body weight gain of rabbits in experimental group (P<0.05) was observed. A non-significant difference (P>0.05) was observed in leukocyte count, differential leukocyte count and platelets of rabbits in both the groups. Erythrocyte count, hemoglobin concentration, packed cell volume and mean corpuscular hemoglobin were significantly decreased in treated rabbits. It was concluded that chronic cyanide intake had a deleterious effect on feed efficiency, growth rate and blood components of rabbits. PMID- 25015440 TI - The preparation of the sustained release metformin hydrochloride microcapsules by the Wurster fluidized bed. AB - The main objective of this study was to prepare sustained release metformin hydrochloride microcapsules by the Wurster fluidized bed and to obtain the optimized coating process and formulation. Fine microcapsules without agglomeration were obtained in a continuous coating process with the atomization air pressure of 0.2Mpa and an appropriate coating speed temperature. With other design variables of coating process fixed, the effects of different fluidizing air volume, coating temperature, coating speed, coating material, coating materials amount, plasticizer type and plasticizer amount on drug release were investigated respectively. Coating solution was achieved by dissolving EC45cps of 21 g, EC100cps of 7 g, DBS of 2.8 g and talcum powder of 8 g in ethanol to get a final volume of 500 ml. Particles of 150g along with 500mL coating solution would be fine. The results showed that with the air volume of 35 m3*h-1, coating temperature of 35o, coating speed of 6 mL*min-1 and proper amount of coating solution, fine microcapsules were obtained. The mean diameter of the microcapsules obtained eventually were 213 MUm and the drug content were 23%, which was suitable for producing a suspension. Particle diameter distribution corresponded to the normal distribution and obviously prolonged drug-release was achieved. PMID- 25015441 TI - Formulation development of intermediate release Nimesulide tablets by CCRD for IVIVC studies. AB - Simple and cost effective study consisting of three steps, comparison of micromeritic properties of different blends i.e. placebo without API and Nimesulide containing, Use of central composite design (CCRD) for intermediate release Nimesulide tablets and stability results of three selected Nimesulide tablet formulations which were calculated by using R Gui. Different concentrations of Avicel, hydroxypropyl methyl cellulose (HPMC) and magnesium stearate were used as variables in central composite design and two types blend i.e., with or without Nimesulide were selected for bulk density, tap density, percentage compressibility; angle of repose and Hausner's ratio. Blending rate constant was performed after applying the different mixing times like 3, 6, 9 and 12 minutes. Twenty intermediate release formulations were designed and three formulations were chosen for compression by direct compression method on the basis of compressibility index. Physicochemical properties and best release pattern in four hours in different dissolution medium were successfully measured. Relative densities, porosity of tablets were compared with tensile strength of tablet and weight variation, hardness, friability and dissolution was performed by simple experiments. Presence of Nimesulide in the bulk increased all micromeratic tests while 9 minutes was best mixing time. The hardness of NM containing tablets increased with the increase of relative density. The release pattern was further analyzed by model dependent i.e. zero order, first order and Higuchi, Korse-meyer and Pappas, Hixson Crowell and model independent kinetic model i.e., f2 value respectively. R Gui explained the F16 formulation shows the best result in stability studies with shelf life 72 months. PMID- 25015442 TI - Formulation, characterization and comparative evaluation of Trivanga bhasma: a herbo-mineral Indian traditional medicine. AB - Bhasmas are unique Ayurvedic-metallic preparations with herbal juices/fruits, widely recommended to treat variety of chronic ailments. Trivanga bhasma, a calcinated preparation, is used to treat Diabetes mellitus and as Diuretic. In the present research an attempt has been made to carry out a comparative standardization of formulated Trivanga bhasma (TB1) prepared as per Ayurvedic formulary and marketed Trivanga bhasma (TB2) integrating conventional and modern analytical tools. The formulations were evaluated for physical properties, chemical characterization using FTIR, AAS, SEM, TGA, XRD and AFM along with anti diabetic, diuretic and toxicology studies. The X-ray Diffraction analysis of both formulations exhibited crystalline nature and nano-sized particles by Scherrer's equation. In SEM studies, Lead, zinc and tin oxides show well-defined plate like structures while TB1 showed spongy, relatively compact microcrystalline aggregates with loss of grain boundaries. AFM analysis confirmed the spherical morphology of TB1 and TB2 with an average particle size of 500 nm. The present study is the first report of fingerprinting of Trivanga bhasma using sophisticated analytical techniques. In vivo pharmacological screening revealed that both TB1 and TBK2 possess anti-diabetic and diuretic activity and less toxicity, thereby facilitating standardization of Trivanga bhasma. PMID- 25015443 TI - Cytotoxic activity of plants of family zygophyllaceae and euphorbiaceae. AB - The methanolic and n-hexane extracts of studied plants showed significant toxicity to brine shrimps. The methanolic extract of Fagonia cretica had highest LD50 (117.72) value, while Peganum harmala showed low LD50 value (41.70) compared to n-hexane extract. The methanolic and n-hexane extracts of Tribulus terrestris showed similar LD50 values. The methanolic extract of Chrozophora tinctoria showed low LD50 value than the n-hexane extract. The methanolic extract of Ricinus communis showed highest LD50 value while the n-hexane extract showed lowest LD50 value. The LD50 value less than 100 was obtained for n-hexane extracts of Fagonia cretica, Peganum harmala and Ricinus communis. The n-hexane extracts of these plants also showed the highest toxicity as compare to methanolic extracts. The chemical constituents detected in the present investigation might be responsible for cytotoxic activity. PMID- 25015444 TI - Composition and antioxidant activities of Iranian Pulicaria gnaphalodes essential oil in Soybean oil. AB - The essential oil from aerial parts of Pulicaria gnaphalodes was studied in soybean oil. The aim of this study was to evaluate the antioxidant activitiey of Iranian Pulicaria gnaphalodes essential oil in soybean oil during the storage period. The essential oil obtained from Pulicaria gnaphalodes by hydrodistillation and analyzed by GC/Mass. Fifty-eight compounds representing 90.7% of total was identified. Main ingredient in the oil were involved alpha Pinene (30.2%), 1,8-Cineole (12.1%), Beta-Citronellol (9.6%), Mertenol (6.6%), alpha-Terpineol (6.1%), 4-Terpineol (5.9%) and Chrysanthenone (2.9%). Different concentrations (0.200, 400 and 800 ppm) of essential oil and beta hydroxyl toluene (BHT; 100 and 200 ppm) was added to soybean oil and incubated for 35 days at 65 degrees C. Peroxide values (PVs) and thiobarbitoric acid-reactive substances (TBARs) levels were measured every week during the time period of the study. Moreover, antioxidant capacity of the essential oil was determined using 1,1 diphenyl-2- picryl hydrazyl (DPPH) and beta-carotene-linoleic acid methods. Values were compared among groups in each incubation time using ANOVA test. Results revealed that DPPH beta-carotene-linolic acid assay findings on the P. gnaphalodes essential oil were lower than these of synthetic antioxidant, BHT. Moreover, during the incubation time, P. gnaphalodes essential oil lowered PVs and TBARs levels when compared to the control (p<0.001). According to our results essential oil was less effective than synthetic antioxidant. Therefore it may be used as a food flavor, natural antioxidant and a preventive agent for many diseases caused by free radicals. PMID- 25015445 TI - Evaluation of carrier added and no carrier added 90Y-EDTMP as bone seeking therapeutic radiopharmaceutical. AB - The optimum conditions to label ethylenediaminetetramethylene phosphonate (EDTMP) compound with (90)y as a potential candidate for bone metastases therapy were investigated. Yttrium-90 is a pure beta-emitter and can be obtained by (89)y (n,gamma) (90)y nuclear reaction in a reactor or from an in-house generator system ((90)sr?(90)y). The preparation of (90)Y-EDTMPis described using (90)y, which was obtained from neutron irradiation of y2o3 as well as from a laboratory scale organic resin-based (90)sr--(90)y generator. Because of the radiolabeling yield of 90Y-EDTMP on ligand/metal molar ratio, incubation time and ph was evaluated. Under optimum parameters, the radiolabeling yields of (90)Y-EDTMP were <95% for no-carrier-added as well as carrier-added (90)y. The biodistribution of no-carrier-added and carrier-added (90)Y-EDTMP complexes in rats was identical. The results indicate that (90)y (carrier-added)-edtmp is also an effective bone pain palliation agent because of its rapid blood clearance, greater uptake in bones and little absorption in soft tissues. PMID- 25015446 TI - Simultaneous determination of liquiritin, nodakenin and glycyrrhizinin Guibi tang, a traditional herbal prescription by HPLC-PDA. AB - A simple, convenient, rapid and accurate high-performance liquid chromatographic (HPLC) method was established for the simultaneous determination about three ingredients of a traditional herbal prescription, Guibi-tang (GBT): liquiritin (1), nodakenin (2) and glycyrrhizin (3). Chromatographic analysis on the three components was separated within 35 min on a Gemini C18 column and maintained at 40 degrees C. The mobile phase consisted of water with 1.0% (v/v) acetic acid (solvent A) and acetonitrile with 1.0% (v/v) acetic acid (solvent B) in gradient mode at a flow-rate of 1.0 mL/min. Chromatograms were acquired at 254, 280 and 330 nm in a photodiode array (PDA) detector. The calibration curves showed excellent linearity (R(2)=1.0000). The average recovery of three compounds was >93.5%, with a relative standard deviation (RSD) of <2.0%. The intra-day and inter-day precision (RSD) of the three components were 0.04%-3.04% and 0.11% 2.48%, respectively. The contents of compounds 1-3 in GBT were 1.09-1.10, 2.35 2.37 and 0.81-0.82 mg/g, respectively. PMID- 25015447 TI - Effect of leaf extracts of Taraxacum officinale on CCl4 induced hepatotoxicity in rats, in vivo study. AB - Taraxacum officinale L is a medicinal plant, which has enormous medicinal values against various types of liver disorders and it has traditionally been used for the treatment of liver problems by people from the South East Asia. Previously we have screened the crude methanolic extract of T. officinale against cytotoxicity induced by CCl4. Present study was designed to compare the protective effect of ethanolic and n-hexane extract of leaves in carbon tetrachloride (CCl4) induced liver toxicity in rats. The extract (200 mg/kg and 400mg/kg body weight) along with silymarin (100 mg/kg) a standard drug was administered to experimental animals. It was observed that ethanolic plant extract has significantly reduced the negative effect of CCl4 as compared to n-hexane extract and effect of extract was increased with increasing dose level. Although both leaf extracts decreased the concentration of TBARS, H2O2 and nitrite contents which enhance due to CCl4 toxicity but effect was higher in ethanolic extract. The results clearly indicated that Taraxacum officinale ethanolic leaves extract has better protective effect against CCl4 induced liver tissues toxicity. This claim was also supported by histopathological results obtained during this study and this might be due to presence of various polar phytochemicals that might be more prevent in this extract. PMID- 25015448 TI - Effect of aqueous extract of Dicranopteris linearis leaves against paracetamol and carbon tetrachloride-induced liver toxicity in rats. AB - The present study aimed to determine the hepatoprotective activity of Dicranopteris linearis L. (family Gleicheniaceae) leaf aqueous extract (DLAE) using two models of liver injury in rats. Rats were divided into ten groups (n=6) and received dH2O (negative control), 200 mg/kg silymarin (positive control) or DLAE (50, 250 and 500 mg/kg) orally once daily for 7 consecutive days and on the 8th day subjected to the hepatotoxic induction either using carbon tetrachloride (CCl4) or paracetamol (PCM). The bloods and livers were collected and subjected to biochemical and microscopical analysis. From the data obtained, only the highest dose of DLAE significantly (P<0.05) reduced the ALP, ALT and AST levels in CCl4-and PCM-induced hepatotoxic rats while the other doses caused significant (P<0.05) reduction only in the levels of ALT and AST. The histological results obtained were in line with the biochemical analysis wherein reduction in the CCl4 and PCM-induced tissue formation of necrosis, steatosis and inflammation occurred in a dose-dependent manner. In conclusion, the DLAE possesses hepatoprotective activity, which could be attributed to its free radicals scavenging and antioxidant activities, and high flavonoids content. Thus, in depth studies regarding the hepatoprotective activity of DLAE are warranted. PMID- 25015449 TI - Senescence related alteration in hippocampal biogenic amines produces neuropsychological deficits in rats. AB - Aging is a natural complex process that is regulated at genetic, cellular, molecular and systemic levels and leads to the development of a variety of changes including structural, chemical and genetic in the senescent brain. The major goal of the present study was to investigate the age associated cognitive dysfunction and other behavioral changes and their association with age related alterations in levels of neurotransmitters, such as dopamine (DA) and serotonin (5-HT) in the hippocampal region. Twelve male Albino Wistar rats were taken for the study including six young rats (04-05 months old) and six aged (20-22 months old) rats in each group. The learning and memory performance of rats was assessed by passive avoidance test (PA) and novel objective recognition task (NOR). Ambulatory activity was monitored by Open field test. Light/Dark transition test was used to monitor anxiety, whereas depression like symptoms was examined by Forced Swim Test (FST). Results showed that aged rats exhibited learning and memory impairment in PA and NOR. There was a negative relation between aging process and locomotion, consistent with previous findings. Moreover, an augmented increase in level of anxiety and depression was also observed in senescent rats. A marked decrease in DA and 5-HT was observed in the hippocampus of aged rats. Similarly, levels of 5-HIAA and DOPAC were also found to be decreased in aged rats. It is therefore concluded that age has a negative influence on cognitive function, depression, anxiety and locomotion in rats. Cells in all brain regions, especially hippocampus are affected by aging. In general aging exhibits a decline in sensory, motor and cognitive functions. These behavioral changes or functional deficits may be attributed to the age related decline in the levels of different neurotransmitters in brain/hippocampus. The present findings of behavioral deficits and altered neurotransmission in hippocampus of aged rats suggest a relationship between senescence, altered brain neurotransmitters and behavioral deficits. PMID- 25015450 TI - Simultaneous determination and pharmacokinetics of five rhubarb anthraquinones in dog plasma by HPLC after orally administration the rhubarb extract. AB - Rhubarb is widely used in the treatment of obstipation, gastrointestinal indigestion and other diseases in China and other Asian countries for thousands of years. Anthraquinones are the major group of polyphenol constituents including aloe-emodin, rhein, emodin, chrysophanol and physcion. In order to evaluate the pharmacokinetics of five rhubarb anthraquinones, a high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method for simultaneous determination of aloe-emodin, rhein, emodin, chrysophanol and physcion in dog plasma was established. Solid phase extraction (SPE) was applied to the extraction and purification of samples. The calibration curves of five anthraquinones showed good linearity with r greater than 0.9925. The average extraction recoveries, examined at three concentration levels, carried from 92.1% to 102.3%, and the accuracies ranged from 87.7% to 102.5% with precision (RSD) <10%. The pharmacokinetic paremeters of five anthraquinones were investigated systematically after orally administration the rhubarb extract. Five anthraquinones were rapidly absorbed and Tmax for aloe-emodin, rhein, emodin, chrysophanol and physcion was at 0.75, 1.50, 0.75, 1.0 and 2.0 h respectively. The Cmax of five anthraquinones was 0.031, 3.39, 0.27, 0.036 and 0.032 MUg/mL while the AUC of five anthraquinones was 0.35 +/- 0.058, 32.22 +/- 8.29, 2.97 +/- 0.66, 0.43 +/- 0.10 and 0.41 +/- 0.12 mg h/L, respectively. PMID- 25015451 TI - Preliminary antioxidant profile of Pistacia integerrima Stewart. AB - To explore the free radical scavenging properties of crude ethanolic extract of galls, bark, leaves, roots of Pistacia integerrima and its subsequent solvent fractions viz., n-hexane, chloroform, ethyl acetate and methanol against 1, 1 diphenyl-2-picrylhydrazyl (DPPH) stable. In vitro DPPH based free radical was employed using querceitin as standard antioxidant while methanol as negative control. Different parts of P. integerrima showed marked scavenging on DPPH in a concentration dependent manner. The ethanolic extract exhibited 60.51 88.51% scavenging effect on DPPH which differentiated upon fractionation. of the part used, leaves of the plant were the least effective while n-hexane was the least dominant fraction. However, the rest of the parts and fractions demonstrated profound scavenging potential. This in-vitro study revealed an outstanding free radical scavenging potential of various solvent fractions of different parts of whole plant P. integerrima. PMID- 25015452 TI - Hypoglycemic effect of triterpenoid-rich extracts from Euryale ferox shell on normal and streptozotocin-diabetic mice. AB - The antioxidant effects of the triterpenoid-rich extracts from Euryale ferox shell (ES) have been confirmed in vitro. This study examined whether the triterpenoid-rich extract from ES eases human hyperglycemia and diabetes caused by metabolic disorders. Normal and streptozocin (STZ)-induced diabetic mice were used as controls for the four groups that received the triterpenoid-rich extracts of ES suspended in distilled water orally at doses of 200, 300, 400, 500+/-2 mg/L. Body weight, blood glucose and pancreatic tissue morphology were observed after 4 weeks. The expression of protein tyrosine phosphatase-1B (PTP1B) and insulin receptor substrate (IRS-1) proteins, which are related to the regulation of glucose metabolism in vivo, were also investigated. Compared with the model group (LD50 900+/-2 mg/L), it was found that the triterpenoid-rich extracts of ES could regulate glucose metabolism (P<0.01) and cause body weight to return to normal levels (P<0.05). Islet morphology recovered well, the expression of the negative regulation protein PTP1B gene was reduced and insulin receptor IRS-1 protein expression was increased. These data prove that the triterpenoid-rich extracts from ES have a therapeutic effect on diabetes by insulin resistance. PMID- 25015453 TI - Determination of total polyphenolic compounds and flavonoids in Juglans regia leaves. AB - Juglans regia leaves have been widely used in traditional medicines because of its antimicrobial, antihelmintic, astringent, keratolytic, antidiarrhoeal, hypoglycaemic, depurative, tonic, carminative activity. Total polyphenolic compounds were determined using the Folin-Ciocalteau method and flavonoids were quantified using the HPLC-PDA after the hydrolysis of the plant material with HCl. Among the flavonoids myricetin, quercetin, apigenin and kaempferol were found in appreciable amount. PMID- 25015454 TI - Paclitaxel-resistant HeLa cells have up-regulated levels of reactive oxygen species and increased expression of taxol resistance gene 1. AB - This study is to establish a paclitaxel (PTX)-resistant human cervical carcinoma HeLa cell line (HeLa/PTX) and to investigate its redox characteristics and the expression of taxol resistance gene 1 (Txr1). HeLa cells were treated with PTX and effects of PTX on cell proliferation were detected through cell counting and the MTT assay. Levels of cellular reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG) as well as the ratio of GSH to GSSG were measured by the 2,7-difluorescein diacetate (DCFH-DA) method and the 5,5'dithiobis(2-nitrobenzoic acid) (DTNB) method. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined by the nitrite formation method, the molybdate colorimetric method, and the DTNB colorimetric method, respectively. The level of Txr1 mRNA was determined by real time PCR. Compared with the regular HeLa cells, HeLa/PTX cells were larger in size and had more cytoplasmic granules. The population doubling time for HeLa/PTX cells was 1.32 times of that of HeLa cells (P<0.01). HeLa/PTX cells showed stronger resistance to PTX than HeLa cells with a resistance index of 122.69. HeLa/PTX cells had higher levels of ROS (P<0.01) and Txr1 mRNA (P<0.01), lower level of GSH (P < 0.05), and lower activities of SOD (P<0.01) and GPx (P < 0.05) than HeLa cells. HeLa/PTX cells, with higher levels of ROS and Txr1 mRNA expression, are more resistant to PTX than HeLa cells. PMID- 25015455 TI - Unpredictable chronic mild stress induced behavioral deficits: a comparative study in male and female rats. AB - Stress is an important precipitant factor for depression. Changes in various body systems that occur in depression are similar to those observed in response to stress. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Unpredictable chronic mild stress (UCMS) also produces alteration in the serotonergic (5-HT; 5 hydroxytryptamine) neurotransmission. Unpredictable chronic mild stress (UCMS) could be used as an animal model of depression. Neurochemical and behavioral effects of UCMS can be reversed by antidepressant agents, suggesting an important role of serotonin. In rodents, UCMS can elicit depression-like symptoms. The objective of the present study was to evaluate and compare the behavioral deficits induced by chronic mild stress in male and female rats and finding out the vulnerability of the two groups. Male and female rats exposed to UCMS exhibited a significant decrease in cumulative food intake as well as in growth rate. Loco motor activity in home cage and open field was also decreased. Results may contribute to our understanding of the interaction between stress and behavioral functions have to depressive disorders. PMID- 25015456 TI - Synthesis, anticancer activity and structure-activity relationship of some anticancer agents based on cyclopenta (b) thiophene scaffold. AB - Methods for the synthesis of new heterocyclic systems of thieno (3,2-d)- (1,2,3) triazine derivatives and N-(3-cyano-5,6-dihydro-4H-cyclopenta (b) thiophene derivatives have been developed. The newly synthesized compounds were tested in vitro against human breast carcinoma cell line (MCF-7). Compounds 7 and 9 have shown the highest activity among the two synthesized series. The results of this study have led to the identification of two lead compounds with good inhibitory activities that can confirm the design of the next generation inhibitors of tyrosine kinase with fewer side effects such as hepatotoxicity and resistance. PMID- 25015457 TI - In vitro antimutagenic, antioxidant activities and total phenolics of clove (Syzygium aromaticum L.) seed extracts. AB - The present work explores antimutagenic and antioxidant potential as well as total phenolics of aqueous and acidified methanol extractable components from clove (Syzygium aromaticum L.) seed. The magnitude of antimutagenic activity of clove seed extracts (CSE) against two mutant bacterial strains: S. typhimurium TA98 and S. typhimurium TA100 (Ames bacterial test) ranged from 34.11-79.74%. Antioxidant activity in terms of measurement of DPPH radical scavenging capacity and inhibition of linoleic acid peroxidation was noted to be 71.16-94.58% and 54.96-86.89%, respectively. CSE also exhibited an appreciable amount of total phenolics with contribution between 22.80 and 115.33 GAE mg/100g. A strong correlation between total phenolics and tested biological activities were recorded. The results of this study advocate that clove seed can be explored as a viable source of bioactives for the development of chemotherapeutic drugs against cancer in addition to acting as nutraceutical and functional food ingredient. PMID- 25015458 TI - Development and validation of simultaneous estimation method for curcumin and piperine by RP-UFLC. AB - Curcumin and piperine are proven for their potent medicinal benefits to treat various diseases and they are most commonly used combination in various Indian systems of medicine such as Ayurveda, Siddha and Unani. The objective of the present work is to develop a simultaneous estimation of curcumin and piperine by reverse phase Ultra-fast liquid chromatographic (RP-UFLC) method. The chromatographic separation was performed on a C8 column (250 x 4.6 mm, 5u i.d.) stationary phase using a mobile phase of 25mM potassium dihydrogen ortho phosphate buffer (pH 3.5) and acetonitrile (30: 70 v/v) at a flow rate of lml/min at detection wave length of 280nm. The calibration curve was plotted in the concentration range of 0-2200ng/ml and found to be linear for both curcumin (r(2)=0.996) and piperine (r(2)=0.999). The method was validated for parameters such as accuracy, sensitivity, precision, linearity, specificity, ruggedness and robustness as per ICH guidelines. The developed simple, precise and specific method can be used as a quality control tool for qualitative and quantitative estimation of curcumin and piperine in various food products, herbal medicines and nutraceuticals. PMID- 25015459 TI - In vitro/in vivo effect of Citrus limon (L. Burm. f.) juice on blood parameters, coagulation and anticoagulation factors in rabbits. AB - The genus Citrus of the family Rutaceae includes many species e.g. Citrus indica, Citrus aurantifolia and Citrus limon, among which Citrus limon L. Burm. f. has been reported to have highest antimicrobial activity. It is used as antidote against certain venom, due to its platelet inhibitory effect and also reported to have hypocholesterolemic effect. However its anticoagulant and thrombolytic effect were not been investigated, hence a prospective in-vitro/in-vivo study was designed to determine the effect of Citrus limon on blood parameters, coagulation and anticoagulation factors. In-vitro tests revealed highly significant increase in thrombin time and activated partial thromboplastin time by Citrus limon, whereas fibrinogen concentration was significantly reduced in comparison to control, however prothrombin time was not affected significantly. In-vivo testing of Citrus limon was done at three different doses i.e. 0.2ml/kg, 0.4ml/kg and 0.6ml/kg in healthy rabbits. Significant changes were observed in hematological parameters such as erythrocytes, hemoglobin and mean corpuscular hemoglobin concentration. Bleeding time and thrombin time was significantly prolonged and there was increase in protein C and thrombin antithrombin complex levels. These results may be due to inactivation of thrombin because it significantly decreases fibrinogen concentration and inhibit platelet aggregation. Citrus limon showed maximal anticoagulant effect at 0.4ml/kg, which suggest that Citrus limon possesses an anti-thrombin component and could prevent thrombosis playing a cardio protective role. PMID- 25015460 TI - Formulation and evaluation of suspensions: mefenamic acid prodrugs. AB - Gastrosparing novel prodrugs (MAM and MAT) synthesized consisted of mefenamic acid (MA) with menthol (M) and thymol (T). Structural characterizations of synthesized esters were done by Infra red spectroscopy (IR), proton nuclear magnetic resonance (1HNMR), mass spectroscopy. After evaluation of pharmacological i.e. anti-inflammatory, analgesic and ulcerogenic activities, the preformulation studies were undertaken. Based on these a few formulation (suspensions) were designed and prepared. The formulated suspensions were evaluated for content uniformity, sedimentation volume, recovery studies, redispersibility, viscosity, pH, particle size, zeta potential, effect of temperature and in-vitro dissolution rate. All the above parameters were found to be within the limit these indicated that the synthesized esters are good candidate for liquid dosage form. Thus it can be concluded synthesized prodrugs can be formulated in suspension form. PMID- 25015461 TI - Determination of pKa values of new phenacyl-piperidine derivatives by potentiometric titration method in aqueous medium at room temperature (25+/ 0.5oC). AB - Dissociation constant (pKa) of ten novel phenacyl derivatives of piperidine were determined by potentiometric titration method in aqueous medium at room temperature (25 +/-0.5 degrees C). The sample solutions were prepared in deionized water with ionic strength 0.01M and titrated with 0.1M NaOH solution. In addition, DeltaG values were also calculated. Different prediction software programs were used to calculate pKa values too and compared to the experimentally observed pKa values. The experimental and theoretical values were found in close agreement. The results obtained in this research would help to predict the good absorption of the studied compounds and can be selected as lead molecules for the synthesis of CNS active agents because of their lipophilic nature especially compound VII. PMID- 25015462 TI - Antipyretic activity of hydro-alcoholic extracts of Moringa oleifera in rabbits. AB - Pyrexia and inflammation are indicatives of various disorders. Modern medicines are available for treatment of pyrexia, but they have few side effects. Several studies are ongoing Worldwide to search natural antipyretic agents with better efficacy and fewer or no side effects. This study was aimed at evaluating the antipyretic activity of Moringa oleifera bark in rabbits against E. coli induced pyrexia. Rectal temperature was recorded with digital thermometer at 0 h and E. coli suspension was injected. After 1 h again rectal temperature of the animals was recorded and hydro-alcoholic extract were administered to the treatment groups and paracetamol hydro-alcoholic 50 mg/kg orally to the positive control group. Then rectal temperature was recorded at the interval of one h for 4 h. After the drug administration (at h 1), the decrease in body temperature with the dose of 25mg/kg(-1) during next four h ranged between 1.9-2.6of as compared to the negative control. At the dose of 50mg/kg(-1) the decrease in temperature was 1.9-3.0 of. The decrease in body temperature at the dose of 100mg/kg(-1) was high, which ranged from 2.3-3.1of as compared to negative control. Paracetamol, a standard drug , also significantly lowered the temperature but Moringa oleifera at the concentration of 100mg/kg(-1) lowered the body temperature significantly as compared to the negative as well as positive control. Moringa oleifera bark has marked antipyretic activity in animal models and this strongly supports the ethnopharmacological uses of Moringa oleifera bark as an antipyretic plant. PMID- 25015463 TI - Evaluation and comparison of different brands of domperidone tablets available in Karachi, Pakistan. AB - Domperidone is an anti-dopaminergic drug used for the treatment of nausea, vomiting and dyspepsia. It has also been used in Parkinson's disease. In this study, five different brands of Domeperidone tablets were selected from the local market for evaluation of their quality as the local market is occupied of many competitors for a single generic. The evaluation of Domperidone tablets was done using various pharmacopoeial and non-pharmacopoeial tests. All the test results fell within BP specified limits for all the selected brands i.e. the results for Brands A to E for weight variation, thickness and diameter were satisfactory and within limits. For Brands A to E, the results for hardness and friability were also satisfactory i.e. 4-10kg/cm2and 0.1-0.6% respectively. The results for Brands A to E for disintegration were 2-6 minutes; for dissolution and assay, the results were 89-92% and 95-99% respectively. The results of similarity factor (f2) also showed that all brands of Domperidone have comparative dissolution profiles. PMID- 25015464 TI - Antimicrobial potentials of Mentha longifolia by disc diffusion method. AB - This study was conducted for the assessment of the antimicrobial activities of different solvents extracted samples from the aerial parts of Mentha longifolia against ten microbial species through the disc diffusion assay using two different concentrations of 1 and 2 mg disc1. All extracts from Mentha longifolia showed different ranges of antimicrobial activities. Butanol and ethyl acetate fractions showed inhibitory activities against all microbial species. Methanol fraction showed inhibitory effects against all the tested microbial species except Salmonella typhi. Salmonella typhi was also not controlled by methanol, petroleum ether and dichloromethane extracted samples. The most susceptible gram positive bacteria was Bacillus atropheus and Bacillus subtilis and were inhibited by all extracts and Staphylococus aureus was least susceptible among gram positive bacteria. Klebsiella pneumoniae was the most susceptible gram negative bacterium and Salmonella typhi was highly resistant among the gram negative bacteria. Erwinia carotovora and Agrobacterium tumefaciene were susceptible to all fractions. All fractions showed antifungal activities against Candida albicans except water extracted samples. PMID- 25015465 TI - Preliminary phytochemical screening, antimicrobial and antioxidant activities of Euphorbia milli. AB - Euphorbia milii is a Pakistani herb used for various infectious diseases. In this study we have carried out phytochemical, antibacterial and antioxidant investigation of different extracts/fractions. Phytochemical studies showed the presence of cardiac glycosides, steroids/phytosterols, anthocyanin, proteins, terpenoids, flavonoids and tannins. Susceptibility testing by well diffusion assay of its chloroform and methanol fractions revealed good antimicrobial activity against Klebsiella pneumonia and Staph epidermis. Ethyl acetate fraction of roots also exhibited considerable antimicrobial activity against most of tested pathogens. Various fractions (Hexane, chloroform, methanol and water) of E. milii were screen for their antioxidant potential using DPPH radical scavenging assay at different concentrations among these, chloroform fraction exhibited good scavenging activity. The IR spectroscopy of the various extracts/fractions indicated the presence of OH, saturated CH stretching, C=C, C=O, NO2, C-N, Ar-O, C-O- and R-O-Stretching respectively. The findings provide helpful evidence for the use of E. milii in traditional medicines. PMID- 25015466 TI - Effect of phenological stages on nutritional assessment of ten plant species in Tehsil Takht-e-Nasrati, District Karak, Pakistan. AB - The proximate analysis of ten plant species from Tehsil takht-e-Nasrati, district Karak was conducted at three phenological stages using standard techniques. The species showed variable results. In the test species, the moisture content varied from 2.11-14.12 %, 1.85-11.51 and 1.12-11.51%; the ash contents varied from 3.08 17.16%, 5.09-18.12% and 6.13-19.09%; the fibre contents varied from 2.14-11.09%, 2.43-12.31% and 2.78-13.01%; the carbohydrate contents varied from 54-85.1%, (50 84.1) and 47.1-81.1%; the fat contents varied from 1.06-5.46%, 1.09-5.98% and 1.56- 6.57 %; the protein contents varied from 2.11-12.41%, 3.14-15.87% and 4.12 18.54%; the energy value varied from 305.12-394.23 KCal/100g, 314.21-423.13 KCal /100g and 321.23-434.26 KCal /100g at vegetative stage, reproductive stage and post reproductive stage respectively. Proximate analysis of such plant species can help us to determine the health benefits achieved from their use in society. It is concluded that the poor livestock productivity in research area is partially due to insufficient amount of available poor quality forage that requires attention of the range mangers to improve the habitat and livestock breeds. PMID- 25015467 TI - Comparative evaluation of various solubility enhancement strategies for furosemide. AB - Drugs with good solubility exhibit good oral absorption, and subsequently good bioavailability. Thus, most exigent phase of drug development practice particularly for oral dosage forms is the enhancement of drug solubility. This review describes various traditional and novel methodologies proposed for the solubility enhancement of furosemide. For furosemide, solubility and permeability are crucial rate limiting factors to achieve its desired level in systemic circulation for pharmacological response. Thus, problematic solubility of furosemide is one of the main challenges for dosage form developing researchers. Various procedures, illustrated in this review, have been successfully employed to improve the furosemide solubility; however successful improvement essentially depends on the assortment of technique. It is concluded from the results that dissolution rate of drug increases by increasing the quantity of solubility enhancer. Dissolution rate also depends upon the type of enhancer and dissolution medium. In order to achieve relatively enhanced percentage drug release after 30 min (DP30), complexation by solvent evaporation using beta-cyclodextrin is the best method. Solid dispersion is found the best if polyethylene glycol is used as enhancer along with microcrystalline cellulose as hydrophilic adsorbent. All the approaches narrated in this article possess good perceptions for additional research i.e. in-vivo studies should be carried out focusing on delivery system development. PMID- 25015469 TI - Coverage of common cancer types in UK national newspapers: a content analysis. AB - OBJECTIVE: To determine whether recent newspaper coverage of the four most common cancer types relates to their relative burden and national awareness months, and to identify the subject focus during high-coverage periods. DESIGN: Content analysis using the Nexis newspaper article database. SETTING: UK 2011-2012. OUTCOME MEASURES: Annual number and ranking, monthly proportions and subject of articles on breast, lung, bowel and prostate cancers. RESULTS: 9178 articles were identified during 2011 and 2012 featuring breast (4237), prostate (1757), lung (1746) and bowel (1438) cancer. Peaks in monthly proportions above the 99% upper confidence limit were identified for each. Breast cancer had the highest coverage of 12% and 17% during its awareness month. Smaller peaks (11%) were identified during Bowel Cancer Awareness month. Prostate cancer received high coverage in relation to the case of the man convicted of the Lockerbie bombing who had been diagnosed with the cancer, and lung cancer in relation to the deaths of celebrities. Breast cancer was covered most often overall and by newspaper category while the lower coverage of other cancer types did not consistently mirror the relative number of new cases each year. The peaks by newspaper category were similar to the overall coverage with few exceptions. CONCLUSIONS: UK newspaper coverage of common cancer types other than of the breast appears under-represented relative to their population burden. Coverage of breast cancer and bowel cancer appears to be influenced by their awareness months, while that of prostate cancer and lung cancer is influenced by other media stories. Health promoting public bodies and campaigners could learn from the success of Breast Cancer Awareness Month and work more closely with journalists to ensure that the relevant messages reach wider audiences. PMID- 25015470 TI - Examining different measures of multimorbidity, using a large prospective cross sectional study in Australian general practice. AB - OBJECTIVES: Prevalence estimates of multimorbidity vary widely due to inconsistent definitions and measurement methods. This study examines the independent effects on prevalence estimates of how 'disease entity' is defined-as a single chronic condition or chapters/domains in the International Classification of Primary Care (V.2; ICPC-2), International Classification of Disease (10th revision; ICD-10) or the Cumulative Illness Rating Scale (CIRS), the number of disease entities required for multimorbidity, and the number of chronic conditions studied. DESIGN: National prospective cross-sectional study. SETTING: Australian general practice. PARTICIPANTS: 8707 random consenting deidentified patient encounters with 290 randomly selected general practitioners. MAIN OUTCOME MEASURES: Prevalence estimates of multimorbidity using different definitions. RESULTS: Data classified to ICPC-2 chapters, ICD-10 chapters or CIRS domains produce similar multimorbidity prevalence estimates. When multimorbidity was defined as two or more (2+) disease entities: counting individual chronic conditions and groups of chronic conditions produced similar estimates; the 12 most prevalent chronic conditions identified about 80% of those identified using all chronic conditions. When multimorbidity was defined as 3+ disease entities: counting individual chronic conditions produced significantly higher estimates than counting groups of chronic conditions; the 12 most prevalent chronic conditions identified only two-thirds of patients identified using all chronic conditions. CONCLUSIONS: Multimorbidity defined as 2+ disease entities can be measured using different definitions of disease entity with as few as 12 prevalent chronic conditions, but lacks specificity to be useful, especially in older people. Multimorbidity, defined as 3+, requires more measurement conformity and inclusion of all chronic conditions, but provides greater specificity than the 2+ definition. The proposed concept of "complex multimorbidity", the co occurrence of three or more chronic conditions affecting three or more different body systems within one person without defining an index chronic condition, may be useful in identifying high-need individuals. PMID- 25015471 TI - Is the growth of the child of a smoking mother influenced by the father's prenatal exposure to tobacco? A hypothesis generating longitudinal study. AB - OBJECTIVES: Transgenerational effects of different environmental exposures are of major interest, with rodent experiments focusing on epigenetic mechanisms. Previously, we have shown that if the study mother is a non-smoker, there is increased mean birth weight, length and body mass index (BMI) in her sons if she herself had been exposed prenatally to her mother's smoking. The aim of this study was to determine whether the prenatal smoke exposure of either parent influenced the growth of the fetus of a smoking woman, and whether any effects were dependent on the fetal sex. DESIGN: Population-based prebirth cohort study. SETTING: Avon Longitudinal Study of Parents and Children. PARTICIPANTS: Participants were residents of a geographic area with expected date of delivery between April 1991 and December 1992. Among pregnancies of mothers who smoked during pregnancy, data were available concerning maternal and paternal prenatal exposures to their own mother smoking for 3502 and 2354, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Birth weight, length, BMI and head circumference. RESULTS: After controlling for confounders, there were no associations with birth weight, length or BMI. There was a strong adjusted association of birth head circumference among boys whose fathers had been exposed prenatally (mean difference -0.35 cm; 95% CI -0.57 to -0.14; p=0.001). There was no such association with girls (interaction p=0.006). Similar associations were found when primiparae and multiparae were analysed separately. In order to determine whether this was reflected in child development, we examined the relationships with IQ; we found that the boys born to exposed fathers had lower IQ scores on average, and that this was particularly due to the verbal component (mean difference in verbal IQ -3.65 points; 95% CI -6.60 to -0.70). CONCLUSIONS: Head size differences concerning paternal fetal exposure to smoking were unexpected and, as such, should be regarded as hypothesis generating. PMID- 25015474 TI - Should both iodised and non-iodised salt be made available in Chinese cities? A cross-sectional survey. AB - OBJECTIVE: To contribute evidence relevant to the policy of supplying iodised salt (IS), non-iodised salt (NIS) or both in Chinese cities. DESIGN: Subnational telephone interview survey. SETTING: China. PARTICIPANTS: Totally, 24 557 telephone numbers were dialled and 4833 citizens accepted the telephone interview. The telephone numbers were randomly selected by random digit dialling and a Mitofsky-Waksberg two-stage sampling method in 17 capital cities and 6 coastal cities from 17 iodine deficiency disorder (IDD)-eliminated provinces (municipalities). RESULTS: The 4833 citizens finished the telephone interview. Among them, 3738 (77.3%) citizens chose IS, 481 (10%) citizens chose NIS, and the others chose both IS and NIS. The citizens' awareness rates of IDD and IDD preventive measures were 68.7% and 62.5%, respectively. CONCLUSIONS: It is not a suitable time to supply IS and NIS simultaneously in the developed cities of China, but a pilot project may be conducted in the cities where IDD has been sustainably eliminated, there is strong awareness of IDD and the population can make informed decisions regarding IS. IDD health education should be further strengthened, especially regarding the potential for IQ damage. PMID- 25015472 TI - Observational longitudinal cohort study to determine progression to heart failure in a screened community population: the Echocardiographic Heart of England Screening Extension (ECHOES-X) study. AB - OBJECTIVES: Rescreen a large community cohort to examine the progression to heart failure over time and the role of natriuretic peptide testing in screening. DESIGN: Observational longitudinal cohort study. SETTING: 16 socioeconomically diverse practices in central England. PARTICIPANTS: Participants from the original Echocardiographic Heart of England Screening (ECHOES) study were invited to attend for rescreening. OUTCOME MEASURES: Prevalence of heart failure at rescreening overall and for each original ECHOES subgroup. Test performance of N Terminal pro-B-type Natriuretic Peptide (NT-proBNP) levels at different thresholds for screening. RESULTS: 1618 of 3408 participants underwent screening which represented 47% of survivors and 26% of the original ECHOES cohort. A total of 176 (11%, 95% CI 9.4% to 12.5%) participants were classified as having heart failure at rescreening; 103 had heart failure with reduced ejection fraction (HFREF) and 73 had heart failure with preserved ejection fraction (HFPEF). Sixty eight out of 1232 (5.5%, 95% CI 4.3% to 6.9%) participants who were recruited from the general population over the age of 45 and did not have heart failure in the original study, had heart failure on rescreening. An NT-proBNP cut-off of 400 pg/mL had sensitivity for a diagnosis of heart failure of 79.5% (95% CI 72.4% to 85.5%) and specificity of 87% (95% CI 85.1% to 88.8%). CONCLUSIONS: Rescreening identified new cases of HFREF and HFPEF. Progression to heart failure poses a significant threat over time. The natriuretic peptide cut-off level for ruling out heart failure must be low enough to ensure cases are not missed at screening. PMID- 25015475 TI - Chronic condition comorbidity and multidrug therapy in general practice populations: a cross-sectional linkage study. AB - OBJECTIVES: The study investigated (1) the association between comorbidity and multidrug prescribing compared with the index condition, and (2) the association between vascular comorbidity and non-vascular condition key drug prescribing. DESIGN: Cross-sectional study linking anonymised computer consultations with prescription records for a 2-year time period. SETTING: 11 general practices in North Staffordshire, England. PARTICIPANTS: Study groups aged 40 years and over (N=12 875). Within six conditions, comorbid group with the other five conditions was compared with an 'alone' group without them. Additionally, how the 'vascular' (one of diabetes, cardiovascular disease and cerebrovascular disease) comorbidity influenced chronic obstructive pulmonary disease (COPD), osteoarthritis (OA) or depression drug prescribing was investigated. OUTCOME MEASURES: Based on the British National Formulary, five main drug chapters constituted a measure of drug counts, with low count as 2 or less and high multidrug count as 3 or more. Key drugs prescribed for COPD, OA and depression were derived from guidelines. RESULTS: The adjusted associations between the comorbid groups and higher multidrug count compared with their respective 'alone' group were: odds ratio (OR) 7.1 (95% CI 5.6 to 9.0) for depression, OR 5.4 (95% CI 4.6 to 6.3) for cardiovascular disease, OR 3.7 (95% CI 2.8 to 5.0) for cerebrovascular disease, OR 3.6 (95% CI 3.1 to 4.3) for OA, OR 3.5 (95% CI 3.0 to 4.2) for diabetes and OR 3.2 (95% CI 2.6 to 4.0) for COPD. In COPD, vascular comorbidity was associated with a significant reduction in key COPD drug treatments (adjusted OR 0.6 (95% CI 0.4 to 0.8). In depression, vascular comorbidity was associated with a reduction in key depression drug treatments (OR 0.6 (95% CI 0.4 to 0.7)). CONCLUSIONS: Our findings show that multidrug prescribing for different body systems is higher with comorbidity and may be associated with lower likelihood of prescribing for specific conditions. Further research is required on whether multidrug prescribing influences the outcomes of care for chronic conditions. PMID- 25015476 TI - The effect of exercise training on lower trunk muscle morphology. AB - BACKGROUND: Skeletal muscle plays an important role in maintaining the stability of the lumbar region. However, there is conflicting evidence regarding the effects of exercise on trunk muscle morphology. OBJECTIVE: To systematically review the literature on the effects of exercise training on lower trunk muscle morphology to determine the comparative effectiveness of different exercise interventions. DATA SOURCE AND STUDY SELECTION: A systematic search strategy was conducted in the following databases: PubMed, SportDiscus, CINAHL, the Cochrane Library and PEDro. We included full, peer-reviewed, prospective longitudinal studies, including randomized controlled trials and single-group designs, such as pre- to post-intervention and crossover studies, reporting on the effect of exercise training on trunk muscle morphology. STUDY APPRAISAL AND SYNTHESIS: Study quality was assessed with the Cochrane risk-of-bias tool. We classified each exercise intervention into four categories, based on the primary exercise approach: motor control, machine-based resistance, non-machine-based resistance or cardiovascular. Treatment effects were estimated using within-group standardized mean differences (SMDs). RESULTS: The systematic search identified 1,911 studies; of which 29 met our selection criteria: motor control (n = 12), machine-based resistance (n = 10), non-machine-based resistance (n = 5) and cardiovascular (n = 2). Fourteen studies (48 %) reported an increase in trunk muscle size following exercise training. Among positive trials, the largest effects were reported by studies testing combined motor control and non-machine based resistance exercise (SMD [95 % CI] = 0.66 [0.06 to 1.27] to 3.39 [2.80 to 3.98]) and machine-based resistance exercise programmes (SMD [95 % CI] = 0.52 [0.01 to 1.03] to 1.79 [0.87 to 2.72]). Most studies investigating the effects of non-machine-based resistance exercise reported no change in trunk muscle morphology, with one study reporting a medium effect on trunk muscle size (SMD [95 % CI] = 0.60 [0.03 to 1.16]). Cardiovascular exercise interventions demonstrated no effect on trunk muscle morphology (SMD [95 % CI] = -0.16 [-1.14 to 0.81] to 0.09 [-0.83 to 1.01]). LIMITATIONS: We excluded studies published in languages other than English, and therefore it is possible that the results of relevant studies are not represented in this review. There was large clinical heterogeneity between the included studies, which prevented data synthesis. Among the studies included in this review, common sources of potential bias were random sequence generation, allocation concealment and blinding. Finally, the details of the exercise parameters were poorly reported in most studies. CONCLUSION: Approximately half of the included studies reported an increase in lower trunk muscle size following participation in an exercise programme. Among positive trials, studies involving motor control exercises combined with non-machine-based resistance exercise, as well as machine-based resistance exercises, demonstrated medium to large effects on trunk muscle size. Most studies examining the effect of non-machine-based resistance exercise and all studies investigating cardiovascular exercise reported no effect on trunk muscle morphology. However, these results should be interpreted with caution because of the substantial risk of bias and suboptimal reporting of exercise details in the included studies. Additional research, using methods ensuring a low risk of bias, are required to further elucidate the effects of exercise on trunk muscle morphology. PMID- 25015477 TI - Conventional and genetic talent identification in sports: will recent developments trace talent? AB - The purpose of talent identification (TI) is the earliest possible selection of auspicious athletes with the goal of systematically maximizing their potential. The literature proposes excellent reviews on various facets of talent research on different scientific issues such as sports sciences or genetics. However, the approaches of conventional and genetic testing have only been discussed separately by and for the respective groups of interest. In this article, we combine the discoveries of these disciplines into a single review to provide a comprehensive overview and elucidate the prevailing limitations. Fundamental problems in TI reside in the difficulties of defining the construct 'talent' or groups of different performance levels that represent the target variable of testing. Conventional and genetic testing reveal a number of methodological and technical limitations, and parallels are summarised in terms of the test designs, the point in time of testing, psychological skills or traits and unknown interactions between different variables. In conclusion, many deficiencies in the current talent research have gained attention. Alternative solutions include the talent development approach, while genetic testing is re-emphasised as a tool for risk stratification in sport participation. Future research needs to clearly define the group of interest and comprehensively implement all methodological improvement suggestions. PMID- 25015479 TI - A history of viral infections of the central nervous system: foundations, milestones, and patterns. PMID- 25015478 TI - Knee mechanics during planned and unplanned sidestepping: a systematic review and meta-analysis. AB - BACKGROUND: Knee joint mechanics during sidestepping are associated with anterior cruciate ligament injury. Unplanned sidestepping more closely emulates game scenarios when compared with planned sidestepping by limiting decision time, increasing knee loading and challenging the integrity of soft-tissue structures in the knee. It is important to quantify the loads that may challenge the integrity of the knee during planned and unplanned sidestepping. OBJECTIVE: Our objective was to review literature on knee mechanics during planned and unplanned phases of sidestepping. DATA SOURCES: PubMed, CINAHL, MEDLINE (EBSCO), SPORTDiscus and Web of Science were searched using the terms knee mechanics OR knee kine*, AND plan*, unplan*, anticipat*, unanticipat*, side*, cut* or chang*. STUDY SELECTION: A systematic approach was used to evaluate 4,629 records. Records were excluded when not available in English, only available in abstract of conference proceedings, not involving a change-of-direction sidestep, not comparing planned and unplanned or maintaining a running velocity greater than 2 m s(-1). DATA EXTRACTION: Included studies were evaluated independently by two authors using a custom-designed methodological quality assessment derived from the Physiotherapy Evidence Database (PEDro) scale and then confirmed by a third author. DATA SYNTHESIS: Only six studies met the inclusion criteria and were retained for meta-analysis. Magnitude-based inferences were used to assess the standardised effect of the differences between planned and unplanned sidestepping. Knee angles and knee moments were extracted and reported for flexion/extension, abduction/adduction and internal/external rotation for initial contact, weight acceptance, peak push-off and final push-off phases of sidestepping. RESULTS: For kinematic variables, unplanned sidestepping produced a wide range of small to large increases in knee extension angles, small and moderate increases in knee abduction angles and a small increase in internal rotation angle relative to planned sidestepping during the sidestepping manoeuvre. For kinetic variables, unplanned sidestepping produced mostly small (small to large) increases in knee flexor moments, small to moderate increases in knee abductor moments and mostly moderate (small to large) increases in internal rotator moments relative to planned sidestepping. LIMITATIONS: Approach velocity constraints during the sidestepping manoeuvre were lifted due to the low number of eligible studies. The varying approach velocities included (ranging from 3.0 to 5.5 m s(-1)) may impact the kinematic and kinetic variables examined in this review. CONCLUSIONS: Differences in knee mechanics between planned and unplanned sidestepping exist. The most substantial effects occurred during the weight acceptance phase of sidestepping. It seems that biomechanical factors commonly associated with anterior cruciate ligament injury risk are affected the most during the loading phase compared with peak push-off; made evident in the coronal (abductor) and transverse (internal rotator) knee kinetic data presented in this review. The authors of this review propose a rationale for the incorporation of unplanned sport tasks in the development of anterior cruciate ligament injury screening and in prophylactic training programmes. PMID- 25015480 TI - Basics of virology. PMID- 25015482 TI - Clinical approach to the syndromes of viral encephalitis, myelitis, and meningitis. PMID- 25015483 TI - Laboratory diagnosis of viral infection. PMID- 25015481 TI - Neuroepidemiology and the epidemiology of viral infections of the nervous system. AB - The field of neurovirology will undoubtedly experience evolution and change in the years to come. The epidemiology of viral CNS diseases continues to change, and as our understanding of the pathogenesis and pathophysiology associated with viral agents grows, so does our understanding of the behavior of these pathogens among populations. The appearance of viral pathogens in newsettings, new or unrecognized modes of transmission,and the emergence of previously unrecognized pathogens will continue to challenge our laboratory diagnostic and epidemiologic capabilities. However, each lesson that is learned from this evolving epidemiology will hopefully result in improved surveillance, diagnostic,and treatment and prevention capabilities. PMID- 25015484 TI - Neuroimaging of viral infections of the central nervous system. PMID- 25015485 TI - Viral neuropathogenesis. PMID- 25015486 TI - Neuropathology of viral infections. PMID- 25015487 TI - Innate immune viral recognition: relevance to CNS infections. AB - Innate immune responses mediated by mononuclear phagocytes represent the initial host response to acute viral infection. PRRs, including TLRs, retinoic RLRs,and NOD-like receptors, recognize viral nucleic acid and localized injury signals to initiate proinflammatory responses and activation of adaptive immunity. These responses are host- and viral-dependent. Neurotropic viruses, such as HSV, West Nile virus, and HIV activate and evade innate immune signaling mechanisms by distinct mechanisms. These highly complex pathogen-host interactions determine establishment of infection, severity of clinical disease, development of chronic inflammatory processes, and success of vaccination strategies. PMID- 25015489 TI - Herpes simplex virus. PMID- 25015488 TI - Adaptive immune response to viral infections in the central nervous system. PMID- 25015491 TI - Epstein-Barr virus infections of the nervous system. PMID- 25015492 TI - Cytomegalovirus infections of the adult human nervous system. PMID- 25015493 TI - Congenital cytomegalovirus infection. PMID- 25015494 TI - Human herpesvirus 6 and the nervous system. PMID- 25015490 TI - Varicella-zoster. PMID- 25015495 TI - Progressive multifocal leukoencephalopathy. PMID- 25015496 TI - Enterovirus/picornavirus infections. PMID- 25015497 TI - The equine encephalitides. PMID- 25015498 TI - West Nile and St. Louis encephalitis viruses. PMID- 25015499 TI - The Bunyaviridae. PMID- 25015501 TI - Central nervous system HIV-1 infection. PMID- 25015502 TI - Neurologic disease due to HTLV-1 infection. PMID- 25015503 TI - Tick-borne encephalitis. PMID- 25015504 TI - Japanese encephalitis virus infection. PMID- 25015500 TI - Human endogenous retroviruses and the nervous system. PMID- 25015505 TI - Measles virus and the nervous system. PMID- 25015506 TI - Mumps and rubella. PMID- 25015507 TI - Rabies. PMID- 25015508 TI - Neurologic aspects of influenza viruses. PMID- 25015509 TI - Neurologic complications of hepatic viruses. PMID- 25015510 TI - Henipavirus encephalitis. PMID- 25015511 TI - Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses. PMID- 25015512 TI - Nervous system viral infections in immunocompromised hosts. PMID- 25015513 TI - Acute disseminated encephalomyelitis. PMID- 25015514 TI - Vaccines and viral / toxin-associated neurologic infections. PMID- 25015515 TI - Encephalitis lethargica (von Economo's encephalitis). PMID- 25015516 TI - Bell's palsy and vestibular neuronitis. PMID- 25015517 TI - Preface. PMID- 25015519 TI - The role of abdominal drainage to prevent of intra-abdominal complications after laparoscopic cholecystectomy for acute cholecystitis: prospective randomized trial. AB - BACKGROUND: Routine drainage of the abdominal cavity after surgery has been a robust dogma for many decades. Nevertheless, the policy of routine abdominal drainage is increasingly questioned. Many surgeons believe that routine drainage after surgery may prevent postoperative intra-abdominal infection. The goal of this study was to assess the role of drains in laparoscopic cholecystectomy (LC) for acute cholecystitis. MATERIALS AND METHODS: From May 2008 to July 2012, 160 patients that underwent LC due to acute cholecystitis at Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea, were enrolled in this study. After surgery, patients were randomly allocated to undergo drain placement in the subhepatic space (Group A) or no drainage (Group B). RESULTS: There was no significant difference in the intra-abdominal abscess rate, which was 0.0 % with Group A and 1.3 % with Group B (P = 0.319). The median subhepatic fluid collection was 4.1 mL (1.1-60 mL) in Group A and 4.5 mL (1.1-80.0 mL) in Group B (P = 0.298). However, the median hospital stay was 2 days (1-4 days) in Group B and 3 days (2-7 days) in group A (P = 0.001). The subgroup of empyema patients did not have any significant differences in intra-abdominal fluid collection or intra-abdominal abscess rate. CONCLUSIONS: This study suggests that postoperative routine drainage of the abdominal cavity for acute cholecystitis does not prevent intra-abdominal infections. PMID- 25015520 TI - A preoperative hernia symptom score predicts inguinal hernia anatomy and outcomes after TEP repair. AB - BACKGROUND: The Carolinas comfort scale (CCS) is an ideal tool for assessing patients' quality-of-life post hernia repair, but its use has been barely investigated preoperatively. The aim was to quantify preoperative symptoms and assess their relevance in predicting postoperative clinical outcomes following totally extraperitoneal (TEP) inguinal hernia repair. METHODS: The CCS was modified for preoperative use (modified or MCCS) by omitting mesh sensation questioning. Data collection was prospective over a 16 months period. (M)CCS questionnaires were completed preoperatively and at 2 then 6 weeks post repair. Intraoperative findings were also recorded. One hundred and four consecutive patients consented for TEP repair were included using a fibrin glue mesh fixation technique. RESULTS: All three questionnaires were completed by 88 patients (84.6 %). Preoperative MCCS scores did not differ with age, obesity, the presence of bilateral or recurrent inguinal herniae or hernia type. Higher MCCS grouping [OR 4.3 (95 % CI 1.5-12.6)] and the presence of bilateral herniae [OR 8.5 (1.2-61.8)] were predictors of persisting discomfort at 6 weeks, with lower scores on MCCS [OR 16.4 (3.9-67.6), obesity (OR 9.9 91.6-63.2)] and recurrent hernia repair [OR 11.4 (1.4-91.0)] predicting increased discomfort at 2 weeks versus preoperatively. MCCS scores were inversely correlated with the size of a direct defect (r -0.42, p = 0.011) but did not differ with the intraoperative finding of an incidental femoral and/or obturator hernia. Female sex was strongly associated with recognition of a synchronous incidental hernia (5 vs 57 %, p = 0.001). CONCLUSIONS: Pre- and post-operative scoring of hernia specific symptoms should be considered as part of routine surgical practice, to counsel patients on their expectations of pain and discomfort post repair and to select those who might be more appropriate for a watchful waiting approach. Females with inguinal hernia warrant complete assessment of their groin hernial orifices intraoperatively due to a high rate of synchronous incidental hernia. PMID- 25015521 TI - What are the risk factors for residual tumor cells after endoscopic complete resection in gastric epithelial neoplasia? AB - BACKGROUND: In early gastric cancer (EGC) and gastric adenoma, residual tumors may develop despite complete endoscopic resection (ER). To improve the chance of curative resection, we investigated the risk factors of residual tumor development in completely resected gastric epithelial neoplasia after ER. METHODS: In total, 3,879 gastric epithelial neoplasms showing complete resection after ER were examined; 46 (1.2 %) residual tumors were found upon follow-up endoscopy. Clinicopathological characteristics were evaluated between those with and without residual tumors. RESULTS: For gastric adenoma, high-grade dysplasia and severe intestinal metaplasia (IM) in the background mucosa were significantly associated with residual tumors. For EGC, poorly differentiated adenocarcinoma (PD), signet ring cell carcinoma (SRC), having a minimum lateral safety margin of <3 mm, and localization in the upper third of the stomach were significantly associated with residual tumors. Multivariate analysis revealed that a lateral safety margin of <3 mm (OR 13.8; p < 0.001), PD (OR 16.3; p = 0.014), and SRC (OR 9.8; p = 0.009) among EGC patients, and severe IM in the background mucosa (OR 9.0; p = 0.024) among gastric adenoma patients, were significantly associated with residual tumors. CONCLUSIONS: For neoplasms with undifferentiated histology (PD or SRC), short-term endoscopic follow-up may help to detect residual tumors that form after complete resection via ER. For EGC, the lateral margin may be considered safe if greater than 3 mm. However, the possibility of satellite lesions should be investigated when the gastric adenoma to be resected is surrounded by severe IM. PMID- 25015522 TI - Laparoscopy mitigates adverse oncological effects of delayed adjuvant chemotherapy for colon cancer. AB - BACKGROUND: Delaying initiation of adjuvant chemotherapy more than 8 weeks after surgical resection for colorectal cancer adversely affects overall patient survival. The effect of a laparoscopic surgical approach on initiation of chemotherapy has not been studied. The goal of this study was to determine if a laparoscopic approach to colon cancer resection affects the timing of adjuvant chemotherapy and outcomes. METHODS: Patients who underwent curative surgery for stage II or III colon cancer and received adjuvant chemotherapy between 2003 and 2010 were identified from a prospectively maintained database. Patients were categorized according to surgical approach: open or laparoscopic. Patient demographics, clinicopathologic variables, postoperative complications, time from surgery to initiation of chemotherapy, and long-term oncologic outcomes were compared. RESULTS: Age, gender, ASA class, BMI, tumor stage, and postoperative complications were similar for laparoscopic and open cases, while length of stay was 2 days shorter for laparoscopic cases (5.4 vs 7.6 days, p < 0.01). The proportion of patients who received adjuvant chemotherapy more than 8 weeks after surgery did not differ between the groups (35.6 % open vs 38.7 % laparoscopic, p = 0.77). In the open group, delay in chemotherapy after surgery was associated with decreased disease-free and overall survival (p = 0.01, 0.01, respectively). However, delay in chemotherapy more than 8 weeks did not affect disease-free or overall survival in the laparoscopy group (p = 0.93, 0.51, respectively). CONCLUSIONS: The benefits of quicker recovery after laparoscopic surgery did not translate into earlier initiation of adjuvant chemotherapy in this retrospective study. However, a laparoscopic approach negated the inferior oncologic outcomes of patients who received delayed initiation of chemotherapy. PMID- 25015523 TI - Comparison of perioperative surgical outcomes between a bipolar device and an ultrasonic device during laparoscopic gastrectomy for gastric cancer. AB - BACKGROUND: The use of energy devices during laparoscopic gastrectomy for gastric cancer has increased as the frequency of laparoscopic surgery has increased. Our aim was to compare the perioperative surgical outcomes between using a bipolar device and an ultrasonic device during laparoscopic gastrectomy. METHODS: Retrospective review of a prospectively maintained database identified 186 patients who underwent laparoscopic gastrectomy performed by a single surgeon between November 2010 and August 2013. A bipolar device was used for 116 patients, and an ultrasonic device was used for 70 patients. Patient characteristics and perioperative surgical outcomes were compared between groups. RESULTS: Clinicopathologic characteristics were similar for both groups. The bipolar group had a significantly shorter operation time (154.9 vs. 167.8 min, p = 0.028) and higher rate of D2 lymph node dissection (29.3 vs. 15.7 %, p = 0.012). The bipolar device group experienced significantly less pain at 12 h [visual analog scale (VAS) pain score: 3.9 vs. 4.7, p = 0.027) and 18 h (VAS pain score: 3.5 vs. 4.1, p = 0.036) postoperatively. The bipolar group had earlier abdominal drain removal (p = 0.001) and a shorter hospital stay (p = 0.024). No significant differences in laboratory value changes, morbidity, or mortality were observed between the groups. CONCLUSION: Compared with the ultrasonic device, the bipolar device provided advantages in operation time, degree of postoperative pain, time of drain removal, and length of hospital stay. The bipolar device may be a useful and efficient energy device for laparoscopic gastrectomy. However, larger studies to confirm the safety of bipolar device during laparoscopic gastrectomy are warranted. PMID- 25015524 TI - Liquid-injection for preperitoneal dissection of transabdominal preperitoneal (TAPP) inguinal [corrected] hernia repair. AB - BACKGROUND: The creation of an adequate peritoneal flap during laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair, while avoiding injuring surrounding structures can be technically challenging. Liquid infiltration of the preperitoneal space can help facilitate dissection and avoid inadvertent injuries. We describe a novel technique for TAPP inguinal hernia repair using liquid-injection for preperitoneal [corrected] dissection and report our initial experience. METHODS: TAPP inguinal hernia repair using a liquid injection technique during preperitoneal dissection was performed by a single surgical resident without prior TAPP repair experience from July 2013 to January 2014. After trocar placement, 60 mL of 0.3 % lidocaine with 1:300,000 dilution of epinephrine was injected percutaneously using a blunt needle under laparoscopic visualization into the preperitoneal space to assist with the dissection and parietalization of the vas deferens, spermatic vessels, and epigastric vessels. The initial peritoneal incision is performed at the lateral side of the inguinal canal, followed by blunt dissection of the preperitoneal space. RESULTS: Eleven patients (median age: 69; 8 male) with a total of 12 inguinal hernias underwent a TAPP repair using a liquid-injection preperitoneal dissection technique. Ten patients had unilateral hernias (4 indirect, 6 direct), and one patient had bilateral direct hernias. The median operative time, median injection time, and median dissection time were 116, 3.5, and 42 min, respectively. Estimated blood loss was less than 10 mL for all cases. No intraoperative injuries, conversions to open repair, or 30-day postoperative complications occurred. There were no hernia recurrences after a median follow-up of 143 days. CONCLUSION: Our preliminary experience suggests that liquid-injection to assist preperitoneal dissection during TAPP inguinal hernia repair appears to be safe and feasible. This novel method facilitates the dissection of spermatic cord structures, and can be used to minimize trauma to surrounding structures, especially when performed by trainees with limited operative experience. PMID- 25015526 TI - Distinct variation in vector competence among nine field populations of Aedes aegypti from a Brazilian dengue-endemic risk city. AB - BACKGROUND: In Brazil, dengue epidemics erupt sporadically throughout the country and it is unclear if outbreaks may initiate a sustainable transmission cycle. There are few studies evaluating the ability of Brazilian Aedes aegypti populations to transmit dengue virus (DENV). The aim of this study was to compare DENV susceptibility of field-captured Ae. aegypti populations from nine distinct geographic areas of the city of Belo Horizonte in 2009 and 2011. Infection Rate (IR), Vector Competence (VC) and Disseminated Infection Rate (DIR) were determined. METHODS: Aedes aegypti eggs from each region were collected and reared separately in an insectary. Adult females were experimentally infected with DENV-2 and the virus was detected by qPCR in body and head samples. Data were analyzed with the Statistical Package for the Social Sciences version 17. RESULTS: IR varied from 40.0% to 82.5% in 2009 and 60.0% to 100.0% in 2011. VC ranged from 25.0% to 77.5% in 2009 and 25.0% to 80.0% in 2011. DIR oscillated from 68.7% to 100.0% in 2009 and 38.4% to 86.8 in 2011. When the results were evaluated by a logistic model using IR as covariate, North, Barreiro, South Central and Venda Nova showed the strongest association in 2009. In 2011, a similar association was observed for South-Central, Venda Nova, West and Northeast regions. Using VC as covariate, South-Central and Venda Nova showed the most relevant association in 2009. In 2011, South-Central, Venda Nova and Barreiro presented the greatest revelation associations. When DIR data were analyzed by logistic regression models, Pampulha, South-Central, Venda Nova, West, Northeast and East (2009) as well as South-Central, Venda Nova and West (2011) were the districts showing the strongest associations. CONCLUSIONS: We conclude that Ae. aegypti populations from Belo Horizonte exhibit wide variation in vector competence to transmit dengue. Therefore, vector control strategies should be adapted to the available data for each region. Further analysis should be conducted to better understand the reasons for this large variability in vector competence and how these parameters correlate with epidemiological findings in subsequent years. PMID- 25015527 TI - Importance of the polarity of the glycosaminoglycan chain on the interaction with FGF-1. AB - Heparin-like saccharides play an essential role in binding to the fibroblast growth factor (FGF)-1 and to their membrane receptors fibroblast growth factor receptor forming a ternary complex that is responsible of the internalization of the signal, via the dimerization of the intracellular regions of the receptor. In this study, we report the binding affinities between five synthetic hexasaccharides with human FGF-1 obtained by surface plasmon resonance experiments, and compare with the induced mitogenic activity previously obtained. These five oligosaccharides differ in sulfation pattern and in sequence. We have previously demonstrated that all the five hexasaccharides have similar 3D structure of the backbone. Consequently, the differences in binding affinity should have their origin in the substitution pattern. Subsequently, the different capacity for induction of mitogenic activity can be, at least partially, explained from these binding affinities. Interestingly, one of the oligosaccharides lacking axially symmetry ( 3: ) was biologically inactive, whereas the other ( 2: ) was the most active. The difference between both compounds is the order of the FGF-binding motifs along the chain relative to the carbohydrate polarity. We can conclude that the directionality of the GAG chain is essential for the binding and subsequent activation. The relative biological activity of the compounds with regular substitution pattern can be inferred from their values of IC50. Remarkably, the sulfate in position 6 of d-glucosamine was essential for the mitogenic activity but not for the interaction with FGF-1. PMID- 25015528 TI - Comparative genomic analysis of Klebsiella pneumonia (LCT-KP214) and a mutant strain (LCT-KP289) obtained after spaceflight. AB - BACKGROUND: With the development of space science, it is important to analyze the relationship between the space environment and genome variations that might cause phenotypic changes in microbes. Klebsiella pneumoniae is commonly found on the human body and is resistant to multiple drugs. To study space-environment-induced genome variations and drug resistance changes, K. pneumoniae was carried into outer space by the Shenzhou VIII spacecraft. RESULTS: The K. pneumoniae strain LCT-KP289 was selected after spaceflight based on its phenotypic differences compared to the ground-control strain. Analysis of genomic structural variations revealed one inversion, 25 deletions, fifty-nine insertions, two translocations and six translocations with inversions. In addition, 155 and 400 unique genes were observed in LCT-KP214 and LCT-KP289, respectively, including the gene encoding dihydroxyacetone kinase, which generates the ATP and NADH required for microbial growth. Furthermore, a large number of mutant genes were related to transport and metabolism. Phylogenetic analysis revealed that most genes in these two strains had a dN/dS value greater than 1, indicating that the strain diversity increased after spaceflight. Analysis of drug-resistance phenotypes revealed that the K. pneumoniae strain LCT-KP289 was resistant to sulfamethoxazole, whereas the control strain, LCT-KP214, was not; both strains were resistant to benzylpenicillin, ampicillin, lincomycin, vancomycin, chloramphenicol and streptomycin. The sulfamethoxazole resistance may be associated with sequences in Scaffold7 in LCT-KP289, which were not observed in LCT-K214; this scaffold contained the gene sul1. In the strain LCT-KP289, we also observed a drug-resistance integron containing emrE (confers multidrug resistance) and ant (confers resistance to spectinomycin, streptomycin, tobramycin, kanamycin, sisomicin, dibekacin, and gentamicin). The gene ampC (confers resistance to penicillin, cephalosporin-ii and cephalosporin-i) was present near the integron. In addition, 30 and 26 drug-resistance genes were observed in LCT-KP289 and LCT-KP214, respectively. CONCLUSIONS: Comparison of a K. pneumoniae strain obtained after spaceflight with the ground-control strain revealed genome variations and phenotypic changes and elucidated the genomic basis of the acquired drug resistance. These data pave the way for future studies on the effects of spaceflight. PMID- 25015529 TI - Embryo cell wall properties in relation to development and desiccation in the recalcitrant-seeded Encephalartos natalensis (Zamiaceae) Dyer and Verdoorn. AB - Plant cell walls are dynamic entities that may change with development, differ between plant species and tissue type and play an important role in responses to various stresses. In this regard, the present investigation employed immunocytochemistry to determine wall composition and possible changes during development of immature and mature embryos of the recalcitrant-seeded cycad Encephalartos natalensis. Fluorescent and gold markers, together with cryo scanning and transmission electron microscopy (TEM) were also used to analyse potential changes in the cell walls of mature embryos upon desiccation. Immature cell walls were characterised by low- and high methyl-esterified epitopes of pectin, rhamnogalacturonan-associated arabinan, and the hemicellulose xyloglucan. Arabinogalactan protein recognised by the LM2 antibody, along with rhamnogalacturonan-associated galactan and the hemicellulose xylan, were not positively localised using immunological probes, suggesting that the cell walls of the embryo of E. natalensis do not possess these epitopes. Interestingly, mature embryos appeared to be identical to immature ones with respect to the cell wall components investigated, implying that these may not change during the protracted post-shedding embryogenesis of this species. Drying appeared to induce some degree of cell wall folding in mature embryos, although this was limited by the abundant amyloplasts, which filled the cytomatrical space. Folding, however, was correlated with relatively high levels of wall plasticisers typified by arabinose polymers. From the results of this study, it is proposed that the embryo cell walls of E. natalensis are constitutively prepared for the flexibility required during cell growth and expansion, which may also facilitate the moderate cell wall folding observed in mature embryos upon drying. This, together with the abundant occurrence of amyloplasts in the cytomatrix, may provide sufficient mechanical stabilisation if water is lost, even though the seeds of this species are highly desiccation-sensitive. PMID- 25015531 TI - Pairwise binding competition experiments for sorting hub-protein/effector interaction hierarchy and simultaneous equilibria. AB - NMR experiments on proteins in simultaneous equilibria with multiple binding partners can provide a tool to understand complex biological interaction networks. Competition among proteins for binding to signaling hubs is often at the basis of the information transmission across signaling networks in every organism. Changes in affinity towards one or more partners, as well as changes of the relative concentration of the competing partners, can determine pathways alterations that lead to pathological consequences. Overall, the knowledge of the interaction hierarchy of the multiple partners to a single signaling hub can lead to new therapeutic strategies. Smith and Ikura (Nat Chem Biol 10:223-230, 2014) have recently proposed pairwise competition NMR experiments to determine the binding hierarchy in network interactions. We have taken the moves from their approach to show how from pairwise competition NMR experiments the ratios between the equilibrium constants for multiple binding partners can be determined, and thus, given their concentration in solution, the concentrations of all the possible complexes can be obtained. PMID- 25015530 TI - Cryoprotection of lipid membranes for high-resolution solid-state NMR studies of membrane peptides and proteins at low temperature. AB - Solid-state NMR spectra of membrane proteins often show significant line broadening at cryogenic temperatures. Here we investigate the effects of several cryoprotectants to preserve the spectral resolution of lipid membranes and membrane peptides at temperatures down to ~200 K. Trehalose, glycerol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), and polyethylene glycol (PEG), were chosen. These compounds are commonly used in protein crystallography and cryobiology. 13C and 1H magic-angle-spinning spectra of several types of lipid membranes show that DMSO provides the best resolution enhancement over unprotected membranes and also best retards ice formation at low temperature. DMF and PEG-400 show slightly weaker cryoprotection, while glycerol and trehalose neither prevent membrane line broadening nor prevent ice formation under the conditions of our study. Neutral saturated-chain phospholipids are the most amenable to cryoprotection, whereas negatively charged and unsaturated lipids attenuate cryoprotection. 13C-1H dipolar couplings and 31P chemical shift anisotropies indicate that high spectral resolution at low temperature is correlated with stronger immobilization of the lipids at high temperature, indicating that line narrowing results from reduction of the conformational space sampled by the lipid molecules at high temperature. DMSO selectively narrowed the linewidths of the most disordered residues in the influenza M2 transmembrane peptide, while residues that exhibit narrow linewidths in the unprotected membrane are less impacted. A relatively rigid beta-hairpin antimicrobial peptide, PG-1, showed a linewidth increase of ~0.5 ppm over a ~70 K temperature drop both with and without cryoprotection. Finally, a short-chain saturated lipid, DLPE, exhibits excellent linewidths, suggesting that it may be a good medium for membrane protein structure determination. The three best cryoprotectants found in this work-DMSO, PEG, and DMF-should be useful for low temperature membrane-protein structural studies by SSNMR without compromising spectral resolution. PMID- 25015532 TI - Comparison of the sensitivities of WaterLOGSY and saturation transfer difference NMR experiments. AB - The WaterLOGSY (WL) and saturation transfer difference (STD) NMR experiments have proven to be extremely useful techniques to characterize interactions between small molecules and large biomolecules. In this work we compare the relative sensitivities of WL and STD NMR using 3 experimental systems: ketoprofen (KET) bovine serum albumin (BSA), tert-butyl hydroquinone (TBHQ)-hemagglutinin (HA), and chloramphenicol (CAM)-ribosome (70S). In all cases we find that WL is more sensitive than STD for a given experimental time with the ratios ranging from 3.2 for KET-BSA to 16 for TBHQ-HA and CAM-70S. We attribute the increased sensitivity of WL to be due to simultaneous saturation of multiple sources of cross correlation, including direct NOEs of 1H of water and exchangeable groups and indirect NOEs of 1H-C groups. We suggest that the outstanding sensitivity of WL make it ideally suited for drug screening efforts targeting very large biomolecules at relatively low concentrations. PMID- 25015533 TI - Constipation in adults: diagnosis and management. AB - OPINION STATEMENT: Symptoms of constipation occur at all ages, with the greatest prevalence in individuals older than 60 years of age. It is estimated that 35 million individuals suffer from constipation in the USA, but only a small number will ever be diagnosed. Patients identify constipation symptoms differently than physicians. Whereas a patient may define their constipation by symptoms of bloating, distension, feeling of incomplete evacuation, abdominal discomfort, hard stools, and excessive straining, physicians often interpret prolonged timing between movements as the most essential criteria. An evaluation of constipation begins with a focused history of a person's bowel habit, medications, diet, physical activity, and an anorectal examination. In the absence of alarm signs, diagnostic testing for constipation is not routinely recommended in the initial evaluation. First-line management includes lifestyle changes of increased physical activity, high-fiber diets, adequate fluid intake, and bowel management techniques such as a straight back sitting position, using known triggers to stimulate bowel contractions, and a foot stool to elevate knees above bottom during toileting. When refractory to initial management, patients should have anorectal manometry to assess outlet function; additional testing may be required. Biofeedback is an effective treatment option for dyssynergic defecation. A range of traditional and new pharmacologic therapies are available to remedy constipation, from stool softeners to agents that increase intestinal transit. Managing the primary and secondary causes of constipation, incorporating effective bowel management techniques, along with the judicious use of laxatives can reduce constipation symptoms and improve quality of life. PMID- 25015534 TI - Assessment of copper corrosion from frameless copper IUDs after long-term in utero residence. AB - OBJECTIVE: To assess the site-specific corrosive behavior of the frameless intrauterine device (IUD) following long-term exposure to the uterine environment. STUDY DESIGN: A qualitative and morphological study using X-ray diffraction (XRD) and scanning electron microscopy (SEM). RESULTS: Three GyneFix(r) IUDs that were in site up to 150 months were examined. In utero corroded copper sleeves were divided into 10 different groups based on their shape (U or O), orientation (inside or outside) and in utero residence time. XRD indicated the presence of solely cuprite (Cu2O) as corrosion product on both the inside and the outside of the copper sleeves, regardless of their shape. These results were confirmed by backscattered electron micrographs recorded on the inside, the outside and the cross-section of the IUD sleeve. SEM results suggest that shape and orientation slightly affect the corrosion rate. CONCLUSION: The apparent copper loss from both sides of GyneFix copper tubes proves that both sides are a potential copper source and therefore justifies the design of GyneFix IUD. This could be beneficial for women as the IUD could be reduced in size and therefore better tolerated. The impact on bleeding could also be minimized. IMPLICATION STATEMENT: Release of copper ions from both sides of the copper tubes of the frameless GyneFix(r) IUD allows the IUD to be reduced in size, contributing to better toleration. The impact on menstrual bleeding is also minimized by a smaller size of the foreign body. PMID- 25015536 TI - Antiviral treatment of influenza in children: a retrospective cohort study. AB - INTRODUCTION: Influenza is a common and potentially serious disease in children. This retrospective cohort study examined the incidence of complications and associated risk factors in this population, and the effects of antiviral treatment. METHODS: Data for children aged <=17 years with a clinical diagnosis of influenza (ICD-9-CM codes 487.xx or 488.xx) during the 2006-2010 influenza seasons (including the 2009-2010 pandemic season) were obtained from US insurance claims databases. Unconditional logistic regression was used to evaluate the effect of antiviral treatment on the incidence of complications and healthcare resource utilization during the 30 days post the index influenza diagnosis. A sub analysis in children aged <1 year was performed. RESULTS: Antiviral treatment was used in 315,128 (39.53%) of 797,284 cases. The risk of complications was higher in children with pre-existing conditions, e.g., asthma (odds ratio [OR] = 1.86) or cystic fibrosis (OR = 1.67) than otherwise healthy children. Antiviral treatment reduced the 30-day risk of complications, hospitalization, emergency department visits, and >=2 outpatient visits versus no treatment (ORs = 0.76, 0.69, 0.76, and 0.81, respectively); 30-day risks were further reduced by early treatment (within 2 days of diagnosis). The sub-analysis included 19,666 children aged <1 year; 7.38% received antiviral treatment during the pre-pandemic seasons and 33.00% during the pandemic season. Findings were similar to the main analyses; however, healthcare resource utilization was only significantly reduced by early treatment. CONCLUSIONS: Antiviral treatment is associated with reduced risk of complications and healthcare resource utilization in children of all ages with influenza, especially when initiated early. PMID- 25015537 TI - Coming Soon, to a Pharmacy Near You. AB - Abstract PMID- 25015535 TI - Quetiapine versus aripiprazole in children and adolescents with psychosis- protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial. AB - BACKGROUND: The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. METHODS/DESIGN: The TEA trial is a Danish investigator initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naive or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014. DISCUSSION: Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119014. PMID- 25015538 TI - What is the extent of the advantage of video-assisted thoracoscopic surgical resection over thoracotomy in terms of delivery of adjuvant chemotherapy following non-small-cell lung cancer resection? AB - OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) lobectomy for early stage non-small cell lung cancer (NSCLC) is a safe and effective alternative to open lobectomy. Adjuvant chemotherapy is part of the treatment recommended for patients with performance status (PS) 0-1 following resection of NSCLC of stages T1-3 N1-2 M0 and T2-3 N0 M0. If VATS reduces morbidity, does it help delivery of postoperative chemotherapy? We studied our data to compare the delivery and toxicity of chemotherapy in patients following VATS or open lung resections. METHODS: We performed a retrospective study of all patients who had resection of primary NSCLC in a single surgical centre between October 2008 and August 2013. Surgical and chemotherapy databases were reviewed to extract data on patient characteristics, operative details, pathological stage, chemotherapy delivery and toxicity. RESULTS: Three hundred and twenty-three resections were undertaken for NSCLC; 142 (44%) underwent VATS resection and 181 (56%) open thoracotomy; 16 (11.3%) and 28 (15.5%) of each group received adjuvant chemotherapy, respectively. Patient demographics and tumour stage were as follows: median age (range) was 65.5 (44-77) vs 67.5 (49-76); male: 43.8 vs 50% (P = 1.0); Stage I/II 75 vs 76.9%; Stage III 12.5 vs 30.8%; pre-chemotherapy PS 0 75 vs 78.2% for VATS and thoracotomy groups, respectively. All patients received platinum/vinorelbine therapy. Chemotherapy was initiated significantly earlier in the VATS group (mean 55.7 +/- 3.1 vs 68.2 +/- 4.3 days, P = 0.046); 68.8% of patients in the VATS group completed four cycles of chemotherapy compared with 60.1% in the open group (P = 0.75). There was a non-significant trend towards reduction in Grade 3/4 haematological toxicity in the VATS group compared with the open group (12.5 vs 39.3%, P = 0.09). CONCLUSIONS: Adjuvant chemotherapy was started significantly earlier in patients following VATS lung resections for NSCLC compared with thoracotomy. There was also a trend towards improved tolerance with more complete courses and reduced haematological toxicity. PMID- 25015539 TI - Vascular-penetration defect detected in parietal pleura of primary spontaneous pneumothorax. AB - Primary spontaneous pneumothorax (PSP) is one of the most frequent diseases that thoracic surgeons handle, but the aetiology is not really known. We prospectively examined intraoperative images and collected the data of PSP patients who received bullectomy and mechanical pleurodesis with the thoracoscope at the Department of Thoracic Surgery at our hospital. Vascular-penetration defects (VPDs) were 2-6 mm vessel-converged holes that we found on the apex of the parietal pleura of PSP patients exclusively. The VPDs were solely located in the apex of the parietal pleura on the chest wall above the first rib. As many as up to four in number could be present. The VPDs were sometimes complementary to blebs and were not found in any of the other thoracoscopic surgeries for diseases other than PSP. We postulate that the presence of VPDs may be a contributing factor to the formation of a subgroup of emphysematous-like changes and the recurrence of PSP. PMID- 25015540 TI - 'Fast-implantable' aortic valve implantation and concomitant mitral procedures. AB - Concomitant aortic and mitral valve replacement or concomitant aortic valve replacement and mitral repair can be a challenge for the cardiac surgeon: in particular, because of their structure and design, two bioprosthetic heart valves or an aortic valve prosthesis and a rigid mitral ring can interfere at the level of the mitroaortic junction. Therefore, when a mitral bioprosthesis or a rigid mitral ring is already in place and a surgical aortic valve replacement becomes necessary, or when older high-risk patients require concomitant mitral and aortic procedures, the new 'fast-implantable' aortic valve system (Intuity valve, Edwards Lifesciences, Irvine, CA, USA) can represent a smart alternative to standard aortic bioprosthesis. Unfortunately, this is still controversial (risk of interference). However, transcatheter aortic valve replacements have been performed in patients with previously implanted mitral valves or mitral rings. Interestingly, we learned that there is no interference (or not significant interference) among the standard valve and the stent valve. Consequently, we can assume that a fast-implantable valve can also be safely placed next to a biological mitral valve or next to a rigid mitral ring without risks of distortion, malpositioning, high gradient or paravalvular leak. This paper describes two cases: a concomitant Intuity aortic valve and bioprosthetic mitral valve implantation and a concomitant Intuity aortic valve and mitral ring implantation. PMID- 25015542 TI - Plasma pharmacokinetics, faecal excretion and efficacy of pyrantel pamoate paste and granule formulations following per os administration in donkeys naturally infected with intestinal strongylidae. AB - The plasma disposition, faecal excretion and efficacy of two formulations of pyrantel pamoate in donkeys were examined in a controlled trial. Three groups of seven donkeys received either no medication (control) or pyrantel paste or granule formulations at horse dosage of 20mg/kg B.W. (equals 6.94 mg/kg PYR base) of body weight. Heparinized blood and faecal samples were collected at various times between 1 and 144 h after treatment. The samples were analysed by high performance liquid chromatography. The last detectable plasma concentration (tmax) of paste formulation was significantly earlier (36.00 h) compared with granule formulation (46.29 h). Although, there was no significant difference on terminal half lives (t1/2: 12.39 h vs. 14.86 h), tmax (14.86 h vs. 14.00) and MRT (24.80 h vs. 25.44 h) values; the Cmax (0.09 MUg/ml) AUC (2.65 MUgh/ml) values of paste formulation were significantly lower and smaller compared with those of granule formulation (0.21 MUg/ml and 5.60 MUgh/ml), respectively. The highest dry faecal concentrations were 710.46 MUg/g and 537.21 MUg/g and were determined at 48 h for both paste and granule formulation of PYR in donkeys, respectively. Pre treatment EPG of 1104, 1061 and 1139 were observed for the control, PYR paste and PYR granule groups, respectively. Pre-treatment EPG were not significantly different (P>0.1) between groups. Post-treatment EPG for both PYR treatment groups were significantly different (P<0.001) from the control group until day 35. Following treatments the PYR formulations were efficient (>95% efficacy) until day 28. In all studied donkeys, coprocultures performed at day-3 revealed the presence of Cyathostomes, S. vulgaris. Faecal cultures performed on different days from C-group confirmed the presence of the same genera. Coprocultures from treated animals revealed the presence of few larvae of Cyathostomes. PMID- 25015541 TI - Increased suicide risk in cancer patients in Tyrol/Austria. AB - OBJECTIVES: To investigate whether suicide risk in Tyrol/Austria was increased for cancer patients as compared to the general population and whether subgroups at excess risk could be defined. STUDY DESIGN AND SETTING: Cohort design based on all malignant cancer cases diagnosed in Tyrol between 1991 and 2010 and excluding nonmelanoma skin cancer. Entry date was date of diagnosis of the index cancer; exit date was either date of suicide or date of death for reasons other than suicide or end of follow-up (Dec 31, 2011). Standardized mortality ratios (SMRs) were computed in the classical way after adjustment for sex, age and year of follow-up. RESULTS: For all cancer sites except nonmelanoma skin cancer, we observed a SMR of 1.86 [95% confidence interval (CI), 1.57-2.19]. Suicide risk was greatest during the first 6 months after diagnosis with an SMR of 4.74 (95% CI, 3.27-6.66) and was more than fivefold in cases with advanced Stage IV. We observed the greatest excess risk for suicide in patients with head and neck cancers (13 suicides; SMR, 4.73; 95% CI, 2.52-8.09) and lung cancer (14 suicides; SMR, 4.16; 95% CI, 2.27-6.98). CONCLUSION: In our study population in Tyrol/Austria, we observed a twofold suicide risk in cancer patients as compared with the general population, with the excess risk concentrated in the period shortly after diagnosis and in patients with poor prognosis. Therefore, psychooncological care should be intensified in this group of patients. PMID- 25015543 TI - Inter-laboratory ring trials to evaluate serological methods for dourine diagnosis. AB - To evaluate the reproducibility of routine serological methods to detect Trypanosoma equiperdum antibodies in equine sera, two inter-laboratory ring trials were organized involving 22 European and 4 non-European reference laboratories for dourine. The serological methods were the complement fixation test (CFT; 25 laboratories) and the indirect fluorescent antibody test (IFAT; 4 laboratories). Three of the laboratories applied both these methods. The sample panels were composed of sera that were negative, positive or suspected for dourine. Of the negative sera, one was from a donkey naturally infected with Trypanosoma evansi. This study confirmed the reliability of CFT and highlighted its inter-laboratory reproducibility for known T. equiperdum positive and negative sera. However the reproducibility was less good for sera positive for T. evansi or of unknown status, e.i. nine out of 22 laboratories observed a false positive result with the T. evansi-positive serum, whether by CFT or IFAT. This interesting result suggests that the specificity of dourine serodiagnosis may be improved by standardizing the critical reagents, including antigens and by developing a standard T. equiperdum serum which could be used calibrate test systems across multiple laboratories. Trial data confirmed seropositivity in one of the three horses suspected of dourine. It may be beneficial to generalize the use of a suitable low-titer serum control, derived from a standard serum in order to standardize the method's detection limit. PMID- 25015544 TI - Inflammatory, procoagulant markers and HIV residual viremia in patients receiving protease inhibitor monotherapy or triple drug therapy: a cross-sectional study. AB - BACKGROUND: Protease inhibitor monotherapy is associated with more frequent episodes of viral rebounds above 50 copies/mL than triple therapy. OBJECTIVE: To evaluate if, compared to triple-drug therapy, protease inhibitor monotherapy is associated with increased levels of inflammatory/procoagulant markers and more frequent plasma residual viremia detection. METHODS: In this cross-sectional study, we included patients treated for >= 1 year with darunavir/ritonavir or lopinavir/ritonavir as monotherapy (n=72) or with two nucleos(t)ides (n=74). All samples were tested for CRP, IL-6, fibrinogen and D-dimer. Residual viremia was determined using an ultrasensitive qualitative nested-PCR of the HIV pol gene with a limit of detection of 1 copy of HIV-RNA. RESULTS: We found no differences in levels of inflammatory/procoagulant markers or in the proportion of patients with plasma residual viremia detection by treatment group. CONCLUSION: The long term treatment with protease inhibitor monotherapy in the setting of routine clinical practice is not associated with a higher prevalence of plasma residual viremia or more elevated inflammatory/procoagulant markers levels than triple drug therapy. PMID- 25015545 TI - Behavioral inhibition errors in Parkinson's disease tested using an antisaccade and antitapping task. AB - BACKGROUND: The antisaccade (AS) paradigm is frequently used to assess errors in reflexive behavioral responses in Parkinson's disease (PD) patients. Although PD pathology of frontal-striatal circuits suggests increased errors, reports on sensitivity and specificity of the AS task are lacking. We increased the level of cognitive complexity by adding to the AS task an antitapping instruction, i.e. an antisaccade and antitapping (ASAT) task. OBJECTIVE: In this study, we compared saccadic error rates between PD patients and age-matched controls in 1) an AS task, using only eye movements and 2) an ASAT task, using eye and hand movements. METHODS: 30 PD patients en 30 healthy age-matched controls performed an AS task and an ASAT task. The measurement setup consisted of a touch screen, an eye tracking system and a motion capture system. Error rates and eye - and hand latencies were compared between groups. RESULTS: PD patients show higher error rates in the ASAT task, but not in the AS task compared to controls. In correctly performed ASAT task trials, PD patients are on average 60 milliseconds faster to initiate an eye movement. Subject classification based on error rates and eye latencies in the ASAT task results in a sensitivity of 0.77 and a specificity of 0.63. CONCLUSIONS: The results suggest that saccadic error rates and eye latencies in the cognitively more demanding ASAT task are sensitive measures to differentiate PD patients from controls. This task is a potentially useful addition to current methods to investigate visuomotor deficits in PD. PMID- 25015546 TI - Characterization and expression analysis of two distinct neuropeptide Ya paralogues in Jian carp (Cyprinus carpio var. Jian). AB - Two distinct neuropeptide Ya paralogues (jlNPYa1 and jlNPYa2) were cloned and characterized in Jian carp (Cyprinus carpio var. Jian), with a highly conserved organization encoded by four exons and three introns. The cDNAs for jlNPYa1 and jlNPYa2 were 693 and 730 bp in size, respectively. jlNPYa1 and jlNPYa2 both encoded a 96-amino acid protein, which shared 97.9 % identity. Phylogenetic tree showed that it has two NPYa genes, called jlNPYa1 and jlNPYa2, that presumably resulted from the tetraploidization event in the carp lineage. Analysis of expression profiles of jlNPYa1 and jlNPYa2 showed that the two NPY genes had a broad tissue distribution but expressed primarily in the forebrain, hypothalamus, testis and liver. The expression pattern was different in juvenile and adult (female and male) Jian carp. In juvenile, the highest expression level of jlNPYa1 and jlNPYa2 was detected in the testis. In adult, it was detected in the forebrain. In female hypothalamus, the expression level of jlNPYa1 was significantly higher than that of jlNPYa2. However, the opposite was true in male hypothalamus. The differing distribution patterns of the two NPY genes suggested that jlNPYa1 and jlNPYa2 might play different roles in Jian carp. PMID- 25015547 TI - Calorie labeling and consumer estimation of calories purchased. AB - BACKGROUND: Studies rarely find fewer calories purchased following calorie labeling implementation. However, few studies consider whether estimates of the number of calories purchased improved following calorie labeling legislation. FINDINGS: Researchers surveyed customers and collected purchase receipts at fast food restaurants in the United States cities of Philadelphia (which implemented calorie labeling policies) and Baltimore (a matched comparison city) in December 2009 (pre-implementation) and June 2010 (post-implementation). A difference-in difference design was used to examine the difference between estimated and actual calories purchased, and the odds of underestimating calories.Participants in both cities, both pre- and post-calorie labeling, tended to underestimate calories purchased, by an average 216-409 calories. Adjusted difference-in-differences in estimated-actual calories were significant for individuals who ordered small meals and those with some college education (accuracy in Philadelphia improved by 78 and 231 calories, respectively, relative to Baltimore, p = 0.03-0.04). However, categorical accuracy was similar; the adjusted odds ratio [AOR] for underestimation by >100 calories was 0.90 (p = 0.48) in difference-in-difference models. Accuracy was most improved for subjects with a BA or higher education (AOR = 0.25, p < 0.001) and for individuals ordering small meals (AOR = 0.54, p = 0.001). Accuracy worsened for females (AOR = 1.38, p < 0.001) and for individuals ordering large meals (AOR = 1.27, p = 0.028). CONCLUSIONS: We concluded that the odds of underestimating calories varied by subgroup, suggesting that at some level, consumers may incorporate labeling information. PMID- 25015548 TI - Nasal insufflation treatment adherence in obstructive sleep apnea. AB - BACKGROUND: Nasal insufflation (NI) is a novel treatment method that has been introduced for improving respiration during sleep. NI's warmed and humidified nasal airflow provides ventilatory assistance delivered as a rapidly dispersed pressure head, with minimal side wall pressures, that may affect treatment tolerability. The aim of the current study was to investigate objective and subjective adherence rates for NI therapy in mild to moderate obstructive sleep apnea (OSA). METHODS: Ten patients (three men and seven women; age, 51.3 +/- 9.6 years; BMI, 32.2 +/- 7.7 kg/m2 [mean +/- sd]) with recently diagnosed mild to moderate OSA (10.9 +/- 5.8 events/h) were investigated. A crossover design was used to compare adherence to NI and continuous positive airway pressure (CPAP) therapy using a range of objective and subjective measurements. Objective (sleep efficiency (%) and arousal indices (arousal/h)) and subjective evaluations of sleep quality were carried out each night in the laboratory. During in-home treatment, adherence for both therapies was assessed objectively (time on therapy) and subjectively (self-reported sleep diary). RESULTS: Objectively derived adherence values were comparable for CPAP and NI, with both treatment devices sharing similar usage per night (3.5 +/- 2.5 vs. 3.6 +/- 1.6 h/night; respectively) and the number of nights with at least 4 h of treatment (5.5 +/- 4.3 vs. 6.8 +/- 3.3 nights/trial, respectively). Self-reported adherence was significantly higher than objectively assessed adherence (p < 0.03). CONCLUSIONS: This study showed similar adherence to NI and CPAP over a short period of usage. A randomized clinical trial is now essential for determining the comparative effectiveness of NI therapy in relation to treatment with CPAP. PMID- 25015550 TI - A histopathologic and immunohistochemical study on liquification of human adipose tissue ex vivo. AB - BACKGROUND: This preliminary ex vivo study aimed to clarify the pathophysiologic mechanisms of fat tissue depletion by subcutaneous drug application. Therefore, the lipolytic effects of phosphatidylcholine plus deoxycholate (Lipostabil) (L) and of deoxycholate (DC) alone were compared with those of sodium chloride (NaCl) and hydrogen peroxide (H2O2) as control agents. The study enrolled 10 patients receiving abdominoplasty. The treatment periods for each sample and solution were 1, 3, 5, and 7 h. The samples were analyzed morphologically using hematoxylin eosin (H&E) staining and also immunohistochemically using Caspase 3 and tumor necrosis factor (TNF)-alpha. Morphologic changes were seen best after 5 h of application time. Except for NaCl, all the samples in the H&E staining showed marked damage of adipocyte cell membranes, with the greatest disruption of normal cell architecture after hydrogen peroxide (H2O2) application. Immunohistochemistry using TNF-alpha showed positive results for the deoxycholate and Lipostabil samples and highly positive results for the H2O2 sample. Data from this study indicate that Lipostabil and deoxycholate induce pathways of cell necrosis involving TNF-alpha. These short-term experiments indicate that Lipostabil affects fat tissue in the way of a chemical-toxic destruction rather than via a physiologically induced, programmed cell death. PMID- 25015549 TI - Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis. AB - Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC 3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer. PMID- 25015551 TI - A rare phenomenon: oculonasal synkinesis. AB - Oculonasal synkinesis is the simultaneous contraction of the orbicularis oculi and the compressor narium minor muscles. The etiology of this phenomenon is still unclear; congenital and traumatic reasons are considered to be responsible. Here we report a case of oculonasal synkinesis. PMID- 25015553 TI - Cell death in human articular chondrocyte: a morpho-functional study in micromass model. AB - Chondrocyte death and loss of extracellular matrix are the central features in articular cartilage degeneration during osteoarthritis pathogenesis. Cartilage diseases and, in particular, osteoarthritis are widely correlated to apoptosis but, chondrocytes undergoing apoptosis "in vivo" more often display peculiar features that correspond to a distinct process of programmed cell death termed "chondroptosis". Programmed cell death of primary human chondrocyte has been here investigated in micromasses, a tridimensional culture model, that represents a convenient means for studying chondrocyte biology. Cell death has been induced by different physical or chemical apoptotic agents, such as UVB radiation, hyperthermia and staurosporine delivered at both 1 and 3 weeks maturation. Conventional electron microscopy was used to analyse morphological changes. Occurrence of DNA fragmentation and caspase involvement were also investigated. At Transmission Electron Microscopy, control cells appear rounding or slightly elongated with plurilobated nucleus and diffusely dispersed chromatin. Typically UVB radiation and staurosporine induce chromatin apoptotic features, while hyperthermia triggers the "chondroptotic" phenotype. A weak TUNEL positivity appears in control, correlated to the well known cell death patterns occurring along cartilage differentiation. UVB radiation produces a strong positivity, mostly localized at the micromass periphery. After hyperthermia a higher number of fluorescent nuclei appears, in particular at 3 weeks. Staurosporine evidences a diffuse, but reduced, positivity. Therefore, DNA fragmentation is a common pattern in dying chondrocytes, both in apoptotic and "chondroptotic" cells. Moreover, all triggers induce caspase pathway activation, even if to a different extent, suggesting a fundamental role of apoptotic features, in chondrocyte cell death. PMID- 25015552 TI - Evidence for the existence of powder sub-populations in micronized materials: aerodynamic size-fractions of aerosolized powders possess distinct physicochemical properties. AB - PURPOSE: To investigate the agglomeration behaviour of the fine (<5.0 MUm) and coarse (>12.8 MUm) particle fractions of salmeterol xinafoate (SX) and fluticasone propionate (FP) by isolating aerodynamic size fractions and characterising their physicochemical and re-dispersal properties. METHODS: Aerodynamic fractionation was conducted using the Next Generation Impactor (NGI). Re-crystallized control particles, unfractionated and fractionated materials were characterized for particle size, morphology, crystallinity and surface energy. Re dispersal of the particles was assessed using dry dispersion laser diffraction and NGI analysis. RESULTS: Aerosolized SX and FP particles deposited in the NGI as agglomerates of consistent particle/agglomerate morphology. SX particles depositing on Stages 3 and 5 had higher total surface energy than unfractionated SX, with Stage 5 particles showing the greatest surface energy heterogeneity. FP fractions had comparable surface energy distributions and bulk crystallinity but differences in surface chemistry. SX fractions demonstrated higher bulk disorder than unfractionated and re-crystallized particles. Upon aerosolization, the fractions differed in their intrinsic emission and dispersion into a fine particle fraction (<5.0 MUm). CONCLUSIONS: Micronized powders consisted of sub populations of particles displaying distinct physicochemical and powder dispersal properties compared to the unfractionated bulk material. This may have implications for the efficiency of inhaled drug delivery. PMID- 25015555 TI - [The administration of intravenous contrast agents: extravasations]. AB - Local extravasation of intravenous contrast material is a relatively common complication that radiologists need to know about. The risk of extravasation is greater in children, the elderly, and unconscious patients. Although most extravasations are mild and do not lead to further complications, some can result in severe lesions that require surgery, especially in cases that are associated with compartment syndrome. We describe the main characteristics of extravasations, comment on different treatments, and propose a protocol for dealing with them. PMID- 25015554 TI - [Acoustic radiation force impulse imaging elastography is efficacious in detecting hepatic fibrosis in children]. AB - OBJECTIVE: To evaluate the diagnostic performance of acoustic radiation force impulse imaging (ARFI) in detecting significant hepatic fibrosis in children. MATERIAL AND METHODS: Our hospital's ethics committee approved the study and all patients or their representatives provided informed written consent. We included 96 children (50 boys, 46 girls; mean age, 8 y). We also studied 16 volunteers without liver disease as controls and 80 patients with diseases that can lead to fibrosis and cirrhosis of the liver. The final sample included 31 patients with biopsies and the 16 controls. All patients underwent abdominal ultrasonography including Doppler imaging and elastography with ARFI. The ARFI value, expressed as velocity (m/s) of shear wave propagation through the tissue, was calculated by averaging 16 measurements in both liver lobes. We used one-way analysis of variance to compare means between groups; we set statistical significance at P<.05. We used Student's t-tests and chi-square tests for categorical data. RESULTS: The ARFI value in children with fibrosis >= F2 was higher (1.80+/ 0.45m/s) than in controls and higher than in patients with F0-F1 (1.38+/ 0.22m/s). The difference was significant (P<.001) for detecting F >= 2. Steatosis was not related with the ARFI value (Student's t-test, P>.84). Necroinflammatory activity was strongly associated with the ARFI value (Student's t-test, P<.01). Fibrosis and necroinflammatory activity were strongly associated with each other (chi-square test, P<.0001). CONCLUSION: The speed of shear wave propagation is significantly associated with the degree of hepatic fibrosis in children. PMID- 25015556 TI - Clinical significance of melatonin receptors in the human myometrium. AB - OBJECTIVE: To review and update the research on melatonin receptor expression in the human myometrium, in particular as it pertains to uterine contractility at labor. DESIGN: Summary of previous studies with the addition of new data on the transcriptional regulation of melatonin receptor expression in human myometrial cells. SETTING: Not applicable. PATIENT(S): Late-term pregnant volunteers. INTERVENTION(S): Biopsy collection for in vitro analyses provided the original data. More recently, uterine contractions in late-term pregnant volunteers were assessed before, during, and after acute white-light exposure. MAIN OUTCOME MEASURE(S): Melatonin receptor signaling in myometrial cells and uterine contractions in late-term pregnant volunteers. RESULT(S): Melatonin acts through the MTNR1B melatonin receptor that is expressed in the myometrium at late term to synergistically enhance oxytocin-dependent signaling and contractions. Acute inhibition of endogenous melatonin levels with light reversibly suppresses uterine contractions. CONCLUSION(S): These results point to a significant role for circulating melatonin in the timing and degree of uterine contractions in late-term pregnancy. Understanding the regulation of melatonin receptors remains a future objective. PMID- 25015557 TI - Spectral modulation of light wavelengths using optical filters: effect on melatonin secretion. AB - Shiftwork has been identified as a risk factor for various medical problems, such as cancer, heart disease, metabolic disturbances, depression, and anxiety disorders, and as reviewed this month, adverse reproductive function. Shiftwork misaligns physiological rhythms with respect to each other and to external environmental rhythms such as the 24-hour light/dark cycle. Light is the strongest time cue for entraining circadian rhythms in mammals, and aberrant light exposure patterns during shiftwork is one of the key factors that induce circadian misalignment. We have recently demonstrated, in both animal and clinical models, that filtering short wavelengths (below 480 nm) from nocturnal lighting can attenuate alterations in hormone secretion (melatonin and glucocorticoids) and in central and peripheral clock gene expression induced by nighttime light exposure. We also demonstrated that the use of optical filters led to an improvement in mood and in cognitive performance under controlled laboratory conditions and during field-based shiftwork studies. Moreover, there was an increase in sleep duration and quality on nights immediately following night shifts. We believe it is likely that optical filters incorporated into glasses or as coverings for light bulbs could be used as a method to improve or prevent many of the medical problems associated with circadian misalignment and rotating shiftwork. PMID- 25015558 TI - First-passage time of run-and-tumble particles. AB - We solve the problem of first-passage time for run-and-tumble particles in one dimension. Exact expression is derived for the mean first-passage time in the general case, considering external force fields and chemotactic fields, giving rise to space-dependent swim speed and tumble rate. Agreement between theoretical formulae and numerical simulations is obtained in the analyzed case studies - constant and sinusoidal force fields, constant gradient chemotactic field. Reported findings can be useful to get insights into very different phenomena involving active particles, such as bacterial motion in external fields, intracellular transport, cell migration, animal foraging. PMID- 25015559 TI - Pregnancy-associated malaria and malaria in infants: an old problem with present consequences. AB - Albeit pregnancy-associated malaria (PAM) poses a potential risk for over 125 million women each year, an accurate review assessing the impact on malaria in infants has yet to be conducted. In addition to an effect on low birth weight (LBW) and prematurity, PAM determines foetal exposure to Plasmodium falciparum in utero and is correlated to congenital malaria and early development of clinical episodes during infancy. This interaction plausibly results from an ongoing immune tolerance process to antigens in utero, however, a complete explanation of this immune process remains a question for further research, as does the precise role of protective maternal antibodies. Preventive interventions against PAM modify foetal exposure to P. falciparum in utero, and have thus an effect on perinatal malaria outcomes. Effective intermittent preventive treatment in pregnancy (IPTp) diminishes placental malaria (PM) and its subsequent malaria associated morbidity. However, emerging resistance to sulphadoxine-pyrimethamine (SP) is currently hindering the efficacy of IPTp regimes and the efficacy of alternative strategies, such as intermittent screening and treatment (IST), has not been accurately evaluated in different transmission settings. Due to the increased risk of clinical malaria for offspring of malaria infected mothers, PAM preventive interventions should ideally start during the preconceptual period. Innovative research examining the effect of PAM on the neurocognitive development of the infant, as well as examining the potential influence of HLA-G polymorphisms on malaria symptoms, is urged to contribute to a better understanding of PAM and infant health. PMID- 25015560 TI - Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma. AB - BACKGROUND: New biomarkers are needed for the prognosis of advanced colorectal cancer, which remains incurable by conventional treatments. O6-methylguanine DNA methyltransferase (MGMT) methylation and protein expression have been related to colorectal cancer treatment failure and tumor progression. Moreover, the presence in these tumors of cancer stem cells, which are characterized by CD133 expression, has been associated with chemoresistance, radioresistance, metastasis, and local recurrence. The objective of this study was to determine the prognostic value of CD133 and MGMT and their possible interaction in colorectal cancer patients. METHODS: MGMT and CD133 expression was analyzed by immunohistochemistry in 123 paraffin-embedded colorectal adenocarcinoma samples, obtaining the percentage staining and intensity. MGMT promoter methylation status was obtained by using bisulfite modification and methylation-specific PCR (MSP). These values were correlated with clinical data, including overall survival (OS), disease-free survival (DFS), tumor stage, and differentiation grade. RESULTS: Low MGMT expression intensity was significantly correlated with shorter OS and was a prognostic factor independently of treatment and histopathological variables. High percentage of CD133 expression was significantly correlated with shorter DFS but was not an independent factor. Patients with low-intensity MGMT expression and >=50% CD133 expression had the poorest DFS and OS outcomes. CONCLUSIONS: Our results support the hypothesis that MGMT expression may be an OS biomarker as useful as tumor stage or differentiation grade and that CD133 expression may be a predictive biomarker of DFS. Thus, MGMT and CD133 may both be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility. PMID- 25015561 TI - Transcription factors with conserved binding sites near ATOH1 on the POU4F3 gene enhance the induction of cochlear hair cells. AB - Overexpression of the transcription factor (TF) ATOH1 is known to induce the transformation of nonsensory cells in the organ of Corti into hair cells (HCs). Evaluating DNA 5?OE to the coding sequence of the pou4f3 gene, a target of ATOH1 in HCs, we identified in three regions containing clustered binding sites for ATOH1 and several other TFs that are expressed in developing inner ear sensory epithelia at the time of HC specification. These regions and sites are highly conserved across evolutionarily distant mammalian species. To test the hypothesis that the identified TFs act in combination to regulate the pou4f3 gene, we transfected by electroporation neonatal cochlear sensory epithelium from mice expressing green fluorescent protein (GFP) under the control of an 8.5-kb 5' pou4f3 genomic fragment. Plasmids encoding 21 TFs c-transfected with human ATOH1 (hATOH1). Cotransfection with hETV4, hNMYC, or hETS2 produced significantly more pou4f3/GFP and myosin 7A-positive nonsensory cells than hATOH1 alone. Co transfection of hATOH1 with hHES1, hHES5, or hNEUROD1 reduced the effects of hATOH1. Chromatin immunoprecipitation (ChIP)of DNA from an inner ear cell line transfected with hNMYC,hETV4, or hETS2 revealed binding to a conserved region immediately proximal to the coding sequence. ChIP similarly revealed binding of hGATA3, hNMYC, and hTFE2 to a region several kilobases distal to the coding sequence, which we have previously shown to bind ATOH1. The results suggest that ATOH1 acts in concert with a subset of other TFs to directly regulate the pou4f3 gene and more broadly to regulate the HC phenotype. PMID- 25015562 TI - A case of dedifferentiated solitary fibrous tumor in the pelvis with TP53 mutation. AB - Solitary fibrous tumors (SFTs), initially observed in the pleura, were later found to develop in almost any extrapleural site. Dedifferentiation within SFTs was characterized only recently. We report a case of dedifferentiated SFT arising within the pelvis of a 70-year-old Japanese woman. Macroscopically, the resected tumor measured 17 * 17 * 13 cm. Histologically, the tumor displayed distinct heterologous osteosarcomatous and chondrosarcomatous components on a background of conventional SFT. Immunohistochemistry uncovered a loss of CD34 expression in the dedifferentiated area, whereas the nuclear expression of signal transducer and activator of transcription-6 (STAT6) and NGFI-A-binding protein 2 (NAB2) was maintained in both components. The p53 mutation 158 CGC > CAC (A158H) was found only in the dedifferentiated component. Furthermore, a fusion gene of NAB2(exon6) STAT6(exon18) was detected in both the conventional and dedifferentiated components. The patient died of the disease 4 months after surgery. This case identifies a possible role of p53 dysfunction in the dedifferentiation process of SFT as reported in other sarcomas. PMID- 25015563 TI - Within-family obesity associations: evaluation of parent, child, and sibling relationships. AB - BACKGROUND: How parent and sibling obesity status comparatively shape a child's obesity is unknown. PURPOSE: To investigate how the obesity status of different children within the same family is related to a parent or sibling's obesity. METHODS: A national sample of adults in 10,244 American households was surveyed during 2011; data were analyzed in 2012-2013. Of these households, 1,948 adults had one or two children; provided sociodemographic information; and reported on adult and child height and weight, physical activity, and food environment. Logistic regression models were estimated in which the outcome of interest was child obesity status, with parent and sibling obesity as key predictors, adjusting for a range of both adult and child social and demographic confounders. RESULTS: In one-child households, it was 2.2 times more likely (SE=0.5) that the child would be obese if a parent was obese. In households with two children, having an obese younger sibling was more strongly associated with elder-child obesity (OR=5.4, SE=1.9) than parent's obesity status (OR=2.3, SE=0.8). Having an obese elder sibling was associated with younger-child obesity (OR=5.6, SE=1.9), and parent obesity status was no longer significant. Within-family sibling obesity was more strongly patterned between siblings of the same gender than between different genders, and child physical activity was significantly associated with obesity status. CONCLUSIONS: Considering offspring composition and sibling gender may be beneficial in childhood obesity prevention and intervention. PMID- 25015564 TI - Impact of the National Breast and Cervical Cancer Early Detection Program on cervical cancer mortality among uninsured low-income women in the U.S., 1991 2007. AB - BACKGROUND: The benefits of the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) on cervical cancer screening for participating uninsured low-income women have never been measured. PURPOSE: To estimate the benefits in life-years (LYs) gained; quality-adjusted life-years (QALYs) gained; and deaths averted. METHODS: A cervical cancer simulation model was constructed based on an existing cohort model. The model was applied to NBCCEDP participants aged 18-64 years. Screening habits for uninsured low-income women were estimated using National Health Interview Survey data from 1990 to 2005 and NBCCEDP data from 1991 to 2007. The study was conducted during 2011-2012 and covered all 68 NBCCEDP grantees in 50 states, the District of Columbia, five U.S. territories, and 12 tribal organizations. Separate simulations were performed for the following three scenarios: (1) women who received NBCCEDP (Program) screening; (2) women who received screening without the program (No Program); and (3) women who received no screening (No Screening). RESULTS: Among 1.8 million women screened in 1991-2007, the Program added 10,369 LYs gained compared to No Program, and 101,509 LYs gained compared to No Screening. The Program prevented 325 women from dying of cervical cancer relative to No Program, and 3,829 relative to No Screening. During this time period, the Program accounted for 15,589 QALYs gained when compared with No Program, and 121,529 QALYs gained when compared with No Screening. CONCLUSIONS: These estimates suggest that NBCCEDP cervical cancer screening has reduced mortality among medically underserved low income women who participated in the program. PMID- 25015565 TI - Histone demethylase RBP2 induced by Helicobactor Pylori CagA participates in the malignant transformation of gastric epithelial cells. AB - Gastric epithelial cell malignant transformation induced by Helicobactor Pylori contributes to tumor development, but the underlying mechanisms for this remain unclear. Here we demonstrate that RBP2, a newly identified histone demethylase, can be induced by CagA via PI3K/AKT-Sp1 pathway depending on AKT phosphorylation. Sp1 directly binds to RBP2 promoter and enhances its expression then the upregulated RBP2 significantly increases Cyclin D1 transcription, which contributes to gastric epithelial cell malignant transformation. Further data indicate that knockdown of endogenous RBP2 dominantly inhibits gastric cancer (GC) development both in vitro and in vivo. In conclusion, this CagA- PI3K/AKT Sp1-RBP2-Cyclin D1 pathway may serve as a novel mechanism for gastric epithelial cell malignant transformation and then gastric cancer (GC). Therefore, RBP2 may link chronic inflammation to tumor development and its inhibition may have potential therapeutic advantages. PMID- 25015566 TI - A web-based e-learning application for wound diagnosis and treatment. AB - Pressure ulcers (PrU) are considered as one of the most challenging problems that Nursing professionals have to deal with in their daily practice. Nowadays, the education on PrUs is mainly based on traditional lecturing, seminars and face-to face instruction, sometimes with the support of photographs of wounds being used as teaching material. This traditional educational methodology suffers from some important limitations, which could affect the efficacy of the learning process. This current study has been designed to introduce information and communication technologies (ICT) in the education on PrU for undergraduate students, with the main objective of evaluating the advantages an disadvantages of using ICT, by comparing the learning results obtained from using an e-learning tool with those from a traditional teaching methodology. In order to meet this major objective, a web-based learning system named ePULab has been designed and developed as an adaptive e-learning tool for the autonomous acquisition of knowledge on PrU evaluation. This innovative system has been validated by means of a randomized controlled trial that compares its learning efficacy with that from a control group receiving a traditional face-to-face instruction. Students using ePULab gave significantly better (p<0.01) learning acquisition scores (from pre-test mean 8.27 (SD 1.39) to post-test mean 15.83 (SD 2.52)) than those following traditional lecture-style classes (from pre-test mean 8.23 (SD 1.23) to post-test mean 11.6 (SD 2.52)). In this article, the ePULab software is described in detail and the results from that experimental educational validation study are also presented and analyzed. PMID- 25015567 TI - Cerebral arterial inflow assessment with 18F-FDG PET: methodology and feasibility. AB - Positron emission tomography (PET) with 18fluorodeoxyglucose (18F-FDG) is increasingly used in neurology. The measurement of cerebral arterial inflow (QA) using 18F-FDG complements the information provided by standard brain PET imaging. Here, injections were performed after the beginning of dynamic acquisitions and the time to arrival (t0) of activity in the gantry's field of view was computed. We performed a phantom study using a branched tube (internal diameter: 4mm) and a 18F-FDG solution injected at 240 mL/min. Data processing consisted of (i) reconstruction of the first 3s after t0, (ii) vascular signal enhancement and (iii) clustering. This method was then applied in four subjects. We measured the volumes of the tubes or vascular trees and calculated the corresponding flows. In the phantom, the flow was calculated to be 244.2 mL/min. In each subject, our QA value was compared with that obtained by quantitative cine-phase contrast magnetic resonance imaging; the mean QA value of 581.4+/-217.5 mL/min calculated with 18F-FDG PET was consistent with the mean value of 593.3+/-205.8 mL/min calculated with quantitative cine-phase contrast magnetic resonance imaging. Our 18F-FDG PET method constitutes a novel, fully automatic means of measuring QA. PMID- 25015568 TI - Forming and developing your professional identity: easy as PI. AB - Health education and promotion specialists and professional organizations have worked hard to successfully establish and maintain the status of health education/promotion (HE/P) as a unique and essential profession and to solidify practitioners' sense of professional identity. A professional identity is critical to a person's sense of self: It is about connecting with roles, responsibilities, values, and ethical standards unique to a specific profession. Professional identity is a complex issue in the HE/P profession; the distinction between personal and professional identities has been debated repeatedly over the years (e.g., should HE/P professionals be role models for clients?). The purpose of this Tool is to explain the concept of professional identity; provide new, emerging, and experienced HE/P with a greater understanding of what it means to have a professional identity; present processes and benchmarks of professional identity development; and offer specific tips and strategies for developing and enhancing an HE/P professional identity. PMID- 25015570 TI - Mucosal Schwann cell hamartoma: just benign or more? PMID- 25015569 TI - Anti-tumor activity of fenretinide complexed with human serum albumin in lung cancer xenograft mouse model. AB - Sufficient knowledge regarding cellular and molecular basis of lung cancer progression and metastasis would help in the development of novel and effective strategies for the treatment of lung cancer. 4HPR is a synthetic retinoid with potential anti-tumor activity but is still limited because of its poor bioavailability. The use of albumin as a complexing agent for a hydrophobic drug is expected to improve the water solubility and consequently their bioavailability.This study investigated the antitumor activity of a novel complex between albumin and 4-HPR in a mouse model of human lung cancer and focuses on role and mechanism of Cav-1 mainly involved in regulating cancer and ACSVL3 mainly connected with tumor growth. Their expressions were assayed by immunohistochemistry and qRT-PCR, to demonstrate the reduction of the tumor growth following the drug treatment. Our results showed a high antitumor activity of 4HPR-HSA by reduction of the volume of tumor mass and the presence of a high level of apoptotic cell by TUNEL assay. The downregulation of Cav-1 and ACSVL3 suggested a reduction of tumor growth. In conclusion, we demonstrated the great potential of 4HPR-HSA in the treatment of lung cancer. More data about the mechanism of drug delivery the 4HPR-HSA are necessary. PMID- 25015571 TI - Isolated gigantism of digits. PMID- 25015572 TI - Reply: To PMID 23998517. PMID- 25015573 TI - Imbalanced coagulation profile as a biomarker of migraine in children with sickle cell: Is this a link with cerebral ischemia? PMID- 25015574 TI - Cardiac autonomic dysfunction and arterial stiffness among children and adolescents with attention deficit hyperactivity disorder treated with stimulants. AB - OBJECTIVE: To compare markers of cardiovascular health in youth diagnosed with attention deficit hyperactivity disorder (ADHD) by the use of stimulant medication with healthy controls. STUDY DESIGN: Children and adolescents (n = 85; mean age 11.2 +/- 2.8 years; 66 boys) diagnosed with ADHD using a stimulant and 53 siblings without ADHD (mean age 11.1 +/- 3.8 years; 28 boys) were included in this cross-sectional study. Measured variables included blood pressure, heart rate (HR), HR variability: SD of the RR interval and low frequency to high frequency ratio, carotid-radial pulse wave velocity, carotid artery augmentation index (AIx), radial artery AIx, brachial artery flow-mediated dilation, and digital reactive hyperemic index. RESULTS: Compared with control patients, participants with ADHD had greater resting systolic blood pressure (3.9 mm Hg, 95% CI [1.2-6.7], P = .005), diastolic blood pressure (5.5 mm Hg, 95% CI [3.2 7.8], P < .001), HR (9.2 beats/min, 95% CI [6.0-12.3], P < .001), low frequency to high frequency ratio (0.55, 95% CI [0.22-0.89], P = .001), carotid AIx (7.2%, 95% CI [1.9-12.5], P = .008), and pulse wave velocity (0.36 m/s, 95% CI [-0.05, 0.78], P = .089), and lower SD of the RR interval (-33.7 milliseconds, 95% CI [ 46.1, -21.3], P < .001). Neither flow-mediated dilation nor reactive hyperemic index was significantly different. CONCLUSIONS: Children and adolescents being treated with a stimulant medication for ADHD exhibited signs of altered cardiac autonomic function, characterized by increased sympathetic tone, and showed evidence of arterial stiffening. PMID- 25015576 TI - Surfactant protein-D-encoding gene variant polymorphisms are linked to respiratory outcome in premature infants. AB - OBJECTIVE: Associations between the genetic variation within or downstream of the surfactant protein-D-encoding gene (SFTPD), which encodes the collectin surfactant protein-D (SP-D) and may lead to respiratory distress syndrome or bronchopulmonary dysplasia, recently were reported. Our aim was to investigate whether SFTPD variations affect serum SP-D levels in infants and pulmonary outcome in premature infants. STUDY DESIGN: Serum SP-D levels were measured in 211 mature and 202 premature infants, and 7 SFTPD single-nucleotide polymorphisms (SNPs) were genotyped. SNP analysis and haplotype analysis were used to associate genetic variation to SP-D, respiratory distress (RD), oxygen requirement, and respiratory support. RESULTS: The 5'-upstream SFTPD SNP rs1923534 and the 3 structural SNPs rs721917, rs2243639, and rs3088308 were associated with the SP-D level. The same SNPs were associated with RD, a requirement for supplemental oxygen, and a requirement for respiratory support. Haplotype analyses identified 3 haplotypes that included the minor alleles of rs1923534, rs721917, and rs3088308 that exhibited highly significant associations with decreased SP-D levels and decreased ORs for RD, oxygen supplementation, and respiratory support. CONCLUSION: These findings extend and validate previous observations of SFTPD association with the risk of respiratory outcomes and suggest SFTPD as an essential factor affecting pulmonary adaptation in premature infants. PMID- 25015577 TI - Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: report of an international conference. PMID- 25015579 TI - The appraisal of public health interventions: the use of theory. AB - BACKGROUND: Public health decision-making is hampered by inappropriate adherence to underpowered randomized controlled trials (RCTs) which give inconclusive results and lead to decision-makers being loath to recommend interventions with strong theoretical and observational support. METHODS: We outline situations in which robust decisions about health interventions can be made without trial evidence. We present a new approach in which theory, causal models and past observations are given proper regard in the decision-making process. RESULTS: Using our approach, we provide examples where the use of causal theories and observations in areas, such as salt reduction, smoking cessation and gardening to improve mental health, is sufficient for deciding that such interventions are effective for improving health without needing the support of underpowered RCTs. Particularly where RCT evidence is inconclusive, our approach may provide similar aggregate health outcomes for society for vastly lower cost. CONCLUSIONS: When knowledge and theoretical understanding are unable sufficiently to reduce doubt about the direction of effect from an intervention, decisions should be made using evidence-based medicine approaches. There are, however, many cases where the combination of robust theory, causal understanding and observation are able to provide sufficient evidence of the direction of effect from an intervention that current practice should be altered. PMID- 25015580 TI - Geographical inequalities in uptake of NHS-funded eye examinations: small area analysis of Leeds, UK. AB - BACKGROUND: Preventable sight loss is an indicator within the Public Health Outcome Framework 2013-2018 for England. Routinely available optometric data do not permit small area analysis of access inequalities. METHODS: Data were extracted from 17 680 General Ophthalmic Services (GOS1) claim forms for eye examinations conducted in Leeds during February and March 2011. The expected number of GOS1 uptake for each lower super output area was based on the GOS1 national annual uptake. A Poisson regression model was used to explore associations in the GOS1 uptake ratio with deprivation and gender. RESULTS: People aged 60 or over or under 16 living in the least deprived quintile are 71 and 23%, respectively, more likely to have an NHS-funded eye examination than someone in that age group in the most deprived quintile, although all are equally entitled. Uptake is higher in the more deprived quintiles among 16-59 year olds, as means tested social benefits are the main eligibility criteria in this age group. There were no statistically significant gender differences in uptake. CONCLUSIONS: Interventions are needed to address eye examination uptake inequalities. However, in order to better inform commissioning and planning eye care services more complete data with additional detail are required. GOS1 forms ought to be submitted electronically linked to additional demographic and clinical data to allow public health analysis. Ideally, private eye examination data should also be captured. PMID- 25015578 TI - Variation in the management of infants hospitalized for bronchiolitis persists after the 2006 American Academy of Pediatrics bronchiolitis guidelines. AB - OBJECTIVE: To describe variation across US pediatric hospitals in the utilization of resources not recommended for routine use by the American Academy of Pediatrics guideline for infants hospitalized with bronchiolitis and to examine the association between resource utilization and disposition outcomes. STUDY DESIGN: We conducted a cross-sectional study of infants <=12 months hospitalized for bronchiolitis from 2007-2012 at 42 hospitals contributing data to the Pediatric Health Information System. Patients with asthma were excluded. The primary outcome was hospital-level variation in utilization of 5 resources not recommended for routine use: albuterol, racemic epinephrine, corticosteroids, chest radiography, and antibiotics. We also examined the association of resource utilization with length of stay (LOS) and readmission. RESULTS: In total, 64,994 hospitalizations were analyzed. After adjustment for patient characteristics, albuterol (median, 52.4%; range, 3.5%-81%), racemic epinephrine (20.1%; 0.6% 78.8%), and chest radiography (54.9%; 24.1%-76.7%) had the greatest variation across hospitals. Utilization of albuterol, racemic epinephrine, and antibiotics did not change significantly over time compared with small decreases in corticosteroid (3.3%) and chest radiography (8.6%) use over the study period. Utilization of each resource was significantly associated with increased LOS without concomitant decreased odds of readmission. CONCLUSIONS: Substantial use and variation in 5 resources not recommended for routine use by the American Academy of Pediatrics bronchiolitis guideline persists with increased utilization associated with increased LOS without the benefit of decreased readmission. Future work should focus on developing processes that can be widely disseminated and easily implemented to minimize unwarranted practice variation when evidence and guidelines exist. PMID- 25015581 TI - Sleep Problems and Daily Functioning in Children With ADHD: An Investigation of the Role of Impairment, ADHD Presentations, and Psychiatric Comorbidity. AB - OBJECTIVE: Little systematic information is available regarding how sleep problems influence daytime functioning in children with ADHD, as the role of ADHD presentations and comorbidity is unclear. METHOD: In total, 397 children were assessed with the Children's Sleep Habits Questionnaire, the Weiss Functional Impairment Rating Scale, and the ADHD Rating Scale. RESULTS: We found a moderate, positive correlation between sleep problems and impaired functioning in both children with ADHD and in typically developed children. ADHD presentations did not differ significantly with respect to sleep problem profile, but having a comorbid internalizing or autistic disorder lead to higher sleep problem score. CONCLUSION: Sleep problems and impaired daily functioning were more common in children with ADHD, but the overall association between sleep problems and impaired daily functioning was similar in clinical and nonclinical children. Internalizing or autistic comorbid disorders added significantly to the sleep problems. PMID- 25015575 TI - Medical status of 219 children with biliary atresia surviving long-term with their native livers: results from a North American multicenter consortium. AB - OBJECTIVES: To examine the medical status of children with biliary atresia (BA) with their native livers after hepato- portoenterostomy (HPE) surgery. STUDY DESIGN: The Childhood Liver Disease Research and Education Network database was utilized to examine subjects with BA living with their native livers 5 or more years after HPE and to describe the prevalence of subjects with BA with an "ideal" outcome, defined as no clinical evidence of chronic liver disease, normal liver biochemical indices (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, platelet count, total bilirubin, international normalized ratio, and albumin), and normal health-related quality of life 5 or more years after HPE. RESULTS: Children with BA (n = 219; 43% male) with median age 9.7 years were studied. Median age at HPE was 56 (range 7-125) days. Median age- and sex-adjusted height and weight z-scores at 5-year follow-up were 0.487 (IQR -0.27 to 1.02) and 0.00 (IQR -0.74 to 0.70), respectively. During the 12 preceding months, cholangitis and bone fractures occurred in 17% and 5.5%, respectively. Health-related quality of life was reported normal by 53% of patients. However, only 1.8% met the study definition of "ideal" outcome. Individual tests of liver synthetic function (total bilirubin, albumin, and international normalized ratio) were normal in 75%, 85%, and 73% of the study cohort. CONCLUSION: Cholangitis and fractures in long-term survivors underscore the importance of ongoing medical surveillance. Over 98% of this North American cohort of subjects with BA living with native livers 5 or more years after HPE have clinical or biochemical evidence of chronic liver disease. PMID- 25015582 TI - Bipolar Disorder in Children With ADHD: A Clinical Sample Study. AB - OBJECTIVE: To explore the impact of early-onset bipolar disorder (pediatric bipolar disorder [PBD]) on ADHD. METHOD: We compared ADHD symptom severity, ADHD subtype distribution, and rates of comorbid and familial psychiatric disorders between 49 ADHD children with comorbid PBD and 320 ADHD children without PBD. RESULTS: Children with ADHD and PBD showed higher scores in the Hyperactive and Inattentive subscales of the ADHD Rating Scale, than children with ADHD alone. The frequency of combined subtype was significantly higher in ADHD children with PBD, than in those with ADHD alone. ADHD children with PBD showed a higher rate of familial psychiatric disorders than ADHD children without PBD. The rate of conduct disorder was significantly greater in children with PBD and ADHD compared with children with ADHD alone. CONCLUSION: ADHD along with PBD presents with several characteristics that distinguish it from ADHD alone, suggesting that these may be distinct disorders. PMID- 25015583 TI - An Integrated Model of Executive Functioning is Helpful for Understanding ADHD and Associated Disorders. AB - OBJECTIVE: The aim of this study is to test the discriminative capacity of executive function (EF) tasks to better define the cognitive functioning of children with ADHD and comorbidities. METHOD: One hundred four children were presented with a battery of new EF tasks and a rating scale filled out by parents. RESULTS: Preliminary analysis of the neuropsychological tasks revealed the presence of five factors: Speed of Processing, Inhibition, Planning, Execution, and Retrospective Memory. All children with ADHD were impaired in Execution (a measure describing the capacity to achieve a goal). ADHD-only children were specifically impaired in Planning, while ADHD + reading disorder (RD) children were impaired in Speed of Processing and Retrospective Memory. Children with ADHD + oppositional defiant disorder (ODD) did not show impairment in any other EF domains. The five EF processes correlated with the EF Questionnaire. CONCLUSION: The present study describes different cognitive profiles in children with ADHD with or without comorbid disorders using neuropsychological EF measures. PMID- 25015584 TI - Self- and Parent-Rated Quality of Life of a Treatment Naive Sample of Children With ADHD: The Impact of Age, Gender, Type of ADHD, and Comorbid Psychiatric Conditions According to Both a Categorical and a Dimensional Approach. AB - OBJECTIVE: Our aim was to evaluate the Quality of Life (QoL) of treatment naive children with ADHD. METHOD: Data from 178 parent-child dyads were analyzed using multiple regression to assess the relationships between QoL, and characteristics of ADHD and comorbid psychopathology. RESULTS: Lower self-reported QoL was associated with female gender, higher age, more symptoms of anxiety and trauma related disorders in dimensional approach, and with the comorbid diagnoses of trauma-related disorders and oppositional defiant disorder (ODD)/conduct disorder (CD) in categorical approach. Lower parent-reported QoL was related to older age and increasing number of symptoms of mood and anxiety disorders on one hand, and any diagnosis of mood and anxiety disorders and ODD/CD on the other. CONCLUSION: Our results draw the attention to the importance of taking into account age, gender, and both self- and parent reports when measuring QoL of children with ADHD and both dimensional and categorical approaches should be used. PMID- 25015585 TI - [Utilisation of immunosuppressants in the prevention of a graft versus host reaction: report by the SFGM-TC]. AB - In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille. Here we report our recommendations regarding the use of immunosuppressive treatment in the prevention of graft versus host disease: report by the SFGM-TC. PMID- 25015586 TI - Thioglycosides in Carbohydrate research. AB - The promoters that have been developed for the glycosidation of alkyl/aryl 1 thioglycosides, the applications of thioglycosides in the synthesis of glycans and glycoconjugates, and the advantages and disadvantages of thioglycosides as donors in the syntheses are reviewed briefly, with examples being selected, to a large extent, from those published in Carbohydrate Research. PMID- 25015587 TI - Glycosidic bond hydrolysis in septanosides: a comparison of mono-, di-, and 2 chloro-2-deoxy-septanosides. AB - A kinetic study of the hydrolytic stabilities of mono-, di-, and 2-chloro-2-deoxy septanosides, under acid-catalysis, is reported herein. A comparison of mono- and diseptanosides, shows that the glycosidic bond in the disaccharide is more stable than the monosaccharide. Further the glycosidic bond at the reducing end hydrolyzes almost twice as faster than that of the non-reducing end of the disaccharide. 2-Chloro-2-deoxy septanoside is found to be the most stable and its glycosidic bond hydrolysis occurs at elevated temperatures only. The orientation of the exo-cyclic hydroxymethyl group and the inductive effect are suggested to play a role in the rates of hydrolysis. PMID- 25015590 TI - MCA: Multiresolution Correlation Analysis, a graphical tool for subpopulation identification in single-cell gene expression data. AB - BACKGROUND: Biological data often originate from samples containing mixtures of subpopulations, corresponding e.g. to distinct cellular phenotypes. However, identification of distinct subpopulations may be difficult if biological measurements yield distributions that are not easily separable. RESULTS: We present Multiresolution Correlation Analysis (MCA), a method for visually identifying subpopulations based on the local pairwise correlation between covariates, without needing to define an a priori interaction scale. We demonstrate that MCA facilitates the identification of differentially regulated subpopulations in simulated data from a small gene regulatory network, followed by application to previously published single-cell qPCR data from mouse embryonic stem cells. We show that MCA recovers previously identified subpopulations, provides additional insight into the underlying correlation structure, reveals potentially spurious compartmentalizations, and provides insight into novel subpopulations. CONCLUSIONS: MCA is a useful method for the identification of subpopulations in low-dimensional expression data, as emerging from qPCR or FACS measurements. With MCA it is possible to investigate the robustness of covariate correlations with respect subpopulations, graphically identify outliers, and identify factors contributing to differential regulation between pairs of covariates. MCA thus provides a framework for investigation of expression correlations for genes of interests and biological hypothesis generation. PMID- 25015591 TI - [Ear eczema. Impact on patient quality of life and healthcare costs]. PMID- 25015592 TI - Rethinking "Commercial" Surrogacy in Australia. AB - This article proposes reconsideration of laws prohibiting paid surrogacy in Australia in light of increasing transnational commercial surrogacy. The social science evidence base concerning domestic surrogacy in developed economies demonstrates that payment alone cannot be used to differentiate "good" surrogacy arrangements from "bad" ones. Compensated domestic surrogacy and the introduction of professional intermediaries and mechanisms such as advertising are proposed as a feasible harm-minimisation approach. I contend that Australia can learn from commercial surrogacy practices elsewhere, without replicating them. PMID- 25015593 TI - The change in upper tract urolithiasis composition, surgical treatments and outcomes of para and quadriplegic patients over time. AB - Stone disease in patients with spinal cord injury is a source of morbidity and mortality. Previous studies have indicated a decrease in infection-based urolithiasis in recent decades. We aimed to identify changes in stone composition and surgical outcomes in patients with para and quadriplegia over time. A retrospective review of para and quadriplegic patients from 1986 to 2011 who underwent surgical intervention for urolithiasis was performed, identifying 95 patients. The Mantel-Haenszel Chi square test was used to compare change in stone composition over time. The mean patient age was 44.0 years (range 18-88) and treatment included percutaneous nephrolithotomy (PCNL) 40 (42.1 %), ureteroscopy 28 (29.5 %), shock wave lithotripsy (SWL) 26 (27.4 %), and nephrectomy 1 (1 %). Overall stone-free status was found in 47.4 % with 19.0 % requiring a repeat procedure. The median hospital stay for patients undergoing SWL was 2.5 days, ureteroscopy 5 days, and PCNL 6 days. Infection-based stone composition was identified in 23 patients (36.5 %). We evaluated the linear change in percent of each stone component over time and identified increasing components of calcium oxalate dihydrate (p = 0.002) and calcium carbonate (p = 0.009). However, over a period of 25 years, the incidence of infection-based stone did not change (p = 0.57). Para and quadriplegic patients with urolithiasis can be difficult to treat surgically with prolonged hospitalizations, low stone-free status, and often require additional procedures. Despite improvements in antibiotic agents and management of neurogenic bladders, infection-based calculi continue to be a significant source of morbidity to this patient population. PMID- 25015594 TI - Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-controlled Studies. AB - PURPOSE: Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. METHODS: Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of <=102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). FINDINGS: Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving >=1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. IMPLICATIONS: This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin. PMID- 25015596 TI - Misplaced nephrostomy catheter in left renal vein: a case report of an uncommon complication following percutaneous nephrolithotomy. PMID- 25015595 TI - Treadmill walking during vocabulary encoding improves verbal long-term memory. AB - Moderate physical activity improves various cognitive functions, particularly when it is applied simultaneously to the cognitive task. In two psychoneuroendocrinological within-subject experiments, we investigated whether very low-intensity motor activity, i.e. walking, during foreign-language vocabulary encoding improves subsequent recall compared to encoding during physical rest. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum and salivary cortisol. Previous research has associated both substances with memory performance.In both experiments, subjects performed better when they were motorically active during encoding compared to being sedentary. BDNF in serum was unrelated to memory performance. In contrast we found a positive correlation between salivary cortisol concentration and the number of correctly recalled items. In summary, even very light physical activity during encoding is beneficial for subsequent recall. PMID- 25015597 TI - Percutaneous nephrolithotomy: is distilled water as safe as saline for irrigation? AB - PURPOSE: To compare dilutional effect of distilled water with saline solution as an irrigation fluid in percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: Three hundred twenty eight adult patients (191 men, 137 women) who were candidates for PCNL were randomly assigned into two groups (distilled water, n = 158, group 1; saline solution, n = 162, group 2). Stone size, operation time, irrigation fluid volume, blood hemoglobin level, urea nitrogen, creatinine, sodium and potassium levels were checked before and at 6 and 12 hours after operation. RESULTS: The mean age of the patients was 37.8 years, and the mean stone diameter was 31.5 mm. There was no clinical case of transurethral resection (TUR) syndrome. Serum sodium depletion was significantly more in group 1 than group 2 (P < .0001). Group 1 had significant decreased post-operative serum sodium levels (P < .0003). Similarly in group 2, postoperative serum sodium levels were significantly lower than the preoperative concentration (P < .01), but it was not the same 6 hours after the operation (P = .23). Serum sodium concentrations remained within normal limits in all cases, without causing clinical signs and symptoms of hyponatremia. CONCLUSION: We found that distilled water is safe irrigation fluid for PCNL in adults. In addition, it is more available and cost effective. PMID- 25015598 TI - Percutaneous nephrolithotomy success rate and complications in patients with previous open stone surgery. AB - PURPOSE: To determine the effect of previous single or multiple open stone surgeries on percutaneous nephrolithotomy (PCNL) results and complications. MATERIALS AND METHODS: We reviewed medical records of 1422 patients who had been undergone PCNL in our institute between 1998 and 2011 by the same surgeon. Patients were divided into 3 groups. The first group included patients with no history of previous ipsilateral open stone surgery (n = 711). Patients in second group had been undergone only one open stone surgery before PCNL (n = 405) and patients with more than one previous open stone surgery were placed in third group (n = 306). We compared operation duration, stone free rate (SFR), number of attempts to access the collecting system and intraoperative and postoperative complications between 3 groups. RESULTS: There were no differences in sex, body mass index, stone burden and laterality between 3 groups. Operation time was significantly shorter in the first group (P = .000) while there was no statistically significant differences in operation duration between second and third groups (P > .973). The number of attempts to enter the collecting system was significantly lower in the first group in comparison to other two groups (P = .00). We didn’t find significant differences between 3 groups in hospital stay, SFR, intraoperative and postoperative complications. CONCLUSION: Our findings demonstrated that PCNL can be performed in patients with one or more open stone surgery history successfully without further complications. PMID- 25015599 TI - Can we reduce secondary surgical interventions and length of hospitalization in percutaneous nephrolithotomy? AB - PURPOSE: To evaluate the success and complication rates of percutaneous nephrolithotomy (PNL) operations and to determine the effect of postoperative late removal of an open-end ureter catheter on hospital stay and on secondary interventions. MATERIALS AND METHODS: The records of 198 patients (97 female, 101 male) who had PNL between May 2009 and February 2012 were retrospectively reviewed. The open-end ureter catheter which was placed during the operation was removed at the end of the operation in the first 53 patients ( group 1) and 12 hours after the nephrostomy catheter in 145 patients ( group 2). RESULTS: PNL intervention was performed in 198 patients with a mean age of 40.83 +/- 13.64 years and mean stone load of 9.82 +/- 5.37cm2 (range 2 to 26 cm2). When clinically insignificant stone pieces < 4 mm were accepted as successful, the total success rate was 80.80 % (79.2% in group1 and 81.4% in group 2, P = .50). The hospitalization period was significantly reduced in group 2 (3.45 +/- 0.95 days vs. 2.61 +/- 0.65 days; P = .006). While secondary surgical intervention was not necessary in any of the patients in group 2 (0.0%), but 4 patients (7.5%) required ureterorenoscopy plus double-J stent placement following the primary procedure in group 1 (P = .006). CONCLUSION: PNL is a safe procedure with a high success rate and a short hospitalization period. There was a significant decrease in the hospitalization period and secondary surgical intervention rates with the postoperative late removal of the open-end ureter catheter. PMID- 25015600 TI - Capsulotomy for treatment of compartment syndrome in patients with post extracorporeal shock wave lithotripsy renal hematomas: safe and effective, but also advisable? AB - PURPOSE: To examine whether surgical decompression of hematomas by capsulotomy can help to improve long-term renal function following extracorporeal shock wave lithotripsy (SWL). MATERIALS AND METHODS: This study retrospectively identified 7 patients who underwent capsulotomy for post SWL renal hematomas between 2008 and 2012. The control group comprised 8 conservatively treated patients. The median follow-up time was 22 months. RESULTS: The two groups were comparable in age, gender, body mass index, risk factors for developing hematomas (renal failure, urinary flow impairment, indwelling ureteral stent and diabetes mellitus) and the selected SWL modalities. Hematoma size was also similar. However, significantly more patients in the surgical group had purely intracapsular hematomas (85.7% vs. 37.5%) without a potentially pressure-relieving capsular rupture. There were no significant differences in the post-interventional drop in hemoglobin, rise in retention parameters or drop in glomerular filtration rate (GFR). No capsulotomy related complications were observed, but surgery required a significantly longer hospital stay than conservative management (median, 9 days vs. 5 days). The two groups also showed comparable recovery of renal function at long-term follow-up (median change in GFR from baseline, 97.1% and 97.8%, respectively). CONCLUSION: Since renal function did not differ between the two treatment groups, the conservative management remains the standard treatment for post-SWL renal hematoma. PMID- 25015601 TI - One-shot dilation in modified supine position for percutaneous nephrolithotomy: experience from over 300 cases. AB - PURPOSE: To evaluate the feasibility, safety and efficacy of one-shot dilation (OSD) in modified supine position percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: A total of 320 PCNL in a total of 291 patients were performed between October 2008 and July 2011. There were no specific exclusion criteria. Patients with kidney anomalies or solitary kidney, with history of renal surgery or extracorporeal shockwave lithotripsy (SWL), those with staghorn calculi or needing more than one access, were eligible for inclusion. Data collected included patient demographics and stone characteristics, access time, radiation exposure, total operating time, preoperative and postoperative hemoglobin concentrations, tract dilatation failures, complications and transfusions. RESULTS: Mean stone size was 38 mm (16-110 mm). The mean time access was 2.1 min (range 0.7-6.2 min). Tract dilatation fluoroscopy time was 25 +/- 17 sec. The targeted calix could be entered with a success rate of 97.81%. The mean hemoglobin decrease was -1.17 g/dL +/- 0.84. There were no visceral, pleural, collecting systems or vascular injuries. Major complications included, transfusion in 4 (1.25%) patients, pseudoaneurysm with persistent bleeding necessitating nephrectomy in 1 (0.3%) patient and two deaths (0.62%) after surgery. There was no significant difference in successful access and complications between patients with and without previous open surgery and in those with or without staghorn stones (P > .05). CONCLUSION: The use of one shot and modified supine position combines the advantages of these both methods including less radiation exposure and shorter access and operative time. The one shot dilation is safe, easy to learn, cost effective and offers a potential alternative to the standard devices particularly in developing countries. PMID- 25015602 TI - Evaluation of safety and efficacy of open mini-access ureterolithotomy in the era of minimally invasive surgery. AB - PURPOSE: To evaluate the effectiveness and safety evaluation of mini-access ureterolithotomy in the management of ureteric calculus. MATERIALS AND METHODS: This was a cross-sectional study conducted at Department of Urology, Regional Institute of Medical Sciences, Imphal. A total number of one hundred and forty three patients with radiologically confirmed ureteral calculus (size > 1 cm) were enrolled in this study. RESULTS: The mean age of male and female patients was 44.97 +/- 11.24 and 43.89 +/- 14.49 years, respectively. In the majority of cases stone was in the upper ureter irrespective of the side. The stone size ranged from 10 to 30 mm in diameter. The most common indication for open mini-access ureterolithotomy in the present study was impacted large stone (45%). The mean operation duration was 25.39 +/- 5.11 min, with an incision length of 4.78 +/- 0.25 mm; the estimated blood loss was 50.55 +/- 8 mL and none of the patient's required post-operative blood transfusion. The overall complication rate was 5.6%. CONCLUSION: Open mini-access ureterolithotomy is a safe procedure with fewer complications and cosmetically acceptable results. Although in this minimally invasive era, the specific indications for open stone surgery are a few, but when the situation mandates, an open mini-access ureterolithotomy might be considered the best option. PMID- 25015603 TI - Reduced radiation fluoroscopy protocol during retrograde intrarenal surgery for the treatment of kidney stones. AB - PURPOSE: To discuss whether fluoroscopic imaging is essential during the ureteroscopic treatment of kidney stones in an effort to diminish radiation exposure. MATERIALS AND METHODS: Seventy-six patients with kidney stones were treated with retrograde intrarenal surgery (RIRS). In the operation room, a mobile C-arm fluoroscopy system was ready to use in case fluoroscopic imaging was needed. The manipulations were performed with tactile and visual cues. The perioperative and postoperative parameters were retrospectively evaluated. RESULTS: The mean age of the patients was 39.9 +/- 13.8 years. The mean stone size was 14.1 +/- 4.1 mm. The insertion of the access sheath was performed over the guidewire under single shoot fluoroscopic imaging in all patients. Additional fluoroscopic imaging was required to localize the stone (n = 2) and to determine the collecting system anatomy (n = 2) for 4 (5.2%) patients with previous renal surgery and severe hydronephrosis. Stone-free status was accomplished in 63 (82.9%) patients. CONCLUSION: The RIRS with low-dose fluoroscopy protocol for kidney stones can be safely and effectively performed in patients with no special circumstances such as anatomical abnormalities or calyceal diverticular stones. PMID- 25015604 TI - Hand-assisted, conventional and laparoendoscopic single-site surgery for partial nephrectomy without ischemia using a microwave tissue coagulator. AB - PURPOSE: We report our experience of minimally invasive partial nephrectomy without ischemia using a microwave tissue coagulator (MTC) for hand-assisted laparoscopic partial nephrectomy (HALPN), conventional laparoscopic partial nephrectomy (CLPN), and laparoendoscopic single-site surgery for partial nephrectomy (LESSPN). We retrospectively compared the results of these techniques to better define the individual role and the benefits. MATERIALS AND METHODS: From July 2005 to September 2012, 28 patients with small and exophytic renal tumors underwent HALPN (n = 12), CLPN (n = 10) and LESSPN (n = 6). In these procedures, the surgeon used an MTC for circumferential coagulation around the tumor. After coagulation, the tumor was resected without renal pedicle clamping. RESULTS: The mean operative time was 259, 194 and 174 min for the HALPN, CLPN and LESSPN groups respectively. Two patients (one in HALPN group and one in LESSPN group) converted to laparotomy due to an inability to maintain hemostasis; however, there were no conversions to ischemic partial nephrectomy or radical nephrectomy. No differences between HALPN, CLPN and LESSPN were noted in terms of estimated blood loss, measured analgesic requirements, outcomes, or complications. CONCLUSION: We believe that these techniques are feasible and that they minimize the risk of unexpected collateral thermal damage by appropriate MTC needle puncture. When deciding to use HALPN, CLPN or LESSPN, our findings suggest that the choice of surgical approach should depend on the patient's individual circumstance. PMID- 25015605 TI - Prevalence of urinary incontinence and lower urinary tract symptoms in school-age children. AB - PURPOSE: To investigate the prevalence of lower urinary tract symptoms (LUTS) and urinary incontinence (UI) in elementary school aged children in Manisa. MATERIALS AND METHODS: Dysfunctional Voiding and Incontinence Scoring System (DVIS) which was developed in Turkey is used. A total of 416 children, 216 (51.9%) male and 200 (48.1%) female were recruited in this study. RESULTS: Mean age of children was 10.35 +/- 2.44 years (median10 years). Daytime UI frequency was 6.7% (28 child), nocturnal incontinence 16.6% (69 child) and combined daytime and nocturnal incontinence 4.1% (17 child). There was no statistically significant difference in the prevalence of nocturnal and or daytime UI between male and female gender. Mean DVIS score was 2.65 +/- 3.95 and gender did not affect total DVIS points. The mean ages of achieving daytime bowel and bladder control were all significantly correlated with DVIS points. DVIS points were positively correlated with the history of UI of the family. Total points were increased when the father was unemployed. CONCLUSION: UI negatively influences health related quality of life of the family and child, so it is important that awareness of the UI and symptoms of lower urinary tract dysfunction. PMID- 25015606 TI - Comparison of 12- and 16-core prostate biopsy in japanese patients with serum prostate-specific antigen level of 4.0-20.0 ng/mL. AB - PURPOSE: In the present study, we compared 12- with 16-core biopsy in patients with prostate- specific antigen (PSA) levels of 4.0-20.0 ng/mL. MATERIALS AND METHODS: Between 2003 and 2010, 332 patients whose serum PSA level was between 4.0 and 20.0 ng/mL underwent initial transrectal ultrasound (TRUS)-guided needle biopsy. Of those patients, 195 underwent 12-core biopsy and 137 underwent 16-core biopsy. RESULTS: In the 12-core prostate biopsy group, 66 (33.8%) patients were found to have prostate cancer. On the other hand, in the 16-core prostate biopsy group of 137 patients, 61 (44.5%) were found to have prostate cancer. Among all patients, the prostate cancer detection rate was slightly higher in the 16-core biopsy group than in the 12-core biopsy group. Moreover, in patients with prostate volume > 30 mL or PSA density (PSAD) < 0.2, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group. There was no significant difference in pathological tumor grade, indolent cancer probability, or biopsy complication rate between the two groups. CONCLUSION: In order to detect prostate cancer, 16-core prostate biopsy is safe and feasible for Japanese patients with serum PSA level of 4.0-20.0 ng/mL. PMID- 25015607 TI - Pre-operative tumor localization and evaluation of extra-capsular extension of prostate cancer: how misleading can it be? AB - PURPOSE: To verify the accuracy of transrectal ultrasound-guided prostatic biopsy (TRUS Bx), magnetic resonance imaging (MRI) and their combination in evaluating the laterality of prostate cancer and to determine the accuracy of MRI in assessing extra-capsular extension of prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed our past 100 consecutive series of radical prostatectomy performed between February 2010 and April 2012 at our institution. Their TRUS Bx and MRI results were compared with the pathology of the radical prostatectomy specimens. For tumor localization, we calculated the accuracies in unilateral diseases, bilateral diseases, overall accuracies and Cohen Kappa concordance coefficient of TRUS Bx, MRI and their combination. For the assessment of extra capsular extension, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, overall accuracy, likelihood ratio positive and likelihood ratio negative of MRI. RESULTS: Eighty-two percent of our radical prostatectomy specimens had bilateral tumor involvement and 32% had extra capsular extension. The accuracies of TRUS Bx in unilateral disease, bilateral disease and overall accuracy were 15.2%, 91.4% and 43.6%, respectively. The accuracies of MRI in unilateral disease, bilateral disease and overall accuracy were 11.1%, 66.7% and 38.9%, respectively. When combining the assessment of TRUS Bx and MRI, the accuracies in unilateral disease, bilateral disease and overall accuracy were 16.7%, 75% and 55.6%, respectively. The Cohen Kappa concordance co efficient of TRUS Bx, MRI, and combination of them were 0.1165, -0.2047 and 0.1084, respectively. The positive predictive value, negative predictive value, sensitivity, specificity, overall accuracy, likelihood ratio positive and likelihood ratio negative of MRI in assessing extra-capsular extension were 33.3%, 69.8%, 5.9%, 94.9%, 67.9%, 1.16 and 0.99, respectively. CONCLUSION: TRUS Bx, MRI, and their combination had poor concordance and limited accuracies in assessment of the laterality of tumor involvement. The combination of TRUS Bx and MRI offered a better of accuracy when compared to either modality alone. MRI was a specific, but not sensitive tool in assessing the presence of extra-capsular extension. PMID- 25015608 TI - Comparing supportive properties of poly lactic-co-glycolic acid (PLGA), PLGA/collagen and human amniotic membrane for human urothelial and smooth muscle cells engineering. AB - PURPOSE: To compare human urothelial and smooth muscle cells attachment and proliferation using three different matrices; poly lactic-co-glycolic acid (PLGA), PLGA/collagen and human amniotic membrane (hAM). MATERIALS AND METHODS: Human urothelial and smooth muscle cells were cultured and examined for expression of urothelium (pancytokeratin and uroplakin III) and smooth muscle cells [desmin and alpha smooth muscle actin (alpha-SMA)] markers. Cells were cultured on three scaffolds; PLGA, PLGA/collagen and hAM. Thereafter, they were analyzed for cell growth on days 1, 3, 7, 14 and 21 after seeding by 3-(4, 5 dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Scaffolds were fixed and processed for hematoxylin and eosin (H&E) staining and immunohistochemistry against their cell specific markers after 7 and 14 days of culture. RESULTS: MTT assay results revealed that collagen has improved cell attachment features of PLGA and led to significant increase of MTT signal in PLGA/collagen compared to PLGA (P < .001) and hAM (P < .001). hAM was a weaker matrix for both cell types as demonstrated in MTT assay and scanning electron microscope (SEM) images. SEM micrographs showed normal phenotype and distribution on PLGA and PLGA/collagen. In the same line, cells formed a well-developed layer either on PLGA or PLGA/collagen, which maintained expression of their corresponding markers. CONCLUSION: Our findings demonstrated significant improvement of cell attachment and growth achieved by collagen coating (PLGA/collagen) compared to PLGA and hAM. hAM despite of its natural entity was a weaker matrix for bladder engineering purposes. PMID- 25015609 TI - Long-term follow-up on the effects of sigmoid-rectal pouch for urinary diversion. AB - PURPOSE: The aim of this study was to investigate the long-term clinical effects of sigmoidrectal pouch for urinary diversion. MATERIALS AND METHODS: A total of 45 patients, including 40 males and 5 females, underwent sigmoid-rectal pouch procedure. The patients aged from 38 to 70 years with a mean age of 59 years. The postoperative follow-up ranged from 6 months to 19 years with an average of 6 years. Postoperative continence and voiding were analyzed, urinary reservoir pressure was measured and the complications of upper urinary tract were determined. The index of quality of life (QoL) in the International Prostate Symptom Score (IPSS) was used to evaluate the degree of satisfaction to urinate. RESULTS: Forty patients had slight incontinence in the early postoperative stage and could control urination well 30 days postoperatively. The volume of pouch was 270-600 mL with an average of 375 mL. The basic pressure during filling period was 6-20 cmH2O with an average 15 cmH2O, the maximum filling pressure was 15-30 cmH2O with an average 26 cmH2O. The compliance of sigmoid-rectal pouch was fine with an average of 30 (range 18-40) mL/ cmH2O. There were no severe complications such as hyperchloremic acidosis or retrograde pyelonephritis. Six patients had slight hydronephrosis. The index of QoL were 0-2 in 20 patients, 3 in five patients and 4 in two patients. CONCLUSION: The sigmoid-rectal pouch operation was simple and acceptable by surgeons and patients. It may be an ideal urinary diversion for patients with muscle-invasive bladder cancer, especially for patients on whom urethrectomy should be done. PMID- 25015610 TI - The alpha1 adrenoceptor antagonist tamsulosin for the treatment of voiding symptoms improves nocturia and sleep quality in women. AB - PURPOSE: Nocturia is the main cause of disturbance of sleep maintenance and negatively impacts quality of life (QoL). We assessed the effects of the alpha1 adrenoceptor antagonist, tamsulosin, on nocturia and quality of sleep, for the treatment of lower urinary tract symptoms (LUTS) in women with a maximal flow rate (Qmax) less than 15 mL/sec. MATERIALS AND METHODS: From January 2008 to December 2009, women with LUTS [Qmax <= 15 mL/s, International Prostate Symptom Score (IPSS) >= 8] and nocturia (void/night >= 1) were selected for this study. Two hundred ninety six patients completed voiding diary, a questionnaire on the Medical Outcomes Study (MOS) sleep scale and underwent follow-up evaluation after 4 weeks of treatment (tamsulosin, 0.2 mg, once daily). Effectiveness was assessed by analysis of the IPSS, the bother score, the Qmax, and postvoid residual urine (PVR). RESULTS: The mean number of voids per night was 2.66 +/- 1.3, and the total IPSS and bother scores were 15.2 +/- 8.9 and 3.4 +/- 1.2, respectively. Clinical parameters, including the IPSS, the bother score, the Qmax and the PVR, improved significantly from baseline after treatment (P < .05). The change in nocturia was -1.12 (P < .05). Concerning sleep quality, the sleep problem index showed a significant decrease. Among the items on the sleep subscale, sleep disturbance, somnolence, and sleep adequacy were significantly changed (P < .05). CONCLUSION: The alpha1-adrenoceptor antagonist tamsulosin significantly improved nocturia and sleep quality as well as LUTS in women with low Qmax. PMID- 25015611 TI - Expression and function of muscarinic subtype receptors in bladder interstitial cells of cajal in rats. AB - PURPOSE: To locate the muscarinic (M) M2 and M3 receptors in bladder interstitial cells of Cajal (ICCs) and to determine the effects of M2 and M3 agonists on bladder ICCs. MATERIALS AND METHODS: A total of 30 adult male Sprague-Dawley rats weighing 225-250 g were used in this study. Double-labeled fluorescence of muscarinic receptors and c-kit was performed for co-localization. To evaluate the effect of muscarinic agents on the excitation of bladder ICCs, we analyzed the inward current of bladder ICCs using the whole-cell patch clamp. The effect of muscarinic agents on the carbachol-induced inward currents was evaluated with the whole-cell patch clamp. RESULTS: M2 and M3 receptors were confirmed in the stroma ICCs in rats' bladders with double-labeled immunofluorescence. Spontaneous action potential was observed in freshly isolated bladder ICCs. The carbachol-induced inward Ca2+ current in ICCs can be blocked by atropine. The M2 receptor antagonist methoctramine (1 MUM) showed a weak inhibitory capability on the inward Ca2+ current [from 74.8 +/- 9.6 to 63.3 +/- 13.8 Pascal (pA), n = 12, P = .03]. While the M3 receptor antagonist 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (4-DAMP) (1 MUM) significantly inhibited the inward Ca2+ current (from 78.4 +/- 11.2 to 17.3 +/- 7.9 pA, n = 12, P < .001). CONCLUSION: Bladder ICCs express M2 and M3 cholinergic receptors. Most muscarinic cholinergic receptor antagonists, especially the M3 antagonists, can effectively inhibit the carbamylcholine- induced inward current of bladder ICCs. PMID- 25015612 TI - Recruiting testicular torsion introduces an azoospermic mouse model for spermatogonial stem cell transplantation. AB - PURPOSE: To investigate the long-term effect of testicular torsion on sperm parameters and testis structure in order to introduce a novel mice azoospermic model for spermatogonial stem cell transplantation. MATERIALS AND METHODS: Unilateral testicular torsion was created. The animals were divided into two groups each containing 15 mice. They underwent 2 and 4 hours of unilateral testicular ischemia, respectively. All animals in this experiment were aged matched. The experimental (n = 5) groups were studied 2, 4 and 10 weeks after testicular ischemia reperfusion. Moreover, the left testes and epididymis were removed for sperm analysis and for weight and histopathological evaluation. Finally isolated spermatogonial stem cells were transplanted in the testes that underwent 2 hours of ischemia reperfusion, two weeks post-surgery. RESULTS: All the investigated parameters demonstrated a sharp decline at 2, 4 and 10 weeks after testicular torsion, whereas 2-hour ischemia was found to be less injurious in testicular tissue structure. Two months after xenotransplantation, the transplanted cells were localized in the basal of the seminiferous tubules of the recipient ischemic testes. CONCLUSION: Torsion can cause permanent azoospermia in mouse. Also Testicular torsion 2 weeks after the 2 hours ischemia reperfusion may prove useful for recipient preparation for SSCs transplantation in mouse. PMID- 25015613 TI - Editorial comment to: Recruiting testicular torsion introduces an azoospermic mouse model for spermatogonial stem cell transplantation. PMID- 25015614 TI - The value of neutrophil elastase in diagnosis of type III prostatitis. AB - PURPOSE: To explore the value and significance of neutrophil elastase (NE) in diagnosis of type III prostatitis. MATERIALS AND METHODS: The prospective study recruited 123 patients diagnosed with type III prostatitis (IIIA, 36 cases; IIIB, 87 cases) and 84 healthy controls, between April 2008 and July 2012. NE concentrations in expressed prostatic secretions (EPS), EPS routine examination, bacterial culture and The National Institute of Health Chronic Prostatitis Symptom Index (NIHCPSI) score were detected in all the subjects. Difference of NE, CPSI score, and withe blood cell (WBC) count between 2 or more than 2 groups and relationships between NE concentrations and WBC count were all analyzed. RESULTS: There was significant difference in levels of NE (P < .05) between IIIA and IIIB groups, and obviously positive correlation between the level of NE and number of leukocyte in type IIIA prostatitis group was observed (P < .05). The values of CPSI score between IIIA and IIIB groups was statistically significant (P = .037). The levels of leukocyte mount, NE and CPSI were statistically significant between IIIA and the control group (P < .05). NE concentration and CPSI score were statistically significant between IIIB and control group (P < .05), while the numbers of leukocyte was not statistically significant (P = .360). CONCLUSION: The level of NE in EPS is a significant indicator in diagnosis of type IIIA and IIIB prostatitis. PMID- 25015615 TI - Is the double dose alpha-blocker treatment superior than the single dose in the management of patients suffering from acute urinary retention caused by benign prostatic hyperplasia? AB - PURPOSE: To compare the efficacy and safety of single (tamsulosin) and double dose (tamsulosin + alfuzosin) alpha-blocker therapy for treating catheterized patients with acute urinary retention (AUR) due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Seventy patients with AUR due to BPH were catheterized and randomized into two groups: the single dose group (0.4 mg tamsulosin, 35 patients) and the double dose group (0.4 mg tamsulosin + 10 mg alfuzosin, 35 patients). The catheter was removed after 3 days, and the patients were put on trial without catheter (TWOC). RESULTS: Seventy males (mean age, 71.2 years) were randomly assigned to receive double or single dose alpha-blocker (35 patients per group). The intent-to-treat population consisted of 70 males. Twenty seven individuals in the double dose group and 19 in the single dose group did not require re-catheterization on the day of the TWOC (77% and 54%, respectively; P = .003). Success using free-flow variables was also higher in the males who received double dose alpha-blocker compared with single dose therapy (48% vs. 40%; P = .017). CONCLUSION: TWOC was more successful in males treated with double dose alpha-blockers, and the subsequent need for re-catheterization was also reduced. The side-effect profiles were similar in the single and double dose alpha-blocker groups and were consistent with the known pharmacology. These results state that double dose alpha-blocker treatment can be recommended for treating males after catheterization for AUR, which may reduce the need for re catheterization. PMID- 25015616 TI - Biaxial mechanical properties of human ureter under tension. AB - PURPOSE: The Mechanical properties of the ureteral wall may be altered by certain diseases such as megaureter. Ureter compliance and wall tension alterations can occur, leading to some abnormalities such as reflex mechanisms. Familiarizing with the mechanical properties of the ureter can help us advance in the understanding of urinary tract diseases. MATERIALS AND METHODS: A constitutive model that can predict the mechanical response of ureteral tissue under complex mechanical loading is required. Parameters characterizing the mechanical behaviour of the material were estimated from planar biaxial test data, where human ureter specimens were simultaneously loaded along the longitudinal and circumferential directions. RESULTS: The biaxial stress-stretch curve was plotted and fitted to a hyperelastic four-parameter Fung type model and five-parameter Mooney-Rivlin model. The average strength in the longitudinal direction was 3.48 +/- 0.47 MPa and 2.31 +/- 0.46 MPa (P <.05) for the circumferential direction.In the Fung model the value of parameter a2 (0.699 +/- 0.17) was higher than a1 (0.279 +/- 0.07), which may be due to the collagen fiber orientation's preference along the longitudinal axis. CONCLUSION: According to this study, it seems that ureter tissue is stiffer in the longitudinal than in the circumferential direction and maybe the collagen fiber are along the axial axes. Also the specimens showed some degree of anisotropy. PMID- 25015617 TI - Role of frozen section examination in the management of testicular nodules: a useful procedure to identify benign lesions. AB - PURPOSE: To assess the validity of frozen section examination (FSE) on testis nodules. MATERIALS AND METHODS: A series of 86 preselected patients with testicular nodules were recruited in this study. Nodules smaller than 2 cm had been surgically removed and biopsies of the margins performed. Larger nodules were just biopsied. Orchiectomy was the treatment of choice for malignant lesions and stromal tumors. Conservative surgery was performed on 2 previously monorchid patients with Leydig cell tumor because of the presence of just one testis. Conservative surgery was the treatment of choice for benign lesions in 32 cases. RESULTS: At FSE we observed that nodules were malignant germinal tumors in 47% of the cases, stromal tumors in 7% of the cases, benign lesions in 45% of the cases and doubtful for lymphoproliferative lesion in 1 case. The diagnosis made by FSE were confirmed in the definitive ones in all of them, we reported just 2 cases of Leydig cell tumor and benign fibrosis lesion. In these 2 cases, definitive histology of the collected specimens revealed areas of Leydig cell hyperplasia and seminomatous foci, respectively. CONCLUSION: Our data suggest that FSE is a valid tool to discriminate between benign and malignant neoplastic lesions, particularly when an adequate sample is available. PMID- 25015618 TI - Laparoscopic repair of a rare case of bladder rupture due to intravesical explosion during transurethral resection of the prostate. PMID- 25015619 TI - Donor specific antibodies median fluorescence intensity levels are the best indicator for monitoring desensitization treatment in kidney transplant. PMID- 25015620 TI - Transumbilical laparoendoscopic single-site decortication of peripelvic renal cyst: a case report. PMID- 25015621 TI - Appendico-vesical fistula in a woman. PMID- 25015622 TI - Epidermoid cyst of the scrotum: a clinical case. PMID- 25015623 TI - Aggressive vaginal angiomyxoma mimicking a bladder mass. PMID- 25015624 TI - Acute jejunal obstruction following laparoscopic nephrectomy. PMID- 25015625 TI - Tumor enucleation with zero ischemia for renal cell carcinoma by robotic retroperitoneal approach. PMID- 25015626 TI - Uretero-caval fistula after radical cystectomy with bricker ileal conduit: a case report. PMID- 25015627 TI - The Whitaker test. AB - PURPOSE: The Whitaker test was conceived and developed by Roger H. Whitaker (May 25, 1939) while he was a resident at Cambridge University in the late 1960s and early 1970s. The test combines a urodynamic study with antegrade pyelography to measure the pressure differential between the renal pelvis and the bladder. The test can differentiate between patients with residual or recurrent obstruction and those with dilatation secondary to permanent changes in the musculature. MATERIALS AND METHODS: We present the history of the Whitaker test and its place in modern practice. RESULTS: It is useful in evaluating patients with questionable ureteropelvic or ureterovesical junction obstruction and primary defects in the ureteral musculature. It can also be used to determine when percutaneous nephrostomy tubes can be safely discontinued in postoperative patients. CONCLUSION: The merit of the Whitaker test in comparison to other less invasive tests, specifically diuretic renography, is the subject of much debate. However, such debate erroneously presupposes that the tests are directly comparable, which they are not. The correct use for the Whitaker test is to assesses potential upper tract obstruction in equivocal cases and should only be utilized when equivocal results are obtained by other less invasive tests, obstruction is suspected in a poorly functioning kidney, a negative renogram with colic, intermittent obstruction, and percutaneous access already exists and the cause of dilatation needs investigating. PMID- 25015628 TI - A circumcision method in an old surgical textbook (Cerrahiyyetul Haniyye): reminding of a forgotten procedure. AB - PURPOSE: Circumcision is one of the historical surgical procedures. Some sources throughout the history contain various definitions about different circumcision methods. we described the details of the method, and aimed to remind the possibility of contemporary usage. MATERIALS AND METHODS: We compared circumcision chapters of Sabuncuoglu and Zahrawi to explain the historical origin of Sabuncuoglu's favorite circumcision method. RESULTS: We found a method which might be summarized as "knotting with rope technique" in one of historical textbooks named as Cerrahiyyetul Haniyye (Imperial Surgery) written by Serefeddin Sabuncuoglu (1385-1468?) in 1465. CONCLUSION: This circumcision method is not used currently. In addition this method has not been defined in the history of medical literature yet. PMID- 25015629 TI - Renal angiomyolipoma embolization with flexible microcatheter. PMID- 25015630 TI - Remission of a renal artery stenosis after laparoscopic removal of an extra adrenal paraganglioma. PMID- 25015631 TI - Megalourethra: a rare clinical entity. PMID- 25015634 TI - Development and validation of a tetra-primer amplification refractory mutation system-polymerase chain reaction combined with melting analysis-assay for clinical JAK2 V617F mutation detection. AB - BACKGROUND AND OBJECTIVE: JAK2 V617F mutation is a molecular marker for myeloproliferative neoplasms (MPNs). As there are no China Food and Drug Administration-approved assays for the detection of JAK2 V617F mutation in China, validation of the analytic performance of this assay is important for the clinical laboratory before its clinical implementation. We have established a method for detecting JAK2 V617F using tetra-primer amplification refractory mutation system-polymerase chain reaction (tetra-primer ARMS-PCR) combined with melting-curve analysis. METHODS: A total of 202 blood samples and 20 bone marrow aspirates were obtained from MPNs patients at Huashan Hospital, Fudan University. The accuracy, precision, reproducibility, analytical sensitivity, lower limit of detection, analytical specificity, interfering substances, ruggedness, robustness, reportable range and reporting of this assay were validated. RESULTS: There was a close agreement between the reference method (sequencing) and melting curve analysis (kappa = 0.89). The precision was 100 % and the results of the assay were unaffected by lipoprotein (<27 mmol/L) or bilirubin (<450 umol/L). The analytical sensitivity of the JAK2 mutation was 1.25 %. CONCLUSIONS: Tetra-primer amplification refractory mutation system-polymerase chain reaction (tetra-primer ARMS-PCR) combined with melting-curve analysis can be used in the clinical laboratory for detection of the JAK2 V617F mutation. PMID- 25015635 TI - Micro-imaging of implanted scaffolds using combined MRI and micro-CT. AB - RATIONALE AND OBJECTIVES: Thanks to the advanced studies in biomaterial engineering a panoply of polymers can be used to manufacture porous scaffolds for bone tissue regeneration. Suitability of the scaffold for its purpose is determined by factors like size of the pores, its orientation and shape, as well as biocompatibility of the material. Even though a variety of analysis methods is available for in vitro studies, investigating the process of bone reconstruction on implanted scaffold meets with difficulties. METHODS AND MATERIALS: Polylactide porous sponges imbued in hydroxyapatite were implanted into long bones of white New Zealand rabbits for 3 months. The bones obtained from the animals were subjected to MRI and MUCT imaging. The obtained images were subsequently fused together. RESULTS AND CONCLUSIONS: Combined MRI and MUCT resulted in high resolution diagnostic images which allow for: implant positioning, inflammation divulgement, rating degree of implant resorption, observation of newly formed trabeculae, texture analysis and other quantitative measurements. PMID- 25015636 TI - Scarring alopecia in classic adult type I pityriasis rubra pilaris. PMID- 25015637 TI - The usefulness of high-resolution ultrasound in detecting invasive disease in recurrent basal cell carcinoma after nonsurgical treatment. AB - INTRODUCTION AND OBJECTIVES: Accurate subtyping of basal cell carcinoma (BCC) is crucial for the effective management of this disease and it is particularly important to distinguish between aggressive and nonaggressive histologic variants. Histologic subtype is not always accurately identified by biopsy and this can have serious implications. High-resolution ultrasound (HRUS) is a recent technique that has proven to be of value in differentiating between variants of BCC. The aim of this study was to investigate the potential usefulness of HRUS for detecting invasive disease in recurrent BCC treated nonsurgically following an initial diagnosis of noninvasive BCC by biopsy. MATERIAL AND METHODS: This was a prospective observational study of consecutive cases of BCC with clinical suspicion of recurrence following nonsurgical treatment and a pretreatment diagnosis of superficial BCC by punch biopsy. Before surgical excision, the recurrent lesions were evaluated by HRUS followed by a punch biopsy of the site of suspected recurrence. The diagnostic agreement between HRUS, punch biopsy, and excisional biopsy was then evaluated. RESULTS: Eight lesions were studied. HRUS identified invasive disease in 3 of the 4 cases that were incorrectly classified as superficial subtypes by punch biopsy. CONCLUSION: HRUS could be useful for detecting persistent tumor after nonsurgical treatment and for choosing the site most likely to harbor invasive disease for punch biopsy. PMID- 25015638 TI - Maternal extraversion, emotional stability and conscientiousness are associated with initiation and continuation of breastfeeding. AB - Implications for practice and research: Understanding maternal trait personality could inform targeted interventions for women identified as requiring additional breastfeeding support and help to facilitate discussion of barriers to breastfeeding. Further research is needed to explore the impact of maternal personality on effectiveness of interventions designed to increase coping strategies and influence of social networks among women who wish to start and continue to breastfeed. PMID- 25015639 TI - Laminin-111 improves skeletal muscle stem cell quantity and function following eccentric exercise. AB - Laminin-111 (alpha1, beta1, gamma1; LM-111) is an important component of the extracellular matrix that is required for formation of skeletal muscle during embryonic development. Recent studies suggest that LM-111 supplementation can enhance satellite cell proliferation and muscle function in mouse models of muscular dystrophy. The purpose of this study was to determine the extent to which LM-111 can alter satellite and nonsatellite stem cell quantity following eccentric exercise-induced damage in young adult, healthy mice. One week following injection of LM-111 or saline, mice either remained sedentary or were subjected to a single bout of downhill running (EX). While one muscle was preserved for evaluation of satellite cell number, the other muscle was processed for isolation of mesenchymal stem cells (MSCs; Sca-1+CD45-) via FACS at 24 hours postexercise. Satellite cell number was approximately twofold higher in LM-111/EX compared with all other groups (p<.05), and the number of satellite cells expressing the proliferation marker Ki67 was 50% to threefold higher in LM-111/EX compared with all other groups (p<.05). LM-111 also increased the quantity of embryonic myosin heavy chain-positive (eMHC+) fibers in young mice after eccentric exercise (p<.05). Although MSC percentage and number were not altered, MSC proinflammatory gene expression was decreased, and hepatocyte growth factor gene expression was increased in the presence of LM-111 (p<.05). Together, these data suggest that LM-111 supplementation provides a viable solution for increasing skeletal muscle stem cell number and/or function, ultimately allowing for improvements in the regenerative response to eccentric exercise. PMID- 25015640 TI - Alteration of naive and memory B-cell subset in chronic graft-versus-host disease patients after treatment with mesenchymal stromal cells. AB - Although mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the immune changes by which MSCs ameliorate cGVHD in vivo. Recent studies have suggested that B lymphocytes might play an important role in the pathogenesis of cGVHD. In this study, we investigated changes in the numbers, phenotypes, and subpopulations of B lymphocytes in cGVHD patients who showed a complete response (CR), partial response (PR), or no response (NR) after MSC treatment. We found that the frequencies and numbers of CD27+ memory and pre germinal center B lymphocytes were significantly increased in the CR and PR cGVHD patients after MSC treatment but decreased in the NR patients. A further analysis of CR/PR cGVHD patients showed that MSC treatment led to a decrease in the plasma levels of B cell-activating factor (BAFF) and increased expression of the BAFF receptor (BAFF-R) on peripheral B lymphocytes but no changes in plasma BAFF levels or BAFF-R expression on B lymphocytes in NR patients. Overall, our findings imply that MSCs might exert therapeutic effects in cGVHD patients, accompanied by alteration of naive and memory B-cell subsets, modulating plasma BAFF levels and BAFF-R expression on B lymphocytes. PMID- 25015641 TI - Concise review: injectable biomaterials for the treatment of myocardial infarction and peripheral artery disease: translational challenges and progress. AB - Recently, injectable biomaterial-based therapies for cardiovascular disease have been gaining attention, because they have shown therapeutic potential in preclinical models for myocardial infarction (MI) and peripheral artery disease (PAD). Naturally derived (e.g., alginate, hyaluronic acid, collagen, or extracellular matrix-based) or synthetic (e.g., peptide or polymer-based) materials can enhance stem cell survival and retention in vivo, prolong growth factor release from bulk hydrogel or particle constructs, and even stimulate endogenous tissue regeneration as a standalone therapy. Although there are many promising preclinical examples, the therapeutic potential of biomaterial-based products for cardiovascular disease has yet to be proved on a clinical and commercial scale. This review aims to briefly summarize the latest preclinical and clinical studies on injectable biomaterial therapies for MI and PAD. Furthermore, our overall goal is to highlight the major challenges facing translation of these therapies to the clinic (e.g., regulatory, manufacturing, and delivery), with the purpose of increasing awareness of the barriers for translating novel biomaterial therapies for MI and PAD and facilitating more rapid translation of new biomaterial technologies. PMID- 25015642 TI - Mechanisms of activation of mouse and human enteroendocrine cells by nutrients. AB - OBJECTIVE: Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. DESIGN AND RESULTS: mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p ERK in human in all EEC types and evoked potent release of all three mediators. CONCLUSIONS: Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes. PMID- 25015643 TI - A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling. AB - To discover new tumor-suppressor genes (TSG), we developed a functional genomics approach in which immortalized but nontumorigenic cells were stably transduced with large-scale shRNA pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly downregulated in human lung squamous cell carcinomas (hLSCC). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 amplification or activating mutations. SIGNIFICANCE: A functional genomics approach identifies new lung TSGs whose loss aberrantly increases FGFR signaling to promote tumorigenesis. These TSGs are frequently downregulated in hLSCCs, indicating that increased FGFR signaling promotes tumorigenesis in many hLSCCs lacking FGFR1 amplification or activating mutations. PMID- 25015644 TI - Cytonuclear evolution of rubisco in four allopolyploid lineages. AB - Allopolyploidization in plants entails the merger of two divergent nuclear genomes, typically with only one set (usually maternal) of parental plastidial and mitochondrial genomes and with an altered cytonuclear stoichiometry. Thus, we might expect cytonuclear coevolution to be an important dimension of allopolyploid evolution. Here, we investigate cytonuclear coordination for the key chloroplast protein rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), which is composed of nuclear-encoded, small subunits (SSUs) and plastid-encoded, large subunits. By studying gene composition and diversity as well as gene expression in four model allopolyploid lineages, Arabidopsis, Arachis, Brassica, and Nicotiana, we demonstrate that paralogous nuclear-encoded rbcS genes within diploids are subject to homogenization via gene conversion and that such concerted evolution via gene conversion characterizes duplicated genes (homoeologs) at the polyploid level. Many gene conversions in the polyploids are intergenomic with respect to the diploid progenitor genomes, occur in functional domains of the homoeologous SSUs, and are directionally biased, such that the maternal amino acid states are favored. This consistent preferential maternal-to-paternal gene conversion is mirrored at the transcriptional level, with a uniform transcriptional bias of the maternal-like rbcS homoeologs. These data, repeated among multiple diverse angiosperm genera for an important photosynthetic enzyme, suggest that cytonuclear coevolution may be mediated by intergenomic gene conversion and altered transcription of duplicated, now homoeologous nuclear genes. PMID- 25015645 TI - Evolution of Escherichia coli to 42 degrees C and subsequent genetic engineering reveals adaptive mechanisms and novel mutations. AB - Adaptive laboratory evolution (ALE) has emerged as a valuable method by which to investigate microbial adaptation to a desired environment. Here, we performed ALE to 42 degrees C of ten parallel populations of Escherichia coli K-12 MG1655 grown in glucose minimal media. Tightly controlled experimental conditions allowed selection based on exponential-phase growth rate, yielding strains that uniformly converged toward a similar phenotype along distinct genetic paths. Adapted strains possessed as few as 6 and as many as 55 mutations, and of the 144 genes that mutated in total, 14 arose independently across two or more strains. This mutational recurrence pointed to the key genetic targets underlying the evolved fitness increase. Genome engineering was used to introduce the novel ALE acquired alleles in random combinations into the ancestral strain, and competition between these engineered strains reaffirmed the impact of the key mutations on the growth rate at 42 degrees C. Interestingly, most of the identified key gene targets differed significantly from those found in similar temperature adaptation studies, highlighting the sensitivity of genetic evolution to experimental conditions and ancestral genotype. Additionally, transcriptomic analysis of the ancestral and evolved strains revealed a general trend for restoration of the global expression state back toward preheat stressed levels. This restorative effect was previously documented following evolution to metabolic perturbations, and thus may represent a general feature of ALE experiments. The widespread evolved expression shifts were enabled by a comparatively scant number of regulatory mutations, providing a net fitness benefit but causing suboptimal expression levels for certain genes, such as those governing flagellar formation, which then became targets for additional ameliorating mutations. Overall, the results of this study provide insight into the adaptation process and yield lessons important for the future implementation of ALE as a tool for scientific research and engineering. PMID- 25015646 TI - Large-scale genetic survey provides insights into the captive management and reintroduction of giant pandas. AB - The captive genetic management of threatened species strives to preserve genetic diversity and avoid inbreeding to ensure populations remain available, healthy, and viable for future reintroduction. Determining and responding to the genetic status of captive populations is therefore paramount to these programs. Here, we genotyped 19 microsatellite loci for 240 captive giant pandas (Ailuropoda melanoleuca) (~64% of the captive population) from four breeding centers, Wolong (WL), Chengdu (CD), Louguantai (LGT), and Beijing (BJ), and analyzed 655 bp of mitochondrial DNA control region sequence for 220 of these animals. High levels of genetic diversity and low levels of inbreeding were estimated in the breeding centers, indicating that the captive population is genetically healthy and deliberate further genetic input from wild animals is unnecessary. However, the LGT population faces a higher risk of inbreeding, and significant genetic structure was detected among breeding centers, with LGT-CD and WL-BJ clustering separately. Based on these findings, we highlight that: 1) the LGT population should be managed as an independent captive population to resemble the genetic distinctness of their Qinling Mountain origins; 2) exchange between CD and WL should be encouraged because of similar wild founder sources; 3) the selection of captive individuals for reintroduction should consider their geographic origin, genetic background, and genetic contribution to wild populations; and 4) combining our molecular genetic data with existing pedigree data will better guide giant panda breeding and further reduce inbreeding into the future. PMID- 25015647 TI - The loss of adipokine genes in the chicken genome and implications for insulin metabolism. AB - Gene loss is one of the main drivers in the evolution of genomes and species. The demonstration that a gene has been lost by pseudogenization is truly complete when one finds the pseudogene in the orthologous genomic region with respect to active genes in other species. In some cases, the identification of such orthologous loci is not possible because of chromosomal rearrangements or if the gene of interest has not yet been sequenced. This question is particularly important in the case of birds because the genomes of avian species possess only about 15,000 predicted genes, in comparison with 20,000 in mammals. Yet, gene loss raises the question of which functions are affected by the changes in gene counts. We describe a systematic approach that makes it possible to demonstrate gene loss in the chicken genome even if a pseudogene has not been found. By using phylogenetic and synteny analysis in vertebrates, genome-wide comparisons between the chicken genome and expressed sequence tags, RNAseq data analysis, statistical analysis of the chicken genome, and radiation hybrid mapping, we show that resistin, TNFalpha, and PAI-1 (SERPINE1), three genes encoding adipokines inhibiting insulin sensitivity, have been lost in chicken and zebra finch genomes. Moreover, omentin, a gene encoding an adipokine that enhances insulin sensitivity, has also been lost in the chicken genome. Overall, only one adipokine inhibiting insulin sensitivity and five adipokines enhancing insulin sensitivity are still present in the chicken genome. These genetic differences between mammals and chicken, given the functions of the genes in mammals, would have dramatic consequences on chicken endocrinology, leading to novel equilibriums especially in the regulation of energy metabolism, insulin sensitivity, as well as appetite and reproduction. PMID- 25015648 TI - selscan: an efficient multithreaded program to perform EHH-based scans for positive selection. AB - Haplotype-based scans to detect natural selection are useful to identify recent or ongoing positive selection in genomes. As both real and simulated genomic data sets grow larger, spanning thousands of samples and millions of markers, there is a need for a fast and efficient implementation of these scans for general use. Here, we present selscan, an efficient multithreaded application that implements Extended Haplotype Homozygosity (EHH), Integrated Haplotype Score (iHS), and Cross-population EHH (XPEHH). selscan accepts phased genotypes in multiple formats, including TPED, and performs extremely well on both simulated and real data and over an order of magnitude faster than existing available implementations. It calculates iHS on chromosome 22 (22,147 loci) across 204 CEU haplotypes in 353 s on one thread (33 s on 16 threads) and calculates XPEHH for the same data relative to 210 YRI haplotypes in 578 s on one thread (52 s on 16 threads). Source code and binaries (Windows, OSX, and Linux) are available at https://github.com/szpiech/selscan. PMID- 25015649 TI - Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization. AB - PURPOSE: In 2010, we reported that selenium (Se) supplementation during radiation therapy (RT) is effective for increasing blood Se levels in Se-deficient cervical and uterine cancer patients, and reduced the number of episodes and severity of RT-induced diarrhea. In the current study, we examine whether of Se supplementation during adjuvant RT affects long-term survival of these patients. PATIENTS AND METHODS: Former patients were identified and questioned with respect to their health and well-being. RESULTS: A total of 81 patients were randomized in the initial supplementation study, 39 of whom received Se (selenium group, SeG) and 42 of whom served as controls (control group, CG). When former patients were reidentified after a median follow-up of 70 months (range = 0-136), the actuarial 10-year disease-free survival rate in the SeG was 80.1% compared to 83.2% in the CG (P = .65), and the actuarial 10-year overall survival rate of patients in the SeG was 55.3% compared to 42.7% in the CG (P = .09). CONCLUSIONS: Our extended follow-up analysis demonstrates that Se supplementation had no influence on the effectiveness of the anticancer irradiation therapy and did not negatively affect patients' long-term survival. In view of its positive effects on RT-induced diarrhea, we consider Se supplementation to be a meaningful and beneficial adjuvant treatment in Se-deficient cervical and uterine cancer patients while undergoing pelvic radiation therapy. PMID- 25015650 TI - Upper limb robot-assisted therapy in cerebral palsy: a single-blind randomized controlled trial. AB - BACKGROUND: Several pilot studies have evoked interest in robot-assisted therapy (RAT) in children with cerebral palsy (CP). OBJECTIVE: To assess the effectiveness of RAT in children with CP through a single-blind randomized controlled trial. PATIENTS AND METHODS: Sixteen children with CP were randomized into 2 groups. Eight children performed 5 conventional therapy sessions per week over 8 weeks (control group). Eight children completed 3 conventional therapy sessions and 2 robot-assisted sessions per week over 8 weeks (robotic group). For both groups, each therapy session lasted 45 minutes. Throughout each RAT session, the patient attempted to reach several targets consecutively with the REAPlan. The REAPlan is a distal effector robot that allows for displacements of the upper limb in the horizontal plane. A blinded assessment was performed before and after the intervention with respect to the International Classification of Functioning framework: body structure and function (upper limb kinematics, Box and Block test, Quality of Upper Extremity Skills Test, strength, and spasticity), activities (Abilhand-Kids, Pediatric Evaluation of Disability Inventory), and participation (Life Habits). RESULTS: During each RAT session, patients performed 744 movements on average with the REAPlan. Among the variables assessed, the smoothness of movement (P < .01) and manual dexterity assessed by the Box and Block test (P = .04) improved significantly more in the robotic group than in the control group. CONCLUSIONS: This single-blind randomized controlled trial provides the first evidence that RAT is effective in children with CP. Future studies should investigate the long-term effects of this therapy. PMID- 25015651 TI - The acceptability of different HIV testing approaches: cross-sectional study among GMSM in Australia. AB - BACKGROUND: We explored the attitudes of Australian gay and other men who have sex with men (GMSM) about the current standard-of-care (non-rapid tests at healthcare settings) and alternative approaches (rapid tests and testing in non healthcare settings) to better understand the acceptability of alternative testing approaches. METHODS: The Contemporary Norms in Networks and Communities of GMSM study enrolled GMSM in Sydney, Melbourne and Perth in 2011-2012 using peer referrals. We explored the self-reported preferences for testing: rapid versus non-rapid and in non-healthcare settings (community-based or home-based testing) versus in healthcare settings, and examined factors associated with preferences for these approaches. Analyses of associations used standard univariate and age-adjusted logistic regression models. RESULTS: Among 827 sexually active non-HIV-positive participants, 89% had been tested for HIV. Most preferred by participants was home rapid testing (46%), followed by standard-of care (23%) and rapid testing in healthcare (20%) or community settings (7%). About 73% of participants preferred rapid over non-rapid testing, and 56% preferred testing in non-healthcare settings rather than in healthcare settings. Preference for rapid testing was associated with being fully employed (adjusted OR (aOR): 1.81; 95% CI 1.16 to 2.82), managerial/professional occupation (aOR: 2.03; 95% CI 1.19 to 3.46) and engaging in unprotected anal intercourse with casual partners (aOR: 1.89; 95% CI 1.29 to 2.78). The same factors were associated with preference for testing in non-healthcare settings. CONCLUSIONS: Australian GMSM prefer alternative testing approaches, possibly due to their convenience. The availability of new testing approaches may provide more options for GMSM at risk for HIV infection, improve access to HIV testing and potentially increase HIV testing rates. PMID- 25015652 TI - Cellulose acetate butyrate/poly(caprolactonetriol) blends: Miscibility, mechanical properties, and in vivo inflammatory response. AB - This study reports the results of the characterization of cellulose acetate butyrate and polycaprolactone-triol blends in terms of miscibility, swelling capacity, mechanical properties, and inflammatory response in vivo. The cellulose acetate butyrate film was opaque and rigid, with glass transition (T g ) at 134C and melting temperature of 156C. The cellulose acetate butyrate/polycaprolactone triol films were transparent up to a polycaprolactone-triol content of 60%. T g of the cellulose acetate butyrate films decreased monotonically as polycaprolactone-triol was added to the blend, thus indicating miscibility. FTIR spectroscopy revealed a decrease in intramolecular hydrogen bonding in polycaprolactone-triol, whereas no hydrogen bonding was observed between cellulose acetate butyrate and -OH from polycaprolactone-triol. The increase in polycaprolactone-triol content in the blend decreased the water uptake. An increase in polycaprolactone-triol content decreased the modulus of elasticity and increased the elongation at break. A cellulose acetate butyrate/polycaprolactone-triol 70/30 blend implanted in rats showed only an acute inflammatory response 7 days after surgery. No change in inflammation mediators was observed. PMID- 25015653 TI - Enhanced bone healing around nanohydroxyapatite-coated polyetheretherketone implants: An experimental study in rabbit bone. AB - OBJECTIVE: To investigate the bone response to threaded polyetheretherketone (PEEK) implants coated with nanohydroxyapatite. MATERIALS AND METHODS: A total of 39 PEEK implants were coated with nanocrystalline hydroxyapatite and 39 uncoated implants were used as controls. The implant surface was characterized by optical interferometry and scanning electron microscope. The implants were inserted in the tibia and femur of 13 rabbits. After 6 weeks of healing, quantitative and qualitative analyses were performed. RESULTS: The test implants showed significantly higher removal torque test values compared with the control group. Histomorphometric evaluation demonstrated higher bone-to-implant contact for the test implants; however, there were no differences in bone area between the groups. Qualitative histological analyses demonstrated inflammatory cellular reactions in close vicinity of both implant surfaces. A two-cell layer of foreign body giant cells was observed irrespective of sample type. CONCLUSION: Our findings demonstrate that implants with a threaded design render good stability to PEEK in both coated and uncoated implants. Nanohydroxyapatite-coated PEEK implants demonstrated improved bone formation compared with uncoated controls. PMID- 25015654 TI - Aortic root thrombosis after HeartWare implantation. PMID- 25015655 TI - A mouse strain less responsive to dioxin-induced prostaglandin E2 synthesis is resistant to the onset of neonatal hydronephrosis. AB - Dioxin is a ubiquitous environmental pollutant that induces toxicity when bound to the aryl hydrocarbon receptor (AhR). Significant differences in susceptibility of mouse strains to dioxin toxicity are largely accounted for by the dissociation constant of binding to dioxins of AhR subtypes encoded by different alleles. We showed that cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), components of a prostanoid synthesis pathway, play essential roles in the onset of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hydronephrosis of neonatal mice. Although C57BL/6J and BALB/cA mice harbor AhR receptors highly responsive to TCDD, they were found by chance to differ significantly in the incidence of TCDD-induced hydronephrosis. Therefore, the goal of the present study was to determine the molecular basis of this difference in susceptibility to TCDD toxicity. For this purpose, we administered C57BL/6J and BALB/cA dams' TCDD at an oral dose of 15 or 80 MUg/kg on postnatal day (PND) 1 to expose pups to TCDD via lactation, and the pups' kidneys were collected on PND 7. The incidence of hydronephrosis in C57BL/6J pups (64%) was greater than in BALB/cA pups (0%, p < 0.05), despite similarly increased levels of COX-2 mRNA. The incidence of hydronephrosis in these mouse strains paralleled the levels of renal mPGES-1 mRNA and early growth response 1 (Egr-1) that modulates mPGES-1 gene expression, as well as PGE2 concentrations in urine. Although these mouse strains possess AhR alleles tightly bound to TCDD, their difference in incidence and severity of hydronephrosis can be explained, in part, by differences in the expression of mPGES-1 and Egr-1. PMID- 25015656 TI - MicroRNA-155 deficient mice experience heightened kidney toxicity when dosed with cisplatin. AB - The development of nephrotoxicity limits the maximum achievable dosage and treatment intervals for cisplatin chemotherapy. Therefore, identifying mechanisms that regulate this toxicity could offer novel methods to optimize cisplatin delivery. MicroRNAs are capable of regulating many different genes, and can influence diverse cellular processes, including cell death and apoptosis. We previously observed miR-155 to be highly increased following ischemic or toxic injury to the kidneys and, therefore, sought to determine whether mice deficient in miR-155 would respond differently to kidney injury. We treated C57BL/6 and miR 155(-/-) mice with 20 mg/kg of cisplatin and found a significantly higher level of kidney injury in the miR-155(-/-) mice. Genome-wide expression profiling and bioinformatic analysis indicated the activation of a number of canonical signaling pathways relating to apoptosis and oxidative stress over the course of the injury, and identified potential upstream regulators of these effects. One predicted upstream regulator was c-Fos, which has two confirmed miR-155 binding sites in its 3' UTR and, therefore, can be directly regulated by miR-155. We established that the miR-155(-/-) mice had significantly higher levels of c-Fos mRNA and protein than the C57BL/6 mice at 72 h after cisplatin exposure. These data indicate a role for miR-155 in the cisplatin response and suggest that targeting of c-Fos could be investigated to reduce cisplatin-induced nephrotoxicity. PMID- 25015657 TI - MDR1 transporter protects against paraquat-induced toxicity in human and mouse proximal tubule cells. AB - Paraquat is a herbicide that is highly toxic to the lungs and kidneys following acute exposures. Prior studies have demonstrated that the organic cation transporter 2 and multidrug and toxin extrusion protein 1 contribute to the urinary secretion of paraquat in the kidneys. The purpose of this study was to determine whether the multidrug resistance protein 1 (MDR1/Mdr1, ABCB1, or P glycoprotein) also participates in the removal of paraquat from the kidneys and protects against renal injury. Paraquat transport and toxicity were quantified in human renal proximal tubule epithelial cells (RPTEC) that endogenously express MDR1, HEK293 cells overexpressing MDR1, and Mdr1a/1b knockout mice. In RPTEC cells, reduction of MDR1 activity using the antagonist PSC833 or siRNA transfection increased the cellular accumulation of paraquat by 50%. Reduced efflux of paraquat corresponded with enhanced cytotoxicity in PSC833-treated cells. Likewise, stable overexpression of the human MDR1 gene in HEK293 cells reduced intracellular levels of paraquat by 50%. In vivo studies assessed the renal accumulation and subsequent nephrotoxicity of paraquat (10 or 30 mg/kg ip) in wild-type and Mdr1a/1b knockout mice. At 4 h after paraquat treatment, renal concentrations of paraquat in the kidneys of Mdr1a/1b knockout mice were 750% higher than wild-type mice. By 72 h, paraquat-treated Mdr1a/1b knockout mice had more extensive tubular degeneration and significantly greater mRNA expression of kidney injury-responsive genes, including kidney injury molecule-1, lipocalin-2, and NAD(P)H quinone oxidoreductase 1, compared with wild-type mice. In conclusion, MDR1/Mdr1 participates in the elimination of paraquat from the kidneys and protects against subsequent toxicity. PMID- 25015658 TI - Fas-induced apoptosis increases hepatocyte tissue factor procoagulant activity in vitro and in vivo. AB - Hepatocyte (HPC) apoptosis occurs in association with hepatotoxic responses and chronic liver disease, and is coupled to activation of the blood coagulation cascade. HPCs have been shown to express tissue factor (TF), the primary activator of blood coagulation, in a form that lacks procoagulant activity. In this study, we determined the effect of inducing HPC apoptosis on the procoagulant activity of TF. Treatment of primary mouse HPCs with the Fas death receptor agonist (anti-CD95 antibody, Jo2) triggered apoptosis as shown by cleavage of caspase-3, increased caspase-3 proteolytic activity, and cell surface exposure of phosphatidylserine (PS). Jo2-induced apoptosis significantly increased TF-dependent factor Xa generation by HPCs. Moreover, Jo2 treatment was associated with increased levels of microparticle-associated TF procoagulant activity in the culture medium. Pretreatment with a caspase-3 inhibitor significantly reduced Jo2-induced HPC TF activity and prevented the increase in microparticle-associated TF procoagulant activity. Application of the high affinity PS-binding protein lactadherin inhibited TF-dependent factor Xa generation by Jo2-treated HPCs and dramatically reduced microparticle-associated TF procoagulant activity. Treatment of wild-type mice with a sublethal dose of Jo2 was associated with a robust increase in the activation of coagulation as measured by plasma thrombin-antithrombin (TAT) levels; whereas mice with liver specific TF deficiency had significantly lower TAT levels. Overall, the results indicate that Fas-initiated, caspase-3-dependent HPC apoptosis increases TF procoagulant activity through a mechanism involving PS externalization. This suggests that activation of liver TF likely contributes to the procoagulant state associated with HPC apoptosis in liver toxicity and disease. PMID- 25015659 TI - Initial biological qualification of SBDP-145 as a biomarker of compound-induced neurodegeneration in the rat. AB - Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid alpha-II spectrin is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic acid, bromethalin, and pentylenetetrazole) known to affect different portions of the brain were administered to rats in dose-response and time-course studies in which neurodegeneration was measured by histopathology and SBDP-145 concentrations in CSF were measured by ELISA. We consistently observed >3-fold increases in SBDP 145 concentration in rats with minimal to slight neurodegenerative lesions, and 20 to 150-fold increases in animals with more severe lesions. In contrast, compounds that caused non-degenerative changes in central nervous system (CNS) did not increase SBDP-145 in CSF. These data support expanded use of SBDP-145 as a biomarker for monitoring compound-induced neurodegeneration in pre-clinical studies, and support the investigation of clinical applications of this biomarker to promote safe dosing of patients with compounds that have potential to cause neurodegeneration. PMID- 25015660 TI - Physiologically-based toxicokinetic model for cadmium using Markov-chain Monte Carlo analysis of concentrations in blood, urine, and kidney cortex from living kidney donors. AB - The health effects of low-level chronic exposure to cadmium are increasingly recognized. To improve the risk assessment, it is essential to know the relation between cadmium intake, body burden, and biomarker levels of cadmium. We combined a physiologically-based toxicokinetic (PBTK) model for cadmium with a data set from healthy kidney donors to re-estimate the model parameters and to test the effects of gender and serum ferritin on systemic uptake. Cadmium levels in whole blood, blood plasma, kidney cortex, and urinary excretion from 82 men and women were used to calculate posterior distributions for model parameters using Markov chain Monte Carlo analysis. For never- and ever-smokers combined, the daily systemic uptake was estimated at 0.0063 MUg cadmium/kg body weight in men, with 35% increased uptake in women and a daily uptake of 1.2 MUg for each pack-year per calendar year of smoking. The rate of urinary excretion from cadmium accumulated in the kidney was estimated at 0.000042 day(-1), corresponding to a half-life of 45 years in the kidneys. We have provided an improved model of cadmium kinetics. As the new parameter estimates derive from a single study with measurements in several compartments in each individual, these new estimates are likely to be more accurate than the previous ones where the data used originated from unrelated data sets. The estimated urinary excretion of cadmium accumulated in the kidneys was much lower than previous estimates, neglecting this finding may result in a marked under-prediction of the true kidney burden. PMID- 25015661 TI - Epigenetic changes in p21 expression in renal cells after exposure to bromate. AB - This study tested the hypothesis that bromate (KBrO3)-induced renal cell death is mediated by epigenetic mechanisms. Global DNA methylation, as assessed by 5 methylcytosine staining, was not changed in normal rat kidney cells treated with acute cytotoxic doses of KBrO3 (100 and 200 ppm), as compared with controls. However, KBrO3 treatment did increase p38, p53 and histone 2AX (H2AX) phosphorylation, and p21 expression. Treatment of cells with inhibitors of DNA methyltransferase (5-azacytidine or 5-Aza) and histone deacetylase (trichostatin A or TSA) in addition to KBrO3 increased cytotoxicity, as compared with cells exposed to KBrO3 alone. 5-Aza and TSA co-treatment did not alter p38 or p53 phosphorylation, but slightly decreased H2AX phosphorylation and significantly decreased p21 expression. We also assessed epigenetic changes in cells treated under sub-chronic conditions with environmentally relevant concentrations of KBrO3. Under these conditions (0-10ppm KBrO3 for up to 18 days), we detected no increases in cell death or DNA damage. In contrast, slight alterations were detected in the phosphorylation of H2AX, p38, and p53. Sub-chronic low-dose KBrO3 treatment also induced a biphasic response in p21 expression, with lower concentrations increasing expression, but higher concentrations decreasing expression. Methylation-specific PCR demonstrated that sub-chronic KBrO3 treatment altered the methylation of cytosine bases in the p21 gene, as compared with controls, correlating to alterations in p21 protein expression. Collectively, these data show the novel finding that KBrO3-induced renal cell death is altered by inhibitors of epigenetic modifying enzymes and that KBrO3 itself induces epigenetic changes in the p21 gene. PMID- 25015662 TI - In vivo interactions between cobalt or ferric compounds and the pools of sulphide in the blood during and after H2S poisoning. AB - Hydrogen sulphide (H2S), a chemical hazard in oil and gas production, has recently become a dreadful method of suicide, posing specific risks and challenges for the first responders. Currently, there is no proven effective treatment against H2S poisoning and its severe neurological, respiratory or cardiac after-effects. We have recently described that H2S is present in various compartments, or pools, in the body during sulphide exposure, which have different levels of toxicity. The general goals of our study were to (1) determine the concentrations and kinetics of the various pools of hydrogen sulphide in the blood, i.e., gaseous (CgH2S) versus total sulphide, i.e., reacting with monobromobimane (CMBBH2S), during and following H2S exposure in a small and large mammal and (2) establish the interaction between the pools of H2S and a methemoglobin (MetHb) solution or a high dose of hydroxocobalamin (HyCo). We found that CgH2S during and following H2S infusion was similar in sedated sheep and rats at any given rate of infusion/kg and provoked symptoms, i.e., hyperpnea and apnea, at the same CgH2S. After H2S administration was stopped, CgH2S disappeared within 1 min. CMBBH2S also dropped to 2-3MUM, but remained above baseline levels for at least 30 min. Infusion of a MetHb solution during H2S infusion produced an immediate reduction in the free/soluble pool of H2S only, whereas CMBBH2S increased by severalfold. HyCo (70 mg/kg) also decreased the concentrations of free/soluble H2S to almost zero; CgH2S returned to pre-HyCo levels within a maximum of 20 min, if H2S infusion is maintained. These results are discussed in the context of a relevant scenario, wherein antidotes can only be administered after H2S exposure. PMID- 25015664 TI - Imaging cone photoreceptor inner segments in the living human eye. PMID- 25015663 TI - Reduced foodborne toxin exposure is a benefit of improving dietary diversity. AB - Naturally occurring foodborne toxins are common in subsistence diets of low income human populations worldwide. Often, these populations rely on one or two staple foods for the bulk of their calories, making them more susceptible to chronic intake of certain toxins. Exposure to common foodborne toxins is associated with diverse conditions such as cancer, immunotoxicity, growth impairment, and neurological deficits. Interventions focused solely on reducing toxin levels have proven difficult to sustain. Using case studies of two foodborne toxins, aflatoxin and cassava cyanide, this article addresses the heightened risk of particular diseases from eating monotonous diets based in maize, groundnuts, and cassava: common in sub-Saharan Africa and parts of Asia. We also discuss the potential role of increased dietary diversity in counteracting these diseases. Increased dietary diversity can reduce consumption of toxins and increase intake of nutrients that could counteract the toxicity of such chemicals. In Qidong, China, a population that previously consumed a monotonous maize-based diet and increased dietary diversity since the 1980s has experienced a dramatic reduction in liver cancer mortalities. That liver cancer decreased as dietary diversity increased is the catalyst for the hypothesis that dietary diversity could have a direct impact on reducing health effects of foodborne toxins. Future research, agricultural development, and food policy reforms should take into consideration the multifaceted benefits associated with improved dietary diversity. Collaborations between toxicologists, nutritionists, and policymakers are important to development of sustainable interventions to reduce foodborne toxin exposure and promote health through increased dietary diversity. PMID- 25015665 TI - Accuracy and reproducibility of a rapid chromatographic immunoassay for the diagnosis of canine visceral leishmaniasis in Brazil. AB - BACKGROUND: Visceral leishmaniasis is a major public health concern in Brazil and the domestic dog is the main source of infection. In this study, we aimed to evaluate the accuracy and reliability of a rapid chromatographic immunoassay based on a dual-path platform for the diagnosis of canine visceral leishmaniasis (CVL). METHODS: Sampling consisted of 428 domestic dogs selected from two neighborhoods in the municipality of Fortaleza, Ceara state, Brazil. The reference standard was composed of three parasitological tests and was applied samples from 333 dogs. The rapid test was used to analyse whole blood and serum samples. RESULTS: Accuracy of the rapid test in whole blood samples through visual reading (n=305), serum samples through electronic reading (n=333) and serum samples through visual reading (n=333), yielded sensitivities of 87.5% (21/24; 95% CI: 66.5 to 96.7), 88% (22/25; 95% CI: 67.5 to 96.8) and 88% (22/25; 95% CI: 67.5 to 96.8), and specificities of 73.3% (206/281; 95% CI: 67.7 to 78.4), 68.2% (210/308; 95% CI: 62.2 to 74.3) and 69.2% (213/308; 95% CI: 63.7 to 74.3), respectively. Agreement between the visual and electronic readings in 428 serum samples were classified as almost perfect (Kappa Index=0.88; 95% CI: 0.83 to 0.93). The positive predictive value of the test using whole blood samples was 21.9% for the 7.9% prevalence detected by the reference standard in the study sample. A sensitivity analysis of the positive predictive value revealed that it remained below 50% in scenarios with a prevalence of up to 20%. CONCLUSIONS: The similarity of the accuracy values of the rapid test using whole blood or serum samples, together with its reliable performance in sera through visual and electronic reading, suggests that it may contribute as a screening test for routine use under field-conditions. However, future studies need to improve the accuracy of the test so that it can be successfully implemented in public health programs. PMID- 25015666 TI - A novel periodic boundary condition for computational hemodynamics studies. AB - In computational fluid dynamics models for hemodynamics applications, boundary conditions remain one of the major issues in obtaining accurate fluid flow predictions. For major cardiovascular models, the realistic boundary conditions are not available. In order to address this issue, the whole computational domain needs to be modeled, which is practically impossible. For simulating fully developed turbulent flows using the large eddy simulation and dynamic numerical solution methods, which are very popular in hemodynamics studies, periodic boundary conditions are suitable. This is mainly because the computational domain can be reduced considerably. In this study, a novel periodic boundary condition is proposed, which is based on mass flow condition. The proposed boundary condition is applied on a square duct for the sake of validation. The mass-based condition was shown to obtain the solution in 15% less time. As such, the mass based condition has two decisive advantages: first, the solution for a given Reynolds number can be obtained in a single simulation because of the direct specification of the mass flow, and second, simulations can be made more quickly. PMID- 25015669 TI - Colonic cribriform carcinoma, a morphologic pattern associated with low survival. AB - Colorectal carcinoma is one of the most common cancers in the human body. Colorectal carcinoma is a heterogeneous disease with variegated morphological patterns; some have shown themselves to have prognostic value. The World Health Organization classification recognizes many histological variants associated with adverse prognostic factors, one is the cribriform colonic carcinoma (CCC). In this work, we analyzed 18 cases of CCC compared with 228 conventional adenocarcinomas of colon, with the hypotheses that CCC compared with non-CCC have worse prognosis and decreased overall survival. CCC represent 7.3% of all colonic adenocarcinomas in this series, it presents in a median age of 56.3 years, all cases are in clinical stage III and IV, all invade subserosal adipose tissues or serosa, 90% have >5 positive lymph nodes and 89% have lymphovascular invasion. These known adverse prognostic factors reflect a lower 5-year survival, stage by stage, than conventional intestinal-type adenocarcinoma (56.8% vs 83.3%, P = .035). Cribriform carcinoma is a morphologic pattern that is underrecognized; in this work, we demonstrate its association with low survival, extensive lymphovascular invasion, and extensive lymph node metastasis, strong indicators of aggressive disease. Their proper recognition is mandatory to increase the number of cases and series to support our findings and include it in the current classifications. PMID- 25015670 TI - Jaw cysts diagnosed in an Italian population over a 20-year period. AB - BACKGROUND: Cysts of the jaws (JCs) are an important topic of oral pathology, but few epidemiological data are present in the literature, in particular about the potential of recurrence. The aim of this study was to describe a case series of JCs from a single institution, evaluating the frequency, the site, the age distribution, and the percentage of recurrence of all types of JCs. METHODS: All JCs present in the histological records of the Section of Anatomic Pathology of the University of Bologna at Bellaria Hospital from 1992 to 2012 were retrieved. RESULTS: A total of 1136 jaws cysts were obtained, of which 1117 (98.3%) were odontogenic and 19 (1.7%) were nonodontogenic. About odontogenic cysts (OCs), the most frequent was the radicular cyst (538 cases), followed by parakeratinized keratocystic odontogenic tumor (pKOT, 193 cases) and dentigerous cyst (120 cases). Among pKOT, 21 out of 193 cases (10.89%) showed a recurrence after a mean time of 4.5 years (range, 1-12 years). During follow-up (mean 11 years, range 1 19 years), all 3 cases of botrioid cysts, 12 out of 46 cases of unicystic ameloblastoma (26.09%), 2 out of 20 cases of calcifying OCs (10%) and 2 out of 538 cases of radicular cyst (0.37%) showed a recurrence. CONCLUSION: Our study confirms that the distribution pattern of JCs in Italy is relatively similar to other studies worldwide and emphasizes the importance of recognizing the different histological types of JCs for their potential local aggressive behavior. PMID- 25015668 TI - Enhancing reproducibility in cancer drug screening: how do we move forward? AB - Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers. Subsequent evaluation, however, found only moderate interlaboratory concordance in the drug response phenotypes, possibly due to differences in the experimental protocols used in the two studies. This highlights the need for community-wide implementation of standardized assays for measuring drug response phenotypes so that the full potential of HTS is realized. We suggest that the path forward is to establish best practices and standardization of the critical steps in these assays through a collective effort to ensure that the data produced from large-scale screens would not only be of high intrastudy consistency, so that they could be replicated and compared successfully across multiple laboratories. PMID- 25015667 TI - Evolution of HIV-1 tropism at quasispecies level after 5 years of combination antiretroviral therapy in patients always suppressed or experiencing episodes of virological failure. AB - OBJECTIVES: Tropism evolution of HIV-1 quasispecies was analysed by ultra-deep pyrosequencing (UDPS) in patients on first-line combination antiretroviral therapy (cART) always suppressed or experiencing virological failure episodes. METHODS: Among ICONA patients, two groups of 20 patients on cART for >=5 years, matched for baseline viraemia and therapy duration, were analysed [Group I, patients always suppressed; and Group II, patients experiencing episode(s) of virological failure]. Viral tropism was assessed by V3 UDPS on plasma RNA before therapy (T0) and on peripheral blood mononuclear cell proviral DNA before-after therapy (T0-T1), using geno2pheno false positive rate (FPR) (threshold for X4: 5.75). For each sample, quasispecies tropism was assigned according to X4 variant frequency: R5, <0.3% X4; minority X4, 0.3%-19.9% X4; and X4, >=20% X4. An R5-X4 switch was defined as a change from R5/minority X4 in plasma/proviral genomes at T0 to X4 in provirus at T1. RESULTS: At baseline, mean FPR and %X4 of viral RNA were positively correlated with those of proviral DNA. After therapy, proviral DNA load significantly decreased in Group I; mean FPR of proviral quasispecies significantly decreased and %X4 increased in Group II. An R5-X4 switch was observed in five patients (two in Group I and three in Group II), all harbouring minority X4 variants at T0. CONCLUSIONS: UDPS analysis reveals that the tropism switch is not an 'on-off' phenomenon, but may result from a profound re-shaping of viral quasispecies, even under suppressive cART. However, episodes of virological failure seem to prevent reduction of proviral DNA and to accelerate viral evolution, as suggested by decreased FPR and increased %X4 at T1 in Group II patients. PMID- 25015672 TI - Late-onset radiation-induced vasculopathy and stroke in a child with medulloblastoma. AB - We report a case of a 15-year-old boy who presented to our institution with left sided weakness and slurred speech. He had a history of medulloblastoma diagnosed at 3 years of age, status postsurgical resection and craniospinal radiation. Magnetic resonance imaging (MRI) of brain revealed a right paramedian pontine infarction, suspected secondary to late-onset radiation-induced vasculopathy of the vertebrobasilar system. Radiation to the brain is associated with increased incidence of ischemic stroke. Clinicians should have a high index of suspicion for stroke when these patients present with new neurologic symptoms. PMID- 25015671 TI - Epidemiology of Giardia duodenalis infection in ruminant livestock and children in the Ismailia province of Egypt: insights by genetic characterization. AB - BACKGROUND: Giardia duodenalis is a common flagellated protozoan parasite that infects the small intestine of a wide range of vertebrate hosts. This study aimed to determine whether tracing of G. duodenalis isolates by current genetic typing tools is possible using an exemplary set of samples from infected cattle, buffalo and children from the Ismailia province, Egypt. METHOD: A total of 804 fecal samples from ruminant animals was collected from 191 herds and 165 samples from diarrheal children below the age of 10 years. Parasites were detected in these samples using the copro-antigen RIDA(r)QUICK test and by real-time PCR. Samples were then genetically characterized based on the triosephosphate isomerase, glutamate dehydrogenase and beta-giardin genes. RESULTS: The prevalence of G. duodenalis was 53% in ruminants and 21% in symptomatic children and infection was not positively correlated with diarrheal symptoms. Sequence typing analysis confirmed predominance of B-type sequences (>67%) in humans and E-type sequences (>81%) in ruminants over A-type sequences. For 39 samples the complete sequence information of the three marker gene fragments could be derived. Integration of the concatenated sequence information of the three marker gene fragments with the spatial data of the respective sample revealed that identical or near identical (only up to 1 out of 1358 bp different) concatenated sequencing types were spatially related in 4 out of 5 cases. CONCLUSION: The risk of zoonotic infection emanating from ruminants even in high prevalence areas is negligible. Genetic characterization indicated a predominant anthropogenic cycle of infection within the pediatric population studied. Integration of sequence typing data with information on geographic origins of samples allows parasite sub-population tracing using current typing tools. PMID- 25015673 TI - Three patients with lafora disease: different clinical presentations and a novel mutation. AB - Lafora disease is a rare, fatal, autosomal recessive hereditary disease characterized by epilepsy, myoclonus and progressive neurological deterioration. Diagnosis is made by polyglucosan inclusion bodies (Lafora bodies) shown in skin biopsy. Responsible mutations of Lafora disease involves either the EPM2A or NHLRC1 (EPM2B) gene. Mutations in the NHLRC1 gene are described as having a more benign clinical course and a later age of death compared with EPM2A mutations. We report 2 genetic mutations and clinical courses of Lafora disease in 3 adolescents with homozygote NHLRC1 mutation and novel homozygous EPM2A mutation. PMID- 25015674 TI - Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma. AB - Uterine leiomyoma (UL), the most common benign tumour found in females, is associated with many recurrent genetic aberrations, such as translocations, interstitial deletions and specific germline mutations. Among these, mutations affecting exon 2 of the mediator complex subunit 12 (MED12) gene are commonly detected in the majority of ULs. Mutational analysis of the MED12 gene, performed on 36 UL samples, revealed that 12 leiomyomas (33.4%) exhibited heterozygous missense mutations in codon 44 of exon 2 of the MED12 gene, four leiomyomas (11.1%) showed internal in-frame deletions, and two leiomyomas (5.5%) exhibited deletions involving intron 1-exon 2 junction, which caused a predicted loss of the splice acceptor. No mutations were detected in uterine myometrium (UM) and pseudocapsule (PC) samples, including those from women with a MED12 mutation in UL. These data showed that the PC is a healthy tissue that surrounds the UL to maintain UM integrity. Analysis of insulin-like growth factor 2 (IGF-2) and collagen type IV alpha 2 (COL4A2) mRNA expression levels in the same set of ULs revealed that only those with MED12 missense mutations expressed significantly higher levels of IGF-2 mRNA. In contrast, MED12 gene status does not appear to affect mRNA expression levels of the COL4A2 gene. On the basis of this finding, we suggest that the MED12 status stratifies the ULs into two mutually exclusive pathways of leiomyoma genesis, one with IGF-2 overexpression and the other with no IGF-2 activation. The occurrence of IGF-2 overexpression could be therapeutically targeted for the non-surgical treatment of leiomyomas. PMID- 25015675 TI - High-resolution helium ion microscopy of epididymal epithelial cells and their interaction with spermatozoa. AB - We examined the rat and mouse epididymis using helium ion microscopy (HIM), a novel imaging technology that uses a scanning beam of He(+) ions to produce nanometer resolution images of uncoated biological samples. Various tissue fixation, sectioning and dehydration methods were evaluated for their ability to preserve tissue architecture. The cauda epididymidis was luminally perfused in vivo to remove most spermatozoa and the apical surface of the epithelial lining was exposed. Fixed epididymis samples were then subjected to critical point drying (CPD) and HIM. Apical stereocilia in principal cells and smaller apical membrane extensions in clear cells were clearly distinguishable in both rat and mouse epididymis using this technology. After perfusion with an activating solution containing CPT-cAMP, a permeant analog of cAMP, clear cells exhibited an increase in the number and size of membrane ruffles or microplicae. In contrast, principal cells did not exhibit detectable structural modifications. High resolution HIM imaging clearly showed the ultrastructure of residual sperm cells, including the presence of concentric rings on the midpiece, and of cytoplasmic droplets in some spermatozoa. Close epithelium-sperm interactions were also detected. We found a number of sperm cells whose heads were anchored within the epididymal epithelium. In certain cases, the surface of the sperm cytoplasmic droplet was covered with vesicle-like structures whose size is consistent with that of epididymosomes. In conclusion, we describe here the first application of HIM technology to the study of the structure and morphology of the rodent epididymis. HIM technology represents a major imaging breakthrough that can be successfully applied to study the epididymis and spermatozoa, with the goal of advancing our understanding of their structure and function. PMID- 25015676 TI - Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients. AB - BACKGROUND: To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC). METHODS: CTCBL and CTC1C status was determined as negative (-) or positive (+) for < 5 or >= 5 CTCs/7.5 ml blood using CellSearchTM (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2-3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS. RESULTS: 133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5-3.2) and 2.9 (0.5-4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7-6.1] vs. 7.8 [6.4-9.2]; OS 10.4 [7.9 15.0] vs. 27.2 [22.3-29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6 6.0] vs. 8.5 [6.6-10.4]; OS 7.7 [6.4-13.9] vs. 30.6 [22.6-not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, >= 3rd-line therapy, and triple negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, >= 3rd-line therapy, and triple negative receptor status). CONCLUSIONS: CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC. TRIAL REGISTRATION: Not applicable. PMID- 25015677 TI - Idiomarina planktonica sp. nov., isolated from a saline lake. AB - A Gram-stain-negative bacterium, strain TS-T11(T), was isolated from Tuosu lake, a saline lake (salinity 5.4%, w/v) in the Qaidam basin, Qinghai province, China. Its taxonomic position was determined by using a polyphasic approach. Cells of strain TS-T11(T) were non-spore-forming rods, 0.6-0.8 um wide and 0.8-2.2 um long, and motile by means of a single polar flagellum. Strain TS-T11(T) was strictly heterotrophic and aerobic. Cells were positive for catalase and oxidase. Growth was observed in the presence of 0.5-11.0% (w/v) NaCl (optimum 4.0-6.0%), at 4-40 degrees C (optimum 30-35 degrees C) and at pH 6.0-10.5 (optimum pH 7.5 8.5). Strain TS-T11(T) contained iso-C15:0, iso-C17:0 and iso-C17:1omega9c as the predominant fatty acids (>10%). The major respiratory quinone was Q-8. The polar lipids consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and nine uncharacterized phospholipids. The G+C content of genomic DNA was 46.8 mol% (Tm). Phylogenetic trees based on 16S rRNA gene sequences showed that strain TS-T11(T) was associated with the genus Idiomarina, and showed highest 16S rRNA gene sequence similarity to Idiomarina aestuarii KYW314(T) (97.4%) and Idiomarina salinarum ISL-52(T) (97.4%). DNA-DNA relatedness of strain TS-T11(T) to I. aestuarii JCM 16344(T) and I. salinarum DSM 21900(T) was 22.2 +/- 2.4 and 11.5 +/- 1.6%, respectively. Based on the data presented above, it was concluded that strain TS-T11(T) represents a novel species of the genus Idiomarina, for which the name Idiomarina planktonica sp. nov. is proposed. The type strain is TS-T11(T) ( = CGMCC 1.12458(T) = JCM 19263(T)). PMID- 25015678 TI - Acinetobacter guangdongensis sp. nov., isolated from abandoned lead-zinc ore. AB - A Gram-stain-negative, non-motile bacterial strain designated 1NM-4(T) was isolated from an abandoned lead-zinc ore mine site in Mei County, Meizhou, Guangdong Province, southern China. The isolate was light yellow, strictly aerobic, oxidase-negative and catalase-positive. Phylogenetic analyses based on 16S rRNA, rpoB and gyrB gene sequences, together with DNA-DNA hybridization values less than 70%, revealed that strain 1NM-4(T) belongs to the genus Acinetobacter and may represent a novel species. The major respiratory quinone was ubiquinone 9 (Q-9) and the major cellular fatty acids consisted of C18:1omega9c, summed feature 3 (C16:1omega7c and/or C16:1omega6c), C16:0 and C12:0. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, an unidentified aminolipid and two unidentified phospholipids. The genomic DNA G+C content of strain 1NM-4(T) was 47.17 +/- 0.02 mol%. Based on phenotypic, phylogenetic and chemotaxonomic characteristics, strain 1NM-4(T) should be assigned to a novel species of the genus Acinetobacter, for which the name Acinetobacter guangdongensis sp. nov. is proposed. The type strain is 1NM-4(T) ( = GIMCC 1.656(T) = CCTCC AB 2014199(T) = KCTC 42012(T)). PMID- 25015679 TI - Halovivax limisalsi sp. nov., an extremely halophilic archaeon from hypersaline mud. AB - A Gram-stain-negative, cream-pigmented, motile, extremely halophilic archaeon, designated strain IC38(T), was isolated from a saline mud sample taken from a hypersaline lake, Aran-Bidgol, in Iran. The strain required at least 2.5 M NaCl for growth. However, MgCl2 was not required. Optimal growth occurred with 4.3 M NaCl and 0.2 M MgCl2. The optimum pH and temperature for growth were pH 7.0 and 35 degrees C, respectively, and strain IC38(T) was able to grow over a pH range of 6.5-9.0, and a temperature range of 25-45 degrees C. Analysis of the 16S rRNA gene sequence revealed that strain IC38(T) clustered with the two species of the genus Halovivax, Halovivax asiaticus EJ-46(T) and Halovivax ruber XH-70(T), with sequence similarities of 96.4% and 96.1%, respectively. The similarities between the rpoB' gene of the novel strain and Halovivax asiaticus and Halovivax ruber were 90.7% and 90.3%, respectively. The polar lipid pattern of strain IC38(T) consisted of phosphatidylglycerol and phosphatidylglycerol phosphate methyl ester. Three unidentified glycolipids and two minor phospholipids were also observed. The DNA G+C content of strain IC38(T) was 62.6 mol%. On the basis of the phylogenetic analysis, as well as the biochemical and physiological characteristics, the new isolate is suggested to be a representative of a novel species of the genus Halovivax, for which the name Halovivax limisalsi sp. nov. is proposed. The type strain of Halovivax limisalsi is IC38(T) ( = IBRC-M 10022(T) = KCTC 4051(T)). PMID- 25015680 TI - No effect of oral tyrosine on total tyrosine levels in breast milk: implications for dietary supplementation in early postpartum. AB - Postpartum depression (PPD) is the most common complication of childbearing with a 13 % prevalence rate, and there is no widespread approach for prevention. There is an appealing theoretical rationale for oral tyrosine to help prevent PPD. However, the effect of oral tyrosine on its total and free concentrations in breast milk and plasma of breastfeeding mothers is not known. Twenty-four healthy breastfeeding women were randomly assigned to 0, 2, 5, or 10 g of oral tyrosine. Free and total tyrosine in breast milk and free tyrosine in plasma were measured. Free tyrosine was also measured in 12 different infant formulas. Total tyrosine in breast milk did not rise, but there was a slight tendency towards a reduction (up to -12 %; repeated measures ANOVA (RMANOVA): p = 0.074). Maternal plasma tyrosine rose (RMANOVA: p < 0.005). In breast milk, 98 % of tyrosine was in proteins or peptides and 2 % was free. Free tyrosine levels in breast milk rose in each group (RMANOVA: p < 0.005), but levels were within the range found in common infant formulas. The negligible effect of oral tyrosine on its concentration in breast milk supports further development of oral tyrosine as part of a prevention strategy for PPD. PMID- 25015681 TI - The utility of ADMIRE-HF risk score in predicting serious arrhythmic events in heart failure patients: incremental prognostic benefit of cardiac 123I-mIBG scintigraphy. AB - BACKGROUND: A minority of heart failure (HF) patients who undergo implantable cardioverter defibrillator (ICD) implantation for primary prevention of sudden cardiac death (SCD) receive device therapy. Whether the addition of mIBG scintigraphy to conventional markers of arrhythmic risk can provide incremental risk stratification in HF patients has not been investigated. METHODS: We identified 778 patients from the ADMIRE-HF study with LVEF < 35% and class II or III HF symptoms who did not have an ICD at the time of enrollment. Patients were followed up prospectively (median 5 17 months) for occurrence of arrhythmic events (ArE). Heart-to-mediastinum ratio (HMR) was determined as a measure of relative myocardial sympathetic nerve activity at baseline using 123I-mIBG. The primary endpoint was the first occurrence of ArE: a composite of SCD, appropriate ICD therapy, resuscitated cardiac arrest or sustained ventricular tachycardia. Multivariate regression was used to determine independent predictors of ArE and to derive a risk score for ArE prediction. The score was used to group patients according to their risk for ArE. Integrated discrimination improvement (IDI) was used to quantify improvement in risk assessment with addition of HMR. RESULTS: ArE occurred in 54 patients (6.9%). ArE predictors were:HMR < 1.6 (HR 3.5, 95%CI [1.52-8], P 5 .02), LVEF < 25% (HR 2.0, 95% CI [1.28-3.05], P 5 .04) and SBP < 120 (HR 1.2,95%CI [1.03-1.39], P 5 .02). Event rates in the low-, intermediate-, and high risk groups were 2, 10 and 16%, respectively (P 5 .001). The score significantly improved risk prediction(IDI 5 45%, P 0.03). CONCLUSION: 123I-mIBG significantly provides incremental risk stratification for ArE in HF patients. PMID- 25015682 TI - A household survey on screening practices of household contacts of smear positive tuberculosis patients in Vietnam. AB - BACKGROUND: Close contacts of tuberculosis (TB) patients are at increased risk of developing tuberculosis. Although passive contact screening guidelines are incorporated in the national TB control program, currently it is unknown how frequent close contacts are screened for TB in Vietnam. This study assesses current contact screening practices in Vietnam and determines the proportion of household contacts screened of newly registered TB patients. METHOD: Survey of household contacts of smear-positive TB patients (index patients) registered for treatment in 2008 in three Vietnamese cities. Households were interviewed in 2010 about screening for TB since treatment registration date of the index patient. RESULTS: We interviewed 4,118 household contacts of 1,091 identified index cases. Contact screening mainly relied on self-referral by household contacts. Of the 4,118 household contacts, 474 (11.5%) self-referred for TB screening, while this screening proportion was only 5.5% among contacts under 5 years old (16/293). Sputum examinations were performed in 374 (78.9%) of the screened contacts. Contact screening identified 27 cases of pulmonary TB (0.7%; or 656 cases/100,000 contacts), of which 20 were detected by sputum smear. CONCLUSIONS: The low proportion of household TB contacts screened for TB illustrates the limitations of passive contact screening as currently practiced in Vietnam. Children under 5 years of age are particularly neglected with this approach. Active contact screening with fixed follow-up times of close contacts of newly diagnosed TB patients should be considered in Vietnam, particularly in case of young children and drug-resistant TB. PMID- 25015683 TI - Diagnostic and clinical implications of functional neuroimaging in bipolar disorder. AB - Advances in functional neuroimaging have ushered in studies that have enhanced our understanding of the neuropathophysiology of bipolar disorder, but do not yet have clinical applications. We describe the major circuits (ventrolateral, dorsolateral, ventromedial, and anterior cingulate) thought to be involved in the corticolimbic dysregulation that may underlie mood states in patients with bipolar disorder. The potential clinical application of functional neuroimaging in bipolar disorder is considered in terms of prognostic, predictive, and treatment biomarkers. To date, most research has focused on prognostic biomarkers to differentiate patients with bipolar disorder from those with other affective or psychotic diagnoses, or healthy subjects. The search for treatment biomarkers, which suggest mechanisms of pharmacodynamic or treatment response, and predictive biomarkers has thus far involved only pediatric patients diagnosed with bipolar disorder. The results to date are encouraging and suggest that functional neuroimaging may be of eventual benefit in determining biomarkers of treatment response. Further refinement of biomarker identification, and perhaps even illness characterization are needed to find prognostic and predictive biomarkers of bipolar disorder. PMID- 25015684 TI - Melanoma: the role of surgery in the era of new therapies. PMID- 25015685 TI - Stimulus typicality determines how broadly fear is generalized. AB - The ability to represent knowledge at the category level promotes the transfer of learning. How this ability integrates with basic forms of conditioned learning is unknown but could explain why conditioned fear is overgeneralized after aversive experiences. We examined the impact of stimulus typicality--an important determinant of category-based induction--on fear learning and generalization. Typicality is known to affect the strength of categorical arguments; a premise involving typical exemplars (e.g., sparrow) is believed to apply to other members, whereas a premise about atypical exemplars (e.g., penguin) generalizes more narrowly to similar items. We adopted this framework to human fear conditioning and found that fear conditioned to typical exemplars generalized more readily to atypical members than vice versa, despite equal feature overlap across conditions. These findings have implications for understanding why some fearful events lead to broad overgeneralization of fear whereas others are regarded as isolated episodes. PMID- 25015686 TI - Don't look at my answer: subjective uncertainty underlies preschoolers' exclusion of their least accurate memories. AB - Preschoolers' ability to introspect and make decisions on the basis of these introspections has traditionally been questioned. The present research introduces a novel paradigm to examine the development of the connection between subjective uncertainty about memory and decision making in preschoolers. Three-, 4-, and 5 year-olds (N = 81) encoded items presented once or twice. They then completed a forced-choice test, provided confidence judgments for each response, and decided whether to select or exclude answers to be evaluated for the possibility of reward. Four- and 5-year-olds, but not 3-year-olds, reported lower certainty for incorrect and weaker memories than for correct and stronger memories, and they judiciously excluded their least confident memories, which resulted in accuracy gains for selected memories; these findings highlight age-related improvements in introspection on memory accuracy. Among accurate responses only, even 3-year-olds excluded their least confident answers, which suggests that the connection between uncertainty and decision making precedes the ability to monitor memory accuracy. PMID- 25015687 TI - A latent class analysis of self-reported clinical indicators of psychosocial stability and adherence among opioid substitution therapy patients: do stable patients receive more unsupervised doses? AB - AIMS: To develop a stability typology among opioid substitution therapy patients using a range of adherence indicators derived from clinical guidelines, and determine whether stable patients receive more unsupervised doses. METHODS: An interviewer-administered cross-sectional survey was used in opioid substitution therapy programmes in three Australian jurisdictions, totalling 768 patients in their current treatment episode for >=4 weeks. A structured questionnaire collated data from patients about their demographics, treatment characteristics, past 6-month drug use and medication adherence, psychosocial stability, comorbidity, child welfare concerns and levels of supervised dosing. Latent class analysis (LCA) was used to derive a stability typology. Linear regression models examined predictors of unsupervised dosing in the past month. RESULTS: LCA identified two classes: (i) a higher-adherence group (67%) who had low-moderate probabilities of endorsing the opioid substitution therapy stability indicators and (ii) a lower-adherence group (33%) who had moderate-high probabilities of endorsing the stability indicators. There was no association between adherence profile and the number of unsupervised doses. Significant predictors of receiving larger numbers of unsupervised doses included being older, living in New South Wales or South Australia (vs. Victoria), receiving methadone (vs. mono buprenorphine), being prescribed in private clinic or general practice (vs. public clinic), reporting a longer current treatment episode, not receiving a urine drug screen in the past month, being currently employed and not having a prison history. CONCLUSIONS: This study suggested that system-level factors and observable indicators of social functioning were more strongly associated with the receipt of less supervised treatment. Future research should examine this issue using prospectively collected data. PMID- 25015688 TI - Anxiety sensitivity as an amplifier of subjective and behavioral tobacco abstinence effects. AB - BACKGROUND: Anxiety sensitivity, a transdiagnostic cognitive vulnerability factor described as an amplifier of negative emotional states, is implicated in the maintenance of cigarette smoking and cessation difficulties. The current study aimed to examine the role of anxiety sensitivity in predicting abstinence-induced changes in nicotine withdrawal, smoking urges and smoking behavior during an experimental relapse analogue task (RAT). METHOD: Participants were 258 non treatment seeking smokers (M [SD] age=44.0 [10.73]; 69.8% male). Participants attended two counterbalanced experimental sessions including smoking deprivation (16 h of smoking abstinence) and smoking as usual. The Minnesota Nicotine Withdrawal Scale (MNWS) and Brief Questionnaire of Smoking Urges (QSU) were completed at each session in addition to the RAT. Hierarchical regressions were conducted to examine the predictive impact of anxiety sensitivity on withdrawal and urges during smoking deprivation. Follow-up mediational analyses were conducted to examine whether abstinence-induced withdrawal and urges mediated responding during the RAT. RESULTS: Anxiety sensitivity amplified the effects of experimentally manipulated acute abstinence on subjective nicotine withdrawal symptoms and smoking urges. Additionally, higher levels of anxiety sensitivity indirectly predicted shorter latency to smoking initiation after deprivation during the RAT through the effects of greater abstinence-induced nicotine withdrawal and smoking urges. Anxiety sensitivity was unrelated to increased smoking during the RAT, although this may be partially attributed to the type of laboratory assessment employed. CONCLUSIONS: Elevated anxiety sensitivity appears to impact initiation of smoking after nicotine deprivation through the effects of abstinence-induced withdrawal and smoking urges. PMID- 25015689 TI - Circulating levels of matrix gla protein and progression of aortic stenosis: a substudy of the Aortic Stenosis Progression Observation: Measuring Effects of rosuvastatin (ASTRONOMER) trial. AB - BACKGROUND: Matrix gamma-carboxyglutamate protein is an inhibitor of cardiovascular calcification. The objective of this substudy of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial was to examine the relationship between total (ie, carboxylated [active] form + uncarboxylated [inactive] form) circulating desphosphorylated matrix gamma carboxyglutamate protein (dpMGP) level and the progression rate of aortic stenosis (AS). METHODS: Among the patients included in the ASTRONOMER trial, 215 patients had measures of baseline circulating total dpMGP level and an echocardiographic follow-up (mean follow-up: 3.5 +/- 1.3 years). Progression of AS was assessed according to the measurement of the annualized increase in peak aortic jet velocity. RESULTS: In the whole cohort, baseline dpMGP level was associated with faster progression rate of peak aortic jet velocity (r = 0.16; P = 0.02) in individual analysis but not in multivariable analysis (P = 0.40). However, there was a significant interaction (P = 0.03) between dpMGP level and age, with respect to the effect on AS progression. After dichotomization according to median value of age (ie, 57 years old), total dpMGP level was associated with faster AS progression rate (r = 0.24; P = 0.008) in the younger patients, and this association remained significant in multivariable analysis (P = 0.04), but not in the older ones. The independent correlates of dpMGP level were fasting glucose (P = 0.009) and oxidized low-density lipoprotein (P = 0.01). CONCLUSIONS: This is the first prospective study to demonstrate a relationship between increased circulating levels of total dpMGP and faster progression rate of AS in younger individuals. Future studies are needed to determine if dpMGP is simply a marker or a contributing factor to ectopic mineralization of aortic valve. PMID- 25015690 TI - Advances in the understanding of the pathophysiology and management of aortic stenosis: role of novel imaging techniques. AB - The management of asymptomatic patients with aortic stenosis (AS) is controversial and the mechanisms leading to symptom generation and adverse outcome are not fully understood. Novel imaging techniques offer a noninvasive tool for in vivo assessment of AS and its pathophysiological consequences on the myocardium. Exercise echocardiography provides insight into the mechanisms responsible for exercise limitation and symptom generation. Speckle tracking allows the detection of reduced myocardial strain, which is associated with adverse events in asymptomatic patients. Computed tomography scanning can accurately quantify valve calcification and is associated with disease severity. Positron emission tomography/computed tomography imaging has the potential to monitor disease activity (inflammation and microcalcification) for the first time. Cardiac magnetic resonance (CMR) imaging uniquely allows tissue characterization with identification of fibrosis, a key characteristic of failing myocardium. T1 mapping allows estimation of diffuse interstitial fibrosis and late gadolinium enhancement demonstrates focal fibrosis/scarring. Myocardial steatosis, assessed using CMR spectroscopy, is increased in severe AS and might contribute to myocardial dysfunction. Positron emission tomography and CMR imaging can quantify myocardial blood flow and assess microvascular dysfunction, which might contribute to symptom development and myocardial remodelling. These novel imaging techniques are now being assessed in prospective prognostic studies that will clarify their utility in risk stratification in AS, and lead to improved management and outcomes for these patients. PMID- 25015691 TI - Symptomless endophytic fungi suppress endogenous levels of salicylic acid and interact with the jasmonate-dependent indirect defense traits of their host, lima bean (Phaseolus lunatus). AB - Symptomless 'type II' fungal endophytes colonize their plant host horizontally and exert diverse effects on its resistance phenotype. Here, we used wild Lima bean (Phaseolus lunatus) plants that were experimentally colonized with one of three strains of natural endophytes (Bartalinia pondoensis, Fusarium sp., or Cochliobolus lunatus) to investigate the effects of fungal colonization on the endogenous levels of salicylic acid (SA) and jasmonic acid (JA) and on two JA dependent indirect defense traits. Colonization with Fusarium sp. enhanced JA levels in intact leaves, whereas B. pondoensis suppressed the induction of endogenous JA in mechanically damaged leaves. Endogenous SA levels in intact leaves were significantly decreased by all strains and B. pondoensis and Fusarium sp. decreased SA levels after mechanical damage. Colonization with Fusarium sp. or C. lunatus enhanced the number of detectable volatile organic compounds (VOCs) emitted from intact leaves, and all three strains enhanced the relative amount of several VOCs emitted from intact leaves as well as the number of detectable VOCs emitted from slightly damaged leaves. All three strains completely suppressed the induced secretion of extrafloral nectar (EFN) after the exogenous application of JA. Symptomless endophytes interact in complex and strain-specific ways with the endogenous levels of SA and JA and with the defense traits that are controlled by these hormones. These interactions can occur both upstream and downstream of the defense hormones. PMID- 25015692 TI - Prognostic significance of impaired baroreflex sensitivity assessed from Phase IV of the Valsalva maneuver in a population-based sample of middle-aged subjects. AB - Depressed baroreflex sensitivity (BRS) is associated with an increased risk of mortality in patients with a known cardiac disease. The prognostic significance of BRS in subjects without history of major cardiovascular (CV) events is unknown. The present study tested the hypothesis that impaired BRS predicts the CV mortality in a population-based sample of middle-aged subjects. The present study is a part of the Oulu Project Elucidating Risk of Atherosclerosis study, where middle-aged hypertensive and age- and gender-matched control subjects were randomly selected. Along with clinical and laboratory assessments, BRS was measured from the blood pressure overshoot of Valsalva maneuver in 559 subjects (age 51 +/- 6 years; 300 men). The causes of death (n = 72) were registered during a follow-up of up to 19 years. CV death (n = 23) was defined as the primary end point. CV death was predicted by smoking status, alcohol consumption, high-sensitivity C-reactive protein, use of diuretics, waist circumference, and fasting glucose. Among all measured risk factors, impaired Valsalva BRS (<3 ms/mm Hg) was the most potent predictor of CV death (hazard ratio 9.1, 95% confidence interval 3.8 to 21.7, p <0.001) and remained so after adjustments for the other significant predictors (hazard ratio 5.3, 95% confidence interval 2.1 to 13.3, p <0.001). In conclusion, impaired Valsalva BRS is a potent and independent predictor of CV death in a population-based sample of middle-aged subjects without history of major CV complications and may have important clinical implications in early risk stratification. PMID- 25015693 TI - Impact of statin use on exercise-induced cardiac troponin elevations. AB - Marathon running commonly causes a transient elevation of creatine kinase and cardiac troponin I (cTnI). The use of statins before marathon running exacerbates the release of creatine kinase from skeletal muscle, but the effect of statin use on exercise-induced cTnI release is unknown. We therefore measured cTnI concentrations in statin-using (n = 30) and nonstatin-using (n = 41) runners who participated in the 2011 Boston Marathon. All runners provided venous blood samples the day before, within an hour of finishing, and 24 hours after the marathon. cTnI was assessed at each time point via both a contemporary cTnI and high-sensitivity cTnI (hsTnI) assay. Before the marathon, cTnI was detectable in 99% of runners with the use of the hsTnI assay. All participants completed the marathon (finish time: 4:04:09 +/- 0:41:10), and none had symptoms of an acute coronary syndrome. cTnI increased in all runners (p <0.001) immediately after the marathon, and half (hsTnI = 54% vs contemporary cTnI = 47%) exceeded the diagnostic cut-point for an acute myocardial infarction. Statin use did not affect the magnitude of cTnI release (group*time p = 0.47) or the incidence of runners with cTnI elevation greater than the diagnostic cut-point for myocardial infarction (57% vs 51%, p = 0.65). In addition, there was no significant association between statin potency and cTnI release (r = 0.09, p = 0.65). In conclusion, marathon-induced cTnI increases are not altered by statin use. PMID- 25015695 TI - Quality of life in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention--radial versus femoral access (from the OCEAN RACE Trial). AB - Numerous studies have compared transradial (TR) versus transfemoral (TF) access for percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction. These studies have focused on clinical efficacy and safety; yet little is known about the effect of the vessel access on the health-related quality of life (HRQoL). In the present study, patients were randomly assigned to TR (n = 52) or TF (n = 51) access groups. Generic (EQ-5D-3L) and cardiac-specific (Quality of Life Index and MacNew) tools were used to assess HRQoL before PCI and 2 hours and 4 days after PCI. Baseline HRQoL was comparable in both groups and improved after PCI. The mean +/- SD EQ-5D-3L health utility score 2 hours after PCI was 0.46 +/- 0.291 and was higher in the TR group (TR: 0.60 +/- 0.299 versus TF: 0.32 +/- 0.283, p <0.001). Patients in the TR group reported fewer problems with mobility (TR: 71.7% vs TF: 94.4%, p <0.01) and self care (TR: 62.5% vs TF: 97.2%, p <0.001). At day 4, fewer patients reported problems with anxiety and/or depression in the TR group than in the TF group (TR: 42.9% vs TF: 75.0%, p <0.001); no differences between groups in other measures were observed (Quality of Life Index and MacNew). The N-terminal of the prohormone brain natriuretic peptide levels were inversely correlated with EQ-5D 3L visual analog scale (r = -0.348, p <0.05) and EQ-5D-3L health utility score (r = -0.322, p <0.05). There was a correlation between in-hospital mortality and 2 MacNew domains: physical (r = -0.329, p <0.05) and emotional (r = -0.374, p <0.01). In conclusion, radial access should be the preferred approach in patients with ST-segment elevation myocardial infarction undergoing PCI when considering HRQoL. Radial access is associated with fewer problems with mobility and self care and better psychological outcome after PCI. PMID- 25015694 TI - A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation. AB - For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with <=2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p <5 * 10(-8). Sixty-three SNPs with p <10(-5) at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, p = 9.36 * 10( 8)), 4q12 (IGFBP7, p = 1.75 * 10(-7)), 6q22.33 (C6orf174, p = 4.86 * 10(-7)), 3p21.31 (CDCP1, p = 1.18 * 10(-6)), 12p12.1 (SOX5, p = 1.62 * 10(-6)), and 7p11 (LANCL2, p = 6.51 * 10(-6)). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5, which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance. PMID- 25015696 TI - Impact of co-morbidity on the risk of first-time myocardial infarction, stroke, or death after single-photon emission computed tomography myocardial perfusion imaging. AB - The impact of co-morbidity on the cardiovascular risk after single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) remains unclear. We examined the association between a normal versus abnormal SPECT MPI scan on 10-year risk of myocardial infarction, stroke, and all-cause death, overall and according to co-morbidity level. We identified all patients without previous myocardial infarction or cerebrovascular disease, who had an SPECT MPI performed at Aarhus University Hospital Skejby during 1999 to 2011. We categorized the SPECT MPI scan as normal (no defects) or abnormal (reversible and/or fixed defects). Using nationwide medical registries, we obtained information on co-morbidity level (using Charlson co-morbidity index) and outcomes. We used Cox regression to compute hazard ratios with 95% confidence intervals (CIs), adjusting for gender, age, and co-morbidity level. Among 7,040 patients, 4,962 (70%) had normal scans and 2,078 (30%) abnormal scans. Patients with a normal versus abnormal scan had a 10-year risk of 5.7% versus 10.9% for myocardial infarction, 6.0% versus 7.8% for stroke, and 16.5% versus 29.0% for all-cause death. After adjustment, an abnormal scan was associated with increased risk of myocardial infarction (adjusted hazard ratio 1.73, 95% CI 1.37 to 2.18) and all-cause death (1.42, 95% CI 1.23 to 1.65) but not stroke (1.12, 95% CI 0.86 to 1.45). Co-morbidity level did not affect substantially the association between the scan result and the outcomes. In conclusion, independently of co-morbidity level, an abnormal SPECT MPI scan was associated with an increased 10-year risk of myocardial infarction and all-cause death but not stroke. PMID- 25015697 TI - [Capstesia, a new APP for advanced hemodynamic monitoring]. PMID- 25015698 TI - [Rupture of left main bronchus due to a left double-lumen tube in patient with a history of radiotherapy]. AB - Airway injury caused by double-lumen tubes is a rare but potentially serious complication. We describe the case of a patient who had a bronchial rupture during one-lung ventilation with left double-lumen tube, complicated with a secondary cardiac arrest. She had a full recovery without sequelae. Underlying causes of the patient were a history of radiotherapy, and a possible overinflation of bronchial cuff, that it could contribute to the development of this complication. The possible airway injury should be considered by all practitioners who employ double-lumen tubes for the care of their patients. PMID- 25015699 TI - From assistance towards restoration with epidural brain-computer interfacing. AB - PURPOSE: Today's implanted brain-computer interfaces make direct contact with the brain or even penetrate the tissue, bearing additional risks with regard to safety and stability. What is more, these approaches aim to control prosthetic devices as assistive tools and do not yet strive to become rehabilitative tools for restoring lost motor function. METHODS: We introduced a less invasive, implantable interface by applying epidural electrocorticography in a chronic stroke survivor with a persistent motor deficit. He was trained to modulate his natural motor-related oscillatory brain activity by receiving online feedback. RESULTS: Epidural recordings of field potentials in the beta-frequency band projecting onto the anatomical hand knob proved most successful in discriminating between the attempt to move the paralyzed hand and to rest. These spectral features allowed for fast and reliable control of the feedback device in an online closed-loop paradigm. Only seven training sessions were required to significantly improve maximum wrist extension. CONCLUSIONS: For patients suffering from severe motor deficits, epidural implants may decode and train the brain activity generated during attempts to move with high spatial resolution, thus facilitating specific and high-intensity practice even in the absence of motor control. This would thus transform them from pure assistive devices to restorative tools in the context of reinforcement learning and neurorehabilitation. PMID- 25015700 TI - Rubber hand illusion highlights massive visual capture and sensorimotor face-hand remapping in a tetraplegic man. AB - PURPOSE: The illusory ownership of a fake hand as part the body follows synchronous tactile stimulation over a visible rubber hand and a covered hand. Whether brain plasticity mechanisms after sensory and motor disconnection modulates this illusion remain unexplored. METHODS: We tested a tetraplegic man after synchronous and asynchronous stimulation of the hand and face. RESULTS: The illusory ownership of the fake hand was tested four times in separate days and always reported. To verify whether this ownership feeling generalized also to object not resembling the human body we tested this illusion with a plastic bottle and a rubber hand. The illusionary perception of owning an external object using the rubber hand paradigm showed that the temporally matched tactile stimulation on a fake hand and visual capture mechanism create the illusionary feeling that the rubber hand was part of his body. CONCLUSIONS: Despite lesions that dramatically disconnect the access to sensory inputs and motor outputs our data suggests a strong visual capture of a rubber hand and a possible remapping of hand-face representations after the spinal lesion. We suggest that vision and brain plasticity may represent a supportive tool for motor rehabilitation in patients with sensory deficits. PMID- 25015702 TI - Specificity and generalization of perceptual learning in low myopia. AB - PURPOSE: In this study we investigated in observers with low myopia: (i) the pattern of lateral interactions between stimuli activating early cortical analyzers and its modulation by perceptual learning (PL), and (ii) whether PL transferred to untrained stimuli and tasks and whether it exhibits interocular transfer. METHOD: Participants (seven adults with low myopia) performed 12 training sessions. Participants were trained on a contrast detection task of a central Gabor target flanked by two co-oriented and co-aligned high contrast Gabor patches. Target-to-flankers separation along the vertical axis was varied from 2 wavelengths (lambda) to 8lambda. RESULTS: The results showed that before PL facilitatory lateral interactions in the myopic eye were reduced in strength, but PL increased contrast sensitivity and improved facilitatory lateral interactions. However, PL did not transfer to different local/global orientations and lower spatial frequencies. On the other hand, PL resulted in an enhancement of the contrast sensitivity function (CSF) and of the uncorrected visual acuity (UCVA) both in the trained and untrained eye. CONCLUSIONS: Such improvements seem to be associated to a modulation of lateral interactions between target and flankers and it is likely to take place at a level in which the inputs from the two eyes converge. PMID- 25015701 TI - Language improvements after TMS plus modified CILT: Pilot, open-protocol study with two, chronic nonfluent aphasia cases. AB - PURPOSE: The purpose of this study was to investigate: 1) the feasibilty of administering a modified CILT (mCILT) treatment session immediately after TMS; and 2) if this combined therapy could improve naming and elicited propositional speech in chronic, nonfluent aphasia. METHODS: Two chronic stroke patients with nonfluent aphasia (mild-moderate and severe) each received twenty minutes of rTMS to suppress the right pars triangularis, followed immediately by three hours of mCILT (5 days/week, 2 weeks). (Each patient had received TMS alone, 2-6 years prior.) Language evaluations were performed pre- TMS+mCILT, and post- at 1-2 months, and 6 or 16 months. RESULTS: Both patients showed significant improvements in naming pictures, and elicited propositional speech at 1-2 months post- TMS+mCILT. The improved naming was still present at 6 months post- TMS+mCILT for P2; but not at 16 months post- TMS+mCILT for P1. CONCLUSIONS: It is feasible to administer mCILT for three hours immediately after a TMS session. It is unknown if the significant improvements in naming pictures, and elicited propositional speech were associated with the second series of TMS, or this first series of mCILT, or a combination of both. A larger, sham controlled clinical trial is warranted. PMID- 25015703 TI - Functional protection of learning and memory abilities in rats with vascular dementia. AB - PURPOSE: The present study clarified the effects of repetitive transcranial magnetic stimulation (rTMS) in rats with vascular dementia (VaD) and explored the underlying mechanisms. METHODS: Two-vessel occlusion was used as a VaD model. Two weeks after carotid artery occlusion, high (5 Hz) or low (1 Hz) frequency rTMS were applied for 10 days. Spatial learning and memory abilities were tested with a Morris water maze. Hippocampal CA1 neurons were histologically examined. The expressions of mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E (eIF-4E) in CA1 were detected by western blot, and immunohistochemistry. RESULTS: Unlike unlesioned control animals, VaD rats had an impaired morphology of CA1 neurons and a reduced ability of spatial memory. rTMS significantly improved both, the morphology and the learning and memory abilities of VaD rats compared to untreated lesioned rats. Protein expressions of mTOR and eIF-4E in CA1 of VaD rats were lower than in control rats but rTMS significantly increased the expression compared to untreated VaD rats. CONCLUSIONS: rTMS promotes recovery of learning and memory abilities of VaD rats. Molecular analysis suggests that the beneficial effect of rTMS may be partly induced by upregulation of protein expressions of mTOR and eIF-4E in CA1. PMID- 25015704 TI - Cognitive and brain reserve for mind-body therapeutic approaches in multiple sclerosis: a review. AB - PURPOSE: Cognitive impairment is one of the most disabling symptoms of multiple sclerosis (MS), affecting a large proportion of patients and having a severe impact on their quality of life. Nevertheless, there exists a large variability in the neuropsychological profiles of MS patients and some of them appear to withstand better than others the MS-related brain pathology before showing cognitive decline. In recent years, many studies have made use of concepts such as cognitive reserve and brain reserve to take account of the inter-individual discrepancy between cognitive impairment and MS pathology. Critically, these studies have left open the fundamental issue of the clinical implications of this research for the treatment of cognitive dysfunction in MS. METHODS AND RESULTS: We provide an updated and extensive overview of the studies that have explored cognitive and brain reserve in MS and discuss their implications for non pharmacological therapeutic strategies aimed at potentiating patients' reserve. In particular, the possible utility of integrated approaches based on mind-body techniques such as mindfulness-meditation is considered. CONCLUSIONS: We conclude that these techniques represent challenging mental enriching activities that may help cultivating cognitive reserve and more systematic research on their efficacy to protect against cognitive degradation in MS is encouraged. PMID- 25015705 TI - Optimal management of skin cancer in immunosuppressed patients. AB - Skin cancer is the most common malignancy in humans with basal cell carcinoma representing the majority of cases in the general population. The prevalence of skin cancer is increased amongst immunosuppressed patients such as those with lymphoproliferative disorders including non-Hodgkin lymphoma and chronic lymphocytic leukemia or those with iatrogenic immunosuppression following organ transplantation. In addition, these patients experience greater morbidity and mortality associated with skin cancers. The most common skin cancer in immunosuppressed patients is squamous cell carcinoma, which often presents with more aggressive features and has a greater rate of metastasis. This article reviews the risk factors, etiology, clinical presentation, and prevalence of skin cancer amongst immunosuppressed patients, including organ transplant, lymphoproliferative disorders, autoimmune disorders, and human immunodeficiency virus. We also provide a comprehensive review of treatment guidelines for immunosuppressed patients with cutaneous malignancy. Surgical therapy is the cornerstone of treatment; however, we also discuss pharmacologic treatment options, lifestyle modifications, and revision of immunosuppressive regimens. PMID- 25015706 TI - Efficacy of purified lactonase and ciprofloxacin in preventing systemic spread of Pseudomonas aeruginosa in murine burn wound model. AB - Pseudomonas aeruginosa is an important etiological agent associated with systemic infection in burn patients. Quorum sensing (QS) mechanism of P. aeruginosa contributes to its virulence. Inhibition of QS signals can serve as an effective anti-virulence strategy. Aim of the present study was to evaluate the efficacy of lactonase alone and in combination with ciprofloxacin in treating P. aeruginosa murine burn wound infection. Topical application of lactonase alone and ciprofloxacin alone prevented systemic spread of P. aeruginosa through burned skin and also reduced the mortality. When lactonase (topical) and ciprofloxacin (I/P) were used in combination, zero mortality was observed. It not only significantly reduced systemic dissemination and severity of histopathologic lesions but also resulted in skin regeneration. Decreased production of pathologic index factors (malondialdehyde and reactive nitrogen intermediates) and interleukins (IL-10, IL-6 and MIP-2) was also observed in comparison to control. The results of present study suggest that combination of lactonase and ciprofloxacin can potentially attenuate the virulence of P. aeruginosa. This is the first report of topical administration of lactonase along with antibiotic for the efficient control of burn wound infection. PMID- 25015707 TI - Effect of current pathway on mortality and morbidity in electrical burn patients. AB - INTRODUCTION: Electrical injury is relatively uncommon but it is a devastating form of thermal injury. The aim of this study is to analyze specific aspects of electrical injuries, especially the effect of current pathways on morbidity and mortality. METHOD: This descriptive-analytical study was performed on patients with electrical burns who were admitted to the Shahid Motahary Burn Center from April 2010 to March 2012. Demographic and clinical data including gender, age, length of hospital stay, total body surface area (TBSA), grading of burn, electrical voltage, inlet electrical mark, outflow electrical mark, current pathway, surgical procedures, and place of electrical burn have been gathered from medical records. The site of inlet and outlet of current on the body is divided into six groups: Rt (right) upper limb, Lt (left) upper limb, Rt lower limb, Lt lower limb, head and neck, and trunk. According to these sites, the current pathway is defined to seven groups. Data were analyzed with SPSS software, version 20. RESULTS: From 287 patients, 283 were men and 4 were women. The mean age was 30+/-12 years (range 1-71) and mean TBSA was 13.56+/-12.97% (range 1-100). There were 233 patients (81.2%) with passage of the electrical current through the body and 54 patients (18.8%) with flash burns. A total of 859 surgical procedures were performed on 232 patients. One hundred and eighteen amputations were performed in 83 patients. The most common inlet electrical marks were in Rt upper limb and the most common outlet electrical marks were in Lt lower limbs, and consequently, the most common pathway was upper limb to lower limb. CONCLUSIONS: Electrical injuries are mainly occupation-related injuries and in this research majority of injuries occurred outdoor by high voltage cables in young men. Thus the government should consider a distinct strategy for this group. Also it is observed that there were no significant differences in mortality and complications such as amputation between different pathways. PMID- 25015708 TI - The effects of bariatric surgery on colorectal cancer risk: systematic review and meta-analysis. AB - Obesity is an established risk factor for colorectal cancer (CRC) but the effects of bariatric surgery on CRC incidence are uncertain. A systematic review of six electronic databases identified 3691 articles. Four observational studies met our inclusion criteria and results were pooled using a random effects model. Meta analysis of these four studies revealed that bariatric surgery was associated with a significantly (p = 0.004) lower CRC incidence (RR = 0.73, 95 % confidence interval, 0.58 - 0.90) when compared with obese non-operated individuals, i.e., bariatric surgery is associated with a 27 % lower CRC risk. However the evidence base is limited and these findings should be confirmed by future studies with improved designs. PMID- 25015709 TI - Efficacy and acceptability of atypical antipsychotics for the treatment of post traumatic stress disorder: a meta-analysis of randomized, double-blind, placebo controlled clinical trials. AB - As some evidences demonstrated that atypical antipsychotics (AA) may be efficacious in treating post-traumatic stress disorder (PTSD), we preformed a meta-analysis of randomized, double-blind, placebo-controlled clinical trials (RCTs) of AAs for the treatment of PTSD. Two hundred and fifty one papers were searched and screened. Eight RCTs met the inclusion criteria. AAs may be superior to placebo in the treatment of PTSD, as indicated by the changes in Clinician Administered PTSD Scale (CAPS) total scores (weighted mean differences (WMD)= 5.89, 95% confidence interval (CI) [-9.21, -2.56], P=0.0005) and also in CAPS subscale intrusion (WMD=-2.58, 95% CI[-3.83, -1.33], P<0.0001 ) and subscale hyperarousal (WMD=-2.94, 95% CI[-5.45, -0.43], P=0.02). The acceptability measured by dropout rates between AAs and placebo showed no statistical difference (OR=1.24, 95%CI [0.78, 1.97], P=0.36). PTSD symptom cluster, especially in intrusion and hyperarousal. However, we should be careful to generalize the conclusion because of the small number of included trails. We expect more RCTs will be done in the future so as to clarify the specific value of AAs for PTSD. PMID- 25015711 TI - Cognitive and affective empathy in children with conduct problems: additive and interactive effects of callous-unemotional traits and autism spectrum disorders symptoms. AB - Callous-unemotional (CU) traits and autism spectrum disorders (ASD) symptoms are characterized by problems in empathy; however, these behavioral features are rarely examined together in children with conduct problems. This study investigated additive and interactive effects of CU traits and ASD symptoms in relation to cognitive and affective empathy in a non-ASD clinic-referred sample. Participants were 134 children aged 3 to 9 years (M=5.60; 79% boys) with oppositional defiant/conduct disorder, and their parents. Clinicians, teachers, and parents reported on dimensions of child behavior, and parental reports of family dysfunction and direct observations of parental warmth/responsiveness assessed quality of family relationships. Results from multiple regression analysis showed that, over and above the effects of child conduct problem severity and quality of family relationships, both ASD symptoms and CU traits were uniquely associated with deficits in cognitive empathy. Moreover, CU traits demonstrated an independent association with affective empathy, and this relationship was moderated by ASD symptoms. That is, there was a stronger negative association between CU traits and affective empathy at higher versus lower levels of ASD symptoms. These findings suggest including both CU traits and ASD-related social impairments in models delineating the atypical development of empathy in children with conduct problems. PMID- 25015710 TI - Eating disorders and associated mental health comorbidities in female veterans. AB - Eating disorders (EDs) remain understudied among veterans, possibly due to the perception that primarily male population does not suffer from EDs. However, previous research suggests that male and female veterans do experience EDs. The high rates of posttraumatic stress disorder (PTSD), depression, and obesity observed among veterans may make this group vulnerable to disordered eating. Retrospective chart review was used to obtain data from 492 female veterans who were presented to a women's primary care center at a large, urban VA medical center between 2007 and 2009. A total of 2.8% of this sample had been diagnosed with an ED. In bivariate analyses, presence of PTSD and depression were significantly associated with having an ED diagnosis. However, when these two disorders were included in a multivariate model controlling for age, only depression diagnosis and lower age were significantly related to ED status. In sum, the rate of EDs in this sample is comparable to prevalence estimates of EDs in the general population. Current findings underscore the importance of assessing for EDs among VA patients and the need for further research among veterans. PMID- 25015712 TI - Neural processing of facial expressions of emotion in first onset psychosis. AB - Schizophrenia is characterized by deficits in face and facial emotion processing. This is the first study using event-related potentials (ERPs) to investigate the corresponding neural activation in first onset psychosis. ERPs for 108 first onset psychosis participants and 108 matched healthy controls were recorded while they viewed facial expressions. Group differences on general (neutral) face processing and emotional valence were examined under both unmasked (conscious) and backward-masked (nonconscious implicit) conditions over frontal and temporo occipital regions. Clinical significance was assessed by comparing diagnoses and correlating ERPs with symptoms. During general face processing, patients showed reduced activation within 70 ms and exaggerated later processing from 160 ms over the frontal region, with a negative shift in voltage over left temporal and occipital regions across the time course. In addition, from 70 ms onwards, patients showed a positive shift in voltage for disgust whereas controls showed a negative shift in voltage for fear and anger (both compared to happy) over temporo-occipital regions. Effects were related to disorganization and depression symptoms and (preliminarily) were apparent across psychotic diagnoses. These results suggest that first onset psychosis is characterized by general as well as emotion-specific face processing impairments from the earliest, automatic processing period. PMID- 25015713 TI - Incense burning at home and the blood lead level of preschoolers in Taiwan. AB - The growth and intellectual development of children less than 6 years old may be affected by exposure to low levels of lead. To further reduce environmental lead exposure, this study examined possible household-related factors that affect the blood lead levels of Taiwanese children. In total, based on a stratified random sampling strategy, 934 kindergarten students were recruited throughout Taiwan from April to October 2011 after their parents signed a statement of consent. A venous blood sample was drawn from each participant and analyzed for lead content using inductively coupled plasma mass spectrometry. Information on the demographics and household environment of the study subjects was collected by administering a questionnaire (Table 1). The geometric mean lead level in the blood samples of the study subjects was 1.84 MUg/dL with a geometric standard deviation of 1.55. The blood lead level was negatively correlated with household income and parental educational levels (p < 0.0001). Study subjects with more siblings also tended to have higher blood lead levels (p < 0.0001). Incense burning in the home, an ethnic tradition, was also identified as a significant factor for increased blood lead levels (p < 0.0003) and demonstrated a dose dependent relationship with frequency of incense burning at home (p = 0.0022). Because the health effects of low levels of lead exposure have been reported in recent years and because no consensus has been reached regarding a safety threshold for blood lead level in children, any trivial factor is worth investigating to further prevent lead exposure in children. Incense burning at home is a common traditional religious activity in Taiwan; therefore, more study is warranted to further eliminate the lead content in incense and reduce lead exposure for the families who practice this activity. PMID- 25015714 TI - Effects of chemical stress and food limitation on the energy reserves and growth of turbot, Scophthalmus maximus. AB - The objective of the present study is to examine the growth and energetic performance of juvenile turbot after exposure to contaminated sediment and during the subsequent recovery period with or without food limitation. We designed a two step experiment by first exposing juvenile turbot to harbour sediment for 26 days and then transferring them to clean sea water with different frequencies of feeding for 35 days. Without food limitation, fish previously exposed to contaminated sediment compensated for weight, length and lipid reserve losses; we did not record any differences in size, Fulton's K condition index and triacylglycerol/sterol (TAG/ST) ratio after the 35-day depuration period compared to the reference fish. This result could be related to the compensatory growth mechanism observed in a wide range of fish species following a period of growth depression. With food limitation during the 35-day depuration period, recovery growth was not sufficient to restore length and weight values similar to the reference fish. Moreover, turbot previously exposed to contaminated sediment and subsequently fed twice or once a week exhibited extremely low TAG/ST ratios, but the reference fish submitted to the same restrictive feeding conditions did not. This study indicates that juvenile fish affected by chemical pollution can improve their biological performance if pollution events are followed by a period of abundant food. However, if pollution events occur during periods of food scarcity, e.g. in winter, storage of energy reserves will be compromised. PMID- 25015715 TI - Polycyclic aromatic hydrocarbon (PAH) exposure and oxidative stress for a rural population from the North China Plain. AB - Polycyclic aromatic hydrocarbons (PAHs) belong to a class of ubiquitous pollutants and are possibly associated with adverse health effects. In this study, we aimed to assess PAH exposure by measuring the hydroxylated metabolites (hydroxy-PAHs) in urine samples of a rural population from the North China Plain and to explore the possible associations between PAH exposure and oxidative stress indicated by urinary malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). High levels of urinary hydroxy-PAHs were observed, with the geometric mean concentrations of 0.57, 2.2, 5.0, 7.0, and 16.6 MUg g-1 creatinine for 1 hydroxypyrene, hydroxyphenanthrenes, hydroxyfluorenes, hydroxybiphenyls, and hydroxynaphthalenes, respectively. Particularly in the winter season, the exposures were 2.3-6.0-fold of those in the spring. Corresponding to PAH exposure, levels of urinary MDA were positively associated with hydroxy-PAHs after controlling for confounders in the linear regression models (p < 0.05). An estimation indicated 21.3-39.3 % increment of urinary MDA per one-fold increase of hydroxy-PAHs. In contrast, no significant correlation was found between urinary 8-OHdG and hydroxy-PAHs; alternatively, living at the e-waste recycling site was found a significant factor on this oxidative DNA damage. These results provide evidence on high PAH exposure and the induction of oxidative stress on lipid peroxidation for this rural population. PMID- 25015716 TI - High prevalence of vitamin D insufficiency/deficiency in Dutch multi-ethnic obese children. AB - Vitamin D insufficiency/deficiency is common among non-white children; however, little is known about the prevalence of vitamin D insufficiency/deficiency in non white obese children living in the Netherlands. Therefore, a retrospective analysis was performed on data from multi-ethnic Dutch children and adolescents 6 18 years who visited the obesity outpatient clinic in 2012-2013. We performed anthropometric measurements, oral glucose tolerance test, and measured 25(OH)D and lipid levels. Vitamin D insufficiency was defined as 25(OH)D levels 37.5- <50 nmol/L and vitamin D deficiency as 25(OH)D <37.5 nmol/L. In total, data from 387 children were obtained (mean age 11.6 years, 41.1 % boys, 10.3 % Dutch native, 25.6 % Turkish, 24.5 % Moroccan, 7.5 % African Surinamese, and 7.0 % West African). The median 25(OH)D level was 34 (range 12-105) nmol/L. In total, 17.8 % were vitamin D sufficient, 24.5 % with vitamin D insufficiency, and 57.6 % with vitamin D deficiency. Obese ethnic children showed the highest (87.5 %) and normal weight white children showed the lowest (20.0 %) prevalence of vitamin D insufficiency/deficiency . Conclusion: Vitamin D insufficiency and deficiency is extremely prevalent in treatment-seeking obese ethnic children. However, there was no evidence of an effect of vitamin D status on various components of the metabolic syndrome in our cohort. PMID- 25015717 TI - Assessment of synergistic combination potential of probiotic and bacteriophage against antibiotic-resistant Staphylococcus aureus exposed to simulated intestinal conditions. AB - This study was designed to evaluate the combined effect of probiotic Lactobacillus rhamnosus and bacteriophage SA11 on the control of antibiotic sensitive Staphylococcus aureus (ASSA) and antibiotic-resistant S. aureus (ARSA) under the simulated intestinal conditions. The survivability of ASSA and ARSA were determined in the simulated phosphate-buffered saline (PBS)-, trypticase soy broth (TSB)-, and milk-based gastric juices adjusted to pH 2.0, 3.0, and 5.0 at 37 degrees C for 30 min. The inhibitory effect of bacteriophage SA11 and probiotic on the growth of ASSA and ARSA was evaluated in the simulated intestinal juices at 37 degrees C for 20 h. The least reductions in the numbers of ASSA and ARSA were observed in the milk-based gastric juices at pH 2.0 (<1 log). No significant changes in the teichoic acid-mediated sliding motility were observed for ASSA and ARSA after 30-min exposure to the simulated gastric juices (pH 2.0, 3.0, and 5.0), responsible for the enhanced bacterial attachment to the epithelial cells. The bacteriophage SA11 was stable down to pH 5.0 and up to 0.06 % bile salts. The bacteriophage SA11 combined with probiotic effectively inhibited the growth of ASSA and ARSA in the simulated intestinal conditions, showing more than 4 log reduction. The relative expression levels of adhesion related genes (clfA, eno, and fnbA) and efflux-related genes (mdeA, norB, and norC) were less decreased in ARSA than in ASSA after exposure to the simulated gastrointestinal conditions. These results might shed light on the application of bacteriophage to control the ingested antibiotic-resistant foodborne pathogens in the intestinal tract. PMID- 25015718 TI - Morphologic and phenotypic characteristics of myocarditis in two pigs infected by foot-and mouth disease virus strains of serotypes O or A. AB - Myocarditis is often cited as the cause of fatalities associated with foot-and mouth disease virus (FMDV) infection. However, the pathogenesis of FMDV associated myocarditis has not been described in detail. The current report describes substantial quantities of FMDV in association with a marked mononuclear inflammatory reaction, interstitial edema and cardiomyocyte degeneration in the myocardium of two pigs that died during acute infection with either of two different strains of FMDV. Despite similar clinical progression, there was a marked variation in morphological characteristics of myocarditis with a significant difference in intensity of myocardial inflammation between the two cases. Phenotypic characterization of leukocyte populations revealed that in both cases, the inflammatory infiltrate consisted mainly of combinations of CD172a+, CD163+ and CD44+ cells, with a distinct subset of CD8+ cells, but with consistent lack of detection of CD3+ and CD21+ cells. This suggests that the FMDV-associated acute myocardial inflammation in the two observed cases consisted mainly of leukocytes of monocyte lineage, with a distinct population of CD8+ cells which, based on lack of CD3 detection in serial sections, are likely to represent NK cells. PMID- 25015720 TI - Apropos: An update on the incidence of dengue gaining strength in Saudi Arabia and current control approaches for its vector mosquito. PMID- 25015719 TI - JMY is involved in anterograde vesicle trafficking from the trans-Golgi network. AB - Junction-mediating and regulatory protein (JMY) was originally identified as a transcriptional co-factor in the p53-response to DNA damage. Aside from this nuclear function, recent years have uncovered an additional function of JMY, namely in cytoskeleton remodelling and actin assembly. The C-terminus of JMY comprises a canonical VCA-module, the sequence signature of Arp2/3 complex activators. Furthermore, tandem repeats of 3 WH2 (V, or more recently also W) domains render JMY capable of Arp2/3 independent actin assembly. The motility promoting cytoplasmic function of JMY is abrogated upon DNA-damage and nuclear translocation of JMY. To address the precise cellular function of JMY in cellular actin rearrangements, we have searched for potential new interaction partners by mass spectrometry. We identified several candidates and correlated their localization with the subcellular dynamics of JMY. JMY is localized to dynamic vesiculo-tubular structures throughout the cytoplasm, which are decorated with actin and Arp2/3 complex. Moreover, JMY partially colocalizes and interacts with VAP-A, which is involved in vesicle-based transport processes. Finally, overexpression of JMY results in Golgi dispersal by loss from the trans-site and affects VSV-G transport. These analyses, together with biochemical experiments, indicate that JMY drives vesicular trafficking in the trans-Golgi region and at ER-membrane contact sites (MCS), distinct from other Arp2/3 activators involved in vesicle transport processes such as the related WHAMM or WASH. PMID- 25015721 TI - Interleukin-17 is a favorable prognostic marker for colorectal cancer. AB - PURPOSE: The role of interleukin-17 (IL-17) in the tumor microenvironment is controversial. We analyzed the in situ tumor expression of IL-17 in colorectal cancer (CRC), adenoma and non-tumor tissue to explore the possible correlation of IL-17 expression to clinicopathological characteristics, tumor-infiltrating neutrophils (TINs) and survival in CRC. METHODS: We reviewed the records of 78 consecutive patients diagnosed with CRC. Archival tissues were used. Thirty-six patients with colorectal adenoma were also included. From the 78 CRC patients, we randomly chose 40 cases and collected non-tumor tissue at 10 cm from the edge of the resected tumor. Immunohistochemistry was performed using anti-IL-17 and anti CD15 (targeting neutrophils) antibody, respectively. Real-time PCR was used to detect IL-17 mRNA in different tissues. Associations between IL-17 expression, clinicopathological parameters and prognosis were evaluated. RESULTS: The level of IL-17 mRNA was higher in CRC than in adenoma and non-tumor tissue (P < 0.05). Positive IL-17 protein expression was observed more frequently in CRC as compared to colorectal adenoma and non-tumor tissue, respectively (P < 0.01). IL-17 expression correlated to well differentiation and early stage CRC. The number of CD15+ neutrophils significantly increased in CRC and positively correlated to the expression of IL-17 (P < 0.05). Both Kaplan-Meier analysis and multivariate Cox regression analysis indicated that patients with positive IL-17 expression showed better overall survival. CONCLUSIONS: The association between IL-17 expression and the clinicopathological parameters, as well as the clinical outcome suggests a significant role of IL-17 in CRC. IL-17 is a marker of favorable prognosis. PMID- 25015722 TI - Activation of shape and semantic information during ambiguous homophone processing: eye tracking evidence from Hindi. AB - In two visual world eye tracking studies, we examined the activation of subordinate meanings of ambiguous homophones in Hindi and particularly when the sentence context is biased towards the dominant meaning. Participants listened to sentences that were either neutral or biased towards the dominant meaning of the homophone and saw a display containing four pictures. In experiment 1, the display had a shape competitor of the subordinate meaning of the homophone in both neutral and biased conditions along with three unrelated distractors. Experiment 2 had semantic competitors of the subordinate meaning of the homophones along with three distractors. Proportion of fixations to different objects overtime suggested that participants activated the subordinate meanings and oriented their attention to the shape and semantic competitors even when the prior context was biased towards the dominant meaning. Overall, these data from Hindi provide further support to those models of lexical access that assume exhaustive access of both the meanings of an ambiguous homophone. These data suggest even a dominant bias does not eliminate the activation of perceptual and conceptual features of the subordinate meaning. PMID- 25015724 TI - Sexual aversion and the DSM-5: an excluded disorder with unabated relevance as a trans-diagnostic symptom. PMID- 25015725 TI - Identification and characterization of CYP79D16 and CYP71AN24 catalyzing the first and second steps in L-phenylalanine-derived cyanogenic glycoside biosynthesis in the Japanese apricot, Prunus mume Sieb. et Zucc. AB - Japanese apricot, Prunus mume Sieb. et Zucc., belonging to the Rosaceae family, produces as defensive agents the cyanogenic glycosides prunasin and amygdalin, which are presumably derived from L-phenylalanine. In this study, we identified and characterized cytochrome P450s catalyzing the conversion of L-phenylalanine into mandelonitrile via phenylacetaldoxime. Full-length cDNAs encoding CYP79D16, CYP79A68, CYP71AN24, CYP71AP13, CYP71AU50, and CYP736A117 were cloned from P. mume 'Nanko' using publicly available P. mume RNA-sequencing data, followed by 5' and 3'-RACE. CYP79D16 was expressed in seedlings, whereas CYP71AN24 was expressed in seedlings and leaves. Enzyme activity of these cytochrome P450s expressed in Saccharomyces cerevisiae was evaluated by liquid and gas chromatography-mass spectrometry. CYP79D16, but not CYP79A68, catalyzed the conversion of L-phenylalanine into phenylacetaldoxime. CYP79D16 showed no activity toward other amino acids. CYP71AN24, but not CYP71AP13, CYP71AU50, and CYP736A117, catalyzed the conversion of phenylacetaldoxime into mandelonitrile. CYP71AN24 also showed lower conversions of various aromatic aldoximes and nitriles. The K m value and turnover rate of CYP71AN24 for phenylacetaldoxime were 3.9 uM and 46.3 min(-1), respectively. The K m value and turnover of CYP71AN24 may cause the efficient metabolism of phenylacetaldoxime, avoiding the release of the toxic intermediate to the cytosol. These results suggest that cyanogenic glycoside biosynthesis in P. mume is regulated in concert with catalysis by CYP79D16 in the parental and sequential reaction of CYP71AN24 in the seedling. PMID- 25015726 TI - Lateral incisional hernia after renal transplantation: a comparative study. AB - BACKGROUND: Because of the lack of published data and the relative rarity of lateral incisional hernias (LIHs), especially after renal transplantation, mesh repair of LIH remains a challenge for surgeons. The aim of the present study was to evaluate the outcomes of LIH treated by mesh repair after renal transplantation. METHODS: All consecutive patients who had undergone LIH mesh repair after renal transplantation were compared with patients who had undergone LIH mesh repair without renal transplantation. Demographic data, incisional hernia characteristics, operative data, and postoperative outcomes were prospectively recorded. Early complications and recurrence rates were evaluated. RESULTS: Altogether, 112 patients were treated for LIH with mesh repair. Among these patients, 61 (54.4 %) underwent LIH after renal transplantation. The early complications were similar for the patients with and without renal transplantation (24.5 vs. 23.5 %, respectively; p = 0.896). The recurrence rates also were similar for the patients with and without renal transplantation (9.8 vs. 9.8 %, respectively; p = 1). CONCLUSIONS: Mesh graft repair is feasible in patients with LIH after renal transplantation. Postoperative complications and recurrences were not more frequent in renal transplantation patients than in those without renal transplantation. PMID- 25015727 TI - Definition of Barrett's esophagus dysplasia: are we speaking the same language? AB - The definition of Barrett's esophagus (BE) is still a matter of debate. The diagnostic criteria adopted around the world for both BE and BE-related pre cancerous lesions are inconsistent, particularly between Eastern and Western pathologists. From a clinical perspective, these different clinico-biological approaches may affect how the literature is interpreted, with detrimental effects on the clinical management of patients. The present review focuses on the major discrepancies in the field, covering both the non-neoplastic and the pre cancerous lesions associated with Barrett's disease. PMID- 25015728 TI - Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL 23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients. AB - IL-23 is a heterodimeric cytokine involved in inflammatory diseases; its role in cancer progression is controversial. Here we analyse the expression of IL-23 subunits (p40 and p19) and IL-23R in colorectal cancer with regard to disease progression, clinical-pathological and molecular aspects. Immunohistochemistry for IL-23p19, IL-23p40, IL-23R and CD8 was performed on a multi-punch tissue microarray of 195 colorectal cancers (cohort 1), matched normal tissue, adenoma and lymph node metastases. Results were compared with clinical-pathological features and CD8+ T-cell counts, then validated on two patient cohorts (cohort 2: n=341, cohort 3: n=139). Cytoplasmic/membranous expression of IL-23 (p19 and p40 subunits) and IL-23R, respectively were over-expressed in carcinomas versus adenomas and normal tissues (p<0.0001) but were reduced in lymph node metastases (p<0.0001). Nuclear IL-23p19 expression was observed in 23.1% and was associated with early TNM stage (p=0.0186), absence of venous (p=0.0124) and lymphatic invasion (p=0.01493), favorable survival (p=0.014) and absence of distant metastasis (p=0.0146; specificity: 100%). This unexpected cellular localization was confirmed by cell fractionation. The beneficial effect of nuclear IL-23p19 was restricted to tumours with CD8+ high counts. Results were validated on Cohorts 2/3. This multicenter study underlines the possible CD8(+)--dependency and beneficial effect of nuclear IL-23p19 on overall patient survival. PMID- 25015729 TI - Molecular evidence for convergent evolution and allopolyploid speciation within the Physcomitrium-Physcomitrella species complex. AB - BACKGROUND: The moss Physcomitrella patens (Hedw.) Bruch & Schimp. is an important experimental model system for evolutionary-developmental studies. In order to shed light on the evolutionary history of Physcomitrella and related species within the Funariaceae, we analyzed the natural genetic diversity of the Physcomitrium-Physcomitrella species complex. RESULTS: Molecular analysis of the nuclear single copy gene BRK1 reveals that three Physcomitrium species feature larger genome sizes than Physcomitrella patens and encode two expressed BRK1 homeologs (polyploidization-derived paralogs), indicating that they may be allopolyploid hybrids. Phylogenetic analyses of BRK1 as well as microsatellite simple sequence repeat (SSR) data confirm a polyphyletic origin for three Physcomitrella lineages. Differences in the conservation of mitochondrial editing sites further support hybridization and cryptic speciation within the Physcomitrium-Physcomitrella species complex. CONCLUSIONS: We propose a revised classification of the previously described four subspecies of Physcomitrella patens into three distinct species, namely Physcomitrella patens, Physcomitrella readeri and Physcomitrella magdalenae. We argue that secondary reduction of sporophyte complexity in these species is due to the establishment of an ecological niche, namely spores resting in mud and possible spore dispersal by migratory birds. Besides the Physcomitrium-Physcomitrella species complex, the Funariaceae are host to their type species, Funaria hygrometrica, featuring a sporophyte morphology which is more complex. Their considerable developmental variation among closely related lineages and remarkable trait evolution render the Funariaceae an interesting group for evolutionary and genetic research. PMID- 25015730 TI - Assessment of urinary metabolite excretion after rat acute exposure to perfluorooctanoic acid and other peroxisomal proliferators. AB - Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant. Activation of the peroxisome proliferator activated receptor alpha (PPARalpha) resulting from exposure to PFOA has been extensively studied in rodents. However, marked differences in response to peroxisome proliferators prevent extrapolation of rodent PPARalpha activation to human health risks and additional molecular mechanisms may also be involved in the biological response to PFOA exposure. To further explore the potential involvement of such additional pathways, the effects of PFOA exposure on urinary metabolites were directly compared with those of other well-known PPARalpha agonists. Male rats were administered PFOA (10, 33, or 100 mg/kg/d), fenofibrate (100 mg/kg/d), or di(2-ethylhexyl) phthalate (100 mg/kg/d) by gavage for 3 consecutive days and allowed to recover for 4 days, and overnight urine was collected. Greater urinary output was observed exclusively in PFOA-treated rats as the total fraction of PFOA excreted in urine increased with the dose administered. Assessment of urinary metabolites (ascorbic acid, quinolinic acid, 8-hydroxy-2'-deoxyguanosine, and malondialdehyde) provided additional information on PFOA's effects on hepatic glucuronic acid and tryptophan-nicotinamide adenine dinucleotide (NAD) pathways and on oxidative stress, whereas increased liver weight and palmitoyl-CoA oxidase activity indicative of PPARalpha activation and peroxisomal proliferation persisted up to day five after the last exposure. PMID- 25015731 TI - Effects of soil organic matter content on cadmium toxicity in Eisenia fetida: implications for the use of biomarkers and standard toxicity tests. AB - Bioavailability is affected by soil physicochemical characteristics such as pH and organic matter (OM) content. In addition, OM constitutes the energy source of Eisenia fetida, a well established model species for soil toxicity assessment. The present work aimed at assessing the effects of changes in OM content on the toxicity of Cd in E. fetida through the measurement of neutral red uptake (NRU) and mortality, growth, and reproduction (Organisation for Economic Co-operation and Development [OECD] Nos. 207 and 222). Complementarily, metallothionein (MT) and catalase transcription levels were measured. To decrease variability inherent to natural soils, artificial soils (Organization for Economic Cooperation and Development 1984) with different OM content (6, 10, and 14%) and spiked with Cd solutions at increasing concentrations were used. Low OM in soil decreased soil ingestion and Cd bioaccumulation but also increased Cd toxicity causing lower NRU of coelomocytes, 100 % mortality, and stronger reproduction impairment, probably due to the lack of energy to maintain protection mechanisms (production of MT).Cd bioaccumulation did not reflect toxicity, and OM played a pivotal role in Cd toxicity. Thus, OM content should be taken into account when using E. fetida in in vivo exposures for soil health assessment. PMID- 25015732 TI - Annual fluctuations of endocrine-disrupting compounds at the lower end of the Lima River, Portugal, and in adjacent coastal waters. AB - The Lima River is a Spanish-Portuguese water body. Notwithstanding the fact that the river incorporates protected natural areas, levels of endocrine-disrupting compounds (EDCs) within its waters have never been measured; such EDCs include the following: natural and pharmaceutical oestrogens (17beta-estradiol, E1, and 17alpha-ethynylestradiol), industrial and household pollutants (4-octylphenol, 4 nonylphenol, and their monoethoxylates and diethoxylates, and bisphenol A), phytoestrogens (formononetin, biochanin A, daidzein, genistein), and phytosterols (namely, sitosterol). To obtain an understanding of levels of EDCs, water samples were taken from eight sampling sites along the river every 2 months during a 1 year period (2011). The water samples were preconcentrated (Oasis HLB cartridges), cleaned (silica cartridges), and analysed using gas chromatography. Results showed that levels of oestrogens and industrial and household pollutants were higher in summer than in other seasons. Although oestrogens were more abundant (approximately 40 ng/L) on the southern margin of the river, levels of other pollutants were higher (approximately 124 ng/L) in the north. Phytoestrogens and sitosterol showed clear seasonal fluctuations with higher amounts of formononetin (approximately 389 ng/L), biochanin A (approximately 160 ng/L), and sitosterol (>=5 ug/L) measured in summer. The overall oestrogenic load, expressed in ethynylestradiol equivalents, was 18 ng/L for oestrogens, 0.5 ng/L for industrial and household pollutants, and 13 ng/L for phytoestrogens. Water physicochemical parameters indicate anthropogenic pollution because Sigmanitrites,nitrates (>1 mg/L) and phosphates (approximately 0.4 mg/L) were high. The study showed that the waters of the Lima River are subject to impacts and that levels of EDCs pose risks to the river's biota. PMID- 25015733 TI - TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury. AB - NLRP3 inflammasome is necessary for initiating acute sterile inflammation. Recent studies have demonstrated that NLRP3 inflammasome is up-regulated and mediates myocardial ischemia/reperfusion (MI/R) injury. However, the signaling pathways that lead to the activation of NLRP3 inflammasome by MI/R injury have not been fully elucidated. C57BL/6J mice were subjected to 30 min ischemia and 3 or 24 h reperfusion. The ischemic heart exhibited enhanced inflammasome activation as evidenced by increased NLRP3 expression and caspase-1 activity and increased IL 1beta and IL-18 production. Intramyocardial NLRP3 siRNA injection or an intraperitoneal injection of BAY 11-7028, an inflammasome inhibitor, attenuated macrophage and neutrophil infiltration and decreased MI/R injury, as measured by cardiomyocyte apoptosis and infarct size. The ischemic heart also exhibited enhanced interaction between Txnip and NLRP3, which has been shown to be a mechanism for activating NLRP3. Intramyocardial Txnip siRNA injection also decreased infarct size and NLRP3 activation. In vitro experiments revealed that NLRP3 was expressed in cardiac microvascular endothelial cells (CMECs), but was hardly expressed in cardiomyocytes. Simulated ischemia/reperfusion (SI/R) stimulated NLRP3 inflammasome activation in CMECs, but not in cardiomyocytes. Moreover, CMECs subjected to SI/R injury increased interactions between Txnip and NLRP3. Txnip siRNA diminished NLRP3 inflammasome activation and SI/R-induced injury, as measured by LDH release and caspase-3 activity in CMECs. ROS scavenger dissociated TXNIP from NLRP3 and inhibited the activation of NLRP3 inflammasome in the CMECs. For the first time, we demonstrated that TXNIP-mediated NLRP3 inflammasome activation in CMECs was a novel mechanism of MI/R injury. Interventions that block Txnip/NLRP3 signaling to inhibit the activation of NLRP3 inflammasomes may be novel therapies for mitigating MI/R injury. PMID- 25015734 TI - Chronic obstructive sleep apnea causes atrial remodeling in canines: mechanisms and implications. AB - Obstructive sleep apnea (OSA) is closely related to atrial fibrillation (AF). However, the roles and mechanisms of chronic OSA in atrial remodeling are still unclear. Canine model of chronic OSA was simulated by stopping the ventilator and closing the airway for 4 h per day and lasting for 12 weeks. AF inducibility and duration was increased while atrial effective refractory period (AERP) was shortened after chronic apnea. Meanwhile, upregulation of proteins encoding inward rectifier K(+) current (IK1), delayed rectifier K(+) current (IKr and IKs), acetylcholine activated K(+) current (IKACh), transient outward K(+) current (Ito) and ultra-rapid delayed rectifier potassium current (IKur) as well as downregulation of protein encoding L-type Ca(2+) current (ICa,L) were found after chronic OSA. Besides abnormal electrical activity, chronic OSA induced apoptosis and interstitial fibrosis of atrial myocytes, which was partly mediated by caspase 9, phosphorylation of extracellular-regulated kinase 1/2, and alpha smooth muscle actin. In addition, atrial sympathetic and parasympathetic hyperinnervation were found manifesting by enhanced growth-associated protein 43, tyrosine hydroxylase and elevated choline acetyltransferase. Moreover, protein expression of beta1, beta2, and M2 receptor were markedly increased by chronic OSA. In summary, we firstly demonstrated in canine model that chronic OSA could shorten AERP and lead to altered expression of important channel proteins, moreover, induce atrial structure remodeling by increased atrial apoptosis, fibrosis, and autonomic remodeling, eventually promoting the development of a substrate of AF. Our findings suggested that reversing atrial remodeling might be a potential therapeutic strategy for OSA-induced AF. PMID- 25015735 TI - Postprandial glucose-lowering effects of fermented red ginseng in subjects with impaired fasting glucose or type 2 diabetes: a randomized, double-blind, placebo controlled clinical trial. AB - BACKGROUND: Red ginseng is prepared by steaming raw ginseng, a process believed to increase the pharmacological efficacy. Further bioconversion of red ginseng through fermentation is known to increase its intestinal absorption and bioactivity, and bioconversion diminishes the toxicity of red ginseng's metabolite. This study was conducted to investigate the effects of daily supplementation with fermented red ginseng (FRG) on glycemic status in subjects with impaired fasting glucose or type 2 diabetes. METHODS: This study was a four week long, randomized, double-blind, placebo-controlled trial. Forty-two subjects with impaired fasting glucose or type 2 diabetes were randomly allocated to two groups assigned to consume either the placebo or fermented red ginseng (FRG) three times per day for four weeks. Fasting and postprandial glucose profiles during meal tolerance tests were assessed before and after the intervention. RESULTS: FRG supplementation led to a significant reduction in postprandial glucose levels and led to an increase in postprandial insulin levels compared to the placebo group. There was a consistently significant improvement in the glucose area under the curve (AUC) in the FRG group. However, fasting glucose, insulin, and lipid profiles were not different from the placebo group. CONCLUSION: Daily supplementation with FRG lowered postprandial glucose levels in subjects with impaired fasting glucose or type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01826409. PMID- 25015736 TI - [Diagnostics and treatment decisions in acute compartment syndrome. Results of a survey in German hospitals]. AB - BACKGROUND AND OBJECTIVES: The presented survey was intended to evaluate whether a standardization of diagnostics and therapy for acute compartment syndrome has been achieved. MATERIALS AND METHODS: University hospitals, academic teaching hospitals, and county hospitals in Germany were included. RESULTS: A total of 38% (n=120) of all contacted hospitals participated in this study with questions mainly answered by consulting physicians (68%). In general the importance of the clinical examination was considered as being more important than other diagnostic measures. In cases where further diagnostics were necessary, the intramuscular pressure measurement was used most frequently. Of the participants 50% performed surgical fasciotomy based on the clinical examination in combination with the intramuscular pressure measurement; however, there were considerable differences between the participating hospitals with respect to the anatomical position of intramuscular measurements, the limiting value of the intramuscular pressure and the surgical technique for performing fasciotomy. CONCLUSION: According to the presented analysis the diagnosis and indications for surgical treatment in patients developing an acute compartment syndrome do not seem to be sufficiently clarified. The establishment of unified treatment guidelines could help to reduce the number of delayed diagnoses of compartment syndrome. PMID- 25015737 TI - Comparative performance of aldolase and lactate dehydrogenase rapid diagnostic tests in Plasmodium vivax detection. AB - BACKGROUND: Misdiagnosis of malaria by commercial rapid diagnostic tests (RDTs) is a major cause of concern in the diagnosis of malaria. This retrospective study was aimed at assessing the relative performance of four RDTs with emphasis on the detection of two Plasmodium vivax antigens: aldolase and lactate dehydrogenase (LDH). METHODS: Three commercially available Plasmodium LDH or aldolase antigen detection kits (One Step Malaria P.f/P.v, ParaHit Total ver. 1.0, SD Bioline Malaria) and an anti-P. vivax aldolase-specific monoclonal antibody (mAb) pair 1C3-12 F10 were evaluated with P. vivax positive as well as non-P. vivax samples and healthy samples using blood smear examination as standard. Each test was read according to the manufacturer's instructions. RESULTS: MAb 1C3-12 F10 pair targeting P. vivax-specific aldolase exhibited very good specificity and sensitivity of 100 and 97.4%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of 100 and 99.5%, respectively, were also observed. The anti-P. vivax LDH in the One-Step Malaria P.f/P.v test showed sensitivity, specificity, PPV and NPV of 93.5, 98.0, 88.9 and 98.8%, respectively. ParaHit Total ver. 1.0 targeting the pan-aldolase antigen showed sensitivity, specificity of 97.4 and 99.6%, respectively. PPV and NPV were both 99.5%. SD Bioline had sensitivity, specificity, PPV and NPV of 93.5, 100, 100 and 98.8%, respectively. The overall sensitivity and specificity of all four RDTs were acceptable, especially for the aldolase detection tests. Five (6.5%) of the P. vivax-positive samples (n = 77) that were confirmed by microscopic examination as well as the two aldolase detection RDTs (mAb 1C3-12 F10 and ParaHit Total ver.1.0) were undetected by the two LDH detection RDTs (One Step Malaria P.f/P.v and SD Bioline). Similarly, two positive samples (2.6%) that were positively confirmed by the LDH detection RDTs were also undetected by the aldolase detection test kits. CONCLUSION: Aldolase and LDH antigens perform differently in different P. vivax samples; hence there is a high risk of misdiagnosis when monoclonal antibodies are used against only one particular antigen in the test. A combination of both aldolase and LDH in RDTs for the rapid diagnosis of P. vivax will enhance the sensitivity of the assay and reduce misdiagnosis. PMID- 25015738 TI - Clinical and haematological responses of feline blood donors anaesthetised with a tiletamine and zolazepam combination. AB - This prospective study investigated the effect on clinical and haematological variables of the anaesthetic combination of tiletamine and zolazepam in feline blood donors. Blood (10 ml/kg bodyweight to a maximum volume of 60 ml) was collected from the jugular vein of 31 owned healthy cats anaesthetised with 2.5 mg/kg of tiletamine and 2.5 mg/kg of zolazepam intramuscularly. Rectal temperature (RT), systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), heart rate (HR) and complete blood count (including red blood cells [RBC], haemoglobin [HB], haematocrit [HT], platelet [PLT] count, white blood cells [WBC], lymphocytes, neutrophils, eosinophils, monocytes and basophils) were evaluated pre- and postdonation. RT decreased significantly (P <0.01) after blood donation (mean change in RT -0.7 degrees C). Significant increases in SAP (P = 0.03), MAP (P <0.01) and DAP (P <0.01) occurred after blood donation (mean increase 13 mmHg, 12 mmHg and 11 mmHg, respectively). Although RBC, HT, HB, WBC, PLT, neutrophil and monocyte counts decreased, and HR, and lymphocyte, eosinophil and basophil counts increased after blood donation this change was not statistically significant. Mean time from pre- to postdonation evaluation was 39 +/- 11 mins (range 24-76 mins). None of the cats had evidence of pallor or collapse after recovery from anaesthesia. The collection of blood at 10 ml/kg bodyweight to a maximum volume of 60 ml in healthy cats using a low dose tiletamine and zolazepam anaesthetic appears to be well tolerated by feline blood donors. PMID- 25015740 TI - A cohort analysis to identify eligible patients for intraoperative radiotherapy (IORT) of early breast cancer. AB - BACKGROUND: Since the results from the randomized TARGIT A trial were published, intraoperative radiotherapy (IORT) is used more often. IORT can be provided as accelerated partial breast irradiation (APBI) or as a boost. The definition of suitable patients for IORT as APBI differs between different national societies (e.g. ESTRO and ASTRO) and different inclusion criteria of trials and so does the eligibility of patients. This analysis identifies eligible patients for IORT according to available consensus statements and inclusion criteria of the ongoing TARGIT trials. METHODS: Between 01/03 - 12/09, 1505 breast cancer cases were treated at the breast cancer center at the University Medical Center Mannheim. Complete data sets for age, stage (T, N, and M), histology and hormone receptor status were available in 1108 cases. Parameters to identify eligible patients are as follows: ESTRO: >50 years, invasive ductal carcinoma/other favorable histology (IDC), T1-2 (<=3 cm), N0, any hormone receptor status, M0; ASTRO: >=60 years, IDC, T1, N0, positive estrogen hormone receptor status, M0; TARGIT E "elderly", risk adapted radiotherapy with IORT followed by external beam radiotherapy in case of risk factors in final histopathology, phase II: >=70 years, IDC, T1, N0, any hormone receptor status, M0; TARGIT C "consolidation", risk adapted radiotherapy, phase IV: >=50 years, IDC, T1, N0, positive hormone receptor status, M0; TARGIT BQR "boost quality registry": every age, every histology, T1-2 (max. 3.5 cm), any hormone receptor status, N0/+, M0/+. RESULTS: Out of the 1108 cases, 379 cases (34.2%) were suitable for IORT as APBI regarding the ESTRO and 175 (15.8%) regarding the ASTRO consensus statements. 82 (7.4%) patients were eligible for the TARGIT E trial, 258 (23.3%) for the TARGIT C trial and 671 (60.6%) for the TARGIT BQR registry. According to the consensus statements of ASTRO (45.1%) and ESTRO (41.4%) about half of the eligible patients were treated with IORT as APBI. From the eligible patients fulfilling the criteria for IORT boost (35%) about one third was eventually treated. CONCLUSIONS: Patient selection for IORT should be restrictive. For IORT as APBI the TARGIT trials are even more restrictive including patients than the ESTRO and ASTRO consensus statements. PMID- 25015739 TI - Comparative genome sequencing reveals chemotype-specific gene clusters in the toxigenic black mold Stachybotrys. AB - BACKGROUND: The fungal genus Stachybotrys produces several diverse toxins that affect human health. Its strains comprise two mutually-exclusive toxin chemotypes, one producing satratoxins, which are a subclass of trichothecenes, and the other producing the less-toxic atranones. To determine the genetic basis for chemotype-specific differences in toxin production, the genomes of four Stachybotrys strains were sequenced and assembled de novo. Two of these strains produce atranones and two produce satratoxins. RESULTS: Comparative analysis of these four 35-Mbp genomes revealed several chemotype-specific gene clusters that are predicted to make secondary metabolites. The largest, which was named the core atranone cluster, encodes 14 proteins that may suffice to produce all observed atranone compounds via reactions that include an unusual Baeyer-Villiger oxidation. Satratoxins are suggested to be made by products of multiple gene clusters that encode 21 proteins in all, including polyketide synthases, acetyltransferases, and other enzymes expected to modify the trichothecene skeleton. One such satratoxin chemotype-specific cluster is adjacent to the core trichothecene cluster, which has diverged from those of other trichothecene producers to contain a unique polyketide synthase. CONCLUSIONS: The results suggest that chemotype-specific gene clusters are likely the genetic basis for the mutually-exclusive toxin chemotypes of Stachybotrys. A unified biochemical model for Stachybotrys toxin production is presented. Overall, the four genomes described here will be useful for ongoing studies of this mold's diverse toxicity mechanisms. PMID- 25015741 TI - Reprint of: Monocyte subsets in man and other species. AB - Monocytes are white blood cells that belong to the mononuclear phagocyte system. They derive from precursors in bone marrow, from there they go into blood, where they have a half-life of 1-2 days, and then they migrate into the various tissues. Monocyte subsets were discovered by means of flow cytometry in human blood some 20 years ago and their phenotype and function has been characterized in detail in health and disease. The subset classification as classical, intermediate and non-classical monocytes appears to apply to other species as well, as reviewed in here by comparing data on human monocytes with the respective cells in the mouse, the rat, the pig, the cow and the horse. The data show that the subsets are homologous between the species but there are important differences in subset-specific gene expression such that findings in a given species cannot be directly translated to man. PMID- 25015744 TI - Endoscopic ultrasound-guided pelvic and prostatic abscess drainage: experience in 30 patients. AB - BACKGROUND: Endoscopic ultrasound (EUS)-guided drainage is an effective treatment for many abscesses in the abdomen. We review our experience with EUS-guided drainage of pelvic abscesses. METHODS: Thirty consecutive patients who underwent EUS-guided pelvic abscess drainage were evaluated after excluding three patients with distance to transducer >2 cm or organized abscess. RESULTS: Thirty patients (25 male) aged 60 +/- 4.5 years (mean +/- SD) had 4 prostatic abscesses, 7 perisigmoid abscesses, and 19 perirectal abscesses with mean +/- SD sizes of 2.5 +/- 0.3, 4.7 +/- 0.6, and 5.4 +/- 0.4 cm, respectively. Surgery was the most common predisposing factor (n = 14, 46.6 %) followed by diverticulitis (n = 5, 16.6 %). Interventions included aspiration only (2 prostatic and 3 perisigmoid), aspiration and dilatation (2 patients in each group), and dilatation and stenting (2 perisigmoid and 17 perirectal). Five (16.6 %) patients needed re-intervention, and two (6.6 %) needed surgery. There were no recurrences. Technical success of EUS-guided pelvic abscess drainage overall was 90.9 % (30/33) and was 93.3 % (27/30) in patients in whom EUS-guided drainage was attempted, with 16.5 % (n = 5) re-intervention rate. CONCLUSION: EUS-guided drainage has an excellent success rate in drainage of pelvic abscesses. PMID- 25015743 TI - Long-term storage of authentic postmortem forensic blood samples at -20 degrees C: measured concentrations of benzodiazepines, central stimulants, opioids and certain medicinal drugs before and after storage for 16-18 years. AB - The long-term stability of benzodiazepines, opioids, central stimulants and medicinal drugs in authentic postmortem blood samples was studied. All together, 73 samples were reanalyzed after storage at -20 degrees C for 16-18 years. At reanalysis samples containing diazepam, nordiazepam and flunitrazepam demonstrated only small changes during long-term storage when mean and median drug concentrations were compared, while clonazepam concentrations tended to decrease. Samples containing amphetamine, morphine, codeine and 'acidic' medicinal drugs as paracetamol and meprobamate also showed small changes over 16 18 years in mean and median drug concentrations at a group level. For many drugs, however, single samples could demonstrate marked concentration changes, both increases and decreases during storage. For 'alkaline' medicinal drugs, concentration losses were observed in most cases. PMID- 25015745 TI - Efficacy and safety of hepatitis C antiviral therapy in moderate and severe chronic kidney disease. AB - Hepatitis C virus (HCV) infection is an important cause of liver-related morbidity and mortality in patients with end-stage renal disease (ESRD). Though indicated, antiviral therapy adds to the existing financial burden and is poorly tolerated in these patients. We studied HCV treatment outcomes in patients with moderate and severe chronic kidney disease (CKD) between June 2010 and June 2012. Out of 46 patients with CKD, only 16 (genotype 1:6, 3:9, indeterminate 1) received interferon treatment (conventional 9, pegylated 7; with low-dose ribavirin 5). End of treatment response was achieved in 50 % and sustained viral response in 44 %. Adverse effects such as tuberculosis, anemia, and cardiac failure resulting in discontinuation of therapy were seen in three. The dropout rate was 38 %. Though interferon therapy was efficacious and safe, it was received by only 35 % of patients with CKD. We suggest that antiviral therapy be offered under close monitoring in the absence of contraindications in patients with moderate and severe CKD. PMID- 25015747 TI - Adding L-carnitine to clomiphene resistant PCOS women improves the quality of ovulation and the pregnancy rate. A randomized clinical trial. AB - OBJECTIVE: To evaluate the effectiveness of L-carnitine on improving the ovulation and pregnancy rates as well as adverse metabolic indices in clomiphene resistant PCOS. DESIGN: Single center, double blinded, superiority, randomized controlled clinical trial. SETTING: Women's Health Hospital, Assiut University. METHODS: One hundred and seventy women diagnosed with PCOS were found to be clomiphene resistant. The women were randomly allocated into two groups: Group A (n=85), where patients received 250 mg clomiphene citrate from day three until day seven of the cycle plus L-carnitine (LC) 3g daily; and Group B (n=85) received 250 mg clomiphene citrate with placebo. OUTCOME: Primary outcome is cumulative clinical pregnancy rate. Secondary outcomes are changes in serum glucose level and lipid profile. RESULTS: The combination of L-carnitine and CC significantly improve both the ovulation and the cumulative pregnancy rates in clomiphene resistant PCOS (55 (64.4%) vs. 15 (17.4%) and 44 (51.5) % vs. 5 (5.8) %). The number of stimulated follicles reaching >=17 mm diameter was significantly more in Group A to Group B (2.2 +/- 0.77 vs. 0.16 +/- 0.79; p<0.0001). Group A needed significantly fewer days for adequate follicular maturation, had a thicker endometrium and higher oestradiol concentration at the time of human chorionic gonadotrophin injection (10.1 +/- 0.1mm vs. 6.8 +/- 0.4mm; p<0.0001). The same group had a higher mean luteal-phase serum progesterone compared with the control group (13.55 +/- 0.99 vs. 10.6 +/- 0.98 ng; p<0.0001). A significant difference was found regarding the clinical pregnancy rates (42 (49.4%) vs. (1) 1.1% respectively p value <0.0001). CONCLUSION: Adding L-carnitine when treating clomiphene-resistant PCOS patients not only improved the quality of ovulation and the pregnancy rate with an acceptable patient tolerability, but also enhanced the patient lipid profile and body mass index. PMID- 25015746 TI - Use of narrow band imaging in assessing duodenal villous atrophy. AB - BACKGROUND AND OBJECTIVE: Narrow band imaging endoscopy with magnification (NBI ME) has already been established in Barrett's esophagus, stomach, and colonic mucosa, but limited work has been done in the mucosal evaluation of duodenum. A study was done to determine the correlation between NBI and histology in grading villous architecture in varied etiology. METHOD: A prospective observational study comprising 105 subjects with suspected malabsorption. The presence of a diagnosed celiac disease, severe life threatening comorbidity, or pregnancy was considered as exclusion criteria. Standard endoscopy (SE), NBI-ME, multiple duodenal biopsies with histopathological examination were done in all. RESULTS: Fifty-one patients had celiac disease while 54 patients comprised mainly functional dyspepsia, iron deficiency anemia, tropical malabsorption syndrome, and irritable bowel syndrome. Four NBI-ME image subtypes of villous morphology have been proposed (NBI type I/II/III/IV). NBI-ME had 95 % sensitivity, 90.2 % specificity, 91.2 % positive predictive value, and 94.2 % negative predictive value for diagnosing altered villous morphology. Intraobserver kappa agreement coefficient (kappa) for NBI-ME was 0.83 while interobserver agreement was 0.89 (95 % CI 0.8-0.97). CONCLUSION: NBI-ME has good performance characteristics and very good kappa intra/interobserver agreement coefficient for varied subtypes of villous morphology. NBI-ME is most useful for obtaining a targeted biopsy which can be missed by conventional white light endoscopy. PMID- 25015748 TI - A novel in vivo model of permanent intestinal aganglionosis. AB - BACKGROUND: Enteric neuromuscular disease is a characteristic of several disease states, including Hirschsprung disease, esophageal achalasia, Chagas disease, and gastroparesis. Medical therapy for these conditions is limited, and surgical intervention may incur significant morbidity. Alternatively, transplantation of neural progenitor cells may regenerate enteric ganglia. Existing aganglionosis model systems are limited by swift animal demise or by spontaneous regeneration of native ganglia. We propose a novel protocol to induce permanent aganglionosis in a segment of rat jejunum, which may serve as an experimental transplantation target for cellular therapy. MATERIALS AND METHODS: This protocol was performed in 17 adult female Sprague-Dawley rats. A laparotomy was performed and a 1-cm segment of jejunum was isolated from continuity. Among 14 rats, the isolated segments were treated with benzalkonium chloride (BAC) for 20 min to induce aganglionosis. Jejunal segment isolation was performed without BAC treatment in three rats. The animals were euthanized at posttreatment days 21-166. Muscle layer diameter was compared among normal, isolated, and BAC-treated isolated jejunal segments. The presence of jejunal ganglia was documented by immunohistochemical staining (IHC) for beta-III tubulin (TUJ1) and S100, markers of neuronal and glial cell lineages, respectively. RESULTS: Ganglia were identified by IHC in normal and isolated jejunal segments. Isolated segments had significantly hypertrophied smooth muscle layers compared with normal jejunum (diameter 343 +/- 53 MUm versus 211 +/- 37 MUm, P < 0.0001). BAC-treated jejunal segments had no IHC evidence of ganglionic structures. Aganglionosis was persistent in all specimens up to 166 days after treatment. CONCLUSIONS: The exclusion of a jejunal segment from continuity and concurrent treatment with BAC results in an effective, reproducible, and permanent model of aganglionosis. Muscular hypertrophy and aganglionosis in the isolated jejunal segment make it an ideal recipient site for transplantation of neuroglial precursor cells. PMID- 25015749 TI - Trauma capacity in the central plateau department of Haiti. AB - BACKGROUND: Surgical burden is a large and neglected global health problem in low and middle-income countries. With the increasing trauma burden, the goal of this study was to evaluate the trauma capacity of hospitals in the central plateau of Haiti. MATERIALS AND METHODS: The World Health Organization Emergency and Essential Surgical Care survey was adapted with a focus on trauma capacity. Interviewers along with translators administered the survey to key hospital staff. RESULTS: Seven hospitals in the region were surveyed. Of the hospitals surveyed, 3/7 had functioning surgical facilities. None of the hospitals had trauma registries. 71% of the hospitals had no formal trauma guidelines. 2/7 hospitals had a general surgeon available 100% of the time. All surgical facilities had oxygen cylinders available 100% of the time, but three of the primary level hospitals only had it available 51%-90% of the time. Intubation equipment was available at 57% of the facilities. Ventilators were only available in the operating room. Only the largest hospital had a computed tomography scanner. Other hospitals (66%) had a functioning x-ray machine 76%-90% of the time. Hospitals (57%) had an ultrasound machine. The most common reasons for referral were lack of appropriate facilities and supplies at the primary level care centers or lack of trained personnel at higher-level facilities. CONCLUSIONS: Trauma capacity in the central plateau of Haiti is limited. There is a great need for more personnel, trauma training at all staff levels, emergency care guidelines, trauma registries, and imaging equipment and training, specifically in ultrasonography. To accomplish this, coordination is needed between the Haitian government and local and international nongovernmental organizations. PMID- 25015750 TI - Analytic morphomics corresponds to functional status in older patients. AB - BACKGROUND: Older patients account for nearly half of the United States surgical volume, and age alone is insufficient to predict surgical fitness. Various metrics exist for risk stratification, but little work has been done to describe the association between measures. We aimed to determine whether analytic morphomics, a novel objective risk assessment tool, correlates with functional measures currently recommended in the preoperative evaluation of older patients. MATERIALS AND METHODS: We retrospectively identified 184 elective general surgery patients aged >70 y with both a preoperative computed tomography scan and Vulnerable Elderly Surgical Pathways and outcomes Assessment within 90 d of surgery. We used analytic morphomics to calculate trunk muscle size (or total psoas area [TPA]) and univariate logistic regression to assess the relationship between TPA and domains of geriatric function mobility, basic and instrumental activities of daily living (ADLs), and cognitive ability. RESULTS: Greater TPA was inversely correlated with impaired mobility (odds ratio [OR] = 0.46, 95% confidence interval [CI] 0.25-0.85, P = 0.013). Greater TPA was associated with decreased odds of deficit in any basic ADLs (OR = 0.36 per standard deviation unit increase in TPA, 95% CI 0.15-0.87, P <0.03) and any instrumental ADLs (OR = 0.53, 95% CI 0.34-0.81; P <0.005). Finally, patients with larger TPA were less likely to have cognitive difficulty assessed by Mini-Cog scale (OR = 0.55, 95% CI 0.35-0.86, P <0.01). Controlling for age did not change results. CONCLUSIONS: Older surgical candidates with greater trunk muscle size, or greater TPA, are less likely to have physical impairment, cognitive difficulty, or decreased ability to perform daily self-care. Further research linking these assessments to clinical outcomes is needed. PMID- 25015751 TI - The incidence and risk factors of gastrointestinal complications after hepatectomy: a retrospective observational study of 1329 consecutive patients in a single center. AB - BACKGROUND: Despite of the importance of gastrointestinal (GI) complications in morbidity and mortality after major and moderate surgeries, it is not yet specifically studied in patients undergoing hepatectomy. This study was aimed to investigate the in-hospital incidence and potential risk factors of GI complications after open hepatectomy in our hospital. SUBJECTS AND METHODS: Prospectively recorded perioperative data from 1329 patients undergoing elective hepatectomy were retrospectively reviewed. The in-hospital incidence of GI complications was investigated, and independent risk factors were analyzed by multiple logistic regression. RESULTS: GI complications occurrence was 46.4%. Univariate analysis showed that preoperative Child-Pugh score, total bilirubin, aspartate transaminase, anesthesia duration, operation duration, intraoperative blood loss, crystalloid and colloid infusion, blood transfusion, urine output, use of Pringle maneuver were statistically different between patients with and without GI complications (P < 0.05). Moreover, patients with GI complications had a more prolonged postoperative parenteral nutrient supporting time, hospital stay and ICU stay, and higher incidence of other complications than those without GI complications (P < 0.05). Multivariate regression indicated that long duration of anesthesia (odds ratio 2.51, P < 0.001) and use of Pringle maneuver (odds ratio 1.37, P = 0.007) were independent risk factors of GI complications after hepatectomy. CONCLUSIONS: The incidence of GI complications after hepatectomy is high, which is related to an increase of other complications and a prolonged hospital stay. Avoidance of routinely use of Pringle maneuver and shortening the duration of anesthesia are important measures to reduce the postoperative GI complications. PMID- 25015752 TI - Cholecystectomy and wound complications: smoking worsens risk. AB - BACKGROUND: In the United States, approximately 800,000 cholecystectomies are performed annually. We sought to determine the influence of preoperative smoking on postcholecystectomy wound complication rates. MATERIALS AND METHODS: Using the National Surgical Quality Improvement Program database (2005-2011), patients aged >=18 y who underwent elective open or laparoscopic cholecystectomy (LC) for benign gallbladder disease were identified using current procedural terminology codes. Multivariate regression was performed to determine the association between smoking status and wound complications, by surgical approach. RESULTS: Of 143,753 identified patients, 128,692 (89.5%) underwent LC, 27,788 (19.3%) were active smokers, and 100,710 (70.2%) were females. Active smokers were younger than nonsmokers (mean + standard deviation age: 44.2 (14.9) versus 51.6 (17.9) years); P < 0.001) and had fewer comorbidities. Within 30-d postcholecystectomy, wound complications were reported in 2011 (1.4%) patients. Compared with nonsmokers, active smokers demonstrated increased odds of wound complications after both open cholecystectomy (odds ratio 1.28; P = 0.010) and LC (odds ratio 1.20; P = 0.020) after adjustment for demographic and clinical characteristics. Having wound complications increased the average postoperative length of stay by 2-4 d (P <0.001). CONCLUSIONS: Active smokers are more likely to develop wound complications after cholecystectomy, regardless of surgical approach. Occurrence of wound complications consequently increases postoperative length of stay. Smoking abstinence before cholecystectomy may reduce the burden associated with wound complications. PMID- 25015753 TI - Early weight-bearing after periacetabular osteotomy leads to a high incidence of postoperative pelvic fractures. AB - BACKGROUND: It has not been shown whether accelerated rehabilitation following periacetabular osteotomy (PAO) is effective for early recovery. The purpose of this retrospective study was to compare complication rates in patients with standard and accelerated rehabilitation protocols who underwent PAO. METHODS: Between January 2002 and August 2011, patients with a lateral center-edge (CE) angle of < 20 degrees , showing good joint congruency with the hip in abduction, pre- or early stage of osteoarthritis, and age younger than 60 years were included in this study. We evaluated 156 hips in 138 patients, with a mean age at the time of surgery of 30 years. Full weight-bearing with two crutches started 2 months postoperatively in 73 patients (80 hips) with the standard rehabilitation protocol. In 65 patients (76 hips) with the accelerated rehabilitation protocol, postoperative strengthening of the hip, thigh and core musculature was begun on the day of surgery as tolerated. The exercise program included active hip range of motion, and gentle isometric hamstring and quadriceps muscle sets; these exercises were performed for 30 minutes in the morning and 30 minutes in the afternoon with a physical therapist every weekday for 6 weeks. Full weight bearing with two axillary crutches started on the day of surgery as tolerated. Complications were evaluated for 2 years. RESULTS: The clinical results at the time of follow-up were similar in the two groups. The average periods between the osteotomy and full-weight-bearing walking without support were 4.2 months and 6.9 months in patients with the accelerated and standard rehabilitation protocols (P < 0.001), indicating that the accelerated rehabilitation protocol could achieve earlier recovery of patients. However, postoperative fractures of the ischial ramus and posterior column of the pelvis were more frequently found in patients with the accelerated rehabilitation protocol (8/76) than in those with the standard rehabilitation protocol (1/80) (P = 0.013). CONCLUSION: The accelerated rehabilitation protocol seems to have advantages for early muscle recovery in patients undergoing PAO; however, postoperative pelvic fracture rates were unacceptably high in patients with this protocol. PMID- 25015754 TI - Total joint arthroplasty surgery: does day of surgery matter? AB - Length of stay (LOS) after total joint arthroplasty (TJA) impacts the expense to the hospital. Our purpose was to evaluate the impact that day of surgery has on postoperative LOS. 547 patients who had a primary TJA at two tertiary care hospitals were identified retrospectively. TJA patients admitted on day of surgery and who had primary elective surgery were included in our sample. Patients were subdivided into one of four groups: those who had operations on Monday, Tuesday, Thursday, and Friday respectively. Patients who had surgery on Thursday and Friday had significantly longer LOS when compared to Monday and Tuesday. This variation in LOS between the groups may be due to inconsistencies in weekend functionality, less experienced part-time staffing, and inaccessibility of rehabilitation personnel. PMID- 25015755 TI - Revising an HTO or UKA to TKA: is it more like a primary TKA or a revision TKA? AB - Forty-nine patients revised from UKA to TKA and 43 from HTO to TKA were matched to 43 aseptic, both component revision TKAs (rTKA) and 97 primary TKAs. At a mean of 4.8 years, the KSS and function scores in the UKA to TKA, HTO to TKA and primary TKA cohorts were similar. Total operative times were significantly higher in the HTO to TKA and rTKA groups. LOS was shorter in the primary TKA cohort. The rate of complications and reoperations were higher in HTO to TKA and rTKA compared to UKA to TKA and primary TKA. Thus, revising an HTO and UKA both had functional outcomes more similar to a primary TKA, however, the complication rate of revising an HTO was similar to an rTKA. PMID- 25015756 TI - Prospective, randomized trial to evaluate efficacy of a thrombin-based hemostatic agent in total knee arthroplasty. AB - Total knee arthroplasty (TKA) can be associated with substantial blood loss, leading to increased morbidity and transfusion rates. The study objective was to evaluate routine use of a thrombin-based topical hemostatic matrix in reducing blood loss and transfusion requirements in primary TKA. 108 patients were enrolled in a prospective, randomized, single-center trial. Patients receiving the hemostatic agent demonstrated a lower mean calculated blood loss (1325.2+/ 464.8mL vs. control, 1509.3+/-432.8mL; P=0.02), drain output (415.6+/-202.0mL vs. control, 579.9+/-306.7mL; P=0.008), and length of stay (3.3+/-0.8days vs. control, 3.7+/-1.1days; P=0.03), without a statistically significant difference in mean hemoglobin loss or transfusion requirements. The clinical utility of this hemostatic agent to reduce transfusions after uncomplicated, primary TKA continues to remain unclear. PMID- 25015757 TI - Revision total knee arthroplasty for failure of primary treatment of periprosthetic knee fractures. AB - Periprosthetic knee fractures and their complications are expected to increase as the numbers of knee arthroplasties continue to rise. We report our experience with revision knee arthroplasty for failure of primary fracture treatment. Five periprosthetic knee non-unions and 1 mal-union in 6 patients, with ages ranging from 65 to 83years (average 74.6years) were treated with revision total knee arthroplasty, and were followed up for 3 to 10years (average 4.5years). Union occurred in 8 to 18weeks (average 12.5weeks). All patients were ambulatory at the latest follow-up, with a range of motion averaging 84.2 degrees (P = 0.03), and an Oxford Knee Score averaging 35 (P = 0.03). We conclude that union complications of periprosthetic knee fractures can be satisfactorily addressed with revision arthroplasty. PMID- 25015758 TI - Length of storage of transfused red blood cells and risk of prosthetic joint infection after primary knee arthroplasty. AB - The aim of our study was to determine the potential influence of blood transfusion and the length of storage of packed red blood cells (RBC) on prosthetic joint infection after primary knee arthroplasty. From November 2007 to November 2009, all variables potentially associated with deep infection were registered in 1331 consecutive patients who underwent total knee arthroplasty. Infection was diagnosed in 32 (2.4%) patients. After adjusting for important variables, blood transfusion with RBCs stored >14days was the strongest predictive factor for prosthetic joint infection within 90days after primary knee arthroplasty (OR: 5.9, 95% CI: 2.6-13.2, P < 0.001). Blood saving techniques are desirable to reduce perioperative blood transfusion. PMID- 25015759 TI - Decreased blood transfusion following revision total knee arthroplasty using tranexamic acid. AB - Tranexamic acid (TXA) has been used successfully in primary total knee arthroplasty (TKA) to minimize blood loss and transfusions. The purpose of this study is to determine its efficacy in patients undergoing revision TKA. In a retrospective review of 111 patients (68 control and 43 TXA), treatment patients receiving a single intravenous TXA dose of 10mg/kg required less transfusions (P=0.03) and less total blood units consumed than controls (P=0.03). When stratified by type of revision, treatment patients undergoing femoral and tibial component revision had lower transfusion rates than the controls (P=0.03). Given the drawbacks of allogenic blood transfusion, we highly recommend the use of TXA in revision TKA, especially when both components are being revised. PMID- 25015760 TI - Erratum to: Chemical characterization of milk oligosaccharides of the common brushtail possum (Trichosurus vulpecula). PMID- 25015761 TI - Cloud-based hospital information system as a service for grassroots healthcare institutions. AB - Grassroots healthcare institutions (GHIs) are the smallest administrative levels of medical institutions, where most patients access health services. The latest report from the National Bureau of Statistics of China showed that 96.04 % of 950,297 medical institutions in China were at the grassroots level in 2012, including county-level hospitals, township central hospitals, community health service centers, and rural clinics. In developing countries, these institutions are facing challenges involving a shortage of funds and talent, inconsistent medical standards, inefficient information sharing, and difficulties in management during the adoption of health information technologies (HIT). Because of the necessity and gravity for GHIs, our aim is to provide hospital information services for GHIs using Cloud computing technologies and service modes. In this medical scenario, the computing resources are pooled by means of a Cloud-based Virtual Desktop Infrastructure (VDI) to serve multiple GHIs, with different hospital information systems dynamically assigned and reassigned according to demand. This paper is concerned with establishing a Cloud-based Hospital Information Service Center to provide hospital information software as a service (HI-SaaS) with the aim of providing GHIs with an attractive and high-performance medical information service. Compared with individually establishing all hospital information systems, this approach is more cost-effective and affordable for GHIs and does not compromise HIT performance. PMID- 25015762 TI - Morphology of the male reproductive system, sperm ultrastructure and gamma irradiation of the red palm weevil Rhynchophorus ferrugineus Oliv. (Coleoptera: Dryophthoridae). AB - In the present study we describe the morphology of the male reproductive apparatus and sperm ultrastructure of the red palm weevil - an invasive pest of several palm tree species - as well as the most important steps of spermatogenesis. The reproductive apparatus consists of a pair of testes (each formed by two lobes) a long tube-like accessory gland, a prostate gland and a small accessory gland. Characteristic features of the sperm are 90-100 MUm total length, 10 MUm nucleus, two mitochondrial derivatives, two accessory bodies, one well-developed puff-like structure and a typical insect 9+9+2 flagellar axoneme. One of the methods used for the biological control of pests is the Sterile Insect Technique (SIT), for the evaluation of which we make a preliminary comparison of the sperm ultrastructure of non-irradiated and irradiated weevils (at a dose of 80 Gray). PMID- 25015763 TI - Effect of repaglinide, administered two or three times daily for 3 months, on glycaemic control in Japanese patients with type 2 diabetes mellitus. AB - OBJECTIVES: To compare the efficacy, safety and compliance of repaglinide, administered either two or three times daily, regarding glycaemic control in patients with type 2 diabetes mellitus. METHODS: Japanese adults with type 2 diabetes mellitus, who had been treated without sulphonylureas or glinides for >3 months, were randomly assigned to two groups to receive either 0.25 mg repaglinide, oral, twice daily (group A) or 0.25 mg repaglinide, oral, three times daily (group B). Glycosylated haemoglobin (HbA1c), glycoalbumin (GA) and 1,5-anhydroglucitol (1,5-AG) levels were measured at 0, 1, 2 and 3 months after treatment commenced. RESULTS: Out of 43 patients who enrolled (group A, n = 22; group B, n = 21), 33 patients completed the trial (group A, n = 16; group B, n = 17). No significant between-group differences in HbA1c, GA, or 1,5-AG levels were seen at 1-3 months. No severe hypoglycaemic episodes or other adverse events were observed. CONCLUSIONS: Minimal-dose repaglinide administered twice daily was similar in efficacy and safety to three-times-daily administration, in Japanese patients with type 2 diabetes mellitus. Administration of repaglinide twice daily could be an alternative regimen for patients who cannot take repaglinide three times daily. PMID- 25015764 TI - Aberrant promoter methylation of the cadherin 13 gene in serum and its relationship with clinicopathological features of prostate cancer. AB - OBJECTIVE: To investigate the clinical significance of cadherin 13 (CDH13) gene promoter methylation in the serum of patients with prostate cancer. METHODS: This prospective study examined the methylation status of CDH13 in serum samples obtained from patients with primary prostate cancer and age-matched control subjects, using methylation-specific polymerase chain reaction. Associations between methylation status of CDH13 and various clinicopathological features and patient survival were evaluated. RESULTS: A total of 98 patients with prostate cancer and 47 control subjects were enrolled in the study. CDH13 promoter methylation was detected in 44 out of 98 (44.9%) patients with prostate cancer; no methylation was found in control subjects. Methylation of CDH13 was significantly associated with an increased Gleason score, an advanced tumour stage, and a high prostate-specific antigen level. CDH13 methylation was associated with a worse survival outcome and a relative risk of death of 6.132 (95% confidence interval: 3.160, 12.187). CONCLUSIONS: Promoter methylation of CDH13 occurred frequently in the serum of patients with prostate cancer, was associated with an increased risk of death, and may become a useful independent predictor of a poor prognosis. PMID- 25015765 TI - Platinum nanoparticles supported on Ca(Mg)-zeolites for efficient room temperature alcohol oxidation under aqueous conditions. AB - Platinum nanoparticles supported on Ca(Mg)-ZSM-5 is an efficient, highly selective and stable catalyst for room-temperature oxidation of alcohols in water. Based on in situ EPR measurement and the radical trapping technique, we propose that the generation of OH radicals by cleavage of the O-O bond in the H2O2 intermediate is the rate determining step, which participated in the abstraction of H from the alpha-C-H bond of alcohol molecules to produce aldehydes/ketones. PMID- 25015766 TI - Diagnostic needle arthroscopy and the economics of improved diagnostic accuracy: a cost analysis. AB - BACKGROUND: Hundreds of thousands of surgical arthroscopy procedures are performed annually in the United States (US) based on MRI findings. There are situations where these MRI findings are equivocal or indeterminate and because of this clinicians commonly perform the arthroscopy in order not to miss pathology. Recently, a less invasive needle arthroscopy system has been introduced that is commonly performed in the physician office setting and that may help improve the accuracy of diagnostic findings. This in turn may prevent unnecessary follow-on arthroscopy procedures from being performed. OBJECTIVE: The purpose of this analysis is to determine whether the in-office diagnostic needle arthroscopy system can provide cost savings by reducing unnecessary follow on arthroscopy procedures. METHODS: Data obtained from a recent trial and from a systematic review were used in comparing the accuracy of MRI and VisionScope needle arthroscopy (VSI) with standard arthroscopy (gold standard). The resultant false positive and false negative findings were then used to evaluate the costs of follow-on procedures. These differences were then modeled for the US patient population diagnosed and treated for meniscal knee pathology (most common disorder) to determine if a technology such as VSI could save the US healthcare system money. Data on surgical arthroscopy procedures in the US for meniscal knee pathology were used (calendar year [CY] 2010). The costs of performing diagnostic and surgical arthroscopy procedures (using CY 2013 Medicare reimbursement amounts), costs associated with false negative findings, and the costs for treating associated complications arising from diagnostic and therapeutic arthroscopy procedures were assessed. RESULTS: In patients presenting with medial meniscal pathology (International Classification of Diseases, 9th edition, Clinical Modification [ICD9CM] diagnosis 836.0), VSI in place of MRI (standard of care) resulted in a net cost savings to the US system of US$115-US$177 million (CY 2013) (use of systematic review and study data, respectively). In patients presenting with lateral meniscus pathology (ICD9CM 836.1), VSI in place of MRI cost the healthcare system an additional US$14-US$97 million (CY 2013). Overall aggregate savings for meniscal (lateral plus medial) pathology were identified in representative care models along with more appropriate care as fewer patients were exposed to higher risk surgical procedures. CONCLUSIONS: Since in-office arthroscopy is significantly more accurate, patients can be treated more appropriately and the US healthcare system can save money, most especially in medial meniscal pathology. PMID- 25015767 TI - GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets. AB - Third World quasi-vegan cultures have been characterized by low risks for "Western" cancers, autoimmune disorders, obesity, and diabetes. The relatively low essential amino acid contents of many vegan diets may play a role in this regard. It is proposed that such diets modestly activate the kinase GCN2 - a physiological detector of essential amino acid paucity - within the liver, resulting in up-regulated production of fibroblast growth factor 21 (FGF21). FGF21, by opposing the stimulatory effect of growth hormone on hepatic IGF-I production, may be responsible for the down-regulation of plasma IGF-I observed in vegans consuming diets of modest protein content. Decreased IGF-I bioactivity throughout life can be expected to have a favorable impact on cancer risk, as observed in rodents that are calorie restricted or genetically defective in IGF-I activity. Increased FGF21 in vegans might also contribute to their characteristic leanness and low LDL cholesterol by promoting hepatic lipid oxidation while inhibiting lipogenesis. Direct trophic effects of FGF21 on pancreatic beta-cells may help to explain the low risk for diabetes observed in vegans, and the utility of vegan diets in diabetes management. And up-regulation of GCN2 in immune cells, by boosting T regulatory activity, might play some role in the reduced risk for autoimmunity reported in some quasi-vegan cultures. The fact that bone density tends to be no greater in vegans than omnivores, despite consumption of a more "alkaline" diet, might be partially attributable to the fact that FGF21 opposes osteoblastogenesis and decreases IGF-I. If these speculations have merit, it should be possible to demonstrate that adoption of a vegan diet of modest protein content increases plasma FGF21 levels. PMID- 25015768 TI - Tocotrienol rich fraction reverses age-related deficits in spatial learning and memory in aged rats. AB - Little is known about the effect of vitamin E on brain function. Therefore, in this study we evaluated the effect of tocotrienol rich fraction (TRF) on behavioral impairment and oxidative stress in aged rats. Thirty-six male Wistar rats (young: 3-months-old; aged: 21-months-old) were treated with either the control (olive oil) or TRF (200 mg/kg) for 3 months. Behavioral studies were performed using the open field test and Morris water maze (MWM) task. Blood was taken for assessment of DNA damage, plasma malondialdehyde (MDA) and vitamin E, and erythrocyte antioxidant enzyme activity. Brains were also collected to measure vitamin E levels. Results showed that aged rats exhibited reduced exploratory activity, enhanced anxiety and decreased spatial learning and memory compared with young rats. DNA damage and plasma MDA were increased, and vitamin E levels in plasma and brain were reduced in aged rats. Aged rats supplemented with TRF showed a markedly reduced level of anxiety, improved spatial learning and memory, reduced amount and severity of DNA damage, a reduced level of MDA, and increased levels of antioxidant enzyme activity and plasma/brain vitamin E compared with age-matched controls. In conclusion, TRF supplementation reverses spatial learning and memory decline and decreases oxidative stress in aged rats. PMID- 25015769 TI - Bifunctional roles of survivin-DeltaEx3 and survivin-2B for susceptibility to apoptosis in endometrial carcinomas. AB - PURPOSE: Alternative splicing variants of survivin have different biological roles on cell kinetics. Here, we focused on the effects of different variants, including wild type (wt), survivin-DeltaEx3, and survivin-2B, on apoptosis and cell proliferation in endometrial carcinomas (Em Cas). METHODS: Expression of survivin-wt, survivin-DeltaEx3, and survivin-2B with reference to cell death and proliferation was investigated, using Em Ca cell lines and its clinical tissues. RESULTS: Ishikawa cells stably overexpressing either survivin-DeltaEx3 (Surv DeltaEx3#34) or survivin-2B (Surv-2B#17) demonstrated considerably lower proliferative activity, along with up-regulation of p21waf1. After TNF-alpha treatment, Surv-DeltaEx3#34 cells showed an increase in apoptotic cells, while the effects were relatively minor in Surv-2B#17 cells. In contrast, doxorubicin treatment resulted in increased apoptotic cells in Surv-2B#17 but not Surv DeltaEx3#34 cells, along with decreased expression of bcl-2 relative to bax. Control Ishikawa cells also showed relatively higher endogenous mRNA expression of survivin-DeltaEx3 and survivin-2B during treatment of TNF-alpha and doxorubicin, respectively. In addition, exogenous overexpression of each survivin variant resulted in inhibition of other endogenous isoforms, indicating that the relative proportion may contribute to regulation of the splicing machinery. In clinical samples, level of survivin-DeltaEx3 relative to either survivin-wt or survivin-2B was significantly higher in Em Cas than non-neoplastic lesions. Moreover, survivin-DeltaEx3 and survivin-wt were positively correlated with apoptosis and cell proliferation, respectively, in Em Cas. CONCLUSIONS: These findings provided evidence that the balance among expression level of survivin variants may contribute to modulation of cell kinetics in Em Ca cells. PMID- 25015770 TI - Alzheimer disease and cancer risk: a meta-analysis. AB - PURPOSE: Alzheimer disease (AD) and cancer are seemingly two opposite ends of one spectrum. Studies have suggested that patients with AD showed a reduced risk of cancer and vice versa. However, available evidences are not conclusive. So we conducted a meta-analysis using published literatures to systematically examine cancer risk in AD patients. METHODS: A PubMed, EMBASE, and Web of Science search were conducted in May 2014. Pooled risk ratios (RRs) with their corresponding 95 % confidence intervals (CIs) were obtained using random-effects meta-analysis. We tested for publication bias and heterogeneity, and stratified for study characteristics, smoking-related cancers versus nonsmoking-related cancers, and site-specific cancers. RESULTS: Nine studies were included in this meta-analysis. Compared with controls, the pooled RR of cancer in AD patients was 0.55 (95 % CI 0.41-0.75), with significant heterogeneity among these studies (P < 0.001, I(2) = 83.5 %). The reduced cancer risk was more substantial when we restricted analyses to cohort studies, studies with adjusted estimates, studies defining AD by generally accepted criteria, and studies with longer length of follow-up. In sub analyses for site-specific cancers, only lung cancer showed significant decreased risk (RR 0.72; 95 % CI 0.56-0.91). We did not find significant publication bias (P = 0.251 for Begg and Mazumdar's test and P = 0.143 for Egger's regression asymmetry test). CONCLUSION: These results support an association between AD and decreased cancer risk. PMID- 25015771 TI - Mutation analysis of seven consanguineous Uyghur families with non-syndromic deafness. AB - OBJECTIVE: To investigate the genetic causes of consanguineous Uyghur families with nonsyndromic deafness. METHOD: Seven consanguineous Uyghur families with nonsyndromic deafness were recruited in this study and characterized for their audiometric phenotype. Mutation analysis of common deafness genes GJB2, SLC26A4 and MT-RNR1 was performed in all families by direct sequencing. RESULT: Bi allelic mutations in SLC26A4, including p.N392Y/p.N392Y, p.S57X/p.S57X and p.Q413R/p.L676Q, were detected in three families as the pathogenic causes for the deafness. No mutations were identified in GJB2 and MT-RNR1. CONCLUSION: Mutations in SLC26A4 was the most common causes of the Uyghur consanguineous deaf families. PMID- 25015772 TI - Efficiency of external nasal dilators in pediatric nasal septal deviation. AB - INRODUCTION: Nasal septal deviation results from irregular development of the nasomaxillary complex and trauma. Treatment of nasal septal deviation in pediatric patients is one of the biggest challenges in rhinology. Surgery may alter craniofacial growth patterns, and so it may be indicated only in the selected cases. The use of external nasal dilators is a relatively new treatment modality in nasal obstruction. OBJECTIVE: This study was performed to assess the efficacy of external nasal dilator in pediatric nasal septal deviation patients. METHODS: Seventy-six children who were diagnosed with nasal septal deviation at our outpatient clinic were included in the study. The patients were divided into 2 groups: the external nasal dilator group was composed of 48 children that had used an external nasal dilator for at least 1 month and still been using, while the control group was comprised of 28 children that had not received any treatment and had not used an external nasal dilator. The parents of the children were asked to complete the obstructive sleep apnea 18 questionnaire. In addition, the external nasal dilator group was asked to complete the questionnaire after stopping external nasal dilator use for 2 weeks and the control group also repeated the obstructive sleep apnea 18 questionnaire. RESULTS: The obstructive sleep apnea 18 questionnaire results were significantly different between the external nasal dilator group and the control group at the beginning of the study (i.e., when patients in the external nasal dilator group were still using their dilators, P = 0.000). On the other hand, there was no difference between the 2 groups after the patients in the external nasal dilator group had stopped using their external nasal dilator (P = 0.670). CONCLUSION: External nasal dilator use relieved nasal septal deviation, which narrows the nasal valve. The results of this study suggest that external nasal dilator could be used in patients that are not candidates for septoplasty. PMID- 25015773 TI - Pneumococcal PspA and PspC proteins: potential vaccine candidates for experimental otitis media. AB - OBJECTIVE: Otitis media is the most commonly diagnosed disease in ambulatory care and Streptococcuspneumoniae continues to be the most common bacterial agent. Bacterial resistance to antibiotics underscores the need for better vaccines. Current pneumococcal conjugate vaccines are modestly protective against otitis media; however, limited serotype coverage and serotype replacement have led to the investigation of pneumococcal proteins as potential vaccine candidates. Two proteins, pneumococcal surface proteins A (PspA) and C (PspC) are important virulence factors, expressed by virtually all strains. Although a number of pneumococcal proteins have been investigated in other infection sites, these proteins can have diverse organ-specific effects. In this study, we investigated the viability and virulence of single (PspA(-) and PspC(-)) and double (PspA( )/PspC(-)) mutants of pneumococcal PspA and PspC proteins in the chinchilla middle ear. METHODS: Bullae of 24 chinchillas were inoculated with 0.5 ml of 10(6) colony forming units (CFUs)/ml bacteria: 6 with wild-type D39 strain; 6 with PspA(-); 6 with PspC(-); and 6 with PspA(-)/PspC(-) isogenic mutant strains. Bacterial CFU levels in middle ear effusions and light microscopic analysis of the number of inflammatory cells in the round window membrane (RWM) were compared 48 h after inoculation. RESULTS: At 48 h, CFUs in middle ears were increased for wild-type and PspC(-) strains compared to inoculum levels; however, they were significantly less for the group inoculated with the PspC(-) strain compared to wild-type strain. No bacteria were detected in the PspA(-) and PspA(-)/PspC(-) groups. The number of inflammatory cells in the RWM was significantly higher in wild-type compared to the PspA(-), PspC(-), and PspA(-)/PspC(-) groups. No significant difference in number of inflammatory cells was observed between any pairs of groups inoculated with mutant strains. CONCLUSION: Viability and virulence of the PspC(-) strain were similar to the wild-type strain. The single PspA(-) and double PspA(-)/PspC(-) mutants were highly attenuated in the ear. Bacterial clearance of the PspA(-)/PspC(-) double mutant was indistinguishable from that of the PspA mutant. These studies provide no reason to exclude PspC from a multi-component protein vaccine containing PspA. PMID- 25015775 TI - Drinking and the brain: careful selection of research participants required. PMID- 25015774 TI - ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning. AB - Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H2O2)-induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H2O2 caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC. Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF- or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H2O2-stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death. PMID- 25015776 TI - Metallothionein 3 expression in normal skin and malignant skin lesions. AB - Metallothionein-3 (MT-3) has been shown to be expressed in several malignancies and to have an impact on patients' survival in breast and urinary bladder cancer cases. However, its expression has not been determined in normal skin or in its malignant lesions. MT-3 expression was studied using immunohistochemistry in 17 cases of normal skin, 18 of actinic keratosis (AK), 39 of squamous cell carcinoma (SCC), and 23 of basal cell carcinoma (BCC). Low MT-3 expression was observed in normal skin epidermis with faint or no expression in the epidermis basal layer. Significantly higher MT-3 expression was noted in AK (P=0.007) and SCC (P<0.0001), as compared with normal skin epidermis. BCC cases were characterized by the lowest MT-3 expression of all the examined groups, which was significantly lower in comparison to normal skin epidermis, AK, and SCC (P=0.009;P<0.0001 and P<0.0001, respectively). In conclusion, MT-3 may be involved in the development of SCC. PMID- 25015779 TI - Mary's Little Worlds: Changing Person-Space Relationships When Living With Dementia. AB - With the case study presented in this article we explore how people with dementia experience and use their environment to expand our understanding of how architectural environments can improve their well-being. We focus on how relationships between people and spaces change for people with dementia. Using a qualitative analysis of three in-depth interviews with a woman living with dementia, we obtained an insider's perspective and a rich account of the changes in her life, including her lived experiences and interventions in her home environment. We contend that looking at people with dementia in relation to and interaction with their environment, combined with an explorative research approach, might reveal multiple and innovative possibilities in designing for people with dementia. To that end, and to build on existing architectural expertise, we suggest focusing on architectural ordering principles across different cases. PMID- 25015778 TI - Update on the molecular pathogenesis and targeted approaches of mantle cell lymphoma: summary of the 12th annual conference of the European Mantle Cell Lymphoma Network. AB - Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma which is characterized by the chromosomal translocation t(11;14)(q13;q32) resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in almost all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of 15% long-term survivors has been identified with a rather indolent clinical course. Targeted strategies include the proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and especially inhibitors of the B-cell receptor pathway. Our recent annual conference focused on the molecular pathogenesis of the disease and how these underlying molecular alterations may guide the selection and integration of innovative approaches for therapy. This review of the meeting covers in particular the identification of indolent cases, and deals with the role of the B cell receptor pathway in MCL, as well as the detection of minimal residual disease and implementation of molecular approaches in current clinical trials. PMID- 25015780 TI - Self-Reflective Meaning Making in Troubled Times: Change in Self-Identity After Traumatic Brain Injury. AB - Our aim with this article is to clarify the concept of change in self-identity following traumatic brain injury (TBI). We used concept analysis methodology predominantly concept clarification. We identified 110 articles using a systematic literature search, and used critical appraisal, content analysis, and analytical questioning to explore attributes and boundaries. A reported change in self-identity is the ultimate expression of a variety of cognitive, psychological, and social sequelae of TBI. We present an integrative model of this process, identifying three potential levels of change: (a) component parts (egocentric self, sociocentric self, and "identity as shared with others"); (b) integral processes (self-awareness and expression via meaningful occupation and narratives); and (c) whole-system disruption. Change in self-identity after TBI is a highly individualistic process. The driver of this process is "self reflective meaning making," giving a purpose and direction in life, providing motivation and goals for future behavior. PMID- 25015781 TI - Mitochondrial function and mitochondrial DNA maintenance with advancing age. AB - We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities. Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity. PMID- 25015782 TI - Child sexual abuse prevention training for childcare professionals: an independent multi-site randomized controlled trial of Stewards of Children. AB - Given the significant rates and deleterious consequences of childhood sexual abuse (CSA), identifying effective primary prevention approaches is a clear priority. There isa growing awareness that childcare professionals (e.g.,teachers, childcare personnel, clergy) are in a unique position to engage in prevention efforts due to high accessibility to children and expertise in child development. However, CSA prevention programs targeting childcare professionals have received insufficient attention. The goal of this study was toc on duct an independent multi-site controlled evaluation of an existing CSA prevention program, Stewards of Children, offered through both in-person and web based formats. This study included 352 childcare professionals recruited from children's advocacy centers across three states. Participants were randomly assigned to one of three conditions: (1) inperson training, (2) web-based training, or (3) waitlist control. Dependent variables included CSA knowledge, CSA attitudes,and self-reported CSA preventive behaviors. Results indicated that Stewards impacted knowledge, attitudes, and preventive behaviors. No differences were found between training modalities (i.e., in-person versus web-based) on knowledge and preventive behaviors. Results indicate that brief trainings for childcare professionals may impact CSA prevention efforts. PMID- 25015783 TI - Edentulousness in relation to remodeling of the gonial angles and incisures in dentate and edentate mandibles: morphometric study using the Image J software. AB - PURPOSE: The human mandible is subject to stimuli during its growth phase and also in adulthood. One of these stimuli may be absence of teeth, which gives rise to mandibular remodeling. Morphological changes may occur in different areas of this bone, such as in the gonial, condylar and ramus regions. OBJECTIVE: To investigate the influence of edentulousness on remodeling of the gonial angle of the mandible and the angle formed by the mandibular incisure. MATERIALS AND METHOD: Eighty-five dry mandibles from adults were examined: 42 from males and 43 from females. The mandibles were photographed using a camera coupled to a static support that was positioned 20 cm from the object to be photographed. The images were digitized and transferred to the Image J 1.42q software, in which the gonial angle of the mandible and the mandibular incisure angle were measured. RESULTS: There were no differences in the mandibular and mandibular incisure angles in relation to presence or absence of teeth, or between the right and left sides. The mandibular incisure angle was greater in the women. CONCLUSION: Edentulousness did not cause remodeling of the gonial angle of the mandible or in the mandibular incisure angle. PMID- 25015784 TI - Proteomic analysis of the early bovine yolk sac fluid and cells from the day 13 ovoid and elongated preimplantation embryos. AB - The bovine blastocyst hatches 8 to 9 days after fertilization, and this is followed by several days of preimplantation development during which the embryo transforms from a spherical over an ovoid to an elongated shape. As the spherical embryo enlarges, the cells of the inner cell mass differentiate into the hypoblast and epiblast, which remain surrounded by the trophectoderm. The formation of the hypoblast epithelium is also accompanied by a change in the fluid within the embryo, i.e., the blastocoel fluid gradually alters to become the primitive yolk sac (YS) fluid. Our previous research describes the protein composition of human and bovine blastocoel fluid, which is surrounded by the trophectoderm and undifferentiated cells of the inner cell mass. In this study, we further examine the changes in the protein composition in both the primitive YS fluid and the embryonic cells during early and slightly later stage cell differentiation in the developing bovine embryo. In vitro-produced Day 6 embryos were transferred into a recipient heifer and after 7 days of further in vivo culture, ovoid and elongated Day 13 embryos were recovered by flushing both uterine horns after slaughter. The primitive YS fluid and cellular components were isolated from 12 ovoid and three elongated embryos and using nano-high performance liquid chromatography, tandem mass spectrometry, and isobaric tag for relative and absolute quantitation proteomic analysis, a total of 9652 unique proteins were identified. We performed GO term and keyword analyses of differentially expressed proteins in the fluid and the cells of the two embryonic stages, along with a discussion of the biological perspectives of our data with relation to morphogenesis and embryo-maternal communication. Our study thereby provides a considerable contribution to the current knowledge of bovine preimplantation development. PMID- 25015785 TI - Effect of alpha-linolenic acid on oocyte maturation and embryo development of prepubertal sheep oocytes. AB - The purpose of this study was to evaluate the effect of omega-3 alpha-linolenic acid (ALA) added to the IVM medium on embryo development of prepubertal sheep oocytes. Experiment 1 investigated the effect of ALA at different concentrations (0 [control], 50, 100, and 200 MUM) and DMSO (100 MUM) in IVM media on cumulus cell expansion and oocyte nuclear maturation and on synthesis of prostaglandins (PGE2 and PGF2alpha). Experiment 2 investigated the effects of ALA at different concentrations in the IVM medium on oocyte fertilization, cleavage, and developmental potential to blastocyst stage and changes in estradiol and progesterone concentrations in the spent IVM media. IVM oocytes were fertilized with frozen-thawed spermatozoa capacitated in a serum-free sperm medium. Presumptive zygotes were cultured 8 days in synthetic oviductal fluid (SOF) medium without serum. Blastocyst quality was assessed by counting total cell number and the number of apoptotic cells using Hoechst and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Nuclear maturation of oocytes and the number of fully expanded cumulus cells were reduced after treatment with 200 MUM of ALA compared with other groups (P <= 0.05). Supplementation with ALA increased both PGE2 and PGF2alpha concentrations in the spent media (P <= 0.05). No differences were observed in blastocyst development among control (12.2%) and 50, 100, and 200 MUM ALA groups (6.9%, 11.5% and 14.0%, respectively). However, the total cell number (46.50 +/- 5.85, 67.94 +/- 6.71, 45.20 +/- 6.37, and 59.80 +/- 5.51, respectively; P <= 0.05) and apoptotic cell number (6.45 +/- 0.89, 2.48 +/- 0.81, 4.02 +/- 1.15, and 3.67 +/- 1.15, respectively; P <= 0.05) were significantly improved. After IVM, estradiol concentration was lower and progesterone concentration was higher in ALA groups compared with the control group (P <= 0.05). In conclusion, these results revealed that ALA affects prepubertal sheep embryo quality associated with alteration of releasing reproductive hormones. PMID- 25015786 TI - Influenza pathobiology and pathogenesis in avian species. AB - Wild birds in the orders Anseriformes and Charadriiformes are the natural and asymptomatic reservoirs of influenza A viruses representing all of the avian hemagglutinin (HA) and neuraminidase (NA) subtypes. Transmission of avian influenza (AI) viruses from wild birds to gallinaceous poultry species occurs regularly and outcomes vary, ranging from asymptomatic infections to mortality. Circulation of H5 and H7 low pathogenic AI (LPAI) viruses in gallinaceous poultry may result in mutations in the HA protein cleavage site and the emergence of highly pathogenic AI (HPAI) viruses, which in poultry can cause severe disease with high economic losses. Since 2002, various wild bird species also have succumbed to infection with the Eurasian H5N1 HPAI viruses. The pathogenesis of AI is complex and the ability of these viruses to produce disease and death in avian species is dependent on various host, viral and environmental factors, which are not completely understood. PMID- 25015787 TI - Mucosal immunization and adjuvants. AB - The goal of the influenza vaccine is to prevent influenza virus infection and control the yearly seasonal epidemic and pandemic. However, the presently available parenteral influenza vaccine induces only systemic humoral immunity, which does not prevent influenza virus infection on the mucosal surface. Secretary IGA antibodies play an important role in preventing natural infection. Moreover, the IgA antibody response mediates cross-protection against variant viruses in animal models. Thus, a mucosal influenza vaccine that induces mucosal immunity would be a powerful tool to protect individuals from the influenza virus. Although the function of the mucosal immune system, especially in the respiratory tract, is not completely understood, there are several studies underway to develop mucosal influenza vaccines. Here, we will review current knowledge concerning the induction of IgA, the role of B-cell production of influenza virus specific IgA antibodies in anti-influenza immunity, and the role of humoral memory responses induced upon vaccination. PMID- 25015788 TI - Comparative structural analysis of the putative mono-ADP-ribosyltransferases of the ARTD/PARP family. AB - The existence and significance of endogenous cytosolic and nuclear mono-ADP ribosylation has been a matter of debate. Today, evidence suggests that the human enzymes that catalyze the reaction have been rounded up. Moreover, substrate proteins and specific functions for mono-ADP-ribosyltransferases are beginning to be defined. Reader domains that specifically recognize mono-ADP-ribosylated target proteins and erasers that remove the mono-ADP-ribosyl mark have been identified. Here, we review the contribution of crystal structures to our understanding of the putative mono-ADP-ribosyltransferases with Diphtheria toxin and ARTD1/PARP1 homology. PMID- 25015789 TI - Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine. AB - According to the cancer stem cell (CSC) hypothesis, the aggressive growth and early metastasis of pancreatic ductal adenocarcinoma (PDA) is due to the activity of CSCs, which are not targeted by current therapies. Otto Warburg suggested that the growth of cancer cells is driven by a high glucose metabolism. Here, we investigated whether glycolysis inhibition targets CSCs and thus may enhance therapeutic efficacy. Four established and 3 primary PDA cell lines, non malignant cells, and 3 patient-tumor-derived CSC-enriched spheroidal cultures were analyzed by glucose turnover measurements, MTT and ATP assays, flow cytometry of ALDH1 activity and annexin positivity, colony and spheroid formation, western blotting, electrophoretic mobility shift assay, xenotransplantation, and immunohistochemistry. The effect of siRNA-mediated inhibition of LDH-A and LDH-B was also investigated. The PDA cells exhibited a high glucose metabolism, and glucose withdrawal or LDH inhibition by siRNA prevented growth and colony formation. Treatment with the anti-glycolytic agent 3 bromopyruvate almost completely blocked cell viability, self-renewal potential, NF-kappaB binding activity, and stem cell-related signaling and reverted gemcitabine resistance. 3-bromopyruvate was less effective in weakly malignant PDA cells and did not affect non-malignant cells, predicting minimal side effects. 3-bromopyruvate inhibited in vivo tumor engraftment and growth on chicken eggs and mice and enhanced the efficacy of gemcitabine by influencing the expression of markers of proliferation, apoptosis, self-renewal, and metastasis. Most importantly, primary CSC-enriched spheroidal cultures were eliminated by 3 bromopyruvate. These findings propose that CSCs may be specifically dependent on a high glucose turnover and suggest 3-bromopyruvate for therapeutic intervention. PMID- 25015790 TI - Disability and depression after orthopaedic trauma. AB - INTRODUCTION: Musculoskeletal injury is a common cause of impairment (pathophysiology), but the correlation of impairment with pain intensity and magnitude of disability is limited. Psychosocial factors explain a large proportion of the variance in disability for various orthopaedic pathologies. The aim of this study is to prospectively assess the relationship between psychological factors and magnitude of disability in a sample of orthopaedic trauma patients in The Netherlands. MATERIAL AND METHODS: One hundred and one adult patients between 1 and 2 months after one or more fractures, tendon or ligament injuries were enrolled. Four eligible patients refused to participate. Thirty-five women and 30 men with an average age of 50 years (range, 22-92 years) completed the follow-up evaluation between 5 and 8 months after their injury and their data was analyzed. The patients completed a measure of disability (the Short Musculoskeletal Function Assessment-Netherlands, SMFA-NL), the Dutch Centre for Epidemiologic Study of Depression-scale (CES-D), the Dutch Impact of Event Scale (SVL), and the Dutch Pain Catastrophizing Scale (PCS) at the time of enrollment and again 5-8 months after injury. RESULTS: There were moderate correlations between symptoms of depression (CES-D, r=0.48, p<0.001) and symptoms of PTSD (SVL, r=0.35, p=0.004) at enrollment and magnitude of disability 5-8 months after trauma. Catastrophic thinking (PCS) at enrollment and magnitude of disability 5-8 months after trauma showed a small correlation (PCS, r=0.26, p=0.034). The Pain Catastrophizing Scale (Beta=0.29; p=0.049), surgery (Beta=0.26; p=0.034), additional surgery (Beta=0.26; p=0.019) and other pain conditions (Beta=0.31; p=0.009) were the significant predictors in the final model (adjusted R-squared=0.35; p<0.001) for greater disability 5-8 months after trauma. DISCUSSION AND CONCLUSIONS: In The Netherlands, symptoms of depression measured 1-2 months after musculoskeletal trauma correlate with disability 5-8 months after this trauma. The psychological aspects of recovery from musculoskeletal injury merit greater attention. LEVEL OF EVIDENCE: Level II, Prognostic study. PMID- 25015791 TI - Stability of two angular stable locking plates for open wedge high tibial osteotomy (HTO): TomoFixTM versus LOQTEQ(r) HTO plate. AB - INTRODUCTION: The aim of this study was to test the mechanical stability of LOQTEQ(r) HTO plate in comparison to the TomoFixTM internal plate fixator. MATERIALS AND METHODS: An unstable fracture gap model with two standardized polyoxymethylene (POM) cylinders was used for this study. With this model 5 LOQTEQ(r) HTO plates and 5 TomoFixTM were cyclically loaded. The start load was 100 N and increased by 50 N after each successful completed cycle. Each load step included 250,000 cycles. All tests were performed in accordance with the American Society for Testing and Materials (ASTM) Standard Specification and Test Method for Metallic Bone Plates F382-99(2003)e1. RESULTS: The mean fatigue strength of the LOQTEQ(r) HTO Plate was 155 % of the value gained by the TomoFixTM implant. This difference was statistically significant (t test <0.001). There was also a significant difference in the cycles but both implants survived. The LOQTEQ(r) HTO Plate system survived 1,520,336.8 (+/-121,687.7) cycles, whereas the TomoFixTM group passed on average 847,802,600 (+/-134,660.7) cycles. In both groups, the only failure mode was plate breakage in a shaft hole. CONCLUSIONS: The results of the present study showed that fatigue strength of the LOQTEQ(r) HTO plate was significantly higher in comparison to TomoFixTM. These results justify the clinical use of the LOQTEQ(r) HTO plate. PMID- 25015792 TI - Arthroscopic Brostrom repair with Gould augmentation via an accessory anterolateral port for lateral instability of the ankle. AB - Although several arthroscopic surgical techniques for the treatment of lateral instability of the ankle have been introduced recently, some concern remains over their procedural complexity, complications, and unclear clinical outcomes. We have simplified the arthroscopic technique of Brostrom repair with Gould augmentation. This technique requires only two small skin incisions for two ports (medial midline and accessory anterolateral ports), without needing a percutaneous procedure or extension of the skin incisions. The anterior talofibular ligament is reattached to its anatomical footprint on the fibula with suture anchor, under arthroscopic view. The inferior extensor retinaculum is directly visualized through the accessory anterolateral port and is attached to the fibula with another suture anchor under arthroscopic view via the anterolateral port. The use of two small ports offers a procedure that is simple to perform and less morbid for patients. PMID- 25015793 TI - [Objective grading of prostate carcinoma based on fractal dimensions: Gleason 3 + 4= 7a ? Gleason 4 + 3 =7b]. AB - BACKGROUND: Significant intra- and interobserver variability ranging between 40 and 80% is observed in tumor grading of prostate carcinoma. By combining geometric and statistical methods, an objective system of grading can be designed. MATERIAL AND METHODS: The distributions of cell nuclei in two dimensional patterns of prostate cancer classified subjectively as Gleason score 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, and 5+5 were analyzed with algorithms measuring the global fractal dimensions of the Renyi family and with the algorithm for the local connected fractal dimension (LCFD). RESULTS: The dimensions for global fractal capacity, information, and correlation (standard deviation) were 1.470 (045), 1.528 (046), and 1.582 (099) for homogenous Gleason grade 3 (n = 16), 1.642 (034), 1.678 (041), and 1.673 (084) for homogenous Gleason grade 4 (n=18), and 1.797 (042), 1.791 (026), and 1.854 (031) for homogenous Gleason grade 5 (n=12), respectively. The LCFD algorithm can be used to distinguish both qualitatively and quantitatively between mixed and heterogeneous patterns, such as Gleason score 3+4=7a (intermediate risk cancer) and Gleason score 4+3=7b (high risk cancer). Sensitivity of the method is 89.3%, and specificity 84.3%. CONCLUSION: The method of fractal geometry enables both an objective and quantitative grading of prostate cancer. PMID- 25015794 TI - The interface with naturopathy in rural primary health care: a survey of referral practices of general practitioners in rural and regional New South Wales, Australia. AB - BACKGROUND: Naturopathy forms an increasingly significant part of the Australian healthcare setting, with high utilisation of naturopaths by the Australian public and a large therapeutic footprint in rural and regional Australia. However, despite these circumstances, there has been little exploration of the interface between naturopathy providers and conventional primary health care practitioners in rural and regional Australia. The study reported here examined the referral practices and factors that underlie referral to naturopaths amongst a sample of rural and regional Australian general practitioners (GPs). METHODS: A 27-item questionnaire was sent to all 1,486 GPs currently practising in rural and regional Divisions of General Practice in New South Wales, Australia. RESULTS: A total of 585 GPs responded to the questionnaire, with 49 questionnaires returned as "no longer at this address" (response rate: 40.7%). One-quarter of GPs (25.8%) referred to a naturopath at least a few times per year while nearly half (48.8%) stated that they would not refer to a naturopath under any circumstances. GPs were more likely to refer to a naturopath if the GP: was not initially from a rural area (OR=1.78; 95% CI: 0.95, 3.33); believes in the efficacy of naturopathy (OR=5.62; 95% CI: 2.42, 11.36); has seen positive results from naturopathy previously (OR=2.61; 95% CI: 1.35, 5.05); perceives a lack of other treatment options for their patient (OR=5.25; 95% CI: 2.42; 11.36); uses peer-reviewed literature as their major source of CAM information (OR=3.03; 95% CI: 1.65, 5.55); uses CAM practitioners as a major source of CAM information (OR=6.09; 95% CI: 2.91, 12.72); and does not have an existing relationship with any CAM provider (OR=3.03; 95% CI: 1.53, 6.25). CONCLUSIONS: There is little interaction (both via referrals as well as the development of professional relationships) between the naturopathic and GP communities in rural and regional Australia, with significant levels of both support and opposition for naturopathic referral amongst GPs. The significant presence and high utilisation of naturopathy in rural primary health care, which appears to work in parallel to conventional medical care rather than in conjunction with it, should serve as an impetus for increased research into naturopathy practice, policy and regulation in rural and regional health. PMID- 25015795 TI - Low roads and higher order thoughts in emotion. PMID- 25015796 TI - "Surprised by joy"*: four decades of contributions to developmental physiology. AB - Presented at the 40th Anniversary Celebration of the Center for Perinatal Biology of Loma Linda University School of Medicine, honoring Dr. Longo for his 40 years of extraordinary leadership and service, February 11, 2013. PMID- 25015797 TI - sGC-cGMP signaling: target for anticancer therapy. AB - The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The alpha1beta1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe(2+)) heme at histidine 105 of the beta1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC cGMP signaling in the chromatin-microenvironment. PMID- 25015798 TI - Lawrence D. Longo: from chronic fetal hypoxia to proteomic predictors of fetal distress syndrome - a life devoted to research and mentoring based on virtue ethics. AB - The present chapter presents the experience of the author during his fellowship granted by the Fogarty Foundation of the NIH in the Division of Perinatal Biology, Loma Linda University, from 1989 to 1991. Experiments on maternal and fetal responses to long-term hypoxemia (including high-altitude) were performed successfully in pregnant sheep and their fetuses.Cardiovascular, hormonal and blood flow distribution responses were studied under a strict experimental protocol. As result of this research, four papers were accepted for publication in major scientific journals, and have served as basis for further research.Most of all, the leadership, virtue-based ethics, perseverance and continuous stimulus of Lawrence D. Longo is presented as an example to follow for future generations. PMID- 25015799 TI - Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. AB - We have previously reported that the increase in vasodilator production in an ovine model pregnancy is underpinned by an increase in connexin 43 (Cx43) gap junction function, so allowing more uterine artery endothelial cells to produce a more sustained Ca(2+) burst response to agonist stimulation. Since activation of endothelial nitric oxide synthase (eNOS) requires elevated [Ca(2+)]i, it follows that the direct result of enhanced bursting in turn is an increase in nitric oxide (NO) production per cell from more cells, and for a longer period of time. Preeclampsia (PE) is associated with endothelial vasodilatory dysfunction, and the endocrine profile of women with PE includes an increase in a number of factors found in wound sites. The common action of these growth factors and cytokines in wound sites is to mediate Cx43 dysfunction through kinase phosphorylation and closure. Translational studies are now needed to establish if inhibitory phosphorylation of Cx43 in human endothelium is the cause of endothelial dysfunction in PE subjects and if so, to identify the kinase pathways best targeted for therapy in PE subjects. Consistent with this we have already shown endothelial Ca(2+) and NO responses of human umbilical vein from normal subjects are similar to that of ovine pregnant uterine artery, and that those same responses in cords from PE subjects are blunted to levels more typical of nonpregnant uterine artery. In this review we summarize the further evidence that growth factors and cytokines may indeed mediate endothelial dysfunction in PE subjects through closure of Cx43 gap junctions. We also consider how we may clinically translate our studies to humans by using intact umbilical vein and isolated HUVEC in primary culture for an initial screen of drugs to prevent deleterious Cx43 phosphorylation, with the ultimate goal of reversing PE-related endothelial dysfunction. PMID- 25015800 TI - Regulation of amniotic fluid volume: evolving concepts. AB - Studies in late gestation fetal sheep have provided several new insights into the regulation of amniotic fluid (AF) volume (AFV): There are four quantitatively important amniotic inflows and outflows that include fetal urine production, lung liquid secretion, swallowing, and intramembranous absorption. Of these, AFV is regulated primarily by modulating the rate of intramembranous absorption of AF water and solutes across the amniotic epithelial cells into the underlying fetal vasculature. Modulation of the rate of intramembranous absorption depends on the presence of stimulators and inhibitors present in the AF. A stimulator of intramembranous absorption is present in fetal urine. In addition, AF contains a non-renal, non-pulmonary inhibitor of intramembranous absorption presumably secreted by the fetal membranes. Although passive bidirectional movements of water and solutes occur across the intramembranous pathway, intramembranous absorption is primarily a unidirectional, vesicular, bulk transport process mediated through VEGF activation of transcytotic transport via caveolae. Further, the stimulators and inhibitors of intramembranous absorption alter only the active, unidirectional component of intramembranous absorption while the passive components are not altered under experimental conditions studied thus far. Future progress depends on identifying the cellular and molecular mechanisms that regulate active and passive intramembranous absorption as well as their regulatory components. PMID- 25015801 TI - Gestational diabetes, preeclampsia and cytokine release: similarities and differences in endothelial cell function. AB - Gestational diabetes, pre-eclampsia as well as intra-uterine infection during pregnancy affects the function of the endothelium both in the mother and the fetus leading to endothelial dysfunction. Gestational diabetes is also associated with an increased incidence of pre-eclampsia and it is likely that both the hyperglycemia as well as the release of cytokines especially TNFalpha during hyperglycemia may play an important role in the pathogenesis of endothelial dysfunction leading to preeclampsia. Similarly, some but not all studies have suggested that infection of the mother under certain circumstances can also lead to preeclampsia as women with either a bacterial or viral infection were at a higher risk of developing preeclampsia, compared to women without infection and infection also leads to a release in TNFalpha. Endothelial cells exposed to either high glucose or TNFalpha leads to an increase in the production of H2O2 and to a decrease in endothelial cell proliferation. The cellular and molecular mechanisms involved in this phenomenon are discussed.Gestational diabetes, pre eclampsia as well as intra-uterine infection during pregnancy has profound effects on the fetus and long term effects on the neonate. All three conditions affect the function of the endothelium both in the mother and the fetus leading to endothelial dysfunction. Gestational diabetes is also associated with an increased incidence of pre-eclampsia and it is likely that both the hyperglycemia as well as the release of cytokines especially TNFalpha during hyperglycemia may play an important role in the pathogenesis of endothelial dysfunction leading to preeclampsia. It has also been suggested although not universally accepted that under certain circumstances maternal infection may also predispose to pre eclampsia. Pre-eclampsia is also associated with the release of TNFalpha and endothelial dysfunction. However, the cellular and molecular mechanism(s) leading to the endothelial dysfunction by either hyperglycemia or by the cytokine TNFalpha appear to be different. In this chapter, we explore some of the similarities and differences leading to endothelial dysfunction by both hyperglycemia and by the inflammatory cytokine TNFalpha and the cellular and molecular mechanism(s) involved. PMID- 25015802 TI - Heart disease link to fetal hypoxia and oxidative stress. AB - The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia. PMID- 25015804 TI - From fetal physiology to gene therapy: it all started in Loma Linda. AB - Just having finished medical school in the Netherlands, without basically any serious research experience, Lawrence Longo, Gordon Power and Ray Gilbert received this 25 year young man with open arms at the end of July 1977. The Center for Perinatal Biology of Loma Linda University (CPB) would become for the next 3 years not the just the center of my postdoctoral activities, it would also lay the foundation for the following decades. The next paragraphs will describe three key success factors that can be traced back to these formative years that have contributed so much to my professional career. PMID- 25015803 TI - Fetal breathing movements and changes at birth. AB - The fetus, which develops within a fluid-filled amniotic sac, relies on the placenta for respiratory gas exchange rather than the lungs. While not involved in fetal oxygenation, fetal breathing movements (FBM) nevertheless have an important role in lung growth and in development of respiratory muscles and neural regulation. FBM are regulated differently in many respects than postnatal respiration, which results from the unique intrauterine environment. Prominent distinctions of FBM include its episodic nature and apnea-sensitivity to hypoxia. The latter characteristic is the basis for using FBM in the assessment of fetuses at risk for hypoxic injury. At birth, the transition to continuous postnatal respiration involves a fall in temperature, gaseous distention of the lungs, activation of the Hering-Breuer reflexes, and functional connectivity of afferent O2 chemoreceptor activity with respiratory motoneurons and arousal centers. Importantly, exposure to drugs or adverse conditions in utero not only can change patterns of FBM but also can lead to epigenetic dysregulation in postnatal respiration. Such changes, can blunt respiratory and arousal defenses against hypoxic challenges in sleep. Thus, fetal hypoxia and/or drug exposure may in later life dispose sleeping infants, children, and adults to hypertension, diabetes mellitus, brain injury, and sudden death. PMID- 25015805 TI - 30(+) years of exercise in pregnancy. AB - In 1980 I came to Loma Linda to study maternal exercise, with Dr. Longo as my mentor. For millennia strenuous exercise was considered harmful for the fetus. Early studies reinforced that idea, by showing that exercise reduced uterine blood flow and fetal PO2 by up to 40 and 29 %, respectively. But utero-placental reserve is ~50 %. So why was fetal PO2 so much reduced during exercise?Methods proved to be important. It took chronically instrumented animals accustomed to the laboratory environment, experiments standardized to fitness of the individual (%VO2max), measurement of total uterine blood flow, and blood gas values corrected for body temperature. The results were simple and hold till this day. Uterine blood flow decreases linearly with maternal heart rate increase, which depends on exercise intensity and duration. Maximal reduction in uterine blood flow is ~20 % and uterine O2-uptake remains unaltered because blood flow reduction is compensated by increases in hematocrit and uterine O2-extraction. Fetal body temperature increases with that of the mother by ~2 degrees C at maximal exercise and fetal blood gas values are little affected by exhaustive maternal exercise, if properly corrected for temperature. So I left Loma Linda knowing that pregnant sheep can exercise to exhaustion without harm to the fetus, thanks to effective compensatory mechanisms.After returning to Erasmus University Rotterdam further studies in humans showed that physical fitness is unaffected by pregnancy, weight-gain affects performance, and strenuous exercise in healthy pregnant women does not harm the fetus. Thus, the millennia-old perspective has changed. PMID- 25015807 TI - Effect of preeclampsia on placental function: influence of sexual dimorphism, microRNA's and mitochondria. AB - In pregnancy fetal growth and development occur in a sexually dimorphic manner. Male and female fetuses respond differently to the intrauterine environment with males disproportionately suffering from perinatal morbidity and mortality. We have demonstrated placental dysfunction and sexually dimorphic responses in pregnancies complicated by severe preeclampsia. Production of cytokines and apoptosis in the male placenta is heightened relative to that of the female placenta. We also find increased expression and stabilization and a sexual dimorphism in expression of the transcription factor HIF-1alpha, but a defect in binding to the hypoxia response element with corresponding reduced expression of HIF-1alpha target genes including VEGF and Glut-1. HIF-1alpha is involved in crosstalk with the redox sensitive transcription factor NFkappaB in regulation by cytokines, reactive oxygen species and expression of inflammatory genes. We find increased placental expression and DNA binding of NFkappaB and a sexually dimorphic response suggesting a role for NFkappaB in placental dysfunction with preeclampsia. Placental mitochondrial complex III activity and complex I and IV expression are reduced and alterations in mitochondrial morphology are found in preeclampsia and are linked to the hypoxamir miR-210. We propose that with severe PE placental HIF-1alpha is stabilized by excessive ROS, inflammation and relative hypoxia. This increases the expression of miR-210 in the placenta causing repression of mitochondria-associated target genes, potentially leading to mitochondrial and placental dysfunction. This placental dysfunction may lead to a fetal programming effect that results in disease in later life. PMID- 25015808 TI - Altitude, attitude and adaptation. AB - The fetus has the extraordinary capacity to respond to stress during development, which, in a large part, is mediated by the hypothalamo- pituitary-adrenal (HPA) axis. Hypoxia represents a significant risk to fetal homeostasis and can occur in a wide range of settings including maternal smoking, preeclampsia, preterm labor and high altitude. To study fetal adaptation to chronic, gestational hypoxia, we developed a model of high-altitude, long-term hypoxia (LTH) in pregnant sheep. We discuss the role of LTH on the HPA axis and potential programming of adaptive responses. LTH causes significant activation of the hypothalamic paraventricular nucleus (PVN) and anterior pituitary. In marked contrast, there is an adaptive inhibition in the adrenal, thus balancing the potentially maladaptive centrally mediated responses to LTH. Additionally, we discuss effects of LTH on adipose tissue development. LTH enhances leptin production, which in turn has a regulatory role on the adrenal cortex. Importantly, LTH also has a significant impact on programming of adipose tissue function. Together, our studies show that LTH induces a number of adaptive responses in the ovine fetus. Although they may be beneficial during fetal life, these adaptations could prove to be deleterious in the postnatal period and adulthood. PMID- 25015806 TI - Gap junction regulation of vascular tone: implications of modulatory intercellular communication during gestation. AB - In the vasculature, gap junctions (GJ) play a multifaceted role by serving as direct conduits for cell-cell intercellular communication via the facilitated diffusion of signaling molecules. GJs are essential for the control of gene expression and coordinated vascular development in addition to vascular function. The coupling of endothelial cells to each other, as well as with vascular smooth muscle cells via GJs, plays a relevant role in the control of vasomotor tone, tissue perfusion and arterial blood pressure. The regulation of cell-signaling is paramount to cardiovascular adaptations of pregnancy. Pregnancy requires highly developed cell-to-cell coupling, which is affected partly through the formation of intercellular GJs by Cx43, a gap junction protein, within adjacent cell membranes to help facilitate the increase of uterine blood flow (UBF) in order to ensure adequate perfusion for nutrient and oxygen delivery to the placenta and thus the fetus. One mode of communication that plays a critical role in regulating Cx43 is the release of endothelial-derived vasodilators such as prostacyclin (PGI2) and nitric oxide (NO) and their respective signaling mechanisms involving second messengers (cAMP and cGMP, respectively) that are likely to be important in maintaining UBF. Therefore, the assertion we present in this review is that GJs play an integral if not a central role in maintaining UBF by controlling rises in vasodilators (PGI2 and NO) via cyclic nucleotides. In this review, we discuss: (1) GJ structure and regulation; (2) second messenger regulation of GJ phosphorylation and formation; (3) pregnancy-induced changes in cell-signaling; and (4) the role of uterine arterial endothelial GJs during gestation. These topics integrate the current knowledge of this scientific field with interpretations and hypotheses regarding the vascular effects that are mediated by GJs and their relationship with vasodilatory vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion and blood flow observed during normal pregnancy. PMID- 25015809 TI - The separation of sexual activity and reproduction in human social evolution. AB - In industrialized societies the progression of natural selection has been determined and in many cases superseded by social evolution. In the case of reproduction, there has been a decline and delay of childbearing without diminished sexual activity. While this has value for these societies, there are penalties associated with barren cycles. These include increases in endometriosis and breast and genital cancer. There also are associated issues regarding population movements that fill the "vacuums" left by underpopulation. These matters are of more than passing interest as we cope with unintended consequences of Man's dominance over the environment and other life forms. PMID- 25015810 TI - The influence of growth hormone on bone and adipose programming. AB - In utero growth hormone exposure is associated with distinct immediate growth responses and long term impacts on adult physiological parameters that include obesity, insulin resistance, and bone function. Growth hormone accelerates cellular proliferation in many tissues but is exemplified by increases in the number of cells within the cartilaginous growth plate of bone. In some cases growth hormone also potentiates differentiation as seen in the differentiation of adipocytes that rapidly fill upon withdrawal of growth hormone. Growth hormone provokes these changes either by direct action or through intermediaries such as insulin-like growth factor-I and other downstream effector molecules. The specific mechanism used by growth hormone in programming tissues is not yet fully characterized and likely represents a multipronged approach involving DNA modification, altered adult hormonal milieu, and the development of an augmented stem cell pool capable of future engagement as is seen in adipose accrual. This review summarizes findings of growth hormone's influence on in utero and neonatal cellular and metabolic profiles related to bone and adipose tissue. PMID- 25015812 TI - Placental vascular defects in compromised pregnancies: effects of assisted reproductive technologies and other maternal stressors. AB - Many factors negatively affect pregnancy establishment and subsequent fetal growth and development, including maternal factors such as nutritional stress, age, body mass index, and genetic background, and external factors including environmental stress, psychosocial stress, multiple fetuses, medical conditions (e.g., polycystic ovary syndrome), lifestyle choices (e.g., alcohol consumption, smoking), and assisted reproductive technologies. These same factors have similar consequences for placental growth and development, including vascular development. We and others have shown that placental vascular development begins very early in pregnancy and determines, to a large extent, placental function that is, the magnitude of the increase in placental blood flow and thus nutrient transport to the fetus. During the peri-implantation period and also later in pregnancy, cloned (somatic cell nuclear transfer) embryos exhibit a variety of placental defects including reduced vascularization and altered expression of angiogenic factors. Although placental defects are less pronounced in pregnancies resulting from the transfer of in vitro fertilized embryos, we and others have recently demonstrated that vascularization, expression of angiogenic factors, sex steroid receptors, several epigenetic markers, and growth of utero-placental tissues all were altered during early pregnancy after transfer of embryos obtained through natural mating, in vitro fertilization, or other assisted reproductive techniques. These observations are in agreement with the recent reports that in humans even singleton pregnancies established with assisted reproductive techniques are at increased risk of preterm delivery and low birth weight, and seem especially relevant considering the rapidly expanding use of these techniques in humans and animals. PMID- 25015813 TI - How to build a healthy heart from scratch. AB - By any of several measures, the health of the American population has been worsening over the last two decades. Obesity, type 2 diabetes and heart failure have risen dramatically. All the while, the average birthweight at all gestational ages has declined. The relationship between robust growth in the womb and lifelong health is now well established. Likewise, babies born at the low end of the birthweight scale are known to have highly elevated risks for ischemic heart disease, hypertension, stroke and metabolic disease. The biological mechanisms by which developmental plasticity becomes a risk for cardiovascular disease are only now being understood. Translating from animal and human studies, low birthweight babies are likely to have endothelial dysfunction, fewer nephrons, fewer pancreatic beta cells, less vascular elastin, fewer cardiomyocytes, increased sympathetic tone and liver-derived dyslipidemias. Only in the past few years, however, has it become known that maternal and placenta phenotypes are associated with adult onset cardiovascular disease. Helsinki Birth Cohort studies have been especially important in the discovery of these relationships. Sudden cardiac death is associated with a thin placenta and heart failure is associated with a small placenta in short mothers. Coronary heart disease is associated with three combinations of maternal-placental phenotypes. Because the diet is important in providing nutrients for the development of the female body before pregnancy and for providing nutrients during pregnancy, there is increasing evidence that the western diet is an underlying cause for the increase in metabolic disease in the American population. A large segment of the American population suffers from high calorie malnutrition. Scientists in this field now have a responsibility to educate the public on the topic of nutrition and health. This chapter honors Lawrence Longo for decades of work in bringing health to pregnant women and their babies. PMID- 25015814 TI - Estrogen in the fetus. AB - Estradiol and other estrogens are important modulators of fetal and maternal physiology in pregnancy. Much is known about the biosynthesis of estrogens in fetus and mother, and much is known about the role that estrogen plays in labor and delivery. However, much less is known about the regulation of estrogen biosynthesis throughout the latter half of gestation, and the role that estrogen plays in homeostatic and neuroendocrine control in the fetus. This review focuses on the biosynthesis and actions of estrogen in the fetal circulation, the role that it plays in the development of the fetus in the latter half of gestation, and the role that is played by the estrogen milieu in the control of the timing of birth. Estrogen circulates in fetal blood in both unconjugated and conjugated molecular forms, with the conjugated steroids far more abundant than the unconjugated steroids. This review therefore also addresses the biological significance of the variety of molecular forms of estrogen circulating in fetal and maternal blood. PMID- 25015811 TI - The fetal cerebral circulation: three decades of exploration by the LLU Center for Perinatal Biology. AB - For more than three decades, research programs in the Center of Perinatal Biology have focused on the vascular biology of the fetal cerebral circulation. In the 1980s, research in the Center demonstrated that cerebral autoregulation operated over a narrower pressure range, and was more vulnerable to insults, in fetuses than in adults. Other studies were among the first to establish that compared to adult cerebral arteries, fetal cerebral arteries were more hydrated, contained smaller smooth muscle cells and less connective tissue, and had endothelium less capable of producing NO. Work in the 1990s revealed that pregnancy depressed reactivity to NO in extra-cerebral arteries, but elevated it in cerebral arteries through effects involving changes in cGMP metabolism. Comparative studies verified that fetal lamb cerebral arteries were an excellent model for cerebral arteries from human infants. Biochemical studies demonstrated that cGMP metabolism was dramatically upregulated, but that contraction was far more dependent on calcium influx, in fetal compared to adult cerebral arteries. Further studies established that chronic hypoxia accelerates functional maturation of fetal cerebral arteries, as indicated by increased contractile responses to adrenergic agonists and perivascular adrenergic nerves. In the 2000s, studies of signal transduction established age-dependent roles for PKG, PKC, PKA, ERK, ODC, IP3, myofilament calcium sensitivity, and many other mechanisms. These diverse studies clearly demonstrated that fetal cerebral arteries were functionally quite distinct compared to adult cerebral arteries. In the current decade, research in the Center has expanded to a more molecular focus on epigenetic mechanisms and their role in fetal vascular adaptation to chronic hypoxia, maternal drug abuse, and nutrient deprivation. Overall, the past three decades have transformed thinking about, and understanding of, the fetal cerebral circulation due in no small part to the sustained research efforts by faculty and staff in the Center for Perinatal Biology. PMID- 25015815 TI - Calcitonin gene related family peptides: importance in normal placental and fetal development. AB - Synchronized molecular and cellular events occur between the uterus and the implanting embryo to facilitate successful pregnancy outcome. Nevertheless, the molecular signaling network that coordinates strategies for successful decidualization, placentation and fetal growth are not well understood. The discovery of calcitonin/calcitonin gene-related peptides (CT/CGRP) highlighted new signaling mediators in various physiological processes, including reproduction. It is known that CGRP family peptides including CGRP, adrenomedulin and intermedin play regulatory functions during implantation, trophoblast proliferation and invasion, and fetal organogenesis. In addition, all the CGRP family peptides and their receptor components are found to be expressed in decidual, placental and fetal tissues. Additionally, plasma levels of peptides of the CGRP family were found to fluctuate during normal gestation and to induce placental cellular differentiation, proliferation, and critical hormone signaling. Moreover, aberrant signaling of these CGRP family peptides during gestation has been associated with pregnancy disorders. It indicates the existence of a possible regulatory role for these molecules during decidualization and placentation processes, which are known to be particularly vulnerable. In this review, the influence of the CGRP family peptides in these critical processes is explored and discussed. PMID- 25015816 TI - Cell cycle control and HIV-1 susceptibility are linked by CDK6-dependent CDK2 phosphorylation of SAMHD1 in myeloid and lymphoid cells. AB - Proliferating cells are preferentially susceptible to infection by retroviruses. Sterile alpha motif and HD domain-containing protein-1 (SAMHD1) is a recently described deoxynucleotide phosphohydrolase controlling the size of the intracellular deoxynucleotide triphosphate (dNTP) pool, a limiting factor for retroviral reverse transcription in noncycling cells. Proliferating (Ki67(+)) primary CD4(+) T cells or macrophages express a phosphorylated form of SAMHD1 that corresponds with susceptibility to infection in cell culture. We identified cyclin-dependent kinase (CDK) 6 as an upstream regulator of CDK2 controlling SAMHD1 phosphorylation in primary T cells and macrophages susceptible to infection by HIV-1. In turn, CDK2 was strongly linked to cell cycle progression and coordinated SAMHD1 phosphorylation and inactivation. CDK inhibitors specifically blocked HIV-1 infection at the reverse transcription step in a SAMHD1-dependent manner, reducing the intracellular dNTP pool. Our findings identify a direct relationship between control of the cell cycle by CDK6 and SAMHD1 activity, which is important for replication of lentiviruses, as well as other viruses whose replication may be regulated by intracellular dNTP availability. PMID- 25015817 TI - Does beta-hexosaminidase function only as a degranulation indicator in mast cells? The primary role of beta-hexosaminidase in mast cell granules. AB - beta-Hexosaminidase, which is generally present in the lysosome, is essential for glycoprotein metabolism in the maintenance of cell homeostasis. In mast cells (MCs), large amounts of beta-hexosaminidase are present in the granules as opposed to the lysosome, and the biological role of MC beta-hexosaminidase has yet to be fully elucidated. Therefore, we investigated the biological role of beta-hexosaminidase in MC granules. Bone marrow-derived MCs from C57BL/6 (BL/6 BMMC) or beta-hexosaminidase gene-deficient (hexb(-/-)-BMMC) mice were transplanted into MC-deficient (WBB6F1/J-Kit(W)/Kit(W-v) [W/W(v)]) mice to generate MC-reconstituted models. In asthma model experiments, no differences were observed in the symptoms of BL/6, W/W(v), BL/6-BMMC-reconstituted W/W(v), or hexb(-/-)-BMMC-reconstituted W/W(v) mice. In Staphylococcus epidermidis experimental infection model experiments, the severity of symptoms and frequency of death were markedly higher in W/W(v) and hexb(-/-)-BMMC-reconstituted W/W(v) mice than in BL/6 and BL/6-BMMC-reconstituted W/W(v) mice. The growth of S. epidermidis in an in vitro study was clearly inhibited by addition of BL/6-BMMC lysate, but not by addition of hexb(-/-)-BMMC lysate. Moreover, suppression of bacterial proliferation was completely recovered when bacteria were incubated with hexb(-/-)-BMMC lysate plus beta-hexosaminidase. Transmission electron microscopy indicated that the cell wall of S. epidermidis was heavily degraded following coincubation of bacteria with BL/6-BMMC lysate, but not following coincubation with hexb(-/-)-BMMC lysate. These findings strongly suggest that MC granule beta-hexosaminidase is crucial for defense against bacterial invasion, but is not involved in the allergic response. Our results also suggest that the bactericidal mechanism of beta-hexosaminidase involves degradation of bacterial cell wall peptidoglycan. PMID- 25015818 TI - Leukocyte beta7 integrin targeted by Kruppel-like factors. AB - Constitutive expression of Kruppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin beta7 (Itgb7, Ly69) by binding to the beta7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the beta7 promoter, indicating that these factors may compete for target sequence(s). Whereas beta7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because beta7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when beta7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer's patches, much like beta7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of beta7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of beta7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression. PMID- 25015819 TI - Structure of the superantigen staphylococcal enterotoxin B in complex with TCR and peptide-MHC demonstrates absence of TCR-peptide contacts. AB - Superantigens are immune-stimulatory toxins produced by Staphylococcus aureus, which are able to interact with host immune receptors to induce a massive release of cytokines, causing toxic shock syndrome and possibly death. In this article, we present the x-ray structure of staphylococcal enterotoxin B (SEB) in complex with its receptors, the TCR and MHC class II, forming a ternary complex. The structure, in combination with functional analyses, clearly shows how SEB adopts a wedge-like position when binding to the beta-chain of TCR, allowing for an interaction between the alpha-chain of TCR and MHC. Furthermore, the binding mode also circumvents contact between TCR and the peptide presented by MHC, which enables SEB to initiate a peptide-independent activation of T cells. PMID- 25015820 TI - Mammalian target of rapamycin complex 1 orchestrates invariant NKT cell differentiation and effector function. AB - Invariant NKT (iNKT) cells play critical roles in bridging innate and adaptive immunity. The Raptor containing mTOR complex 1 (mTORC1) has been well documented to control peripheral CD4 or CD8 T cell effector or memory differentiation. However, the role of mTORC1 in iNKT cell development and function remains largely unknown. By using mice with T cell-restricted deletion of Raptor, we show that mTORC1 is selectively required for iNKT but not for conventional T cell development. Indeed, Raptor-deficient iNKT cells are mostly blocked at thymic stage 1-2, resulting in a dramatic decrease of terminal differentiation into stage 3 and severe reduction of peripheral iNKT cells. Moreover, residual iNKT cells in Raptor knockout mice are impaired in their rapid cytokine production upon alphaGalcer challenge. Bone marrow chimera studies demonstrate that mTORC1 controls iNKT differentiation in a cell-intrinsic manner. Collectively, our data provide the genetic evidence that iNKT cell development and effector functions are under the control of mTORC1 signaling. PMID- 25015821 TI - Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF induced necroptosis in vivo. AB - The serine/threonine kinase RIPK1 is recruited to TNFR1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. A RIPK1 deficiency results in perinatal lethality, impaired NFkappaB and MAPK signaling, and sensitivity to TNF-induced apoptosis. Chemical inhibitor and in vitro reconstitution studies suggested that RIPK1 displays distinct kinase activity dependent and -independent functions. To determine the contribution of RIPK1 kinase to inflammation in vivo, we generated knock-in mice endogenously expressing catalytically inactive RIPK1 D138N. Unlike Ripk1(-/-) mice, which die shortly after birth, Ripk1(D138N/D138N) mice are viable. Cells expressing RIPK1 D138N are resistant to TNF- and polyinosinic-polycytidylic acid-induced necroptosis in vitro, and Ripk1(D138N/D138N) mice are protected from TNF-induced shock in vivo. Moreover, Ripk1(D138N/D138N) mice fail to control vaccinia virus replication in vivo. This study provides genetic evidence that the kinase activity of RIPK1 is not required for survival but is essential for TNF-, TRIF-, and viral-initiated necroptosis. PMID- 25015822 TI - Marginal zone B cells transport IgG3-immune complexes to splenic follicles. AB - Ag administered together with specific IgG3 induces a higher Ab response than Ag administered alone, an effect requiring the presence of complement receptors 1 and 2 (CR1/2). In this study, we have investigated the fate of Ag, the development of germinal centers (GCs), and the Ab response after i.v. administration of IgG3 anti-trinitrophenyl (TNP) in complex with OVA-TNP. After 2 h, OVA-TNP was detected on marginal zone (MZ) B cells, and a substantial amount of Ag was detected in splenic follicles and colocalized with follicular dendritic cells (FDCs). After 10 d, the percentage of GCs and the IgG responses were markedly higher than in mice immunized with uncomplexed OVA-TNP. The effects of IgG3 were dependent on CR1/2 known to be expressed on B cells and FDCs. Using bone marrow chimeric mice, we demonstrate that an optimal response to IgG3-Ag complexes requires that CR1/2 is expressed on both cell types. These data suggest that CR1/2(+) MZ B cells transport IgG3-Ag-C complexes from the MZ to the follicles, where they are captured by FDCs and induce GCs and IgG production. This pathway for initiating the transport of Ags into splenic follicles complements previously known B-cell dependent pathways where Ag is transported by 1) MZ B cells, binding large Ags-IgM-C complexes via CR1/2; 2) recirculating B cells, binding Ag via BCR; or 3) recirculating B cells, binding IgE-Ag complexes via the low-affinity receptor for IgE, CD23. PMID- 25015824 TI - Neutrophils exhibit differential requirements for homing molecules in their lymphatic and blood trafficking into draining lymph nodes. AB - Although much is described about the molecules involved in neutrophil migration from circulation into tissues, less is known about the molecular mechanisms that regulate neutrophil entry into lymph nodes (LNs) draining a local inflammatory site. In this study, we investigated neutrophil migration toward LNs in a context of inflammation induced by immunization of BALB/c mice with OVA emulsified in CFA. We demonstrated that neutrophils can enter LNs of OVA/CFA-immunized mice not only via lymphatic vessels but also from blood, across high endothelial venules. By adoptive transfer experiments, we showed that this influx was dependent on an inflammatory-state condition and previous neutrophil stimulation with OVA/anti OVA immune complexes. Importantly, we have demonstrated that, in the migratory pattern to LNs, neutrophils used L-selectin and P-selectin glycoprotein ligand-1, macrophage-1 Ag and LFA-1 integrins, and CXCR4 to get access across high endothelial venules, whereas macrophage-1 Ag, LFA-1, and CXCR4 were involved in their trafficking through afferent lymphatics. Strikingly, we found that stimulation with immune complexes significantly upregulated the expression of sphingosine-1-phosphate receptor 4 on neutrophils, and that treatment with the sphingosine-1-phosphate agonist FTY720 altered neutrophil LN-homing ability. These findings summarized in this article disclose the molecular pattern that controls neutrophil recruitment to LNs. PMID- 25015823 TI - TRIL is involved in cytokine production in the brain following Escherichia coli infection. AB - TLR4 interactor with leucine-rich repeats (TRIL) is a brain-enriched accessory protein that is important in TLR3 and TLR4 signaling. In this study, we generated Tril(-/-) mice and examined TLR responses in vitro and in vivo. We found a role for TRIL in both TLR4 and TLR3 signaling in mixed glial cells, consistent with the high level of expression of TRIL in these cells. We also found that TRIL is a modulator of the innate immune response to LPS challenge and Escherichia coli infection in vivo. Tril(-/-) mice produce lower levels of multiple proinflammatory cytokines and chemokines specifically within the brain after E. coli and LPS challenge. Collectively, these data uncover TRIL as a mediator of innate immune responses within the brain, where it enhances neuronal cytokine responses to infection. PMID- 25015825 TI - The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires. AB - Thymic selection is designed to ensure TCR reactivity to foreign Ags presented by self-MHC while minimizing reactivity to self-Ags. We hypothesized that the repertoire of T cells with unwanted specificities such as alloreactivity or autoreactivity are a consequence of simultaneous rearrangement of both TCRalpha loci. We hypothesized that this process helps maximize production of thymocytes capable of successfully completing thymic selection, but results in secondary TCRs that escape stringent selection. In T cells expressing two TCRs, one TCR can mediate positive selection and mask secondary TCR from negative selection. Examination of mice heterozygous for TRAC (TCRalpha(+/-)), capable of only one functional TCRalpha rearrangement, demonstrated a defect in generating mature T cells attributable to decreased positive selection. Elimination of secondary TCRs did not broadly alter the peripheral T cell compartment, though deep sequencing of TCRalpha repertoires of dual TCR T cells and TCRalpha(+/-) T cells demonstrated unique TCRs in the presence of secondary rearrangements. The functional impact of secondary TCRs on the naive peripheral repertoire was evidenced by reduced frequencies of T cells responding to autoantigen and alloantigen peptide-MHC tetramers in TCRalpha(+/-) mice. T cell populations with secondary TCRs had significantly increased ability to respond to altered peptide ligands related to their allogeneic ligand as compared with TCRalpha(+/-) cells, suggesting increased breadth in peptide recognition may be a mechanism for their reactivity. Our results imply that the role of secondary TCRs in forming the T cell repertoire is perhaps more significant than what has been assumed. PMID- 25015826 TI - NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma. AB - STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell-deficient nude mice, a unique NK cell mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-beta cytokines were reduced in mice bearing STAT3 blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo. PMID- 25015827 TI - Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue. AB - Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations, from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet-monocyte interactions to inflammatory responses in dengue have not been addressed. Patients with dengue were investigated for platelet-monocyte aggregate formation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. We observed increased levels of platelet-monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1beta, IL-8, IL-10 and MCP-1, whereas exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet-monocyte aggregates. Moreover, IL-10 secretion required platelet-monocyte contact but not phagocytosis. Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue. PMID- 25015828 TI - Antigen-specific naive CD8+ T cells produce a single pulse of IFN-gamma in vivo within hours of infection, but without antiviral effect. AB - In vitro studies have shown that naive CD8(+) T cells are unable to express most of their effector proteins until after at least one round of cell division has taken place. We have reassessed this issue in vivo and find that naive CD8(+) T cells mount Ag-specific responses within hours of infection, before proliferation has commenced. Newly activated naive Ag-specific CD8(+) T cells produce a rapid pulse of IFN-gamma in vivo and begin to accumulate granzyme B and perforin. Later, in vivo cytolytic activity is detectable, coincident with the initiation of cell division. Despite the rapid development of these functional attributes, no antiviral effect was observed early during infection, even when the cells are present in numbers similar to those of virus-specific memory cells. The evolutionary reason for the pulse of IFN-gamma synthesis by naive T cells is uncertain, but the lack of antiviral impact suggests that it may be regulatory. PMID- 25015829 TI - Differential role for p120-catenin in regulation of TLR4 signaling in macrophages. AB - Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-kB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-kappaB activation and release of TNF-alpha and IL-6, but enhanced TIR domain-containing adapter inducing IFN-beta-dependent IFN regulatory factor 3 activation and release of IFN beta upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-beta signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin. PMID- 25015830 TI - IL-2 induction of Blimp-1 is a key in vivo signal for CD8+ short-lived effector T cell differentiation. AB - During infection or vaccination, only a small proportion of CD8(+) T cells differentiate into memory cells. The mechanisms underlying the differentiation of CD8(+) T cells into short-lived effector cells (SLECs) or memory precursor effector cells are poorly defined. It was recently shown in infectious models that the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) enhances the formation of SLECs. The factors controlling Blimp-1 expression leading to the in vivo formation of SLECs are still not known. However, it has been shown that cytokines such as IL-2 induce Blimp-1 expression in vitro. In this study, we took advantage of the low-inflammation model of dendritic cell immunization to study the role of the IL-2/Blimp-1 axis in SLEC differentiation as well as the importance of Blimp-1 expression in memory precursor effector cells for proper CD8(+) memory generation. Our results show that Blimp-1 deficiency affects effector differentiation and function in the absence of inflammation. Unexpectedly, memory generation was not affected in Blimp-1-deficient OT-I cells responding to vaccination. In addition, modulation of the bioavailability of IL-2 by injection either of a blocking Ab or of the cytokine, demonstrates a link between IL-2, Blimp-1 induction, and SLEC formation in wild-type cells. Conversely, injection of IL-2 had less effect on Blimp-1 deficient CD8(+) T cells, indicating that the effect of IL-2 on in vivo SLEC differentiation is mediated by Blimp-1. In conclusion, IL-2 induction of Blimp-1 expression is a key regulator of SLEC differentiation in vivo. PMID- 25015831 TI - IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure. AB - Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4(+) T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R (Il1rl1(-/-)) and thymic stromal lymphopoietin receptor (Tslpr(-/-)) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and thymic stromal lymphopoietin most likely play key roles in this process. PMID- 25015832 TI - Inhibition of the classical pathway of complement by meningococcal capsular polysaccharides. AB - Almost all invasive Neisseria meningitidis isolates express capsular polysaccharide. Ab is required for complement-dependent killing of meningococci. Although alternative pathway evasion has received considerable attention, little is known about classical pathway (CP) inhibition by meningococci, which forms the basis of this study. We engineered capsulated and unencapsulated isogenic mutant strains of groups A, B, C, W, and Y meningococci to express similar amounts of the same factor H-binding protein (fHbp; a key component of group B meningococcal vaccines) molecule. Despite similar anti-fHbp mAb binding, significantly less C4b was deposited on all five encapsulated mutants compared with their unencapsulated counterparts (p < 0.01) when purified C1 and C4 were used to deposit C4b. Reduced C4b deposition was the result of capsule-mediated inhibition of C1q engagement by Ab. C4b deposition correlated linearly with C1q engagement by anti-fHbp. Whereas B, C, W, and Y capsules limited CP-mediated killing by anti-fHbp, the unencapsulated group A mutant paradoxically was more resistant than its encapsulated counterpart. Strains varied considerably in their susceptibility to anti-fHbp and complement despite similar Ab binding, which may have implications for the activity of fHbp-based vaccines. Capsule also limited C4b deposition by anti-porin A mAbs. Capsule expression decreased binding of an anti lipooligosaccharide IgM mAb (~ 1.2- to 2-fold reduction in fluorescence). Akin to observations with IgG, capsule also decreased IgM-mediated C4b deposition when IgM binding to the mutant strain pairs was normalized. In conclusion, we show that capsular polysaccharide, a critical meningococcal virulence factor, inhibits the CP of complement. PMID- 25015833 TI - gammadeltaT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance. AB - The mechanisms of liver hepatitis B virus (HBV)-induced systemic immune tolerance are still elusive, and the role of gammadeltaT cells has not yet been described. We examined the function of gammadeltaT cells in HBV-carrier mice- immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that gammadeltaT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8(+) T cells. Of interest, IL-17(-/-) mice phenocopied TCRdelta(-/-) mice in terms of losing HBV persistence, and adoptive transfer of gammadeltaT cells restored HBV persistent expression in TCRdelta(-/-) mice. We further observed that hepatic CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRdelta(-/-) and IL-17(-/-) mice. MDSC numbers also recovered after adoptive transfer of gammadeltaT cells, particularly Vgamma4(+) T cells. Furthermore, anti-Gr1 mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to gammadeltaT cell-deficient mice restored HBV induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8(+) T cells and promoted HBV clearance. We also observed enhanced CD8(+) T cell number with a notable decline of MDSCs in TCRdelta(-/-) mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV carrier TCRdelta(-/-) mice not only exhibited increased anti-HBV CD8(+) T cells but also markedly reduced MDSCs. Overall, the current study reveals that gammadeltaT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8(+) T cell exhaustion. PMID- 25015834 TI - Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. AB - The activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN(-/-) macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBPbeta and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity. PMID- 25015835 TI - Activation of rheumatoid factor-specific B cells is antigen dependent and occurs preferentially outside of germinal centers in the lupus-prone NZM2410 mouse model. AB - AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) strain in comparison with C57BL/6 (B6) controls, each expressing the AM14 H chain transgene in the presence or absence of the IgG2a(a) autoantigen. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoantigen. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers, but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC.AM14 H chain transgenic mice with IgG2a(a) anti chromatin immune complexes (ICs) activated RF B cells in a BCR- and TLR9 dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2a(a) anti-chromatin ICs for full differentiation of RF AFCs. PMID- 25015836 TI - Assessment and outcome of children with intestinal failure referred for intestinal transplantation. AB - BACKGROUND & AIMS: Chronic intestinal failure (CIF) requires long term parenteral nutrition (PN) and, in some patients, intestinal transplantation (ITx). Indications and timing for ITx remain poorly defined. In the present study we aimed to analyze causes and outcome of children with CIF. METHODS: 118 consecutive patients referred to our institution were assessed by a multidisciplinary team and four different categories were defined retrospectively based on their clinical course: Group 1: patients with reversible intestinal failure; group 2: patients unsuitable for ITx, group 3: patients listed for ITx; group 4: patients stable under PN. Analysis involved comparison between groups for nutritional status, central venous catheter (CVC) related complications, liver disease, and outcome after transplantation by using non parametric tests, Mann-Whitney tests, Kruskal-Wallis, Wilcoxon signed rank tests and chi square distribution for percentage. RESULTS: 118 children (72 boys) with a median age of 15 months at referral (2 months-16 years) were assessed. Etiology of IF was short bowel syndrome [n = 47], intractable diarrhea of infancy [n = 37], total intestinal aganglionosis [n = 18], and chronic intestinal pseudoobstruction [n = 17]. Most patients (89.8%) were totally PN dependent, with 48 children (40.7%) on home-PN prior to admission. Nutritional status was poor with a median body weight at -1.5 z-score (ranges: -5 to +2.5) and median length at -2.0 z-score (ranges: 5.5 to +2.3). The mean number of CVC inserted per patient was 5.2 (range 1-20) and the mean number of CRS per patient was 5.5 (median: 5; range 0-12) Fifty-five patients (46.6%) had thrombosis of >=2 main venous axis. At admission 34.7% of patients had elevated bilirubin (>=50 MUmol/l), and 19.5% had platelets <100,000/ml, and 15% had both. Liver biopsy performed in 79 children was normal (n = 4), or showed F1 or F2 fibrosis (n = 29), bridging fibrosis F3 (n = 20), or cirrhosis (n = 26). Group 1 included 10 children finally weaned from PN (7-years survival: 100%). Group 2 included 12 children with severe liver disease and associated disorders unsuitable for transplantation (7-years survival: 16.6%). Group 3 included 66 patients (56%) who were listed for small bowel or liver-small bowel transplantation, 62/66 have been transplanted (7 years survival: 74.6%). Factors influencing outcome after liver-ITx were body weight (p < .004), length (p < .001), pre-Tx bilirubin plasma level (p < .001) and thrombosis (p < .01) for isolated ITx, Group 4 included 30 children (25.4%) with irreversible IF considered as potential candidates for isolated ITx. Four children were lost from follow up and 3 died within 2 years (survival 88.5%). Among potential candidates, the following parameters improved significantly during the first 12 months of follow up: Body weight (p.0001), length (p < .0001) and bilirubin (p < .0001). CONCLUSIONS: many patients had a poor nutritional status with severe complications especially liver disease. PN related complications were the most relevant indication for ITx, but also a negative predictor for outcome. Early patient referral for Tx-assessment might help to identify and separate children with irreversible IF from children with transient IF or uncomplicated long-term PN, allowing to adapt a patient-based treatment strategy including or not ITx. PMID- 25015837 TI - Sucrose concentration in the growth medium affects the cell wall composition of tobacco pollen tubes. AB - The cell wall of pollen tubes is organized in both spatial and temporal order to allow the pollen tube to grow according to external conditions. The deposition of methyl-esterified and acid pectins in addition to callose/cellulose occurs according to a series of temporally succeeding events. In this work, we attempted to determine how the composition of the external growth medium (in terms of osmolarity) could affect the deposition of cell wall components. Pollen tubes of tobacco were grown in a hypotonic medium and then analyzed for the distribution of pectins and callose/cellulose [as well as for the distribution of the enzyme callose synthase (CALS)]. The data indicate that pollen tubes grown in a hypotonic medium show changes of the initial growth rate followed by modification of the deposition of acid pectins and, to a lesser extent, of CALS. These observations indicate that, under the osmolarity determined by the growth medium, pollen tubes adapt their cell wall to the changing conditions of growth. PMID- 25015838 TI - Sepsis survivors monitoring and coordination in outpatient health care (SMOOTH): study protocol for a randomized controlled trial. AB - BACKGROUND: Sepsis sequelae include critical illness polyneuropathy, myopathy, wasting, neurocognitive deficits, post-traumatic stress disorder, depression and chronic pain. Little is known howlong-term sequelae following hospital discharge are treated. The aim of our study is to determine the effect of a primary care based, long-term program on health-related quality of life in sepsis survivors. METHODS/DESIGN: In a two-armed randomized multicenter interventional study, patients after sepsis (n = 290) will be assessed at 6, 12 and 24 months. Patients are eligible if severe sepsis or septic shock (ICD-10), at least two criteria of systemic inflammatory response syndrome (SIRS), at least one organ dysfunction and sufficient cognitive capacity are present. The intervention comprises 1) discharge management, 2) training of general practitioners and patients in evidence-based care for sepsis sequelae and 3) telephone monitoring of patients. At six months, we expect an improved primary outcome (health-related quality of life/SF-36) and improved secondary outcomes such as costs, mortality, clinical-, psycho-social- and process-of-care measures in the intervention group compared to the control group. DISCUSSION: This study evaluates a primary care-based, long term program for patients after severe sepsis. Study results may add evidence for improved sepsis care management. General practitioners may contribute efficiently to sepsis aftercare. TRIAL REGISTRATION: U1111-1119-6345. DRKS00000741, CCT-NAPN 20875 (25 February 2011). PMID- 25015839 TI - Do long term survivors of ewing family of tumors experience low bone mineral density and increased fracture risk? AB - BACKGROUND: Multimodal treatment regimens for Ewing's sarcoma have led to survival rates approaching 70% of patients with no metastases at diagnosis. However, these treatments have long-term side effects. Low bone mineral density (BMD) and risk of fractures can occur owing in part to chemotherapy and limited mobility from local control of the primary tumor. QUESTIONS/PURPOSES: We performed this study to answer the following questions: (1) Do long-term survivors of the Ewing family of tumors sustain low BMD? (2) Which factors are associated with BMD in these patients? (3) Do they experience fractures? (4) Are BMD and fractures associated with each other? METHODS: We queried our institutional registry to identify all known survivors of Ewing tumors who were treated before 2005. Of 100 such patients, 67 (67%) responded to a postal survey to participate in this study, and an additional 11 (11%) patients were excluded according to prespecified criteria. In the remaining 56 long-term survivors (27 females, 29 males; mean+/-SD age at followup, 32+/-10 years; mean followup, 15+/ 7 years), BMD was measured by dual-energy x-ray absorptiometry and history of fractures was assessed using a questionnaire. Associations were tested using univariate and multivariate models by stepwise variable selection procedure, including Bonferroni correction. RESULTS: Thirty-one of 56 (56%) patients had a pathologic BMD. Seven (13%) had osteoporosis and 24 (43%) had osteopenia. Factors related to low BMD after Bonferroni correction were the length of time between surgery and followup and the BMI at followup. Twenty-one patients reported 29 fractures. With the numbers available, BMD levels were not associated with fractures. CONCLUSIONS: We could not confirm some potentially important predictors for fractures to be associated with clinical events of interest. However, the data are valuable as hypothesis-generating pilot data for future, multicenter prospective studies. If BMD changes cannot explain the propensity of fractures, there may be other bone characteristics like microarchitectural changes of bone to more accurately explain the effect. LEVEL OF EVIDENCE: Level IV, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 25015840 TI - Genetic stability of Brucella abortus isolates from an outbreak by multiple-locus variable-number tandem repeat analysis (MLVA16). AB - BACKGROUND: Brucellosis caused by Brucella abortus is one of the most important zoonoses in the world. Multiple-locus variable-number tandem repeat analysis (MLVA16) has been shown be a useful tool to epidemiological traceback studies in B. abortus infection. Thus, the present study aimed (i) to evaluate the genetic diversity of B. abortus isolates from a brucellosis outbreak, and (ii) to investigate the in vivo stability of the MLVA16 markers. RESULTS: Three-hundred and seventy-five clinical samples, including 275 vaginal swabs and 100 milk samples, were cultured from a brucellosis outbreak in a cattle herd, which adopted RB51 vaccination and test-and-slaughter policies. Thirty-seven B. abortus isolates were obtained, eight from milk and twenty-nine from post-partum/abortion vaginal swabs, which were submitted to biotyping and genotyping by MLVA16. Twelve B. abortus isolates obtained from vaginal swabs were identified as RB51. Twenty four isolates, seven obtained from milk samples and seventeen from vaginal swabs, were identified as B. abortus biovar 3, while one isolate from vaginal swabs was identified as B. abortus biovar 1. Three distinct genotypes were observed during the brucellosis outbreak: RB observed in all isolates identified as RB51; W observed in all B. abortus biovar 3 isolates; and Z observed in the single B. abortus biovar 1 isolate. Epidemiological and molecular data show that the B. abortus biovar 1 genotype Z strain is not related to the B. abortus biovar 3 genotype W isolates, and represents a new introduction B. abortus during the outbreak. CONCLUSIONS: The results of the present study on typing of multiple clinical B. abortus isolates from the same outbreak over a sixteen month period indicate the in vivo stability of MLVA16 markers, a low genetic diversity among B. abortus isolates and the usefulness of MLVA16 for epidemiological studies of bovine brucellosis. PMID- 25015841 TI - Attitudes toward cancer and implications for mental health outcome in African American cancer patients. AB - This study examined African-American cancer patients' attitudes toward cancer and their relationship with long-term mental health outcomes. Using mixed methods, 74 breast and prostate cancer patients including 34 depressed and 23 nondepressed African-Americans and 17 depressed Whites were interviewed. The interviews were audiotaped and transcribed. Qualitative data analysis identified themes that were coded. The codes were entered into SPSS software. Fisher's exact test was performed to examine group differences in the identified themes. Nondepressed African-Americans more frequently reported cancer as an adaptive experience (p = 0.047) and less frequently as a struggle (p = 0.012) than the depressed African Americans and Whites. Groups did not significantly differ in the belief that cancer has no cure (p = 0.763), but depressed African-Americans more frequently reported unwillingness to share a cancer diagnosis with family or friends than depressed Whites (p = 0.50). African-Americans' adaptive attitudes to cancer exhibit a pragmatist approach and a worldview shaped by their lived experience. Participants' narratives were examined to illuminate the meanings of these findings. Adaptive attitudes to cancer are associated with better long-term mental health outcomes, and conversely, unpreparedness and inability to cope are associated with a higher risk of depression among African-American cancer patients. Education about cancer and supports for treatment navigation are important measures for improving the long-term mental health of African-Americans living with cancer. PMID- 25015842 TI - GM-CSF and MEF-conditioned media support feeder-free reprogramming of mouse granulocytes to iPS cells. AB - Induced pluripotent stem cells (iPSCs) are characterised by their ability to differentiate into any cell type of the body. Accordingly, iPSCs possess immense potential for disease modelling, pharmaceutical screening and autologous cell therapies. The most common source of iPSCs derivation is skin fibroblasts. However, from a clinical point of view, skin fibroblasts may not be ideal, as invasive procedures such as skin biopsies are required for their extraction. Moreover, fibroblasts are highly heterogeneous with a poorly defined developmental pathway, which makes studying reprogramming mechanistics difficult. Granulocytes, on the other hand, are easily obtainable, their developmental pathway has been extensively studied and fluorescence activated cell sorting allows for the isolation of these cells at high purity; thus iPSCs derivation from granulocytes could provide an alternative to fibroblast-derived iPSCs. Previous studies succeeded in producing iPSC colonies from mouse granulocytes but with the use of a mitotically inactivated feeder layer, restricting their use for studying reprogramming mechanistics. As granulocytes display poor survival under culture conditions, we investigated the influence of haematopoietic cytokines to stabilise this cell type in vitro and allow for reprogramming in the absence of a feeder layer. Our results show that treatment with MEF-conditioned media and/or initial exposure to GM-CSF allows for reprogramming of granulocytes under feeder free conditions. This work can serve as a basis for future work aimed at dissecting the reprogramming mechanism as well as obtaining large numbers of iPSCs from a clinically relevant cell source. PMID- 25015844 TI - Utility of the Spanish version of the FTLD-modified CDR in the diagnosis and staging in frontotemporal lobar degeneration. AB - INTRODUCTION: The Clinical Dementia Rating Scale (CDR) is a tool designed to quantify the severity of dementia symptoms and is also useful to assess disease progression, in Alzheimer's disease (AD). A new version of the scale was developed by adding two extra domains that focused on the core aspects of frontotemporal dementia symptomatology, Language and Behavior/Comportment/Personality. OBJECTIVES: In this study, we adapted and validated the modified CDR scale in our setting and language (Rioplatense Spanish). MATERIALS AND METHODS: 46 patients with probable AD, 27 behavioral variant of Frontotemporal Dementia (bvFTD), 18 Primary Progressive Aphasia (PPA) and 40 healthy participants were included. The adapted version of the scale was administered by a blind rater who interviewed patients together with patient's caregiver. RESULTS: Using ROC curves, the domain language and behavior were superior to the memory domain in accuracy for detecting PPA and bvFTD, respectively, but both of them had equivalent diagnostic accuracies for probable AD. Logistic regression analyses showed that either the LANG or BEHAV domains significantly improved the discrimination between probable AD, bvFTD and PPA. CONCLUSIONS: The Spanish version of the modified CDR adds value for the characterization of the non-amnestic symptoms in patients with neurodegenerative dementias. PMID- 25015845 TI - The role of hydrocephalus in the development of Chiari I malformation and syringomyelia. PMID- 25015843 TI - Alpha-theta border EEG abnormalities in preclinical Huntington's disease. AB - BACKGROUND: Brain dysfunction precedes clinical manifestation of Huntington's disease (HD) by decades. This study was aimed to determine whether resting EEG is altered in preclinical HD mutations carriers (pre-HD). METHODS: We examined relative power of broad traditional EEG bands as well as 1-Hz sub-bands of theta and alpha from the resting-state EEG of 29 pre-HD individuals and of 29 age matched normal controls. RESULTS: The relative power of the narrow sub-band in the border of theta-alpha (7-8 Hz) was significantly reduced in pre-HD subjects as compared to normal controls, while the alterations in relative power of the broad frequency bands were not significant. In pre-HD subjects, the number of CAG repeats in the huntingtin (HTT) gene as well as the disease burden score (DBS) showed a positive correlation with relative power of the delta and theta frequency bands and their sub-bands and a negative correlation with alpha band relative power and the differences of relative power of the 7-8 Hz and 4-5 Hz frequency sub-bands. CONCLUSION: The obtained results suggest that EEG alterations in pre-HD individuals may be related to the course of the pathological process and to HD endophenotype. Analysis of the narrow EEG bands was found to be more useful for assessing EEG alterations in pre-HD individuals than a more traditional approach using broad bandwidths. PMID- 25015846 TI - Sperm attributes and morphology on Rusa timorensis: light and scanning electron microscopy. AB - This study provides standard information on the attributes of sperm and describes the surface structure of normal and abnormal spermatozoa of Rusa timorensis. Two fertile stags were used as the source of semen collected during the first breeding season commencing from April 5 to July 2, 2012. Another five stags were used as the source of semen collected during the second breeding season commencing from April 1 to June 27, 2013. Semen samples were collected from the stags using an electro-ejaculator. The ejaculate was processed and samples prepared for light and scanning electron microscopy (SEM) according to standard methods. No significant difference (P>0.05) was found between sperm attributes in comparison between different stags and different months of the fertile seasons. The results of this study have also demonstrated that there are no differences in size, shape and surface structure between spermatozoa of the different stags and different months of the fertile seasons. Sperm attributes (volume, pH, sperm concentration, general motility, progressive motility and viability) were 2.2+/ 0.29 ml, 7.2+/-0.17, 886.3+/-39.7*10(6) spermatozoa/ml, 78.7+/-2.01%, 80.8+/ 1.85% and 83.2+/-0.85%, respectively. Morphological analysis showed low percentage of abnormal spermatozoa 13.9+/-2.88%. Scanning electron microscopy revealed spermatozoa which consisted of a flat paddle-shaped head, short neck and a tail, which was subdivided into midpiece, principal piece and endpiece. The average spermatozoon was 66.2+/-0.69 MUm in total length. The flat paddle-shaped head was 7.8+/-0.28 MUm long, 4.2+/-0.15 MUm at its widest width, 2.4+/-0.18 MUm basal width and 0.7+/-0.0 2MUm thick. As for the tail, the midpiece length was 13.2+/-0.14 MUm, 0.6+/-0.04 MUm in diameter; the principal piece was 42.6+/ 0.04MUm, and 2.8+/-0.06 MUm for the endpiece. Abnormal spermatozoa such as tapered head, microcephalic head, decapitated spermatozoa and bent tails were observed. Results provide standard information useful for development of strategies for semen cryopreservation and assisted reproductive technology in this species. PMID- 25015847 TI - Dynamic transcriptional signatures and network responses for clinical symptoms in influenza-infected human subjects using systems biology approaches. AB - Recent studies demonstrate that human blood transcriptional signatures may be used to support diagnosis and clinical decisions for acute respiratory viral infections such as influenza. In this article, we propose to use a newly developed systems biology approach for time course gene expression data to identify significant dynamically response genes and dynamic gene network responses to viral infection. We illustrate the methodological pipeline by reanalyzing the time course gene expression data from a study with healthy human subjects challenged by live influenza virus. We observed clear differences in the number of significant dynamic response genes (DRGs) between the symptomatic and asymptomatic subjects and also identified DRG signatures for symptomatic subjects with influenza infection. The 505 common DRGs shared by the symptomatic subjects have high consistency with the signature genes for predicting viral infection identified in previous works. The temporal response patterns and network response features were carefully analyzed and investigated. PMID- 25015848 TI - Empirical antifungal therapy with an echinocandin in critically-ill patients: prospective evaluation of a pragmatic Candida score-based strategy in one medical ICU. AB - BACKGROUND: Invasive candidiasis (IC) is a life-threatening ICU-acquired infection. A strong correlation between time to antifungal therapy (AFT) administration and outcome has been established. Empirical therapy benefit should be balanced with the risk of echinocandin overuse. We assessed therefore a decision rule that aimed at guiding empirical therapy. METHODS: A 45-month prospective cohort study in a teaching medical ICU. All of the patients with suspected IC (uncontrolled sepsis despite broad spectrum antibiotics without any bacterial proven infection in patients with Candida score >= 3 points including multifocal Candida sp. colonization) were eligible. The primary endpoint was proven IC diagnosis (i.e., candidemia) following treatment onset. Timing of AFT administration was also investigated in those latter patients. Antifungal therapy step-down and discontinuation was done according to international guidelines in patients with candidemia. Otherwise, echinocandin discontinuation was encouraged in patients without proven IC, excepting when a clinical improvement was achieved without any other explanation that antifungals initiation (i.e., probable IC). In addition, a survival multivariate analysis using a Cox model was conducted. RESULTS: Fifty-one patients were given an echinocandin with respect to our decision rule. Among them, candidemia was diagnosed thereafter in 9 patients. Over the same period, antifungal therapy was triggered by candidemia announcement (i.e., definite therapy) in 12 patients who did not fulfill criteria for empirical therapy before. Time elapsed from candidemia onset to echinocandin therapy initiation was shortened (0.4 [0.5] vs. 2.4 [2.8] hours; p = 0.04) when it was given empirically. In addition, 18 patients clinically improved under empirical antifungal therapy without any obvious other explanation, despite IC remained unproven. Moreover, echinocandin exposure duration was independently related to survival in those patients. Over the same period, our predefined criteria for empirical therapy were overruled in 55 cases. None of them develop IC thereafter. Finally, Our decision rule allowed IC early recognition of proven/probable IC with sensitivity, specificity, positive and negative predictive value of 69.2%, 82.1%, 69.2% and 82.1%, respectively. CONCLUSION: Implementation of pragmatic guidelines for empirical AFT based on CS and fungal colonization assessment could be useful in selecting patients who really benefit from an echinocandin. PMID- 25015849 TI - Direct and indirect assessments of activities of daily living in behavioral variant frontotemporal dementia and Alzheimer disease. AB - BACKGROUND: There is limited information about the functional profile of behavioral variant frontotemporal dementia (bvFTD). OBJECTIVE: To compare direct and indirect assessments of activities of daily living (ADLs) in bvFTD and Alzheimer disease (AD) and their relationship with cognitive performance. METHODS: In all, 20 patients with bvFTD, 30 patients with AD, and 34 normal controls (NCs), matched for age, education, and severity of dementia, completed the Direct Assessment of Functional Performance (DAFS-BR) and usual cognitive measures. The Disability Assessment for Dementia (DAD) was completed by caregivers. RESULTS: In DAFS-BR, patients with bvFTD and AD had similar performance but lower than NCs. In DAD, there were no significant differences for effective performance, but patients with bvFTD had lower scores for initiation and planning/organization. Patients with bvFTD were less impaired than AD in cognition. CONCLUSION: Functional changes in bvFTD seem to be better documented by indirect measures. PMID- 25015850 TI - First case report of de novo ulcerative colitis developing after orthotopic liver transplantation successfully treated by granulocyte and monocyte apheresis. AB - BACKGROUND: Immunosuppressants such as tacrolimus and cyclosporine are prescribed long-term after orthotopic liver transplantation (OLT) to prevent allograft rejection. Although these immunosuppressants are known to effectively control ulcerative colitis (UC), some post-OLT patients develop exacerbation of preexisting UC or de novo UC. Although aminosalicylates and corticosteroid courses are usually effective to treat such UC, several patients have developed uncontrollable disease and required colectomies. CASE REPORT: We have reported a patient who developed de novo UC after OLT to treat liver cirrhosis and hepatocellular carcinoma associated with hepatitis B virus (HBV) infection. Existence of the HBV infection made us avoid to increase the corticosteroid dose or to use other immunosuppressants such as azathioprine or infliximab. CONCLUSIONS: In this patient, granulocyte and monocyte apheresis was highly effective in terms of inducing remission of de novo UC. No adverse event was noted. PMID- 25015851 TI - Clinical laboratory directors. PMID- 25015852 TI - Large B-cell lymphoma rich in PD-1+ T cells: an overlooked subtype of diffuse large B-cell lymphoma? PMID- 25015853 TI - The practice of clinical pathology: a quantitative description of laboratory director activities at a large academic medical center. AB - OBJECTIVES: The scope of activities performed by clinical laboratory directors is sometimes unfamiliar to other physicians or hospital administrators. Consequently, hospital leadership may undervalue the role and assume that many director level activities could be delegated to a professional manager. In this study, we sought to define the activities of academic laboratory directors, and to determine which activities require doctorate level medical or scientific expertise. METHODS: We performed an audit of laboratory director activities at a large academic medical center by reviewing electronic calendars and other available records from the preceding 12 consecutive months. For episodic activities, the directors estimated the average number of hours devoted over the 1-year period. RESULTS: On average, directors worked 54.9 hours per week and performed at least some service work 47.7 weeks per year. Administrative duties accounted for the greatest proportion of effort (47.1%), followed by clinical activities (33.1%) and academic activities (19.8%). Among administrative duties, those that required doctorate level medical or scientific expertise comprised 60.3% of the total administrative effort, whereas the remaining 39.7% (18.7% of total activity) could be performed by a professional manager.. CONCLUSIONS: Although the activities of clinical laboratory directors have been described elsewhere, this is the first study detailing the effort allocated to these various activities in quantitative terms. The study demonstrated that less than 20% of an academic laboratory director's effort involves administrative activities that could potentially be performed by a professional manager lacking doctorate level medical or scientific expertise. PMID- 25015854 TI - Large B-cell lymphomas poor in B cells and rich in PD-1+ T cells can mimic T-cell lymphomas. AB - OBJECTIVES: To characterize the clinicopathologic features of cases of large B cell lymphomas, poor in B cells and densely rich in programmed cell death-1 (PD 1)+ reactive T cells, which can mimic T-cell lymphomas. METHODS: A single institute retrospective review of cases between 2010 and 2013 was performed. RESULTS: Of 178 cases of large B-cell lymphomas, eight cases of large B-cell lymphomas poor in B cells and diffusely rich in sheets of PD-1+ T cells were identified. These cases either were initially misdiagnosed as a T-cell lymphoma or substantiated a broader differential diagnosis including a T-cell lymphoma. Five cases were T-cell histiocyte-rich large B-cell lymphomas, and three cases were diagnosed as large B-cell lymphomas rich in T cells. In three of these cases, a subset of the PD-1+ T cells showed either morphologic nuclear atypia or atypical expression of T-cell antigens on flow cytometry and/or immunohistochemistry. CONCLUSIONS: Large B-cell lymphomas poor in B cells and rich in T cells can have diffuse sheets of reactive PD-1+ T cells, some with atypical morphologic and immunophenotypic features mimicking a T-cell lymphoma. Careful assessment of the immunoarchitecture and background inflammatory and stromal cells can prevent erroneous diagnoses in such cases. PMID- 25015855 TI - Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression. AB - OBJECTIVES: To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. METHODS: We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. RESULTS: Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P=.026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (P<.001) and 61 (73%) of 84 non-muscle-invasive (NMI) tumors vs 26 (40%) of 65 muscle-invasive (MI) carcinomas (P<.001) were moderately to strongly immunoreactive for GR. Kaplan Meier and log-rank tests revealed that loss or weak positivity of GR significantly or marginally correlated with recurrence of NMI tumors (P=.025), progression of MI tumors (P=.082), and cancer-specific survival of MI tumors (P=.067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P=.034). CONCLUSIONS: GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth. PMID- 25015857 TI - Evaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas. AB - OBJECTIVES: New immunohistochemical (IHC) markers of urothelial carcinoma (UCa) and prostatic adenocarcinoma (PCa) have emerged in recent years, yet comparative studies to establish markers remain lacking. We aimed to identify an effective but parsimonious approach for poorly differentiated bladder neck lesions, to establish a best practice panel approach in a setting simulating prospective use. METHODS: We tested the performance of a panel of IHC markers on whole sections of a consecutive cohort of transurethral resection specimens of poorly differentiated, challenging bladder neck resections (n=36). RESULTS: In the setting of poorly differentiated bladder neck carcinomas, biomarker sensitivities for UCa were as follows: GATA3, 100%; S100P, 88%; p63, 75%; and cytokeratin (CK) 5/6, 56%; specificities of each were 100%. CK7 and CK20 showed sensitivities of 75% and 63%, though these were only 85% and 80% specific. For PCa markers, NKX3.1, p501S, prostate-specific membrane antigen, and androgen receptor (AR) each showed 100% sensitivity, outperforming ERG (35%) and prostate-specific antigen (PSA; 25%). All the prostate histogenesis markers were 100% specific, except for AR, which was positive in 13% of the UCa cases. CONCLUSIONS: Novel IHC markers show improved diagnostic performance that enables positive and negative support for identifying histogenesis with the use of as few as two markers for this critical therapeutic distinction. PSA underperforms newer markers. PMID- 25015858 TI - Total arsenic screening prior to fractionation enhances clinical utility and test utilization in the assessment of arsenic toxicity. AB - OBJECTIVES: The objective was to evaluate the utility of a screen with reflex-to fractionation testing compared with direct-to-fractionation testing for suspected toxic exposure. METHODS: This study was based on a retrospective data analysis of urine arsenic results from previously tested samples (n=12,960). Total urine arsenic by inductively coupled plasma mass spectrometry was used as a screening method to identify elevated arsenic concentrations. Arsenic fractionation was the speciation assay to differentiate toxic and benign arsenic species. RESULTS: Screening samples based on total arsenic concentration resulted in less than 10% of samples requiring arsenic fractionation, with a final positivity rate of less than 1% for toxic arsenic. Samples with fractionation ordered directly had a positivity rate for toxic arsenic of 3.3%. The overall positivity rate for exposure to toxic arsenic was less than 1%. CONCLUSIONS: A total arsenic screen before fractionation reduces the number of samples requiring fractionation by more than 91%, supporting the use of a screen with a reflex-to-fractionation approach for urine arsenic. PMID- 25015856 TI - Severity of rhinovirus infection in hospitalized adults is unrelated to genotype. AB - OBJECTIVES: To determine whether rhinovirus (RV) species is associated with more severe clinical illness in adults. METHODS: Seventy-two RV-positive viral respiratory samples from adult patients were sequenced and analyzed phylogenetically after reverse transcriptase polymerase chain reaction of the region spanning the VP4 gene and 5' terminus of the VP2 gene. The clinical features and severity of illness associated with the different RV species were compared. RESULTS: Phylogenetic analysis identified three distinct clusters as RV A (54%), B (11%), or C (35%) species. In an unadjusted model, patients with RV-B infection were significantly more likely to have the composite outcome variable of death or intensive care unit admission (P=.03), but this effect diminished when controlling for patient sex. A logistic model of the relationship between RV species and adverse outcomes produced nonsignificant odds ratios when controlling for patient sex. CONCLUSIONS: Infection with RV-A or RV-B was associated with greater severity of illness in our adult population; however, the association disappeared after controlling for confounders. PMID- 25015859 TI - Acute myeloid leukemia with monosomal karyotype: morphologic, immunophenotypic, and molecular findings. AB - OBJECTIVES: Acute myeloid leukemia (AML) with monosomal karyotype (MK) recently has been reported to be associated with worse outcome than the traditional complex karyotype. METHODS: In this retrospective study of 111 patients with AML, we identified 14 patients with MK (13% of all patients with AML) using the definition proposed by Breems et al. RESULTS: Five (36%) of these 14 patients had a loss of a single chromosome in the presence of other structural abnormalities, and nine (64%) had a loss of two or more autosomal chromosomes. Patients with AML MK presented at an older age, with lower bone marrow blasts, and their blasts less frequently expressed CD34. Most patients with AML-MK had morphologic multilineage dysplasia and were predominantly subclassified as having AML with myelodysplasia-related changes (AML-MRC). Molecular analysis showed a significant absence of NPM1 and FLT3 in patients with AML-MK. CONCLUSIONS: Outcome data showed that patients with AML-MK had significantly worse overall survival, disease-free survival, and complete response compared with the rest of the patients with AML as well as within the AML-MRC group. PMID- 25015860 TI - Successful triage of suspected hantavirus cardiopulmonary syndrome by peripheral blood smear review: a decade of experience in an endemic region. AB - OBJECTIVES: In 2001, the University of New Mexico Hospitals implemented a rapid screening tool for the triage of suspected hantavirus cardiopulmonary syndrome based on peripheral blood smear morphology. Five criteria guided clinical decisions: thrombocytopenia, hemoconcentration, granulocytic left shift, absence of toxic changes, and more than 10% immunoblasts. Smears meeting four of five criteria were previously shown to have high predictive value for infection. Our retrospective study aimed to determine clinical performance of this test over the past decade. METHODS: Computerized records of 188 smear results were compared with serology. RESULTS: Receiver operator characteristic curve analysis confirmed that the four of five cutoff was the most clinically useful, with sensitivity and specificity of 89% and 93%, respectively. All patients meeting five of five criteria had confirmed infections. Fifteen discordant results were uncovered, explained by positive subsequent tests in the same patient or severe disease without further testing. CONCLUSIONS: Our findings confirm that peripheral smear analysis is clinically useful in this endemic region. PMID- 25015861 TI - Frozen section of placental membranes and umbilical cord: an aid to early postpartum diagnosis of intra-amniotic infection. AB - OBJECTIVES: We devised a rapid frozen section (FS) assessment technique of placental tissues and performed the first rigorous assessment of FS relative to conventional workup. METHODS: We evaluated 49 placentas with clinical/gross suspicion of intra-amniotic infection by FS. Relative to formalin-fixed and paraffin-embedded tissues, we compared the grading, staging, and interobserver variability. RESULTS: FS assessment demonstrated a sensitivity of 0.91 (95% CI, 0.77-0.97) and a specificity of 0.60 (95% CI, 0.36-0.80) for the presence of chorioamnionitis and a sensitivity of 0.89 (95% CI, 0.75-0.96) and a specificity of 0.69 (95% CI, 0.42-0.87) for the presence of funisitis. The chi2 goodness of fit for grade and stage in both placental membrane and umbilical cord sections was significant (P<.001). There was no significant difference in interobserver variability in comparison with permanent section results (P=0.06). CONCLUSIONS: We conclude that FS is a reasonably sensitive screening technique, correlating well with conventional assessment, without significantly different interobserver variability. PMID- 25015862 TI - Sporadic lymphoplasmacytic cholecystitis: a clinicopathologic entity. AB - OBJECTIVES: To describe a sporadic form of lymphoplasmacytic cholecystitis (LPC), a condition known to occur in patients with chronic biliary tract disease. METHODS: One year's worth of cholecystectomies was reviewed for sporadic cases of LPC. Histologic, radiologic, and clinical findings were reviewed and compared with noninflamed controls. Sporadic cases were also compared histologically with obstructive LPC cases. RESULTS: Sporadic LPC made up 7% of cholecystectomies, had a male predominance (54.2%), and more often presented with clinical signs of acute inflammation compared with controls. Radiologic findings identified gallstones in 71.4% of patients. The second most common finding was unexplained extrahepatic biliary dilation. There were no unique histologic findings to separate sporadic cases from those associated with pancreatobiliary disease. CONCLUSIONS: While obstructive LPC is traditionally described as acalculous, chronic cholecystitis, we show this inflammatory pattern occurs both in the presence of gallstones and outside of previously described disease categories. In addition, LPC occurs in a unique patient demographic (older men), often presenting similarly to acute cholecystitis. PMID- 25015863 TI - High prevalence of atypical hyperplasia in the endometrium of patients with epithelial ovarian cancer. AB - OBJECTIVES: The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). METHODS: Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. RESULTS: In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P=.001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. CONCLUSIONS: Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC. PMID- 25015864 TI - Abnormal cervical cytology after allogeneic bone marrow transplantation. AB - OBJECTIVES: Allogeneic bone marrow transplantation (BMT) is a procedure mostly used for high-risk hematologic malignances. In women, follow-up protocols after BMT include gynecologic checkups with Papanicolaou (Pap) smears. METHODS: We evaluated 117 Pap smears in 54 women who underwent allogeneic BMT and correlated the smear morphology with the BMT-related medical treatment. RESULTS: Abnormal Pap smears after BMT were found in 13 (24.1%) women. Four (7.4%) women had at least one smear with atypical squamous cells of unknown significance, six (11.1%) had a low-grade squamous intraepithelial lesion, and three (5.6%) had atypical squamous cells/high-grade lesion cannot be excluded (ASC-H). The three patients with ASC-H showed high-grade atypia mimicking cancer but had a negative follow up. Nine women, including the three with ASC-H, had undergone a conditioning therapy for BMT that included busulfan. No association between other drugs and therapy-related atypia was found. CONCLUSIONS: Pap smears after BMT show a high incidence of dysplastic lesions. Moreover, conditioning including busulfan is often associated with therapy-related cytologic atypia, which may lead to unnecessary colposcopies and biopsies. Knowledge of the patient's history and a careful evaluation of the smears are mandatory in these cases. PMID- 25015865 TI - Alternate clonal dominance in richter transformation presenting as extranodal diffuse large B-cell lymphoma and synchronous classic Hodgkin lymphoma. AB - OBJECTIVES: Richter transformation (RT) represents the rare occurrence of a secondary aggressive lymphoma in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). METHODS: Here we describe the peculiar case of a patient with trisomy 12+ and atypical (CD5+, CD23-) CLL/SLL who developed a two-step RT with complex morphologic and molecular features. RESULTS: Molecular analysis of a CLL/SLL population detected two different immunoglobulin rearrangement patterns corresponding to a main peak and a minor peak. Transformation took place both as gastric diffuse large B-cell lymphoma and as a synchronous bone marrow classic Hodgkin lymphoma with the same immunoglobulin rearrangement pattern corresponding to the minor peak detected in CLL/SLL at diagnosis. During chemotherapy, progression occurred as axillary nodal involvement by a CD5+ high-grade lymphoma with an immunoglobulin rearrangement pattern corresponding to the main CLL peak. CONCLUSIONS: In this case, the elaborate clinical and molecular picture may be correlated to an alternate dominance of two distinct clonal populations probably influenced by therapeutic and environmental factors. PMID- 25015866 TI - Well-differentiated papillary mesothelioma of the peritoneum: a diagnostic dilemma on fine-needle aspiration cytology. AB - OBJECTIVES: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is an uncommon subtype of epithelioid mesothelioma. Usually, WDPMP has a benign course, while a few patients have multiple recurrence and malignant transformation on long-term follow-up. The histology of WDPMP has been well studied compared with the cytology. Although accurate diagnosis is based only on histology and immunohistochemical stains, knowledge of the cytologic features of WDPMP in context with clinical and radiologic features is essential to predict a preoperative diagnosis and guide proper management, after excluding reactive mesothelial hyperplasia, malignant mesothelioma, and serous neoplasms of the ovaries and peritoneum. Surgical excision gives a favorable outcome. METHODS: We describe a case of 28-year-old woman who sought treatment for chronic lower abdominal pain, dysuria, and dyspareunia. RESULTS: Radiologic findings suggested multiple metastatic peritoneal deposits. Ultrasound-guided fine-needle aspiration cytology showed many papillae, tubulopapillary and spheroid groups, monolayered pavement-like sheets, and many dispersed cells. Papillae showed many layers of round to ovoid cells, with minimal atypia. Atypical mitoses and necrosis were not found. A cytologic diagnosis of WDPMP was suggested. After complete resection of all the tumor nodules, histopathology and immunohistochemical findings were compatible with WDPMP. On follow-up, she developed tumor recurrence at 9 months and was managed successfully with adjuvant chemotherapy. CONCLUSIONS: This article highlights the cytologic features of WDPMP with relevant review of the literature and differential diagnosis. PMID- 25015867 TI - Cutaneous intravascular natural killer-cell lymphoma: a case report and review of the literature. AB - OBJECTIVES: To our knowledge, since 2003, there have been 11 reported cases of intravascular natural killer (NK)-cell lymphoma (IVNKL). Herein we describe the 12th case. METHODS: H&E and Envision immunohistochemical stains as well as in situ hybridization were used to study this disease in combination with review of the literature. RESULTS: Half of the cases reported to date are from China and Taipei. The clinical manifestation of IVNKL is erythema in the limbs and trunk, although patients' conditions have varied notably from each other. One-year survival rate is about 40%. CONCLUSIONS: IVNKL should be distinguished from extranodal NK/T-cell lymphoma (nasal type) and aggressive NK-cell leukemia. These three diseases have a similar phenotype and are all related to Epstein-Barr virus infection. However, the pathogenesis of similarities and differences needs further study. In particular, IVNKL is quite unusual. The treatment of IVNKL is difficult, and the prognosis is poor. Currently, IVNKL is not included in the World Health Organization classification subtypes and has been classified into NK/T-cell lymphoma (nasal type). However, in view of the unique characteristics of this disease, we propose that the diagnosis be independent, since this will facilitate further study of this disease. PMID- 25015868 TI - Neonatal Silver-Russell syndrome with maternal uniparental heterodisomy, trisomy 7 mosaicism, and dysplasia of the cerebellum. AB - OBJECTIVES: We report here the unusual association of Silver-Russell syndrome (SRS) and cerebellar dysplasia with trisomy 7 mosaicism and maternal uniparental disomy of chromosome 7 [UPD(7)m]. METHODS: Low-level trisomy 7 mosaicism was diagnosed prenatally on amniocytes, and UPD(7)m was confirmed after birth. RESULTS: Medical examination at birth showed dysmorphic facial features of SRS. Cytogenetic analysis on several tissues and cells confirmed mosaic trisomy 7. Unusual severe psychomotor retardation, hypotonia, and choreoathetoid movement were noted at 6 months. Brain magnetic resonance imaging showed both cerebellar hypoplasia and dysplasia. CONCLUSIONS: This unusual association of SRS and dysplasia of the cerebellum might be related to the presence of the trisomy 7 mosaicism on the cerebellum. Our observation strengthens the hypothesis that the phenotype observed in patients with SRS with UPD(7)m might also result from an undetected low level of trisomy 7 mosaicism that could best be revealed by performing cytogenetic investigations. PMID- 25015869 TI - Massive dissemination from spinal cord gangliogliomas negative for BRAF V600E: report of two rare adult cases. AB - OBJECTIVES: Metastatic leptomeningeal spread from spinal cord gangliogliomas (GGs) is exceedingly rare. METHODS: Two adult women, aged 27 and 51 years, died of massive disseminations of cervicothoracic GGs 4 and 6 years, respectively, after initial diagnoses; full autopsies were performed. BRAF status was assessed by VE1 immunohistochemistry (IHC), Sanger sequencing, and a single-nucleotide base extension assay (SNaPshot, Applied Biosystems, Princeton, NJ). RESULTS: The 27-year-old underwent two biopsies, chemotherapy, radiation, and ventriculoperitoneal shunt placement; she developed craniospinal and peritoneal dissemination. Autopsy confirmed shunt-mediated peritoneal metastases, microscopic bone marrow involvement, and profuse spinal and supratentorial leptomeningeal and parenchymal spread. The 51-year-old underwent two resections, radiation, and chemotherapy and developed pancytopenia with biopsy-proven bony metastases 15 months before death. Autopsy demonstrated leptomeningeal, subpial, and subependymal metastases. The tumors in both primary and metastatic sites were BRAF negative by VE1 IHC and two different mutational analyses. This compared with negative BRAF results for an additional four nonmetastatic adult nonsupratentorial GGs and in our study. CONCLUSIONS: We document two rare cases of massively metastatic spinal cord GGs in adult patients who were negative for BRAF V600E mutations via multiple methods. PMID- 25015870 TI - Misleading hemoglobin A1c levels in a patient with paroxysmal nocturnal hemoglobinuria. AB - OBJECTIVES: We report a case of a patient with diabetes mellitus and unexpectedly low hemoglobin A1c results associated with paroxysmal nocturnal hemoglobinuria (PNH). We review the impact of shortened RBC half-life on the interpretation of hemoglobin A1c levels. METHODS: Patient history and laboratory test results were obtained from electronic medical records and analyzed. RESULTS: The patient's hemoglobin A1c declined in parallel to worsening anemia after the diagnosis of PNH. However, elevated serum glucose (random), fructosamine, and glycated albumin suggest ongoing hyperglycemia. Together, these results argue that the decline in hemoglobin A1c was due to decreased RBC survival secondary to PNH. CONCLUSIONS: Hemoglobin A1c levels must be interpreted with caution in patients with hematologic diseases that change RBC survival. Serum fructosamine and glycated albumin measurements are alternative measures of time-averaged blood glucose control and may be useful in this subset of patients. PMID- 25015871 TI - Multiple macroenzymes in a patient with AIDS: diagnosis using ultrafiltration. AB - OBJECTIVES: Multiple immunoglobulin-bound enzymes (macroenzymes) are reported for the first time in an individual with AIDS. Possible causes and suitable methods of detection are addressed. METHODS: An asymptomatic man with a history of AIDS with hypergammaglobulinemia and elevated creatine kinase, amylase, and liver enzyme concentrations was evaluated before enrollment in a clinical trial. Macroenzymes were considered a possible source of these elevated concentrations. RESULTS: Polyethylene glycol (PEG) precipitation and ultrafiltration (UF) were used to evaluate the presence of seven macroenzymes. PEG results suggested the presence of six of seven macroenzymes tested, while UF revealed three. UF results supported the clinical presentation. CONCLUSIONS: A previous report shows that in cases of excess immunoglobulin, PEG coprecipitates monomeric enzymes along with serum globulins, causing false-positive reporting of macroenzymes. This may explain the discrepancy between PEG and UF results in the presence of hypergammaglobulinemia, making UF a better method of detection in these circumstances. PMID- 25015872 TI - Necrotizing fasciitis after breast augmentation: rapid microbiologic detection by using sonication of removed implants and microcalorimetry. AB - OBJECTIVES: To describe the use of sonication and microcalorimetry in diagnosing necrotizing fasciitis in a 27-year-old woman with bilateral breast implants. METHODS: The removed breast implants were subjected to sonication and microcalorimetry. The microcalorimetry findings were correlated with conventional microbiologic methods. The time to detection of infection was noted. RESULTS: The patient had painful cellulitis of the right breast that enlarged within hours. Her C-reactive protein level was increased. Chest radiograph showed gas formation in the soft tissue lateral of the right breast. Surgery was performed: 300 mL (right breast) and 100 mL (left breast) of serous-purulent fluid were evacuated. Streptococcus pyogenes was cultured from the fluid 1 day after clinical presentation. Infection was diagnosed by microcalorimetry of sonication fluid in 1 hour and 21 minutes. The microcalorimetry curve from the right implant reached the peak earlier than did the left implant. CONCLUSION: Microcalorimetry will have a benefit in conditions in which rapid diagnosis of infection is important. PMID- 25015874 TI - The interpretation of LSIL-H. PMID- 25015875 TI - Balancing consumer and societal requirements for sheep meat production: an Australasian perspective. AB - Although there has been a decline in sheep numbers in Australia and New Zealand, both countries remain significant producers and exporters of sheep meat. The ongoing demand for more sustainable and ethical animal farming systems and practices requires sheep production industries to be both vigilant and responsive to consumer and the broader societal needs. Demonstration of continuous improvement in animal welfare is paramount and the welfare risks and challenges confronting Australasian sheep industries now and into the future are discussed. PMID- 25015876 TI - Periodontal disease and systemic diseases in an older population. AB - OBJECTIVE: To evaluate the relationship between older adults' medical and oral conditions and their self-reports of periodontal conditions with clinically obtained data. BACKGROUND: Concerns about oral health of elders and its association with systemic diseases have been gaining more attention. METHODS: A total of 201 older subjects were interviewed about their previous medical and dental histories and were asked to complete a health questionnaire. Each subject received full mouth exam, including counting number of natural teeth remaining, gingival (GI) and plaque index (PI), CPITN and denture status. RESULTS: Elders who completed health questionnaires had mean age of 62.5. Mean CPITN score was 1.62(+/- 1.12), PI was 1.57(+/- 1.48), and GI was 1.55(+/- 1.31). Women had higher prevalence of CVD and osteoporosis than men (p=0.008, p=0.0001, respectively). Subjects who reported bleeding upon brushing had higher PI and GI scores (p=0.03, p=0.05, respectively). Smokers were more likely to describe their periodontal tissues as unhealthy (72.3% vs. 27.7%, p=0.01), whereas self-reports of healthy vs. unhealthy gums did not differ between non-smokers. CONCLUSION: These findings suggest that a number of systemic conditions are associated with indicators of periodontal disease, and self-reports of oral conditions are independent of systemic diseases. PMID- 25015877 TI - Reinforcement of experimental composite materials based on amorphous calcium phosphate with inert fillers. AB - OBJECTIVES: The aim of this study was to examine the influence of the addition of glass fillers with different sizes and degrees of silanization percentages to remineralizing composite materials based on amorphous calcium phosphate (ACP). METHODS: Four different materials were tested in this study. Three ACP based materials: 0-ACP (40 wt% ACP, 60 wt% resin), Ba-ACP (40 wt% ACP, 50 wt% resin, 10 wt% barium-glass) and Sr-ACP (40 wt% ACP, 50 wt% resin, 10 wt% strontium-glass) were compared to the control material, resin modified glass ionomer (Fuji II LC capsule, GC, Japan). The fillers and composites were characterized using scanning electron microscopy. Flexural strength and modulus were determined using a three point bending test. Calcium and phosphate ion release from ACP based composites was measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: The addition of barium-glass fillers (35.4 (29.1-42.1) MPa) (median (25 75%)) had improved the flexural strength in comparison to the 0-ACP (24.8 (20.8 36.9) MPa) and glass ionomer control (33.1 (29.7-36.2) MPa). The admixture of strontium-glass (20.3 (19.5-22.2) MPa) did not have any effect on flexural strength, but significantly improved its flexural modulus (6.4 (4.8-6.9) GPa) in comparison to 0-ACP (3.9 (3.4-4.1) GPa) and Ba-ACP (4.6 (4.2-6.9) GPa). Ion release kinetics was not affected by the addition of inert fillers to the ACP composites. SIGNIFICANCE: Incorporation of barium-glass fillers to the composition of ACP composites contributed to the improvement of flexural strength and modulus, with no adverse influence on ion release profiles. PMID- 25015878 TI - Evaluation of in vitro resistance of different 2.0-mm titanium plates on the mandibular angle sectioning. AB - OBJECTIVE: The purpose of this study was to compare, by mechanical in vitro testing, a regular 5-hole plate and a long 4-hole plate with a regular 4-hole plate, applied to stabilize a simulated mandibular angle fracture. STUDY DESIGN: The plates from the 2.0-mm titanium-based system were adapted and stabilized passively in the same site in both groups using four screws, 6 mm long. During the resistance-to-load test, the force was applied perpendicular to the occlusal plane at three different points: first molar at the plated side, first molar at the contralateral side, and between the central incisors. RESULTS: The regular 5 hole plates and longer 4-hole plates were superior to the regular 4-hole plates. Furthermore, no statistically significant difference was found between the regular 5-hole plates and long 4-hole plate. CONCLUSIONS: The length and shape of plates did not interfere with the effectiveness to stabilize the fragments. OBJECTIVE: The purpose of this study was to compare, by mechanical in vitro testing, a regular 5-hole plate and a long 4-hole plate with a regular 4-hole plate, applied to stabilize a simulated mandibular angle fracture.Study design The plates from the 2.0-mm titanium-based system were adapted and stabilized passively in the same site in both groups using four screws, 6 mm long. During the resistance-to-load test, the force was applied perpendicular to the occlusal plane at three different points: first molar at the plated side, first molar at the contralateral side, and between the central incisors. RESULTS: The regular 5 hole plates and longer 4-hole plates were superior to the regular 4-hole plates. Furthermore, no statistically significant difference was found between the regular 5-hole plates and long 4-hole plate.Conclusions The length and shape of plates did not interfere with the effectiveness to stabilize the fragments. PMID- 25015879 TI - Middle ear cholesteatoma: Compared diagnostic performances of two incremental MRI protocols including non-echo planar diffusion-weighted imaging acquired on 3T and 1.5T scanners. AB - BACKGROUND AND PURPOSE: To compare diagnostic performances for cholesteatoma diagnosis of incremental MRI protocols including non-echo planar diffusion weighted imaging (DWI) performed on 3T and 1.5T scanners. MATERIALS AND METHODS: Thirty-nine patients with suspected cholesteatoma underwent 3T and 1.5T non-echo planar DWI and additional unenhanced T1-, delayed gadolinium-enhanced T1- and high-resolution T2-weighted standard acquisitions. Patients either underwent surgical tympanoplasty (n=21) or close clinicoradiological follow-up (n=18). Four radiologists independently and prospectively interpreted two incremental MRI protocols, differing in the magnetic field strength of the diffusion-weighted acquisition and comprising the three standard sequences. At each step, diagnostic performances were expressed as sensitivity, specificity, positive predictive value, negative predictive value and accuracy. RESULTS: Forty middle ear lesions including 21 cholesteatomas were identified. Univariate and multivariate analysis did not demonstrate significant reader, sequence addition or DWI magnetic field effect on diagnostic performances. Concerning non-echo planar DWI alone, sensitivity, specificity, positive predictive value, negative predictive value and accuracy ranged between 90.5-100%, 68.4-100%, 76.9-100%, 90.0-100% and 82.5 95.0, respectively. CONCLUSION: Non-echo planar DWI for cholesteatoma diagnosis can be performed on 1.5T or 3T scanners indifferently. High sensitivity and negative predictive value and relatively lower specificity and positive predictive value are achieved by a single non-echo planar DWI protocol. PMID- 25015880 TI - Endoscopic excavation for gastric heterotopic pancreas: an analysis of 42 cases from a tertiary center. AB - BACKGROUND: Because of the difficulty associated with making an accurate diagnosis of gastric heterotopic pancreas (HP) before surgery, surgical resection is usually performed in suspected cases. However, this is an invasive procedure and prone to certain surgical complications. AIMS: This study was designed to evaluate the feasibility of endoscopic excavation for gastric HP, as well as the value of endoscopic ultrasonography (EUS) in diagnosing gastric HP. METHODS: Between January 2007 and January 2013, 42 consecutive patients with gastric HP were enrolled in this retrospective study. Key steps: (1) Injection of a solution (100 ml saline + 2 ml indigo carmine + 1 ml epinephrine) into the submucosal layer after making several dots around the lesion; (2) Incision of the mucosa outside the marker dots with a needle-knife, and then circumferential excavation until complete resection of the lesion; (3) Closure of the artificial ulcer with several clips after tumor removal. RESULTS: In this study, 18 cases (42.9%) were suspected as gastric HP (assessed by two experienced endoscopists before endoscopic excavation), 8 (19.0%) were suspected as gastrointestinal stromal tumors, 7 (16.7%) as gastric polyp, and the remaining 9 cases (21.4%) were still unknown. The mean procedure duration was 28.6 min. En bloc resection by endoscopic excavation was achieved in 40 cases (95.2%), and no massive bleeding, delayed bleeding, perforation, or other severe complication occurred in these patients. Among the 42 lesions, a tube echo could be detected in 11 cases by EUS. Those 11 cases were diagnosed as gastric HP by histopathology. CONCLUSIONS: Endoscopic excavation appears to be a safe and feasible procedure for accurate histopathologic evaluation and curative treatment in gastric HP. Use of EUS has some value in the diagnosis of gastric HP before the procedure PMID- 25015881 TI - Vanadium methyl-bipyridine organoligand and its influence on energy balance and organs mass. AB - In the treatment of lifestyle diseases, including metabolic syndrome and type 2 diabetes, it is important to lower body mass and fat tissue, and consequently, to increase insulin-sensitivity. Unfortunately, it often happens that low-energy diet which would lower overweight is not observed and, thus, it does not bring the expected effects. This paper discusses the influence of three diets-control, high-fructose, and high-fatty diet-on absorption of energy from food in order to transform it into body mass. The kJ/g ratio which describes this process has been calculated. In the tested diets, the addition of fructose (79.13 +/- 2.47 kJ/g) or fat (82.48 +/- 2.28 kJ/g) results in higher transformation of energy into body mass than in the case of control diet (89.60 +/- 1.86 kJ/g). The addition of Na[VO(O2)2(4,4'-Me2-2,2'-bpy)]*8H2O (where 4,4'-Me2-2,2'-bpy = 4,4'-dimethyl-2,2' bipyridine) results in statistical increase of that ratio: fructose diet (86.88 +/- 0.44 kJ/g), fat diet (104.68 +/- 3.01 kJ/g), and control diet (115.98 +/- 0.56 kJ/g), respectively. Fat diet statistically influences the decrease of kidney mass in comparison to the other diets. The application of the tested vanadium compound results also in the statistical decrease of the fatty liver caused by fructose and fat diet. PMID- 25015882 TI - Anti-apoptotic potency of TNFR:Fc gene in ischemia/ reperfusion-induced myocardial cell injury. AB - The aim of the study was to investigate the anti-apoptotic potency of TNFR:Fc gene in ischemia/reperfusion-induced myocardial cell injury and hypoxia/reoxygenation-induced H9c2 rat cardiomyocytes injury. Rats were randomly divided into the following groups (n=8): (1) sham operation group; (2) ischemia reperfusion (I/R) rats treated with rAAV-EGFP; (3) I/R rats treated with rAAV TNFR:Fc group. rAAV-EGFP or rAAV-TNFR:Fc was injected intra-myocardial at four sites on the anterior and posterior walls of left ventricle immediately after the construction of I/R-induced AMI model in rats. The effects of TNFR:Fc on apoptosis and cardiacfunction were observed after 72 h of coronary reperfusion. In the in vitro study, apoptosis was analyzed in H9c2 rat cardiomyocytes treated either with nomoxia alone, or hypoxia/reoxygenation in the presence of rAAV-GFP or rAAV-TNFR:Fc. We found that (1) TNFR:Fc gene improved cardiac function (EF, LVESP, LVEDP and dp/dt max) post I/R-induced AMI; (2) TNFR:Fc gene inhibited I/R induced apoptosis and attenuated the level of TNF-alpha in serum and cardiac tissue; (3) TNFR:Fc gene prevented apoptosis in hypoxia/reoxygenation-induced H9c2 rat cardiomyocytes associated with inhibition of caspase-3 activation and normalization of ratio of the Bcl-2/Bax. We concluded that TNFR:Fc gene transfection has anti-apoptotic potency in ischemia/reperfusion-induced myocardial cell injury. PMID- 25015883 TI - Comprehensive comparison of cultivable norovirus surrogates in response to different inactivation and disinfection treatments. AB - Human norovirus is the leading cause of epidemic and sporadic acute gastroenteritis. Since no cell culture method for human norovirus exists, cultivable surrogate viruses (CSV), including feline calicivirus (FCV), murine norovirus (MNV), porcine enteric calicivirus (PEC), and Tulane virus (TuV), have been used to study responses to inactivation and disinfection methods. We compared the levels of reduction in infectivities of CSV and Aichi virus (AiV) after exposure to extreme pHs, 56 degrees C heating, alcohols, chlorine on surfaces, and high hydrostatic pressure (HHP), using the same matrix and identical test parameters for all viruses, as well as the reduction of human norovirus RNA levels under these conditions. At pH 2, FCV was inactivated by 6 log10 units, whereas MNV, TuV, and AiV were resistant. All CSV were completely inactivated at 56 degrees C within 20 min. MNV was inactivated 5 log10 units by alcohols, in contrast to 2 and 3 log10 units for FCV and PEC, respectively. TuV and AiV were relatively insensitive to alcohols. FCV was reduced 5 log10 units by 1,000 ppm chlorine, in contrast to 1 log10 unit for the other CSV. All CSV except FCV, when dried on stainless steel surfaces, were insensitive to 200 ppm chlorine. HHP completely inactivated FCV, MNV, and PEC at >=300 MPa, and TuV at 600 MPa, while AiV was completely resistant to HHP up to 800 MPa. By reverse transcription-quantitative PCR (RT-qPCR), genogroup I (GI) noroviruses were more sensitive than GII noroviruses to alcohols, chlorine, and HHP. Although inactivation profiles were variable for each treatment, TuV and MNV were the most resistant CSV overall and therefore are the best candidates for studying the public health outcomes of norovirus infections. PMID- 25015884 TI - Biosynthesis of novel Pyoverdines by domain substitution in a nonribosomal peptide synthetase of Pseudomonas aeruginosa. AB - Pyoverdine is a fluorescent nonribosomal peptide siderophore made by fluorescent pseudomonads. The Pseudomonas aeruginosa nonribosomal peptide synthetase (NRPS) PvdD contains two modules that each incorporate an l-threonine residue at the C terminal end of pyoverdine. In an attempt to generate modified pyoverdine peptides, we substituted alternative-substrate-specifying adenylation (A) and peptide bond-catalyzing condensation (C) domains into the second module of PvdD. When just the A domain was substituted, the resulting strains produced only wild type pyoverdine-at high levels if the introduced A domain specified threonine or at trace levels otherwise. The high levels of pyoverdine synthesis observed whenever the introduced A domain specified threonine indicated that these nonnative A domains were able to communicate effectively with the PvdD C domain. Moreover, the unexpected observation that non-threonine-specifying A domains nevertheless incorporated threonine into pyoverdine suggests that the native PvdD C domain exhibited stronger selectivity than these A domains for the incorporated amino acid substrate (i.e., misactivation of a threonine residue by the introduced A domains was more frequent than misincorporation of a nonthreonine residue by the PvdD C domain). In contrast, substitution of both the C and A domains of PvdD generated high yields of rationally modified pyoverdines in two instances, these pyoverdines having either a lysine or a serine residue in place of the terminal threonine. However, C-A domain substitution more commonly yielded a truncated peptide product, likely due to stalling of synthesis on a nonfunctional recombinant NRPS template. PMID- 25015885 TI - Directed evolution of brain-derived neurotrophic factor for improved folding and expression in Saccharomyces cerevisiae. AB - Brain-derived neurotrophic factor (BDNF) plays an important role in nervous system function and has therapeutic potential. Microbial production of BDNF has resulted in a low-fidelity protein product, often in the form of large, insoluble aggregates incapable of binding to cognate TrkB or p75 receptors. In this study, employing Saccharomyces cerevisiae display and secretion systems, it was found that BDNF was poorly expressed and partially inactive on the yeast surface and that BDNF was secreted at low levels in the form of disulfide-bonded aggregates. Thus, for the purpose of increasing the compatibility of yeast as an expression host for BDNF, directed-evolution approaches were employed to improve BDNF folding and expression levels. Yeast surface display was combined with two rounds of directed evolution employing random mutagenesis and shuffling to identify BDNF mutants that had 5-fold improvements in expression, 4-fold increases in specific TrkB binding activity, and restored p75 binding activity, both as displayed proteins and as secreted proteins. Secreted BDNF mutants were found largely in the form of soluble homodimers that could stimulate TrkB phosphorylation in transfected PC12 cells. Site-directed mutagenesis studies indicated that a particularly important mutational class involved the introduction of cysteines proximal to the native cysteines that participate in the BDNF cysteine knot architecture. Taken together, these findings show that yeast is now a viable alternative for both the production and the engineering of BDNF. PMID- 25015886 TI - Exopolysaccharides synthesized by Lactobacillus reuteri protect against enterotoxigenic Escherichia coli in piglets. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in piglets; ETEC cells colonize the intestinal mucosa with adhesins and deliver toxins that cause fluid loss. This study determined the antiadhesive properties of bacterial exopolysaccharides (reuteran and levan) and related glycans (dextran and inulin) in a small intestinal segment perfusion (SISP) model. The SISP model used 10 jejunal segments from 5-week-old piglets. Five segments were infected with ETEC expressing K88 fimbriae (ETEC K88), while five segments were treated with saline. Every two segments (ETEC and non-ETEC infected) were infused with 65 ml of 10 g liter(-1) of glycans or saline (control) for 8 h. High-resolution melting-curve (HRM) quantitative PCR (qPCR) indicated that E. coli is the dominant bacterium in infected segments, while other bacteria were predominant in noninfected segments. Infection by ETEC K88 was also verified by qPCR; gene copy numbers of K88 fimbriae and the heat-labile toxin (LT) in mucosal scrapings and outflow fluid of infected segments were significantly higher than those in noninfected segments. Genes coding for K88 fimbriae and LT were also detected in noninfected segments. LT amplicons from infected and noninfected segments were 99% identical over 481 bp, demonstrating the presence of autochthonous ETEC K88. All glycans reduced fluid loss caused by ETEC K88 infection. Reuteran tended (P = 0.06) to decrease ETEC K88 levels in mucosal scraping sample, as judged by qPCR. Fluorescent in situ hybridization analysis demonstrated that reuteran significantly (P = 0.012) decreased levels of adherent ETEC K88. Overall, reuteran may prevent piglet diarrhea by reducing adhesion of ETEC K88. PMID- 25015887 TI - SmoXYB1C1Z of Mycobacterium sp. strain NBB4: a soluble methane monooxygenase (sMMO)-like enzyme, active on C2 to C4 alkanes and alkenes. AB - Monooxygenase (MO) enzymes initiate the aerobic oxidation of alkanes and alkenes in bacteria. A cluster of MO genes (smoXYB1C1Z) of thus-far-unknown function was found previously in the genomes of two Mycobacterium strains (NBB3 and NBB4) which grow on hydrocarbons. The predicted Smo enzymes have only moderate amino acid identity (30 to 60%) to their closest homologs, the soluble methane and butane MOs (sMMO and sBMO), and the smo gene cluster has a different organization from those of sMMO and sBMO. The smoXYB1C1Z genes of NBB4 were cloned into pMycoFos to make pSmo, which was transformed into Mycobacterium smegmatis mc(2) 155. Cells of mc(2)-155(pSmo) metabolized C2 to C4 alkanes, alkenes, and chlorinated hydrocarbons. The activities of mc(2)-155(pSmo) cells were 0.94, 0.57, 0.12, and 0.04 nmol/min/mg of protein with ethene, ethane, propane, and butane as substrates, respectively. The mc(2)-155(pSmo) cells made epoxides from ethene, propene, and 1-butene, confirming that Smo was an oxygenase. Epoxides were not produced from larger alkenes (1-octene and styrene). Vinyl chloride and 1,2-dichloroethane were biodegraded by cells expressing Smo, with production of inorganic chloride. This study shows that Smo is a functional oxygenase which is active against small hydrocarbons. M. smegmatis mc(2)-155(pSmo) provides a new model for studying sMMO-like monooxygenases. PMID- 25015888 TI - Effect of lineage-specific metabolic traits of Lactobacillus reuteri on sourdough microbial ecology. AB - This study determined the effects of specific metabolic traits of Lactobacillus reuteri on its competitiveness in sourdoughs. The competitiveness of lactobacilli in sourdough generally depends on their growth rate; acid resistance additionally contributes to competitiveness in sourdoughs with long fermentation times. Glycerol metabolism via glycerol dehydratase (gupCDE) accelerates growth by the regeneration of reduced cofactors; glutamate metabolism via glutamate decarboxylase (gadB) increases acid resistance by generating a proton motive force. Glycerol and glutamate metabolisms are lineage-specific traits in L. reuteri; therefore, this study employed glycerol dehydratase-positive sourdough isolates of human-adapted L. reuteri lineage I, glutamate decarboxylase-positive strains of rodent-adapted L. reuteri lineage II, as well as mutants with deletions in gadB or gupCDE. The competitivenesses of the strains were quantified by inoculation of wheat and sorghum sourdoughs with defined strains, followed by propagation of doughs with a 10% inoculum and 12-h or 72-h fermentation cycles. Lineage I L. reuteri strains dominated sourdoughs propagated with 12-h fermentation cycles; lineage II L. reuteri strains dominated sourdoughs propagated with 72-h fermentation cycles. L. reuteri 100-23DeltagadB was outcompeted by its wild-type strain in sourdoughs fermented with 72-h fermentation cycles; L. reuteri FUA3400DeltagupCDE was outcompeted by its wild type strain in sourdoughs fermented with both 12-h and 72-h fermentation cycles. Competition experiments with isogenic pairs of strains resulted in a constant rate of strain displacement of the less competitive mutant strain. In conclusion, lineage-specific traits of L. reuteri determine the competitiveness of this species in sourdough fermentations. PMID- 25015889 TI - Lactobacillus rhamnosus GG inhibits the toxic effects of Staphylococcus aureus on epidermal keratinocytes. AB - Few studies have evaluated the potential benefits of the topical application of probiotic bacteria or material derived from them. We have investigated whether a probiotic bacterium, Lactobacillus rhamnosus GG, can inhibit Staphylococcus aureus infection of human primary keratinocytes in culture. When primary human keratinocytes were exposed to S. aureus, only 25% of the keratinocytes remained viable following 24 h of incubation. However, in the presence of 10(8) CFU/ml of live L. rhamnosus GG, the viability of the infected keratinocytes increased to 57% (P = 0.01). L. rhamnosus GG lysates and spent culture fluid also provided significant protection to keratinocytes, with 65% (P = 0.006) and 57% (P = 0.01) of cells, respectively, being viable following 24 h of incubation. Keratinocyte survival was significantly enhanced regardless of whether the probiotic was applied in the viable form or as cell lysates 2 h before or simultaneously with (P = 0.005) or 12 h after (P = 0.01) S. aureus infection. However, spent culture fluid was protective only if added before or simultaneously with S. aureus. With respect to mechanism, both L. rhamnosus GG lysate and spent culture fluid apparently inhibited adherence of S. aureus to keratinocytes by competitive exclusion, but only viable bacteria or the lysate could displace S. aureus (P = 0.04 and 0.01, respectively). Furthermore, growth of S. aureus was inhibited by either live bacteria or lysate but not spent culture fluid. Together, these data suggest at least two separate activities involved in the protective effects of L. rhamnosus GG against S. aureus, growth inhibition and reduction of bacterial adhesion. PMID- 25015890 TI - Factors limiting the spread of the protective symbiont Hamiltonella defensa in Aphis craccivora Aphids. AB - Many insects are associated with heritable symbionts that mediate ecological interactions, including host protection against natural enemies. The cowpea aphid, Aphis craccivora, is a polyphagous pest that harbors Hamiltonella defensa, which defends against parasitic wasps. Despite this protective benefit, this symbiont occurs only at intermediate frequencies in field populations. To identify factors constraining H. defensa invasion in Ap. craccivora, we estimated symbiont transmission rates, performed fitness assays, and measured infection dynamics in population cages to evaluate effects of infection. Similar to results with the pea aphid, Acyrthosiphon pisum, we found no consistent costs to infection using component fitness assays, but we did identify clear costs to infection in population cages when no enemies were present. Maternal transmission rates of H. defensa in Ap. craccivora were high (ca. 99%) but not perfect. Transmission failures and infection costs likely limit the spread of protective H. defensa in Ap. craccivora. We also characterized several parameters of H. defensa infection potentially relevant to the protective phenotype. We confirmed the presence of H. defensa in aphid hemolymph, where it potentially interacts with endoparasites, and performed real-time quantitative PCR (qPCR) to estimate symbiont and phage abundance during aphid development. We also examined strain variation of H. defensa and its bacteriophage at multiple loci, and despite our lines being collected in different regions of North America, they were infected with a nearly identical strains of H. defensa and APSE4 phage. The limited strain diversity observed for these defensive elements may result in relatively static protection profile for this defensive symbiosis. PMID- 25015891 TI - Transcriptome-based analysis of the Pantoea stewartii quorum-sensing regulon and identification of EsaR direct targets. AB - Pantoea stewartii subsp. stewartii is a proteobacterium that causes Stewart's wilt disease in corn plants. The bacteria form a biofilm in the xylem of infected plants and produce capsule that blocks water transport, eventually causing wilt. At low cell densities, the quorum-sensing (QS) regulatory protein EsaR is known to directly repress expression of esaR itself as well as the genes for the capsular synthesis operon transcription regulator, rcsA, and a 2,5 diketogluconate reductase, dkgA. It simultaneously directly activates expression of genes for a putative small RNA, esaS, the glycerol utilization operon, glpFKX, and another transcriptional regulator, lrhA. At high bacterial cell densities, all of this regulation is relieved when EsaR binds an acylated homoserine lactone signal, which is synthesized constitutively over growth. QS-dependent gene expression is critical for the establishment of disease in the plant. However, the identity of the full set of genes controlled by EsaR/QS is unknown. A proteomic approach previously identified around 30 proteins in the QS regulon. In this study, a whole-transcriptome, next-generation sequencing analysis of rRNA depleted RNA from QS-proficient and -deficient P. stewartii strains was performed to identify additional targets of EsaR. EsaR-dependent transcriptional regulation of a subset of differentially expressed genes was confirmed by quantitative reverse transcription-PCR (qRT-PCR). Electrophoretic mobility shift assays demonstrated that EsaR directly bound 10 newly identified target promoters. Overall, the QS regulon of P. stewartii orchestrates three major physiological responses: capsule and cell envelope biosynthesis, surface motility and adhesion, and stress response. PMID- 25015892 TI - Metatranscriptomic analysis of arctic peat soil microbiota. AB - Recent advances in meta-omics and particularly metatranscriptomic approaches have enabled detailed studies of the structure and function of microbial communities in many ecosystems. Molecular analyses of peat soils, ecosystems important to the global carbon balance, are still challenging due to the presence of coextracted substances that inhibit enzymes used in downstream applications. We sampled layers at different depths from two high-Arctic peat soils in Svalbard for metatranscriptome preparation. Here we show that enzyme inhibition in the preparation of metatranscriptomic libraries can be circumvented by linear amplification of diluted template RNA. A comparative analysis of mRNA-enriched and nonenriched metatranscriptomes showed that mRNA enrichment resulted in a 2 fold increase in the relative abundance of mRNA but biased the relative distribution of mRNA. The relative abundance of transcripts for cellulose degradation decreased with depth, while the transcripts for hemicellulose debranching increased, indicating that the polysaccharide composition of the peat was different in the deeper and older layers. Taxonomic annotation revealed that Actinobacteria and Bacteroidetes were the dominating polysaccharide decomposers. The relative abundances of 16S rRNA and mRNA transcripts of methanogenic Archaea increased substantially with depth. Acetoclastic methanogenesis was the dominating pathway, followed by methanogenesis from formate. The relative abundances of 16S rRNA and mRNA assigned to the methanotrophic Methylococcaceae, primarily Methylobacter, increased with depth. In conclusion, linear amplification of total RNA and deep sequencing constituted the preferred method for metatranscriptomic preparation to enable high-resolution functional and taxonomic analyses of the active microbiota in Arctic peat soil. PMID- 25015893 TI - Influence of Populus genotype on gene expression by the wood decay fungus Phanerochaete chrysosporium. AB - We examined gene expression patterns in the lignin-degrading fungus Phanerochaete chrysosporium when it colonizes hybrid poplar (Populus alba * tremula) and syringyl (S)-rich transgenic derivatives. A combination of microarrays and liquid chromatography-tandem mass spectrometry (LC-MS/MS) allowed detection of a total of 9,959 transcripts and 793 proteins. Comparisons of P. chrysosporium transcript abundance in medium containing poplar or glucose as a sole carbon source showed 113 regulated genes, 11 of which were significantly higher (>2-fold, P < 0.05) in transgenic line 64 relative to the parental line. Possibly related to the very large amounts of syringyl (S) units in this transgenic tree (94 mol% S), several oxidoreductases were among the upregulated genes. Peptides corresponding to a total of 18 oxidoreductases were identified in medium consisting of biomass from line 64 or 82 (85 mol% S) but not in the parental clone (65 mol% S). These results demonstrate that P. chrysosporium gene expression patterns are substantially influenced by lignin composition. PMID- 25015895 TI - Letter to the editor in response to: The correlation between prolonged corrected QT interval with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose. PMID- 25015894 TI - Hydrogen photoproduction by immobilized n2-fixing cyanobacteria: understanding the role of the uptake hydrogenase in the long-term process. AB - We have investigated two approaches to enhance and extend H2 photoproduction yields in heterocystous, N2-fixing cyanobacteria entrapped in thin alginate films. In the first approach, periodic CO2 supplementation was provided to alginate-entrapped, N-deprived cells. N deprivation led to the inhibition of photosynthetic activity in vegetative cells and the attenuation of H2 production over time. Our results demonstrated that alginate-entrapped DeltahupL cells were considerably more sensitive to high light intensity, N deficiency, and imbalances in C/N ratios than wild-type cells. In the second approach, Anabaena strain PCC 7120, its DeltahupL mutant, and Calothrix strain 336/3 films were supplemented with N2 by periodic treatments of air, or air plus CO2. These treatments restored the photosynthetic activity of the cells and led to a high level of H2 production in Calothrix 336/3 and DeltahupL cells (except for the treatment air plus CO2) but not in the Anabaena PCC 7120 strain (for which H2 yields did not change after air treatments). The highest H2 yield was obtained by the air treatment of DeltahupL cells. Notably, the supplementation of CO2 under an air atmosphere led to prominent symptoms of N deficiency in the DeltahupL strain but not in the wild type strain. We propose that uptake hydrogenase activity in heterocystous cyanobacteria not only supports nitrogenase activity by removing excess O2 from heterocysts but also indirectly protects the photosynthetic apparatus of vegetative cells from photoinhibition, especially under stressful conditions that cause an imbalance in the C/N ratio in cells. PMID- 25015896 TI - Improved perception of communication and compliance with a revised, intensive care unit-specific bedside communication sheet. AB - Although many pediatric intensive care units (PICUs) use beside communication sheets (BCSs) to highlight daily goals, the optimal format is unknown. A site specific BCS could improve both PICU communication and compliance completing the BCS. Via written survey, PICU staff at an academic children's hospital provided recommendations for improving and revising an existing BCS. Pre- and post-BCS revision, PICU staff were polled regarding PICU communication and BCS effectiveness, and daily compliance for completing the BCS was monitored. After implementation of the revised BCS, staff reporting "excellent" or "very good" day to-day communication within the PICU increased from 57% to 77% (P = .02). Compliance for completing the BCS also increased significantly (75% vs 83%, P = .03). Introduction of a focused and concise BCS tailored to a specific PICU leads to improved perceptions of communication by PICU staff and increased compliance completing the daily BCS. PMID- 25015897 TI - Self-reported quality of care for older adults from 2004 to 2011: a cohort study. AB - BACKGROUND: little is known about changes in the quality of medical care for older adults over time. OBJECTIVE: to assess changes in technical quality of care over 6 years, and associations with participants' characteristics. DESIGN: a national cohort survey covering RAND Corporation-derived quality indicators (QIs) in face-to-face structured interviews in participants' households. PARTICIPANTS: a total of 5,114 people aged 50 or more in four waves of the English Longitudinal Study of Ageing. METHODS: the percentage achievement of 24 QIs in 10 general medical and geriatric clinical conditions was calculated for each time point, and associations with participants' characteristics were estimated using logistic regression. RESULTS: participants were eligible for 21,220 QIs. QI achievement for geriatric conditions (cataract, falls, osteoarthritis and osteoporosis) was 41% [95% confidence interval (CI): 38-44] in 2004-05 and 38% (36-39) in 2010-11. Achievement for general medical conditions (depression, diabetes mellitus, hypertension, ischaemic heart disease, pain and cerebrovascular disease) improved from 75% (73-77) in 2004-05 to 80% (79-82) in 2010-11. Achievement ranged from 89% for cerebrovascular disease to 34% for osteoarthritis. Overall achievement was lower for participants who were men, wealthier, infrequent alcohol drinkers, not obese and living alone. CONCLUSION: substantial system-level shortfalls in quality of care for geriatric conditions persisted over 6 years, with relatively small and inconsistent variations in quality by participants' characteristics. The relative lack of variation by participants' characteristics suggests that quality improvement interventions may be more effective when directed at healthcare delivery systems rather than individuals. PMID- 25015898 TI - The Irish national stroke awareness campaign: a stroke of success? AB - INTRODUCTION: Mass media campaigns are widely used to expose large populations to health-risk behaviour messages through routine uses of media. The Act F.A.S.T stroke campaign, which highlights the symptoms of stroke, has been endorsed globally. The aim of this study was to identify the influence of the campaign on the general public in Ireland. METHODS: Descriptive pre and post comparative study design was conducted. Phase one was conducted in April 2010 prior to the campaign. Data were collected on a cross-section of the public (n=1925) to obtain baseline information on stroke warning signs. Phase two involved collecting data from participants (n=688) 18 months after the campaign launch. RESULTS: The majority of participants from both phases were between 30 and 50 years of age. Results from phase two reported that 93% heard or saw the campaign yet only 37% could recall the campaign name or the slogan. Post the campaign over 80% recognized the warning signs of stroke. The increase in symptom recognition is evident from pre campaign to post campaign with an increase in knowledge across all the stroke symptoms. Post the campaign there was an increase of 54% of who stated that they would go straight to hospital for stroke symptoms. CONCLUSION: Findings suggest the campaign was well executed given the high percentage of participants recall and the increase in the recognition of stroke symptoms. However, the influence of the campaign in changing behaviour was not as evident. Further research is needed to examine factors that influence behaviour when a stroke strikes. PMID- 25015899 TI - Use of social media and internet to obtain health information by rural adolescent mothers. AB - BACKGROUND: Adolescent mothers residing in rural areas need accurate health information to care for themselves and their babies. The purpose of this study was to determine the use of social media and Internet by adolescent mothers residing in rural areas, particularly in regard to obtaining health information. METHODS: Using a cross-sectional design, a convenience sample of adolescent mothers living in a rural county in a state located in the southern U.S. (n = 15), completed the Pew Internet Survey during home visits with nurses from a community health agency. RESULTS: All adolescent mothers accessed Internet using cell phones (93%) or computers (100%). Many adolescent mothers sent or received over 50 text messages per day. Thirty-three percent of adolescent mothers searched for health information on the Internet every few weeks; 27% received health information from Facebook. CONCLUSIONS: Communication of health information using the Internet and social media may be effective with adolescent mothers residing in rural areas. PMID- 25015900 TI - Progesterone receptor B promoter hypermethylation in human placenta after labor onset. AB - To determine the methylation status of progesterone receptor B (PR-B) promoter and how PR-B regulates progesterone action in placenta during human pregnancy. Placentas were obtained from the pregnancy women at term who underwent cesarean delivery and vaginal delivery. The methylation status of the PR-B promoter was analyzed using the methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing PCR. And the messenger RNA (mRNA) and protein expression of the PR-B and DNA methyltransferases (DNMTs) were determined by quantitative real time PCR and Western blot. Compared with the cesarean group, the placentas of vaginal delivery group had greater levels of PR-B DNA methylation, and the PR-B, DNMT1, DNMT3a, and DNMT3b mRNA and protein expression were significantly decreased. Progesterone receptor B methylation occurs with high frequency after labor onset and may play an important epigenetic mechanism of labor-related PR-B negative expression, thereby mediating the biological process of functional progesterone withdrawal at term for parturition. PMID- 25015901 TI - Comparison of blastocyst and Sage media for in vitro maturation of human immature oocytes. AB - In vitro maturation (IVM) of human oocytes is an attractive alternative to conventional assisted reproductive technology (ART) treatment, as it involves no or minimal ovarian stimulation. Currently, commercialized media specifically designed for IVM are often used. These media are expensive, have limited shelf life, and must be ordered in advance. If standard culture media can be used in place of the specialized IVM media, it would simplify management and make IVM more feasible and more widely employed in ART centers around the world, especially in developing countries where resources are scarce. This study was, therefore, conducted to test the hypothesis that blastocyst medium was as good as commercial IVM medium to support maturation and developmental competence of human immature oocytes as previously shown in the mouse system. Immature oocytes were obtained by needle aspiration from 89 pregnant women during cesarean deliveries between April 2012 and February 2013. Sibling oocytes were allocated to Sage IVM media (512 oocytes) or blastocyst medium (520 oocytes) and assessed for maturation 36 hours later. Mature oocytes were inseminated by intracytoplasmic sperm injection and cultured up to 144 hours. There was no difference in maturation rate (65.0% vs 68.7%; P = .218) or fertilization rate (66.9% vs 66.4%; P = .872) of oocytes matured in vitro in both media. There was also no difference in the formation of good-quality blastocysts (46.6% vs 45.9%; P = .889) in the 2 groups. Further study should be done to ascertain implantation and pregnancy potential of these embryos. PMID- 25015902 TI - Stress management affects outcomes in the pathophysiology of an endometriosis model. AB - We have previously shown detrimental effects of stress in an animal model of endometriosis. We now investigated whether the ability to control stress can affect disease parameters. Endometriosis was surgically induced in female Sprague Dawley rats before exposing animals to a controllable (submerged platform) or uncontrollable (no platform) swim stress protocol. Corticosterone levels and fecal pellet numbers were measured as an indicator of stress. Uncontrollable stress increased the number and size of the endometriotic cysts. Rats receiving uncontrollable stress had higher anxiety than those exposed to controllable stress or no stress and higher corticosterone levels. Uncontrollable stressed rats had more colonic damage and uterine cell infiltration compared to no stress, while controllable stress rats showed less of an effect. Uncontrollable stress also increased both colonic and uterine motility. In summary, the level of stress controllability appears to modulate the behavior and pathophysiology of endometriosis and offers evidence for evaluating therapeutic interventions. PMID- 25015903 TI - A subpathway-based method of drug reposition for polycystic ovary syndrome. AB - The need for development of new therapeutic agents for polycystic ovary syndrome (PCOS) is urgent due to general lack of efficient and specialized drugs currently available. We aimed to explore the metabolic mechanism of PCOS and inferred drug reposition for PCOS by a subpathway-based method. Using the GSE34526 microarray data from the Gene Expression Omnibus database, we first identified the differentially expressed genes (DEGs) between PCOS and normal samples. Then, we identified 13 significantly enriched metabolic subpathways that may be involved in the development of PCOS. Finally, by an integrated analysis of PCOS-involved subpathways and drug-affected subpathways, we identified 54 novel small molecular drugs capable to target the PCOS-involved subpathways. We also mapped the DEGs of PCOS and a potential novel drug (alprostadil) into purine metabolism pathway to illustrate the potentially active mechanism of alprostadil on PCOS. Candidate agents identified by our approach may provide insights into a novel therapy approach for PCOS. PMID- 25015905 TI - FDG-PET/CT in staging of clear cell odontogenic carcinoma. AB - Clear cell odontogenic carcinoma (CCOC) is a rare neoplasm; only 75 cases have been reported in the English language literature. They have a tendency for recurrence and a capacity to metastasize. There is very little known regarding the metabolic features of this tumour or the utility of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans in the staging and follow-up of these tumours. We present two cases of CCOC with their relevant FDG-PET/CT scan findings. The first patient had primary CCOC of the mandible that was FDG-avid, and the other had recurrence of CCOC of the anterior mandible and superomedial orbit that was not FDG-avid. FDG uptake in CCOC appears to be variable. Although FDG-PET/CT is useful in other head and neck cancers and has benefits compared to other imaging modalities, further studies are needed to investigate the sensitivity of FDG-PET/CT in CCOC. PMID- 25015906 TI - Dental image replacement on cone beam computed tomography with three-dimensional optical scanning of a dental cast, occlusal bite, or bite tray impression. AB - The goal of the present study was to compare the accuracy of dental image replacement on a cone beam computed tomography (CBCT) image using digital image data from three-dimensional (3D) optical scanning of a dental cast, occlusal bite, and bite tray impression. A Bracket Typodont dental model was used. CBCT of the dental model was performed and the data were converted to stereolithography (STL) format. Three experimental materials, a dental cast, occlusal bite, and bite tray impression, were optically scanned in 3D. STL files converted from the CBCT of the Typodont model and the 3D optical-scanned STL files of the study materials were image-registered. The error range of each methodology was measured and compared with a 3D optical scan of the Typodont. For the three materials, the smallest error observed was 0.099+/-0.114mm (mean error+/-standard deviation) for registering the 3D optical scan image of the dental cast onto the CBCT dental image. Although producing a dental cast can be laborious, the study results indicate that it is the preferred method. In addition, an occlusal bite is recommended when bite impression materials are used. PMID- 25015911 TI - Editorial commentary: Cystatin C and statins in HIV disease. PMID- 25015912 TI - Rosuvastatin preserves renal function and lowers cystatin C in HIV-infected subjects on antiretroviral therapy: the SATURN-HIV trial. AB - BACKGROUND: In chronic human immunodeficiency virus (HIV) infection, plasma cystatin C may be influenced by factors other than glomerular filtration rate such as inflammation. Statins may improve cystatin C by improving glomerular function or by decreasing inflammation. METHODS: The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy (ART) with low-density lipoprotein cholesterol <=130 mg/dL to blinded 10 mg daily rosuvastatin or placebo. We analyzed relationships of baseline and 0- to 24-week changes in plasma cystatin C concentration with measures of vascular disease, inflammation, and immune activation. RESULTS: Median age was 46 (interquartile range, 40-53) years; 78% were male, 68% African American. Tenofovir and protease inhibitors were used in 88% and 49% of subjects, respectively. Baseline cystatin C was associated with higher carotid intima-media thickness and epicardial adipose tissue independent of age, sex, and race. Biomarkers of endothelial activation and inflammation were associated with cystatin C in a multivariable model independent of creatinine based estimated glomerular filtration rate (eGFRcr). After 24 weeks, statin use slowed mean eGFRcr decline (1.61 vs -3.08 mL/minute/1.73 m(2) for statin vs placebo; P = .033) and decreased mean cystatin C (-0.034 mg/L vs 0.010 mg/L; P = .008). Within the statin group, changes in cystatin C correlated with changes in endothelial activation, inflammation, and T-cell activation. CONCLUSIONS: Rosuvastatin 10 mg daily reduces plasma cystatin C and slows kidney function decline in HIV-infected patients on ART. Reductions in cystatin C with statin therapy correlate with reductions in inflammatory biomarkers. Relationships between cystatin C, kidney function, and cardiovascular risk in HIV may be mediated in part by inflammation. Clinical Trials Registration. NCT01218802. PMID- 25015914 TI - Reply to Marcellin et al. PMID- 25015915 TI - New "One Health" strategies needed for detection and control of emerging pathogens at Cantonese live animal markets, China. PMID- 25015913 TI - High levels of alcohol consumption increase the risk of advanced hepatic fibrosis in HIV/hepatitis C virus-coinfected patients: a sex-based analysis using transient elastography at enrollment in the HEPAVIH ANRS CO13 cohort. PMID- 25015916 TI - The contributions of filaments and cross-bridges to sarcomere compliance in skeletal muscle. AB - Force generation in the muscle sarcomere is driven by the head domain of the myosin molecule extending from the thick filament to form cross-bridges with the actin-containing thin filament. Following attachment, a structural working stroke in the head pulls the thin filament towards the centre of the sarcomere, producing, under unloaded conditions, a filament sliding of ~ 11 nm. The mechanism of force generation by the myosin head depends on the relationship between cross-bridge force and movement, which is determined by compliances of the cross-bridge (C(cb)) and filaments. By measuring the force dependence of the spacing of the high-order myosin- and actin-based X-ray reflections from sartorius muscles of Rana esculenta we find a combined filament compliance (Cf) of 13.1 +/- 1.2 nm MPa(-1), close to recent estimates from single fibre mechanics (12.8 +/- 0.5 nm MPa(-1)). C(cb) calculated using these estimates is 0.37 +/- 0.12 nm pN(-1), a value fully accounted for by the compliance of the myosin head domain, 0.38 +/- 0.06 nm pN(-1), obtained from the intensity changes of the 14.5 nm myosin-based X-ray reflection in response to 3 kHz oscillations imposed on single muscle fibres in rigor. Thus, a significant contribution to C(cb) from the myosin tail that joins the head to the thick filament is excluded. The low C(cb) value indicates that the myosin head generates isometric force by a small sub step of the 11 nm stroke that drives filament sliding at low load. The implications of these results for the mechanism of force generation by myosins have general relevance for cardiac and non-muscle myosins as well as for skeletal muscle. PMID- 25015917 TI - Effects of 5-hydroxymethyl-2-furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease. AB - The heterocyclic aldehyde 5-hydroxymethyl-2-furfural (5HMF) interacts allosterically with the abnormal form of haemoglobin (Hb), HbS, in red blood cells (RBCs) from patients with sickle cell disease (SCD), thereby increasing oxygen affinity and decreasing HbS polymerization and RBC sickling during hypoxia. We hypothesized that should 5HMF also inhibit the main cation pathways implicated in the dehydration of RBCs from SCD patients - the deoxygenation induced cation pathway (Psickle), the Ca(2+)-activated K(+) channel (the Gardos channel) and the K(+)-Cl(-) cotransporter (KCC) - it would have a synergistic effect in protection against sickling, directly through interacting with HbS, and indirectly through maintaining hydration and reducing [HbS]. This study was therefore designed to investigate the effects of 5HMF on RBC volume and K(+) permeability in vitro. 5HMF markedly reduced the deoxygenation-induced dehydration of RBCs whether in response to maintained deoxygenation or to cyclical deoxygenation/re-oxygenation. 5HMF was found to inhibit Psickle, an effect which correlated with its effects on sickling. Deoxygenation-induced activation of the Gardos channel and exposure of phosphatidylserine were also inhibited, probably indirectly via reduced entry of Ca(2+) through the Psickle pathway. Effects of 5HMF on KCC were more modest with a slight inhibition in N ethylmaleimide (NEM, 1 mm)-treated RBCs and stimulation in RBCs untreated with NEM. These findings support the hypothesis that 5HMF may also be beneficial through effects on RBC ion and water homeostasis. PMID- 25015919 TI - Complete reversal of Lambert-Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder in which a significant fraction of the presynaptic P/Q-type Ca(2+) channels critical to the triggering of neurotransmitter release at the neuromuscular junction (NMJ) are thought to be removed. There is no cure for LEMS, and the current most commonly used symptomatic treatment option is a potassium channel blocker [3,4 diaminopyridine (3,4-DAP)] that does not completely reverse symptoms and can have dose-limiting side-effects. We previously reported the development of a novel Ca(2+) channel agonist, GV-58, as a possible alternative treatment strategy for LEMS. In this study, we tested the hypothesis that the combination of GV-58 and 3,4-DAP will elicit a supra-additive increase in neurotransmitter release at LEMS model NMJs. First, we tested GV-58 in a cell survival assay to assess potential effects on cyclin-dependent kinases (Cdks) and showed that GV-58 did not affect cell survival at the relevant concentrations for Ca(2+) channel effects. Then, we examined the voltage dependence of GV-58 effects on Ca(2+) channels using patch clamp techniques; this showed the effects of GV-58 to be dependent upon Ca(2+) channel opening. Based on this mechanism, we predicted an interaction between 3,4 DAP and GV-58. We tested this hypothesis using a mouse passive transfer model of LEMS. Using intracellular electrophysiological ex vivo recordings, we demonstrated that a combined application of 3,4-DAP plus GV-58 had a supra additive effect that completely reversed the deficit in neurotransmitter release magnitude at LEMS model NMJs. This reversal contrasts with the less significant improvement observed with either compound alone. Our data indicate that a combination of 3,4-DAP and GV-58 represents a promising treatment option for LEMS and potentially for other disorders of the NMJ. PMID- 25015920 TI - Time course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat. AB - Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time-resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long-term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9-14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X-ray diffraction analyses demonstrate that myosin can bind to actin in an ATP-dependent manner even after 9-14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long-term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days. PMID- 25015921 TI - Osmotic activation of phospholipase C triggers structural adaptation in osmosensitive rat supraoptic neurons. AB - The magnocellular neurosecretory cells of the hypothalamus (MNCs) synthesize and secrete vasopressin or oxytocin. A stretch-inactivated cation current mediated by TRPV1 channels rapidly transduces increases in external osmolality into a depolarization of the MNCs leading to an increase in action potential firing and thus hormone release. Prolonged increases in external osmolality, however, trigger a reversible structural and functional adaptation that may enable the MNCs to sustain high levels of hormone release. One poorly understood aspect of this adaptation is somatic hypertrophy. We demonstrate that hypertrophy can be evoked in acutely isolated rat MNCs by exposure to hypertonic solutions lasting tens of minutes. Osmotically evoked hypertrophy requires activation of the stretch-inactivated cation channel, action potential firing, and the influx of Ca(2+). Hypertrophy is prevented by pretreatment with a cell-permeant inhibitor of exocytotic fusion and is associated with an increase in total membrane capacitance. Recovery is disrupted by an inhibitor of dynamin function, suggesting that it requires endocytosis. We also demonstrate that hypertonic solutions cause a decrease in phosphatidylinositol 4,5-bisphosphate in the plasma membranes of MNCs that is prevented by an inhibitor of phospholipase C (PLC). Inhibitors of PLC or protein kinase C (PKC) prevent osmotically evoked hypertrophy, and treatment with a PKC-activating phorbol ester can elicit hypertrophy in the absence of changes in osmolality. These studies suggest that increases in osmolality cause fusion of internal membranes with the plasma membrane of the MNCs and that this process is mediated by activity-dependent activation of PLC and PKC. PMID- 25015922 TI - Genesis of the characteristic pulmonary venous pressure waveform as described by the reservoir-wave model. AB - Conventional haemodynamic analysis of pulmonary venous and left atrial (LA) pressure waveforms yields substantial forward and backward waves throughout the cardiac cycle; the reservoir wave model provides an alternative analysis with minimal waves during diastole. Pressure and flow in a single pulmonary vein (PV) and the main pulmonary artery (PA) were measured in anaesthetized dogs and the effects of hypoxia and nitric oxide, volume loading, and positive-end expiratory pressure (PEEP) were observed. The reservoir wave model was used to determine the reservoir contribution to PV pressure and flow. Subtracting reservoir pressure and flow resulted in 'excess' quantities which were treated as wave-related.Wave intensity analysis of excess pressure and flow quantified the contributions of waves originating upstream (from the PA) and downstream (from the LA and/or left ventricle (LV)).Major features of the characteristic PV waveform are caused by sequential LA and LV contraction and relaxation creating backward compression (i.e.pressure-increasing) waves followed by decompression (i.e. pressure decreasing) waves. Mitral valve opening is linked to a backwards decompression wave (i.e. diastolic suction). During late systole and early diastole, forward waves originating in the PA are significant. These waves were attenuated less with volume loading and delayed with PEEP. The reservoir wave model shows that the forward and backward waves are negligible during LV diastasis and that the changes in pressure and flow can be accounted for by the discharge of upstream reservoirs. In sharp contrast, conventional analysis posits forward and backward waves such that much of the energy of the forward wave is opposed by the backward wave. PMID- 25015923 TI - Mechanical regulation of human vocal fold stellate cells. AB - OBJECTIVE: It is generally accepted that tensile and compressive strains have direct effects on cell morphology and structure, including changes in cytoskeletal structure and organization. Cytoskeletons play the role of mechanoreceptor of the cells. Vocal fold stellate cells (VFSCs) in the human maculae flavae (MFe) are inferred to be involved in the metabolism of extracellular matrices essential for the viscoelasticity of the vocal fold mucosa. Our previous studies have supported the hypothesis that the tension caused by phonation (vocal fold vibration) regulates the behavior of the VFSCs. The microstructure of the intermediate filaments and the expression of their proteins were investigated in VFSCs in the MFe, which had remained unphonated since birth. METHODS: Three adult vocal fold mucosae that had remained unphonated since birth were investigated by immunohistochemistry and electron microscopy. RESULTS: The intermediate filaments of the VFSCs were fewer in number. The expression of their characteristic proteins (vimentin, desmin, and glial fibrillary acidic protein) was also reduced. CONCLUSION: Vocal fold vibration seems to affect VFSC morphology and structure, such as cytoskeletal structure and organization. This supports the hypothesis that vocal fold vibration regulates VFSC behavior in the human MFe. In addition to chemical factors, mechanical factors also appear to modulate VFSC behavior. PMID- 25015924 TI - Headache during a cluster of benign paroxysmal positional vertigo attacks. AB - OBJECTIVE: In view of patients' recurrent complaints, we were interested in investigating the frequency and headache characteristics in patients during a benign paroxysmal positional vertigo (BPPV) cluster. METHODS: Patients with BPPV treated at an outpatient dizziness clinic were interviewed about the presence of headache; its quality, localization, severity, time course, and aggravating and alleviating factors; and headache-related disability during their present vertigo cluster. RESULTS: Among 152 patients with BPPV, 53 (34.8%) reported headache associated with vertigo. According to The International Classification of Headache Disorders, 8 (15%) patients could be classified as migraine without aura (1.1), 14 (26%) were classified as infrequent episodic tension-type headache associated with pericranial tenderness (2.1.1), 23 (43%) were classified as infrequent episodic tension-type headache without pericranial tenderness (2.1.2), 6 (11%) had cervicogenic headache (11.2.1), and in 2 (4%) patients, the headache could not be specified (14.2). Fifty-two age-matched BPPV patients without headache did not differ in history of headaches, BPPV history, or background diseases. The distribution of canal involvement and number of treatment maneuvers was also similar in both groups. CONCLUSION: Headache is frequent in BPPV. The most common is tension-type headache, followed by migraine and cervicogenic headache. Head pain seems to be an independently associated epiphenomenon of BPPV that can worsen patients' distress. PMID- 25015925 TI - Facial cutaneous necrosis associated with suspected levamisole toxicity from tainted cocaine abuse. AB - OBJECTIVE: This study aimed to illustrate the otorhinolaryngologic manifestations of levamisole toxicity and illuminate the features of this diagnosis. METHODS: We describe a case of a known cocaine abuser with suspected levamisole toxicity who developed cutaneous necrosis of the cheeks, earlobes, nose, upper and lower lip, and the midline hard palate. We also review the existing clinical literature about this emerging phenomenon. RESULTS: Levamisole is a common adulterant in cocaine distributed in the United States and has been reported to cause microvascular thrombosis and vasculitis with resultant skin necrosis in cocaine abusers. The distribution of skin findings characteristically involves the cheeks, earlobes, nose, lips, and hard palate and responds variably to cessation of cocaine use. In its most severe cases, immune suppression and/or surgical debridement may be required. CONCLUSION: Levamisole toxicity can frequently involve the ears, nose, and throat tissues. Otorhinolaryngologists should recognize these manifestations to expeditiously diagnose and manage this condition. Failure to do so promptly can lead to complications that may necessitate reconstructive or amputation surgery. PMID- 25015926 TI - Predictors of adverse events after parotidectomy: a review of 2919 cases. AB - OBJECTIVE: There is a current paucity of large-scale, multi-institutional studies that explore the risk factors for major complications following parotidectomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program participant use file was reviewed to identify all patients who had undergone parotidectomy between 2006 and 2011. Risk factors that predicted adverse events were estimated by using multivariate logistic regression. RESULTS: Of 2919 included patients, 202 patients experienced adverse outcomes within the first 30 days of surgery. These included surgical complications in 76 (2.6%) patients; medical complications in 90 (3.1%) patients; death in 7 (0.2%) patients; and reoperation in 77 (2.6%) patients. Predictors of any complication included disseminated cancer (odds ratio [OR] = 2.28; 95% confidence interval [CI], 1.05-4.95; P = .036) and increasing total relative value units (OR = 1.01; 95% CI, 1.00-1.02; P = .027). Active smoking was a major risk factor for surgical complications (OR = 1.81; 95% CI, 1.08-3.05; P = .025). Dyspnea (OR = 2.93; 95% CI, 1.37-6.27; P = .006) significantly predicted medical complications. CONCLUSION: Although complication rates after parotidectomy are generally low, avoidance of specific and nonspecific postoperative complications still remains an area for improvement. Future outcomes databases should include procedure specific complications, including facial nerve injury. PMID- 25015927 TI - Heterotopic ossification: a systematic review. AB - Heterotopic ossification (HO) is the formation of mature lamellar bone in extraskeletal soft tissues. It was first described 1000 years ago in the healing of fractures, and in relation to military wounds, texts from the American Civil War and World War I refer to HO specifically. It continues to cause problems to injured service personnel; the consequences of wound and soft tissue complications in traumatic amputations pose particular problems to rehabilitation and prosthetic use. While HO is seen in rare genetic conditions, it is most prevalent after joint replacement surgery and trauma. In the civilian setting HO has been commonly described in patients after traumatic brain injuries, spinal cord injuries and burns. Militarily, as a consequence of recent operations, and the characteristic injury of blast-related amputations, a renewed interest in HO has emerged due to an increased incidence seen in casualties. The heterogeneous nature of a blast related amputation makes it difficult for a single aetiological event to be identified, although it is now accepted that blast, amputation through the zone of injury, increased injury severity and associated brain injuries are significant risk factors in HO formation. The exact cellular event leading to HO has yet to be identified, and as a consequence its prevention is restricted to the use of anti-inflammatory medication and radiation, which is often contraindicated in the acute complex military casualty. A systematic review in PubMed and the Cochrane Database identified research articles related to HO to illustrate the military problem of HO and its management, current research concepts and experimental theories regarding HO. This also served as a gap analysis providing the researchers detail of any knowledge deficit in this field, in particular to the military aspects of HO; 637 out of 7891 articles initially identified that referenced HO were relevant to this review. PMID- 25015928 TI - Acoustic neuroma: potential risk factors and audiometric surveillance in the aluminium industry. AB - OBJECTIVES: To look for an association between acoustic neuroma (AN) and participation in a hearing conservation programme (HCP) and also for an association between AN and possible occupational risk factors in the aluminium industry. METHODS: We conducted a case-control analysis of a population of US aluminium production workers in 8 smelters and 43 other plants. Using insurance claims data, 97 cases of AN were identified between 1996 and 2009. Each was matched with four controls. Covariates included participation in a HCP, working in an aluminium smelter, working in an electrical job and hearing loss. RESULTS: In the bivariate analyses, covariates associated with AN were participation in the HCP (OR=1.72; 95% CI 1.09 to 2.69) and smelter work (OR=1.88; 95% CI 1.06 to 3.36). Electrical work was not significant (OR=1.60; 95% CI 0.65 to 3.94). Owing to high participation in the HCP in smelters, multivariate subanalyses were required. In the multivariate analyses, participation in the HCP was the only statistically significant risk factor for AN. In the multivariate analysis restricted to employees not working in a smelter, the OR was 1.81 (95% CI 1.04 to 3.17). Hearing loss, an indirect measure of in-ear noise dose, was not predictive of AN. CONCLUSIONS: Our results suggest the incidental detection of previously undiagnosed tumours in workers who participated in the company-sponsored HCP. The increased medical surveillance among this population of workers most likely introduced detection bias, leading to the identification of AN cases that would have otherwise remained undetected. PMID- 25015929 TI - Exposure to chlorinated solvents and lung cancer: results of the ICARE study. AB - OBJECTIVE: To investigate the role of occupational exposure to chlorinated solvents in lung cancer aetiology. METHODS: ICARE (Investigation of occupational and environmental CAuses of REspiratory cancers) is a French, multicentre, population-based, case-control study. Information on the lifelong work history of 2926 cases and 3555 controls was collected using standardised questionnaires. Occupational exposures were assessed using job-exposure matrices for five chlorinated solvents. Solvents were studied separately and in combinations. ORs were computed using unconditional logistic regression models adjusted for classic risk factors, including a history of cigarette smoking and exposure to asbestos. Adjustment for socioeconomic status (SES) was also made. RESULTS: After adjustment for exposure to asbestos, we observed a positive, statistically significant association with lung cancer for men and women exposed to a combination of perchloroethylene (PCE), trichloroethylene and dichloromethane (DCM). Further adjustment for SES slightly decreased this association. In contrast, no statistically significant associations were found for other solvent combinations. CONCLUSIONS: These results suggest that exposure to PCE may constitute a risk factor for lung cancer, especially among women, who seem to have a higher prevalence of exposure than men. PMID- 25015930 TI - Rare etiology of abdominal pain in an adolescent female. PMID- 25015931 TI - Telomere length in Chernobyl accident recovery workers in the late period after the disaster. AB - The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45-54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and age-matched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking 'dirty' tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis. PMID- 25015932 TI - HIV care engagement within 30 days after hospital discharge among patients from a Thai tertiary-care centre. AB - A cohort study was conducted to assess the rate of follow-up visit within 30 days after hospital discharge and to determine factors associated with no follow-up among Thai HIV-infected adults during the period from November 2012 to October 2013. Of the 120 eligible patients, 76 (63%) were males, median age was 40 years, and 57 (48%) were newly diagnosed with HIV infection. The rate of follow-up within 30 days after hospital discharge was 69%. Independent factors associated with no follow-up were no caregiver (adjusted odds ratio [aOR] 7.82; p = 0.002), age (aOR 1.06; p = 0.007 for each year younger), being immigrant (aOR 5.10; p = 0.03) and monthly household income less than $US 300 (aOR 2.99; p = 0.04). These findings suggest the need for interventions to improve care engagement including close monitoring for follow-up, pre-discharge financial and medical coverage planning, assessment for the need for caregiver and patient education about the importance of care engagement. PMID- 25015933 TI - Vaginal douching and sexually transmitted infections among female sex workers: a cross-sectional study in three provinces in China. AB - Though vaginal douching is a common practice among female sex workers that could increase the risk of HIV and adverse reproductive health outcomes, it has drawn limited attention. From November 2010 to January 2011, a convenience sample of female sex workers was recruited in three cities in China. Face-to-face interviews were conducted to gather socio-demographic and behavioural information. Blood samples were collected for syphilis serological tests. Endo cervical swabs were collected and tested for Neisseria gonorrhoeae and Chlamydia trachomatis by polymerase chain reaction. A logistic regression model was used to determine factors associated with vaginal douching and the association between vaginal douching and sexually transmitted infection. A total of 1032 eligible female sex workers were enrolled. The overall prevalence of any sexually transmitted infection (syphilis, Chlamydia trachomatis or Neisseria gonorrhoeae) and vaginal douching with disinfectant were 23.4% and 23.1%, respectively. Factors independently associated with douching practice included study sites, venue types, ethnicity, having regular partner and sexually transmitted infection history. No significant association was found between vaginal douching and current sexually transmitted infection. Vaginal douching with disinfectant after sex with clients seemed to be a prevalent practice among female sex workers in China. Prevention programmes targeting female sex workers should incorporate components about the adverse health outcomes associated with vaginal douching. PMID- 25015934 TI - Malignant lues in an immunocompetent patient. AB - Malignant lues is a rare form of secondary syphilis mostly associated with HIV infection. It is an uncommon presentation of syphilis even rarer in immunocompetent patients. We present the case of a 57-year-old homosexual man referred to our department due to a 4-month history of a disseminated, slightly painful, nodular-ulcerative cutaneous eruption associated with low-grade fever, malaise and aesthenia. Regarding the clinical features and serological and histopathological findings, the diagnosis of syphilis maligna was assumed. Serology for HIV was repeatedly negative. This case is interesting, not only because a very uncommon form of secondary syphilis was identified but also for being diagnosed in an immunocompetent patient. Lack of awareness of this type of presentation delays the diagnosis and treatment, leading to an increase in morbidity and spread of infection. PMID- 25015935 TI - Urinary protein-to-creatinine ratio versus 24-h proteinuria in the screening for nephropathy in HIV patients. AB - To determine the correlation between protein-to-creatinine ratio and 24-h urinary protein, proteinuria was measured in 45 patients attending a public HIV clinic in Porto Alegre, Brazil, using 24-h urinary protein excretion (24hUP) and urinary protein-to-creatinine ratio. Spearman's correlation test was done to evaluate the association between spot protein-to-creatinine ratio and 24hUP. The limits of agreement between the two methods were analysed by the Bland-Altman method. For protein excretion <1 g/day, limits (95%) of agreement of protein-to-creatinine ratio and 24hUP were +0.112 and -0.097 g/day. A strong correlation (r = 0.957) was found between protein-to-creatinine ratio and 24hUP excretion. The conclusion is that the protein-to-creatinine ratio in spot urine specimens is an accurate, convenient and reliable screening method to estimate the urinary protein excretion in HIV patients to detect abnormal urinary protein loss. Further studies are required to evaluate renal disease in HIV patients with chronic renal disease and higher urinary protein excretion. PMID- 25015936 TI - Spectrum of mucocutaneous manifestations in human immunodeficiency virus-infected patients and its correlation with CD4 lymphocyte count. AB - In this study, 100 HIV-positive cases (63 men, 37 women) with skin findings were included. The mean CD4 T cell count was 253 cells/mm(3). A total of 235 dermatological manifestations were seen. The common infectious dermatoses were candidiasis (21%), Staphylococcal skin infections (20%), dermatophytoses (14%) and herpes zoster (6%). Among the non-infectious dermatoses were papular pruritic eruptions (20%), xerosis/ichthyosis (20%) and seborrhoeic dermatitis (16%). Statistically significant association (p < 0.05) with CD4 T cell count was seen in pyodermas, dermatophytoses and papular pruritic eruptions. Adverse drug reactions, diffuse hair loss, straightening of hairs and pigmentary changes were also noted. Although there was an absence of Kaposi's sarcoma in our study, a case of verrucous carcinoma of penis was noted. PMID- 25015937 TI - Use of sorafenib for post-transplant relapse in FLT3/ITD-positive acute myelogenous leukemia: maturation induction and cytotoxic effect. PMID- 25015938 TI - Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies. AB - Multiple myeloma is a plasma cell disorder characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly patients (>65 years) with newly diagnosed multiple myeloma enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone or bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. A multivariate Cox model showed that chromosome 1 abnormalities, age >75 years and a CD19(+)/CD117( ) immunophenotype of bone marrow plasma cells were independent risk factors for overall survival in elderly patients with newly diagnosed multiple myeloma. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in patients with abnormal chromosome 1 as well as in those with 17p deletion, while the benefit of adding thalidomide to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19(+)/CD117(-) bone marrow plasma cell immunophenotype. This trial was registered at www.clinicaltri-als.gov as #NCT01063179. PMID- 25015939 TI - Analysis of outcomes following autologous stem cell transplantation in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia during first complete remission. PMID- 25015940 TI - Clinical importance of different calreticulin gene mutation types in wild-type JAK2 essential thrombocythemia and myelofibrosis patients. PMID- 25015941 TI - EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia. PMID- 25015943 TI - Achievements and perspectives in biochemistry concerning anthocyanin modification for blue flower coloration. AB - Genetic engineering of roses and other plants of floricultural importance to give them a truly blue petal color is arguably one of the holy grails of plant biotechnology. Toward this goal, bluish carnations and roses were previously engineered by establishing an exclusive accumulation of delphinidin (Dp)-type anthocyanins in their petals via the heterologous expression of a flavonoid 3',5' hydroxylase gene. Very recently, purple-blue varieties of chrysanthemums were also genetically engineered via a similar biochemical strategy. Although the floral colors of these transgenic plants still lack a true blue color, the basis for the future molecular breeding of truly blue flowers is via the engineering of anthocyanin pathways. Anthocyanins with multiple aromatic acyl groups (often referred to as polyacylated anthocyanins) in the 3'- or 7-position tend to display a more stable blue color than non-acylated anthocyanins. The 7 polyacylation process during the biosynthesis of purple-blue anthocyanins in delphinium (Delphinium grandiflorum) was found to occur in vacuoles using acyl glucose as both the glucosyl and acyl donor. Glucosyltransferases and acyltransferases involved in anthocyanin 7-polyacylation in delphinium are vacuolar acyl-glucose-dependent enzymes belonging to the glycoside hydrolase family 1 and serine carboxypeptidae-like protein family, respectively. The 7 polyacylation proceeds through the alternate glucosylation and p hydroxybenzoylation catalyzed by these enzymes. p-Hydroxybenzoyl-glucose serves as the p-hydroxybenzoyl and glucosyl donor to produce anthocyanins modified with a p-hydroxybenzoyl-glucose concatemer at the 7-position. This novel finding has provided a potential breakthrough for the genetic engineering of truly blue flowers, where polyacylated Dp-type anthocyanins are accumulated exclusively in the petals. PMID- 25015942 TI - Erythrocytosis associated with a novel missense mutation in the BPGM gene. PMID- 25015944 TI - Current management of focal atrial tachycardia in children: a multicenter experience. AB - BACKGROUND: Focal atrial tachycardia (FAT) is an uncommon cause of supraventricular tachycardia in children. Incessant FAT can lead to tachycardia induced cardiomyopathy. There is limited information regarding the clinical course and management of FAT. This study characterizes current management strategies for FAT in children including the prevalence of spontaneous resolution and the role of catheter ablation. METHODS AND RESULTS: This is a retrospective chart review of pediatric patients with FAT managed between January 2000 and November 2010 at 10 pediatric centers. There were 249 patients with a median age at diagnosis of 7.2 (95% confidence interval, 5.8-10.4) years. Cardiomyopathy was observed in 28%. Resolution of FAT occurred in 89%, including spontaneous resolution without catheter ablation in 34%. Antiarrhythmic medications were used for initial therapy in 154 patients with control of FAT in 72%. Among first-line medications, beta-blockers were the most common (53%) and effective (42%). Catheter ablation was successful in 80% of patients. FAT recurrence was less common with electroanatomic mapping compared with conventional mapping techniques (16% versus 35%; P=0.02). Patients were followed for a median of 2.1 (95% confidence interval, 1.8-2.6) years. CONCLUSIONS: FAT is managed successfully in most children. Current approaches are variable. Many patients have control of FAT with medications; however, catheter ablation is used for most patients. Spontaneous resolution is common for young children, emphasizing the role for delayed ablation in this group. Ablation is successful for all ages. Lower recurrence occurs when electroanatomic mapping techniques are used. PMID- 25015945 TI - Myocardial lesion size after epicardial electroporation catheter ablation after subxiphoid puncture. AB - BACKGROUND: Irreversible electroporation is a promising nonthermal ablation modality able to create deep myocardial lesions. We investigated lesion size after epicardial electroporation catheter ablation with various energy levels after subxiphoid pericardial puncture. METHODS AND RESULTS: In six 6-month-old pigs (60-75 kg), a custom deflectable octopolar 12-mm circular catheter with 2-mm ring electrodes was introduced via a deflectable sheath after pericardial access by subxiphoid puncture. Nonarcing, nonbarotraumatic, cathodal 50, 100, and 200 J electroporation applications were delivered randomly on the basal, mid and lateral left ventricle. After 3-month survival, myocardial lesion size and degree of intimal hyperplasia of the coronary arteries were analyzed histologically. Five animals survived the follow-up without complications and 1 animal died of shock after the subxiphoid puncture. At autopsy, whitish circular scars with indentation of the epicardium could be identified. Average lesion depths of the 50-, 100-, and 200-J lesions were 5.0+/-2.1, 7.0+/-2.0, and 11.9+/-1.5 mm, respectively. Average lesion widths of the 50-, 100-, and 200-J lesions were 16.6+/-1.1, 16.2+/-4.3, and 19.8+/-1.8 mm, respectively. In the 100- and 200-J cross sections, transmural left ventricular lesions and significant tissue shrinkage were observed. No intimal hyperplasia of the coronary arteries was observed. CONCLUSIONS: Epicardial electroporation ablation after subxiphoid pericardial puncture can create deep, wide, and transmural ventricular myocardial lesions. There is a significant relationship between the amounts of electroporation energy delivered epicardially and lesion size in the absence of major adverse events. PMID- 25015946 TI - Resumption of chest compressions after successful defibrillation and risk for recurrence of ventricular fibrillation in out-of-hospital cardiac arrest. AB - BACKGROUND: Prior investigation of out-of-hospital cardiac arrest has raised the concern that ventricular fibrillation (VF) recurrence may be triggered by chest compression (CC) resumption. We investigated predictors of VF recurrence after defibrillation, including timing of CC resumption. METHODS AND RESULTS: Patients with witnessed out-of-hospital cardiac arrest and initial rhythm of VF from an Utstein-style database were analyzed. For each shock that defibrillated VF, CC resumption and VF recurrence times were determined. Shocks were classified according to postshock rhythm. Factors (age, sex, time from dispatch to monitor/defibrillator application, and CC resumption) that could predict VF recurrence were analyzed. CC resumption was categorized into groups: CC1, 1 to 5 seconds; CC2, 6 to 10 seconds; CC3, 11 to 30 seconds; and CC4, >30 seconds. Eighty-eight subjects were analyzed, with a total of 285 shocks, with 226 shocks that achieved asystole (n=102), organized rhythm (n=120), or monomorphic ventricular tachycardia (n=4). After a successful shock, CC resumption occurred at a median (interquartile range) of 8 (5-18) seconds. VF recurred after 166 shocks (74%) and recurred within 30 seconds in 69 shocks. There was no significant relationship between VF recurrence and factors analyzed including CC resumption time, nor stratified by postshock rhythm. The hazard ratios (HRs) for VF recurrence within 30 seconds for later CC groups (CC2, CC3, and CC4) relative to early CC resumption (CC1) were as follows: HR(CC2)=1.05 (P=0.9); HR(CC3)=1.75 (P=0.1); and HR(CC4)=0.67 (P=0.4). CONCLUSIONS: VF recurrence within 30 seconds of a defibrillatory shock was not dependent on timing of CC resumption in patients with witnessed arrest and initial rhythm of VF. PMID- 25015947 TI - Reply to Kirby et al. PMID- 25015948 TI - Aberrant serum immunoglobulin G glycosylation in chronic hepatitis B is associated with histological liver damage and reversible by antiviral therapy. AB - BACKGROUND: Aberrant serum immunoglobulin G (IgG) glycosylation and its immunomodulatory effect are rarely addressed in chronic hepatitis B virus (HBV) infection. METHODS: Serum IgG-Fc glycosylation profiles in 76 patients with HBV related liver cirrhosis and 115 patients with chronic hepatitis B (CHB) before and after 48 weeks of anti-HBV nucleos(t)ide analogue treatment were analyzed using high-throughput liquid chromatography-mass spectrometry and were compared to profiles in 108 healthy controls. RESULTS: The level of aberrant serum IgG-Fc glycosylation ,: particularly galactose deficiency, was higher in patients with CHB and those with cirrhosis (P < .001 for both) than in healthy controls. IgG galactose deficiency was correlated with the severity of liver necroinflammation and fibrosis in CHB. Multivariate logistic regression analyses showed that the IgG-Fc glycoform with fucosylation and fully galactosylation was an independent factor for a total Knodell necroinflammation score of >= 7 (odds ratio, 0.74; 95% confidence interval, .56-.97) and an Ishak fibrosis score of >= 3 (odds ratio, 0.69; 95% confidence interval, .49-.97). Administration of antiviral therapy for 48 weeks reversed aberrant IgG-Fc glycosylation in patients with CHB from week 12 onward but did not reverse glycosylation in patients with cirrhosis. Attenuated IgG opsonization in patients with CHB, which was correlated with aberrant Fc glycosylation, was reversed after treatment as well. CONCLUSIONS: Aberrant serum IgG-Fc glycosylation in CHB, which is highly associated with histological liver damage, affects IgG opsonizing activity and can be reversed by antiviral therapy. PMID- 25015949 TI - Care homes and the Mental Capacity Act 2005: Changes in understanding and practice over time. AB - The Mental Capacity Act 2005 provides the legal framework in England and Wales for the making of decisions in respect of people who have never had or have lost decision-making capacity. As part of a 5-year research program investigating the implementation and adoption of the Mental Capacity Act in dementia practice, we interviewed staff working in different care homes at two time points (32 staff at Time 1 in 2008 and 27 staff at Time 2 in 2012) in South East England. At baseline Time 1, daily practice seemed to resonate with Mental Capacity Act principles of respecting decisions and trying to act in a person's best interests. This paper reports Time 2 findings. We found that few care home staff interviewed specifically reported finding the Mental Capacity Act helpful in crystallizing the legal basis of their work. Most continued to offer illustrations of day-to day practice in which they paid attention to individual choices, took account of the wishes of residents' families, and tried to act in residents' best interests but referred major decisions to their seniors. This study highlights the potential of referring to specific day-to-day practice in care homes when offering training or scrutinizing practice in dementia care more generally so that the work is set in its legal as well as moral framework. Care home staff in this study reported that advanced planning and pre-specifying preferences were more common among new care home residents, especially those with dementia, indicating that greater understanding of these is required by staff. PMID- 25015950 TI - A meta-analysis of debulking surgery versus surgical biopsy for unresectable thymoma. AB - Observational studies on long-term outcomes following debulking surgery or surgical biopsy for unresectable thymoma showed various results. This meta analysis was designed to determine the effect of debulking surgery against surgical biopsy on overall survival in patients with unresectable thymoma. The PubMed database was queried for studies published in the English language on unresectable thymoma and overall survival. We compared overall survival following surgery in patients undergoing debulking surgery and patients undergoing surgical biopsy for unresectable thymoma. Meta-analysis was performed using the Mantel Haenszel method, and potential publication bias was evaluated with a funnel plot of precision. No randomized trials on this topic were identified. Thirteen retrospective observational studies containing a sum of 314 patients with information on the number of deaths and person-years were suitable for analysis. Information on Masaoka stages, World Health Organization histology and indications for debulking surgery versus surgical biopsy was lacking in most studies. Diversity of neoadjuvant and adjuvant treatments was noted among the eligible studies. One hundred and seventy-two (54.8%) patients underwent debulking surgery and 142 (45.2%) underwent surgical biopsy. The pooled hazard ratio was 0.451 (95% confidence interval: 0.336-0.605, P < 0.001), favouring patients undergoing debulking surgery compared with patients undergoing surgical biopsy. The funnel plot of precision demonstrated no important publication bias. Our results suggest that debulking surgery for unresectable thymoma may be associated with improved overall survival and be considered for patients with unresectable thymoma. PMID- 25015951 TI - Which cannulation (axillary cannulation or femoral cannulation) is better for acute type A aortic dissection repair? A meta-analysis of nine clinical studies. AB - There is a trend towards using the axillary artery cannulation (AXC) site for cardiopulmonary bypass surgery in patients requiring acute type A aortic dissection (AAD) repair. However, AXC has not been established as a routine procedure, because there is controversy about its clinical advantage when compared with femoral artery cannulation (FAC). This meta-analysis assesses major short-term outcomes in patients undergoing acute AAD repair with AXC or FAC using non-randomized retrospective studies dating from 1992 to 2011 comparing AXC and FAC for major outcomes. Outcomes of interest were short-term mortality, neurological dysfunction and malperfusion. The fixed-effects model was used. Sensitivity and heterogeneity were analysed. Analysis of nine non-randomized studies comprising 715 patients [AXC, 359 (50.2%) and FAC, 356 (49.8%)] showed a significantly lower incidence of short-term mortality in the AXC group [odds ratio, 0.25, 95% confidence interval (CI) (0.15, 0.42), chi(2) = 7.23, P < 0.01]. The pattern of incidence of neurological dysfunction among the AXC group [odds ratio, 0.46, 95% CI (0.29, 0.72), chi(2) = 9.01, P < 0.01] was similar. The incidence of malperfusion did not differ [odds ratio, 0.84, 95% CI (0.37, 1.90), chi(2) = 2.25, P = 0.67]. Because no study was a randomized trial, our results are more uncertain than indicated by the 95% CI. Nevertheless, AXC seems to give better short-term mortality and neurological dysfunction rates than FAC. PMID- 25015952 TI - Simplified surgical-hybrid Melody valve implantation for paediatric mitral valve disease. AB - Children suffering from left atrioventricular valve (LAVV) disease not amenable to repair represent a significant challenge. The results of surgical reconstruction are not optimal. Valve replacement as an alternative is associated with poor results. The surgical-hybrid approach with implantation of a stented biological valve (bovine jugular vein graft, Melody valve) seems to represent a new therapeutic option. Here we demonstrate our case, the consideration and the approach to extreme clinical findings in a small child. We describe a simplified surgical-hybrid Melody valve implantation in a LAVV position. The technique of implantation is relatively simple and the immediate postoperative result very good. PMID- 25015953 TI - Electrocardiographic features and prevalence of bilateral bundle-branch delay. AB - BACKGROUND: Definitive diagnosis of bilateral bundle-branch delay/block may be made when catheter-induced right bundle-branch block (RBBB) develops in patients with baseline left bundle-branch (LBB) block. We hypothesized that a RBBB pattern with absent S waves in leads I and aVL will identify bilateral bundle-branch delay/block. METHODS AND RESULTS: Fifty patients developing transient RBBB pattern in lead V1 during right heart catheterization were studied. Patients were grouped according to whether the baseline ECG demonstrated a normal QRS, left fascicular blocks, or LBB block pattern. The RBBB morphologies in each group were compared. The prevalence of bilateral bundle-branch delay/block pattern was examined in our hospital ECG database. All patients with baseline normal QRS complexes (n=30) or left fascicular blocks (4 anterior, 5 posterior) developed a typical RBBB pattern. Among the 11 patients with a baseline LBB block pattern, 7 developed an atypical RBBB pattern with absent S waves in leads I and aVL and the remaining 4 demonstrated a typical RBBB. The absence of S waves in leads I and aVL during RBBB was 100% specific and 64% sensitive for the presence of pre existing LBB block. Among the consecutive 2253 hospitalized patients with RBBB, 34 (1.5%) had the bilateral bundle-branch delay/block pattern. CONCLUSIONS: An ECG pattern of RBBB in lead V1 with absent S wave in leads I and aVL indicates concomitant LBB delay. Pure RBBB and bifascicular blocks are associated with S waves in leads I and aVL. PMID- 25015954 TI - A google glass application to support shoppers with dietary management of diabetes. PMID- 25015955 TI - Folate receptor-beta constitutes a marker for human proinflammatory monocytes. AB - Activated macrophages are commonly involved in the pathogenesis of inflammatory and autoimmune diseases and have been frequently reported to overexpress FR-beta. Although FR-targeted therapies aimed at eliminating activated macrophages have shown promise for treating inflammatory diseases, little work has been performed to evaluate whether other hematopoietic cells might also express FR-beta. Analysis of peripheral blood cells with a mAb to human FR-beta reveals that only monocytes express FR-beta. Molecular characterization of these circulating monocytes further demonstrates that solely the classic/proinflammatory subset (CD14(high)CD16(-)) expresses the FR and that only CD14(high)CD16(-) FR-beta(+) monocytes also display the ability to bind folate-linked molecules. Confirmation that this subset of monocytes indeed constitutes the proinflammatory subpopulation was obtained by demonstrating coexpression of FR-beta with other proinflammatory markers, including CCR2 and HLA-DR. Synovial monocytes from the joints of patients with RA were also shown to express FR-beta. As inhibition of the chemotaxis of proinflammatory monocytes into sites of inflammation has been explored frequently as a means of controlling autoimmune diseases, demonstration that FR-beta is uniquely expressed on this proinflammatory subpopulation offers a new strategy to suppress migration of inflammatory monocytes into sites of inflammation. PMID- 25015957 TI - TLR4 regulates IFN-gamma and IL-17 production by both thymic and induced Foxp3+ Tregs during intestinal inflammation. AB - Tregs play a crucial role in the maintenance of intestinal immune homeostasis. However, significant numbers of Foxp3(+) Tregs accumulate in the inflamed lesions in experimental colitis and in IBD patients. Treg production of the proinflammatory cytokines IFN-gamma and/or IL-17 may arguably explain their ineffectiveness in suppressing intestinal inflammation. However, it remains unknown whether iTreg and tTreg produce proinflammatory cytokines and how TLR signaling regulates this process. Here, we found that Foxp3(+)Tregs were increased in the intestines of B6.TLR4(-/-) and B6.IL-10(-/-) mice when compared with WT B6 mice. TLR4(-/-) and IL-10(-/-) resulted in more Tregs within inflamed intestines. The majority of Foxp3(+) Tregs in the spleen was Helios(+)Nrp1(+), whereas most Foxp3(+) Tregs in the intestinal LP were Helios(-)Nrp1(-). More Helios(+)Nrp1(+) Tregs expressed IFN-gamma and/or IL-17 than did Helios(-)Nrp1(-) Tregs in the spleen and intestine, which was increased with TLR4(-/-). TLR4 signaling in T cells and APCs inhibited Foxp3(+) induction via MyD88-dependent, TRIF-independent pathways, which was negatively regulated by SOCS3. Collectively, these data demonstrate Helios(+)Nrp1(+) tTregs and Helios(-)Nrp1(-) iTregs produce proinflammatory cytokines in the intestines during inflammation, which was regulated by TLR4 signaling. PMID- 25015958 TI - Lower-limb veins are thicker and vascular reactivity is decreased in a rat PCOS model: concomitant vitamin D3 treatment partially prevents these changes. AB - Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3 (vitD). PCOS was induced in female Wistar rats by DHT treatment (83 MUg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of N(G)-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration. PMID- 25015959 TI - Sex-dependent, zinc-induced dephosphorylation of phospholamban by tissue nonspecific alkaline phosphatase in the cardiac sarcomere. AB - We have previously reported that Zn(2+) infused into the coronary arteries of isolated rat hearts leads to the potent dephosphorylation of phospholamban (PLB) as well as a noticeable but less potent dephosphorylation of the ryanodine receptor 2. We hypothesized in the present study that a Zn(2+)-activated phosphatase is located in the vicinity of the sarcoplasmic reticulum (SR) where PLB and ryanodine receptor 2 reside. We report here the novel finding of tissue nonspecific alkaline phosphatase (TNAP), a zinc-dependent enzyme, localized to the SR in the cardiac sarcomere of mouse myocardium. TNAP activity was enhanced by injection of Zn acetate into a tail vein before harvesting the heart and imaged using electron microscopy of electron dense deposits indicative of the hydrolysis of exogenous beta-glycerophosphate. TNAP activity was observed localized to the ends of the Z-line corresponding to SR and was qualitatively more visible in myocardium of males compared with females. Correspondingly, PLB phosphorylation status was potently reduced in myocardium of males injected with Zn acetate, whereas there was no apparent effect of Zn acetate injection on PLB phosphorylation in females. Surprisingly, Western blot analysis of TNAP content suggested a significantly lower TNAP content in males compared with females. These data suggest that TNAP plays a role in governing the phosphorylation status of calcium handling proteins in the SR. Furthermore, the content and activity of TNAP are differentially regulated between the sexes and thus may account for some sex differences in cardiopathologies associated with calcium handling. PMID- 25015956 TI - Immune control and failure in HCV infection--tipping the balance. AB - Despite the development of potent antiviral drugs, HCV remains a global health problem; global eradication is a long way off. In this review, we discuss the immune response to HCV infection and particularly, the interplay between viral strategies that delay the onset of antiviral responses and host strategies that limit or even eradicate infected cells but also contribute to pathogenesis. Although HCV can disable some cellular virus-sensing machinery, IFN-stimulated antiviral genes are induced in the infected liver. Whereas epitope evolution contributes to escape from T cell-mediated immunity, chronic high antigen load may also blunt the T cell response by activating exhaustion or tolerance mechanisms. The evasive maneuvers of HCV limit sterilizing humoral immunity through rapid evolution of decoy epitopes, epitope masking, stimulation of interfering antibodies, lipid shielding, and cell-to-cell spread. Whereas the majority of HCV infections progress to chronic hepatitis with persistent viremia, at least 20% of patients spontaneously clear the infection. Most of these are protected from reinfection, suggesting that protective immunity to HCV exists and that a prophylactic vaccine may be an achievable goal. It is therefore important that we understand the correlates of protective immunity and mechanisms of viral persistence. PMID- 25015960 TI - Hypoxia and ischemia-reperfusion: a BiK contribution? AB - Over the last decades, cardiovascular disease has become the primary cause of death in the Western world, and this trend is expanding throughout the world. In particular, atherosclerosis and the subsequent vessel obliterations are the primary cause of ischemic disease (stroke and coronary heart disease). Excess calcium influx into the cells is one of the major pathophysiological mechanisms important for ischemic injury in the brain and heart in humans. The large conductance calcium-activated K(+) channels (BK) are thus interesting candidates to protect against excess calcium influx and the events leading to ischemic injury. Indeed, the mitochondrial BK channels (mitoBK) have recently been shown to play a protective function against ischemia-reperfusion injury both in vitro and in animal models, although the exact mechanism of this protection is still under scrutiny. In addition, in both the plasma membrane and mitochondrial BK channel, the alpha-subunit itself is sensitive to hypoxia. This sensitivity is tissue specific and conferred by a highly conserved motif within an alternatively spliced cysteine-rich insert (STREX) in the intracellular C terminus of the channel. This review describes recent developments of the increasing relevance of BK channels in hypoxia and ischemia-reperfusion injury. PMID- 25015961 TI - Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca2+ handling and calcineurin-NFAT signaling pathway. AB - Polydatin (PD), a resveratrol glucoside extracted from the perennial herbage Polygonum cuspidatum, has been suggested to have wide cardioprotective effects. This study aimed to explore the direct antihypertrophic role of PD in cultured neonatal rat ventricular myocytes (NRVMs) and its therapeutic effects against pressure overload (PO)-induced hypertrophic remodeling and heart failure. Furthermore, we investigated the mechanisms underlying the actions of PD. Treatment of NRVMs with phenylephrine for 72 h induced myocyte hypertrophy, where the cell surface area and protein levels of atrial natriuretic peptide and beta myosin heavy chain (beta-MHC) were significantly increased. The amplitude of systolic Ca(2+) transient was increased, and sarcoplasmic reticulum Ca(2+) recycling was prolonged. Concomitantly, calcineurin activity was increased and NFAT protein was imported into the nucleus. PD treatment restored Ca(2+) handling and inhibited calcineurin-NFAT signaling, thus attenuating the hypertrophic remodeling in NRVMs. PO-induced cardiac hypertrophy was produced by transverse aortic constriction (TAC) in C57BL/6 mice, where the left ventricular posterior wall thickness and heart-to-body weight ratio were significantly increased. The cardiac function was increased at 5 wk of TAC, but significantly decreased at 13 wk of TAC. The amplitude of Ca(2+) transient and calcineurin activity were increased at 5 wk of TAC. PD treatment largely abolished TAC-induced hypertrophic remodeling by inhibiting the Ca(2+)-calcineurin pathway. Surprisingly, PD did not inhibit myocyte contractility despite that the amplitude of Ca(2+) transient was decreased. The cardiac function remained intact at 13 wk of TAC. In conclusion, PD is beneficial against PO-induced cardiac hypertrophy and heart failure largely through inhibiting the Ca(2+)-calcineurin pathway without compromising cardiac contractility. PMID- 25015962 TI - Electrophysiological effects of right and left vagal nerve stimulation on the ventricular myocardium. AB - Vagal nerve stimulation (VNS) has been proposed as a cardioprotective intervention. However, regional ventricular electrophysiological effects of VNS are not well characterized. The purpose of this study was to evaluate effects of right and left VNS on electrophysiological properties of the ventricles and hemodynamic parameters. In Yorkshire pigs, a 56-electrode sock was used for epicardial (n = 12) activation recovery interval (ARI) recordings and a 64 electrode catheter for endocardial (n = 9) ARI recordings at baseline and during VNS. Hemodynamic recordings were obtained using a conductance catheter. Right and left VNS decreased heart rate (84 +/- 5 to 71 +/- 5 beats/min and 84 +/- 4 to 73 +/- 5 beats/min), left ventricular pressure (89 +/- 9 to 77 +/- 9 mmHg and 91 +/- 9 to 83 +/- 9 mmHg), and dP/dtmax (1,660 +/- 154 to 1,490 +/- 160 mmHg/s and 1,595 +/- 155 to 1,416 +/- 134 mmHg/s) and prolonged ARI (327 +/- 18 to 350 +/- 23 ms and 327 +/- 16 to 347 +/- 21 ms, P < 0.05 vs. baseline for all parameters and P = not significant for right VNS vs. left VNS). No anterior-posterior lateral regional differences in the prolongation of ARI during right or left VNS were found. However, endocardial ARI prolonged more than epicardial ARI, and apical ARI prolonged more than basal ARI during both right and left VNS. Changes in dP/dtmax showed the strongest correlation with ventricular ARI effects (R(2) = 0.81, P < 0.0001) than either heart rate (R(2) = 0.58, P < 0.01) or left ventricular pressure (R(2) = 0.52, P < 0.05). Therefore, right and left VNS have similar effects on ventricular ARI, in contrast to sympathetic stimulation, which shows regional differences. The decrease in inotropy correlates best with ventricular electrophysiological effects. PMID- 25015963 TI - Thymosin-beta4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction. AB - Thymosin-beta4 (Tbeta4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tbeta4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tbeta4 (1.6 mg.kg(-1).day(-1) ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tbeta4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tbeta4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tbeta4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tbeta4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI. PMID- 25015964 TI - Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt- and PKA-mediated phosphorylation of eNOS at serine 1177. AB - Urocortin 2 (Ucn2) is a cardioactive peptide exhibiting beneficial effects in normal and failing heart. In cardiomyocytes, it elicits cAMP- and Ca(2+) dependent positive inotropic and lusitropic effects. We tested the hypothesis that, in addition, Ucn2 activates cardiac nitric oxide (NO) signaling and elucidated the underlying signaling pathways and mechanisms. In isolated rabbit ventricular myocytes, Ucn2 caused concentration- and time-dependent increases in phosphorylation of Akt (Ser473, Thr308), endothelial NO synthase (eNOS) (Ser1177), and ERK1/2 (Thr202/Tyr204). ERK1/2 phosphorylation, but not Akt and eNOS phosphorylation, was suppressed by inhibition of MEK1/2. Increased Akt phosphorylation resulted in increased Akt kinase activity and was mediated by corticotropin-releasing factor 2 (CRF2) receptors (astressin-2B sensitive). Inhibition of phosphatidylinositol 3-kinase (PI3K) diminished both Akt as well as eNOS phosphorylation mediated by Ucn2. Inhibition of protein kinase A (PKA) reduced Ucn2-induced phosphorylation of eNOS but did not affect the increase in phosphorylation of Akt. Conversely, direct receptor-independent elevation of cAMP via forskolin increased phosphorylation of eNOS but not of Akt. Ucn2 increased intracellular NO concentration ([NO]i), [cGMP], [cAMP], and cell shortening. Inhibition of eNOS suppressed the increases in [NO]i and cell shortening. When both PI3K-Akt and cAMP-PKA signaling were inhibited, the Ucn2-induced increases in [NO]i and cell shortening were attenuated. Thus, in rabbit ventricular myocytes, Ucn2 causes activation of cAMP-PKA, PI3K-Akt, and MEK1/2-ERK1/2 signaling. The MEK1/2-ERK1/2 pathway is not required for stimulation of NO signaling in these cells. The other two pathways, cAMP-PKA and PI3K-Akt, converge on eNOS phosphorylation at Ser1177 and result in pronounced and sustained cellular NO production with subsequent stimulation of cGMP signaling. PMID- 25015965 TI - Histone deacetylase 1 reduces NO production in endothelial cells via lysine deacetylation of NO synthase 3. AB - The lysine acetylation state of nonhistone proteins may be regulated through histone deacetylases (HDACs). Evidence suggests that nitric oxide (NO) synthase 3 (NOS3; endothelial NOS) is posttranslationally lysine acetylated, leading to increased NO production in the endothelium. We tested the hypothesis that NOS3 is lysine acetylated and that upregulated HDAC1-mediated deacetylation leads to reduced NO production in endothelial cells. We determined that NOS3 is basally lysine acetylated in cultured bovine aortic endothelial cells (BAECs). In BAECs, HDAC1 is expressed in the nucleus and cytosol and forms a novel protein-protein interaction with NOS3. Overexpression of HDAC1 in BAECs resulted in a significant reduction in NOS3 lysine acetylation (control = 1.0 +/- 0.1 and HDAC1 = 0.59 +/- 0.08 arbitrary units, P < 0.01) and significantly blunted basal nitrite production (control 287.7 +/- 29.1 and HDAC1 172.4 +/- 31.7 pmol.mg(-1).h(-1), P < 0.05) as well as attenuating endothelin-1-stimulated nitrite production (control = 481.8 +/- 50.3 and HDAC1 243.1 +/- 48.2 pmol.mg(-1).h(-1), P < 0.05). While HDAC1 knockdown with small-interfering RNA resulted in no change in NOS3 acetylation level, yet increased basal nitrite production (730.6 +/- 99.1 pmol.mg(-1).h(-1)) and further exaggerated increases in endothelin-1 stimulated nitrite production (1276.9 +/- 288.2 pmol.mg(-1).h(-1)) was observed. Moreover, overexpression or knockdown of HDAC1 resulted in no significant effect on NOS3 protein expression or NOS3 phosphorylation sites T497, S635, or S1179. Thus these data indicate that upregulated HDAC1 decreases NOS3 activity, most likely through direct lysine deacetylation of NOS3. We propose that HDAC1-mediated deacetylation of NOS3 may represent a novel target for endothelial dysfunction. PMID- 25015967 TI - Tumor necrosis factor-alpha inhibition attenuates middle cerebral artery remodeling but increases cerebral ischemic damage in hypertensive rats. AB - Hypertension causes vascular inflammation evidenced by an increase in perivascular macrophages and proinflammatory cytokines in the arterial wall. Perivascular macrophage depletion reduced tumor necrosis factor (TNF)-alpha expression in cerebral arteries of hypertensive rats and attenuated inward remodeling, suggesting that TNF-alpha might play a role in the remodeling process. We hypothesized that TNF-alpha inhibition would improve middle cerebral artery (MCA) structure and reduce damage after cerebral ischemia in hypertensive rats. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with the TNF-alpha inhibitor etanercept (ETN; 1.25 mg.kg(-1).day(-1) ip daily) or PBS (equivolume) for 6 wk. The myogenic tone generation, postischemic dilation, and passive structure of MCAs were assessed by pressure myography. Cerebral ischemia was induced by MCA occlusion (MCAO). Myogenic tone was unchanged, but MCAs from SHRSP + ETN had larger passive lumen diameter and reduced wall thickness and wall-to-lumen ratio. Cerebral infarct size was increased in SHRSP + ETN after transient MCAO, despite an improvement in dilation of nonischemic MCA. The increase in infarct size was linked to a reduction in the number of microglia in the infarct core and upregulation of markers of classical macrophage/microglia polarization. There was no difference in infarct size after permanent MCAO or when untreated SHRSP subjected to transient MCAO were given ETN at reperfusion. Our data suggests that TNF-alpha inhibition attenuates hypertensive MCA remodeling but exacerbates cerebral damage following ischemia/reperfusion injury likely due to inhibition of the innate immune response of the brain. PMID- 25015966 TI - NADPH oxidase-2 inhibition restores contractility and intracellular calcium handling and reduces arrhythmogenicity in dystrophic cardiomyopathy. AB - Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in humans and the mdx mouse. We tested the hypothesis that oxidative stress participates in disrupting calcium handling and contractility in the mdx mouse with established cardiomyopathy. We found increased expression (fivefold) of the NADPH oxidase (NOX) 2 in the mdx hearts compared with wild type, along with increased superoxide production. Next, we tested the impact of NOX2 inhibition on contractility and calcium handling in isolated cardiomyocytes. Contractility was decreased in mdx myocytes compared with wild type, and this was restored toward normal by pretreating with apocynin. In addition, the amplitude of evoked intracellular Ca(2+) concentration transients that was diminished in mdx myocytes was also restored with NOX2 inhibition. Total sarcoplasmic reticulum (SR) Ca(2+) content was reduced in mdx hearts and normalized by apocynin treatment. Additionally, NOX2 inhibition decreased the production of spontaneous diastolic calcium release events and decreased the SR calcium leak in mdx myocytes. In addition, nitric oxide (NO) synthase 1 (NOS-1) expression was increased eightfold in mdx hearts compared with wild type. Nevertheless, cardiac NO production was reduced. To test whether this paradox implied NOS-1 uncoupling, we treated cardiac myocytes with exogenous tetrahydrobioterin, along with the NOX inhibitor VAS2870. These agents restored NO production and phospholamban phosphorylation in mdx toward normal. Together, these results demonstrate that, in mdx hearts, NOX2 inhibition improves the SR calcium handling and contractility, partially by recoupling NOS-1. These findings reveal a new layer of nitroso-redox imbalance in dystrophic cardiomyopathy. PMID- 25015968 TI - Aging alters reactivity of microvascular resistance networks in mouse gluteus maximus muscle. AB - Aging occurs with enhanced sympathetic nerve activity and endothelial dysfunction; however, little is known of how successive branches of microvascular resistance networks are affected in vivo. We questioned whether vascular reactivity is altered differentially along resistance networks with advanced age. The left gluteus maximus muscle of anesthetized 4-mo-old and 24-mo-old male C57BL/6 mice (Young and Old, respectively) was exposed for intravital microscopy and superfused with physiological salt solution (3 ml/min; pH 7.4, 34 degrees C). Spontaneous vasomotor tone increased progressively from proximal feed arteries (FA) and first-order (1A) arterioles through distal second-order (2A) and third order (3A) arterioles and was ~15% greater in 2A and 3A of Old versus Young. Vasoconstriction during elevated superfusion Po2 increased with branch order and to a greater extent in Young. Peak constrictions to phenylephrine [alpha1 adrenoreceptor (alpha1AR) agonist] were similar for FA and 1A of both ages and ~20% greater for 2A and 3A of Young. Across arterioles (but not FA), constrictions to UK 14304 (alpha2AR agonist) were depressed ~30% in Old versus Young. Thus advanced age attenuated vasoconstriction to O2 throughout networks while blunting vasoconstriction to alpha1AR and alpha2AR activation in arterioles. With ACh, endothelium-dependent dilation (EDD) was ~20% greater in FA of Young yet was approximately twofold greater for 2A and 3A of Old. Sodium nitroprusside evoked maximal dilations similar to ACh. Thus, with advanced age, EDD was attenuated in FA while robust in distal arterioles having enhanced vasomotor tone. We conclude that advanced age differentially alters reactivity among branches of microvascular resistance networks. PMID- 25015969 TI - High-protein-low-carbohydrate diet: deleterious metabolic and cardiovascular effects depend on age. AB - High-protein-low-carbohydrate (HP-LC) diets have become widespread. Yet their deleterious consequences, especially on glucose metabolism and arteries, have already been underlined. Our previous study (2) has already shown glucose intolerance with major arterial dysfunction in very old mice subjected to an HP LC diet. The hypothesis of this work was that this diet had an age-dependent deleterious metabolic and cardiovascular outcome. Two groups of mice, young and adult (3 and 6 mo old), were subjected for 12 wk to a standard or to an HP-LC diet. Glucose and lipid metabolism was studied. The cardiovascular system was explored from the functional stage with Doppler-echography to the molecular stage (arterial reactivity, mRNA, immunohistochemistry). Young mice did not exhibit any significant metabolic modification, whereas adult mice presented marked glucose intolerance associated with an increase in resistin and triglyceride levels. These metabolic disturbances were responsible for cardiovascular damages only in adult mice, with decreased aortic distensibility and left ventricle dysfunction. These seemed to be the consequence of arterial dysfunctions. Mesenteric arteries were the worst affected with a major oxidative stress, whereas aorta function seemed to be maintained with an appreciable role of cyclooxygenase-2 to preserve endothelial function. This study highlights for the first time the age-dependent deleterious effects of an HP-LC diet on metabolism, with glucose intolerance and lipid disorders and vascular (especially microvessels) and cardiac functions. This work shows that HP-LC lead to equivalent cardiovascular alterations, as observed in very old age, and underlines the danger of such diet. PMID- 25015970 TI - Ketone strong: emerging evidence for a therapeutic role of ketone bodies in neurological and neurodegenerative diseases. PMID- 25015971 TI - Great Debate: a new section in the EJCTS. PMID- 25015972 TI - Operative techniques in patients with type A dissection complicated by cerebral malperfusion. PMID- 25015973 TI - Measurement of vibrational spectrum of liquid using monochromated scanning transmission electron microscopy-electron energy loss spectroscopy. AB - Investigations on the dynamic behavior of molecules in liquids at high spatial resolution are greatly desired because localized regions, such as solid-liquid interfaces or sites of reacting molecules, have assumed increasing importance with respect to improving material performance. In application to liquids, electron energy loss spectroscopy (EELS) observed with transmission electron microscopy (TEM) is a promising analytical technique with the appropriate resolutions. In this study, we obtained EELS spectra from an ionic liquid, 1 ethyl-3-methylimidazolium bis (trifluoromethyl-sulfonyl) imide (C2mim-TFSI), chosen as the sampled liquid, using monochromated scanning TEM (STEM). The molecular vibrational spectrum and the highest occupied molecular orbital (HOMO) lowest unoccupied molecular orbital (LUMO) gap of the liquid were investigated. The HOMO-LUMO gap measurement coincided with that obtained from the ultraviolet visible spectrum. A shoulder in the spectrum observed ~0.4 eV is believed to originate from the molecular vibration. From a separately performed infrared observation and first-principles calculations, we found that this shoulder coincided with the vibrational peak attributed to the C-H stretching vibration of the [C2mim(+)] cation. This study demonstrates that a vibrational peak for a liquid can be observed using monochromated STEM-EELS, and leads one to expect observations of chemical reactions or aids in the analysis of the dynamic behavior of molecules in liquid. PMID- 25015975 TI - Fibroblasts that resist cigarette smoke-induced senescence acquire profibrotic phenotypes. AB - This study assessed the effect of extended exposure to cigarette smoke extract (CSE) on tissue repair functions in lung fibroblasts. Human fetal (HFL-1) and adult lung fibroblasts were exposed to CSE for 14 days. Senescence-associated beta-galactosidase (SA beta-gal) expression, cell proliferation, and tissue repair functions including chemotaxis and gel contraction were assessed. HFL-1 proliferation was inhibited by CSE and nearly half of the CSE-exposed cells were SA beta-gal positive after 14 days exposure, whereas 33% of adult lung fibroblasts were SA beta-gal positive in response to 10% CSE exposure. The SA beta-gal-positive cells did not proliferate as indicated by bromodeoxyuridine incorporation. In contrast, cells negative for SA beta-gal after CSE exposure proliferated faster than cells never exposed to CSE. These nonsenescent cells migrated more and contracted collagen gels more than control cells. CSE exposure stimulated TGF-beta1 production, and both inhibition of TGF-beta receptor kinase and TGF-beta1 siRNA blocked CSE modulation of fibroblast function. Extended exposure to CSE might induce two different fibroblast phenotypes, a senescent and a profibrotic phenotype. The fibroblasts that resist CSE-induced cellular senescence may contribute to the pathogenesis of idiopathic pulmonary fibrosis and could contribute to fibrotic lesions in chronic obstructive pulmonary disease acting through a TGF-beta1-mediated pathway. In contrast, the senescent cells may contribute to the pathogenesis of emphysema. PMID- 25015974 TI - alpha-Tocopherol supplementation of allergic female mice inhibits development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates. AB - alpha-Tocopherol blocks responses to allergen challenge in allergic adult mice, but it is not known whether alpha-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether alpha tocopherol blocked development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with alpha-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to the allergen challenge, and alpha-tocopherol supplementation of allergic female mice resulted in a dose-dependent reduction in eosinophils in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also a reduction in pup lung CD11b(+) dendritic cell subsets that are critical to development of allergic responses, but there was no change in several CD11b(-) dendritic cell subsets. Furthermore, maternal supplementation with alpha-tocopherol reduced the number of fetal liver CD11b(+) dendritic cells in utero. In the pups, there was reduced allergen-induced lung mRNA expression of IL-4, IL-33, TSLP, CCL11, and CCL24. Cross-fostering pups at the time of birth demonstrated that alpha-tocopherol had a regulatory function in utero. In conclusion, maternal supplementation with alpha-tocopherol reduced fetal development of subsets of dendritic cells that are critical for allergic responses and reduced development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with alpha-tocopherol. PMID- 25015976 TI - ENaC activity and expression is decreased in the lungs of protein kinase C-alpha knockout mice. AB - We used a PKC-alpha knockout model to investigate the regulation of alveolar epithelial Na(+) channels (ENaC) by PKC. Primary alveolar type II (ATII) cells were subjected to cell-attached patch clamp. In the absence of PKC-alpha, the open probability (Po) of ENaC was decreased by half compared with wild-type mice. The channel density (N) was also reduced in the knockout mice. Using in vivo biotinylation, membrane localization of all three ENaC subunits (alpha, beta, and gamma) was decreased in the PKC-alpha knockout lung, compared with the wild-type. Confocal microscopy of lung slices showed elevated levels of reactive oxygen species (ROS) in the lungs of the PKC-alpha knockout mice vs. the wild-type. High levels of ROS in the knockout lung can be explained by a decrease in both cytosolic and mitochondrial superoxide dismutase activity. Elevated levels of ROS in the knockout lung activates PKC-delta and leads to reduced dephosphorylation of ERK1/2 by MAP kinase phosphatase, which in turn causes increased internalization of ENaC via ubiquitination by the ubiquitin-ligase Nedd4-2. In addition, in the knockout lung, PKC-delta activates ERK, causing a decrease in ENaC density at the apical alveolar membrane. PKC-delta also phosphorylates MARCKS, leading to a decrease in ENaC Po. The effects of ROS and PKC-delta were confirmed with patch-clamp experiments on isolated ATII cells in which the ROS scavenger, Tempol, or a PKC-delta-specific inhibitor added to patches reversed the observed decrease in ENaC apical channel density and Po. These results explain the decrease in ENaC activity in PKC-alpha knockout lung. PMID- 25015979 TI - Hospital care for primary hyperparathyroidism in Italy: a 6-year register-based study. AB - OBJECTIVE: Primary hyperparathyroidism (PHPT) is one of the most frequently diagnosed endocrine disorders, but few studies have focused on hospital management of the disease in Europe. We investigated the frequency of hospital admission for diagnosis and surgical treatment of PHPT in Italy. DESIGN: A retrospective study was conducted for investigating the hospital care for PHPT in Italy. METHODS: We retrieved data from the 'Record of Hospital Discharge' of the Italian Health Ministry, from 2006 to 2011, and analyzed the codes corresponding to PHPT-related diagnoses and surgical procedures. RESULTS: Overall, 46 275 hospitalization episodes for PHPT were identified during the entire period (69% in women and 31% in men; mean age 63.3+/-39.8 years). Patients' mean age significantly increased during the years (P<0.001). The mean length of stay was 8.2+/-10.5 days (28% of the episodes requiring <3 days of stay). Admissions for surgical procedures were 12 457 accounting for 26.9% of the total hospitalizations. There was a trend to a significant increase in the percentage of surgery (P<0.05). The mean hospitalization rate for PHPT was 12.9/100 000 inhabitants per year and the trend showed a significant decrease during the period of 2006-2011 (P<0.0001). The mean hospitalization rate for PHPT surgery was 3.65/100 000 per year, which significantly increased over time (P<0.001). CONCLUSIONS: PHPT considerably influences the Italian Hospital healthcare system. We observed a tendency to a decrease in the frequency of hospitalization during the period of 2006-2011, most probably because of economic issues, a concomitant increased age of patients, and, interestingly, also a progressive increase in the percentage of surgical treatment among patients admitted for PHPT. PMID- 25015980 TI - Investigating underage youth access to alcohol in Switzerland: inventory of modes of access and association with youth characteristics. AB - AIMS: While laws restrict alcohol access to youth under the age of 16/18 (fermented/distilled beverages) in Switzerland, direct underage accessibility is high. Focusing on underage youth, our study presents an inventory of primary and alternative modes of access to alcohol and investigates associations with youth characteristics. METHODS: Data were collected using semi-structured interviews and self-report questionnaires. In total, 223 underage youth aged 15-17 years were interviewed. RESULTS: Overall, about half of the participants reported illegal commercial purchase, either direct or by underage peer, in on- (49.3%) and/or off-premise (48.0%) contexts. Off-premise purchase by proxy of legal age (30.5%; excluding shoulder-tapping), social supply off-premise (i.e. receiving/exchanging alcohol; 26.5%) and direct purchases in on- (13.9%) and off premise (11.2%) contexts were the most recurrent primary modes of access. Significant associations of direct purchases with frequency of consumption and perceived alcohol availability were recorded. Associations between primary and alternative ways to access alcohol, in particular, between on-premise modes, were also evidenced. CONCLUSION: Providing an overview of the context of underage alcohol access in Switzerland and an indirect view of youth perceptions of limitations of existing structural measures has identified particularly the need for enforcement of existing legislation. PMID- 25015981 TI - Alcohol consumption and risky drinking patterns in Malaysia: findings from NHMS 2011. AB - AIMS: To identify the characteristics of current drinker and risky alcohol drinking pattern by profiles in Malaysia. METHODS: We analyzed data from the National Health and Morbidity Survey 2011. It was a cross-sectional population based with two stages stratified random sampling design. A validated Alcohol Use Disorder Identification Test Malay questionnaire was used to assess the alcohol consumption and its alcohol related harms. Analysis of complex survey data using Stata Version 12 was done for descriptive analysis on alcohol use and risky drinking by socio-demography profiles. Logistic regression analysis was used to measure the association of risky drinking status with the socio-demography characteristics. RESULTS: The prevalence of current alcohol use was 11.6% [95% confidence interval (CI): 10.5, 12.7], among them 23.6% (95% CI: 21.0, 26.4) practiced risky drinking. The onset for alcohol drinking was 21 years old (standard deviation 7.44) and majority preferred Beer. Males significantly consumed more alcohol and practiced risky drinking. Current alcohol use was more prevalent among urbanites, Chinese, those with high household income, and high education. Conversely, risky drinking was more prevalent among rural drinkers, Bumiputera Sabah and Sarawak, low education and low household income. The estimated odds of risky drinking increased by a factor of 3.5 among Males while a factor of 2.7 among Bumiputera Sabah and Sarawak. Education status and household income was not a significant predictor to risky drinking. CONCLUSION: There was an inverse drinking pattern between current drinker and risky drinking by the socio-demography profiles. Initiating early screening and focused intervention might avert further alcohol related harms and dependence among the risky drinkers. PMID- 25015987 TI - MAGNA: Maximizing Accuracy in Global Network Alignment. AB - MOTIVATION: Biological network alignment aims to identify similar regions between networks of different species. Existing methods compute node similarities to rapidly identify from possible alignments the high-scoring alignments with respect to the overall node similarity. But, the accuracy of the alignments is then evaluated with some other measure that is different than the node similarity used to construct the alignments. Typically, one measures the amount of conserved edges. Thus, the existing methods align similar nodes between networks hoping to conserve many edges (after the alignment is constructed!). RESULTS: Instead, we introduce MAGNA to directly 'optimize' edge conservation while the alignment is constructed, without decreasing the quality of node mapping. MAGNA uses a genetic algorithm and our novel function for 'crossover' of two 'parent' alignments into a superior 'child' alignment to simulate a 'population' of alignments that 'evolves' over time; the 'fittest' alignments survive and proceed to the next 'generation', until the alignment accuracy cannot be optimized further. While we optimize our new and superior measure of the amount of conserved edges, MAGNA can optimize any alignment accuracy measure, including a combined measure of both node and edge conservation. In systematic evaluations against state-of-the-art methods (IsoRank, MI-GRAAL and GHOST), on both synthetic networks and real-world biological data, MAGNA outperforms all of the existing methods, in terms of both node and edge conservation as well as both topological and biological alignment accuracy. AVAILABILITY: Software: http://nd.edu/~cone/MAGNA CONTACT: : tmilenko@nd.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25015988 TI - proovread: large-scale high-accuracy PacBio correction through iterative short read consensus. AB - MOTIVATION: Today, the base code of DNA is mostly determined through sequencing by synthesis as provided by the Illumina sequencers. Although highly accurate, resulting reads are short, making their analyses challenging. Recently, a new technology, single molecule real-time (SMRT) sequencing, was developed that could address these challenges, as it generates reads of several thousand bases. But, their broad application has been hampered by a high error rate. Therefore, hybrid approaches that use high-quality short reads to correct erroneous SMRT long reads have been developed. Still, current implementations have great demands on hardware, work only in well-defined computing infrastructures and reject a substantial amount of reads. This limits their usability considerably, especially in the case of large sequencing projects. RESULTS: Here we present proovread, a hybrid correction pipeline for SMRT reads, which can be flexibly adapted on existing hardware and infrastructure from a laptop to a high-performance computing cluster. On genomic and transcriptomic test cases covering Escherichia coli, Arabidopsis thaliana and human, proovread achieved accuracies up to 99.9% and outperformed the existing hybrid correction programs. Furthermore, proovread corrected sequences were longer and the throughput was higher. Thus, proovread combines the most accurate correction results with an excellent adaptability to the available hardware. It will therefore increase the applicability and value of SMRT sequencing. AVAILABILITY AND IMPLEMENTATION: proovread is available at the following URL: http://proovread.bioapps.biozentrum.uni-wuerzburg.de. PMID- 25015989 TI - Network-based analysis identifies epigenetic biomarkers of esophageal squamous cell carcinoma progression. AB - MOTIVATION: A rapid progression of esophageal squamous cell carcinoma (ESCC) causes a high mortality rate because of the propensity for metastasis driven by genetic and epigenetic alterations. The identification of prognostic biomarkers would help prevent or control metastatic progression. Expression analyses have been used to find such markers, but do not always validate in separate cohorts. Epigenetic marks, such as DNA methylation, are a potential source of more reliable and stable biomarkers. Importantly, the integration of both expression and epigenetic alterations is more likely to identify relevant biomarkers. RESULTS: We present a new analysis framework, using ESCC progression-associated gene regulatory network (GRN escc), to identify differentially methylated CpG sites prognostic of ESCC progression. From the CpG loci differentially methylated in 50 tumor-normal pairs, we selected 44 CpG loci most highly associated with survival and located in the promoters of genes more likely to belong to GRN escc. Using an independent ESCC cohort, we confirmed that 8/10 of CpG loci in the promoter of GRN escc genes significantly correlated with patient survival. In contrast, 0/10 CpG loci in the promoter genes outside the GRN escc were correlated with patient survival. We further characterized the GRN escc network topology and observed that the genes with methylated CpG loci associated with survival deviated from the center of mass and were less likely to be hubs in the GRN escc. We postulate that our analysis framework improves the identification of bona fide prognostic biomarkers from DNA methylation studies, especially with partial genome coverage. PMID- 25015990 TI - GlycoDigest: a tool for the targeted use of exoglycosidase digestions in glycan structure determination. AB - Sequencing oligosaccharides by exoglycosidases, either sequentially or in an array format, is a powerful tool to unambiguously determine the structure of complex N- and O-link glycans. Here, we introduce GlycoDigest, a tool that simulates exoglycosidase digestion, based on controlled rules acquired from expert knowledge and experimental evidence available in GlycoBase. The tool allows the targeted design of glycosidase enzyme mixtures by allowing researchers to model the action of exoglycosidases, thereby validating and improving the efficiency and accuracy of glycan analysis. AVAILABILITY AND IMPLEMENTATION: http://www.glycodigest.org. PMID- 25015992 TI - A new approach for detecting riboswitches in DNA sequences. AB - MOTIVATION: Riboswitches are short sequences of messenger RNA that can change their structural conformation to regulate the expression of adjacent genes. Computational prediction of putative riboswitches can provide direction to molecular biologists studying riboswitch-mediated gene expression. RESULTS: The Denison Riboswitch Detector (DRD) is a new computational tool with a Web interface that can quickly identify putative riboswitches in DNA sequences on the scale of bacterial genomes. Riboswitch descriptions are easily modifiable and new ones are easily created. The underlying algorithm converts the problem to a 'heaviest path' problem on a multipartite graph, which is then solved using efficient dynamic programming. We show that DRD can achieve ~ 88-99% sensitivity and >99.99% specificity on 13 riboswitch families. AVAILABILITY AND IMPLEMENTATION: DRD is available at http://drd.denison.edu. PMID- 25015993 TI - Electromagnetic fields do not affect bone micro-architecture in osteoporotic rats. AB - OBJECTIVES: Electromagnetic fields (EMF) are widely used in musculoskeletal disorders. There are indications that EMF might also be effective in the treatment of osteoporosis. To justify clinical follow-up experiments, we examined the effects of EMF on bone micro-architectural changes in osteoporotic and healthy rats. Moreover, we tested the effects of EMF on fracture healing. METHODS: EMF (20 Gauss) was examined in rats (aged 20 weeks), which underwent an ovariectomy (OVX; n = 8) or sham-ovariectomy (sham-OVX; n = 8). As a putative positive control, all rats received bilateral fibular osteotomies to examine the effects on fracture healing. Treatment was applied to one proximal lower leg (three hours a day, five days a week); the lower leg was not treated and served as a control. Bone architectural changes of the proximal tibia and bone formation around the osteotomy were evaluated using in vivo microCT scans at start of treatment and after three and six weeks. RESULTS: In both OVX and sham-OVX groups, EMF did not result in cancellous or cortical bone changes during follow up. Moreover, EMF did not affect the amount of mineralised callus volume around the fibular osteotomy. CONCLUSIONS: In this study we were unable to reproduce the strong beneficial findings reported by others. This might indicate that EMF treatment is very sensitive to the specific set-up, which would be a serious hindrance for clinical use. No evidence was found that EMF treatment can influence bone mass for the benefit of osteoporotic patients. Cite this article: Bone Joint Res 2014;3:230-5. PMID- 25015994 TI - A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. AB - A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (n=41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included chi(2), non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96+/-0.025, CgA: 0.67+/ 0.06, PST 0.56+/-0.06, NKA: 0.66+/-0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P<0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest >95% sensitivity and specificity, AUC =0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (>93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy. PMID- 25015995 TI - The role of corticotropin-releasing hormone receptor 1 in the development of colitis-associated cancer in mouse model. AB - Patients with ulcerative colitis are at a very high risk of developing colorectal cancer. Corticotrophin-releasing hormone (CRH) family peptides and their receptors (CRHRs) are found to modulate inflammation and tumor cell growth. However, the role of CRH family peptides and their receptors in the inflammation related colon cancer is still unknown. The aim of this study was to investigate the functions of CRHR1 signaling on the development of colitis-associated cancer (CAC). Crhr1-deficient (Crhr1(-/-)) mice were used to explore the role of CRHR1 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. WT (Crhr1(+/+)) littermates were set as control. We found that the expression of CRHR1 and its endogenous ligands: urocortin and CRH were enhanced in the colon of Crhr1(+/+) mice during treatment with AOM and DSS. Tumorigenesis was significantly reduced in Crhr1(-/-) mice, determined by analysis of survival rate (increased by 20%), weight loss (decreased by 10%), tumor formation (decreased by 60% in tumor number), histological scores (decreased by 58%), and cytokine production. During early CAC tumorigenesis, Crhr1(-/-) mice exhibited much less tumorigenesis, accompanied by lower inflammatory response, including decreased IL1beta, IL6 and TNFalpha expression and macrophage infiltration and increased IL10 expression. Moreover, Crhr1(-/-) mice displayed a reduced activation of NFkappaB and STAT3 phosphorylation with decreased proliferating and enhanced apoptotic cells in the colon. In conclusion, CRHR1 has a proinflammatory and therefore a protumorigenesis effect in terms of CAC, which may be helpful to develop new therapeutic approaches for inflammation and cancer prevention and treatment. PMID- 25015996 TI - Rooming-In-Are You Really? PMID- 25015997 TI - Early Life Nutrition: Does It Program Childhood Eating Attitudes? PMID- 25015998 TI - A Request for More Research Concerning Teaching about Breastfeeding in Schools. PMID- 25015999 TI - Overly Full Breasts (Engorgement). PMID- 25016002 TI - Order Form (August 2014). PMID- 25016000 TI - Independent Study Module for Lactation Consultants: "Six-Step Recanalization Manual Therapy: A Novel Method for Treating Plugged Ducts in Lactating Women" PMID- 25016003 TI - Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma. AB - Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC 714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014. PMID- 25016005 TI - Hydration history and attachment morphology regulate seed release in Chorizanthe rigida (Polygonaceae), a serotinous desert annual. AB - * Premise of the study: Most seed dispersal studies focus on the spatial aspects of propagule dissemination, i.e., the movement of seeds away from the mother plant. However, the timing of seed release can also be a critical variable influencing the probability of seedling survival. We used a biomechanical approach to analyze seed release in Chorizanthe rigida, a serotinous desert annual, to understand the adaptive significance of seed retention in this species.* Methods: We performed pull-to-break tests on individual propagules (i.e., involucres and achene) from newly developed and older plants, under dry and wet conditions, and recorded the breaking force. We measured the involucral base area using digital images and image processing software.* Key results: There is a positive correlation between the force required to detach an involucre and the size of its base area. The force required to detach involucres from soaked and older plants was lower than that for dry and new plants. This pattern provides a mechanism for the plant to regulate the number of involucres released in different rain events.* Conclusions: Seed release in C. rigida is mediated by propagule morphology, rainfall conditions, and age of the dry plant. These factors allow this species to cope with desert environmental variability by influencing the timing and number of seeds released. PMID- 25016006 TI - High but variable outcrossing rates in the invasive Geranium carolinianum (Geraniaceae). AB - * Premise of the study: Mating system plays an important role in population establishment and persistence, maintenance of genetic variation, and adaptive ability, especially for invasive species that colonize new environments to which they may be poorly adapted. In mixed-mating species, population differences in self-fertilization rates often arise due to variation in local ecological conditions (e.g., pollinator or mate availability) or genetic variation in traits promoting selfing or outcrossing. Knowledge of how and why selfing rates vary can help us understand how populations respond to different environments, how this affects patterns of genetic variation, and the role of mating systems in biological invasions.* Methods: We determined outcrossing rates in invasive (China) and native (US) populations of the weedy annual Geranium carolinianum in natural populations and an open-pollinated common garden to answer the following questions: To what extent do populations vary in mating system? Do invasive populations differ from native populations? Is interpopulation variation in mating system under genetic control?* Key results: Despite having many characteristics of selfing species, we found high variation in outcrossing rates (tm from 0.1 to 1.0) resulting from both environmental and genetic variation. Outcrossing rates were generally high and plastic in the Chinese populations.* Conclusions: A delayed selfing mechanism provides reproductive assurance while allowing facultative outcrossing when mates are not limiting. In invasive populations, high outcrossing rates were facilitated by large admixed founding populations, promoting local adaptation and the maintenance of genetic diversity. PMID- 25016004 TI - The underlying structure of adaptation under strong selection in 12 experimental yeast populations. AB - The aims of this study were to determine (i) whether adaptation under strong selection occurred through mutations in a narrow target of one or a few nucleotide sites or a broad target of numerous sites and (ii) whether the programs of adaptation previously observed from three experimental populations were unique or shared among populations that underwent parallel evolution. We used archived population samples from a previous study, representing 500 generations of experimental evolution in 12 populations under strong selection, 6 populations in a high-salt environment and 6 populations in a low-glucose environment. Each set of six populations included four with sexual reproduction and two with exclusively asexual reproduction. Populations were sampled as resequenced genomes of 115 individuals and as bulk samples from which frequencies of mutant alleles were estimated. In a high-salt environment, a broad target of 11 mutations within the proton exporter, PMA1, was observed among the six populations, in addition to expansions of the ENA gene cluster. This pattern was shared among populations that underwent parallel evolution. In a low-glucose environment, two programs of adaptation were observed. The originally observed pattern of mutation in MDS3/MKT1 in population M8 was a narrow target of a single nucleotide, unique to this population. Among the other five populations, the three mutations were shared in a broad target, sensing/signaling genes RAS1 and RAS2. RAS1/RAS2 mutations were not observed in the high-salt populations; PMA1 mutations were observed only in a high-salt environment. PMID- 25016007 TI - Roles of maternal effects and nuclear genetic composition change across the life cycle of crop-wild hybrids. AB - * Premise of the study: The fitness of an offspring may depend on its nuclear genetic composition (via both parental genotypes) as well as on genetic maternal effects (via only the maternal parent). Understanding the relative importance of these two genetic factors is particularly important for research on crop-wild hybridization, since traits with important genetic maternal effects (e.g., seed size) often differ among crops and their relatives. We hypothesized that the effects of these genetic factors on fitness components would change across the life cycle of hybrids.* Methods: We followed seed, plant size, and reproductive traits in field experiments with wild and four crop-wild hybrids of sunflower (Helianthus annuus), which differed in nuclear genetic composition and maternal parent (wild or F1 hybrid).* Key results: We identified strong genetic maternal effects for early life cycle characteristics, with seeds produced on an F1 mother having premature germination, negligible seed dormancy, and greater seedling size. Increased percentages of crop alleles also increased premature germination and reduced dormancy in seeds produced on a wild mother. For mature plants, nuclear genetic composition dominated: greater percentages of crop alleles reduced height, branching, and fecundity.* Conclusions: Particular backcrosses between hybrids and wilds may differentially facilitate movement of crop alleles into wild populations due to their specific features. For example, backcross seeds produced on wild mothers can persist in the seed bank, illustrating the importance of genetic maternal effects, whereas backcross individuals with either wild or F1 mothers have high fecundity, resulting from their wild-like nuclear genetic composition. PMID- 25016008 TI - Ecological specialization in Trebouxia (Trebouxiophyceae) photobionts of Ramalina menziesii (Ramalinaceae) across six range-covering ecoregions of western North America. AB - * Premise of the study: Many lichens exhibit extensive ranges spanning several ecoregions. It has been hypothesized that this wide ecological amplitude is facilitated by fungal association with locally adapted photobiont strains.* Methods: We studied the identity and geographic distribution of photobionts of the widely distributed North American lichen Ramalina menziesii based on rbcL (chloroplast DNA) and nuclear ribosomal ITS DNA sequences. To test for ecological specialization, we associate photobiont genotypes with local climate and phorophyte.* Key results: Of the photobiont lineages of R. menziesii, 94% belong to a clade including Trebouxia decolorans. The remaining are related to T. jamesii. The photobionts showed (1) significant structure according to ecoregion and phorophyte species and (2) genetic associations with phorophyte species and climate.* Conclusions: Geography, climate, and ecological specialization shape genetic differentiation of lichen photobionts. One great advantage of independent dispersal of the fungus is symbiotic association with locally adapted photobiont strains. PMID- 25016009 TI - Phylogeny and historical biogeography of the lastreopsid ferns (Dryopteridaceae). AB - * Premise of the study: As currently circumscribed, Lastreopsis has about 45 species and occurs in Australia, southern Asia, Africa, Madagascar, and the neotropics. Previous molecular phylogenetic studies suggested that Lastreopsis is paraphyletic. Our study focuses on resolving relationships among the lastreopsid ferns (Lastreopsis, Megalastrum, and Rumohra), the evolution of morphological characters, and an understanding of the temporal and spatial patterns that have led to the current diversity and geographical distribution of its extant species.* Methods: Phylogenetic relationships were recovered under Bayesian, maximum likelihood, and maximum parsimony methods, using a data set of four plastid markers. Divergence time estimates were made using BEAST, and the biogeographic hypotheses were tested under the DEC model and the RASP/S-DIVA methods.* Key results: Lastreopsis was recovered as paraphyletic, and at least one of its clades should be recognized as a distinct genus, Parapolystichum. Coveniella poecilophlebia and Oenotrichia tripinnata were nested within Lastreopsis s.s., Megalastrum and Rumohra as sister to the Lastreopsis s.s., and the Lastreopsis amplissima clades. The initial diversification of the lastreopsids took place at about 56.55 Ma, from a neotropical ancestor.* Conclusions: Taxonomic recognition of Parapolystichum is warranted to preserve the monophyly of Lastreopsis. Diversification among the main clades of the lastreopsid ferns was influenced by climatic and geological changes in the southern hemisphere. The biogeographic history of the group is intimately related to the trans-Antarctic corridor between Australia and South America, with evidence for multiple lineage interchanges between Australia and South America during the Oligocene and the Eocene epochs. PMID- 25016010 TI - Habitat fragmentation threatens wild populations of Carica papaya (Caricaceae) in a lowland rainforest. AB - * Premise of the study: Wild populations of domesticated species constitute a genetic reservoir and are fundamental to the evolutionary potential of species. Wild papaya (Carica papaya) is a rare, short-lived, gap-colonizing, dioecious tree that persists in the forest by continuous dispersal. Theoretically, these life-history characteristics render wild papaya highly susceptible to habitat fragmentation, with anticipated negative effects on its gene pool. Further, species dioecy may cause founder effects to generate local biases in sex ratio, decreasing effective population size.* Methods: We contrasted the genetic diversity and structure of C. papaya between wild populations from rainforest fragments and continuous forest at Los Tuxtlas, Mexico. We evaluated recent migration rates among populations as well as landscape resistance to gene flow. Finally, we calculated the sex ratio of the populations in both habitats.* Key results: Populations of wild papaya in rainforest fragments showed lower genetic diversity and higher population differentiation than populations in continuous rainforest. Estimates of recent migration rates showed a higher percentage of migrants moving from the continuous forest to the forest fragments than in the opposite direction. Agricultural land and cattle pasture were found to be the most resistant matrices to gene flow. Finally, biased sex ratios were seen to affect the effective population size in both habitats.* Conclusions: The mating system, rarity, and short life cycle of C. papaya are exacerbating the effects of rainforest fragmentation on its genetic diversity, threatening the persistence of its natural populations in the proposed place of origin as well as its genetic reservoir. PMID- 25016011 TI - Phylogenetic placement, species delimitation, and cyanobiont identity of endangered aquatic Peltigera species (lichen-forming Ascomycota, Lecanoromycetes). AB - * Premise of this study: Aquatic cyanolichens from the genus Peltigera section Hydrothyriae are subject to anthropogenic threats and, therefore, are considered endangered. In this study we addressed the phylogenetic placement of section Hydrothyriae within Peltigera. We delimited species within the section and identified their symbiotic cyanobacteria.* Methods: Species delimitation and population structure were explored using monophyly as a grouping criterion (RAxML) and Structurama based on three protein-coding genes in combination with two nuclear ribosomal loci. The 16S and rbcLX sequences for the cyanobionts were analyzed in the broad phylogenetic context of free-living and symbiotic cyanobacteria.* Key results: We confirm with high confidence the placement of section Hydrothyriae within the monophyletic genus Peltigera; however, its phylogenetic position within the genus remains unsettled. We recovered three distinct monophyletic groups corresponding to three species: P. hydrothyria, P. gowardii s.s., and P. aquatica Miadl. & Lendemer, the latter being formally introduced here. Each species was associated with an exclusive set of Nostoc haplotypes.* Conclusions: The ITS region alone provides sufficient genetic information to distinguish the three morphologically cryptic species within section Hydrothyriae. Section Hydrothyriae seems to be associated with a monophyletic lineage of Nostoc, that has not been found in symbiotic association with other members of Peltigera. Capsosira lowei should be transferred to the genus Nostoc. Potential threats to P. aquatica should be re-examined based on the recognition of two aquatic species in western North America. PMID- 25016012 TI - The Effects of Level of Competition, Sport, and Sex on the Incidence of First Time Noncontact Anterior Cruciate Ligament Injury. AB - BACKGROUND: Anterior cruciate ligament (ACL) injuries are disabling and are associated with the early onset of posttraumatic osteoarthritis. Little is known regarding the incidence rate of first-time noncontact ACL injuries sustained during athletic events and how they are independently influenced by level of competition, type of sport, and the participant's sex. HYPOTHESIS: Level of competition (college or high school), type of sport (soccer, basketball, lacrosse, field hockey, football, rugby, volleyball), and the athlete's sex independently influence the incidence rate of first-time noncontact ACL injuries. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Between fall 2008 and spring 2012, first-time noncontact ACL injury data were collected from 8 colleges and 18 high schools across 7 sports. Athlete exposure was computed retrospectively using team rosters and numbers of scheduled practices and games. Injury incidence rates (IRs) were computed per 1000 athlete exposures. The independent effects of level of competition, sport, and sex on ACL injury risk were estimated by Poisson regression. RESULTS: Colleges reported 48 ACL injuries with 320,719 athlete exposures across all sports studied (IR = 0.150 per 1000 person-days), while high schools reported 53 injuries with 873,057 athlete exposures (IR = 0.061). After adjustment for differences in sport and sex, college athletes had a significantly higher injury risk than did high school athletes (adjusted relative risk [RR], 2.38; 95% CI, 1.55-3.54). The overall IR for female athletes was 0.112 compared with 0.063 for males. After adjustment for sport and level of play, females were more than twice as likely to have a first time ACL injury compared with males (RR, 2.10; 95% CI, 1.34-3.27). With lacrosse as the reference group, risk of first-time noncontact ACL injury was significantly higher for soccer players (RR, 1.77) and for rugby players (RR, 2.23), independent of level of play and sex. CONCLUSION: An athlete's risk of having a first-time noncontact ACL injury is independently influenced by level of competition, the participant's sex, and type of sport, and there are no interactions between their effects. Female college athletes have the highest risk of having a first-time noncontact ACL injury among the groups studied. PMID- 25016013 TI - Delayed-onset ulnar neuritis after release of elbow contractures: clinical presentation, pathological findings, and treatment. AB - BACKGROUND: Little information exists regarding delayed-onset ulnar neuritis (DOUN) after arthroscopic release of elbow contractures. PURPOSE: To describe, in a large cohort of patients, the clinical presentation of and risk factors for developing DOUN after arthroscopic release of elbow contractures. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A retrospective study of 565 consecutive arthroscopic releases of elbow contractures was conducted. Essentially, DOUN was defined as ulnar neuritis or neuropathy, or worsening of pre-existing ulnar nerve symptoms, that developed postoperatively in patients with normal neurological examination findings immediately after surgery. After inclusion and exclusion criteria were met, 235 contracture releases in patients who had not undergone any ulnar nerve surgery remained and were used for the analysis of risk factors with a multivariate logistic regression analysis. RESULTS: Twenty-six patients (11%) developed DOUN. The patients fell into 1 of 3 distinct groups. Fifteen (58%) presented with rapidly progressive DOUN, characterized by rapidly progressive sensorimotor ulnar neuropathy, increasing pain at the cubital tunnel during end-range flexion and/or extension, and rapidly deteriorating range of motion within the first week after surgery. Urgent ulnar subcutaneous nerve transposition was performed within 1 or 2 days of diagnosis. Eight (31%) presented with nonprogressive DOUN, characterized by mild sensory ulnar neuropathy, neither motor weakness nor substantial pain at the cubital tunnel, or loss of motion. Three (12%) presented with slowly progressive DOUN, characterized by the insidious onset of mild ulnar neuropathy. Significant risk factors for DOUN included a diagnosis of heterotopic ossification (odds ratio, 31; 95% CI, 5-191; P < .001), preoperative neurological symptoms (odds ratio, 6; 95% CI, 2-19; P = .001), and preoperative arc of motion (odds ratio, 0.97 per degree of motion; 95% CI, 0.96-0.99; P = .02). CONCLUSION: Delayed-onset ulnar neuritis is an important complication of arthroscopic release of elbow contractures. We recommend a high index of suspicion and monitoring patients with progressive loss of elbow motion and end-range pain for evidence of subclinical ulnar neuritis. PMID- 25016014 TI - Bile acid-regulated peroxisome proliferator-activated receptor-alpha (PPARalpha) activity underlies circadian expression of intestinal peptide absorption transporter PepT1/Slc15a1. AB - Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor alpha (PPARalpha). Nocturnally active mice mainly consumed their food during the dark phase. PPARalpha activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARalpha-mediated transactivation of Slc15a1. The time-dependent suppression of PPARalpha-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock independent mechanism by which bile acid-regulated PPARalpha activity governs the circadian expression of intestinal peptide transporter. PMID- 25016015 TI - Ion conductivity of the bacterial translocation channel SecYEG engaged in translocation. AB - While engaged in protein transport, the bacterial translocon SecYEG must maintain the membrane barrier to small ions. The preservation of the proton motif force was attributed to (i) cation exclusion, (ii) engulfment of the nascent chain by the hydrophobic pore ring, and (iii) a half-helix partly plugging the channel. In contrast, we show here that preservation of the proton motif force is due to a voltage-driven conformational change. Preprotein or signal peptide binding to the purified and reconstituted SecYEG results in large cation and anion conductivities only when the membrane potential is small. Physiological values of membrane potential close the activated channel. This voltage-dependent closure is not dependent on the presence of the plug domain and is not affected by mutation of 3 of the 6 constriction residues to glycines. Cellular ion homeostasis is not challenged by the small remaining leak conductance. PMID- 25016016 TI - Plasticity and evolution of (+)-3-carene synthase and (-)-sabinene synthase functions of a sitka spruce monoterpene synthase gene family associated with weevil resistance. AB - The monoterpene (+)-3-carene is associated with resistance of Sitka spruce against white pine weevil, a major North American forest insect pest of pine and spruce. High and low levels of (+)-3-carene in, respectively, resistant and susceptible Sitka spruce genotypes are due to variation of (+)-3-carene synthase gene copy number, transcript and protein expression levels, enzyme product profiles, and enzyme catalytic efficiency. A family of multiproduct (+)-3-carene synthase-like genes of Sitka spruce include the three (+)-3-carene synthases, PsTPS-3car1, PsTPS-3car2, PsTPS-3car3, and the (-)-sabinene synthase PsTPS-sab. Of these, PsTPS-3car2 is responsible for the relatively higher levels of (+)-3 carene in weevil-resistant trees. Here, we identified features of the PsTPS 3car1, PsTPS-3car2, PsTPS-3car3, and PsTPS-sab proteins that determine different product profiles. A series of domain swap and site-directed mutations, supported by structural comparisons, identified the amino acid in position 596 as critical for product profiles dominated by (+)-3-carene in PsTPS-3car1, PsTPS-3car2, and PsTPS-3car3, or (-)-sabinene in PsTPS-sab. A leucine in this position promotes formation of (+)-3-carene, whereas phenylalanine promotes (-)-sabinene. Homology modeling predicts that position 596 directs product profiles through differential stabilization of the reaction intermediate. Kinetic analysis revealed position 596 also plays a role in catalytic efficiency. Mutations of position 596 with different side chain properties resulted in a series of enzymes with different product profiles, further highlighting the inherent plasticity and potential for evolution of alternative product profiles of these monoterpene synthases of conifer defense against insects. PMID- 25016017 TI - Cooperative signaling via transcription factors NF-kappaB and AP1/c-Fos mediates endothelial cell STIM1 expression and hyperpermeability in response to endotoxin. AB - Stromal interacting molecule 1 (STIM1) regulates store-operated Ca(2+) entry (SOCE). Here we show that STIM1 expression in endothelial cells (ECs) is increased during sepsis and, therefore, contributes to hyperpermeability. LPS induced STIM1 mRNA and protein expression in human and mouse lung ECs. The induced STIM1 expression was associated with augmented SOCE as well as a permeability increase in both in vitro and in vivo models. Because activation of both the NF-kappaB and p38 MAPK signaling pathways downstream of TLR4 amplifies vascular inflammation, we studied the influence of these two pathways on LPS induced STIM1 expression. Inhibition of either NF-kappaB or p38 MAPK activation by pharmacological agents prevented LPS-induced STIM1 expression. Silencing of the NF-kappaB proteins (p65/RelA or p50/NF-kappaB1) or the p38 MAPK isoform p38alpha prevented LPS-induced STIM1 expression and increased SOCE in ECs. In support of these findings, we found NF-kappaB and AP1 binding sites in the 5' regulatory region of human and mouse STIM1 genes. Further, we demonstrated that LPS induced time-dependent binding of the transcription factors NF-kappaB (p65/RelA) and AP1 (c-Fos/c-Jun) to the STIM1 promoter. Interestingly, silencing of c-Fos, but not c-Jun, markedly reduced LPS-induced STIM1 expression in ECs. We also observed that silencing of p38alpha prevented c-Fos expression in response to LPS in ECs, suggesting that p38alpha signaling mediates the expression of c Fos. These results support the proposal that cooperative signaling of both NF kappaB and AP1 (via p38alpha) amplifies STIM1 expression in ECs and, thereby, contributes to the lung vascular hyperpermeability response during sepsis. PMID- 25016018 TI - Differential regulation of endosomal GPCR/beta-arrestin complexes and trafficking by MAPK. AB - beta-Arrestins are signaling adaptors that bind to agonist-occupied G protein coupled receptors (GPCRs) and target them for endocytosis; however, the mechanisms regulating receptor/beta-arrestin complexes and trafficking in endosomes, remain ill defined. Here we show, in live cells, differential dynamic regulation of endosomal bradykinin B2 receptor (B2R) complexes with either beta arrestin-1 or -2. We find a novel role for MAPK in the B2R/beta-arrestin-2 complex formation, receptor trafficking and signaling mediated by an ERK1/2 regulatory motif in the hinge domain of the rat beta-arrestin-2 (PET(178)P), but not rat beta-arrestin-1 (PER(177)P). While the ERK1/2 regulatory motif is conserved between rat and mouse beta-arrestin-2, it is surprisingly not conserved in human beta-arrestin-2 (PEK(178)P). However, mutation of lysine 178 to threonine is sufficient to confer MAPK sensitivity to the human beta-arrestin-2. Furthermore, substitution for a phosphomimetic residue in both the rat and the human beta-arrestin-2 (T/K178D) significantly stabilizes B2R/beta-arrestin complexes in endosomes, delays receptor recycling to the plasma membrane and maintains intracellular MAPK signaling. Similarly, the endosomal trafficking of beta2-adrenergic, angiotensin II type 1 and vasopressin V2 receptors was altered by the beta-arrestin-2 T178D mutant. Our findings unveil a novel subtype specific mode of MAPK-dependent regulation of beta-arrestins in intracellular trafficking and signaling of GPCRs, and suggest differential endosomal receptor/beta-arrestin 2 signaling roles among species. PMID- 25016019 TI - Paradoxical role of DNA methylation in activation of FoxA2 gene expression during endoderm development. AB - The transcription factor FoxA2 is a master regulator of endoderm development and pancreatic beta cell gene expression. To elucidate the mechanisms underlying the activation of the FoxA2 gene during differentiation, we have compared the epigenetic status of undifferentiated human embryonic stem cells (hESCs), hESC derived early endoderm stage cells (CXCR4+ cells), and pancreatic islet cells. Unexpectedly, a CpG island in the promoter region of the FoxA2 gene displayed paradoxically high levels of DNA methylation in expressing tissues (CXCR4+, islets) and low levels in nonexpressing tissues. This CpG island region was found to repress reporter gene expression and bind the Polycomb group protein SUZ12 and the DNA methyltransferase (DNMT)3b preferentially in undifferentiated hESCs as compared with CXCR4+ or islets cells. Consistent with this, activation of FoxA2 gene expression, but not CXCR4 or SOX17, was strongly inhibited by 5-aza-2' deoxycytidine and by knockdown of DNMT3b. We hypothesize that in nonexpressing tissues, the lack of DNA methylation allows the binding of DNA methyltransferases and repressing proteins, such as Polycomb group proteins; upon differentiation, DNMT activation leads to CpG island methylation, causing loss of repressor protein binding. These results suggest a novel and unexpected role for DNA methylation in the activation of FoxA2 gene expression during differentiation. PMID- 25016020 TI - Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice. AB - PALB2 links BRCA1 and BRCA2 in homologous recombinational repair of DNA double strand breaks (DSBs). Mono-allelic mutations in PALB2 increase the risk of breast, pancreatic, and other cancers, and biallelic mutations cause Fanconi anemia (FA). Like Brca1 and Brca2, systemic knock-out of Palb2 in mice results in embryonic lethality. In this study, we generated a hypomorphic Palb2 allele expressing a mutant PALB2 protein unable to bind BRCA1. Consistent with an FA like phenotype, cells from the mutant mice showed hypersensitivity and chromosomal breakage when treated with mitomycin C, a DNA interstrand crosslinker. Moreover, mutant males showed reduced fertility due to impaired meiosis and increased apoptosis in germ cells. Interestingly, mutant meiocytes showed a significant defect in sex chromosome synapsis, which likely contributed to the germ cell loss and fertility defect. Our results underscore the in vivo importance of the PALB2-BRCA1 complex formation in DSB repair and male meiosis. PMID- 25016021 TI - AAA peroxins and their recruiter Pex26p modulate the interactions of peroxins involved in peroxisomal protein import. AB - Pex1p and Pex6p are required for the relocation of the import receptor Pex5p from the peroxisomal membrane to the cytosol. We herein show that mammalian Pex26p directly binds to Pex14p, the initial docking receptor of Pex5p, and interacts with Pex5p via Pex14p. The binding affinity of Pex26p to Pex14p is altered by Pex5p. Further evidence suggests that the N-terminal region in Pex26p acts as a scaffold protein to recruit Pex14p.Pex5p complex together with Pex1p.Pex6p complexes on peroxisomes. Pex26p binding to Pex14p was suppressed by overexpression of Pex1p and Pex6p in an ATP-dependent manner, whereas Pex14p was not competed out by Pex1p and Pex6p from Pex26p mutant defective in peroxisomal matrix protein import. These results suggested that peroxisome biogenesis requires Pex1p- and Pex6p-regulated dissociation of Pex14p from Pex26p. Pex1p homo-oligomer directly binds to Pex5p as assessed by a surface plasmon resonance based assay. Moreover, cytosolic Pex1p is likely to maintain the functional oligomer of Pex5p. Taken together, in the peroxisomal protein import, AAA peroxins modulate the interaction between Pex26p and Pex14p on peroxisome membrane as well as Pex5p oligomer in the cytosol. PMID- 25016022 TI - Prolactin (PRL)-stimulated ubiquitination of ZnT2 mediates a transient increase in zinc secretion followed by ZnT2 degradation in mammary epithelial cells. AB - The zinc transporter ZnT2 imports zinc into secretory vesicles and regulates zinc export from the mammary epithelial cell. Mutations in ZnT2 substantially impair zinc secretion into milk. The lactogenic hormone prolactin (PRL) transcriptionally increases ZnT2 expression through the Jak2/STAT5 signaling pathway, increasing zinc accumulation in secretory vesicles and zinc secretion. Herein, we report that PRL post-translationally stimulated ZnT2 ubiquitination, which altered ZnT2 trafficking and augmented vesicular zinc accumulation and secretion from mammary epithelial cells in a transient manner. Ubiquitination then down-regulated zinc secretion by stimulating degradation of ZnT2. Mutagenesis of two N-terminal lysine residues (K4R and K6R) inhibited ZnT2 ubiquitination, vesicular zinc accumulation and secretion, and protein degradation. These findings establish that PRL post-translationally regulates ZnT2-mediated zinc secretion in a multifactorial manner, first by enhancing zinc accumulation in vesicles to transiently enhance zinc secretion and then by activating ubiquitin-dependent ZnT2 degradation. This provides insight into novel mechanisms through which ZnT2 and zinc transport is tightly regulated in mammary epithelial cells. PMID- 25016023 TI - Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats. AB - Brainstem hypoperfusion is a major excitant of sympathetic activity triggering hypertension, but the exact mechanisms involved remain incompletely understood. A major source of excitatory drive to preganglionic sympathetic neurons originates from the ongoing activity of premotor neurons in the rostral ventrolateral medulla (RVLM sympathetic premotor neurons). The chemosensitivity profile of physiologically characterized RVLM sympathetic premotor neurons during hypoxia and hypercapnia remains unclear. We examined whether physiologically characterized RVLM sympathetic premotor neurons can sense brainstem ischaemia intrinsically. We addressed this issue in a unique in situ arterially perfused preparation before and after a complete blockade of fast excitatory and inhibitory synaptic transmission. During hypercapnic hypoxia, respiratory modulation of RVLM sympathetic premotor neurons was lost, but tonic firing of most RVLM sympathetic premotor neurons was elevated. After blockade of fast excitatory and inhibitory synaptic transmission, RVLM sympathetic premotor neurons continued to fire and exhibited an excitatory firing response to hypoxia but not hypercapnia. This study suggests that RVLM sympathetic premotor neurons can sustain high levels of neuronal discharge when oxygen is scarce. The intrinsic ability of RVLM sympathetic premotor neurons to maintain responsivity to brainstem hypoxia is an important mechanism ensuring adequate arterial pressure, essential for maintaining cerebral perfusion in the face of depressed ventilation and/or high cerebral vascular resistance. PMID- 25016024 TI - Respiratory pump contributes to increased physiological reserve for compensation during simulated haemorrhage. AB - Intrathoracic pressure regulation (IPR) represents a therapy for increasing systemic circulation through the creation of negative intrathoracic pressure. We hypothesized that using this 'respiratory pump' effect would slow the diminution of the physiological reserve to compensate during progressive reductions in central blood volume. The compensatory reserve index (CRI) algorithm was used to measure the proportion (from 100 to 0%) of reserve capacity that remained to compensate for central volume loss before the onset of cardiovascular decompensation. Continuous analog recordings of arterial waveforms were extracted from data files of seven healthy volunteers. Subjects had previously participated in experiments designed to induce haemodynamic decompensation (presyncope) by progressive reduction in central blood volume using graded lower-body negative pressure. The lower-body negative pressure protocol was completed while breathing spontaneously through a standard medical face mask without (placebo) and with a resistance (approximately -7 cmH2O; active IPR) applied during inspiration. At the onset of presyncope in the placebo conditions, CRI was smaller than the CRI observed at the same time point in the active IPR conditions. The CRI at the onset of presyncope during active IPR (0.08 +/- 0.01) was similar to the CRI at presyncope with placebo. Kaplan-Meier and log rank tests indicated that CRI survival curves were shifted to the right by active IPR. Optimizing the respiratory pump contributed a small but significant effect of increasing tolerance to progressive reductions in central blood volume by extending the compensatory reserve. PMID- 25016025 TI - Discharge characteristics of motor units during long-duration contractions. AB - The purpose of the study was to determine how long humans could sustain the discharge of single motor units during a voluntary contraction. The discharge of motor units in first dorsal interosseus of subjects (27.8 +/- 8.1 years old) was recorded for as long as possible. The task was terminated when the isolated motor unit stopped discharging action potentials, despite the ability of the individual to sustain the abduction force. Twenty-three single motor units were recorded. Task duration was 21.4 +/- 17.8 min. When analysed across discharge duration, mean discharge rate (10.6 +/- 1.8 pulses s(-1)) and mean abduction force (5.5 +/- 2.8% maximum) did not change significantly (discharge rate, P = 0.119; and abduction force, P = 0.235). In contrast, the coefficient of variation for interspike interval during the initial 30 s of the task was 22.2 +/- 6.0% and increased to 31.9 +/- 7.0% during the final 30 s (P < 0.001). All motor units were recruited again after 60 s of rest. Although subjects were able to sustain a relatively constant discharge rate, the cessation of discharge was preceded by a gradual increase in discharge variability. The findings also showed that the maximal duration of human motor unit discharge exceeds that previously reported for the discharge elicited in motor neurons by intracellular current injection in vitro. PMID- 25016026 TI - Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment. AB - We report a new inflammatory activity for extracellular d-dopachrome tautomerase (D-DT), the recruitment of neutrophils to the lung on D-DT intratracheal installation of C57BL/6J mice with an EC50 of 5.6 MUg. We also find that D-DT and macrophage migration inhibitory factor (MIF) have additive effects in neutrophil recruitment. Although the tautomerase site of D-DT and its homologue MIF are biophysically very different, 4-iodo-6-phenylpyrimidine (4-IPP) forms a covalent bond with Pro-1 of both proteins, resulting in a 6-phenylpyrimidine (6-PP) adduct. Recruitment of neutrophils to the lung for the 6-PP adducts of D-DT and MIF are reduced by ~ 50% relative to the apo proteins, demonstrating that an unmodified Pro-1 is important for this activity, but there is no cooperativity in inhibition of the proteins together. The differences in the binding mode of the 6 PP adduct for D-DT was determined by crystallographic studies at 1.13 A resolution and compared to the structure of the MIF-6-PP complex. There are major differences in the location of the 6-PP adduct to the D-DT and MIF active sites that provide insight into the lack of cooperativity by 4-IPP and into tuning the properties of the covalent inhibitors of D-DT and MIF that are necessary for the development of therapeutic small molecules against neutrophil damage from lung infections such as Pseudomonas aeruginosa in cystic fibrosis and immunocompromised patients. PMID- 25016028 TI - The Q loops of the human multidrug resistance transporter ABCB1 are necessary to couple drug binding to the ATP catalytic cycle. AB - For a primary active pump, such as the human ATP-binding-cassette (ABC) transporter ABCB1, coupling of drug-binding by the two transmembrane domains (TMDs) to the ATP catalytic cycle of the two nucleotide-binding domains (NBDs) is fundamental to the transport mechanism, but is poorly understood at the biochemical level. Structure data suggest that signals are transduced through intracellular loops of the TMDs that slot into grooves on the NBDs. At the base of these grooves is the Q loop. We therefore mutated the eponymous glutamine in one or both NBD Q loops and measured the effect on conformation and function by using a conformation-sensitive antibody (UIC2) and a fluorescent drug (Bodipy verapamil), respectively. We showed that the double mutant is trapped in the inward-open state, which binds the drug, but cannot couple to the ATPase cycle. Our data also describe marked redundancy within the transport mechanism, because single-Q-loop mutants are functional for Bodipy-verapamil transport. This result allowed us to elucidate transduction pathways from twin drug-binding cavities to the Q loops using point mutations to favor one cavity over the other. Together, the data show that the Q loop is the central flexion point where the aspect of the drug-binding cavities is coupled to the ATP catalytic cycle. PMID- 25016027 TI - Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways. AB - Angiogenesis is a hallmark of many diseases, including cancer, ischemic heart disease, inflammation, and others. It is well known that vascular endothelial growth factor (VEGF) is the most important angiogenic factor. Recently, we demonstrated that orphan nuclear receptor TR3 (mouse Nur77 and rat NGFI-B) plays critical roles in tumor growth and angiogenesis induced by VEGF-A in vitro and in vivo. However, the signaling pathways that mediate the expression of TR3 induced by VEGF are still not completely understood. Here we reported that 3 TR3 transcript variants (TR3-TVs) are expressed at differential levels, and regulated differentially in endothelial cells. While the expression of TR3-TV1 is relatively low, the expression of TR3-TV2 is up-regulated markedly, and the expression of TR3-TV3 is up-regulated moderately in endothelial cells induced by VEGF-A. The kinetics of the induction of these TR3-TVs is different. We also found that several signaling pathways, including calcium-PLC-PKC-PKD1 pathway, NF kappaB pathway, and MAP kinase (ERK, p38, and JNK) pathways are important for VEGF-A-induced TR3-TV2 and TR3-TV3 mRNA induction. More important, we found that VEGF-A or VEGF-E, but not VEGF-B, nor placenta growth factor (PlGF), induces the phosphorylation of insulin-like growth factor-1 receptor (IGF-1R) and the interaction of VEGF receptor 2/kinase insert domain receptor (VEGFR2/KDR) with IGF-1R, which mediates the expression of TR3-TV2, but not TR3-TV3. Taking together, we demonstrate that TR3-TVs are differentially regulated by VEGF-A and identify a novel signaling pathway by which VEGF-A and VEGF-E, but neither VEGF B, nor PlGF, induce the interaction of VEGFR2/KDR with IGF-1R, resulting in IGF 1R transactivation to induce the high level expression of TR3-TV2. Our data not only elucidate the signaling pathways by which TR3-TVs are regulated, but extend the molecular mechanism, by which VEGF-A-induced angiogenesis. These studies should permit the development of screening assays for compounds that inhibit VEGF signaling. PMID- 25016029 TI - The human skeletal muscle transcriptome: sex differences, alternative splicing, and tissue homogeneity assessed with RNA sequencing. AB - Human skeletal muscle health is important for quality of life and several chronic diseases, including type II diabetes, heart disease, and cancer. Skeletal muscle is a tissue widely used to study mechanisms behind different diseases and adaptive effects of controlled interventions. For such mechanistic studies, knowledge about the gene expression profiles in different states is essential. Since the baseline transcriptome has not been analyzed systematically, the purpose of this study was to provide a deep reference profile of female and male skeletal muscle. RNA sequencing data were analyzed from a large set of 45 resting human muscle biopsies. We provide extensive information on the skeletal muscle transcriptome, including 5 previously unannotated protein-coding transcripts. Global transcriptional tissue homogeneity was strikingly high, within both a specific muscle and the contralateral leg. We identified >23,000 known isoforms and found >5000 isoforms that differ between the sexes. The female and male transcriptome was enriched for genes associated with oxidative metabolism and protein catabolic processes, respectively. The data demonstrate remarkably high tissue homogeneity and provide a deep and extensive baseline reference for the human skeletal muscle transcriptome, with regard to alternative splicing, novel transcripts, and sex differences in functional ontology.transcriptome: sex differences, alternative splicing, and tissue homogeneity assessed with RNA sequencing. PMID- 25016034 TI - A review of the nonclinical safety of Transcutol(r), a highly purified form of diethylene glycol monoethyl ether (DEGEE) used as a pharmaceutical excipient. AB - Transcutol(r) (Diethylene glycol monoethyl ether, DEGEE), CAS # 111-90-0, is commonly used as a vehicle in the formulation or manufacturing process of pharmaceuticals, cosmetics, and food additives. This paper presents unpublished nonclinical safety data using a form of DEGEE which includes a significantly decreased level of impurities, specifically ethylene glycol and diethylene glycol. It also reviews the history of use, regulatory status, and previously published toxicity data for DEGEE. The review supports that DEGEE is well tolerated across animal species and gender with toxicity occurring only at levels well above those intended for human use. At high levels of exposure, the kidney is identified as the critical target organ of DEGEE toxicity. DEGEE is negative for genotoxicity in in vitro and in vivo studies. Subchronic and chronic toxicity studies produced no reports of preneoplastic changes in organs, but the animal data is insufficient to allow a definitive opinion as to carcinogenicity. In silico data suggested that DEGEE is not carcinogenic or genotoxic. Developmental toxicity was seen in rats but only at levels 200 times greater than the estimated oral Permissible Daily Exposure Level of 10 mg/kg/day. The nonclinical data along with the long history of DEGEE use as a vehicle and solvent by multiple routes provide evidence of its safety. Furthermore, the novel data discussed herein provides evidence that toxicity previously associated with high levels of DEGEE in nonclinical studies conducted prior to 1990 could possibly be attributed to the presence of significant amounts of ethylene glycol or other impurities. PMID- 25016030 TI - Deficiency in adipocyte chemokine receptor CXCR4 exacerbates obesity and compromises thermoregulatory responses of brown adipose tissue in a mouse model of diet-induced obesity. AB - The chemokine receptor CXCR4 is expressed on adipocytes and macrophages in adipose tissue, but its role in this tissue remains unknown. We evaluated whether deficiency in either adipocyte or myeloid leukocyte CXCR4 affects body weight (BW) and adiposity in a mouse model of high-fat-diet (HFD)-induced obesity. We found that ablation of adipocyte, but not myeloid leukocyte, CXCR4 exacerbated obesity. The HFD-fed adipocyte-specific CXCR4-knockout (AdCXCR4ko) mice, compared to wild-type C57BL/6 control mice, had increased BW (average: 52.0 g vs. 35.5 g), adiposity (average: 49.3 vs. 21.0% of total BW), and inflammatory leukocyte content in white adipose tissue (WAT), despite comparable food intake. As previously reported, HFD feeding increased uncoupling protein 1 (UCP1) expression (fold increase: 3.5) in brown adipose tissue (BAT) of the C57BL/6 control mice. However, no HFD-induced increase in UCP1 expression was observed in the AdCXCR4ko mice, which were cold sensitive. Thus, our study suggests that adipocyte CXCR4 limits development of obesity by preventing excessive inflammatory cell recruitment into WAT and by supporting thermogenic activity of BAT. Since CXCR4 is conserved between mouse and human, the newfound role of CXCR4 in mouse adipose tissue may parallel the role of this chemokine receptor in human adipose tissue. PMID- 25016035 TI - Replication-associated proteins encoded by Wheat dwarf virus act as RNA silencing suppressors. AB - Wheat dwarf virus (WDV) is an economically important and widespread single stranded DNA virus in the genus Mastrevirus, family Geminiviridae. So far, an RNA silencing suppressor in the genus Mastrevirus has not been reported. In this study, the viral replication-associated proteins of WDV, Rep and RepA proteins, were demonstrated to have RNA silencing suppressor activities when expressed in agro-infiltrated leaves of Nicotiana benthamiana line 16c, by their ability to inhibit posttranscriptional gene silencing (PTGS) of green fluorescent protein (GFP). On the basis of the analysis of GFP expression and siRNA accumulation, we concluded that both Rep and RepA proteins suppressed local silencing induced by either single-stranded GFP (ssGFP) or inverted repeat GFP (dsGFP) constructs, although their activity can be characterized as relatively weak in comparison to HC-Pro of tobacco etch virus. PMID- 25016036 TI - Rotaviruses. AB - Recent advances of rotavirus (RV) basic and applied research are reviewed. They consist of determination of the RV particle structure and functions of structural proteins, classification into genotypes based on whole genome analyses, description of the RV genome and gene protein assignments, description of the viral replication cycle and of functions of RV-encoded non-structural proteins as well as cellular proteins and cellular organelles involved, the present status of RV genetics and reverse genetics, molecular determinants of pathogenesis and pathophysiology, the RV-specific humoral and cell-mediated immune responses, innate immune responses and correlates of protection, laboratory diagnosis, differential diagnosis and present status of treatment, the molecular epidemiology and mechanisms of evolution of RVs, the development and universal application of RV vaccines as well as issues arising from present universal RV vaccination programs and work on alternative vaccines. The review concludes by presenting problems requiring further exploration and perspectives of future basic and translational research. PMID- 25016037 TI - Role of the nucleocapsid region in HIV-1 Gag assembly as investigated by quantitative fluorescence-based microscopy. AB - The Gag precursor of HIV-1, formed of the four proteic regions matrix (MA), capsid (CA), nucleocapsid (NC) and p6, orchestrates virus morphogenesis. This complex process relies on three major interactions, NC-RNA acting as a scaffold, CA-CA and MA-membrane that targets assembly to the plasma membrane (PM). The characterization of the molecular mechanism of retroviral assembly has extensively benefited from biochemical studies and more recently an important step forward was achieved with the use of fluorescence-based techniques and fluorescently labeled viral proteins. In this review, we summarize the findings obtained with such techniques, notably quantitative-based approaches, which highlight the role of the NC region in Gag assembly. PMID- 25016038 TI - Bacillus cereus panophthalmitis associated with injection drug use. AB - We report a case of rapidly progressive vision loss in a young woman with a history of injection drug use. Subsequent enucleation of the affected eye was done and Bacillus cereus grew on tissue culture. B. cereus is a rare cause of endogenous endophthalmitis due to hematogenous seeding of the vitreous in the setting of injection drug use. PMID- 25016040 TI - Petechial rash of the hands and soles of the feet. PMID- 25016039 TI - Heterogeneity of cag genotypes of Helicobacter pylori in the esophageal mucosa of dyspeptic patients and its relation to histopathological outcomes. AB - BACKGROUND: A high prevalence of Helicobacter pylori in the esophageal mucosa of dyspeptic Venezuelan patients has been reported. We aimed to assess the genetic composition of the cag genotypes of H. pylori and its relation to histopathological outcomes in the gastroesophageal mucosa. METHODS: The presence of cagA, cagE, and virB11 cag pathogenicity island (PAI) genes was detected by PCR in 80 of 150 H. pylori-positive dyspeptic patients in both mucosae. Alterations of the gastroesophageal mucosa were assessed by histological techniques. RESULTS: The frequency of intact, partial, and deleted cag-PAI genes in the stomach of dyspeptic patients was found to be 57.5%, 21.3%, and 21.3%, respectively, whereas in the esophagus, frequencies were 33.8%, 33.8%, and 32.5% respectively. The genetic composition in the stomach was 57.5% cagA-positive, 20.0% cagA-negative, 75.0% cagE, and 77.5% virB11, whereas in the esophagus the distribution was 36.3% cagA-positive, 30.0% cagA-negative, 61.3% cagE, and 63.8% virB11. The gene with the largest difference between the two mucosae was cagA, with 58.8% in the stomach and 37.5% in the esophagus; cagE and virB11 were less variable. The correlation among single and/or mixed cag genotypes with histopathological outcomes in both mucosae from the same patient was higher for intact single cag-PAI genotypes, showing severe alterations. CONCLUSIONS: H. pylori may coexist in similar proportions without dominance of one cag genotype, suggesting a heterogeneous distribution in the esophagus. The cagE and virB11 genes can be used as markers of cag-PAI in the esophagus. The single cag-PAI genotype in both mucosae confers an increased risk of developing histological damage. PMID- 25016041 TI - Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. AB - An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable in unravelling the molecular mechanisms underlying the disorder. Multiple defects in this inhibitory system have been identified in Fmr1 knockout mice, including altered expression of various components, aberrant GABAA receptor-mediated signalling, altered GABA concentrations and anatomical defects in GABAergic neurons. Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated. PMID- 25016042 TI - Examining the timing of changes in cigarette smoking upon learning of pregnancy. AB - OBJECTIVE AND METHOD: Timeline Follow-back interviews were conducted with 107 pregnant women enrolling in smoking cessation and relapse prevention clinical trials in the Burlington, VT area between 2006 and 2009 to examine the time course of changes in smoking between learning of pregnancy and the first prenatal care visit. We know of no systematic studies of this topic. RESULTS: Women reported learning of pregnancy at 5.1+/-2.2 weeks gestation and attending a first prenatal care visit at 10.1+/-3.6 weeks gestation. In the intervening five weeks, 22% of women became abstainers, 62% reduced their smoking, and 16% maintained or increased their smoking. Women who made changes typically reported doing so within the first 2 days after learning of pregnancy, with few changes occurring beyond the first week after learning of pregnancy. CONCLUSION: In this first effort to systematically characterize the time course of changes in smoking upon learning of pregnancy, the majority of pregnant smokers who quit or made reductions reported doing so soon after receiving the news. Further research is needed to assess the reliability of these results and to examine whether devising strategies to provide early interventions for women who continue smoking after learning of pregnancy is warranted. PMID- 25016043 TI - Association between self-reported physical activity and indicators of body composition in Malaysian adolescents. AB - BACKGROUND: Obesity and lack of physical activity are fast becoming a concern among Malaysian adolescents. OBJECTIVE: This study aims to assess physical activity levels among Malaysian adolescents and investigate the association between physical activity levels and body composition such as body mass index (BMI), waist circumference (WC) and percentage of body fat. SUBJECTS AND METHODS: 1361 school-going 13 year old multi-ethnic adolescents from population representative samples in Malaysia were involved in our study. Self-reported physical activity levels were assessed using the validated Malay version of the Physical Activity Questionnaire for Older Children (PAQ-C). Height, weight, body fat composition and waist circumference (WC) were measured. Data collection period was from March to May 2012. RESULTS: 10.8% of the males and 7.4% of the females were obese according to the International Obesity Task Force standards. A majority of the adolescents (63.9%) were physically inactive. There is a weak but significant correlation between physical activity scores and the indicators of obesity. The adjusted coefficient for body fatness was relatively more closely correlated to physical activity scores followed by waist circumference and lastly BMI. CONCLUSION: This study demonstrates that high physical activity scores were associated with the decreased precursor risk factors of obesity. PMID- 25016044 TI - Stochastic population switch may explain the latent reservoir stability and intermittent viral blips in HIV patients on suppressive therapy. AB - Highly active antiretroviral therapy can suppress plasma viral loads of HIV-1 infected individuals to below the detection limit of standard clinical assays. However, low-level viremia still persists. Many patients also have transient viral load measurements above the detection limit (the so-called "viral blips"). The latent reservoir consisting of latently infected CD4+ T cells represents a major obstacle to HIV-1 eradication. These cells can be activated to produce virions but the size of the latent reservoir is relatively stable. The mechanisms underlying low viral load persistence, emergence of intermittent viral blips and stability of the latent reservoir are not well understood. Cellular and viral transcription factors play an important role in the establishment and maintenance of HIV-1 latency. Infected cells with intermediate transcriptional activities may either revert to a latent state or become highly activated and produce virions due to intracellular perturbations. Here we develop a mathematical model that includes such stochastic population switch. We demonstrate that the model can generate a stable latent reservoir, intermittent viral blips, as well as low level viremia persistence. Latently infected cells with intermediate transcription activities may maintain their size through a high level of homeostatic proliferation, while cells with low transcriptional activities are likely to be maintained through the reversion from cells with intermediate transcription activities. Simulations also suggest that treatment intensification or activation therapy may not help to eradicate the latent reservoir. Blocking the proliferation of latently infected cells might be a good strategy. These results provide more insights into the long-term dynamics of virus and latently infected cells in HIV patients on suppressive therapy and may help to develop novel treatment strategies. PMID- 25016045 TI - Core and specific network markers of carcinogenesis from multiple cancer samples. AB - Cancer is the leading cause of death worldwide and is generally caused by mutations in multiple proteins or the dysregulation of pathways. Understanding the causes and the underlying carcinogenic mechanisms can help fight this disease. In this study, a systems biology approach was used to construct the protein-protein interaction (PPI) networks of four cancers and the non-cancers by their corresponding microarray data, PPI modeling and database-mining. By comparing PPI networks between cancer and non-cancer samples to find significant proteins with large PPI changes during carcinogenesis process, core and specific network markers were identified by the intersection and difference of significant proteins, respectively, with carcinogenesis relevance values (CRVs) for each cancer. A total of 28 significant proteins were identified as core network markers in the carcinogenesis of four types of cancer, two of which are novel cancer-related proteins (e.g., UBC and PSMA3). Moreover, seven crucial common pathways were found among these cancers based on their core network markers, and some specific pathways were particularly prominent based on the specific network markers of different cancers (e.g., the RIG-I-like receptor pathway in bladder cancer, the proteasome pathway and TCR pathway in liver cancer, and the HR pathway in lung cancer). Additional validation of these network markers using the literature and new tested datasets could strengthen our findings and confirm the proposed method. From these core and specific network markers, we could not only gain an insight into crucial common and specific pathways in the carcinogenesis, but also obtain a high promising PPI target for cancer therapy. PMID- 25016046 TI - Evolutionary dynamics of infectious diseases in finite populations. AB - In infectious disease epidemiology the basic reproductive ratio, R0, is defined as the average number of new infections caused by a single infected individual in a fully susceptible population. Many models describing competition for hosts between non-interacting pathogen strains in an infinite population lead to the conclusion that selection favors invasion of new strains if and only if they have higher R0 values than the resident. Here we demonstrate that this picture fails in finite populations. Using a simple stochastic SIS model, we show that in general there is no analogous optimization principle. We find that successive invasions may in some cases lead to strains that infect a smaller fraction of the host population, and that mutually invasible pathogen strains exist. In the limit of weak selection we demonstrate that an optimization principle does exist, although it differs from R0 maximization. For strains with very large R0, we derive an expression for this local fitness function and use it to establish a lower bound for the error caused by neglecting stochastic effects. Furthermore, we apply this weak selection limit to investigate the selection dynamics in the presence of a trade-off between the virulence and the transmission rate of a pathogen. PMID- 25016047 TI - Environmental evolutionary graph theory. AB - Understanding the influence of an environment on the evolution of its resident population is a major challenge in evolutionary biology. Great progress has been made in homogeneous population structures while heterogeneous structures have received relatively less attention. Here we present a structured population model where different individuals are best suited to different regions of their environment. The underlying structure is a graph: individuals occupy vertices, which are connected by edges. If an individual is suited for their vertex, they receive an increase in fecundity. This framework allows attention to be restricted to the spatial arrangement of suitable habitat. We prove some basic properties of this model and find some counter-intuitive results. Notably, (1) the arrangement of suitable sites is as important as their proportion, and (2) decreasing the proportion of suitable sites may result in a decrease in the fixation time of an allele. PMID- 25016048 TI - Novel galanin receptors in teleost fish: identification, expression and regulation by sex steroids. AB - In fish, the onset of puberty, the transition from juvenile to sexually reproductive adult animals, is triggered by the activation of pituitary gonadotropin secretion and its timing is influenced by external and internal factors that include the growth/adiposity status of the animal. Kisspeptins have been implicated in the activation of puberty but peripheral signals coming from the immature gonad or associated to the metabolic/nutritional status are also thought to be involved. Therefore we hypothesize the importance of the galinergic system in the brain and testis of pre-pubertal male sea bass as a candidate to translate the signals leading to activation of testicular maturation. Here, the transcripts for four galanin receptors (GALR), named GALR1a, 1b, 2a and 2b, were isolated from European sea bass, Dicentrarchus labrax. Phylogenetic analysis confirmed the previously reported duplication of GALR1 in teleost fish, and unravelled the duplication of GALR2 in teleost fish and in some tetrapod species. Comparison with human showed that the key amino acids involved in ligand binding are present in the corresponding GALR1 and GALR2 orthologs. Transcripts for all four receptors are expressed in brain and testes of adult fish with GALR1a and GALR1b abundant in testes and hardly detected in ovaries. In order to investigate whether GALR1 dimorphic expression was dependent on steroid context we evaluated the effect of 11-ketotestosterone and 17beta-estradiol treatments on the receptor expression in brain and testes of pre-pubertal males. Interestingly, steroid treatments had no effect on the expression of GALRs in the brain while in the testes, GALR1a and GALR1b were significantly up regulated by 11KT. Altogether, these results support a role for the galaninergic system, in particular the GALR1 paralog, in fish reproductive function. PMID- 25016049 TI - Reprint of "The distribution and physiological effects of three evolutionarily and sequence-related neuropeptides in Rhodnius prolixus: Adipokinetic hormone, corazonin and adipokinetic hormone/corazonin-related peptide". AB - We have examined the distribution and physiological effects of three evolutionarily and sequence-related neuropeptides in Rhodnius prolixus. These neuropeptides, adipokinetic hormone (RhoprAKH), corazonin (CRZ) and adipokinetic hormone/corazonin-related peptide (RhoprACP) are present in distinct, non overlapping neuronal subsets in the central nervous system (CNS), as determined by immunohistochemistry. Corazonin-like immunoreactive cell bodies are present in the brain and ventral nerve cord, whereas ACP-like immunoreactive cell bodies are only present in the brain, and AKH-like immunoreactive cell bodies only present in the corpus cardiacum (CC). The immunoreactivity to ACP, CRZ and AKH in R. prolixus suggests that ACP and CRZ are released within the CNS, and that CRZ and AKH are released as neurohormones from the CC. Injection of RhoprAKH into adult males elevated haemolymph lipid levels, but injection of CRZ or RhoprACP failed to have any effect on haemolymph lipid levels. Corazonin stimulated an increase in heart-beat frequency in vitro, but RhoprAKH and RhoprACP failed to do so. Thus, although all three neuropeptides share sequence similarity, the AKH and CRZ receptors only respond to their own ligand. PMID- 25016050 TI - Hormone-sensitive lipase in yellow catfish Pelteobagrus fulvidraco: molecular characterization, mRNA tissue expression and transcriptional regulation by leptin in vivo and in vitro. AB - Hormone-sensitive lipase (hsl) plays a pivotal role in regulation of lipolysis in mammals, but information is very scarce about its gene structure and function in fish. In this study, two distinct hsl cDNAs, designated hsl1 and hsl2, were firstly isolated and characterized from yellow catfish Pelteobagrus fulvidraco. The validated cDNAs encoding for hsl1 and hsl2 were 2739 and 2629bp in length, encoding peptides of 679 and 813 amino acid residues, respectively, and shared 57.7% amino acid identity. The phylogenetic analysis revealed that hsl1 and hsl2 derived from paralogous genes that might have arisen during a teleost-specific genome duplication event. Both hsl mRNAs were expressed in a wide range of tissues, but the abundance of each hsl mRNA showed the tissue- and developmental stage-dependent expression patterns. Intraperitoneal injection in vivo and incubation in vitro of recombinant human leptin (rb-hLEP) stimulated the mRNA expression of hsl2, but not hsl1, in the liver and hepatocytes of P. fulvidraco, respectively, suggesting that two hsl isoforms might serve different roles in lipid metabolism. To our knowledge, for the first time, the present study provides evidence that two hsl mRNAs are differentially expressed with and among tissues during different developmental stages and also differentially regulated by leptin both in vivo and in vitro, which serves to increase our understanding on hsl physiological function in fish. PMID- 25016051 TI - Relationship of p53 accumulation in peripheral tissues of high-fat diet-induced obese rats with decrease in metabolic and oncogenic signaling of insulin. AB - This paper aimed to explore the role of p53 in adipose and some other peripheral tissues of a diet-induced obese model and targeted it using pharmacological approach to ameliorate diet-induced insulin resistance. Five week old male Wistar rats were randomly divided into three groups and fed on low-fat diet (13% control lean group), high-fat diet (41% obese group), or high-fat diet plus a single dose of pifithrin-alpha in the end of experiments (PFT group). Insulin, glucose, and other serum parameters were analyzed by standard colorimetric kits. Protein levels were evaluated by immunoblotting and immunofluorescence methods. After 12weeks, both body weight and insulin resistance were significantly higher in obese rats than in the control ones. P53 and PTEN protein levels were markedly elevated in peripheral tissues in addition to adipose tissues. AKT activation was decreased in the peripheral tissues of obese rats and was in correlation with the increase of p53 and PTEN level. Systemic pifithrin-alpha administration considerably diminished p53 levels and ameliorated AKT phosphorylation in all peripheral tissues including adipose tissues. Interestingly, the systemic inhibition of p53 was in correlation with improving insulin glucose at serum level. The present results clearly showed that p53 activation in peripheral tissues was in correlation with decreased insulin action. These results indicated p53 activation in the peripheral tissues of obese subjects as a protective mechanism against chronic insulin elevation, suggested that p53 could be a new target for the treatment of type 2 diabetes. PMID- 25016052 TI - Galleria mellonella apolipophorin III - an apolipoprotein with anti-Legionella pneumophila activity. AB - The greater wax moth Galleria mellonella has been exploited worldwide as an alternative model host for studying pathogenicity and virulence factors of different pathogens, including Legionella pneumophila, a causative agent of a severe form of pneumonia called Legionnaires' disease. An important role in the insect immune response against invading pathogens is played by apolipophorin III (apoLp-III), a lipid- and pathogen associated molecular pattern-binding protein able to inhibit growth of some Gram-negative bacteria, including Legionella dumoffii. In the present study, anti-L. pneumophila activity of G. mellonella apoLp-III and the effects of the interaction of this protein with L. pneumophila cells are demonstrated. Alterations in the bacteria cell surface occurring upon apoLp-III treatment, revealed by Fourier transform infrared (FTIR) spectroscopy and atomic force microscopy, are also documented. ApoLp-III interactions with purified L. pneumophila LPS, an essential virulence factor of the bacteria, were analysed using electrophoresis and immunoblotting with anti-apoLp-III antibodies. Moreover, FTIR spectroscopy was used to gain detailed information on the type of conformational changes in L. pneumophila LPS and G. mellonella apoLp-III induced by their mutual interactions. The results indicate that apoLp-III binding to components of bacterial cell envelope, including LPS, may be responsible for anti L. pneumophila activity of G. mellonella apoLp-III. PMID- 25016053 TI - Structure-dependent interactions of polyphenols with a biomimetic membrane system. AB - Polyphenols are naturally-occurring compounds, reported to be biologically active, and through their interactions with cell membranes. Although association of the polyphenols with the bilayer has been reported, the detailed mechanism of interaction is not yet well elucidated. We report on spatio-temporal real-time membrane dynamics observed in the presence of polyphenols. Two distinct membrane dynamics, corresponding to the two classes of polyphenols used, were observed. Flavonoids (epi-gallocatechin-3-gallate, gallocatechin, theaflavin and theaflavin 3-gallate) caused lipid membrane aggregation and rigidification. As simple structural modification through opening of the aromatic C-ring into an olefin bond, present in trans-stilbenes (resveratrol and picead), completely changed the membrane properties, increasing fluidity and inducing fluctuation. There were differences in the membrane transformations within the same class of polyphenols. Structure-dependent classification of membrane dynamics may contribute to a better understanding of the physicochemical mechanism involved in the bioactivity of polyphenols. In general, an increase in the number of hydrophilic side chains (galloyl, hydroxyl, glucoside, gallate) increased the reactivity of the polyphenols. Most notable was the difference observed through a simple addition of the gallate group. Unraveling the importance of these polyphenols, at a functional group level further opens the key to tailored design of bioactive compounds as potential drug candidates. PMID- 25016054 TI - Galleria mellonella native and analogue peptides Gm1 and DeltaGm1. II) anti bacterial and anti-endotoxic effects. AB - Antimicrobial peptides (AMPs) are important components of the innate immune system of animals, plants, fungi and bacteria and are recently under discussion as promising alternatives to conventional antibiotics. We have investigated two cecropin-like synthetic peptides, Gm1, which corresponds to the natural overall uncharged Galleria mellonella native peptide and DeltaGm1, a modified overall positively charged Gm1 variant. We have analysed these peptides for their potential to inhibit the endotoxin-induced secretion of tumour necrosis factor alpha (TNF-alpha) from human mononuclear cells. Furthermore, in a conventional microbiological assay, the ability of these peptides to inhibit the growth of the rough mutant bacteria Salmonella enterica Minnesota R60 and the polymyxin B resistant Proteus mirabilis R45 was investigated and atomic force microscopy (AFM) measurements were performed to characterize the morphology of the bacteria treated by the two peptides. We have also studied their cytotoxic properties in a haemolysis assay to clarify potential toxic effects. Our data revealed for both peptides minor anti-inflammatory (anti-endotoxin) activity, but demonstrated antimicrobial activity with differences depending on the endotoxin composition of the respective bacteria. In accordance with the antimicrobial assay, AFM data revealed a stronger morphology change of the R45 bacteria than for the R60. Furthermore, Gm1 had a stronger effect on the bacteria than DeltaGm1, leading to a different morphology regarding indentations and coalescing of bacterial structures. The findings verify the biophysical measurements with the peptides on model systems. Both peptides lack any haemolytic activity up to an amount of 100MUg/ml, making them suitable as new anti-infective agents. PMID- 25016055 TI - Rapid method for assessing rod function using recovery of spatial contrast thresholds following a bleach. AB - Poor vision in low light is a common complaint of elderly people. This poorly understood phenomenon is likely to involve both receptoral and post receptoral mechanisms. We investigated the recovery of contrast thresholds for sine-wave gratings of low spatial frequencies and low mean luminance as a function of time in darkness after photo pigment bleaching. Thirteen subjects aged 30.4 (+/-10.7) years took part in the study. Contrast thresholds were measured for 15 min following almost complete photo pigment bleaching. The stimuli were achromatic sinusoidal gratings of 0.5, 1 and 2 cycle per degree (cpd) generated on a CRT monitor. They had mean luminance 0.01 cd m(-2) and subtended 10 degrees in diameter. The dynamics of the recovery at each spatial frequency were modelled using monophasic and biphasic exponential decay functions. The data were best modelled by a bi-phasic decay with a distinct transition point around 7 min after the bleach. Both phases followed an exponential decay. The time constant (mean, standard error) for the first phase was 0.35 (0.04) min while for the second phase it was 5.15 (0.27) min. This difference was statistically significant (p < 0.001). A control experiment revealed the second, slower phase was mediated by rod photoreceptors. Maximum contrast sensitivity was reached 15 min after a photic bleach. The dynamics of contrast sensitivity recovery follow two phases and these may be attributed to the cone and rod systems. PMID- 25016056 TI - Anticancer activity of HS-527, a novel inhibitor targeting PI3-kinase in human pancreatic cancer cells. AB - Pancreatic cancer is known to have low 5-year survival rate and poor response to treatment. In this study, we synthesized HS-527, a new PI3-kinase inhibitor, and investigated not only its anticancer activity, but also its mechanism of action in pancreatic cancer cells. HS-527 had higher specificity for PI3K than other kinases and inhibited PI3K/Akt signaling pathway by down-regulating Akt and P70S6K. And HS-527 inhibited the cell growth and proliferation of the pancreatic cancer in a time- and dose-dependent manner, with greater activity than gemcitabine. Even HS-527 showed lower cytotoxicity than gemcitabine in normal cells. When treated with HS-527, the cancer cells appeared apoptotic, increasing the expression of cleaved PARP, cleaved caspase-3, and Bax. Furthermore, HS-527 showed an anti-angiogenic activity by decreasing the expression of HIF-1alpha and VEGF, and inhibited the migration of endothelial cells, and the formation of new blood vessel in mouse Matrigel plug assay. In this study, we found that HS-527 showed anti-cancer activity through an inhibition of the PI3K/Akt pathway in pancreatic cancer cells, suggesting that HS-527 could be used as a promising therapeutic agent for pancreatic cancer. PMID- 25016057 TI - Adipose tissue-derived mesenchymal stem cells cultured at high density express IFN-beta and suppress the growth of MCF-7 human breast cancer cells. AB - Although it has been reported that mesenchymal stem cells (MSCs) suppress tumor growth in vitro and in vivo, little is known about the underlying molecular mechanisms. We found that type I interferon is expressed in adipose tissue derived stem cells (ASCs) cultured at high density, and ASCs and their conditioned medium (ASC-CM) suppress the growth of MCF-7 cells in vitro. Growth inhibition was amplified by glucose deprivation that resulted from high density culture of ASCs after 3days. The cytotoxic effect of the ASC-CM obtained from high density culture of ASCs was neutralized by anti-IFN-beta antibody. STAT1 was phosphorylated in MCF-7 cells treated with ASC-CM, and JAK1/JAK2 inhibitor treatment decreased STAT1 phosphorylation. The cytotoxic effect of ASC-CM was reduced especially by JAK1 inhibitors in MCF-7 cells. Our findings suggest that ASCs cultured at high density express type I interferons, which suppresses tumor growth via STAT1 activation resulting from IFN-beta secretion in MCF-7 breast cancer cells. PMID- 25016058 TI - A CSPG4-specific immunotoxin kills rhabdomyosarcoma cells and binds to primary tumor tissues. AB - The treatment of rhabdomyosarcoma (RMS) remains challenging, with metastatic and alveolar RMS offering a particularly poor prognosis. Therefore, the identification and evaluation of novel antigens, which are suitable targets for immunotherapy, is one attractive possibility to improve the treatment of this disease. Here we show that chondroitin sulfate proteoglycan 4 (CSPG4) is expressed on RMS cell lines and RMS patient material. We evaluated the immunotoxin (IT) alphaMCSP-ETA', which specifically recognizes CSPG4 on the RMS cell lines RD, FL-OH1, TE-671 and Rh30. It is internalized rapidly, induces apoptosis and thus kills RMS cells selectively. We also demonstrate the specific binding of this IT to RMS primary tumor material from three different patients. PMID- 25016059 TI - Development of a prediction model for lymph node metastasis in luminal A subtype breast cancer: the possibility to omit sentinel lymph node biopsy. AB - The present study aimed to construct a prediction model for axillary lymph node metastasis (ALNM) using a DNA microarray assay for gene expression in breast tumor tissues. Luminal A breast cancers, diagnosed by PAM50 testing, were analyzed, and a prediction model (genomic nodal index (GNI)) consisting of 292 probe sets for ALNM was constructed in a training set of patients (n=388), and was validated in the first (n=59) and the second (n=103) validation sets. AUCs of ROC were 0.820, 0.717, and 0.749 in the training, first, and second validation sets, respectively. GNI was most significantly associated with ALNM, independently of the other conventional clinicopathological parameters in all cohorts. It is suggested that GNI can be used to identify the patients with a low risk for ALNM so that sentinel lymph node biopsy can be spared safely. PMID- 25016060 TI - Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression. AB - The heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a nucleic acid-binding protein that serves as a docking platform integrating transduction pathways to nucleic acid -directed processes. Recently, this protein has emerged as an important player in carcinogenesis process. HnRNP K is overexpressed in several human cancers and its aberrant cytoplasmic localization has been associated with a worse prognosis for patients, suggesting that it has a role in cancer progression. Herein, we provide a brief overview of the multifunctional roles of hnRNP K and discuss clinical studies that have demonstrated its involvement in cancer development and progression. PMID- 25016061 TI - Both sunitinib and sorafenib are effective treatments for pheochromocytoma in a xenograft model. AB - Pheochromocytomas and paragangliomas are rare neuroendocrine tumors which develop from chromaffin cells of the adrenal medulla and extra-adrenal sites, leading to excess catecholamine release and hypertension. Many of the tumors are characterized by a high vascularity, suggesting the possible implementation of anti-angiogenic therapies for patients. Here, the efficacy of the tyrosine kinase inhibitors sunitinib and sorafenib was investigated in vivo and in vitro. Oral treatment with either sunitinib or sorafenib (40mg/kg/day) for 14days induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Assessment of tumoral neo-angiogenesis, assessed by morphometric analysis of the vascular network after CD31 immunolabeling, showed that both sunitinib and sorafenib reduced the microvessel area (-85% and -80%, respectively) and length (-80% and -78%, respectively) in treated compared to control tumors. In addition, the number of vessel nodes was significantly lower in treated tumors (-95% and -84%, respectively). Furthermore, cleaved caspase 3 immunolabeling revealed a marked increase in the number of apoptotic cells in tumors from treated animals. Sunitinib and sorafenib could exert a direct effect on PC12 cell viability in vitro. While sunitinib induced a rapid (4h) and pronounced (5-fold) increase in caspase-3/7-dependent apoptosis, sorafenib seems to exert its cytotoxic activity through a different mechanism. Altogether, our data demonstrate that sunitinib and sorafenib have the ability to impair pheochromocytoma development by inhibiting angiogenesis and reducing tumor cell viability. These results strongly suggest that both sunitinib and sorafenib could represent valuable therapeutic tools for pheochromocytoma. PMID- 25016062 TI - Functional characterisation of different MLL fusion proteins by using inducible Sleeping Beauty vectors. AB - Our focus is the identification, characterisation and functional analysis of different MLL fusions. In general, MLL fusion proteins are encoded by large cDNA cassettes that are difficult to transduce into haematopoietic stem cells. This is due to the size limitations of the packaging process of those vector-encoded RNAs into retro- or lentiviral particles. Here, we present our efforts in establishing a universal vector system to analyse different MLL fusions. The universal cloning system was embedded into the backbone of the Sleeping Beauty transposable element. This transposon has no size limitation and displays no integration preference, thereby avoiding the integration into active genes or their promoter regions. We utilised this novel system to test different MLL fusion alleles (MLL NEBL, NEBL-MLL, MLL-LASP1, LASP1-MLL, MLL-MAML2, MAML2-MLL, MLL-SMAP1 and SMAP1 MLL) in appropriate cell lines. Stable cell lines were analysed for their growth behaviour, focus formation and colony formation capacity and ectopic Hoxa gene transcription. Our results show that only 1/4 tested direct MLL fusions, but 3/4 tested reciprocal MLL fusions exhibit oncogenic functions. From these pilot experiments, we conclude that a systematic analysis of more MLL fusions will result in a more differentiated picture about the oncogenic capacity of distinct MLL fusions. PMID- 25016064 TI - Targeted biopharmaceuticals for cancer treatment. AB - Cancer is a complex invasive genetic disease that causes significant mortality rate worldwide. Protein-based biopharmaceuticals have significantly extended the lives of millions of cancer patients. This article reviews the biological function and application of targeted anticancer biopharmaceuticals. We first discuss the specific antigens and core pathways that are used in the development of targeted cancer therapy. The innovative monoclonal antibodies, non-antibody proteins, and small molecules targeting these antigens or pathways are then reviewed. Finally, the current challenges in anticancer biopharmaceuticals development and the potential solutions to address these challenges are discussed. PMID- 25016063 TI - Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy. AB - With prostate cancer (PCa), circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) portend a poor clinical prognosis. Their unknown biology precludes rational therapeutic design. We demonstrate that CTC and DTC cell lines, established from mice bearing human PCa orthotopic implants, exhibit increased cellular invasion in vitro, increased metastasis in mice, and express increased epithelial to mesenchymal transition biomarkers. Further, they are selectively resistant to growth inhibition by mitoxantrone-like agents. These findings demonstrate that CTC formation is accompanied by phenotypic progression without obligate reversion. Their increased metastatic potential, selective therapeutic resistance, and differential expression of potential therapeutic targets provide a rational basis to test further interventions. PMID- 25016065 TI - Development of tailored real-time RT-PCR assays for the detection and differentiation of serotype O, A and Asia-1 foot-and-mouth disease virus lineages circulating in the Middle East. AB - Rapid and accurate diagnosis is essential for effective control of foot-and-mouth disease (FMD). In countries where FMD is endemic, identification of the serotypes of the causative virus strains is important for vaccine selection and tracing the source of outbreaks. In this study, real-time reverse transcription polymerase chain reaction (rRT-PCR) assays using primer/probe sets designed from the VP1 coding region of the virus genomes were developed for the specific detection of serotype O, A and Asia-1 FMD viruses (FMDVs) circulating in the Middle East. These assays were evaluated using representative field samples of serotype O strains belonging exclusively to the PanAsia-2 lineage, serotype A strains of the Iran-05 lineage and serotype Asia-1 viruses from three relevant sub-groups. When RNA extracted from archival and contemporary field strains was tested using one- or two-step rRT-PCR assays, all three primer/probe sets detected the RNA from homotypic viruses and no cross-reactivity was observed with heterotypic viruses. Similar results were obtained using both single- and multiplex assay formats. Using plasmid standards, the minimum detection level of these tests was found to be lower than two copies. The results illustrate the potential of tailored rRT PCR tools for the detection and categorization of viruses circulating in the Middle East belonging to distinct subgroups of serotypes O, A and Asia-1. These assays can also overcome the problem of serotyping samples which are found positive by the generic rRT-PCR diagnostic assays but negative by virus isolation and antigen-detection ELISA which would otherwise have to be serotyped by nucleotide sequencing. A similar approach could be used to develop serotyping assays for FMDV strains circulating in other regions of the world. PMID- 25016066 TI - An evaluation of the Qiagen HPV sign for the detection and genotyping of cervical lesions and oropharyngeal squamous cell carcinomas. AB - HPV genotyping is an important tool in the epidemiology and surveillance of HPV associated cancers and for the risk-stratification of HPV infections. HPV sign Genotyping Test (QIAGEN) is a new pyrosequencing assay for the detection and genotyping of HPV. The sensitivity and comparative performance of HPV sign was determined using a sample panel derived from histologically confirmed cervical lesions (cervical intraepithelial neoplasia 2 or worse) and oropharyngeal squamous cell carcinomas. Comparative analysis showed that 80% of cervical intraepithelial neoplasia 2+ and 81% of oropharyngeal squamous cell carcinomas were HPV-positive by HPV sign compared to 100% of the cervical intraepithelial neoplasia 2+ and 81% of oropharyngeal squamous cell carcinomas by the digene HPV Genotyping RH Test (RH), and INNO-LiPA HPV Genotyping Extra assay, respectively. Fewer genotypes were detected overall by HPV sign than via the relevant comparator assays (10 vs 21 for cervical intraepithelial neoplasia 2+; 4 vs 9 for oropharyngeal squamous cell carcinomas) and also fewer multiple infections (9 vs 28 for cervical intraepithelial neoplasia 2+; 0 vs 4 for oropharyngeal squamous cell carcinomas). HPV sign results were more compatible with the comparator assay for the oropharyngeal squamous cell carcinoma samples (100%) than for the cervical samples (73%). These results suggest that HPV sign in its current form is suited to samples that harbour multiple infection. PMID- 25016067 TI - Directing mouse embryonic neurosphere differentiation toward an enriched neuronal population. AB - Neural stem cells (NSC) are self-renewing multipotent cells that have emerged as a powerful tool to repair the injured brain. These cells can be cultured as neurospheres, which are floating aggregates of neural stem/progenitor cells (NSPCs). Despite their high clonal expansion capacity, it has been suggested that in neurospheres, only a small percentage of cells are capable of proliferation and that this system is not efficient in terms of neurogenic competence. Thus, our aim was to develop a neurosphere culture method with a highly proliferative stem/progenitor cell population and particularly with a prominent neurogenic potential, surpassing some of the claimed weaknesses of the neurosphere assay. In our model, mouse neurospheres were harvested from neural tissue at E15 and after only 4 days in vitro (DIV), we have achieved highly proliferative primary neurospheres (81% Sox2 and 76% Ki67 positive cells) and a rather low number of cells expressing glial and neuronal markers (~10%). After inducing differentiation, we have attained an enriched neuronal population (45% beta-III tubulin positive cells at 15 DIV). Using a simple methodology, we have developed a NSPC model that can provide a valuable source of neuronal precursors, thus offering a potential starting point for cell replacement therapies following CNS injury. PMID- 25016068 TI - EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome. AB - We describe the seizure and EEG characteristics in a population of children with known Fragile X. The medical records of 135 genetically confirmed FXS patients receiving care in a Fragile X clinic and their available EEG reports were reviewed. The mean age was 5.94 years old including 18 males and 1 female. The mean age was 4-9 years old with an age range of 15 months to 13 years old. Twenty two patients (16.3%) in the series had parent-reported behavior suspicious of seizures. Sixteen patients (14.1%, 1 female) had at least one EEG recorded for evaluation of clinical events suspicious for seizure, and three patients (2.2%) had an EEG in the context of a polysomnography for diagnosing sleep apnea. The mean age at EEG evaluation was 6.0 years (standard deviation 3.8 years). EEG findings included slowing of background rhythm (n=9) and epileptiform discharges (n=7). Four patients had normal EEGs (n=4). Six patients (4.4% of the sample population) were diagnosed with epilepsy by both clinical seizure semiology and documented EEG abnormalities. Thirteen patients (68.4% of total) had episodes of staring and behavioral arrest with no EEG correlate, indicating non-epileptic events. Of the eight patients who underwent a repeat EEG, five patients had showed normalization in the posterior dominant rhythm over time, two patients had unchanged findings and one patient had worsening of his EEG. Our data warrant further prospective validation. PMID- 25016069 TI - High-throughput sequence analysis of small RNAs in skotomorphogenic seedlings of Brassica rapa ssp. rapa. AB - Skotomorphogenic development is the process by which seedlings adapt to a stressful dark environment. Such metabolic responses to abiotic stresses in plants are known to be regulated in part by microRNAs (miRNAs); however, little is known about the involvement of miRNAs in the regulation of skotomorphogenesis. To identify miRNAs at the genome-wide level in skotomorphogenic seedlings of turnip (Brassica rapa subsp. rapa), an important worldwide root vegetable, we used Solexa sequencing to sequence a small RNA library from seedlings grown in the dark for 4 days. Deep sequencing showed that the small RNAs (sRNAs) were predominantly 21 to 24 nucleotides long. Specifically, 13,319,035 reads produced 359,531 unique sRNAs including rRNA, tRNA, miRNA, small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and unannotated sRNAs. Sequence analysis identified 96 conserved miRNAs belonging to 36 miRNA families and 576 novel miRNAs. qRT-PCR confirmed that the miRNAs were expressed during skotomorphogenesis similar to the trends shown by the Solexa sequencing results. A total of 2013 potential targets were predicted, and the targets of BrmiR157, BrmiR159 and BrmiR160 were proved to be regulated by miRNA-guided cleavage. These results show that specific regulatory miRNAs are present in skotomorphogenic seedlings of turnip and may play important roles in growth, development, and response to dark environment. PMID- 25016070 TI - Evidence for species-specific clock gene expression patterns in hamster peripheral tissues. AB - Rhythmic oscillations that repeat every 24h can be found in numerous behavioral and physiological functions. Beside the endogenous master clock in the suprachiasmatic nucleus (SCN), peripheral oscillators exist that can disengage from the master clock rhythm by different mechanisms. The fact that core clock genes in peripheral tissues do not always have the same characteristics as in the SCN suggests that their function may vary in different organs. Additionally, suggestions about species-specific variation in expression peak and nadir times, especially in the testis, led to the need for systematical investigations on clock gene expression patterns in different organs and species under standardized methodological conditions. Therefore, daily gene expression patterns of the clock genes Bmal1, Period1, Period2, Clock, Cryptochrome1 and Cryptochrome2 were recorded at each of eight time points during a 24 hour period in the testis, kidney, liver, spleen and heart of three hamster species (Phodopus sungorus, Phodopus roborovskii and Cricetulus griseus; family: Cricetidae). Clock gene expression was found to be rhythmic in all investigated organs, however with inconsistent results in the testis. Complex cosinor analysis revealed species differences in temporal gene expression patterns regarding their orthophase, number of peaks, and amplitude for all genes and organs with most pronounced differences in the testis. The results of this study strongly indicate that clock gene expression in peripheral tissues is species-specific and that their functions might be at least partly connected to clock-unrelated traits that vary between the investigated species. Further studies should aim at clarifying the specific roles of clock genes in the testis. PMID- 25016071 TI - Should we bag tissue morcellation? Looking backward and forward. PMID- 25016072 TI - Disrupted-In-Schizophrenia-1 (DISC1) interactome and mental disorders: impact of mouse models. AB - Disrupted-In-Schizophrenia-1 (DISC1) has captured much attention because it predisposes individuals to a wide range of mental illnesses. Notably, a number of genes encoding proteins interacting with DISC1 are also considered to be relevant risk factors of mental disorders. We reasoned that the understanding of DISC1 associated mental disorders in the context of network principles will help to address fundamental properties of DISC1 as a disease gene. Systematic integration of behavioural phenotypes of genetic mouse lines carrying perturbation in DISC1 interacting proteins would contribute to a better resolution of neurobiological mechanisms of mental disorders associated with the impaired DISC1 interactome and lead to a development of network medicine. This review also makes specific recommendations of how to assess DISC1 associated mental disorders in mouse models and discuss future directions. PMID- 25016073 TI - PEPT1- and OAT1/3-mediated drug-drug interactions between bestatin and cefixime in vivo and in vitro in rats, and in vitro in human. AB - The purpose of the present study was to elucidate the transporter-mediated pharmacokinetics mechanism of drug-drug interactions (DDIs) between bestatin and cefixime. The plasma concentrations and bioavailabilities of bestatin and cefixime were decreased after oral co-administration in rats. The uptake in rat everted intestinal sacs of bestatin and cefixime were dramatically declined after co-administration of the two drugs. Bestatin and cefixime can mutually competitively inhibit the uptake by hPEPT1-HeLa cells. The plasma concentrations of bestatin and cefixime were increased; however, the cumulative biliary excretion had no significant change, and the cumulative urinary excretion and renal clearance of the two drugs in rats decreased after intravenous coadministration. Moreover, decreased uptake of the two drugs was observed in human kidney slices, rat kidney slices and hOAT1/hOAT3-transfected HEK293 cells when bestatin and cefixime were coadministered. The accumulation of bestatin and cefixime in kidney slices can be inhibited by p-aminohippurate, benzylpenicillin and probenecid, but not by tetraethyl ammonium. The results suggest that intestinal absorption and renal excretion of bestatin and cefixime can be inhibited when the two drugs were co-administered in rats. The pharmacokinetic mechanism indicates that the DDIs between bestatin and cefixime are mainly mediated by Pept1 and Oat1/3 in rats. PEPT1 and OAT1/3 are the target transporters of DDIs between bestatin and cefixime in human kidney slices and human transfected cells, proposing possible drug-drug interaction in humans. PMID- 25016074 TI - Epigenetic modifications of Nrf2-mediated glutamate-cysteine ligase: implications for the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression. AB - Diabetes increases oxidative stress in the retina and decreases the levels of the intracellular antioxidant glutathione (GSH). The transcriptional factor Nrf2 regulates the expression of Gclc, the enzyme important in the biosynthesis of GSH, and in diabetes the binding of Nrf2 at the antioxidant response element region 4 (ARE4) is decreased. Our aim was to investigate the role of epigenetic modifications in the decreased Nrf2 binding at Gclc-ARE4 in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression. The effect of hyperglycemia on H3K4 methylation in Nrf2 binding at Gclc-ARE4 was investigated by chromatin immunoprecipitation in the rat retina and was confirmed in retinal endothelial cells in which histone demethylase (LSD1) was manipulated. The role of histone methylation at Gclc-ARE4 in the metabolic memory was examined in rats maintained under poor control for 3 months followed by good control (GC) for 3 months. Although H3K4me2 at Gclc-ARE4 was increased in diabetes, H3K4me3 and H3K4me1 were decreased. LSD1 siRNA abrogated the glucose induced decrease in H3K4me1 at Gclc-ARE4 and ameliorated decreases in Nrf2 binding at Gclc-ARE4 and Gclc transcripts. Reestablishment of GC failed to provide any benefits to histone methylation, and Nrf2 binding activity remained compromised. Thus, in diabetic retinopathy, histone methylation at Gclc-ARE4 plays an important role in regulating the Nrf2-Gclc-GSH cascade. Targeting histone methylation could help inhibit/slow down this blinding disease. PMID- 25016075 TI - Impact of protective agents and drying methods on desiccation tolerance of Salix nigra L. seeds. AB - Willow seeds are classified as orthodox, but they show some recalcitrant characteristics, as they lose viability in a few weeks at room temperature. The aim of this work was to improve the desiccation tolerance of willow seeds (Salix nigra L.), as a model of sensitive materials to dehydration, through imbibition in solutions and later vacuum (VD) or freeze-drying (FD). Imbibition was conducted with 45% w/v trehalose or polyethylene glycol 400 -PEG- or water prior to dehydration treatments. Water- and especially trehalose-imbibed seeds subjected to VD showed better germination capability with respect to the freeze dried ones. Water crystallization was mainly responsible for the great loss of capability germination observed in water- or trehalose-imbibed seeds subjected to FD. PEG behavior was better when seeds were FD instead of VD. DSC thermograms of seeds allowed to identify two thermal transitions corresponding to lipids melting and to proteins denaturation. This last transition reveals information about proteins state/functionality. Dehydration of control and PEG- or water-imbibed seeds affected proteins functionality leading to lower germinability. In the case of trehalose-imbibed seeds subjected to VD, proteins maintained their native state along dehydration, and the seeds showed a great germination capacity for all the water content range. Germinated seeds showed higher luminosity (L*), greenness (a*) and yellowness (b*) values than not-germinated seeds independently of the employed agent. Present work reveals that the presence of adequate protective agents as well the dehydration method were the main critical factors involved in willow seed desiccation tolerance. PMID- 25016076 TI - Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats. AB - Many recent studies demonstrate that most nanoparticles (NPs) have an adverse or toxic action on liver. The aim of this study was to investigate the hepatoprotective effect of glycyrrhizic acid (GA) against hepatic injury induced by titanium dioxide nanoparticles (NTiO2) in rats. Thirty-two Wistar rats were randomly divided into 4 groups. NTiO2-intoxicated rats received 300 mg/kg of NTiO2 for 14 days by gavage method. Protection group pretreated with GA for 7 days before NTiO2 administration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were detected as biomarkers in the blood to indicate hepatic injury. Product of lipid peroxidation (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were evaluated for oxidative stress in hepatic injury. Light microscopy for histopathological studies and TUNEL assay was also done. Administration of NTiO2 induced a significant elevation in plasma AST, ALT and ALP. In the liver, NTiO2 increased oxidative stress through the increase in lipid peroxidation and decrease in SOD and GPx enzymes. Histopathological studies showed that treatment with NTiO2 caused liver damage including centrilobular necrosis, which was accompanied by congestion and accumulation of inflammatory cells. Apoptotic index was also significantly increased in this group. Pretreatment of GA significantly decreased ALT, AST and ALP, attenuated the histopathology of hepatic injury, decreased apoptotic index, ameliorated oxidative stress in hepatic tissue, and increased the activities of SOD and GPx. These findings indicate that GA effectively protects against NTiO2-induced hepatotoxicity. GA has a potent protective effect against the NPs induced hepatotoxicity and might be clinically useful. PMID- 25016077 TI - DNA-binding studies of AV-153, an antimutagenic and DNA repair-stimulating derivative of 1,4-dihydropiridine. AB - The ability to intercalate between DNA strands determines the cytotoxic activity of numerous anticancer drugs. Strikingly, intercalating activity was also reported for some compounds considered to be antimutagenic. The aim of this study was to determine the mode of interaction of DNA with the antimutagenic and DNA repair-stimulating dihydropyridine (DHP) AV-153. DNA and AV-153 interactions were studied by means of UV/VIS spectroscopy, fluorimetry and infrared spectroscopy. Compound AV-153 is a 1,4 dihydropyridine with ethoxycarbonyl groups in positions 3 and 5. Computer modeling of AV-153 and DNA interactions suggested an ability of the compound to dock between DNA strands at a single strand break site in the vicinity of two pyrimidines, which was confirmed in the present study. AV-153 evidently interacted with DNA, as addition of DNA to AV-153 solutions resulted in pronounced hyperchromic and bathochromic effects on the spectra. Base modification in a plasmid by peroxynitrite only minimally changed binding affinity of the compound; however, induction of single-strand breaks using Fenton's reaction greatly increased binding affinity. The affinity did not change when the ionic strength of the solution was changed from 5 to 150 mM NaCl, although it increased somewhat at 300 mM. Neither was it influenced by temperature changes from 25 to 40 degrees C, however, it decreased when the pH of the solution was changed from 7.4 to 4.7. AV-153 competed with EBr for intercalation sites in DNA: 116 mM of the compound caused a two-fold decrease in fluorescence intensity. FT-IR spectral data analyses indicated formation of complexes between DNA and AV-153. The second derivative spectra analyses indicated interaction of AV-153 with guanine, cytosine and thymine bases, but no interaction with adenine was detected. CONCLUSIONS: The antimutagenic substance AV-153 appears to intercalate between the DNA strands at the site of a DNA nick in the vicinity of two pyrimidines. PMID- 25016078 TI - A 1H NMR study of the specificity of alpha-l-arabinofuranosidases on natural and unnatural substrates. AB - BACKGROUND: The detailed characterization of arabinoxylan-active enzymes, such as double-substituted xylan arabinofuranosidase activity, is still a challenging topic. Ad hoc chromogenic substrates are useful tools and can reveal subtle differences in enzymatic behavior. In this study, enzyme selectivity on natural substrates has been compared with enzyme selectivity towards aryl-glycosides. This has proven to be a suitable approach to understand how artificial substrates can be used to characterize arabinoxylan-active alpha-l-arabinofuranosidases (Abfs). METHODS: Real-time NMR using a range of artificial chromogenic, synthetic pseudo-natural and natural substrates was employed to determine the hydrolytic abilities and specificity of different Abfs. RESULTS: The way in which synthetic di-arabinofuranosylated substrates are hydrolyzed by Abfs mirrors the behavior of enzymes on natural arabinoxylo-oligosaccharide (AXOS). Family GH43 Abfs that are strictly specific for mono-substituted d-xylosyl moieties (AXH-m) do not hydrolyze synthetic di-arabinofuranosylated substrates, while those specific for di-substituted moieties (AXH-d) remove a single l-arabinofuranosyl (l-Araf) group. GH51 Abfs, which are supposedly AXH-m enzymes, can release l-Araf from disubstituted d-xylosyl moieties, when these are non-reducing terminal groups. CONCLUSIONS AND GENERAL SIGNIFICANCE: The present study reveals that although the activity of Abfs on artificial substrates can be quite different from that displayed on natural substrates, enzyme specificity is well conserved. This implies that carefully chosen artificial substrates bearing di-arabinofuranosyl d xylosyl moieties are convenient tools to probe selectivity in new Abfs. Moreover, this study has further clarified the relative promiscuity of GH51 Abfs, which can apparently hydrolyze terminal disubstitutions in AXOS, albeit less efficiently than mono-substituted motifs. PMID- 25016079 TI - Iatrogenic rectovaginal fistula repair by trans-perineal approach and pubo coccygeus muscle interposition. AB - INTRODUCTION: Rectovaginal fistula (RVF) is a rare but debilitating complication of a variety of pelvic surgical procedures. PRESENTATION OF CASE: We report the case of a 45-year-old female who underwent the STARR (Stapled Trans Anal Rectal Resection) procedure, that was complicated by a 30mm rectovaginal fistula (RVF). We successfully repaired the fistula by trans-perineal approach and pubo coccygeus muscle interposition. Seven months later we can confirm the complete fistula healing and good patient's quality of life. We carefully describe our technique showing the advantages over alternative suturing, flap reconstruction or resection procedures. DISCUSSION: This technique is fairly easy to perform and conservative. The pubo-coccygeus muscle is quickly recognizable during the dissection of the recto-vaginal space and the tension-free approximation of this muscle by single sutures represents an easy way of replacement of the recto vaginal septum. CONCLUSION: In our experience the use of pubo-coccygeus muscle interposition is an effective technique for rectovaginal space reconstruction and it should be considered as a viable solution for RVF repair. PMID- 25016080 TI - Fatal skin and soft tissue infection of multidrug resistant Acinetobacter baumannii: A case report. AB - INTRODUCTION: Acinetobacter baumannii is usually associated with respiratory tract, urinary tract and bloodstream infections. Recent reports suggest that it is increasingly causing skin and soft tissue infections. It is also evolving as a multidrug resistant organism that can be difficult to treat. We present a fatal case of multidrug resistant A. baumannii soft tissue infection and review of relevant literature. PRESENTATION OF CASE: A 41 year old morbidly obese man, with history of alcoholic liver disease presented with left superficial pre-tibial abrasions and cellulitis caused by multidrug resistant (MDR) A. baumannii. In spite of early antibiotic administration he developed extensive myositis and fat necrosis requiring extensive and multiple surgical debridements. He deteriorated despite appropriate antibiotic therapy and multiple surgical interventions with development of multi-organ failure and died. DISCUSSION: Managing Acinetobacter infections remains difficult due to the array of resistance and the pathogens ability to develop new and ongoing resistance. The early diagnosis of necrotizing soft tissue infection may be challenging, but the key to successful management of patients with necrotizing soft tissue infection are early recognition and complete surgical debridement. CONCLUSION: A. baumannii is emerging as an important cause of severe, life-threatening soft tissue infections. Multidrug resistant A. baumannii soft tissue infections may carry a high mortality in spite of early and aggressive treatment. Clinicians need to consider appropriate early empirical antibiotic coverage or the use of combination therapy to include MDR A. baumannii as a cause of skin and soft tissue infections. PMID- 25016081 TI - The tail of neuroendocrine tumors from lung to pancreas: Two rare case reports. AB - INTRODUCTION: Primary pancreatic neuroendocrine tumors are a well-established disease entity, however, neuroendocrine metastases to the pancreas from other sites have been scarcely documented. Specifically, pancreatic metastases from a pulmonary carcinoid tumor have only previously been described in a single case report. PRESENTATION OF CASE: We sought to outline our institutional experience of two patients with pulmonary neuroendocrine tumors that developed metastases to the pancreas, confirmed by gross pathology and immunohistochemistry. In both cases, the pancreatic metastases were surgically resected and their pulmonary origin were discovered post-operatively. DISCUSSION: Our findings should raise awareness to the possibility of metastatic disease when evaluating a pancreatic mass in a patient with a clinical history of pulmonary carcinoid tumor. Expert opinion on immunohistochemically differentiating a primary pancreatic neuroendocrine malignancy from a metastasis should be employed in these cases. CONCLUSION: Establishing this diagnosis pre-operatively could affect the decision to proceed with surgical resection, given the morbidity of pancreatectomy and the unknown long-term clinical outcome of patients with pulmonary carcinoid tumors metastatic to the pancreas. PMID- 25016082 TI - Perforated duodenal diverticulum: Surgical treatment and literature review. AB - INTRODUCTION: Duodenum is the second most frequent location for a diverticulum in the digestive tract. Complications are rare and perforation was only reported in less than 200 cases. PRESENTATION OF CASE: A 79-year-old female was admitted to Emergency Department with abdominal pain and vomiting for the last 24h. A CT scan was performed and moderated extra-luminal air was identified. During surgery a fourth portion perforated duodenal diverticulum was diagnosed and duodenal resection was performed. DISCUSSION: First reported in 1710, the incidence of duodenal diverticula can be as high as 22%. Nevertheless complications are extremely rare and include haemorrhage, inflammation, compression of surrounding organs, neoplastic progression, cholestasis and perforation. As perforations are often retroperitoneal, symptoms are nonspecific and rarely include peritoneal irritation, making clinical diagnose a challenge. CT scan will usually present extra-luminal retroperitoneal air and mesenteric fat stranding, providing clues for the diagnosis. Although non-operative treatment has been reported in selected patients, standard treatment is surgery and alternatives are diverse including diverticulectomy or duodenopancreatectomy. CONCLUSION: Perforated diverticula of the fourth portion of the duodenum are extremely rare and current evidence still supports surgery as the primary treatment modality. PMID- 25016084 TI - In vitro activity of MCB3681 against Clostridium difficile strains. AB - One hundred fourteen Clostridium difficile strains were collected from 67 patients and analyzed for the presence of C. difficile toxin B by the cell cytotoxoicity neutralization assay, genes for toxin A, toxin B, binary toxin and TcdC deletion by PCR. All strains were also PCR-ribotyped. The MICs of the isolates were determined against MCB3681 and nine other antimicrobial agents by the agar dilution method. All isolates were positive for toxin B as well as for toxin A and B genes. In addition, 13 isolates were positive for the binary toxin genes. Thirty-two different ribotypes were identified. No strain of ribotype 027 was found. All 114 isolates were sensitive to MCB3681 (0.008-0.5 mg/l), cadazolid (0.064-0.5 mg/l), fidaxomicin (0.008-0.125 mg/l), metronidazole (0.125-2 mg/l), vancomycin (0.125-1 mg/l) and tigecycline (0.032-0.25 mg/l). Three isolates were resistant to linezolid (8 mg/l), 12 isolates were resistant to moxifloxacin (8-32 mg/l), 87 isolates were resistant to clindamycin (8-256 mg/l) and 107 isolates were resistant to ciprofloxacin (8-256 mg/l). No association between toxins A, B and binary toxin, ribotypes and the sensitivity to MCB3681 could be found. MCB3681 has a potent in vitro activity against C. difficile. PMID- 25016085 TI - Defects in triacylglycerol lipolysis affect synthesis of triacylglycerols and steryl esters in the yeast. AB - Tgl3p, Tgl4p and Tgl5p are the major triacylglycerol lipases of the yeast Saccharomyces cerevisiae catalyzing degradation of triacylglycerols stored in lipid droplets. Previous results from our laboratory (Athenstaedt and Daum, 2005, J. Biol. Chem. 280, 37301-37309) demonstrated that a yeast strain lacking all three triacylglycerol lipases accumulates not only triacylglycerols at high amount, but also steryl esters. Here we show a metabolic link between synthesis and mobilization of non-polar lipids. In particular, we demonstrate that a block in tri-acylglycerol degradation in a tgl3?tgl4?tgl5? triple mutant lacking all major triacylglycerol lipases causes marked changes in non-polar lipid synthesis. Under these conditions formation of triacylglycerols is reduced, whereas steryl ester synthesis is enhanced as shown by quantification of non-polar lipids, in vivo labeling of lipids using [(14)C]oleic acid and [(14)C]acetic acid as precursors, and enzyme analyses in vitro. In summary, this study demonstrates that triacylglycerol metabolism and steryl ester metabolism are linked processes. The importance of balanced storage and degradation of these components for lipid homeostasis in the yeast is highlighted. PMID- 25016086 TI - Alterations of contractions and L-type Ca2+ currents by murrayafoline-A in rat ventricular myocytes. AB - We examined the effects of murrayafoline-A (1-methoxy-3-methylcarbazole, Mu-A), which is isolated from the dried roots of Glycosmis stenocarpa, on cell shortenings and L-type Ca2+ currents (ICa,L) in rat ventricular myocytes. Cell shortenings and ICa,L were measured using the video edge detection method and patch-clamp techniques, respectively. Mu-A transiently increased cell shortenings in a concentration-dependent manner with an EC50 of ~20 MUM. The maximal effect of Mu-A, approximately 175% of the control, was observed at >=100 MUM. The positive inotropic effect of Mu-A (25 MUM) reached a maximum after ~2-min exposures, and then decayed after a ~1-min steady-state. During the Mu-A-induced positive inotropy, the rate of contraction was accelerated, whereas the rate of relaxation was not significantly altered. To understand the possible mechanism for the Mu-A-induced positive inotropy, the ICa,L was assessed. Mu-A transiently enhanced the ICa,L. Concentration-dependence of the increase in ICa,L by Mu-A was similar to that of positive inotropic effect of Mu-A. The maximal effect of Mu-A (25 MUM) on ICa,L was observed at 2-3 min after the application of Mu-A. A partial inhibition of ICa,L using verapamil (1 MUM) induced a right shift of concentration-response curve of the positive inotropic effect of Mu-A and significantly attenuated the effect. These results suggest that Mu-A may transiently enhance contractility, at least in part, by increasing the Ca2+ influx through the L-type Ca2+ channels in rat ventricular myocytes. PMID- 25016087 TI - "Chemokine receptors as therapeutic targets: Why aren't there more drugs?". AB - Chemokines are a family of around 40 small proteins, which are secreted by a variety of cells, including structural cell types and leukocytes of the immune system. Chemokines bind to their specific 7-transmembrane G protein-coupled receptors (GPCRs) and induce a variety of downstream signals which notably modulate polymerization of the actin cytoskeleton and thus drive cellular motility. Excessive or inappropriate release of chemokines is observed in many inflammatory diseases and so there has been a great effort in industry to target chemokine receptors. The large family of GPCRs regulate many physiological cellular processes and they have proved to be highly amenable to pharmacological intervention with small chemicals. Consequently GPCRs make attractive targets for drug discovery and indeed a large number of successful current therapeutics are either agonists or antagonists of GPCRs. The apparent lack of success with chemokine receptors has been frustrating and in this paper we discuss potential reasons for previous failures and also why there is considerable cause for optimism. PMID- 25016083 TI - Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles. AB - One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors. PMID- 25016088 TI - 15-deoxy-Delta12,14-prostaglandin J2 reduces albumin-induced arthritis in temporomandibular joint of rats. AB - The aim of this study was to evaluate the peripheral effect of 15-deoxy Delta12,14-prostaglandin J2 (15d-PGJ2) in albumin-induced arthritis in temporomandibular joint (TMJ) of rats. Antigen-induced arthritis (AIA) was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund's adjuvant. Pretreatment with an intra-articular injection of 15d-PGJ2 (100 ng/TMJ) before mBSA intra-articular injection (10 ug/TMJ) (challenge) in immunized rats significantly reduced the albumin-induced arthritis inflammation. The results demonstrated that 15d-PGJ2 was able to inhibit plasma extravasation, leukocyte migration and the release of inflammatory cytokines IL-6, IL-12, IL-18 and the chemokine CINC-1 in the TMJ tissues. In addition, 15d-PGJ2 was able to increase the expression of the anti-adhesive molecule CD55 and the anti inflammatory cytokine IL-10. Taken together, it is possible to suggest that 15d PGJ2 inhibit leukocyte infiltration and subsequently inflammatory process, through a shift in the balance of the pro- and anti-adhesive properties. Thus, 15d-PGJ2 might be used as a potential anti-inflammatory drug to treat arthritis induced inflammation of the temporomandibular joint. PMID- 25016089 TI - Assessment of pregnenolone effects on alcohol intake and preference in male alcohol preferring (P) rats. AB - Neuroactive steroids can modulate a variety of neurobehavioral functions via the GABAergic system. This study was conducted to determine the importance of the neurosteroid pregnenolone on the regulation of alcohol intake. The effects of acute and chronic administration of pregnenolone on alcohol intake were assessed in alcohol preferring (P) rats. The rats were injected i.p. with the vehicle or pregnenolone (25, 50 or 75 mg/kg) and their alcohol and water intake were recorded at 2, 4, 6 and 24 h. Also, the chronic effects of 50 mg/kg (i.p.) pregnenolone on alcohol intake were determined. Our results show that although the main effect of i.p. injection of pregnenolone in reducing alcohol intake was not quite significant compared with the vehicle, pregnenolone at 75 mg/kg significantly (P<0.025) reduced alcohol intake. Regarding alcohol preference, acute administration of pregnenolone both at 50 mg/kg (P<0.05) and at 75 mg/kg (P<0.025) significantly reduced alcohol preference. In chronic experiments pregnenolone given for 10 consecutive days did not show a significant effect on alcohol intake and alcohol preference. Overall, although pregnenolone given i.p. acutely and significantly reduced alcohol intake and preference, the fact that chronic treatment did not show an effect diminishes its promise to be considered for the treatment of alcoholism. However, its profile of effects might be different in human alcoholics. PMID- 25016090 TI - Bupropion-induced inhibition of alpha7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus. AB - The pharmacological activity of bupropion was compared between alpha7 nicotinic acetylcholine receptors expressed in heterologous cells and hippocampal and dorsal raphe nucleus neurons. The inhibitory activity of bupropion was studied on GH3-alpha7 cells by Ca2+ influx, as well as on neurons from the dorsal raphe nucleus and interneurons from the stratum radiatum of the hippocampal CA1 region by using a whole-cell voltage-clamp technique. In addition, the interaction of bupropion with the alpha7 nicotinic acetylcholine receptor was determined by [3H]imipramine competition binding assays and molecular docking. The fast component of acetylcholine- and choline-induced currents from both brain regions was inhibited by methyllycaconitine, indicating the participation of alpha7 containing nicotinic acetylcholine receptors. Choline-induced currents in hippocampal interneurons were partially inhibited by 10 uM bupropion, a concentration that could be reached in the brain during clinical administration. Additionally, both agonist-induced currents were reversibly inhibited by bupropion at concentrations that coincide with its inhibitory potency (IC50=54 uM) and binding affinity (Ki=63 uM) for alpha7 nicotinic acetylcholine receptors from heterologous cells. The [3H]imipramine competition binding and molecular docking results support a luminal location for the bupropion binding site(s). This study may help to understand the mechanisms of actions of bupropion at neuronal and molecular levels related with its therapeutic actions on depression and for smoking cessation. PMID- 25016091 TI - The phosphoinositide-dependent protein kinase 1 inhibitor, UCN-01, induces fragmentation: possible role of metalloproteinases. AB - Phosphoinositide-dependent protein kinase 1 (PDK1) is a key enzyme, master regulator of cellular proliferation and metabolism; it is considered a key target for pharmacological intervention. Using membranes obtained from DDT1 MF-2 cells, phospho-PDK1 was identified by Western blotting, as two major protein bands of Mr 58-68 kDa. Cell incubation with the PDK1 inhibitor, UCN-01, induced a time- and concentration-dependent decrease in the amount of phospho-PDK1 with a concomitant appearance of a ~42 kDa phosphorylated fragment. Knocking down PDK1 diminished the amount of phospho-PDK1 detected in membranes, accompanied by similarly decreased fragment generation. UCN-01-induced fragment generation was also observed in membranes from cells stably expressing a myc-tagged PDK1 construct. Other PDK1 inhibitors were also tested: OSU-03012 induced a clear decrease in phospho-PDK1 and increased the presence of the phosphorylated fragment in membrane preparations; in contrast, GSK2334470 and staurosporine induced only marginal increases in the amount of PDK1 fragment. Galardin and batimastat, two metalloproteinase inhibitors, markedly attenuated inhibitor-induced PDK1 fragment generation. Metalloproteinases 2, 3, and 9 co-immunoprecipitated with myc-PDK1 under baseline conditions and this interaction was stimulated by UCN-01; batimastat also markedly diminished this effect of the PDK1 inhibitor. Our results indicate that a series of protein kinase inhibitors, namely UCN-01 and OSU-03012 and to a lesser extent GSK2334470 and staurosporine induce PDK1 fragmentation and suggest that metalloproteinases could participate in this effect. PMID- 25016093 TI - High frequency gamma activity in the left hippocampus predicts visual object naming performance. AB - Access to an object's name requires the retrieval of an arbitrary association between it's identity and a word-label. The hippocampus is essential in retrieving arbitrary associations, and thus could be involved in retrieving the link between an object and its name. To test this hypothesis we recorded the iEEG signal from epileptic patients, directly implanted in the hippocampus, while they performed a picture naming task. High-frequency broadband gamma (50-150 Hz) responses were computed as an index of population-level spiking activity. Our results show, for the first time, single-trial hippocampal dynamics between visual confrontation and naming. Remarkably, the latency of the hippocampal response predicts naming latency, while inefficient hippocampal activation is associated with "tip-of-the-tongue" states (a failure to retrieve the name of a recognized object) suggesting that the hippocampus is an active component of the naming network and that its dynamics are closely related to efficient word production. PMID- 25016092 TI - The role of the insula in speech and language processing. AB - Lesion and neuroimaging studies indicate that the insula mediates motor aspects of speech production, specifically, articulatory control. Although it has direct connections to Broca's area, the canonical speech production region, the insula is also broadly connected with other speech and language centres, and may play a role in coordinating higher-order cognitive aspects of speech and language production. The extent of the insula's involvement in speech and language processing was assessed using the Activation Likelihood Estimation (ALE) method. Meta-analyses of 42 fMRI studies with healthy adults were performed, comparing insula activation during performance of language (expressive and receptive) and speech (production and perception) tasks. Both tasks activated bilateral anterior insulae. However, speech perception tasks preferentially activated the left dorsal mid-insula, whereas expressive language tasks activated left ventral mid insula. Results suggest distinct regions of the mid-insula play different roles in speech and language processing. PMID- 25016094 TI - Human proximal femur bone adaptation to variations in hip geometry. AB - The study of bone mass distribution at proximal femur may contribute to understand the role of hip geometry on hip fracture risk. We examined how bone mineral density (BMD) of proximal femur adapts to inter individual variations in the femoral neck length (FNL), femoral neck width (FNW) and neck shaft angle (NSA). A parameterized and dimensionally scalable 3-D finite element model of a reference proximal femur geometry was incrementally adjusted to adopt physiological ranges at FNL (3.90-6.90cm), FNW (2.90-3.46cm), and NSA (109-141o), yielding a set of femora with different geometries. The bone mass distribution for each femur was obtained with a suitable bone remodelling model. The BMDs at the integral femoral neck (FN) and at the intertrochanteric (ITR) region, as well as the BMD ratio of inferomedial to superolateral (IM:SL) regions of FN and BMD ratio of FN:ITR were used to represent bone mass distribution. Results revealed that longer FNLs present greater BMD (g/cm(3)) at the FN, mainly at the SL region, and at the ITR region. Wider FNs were associated with reduced BMD at the FN, particularly at the SL region, and at the ITR region. Larger NSAs up to 129 degrees were associated with BMD diminutions at the FN and ITR regions and with increases of the IM:SL BMD ratio while NSAs larger than 129 degrees resulted in decrease of the IM:SL BMD ratio. These findings suggest hip geometry as moderator of the mechanical loading influence on bone mass distribution at proximal femur with higher FNL favoring the BMD of FN and ITR regions and greater FNW and NSA having the opposite effect. Augmented values of FNL and FNW seem also to favor more the BMD at the superolateral than at the inferomedial FN region. PMID- 25016096 TI - Activation of p38 MAPK-regulated Bcl-xL signaling increases survival against zoledronic acid-induced apoptosis in osteoclast precursors. AB - The nitrogen-containing bisphosphonate zoledronic acid (ZA) induces apoptosis in osteoclasts and inhibits osteoclast-mediated bone resorption. It is widely used to treat osteoporosis. However, some patients are less responsive to ZA treatment, and the mechanisms of resistance are still unclear. Here, we identified that murine osteoclast precursors may develop resistance to ZA-induced apoptosis. These resistant cells survived the apoptotic effect of ZA following an increase in anti-apoptotic Bcl-xL. Pharmacologically inhibiting Bcl-xL facilitated ZA-induced apoptosis. Treatment with ZA activated p38 MAPK, increasing Bcl-xL expression and cell survival. Nuclear import of beta-catenin regulated by p38 MAPK determined Bcl-xL mRNA expression and cell survival in response to ZA. ZA also inactivated glycogen synthase kinase (GSK)-3beta, a negative upstream regulator of beta-catenin, in a p38 MAPK-mediated manner. Synergistic pharmacological inhibition of p38 MAPK with ZA attenuated receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and facilitated ZA-induced apoptosis. These results demonstrate that elevated Bcl-xL expression mediated by p38 MAPK-regulated GSK-3beta/beta catenin signaling is required for cell survival of ZA-induced apoptosis in both osteoclast precursors and osteoclasts. Finally, we demonstrated that inhibiting p38 MAPK-mediated pathway enhanced ZA effect on increasing the bone mineral density of ovariectomized mice. This result suggests that targeting these pathways may represent a potential therapeutic strategy. PMID- 25016095 TI - Inkjet-based biopatterning of SDF-1beta augments BMP-2-induced repair of critical size calvarial bone defects in mice. AB - BACKGROUND: A major problem in craniofacial surgery is non-healing bone defects. Autologous reconstruction remains the standard of care for these cases. Bone morphogenetic protein-2 (BMP-2) therapy has proven its clinical utility, although non-targeted adverse events occur due to the high milligram-level doses used. Ongoing efforts explore the use of different growth factors, cytokines, or chemokines, as well as co-therapy to augment healing. METHODS: Here we utilize inkjet-based biopatterning to load acellular DermaMatrix delivery matrices with nanogram-level doses of BMP-2, stromal cell-derived factor-1beta (SDF-1beta), transforming growth factor-beta1 (TGF-beta1), or co-therapies thereof. We tested the hypothesis that bioprinted SDF-1beta co-delivery enhances BMP-2 and TGF-beta1 driven osteogenesis both in-vitro and in-vivo using a mouse calvarial critical size defect (CSD) model. RESULTS: Our data showed that BMP-2 bioprinted in low doses induced significant new bone formation by four weeks post-operation. TGF beta1 was less effective compared to BMP-2, and SDF-1beta therapy did not enhance osteogenesis above control levels. However, co-delivery of BMP-2+SDF-1beta was shown to augment BMP-2-induced bone formation compared to BMP-2 alone. In contrast, co-delivery of TGF-beta1+SDF-1beta decreased bone healing compared to TGF-beta1 alone. This was further confirmed in vitro by osteogenic differentiation studies using MC3T3-E1 pre-osteoblasts. CONCLUSIONS: Our data indicates that sustained release delivery of a low-dose growth factor therapy using biopatterning technology can aid in healing CSD injuries. SDF-1beta augments the ability for BMP-2 to drive healing, a result confirmed in vivo and in vitro; however, because SDF-1beta is detrimental to TGF-beta1-driven osteogenesis, its effect on osteogenesis is not universal. PMID- 25016098 TI - Robust evaluation of 3D electron cryomicroscopy data using tilt-pairs. AB - Determining the structure of a protein complex using electron microscopy requires the calculation of a 3D density map from 2D images of single particles. Since the individual images are taken at low electron dose to avoid radiation damage, they are noisy and difficult to align with each other. This can result in incorrect maps, making validation essential. Pairs of electron micrographs taken at known angles to each other (tilt-pairs) can be used to measure the accuracy of assigned projection orientations and verify the soundness of calculated maps. Here we establish a statistical framework for evaluating images and density maps using tilt-pairs. The directional distribution of such angular data is modelled using a Fisher distribution on the unit sphere. This provides a simple, quantitative and easily comparable metric, the concentration parameter kappa, for evaluating the quality of datasets and density maps that is independent of the data collection and analysis methods. A large kappa is indicative of good agreement between the particle images and the 3D density map. For structure validation, we recommend kappa>10 and a p-value <0.01. The statistical framework herein allows one to objectively answer the question: Is a reconstructed density map correct within a particular confidence interval? PMID- 25016097 TI - White matter microstructure complements morphometry for predicting verbal memory in epilepsy. AB - Verbal memory is the most commonly impaired cognitive domain in patients with temporal lobe epilepsy (TLE). Although damage to the hippocampus and adjacent temporal lobe structures is known to contribute to memory impairment, little is known of the relative contributions of white versus gray matter structures, or whether microstructural versus morphometric measures of temporal lobe pathology are stronger predictors of impairment. We evaluate whether measures of temporal lobe pathology derived from diffusion tensor imaging (DTI; microstructural) versus structural MRI (sMRI; morphometric) contribute the most to memory performances in TLE, after controlling for hippocampal volume (HCV). DTI and sMRI were performed on 26 patients with TLE and 35 controls. Verbal memory was measured with the Logical Memory (LM) subtest of the Wechsler Memory Scale-III. Hierarchical regression analyses were performed to examine unique contributions of DTI and sMRI measures to verbal memory with HCV entered in block 1. In patients, impaired recall was associated with increased mean diffusivity (MD) of multiple fiber tracts that project through the temporal lobes. In addition, increased MD of the left cortical and bilateral pericortical white matter was associated with impaired recall. After controlling for left HCV, only microstructural measures of white matter pathology contributed to verbal recall. The best predictive model included left HCV and MD of the left inferior longitudinal fasciculus (ILF) and pericortical white matter beneath the left entorhinal cortex. This model explained 60% of the variance in delayed recall and revealed that MD of the left ILF was the strongest predictor. These data reveal that white matter microstructure within the temporal lobe can be used in conjunction with left HCV to enhance the prediction of verbal memory impairment, and speak to the complementary nature of DTI and sMRI for understanding cognitive dysfunction in epilepsy and possibly other memory disorders. PMID- 25016099 TI - Sulforaphane inhibits endothelial protein C receptor shedding in vitro and in vivo. AB - Sulforaphane (SFN), a natural isothiocyanate present in cruciferous vegetables such as broccoli and cabbage, is effective in preventing carcinogenesis, diabetes, and inflammatory responses. Increasing evidence has demonstrated that beyond its role in the activation of protein C, endothelial cell protein C receptor (EPCR) is also involved in vascular inflammation. EPCR activity is markedly changed by ectodomain cleavage and its release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor alpha converting enzyme (TACE). However, little is known about the effects of SFN on EPCR shedding. Our results demonstrated that SFN induced potent inhibition of phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-alpha-, interleukin (IL)-1beta, and cecal ligation and puncture (CLP)-induced EPCR shedding. SFN also inhibited the expression and activity of PMA-induced TACE in endothelial cells. In addition, treatment with SFN resulted in reduced PMA stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of SFN as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding. PMID- 25016100 TI - A multi-biomarker risk assessment of the impact of brominated flame retardant decabromodiphenyl ether (BDE209) on the antioxidant system of earthworm Eisenia fetida. AB - Decabromodiphenyl ether (BDE209) is the major contaminant at e-waste recycling sites (EWRSs), and its potential toxicological effects on terrestrial organisms have received extensive attention. However, the impacts of BDE209 on the antioxidant defense system in terrestrial organisms remain vague. Therefore, indoor incubation tests were performed systematically on control and contaminated soil samples to determine the effects of BDE209 on the antioxidant system of earthworm Eisenia fetida. The results showed that compared to the controls, superoxide dismutase (SOD) activities in all treated groups were elevated significantly after 21 and 28 days exposure; catalase (CAT) activities were much higher in all tests during the entire exposure period; peroxidase (POD) and glutathione-s-transferase (GST) activities generally decreased and indicated contrary response trend; the total antioxidant capacity (T-AOC) after exposure to low level of BDE209 (1 mg kg(-1)) was induced, whereas at 10 and 100 mg kg(-1) concentrations it showed suppression status; electron paramagnetic resonance (EPR) spectra suggested that hydroxyl radicals (OH) in earthworms were significantly induced by BDE209; the changes in malondialdehyde (MDA) contents suggested that reactive oxygen species (ROS) might lead to cellular lipid peroxidation in earthworms. The results of these observations suggested that severe oxidative stress occurred in E. fetida, and it may play an important role in inducing the BDE209 toxicity to earthworms. PMID- 25016101 TI - Risk assessment of marine environments from ballast water discharges with laboratory-scale hydroxyl radicals treatment in Tianjin Harbor, China. AB - For the majority of ballast water treatment system (BWTS) that employ active substances (e.g., oxidative compounds), relevant chemicals (RCs) formation is an issue owing to their potential adverse effects on aquatic organisms. Accordingly, BWTS must be approved by the International Maritime Organization (IMO), and the approval procedure requires environmental risk assessment. The most commonly employed harbor used to calculate predicted environmental concentrations (PECs) for RCs in treated ballast water is the GESAMP-BWWG (Group of Experts on Scientific Aspects of Marine Environmental Protection-Ballast Water Working Group) model harbor. However, there is very little assessment data available regarding the associated environmental impacts in ports and harbors of China. Therefore, in this study the concentration of fifteen RCs from the existing laboratory-scale BWTS using hydroxyl radicals was obtained and input into the MAMPEC (Marine Antifoulant Model to Predict Environmental Concentrations) model to compute PECs in Tianjin Harbor, China. The potential risks to the aquatic environment posed by treated ballast water in Tianjin Harbor were further assessed based on the calculated ratio of PECs and predicted no effect concentrations (PNECs). Only monochloroacetic acid and dichloroacetic acid were found to have potential risks, and the ratios of PECs and PNECs to the other measured RCs were less than 1, indicating that the environmental risk posed by treated ballast water discharged into Tianjin Harbor is of little concern. The concentration of total residual oxidant recommended by the IMO (<0.2 mg/L) in treated ballast water at discharge was found to be at levels that may pose a risk to the aquatic environment in Tianjin Harbor. PMID- 25016102 TI - Urban nutrient recovery from fresh human urine through cultivation of Chlorella sorokiniana. AB - High rate food consumption in urban cities causes vast amounts of nitrogen and phosphorus used in agriculture to end up in urban wastewaters. To substantially recover these nutrients, source-separated human urine should be targeted. The present study was to investigate the feasibility of recovering nitrogen and phosphorus in urine via microalgae cultivation. In concentrated urine, urea hydrolysis and precipitation occur rapidly, making microalgal growth difficult and nutrient recovery ineffective. However, when fresh urine was added as nutrient stock for 1-day growth requirement, biomass of Chlorella sorokiniana grew from 0.44 to 0.96 g L(-1) utilising 62.64 mg L(-1) of N and 10.64 mg L(-1) of P, achieving 80.4% and 96.6% recoveries, respectively in a 1-day non-sterile cultivation cycle. Overall, microalgae grown with urine added as nutrient supplement show no signs of inferiority as compared to those grown in recipe medium BG11 in terms of mass and chlorophyll a growth rates as well as resulting lipids (36.8%) and energy contents (21.0 kJ g(-1)). PMID- 25016103 TI - Occurrence of antibiotics and antibiotic resistances in soils from wastewater irrigation areas in Beijing and Tianjin, China. AB - Non-irrigated and wastewater-irrigated soils were collected from five wastewater irrigation areas in Beijing and Tianjin, China. The concentrations of sulfadiazine, sulfamethoxazole, oxytetracycline and chlortetracycline in the soils were determined. Abundances of antibiotic resistant bacteria and corresponding resistance genes were also measured to examine the impact of wastewater irrigation. No significant difference in antibiotic resistance bacteria was observed between irrigated and non-irrigated soils. However, the concentrations of antibiotics and abundances of resistance genes were significantly greater in irrigated soils, indicating that agricultural activities enhanced the occurrence of antibiotics and resistance genes in the soils. In addition, no significant difference was observed between previously and currently wastewater-irrigated soils. Therefore, cessation of wastewater irrigation did not significantly reduce the levels of antibiotic concentrations and resistance gene abundances. Other factors, e.g., manure application, may explain the lack of significant difference in the occurrence of antibiotics and resistance genes between previously and currently wastewater-irrigated soils. PMID- 25016104 TI - Mechanistic considerations of photosensitized transformation of microcystin-LR (cyanobacterial toxin) in aqueous environments. AB - Microcystin-LR (MC-LR), one of the most common cyanotoxins, is produced by harmful cyanobacteria. The current study focuses on the photosensitized transformation of MC-LR in dissolved organic matter (DOM) enriched solutions under solar simulated irradiation. It appears that the direct energy transfer of triplet excited state DOM with MC-LR plays a key role and leads to photosensitized isomerization of Adda side chain. Furthermore a micro heterogeneous mechanism has been proposed. Size exclude chromatograph (SEC) has been applied to explore the adsorption of MC-LR on the DOM. The adsorption phenomenon supported the fact that the pseudo first-order photodegradation rates showed positive correlation with the adsorption. The photo-transformation rate of MC-LR increases as pH decreases which is also the result of the adsorptive interaction of MC-LR with DOM. Finally two bulk water parameters (TOC and UV350 nm) have been applied to predict the photodegradation rates of MC-LR in the varied water matrixes. PMID- 25016105 TI - Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction. AB - Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor beta (TRbeta) gene. TRbeta is a key protein mediating down regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy 4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD. PMID- 25016106 TI - Correlation of transcriptomic responses and metal bioaccumulation in Mytilus edulis L. reveals early indicators of stress. AB - Marine biomonitoring programs in the U.S. and Europe have historically relied on monitoring tissue concentrations of bivalves to monitor contaminant levels and ecosystem health. By integrating 'omic methods with these tissue residue approaches we can uncover mechanistic insight to link tissue concentrations to potential toxic effects. In an effort to identify novel biomarkers and better understand the molecular toxicology of metal bioaccumulation in bivalves, we exposed the blue mussel, Mytilus edulis L., to sub-lethal concentrations (0.54 MUM) of cadmium, lead, and a Cd+Pb mixture. Metal concentrations were measured in gill tissues at 1, 2, and 4 weeks, and increased linearly over the 4 week duration. In addition, there was evidence that Pb interfered with Cd uptake in the mixture treatment. Using a 3025 sequence microarray for M. edulis, we performed transcriptomic analysis, identifying 57 differentially expressed sequences. Hierarchical clustering of these sequences successfully distinguished the different treatment groups demonstrating that the expression profiles were reproducible among the treatments. Enrichment analysis of gene ontology terms identified several biological processes that were perturbed by the treatments, including nucleoside phosphate biosynthetic processes, mRNA metabolic processes, and response to stress. To identify transcripts whose expression level correlated with metal bioaccumulation, we performed Pearson correlation analysis. Several transcripts correlated with gill metal concentrations including mt10, mt20, and contig 48, an unknown transcript containing a wsc domain. In addition, three transcripts directly involved in the unfolded protein response (UPR) were induced in the metal treatments at 2 weeks and were further up-regulated at 4 weeks. Overall, correlation of tissue concentrations and gene expression responses indicates that as mussels accumulate higher concentrations of metals, initial stress responses are mobilized to protect tissues. However, given the role of UPR in apoptosis, it serves as an early indicator of stress, which once overwhelmed will result in adverse physiological effects. PMID- 25016108 TI - Genetically biodiverse potato cultivars grown on a suitable agricultural soil under compost amendment or mineral fertilization: yield, quality, genetic and epigenetic variations, soil properties. AB - The use of compost for soil amendment is a promising agricultural practice environmentally and economically viable. In the framework of a wide research project designed to evaluate the effects of soil amendment with municipal solid waste compost in comparison with traditional mineral fertilization practices, 54 different cultivars (Cvs) of potatoes were AFLP (amplified fragment length polymorphism) molecularly fingerprinted. The seven most genetically biodiverse potato Cvs were used to establish an experimental field in southern Italy. The field area was divided into two portions fertilized with compost (20 Mg ha(-1)) or with ammonium sulphate (200 kg ha(-1)). No significant differences in productivity, organoleptic characteristics and element concentrations were observed between the potato tubers obtained with both kinds of soil fertilization, while the tubers grown on compost amended soil showed, on average, higher K concentrations with respect to those grown on mineral fertilised soil. cDNA-AFLP (complementary DNA-AFLP) and MSAP (methylation sensitive amplified polymorphism) analyses were carried out on both leaves and tubers of one selected Cv to estimate if any transcriptome alterations or epigenetic modifications were induced by the two kinds of fertilization, however no variations were detected. Chemical and biological soil qualities (i.e., microbial respiration, FDA hydrolysis, alkaline and acid phosphatase) were assessed on soil samples at the start of the experiment and at the end of potato crop cycle. No significant differences in soil pH and limited ones, in the available fraction of some trace elements, were observed; while conductivity was much higher for the compost amended portion of the experimental field. Microbial respiration, FDA hydrolysis and acid phosphatase activities were significantly increased by compost amendment, in comparison with mineral fertilization. Finally, a sensory panel of potato Cvs detected no significant differences among qualitative descriptors and among potatoes coming from the two differently fertilized soils. PMID- 25016107 TI - Development of sensitive and reliable LC-MS/MS methods for the determination of three fluoroquinolones in water and fish tissue samples and preliminary environmental risk assessment of their presence in two rivers in northern Poland. AB - Antibiotic consumption (e.g. fluoroquinolones (FQs)) and, as a consequence, their presence in the environment, have received a lot of attention in the last several years due to increasing numbers of diseases and infections that are becoming resistant to traditional treatments for both humans and animals. In addition, even though antibiotics are safe for human and veterinary usage, ecosystems may be exposed to these substances. In this study, analytical methods for determining enrofloxacin (ENR), norfloxacin (NOR) and ciprofloxacin (CIP) in water samples and fish tissue based on the LC-MS/MS technique were developed and validated. As there is no data available concerning the risks posed by antibiotics in Poland, the proposed methods were applied for monitoring drug presence in environmental samples collected from two rivers in northern Poland. Evaluations of the ecotoxicity of ENR, NOR and CIP towards four different species of aquatic organisms: marine bacteria (Vibrio fischeri), green algae (Scenedesmus vacuolatus), duckweed (Lemna minor) and crustacean (Daphnia magna), were also carried out. All the investigated compounds were detected at least once in the survey. NOR was found to be the most ubiquitous drug with concentrations of up to 442.8 ng L(-1). Moreover, it was established that L. minor is the most sensitive species to the investigated drugs (EC50NOR = 0.13 mg L(-1), EC50ENR = 0.22 mg L( 1) and EC50CIP = 0.34 mg L(-1)). The calculated risk quotient (RQ) values confirmed that the concentrations of the investigated FQs in the environmental samples were at a level of moderate environmental risk (10.95) between meteorological variables and particulate matter concentration being humidity, humidity of the previous day and temperature, the meteorological variables that contributed most significantly in the variance of the particulate matter concentration measured in the mining area while the contribution of the AERMOD estimations to the short term TSP (Total Suspended Particles) measured concentrations was negligible (<5%). The multiple regression model was used to identify the meteorological condition that leads to pollution episodes. It was found that conditions drier than 54% lead to pollution episodes while humidities greater than 70% maintain safe air quality conditions in the mining region in northern Colombia. PMID- 25016111 TI - [Evaluation of anti-Toxoplasma gondii antibody distribution and risk factors among pregnant women admitted to obstetrics polyclinic of Canakkale Onsekiz Mart University Hospital]. AB - OBJECTIVE: In this study, we aimed to investigate Toxoplasma gondii seroprevalence and risk factors in pregnant women. METHODS: A total of 196 patients, admitted to the clinic in the first trimester and with ongoing pregnancy follow-up of between May 2012 and January 2013, were included in the study. Toxoplasma IgG and IgM antibodies were detected by ELISA test in blood samples obtained from patients during routine screening. SPSS statistical software, version 19.0 was used to analyze the data. Descriptive statistics were used to present the data, percentage, mean, and standard deviation. Chi-square test was used for categorical variables. p-value for statistical significance was defined as p<0.05. RESULTS: The mean age was 29.07+/-5.3 years in our study group. Anti-Toxoplasma IgG and IgM antibodies were found in 28.8% and 2.7%, respectively; 58.9% of pregnant women in the study reported that they had done at least one risky behavior during their pregnancy. However, there was no significant association between T. gondii IgG antibody positivity and risk factors, such as pregnancy, feeding animals in the past years, and consumption of raw food products (p>0.05). CONCLUSION: We found that Toxoplasma IgG antibody seropositivity (28.8%) was similar to that found in the other studies from western Turkey. PMID- 25016112 TI - [The epidemiology of malaria in Bursa--2009-2012]. AB - OBJECTIVE: Malaria is a common disease in many tropical and subtropical areas, which may threaten life. In this study, we examined the epidemiology of malaria in Bursa province using the data provided by the Province Health Directorate, collected over 2009 to 2012. METHODS: The data include a total of 29.683 blood samples taken by active and passive surveillance. Giemsa-stained thin and thick blood smears were examined with a 100X oil immersion objective using a standard microscope. RESULTS: A total of 21 (0.07%) malaria cases were detected. Of these, 20 (95.2%) cases were male and 1 (4.8%) case was female, with highest rates occurring in June and September. All of the cases were imported, of whom 10 (47.6%) were caused by Plasmodium vivax and 11 (52.4%) by P. falciparum. All P. falciparum cases were found to be imported cases that traveled to African nations (Cote d'Ivoire, Sudan, Equatorial Guinea, Nigeria, Senegal, Mali, Somalia). Malaria cases were mainly observed in the 15-to-44-year-old range. CONCLUSION: We believe that these results will lead to better-targeted and more effective malaria control programs. PMID- 25016113 TI - [The effects of intestinal parasites on anemia of children]. AB - OBJECTIVE: In this case-control epidemiological study, we aimed to investigate the effects of intestinal parasites on the anemia of children and show the association between intestinal parasites and anemia. METHODS: A total of 50 healthy and 50 malnourished children aged 0-72 months who went to physicians of Tilfindir Primary Health Care Center were enrolled in this study. The stool specimens were examined by using native-lugol, concentration, cellophane tape, and acid fast and trichrome staining methods. The complete blood count was measured by an automatic blood device. RESULTS: A total of 58% of the children were infected with intestinal parasites; 55.2% of these were infected with only one parasite, and 44.8% of them were infected with polyparasites. Also, 50.0% of the children with parasitic infection and 19.0% of children without parasitic infection were anemic. There was a positive association between intestinal parasites and anemia statistically (p<0.05). The mean hemoglobin level of the children with parasitic infection was 11.15+/-1.30, and the mean hemoglobin level of the children without parasitic infection was 12.13+/-1.47. There was a significant difference between mean hemoglobin levels of the two groups statistically (p<0.001). CONCLUSION: Consequently, this study emphasized that intestinal parasites can affect the anemia of children adversely, and there was a positive association between intestinal parasites and anemia of children. PMID- 25016114 TI - [Seroprevalance of brucellosis, listeriosis and toxoplasmosis in cattle in Adana province of Turkey]. AB - OBJECTIVE: This study was conducted to identify the seroprevalance of diseases which are zoonotic and responsible from abortion such as toxoplasmosis, listeriosis and brucellosis in Holstein crossbred cattle of different age and sex in Adana province, between 2008 April-September. METHODS: For this purpose, blood serum samples were collected from 132 cattle and analyzed for Toxoplasma gondii, Listeria monocytogenes and Brucella abortus antibodies. T. gondii, L. monocytogenes and Brucella abortus antibodies were determined by the standard Sabin- Feldman Dye Test (SFDT), Osebold method and Microtube Agglutination Test (MAT) respectively, from the blood serum samples. RESULTS: 132 serum tested 56.06% samples of T. gondii, 40.9% and 3.03% of L. monocytogenes and defined the B.abortus antibodies were found to be seropositive terms. There were no statistically significant difference between seropositive T. gondii, L. monocytogenes and B.abortus antibodies among age groups (p>0.05). CONCLUSION: In this study, for the first time in cattle in the region of Adana serological methods revealed the presence L. monocytogenes, toxoplasmosis and listeriosis were higher than brucellosis seropositivity. Moreover, the prevalence of these diseases in the same animal at the highest rate was determined for T. gondii and L. monocytogenes. PMID- 25016115 TI - [Twenty-five years of intestinal parasite prevalence in Istanbul University, Istanbul Faculty of Medicine: a retrospective study]. AB - OBJECTIVE: The aim of our study is to determine the general intestinal parasite prevalence in Istanbul University Istanbul Faculty of Medicine Hospital, which is located in European and Asian geographical features of Turkey. METHODS: Between January 1988 and December 2012, a total of 111,889 stool samples from patients who were admitted to the Istanbul University Istanbul Faculty of Medicine Hospital were examined microscopically by using native lugol and formalin-ether concentration technique; in addition, the cellophane tape test technique was used to examine the perianal area. RESULTS: The prevalence of intestinal parasites was found to be 5% (5486/111,889) in Istanbul. Giardia intestinalis was the leading parasite (62%), and the prevalence of the rest of the intestinal parasites was as follows: Enterobius vermicularis, Ascaris lumbricoides, and Blastocystis hominis: 16%, 7%, and 6%, respectively. Between 2000 and 2012, a highly significant reduction in general parasite prevalence was determined, compared to the 1988 and 2000 time period (p<0.001). CONCLUSION: Socio-economic conditions might be related with the both the lower prevalence of intestinal parasites in our hospital, which is located in Marmara region, and the steady decrease of the prevalence ratio in the 2000s. The results indicate the necessity of further studies to develop effective parasitic disease control measurements. PMID- 25016116 TI - Prevalence of intestinal parasites in hamsters and rabbits in some pet shops of Turkey. AB - OBJECTIVE: In this study, we aimed to determine the parasite species carried by hamsters and rabbits purchased from some commercial pet shops in Turkey. METHODS: For this purpose, the fecal samples of clinically healthy Syrian hamsters, dwarf hamsters, and crossbred rabbits were collected from 22 pet shops randomly selected in Ankara and Kirikkale provinces, located in Central Anatolia Region of Turkey. The fecal samples were examined with centrifuge flotation technique using saturated salt solution. RESULTS: Parasitic infection rate was 57.5% in dwarf hamsters, 54.9% in Syrian hamsters, and 56.3% in crossbreed rabbits. Trichurid eggs were the most prevalent parasite in the feces of Syrians hamsters (28.1%). The other parasites of Syrian hamsters were as follows: Eimeria spp. oocysts (15.4%) and the eggs of H. nana (11.2%), Syphacia spp. (11%). and Aspiculuris spp. (5.6 %). Only trichurid eggs were observed in the fecal samples of dwarf hamsters (51.5%). Oocysts of Eimeria spp. (52.7%) and the eggs of P. ambiguus (3.6%) were detected in the feces of rabbits. CONCLUSION: Within the scope of this study, the detection of H. nana eggs, a zoonotic parasite, in the feces of Syrian hamster was quite remarkable for public health. PMID- 25016117 TI - [Investigation of the abundance of proteins secreted by Fasciola hepatica, which is exposed to environmental change in experimental studies, with an advanced proteomic approach]. AB - OBJECTIVE: Investigation of the abundance of proteins secreted by Fasciola hepatica, which is exposed to environmental change after it is removed from the main host, with an advanced proteomic approach. METHODS: Adult Fasciola hepatica parasites, obtained from the main host, were directly placed in phosphate buffered saline (PBS, at room temperature) and incubated at 37 degrees C for 2 hours (after arrival at the Institute within 1 hour). After this, without applying extra procedures, such as washing the parasites, secreted parasite proteins in PBS were investigated using an advanced proteomic method [a mass spectrometry system with electrospray ionization and quadrupole time-of-flight source coupled to ultra performance liquid chromatography, nano UPLC-ESI-QTOF-MS] with a reviewed F. hepatica protein database (Universal Protein Resource; UniProt) and data-independent acquisition method. RESULTS: With the proteomic analysis of the PBS, after incubation with the parasites, cathepsin L protease 1, fatty acid-binding protein 1 and 2, thioredoxin peroxidase (TPx), and kunitz-type proteinase inhibitor were identified. The abundance of Fasciola hepatica TPx was approximately 2-6 times higher than that of the other proteins identified in this study (p<0.01). CONCLUSION: The stress on the parasite stem from environmental change could be associated with the stimulation of the secretion of TPx. The application of advanced proteomic approaches could provide useful data in the development of effective protective methods against the parasite. PMID- 25016118 TI - [Malathion and propoxur resistance in Turkish populations of the Anopheles maculipennis Meigen (Diptera: Culicidae) and relation to the insensitive acetylcholinesterase]. AB - OBJECTIVE: The objective of this study was to evaluate insecticide resistance related to acetylcholinesterase (AChE) sensitivity and annual changes in An. maculipennis from six different populations. METHODS: Larvae and adult samples of An. maculipennis were collected from six different localities (Birecik, Beysehir, Cankiri, Avariz, Tatarkoy, Derekoy) in Turkey. Insecticide susceptibility against malathion and propoxur was determined. AChE and insensitive AChE levels were measured individually. RESULTS: All Anopheles maculipennis population mortality rates were placed in the suspected resistance category for malathion and propoxur in 2007. While Thrace region populations (Avariz, Tatarkoy, Derekoy) were placed in the surveillance category in 2008, the Birecik, Beysehir, and Cankiri populations were identified in the resistance category. According to the biochemical assay, AChE inhibition rates were high in 2007 and decreased in 2008, except in Derekoy. CONCLUSION: Our results revealed that insecticide resistance against malathion and propoxur increased from 2007 to 2008. Biochemical assay results showed that the AChE insensitivity for 2 test years and insensitive AChE frequency had increased annually. Our results also showed that extensive usage of organophosphate and carbamate for pest control in agriculture is a key factor for malathion and propoxur resistance in all tested populations rather than direct usage of mosquito control. PMID- 25016119 TI - [Economic losses during an outbreak of Simulium (Wilhelmia) species (Diptera: Simuliidae) in the Cappadocia region of Turkey]. AB - OBJECTIVE: The aim of this study was to calculate the economic losses during an outbreak of Simulium (Wilhelmia) spp. in the Cappadocia Region of Turkey. METHODS: The economic costs associated with a 2006-2007 outbreak of Simulium (Wilhelmia) spp. in the Cappadocia region of Turkey were calculated by summing losses to the livestock (dairy) industry and tourism (hotels), plus ongoing control expenditures. RESULTS: More than 2.000.000 domestic and foreign tourists, 60.000 animals, and the local population were disturbed by the flies. Tourism was the most affected sector from the Simulium outbreak. CONCLUSION: The calculated cost of the outbreak according to 2013 prices was 10.626.966 TL (US$ 5.45 million). PMID- 25016120 TI - [Two imported and relapsed of Plasmodium vivax malaria cases and primaquine prophylaxis]. AB - Malaria is a worldwide infection causing serious health and financial problems. Turkey is in the elimination phase, and malaria cases have been observed in patients who have come from abroad recently. In this study, 2 relapsed Plasmodium vivax (Pv) cases that returned from Afghanistan to our country at least 6 months ago were presented. The first case had received irregular chemoprophylaxis during travel, 6 months after returning to Turkey occurred malaria clinic. The second case had not received chemoprophlaxis during his travel, and he had experienced 2 previous episodes of malaria. He had used inappropriate anti-malarial drugs before returning to Turkey. Two separate incubation periods for P. vivax and P. ovale have been described. One of them is defined as late infection, or relapse, which is maturation of dormant bacilli in the liver, known as the hypnozoite stage. We thought that relapses of Pv infection could result from activation of hypnozoites in these cases. These 2 cases were treated with chloroquine and primaquine. The purpose of presenting these 2 cases is that primaquine should be considered for primer prophylaxis in short travels, especially after traveling to endemic areas, and the patient's relapse should be considered. PMID- 25016121 TI - [Isolated giant hydatid in kidney]. AB - Cyst hydatid of the kidney is parasitic condition caused by Echinococcus granulosus and identified in many countries, especially associated with sheep farming. Echinococcal larvae enter the bloodstream using the digestive system and invade any organs in the human body. The urinary system is the third most common area affected by parasitic infection after liver and lungs, but isolated renal involvement is a very rare situation, even in endemic areas. In our case, we aimed to report a 57-year-old female patient with an 18-centimeter isolated renal cyst hydatid treated by retroperitoneal nephrectomy. The diagnosis was based on imaging findings and confirmed by histopathologically. PMID- 25016122 TI - [Intestinal strongyloidiasis in a psoriasis patient with diabetes]. AB - This case study underlined the importance of parasitological examination before starting immunosuppressive treatment since a heavy burden of strongyloidiasis could lead to fatal infections. It represents the first strongyloidiasis from a patient with psoriasis and diabetes mellitus in this country. In the case, 59 years old female subject had psoriasis for six years and during the treatment with topical corticosteroid and anti-psorial medication, psoriatic lesions flared up. The patient had constipation and foul smelling stool complaints. Blood tests showed an increase in eosinophil and a decrease of vitamin B12 level. Stool examination indicated the presence of abundant amount of S. stercoralis larvae. The patient was given albendazole for two weeks. After treatment, the symptoms decreased and S. stercoralis larvae were not detected in stool. In this case, it was emphasized that the clinicians planning immunosuppressive regimens should bear in mind that parasitic examination could be present in the subjects. PMID- 25016123 TI - [A case of Fasciola hepatica mimicking sepsis without eosinophilia]. AB - Fasciolosis is a rare cause of hepatobiliary system infections and caused by the trematode Fasciola hepatica. It primarily infects sheeps or goats, and humans are accidental hosts. On laboratory findings, marked eosinophilia is present in most of the cases. Here, we report a case of fasciolosis without eosinophilia who was presented as sepsis and responded to therapy in second dose of triclabendazole. Sepsis like clinical presentation has been reported in few cases. Forty-eight year old female patient presented with high fever, abdominal pain, hypotension and tachycardia. The patient was considered as sepsis secondary to liver abscess, which was demonstrated on the initial abdominal ultrasonography (USG) findings. Therefore, empirical antibiotic therapy was started. Due to failure of the treatment, the image was found to be compatible with fasciolosis on control magnetic resonance imaging (MRI) and USG. On detailed anamnesis, history of eating watercress was learned and the diagnosis of fasciolosis was confirmed by serological tests. PMID- 25016124 TI - [An unusual Wohlfahrtia magnifica myiasis case localized in cutaneous and subcutaneous tissues in a patient with head-neck cancer]. AB - Auricular tumors constitute 6% of all head-neck tumors. Malignant tumors of the auricula are generally squamous or basal cell carcinomas. Myiasis rarely occurs in healthy individuals. In general, it is a parasite that is seen in patients with mental retardation or psychiatric disorders, elderly individuals, those with poor self-care and hygiene, and those with immune system disorders. In humans, it is mainly seen in tropical and subtropical regions; however, in rare instances, it may be seen in other regions of the world. In the literature, there are limited numbers of myiasis cases reported from Turkey. In this study, we aimed to present a myiasis case (Wohlfahrtia magnifica) involving cutaneous and subcutaneous tissues with an underlying head-neck cancer, which, to the best of our knowledge, has not been reported before in the literature. PMID- 25016125 TI - [Furuncle persistent to long-term antibiotic therapy in a non-tropical region: a diagnosis that must not be overlooked: furuncular cutaneous myiasis]. AB - We present the case of a 12-year-old boy with furuncular myiasis living in an area with continental climate. The boy was admitted to our clinic with a wound on his nape, which started as a little acne and progressed to a large wound in which pus flowed continuously. He complained of itching and was treated with penicillin, clarithromycin, terbinafine, and ibuprofen in the last 2 months, with no big success. Otherwise, the patient was healthy, and his hygienic conditions were within normal standards. The dermatologic examination revealed an off-white ulcer measuring approximately 1x2 cm in the occipital region with regular contours, elevated borders, and purulent flow, while the skin surrounding the ulcer was normal. In the course of the examination, a living larva was removed using a forceps. The ulcer and the surroundings were washed with polyvinylprolidone iodine solution, while fusidic acid pomade was topically applied. The ulcer regressed significantly after 15 days of treatment. PMID- 25016126 TI - The role of clinical, genetic and segregation evaluation in sudden infant death. AB - Sudden infant death syndrome (SIDS) is the leading cause of death in the first year of life. Several arrhythmogenic genes have been associated with cardiac pathologies leading to infant sudden cardiac death (SCD). Our aim was to take advantage of next generation sequencing (NGS) technology to perform a thorough genetic analysis of a SIDS case. A SIDS case was referred to our institution after negative autopsy. We performed a genetic analysis of 104 SCD-related genes using a custom panel. Confirmed variants in index case were also analyzed in relatives. Clinical evaluation of first-degree family members was performed. Relatives did not show pathology. NGS identified seven variants. Two previously described as pathogenic. Four previously catalogued without clinical significance. The seventh variation was novel. Familial segregation showed that the index case's mother carried all same genetic variations except one, which was inherited from the father. The sister of the index case carried three variants. We believe that molecular autopsy should be included in current forensic protocols after negative autopsy. In addition to NGS technologies, familial genetic testing should be also performed to clarify potential pathogenic role of new variants and to identify genetic carriers at risk of SCD. PMID- 25016128 TI - Structural and microstructural brain changes predict impairment in daily functioning. AB - BACKGROUND: Brain changes on magnetic resonance imaging (MRI) reflect accumulating pathology and have clinically disabling consequences, such as dementia. However, little is known on the relation of these MRI markers with daily functioning in nondemented individuals. We investigated whether structural and microstructural brain changes are associated with impairment in activities of daily living in a community-dwelling population. METHODS: Between 2005 and 2009, 2025 stroke-free nondemented participants (aged 59.9 years) from the population based Rotterdam Study underwent brain MRI, yielding global MRI markers, focal MRI markers, and microstructural MRI markers. We used the Stanford Health Assessment Questionnaire to assess basic activities of daily living, and the Instrumental Activities of Daily Living Scale to assess instrumental activities of daily living. Follow-up on activities of daily living was obtained between 2008 and 2013 (mean follow-up 5.7 years). We used linear regression to analyze continuous scores of daily living and logistic regression for incident impairment. RESULTS: Eighty-two participants became impaired in basic and 33 in instrumental activities of daily living. Smaller brain and hippocampal volume and higher diffusivity were associated with larger change in activities of daily living. Smaller brain volume (odds ratio [OR] 4.05 per SD; 95% confidence interval [CI], 1.81-9.02), larger white matter lesion volume (OR 1.33/SD; 95% CI 1.02-1.72) and higher mean (OR 1.55/SD; 95% CI, 1.11-2.15), axial (OR 1.49/SD; 95% CI, 1.08 2.07), and radial diffusivity (OR 1.51/SD; 95% CI, 1.09-2.10) were associated with higher risk of impairment in basic activities of daily living. CONCLUSIONS: In community-dwelling individuals, brain changes are associated with deterioration and incident impairment in daily functioning. PMID- 25016129 TI - Quantifying the pattern of microbial cell dispersion, density and clustering on surfaces of differing chemistries and topographies using multifractal analysis. AB - The effects of surface topography on bacterial distribution across a surface are of extreme importance when designing novel, hygienic or antimicrobial surface coatings. The majority of methods that are deployed to describe the pattern of cell dispersion, density and clustering across surfaces are currently qualitative. This paper presents a novel application of multifractal analysis to quantitatively measure these factors using medically relevant microorganisms (Staphylococcus aureus or Staphylococcus epidermidis). Surfaces (medical grade 316 stainless steel) and coatings (Ti-ZrN, Ti-ZrN/6.0%Ag, Ti-ZrN/15.6%Ag, TiZrN/24.7%Ag) were used in microbiological retention assays. Results demonstrated that S. aureus displayed a more heterogeneous cell dispersion (?alphaAS<1) whilst the dispersion of S. epidermidis was more symmetric and homogeneous (?alphaAS>=1). Further, although the surface topography and chemistry had an effect on cell dispersion, density and clustering, the type of bonding that occurred at the surface interface was also important. Both types of cells were influenced by both surface topographical and chemical effects; however, S. aureus was influenced marginally more by surface chemistry whilst S. epidermidis cells was influenced marginally more by surface topography. Thus, this effect was bacterially species specific. The results demonstrate that multifractal analysis is a method that can be used to quantitatively analyse the cell dispersion, density and clustering of retained microorganisms on surfaces. Using quantitative descriptors has the potential to aid the understanding the effect of surface properties on the production of hygienic and antimicrobial coatings. PMID- 25016127 TI - Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. AB - BACKGROUND: Recent descriptions of the clinical and laboratory features of subjects with acute porphyrias in the US are lacking. Our aim was to describe clinical, biochemical, and genetic features of 108 subjects. METHODS: Between September 2010 and December 2012, 108 subjects with acute porphyrias (90 acute intermittent porphyrias, 9 hereditary coproporphyrias, 9 variegate porphyrias) were enrolled into an observational study. Genetic testing was performed at a central genetic testing laboratory and clinical information entered into a central database. Selected features were compared with data for adults in the US. RESULTS: Most subjects (88/108, 81%) were female, with self-reported onset of symptoms in the second through fourth decades of life. The most common symptom was abdominal pain. Appendectomies and cholecystectomies were common before a diagnosis of porphyria. The diagnosis was delayed by a mean of 15 years. Anxiety and depression were common, and 18% complained of chronic symptoms, especially neuropathic and other pains. The incidences of systemic arterial hypertension, chronic kidney disease, seizure disorders, and psychiatric conditions were markedly increased. Mutations of the known causative genes were found in 102/105 of those tested, with novel mutations being found in 37, including in 7/8 subjects with hereditary coproporphyria. Therapy with intravenous hematin was the most effective therapy both for treatment of acute attacks and for prevention of recurrent attacks. CONCLUSIONS: Acute porphyrias often remain undiagnosed for more than a decade after first symptoms develop. Intravenous hematin is the treatment of choice, both for treatment of acute attacks and for prevention of recurrent attacks. PMID- 25016130 TI - Quantification of Staphylococcus aureus in white cheese by the improved DNA extraction strategy combined with TaqMan and LNA probe-based qPCR. AB - Four different bacterial DNA extraction strategies and two different qPCR probe chemistries were studied for detection of Stapylococcus aureus from white cheeses. Method employing trypsin treatment followed by a commercial kit application and TaqMan probe-based qPCR was the most sensitive one detecting higher counts than standards in naturally contaminated samples. PMID- 25016131 TI - Rapid, sensitive and specific detection of OXA-48-like-producing Enterobacteriaceae by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - The emergence of Enterobacteriaceae producing the class D carbapenemase OXA-48 has become a public health concern, particularly in southern Europe and in the Mediterranean area. The existing MALDI-TOF MS assays that detect carbapenemase activity have disregarded the Enterobacteriaceae producing OXA-48-like enzymes. Here, we assessed the ability of an optimized MALDI-TOF MS imipenem hydrolysis assay to detect OXA-48-like-producing Enterobacteriaceae. We tested 372 non duplicate isolates of Enterobacteriaceae from 9 species, among which 92 harbored a blaOXA-48-like gene and 180 were non-susceptible to ertapenem. The vast majority (98.9%) of the OXA-48-like producers were detected and 97.8% of the ertapenem non-susceptible isolates were correctly classified. From the agar plate to the final result, the turnaround time of the test was 90min. This quick, easy and accurate MALDI-TOF MS test can expedite the implementation of hygiene measures to prevent dissemination of OXA-48-like-producing Enterobacteriaceae and limit outbreaks. PMID- 25016132 TI - MicroRNA Let-7 regulates molting and metamorphosis in the silkworm, Bombyx mori. AB - MicroRNAs (miRNAs) are a class of endogenous, non-coding, regulatory RNA molecules that post-transcriptionally regulate gene expression by binding to the 3'UTRs of mRNA targets and thus cause their degradation or translational inhibition. In insects, important roles of miRNAs in various biological processes have been demonstrated in Drosophila melanogaster. However, biological roles of miRNAs are barely unveiled in the majority of insect species due to limited genetic tools. In the present study, we introduce the transgenic miRNA sponge (miR-SP) technology combining with the binary GAL4/UAS system in the domesticated silkworm, Bombyx mori, to exploit the biological function of an evolutionally conserved miRNA, let-7. We successfully established transgenic silkworm lines in which a miRNA sponge construct targeting BmLet-7 seed region was expressed in a ubiquitous manner directed by A3-GAL4 driver. Transgenic animals showed decreased expression of BmLet-7, leading to developmental arrestment during the larval larval and larval-pupal transition. Simultaneously, expression levels of the predicted BmLet-7 target genes, FTZ-F1 and Eip74EF (E74), key regulatory factors in the ecdysone pathway, were elevated in transgenic animals. The current study is the first report on application of the transgenic miR-SP technology in non drosophilid insects, which will not only contribute to better understanding of let-7 biological roles, but also greatly facilitate future miRNA functional analysis in insects. PMID- 25016133 TI - Elevated biomarkers of endothelial dysfunction/activation at ICU admission are associated with sepsis development. AB - Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endothelium-related molecules have been investigated as potential biomarkers for early diagnosis and/or prognosis of sepsis, providing different results depending on study designs. Such factors include endothelial adhesion molecules like E- and P-selectin, and the intercellular adhesion molecule-1, vascular endothelial cadherin, growth factors such as Angiopoietin-1 and -2 and vascular endothelial growth factor, as well as von Willebrand factor antigen. We sought to investigate whether circulating biomarkers of endothelial activation/dysfunction measured at ICU admission are associated with subsequent sepsis development. Eighty-nine critically-ill patients admitted to a general ICU who met no sepsis criteria were studied. Plasma or serum levels of the above mentioned endothelium-derived molecules were measured during the first 24h post ICU; acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, age, sex, diagnostic category, and circulating procalcitonin (PCT) and C-reactive protein (CRP) levels were additionally measured or recorded. Forty-five patients subsequently became septic and 44 did not. Soluble (s) E- and P-selectin levels, circulating PCT, SOFA score and diagnostic category were significantly different between the two groups. Multiple logistic regression analysis associated elevated sE- and sP-selectin levels and SOFA with an increased risk of developing sepsis, while multiple Cox regression analysis identified sE- and sP-selectin levels as the only parameters related to sepsis appearance with time [RR=1.026, 95%CI=1.008-1.045, p=0.005; RR=1.005 (by 10 units), 95%CI=1.000-1.010, p=0.034, respectively]. When trauma patients were independently analyzed, multiple Cox regression analysis revealed sE-selectin to be the only molecule associated with sepsis development with time (RR=1.041, 95%CI: 1.019-1.065; p<0.001). In conclusion, in our cohort of initially non-septic critically-ill patients, high levels of the circulating endothelial adhesion molecules E- and P-selectin, measured at ICU admission, appear to be associated with sepsis development in time. PMID- 25016134 TI - In vitro cytotoxicity of hydrothermally synthesized ZnO nanoparticles on human periodontal ligament fibroblast and mouse dermal fibroblast cells. AB - The use of metal oxide nanoparticles (NPs) in industrial applications has been expanding, as a consequence, risk of human exposure increases. In this study, the potential toxic effects of zinc oxide (ZnO) NPs on human periodontal ligament fibroblast cells (hPDLFs) and on mouse dermal fibroblast cells (mDFs) were evaluated in vitro. We synthesized ZnO NPs (particle size; 7-8 nm) by the hydrothermal method. Characterization assays were performed with atomic force microscopy, Braun-Emmet-Teller analysis, and dynamic light scattering. The hPDLFs and mDFs were incubated with the NPs with concentrations of 0.1, 1, 10, 50 and 100 MUg/mL for 6, 24 and 48h. Under the control and NP-exposed conditions, we have made different types of measurements for cell viability and morphology, membrane leakage and intracellular reactive oxygen species generation. Also, we monitored cell responses to ZnO NPs using an impedance measurement system in real time. While the morphological changes were visualized using scanning electron microscopy, the subcellular localization of NPs was investigated by transmission electron microscopy. Results indicated that ZnO NPs have significant toxic effects on both of the primary fibroblastic cells at concentrations of ~50-100 MUg/mL. The cytotoxicity of ZnO NPs on fibroblasts depended on concentration and duration of exposure. PMID- 25016136 TI - Robotic intracorporeal orthotopic neobladder during radical cystectomy in 132 patients. AB - PURPOSE: We present a 2-institution experience with completely intracorporeal robotic orthotopic ileal neobladder after radical cystectomy in 132 patients. MATERIALS AND METHODS: Established open surgical techniques were duplicated robotically with all neobladders suture constructed intracorporeally in a globular configuration. Nerve sparing was performed in 56% of males. Lymphadenectomy was extended (up to aortic bifurcation in 51, 44%) and superextended (up to the inferior mesenteric artery in 20, 17%). Ureteroileal anastomoses were Wallace-type (86, 65%) or Bricker-type (46, 35%). The learning curve at each institution was assessed using chronological subgroups and by trends across the entire cohort. Data were prospectively collected and retrospectively queried. RESULTS: Mean operating time was 7.6 hours (range 4.4 to 13), blood loss was 430 cc (range 50 to 2,200) and hospital stay was 11 days (median 8, range 3 to 78). Clavien grade I, II, III, IV and V complications within 30 days were 7%, 25%, 13%, 2% and 0%, respectively, and between 30 and 90 days were 5%, 9%, 11%, 1% and 2%, respectively. Mean nodal yield was 29 (range 7 to 164) and the node positivity rate was 17%. Operative time, blood loss, hospital stay and prevalence of late complications improved with experience. During a mean followup of 2.1 years (range 0.1 to 9.8) cancer recurred in 20 patients (15%). Five-year overall, cancer specific and recurrence-free survival was 72%, 72% and 71%, respectively. CONCLUSIONS: We developed a refined technique of robotic intracorporeal orthotopic neobladder diversion, duplicating open principles. Operative efficiency and outcomes improved with experience. Going forward, we propose a prospective randomized comparison between open and robotic intracorporeal neobladder surgery. PMID- 25016137 TI - Emergent care patterns in patients with spina bifida: a case-control study. AB - PURPOSE: Individuals with spina bifida are typically followed closely as outpatients by multidisciplinary teams. However, emergent care of these patients is not well defined. We describe patterns of emergent care in patients with spina bifida and healthy controls. MATERIALS AND METHODS: We reviewed Nationwide Emergency Department Sample data from 2006 to 2010. Subjects without spina bifida (controls) were selected from the sample using stratified random sampling and matched to each case by age, gender and treatment year at a 1:4 ratio. Missing emergency department charges were estimated by multiple imputation. Statistical analyses were performed to compare patterns of care among emergency department visits and charges. RESULTS: A total of 226,709 patients with spina bifida and 888,774 controls were identified. Mean age was 28.2 years, with 34.6% of patients being younger than 21. Patients with spina bifida were more likely than controls to have public insurance (63.7% vs 35.4%, p <0.001) and to be admitted to the hospital from the emergency department (37.0% vs 9.2%, p <0.001). Urinary tract infections were the single most common acute diagnosis in patients with spina bifida seen emergently (OR 8.7, p <0.001), followed by neurological issues (OR 2.0, p <0.001). Urological issues were responsible for 34% of total emergency department charges. Mean charges per encounter were significantly higher in spina bifida cases vs controls ($2,102 vs $1,650, p <0.001), as were overall charges for patients subsequently admitted from emergent care ($36,356 vs $29,498, p <0.001). CONCLUSIONS: Compared to controls, patients with spina bifida presenting emergently are more likely to have urological or neurosurgical problems, to undergo urological or neurosurgical procedures, to be admitted from the emergency department and to incur higher associated charges. PMID- 25016138 TI - Different colors of light lead to different adaptation and activation as determined by high-density EEG. AB - Light adaptation is crucial for coping with the varying levels of ambient light. Using high-density electroencephalography (EEG), we investigated how adaptation to light of different colors affects brain responsiveness. In a within-subject design, sixteen young participants were adapted first to dim white light and then to blue, green, red, or white bright light (one color per session in a randomized order). Immediately after both dim and bright light adaptation, we presented brief light pulses and recorded event-related potentials (ERPs). We analyzed ERP response strengths and brain topographies and determined the underlying sources using electrical source imaging. Between 150 and 261 ms after stimulus onset, the global field power (GFP) was higher after dim than bright light adaptation. This effect was most pronounced with red light and localized in the frontal lobe, the fusiform gyrus, the occipital lobe and the cerebellum. After bright light adaptation, within the first 100 ms after light onset, stronger responses were found than after dim light adaptation for all colors except for red light. Differences between conditions were localized in the frontal lobe, the cingulate gyrus, and the cerebellum. These results indicate that very short-term EEG brain responses are influenced by prior light adaptation and the spectral quality of the light stimulus. We show that the early EEG responses are differently affected by adaptation to different colors of light which may contribute to known differences in performance and reaction times in cognitive tests. PMID- 25016139 TI - Fracture analysis of randomized implant-supported fixed dental prostheses. AB - OBJECTIVE: Fractures of posterior fixed dental all-ceramic prostheses can be caused by one or more factors including prosthesis design, flaw distribution, direction and magnitude of occlusal loading, nature of supporting infrastructure (tooth root/implant), and presence of adjacent teeth. This clinical study of implant-supported, all-ceramic fixed dental prostheses, determined the effects of (1) presence of a tooth distal to the most distal retainer; (2) prosthesis loading either along the non-load bearing or load bearing areas; (3) presence of excursive contacts or maximum intercuspation contacts in the prosthesis; and (4) magnitude of bite force on the occurrence of veneer ceramic fracture. METHODS: 89 implant-supported FDPs were randomized as either a three-unit posterior metal ceramic (Au-Pd-Ag alloy and InLine POM, Ivoclar, Vivadent) FDP or a ceramic ceramic (ZirCAD and ZirPress, Ivoclar, Vivadent) FDP. Two implants (Osseospeed, Dentsply) and custom abutments (Atlantis, Dentsply) supported these FDPs, which were cemented with resin cement (RelyX Universal Cement). Baseline photographs were made with markings of teeth from maximum intercuspation (MI) and excursive function. Patients were recalled at 6 months and 1-3 years. Fractures were observed, their locations recorded, and images compared with baseline photographs of occlusal contacts. CONCLUSION: No significant relationship existed between the occurrence of fracture and: (1) the magnitude of bite force; (2) a tooth distal to the most distal retainer; and (3) contacts in load-bearing or non-load-bearing areas. However, there was a significantly higher likelihood of fracture in areas with MI contacts only. CLINICAL SIGNIFICANCE: Because of the absence of a periodontal ligament, this clinical study demonstrates that there is a need to evaluate occlusion differently with implant-supported prostheses than with natural tooth supported prostheses. Implant supported prostheses should have minimal occlusion and lighter contacts than those supported by natural dentition. CLINICAL TRIALSGOV NO: K23 D2007-46. PMID- 25016140 TI - Racial/ethnic disparities in human DNA methylation. AB - The racial/ethnic disparities in DNA methylation patterns indicate that molecular markers may play a role in determining the individual susceptibility to diseases in different ethnic groups. Racial disparities in DNA methylation patterns have been identified in prostate cancer, breast cancer and colorectal cancer and are related to racial differences in cancer prognosis and survival. PMID- 25016141 TI - Neem components as potential agents for cancer prevention and treatment. AB - Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-kappaB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment. PMID- 25016142 TI - Inner ear tissue preservation by rapid freezing: improving fixation by high pressure freezing and hybrid methods. AB - In the preservation of tissues in as 'close to life' state as possible, rapid freeze fixation has many benefits over conventional chemical fixation. One technique by which rapid freeze-fixation can be achieved, high pressure freezing (HPF), has been shown to enable ice crystal artefact-free freezing and tissue preservation to greater depths (more than 40 MUm) than other quick-freezing methods. Despite increasingly becoming routine in electron microscopy, the use of HPF for the fixation of inner ear tissue has been limited. Assessment of the quality of preservation showed routine HPF techniques were suitable for preparation of inner ear tissues in a variety of species. Good preservation throughout the depth of sensory epithelia was achievable. Comparison to chemically fixed tissue indicated that fresh frozen preparations exhibited overall superior structural preservation of cells. However, HPF fixation caused characteristic artefacts in stereocilia that suggested poor quality freezing of the actin bundles. The hybrid technique of pre-fixation and high pressure freezing was shown to produce cellular preservation throughout the tissue, similar to that seen in HPF alone. Pre-fixation HPF produced consistent high quality preservation of stereociliary actin bundles. Optimising the preparation of samples with minimal artefact formation allows analysis of the links between ultrastructure and function in inner ear tissues. PMID- 25016143 TI - Morphological brain network assessed using graph theory and network filtration in deaf adults. AB - Prolonged deprivation of auditory input can change brain networks in pre- and postlingual deaf adults by brain-wide reorganization. To investigate morphological changes in these brains voxel-based morphometry, voxel-wise correlation with the primary auditory cortex, and whole brain network analyses using morphological covariance were performed in eight prelingual deaf, eleven postlingual deaf, and eleven hearing adults. Network characteristics based on graph theory and network filtration based on persistent homology were examined. Gray matter density in the primary auditor cortex was preserved in prelingual deafness, while it tended to decrease in postlingual deafness. Unlike postlingual, prelingual deafness showed increased bilateral temporal connectivity of the primary auditory cortex compared to the hearing adults. Of the graph theory-based characteristics, clustering coefficient, betweenness centrality, and nodal efficiency all increased in prelingual deafness, while all the parameters of postlingual deafness were similar to the hearing adults. Patterns of connected components changing during network filtration were different between prelingual deafness and hearing adults according to the barcode, dendrogram, and single linkage matrix representations, while these were the same in postlingual deafness. Nodes in fronto-limbic and left temporal components were closely coupled, and nodes in the temporo-parietal component were loosely coupled, in prelingual deafness. Patterns of connected components changing in postlingual deafness were the same as hearing adults. We propose that the preserved density of auditory cortex associated with increased connectivity in prelingual deafness, and closer coupling between certain brain areas, represent distinctive reorganization of auditory and related cortices compared with hearing or postlingual deaf adults. The differential network reorganization in the prelingual deaf adults could be related to the absence of auditory speech experience. PMID- 25016144 TI - Vitamin D supplementation promotes macrophages' anti-mycobacterial activity in type 2 diabetes mellitus patients with low vitamin D receptor expression. AB - The increasing number of people with type 2 diabetes (DM2) is alarming and if it is taken into account that the relative odds of developing tuberculosis in diabetic patients ranges from 2.44 to 8.33 compared with non-diabetic patients, thus in developing countries where these two diseases are encountering face to face, there is a need for prophylaxis strategies. The role of vitamin D has been widely implicated in growth control of Mycobacterium tuberculosis (Mtb) during primary infection mainly through the induction of certain antimicrobial peptides (AMPs). In this study we evaluated the vitamin D serum levels, CYP27B1 hydroxylase enzyme, vitamin D receptor (VDR) and AMPs gene expression in Healthy donors, DM2 and TB patients. Results showed that DM2 group has lower VDR and AMPs expression levels. When Monocytes Derived Macrophages (MDM) from DM2 patients with low VDR expression were supplemented with vitamin D, MDMs eliminate efficiently M. tuberculosis. This preliminary study suggests the use of vitamin D as prophylaxis for tuberculosis in high DM2 endemic countries. PMID- 25016145 TI - AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. AB - Lipid accumulation is a central event in the development of chronic metabolic diseases, including obesity and type 2 diabetes, but the mechanisms responsible for lipid accumulation are incompletely understood. This study was designed to investigate the mechanisms for excess nutrient-induced lipid accumulation and whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic lipid accumulation in excess nutrient-treated HepG2 cells and high fat diet (HFD) fed mice. Exposure of HepG2 cells to high levels of glucose or palmitate induced the endoplasmic reticulum (ER) stress response, activated sterol regulatory element-binding protein-1 (SREBP-1), and enhanced lipid accumulation, all of which were sensitive to ER stress inhibitor and gene silencing of eukaryotic initiation factor 2alpha. The increases in ER stress response and lipid accumulation were associated with activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Inhibition of mTORC1 signaling attenuated the ER stress response and lipid accumulation induced by high glucose or by deletion of tuberous sclerosis 2. In addition, AMPK activation prevented the mTORC1 activation, ER stress response, and lipid accumulation. This effect was mimicked or abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Finally, treatment of HFD-fed mice with 5 aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibited the mTORC1 pathway, suppressed the ER stress response, and prevented insulin resistance and hepatic lipid accumulation. We conclude that activation of AMPK prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 and ER stress response. PMID- 25016146 TI - Uninephrectomy augments the effects of high fat diet induced obesity on gene expression in mouse kidney. AB - Obesity has been reported as an independent risk factor for chronic kidney disease, leading to glomerulosclerosis and renal insufficiency. To assess the relationship between a reduced nephron number and a particular susceptibility to obesity-induced renal damage, mice underwent uninephrectomy (UNX) followed by either normal chow or high-fat diet (HFD) and were compared with sham-operated control mice. After 20 weeks of dietary intervention, HFD-fed control mice presented characteristic features of progressive nephropathy, including albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. These changes were more pronounced in HFD-fed mice that had undergone uninephrectomy. Analysis of gene expression in mouse kidney by whole genome microarrays indicated that high fat diet led to more changes in gene expression than uninephrectomy. HFD affected mainly genes involved in lipid metabolism and transport, whereas the combination of UNX and HFD additionally altered the expression of genes belonging to cytoskeleton remodeling, fibrosis and hypoxia pathways. Canonical pathway analyses identified the farnesoid X receptor (FXR) as a potential key mediator for the observed changes in gene expression associated with UNX-HFD. In conclusion, HFD-induced kidney damage is more pronounced following uninephrectomy and is associated with changes in gene expression that implicate FXR as a central regulatory pathway. PMID- 25016147 TI - Catecholaminergic polymorphic ventricular tachycardia in a child with Brugada pattern on ECG: one patient with two diseases? PMID- 25016148 TI - Prevalence of type 1 Brugada ECG pattern after administration of Class 1C drugs in patients with type 1 myotonic dystrophy: Myotonic dystrophy as a part of the Brugada syndrome. AB - BACKGROUND: Both type 1 myotonic dystrophy (MD1) and Brugada syndrome (BrS) may be complicated by conduction disturbances and sudden death. Spontaneous BrS has been observed in MD1 patients, but the prevalence of drug-induced BrS in MD1 is unknown. OBJECTIVE: The purpose of this study was to prospectively assess the prevalence of type 1 ST elevation as elicited during pharmacologic challenge with Class 1C drugs in a subgroup of MD1 patients and to further establish correlations with ECG and electrophysiologic variables and prognosis. METHODS: From a group of unselected 270 MD1 patients, ajmaline or flecainide drug challenge was performed in a subgroup of 44 patients (27 men, median age 43 years) with minor depolarization/repolarization abnormalities suggestive of possible BrS. The presence of type 1 ST elevation after drug challenge was correlated to clinical, ECG, and electrophysiologic variables. RESULTS: Eight of 44 patients (18%) presented with BrS after drug challenge. BrS was seen more often in men (26% vs 6%, P = .09) and was related to younger age (35 vs 48 years, P = .07). BrS was not correlated to symptoms, baseline ECG, HV interval, results of signal-averaged ECG, or abnormalities on ambulatory recordings. MD1 patients with BrS had longer corrected QT intervals, greater increase in PR interval after drug challenge, and higher rate of inducible ventricular arrhythmias (62% vs 21%, P = .03). Twelve patients were implanted with a pacemaker and 5 with an implantable cardioverter-defibrillator. Significant bradycardia did not occur in any patients, and malignant ventricular arrhythmia never occurred during median 7 year follow-up (except 1 hypokalemia-related ventricular fibrillation). CONCLUSION: BrS is elicited by a Class 1 drug in 18% of MD1 patients presenting with minor depolarization/repolarization abnormalities at baseline, but the finding seems to be devoid of a prognostic role. PMID- 25016149 TI - To the editor- does the cervical vagus contain sympathetic fibers that act on the heart? PMID- 25016150 TI - Catheter ablation of postinfarction ventricular tachycardia: ten-year trends in utilization, in-hospital complications, and in-hospital mortality in the United States. AB - BACKGROUND: There is a paucity of data regarding the complications and in hospital mortality after catheter ablation for ventricular tachycardia (VT) in patients with ischemic heart disease. OBJECTIVE: The purpose of this study was to determine the temporal trends in utilization, in-hospital mortality, and complications of catheter ablation of postinfarction VT in the United States. METHODS: We used the 2002-2011 Nationwide Inpatient Sample (NIS) database to identify all patients >=18 years of age with a primary diagnosis of VT (International Classification of Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code 427.1) and who also had a secondary diagnosis of prior history of myocardial infarction (ICD-9-CM 412). Patients with supraventricular arrhythmias were excluded. Patients who underwent catheter ablation were identified using ICD 9-CM procedure code 37.34. Temporal trends in catheter ablation, in-hospital complications, and in-hospital mortality were analyzed. RESULTS: Of 81,539 patients with postinfarct VT, 4653 (5.7%) underwent catheter ablation. Utilization of catheter ablation increased significantly from 2.8% in 2002 to 10.8% in 2011 (Ptrend < .001). The overall rate of any in-hospital complication was 11.2% (523/4653), with vascular complications in 6.9%, cardiac in 4.3%, and neurologic in 0.5%. In-hospital mortality was 1.6% (75/4653). From 2002 to 2011, there was no significant change in the overall complication rates (8.4% to 10.2%, Ptrend = .101; adjusted odds ratio [per year] 1.02, 95% confidence interval 0.98 1.06) or in-hospital mortality (1.3% to 1.8%, Ptrend = .266; adjusted odds ratio [per year] 1.03, 95% confidence interval 0.92-1.15). CONCLUSION: The utilization rate of catheter ablation as therapy for postinfarct VT has steadily increased over the past decade. However, procedural complication rates and in-hospital mortality have not changed significantly during this period. PMID- 25016151 TI - Reply to the editor-does the cervical vagus contain sympathetic fibers that act on the heart? PMID- 25016152 TI - Comparison of sphere-forming capabilities of the cochlear stem cells derived from apical, middle and basal turns of murine organ of Corti. AB - The presence of stem cells in the organ of Corti raises the hope of regeneration of mammalian inner ear cells. However, little is known about the distribution of endogenous stem cells in the inner ear as well as their sphere-forming abilities. The aim of this study is to evaluate the stem cells derived from different turns of the organ of Corti and analyze the sphere-forming capabilities of these stem cells. We dissected and isolated cochleae from postnatal day 1, 7 and 14 mice to separate organ of Corti into apical, middle and basal turns for cell isolation. Our results show that different turns of the organ of Corti harbor distinctly different populations of stem cells. Apical turn-derived cells give rise to more sphere-forming cells than middle and basal turn-derived cells, and middle turn derived cells give rise to sphere cells number significantly higher than basal turn. Our findings indicate that apical turn of young age murine organ of Corti is best suited for isolation of endogenous stem cells for regeneration of hearing loss. PMID- 25016153 TI - Nitric oxide show its survival role by NO-PKC pathway through cGMP-dependent or independent on the culture of cerebella granular neurons. AB - The role of nitric oxide in the development of neurons is conflicting. In the present work, cerebellar granule neurons (CGNs) were used as a model to assess the survival role of nitric oxide and to find novel signal transduction pathways related to this role. It is reported that sustained inhibition of nitric oxide production induces apoptosis in differentiated cerebellar granule neurons. The antagonist (MK-801, or ODQ)-induced decrease of cell viability, caspase-3 activated, the expression of P-PKC decreased, which were normalized by the provision of the sodium nitroprusside, an NO donor. The data show that blockade of NO production induces apoptotic death in differentiating CGC through activation of caspase-3. This study provides direct evidence that NO plays an active role in sustaining the survival of developing CGNs and that NO-PKC pathway is important for the survival of CGNs in vitro. The endogenous NO exerts its effects in cGMP-dependent manner while the exogenous NO in cGMP-independent manner. PMID- 25016154 TI - A fast method for the determination of the PC/LPC ratio in intact serum by MALDI TOF MS: an easy-to-follow lipid biomarker of inflammation. AB - The PC/LPC ratio of blood serum is increasingly considered to represent an important clinical parameter that reflects various kinds of diseases. Here, a simple and fast method of lipid analyses of "intact" blood serum (i.e. without extraction) by MALDI-TOF mass spectrometry is described. The novel procedure allows the accurate determination of the PC/LPC ratio, utilizing only a tiny amount of blood. The serum is diluted with distilled water and directly applied onto the MALDI target and, after drying, covered by a thin layer of the matrix solution (either 9-aminoacridine or 2,5-dihydroxybenzoic acid). Positive ion mass spectra acquired by using this procedure give similar peak patterns as the spectra of the lipid extracts of horse blood serum. Blood serum from fourteen different horses was used to set up and validate the new method of lipid analysis. The PC/LPC ratios determined with the fast "intact" method were compared with those obtained with classical MALDI-TOF MS and (31)P NMR analyses of the corresponding lipid extracts. As comparable data were obtained, this is a clear indication that extraction is not an absolute necessity. PMID- 25016155 TI - Interactions of isoniazid with membrane models: implications for drug mechanism of action. AB - This work focuses on the application of biophysical techniques to assess the interaction of isoniazid (INH) with three-dimensional cell membrane mimetic models. Liposomes made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were used as cell membrane lipids, being the interactions of the drug studied under different pH conditions to mimic the in vivo near neutral physiological pH found in the cytoplasm and the acidic conditions encountered in the protective gastric barrier and in the macrophage intracellular acidic compartments (i.e., phagosomes and phagolysomes). The effect of INH on the biophysical parameters of the cell membrane lipids was assessed by dynamic light scattering (DLS) and small-angle X ray scattering (SAXS). The overall results highlighted the importance of the pH for the interactions of INH with biological membranes. A relationship between the effect of INH on the biophysical properties of the membranes and the pH was established. In fact, the experimental results point to a higher affinity of the drug to the acidic environments, which not only explain its sequestration in the infected cells but also some of its side-effects. PMID- 25016156 TI - Comparison of lab, pilot, and industrial scale low consistency mechanical refining for improvements in enzymatic digestibility of pretreated hardwood. AB - Mechanical refining has been shown to improve biomass enzymatic digestibility. In this study industrial high-yield sodium carbonate hardwood pulp was subjected to lab, pilot and industrial refining to determine if the mechanical refining improves the enzymatic hydrolysis sugar conversion efficiency differently at different refining scales. Lab, pilot and industrial refining increased the biomass digestibility for lignocellulosic biomass relative to the unrefined material. The sugar conversion was increased from 36% to 65% at 5 FPU/g of biomass with industrial refining at 67.0 kWh/t, which was more energy efficient than lab and pilot scale refining. There is a maximum in the sugar conversion with respect to the amount of refining energy. Water retention value is a good predictor of improvements in sugar conversion for a given fiber source and composition. Improvements in biomass digestibility with refining due to lab, pilot plant and industrial refining were similar with respect to water retention value. PMID- 25016157 TI - Synthesis and sigma receptor affinity of regioisomeric spirocyclic furopyridines. AB - In order to investigate systematically the effect of the position of the pyridine N-atom on the sigma1 receptor affinity four regioisomeric furopyridines 2a-d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a-d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a-d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a-d showed 7- to 12-fold lower sigma1 affinity than the benzofuran analog 1. The reduced sigma1 affinity of the furopyridines 2a-d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same sigma1 affinity (Ki = 4.9-10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded. PMID- 25016158 TI - Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles. AB - There is no effective clinical therapy yet for triple-negative breast cancer (TNBC) without particular human epidermal growth factor receptor-2, estrogen and progesterone receptor expression. In this study, we report a molecularly targeted and synthetic lethality-based siRNA therapy for TNBC treatment, using cationic lipid assisted poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the siRNA carrier. It is demonstrated that only in c-Myc overexpressed TNBC cells, while not in normal mammary epithelial cells, delivery of siRNA targeting cyclin-dependent kinase 1 (CDK1) with the nanoparticle carrier (NPsiCDK1) induces cell viability decreasing and cell apoptosis through RNAi-mediated CDK1 expression inhibition, indicating the synthetic lethality between c-Myc with CDK1 in TNBC cells. Moreover, systemic delivery of NPsiCDK1 is able to suppress tumor growth in mice bearing SUM149 and BT549 xenograft and cause no systemic toxicity or activate the innate immune response, suggesting the therapeutic promise with such nanoparticles carrying siCDK1 for c-Myc overexpressed triple negative breast cancer. PMID- 25016159 TI - Structure and evolution analysis of pollen receptor-like kinase in Zea mays and Arabidopsis thaliana. AB - Receptor-like kinase (RLKs) is an important member in protein kinase family which is widely involved in plant growth, development and defense responses. It is significant to analyze the kinase structure and evolution of pollen RLKs in order to study their mechanisms. In our study, 64 and 73 putative pollen RLKs were chosen from maize and Arabidopsis. Phylogenetic analysis showed that the pollen RLKs were conservative and might had existed before divergence between monocot and dicot which were mainly concentrated in RLCK-VII and LRR-III two subfamilies. Chromosomal localization and gene duplication analysis showed the expansion of pollen RLKs were mainly caused by segmental duplication. By calculating Ka/Ks value of extracellular domain, intracellular domain and kinase domain in pollen RLKs, we found that the pollen RLKs duplicated genes had mainly experienced the purifying selection, while maize might have experienced weaker purifying selection. Meanwhile, extracellular domain might have experienced stronger diversifying selection than intracellular domain in both species. Estimation of duplication time showed that the duplication events of Arabidopsis have occurred approximately between 18 and 69 million years ago, compared to 0.67-170 million years ago of maize. PMID- 25016160 TI - Hemolymph chemistry and histopathological changes in Pacific oysters (Crassostrea gigas) in response to low salinity stress. AB - This study described seasonal differences in the histopathological and hemolymph chemistry changes in different family lines of Pacific oysters, Crassostrea gigas, in response to the stress of an abrupt change to low salinity, and mechanical grading. The most significant changes in pallial cavity salinity, hemolymph chemistry and histopathological findings occurred in summer at low salinity. In summer (water temperature 18 degrees C) at low salinity, 9 (25.7% of full salinity), the mean pallial cavity salinity in oysters at day 3 was 19.8+/ 1.6 (SE) and day 10 was 22.8+/-1.6 (SE) lower than oysters at salinity 35. Associated with this fall in pallial cavity salinity, mean hemolymph sodium for oysters at salinity 9 on day 3 and 10 were 297.2mmol/L+/-20(SE) and 350.4mmol/L+/ 21.3(SE) lower than oysters at salinity 35. Similarly mean hemolymph potassium in oysters held at salinity 9 at day 3 and 10 were 5.6mmol/L+/-0.6(SE) and 7.9mmol/L+/-0.6 (SE) lower than oysters at salinity 35. These oysters at low salinity had expanded intercellular spaces and significant intracytoplasmic vacuolation distending the cytoplasm of epithelial cells in the alimentary tract and kidney and hemocyte infiltrate (diapedesis) within the alimentary tract wall. In contrast, in winter (water temperature 8 degrees C) oyster mean pallial cavity salinity only fell at day 10 and this was by 6.0+/-0.6 (SE) compared to that of oysters at salinity 35. There were limited histopathological changes (expanded intercellular spaces and moderate intracytoplasmic vacuolation of renal epithelial cells) in these oysters at day 10 in low salinity. Mechanical grading and family line did not influence the oyster response to sudden low salinity. These findings provide additional information for interpretation of non-lethal, histopathological changes associated with temperature and salinity variation. PMID- 25016161 TI - A folding study of Antarctic krill (Euphausia superba) alkaline phosphatase using denaturants. AB - To gain insight into the structural and folding mechanisms of Antarctic krill alkaline phosphatase (ALP), the enzyme was properly purified by (NH4)2SO4 fractionation and by both Sephadex G-75 and DEAE anion exchange chromatography. The purified enzyme (62.6 kDa; 2.62 unit/mg) was unstable at temperatures exceeding 30 degrees C. Denaturants, such as sodium dodecyl sulfate (SDS), guanidine HCl, and urea, were applied to evaluate the folding mechanism, including kinetics and thermodynamics, of krill ALP. Sodium dodecyl sulfate elicited no significant effect on ALP activity even at excessively high concentrations (300 mM), whereas guanidine HCl and urea effectively inactivated the enzyme at concentrations of 2 and 3.5 M, respectively. Kinetic studies showed that the enzymatic inhibition by guanidine HCl and urea represented a first-order reaction that was a monophasic unfolding process. This process was found to be associated with conformational changes without significant transient free-energy changes. Additionally, the overall structural changes occurred proximally to the active site pocket. Our study provides new insight into ALP of the Antarctic krill, which lives in extreme environmental conditions. PMID- 25016162 TI - Definitions of deafblindness and congenital deafblindness. AB - In order to compile knowledge on deafblindness (DB) and congenital deafblindness (CDB), one important factor is comparison of results between different scientific studies. In an attempt to do a systematic review of the literature on cognitive assessment and CDB, considerable difficulties in determining eligibility of the studies were encountered due to heterogeneity in definitions and inclusion criteria used in the articles. The present systematic review aims to provide both an overview of this terminological and methodological heterogeneity and suggestions for better future research practices. A systematic review of definitions used in (N=30) studies employing psychological assessment of people with CDB served as a sample of the scientific literature on DB and CDB. Absent or heterogeneous definitions and inclusion criteria regarding both DB and CDB are evident in the sample. Fifty percent of the studies reported no definition of DB and 76.7% reported no definition of CDB. Main discrepancies are: (1) medical/functional versus ability/functioning definitions regarding DB; and (2) different criteria for onset of DB in the case of defining CDB (e.g. age versus developmental level). The results of this study call attention to a scientifically inadequate approach to the study of DB and CDB. Findings indicate that clear guidelines for sample descriptions of the DB and/or CDB populations are needed. It is suggested that studies including DB and CDB participants provide the following information: definitions of DB and CDB used; severity of sensory impairments; level of sensory ability in relation to mobility, access to information, and communication; age at onset of DB; and communication as well as language ability at onset of DB. PMID- 25016163 TI - Enantioselective analysis of tolvaptan in rat and dog sera by high-performance liquid chromatography and application to pharmacokinetic study. AB - Tolvaptan is a competitive vasopressin V2-receptor antagonist that inhibits water reabsorption in the renal collecting ducts. A selective high-performance liquid chromatography method for determining tolvaptan enantiomers in rat and dog sera was developed and validated. Benzyl salicylate was used as an internal standard. Sample preparation involved liquid-liquid extraction with an n-hexane:diethyl ether (1:1, v/v) solution, followed by solid-phase extraction using a silica-gel cartridge. Chromatographic separation was performed on a cellulose-based chiral stationary phase in the reversed phase mode. The analytes were monitored with UV detection. The calibration curve showed linearity over the concentration range from 0.025 to 2.5 MUg/mL for each analyte. Precision as the percentage coefficient of variation did not exceed 14.8%, and accuracy as relative error was within +/-14.6% for the analytes. The validated method was successfully applied to evaluate the pharmacokinetics of oral tolvaptan enantiomers in rats and dogs, indicating gender and species differences in the systemic exposure to tolvaptan enantiomers. PMID- 25016164 TI - Simultaneous determination of timosaponin B-II and A-III in rat plasma by LC MS/MS and its application to pharmacokinetic study. AB - A rapid, specific and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the simultaneous determination of timosaponin B-II (TB-II) and A-III (TA-III) in rat plasma. Plasma samples were pretreated via simple protein precipitation with acetonitrile and ginsenoside Rg2 was used as internal standard. Chromatographic separation was carried out on an Agilent XDB-C8 (150 mm * 2.1mm i.d., 5 MUm) column by isocratic elution with acetonitrile-2 mmol/L ammonium acetate (55:45, v/v). The detection was performed on a Sciex API 4000(+) triple-quadrupole tandem mass spectrometer with TurboIonSpray ionization (ESI) inlet via the negative ion multiple reaction monitoring (MRM) mode. The results showed that the calibration curve was linear in the concentration range of 3-3,000 ng/mL for TB-II and 0.3-3,000 ng/mL for TA III, respectively. The intra- and inter-day precisions were less than 13.25%, and the accuracy ranged from 100.88% to 104.07% at three QC levels for both. The pharmacokinetic profiles of TB-II and TA-III in timosaponins (total timosaponin) at three dose levels (TB-II 150, 300, 600 mg/kg and TA-III 0.59, 1.17, 2.34 mg/kg, respectively) and in timosaponins-Huangbai alkaloids mixtures (1:1, 1:3, w/w, TB-II 300 mg/kg and TA-III 1.17 mg/kg) were studied for the first time in rats by this LC-MS/MS method. After single oral administration of timosaponins, mean Cmax and AUC0-t of TB-II and TA-III increased but non-proportional to the oral doses. When timosaponins-Huangbai alkaloids (1:1, 1:3, w/w) mixtures were administered, Cmax and AUC0-t of TB-II in the mixtures were obviously higher than the corresponding values in timosaponins at the same dose level. PMID- 25016165 TI - Quantitative determination of microbicidal spermicide 'nonoxynol-9' in rabbit plasma and vaginal fluid using LC-ESI-MS/MS: application to pharmacokinetic study. AB - Nonoxynol-9 (N-9), a microbicidal spermicide, has been in use as an over-the counter contraceptive since the 1960s. A detailed account of its pharmacokinetic profile using highly sensitive detection method has not been reported yet. We developed and validated a rapid, selective and sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for N-9 detection in plasma and simulated vaginal fluid. The analytes were quantified using reverse phase Thermo Accucore C18 (150 mm * 4.6mm, 5 MUm) column with isocratic elution using acetonitrile: 0.1% formic acid in triple distilled water (90:10, v/v) as mobile phase. The ionization was optimized using ESI (+) and selectivity was achieved by tandem mass spectrometric analysis using MRM transition, m/z 617.4->133.2 for N-9 and m/z 180.1->138.1 for phenacetin. The method was linear over the range 0.195-100 ng/mL. The method was accurate and precise with intra-batch and inter-batch accuracy (% bias) of less than +/- 15% and precision (% CV) of <15% for N-9. The mean peak plasma concentration (Cmax) 4.87 +/- 0.37 ng/mL was achieved 1.0h after vaginal application with terminal half-life 1.45 +/- 0.07 h in rabbits. The validated method was successfully applied for pharmacokinetic study of N-9 in rabbits after vaginal administration. PMID- 25016166 TI - Simultaneous determination of metformin and vildagliptin in human plasma by a HILIC-MS/MS method. AB - The objective of this work was to develop and validate a HILIC-MS/MS method for the simultaneous determination of metformin and vildagliptin in human plasma. Chromatographic separation was achieved using an Atlantis HILIC Silica 150-mm * 2.1-mm, 3-MUm particle size column maintained at 40 degrees C. The isocratic mobile phase consisted of 20% water and 80% acetonitrile/water solution 95:5 (v/v), containing both 0.1% formic acid and 3mM ammonium formate. The flow rate was maintained at 400 MUL min(-1). Data from validation studies demonstrated that the new method is highly selective, sensitive (limits of detection <1.5 ng mL( 1)) and free of matrix and residual effects. The new method was also precise (RSD<9.0%), accurate (RE<11.2%) and linear (r >= 0.99) over the ranges of 5-500 ng mL(-1) for each compound. The developed method was successfully applied to determine metformin and vildagliptin in plasma volunteers who orally received a single dose of metformin (850 mg), vildagliptin (50mg) or drug association (metformin 850 mg+vildagliptin 50mg). The new method can thus also be used as a tool for the clinical monitoring of metformin and vildagliptin. PMID- 25016167 TI - Lysine-based chiral vesicles. AB - Uni-lamellar and multi-lamellar vesicles were prepared by the enantiomers of a biological molecule, L-lysine or D-lysine, with a double-tail weak monoacid, di (2-ethylhexyl) phosphoric acid (abbreviated as DEHPA), in water. With the addition of DEHPA to lysine aqueous solutions, ion-pairs are formed through the acid-base reaction between the lysine cations and DEHP(-) anions. The self assembled vesicles were proved to be driven by the hydrogen bonding between the side-chain amino groups in lysine molecules and the polar groups of DEHP(-) species. The combination of DEHPA and lysine through electrostatic interactions and hydrogen bonding reduces the cross-sectional area of the hydrophilic groups, improving the surface activity and inducing a microstructural transition from primitive aggregates to micelles, and to vesicles in solution. Due to the chirality of the lysine molecules, the aggregates exhibited diverse chiral properties along with the microstructural transitions. PMID- 25016168 TI - Electrochemically active biofilm assisted synthesis of Ag@CeO2 nanocomposites for antimicrobial activity, photocatalysis and photoelectrodes. AB - Ag@CeO2 nanocomposites were synthesized by a biogenic and green approach using electrochemically active biofilms (EABs) as a reducing tool. The as-synthesized Ag@CeO2 nanocomposites were characterized and used in antimicrobial, visible light photocatalytic and photoelectrode studies. The Ag@CeO2 nanocomposites showed effective and efficient bactericidal activities and survival test against Escherichia coli O157:H7, and Pseudomonas aeruginosa. The as-synthesized Ag@CeO2 nanocomposites also exhibited enhanced visible light photocatalytic degradation of 4-nitrophenol and methylene blue than pure CeO2. A photocatalytic investigation showed that the Ag@CeO2 nanocomposites possessed excellent visible light photocatalytic activities compared to pure CeO2. Electrochemical impedance spectroscopy and photocurrent measurements showed that the as-synthesized Ag@CeO2 nanocomposites exhibited excellent and enhanced responses to visible light irradiation. These results suggest that the AgNPs anchored at CeO2 induced visible light photoactivity by decreasing the recombination of photogenerated electrons and holes, and extending the response of pure CeO2 to visible light. Overall, as-synthesized Ag@CeO2 nanocomposites are smart materials that can be used for a range of applications, such as antimicrobial activity, visible light photocatalysis and photoelectrode. PMID- 25016169 TI - The effect of environmental mycotoxins on selected ovarian tissue fragments of multiparous female wild boars at the beginning of astronomical winter. AB - The contamination of plant material with mycotoxins, in particular of the genus Fusarium, is common in the natural environment. Multiparous female wild boars are exposed to feed contaminated with zearalenone (ZEN) and deoxynivalenol throughout the year. The aim of this study was to determine the concentrations of the above mycotoxins in multiparous female wild boars and to describe their effect on the histological structure of the ovaries at the beginning of astronomical winter. Toxicological examinations revealed 0.291 ng/ml of ZEN, 0.406 ng/ml of alpha zearalenol (alpha-ZEL), 0.392 ng/ml beta-zearalenol (beta-ZEL) and an absence of deoxynivalenol (values below the sensitivity of the method) in the blood plasma of multiparous female wild boars. Numerous ovarian follicles at various stages of development, characterized by different degree of damage, were observed. Numerous deformed resting ovarian follicles were noted directly under the epithelium, and signs of follicular atresia and hyalinization were observed. Blood vessels in the medulla of the ovary were dilated, which probably improved the distribution of ZEN in the ovaries. Higher substrate (ZEN) concentrations in the ovaries led to an insignificant increase in the staining intensity of 3beta-HSD and 17beta-HSD clusters. The observed changes could contribute to prolonging the initial stage of late anestrus in multiparous female wild boars. PMID- 25016170 TI - HIV prevention and marriage: peer group effects on condom use acceptability in rural Kenya. AB - The twofold function of condom use - contraception and sexually transmitted disease protection - should be taken into account when understanding attitudes towards this practice. Emphasis on the interpretation of condom use as a protective practice conflicts with the norms of fidelity and trust, which regulate marriage. The alternative interpretation of condom use as a contraceptive method may be less problematic. This paper analyzes the extent to which the attitude of married men and women towards condom use with their spouses, and their actual use of condoms within marriage, are affected by their expectations about the dominant attitudes and behaviors in their peer group. I expect that a social consensus on understanding condom use as an HIV-preventive behavior will not make this practice more acceptable within marriage, while social acceptance of modern contraception and, more specifically, of the use of condoms for contraceptive purposes will. Two waves of a longitudinal survey from 1996 to 1999 in rural Kenya are analyzed using fixed-effects regression. Social support for each function of condom use is measured with indicators of the proportion of individuals in the peer group that use condoms for a particular purpose or have a positive attitude towards each of the uses, according to the respondent. The results support the hypothesis for men, but are inconclusive for women. PMID- 25016171 TI - Ultrastructural characterization of cells in primary cultures from different adult tissues of Biomphalaria tenagophila TAIM, a strain that is absolutely resistant to Schistosoma mansoni infection. AB - The etiological agent of schistosomiasis in Brazil, Schistosoma mansoni, requires an obligatory passage through Biomphalaria snails to complete its life cycle. In these intermediate hosts, interaction with the parasite is mediated by humoral factors and hemocytes by mechanisms that are not yet fully understood. Extant studies exploring these processes are usually conducted through experimental infection of Biomphalaria with S. mansoni miracidia. Thus, tissue-derived cultures of Biomphalaria may be useful in increasing the understanding of that interaction at cellular level. However, in the absence of morphological characterization of those cells in culture, the application of such models is delayed. In the present work, we cultured different tissues of B. tenagophila, the second most important host of S. mansoni in Brazil, using a strain that is naturally and absolutely resistant to S. mansoni infection. This decision was driven by the view that this strain might be provided with the most effective response against parasite infection. Primary cultures were successfully established from nine Biomphalaria tissues and the respective cells in culture were ultra structurally described. Attention was particularly devoted to cells derived from mantle cavity and kidney tissues. Although they have been considered important centers for hemocyte production in Biomphalaria, no detailed cell characterization is available in the pertinent literature. Herein, kidney-derived cells partially shared hematoblast characteristics. Moreover, under optical microscopy, kidney cells in culture were very similar to those derived from amebocyte-producing organ (APO) cultures, which have been recently shown to be capable of eliminating S. mansoni sporocysts in vitro. Based on the close resemblance of those cultures and their anatomical proximity inside the mantle cavity, we suggest the effective participation of Biomphalaria kidney cells in hematopoiesis and in host response to S. mansoni infection. PMID- 25016172 TI - A model-guided analysis and perspective on the evolution and epidemiology of antibiotic resistance and its future. AB - A simple epidemiological model is used as a framework to explore the potential efficacy of measures to control antibiotic resistance in community-based self limiting human infections. The analysis of the properties of this model predict that resistance can be maintained at manageable levels if: first, the rates at which specific antibiotics are used declines with the frequency of resistance to these drugs; second, resistance rarely emerges during therapy; and third, external sources rarely contribute to the entry of resistant bacteria into the community. We discuss the feasibility and limitations of these measures to control the rates of antibiotic resistance and the potential of advances in diagnostic procedures to facilitate this endeavor. PMID- 25016173 TI - Microbial metabolomics: innovation, application, insight. AB - Most textbooks depict metabolism as a well understood housekeeping function of cells. However, organisms vary in their metabolic needs according to the specific niches they reside in and selective pressures encountered therein. Recent advances in analytical chemistry have begun to reveal an unexpected diversity in the composition, structure and regulation of metabolic networks. Here, we review key technological developments in the area of metabolism and their impact on our understanding of the fundamental roles of metabolism in cellular physiology. PMID- 25016174 TI - Tribological characteristics of polyethylene glycol (PEG) as a lubricant for wear resistance of ultra-high-molecular-weight polyethylene (UHMWPE ) in artificial knee join. AB - For the longevity of total knee joint prostheses, we have developed an artificial lubricant using polyethylene glycol (PEG) for the prevention of wear of ultra high-molecular-weight polyethylene (UHMWPE). In the present study, the lubricative function of this PEG lubricant was evaluated by a wear test using Co Cr alloy and UHMWPE counter surface samples. As a result, human synovial fluid including the PEG lubricant showed good result regarding the wear volume and a worn surface of UHMWPE. Considering its lubrication mechanism, it is suspected that interaction between the PEG molecules and the proteins in synovial fluid was involved. Since PE molecules are also organic compounds having a hydroxyl group at one or both ends, the albumin and PEG molecule complex would have bound more strongly to the metal oxide surface and UHMWPE surfaces might enhance and stabilize the lubricating film between the contact surfaces under the boundary lubrication. This study suggests that PEG lubricant as an intra-articular viscous supplement has the potential to prevent wear of UHMWPE by mixing with synovial fluid and to contribute to the longevity of knee joint prostheses. PMID- 25016175 TI - Limiting extensibility constitutive model with distributed fibre orientations and ageing of abdominal aorta. AB - The abdominal aorta is susceptible to age-related pathological changes (arteriosclerosis, atherosclerosis, aneurysm, and tortuosity). Computational biomechanics and mechanobiology provide models capable of predicting mutual interactions between a changing mechanical environment and patho-physiological processes in ageing. However, a key factor is a constitutive equation which should reflect the internal tissue architecture. Our study investigates three microstructurally-motivated invariant-based hyperelastic anisotropic models suitable for description of the passive mechanical behaviour of the human abdominal aorta at a multiaxial state of stress known from recent literature. The three adopted models have also been supplemented with a newly proposed constitutive model (limiting extensibility with fibre dispersion). All models additively decouple the mechanical response of the isotropic (elastin and smooth muscle cells represented by the neo-Hookean term) and the anisotropic (collagen) parts. Two models use exponential functions to capture large strain stiffening ascribed to the engagement of collagen fibres into the load-bearing process. The other two models are based on the concept of limiting extensibility. Perfect alignment of reinforcing fibres with two preferred directions as well as fibre dispersion are considered. Constitutive models are calibrated to the inflation extension response adopted from the literature based on the computational model of the residually-stressed thick-walled tube. A correlation analysis of determined material parameters was performed to reveal dependence on the age. The results of the nonlinear regression suggest that limiting fibre extensibility is the concept which is suitable to be used for the constitutive description of the aorta at multiaxial stress states and is highly sensitive to ageing-induced changes in mechanical response. PMID- 25016176 TI - Circadian control of tissue homeostasis and adult stem cells. AB - The circadian timekeeping mechanism adapts physiology to the 24-hour light/dark cycle. However, how the outputs of the circadian clock in different peripheral tissues communicate and synchronize each other is still not fully understood. The circadian clock has been implicated in the regulation of numerous processes, including metabolism, the cell cycle, cell differentiation, immune responses, redox homeostasis, and tissue repair. Accordingly, perturbation of the machinery that generates circadian rhythms is associated with metabolic disorders, premature ageing, and various diseases including cancer. Importantly, it is now possible to target circadian rhythms through systemic or local delivery of time cues or compounds. Here, we summarize recent findings in peripheral tissues that link the circadian clock machinery to tissue-specific functions and diseases. PMID- 25016177 TI - Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling. AB - To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats. PMID- 25016178 TI - The sympathy of policy-makers towards animal-rights activists, and the future of biomedical research. PMID- 25016179 TI - Respiratory patterns reflect different levels of aggressiveness and emotionality in Wild-type Groningen rats. AB - Respiratory patterns represent a promising physiological index for assessing emotional states in preclinical studies. Since disturbed emotional regulation may lead to forms of excessive aggressiveness, in this study we investigated the hypothesis that rats that differ largely in their level of aggressive behavior display matching alterations in respiration. Respiration was recorded in male high-aggressive (HA, n = 8) and non-aggressive (NA, n = 8) Wild-type Groningen rats using whole-body plethysmography. Subsequently, anxiety-related behaviors were evaluated in the elevated plus maze and social avoidance-approach tests. During respiratory testing, HA rats showed elevated basal respiratory rate, reduced sniffing, exaggerated tachypnoeic response to an acoustic stimulus and a larger incidence of sighs. In addition, HA rats spent less time in the open arms of the plus maze and displayed higher levels of social avoidance behavior compared to NA rats. These findings indicate that HA rats are characterized by alterations in respiratory functioning and behavior that are overall indicative of an anxiety-like phenotype. PMID- 25016180 TI - Dengue fever and bone marrow myelofibrosis. AB - Myelofibrosis is characterized by reticulin and/or collagen fibrosis in the bone marrow stroma resulting in secondary cytopenia. In addition to clonal hematologic neoplasms, myelofibrosis may also develop in association with other clinical conditions, including hematological disorders, solid malignancies, Down syndrome, autoimmune diseases and others. We report the first case to our knowledge of myelofibrosis associated with dengue fever. We briefly describe dengue infections and hypothesize the causes of myelofibrosis in this condition. PMID- 25016181 TI - Long-term risk of fibroid recurrence after laparoscopic myomectomy. AB - OBJECTIVE: The use of laparoscopic myomectomy as a surgical treatment for uterine leiomyoma is associated with low intraoperative morbidity and short hospitalization. Limited data about the long-term outcome of this surgical approach are available. The aims of this study were to estimate the risk of uterine fibroid recurrence after laparoscopic myomectomy and to identify factors contributing to the rate of fibroid relapse. STUDY DESIGN: Between 1996 and 2003, 331 patients underwent laparoscopic myomectomy to treat uterine leiomyoma in our hospital; 224 of these patients consented to participate in our 2009 follow-up survey. Clinical symptomatic uterine leiomyoma recurrence was defined as relapse. Recurrence rates at 24 and 60 months post-operatively were calculated for the study population. Fisher's exact tests were used to examine the impacts of factors previously linked to an increased risk of fibroid recurrence, including (1) patient age at the time of initial surgery, (2) pre-operative body mass index, (3) number and localization of uterine leiomyoma removed, and (4) pregnancy and (5) delivery after laparoscopic myomectomy on fibroid recurrence in our study cohort. RESULTS: We observed 75 recurrences in 224 patients. The cumulative risk of recurrence was 4.9% at 24 months and 21.4% at 60 months post operatively. An age of 30-40 years and the presence of more than one fibroid at the time of initial laparoscopic myomectomy were identified as factors significantly increasing the risk of symptomatic recurrence after laparoscopic myomectomy (31.25% and 38.71%, respectively; both p<0.01). CONCLUSION: Patients with multiple uterine leiomyoma and those in the third decade of life should be counselled thoroughly about the risk of recurrence prior to laparoscopic myomectomy. The low observed recurrence rate in peri- and postmenopausal patients in our study may support the use of laparoscopic myomectomy as a uterus preserving surgical alternative beyond the reproductive period. PMID- 25016182 TI - Development and classes of epigenetic drugs for cancer. AB - Emerging evidence supports an important, etiologic role for epigenetic modifications in cancer. Various post translational modifications of histone proteins together with DNA methylation constitute an 'epigenetic code' regulating the transcriptional status of the cell and aberrant writing and/or interpretation of the code can contribute to a dysregulated, hyperproliferative state. In some cases, epigenetic deregulation has also been reported to result in tumor initiation. The discovery of somatic mutations in some chromatin binding proteins associated with subtypes of lymphomas and the ability to regulate expression of proto oncogenes such as Myc has spurred the development of specific small molecule modulators of histone binding proteins. Several of these compounds have entered clinical development for the treatment of heme malignancies. This review summarizes progress in the discovery and advancement of epigenetic therapeutics for cancer and provides a perspective for future development. PMID- 25016183 TI - Biological significance of the CpG island methylator phenotype. AB - Cancers exhibiting the CpG island methylator phenotype (CIMP) are found among a wide variety of human malignancies and represent a subclass of tumors showing concurrent hypermethylation of multiple CpG islands. These CIMP-positive tumors often exhibit characteristic molecular and clinicopathological features, suggesting CIMP represents a distinct carcinogenic pathway. However, marker genes to define CIMP have been largely inconsistent among studies, which has caused results to vary. Nonetheless, recent advances in genome-wide methylation analysis have enabled the existence of CIMP to be confirmed, and large-scale cancer genome analyses have begun to unravel the previously unknown molecular basis of CIMP tumors. CIMP is strongly associated with clinical outcome, suggesting it may be a predictive biomarker. PMID- 25016184 TI - Rtp801 suppression of epithelial mTORC1 augments endotoxin-induced lung inflammation. AB - The mechanistic target of rapamycin (mTOR) is a central regulator of cellular responses to environmental stress. mTOR (and its primary complex mTORC1) is, therefore, ideally positioned to regulate lung inflammatory responses to an environmental insult, a function directly relevant to disease states such as the acute respiratory distress syndrome. Our previous work in cigarette smoke-induced emphysema identified a novel protective role of pulmonary mTORC1 signaling. However, studies of the impact of mTORC1 on the development of acute lung injury are conflicting. We hypothesized that Rtp801, an endogenous inhibitor of mTORC1, which is predominantly expressed in alveolar type II epithelial cells, is activated during endotoxin-induced lung injury and functions to suppress anti inflammatory epithelial mTORC1 responses. We administered intratracheal lipopolysaccharide to wild-type mice and observed a significant increase in lung Rtp801 mRNA. In lipopolysaccharide-treated Rtp801(-/-) mice, epithelial mTORC1 activation significantly increased and was associated with an attenuation of lung inflammation. We reversed the anti-inflammatory phenotype of Rtp801(-/-) mice with the mTORC1 inhibitor, rapamycin, reassuring against mTORC1-independent effects of Rtp801. We confirmed the proinflammatory effects of Rtp801 by generating a transgenic Rtp801 overexpressing mouse, which displayed augmented inflammatory responses to intratracheal endotoxin. These data suggest that epithelial mTORC1 activity plays a protective role against lung injury, and its inhibition by Rtp801 exacerbates alveolar injury caused by endotoxin. PMID- 25016185 TI - KDM5C is overexpressed in prostate cancer and is a prognostic marker for prostate specific antigen-relapse following radical prostatectomy. AB - Currently, few prognostic factors are available to predict the emergence of castration-resistant prostate cancer and no curative options are available. Epigenetic gene regulation has been shown to trigger prostate cancer metastasis and androgen independence. Histone lysine demethylases (KDMs) are epigenetic enzymes that can remove both repressive and activating histone marks. KDM5 family members are capable of removing the histone H3 lysine 4 dimethylation-activating mark, rendering them potential players in the down-regulation of tumor suppressors and suggesting that their activity could repress oncogenes. Here, we systematically investigated KDM5C expression patterns in two independent radical prostatectomy cohorts (822 prostate tumors in total) by immunohistochemistry. Positive nuclear KDM5C staining was significantly associated with a reduced prostate-specific antigen relapse-free survival. Our study confirmed that nuclear KDM5C expression is an independent prognostic parameter. Most strikingly, the prognostic value of nuclear KDM5C expression for progression-free survival was exclusively pronounced for the Gleason group 7. In addition, KDM5C knockdown resulted in growth retardation of prostate cancer cells in vitro and induced regulation of several proliferation-associated genes. Our data indicate that KDM5C is functionally involved in proliferation control of prostate cancer cells and might represent a novel attractive therapy target. Moreover, overexpression of KDM5C is an independent new predictive marker for therapy failure as determined by biochemical recurrence in patients after prostatectomy. PMID- 25016186 TI - Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. AB - Vortioxetine, a novel antidepressant for the treatment of major depressive disorder (MDD), is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and serotonin (5-HT) transporter (SERT) inhibitor. Here we review its preclinical and clinical properties and discuss translational aspects. Vortioxetine increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic and glutamatergic neurotransmission in brain structures associated with MDD. These multiple effects likely derive from its interaction with 5-HT-receptor-mediated negative feedback mechanisms controlling neuronal activity. In particular, 5-HT3 receptors may play a prominent role, since their blockade i) increases pyramidal neuron activity by removing 5-HT3 receptor-mediated excitation of GABA interneurons, and ii) augments SSRI effects on extracellular 5-HT. However, modulation of the other 5 HT receptor subtypes also likely contributes to vortioxetine's pharmacological effects. Preclinical animal models reveal differences from SSRIs and SNRIs, including antidepressant-like activity, increased synaptic plasticity and improved cognitive function. Vortioxetine had clinical efficacy in patients with MDD: 11 placebo-controlled studies (including one in elderly) with efficacy in 8 (7 positive, 1 supportive), 1 positive active comparator study plus a positive relapse prevention study. In two positive studies, vortioxetine was superior to placebo in pre-defined cognitive outcome measures. The clinically effective dose range (5-20mg/day) spans ~50 to >80% SERT occupancy. SERT and 5-HT3 receptors are primarily occupied at 5mg, while at 20mg, all targets are likely occupied at functionally relevant levels. The side-effect profile is similar to that of SSRIs, with gastrointestinal symptoms being most common, and a low incidence of sexual dysfunction and sleep disruption possibly ascribed to vortioxetine's receptor modulation. PMID- 25016187 TI - Demonstrator skill modulates observational aversive learning. AB - Learning to avoid danger by observing others can be relatively safe, because it does not incur the potential costs of individual trial and error. However, information gained through social observation might be less reliable than information gained through individual experiences, underscoring the need to apply observational learning critically. In order for observational learning to be adaptive it should be modulated by the skill of the observed person, the demonstrator. To address this issue, we used a probabilistic two-choice task where participants learned to minimize the number of electric shocks through individual learning and by observing a demonstrator performing the same task. By manipulating the demonstrator's skill we varied how useful the observable information was; the demonstrator either learned the task quickly or did not learn it at all (random choices). To investigate the modulatory effect in detail, the task was performed under three conditions of available observable information; no observable information, observation of choices only, and observation of both the choices and their consequences. As predicted, our results showed that observable information can improve performance compared to individual learning, both when the demonstrator is skilled and unskilled; observation of consequences improved performance for both groups while observation of choices only improved performance for the group observing the skilled demonstrator. Reinforcement learning modeling showed that demonstrator skill modulated observational learning from the demonstrator's choices, but not their consequences, by increasing the degree of imitation over time for the group that observed a fast learner. Our results show that humans can adaptively modulate observational learning in response to the usefulness of observable information. PMID- 25016188 TI - The impact of preoperative depression on quality of life outcomes after posterior cervical fusion. AB - BACKGROUND CONTEXT: Posterior cervical fusion (PCF) has been shown to be an effective treatment for cervical spondylosis, but is associated with a 9% complication rate and high costs. To limit such complications and costs, it is imperative that proper selection of surgical candidates occur for those most likely to do well with the surgery. Affective disorders, such as depression, are associated with worsened outcomes after lumbar surgery; however, this effect has not been evaluated in patients undergoing cervical spine surgery. PURPOSE: To assess the predictive value of preoperative depression and the health state on 1 year quality of life (QOL) outcomes after PCF. STUDY DESIGN: A retrospective cohort analysis. PATIENT SAMPLE: Eighty-eight patients who underwent PCF for cervical spondylosis were reviewed. OUTCOME MEASURES: Preoperative and 1-year postoperative health outcomes were assessed based on the Pain Disability Questionnaire (PDQ), the Patient Health Questionnaire-9 (PHQ-9), and the EuroQol five-dimensions (EQ-5D) questionnaire. METHODS: Univariable and multivariable regression analyses were performed to assess for preoperative predictors of 1 year change in health status. RESULTS: Compared with preoperative health states, the PCF cohort showed statistically significant improved PDQ (87.8 vs. 73.6), PHQ 9 (7.7 vs. 6.6), and EQ-5D (0.50 vs. 0.60) scores at 1 year postoperatively. Only 10/88 (11%) patients achieved or surpassed the minimum clinically important difference for the PHQ-9 (5). Multiple linear and logistic regression analyses showed that increasing PHQ-9 and EQ-5D preoperative scores were associated with reduced 1-year postoperative improvement in health status (EQ-5D index). CONCLUSIONS: Of patients who undergo PCF, those with a greater degree of preoperative depression have lower improvements in postoperative QOL compared with those with less depression. Additionally, patients with better preoperative health states also attain lower 1-year QOL improvements. PMID- 25016189 TI - The hepatoprotective activity of blue green algae in Schistosoma mansoni infected mice. AB - This study aims to evaluate the immunomodulatory effects of a natural product, blue green algae (BGA) (100 mg/kg BW), alone or combined with praziquantel PZQ (250 mg/kg BW) on granulomatous inflammation, liver histopathology, some biochemical and immunological parameters in mice infected with Schistosoma mansoni. Results showed that the diameter and number of egg granuloma were significantly reduced after treatment of S. mansoni-infected mice with BGA, PZQ and their combination. The histopathological alterations observed in the liver of S. mansoni-infected mice were remarkably inhibited after BGA treatments. BGA decreased the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) as well as the level of total protein (TP) while the level of albumin was increased. Treatment of infected mice with BGA, PZQ as well as their combination led to significant elevation in the activities of hepatic antioxidant enzymes glutathione peroxidase (GPX) and glutathione-S-transferase (GST) as compared with control group. Combination of BGA and PZQ resulted in significant reduction in the level of intercellular adhesion molecules-1 (ICAM-1), vascular adhesion molecules-1 (VCAM 1) and tumor necrosis factor-alpha (TNF-alpha) when compared to those of the S. mansoni-infected group. Overall, BGA significantly inhibited the liver damage accompanied with schistosomiasis, exhibited a potent antioxidant and immunoprotective activities. This study suggests that BGA can be considered as promising for development a complementary and/or alternative medicine against schistosomiasis. PMID- 25016190 TI - iTIS-PseTNC: a sequence-based predictor for identifying translation initiation site in human genes using pseudo trinucleotide composition. AB - Translation is a key process for gene expression. Timely identification of the translation initiation site (TIS) is very important for conducting in-depth genome analysis. With the avalanche of genome sequences generated in the postgenomic age, it is highly desirable to develop automated methods for rapidly and effectively identifying TIS. Although some computational methods were proposed in this regard, none of them considered the global or long-range sequence-order effects of DNA, and hence their prediction quality was limited. To count this kind of effects, a new predictor, called "iTIS-PseTNC," was developed by incorporating the physicochemical properties into the pseudo trinucleotide composition, quite similar to the PseAAC (pseudo amino acid composition) approach widely used in computational proteomics. It was observed by the rigorous cross validation test on the benchmark dataset that the overall success rate achieved by the new predictor in identifying TIS locations was over 97%. As a web server, iTIS-PseTNC is freely accessible at http://lin.uestc.edu.cn/server/iTIS-PseTNC. To maximize the convenience of the vast majority of experimental scientists, a step-by-step guide is provided on how to use the web server to obtain the desired results without the need to go through detailed mathematical equations, which are presented in this paper just for the integrity of the new prection method. PMID- 25016191 TI - A simple in vitro acylation assay based on optimized HlyA and HlyC purification. AB - HlyA is a toxin secreted by uropathogenic Escherichia coli strains. HlyA belongs to the repeats in the toxin protein family and needs (i) a posttranslational, fatty acylation at two internal lysines by the acyltransferase HlyC and (ii) extracellular ion binding to achieve its active conformation. Both processes are not fully understood and experiments are often limited due to the low amounts of protein available. Here, we present an optimized purification protocol for the proteins involved in HlyA activation as well as a quick and nonradioactive assay for in vitro HlyA acylation. These may simplify future experiments, e.g., activity scanning and characterization of HlyA or HlyC mutants as demonstrated with single and double HlyA lysine mutants. PMID- 25016192 TI - Identifying protein domains by global analysis of soluble fragment data. AB - The production and analysis of individual structural domains is a common strategy for studying large or complex proteins, which may be experimentally intractable in their full-length form. However, identifying domain boundaries is challenging if there is little structural information concerning the protein target. One experimental procedure for mapping domains is to screen a library of random protein fragments for solubility, since truncation of a domain will typically expose hydrophobic groups, leading to poor fragment solubility. We have coupled fragment solubility screening with global data analysis to develop an effective method for identifying structural domains within a protein. A gene fragment library is generated using mechanical shearing, or by uracil doping of the gene and a uracil-specific enzymatic digest. A split green fluorescent protein (GFP) assay is used to screen the corresponding protein fragments for solubility when expressed in Escherichia coli. The soluble fragment data are then analyzed using two complementary approaches. Fragmentation "hotspots" indicate possible interdomain regions. Clustering algorithms are used to group related fragments, and concomitantly predict domain location. The effectiveness of this Domain Seeking procedure is demonstrated by application to the well-characterized human protein p85alpha. PMID- 25016193 TI - Development of simplified HPLC methods for the detection of counterfeit antimalarials in resource-restraint environments. AB - Regular quality control and post-marketing surveillance of pharmaceuticals has been a critical challenge for countries of the developing world ever since. Counterfeit and substandard medicines are widely distributed and the real extent of their prevalence still remains unknown. Compendial protocols and methods utilizing high-performance liquid chromatography (HPLC) which are described in the major pharmacopoeias are widely applied for the quality control of a compound. They often require expensive solvents, delicate reagents and/or sophisticated apparatus, and may not be applicable and affordable for laboratories with limited capabilities. Simple but robust HPLC methods for the determination of five commonly used antimalarial agents, i.e. amodiaquine, mefloquine, proguanil, artemether and lumefantrine, were developed and their suitability for routine use in resource-restraint environments is discussed. They solely require readily available chemicals and solvents and exhibit a high grade of ruggedness. PMID- 25016194 TI - Outcomes after hematopoietic stem cell transplantation for children with I-cell disease. AB - Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients. PMID- 25016195 TI - Nonmyeloablative peripheral blood haploidentical stem cell transplantation for refractory severe aplastic anemia. AB - New transplant approaches are urgently needed for patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor (UD) or who have failed UD or cord blood transplant. Patients with refractory SAA are at risk of later clonal evolution to myelodysplastic syndrome and acute leukemia. We report our pilot findings with haploidentical hematopoietic stem cell transplantation (haploHSCT) using uniform reduced-intensity conditioning with postgraft high-dose cyclophosphamide in 8 patients with refractory SAA or patients who rejected a prior UD or cord blood transplant. Six of 8 patients engrafted. Graft failure was associated with donor-directed HLA antibodies, despite intensive pre-HSCT desensitization with plasma exchange and rituximab. There was only 1 case of grade II skin graft-versus-host disease. We show that haploHSCT can successfully rescue refractory SAA patients who lack donor-directed HLA antibodies but not in the presence of donor-directed HLA antibodies. This novel protocol for haploHSCT for SAA has been adopted by the European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party for a future noninterventional, observational study to further evaluate its efficacy. PMID- 25016196 TI - Next generation MRD. PMID- 25016197 TI - Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reduced-intensity conditioning. AB - The success of hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day 30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT. PMID- 25016198 TI - Region specific mitochondrial impairment in mice with widespread overexpression of alpha-synuclein. AB - Parkinson's disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons leading to motor deficits. The mechanisms underlying the preferential vulnerability of nigrostriatal dopaminergic neurons in PD remain poorly understood. Recent evidence supports a role for mitochondrial dysfunction and increased oxidative stress in PD pathogenesis. Genetic and pathological studies also point to alpha-synuclein as a critical factor in both familial and sporadic forms of the disease; alpha-synuclein pathology affects mitochondrial function but is widespread in PD brain, raising the question of its role in the greater vulnerability of nigrostriatal neurons in PD. We have examined mitochondrial function and oxidative damage in mice overexpressing human wild type alpha-synuclein broadly throughout the nervous system under the Thy1 promoter (Thy1-aSyn mice) between 4 and 8months of age. Similar levels of alpha synuclein accumulation in mitochondria were detected in the ventral midbrain, striatum and cortex of Thy1-aSyn mice. However, analysis of mitochondrial respiration using Seahorse XF analyzer showed defects in mitochondrial respiratory complexes I, II, IV and V specifically in the midbrain, and IV and V in the striatum, of Thy1-aSyn mice compared to wild type littermates; mitochondrial complex I activity assay by ELISA confirmed a 40% inhibition specifically in the ventral midbrain. Mitochondrial dysfunction can contribute to oxidative stress and we observed a 40% increase in 4-hydroxynenal and 2-fold increase in malondialdehyde levels, indicative of a high level of lipid peroxidation, specifically in the ventral midbrain of Thy1-aSyn mice. The levels of peroxiredoxin 2, a neuronal antioxidant enzyme that is involved in removal of H2O2 and other toxic peroxides were decreased in the midbrain whereas its oxidized form increased 4-fold, suggesting that antioxidant defenses were compromised in this region. In contrast, peroxiredoxin 2 increased in the striatum and cortex, which may contribute to their protection in the presence of high levels of alpha-synuclein. Thus, in mice over-expressing alpha-synuclein, mitochondrial dysfunction occurred preferentially in nigrostriatal dopaminergic neurons many months before striatal dopamine loss occurs at 14months of age. This may contribute to a higher level of oxidative stress that overwhelms antioxidant defense in these neurons, leading to their increased vulnerability in PD. PMID- 25016199 TI - Bacillus Calmette-Guerin vaccine induces a selective serotonin reuptake inhibitor (SSRI)-resistant depression like phenotype in mice. AB - Preclinical studies have shown that administration of Bacillus Calmette-Guerin (BCG) vaccine induces depression-like behaviors in mice; however, the effect of antidepressant drug treatment has not been reported earlier. In the present study, we induced depression-like behavior by administering BCG vaccine to BALB/c mice. BCG treatment produced robust serum sickness as shown by a decrease in body weight, reduced spontaneous locomotor activity and reduced voluntary wheel running activity. BCG treatment also elevated plasma IL6 and IFNgamma levels and produced a marked activation of lung IDO activity. At a time point when serum sickness-related behaviors had fully recovered (i.e., day 14) BCG-treated mice showed a significant increase in immobility in the forced swim test (FST) and tail suspension test (TST) indicative of a pro-depressant phenotype. We observed significant increase in [(3)H]PK11195 binding in cortex and hippocampus regions of BGC-treated mice in comparison to saline-treated mice indicating prominent neuroinflammation. Pharmacological evaluation of FST behavior in BCG-treated mice demonstrated selective resistance to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and escitalopram. In contrast the tricyclic antidepressant imipramine, the dual serotonin/norepinephrine reuptake inhibitor (SNRI) duloxetine, and the dual dopamine/norepinephrine reuptake inhibitor (DNRI) nomifensine retained antidepressant efficacy in these mice. The lack of efficacy with acute treatment with SSRIs could not be explained either by differences in drug exposure or serotonin transporter (SERT) occupancy. Our results demonstrate that BCG-vaccine induced depression like behavior is selectively resistant to SSRIs and could potentially be employed to evaluate novel therapeutic agents being developed to treat SSRI-resistance in humans. PMID- 25016201 TI - Comparison of the performance of particle filter algorithms applied to tracking of a disease epidemic. AB - We present general methodology for sequential inference in nonlinear stochastic state-space models to simultaneously estimate dynamic states and fixed parameters. We show that basic particle filters may fail due to degeneracy in fixed parameter estimation and suggest the use of a kernel density approximation to the filtered distribution of the fixed parameters to allow the fixed parameters to regenerate. In addition, we show that "seemingly" uninformative uniform priors on fixed parameters can affect posterior inferences and suggest the use of priors bounded only by the support of the parameter. We show the negative impact of using multinomial resampling and suggest the use of either stratified or residual resampling within the particle filter. As a motivating example, we use a model for tracking and prediction of a disease outbreak via a syndromic surveillance system. Finally, we use this improved particle filtering methodology to relax prior assumptions on model parameters yet still provide reasonable estimates for model parameters and disease states. PMID- 25016200 TI - Greater amygdala activity and dorsomedial prefrontal-amygdala coupling are associated with enhanced inflammatory responses to stress. AB - Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n=31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression. PMID- 25016202 TI - Dicrocoelium chinensis and Dicrocoelium dendriticum (Trematoda: Digenea) are distinct lancet fluke species based on mitochondrial and nuclear ribosomal DNA sequences. AB - Lancet flukes parasitize the bile ducts and gall bladder of a range of mammals, including humans, causing dicrocoeliosis. In the present study, we sequenced and characterized the complete mitochondrial (mt) genomes as well as the first and second internal transcribed spacers (ITS-1 and ITS-2=ITS) of nuclear ribosomal DNA (rDNA) of two lancet flukes, Dicrocoelium chinensis and D. dendriticum. Sequence comparison of a conserved mt gene and nuclear rDNA sequences among multiple individual lancet flukes revealed substantial nucleotide differences between the species but limited sequence variation within each of them. Phylogenetic analysis of the concatenated amino acid and multiple mt rrnS sequences using Bayesian inference supported the separation of D. chinensis and D. dendriticum into two distinct species-specific clades. Results of the present study support the proposal that D. dendriticum and D. chinensis represent two distinct lancet flukes. While providing the first mt genomes from members of the superfamily Plagiorchioidea, the novel mt markers described herein will be useful for further studies of the diagnosis, epidemiology and systematics of the lancet flukes and other trematodes of human and animal health significance. PMID- 25016203 TI - Preparation and structure investigation of novel Schiff bases using spectroscopic, thermal analyses and molecular orbital calculations and studying their biological activities. AB - Two novel Schiff's bases (EB1 and L1) as new macrocyclic compounds were prepared via condensation reactions between bisaldehyde (2,2'-(ethane-1,2 diylbis(oxy))dibenzaldehyde): firstly with hydrazine carbothioamide to give (EB1), secondly with 4,6-diaminopyrimidine-2-thiol to give (L1). EB1 has a general formula C18H20N6O2S2 of mole mass=416.520, and IUPAC name ((N,N'Z,N,N'E) N,N' (((ethane1,2diylbis(oxy))bis(2,1phenylene))bis(methanylylidene))bis(1hydrazinylme hanethioamide). L1 has a general formula C20H16N4O2S of mole mass=376.10; and IUPAC name 1,2-bis(2-vinylphenoxy)ethane4,6-diaminopyrimidine-2-thiol). The structures of the compounds obtained were characterized based on elemental analysis, FT-IR and (1)H NMR spectra, mass, and thermogravimetric analysis (TG, DTG). The activation thermodynamic parameters, such as, DeltaE(*), DeltaH(*), DeltaS(*) and DeltaG(*) were calculated from the TG curves using Coats-Redfern method. It is important to investigate their structures to know the active groups and weak bond responsible for their biological activities. The obtained thermal (TA) and mass (MS) practical results are confirmed by semi-empirical MO calculation using PM3 procedure, on the neutral and positively charged forms of these novel Schiff bases. Therefore, comparison between MS and TA helps in selection of the proper pathway representing the decomposition of these compounds to give indication about their structures and consequently their biological activities. Their biological activities have been tested in vitro against Escherichia coli, Proteus vulgaris, Bacillissubtilies and Staphylococcus aurous bacteria in order to assess their antimicrobial potential. PMID- 25016204 TI - Induction of protection against foot-and-mouth disease virus in cell culture and transgenic suckling mice by miRNA targeting integrin alphav receptor. AB - Foot-and-mouth disease virus (FMDV) is an RNA virus that causes a highly contagious disease in domestic and wild cloven-hoofed animals. Although vaccination has been used to protect animals against FMDV, there are shortcomings in the efficacy of the available vaccines. RNA interference (RNAi) is triggered by small RNA molecules, including short interfering RNAs and microRNAs (miRNAs), and the use of RNAi-based methods have demonstrated promise as an alternative method of controlling the transmission of FMDV. However, the method of delivery, short duration of siRNA and miRNA in vivo, and the genetic variability of FMDV confound the use of RNAi-based strategies for FMDV control. FMDV has been shown to exploit host-cell integrins as cell-surface receptors to initiate infection. We selected the gene for the integrin alphav subunit as an RNAi target, and constructed three alphav-specific miRNA expression plasmids. The effects of these miRNAs on FMDV infection were examined in PK-15 cells and transgenic suckling mice. In PK-15 cells, the expression of the alphav-specific miRNAs significantly inhibited the expression of integrin alphav receptor and decreased FMDV infection. The transgenic mice were generated by integrating the alphav-specific miRNA expression cassette using pronuclear microinjection. When challenged with a dose of FMDV ten times greater than the LD50, the survival rate of transgenic suckling mice was approximately six-fold higher than that of their non-transgenic littermates, indicating that the interference of the miRNAs significantly reduced FMDV infection in the transgenic mice. This is the first report of limiting FMDV attachment to cellular receptors using miRNA-mediated gene knock down of cell surface receptors to significantly reduce FMDV infection in cell culture and transgenic suckling mice. PMID- 25016205 TI - Enhanced isoprene biosynthesis in Saccharomyces cerevisiae by engineering of the native acetyl-CoA and mevalonic acid pathways with a push-pull-restrain strategy. AB - To explore the capacity of isoprene production in Saccharomyces cerevisiae, a rational push-pull-restrain strategy was proposed to engineer the mevalonic acid (MVA) and acetyl-CoA pathways. The strategy can be decomposed into the up regulation of precursor supply in the acetyl-CoA module and the MVA pathway (push strategy), increase of the isoprene branch flux (pull-strategy), and down regulation of the competing pathway (restrain-strategy). Furthermore, to reduce the production cost arising from galactose addition and meanwhile maintain the high expression of Gal promoters, the galactose regulatory network was modulated by Gal80p deletion. Finally, the engineered strain YXM10-ispS-ispS could accumulate up to 37 mg/L isoprene (about 782-fold increase compared to the parental strain) under aerobic conditions with glycerol-sucrose as carbon source. In this way, a new potential platform for isoprene production was established via metabolic engineering of the yeast native pathways. PMID- 25016206 TI - Assessment of Salmonella and Listeria monocytogenes level in ready-to-cook poultry meat: effect of various high pressure treatments and potassium lactate concentrations. AB - The objective of this study was to develop a probabilistic model in order to determine the contamination level of Salmonella and Listeria monocytogenes in ready-to-cook poultry meat, after a high pressure (HP) treatment. The model included four steps: i) Reception of raw meat materials, mincing and mixing meat, ii) Partitioning and packaging into 200-g modified atmosphere packs, iii) High pressure treatment of the meat, and iv) Storage in chilled conditions until the end of the shelf-life. The model excluded the cooking step and consumption at consumer's home as cooking practices and heating times are highly variable. The initial contamination level of Salmonella and L. monocytogenes was determined using data collected in meat primary processing plants. The effect of HP treatment and potassium lactate on microbial reduction was assessed in minced meat, using a full factorial design with three high pressure treatments (200, 350 and 500 MPa), three holding times (2, 8 and 14 min) and two potassium lactate concentrations (0 or 1.8% w/w). The inactivation curves fitted with a Weibull model highlighted that the inactivation rate was significantly dependent on the HP treatment. From the literature, it was established that Salmonella was not able to grow in the presence of lactate, under modified atmosphere and chilled conditions whereas the growth of L. monocytogenes was determined using an existing model validated in poultry (available in Seafood Spoilage and Safety Predictor software, V. 3.1). Once implemented in the Excel add-in @Risk, the model was run using Monte Carlo simulation. The probability distribution of contamination levels was determined for various scenarios. For an average scenario such as an HP treatment of 350 MPa for 8 min, of 200 g minced meat containing 1.8% lactate (pH 6.1; aw 0.96), conditioned under 50% CO2, the prevalence rate of Salmonella and L. monocytogenes, after a 20-day storage at 6 degrees C was estimated to be 4.1% and 7.1%, respectively. The contamination level was low considering that the product is going to be cooked by the consumer afterwards: the 99th percentile of the distribution was equal to -2.3log cfu/g for Salmonella and 0.5log cfu/g for L. monocytogenes. More generally, the model developed here from raw material reception up to the end of the shelf-life enables to recommend combinations of HP treatment and lactate formulation to guarantee an acceptable microbial concentration before cooking. PMID- 25016207 TI - Analysing and modelling the growth behaviour of Listeria monocytogenes on RTE cooked meat products after a high pressure treatment at 400 MPa. AB - Various predictive models are available for high pressure inactivation of Listeria monocytogenes in food, but currently available models do not consider the growth kinetics of surviving cells during the subsequent storage of products. Therefore, we characterised the growth of L. monocytogenes in sliced cooked meat products after a pressurization treatment. Two inoculum levels (10(7) or 10(4) CFU/g) and two physiological states before pressurization (freeze-stressed or cold-adapted) were evaluated. Samples of cooked ham and mortadella were inoculated, high pressure processed (400 MPa, 5 min) and subsequently stored at 4, 8 and 12 degrees C. The Logistic model with delay was used to estimate lag phase (lambda) and maximum specific growth rate (MUmax) values from the obtained growth curves. The effect of storage temperature on MUmax and lambda was modelled using the Ratkowsky square root model and the relative lag time (RLT) concept. Compared with cold-adapted cells the freeze-stressed cells were more pressure resistant and showed a much longer lag phase during growth after the pressure treatment. Interestingly, for high-pressure inactivation and subsequent growth, the time to achieve a concentration of L. monocytogenes 100-fold (2-log) higher than the cell concentration prior to the pressure treatment was similar for the two studied physiological states of the inoculum. Two secondary models were necessary to describe the different growth behaviour of L. monocytogenes on ready to-eat cooked ham (lean product) and mortadella (fatty product). This supported the need of a product-oriented approach to assess growth after high pressure processing. The performance of the developed predictive models for the growth of L. monocytogenes in high-pressure processed cooked ham and mortadella was evaluated by comparison with available data from the literature and by using the Acceptable Simulation Zone approach. Overall, 91% of the relative errors fell into the Acceptable Simulation Zone. PMID- 25016208 TI - Modeling growth of three bakery product spoilage molds as a function of water activity, temperature and pH. AB - The objective of this study was to quantify the effect of water activity, pH and storage temperature on the growth of Eurotium repens, Aspergillus niger and Penicillium corylophilum, isolated from spoiled bakery products. Moreover, the behaviors of these three mold species were compared to assess whether a general modeling framework may be set and re-used in future research on bakery spoilage molds. The mold growth was modeled by building two distinct Gamma-type secondary models: one on the lag time for growth and another one on the radial growth rate. A set of 428 experimental growth curves was generated. The effect of temperature (15-35 degrees C), water activity (0.80-0.98) and pH (3-7) was assessed. Results showed that it was not possible to apply the same set of secondary model equations to the three mold species given that the growth rate varied significantly with the factors pH and water activity. In contrast, the temperature effect on both growth rate and lag time of the three mold species was described by the same equation. The equation structure and model parameter values of the Gamma models were also compared per mold species to assess whether a relationship between lag time and growth rate existed. There was no correlation between the two growth responses for E. repens, but a slight one for A. niger and P. corylophilum. These findings will help in determining bakery product shelf life and guiding future work in the predictive mycology field. PMID- 25016209 TI - Enteric porcine viruses in farmed shellfish in Denmark. AB - Bivalve shellfish are at constant risk of being exposed to pathogens as a consequence of contamination of the shellfish beds with human or animal waste originating from sewage treatment plants or slurry fertilized fields. Consumption of contaminated oysters and mussels are frequently reported as causes of disease outbreaks caused by norovirus or hepatitis A virus. Other zoonotic pathogens such as hepatitis E virus (HEV), rotavirus (RV) and Salmonella from livestock may also be transmitted to shellfish via this route. In this study, 29 pooled samples from commercial Danish blue mussels were tested for porcine pathogens and indicator bacteria Escherichia coli (E. coli). All samples tested negative for HEV, RV and Salmonella, whereas E. coli and the highly stable porcine circovirus type 2 (PCV2) were detected in eight and 12 samples, respectively. This is the first study to report the detection of PCV2 in commercial mussels. Based on the detection of PCV2 in clean areas with low prevalence of the normally applied fecal indicator E. coli, testing for PCV2 may be a more sensitive and robust specific porcine waste indicator in shellfish harvesting areas. PMID- 25016210 TI - Bi-phasic growth of Listeria monocytogenes in chemically defined medium at low temperatures. AB - The present work reports a novel observation regarding the growth of L. monocytogenes in modified Welshimer's broth (MWB) at low temperatures. Specifically, the direct monitoring of the growth of L. monocytogenes Scott A using plate count data revealed that the pathogen displays a bi-phasic growth pattern in MWB at 7 degrees C. This bi-phasic growth pattern is masked (not observed) when optical density (OD) measurements are used to monitor growth due to the inability of OD readings to detect L. monocytogenes population density increases up to 10(7) CFU/mL. This bi-phasic growth phenomenon was further investigated as a function of growth temperature (4 degrees C, 7 degrees C, 10 degrees C, 14 degrees C and 18 degrees C), medium composition (by altering the MWB composition by ten-fold increases in different sets of medium constituents), inoculum level (10(2), 10(3), 10(4), 10(5), 10(6), and 10(7) CFU/mL) and L. monocytogenes strain (10 strains). The growth of L. monocytogenes Scott A in MWB at 7 degrees C, 10 degrees C and 14 degrees C was consistently bi-phasic and independent of growth rate; at 18 degrees C, growth was consistently mono-phasic (single-phase, typical sigmoid growth curves), whereas no growth was observed at 4 degrees C. The tested modifications in the composition of MWB did not influence the bi-phasic nature of L. monocytogenes Scott A growth at 7 degrees C, and, overall, we could not point out any strain-, or serotype-specific effects. On the other hand, the initial inoculum level appears to affect the form of the growth curve, as there was a shift towards mono-phasic growth in trials with increasing initial inocula. A mathematical model, based on a stepwise response and described through two sequential sigmoid curves, was used to describe bi-phasic growth and estimate the kinetic parameters of L. monocytogenes growth. An alternative hypothesis, based on the assumption of the existence of two subpopulations, possessing different growth kinetics, materialized under the stress imposed on L. monocytogenes cells due to the combined effect of three factors (defined medium, low temperature and low initial inoculum) was also proposed and formulated. PMID- 25016211 TI - Hemokinin-1 mediates pruriceptive processing in the rat spinal cord. AB - Hemokinin-1 (HK-1) is a new mammalian tachykinin peptide consisting of the amino acid sequence similar to substance P (SP). Although the function of SP, a representative tachykinin peptide, has been well established in the pain system, that of HK-1 has not yet been elucidated. [Leu(11)]-SP had an antagonistic effect on SP-induced scratching behavior, suggesting that [Leu(11)]-HK-1 may also attenuate the induction of scratching behavior by HK-1. Thus, the effects of a pretreatment with [Leu(11)]-HK-1 were evaluated to clarify the function of HK-1. The intrathecal administration of [Leu(11)]-HK-1 attenuated the induction of scratching by HK-1, but not SP, while [Leu(11)]-SP reduced the induction of scratching by SP, but not HK-1. These results indicated that [Leu(11)]-HK-1 may be a more specific antagonist of HK-1-preferred receptors and [Leu(11)]-SP has an antagonistic effect on the SP-preferred receptor, the neurokinin 1 receptor. In the formalin test for examining noxious response, the intrathecal administration of [Leu(11)]-SP, but not [Leu(11)]-HK-1, reduced the number of flinchings and c Fos-positive cells in the spinal dorsal horn following formalin injection into the plantar region of the hind paw. These results indicated that SP, but not HK 1, is involved in nociceptive processing at the spinal level. To evaluate the involvement of HK-1 and SP in pruritic processing, the effect of [Leu(11)]-HK-1 and [Leu(11)]-SP on the induction of scratching behavior and c-Fos expression by serotonin (5-HT) and histamine was evaluated. The increased induction of scratching behavior and c-Fos expression by 5-HT and histamine was markedly attenuated by pretreatment with both [Leu(11)]-HK-1 and [Leu(11)]-SP, suggesting that HK-1 and SP may be involved in pruritic processing. These results indicate that HK-1 is involved in pruritic processing and [Leu(11)]-HK-1 is a valuable tool for clarifying the mechanisms underlying pruritic processing. PMID- 25016212 TI - Suppression of glia maturation factor expression prevents 1-methyl-4 phenylpyridinium (MPP+)-induced loss of mesencephalic dopaminergic neurons. AB - Inflammation mediated by glial activation appears to play a critical role in the pathogenesis of Parkinson disease (PD). Glia maturation factor (GMF), a proinflammatory protein predominantly localized in the central nervous system was isolated, sequenced and cloned in our laboratory. We have previously demonstrated immunomodulatory and proinflammatory functions of GMF, but its involvement in 1 methyl-4-phenylpyridinium (MPP(+)), active metabolite of classical parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inducing loss of dopaminergic (DA) neurons has not been studied. Here we show that altered expression of GMF has direct consequences on the production of reactive oxygen species (ROS) and nuclear factor-kappa B (NF-kappaB)- mediated production of inflammatory mediators by MPP(+). We examined MPP(+)-induced DA neuronal loss in primary cultures of mouse mesencephalic neurons/glia obtained from GMF-deficient (GMF knockout (GMF-KO)) and GMF-containing wild-type (Wt) mice. We demonstrate that deficiency of GMF in GMF-KO neurons/glia led to decreased production of ROS and downregulation of NF-kappaB-mediated production of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) as compared to Wt neurons/glia. Additionally, overexpression of GMF induced DA neurodegeneration, whereas GMF downregulation by GMF-specific shRNA protected DA neurons from MPP induced toxicity. Subsequently, GMF deficiency ameliorates antioxidant balance, as evidenced by the decreased level of lipid peroxidation, less ROS production along with increased level of glutathione; and attenuated the DA neuronal loss via the downregulation of NF-kappaB-mediated inflammatory responses. In conclusion, our overall data indicate that GMF modulates oxidative stress and release of deleterious agents by MPP(+) leading to loss of DA neurons. Our study provides new insights into the potential role of GMF and identifies targets for therapeutic interventions in neurodegenerative diseases. PMID- 25016213 TI - Blood levels of lead, cadmium, and mercury in the elderly living in institutionalized care in the Czech Republic. AB - BACKGROUND: There is limited research examining the chemical load of toxic metals in the elderly. The aim of the present study was two-fold: to determine the body burden of lead, cadmium and mercury in association with age, gender, locality, lifestyle factors and potential health impacts among this population and to compare the values with blood values from the general Czech population aged 18-64 years. METHODS: Lead, cadmium and mercury were examined in the blood of institutionalized senior citizens (46 males, 151 females aged 61-100 years) from two localities in the Czech Republic (Prague and Teplice) from 2009 through 2011. Measurements were made using inductively coupled plasma mass spectrometry (Pb, Cd) and a single purpose spectrometer AMA 254 (Hg). RESULTS: Geometric means (GM) of whole blood lead (B-Pb), cadmium (B-Cd) and mercury (B-Hg) levels were 25.3MUg/l, 0.55MUg/l and 0.21MUg/l, respectively. No age-related differences were found for B-Pb and B-Cd levels but a negative correlation with age was observed for B-Hg levels (p=0.04). B-Pb levels in men were significantly higher than in women (GM 29.9MUg/l vs. 24.1MUg/l). B-Cd was significantly higher in women (GM 0.57MUg/l) than in men (0.50MUg/l) (p=0.007) and in smokers (GM 1.29MUg/l) than in nonsmokers (GM 0.53MUg/l) (p=<0.001) and in seniors from Prague (GM 0.60MUg/l) compared to those from Teplice (GM 0.43MUg/l) (p=<0.001). Seniors with a history of chronic kidney disease, stroke and those using psycho-pharmaceuticals had higher B-Pb levels (p=0.008, 0.04 and 0.05, resp.), seniors diagnosed with atherosclerosis had higher B-Cd levels (p=0.002) and seniors using psycho pharmaceuticals had higher B-Hg levels (p=0.07). B-Hg levels were also positively correlated with blood albumin levels (p=0.015). CONCLUSIONS: This study provides data on levels of heavy metals in a group of elderly people. Such information is very scarce. Associations with diseases should be the subject of further investigation. PMID- 25016214 TI - Endothelin-1 driven proliferation of pulmonary arterial smooth muscle cells is c fos dependent. AB - Pulmonary hypertension (PH) is characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascular remodeling. Although, multiple factors have been associated with pathogenesis of PH the underlying mechanisms are not fully understood. Here, we hypothesize that already very short exposure to hypoxia may activate molecular cascades leading to vascular remodeling. Microarray studies from lung homogenates of mice exposed to only 3h of hypoxia revealed endothelin-1 (ET-1) and connective tissue growth factor (CTGF) as the most upregulated genes, and the mitogen-activated protein kinase (MAPK) pathway as the most differentially regulated pathway. Evaluation of these results in vitro showed that ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferation markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated extracellular signal-regulated kinase (Erk)-dependent c-fos expression and phosphorylation of c fos and c-jun transcription factors. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMCs. Expression and immunohistochemical analyses revealed higher levels of total and phosphorylated c-fos and c-jun in the vessel wall of lung samples of human idiopathic pulmonary arterial hypertension patents, hypoxia-exposed mice and monocrotaline-treated rats as compared to control subjects. These findings shed the light on the involvement of c-fos/c-jun in the proliferative response of PASMCs to ET-1 indicating that already very short hypoxia exposure leads to the regulation of mediators involved in vascular remodeling underlying PH. PMID- 25016215 TI - A developmental genetic analysis of the lysine demethylase KDM2 mutations in Drosophila melanogaster. AB - Post-translational modification of histones plays essential roles in the transcriptional regulation of genes in eukaryotes. Methylation on basic residues of histones is regulated by histone methyltransferases and histone demethylases, and misregulation of these enzymes has been linked to a range of diseases such as cancer. Histone lysine demethylase 2 (KDM2) family proteins have been shown to either promote or suppress tumorigenesis in different human malignancies. However, the roles and regulation of KDM2 in development are poorly understood, and the exact roles of KDM2 in regulating demethylation remain controversial. Since KDM2 proteins are highly conserved in multicellular animals, we analyzed the KDM2 ortholog in Drosophila. We have observed that dKDM2 is a nuclear protein and its level fluctuates during fly development. We generated three deficiency lines that disrupt the dKdm2 locus, and together with 10 transposon insertion lines within the dKdm2 locus, we characterized the developmental defects of these alleles. The alleles of dKdm2 define three phenotypic classes, and the intragenic complementation observed among these alleles and our subsequent analyses suggest that dKDM2 is not required for viability. In addition, loss of dKDM2 appears to have rather weak effects on histone H3 lysine 36 and 4 methylation (H3K36me and H3K4me) in the third instar wandering larvae, and we observed no effect on methylation of H3K9me2, H3K27me2 and H3K27me3 in dKdm2 mutants. Taken together, these genetic, molecular and biochemical analyses suggest that dKDM2 is not required for viability of flies, indicating that dKdm2 is likely redundant with other histone lysine demethylases in regulating normal development in Drosophila. PMID- 25016217 TI - Attention effects on vicarious modulation of nociception and pain. AB - The observation of others' facial expressions of pain has been shown to facilitate the observer's nociceptive responses and to increase pain perception. We investigated how this vicarious facilitation effect is modulated by directing the observer's attention toward the meaning of pain expression or the facial movements. In separate trials, participants were instructed to assess the "intensity of the pain expression"(meaning) or to "discriminate the facial movements" in the upper vs lower part of the face shown in 1-second dynamic clips displaying mild, moderate, or strong pain expressions or a neutral control. In 50% of the trials, participants received a painful electrical stimulation to the sural nerve immediately after the presentation of the expression. Low-level nociceptive reactivity was measured with the RIII-response, and pain perception was assessed using pain ratings. Pain induced by the electrical stimulation increased after viewing stronger pain expressions in both tasks, but the RIII response showed this vicarious facilitation effect only in the movement discrimination task at the strongest expression intensity. These findings are consistent with the notion that vicarious processes facilitate self-pain and may prime automatic nociceptive responses. However, this priming effect is influenced by top-down attentional processes. These results provide another case of dissociation between reflexive and perceptual processes, consistent with the involvement of partly separate brain networks in the regulation of cortical and lower-level nociceptive responses. Combined with previous results, these findings suggest that vicarious pain facilitation is an automatic process that may be diminished by top-down attentional processes directed at the meaning of the expression. PMID- 25016216 TI - Culturally relevant treatment services for perinatal depression in socio economically disadvantaged women: the design of the MOMCare study. AB - BACKGROUND: Depression during pregnancy has been demonstrated to be predictive of low birthweight, prematurity, and postpartum depression. These adverse outcomes potentially have lasting effects on maternal and child well-being. Socio economically disadvantaged women are twice as likely as middle-class women to meet diagnostic criteria for antenatal major depression (MDD), but have proven difficult to engage and retain in treatment. Collaborative care treatment models for depression have not been evaluated for racially/ethnically diverse, pregnant women on Medicaid receiving care in a public health system. This paper describes the design, methodology, culturally relevant enhancements, and implementation of a randomized controlled trial of depression care management compared to public health Maternity Support Services (MSS). METHODS: Pregnant, public health patients, >18 years with a likely diagnosis of MDD or dysthymia, measured respectively by the Patient Health Questionnaire-9 (PHQ-9) or the Mini International Neuropsychiatric Interview (MINI), were randomized to the intervention or to public health MSS. The primary outcome was reduction in depression severity from baseline during pregnancy to 18-months post-baseline (one-year postpartum). BASELINE RESULTS: 168 women with likely MDD (96.4%) and/or dysthymia (24.4%) were randomized. Average age was 27.6 years and gestational age was 22.4 weeks; 58.3% racial/ethnic minority; 71.4% unmarried; 22% no high school degree/GED; 65.3% unemployed; 42.1% making <$10,000 annually; 80.4% having recurrent depression; 64.6% PTSD, and 72% unplanned pregnancy. CONCLUSIONS: A collaborative care team, including a psychiatrist, psychologist, project manager, and 3 social workers, met weekly, collaborated with the patients' obstetrics providers, and monitored depression severity using an electronic tracking system. Potential sustainability of the intervention within a public health system requires further study. PMID- 25016218 TI - Pathological mechanism of musculoskeletal manifestations associated with CRPS type II: an animal study. AB - Patients with complex regional pain syndrome (CRPS) often complain of abnormal sensations beyond the affected body part, but causes of this spread of musculoskeletal manifestations into contiguous areas remain unclear. In addition, immobilization can predispose to the development of CRPS. We examined functional, biochemical, and histological alterations in affected parts, including contiguous zones, using an animal model. Ten-week-old male Wistar rats were assigned to 5 groups: a normal group receiving no treatment, a sham operation group with surgical exploration, an immobilization group with surgical exploration plus internal knee joint immobilization, a surgical neuropathy group prepared by spinal nerve ligation (SNL) of the left L5 nerve root, and a surgical neuropathy+immobilization group with simultaneous SNL and knee joint immobilization. Mechanical allodynia and knee contracture were compared between groups, and tissues were harvested for histological assessments and gene and protein expression analyses. Neither surgical procedures nor immobilization induced detectable mechanical sensitivity. However, the addition of nerve injury resulted in detectable mechanical allodynia, and immobilization not only accelerated hyperalgesia, but also resulted in muscle fibrosis. Nerve growth factor (NGF) and other mediators of neurogenic inflammation were highly expressed not only in denervated muscles, but also in innervated muscles in contiguous areas, suggesting the spread of NGF production beyond the myotome of the injured nerve. Transforming growth factor beta was involved in the development of contracture in CRPS. These findings imply that neuroinflammatory components play major roles in the progression and dispersion of both sensory pathologies and pathologies that are exacerbated by immobilization. PMID- 25016219 TI - Simultaneous saccharification and co-fermentation of aqueous ammonia pretreated corn stover with an engineered Saccharomyces cerevisiae SyBE005. AB - Co-fermentation of glucose and xylose from lignocelluloses is an efficient approach to increasing ethanol production. Simultaneous saccharification and co fermentation (SSCF) of corn stover pretreated with aqueous ammonia was performed using engineered yeast with xylose utilization pathway. Thus far, the effect of the several key factors on SSCF was investigated, including temperature, inoculation size, pre-hydrolysis and pH. Ethanol concentration was achieved to 36.5 g/L during SSCF process with 6% glucan loading. The addition of Tween 20 reduced enzyme loading, i.e., from 15 to 7.5 FPU/gglucan with the same final ethanol concentration. The ethanol concentration was achieved to 70.1g/L at 12% glucan loading. Yeast feeding, combined with substrate and enzyme feeding, was proved to be an efficient approach for SSCF with high solid loading. PMID- 25016220 TI - Thyrotropin increases hepatic triglyceride content through upregulation of SREBP 1c activity. AB - BACKGROUND & AIMS: Hallmarks of non-alcoholic fatty liver disease (NAFLD) are increased triglyceride accumulation within hepatocytes. The prevalence of NAFLD increases steadily with increasing thyrotropin (TSH) levels. However, the underlying mechanisms are largely unknown. Here, we focused on exploring the effect and mechanism of TSH on the hepatic triglyceride content. METHODS: As the function of TSH is mediated through the TSH receptor (TSHR), Tshr(-/-) mice (supplemented with thyroxine) were used. Liver steatosis and triglyceride content were analysed in Tshr(-/-) and Tshr(+/+) mice fed a high-fat or normal chow diet, as well as in Srebp-1c(-/-) and Tshr(-/-)Srebp-1c(-/-) mice. The expression levels of proteins and genes involved in liver triglyceride metabolism was measured. RESULTS: Compared with control littermates, the high-fat diet induced a relatively low degree of liver steatosis in Tshr(-/-) mice. Even under chow diet, hepatic triglyceride content was decreased in Tshr(-/-) mice. TSH caused concentration- and time-dependent effects on intracellular triglyceride contents in hepatocytes in vitro. The activity of SREBP-1c, a key regulator involved in triglyceride metabolism and in the pathogenesis of NAFLD, was significantly lower in Tshr(-/-) mice. In Tshr(-/-)Srebp-1c(-/-) mice, the liver triglyceride content showed no significant difference compared with Tshr(+/+)Srebp-1c(-/-) mice. When mice were injected with forskolin (cAMP activator), H89 (inhibitor of PKA) or AICAR (AMPK activator), or HeG2 cells received MK886 (PPARalpha inhibitor), triglyceride contents presented in a manner dependent on SREBP-1c activity. The mechanism, underlying TSH-induced liver triglyceride accumulation, involved that TSH, through its receptor TSHR, triggered hepatic SREBP-1c activity via the cAMP/PKA/PPARalpha pathway associated with decreased AMPK, which further increased the expression of genes associated with lipogenesis. CONCLUSIONS: TSH increased the hepatic triglyceride content, indicating an essential role for TSH in the pathogenesis of NAFLD. PMID- 25016221 TI - Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology. AB - BACKGROUND & AIMS: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology. METHODS: Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months. RESULTS: Unbiased whole exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations. CONCLUSIONS: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases. PMID- 25016222 TI - How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma. AB - BACKGROUND & AIMS: We aimed to establish an objective point score to guide the decision for the first treatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: 277 patients diagnosed with HCC and treated with transarterial treatments between 1/2002 and 12/2011 at the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the impact of baseline liver function and tumour load on overall survival (OS, log-rank test) and developed a point score (STATE-score: Selection for TrAnsarterial chemoembolisation TrEatment) in the training-cohort (n=131, Vienna) by using a stepwise Cox regression model. The STATE-score was externally validated in an independent validation cohort (n=146, Innsbruck) and thereafter combined with the Assessment for Retreatment with TACE (ART)-score to identify patients who are (un)suitable for TACE. RESULTS: The STATE-score starts with the serum-albumin level (g/L), which is reduced by 12 points each, if the tumour load exceeds the up-to-7 criteria and/or C-reactive protein (CRP) levels are ?1 mg/dl (maximum reduction: 24 points). The STATE-score differentiated 2 groups (<18, ?18 points) with distinct prognosis (median OS: 5.3 vs. 19.5 months; p<0.001) and a lower STATE-score was associated with short-term harm and increased mortality after TACE-1 (39% vs. 14% p<0.001). Sequential use of the STATE and the ART-score (START-strategy) identified the most (un)suitable patients for TACE. Results were confirmed in the external validation-cohort and were independent from recently proposed baseline selection tools. CONCLUSION: The STATE-score identifies patients who are (un)suitable for the first TACE. The START-strategy identified the best candidates for multiple TACE sessions. PMID- 25016223 TI - Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. AB - BACKGROUND & AIMS: The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV. METHODS: 98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro. RESULTS: In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation. CONCLUSIONS: Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy. PMID- 25016224 TI - Staging chronic hepatitis B into seven categories, defining inactive carriers and assessing treatment impact using a fibrosis biomarker (FibroTest(r)) and elastography (FibroScan(r)). AB - BACKGROUND & AIMS: The first aim was to extend the validation of FibroTest(r) (FT) and transient elastography (TE) as markers of occurrence of cirrhosis without complications (F4.1), oesophageal varices (F4.2), and severe complications (F4.3) in patients with chronic hepatitis B (CHB). The second aim was to validate a previous definition of an inactive carrier based on normal FT and ActiTest(r) (normal-FT-AT). The third aim was to assess the long-term dynamics of fibrosis in patients with sustained virological response. METHODS: The 10-year updated individual data of 1434 patients were pooled from two prospective cohorts. RESULTS: Of the 1312 patients without a history of complications, varices had occurred after 10 years in 14 patients (F4.2, incidence of 1.7%, 95% CI [0.6-2.8]), and severe complications in 25 (F4.3 3.7% [1.8-5.7]), including hepatocellular carcinoma (HCC) in 21 (3.7% [1.5-5.8]). Using Cox-multivariate analysis adjusted for treatment, viral load, HBeAg status and ALT, FT, and TE were predictive of liver complications (n=37; AUROC=0.83 [0.71-0.90]; p<0.0001) and (n=8/844; AUROC=0.82 [0.72-0.89]; p<0.0001) respectively. Normal FT-AT better identified patients with lower fibrosis progression than the ALT-based standard: 3/163 (1.8%) vs. 16/181 (8.8%; p=0.004) in the Paris cohort, and 5/195 (2.6%) vs. 15/228 (6.6%; p=0.05) in the Bordeaux cohort. Of the 582 responders, 23 had complications (incidence 6.2% [3.2-9.1]) including 19 HCC (5.8% [2.6-9.0]) and 10 with varices (2.6% [0.8-4.4]). Of the 138 responders with advanced fibrosis, only 31% (15-47%) had fibrosis regression. CONCLUSIONS: FibroTest(r) and TE identified three categories of cirrhosis with increasing morbidity. Normal FibroTest(r) and ActiTest(r) were better able to identify inactive hepatitis B carriers than the standard definition. Despite virological response, the overall incidence of cirrhosis increased, with a remaining 5.8% risk of HCC. PMID- 25016225 TI - Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. AB - Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child's diagnosis and treatment, and likely improved her prognosis. PMID- 25016227 TI - Design, synthesis and characterization of fluoro substituted novel pyrazolylpyrazolines scaffold and their pharmacological screening. AB - A novel series of fluoro substituted pyrazolylpyrazolines 7a-l was synthesized in good to excellent yield (77-88%) from pyrazole chalcones 5a-d and substituted phenyl hydrazine hydrochlorides 6a-c under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic stains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. Compounds 7a, 7b, 7g, 7h, 7j and 7k displayed excellent activity against P. falciparum stain as compared to quinine IC50 0.268. Good antitubercular activity was exhibited by compounds 7a, 7e, 7h and 7k. Some of them also exhibited superior antibacterial activity as compared to the first line drugs. PMID- 25016228 TI - Synthesis of a new series of N4-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. AB - A series of novel N(4)-substituted 4-(2-aminoethyl)benzenesulfonamides 5-17 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic CA I and II, and tumor associated isozymes CA IX and XII. Against the human CA I investigated compounds displayed KI values from 96.3 to 3520 nM, toward hCA II at range of 18.1-2055 nM, while against hCA IX ranging from 5.9 to 419 nM and against hCA XII in the range of 4.0-414 nM. The very good inhibitory activity against tumor-associated hCA IX and hCA XII was found. The six new compounds displayed a powerful inhibitory potency toward hCA IX (K(I) = 5.9-10.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). The most potent hCA IX and hCA XII inhibitors 11 and 12 (K(I): 5.9 and 6.2 nM for hCA IX and 4.3 and 4.0 nM for hCA XII, respectively) belonged to the compounds with cationic character and presented meaningful affinity to the transmembrane isoforms hCA IX and XII than to physiologically dominant isozymes hCA I and II with the selectivity ratios hCA IX versus hCA II and hCA XII versus hCA II for 11 and 12 in the range of 10-15. PMID- 25016226 TI - Hyper-IL-15 suppresses metastatic and autochthonous liver cancer by promoting tumour-specific CD8+ T cell responses. AB - BACKGROUND & AIMS: Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor alpha chain, on metastatic and autochthonous liver cancers. METHODS: Liver metastatic tumour models were established by intraportally injecting syngeneic mice with murine CT26 colon carcinoma cells or B16-OVA melanoma cells. Primary hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DEN). A hydrodynamics-based gene delivery method was used to achieve sustained hyper-IL-15 expression in the liver. RESULTS: Liver gene delivery of hyper-IL-15 robustly expanded CD8(+) T and NK cells, leading to a long-term (more than 40 days) accumulation of CD8(+) T cells in vivo, especially in the liver. Hyper-IL-15 treatment exerted remarkable therapeutic effects on well-established liver metastatic tumours and even on DEN-induced autochthonous HCC, and these effects were abolished by depletion of CD8(+) T cells but not NK cells. Hyper-IL-15 triggered IL-12 and interferon-gamma production and reduced the expression of co-inhibitory molecules on dendritic cells in the liver. Adoptive transfer of T cell receptor (TCR) transgenic OT-1 cells showed that hyper-IL-15 preferentially expanded tumour-specific CD8(+) T cells and promoted their interferon-gamma synthesis and cytotoxicity. CONCLUSIONS: Liver delivery of hyper-IL-15 provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by preferentially expanding tumour specific CD8(+) T cells and promoting their anti-tumour effects. PMID- 25016229 TI - Synthesis, in vitro antiproliferative activity, and in silico studies of fused tricyclic coumarin sulfonate derivatives. AB - A series of fused tricyclic coumarin sulfonate derivatives was synthesized. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 1e, 1f, 1h, 1i, and 1o showed the highest mean percentage of inhibition values over the 57 cell line panel at 10 MUM, and they were further tested in 5-dose testing mode to determine their IC50 values. Compounds 1e, 1f, and 1o were more selective against leukemia and colon cancer subpanels, while compounds 1h and 1i showed broad-spectrum anticancer activities. Compounds 1e, 1f, 1h, 1i, and 1o demonstrated high selectivity towards cancer cell lines than RAW 264.7 macrophages. Compound 1h exerted lethal effect over NCI-H522 NSCLC, SK-MEL-5 melanoma, and A498 renal cancer cell lines with percentage of inhibition values of 114.10%, 103.23%, and 100.52% at 10 MUM concentration, respectively. Moreover, the IC50 value of compound 1o against HT29 colon cancer cell line was 532 nM. Compounds 1e, 1f, 1h, 1i, and 1o were tested for inhibitory effect over cyclooxygenase-2 (COX-2) enzyme as a possible mechanism of action. Furthermore, in silico studies were conducted to check the compliance of those five compounds with Lipinski's rule of five, and hence estimate their oral bioavailability. PMID- 25016230 TI - Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. AB - Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological characterization of an extended set of this class of compounds, including lipophilic derivatives of the known RGGT inhibitors. From this new panel of PCs, we have identified an inhibitor of RGGT that is of similar potency as the most active published phosphonocarboxylate, but of higher selectivity towards this enzyme compared to prenyl pyrophosphate synthases. New insights into structural requirements are also presented, showing that only PC analogs of the most potent 3rd generation bisphosphonates inhibit RGGT. In addition, the first phosphonocarboxylate-derived GGPPS inhibitor is reported. PMID- 25016231 TI - Synthesis and characterization of silver nanoparticles using crystal compound of sodium para-hydroxybenzoate tetrahydrate isolated from Vitex negundo. L leaves and its apoptotic effect on human colon cancer cell lines. AB - Metallic nanoparticles are major concern, particularly silver nanoparticles (AgNPs) are used in various applications. In the present investigation, we report a novel strategy with biological approach for synthesis of AgNPs using sodium para-hydroxybenzoate tetrahydrate (SPHT) isolated from Vitex negundo leaves. The synthesized SPHT-AgNPs were characterized by UV-vis spectroscopy, high resolution transmission electron microscopy (HRTEM) with selected area electron diffraction (SAED) pattern, field emission scanning electron microscopy (FESEM) with energy dispersive X-ray spectroscopy (EDX), zeta potential and Fourier transform infrared spectroscopy (FT-IR) analysis. The various pH and temperature were evaluated to find their stability effects on SPHT-AgNPs synthesis peak at 430 nm. The size of SPHT-AgNPs were ranging from 26 to 39 nm and were spherical in shape. The hydroxyl and carboxylic functional groups from bio-reducing mediators of SPHT have a stronger ability towards synthesis of AgNPs, which was confirmed using FT IR spectrum. In addition, anticancer activity were determined by MTT assay, Annexin V-FITC/PI and cell cycle analysis. PMID- 25016232 TI - CoMFA and CoMSIA analysis of ACE-inhibitory, antimicrobial and bitter-tasting peptides. AB - Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to the ACE-inhibitory, antimicrobial, and bitter-tasting peptides. Predictive 3D-QSAR models were established using SYBYL multifit molecular alignment rule over a training set and a test set. The optimum models were all statistically significant with cross-validated coefficients (Q(2)) >0.5 and conventional coefficients (R(2)) >0.9, indicating that they were reliable enough for activity prediction. The obtained results may aid in the design of novel bioactive peptides. PMID- 25016233 TI - Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies. AB - Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O -> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4 tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Abeta42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti Alzheimer drug candidates with more balanced biological activities. PMID- 25016234 TI - One-pot synthesis and antiproliferative activity of novel 2,4-diaminopyrimidine derivatives bearing piperidine and piperazine moieties. AB - A series of novel 2,4-diaminopyrimidines containing piperidine and piperazine moieties were synthesized via an efficient one-pot methodology. The bioassay tests demonstrated that compounds 27 and 28 displayed much stronger antitumor activities against four human cancer cell lines (HepG2, A549, MDA-MB-231 and MCF 7) than positive control fluorouracil. Particularly, compound 28 showed a two fold improvement compared to fluorouracil in inhibiting MDA-MB-231 and A549 cell proliferation with IC50 values of 7.46 and 12.78 MUM, respectively. Further flow activated cell sorting analysis revealed that the most promising compound 28 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in MDA-MB-231 cells. PMID- 25016235 TI - Activated platelet supernatant can augment the angiogenic potential of human peripheral blood stem cells mobilized from bone marrow by G-CSF. AB - Platelets not only play a role in hemostasis, but they also promote angiogenesis and tissue recovery by releasing various cytokines and making an angiogenic milieu. Here, we examined autologous 'activated platelet supernatant (APS)' as a priming agent for stem cells; thereby enhance their pro-angiogenic potential and efficacy of stem cell-based therapy for ischemic diseases. The mobilized peripheral blood stem cells ((mob)PBSCs) were isolated from healthy volunteers after subcutaneous injection of granulocyte-colony stimulating factor. APS was collected separately from the platelet rich plasma after activation by thrombin. (mob)PBSCs were primed for 6h before analysis. Compared to naive platelet supernatants, APS had a higher level of various cytokines, such as IL8, IL17, PDGF and VEGF. APS-priming for 6h induced (mob)PBSCs to express key angiogenic factors, surface markers (i.e. CD34, CD31, and CXCR4) and integrins (integrins alpha5, beta1 and beta2). Also (mob)PBSCs were polarized toward CD14(++)/CD16(+) pro-angiogenic monocytes. The priming effect was reproduced by an in vitro reconstruction of APS. Through this phenotype, APS-priming increased cell-cell adhesion and cell-extracellular matrix adhesion. The culture supernatant of APS primed (mob)PBSCs contained high levels of IL8, IL10, IL17 and TNFalpha, and augmented proliferation and capillary network formation of human umbilical vein endothelial cells. In vivo transplantation of APS-primed (mob)PBSCs into athymic mice ischemic hindlimbs and Matrigel plugs elicited vessel differentiation and tissue repair. In safety analysis, platelet activity increased after mixing with (mob)PBSCs regardless of priming, which was normalized by aspirin treatment. Collectively, our data identify that APS-priming can enhance the angiogenic potential of (mob)PBSCs, which can be used as an adjunctive strategy to improve the efficacy of cell therapy for ischemic diseases. PMID- 25016236 TI - Type I and type II crustins from Penaeus monodon, genetic variation and antimicrobial activity of the most abundant crustinPm4. AB - An antimicrobial protein, crustin, is involved in the innate immunity of crustacean by defending the host directly against the microbial pathogens. By data mining the Penaeus monodon EST database, two type I crustins, carcininPm1 and 2, and ten type II crustins, crustinPm1-10, were identified. The abundant crustins were crustinPm1, 4 and 7, each with variation in the length of Gly-rich repeat among its members. A few crustinPm1, 4 and 7 with deletion in the Cys-rich region were also observed. Furthermore, the crustinPm4 with the longest N terminal Gly-rich region was characterized. The crustinPm4 allelic genes were expressed mainly from the hemocytes. Its expression was up-regulated readily by WSSV infection and gradually decreased to normal level afterwards. The recombinant crustinPm4-1 (rcrustinPm4-1) isoform was produced using the Escherichia coli expression system and tested for its antimicrobial activity. The rcrustinPm4-1 was able to inhibit the growth of a Gram-positive bacterium, Bacillus megaterium but not Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus. It also inhibited the growth of two Gram-negative bacteria, E. coli 363 and Vibrio harveyi 639 at lower potency. The rcrustinPm4-1 affected the WSSV infection because the expression of an intermediate early gene ie1 in WSSV-infected hemocyte cell culture was reduced. It was shown further that the rcrustinPm4-1 could delay by about one and a half days the manifestation of disease by WSSV. PMID- 25016237 TI - Clinical features associated with sleep disturbances in Parkinson's disease. AB - OBJECTIVE: Sleep disturbances, such as REM sleep behavior disorder (RBD) and excessive daytime sleepiness, are more common in patients with Parkinson's disease (PD) than in the general population. Apart from that, their relation to PD seems to diverge considerably. Our aim was to explore the frequency and associated motor- and non-motor features of sleep related symptoms in PD. METHODS: One hundred and seven patients with PD, 65 men and 42 women, were included in a cross-sectional study. Excessive daytime sleepiness was examined by the Epworth sleepiness scale. Probable RBD (pRBD) was diagnosed by the validated REM sleep behavior disorder screening questionnaire. Further sleep symptoms were explored by the Parkinson's disease sleep scale. Motor- and non-motor symptoms were assessed and compared in patients with and without pRBD and excessive daytime sleepiness, respectively. RESULTS: pRBD was present in 38% and excessive daytime sleepiness was present in 29% of the patients. As opposed to excessive daytime sleepiness, pRBD showed no association to disease duration or severity. PD patients with pRBD reported more cognitive problems. There was a trend towards more autonomic dysfunction in patients with pRBD. Nocturia and sleep fragmentation were the most frequent general sleep problems reported by the patients. CONCLUSIONS: Our results suggest that excessive daytime sleepiness is related to disease duration, and possibly caused by progressive neurodegeneration. pRBD seems to be a distinct feature present in only a proportion of PD patients. PMID- 25016238 TI - Post-traumatic syringomyelia: outcome predictors. AB - OBJECTIVE: To identify risk factors that predispose to post-traumatic syringomyelia (PTS) and describe the outcome of surgical management. METHODS: Retrospective cohort study of 27 patients with post-traumatic syringomyelia. Spinal cord injury of these patients spanned the period from 1963 to 2008. All data were collected retrospectively using available medical records and radiological images. RESULTS: There were 24 males and 3 females. The level of initial spine injury was thoracic in 21, cervical in 4, and lumbar in 2. The average age (+/-SD) at diagnosis of PTS was 40+/-13 years. The mean follow-up +/ SD from injury was 18+/-11 years. On admission after injury, there were 14 patients with American Spinal Injuries Association (ASIA) disability scores of A, 3 with ASIA C, and 10 with ASIA score of D. At the time of diagnosis of PTS, local kyphosis at the site of injury measured 28+/-12 degrees , and the residual canal was 67+/-19% compared to the average rostral and caudal anteroposterior diameter. Fourteen patients underwent a single operation for PTS, and 13 needed two or more procedures. In the 11 patients in whom the initial surgery included a duraplasty, 3 required reoperation for unsuccessful reduction in the size of the syrinx and failure to improve symptoms. In the 16 patients in whom the initial procedure was that of a shunt alone, 10 required revision (p=0.0718 rate of revision between shunting and duraplasty). As a result of treatment for PTS, improvement in symptoms of PTS occurred in 14, symptoms were unchanged in 10, and progressed in 3. In the 11 patients with sequential MRI scans, a significant correlation was shown between the reduction in the size of the syrinx and clinical improvement (p<0.001). CONCLUSION: PTS is often the result of severe spinal cord injuries, with over half of patients having an ASIA disability score of A. Our review corroborates other published reports showing that PTS is associated with significant deformity and stenosis. Irrespective of treatment, over half of the patients required reoperation for their PTS. Duraplasty and arachnolysis are the preferred treatment for PTS over shunting alone. Treatment was associated with cessation of symptoms or improvement in nearly 90% of the patients. PMID- 25016239 TI - The role of diffusion tensor imaging in brain tumor surgery: a review of the literature. AB - Diffusion tensor imaging (DTI) is a recent technique that utilizes diffusion of water molecules to make assumptions about white matter tract architecture of the brain. Early on, neurosurgeons recognized its potential value in neurosurgical planning, as it is the only technique that offers the possibility for in vivo visualization of white matter tracts. In this review we give an overview of the current advances made with this technique in neurosurgical practice. The effect of brain shift and the limitations of the technique are highlighted, followed by a comprehensive discussion on its objective value. Although there are many limitations and pitfalls associated with this technique, DTI can provide valuable additional diagnostic information to the neurosurgeon. We conclude that current evidence supports a role for DTI in the multimodal navigation during tumor surgery. PMID- 25016240 TI - Application of diffusion tensor imaging and tractography of the optic radiation in anterior temporal lobe resection for epilepsy: a systematic review. AB - BACKGROUND: Approximately 50-100% of patients with temporal lobe epilepsy undergoing anterior temporal lobe resection (ATLR) will suffer a postoperative visual field defect (VFD) due to disruption of the optic radiation (OpR). OBJECTIVE: We conducted a systematic review of the literature to examine the role of DTI and tractography in ATLR and its potential in reducing the incidence of postoperative VFD. METHODS: We conducted an electronic literature search using PubMed, Embase, Web of Science and BMJ case report databases. Eligibility for study inclusion was determined on abstract screening using the following criteria: the study must have been (1) an original investigation or case report in humans; (2) investigating the OpR with DTI in cases of ATLR in temporal lobe epilepsy; (3) investigating postoperative VFD. All forms of ATLR and ways of assessing VFD were included to reflect clinical practice. RESULTS: 13 studies (four case reports, eight prospective observational studies, one prospective comparative trial) were included in the review, 179 (mean+/-SD, 13.8+/-12.6; range, 1-48) subjects were investigated using DTI. The time of postoperative VFD measurement differed between the detected studies, ranging from two weeks to nine years following ATLR. A modest number of studies and insufficient statistical homogeneity precluded meta-analysis. However, DTI methods were consistently accurate at quantifying and predicting postoperative damage to the OpR. These methods revealed a correlation between the extent of OpR damage and the severity of postoperative VFD. The first and only trial with 15 subjects compared to 23 controls reported that using intraoperative tractography in ATLR significantly reduces the occurrence of postoperative VFD on comparison to conventional surgical planning. CONCLUSIONS: DTI shows potential to be an effective method used in planning ATLR. Findings from a single modest sized study suggest that tractography may be employed as part of intraoperative navigation techniques in order to avoid injury to the OpR. Further research needs to be conducted to ensure the applicability and effectiveness of this technology before implementation in routine clinical practice. PMID- 25016241 TI - Retigabine calms seizure-induced behavior following status epilepticus. AB - In adult rats, intraperitoneal injection of kainate (KA) results in sustained status epilepticus and persistent behavioral comorbidities such as hyperexcitability, anxiety, and altered response to environmental cues. Intrahippocampal KA also results in sustained status epilepticus and continuous high frequency oscillations in the electroencephalograph (EEG), although subsequent behavioral side effects are unknown. We hypothesized that retigabine, a recently discovered anticonvulsant and potent positive modulator of Kv7 channels, may attenuate seizure-induced behavioral abnormalities. Status epilepticus was induced by administration of KA either intraperitoneally (15 mg/kg) or by single intrahippocampal injection (1.0 MUg/0.5 MUL). After 24 h, half of systemically KA-treated animals that reached stage 6 seizures were injected once daily with retigabine (5 mg/kg) for 14 continuous days. All groups underwent three behavioral tests--capture and handling, open field, and elevated plus maze--24 h following the last retigabine treatment and were sacrificed at 25 28 days. In the capture and handling test, systemic KA treatment resulted in frisky behavior and resistance to capture with wild attempts to escape during the 1st, 2nd, and 3rd weeks of the observation period. In contrast, these behaviors were attenuated in KA+retigabine-treated animals. In the open-field test, KA treated animals spent more time in the center zone, but KA+retigabine-treated rats had greater overall activity compared with those having vehicle, KA, or retigabine-only treatment. In the elevated plus maze, KA+retigabine-treated animals traveled greater distances in open and closed arms (proximal and distal) compared with controls, also signifying anxiety reduction. Retigabine-only treated rats traveled more in the open proximal arms compared with controls, indicating increased hyperlocomotion in normotensive rats. Although treatment with KA+retigabine resulted in anxiolytic-like effects in all three behavioral tasks compared with vehicle, this group did not significantly differ from systemically KA-treated rats in most measurements in open-field and elevated plus maze tasks, suggesting that retigabine may also cause hyperlocomotion unrelated to anxiety level. Despite that intrahippocampal KA-treated rats displayed comparable seizure behavior, epileptiform activity, and hippocampal injury, their behavior resembled the controls, suggesting that molecular and subsequent cellular changes are also partially responsible for anxiolytic-like effects and that these results are likely independent of the hippocampus. PMID- 25016243 TI - Testing quality of a self-monitoring blood glucose sensor with an auto-coding mechanism when used by patients versus technicians. AB - BACKGROUND: In response to the problem of erroneous readings due to miscoding when performing self-monitoring blood glucose (SMBG), this study introduces a user-friendly SMBG biosensor with an innovative auto-coding module on the meter and strip. Actual users characterized the performance of the SMBG systems. METHODS: A total of 105 patients were incorporated in the study and Clarke error grid analysis (EGA) was administered to evaluate the clinical accuracy of the results obtained by the patients versus the technicians. All patients used the questionnaires to comment on the use of the auto-coding sensor. RESULTS: In the imprecision test, the total CV of the 5 BG levels was 2.1%. In the EGA plot, the results of the auto-coding sensor were 96.2%, both lots A and B, in zone A for the patients and 99.0% and 97.1% for the technician. The paired t-test demonstrated no statistically significant difference between the patient and technician measurements. Regression analysis also demonstrated that the measurements taken by the patients agreed with those obtained using the laboratory method. CONCLUSIONS: The patients achieved satisfactory performance using the auto-coding SMBG sensor and derived similar results with both laboratory reference and operation by a technician. PMID- 25016244 TI - Decreased serum levels of free fatty acids are associated with breast cancer. AB - BACKGROUND: Changes in the levels of lipids are associated with breast cancer (BC). METHODS: Disease-specific serum free fatty acids (FFAs) were quantified using chip-based direct-infusion nanoelectrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (CBDInanoESI-FTICR MS) in the negative ion mode. Multiple point internal standard calibration curves between the concentration ratios of fatty acids (i.e., C16:1, C18:3, C18:2, C18:1, C20:4, and C22:6) to internal standards (C17:1 for C16:1, C18:3, C18:2, and C18:1, C21:0 for C20:4 and C22:6) and their corresponding intensity ratios were established with a correlation coefficient of greater than 0.986. RESULTS: Data from 342 serum samples including 202 healthy controls and 140 BC patients indicate that serum concentrations of FFAs in patients with BC were significantly decreased compared with those in healthy controls. A panel of C16:1, C18:3, C18:2, C20:4, and C22:6 showed an excellent diagnostic ability to differentiate the patients with early stage BC from healthy controls, with the area under the receiver operating characteristics (ROC) curve of 0.953, a sensitivity of 83.3%, and a specificity of 87.1%. CONCLUSION: Our findings suggest that these FFAs may be a valuable biomarker panel for the early-stage detection of BC. PMID- 25016242 TI - Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline. AB - We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca(2+)]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations. PMID- 25016245 TI - Association between the arginine vasopressin receptor 1A (AVPR1A) gene and preschoolers' executive functioning. AB - Recent evidence implicates the arginine vasopressin (AVP) system in complex neuropsychological disorders which are characterized by deficits in executive functioning (EF). Despite the genetic contribution to EF, little is currently known about its molecular genetic basis. Drawing on research from social neuroscience and the role of related physiological systems in psychopathology, the current study hypothesized that variability in the AVP receptor 1a gene (AVPR1A) would be associated with EF in an epidemiological sample of 323 normally developing preschool-aged children. Using a family-based association design, the current study found that variability in the rs7298346 marker, located in the 5' flanking region, was significantly related to a composite measure of EF in 4-year old children after controlling for a variety of covariates and children's theory of mind. The converse association between AVPR1A and theory of mind (after controlling for EF) was not significant, suggesting a level of specificity in this relationship. The results are discussed in terms of the difficulties faced by genetic association studies in teasing apart the behavioral phenotypes that characterize complex psychological diseases and the involvement of multiple physiological systems in human behavior. PMID- 25016246 TI - Photo-, cathodo- and thermoluminescent properties of dysprosium-doped HfO2 films deposited by ultrasonic spray pyrolysis. AB - In this work, the photoluminescent (PL), cathodoluminescent (CL) and thermoluminescent (TL) properties of hafnium oxide films doped with trivalent dysprosium ions are reported. The films were deposited on glass substrates at temperatures ranging from 300 to 600 degrees C, using chlorides as precursor reagents. The surface morphology of films showed a veins shaped microstructure at low deposition temperatures, while at higher temperatures the formation of spherical particles was observed on the surface. X-ray diffraction showed the presence of HfO2 monoclinic phase in the films deposited at temperatures greater than 400 degrees C. The PL and CL spectra of the doped films showed the highest emission band centered at 575nm corresponding to the transitions (4)F9/2 >(6)H13/2, which is a characteristic transition of Dy(3+) ion. The greatest emission intensities were observed in samples doped with 1 atomic percent (at%) of DyCl3 in the precursor solution. Regarding the TL behavior, the glow curve of HfO2:Dy(+3) films exhibited spectrum with one broad band centered at about 150 degrees C. The highest intensity TL response was observed on the films deposited at 500 degrees C. PMID- 25016247 TI - Entamoeba histolytica adaptation to glucose starvation: a matter of life and death. AB - Parasites are often challenged by constant changes of the glucose concentration in their different hosts and/or within the different biotopes in the same host. During its life cycle, Entamoeba histolytica, the causative protozoan parasite of human amoebiasis, is exposed to both a glucose-poor environment in the colon and a glucose-rich environment in the liver. High-throughput 'omics' technologies are now widely used to characterize the cell's global response to various stresses and these technologies can survey E. histolytica's global response to fluctuations in glucose concentration in its environment. In this review, we discuss the phenotypic and metabolic responses of E. histolytica to glucose challenges, and compare these responses to those of other protozoan parasites. PMID- 25016249 TI - Evaluation of a novel material, Diomics X-SwabTM, for collection of DNA. AB - Success of DNA typing is related to the amount of target material recovered from an evidentiary item. Generally, the more DNA that is recovered, the better the chance is of obtaining a typing result that will be robust and reliable. One method of collecting stain materials is by swabbing. Recovery of DNA from a number of commercially available swabs is not an efficient process. The X-SwabTM (Diomics Corporation, La Jolla, CA) is a unique bio-specimen collection material with highly absorptive properties and can be dissolved during certain extraction conditions. Therefore, more DNA may be collected from a substrate and be released from the swab matrix than other swabs. The ability to recover DNA from X-Swab material and success in STR typing were compared with the Copan 4N6FLOQSwabTM (Brescia, Italy), a device which utilizes a proprietary flocked-swab technology to maximize DNA collection and elution efficiency. Both types of swabs were impregnated with known amounts of DNA and body fluids and allowed to air dry. In addition, blood was placed onto glass slides, allowed to dry and collected using both types of swabs. DNA recovery was assessed by DNA quantitation and by STR typing. Results suggested that X-Swab material yielded greater DNA recovery, particularly of low quantity samples (defined as diluted neat samples), compared with the 4N6FLOQSwab. Results also indicated that X-Swab material itself enhances yield of PCR products. PMID- 25016248 TI - Motor fMRI and cortical grey matter volume in adults born very preterm. AB - The primary aim of this study was to investigate the functional neuroanatomy of motor planning, initiation and execution in a cohort of young adults (mean age 20 years) who were born very preterm (VPT; <33 weeks of gestation), as these individuals are at increased risk of experiencing neuromotor difficulties compared to controls. A cued motor task was presented to 20 right-handed VPT individuals and 20 controls within a functional magnetic resonance imaging (fMRI) paradigm. Whole-brain grey matter volume was also quantified and associations with functional data were examined. Despite comparable task performance, fMRI results showed that the VPT group displayed greater brain activation compared to controls in a region comprising the right cerebellum and the lingual, parahippocampal and middle temporal gyri. The VPT group also displayed decreased grey matter volume in the right superior frontal/premotor cortex and left middle temporal gyri. Grey matter volume in the premotor and middle temporal clusters was significantly negatively correlated with BOLD activation in the cerebellum. Overall, these data suggest that preterm birth is associated with functional neuronal differences that persist into adulthood, which are likely to reflect neural reorganisation following early brain injury. PMID- 25016250 TI - Strong genetic admixture in the Altai at the Middle Bronze Age revealed by uniparental and ancestry informative markers. AB - The Altai Mountains have been a long-term boundary zone between the Eurasian Steppe populations and South and East Asian populations. To disentangle some of the historical population movements in this area, 14 ancient human specimens excavated in the westernmost part of the Mongolian Altai were studied. Thirteen of them were dated from the Middle to the End of the Bronze Age and one of them to the Eneolithic period. The environmental conditions encountered in this region led to the good preservation of DNA in the human remains. Therefore, a multi markers approach was adopted for the genetic analysis of identity, ancestry and phenotype markers. Mitochondrial DNA analyses revealed that the ancient Altaians studied carried both Western (H, U, T) and Eastern (A, C, D) Eurasian lineages. In the same way, the patrilineal gene pool revealed the presence of different haplogroups (Q1a2a1-L54, R1a1a1b2-Z93 and C), probably marking different origins for the male paternal lineages. To go further in the search of the origin of these ancient specimens, phenotypical characters (i.e. hair and eye color) were determined. For this purpose, we adapted the HIrisPlex assay recently described to MALDI-TOF mass spectrometry. In addition, some ancestry informative markers were analyzed with this assay. The results revealed mixed phenotypes among this group confirming the probable admixed ancestry of the studied Altaian population at the Middle Bronze Age. The good results obtained from ancient DNA samples suggest that this approach might be relevant for forensic casework too. PMID- 25016251 TI - Label-free chemiluminescent aptasensor for platelet-derived growth factor detection based on exonuclease-assisted cascade autocatalytic recycling amplification. AB - Here an exonuclease III (Exo III)-assisted cascade autocatalytic recycling amplification (Exo-CARA) strategy is proposed for label-free chemiluminescent (CL) detection of platelet-derived growth factor BB (PDGF-BB) by taking advantage of both recognition property of aptamer and cleavage function of Exo III. Functionally, this system consists of a duplex DNA (aptamer-blocker hybrid), two kinds of hairpin structures (MB1 and MB2), and Exo III. Upon recognizing and binding with PDGF-BB, aptamer folds into a close configuration, which initiates the proposed Exo-CARA reaction (Recyclings I->II->III->II). Finally, numerous "caged" G-quadruplex sequences on DNAzyme1 and DNAzyme2 release that intercalate hemin to catalyze the oxidation of luminol by H2O2 to generate an amplified CL signal, achieving excellent specificity and high sensitivity with a detection limit of 6.8*10(-13) M PDGF-BB. The proposed strategy has the advantages of simple design, isothermal conditions, homogeneous reaction without separation and washing steps, effective-cost without the need of labeling, and high amplification efficiency, which might be a universal and promising protocol for the detection of a variety of biomolecules whose aptamers undergo similar conformational changes. PMID- 25016252 TI - Hybrid microfluidic fuel cell based on Laccase/C and AuAg/C electrodes. AB - A hybrid glucose microfluidic fuel cell composed of an enzymatic cathode (Laccase/ABTS/C) and an inorganic anode (AuAg/C) was developed and tested. The enzymatic cathode was prepared by adsorption of 2,2'-Azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) and Laccase on Vulcan XC-72, which act as a redox mediator, enzymatic catalyst and support, respectively. The Laccase/ABTS/C composite was characterised by Fourier Transform Infrared (FTIR) Spectroscopy, streaming current measurements (Zeta potential) and cyclic voltammetry. The AuAg/C anode catalyst was characterised by Transmission electron microscopy (TEM) and cyclic voltammetry. The hybrid microfluidic fuel cell exhibited excellent performance with a maximum power density value (i.e., 0.45 mW cm(-2)) that is the highest reported to date. The cell also exhibited acceptable stability over the course of several days. In addition, a Mexican endemic Laccase was used as the biocathode electrode and evaluated in the hybrid microfluidic fuel cell generating 0.5 mW cm(-2) of maximum power density. PMID- 25016253 TI - Evanescent wave DNA-aptamer biosensor based on long period gratings for the specific recognition of E. coli outer membrane proteins. AB - An evanescent wave fiber optic sensor for detection of Escherichia coli (E. coli) outer membranes proteins (EcOMPs) using long period gratings (LPGs) as a refractometric platform is presented. The sensing probes were attained by the functionalization of LPGs inscribed in single mode fiber using two different methods of immobilization; electrostatic assembly and covalent binding. The resulting label-free configuration enabled the specific recognition of EcOMPs in water by monitoring the resonance wavelength shift due to refractive index changes induced by binding events. The sensors displayed linear responses in the range of 0.1 nM to 10 nM EcOMPs with sensitivities of -0.1563+/-0.005 nm decade( 1) [EcOMP, M] (electrostatic method) and -0.1597+/-0.004 nm decade(-1) [EcOMP, M] (covalent method). The devices could be regenerated (under low pH conditions) with a deviation less than 0.1% for at least three subsequent detection events. The sensors were also applied to spiked environmental water samples. PMID- 25016254 TI - Continuous immunosensing of myoglobin in human serum as potential companion diagnostics technique. AB - To attain early diagnosis of acute myocardial infarction (AMI) with enhanced accuracy, continuous immunosensing has been investigated to measure myoglobin concentration in real-time. To this end, a capture antibody showing rapid reaction kinetics was immobilized on the surface of a surface plasmon resonance sensor. Three problems associated with the continuous sensing of myoglobin in human serum needed to be overcome: non-specific binding of the analyte, aggregation of serum components, and drift of the sensor baseline. Non-specific binding was controlled by pretreating the sample with a detergent mixture consisting of sodium dodecyl sulfate and P20, and adjusting the micelle size and net charge. Aggregation was managed by inactivating certain serum constituents through chelation of heavy metals. Baseline drift perceived in the sensorgram was able to be corrected by compensating for the slope calculated by a linear regression. Under the optimal conditions, the continuous sensor reproducibly traced the varying doses of myoglobin over about 8h with periodic one-point calibration every 3h. The dose-response curve of the sensor was linear with acceptable variations (CVs<4.91% in average) between the detection limit (31.0 ng/mL) and about 2000 ng/mL in the arithmetic scale (R(2)>0.98), covering the clinical concentration range. The immunosensor performance correlated with the Pathfast reference system (R(2)>0.98) and analytical consistency could be maintained for longer than a month if appropriately calibrated. Such immunosensing could be used as a companion diagnostic means along with real-time electrocardiographic measurement, significantly enhancing the sensitivity of AMI diagnosis and thereby enabling treatment at an early stage. PMID- 25016255 TI - Molecular bonding characteristics of Self-plasticized bamboo composites. AB - Bamboo biomass fibers were gradually separated, prepared, and then self plasticized for immune composites. The molecular bonding characteristics of the self-plasticized bamboo composites were investigated by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR), and thermo gravimetric analysis (TG). The important results were as follows. (1) During self-plasticizing of bamboo biomass, the cross-linking between celluloses mainly depended on carboxylic acid anhydrides and carboxylic acid esters, that between cellulose and lignin depended on carboxylic acid esters and C=O groups of aliphatic hydrocarbons, and that of hemi cellulose had a ether bond and ester bond bridging effect between lignin and cellulose. The cross-linking effects of hemi cellulose, lignin, and cellulose could be stacked and coupled. (2) After self-plasticization, the crystallinity of the lingo cellulosic biomass, lignin cellulose, and cellulose were increased by 5.8%, 2.28%, and 11.67%, respectively. While the TG curves of all samples were basically similar in shape, the weight loss rate turning points of the self-plasticized samples were delayed compared with those of the bamboo biomass fibers. This result demonstrated that the molecular integration of the bamboo biomass was increased after self plasticization, and confirmed that bond cross-linking between the hemi cellulose, lignin and cellulose of the bamboo biomass had occurred. PMID- 25016256 TI - Isolation and characterization of a novel lectin with mitogenic activity from Pleurotus ferulae. AB - Lectins are the tools for the determination of sugar chain structure. Recently, lectin arrays have become a popular new technology; therefore, lectins with specific sugar-binding properties are required. The objective of the study was to isolate a novel lectin from Pleurotus ferulae mushrooms and characterize its various biological activities. A novel lectin was extracted with deionized water, precipitated from the aqueous extract using 75% saturated (NH4)2SO4, and subjected on DEAE-cellulose followed by affinity chromatography on sepharose-6B. The activity was tested using hemagglutination assays, and carbohydrate-binding specificity was determined by glycan microarray analysis. Its effects on the mitogenic activity of mouse splenocytes were determined by MTT assay. The novel lectin was adsorbed on ion-exchange chromatography DEAE-cellulose and shown as a band with the molecular mass of 17.5 kDa on a SDS-PAGE and as a single 35.0-kDa peak in gel filtration on Superdex G-75. The hemagglutinating activity of the lectin was inhibited by D-glucose, lactose, D-galactose, and galactosamine. The lectin was stable on 60 degrees C. The hemagglutinating activity of lectin was reduced by 50% at 70 degrees C. At 80 degrees C, it was further reduced to 6.25% of its original activity. The hemagglutinating activity was the highest at pH 6 9. Moreover, its hemagglutinating activity was inhibited by Mg2+ and Ca2+ ions. The lectin isolated from P. ferulae in the current study possessed highly potent hemagglutinating and proliferative activities toward mouse splenocytes. PMID- 25016257 TI - Immune effects of extractives on bamboo biomass self-plasticization. AB - Bamboo is a fast-growing renewable bioresource. However, bamboo resources are wasted, and bamboo products release toxic gases. Bamboo biomass was therefore extracted and self-plasticized, and the immune effects of bamboo extractives were determined and investigated using nuclear magnetic resonance (NMR) and Fourier transform infrared (FT-IR) spectroscopies, X-ray diffraction (XRD), and scanning electron microscopy (SEM). The results showed the following. (1) The 1H-NMR signals at ~5.5, 4-8, 7.4-10.2, and 12.22-12.37 ppm were attributed to the chemical shifts of active protons on carbons adjacent to R-OH, RAr-OH, oximes, and -COOH, respectively. This showed that there were highly reactive hydrogen atoms in bamboo benzene/ethanol extractives. The 13C-NMR spectrum gave further confirmation. (2) The extents of the effects of key process parameters were different: temperature > hot pressure > time. The optimal self-plasticizing conditions were temperature 170 degrees C, hot pressure 9 MPa, time 40 min, and extraction of bamboo. (3) SEM, FT-IR, and XRD showed that contact and linkages among bamboo cells were significantly decreased by extractives, so the internal bond strengths of the self-plasticized samples were all higher after bamboo extraction. It was also found that the extractives created a significant barrier to bamboo self-plasticization as a result of their structure and chemical linkage reactions. PMID- 25016258 TI - Dynamic matching algorithm for viral structure prediction. AB - Most viruses have RNA genomes, their biological functions are expressed more by folded architecture than by sequence. Among the various RNA structures, pseudoknots are the most typical. In general, RNA secondary structures prediction doesn't contain pseudoknots because of its difficulty in modeling. Here we present an algorithm of dynamic matching to predict RNA secondary structures with pseudoknots by combining the merits of comparative and thermodynamic approaches. We have tested and verified our algorithm on some viral RNA. Comparisons show that our algorithm and loop matching method has similar accuracy and time complexity, and are more sensitive than the maximum weighted matching method and Rivas algorithm. Among the four methods, our algorithm has the best prediction specificity. The results show that our algorithm is more reliable and efficient than the other methods. PMID- 25016259 TI - Polymorphism analysis of CTLA-4 in childhood acute lymphoblastic leukemia. AB - To investigate the correlation between cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism and children with acute lymphoblastic leukemia (ALL). A total of 86 children of ALL (23 HR, 54SR) and 112 healthy controls was selected. The genptypes were determined by means of polymerase chain reaction (PCR) and the PCR product sequencing. Genotype and alleles frequency of SNP-318, SNP+49 and SNP CT60 were compares among different groups. The frequency of TC, TT genotype and T allele in ALL children at SNP-318 position were statistically higher than controls. In HR group, the frequency of TC, TT genotype at SNP-318 position was statistically higher than SR group. There was no significantly difference in genotype and allele distribution of SNP+49 position among the HR patients, SR patients and control group. (2) The frequency of GG genotype and G allele in ALL children at SNP-CT60 position were significantly higher than controls. The genotype and allele distribution of SNP-CT60 position between different clinical risk groups were no significantly different. As a result of the increased frequency of TC, TT genotype and T allele at SNP-318, ALL children synthesized more CTLA-4 to deliver the inhibitive signal, and this lead to restraint of T cell activation. Such difference at SNP-318 position was obvious in HR children. The SNP+49 position is probably not the main regulating point in ALL. (2) In SNP CT60 position, the G allele played the main part. The increase of G allele frequency result in the high expression of CTLA-4. such difference at SNP-318 position was obvious in HR children. PMID- 25016260 TI - History of Pu'er Tea and comparative study for the effect of its various extracts on lipid-lowering diet. AB - Pu'er Tea is a kind of traditional historical famous tea which gains its name for native government jurisdiction in Pu'er (now Xishuangbanna in Yunnan, Pu'er city etc), and takes Pu'er (now Ninger county of Pu'er city) city as its collecting and distributing center .It is famous all over the world because of its good benefits for reducing blood lipid, slimming weight, antibacterial, aid digestion, detoxification and other functions, it is even known as the health care beverage with "the fine quality goods for preserving people's health", "a health drink demanded everyday". Although there are a lot of current study literature about the effect of Pu'er Tea on lipid-lowering and reducing weight, but there is rarely contrast study about the effect of lipid-lowering diet with its various extracts. Therefore, this article uses the acetone, water, chloroform, ethyl acetate and n-butanol to continuously extract Pu'er Tea, then freeze and dry them into four major separate components which include the chloroform layer, ethyl acetate layer, butanol layer and the remaining water layer. Take advantage of different components for filling and feeding the ICR mice which are treated with the processing of obesity molding, then compare the extract of Pu'er Tea with the weight-loss drug L-carnitine which is popular all over the market, explore the slimming effect of each component in Pu'er Tea on the cells of ICR fat mice. The results show that the total water extract of Pu'er Tea, ethyl acetate extract, residual water extract all have obvious effect on reducing body weight and body fat of experimental mice, it also has significant lowering effect on blood lipid and liver lipid in mice, that could significantly inhibit the accumulation of lipid in fat cells and hypertrophy of fat cells, reveal that the Pu'er Tea has good function of lipid-lowering and reducing weight. At the same time, the comprehensive effect of lipid-lowering and reducing weight through Pu 'er Tea is superior to commercial weight loss drug L-carnitine, and weight reducing effect of ethyl acetate extracts in Pu'er Tea and residual water layer is better than total water extract of Pu'er Tea. But n-butyl extract doesn't show a significant effect of lipid-lowering and reducing weight, inferring that efficacy component of Pu'er Tea which plays a major role of the effective component of lipid lowering and reducing weight may exist in ethyl acetate extract and residual layer material. PMID- 25016261 TI - Effect of Glutamine's nutrition support on the postoperative nutrition and immune function in malignant tumor of gynecology patients. AB - This paper is mainly to study the influence of Glutamine's reinforcing role in enteral nutrition on postoperative nutrition and immune function of patients with gynecologic malignant tumor. The adopted method is through selecting 60 patients with gynecological malignant tumor, they are randomly divided into groups of enteral immune nutrition (EIN group) and conventional enteral nutrition (EN group), which are given enteral nutrition of equal nitrogen and heat respectively in postoperative 24 hours, the total period of nutritional support are 7 days. The research results represent that nutrition and immunity index in both groups on the first day after operation is lower than the day before operation, and all indicators have picked up on the ninth day after operation. PMID- 25016262 TI - A study on relation of dietary fiber from different sources, acceptable daily intake of calcium and colorectal cancer of 30 to 45 years old. AB - This paper selects Jiashan, Zhejiang, the high incidence area of colorectal cancer in China, as research site and adopts case control as research method to study relative hazards of colorectal cancer, especially the relation between dietary factor and colorectal cancer. It makes a further understanding of the possible cause of high incidence of colorectal cancer in Jiashan in order to provide a scientific basis for the prevention of colorectal cancer. PMID- 25016263 TI - The development of Bio-pharmaceutical industry in China: problems and solutions. AB - Known as the "sunrise industry" of the 21st century, bio-pharmaceutical industry has been a fast-growing global industry, and many countries have been developing this industry as the focus of their national economies. In China, there exists a huge market demand for the development of bio-pharmaceutical industry, but at the present stage the industry is faced with some problems, such as low level of R & D for innovative drugs, and inappropriate capital investment in the industrialization. In order to accelerate the development of China's bio pharmaceutical industry, it is necessary to take strategic initiatives of improving the technology transfer system, developing the bio-pharmaceutical outsourcing, and building a diversified industrial financing system. PMID- 25016264 TI - Effect of Pakistani medicinal plants on IgE/antigen- and ionophore-induced mucosal mast cells degranulation. AB - Cumulative evidence has now demonstrated the stimulation of mucosal mast cells by both allergic and non-allergic triggers and their inhibition as a potential therapeutic target in many diseases like food allergy and ulcerative colitis. Hence, we screened medicinal plants from Pakistan against antigen- and ionophore induced degranulation of mucosal mast cells. Aqueous ethanol extracts were screened. IgE/antigen- and A23187-induced degranulation of mucosal-type murine bone marrow derived mast cells (mBMMCs) were screening assays and beta hexosaminidase released from degranulated mBMMCs was measured. Real time polymerase chain reaction was employed to examine the expression of TNF-alpha and IL-4 mRNA. Acetoxychavicol acetate, was examined by degranulation assays and real time-PCR. Among the ten plants screened against IgE/antigen stimulated degranulation, five plants; Alpinia galangal, Mentha arvensis, Myrtus communis, Polygonum bistorta and Syzygium aromaticum demonstrated significant (p<0.01) suppression of the degranulation at 100 MUg/ml. Of them, Alpinia galangal showed significant (p<0.01) inhibition at 32 mg/ml. In A23187-induced degranulation, all plants showed significant (p<0.01) inhibition at 100 MUg/ml except Tamarix dioica. Again Alpinia galangal exhibited significant (p<0.01) suppression at 32 MUg/ml. In a concentration dependent assay, Alpinia galangal revealed significant suppression at 10 MUg/ml against A23187-stimulated degranulation. Acetoxychavicol acetate demonstrated significant (p<0.01) inhibition at 3.2 MUM in IgE/antigen treated cells and at 10 MUM in A23187-treated cells. Furthermore, both Alpinia galangal and acetoxychavicol acetate suppressed the IgE/antigen- and A23187 enhanced mRNA expression of inflammatory cytokines, TNF-a and IL-4, in mBMMCs. Our findings revealed the suppressive effect of Alpinia galangal and acetoxychavicol acetate on degranulation of mBMMCs by allergic and non-allergic stimuli, which can be utilized for future drug development against food allergy or ulcerative colitis. PMID- 25016265 TI - Development paths of China's agricultural Pharmaceutical industry under Eco agriculture background. AB - Using pesticides has double effects. On one hand, it contributes to pests control and regulates the growth of crops; On the other hand, it does harm to the environment. To develop ecological agriculture should not only emphasize the output level of agriculture to pursuit of economic efficiency, but also need to keep the ecological environment protected and focus on the social benefits during the development of the industry. As a large agricultural country in the world, China is vigorously promoting the development of ecological agriculture, which is bound to put forward to developing the pesticide industry and green ecological development requirements to promote the transformation and upgrading of agricultural pharmaceutical industry. This paper discusses the mechanism of pesticide pollution on the ecological environment and analyzes China's agricultural problems in the pharmaceutical industry. Then study on the development of Chinese green pesticides and try to find the proper paths of agricultural pharmaceutical to achieve industrial upgrading. PMID- 25016266 TI - The research for the clinical curative effect through combing traditional Chinese medicine with insulin to cure diabetes. AB - The clinical curative effect is observed through curing type 2 diabetes mellitus with the therapy of combing Traditional Chinese Medicine (TCM) with insulin. METHOD: Both the insulin prescription and the treatment of traditional Chinese medicine prescription are applied as mutual comparison. And the dosage, time, blood sugar level and curative effect etc are recorded. Healthy human body is taken as comparison for monitoring physical indicators. RESULTS: Through comparing insulin prescription and the combing therapy of insulin and traditional Chinese medicine, the insulin treatment group is better than contrast group (P<0.05). For the blending use group, the ISI in each group is significantly lower than that of health control group (P<0.01), where accumulation of damp heat in spleen type is the lowest; the BM I, H bA1C of type 2 diabetic patient is higher than health control group, its accumulation of damp heat in spleen type is the highest, TC, TG typical accumulation of damp heat in spleen are higher than other pattern of syndrome. CONCLUSION: the treatment method of combing TCM with insulin in curing type 2 diabetes mellitus has better effect than using insulin treatment alone; the resistance degree of insulin demonstrates the changing trend of first increase and later decrease with the development of disease course. Accumulation of damp heat in spleen type accounts for the highest proportion in type 2 diabetic patients, and there exists serious insulin resistance. PMID- 25016268 TI - Effect of a residue after evaporation from industrial vitamin C fermentation on chemical and microbial properties of alkali-saline soil. AB - Residue after evaporation (RAE) from industrial vitamin C fermentation is emitted as a waste product at an amount of 60,000 tons per year in China. The disposal of RAE is difficult because of its high chemical oxygen demand (1.17*10(6) mg/l) and low pH (0.27). We hypothesized that RAE could be used as an ameliorant for alkali saline soils, and tried to verify it by carrying out a pot experiment of pakchoi cultivation and to explore its effect on soil chemical and microbial properties. The results showed that pakchoi yield was increased by 28.13% and pakchoi quality was also enhanced under RAE treatment. The improved chemical and microbial properties of treated soil were also observed: soil pH was decreased from 9.19 to 9.03; total organic carbon, available phosphorus and available potassium were increased by 49.15%, 34.91% and 42.02%, respectively; number of culturable bacteria, actinomycetes and fungi, microbial biomass carbon and enzyme activity number were improved by 52.97%, 104.05%, 79.09%, 57.82% and 31.16%, respectively. These results suggested the residue application led to an improved soil quality and subsequently a higher yield and quality of pakchoi. This study provided a strong evidence for the feasibility of RAE as an ameliorant for alkali-saline soil. PMID- 25016267 TI - Studies of traditional Chinese medicine monomer on HeLa cell of cervical cancer. AB - This paper is to study the effect of traditional Chinese medicine monomer including quercetin, curcumin and Glaucocalyxin A on Hela cell of cervical cancer. The inhibiting effect of quercetin, curcumin and Glaucocalyxin A on HeLa cells' proliferation is detected through using MTT method. Analysis for the effect of quercetin, curcumin and Glaucocalyxin A on proliferation cycle of Hela cell is performed through adopting flow cytometry. Three kinds of traditional Chinese medicine monomer can inhibit the growth of Hela cell, and they show dependent relationship between time and dose. Quercetin, curcumin and Glaucocalyxin A could inhibit cell proliferation, probably through making Hela cell be in stagnation and inducing its apoptosis. PMID- 25016269 TI - The role of Ki-67 in women with a resistant prolactinoma: a retrospective analysis in 199 hospitalized patients over a period of 5 years. AB - Proliferation-associated antigen Ki-67 is used for the histological evaluation of different tumors. Few studies have been conducted on women with a resistant prolactinoma. To better define the characteristics and to evaluate the differences between patients with different Ki-67 labeling index (LI), a retrospective study was designed to recruit 199 females with a resistant prolactinoma. The patients were divided into two groups, patients with Ki-67 LI>=3% and patients with Ki-67 LI<3%. Tumors in the LI>3% group were also larger (p=0.043), had a higher rate of invasion (p=0.014), and were associated with more frequent polyuria and polydipsia (p=0.008) compared to the LI<3% group. The pre- and post-operative PRL levels in the LI>3% group remained significantly higher compared to patients with LI<3% (p<0.05). The incidences of transient diabetes insipidus and hyponatremia in the LI>3% group were also significantly higher (p=0.037, p=0.041). Additionally, the postoperative PRL normalization rate was lower in patients with LI>3% compared with patients with LI<3% (p=0.028). The recurrence rate in the LI>3% and LI<3% groups were 27.27% and 8.47%, respectively. In conclusion, high Ki-67 LI is predictive sign of a poor prognosis in women with resistant prolactinoma. PMID- 25016270 TI - Weibull statistical analysis of tensile strength of vascular bundle in inner layer of moso bamboo culm in molecular parasitology and vector biology. AB - Bamboo is a radial gradient variation composite material against parasitology and vector biology, but the vascular bundles in inner layer are evenly distributed. The objective is to determine the regular size pattern and Weibull statistical analysis of the vascular bundle tensile strength in inner layer of Moso bamboo. The size and shape of vascular bundles in inner layer are similar, with an average area about 0.1550 mm2. A statistical evaluation of the tensile strength of vascular bundle was conducted by means of Weibull statistics, the results show that the Weibull modulus m is 6.1121 and the accurate reliability assessment of vascular bundle is determined. PMID- 25016271 TI - Identification and crude protein extract of endophytic bacteria strain KLXD06 antagonistic against MRSA isolated from Hemsleya sinesis. AB - Hemsleya sinesis Cogn has a variety of medicinal value. Strain KLXD06 is an endophytic bacteria isolated from H. sinesis exhibited significant inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA). This strain was identified by methods including 16S rDNA sequence homology and phylogenetic analysis morphological, biochemical and physiological characteristics analysis. Ccrude protein from KLXD06 was extracted by ammon ium sulfate salting-out. The results showed that strain KLXD06 was identified as Serratia marcescens. Antibacterial crude protein from KLXD06 was extracted by ammon ium sulfate salting-out, has a thermal stability. PMID- 25016272 TI - Comparative research for the dietary pattern of patients with esophageal cancer at different developing stages and the daily intake of vitamin A, E and beta carotene. AB - This paper discusses the different stages of normal esophageal's developing to esophageal cancer, and the difference among dietary patterns of patients with esophageal cancer and acceptable daily intake of vitamin A, E and beta carotene intake in diet. This paper takes advantage of food composition table, calculates the intake amount of dietary vitamin A, E and beta carotene in all kinds of food for patients with esophageal cancer, and analyzes the intake amount difference of dietary vitamin A, E and beta carotene in each kind of food for different groups of people. Research conclusions: the low content level of dietary vitamin A, E beta-carotene and low intake amount of beans, vegetables and fruit intake may increase the risk of esophageal cancer' occurring, while the relationship among dietary vitamin E, the occurrence and development of esophageal cancer needs further discussion. PMID- 25016273 TI - Research on effect of ginkgo aglucone flavone to human body organs and immune function. AB - Ginkgo aglucone flavone is a kind of effective natural antioxidant. Lots of researches show that ginkgo aglucone flavone has various biological activities and it is of great importance to antioxidant, anti-aging, free radial scavenging and immunoregulation. However, researches on effect of ginkgo aglucone flavone to immune function are rare so far. Thus, it is important to go into the effect of ginkgo aglucone flavone to immune function. We can find out more effective measurement that resist immunosuppression through research and provide referable science activity form and suggestion of sports nutrition supplements. It can guide people to improve habitus through supports and establish important basis for new area development of folium ginkgo extract. This paper aims to discuss the effect of ginkgo aglucone flavone to human body organs and immune function. Patients with ginkgo aglucone flavone indications are selected for experiment. Their peripheral blood T lymphocyte subsets and content of serum immunoglobin is detected before and two weeks after drug use. The result shows that specific ratio of T lymphocyte subsets CD3 and CD4 and the content of serum IgG significantly increase after pharmacy of patients. It can be concluded that ginkgo aglucone flavone have acceleration on immune system function. PMID- 25016274 TI - Comparing the effects of manual therapy versus electrophysical agents in the management of knee osteoarthritis. AB - To evaluate the effectiveness of Manual Therapy in comparison to Electrophysical agents in Knee Osteoarthritis. Total 50 patients with knee osteoarthritis were recruited from OPD of orthopedics civil hospital and Institute Of Physical Medicine & Rehabilitation, Dow University of Health Sciences Karachi. All those patients who fulfilled inclusion criteria were selected on voluntary basis. Selected patients were equally divided and randomly assigned into two groups with age and gender matching. The Manual therapy group received program of Maitland joint mobilization whereas Electrophysical Agent group received a program of TENS and cold pack. Both group received a program of exercise therapy as well. Patients received 3 treatment sessions per week for 4 successive weeks. Clinical assessment was performed using WOMAC index at baseline and on 12th treatment session. Both study groups showed clinically and statistically considerable improvements in WOMAC index. However, Related 2 sample t-test showed better clinical results in Manual Therapy group (p = 0.000) than Electrophysical Agents group (p = 0.008). The mean improvement in total WOMAC index was relatively higher in Manual Therapy group (22.36 +/- 13.91) than Electrophysical Agent group (9.72 +/- 6.10). This study concluded that manual therapy is clinically more effective in decreasing pain, stiffness and improving physical function in knee osteoarthritis. PMID- 25016275 TI - The clinical research for Ganoderan's effect on preventing and treating cerebral arteriosclerosis through inhibiting NADPH oxidizing enzyme expression. AB - A lot of researches have verified that produced excessive reactive oxygen is one of the hazard factors causing atherosclerosis. NADPH oxidase is the main protease of vascular cell's producing reactive oxygen, the expression of its relevant subunits is closely correlated with the occurring and development process of atherosclerosis. Oxidizing reaction could damage organism tissue cells, ganoderan has very significant effect on the anti-oxidizing function of cell. The pharmaceutical research of ganoderan has significant meaning in curing diabetes mellitus, preventing and controlling arteriosclerosis. This paper is mainly to discuss the effect of anoderan's inhibiting NADPH oxidizing enzyme expression on preventing and treating cerebral arteriosclerosis and its action mechanism. PMID- 25016276 TI - The effectiveness of Cognitive Behavioral Therapy (CBT) with general exercises versus general exercises alone in the management of chronic low back pain. AB - To evaluate the effectiveness of Cognitive Behavioural Therapy (CBT) along with General exercises and General exercises alone in chronic low back pain. Total 54 patients with chronic low back pain who fulfilled inclusion criteria were recruited from Physiotherapy, Department of Alain Poly Clinic Karachi and Institute of Physical Medicine & Rehabilitation Dow University of Health Sciences Karachi. Selected patients were equally divided and randomly assigned into two groups with simple randomisation method. The Cognitive Behavioural Therapy (CBT) and General exercises group received Operant model of CBT and General Exercises whereas General exercises group received General exercises only. Both groups received a home exercise program as well. Patients in both groups received 3 treatment sessions per week for 12 consecutive weeks. Clinical assessment was performed using Visual Analogue Scale (VAS) and Ronald Morris Disability Questionnaire at baseline and after 12 weeks. Both study groups showed statistically significant improvements in both outcomes measures p=0.000. However, mean improvements in post intervention VAS score and Ronald Morris score was better in CBT and exercises group as compared to General exercise group. In conclusion, both interventions are effective in treating chronic low back pain however; CBT & General exercises are clinically more effective than General exercises alone. PMID- 25016277 TI - Studies on nano-additive for the substitution of hazardous chemical substances in antifouling coatings for the protection of ship hulls. AB - Adhesion and growth of biofouling organisms have severe influence on the reliability, service life and environmental adaptability of marine ships. Based on the bactericidal capacity of cuprous oxide and photochemical effect of nano additive, environment-friendly and efficient marine antifouling paints were prepared in this study. The evaluation of the antifouling paints was carried out by the laboratory method using bacteria and phytoplanktonic microorganisms as target organisms, as well as measurements with panels in shallow submergence in natural seawater. Results showed good agreement of all the tests, indicating the remarkable antifouling performance of the paints. To our knowledge, this was one of the first systematic studies on effects of nano-additive for the substitution of hazardous chemical substances in antifouling coatings for the protection of ship hulls by measurements on bacterial inhibition, algal adhesion and growth of large organisms. PMID- 25016278 TI - Use of candidate gene markers to guide antipsychotic dosage adjustment. AB - OBJECTIVE: To improve antipsychotic treatment in schizophrenia patients, many studies have investigated genetic polymorphisms associated with antipsychotic metabolizing enzymes and receptors. While these studies have typically focused on drug response, few have investigated genetic influences on antipsychotic dosage. This study set out to analyze the association between 134 SNPs in 38 candidate genes and antipsychotic dosage in schizophrenia patients. METHODS: For our analysis, 300 patients with a diagnosis of either schizophrenia or schizoaffective disorder were recruited between the ages of 18 and 75. A cross sectional assessment was used, in which data were collected from each participant through an interview and self-report questionnaire. Antipsychotic dose was standardized according to the chlorpromazine equivalents, defined daily dose and relative to the maximum dose specified in the product monograph. Participants were genotyped using a Customized Illumina Chip comprising 134 SNPs, and all markers were screened for nominal significance. RESULTS: The analysis showed a nominally significant association with the GFRA1 gene. CONCLUSION: The common variants investigated in this study had no major influence on the antipsychotic dosage prescribed in study participants. It remains, though, that this strategy may prove valuable clinically and warrants further investigation. PMID- 25016279 TI - Characterization of living skin using multi-view stereo and isogeometric analysis. AB - Skin is our interface with the outside world. In its natural environment, it displays unique mechanical characteristics, such as prestretch and growth. While there is a general agreement on the physiological importance of these features, they remain poorly characterized, mainly because they are difficult to access with standard laboratory techniques. Here we present a new, inexpensive technique to characterize living skin using multi-view stereo and isogeometric analysis. Based on easy-to-create hand-held camera images, we quantify prestretch, deformation and growth in a controlled porcine model of chronic skin expansion. Over a period of 5 weeks, we gradually inflate an implanted tissue expander, take weekly photographs of the experimental scene, reconstruct the geometry from a tattooed surface grid and create parametric representations of the skin surface. After 5 weeks of expansion, our method reveals an average area prestretch of 1.44, an average area stretch of 1.87 and an average area growth of 2.25. Area prestretch is maximal in the ventral region with a value of 2.37, whereas area stretch and area growth are maximal above the center of the expander, with values of 4.05 and 4.81, respectively. Our study has immediate impact on understanding living skin to optimize treatment planning and decision making in plastic and reconstructive surgery. Beyond these direct implications, our experimental design has broad applications in clinical research and basic sciences: it serves as a simple, robust, low cost, easy-to-use tool to reconstruct living membranes, which are difficult to characterize in a conventional laboratory setup. PMID- 25016280 TI - Photopatterning of vascular endothelial growth factor within collagen glycosaminoglycan scaffolds can induce a spatially confined response in human umbilical vein endothelial cells. AB - Biomolecular signals within the native extracellular matrix are complex, with bioactive factors found in both soluble and sequestered states. In the design of biomaterials for tissue engineering applications it is increasingly clear that new approaches are required to locally tailor the biomolecular environment surrounding cells within the matrix. One area of particular focus is strategies to improve the speed or quality of vascular ingrowth and remodeling. While the addition of soluble vascular endothelial growth factor (VEGF) has been shown to improve vascular response, strategies to immobilize such signals within a biomaterial offer the opportunity to optimize efficiency and to explore spatially defined patterning of such signals. Here we describe the use of benzophenone (BP) photolithography to decorate three-dimensional collagen-glycosaminoglycan (CG) scaffolds with VEGF in a spatially defined manner. In this effort we demonstrate functional patterning of a known agonist of vascular remodeling and directly observe phenotypic effects induced by this immobilized cue. VEGF was successfully patterned in both stripes and square motifs across the scaffold with high specificity (on:off pattern signal). The depth of patterning was determined to extend up to 500 MUm into the scaffold microstructure. Notably, photopatterned VEGF retained native functionality as it was shown to induce morphological changes in human umbilical vein cells indicative of early vasculogenesis. Immobilized VEGF led to greater cell infiltration into the scaffold and the formation of immature vascular network structures. Ultimately, these results suggest that BP-mediated photolithography is a facile method to spatially control the presentation of instructive biological cues to cells within CG scaffolds. PMID- 25016282 TI - Geraniin suppresses RANKL-induced osteoclastogenesis in vitro and ameliorates wear particle-induced osteolysis in mouse model. AB - Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniin inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-kappaB and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure. PMID- 25016281 TI - The Mre11/Rad50/Nbs1 complex: recent insights into catalytic activities and ATP driven conformational changes. PMID- 25016283 TI - TTDA: big impact of a small protein. AB - Nucleotide excision repair (NER) is a highly versatile DNA repair process which is able to remove a broad spectrum of structurally unrelated DNA helix destabilizing lesions. The multi-subunit transcription/repair factor IIH (TFIIH) is an important decision maker in NER, by opening the DNA double helix after the initial damage recognition and subsequently verifying the lesion. Inherited mutations in TFIIH subunits are associated with NER-deficiency and a perplexing clinical heterogeneity, ranging from cancer-prone Xeroderma Pigmentosum to the progeroid diseases Cockayne Syndrome and Trichothiodystrophy (TTD). Three different TFIIH coding genes are implicated in TTD: XPD, XPB and TTDA. The latter gene encodes for a small (71 amino-acid) subunit and appeared important for the stabilization of the entire TFIIH complex. Based on analyzing TTD group A patient derived cells it was initially thought that TTDA has only a NER-stimulating role. In this review we summarize recent data showing that full disruption of TTDA expression in a knock-out mouse-model completely inactivates NER. Surprisingly, next to being essential for NER, TTDA appeared to be required also for embryonic development, indicative for the big impact this small protein has on basal biological processes. PMID- 25016285 TI - Oral cancer/endothelial cell fusion experiences nuclear fusion and acquisition of enhanced survival potential. AB - Most previous studies have linked cancer-macrophage fusion with tumor progression and metastasis. However, the characteristics of hybrid cells derived from oral cancer and endothelial cells and their involvement in cancer remained unknown. Double-immunofluorescent staining and fluorescent in situ hybridization (FISH) were performed to confirm spontaneous cell fusion between eGFP-labeled human umbilical vein endothelial cells (HUVECs) and RFP-labeled SCC9, and to detect the expression of vementin and cytokeratin 18 in the hybrids. The property of chemo resistance of such hybrids was examined by TUNEL assay. The hybrid cells in xenografted tumor were identified by FISH and GFP/RFP dual-immunofluoresence staining. We showed that SCC9 cells spontaneously fused with cocultured endothelial cells, and the resultant hybrid cells maintained the division and proliferation activity after re-plating and thawing. Such hybrids expressed markers of both parental cells and became more resistant to chemotherapeutic drug cisplatin as compared to the parental SCC9 cells. Our in vivo data indicated that the hybrid cells contributed to tumor composition by using of immunostaining and FISH analysis, even though the hybrid cells and SCC9 cells were mixed with 1:10,000, according to the FACS data. Our study suggested that the fusion events between oral cancer and endothelial cells undergo nuclear fusion and acquire a new property of drug resistance and consequently enhanced survival potential. These experimental findings provide further supportive evidence for the theory that cell fusion is involved in cancer progression. PMID- 25016284 TI - microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKbeta mTORC1 axis to regulate renal cancer cell invasion. AB - Renal cancer metastasis may result from oncogenic forces that contribute to the primary tumor. We have recently identified microRNA-21 as an oncogenic driver of renal cancer cells. The mechanism by which miR-21 controls renal cancer cell invasion is poorly understood. We show that miR-21 directly downregulates the proapoptotic protein PDCD4 to increase migration and invasion of ACHN and 786-O renal cancer cells as a result of phosphorylation/activation of Akt and IKKbeta, which activate NFkappaB-dependent transcription. Constitutively active (CA) Akt or CA IKKbeta blocks PDCD4-mediated inhibition and restores renal cancer cell migration and invasion. PDCD4 inhibits mTORC1 activity, which was reversed by CA IKKbeta. Moreover, CA mTORC1 restores cell migration and invasion inhibited by PDCD4 and dominant negative IKKbeta. Moreover, PDCD4 negatively regulates mTORC2 dependent Akt phosphorylation upstream of this cascade. We show that PDCD4 forms a complex with rictor, an exclusive component of mTORC2, and that this complex formation is reduced in renal cancer cells due to increased miR-21 expression resulting in enhanced phosphorylation of Akt. Thus our results identify a previously unrecognized signaling node where high miR-21 levels reduce rictor PDCD4 interaction to increase phosphorylation of Akt and contribute to metastatic fitness of renal cancer cells. PMID- 25016286 TI - Statistical allosteric coupling to the active site indole ring flip equilibria in the FK506-binding domain. AB - In solution, the Trp 59 indole ring at the base of the active site cleft in the FKBP domain protein FKBP12 is rotated by ~90 degrees at a population level of 20%, relative to its canonical crystallographic orientation. NMR measurements on the homologous FK1 domains of human FKBP51 and FKBP52 indicate no observable indole ring flip conformation, while the V101I variant of FKBP12 decreases the population having a perpendicular indole orientation by 10-fold. A set of three parallel 400 ns CHARMM27 molecular simulations for both wild type FKBP12 and the V101I variant examined how this ring flip might be energetically coupled to a transition of the Glu 60 sidechain which interacts with the backbone of the 50's loop located ~12 A from the indole nitrogen. Analysis of the transition matrix for the local dynamics of the Glu 60 sidechain, the Trp 59 sidechain, and of the structurally interposed alpha-helix hydrogen bonding pattern yielded a statistical allosteric coupling of 10 kJ/mol with negligible concerted dynamical coupling for the transitions of the two sidechains. PMID- 25016287 TI - SMTP-7, a new thrombolytic agent, decreases hemorrhagic transformation after transient middle cerebral artery occlusion under warfarin anticoagulation in mice. AB - Stachybotrys microspora triprenyl phenol-7 (SMTP-7) is a new thrombolytic agent that exhibits anti-inflammatory effects. We previously demonstrated that the hemorrhagic transformation was fewer with SMTP-7 than with recombinant tissue plasminogen activator (rt-PA) following ischemia-reperfusion in animal models. We hypothesized that SMTP-7 may decrease hemorrhagic transformation after ischemia reperfusion under the warfarin-treated condition. Transient middle cerebral artery occlusion (MCAO) was induced for 3h using an intraluminal suture in warfarin-treated mice to produce hemorrhagic transformation. Warfarin was administered orally for a 24-h feeding period before MCAO through bottled drinking water (5mg in 375 ml tap water), resulting in a mean INR of 5.6+/-0.2. Mice were treated with vehicle, rt-PA, or SMTP-7 5h before reperfusion. Twenty percent of vehicle-treated and 50.0% of rt-PA-treated mice died 24h after reperfusion, while all SMTP-7-treated mice survived. Hemorrhagic severity in SMTP 7-treated mice was significantly lower than that in rt-PA-treated mice. Neurological deficit was significantly lower in SMTP-7-treated mice than vehicle- and rt-PA-treated mice. These results indicate that SMTP-7 decreases mortality, hemorrhagic transformation, and neurological deficits, and can be a safe thrombolytic agent following MCAO under the warfarin-treated condition. PMID- 25016288 TI - Automatic sleep classification using a data-driven topic model reveals latent sleep states. AB - BACKGROUND: The golden standard for sleep classification uses manual scoring of polysomnography despite points of criticism such as oversimplification, low inter rater reliability and the standard being designed on young and healthy subjects. NEW METHOD: To meet the criticism and reveal the latent sleep states, this study developed a general and automatic sleep classifier using a data-driven approach. Spectral EEG and EOG measures and eye correlation in 1s windows were calculated and each sleep epoch was expressed as a mixture of probabilities of latent sleep states by using the topic model Latent Dirichlet Allocation. Model application was tested on control subjects and patients with periodic leg movements (PLM) representing a non-neurodegenerative group, and patients with idiopathic REM sleep behavior disorder (iRBD) and Parkinson's Disease (PD) representing a neurodegenerative group. The model was optimized using 50 subjects and validated on 76 subjects. RESULTS: The optimized sleep model used six topics, and the topic probabilities changed smoothly during transitions. According to the manual scorings, the model scored an overall subject-specific accuracy of 68.3 +/- 7.44 (% MU +/- sigma) and group specific accuracies of 69.0 +/- 4.62 (control), 70.1 +/- 5.10 (PLM), 67.2 +/- 8.30 (iRBD) and 67.7 +/- 9.07 (PD). COMPARISON WITH EXISTING METHOD: Statistics of the latent sleep state content showed accordances to the sleep stages defined in the golden standard. However, this study indicates that sleep contains six diverse latent sleep states and that state transitions are continuous processes. CONCLUSIONS: The model is generally applicable and may contribute to the research in neurodegenerative diseases and sleep disorders. PMID- 25016290 TI - A user-operated test of suprathreshold acuity in noise for adult hearing screening: The SUN (Speech Understanding in Noise) test. AB - A novel, user-operated test of suprathreshold acuity in noise for use in adult hearing screening (AHS) was developed. The Speech Understanding in Noise test (SUN) is a speech-in-noise test that makes use of a list of vowel-consonant-vowel (VCV) stimuli in background noise presented in a three-alternative forced choice (3AFC) paradigm by means of a touch sensitive screen. The test is automated, easy to-use, and provides self-explanatory results (i.e., 'no hearing difficulties', or 'a hearing check would be advisable', or 'a hearing check is recommended'). The test was developed from its building blocks (VCVs and speech-shaped noise) through two main steps: (i) development of the test list through equalization of the intelligibility of test stimuli across the set and (ii) optimization of the test results through maximization of the test sensitivity and specificity. The test had 82.9% sensitivity and 85.9% specificity compared to conventional pure tone screening, and 83.8% sensitivity and 83.9% specificity to identify individuals with disabling hearing impairment. Results obtained so far showed that the test could be easily performed by adults and older adults in less than one minute per ear and that its results were not influenced by ambient noise (up to 65dBA), suggesting that the test might be a viable method for AHS in clinical as well as non-clinical settings. PMID- 25016289 TI - A preliminary study on the differences in male and female muscle force distribution patterns during squatting and lunging maneuvers. AB - In the United States, 250,000 people tear their anterior cruciate ligament (ACL) annually with females at higher risk of ACL failure than males. By predicting muscle forces during low impact maneuvers we may be able to estimate possible muscle imbalances that could lead to ACL failure during highly dynamic maneuvers. The purpose of this initial study was to predict muscle forces in males and females similar in size and activity level, during squat and lunge maneuvers. We hypothesized that during basic low impact maneuvers (a) distribution of quadriceps forces are different in males and females and (b) females exhibit quadriceps dominance when compared to males. Two males and three females performed squatting and lunging maneuvers while electromyography (EMG) data, motion capture data, and ground reaction forces were collected. Nine individual muscle forces for muscles that cross the knee were estimated using an EMG-driven model. Results suggest that males activate their rectus femoris muscle more than females, who in turn activate their vastus lateralis muscle at their maximum flexion angle, and more their vastus medialis muscle when ascending from a squat. During the lunge maneuver, males used greater biceps femoris force than females, throughout the lunge, and females exhibited higher semitendinosus force. Quadriceps dominance was evident in both males and females during the prescribed tasks, and there was no statistical difference between genders. Understanding individual muscle force distributions in males and females during low impact maneuvers may provide insights regarding failure mechanisms during highly dynamic maneuvers, when ACL injuries are more prevalent. PMID- 25016291 TI - Numerical investigation of regional particle deposition in the upper airway of a standing male mannequin in calm air surroundings. AB - A 3-D realistic computational model of the airway system integrated into a standing male mannequin was developed. The computational domain includes the regions around the mannequin and the inside of the airway passages. The simulation was performed for low activity breathing rates with calm air around the mannequin. The flowfield of the inhaled air was first obtained from solving the Navier-Stokes and continuity equations. Then the particles were released in the domain around the mannequin and their trajectories were evaluated by using the Lagrangian approach for solving the particle equation of motion. The regional aerosols deposition was evaluated for different parts of the human airway system and the results were compared with those obtained from the separate modeling of the airway system without the interaction of the airflow with the mannequin external face. The results showed when the upper airway is integrated into the mannequin, the regional deposition of inhaled particles mainly changes in the airway system. PMID- 25016292 TI - Evolution of the mir-181 microRNA family. AB - Mir-181 is an ancient microRNA (miRNA) gene family that originated in urochordata. Although their functions were subjected to extensive studies in recent years, their evolutionary process remains largely unknown. Here we systematically investigated the homologous genes of the mir-181 family by a sequence similarity search. Representative sequences of the mir-181 gene family were used to reconstruct their evolutionary history. Our results indicated that this family could have derived from multiple duplications, which include two rounds of whole genome duplications and one round of segmental replication. Functional annotation of the target genes of the mir-181 family suggested that this family could participate in some important biological processes including transcriptional and translational regulation, signaling transduction etc. This analysis presented a complex evolutionary dynamics for the origination of a miRNA gene family. PMID- 25016293 TI - Text summarization in the biomedical domain: a systematic review of recent research. AB - OBJECTIVE: The amount of information for clinicians and clinical researchers is growing exponentially. Text summarization reduces information as an attempt to enable users to find and understand relevant source texts more quickly and effortlessly. In recent years, substantial research has been conducted to develop and evaluate various summarization techniques in the biomedical domain. The goal of this study was to systematically review recent published research on summarization of textual documents in the biomedical domain. MATERIALS AND METHODS: MEDLINE (2000 to October 2013), IEEE Digital Library, and the ACM digital library were searched. Investigators independently screened and abstracted studies that examined text summarization techniques in the biomedical domain. Information is derived from selected articles on five dimensions: input, purpose, output, method and evaluation. RESULTS: Of 10,786 studies retrieved, 34 (0.3%) met the inclusion criteria. Natural language processing (17; 50%) and a hybrid technique comprising of statistical, Natural language processing and machine learning (15; 44%) were the most common summarization approaches. Most studies (28; 82%) conducted an intrinsic evaluation. DISCUSSION: This is the first systematic review of text summarization in the biomedical domain. The study identified research gaps and provides recommendations for guiding future research on biomedical text summarization. CONCLUSION: Recent research has focused on a hybrid technique comprising statistical, language processing and machine learning techniques. Further research is needed on the application and evaluation of text summarization in real research or patient care settings. PMID- 25016294 TI - Improved method for screening mitochondrial cytochrome b markers to identify regional populations of the Old World screwworm fly and other myiasis agents. AB - A new protocol was developed to overcome obstacles to the high-throughput sequence analysis of the 716-717 nucleotides at the carboxyl terminal of the mitochondrial gene cytochrome b (cyt b) of the myiasis flies Chrysomya bezziana and Wohlfahrtia magnifica. For both of these obligate parasites, cyt b haplotypes provide diagnostic markers for phylogeographic populations, markers that identify the origins of emerging populations causing economically important myiasis in livestock and, in the case of C. bezziana (Old World screwworm fly), could help select reproductively-compatible populations for use in the Sterile insect technique as part of area wide integrated pest management. High sequence quality is important for unambiguously detecting the few mutations that are diagnostic for regional cyt b haplotypes and their lineages. A key innovation is the design of a new forward primer for the specific PCR amplification and high-quality sequencing of cyt b. The improved protocol will facilitate the use of this established comparative cyt b sequence analysis, not only by teams lacking the resources for whole genome sequencing (WGS) but also by those requiring reference sequences for developing comparative mitogenomics based on WGS. PMID- 25016296 TI - Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma. AB - The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1alpha, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity. PMID- 25016295 TI - Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. AB - BACKGROUND & AIMS: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice. RESULTS: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 MUM (0.38-0.50 MUM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2-M-phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS: In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer. PMID- 25016298 TI - Chelating polymer modified P84 nanofiltration (NF) hollow fiber membranes for high efficient heavy metal removal. AB - High performance nanofiltration (NF) membranes for heavy metal removal have been molecularly designed by adsorption of chelating polymers containing negatively charged functional groups such as poly (acrylic acid-co-maleic acid) (PAM), poly (acrylic acid) (PAA) and poly (dimethylamine-co-epichlorohydrin-co ethylenediamine) (PDMED) on the positively charged polyethyleneimine (PEI) cross linked P84 hollow fiber substrates. Not only do these chelating polymers change the membrane surface charge and pore size, but also provide an extra mean to remove heavy metal ions through adsorption in addition to traditional steric effect and Donnan exclusion. The adsorbed membranes have comparable water permeability and superior rejections to heavy metals, for instance, Pb(NO3)2, CuSO4, NiCl2, CdCl2, ZnCl2, Na2Cr2O7 and Na2HAsO4, with rejections higher than 98%. The membranes also display excellent rejections to mixed ions with rejections more than 99%. The newly developed membranes show reasonably stability during 60-h tests as well as multiple washes. PMID- 25016297 TI - Making models match measurements: model optimization for morphogen patterning networks. AB - Mathematical modeling of developmental signaling networks has played an increasingly important role in the identification of regulatory mechanisms by providing a sandbox for hypothesis testing and experiment design. Whether these models consist of an equation with a few parameters or dozens of equations with hundreds of parameters, a prerequisite to model-based discovery is to bring simulated behavior into agreement with observed data via parameter estimation. These parameters provide insight into the system (e.g., enzymatic rate constants describe enzyme properties). Depending on the nature of the model fit desired - from qualitative (relative spatial positions of phosphorylation) to quantitative (exact agreement of spatial position and concentration of gene products) - different measures of data-model mismatch are used to estimate different parameter values, which contain different levels of usable information and/or uncertainty. To facilitate the adoption of modeling as a tool for discovery alongside other tools such as genetics, immunostaining, and biochemistry, careful consideration needs to be given to how well a model fits the available data, what the optimized parameter values mean in a biological context, and how the uncertainty in model parameters and predictions plays into experiment design. The core discussion herein pertains to the quantification of model-to-data agreement, which constitutes the first measure of a model's performance and future utility to the problem at hand. Integration of this experimental data and the appropriate choice of objective measures of data-model agreement will continue to drive modeling forward as a tool that contributes to experimental discovery. The Drosophila melanogaster gap gene system, in which model parameters are optimized against in situ immunofluorescence intensities, demonstrates the importance of error quantification, which is applicable to a wide array of developmental modeling studies. PMID- 25016299 TI - Removal of emerging pollutants by Ru/TiO2-catalyzed permanganate oxidation. AB - TiO2 supported ruthenium nanoparticles, Ru/TiO2 (0.940/00 as Ru), was synthesized to catalyze permanganate oxidation for degrading emerging pollutants (EPs) with diverse organic moieties. The presence of 1.0 g L(-1) Ru/TiO2 increased the second order reaction rate constants of bisphenol A, diclofenac, acetaminophen, sulfamethoxazole, benzotriazole, carbamazepine, butylparaben, diclofenac, ciprofloxacin and aniline at mg L(-1) level (5.0 MUM) by permanganate oxidation at pH 7.0 by 0.3-119 times. The second order reaction rate constants of EPs with permanganate or Ru/TiO2-catalyzed permanganate oxidation obtained at EPs concentration of mg L(-1) level (5.0 MUM) underestimated those obtained at EPs concentration of MUg L(-1) level (0.050 MUM). Ru/TiO2-catalyzed permanganate could decompose a mixture of nine EPs at MUg L(-1) level efficiently and the second order rate constant for each EP was not decreased due to the competition of other EPs. The toxicity tests revealed that Ru/TiO2-catalyzed permanganate oxidation was effective not only for elimination of EPs but also for detoxification. The removal rates of sulfamethoxazole by Ru/TiO2-catalyzed permanganate oxidation in ten successive cycles remained almost constant in ultrapure water and slightly decreased in Songhua river water since the sixth run, indicating the satisfactory stability of Ru/TiO2. Ru/TiO2-catalyzed permanganate oxidation was selective and could remove selected EPs spiked in real waters more efficiently than chlorination. Therefore, Ru/TiO2-catalyzed permanganate oxidation is promising for removing EPs with electron-rich moieties. PMID- 25016300 TI - Integrated hydraulic and organophosphate pesticide injection simulations for enhancing event detection in water distribution systems. AB - As a complementary step towards solving the general event detection problem of water distribution systems, injection of the organophosphate pesticides, chlorpyrifos (CP) and parathion (PA), were simulated at various locations within example networks and hydraulic parameters were calculated over 24-h duration. The uniqueness of this study is that the chemical reactions and byproducts of the contaminants' oxidation were also simulated, as well as other indicative water quality parameters such as alkalinity, acidity, pH and the total concentration of free chlorine species. The information on the change in water quality parameters induced by the contaminant injection may facilitate on-line detection of an actual event involving this specific substance and pave the way to development of a generic methodology for detecting events involving introduction of pesticides into water distribution systems. Simulation of the contaminant injection was performed at several nodes within two different networks. For each injection, concentrations of the relevant contaminants' mother and daughter species, free chlorine species and water quality parameters, were simulated at nodes downstream of the injection location. The results indicate that injection of these substances can be detected at certain conditions by a very rapid drop in Cl2, functioning as the indicative parameter, as well as a drop in alkalinity concentration and a small decrease in pH, both functioning as supporting parameters, whose usage may reduce false positive alarms. PMID- 25016301 TI - Disinfection byproduct formation from lignin precursors. AB - Lignin is the most abundant aromatic plant component in terrestrial ecosystems. This study was conducted to determine the contribution of lignin residues in natural water to the formation of disinfection byproducts (DBPs) in drinking water. We investigated the formation of different classes of DBPs from lignin model compounds, lignin polymers, and humic substances using two common disinfection techniques, chlorination and chloramination. The contributions of lignin to the overall formation of DBPs from these organic products were determined based on the observed abundances of individual lignin phenols and their DBP yields. Model lignin phenols generally produced higher trichloroacetic acid (TCAA) yields than chloroform and dichloroacetic acid (DCAA) during chlorination. Lignin phenols generally produced higher DBP yields but lower percentages of unknown total organic halogen compared to bulk humic substances and lignin polymers. The relative significance of lignin phenols as chlorination DBP precursors generally follows the order of TCAA > DCAA&chloroform. The relative significance of lignin phenols to DBP formation by chloramination follows the order: TCAA > DCAA&DCAN > chloroform. Overall, lignin phenols are more important as TCAA precursors than as chloroform and DCAA precursors. PMID- 25016302 TI - Stress and wellbeing among Turkish and German adolescents living in rural and urban areas. AB - INTRODUCTION: This study focuses on stress experiences and the psychological wellbeing of adolescents from rural and urban areas of Turkey and Germany. It also analyzes the role of social support, family problem solving and self construals (independent vs interdependent) for stress and wellbeing in the different subsamples. METHODS: The total sample included 1850 high school students (500 Turkish urban, 771 Turkish rural, 268 German urban, and 311 German rural). The participants filled in questionnaires related to coping, self construal, stress and wellbeing. RESULTS: The results indicated that the perception of stress is higher for Turkish adolescents than for German adolescents. Moreover, it was found that adolescents who live in rural parts experience more stress than their urban counterparts of both countries. In line with this, adolescents in rural regions report lower wellbeing than adolescents in urban regions. However, the latter difference between urban and rural regions is only salient for adolescents who live in Turkey. The search for possible factors associated with stress and wellbeing showed that coping variables related to social support and to solving family problems as well as variables related to the interdependent-independent distinction might be relevant as predictors. Most of the predicting variables showed non-moderated associations. There were only few moderations related to nation (Turkey vs Germany), location (urban vs rural) or sex. CONCLUSIONS: The current study leads to a better understanding of stress experiences and wellbeing of adolescents living in rural and urban areas. As a consequence, improving social systems, especially in developing countries, may support youths to cope with stress effectively and to improve their psychological wellbeing. PMID- 25016303 TI - Improving Well-being and Health for People with Dementia (WHELD): study protocol for a randomised controlled trial. AB - BACKGROUND: People with dementia living in care homes often have complex mental health problems, disabilities and social needs. Providing more comprehensive training for staff working in care home environments is a high national priority. It is important that this training is evidence based and delivers improvement for people with dementia residing in these environments. Well-being and Health for People with Dementia (WHELD) combines the most effective elements of existing approaches to develop a comprehensive but practical staff training intervention. This optimised intervention is based on a factorial study and qualitative evaluation, to combine: training on person-centred care, promoting person-centred activities and interactions, and providing care home staff and general practitioners with updated knowledge regarding the optimal use of psychotropic medications for persons with dementia in care homes. DESIGN: The trial will be a randomised controlled two-arm cluster single blind trial that will take place for nine months across 80 care homes in the United Kingdom. DISCUSSION: The overarching goal of this trial is to determine whether this optimised WHELD intervention is more effective in improving the quality of life and mental health than the usual care provided to people with dementia living in nursing homes. This study will be the largest and best powered randomised controlled trial (RCT) evaluating the benefits of an augmented person-centred care training intervention in care homes worldwide. TRIAL REGISTRATION: Current controlled trials ISRCTN62237498 Date registered: 5 September 2013. PMID- 25016304 TI - Differences in residents' self-reported confidence and case experience between two post-graduate rotation curricula: results of a nationwide survey in Japan. AB - BACKGROUND: In Japan, all trainee physicians must begin clinical practice in a standardized, mandatory junior residency program, which encompasses the first two years of post-graduate medical training (PGY1 - PGY2). Implemented in 2004 to foster primary care skills, the comprehensive rotation program (CRP) requires junior residents to spend 14 months rotating through a comprehensive array of clinical departments including internal medicine, surgery, anesthesiology, obstetrics-gynecology (OBGYN), pediatrics, psychiatry, and rural medicine. In 2010, Japan's health ministry relaxed this curricular requirement, allowing training programs to offer a limited rotation program (LRP), in which core departments constitute 10 months of training, with electives geared towards residents' choice of career specialty comprising the remaining 14 months. The effectiveness of primary care skill acquisition during early training warrants evaluation. This study assesses self-reported confidence with clinical competencies, as well as case experience, between residents in CRP versus LRP curricula. METHODS: A nation-wide cross-sectional study of all PGY2 physicians in Japan was conducted in March 2011. Primary outcomes were self-report confidence for 98 clinical competency items, and number of cases experienced for 85 common diseases. We compared confidence scores and case experience between residents in CRP and LRP programs, adjusting for parameters relevant to training. RESULTS: Among 7506 PGY2 residents, 5052 replied to the survey (67.3%). Of 98 clinical competency items, CRP residents reported higher confidence in 12 items compared to those in an LRP curriculum, 10 of which remained significantly higher after adjustment. CRP trainees reported lower confidence scores in none of the items. Out of 85 diseases, LRP residents reported less experience with 11 diseases. CRP trainees reported lower case experience with one disease, though this did not remain significant on adjusted analysis. Confidence and case experience with OBGYN- and pediatrics-related items were particularly low among LRP trainees. CONCLUSIONS: Residents in the specialty-oriented LRP curriculum showed less confidence and less case experience compared to peers training in the broader CRP residency curriculum. In order to foster competence in independent primary care practice, junior residency programs requiring experience in a breadth of core departments should continue to be mandated to ensure adequate primary care skills. PMID- 25016305 TI - HPV genotypes and associated cervical cytological abnormalities in women from the Pearl River Delta region of Guangdong province, China: a cross-sectional study. AB - BACKGROUND: It is important to understand the specific HPV genotype distribution in screen-detected lesions. HPV Genotype is helpful for separating HPV-positive women at greater risk of cancer from those who can regress spontaneously and for preventing cervical cancer at early stage. The aim of this study was to investigate the high-risk HPV genotype distribution among cervical cytology abnormality in Pearl River Delta Region, Southern China METHODS: 5585 HPV infected women were screened from 77069 women in Pearl River Delta Region. Information was obtained from 3226 screened subjects through questionnaires and personal interviews. Exfoliated cervical cells were collected by doctors for HPV test with MassARRAY (Sequenom, Sandiego, CA) technique based on the matrix assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectrometry (MS). The ThinPrep cytology test was performed to screen for cervical cancer. Unconditional logistic was used to determine the most common HPV carcinogenic types. RESULTS: Of the 3226 HPV-positive samples tested, 1744 (54.1%) with normal cervical cytology, 1482 (45.9%) with abnormal cytology. The five most common HPV types in this study were HPV16 (20.2%), HPV52 (17.1%), HPV58 (13.2%), HPV18 (9.5%), HPV6 (7.6%). Overall, HPV16 (OR = 10.5, 95% CI: 3.7 ~ 29.6), HPV33 (OR = 9.1, 95% CI: 2.8 ~ 29.2), HPV58 (OR = 6.3, 95% CI: 2.1 ~ 18.6), HPV31 (OR = 4.5, 95% CI: 1.3 ~ 15.5), multiple genotype infection (OR = 3.0, 95% CI: 1.7 ~ 14.7), especially HPV16 and HPV33, increased the risk of cytology abnormalities. CONCLUSIONS: HPV16, HPV31, HPV33, HPV58, and multiple HPV genotype infection increased the risk of cytology abnormalities in Pearl River Delta Region and might be useful for the screening, preventing, treating, and monitoring of pre cancer lesions in southern China. PMID- 25016307 TI - A swarm intelligence-based tuning method for the Sliding Mode Generalized Predictive Control. AB - This work presents an automatic tuning method for the discontinuous component of the Sliding Mode Generalized Predictive Controller (SMGPC) subject to constraints. The strategy employs Particle Swarm Optimization (PSO) to minimize a second aggregated cost function. The continuous component is obtained by the standard procedure, by Quadratic Programming (QP), thus yielding an online dual optimization scheme. Simulations and performance indexes for common process models in industry, such as nonminimum phase and time delayed systems, result in a better performance, improving robustness and tracking accuracy. PMID- 25016306 TI - Genetic diversity, genetic structure and demographic history of Cycas simplicipinna (Cycadaceae) assessed by DNA sequences and SSR markers. AB - BACKGROUND: Cycas simplicipinna (T. Smitinand) K. Hill. (Cycadaceae) is an endangered species in China. There were seven populations and 118 individuals that we could collect were genotyped in this study. Here, we assessed the genetic diversity, genetic structure and demographic history of this species. RESULTS: Analyses of data of DNA sequences (two maternally inherited intergenic spacers of chloroplast, cpDNA and one biparentally inherited internal transcribed spacer region ITS4-ITS5, nrDNA) and sixteen microsatellite loci (SSR) were conducted in the species. Of the 118 samples, 86 individuals from the seven populations were used for DNA sequencing and 115 individuals from six populations were used for the microsatellite study. We found high genetic diversity at the species level, low genetic diversity within each of the seven populations and high genetic differentiation among the populations. There was a clear genetic structure within populations of C. simplicipinna. A demographic history inferred from DNA sequencing data indicates that C. simplicipinna experienced a recent population contraction without retreating to a common refugium during the last glacial period. The results derived from SSR data also showed that C. simplicipinna underwent past effective population contraction, likely during the Pleistocene. CONCLUSIONS: Some genetic features of C. simplicipinna such as having high genetic differentiation among the populations, a clear genetic structure and a recent population contraction could provide guidelines for protecting this endangered species from extinction. Furthermore, the genetic features with population dynamics of the species in our study would help provide insights and guidelines for protecting other endangered species effectively. PMID- 25016308 TI - Human activity recognition based on feature selection in smart home using back propagation algorithm. AB - In this paper, Back-propagation(BP) algorithm has been used to train the feed forward neural network for human activity recognition in smart home environments, and inter-class distance method for feature selection of observed motion sensor events is discussed and tested. And then, the human activity recognition performances of neural network using BP algorithm have been evaluated and compared with other probabilistic algorithms: Naive Bayes(NB) classifier and Hidden Markov Model(HMM). The results show that different feature datasets yield different activity recognition accuracy. The selection of unsuitable feature datasets increases the computational complexity and degrades the activity recognition accuracy. Furthermore, neural network using BP algorithm has relatively better human activity recognition performances than NB classifier and HMM. PMID- 25016309 TI - Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. AB - In many patients with brain metastases, the primary therapeutic aim is symptom palliation and maintenance of neurologic function, but in a subgroup, long-term survival is possible. Local control in the brain, and absent or controlled extracranial sites of disease are prerequisites for favorable survival. Stereotactic radiosurgery (SRS) is a focal, highly precise treatment option with a long track record. Its clinical development and implementation by several pioneering institutions eventually rendered possible cooperative group randomized trials. A systematic review of those studies and other landmark studies was undertaken. Most clinicians are aware of the potential benefits of SRS such as a short treatment time, a high probability of treated-lesion control and, when adhering to typical dose/volume recommendations, a low normal tissue complication probability. However, SRS as sole first-line treatment carries a risk of failure in non-treated brain regions, which has resulted in controversy around when to add whole-brain radiotherapy (WBRT). SRS might also be prescribed as salvage treatment in patients relapsing despite previous SRS and/or WBRT. An optimal balance between intracranial control and side effects requires continued research efforts. PMID- 25016312 TI - Physical activity and associated levels of disability and quality of life in people with multiple sclerosis: a large international survey. AB - BACKGROUND: Multiple Sclerosis (MS) is a common neurodegenerative disease, which often has a devastating effect on physical and emotional wellbeing of people with MS (PwMS). Several studies have shown positive effects of physical activity (PA) on disability, health related quality of life (HRQOL), and other outcomes. However, many studies include only people with mild disability making it difficult to generalize findings to those with moderate or severe disability. This study investigated the associations between PA and HRQOL, relapse rate (RR), disability, and demographic variables in PwMS with varying disability. METHODS: Through online platforms this large international survey recruited 2232 participants with MS who completed items regarding PA, MS and other health characteristics. RESULTS: PwMS who were younger (p < .001), male (p = 0.006), and with lower body mass index (BMI) (p < .001) undertook more PA, which was associated with decreased disability (p < 0.001) and increased HRQOL measures (all p < 0.001). For the subsample of people with relapsing-remitting MS, PA was associated with a decreased RR (p = 0.009). Regression analyses showed that increased PA predicted clinically significant improvements in HRQOL while controlling for level of disability, age and gender. More specifically, increasing from low to moderate and to high PA increased estimated mean physical health composite from 47.7 to 56.0 to 59.9 respectively (25.6% change), mental health composite from 60.6 to 67.0 to 68.8 (13.5% change), energy subscale from 35.9 to 44.5 to 49.8 (38.7% change), social function subscale from 57.8 to 66.1 to 68.4 (18.3% change), and overall QOL subscale from 58.5 to 64.5 to 67.7 (15.7% change). CONCLUSIONS: For PwMS, regardless of disability level, increased PA is related to better HRQOL in terms of energy, social functioning, mental and physical health. These are important findings that should be taken into consideration by clinicians treating PwMS. PMID- 25016313 TI - Comparison of oxygen-induced radical intermediates in iNOS oxygenase domain with those from nNOS and eNOS. AB - Inducible nitric-oxide synthase (iNOS) produces the reactive oxygen and nitrogen species (ROS/RNS) involved in bacteria killing and is crucial in the host defense mechanism. However, high level ROS/RNS can also be detrimental to normal cells and thus their production has to be tightly controlled. Availability or deficiency of tetrahydrobiopterin (BH4) cofactor and l-arginine substrate controls coupling or uncoupling of NOS catalysis. Fully coupled reaction, with abundant BH4 and l-arginine, produces NO whereas the uncoupled NOS (in the absence of BH4 and/or l-arginine) generates ROS/RNS. In the current work we focus on direct rapid freeze EPR to characterize the structure and kinetics of oxygen induced radical intermediates produced by ferrous inducible NOS oxygenase domain (iNOSox) in the presence or absence of BH4 and/or l-arginine. Fully reconstituted iNOSox (+BH4, +L-Arg) forms a dimer and yields a typical BH4 radical that indicates coupled reaction. iNOSox (-BH4) remains mainly monomeric and produces exclusively superoxide, that is only marginally affected by the presence of l arginine. iNOSox (+BH4, -L-Arg) exists as a monomer/dimer mixture and yields both BH4 radical and superoxide. Present study is a natural extension of our previous work on the ferrous endothelial NOSox (eNOSox) [V. Berka, G. Wu, H.C. Yeh, G. Palmer, A.L. Tsai, J. Biol. Chem. 279 (2004) 32243-32251] and ferrous neuronal NOSox (nNOSox) [V. Berka, L.H. Wang, A.L. Tsai, Biochemistry 47 (2008) 405-420]. Overall, our data suggests different regulatory roles of l-arginine and BH4 in the production of oxygen-induced radical intermediates in NOS isoforms which nicely serve individual functional role. PMID- 25016314 TI - Lipid body accumulation alters calcium signaling dynamics in immune cells. AB - There is well-established variability in the numbers of lipid bodies (LB) in macrophages, eosinophils, and neutrophils. Similarly to the steatosis observed in adipocytes and hepatocytes during hyperinsulinemia and nutrient overload, immune cell LB hyper-accumulate in response to bacterial and parasitic infection and inflammatory presentations. Recently we described that hyperinsulinemia, both in vitro and in vivo, drives steatosis and phenotypic changes in primary and transformed mast cells and basophils. LB reach high numbers in these steatotic cytosols, and here we propose that they could dramatically impact the transcytoplasmic signaling pathways. We compared calcium release and influx responses at the population and single cell level in normal and steatotic model mast cells. At the population level, all aspects of FcERI-dependent calcium mobilization, as well as activation of calcium-dependent downstream signaling targets such as NFATC1 phosphorylation are suppressed. At the single cell level, we demonstrate that LB are both sources and sinks of calcium following FcERI cross-linking. Unbiased analysis of the impact of the presence of LB on the rate of trans-cytoplasmic calcium signals suggest that LB enrichment accelerates calcium propagation, which may reflect a Bernoulli effect. LB abundance thus impacts this fundamental signaling pathway and its downstream targets. PMID- 25016315 TI - Termination of calcium puffs and coupled closings of inositol trisphosphate receptor channels. AB - Calcium puffs are localized Ca(2+) signals mediated by Ca(2+) release from the endoplasmic reticulum (ER) through clusters of inositol trisphosphate receptor (IP3R) channels. The recruitment of IP3R channels during puffs depends on Ca(2+) induced Ca(2+) release, a regenerative process that must be terminated to maintain control of cell signaling and prevent Ca(2+) cytotoxicity. Here, we studied puff termination using total internal reflection microscopy to resolve the gating of individual IP3R channels during puffs in intact SH-SY5Y neuroblastoma cells. We find that the kinetics of IP3R channel closing differ from that expected for independent, stochastic gating, in that multiple channels tend to remain open together longer than predicted from their individual open lifetimes and then close in near-synchrony. This behavior cannot readily be explained by previously proposed termination mechanisms, including Ca(2+) inhibition of IP3Rs and local depletion of Ca(2+) in the ER lumen. Instead, we postulate that the gating of closely adjacent IP3Rs is coupled, possibly via allosteric interactions, suggesting an important mechanism to ensure robust puff termination in addition to Ca(2+)-inactivation. PMID- 25016316 TI - Disruption of the microRNA 137 primary transcript results in early embryonic lethality in mice. PMID- 25016318 TI - Language and vertical space: on the automaticity of language action interconnections. AB - Grounded models of language processing propose a strong connection between language and sensorimotor processes (Barsalou, 1999, 2008; Glenberg & Kaschak, 2002). However, it remains unclear how functional and automatic these connections are for understanding diverse sets of words (Ansorge, Kiefer, Khalid, Grassl, & Konig, 2010). Here, we investigate whether words referring to entities with a typical location in the upper or lower visual field (e.g., sun, ground) automatically influence subsequent motor responses even when language-processing levels are kept minimal. The results show that even subliminally presented words influence subsequent actions, as can be seen in a reversed compatibility effect. These finding have several implications for grounded language processing models. Specifically, these results suggest that language-action interconnections are not only the result of strategic language processes, but already play an important role during pre-attentional language processing stages. PMID- 25016321 TI - Bacterial adhesion onto nanofiltration and reverse osmosis membranes: effect of permeate flux. AB - The influence of permeate flux on bacterial adhesion to NF and RO membranes was examined using two model Pseudomonas species, namely Pseudomonas fluorescens and Pseudomonas putida. To better understand the initial biofouling profile during NF/RO processes, deposition experiments were conducted in cross flow under permeate flux varying from 0.5 up to 120 L/(h m(2)), using six NF and RO membranes each having different surface properties. All experiments were performed at a Reynolds number of 579. Complementary adhesion experiments were performed using Pseudomonas cells grown to early-, mid- and late-exponential growth phases to evaluate the effect of bacterial cell surface properties during cell adhesion under permeate flux conditions. Results from this study show that initial bacterial adhesion is strongly dependent on the permeate flux conditions, where increased adhesion was obtained with increased permeate flux, until a maximum of 40% coverage was reached. Membrane surface properties or bacterial growth stages was further found to have little impact on bacterial adhesion to NF and RO membrane surfaces under the conditions tested. These results emphasise the importance of conducting adhesion and biofouling experiments under realistic permeate flux conditions, and raises questions about the efficacy of the methods for the evaluation of antifouling membranes in which bacterial adhesion is commonly assessed under zero-flux or low flux conditions, unrepresentative of full-scale NF/RO processes. PMID- 25016317 TI - Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. AB - BACKGROUND: Peripheral biomarkers for major psychiatric disorders have been an elusive target for the last half a century. Dermal fibroblasts are a simple, relevant, and much underutilized model for studying molecular processes of patients with affective disorders, as they share considerable similarity of signal transduction with neuronal tissue. METHODS: Cultured dermal fibroblast samples from patients with major depressive disorder (MDD) and matched control subjects (n = 16 pairs, 32 samples) were assayed for genome-wide messenger RNA (mRNA) expression using microarrays. In addition, a simultaneous quantitative polymerase chain reaction-based assessment of >1000 microRNA (miRNA) species was performed. Finally, to test the relationship between the mRNA-miRNA expression changes, the two datasets were correlated with each other. RESULTS: Our data revealed that MDD fibroblasts, when compared with matched control subjects, showed a strong mRNA gene expression pattern change in multiple molecular pathways, including cell-to-cell communication, innate/adaptive immunity, and cell proliferation. Furthermore, the same patient fibroblasts showed altered expression of a distinct panel of 38 miRNAs, which putatively targeted many of the differentially expressed mRNAs. The miRNA-mRNA expression changes appeared to be functionally connected, as the majority of the miRNA and mRNA changes were in the opposite direction. CONCLUSIONS: Our data suggest that combined miRNA-mRNA assessments are informative about the disease process and that analyses of dermal fibroblasts might lead to the discovery of promising peripheral biomarkers of MDD that could be potentially used to aid the diagnosis and allow mechanistic testing of disturbed molecular pathways. PMID- 25016322 TI - Temperature dependence of adsorption of PEGylated lysozyme and pure polyethylene glycol on a hydrophobic resin: comparison of isothermal titration calorimetry and van't Hoff data. AB - The influence of temperature on the adsorption of PEGylated lysozyme and pure PEG on Toyopearl PPG-600M, a hydrophobic resin, is studied by batch equilibrium measurements and pulse response experiments. Differently PEGylated lysozymes are used for the studies, enabling a systematic variation of the solute properties. Either ammonium sulfate or sodium chloride are added. The enthalpy of adsorption is calculated from a van't Hoff analysis based on these data. It is also directly measured by Isothermal Titration Calorimetry. In the investigated temperature range from 5 degrees C to 35 degrees C adsorption is favored by higher temperatures and hence endothermic. The results of the van't Hoff analysis of the equilibrium and the pulse response data agree well. Discrepancies between enthalpies of adsorption obtained by calorimetry and van't Hoff analysis are found and discussed. We conclude that the most likely explanation is that thermodynamic equilibrium is not reached in the experiments even though they were carried out carefully and in the generally accepted way. PMID- 25016323 TI - Microfunnel-supported liquid-phase microextraction: application to extraction and determination of Irgarol 1051 and diuron in the Persian Gulf seawater samples. AB - In the present work, microfunnel-supported liquid-phase microextraction method (MF-LPME) based on applying low density organic solvent was developed for the determination of antifoulings (Irgarol 1051, diuron and 3,4-dichloroaniline) from seawater samples. In this method, home-designed MF device was used for facile loading and retrieving of organic solvent during the extraction procedure. The extraction was carried out with introduction of 400 MUL of toluene via syringe into the MF device placed on the surface of sample solution (300 mL) containing analytes. After the extraction, extractant layer was narrowed into the capillary part of MF by pushing the device inside the sample and withdrawn by using a syringe to evaporate by nitrogen purging. The residual redissolved into 50 MUL methanol, diluted to 100 MUL with deionized water and injected into the high performance liquid chromatography with UV detection (HPLC-UV). Several factors influencing the extraction such as the type and volume of extraction solvent, sample pH, extraction time and ionic strength were investigated and optimized. Under the optimized conditions, the limits of detection in seawater were 1.4, 4.8 and 1.0 ng L(-1) for 3,4-dichloroaniline (DCA), diuron and Irgarol 1051, respectively. Enrichment factors were obtained 333, 150 and 373 for DCA, diuron and Irgarol 1051, respectively. The precision of the technique was evaluated in terms of repeatability which was less than 12.0% (n=5). The applicability of the proposed method was evaluated by the extraction and determination of antifoulings from seawater samples collected from harbors of Bushehr located in northern Persian Gulf coast. PMID- 25016324 TI - Separation and characterization of phenolic compounds from dry-blanched peanut skins by liquid chromatography-electrospray ionization mass spectrometry. AB - A large variety of phenolic compounds, including phenolic acids (hydroxybenzoic acids, hydroxycinnamic acids, and their esters), stilbenes (trans-resveratrol and trans-piceatannol), flavan-3-ols (e.g., (-)-epicatechin, (+)-catechin, and their polymers {the proanthocyanidins, PACs}), other flavonoids (e.g., isoflavones, flavanols, and flavones, etc.) and biflavonoids (e.g., morelloflavone), were identified in dry-blanched peanut skins (PS) by this study. High-performance liquid chromatography (HPLC) coupled with electrospray ionization mass spectrometry (ESI-MS(n)) was applied to separate and identify the phenolic constituents. Reversed-phase HPLC was employed to separate free phenolic compounds as well as PAC monomers, dimers, and trimers. PACs with a degree of polymerization (DP) of >4 were chromatographed via hydrophilic interaction liquid chromatography (HILIC). Tentative identification of the separated phenolics was based solely on molecular ions and MS(n) fragmentation patterns acquired by ESI MS in the negative-ion mode. The connection sequence of PAC oligomers (DP <5) could be deduced mainly through characteristic quinone methide (QM) cleavage ions. When the DP reached 6, only a proportion of the flavan-3-ols could be ascertained in the PACs because of the extremely complicated fragmentation patterns involved. The identification of free phenolic acids, stilbenes, and flavonoids was achieved by authentic commercial standards and also by published literature data. Quantification was performed based on peak areas of the UV (free phenolic compounds) or fluorescence (PACs) signals from the HPLC chromatograms and calibration curves of commercial standards. Overall, PS contain significantly more PACs compared to free phenolic compounds. PMID- 25016325 TI - Counselee participation in follow-up breast cancer genetic counselling visits and associations with achievement of the preferred role, cognitive outcomes, risk perception alignment and perceived personal control. AB - The purpose of the study was to assess the counselee participation in the follow up visits, compared to the first visits, for breast cancer genetic counselling and to explore associations with counselees' achievement of their preferred role in decision making, information recall, knowledge, risk perception alignment and perceived personal control. First and follow-up visits for breast cancer genetic counselling of 96 counselees of a Dutch genetics center were videotaped (2008 2010). Counselees completed questionnaires before counselling (T1), after the follow-up visit (T2) and one year after the follow-up visit (T3). Consultations were rated with the Roter Interaction Analysis System (RIAS). Counselee participation was measured as the percentage of counselee utterances, the percentage of counselee questions and the interactivity (number of turns per minute). Follow-up visits had higher levels of counselee participation than first visits as assessed by the percentage of counselee talk, the interactivity and counselee questions. More counselee talk in the follow-up visit was related to higher achievement of the preferred role (T2) and higher perceived personal control (T3). Higher interactivity in the follow-up visit was related to lower achievement of the preferred role in decision making and lower information recall (T2). There were no significant associations with the percentage of questions asked and none of the participation measures was related to knowledge, risk perception alignment and perceived personal control (T2). In line with the interviewing admonishment 'talk less and listen more', the only assessment of counselee participation associated to better outcomes is the percentage of counselee talk. High interactivity might be associated with lower recall in breast cancer genetic counselees who are generally highly educated. However, this study was limited by a small sample size and a heterogeneous group of counselees. Research is needed on the interactions causing interactivity and its relationships with involvement in decision making and recall. PMID- 25016326 TI - The convergent validity of three surveys as alternative sources of health information to the 2011 UK census. AB - Censuses have traditionally been a key source of localised information on the state of a nation's health. Many countries are now adopting alternative approaches to the traditional census, placing such information at risk. The purpose of this paper is to inform debate about whether existing social surveys could provide an adequate 'base' for alternative model-based small area estimates of health data in a post traditional census era. Using a case study of 2011 UK Census questions on self-assessed health and limiting long term illness, we examine the extent to which the results from three large-scale surveys - the Health Survey for England, the Crime Survey for England and Wales and the Integrated Household Survey - conform to census output. Particularly in the case of limiting long term illness, the question wording renders comparisons difficult. However, with the exception of the general health question from the Health Survey for England all three surveys meet tests for convergent validity. PMID- 25016328 TI - Development of a large-area silicon alpha-particle detector. AB - Circular ion-implanted silicon detector of alpha-particles with a large, 5-cm(2), sensitive area has been developed. An advantage of the detector is that the detector surface is easily cleanable with chemicals. The hardened surface of the detector shows no signs of deterioration of the spectroscopic and electrical characteristics upon repeated cleaning. The energy resolution along the diameters of the detector was (1.0+/-0.1)% for the 5.486-MeV alpha-particles. Detailed tests of the charge collection efficiency and uniformity of the detector entrance window were also performed with a 5.5-MeV He(2+) microbeam. PMID- 25016327 TI - Willingness to pay for publicly financed health care services in Central and Eastern Europe: evidence from six countries based on a contingent valuation method. AB - The increased interest in patient cost-sharing as a measure for sustainable health care financing calls for evidence to support the development of effective patient payment policies. In this paper, we present an application of a stated willingness-to-pay technique, i.e. contingent valuation method, to investigate the consumer's willingness and ability to pay for publicly financed health care services, specifically hospitalisations and consultations with specialists. Contingent valuation data were collected in nationally representative population based surveys conducted in 2010 in six Central and Eastern European (CEE) countries (Bulgaria, Hungary, Lithuania, Poland, Romania and Ukraine) using an identical survey methodology. The results indicate that the majority of health care consumers in the six CEE countries are willing to pay an official fee for publicly financed health care services that are of good quality and quick access. The consumers' willingness to pay is limited by the lack of financial ability to pay for services, and to a lesser extent by objection to pay. Significant differences across the six countries are observed, though. The results illustrate that the contingent valuation method can provide decision-makers with a broad range of information to facilitate cost-sharing policies. Nevertheless, the intrinsic limitations of the method (i.e. its hypothetical nature) and the context of CEE countries call for caution when applying its results. PMID- 25016329 TI - Induction of CYP1A and ABC transporters in European sea bass (Dicentrarchus labrax) upon 2,3,7,8-TCDD waterborne exposure. AB - The aim of this study was to characterize the responsiveness of CYP1A and ABC transport proteins in European Sea bass (Dicentrarchus labrax) waterborne exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) (46 pg/L) for 24 h and 7 days. Genes modulation (abcb1, abcc1-2, cyp1a), EROD activity were investigated in liver and 2,3,7,8-TCDD bioconcentration in liver and muscle. TCDD induced significantly cyp1a gene expression and EROD activity at 24 h and 7 d. A significant up-regulation of abcb1 was also observed but only after 7 days. No modulation of abcc1 and abcc2 genes was observed. Waterborne TCDD exposure was able to induce CYP1A and abcb1 encoding for P-glycoprotein in juvenile of European sea bass. PMID- 25016330 TI - Nosocomial endocarditis: still a challenging diagnosis. PMID- 25016331 TI - Voltammetric detection of As(III) with Porphyridium cruentum based modified carbon paste electrode biosensor. AB - A novel biosensor based on carbon paste electrode modified with Porphyridium cruentum biomass was developed for the determination of As(III) in contaminated water. As(III) was first biosorbed-accumulated on the electrode surface at open circuit potential and then stripped off by applying anodic scan range of -0.8 to +0.8 V using differential pulse anodic stripping voltammetric technique. The best result was obtained at pH 6.0 with 0.1M HNO3 solution as stripping medium, allowing biosorption-accumulation time of 8 min using 5% P. cruentum biomass in graphite-mineral oil paste. Linear range for As(III) detection with the modified electrode-biosensor was observed between 2.5 and 20 ug L(-1). The FTIR spectrum of P. cruentum biomass confirmed the presence of active functional groups that participate in the binding of As(III). Scanning Electron Microscopy (SEM) indulged the surface morphology of modified electrode-biosensor before and after As(III) adsorption. Similarly, Atomic Force Microscopy (AFM) showed that the average roughness of the modified electrode decreased indicating the successful incorporation of P. cruentum biomass. Efficiency of the biosensor in the presence of different interfering metal (Na(+), K(+), Ca(2+), and Mg(2+)) ions were also evaluated. The application of P. cruentum modified biosensor was successfully used for the detection of As(III) in the binary metal (Fe(3+), Mn(2+), Cd(2+), Cu(2+), Ni(2+), Hg(2+), and Pb(2+)) contaminated system. The accuracy of application of biosorption based biosensor for the detection of As(III) is as low as 2.5 ug L(-1). PMID- 25016332 TI - A low-cost miniaturized potentiostat for point-of-care diagnosis. AB - This paper presents a novel approach of using a miniaturized potentiostat (M-P) chip (LMP91000) to perform full range cyclic voltammetry (CV) measurements for the detection of biomarkers. The LMP91000 evaluation board was reconfigured to perform three-electrode CV measurements in order to achieve electrochemical cortisol immunosensing. The microelectrodes for cortisol estimation were fabricated by immobilizing monoclonal anti-cortisol antibody (Anti-M-Cab) onto self-assembled monolayer (SAM) modified Au microelectrodes. The results obtained using the M-P were compared to those obtained using a conventional potentiostat. The M-P was successful in measuring cortisol levels in the range of pM. The outcomes of the studies suggest that M-P can effectively perform biochemical measurements on three electrode systems, enabling the development of miniature systems for point-of-care (POC) diagnosis. PMID- 25016333 TI - Surface-enhanced fluorescence immunosensor using Au nano-crosses for the detection of microcystin-LR. AB - A surface-enhanced fluorescence (SEF) immunosensor for the detection of microcystin-LR was developed using Au nano-crosses as fluorescence enhancement nanoparticles and cy5 as a fluorescence label molecule. The SEF effects of cy5 in the proximity of Au nanorods and gold nano-crosses was investigated by using Au nanorods or nano-crosses coated negative-charged glass surfaces. Fluorescence measurements indicated that SEF was influenced by the size, shape and distribution of the Au nanoparticles, with an appropriate spacer layer between the Au nanoparticles and the cy5. The enhancement factor was from 2.3- to 35 fold. Under optimal conditions, the SEF immunosensor exhibited a good linear response at microcystin-LR concentrations of 0.02-16 ng mL(-1) (R(2)=0.9981). The limit of detection was 0.007 ng mL(-1) with little adsorption of microcystin-RR, microcystin-LW, and microcystin-LF. High microcystin-LR recoveries were obtained from naturally contaminated fish samples. The SEF immunosensor allows the reliable detection of microcystin-LR in seafood, and has potential in simple, sensitive detection applications. PMID- 25016334 TI - The simultaneous detection of free and total prostate antigen in serum samples with high sensitivity and specificity by using the dual-channel surface plasmon resonance. AB - Free/total prostate antigen (f/t-PSA) ratio in serum as a promising parameter has been used to improve the differentiation of benign and malignant prostate disease. In order to obtain the accurate and reliable f/t-PSA ratio, the simultaneous detection of f-PSA and t-PSA with high sensitivity and specificity is required. In this work, the dual-channel surface plasmon resonance (SPR) has been employed to meet the requirement. In one channel, t-PSA was directly measured with a linear range from 1.0 to 20.0 ng/mL. In another channel, due to the low concentration of f-PSA in serum, the asynchronous competitive inhibition immunoassay with f-PSA@Au nanoparticles (AuNPs) was developed. As expected, the detection sensitivity of f-PSA was greatly enhanced, and a linear correlation with wider linear range from 0.010 to 0.40 ng/mL was also achieved. On the other hand, a simple method was explored for significantly reducing the non-specific adsorption of co-existing proteins. On basis of this, the f/t-PSA ratios in serum samples from prostate cancer (PCa) or benign prostatic hyperplasia (BPH) patients were measured. And it was found that there was significant difference between the distributions of f/t-PSA ratio in BPH patients (16.44+/-1.77%) and those in PCa patients (24.53+/-4.97%). This present work provides an effective method for distinguishing PCa from BPH, which lays a potential foundation for the early diagnosis of PCa. PMID- 25016335 TI - Complications and predictors associated with persistent hemodynamic depression after carotid artery stenting. AB - We aimed to investigate the complications and predictors associated with persistent hemodynamic depression (PHD) after carotid artery stenting (CAS). A total of 204 patients undergoing CAS in two centers between January 2011 and November 2013 were enrolled for study into two cohorts: PHD (systolic blood pressure <90 mm Hg and heart beat rate <60/min, which lasted more than 1h) and non-PHD according to their periprocedure detections. The complications were recorded and compared between the two groups. The predictors of PHD were analyzed by univariate analysis and logistic regression model. 43 patients developed PHD, which lasted for 17.22 h on average. The complications occurred in 9 patients of PHD group (angina pectoris 2, myocardial infarction 1, cerebral infarction 3, transient ischemic attack 2 and intestinal obstruction 1), which was significantly more than non- PHD group (angina pectoris 1, cerebral infarction 1, transient ischemic attack 5, p=0.001). Regression analysis revealed that diabetes, severe calcified plaque and a balloon dilation pressure of more than 8 atmospheres (atm) were the independent predictors for PHD after CAS. We concluded that PHD may be related to increased complications of CAS. Patients with diabetes, more severe calcified plaque and more balloon dilation pressure are more prone to develop PHD after CAS. PMID- 25016336 TI - Acute aquatic toxicity studies of Gulf of Mexico water samples collected following the Deepwater Horizon incident (May 12, 2010 to December 11, 2010). AB - The potential for the Deepwater Horizon MC-252 oil incident to affect ecosystems in the Gulf of Mexico (GOM) was evaluated using Americamysis bahia, Menidia beryllina and Vibrio fischeri (Microtox(r) assay). Organisms were exposed to GOM water samples collected in May-December 2010. Samples were collected where oil was visibly present on the water surface or the presence of hydrocarbons at depth was indicated by fluorescence data or reduced dissolved oxygen. Toxicity tests were conducted using water-accommodated fractions (WAFs), and oil-in-water dispersions (OWDs). Water samples collected from May to June 2010 were used for screening tests, with OWD samples slightly more acutely toxic than WAFs. Water samples collected in July through December 2010 were subjected to definitive acute testing with both species. In A. bahia tests, total PAH concentrations for OWD exposures ranged from non-detect to 23.0 MUg L(-1), while WAF exposures ranged from non-detect to 1.88 MUg L(-1). Mortality was >20% in five OWD exposures with A. bahia and three of the WAF definitive tests. Total PAH concentrations were lower for M. beryllina tests, ranging from non-detect to 0.64 MUg L(-1) and non-detect to 0.17 MUg L(-1) for OWD and WAF exposures, respectively. Only tests from two water samples in both the WAFs and OWDs exhibited >20% mortality to M. beryllina. Microtox(r) assays showed stimulatory and inhibitory responses with no relationship with PAH exposure concentrations. Most mortality in A. bahia and M. beryllina occurred in water samples collected before the well was capped in July 2010 with a clear decline in mortality associated with a decline in total PAH water concentrations. PMID- 25016337 TI - Comparative analysis of two weight-of-evidence methodologies for integrated sediment quality assessment. AB - The results of sediment quality assessment by two different weight-of-evidence methodologies were compared. Both methodologies used the same dataset but as criteria and procedures were different, the results emphasized different aspects of sediment contamination. One of the methodologies integrated the data by means of a multivariate analysis and suggested bioavailability of contaminants and their spatial distribution. The other methodology, used in the dredged material management framework recently proposed in Spain, evaluated sediment toxicity in general by assigning categories. Despite the differences in the interpretation and presentation of results, the methodologies evaluated sediment risk similarly, taking into account chemical concentrations and toxicological effects. Comparison of the results of different approaches is important to define their limitations and thereby avoid implications of potential environmental impacts from different management options, as in the case of dredged material risk assessment. Consistent results of these two methodologies emphasized validity and robustness of the integrated, weight-of-evidence, approach to sediment quality assessment. Limitations of the methodologies were discussed. PMID- 25016338 TI - Cytotoxic effects of cylindrospermopsin in mitotic and non-mitotic Vicia faba cells. AB - Cylindrospermopsin (CYN) is a cyanobacterial toxin known as a eukaryotic protein synthesis inhibitor. We aimed to study its effects on growth, stress responses and mitosis of a eukaryotic model, Vicia faba (broad bean). Growth responses depended on exposure time (3 or 6d), cyanotoxin concentration, culture conditions (dark or continuous light) and V. faba cultivar ("Standard" or "ARC Egypt Cross"). At 6d of exposure, CYN had a transient stimulatory effect on root system growth, roots being possibly capable of detoxification. The toxin induced nucleus fragmentation, blebbing and chromosomal breaks indicating double stranded DNA breaks and programmed cell death. Root necrotic tissue was observed at 0.1-20 MUg mL(-1) CYN that probably impeded toxin uptake into vascular tissue. Growth and cell death processes observed were general stress responses. In lateral root tip meristems, lower CYN concentrations (0.01-0.1 MUg mL(-1)) induced the stimulation of mitosis and distinct mitotic phases, irrespective of culture conditions or the cultivar used. Higher cyanotoxin concentrations inhibited mitosis. Short-term exposure of hydroxylurea-synchronized roots to 5 MUg mL(-1) CYN induced delay of mitosis that might have been related to a delay of de novo protein synthesis. CYN induced the formation of double, split and asymmetric preprophase bands (PPBs), in parallel with the alteration of cell division planes, related to the interference of cyanotoxin with protein synthesis, thus it was a plant- and CYN specific alteration. PMID- 25016339 TI - Chromium-induced physio-chemical and ultrastructural changes in four cultivars of Brassica napus L. AB - In nature, plants are continuously exposed to several biotic and abiotic stresses. Among these stresses, chromium (Cr) stress is one of the most adverse factors that affects the plant growth, and productivity, and imposes a severe threat for sustainable crop production. In the present study, toxic effects of Cr were studied in hydroponically grown seedlings of four different cultivars of Brassica napus L. viz. ZS 758, Zheda 619, ZY 50 and Zheda 622. The study revealed that elevated Cr concentrations reduced the plant growth rate and biomass as compared to respective controls in all the cultivars and this decline was more obvious in Zheda 622. It was observed that reduction of photosynthetic attributes was more pronounced in Zheda 622 as compared to other cultivars; while, cultivar ZS 758 performed better under Cr-toxicity. Results showed that Cr contents in different parts of seedlings were higher in Zheda 622 as compared to other cultivars and Cr contents were higher in roots than shoots in all the cultivars. Accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) were induced under different Cr concentrations. Results showed that some of anti oxidant enzyme activities in leaves and roots were increased under the Cr toxicity. The electron microscopic study showed that ultrastructural damages in leaf mesophyll and root tip cells were more prominent in Zheda 622 as compared to other cultivars under 400 MUM Cr stress. Under 400 MUM Cr concentration, changes like broken cell wall, immature nucleus, a number of mitochondria, ruptured thylakoid membranes and large size of vacuole and starch grains were observed in leaf ultrastructures. The damages in root cells were observed in the form of disruption of golgibodies and diffused cell wall under the higher concentration of Cr (400 MUM). On the basis of these observations, it was concluded that Zheda 622 was found to be more sensitive as followed by ZY 50, Zheda 619 and ZS 758 under Cr-toxicity. PMID- 25016341 TI - BbSNF1 contributes to cell differentiation, extracellular acidification, and virulence in Beauveria bassiana, a filamentous entomopathogenic fungus. AB - SNF1/AMPK protein kinase plays important roles in fungal development and activation of catabolite-repressed genes. In this study, we characterized the role of the Beauveria bassiana SNF1 ortholog. The vegetative growth of the DeltaBbSNF1 mutant was reduced by 16 to 50 % on diverse carbon/nitrogen sources. Transcriptional analysis revealed a collection of proteases and chitinases that were not induced when the mutant was grown on complex carbon/nitrogen sources. BbSNF1 also contributes to extracellular acidification. The DeltaBbSNF1 mutant had enhanced production of lactic, pyruvic, and citric acid, but oxalic acid production was partially repressed. Transcriptional analysis showed that a set of genes involved in acid biosynthesis and secretion was changed in the disruption mutant, indicating that BbSNF1 controls the production of different organic acids with different mechanisms. Deletion of BbSNF1 resulted in a significant reduction in conidiation (57-75 %) and blastospore yield (80-95 %) in the mutant. Additionally, BbSNF1 regulates the morphology of blastospore-forming structures and the in vitro blastospore size. Insect bioassays revealed that the DeltaBbSNF1 strain exhibited an approximately doubled median lethal time in topical bioassays, but the decreased virulence in intrahemocoel assays (~20 % change) was not as great as in the topical bioassays. These data suggest that BbSNF1 is important in penetration through the host cuticle. Moreover, a series of genes regulated by BbSNF1 and associated with blastospore formation were primarily involved in metabolism, cell cycle, and transportation. In conclusion, the SNF1/AMPK kinase contributes to the biocontrol potential of B. bassiana by mediating cellular differentiation and utilization of carbon/nitrogen sources. PMID- 25016342 TI - Artificial citrate operon and Vitreoscilla hemoglobin gene enhanced mineral phosphate solubilizing ability of Enterobacter hormaechei DHRSS. AB - Mineral phosphate solubilization by bacteria is mediated through secretion of organic acids, among which citrate is one of the most effective. To overproduce citrate in bacterial systems, an artificial citrate operon comprising of genes encoding NADH-insensitive citrate synthase of E. coli and Salmonella typhimurium sodium-dependent citrate transporter was constructed. In order to improve its mineral phosphate solubilizing (MPS) ability, the citrate operon was incorporated into E. hormaechei DHRSS. The artificial citrate operon transformant secreted 7.2 mM citric acid whereas in the native strain, it was undetectable. The transformant released 0.82 mM phosphate in flask studies in buffered medium containing rock phosphate as sole P source. In fermenter studies, similar phenotype was observed under aerobic conditions. However, under microaerobic conditions, no citrate was detected and P release was not observed. Therefore, an artificial citrate gene cluster containing Vitreoscilla hemoglobin (vgb) gene under its native promoter, along with artificial citrate operon under constitutive tac promoter, was constructed and transformed into E. hormaechei DHRSS. This transformant secreted 9 mM citric acid under microaerobic conditions and released 1.0 mM P. Thus, incorporation of citrate operon along with vgb gene improves MPS ability of E. hormaechei DHRSS under buffered, microaerobic conditions mimicking rhizospheric environment. PMID- 25016343 TI - Saturation mutagenesis of Bradyrhizobium sp. BTAi1 toluene 4-monooxygenase at alpha-subunit residues proline 101, proline 103, and histidine 214 for regiospecific oxidation of aromatics. AB - A novel toluene monooxygenase (TMO) six-gene cluster from Bradyrhizobium sp. BTAi1 having an overall 35, 36, and 38 % protein similarity with toluene o-xylene monooxygenase (ToMO) of Pseudomonas sp. OX1, toluene 4-monooxygenase (T4MO) of Pseudomonas mendocina KR1, and toluene-para-monooxygenase (TpMO) of Ralstonia pickettii PKO1, respectively, was cloned and expressed in Escherichia coli TG1, and its potential activity was investigated for aromatic hydroxylation and trichloroethylene (TCE) degradation. The natural substrate toluene was hydroxylated to p-cresol, indicating that the new toluene monooxygenase (T4MO.BTAi1) acts as a para hydroxylating enzyme, similar to T4MO and TpMO. Some shifts in regiospecific hydroxylations were observed compared to the other wild type TMOs. For example, wild-type T4MO.BTAi1 formed catechol (88 %) and hydroquinone (12 %) from phenol, whereas all the other wild-type TMOs were reported to form only catechol. Furthermore, it was discovered that TG1 cells expressing wild-type T4MO.BTAi1 mineralized TCE at a rate of 0.67 +/- 0.10 nmol Cl(-)/h/mg protein. Saturation and site directed mutagenesis were used to generate eight variants of T4MO.BTAi1 at alpha-subunit positions P101, P103, and H214: P101T/P103A, P101S, P101N/P103T, P101V, P103T, P101V/P103T, H214G, and H214G/D278N; by testing the substrates phenol, nitrobenzene, and naphthalene, positions P101 and P103 were found to influence the regiospecific oxidation of aromatics. For example, compared to wild type, variant P103T produced four fold more m-nitrophenol from nitrobenzene as well as produced mainly resorcinol (60 %) from phenol whereas wild-type T4MO.BTAi1 did not. Similarly, variants P101T/P103A and P101S synthesized more 2-naphthol and 2.3-fold and 1.6-fold less 1-naphthol from naphthalene, respectively. PMID- 25016344 TI - A study of the relationship among sludge retention time, bacterial communities, and hydrolytic enzyme activities in inclined plate membrane bioreactors for the treatment of municipal wastewater. AB - Inclined plate membrane bioreactors (ip-MBRs) have been proposed as a highly effective method in wastewater treatment. With the help of settling enhancer inclined plates, dense excess sludge can be kept in the mainstream of the process, and consequently, suitable sludge mass can be maintained in the membrane tank. In this study, the relationship among sludge retention time (SRT), bacterial communities, and hydrolytic enzyme activities was investigated. Two identical bench-scale ip-MBRs were operated 1 year in real municipal wastewater treatment. Multidimensional scaling (MDS) plots of terminal restriction fragment length polymorphism (T-RFLP) fingerprints showed similar changes in the bacterial communities in terms of bacterial members and abundance over time in both the reactors, which was primarily caused by the changes of wastewater composition. However, the impact of SRT revealed significant differences in the dominant bacterial communities when both the reactors were operated with a largely different SRT (infinite SRT and SRT of 20 days). The sequences of bacterial 16S rRNA gene were classified into six libraries of A-F. The largest group of sequences belonged to the phylum Proteobacteria. The phylum Bacteroidetes was dominant in the seed sludge retrieved from the conventional activated sludge (CAS) as Flavobacterium-like bacterium was dominantly observed. Under the MBR operation (libraries B-F), bacterial communities belonging to the phyla Proteobacteria and Chloroflexi were dominant. Most of them may be responsible for protein degradation because aminopeptidase activity increased in proportion with the abundance of these bacteria. PMID- 25016345 TI - Development of an in vitro method for the prediction of mycotoxin binding on yeast-based products: case of aflatoxin B1, zearalenone and ochratoxin A. AB - To date, no official method is available to accurately define the binding capacity of binders. The goal is to define general in vitro parameters (equilibrium time, pH, mycotoxin/binder ratio) for the determination of binding efficacy, which can be used to calculate the relevant equilibrium adsorption constants. For this purpose, aflatoxin B1 (AFB1), zearalenone (ZEA) or ochratoxin A (OTA) were incubated with one yeast cell wall in pH 3, pH 5 or pH 7 buffers. The percentage of adsorption was recorded by quantitation of remaining mycotoxins in the supernatant and amount of mycotoxin adsorbed on the residue. The incubation of yeast cell wall in the presence of mycotoxins solved in buffer, lead to unexpected high adsorption percentage when the analysis was based only on remaining mycotoxins in the supernatant. The decrease of mycotoxins in the supernatant was not correlated to the amount of mycotoxins found in the residue. For this reason we modified the conditions of incubation. Yeast cell wall (5 mg) was pre-incubated in buffer (990 MUl) at 37 degrees C during 5 min and then 10 MUl of an alcoholic solution of mycotoxin (concentration 100 times higher than the final concentration required in the test tube) were added. After incubation, the solution was centrifuged, and the amount of mycotoxins were analysed both in the supernatant and in the residue. A plateau of binding was reached after 15 min of incubation whatever the mycotoxins and the concentrations tested. The adsorption of ZEA was better at pH 5 (75 %), versus 60 % at pH 3 and 7. OTA was only significantly adsorbed at pH 3 (50 %). Depending on the pH, the adsorptions of OTA or ZEA were increased or decreased when they were together, indicative of a cooperative effect. PMID- 25016347 TI - A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. AB - Broad neuropsychological deficits have been consistently demonstrated in well established bipolar disorder. The aim of the current study was to systematically review neuropsychological studies in first-episode bipolar disorders to determine the breadth, extent and predictors of cognitive dysfunction at this early stage of illness through meta-analytic procedures. Electronic databases were searched for studies published between January 1980 and December 2013. Twelve studies met eligibility criteria (N = 341, mean age = 28.2 years), and pooled effect sizes (ES) were calculated across eight cognitive domains. Moderator analyses were conducted to identify predictors of between-study heterogeneity. Controlling for known confounds, medium to large deficits (ES >= 0.5) in psychomotor speed, attention and working memory, and cognitive flexibility were identified, whereas smaller deficits (ES 0.20-0.49) were found in the domains of verbal learning and memory, attentional switching, and verbal fluency. A medium to large deficit in response inhibition was only detected in non-euthymic cases. Visual learning and memory functioning was not significantly worse in cases compared with controls. Overall, first-episode bipolar disorders are associated with widespread cognitive dysfunction. Since euthymia was not associated with superior cognitive performance in most domains, these results indicate that even in the earliest stages of disease, cognitive deficits are not mood-state dependent. The current findings have important implications for whether cognitive impairments represent neurodevelopmental or neurodegenerative processes. Future studies need to more clearly characterise the presence of psychotic features, and the nature and number of previous mood episodes. PMID- 25016348 TI - Recommendations for training psychiatry residents in psychosomatic medicine. AB - BACKGROUND: The Accreditation Council of Graduate Medical Education (ACGME) mandates that residents in psychiatry training programs learn to provide psychiatric consultation to other medical and surgical services. The ACGME, however, offers little information to instruct academic faculty and institutions to what constitutes a quality educational experience in psychosomatic medicine/consultation-liaison psychiatry for the resident trainee. METHODS: These recommendations were developed through a collaborative process between educators in C-L psychiatry and members of the Academy of Psychosomatic Medicine's Residency Education Subcommittee. RESULTS: This manuscript provides a broad framework for what constitutes a well-rounded clinical and academic resident rotation on psychiatric consultation-liaison services. A rotation that is viewed positively by residents is important as it likely provides a foundation for a growing interest in Psychosomatic Medicine and the development of future fellows and subspecialty trained physicians. PMID- 25016349 TI - Microthinking about micronutrients: a case of transition from obsessions about healthy eating to near-fatal "orthorexia nervosa" and proposed diagnostic criteria. PMID- 25016350 TI - Ingestion of Hawaiian Baby Woodrose seeds to obtain a legal high. PMID- 25016351 TI - Valproic acid-induced thrombocytopenia may cause wound nonhealing in individuals with schizophrenia. PMID- 25016352 TI - Characteristics and trends in peer-reviewed publications in the field of psychosomatic medicine. AB - BACKGROUND: The field of psychosomatic medicine/consultation-liaison psychiatry, now a subspecialty in psychiatry, has focused its efforts on clinical care, education, and research at the interface of psychiatry, medicine, and neurology. OBJECTIVE: We sought to categorize characteristics and trends (over the past decade) in several journals intended primarily for practitioners of psychosomatic medicine. METHODS: We reviewed all articles published in 3 peer-reviewed journals (i.e., Psychosomatics, General Hospital Psychiatry, and the Journal of Psychosomatic Research) in 2002 and 2012. RESULTS: Each of the 3 journals has a different approach to publication of original research, clinical reviews, and case reports. CONCLUSIONS: The 3 journals demonstrate differing levels of international involvement, publish a different number of articles of different types (e.g., case reports, reviews, and original research), and focus on different types of medical-psychiatric problems. PMID- 25016353 TI - Liver transplant for intentional acetaminophen overdose: a survey of transplant clinicians' experiences with recommendations. AB - BACKGROUND: In the case of fulminant hepatic failure from acetaminophen, the ability to fully evaluate patients is often compromised. When hepatic recovery is not possible and liver transplantation (LT) is required, these patients present significant medical and psychosocial challenges to liver transplant teams. In this context, decisions about candidacy are often under emergency circumstances. To date, little empirical data exist to illustrate the experiences and approaches of those clinicians responsible for performing the psychosocial assessments of these LT candidates. METHODS: We surveyed transplant mental health clinicians and discovered a wide range of opinions, approaches, and treatment planning when addressing acetaminophen overdose LT patients. RESULTS: Although LT candidacy is commonly supported, there were distinct differences in considering the contributions of suicide risk factors. In addition, although poor post-LT outcomes (repeat suicide attempts and graft failure due to nonadherence) were known to have occurred in acetaminophen overdose LT cases, many respondents did not provide long-term mental health treatment to these patients following LT. CONCLUSION: The results of the survey suggest that careful treatment planning in both the immediate and long term could improve the long-term care of these complex patients. PMID- 25016354 TI - Lyme disease: a review of its epidemiology, evaluation, and treatment. AB - BACKGROUND: Lyme disease, a tick-borne illness transmitted to humans, has become increasingly recognized. OBJECTIVE: Given the myriad neurovegetative and neuropsychiatric symptoms that can be associated with Lyme disease, we sought to review the epidemiology, evaluation, and treatment of the disorder. METHODS: A case vignette that highlights manifestations of the condition and dilemmas associated with its treatment is presented. CONCLUSIONS: Knowledge about its symptoms, its abnormal laboratory tests, and its course can help to guide the timely and appropriate management of this spirochetal infection. PMID- 25016356 TI - A case series of pharmaceutical gamma-hydroxybutyrate in 3 patients with severe benzodiazepine-resistant gamma-hydroxybutyrate withdrawal in the hospital. PMID- 25016355 TI - Pharmacologic management of bipolar disorder in a Medicare Advantage population. AB - OBJECTIVE: The purpose of this study was to examine patterns of pharmacotherapy for beneficiaries in a high-risk Medicare Advantage program who were diagnosed with bipolar disorder. METHODS: This was a cross-sectional study of 2338 Medicare Advantage beneficiaries diagnosed with bipolar disorder. Pharmacotherapy treatment was assessed via receipt of (1) a mood stabilizer or antipsychotic or both (i.e., guideline concordant bipolar care) and (2) unopposed antidepressant (i.e., without prescription of a mood stabilizer or an antipsychotic). Logistic regression was used to examine correlates of bipolar disorder care. RESULTS: Among those younger than 65 years of age (n = 1395), 54% received guideline concordant therapy and 29% received unopposed antidepressant therapy. Among those 65 years and older (n = 943), 40% received guideline concordant therapy and 33% received unopposed antidepressant therapy. CONCLUSION: Overall, about half of beneficiaries in this Medicare Advantage plan received guideline concordant pharmacotherapy for bipolar disorder, while approximately one-third received an unopposed antidepressant prescription. Antipsychotic medications accounted for most of the monotherapy observed. This study identifies opportunities for further improvements in the pharmacotherapy of bipolar disorder in high-risk Medicare patients. PMID- 25016357 TI - Depression among patients with diabetes attending a safety-net primary care clinic: relationship with disease control. AB - BACKGROUND: Depression and diabetes are highly comorbid, with depression increasing risk of diabetes-related complications and mortality. Few studies have examined the relationship between depression and diabetes in safety-net populations with high rates of trauma exposure, anxiety, and substance use disorders. METHODS: Using a cross-sectional survey of 261 patients with diabetes attending safety-net clinics, associations between depression and key diabetes control parameters were examined in bivariate and multivariable analyses adjusting for relevant confounders and significant interactions. RESULTS: Among the participants, 57% were men, 51% were white, and the average age was 57 years. Most respondents were unemployed (81%) and earned less than $10,000 per year (51%). Overall, 28% screened positive for depression, with a high overlap of posttraumatic stress (58%) and generalized anxiety (77%) symptoms. After adjustment for socioeconomic and clinical variables, depression was associated with higher mean body mass index (p = 0.01), severe obesity (body mass index >= 35kg/m(2)) (odds ratio = 2.34, 95% CI: 1.09-5.04, p = 0.03) and uncontrolled diastolic blood pressure (odds ratio = 2.49, 95% CI: 1.15-5.39, p = 0.02). There was a nonsignificant trend for those with depression to have worse control of blood glucose. Associations with depression and diabetes clinical outcomes were not significantly worsened in the presence of comorbid anxiety disorders. CONCLUSIONS: Within a highly comorbid safety-net population, significant associations between depression and key diabetes outcomes remained after accounting for relevant covariates. Further research will help elucidate the relationship between depression and diabetes control measures in safety-net populations. PMID- 25016358 TI - Two cases of catatonia with thyroid dysfunction. PMID- 25016359 TI - The pain self-efficacy questionnaire: validation of an abbreviated two-item questionnaire. AB - BACKGROUND: The Pain Self-Efficacy Questionnaire (PSEQ) is a validated tool to assess pain self-efficacy and is strongly correlated with disability. Reducing the number of questions of the original PSEQ to screen for self-efficacy will result in more efficient screening and less burden for the patient. OBJECTIVE: The aim of this study was to prospectively validate the shortened version of the PSEQ. METHOD: Overall, 249 new and follow-up patients visiting our outpatient orthopedic hand surgery clinic were prospectively enrolled and asked to complete the PSEQ, short version of the Disabilities of the Arm Shoulder and Hand, and 2 question version of the Patient Health Questionnaire (PHQ-2) depression questionnaires. The patients completed the questionnaires in the office and online 2 weeks after their visit. At the follow-up visit, the PSEQ was substituted with the 2-question version of the Pain Self-Efficacy Questionnaire (PSEQ-2). The factors associated with higher short forms of the Disabilities of the Arm, Shoulder and Hand scores were investigated in a bivariate and multivariable analysis. Paired t-test was used to compare the mean values of the short and long questionnaires at enrollment. RESULTS: There was a large correlation (r = 0.90; p < 0.001) between the original PSEQ and the PSEQ-2 at enrollment. The Cronbach alpha were comparable for the PSEQ and the PSEQ-2 (alpha = 0.95 compared with alpha = 0.91). There was a small but statistically significant difference between the average scores of the PSEQ and PSEQ-2 (4.4 vs 4.8; p < 0.001). For the shortened PSEQ, a smaller-but still large-correlation was found with the short forms of the Disabilities of the Arm, Shoulder and Hand (r = 0.71 vs r = 0.61). Both the PSEQ-2 and the PSEQ were the most important predictors of the short forms of the Disabilities of the Arm, Shoulder and Hand scores. A substantial test-retest reliability was found for the PSEQ-2 (0.66). CONCLUSION: The PSEQ-2 can be used to quickly assess patients' pain self efficacy. PMID- 25016360 TI - Comment on: Psychiatric Manifestations of Anti-NMDA Receptor Encephalitis: Neurobiological Underpinnings and Differential Diagnostic Implications (Maneta and Garcia, Psychosomatics 2014;55:37-44). PMID- 25016362 TI - Positive remodeling at 3 year follow up is associated with plaque-free coronary wall segment at baseline: a serial IVUS study. AB - AIMS: At present it is unknown what limits the arterial remodeling process during atherosclerotic plaque formation. In healthy arteries remodeling is regulated by the shear stress induced response by the endothelium. As endothelium at the plaque site is assumed to be dysfunctional, we tested the hypothesis that plaque free wall (PFW) determines vascular remodeling during atherosclerotic plaque build-up. METHODS & RESULTS: 66 human coronary ROIs (38 patients) were studied at baseline and at 3 years follow up applying intravascular ultrasound (IVUS). From the IVUS images the lumen and external elastic membrane contours were delineated to assess wall thickness (WT), vessel area (VA), Plaque Area (PA) and plaque burden (PA/VA*100%). WT < 0.5 mm was defined as normal and determined the arc of the PFW (0-360 degrees ). Positive remodeling was defined as relative difference of VA over time >5%. At baseline, IVUS-PFW was inversely related to plaque burden (p < 0.05). Positive remodeling was most frequently observed in ROIs with IVUS PFW > 180 degrees (i.e. larger than half of the circumference) compared to PFW < 180 degrees (55% vs. 12%, p < 0.05). Accordingly, plaques with IVUS-PFW > 180 degrees at baseline had the largest change in VA (1.1 +/- 2.1 vs. -0.4 +/- 0.6 mm(2), p < 0.05) with an odds ratio of 9.2 to develop positive remodeling. CONCLUSIONS: Our serial IVUS data show that IVUS-PFW is a determinant of vascular remodeling. ROIs with PFW > 180 at baseline had the highest probability to undergo positive remodeling. PMID- 25016361 TI - Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF kappaB signal pathway in rat vascular smooth muscle cells. AB - OBJECTIVE: Homocysteine (Hcy) is known as an independent risk factor for atherosclerosis. C-reactive protein (CRP) directly participates in initiation and progression of atherosclerosis. However, there is no direct evidence to demonstrate pro-inflammatory effect of Hcy on vascular smooth muscle cells (VSMCs) through CRP. In the present study, we examined the effect of Hcy on CRP expression and investigated the related mechanism in VSMCs. METHODS AND RESULTS: Protein expression and secretion were detected by Western blot and ELISA, respectively. mRNA expression was detected by RT-PCR. Superoxide anion was detected by lucigenin chemiluminometry and the immunofluorescence staining was observed by a fluorescence microscope. The results revealed that Hcy significantly induced mRNA and protein expressions of CRP in VSMCs both in vitro and in vivo, and anti-IL-1beta or anti-IL-6 neutralizing antibody alone or in combination partially reduced Hcy-induced CRP expression. Hcy increased the expression of NR1 subunit of N-methyl-d-aspartate receptor (NMDAr), and MK-801 alleviated Hcy-induced CRP expression in VSMCs. Further studies showed that Hcy stimulated superoxide anion generation in VSMCs. Nevertheless, pretreatment of the cells with MK-801, TTFA and DPI significantly reduced Hcy-stimulated superoxide anion generation, and antioxidant NAC decreased Hcy-induced CRP expression in VSMCs. Additionally, PD98059, SB205380 or PDTC antagonized Hcy induced CRP expression, and MK-801, NAC, PD98059 or SB205380 inhibited Hcy activated phosphorylations of ERK1/2 and p38. CONCLUSION: The present study demonstrates that Hcy is able to initiate an inflammatory response in VSMCs by stimulating CRP production, which is mediated through NMDAr-ROS-ERK1/2/p38-NF kappaB signal pathway. These findings provide new evidence for a role of Hcy in pathogenesis of atherosclerosis. PMID- 25016363 TI - A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. AB - Despite the benefit of statins in reducing cardiovascular risk, a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries, inducing pre-beta particles, may reduce the risk of CVD. A novel BET bromodomain antagonist, RVX-208, was reported to raise apoA-I and increase prebeta-HDL particles in non-human primates and humans. In the present study, we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE(-/-) mice. Oral treatments of apoE(-/-) mice with 150 mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation, accompanied by 2-fold increases in the levels of circulating HDL-C, and ~50% decreases in LDL-C, although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction. Haptoglobin, a proinflammatory protein, known to bind with HDL/apoA-I, decreased >2.5-fold in the RVX-208 treated group. With a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks, RVX-208 similarly reduced lesion formation by 39% in the whole aorta without significant changes in the plasma lipid parameters. RVX-208 significantly reduced the proinflammatory cytokines IP-10, MIP1((r)) and MDC. These results show that the antiatherogenic activity of BET inhibitor, RVX-208, occurs via a combination of lipid changes and anti-inflammatory activities. PMID- 25016364 TI - Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade. AB - OBJECTIVE: Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR). METHODS: We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence. RESULTS: Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan. CONCLUSION: ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs. PMID- 25016365 TI - Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation. AB - BACKGROUND: A number of studies have suggested that angiotensin II (AII) receptor type 1 (ATR1) blocking drugs (ARBs) have anti-inflammatory effects however the mechanisms responsible are poorly investigated. OBJECTIVE: To determine the role of extracellular signal regulated kinase (ERK)1/2 in ARB induced anti inflammatory effects within human carotid atherosclerosis. METHODS: Atheroma samples obtained from patients undergoing carotid endarterectomy were cultured with and without ATR1 (irbesartan), ERK1/2 (PD98059), AII ([Sar(1), Ile(8)]-AII) and angiotensin converting enzyme (ACE)2 (DX600) blockade. The in vitro effects of ATR1 and ERK1/2 blockade and exogenous AII on serum stimulated healthy, primary vascular cells were also investigated. Outcome was assessed by measuring cytokine, (interleukin (IL)-6, IL-8, C-C motif chemokine (CCL)2, C-X-C motif chemokine (CXCL)5, osteoprotegerin (OPG), osteopontin (OPN), CXCL16), concentrations in supernatants and phosphorylated ERK1/2 in the tissue lysates using ELISA. ERK1/2 expression in the tissue was assessed using Western blotting. RESULTS: Irbesartan reduced concentrations of IL-6, IL-8, CCL2, CXCL5, OPG, OPN and CXCL16 in both atheroma and primary vascular cell culture supernatants. The reduction in cytokine levels in the atheroma supernatant was correlated to a reduction in ERK1/2 expression in the tissue. Inhibition of ERK1/2 downregulated IL-6, IL-8 and CXCL5 in both atheroma and cell culture supernatants. AII and ACE2 blockade had no impact on cytokine or active ERK1/2 levels in the atheroma culture. CONCLUSION: Our findings suggest that ATR1 blockade downregulates atheroma tissue ERK1/2 expression leading to a reduction in cytokine production and that a non-AII agonist ATR1 signalling response may induce expression of these inflammation associated cytokines in the atheroma. PMID- 25016366 TI - Low vision depression prevention trial in age-related macular degeneration: a randomized clinical trial. AB - PURPOSE: To compare the efficacy of behavior activation (BA) + low vision rehabilitation (LVR) with supportive therapy (ST) + LVR to prevent depressive disorders in patients with age-related macular degeneration (AMD). DESIGN: Single masked, attention-controlled, randomized, clinical trial with outcome assessment at 4 months. PARTICIPANTS: Patients with AMD and subsyndromal depressive symptoms attending retina practices (n = 188). INTERVENTIONS: Before randomization, all subjects had 2 outpatient LVR visits, and were then randomized to in-home BA+LVR or ST+LVR. Behavior activation is a structured behavioral treatment that aims to increase adaptive behaviors and achieve valued goals. Supportive therapy is a nondirective, psychological treatment that provides emotional support and controls for attention. MAIN OUTCOME MEASURES: The Diagnostic and Statistical Manual IV defined depressive disorder based on the Patient Health Questionnaire-9 (primary outcome), Activities Inventory, National Eye Institute Vision Function Questionnaire-25 plus Supplement (NEI-VFQ), and NEI-VFQ quality of life (secondary outcomes). RESULTS: At 4 months, 11 BA+LVR subjects (12.6%) and 18 ST+LVR subjects (23.4%) developed a depressive disorder (relative risk [RR], 0.54; 95% CI, 0.27-1.06; P = 0.067). In planned adjusted analyses the RR was 0.51 (95% CI, 0.27-0.98; P = 0.04). A mediational analysis suggested that BA+LVR prevented depression to the extent that it enabled subjects to remain socially engaged. In addition, BA+LVR was associated with greater improvements in functional vision than ST+LVR, although there was no significant between-group difference. There was no significant change or between-group difference in quality of life. CONCLUSIONS: An integrated mental health and low vision intervention halved the incidence of depressive disorders relative to standard outpatient LVR in patients with AMD. As the population ages, the number of persons with AMD and the adverse effects of comorbid depression will increase. Promoting interactions between ophthalmology, optometry, rehabilitation, psychiatry, and behavioral psychology may prevent depression in this population. PMID- 25016367 TI - Photosynthetic acclimation of Nannochloropsis oculata investigated by multi wavelength chlorophyll fluorescence analysis. AB - Multi-wavelength chlorophyll fluorescence analysis was utilised to examine the photosynthetic efficiency of the biofuel-producing alga Nannochloropsis oculata, grown under two light regimes; low (LL) and high (HL) irradiance levels. Wavelength dependency was evident in the functional absorption cross-section of Photosystem II (sigmaII(lambda)), absolute electron transfer rates (ETR(II)), and non-photochemical quenching (NPQ) of chlorophyll fluorescence in both HL and LL cells. While sigmaII(lambda) was not significantly different between the two growth conditions, HL cells upregulated ETR(II) 1.6-1.8-fold compared to LL cells, most significantly in the wavelength range of 440-540 nm. This indicates preferential utilisation of blue-green light, a highly relevant spectral region for visible light in algal pond conditions. Under these conditions, the HL cells accumulated saturated fatty acids, whereas polyunsaturated fatty acids were more abundant in LL cells. This knowledge is of importance for the use of N. oculata for fatty acid production in the biofuel industry. PMID- 25016369 TI - A persistent sciatic artery aneurysm containing a free-floating thrombus: report of a case. AB - A persistent sciatic artery is a rare vascular anomaly in which the sciatic artery, which involutes in the embryonic stage, persists as the blood supply to the lower limb. This vascular anomaly is often associated with aneurysm formation. A persistent sciatic artery aneurysm is a rare cause of peripheral arterial embolic disease. We herein describe the case of a 72-year-old female with a free-floating thrombus in a persistent sciatic artery aneurysm. She underwent iliac-popliteal artery bypass and exclusion of the aneurysm to prevent an embolic event. PMID- 25016368 TI - Epigenetics modifications and Subclinical Atherosclerosis in Obstructive Sleep Apnea: The EPIOSA study. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk for cardiovascular morbidity and mortality. Epidemiological and animal models studies generate hypotheses for innovative strategies in OSA management by interfering intermediates mechanisms associated with cardiovascular complications. We have thus initiated the Epigenetics modification in Obstructive Sleep Apnea (EPIOSA) study (ClinicalTrials.gov identifier: NCT02131610). METHODS/DESIGN: EPIOSA is a prospective cohort study aiming to recruit 350 participants of caucasian ethnicity and free of other chronic or inflammatory diseases: 300 patients with prevalent OSA and 50 non-OSA subjects. All of them will be follow-up for at least 5 years. Recruitment and study visits are performed in single University-based sleep clinic using standard operating procedures. At baseline and at each one year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized questionnaire and physical examination to determine incident comorbidities and health resources utilization, with a primary focus on cardiovascular events. Confirmatory outcomes information is requested from patient records and the regional Department of Health Services. Every year, OSA status will be assessed by full sleep study and blood samples will be obtained for immediate standard biochemistry, hematology, inflammatory cytokines and cytometry analysis. For biobanking, aliquots of serum, plasma, urine, mRNA and DNA are also obtained. Bilateral carotid echography will be performed to assess subclinical atherosclerosis and atherosclerosis progression. OSA patients are treated according with national guidelines. DISCUSSION: EPIOSA will enable the prospective evaluation of inflammatory and epigenetics mechanism involved in cardiovascular complication of treated and non-treated patients with OSA compared with non OSA subjects. PMID- 25016370 TI - Design, synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives. AB - A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q &5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 MUM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line. PMID- 25016371 TI - New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni. AB - A series of NO-donor praziquantel hybrid compounds was obtained by combining praziquantel (PZQ) and furoxan moieties in a single entity. NO-donor properties of the furoxan derivatives were evaluated by detecting nitrite after incubation of the products in 7.4 pH buffered solution in the presence of L-cysteine. Structurally-related furazans, devoid of NO release capacity, were also synthesized for control purposes. All products were studied for their ability to inhibit recombinant Schistosoma mansoni thioredoxin glutathione reductase (TGR). Mobility and death of adult Schistosoma mansoni worms cultured in the presence of the products were evaluated versus PZQ. Analysis of the results showed that some products were endowed with both PZQ and NO-dependent antiparasitic properties. Compounds 6, 7, 18, and 24 emerged as the most interesting balanced hybrids, worthy of additional study on PZQ-resistant parasites. PMID- 25016372 TI - Zwitterionic pyrimidinium adducts as antioxidants with therapeutic potential as nitric oxide scavenger. AB - A variety of zwitterionic adducts were synthesized by using means green chemistry method. The products contain the biologically active barbituric acid moiety embedded in zwitterion products. Both features are pharmaceutically relevant. The chemical structures were deduced by (1)H-, (13)C-, NMR and HRMS spectral analysis, and X-ray diffraction techniques. In vitro evaluation for the antioxidant activities were carried out towards the inhibition of nitric oxide (NO) radical, known to regulate a mechanism of signals for various cellular functions. NO also play an important role as a mediator of various pathological conditions responsible for cellular damages such as strokes, cancers, diabetes, chronic heart failure and inflammatory disease and various neurodegenerative disorders. All tested compounds were found to be more potent nitric oxide scavengers as compared to standard drug ascorbic acid (IC50 = 618 +/- 2.0 MUM). Compounds 4c and e exhibiting several hundred fold more activity against nitric oxide radical with IC50 values of 69 +/- 1.66 and 70.1 +/- 0.89 MUM respectively, as compared to standard drug ascorbic acid (IC50 = 618 +/- 2.0 MUM). PMID- 25016373 TI - "On water" expedient synthesis of 3-indolyl-3-hydroxy oxindole derivatives and their anticancer activity in vitro. AB - A series of 3-indolyl-3-hydroxy oxindole derivatives (n = 41) were synthesized by the green aminocatalytic method with excellent yields under mild reaction conditions. All the newly synthesized derivatives were subjected to evaluate their cytotoxic properties against different human cancer cell lines. Results indicated that about 73% of the derivatives exhibited significant anti proliferative activities against leukemia (U937, THP-1), lung (A549) and breast cancer (MCF7) cell lines. Among them a few of the derivatives exhibited the most potent and effective cytotoxic activities on U937 (34, 36, 38 and 41) and MCF7 (12, 35, 40 and 41) cell lines, and their anti-proliferation activities are better than the positive control, Etoposide. PMID- 25016374 TI - Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core. AB - A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase 2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency. The lead compound demonstrated very good oral bioavailability in mice, slow metabolic degradation, modest distribution into the brain and a remarkable anti-inflammatory efficacy in carrageenan-induced mouse paw edema model. A foundation has therefore been laid for a chemically novel series of COX-2 inhibitors that has a potential for diverse therapeutic applications in inflammatory disease area. PMID- 25016375 TI - Methylenedioxy flavonoids: assessment of cytotoxic and anti-cancer potential in human leukemia cells. AB - A new series of chalcones, flavanones and flavones with methylenedioxy group at the 3',4' position in chalcone, 7,8 position in flavanones and flavones with mono , di- and trimethoxy groups in the benzaldehyde ring have been assessed for their effect on proliferation, cytotoxic potential and apoptosis in human leukemia cells. Among the tested compounds, the chalcone series showed the best activity and chalcone 3 (mono methoxy group at the ortho position in A-ring) showed a significant effect on down-regulation of cancer cell proliferation and viability in three different leukemia cell lines (K562, Jurkat, U937). The executioner caspase cleavage analyses indicated that the cytotoxic effect mediated by chalcone 3 is due to induction of apoptotic cell death. Interestingly, the cytotoxic effect was cell type-specific and targeted preferentially cancer cells as peripheral blood mononuclear cells (PBMCs) from healthy donors were less affected by the treatment compared to K562, Jurkat and U937 leukemia cells. Altogether our results indicate a potential drug candidate with interesting differential toxicity obeying Lipinski's rule of five. PMID- 25016376 TI - Synthesis and SAR study of novel tricyclic pyrazoles as potent phosphodiesterase 10A inhibitors. AB - Novel pyrazolo[5,1-f][1,6]naphthyridines, pyrazolo[5,1-a][2,6]naphthyridines, pyrazolo[5,1-a][2,7]naphthyridines and pyrazolo[5,1-a]isoquinolines phenylimidazole/benzimidazole ethylene-linked were designed and synthesized for PDE10A interaction. An AgOTf and proline-cocatalyzed multicomponent methodology based on use of o-alkynylaldehydes, tosylhydrazide and ketones was developed and proved to be a convenient route for assembly of most of the novel tricyclic pyrazoles synthesized. Pyrazolo[5,1-f][1,6]naphthyridine 43 and 59, pyrazolo[5,1 a][2,6]naphthyridine 66, and pyrazolo[5,1-a][2,7]naphthyridine 42 showed the highest affinity for PDE10A enzyme (IC50 = 40, 42, 40, 55 nM, respectively). PMID- 25016377 TI - When something is not quite right: an ankle sprain. AB - Ankle sprains are a common musculoskeletal injury in sport. Older people are increasingly participating in sports such as running. The specificities of musculoskeletal injuries in older people pose a different diagnostic challenge from that in young people participating in the same activities. A clinical case is presented of a 64-year-old patient diagnosed with a grade 1, plantar flexion/inversion ankle sprain that was later diagnosed as a quite different and rare injury. Fractures of the fibular malleolus, talar neck and dome are possible differential diagnoses for an ankle sprain, as are talar dome chondral defects. Response to treatment may help to guide the diagnostic procedure when pain persists after appropriate treatment. PMID- 25016378 TI - Genetic diversity of the conserved motifs of six bacterial leaf blight resistance genes in a set of rice landraces. AB - BACKGROUND: Bacterial leaf blight (BLB) caused by the vascular pathogen Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious diseases leading to crop failure in rice growing countries. A total of 37 resistance genes against Xoo has been identified in rice. Of these, ten BLB resistance genes have been mapped on rice chromosomes, while 6 have been cloned, sequenced and characterized. Diversity analysis at the resistance gene level of this disease is scanty, and the landraces from West Bengal and North Eastern states of India have received little attention so far. The objective of this study was to assess the genetic diversity at conserved domains of 6 BLB resistance genes in a set of 22 rice accessions including landraces and check genotypes collected from the states of Assam, Nagaland, Mizoram and West Bengal. RESULTS: In this study 34 pairs of primers were designed from conserved domains of 6 BLB resistance genes; Xa1, xa5, Xa21, Xa21(A1), Xa26 and Xa27. The designed primer pairs were used to generate PCR based polymorphic DNA profiles to detect and elucidate the genetic diversity of the six genes in the 22 diverse rice accessions of known disease phenotype. A total of 140 alleles were identified including 41 rare and 26 null alleles. The average polymorphism information content (PIC) value was 0.56/primer pair. The DNA profiles identified each of the rice landraces unequivocally. The amplified polymorphic DNA bands were used to calculate genetic similarity of the rice landraces in all possible pair combinations. The similarity among the rice accessions ranged from 18% to 89% and the dendrogram produced from the similarity values was divided into 2 major clusters. The conserved domains identified within the sequenced rare alleles include Leucine-Rich Repeat, BED-type zinc finger domain, sugar transferase domain and the domain of the carbohydrate esterase 4 superfamily. CONCLUSIONS: This study revealed high genetic diversity at conserved domains of six BLB resistance genes in a set of 22 rice accessions. The inclusion of more genotypes from remote ecological niches and hotspots holds promise for identification of further genetic diversity at the BLB resistance genes. PMID- 25016379 TI - Association between gastro-intestinal symptoms and menstruation in patients with ileal pouches. AB - BACKGROUND AND AIMS: Gastro-intestinal (GI) symptoms are often experienced by healthy women during menstruation. An increased frequency of GI symptoms during menses has also been reported in women with irritable bowel syndrome or inflammatory bowel disease (IBD); however, IBD patients with restorative proctocolectomy and ileal pouch-anal anastomoses (IPAA) have not been studied. We aimed to examine the association between GI symptoms before and during menses in patients with IPAA, and to assess factors for exacerbation of GI symptoms in those patients. METHODS: Adult women recorded in the Pouchitis Registry were invited to participate in a mailed survey. Participants reported on GI symptoms 1 5 days prior to- (pre-menses) and during the days of their menses in recent months. Demographic and clinical variables were obtained through the survey and chart review. RESULTS: One hundred and twenty-eight (21.3%) out of 600 women with IPAA responded to the survey questionnaire. Forty-three (33.5%) were excluded for reasons including post-menopausal (n = 25), hysterectomy (n = 14) and use of contraceptives (n = 4). Abdominal pain (P = 0.001), diarrhea (P = 0.021), and urgency (P = 0.031) were more commonly reported during menses than pre-menses by the participants. Only a history of painful menses was significantly associated with increased GI symptoms during menses for patients with ileal pouch (odds ratio = 5.67; 95% confidence interval: 1.41-22.88; P = 0.015). CONCLUSION: GI symptoms such as abdominal pain, diarrhea, and urgency are commonly associated with menses in patients with ileo-anal pouch. Painful menses may be associated with worsening of GI symptoms. PMID- 25016380 TI - Inhibition of the central melanocortin system decreases brown adipose tissue activity. AB - The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.CETP transgenic mice were fed a Western type diet for 4 weeks and infused intracerebroventricularly with the melanocortin 3/4 receptor (MC3/4R) antagonist SHU9119 or vehicle for 2 weeks. SHU9119 increased food intake (+30%) and body fat (+50%) and decreased EE by reduction in fat oxidation (-42%). In addition, SHU9119 impaired the uptake of VLDL-TG by BAT. In line with this, SHU9119 decreased uncoupling protein-1 levels in BAT (-60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Finally, SHU9119-treated mice pair-fed to the vehicle-treated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specific to the APOE*3-Leiden.CETP background as SHU9119 also inhibited BAT activity in wild-type mice. We conclude that inhibition of central MC3/4R signaling impairs BAT function, which is accompanied by reduced EE, thereby promoting adiposity. We anticipate that activation of MC4R is a promising strategy to combat obesity by increasing BAT activity. PMID- 25016381 TI - From miRNA regulation to miRNA-TF co-regulation: computational approaches and challenges. AB - microRNAs (miRNAs) are important gene regulators. They control a wide range of biological processes and are involved in several types of cancers. Thus, exploring miRNA functions is important for diagnostics and therapeutics. To date, there are few feasible experimental techniques for discovering miRNA regulatory mechanisms. Alternatively, predictions of miRNA-mRNA regulatory relationships by computational methods have increasingly achieved promising results. Computational approaches are proving their ability as effective tools in reducing the number of biological experiments that must be conducted and to assist with the design of the experiments. In this review, we categorize and review different computational approaches to identify miRNA activities and functions, including the co regulation of miRNAs and transcription factors. Our main focuses are on the recent approaches that use multiple data types for exploring miRNA functions. We discuss the remaining challenges in the evaluation and selection of models based on the results from a case study. Finally, we analyse the remaining challenges of each computational approach and suggest some future research directions. PMID- 25016382 TI - Iatrogenic Cushing's syndrome due to overuse of topical steroid in the diaper area. PMID- 25016383 TI - Revisiting advance decision making under the Mental Capacity Act 2005: a tale of mixed messages. AB - Whilst most of the existing literature relating to advance decisions has focused on philosophical questions, this article reflects on the significant legal developments that have occurred since the introduction of the Mental Capacity Act 2005. The article provides a critique of the controversial issues which have emerged within contemporary case law. The focus of the discussion centres on capacity, the interpretation of the safeguards, and the bias towards preservation of life. PMID- 25016384 TI - Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis. AB - OBJECTIVES: In cystic fibrosis (CF) patients the paranasal sinuses can constitute a niche for bacteria, which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. The objective of this study was to investigate the systemic absorption of nasally administered tobramycin, colistin (administered as colistin sulfomethate sodium; CMS) and a combination of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. METHODS: Ten adult CF patients performed three different nasal irrigations: 300 mg of tobramycin; 160 mg of CMS; and 300 mg of tobramycin combined with 160 mg of CMS. Serum concentrations of tobramycin and colistin A and B (the main components of colistin) were analysed. Tolerability was measured using a visual analogue scale. Dutch Trial Register: NTR 4008. RESULTS: Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable. All three nasal irrigation solutions were well tolerated with a higher tolerability for CMS compared with tobramycin. CONCLUSIONS: Nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated. PMID- 25016385 TI - Fitness consequences of maternal and embryonic responses to environmental variation: using reptiles as models for studies of developmental plasticity. AB - Environmental factors strongly influence phenotypic variation within populations. The environment contributes to this variation in two ways: (1) by acting as a determinant of phenotypic variation (i.e., plastic responses) and (2) as an agent of selection that "chooses" among existing phenotypes. Understanding how these two environmental forces contribute to phenotypic variation is a major goal in the field of evolutionary biology and a primary objective of my research program. The objective of this article is to provide a framework to guide studies of environmental sources of phenotypic variation (specifically, developmental plasticity and maternal effects, and their adaptive significance). Two case studies from my research on reptiles are used to illustrate the general approaches I have taken to address these conceptual topics. Some key points for advancing our understanding of environmental influences on phenotypic variation include (1) merging laboratory-based research that identifies specific environmental effects with field studies to validate ecological relevance; (2) using controlled experimental approaches that mimic complex environments found in nature; (3) integrating data across biological fields (e.g., genetics, morphology, physiology, behavior, and ecology) under an evolutionary framework to provide novel insights into the underlying mechanisms that generate phenotypic variation; (4) assessing fitness consequences using measurements of survival and/or reproductive success across ontogeny (from embryos to adults) and under multiple ecologically-meaningful contexts; and (5) quantifying the strength and form of natural selection in multiple populations over multiple periods of time to understand the spatial and temporal consistency of phenotypic selection. Research programs that focus on organisms that are amenable to these approaches will provide the most promise for advancing our understanding of the environmental factors that generate the remarkable phenotypic diversity observed within populations. PMID- 25016386 TI - Chronic Broca's Aphasia Is Caused by Damage to Broca's and Wernicke's Areas. AB - Despite being perhaps the most studied form of aphasia, the critical lesion location for Broca's aphasia has long been debated, and in chronic patients, cortical damage often extends far beyond Broca's area. In a group of 70 patients, we examined brain damage associated with Broca's aphasia using voxel-wise lesion symptom mapping (VLSM). We found that damage to the posterior portion of Broca's area, the pars opercularis, is associated with Broca's aphasia. However, several individuals with other aphasic patterns had considerable damage to pars opercularis, suggesting that involvement of this region is not sufficient to cause Broca's aphasia. When examining only individuals with pars opercularis damage, we found that patients with Broca's aphasia had greater damage in the left superior temporal gyrus (STG; roughly Wernicke's area) than those with other aphasia types. Using discriminant function analysis and logistic regression, based on proportional damage to the pars opercularis and Wernicke's area, to predict whether individuals had Broca's or another types of aphasia, over 95% were classified correctly. Our findings suggest that persons with Broca's aphasia have damage to both Broca's and Wernicke's areas, a conclusion that is incongruent with classical neuropsychology, which has rarely considered the effects of damage to both areas. PMID- 25016387 TI - Colloid cyst of the third ventricle. PMID- 25016388 TI - Can emergency physicians 'rule in' and 'rule out' acute myocardial infarction with clinical judgement? AB - OBJECTIVE: To determine the diagnostic accuracy of emergency physician gestalt in emergency department (ED) patients with suspected cardiac chest pain, both alone and in combination with initial troponin level and ECG findings. METHODS: We prospectively included patients presenting to the ED with suspected cardiac chest pain. Clinicians recorded their 'gestalt' at the time of presentation using a five-point Likert scale, blinded to outcome. Troponin T and high-sensitivity troponin T (hs-cTnT; both Roche Diagnostics Elecsys) levels were measured in admission blood samples. All patients underwent troponin testing at least 12 h after peak symptoms. The primary outcome was acute myocardial infarction (AMI). RESULTS: 458 patients were included in this study, 81 (17.7%) of whom had AMI. Clinician gestalt alone had an area under the receiver operating characteristic curve of 0.76 (95% CI 0.70 to 0.82) for AMI. Immediately discharging patients with normal initial troponin and ECG in whom the clinician felt the diagnosis was 'probably not' or 'definitely not' acute coronary syndrome (ACS) would have avoided admission for 23.1% (95% CI 19% to 28%) patients with 100% sensitivity (95% CI 95.6% to 100%). With hs-cTnT, 100% sensitivity could have been achieved even if only patients with 'probable' or 'definite' ACS were investigated further, which would have allowed 41.7% patients to be discharged immediately. CONCLUSIONS: Gestalt alone cannot be used to 'rule in' or 'rule out' ACS. By combining clinician gestalt with the admission ECG and troponin level, we found 100% sensitivity without the need for serial troponin testing. These findings have the potential to reduce unnecessary hospital admissions for suspected ACS but must be prospectively validated before considering clinical implementation. PMID- 25016389 TI - Ultrasound-guided hematoma block in distal radial fracture reduction: a randomised clinical trial. AB - OBJECTIVE: We compared the efficacy and safety of ultrasound-guided haematoma block with that of procedural sedation and analgesia in patients with acute distal radial fracture reduction pain control. METHODS: This was a randomised clinical trial on adult patients conducted in two teaching hospitals. Patients received intravenous midazolam plus fentanyl in the procedural sedation and analgesia group, and fracture site injection of lidocaine 10% in the ultrasound guided haematoma block group. We measured pain scores before reduction, during reduction and 5, 10 and 15 min after reduction by a numeric rating scale, and patient and physician satisfaction by a four-level Likert scale. Time to discharge, early adverse effects and late complications were also compared. RESULTS: We enrolled 160 patients with distal radial fracture and randomised 143 patients into two groups (after excluding 17 patients). Pain was effectively controlled in both groups. Pain scores had no statistically significant difference before and during reduction and 5 and 15 min after reduction in the procedural sedation and analgesia and ultrasound guided haematoma block groups. Patient and physician overall satisfaction were similar in the two groups. Time to discharge was significantly lower in the ultrasound guided haematoma block group. Four patients (5.5%) in the procedural sedation and analgesia group showed early adverse effects. No patient in either group showed any late complications. CONCLUSIONS: Ultrasound guided haematoma block may be a safe and effective alternative to procedural sedation and analgesia. TRIAL REGISTRATION NUMBER: 201112308104N5. PMID- 25016390 TI - Deep sequencing of hepatitis C virus hypervariable region 1 reveals no correlation between genetic heterogeneity and antiviral treatment outcome. AB - BACKGROUND: Hypervariable region 1 (HVR1) contained within envelope protein 2 (E2) gene is the most variable part of HCV genome and its translation product is a major target for the host immune response. Variability within HVR1 may facilitate evasion of the immune response and could affect treatment outcome. The aim of the study was to analyze the impact of HVR1 heterogeneity employing sensitive ultra-deep sequencing, on the outcome of PEG-IFN-alpha (pegylated interferon alpha) and ribavirin treatment. METHODS: HVR1 sequences were amplified from pretreatment serum samples of 25 patients infected with genotype 1b HCV (12 responders and 13 non-responders) and were subjected to pyrosequencing (GS Junior, 454/Roche). Reads were corrected for sequencing error using ShoRAH software, while population reconstruction was done using three different minimal variant frequency cut-offs of 1%, 2% and 5%. Statistical analysis was done using Mann-Whitney and Fisher's exact tests. RESULTS: Complexity, Shannon entropy, nucleotide diversity per site, genetic distance and the number of genetic substitutions were not significantly different between responders and non responders, when analyzing viral populations at any of the three frequencies (>=1%, >=2% and >=5%). When clonal sample was used to determine pyrosequencing error, 4% of reads were found to be incorrect and the most abundant variant was present at a frequency of 1.48%. Use of ShoRAH reduced the sequencing error to 1%, with the most abundant erroneous variant present at frequency of 0.5%. CONCLUSIONS: While deep sequencing revealed complex genetic heterogeneity of HVR1 in chronic hepatitis C patients, there was no correlation between treatment outcome and any of the analyzed quasispecies parameters. PMID- 25016391 TI - An analysis of pre-service family planning teaching in clinical and nursing education in Tanzania. AB - BACKGROUND: Promoting family planning (FP) is a key strategy for health, economic and population growth. Sub-Saharan Africa, with one of the lowest contraceptive prevalence and highest fertility rates globally, contributes half of the global maternal deaths. Improving the quality of FP services, including enhancing pre service FP teaching, has the potential to improve contraceptive prevalence. In efforts to improve the quality of FP services in Tanzania, including provider skills, this study sought to identify gaps in pre-service FP teaching and suggest opportunities for strengthening the training. METHODS: Data were collected from all medical schools and a representative sample of pre-service nursing, Assistant Medical Officer (AMO), Clinical Officer (CO) and assistant CO schools in mainland Tanzania. Teachers responsible for FP teaching at the schools were interviewed using a semi-structured questionnaire. Observations on availability of teaching resources and other evidence of FP teaching and evaluation were documented. Relevant approved teaching documents were assessed for their suitability as competency-based FP teaching tools against predefined criteria. Quantitative data were analyzed using EPI Info 6 and qualitative data were manually analyzed using content analysis. RESULTS: A total of 35 pre-service schools were evaluated for FP teaching including 30 technical education and five degree offering schools. Of the assessed 11 pre-service curricula, only one met the criteria for suitability of FP teaching. FP teaching was typically theoretical with only 22.9% of all the schools having systems in place to produce graduates who could skillfully provide FP methods. Across schools, the target skills were the same level of competence and skewed toward short acting methods of contraception. Only 23.3% (n = 7) of schools had skills laboratories, 76% (n = 22) were either physically connected or linked to FP clinics. None of the degree providing schools practiced FP at its own teaching hospital. Teachers were concerned with poor practical exposure and lack of teaching material. CONCLUSIONS: Pre-service FP teaching in Tanzania is theoretical, poorly guided, and skewed toward short acting methods; a majority of the schools are unable to produce competent FP service providers. Pre-service FP training should be strengthened with more focus on practical skills. PMID- 25016392 TI - MIP-3beta/CCL19 is associated with the intrathecal invasion of mononuclear cells in neuroinflammatory and non-neuroinflammatory CNS diseases in dogs. AB - BACKGROUND: Chemokines such as MIP-3beta/CCL19 are important factors in the mechanism of cell migration and pathogenesis of central nervous system (CNS) inflammatory reactions. The hypothesis of this study is that CCL19, also known as MIP-3beta, is involved in the pathogenesis of inflammatory and non-inflammatory CNS diseases of dogs. Experiments were performed on cerebrospinal fluid (CSF) and serum samples of dogs affected with steroid responsive meningitis-arteritis (SRMA) during the acute phase as well as during treatment. Dogs with SRMA were compared to dogs with presumed meningoencephalomyelitis of unknown origin (MUO), and both groups sub-categorized into dogs receiving no therapy and with patients receiving prednisolone therapy. Idiopathic epilepsy (IE), a group with normal CSF cell count, was used as a control. Additionally, dogs with intervertebral disc disease (IVDD) of varying severity were analyzed. Chemokine concentrations were determined by enzyme linked immunosorbent assay. Migration assays were performed on seven selected CSF samples using a disposable 96-well chemotaxis chamber. RESULTS: CCL19 was detectable in CSF samples of all dogs. Dogs with untreated SRMA and MUO displayed pronounced CCL19 elevations compared to the control group and patients receiving glucocorticosteroid treatment. CSF cell counts of untreated SRMA and MUO patients were significantly positively correlated with the CCL19 CSF concentration. IVDD patients also had elevated CCL19 concentration compared to controls, but values were considerably lower than in inflammatory CNS diseases. Selected CSF samples displayed chemotactic activity for mononuclear cells in the migration assay. CONCLUSIONS: CCL19 CSF concentrations were markedly elevated in patients affected with the neuroinflammatory diseases SRMA and MUO and showed a strong correlation with the CSF cell count. This chemokine may play an important role in the pathogenesis of SRMA and MUO. The elevation of CSF CCL19 in IVDD suggests that it may also be involved in the secondary wave of spinal cord injuries. PMID- 25016393 TI - Management of sentinel node re-mapping in patients who have second or recurrent breast cancer and had previous axillary procedures. AB - BACKGROUND: In patients with recurrent or second primary ipsilateral breast cancer, axillary staging is the key factor in locoregional control and a strong prognostic characteristic. The efficient evaluation of lymphatic drainage of re sentinel lymph node biopsies (re-SLNBs) has remained a challenge in the management of ipsilateral primary or recurrent breast cancer patients who are clinically lymph node negative. This study explores whether a SLNB for patients with primary or recurrent breast cancer is possible after previous axillary surgery. It evaluates potential reasons for mapping failure that might be associated with patients in this group. METHODS: Between March 2006 and November 2013, 458 patients were subjected to a breast SLNB. A lymphoscintigraphy procedure was performed on 330 patients for sentinel lymph node (SLN) mapping on the day of surgery. Seven patients with either a second primary cancer in the same breast or recurrent breast cancer were described. Two of these seven patients had axillary lymph node dissection (ALND) during previous treatments and five had SLNB. A dual mapping method was used for all patients. Preoperative lymphoscintigraphy was performed four hours before surgery. RESULTS: SLNs were successfully remapped in six of seven (85.7%) patients, of whom five (71.43%) had previously undergone SLNB and two (28.57%) previous ALND. Localizations of SLNs were ipsilateral axillary in three patients, ipsilateral internal mammary in one patient, and contralateral axillary in two patients. An altered distribution of lymph nodes was discovered in both patients with previous ALND. In one of the two patients, metastases were found in an aberrant lymph drainage basin at the location of a non-ipsilateral axillary node (contralateral axillary SLN). The second previously ALND patient had an internal mammary SLN. In one patient, mapping was unsuccessful and the SLN was not identified. CONCLUSIONS: Altered lymphatic drainage incidence increases following breast-conserving surgery for an initial breast cancer, and the location of SLNs becomes unpredictable at the time of a second primary or recurrent ipsilateral breast cancer. This leads to the necessity of using a radionuclide (lymphoscintigraphy) for a successful re mapping procedure. A re-SLNB is precise and beneficial even though there are few patients. A lymphoscintigraphy can identify SLNs at their new unpredicted location. PMID- 25016394 TI - Selection criteria for radiofrequency ablation for colorectal liver metastases in the era of effective systemic therapy: a clinical score based proposal. AB - BACKGROUND: At present, there are no widely accepted criteria for the use of radiofrequency ablation (RFA) for the treatment of colorectal liver metastases (CLM) in the context of effective modern-agent therapies. We aimed to define selection criteria for patients with liver-limited CLM who may benefit from adding RFA to systemic therapy with respect to long-term disease control. METHODS: Between 2002 and 2007, 88 consecutive patients received RFA for liver only CLM during partial remission (PR), stable disease (SD), or progressive disease (PD) after systemic therapy. At a median follow-up of 8.2 years (range 5.2-11.1 years), clinical data were correlated to overall survival (OS) and recurrence-free survival (RFS). RESULTS: Poor OS and RFS correlated significantly with PD to systemic therapy before RFA (HR 5.46; p < 0.0001; and HR 6.46; p < 0.0001), number of >=4 CLM (HR 3.13; p = 0.0005; and HR 1.77; p = 0.0389), and carcinoembryonic antigen (CEA) level of >=100 ng/ml (HR 1.67; p = 0.032; and HR 1.67; p = 0.044). The presence of four criteria (PR, <=3 CLM, <=3 cm maximum size, and CEA <=100 ng/ml) selected a subgroup (n = 23) with significantly higher probabilities for OS and RFS at 5 years (39% and 22%,respectively) compared to those without any or up 3 of these criteria (0-27% and 0-9%, p < 0.001, respectively). CONCLUSIONS: A score based on four criteria (response to systemic therapy, <=3 CLM, <=3 cm size, low CEA value) may allow to select patients with liver-only CLM for whom additional use of RFA most likely adds benefit in an attempt to achieve long-term disease control. Almost one-fourth of patients fulfilling these four criteria may achieve 5-year survival without disease recurrence following effective systemic plus local RFA treatment. PMID- 25016396 TI - The role of aldosterone in the spectrum of cardiovascular and kidney disease risk: introduction. PMID- 25016395 TI - Intramuscular fat in ambulant young adults with bilateral spastic cerebral palsy. AB - BACKGROUND: It is known that individuals with bilateral spastic cerebral palsy (BSCP) have small and weak muscles. However, no studies to date have investigated intramuscular fat infiltration in this group. The objective of this study is to determine whether adults with BSCP have greater adiposity in and around their skeletal muscles than their typically developing (TD) peers as this may have significant functional and cardio-metabolic implications for this patient group. METHODS: 10 young adults with BSCP (7 male, mean age 22.5 years, Gross Motor Function Classification System (GMFCS) levels I-III), and 10 TD young adults (6 male, mean age 22.8 years) took part in this study. 11 cm sections of the left leg of all subjects were imaged using multi-echo gradient echo chemical shift imaging (mDixon). Percentage intermuscular fat (IMAT), intramuscular fat (IntraMF) and a subcutaneous fat to muscle volume ratio (SF/M) were calculated. RESULTS: IntraMF was higher with BSCP for all muscles (p = 0.001-0.013) and was significantly different between GMFCS levels (p < 0.001), with GMFCS level III having the highest IntraMF content. IMAT was also higher with BSCP p < 0.001). No significant difference was observed in SF/M between groups. CONCLUSION: Young adults with BSCP have increased intermuscular and intramuscular fat compared to their TD peers. The relationship between these findings and potential cardio metabolic and functional sequelae are yet to be investigated. PMID- 25016397 TI - The prevalence, incidence, prognosis, and associated conditions of resistant hypertension. AB - Resistant hypertension is a relevant condition gaining special attention given its clinical and economic impact. Although the true prevalence is unknown, clinical trials and population-based studies have shown that it is a common clinical problem that likely will increase in incidence with an aging and more obese population. A complex interaction of various risk factors including lifestyle, associated conditions, and identifiable secondary causes can lead to uncontrolled hypertension. Important factors including improper blood pressure measuring technique, poor medication adherence, and the white coat phenomenon can lead to pseudoresistance, or a false impression of treatment resistance, which must be excluded. Patients with true resistant hypertension have a greater risk for developing adverse cardiovascular events compared with those with controlled blood pressure, leading to an unfavorable prognosis without adequate treatment. This article reviews the current understanding of the epidemiology of resistant hypertension. PMID- 25016398 TI - The impact of sodium and potassium on hypertension risk. AB - The pathogenic role of sodium surfeit in primary hypertension is widely recognized but that of potassium deficiency usually has been ignored or at best assigned subsidiary status. Weighing the available evidence, we recently proposed that the chief environmental factor in the pathogenesis of primary hypertension and the associated cardiovascular risk is the interaction of the sodium surfeit and potassium deficiency in the body. Here, we present the major evidence highlighting the relationship between high-sodium intake and hypertension. We then examine the blood pressure-lowering effects of potassium in conjunction with the pernicious impact of potassium deficiency on hypertension and cardiovascular risk. We conclude with summarizing recent human trials that have probed the joint effects of sodium and potassium intake on hypertension and its cardiovascular sequelae. The latter studies lend considerable fresh support to the thesis that the interaction of the sodium surfeit and potassium deficiency in the body, rather than either disturbance by itself, is the critical environmental factor in the pathogenesis of hypertension. PMID- 25016399 TI - Role of aldosterone blockade in resistant hypertension. AB - Apparent treatment-resistant hypertension (aTRH), defined as uncontrolled blood pressure using 3 or more antihypertensive medications or controlled using 4 or more antihypertensive medications, affects approximately 30% of uncontrolled and 12% of controlled blood pressure (BP) patients. aTRH is used when pseudoresistance cannot be excluded (eg, BP measurement artifacts, mainly office resistance, suboptimal adherence, suboptimal treatment regimens, and true TRH). True TRH comprises approximately 30% to 50% of TRH. Patients with TRH have a high prevalence of obesity, insulin resistance, sleep apnea, and volume expansion. Aldosterone, a mineralocorticoid, is an important contributor to TRH, with primary aldosteronism present in approximately 20% of patients. Spironolactone, a mineralocorticoid-receptor antagonist, as a fourth-line agent, decreases BP 20 to 25/10 to 12 mm Hg in TRH patients with and without primary aldosteronism. The BP response to spironolactone is roughly double that of other classes of antihypertensive medications in TRH. Although approximately 70% of patients with uncontrolled TRH have estimated glomerular filtration rate of 50 or greater and a serum potassium level of 4.5 or less, which are associated with a low risk for hyperkalemia, only a small percentage receive a mineralocorticoid-receptor antagonist. This review examines the clinical epidemiology and pharmacotherapy of controlled and uncontrolled hypertension with an emphasis on aTRH, the role of aldosterone in blood pressure regulation, and the potential benefits of mineralocorticoid-receptor antagonist in uncontrolled TRH. PMID- 25016400 TI - Comparison of agents that affect aldosterone action. AB - The first aldosterone blocker, spironolactone, initially was used as a diuretic but was accompanied by a significant amount of side effects that necessitated the withdrawal of the drug in a relevant number of patients. The discovery of the many receptor-mediated actions of aldosterone in several different organs greatly contributed to expand the indications of aldosterone blockers. Eplerenone was the second component of this class of drugs and differed from spironolactone because of its significantly better safety, albeit this was accompanied by a lower potency when used at equinumeric doses. Although these two drugs were being used in clinical practice, the epithelial sodium channel blockers, amiloride and triamterene, with a similar antialdosterone action, continued to be used in clinical practice in combination with thiazides and loop diuretics. New members of the third and fourth generation of mineralocorticoid receptor antagonists and aldosterone synthase inhibitors are in development. These new compounds, which include the new nonsteroidal mineralocorticoid-receptor antagonists and aldosterone synthase inhibitors, try to maintain adequate efficacy, avoiding the drawbacks of spironolactone and eplerenone. Ongoing studies will show the certainty of the capacities of these new compounds to override the virtues of the first mineralocorticoid-receptor spironolactone while avoiding the side effects leading so frequently to the withdrawal of the drug, including a significantly lower prevalence of hyperkalemia when chronic kidney disease is present. PMID- 25016401 TI - Aldosterone blockade in chronic kidney disease. AB - Although blockade of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors or angiotensin-receptor blockers has become standard therapy for chronic kidney disease (CKD), renewed interest in the role of aldosterone in mediating the injuries and progressive insults of CKD has highlighted the potential role of treatments targeting the mineralocorticoid receptor (MR). Although salt restriction is an important component of mitigating the profibrotic effects of MR activation, a growing body of literature has shown that MR antagonists, spironolactone and eplerenone, can reduce proteinuria and blood pressure in patients at all stages of CKD. These agents carry a risk of hyperkalemia, but this risk likely can be predicted based on baseline renal function and mitigated using dietary modifications and adjustments of concomitant medications. Data on hard outcomes, such as progression to end-stage renal disease and overall mortality, still are lacking in patients with CKD. PMID- 25016402 TI - Aldosterone and volume management in hypertensive heart disease. AB - Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels. PMID- 25016403 TI - Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. AB - Hyperkalemia commonly limits optimizing treatment to slow stage 3 or higher chronic kidney disease (CKD) progression. The risk of hyperkalemia is linked to dietary potassium intake, level of kidney function, concomitant diseases that may affect potassium balance such as diabetes, and use of medications that influence potassium excretion. The risk predictors for developing hyperkalemia are an estimated glomerular filtration rate of less than 45 mL/min/1.73 m(2) and a serum potassium level greater than 4.5 mEq/L in the absence of blockers of the renin angiotensin-aldosterone system (RAAS). Generally, monotherapy with RAAS blockers does not increase risk substantially unless hypotension or volume depletion occur. Dual RAAS blockade involving any combination of an angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, renin inhibition, or aldosterone receptor blocker markedly increases the risk of hyperkalemia in patients with stage 3 or higher CKD. Moreover, dual RAAS blockade further reduces albuminuria by 25% to 30% compared with monotherapy, it has failed to show a benefit on CKD progression or cardiovascular outcome, and thus is not indicated in such patients because of its marked increase in hyperkalemia potential. Although sodium polystyrene resins exist to manage hyperkalemia in patients requiring therapy that increases serum potassium levels, they are not well tolerated. Newer, more predictable, better-tolerated polymers to bind potassium are on the horizon and may be approved within the next 1 to 2 years. PMID- 25016404 TI - Increased aldosterone: mechanism of hypertension in obesity. AB - The prevalence of both obesity and hypertension are increasing worldwide. Hypertension is a common consequence of obesity. Increased central adiposity is associated with increased aldosterone levels and blood pressure in human beings. A number of small studies have shown an association between obesity-mediated hypertension and mechanisms directly linked to increased levels of aldosterone. These studies have shown a trend toward relatively greater blood pressure reduction using aldosterone-receptor blockers compared with other classes of antihypertensive agents. Other than treatment for weight loss, treatment of hypertension with specific antihypertensive medications that block or reduce aldosterone action are appropriate in obese patients. Further research is needed to understand the exact role of the adipocyte in obesity-mediated hypertension. PMID- 25016405 TI - Transoral incisionless fundoplication for treatment of refractory GERD after peroral endoscopic myotomy. PMID- 25016406 TI - Endoscopic sleeve plication for revision of sleeve gastrectomy. PMID- 25016407 TI - Characterization of culture supernatant proteins from Brucella abortus and its protection effects against murine brucellosis. AB - In this study, we characterized the secreted proteins of Brucella abortus into the enriched media under the bacterial laboratory growth condition and investigated the pathogenic importance of culture supernatant (CS) proteins to B. abortus infection. CS proteins from stationary phase were concentrated and analyzed using 2D electrophoresis. In MALDI TOF/TOF analysis, more than 27 proteins including CuZn SOD, Dps, Tat, OMPs, Adh, LivF, Tuf, SucC, GroEL and DnaK were identified. Cytotoxic effects of CS proteins were found to increase in a dose-dependent manner in RAW 264.7 cells. Upon B. abortus challenge into phagocytes, however, CS proteins pre-treated cells exhibited lower bacterial uptake and intracellular replication compared to untreated cells. Immunization with CS proteins induced a strong humoral and cell mediated immune responses and exhibited significant higher degree of protection against virulence of B. abortus infection compared to mice immunized with Brucella broth protein (BBP). Taken together, these results indicate that B. abortus secreted a number of soluble immunogenic proteins under laboratory culture condition, which can promote antibody production resulted in enhancing host defense against to subsequently bacterial infection. Moreover, further analysis of CS proteins may help to understand the pathogenic mechanism of B. abortus infection and host-pathogen interaction. PMID- 25016410 TI - Role of leptin in the regulation of sterol/steroid biosynthesis in goose granulosa cells. AB - Leptin is critical for reproductive endocrinology. The aim of this study is to assess the expression patterns of leptin receptor (Lepr) during ovarian follicle development and to reveal the mechanism by which leptin affects steroid hormone secretion in goose granulosa cells. Transcripts of Lepr were ubiquitous in all tested tissues, with pituitary and adrenal glands being the predominant sites. Goose ovarian follicles were divided into several groups by diameter including prehierarchical (4 to 6, 6 to 8, and 8 to 10 mm) and hierarchical (F5-F1) follicles. Lepr gene expression was significantly higher in granulosa cells than in theca cells from follicles of 4 to 8 mm in diameter. Expression of Lepr in granulosa cells decreased gradually as follicles developed, with fluctuating expression in F5 and F3 follicles. Lepr mRNA in theca cells underwent a slight decrease from the 6- to 8-mm cohorts to F5 follicle and then exhibited a transient increase and declined later. In vitro experiments in cultured goose granulosa cells showed that estradiol release was significantly stimulated, whereas progesterone increased slightly and testosterone decreased dramatically after leptin treatment. In accordance with the data for steroids, expression of Lepr, Srebp1, Cyp51, StAR, and Cyp19a1 were induced by the addition of leptin, and the concomitant changes in Hmgcs1, Dhcr24, Cyp11a1, 17beta-hsd, Cyp17, and 3beta-hsd gene expression were seen. These results suggested that leptin is involved in the development of goose ovarian follicles, and leptin's effect on steroid hormone secretion could be due to altered sterol/steroidogenic gene expression via interaction with its receptor. PMID- 25016411 TI - Sperm motility parameters and spermatozoa morphometric characterization in marine species: a study of swimmer and sessile species. AB - The biodiversity of marine ecosystems is diverse and a high number of species coexist side by side. However, despite the fact that most of these species share a common fertilization strategy, a high variability in terms of the size, shape, and motion of spermatozoa can be found. In this study, we have analyzed both the sperm motion parameters and the spermatozoa morphometric features of two swimmer (pufferfish and European eel) and two sessile (sea urchin and ascidian) marine species. The most important differences in the sperm motion parameters were registered in the swimming period. Sessile species sperm displayed notably higher values than swimmer species sperm. In addition, the sperm motilities and velocities of the swimmer species decreased sharply once the sperm was activated, whereas the sessile species were able to maintain their initial values for a long time. These results are linked directly to the species-specific lifestyles. Although sessile organisms, which show limited or no movement, need sperm with a capacity to swim for long distances to find the oocytes, swimmer organisms can move toward the female and release gametes near it, and therefore the spermatozoa does not need to swim for such a long time. At the same time, sperm morphology is related to sperm motion parameters, and in this study an in-depth morphometric analysis of ascidian, sea urchin, and pufferfish spermatozoa, using computer assisted sperm analysis software, has been carried out for the first time. A huge variability in shapes, sizes, and structures of the studied species was found using electron microscopy. PMID- 25016413 TI - Reactive and regulative temperament in patients with compulsive buying and non clinical controls measured by self-report and performance-based tasks. AB - OBJECTIVE: To examine reactive and regulative temperament in patients with compulsive buying (CB) by means of self-report measures and performance-based tasks and to explore the relationship between both measurement approaches. METHOD: The study included 31 treatment-seeking patients with CB (25 women, 6 men) and an age and gender matched non-clinical control group without CB (CG). All participants answered the Compulsive Buying Scale (CBS). Reactive temperament was assessed using the Behavioral Inhibition System/Behavioral Activation System Scales (BIS/BAS) and the Iowa Gambling Task (IGT). Regulative temperament was measured using the Effortful Control subscale of the Adult Temperament Questionnaire (ATQ-EC) and a computerized version of the Stroop Task. To control the results for depression, the Patient Health Questionnaire-Depression Scale (PHQ-9) was administered. RESULTS: Crude group comparisons revealed higher BIS and BAS scores, poorer IGT performance and lower ATQ-EC scores in the CB-group compared to the CG. The groups did not differ in their performance on the Stroop task. After controlling for depressive symptoms that were significantly higher in the CB-group, only the group differences in BAS reactivity remained significant. No significant associations were found between questionnaires and performance based tasks. CONCLUSION: Overall, the findings indicate that CB in the present clinical sample of treatment-seeking patients was mainly associated with higher approach tendencies and more depressive symptoms. The lacking correlation between self-reports and performance-based tasks is in line with prior research and suggests that both methodologies tap into different aspects of temperament. PMID- 25016412 TI - Coral-zooxanthellae meta-transcriptomics reveals integrated response to pollutant stress. AB - BACKGROUND: Corals represent symbiotic meta-organisms that require harmonization among the coral animal, photosynthetic zooxanthellae and associated microbes to survive environmental stresses. We investigated integrated-responses among coral and zooxanthellae in the scleractinian coral Acropora formosa in response to an emerging marine pollutant, the munitions constituent, 1,3,5-trinitro-1,3,5 triazine (RDX; 5 day exposures to 0 (control), 0.5, 0.9, 1.8, 3.7, and 7.2 mg/L, measured in seawater). RESULTS: RDX accumulated readily in coral soft tissues with bioconcentration factors ranging from 1.1 to 1.5. Next-generation sequencing of a normalized meta-transcriptomic library developed for the eukaryotic components of the A. formosa coral holobiont was leveraged to conduct microarray based global transcript expression analysis of integrated coral/zooxanthellae responses to the RDX exposure. Total differentially expressed transcripts (DET) increased with increasing RDX exposure concentrations as did the proportion of zooxanthellae DET relative to the coral animal. Transcriptional responses in the coral demonstrated higher sensitivity to RDX compared to zooxanthellae where increased expression of gene transcripts coding xenobiotic detoxification mechanisms (i.e. cytochrome P450 and UDP glucuronosyltransferase 2 family) were initiated at the lowest exposure concentration. Increased expression of these detoxification mechanisms was sustained at higher RDX concentrations as well as production of a physical barrier to exposure through a 40% increase in mucocyte density at the maximum RDX exposure. At and above the 1.8 mg/L exposure concentration, DET coding for genes involved in central energy metabolism, including photosynthesis, glycolysis and electron-transport functions, were decreased in zooxanthellae although preliminary data indicated that zooxanthellae densities were not affected. In contrast, significantly increased transcript expression for genes involved in cellular energy production including glycolysis and electron-transport pathways was observed in the coral animal. CONCLUSIONS: Transcriptional network analysis for central energy metabolism demonstrated highly correlated responses to RDX among the coral animal and zooxanthellae indicative of potential compensatory responses to lost photosynthetic potential within the holobiont. These observations underscore the potential for complex integrated responses to RDX exposure among species comprising the coral holobiont and highlight the need to understand holobiont-species interactions to accurately assess pollutant impacts. PMID- 25016414 TI - Atherogenic dyslipidemia: prevalence and management in lipid clinics. AB - BACKGROUND AND OBJECTIVE: Atherogenic dyslipidemia, which is characterized by increased triglyceride levels and reduced HDL cholesterol levels, is underestimated and undertreated in clinical practice. We assessed its prevalence and the achievement of therapeutic objectives for HDL cholesterol and triglyceride levels in patients treated at lipid and vascular risk units in Spain. PATIENTS AND METHOD: This was an observational, longitudinal, retrospective, multicenter study performed in 14 autonomous Spanish communities that consecutively included 1828 patients aged >=18 years who were referred for dyslipidemia and vascular risk to 43 lipid clinics accredited by the Spanish Society of Arteriosclerosis. We collected information from the medical records corresponding to 2 visits conducted during 2010 and 2011-12, respectively. RESULTS: Of the 1649 patients who had a lipid profile in the first visit (90.2%), 295 (17.9%) had atherogenic dyslipidemia. The factors associated with atherogenic dyslipidemia were excess weight/obesity, not taking hypolipidemic drugs (statins and/or fibrates), diabetes, myocardial infarction and previous heart failure. Of the 273 (92.5%) patients with atherogenic dyslipidemia that had a lipid profile in the last visit, 44 (16.1%) achieved the therapeutic objectives for HDL cholesterol and triglyceride levels. The predictors of therapeutic success were normal weight and normoglycemia. CONCLUSION: One of every 6 patients treated in lipid and vascular risk units had atherogenic dyslipidemia. The degree to which the therapeutic goals for HDL cholesterol and triglyceride levels were achieved in these patients was very low. PMID- 25016415 TI - Glycemic control in patients with type 2 diabetes mellitus in Spain. AB - OBJECTIVE: To evaluate the degree of glycemic control in patients with type 2 diabetes in Spain and identify factors associated with glycemic control. PATIENTS AND METHODS: This was a cross-sectional, multicenter, epidemiological study that used consecutive sampling and was conducted in primary care practices in Spain. A total of 5591 patients with type 2 diabetes mellitus lasting more than 1 year and who were treated with hypoglycemic agents for more than 3 months were included in the study. At a single visit, HbA1c levels were measured (A1cNow+ system) and demographic and clinical variables related to diabetes and its treatment were recorded. During the visit, CV risk factors (CVRF), the presence of target-organ damage (TOD), the presence of hypoglycemia and body weight changes within the previous year were recorded. RESULTS: We analyzed data from 5382 patients (mean age 66.7 [10.8] years, mean duration of the diabetes 8.8 [6.3] years). TOD was present in 43.6% of the patients and 59.1% were taking 2 or more drugs. The patients' mean HbA1c was 7.1 (1.1)%, and 48.6% had HbA1c levels <7.0%. The patients with HbA1c levels >=7.0% had longer-standing diabetes, a higher prevalence of TOD and CVRF, used more complex therapies, experienced more hypoglycemic episodes in the previous year and had more weight gain. In the multivariate analysis, the absence of insulin treatment, the absence of abdominal obesity and atherogenic dyslipidemia, a duration of the diabetes <10 years and an age >70 years were associated with improved glycemic control. CONCLUSIONS: Patients with poorly controlled type 2 diabetes mellitus are highly prevalent in Spain. Factors associated with poorer glycemic control include the complexity of both the disease and the hypoglycemic therapy, a history of hypoglycemia and weight gain. PMID- 25016417 TI - Comments on "Monitoring of impact of anthropogenic inputs on water quality of mangrove ecosystem of Uran, Navi Mumbai, west coast of India" published in Marine Pollution Bulletin (2013), 75: 291-300 by Prabhakar R. Pawar. PMID- 25016416 TI - Modelling exposure of oceanic higher trophic-level consumers to polychlorinated biphenyls: pollution 'hotspots' in relation to mass mortality events of marine mammals. AB - Marine mammals in the past mass mortality events may have been susceptible to infection because their immune systems were suppressed through the bioaccumulation of environmental pollutants such as polychlorinated biphenyls (PCBs). We compiled mortality event data sets of 33 marine mammal species, and employed a Finely-Advanced Transboundary Environmental model (FATE) to model the exposure of the global fish community to PCB congeners, in order to define critical exposure levels (CELs) of PCBs above which mass mortality events are likely to occur. Our modelling approach enabled us to describe the mass mortality events in the context of exposure of higher-trophic consumers to PCBs and to identify marine pollution 'hotspots' such as the Mediterranean Sea and north western European coasts. We demonstrated that the CELs can be applied to quantify a chemical pollution Planetary Boundary, under which a safe operating space for marine mammals and humanity can exist. PMID- 25016418 TI - Bioconcentration of the anionic surfactant linear alkylbenzene sulfonate (LAS) in the marine shrimp Palaemonetes varians: a radiotracer study. AB - Uptake and depuration kinetics of dissolved [(14)C]C12-6-linear alkylbenzene sulfonate (LAS) were determined in the shrimp Palaemonetes varians using environmentally relevant exposure concentration. The shrimp concentrated LAS from seawater with a mean BCF value of 120 L kg(-1) after a 7-day exposure. Uptake biokinetics were best described by a saturation model, with an estimated BCFss, of 159 +/- 34 L kg(-1), reached after 11.5 days. Shrimp weight influenced significantly BCF value with smaller individuals presenting higher affinity to LAS. To the light of a whole body autoradiography, major accumulation of LAS occurred in the cephalothorax circulatory system (gills, heart, hepatopancreas) and ocular peduncle, but not in the flesh, limiting potential transfer to human consumers. LAS depuration rate constant value of the shrimp was 1.18 +/- 0.08 d( 1) leading to less than 1% of remaining LAS in its tissues after 8 days of depuration. PMID- 25016419 TI - Anthropogenic lead concentrations and sources in Baltic Sea sediments based on lead isotopic composition. AB - The Gulf of Gdansk is influenced by heavy metals of anthropogenic origin. In this study, temporal concentration changes of Pb, Zn, Cd, and Cu were studied in six, 50 cm long sediment cores. The main aim of the study was to concentrate on the history of Pb fluxes and Pb isotopic composition ((206)Pb/(207)Pb and (208)Pb/(206)Pb) to trace Pb sources. The lowest Pb concentrations (19 MUg g(-1)) were measured in sediments deposited circa 1860, while the highest Pb concentrations (63-147 MUg g(-1)) were measured in sediments deposited between 1960s and 70s. Pre-industrial Pb fluxes were 7 Pb m(2)year(-1), while after WWII they reached 199 Pb m(2)year(-1). Highest (206)Pb/(207)Pb ratios (~1.22) were measured in the oldest sediment layers, and the lowest (206)Pb/(207)Pb ratios (~1.165) were measured in the sediments deposited in 1970s-90s. During the period of highest Pb contamination, the anthropogenic Pb fraction reached up to 93%. A general discussion of the Pb sources, emissions, and loads for Poland is included. PMID- 25016420 TI - An investigation into the lower peer liking of anxious than nonanxious children. AB - Peer dislike of anxious behaviour was investigated in 7-12 year olds. Child actors delivered an identical verbal presentation: once in an anxious manner and once confidently. The videos were rated for liking and seven potential mediators by three groups of children: 32 anxiety-disordered peers with social phobia; 16 anxiety-disordered peers without social phobia; and 48 nonclinical peers. A mediation model with moderation effects was tested within a within-subjects framework. "Anxious" actors were liked significantly less than "confident" actors. This effect differed by group rater, in that relative dislike of the anxious actor was significantly greater for the nonclinical than socially phobic raters. Physical attractiveness and friend acceptance mediated the effect for all group raters. Other identified mediators differed depending upon the group rater. The findings direct future efforts to help anxiety-disordered children circumvent an increased risk of negative peer relations, and testify to consideration of the rater in sociometric studies. PMID- 25016423 TI - Necrotizing and eosinophilic masticatory myositis in farmed mink: a preliminary description. AB - This report describes necrotizing and eosinophilic myositis affecting the masticatory muscles of a group of mink. Affected animals demonstrated sudden death with marked subcutaneous oedema over the dorsal head. The temporalis and masseter muscles were pale, swollen and friable. Histologic changes consisted of varying degrees of myodegeneration, myonecrosis and inflammation. Eosinophils were prominent in the inflammatory infiltrate. Similar to dogs, masticatory muscles in mink were found to contain unique type 2M fibres, suggesting a possible target for an immune response. Aerobic and anaerobic tissue cultures of the affected musculature revealed no significant pathogens. Histological and nutritional analyses were not typical of vitamin E/selenium deficiency. This case series supports the existence of a novel disease entity in mink with some features comparable with masticatory muscle myositis in dogs. PMID- 25016424 TI - Adapalene loaded solid lipid nanoparticles gel: an effective approach for acne treatment. AB - Salient features such as controlled release, target ability, potential of penetration, improved physical stability, low cost compared to phospholipids, and ease of scaling-up makes solid lipid nanoparticles (SLNs) a viable alternative to liposomes for effective drug delivery. Adapalene (ADA) is a second generation retinoid effective in treating various dermatologic disorders such as Acne vulgaris with a few noticeable dose-mediated side effects. The present study was aimed at developing and characterizing ADA loaded SLNs for effective topical delivery. The formulated SLN system was characterized for particle size, poly dispersity index, entrapment efficiency and drug release properties. The resultant formulation (ADA loaded SLNs incorporated into carbopol hydrogel) was evaluated for in vitro drug release, skin permeation and bio-distribution, rheological behaviour, and texture profile analysis. The SLNs based ADA gel has shown its potential in targeting skin epidermal layer, and reducing systemic penetration. The developed system can avoid systemic uptake of ADA in skin layers, and can localize drug in skin epidermis as confirmed by rat skin model. Our results advocate potential of SLNs as a novel carrier for topical delivery of ADA in topical therapeutic approaches. This study open new avenues for drug delivery which better meets the need of anti-acne research. PMID- 25016425 TI - Design of sterile mucoadhesive hydrogels for use in drug delivery: effect of radiation on network structure. AB - Radiation induced graft copolymerization is pure, sterile and additive free method for the synthesis of hydrogels for biomedical applications. In the present work, attempt has been made to prepare the biocompatible, mucoadhesive hydrogels based on natural polysaccharide sterculia gum and polyvinylpyrrolidone (PVP) for use as drug delivery devices. The effect of gamma radiation on swelling and various network parameters of hydrogels such as the polymer volume fraction in the swollen state (phi), molecular weight of the polymer chain between two neighboring cross links (M-c), crosslink density (rho), and mesh size (xi) have been studied. Hydrogels have been characterized with scanning electron micrographs (SEMs), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction study (XRD), thermo gravimetric analysis (TGA) and swelling studies. Swelling and mesh size decreased while gel strength and crosslink density increased with increase in radiation dose. The swelling of hydrogels and release of drug ciprofloxacin from drug loaded hydrogels occurred through non-Fickian diffusion mechanism. These hydrogels have been observed to have non-thrombogenic, haemo-compatible and mucoadhesive nature and could be used as mucoadhesive drug delivery system to deliver drug to gastro intestinal tract (GIT) in controlled manner. PMID- 25016426 TI - Atomic layer deposition enhanced grafting of phosphorylcholine on stainless steel for intravascular stents. AB - In-stent restenosis (ISR) and re-endothelialization delay are two major issues of intravascular stent in terms of clinical safety and effects. Construction of mimetic cell membrane surface on stents using phosphorylcholine have been regarded as one of the most powerful strategies to resolve these two issues and improve the performance of stents. In this study, atomic layer deposition (ALD) technology, which is widely used in semiconductor industry, was utilized to fabricate ultra-thin layer (10nm) of alumina (Al2O3) on 316L stainless steel (SS), then the alumina covered surface was modified with 3 aminopropyltriethoxysilane (APS) and 2-methacryloyloxyethyl phosphorylcholine (MPC) sequentially in order to produce phosphorylcholine mimetic cell membrane surface. The pristine and modified surfaces were characterized using X-ray photoelectron spectroscopy, atomic force microscope and water contact angle measurement. Furthermore, the abilities of protein adsorption, platelet adhesion and cell proliferation on the surfaces were investigated. It was found that alumina layer can significantly enhance the surface grafting of APS and MPC on SS; and in turn efficiently inhibit protein adsorption and platelet adhesion, and promote the attachment and proliferation of human umbilical vein endothelial cells (HUVEC) on the surfaces. In association with the fact that the deposition of alumina layer is also beneficial to the improvement of adhesion and integrity of drug-carrying polymer coating on drug eluting stents, we expect that ALD technology can largely assist in the modifications on inert metallic surfaces and benefit implantable medical devices, especially intravascular stents. PMID- 25016427 TI - Decomposition reaction of the veterinary antibiotic ciprofloxacin using electron ionizing energy. AB - The application of electron ionizing energy for degrading veterinary antibiotic ciprofloxacin (CFX) in aqueous solution was elucidated. The degradation efficiency of CFX after irradiation with electron ionizing energy was 38% at 1 kGy, 80% at 5kGy, and 97% at 10 kGy. Total organic carbon of CFX in aqueous solution after irradiation with electron ionizing energy decreased 2% at 1 kGy, 18% at 5 kGy, and 53% at 10 kGy. The CFX degradation products after irradiation with electron ionizing energy were CFX1 ([M+H] m/z 330), CFX2 ([M+H] m/z 314), and CFX3 ([M+H] m/z 263). CFX1 had an F atom substituted with OH and CFX2 was expected to originate from CFX via loss of F or H2O. CFX3 was expected to originate from CFX via loss of the piperazynilic ring. Among the several radicals, hydrate electron (eaq(-)) is expected to play an important role in degradation of veterinary antibiotic during irradiation with electron ionizing energy. The toxicity of the degraded products formed during irradiation with electron ionizing energy was evaluated using microbes such as Escherichia coli, Pseudomonas putida, and Bacillus subtilis, and the results revealed that the toxicity decreased with irradiation. These results demonstrate that irradiation technology using electron ionizing energy is an effective was to remove veterinary antibiotics from an aquatic ecosystem. PMID- 25016428 TI - Changes in the physiology and gene expression of Microcystis aeruginosa under EGCG stress. AB - EGCG (Epigallocatechin-3-gallate) has an allelopathic inhibitory effect on Microcystis aeruginosa. Cellular structure, physiological and biochemical reactions and gene expression were examined to explore the mechanism of inhibition. As was shown in electron microscopy, the structure of the cell wall, cell membrane and thylakoid was disrupted by EGCG. EGCG also reduced the efficiency of photosynthesis and the electron transfer rate in M. aeruginosa cells, as was determined with a flow cytometer. Quantitative real-time PCR analysis demonstrated that gene expression of the core proteins of the photosynthesis centers PSI and PSII and ATP synthase were reduced, while the expression of the phycobilisome degradation protein A gene (nbl A) was elevated. The expression of the universal stress protein gene increased, which would enhance the adaptive capacity of Microcystis cells to polyphenols and oxidative stress. Furthermore, EGCG elevated the level of reactive oxygen species (ROS) in M. aeruginosa cells, and thus caused oxidative cellular damage. When treated with EGCG at low concentrations (10 and 40 mg L(-)(1)), the cells were able to activate defense systems to degrade the excess ROS. But at a concentration of 70 mg L(-)(1), oxidative stress exceeded tolerance limits, and the cells were severely damaged. We concluded that damage to photosynthesis and oxidative stress were the primary mechanisms for the allelopathic effect of EGCG on M. aeruginosa. PMID- 25016430 TI - Caregiving. PMID- 25016429 TI - Influence of naturally occurring dissolved organic matter, colloids, and cations on nanofiltration of pharmaceutically active and endocrine disrupting compounds. AB - This study examined the rejection of selected pharmaceutically active (PhAC) and endocrine disrupting compounds (EDCs) when using nanofiltration as a function of naturally occurring dissolved organic matter (DOM), colloidal particles, cations and their interactions. Lake Ontario water served as a source of natural DOM and colloidal particles. PhAC/EDC rejection experiments were conducted using raw Lake Ontario water and Lake Ontario water that was pre-treated with either ultrafiltration to remove colloidal particles, or fluidized ion exchange resins to remove DOM. Additionally, the concentration of cations (Ca(2+), Mg(2+), and Na(+)) in the raw and pre-treated water matrices was varied. While ionic PhACs and EDCs exhibited high rejections from all the water matrices examined, neutral compounds were most effectively rejected in water containing DOM and no colloids, and least effectively rejected from colloid-containing water with increased cations but no DOM. The presence of DOM significantly improved compound rejection and the increase in cation concentration significantly decreased rejection. The presence of colloids had comparatively little effect except to mitigate the impact of increased cation concentration, apparently providing some cation buffering capacity. The sequence in which constituents are removed from waters during treatment may significantly impact PhAC and EDC removal, especially of neutral compounds. PMID- 25016431 TI - A phosphorescent iridium(III) solvent complex for multiplex assays of cell death. AB - Cell death involves loss of transport function and physical integrity of the plasma membrane, and plays a critical role in many human diseases. At present, the development of an effective visualization tool to monitor cell death remains a significant challenge. Here, a cyclometalated iridium(III) solvent complex [Ir(pdz)2(H2O)2](+)[OTf](-) (IrC1) was designed and synthesized as a phosphorescent indicator of cell death. IrC1 specifically stained the nuclei of dead cells over living cells rapidly (<10 min) and at low concentrations (10 MUM), as observed using confocal luminescence microscopy. Moreover, the IrC1 uptake behavior leads to its further application in quantifying the population of early apoptotic cells using flow cytometry. In particular, successful application in time-gated fluorescence microscopy by virtue of its microsecond lifetime rendered IrC1 attractive as a luminescent probe. IrC1 additionally exhibited excellent long-term photostability, in contrast to traditional dyes. We conclude that in combination with luminescent microscopy and flow cytometry, IrC1 provides an effective, straightforward alternative to cell death assays. PMID- 25016432 TI - Exploiting endogenous anti-inflammatory pathways as a therapeutic approach to multiorgan inflammatory disease. AB - This Commentary highlights the article by Montero-Melendez et al, revealing novel protective properties of endogenous melanocortin receptor 3 on periodontal status in health and disease and suggesting a new genus of anti-arthritic bone-sparing therapeutics. PMID- 25016433 TI - History of the pineal region tumor. AB - The pineal gland has interested humans from millenniums. In this paper we review back in the history and the evolution of the pineal gland surgery. Originally, this surgery used to carry a high rate of morbidity and mortality. Nowadays the development of the anesthetic, radiological, surgical and intensive care techniques have been responsible of an improvement of the surgical results and better quality of life. It is always interesting to know from where we come. PMID- 25016435 TI - Evaluation of language and communication skills in adult key word signing users with intellectual disability: advantages of a narrative task. AB - The evaluation of language and communication skills in adults who use augmentative and alternative communication (AAC) in general and key word signing (KWS) in particular, can be an elaborate task. Besides being time-consuming and not very similar to natural communication, standard language tests often do not take AAC or KWS into account. Therefore, we developed a narrative task specifically for adults with intellectual disability (ID) who use KWS. The task was evaluated in a group of 40 adult KWS users. Outcome measures on the narrative task correlated significantly with measures of standard language and communication tests for verbal language, but not for use of manual signs. All narrative measures, for both verbal language and manual signing, correlated highly with similar measures from a conversation sample. The developed narrative task proved useful and valid to evaluate the language and communication skills of adults with ID taking into account both their verbal language and manual sign use. PMID- 25016436 TI - [Eponyms in musculoskeletal radiology: stories of bones, persons, and civilizations]. AB - Eponyms reflect the history of medicine, of disease, and of physicians, but eponyms also reflect the history of the societies in which these physicians lived. Both loved and hated, eponyms are at the center of an interminable debate about whether they should continue to be used or whether they should disappear, and this debate has become more intense since some scientific societies have purged their terminologies of eponyms related to Nazism. Eponyms abound in conventional musculoskeletal radiology. In this article, rather than attempt an exhaustive review of all these eponyms, we take a few representative examples to illustrate the contributions of eponyms to medicine and the history of medicine. PMID- 25016437 TI - Chromatin: a capacitor of acetate for integrated regulation of gene expression and cell physiology. AB - Cancer tissues with lower global levels of histone acetylation display significantly increased rate of tumor recurrence or cancer-related mortality. The function global regulation of histone acetylation serves for the cell or how lower levels of histone acetylation may contribute to a more aggressive cancer phenotype has been unclear. Chromatin and histone modifications are currently thought to regulate only DNA-based processes. However, recent findings have revealed a novel function for global histone acetylation in direct regulation of cellular physiology. I will discuss how chromatin, by regulating the cellular flux of acetate, may integrate control of cellular physiologic state with gene expression and help explain the observations in cancer tissues. PMID- 25016438 TI - Single cell sequencing approaches for complex biological systems. AB - Biological phenotype is the output of complex interactions between heterogeneous cells within a specified niche. These interactions are tightly governed and regulated by the genetic, epigenetic, and transcriptional states of single cells, with deregulation of these states resulting in disease. As such, genome wide single cell investigations are bound to enhance our knowledge of the underlying principles that govern biological systems. Recent technological advances have enabled such investigations in the form of single-cell sequencing. Here, we review the most recent developments in genome wide profiling of single cells, discuss some of the novel biological observations gleaned by such investigations, and touch upon the promise of single cell sequencing in unraveling biological systems. PMID- 25016439 TI - Paraspinous muscle as a predictor of surgical outcome. AB - BACKGROUND: Objective measures for preoperative risk assessment are needed to inform surgical risk stratification. Previous studies using preoperative imaging have shown that the psoas muscle is a significant predictor of postoperative outcomes. Because psoas measurements are not always available, additional trunk muscles should be identified as alternative measures of risk assessment. Our research assessed the relationship between paraspinous muscle area, psoas muscle area, and surgical outcomes. METHODS: Using the Michigan Surgical Quality Collaborative database, we retrospectively identified 1309 surgical patients who had preoperative abdominal computerized tomography scans within 90 d of operation. Analytic morphomic techniques were used to measure the cross-sectional area of the paraspinous muscle at the T12 vertebral level. The primary outcome was 1-y mortality. Analyses were stratified by sex, and logistic regression was used to assess the relationship between muscle area and postoperative outcome. RESULTS: The measurements of paraspinous muscle area at T12 were normally distributed. There was a strong correlation between paraspinous muscle area at T12 and total psoas area at L4 (r = 0.72, P <0.001). Paraspinous area was significantly associated with 1-y mortality in both females (odds ratio = 0.70 per standard deviation increase in paraspinous area, 95% confidence interval 0.50 0.99, P = 0.046) and males (odds ratio = 0.64, 95% confidence interval 0.47-0.88, P = 0.006). CONCLUSIONS: Paraspinous muscle area correlates with psoas muscle area, and larger paraspinous muscle area is associated with lower mortality rates after surgery. This suggests that the paraspinous muscle may be an alternative to the psoas muscle in the context of objective measures of risk stratification. PMID- 25016440 TI - Plasma levels of high mobility group box 1 increase in patients with posttraumatic stress disorder after severe blunt chest trauma: a prospective cohort study. AB - BACKGROUND: High-mobility group box 1 (HMGB1), a key late mediator of systemic inflammation, is a potentially useful biomarker for predicting outcome in patients with severe blunt chest trauma. The purpose of this study was to define the relationship between plasma levels of HMGB1 and posttraumatic stress disorder (PTSD) in patients with severe blunt chest trauma. METHODS: All patients with severe blunt chest trauma (abbreviated injury score >=3) who were admitted to traumatic surgery department and ultimately survived to follow-up at 6 mo were eligible for the study. HMGB1 was sampled every other day from day 1-day 7 after admission, and plasma concentrations of HMGB1 were measured by a quantitative enzyme-linked immunosorbent assay test. Multivariate regression analysis was used to define the independent contribution of possible risk factors selected by univariate analysis. RESULTS: PTSD was identified in 43 patients including acute PTSD (n = 21), chronic PTSD (n = 18), and delayed-onset PTSD (n = 4) after 6-mo follow-up, in whom significant higher plasma levels of HMGB1 on days three, five, and seven after blunt chest trauma were noted compared with those seen in patients without PTSD (n = 10). Multivariate logistic analysis showed that transfusion, injury severity score, and HMGB1 levels at day 7 were the valuable risk factors for PTSD. CONCLUSIONS: In blunt chest trauma, plasma HMGB1 levels were significantly higher in patients with PTSD compared with patients with non PTSD. Our data indicate that patients with high plasma levels of HMGB1 may be more prone to develop PTSD including acute and chronic PTSD. PMID- 25016441 TI - Hydrophobically-modified chitosan foam: description and hemostatic efficacy. AB - BACKGROUND: Trauma represents a significant public health burden, and hemorrhage alone is responsible for 40% of deaths within the first 24 h after injury. Noncompressible hemorrhage accounts for the majority of hemorrhage-related deaths. Thus, materials which can arrest bleeding rapidly are necessary for improved clinical outcomes. This preliminary study evaluated several self expanding hydrophobically modified chitosan (HM-CS) foams to determine their efficacy on a noncompressible severe liver injury under resuscitation. METHODS: Six HM-CS foam formulations (HM-CS1, HM-CS2, HM-CS3, HM-CS4, HM-CS5, and HM-CS6) of different graft types and densities were synthesized, characterized, and packaged into spray canisters using dimethyl ether as the propellant. Expansion profiles of the foams were evaluated in bench testing. Foams were then evaluated in vitro, interaction with blood cells was determined via microscopy, and cytotoxicity was assessed via live-dead cell assay on MCF7 breast cancer cells. For in vivo evaluation, rats underwent a 14 +/- 3% hepatectomy. The animals were treated with either: (1) an HM-CS foam formulation, (2) CS foam, and (3) no treatment (NT). All animals were resuscitated with lactated Ringer solution. Survival, total blood loss, mean arterial pressures (MAP), and resuscitation volume were recorded for 60 min. RESULTS: Microscopy showed blood cells immobilizing into colonies within tight groups of adjacent foam bubbles. HM-CS foam did not display any toxic effects in vitro on MCF7 cells over a 72 h period studied. Application of HM-CS foam after hepatectomy decreased total blood loss (29.3 +/- 7.8 mL/kg in HM-CS5 group versus 90.9 +/- 20.3 mL/kg in the control group; P <0.001) and improved survival from 0% in controls to 100% in the HM-CS5 group (P <0.001). CONCLUSIONS: In this model of severe liver injury, spraying HM CS foams directly on the injured liver surface decreased blood loss and increased survival. HM-CS formulations with the highest levels of hydrophobic modification (HM-CS4 and HM-CS5) resulted in the lowest total blood loss and highest survival rates. This pilot study suggests HM-CS foam may be useful as a hemostatic adjunct or solitary hemostatic intervention. PMID- 25016442 TI - Anti-inflammation effects of naloxone involve phosphoinositide 3-kinase delta and gamma. AB - BACKGROUND: Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110delta and p110gamma isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kdelta and PI3Kgamma in mediating the anti-inflammation effects of naloxone. MATERIALS AND METHODS: Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kdelta inhibitor IC87114, the PI3Kgamma inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-kappaB (NF kappaB) activation and Akt activation (indicator of PI3K activity) among these groups were compared. RESULTS: The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-alpha, interleukin 1beta, and cyclooxygenase-2/prostaglandin E2) and the levels of NF-kappaB activation (p-NF-kappaB p65 and p-inhibitor-kappaB concentrations and NF-kappaB DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kdelta and PI3Kgamma, as the concentrations of inflammatory molecules and the levels of NF-kappaB activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). CONCLUSIONS: PI3Kdelta and PI3Kgamma play crucial roles in mediating the anti inflammation effects of naloxone. PMID- 25016443 TI - [Editor's commentary. The current state of obstetrics and gynecology in Hungary]. PMID- 25016444 TI - [Pediatric gynecological operations based on 40 years' experience]. AB - The author analyzes more than 40 years of his own experience concerning the outcome of pediatric gynecology patients who underwent surgery in the Department of Gynecology and Obstetrics, Debrecen University in Hungary. Traditional surgical interventions were performed, and, some new methods elaborated by the author. The age of patients who underwent surgery ranged from infancy to 18 years. The objective of this publication is to describe general principles to support the work of those who are currently active in this area or have chosen the area for their future activity. Types of surgical interventions, conditions of proper management and insitutional background, together with requirements of qualified personnel and diagnostic performance are analyzed. Possible sources of errors and their prevention are pointed out. Different procedures are discussed in separate groups. The author's own procedure modifications based on the original procedure elaborated by Vecchietti for treatment of vaginal aplasia are described. Concluding from results of more than 60 successful modified Vecchietti procedures the author recommends his own procedure. PMID- 25016445 TI - [Changing trends and indications for cesarean section in the last few decades]. AB - Cesarean section rates are increasing worldwide, which has been paralelled by an increase in primary cesarean delivery and decrease in vaginal birth after cesarean section. Behind the different frequencies there is a number of interrelated factors including advanced maternal age, increasing incidence of obesity, assisted reproductive technologies, and maternal request for non-medical reasons. The sub-optimal management of labor and the concerns about medical liability claims and litigations increase the number of abdominal deliveries. The author reviews the changing indications for cesarean deliveries in the last few decades and summarizes the effects on the obstetrical clinical practice. PMID- 25016446 TI - [Obstetrical aspects of perioperative medicine]. AB - Recently the most frequently applied surgical procedure worldwide has been Cesarean section. It is essential to perform the operation without any complication. In addition, a fast postoperative recovery must be provided, because all mothers must have the chance for being together with their newborn infant even on the first day. The maternal mortality rates of Cesarean section significantly decreased in the last decades due to the planned team work as well as the widely applied regional (spinal and epidural) anesthetic procedures. Apart from the obstetrician and neonatologist the anesthesiologist is the member of the perinatal team, too, who is responsible for the patient's perioperative care. To prevent complications and have an early successful treatment the anesthesiologist should be informed by the pregnant woman' s health status in time in order to be able to plan the perioperative management. The high-risk groups of pregnant women, the most common causes of maternal death and possibilities of prevention and treatment are discussed. PMID- 25016447 TI - [Indications and methods of hysterectomy]. AB - Hysterectomy is one of the most frequently performed gynecological operations. The most common indications for hysterectomy are symptomatic uterine fibroids, endometriosis, and uterine and pelvic organ prolapse. The procedure can be performed by vaginally or abdominally and with laparoscopic assistance. Choosing the perfect method the gynecologist should take into consideration how the procedure can be performed most safely to fulfill the needs of the patient. In the last few years the number of the laparoscopic procedures has been increasing. PMID- 25016448 TI - [Early diagnosis of ectopic pregnancy]. AB - Ectopic pregnancy is a high-risk condition that occurs in 2% of reported pregnancies. This percentage is fivefold higher than that registered in the 1970s. Since 1970 there has been a two-fold increase in the ratio of ectopic pregnancies to all reported pregnancies in Hungary and in 2012 7.4 ectopic pregnancies per thousand registered pregnancies were reported. Recently, the majority (80%) of cases can be diagnosed in early stage, and the related mortality objectively decreased in the past few decades to 3.8/10,000 ectopic pregnancies. If a woman with positive pregnancy test has abdominal pain and/or vaginal bleeding the physician should perform a work-up to safely exclude the possibility of ectopic pregnancy. The basis of diagnosis is ultrasonography, especially vaginal ultrasound examination and measurement of the beta-subunit of human chorionic gonadotropin. The ultrasound diagnosis is based on the visualization of an ectopic mass rather than the inability to visualize an intrauterine pregnancy. In some questionable cases the diagnostic uterine curettage or laparoscopy may be useful. The actuality of this topic is justified by practical difficulties in obtaining correct diagnosis, especially in the early gestational time. PMID- 25016449 TI - [Prevention of neonatal group B streptococcal sepsis in Hungary in 2012. Preliminary data of a nation-wide survey]. AB - INTRODUCTION: At present, there is no obligatory guideline for the prevention of early-onset neonatal group B streptococcal disease in Hungary. AIM: The aim of the present study was to gain insight into the spontaneously developed preventive strategy of the domestic obstetric divisions and departments in Hungary. METHOD: Standardized questionnaire was sent out to each of the 71 obstetric divisions and departments in Hungary. RESULTS: Overall, 20 (27.4%) of the chairpersons replied, and thus, 39.9% of the total number of live births in Hungary were included in the study. Despite missing public health guidelines, each of the divisions and departments developed their own strategy to prevent neonatal group B streptococcal disease. In 95% of cases, bacterial culture of the lower vagina was the method of identifying pregnant women at risk. In 5% of the cases intrapartum antibiotic prophylaxis was based on risk assessment only. Of the departments using culture-based prophylaxis, 58% departments sampled women after completion of 36th gestational weeks. Antibiotic of choice was penicillin or ampicillin in 100% of cases. Of the study participants, 80% reported on multiple administration of colonized pregnant women after onset of labor or rupture of the membranes. CONCLUSIONS: The authors concluded that the rate of participation in the study was low. However, prevention of early-onset neonatal group B streptococcal infection is a priority of obstetric care in Hungary. Lack of a nation-wide public health policy did not prevent obstetric institutions in this country to develop their own prevention strategy. In the majority of cases and institutions, the policy is consistent with the widely accepted international standards. PMID- 25016450 TI - Chlorinated volatile organic compounds (Cl-VOCs) in environment - sources, potential human health impacts, and current remediation technologies. AB - Chlorinated volatile organic compounds (Cl-VOCs), including polychloromethanes, polychloroethanes and polychloroethylenes, are widely used as solvents, degreasing agents and a variety of commercial products. These compounds belong to a group of ubiquitous contaminants that can be found in contaminated soil, air and any kind of fluvial mediums such as groundwater, rivers and lakes. This review presents a summary of the research concerning the production levels and sources of Cl-VOCs, their potential impacts on human health as well as state-of the-art remediation technologies. Important sources of Cl-VOCs principally include the emissions from industrial processes, the consumption of Cl-VOC containing products, the disinfection process, as well as improper storage and disposal methods. Human exposure to Cl-VOCs can occur through different routes, including ingestion, inhalation and dermal contact. The toxicological impacts of these compounds have been carefully assessed, and the results demonstrate the potential associations of cancer incidence with exposure to Cl-VOCs. Most Cl-VOCs thus have been listed as priority pollutants by the Ministry of Environmental Protection (MEP) of China, Environmental Protection Agency of the U.S. (U.S. EPA) and European Commission (EC), and are under close monitor and strict control. Yet, more efforts will be put into the epidemiological studies for the risk of human exposure to Cl-VOCs and the exposure level measurements in contaminated sites in the future. State-of-the-art remediation technologies for Cl-VOCs employ non-destructive methods and destructive methods (e.g. thermal incineration, phytoremediation, biodegradation, advanced oxidation processes (AOPs) and reductive dechlorination), whose advantages, drawbacks and future developments are thoroughly discussed in the later sections. PMID- 25016451 TI - The implicit affiliation motive moderates cortisol responses to acute psychosocial stress in high school students. AB - It has been previously shown that the implicit affiliation motive - the need to establish and maintain friendly relationships with others - leads to chronic health benefits. The underlying assumption for the present research was that the implicit affiliation motive also moderates the salivary cortisol response to acute psychological stress when some aspects of social evaluation and uncontrollability are involved. By contrast we did not expect similar effects in response to exercise as a physical stressor. Fifty-nine high school students aged M=14.8 years were randomly assigned to a psychosocial stress (publishing the results of an intelligence test performed), a physical stress (exercise intensity of 65-75% of HRmax), and a control condition (normal school lesson) each lasting 15min. Participants' affiliation motives were assessed using the Operant Motive Test and salivary cortisol samples were taken pre and post stressor. We found that the strength of the affiliation motive negatively predicted cortisol reactions to acute psychosocial but not to physical stress when compared to a control group. The results suggest that the affiliation motive buffers the effect of acute psychosocial stress on the HPA axis. PMID- 25016452 TI - Synthesis of amino functionalized magnetic graphenes composite material and its application to remove Cr(VI), Pb(II), Hg(II), Cd(II) and Ni(II) from contaminated water. AB - In the present study, a kind of graphenes magnetic material (Fe3O4-GS) was prepared by compositing graphene sheet with ferroferric oxide, and shown to be effective for removing Cr(VI), Pb(II), Hg(II), Cd(II) and Ni(II) ions from aqueous solution. The synthesized sorbent was characterized by SEM, TEM, FTIR, XRD, XPS and BET, respectively. The pHZPC value of the sorbent was estimated to be 3.5 by alkaline-titration methods. Fe3O4-GS can be simply recovered from water with magnetic separation at low magnetic field within one minute. The sorption capacities of the metals were 17.29, 27.95, 23.03, 27.83 and 22.07 mg g(-1) for Cr(VI), Pb(II), Hg(II), Cd(II) and Ni(II), respectively. Kinetic data showed good correlation with pseudo-second-order equation and the Freundlich model was found to fit for the isotherm data of all the heavy metal ions. It was found that the metals sorption was accomplished mainly via chelation or ion exchange. The results of thermodynamic studies illustrate that the adsorption process was endothermic and spontaneous in nature. PMID- 25016453 TI - Using one waste to tackle another: preparation of a CO2 capture material zeolite X from laterite residue and bauxite. AB - In this work, zeolite X, a benchmark adsorbent for carbon capture, has been successfully prepared from low cost waste minerals namely laterite residue and bauxite using alkali fusion process followed by hydrothermal treatment. The structure and morphology of the as-synthesized zeolite X were verified and characterized with a range of experimental techniques such as X-ray diffraction, scanning electronic microscopy and infrared spectroscopy. The surface area and (N2 and CO2) gas adsorption isotherms of this product were found comparable to that of commercial ones, demonstrating the effectiveness of synthesizing zeolite X from laterite and bauxite. Further improvement of the product purity was also accomplished by optimizing the process conditions. PMID- 25016454 TI - Phosphinic acid functionalized carbon nanotubes for sensitive and selective sensing of chromium(VI). AB - Single-walled carbon nanotubes (SWCNTs) have been functionalized with a phosphinic acid derivative 'bis(2,4,4-trimethylpentyl) phosphinic acid' (PA/d). It has been achieved by treating the chlorinated SWCNTs with PA/d at 80 degrees C. Successful functionalization and different nanomaterial properties have been investigated by UV-vis-NIR, FTIR, Raman spectroscopy, AFM and FE-SEM. PA/d conjugated SWCNTs (CNT-PA) are dispersible in some common organic solvents, e.g. CH2Cl2, DMF, CHCl3, and THF. The 'CNT-PA' complex was spin-casted on boron doped silicon wafer. Thus fabricated sensing electrode is demonstrated for sensitive and selective electrochemical sensing of chromium(VI) ions. A linear response is obtained over a wide range of Cr(VI) concentration (0.01-10 ppb). The sensor's sensitivity and the limit of detection are observed to be 35 +/- 4 nA/ppb and 0.01 ppb, respectively. The practical utility of the proposed sensor is demonstrated by determining the Cr(VI) concentration in an industrial effluent sample and an underground water sample. PMID- 25016455 TI - Application of annular centrifugal contactors in the hot test of the improved total partitioning process for high level liquid waste. AB - High level liquid waste (HLLW) produced from the reprocessing of the spent nuclear fuel still contains moderate amounts of uranium, transuranium (TRU) actinides, (90)Sr, (137)Cs, etc., and thus constitutes a permanent hazard to the environment. The partitioning and transmutation (P&T) strategy has increasingly attracted interest for the safe treatment and disposal of HLLW, in which the partitioning of HLLW is one of the critical technical issues. An improved total partitioning process, including a TRPO (tri-alkylphosphine oxide) process for the removal of actinides, a CESE (crown ether strontium extraction) process for the removal of Sr, and a CECE (calixcrown ether cesium extraction) process for the removal of Cs, has been developed to treat Chinese HLLW. A 160-hour hot test of the improved total partitioning process was carried out using 72-stage 10-mm-dia annular centrifugal contactors (ACCs) and genuine HLLW. The hot test results showed that the average DFs of total alpha activity, Sr and Cs were 3.57 * 10(3), 2.25 * 10(4) and 1.68 * 10(4) after the hot test reached equilibrium, respectively. During the hot test, 72-stage 10-mm-dia ACCs worked stable, continuously with no stage failing or interruption of the operation. PMID- 25016456 TI - Adsorption and enhanced photocatalytic activity of the {0 0 0 1} faceted Sm-doped ZnIn2S4 microspheres. AB - In this study, the doping effect of samarium on the structure, morphology, adsorption and photocatalytic performance of hexagonal ZnIn2S4 microspheres was studied. The photocatalytic activity of Sm-doped ZnIn2S4 microspheres was evaluated for the photodegradation of Rhodamine B (RhB) and methyl orange (MO) under visible light irradiation. The samples were characterized by XRD, SEM, XPS, UV-vis, TEM, and N2 adsorption-desorption analysis. The results show that the hexagonal ZnIn2S4 microspheres are composed of nanoplates growing along c-axis with the predominant negative-charged S plane. Compared with the photodegadation of MO dye, the negative-charged {0 0 0 1} facets not only are beneficial for the adsorption of RhB by -N(Et)2 groups but also can accumulate the separation of photogenerated electrons and holes, enhancing photodegradation efficiency by direct-hole photocatalysis. Moreover, Sm is partially substituted for In in the crystal lattice for forming the doping energy level which promotes the separation of photoinduced electron-hole pairs and enhances absorption of visible light. Hexagonal 2% Sm-doped ZnIn2S4 microspheres with exposed {0 0 0 1} facets resulted in higher photodegradation efficiency of RhB under visible light irradiation. PMID- 25016457 TI - A multinomial logit analysis of risk factors influencing road traffic injury severities in the Erzurum and Kars Provinces of Turkey. AB - A retrospective cross-sectional study is conducted analysing 11,771 traffic accidents reported by the police between January 2008 and December 2013 which are classified into three injury severity categories: fatal, injury, and no injury. Based on this classification, a multinomial logit analysis is performed to determine the risk factors affecting the severity of traffic injuries. The estimation results reveal that the following factors increase the probability of fatal injuries: drivers over the age of 65; primary-educated drivers; single vehicle accidents; accidents occurring on state routes, highways or provincial roads; and the presence of pedestrian crosswalks. The results also indicate that accidents involving cars or private vehicles or those occurring during the evening peak, under clear weather conditions, on local city streets or in the presence of traffic lights decrease the probability of fatal injuries. This study comprises the most comprehensive database ever created for a Turkish sample. This study is also the first attempt to use an unordered response model to determine risk factors influencing the severity of traffic injuries in Turkey. PMID- 25016458 TI - Intelligent speed assistance for serious speeders: the results of the Dutch Speedlock trial. AB - One of the most important policy questions regarding Intelligent Speed Assistance (ISA) is whether or not it should be implemented, and if so how. In 2010 the Dutch Ministry of Infrastructure and the Environment decided to perform a field operational test to investigate the possibility of using ISA as a penalty system for serious speed offenders. This paper presents the results of this research, focusing on the effects on road safety. The results show that the two types of ISA systems that were tested have a huge effect on driver behavior and have the potential to improve road safety by reducing the level of speeding, mean speed, as well as the standard deviation of speed. However, the users show little sign of learning after the systems are turned off. Moreover, the serious offenders frequently use the emergency button to override the system which might seriously affect the efficacy of the system. PMID- 25016459 TI - Mixed logit model-based driver injury severity investigations in single- and multi-vehicle crashes on rural two-lane highways. AB - Crashes occurring on rural two-lane highways are more likely to result in severe driver incapacitating injuries and fatalities. In this study, mixed logit models are developed to analyze driver injury severities in single-vehicle (SV) and multi-vehicle (MV) crashes on rural two-lane highways in New Mexico from 2010 to 2011. A series of significant contributing factors in terms of driver behavior, weather conditions, environmental characteristics, roadway geometric features and traffic compositions, are identified and their impacts on injury severities are quantified for these two types of crashes, respectively. Elasticity analyses and transferability tests were conducted to better understand the models' specification and generality. The research findings indicate that there are significant differences in causal attributes determining driver injury severities between SV and MV crashes. For example, more severe driver injuries and fatalities can be observed in MV crashes when motorcycles or trucks are involved. Dark lighting conditions and dusty weather conditions are found to significantly increase MV crash injury severities. However, SV crashes demonstrate different characteristics influencing driver injury severities. For example, the probability of having severe injury outcomes is higher when vans are identified in SV crashes. Drivers' overtaking actions will significantly increase SV crash injury severities. Although some common attributes, such as alcohol impaired driving, are significant in both SV and MV crash severity models, their effects on different injury outcomes vary substantially. This study provides a better understanding of similarities and differences in significant contributing factors and their impacts on driver injury severities between SV and MV crashes on rural two-lane highways. It is also helpful to develop cost-effective solutions or appropriate injury prevention strategies for rural SV and MV crashes. PMID- 25016460 TI - Is self-rated health a stable and predictive factor for allostatic load in early adulthood? Findings from the Nord Trondelag Health Study (HUNT). AB - Self-rated health (SRH) is a widely used health indicator predicting morbidity and mortality in a wide range of populations. However, little is known about the stability and biological basis of SRH. The aim of this study was to map the stability of SRH from adolescence to early adulthood, and to examine the relationships between SRH and biological dysregulation, in terms of allostatic load (AL). The AL score comprises the eleven biomarkers systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, waist-hip ratio (WHR), diabetes risk profile, glucose, C-reactive protein (CRP) and body mass index (BMI). Eleven years prospective data from the Nord-Trondelag Health Study (HUNT), Norway, were utilised. Baseline data were gathered from 9141 adolescents (mean age 15.9 years) in the Young-HUNT I survey (1995-1997) and follow-up data were gathered from the adult HUNT3 survey (2006-2008). Altogether, 1906 respondents completed both questionnaires and clinical measurements in both studies. Cross-tables for SRH at baseline and follow-up showed that SRH remained unchanged in 57% of the respondents. Only 3% of the respondents changed their ratings by two steps or more on a four-level scale. Further, linear regression analyses adjusted for age and gender revealed that SRH in adolescence predicted AL in young adulthood. Similar patterns were found for most of the individual biomarkers. The consistency found in SRH from adolescence to young adulthood, and its association with AL across time, indicate that routines for dealing with SRH early in life may be a central strategy to prevent morbidity in the adult population. PMID- 25016461 TI - Do welfare regimes influence the association between disability and self perceived health? A multilevel analysis of 57 countries. AB - Disability is usually associated with poorer self-rated health. However, as many people with disabilities do not consider themselves unhealthy, the association may not be as straightforward as it appears. This study examines whether the relationship between disability and self-rated health is dependent on a country's welfare regime. Welfare regimes can play a significant role in securing the needs of disabled people and lessening their social exclusion. However, welfare regimes also label disabled people accordingly, before they become entitled to specific provisions and services. Being given a low status label and being dependent on welfare provisions might trigger a negative self-evaluation of health. Using data from 57 countries of the World Health Survey of 2002-2004, the multilevel regression analyses show that people with a disability tend to rate their health worse than people without any disability. Moreover, the strength of this negative association varies significantly across countries and is affected by a country's welfare regime. The association is the strongest in the various Welfare State regimes (mostly European countries) and the weakest in Informal-Security regimes (Latin-American and Asian countries) and in Insecurity regimes (African countries). Disabled people living in Welfare States regimes tend to rate their health worse than people in other regimes. These findings confirm that welfare regimes play a role in shaping the health perception of disabled people and that processes of labeling may result in unintended and negative consequences of welfare programs. Research on the nexus between disability and self-rated health that neglects this macro-social context of welfare regimes may lead to undifferentiated and even incorrect conclusions. PMID- 25016462 TI - Quantitative characterization of the impact of pulp refining on enzymatic saccharification of the alkaline pretreated corn stover. AB - In this work, corn stover was refined by a pulp refining instrument (PFI refiner) after NaOH pretreatment under varied conditions. The quantitative characterization of the influence of PFI refining on enzymatic hydrolysis was studied, and it was proved that the enhancement of enzymatic saccharification by PFI refining of the pretreated corn stover was largely due to the significant increment of porosity of substrates and the reduction of cellulose crystallinity. Furthermore, a linear relationship between beating degree and final total sugar yields was found, and a simple way to predict the final total sugar yields by easily testing the beating degree of PFI refined corn stover was established. Therefore, this paper provided the possibility and feasibility for easily monitoring the fermentable sugar production by the simple test of beating degree, and this will be of significant importance for the monitoring and controlling of industrial production in the future. PMID- 25016463 TI - Microalgal biomass and lipid production in mixed municipal, dairy, pulp and paper wastewater together with added flue gases. AB - The aim of the study was to grow microalgae on mixed municipal and industrial wastewater to simultaneously treat the wastewater and produce biomass and lipids. All algal strains grew in all wastewater mixtures; however, Selenastrum minutum had the highest biomass and lipids yields, up to 37% of the dry matter. Nitrogen and phosphorus removal were high and followed a similar trend in all three strains. Ammonium was reduced from 96% to 99%; this reduction was due to algal growth and not to stripping to the atmosphere, as confirmed by the amount of nitrogen in the dry algal biomass. Phosphate was reduced from 91% to 99%. In all strains used the lipid content was negatively correlated to the nitrogen concentration in the algal biomass. Mixtures of pulp and paper wastewater with municipal and dairy wastewater have great potential to grow algae for biomass and lipid production together with effective wastewater treatment. PMID- 25016464 TI - A novel surfactant-assisted ionic liquid pretreatment of sugarcane bagasse for enhanced enzymatic hydrolysis. AB - This study investigated a novel pretreatment method, as an essential step, for production of second generation bioethanol from sugarcane bagasse (SCB). Effect of tween 80 (TW) and polyethylene glycol 4000 (PEG) on SCB pretreatment was assessed using 1-butyl-3-methyl imidazolium chloride ([BMIM]Cl) as an ionic liquid (IL). Different concentrations of TW and PEG were used to determine the optimum concentration of surfactant for the highest percentage of cellulose conversion. TW and PEG increased lignin removal by 12.5% over the IL-only pretreated sample. The 3% (w/w) PEG showed a significant increase in enzymatic digestibility with an efficiency of 96.2% after 12h of hydrolysis; this was 23% higher than the efficiency of SCB pretreated with IL. The increase in digestibility of surfactant assisted IL pretreatment method can be attributed to the decrease in cellulose crystallinity, changes in the cellulose lattice, and delignification; which was confirmed by FT-IR, XRD and FE-SEM analysis. PMID- 25016465 TI - Tree and forest effects on air quality and human health in the United States. AB - Trees remove air pollution by the interception of particulate matter on plant surfaces and the absorption of gaseous pollutants through the leaf stomata. However, the magnitude and value of the effects of trees and forests on air quality and human health across the United States remains unknown. Computer simulations with local environmental data reveal that trees and forests in the conterminous United States removed 17.4 million tonnes (t) of air pollution in 2010 (range: 9.0-23.2 million t), with human health effects valued at 6.8 billion U.S. dollars (range: $1.5-13.0 billion). This pollution removal equated to an average air quality improvement of less than one percent. Most of the pollution removal occurred in rural areas, while most of the health impacts and values were within urban areas. Health impacts included the avoidance of more than 850 incidences of human mortality and 670,000 incidences of acute respiratory symptoms. PMID- 25016466 TI - Correlation of noise levels and particulate matter concentrations near two major freeways in Los Angeles, California. AB - Near-freeway environments are important from public health and environmental justice perspectives. This study investigated the spatial profile of and correlations between noise levels and particulate matter concentrations near two major freeways in Los Angeles, CA. Five minutes averages of A-weighted equivalent continuous sound level (LeqA), ultrafine particle (UFP) number concentrations, and fine particle (PM2.5) mass concentrations were measured concurrently at increasing distances from the freeways on four streets with or without sound wall. Under upwind conditions, UFP showed relatively low concentrations and no obvious gradient, while LeqA showed decay with increasing distance as it did under downwind conditions. Moderate correlations between LeqA and UFP were observed under downwind conditions on all four streets. The presence of a sound wall changed the linear relationship between LeqA and UFP. These data may be used to study the independent and synergistic health impacts of noise and air pollutants near roadways. PMID- 25016467 TI - Quantifying the effects of soil temperature, moisture and sterilization on elemental mercury formation in boreal soils. AB - Soils are a source of elemental mercury (Hg(0)) to the atmosphere, however the effects of soil temperature and moisture on Hg(0) formation is not well defined. This research quantifies the effect of varying soil temperature (278-303 K), moisture (15-80% water filled pore space (WFPS)) and sterilization on the kinetics of Hg(0) formation in forested soils of Nova Scotia, Canada. Both, the logarithm of cumulative mass of Hg(0) formed in soils and the reduction rate constants (k values) increased with temperature and moisture respectively. Sterilizing soils significantly (p < 0.05, n = 10) decreased the percent of total Hg reduced to Hg(0). We describe the fundamentals of Hg(0) formation in soils and our results highlight two key processes: (i) a fast abiotic process that peaks at 45% WFPS and depletes a small pool of Hg(0) and; (ii) a slower, rate limiting biotic process that generates a large pool of reducible Hg(II). PMID- 25016468 TI - First description of PVL-positive methicillin-resistant Staphylococcus aureus (MRSA) in wild boar meat. AB - Staphylococcus aureus is an important food-borne pathogen due to the ability of enterotoxigenic strains to produce staphylococcal enterotoxins (SEs) in food. Methicillin-resistant S. aureus (MRSA) is also an important pathogen for humans, causing severe and hard to treat diseases in hospitals and in the community due to its multiresistance against antimicrobials. In particular, strains harbouring genes encoding for the Panton-Valentine leukocidin (PVL) toxin are of concern from a public health perspective as they are usually capable of causing severe skin and soft tissue infections (sSSTIs) and occasionally necrotizing pneumonia which is associated with high mortality. This is the first report on the detection of MRSA with genes encoding for PVL in wild boar meat. Among the 28 MRSA isolated from wild boar meat in the course of a national monitoring programme in Germany, seven harboured PVL-encoding genes. Six of the isolates were identical according to the results of spa-, MLST-, microarray- and PFGE typing. They could be assigned to the epidemic MRSA clone USA300. Epidemiological investigations revealed that people handling the food were the most likely common source of contamination with these MRSA. These findings call again for suitable hygienic measures at all processing steps of the food production chain. The results of the study underline that monitoring along the food chain is essential to closely characterise the total burden of MRSA for public health. PMID- 25016469 TI - Effects of future climate and land use scenarios on riverine source water quality. AB - Surface water quality is particularly sensitive to land use practices and climatic events that affect its catchment. The relative influence of a set of watershed characteristics (climate, land use, morphology and pedology) and climatic variables on two key water quality parameters (turbidity and fecal coliforms (FC)) was examined in 24 eastern Canadian catchments at various spatial scales (1 km, 5 km, 10 km and the entire catchment). A regression analysis revealed that the entire catchment was a better predictor of water quality. Based on this information, linear mixed effect models for predicting turbidity and FC levels were developed. A set of land use and climate scenarios was considered and applied within the water quality models. Four land use scenarios (no change, same rate of variation, optimistic and pessimistic) and three climate change scenarios (B1, A1B and A2) were tested and variations for the near future (2025) were assessed and compared to the reference period (2000). Climate change impacts on water quality remained low annually for this time horizon (turbidity: +1.5%, FC: +1.6%, A2 scenario). On the other hand, the influence of land use changes appeared to predominate. Significant benefits for both parameters could be expected following the optimistic scenario (turbidity: -16.4%, FC: -6.3%; p < 0.05). However, pessimistic land use scenario led to significant increases on an annual basis (turbidity: +11.6%, FC: +15.2%; p < 0.05). Additional simulations conducted for the late 21st century (2090) revealed that climate change impacts could become equivalent to those modeled for land use for this horizon. PMID- 25016470 TI - Assessing the effects of regional payment for watershed services program on water quality using an intervention analysis model. AB - Much attention has been recently paid to ex-post assessments of socioeconomic and environmental benefits of payment for ecosystem services (PES) programs on poverty reduction, water quality, and forest protection. To evaluate the effects of a regional PES program on water quality, we selected chemical oxygen demand (COD) and ammonia-nitrogen (NH3-N) as indicators of water quality. Statistical methods and an intervention analysis model were employed to assess whether the PES program produced substantial changes in water quality at 10 water-quality sampling stations in the Shaying River watershed, China during 2006-2011. Statistical results from paired-sample t-tests and box plots of COD and NH3-N concentrations at the 10 stations showed that the PES program has played a positive role in improving water quality and reducing trans-boundary water pollution in the Shaying River watershed. Using the intervention analysis model, we quantitatively evaluated the effects of the intervention policy, i.e., the watershed PES program, on water quality at the 10 stations. The results suggest that this method could be used to assess the environmental benefits of watershed or water-related PES programs, such as improvements in water quality, seasonal flow regulation, erosion and sedimentation, and aquatic habitat. PMID- 25016471 TI - Assessment of historical fecal contamination in Curitiba, Brazil, in the last 400 years using fecal sterols. AB - A 400-year sedimentary record of the Barigui River was investigated using fecal biomarkers and nutrient distribution. The temporal variability in cholesterol, cholestanol, coprostanol, epicoprostanol, stigmastanol, stigmasterol, stigmastenol, sitosterol, and campesterol between 1600 and 2011 was assessed. Anthropogenic influences, such as deforestation and fecal contamination from humans and livestock, were observed from 1840. The sterol ratios exhibit evidence of hens, horses, cows, and an unknown herbivore, which may be a capybara (Hydrochoerus hydrochaeris), from 1820 and has been observed more markedly from 1970 onward. Human fecal contamination was detected from 1840 and was observed more markedly from 1930 due to population growth. Thus, the sanitation conditions and demographic growth of Curitiba seemed to be the main factors of human sewage pollution, as the coprostanol concentration over time was strongly correlated with the population growth (r=0.71, p<0.001) although diagenetic processes have also been observed.(1.) PMID- 25016472 TI - The pathogenicity of Staphylococcus epidermidis on the intestinal organs of rats and mice: an experimental investigation. AB - BACKGROUND: Staphylococcus epidermidis is the most frequently isolated species of the coagulase negative staphylococci from human stool. However, it is not clear how its presence in the gut affects the cellular structures and functions of this organ. In this study therefore, the pathogenicity of strains of S. epidermidis which were isolated from the stool samples of apparently healthy children was investigated in mice and rats. METHODS: The albino mice (22-30 g) and albino rats (100-155 g) of both sexes were infected orally and intraperitoneally with graded doses of the bacteria and subjected to behavioral and histopathological examinations. RESULTS: Acute infection in these animals caused temporary behavioural changes as shown by restlessness and abdominal stretchings but did not result in death even at a dosage of 2 * 109 cfu/kg. Daily administration of the same dose for 14 days resulted in the death of 11 out of 21 (52.4%) mice. Histopathological examination of the affected organs showed congestions, aggregations and multinucleated hepatocytes in the liver, infiltration of the kidney tubule interstitial by chronic inflammatory cells, coagulative necrosis of the kidney, spleen, intestine and stomach cells as well as marked stroma fibrosis of the spleen. Coagulative necrosis of cells was the most frequently occurring pathological alteration. Lethality and pathological effects reflected the virulence factors expressed by the organism which are biofilm formation, haemagglutination properties and capsule production. CONCLUSIONS: The results indicate that strains of S. epidermidis colonising the gut can cause serious pathological changes on certain organs such as kidney, liver, intestine, stomach and spleen which, depending on their severity, could be fatal. PMID- 25016473 TI - Chemiluminescent microparticle immunoassay based detection and prevalence of HCV infection in district Peshawar Pakistan. AB - BACKGROUND: Due to the high rate of asymptomatic infections an advanced screening assay is of prompt importance to be used for the clinical diagnosis of HCV. Early detection of anti HCV is the first step in the management of chronic hepatitis and in the selection of patients needing treatments. In the current study we have first time used the advanced serological diagnostic technique i.e. Chemiluminescent Microparticle Immuno Assay (CMIA) for the detection of HCV infection in Peshawar Pakistan. METHODS: A total number of 982 samples were collected among the general public belongs to the different areas of district Peshawar. The samples were centrifuged at high speed to obtain a clear supernatant serum. All the samples were run on Architect system a fully automated immuno analyzer CMIA base technology. RESULTS: Out of 982 blood samples analyzed in this study, 160 (15.9%) were confirmed to be positive for active HCV infection. The overall prevalence was found to be 13.4%. Gender wise prevalence was recorded to be higher in male (19.1%) than female (12.7%). The age group 21 30 years was identified as the highest risk group among the studied population. CONCLUSION: Among the tested samples, overall prevalence of active HCV infection was found to be 13.4% in the general population of Peshawar Pakistan. The young middle aged population of this region was at higher risk of HCV ailments compared to the other age groups. PMID- 25016474 TI - Evaluation of recombinant granule antigens GRA1 and GRA7 for serodiagnosis of Toxoplasma gondii infection in dogs. AB - BACKGROUND: Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, is an important zoonotic disease worldwide. The precise detection of T. gondii infection in dogs has important public health significance. In this study, recombinant granule antigen proteins GRA1 and GRA7 were evaluated as potential diagnostic markers for T. gondii infection in dogs by an indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: GRA1 and GRA7 were cloned and expressed in Escherichia coli, and the recombinant GRA1, GRA7- and Toxoplasma lysate antigen (TLA)-based ELISAs were developed and evaluated using the canine positive and negative serum samples for anti-T. gondii antibodies determined by modified agglutination test (MAT) and indirect fluorescent antibody test (IFAT), showing a seroprevalence of 15.1% by TLA- and GRA1-ELISA, and 15.8% by GRA7-ELISA, and no significant difference was observed (P > 0.05). When compared with the two reference assays, MAT and IFAT, the GRA7 ELISA showed the highest co-positivity and co-negativity rates. Receiver operating characteristic (ROC) analysis revealed a largest area under curve (AUC) of 0.973 (95% CI, 0.955 to 0.991), and a highest relative sensitivity (93.2%) and specificity (94.0%) for a cut-off value of 0.809 in GRA7-ELISA. CONCLUSIONS: The results of the present study showed that GRA7-ELISA is highly sensitive and specific, and GRA7 is a potential serodiagnostic marker for the detection of T. gondii infection in dogs. PMID- 25016475 TI - Array-CGH analysis in Rwandan patients presenting development delay/intellectual disability with multiple congenital anomalies. AB - BACKGROUND: Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development delay/intellectual disability and congenital malformation in East Africa. METHODS: Array comparative genomic hybridization was performed in 50 Rwandan patients with development delay/intellectual disability and multiple congenital abnormalities, using the Agilent's 180 K microarray platform. RESULTS: Fourteen patients (28%) had a global development delay whereas 36 (72%) patients presented intellectual disability. All patients presented multiple congenital abnormalities. Clinically significant copy number variations were found in 13 patients (26%). Size of CNVs ranged from 0,9 Mb to 34 Mb. Six patients had CNVs associated with known syndromes, whereas 7 patients presented rare genomic imbalances. CONCLUSION: This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries. PMID- 25016476 TI - Pharmacokinetics and pharmacodynamics of oral and intravenous cefetamet in dog. AB - The pharmacokinetic (PK) and pharmacodynamic (PD) properties of intravenously (IV) administered cefetamet-Na and per os (PO) administered cefetamet pivoxil were investigated in eighteen healthy dogs at three different dose levels. The three doses for IV cefetamet-Na were 95, 190 and 380 mg, while those for oral cefetamet pivoxil were 125, 250 and 500 mg (both equivalent to 90, 180 and 360 mg of cefetamet). An efficacy predictor, measured as the ratios of the time that the concentration of the free drug is over the MIC90 (T > MIC90) and the dosing interval (f% T > MIC90) of IV and PO administration were calculated. The PK parameters' maximum concentration (C max), half-life (t 1/2) and area under the curve (AUC0-t ) after three IV doses were 42.85 +/- 11.79 MUg/mL, 1.66 +/- 0.36 h and 80.10 +/- 28.92 mg h/L (95 mg); 93.50 +/- 30.51 MUg/mL, 1.47 +/- 0.13 h and 1.47 +/- 0.13 mg h/L (190 mg); 185.74 +/- 113.83 MUg/mL, 1.60 +/- 0.38 h and 263.20 +/- 73.27 mg h/L (380 mg). After PO administration, the C max, t 1/2 and AUC0-t at three doses were 9.25 +/- 1.02 MUg/mL, 1.79 +/- 0.50 h and 31.90 +/- 4.76 mg h/L (125 mg); 9.75 +/- 1.77 MUg/mL, 1.93 +/- 0.65 h and 42.69 +/- 8.93 mg h/L (250 mg); 15.55 +/- 6.65 MUg/mL, 2.02 +/- 0.54 h, and 68.72 +/- 24.11 mg h/L (500 mg). The IV f% T > MIC90 was greater than PO f% T > MIC90 when MIC90 was within the range of 0.25-256 mg/L. PMID- 25016477 TI - Association between hospital case volume and mortality in non-elderly pneumonia patients stratified by severity: a retrospective cohort study. AB - BACKGROUND: The characteristics and aetiology of pneumonia in the non-elderly population is distinct from that in the elderly population. While a few studies have reported an inverse association between hospital case volume and clinical outcome in elderly pneumonia patients, the evidence is lacking in a younger population. In addition, the relationship between volume and outcome may be different in severe pneumonia cases than in mild cases. In this context, we tested two hypotheses: 1) non-elderly pneumonia patients treated at hospitals with larger case volume have better clinical outcome compared with those treated at lower case volume hospitals; 2) the volume-outcome relationship differs by the severity of the pneumonia. METHODS: We conducted the study using the Japanese Diagnosis Procedure Combination database. Patients aged 18-64 years discharged from the participating hospitals between July to December 2010 were included. The hospitals were categorized into four groups (very-low, low, medium, high) based on volume quartiles. The association between hospital case volume and in-hospital mortality was evaluated using multivariate logistic regression with generalized estimating equations adjusting for pneumonia severity, patient demographics and comorbidity score, and hospital academic status. We further analyzed the relationship by modified A-DROP pneumonia severity score calculated using the four severity indices: dehydration, low oxygen saturation, orientation disturbance, and decreased systolic blood pressure. RESULTS: We identified 8,293 cases of pneumonia at 896 hospitals across Japan, with 273 in-hospital deaths (3.3%). In the overall population, no significant association between hospital volume and in-hospital mortality was observed. However, when stratified by pneumonia severity score, higher hospital volume was associated with lower in hospital mortality at the intermediate severity level (modified A-DROP score = 2) (odds ratio (OR) of very low vs. high: 2.70; 95% confidence interval (CI): 1.12 6.55, OR of low vs. high: 2.40; 95% CI:0.99-5.83). No significant association was observed for other severity strata. CONCLUSIONS: Hospital case volume was inversely associated with in-hospital mortality in non-elderly pneumonia patients with intermediate pneumonia severity. Our result suggests room for potential improvement in the quality of care in hospitals with lower volume, to improve treatment outcomes particularly in patients admitted with intermediate pneumonia severity. PMID- 25016478 TI - Forty-two-month outcome of intravitreal bevacizumab in myopic choroidal neovascularization. AB - PURPOSE: To evaluate the long-term efficacy of bevacizumab in the treatment of choroidal neovascularization (CNV) secondary to pathological myopia. METHODS: In this retrospective single-center non-comparative study the medical records of 29 eyes from 29 patients with naive CNV secondary to high myopia and at least 42 months of follow up were reviewed. All eyes received a loading dose of one intravitreal injection per month for two consecutive months and were retreated on an as-needed basis during the course of follow up. The main outcome measures were post-treatment ETDRS best-corrected visual acuity (BCVA) and visual stabilization over time. Stepwise linear regression analysis was performed to identify prognostic factors for visual acuity gain and final visual acuity outcome at 42 months. RESULTS: At 42 months of follow-up bevacizumab was associated with the maintenance of significant benefits in visual acuity compared to baseline. No adverse ocular or systemic effects from treatment were encountered. No statistically significant correlations were found between BCVA change and any of the quantitative variables. However, when final BCVA was taken as a dependent variable and CNV size and pre-treatment VA were included as predictors, a bivariate model was identified by stepwise regression which gave a 75 % of explained variance. CONCLUSIONS: Bevacizumab treatment was found to be efficacious in the treatment of myopic CNV, resulting in stable gains in visual acuity lasting at least 42 months, without any adverse ocular or general events. Myopic CNV size was identified as a significant prognostic factor. PMID- 25016479 TI - Laser therapy versus observation for symptomatic retinal artery macroaneurysms. AB - PURPOSE: The optimal management approach to retinal arterial macroaneurysms (RAM) is unknown. This paper compares long-term outcomes in RAM treated with laser therapy versus observation. METHODS: This is an IRB-approved retrospective study of patients with symptomatic RAM. Charts of patients with a diagnosis of RAM causing symptomatic visual loss were reviewed. Patients with less than 6 months follow up, other confounding diagnoses, or additional therapy beyond thermal laser were excluded. Statistical analysis was done using chi(2) or Student's t test as appropriate. RESULTS: Forty-eight patients with RAM were identified and 27 were included in the study (13 treated, 14 observed). Mean visual acuity in the observation group improved from 20/120 to 20/96 (p = 0.53) compared to 20/280 to 20/54 (p = 0.0003) in the treated group. Subgroup analysis showed that visual acuity in primarily hemorrhagic lesions treated with laser therapy improved by 1.21 logMAR compared to a loss of 0.11 logMAR (p = 0.002) in those that were observed. In primarily exudative lesions, both treated and observed lesions showed an improvement of 0.32 logMAR. No patients in the treatment group had a final visual acuity below 20/200 compared to four in the observation group. CONCLUSION: Treatment with direct laser photocoagulation was associated in this study with greater improvement in visual acuity and may decrease the risk of severe visual loss especially in primarily hemorrhagic RAM lesions. Compared to observation alone. PMID- 25016480 TI - Cleavage site and Ectodomain of HA2 sub-unit sequence of three equine influenza virus isolated in Morocco. AB - BACKGROUND: The equine influenza (EI) is an infectious and contagious disease of the upper respiratory tract of horses. Two outbreaks were notified in Morocco during 1997 and 2004 respectively in Nador and Essaouira. The aims of the present study concern the amino acids sequences comparison with reference strain A/equine/Miami/1963(H3N8) of the HA2 subunit including the cleavage site of three equine influenza viruses (H3N8) isolated in Morocco: A/equine/Nador/1/1997(H3N8), A/equine/Essaouira/2/2004 (H3N8) and A/equine/Essaouira/3/2004 (H3N8). RESULTS: The obtained results demonstrated that the substitutions were located at Ectodomain (ED) and transmembrane domain (TD), and they have only one arginine in cleavage site (HA1-PEKQI-R329-GI-HA2). In the Ectodomain, the mutation N/1542/T deleted the NGT glycosylation site at position 154 for both strains A/equine/Essaouira/2/2004(H3N8) and A/equine/Essaouira/3/2004(H3N8). Except for mutation D/1602/Y of the A/equine/Nador/1/1997(H3N8) strain, the other mutations were involved in non conserved sites. While the transmembrane domain (TM) of the strain A/equine/Essaouira/3/2004(H3N8) exhibits a substitution at residue C/1992/F. For the A/equine/Nador/1/1997(H3N8) strain the HA2 shows a mutation at residue M/2072/L. Three Moroccan strains reveals a common substitution at the residue E/2112/Q located between transmembrane domain TM and the cytoplasmic domain (CD). CONCLUSION: The given nature virulence of three Moroccan strains, the identified and reported mutations certainly played a permissive role of infection viral process. PMID- 25016481 TI - Cardiovascular disease medication health literacy among Indigenous peoples: design and protocol of an intervention trial in Indigenous primary care services. AB - BACKGROUND: Cardiovascular diseases (CVD) are leading causes of mortality and morbidity among Indigenous people in New Zealand, Australia and Canada and are a major driver of the inequities in life expectancy between Indigenous and non Indigenous people in these countries. Evidence-based pharmaceutical management of CVD can significantly reduce mortality and morbidity for persons diagnosed with CVD or for those at intermediate or high risk of CVD. Health literacy has been identified as a major barrier in the communication and implementation of appropriate pharmaceutical management plans for CVD. Addressing health literacy is particularly relevant in Indigenous populations where there are unique health and adult literacy challenges. METHODS/DESIGN: This study will examine the effect of a customized, structured CVD medication programme, delivered by health professionals, on the health literacy of Indigenous people with, or at risk, of CVD. Primary outcomes are patient's knowledge about CVD medications; secondary outcomes examine changes in health literacy skills and practices. The study will employ a multi-site pre-post design with multiple measurement points to assess intervention efficacy. Participants will be recruited from four Indigenous primary care services in Australia, Canada and New Zealand. Three educational sessions will be delivered over four weeks. A tablet application will support the education sessions and produce a customized pill card for each participant. Participants will be provided with written information about CVD medications. Medication knowledge scores, and specific health literacy skills and practices will be assessed before and after the three sessions. Statistical analyses will identify significant changes in outcomes over each session, and from the pre session one to post-session three time points. DISCUSSION: This study will make an important contribution to understanding the effect of a structured primary care-based intervention on CVD health literacy in Indigenous populations. The study also illustrates the incorporation of Indigenous health research principles and processes in clinical trials and provides insights that may be useful in other contexts. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (ACTRN12612001309875; date of registration 18/12/2012). PMID- 25016483 TI - Does recurrent laryngeal nerve lymph node metastasis really affect the prognosis in node-positive patients with squamous cell carcinoma of the middle thoracic esophagus? AB - BACKGROUND: Recurrent laryngeal nerve (RLN) lymph node metastasis used to be shown a predictor for poor prognosis in esophageal squamous cell carcinoma. The purpose of this study was to evaluate the prognostic impact of RLN node metastasis and the number of metastatic lymph nodes in node-positive patients with squamous cell carcinoma of middle thoracic esophagus. METHODS: A cohort of 235 patients who underwent curative surgery for squamous cell carcinoma of middle thoracic esophagus was investigated. The prognostic impact was evaluated by univariate and multivariate analyses. RESULTS: Lymph node metastasis was found in 133 patients. Among them, 81 had metastatic RLN nodes, and 52 had at least one positive node but no RLN nodal involvement. The most significant difference in survival was detected between patients with metastatic lymph nodes below and above a cutoff value of six (P < 0.001). Multivariate analysis revealed that the number of metastatic lymph nodes was a significant factor associated with overall survival (P < 0.001), but RLN lymph node metastasis was not (P = 0.865). CONCLUSIONS: RLN Lymph node metastasis is not, but the number of metastatic nodes is a prognostic predictor in node-positive patients with squamous cell carcinoma of the middle thoracic esophagus. PMID- 25016482 TI - Evaluation of atorvastatin efficacy and toxicity on spermatozoa, accessory glands and gonadal hormones of healthy men: a pilot prospective clinical trial. AB - BACKGROUND: Recommendations for cardiovascular disease prevention advocate lowering both cholesterol and low-density lipoprotein cholesterol systemic levels, notably by statin intake. However, statins are the subject of questions concerning their impact on male fertility. This study aimed to evaluate, by a prospective pilot assay, the efficacy and the toxicity of a decrease of cholesterol blood levels, induced by atorvastatin on semen quality and sexual hormone levels of healthy, normocholesterolaemic and normozoospermic men. METHODS: Atorvastatin (10 mg daily) was administrated orally during 5 months to 17 men with normal plasma lipid and standard semen parameters. Spermatozoa parameters, accessory gland markers, semen lipid levels and blood levels of gonadal hormones were assayed before statin intake, during the treatment, and 3 months after its withdrawal. RESULTS: Atorvastatin treatment significantly decreased circulating low-density lipoprotein cholesterol (LDL-C) and total cholesterol concentrations by 42% and 24% (p<0.0001) respectively, and reached the efficacy objective of the protocol. During atorvastatin therapy and/or 3 months after its withdrawal numerous semen parameters were significantly modified, such as total number of spermatozoa (-31%, p<0.05), vitality (-9.5%, p<0.05), total motility (+7.5%, p<0.05), morphology (head, neck and midpiece abnormalities, p<0.05), and the kinetics of acrosome reaction (p<0.05). Seminal concentrations of acid phosphatases (p<0.01), alpha-glucosidase (p<0.05) and L carnitine (p<0.05) were also decreased during the therapy, indicating an alteration of prostatic and epididymal functions. Moreover, we measured at least one altered semen parameter in 35% of the subjects during atorvastatin treatment, and in 65% of the subjects after withdrawal, which led us to consider that atorvastatin is unsafe in the context of our study. CONCLUSIONS: Our results show for the first time that atorvastatin significantly affects the sperm parameters and the seminal fluid composition of healthy men. PMID- 25016484 TI - The influence of substrate elastic modulus on retinal pigment epithelial cell phagocytosis. AB - To better understand if a complex process such as phagocytosis is influenced by substrate stiffness, we investigated the influence of substrate elastic modulus on phagocytosis in the retinal pigment epithelial (RPE) cell line ARPE-19. RPE cells lie on Bruch's membrane, directly under the retina, and phagocytose the shed photoreceptor outer segments. Bruch's membrane is known to increase in stiffness by an order of magnitude with age and thus, this study has potential relevance in explaining retinal changes in age-related macular degeneration. ARPE 19 cells were plated on laminin-coated polyacrylamide substrates of varying elastic modulus. After 14 days in culture, a solution of latex fluorescent beads suspended in PBS was placed in each well. After an incubation time of 4h, flow cytometry was performed to determine the number of cells that phagocytosed a bead. The number of ARPE-19 cells that phagocytosed a bead decreased continuously as a function of increasing substrate elastic modulus (p=0.0135), and this was found to be a linear relationship (slope=-0.03305 +/- 0.01104, R2=0.4726 per 10,000 cells). Our results suggest that RPE cells display decreased phagocytosis when grown on firmer substrates, and thus, RPE cells in older eyes, in which Bruch's membrane is stiffer, may demonstrate decreased phagocytosis. Impaired phagocytosis by RPE cells may contribute to impaired metabolism of photoreceptor outer segments and to development of macular degeneration. Material stiffness may be a critical parameter in the development of neural therapies, including retinal prosthetics and stem cell therapies. PMID- 25016485 TI - Adaptive velocity-based six degree of freedom load control for real-time unconstrained biomechanical testing. AB - Robotic biomechanics is a powerful tool for further developing our understanding of biological joints, tissues and their repair. Both velocity-based and hybrid force control methods have been applied to biomechanics but the complex and non linear properties of joints have limited these to slow or stepwise loading, which may not capture the real-time behaviour of joints. This paper presents a novel force control scheme combining stiffness and velocity based methods aimed at achieving six degree of freedom unconstrained force control at physiological loading rates. PMID- 25016486 TI - How does postural stability following a single leg drop jump landing task relate to postural stability during a single leg stance balance task? AB - We aimed to verify whether the static phase after a single leg drop jump (DJ) landing on a force plate may serve as a proxy for a single leg stance (SLS) balance task, as this would increase the application possibilities of landing tasks in the evaluation of sensorimotor function in relation to injury rehabilitation or performance assessment. Twenty-five healthy participants performed two sessions of five valid trials for both tasks in a reproducibility agreement design. Three postural stability outcome measures ('COP speed', 'COP sway' and 'Horizontal GRF') were calculated for DJ (5-20s after landing) and for SLS (15s), and were averaged per session. Paired T-tests revealed a learning effect of SLS for postural stability (4.6-6.1%; P-values <0.03), in contrast to DJ (P-values >0.27). Only session 2 resulted in superior postural stability for SLS compared to DJ for 'COP speed' (5.0%; P=0.017) and 'Horizontal GRF' (8.2%; P=0.001). Bland and Altman methods demonstrated inter-session SD's of difference for DJ of 11-12% and for SLS of 10-12%, while inter-task SD's of difference ranged 10-17%. Precision ('SD within') was better for SLS concerning 'COP speed' (14-15% vs 13%) and 'Horizontal GRF' (18-20% vs 14-15%). In conclusion, postural stability during DJ and SLS cannot be considered interchangeable, due to a learning effect for SLS and inferior precision for DJ. However, a DJ task may be used as a proxy for static postural stability, although more than three trials are needed to achieve individual errors similar to SLS for 'COP speed' (4) and 'Horizontal GRF' (5). PMID- 25016487 TI - Predicting the permeability of trabecular bone by micro-computed tomography and finite element modeling. AB - The intrinsic permeability of bone plays an important role in the transport of nutrients and minerals within the tissue, and affects the mechanical stimuli that are related to the fate of the stem cells. The objective of this study was to establish a method to assess trabecular bone permeability using experimental and finite element (FE) modeling approaches based on micro computed tomography (uCT) images. Human cadaveric tibia cube specimens (N=23) were scanned with uCT. The permeability was measured experimentally using a custom-developed constant-head permeameter, and computationally by a poroelastic formulation to simulate the fluid flow within the discretized bone matrix and pore phase. The average of the experimentally measured permeability was 4.84 * 10(-10)m(2) with a standard deviation of 3.70 * 10(-10)m(2). A regression model of the uCT determined that the maximum bone area to total area ratio (maxBA/TA) for all slices that are perpendicular to the direction of fluid flow explained 84% of the variability of the natural logarithm of the experimentally measured permeability. The 2D measure of maxBA/TA performed better than 3D measures in general, although some parameters were reasonably well associated with permeability such as bone volume ratio (BV/TV, r=-0.71), the bone surface/bone volume (BS/BV, r=0.73), and the trabecular thickness (TbTh, r=-0.71). The correlation between the permeability predicted with FE models and experimentally measured permeability was reasonable (r=0.69), but the FE approach did not accurately represent the wide variability of permeability measured experimentally. The results of this study suggest that the changes in the trabecular bone microarchitecture have an exponential relationship with permeability, and the use of uCT-based 2D measurement of maxBA/TA performs well at predicting permeability, thus providing a convenient approach to measure this important aspect affecting biomechanical functions in the tissue. PMID- 25016488 TI - Suicide from carbon monoxide poisoning in South Korea: 2006-2012. AB - BACKGROUNDS: Suicide from carbon monoxide poisoning by burning coal briquette or barbecue charcoal increased rapidly in some East Asian countries in the recent decade. The purpose of this study was to examine trends in suicides from carbon monoxide poisoning in South Korea and their epidemiologic characteristics. METHODS: We presented age-standardized mortality rates of carbon monoxide suicide and compared them with those of suicide by other methods using registered death data from Statistics Korea (South Korea) from 2006 to 2012. Logistic regression analysis was conducted to estimate odds ratios of carbon monoxide suicide by socio-demographic characteristics before and after the marked increase in carbon monoxide suicide in September 2008. RESULTS: The number of carbon monoxide suicides in South Korea was only 34 in 2006 but rapidly increased to 267 in 2008 and was 1125 in 2012, with the age-standardized rates of 0.06 (2006), 0.48 (2008), and 1.97 (2012) per 100,000 population respectively (a striking 3,183% increase in 2006-2012). Suicide by carbon monoxide poisoning showed greater odds ratios among men, younger age groups, single or the divorced, and those with high education and non-manual jobs compared with suicides by other methods. LIMITATIONS: This study only used data for fatal self-poisoning by carbon monoxide (non-fatal cases not included) and had no information on the sources of carbon monoxide. CONCLUSIONS: Carbon monoxide suicides substantially increased in South Korea over the relatively short study period and showed some distinct socio demographic characteristics compared with suicides by other methods. PMID- 25016490 TI - The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. AB - BACKGROUND: Dextromethorphan is an over-the-counter antitussive agent that may be a rapidly acting treatment for bipolar depression. Like ketamine, it is an NMDA receptor antagonist. METHODS: We conducted a retrospective chart review of depressed patients with treatment resistant bipolar II or bipolar NOS disorder who were treated with the combination of dextromethorphan 20 mg and quinidine 10 mg (DMQ). One pill of DMQ taken once or twice a day was added to participants' drug regimen. No changes were made to the pre-existing drug regimen during the course of treatment with DMQ. The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) score after 90 days of treatment. RESULTS: Seventy seven participants met the inclusion criteria. All had been experiencing depressive symptoms for at least two years, and the mean number of failed medication trials was 21.2. The average CGI-I score at day 90 was 1.66 (1=slightly improved, 2=much improved). Some patients reported improvement within 1-2 days of starting DMQ. Nineteen patients discontinued treatment due to adverse effects, chiefly nausea. LIMITATIONS: Because this was a retrospective chart review with no control group, conclusions about causation cannot be made. Nevertheless, the duration of depressive symptoms prior to starting DMQ makes spontaneous recovery less likely. CONCLUSIONS: DMQ, an NMDA antagonist, may be effective in the treatment of bipolar depression. Because its putative mechanism does not depend on the monoaminergic system, it may be appropriate for patients who have not responded to other medications. Unlike ketamine, DMQ does not require i.v. administration. PMID- 25016489 TI - Children and adolescents referred for treatment of anxiety disorders: differences in clinical characteristics. AB - BACKGROUND: Reports of the clinical characteristics of children and adolescents with anxiety disorders are typically based on community populations or from clinical samples with exclusion criterion applied. Little is known about the clinical characteristics of children and adolescents routinely referred for treatment for anxiety disorders. Furthermore, children and adolescents are typically treated as one homogeneous group although they may differ in ways that are clinically meaningful. METHODS: A consecutive series of children (n=100, aged 6-12 years) and adolescents (n=100, aged 13-18 years), referred to a routine clinical service, were assessed for anxiety and comorbid disorders, school refusal and parental symptoms of psychopathology. RESULTS: Children with a primary anxiety disorder were significantly more likely to be diagnosed with separation anxiety disorder than adolescents. Adolescents with a primary anxiety disorder had significantly higher self and clinician rated anxiety symptoms and had more frequent primary diagnoses of social anxiety disorder, diagnoses and symptoms of mood disorders, and irregular school attendance. LIMITATIONS: Childhood and adolescence were considered categorically as distinct, developmental periods; in reality changes would be unlikely to occur in such a discrete manner. CONCLUSIONS: The finding that children and adolescents with anxiety disorders have distinct clinical characteristics has clear implications for treatment. Simply adapting treatments designed for children to make the materials more 'adolescent-friendly' is unlikely to sufficiently meet the needs of adolescents. PMID- 25016492 TI - Field triage of the neonatal foal. AB - The purpose of this article is to provide a quick reference for field triage of the sick neonatal foal. Therefore, information is focused toward diagnostics and treatments that can be performed in the field. When evaluating a weak, recumbent, or lethargic foal on a farm, it is often difficult to make a definitive diagnosis. Therefore, the approach should be to treat what is treatable and prevent what is preventable. In many cases, the goal will be to stabilize a foal before referral to a tertiary care facility where more intensive and continuous treatment can be performed. PMID- 25016491 TI - Selected autoantibodies and normal-tension glaucoma. AB - BACKGROUND: Although intraocular pressure is an important risk factor in glaucoma, there is growing body evidence indicating an immunological component in the pathogenesis of normal-tension glaucoma (NTG). The aim of this study was to determine if NTG coexists with elevated levels of autoantibodies detected in rheumatic diseases. MATERIAL AND METHODS: We enrolled 105 patients into the study: 35 with NTG, 34 with primary open-angle glaucoma (POAG), and 36 controls. All patients underwent ophthalmic examination and blood tests. Blood was examined for the level of: antibodies against antinuclear antibodies (ANA), antibodies to extractable nuclear antigens (ENA), immunoglobulins (IgG, IgA, IgM), rheumatoid factor, anti-citrullinated protein antibodies (ACPA), and antiphospholipid antibodies (anticardiolipin antibodies, beta2-glycoprotein I antibodies, antiprothrombin antibodies). RESULTS: The level of ANA was increased among 6 patients in the NTG group (17.1%), 8 in the POAG group (23.5%), and 6 in the control group (16.5%). The difference was not statistically significant (p=0.97). None of the patients in the NTG, POAG, or control group had positive antibodies to ENA. The level of immunoglobulins IgG, IgM, and IgA in the 3 groups was similar and within normal values. The median level of rheumatoid factor and ACPA was the highest in the NTG group, but it was within normal laboratory values. There was a statistically significant difference between antiprothrombin antibodies IgG between the NTG and POAG group (p=0.01), but not between the NTG and control group (p=0.24). CONCLUSIONS: The results of our study do not confirm the hypothesis that NTG coexists with elevated blood levels of antibodies, which are a characteristic feature of rheumatic diseases. PMID- 25016493 TI - CPR in the neonatal foal: has RECOVER changed our approach? AB - RECOVER was created to optimize survival of small animal patients from cardiopulmonary arrest. Several findings from this study are applicable to cardiopulmonary resuscitation in the neonatal foal. In particular, chest compressions should be a priority with no pauses and a "push hard, push fast" approach. The importance of ventilation is minimized with short, infrequent breaths at a rate of 10 to 20 per minute recommended. PMID- 25016494 TI - Update on the management of neonatal sepsis in horses. AB - Despite advances in neonatal intensive care sepsis, severe sepsis and septic shock remain the biggest killers of neonatal foals. Management of this severe syndrome remains difficult, requiring intensive intervention. Key aspects of management include infection control, hemodynamic support, immunomodulatory interventions, and metabolic/endocrine support. Infection control largely consists of early antimicrobial therapy, plasma transfusions, and local therapy for the infected focus. In cases with severe sepsis or septic shock, hemodynamic support with fluids, vasoactive agents, and respiratory support insuring oxygen delivery to vital organs is important. Nutritional support is important, but close monitoring is needed to avoid hyperglycemia and hypoglycemia. PMID- 25016495 TI - Is it the systemic inflammatory response syndrome or endotoxemia in horses with colic? AB - Some veterinarians describe particularly sick horses or neonatal foals as being endotoxemic, whereas others refer to the same animals as having the systemic inflammatory response syndrome. This article reviews the basis for the use of each of these terms in equine practice, and highlights the mechanisms underlying the response of the horse's innate immune system to key structural components of the microorganisms that initiate these conditions, including how some of those responses differ from other species. Current approaches used to treat horses with these conditions are summarized, and caution advised on extrapolating findings from other species to the horse. PMID- 25016496 TI - Ultrasound of the equine acute abdomen. AB - Abdominal ultrasound is an invaluable aid in the evaluation of the colic patient but can be heavily influenced by patient preparation, individual horse-to-horse variation, availability of ultrasound transducers, technique, experience level of the examiner, and complexity of the abdominal disorder. This article describes ultrasonographic anatomy of the normal equine abdomen and technique for examination of the equine colic patient. Common abnormalities of the stomach, small intestine, large intestine, and peritoneal cavity are described along with other abnormalities that may be discovered with abdominal ultrasonography of the colic patient, such as masses, urolithiasis, cholelithiasis, and thoracic or cardiac lesions. PMID- 25016497 TI - Evaluation of the colic in horses: decision for referral. AB - This article presents an overview of key factors that should alert the practitioner toward referral of a colic patient to a facility capable of surgical exploration or intensive medical management. Discussion includes a review of important aspects of colic history, signalment, physical examination findings, and diagnostic test results that indicate that a more serious medical or surgical condition exists, and advanced therapy is necessary. PMID- 25016498 TI - Blood lactate measurement and interpretation in critically ill equine adults and neonates. AB - Admission blood lactate concentration is widely used as a prognostic indicator in equine medicine and can be a useful indicator of disease severity but typically fails to completely discriminate survivors from nonsurvivors. Increased admission lactate concentrations in adult horses typically return to normal within 12 to 24 hours. Lactate concentrations in neonatal foals are higher than adult concentrations for the first 24 to 72 hours of life. Serial measures reflecting both the magnitude and duration of hyperlactatemia might enable more accurate prognostication and provide insight into disease pathogenesis and could be a valuable therapeutic guide. PMID- 25016499 TI - Crystalloid and colloid therapy. AB - Fluid therapy is a cornerstone of emergency medicine, but equine practitioners should be aware of recent developments that have modified previous recommendations. First, new emphasis on the avoidance of hyperchloremia suggests that crystalloids with a lower chloride concentration may be more appropriate for use. Second, modifications to the understanding of the Starling equation suggest that the benefits of colloids may be more limited than previously thought. In addition, the negative effects of fluid overload on morbidity and mortality are becoming increasingly recognized. Although more specific research in horses is needed, these principles are likely to apply across all species. PMID- 25016500 TI - Acute hemorrhage and blood transfusions in horses. AB - Treatment of acute hemorrhage in the horse involves targeted medical management and also may involve surgical stabilization. This article provides an approach to the initial stabilization and information on available topical hemostats. The practice of blood collection and transfusion is also described, with attention to new information on viability of transfused equine blood, potential negative effects of blood transfusion, and methods of cell salvage. PMID- 25016501 TI - Coagulopathies in horses. AB - Although primary coagulopathies are rare in horses, changes in coagulation and fibrinolysis are commonly associated with inflammatory diseases. A clear understanding of the pathophysiology of normal and abnormal hemostasis is required to be able to choose and interpret diagnostic tests evaluating coagulation and fibrinolysis. After diagnosis, treatment of the underlying disease must occur regardless of whether clinical manifestations (excessive bleeding or thrombosis) of the coagulopathy are present or not. Specific treatment may be initiated if there are clinical signs of coagulopathy. PMID- 25016502 TI - Trauma and wound management: gunshot wounds in horses. AB - Bullet wounds in horses can cause a wide array of injuries, determined by the type of projectile, the energy of the bullet on entry, and the type of tissue the bullet encounters. Treatment includes identification of all structures involved, debridement of the permanent cavity, and establishing adequate drainage. Bullet wounds should be treated as contaminated, and broad-spectrum antibiotics, including those with an anaerobic spectrum, are indicated. Although musculoskeletal injuries resulting from gunshots are most common in horses, they carry a good prognosis for survival and return to function. PMID- 25016503 TI - Infection control in equine critical care settings. AB - There is a recognizable standard of practice for infection control in veterinary medicine. Effort must be given to control and prevention of infectious disease transmission within a facility and among animal populations. In the critical care setting, patients typically have a high degree of systemic illness and immune compromise, are commonly subjected to invasive procedures and placement of indwelling devices, and frequently receive antimicrobials and gastric protectants. Every equine critical care unit is distinctive in its physical and operational features and the types of patients that are managed. Infection control programs must therefore be tailored to each facility's needs. PMID- 25016504 TI - Emergency and critical care. PMID- 25016506 TI - Anesthesia, analgesia and surgical stress. PMID- 25016505 TI - Efficacy and safety profile of celecoxib for treating advanced cancers: a meta analysis of 11 randomized clinical trials. AB - PURPOSE: Evidence on the benefits of combining celecoxib, a cyclooxygenase-2 inhibitor, in treating advanced cancer is still controversial. This study aimed to establish the efficacy and safety profile of celecoxib in treating advanced cancers. METHODS: The PubMed, Embase, and Cochrane databases and abstracts from the American Society of Clinical Oncology and European Society for Medical Oncology were searched for reports dated up to January 31, 2014, to find relevant randomized clinical trials. The outcomes included overall response rate (ORR), 1 year mortality, progression-free survival, overall survival, and toxicities. Fixed-effects meta-analytical models were used when indicated, and between-study heterogeneity was assessed. Subgroup analysis was conducted according to cancer type, treatment pattern, and treatment line. FINDINGS: A total of 11 randomized clinical trials consisting of 2570 patients with advanced cancer were included in the final meta-analysis. Addition of celecoxib to the treatment regimen significantly increased the ORR (pooled risk ratio [RR] = 1.20; 95% CI, 1.06 1.36; P = 0.005) but had no effect on 1-year mortality (RR = 1.02; 95% CI, 0.92 1.13; P = 0.68). Subgroup analysis found that the ORR results were significant with non-small cell lung cancer (RR = 1.29; 95% CI, 1.08-1.54; P = 0.005), colorectal cancer (RR = 1.32; 95% CI, 1.02-1.72; P = 0.037), chemotherapy treatment (RR = 1.22; 95% CI, 1.07-1.39; P = 0.003), and first-line treatment (RR = 1.22; 95% CI, 1.07-1.38; P = 0.003). However, celecoxib increased the risk of cardiovascular events (RR = 1.78; 95% CI, 1.30-2.43; P < 0.001) and anemia (RR = 1.88; 95% CI, 0.95-3.74; P = 0.071). IMPLICATIONS: Celecoxib is beneficial in the treatment of advanced cancers but with increased risk of cardiovascular events. Benefit versus harm needs to be carefully considered when celecoxib is recommended in patients with advanced cancers. PMID- 25016507 TI - Comparing the effectiveness of ropivacaine 0.5% versus ropivacaine 0.2% for transabdominis plane block in providing postoperative analgesia after appendectomy. AB - OBJECTIVE: The basis for the transversus abdominis plane (TAP) block involves infiltration of a local anesthetic into the neurofascial plane between the internal oblique and the transversus abdominis muscles, causing a regional block that spreads between the L1 and T10 dermatomes. Thus, the TAP block is said to be suitable for lower abdominal surgery. This study was designed to compare the analgesic efficacy of two different concentrations of ropivacaine for TAP block in patients undergoing appendectomy. METHODS: Fifty-six patients with American Society of Anesthesiologists physical status I or II, aged 18 years and above, undergoing appendectomy were recruited in this prospective, randomized, double blind study. They were divided into two groups: Group A patients who received 0.5 mL/kg of ropivacaine 0.5% and Group B patients who received 0.5 mL/kg of ropivacaine 0.2% via TAP block under ultrasound guidance. Postoperative pain was assessed using the visual analog scale upon arrival at the recovery room in the operating theatre, just prior to being discharged to the ward, and at 6 hours, 12 hours, 18 hours, and 24 hours postoperatively to compare the effectiveness of analgesia. RESULTS: Intraoperatively, patients in Group B required a significantly greater amount of additional intravenous fentanyl than those in Group A. There were no significant statistical differences in pain scores at rest and on movement at all assessment times as well as in the dose of 24-hour intravenous morphine consumption given via patient-controlled analgesia postoperatively between the two groups. CONCLUSION: The effectiveness of two different concentrations of ropivacaine (0.5% versus 0.2%) given via TAP block was comparable in providing postoperative analgesia for patients undergoing appendectomy. PMID- 25016508 TI - Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. AB - OBJECTIVE: Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. METHODS: Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9. RESULTS: The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 MUg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recurarization was observed in any of the patients. Most of the adverse events were found to be mild and such events were not related to the use of sugammadex. None of the patients was eliminated from the study because of an adverse event. One patient died due to cholestatic liver cirrhosis because of repeated hepatic surgery. CONCLUSION: Sugammadex can rapidly reverse NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Sugammadex was found to be safe and well tolerated. However, further studies of sugammadex under similar conditions should be conducted involving a large number of patients with liver dysfunction undergoing hepatic surgery. PMID- 25016509 TI - Comparison of 4% articaine and 0.5% bupivacaine anesthetic efficacy in orthodontic extractions: prospective, randomized crossover study. AB - AIM: Articaine and bupivacaine are both amide-type local anesthetic (LA) agents, of almost equal potency. However, lidocaine is considered the gold standard and is the most widely used anesthetic agent because of its potency, safety, and efficiency. Articaine is fast acting and bupivacaine is a long-lasting LA. The aim of this randomized controlled crossover clinical study was to evaluate and compare the clinical anesthetic efficacy of 4% articaine and 0.5% bupivacaine in orthodontic extractions models. METHODS: Forty systemically healthy patients (age range: 10-18 years), requiring premolar extraction for orthodontic reasons (all 4 premolars) were included. Patients were categorized into two groups (4% articaine and 0.5% bupivacaine) in a crossover manner (160 premolars). Parameters recorded included: time of anesthetic onset, duration of postoperative analgesia, time to first rescue analgesic medication, and visual analog scale (VAS). At the first appointment, both upper and lower premolars were extracted on one side of the jaws (right or left). A fixed volume of 1.4 mL of 4% articaine or 0.5% bupivacaine (based on a computer-generated list) was infiltrated in the buccal vestibule (local infiltration) for extraction. At the second appointment, after a washout period of 15 days, the anesthetic agent that was not administered at the first appointment was administered in a crossover manner. Each patient was evaluated using a 100-mm VAS during and after extraction. RESULTS: The results showed that 4% articaine had significantly faster onset of action and lower VAS scores when compared with bupivacaine. However, the duration of analgesia and time to first rescue analgesic medication was longer in the bupivacaine group. CONCLUSION: Articaine seemed to have better potency and efficacy in terms of onset of action and lower pain scores compared to the bupivacaine group. Further studies are required to confirm these results. PMID- 25016510 TI - Opioid consumption after levobupivacaine scalp nerve block for craniosynostosis surgery. AB - BACKGROUND AND OBJECTIVES: Craniosynostosis surgery is considered a very painful procedure due to extended scalp and periosteal detachment, and is associated with prolonged postoperative consumption of opioids and their side effects. In this observational descriptive case series study, we investigated perioperative opioid consumption in children undergoing craniosynostosis repair under general anesthesia when scalp nerve block with levobupivacaine was involved. METHODS: After standard anesthesia induction, scalp nerve block with levobupivacaine 2 mg/kg plus epinephrine 1:800,000 was performed. Hemodynamic parameters and opioid consumption were noted. Patients were monitored in the recovery room. Requirements of additional analgesia, indicated by the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) pain score of >9, and incidence of side effects (sedation, nausea, and vomiting) were recorded during the first 24 hours. RESULTS: A total of 32 patients were recruited in this study; 88% of them needed morphine rescue in the recovery room because they had high CHEOPS scores. Trigonocephaly was the most frequent type of craniosynostosis (37.5%), requiring 50% more opioids in the postoperative period than other forms of craniosynostosis. CONCLUSION: Scalp nerve block can be proposed as a complement to the routine craniosynostosis anesthetic protocol, because it is easy to perform, seems to reduce the need for supplementary opioids during the perioperative period, and can reduce the risk of developing acute opioid tolerance and chronic pain. In the event of trigonocephaly or craniofacial reconstruction, a complementary infraorbital nerve block can be added. PMID- 25016511 TI - Hypoxia-inducible factor-1: a possible link between inhalational anesthetics and tumor progression? AB - Cancer remains one of the major causes of death worldwide, and the global burden of the disease is rising continuously. Clinical retrospective data suggested that inhalational anesthetics might affect the prognosis of cancer patients, but the underlying molecular mechanism remained unknown. Hypoxia-inducible factor-1 (HIF 1) is a dimeric transcription factor and mediates various cellular responses to hypoxia, including metabolism, cell death and survival, angiogenesis, oxygen delivery, immune evasion, and genomic adaptation. HIF-1 system has been shown to be the driving force of solid tumor progression and substantially contributes to the malignancy of cancer. Inhalational anesthetics such as isoflurane have been demonstrated to confer cytoprotection in a HIF-1-dependent manner in various vital organs. In addition, a recent study has demonstrated the pivotal involvement of HIF-1 in the impact of inhalational anesthetics on cancer cells. This review provides critical insights into the new understanding of cancer sensing of inhalational anesthetics and examines the recent understanding of the underlying molecular mechanisms. However, this area of research is just beginning and warrants further studies preclinically and clinically prior to making any conclusions that inhalational anesthetics may affect cancer outcomes. In addition, it is important to note that there is not enough evidence to support any change in the current clinical practice. PMID- 25016512 TI - Review of aneurysmal subarachnoid hemorrhage--focus on treatment, anesthesia, cerebral vasospasm prophylaxis, and therapy. AB - Aneurysmal subarachnoid hemorrhage (aSAH) is a serious and debilitating condition that leads to the development of many complications, which are followed by mortality and morbidity. As anesthesiologists, we may require to manage aSAH at various settings such as in the perioperative period or in a nonoperative setting such as the neuroradiology suite for diagnostic and therapeutic interventions. Therefore, it is important to understand the pathophysiology of aSAH and anesthetic management for operations and interventions. For decades, early brain injury and cerebral vasospasm have played major roles in the outcome following aSAH. The purpose of this article is to review recent advances and future perspectives in the treatment of aSAH, early brain injury, and cerebral vasospasm. PMID- 25016513 TI - GlideScope-assisted fiberoptic bronchoscope intubation in a patient with severe rheumatoid arthritis. AB - Here, we report that, under the assistance of both the GlideScope and a fiberoptic bronchoscope, tracheal intubation was accomplished successfully in a 50-year-old woman with severe rheumatoid arthritis who underwent tongue lump resection under general anesthesia. Either the GlideScope or the fiberoptic bronchoscope alone failed to secure the airway; the use of both in combination facilitated airway intubation. This case report indicate that, even with careful preoperative assessment, patients who suffer from rheumatoid arthritis may have severe airway difficulty with intubation, and the combined use of the GlideScope and a fiberoptic bronchoscope can be a novel alternative for tracheal intubation in patients with severe airway difficulty. PMID- 25016514 TI - Arthrogryposis multiplex congenita: airway concerns in an emergency situation. AB - Difficult airway is always of special concern to anesthesiologists, but in a trauma setting where having a secured airway is most important, the incidence of difficult airway increases manifold. We report a "cannot ventilate cannot intubate" situation in a trauma patient who was later diagnosed to have arthrogryposis multiplex congenita, a syndrome known to affect the airway, and in whom all measures of securing a nonsurgical airway failed. PMID- 25016515 TI - Anesthetic management of a patient with thoracic aortic aneurysm scheduled for cesarean section. PMID- 25016516 TI - A pregnant 26-year-old with H1N1 influenza. PMID- 25016517 TI - Use of four-factor prothrombin complex concentrate in the emergency department: a review. PMID- 25016518 TI - "I don't have enough time... ": Myths and strategies for improving academic workplace effectiveness. PMID- 25016519 TI - Looking upstream. PMID- 25016520 TI - The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice. AB - OBJECTIVES: Excess fat in the diet can impact neuropsychiatric functions by negatively affecting cognition, mood and anxiety. We sought to show that the free fatty acid (FFA), palmitic acid, can cause adverse biobehaviors in mice that last beyond an acute elevation in plasma FFAs. METHODS: Mice were administered palmitic acid or vehicle as a single intraperitoneal (IP) injection. Biobehaviors were profiled 2 and 24 h after palmitic acid treatment. Quantification of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their major metabolites was performed in cortex, hippocampus and amygdala. FFA concentration was determined in plasma. Relative fold change in mRNA expression of unfolded protein response (UPR)-associated genes was determined in brain regions. RESULTS: In a dose-dependent fashion, palmitic acid rapidly reduced mouse locomotor activity by a mechanism that did not rely on TLR4, MyD88, IL-1, IL-6 or TNFalpha but was dependent on fatty acid chain length. Twenty-four hours after palmitic acid administration mice exhibited anxiety-like behavior without impairment in locomotion, food intake, depressive-like behavior or spatial memory. Additionally, the serotonin metabolite 5-HIAA was increased by 33% in the amygdala 24h after palmitic acid treatment. CONCLUSIONS: Palmitic acid induces anxiety-like behavior in mice while increasing amygdala-based serotonin metabolism. These effects occur at a time point when plasma FFA levels are no longer elevated. PMID- 25016521 TI - Crystal structure of RNase H3-substrate complex reveals parallel evolution of RNA/DNA hybrid recognition. AB - RNases H participate in the replication and maintenance of genomic DNA. RNase H1 cleaves the RNA strand of RNA/DNA hybrids, and RNase H2 in addition hydrolyzes the RNA residue of RNA-DNA junctions. RNase H3 is structurally closely related to RNases H2, but its biochemical properties are similar to type 1 enzymes. Its unique N-terminal substrate-binding domain (N-domain) is related to TATA-binding protein. Here, we report the first crystal structure of RNase H3 in complex with its RNA/DNA substrate. Just like RNases H1, type 3 enzyme recognizes the 2'-OH groups of the RNA strand and detects the DNA strand by binding a phosphate group and inducing B-form conformation. Moreover, the N-domain recognizes RNA and DNA in a manner that is highly similar to the hybrid-binding domain of RNases H1. Our structure demonstrates a remarkable example of parallel evolution of the elements used in the specific recognition of RNA and DNA. PMID- 25016522 TI - The mammalian INO80 chromatin remodeling complex is required for replication stress recovery. AB - A number of studies have implicated the yeast INO80 chromatin remodeling complex in DNA replication, but the function of the human INO80 complex during S phase remains poorly understood. Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. In the absence of the Ino80 protein, cells became hypersensitive to hydroxyurea and displayed hyperactive ATR Chk1 signaling. Using bulk and fiber labeling of DNA, we found that cells deficient for Ino80 and Arp8 had impaired replication restart after treatment with replication inhibitors and accumulated double-strand breaks as evidenced by the formation of gamma-H2AX and Rad51 foci. These data indicate that under conditions of replication stress mammalian INO80 protects stalled forks from collapsing and allows their subsequent restart. PMID- 25016523 TI - The mRNP remodeling mediated by UPF1 promotes rapid degradation of replication dependent histone mRNA. AB - Histone biogenesis is tightly controlled at multiple steps to maintain the balance between the amounts of DNA and histone protein during the cell cycle. In particular, translation and degradation of replication-dependent histone mRNAs are coordinately regulated. However, the underlying molecular mechanisms remain elusive. Here, we investigate remodeling of stem-loop binding protein (SLBP) containing histone mRNPs occurring during the switch from the actively translating mode to the degradation mode. The interaction between a CBP80/20 dependent translation initiation factor (CTIF) and SLBP, which is important for efficient histone mRNA translation, is disrupted upon the inhibition of DNA replication or at the end of S phase. This disruption is mediated by competition between CTIF and UPF1 for SLBP binding. Further characterizations reveal hyperphosphorylation of UPF1 by activated ATR and DNA-dependent protein kinase upon the inhibition of DNA replication interacts with SLBP more strongly, promoting the release of CTIF and eIF3 from SLBP-containing histone mRNP. In addition, hyperphosphorylated UPF1 recruits PNRC2 and SMG5, triggering decapping followed by 5'-to-3' degradation of histone mRNAs. The collective observations suggest that both inhibition of translation and recruitment of mRNA degradation machinery during histone mRNA degradation are tightly coupled and coordinately regulated by UPF1 phosphorylation. PMID- 25016524 TI - The RNA-mediated, asymmetric ring regulatory mechanism of the transcription termination Rho helicase decrypted by time-resolved nucleotide analog interference probing (trNAIP). AB - Rho is a ring-shaped, ATP-dependent RNA helicase/translocase that dissociates transcriptional complexes in bacteria. How RNA recognition is coupled to ATP hydrolysis and translocation in Rho is unclear. Here, we develop and use a new combinatorial approach, called time-resolved Nucleotide Analog Interference Probing (trNAIP), to unmask RNA molecular determinants of catalytic Rho function. We identify a regulatory step in the translocation cycle involving recruitment of the 2'-hydroxyl group of the incoming 3'-RNA nucleotide by a Rho subunit. We propose that this step arises from the intrinsic weakness of one of the subunit interfaces caused by asymmetric, split-ring arrangement of primary RNA tethers around the Rho hexamer. Translocation is at highest stake every seventh nucleotide when the weak interface engages the incoming 3'-RNA nucleotide or breaks, depending on RNA threading constraints in the Rho pore. This substrate governed, 'test to run' iterative mechanism offers a new perspective on how a ring-translocase may function or be regulated. It also illustrates the interest and versatility of the new trNAIP methodology to unveil the molecular mechanisms of complex RNA-based systems. PMID- 25016525 TI - Formation of circular polyribosomes on eukaryotic mRNA without cap-structure and poly(A)-tail: a cryo electron tomography study. AB - The polyribosomes newly formed on recombinant GFP-encoding mRNAs in a wheat germ cell-free translation system were analyzed using cryo-electron tomography, with sub-tomogram averaging of polysomal ribosomes and reconstruction of 3D structures of individual polyribosomes. The achieved level of resolution in the reconstructed polyribosomes allowed deducing the mRNA path by connecting adjacent exit and entry sites at the ribosomes inside each polyribosome. In this way, the circularity of a significant fraction (about 50%) of translating polyribosomes was proved in the case of the capped poly(A)-tailed mRNA, in agreement with the existing paradigm of the circularization via interaction of cap-bound initiation factor eIF4F with poly(A)-binding protein. However, translation of the capped mRNA construct without poly(A) tail, but with unspecific 3'-UTR derived from non coding plasmid sequence, also led to the formation of circular polyribosomes in similar proportion (40%). Moreover, the polyribosomes formed on the uncapped non polyadenylated mRNA with non-synergistic 5'- and 3'-UTRs proved to be circular as well, and appeared in the same proportion as in the previous cases. Thus, the formation of circular polyribosomes was found to be virtually independent of the presence of cap structure and poly(A) tail in mRNA, in contrast to the longstanding paradigm in the field. PMID- 25016526 TI - Microscopic mechanism of DNA damage searching by hOGG1. AB - The DNA backbone is often considered a track that allows long-range sliding of DNA repair enzymes in their search for rare damage sites in DNA. A proposed exemplar of DNA sliding is human 8-oxoguanine ((o)G) DNA glycosylase 1 (hOGG1), which repairs mutagenic (o)G lesions in DNA. Here we use our high-resolution molecular clock method to show that macroscopic 1D DNA sliding of hOGG1 occurs by microscopic 2D and 3D steps that masquerade as sliding in resolution-limited single-molecule images. Strand sliding was limited to distances shorter than seven phosphate linkages because attaching a covalent chemical road block to a single DNA phosphate located between two closely spaced damage sites had little effect on transfers. The microscopic parameters describing the DNA search of hOGG1 were derived from numerical simulations constrained by the experimental data. These findings support a general mechanism where DNA glycosylases use highly dynamic multidimensional diffusion paths to scan DNA. PMID- 25016528 TI - A tripartite paternally methylated region within the Gpr1-Zdbf2 imprinted domain on mouse chromosome 1 identified by meDIP-on-chip. PMID- 25016527 TI - Genome-wide analysis of genetic and epigenetic control of programmed DNA deletion. AB - During the development of the somatic genome from the Paramecium germline genome the bulk of the copies of ~45 000 unique, internal eliminated sequences (IESs) are deleted. IES targeting is facilitated by two small RNA (sRNA) classes: scnRNAs, which relay epigenetic information from the parental nucleus to the developing nucleus, and iesRNAs, which are produced and used in the developing nucleus. Why only certain IESs require sRNAs for their removal has been enigmatic. By analyzing the silencing effects of three genes: PGM (responsible for DNA excision), DCL2/3 (scnRNA production) and DCL5 (iesRNA production), we identify key properties required for IES elimination. Based on these results, we propose that, depending on the exact combination of their lengths and end bases, some IESs are less efficiently recognized or excised and have a greater requirement for targeting by scnRNAs and iesRNAs. We suggest that the variation in IES retention following silencing of DCL2/3 is not primarily due to scnRNA density, which is comparatively uniform relative to IES retention, but rather the genetic properties of IESs. Taken together, our analyses demonstrate that in Paramecium the underlying genetic properties of developmentally deleted DNA sequences are essential in determining the sensitivity of these sequences to epigenetic control. PMID- 25016529 TI - Elevation of human ERV3-1 env protein expression in colorectal cancer. PMID- 25016530 TI - Late haemodynamic performance and survival after aortic valve replacement with the Mosaic bioprosthesis. AB - OBJECTIVES: The objective was to evaluate the long-term haemodynamic performance of the Mosaic aortic bioprosthesis. Secondary objectives were to investigate the long-term survival, the rate of aortic valve reoperations, and the rate of prosthesis-patient mismatch and its effect on long-term survival. METHODS: We included all patients who underwent aortic valve replacement with a Mosaic bioprosthesis at our institution between 2002 and 2008. Valve haemodynamics were assessed by transthoracic echocardiography as mean and peak pressure gradients. Patient characteristics and outcomes were collected from charts and national registers. RESULTS: We included 355 patients and echocardiographic evaluation was performed at early follow-up in 340 patients (96%) and at late follow-up in 161 patients (45%). The mean follow-up time was 7.1 (maximum 11.7) years. The unadjusted survival at 1, 5 and 10 years was 92, 79 and 42%, respectively. At the early postoperative echocardiography, the peak pressure gradient was 39.9 mmHg (SD 14.4) and the mean pressure gradient was 21.1 mmHg (SD 7.7) and, on late echocardiography, the peak pressure gradient was 38.6 mmHg (SD 15.6) and the mean pressure gradient was 22.5 mmHg (SD 10.1). Moderate or severe prosthesis-patient mismatch was found in 250 (70%) and 49 patients (14%), respectively, but was not significantly associated with mortality in multivariable analyses. CONCLUSIONS: We found that the Mosaic aortic bioprosthesis had acceptable clinical performance at late follow-up. However, a substantial proportion of patients had high transvalvular gradients or moderate or severe prosthesis-patient mismatch, although neither were significantly associated with long-term survival in our population. PMID- 25016532 TI - Validated chromatographic methods for simultaneous determination of tolfenamic acid and its major impurities. AB - Two accurate, selective and precise chromatographic methods, namely thin-layer chromatography (TLC)-densitometric method and reversed phase high-performance liquid chromatography (RP-HPLC) method, were developed and validated for the simultaneous determination of tolfenamic acid (TOL) and its two major impurities, 2-chlorobenzoic acid (CBA) and 3-chloro-2-methylaniline (CMA), which are also reported to be its related substances. The developed TLC-densitometric method depended on separation and quantitation of the studied drugs on silica gel 60F254 TLC plates. Hexane:chloroform:acetone:acetic acid (75:25:20:0.1, v/v/v/v) was used as a developing system and the separated bands were UV-scanned at 240 nm. Linear relationships were obtained in the range of 10-100 ug band(-1) for the drug and in the range of 0.1-1 ug band(-1) for the studied impurities. The developed RP-HPLC depended on chromatographic separation of the studied drugs on a C18 column using 0.05 M KH2PO4 buffer (pH 3):acetonitrile (45:55, v/v) as a mobile phase delivered at constant flow rate of 1 mL min(-1) with UV detection at 230 nm. Calibration curves for TOL and the two impurities were constructed over the concentration ranges of 10-100 ug mL(-1) for TOL and 0.01-0.1 ug mL(-1) for both CBA and CMA. Factors affecting the developed methods have been studied and optimized. Further, methods validation has been carried out according to International Conference on Harmonization guidelines. The proposed methods were successfully applied for determination of the studied drug in its bulk powder and in pharmaceutical formulation. The methods showed no significant difference when compared with the reported RP-HPLC one. The developed methods have advantages of being more sensitive and specific than the published methods. PMID- 25016531 TI - MnSOD overexpression reduces fibrosis and pro-apoptotic signaling in the aging mouse heart. AB - Contractility of the heart is impaired with advancing age via mechanical remodeling, as myocytes are lost through apoptosis and collagenous fibers accumulate. Exercise training confers protection against fibrosis and apoptosis in the aging heart, but the mechanisms remain poorly understood. We recently reported that exercise training elevates Mn isoform of superoxide dismutase (MnSOD) in the aging heart, concomitant with reduction in oxidative stress and fibrosis. Here, we tested the hypothesis that overexpression of MnSOD would be causal in protection against fibrosis and apoptosis in the aging heart. Hearts were extracted from young (8 months) wild-type, young mice overexpressing the Sod2 (MnSOD) gene, old (28 months) wild-type, and old transgenic mice. Left ventricle MnSOD protein levels were elevated in young mice overexpressing the Sod2 (MnSOD) gene and old transgenic mice. MnSODTg mice exhibited lower oxidative stress (total hydroperoxides, 4-hydroxynonenal, and 8-isoprostane) in the old group. Age-related cardiac remodeling and fibrosis was mitigated in MnSOD Tg mice with reductions in extramyocyte space (-65%), collagen-I, and transforming growth factor-beta. Pro-apoptotic markers Bax (-38%) and caspase-3 cleavage (-41%) were reduced and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive nuclei, DNA laddering) was mitigated in MnSOD Tg hearts compared with old wild-type. We conclude that MnSOD elevation is indeed protective against oxidative stress, fibrosis, and apoptosis in the aging heart. PMID- 25016536 TI - The application of portable microchip electrophoresis for the screening and comparative analysis of synthetic cathinone seizures. AB - Variation in the chemical composition of illicit tablets and powders is common among samples within a given drug seizure. Using microchip electrophoresis (ME), multiple tablets can be screened in a cost-effective and timely manner. This method could be used in conjunction with reporting methods that focus solely on statistical sampling to infer homogeneity or otherwise of a larger subset of tablets. Some frequently observed synthetic cathinones, often present in illicit tablets seized in New Zealand, were chosen for analysis. An ME device (Agilent Bioanalyzer 2100) was used to electrophoretically separate synthetic cathinones. The background electrolyte was composed of a 50 mM sodium tetraborate buffer with 50 mM sodium dodecyl sulphate at pH 9.66. Analytes were derivatised prior to analysis for 3 min at 90 degrees C, employing fluorescein isothiocyanate isomer I (FITC). A characteristic fluorescent profile was obtained for each tablet, in terms of the number of constituents, relative peak height ratios and migration times. The repeatability of the developed method was assessed for a wide range of tablets and relative standard deviations of 0.4-5.2% and 1.6-5.5% were calculated for migration times and peak height ratios, respectively. The use of microchip tablet profiles in the forensic case comparison of illicit drug seizure samples in realistic scenarios is discussed. PMID- 25016533 TI - Simultaneous association of total energy consumption and activity-related energy expenditure with risks of cardiovascular disease, cancer, and diabetes among postmenopausal women. AB - Total energy consumption and activity-related energy expenditure (AREE) estimates that have been calibrated using biomarkers to correct for measurement error were simultaneously associated with the risks of cardiovascular disease, cancer, and diabetes among postmenopausal women who were enrolled in the Women's Health Initiative at 40 US clinical centers and followed from 1994 to the present. Calibrated energy consumption was found to be positively related, and AREE inversely related, to the risks of various cardiovascular diseases, cancers, and diabetes. These associations were not evident in most corresponding analyses that did not correct for measurement error. However, an important analytical caveat relates to the role of body mass index (BMI) (weight (kg)/height (m)(2)). In the calibrated variable analyses, BMI was regarded, along with self-reported data, as a source of information on energy consumption and physical activity, and BMI was otherwise excluded from the disease risk models. This approach cannot be fully justified with available data, and the analyses herein imply a need for improved dietary and physical activity assessment methods and for longitudinal self reported and biomarker data to test and relax modeling assumptions. Estimated hazard ratios for 20% increases in total energy consumption and AREE, respectively, were as follows: 1.49 (95% confidence interval: 1.18, 1.88) and 0.80 (95% confidence interval: 0.69, 0.92) for total cardiovascular disease; 1.43 (95% confidence interval: 1.17, 1.73) and 0.84 (95% confidence interval: 0.73, 0.96) for total invasive cancer; and 4.17 (95% confidence interval: 2.68, 6.49) and 0.60 (95% confidence interval: 0.44, 0.83) for diabetes. PMID- 25016537 TI - Aging adult skull vaults by applying the concept of fractal geometry to high resolution computed tomography images. AB - INTRODUCTION: Aging human remains is a critical issue in anthropology and forensic medicine, and the search for accurate, new age-estimation methods is ongoing. In our study, we, therefore, explored a new approach to investigate a possible correlation between age-at-death (aad) and geometric irregularities in the bone structure of human skull caps. We applied the concept of fractal geometry and fractal dimension D analysis to describe heterogeneity within the bone structure. METHODS: A high-resolution flat-panel computed tomography scanner (eXplore Locus Ultra) was used to obtain 229,500 images from 221 male and 120 female (total 341) European human skulls. Automated image analysis software was developed to evaluate the fractal dimension D, using the mass radius method. The frontal and the occipital portions of the skull caps of adult females and males were investigated separately. The age dependence of the fractal dimension D was studied by correlation analysis, and the prediction accuracy of age-at-death (aad) estimates for individual observations was calculated. RESULTS: D values for human skull caps scatter strongly as a function of age. We found sex-dependent correlation coefficients (CC) between D and age for adults (females CC=-0.67; males CC=-0.05). Prediction errors for aad estimates for individual observations were in the range of +/-18 years at a 75% confidence interval. CONCLUSIONS: The detailed quantitative description of age-dependent irregularities in the bone microarchitecture of skull vaults through fractal dimension analysis does not, as we had hoped, enable a new aging method. Severe scattering of the data leads to an estimation error that is too great for this method to be of practical relevance in aad estimates. Thus, we disclosed an interesting sex difference. PMID- 25016538 TI - Necrophilous Staphylininae (Coleoptera: Staphylinidae) as indicators of season of death and corpse relocation. AB - Several case studies confirm that habitat and seasonal preferences of necrophilous insects are the source of valuable information about the season of death or corpse relocation. Rove beetles (Staphylinidae) are common predators found on corpses and subfamily Staphylininae includes species of the largest forensic importance. In order to evaluate usefulness of Staphylininae as indicators of season of death or corpse relocation, a pig carrion experiment was made from April to October in open and forest habitats of Central Europe. Forty species of Staphylininae were collected, with hairy rove beetle (Creophilus maxillosus) being the most abundant. Some species exhibited a clear preference towards particular habitats. It was found that Philonthus lepidus was exclusive to open habitats and therefore may be useful as indicator of corpse relocation from open to forest habitats. Philonthus decorus was the only species found exclusively on carcasses in forests. Clear seasonality was present in nine species. Philonthus lepidus, Bisnius nitidulus, Philonthusconcinnus and Gabrius osseticus were spring-early summer species, while Philonthusspinipes and Ocypus olens were late summer-early fall species. Bisnius fimetarius and Staphylinus erythropterus were spring-summer species. Platydracus stercorarius was summer species. These results indicate that some Staphylininae are good candidates for indicators of season of death or corpse relocation. PMID- 25016539 TI - Wetting dynamics of colloidal dispersions on agar gel surfaces. AB - The effects of silica particle addition on the wetting velocity on flat and fractal agar gel surfaces were analyzed along with the applicability of such particles for controlling the wetting dynamics of water. The contact angles (thetaD) of the colloidal dispersions obeyed the power law, i.e., thetaD?t(-x), where t is time and x is a constant. Wetting was inhibited by the addition of a suitable amount of 20-nm-diameter silica particles. Specifically, the exponent x reached a minimum value for a silica composition of 0.1wt%. However, such inhibition effects were not observed upon the addition of silica particles with diameters of 100, 550, and, 1000nm. The mechanism of the inhibition of the liquid wetting on gel surfaces may be attributed to a slight increase in local viscosity around the contact line during wetting. PMID- 25016540 TI - On formulating ophthalmic emulsions. AB - The formulation of dilute, transparent ophthalmic emulsions (eye drops) with long shelf lives is a challenge because of the tendency of the emulsion droplets to aggregate, particularly in the presence of the water-soluble polymers typically used in eye drops. While many functions of eye drops, such as lubricity and residence time in the eye, are promoted by high concentrations of high molecular weight water-soluble polymers, emulsified lipids and drugs aggregate in the eye drop bottle if the polymer concentration is above the critical flocculation concentration (CFC). The purpose is to develop a simple approach to predict the CFC for polymers based on information readily available in the literature. High molecular weight guar was hydrolyzed to give a series of guar samples spanning a wide range of average molecular weights. The CFC values and critical viscosity concentrations were measured as functions guar properties, using electrophoresis, dynamic light scattering and rheology measurements. The higher the guar molecular weight, the lower was the CFC, the maximum concentration that can be tolerated in the eye drop formulation. The guar CFC values were approximately equal to the overlap concentrations where guar molecules start to overlap in solution. We propose that the CFC can be estimated for any water-soluble polymer using the polymer molecular weight and the readily available Mark-Houwink parameters, thus providing a design rule for ophthalmic emulsions. PMID- 25016541 TI - Enhanced antimelanoma activity of methotrexate and zoledronic acid within polymeric sandwiches. AB - New therapies are urgently needed against melanoma, one of the most aggressive tumors. Melanoma cells are resistant to the antifolate methotrexate (MTX), since MTX is taken up by the folate receptor-alpha (FRalpha), sequestered in melanosomes and exported out of the cell. The bisphosphonate zoledronic acid (ZOL) is active in several non-skeletal tumors; however, its antitumoral activity is hampered by its long-term accumulation in bones and low cellular permeability. Recently, we showed that core-shell tecto-dendrimers made of amine-terminated polyamidoamine generation 5 dendrimer (G5) as core and carboxyl-terminated G2.5 dendrimer as shell (G5G2.5) had selective cytotoxicity to melanoma cells. We hypothesized here that the activity of MTX and ZOL on melanoma cells could be enhanced when loaded within G5G2.5. MTX and ZOL were loaded within G5 cores, which were coated by a covalently bound shell of G2.5 dendrimers (drug sandwiches). 12nm mean diameter and -12mV Z potential drug-sandwiches incorporating 6 and 31 molecules of MTX and ZOL, respectively, per G5G2.5, showed higher cytotoxicity (by MTT and apoptosis/necrosis assays) to melanoma (Sk-Mel 28) cells than free drugs and G5G2.5. Only MTX-sandwich was cytotoxic to Sk-Mel 28 cells and harmless to keratinocytes (HaCaT cells). The intracellular pathway of G5G2.5 was followed using chemical inhibitors of endocytosis. The increased cytotoxicity of MTX-sandwich could be due to its uptake by macropinocytosis instead of by FRalpha, avoiding MTX exocytosis. The increased cytotoxicity of ZOL sandwich could be due to an increased intracellular accumulation of ZOL, owed by its endocytic uptake instead of diffusing as free drug. PMID- 25016542 TI - The effect of dendrimer generations on the structure of Q(G) LLC mesophase and drug release. AB - In this paper the cosolubilization of 2nd, 3rd, and 4th generations of polypropyleneimine (PPI: PPI-G2, -G3, and -G4) dendrimers with sodium diclofenac (Na-DFC) into reverse gyroid cubic (Q(G)) liquid crystals is reported. Structural properties and interactions of PPI dendrimers with and without the drug were studied using small-angle X-ray scattering, attenuated total reflected Fourier transform infrared (ATR-FTIR) spectroscopy, and differential scanning calorimetry (DSC) measurements. Incorporation of PPI-G2 (without Na-DFC) into Q(G) mesophase led to a decrease of 78A in the lattice parameter. Solubilization of higher PPI generations, G3 and G4, led to increases in the lattice parameter to 57A and 64A, respectively. At 25wt%, each of the dendrimers caused a phase transition Q(G) >reverse hexagonal (HII). According to ATR-FTIR and DSC, the large lattice parameter values of G3 and G4 (relative to G2) embedment were assigned to their interactions with the carboxyl groups of GMO at the interface in comparison to the strong interaction of PPI-G2 with the water. Cosolubilization of Na-DFC with PPI-G2 revealed enlargement of the lattice parameter (of the new HII mesophase), while in the case of G3 and G4 systems no significant influence was seen with Na DFC. The release of Na-DFC from Q(G) and HII systems was followed by UV-vis spectroscopy and revealed generation-dependence on drug release. As dendrimer generation increased, the cumulative drug release decreased. PMID- 25016543 TI - Films loaded with insulin-coated nanoparticles (ICNP) as potential platforms for peptide buccal delivery. AB - The goal of this investigation was to develop films containing insulin-coated nanoparticles and evaluate their performance in vitro as potential peptide delivery systems. To incorporate insulin into the films, a new antisolvent co precipitation fabrication process was adapted to obtain insulin-coated nanoparticles (ICNPs). The ICNPs were embedded in polymeric films containing a cationic polymethacrylate derivative (ERL) or a combination of ERL with hydroxypropyl methylcellulose (HPMC). ICNP-loaded films were characterized for morphology, mucoadhesion, and insulin release. Furthermore, in vitro insulin permeation was evaluated using a cultured tridimensional human buccal mucosa model. The antisolvent co-precipitation method was successfully adapted to obtain ICNPs with 40% (w/w) insulin load, achieving 323+/-8nm particles with a high zeta potential of 32.4+/-0.8mV, indicating good stability. High yields were obtained after manufacture and the insulin content did not decrease after one month storage. ICNP-embedded films using ERL as the polymer matrix presented excellent mucoadhesive and insulin release properties. A high permeation enhancement effect was observed for ICNP-loaded ERL films in comparison with ICNP-loaded ERL-HPMC films and a control insulin solution. ICNP-loaded ERL formulations were found to be more effective in terms of film performance and insulin permeation through the human buccal mucosa model, and thus are a promising delivery system for buccal administration of a peptide such as insulin. PMID- 25016544 TI - Influence of surfactant composition on physical and oxidative stability of Quillaja saponin-stabilized lipid particles with encapsulated omega-3 fish oil. AB - The purpose of this study was to investigate the potential of a saponin-rich extract of Quillaja saponaria to replace bile salts in the surfactant formulations for stabilization of nanostructured lipid carriers (NLC). The influence of Quillaja extract and/or high-melting lecithin at different concentrations on physical and oxidative stability was evaluated in (i) NLC containing tristearin and omega-3 fish oil, (ii) omega-3 fish oil-in-water emulsion, and (iii) solid lipid nanoparticles (SLN) containing tristearin. Best physical, polymorphic and oxidative stability of NLC were achieved with a surfactant combination of 2.4% (w/w) Quillaja extract and 0.6% (w/w) high-melting lecithin. The results showed that encapsulation of omega-3 fish oil into NLC inhibited the formation of lipid hydroperoxides, propanal and hexanal by 72, 53 and 57%, respectively, compared to the fish oil-in-water emulsion prepared with the same surfactants. This indicated that the low oxidation observed in NLC cannot be due to potential antioxidative effects of the surfactant combination itself. Evidence is accumulating that tristearin is able to form a protective shell around the omega-3 fish oil, when crystallization is induced via high melting phospholipids in the solidified interfacial layer. PMID- 25016545 TI - Enhanced oral bioavailability of nevirapine within micellar nanocarriers compared with Viramune((r)). AB - In this work, Nevirapine (NVP) was encapsulated within three derivatives of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) block copolymers (Tetronic((r)) 904, 1107 and Pluronic((r)) F127) with and without the addition of three pharmaceutical cosolvents (glycerin, propylene glycol and polyethylene glycol 400) over a wider range of concentrations (0-40% v/v). Also, we evaluated the effect of addition of the cosolvents on the micellar size as determined by dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM). The solubilization capacity of the systems was investigated by UV-spectrophotometry (282nm) and the systems stability was evaluated for 1 month at 25 degrees C. Finally, oral bioavailability of the NVP-loaded micellar systems (2mg/mL) was assessed in male Wistar rats (8mg/kg) and compared with a pediatric commercially available formulation (Viramune((r))). The present study demonstrates that PEO-PPO-PEO polymeric micelles were able to enhance apparent aqueous solubility of NVP with the addition of cosolvents. Moreover, micellar nanocarriers significantly (p<0.05) improved the oral bioavailability of the drug versus Viramune((r)). Overall results support the suitability of the strategy toward the development of an optimized NVP aqueous formulation to prevent HIV/AIDS mother-to-child transmission. PMID- 25016546 TI - Formation, characterization and enzyme activity in water-in-hydrophobic ionic liquid microemulsion stabilized by mixed cationic/nonionic surfactants. AB - The phase behavior of the pseudo ternary system 1-tetradecyl-3-methylimidazolium bromide ([C14mim]Br)/Triton X-100/H2O/1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim]PF6) has been studied at 35 degrees C. With the increase in the mole fraction of Triton X-100 in the mixed surfactants, the water solubilization capacity increases and the monophasic area enlarges. The H2O-in [Bmim]PF6 (W/IL) microemulsion was identified via electrical conductivity measurement. The existence of bulk water in the W/IL microemulsion was demonstrated based on the change of the O-D vibration frequency with content of D2O added and confirmed using UV-vis technique with CoCl2 as probe. Laccase can be solubilized in the W/IL microemulsion and exhibits a catalytic activity. The interface of the W/IL microemulsion has an inhibitory effect on the expression of the laccase activity, and the inhibitory effect is varied with the molar ratio of the mixed surfactants. PMID- 25016547 TI - Guiding the behaviors of human umbilical vein endothelial cells with patterned silk fibroin films. AB - Silk fibroin is an ideal blood vessel substitute due to its advantageous qualities including variable size, good suture retention, low thrombogenicity, non-toxicity, non-immunogenicity, biocompatibility, and controllable biodegradation. In this study, silk fibroin films with a variety of surface patterns (e.g. square wells, round wells plus square pillars, square pillars, and gratings) were prepared for in vitro characterization of human umbilical vein endothelial cell's (HUVEC) response. The affects of biomimetic length-scale topographic cues on the cell orientation/elongation, proliferation, and cell substrate interactions have been investigated. The density of cells is significantly decreased in response to the grating patterns (70+/-3nm depth, 600+/-8nm pitch) and the square pillars (333+/-42nm gap). Most notably, we observed the contact guidance response of filopodia of cells cultured on the surface of round wells plus square pillars. Overall, our data demonstrates that the patterned silk fibroin films have an impact on the behaviors of human umbilical vein endothelial cells. PMID- 25016551 TI - Effect of GnRH agonist therapy on the expression of human heat shock protein 70 in eutopic and ectopic endometria of women with endometriosis. AB - OBJECTIVES: Human heat shock protein 70 (HSP70) has been reported to enhance Toll like receptor 4-mediated pelvic inflammation and growth of endometriotic cells. However, information on tissue expression of HSP70 before and after treatment with estrogen suppressing agent is scanty. Here, we investigated tissue expression HSP70 in the eutopic/ectopic endometria of gonadotropin-releasing hormone agonist (GnRHa)-treated and -non-treated women with endometriosis. STUDY DESIGN: Biopsy specimens were collected from peritoneal lesions, cyst walls, and corresponding endometria of 20 women with peritoneal endometriosis, 35 women with ovarian endometrioma, and 15 control women during laparoscopy. Fifteen women with ovarian endometrioma were treated with GnRHa for a variable period of 4-6 months before laparoscopy. The immunoexpressions of HSP70 and CD68-positive macrophages (Mphi) in endometria, peritoneal lesions, and cyst walls were examined by immunohistochemistry. The immunoreactivity of HSP70 in tissues was analyzed by quantitative-histogram (Q-H) score. RESULTS: Tissue expression of HSP70 was found to be the highest in the menstrual phase than in other phases of the menstrual cycle. A significantly higher immunoreactivity of HSP70 was found in the eutopic endometria of women with peritoneal and ovarian endometriosis than in controls and in opaque red lesions than in other peritoneal lesions. A significant correlation between Q-H scores of HSP70 and CD68-positive Mphi numbers was found in the endometria derived from women with peritoneal endometriosis (r=0.481) and in ovarian endometrioma (r=0.560) but not in control women. The Q-H scores of HSP70 expression were significantly lower in cyst walls, coexisting peritoneal lesions and corresponding endometria of women with ovarian endometrioma after GnRHa treatment comparing to similar tissues derived from women without GnRHa treatment. CONCLUSION: These results suggest that as a marker of tissue stress reaction, immunoexpression of HSP70 was highly increased in pathological lesions and endometria of women with endometriosis and had a significant correlation with tissue inflammatory reaction. The higher tissue expression of HSP70 can be effectively suppressed after GnRHa treatment. PMID- 25016552 TI - Gasless laparoendoscopic single-site surgery for management of adnexal masses during pregnancy. AB - OBJECTIVE: To evaluate the safety and feasibility of gasless transumbilical laparoendoscopic single-site (LESS) surgery with abdominal-wall lift method for the management of adnexal masses during pregnancy. STUDY DESIGN: Retrospective study of 29 women each undergoing gasless LESS surgery and multiport laparoscopic surgery for the management of adnexal masses during pregnancy. The two groups were compared for their surgical and pregnancy outcome measures. RESULTS: Conceptions occurred spontaneously in all women including 2 cases each of monochorionic-diamniotic twins in both groups. Three and 2 cases of bilateral adnexal masses were noted in the LESS surgery group and the multiport laparoscopic surgery group, respectively. Estimated gestational age at surgery was significantly older and tumor diameter was significantly larger in the LESS surgery group than in the multiport laparoscopic surgery group. However, significant differences between the two groups were not evident in other patient demographics. There were no significant differences in type of surgery between the two groups. In 28 masses that received LESS adnexal cystectomy, LESS-assisted extracorporeal cystectomy was achieved in 23 masses. Excised tissue weight in the LESS surgery group was significantly heavier than in the multiport laparoscopic surgery group. Significant differences were not observed in other operative parameters between the two groups. Significant differences in postoperative complications were not identified between the two groups. Benign pathologies were obtained in 61 masses from both groups, except for a case of clear cell carcinoma managed by LESS salpingo-oophorectomy. Significant differences in pathological diagnosis were not observed between the two groups. Delivery of 61 neonates occurred in 57 women except for the case of clear cell carcinoma in which termination of the pregnancy was chosen. In the LESS surgery group, threatened premature delivery requiring admission and preterm delivery was noted in 3 and 4 cases, respectively. However, significant differences in pregnancy outcomes were not identified between the two groups. The neonatal course was uneventful in all infants. CONCLUSION: Gasless LESS surgery for adnexal masses during pregnancy is a safe and feasible alternative to multiport laparoscopic surgery, with the avoidance of potential negative effects of carbon dioxide gas insufflation on mother and fetus. PMID- 25016553 TI - Predictive value of volume of cervical tissue removed during LLETZ on subsequent preterm delivery: a cohort study. AB - OBJECTIVE: To evaluate the impact of volume of tissue removed during large loop excision of transformation zone on subsequent preterm birth rates. STUDY DESIGN: A retrospective cohort study was carried out in a single, large tertiary referral unit in UK. A total of 556 women who delivered between January 2008 and December 2011 following a previous large loop excision of transformation zone procedure or punch biopsy were identified from the maternity and colposcopy databases. Demographic data, gestational age at delivery, birthweight, neonatal outcome and dimensions of excised cervical specimen were collected. Pregnancy outcomes for women who had a previous loop excision were compared to a matched control group who had undergone punch biopsies only. RESULTS: There was a significant increase in preterm birth rate in the large loop excision group compared to the control group (9.0% vs. 3.6%, respectively, RR 2.5, 95% CI 1.224-5.107). Women who had undergone at least one previous loop excision had more than a threefold increased risk of spontaneous preterm birth compared with their matched controls. However, no relationship between volume or depth of cervical tissue excised and subsequent gestation at delivery could be demonstrated. CONCLUSIONS: Whilst LLETZ is associated with an increased rate of preterm birth, the volume of tissue removed does not appear to influence the subsequent gestational age at delivery. This should reassure clinicians who should continue to perform LLETZ with adequate tissue margins to ensure complete resection of disease. PMID- 25016554 TI - International note: prevailing with extracurricular activities in an alcohol dominated environment: sex differences in resilience among middle school youth. AB - Extracurricular involvement creates an outlet for adolescents to gain skills and resources that assist them in overcoming certain risks. Resiliency theory is applied to study the promotive effects of extracurricular activity involvement as this may help Polish youth overcome risks for alcohol use. Our data include 2903, 13 and 14 year old Polish adolescents. We use regression analysis to test the main and interaction effects of extracurricular involvement after adjusting for demographics and social influences. Sex differences are examined within the resilience framework. We found protective effects of extracurricular involvement for males, but only a compensatory effect for females. Implications for future research and intervention are discussed. PMID- 25016556 TI - Polonium-210 and selenium in tissues and tissue extracts of the mussel Mytilus galloprovincialis (Gulf of Trieste). AB - Marine organisms such as mussels and fish take up polonium (Po) and selenium (Se), and distribute them into different cellular components and compartments. Due to its high radiotoxicity and possible biomagnification across the marine food chain Po-210 is potentially hazardous, while selenium is an essential trace element for humans and animals. The aim of this study was to investigate and compare the presence and extractability of the elements in the mussels Mytilus galloprovincialis collected in the Gulf of Trieste. The levels of Po-210 in the samples ranged from 220 to 400 Bq kg(-1) and of Se from 2.6 to 8.2 mg kg(-1), both on a dry matter basis. Using various extraction types and conditions in water, buffer or enzymatic media, the best extractability was obtained with enzymatic extraction (Protease XIV, 1h shaking at 40 degrees C) and the worst by water extraction (24 h shaking at 37 degrees C). 90% of Po-210 and 70% of Se was extractable in the first case versus less than 10% of Po-210 and less than 40% of Se in the second. Such evident differences in extractability between the investigated elements point to different metabolic pathways of the two elements. In enzymatic extracts Se speciation revealed three Se compounds (SeCys2, SeMet, one undefined), while Po-210 levels were too low to allow any conclusions about speciation. PMID- 25016555 TI - Arbuscular mycorrhizal symbiosis influences arsenic accumulation and speciation in Medicago truncatula L. in arsenic-contaminated soil. AB - In two pot experiments, wild type and a non-mycorrhizal mutant (TR25:3-1) of Medicago truncatula were grown in arsenic (As)-contaminated soil to investigate the influences of arbuscular mycorrhizal fungi (AMF) on As accumulation and speciation in host plants. The results indicated that the plant biomass of M. truncatula was dramatically increased by AM symbiosis. Mycorrhizal colonization significantly increased phosphorus concentrations and decreased As concentrations in plants. Moreover, mycorrhizal colonization generally increased the percentage of arsenite in total As both in shoots and roots, while dimethylarsenic acid (DMA) was only detected in shoots of mycorrhizal plants. The results suggested that AMF are most likely to get involved in the methylating of inorganic As into less toxic organic DMA and also in the reduction of arsenate to arsenite. The study allowed a deeper insight into the As detoxification mechanisms in AM associations. By using the mutant M. truncatula, we demonstrated the importance of AMF in plant As tolerance under natural conditions. PMID- 25016557 TI - Molecular modeling of interactions between heavy crude oil and the soil organic matter coated quartz surface. AB - Molecular dynamic (MD) simulation was applied to evaluate the mobility, diffusivity and partitioning of SARA (saturates, aromatics, resins, asphaltenes) fractions of heavy crude oil on soil organic matter (SOM) coated quartz surface. Four types of SOM were investigated including Leonardite humic acid, Temple Northeastern-Birmingham humic acid, Chelsea soil humic acid and Suwannee river fulvic acid. The SOM aggregation at oil-quartz interface decreased the adsorption of SARA on the quartz surface by 13-83%. Although the SOM tended to promote asphaltenes aggregation, the overall mobility of SARA was significantly greater on SOM-quartz complex than on pure quartz. Particularly, the diffusion coefficient of asphaltenes and resins increased by up to one-order of magnitude after SOM addition. The SOM increased the overall oil adsorption capacity but also mobilized SARA by driving them from the viscous oil phase and rigid quartz to the elastic SOM. This highlighted the potential of SOM addition for increasing the bioavailability of heavy crude oil without necessarily increasing the environmental risks. The MD simulation was demonstrated to be helpful for interpreting the role of SOM and the host oil phase for the adsorption and partitioning of SARA molecules, which is the key for developing more realistic remediation appraisal for heavy crude oil in soils. PMID- 25016558 TI - Clinical applications of analysis of plasma circulating complete hydatidiform mole pregnancy-associated miRNAs in gestational trophoblastic neoplasia: a preliminary investigation. AB - The aim of this study was to investigate the clinical application of plasma complete hydatidiform mole pregnancy-associated microRNAs (CHM-miRNAs: hsa-miR 520b, hsa-miR-520f and hsa-miR-520c-3p). We measured plasma CHM-miRNA concentration by real-time quantitative reverse transcriptase polymerase chain reaction in two cases of CHM resulting in gestational trophoblastic neoplasia later. As progress of treatments in both cases, the plasma concentrations of CHM miRNAs showed a decreasing tendency similar to the pattern for serum hCG concentration, but exhibited a transient increasing tendency after each course of chemotherapy, suggesting that the plasma CHM-miRNAs could be an additional follow up marker for malignant changes of CHM. PMID- 25016559 TI - We are teachers by design--the time machine approach. PMID- 25016560 TI - Effective feedback strategies for teaching in pediatric and adolescent gynecology. AB - The clinical setting of pediatric and adolescent gynecology poses complex tasks for the physician with its numerous procedures and the communication demands of interacting with an adolescent and/or guardian. Needless to say, teaching within this setting is highly demanding. Regardless of the level of learner or the professional role (e.g., nurse, medical student, resident, physician assistant) represented, clinical teaching requires that the instructor provide feedback in ways that benefit the student. Recent research on feedback suggests a more complex understanding of feedback than in the past. This article highlights key research and its implication for effective feedback by presenting a three part framework; know your learner, understand what is to be learned, and plan for improvement. PMID- 25016561 TI - Experiencing sexuality in youth living in Greece: contraceptive practices, risk taking, and psychosocial status. AB - STUDY OBJECTIVE: To assess initiation of sexual activity and contraception methods used among Greek adolescents. To determine the association of adolescents' emotional and behavioral status with their sexual activity. DESIGN: A descriptive cross-sectional survey was conducted. SETTING, PARTICIPANTS: The population (N = 1074, age 14-16) consisted of a random sample, stratified according to locality and population density, of 20 public junior high and high schools located in the urban district of Athens, Greece. INTERVENTIONS: Anonymous self-reported questionnaires were used to assess sexual activity choices and contraception methods. The Youth Self-Report questionnaire was used to evaluate the psychosocial competencies and difficulties of Greek adolescents. MEASURES: Analyses included frequencies with chi-square tests and multivariate logistic regression analysis. MAIN OUTCOME: Factors that may influence sexual engagement of Greek adolescents were assessed. RESULTS: Of the adolescents who completed the questionnaire 21.8% reported having experienced sexual intercourse. The male/female ratio was 3/1 (P < .001) and the mean age of sexual debut was 14.5 +/ 0.9 years. Condoms were the most preferred contraceptive method (79.9%), followed by withdrawal (38.9%). Emergency contraception was used by 9.6% of participants. Adolescents with separated, divorced or with a deceased parent, and non-Greek nationality have higher possibility of being sexually active. Adolescents who reported sexual intercourse had significantly higher score of thought problems (beta = 1.07, SE = 0.35, P = .002), attention difficulties (beta = 0.67, SE = 0.29, P = .022), delinquent behavior problems (beta = 2.37, SE = 0.34, P < .001), aggressive behavior (beta = 1.97, SE = 0.48, P < .001), and externalizing problems (beta = 4.18, SE = 0.78, P < .001). CONCLUSIONS: Engagement in sexual activities was significantly associated with psychosocial difficulties among adolescents living in Greece. PMID- 25016562 TI - P-wave dispersion and maximum duration are independently associated with insulin resistance in metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MS) is an important risk factor for atrial fibrillation. P-wave indices, including P-wave dispersion (PWD) and P-wave duration, can be used as non-invasive markers of heterogeneous atrial conduction. The aim of our study was to evaluate the relationship between P-wave indices and insulin resistance in patients with MS. METHODS: Seventy-four patients with MS (44 men, 30 women) and 81 patients without MS (48 men, 33 women) were enrolled in the study. A diagnosis of MS was made as defined by the Adult Treatment Panel III of the National Cholesterol Education Program. Insulin resistance was estimated using the homeostasis model assessment (HOMA) index. P-wave maximum duration (Pmax) and P-wave minimum duration (Pmin) were calculated on a 12-lead electrocardiogram, and the difference between the Pmax and the Pmin was defined as PWD. RESULTS: Patients with MS had a longer PWD and a higher Pmax compared with patients without MS (PWD, 35.65+/-4.36 vs. 26.27+/-4.04, P<0.001; Pmax, 117.12+/-10.77 vs. 105.98+/-9.02, P<0.001), whereas no difference was found between Pmin values from MS patients and controls (81.47+/-9.54 vs. 79.70+/-8.76, P=0.231). Stepwise multivariate analysis revealed only the HOMA index to be an independent predictor of PWD (beta=3.115, P<0.001) and Pmax (beta=7.175, P<0.001). CONCLUSION: This study suggests that patients with MS have a prolonged PWD and Pmax. The increase in these parameters may be an indicator for identification of patients at an increased risk for atrial fibrillation. PMID- 25016563 TI - Subthalamic involvement in monetary reward and its dysfunction in parkinsonian gamblers. PMID- 25016564 TI - Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke. AB - BACKGROUND: Orolingual angio-oedema is a recognised complication of tissue plasminogen activator (tPA) for ischaemic stroke. We investigated its incidence, clinical characteristics and relationship with other factors in patients receiving tPA at a UK centre. METHODS: 530 consecutive patients (median age 70 years) receiving tPA treatment for confirmed ischaemic stroke were included. Cases were defined as those developing angio-oedema within 24 h of initiation of tPA. Angio-oedema was retrospectively classified as mild, moderate or severe using predefined criteria. The primary analysis was the association between prior ACE inhibitor (ACE-I) treatment and angio-oedema. RESULTS: Orolingual angio oedema was observed in 42 patients (7.9%; 95% CI 5.5% to 10.6%), ranging from 5 to 189 min after initiation of tPA (median 65 min). 12% of the angio-oedema cases were severe (1% of all patients treated with tPA), requiring urgent advanced airway management. 172 patients (33%) were taking ACE-I. In multifactorial analyses, only prior ACE-I treatment remained a significant independent predictor of angio-oedema (odds ratio (OR) 2.3; 95% CI 1.1 to 4.7). CONCLUSIONS: Angio oedema occurs more frequently than previously reported and is associated with preceding ACE-I treatment. Angio-oedema may be delayed and progress to life threatening airway compromise, which has implications for the assessment and delivery of thrombolysis. PMID- 25016565 TI - New evidence of early Neanderthal disappearance in the Iberian Peninsula. AB - The timing of the end of the Middle Palaeolithic and the disappearance of Neanderthals continue to be strongly debated. Current chronometric evidence from different European sites pushes the end of the Middle Palaeolithic throughout the continent back to around 42 thousand years ago (ka). This has called into question some of the dates from the Iberian Peninsula, previously considered as one of the last refuge zones of the Neanderthals. Evidence of Neanderthal occupation in Iberia after 42 ka is now very scarce and open to debate on chronological and technological grounds. Here we report thermoluminescence (TL) and optically stimulated luminescence (OSL) dates from El Salt, a Middle Palaeolithic site in Alicante, Spain, the archaeological sequence of which shows a transition from recurrent to sporadic human occupation culminating in the abandonment of the site. The new dates place this sequence within MIS 3, between ca. 60 and 45 ka. An abrupt sedimentary change towards the top of the sequence suggests a strong aridification episode coinciding with the last Neanderthal occupation of the site. These results are in agreement with current chronometric data from other sites in the Iberian Peninsula and point towards possible breakdown and disappearance of the Neanderthal local population around the time of the Heinrich 5 event. Iberian sites with recent dates (<40 ka) attributed to the Middle Palaeolithic should be revised in the light of these data. PMID- 25016568 TI - Hargreaves does not evaluate nociception following a surgical laparotomy in Xenopus leavis frogs. AB - The present study was performed to determine the effectiveness of the Hargreaves test for the evaluation of nociception in frogs, more precisely to determine if cutaneous thresholds to a radiant heat stimulus would increase with analgesics following an abdominal laparotomy performed under general anaesthesia. Non breeding female Xenopus leavis frogs (3 groups (non-anaesthetized, anaesthetized with tricaine methanesulfonate (MS222), with or without an abdominal laparotomy) were used to evaluate the effectiveness of the Hargreaves test. Cutaneous thresholds were evaluated at baseline and following anaesthetic recovery (over 8 h) at six different body locations. Increased reaction times were observed in the gular area only at 1 h post-recovery following a MS222 bath immersion in frogs with (p < 0.02) and without the abdominal laparotomy (p < 0.002). In conclusion, the Hargreaves test does not provide an adequate test to evaluate nociception induced by an abdominal laparotomy and consequently cannot be used to evaluate analgesics in X. leavis frogs. PMID- 25016569 TI - Hirayama disease and immunoglobulin A deficiency: a coincidence or a syndrome. PMID- 25016571 TI - Virtual reality walking and dopamine: opening new doorways to understanding freezing of gait in Parkinson's disease. AB - Freezing of gait (FOG) is a disabling form of gait disturbance that is common in the advanced stages of Parkinson's disease (PD). Despite its prevalence, methods of studying and assessing FOG are limited. We have previously shown that a virtual reality paradigm was able to distinguish between those who report FOG ("freezers") and those who do not report FOG ("non-freezers"). In this paradigm, 'freezers' were found to have prolonged footstep latency in response to known triggers of FOG including doorways, sliding doors and dual-tasking. In this study, we employed the same paradigm to assess performance of 27 freezers and 14 non-freezers in their clinical 'on' and 'off' medication states. In this study, only participants in the freezing group demonstrated statistically significant increases in latencies experienced in the 'off' state compared to the 'on' state in response to wide and narrow doorways and the opening of a sliding door. By contrast, these behavioral differences were not apparent in non-freezers. Furthermore the delay was specific to environmental cues and was not due to generalized slowing in the 'off' state. The findings suggest that this motor delay when processing environmentally salient cues is specific to freezers and is partially mediated by dopamine-dependent neurocircuitry. PMID- 25016570 TI - Association between nocturnal/supine hypertension and restless legs syndrome in patients with Parkinson's disease. AB - BACKGROUND AND OBJECTIVE: Autonomic disturbances and sleep problems are common non-motor symptoms in patients with Parkinson's disease (PD). Orthostatic hypotension, supine hypertension (SH), and nocturnal hypertension (NH) are inter related in patients with PD. These abnormalities might be associated with restless legs syndrome (RLS), which occurs predominantly at rest or during sleep. Few reports have suggested an association between circadian blood pressure disturbances and RLS in the general population. We evaluated the relationship between neurocardiovascular blood pressure alterations and RLS in patients with early PD. METHODS: A total of 225 patients, newly diagnosed with PD, were included in the study. RLS was diagnosed by the International Restless Legs Syndrome Study Group's diagnostic criteria. Orthostatic vital signs and ambulatory 24-h blood pressure were monitored and recorded. RESULTS: Thirty-six (16.0%) participating patients had RLS. SH and NH were more frequent in the PD+RLS group than in the group without RLS. Supine blood pressure, orthostatic decline in blood pressure, nighttime blood pressure, and the standard deviation of systolic blood pressure were significantly higher in the PD+RLS group than in the group without RLS. CONCLUSION: RLS is related to nocturnal/supine hypertension and blood pressure fluctuations, suggesting a neuropathological association between autonomic and sleep dysfunctions in patients with PD. RLS may be a determinant of neurocirculatory abnormalities. Detecting and effectively treating RLS might slow the rate of pressure-related neurocardiovascular damage in dysautonomic patients with PD. PMID- 25016572 TI - Association of heme oxygenase-1 gene rs2071746 polymorphism with vascular outcomes in patients with atherosclerotic stroke. AB - As an inducible isoform of heme oxygenase (HO), HO-1 was suggested to have an anti-oxidative stress, anti-inflammatory, anti-apoptotic and anti-proliferative effect. It was regarded as an important cytoprotective enzyme. We undertook this study to investigate whether HO-1 gene rs2071746 polymorphism was associated with clinical outcomes in atherosclerosis ischemic stroke patients. Between December 2009 and October 2012, consecutive atherosclerosis ischemic stroke patients were enrolled. The primary endpoint was the composite of vascular death, nonfatal ischemic stroke and myocardial infarct. A total of 961 patients were enrolled. After an average follow-up of 15.13 (SD=7.42) months, 89 patients (9.26%) had the primary endpoint. The cumulative incidence of the primary endpoint was significantly lower in A carriers (AT+AA) than TT genotype (7.9% vs. 12.2%, HR=0.648, 95% CI: 0.425-0.988, P=0.044). After adjustment for age, sex and other cardiovascular risk factors, we found that A carrier was an independent protective factor for atherosclerosis ischemic stroke (HR=0.646, 95% CI: 0.420 0.994, P=0.047). Age (HR=1.023, P=0.028) and low level of HDL (HR=1.772, P=0.012) were independent risk factors for the primary endpoint. In conclusion, HO-1 gene rs2071746 A allele carrier might be a protective factor for patients with atherosclerotic stroke. PMID- 25016573 TI - Dissecting conformational contributions to glycosidase catalysis and inhibition. AB - Glycoside hydrolases (GHs) are classified into >100 sequence-based families. These enzymes process a wide variety of complex carbohydrates with varying stereochemistry at the anomeric and other ring positions. The shapes that these sugars adopt upon binding to their cognate GHs, and the conformational changes that occur along the catalysis reaction coordinate is termed the conformational itinerary. Efforts to define the conformational itineraries of GHs have focussed upon the critical points of the reaction: substrate-bound (Michaelis), transition state, intermediate (if relevant) and product-bound. Recent approaches to defining conformational itineraries that marry X-ray crystallography of enzymes bound to ligands that mimic the critical points, along with advanced computational methods and kinetic isotope effects are discussed. PMID- 25016575 TI - N-acetyl cysteine regulates the phosphorylation of JAK proteins following CD40 activation of human memory B cells. AB - During their development, human B lymphocytes migrate into various environments, each presenting important variations in their redox balance depending on oxygen availability. The modulation of the cells surroundings redox balance leads to the regulation of reactive oxygen species produced by the cell. These molecules are involved in the state of oxidation of the cytosol and affect many pathways involved in cell development, differentiation and protein secretion. B lymphocytes cultured in presence of interleukin (IL)-2, IL-4, IL-10 and under CD154 stimulation, present increases in their intracellular levels of ROS. However, when N-acetyl cysteine (NAC), an antioxidant, is added, STAT3 phosphorylation is decreased. In this study, we show that in activated human memory B cells, NAC inhibited STAT3 phosphorylation on tyrosine 705 but not on Serine 727. Moreover, higher concentrations of NAC decreased STAT3 synthesis. Two other antioxidants, alpha-tocopherol and Trolox, did not affect STAT3 phosphorylation. Furthermore, two kinases involved in STAT3 activation, known as JAK2 and JAK3, appeared down-regulated in presence of NAC. In parallel, 3h after antioxidants incubation, we have observed a decrease in SOCS1 and SOCS3 protein levels, which seems time-related to antioxidant treatment. The decrease in the phosphorylation of JAK2 and JAK3, earlier in the process, could explain the downregulation of STAT3 and offer a hypothesis on the mechanism of action of NAC antioxidant properties which were confirmed by a decrease in the level of S glutathionylation of proteins. The reduced expression of SOCS1 and SOCS3 appears directly linked to the inhibition of this STAT3-regulated pathway. In summary, NAC appears as a potential regulator of the STAT3 pathway. PMID- 25016574 TI - Both positive and negative effects on immune responses by expression of a second class II MHC molecule. AB - It is perplexing why vertebrates express a limited number of major histocompatibility complex (MHC) molecules when theoretically, having a greater repertoire of MHC molecules would increase the number of epitopes presented, thereby enhancing thymic selection and T cell response to pathogens. It is possible that any positive effects would either be neutralized or outweighed by negative selection restricting the T cell repertoire. We hypothesize that the limit on MHC number is due to negative consequences arising from expressing additional MHC. We compared T cell responses between B6 mice (I-A(+)) and B6.E(+) mice (I-A(+), I-E(+)), the latter expressing a second class II MHC molecule, I E(b), due to a monomorphic Ealpha(k) transgene that pairs with the endogenous I Ebeta(b) chain. First, the naive T cell Vbeta repertoire was altered in B6.E(+) thymi and spleens, potentially mediating different outcomes in T cell reactivity. Although the B6 and B6.E(+) responses to hen egg-white lysozyme (HEL) protein immunization remained similar, other immune models yielded differences. For viral infection, the quality of the T cell response was subtly altered, with diminished production of certain cytokines by B6.E(+) CD4(+) T cells. In alloreactivity, the B6.E(+) T cell response was significantly dampened. Finally, we observed markedly enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE) in B6.E(+) mice. This correlated with decreased percentages of nTreg cells, supporting the concept of Tregs exhibiting differential susceptibility to negative selection. Altogether, our data suggest that expressing an additional class II MHC can produce diverse effects, with more severe autoimmunity providing a compelling explanation for limiting the expression of MHC molecules. PMID- 25016577 TI - Occlusal bite force change after orthodontic treatment with Andresen functional appliance. AB - OBJECTIVES: The aim of this study was to determine the occlusal bite force (OBF) changes, at the incisal and molar regions, after orthodontic treatment with functional appliance therapy in preadolescent subjects. MATERIALS AND METHODS: OBF was measured for patients (17 females and 16 males) before and after the treatment with Andresen functional appliance for an average period of 9 months (mean age was 11.8+/-1.1 years). Three variables were registered; maximum OBF at molar region and the average of three readings at the molar (AOBF) and incisal regions (IOBF). The same variables were measured in two occasions for a matching non-treated control group with a period of 9 months between the two measurements. RESULTS: No significant changes were seen in the OBF measured parameters in the control group. There was a reduction in all measured parameters. The mean reduction in maximum OBF was 76.1+/-12.4 N (P < 0.001), 58.5+/-13.0 N in AOBF (P < 0.001), and 69.3+/-11.6 N IOBF (P < 0.001). CONCLUSIONS: Treatment with functional appliance caused a significant reduction in OBF immediately after treatment. PMID- 25016576 TI - Characterization of a monoclonal antibody to a novel glycan-dependent epitope in the V1/V2 domain of the HIV-1 envelope protein, gp120. AB - Recent studies have described several broadly neutralizing monoclonal antibodies (bN-mAbs) that recognize glycan-dependent epitopes (GDEs) in the HIV-1 envelope protein, gp120. These were recovered from HIV-1 infected subjects, and several (e.g., PG9, PG16, CH01, CH03) target glycans in the first and second variable (V1/V2) domain of gp120. The V1/V2 domain is thought to play an important role in conformational masking, and antibodies to the V1/V2 domain were recently identified as the only immune response that correlated with protection in the RV144 HIV-1 vaccine trial. While the importance of antibodies to polymeric glycans is well established for vaccines targeting bacterial diseases, the importance of antibodies to glycans in vaccines targeting HIV has only recently been recognized. Antibodies to GDEs may be particularly significant in HIV vaccines based on gp120, where 50% of the molecular mass of the envelope protein is contributed by N-linked carbohydrate. However, few studies have reported antibodies to GDEs in humans or animals immunized with candidate HIV-1 vaccines. In this report, we describe the isolation of a mouse mAb, 4B6, after immunization with the extracellular domain of the HIV-1 envelope protein, gp140. Epitope mapping using glycopeptide fragments and in vitro mutagenesis showed that binding of this antibody depends on N-linked glycosylation at asparagine N130 (HXB2 numbering) in the gp120 V1/V2 domain. Our results demonstrate that, in addition to natural HIV-1 infection, immunization with recombinant proteins can elicit antibodies to the GDEs in the V1/V2 domain of gp120. Although little is known regarding conditions that favor antibody responses to GDEs, our studies demonstrate that these antibodies can arise from a short-term immunization regimen. Our results suggest that antibodies to GDEs are more common than previously suspected, and that further analysis of antibody responses to the HIV 1 envelope protein will lead to the discovery of additional antibodies to GDEs. PMID- 25016578 TI - The aesthetic impact of upper lip inclination in orthodontics and orthognathic surgery. AB - BACKGROUND: The nasolabial angle, particularly its lower component, i.e. the upper lip inclination (ULI), is an important keystone in treatment planning. Normative data for this parameter are not available. OBJECTIVES: A quantitative evaluation of the aesthetic impact of ULI on perceived attractiveness and threshold values of desire for treatment was undertaken. METHODS: The ULI of an idealized silhouette profile image was altered incrementally between 61 and 100 degrees. Images were rated on a Likert scale by pre-treatment orthognathic patients (n = 75), laypeople (n = 75), and clinicians (n = 35). RESULTS: An ULI between 79 and 85 degrees is viewed as ideal, with a range of 73-88 degrees deemed acceptable. Angles above or below this range, down to 67 degrees and up to 94 degrees are perceived as slightly unattractive, and anything outside the range of 67-94 degrees is deemed very unattractive. For patients the threshold value of desire for treatment was 91 degrees and above and 64 degrees and below, and for both clinicians and lay people the threshold value was 94 degrees and above and 64 degrees and below. Patients appear to be more critical than lay and clinician groups. This stresses the importance of using patients as observers, as well as laypeople and clinicians, in facial attractiveness research. LIMITATIONS: The results are based on an idealized male Caucasian profile. CONCLUSIONS: It is recommended that in treatment planning, the range of normal variability of the ULI, in terms of observer acceptance, is taken into account as well as the threshold values of the desire for treatment. PMID- 25016579 TI - Palatal surface and volume in mouth-breathing subjects evaluated with three dimensional analysis of digital dental casts-a controlled study. AB - OBJECTIVE: To compare the anatomical characteristics of the maxillary arch, identified as palatal surface area and volume, between mouth-breathing and nose breathing subjects using a three-dimensional (3D) analysis of digital dental casts. METHODS: Twenty-one Caucasian subjects (14 females and 7 males) with a mean age of 8.5 years [standard deviation (SD) 1.6 years] were selected according to the following criteria: mouth-breathing pattern due to allergic rhinitis, early mixed dentition, skeletal Class I relationship, and pre-pubertal stage of cervical vertebral maturation. This study group (SG) was compared with a control group (CG) of 17 nose-breathing subjects (9 females and 8 males, mean age: 8.5 years; SD: 1.7 years). For each subject, initial dental casts were taken and the upper arch was scanned using a 3D laser scanner. On each digital model, 3D measurements were performed to analyse maxillary arch morphology. Between-group differences were tested with the independent sample Student's t-test (P < 0.05). RESULTS: In mouth-breathing subjects, changes in physiological function of the upper respiratory tract resulted in skeletal adaptations of the maxillary arch. In the SG, both palatal surface area and volume were significantly smaller when compared with values of the CG. In particular, the palatal surface area and palatal volume were, respectively, 13.5 and 27.1 per cent smaller in the SG when compared to the CG. CONCLUSIONS: Subjects with prolonged mouth breathing showed a significant reduction of the palatal surface area and volume leading to a different development of the palatal morphology when compared with subjects with normal breathing pattern. PMID- 25016580 TI - Limitations of a method used for adolescent assessment of smile aesthetics. AB - AIMS: To establish whether adolescent orthodontic patients with hypodontia have a preference between the aesthetic outcomes of two treatment strategies for lateral incisor agenesis. MATERIALS/METHODS: Standardized photographs of pre-orthodontic patients with missing lateral incisors were manipulated to produce images that represented space opening and tooth replacement in the lateral incisor space and space closure with canine substitution into the lateral incisor space. Adolescent orthodontic patients with hypodontia were recruited to assess the aesthetics of the images. A control group of subjects without tooth agenesis was recruited. Each examiner undertook two tests to assess the smile aesthetics of the images: (1) rating attractiveness using visual analogue scale (VAS) and (2) choice of preference between pairs of images. RESULTS: Difficulties experienced with image manipulation and poor intra-examiner reliability of the VAS make interpretation of the results challenging. Care should be taken if findings are used to aid clinical decisions, as the validity of the main findings is questionable. Results suggest that although adolescents perceive a difference in the aesthetic result of space opening and space closure for missing lateral incisors, the impact on the smile attractiveness is not clinically significant. When forced to choose between the aesthetics of space opening or space closure, the majority of examiners chose space opening with tooth replacement. No difference was found in smile ratings or preferences between adolescents with hypodontia and those with no missing teeth. CLINICAL IMPLICATIONS: The methods used in this study may not be reliable for adolescent assessment of aesthetics. PMID- 25016581 TI - Multi-factor data normalization enables the detection of copy number aberrations in amplicon sequencing data. AB - MOTIVATION: Because of its low cost, amplicon sequencing, also known as ultra deep targeted sequencing, is now becoming widely used in oncology for detection of actionable mutations, i.e. mutations influencing cell sensitivity to targeted therapies. Amplicon sequencing is based on the polymerase chain reaction amplification of the regions of interest, a process that considerably distorts the information on copy numbers initially present in the tumor DNA. Therefore, additional experiments such as single nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) arrays often complement amplicon sequencing in clinics to identify copy number status of genes whose amplification or deletion has direct consequences on the efficacy of a particular cancer treatment. So far, there has been no proven method to extract the information on gene copy number aberrations based solely on amplicon sequencing. RESULTS: Here we present ONCOCNV, a method that includes a multifactor normalization and annotation technique enabling the detection of large copy number changes from amplicon sequencing data. We validated our approach on high and low amplicon density datasets and demonstrated that ONCOCNV can achieve a precision comparable with that of array CGH techniques in detecting copy number aberrations. Thus, ONCOCNV applied on amplicon sequencing data would make the use of additional array CGH or SNP array experiments unnecessary. PMID- 25016583 TI - Maximum-likelihood inference of population size contractions from microsatellite data. AB - Understanding the demographic history of populations and species is a central issue in evolutionary biology and molecular ecology. In this work, we develop a maximum-likelihood method for the inference of past changes in population size from microsatellite allelic data. Our method is based on importance sampling of gene genealogies, extended for new mutation models, notably the generalized stepwise mutation model (GSM). Using simulations, we test its performance to detect and characterize past reductions in population size. First, we test the estimation precision and confidence intervals coverage properties under ideal conditions, then we compare the accuracy of the estimation with another available method (MSVAR) and we finally test its robustness to misspecification of the mutational model and population structure. We show that our method is very competitive compared with alternative ones. Moreover, our implementation of a GSM allows more accurate analysis of microsatellite data, as we show that the violations of a single step mutation assumption induce very high bias toward false contraction detection rates. However, our simulation tests also showed some limits, which most importantly are large computation times for strong disequilibrium scenarios and a strong influence of some form of unaccounted population structure. This inference method is available in the latest implementation of the MIGRAINE software package. PMID- 25016582 TI - Modular evolution of DNA-binding preference of a Tbrain transcription factor provides a mechanism for modifying gene regulatory networks. AB - Gene regulatory networks (GRNs) describe the progression of transcriptional states that take a single-celled zygote to a multicellular organism. It is well documented that GRNs can evolve extensively through mutations to cis-regulatory modules (CRMs). Transcription factor proteins that bind these CRMs may also evolve to produce novelty. Coding changes are considered to be rarer, however, because transcription factors are multifunctional and hence are more constrained to evolve in ways that will not produce widespread detrimental effects. Recent technological advances have unearthed a surprising variation in DNA-binding abilities, such that individual transcription factors may recognize both a preferred primary motif and an additional secondary motif. This provides a source of modularity in function. Here, we demonstrate that orthologous transcription factors can also evolve a changed preference for a secondary binding motif, thereby offering an unexplored mechanism for GRN evolution. Using protein-binding microarray, surface plasmon resonance, and in vivo reporter assays, we demonstrate an important difference in DNA-binding preference between Tbrain protein orthologs in two species of echinoderms, the sea star, Patiria miniata, and the sea urchin, Strongylocentrotus purpuratus. Although both orthologs recognize the same primary motif, only the sea star Tbr also has a secondary binding motif. Our in vivo assays demonstrate that this difference may allow for greater evolutionary change in timing of regulatory control. This uncovers a layer of transcription factor binding divergence that could exist for many pairs of orthologs. We hypothesize that this divergence provides modularity that allows orthologous transcription factors to evolve novel roles in GRNs through modification of binding to secondary sites. PMID- 25016584 TI - New insights into the roles of CHOP-induced apoptosis in ER stress. AB - Endoplasmic reticulum stress (ER stress) is triggered due to a loss of homeostasis in the ER, resulting in accumulation of misfolded proteins in the ER lumen. ER stress activates a series of adaptive mechanisms known as the unfolded protein response. Perturbation of the ER is a powerful inducer of the transcription factor C/EBP homologous protein (CHOP). Although it has been proved that excessive or adverse stress to the ER triggers apoptosis, the specific mechanisms underlying these processes induced by CHOP remain unclear. By now, CHOP-induced apoptosis in ER stress has been implicated in numerous human diseases, such as neurodegenerative diseases, diabetes, ischemic diseases, tumor, and so on. In this review, we summarized the current understanding of the roles of CHOP in the development of several diseases from the laboratory to the clinic. PMID- 25016585 TI - Calibration for medium resolution off-axis electron holography using a flexible dual-lens imaging system in a JEOL ARM 200F microscope. AB - In this work the calibration of a medium resolution off-axis electron holography using a dual-lens imaging system in a JEOL ARM 200F is shown. The objective dual lens configuration allows adjusting the field of view from 35nm to 2.5MUm. Subsequently, the parameters used in phase shift reconstruction were calibrated considering biprism voltage versus fringe spacing (sigma) and versus fringe width (W). The reliability of the transmission electron microscope performance using these parameters was achieved using gold nanoparticles of known size and adjusting the excitation voltage of the lenses. PMID- 25016587 TI - Goethite colloid enhanced Pu transport through a single saturated fracture in granite. AB - alpha-FeOOH, a stable iron oxide in nature, can strongly absorb the low solubility plutonium (Pu) in aquifers. However, whether Pu transports though a single saturated fracture can be enhanced in the presence of alpha-FeOOH colloids remains unknown. Experimental studies were carried out to evaluate Pu mobilization at different water flow velocity, as affected by goethite colloids with various concentrations. Goethite nanorods were used to prepare (alpha-FeOOH) associated Pu suspensions with alpha-FeOOH concentration of (0-150) mgL(-1). The work experimentally evidenced that alpha-FeOOH colloid does enhance transport of Pu through fractured granites. The fraction of mobile (239)Pu (RPu, m=41.5%) associated with the alpha-FeOOH of an extremely low colloid concentration (0.2mgL(-1)) is much larger than that in absence of alpha-FeOOH (RPu, m=6.98%). However, plutonium mobility began to decrease when alpha-FeOOH concentration was increased to 1.0mgL(-1). On the other hand, the fraction of mobile Pu increased gradually with the water flow velocity. Based on the experimental data, the mechanisms underlying the (alpha-FeOOH)-associated plutonium transport are comprehensively discussed in view of its dynamic deposition onto the granite surfaces, which is decided mainly by the relative interaction between the colloid particle and the immobile surface. This interaction is a balance of electrostatic force (may be repulsive or attractive), the van der Walls force, and the shear stress of flow. PMID- 25016586 TI - The impact of biostimulation on the fate of sulfate and associated sulfur dynamics in groundwater. AB - The impact of electron-donor addition on sulfur dynamics for a groundwater system with low levels of metal contaminants was evaluated with a pilot-scale biostimulation test conducted at a former uranium mining site. Geochemical and stable-isotope data collected before, during, and after the test were analyzed to evaluate the sustainability of sulfate reducing conditions induced by the test, the fate of hydrogen sulfide, and the impact on aqueous geochemical conditions. The results of site characterization activities conducted prior to the test indicated the absence of measurable bacterial sulfate reduction. The injection of an electron donor (ethanol) induced bacterial sulfate reduction, as confirmed by an exponential decrease of sulfate concentration in concert with changes in oxidation-reduction potential, redox species, alkalinity, production of hydrogen sulfide, and fractionation of delta(34)S-sulfate. High, stoichiometrically equivalent hydrogen sulfide concentrations were not observed until several months after the start of the test. It is hypothesized that hydrogen sulfide produced from sulfate reduction was initially sequestered in the form of iron sulfides until the exhaustion of readily reducible iron oxides within the sediment. The fractionation of delta(34)S for sulfate was atypical, wherein the enrichment declined in the latter half of the experiment. It was conjectured that mixing effects associated with the release of sulfate from sulfate minerals associated with the sediments, along with possible sulfide re-oxidation contributed to this behavior. The results of this study illustrate the biogeochemical complexity that is associated with in-situ biostimulation processes involving bacterial sulfate reduction. PMID- 25016588 TI - Understanding the fate of sanitation-related nutrients in a shallow sandy aquifer below an urban slum area. AB - We hypothesized that wastewater leaching from on-site sanitation systems to alluvial aquifers underlying informal settlements (or slums) may end up contributing to high nutrient loads to surface water upon groundwater exfiltration. Hence, we conducted a hydro-geochemical study in a shallow sandy aquifer in Bwaise III parish, an urban slum area in Kampala, Uganda, to assess the geochemical processes controlling the transport and fate of dissolved nutrients (NO3, NH4 and PO4) released from on-site sanitation systems to groundwater. Groundwater was collected from 26 observation wells. The samples were analyzed for major ions (Ca, Mg, Na, Mg, Fe, Mn, Cl and SO4) and nutrients (o-PO4, NO3 and NH4). Data was also collected on soil characteristics, aquifer conductivity and hydraulic heads. Geochemical modeling using PHREEQC was used to determine the level of o-PO4 control by mineral solubility and sorption. Groundwater below the slum area was anoxic and had near neutral pH values, high values of EC (average of 1619MUS/cm) and high concentrations of Cl (3.2mmol/L), HCO3 (11mmol/L) and nutrients indicating the influence from wastewater leachates especially from pit latrines. Nutrients were predominantly present as NH4 (1 3mmol/L; average of 2.23mmol/L). The concentrations of NO3 and o-PO4 were, however, low: average of 0.2mmol/L and 6MUmol/L respectively. We observed a contaminant plume along the direction of groundwater flow (NE-SW) characterized by decreasing values of EC and Cl, and distinct redox zones. The redox zones transited from NO3-reducing in upper flow areas to Fe-reducing in the lower flow areas. Consequently, the concentrations of NO3 decreased downgradient of the flow path due to denitrification. Ammonium leached directly into the alluvial aquifer was also partially removed because the measured concentrations were less than the potential input from pit latrines (3.2mmol/L). We attributed this removal (about 30%) to anaerobic ammonium oxidation (anammox) given that the cation exchange capacity of the aquifer was low (<6meq/100g) to effectively adsorb NH4. Phosphate transport was, on the other hand, greatly retarded and our results showed that this was due to the adsorption of P to calcite and the co-precipitation of P with calcite and rhodochrosite. Our findings suggest that shallow alluvial sandy aquifers underlying urban slum areas are an important sink of excessive nutrients leaching from on-site sanitation systems. PMID- 25016589 TI - Exogenous treatments with phytohormones can improve growth and nickel yield of hyperaccumulating plants. AB - The application of plant growth regulators (PGRs) or phytohormones could be an interesting option for stimulating biomass production of hyperaccumulating plants and, consequently, their metal phytoextraction capacity. The effect of exogenous applications of phytohormones (PGR) on the Ni phytoextraction capacity of four Ni hyperaccumulating species (Alyssum corsicum, Alyssum malacitanum, Alyssum murale and Noccaea goesingense) was evaluated. Four different commercially available phytohormones (B, C, K and P) based on gibberellins, cytokinins and auxins were applied to the plant aerial tissues. Each product was applied at three different concentrations (B1-3, C1-3, K1-3 and P1-3). The effect on biomass production was dependent on the species, the PGR type and the concentration at which it was applied. Two of the four products (K and P) consistently increased biomass production compared to untreated control plants in all four plant species. On the other hand, all four products led to a significant increase in the number of branches (and leaves in the case of N. goesingense) of all four species compared to control plants. Application of phytohormones generally led to a reduction in shoot Ni concentration. Nonetheless, in some cases as a consequence of the increase observed in biomass after the application of phytohormones a significant increase in the Ni phytoextraction efficiency was also observed (but this was species- and PGR type-dependent). The results show that PGRs can be successfully used to improve the growth and biomass production of hyperaccumulating species such as Alyssum and Noccaea. However, an increase in biomass did not always lead to a higher Ni removal, and the most effective PGR for increasing Ni removal was the IAA-based product. PMID- 25016590 TI - Raman-in-SEM, a multimodal and multiscale analytical tool: performance for materials and expertise. AB - The availability of Raman spectroscopy in a powerful analytical scanning electron microscope (SEM) allows morphological, elemental, chemical, physical and electronic analysis without moving the sample between instruments. This paper documents the metrological performance of the SEMSCA commercial Raman interface operated in a low vacuum SEM. It provides multiscale and multimodal analyses as Raman/EDS, Raman/cathodoluminescence or Raman/STEM (STEM: scanning transmission electron microscopy) as well as Raman spectroscopy on nanomaterials. Since Raman spectroscopy in a SEM can be influenced by several SEM-related phenomena, this paper firstly presents a comparison of this new tool with a conventional micro Raman spectrometer. Then, some possible artefacts are documented, which are due to the impact of electron beam-induced contamination or cathodoluminescence contribution to the Raman spectra, especially with geological samples. These effects are easily overcome by changing or adapting the Raman spectrometer and the SEM settings and methodology. The deletion of the adverse effect of cathodoluminescence is solved by using a SEM beam shutter during Raman acquisition. In contrast, this interface provides the ability to record the cathodoluminescence (CL) spectrum of a phase. In a second part, this study highlights the interest and efficiency of the coupling in characterizing micrometric phases at the same point. This multimodal approach is illustrated with various issues encountered in geosciences. PMID- 25016591 TI - Dysfunction of neuronal calcium signaling in aging and disease. PMID- 25016592 TI - Phase-based probabilistic active contour for nerve detection in ultrasound images for regional anesthesia. AB - Ultrasound guided regional anesthesia (UGRA) is steadily growing in popularity, owing to advances in ultrasound imaging technology and the advantages that this technique presents for safety and efficiency. The aim of this work is to assist anaesthetists during the UGRA procedure by automatically detecting the nerve blocks in the ultrasound images. The main disadvantage of ultrasound images is the poor quality of the images, which are also affected by the speckle noise. Moreover, the nerve structure is not salient amid the other tissues, which makes its detection a challenging problem. In this paper we propose a new method to tackle the problem of nerve zone detection in ultrasound images. The method consists in a combination of three approaches: probabilistic, edge phase information and active contours. The gradient vector flow (GVF) is adopted as an edge-based active contour. The phase analysis of the monogenic signal is used to provide reliable edges for the GVF. Then, a learned probabilistic model reduces the false positives and increases the likelihood energy term of the target region. It yields a new external force field that attracts the active contour toward the desired region of interest. The proposed scheme has been applied to sciatic nerve regions. The qualitative and quantitative evaluations show a high accuracy and a significant improvement in performance. PMID- 25016593 TI - Surface roughness and Candida albicans biofilm formation on a reline resin after long-term chemical disinfection and toothbrushing. AB - STATEMENT OF PROBLEM: Routine cleaning of a denture may increase the surface roughness of the material. PURPOSE: The purpose of this study was to investigate the effect of denture cleansers and time on the roughness and Candida albicans biofilm formation on a reline resin. MATERIAL AND METHODS: Specimens of Tokuyama Rebase Fast II (20 * 10 * 2 mm) were prepared and divided into 9 groups (n=15): Test groups were toothbrushed (30 cycles per day) in 1 of the following solutions: water, soap, or toothpaste. After toothbrushing, the specimens were immersed in solutions of water, sodium perborate, or chlorhexidine. These treatments were done once a day for 365 days. The surface roughness was evaluated at 0, 7, 15, 30, 90, 180, 270, and 365 days, and the C albicans biofilm formation was measured after 365 days. The roughness data were analyzed by 3-way repeated measures ANOVA and the Tukey test (alpha=.05), and the C albicans biofilm formation was analyzed by 2-way ANOVA. RESULTS: Significant differences were found in the toothbrush and time interaction and in the toothbrush, immersion, and time interaction (P<.001). No significant differences were found between the toothbrush agent and chemical disinfection (P=.085) or between chemical disinfection and time interaction (P=.604). Brushing with dentifrice (PPb and PCh) showed a gradual decrease in surface roughness. The comparison among groups showed that PCh produced the lowest values of roughness. For C albicans biofilm formation, no significant differences were found among the experimental groups. CONCLUSIONS: The roughness values ranged from 0.31 to 0.69 MUm for all evaluated groups. For all groups, no significant differences were found in the quantification of C albicans. PMID- 25016596 TI - Model-based cost-effectiveness analyses for the treatment of chronic lymphocytic leukaemia: a review of methods to model disease outcomes and estimate utility. AB - Assessing the economic value of treatments for chronic lymphocytic leukaemia (CLL) is necessary to support healthcare decision makers; however, it poses a number of challenges. This paper reviews economic models of CLL treatment to learn the lessons from this experience and support ongoing model efforts. A search of databases and submissions to key health technology assessment agencies identified nine models. The modelling approaches adopted across these studies were fairly similar, with most models adopting a cohort Markov structure, though one example of a discrete event simulation was identified. While the cohort Markov approach has been acceptable to the National Institute for Health and Care Excellence, the review identifies a number of key uncertainties with these models, including the extrapolation of survival outcomes beyond the period observed by the trial, the effectiveness of second-line therapies, and estimates of health state utility. Further work is required to overcome these uncertainties, including comprehensive sensitivity analysis, systematic review of the evidence on the natural progression of CLL, and the collection of longer-term trial and registry data. PMID- 25016595 TI - Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways. AB - AIMS/HYPOTHESIS: This study was designed to ascertain whether human enteroendocrine cells express bitter taste receptors, and whether activation of these receptors with bitter-tasting ligands induces secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). METHODS: We used human enteroendocrine NCI-H716 cells, isolated duodenal segments from mice, and whole mice as our experimental systems for investigating stimuli and mechanisms underlying GLP-1- and PYY-stimulated release. We measured hormone levels by ELISA and determined bitter taste receptor expression by real-time quantitative PCR. We adopted a pharmacological approach using inhibitors and enhancers of downstream signalling pathways known to be involved in bitter taste transduction in taste bud cells to investigate these pathways in NCI-H716 cells. RESULTS: Using a pharmacological approach, we identified signalling pathways triggered by the denatonium benzoate (DB)-activated bitter receptors. This involved activation of alpha-gustducin (Galphagust)-the specific G-protein subunit that is also present in taste bud cells-reduction of intracellular cAMP levels and enhancement of phospholipase C (PLC) activity, which ultimately led to increased intracellular calcium concentrations and hormone release. Gavage of DB, followed by gavage of glucose, to db/db mice stimulated GLP-1 and subsequent insulin secretion, leading to lower blood glucose levels. CONCLUSIONS/INTERPRETATION: Our study demonstrates that activation of gut-expressed bitter taste receptors stimulates GLP-1 secretion in a PLC-dependent manner. In diabetic mice, DB (a ligand of bitter taste receptor cells), when given via gavage, lowers blood glucose levels in diabetic mice after oral glucose administration, through increased secretion of GLP-1. PMID- 25016594 TI - Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance. AB - Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2-enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2) alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa. PMID- 25016597 TI - Diets that differ in their FODMAP content alter the colonic luminal microenvironment. AB - OBJECTIVE: A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet reduces symptoms of IBS, but reduction of potential prebiotic and fermentative effects might adversely affect the colonic microenvironment. The effects of a low FODMAP diet with a typical Australian diet on biomarkers of colonic health were compared in a single-blinded, randomised, cross-over trial. DESIGN: Twenty-seven IBS and six healthy subjects were randomly allocated one of two 21-day provided diets, differing only in FODMAP content (mean (95% CI) low 3.05 (1.86 to 4.25) g/day vs Australian 23.7 (16.9 to 30.6) g/day), and then crossed over to the other diet with >=21-day washout period. Faeces passed over a 5-day run-in on their habitual diet and from day 17 to day 21 of the interventional diets were pooled, and pH, short-chain fatty acid concentrations and bacterial abundance and diversity were assessed. RESULTS: Faecal indices were similar in IBS and healthy subjects during habitual diets. The low FODMAP diet was associated with higher faecal pH (7.37 (7.23 to 7.51) vs. 7.16 (7.02 to 7.30); p=0.001), similar short-chain fatty acid concentrations, greater microbial diversity and reduced total bacterial abundance (9.63 (9.53 to 9.73) vs. 9.83 (9.72 to 9.93) log10 copies/g; p<0.001) compared with the Australian diet. To indicate direction of change, in comparison with the habitual diet the low FODMAP diet reduced total bacterial abundance and the typical Australian diet increased relative abundance for butyrate-producing Clostridium cluster XIVa (median ratio 6.62; p<0.001) and mucus-associated Akkermansia muciniphila (19.3; p<0.001), and reduced Ruminococcus torques. CONCLUSIONS: Diets differing in FODMAP content have marked effects on gut microbiota composition. The implications of long-term reduction of intake of FODMAPs require elucidation. TRIAL REGISTRATION NUMBER: ACTRN12612001185853. PMID- 25016598 TI - Photothermal desorption of single-walled carbon nanotubes and coconut shell activated carbons using a continuous light source for application in air sampling. AB - Many techniques exist to measure airborne volatile organic compounds (VOCs), each with differing advantages; sorbent sampling is compact, versatile, has good sample stability, and is the preferred technique for collecting VOCs for hygienists. Development of a desorption technique that allows multiple analyses per sample (similar to chemical desorption) with enhanced sensitivity (similar to thermal desorption) would be helpful to field hygienists. In this study, activated carbon (AC) and single-walled carbon nanotubes (SWNT) were preloaded with toluene vapor and partially desorbed with light using a common 12-V DC, 50-W incandescent/halogen lamp. A series of experimental chamber configurations were explored starting with a 500-ml chamber under static conditions, then with low ventilation and high ventilation, finally a 75-ml high ventilation chamber was evaluated. When preloaded with toluene and irradiated at the highest lamp setting for 4min, AC desorbed 13.9, 18.5, 23.8, and 45.9% of the loaded VOC mass, in each chamber configuration, respectively; SWNT desorbed 25.2, 24.3, 37.4, and 70.5% of the loaded VOC mass, respectively. SWNT desorption was significantly greater than AC in all test conditions (P = 0.02-<0.0001) demonstrating a substantial difference in sorbent performance. When loaded with 0.435mg toluene and desorbed at the highest lamp setting for 4min in the final chamber design, the mean desorption for AC was 45.8% (39.7, 52.0) and SWNT was 72.6% (68.8, 76.4) (mean represented in terms of 95% confidence interval). All desorption measurements were obtained using a field grade photoionization detector; this demonstrates the potential of using this technique to perform infield prescreening of VOC samples for immediate exposure feedback and in the analytical lab to introduce sample to a gas chromatograph for detailed analysis of the sample. PMID- 25016599 TI - Author's response. PMID- 25016601 TI - Greece's economic crisis and suicide rates: overview and outlook. PMID- 25016602 TI - Doctors as a knowledge and intelligence building group: pragmatic principles underlying decision-making processes. PMID- 25016603 TI - Recommendations for policy development regarding sport-related concussion prevention and management in Canada. AB - The Canadian Concussion Collaborative (CCC) is composed of health-related organisations concerned with the recognition, treatment and management of concussion. Its mission is to create synergy between organisations concerned with concussion to improve education and implementation of best practices for the prevention and management of concussions. Each of the organisations that constitute the CCC has endorsed two recommendations that address the need for relevant authorities to develop policies about concussion management in sports. The recommendations were developed to support advocacy for regulations, policies or legislation to improve concussion prevention and management at all levels of sport. PMID- 25016604 TI - Changes in parent motivation predicts changes in body mass index z-score (zBMI) and dietary intake among preschoolers enrolled in a family-based obesity intervention. AB - OBJECTIVES: To examine whether changes in parent motivation over the course of a pediatric obesity intervention are significantly associated with long-term changes in treatment outcomes. METHODS: Study hypotheses were tested with a secondary data analysis of a randomized controlled trial (N = 42). Study analyses tested whether baseline to posttreatment change in total score for a self-report parent motivation measure (Parent Motivation Inventory [PMI]) was significantly associated with baseline to 6-month follow-up changes in body mass index z-score (zBMI), dietary variables, and physical activity. RESULTS: Increases in PMI were significantly associated with decreased zBMI, decreased consumption of sugar sweetened beverages and sweets, and increased consumption of artificially sweetened beverages. CONCLUSIONS: Given that increases in parent motivation were associated with some treatment benefits, future research should evaluate the impact of directly assessing and targeting parent motivation on weight outcomes for preschoolers participating in a weight management program. PMID- 25016606 TI - Celebrating 20 years of evidence from the Cochrane Collaboration: what has been the impact of systematic reviews on nephrology? AB - It has been 20 years since the Cochrane Collaboration started the global effort to synthesize evidence to improve healthcare. Since 1997, the Cochrane Renal Group has produced over 100 systematic reviews that have collectively had an important impact on nephrology care, guidelines and policy. In this article, we reflect on the ongoing need for randomized trials and systematic reviews in contemporary nephrology and the achievements of the Cochrane Collaboration so far. We also describe some of the challenges in clinical research still faced by the nephrology community today. PMID- 25016605 TI - The influence of parenting on early childhood health and health care utilization. AB - OBJECTIVE: This study examined whether parenting, specifically parental support, structure, and behavioral control, predicted early childhood health care use and moderated the negative effects of socioeconomic disadvantage. METHODS: A sample of 250 parent-child dyads from a longitudinal intergenerational research program participated. RESULTS: Greater parental support was associated with increased rates of nonemergency care and a higher ratio of outpatient to emergency room (ER) services, a pattern reflecting better health and service use. Support also moderated the negative effects of disadvantaged family background. Greater behavioral control by parents predicted lower rates of both nonemergency care and ER visits. Structured parenting and behavioral control were associated with lower rates of respiratory illness. CONCLUSIONS: This study highlights the importance of considering parenting practices when examining variations in early childhood health and health care, and the relevance of parental behavior in designing interventions for high-risk populations. PMID- 25016607 TI - Misdiagnosing renal amyloidosis as minimal change disease. AB - BACKGROUND: Minimal change disease (MCD) accounts for 10-15% of all adult nephrotic syndrome cases and requires normal renal histology by light microscopy and negative immunohistology. Foot process effacement on electron microscopy (EM) is typical. Renal amyloid deposits demonstrate pathognomonic green birefringence when viewed under cross-polarized light after staining tissue with Congo red (CR) and may reveal fibrils on EM. Late diagnosis and delayed treatment of renal amyloidosis negatively impact on renal and patient survival. METHODS: A retrospective analysis was performed on 2116 patients referred to the National Amyloidosis Centre between 2001 and 2013, in whom renal amyloidosis was confirmed histologically. Twenty-seven of these patients had renal histology initially interpreted to be MCD. RESULTS: Among 26 patients in whom biopsy specimens and/or reports were retrieved, the median age at MCD diagnosis was 62 years and presenting proteinuria averaged 7.8 g/24 h. The median time period between the two diagnoses was 241 days (range: 20-2632 days). MCD was diagnosed without CR in 17/26 (65%) biopsies, but all specimens contained amyloid on retrospective CR staining. MCD was diagnosed without EM in 17/26 (65%) cases and all of 10 such biopsies subsequently demonstrated fibrils. Sixteen patients were subjected to two or more renal biopsies when their proteinuria proved steroid refractory. CONCLUSION: This study highlights the need to stain renal biopsies from proteinuric adults with CR, examine them under cross-polarized light and perform EM wherever possible. If the suspicion of renal amyloidosis remains high, despite apparent negative histology, specimens should be reviewed at specialist centres before undertaking a second kidney biopsy. PMID- 25016608 TI - Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors. AB - BACKGROUND: Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS: One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS: By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS: We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli. PMID- 25016610 TI - Ectopic expression of a loblolly pine class II 4-coumarate:CoA ligase alters soluble phenylpropanoid metabolism but not lignin biosynthesis in Populus. AB - 4-Coumarate:CoA ligase (4CL) catalyzes the formation of hydroxycinnamoyl-CoA esters for phenylpropanoid biosynthesis. Phylogenetically distinct Class I and Class II 4CL isoforms occur in angiosperms, and support lignin and non-lignin phenylpropanoid biosynthesis, respectively. In contrast, the few experimentally characterized gymnosperm 4CLs are associated with lignin biosynthesis and belong to the conifer-specific Class III. Here we report a new Pinus taeda isoform Pinta4CL3 that is phylogenetically more closely related to Class II angiosperm 4CLs than to Class III Pinta4CL1. Like angiosperm Class II 4CLs, Pinta4CL3 transcript levels were detected in foliar and root tissues but were absent in xylem, and recombinant Pinta4CL3 exhibited a substrate preference for 4-coumaric acid. Constitutive expression of Pinta4CL3 in transgenic Populus led to significant increases of hydroxycinnamoyl-quinate esters at the expense of hydroxycinnamoyl-glucose esters in green tissues. In particular, large increases of cinnamoyl-quinate in transgenic leaves suggested in vivo utilization of cinnamic acid by Pinta4CL3. Lignin was unaffected in transgenic Populus, consistent with Pinta4CL3 involvement in biosynthesis of non-structural phenylpropanoids. We discuss the in vivo cinnamic acid utilization activity of Pinta4CL3 and its adaptive significance in conifer defense. Together with phylogenetic inference, our data support an ancient origin of Class II 4CLs that pre-dates the angiosperm-gymnosperm split. PMID- 25016612 TI - Euthanasia: 10 myths. PMID- 25016609 TI - Cell cycle arrest and the evolution of chronic kidney disease from acute kidney injury. AB - For several decades, acute kidney injury (AKI) was generally considered a reversible process leading to complete kidney recovery if the individual survived the acute illness. Recent evidence from epidemiologic studies and animal models, however, have highlighted that AKI can lead to the development of fibrosis and facilitate the progression of chronic renal failure. When kidney injury is mild and baseline function is normal, the repair process can be adaptive with few long term consequences. When the injury is more severe, repeated, or to a kidney with underlying disease, the repair can be maladaptive and epithelial cell cycle arrest may play an important role in the development of fibrosis. Indeed, during the maladaptive repair after a renal insult, many tubular cells that are undergoing cell division spend a prolonged period in the G2/M phase of the cell cycle. These tubular cells recruit intracellular pathways leading to the synthesis and the secretion of profibrotic factors, which then act in a paracrine fashion on interstitial pericytes/fibroblasts to accelerate proliferation of these cells and production of interstitial matrix. Thus, the tubule cells assume a senescent secretory phenotype. Characteristic features of these cells may represent new biomarkers of fibrosis progression and the G2/M-arrested cells may represent a new therapeutic target to prevent, delay or arrest progression of chronic kidney disease. Here, we summarize recent advances in our understanding of the biology of the cell cycle and how cell cycle arrest links AKI to chronic kidney disease. PMID- 25016613 TI - Recent advances in the management of graft-versus-host disease. AB - Graft-versus-host disease (GvHD) remains a significant hurdle in overcoming the morbidity and mortality associated with haemopoietic stem cell transplantation in children. Better understanding of its pathobiology is facilitating the development of biomarkers for the severity of acute GvHD and treatment response, and has led to the introduction of a more prognostically relevant grading system for chronic GvHD. These enable stratification of appropriate prophylactic and treatment strategies according to the risk profiles of individual patients. Steroid-refractory acute GvHD has a poor prognosis, but early reports of the use of new immunosuppressive drugs and especially cellular treatments with extracorporeal photopheresis and mesenchymal stem cells suggest improved short term outcomes and offer the promise of increased longer-term survival rates. PMID- 25016615 TI - The complexity of cell composition of the intima of large arteries: focus on pericyte-like cells. AB - Pericytes, which are also known as Rouget cells or perivascular cells, are considered to represent a likely distinct pool of vascular cells that are extremely branched and located mostly in the periphery of the vascular system. The family of pericytes is a heterogeneous cell population that includes pericytes and pericyte-like cells. Accumulated data indicate that networks of pericyte-like cells exist in normal non-atherosclerotic intima, and that pericyte like cells can be involved in the development of atherosclerotic lesions from the very early stages of disease. The pathogenic role of arterial pericytes and pericyte-like cells also might be important in advanced and complicated atherosclerotic lesions via realizing mechanisms of vascular remodelling, ectopic ossification, intraplaque neovascularization, and probably thrombosis. PMID- 25016614 TI - Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. AB - AIMS: Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS: CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR 210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 +/- 6.8 vs. -21.3 +/- 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION: EVs are the active component of the paracrine secretion by human CPCs. As a cell free approach, EVs could circumvent many of the limitations of cell transplantation. PMID- 25016616 TI - T-type calcium channels are involved in hypoxic pulmonary hypertension. AB - AIMS: Pulmonary hypertension (PH) is the main disease of pulmonary circulation. Alteration in calcium homeostasis in pulmonary artery smooth muscle cells (PASMCs) is recognized as a key feature in PH. The present study was undertaken to investigate the involvement of T-type voltage-gated calcium channels (T-VGCCs) in the control of the pulmonary vascular tone and thereby in the development of PH. METHODS AND RESULTS: Experiments were conducted in animals (rats and mice) kept 3-4 weeks in either normal (normoxic) or hypoxic environment (hypobaric chamber) to induce chronic hypoxia (CH) PH. In vivo, chronic treatment of CH rats with the T-VGCC blocker, TTA-A2, prevented PH and the associated vascular hyperreactivity, pulmonary arterial remodelling, and right cardiac hypertrophy. Deletion of the Cav3.1 gene (a T-VGCC isoform) protected mice from CH-PH. In vitro, patch-clamp and PCR experiments revealed the presence of T-VGCCs (mainly Cav3.1 and Cav3.2) in PASMCs. Mibefradil, NNC550396, and TTA-A2 inhibited, in a concentration-dependent manner, T-VGCC current, KCl-induced contraction, and PASMC proliferation. CONCLUSION: The present study demonstrates that T-VGCCs contribute to intrapulmonary vascular reactivity and is implicated in the development of hypoxic PH. Specific blockers of T-VGCCs may thus prove useful for the therapeutic management of PH. PMID- 25016617 TI - Electronic substitutions for SSA-538. Final rules. AB - This final rule adopts, without change, the final rule with request for comments we published in the Federal Register (76 FR 41685) on July 15, 2011. We are revising our regulations to reflect our use of electronic case processing at the initial and reconsideration levels of our administrative review process. We are not changing the requirement that State agency medical and psychological consultants must affirm the accuracy and completeness of their findings of fact and discussion of the supporting evidence, only the manner in which they may provide the required findings and affirmation. This revision will improve our efficiency by increasing our use of electronic resources. PMID- 25016618 TI - Grants for adaptive sports programs for disabled veterans and disabled members of the Armed Forces. Interim final rule. AB - This interim final rule amends Department of Veterans Affairs (VA) regulations to establish a new program to provide grants to eligible entities to provide adaptive sports activities to disabled veterans and disabled members of the Armed Forces. This rulemaking is necessary to implement a change in the law that authorizes VA to make grants to entities other than the United States Olympic Committee for adaptive sports programs. It establishes procedures for evaluating grant applications under this grant program, and otherwise administering the grant program. This rule implements section 5 of the VA Expiring Authorities Extension Act of 2013. PMID- 25016619 TI - Schedule of controlled substances: placement of tramadol into schedule IV. Final rule. AB - With the issuance of this final rule, the Deputy Administrator of the Drug Enforcement Administration places the substance 2-[(dimethylamino)methyl]-1-(3 methoxyphenyl)cyclohexanol (tramadol), including its salts, isomers, and salts of isomers, into schedule IV of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule IV controlled substances on persons who handle (manufacture, distribute, dispense, import, export, engage in research, conduct instructional activities with, or possess) or propose to handle tramadol. PMID- 25016620 TI - Medical devices; neurological devices; classification of the transcutaneous electrical nerve stimulator to treat headache. Final order. AB - The Food and Drug Administration (FDA) is classifying the transcutaneous electrical nerve stimulator to treat headache into class II (special controls). The special controls that will apply to the device are identified in this order, and will be part of the codified language for the transcutaneous electrical nerve stimulator to treat headache classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 25016621 TI - Medical devices; physical medicine devices; classification of the nonpowered lower extremity pressure wrap. Final order. AB - The Food and Drug Administration (FDA) is classifying the nonpowered lower extremity pressure wrap into class I (general controls). The Agency is classifying the device into class I (general controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 25016622 TI - Medical devices; neurological devices; classification of the transcranial magnetic stimulator for headache. Final order. AB - The Food and Drug Administration (FDA) is classifying the transcranial magnetic stimulator for headache into class II (special controls). The special controls that will apply to the device are identified in this order, and will be part of the codified language for the transcranial magnetic stimulator for headache classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 25016623 TI - Final priority; National Institute on Disability and Rehabilitation Research- Rehabilitation Engineering Research Centers. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority under the Disability and Rehabilitation Research Projects and Centers Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for a Rehabilitation Engineering Research Center (RERC) on Improving the Accessibility, Usability, and Performance of Technology for Individuals who are Deaf or Hard of Hearing. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2014 and later years. We take this action to focus research attention on an area of national need. We intend the priority to contribute to improving the accessibility, usability, and performance of technology for individuals who are deaf or hard of hearing. PMID- 25016624 TI - Final priority; National Institute on Disability and Rehabilitation Research- Rehabilitation Research and Training Centers. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for the Rehabilitation Research and Training Center (RRTC) Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for an RRTC on Family Support. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2014 and later years. We take this action to focus research attention on an area of national need. We intend the priority to contribute to improved outcomes for individuals with disabilities and family members who provide assistance to them. PMID- 25016625 TI - Ibrutinib approved for the treatment of mantle cell lymphoma. PMID- 25016626 TI - Marketing and commercial distribution of ponatinib suspended following FDA request. PMID- 25016627 TI - Updated guidelines recommend HER2 testing in all breast cancer patients. PMID- 25016628 TI - Approval of obinutuzumab as a breakthrough therapy for chronic lymphocytic leukemia. PMID- 25016632 TI - Special report: workforce. See, touch, hear. PMID- 25016633 TI - Case studies. Letters of note. PMID- 25016634 TI - Efficiency. We cannot afford to rush community care. PMID- 25016635 TI - The NHS must go mutual. PMID- 25016637 TI - Service design. Join the data dots for the big picture. PMID- 25016636 TI - Patient experience. Maternity services reborn for the 21st century. PMID- 25016638 TI - Older people's services. A mature model for primary care. PMID- 25016639 TI - Acute care. Ambulatory care: all in a day's work. PMID- 25016640 TI - Free NHS research from box ticking. PMID- 25016641 TI - A polymer-protein core-shell nanomedicine for inhibiting cancer migration followed by photo-triggered killing. AB - Migratory capacity of cancer plays a critical role in the process of metastasis. Aberrant focal adhesions activated by the phosphorylation of Src kinase enables cancer cells to anchor on its micro-environment and migrate towards biochemically favorable niche, causing metastasis. Effective blocking of the migratory capacity of cancer cells by inhibiting protein kinases and subsequent application of cytotoxic stress may provide better therapeutic outcome. Here, we report a novel core-shell nanomedicine that inhibits cancer migration by nano-shell and impart reactive oxygen stress by laser assisted photosensitization of nano-core. For this, we have optimized a polymer-protein nanoconstruct where a photosensitizer (5,10,15, 20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP) is loaded into poly(lactic-co-glycolic acid) (PLGA) nano-core and Src kinase inhibitor (dasatinib) is loaded into albumin nano-shell. The polymer-core was prepared by electrospray technique and albumin-shell was formed by alcohol coacervation. Transmission electron microscopy studies revealed the formation of - 80 nm sized nano-core decorated with - 10 nm size nano-shell. Successful incorporation of monomeric mTHPP in nano-core resulted improved photo-physical properties and singlet oxygen release under physiological conditions compared to free-mTHPP. Core-shell nanomedicine also showed dose and time dependent cellular uptake in U87MG glioma cells. Dasatinib released from nano-shell caused down regulation of phospho-Src leading to significant impairment of cancer migration and subsequent laser assisted photosensitization of nano-core resulted in the release of reactive oxygen stress leading to apoptosis of spatially confined cancer cells. In vivo studies on Wistar rats indicated the absence of any significant toxicity caused by the intravenous administration of nanomedicine. These results clearly show the advantage of core-shell nanomedicine mediated combinatorial approach for inhibiting important cancer signalling pathways togother with imparting cytotoxic stress. PMID- 25016642 TI - Actively targeted cetuximab conjugated gamma-poly(glutamic acid)-docetaxel nanomedicines for epidermal growth factor receptor over expressing colon cancer cells. AB - Receptor targeted therapy is advantageous in overcoming the toxicity burden of conventional cancer chemotherapeutics. Over expression of epidermal growth factor receptor (EGFR) on cancer cells and its role in metastasis, malignancy and drug resistance in many human cancers lead to its selection as a promising target for cancer treatment. The present work investigated the preparation and characterization of docetaxel (DTXL) loaded gamma-poly (glutamic acid) (gamma PGA) nanoparticles (Nps) conjugated with EGFR antibody (Cetuximab, CET) targeted to colon cancer cells (HT-29), highly over expressing EGFR. The flow cytometric analysis revealed two fold increased cellular uptake of CET-DTXL-gamma-PGA Nps by HT-29 (EGFR +ve) cells compared to that of IEC-6 (EGFR-ve) cells confirming the active targeting. Cytotoxicity assays (MTT and LDH) showed superior anti proliferative activity of CET-DTXL-gamma-PGA NPs over DTXL-gamma-PGA Nps against HT-29 cells. The cell cycle analysis indicated that CET-DTXL-gamma-PGA NPs induced cell death in enhanced percentage of HT-29 cells by undergoing cell cycle arrest in G2/M phase compared to that of DTXL-gamma-PGA Nps. The mechanism of cancer cell death was analyzed via apoptotic and mitochondrial membrane potential assays and showed that targeted Nps treatment reduced the mitochondrial membrane potential thereby inducing enhanced HT-29 cell death (apoptosis and necrosis). The biodistribution of targeted and non-targeted Nps were analyzed in vivo in Swiss albino mice using NIR imaging. ICG-CET-DTXL-gamma-PGA Nps (targeted) and ICG-DTXL-gamma-PGA Nps (non-targeted) followed the similar biodistribution pattern in vivo, but with different elimination time. In short, CET-DTXL-gamma PGA nanoparticles enhance the tumor selective therapeutic efficacy for colon cancer. PMID- 25016643 TI - Functionalized magnetic iron oxide (Fe3O4) nanoparticles for capturing gram positive and gram-negative bacteria. AB - The development of nanotechnology in biology and medicine has raised the need for conjugation of nanoparticles (NPs) to biomolecules. In this study, magnetic and functionalized magnetic iron oxide nanoparticles were synthesized and used as affinity probes to capture Gram-positive/negative bacteria. The morphology and properties of the magnetic NPs were examined by transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential measurements. Furthermore, this study investigated the interaction between functionalized magnetic nanoparticles and Gram positive/negative bacteria. The positively and negatively charged magnetic nanoparticles include functionalities of Fe3O4, SiO2, TiO2, ZrO2, poly ethyleneimine (PEI) and poly acrylic acid. Their capture efficiencies for bacteria were investigated based on factors such as zeta potential, concentration and pH value. PEI particles carry a positive charge over a range of pH values from 3 to 10, and the particles were found to be an excellent candidate for capturing bacteria over such pH range. Since the binding force is mainly electrostatic, the architecture and orientation of the functional groups on the NP surface are not critical. Finally the captured bacteria were analyzed using matrix-assisted laser desorption/ionization mass spectrometry. The minimum detection limit was 10(4) CFU/mL and the analysis time was reduced to be less than 1 hour. In addition, the detection limit could be reduced to an extremely low concentration of 50 CFU/mL when captured bacteria were cultivated. PMID- 25016644 TI - Synthesis of gold nanorods and their functionalization with bovine serum albumin for optical hyperthermia. AB - Although gold nanorods (GNRs) have been investigated extensively for optical hyperthermia therapies, the synthesis of rods is far from ideal. In this report, we optimized the synthesis of gold nanorods using hydroquinone as a reducing agent. Compared with the GNRs prepared by traditional ways, the as-synthesized rods have a flexibly tunable size and wider range of longitudinal surface plasmon resonance (LSPR). Furthermore, a series of small-length gold nanorods with length ranging from 30 to 90 nm were synthesized and they are more suitable for in vivo biomedical applications. Finally, we exploited a convenient approach for preparing water-soluble GNRs with less toxicity, better dispersion and flexible functionalization by exchanging hexadecyltrimethylammonium bromide (CTAB) on the surface of the rods with carboxylated bovine serum albumin (BSA) derivative, the BSA modified GNRs showed significant anticancer efficacy through near infrared (NIR) hyperthermia. We believe that the as-prepared gold nanorods will find promising applications in biomedical fields, especially in cancer therapy. PMID- 25016645 TI - A comparison of TiO2 and ZnO nanoparticles as photosensitizers in photodynamic therapy for cancer. AB - The TiO2 and ZnO nanoparticles are the most promising next-generation photodynamic therapy (PDT) photosensitizers. This paper reports a one-to-one comparison of TiO2 and ZnO nanoparticles as photosensitizers in photodynamic therapy of cancer. After incubating SMMC-7721 hepatocarcinoma cells with TiO2 and ZnO nanoparticles, we irradiated the cells with ultraviolet (UV) light and formation of intracellular reactive oxygen species (ROS) was monitored using the dichloro-dihydro-fluorescein diacetate (DCFH-DA) method. The cytotoxicities of ZnO and TiO2 nanoparticles as photosensitizers in cancer PDT were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the mRNA and protein expression levels of apoptosis-related gene, including Bax, Bcl-2, and Caspase 3 were examined using RT-PCR and Western blot to elucidate the possible molecular mechanisms involved. Our results demonstrated that both TiO2 and ZnO nanoparticles could generate ROS within the tumor cells after irradiation, which in turn could attack the cancer cells. The caspase dependent apoptosis was thus induced, resulting in anticancer activity. When the therapeutic effects were compared, no differences between the TiO2 and ZnO nanoparticles were observed for PDT. Either TiO2 or ZnO nanoparticles can therefore be used in the near future as alternative photosensitizers in targeted tumor PDT when light is directly focused on the lesion. PMID- 25016646 TI - Preparation of curcumin micelles and the in vitro and in vivo evaluation for cancer therapy. AB - Poor water solubility as well as poor bioavailability of curcumin has greatly hindered its applications in cancer therapy. In the present study, a highly water soluble curcumin nano-formulation was developed and its in vivo anti-cancer efficiency in nude BALB/c mouse model was evaluated. Unlike native curcumin, the developed curcumin micelles were quickly dissolved into aqueous solution with significant improvement of water solubility (-10(4) fold increasement compared to its native form). The developed curcumin micelles had a narrow size distribution (18-28 nm) with high drug encapsulation efficiency (85%-95%). The developed curcumin micelles were characterized by X-raydiffraction (XRD), Differential scanning calorimetric (DSC), and Fluorescence spectral analysis. We observed the enhanced stability of curcumin in micelles formulation in phosphate buffer solution (PBS). In vitro cytotoxicity assay indicated that the curcumin micelles was comparatively more effective than native curcumin against various cancer cell lines due to the enhanced cellular uptake of curcumin yet resulting in the apoptosis of cancer cells. Western blotting study revealed that the induction apoptosis of S-65 cancer cells by curcumin micelles was mainly due to the down regulation of p-Rb, Blc-2, p-AKT expression and caspase-9 activation. In vivo anti-tumor test in nude BALB/c mouse bearing S-65 xenografts indicated the intraperitoneal injection of curcumin micelles (25 mg/kg) could significantly inhibit tumor growth as compared with native curcumin treatment (p < 0.05), which was accompanied by significantly increased apoptosis of tumor cells and diminished vascular endothelial growth factor expression in tumor tissue (p < 0.05). PMID- 25016647 TI - Influence of chondroitin sulfate and hyaluronic acid presence in nanofibers and its alignment on the bone marrow stromal cells: cartilage regeneration. AB - Cartilage degeneration is the major cause of disability and poses several challenges to repair and regenerate. Conventional surgical treatments often induce fibrous tissues and compromise its function. Alternative tissue engineering strategies utilized scaffolds, factors and cells alone or in combination with some degree of success. This study reports the use of nanostructured biomimetic scaffold system in regulating the rat bone marrow stem cells (rBMSCs) differentiation into chondrogenic lineage in vitro. The biometric scaffold is essentially a micro-porous polycaprolactone (PCL) spiral structure decorated with sparsely spaced bioactive PCL nanofibers. The bioactivity stems from the use of two major components of hyaline cartilage extracellular matrix (ECM) namely chondroitin sulfate (CS) and hyaluronic acid (HYA). The PCL spiral structure was surface functionalized with PCL nanofibers encapsulated with CS (20% (w/w)) and HYA (0.2% (w/w)). In order to retain and sustain the release of CS and HYA nanofibers were cross-linked using carbodiimide chemistry. This study also evaluated the effect of nanofiber alignment on rBMSCs differentiation and evaluated the production of characteristic hyaline cartilage proteins namely collagen type II and aggrecan in vitro up to 28 days. Rat bone marrow derived stem cells cultured on the aligned nanofibers expressed significantly elevated levels of collagen type II and aggrecan secretions (western blots) as compared to scaffolds decorated with random fibers and tissue culture polystyrene (TCPS). This fiber alignment dependent expression of collagen type II and aggrecan secretion were further confirmed through immunofluorescence staining. This biomimetic and bioactive scaffold may serve as a serve as an efficient scaffold system for cartilage regeneration. PMID- 25016648 TI - Doxorubicin loaded pH-responsive micelles capable of rapid intracellular drug release for potential tumor therapy. AB - Amphiphilic copolymers have been paid much attention for controlled drug release for many years due to their obvious advantages. In this study, an acid-triggered drug carrier system capable of rapid intracellular drug release is investigated for potential tumor therapy. The amphiphilic diblock copolymer poly(2 diisopropylaminoethyl methacrylate)-b-poly(2-aminoethyl methacrylate hydrochloride) (PDPA-b-PAMA) is prepared by atom transfer radical polymerization (ATRP). The molecular structure of the copolymer is confirmed by 1H NMR and gel permeation chromatography (GPC). The critical micelle concentration (CMC) value of the PDPA-b-PAMA is 0.005 mg/mL, which can ensure the thermodynamical stability of micelles even after significant dilution. The drug loading and encapsulation efficiencies of doxorubicin (DOX)-loaded micelles are 9.96% and 55.31%, respectively. Dynamic light scattering (DLS) and transmission electron microscope (TEM) show that the amphiphilic block copolymers self-assemble into spherical micelles with narrow polydispersity indexes (PDLs) at pH 7.4 and 6.8, but disassemble into random chain aggregations at pH 5.0. The DOX-loaded PDPA-b-PAMA shows obvious pH-responsive drug release profile when the pH value changes from 7.4 to 5.0, since it transforms from amphiphilicity to double hydrophilicity through the protonation of PDPA block (pK(a) - 6.2) in a relatively low pH condition, thus the loaded DOX can be rapidly released from the disassembling micelles. In addition, the micellar system also exhibits relatively low cytotoxicity and rapid drug release behaviour in tumor cells, which make it promising for tumor therapy. PMID- 25016649 TI - Optimization of UV absorptivity of layered double hydroxide by intercalating organic UV-absorbent molecules. AB - Intercalation of Zn/Al layered double hydroxide (LDH) with benzophenone 9 (B9), a strong ultraviolet (UV) absorber, had been carried out by two different routes; co-precipitation and ion exchange method. Powder X-ray diffraction (PXRD) patterns of co-precipitated (ZB9C) and ion exchanged product (ZB91) showed basal spacing of 15.9 angstrom and 16.6 angstrom, respectively, as a result of the intercalation of B9 anions into the lamellae spaces of LDH. Intercalation was further confirmed by Fourier transform infrared spectra (FTIR), carbon, hydrogen, nitrogen and sulfur (CHNS) and thermogravimetric and differential thermogravimetric (TGA/DTG) studies. UV-vis absorption properties of the nanocomposite was investigated with diffuse reflectance UV-visible spectrometer and showed broader UV absorption range. Furthermore, stability of sunscreen molecules in LDH interlayer space was tested in deionized water, artificial sea water and skin pH condition to show slow deintercalation and high retention in host. Cytotoxicity study of the synthesized nanocomposites on human dermal fibroblast (HDF) cells shows no significant cytotoxicity after 24 h exposure for test concentrations up to 25 microg/mL. PMID- 25016650 TI - A new X-ray activated nanoparticle photosensitizer for cancer treatment. AB - Photodynamic therapy (PDT) has attracted ever-growing attention as a promising modality in the treatment of cancer. However, due to the poor tissue penetration by light, PDT has rarely been applied for treating deep-seated tumors. This problem can be solved if photosensitizers are activated by X-rays, which are able to penetrate deeply into tissues. Previous attempts using X-rays to activate photosensitizers were not very successful, since the traditional PDT photosensitizers could not efficiently be activated with X-rays. Here we exploit copper-cysteamine complex (Cu-Cy) nanoparticles as a new type of photosensitizer activated by X-ray for cancer treatment. The newly invented Cu-Cy nanoparticles can be activated directly by X-rays to produce singlet oxygen. In vitro and in vivo study on human breast cancer cells (MCF-7) have shown significant cell destruction using Cu-Cy nanoparticles under X-ray activation. The Cu-Cy nanoparticles are a novel and potent X-ray activated photosensitizer which can enable PDT for deep cancer treatment. PMID- 25016651 TI - Antitumor efficiency of D-alpha-tocopheryl polyethylene glycol 1000 succinate-b poly(epsilon-caprolactone-ran-lactide) nanoparticle-based delivery of docetaxel in mice bearing cervical cancer. AB - Pharmaceutical nanotechnology holds potential in cancer chemotherapy. In this research, the docetaxel-loaded D-alpha-tocopheryl polyethylene glycol 1000 succinate-b-poly(epsilon-caprolactone-ran-lactide) (TPGS-b-(PCL-ran-PLA)) nanoparticles were prepared by a modified nanoprecipitation method and then the particle size, surface morphology, nanoparticle stability, in vitro drug release and cellular uptake of nanoparticles were characterized. Finally, we evaluated the therapeutic effects of nanoparticle formulation in comparison with Taxotere both in vitro and in vivo. The size of TPGS-b-(PCL-ran-PLA) nanoparticles was about 150 nm and much smaller than PCL nanoparticles (about 185 nm) and the absolute value of zeta potential was higher than PCL nanoparticles (16.49 mV vs. 13.17 mV). FESEM images further confirmed the morphology and size of nanoparticles. The drug-loaded nanoparticles were considered to be stable, showing no change in the particle size and surface charge during three-month storage of its aqueous solution. In vitro drug release of TPGS-b-(PCL-ran-PLA) nanoparticles was much faster than PCL and PCL-TPGS nanoparticles. The cumulative drug release of docetaxel-loaded TPGS-b-(PCL-ran-PLA), PCL-TPGS, and PCL NPs were 38.00%, 34.48% and 29.04%, respectively. TPGS-b-(PCL-ran-PLA) nanoparticles showed an obvious increase of cellular uptake. Due to the advantages of TPGS-b (PCL-ran-PLA) nanoparticles, it could achieve significantly higher level of cytotoxicity in vitro and better inhibition effect of tumor growth on xenograft BALB/c nude mice tumor model than commercial Taxotere at the same dose (1.49-fold more effective). The TPGS-b-(PCL-ran-PLA) could be used as a novel and potential biodegradable polymeric material for nanoformulation in cervical cancer chemotherapy. PMID- 25016652 TI - Nanostructured lipid carriers containing a high percentage of a Pluronic copolymer increase the biodistribution of novel PDE4 inhibitors for the treatment of traumatic hemorrhage. AB - Although the application of nanotechnology to drug therapy has been widely investigated, very few nanomedicine-based treatments for traumatic hemorrhage have been reported so far. The aim of this work was to develop nanostructured lipid carriers (NLCs) loaded with phosphodiesterase 4 (PDE4) inhibitors to treat acute inflammation in peripheral organs. The pharmacokinetics and biodistribution of DSM-RX78 and EFB-1, two novel PDE4 inhibitors, were examined using rats as an animal model. Entrapment by NLCs resulted in sustained drug release. The plasma concentrations of DSM-RX78 and EFB-1 in NLCs were lower, and their half-lives were much shorter in the NLC condition than in the control condition. PDE4 inhibitors delivered in NLCs accumulated with high abundance in many organs, especially the brain and lungs. Polyethylene glycol (PEG) coating on the particulate surface (P-NLCs) significantly reduced brain delivery of the drugs. P NLCs enhanced drug distribution to the lungs by 5-fold compared to free control. In vivo real-time imaging confirmed rapid escape of nanoparticles from the blood circulation. Histological examination and aminotransferase measurement revealed that P-NLCs containing EFB-1 improved hemorrhagic shock-induced injuries in the lungs, intestines, and liver. P-NLCs even reversed acute lung inflammation to the level observed in an uninjured condition. Our results indicate that NLC-based delivery of PDE4 inhibitors is a candidate treatment for traumatic hemorrhage. PMID- 25016653 TI - Resveratrol-loaded nanoparticles reduce oxidative stress induced by radiation or amyloid-beta in transgenic Caenorhabditis elegans. AB - Resveratrol (trans-3,4',5-trihydroxystilbene, RES) is a naturally occurring lipophilic antioxidant that has been intensively studied for its promising efficacy in treating oxidative stress-associated disorders. Despite the array of bioactivities that it possesses, RES has low bioavailability due to its poor aqueous solubility and dissolution properties. Recent nanotechnology has led to the effective development of drug delivery systems. In this study, RES-loaded nanoparticles (RES-NPs) were prepared based on amphiphilic methoxy polyethyleneglycol-poly-caprolactone (mPEG-PCL) block copolymers, which improve the physical properties of resveratrol in aqueous solution. The antioxidative capacity of RES-NPs was then evaluated sequentially in vitro and in vivo. RES-NPs exhibited stronger radical scavenging and anti-lipid peroxidization compared to that of raw RES in aqueous solution. The pre-treatment of irradiated Caenorhabditis elegans (C. elegans) with RES-NPs extended both the maximum and mean life span. Furthermore, the RES-NPs were capable of alleviating injury from gamma-ray radiation and amyloid-beta peptide overexpression toxicity in C. elegans through radical scavenging and over-regulation of SOD-3 expression. The enhancement of in vitro antioxidation properties in aqueous solution and protection against oxidative stress in C. elegans induced by both gamma-ray radiation and amyloid-beta peptide confirmed the successful development of antioxidant nanoparticles. PMID- 25016655 TI - Nanoscale helium ion microscopic analysis of collagen fibrillar changes following femtosecond laser dissection of human cornea. AB - Over the last decade, femtosecond lasers have emerged as an important tool to perform accurate and fine dissections with minimal collateral damage in biological tissue. The most common surgical procedure in medicine utilizing femtosecond laser is LASIK. During the femtosecond laser dissection process, the corneal collagen fibers inevitably undergo biomechanical and thermal changes on a sub-micro- or even a nanoscale level, which can potentially lead to post-surgical complications. In this study, we utilized helium ion microscopy, complemented with transmission electron microscopy to examine the femtosecond laser-induced collagen fibrillar damage in ex vivo human corneas. We found that the biomechanical damage induced by laser etching, generation of tissue bridges, and expansion of cavitation bubble and its subsequent collapse, created distortion to the surrounding collagen lamellae. Femtosecond laser-induced thermal damage was characterized by collapsed collagen lamellae, loss of collagen banding, collagen coiling, and presence of spherical debris. Our findings have shown the ability of helium ion microscopy to provide high resolution images with unprecedented detail of nanoscale fibrillar morphological changes in order to assess a tissue damage, which could not be resolved by conventional scanning electron microscopy previously. This imaging technology has also given us a better understanding of the tissue-laser interactions in a nano-structural manner and their possible effects on post-operative wound recovery. PMID- 25016656 TI - Increased delivery of doxorubicin into tumor cells using extracellularly activated TAT functionalized liposomes: in vitro and in vivo study. AB - The development of highly efficient tumor-targeted delivery systems is crucial for successful tumor treatment. Previously, a novel cell-penetrating peptide TAT and cleavable polyethylene glycol (PEG) co-modified liposome delivery system (C TAT-Lipo) showed enhanced accumulation in tumor regions. Under the control of cysteine (Cys), the liposomes were activated extracellularly and achieved increased delivery of their cargo into tumor cells efficiently. In this study, we developed an optimal formulation for the encapsulation of Doxorubicin (DOX) by this delivery system for tumor treatment. The in vitro study showed that the C TAT-Lipo with Cys delivery system not only enhanced the amount of DOX delivered by at least 100% compared to other DOX-containing formulations, but also displayed high cytotoxicity against tumorigenic cell lines. Compared to other groups, the DOX-loaded C-TAT-Lipo formulation in the presence of cysteine enhanced treatment efficacy by lowering the IC50 (1.67 +/- 0.14 microM) and increasing the cancer cell apoptosis percentage (37.10%). Moreover, the in vivo antitumor activity also showed that DOX-loaded C-TAT-Lipo with injection of cysteine achieved the best tumor growth inhibition with a tumor growth rate of only 58.40 +/- 16.33% (% of initial volume/day), which was significant less than that achieved by other DOX formulations. PMID- 25016654 TI - Dynamic contrast enhanced fluorescent molecular imaging of vascular disruption induced by combretastatin-A4P in tumor xenografts. AB - Dynamic contrast enhanced (DyCE) fluorescence imaging was recently demonstrated for identifying the organs in mice based on principal component analysis (PCA) of contrast kinetics following infusion of indocyanine green (ICG). It occurred to us that this approach could be used to evaluate acute effects of vascular disrupting agents (VDAs), since these cause massive vascular shutdown. As proof of principle, we have examined the action of combretastatin-A4P (CA4P) on MCF7 human breast tumors growing in nude mice. Tumors were implanted in the thigh and allowed to grow to about 7 mm diameter. Indocyanine green (ICG; 50 microl 260 microM) was administered as a bolus by tail vein injection to anesthetized mice. The fluorescence time course was acquired over 200 s using a sensitive charge coupled device (CCD) camera system. CA4P was then administered IP (120 mg/kg in 100 microl saline) and DyCE repeated following administration of fresh ICG two and 24 hours later. At 2 hours the developed fluorescence intensity was much reduced in the tumors indicating vascular impairment, which was confirmed histologically. After 24 hours there was considerable recovery. Good reproducibility was found for control mice and normal organs. We believe the method shows promise for developing VDAs by evaluating and optimizing therapeutic drug doses and combinations. PMID- 25016657 TI - Effects of 2,3-dimercaptosuccinic acid-coated Fe3O4 nanoparticles on genes in two mouse cell lines. AB - To evaluate the effects of iron oxide nanoparticles on genes from different cell lines in this study, mouse macrophage RAW264.7 and hepatocyte Hepa1-6 cell lines were treated with DMSA-coated Fe3O4 nanoparticles. Two doses were used, 50 microg/mL and 100 microg/mL, respectively, for 24 hr and gene expression profile was detected by DNA microarrays. The gene expression patterns for the two cell lines greatly differed from each other when compared, revealing distinct cell specific effects of the nanoparticles on the genes. It was found that the nanoparticles significantly influenced expression of genes in the RAW264.7 cells, showing complete difference from those of Hepa1-6 cells. More genes were downregulated in the RAW264.7 cells by two doses of the nanoparticles but up regulated in the Hepa1-6 cells by two doses of the same nanoparticles. Moreover, the increase of nanoparticle dose greatly decreased up-regulation of genes but increased down-regulation of genes in the RAW264.7 cells. The influence of nanoparticles did not result in similar effect in the Hepa1-6 cells. Apart from the difference in gene expression patterns in the two cell lines, there were eight and seven genes which were consistently down-regulated and up-regulated by low-dose and high-dose of nanoparticles in the two cell lines, respectively, revealing the common effects of the nanoparticles on the genes in the two cell lines. These common effects on genes were caused by homeostatic processes, influenced by down-regulation of genes and immune responses, and also cell death, influenced by up-regulation of genes. The data from this study has shed new insights into the potential in vivo nanotoxicolgy of the DMSA-coated Fe3O4 nanoparticles. PMID- 25016658 TI - Improvement of cell infiltration in electrospun polycaprolactone scaffolds for the construction of vascular grafts. AB - The less-than-ideal cell infiltration resulting from inherently small pore size limits the application of electrospinning scaffold in tissue engineering and regeneration medicine. The present study aims to develop a porogenic method which can significantly increase pore size in electrospinning scaffold and enhance cell migration. With this method, composite scaffolds consisting of poly(epsilon caprolactone) (PCL) fibers and poly(ethylene oxide) (PEO) microparticles were prepared by simultaneously electrospinning and electrospraying. Removal of the PEO microparticles from the composites generated large pores. In vitro culture of NIH3T3 cells and in vivo subcutaneous implantation both demonstrated that the porogenic scaffolds markedly facilitated cell infiltration. With the same technique, vascular grafts with alternative dense and loose layers were prepared by turning on or off electrospraying PEO. SEM showed that there was no a clear delamination between the loose and dense layers. The mechanical strength and burst pressure of these vascular grafts could meet the requirements of vascular implantation. In conclusion, electrospinning PCL fibers with electrospraying PEO microparticles may be an effective and controllable method to increase pore size in electrospinning scaffold and provides a useful tool for the fabrication of vascular grafts that meets the need of blood vessel replacement. PMID- 25016659 TI - Nanoencapsulation of tacrolimus in lipid-core nanocapsules showed similar immunosuppressive activity after oral and intraperitoneal administrations. AB - Tacrolimus is widely used in the prophylaxis of solid-organ transplant rejection. Several studies have reported that tacrolimus has variable and poor bioavailability after oral administration, apart from adverse effects such as gastrointestinal disorders, hyperglycemia, nephro- and neurotoxicity. The aim of this work was to encapsulate tacrolimus (TAC) in lipid-core nanocapsules (LNC) as an oral strategy to deliver the drug. To validate our hypothesis, the pharmacodynamic effect of TAC-LNC was determined after oral and intraperitoneal (i.p.) administrations to mice. TAC-LNC had z-average diameter of 210 nm (unimodal), and 99.5% of encapsulation efficiency. In vitro sustained release was determined for TAC-LNC fitting an anomalous transport mechanism (n = 0.8). TAC LNC demonstrated higher immunosuppressive activity after oral and i.p. administrations, when compared to the drug solution. TAC-LNC administered at 6.0 mg kg(-1) day(-1) showed equivalent percent reduction in lymphocyte when both routes of administration were used. After oral administration, drug nanoencapsulation allows reducing the dose by at least 40%. Furthermore, the nanoencapsulation of TAC in lipid-core nanocapsules showed pharmacodynamic effect similar for the oral and the i.p. routes. In conclusion, the lipid-core nanocapsules were able to improve the TAC deliver across the oral absorption barrier. PMID- 25016660 TI - Modulation of gene expression of adenosine and metabotropic glutamate receptors in rat's neuronal cells exposed to L-glutamate and [60]fullerene. AB - L-Glutamate (L-Glu) has been often associated not only to fundamental physiological roles, as learning and memory, but also to neuronal cell death and the genesis and development of important neurodegenerative diseases. Herein we studied the variation in the adenosine and metabotropic glutamate receptors expression induced by L-Glu treatment in rat's cortical neurons. The possibility to have structural alteration of the cells induced by L-Glu (100 nM, 1 and 10 microM) has been addressed, studying the modulation of microtubule associated protein-2 (MAP-2) and neurofilament heavy polypeptide (NEFH), natively associated proteins to the dendritic shape maintenance. Results showed that the proposed treatments were not destabilizing the cells, so the L-Glu concentrations were acceptable to investigate fluctuation in receptors expression, which were studied by RT-PCR. Interestingly, C60 fullerene derivative t3ss elicited a protective effect against glutamate toxicity, as demonstrated by MTT assay. In addition, t3ss compound exerted a different effect on the adenosine and metabotropic glutamate receptors analyzed. Interestingly, A(2A) and mGlu1 mRNAs were significantly decreased in conditions were t3ss neuroprotected cortical neurons from L-Glu toxicity. In summary, t3ss protects neurons from glutamate toxicity in a process that appears to be associated with the modulation of the gene expression of adenosine and metabotropic glutamate receptors. PMID- 25016661 TI - Polymeric vesicles loaded with gadoteridol as reversible and concentration independent magnetic resonance imaging thermometers. AB - The use of temperature sensitive liposomes (TSLs) loaded with paramagnetic Gd(III) complexes have been explored to develop MRI agents able to provide a imaging guide to heating-based therapies. Though the performance of such probes has been already demonstrated in vivo at preclinical level, further improvements (e.g., concentration independent image response, reversibility of the sensor) are necessary to increase the accuracy of the temperature readout. This work reports for the first time, the potential of Gd-loaded polymersomes (bilayered vesicles made of amphiphilic di-block copolymers) as improved thermosensitive MRI probes. Differently from conventional TSLs, such probes do not display a defined gel-to liquid temperature transition and, therefore, they did not release their content in a wide temperature range, thereby allowing reversible temperature readouts. Moreover, a ratiometric approach based on the measurement of the ratio between transverse and longitudinal water protons relaxation rates (R2/R1) allows a temperature readout independent of the probe concentration. The imaging performance of temperature sensitive polymersomes prepared in this work was tested both in vitro and in vivo after subcutaneous injection in healthy mice. PMID- 25016662 TI - Star-shaped polycaprolactone-polyethyleneglycol copolymer micelle-like nanoparticles for picropodophyllin delivery. AB - The purpose of this work was to develop a novel picropodophyllin-loaded micelle like nanoparticle with a biodegradable amphiphilic star-shaped polycaprolactone polyethyleneglycol copolymer (S-PCL-PEG). S-PCL-PEG was synthesized using star shaped polycaprolactone (S-PCL) as a hydrophobic block and monomethoxy polyethyleneglycol (PEG) as a hydrophilic block and characterized by 1H-NMR. It was confirmed by the pyrene fluorescence probe method that the obtained S-PCL-PEG could form micelles through self-assembly in aqueous media. In addition, picropodophyllin (PPP), a hydrophobic anticancer drug, could be entrapped in the hydrophobic inner core of the micelles using the thin film hydration method, forming PPP-loaded micelle-like nanoparticles (PPP-NPs). PPP-NPs had a high encapsulation efficiency of greater than 90%, an average size of 90-110 nm with a symmetrical monodisperse distribution and a zeta potential of -18 mV. Additionally, in vitro release tests showed that approximately 70% of the drug was released from PPP-NPs into PBS (pH 7.4) containing 0.2% Tween 80 at 37 degrees C for 96 h, and the drug release data fit well to the Higuchi equation. Furthermore, an in vitro tumor cell growth inhibition assay showed that the IC50 values of the PPP solution and PPP-NPs against SMMC7721 liver cancer cell lines were 0.4 microg/ml and 0.2 microg/ml respectively, which indicated that the cytotoxicity of PPP-NPs against tumor cells was greater than that of the PPP solution. In conclusion, S-PCL-PEG micelle-like nanoparticles loaded with PPP have a promising future for administration by injection. PMID- 25016663 TI - [Callous and unemotional--do children have psychopathic features?]. AB - The essence of psychopathic personality disorder is considered to consist of emotional deviations, the most central ones of which being the lack of feelings of guilt and empathy along with impoverishment of experiencing emotions. The interest in the occurrence of these callous-unemotional features in children and adolescents has increased over the past few years. According to the most recent studies, parental interventions promoting a positive, warm, and attentive parenting and interaction style are effective in the treatment of children having a conduct disorder accompanied by callous-unemotional features. PMID- 25016664 TI - [Pregnancies and deliveries in Finland and Estonia in 1997 to 2011]. AB - BACKGROUND AND METHODS: Treatment practices of pregnancies and deliveries and newborn health have differed from each other between Finland and Estonia. We examined changes in the differences from 1997 to 2011 from national birth registers and official statistics. RESULTS: Deliveries, abortions and overall fertility remained similar in Finland. In Estonia, the number of deliveries increased and abortions decreased. Problems in the perinatal period continued to be more common in Estonia. CONCLUSIONS: Estonian reproductive health and treatment practices of deliveries have approached the situation in Finland. PMID- 25016665 TI - [Gliomatosis cerebri as cause of neuropsychiatric symptoms]. AB - Gliomatosis cerebri (GC) is a rare cancer of the central nervous system, having already penetrated into various areas of the central nervous system upon becoming manifest. In tissue specimens the histopathologic picture of the tumor appears similar to that seen in diffuse gliomas at different stages of disease. Typical MRI findings in GC include diffuse increases in signal intensity in the brain, and indistinct gray-white matter demarcation in T2-weighted images. Surgical treatment is usually not possible. We describe a patient, in whom CG turned eventually out to be the cause of severe neuropsychiatric symptoms. PMID- 25016666 TI - [Update on current care guideline: atrial fibrillation]. AB - The prevalence and incidence of atrial fibrillation (AF) are increasing rapidly. Key recommendations in management of AF include prompt administration of oral anticoagulation to all patients with elevated risk of thromboembolic complications, proper use of antiarrhythmic drugs and invasive therapies in highly symptomatic patients and adequate rate control in patients with permanent AF. The selection between warfarin and the novel oral anticoagulants (apixaban, dabigatran, rivaroxaban) is based on careful evaluation of the benefits and disadvantages of the drugs in a given patient. PMID- 25016667 TI - [Assessment of ischaemia of ulcerated diabetic foot and its treatment according to recent international guidelines]. AB - Half of diabetic ulcers are ischaemic, almost all neuropathic and the problem is often worsened by infection. Ischaemia can often be repaired if diagnosed and treated early enough. At present, ischaemia is often diagnosed far too late. International recommendations emphasize an immediate need for a paradigm change. Ischaemia should always be suspected as a cause of diabetic ulcer unless proven otherwise. Every diabetic patient with a foot ulcer should undergo an immediate clinical and noninvasive vascular assessment. Early diagnosis and undelayed treatment with vascular consultation and necessary revascularizations are prerequisites for successful treatment as "time is tissue". PMID- 25016668 TI - [Autonomic neuropathy--a problem of the circulatory system and digestive tract]. AB - An autonomic disorder of the circulatory system becomes manifest as aberrant heart rate variability and baroreflex sensitivity already years before progressing into symptomatic disease, in which case the condition is no longer curable. Diagnosis is based on tests of autonomic nervous system function. The main thing in the treatment is management of risk factors of cardiovascular diseases in addition to enhanced glucose homeostasis. Autonomic neuropathy may also affect the digestive tract and be accompanied by esophageal motility disorder, gastroparesis, diarrhea, constipation or fecal incontinence. It is essential in the diagnosis to exclude other diseases of the digestive tract. PMID- 25016669 TI - [Treatment of painful diabetic polyneuropathy]. AB - Painful neuropathy is a common complication of diabetes and causes disability and impaired quality of life. Treatment of neuropathy aims at pain relief, improved function and quality of life and avoidance of foot ulcers. Progression of neuropathy is prevented with good glycemic control and treatment of the risk factors of atherosclerosis. In pain relief the first-line drugs are tricyclic antidepressants, SNRIs and gabapentinoids. Comorbidities, concomitant medications and possible contraindications are taken into account in drug selection. Since treatment with a single agent does not provide sufficient pain relief, combination of two drugs with different mechanism of action is recommended. Most patients need long-term treatment. PMID- 25016670 TI - [Hypoglycemias as a therapeutic issue in type 1 diabetes?]. AB - Patients with type 1 diabetes have an average of two symptomatic hypoglycemias in a week and at least one severe hypoglycemia in a year. The most common causes of hypoglycemia are overcorrection of hyperglycemia, excessive basal insulin dose, and physical exercise. Fear of hypoglycemia is common and leads to poor control of diabetes. On the other hand, recurrent hypoglycemias are often caused by fear of complicating diseases and overcorrection with additional insulin of even a mild hyperglycemia. Active inquiry about hypoglycemias should be made during a medical consultation. Insulin pump therapy should be considered if recurrent symptomless hypoglycemias cannot be resolved some other way. PMID- 25016671 TI - [Who will develop diabetic nephropathy?]. AB - While the pathogenetic mechanisms of diabetic nephropathy are not fully known, the greatest risk factors include long duration of diabetes, prolonged poor glucose homeostasis, hypertension, lipid disorders, smoking and male gender. According to family studies, the development of diabetic nephropathy is also influenced by hereditary factors. Two gene loci associated with end-stage nephropathy have been identified in a genome-wide study. Diabetic nephropathy is a multifactorial disease, whereby elucidation of its pathogenetic of mechanisms requires extensive multidisciplinary studies. For the present it cannot be precisely predicted who will develop diabetic nephropathy. PMID- 25016672 TI - Using the red/yellow/green discharge tool to improve the timeliness of hospital discharges. AB - BACKGROUND: As part of Yale-New Haven Hospital (Connecticut)'s Safe Patient Flow Initiative, the physician leadership developed the Red/Yellow/Green (RYG) Discharge Tool, an electronic medical record-based prompt to identify likelihood of patients' next-day discharge: green (very likely), yellow (possibly), and red (unlikely). The tool's purpose was to enhance communication with nursing/care coordination and trigger earlier discharge steps for patients identified as "green" or "yellow." METHODS: Data on discharge assignments, discharge dates/ times, and team designation were collected for all adult medicine patients discharged in October-December 2009 (Study Period 1) and October-December 2011 (Study Period 2), between which the tool's placement changed from the sign-out note to the daily progress note. RESULTS: In Study Period 1, 75.9% of the patients had discharge assignments, compared with 90.8% in Period 2 (p < .001). The overall 11 A.M. discharge rate improved from 10.4% to 21.2% from 2007 to 2011. "Green" patients were more likely to be discharged before 11 A.M. than "yellow" or "red" patients (p < .001). Patients with RYG assignments discharged by 11 A.M. had a lower length of stay than those without assignments and did not have an associated increased risk of readmission. Discharge prediction accuracy worsened after the change in placement, decreasing from 75.1% to 59.1% for "green" patients (p < .001), and from 34.5% to 29.2% (p < .001) for "yellow" patients. In both periods, hospitalists were more accurate than house staff in discharge predictions, suggesting that education and/or experience may contribute to discharge assignment. CONCLUSIONS: The RYG Discharge Tool helped facilitate earlier discharges, but accuracy depends on placement in daily work flow and experience. PMID- 25016673 TI - Root cause analysis of serious adverse events among older patients in the Veterans Health Administration. AB - BACKGROUND: Preventable adverse events are more likely to occur among older patients because of the clinical complexity of their care. The Veterans Health Administration (VHA) National Center for Patient Safety (NCPS) stores data about serious adverse events when a root cause analysis (RCA) has been performed. A primary objective of this study was to describe the types of adverse events occurring among older patients (age > or = 65 years) in Department of Veterans Affairs (VA) hospitals. Secondary objectives were to determine the underlying reasons for the occurrence of these events and report on effective action plans that have been implemented in VA hospitals. METHODS: In a retrospective, cross sectional review, RCA reports were reviewed and outcomes reported using descriptive statistics for all VA hospitals that conducted an RCA for a serious geriatric adverse event from January 2010 to January 2011 that resulted in sustained injury or death. RESULTS: The search produced 325 RCA reports on VA patients (age > or = 65 years). Falls (34.8%), delays in diagnosis and/or treatment (11.7%), unexpected death (9.9%), and medication errors (9.0%) were the most commonly reported adverse events among older VA patients. Communication was the most common underlying reason for these events, representing 43.9% of reported root causes. Approximately 40% of implemented action plans were judged by local staff to be effective. CONCLUSION: The RCA process identified falls and communication as important themes in serious adverse events. Concrete actions, such as process standardization and changes to communication, were reported by teams to yield some improvement. However, fewer than half of the action plans were reported to be effective. Further research is needed to guide development and implementation of effective action plans. PMID- 25016674 TI - Standardizing documentation and the clinical approach to apnea of prematurity reduces length of stay, improves staff satisfaction, and decreases hospital cost. AB - BACKGROUND: Apnea of prematurity, a common disorder, can severely compromise an infant's condition unless correctly diagnosed and treated. Infants with a history of apnea of prematurity can be discharged home but then be rehospitalized for an apneic event, an apparent life-threatening event, or sudden infant death syndrome. The definition of a clinically significant cardiopulmonary event, such events' documentation, and the treatment approach were standardized, and discharge criteria were refined. METHODS: A prospective, single-center comparison was conducted between a group of premature infants before and after implementation of the standard approach. Data were collected prospectively from August 1, 2005, through July 21, 2006, for the prestandard-approach group and from August 1, 2006, through September 16, 2007, for the standard-approach group. RESULTS: Twenty-two (35%) of the 63 infants in the prestandard-approach group experienced discharge delays because of poor documentation, whereby the clinician could not determine the safety of discharge. This resulted in 59 additional hospital days (mean length-of-stay [LOS] increase, 5.7 days). The standard approach group of 72 infants experienced no discharge delays and no additional hospital days, and LOS decreased (all p < .0001). Annual charges were reduced by more than $58,000 in avoiding unnecessary hospital days. Readmission to the hospital for apnea of prematurity occurred for 5 (7.9%) of the prestandard approach group but none of the standard-approach group (p = .0203). Overall compliance with the standardization process has been maintained at > or = 96%. CONCLUSION: Implementation of a standard approach to the definition of apnea of prematurity and its treatment and documentation decreases LOS and reduces cost. PMID- 25016675 TI - Reductions in invasive device use and care costs after institution of a daily safety checklist in a pediatric critical care unit. AB - BACKGROUND: In the critical care unit, complexity of care can contribute to both medical errors and increased costs, particularly when clinicians are forced to rely on memory. Checklists can be used to improve safety and reduce cost. A number of omission-related adverse events in 2010 prompted the development of a checklist to reduce the possibility of similar future events. METHODS: The PICU Safety Checklist was implemented in the pediatric ICU (PICU) at Children's Hospitals and Clinics of Minnesota. During a 21-month period, the checklist was used to prompt the care team to address quality and safety items during rounds. The initial checklist was paper, with two subsequent versions being incorporated into the electronic medical record (EMR). RESULTS: The daily safety checklist was successfully implemented in the PICU. Work-flow improvements based on regular multidisciplinary feedback led to more consistent use of the checklist. Improvements on all quality and safety metrics were identified, including invasive device use, medication costs, antibiotic and laboratory test use, and compliance with standards of care. Staff satisfaction rates were > 80% for safety, communication, and collaboration. CONCLUSION: By using a daily safety checklist in the pediatric critical care unit, we improved quality and safety, as well as the collaborative culture among all clinicians. Incorporating the checklist into the EMR improved compliance and accountability, ensuring its application to all patients. Clinicians now often individually address many checklist items outside the formal rounding process, indicating that the checklist content has become part of their usual practice. A successful implementation showing tangible clinical improvements can lead to interest and adoption in other clinical areas within the institution. PMID- 25016676 TI - System-based interprofessional simulation-based training program increases awareness and use of rapid response teams. PMID- 25016677 TI - Response to direct stool EHEC testing. PMID- 25016678 TI - Darkfield microscopy for routine microbiological observation. PMID- 25016679 TI - The current and ideal state of anatomic pathology patient safety. PMID- 25016680 TI - Imaging in cancer immunology:phenotyping immune cell subsets in situ in FFPE tissue sections. PMID- 25016681 TI - Vitamin D testing: the controversy continues. PMID- 25016682 TI - An automated approach to body fluid analysis. PMID- 25016683 TI - The evolution of Borrelia serology tests. PMID- 25016684 TI - Array CGH: mechanism and applications. PMID- 25016685 TI - Upgrading urinalysis to support the goals of healthcare reform. PMID- 25016686 TI - Disaster and the laboratory: preparation, response and recovery. PMID- 25016687 TI - The future of software in the laboratory. PMID- 25016688 TI - CLFS reform: the better alternative for the clinical lab industry. PMID- 25016689 TI - Affymetrix develops and manufactures products and systems for translational science and molecular diagnostics. PMID- 25016690 TI - Estimation of the possible economic effects of a sequential testing strategy with NT-proBNP before echocardiography in primary care. AB - BACKGROUND: The object of the study was to estimate the possible economic effects of a sequential testing strategy with NT-proBNP from a primary care payer perspective. METHODS: The study data were collected from primary care physicians in the County of Uppland from 2005 through 2012. Two different cut-off levels were used for negative NT-proBNP in the rule-out test: 300 and 400 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies. RESULTS: The female patients were slightly older than the males. Based on the data from 2012, the estimated costs for NT-proBNP tests and echocardiographies per county were reduced by EUR 300000/100000 inhabitants with the 300 pg/mL cut-off and EUR 350000/100000 inhabitants with the 400 pg/mL. CONCLUSIONS: The use of NT-proBNP as a rule-out test in a sequential testing strategy reduced the cost for diagnostic work-up of primary care patients with suspected heart failure. PMID- 25016691 TI - Metformin suppresses lipid accumulation in skeletal muscle by promoting fatty acid oxidation. AB - BACKGROUND: Obesity is a major risk factor for metabolic syndrome, including insulin resistance (IR), type 2 diabetes mellitus (T2DM), and cardiovascular disease; ectopic fat deposition plays a key role in the development of these conditions. In insulin-resistant and/or T2DM patients, lipid accumulation is increased in skeletal muscle; the intramuscular accumulation of fatty acid metabolites is recognized to play a critical role in metabolic syndrome. Besides improving insulin sensitivity, the anti-diabetic drug metformin can reduce lipid accumulation in skeletal muscle; however, its mechanism of action remains unclear. METHODS: Ob/ob mice and C2C12 cells were used to explore the effects of metformin on the morphological and physiological changes of lipid droplets. To clarify the mechanism by which metformin regulates fatty acid metabolism, a cDNA microarray and quantitative real-time PCR were used to examine the effects of metformin on the transcriptome of C2C12 cells treated with 200 micromol/L oleic acid. RESULTS: Metformin could retard body weight gain, improve insulin sensitivity and reduce intramyocellular lipid accumulation in ob/ob mice. In C2C12 cells, metformin inhibited lipid accumulation, stimulated fatty acid oxidation, and decreased triglyceride synthesis. Twenty-seven differentially expressed genes, including 12 upregulated and 15 downregulated genes, were involved in fatty acid metabolism. Interestingly, several genes involved in acyl CoA synthesis and fatty acid oxidation were also upregulated, such as Ppard, Acsbg1, Ascl3, and Mlycd. However, several genes related to lipolysis were downregulated, such as Ces1d and Cel. Moreover, several important genes related to lipid metabolism were also downregulated, such as Fabp4, Adipoq, and Apoc2. CONCLUSIONS: Metformin retards body weight gain, improves insulin sensitivity, and suppresses lipid accumulation in skeletal muscle by promoting fatty acid oxidation. PMID- 25016692 TI - Plasma total homocysteine: usual values and main determinants in adults living in the Great Tunis region. AB - BACKGROUND: Elevated total plasma homocysteine (tHcy) is an established risk factor for occlusive vascular disease and is thought to increase the risk of pregnancy loss, birth defects, and cognitive impairment in the elderly. OBJECTIVES: To determine tHcy standard values and the prevalence of hyperhomocysteinemia (HHC) and to examine their association with demographic and life style factors in the Greater Tunis population. METHODS: This cross-sectional study included 2712 subjects (1228 males and 1484 females) aged 35 - 70 years, living in the Greater Tunis region. tHcy was analyzed by a fluorescent polarizing immunoassay method. HHC was considered as tHcy > or = 15 micromol/L. RESULTS: HHC was observed in 23.7% of subjects. Plasma tHcy was higher in males than females (median (5th - 95th percentile): 13.5 [8.75 - 26.3] micromol/L vs. 10.7 [6.94 - 19.6] micromol/L). The tHcy concentration was significantly increased in smokers, alcoholics, in subjects with vitamin B12 and folate deficiencies, and hyperuricemia. In multivariate analysis, HHC was associated with male gender, vitamin B12 deficiency, clearance of creatinine, alcohol consumption, and hyperuricemia. CONCLUSIONS: HHC is common in Tunisian adults. Male gender, advanced age, renal insufficiency, low vitamin B12 status, hyperuricemia, and alcohol consumption are the main determinants of HHC in this population. PMID- 25016693 TI - Performance of the AQT90 FLEX cTnI point-of-care assay for the rapid diagnosis of acute myocardial infarction in the emergency room. AB - BACKGROUND: International guidelines stipulate that primarily cardiac troponin (cTn) assays with a coefficient of variation (CV) < or = 10% at the 99th percentile cutoff should be used for diagnosing myocardial infarction. Point-of care (POC) assays usually do not meet these criteria. Here, we sought to confirm the manufacturer-recommended 99th percentile cutoff and CV of the POC assay AQT90 FLEX cTnI. METHODS: 119 healthy persons without cardiac disorders were examined to determine the 99th percentile cutoff and the corresponding CV. This cutoff was validated in a cohort of 80 patients with unstable angina and 71 patients with non-ST-segment elevation myocardial infarction (NSTEMI), who were admitted to a chest pain unit. cTnI concentrations were measured in serial serum samples obtained from these patients at presentation, 3 and 6 hours after admission. RESULTS: A cTnI concentration of 20 ng/L was found as the 99th percentile cutoff (CV 6.7%). cTnI was > or = 20 ng/L in 51 (75%), 59 (87%), and 60 (88%) of the NSTEMI patients 0, 3 and 6 hours after admission, respectively. At admission, sensitivity was 76% and specificity 95%. Three and six hours later, sensitivity and negative predictive values increased to 88% and 98.8%, and to 92% and 97%, respectively. CONCLUSIONS: We confirmed the manufacturer recommended 99th percentile cutoff of 23 ng/L and established a CV of 6.7% at 20 ng/L. These results demonstrated that the POC assay AQT90 FLEX cTnI must be classified as "guideline acceptable". PMID- 25016694 TI - The transcriptional regulation of SOX2 on FOXA1 gene and its application in diagnosis of human breast and lung cancers. AB - BACKGROUND: Recent study demonstrated the important contribution of SOX2 to tumorigenesis and metastasis properties of various types of cancers and strongly supported the concept that SOX2 can be used as an effective marker for diagnosis and predicting prognosis of cancer patients. However, our previous RNA-Seq results from human lung cancer cell line A549 showed that some oncogenes, including FOXA1 are negatively regulated by SOX2. METHODS: To further verify the transcriptional regulation effect of SOX2 on FOXA1 and elucidate its application in the diagnosis of human lung and breast cancer, we performed real-time RT-PCR and Western blotting to test the regulation effect of SOX2 on the expression of FOXA1 gene. OncoPrint analysis was used to reveal the alteration of SOX2 and FOXA1 genes in breast invasive carcinoma cases and lung squamous cell carcinoma cases from the Cancer Genome Atlas (TCGA) data portal. Immunohistochemistry staining was performed to test the expression of SOX2 and FOXA1 in human breast and lung carcinoma. RESULTS: The results showed that there is an inhibitory effect of SOX2 on the expression of FOXA1 gene. In addition, these two genes are altered in 5.8% of 484 breast invasive carcinoma cases and 46.4% of 179 lung squamous cell carcinoma cases from the Cancer Genome Atlas (TCGA) data portal, which showed an increased percentage of carcinoma cases when compared with single gene alteration. Immunohistochemistry staining of SOX2 and FOXA1 in human breast and lung carcinoma further revealed the mutual complementary effect of these two proteins in the diagnosis of carcinoma. CONCLUSIONS: Our study revealed SOX2 as a negative upstream regulator for FOXA1 gene and demonstrated SOX2 and FOXA1 as effective dual markers in improving the diagnosis efficiency for human lung and breast tumor. PMID- 25016695 TI - Therapeutic drug monitoring of topiramate with a new HPLC method, SPE extraction and high sensitivity pre-column fluorescent derivatization. AB - BACKGROUND: Topiramate is a 2nd generation antiepileptic drug (AED) recently approved by the FDA for migraine prophylaxis. Its pharmacological activity already appears significant at low doses. Unfortunately, the difficulty in determining the drug in serum at low concentrations hampers the completion of accurate pharmacokinetic studies in humans. Only chromatographic methods allow reaching the necessary sensitivities. METHODS: Almost all of the HPLC methods proposed were based on the preliminary extraction of topiramate from the sample using organic solvents. In our study, the conditions for purifying topiramate through solid-liquid technique in disposable cartridges (SPE) packed with C18 reversed phase were examinated and optimised. After a pre-column derivatization step with 9-fluorenylmethyl chloroformate (FMOC-Cl) and internal standard addition, topiramate was analysed on a CN column with sodium phosphate buffer 50 mmol/L (pH 2.5) containing acetonitrile (60:40, v/v) as the mobile phase. The column effluent was monitored with a fluorescence detector (excitation and emission 1 260 and 315 nm, respectively). 122 samples from our routine laboratory work were analysed in order to confirm the existence of a relationship between topiramate dose and serum concentration and to evaluate the effect of concomitant therapies with enzyme-inducing AEDs. RESULTS: Sensitivity (2 ng/mL), precision (CV within assay of 3.8% and between assays of 6.6%), linearity and accuracy of the method were better than other analytical procedures previously reported. Serum topiramate levels in the group with enzyme-inducing AEDs showed a reduction with respect to the group with non-enzyme-inducing AEDs and the correlation between doses and mean serum concentration gives a linear trend (r2 = 0.916). CONCLUSIONS: The efficacy of SPE extraction together with the method's reliability proved very advantageous for pharmacokinetics studies and, in principle, for therapeutic drug monitoring and toxicological investigations. PMID- 25016696 TI - Is automated kinetic measurement superior to end-point for advanced oxidation protein product? AB - BACKGROUND: Advanced oxidation protein product (AOPP) was first described as an oxidative protein marker in chronic uremic patients and measured with a semi automatic end-point method. Subsequently, the kinetic method was introduced for AOPP assay. We aimed to compare these two methods by adapting them to a chemistry analyzer and to investigate the correlation between AOPP and fibrinogen, the key molecule responsible for human plasma AOPP reactivity, microalbumin, and HbA1c in patients with type II diabetes mellitus (DM II). The effects of EDTA and citrate anticogulated tubes on these two methods were incorporated into the study. METHODS: This study included 93 DM II patients (36 women, 57 men) with HbA1c levels > or = 7%, who were admitted to the diabetes and nephrology clinics. The samples were collected in EDTA and in citrate-anticoagulated tubes. Both methods were adapted to a chemistry analyzer and the samples were studied in parallel. RESULTS: In both types of samples, we found a moderate correlation between the kinetic and the endpoint methods (r = 0.611 for citrate-anticoagulated, r = 0.636 for EDTA-anticoagulated, p = 0.0001 for both). We found a moderate correlation between fibrinogen-AOPP and microalbumin-AOPP levels only in the kinetic method (r = 0.644 and 0.520 for citrate-anticoagulated; r = 0.581 and 0.490 for EDTA anticoagulated, p = 0.0001). CONCLUSIONS: We conclude that adaptation of the end point method to automation is more difficult and it has higher between-run CV% while application of the kinetic method is easier and it may be used in oxidative stress studies. PMID- 25016697 TI - Clinical significance of the antinuclear antibodies in chronic viral hepatitis B in children. AB - BACKGROUND: The presence of autoantibodies is frequent in chronic viral hepatitis evolution. Defining the role of autoimmunity in disease evolution or response to interferon treatment is still in debate, both in children and in adults. There are few studies about the influence of autoimmunity in children with chronic viral hepatitis. The aim of our study was to establish the clinical significance of antinuclear autoantibodies (ANA) in chronic hepatitis B in children. METHODS: We have studied 80 children with chronic hepatitis B (30 female; mean age 12.31 +/- 4.13 years). For each patient we performed haematological and biochemical tests and in 41 patients we analyzed the liver histology. The immunological parameters analyzed were: circulating immune complexes (CIC), complement, and the serum levels of immunoglobulin G, A, and M. We analysed by indirect fluorescence the presence of ANA and other autoantibodies. The response to treatment (hepatoprotectors, interferon and Lamivudine) was established depending on seroconversion to HBeAb and HBsAb. RESULTS: Positive ANA were found at baseline in 15% of the patients and during follow-up in 21.25%. In ANA-positive patients compared to those without autoantibodies we found lower levels of haemoglobin and platelet numbers (p = 0.0245, p = 0.0236, respectively), higher gamma-glutamyl transferase level (p = 0.040) and higher CIC level (p = 0.0155). During interferon treatment 13.79% of those who initially tested ANA-negative presented ANA, compared to 2.56% in those without interferon (p = 0.042). There was no difference in response to interferon treatment according to the presence of ANA (p = 0.4201). CONCLUSIONS: Searching for ANA in children with chronic hepatitis B is a key element in describing the evolution of these patients, especially when considering interferon therapy. Interferon treatment stimulates the development of ANA, but their presence does not influence the response to this particular treatment. The role of autoimmune processes in the evolution and response to treatment of chronic hepatitis B patients remains controversial. PMID- 25016698 TI - Frequency of beta-thalassemia or beta-hemoglobinopathy carriers simultaneously affected with alpha-thalassemia in Iran. AB - BACKGROUND: Beta-thalassemias are prevalent heritable single gene disorders affecting the quantity of the hemoglobin molecule. Rarely, a co-inheritance of these impairments with alpha-thalassemia and/or a hemoglobinopathy occurs and makes an important double heterozygote or homozygous state. Thus finding these cases is essential for genetic counseling. The present study aimed to identify the prevalence of coexistent alpha-thalassemia mutations, hemoglobinopathies, and beta-thalassemia determinants. METHODS: This descriptive study was performed on 5760 patients. We used complete blood cell count, Hb electrophoresis, and HbA2 measurement for thalassemia carrier identification. Increased HbA2 (> or = 3.5%) is the standard diagnostic marker for beta-thalassemia, while normal HbA2 with low MCH and MCV can indicate an alpha-thalassemia carrier or atypical beta thalassemia minor. Individuals with MCV < 80 fL, MCH < 27 pg, and hemoglobin < or = 15.3 g/dL in men or < or = 14 g/dL in women, were candidates for molecular thalassemia investigations. Patients with abnormal hemoglobin varieties in hemoglobin electrophoresis were referred to a genetics laboratory for hemoglobinopathy detection. RESULTS: 141 subjects out of 5760 were affected by alpha and beta-thalassemia or a beta-hemoglobinopathy simultaneously, including: 13 (11.1%) fetuses, 55 (38.2%) male cases, and 73 (50.7%) females. Among these 141 alpha-thalassemia patients, 92 cases (65.24%) were beta-thalassemia carriers and 3 (2.12%) were beta-thalassemia major, 43(30.49%) had beta hemoglobinopathies, and 3 cases (2.12%) had co-inherited beta-thalassemia and variant hemoglobins. 31 beta-gene mutations were observed in this population, the most common being HbS Cd6 (A > T) (24%). These thalassemia determinants account for about 46% of all detected mutations. As for alpha-gene mutations, -3.7 detection was the most prevalent. CONCLUSIONS: The relatively high prevalence of co-inherited alpha-thalassemia and hemoglobinopathies among beta-thalassemia carriers indicates the importance of molecular analysis to diagnose these double heterozygous or sole homozygous cases for prenatal diagnostic purposes and putting forth strategies to prevent more complicated and dangerous combinations. PMID- 25016699 TI - The measurement of circulating matrix metalloproteinase-8 and its tissue inhibitor and their association with inflammatory mediators in patients with acute coronary syndrome. AB - BACKGROUND: The aim of the present study was to investigate differences of matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS) and its correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. METHODS: 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. RESULTS: The plasma concentrations of matrix metalloproteinase-8, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and WBCs in patients with acute coronary syndrome were significantly higher than those in the control group (p < 0.001). Strong positive associations were observed between MMP-8 and TIMP-1 (r = 0.328, p < 0.001), MMP-8 and CRP (r = 0.171, p < 0.001), MMP-8 and Fibrinogen (r = 0.267, p < 0.001), MMP-8 and WBC (r = 0.163, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1). Other positive correlations were observed between CRP and fibrinogen, CRP and WBC and fibrinogen and WBC in the patients with ACS. CONCLUSIONS: Observations suggest that ACS show an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-8 and inflammatory mediators such as CRP, fibrinogen and WBC in ACS patients suggests that MMP-8 might be an additional marker and/or consequence of inflammatory components in ACS. PMID- 25016700 TI - Serum level of soluble receptor for advanced glycation end products in asthmatic children and its correlation to severity and pulmonary functions. AB - BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) acts as a decoy receptor for RAGE which has several distinct pro-inflammatory ligands in the extracellular compartment, and is believed to afford protection against inflammation and cell injury. This study was conducted to measure serum sRAGE in asthmatic children and to assess its correlation with clinical and functional severity and to asthma phenotype according to sputum cytology. METHODS: The study was conducted on 60 asthmatic children from the Pediatric Chest Clinic, Children's Hospital, Ain Shams University. The patients were divided according to asthma control and severity. RESULTS: sRAGE showed statistically significant lower levels in asthmatic patients (899.1 +/- 399.8 pg/mL) compared to the control group (1406.7 +/- 474.3 pg/mL, p = 0.000), with a cut off value of asthma diagnosis of 1080.4 pg/mL with a sensitivity and specificity of 77% and 75%, respectively. Uncontrolled and severe asthmatic subgroups showed lower levels of sRAGE, cut off value of sRAGE for the severity of asthma was 829 pg/mL with 89% sensitivity and 81% specificity. Asthmatic patients stratified according to sputum cytology revealed that those with > 2% eosinophils and > or = 40% neutrophils showed lower levels of sRAGE (710 +/- 258 pg/mL) compared to those with > 2% eosinophils and < 40% neutrophils (1064 +/- 431 pg/mL) (p = 0.000). There was a highly significant positive correlation between sRAGE levels and FEV 1% (r = 0.41, p < 0.01), a highly significant negative correlation with eosinophilic count and total IgE (r = -0.49 and -0.39, respectively, p < 0.01). CONCLUSIONS: Serum level of sRAGE may correlate with severity of bronchial asthma clinically and functionally. It may be a target of future therapeutic interventions. PMID- 25016701 TI - High frequency of circulating follicular helper T cells in patients with bronchial asthma. AB - BACKGROUND: Bronchial asthma is a chronic airway inflammatory disease primarily characterized by an abnormality in the IgE pathway. Follicular helper T (Tfh) cells are the specialized subset indispensible for providing cognate help to B cells during formation of germinal centers. The more recent work presents clear evidence that human blood CD4+ CXCR5+ T cells, circulating Tfh (cTfh) cells, are counterparts of Tfh cells in germinal centers. METHODS: 11 patients with mild asthma, 15 severe asthma patients, and 20 healthy controls were enrolled in this study. The percentages of cTfh cells were assessed by flow cytometry. The correlation between the percentage of cTfh cells and the level of serum total IgE was also analyzed. Additionally, the serum level of IL-21 was quantified by ELISA. Expression of Bcl-6 mRNA and IL-21 mRNA were assayed by real-time polymerase chain reaction. RESULTS: The frequency of the cTfh cells was significantly higher in severe asthma than in mild asthma patients and in healthy individuals and positively correlated with total IgE in blood. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in asthma patients was increased. CONCLUSIONS: Our findings provide evidence of increased frequency of cTfh cells in asthma patients, which implies that this cell subset might play an important role in the pathogenesis of asthma. PMID- 25016702 TI - Alteration of ischemia modified albumin and nitric oxide levels in hypothyroidism. AB - BACKGROUND: Thyroid disorders especially hypothyroidism is associated with increased generation of oxidants. Nitric oxide and ischemia modified albumin are considered markers for oxidative stress. In addition, nitric oxide is involved in regulation of thyroid function and coagulation profile alteration in thyroid disorders may produce ischemia like conditions. METHODS: Nitric oxide and ischemia modified albumin were estimated in fifty patients of newly diagnosed hypothyroidism using standard photocolorimetric techniques. Results were compared with fifty healthy euthyroid controls and subjected to appropriate statistical analysis. RESULTS: Nitric oxide and ischemia modified albumin were found to be significantly raised (p < 0.05) in hypothyroid patients as compared to controls. A positive, but statistically insignificant correlation was observed between nitric oxide and ischemia modified albumin. CONCLUSIONS: Estmation of nitric oxide and ischemia modified albumin in hypothyroidism may help to throw light on its pathogenesis and assessing the severity of the disease, though further research is needed to establish their role as biomarkers in hypothyroidism. PMID- 25016703 TI - Growth differentiation factor 15, ischemia modified albumin and pregnancy associated plasma protein A in patients with coronary artery disease. AB - BACKGROUND: Growth differentiation factor 15 (GDF-15), ischemia modified albumin (IMA) might aid in the early diagnosis and risk stratification of patients with coronary artery disease (CAD), while pregnancy associated plasma protein-A (PAPP A) can serve as a useful marker of vulnerable plaques and acute coronary syndrome (ACS). We sought to determine serum levels of GDF-15, IMA, PAPP-A and evaluate their diagnostic value in different types of CAD. METHODS: We detected serum levels of GDF-15, IMA and PAPP-A in 348 patients with CAD and 205 controls. Levels of high-sensitivity C reactive protein, creatine kinase isoenzyme MB, and high-sensitivity cardiac troponin-T, which represent biomarkers of inflammation, damage or necrosis, were also evaluated. RESULTS: There were significant differences of GDF-15, IMA and PAPP-A in patients with CAD compared with the controls, where GDF-15 seemed to be associated with severity of CAD. GDF-15 demonstrated a sensitivity of 84.0% and specificity of 84.8% for diagnosis of UAP, while the negative predictive value was 87.4%. The sensitivity and specificity, negative predictive value of IMA in the diagnosis of UAP were 70.0%, 69.5%, and 70.0%, respectively. PAPP-A had the lowest sensitivity and negative predictive value compared with other markers. CONCLUSIONS: GDF-15 demonstrated a significant improvement in earlier prediction and assessment of overall patient risk of UAP comparing to IMA and PAPP-A. PMID- 25016704 TI - Circulating chemerin levels are increased in first-degree relatives of type 2 diabetic patients. AB - BACKGROUND: Chemerin is an important risk factor of insulin resistance and metabolic syndrome. The aim of this study was to explore the potential role of chemerin in the early stage of diabetes development. METHODS: 63 control subjects without any family history of diabetes and with normal glucose tolerance (NGT) and 74 healthy, first-degree relatives (FDRs) of type 2 diabetic patients were recruited in the study. All subjects underwent a 75 g oral glucose tolerance (OGTT) test after having fasted overnight. Plasma glucose, insulin, total cholesterol, HDL cholesterol, triglycerides, chemerin, and adiponectin were measured. RESULTS: FDR subjects had higher BMI, WHR, waist, fasting plasma glucose, fasting insulin, TG, UA, HOMA-IR, LDL-C, and lower HDL- C levels than control subjects (p < 0.05). The FDRs group had significantly lower adiponectin levels while chemerin was higher. Plasma chemerin levels were independently correlated with HOMA-IR, FINS, TG, FPG, and adiponectin level. Multiple stepwise regression analysis showed that HOMA-IR and TG were independent risk factors that influenced circulating chemerin levels. CONCLUSIONS: These findings showed a significant increase of chemerin levels in FDR subjects which suggested that chemerin may be involved in the development and progression of insulin resistance. PMID- 25016705 TI - Bcl-2/IgH expression of diffuse large B-cell lymphoma cells in minimal bone marrow infiltration. AB - BACKGROUND: We sought to investigate the role of the Bcl-2 translocation at the chromosomal and protein levels in minimal bone marrow (BM) infiltration by diffuse large B-cell lymphomas (DLBCL). METHODS: The presence of the Bcl-2/IgH fusion gene was detected in BM samples and paraffin-embedded lymph node (LN) samples from 103 patients with DLBCLs using FISH. Bcl-2 protein levels in BM and paraffin-embedded tissues were quantified using immunocytochemistry (ICC) and immunohistochemistry (IHC), respectively. RESULTS: Bcl-2/IgH translocation in paraffin-embedded LN tissue sections was observed in 43 (41.7%) patients by FISH. Of the 43 patients, the Bcl-2/IgH rearrangement in the bone marrow specimens occurred in 34 patients. The Bcl-2/IgH recombination rate in stage III cancers was not significantly different compared to the rate observed in stage I/II cancers (p = 0.101), respectively showing no statistical differences between stage IV and I/II (p = 0.179). In 64.7% (22/34) of the cases with t(14;18), Bcl-2 was detected based on ICC analysis. Positive Bcl-2 ICC staining and the t(14;18) translocation were positively correlated (p < 0.001). We then applied our FISH method to slides with at least one abnormal cell and were subjected to FISH analysis after staining. During the follow-up, no infiltration by cytomorphology for 16 DLBCL patients whose bone marrow presented Bcl-2/IgH gene rearrangement at diagnosis, and two cases were positive by morphology compared to FISH-positive results 6 months later; 9 out of 16 patients (56.3%) presented with positive Bcl 2/IgH results earlier than the morphology evaluation after 12 months. CONCLUSIONS: Utilizing both FISH and cytologic morphology, the assessment of Bcl 2/IgH translocation status could contribute to the better detection of minimal bone marrow infiltration and relapse receiving treatment by DLBCL cells. PMID- 25016707 TI - Serum levels of tenascin-C variants in congestive heart failure patients: comparative analysis of ischemic, dilated, and hypertensive cardiomyopathy. AB - BACKGROUND: Tissue remodelling in ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertensive heart disease (HHD) is accompanied by the re-occurrence of fetal tenascin-C (Tn-C) variants. The study was aimed to comparatively analyze the serum levels of Tn-C containing the FNIIIB (B+ Tn-C) or FNIIIC (C+ Tn-C) domain in heart failure patients due to ICM, DCM, and HHD. METHODS: 119 male patients with congestive heart failure (45 with ICM, 43 with DCM, 31 with HHD) were included. Measurement of serum levels of B+ and C+ Tn-C was performed using Enzyme Linked Immunosorbent Assay (ELISA). Results were correlated to clinical, laboratory, echocardiographic, and spiroergometric parameters. RESULTS: Analysis of Tn-C concentrations according to heart failure etiology revealed no significant differences. There was an association of C+ Tn-C serum levels to enlargement of the left atrium in DCM (p < 0.01) and the left ventricle in HHD (p < 0.05). In patients with ICM, C+ Tn-C showed a strong negative correlation to the stress test performance (p = 0.002, R2: -0.691). Most strikingly, there was a strong correlation between BNP and B+ Tn-C (p = 0.038, R2: 0.466) as well as C+ Tn-C (p = 0.001, R2: 0.814) in DCM patients. CONCLUSIONS: The present study highlights the impact of Tn-C variants as biomarkers reflecting the extent of cardiac remodeling in heart failure patients. Furthermore, B+ Tn-C can be suggested as an additional tool to estimate ICM performance in patients. Especially in combination with BNP, analysis of Tn-C might pave the way for a more precise evaluation of heart failure patients. PMID- 25016706 TI - Circulating heat shock protein 27 as a biomarker for the differentiation of patients with lung cancer and healthy controls--a clinical comparison of different enzyme linked immunosorbent assays. AB - BACKGROUND: Increased heat shock protein 27 (HSP27) has been described in patients with non-small cell lung cancer (NSCLC). The aim of this study was to evaluate five commercially available assays for HSP27 measurement with respect to their capabilities to differentiate NSCLC patients from healthy controls. METHODS: We measured HSP27 serum concentrations in 40 NSCLC cases and 40 healthy controls by different assays (i.e., R&D, Enzo Life Sciences, Invitrogen, Abcam, and MyBioSource). We analyzed receiver operating characteristic plots and calculated areas under the curve (AUCs) for the five HSP27 assays with the case control status as the classification variable. RESULTS: The following AUCs were obtained: R&D, 0.834 (95% CI, 0.734 - 0.908); Enzo Life Sciences, 0.823 (95% CI, 0.722 - 0.899); Invitrogen, 0.780 (95% CI, 0.674 - 0.856); Abcam, 0.642 (95% CI, 0.528 - 0.747); and MyBioSource 0.523 (95% CI, 0.408 - 0.636). An explorative comparison of the AUCs revealed that the R&D, Enzo Life Sciences, and Invitrogen assays perform better than the Abcam and MyBioSource assays in the setting evaluated. Results obtained by different HSP27 assays had up to 10-fold difference of serum concentrations, and correlation coefficients of pairwise assay comparisons ranged from 0.184 - 0.938. CONCLUSIONS: The results of our clinical method comparison study revealed that commercially available HSP27 assays are not equally useful to differentiate NSCLC patients from healthy controls. Our study suggests that certain HSP27 methods cannot be applied for diagnostic purposes in lung cancer and probably also not in other diseases. PMID- 25016708 TI - Comprehensive analysis of UGT1A1 polymorphisms through high-resolution melting analysis and DNA sequencing. AB - BACKGROUND: Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) is a key conjugating enzyme of bilirubin and the anti-tumor medication irinotecan. Comprehensive analysis of UGT1A1 gene polymorphisms may provide benefit by predicting pharmacokinetics and outcomes of treatment with irinotecan and certain antiviral medications. METHODS: A high-resolution melting (HRM) analysis was designed to characterize the UGT1A1 gene. Genomic DNA from 110 healthy subjects was extracted from peripheral blood samples. The promoter and 11 exons from UGT1A1 were screened by HRM, and all results were subsequently confirmed by direct DNA sequencing. RESULTS: HRM analysis readily identified UGT1A1 gene mutations. We identified 5 different known variants of UGT1A1 including c.211 G > A; G71R, c.686 C > A; P229Q, c.1091 C > T; c.-3279 T > G; and c.-3156 G > A in 110 normal Taiwanese individuals. We also identified 8 new sequence variants, namely, c.-3296 C > T; c.43 C > A; c.45 G > A; c.234 G > A; c.577 G > A; c.614 C > T; c.1011 T > C; and c.1352 C > T. Each UGT1A1 variant was easily identifiable by differences in curves plotted from HRM data. CONCLUSIONS: HRM analysis was rapid, accurate, and economical for screening UGT1A1 gene mutations. PMID- 25016709 TI - Microorganisms in respiratory tract of patients diagnosed with atypical pneumonia: results of a research based on the use of reverse transcription polymerase chain reaction (RT-PCR) DNA microarray method and enzyme-linked immunosorbent assay. AB - BACKGROUND: Numerous molecular-based tests were applied for the laboratory-based diagnosis of viruses. In this cross-sectional case control study, in addition to bacteria, we aimed to determine respiratory viruses using, for the first time in our country, the Reverse Transcription PCR DNA Microarray method, and we also aimed to evaluate its diagnostic performance. METHODS: Respiratory viruses were investigated from nasopharyngeal swabs of 76 patients diagnosed with atypical pneumonia and 64 healthy controls using the CLART Pneumovir (Genomica, Spain) kit and from 10 mL blood samples of the same subjects. M. pneumoniae IgM was detected by ELISA and L. pneumophila IgM and C. pneumoniae IgM by indirect immunofluorescence. Person's chi-square test was used for statistical analysis. RESULTS: Our results showed that the specificity (100%) and the positive predictive value (100%) of the CLART Pneumovir kit were high, but its sensitivity (53%), its negative predictive value (64%), and its kappa value (50%) were low. Parainfluenza Virus type 3 and M. pneumoniae were found alone or together as the most common microorganisms while no cases of human bocavirus, adenovirus, rhinovirus, or coronavirus were detected. CONCLUSIONS: Our results demonstrated that, during the study period, most of our patients had atypical pneumonia due to Parainfluenza Virus type 3 and M. pneumoniae co-infection. PMID- 25016710 TI - Comparison of a new microbiological assay with a standard high-performance liquid chromatographic method for determination of vitamin B6 in serum. AB - BACKGROUND: A high-performance liquid chromatographic (HPLC) assay for vitamin B6 in human serum was compared with a novel microbiological assay (ID-Vit) that uses microtitre plates precoated with a specific microorganism, thus avoiding numerous problems associated with the use of stock cultures utilized by common other microbial assay mit B6. METHODS: Data obtained using HPLC were compared with 1D Vit results in 170 healthy individuals and in 68 patients with coronary artery disease (CAD, 37 with acute coronary syndrome [ACS], 31 with stable CAD). Regression and Bland-Altman analysis were performed. Homocysteine in CAD patients was measured by HPLC. RESULTS: The ID-Vit assay correlated well with the HPLC assay (Pearson's r = 0.89 [p < 0.0001] in healthy and 0.82 [p < 0.001] in CAD individuals). Bland-Altman analyses revealed good agreement between the results of both methods in both cohorts, with > or = 95% of all values grouping within the lines of agreement. In CAD patients, mean homocysteine values did not differ between stable CAD and ACS and were normal. Thirty-seven percent of CAD patients had estimated glomerular filtration rates (GFR) below 60 mL/min/1.73m2. GFR correlated inversely with homocysteine levels (r = -0.80, p < 0.001) whereas neither HPLC nor ID-Vit values for B6 did. CONCLUSIONS: ID-Vit assay and the HPLC standard are in very good agreement. The new assay can easily be automated and is less laborious than common microbiological assays. The lack of correlation between B6 vitamin and homocysteine can be accounted for by the fact that mean vitamin B6 in our CAD patients was in the normal range and that a relevant percentage of patients had chronic renal disease. PMID- 25016711 TI - Serum lipid level in Tunisian patients with psoriasis. AB - BACKGROUND: Psoriasis is a common chronic inflammatory skin disorder that has been associated with oxidative stress, abnormal plasma lipid metabolism, and high frequency of cardiovascular events. The aim of this study was to determine lipid profile variations in Tunisian psoriatic patients. METHODS: This study was designed and conducted as a case-control assay with 91 psoriatic patients and 91 controls. The lipid profiles, including serum level of triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), were assessed in both groups. RESULTS: The two groups consisted of 91 patients and 91 controls, each with 45 males and 46 females. In the psoriatic group, serum triglycerides, low density lipoprotein, and very low density lipoprotein cholesterol were significantly higher than in the control group (p < 0.05), while the high density lipoprotein cholesterol (HDL-cholesterol) was significantly decreased in patients with psoriasis compared to controls (p < 0.001). There were no significant differences concerning insulin or insulin resistance and total cholesterol between the two groups. The insulin secretion was significantly higher in patients with psoriasis than in the control group (p = 0.003). However, there was no significant correlation between severity of psoriasis and serum lipid and insulin secretion. A negative correlation (r = -0.253, p = 0.019) was found between PASI index and HDL-C. CONCLUSIONS: A high serum lipid level is significantly more common in psoriatic patients. This could be responsible for higher prevalence of cardiovascular incidents in psoriatic patients. It may be useful to do early screening and treatment of hyperlipidaemia in psoriatic patients to prevent atherosclerosis and its complications. PMID- 25016712 TI - A case of dispermic chimerism with normal phenotype identified during ABO blood grouping. AB - BACKGROUND: Human chimerism with normal phenotype derived from the fusion of two different zygotes is a rare phenomenon. We describe a case of a phenotypically normal 17-year-old diagnosed with dispermic chimerism during routine ABO blood grouping. METHODS: ABO grouping, ABO genotyping, karyotyping, human leukocyte antigen (HLA) typing, and short tandem repeat (STR) analysis were performed. RESULTS: Forward typing with anti-A and anti-B sera resulted in mixed-field agglutination of red blood cells. The mother and father were blood group O and AB, respectively. The proposita had O1, A201 and B alleles in the ABO locus; O1 was a maternal allele, while A201 and B were the paternal alleles. The proposita karyotype was 46,XX/46,XY. HLA typing revealed that the proposita had three alleles (46, 51, 54) at the HLA-B locus, with the additional allele of paternal origin. STR analysis identified three alleles for five of the 15 markers (D2S1338, TPOX, D8S1179, D19S433, and D21S11) analyzed in the proposita's blood- and skin fibroblast-derived DNA. The additional alleles of TPOX, D8S1179, and D21S11 were of paternal origin. CONCLUSIONS: The genetic findings suggest that this proposita was produced by dispermic fertilization of two identical haploid ova formed by parthenogenetic activation. PMID- 25016713 TI - Serum lactate dehydrogenase in combination with free-to-total serum prostate specific antigen ratio for diagnosis of prostate cancer. AB - BACKGROUND: Evaluate the utility of serum lactate dehydrogenase (LDH) in combination with free-to-total serum prostate specific antigen ratio (%fPSA), for diagnosis of prostate cancer (PC) with serum total prostate specific antigen (PSA) levels in the intermediate range of 4 to 10 ng/mL. METHODS: The following variables were analysed: PSA, %fPSA, and LDH. Two categories of patients were included in the analysis: NOT PC and PC. RESULTS: We studied 134 patients, 112 had NOT PC and 22 had PC. We defined the following multivariable score (S): S = A + B, where A and B are coefficients of LDH and %fPSA, respectively. AUC values were 0.719 (p = 0.0036), 0.749 (p = 0.0082), and 0.816 (p = 0.0001) for %fPSA, LDH, and S, respectively. Using the proposed S increases by 18% specificity compared to only using the %fPSA parameter. CONCLUSIONS: LDH in combination with %fPSA improves diagnostic performance for detection of PC compared to using only %fPSA. PMID- 25016714 TI - Hemotherapy algorithms for coagulopathic cardiac surgery patients. AB - In patients undergoing cardiac surgery, perioperative coagulopathy and the use of allogenic blood products are independently associated with increased mortality and major perioperative cardiac and non-cardiac adverse events. Hemotherapy should be based on specific hemotherapy algorithms rather than "clinical judgments". However, whether hemotherapy should be based on "classical" conventional laboratory coagulation analyses or Point-of-Care (POC) measures is discussed controversially. There is very good evidence from retrospective studies and prospective randomized controlled trials that the implementation of viscoelastic and aggregometric measurements in hemostatic therapy algorithms may reduce the transfusion rate of allogenic blood products. Furthermore, data suggest improved clinical outcome. Unfortunately, the studied hemotherapy- algorithms are very complex and thus hard to integrate into daily practice. In close cooperation of three German University Hospitals, the authors developed and implemented two more comprehensive and practical hemotherapy algorithms that are based on either POC measures or conventional coagulation testing. Here we present and discuss the structure and limitations of these algorithms. PMID- 25016715 TI - Assessment of ischemia-modified albumin levels in patients with rheumatoid arthritis. AB - BACKGROUND: Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis (RA). Abundant amounts of ROS have been identified in the synovial fluid of RA patients. The accumulation of ROS in cells also serves as an important intracellular signaling of molecules that amplify the synovial inflammatory-proliferative response. Thus, the aim of this study was to assess the IMA levels and other oxidative stress and inflammatory biomarkers in RA subjects. METHODS: IMA, AOPP, CRP, hemoglobin, Hct, MCV, RF, creatinine, urea levels were assessed in 16 RA subjects and 20 healthy controls. RESULTS: IMA levels were significantly higher in the RA group than in the control group (0.495 +/- 0.01 vs. 0.433 +/- 0.02 ABSU, p = 0.038). No significant differences were observed for the other markers studied. CONCLUSIONS: This study demonstrated that RA is related to oxidative stress and inflammation. We also showed for the first time an increase of IMA levels in RA subjects, suggesting that this pathology promotes an increase in the oxidative stress process. PMID- 25016716 TI - Acute fluctuation in blood glucose has no effect on platelet aggregation rate. AB - BACKGROUND: Short-term acute blood glucose fluctuations are often found among patients with high risk of thrombosis. Influence of the phenomenon on platelet aggregation rate is of clinical importance and should be clearly evaluated. METHODS: We measured ADP and arachidonic acid-induced platelet aggregation on 58 patients with type II diabetes or acute coronary syndrome before and after oral intake of 75 g of glucose. C-peptide and insulin levels were measured in diabetic patients and glycated hemoglobin was determined in ACS patients. RESULTS: Results showed that short-term acute glucose fluctuation had no significant impact on platelet aggregation in these patients. In diabetes patients, the 2 hours platelet aggregation rate induced by ADP was positively correlated with insulin levels (r = 0.477, p = 0.014). AA-induced platelet aggregation was positively correlated with BMI (r = 0.619, p = 0.024). In ACS cases, there was no correlation between platelet aggregation rates and glycated hemoglobin. CONCLUSIONS: There is probably no need to consider the possible influence of acute blood glucose fluctuation on thrombotic events. PMID- 25016717 TI - "Is the community able to deliver Stevens' vision?". PMID- 25016718 TI - Lack of staff hits community care. PMID- 25016719 TI - Minister promises more nurses for NI. PMID- 25016720 TI - Major inquiry into missing nurse. PMID- 25016721 TI - NICE backs weight-loss programmes. PMID- 25016722 TI - New care plans aim to tackle malnutrition. PMID- 25016723 TI - "Revolutionary" drug for patients with MS. PMID- 25016724 TI - Patients with leg ulcers wanted for trial. PMID- 25016725 TI - DNA testing scheme rolled out by nurses. PMID- 25016726 TI - Review set to clear Homertonover over allegations from midwives. PMID- 25016727 TI - Hunt rubber-stamps maternity unit change. PMID- 25016728 TI - Warning over complacency at Scots nurse rise. PMID- 25016730 TI - Invest in lead nurses to boost dementia care. PMID- 25016729 TI - National framework to ensure agency staff are "fit for purpose". PMID- 25016731 TI - "Failing to invest in the nursing workforce puts patients at risk". PMID- 25016732 TI - "Good dementia care needs human interaction, not apps". PMID- 25016733 TI - Reducing antipsychotic drugs in care homes. AB - Antipsychotic medication should be used in people with dementia only when there is an identified need and the benefits outweigh the risks. An audit-based service provided by pharmacists, working with nursing and care staff in residential homes, resulted in antipsychotic doses reductions of 20% and drug discontinuation in 17% of residents with dementia. PMID- 25016734 TI - A guide to prescribing anti-dementia medication. AB - This article outlines a good practice guide to prescribing anti-dementia medication developed jointly by a lead nurse for memory services and a clinical pharmacist. The guide brings together current evidence to produce a concise prescribing guideline for practitioners. PMID- 25016735 TI - Using one-page profiles to personalise care. AB - One-page profiles are regularly used to communicate information about service users in social care; this simple, concise tool can also be used in healthcare settings. This article describes how one-page profiles can benefit both patients and nurses in hospital. PMID- 25016736 TI - Leadership walkrounds in mental health care. AB - Patient safety leadership walkrounds are designed to assist healthcare leaders to improve patient safety. At 2gether Foundation Trust, walkrounds have been developed in mental health settings. They ensure that executives are informed firsthand about the safety concerns of frontline staff, while ensuring staff are listened to and supported when issues of safety are raised. Patient safety and quality improvements have been implemented over time through this process. PMID- 25016737 TI - 60 seconds with Bill Whitehead. PMID- 25016738 TI - A life's work in child health. PMID- 25016739 TI - Successful leaders get noticed. PMID- 25016740 TI - [Capillaries of living systems: natural nanomechanisms of the functioning]. AB - This article summarizes the literature and research data that concerns role of capillaries in the functioning of natural nanomechanisms in living systems. Physiologically active substances the body--essential and non-essential amino acids, neurotransmitters (epinephrine, norepinephrine, acetylcholine), vitamins (retinol, ergocalciferol, etc.), albumin, ATP, DNA, RNA, fibrinogen and others- are at the nanoscale size. Natural nanostructures are ion channels of biological membranes, colloidal solutions of the body (blood, interstitial fluid). Only in recent years, scientists have begun to more actively explore the role of capillaries in the functioning of organs and body with position of natural nanomechanisms. To the nanomechanisms in functioning capillaries in the body of living systems maybe contribute: wall capillaries, vascular endothelium, as nanostructures, capillary forces, biological nanomotors, ion channels, surface tension and surface energy of nanoparticles, and such processes and phenomena as nanohydrophobic shift or "lotus-effect" double electric layer, entropy that occur in the structures of the body. The significance of water flow processes in capillaries studied enough. Establishing nanomechanisms in functioning capillaries in living systems requires an interdisciplinary approach involving different specialists in physics, chemistry, biology, physiology, pharmacology and toxicology. PMID- 25016741 TI - [Changes of fatty acids spectrum of plasma triglycerides and their pharmacological correction by statins in patients with unstable angina]. AB - The fatty acid composition of plasma triglycerides by gas chromatography, the dynamics of the segment ST, cardiac arrhythmia by daily monitoring of electrocardiogram in patients with unstable angina (progressive) and the effects of treatment with statins were studied. Revealed marked qualitative abnormalities of plasma triglycerides in patients with progressive angina manifest increase in the amount of saturated and reduction--of unsaturated fatty acids. High therapeutic effect of simvastatin and atorvastatin may be due to the identified strong correlation between the dynamics of the fatty acid components of plasma triglycerides and indicators of ischemia, ectopic activity in patients with progressive angina. PMID- 25016742 TI - [The relation of structural and functional status of the left chambers of the heart, the level of circulating NT-pro-BNP and the status of endothelium dependent vasodilation with characteristics of 24 hour blood pressure monitoring in patients with arterial hypertension]. AB - On the certain stage of development of cardiovascular diseases (and not only AH) their further progression depends from the changes of structural and functional status of the left chambers of the heart, the presence of left ventricular hypertrophy (LVH), the functional status of endothelium and plasma concentration of brain natriuretic peptide (some consider the latter is an important prognostic marker of LVH because it takes part in regulation of heart remodeling processes). Because of these we studied the links of mentioned characteristics with the levels of blood pressure (using 24 hour blood pressure monitoring). The analysis of our data showed that higher daytime averag SBP, DBP, PBP are associated with higher concentration of circulating NT-pro-BNP but there is no relationship between mentioned characteristics and EDVD. The daytime average values o SBP > 165 mm Hg, DBP > 98 mm Hg and PBP > 69 mm Hg are linked with higher values of lef ventricular mass index, longer period of LV isovolumic relaxation and significantly higher concentration in plasma of NT-pro-BNP. We did not find statistically significant correlations between daytime average values of SBP, DBP, PBD and LVEF, the dimensions of left chambers of the heart, Doppler indices of diastolic transmitral flow and endothelium dependent vasodilation reaction of a. brachialis (delta %). PMID- 25016744 TI - [Comparative evaluation of the effectiveness of different schemes of correction the portal system pressure in patients with liver cirrhosis]. AB - The data about the complex examination and treatment of 64 patients is given. Proven the efficiency of prescribing angiotensin II receptor blocker compared with angiotensin-converting enzyme inhibitors and beta-blockers in combination with prebiotics, probiotics and L-arginine medical preparations. It is found that more manifested positive changes in indexes of intracardialy hemodynamics in patients with liver cirhhosis usage of valsartan (group III), namely: increased the left ventricular ejection fraction from (58.1 +/- 3.6) % to (65.1 +/- 1.1) % (P < 0.05), the beat index--from (28.99 +/- 2.20) ml/m2 to (36.1 +/- 3.5) ml/m2 (P < 0.05), the heart index to (3.26 +/- 0.70) l/(min2 x m2) from (2.59 +/- 0.80) l/(min2 x m2). Thus, the use of angiotensin II receptor blockers in patients with liver cirrhosis did not significantly reduce the systemic blood pressure, which must be considered in the treatment of this group of patients. PMID- 25016743 TI - [Effect of cardiovascular risk factors on occurrence and course of silent form of ischemic heart disease in patients with postinfarction cardiosclerosis]. AB - Special features of silent myocardial ischemia course were examined depending on the presence of cardiovascular risk factors. Data on interdependence of risk factors presence and figures of holter monitoring of electrocardiography was received. It was ascertained that for the patients with silent myocardial ischemia with such risk factors occurrence of complicated course of ischemic heart disease, such as arterial hypertension, diabetes and hyperlipidemia, the following indicators are typical: higher average daily indicators of ischemic episodes per day, higher aggregate daily duration of ST-segment depression, higher aggregate amplitude of ST-segment depression, higher average duration of one ischemic episode, compared to the persons without risk factors. Probability of antinociceptional system activation processes influence on the risk of accrual of acute coronary syndrome was proved. PMID- 25016745 TI - [Identification of clinical features of cognitive impairment and depressive disorders in patients with metabolic syndrome with insufficiency of cerebral circulation]. AB - Investigation involved 221 patients aged 50-84 with chronic insufficiency of cerebral circulation, who were divided into four groups: patients without metabolic syndrome (MS) and without depressive disorders (DD); subjects with MS without DD; subjects without MS with DD; subjects with MS with DD. All the patients also were divided into three subgroups depending on age. Patients with MS and DD and with MS without DD had significantly more vascular risk factors, comparing with other groups of patients. Mild cognitive impairment (CI) significantly more often were detected in patients without MS and without DD; dementia more often was observed in patients with MS and DD. Significant interrelationship between severity of CI and depression level was observed only in patients with MS. These data underline important role of MS as a risk factor of both DD and CI in patients with chronic insufficiency of cerebral circulation. Severity of DD significantly increased with age only in patients with MS. We observed significant growth of CI severity in all the groups of patients with increasing age. However stage of chronic insufficiency of cerebral circulation significantly influenced the severity of DD in patients with MS and without it. PMID- 25016746 TI - [The frequency of endothelial dysfunction in patients with pseudarthrosis of long bones with hyperhomocysteinemia and associated metabolic disorder]. AB - In article described research of frequency of endothelial dysfunction in 153 patients with pseudarthrosis of long bones and in individuals with consolidated fractures. The reparative regeneration are associated by structural and functional disorders of the central and peripheral vessels as endothelial dysfunction, thickening of the intima-media, prevails at hypoplastic and atrophic types bone nonunion, neurotrofic syndrome and refractures. Endothelial function was significantly dependent on the levels of homocysteine, total cholesterol and interleukin-6 in serum. PMID- 25016747 TI - [Effect of clopidogrel and aspigrel on ectopic cardiac activity in patients with unstable angina pectoris]. AB - The coronary circulation dysfunction in patients with unstable angina pectoris causes development of ventricular and supraventricular cardiac rhythm disorders. Findings from the current study suggest that antianginal therapy of patients with acute coronary syndrome which includes antiaggregant and anticoagulant is effective in the treatment of extrasystolic arrhythmias. PMID- 25016748 TI - Heart left ventricle's diastolic function features in patients with reactive arthritis. AB - Cross-correlation analysis's data indicate for the patients with reactive arthritis features, which determine character the left ventricle's diastolic filling, are end-diastolic pressure and end-diastolic pressure/end-diastolic volume index in the left ventricle. PMID- 25016749 TI - [Dynamics of respiratory function and cardio-vascular system in children with bronchial asthma during prolonged sanatorium treatment]. AB - Children with asthma in remission had a significant increase in VC, FVC, FEV1, PEF, FEF25-FEF75 during prolonged sanatorium rehabilitation (for a year) in case of inclusion in the complex of rehabilitation respiration training "PARI PEP 2". Children who received the standard course of spa treatment don't have same results. Improvement intervals in PQ and QT(c) were demonstrated. It indicates a decrease in the risk of life-threatening arrhythmias. The simulator "PARI PEP 2" should be included in complex rehabilitation of children with asthma. PMID- 25016750 TI - [Features of anxiety-depressive disorders in patients with hypertensive dyscirculatory encephalopathy and hypothyroidism]. AB - The questions about features of anxious-depressive disorders in patients with hypertensive encephalopathy and related dyscirculatory hypothyroidism are examined. PMID- 25016751 TI - [Efficiency of prognostication the probability of smoking ceasation (by example students)]. AB - The paper presents data of the testing of multifactor nonlinear neuronet model for efficiency of prognostication the probability of smoking ceasation by example students. PMID- 25016752 TI - [Diagnostics and treatment of acute odontogenic osteomyelitis of the mandible considering functional state of inferior alveolar nerve]. AB - Evaluation of functional impairment of inferior alveolar nerve in acute odontogenic inflammatory processes was carried out in this clinical study by means of stimulation electroneurography. Possibility of early diagnosis of acute odontogenic osteomyelitis by this method and effectiveness of decompression osteoperforation for its treatment was shown. PMID- 25016753 TI - [Mechanisms of actoprotective action of succinic acid's derivatives]. AB - Research on establishment of mechanisms of metabolitotropic compounds' actoprotective action--derivatives of succinic acid yakton and mexidol, based on the definition of their antihypoxic, antioxidant, mitoprotective, and ergogenic properties are presented in this article. In case of hypoxic, haemic, and circulatory hypoxia yakton and mexidol influence on parameters of prooxidant antioxidant homeostasis, as well as prevent disturbances of glycolysis, content of macroergic compounds, changes of RNA-content in nerve tissue, and development of mitochondrial dysfunction. Yakton's actoprotective effect based on enhancement of adenine nucleotides' content in liver, myocardium, and skeletal muscles is also established with high-speed loading, as well as using preliminary cooling or hyperthermia. Wide range of yakton's effects (antihypoxic, membraneprotective, cardioprotective, etc.) is also confirmed according to the data of quantum chemical research. PMID- 25016754 TI - [Liver stiffness in animals with glutamate-induced obesity (according to shear wave ultrasound elastography)]. AB - We studied changes of liver stiffness measured by SWE in animals with glutamate induced obesity (GIO). We noted significant increase of LS on 63.6% compared to intact rats (P < 0.001). Histologically confirmed non-alcoholic steatosis diagnosed in 93.3% of animals with obesity. The AUROC of SWE for in animals with GIO was 0.983 (95% CI 0.955-0.999; P < 0.001). The optimal LS cutoff point for the prediction of steatosis were > 6.25 kPa, with sensitivity, specificity, PPV and NPV 86.6; 100; 100 and 93.7% respectively. PMID- 25016755 TI - [The dynamics of indices of immune and cytokine status for patients with essential hypertension in combination with osteoarthritis]. AB - In the article the results of estimation of basic indexes of cellular and humoral link of immune system and cytokine status are resulted for patients with essential hypertension in combination with osteoarthritis and also influences of complex therapy of essential hypertension and osteoarthritis on these indexes are resulted. PMID- 25016756 TI - [Immune elements of pathogenesis of multiorgan failure syndrome in newborns]. AB - Expression of clusters determination of T-cells immune links (CD4, CD8, CD95) and level of interferon-alpha at newborns with multiorgan failure syndrome were investigated. It were shown supressive character of immune reactions and reduction the level of interferon-alpha in this contingent of patients. PMID- 25016757 TI - [Mechanisms of immune suppression of systemic inflammation by the action of the narrowband ultraviolet B (311 nm) therapy in patients with psoriasis]. AB - In patients with psoriasis, there is increased secretion of serum cytokine IL-22 of CD4 T helper 17/22 types and pro-inflammatory mediators (IL-6, TNF-alpha). Narrowband UVB therapy during 12 weeks significantly reduced the levels of IL-6, TNF-alpha IL-22 compared to the standard treatment. Patients who are resistant to narrow band UVB therapy, the use of erythmogenic strategy leads to increase of immunosuppressive effects on systemic inflammation than suberythmogenic one. PMID- 25016758 TI - [Modern approaches to wastewater treatment]. AB - The present state and prospects of new methods for cleaning in the water and wastewater using membrane separation, are examples of application of this technology in the treatment of surface and subsurface natural waters, seawater desalination, wastewater treatment plants. PMID- 25016759 TI - [Prognostication of medication costs for elderly patients at in-hospital treatment stage]. AB - Based on data analysis concerning the character and the frequency of diseases as well as medication therapy costs, there has been developed a functional model of the provision of needs in costs on medication aid for elderly and advanced old people in patient care institutions. This model allows take into account age peculiarities of the patients (polymorbidity, disease severity, regional differences in the character of pathology). PMID- 25016760 TI - [Medical errors from positions of mutual relations of patient-lawyer-doctor]. AB - The basic theoretical and practical aspects of problem of malpractice in the system of health protection Ukraine are presented in the article. On specific examples the essence of the term "malpractice" is expounded. It was considered types of malpractice, conditions of beginning and kinds of responsibility to assumption of malpractice. The special attention to the legal and mental and ethical questions of problem from positions of protection of rights for a patient and medical worker is spared. The necessity of qualification malpractices on intentional and unintentional, possible and impermissible is grounded. PMID- 25016761 TI - [Treatment organization for patients with gunshot wounds of the maxillo-facial region evacuated during the military operations in the Far East (1938-1939) and the war with Finland (1939-1940)]. AB - This article describes the path of the maxillo-facial surgery to becoming an independent part of the general surgery. We will look closely at the experience, gained y field surgeons during the events at Lake Hasan and Halkin-Gol river. The war with Finland, that enabled the surgeons to develop the system of specialized dental help for the gunshot wounds, to create standarts of specialized equipment, examples of splints, etc, which were widely used during the World War II. PMID- 25016762 TI - [Bipolar disorder: staging and neuroprogression]. AB - In bipolar disorder illness progression has been associated with a higher number of mood episodes and hospitalizations, poorer response to treatment, and more severe cognitive and functional impairment. This supports the notion of the use of staging models in this illness. The value of staging models has long been recognized in many medical and malignant conditions. Staging models rely on the fact that different interventions may suit different stages of the disorder, and that better outcomes can be obtained if interventions are implemented earlier in the course of illness. Thus, treatment planning would benefit from the assessment of cognition, functioning and comorbidities. Staging may offer a means to refine treatment options, and most importantly, to establish a more precise diagnosis. Moreover, staging could have utility as course specifier and may guide treatment planning and better information to patients and their family members of what could be expected in terms of prognosis. The present study reviews the clinical and biological basis of the concept of illness progression in bipolar disorder. PMID- 25016763 TI - [Bipolar and related disorders and depressive disorders in DSM-5]. AB - In 2013, a version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), having number 5, was published. The DSM is a textbook which aims to present diagnostic criteria for each psychiatric disorder recognized by the U.S. healthcare system. The DSM-5 comprises the most updated diagnostic criteria of psychiatric disorders as well as their description, and provides a common language for clinicians to communicate about the patients. Diagnostic criteria of the DSM-5 have been popular all over the world, including countries where the ICD 10 classification is obligatory, and are widely used for clinical and neurobiological research in psychiatry. In this article, two chapters of the DSM 5 pertained to mood (affective) disorders are presented, such as "Bipolar and related disorders" and "Depressive disorders" replacing the chapter titled "Mood disorders" in the previous version of DSM-IV. The aim of this article is to discuss a structure of new classification, to point out differences compared with previous version (DSM-IV). New diagnostic categories, such as e.g. disruptive mood dysregulation disorder or premenstrual dysphoric disorder were depicted as well as some elements of dimensional approach to mood disorders were presented. PMID- 25016764 TI - [The Temperament Evaluation of Memphis, Pisa and San Diego Autoquestionnaire (TEMPS-A)--an important tool to study affective temperaments]. AB - The aim of the paper is to describe the Temperament Evaluation of Memphis, Pisa and San Diego Autoquestionnaire (TEMPS-A) constructed by prominent researchers of affective disorders, under the direction of Hagop Akiskal, and functioning in full version since 2005. The article refers to the definitions of temperament, including the concept of affective temperament, related to the area of emotionality and conceptualized as the endophenotype of affective disorders. Based on clinical observations, initially four types of temperament had been delineated: hiperthymic, depressed, irritable and cyclothymic, and, subsequently, the anxious temperament was added. Full version of the scale contains 110 items for the five types of temperament, which were discussed in detail. The TEMPS-A has been translated into 32 languages and its verification was performed in many countries, including Poland. The scale has been widely used in epidemiological and clinical studies in general population, in patients with affective disorders, and in other diseases. In affective disorders, different types of temperament show, among others, a relationship to the type and symptomatology of bipolar disorder as well as to a predisposition to suicidal behavior. In Poznan centre, an association between several dimensions of temperament of the TEMPS-A, and prophylacic efficacy of lithium has been shown. Different types of temperament also play a role in other mental disorders and somatic diseases. In the final section of the article, the studies performed so far on the molecular-genetic determinants of temperament dimensions, measured by the TEMPS-A are presented. PMID- 25016765 TI - [Social functioning and quality of life in schizophrenia patients --relationship with symptomatic remission and duration of illness]. AB - AIM: The assessment of social functioning and subjective quality of life in relation to symptomatic remission in schizophrenia patients after a first psychiatric hospitalization, as well as the analysis of connection between intensity of psychopathological symptoms and the level of functioning and quality of life, taking into account the status of remission and duration of illness. METHODS: Sixty-four patients were assessed, at 13 months (1st examination) and at mean 8 years (2nd examination) after the first hospitalization, and compared with two control groups of healthy persons. The following scales were used: Positive and Negative Syndrome Scale (PANSS), Social Functioning Scale (SFS), WHO Quality of Life (WHOQoL--Bref) scale and Global Assessment Scale (GAS). RESULTS: At first examination, the score of SFS domains was not significantly different between patients in remission and without remission while the score of most domains of WHOQoL was significantly higher in patients with remission. At second examination, the scores of both SFS and WHOQoL were significantly higher in patients with remission and did not differ significantly from healthy persons. In both examinations, significant correlations between PANSS and SFS and WHOQoL scores were found, especially in patients without remission. CONCLUSIONS: At mean 8 years after first psychiatric hospitalization, 2/3 of the patients with schizophrenia did not get a symptomatic remission and had worse social functioning and quality of life compared to patients with remission and to healthy controls. Psychopathological symptoms correlated significantly with social functioning and quality of life, especially among patients without remission. PMID- 25016766 TI - [Emotional disorders in patients with cerebellar damage--case studies]. AB - AIM: Growing number of research shows the role of the cerebellum in the regulation of affect. Lesions of the cerebellum can lead to emotional disregulation, a significant part of the Cerebellar Cognitive Affective Syndrome. The aim of this article is to analyze the most recent studies concerning the cerebellar participation in emotional reactions and to present three cases: two female and one male who suffered from cerebellar damage and presented post traumatic affective and personality change. METHOD: The patients' neuropsychological examination was performed with Raven's Progressive Matrices Test--standard version, Trial Making Test, Wisconsin Card Sorting Test, Auditory Verbal Learning Test by Luria, Benton Visual Retention Test, Verbal Fluency Test, Stroop Interference Test, Attention and Perceptivity Test (Test Uwagi i Spostrzegawczosci TUS), Frontal Behavioral Inventory (FBI). RESULTS: The review of the literature suggest cerebellar participation, especially teh vermis and paravermial regions, in the detection, integration and filtration of emotional information and in regulation of autonomic emotional responses. In the described patients we observed: oversensitivity, irritability, impulsivity and self neglect. The man and the woman with right-sided lesions presented similar symptoms: rigidity ofthought, stubbornness, lack of criticism,jocular and inappropriate behavior. The woman with left-sided cerebellar lesion was adynamic, apathic and passive, she presented emotional blunting, social isolation, lack of interests and motivation, general cognitive slowdown. CONCLUSIONS: Both the analyzed research and the described cases indicate the connection between the cerebellum and emotion regulation. The symptoms presented by the described patients were most probably a consequence of damaged cerebellar projections to subcortical structures (the limbic system) and frontal areas. The diversification of symptoms depending on the localization of lesions had not been described yet and seems to indicate an interesting direction for future research. PMID- 25016767 TI - [Psychotic disorder in the course of Systemic Lupus Erythematosus with subcortical calcifications--case report]. AB - Systemic Lupus Erythematosus (SLE) is autoimmunological disease of connective tissue which is characterized with clinical symptoms of many systems and organs injury. There are often neuropsychiatric symptoms. Psychotic disorder is the least frequent syndrome. Neuropsychiatric symptoms are important because they deteriorate the quality of life and are poor prognostic factor. AIM: The aim of the study is to present the patient with chronic, lasting for many years, skin lesions and laboratory tests results characteristic for SLE, who had psychotic disorder diagnosed as schizophrenia and in the next few years there were observed other neuropsychiatric symptoms including cognitive impairment and mood disorder. CONCLUSIONS: Psychotic disorder is rare syndrome of neuropsychiatric SLE (NPSLE). It may primarily originate from SLE or be secondary either to the therapy or the complications of the disease. It is not possible to define if the psychosis is the primary schizophrenic process or secondary to the autoimmune disease in presented patient. However the clinical picture pays attention to the significance of careful diagnostic process, including neuroimaging. In head CT of presented patient there were revealed massive, bilateral, calcifications of subcortical structures which probably substantially enhanced neuropsychiatric symptoms. PMID- 25016768 TI - [Specificity of attention and cognitive inhibition processes in relapsing remitting multiple sclerosis patients with consideration of their mood level]. AB - The results of contemporary neuropsychological analyses lay foundation for a broad discussion of the nature and causes of cognitive deficits in MS patients. AIM: The aim of this study was to determine the level of alternating attention and dominant reaction inhibition in relapsing-remitting multiple sclerosis patients, with consideration of their mood level, age and disease duration. METHOD: Experimental group consisted of 43 adults (30 women and 13 men) diagnosed with relapsing-remitting multiple sclerosis, with Extended Disability Status Scale (EDSS) results ranging between 2.5-6.5. Control group comprised 38 healthy adults (26 women and 12 men) selected according to sex, age and education. The following tasks were used in the study: the Trail Making Test A and B (TMT), Stroop Colour-Word Test (SCWT), and Beck Depression Inventory (BDI). RESULTS: Experimental group was characterized by significantly worse performance in TMT (p < 0.001) and SCWT (p < 0.001) than the control group. No differences were observed in performance of TMT (p > 0.05) and SCWT (p > 0.05) in the experimental group between subjects with depressed and neutral mood. Disease duration proved significantly related to the level of dominant reaction inhibition (p < 0.001). CONCLUSIONS: Cognitive impairments within areas of concentration, attention shifting and dominant reaction inhibition were all revealed in the experimental group. PMID- 25016769 TI - [Neurobehavioral manifestation in early period of Alzheimer disease and vascular dementia]. AB - INTRODUCTION: AD and VD are preceded by a preclinical stage. Small but tangible cognitive impairments sometimes occur many years before the onset and diagnosis ofdementia. The ongoing degenerative process can be conductive to behavioural and psychological symptoms. AIM: The aim of the study was to investigate the rates of neurobehavioral symptoms in the preclinical stages of AD and VD. METHODS: Two hundred and ninety one residents of nursery homes were included in the study. Participants of the study did not display symptoms of dementia in accordance with DSM IV criteria and obtained at least 24 points on the MMSE scale and were on the first or second level of the Global Deterioration Scale. Participants were screened for behavioural and psychological symptoms with the NPI-NH scale, while their cognitive functioning was evaluated by means of the ADAS-cog. Participants of the study were evaluated with the MMSE scale annually. Participants who obtained less than 24 points on the MMSE scale were evaluated by a senior psychiatrist. Diagnosis of dementia was done on the basis of DSM criteria. Alzheimer's Disease was diagnosed on the basis of NINCDS-ADRDA criteria and vascular dementia on the NINDS-AIREN criteria. The study was carried out over a period of seven consecutive years. RESULTS: A hundred and fifty people were included in the final analysis--in 111 of them were found not to be afflicted with dementia, 25 were found to have AD and in 14 VD was diagnosed. The control group differed from the AD and VD group with respect to the initial level of cognitive impairment (ADAS-cog) and the intensity of behavioural and psychological symptoms (NPI -NH scale). Particular items of the NPI -NH scale differentiated the two groups to a different degree. In people with AD the greatest differences were observed with respect to agitation/aggression, mood swings, irritability/emotional liability and the rates of anxiety. People with VD, similarly to people with AD, significantly differed from the control group with respect to mood disorders and irritability/emotional liability, as well as disinhibition and anxiety. People with VD were found not have high rates of agitation/aggression. In the AD group, the shorter the period between the evaluation with the NPI-NH scale and the diagnosis of AD was the greater the rates of agitation/aggression, anxiety, and elevated mood/euphoria were. CONCLUSION: In preclinical stages of both AD and VD behavioural and psychological symptoms occur very frequently. The closer the diagnosis of dementia is the greater the possibility of behavioural and psychological symptoms occurring, especially in AD. PMID- 25016770 TI - [Diagnostic value of neuropsychological tests in mild cognitive impairment comorbid with Parkinson's disease]. AB - Mild cognitive impairment (MCI) is present in on average one-fourth of Parkinson's disease (PD) patients with no dementia diagnosis. Only recently has PD-MCI been treated as a new diagnostic entity. In 2012, unified criteria were adopted which allow both diagnosing MCI in Parkinson's disease (PD-MCI) and further classification taking into account the profile of cognitive dysfunctions and the probability of evolution towards dementia. The diagnostic criteria were presented in the form of stipulations and guidelines assuming that diagnostic process is based on the neuropsychological assessment of the patient. The notion of MCI had been borrowed and for a couple of years had been relying on definitions developed in relation to Alzheimer's disease. For the first time, in the proposed criteria memory dysfunction is not the basis of classification. Only two categories of dysfunctions have been retained, single-domain and multiple domain. Whether the adopted criteria will contribute to an accurate diagnosis of cognitive dysfunctions and PD-specific dementing processes remains an open question. In spite of some limitations, the presented criteria can certainly improve the efficacy of monitoring the patient's state at the same time allowing the hope for an appropriate therapy and a higher quality of life. Moreover, the unification of diagnostic criteria will be crucial in assessing usefulness ofneuropsychological test instruments as a basic method of investigating neurodegenerative processes not only in PD. PMID- 25016771 TI - [Validation of the Polish version of the symptom checklist-27-plus questionnaire]. AB - AIM: The goal of this research is to evaluate the psychometric qualities of the Polish version of the SCL-27-plus questionnaire in terms of its five factor structure, internal consistency and theoretical accuracy. METHOD: A total of 1.350 persons of which 62% were males, participated in the study. 651 persons were tested with a paper version, 699 subjects received an electronic version of the questionnaire. 336 (tested with the paper version) were patients with diagnosed psychiatric disorders. Paper version participants also filled out the General Health Questionnaire (GHQ-28). RESULTS: Confirmatory factor analysis validated the five factor structure of SCL-27-plus when some errors terms within subscales are allowed to correlate (Depending on the sample: 1.64 < or = chi2/df < or = 2.46; 0.05 < or = RMSEA < or = 0.06; 0.91 < or = CFI < or = 0.95). Cronbach's Alpha reliability measures for the Global Severity Index was 0.90 to 0.92 and for the particular subscales 0.71 to 0.88. The GSI and symptom subscales for SCL-27-plus correlated with their equivalences in the GHQ-28 moderately to highly (r = 0.38 to 0.68). Strong differences occurred between the "clinical" and "non-clinical" groups in the levels of general and specific symptoms (Cohen's d from 0.42 to 1.15). CONCLUSIONS: The Polish version of the SCL-27-plus questionnaire demonstrates good psychometric qualities. It can be used to measure the general intensity of psychopathological impairment as well as the specific subscales. PMID- 25016772 TI - [Worrying behaviour in pre-school children aged three to seven years: a factor analysis of the results of a questionnaire]. AB - AIM: The aims of the study were: 1) the assessment of the interaction between the factors specified for behavioural problems observed in pre-school children based on a factor analysis and 2) the assessment of the relationship the specified factors have with the age and gender of the study group. METHOD: A factor analysis based on a Principal Component Analysis of the main results of a Disturbing Behaviour Questionnaire (DBQ) completed by pre-school teachers, which includes categories of behaviour observed among pre-school age children that provoke the greatest concern among parents, guardians and educators. MATERIAL: Nine-hundred and sixty-one children aged from 2.7 to 7.9 years (mean: 5.4; SD 1.13) from randomly chosen pre-schools in all districts of Krak6w. RESULTS: Based on a screen plot, as well as on a substantive analysis of the results, a decision was taken to employ a four-factor analysis (Lagging behind, Excessive behaviour, Eating-avoidance and Overeating) explaining 68% of the common factor variance. A very high Cronbach's alpha value was returned for the reliability of the individual scales. The conducted analysis of the relationship of the scales with age and gender indicated a greater intensity of disturbing behaviour in boys for the Lagging behind factor, the Excessive behaviour factor and the overall scale for the Disturbing Behaviour Questionnaire (DBQ). These were the scales, along with the Eating-avoidance scale, that were found to be related to age. A greater intensity of disturbing behaviour was found to occur in the younger children. The relationship between the Overeating and Excessive behaviour scales that was found among girls but not among boys indicated that--even at such a young age--the characteristics associated with eating in the context of gender were already present. CONCLUSIONS: The authors consider that the coherence of the results obtained and their consistency with other studies ofpre-school age children provide a sound platform for further analyses using the questionnaire described above. PMID- 25016773 TI - [Sense of coherence and ways of coping in the relationship with brother or sister in healthy siblings of mentally ill persons]. AB - AIM: The aim of the present study was to investigate sense of coherence in healthy siblings of persons suffering from schizophrenia as well as their ways of coping in the relationship with ill brother or sister. METHODS: 40 healthy brothers and sisters of persons with ICD- 10 diagnosis of F20 to F29 participated in the present study. Orientation to Life Scale (SOC- 29) was used to assess sense of coherence and Ways of Coping with Stress questionnaire (SRSS) was used to examine stress coping strategies. RESULTS: Mean global score of siblings of persons with schizophrenia was 111 points. Subjects used coping strategies focused on problem significantly more often than those focused on emotions. CONCLUSIONS: Therapeutic work with healthy siblings should focus on strengthening sense of personal competence, development of personal resources and different ways of coping with stress, investigation of emotions that healthy siblings experience in the relationship with ill brother or sister as well as supporting the process of accepting changes in the relationship with the ill sibling. PMID- 25016774 TI - [Research and treatment of war neuroses at the Clinic for Nervous and Mental Diseases at the Jagiellonian University in Krakow before World War II in the context of psychiatry in Europe]. AB - The aim of this article is to offer an overview of the research into diagnosis and treatment of war neuroses at the Clinic for Nervous and Mental Diseases at the Jagiellonian University in Krakow before the outbreak of World War II. It also includes a profile of the work of Prof. Jan Piltz, the then director of the Clinic, and his major scientific achievements. The publications cited in the article date in the main from the period of World War I, and comprise clinical analyses of the consequences of stress suffered at the front as well as a description of the ways in which they were treated. These are presented alongside other major findings related to war neuroses being made in Europe at the time. The article draws attention to the very modern thinking on treatment of war neuroses, far ahead of the average standards of the day, evinced by Prof. Piltz and his team. The most important innovative elements of their treatment of these conditions were the fact that they perceived the cause of the neurosis to lie in previous personality disorders in the patients, their recommendation of psychotherapy as the main method of treatment, and their emphasis on the need for further rehabilitation following the completion of the course of hospital treatment. They also paid significant attention to the importance of drawing up individual therapy plans for each patient. PMID- 25016775 TI - [Contribution of the Polish-German Mental Health Society to changes in Polish psychiatry]. AB - The aim of this presentation is to give a profile of the history and work of the Polish-German Mental Health Society (PNTZP). Founded in 1990, the PNTZP's supreme objective is to develop and reinforce partnership between Polish and German psychiatry on a range of levels. The methods it uses to further this aim include bilateral meetings, seminars, and annual symposia. In view of its historical roots, the PNTZP is constantly mindful of the excesses perpetrated on the mentally ill during the National Socialist period, and believes it has an obligation to promote a brand of psychiatry founded on the person, respect for human dignity, and the will and individuality of every man. For this reason, ethics are an essential element of discussion, including discussions with patients and their families. The society advocates the implementation of the National Programme of Mental Health Care and the development of community psychiatry in Poland. It supports the development of various structures for the treatment and assistance of people with mental illness, as well as scientific and academic reflection on the social and cultural implications of psychiatric thought and action. It is committed to facilitating the exchange of experiences between different professional groups, patients, and their families in order to promote mutual inspiration and support in the challenging task of developing psychiatry. A record of these years of meetings may be found in the twenty issues of the periodical Dialog. This example of cooperation across official state borders may be held up as a benchmark for the development of European psychiatry, and the joint work and discussions may offer help and inspiration in day-to-day therapeutic practice. The PNTZP is open to new people and initiatives, and is always looking for people willing to get involved in its work. PMID- 25016776 TI - [Development of ICD-11 chapter concerning mental disorders - update for WPA members]. PMID- 25016777 TI - Heart rate variability in the course of ST--segment elevation myocardial infarction treated with primary percutaneous transluminal coronary angioplasty in elderly and younger patients. AB - BACKGROUND: The aim of the study was to appraise time domain heart rate variability (HRV) parameters in patients with ST-segment elevation myocardial infarction (STEMI) in different age groups. MATERIAL AND METHODS: Retrospective analysis included 357 consecutive patients in sinus rhythm without diabetes, aged 27-87 years (mean age--63.0 +/- 11.8 years, 243 men) treated with primary percutaneous transluminal coronary angioplasty (PTCA) due to first in their life STEMI. Each patient had an echocardiographic examination and 24-hour ECG monitoring results interpreted. Participants were divided in the analysis applying the WHO old age criterion into two groups: group A < 65 years old (n = 188) and B aged > or = 65 years (n = 169). RESULTS: In the whole study group age negatively correlated with SDNN, SDANNI, SDNNI and EF, whereas positive correlation between EF and SDANN, and EF and SDNNI was observed. Elderly patients as compared to the younger individuals had significantly diminished SDNN, SDANN, SDNNI and more often SDNN < 70 ms (33.7% vs 20.7%, p < 0.0001). When the circumflex artery lesion was the cause of myocardial infarction SDNN and SDANN were significantly lower in the group B, whereas in case of PTCA of RCA, apart from decreased SDNN and SDANN, EF was also compromised in this group. CONCLUSIONS: Elderly patients with myocardial infarction with ST-segment elevation treated with primary PTCA, compared to the younger age group, are characterized by increased sympathetic activation assessed by heart rate variability and heart rate in 24-hour ECG monitoring. PMID- 25016778 TI - [Bilateral neck exploration with intraoperative iPTH assay in patients not eligible for minimally invasive parathyroidectomy]. AB - BACKGROUND AND AIMS: Bilateral neck exploration (BNE) is the preferred surgical technique in patients with primary hyperparathyroidism (pHPT) not eligible for minimally invasive parathyroidectomy (MIP). The aim of this study was to assess indications for BNE in the era of MIP, including short-term outcomes of surgery with intraoperative intact parathyroid hormone (iPTH) monitoring added-value. METHODS: Data of 155 patients with pHPT qualified for BNE with intraoperative iPTH monitoring and treated in 2003-2012 were retrospectively analysed. All patients underwent biochemical and imaging testing in the preoperative work-up. The following endpoints were analysed in this study: indications for BNE, short term outcomes of surgery, and intraoperative iPTH monitoring added-value. RESULTS: Indications for BNE were: negative preoperative imaging in 65 (41.9%) patients, concomitant goitre necessitating surgical removal in 51 (32.9%) patients, MEN 1 syndrome in 17 (11.0%) patients, lithium treatment in 12 (7.7%) patients, lacking consent for MIP in 5 (3.2%) patients, and MEN 2A syndrome in 5 (3.2%) patients. The extent of parathyroidectomy was a solitary parathyroid adenoma removal in 97 (62,6%) patients, subtotal parathyroidectomy in 41 (26.4%) patients, and double-parathyroid adenoma removal in 17 (11,0%) patients. Use of intraoperative iPTH monitoring influenced on the extent of parathyroid tissue resection in 16(10.3%) patients. Normalised total serum calcium values were observed in 154 (99.4%) patients during a 6-month follow-up. CONCLUSIONS: BNE in patients with pHPT is the preferred surgical technique in the following circumstances: a suspicion of multiglandular parathyroid disease (MEN 1 or 2A syndrome, familial hyperparathyroidism, lithium therapy), a negative preoperative imaging, in patients not consenting for MIP, and in cases with concomitant goitre necessitating surgical treatment. Use of intraoperative iPTH monitoring influences on the extent of parathyroid tissue resection in one often patients, hence assuring the highest quality of surgical treatment. PMID- 25016779 TI - [Outcome of patients with acute kidney injury in the course of neoplastic diseases]. AB - Patients with malignancies are a group of increased risk of acute kidney injury (AKI). The aim of this study was to evaluate selected parameters characterizing acute kidney injury in patients with malignancies such as the cause ofAKI, previous kidney function, diuresis, duration of oligoanuria, the number of dialysis sessions, mortality and normalization of renal function in the course of AKI. We analyzed data of 387 patients with AKI (155 women, 232 men) aged 26-96 years treated in hospital wards of nephrological profile in the most requiring dialysis. Among the female the most frequent neoplasm were cervical cancer (26.4%), multiple myeloma (14.8%) and colorectal carcinoma (7.7%). In men the most common cancers localization was: the urinary bladder (25.4%), prostate (23.7%), colon (7.7%), and multiple myeloma (6.9%). In 14 patients 2 tumors were reported while in one 3 different cancers. In total, patients in the study group had 403 cancers, including 162 women and 241 men. Average serum creatinine was 752.1 micromol/l, and diuresis at the start of observation 483 ml/24h. Oligoanuria (less than 500 ml/24h) occurred in 64.9% of patients and lasted from 1 to 117 days, an average of 6.8 days. Because of severe AKI, most of patients (357-92.2%) were dialyzed, an average 4.6 of sessions. Mean hospital stay was 15.4 days. Some patients (20.1%) had impaired renal function, even before the AKI episode which indicate coexistence of chronic kidney disease in the study population. The most common cause of AKI was urine flow disorders seen in 53.2% of patients, especially ureteral obstruction. A numerous AKI episodes (26.1%) were caused by the loss of body fluids. In 21.2% of patients multifactorial causes of AKI were found. The mortality rate in the studied group was 33.9%. PMID- 25016780 TI - [Proinflammatory markers serum concentrations in patients with adenomatous colon polyps]. AB - BACKGROUND: It has been shown that local chronic inflammation may lead to colorectal carcinogenesis via adenomatous polyps. Tumor necrosing factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C-reactive protein (CRP) are biomarkers of inflammation and indicators of the immune response to tumors. Their elevated levels were observed in patients with colon adenomas, however their clinical significance is unclear. METHODS: The study included sixty patients with the colorectal adenomatous polyps found on colonoscopy and confirmed pathologically. The control group consisted of 30 individuals with no positive findings on colonoscopy. The aim of our study was to determine the serum levels of TNF-alpha, IL-6 and CRP in colorectal adenomas patients and to assessed the relationships between them and colorectal adenoma location, dysplasia grading, histological type, and size. RESULTS: One hundred nine adenomas (6-40 mm of size) were found in 60 study patients. The average age of patients with multiple polyps was significantly higher than of those with single pathologies (61.1 vs 56.7 years respectively (p < 0.05)). The prevalence of colon adenomas were observed in distal part of colon (83.3%), compared to the proximal part (16.7%; p < 0.01). The TNF-alpha concentration was similar in both group (24.51 +/- 13.50 pg/ml versus 29.61 +/- 14.94 pg/ml; p > 0.05) and not related to clinical data of patients. In contrast, CRP serum concentrations were higher in patients with adenomas located proximally (8.674 +/- 9.19 microg/ml) compared to control group (4.94 +/- 5.53 microg/ml; p < 0.05). There was also no differences between IL-6 serum level in patients with colon adenomas (19.80 +/- 7.44 pg/ml) and control group (20.46 +/-11.83 pg/ml; p > 0.05). Analyzed cytokines serum levels were not associated with size, number, degree of dysplasia and histological type of colon adenomas. CONCLUSION: Our results indicate that CRP may be associated with development of tumors of proximal part of colon. PMID- 25016781 TI - [Haemorrhage after thyroid surgery]. AB - INTRODUCTION: Haemorrhage after thyroid surgery is rare, but if it occurs it is a life-threatening condition necessitating emergency surgery. The aim of this study was to evaluate prevalence and risk factors of haemorrhage after thyroid surgery. METHODS: A retrospective analysis was undertaken in a group of 8931 consecutive patients with various thyroid diseases treated in 2004-2013 at our institution. Potential risk factors for postoperative haemorrhage after thyroid surgery were analysed using logistic regression model. RESULTS: Haemorrhage after thyroid operation necessitating emergency surgery occurred in 40 (0.45%) of 8931 patients. None of the patients died within the perioperative period. Bleeding occurred within first 24 hours following surgery in 38 (95%) patients, and in the remaining 2 (5%) patients in more than 24 hours after initial surgery. The following risk factors for bleeding after thyroid operation were identified: male sex (OR 3.618; 1.762-7.430; p < 0.001), older age > or = 70 years (OR 3.052; 1.275-7.304; p = 0.012), surgery for hyperthyroidism (OR 2.873; 1.511-5.462; p = 0.001), smoking (OR 2.855; 1.502-5.428; p = 0.001), subtotal thyroidectomy in contrast to total thyroidectomy or lobectomy (OR 2.853; 1.356-6.004; p=0.006), and thyroid operation undertaken by resident in training in general surgery (OR 2.596; 1.393-4.837; p = 0.003). CONCLUSIONS: Haemorrhage after thyroid operation necessitating emergency surgical intervention occurs most frequently within first 24 hour following surgery. Hence, for safety reasons a minimum of 24-hour hospital stay is recommended in all patients with risk factors for postoperative bleeding after thyroid operation. Quality monitoring of thyroid surgery should include also risk factors for postoperative bleeding. PMID- 25016782 TI - [Influence on the results of surgical treatment of osteoarthritis of the hip using anatomical stem ABG]. AB - The aim of this study was to evaluate the clinical and radiological results of treatment and quality of life, and impact of surgical approach in patients after arthroplasty using anatomical stem ABG II in the Department of Orthopaedics and Trauma Regional Hospital. St. Luke in Tarnow of years 2008-2011. The material consisted of 68 patients operated using a Proxima stem (surgical approaches; anterolateral--34 cases, posterior lateral---34 cases similarly). The average age was 62.2 years. Patients stayed in the hospital an average of 8 days. Term follow up was determined after 6 weeks, 3 months and then once a year. Postoperative results were evaluated using the scale: Harris and WOMAC NRS. X-rays were evaluated for setting and migration of the prosthesis components. In assessing patients with HHS to scale achieved 73.5% of very good and good. Compared to the pre-operative assessment resulted in a significant improvement in mobility of the hip after arthroplasty. According to the standardized WOMAC extended the average score of treatment was 77.0 points. During the study showed significant reduction in pain intensity after surgery. Average NRS score before surgery was 6.4 points and 1.4 points after surgery. In the material appropriate settings were 51 and 17 axial axis of the prosthesis. No effect on clinical outcomes set in the HHS and WOMAC scales. There was no effect on the results of surgical treatment. PMID- 25016783 TI - Oncological emergencies: increased intracranial pressure in solid tumours' metastatic brain disease. AB - Increased intracranial pressure due to metastatic brain disease is one of the oncological emergencies. It may cause herniation or insufficient brain blood flow, thus it is a life-threatening condition. This article focuses on diagnostic and treatment options, which should be introduced immediately. The prognosis remains poor. PMID- 25016784 TI - [Iron and inflammation in renal diseases]. AB - Subclinical inflammation is one of the key mechanisms responsible for the development and progression of chronic kidney disease. It may stem from uremia, ongoing inflammation in kidney as well as latent bacterial and viral infections. Inflammation also plays a significant role in the pathogenesis of anemia of chronic disease through its impact on the iron metabolism. The paper presents the current knowledge concerning the involvement of iron in the development of anemia in chronic kidney disease, with particular reference to the role of hepcidin in systemic iron circulation. PMID- 25016785 TI - [Biomarkers of Alzheimer disease]. AB - Cognitive impairment is one of the most abundant age-related psychiatric disorders. The outcome of cognitive impairment in Alzheimer's disease has both individual (the patients and their families) and socio-economic effects. The prevalence of Alzheimer's disease doubles after the age of 65 years, every 4.5 years. An etiologically heterogenic group of disorders related to aging as well as genetic and environmental interactions probably underlie the impairment in Alzheimer's disease. Those factors cause the degeneration of brain tissue which leads to significant cognitive dysfunction. There are two main hypotheses that are linked to the process of neurodegeneration: (i) amyloid cascade and (ii) the role of secretases and dysfunction of mitochondria. From the therapeutic standpoint it is crucial to get an early diagnosis and start with an adequate treatment. The undeniable progress in the field of biomarker research should lead to a better understanding of the early stages of the disorder. So far, the best recognised and described biomarkers of Alzheimer's disease, which can be detected in both cerebrospinal fluid and blood, are: beta-amyloid, tau-protein and phosphorylated tau-protein (phospho-tau). The article discusses the usefulness of the known biomarkers of Alzheimer's disease in early diagnosis. PMID- 25016786 TI - [Light chain amyloidosis--clinical symptoms, update diagnosis, and treatment]. AB - Immunoglobulin (Ig) light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of Ig light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/ autonomic neuropathy. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (SCT) or oral melphalan with dexamethasone (MelDex). The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. PMID- 25016787 TI - [Familial case of oral-facial-digital syndrome type 1 (OFD 1)]. AB - Ciliopathies are phenotypically and genetically heterogeneous disorders that share ciliary dysfunction as a common pathological mechanism. Ciliary dysfunction results in a broad range of malformations including renal, hepatic and pancreatic cysts, visceral abnormalities, retinal degeneration, anosmia, cerebellar or other brain anomalies, polydactyly, bronchiectasis and infertility. The paper presents a familial case of oral-facial-digital syndrome type 1 in 14 year old girl suspected to polycystic kidney disease. CONCLUSIONS: Molecular testing in daughters of known OFD1 mutation carriers and mothers of affected daughters seems to be reasonable. Not each case of policystic kidney disease which looks like autosomal dominant policystic kiedney disease is actually the above disease. The insight into the pathogenesis of ciliopathies is mandatory for understanding these combined congenital anomaly syndromes of seemingly unrelated symptoms of hepatorenal and pancreatic fibrocystic disease. Close interdisciplinary approach is mandatory in terms of efficient and reliable diagnostic and therapeutic interventions in patients presenting with ciliopathies. PMID- 25016788 TI - [Advances in the surgical treatment of dry eye]. PMID- 25016789 TI - [Clinical investigation of extrusion rate and other complications associated with Punctal Plug F]. AB - PURPOSE: To investigate the effectiveness, extrusion rate and other complications of Punctal Plug F (PPF) compared with Punctal Plug (PP), Super-Flex plug (SFP) and SuperEagle plug (SEP). SUBJECTS AND METHODS: This study involved 31 eyes of 24 dry-eye patients treated with PPF at the dry-eye clinic of Kyoto Prefectural University of Medicine, Kyoto, Japan. Intracanalicular migration rate, extrusion rate, granulation rate, accumulation of soft whitish material and enlargement of punctum size after punctal-plug extrusion were investigated and compared with previously published results of PP, SFP and SEP. RESULTS: No migration was observed in the PPF cases at the time of insertion. The extrusion rate was 43.5% during follow-up periods. The average time to extrusion was 158.2 +/- 175.7 (mean +/- SD) days, and the time until 50% of plugs were extruded was 234 days, longer than that in the SFP cases (p = 0.0012). Granulation was seen in 4.3% of the eyes, but the frequency was lower than in the PP(19%, p = 0.015) and SEP cases (34.5%, p < 0.0001). No soft whitish material was seen around the PPF-cases' plugs yet significant, post-extrusion punctum size (mm) enlargement (0.78 +/- 0.14) was observed compared to pre-insertion(0.61 +/- 0.18, p < 0.001). CONCLUSION: Our findings show that insertion of the PPF was easy and without intracanalicular migration, harder to extrude, similar to the PP, yet less susceptible to granulation formation compared with the PP. PMID- 25016790 TI - [Treatment progress of large-size puncta and clinical investigation of the extrusion rate and other complications associated with large-size punctal plugs]. AB - PURPOSE: One complication of punctal plug occlusion (PPO) is enlargement of the punctum. The purpose of the present study was to investigate large-size (over 1.0 mm) puncta after punctal plug extrusion. SUBJECTS AND METHODS: This study involved the treatment progress of 74 large-size (over 1.0 mm) puncta in 55 eyes of 46 patients who underwent PPO. The extrusion rate and other complications of the total 133 punctal plugs used for those puncta were investigated. RESULTS: Of the 74 puncta, 33 (44%) achieved occlusion by PPO alone, 20 (27%) achieved perfect occlusion of granulation, and 21 (29%) required surgical punctal occlusion. Although larger or longer punctal plug sizes have been used for PPO, the average elapsed time until extrusion was 143.5 +/- 217.0 (mean +/- SD) days, and the time until 50% of the plugs were extruded was 50 days. No significant extrusion rate was found among the punctal plugs, and there was 0% migration rate. Granulation was observed in 20.3% of the plugs, yet no soft whitish material was seen around the plugs. CONCLUSION: The findings of this study show that large-size puncta can successfully be occluded for a fixed period of time following PPO. PMID- 25016791 TI - [Causes and prevalence of visual impairment in Japan]. AB - PURPOSE: To investigate the causes of visual impairment in Japan. METHODS: The documents of 4,852 individuals with authorization of visual impairment registered between April 2007 and March 2010 in 7 randomly selected regions were reviewed. RESULTS: The major causes of visual impairment were glaucoma (21.0%), diabetic retinopathy (15.6%), retinitis pigmentosa (12.0%), macular degeneration (9.5%) and chorioretinal atrophy (8.4%). Individuals over 70 years of age were predominant for glaucoma, those aged 50-69 years for diabetic retinopathy and those under 40 years of age for retinitis pigmentosa. Sixty-one percent of persons affected by glaucoma were severely handicapped. Macular degeneration increased with age especially in individuals over 80 years of age. CONCLUSION: There was no difference in the order of major causes as compared with a previous report in 2001-2004. It is important to establish a central database system so that the data can be surveyed to provide more relevant information to understand current issues for handicapped persons and develop new prophylactic and therapeutic modalities. PMID- 25016792 TI - [One year outcomes of pars plana vitrectomy in proliferative diabetic retinopathy]. AB - PURPOSE: To evaluate the 1-year results of pars plana vitrectomy for proliferative diabetic retinopathy. PATIENTS AND METHODS: Two hundred thirty six patients with proliferative diabetic retinopathy received primary vitreous surgery at Shiga University of Medical Science Hospital and had at least 1 year follow-up period. The indications for pars plana vitrectomy included vitreous hemorrhage in 140 eyes, extramacular tractional retinal detachment in 60 eyes, macular tractional retinal detachment in 24 eyes and combined tractional retinal detachment in 12 eyes. The visual acuity and changes in visual acuity at 1-year postoperatively were evaluated. Preoperative bevacizumab injection and postoperative visual outcomes were compared between patients treated with 20 gauge (20 G) surgery and with micro incision vitrectomy surgery (MIVS). RESULTS: The visual acuity improved by 3 lines or more in 166 eyes (70%) and remained unchanged in 56 eyes (24%); it decreased by 3 lines or more in 14 eyes (6%). Tractional retinal detachment in MIVS received more bevacizumab injections. MIVS systems achieved better visual results in the combined tractional retinal detachment group than 20 G system. CONCLUSION: Successful visual improvement at 1 year postoperatively was observed in eyes with proliferative diabetic retinopathy after pars plana vitrectomy. Results of this study may suggest the superior performance of MIVS for pars plana vitrectomy in proliferative diabetic retinopathy. PMID- 25016793 TI - [Transient increase of intraocular pressure with primary open angle glaucoma patients associated with warm and cold seasons after long waiting time in an ophthalmology clinic]. AB - PURPOSE: To retrospectively evaluate the influence of long waiting time on intraocular pressure (IOP) with primary open angle glaucoma (POAG) patients in the waiting room of an ophthalmology clinic. PATIENTS AND METHOD: We reviewed 74 consecutive patients with POAG who visited at Kaimeido Ophthalmic and Dental Clinic within the past 8 years without change of glaucoma medications, 34 men and 40 woman, average age +/- standard deviation) 67.9 +/- 13.4 years. Right eye data of all patients were enrolled and IOP was split into 4 groups, short waiting time (< 30 min ; SH30) and long waiting time (> or = 60 min; LH60) in the hot (> or = 15 degrees C) season. Short waiting time (SC30) and long waiting time (LC60) in the cold (< or = 5 degrees C) season; according to the average outdoor air temperature in Sapporo Japan. All groups were compared each other (paired t test). RESULTS: There was a significant difference between SH30 (14.6 2.4 mmHg) and LH60 (14.9 +/- 2.4 mmHg; p = 0.038), between SC30 (14.6 +/- 2.4 mmHg) and LC60 (15.5 +/- 2.6 mmHg; p = 3.45 x 10(-7)) and between LH60 and LC60 (p = 0.00079). On the other hand, there was no significant difference between SH30 and SC30 (p = 0.89). CONCLUSION: This retrospective study suggests that patients with POAG show a transient IOP elevation after longer waiting time, especially during the cold season. PMID- 25016794 TI - [Development of therapeutic strategies targeting AML stem cells]. PMID- 25016795 TI - [The development history and future perspective of molecularly targeted therapy]. AB - The origin of molecularly targeted drugs dates back to 'magic bullet' theory proposed by Paul Ehrlich. The success of Abl tyrosine kinase inhibitor, imatinib for the treatment of chronic myeloid leukemia realized that small molecules inhibiting ATP binding can become specific inhibitors for the relevant kinases. Subsequently, a number of kinase inhibitors which targets various signal transduction molecules, are in the clinical field or under development. The clinical success of antibody therapeutics has been achieved by the genetic engineering which makes human-mouse chimeric, humanized or human antibody. To augment the therapeutic effects of antibody, radioisotope-conjugate antibody and antibody-drug conjugate have come to the clinical field. In the near future, we have to develop the combination therapy of molecularly targeted drugs and also inhibitors for epigenetic and transcriptional regulators. PMID- 25016796 TI - [Development of molecular targeted therapy for hematological disorder in the era of genomic drug discovery]. AB - The next generation sequencing technologies has provided unprecedented opportunities for high-through-put genomic research. These technologies have been applied to hematological disorders in a variety of contexts and have provided genetic landscape of each disorder in details including the identification of disease specific driver mutations and subsequent chances of drug discovery targeting the pathogenetic lesions. On the other hand, the development of molecular targeted therapies has been successful in only limited fields to date. In this prospect we will review the current situation of molecular targeted therapy against several hematological diseases and discuss about the future challenges to promote drug discovery based on the enormous genomic information. PMID- 25016797 TI - [Leukemia stem cell and clonal evolution]. AB - The introduction of next generation sequencing technology has greatly broadened our view on the genetic landscape of hematological malignancies. The first comprehensive experiment of acute myeloid leukemia(AML) using genome-wide analysis has also shed light on the clonal evolution of AML, which seems to have been underestimated. It is now possible to precisely define clonal size and selection at different stages. This approach demonstrated that AML at diagnosis is either monoclonal or oligoclonal, harboring a selected number of genetically defined subclones. Furthermore, targeted deep sequencing of diagnosis and relapse pairs revealed that founding clones or subclones present at diagnosis obtain some additional mutations that contribute to clonal expansion and/or chemoresistance. Some subclones may be eradicated by treatment, whereas others are resistant to chemotherapeutic agents and ultimately grow out. The molecular heterogeneity in AML will have a great impact on the development of targeted therapies. PMID- 25016798 TI - [New approaches to target leukemia stem cells]. AB - Human acute myeloid leukemia is organized as a hierarchy initiated and maintained by "leukemia stem cells(LSC)" which possesses self-renewal capacity. LSCs are therapeutic targets and must be eliminated to cure the patients. Recent advances in LSC research provided insights into the cell surface antigens preferentially expressed on AML-LSCs compared with normal hematopoietic stem cells and the signaling pathways defining the LSC characteristics. These molecules are potential targets to eradicate LSCs. Especially, monoclonal antibodies targeting surface antigens expressed on LSCs, including CD123, CD44, TIM-3 and CD47 have been shown its efficacy against AML-LSCs in xenotransplant models. PMID- 25016799 TI - [The significance of the epigenetics modifying gene mutations in acute myeloid leukemia]. AB - In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation, and in histone modifications have been reported in myeloid malignancies. Large clinical correlative studies are beginning to clear the clinical importance, prevalence, and potential prognostic significance of these epigenetics modifying gene mutations. Additionally, recent studies shedding light on the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. In this review, we summarize the current understanding of the epigenetics modifying gene mutation, discuss how contribute to its pathogenesis and clinical feature in AML. PMID- 25016800 TI - [FLT3 inhibitors for acute myeloid leukemia]. AB - FLT3 is a class III receptor tyrosine kinase. FLT3 mutation is the most frequent genetic alteration in acute myeloid leukemia (AML), and involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Since FLT3 mutation is strongly associated with leukocytosis and a poor prognosis, it is expected that development of FLT3 kinase inhibitors will make more efficacious therapeutic strategy for leukemia therapy. Although many FLT3 inhibitors have been subjected to clinical trials, their clinical efficacies for AML seem unimpressive, and several problems regarding adverse effects and resistant mechanism are apparent. Here, I would like to summarize recent advances of FLT3 inhibitors in development. PMID- 25016801 TI - [Abnormal p53-HDM2 interaction in hematological malignancy]. AB - The tumor suppressor protein p53 is a multifunctional transcription factor involved in the control of cell survival and death. p53 is inactivated by mutation of the p53 gene in approximately 50% of human cancers. While the rest (including hematological malignancies) encode wild-type p53, p53 is frequently inhibited by its negative regulator human double minute 2 (HDM2). HDM2 is a p53 specific E3 ubiquitin ligase. Therefore, there has been considerable interest in identifying compounds for disrupting the p53-HDM2 interaction. Small-molecule antagonist of HDM2, which binds HDM2 in the p53-binding pocket, negatively controls the activity of HDM2 and prevents p53 degradation. This stabilization of p53 results in its activation, leading to cell cycle arrest, growth inhibition, and apoptosis in wild type p53-haboring hematological malignant cells. Biology of p53-HDM2 interaction and anti-tumor effects of the HDM2 inhibitor in hematological malignant cells are described in this review. PMID- 25016802 TI - [Discovered roles of MLL in pathogenesis of multiple myeloma]. AB - Multiple myeloma is one of incurable hematological malignancies and targeted therapies for novel oncogenes are to be exploited. Analyses of multiple myeloma patients revealed that HOXA9 was overexpressed in patients lacking known IgH translocation and it was evaluated as a candidate oncogene in multiple myeloma. This overexpression of HOXA9 was supposed to be due to dysfunction of histone methyltransferases (HMT) and mutations in MLL encoding HMT were found. Panobinostat, an HDAC inhibitor is currently undergoing preclinical and clinical evaluation as a novel drug for multiple myeloma. We found that panobinostat suppresses expression of MLL protein through modulation of its stability as well as Hsp90 inhibitor. More precise roles of MLL in pathogenesis of multiple myeloma are to be elucidated. PMID- 25016803 TI - [Detection for therapeutic targets specifically expressed in myeloma side population cells]. AB - ATP binding membrane transporter such as multi drug resistant protein (MDR1) and breast cancer resistance protein (BCRP) are highly activated in side population (SP) of various normal organs. It has been demonstrated that various primary as well as cancer cell lines also possess SP. Since SP cells have been also known as the cancer initiating cell rich population in various cancers, the population might play a crucial role in the pathogenesis of multiple myeloma. Recent our works demonstrated that G2/M (e.g. CCNB1, CDC2), centrosome (e.g.AURKB, CENP), polycomb (e.g. EPC1, EZH2) and proteasome (e.g. UBE3C, PSMA5) related genes were upregulated in the SP of myeloma cell lines and CD138-positive primary samples. Although myeloma has been known as incurable disease, discovery of new agents such as immunomodulatory drugs (lenalidomide) and proteasome inhibitor (bortezomib) provide improvement of prognosis of the tumor entity. These drugs might be effective to downregulate aforementioned aberrantly upregulated gene products in myeloma SP. Here we show some evidences of use of these drugs for targeting myeloma-SP cells. PMID- 25016804 TI - [Adaptive response of cancer cells to metabolic stress]. AB - In general, cancer cells proliferate depending on glycolysis, whereas supply of glucose and other nutrients is not always sufficient. Therefore, cancer cells can be often exposed to intracellular energy and/or nutrient imbalance and various forms of stress that is associated with energetic insufficiency. To cope with such metabolic stresses, cells have various mechanisms to sense nutrient status and to adapt stressful cell conditions. These include the nutrient-signaling pathways that are regulated by AMP-activated protein kinase (AMPK) and mechanistic/mammalian target of rapamycin (mTOR) and also the cellular stress responses, such as mitochondria and endoplasmic reticulum stress responses as well as autophagy. PMID- 25016805 TI - [Molecular target drugs for AML--current state and prospects for the future]. AB - Acute myeloblastic leukemia (AML) is a disease which may be completely cured by intensive chemotherapy or stem cell transplantation. However, the prognoses are poor in elderly, refractory or recurrence cases. Molecular targeted drugs have been expected to improve the prognoses of patients with various cancers, but there are few kinds of molecular target drugs for AML. On the other hand, excellent drug exists such as tretinoin for acute promyelocytic leukemia. Molecular mechanisms have been elucidated in AML cells, and the molecules which can be the good target of the treatment have been identified. Novel molecular target drugs are also expected. PMID- 25016806 TI - [Chronic myeloid leukemia]. AB - More than 10 years have passed since imatinib as a first developed BCR-ABL tyrosine kinase inhibitor (TKI) introduced in treatment of patients with chronic myeloid leukemia (CML). In globally, there are tremendous numbers of patients on imatinib therapy. Based upon randomized trials comparing second generation TKIs such as dasatinib and nilotinib versus imatinib, both TKIs produce faster and deeper response than imatinib and they can be selected as first-line therapy for newly diagnosed chronic phase of CML (CP-CML) as imatinib. Bosutinib is a potent for imatinib resistant/intolerant CP-CML and can be used as second or third-line therapy. Ponatinib is the only clinically available TKI that has activity against the T315 mutation that is resistant to all other TKIs. Currently, a choice among these potent TKIs should take into consideration the drug side effect profiles and the patient's comorbidities. PMID- 25016807 TI - [Small molecular compounds for BCR/ABL-negative myeloproliferative neoplasms]. AB - Since the identification of JAK2 V617F mutation in patients with BCR/ABL-negative myeloproliferative neoplasms in 2005, the molecular basis of these hematological disorders has been extensively studied. Consequently, various small molecular compounds including JAK2 inhibitors have been developed. The JAK2 inhibitor ruxolitinib improves survival as well as splenomegaly and the clinical symptomatic burden in intermediate-2 or high risk myelofibrosis patients. This agent also reduces the JAK2 V617F allele burden in some patients, suggesting that it also has a certain molecular effect. Based on the results of clinical studies, ruxolitinib has been approved for treatment of myelofibrosis in the United States and Europe. Clinical and preclinical studies of several other JAK2 inhibitors are currently ongoing. Other small molecular compounds including histone deacetylase inhibitors, mTOR inhibitors and telomerase inhibitors are currently being tested in clinical trials. We also discuss the possibility of combination therapies using JAK2 inhibitors and other agents. PMID- 25016808 TI - [Myelodysplastic syndromes (MDS)]. AB - Myelodysplastic syndromes (MDS) are a group of myeloid neoplasm characterized bone marrow failure and increased risk of transformation of acute myeloid leukemia (AML). Recently, significant advances have been achieved in understanding the molecular pathogenesis and treatment of MDS. Based on these advances, lenalidomide and azacitidine have approved for the patients with chromosome 5q deletion and high-risk MDS, respectively. However, treatment options for MDS still remain limited, therefore, novel therapeutic strategies are needed in clinical setting. In this article, recent progress of development of novel molecular-targeting agents for MDS that may have the potential to improve clinical outcome of this refractory hematologic malignancy is reviewed. PMID- 25016809 TI - [Novel targeted therapy in multiple myeloma]. AB - Recently, new agents have explored in the treatment of multiple myeloma (MM), according to the identification of the novel pathogenetic mechanisms. Proteasome inhibitor (bortezomib) and immunomodulatory drugs (thalidomide and lenalidomide) now play important roles in the treatment of MM, and they have resulted in an improvement of the outcome of the patients. However, MM remains incurable and the prognosis is very poor in the patients who become refractory to bortezomib and IMiDs. New agents with novel mechanism of action in MM (monoclonal antibodies, deacetylase inhibitors, and so on) will be discussed in this review. PMID- 25016810 TI - [Molecular targeted therapy in lymphoid leukemias]. AB - Recent advances in the treatment of lymphoid leukemias have incorporated molecular targeted drugs (CD20-targeting rituximab and BCR-ABL tyrosine kinase inhibitors) into the traditional chemotherapeutic agents. This article reviews novel molecular targeted therapies for patients with lymphoid leukemias including acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairly cell leukemia and HTLV-I-related adult T-cell leukemia. Investigational agents that will be discussed in this review include inotuzumab, blinatumomab, alemtuzumab, ofatumumab, ibrutinib, idelalisib, bafetinib, lenalidomide, ABT-199 and mogamulizumab. Novel approaches warrant continued research to improve outcomes for patients with lymphoid leukemias. PMID- 25016811 TI - [Hodgkin lymphoma]. AB - ABVD regimen has been established as a standard therapy for Hodgkin lymphoma, and over 70% of patients with Hodgkin lymphoma would be curable. But some refractory diseases still exist. Recent developments of molecular target agents have been expecting to improve the clinical outcomes of Hodgkin lymphoma. Anti CD30 antibody-drug conjugate, brentuximab vedotin, is a promising drug for relapsed and refractory Hodgkin lymphoma, and is also explored to be incorporated into first line therapy. Small molecules such as HDACIs and mTOR inhibitors have been proved as active agents for relapsed diseases. Standard care of Hodgkin lymphoma could be changed in next decade by these molecular targeting agents. PMID- 25016812 TI - [Molecular target therapy for non-Hodgkin lymphoma]. AB - Non-Hodgkin lymphomas(NHL) encompass various types of lymphoid neoplasms with different biological behavior. Comprehensive genomic analysis identifies novel mutation and signaling pathways in various tumors, which leads to rational approaches in cancer therapy. Molecular target therapy is a new approach focusing on specific protein or signaling pathways. Molecules of signaling pathways of B cell receptor, PI3K/Akt/mTOR and NF-kappaB are rational target, and many new drugs targeting the pathways are developing in various subtypes of lymphoma. Monoclonal and novel conjugated antibodies for cell surface proteins, epigenetic modulators and immunomodulatory agents also show promising clinical activities. This review will focus on the new molecular target drugs and their activity in NHL. PMID- 25016813 TI - [Molecular-targeted therapies against adult T-cell leukemia]. AB - Adult T-cell leukemia(ATL) is caused by infection with a human retrovirus, human T-cell leukemia virus type 1(HTLV-1). Since replication of HTLV-1 is generally suppressed in vivo, antiviral drugs targeting HTLV-1 replication steps are not effective in individuals chronically infected with HTLV-1. Once aggressive form ATL is developed in HTLV-1 carriers, their prognosis is poor even if they receive the intensive combined chemotherapy. Based on the characteristics of ATL cells, new drugs targeting ATL-specific cell surface markers and several signaling pathways, such as NF-kappaB have been developed. In addition, clinical observations show that ATL cells are highly immunogenic. Thus, establishment of the novel immune therapy is desired. In this review, we summarize recent progress in clinical and basic researches on new molecular-targeted therapies against this aggressive disease. PMID- 25016814 TI - [Kinase inhibitors against hematological malignancies]. AB - Dysregulation of protein phosphorylation, especially on tyrosine residues, plays a crucial role in development and progression of hematological malignancies. Since remarkable success in imatinib therapy of CML and Ph+ALL, extensive efforts have made to explore candidate molecular targets and next breakthrough drugs. Now that next generation ABL kinase inhibitors are available for CML, the therapeutic algorithm has been revolutionized. As for AML and lymphoid malignancies, many kinase inhibitors targeting FLT3, BTK and aurora-A are on early and late clinical trials, and a number of promising drugs including ibrutinib are picked up for further evaluation. PMID- 25016815 TI - [Proteasome inhibitor]. AB - The ubiquitin-proteasome system plays an essential role in degradation of eukaryotic intracellular protein, including cell cycle regulation, cell growth and proliferation, and survival. Cancer cells generally have higher level of proteasome activity compared with normal cells, suggesting proteasome inhibition could be therapeutic target in oncology. Bortezomib, the first proteasome inhibitor introduced into the clinic, is approved for the treatment of patients with multiple myeloma (MM). Although it was approved as single agent in the relapsed setting, bortezomib is now predominantly used in combination with conventional and novel targeted agents because bortezomib has demonstrated additive and synergistic activity in preclinical studies. Recently, several second-generation proteasome inhibitors, such as carfilzomib and MLN9708, have been developed and entered into clinical trials. These agents were investigated in frontline MM in combination with lenalidomide and low-dose dexamethasone. These studies demonstrated positive efficacy and safety, and it is expected that they will be approved in near future. PMID- 25016816 TI - [Immunomodulatory drugs (IMiDs)]. AB - Immunomodulatory drugs (IMiDs) are a new class of anti-inflammatory and antineoplastic agents that have structural and functional similarities with their prototype compound, thalidomide. Although thalidomide and its derivatives, lenalidomide and pomalidomide, are widely used as an essential component in the treatment of selected hematologic neoplasms including multiple myeloma, the precise mechanisms by which these agents exert anti-tumor effects have yet to be clarified. Recently, a component of E3 ubiquitin ligase complex, cereblon (CRBN), has been identified as a direct molecular target for anti-neoplastic activities of IMiDs. CRBN has also been shown to be involved in IMiDs-mediated T-cell co stimulation and cytokine production. Further studies are necessary to elucidate the CRBN-related molecular pathways that are essential for antitumor and immunomodulatory activities of IMiDs. PMID- 25016817 TI - [DNA methyltransferase inhibitors * histone deacetylase inhibitors]. AB - Epigenetics is a cell intrinsic mechanism to maintain genomic integrity by modifying chromatin architecture independently of changes in heritable DNA sequences namely genetic code. Chromatin is composed of nucleosome cores, in which DNA(147bp) is wrapped around a core histone octamer(two each of histones H2A, H2B, H3 and H4), arranged in a "beads-on-a-string array" with linker histones and non-histone nuclear proteins. The chromatin structure could be altered by chemical modifications of DNA and histones, including methylation and acetylation, without affecting genetic codes. In mammals, DNA methylation is mediated via DNA methyltransferases (Dnmt) at CpG dinucleotides. Histones are modified by numerous enzymes, such as histone acetyltransferases (HATs), deacetylases (HDACs), methyltransferases and demethylases, in spatio-temporarily distinct manners. These modifications could alter chromatin structures to regulate a wide variety of biological processes such as gene expression, cell cycle progression and DNA repair. Given the biological importance of epigenetic modifications, it is easy to speculate that the abnormalities of chromatin modifying enzymes and reader proteins underlie several human diseases such as cancer, inflammation and metabolic disorders. Because epigenetic states are reversible and could be modified in response to extrinsic signals, including small molecular compounds, an increased understanding of their molecular framework would allow us to treat pathological conditions caused by epigenetic alterations. Indeed, Dnmt inhibitors and HDAC inhibitors have already applied to the treatment of hematological malignancies with considerable success. PMID- 25016818 TI - [Therapeutic monoclonal antibodies for hematological diseases]. AB - Over the past decade, monoclonal antibodies (mAbs) have been demonstrated to be powerful therapeutic options for hematological diseases. MAbs exert selective therapeutic effects through binding specific molecules, which can minimize the frequency and magnitude of their adverse effects. The major mechanisms of the cytotoxic activity by mAbs against hematological malignancies are complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). To enhance the ADCC activity, the defucosylated version of mAbs have been developed to enhance their binding ability to Fcgamma receptor IIIa. Antibody-drug conjugates and radiolabeled mAbs are also designed to selectively kill tumor cells. Owing to the recent innovation of mAb generation and modification techniques, we can expect more benefical mAbs with diverse functions as important therapeutic strategies. PMID- 25016819 TI - [Mechanisms of resistance to molecular targeted drugs]. AB - Cancer treatments have gradually improved during past decades. However, we are still facing problems to surmount in prevention and therapy of cancers. Recent advances in molecular-based understanding of cell proliferation and survival have provided the rationale for the molecular targeted therapy to control cancer. Contrary to our expectation, molecular targeted drugs, such as EGFR-, ALK-, ROS1 , or BRAF-targeted drugs, could not exhibit sufficient curative effects. This review aims to provide an overview of the recent progress in the development of kinase-targeted drugs and the analysis of the molecular mechanisms of pre existent (intrinsic) and acquired drug resistance. PMID- 25016820 TI - [Pharmacoeconomics of molecular targeting drugs]. PMID- 25016821 TI - [Current status and future perspectives in the research of Marfan syndrome]. AB - Marfan syndrome is an autosomal dominant disorder, characterized by tall stature, long arms and legs, ectopia lentis, and aortic aneurysms and dissections. Recent research has revealed that these phenotypes are caused by mutations in fibrillin 1, the major structural component of elastic microfibrils, and the continuing dysregulation of transforming growth factor beta (TGFbeta) signaling is principally considered to be contributing to the pathophysiological background of the disease. Blockade of TGFbeta signaling by angiotensin II receptor antagonism is a novel promising therapeutic option, and thus such large clinical randomized controlled trials are underway. Here, we review the past development, current status and future perspectives in the research field for Marfan syndrome. PMID- 25016822 TI - [Obtaining the transgenic lines of finger millet Eleusine coracana (L.) Gaertn. With dinitroaniline resistance]. AB - The current data is dedicated to the study of bioballistic and Agrobacterium mediated transformation of finger millet with the constructs carrying the mutant alpha-tubulin gene (TUAm 1), isolated from R-biotype goosegrass (Eleusine indica L.), for the decision of problem of dinitroaniline-resistance. It was found that 10 microM of trifluralin is optimal for the selection of transgene plants of finger millet. PCR analysis of transformed lines confirmed the transgene nature of plants. The analysis of seed of T1 oftransgene lines confirmed heterozygous character of inheritance of the resistance. PMID- 25016823 TI - Superoxide dismutase activity in transgenic canola. AB - Superoxide dismutase (SOD) activity was investigated in leaves of transgenic canola plants which expressed heterologous genes of different origin, namely 1) herbicide resistance genes (bar and simultaneously bar and epsps); 2) DesC desaturase gene (desC) of cyanobacterium Synechococcus vulcanus; 3) human interferon alpha2b gene (huLFN-alpha2b); 4) esxA::fbpB(deltaTMD) fused gene, encoding ESAT-6 and Ag85b Mycobacterium tuberculosis proteins, inducing immune response against tuberculosis; 5) cyp11A1 gene of cytochrome P450(scc) from bovine adrenal cortex mitochondria. Introduction of herbicide resistance genes as well as desaturase gene of cyanobacterium and mycobacterium's genes did not change leaf SOD activity. At the same time it was shown that cyp11A1 and huIFN alpha2b canola have increased leaf SOD activity up 58 and 33%, respectively, compared with control ones in non-stress conditions. It may be a prerequisite for improved resistance of these plants to the stressors of different origin. PMID- 25016824 TI - [Bioinformatic analysis of maize granule-bound starch synthase gene]. AB - Local alignment of Wx gene and its homolog sequences has been conducted. Phylogenetic dendrogram displaying evolutionary relationship between Poaceae members has been built basing on results of the alignment. Ancient Wx gene transfer from Zea mays to Dimeria lawsonii has been assumed. Primers for the exons 8-10 polymorphic region have been designed. In silico PCR has been conducted. PMID- 25016825 TI - The relationship between SNPs in the genes of TLR signal transduction pathway downstream elements and rheumatoid arthritis susceptibility. AB - Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system or adaptive immune responses. Genetic variations within human TLRs have been reported to be associated with rheumatoid arthritis (RA). This study was conducted to investigate correlation between SNP of downstream mononucleotide in signal transduction of Toll-like receptors and predisposing genes of RA. There was obviously correlative between single nucleotide polymorphism and predisposing genes of RA. G-type of IL-1RAP rs766442 may be protecting genes of RA, while T-type alleles of IL-6R rs11265618 and IL 1RAP rs766442 may be susceptible genes of RA. In conclusion, the studies on the nucleis acid polymorphism in TLRs signal pathway contribute to disclose genes' influence on the attack mechanism of RA, early diagnosis and treatment of RA. PMID- 25016826 TI - Supernumerary (B) chromosomes in populations of Picea abies (L.) H. Karst. from Western Rhodopes (Bulgaria). AB - Investigations on B chromosomes found for the first time for Picea abies (L.) H. Karst. have been conducted. Seeds of Picea abies from two populations of Western Rhodopes (Bulgaria) located at the southern border of species range, and protected according to Bern Convention and EC Habitat Directive were collected for this study. Mixoploidy was detected in some germinating seeds of Picea abies. It was found that metaphase cells of germinating seeds contain 0-4 B chromosomes of both metacentric and submetacentric types. The variability of B chromosomes number and their occurrence was observed. Along with B chromosomes, some chromosome aberrations such as fragments and ring chromosomes were revealed in metaphase cells of Picea abies from studied populations. The possible adaptive role of B chromosomes presence for Picea spp. is discussed. PMID- 25016827 TI - In vitro regeneration ability of diploid and autotetraploid plants of Cichorium intybus L. AB - Polyploidy has played a significant role in the evolutionary history of plants and is a valuable tool for obtaining useful characteristics. Because of the novelty of polyploids, comparison of their in vitro culture response with diploids would be notable. In this study, leaf explants from diploid, autotetraploid and mixoploid plants of Cichorium intybus L. were cultured in vitro on the similar media and under same conditions. The ploidy level of the obtained calluses and regenerants were determined by flow cytometry analysis. The callogenic response of leaf explants cultured on the callus induction medium did not depend on the ploidy level of their parental plants. According to the flow cytometry analysis, the increased ploidy levels (4x) and (8x) were observed in the callus cultures with diploid and tetraploid origin, respectively. A considerable difference was observed between the ploidy level of mixoploid plants and their calluses, indicating the dominance of diploid cells in the callus tissue. The results showed that polyploidy led to the loss of organogenic potential as the tetraploid origin calluses failed to regenerate, while the diploid origin calluses successfully regenerated to whole plants. PMID- 25016828 TI - [The influence of low-intensity laser irradiation on the loach embryo cells]. AB - The ultrastructural organization of loach embryo cells (Misgurnus fossilis L) at the stage of the first and the tenth embryo divisions was investigated in the control and under the influence of low intensity helium-neon laser irradiation of 5 min exposure. The effect of laser irradiation led to ultrastructural changes in cell organelles, increasing the number and size of mitochondria, and as a result their shape changes. Under the influence of laser irradiation, the activation of cellular digestion processes took place, the number of vacuoles and lysosomes increased. The results explain the possible mechanism laser irradiation impact at the cellular level. PMID- 25016829 TI - [Meiotic segregation of chromosomes 13 and 14 of heterozygous Robertsonian translocation der(13;14) (q10; q10) carriers]. AB - Meiotic segregation of chromosomes 13 and 14 was assessed by fluorescence in situ hybridization on sperm of five heterozygous carriers of the most frequent Robertsonian translocation der(13;14). Alternate segregation mode was predominant (mean 78.2 +/- 5.7%). The prevalence of balanced sperm varied from 69.4 to 86.5%. Adjacent segregation mode was detected in 18.64 +/- 4.90% of sperm; 3:0 mode was detected in 2.48 +/- 1.20% of sperm. These results are informative for reproductive counseling of Robertsonian translocation der(13;14) carriers, providing information for assessment of probability of receiving normal/balanced embryos in assisted reproduction cycles. PMID- 25016830 TI - Chromosomal damage as prognosis marker in cervical carcinogenesis. AB - Cancer of the uterine cervix is the third most common cancer in women worldwide and the most common cancer among Mexican and Latin American women. Risk factors that have been associated with the development of cervical intraepithelial neoplasia suggest that Human Papillomavirus (HPV) types 16, 18, 31, and 33 entail a high risk of developing a malignancy of this type. The accumulation of genetic alterations allows the growth of neoplastic cells; chromosomal instability is an event that occurs in the precancerous stages. The candidate cancer risk biomarkers include cytogenetic endpoints, such as chromosomal aberrations, sister chromatid exchange, micronuclei, and the outcomes of comet assay and DNA breakage detection-fluorescence in situ hybridization. The patterns identified in these cytogenetic studies indicate that chromosomal instability is a transient and chromosomally unstable intermediate in the development of cervical lesions. In this context, the mechanisms that may underlie the progressive increase in genetic instability in these patients seem to be related directly to HPV infection. The studies discussed in this paper show that chromosomal instability may serve as a biomarker by predicting the progression of cervical intraepithelial neoplasia. Nevertheless, these results should be validated in larger, prospective studies. PMID- 25016831 TI - [Why do people behave altruistically even when nobody would observe their behavior?]. AB - Why do people behave altruistically toward others, even in situations where nobody would observe their behavior? We formulated the following hypothesis regarding this question: "Reputations are decided by behaviors in situations that nobody can observe, rather than by behaviors in situations that can be observed by others." The validity of this hypothesis was examined through a Prisoner's Dilemma experiment. In the first stage, participants played the Prisoner's Dilemma game in a situation where nobody could observe them. In the second stage, participants selected another partner in the game, based on information about their behavior in the first stage. The results indicated that participants tended to choose people that behaved altruistically in situations where nobody could observe them. Furthermore, this tendency was stronger with cooperative participants. These results support the hypothesis of this study. PMID- 25016832 TI - [Negative evaluations and discrimination against smokers]. AB - The present study examined the negative evaluations and discrimination against smokers among the Japanese. In Study 1, 52 students rated one of four target persons differentially depicted in terms of gender and smoking habit using scales to measure coolness, sociability, intellectuality, and earnestness. The results showed that participants rated smokers more negatively than nonsmokers except for sociability. Those who perceived smoking as controllable rated smokers' earnestness even more negatively, suggesting that the negative evaluations are partially moderated by the perceived controllability of smoking. To examine a hypothesis that negative evaluations of smokers would mediate discrimination, in Study 2 we measured how participants (96 students) responded to target persons asking for a loan or a job, as well as their ratings of the targets on the Big Five personality dimensions. The results support the hypothesis of mediation. PMID- 25016833 TI - [Do practices of learning activities improve the cognitive functioning of healthy elderly adults? From the viewpoint of a transfer effect]. AB - The present study examined influences of reading aloud and performing simple calculation on the cognitive functioning of healthy elderly adults, based on the findings that these tasks activated the prefrontal lobe. The elderly adults' memory and inhibitory functions were assesed by Short-Term memory, CST, Stroop, and SRC tasks, before and after intervention for 18 months. The study found that the learning group had significant improvement from the pre- to the post-test for the short-term memory, STM, CST, and Stroop tasks. On the other hand, there was significant decline over the 18 months in the control group which was given only the assessment tasks. These results are discussed in terms of the effectiveness of cognitive training. PMID- 25016834 TI - [Trust in organizations concerned with risks of the Great East Japan Earthquake]. AB - This study investigated the levels of public trust in organizations associated with the Great East Japan Earthquake. In Study 1 (N = 639), the levels of trust in eight organizations as well as the determinants of trust--perceived salient value similarity (SVS), ability, and motivation--were measured twice, first immediately after the earthquake and then a year later. The results indicated that the trust levels for six of the eight organizations had been preserved, supporting the double asymmetric effect of trust. The results of structural equation modeling (SEM) revealed that SVS explained trust more when the organization had been less trusted. Trust in the organization explains well the perceived reduction of the target risk. The results of SEM in Study 2 (N = 1,030) replicated those of Study 1, suggesting the stability of the explanatory power of the determinants of trust. Implications of the study for risk management practices are discussed. PMID- 25016835 TI - [No relationship between blood type and personality: evidence from large-scale surveys in Japan and the US]. AB - Despite the widespread popular belief in Japan about a relationship between personality and ABO blood type, this association has not been empirically substantiated. This study provides more robust evidence that there is no relationship between blood type and personality, through a secondary analysis of large-scale survey data. Recent data (after 2000) were collected using large scale random sampling from over 10,000 people in total from both Japan and the US. Effect sizes were calculated. Japanese datasets from 2004 (N = 2,878-2,938), and 2,005 (N = 3,618-3,692) as well as one dataset from the US in 2004 (N = 3,037 3,092) were used. In all the datasets, 65 of 68 items yielded non-significant differences between blood groups. Effect sizes (eta2) were less than .003. This means that blood type explained less than 0.3% of the total variance in personality. These results show the non-relevance of blood type for personality. PMID- 25016836 TI - [The concept structure of respect-related emotions in Japanese university students]. AB - This study examined the semantic organization of "sonkei" (a feeling of respect) and respect-related emotion words such as "awe" and "admiration" in Japanese university students. Native Japanese university students rated the semantic similarity of 153 pairs of 18 respect-related words having been collected from synonym dictionaries. Hierarchical cluster analysis of similarity ratings revealed two main distinctions at the highest level of abstraction: "person-focus respect, emotional attitude" (sustained respect for a particular person considered to be superior) and "action-focus respect, emotional state" (temporal respect for a praiseworthy action). The former included three basic categories: (a) respect mingled with mild love; (b) idolatry (worship and adoration); and (c) respect mingled with fear (awe). The latter included two basic categories: (d) admiration and (e) respect mingled with surprise (wonder). The word "sonkei" was included in category (a). Also, multidimensional scaling revealed three dimensions of respect-related words: focus, valence, and self-oblivion. These findings suggest that for Japanese university students, respect is typically a kind of emotional attitude, but they sometimes experience respect as an emotional state ("state respect"). PMID- 25016837 TI - [Development and validation of the Reality-Monitoring Error Experience Questionnaire]. AB - This study developed a valid and reliable questionnaire measuring individual differences in reality-monitoring error experiences in everyday life. A 50-item preliminary questionnaire was constructed on the basis of the findings from a pilot diary study. In study 1, we administered the questionnaire to 316 undergraduates, along with a dissociative experience scale to examine criterion referenced validity. Using factor analysis, we obtained the 32-item Reality Monitoring Error Experience Questionnaire (RMEEQ). A significant positive correlation was found between scores on the RMEEQ and the dissociative experience scale, thereby which indicates the RMEEQ's criterion-referenced validity. In Study 2, we examined the test-retest reliability of the RMEEQ by administering it to 66 undergraduates on two occasions separated by three weeks. We found a significant test-retest correlation. Taken together, these results show that the RMEEQ is a valid and reliable measure of reality-monitoring error experiences in everyday life. PMID- 25016838 TI - [Development and psychometric evaluation of a Japanese version of the Personal Growth Initiative Scale-II]. AB - We conducted two studies to develop a Japanese version of the Personal Growth Initiative Scale-II (PGIS-II), and examined its reliability and validity. PGIS-II was developed as a multidimensional measure of the multiple processes of the Personal Growth Initiative (PGI). The PGI describes an active, intentional engagement in the process of personal growth for self-improvement of life experiences. Study 1 (N = 204) reports the confirmatory factor analysis (CFA) of the Japanese version of the PGIS-II. The CFA confirmed that 4-factor model showed acceptable fit indices, with reliability coefficients ranging from .67 to .84. Concurrent validity of the PGIS-II was indicated by the correlation with happiness, the positive score for automatic thoughts. Study 2 (N = 101) reports the concurrent validity of the PGIS-II using scales for locus of control, self esteem and coping. Results suggested significant correlations between scores on the PGIS-II and locus of control, self-esteem and some coping subscales. The overall results suggest that the Japanese version of the PGIS-II has satisfactory statistical reliability and validity. PMID- 25016839 TI - [Development of a Japanese version of the Perceived Vulnerability to Disease Scale]. AB - This study developed a Japanese version of the Perceived Vulnerability to Disease (PVD) scale. Analysis of the data from Japanese university students (N = 435) replicated the two-factor structure of the original scale: one factor that assessed beliefs about one's own susceptibility to infectious diseases (perceived infectability) and the other factor that assessed emotional discomfort in contexts that connoted an especially high potential for pathogen transmission (germ aversion). Tests of reliability and validity for each subscale indicated overall promising results. It would appear that the results reflect at least in part an evolutionary adaptive psychological mechanism for the ancestral environment. PMID- 25016840 TI - [Effects of over-adaptation on subjective well-being in adolescence]. AB - The Over-Adaptation Tendency Scale is designed to assess internal (self inhibitive personality traits) and external (other-directed behavioral adaptation strategies) characteristics of over adaptation. The relationships among over adaptation, subjective well-being, and family relationships were investigated using this scale. The scale was administered to undergraduate and graduate students (N = 408). The results indicated that for both men and women, all internal aspects of over-adaptation were significantly and negatively associated with the participant's cognition of past, present, and future subjective well being. Furthermore, for women, all external aspects of over-adaptation were significantly and positively associated with future subjective well-being and family cohesion was associated with both internal and external aspects. These results are discussed in relation to the characteristics of over-adaptation. PMID- 25016841 TI - [The effect of reading tasks on learning from multiple texts]. AB - This study examined the effect of reading tasks on the integration of content and source information from multiple texts. Undergraduate students (N = 102) read five newspaper articles about a fictitious incident in either a summarization task condition or an evaluation task condition. Then, they performed an integration test and a source choice test, which assessed their understanding of a situation described in the texts and memory for the sources of text information. The results indicated that the summarization and evaluation task groups were not significantly different in situational understanding. However, the summarization task group significantly surpassed the evaluation task group for source memory. No significant correlation between the situational understanding and the source memory was found for the summarization group, whereas a significant positive correlation was found for the evaluation group. The results are discussed in terms of the documents model framework. PMID- 25016842 TI - [Effects of punctuation on the processing of syntactically ambiguous Japanese sentences with a semantic bias]. AB - This study explored the effects of a comma on the processing of structurally ambiguous Japanese sentences with a semantic bias. A previous study has shown that a comma which is incompatible with an ambiguous sentence's semantic bias affects the processing of the sentence, but the effects of a comma that is compatible with the bias are unclear. In the present study, we examined the role of a comma compatible with the sentence's semantic bias using the self-paced reading method, which enabled us to determine the reading times for the region of the sentence where readers would be expected to solve the ambiguity using semantic information (the "target region"). The results show that a comma significantly increases the reading time of the punctuated word but decreases the reading time in the target region. We concluded that even if the semantic information provided might be sufficient for disambiguation, the insertion of a comma would affect the processing cost of the ambiguity, indicating that readers use both the comma and semantic information in parallel for sentence processing. PMID- 25016843 TI - Two doctors take umbrage at Al Lewis's 'treatment trap'. PMID- 25016844 TI - Lewis betrays an unwarranted antiphysician bias that is too much in evidence in today's shifting health care system. PMID- 25016845 TI - Payers consider waiting out budget-busting hepatitis C drug. PMID- 25016846 TI - Overdiagnosing thyroid cancer. What's in a name? PMID- 25016847 TI - Rush to robotic surgery outpaces medical evidence, critics say. PMID- 25016848 TI - The promise and the pitfalls of reference pricing. PMID- 25016849 TI - A conversation with Roy A. Beveridge, MD. Quality, accountability, and leadership. PMID- 25016850 TI - Two tonsillectomy studies reach opposite conclusions. PMID- 25016851 TI - The biologics wave has come ashore. PMID- 25016852 TI - Diabetes patients with authoritarian physicians less likely to adhere to depression medication. PMID- 25016853 TI - First oral medication ok'd to fight psoriatic arthritis. PMID- 25016854 TI - Effect of biologics will be felt worldwide by 2017. PMID- 25016855 TI - [The up-regulation of p-p38 MAPK during the induction of brain ischemic tolerance induced by intermittent hypobaric hypoxia preconditioning in rats]. AB - OBJECTIVE: To explore the expression of p-p38 MAPK protein and the number of astrocytes expressing p-p38 MAPK in CA1 hippocampus in rats during the induction of brain ischemic tolerance induced by intermittent hypobaric hypoxia (IH) preconditioning. METHODS: Thirty healthy adult male Wistar rats were randomly divided into 6 groups (n = 5 in each group): sham 0 min group, IH + sham 0 min group, sham 7 d group, IH + sham 7 d group, Ischemia (Is) 7 d group, and IH + Is 7 d group. Neuropathological evaluation was performed by thionine staining in CA1 hippocampus in rats. The expression of p-p38 MAPK in CA1 hippocampus was observed by immunohistochemical staining. And the number of astrocytes expressing p-p38 MAPK was observed by immunofluorescent double labeling. RESULTS: The results showed that IH preconditioning induced brain ischemic tolerance successfully. At the same time, IH preconditioning obviously up-regulated the expression of p-p38 MAPK protein in CA1 hippocampus, and also increased the number of astrocytes expressing p-p38 MAPK. CONCLUSION: It might be concluded that IH preconditioning induced brain ischemic tolerance by up-regulating the expression of p-p38 MAPK protein in pyramidal neurones and astrocytes. PMID- 25016856 TI - [Genome-wide association study of high altitude pulmonary edema]. AB - OBJECTIVE: High altitue pulmonary edema (HAPE) impacts seriously people's health at high altitude. Screening of susceptibility genes for HAPE will be used for the evaluation and protection of susceptible people. METHODS: We performed a genome wide association study (GWAS) using Affymetrix SNP array 6.0 in 23 HAPE patients and 17 healthy controls. GO and Pathway analysis softwares were used to analyze and draw gene network. RESULTS: Thirty-nine SNPs were found to be significantly different between case and control groups (P < 10(-4)). GO and Pathway analysis of 27 genes around the 39 SNPs indicated that these genes mainly participate in the regulating of cell proliferation, regulation of nitrogen compound metabolic process and G-protein coupled receptor protein signaling pathway and so on. CONCLUSION: It suggests that these SNPs and genes found in this study may be associated with the susceptibility of HAPE. PMID- 25016857 TI - [Effect of high altitude hypoxia on cognitive flexibility]. AB - OBJECTIVE: To explore the effects of high altitude on cognitive flexibility. METHODS: Simulated hypoxia at an altitude of 3 600 m was performed in a hypobaric chamber. Twenty-three volunteers without hypoxic experience were selected and the mean age was about 25.1 years. The physiological parameters (heart rate, blood pressure and oxygen saturation) were measured. Task switch paradigm was used to explore the cognitive flexibility in each phase, and the changing anxiety state was evaluated simultaneously. RESULTS: Reaction time (RT) switch cost in hypoxia phase showed a significant increase compared with the baseline; anxiety level in hypoxia phase was higher than the adaptation phase; a remarkable negative correlation between anxiety level and RT switch cost was found in adaptation phase, whereas a positive correlation was found in landing phase. CONCLUSION: High altitude (3 600 m) affects cognitive flexibility and anxiety state. Anxiety before the hypoxia exposure improves the cognitive flexibility performance, while anxiety after the hypoxia exposure hampers the performance because of the post hypoxia effect. PMID- 25016858 TI - [Glybenclamide regulate ERK1/2 signal pathway during hypoxia hypercapnia pulmonary vasoconstriction in rats]. AB - OBJECTIVE: To investigate the role and significance of ATP-sensitive K+ channels in the pathological process of hypoxia hypercapnia-induced pulmonary vasoconstriction (HHPV) and the relationship with ERK1/2 signal pathway in rats. METHODS: We made the third pulmonary artery rings of SD rats, used the model of pulmonary artery rings perfusion in vitro. Under acute hypoxia hypercapnia condition, and observed the effects of the three stages of HHPV incubated by glybenclamide(Gly) and the combined application of Gly and U0126. At the same time, the values of rings' tension changes were recorded via the method of hypoxia hypercapnia conditions reactivity. RESULTS: Under the normoxia condition, the values of the third pulmonary artery rings tension were relatively stable, but under the hypoxia hypercapnia condition, we observed a biphasic pulmonary artery contractile response compared with N group (P < 0.05, P < 0.01). When the third pulmonary artery rings incubated by Gly, it's phase II persistent vasoconstriction was enhanced compared with the H group (P < 0.05, P < 0.01), and the phase I vasoconstriction was also heightened. Moreover, under the hypoxia hypercapnia condition, U0126 could significantly relieve the phase II persistent vasoconstriction compared with HD group (P < 0.05, P < 0.01) induced by Gly, but the phase I acute vasoconstriction and the phase I vasodilation had no changes (P > 0.05). CONCLUSION: Gly may mediate HHPV via activating ERK1/2 signal transduction pathway. PMID- 25016859 TI - [Effect of JTS caps. treating cerebral ischemia on metabolism and antioxidant system in cerebral ischemia rat]. AB - OBJECTIVE: To study the effects of JTS, Traditional Chinese Medicine caps. treating cerebral ischemia on metabolism and antioxidant system in cerebral ischemia rat. METHODS: I.m. dexamethasone and ligating common carotid artery, the model of cerebral ischemia rats was established to investigate the effects of JTS caps. and its mechanisms through detecting substance metabolism, energy metabolism and antioxidant system. RESULTS: JTS caps. (1.78 - 3.56 g/kg) could upgrade glucose (Glu), total amino acids (T-AA), ATP, Na(+)-K(+) -ATPase, superoxide dismutase (SOD) and catalase (CAT) of brain tissue and degrade lactic acid (LD), malondialdehyde (MDA) and water content of brain tissue in cerebral ischemia rat (P < 0.05, 0.01). JTS caps. (3.56 g/kg) could also depress extenuation of rat's body weight. CONCLUSION: JTS caps. has some protections against the cerebral ischemia in rats, and one of the mechanisms may be improving the metabolism and antioxidant system. PMID- 25016860 TI - [The protective role of interleukin-6 monoclonal antibody on experimental autoimmune myocarditis and its mechanism]. AB - OBJECTIVE: To investigate the therapeutic effect of IL-6 mAb on experimental autoimmune myocarditis (EAM) in rats, and search the mechanism of the role of IL 6, helper T cells 17 (Th17) and regulative T cells (Treg) in EAM pathogenesis. METHODS: Thirty-four Lewis rats were divided into three groups randomly, i.e. control group (n = 6), EAM group (n = 12), and IL-6 mAb intervention group (n = 16). Rats in EAM group and IL-6 mAb intervention group were injected intracutaneously with myosin to establish EAM model. Rats in IL-6 mAb intervention group were injected intraperitoneally with 1 mg IL-6 mAb on 1st, 7th to 20th day after cardiac myosin immune injection. Myocardial inflammation was examined by HE stain, Masson stain, and TdT assay (TUNEL reaction) on 21st and 84th day after IL-6 mAb therapy in order to assess the therapeutic role. Spleen cells were analyzed by flow cytometry to illustrate Th17 and Treg cells? number and function. The serum concentration of IL-6, IL-10, IL-17, and TGF-beta in each group was measured by ELISA, concentration of STAT3, RORgammat, and Foxp3 mRNA in each group was determined with RT-PCR. Spleen cells derived from EAM were stimulated by IL-6 mAb in vitro, and the concentration of IL-10, IL-17 and TGF beta was measured by ELISA. RESULTS: Inflammation score, fibrosis score, and apoptosis index in IL-6 mAb intervention group were significantly decreased as compared with those in EAM group (P < 0.01). The number of Th17 and Treg cells in EAM group on the 21st day (experimental acute peak stage) were increased, and those in intervention group on the 21st day were significantly inhibited (P < 0.01). The concentration of serum IL-6, IL-10, IL-17 and TGF-beta in intervention group on the 21st day was decreased dramatically in comparison with that in EAM group on the same day (P < 0.01). The levels of peripheral blood STAT3, RORgammat, Foxp3 mRNA in intervention group on the 21st day was decreased significantly as compared with that in EAM group (P < 0.01). The expression of IL 10, IL-17 and TGF-beta was increased significantly (P < 0.01) by stimulation of IL-6 mAb on spleen cells derived from EAM in vitro. CONCLUSIONS: IL-6 mAb could neutralize IL-6, and ameliorate myocarditis and reduce heart autoimmune responses. IL-6 mAb has significantly protective effects on EAM by suppressing Th17 and Treg cells. PMID- 25016861 TI - [Role of catecholamine hormone in heroin addicts]. AB - OBJECTIVE: To investigate the effects of catecholamine hormone on the blood and brain of heroin addicts. METHODS: Rats were divided into three groups and treated with the glucose (control group), the heroin (im) (heroin group), and the combination of the intramuscular injection of reserpine and heroin (reserpine group). Changes in the levels of the dopamine (DA), cAMP, and cGMP were detected by the radioimmunoassay (RIA) method in the blood and brain tissue. RESULTS: No significant withdrawal symptoms were observed in the reserpine group. Compared with the control and heroin groups, the blood cAMP levels were increased by 35.36% and 15.53% in the reserpine group, respectively; the cAMP levels in the midbrain ventral tegmental area (VTA), prefrontal cortex (PFC), and hippocampus (Hipp) were increased by 24.08% & 8.53%, 15.66% & 8.13%, and 21.95% & 8.40%, respectively. While compared to the control and heroin groups, the DA levels of the PFC, Hipp, striatum, and nucleus accumbens (NAc) were significantly reduced in the reserpine group, decreasing by 74.09% & 82.86%, 81.06% & 82.23%, 91.62% & 86.55% and 84.35% & 90.63%, respectively. The concentrations of cGMP of the brain tissues in the reserpine group were lower than those in the control group. In addition, the neural electrophysiological testing showed that the electroencephalogram (EEG), electrocardiogram (ECG), and muscle spindle discharge diagram of rats in both the reserpine and heroin groups were apparently changed. CONCLUSION: Catecholamine hormone plays an important role in heroin addiction. PMID- 25016862 TI - [Perioperative cardiovascular abnormality in elder patients with silent coronary heart disease]. AB - OBJECTIVE: To explore the perioperative cardiovascular dysfunction and its relevance to age in patients with silent coronary heart disease (or silent myocardial ischemia), and explore the clinical treatment and recovery of perioperative arrhythmias. METHODS: One hundred and eighty cases were selected from selective surgery patients with silent myocardial ischemia (SMI). Among the cases, 130 patients older than 51 years old were divided into 51 - 60 year-old group, 61- 70 year-old group and 71 - 80 year-old group. Control group was set up by other 50 patients younger than 51 years old. Electrocardiogram data of 24 h before the operation, 24 h after the operation and 48 h after the operation were continuously monitored by dynamic electrocardiogram (DCG). The electrocardiogram data of ST shifting, arrhythmia incidences of different type and at different time were analyzed by professional doctors. At the same time, the treatment and recovery of perioperative arrhythmia were recorded. RESULTS: As the age increase, the magnitude and duration of ST shifting appeared upward trend compared to the control group (P < 0.05, P < 0.01). The incidence of ST elevation in 71 - 80 year old group was higher than the control group (P < 0.05). The ST depression duration in 61 - 70 and 71 - 80 year-old group and ST elevation magnitude in 71 - 80 year-old group were higher than 51 - 60 year-old group (P < 0.05). Compared to the control group, the incidence of accelerated idioventricular rhythm (AIR) in 61 - 70 year-old group and the incidence of sinus bradycardia (SB), ventricular premature beat (VPB), ventricular tachycardia (VT) in 71 - 80 year-old group were higher (P < 0.05, P < 0.01). Compared to the 51 - 60 year-old group, the incidence of atrial fibrillation (AF) in 61 - 70 year-old group and the incidence of VP, VT, AF in 71 - 80 year-old group were higher (P < 0.05, P < 0.01). The arrhythmia incidences in 24 h after operation were higher than 48 h after operation and 24 h before operation (P < 0.01). As the age increase, the recovery incidence by removing inducement was decreased, but the recovery incidences by drug and electric-shock treatment were increased (P < 0.05). CONCLUSION: Old SMI patients have high levels of perioperative myocardial ischemia and arrhythmia, and 24 h after operation is the period of high incidence. PMID- 25016863 TI - [Effects of Shenqi preparation on anti-fatigue and anti-oxidant functions in mice]. AB - OBJECTIVE: To explore effects of Shenqi preparation,Traditional Chinese Medicine, on anti-fatigue and anti-oxidant functions. METHODS: One hundred and twenty mice were randomly divided into control group and 3 experimental groups. The high, medium and low-dose of Shenqi preparation were given to the 3 experimental groups respectively, while distilled water to the control group for 15 d. The loaded swimming time, the level of lactate, serum urea nitrogen (SUN), muscle and liver glycogen, liver super-oxide dismutase (SOD), the content of malondialdehyde (MDA), glutathione peroxidase(GSH-Px) were assayed. RESULTS: The loaded swimming test showed that the exhausted swimming time of 3 experimental groups [(296.0 +/- 25.3)s, (437.0 g 38.9)s, (595.0 +/- 53.9)s respectively] was longer than that of control group [(231.0 +/- 22.5)s, P < 0.05, P < 0.01]. The liver glycogen content of the high and medium-dose experimental groups were higher than that of control group respectively (P < 0.01). The SUN content of each experimental group was less than that of the control group (P < 0.01, P < 0.05). Moreover,in the medium and high dose experimental groups, less accumulation of lactate was found (P < 0.01, P < 0.05), and the content of liver SOD and GSH-Px was higher (P < 0.01, P < 0.05). The content of liver MDA in high-dose experimental group was less than that of the control group (P < 0.05). CONCLUSION: Shenqi preparation, especially the high and medium-dose experimental groups, is able to improve exercise tolerance and has anti-fatigue and anti-oxidant effects in mice. PMID- 25016864 TI - [The analysis of polymorphism of red cell complement receptor type 1 density genomic in Olunchun nationality]. PMID- 25016865 TI - [Cardiac ischemia in type 2 diabetes mellitus rats induced by high sucrose and high fat diet and STZ treated]. AB - OBJECTIVE: To build a type 2 diabetes mellitus rat model with cardiac ischemia. METHODS: Male Wistar rats were fed high sucrose and high fat diet for four weeks and then injected with streptozoticin (STZ) (40 mg/kg .i.p.). The levels of fasting blood glucose and serum insulin were monitored every week. The body weights of rats were also measured every week. The blood levels of creatine kinase and lactate dehydrogenase (LDH) were measured following the electrocardiograph used BL-410 biological experiment system. RESULTS: The serum insulin levels of diabetic rats were 4.05 ng/ml after four weeks high sucrose and high fat diet. The fasting blood glucose levels of diabetic rats were 17.9 mmol/L after injection. Compared with normal group, there was obvious change of S-T segment in the electrocardiograph of diabetic group at the fourteenth week. The levels of creatine kinase and lactate dehydrogenase in diabetic group significantly increased in comparison with those in normal group. CONCLUSION: The cardiac ischemia of diabetic rats model is suitable for investigating cardiac disease of diabetes mellitus. PMID- 25016866 TI - [Association of ACTN3 gene R577X polymorphism and athletic performance of Uyghur nationality in Xinjiang]. PMID- 25016867 TI - [The initial study on mechanism in postpone skeletal muscle aging process of D galactose rats by movement training and soy polypeptide supplement]. AB - OBJECTIVE: To observe the effect of the postpone in skeletal muscle aging process of D-galactose rats by weight training and soy polypeptide supplement in 6 weeks, and discuss the initial mechanism. METHOD: Sixty male SD rats (three month old)were randomly assigned: 6 week control (C6,) and 6 week model (M6) 6 for each group, 12 week model (M12), big load (B12), small load (S12), peptide (P12), peptide + big load (PB12) and peptide + small load group (PS12) 8 for each group, eight fourteen month rats were taken in the natural aging group. The rats were killed by the end of 6th week and 12th week, tested the indicators. RESULT: Compare with group C6, the indicators in group M6 showed aging in different levels; Compare with group M12, weight training or soy polypeptide supplement in all intervention groups could increase the content of skeletal muscle superoxide dismutase (SOD), SOD/MDA, the serum growth hormone(GH), insulin-like growth factor-1 (IGF-I)and skeletal muscle IGF-I mRNA, decreased the malondialdehyde (MDA) content of skeletal muscle, and they had notable interaction. CONCLUSION: Rat skeletal muscle aging model can be copied successfully by D-galactose hypodermic, and go on with 6-week weight training or soy polypeptide supplement, they can postpone the skeletal muscle aging process of D-galactose rats, and the two interference way united can have more obvious effect. Its preliminary mechanism may be related to the reduction of skeletal muscle oxidative stress and lipid peroxidation, the correction of hormones and related factors metabolic disorders, the elevation of skeletal muscle IGF-I mRNA expression and so on. PMID- 25016868 TI - [Effect of sequoyitol on expression of NOX4 and eNOS induced with glucose in human umbilical vein endothelial cells]. AB - OBJECTIVE: To investigate the protective effect and mechanism of sequoyitol (Sep) on high glucose-induced human umbilical vein endothelial cells (HUVECs) injury. METHODS: HUVECs were cultured with high glucose (30 mmol/L) in the presence or absence of sequoyitol (0.1, 1 and 10 micromol/L) for 24 h. Cell proliferation was measured by BrdU marking and cell cycle was detected by flow cytometry. 2', 7' dichlorofluorescein diacetate was used to evaluate intracellular reactive oxygen species (ROS) levels. The NO, malonydialdehyde (MDA) and H2O2 levels were determined by colorimetric method according to the manufacturer's instructions. The expression of endothelial nitric oxide synthase (eNOS) and NADPH oxidase 4 (NOX4) were measured by real-time PCR and Western blot. RESULTS: In the present study, we found that sequoyitol pretreatment for 1 h significantly decreased cell injury, promoted cell proliferation. Meanwhile sequoyitol significantly down regulated NOX4 expression and decreased the level of ROS, MDA and H2O2 and obviously increased NO levels and up-regulated eNOS expression. CONCLUSION: Sequoyitol alleviates high glucose-induced cell injuries in HUVECs via inhibiting oxidative stress and up-regulating eNOS expression. PMID- 25016870 TI - [Experimental study on anti-fatigue and anti-hypoxia effect of rich selenium banqiao-codonopsis pilosula]. PMID- 25016869 TI - [Effects of long-term sleep deprivation on mitochondria stress in locus coeruleus and the tyrosine hydroxylasic projection in mice]. AB - OBJECTIVE: To observe the changes of mitochondria stress in locus coeruleus and the tyrosine hydroxylasic projection after long-term sleep deprivation. METHODS: Sleep deprivation mice model was set up by employing "novel environments" method. The expression of NAD -dependent deacetylase Sirtuin type 3 (SIRT3), which regulates mitochondrial energy production and oxidative stress, and heat shock protein 60 (HSP60), a major biomarker of mitochondrial stress, and the tyrosine hydroxylasic projection from locus coeruleus were analyzed after a 5-day sleep deprivation. RESULTS: Compared to the control group, the expression of SIRT3 in locus coeruleus was significantly decreased in respouse to long-term sleep deprivation, while the expression of HSP60 was significantly increased. In addition, relative to control group, pereentage area of the tyrosine hydroxylasic projection to anterior cingulate cortex was substantial decreased in long-term sleep deprivation group. CONCLUSION: Long-term sleep deprivation induced the decreased level of SIRT3 expression and the elevation of mitochondrial stress in locus coenileus, which may further lead to the loss of tyrosine hydroxylasic projection in mice. PMID- 25016871 TI - [ARMS method verified EGFR gene mutations and its clinical significance in patients with non-small cell lung cancer]. PMID- 25016872 TI - [Effects of total flavones of Elsholtzia splendens in isolated ischemia/reperfusion rat hearts]. AB - OBJECTIVE: To investigate the influence of total flavonoids of Elsholtzia splendens (TFES) on isolated ischemia/reperfusion rat hearts and its underlying mechanisms. METHODS: Hearts isolated from male SD rats were perfused on the Langendorff apparatus and subjected to global ischemia for 30 min followed by 120 min of reperfusion. The cardiac infarct size was measured by TTC staining. Hemodynamic parameters and the level of lactate dehydrogenase (LDH) in the coronary effluent were measured. Absorbance at 520 nm was determined in isolated cardiac mitochondria exposed to 200 micromol/L CaCl2 to detect the opening of the mitochondrial permeability transition pore. RESULTS: Pretreatment with TFES (1, 10, 100 microg/ml) for 5 min decreased infarct size and LDH release and improved the recovery of the left ventricular developed pressure. In mitochondria, the decrease of absorbance at 520 nm evoked by CaCl2 was greatly inhibited by TFES. CONCLUSION: TFES prevents myocardial ischemia/reperfusion injury, and this cardioprotective effect is probably via inhibiting mitochondrial permeability transition pore opening. PMID- 25016873 TI - [Effect of curcumine on the expression of Fas/FasL in rat brain tissue under chronic low O2 and high CO2]. PMID- 25016874 TI - [The dynamic alterations of electrocardiogram during progression of mouse cardiac hypertrophy]. AB - OBJECTIVE: To find the characteristic parameters from electrocardiogram (ECG) which is most related to pathological progress, surface ECG was performed in mice at 2, 5, 9 and 13 week post surgery. METHODS: Electrocardiogram recordings: The mice were anaesthetized with tribromoethanol (250 mg/kg, i.p.). Lead II surface ECG were acquired by using the Biopac System MP150 at a rate of 5 kHz. RESULTS: (1) No arrhythmia was observed in Sham and 2-week Band mice. Spontaneous arrhythmias were observed in ECG recordings, with an incidence of 15%, 28% and 63% in 5-, 9- and 13-week Band mice, respectively. Tachyarrhythmias, such as frequent premature ventricular extrasystole, bigeminy, trigeminy, and paroxysmal tachycardia were found. (2) Analysis of ECG recordings revealed a significant prolongation of QT and QTc intervals. Compared with age-matched Sham mice, the increment in QT and QTc intervals was 20.4%, 32.7%, 49.7%, 61.0% and 27.1%, 32.1%, 43.9%, 59.1% at 2, 5, 9 and 13 week, respectively (P < 0.01). (3) The characteristic change in electrocardiogram was on the J wave. The amplitude of J wave was upward in Sham mice, and it was significantly flattened or inverted in Band mice. (4) Except that RR interval at 2 week showed a slight decrease, there was no significant change in PR interval and RR interval in Band mice. CONCLUSION: In the present study, we found that the increase incidence of spontaneous arrhythmias, prologation of QT interval and changes in the amplitude of the J wave in the surface ECG during progression of mouse cardiac hypertrophy and failure, and the progressive pattern indicated that a gradual aggravation of the ventricular repolarization delay in this mouse model. PMID- 25016875 TI - [Expressions of TERT during the development of rat liver cancer under the interventions of oxymatrine and selenium enriched yeast]. PMID- 25016876 TI - [The effect of Wu-He Dipsacus asper on mice-aging model induced by D-galactose]. AB - OBJECTIVE: To study the effect of Wu-He Dipsacus asper (WHDA), Traditional Chinese Medicine, injection on mice-aging model induced by D-galactose. METHODS: Forty-eight Kunming mice (24 male and 24 female) were randomly divided into control group, model group, positive control group, 7.2 g/kg WHDA group, 3.6 g/kg WHDA group and 1.8 g/kg WHDA group with eight in each group. The model was induced through injecting D-galactose into peritoneal cavity and Morris water maze was used to detect the learning and cognitive ability of mice. The skin hydroxyproline, brain tissue malondialdehyde (MDA), lipofuscin (LP), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels of mice were detected; the IL-2 and IL-6 levels in serum of mice were detected by using double antibody sandwich ELISA method. RESULTS: Each WHDA group was significantly reduced in latency period compared with the model group during Morris water maze test (P < 0.05) and the number of mice in model group through the platform was less than other mice in each group (P < 0.05). The levels of MAD and LP of the control group and each WHDA group were less than model group in the detection of heart, brain tissue oxidation index (SOD, MAD, LP and GSH-Px, P < 0.05). The activity of SOD and GSH-Px in the control group and each WHDA group was significantly higher than that in the model group (P < 0.05). The skin hydroxyproline content of mice which had been injected with D-galactose was significantly lower than that in the control group (P < 0.05) and the skin hydroxyproline content of mice of WHDA group was significantly higher than that in the model group (P < 0.05). The IL-2, IL-6 levels in serum of mice in WHDA group were significantly higher than those in the control group and the model group (P < 0.05) and the IL-2, IL-6 levels in serum of mice in the model group were lower than those in the control group (P < 0.05). CONCLUSION: The effective constituents of WHDA have a variety of biological activity which can have a good effect on anti-aging by different ways, improving learning and memory function, eliminating free radicals antioxidant, and enhancing the body immunity and other aspects. PMID- 25016877 TI - [The supernatant of Lo-2 cells induce human mononuclear cells transformation to the cells like hepatocyte]. PMID- 25016878 TI - [Effects of exercise and low-fat diet on the TNF-alpha expression of insulin resistance in rats]. AB - OBJECTIVE: To investigate the effects of exercise (EX), low-fat diet (LFD) and their combination intervention on the tumor necrosis factor-alpha (TNF-alpha) expression of insulin resistance in rats. METHODS: One hundred and thirty male rats randomly assigned to 2 groups: Control (CON)-10 rats consuming a low-fat diet; HFD-120 rats consuming a high-fat diet (HFD). The dietary regimen was sustained for 8 wk, at which point the 40 HFD group rats gaining the most weight were referred to as the obese rats. Glucose tolerance was assessed by an oral glucose tolerance test (OGTT). During the procedure of OGTT, the blood was drawn for insulin assay (insulin release test). The whole body insulin resistance was assessed by glucose-insulin index. The obese HFD group rats were randomized into one of four intervention groups: HFD-sedentary (HFD-SED), HFD-exercise(HFD-EX), low fat diet-SED (LFD-SED), LFD-EX. Ex rats performed 8-wk exercise training on a motorized treadmill. The CON group had access to low-fat diet for another 8 wk. After 8 wk of exercise and low-fat diet intervention, the OGTT and insulin release test were performed again. To use ELISA technique for detecting TNF-alpha in soleus muscle and adipose tissue. RESULTS: After being fed high-fat diet for 8 wk, glucose-insulin index in the HFD group were significantly greater than that in CON group (P < 0.01). After 8-week exercise and low-fat diet intervention, glucose-insulin index in HFD-SED group was significantly greater than that in CON group (P < 0.01). The index in three intervention groups was significantly less than that in HFD-SED group (P < 0.01) . TNF-alpha content in adipose tissue and the soleus muscle for HFD-SED group was significantly greater than that in CON group (P < 0.01). Three intervention groups were significantly less than HFD-SED group (P < 0.01). CONCLUSION: Exercise and low-fat diet interventions can decrease the TNF-alpha expression in insulin resistance rat. PMID- 25016879 TI - [Novel drug composition ameliorating thrombosis and its molecular mechanisms]. AB - OBJECTIVE: To investigate the antithrombotic effects and its molecular mechanisms of prazosin combined with anisodamine (Ani). METHODS: Isolated rat tail artery rings model was employed to evaluate the vasodilative effects of drugs, mice tail thrombosis model induced by carrageenan was used to study the antithrombotic effects and its molecular mechanisms of the drug composition. RESULTS: Among alpha1-adrenoreceptor antagonists, prazosin(Pra) had the greatest relaxation rate, which was (82.6 +/- 8.9)%, and the EC50 value was 0.44 micromol/L. The drug composition of anisodamine and prazosin of different doses could decrease the length of the tail thrombosis from (24.6 +/- 4.6)mm to (6.9 +/- 2.7)mm, and the rate of thrombosis was decreased from 86.6% to 50.0%. The drug composition could prolong the prothrombin time (PT) distinctively, but it had no effect on the activated partial thromboplastin time (APTT). It also could restrain the decrease of serum levels of tissue plasminogen activator (t-PA) and 6- Keto -PGF1alpha as well as the increase of type-1 plasminogen activator inhibitor (PAI-1) and thromboxane B2 (TXB2) in the mice. CONCLUSION: The drug composition formed by anisodamine and prazosin has good effects of relaxing extremities tiny blood vessels and it can fight against thrombosis, its antithrombotic mechanisms may be related to the influence of the extrinsic coagulation pathway, inhibition of platelet activation functions and the promotion of fibrinolysis function. PMID- 25016880 TI - [The study of catheterization to measure ventricular pressure in mice through venous cannula in external jugular vein]. AB - OBJECTIVE: To study a feasible method of measuring right ventricular pressure by catheterization in mice. METHODS: Measuring the right ventricular pressure and the pulmonary artery pressure by homemade PE pipe through venous cannula in external jugular vein, using catheterization in mice with powerlab multimodal biometric signal recording system. RESULTS: Forty-six out of 51 mice were experimented with this method smoothly and got a total success rate of 90.2%. Thirty of 33 normal mice and 16 of 18 mice with pulmonary arterial hypertension (PAH) were catheterized successfully. The right ventricular pressure were as follow: systolic blood pressure: (23.4 +/- 5.7) mmHg in normal group vs (32.2 +/- 2.8) mmHg in mice with PAH, diastolic blood pressure: (3.7 +/- 2.6) mmHg vs (3.8 +/- 2.0) mmHg, mean pressure: (12.0 +/- 3.7) mmHg vs (14.9 +/- 2.3) mmHg. After autopsy for those 5 failed cases, we found that 2 cases were into the inferior vena cava, another 2 cases pierced the right auricle and the last one punctured the axillary vein into the chest wall. CONCLUSION: Measuring the right ventricular pressure through venous cannula in external jugular vein with homemade PE pipe in mice gets not only a high success rate but also help to save time. Moreover, this method can be popularized easily. It is a good and feasible method for measuring right ventricular pressure in mice. PMID- 25016881 TI - Cleveland Clinic cases highlight flaws in safety oversight. PMID- 25016882 TI - Geographic mismatch exacerbates VA woes. PMID- 25016883 TI - More association CEOs earn $1 million, but some see pay cuts. PMID- 25016884 TI - Outsourcing employee health benefits. More firms see private insurance exchanges as a way to control healthcare costs. PMID- 25016885 TI - Why Medicaid expansion won't swamp state budgets. PMID- 25016886 TI - Reducing costs requires end to fee-for-service. PMID- 25016887 TI - North Shore-LIJ grows its own leaders through novel High Potential program. PMID- 25016888 TI - Open dialogue needed to make physician acquisitions work. PMID- 25016889 TI - Exchanges on HHS inspector general's agenda. PMID- 25016890 TI - Double whammy. PMID- 25016891 TI - Truven Health 100 top hospitals: national benchmarks for success, 2014(1 of 3). PMID- 25016893 TI - Truven Health 15 Top Health Systems. PMID- 25016892 TI - Higher quality, healthier finances. Analysis shows 15 Top Health Systems outperform their peers on clinical and financial measures. PMID- 25016895 TI - [Frequency factor Her-2/neu overexpression in patients with breast cancer]. AB - BACKGROUND: Her-2/neu is an oncogen related with a poor prognosis and high agresivity when overexpressed in breast cancer. Main objective was analyze the frecuency of positivity or negativity ofller/neu in patients with breast cancer after surgery and their relationship with hormone receptors. We perfomed a longitudinal, retrospective, descriptive and observational trial in all patients included in the Patology Service with a determination of Her-2/neu and hormone receptors analysis, between January 1st 2007 and December 31 st 2009.We used descriptive stadistic and association tests with correlation coefficients. We analyze 893 patients. The age range was between 24 and 94 years. The 16.% of all cases overexpressed Her-2/neu (150 patients). The 4.8% (43 patients) were included in the FISII test resulting in 29 positives to Her-2/neu. There were a total of 179 cases overexpressed. Negative estrogen receptores cases were 23%, negative progesterone receptores cases were 28% and triple negative receptors cases were 19%. We analyzed independient variables with Student I resulting age with P = 0.294. We analyzed distribution variables with Pearson test resulting in negative estrogen receptors with a P = 0.0001 negative progesterone receptres with a P = 0.0001 and triple negative receptors P= 0.0001. Relationship between hormone receptors and Her-2/neu in proporlionaly inverse in other vvords when a high hormone receptors negativitvis present there is algo a Her-2/neu highly overexpressed. PMID- 25016896 TI - [Increase S/D ratio in uterine artery as a predictor for preeclampsia in adolescent patients]. AB - BACKGROUND: Pregnancy during adolescence has been rising in the past years, and it is well known that preeclampsia affects teenagers, because maternal age and primigravida are risk factors. There are different ways and methods to predict preeclampsia, for example doppler velocimetry. OBJECTIVE: Determine S/D ratio of uterine artery in pregnant teenagers between 24-28 weeks and correlation with preeclampsia. MATERIAL AND METHOD: Observational study in 50 pregnant teenagers (14-19 years) obtaining uterine artery waveform at 24-28 weeks gestation recording S/D ratio. RESULTS: Sensitivity and specificity of 90% with a positive predictive value of 69.23% and negative predictive value of 97.3%. 13 patients had S/D ratio greater than 2.6, of which 5 had gestational hypertension, 3 with preeclampsia, 1 with Fetal Growth Restriction, 4 with normal pregnancy. Relative Risk was 25.62 (3.58-183.13) with odds ratio of 81.00 (6.83-2260.88) and p value 0.00002. CONCLUSION: analysis of uterine artery flow velocity waveforms is a method to predict preeclampsia. PMID- 25016897 TI - [Patients with inherited trombophilia and recurrent pregnancy loss: incidence]. AB - BACKGROUND: Inherited thrombophilia is a genetic tendency to suffer thrombotic events clinically evident at an early age, with frequent re- currences without apparent cause. In recent years thrombophilia has earned a place as a primary risk factor for abnormal pregnancy. OBJECTIVE: To determine the incidence of hereditary thrombophilia in patients with recurrent pregnancy loss. MATERIAL AND METHOD: A retrospective, linear and descriptive study was conducted at Clinic of Reproduction IMMUNOREP with patients treated from January 2007 to December 2012. The study included patients with a diagnosis of recurrent pregnancy loss and inherited thrombophilia with laboratory studies of thrombophilia including different genes: G1619A (factor V Leiden), R2 H1299R (factor V polymorphism), C677T (methylenetetrahydrofolate reductase enzyme polymorphism), A1298C (methylenetetrahydrofolate reductase enzyme mutation), G20210A (mutation of the prothrombin gene), V34L (factor XIII polymorphism), 455G > A (fibrinogen gene mutation), 4G/5G (plasminogen activator inhibitor) and a/b L33P (ribosomal polymorphism of methylenetetrahydrofolate reductase enzyme). RESULTS: 211 files were reviewed and only 10.4% of patients were negative for hereditary thrombophilia, a percentage that is consistent with the results of different series of studies in patients with unexplained recurrent pregnancy loss. The most prevalent genetic condition was 4G/5G (plasminogen activator inhibitor, 85.5%) in homozygous and heterozygous with 63.4% (120) and 22.4% (42), respectively. CONCLUSIONS: It was demonstrated the direct relationship between thrombophilia and recurrent pregnancy loss depending on whether the patient is heterozygous or homozygous for the disease. PMID- 25016898 TI - [Contraception and breast feeding. Spacing of pregnancies. Present concepts]. AB - The risk of pregnancy in breastfeeding should be a concern of women. Family planning programs in the postnatal period contraceptive choices offer high efficiency. Breastfeeding is a natural contraception method (LAM) as a contraceptive shield has 98 % efficiency. Women should consider using an alternate contraceptive method when feeding requirements for this method to be effective are not met. Some of contraceptive alternatives in lactation include hormonal methods. According to the Medical Eligibility Criteria for Contraceptive Use WHO combined hormonal methods are contraindicated during breast feeding, hormonal progestogen only method are considered only in Group 3 and Group 1 immediate postpartum after 6 weeks postpartum. There are modifications to these criteria by the CDC and the UK for the use of these hormones in early in lactation. PMID- 25016899 TI - [Maternal deaths in Mexico: a question of attitude]. PMID- 25016900 TI - [Small cell carcinoma of the ovary pulmonary type]. AB - Ovarian small cell pulmonary type carcinoma is a rare and aggressive tumor with higher incidence in young women. Multidisciplinary treatment seems to increase survival in a small number of cases. We present the case of a woman diagnosed with this type of tumor of small cells, their clinical evolution and the treatment he received. PMID- 25016901 TI - [Hemorrhagic dengue and vertical transmission to the newborn: a case report and literature review]. AB - OBJECTIVE: To describe the case of a patient with term pregnancy and infection with hemorrhagic dengue and vertical transmission to the newborn. CLINICAL CASE: Thirty-two year old patient with pregnancy at 38 weeks was admitted with fever 2 days earlier (38 degrees C). During her stay she continued with fever of 39 degrees C and platelets of 85,000/mm3. Serology for dengue NS1 antigen was reported positive. Labor was induced getting a new-born, male, 3,220 g, who breathed and cried at birth. During the postpartum period continued with fever, malaise, retro-ocular pain, generalized rash in upper and lower limbs, bleeding gums and petechial on the soft palate and thrombocytopenia of 5,000/mm3, later. At 8 days of stay, platelet concentration increased to 42,000/mm3 without requiring platelet concentrates and she was discharged after ten days in hospital with platelets of 94,000/mm3. The 4th day of extra-uterine live (EUL), neonate shows generalized rash over the trunk; The 5th day starts with 38 degrees C fever and thrombocytopenia (78,000/mm3). Dengue serological tests reported positive for Ag NS1 and negative for Abs IgM and IgG. Neonate was admitted to NICU, he continued with a decrease in platelet of 14,000/mm3- and ecchymotic areas by pressure and veno-punction sites. Four platelet concentrates were transfused. At 10th day of EUL platelet count was reported with 387,000/mm3. CONCLUSIONS: In an endemic area, such as Sinaloa state, in a pregnant woman with fever and thrombocytopenia, we should be alert to possibility of a DV infection and its complications. Although rare, such as this case, infection can be transmitted to fetus (vertical transmission) and produce a primary congenital dengue, even in its severe hemorrhagic types. PMID- 25016902 TI - [Embryo implantation in cesarean section]. AB - BACKGROUND: Ectopic pregnancy continues to be a life threatening emergency as well as a menace to women fertility. Documented cases site tubal ectopic pregnancy as the most frequent location in 97% of cases. Being the previous cesarean scar the most rare location (< 1%), therefore, rarely reported. OBJECTIVE: To explain the process of diagnosis and treatment as well as the discussion of current modalities. CLINICAL CASE: 28 years old patient who goes to the outpatient service at Santa Rosa de Lima Hospital for presenting scarcely transvaginal stain of two days of evolution (which was detected by speculoscopy exploration) without referring pain. Transvaginal ultrasound showed 9.1 weeks of gestation pregnancy, located in the previous cesarean scar, with a heartbeat of 150 beats per minute. Subsequently, a laparotomy was preformed obtaining the product without further complications. PMID- 25016903 TI - [Brenner tumor: one case report and bibliographic review]. AB - Brenner tumor is a rare tumor that represents approximately 1.5% of the tumors of ovary. It is defined as a tumor of transitional cells composed by urothelial cells arranged in solid or cystic groups absorbed in a fibrous stroma. It classifies in benign Brenner tumor (95%), borderline (3-4%) and malignant (1%). Let's sense beforehand the clinical case of a 46-year-old patient who underwent surgery having an adnexal mass of which the pathological intraoperative report brought a benign Brenner tumor. PMID- 25016904 TI - [Symptoms and syndromes in relation to the menstrual cycle]. PMID- 25016905 TI - Raising the bar. PMID- 25016906 TI - Student mental health implications for physician assistant education. AB - PURPOSE: This report examines student mental health and learning disabilities along the continuum from childhood to college by examining diagnosing and prescribing patterns and potential implications for physician assistant (PA) faculty based on the Standards of the Accreditation Review Commission on Education for the Physician Assistant (ARC-PA) and the new Diagnostic and Statistical Manual of Mental Disorders (DSM-5, Section 2, Specific Learning Disorders). METHODS: We reviewed existing data to compare decades of national patterns in diagnosing and prescribing for conditions that have known comorbidities with learning disabilities. By including quantitative and qualitative data from children, adolescents, undergraduate college students, and veterans, we illustrate the potential impact these patterns could have on some current and future applicants to PA educational programs and the requirements for PA faculty to address these needs. RESULTS: Multiple national data sources revealed increasing numbers of children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), psychoactive prescriptions written for those under age 18, and self-reported increases in multiple psychological disorders among college students. More recent evidence shows a twofold increase in military veterans returning to college with posttraumatic stress disorder, traumatic brain injury, and depression. CONCLUSION: The growing numbers of students with conditions described in this report requires academic faculty to be aware of requirements to recognize and address their mental health service needs. PA educators could benefit from supplemental faculty development activities to help prepare them to recognize the pipeline patterns of a growing percentage of postsecondary students with mental health conditions and learning disabilities. PMID- 25016907 TI - Building a research culture in physician assistant education. AB - The mission of most physician assistant (PA) programs is to train clinically competent health care providers. While essential and compelling, we believe this mission is insufficient for modern PA programs and advocate that programs take steps to institute and expand their research capabilities and activities. This will represent a culture shift for many institutions but is necessary for the long-term growth and survival of PA educational programs within US higher education. We discuss the obstacles that exist to create a flourishing research culture in PA programs and offer concrete recommendations for programs to attain such an environment. PMID- 25016908 TI - Job satisfaction levels of physician assistant faculty in the United States. AB - PURPOSE: Understanding job satisfaction in academia is important in order to recruit and retain faculty. Faculty members with greater job dissatisfaction are more likely to leave than faculty members who are satisfied. Physician assistant (PA) faculty job satisfaction needs to be assessed to determine which job facets are satisfying or dissatisfying. METHODS: A quantitative descriptive study was done using a Web-based survey sent to PA faculty. The Job Descriptive Index (JDI), a validated survey, was used to measure levels of job satisfaction. The means for each facet were calculated to indicate levels of satisfaction with the job overall, work, supervision, co-workers, pay, promotion, levels of stress, and trustworthiness in management. Correlations were run among demographic factors, salary, and overall job satisfaction. RESULTS: Of the 1,241 PA faculty that received the survey, 239 responses (19.3% response rate) met the criteria for study inclusion. The highest level of satisfaction was with one's co-workers (mean 46.83, range 0 to 54). The promotion facet received the lowest mean level of satisfaction with a 22.2 (range 0 to 54). A small correlation was found between job satisfaction and academic rank (r = -.153, P = .020). CONCLUSION: Job satisfaction is linked to increased productivity and performance. It is important to understand job satisfaction to make improvements in the appropriate areas. Overall, the results indicate that PA faculty are satisfied with their jobs. Further research is needed to understand the factors that contribute to satisfaction among PA faculty. PMID- 25016909 TI - Evaluation of a targeted curriculum on patient poverty funded by Title VII. AB - PURPOSE: There is limited knowledge about the perceptions of physician assistant (PA) students on poverty issues and the importance of treating the poor. We assessed whether a curriculum focused on these issues improved the perceptions of PA students on issues of poverty. METHODS: The study was designed to measure perception change after PA students were exposed to a patient poverty curriculum. A pre- and postpatient poverty survey of 14 questions was completed by three classes of PA students at one program. RESULTS: The mean posttest scores were significantly lower on all items except two, indicating that student perceptions of their abilities to serve indigent populations improved after experiencing the curriculum in the PA program. CONCLUSION: A targeted curriculum that emphasizes issues related to poverty appears to improve PA students' perceptions of their ability to serve indigent populations. This program's design could serve as a model for other programs striving to attain similar goals. PMID- 25016911 TI - Growing a diverse health workforce. PMID- 25016910 TI - Knowledge and attitude change in physician assistant students after an interprofessional geriatric care experience: a mixed methods study. AB - PURPOSE: To examine changes in physician assistant (PA) student attitudes and knowledge about interprofessional education (IPE) after participation in a longitudinal community-based curriculum. METHODS: Second-year PA students participated in an interprofessional geriatrics curriculum. Faculty-facilitated IPE teams met three times and assessed one adult patient longitudinally over 8 months. Attitudes of student participants and their nonparticipating peers (comparison group) were assessed pre- and postcurriculum using the validated Readiness for Interprofessional Learning Scale (RIPLS). Reflections submitted by participants after each session were analyzed thematically. RESULTS: No significant differences in RIPLS scores were found compared with baseline for either group; participating students had significantly higher baseline scores compared with nonparticipating students. Qualitative analysis of participant reflections revealed two major themes: "roles and scope of practice of other health professions"; and "applicability of team-based care to practice" with a temporal change in theme pattern over one year. CONCLUSION: Volunteer student participants had a more positive attitude toward interprofessional learning than nonparticipants. Primary learning occurred about roles of other professions and the value of team-based care. The mixed evaluation methodology allowed examination of attitudes, knowledge, and underlying ("informal" or "hidden") learning. PMID- 25016912 TI - Attitudes and beliefs of physician assistant students about advance directives. PMID- 25016913 TI - Piloting a support model for physician assistant students. PMID- 25016914 TI - It's all about the students. PMID- 25016915 TI - Teaching compassion: cinemeducation in physician assistant programs. PMID- 25016916 TI - Active learning strategies in the physician assistant classroom--the critical piece to a successful flipped classroom. PMID- 25016917 TI - Rhodium-catalyzed direct synthesis of unprotected NH-sulfoximines from sulfoxides. AB - A novel rhodium-catalyzed imination of sulfoxides using O-(2,4 dinitrophenyl)hydroxylamine is developed under mild conditions with good functional group tolerance. This method provides an efficient access to free NH sulfoximines, an important structural unit in a variety of biologically active compounds. PMID- 25016918 TI - Nanofibers as novel drug carrier--An overview. AB - Presently polymer nanofibers have received much attention due to their unique properties such as large surface area, high porosity, small pore size, superior mechanical properties and ease of addition of surface functionalities compared with any other material. Nanofibers particularly polymeric nanofiber prepared by electrospinning process can be used as carriers for the controlled drug delivery of bioactive molecules such as cytokines, growth factors, anticancer drugs, enzymes and certain vitamins. This article presents an overview of nanofibers, various techniques involved in fabrication of nanofibers, their characterization, parameters affecting electrospinning process and their applications. PMID- 25016919 TI - Low detection of Vibrio cholerae carriage in healthcare workers returning to 12 Latin American countries from Haiti. AB - SUMMARY This investigation was undertaken to characterize the prevalence of intestinal Vibrio cholerae in healthcare workers (HCWs) returning from Haiti due to the ongoing cholera epidemic. Eight hundred and fifty asymptomatic HCWs of the Cuban Medical Brigade, who planned to leave Haiti, were studied by laboratory screening of stool culture for V. cholerae. A very low percentage (0.23%) of toxigenic V. cholerae serogroup O1, serotype Ogawa was found. To the best of our knowledge, this study represents the largest reported screening study for V. cholerae infection in asymptomatic HCWs returning from a cholera-affected country. Cholera transmission to health personnel highlights a possible risk of transmitting cholera during mobilization of the population for emergency response. Aid workers are encouraged to take precautions to reduce their risk for acquiring cholera and special care should be taken by consuming safe water and food and practising regular hand washing. PMID- 25016920 TI - Pediatric cardiac retransplantation: Waitlist mortality stratified by age and era. AB - BACKGROUND: Waitlist mortality among children listed for primary heart transplant (HTx) has been well characterized, whereas limited data exist for cardiac retransplantation (CRTx) after pediatric primary HTx. We sought to characterize the population listed for CRTx and to determine the factors that affect waitlist mortality. METHODS: All individuals listed for CRTx >1 year after pediatric primary HTx between October 1, 1987, and October 14, 2012 were identified in the Organ Procurement and Transplantation Network database. Baseline characteristics and waitlist mortality were compared between age groups (< 11 years, 11-18 years, and > 18 years) and during 3 successive eras (1987-1999, 1999-2006, and 2006 2012). RESULTS: The cohort comprised 632 patients who were listed for CRTx > 1 year after pediatric primary HTx. Median age was 4 years at primary HTx and 14 years at relisting. Median time from primary HTx to relisting was 7.3 years. Median waiting time was 75.3 days. Overall mortality was 25.2% (159 of 632). The most frequent relisting diagnosis was related to graft vasculopathy (62.5%). The leading causes of death were chronic rejection and vasculopathy (52%). Waitlist mortality significantly decreased after 2006 (31% vs 17%; p < 0.01), despite a relatively constant CRTx rate (67% vs 65%). Univariate analysis showed era, age, listing status, and life support (mechanical circulatory support device, extracorporeal membrane oxygenation, mechanical ventilation) were significant predictors of mortality. Multivariate analyses showed that later era (2006-2012), ages 11 to 18 years, and United Network of Organ Sharing listing status 2 predicted decreased mortality, whereas life support increased mortality. CONCLUSIONS: Waitlist mortality for CRTx in children and young adults has decreased by almost 50% over time. Individuals relisted as adults have increased waitlist mortality. PMID- 25016921 TI - Loss of glucocorticoid receptor from pro-inflammatory T cells after lung transplant. AB - BACKGROUND: Pro-inflammatory cytokines in T and natural killer T (NKT)-like cells increase with time post-transplant in otherwise stable patients, suggesting that some patients become relatively resistant to immunosuppressants such as glucocorticoids (GC). We hypothesized that GC receptor (GCR) would be down regulated in peripheral blood pro-inflammatory T and NKT-like cells after lung transplantation and loss of GCR would correlate with time post-transplant. METHODS: Blood was collected from 17 stable lung transplant patients and 17 healthy, aged-matched controls. Intracellular GCR expression and pro-inflammatory cytokines were determined using flow cytometry. RESULTS: There was a loss of GCR in CD8(+) and CD8(-) T and NKT-like cells in transplant patients compared with control subjects (transplants 37 +/- 9%, controls 47 +/- 12%; GCR(+)CD8(+) and CD8(-) T cells: transplants 39 +/- 13%, controls 58 +/- 13%). Loss of GCR was associated with a greater percentage of T cells producing interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF-alpha) but not NKT-like cells. There was a correlation between the percentage of GCR-negative T cells with months post transplant (R = 0.519, p = 0.033) and dose of prednisolone (R = 0.775, p = 0.038). CONCLUSIONS: Time post-transplant and prednisolone dose correlate with loss of GCR in pro-inflammatory T cells in stable transplant patients, suggesting the need for reassessment of the long-term use of steroids after lung transplant in view of their attendant significant side effects. PMID- 25016922 TI - Safety, feasibility, and effect of remote ischemic conditioning in patients undergoing lung transplantation. AB - BACKGROUND: Primary graft dysfunction (PGD) remains a significant problem after lung transplantation. Data from animal and clinical studies suggest that remote ischemic conditioning (RIC) may reduce ischemia-reperfusion injury in solid organ transplantation. METHODS: A pilot randomized controlled trial of 60 patients undergoing bilateral sequential lung transplantation assessed the utility of RIC in attenuating PGD. Treated recipients underwent 3 cycles of lower limb ischemic conditioning before allograft reperfusion. The primary outcome measure was a comparison of the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (P/F ratio) between treatment groups. RESULTS: No adverse effects of tourniquet application were observed. The mean lowest P/F ratio during the first 24 hours after transplantation was 271.3 mm Hg in the treatment arm vs 256.1 mm Hg in the control arm (p = 0.46). PGD grade and severity and the rate of acute rejection also showed a tendency to favor the treatment arm. Sub-group analysis demonstrated a significant benefit of treatment in patients with a primary diagnosis of restrictive lung disease, a group at high risk for the development of PGD. RIC was not accompanied by systemic release of high-molecular-weight group box 1. Levels of cytokines, high-molecular-weight group box 1, and endogenous secretory receptor for advanced glycation end products peaked within 2 hours after reperfusion and likely reflected donor organ quality rather than an effect of RIC. CONCLUSIONS: RIC did not significantly improve P/F ratios or PGD in this randomized controlled trial. However, encouraging results in this small study warrant a large multicenter trial of RIC in lung transplantation. PMID- 25016923 TI - Packaging biological cargoes in mesoporous materials: opportunities for drug delivery. AB - INTRODUCTION: Confinement of biomolecules in structured nanoporous materials offers several desirable features ranging from chemical and thermal stability, to resistance to degradation from the external environment. A new generation of mesoporous materials presents exciting new possibilities for the formulation and controlled release of biological agents. Such materials address niche applications in enteral and parenteral delivery of biologics, such as peptides, polypeptides, enzymes and proteins for use as therapeutics, imaging agents, biosensors, and adjuvants. AREAS COVERED: Mesoporous silica Santa Barbara Amorphous-15 (SBA-15), with its unique, tunable pore diameter, and easily functionalized surface, provides a representative example of this new generation of materials. Here, we review recent advances in the design and synthesis of nanostructured mesoporous materials, focusing on SBA-15, and highlight opportunities for the delivery of biological agents to various organ and tissue compartments. EXPERT OPINION: The SBA-15 platform provides a delivery carrier that is inherently separated from the active biologic due to distinct intra and extra-particle environments. This permits the SBA-15 platform to not require direct modification of the active biological therapeutic. Additionally, this makes the platform universal and allows for its application independent of the desired methods of discovery and development. The SBA-15 platform also directly addresses issues of targeted delivery and controlled release, although future challenges in the implementation of this platform reside in particle design, biocompatibility, and the tunability of the internal and external material properties. Examples illustrating the flexibility in the application of the SBA 15 platform are also discussed. PMID- 25016924 TI - A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR). METHODS: Women who received >= 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks. RESULTS: Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade >= 3), fatigue (56.7%; 3.3% Grade >= 3), diarrhea (28.3%; 1.7% Grade >= 3), hypertension (25.0%; 3.3% Grade >= 3), and nausea (20.0%; no Grade >= 3). Two patients experienced intestinal perforations (3.3% Grade >= 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2. CONCLUSIONS: Although antitumor activity was observed, the predetermined efficacy endpoints were not met. PMID- 25016925 TI - Endocrine disruptors and human reproductive failure: the in vitro effect of phthalates on human luteal cells. AB - OBJECTIVE: To evaluate the influence of phthalates on human luteal cell function. DESIGN: Laboratory study. SETTING: University hospital. PATIENT(S): Twenty-three normally menstruating patients in the midluteal phase. INTERVENTION(S): Human luteal cells isolated from corpora lutea for primary cultures. MAIN OUTCOME MEASURE(S): Progesterone (P4) and prostaglandin release assayed by enzyme immunoassay, vascular endothelial growth factor (VEGF) secretion by enzyme-linked immunosorbent assay (ELISA), and VEGF mRNA expression by real-time polymerase chain reaction. RESULT(S): We investigated the effect of di(2 ethylhexyl)phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) on basal and hCG-induced progesterone (P4) release, as well as DEHP effect on the balance between prostaglandin (PG) E2, vascular endothelial growth factor (VEGF)-luteotrophic factors, and the luteolitic PGF2alpha in isolated human steroidogenc cells. Phthalates influence on VEGF expression has been also evaluated. DEHP, DBP, and BBP were able to reduce both basal and hCG stimulated P4 as well as PGE2 release. PGF2alpha release was reduced after DEHP incubation. VEGF protein release was decreased by the incubation with the tested phthalates. VEGF mRNA expression was not affected by DEHP, DBP, and BBP. As expected, both hCG and cobalt chloride were able to induce P4 release and VEGF release and mRNA expression in human luteal cells respectively. CONCLUSION(S): The results show the ability of phthalates to affect luteal steroidogenesis as well as the balance between luteotrophic and luteolytic factors suggesting an interference of phthalates in human luteal function. These data may contribute to clarify the classically known impaired reproductive health observed after phthalates exposure. PMID- 25016927 TI - NMR assignment of the amylase-binding protein A from Streptococcus parasanguinis. AB - Streptococcus parasanguinis is a primary colonizer of tooth surfaces in the oral cavity. Amylase-binding protein A (AbpA) from S. parasanguinis is responsible for the recruitment of salivary amylase to bacterial surface, which plays an important role in the development of oral biofilms. Here, we describe the essentially complete NMR assignments for AbpA. PMID- 25016926 TI - Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. AB - OBJECTIVE: To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). DESIGN: Molecular analysis and in vitro experiments correlated with phenotype. SETTING: Academic medical center. PATIENT(S): A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. INTERVENTION(S): GNRHR coding region was amplified and sequenced. MAIN OUTCOME MEASURE(S): Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. RESULT(S): Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. CONCLUSION(S): GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP. PMID- 25016928 TI - Caspase-dependent signaling underlies glioblastoma cell death in response to the fungal metabolite, fusarochromanone. AB - Fungal metabolites continue to show promise as a viable class of anticancer agents. In the present study, we investigated the efficacy of the fungal metabolite, fusarochromanone (FC101), for its antitumor activities in glioblastomas, which have a median survival of less than two years and a poor clinical response to surgical resection, radiation therapy and chemotherapy. Using clinically applicable doses, we demonstrated that FC101 induced glioblastoma apoptotic cell death via caspase dependent signaling, as indicated by the cleavage of poly(ADP-ribose) polymerase, glioblastoma (PARP). FC101 also induced differential reactive oxygen species (ROS) levels in glioblastoma cells, contrasting a defined role of oxidative stress in apoptotic cell death observed with other fungal metabolites. Furthermore, the antitumorigenic effects of FC101 on tumor cell migration were assessed. Cell migration assays revealed that FC101 significantly reduced the migratory capacity of glioblastomas, which are incredibly invasive tumors. Taken together, the present study establishes FC101 as a candidate anticancer agent for the cooperative treatment of glioblastomas. PMID- 25016929 TI - Low-dose clarithromycin therapy modulates Th17 response in non-cystic fibrosis bronchiectasis patients. AB - INTRODUCTION: Th17 cells play a crucial role in neutrophilic inflammation and tissue injury in non-cystic fibrosis (non-CF) bronchiectasis. Clarithromycin demonstrates anti-inflammatory and immunomodulatory properties but the effect of long-term clarithromycin prophylaxis on the Th17 response in non-CF bronchiectasis is still unexplored. METHODS: Th17 response was studied in 22 patients with stable non-CF bronchiectasis receiving daily 500-mg clarithromycin for 12 weeks. We analysed IL-17 concentrations in exhaled breath condensate (EBC) and peripheral blood Th17 cells, whereas functional parameters and clinical data were recorded in parallel. RESULTS: Both, post-treatment absolute counts of CD4+IL17+ cells in peripheral blood and IL-17 levels in EBC decreased significantly (post-treatment CD4+IL17+ mean 2.418 +/- 0.414 cells/MUl versus pre treatment 3.202 +/- 0.507 cells/MUl, p = 0.036 and post-treatment IL-17 mean levels 7.16 +/- 0.47 pg/ml versus pre-treatment 9.32 +/- 0.47 pg/ml, p < 0.001, respectively). Post-treatment EBC IL-17 levels decreased significantly in both patients who exhibited exacerbations and those who remained stable during the study period (mean 6.72 +/- 0.37 versus 9.12 +/- 0.64 pg/ml, p = 0.01 and 7.69 +/ 0.9 versus 9.53 +/- 0.72 pg/ml, p = 0.042, respectively), while pre-treatment and post-treatment levels did not differ between the two groups (p = 0.665 and p = 0.465, respectively). PaO(2) improved significantly (post-treatment mean 77.73 +/- 2.23 mmHg versus pre-treatment 73.18 +/- 2.22 mmHg, p = 0.025), while PaCO(2), post-bronchodilation FEV1, and post-bronchodilation FVC remained unaltered. CONCLUSIONS: Our results argue for a reduction of both systemic and local Th17 response after prophylactic, low-dose clarithromycin administration in patients with non-CF bronchiectasis, suggestive of a potential anti-inflammatory and/or immunomodulatory action. PMID- 25016930 TI - Alterations of retinal vasculature in cystathionine-beta-synthase heterozygous mice: a model of mild to moderate hyperhomocysteinemia. AB - Mild to moderate hyperhomocysteinemia is prevalent in humans and is implicated in neurovascular diseases, including recently in certain retinal diseases. Herein, we used hyperhomocysteinemic mice deficient in the Cbs gene encoding cystathionine-beta-synthase (Cbs(+/-)) to evaluate retinal vascular integrity. The Cbs(+/+) (wild type) and Cbs(+/-) (heterozygous) mice (aged 16 to 52 weeks) were subjected to fluorescein angiography and optical coherence tomography to assess vasculature in vivo. Retinas harvested for cryosectioning or flat mount preparations were subjected to immunofluorescence microscopy to detect blood vessels (isolectin-B4), angiogenesis [anti-vascular endothelial growth factor (VEGF) and anti-CD105], gliosis [anti-glial fibrillary acidic protein (GFAP)], pericytes (anti-neural/glial antigen 2), blood-retinal barrier [anti-zonula occludens protein 1 (ZO-1) and anti-occludin], and hypoxia [anti-pimonidazole hydrochloride (Hypoxyprobe-1)]. Levels of VEGF, GFAP, ZO-1, and occludin were determined by immunoblotting. Results of these analyses showed a mild vascular phenotype in young mice, which progressed with age. Fluorescein angiography revealed progressive neovascularization and vascular leakage in Cbs(+/-) mice; optical coherence tomography confirmed new vessels in the vitreous by 1 year. Immunofluorescence microscopy demonstrated vascular patterns consistent with ischemia, including a capillary-free zone centrally and new vessels with capillary tufts midperipherally in older mice. This was associated with increased VEGF, CD105, and GFAP and decreased ZO-1/occludin levels in the Cbs(+/-) retinas. Retinal vein occlusion was observed in some Cbs(+/-) mouse retinas. We conclude that mild to moderate elevation of homocysteine in Cbs(+/-) mice is accompanied by progressive alterations in retinal vasculature characterized by ischemia, neovascularization, incompetent blood-retinal barrier, and vascular occlusion. PMID- 25016931 TI - Targeting of microglial KCa3.1 channels by TRAM-34 exacerbates hippocampal neurodegeneration and does not affect ictogenesis and epileptogenesis in chronic temporal lobe epilepsy models. AB - Blockade of KCa3.1 channels has been suggested as a novel strategy to reduce microglia activation. The concept has been confirmed by neuroprotective effects in a rat brain ischemia-reperfusion model and reduced microglia activation surrounding glioblastomas. Cumulating evidence exists that microglia activation significantly contributes to epileptogenesis as well as intrinsic severity in the chronic epileptic brain. Taken together these data raised the question whether the KCa3.1 channel blocker triarylmethane-34 (TRAM-34) might also exert beneficial effects in chronic epilepsy models. In a rat post-status epilepticus model TRAM-34 treatment following the insult did not result in neuroprotective effects. Whereas status epilepticus-associated neurodegeneration remained unaffected in the piriform cortex, loss of pyramidal cells in the hippocampal CA1 and CA3a region and of neuropeptide Y-positive interneurons in the hilus proved to be exacerbated by pharmacological KCa3.1 blockade. The development of spontaneous seizures and of behavioral and cognitive alterations was comparable in animals receiving TRAM-34 treatment or the respective vehicle. The kindling model of temporal lobe epilepsy with a massive stimulation paradigm with frequent seizure elicitation in fully kindled rats was used to assess a putative disease modifying effect. However, sub-chronic TRAM-34 treatment failed to exert relevant effects on seizure generation and thresholds. In conclusion, the data obtained in two different chronic epilepsy models argue against using KCa3.1 blockers as disease-modifying or antiepileptogenic agents. Exacerbation of neuronal cell loss in TRAM-34 pre-treated epileptic animals rather indicates that translational development of the compound needs to carefully consider the pathophysiological mechanisms associated with different brain insults. PMID- 25016932 TI - Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma. AB - Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive and chemoresistant tumor with dismal prognosis. Most ATCs harbor mutations that activate RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. Therefore, we investigated and correlated the expression of phosphatase and tensin homolog, pERK, and pAKT proteins as well as mutations of BRAF, RAS, and p53 genes in samples of patients with ATC. Furthermore, we evaluated the potential of inhibition of these pathways on chemosensitization of ATC using 2 thyroid carcinoma cell lines (FRO and SW1736). Our results revealed a negative correlation between the activity of RAS MAPK-ERK and PI3K-AKT-mTOR pathways in samples of patients. To be specific, the PI3K-AKT-mTOR pathway was suppressed in patients with activated NRAS or high pERK expression. In vitro results suggest that the inhibition of either RAS-MAPK-ERK or PI3K-AKT-mTOR components may confer sensitivity of thyroid cancer cells to classic chemotherapeutics. This may form a basis for the development of novel genetic-based therapeutic approach for this cancer type. PMID- 25016933 TI - Renal protein reactivity and stability of antibiotic amphenicols: structure and affinity. AB - In the present work, the molecular recognition of the oldest active amphenicols by the most popular renal carrier, lysozyme, was deciphered by using fluorescence, circular dichroism (CD) and molecular modeling at the molecular scale. Steady state fluorescence data showed that the recognition of amphenicol by lysozyme yields a static type of fluorescence quenching. This corroborates time-resolved fluorescence results that lysozyme-amphenicol adduct formation has a moderate affinity of 10(4) M(-1), and the driving forces were found to be chiefly hydrogen bonds, hydrophobic interactions and pi stacking. Far-UV CD spectra confirmed that the spatial structure of lysozyme was slightly changed with a distinct reduction of alpha-helices in the presence of amphenicol, suggesting partial destabilization of the protein. Furthermore, via the extrinsic 8-anilino-1-naphthalenesulfonic acid fluorescence spectral properties and molecular modeling, one could see that the amphenicol binding site was situated at the deep crevice on the protein surface, and the ligand was also near to several crucial amino acid residues, such as Trp-62, Trp-63 and Arg-73. Simultaneously, contrastive studies of protein-amphenicols revealed clearly that some substituting groups, e.g. nitryl in the molecular structure of ligands, may be vitally important for the recognition activity of amphenicols with lysozyme. Due to the connection of amphenicols with fatal detrimental effects and because lysozyme has been applied as a drug carrier for proximal tubular targeting, the discussion herein is necessary for rational antibiotic use, development of safe antibiotics and particularly a better appraisal of the risks associated with human exposure to toxic agrochemicals. PMID- 25016934 TI - Identifying molecular markers for the sensitive detection of residual atypical teratoid rhabdoid tumor cells. AB - Atypical teratoid rhabdoid tumor (AT/RT), a rare and highly malignant tumor entity of the central nervous system that presents in early childhood, has a poor prognosis. AT/RTs are characterized by biallelic inactivating mutations of the gene SMARCB1 in 98% of patients; these mutations may serve as molecular markers for residual tumor cell detection in liquid biopsies. We developed a marker specific method to detect residual AT/RT cells. Seven of 150 patient samples were selected, each with a histological and genetically ascertained diagnosis of AT/RT. Tumor tissue was either formalin fixed or fresh frozen. DNA was extracted from the patients' peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF). Multiplex ligation-dependent probe amplification, DNA sequencing, and fluorescence in situ hybridization were used to characterize the tumors' mutations. Residual tumor cell detection used mutation-specific primers and real time PCR. The detection limit for the residual tumor cell search was 1-18%, depending on the quality of the template provided. The residual tumor cell search in PBL and CSF was negative for all seven patients. The SMARCB1 region of chromosome 22 is prone to DNA double-strand breaks. The individual breakpoints and breakpoint-specific PCR offer the option to detect minimal residual tumor cells in CSF or blood. Even if we did not detect minimal residual tumor cells in the investigated material, proof of principle for this method was confirmed. PMID- 25016935 TI - Influence of short term exposure of TBT on the male reproductive activity in freshwater prawn Macrobrachium rosenbergii (De Man). AB - In the present study, the effect of tributyltin (TBT) on the histopathological and hormonal changes during spermatogenesis in freshwater prawn Macrobrachium rosenbergii was documented. Three experimental concentrations such as 10, 100 and 1,000 ng/L were selected and exposed to prawns for 45 days. After TBT exposure, the reproductive activities like sperm count and sperm length were decreased when compared with control. Further, abnormal structure of the seminiferous tubule, decrease in spermatozoa concentration, diminution of the seminiferous tubule membrane and the abundance of spermatocytes in the testis were noticed in treated prawns. Interestingly, radioimmunoassay clearly revealed the reduction of testosterone level in TBT exposed groups. Thus, TBT has considerably reduced the level of testosterone and caused the impairment of spermatogenesis in the freshwater male prawn M. rosenbergii. PMID- 25016937 TI - An index based on the biodiversity of cetacean species to assess the environmental status of marine ecosystems. AB - The Marine Strategy Framework Directive (MSFD) requires the assessment of the environmental status in relation to human pressures. In this study the biodiversity of the cetacean community is proposed as MSFD descriptor of the environmental status and its link with anthropogenic pressures is investigated. Functional groups are generally favoured over indicator species since they are thought to better reflect to anthropogenic stressors. Cetaceans are in many situations the most well known component of pelagic ecosystems. Their habitat requirements are known and can be used to evaluate the theoretical biodiversity that should be expected in a certain area. The deviations between the theoretical biodiversity and the actual biodiversity may be used to detect the impacts of human activities. Based on this analysis fishery resulted to be by far the most significant of the existing pressures. Among all the species, bottlenose dolphin was found the most correlated with the fishery sector dynamics. PMID- 25016936 TI - A comparative study of oxygen diffusion in tissue engineering scaffolds. AB - Tissue engineering scaffolds are designed to support tissue self-healing within physiological environments by promoting the attachment, growth and differentiation of relevant cells. Newly formed tissue must be supplied with sufficient levels of oxygen to prevent necrosis. Oxygen diffusion is the major transport mechanism before vascularization is completed and oxygen is predominantly supplied via blood vessels. The present study compares different designs for scaffolds in the context of their oxygen diffusion ability. In all cases, oxygen diffusion is confined to the scaffold pores that are assumed to be completely occupied by newly formed tissue. The solid phase of the scaffolds acts as diffusion barrier that locally inhibits oxygen diffusion, i.e. no oxygen passes through the scaffold material. As a result, the oxygen diffusivity is determined by the scaffold porosity and pore architecture. Lattice Monte Carlo simulations are performed to compare the normalized oxygen diffusivities in scaffolds obtained by the foam replication (FR) method, robocasting and sol-gel foaming. Scaffolds made by the FR method were found to have the highest oxygen diffusivity due to their high porosity and interconnected pores. These structures enable the best oxygen supply for newly formed tissue among the scaffold types considered according to the present numerical predictions. PMID- 25016938 TI - Absorption of metals in mulloway (Argyrosomus japonicus) after ingesting nickel plated carbon-steel hooks. AB - Previous research has alluded to the potential of metals being absorbed by fish after ingesting fishing hooks, which may have adverse effects on fish health and the organisms that consume them. Subsequently, this study aimed to quantify the potential of mulloway (Argyrosomus japonicus) to absorb metals during the decay of ingested nickel-plated carbon-steel hooks. Twenty-five treatment fish were allowed to ingest nickel-plated carbon-steel hooks during angling and then monitored with 25 controls (untreated fish) for up to 42 days for hook ejection and mortality. Blood, liver and muscle samples were collected from treatment, control and 14 wild-caught individuals to determine the concentrations of chromium, cobalt, copper, iron, manganese and nickel. The results showed that increased oxidation influenced hook ejection, and that hook-ingested fish had significantly elevated concentrations of nickel in their liver and blood, but not muscle. This research has shown that there is an avenue for metal absorption from ingested hooks. PMID- 25016939 TI - [Morel-Lavallee seroma]. PMID- 25016940 TI - [Casual diagnosis of Gitelman's syndrome]. AB - Gitelman's syndrome is a renal tubule disease of recessive autosomal inheritance in which the fundamental alteration is found in the distal tubule, specifically at the level of the Na/Cl cotransporter, is sensitive to thiazides, and coded in chromosome 16q. It is characterised by a metabolic alkalosis with normal blood pressure, hypokalaemia, as well as hypomagnesaemia and hypocalciuria, which separate it from Bartter's syndrome. Its diagnosis can be delayed up to the adult age, as patients may remain asymptomatic for long periods of time. The treatment consists of oral supplements of potassium and magnesium, and the use of potassium sparing diuretics and indomethacin has also been described. PMID- 25016941 TI - [Perifollicular purpura and "corkscrew" hair as manifestations of scurvy]. PMID- 25016942 TI - [A fever that exposed: presentation of 2 cases of Brugada syndrome]. PMID- 25016943 TI - [What do type II diabetics know about cardiovascular risk factors? Relationship with the level of control of these factors]. PMID- 25016944 TI - [Annular lesion of centrifugal growth]. PMID- 25016945 TI - [Prescription appropriateness: Indication of citicoline in Primary Care]. AB - INTRODUCTION: The economic situation has made it necessary to optimize resources by adjusting the pharmaceutical expenditure. Citicoline was (2011) the 10th drug by rank of billed amount. Its approved indications are stroke (acute and sub acute) and head injury, but not cognitive decline associated with age, the presumed indication for most of its use. OBJECTIVES: To assess the conditions of use of citicoline in the Health Area of Tenerife, in order to detect deviations from the indications of use as stipulated in the prescribing information sheet and the pattern of prescription, with emphasis on the analysis of its use in dementia where currently it has no indication or evidence to support it. METHOD: Cross-sectional study of prescription-indication. A 680 patient sample, segmented by reference hospital (error+/-5%; CI: 0.95%; P=0.5) was taken from the 4036 patients with a prescription of citicoline billed during august-october 2011 (obtained from the prescription database program, Farmacanarias). RESULTS: We found that 123 patients (18.1%) had an appropriate indication. By including the prescription regimen, 28 patients (4.1%) had adequate indication and dose levels, and in only 2 patients (0.2%) an appropriate indication, dosage and duration were found. CONCLUSIONS: "The correct prescription-indication" of citicoline is inappropiate in almost all patients studied. Impact actions are needed in order to optimize prescription, improve patient safety by reducing potential interactions, and the occurrence of adverse effects, and improve efficiency by promoting savings. PMID- 25016946 TI - Toward core inter-professional health promotion competencies to address the non communicable diseases and their risk factors through knowledge translation: curriculum content assessment. AB - BACKGROUND: To increase the global impact of health promotion related to non communicable diseases, health professionals need evidence-based core competencies in health assessment and lifestyle behavior change. Assessment of health promotion curricula by health professional programs is a first step. Such program assessment is a means of 1. demonstrating collective commitment across health professionals to prevent non-communicable diseases; 2. addressing the knowledge translation gap between what is known about non-communicable diseases and their risk factors consistent with 'best' practice; and, 3. establishing core health based competencies in the entry-level curricula of established health professions. DISCUSSION: Consistent with the World Health Organization's definition of health (i.e., physical, emotional and social wellbeing) and the Ottawa Charter, health promotion competencies are those that support health rather than reduce signs and symptoms primarily. A process algorithm to guide the implementation of health promotion competencies by health professionals is described. The algorithm outlines steps from the initial assessment of a patient's/client's health and the indications for health behavior change, to the determination of whether that health professional assumes primary responsibility for implementing health behavior change interventions or refers the patient/client to others.An evidence-based template for assessment of the health promotion curriculum content of health professional education programs is outlined. It includes clinically-relevant behavior change theory; health assessment/examination tools; and health behavior change strategies/interventions that can be readily integrated into health professionals' practices. SUMMARY: Assessment of the curricula in health professional education programs with respect to health promotion competencies is a compelling and potentially cost effective initial means of preventing and reversing non-communicable diseases. Learning evidence-based health promotion competencies within an inter professional context would help students maximize use of non-pharmacologic/non surgical approaches and the contribution of each member of the health team. Such a unified approach would lead patients/clients to expect their health professionals to assess their health and lifestyle practices, and empower and support them in achieving lifelong health. Benefits of such curriculum assessment include a basis for reflection and discussion within and across health professional programs that could impact the epidemic of non-communicable diseases globally, through inter-professional education and evidence-based practice related to health promotion. PMID- 25016947 TI - Occupational safety issues in residential construction surveyed in Wisconsin, United States. AB - Residential construction is a high-risk industry in the U.S. due to the exposure to work-related safety hazards and fall injuries. This study aimed to examine the safety training and safe work practices of construction workers within the small residential construction industry. In order to achieve the study objectives, a survey was designed and sent to approximately 200 Wisconsin based residential construction contractors. About one third of the respondents stated that they did not have any form of safety programs. The study indicated that the most common types of work-related injuries in residential construction were slips/trips/falls and cuts/lacerations. The survey findings also suggested that the residential construction contractors needed to increase the utilization of fall protection safety equipment. Further education and subject matter expert training could provide benefits to improve occupational safety and health of the small business workforce in the residential construction industry. PMID- 25016948 TI - Job demands, job resources, and job performance in japanese workers: a cross sectional study. AB - This study investigated the cross-sectional association of job demands (i.e., psychological demands) and job resources (i.e., decision latitude, supervisor support, co-worker support, and extrinsic reward) with job performance. A total of 1,198 workers (458 males and 740 females) from a manufacturing company in Japan completed a self-administered questionnaire that included the Job Content Questionnaire, Effort-Reward Imbalance Questionnaire, World Health Organization Health and Work Performance Questionnaire, and demographic survey. Hierarchical multiple regression analyses were conducted. After adjusting for demographic characteristics, decision latitude (beta=0.107, p=0.001) and extrinsic reward (beta=0.158, p<0.001) were positively and significantly associated with job performance while supervisor support (beta=-0.102, p=0.002) was negatively and significantly associated with job performance. On the other hand, psychological demands or co-worker support was not significantly associated with job performance. These findings suggest that higher decision latitude and extrinsic reward enhance job performance among Japanese employees. PMID- 25016949 TI - Combination of microtubule associated protein-tau and beta-tubulin III predicts chemosensitivity of paclitaxel in patients with advanced gastric cancer. AB - AIM: To investigate the role of microtubule associated protein-tau (MAP-tau) and beta-tubulin III (TUBB3) in predicting the chemosensitivity of paclitaxel in patients with advanced gastric cancer (GC). METHODS: MAP-tau and TUBB3 expressions were detected using immunohistochemistry in 244 advanced GC patients prior to chemotherapy. The associations of MAP-tau and TUBB3 expressions with paclitaxel sensitivity were assessed using in vitro and in vivo xenograft analysis. RESULTS: A total of 149 patients receiving paclitaxel plus capecitabine (cohort 1) and 95 patients receiving cisplatin plus capecitabine (cohort 2) were included in this study. In cohort 1, the clinical benefit rate (CBR), median progression-free survival (PFS) and overall survival (OS) were found to be significantly higher in patients with low levels of MAP-tau and TUBB3 expressions and were significantly higher than those in patients with high levels of MAP-tau and TUBB3 expressions (CBR: 72.2% versus 35.9%; PFS: 271 versus 102 days; OS: 394 versus 173 days; all P<0.05). This was not observed in cohort 2. In in vitro studies, the sensitivity of paclitaxel in human gastric cancer cells was inversely correlated with the expression levels of MAP-tau and TUBB3, as in in vivo animal xenografts. CONCLUSIONS: The combination of MAP-tau and TUBB3 was found to predict chemosensitivity to paclitaxel in gastric cancer in vitro and in vivo. This merits further study and may help guide individual therapy. PMID- 25016950 TI - Employment and educational outcomes in early intervention programmes for early psychosis: a systematic review. AB - AIMS: Young adults with early psychosis want to pursue normal roles - education and employment. This paper summarises the empirical literature on the effectiveness of early intervention programmes for employment and education outcomes. METHODS: We conducted a systematic review of employment/education outcomes for early intervention programmes, distinguishing three programme types: (1) those providing supported employment, (2) those providing unspecified vocational services and (3) those without vocational services. We summarised findings for 28 studies. RESULTS: Eleven studies evaluated early intervention programmes providing supported employment. In eight studies that reported employment outcomes separately from education outcomes, the employment rate during follow-up for supported employment patients was 49%, compared with 29% for patients receiving usual services. The two groups did not differ on enrolment in education. In four controlled studies, meta-analysis showed that the employment rate for supported employment participants was significantly higher than for control participants, odds ratio = 3.66 [1.93-6.93], p < 0.0001. Five studies (four descriptive and one quasi-experimental) of early intervention programmes evaluating unspecified vocational services were inconclusive. Twelve studies of early intervention programmes without vocational services were methodologically heterogeneous, using diverse methods for evaluating vocational/educational outcomes and precluding a satisfactory meta-analytic synthesis. Among studies with comparison groups, 7 of 11 (64%) reported significant vocational/education outcomes favouring early intervention over usual services. CONCLUSIONS: In early intervention programmes, supported employment moderately increases employment rates but not rates of enrolment in education. These improvements are in addition to the modest effects early programmes alone have on vocational/educational outcomes compared with usual services. PMID- 25016951 TI - Norcassane- and cassane-type furanoditerpenoids from the seeds of Caesalpinia sappan. AB - Three novel furanoditerpenoids, norcaesalpinin J (1) featuring an unusual 20 norcassane hydroperoxide and phangininoxys B (2) and C (3) possessing cassane hemiketal skeletons, were isolated from the seeds of Caesalpinia sappan. Their structures were elucidated by extensive spectroscopic methods. All isolates were evaluated for the cytotoxic activities on three human cancer cell lines. PMID- 25016952 TI - Iridoid glycosides isolated from Scrophularia dentata Royle ex Benth. and their anti-inflammatory activity. AB - Scrodentosides A-E (1-5), five new acylated iridoid glycosides, together with 19 known ones, were isolated from the whole plant of Scrophularia dentata Royle ex Benth. The structures of these isolated glycosides were elucidated by spectroscopic methods. Bioassay showed that compounds 7 and 11 had significant inhibitory effect against NF-kappaB activation with IC50 value of 43.7 MUM and 1.02 MUM respectively. PMID- 25016953 TI - The value of nature's natural product library for the discovery of New Chemical Entities: the discovery of ingenol mebutate. AB - In recent decades, 'Big Pharma' has invested billions of dollars into ingenious and innovative strategies designed to develop drugs using high throughput screening of small molecule libraries generated on the laboratory bench. Within the same time frame, screening of natural products by pharmaceutical companies has suffered an equally significant reduction. This is despite the fact that the complexity, functional diversity and druggability of nature's natural product library are considered by many to be superior to any library any team of scientists can prepare. It is therefore no coincidence that the number of New Chemical Entities reaching the market has also suffered a substantial decrease, leading to a productivity crisis within the pharmaceutical sector. In fact, the current dearth of New Chemical Entities reaching the market in recent decades might be a direct consequence of the strategic decision to move away from screening of natural products. Nearly 700 novel drugs derived from natural product New Chemical Entities were approved between 1981 and 2010; more than 60% of all approved drugs over the same time. In this review, we use the example of ingenol mebutate, a natural product identified from Euphorbia peplus and later approved as a therapy for actinic keratosis, as why nature's natural product library remains the most valuable library for discovery of New Chemical Entities and of novel drug candidates. PMID- 25016954 TI - Assay development for the discovery of semaphorin 3B inducing agents from natural product sources. AB - Semaphorins are a class of membrane-bound and secreted proteins. They have been found to regulate basic cell functions such as axonal growth cone guidance and recent studies have focused on their effect on tumor progression. Semaphorin 3B (Sema3B) particularly is a secreted protein that has been known to modulate proliferation and apoptosis, processes that are critical for tumor progression and development. In spite of its importance, there is yet no high-throughput screening assay available to detect or quantify the expression of Sema3B for natural product anticancer drug discovery purposes. Therefore, the development of a new high-throughput bioassay for the discovery of Sema3B inducing agents from natural product sources is described herein. A wide variety of pure compounds and extracts from plants and microorganisms has been found suitable for screening using this Sema3B assay to detect and quantify the effect of Sema3B inducing agents and thereby identify new selective bioactive Sema3B lead compounds for anticancer drug discovery and development. Also, this new bioassay procedure is based on a high-throughput platform using an enzyme-linked immunosorbent assay that involves the optimization of sensitivity and selectivity levels as well as accuracy, reproducibility, robustness, and cost effectiveness. PMID- 25016955 TI - Thermal stability of ginkgolic acids from Ginkgo biloba and the effects of ginkgol C17:1 on the apoptosis and migration of SMMC7721 cells. AB - Ginkgolic acids are alkylsalicylic acid derivatives with a thermolabile carboxylic group from Ginkgo biloba L., and they exhibit anticancer activity. Their anticancer effects are closely associated with their thermal stability. In this study, the thermal decomposition of ginkgolic acids was analyzed at temperatures of 30, 50, 70 and 250 degrees C. The results clearly showed that an obvious slow decarboxylation of the ginkgolic acids was detected at 70 degrees C. When the temperature increased to 250 degrees C, the decarboxylation reaction was rapidly completed. The ginkgolic acids were decarboxylated to yield ginkgols. The ginkgols C13:0, C15:1 and C17:1 were separated and definitively identified by IR, NMR and GC-MS. The cytotoxic effects of ginkgols C13:0, C15:1 and C17:1 were tested and compared with those of the corresponding ginkgolic acids. An MTT assay showed that ginkgol C17:1 (48-h IC50=8.5 MUg.ml(-1)) has the strongest inhibition on SMMC-7721 cells in a dose- and time-dependent manner. The anticancer action may occur via the induction of apoptosis by the activation of caspases-3, the upregulation of Bax expression, and the inhibition migration of SMMC7721 cells. The results indicated that ginkgol C17:1 might be useful for the further development of a hepatocellular carcinoma preventive agent. PMID- 25016956 TI - Literature-based biomedical image classification and retrieval. AB - Literature-based image informatics techniques are essential for managing the rapidly increasing volume of information in the biomedical domain. Compound figure separation, modality classification, and image retrieval are three related tasks useful for enabling efficient access to the most relevant images contained in the literature. In this article, we describe approaches to these tasks and the evaluation of our methods as part of the 2013 medical track of ImageCLEF. In performing each of these tasks, the textual and visual features used to represent images are an important consideration often left unaddressed. Therefore, we also describe a gradient-based optimization strategy for determining meaningful combinations of features and apply the method to the image retrieval task. An evaluation of our optimization strategy indicates the method is capable of producing statistically significant improvements in retrieval performance. Furthermore, the results of the 2013 ImageCLEF evaluation demonstrate the effectiveness of our techniques. In particular, our text-based and mixed image retrieval methods ranked first among all the participating groups. PMID- 25016957 TI - A fast schema for parameter estimation in diffusion kurtosis imaging. AB - Diffusion kurtosis imaging (DKI) is a new model in magnetic resonance imaging (MRI) characterizing restricted diffusion of water molecules in living tissues. We propose a method for fast estimation of the DKI parameters. These parameters - apparent diffusion coefficient (ADC) and apparent kurtosis coefficient (AKC) - are evaluated using an alternative iteration schema (AIS). This schema first roughly estimates a pair of ADC and AKC values from a subset of the DKI data acquired at 3 b-values. It then iteratively and alternately updates the ADC and AKC until they are converged. This approach employs the technique of linear least square fitting to minimize estimation error in each iteration. In addition to the common physical and biological constrains that set the upper and lower boundaries of the ADC and AKC values, we use a smoothing procedure to ensure that estimation is robust. Quantitative comparisons between our AIS methods and the conventional methods of unconstrained nonlinear least square (UNLS) using both synthetic and real data showed that our unconstrained AIS method can significantly accelerate the estimation procedure without compromising its accuracy, with the computational time for a DKI dataset successfully reduced to only 1 or 2min. Moreover, the incorporation of the smoothing procedure using one of our AIS methods can significantly enhance the contrast of AKC maps and greatly improve the visibility of details in fine structures. PMID- 25016958 TI - The preparation of graft copolymers of cellulose and cellulose derivatives using ATRP under homogeneous reaction conditions. AB - In this comprehensive review, we report on the preparation of graft-copolymers of cellulose and cellulose derivatives using atom transfer radical polymerization (ATRP) under homogeneous conditions. The review is divided into four sections according to the cellulosic material that is graft-copolymerised; (i) cellulose, (ii) ethyl cellulose, (iii) hydroxypropyl cellulose and (iv) other cellulose derivatives. In each section, the grafted synthetic polymers are described as well as the methods used for ATRP macro-initiator formation and graft copolymerisation. The physical properties of the graft-copolymers including their self-assembly in solution into nanostructures and their stimuli responsive behaviour are described. Potential applications of the self-assembled graft copolymers in areas such as nanocontainers for drug delivery are outlined. PMID- 25016960 TI - Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache. AB - The primary aim of this study (TA-CH, Tryptophan Amine in Chronic Headache) was to investigate a possible role of tryptophan (TRP) metabolism in chronic migraine (CM) and chronic tension-type headache (CTTH). It is not known if TRP metabolism plays any role in CM and/or CTTH. Plasma levels of serotonin (5-HT), 5 hydroxyindolacetic acid (5-HIAA), metabolite of 5-HT, and tryptamine (TRY) were tested in 73 patients with CM, 15 patients with CTTH and 37 control subjects. Of these, plasmatic TRY was significantly lower in CM (p < 0.001) and in CTTH (p < 0.002) patients with respect to control subjects, while 5-HIAA levels in plasma were within the same range in all groups. 5-HT was undetectable in the plasma of almost all subjects. Our results support the hypothesis that TRP metabolism is altered in CM and CTTH patients, leading to a reduction in plasma TRY. As TRY modulates the function of pain matrix serotonergic system, this may affect modulation of incoming nociceptive inputs from the trigeminal endings and posterior horns of the spinal cord. We suggest that these biochemical abnormalities play a role in the chronicity of CM and CTTH. PMID- 25016959 TI - Par3-mInsc and Galphai3 cooperate to promote oriented epidermal cell divisions through LGN. AB - Asymmetric cell divisions allow stem cells to balance proliferation and differentiation. During embryogenesis, murine epidermis expands rapidly from a single layer of unspecified basal layer progenitors to a stratified, differentiated epithelium. Morphogenesis involves perpendicular (asymmetric) divisions and the spindle orientation protein LGN, but little is known about how the apical localization of LGN is regulated. Here, we combine conventional genetics and lentiviral-mediated in vivo RNAi to explore the functions of the LGN interacting proteins Par3, mInsc and Galphai3. Whereas loss of each gene alone leads to randomized division angles, combined loss of Gnai3 and mInsc causes a phenotype of mostly planar divisions, akin to loss of LGN. These findings lend experimental support for the hitherto untested model that Par3-mInsc and Galphai3 act cooperatively to polarize LGN and promote perpendicular divisions. Finally, we uncover a developmental switch between delamination-driven early stratification and spindle-orientation-dependent differentiation that occurs around E15, revealing a two-step mechanism underlying epidermal maturation. PMID- 25016961 TI - Association between angiotensin converting enzyme gene insertion/deletion polymorphism and intracerebral haemorrhage in North Indian population: a case control study and meta-analysis. AB - The purpose of this study was to determine the relationship between Angiotensin converting enzyme (ACE) insertion/deletion polymorphism and ICH with an ACE level in a North Indian population. Patient with ICH and age- and sex- matched control subjects were recruited. Case control study design was used. Genotyping was performed by using Polymerase chain reaction. Serum ACE levels were measured by colorimetric method. Our results were integrated with other reported studies across different countries in a meta-analysis. One hundred and six patients with ICH and 106 age- and sex- matched control subjects were recruited. Mean age of cases and control subjects were 53.4 +/- 1 and 52.9 +/- 13.4, respectively. The DD genotypes were more frequency distributed in cases compared with controls (OR 2; 95 % CI, 1.02-3.8, P = 0.04) under a recessive model of inheritance. Meta analysis suggests significant association between ACE I/D polymorphism and risk of ICH (OR 1.98; 95 % CI, 1.53-2.57) under the recessive model of inheritance and under the dominant model of inheritance (OR 1.31; 95 % CI, 1.18-1.45). The findings of the present study show a significant association between ACE insertion/deletion polymorphism and ICH. Meta-analysis indicate that ACE I/D polymorphism may be a susceptible marker for risk factor of ICH in Asian population. PMID- 25016962 TI - The temporal and spatial development of vascularity in a healing displaced fracture. AB - Underlying vascular disease is an important pathophysiologic factor shared among many co-morbid conditions associated with poor fracture healing, such as diabetes, obesity, and age. Determining the temporal and spatial patterns of revascularization following a fracture is essential for devising therapeutic strategies to augment this critical reparative process. Seminal studies conducted in the last century have investigated the pattern of vascularity in bone following a fracture. The consensus model culminating from these classical studies depicts a combination of angiogenesis emanating from both the intact intramedullary and periosteal vasculature. Subsequent to the plethora of experimental fracture angiography in the early to mid-20th century there has been a paucity of reports describing the pattern of revascularization of a healing fracture. Consequently the classical model of revascularization of a displaced fracture has remained largely unchanged. Here, we have overcome the limitations of animal fracture models performed in the above described classical studies by combining novel techniques of bone angiography and a reproducible murine femur fracture model to demonstrate for the first time the complete temporal and spatial pattern of revascularization in a displaced/stabilized fracture. These studies were designed specifically to i) validate the classical model of fracture revascularization of a displaced/stabilized fracture, ii) assess the association between intramedullary and periosteal angiogenesis and iii) elucidate the expression of VEGF/VEGF-R in relation to the classical model. From the studies, in conjunction with classic studies of angiogenesis during fracture repair, we propose a novel model (see abstract graphic) that defines the process of bone revascularization subsequent to injury to guide future approaches to enhance fracture healing. This new model validates and advances the classical model by providing evidence that during the process of revascularization of a displaced fracture 1) periosteal angiogenesis occurs in direct communication with the remaining intact intramedullary vasculature as a result of a vascular shunt and 2) vascular union occurs through an intricate interplay between intramembranous and endochondral VEGF/VEGF-R mediated angiogenesis. PMID- 25016963 TI - Outcome of glucose homeostasis in patients with glucocorticoid-induced osteoporosis undergoing treatment with bone active-drugs. AB - Over the last few years, there has been experimental evidence for the existence of cross-talking between bone remodeling and glucose metabolism. Whether this experimental model can be translated to humans is still debated, and it is also unclear whether the modulation of bone turnover by anti-osteoporotic drugs may lead to changes in glucose metabolism. The aim of this 12-month prospective study was to investigate whether treatment of glucocorticoid-induced osteoporosis (GIO) with bipshosphonates or teriparatide may influence serum glycated hemoglobin (HbA1c) and fasting plasma glucose. One-hundred-eleven patients (70 F, 41 M, median age 70, range: 55-89) chronically treated with glucocorticoids were evaluated for changes in serum HbA1c and fasting plasma glucose during treatment with bisphosphonates (45 cases) or teriparatide (33 cases) as compared to those occurring during treatment with calcium and vitamin D alone (33 cases). In patients treated with teriparatide, but not in those treated with bisphosphonates or calcium and vitamin D alone, a statistically significant (p=0.01) decrease in serum HbA1c was observed during the follow-up, the change being greater (p=0.01) in patients with diabetes as compared to those without diabetes. In most cases, the decrease of serum HbA1c was relatively limited and in some patients the improvement of glucose homeostasis was concomitant with implementation of anti diabetic treatments. Fasting plasma glucose did not change significantly during either bisphosphonates or teriparatide treatments. In conclusion, currently used bone active drugs may produce limited effects on glucose metabolism in patients with GIO. Interestingly, the bone anabolic drug teriparatide was shown to be associated with some improvement in serum HbA1c in this clinical context. PMID- 25016964 TI - Osteonecrosis repair with bone marrow cell therapies: state of the clinical art. AB - INTRODUCTION: Hip osteonecrosis is a pathological condition resulting from cellular impairment due to reduction in osteoblast activity and local mesenchymal stem cell populations. Cell-based therapies might aid in overcoming these deficiencies by providing stem cells and other progenitor cells to potentially improve the local cellular environment in the affected hip. METHODS: A PubMed search, using the search terms "hip osteonecrosis" and "mesenchymal stem cells", was conducted in December 2013. A total of 15 publications were identified and reviewed for clinical outcomes. FINDINGS: Clinical studies of patients with osteonecrosis treated with mesenchymal stem cells showed beneficial effects. No unexpected adverse events were identified in these studies. Core decompression was the usual method for autologous bone marrow cell implantation into the femoral head. However, other methods have been used such as arterial or venous delivery. A rationale for the use of cytotherapy, as well as the different descriptions of the techniques of implantation MSCs (autologous vs. allogenic, concentration vs. expansion), is provided in the context of treating hip osteonecrosis. Current problems and future challenges with cytotherapy and associated techniques are discussed. This article is part of a Special Issue entitled "Stem Cells and Bones". PMID- 25016966 TI - The effect of heat treatment of thylakoids on their ability to inhibit in vitro lipase/co-lipase activity. AB - Thylakoids has been shown to prolong lipolysis by the inhibition of lipase/co lipase, which makes thylakoids suitable as a functional food ingredient with satiating properties. The components of thylakoids that provide its function as a lipolysis modulator are primarily photosystems I and II, which are structurally stabilised by chlorophyll. However, chlorophyll is known to be heat sensitive yet the enzymatic inhibiting capacity after heat treatment has not been previously studied. It was hypothesised that the retained function of thylakoids after heat treatment could be correlated to the degree of degradation. Heat treatment at either 60 degrees C, 75 degrees C or 90 degrees C for time interval ranging from 15 s to 120 min induced a color shift from bright green to olive brown which was attributed to degradation. The ability of heat-treated thylakoids to inhibit lipolysis in vitro was also reduced. A correlation between chlorophyll a degradation and the enzymatic inhibiting capacity could be established which opens possibilities to use a spectrophotometric method to quantify the ability of thylakoids to inhibit lipase/co-lipase in a more rapid and cost effective way to complement the pH-stat method used today. With the degradation pattern investigated, it is then possible to design a thermal treatment process to ensure a microbiological safe appetite-reducing product and at the same time minimize the loss of functionality. PMID- 25016965 TI - Effect of sequential treatments with alendronate, parathyroid hormone (1-34) and raloxifene on cortical bone mass and strength in ovariectomized rats. AB - Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. METHODS: Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. RESULTS: Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. SUMMARY: Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent. PMID- 25016967 TI - Use of neutrophil gelatinase-associated lipocalin (NGAL) in CF. PMID- 25016968 TI - Translocation of cell-penetrating peptides across the plasma membrane is controlled by cholesterol and microenvironment created by membranous proteins. AB - Despite the extensive research in the field of CPPs' cell entry the exact mechanisms underlying their cellular uptake and the role of involved cell surface molecules in the internalization process have remained controversial. The present study focused on the interactions between CPPs and plasma membrane compounds using giant plasma membrane vesicles (GPMVs). GPMVs have shown to be a suitable model to study the translocation of CPPs across the plasma membrane in conditions lacking endocytosis. Our results show that higher cholesterol content and tighter packing of membrane predominantly reduce the accumulation of transportan, TP10 and model amphipathic peptide (MAP) in vesicles, indicating that the internalization of CPPs takes place preferentially via the more dynamic membrane regions. The partial digestion of membrane proteins from GPMVs' surface, on the other hand, drastically reduced the accumulation of nona-arginine and Tat peptide into vesicles, suggesting that proteins play a crucial role in the uptake of arginine-rich CPPs. PMID- 25016970 TI - Assessment of anti-amyloidogenic activity of marine red alga G. acerosa against Alzheimer's beta-amyloid peptide 25-35. AB - OBJECTIVE: The amyloid hypothesis stimulates the discovery of compounds, which promotes beta-amyloid peptide (Abeta) clearance, thereby altering the underlying pathophysiology of Alzheimer's disease (AD). Hence, the present study aims at the evaluation of anti-amyloidogenic potential of Gelidiella acerosa. METHODS: Prevention of Abeta 25-35 aggregate formation and disaggregation of pre-formed fibrils by G. acerosa was evaluated in three phases by thioflavin T spectrophotometric assay. The results were further validated by confocal microscopic analysis. The conformational changes in the aggregated and non aggregated Abeta in the presence of G. acerosa were analyzed by Fourier transform infrared (FTIR) spectroscopic analysis. RESULTS: Phase-I study shows that G. acerosa reverts (4.56 +/- 0.35 AU at 96 hours) the increase in fluorescence intensity of aggregated Abeta (18.76 +/- 0.99 AU) significantly (P < 0.05) as that of non-aggregated peptides, which suggests that G. acerosa prevents the formation of oligomers from monomers. The seaweed also prevents the fibril formation even after the aggregation process was initiated at 20 hours, which was verified by the significant (P < 0.05) decrease in the fluorescence intensity (2.94 +/- 0.0721 AU) at 36 hours (Phase II). In addition, G. acerosa promotes fibrillar destabilization (Phase III), which was further substantiated by confocal microscopic analysis. Fourier transform infrared spectroscopy reveals that alteration in amide I and amide II band spectrum, which occurs due to Abeta 25-35 aggregation was restored upon co-treatment with G. acerosa benzene extract. CONCLUSION: Overall, the results suggest that G. acerosa might have direct interaction with the aggregated peptide, thereby preventing oligomerization and fibrillation of Abeta 25-35. PMID- 25016971 TI - Validity of predictive equations for resting energy expenditure according to the body mass index in a population of 1726 patients followed in a Nutrition Unit. AB - BACKGROUND & AIMS: The resting energy expenditure (REE) predictive formulas are often used in clinical practice to adapt the nutritional intake of patients or to compare to REE measured by indirect calorimetry. We aimed to evaluate which predictive equations was the best alternative to REE measurements according to the BMI. METHODS: 28 REE prediction equations were studied in a population of 1726 patients without acute or chronic high-grade inflammatory diseases followed in a Nutrition Unit for malnutrition, eating disorders or obesity. REE was measured by indirect calorimetry for 30 min after a fasting period of 12 h. Some formulas requiring fat mass and free-fat mass, body composition was measured by bioelectrical impedance analysis. The percentage of accurate prediction (+/ 10%/REE measured) and Pearson r correlations were calculated. RESULTS: Original Harris & Benedict equation provided 73.0% of accurate predictions in normal BMI group but only 39.3% and 62.4% in patients with BMI < 16 kg m(-2) and BMI >= 40 kg m(-2), respectively. In particularly, this equation overestimated the REE in 51.74% of patients with BMI < 16 kg m(-2). Huang equation involving body composition provided the highest percent of accurate prediction, 42.7% and 66.0% in patients with BMI < 16 and >40 kg m(-2), respectively. CONCLUSION: Usual predictive equations of REE are not suitable for predicting REE in patients with extreme BMI, in particularly in patients with BMI <16 kg m(-2). Indirect Calorimetry may still be recommended for an accurate assessment of REE in this population until the development of an adapted predictive equation. PMID- 25016969 TI - An amphipathic alpha-helical peptide from apolipoprotein A1 stabilizes protein polymer vesicles. AB - L4F, an alpha helical peptide inspired by the lipid-binding domain of the ApoA1 protein, has potential applications in the reduction of inflammation involved with cardiovascular disease as well as an antioxidant effect that inhibits liver fibrosis. In addition to its biological activity, amphipathic peptides such as L4F are likely candidates to direct the molecular assembly of peptide nanostructures. Here we describe the stabilization of the amphipathic L4F peptide through fusion to a high molecular weight protein polymer. Comprised of multiple pentameric repeats, elastin-like polypeptides (ELPs) are biodegradable protein polymers inspired from the human gene for tropoelastin. Dynamic light scattering confirmed that the fusion peptide forms nanoparticles with a hydrodynamic radius of approximately 50nm, which is unexpectedly above that observed for the free ELP (~5.1nm). To further investigate their morphology, conventional and cryogenic transmission electron microscopy were used to reveal that they are unilamellar vesicles. On average, these vesicles are 49nm in radius with lamellae 8nm in thickness. To evaluate their therapeutic potential, the L4F nanoparticles were incubated with hepatic stellate cells. Stellate cell activation leads to hepatic fibrosis; furthermore, their activation is suppressed by anti-oxidant activity of ApoA1 mimetic peptides. Consistent with this observation, L4F nanoparticles were found to suppress hepatic stellate cell activation in vitro. To evaluate the in vivo potential for these nanostructures, their plasma pharmacokinetics were evaluated in rats. Despite the assembly of nanostructures, both free L4F and L4F nanoparticles exhibited similar half-lives of approximately 1h in plasma. This is the first study reporting the stabilization of peptide-based vesicles using ApoA1 mimetic peptides fused to a protein polymer; furthermore, this platform for peptide-vesicle assembly may have utility in the design of biodegradable nanostructures. PMID- 25016972 TI - Human leptin protein activates the growth of HepG2 cells by inhibiting PERK mediated ER stress and apoptosis. AB - Current treatment modalities for various types of hepatic cancer, which has an increasing incidence rate, are inadequate and novel therapies are required. Therefore, identifying targets for liver cancer is becoming increasingly valuable to develop novel methods for therapy. The aim of the present study was to examine the growth activation mechanism of the leptin protein in the liver cancer cell line HepG2. The effects of the leptin protein on cell death were investigated by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide analysis. DNA fragmentation and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis were also performed to detect cell apoptosis. The expression of leptin and three endoplasmic reticulum (ER) stress unfolded protein response (UPR) proteins, including activating transcription factor 6, phosphorylated-PKR-like ER kinase (p-PERK) and inositol requiring protein 1, were investigated for the examination of ER stress. The mRNA UPR proteins were also detected by reverse transcription polymerase chain reaction. The apoptosis associated caspase 12 and C/EBP homologous protein (CHOP) was detected by western blot analysis. The expression of or incubation with the leptin protein was able to activate cell growth and inhibit cell death and apoptosis. In cells that expressed leptin or were incubated with leptin protein (pep-LPT), cisplatin induced ER stress-associated mRNA transcription and protein activation were inhibited. Levels of the ER stress UPR pathway protein, PERK, increased significantly in leptin-silenced cells when treated with cisplatin as compared with those in the leptin-expressing or pep-LPT cells. Furthermore, caspase 12 activation was inhibited in ex-LPT, pep-LPT and HepG2 cells. In conclusion, human leptin protein is involved in promoting the proliferation of HepG2 cells through inhibiting the ER stress-associated apoptotic pathway. The PERK UPR pathway and the apoptotic factor caspase 12 were found to be involved in the inhibition of apoptosis and enhancement of proliferation. PMID- 25016973 TI - Altered microRNA expression profiles are involved in resistance to low-dose ionizing radiation in the absence of BMI1 in human dermal fibroblasts. AB - The polycomb group RING finger protein, B-cell-specific moloney murine leukemia virus integration site 1 (BMI1), has emerged as a key regulator of cell proliferation, cell cycle, cell immortalization, chemoresistance and radioresistance. Although the radioresistant effect of BMI1 has been thoroughly investigated, the effectiveness of this factor on low-dose radiation (LDR) resistance has not been explored. Here, we demonstrate that BMI1 is not critical for altering cell viability or cell growth in response to LDR, but BMI1 changes cellular gene expression profiles in response to LDR. Normal human dermal fibroblasts (NHDFs) stably expressing BMI1 short hairpin RNA (shRNA) did not exhibit changes in cell viability or cell cycle distribution assays following exposure to 0.1 Gy of gamma-radiation. However, microRNA (miRNA) microarrays revealed that a lack of BMI1 leads to changes in miRNA expression in response to LDR. Bioinformatics analyses demonstrated that predicted target genes of the altered miRNAs are functionally involved in both negative and positive regulation of cell growth, cell proliferation, cell cycle and apoptosis. Therefore, these results indicate that low radiosensitivity even in the absence of the radioresistant factor BMI1 is related with the altered miRNA expression profiles in NHDF. PMID- 25016974 TI - Long-term outcome of psychodynamic therapy and cognitive-behavioral therapy in social anxiety disorder. AB - OBJECTIVE: Relatively few studies have examined the long-term outcome of psychotherapy in social anxiety disorder. The authors previously reported findings of a clinical trial comparing cognitive-behavioral therapy (CBT), psychodynamic therapy, and a wait-list control. The purpose of the present study was to follow the participants' status over the ensuing 24 months. METHOD: Outpatients with social anxiety disorder who were treated with CBT (N=209) or psychodynamic therapy (N=207) in the previous trial were assessed 6, 12, and 24 months after the end of therapy. Primary outcome measures were rates of remission and response. RESULTS: For both CBT and psychodynamic therapy, response rates were approximately 70% by the 2-year follow-up. Remission rates were nearly 40% for both treatment conditions. Rates of response and remission were stable or tended to increase for both treatments over the 24-month follow-up period, and no significant differences were found between the treatment conditions after 6 months. CONCLUSIONS: CBT and psychodynamic therapy were efficacious in treating social anxiety disorder, in both the short- and long-term, when patients showed continuous improvement. Although in the short-term, intention-to-treat analyses yielded some statistically significant but small differences in favor of CBT in several outcome measures, no differences in outcome were found in the long-term. PMID- 25016975 TI - Oral delivery of probiotic expressing M cell homing peptide conjugated BmpB vaccine encapsulated into alginate/chitosan/alginate microcapsules. AB - Oral administration of live probiotics as antigen delivery vectors is a promising approach in vaccine development. However, the low survival of probiotics in the gastrointestinal tract limits this approach. Therefore, the aim of this study was the encapsulation of probiotic expressing vaccine into alginate/chitosan/alginate (ACA) microcapsules (MCs) for efficient oral vaccine delivery. Here, recombinant Lactobacillus plantarum 25 (LP25) expressing M cell homing peptide fused BmpB protein was used as a model probiotic. The viability of LP25 in ACA MCs was more than 65% in simulated gastric fluid (SGF, pH 2.0) and 75% in simulated small intestinal fluid (SIF, pH 7.2) up to 2h. Encapsulated LP25 was completely released from ACA MCs in SIF within 12h. When stored at room temperature (RT) or 4 degrees C, the viability of LP25 in ACA MCs was higher than free LP25. Interestingly, the viability of LP25 in ACA MCs at 4 degrees C for 5weeks was above 58%, whereas viability of free LP25 stored at RT up to 5weeks was zero. After 4weeks from the first immunization, LP25-M-BmpB-loaded ACA MCs induced a stronger BmpB-specific IgG and IgA production in mice. Collectively, these findings suggest that encapsulation of probiotic by ACA MCs is a promising delivery system for oral administration of probiotic expressing vaccine. PMID- 25016977 TI - Assessment of the relative performance of a confined impinging jets mixer and a multi-inlet vortex mixer for curcumin nanoparticle production. AB - The relative performance of two specially designed mixers for nanoparticle production, namely, two-stream confined impinging jets with dilution mixer (CIJ-D M) and four-stream multi-inlet vortex mixer (MIVM), was evaluated using the model compound, curcumin (CUR), under defined conditions of varying mixing rate and organic solvent. In the absence of turbulent fluctuations, higher mixing rate tended to generate finer particles. Among the three water-miscible organic solvents tested, acetone afforded the smallest particle size and the narrowest particle size distribution. Both mixers were capable of reproducibly fabricating CUR nanoparticles with particle size below 100 nm and high encapsulation efficiency (>99.9%). Specifically, CIJ-D-M yielded nanoparticles with smaller size and polydispersity index while the particles obtained by the MIVM displayed better short-term stability. In addition, CIJ-D-M tended to produce a mixture of irregular nanoaggregates and primary nanoparticles while roughly spherical nanoparticles were generated with the MIVM. The observed particle size and morphological differences could be attributed to the differences in the configuration of the mixing chamber and the related mixing order. PMID- 25016978 TI - Dermal nanocrystals from medium soluble actives - physical stability and stability affecting parameters. AB - Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 MUg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20 degrees C). Penetration should be increased by (a) further increase in solubility and (b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4 degrees C and room temperature. Storage at 40 degrees C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept. PMID- 25016979 TI - MicroRNA-1290 promotes asiatic acid-induced apoptosis by decreasing BCL2 protein level in A549 non-small cell lung carcinoma cells. AB - Asiatic acid, a triterpenoid derived from Centella asiatica, is a putative anticancer agent in several types of cancer cells. Investigations of its biological role in negative regulation of cell growth have focused on the extent of induction of apoptosis in a cell-type-specific manner. In this study, we identified an important regulator of asiatic acid-induced cell death, microRNA (miR)-1290, which sensitizes cells to asiatic acid-induced cytotoxicity and negatively regulates BCL2 expression. Asiatic acid significantly upregulated miR 1290, and asiatic acid-induced cell death was shown to be dependent on miR-1290 activity. Molecular assays demonstrated that BCL2 mRNA is a direct target of miR 1290-mediated RNA interference. The results of functional studies suggest that miR-1290 suppresses cell viability and cell cycle progression. These data provide insight into miR-1290-mediated cellular mechanisms in asiatic acid-treated A549 non-small cell lung carcinoma cells. PMID- 25016976 TI - The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors. AB - Multicellular 3D cancer cell culture (spheroids) resemble to in vivo tumors in terms of shape, cell morphology, growth kinetics, gene expression and drug response. However, these characteristics cause very limited drug penetration into deeper parts of the spheroids. In this study, we used multi drug resistant (MDR) ovarian cancer cell spheroid and in vivo tumor models to evaluate the co-delivery of paclitaxel (PCL) and a potent NF-kappaB inhibitor curcumin (CUR). PCL and CUR were co-loaded into the polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) based polymeric micelles modified with transferrin (TF) as the targeting ligand. Cytotoxicity, cellular association and accumulation into the deeper layers were investigated in the spheroids and compared with the monolayer cell culture. Comparing to non-targeted micelles, flow cytometry and confocal imaging proved significantly deeper and higher micelle penetration into the spheroids with TF targeting. Both in monolayers and in spheroids, PCL cytotoxicity was significantly increased when co-delivered with CUR in non-targeted micelles or as single agent in TF-targeted micelles, whereas TF-modification of co-loaded micelles did not further enhance the cytotoxicity. In vivo tumor inhibition studies showed good correlation with the 3D cell culture experiments, which suggests the current spheroid model can be used as an intermediate model for the evaluation of co-delivery of anticancer compounds in targeted micelles. PMID- 25016980 TI - Dock GEFs and their therapeutic potential: neuroprotection and axon regeneration. AB - The dedicator of cytokinesis (Dock) family is composed of atypical guanine exchange factors (GEFs) that activate the Rho GTPases Rac1 and Cdc42. Rho GTPases are best documented for their roles in actin polymerization and they regulate important cellular functions, including morphogenesis, migration, neuronal development, and cell division and adhesion. To date, 11 Dock family members have been identified and their roles have been reported in diverse contexts. There has been increasing interest in elucidating the roles of Dock proteins in recent years and studies have revealed that they are potential therapeutic targets for various diseases, including glaucoma, Alzheimer's disease, cancer, attention deficit hyperactivity disorder and combined immunodeficiency. Among the Dock proteins, Dock3 is predominantly expressed in the central nervous system and recent studies have revealed that Dock3 plays a role in protecting retinal ganglion cells from neurotoxicity and oxidative stress as well as in promoting optic nerve regeneration. In this review, we discuss the current understanding of the 11 Dock GEFs and their therapeutic potential, with a particular focus on Dock3 as a novel target for the treatment of glaucoma and other neurodegenerative diseases. PMID- 25016982 TI - Palliative care: more than one chance to get it right. PMID- 25016981 TI - Fractal analysis as a complementary approach to predict the stability of drug delivery nano systems in aqueous and biological media: a regulatory proposal or a dream? AB - The morphology of drug nanocarriers correlates with their functionality, which is mainly shuttled on their surface where most of the interactions and interfacial phenomena occur. The quantification of their morphological fingerprint requires an analytical tool that should be established based on experimental data and can be correlated with their stability. The morphological quantification picture of the advanced Drug Delivery nano Systems (aDDnSs) could be achieved via fractal analysis and by introducing a novel proposed parameter, defined as omegaD. This parameter is based on mathematical limits determined experimentally and on already existing theories on the colloidal fractal aggregation process which can correlate the morphological characteristics of aDDnSs with their physicochemical stability in aqueous and biological media. This review article proposes the fractal analysis and the omegaD as an analytical tool and prediction parameter, respectively, which are able to promote an attractive and alternative path for studying drug delivery nanocarriers. Moreover, these approaches could facilitate the scale up process of pharmaceutical industry, and could shed more light in the quantification of drug delivery nanosystems. PMID- 25016983 TI - Retractions: the lessons for research institutions. PMID- 25016984 TI - The realities and needs of children living with ADHD. PMID- 25016986 TI - Karen Sliwa: cardiology from the heart of South Africa. PMID- 25016987 TI - The right to participate in high-risk research. PMID- 25016988 TI - Legalisation of assisted suicide: a safeguard to euthanasia? PMID- 25016989 TI - The right to participate in high-risk research - Author's reply. PMID- 25016990 TI - The right to participate in high-risk research. PMID- 25016991 TI - Compression stockings to prevent post-thrombotic syndrome. PMID- 25016992 TI - Compression stockings to prevent post-thrombotic syndrome. PMID- 25016993 TI - Compression stockings to prevent post-thrombotic syndrome - Authors' reply. PMID- 25016994 TI - Twitter: an opportunity for public health campaigns. PMID- 25016995 TI - The tragedy of African migrants in Yemen. PMID- 25016996 TI - Sudden knee pain in an underweight, older woman: obturator hernia. PMID- 25016997 TI - Comprehensive identification of essential pathways and transcription factors related to epilepsy by gene set enrichment analysis on microarray datasets. AB - Epilepsy is a common chronic neurological disorder characterized by seizures or convulsions, and is known to affect patients with primary brain tumors. The etiology of epilepsy is superficially thought to be multifactorial; however, the genetic factors which may be involved in the pathogenesis of seizures have not yet been elucidated, particularly at the pathway level. In the present study, in order to systematically investigate the gene regulatory networks involved in epilepsy, we employed a microarray dataset from the public database library of Gene Expression Omnibus (GEO) associated with tumor-induced epileptogenesis and applied gene set enrichment analysis (GSEA) on these data sets and performed candidate transcription factor (TF) selection. As a result, 68 upregulated pathways, including the extracellular matrix (ECM)-receptor interaction (P=0.004) and peroxisome proliferator-activated receptor (PPAR) signaling pathways (P=0.045), as well as 4 downregulated pathways, including the GnRH signaling pathway (P=0.029) and gap junction (P=0.034) were identified as epileptogenesis related pathways. The majority of these pathways identified have been previously reported and our results were in accordance with those reports. However, some of these pathways identified were novel. Finally, co-expression networks of the related pathways were constructed with the significant core genes and TFs, such as PPAR-gamma and phosphatidylethanolamine-binding protein. The results of our study may contribute to the improved understanding of the molecular mechanisms of epileptogenesis on a genome-wide level. PMID- 25016998 TI - The role of Facebook in Crush the Crave, a mobile- and social media-based smoking cessation intervention: qualitative framework analysis of posts. AB - BACKGROUND: Social networking sites, particularly Facebook, are increasingly included in contemporary smoking cessation interventions directed toward young adults. Little is known about the role of Facebook in smoking cessation interventions directed toward this age demographic. OBJECTIVE: The aim of this study was to characterize the content of posts on the Facebook page of Crush the Crave, an evidence-informed smoking cessation intervention directed toward young adults aged 19 to 29 years. METHODS: Crush the Crave Facebook posts between October 10, 2012 and June 12, 2013 were collected for analysis, representing page activity during the pilot phase of Crush the Crave. Of the 399 posts included for analysis, 121 were original posts, whereas the remaining 278 were reply posts. Posts were coded according to themes using framework analysis. RESULTS: We found that the original Crush the Crave Facebook posts served two main purposes: to support smoking cessation and to market Crush the Crave. Most of the original posts (86/121, 71.1%) conveyed support of smoking cessation through the following 7 subthemes: encouraging cessation, group stimulation, management of cravings, promoting social support, denormalizing smoking, providing health information, and exposing tobacco industry tactics. The remaining original posts (35/121, 28.9%) aimed to market Crush the Crave through 2 subthemes: Crush the Crave promotion and iPhone 5 contest promotion. Most of the reply posts (214/278, 77.0%) were in response to the supporting smoking cessation posts and the remaining 64 (23.0%) were in response to the marketing Crush the Crave posts. The most common response to both the supporting smoking cessation and marketing Crush the Crave posts was user engagement with the images associated with each post at 40.2% (86/214) and 45% (29/64), respectively. The second most common response consisted of users sharing their smoking-related experiences. More users shared their smoking-related experiences in response to the supporting smoking cessation posts (81/214, 37.9%) compared to the marketing Crush the Crave posts (11/64, 17%). With the exception of 4 posts, a moderator posted all the original posts. In addition, although 56.00% (18,937/33,815) of Crush the Crave Facebook page users were men, only 19.8% (55/278) of the reply posts were made by men. Finally, men were found to be more likely to express sarcasm or make strong assertions about quitting smoking and Crush the Crave than women. CONCLUSIONS: The CTC Facebook page presents as a unique platform for supporting young adult smoking cessation at all stages of the cessation process. The findings of this study indicate that social networking sites, especially Facebook, warrant inclusion in tobacco control efforts directed towards young adults. Research on effectiveness of the Facebook page for quitting smoking is needed. PMID- 25016999 TI - Shot noise in a quantum dot system coupled with Majorana bound states. AB - We investigate the spectral density of shot noise and current for the system of a quantum dot coupled to Majorana bound states (MBS) employing the nonequilibrium Green's function. The Majorana bound states at the end of the wire strongly affect the shot noise. There are two types of coupling in the system: dot-MBS and MBS-MBS coupling. The curves of shot noise and current versus coupling strength have novel steps owing to the energy-level splitting caused by dot-MBS coupling. The magnitude of these steps increases with the strength of dot-MBS coupling lambda but decreases with the strength of MBS-MBS coupling. The steps shift toward the large ?eV? region as lambda or epsilon(M) increases. In addition, dot MBS coupling enhances the shot noise while MBS-MBS coupling suppresses the shot noise. In the absence of MBS-MBS coupling, a sharp jump emerges in the curve of the Fano factor at zero bias owing to the differential conductance being reduced by a factor of 1/2. This provides a novel technique for the detection of Majorana fermions. PMID- 25017000 TI - Cryptosporidium hominis genotypes involved in increased incidence and clusters of cases, Navarra, Spain, 2012. AB - SUMMARY Two clusters of confirmed cryptosporidiosis infections were detected in Navarra, Spain, in the summer of 2012, in the context of an increased incidence in the region. Molecular subtyping of Cryptosporidium hominis determined that one cluster, occurring in an urban area, was due to the predominant circulating subtype IbA10G2R2 and the other cluster, with cases occurring in a rural area, was due to a rare subtype IaA18R3. No single exposure was associated with infection, although exposure to certain children's pools was reported by a majority of patients interviewed in each cluster. Genotyping tools were useful in the investigation and could aid investigation of cryptosporidiosis outbreaks in Spain in the future. PMID- 25017002 TI - Hierarchically porous aminosilica monolith as a CO2 adsorbent. AB - A facile strategy is successfully developed for the centimeter-scale preparation of hierarchically porous aminosilica monolith as a CO2 adsorbent just by simple processes of solvent-evaporation-induced coating, self-assembly, and concentration of tetraethyl orthosilicate sol on the surface of a polymer foam template without any adhesive composite material or hydrothermal treatment. (3 Aminopropyl) trimethoxysilane is immobilized on the surface of silica monolith via a gas-phase procedure. The silica frameworks of the monolith mimic those of the polymer foam template at the macroscale, and the frameworks are composed of the SBA-15 structure at the nanoscale. The hierarchically porous structure demonstrates improved properties over the single-mode porous component, with the macroporous framework ensuring mechanical stability and good mass transport properties, while the smaller pores provide the functionality for CO2 adsorption. PMID- 25017001 TI - An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. AB - OBJECTIVE: Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). METHOD: The hypothesis was tested in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open label randomized clinical trial. CRP was measured with a high-sensitivity method in serum samples from 241 adult men and women with major depressive disorder randomly allocated to 12-week treatment with escitalopram (N=115) or nortriptyline (N=126). The primary outcome measure was the score on the Montgomery-Asberg Depression Rating Scale (MADRS), administered weekly. RESULTS: CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: beta=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome. CONCLUSIONS: An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice. PMID- 25017003 TI - Probing surface states in PbS nanocrystal films using pentacene field effect transistors: controlling carrier concentration and charge transport in pentacene. AB - We used a bilayer field effect transistor (FET) consisting of a thin PbS nanocrystals (NCs) film interfaced with vacuum-deposited pentacene to probe trap states in NCs. We interpret the observed threshold voltage shift in context of charge carrier trapping by PbS NCs and relate the magnitude of the threshold voltage shift to the number of trapped carriers. We explored a series of NC surface ligands to modify the interface between PbS NCs and pentacene and demonstrate the impact of interface chemistry on charge carrier density and the FET mobility in a pentacene FET. PMID- 25017006 TI - Single-session, transgastric ERCP using sutured gastropexy for treatment of pancreatic duct leak in a patient with Roux-en-Y gastric bypass anatomy and pancreatic divisum. PMID- 25017005 TI - Layer-by-layer polyelectrolyte encapsulation of Mycoplasma pneumoniae for enhanced Raman detection. AB - Mycoplasma pneumoniae is a major cause of respiratory disease in humans and accounts for as much as 20% of all community-acquired pneumonia. Existing mycoplasma diagnosis is primarily limited by the poor success rate at culturing the bacteria from clinical samples. There is a critical need to develop a new platform for mycoplasma detection that has high sensitivity, specificity, and expediency. Here we report the layer-by-layer (LBL) encapsulation of M. pneumoniae cells with Ag nanoparticles in a matrix of the polyelectrolytes poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS). We evaluated nanoparticle encapsulated mycoplasma cells as a platform for the differentiation of M. pneumoniae strains using surface enhanced Raman scattering (SERS) combined with multivariate statistical analysis. Three separate M. pneumoniae strains (M129, FH and II-3) were studied. Scanning electron microscopy and fluorescence imaging showed that the Ag nanoparticles were incorporated between the oppositely charged polyelectrolyte layers. SERS spectra showed that LBL encapsulation provides excellent spectral reproducibility. Multivariate statistical analysis of the Raman spectra differentiated the three M. pneumoniae strains with 97-100% specificity and sensitivity, and low (0.1-0.4) root mean square error. These results indicated that nanoparticle and polyelectrolyte encapsulation of M. pneumoniae is a potentially powerful platform for rapid and sensitive SERS-based bacterial identification. PMID- 25017007 TI - Nutritional quality of salmon products available from major retailers in the UK: content and composition of n-3 long-chain PUFA. AB - In the present study, salmon products available from UK retailers were analysed to determine the levels of n-3 long-chain PUFA (LC-PUFA), a key determinant of nutritional quality. There was a wide variation in the proportions and absolute contents of EPA and DHA in the products. Relatively high contents of 18 : 1n-9, 18 : 2n-6 and 18 : 3n-3, characteristic of vegetable oils (VO), were found in several farmed salmon products, which also had generally lower proportions of EPA and DHA. In contrast, farmed salmon products with higher levels of 16 : 0 and 22 : 1, characteristic of fish oil (FO), had higher proportions of EPA and DHA. Therefore, there was a clear correlation between the levels of VO and FO in feeds and the proportions of n-3 LC-PUFA in products. Although wild salmon products were characterised by higher proportions of n-3 LC-PUFA (20-40%) compared with farmed fish (9-26%), they contained lower total lipid contents (1-6% compared with 7-17% in farmed salmon products). As a result, farmed salmon products invariably had higher levels of n-3 LC-PUFA in absolute terms (g/100 g fillet) and, therefore, delivered a higher 'dose' of EPA and DHA per portion. Overall, despite the finite and limiting supply of FO and increasing use of VO, farmed salmon continue to be an excellent source of and delivery system for n-3 LC-PUFA to consumers. PMID- 25017004 TI - Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates. AB - A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed. Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy. Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach. PMID- 25017008 TI - A clinical grading system based on ultra-wide field retinal imaging for sunset glow fundus in Vogt-Koyanagi-Harada disease. AB - BACKGROUND: To develop a grading system for sunset glow fundus (SGF) based on the results of ultra-wide field retinal imaging and to investigate the factors related to the severity of SGF in patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: Records of 55 eyes with VKH disease were retrospectively reviewed. All patients had undergone serial fundus photography, ultra-wide field retinal imaging and spectral-domain optical coherence tomography. The morphologic characteristics of SGF and associated features related to the severity of the condition were evaluated. RESULTS: Sunset glow fundi were classified into 3 groups based on the extent and severity of depigmentary changes: early (n = 7), intermediate (n = 10) and advanced (n = 20). Grade 0 indicates the absence of sunset glow appearance. Eyes with a higher SGF grade were more likely to exhibit chronic recurrence (P < 0.001) and an anterior chamber reaction >= 2+ (P < 0.001), and were less likely to exhibit exudative retinal detachment (P < 0.001) at the initial presentation. Higher grades were more likely to exhibit cataracts (P < 0.001), glaucoma (P = 0.010), patchy chorioretinal atrophic lesions (P = 0.012), depigmented atrophic lesions (P < 0.001), an increased peripapillary atrophy/disc area ratio (P < 0.001), a decreased subfoveal choroidal thickness (P < 0.001), more frequent uveitis recurrences (P = 0.012) and a longer disease duration (P < 0.001). SGF progression was faster in eyes with a longer active inflammatory period. CONCLUSIONS: We present a simple and logical grading system for SGF as determined by using ultra-wide field retinal imaging. This grading system offers a means of assessing the degree of inflammation and facilitates speculation about the duration of VKH disease. PMID- 25017009 TI - Optical coherence tomography-guided selective focal laser photocoagulation: a novel laser protocol for diabetic macular edema. AB - BACKGROUND: To compare the anatomic and functional results between optical coherence tomography (OCT)-guided selective focal laser photocoagulation (OCT laser) and conventional modified Early Treatment Diabetic Retinopathy Study (mETDRS) laser treatment for diabetic macular edema (DME). METHODS: We analyzed treatment outcomes in 47 consecutive eyes treated with OCT-laser compared to 31 matched eyes treated with mETDRS. In the OCT-laser group, we identified 'significant actively-leaking microaneurysms on OCT' (SALMO) which are responsible for edema in OCT B-scan images, and thoroughly ablated them with photocoagulation. Best-corrected visual acuity (BCVA) and retinal thickness by OCT were compared at baseline and 12 months after treatment between two groups. RESULTS: OCT-laser treatment resulted in significant improvements in BCVA, central subfield thickness (CST), and maximum retinal thickness (MRT) from baseline at 12 months from the time of therapy (+2.5 letter score, p = 0.04; 45.56 MUm in CST, p < 0.001; -91.6 MUm in MRT, p < 0.001). The mean number of treated 'SALMO' was 5.6 +/- 4.0 (range 1-26), while the number of MAs in 'treatable lesions' by fluorescein angiography (FA) in the same eye was 16.3 +/- 11.8 (range 2-42). There was no difference between OCT-laser and mETDRS groups in changes of these parameters from baseline at 12 months (p = 0.56, p = 0.89, p = 0.43 respectively). Fundus autofluorescence (FAF) and OCT revealed less tissue damage in OCT-laser-treated eyes, compared to eyes treated with mETDRS (p < 0.001). CONCLUSIONS: OCT-laser shows similar anatomic and functional outcomes compared to conventional laser (modified ETDRS), with significantly less retinal damages. PMID- 25017010 TI - Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. AB - In Huntington's disease (HD), whether transneuronal spreading of mutant huntingtin (mHTT) occurs and its contribution to non-cell autonomous damage in brain networks is largely unknown. We found mHTT spreading in three different neural network models: human neurons integrated in the neural network of organotypic brain slices of HD mouse model, an ex vivo corticostriatal slice model and the corticostriatal pathway in vivo. Transneuronal propagation of mHTT was blocked by two different botulinum neurotoxins, each known for specifically inactivating a single critical component of the synaptic vesicle fusion machinery. Moreover, healthy human neurons in HD mouse model brain slices displayed non-cell autonomous changes in morphological integrity that were more pronounced when these neurons bore mHTT aggregates. Altogether, our findings suggest that transneuronal propagation of mHTT might be an important and underestimated contributor to the pathophysiology of HD. PMID- 25017011 TI - miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling. AB - We investigated whether microRNAs could regulate AMPA receptor expression during activity blockade. miR-92a strongly repressed the translation of GluA1 receptors by binding the 3' untranslated region of rat GluA1 (also known as Gria1) mRNA and was downregulated in rat hippocampal neurons after treatment with tetrodotoxin and AP5. Deleting the seed region in GluA1 or overexpressing miR-92a blocked homeostatic scaling, indicating that miR-92a regulates the translation and synaptic incorporation of new GluA1-containing AMPA receptors. PMID- 25017012 TI - An iron stable isotope comparison between human erythrocytes and plasma. AB - We present precise iron stable isotope ratios measured by multicollector-ICP mass spectrometry (MC-ICP-MS) of human red blood cells (erythrocytes) and blood plasma from 12 healthy male adults taken during a clinical study. The accurate determination of stable isotope ratios in plasma first required substantial method development work, as minor iron amounts in plasma had to be separated from a large organic matrix prior to mass-spectrometric analysis to avoid spectroscopic interferences and shifts in the mass spectrometer's mass-bias. The (56)Fe/(54)Fe ratio in erythrocytes, expressed as permil difference from the "IRMM-014" iron reference standard (delta(56/54)Fe), ranges from -3.10/00 to 2.20/00, a range typical for male Caucasian adults. The individual subject erythrocyte iron isotope composition can be regarded as uniform over the 21 days investigated, as variations (+/-0.059 to +/-0.150/00) are mostly within the analytical precision of reference materials. In plasma, delta(56/54)Fe values measured in two different laboratories range from -3.00/00 to -2.00/00, and are on average 0.240/00 higher than those in erythrocytes. However, this difference is barely resolvable within one standard deviation of the differences (0.220/00). Taking into account the possible contamination due to hemolysis (iron concentrations are only 0.4 to 2 ppm in plasma compared to approx. 480 ppm in erythrocytes), we model the pure plasma delta(56/54)Fe to be on average 0.40/00 higher than that in erythrocytes. Hence, the plasma iron isotope signature lies between that of the liver and that of erythrocytes. This difference can be explained by redox processes involved during cycling of iron between transferrin and ferritin. PMID- 25017013 TI - Comparison of the effects of face mask treatment started simultaneously and after the completion of the alternate rapid maxillary expansion and constriction procedure. AB - OBJECTIVE: To test the null hypothesis that there were significant differences for skeletal, dentoalveolar, and soft tissue changes induced by face mask (FM) started simultaneously and after an alternate rapid maxillary expansion and constriction (Alt-RAMEC) procedure. MATERIALS AND METHODS: Thirty-six patients with Class III malocclusion due to maxillary deficiency were randomly assigned to Group I (FM started after the completion of the Alt-RAMEC) and Group II (FM started simultaneously with the Alt-RAMEC). The screw of the RME appliance was alternately activated and deactivated twice daily (0.20 mm per turn) for 1 week over the course of 8 weeks. The changes observed in both groups were assessed using the cephalometric lateral films and statistically evaluated using the paired t-test and Student's t-test. RESULTS: Thirty patients completed the present prospective study. No significant differences were observed between the groups. Class III malocclusion and negative overjet were improved by means of skeletal changes in conjunction with upper incisor proclination in both groups. Skeletal contribution to overjet correction in Groups I and II was 91.70% and 86.10%, respectively. Maxilla showed a forward movement of 3.84 mm and 3.02 mm in Groups I and II, respectively. CONCLUSIONS: The null hypothesis was rejected. Both groups showed similar results, and, thus, waiting until completion of the Alt-RAMEC procedure for the FM treatment is not necessary. PMID- 25017014 TI - The effect of light-emitting diode and laser on mandibular growth in rats. AB - OBJECTIVE: To evaluate the effect of a light-emitting diode (LED) and/or low level laser (LLL) with or without the use of anterior bite jumping appliances (also known as functional appliances [FAs]) on mandibular growth in rats. MATERIALS AND METHODS: Thirty-six 8-week-old male Sprague-Dawley rats weighing 200 g were obtained from Charles River Canada (St. Constant, QC, Canada) and were divided into six groups of six animals each. Groups were as follows: group 1: LLL; group 2: LLL + FA; group 3: LED; group 4: LED + FA; group 5: FA; and group 6: control (no treatment). Mandibular growth was evaluated by histomorphometric and micro computed tomographic (microCT) analyses. RESULTS: The LED and LED + FA groups showed an increase in all condylar tissue parameters compared with other groups. CONCLUSION: The LED-treated groups showed more mandibular growth stimulation compared with the laser groups. PMID- 25017015 TI - Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century? AB - INTRODUCTION: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk. AREAS COVERED: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence. EXPERT OPINION: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD. PMID- 25017016 TI - A comprehensive operating room information system using the Kinect sensors and RFID. AB - Occasionally, surgeons do need various types of information to be available rapidly, efficiently and safely during surgical procedures. Meanwhile, they need to free up hands throughout the surgery to necessarily access the mouse to control any application in the sterility mode. In addition, they are required to record audio as well as video files, and enter and save some data. This is an attempt to develop a comprehensive operating room information system called "Medinav" to tackle all mentioned issues. An integrated and comprehensive operating room information system is introduced to be compatible with Health Level 7 (HL7) and digital imaging and communications in medicine (DICOM). DICOM is a standard for handling, storing, printing, and transmitting information in medical imaging. Besides, a natural user interface (NUI) is designed specifically for operating rooms where touch-less interactions with finger and hand tracking are in use. Further, the system could both record procedural data automatically, and view acquired information from multiple perspectives graphically. A prototype system is tested in a live operating room environment at an Iranian teaching hospital. There are also contextual interviews and usability satisfaction questionnaires conducted with the "MediNav" system to investigate how useful the proposed system could be. The results reveal that integration of these systems into a complete solution is the key to not only stream up data and workflow but maximize surgical team usefulness as well. It is now possible to comprehensively collect and visualize medical information, and access a management tool with a touch-less NUI in a rather quick, practical, and harmless manner. PMID- 25017017 TI - Dual functions of NME1 in suppression of cell motility and enhancement of genomic stability in melanoma. AB - The NME1 gene represents the prototypical metastasis suppressor, whose expression inhibits cell motility and metastasis without impact on primary tumor growth in a number of different human cancers. This report outlines our recent efforts to define the molecular mechanisms through which NME1 both suppresses cell motility and promotes genomic integrity in the setting of human melanoma. Forced NME1 expression in a variety of melanoma-derived cell lines was shown to induce dynamic changes in cell morphology and reorganization of the actin cytoskeleton, with formation of a network of thick stress fibers and assembly of fibronectin fibrils at large focal adhesions. Moreover, NME1 expression results in adhesion reprogramming through an impact on integrin repertoire and focal adhesion dynamics. Having previously demonstrated that NME1 expression promotes repair of DNA damage induced by ultraviolet radiation (UVR) in both yeast and mammalian cells, probably via the nucleotide excision repair pathway, we have more recently demonstrated that NME1 is rapidly recruited to double-strand breaks. This preliminary result represents the first evidence of direct interactions between NME1 and DNA in the context of DNA repair and has set the stage for current efforts to probe its functional interactions with double-strand break repair pathways. Discussed herein are molecular models to explain the interactions of NME1 with such diverse cellular functions as cell motility and DNA repair, potentially through its nucleoside diphosphate kinase and 3'-5' exonuclease activities. PMID- 25017018 TI - Is cIMP a second messenger with functions opposite to those of cGMP? PMID- 25017019 TI - cCMP is a substrate for MRP5. AB - The cyclic pyrimidine nucleotide cCMP has been suggested to serve as second messenger. However, phosphodiesterases studied so far do not hydrolyze cCMP. Therefore, we searched for alternative cCMP inactivation mechanisms. cCMP is a substrate for multidrug resistance protein 5, indicating that export from the cytosol into the extracellular space is an important inactivation mechanism for cCMP. PMID- 25017020 TI - Influence of abutment model materials on the fracture loads of three-unit fixed dental prostheses. AB - This study evaluated and compared the influence of different supporting abutment models on the fracture loads of three-unit fixed dental prostheses (FDPs) fabricated from the following materials (n=24/material): (i) IPS e.max CAD-on, (ii) IPS e.max ZirCAD, and (iii) Telio CAD. Twelve FDPs of each group were adhesively cemented on a polymeric model and on a base metal alloy one. For the fracture load test the FDPs were loaded at the centre of the pontic (1 mm/min). The data were analyzed using descriptive statistics, two- and one-way ANOVA followed by post-hoc Scheffe test and Weibull statistics. Fracture loads were found to be affected by the choice of materials used for the abutment models. The fracture load for zirconia FDPs cemented on metal abutments was higher than on polymeric abutment group. In contrast, Telio CAD cemented on polymeric abutments presented higher fracture loads than group on base metal alloy support. PMID- 25017021 TI - Effects of zinc oxide-eugenol and calcium hydroxide/ iodoform on delaying root resorption in primary molars without successors. AB - The purpose of this study was to compare the effects of zinc oxide-eugenol (ZOE) and calcium hydroxide/iodoform paste (Vitapex), as root canal filling materials in pulpectomy, on delaying the root resorption of primary molars without permanent successors. Animal models without permanent successors were surgically established in beagle dogs. Root resorption was observed via periapical radiographs. The onset of root resorption of primary mandibular molars without successors occurred later (p<0.05) than physiologic resorption. ZOE pulpectomy clearly delayed the root resorption of primary molars without permanent successors (p<0.05), whereas resorption of primary molars with Vitapex pulpectomy started at almost the same time as physiologic resorption. Compared with Vitapex, ZOE was a more effective root canal filling material in delaying the root resorption of primary molars. PMID- 25017022 TI - BTG1 expression in thyroid carcinoma: diagnostic indicator and prognostic marker. AB - We determined the expression and function of B cell translocation gene 1 (BTG1) in thyroid carcinoma. Thyroid samples were obtained from cancer lesions (n=83) and adjacent normal tissue (n=35) in thyroid cancer patients immediately after endoscopic biopsy. BTG1 expression was determined by immunohistochemistry and western blotting. The effect of BTG1 overexpression was examined in vitro utilizing the human thyroid cancer cell line FTC-133, stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector transfected controls (LeEmpty). BTG1 overexpression was verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. The expression of proteins involved in cell cycle regulation (cyclin D1), apoptosis (Bcl-2) and cell migration (MMP-9) in LeBTG1 cells was analyzed by western blotting. The effect of BTG1 overexpression on cell viability and proliferation was assessed by MTT assay in LeBTG1 and LeEmpty cells. Flow cytometric analyses were used to evaluate the effect of BTG1 expression on cell cycle distribution and apoptosis. The migration and invasion potential of LeBTG1 cells was examined by plating cells in Matrigel-coated chambers. BTG1 protein expression was significantly lower in thyroid cancer tissue biopsies compared to normal tissue as measured by immunohistochemistry (36.1 vs. 80.0% of tissues; P<0.05) and western blotting (0.251+/-0.021 vs. 0.651+/-0.065; P<0.05). Decreased expression of BTG1 was significantly correlated with thyroid cancer lymph node metastasis, clinical stage and pathological differentiation (P<0.05), as well as with reduced overall 10-year survival rates compared to patients with higher expression levels (30.2 vs. 66.7%; P<0.05). In vitro analyses revealed that LeBTG1 cells had a reduced survival fraction compared to control LeEmpty cells, with higher rates of apoptosis (11.6+/-2.1 vs. 2.1+/-0.4%; P<0.05). The proportion of LeBTG1 cells in G0/G1 stage and S phase was also significantly different from LeEmpty cells (81.8+/-6.3 and 10.2+/-1.0%, vs. 62.4+/-4.9 and 25.5+/-2.6%, respectively; P<0.05), and the migration and invasion of LeBTG1 cells was significantly impaired with respect to LeEmpty cells (72.0+/-8.0 and 55.0+/-7.0 vs. 113.0+/ 16.0 and 89.0+/-9.0, respectively; P<0.05). These effects were accompanied by decreased protein expression of cyclin D1, Bcl-2 and MMP-9 in LeBTG1 cells (0.234+/-0.018, 0.209+/-0.021, 0.155+/-0.017, respectively) compared to control LeEmpty cells (0.551+/-0.065, 0.452+/-0.043, 0.609+/-0.072, respectively; P<0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of thyroid cancer and can serve as a prognostic indicator. PMID- 25017023 TI - Platelet-derived growth factor promotes osteoblast proliferation by activating G protein-coupled receptor kinase interactor-1. AB - Platelet-derived growth factor (PDGF) has been reported to stimulate bone fracture-healing. Multiple studies have demonstrated that PDGF has a critical role in osteoblast or osteoprogenitor cell activation, although the underlying mechanism remains unclear. Studies have found that G-protein-coupled receptor kinase interactor-1 (GIT1) is activated by PDGF and described as an important factor in bone metabolism. In the present study, the effects of PDGF and GIT1 on the proliferation and apoptosis of osteoblasts were investigated in cultured osteoblasts isolated from rat calvaria with PDGF stimulation and GIT1 small interfering RNA transfection. The results demonstrated that PDGF rapidly stimulated GTI1 expression in osteoblasts, increased osteoblast proliferation and inhibited cell apoptosis. Furthermore, cyclin D1 expression was significantly upregulated, the number of cells in the G0/G1 phase was decreased, while the number in the S phase was increased. In cells with knockdown of GIT1, the change stimulated by PDGF was not evident. The results indicate that, PDGF stimulated GIT1 activation of cyclin D1 expression, thereby promoting osteoblasts to enter the S phase from the stationary G0/G1 phase, leading to the proliferation of osteoblasts. PMID- 25017024 TI - Malunited extra-articular distal radius fractures: corrective osteotomies using volar locking plate. AB - BACKGROUND: Multiple techniques for corrective osteotomy have been developed in recent years with the same aims: to improve the radiographic parameters and improve motion, pain and grip strength. Volar fixed-angle plates have added a new concept to the treatment of distal radius fractures thanks to the low morbidity of the surgical approach and the strength of the final construct, allowing early mobilization and return to function. MATERIALS AND METHODS: Between 2005 and 2012, 20 patients with symptomatic dorsally malunited extra-articular fractures of the distal radius underwent corrective osteotomy using a volar locking plate without additional bone graft. At a mean follow-up of 50 months, all the patients were clinically and functionally evaluated. RESULTS: All measurements of pain, final range of motion and grip strength significantly improved compared with preoperative measurements. The mean preoperative DASH score reduced from 54 points preoperatively to 25 postoperatively. Based on the modified Mayo wrist score, we obtained 14 excellent and six good results. Palmar tilt improved from an average of 23 degrees to 11 degrees . Radial inclination improved from an average of 29 degrees to 22 degrees , and ulnar variance decreased from an average of 3.6 mm to 0.9 mm. There were two cases of transient median neuroapraxia that resolved before the 6-week follow-up appointment. No other major complications, including non-union and infection, were observed. CONCLUSION: The volar approach and locking plate, without necessarily the use of bone grafting, proved to be an effective approach for addressing symptomatic and even severe deformities of the distal radius. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25017025 TI - Aseptic lysis L2-L3 as complication of abdominal aortic aneurysm repair. AB - Osteolytic vertebral erosion is usually related to tumours, spondylitis or spondylodiscitis. Few reports in the literature describe lytic lesions of anterior lumbar vertebral bodies resulting from abdominal aortic aneurysm or false aneurysm. We report a case of abdominal aortic false aneurysm that caused lytic lesions of the second and third vertebral bodies in an 80-year-old man who underwent endovascular aneurysm repair. Fluoroscopy guided biopsy excluded infection or tumour. We performed a posterior spinal fusion and decompression because of bone loss of the second and third lumbar vertebral bodies and central stenosis. Postoperatively the patient showed satisfactory relief in low-back and thigh pain but, unfortunately, he died 1 month after surgery because of respiratory complications. This case suggests that when a lytic lesion of a lumbar vertebral body is discovered in a patient who has undergone endovascular aneurysm repair, an abdominal aortic false aneurysm may be the cause of the vertebral erosion even in cases without infective pathogenesis. PMID- 25017026 TI - Ossifying tendinitis of the rotator cuff after arthroscopic excision of calcium deposits: report of two cases and literature review. AB - Ossifying tendinitis (OT) is a type of heterotopic ossification, characterized by deposition of hydroxyapatite crystals in a histologic pattern of mature lamellar bone. It is usually associated with surgical intervention or trauma and is more commonly seen in Achilles or distal biceps tendons, and also in the gluteus maximus tendon. To our knowledge, there is no description of OT as a complication of calcifying tendinitis of the rotator cuff. In this report, we describe two cases in which the patients developed an OT of the supraspinatus after arthroscopic removal of calcium deposits. The related literature is reviewed. PMID- 25017027 TI - A new volar plate made of carbon-fiber-reinforced polyetheretherketon for distal radius fracture: analysis of 40 cases. AB - BACKGROUND: Implants based on the polyetheretherketon (PEEK) polymer have been developed in the last decade as an alternative to conventional metallic devices. PEEK devices may provide several advantages over the use of conventional orthopedic materials, including the lack of metal allergies, radiolucency, low artifacts on magnetic resonance imaging scans and the possibility of tailoring mechanical properties. The purpose of this study was to evaluate the clinical results at 12-month follow-up using a new plate made of carbon-fiber-reinforced polyetheretherketon for the treatment of distal radius fractures. MATERIALS AND METHODS: We included 40 consecutive fractures of AO types B and C that remained displaced after an initial attempt at reduction. The fractures were classified according to the AO classification: 21 fractures were type C1, 9 were type C2, 2 were type C3, 2 were type B1 and 6 were type B2. RESULTS: At a 12-month follow-up no cases of hardware breakage or loss of the surgically achieved fracture reduction were documented. All fractures healed, and radiographic union was observed at an average of 6 weeks. The final Disabilities of Arm, Shoulder and Hand score was 6.0 points. The average grip strength, expressed as a percentage of the contralateral limb, was 92 %. Hardware removal was performed only in one case, for the occurrence of extensor tenosynovitis. CONCLUSION: At early follow up this device showed good clinical results and allowed maintenance of reduction in complex, AO fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25017028 TI - A novel collaborative e-learning platform for medical students - ALERT STUDENT. AB - BACKGROUND: The increasing complexity of medical curricula would benefit from adaptive computer supported collaborative learning systems that support study management using instructional design and learning object principles. However, to our knowledge, there are scarce reports regarding applications developed to meet this goal and encompass the complete medical curriculum. The aim of ths study was to develop and assess the usability of an adaptive computer supported collaborative learning system for medical students to manage study sessions. RESULTS: A study platform named ALERT STUDENT was built as a free web application. Content chunks are represented as Flashcards that hold knowledge and open ended questions. These can be created in a collaborative fashion. Multiple Flashcards can be combined into custom stacks called Notebooks that can be accessed in study Groups that belong to the user institution. The system provides a Study Mode that features text markers, text notes, timers and color-coded content prioritization based on self-assessment of open ended questions presented in a Quiz Mode. Time spent studying and Perception of knowledge are displayed for each student and peers using charts. Computer supported collaborative learning is achieved by allowing for simultaneous creation of Notebooks and self-assessment questions by many users in a pre-defined Group. Past personal performance data is retrieved when studying new Notebooks containing previously studied Flashcards. Self-report surveys showed that students highly agreed that the system was useful and were willing to use it as a reference tool. CONCLUSIONS: The platform employs various instructional design and learning object principles in a computer supported collaborative learning platform for medical students that allows for study management. The application broadens student insight over learning results and supports informed decisions based on past learning performance. It serves as a potential educational model for the medical education setting that has gathered strong positive feedback from students at our school.This platform provides a case study on how effective blending of instructional design and learning object principles can be brought together to manage study, and takes an important step towards bringing information management tools to support study decisions and improving learning outcomes. PMID- 25017029 TI - Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors. AB - A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse. PMID- 25017030 TI - Thieno[2,3-b]pyridines as negative allosteric modulators of metabotropic GluR5 receptors: hit-to-lead optimization. AB - An HTS campaign of our corporate compound library resulted in thieno[2,3 b]pyridines derivative hits with mGluR5 negative allosteric modulator effects. During the hit-to-lead development our objective was to improve affinity, and to keep the ligand efficiency values at an acceptable level. After different modifications of the linker resulted in a 2-sulfonyl-thieno[2,3-b]pyridines derivative, which fulfilled the lead criteria. PMID- 25017031 TI - Non-pretreated O-acyl isopeptide of amyloid beta peptide 1-42 is monomeric with a random coil structure but starts to aggregate in a concentration-dependent manner. AB - An isopeptide of amyloid beta peptide 1-42 (isoAbeta42) was considered as a non aggregative precursor molecule for the highly aggregative Abeta42. It has been applied to biological studies after several pretreatments. Here we report that isoAbeta42 is monomeric with a random coil structure at 40 MUM without any pretreatment. But we also found that isoAbeta42 retains a slight aggregative nature, which is significantly weaker than that of the native Abeta42. PMID- 25017032 TI - Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists. AB - Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility. PMID- 25017034 TI - Confronting the challenges of discovery of novel antibacterial agents. AB - Bacterial resistance is inevitable and is a growing concern. It can be addressed only by discovery and development of new agents. However the discovery and development of new antibacterial agents are at an all time low. This article broadly examines the historical as well as current status of antibacterial discovery and provides some perspective as how to address some of the challenges. PMID- 25017033 TI - Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. AB - TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK 3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50=16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay. PMID- 25017035 TI - Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARgamma agonists. AB - We previously reported that a alpha-benzylphenylpropanoic acid-type hPPARgamma selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARgamma agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARgamma ligand binding domain (LBD) complexed with 3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of alpha benzylphenylpropanoic acid derivatives 8. As expected, most of the newly synthesized compounds exhibited more potent hPPARgamma agonistic activity and greater hPPARgamma binding affinity than 3. Some of these compounds also showed comparable aqueous solubility to 3. PMID- 25017036 TI - Discovery of novel 1,5-benzodiazepine-2,4-dione derivatives as potential anticancer agents. AB - A series of novel 1,5-benzodiazepine-2,4-dione derivatives with C-6 amide substituents were designed and synthesized using three-component reactions. The preliminary assays showed that most of them displayed moderate to good antitumor activities against human lung carcinoma (A549), human breast epithelial carcinoma (MCF-7), human colon carcinoma (HCT116), human cervical carcinoma (Hela) and Lewis lung carcinoma (2LL). Exhilaratingly, the activity level of 6m rivaled that of 5-Fluorouracil (5-Fu) against MCF-7 cell lines, which might be used as novel lead scaffold for potential anticancer development. PMID- 25017037 TI - Antidepressant dose and the risk of deliberate self-harm. AB - Although the mechanism by which antidepressants (ADs) may increase the risk of suicide-related outcomes is unknown, it has been hypothesised that some adverse effects, including akathisia, insomnia and panic attacks, as well as an early energising effect that might allow patients with depression to act on suicidal impulses, may have a key role. Considering that these adverse effects are dose related, it might be hypothesised that the risk of suicidal behaviour is similarly related to the AD dose. This research question has recently been addressed by a propensity score-matched observational cohort study that involved 162 625 patients aged 10-64 years with a depression diagnosis who initiated therapy with citalopram, sertraline or fluoxetine. In this commentary, we discuss the main findings of this study in view of its methodological strengths and limitations, and we suggest possible implications for day-to-day clinical practice. PMID- 25017038 TI - A potential therapeutic effect of CYP2C8 overexpression on anti-TNF-alpha activity. AB - Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid catalysed by cytochrome P450 (CYP) epoxygenases. In addition to regulating vascular tone EETs may alleviate inflammation and ROS. The present study was conducted to determine whether CYP2C8 gene overexpression was able to increase the level of EETs, and subsequently prevent TNF-alpha induced inflammation and reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) and macrophages. Peroxisome proliferator-activated receptor gamma (PPARgamma) activation, nuclear factor-kappaB (NF-kappaB) activation, endothelial nitric oxide synthase (eNOS) activation, gp-91 activation, and inflammatory cytokine expression were detected by western blot analysis or enzyme-linked immuno-sorbent assay. Intracellular reactive oxygen species (ROS) was measured by flow cytometry, while the migration of vascular smooth muscle cells (VSMCs) was detected by transwell assay. pCMV mediated CYP2C8 overexpression and its metabolites, EETs, markedly suppressed TNF alpha induced inflammatory cytokines IL-6 and MCP-1 expression via the activation of NF-kappaB and degradation of IkappaBalpha. Moreover, pretreatment with 11,12 EET significantly blocked TNF-alpha-induced ROS production. CYP2C8-derived EETs also effectively alleviated the migration of VSMCs and improved the function of endothelial cells through the upregulation of eNOS, which was significantly decreased under the stimulation of TNF-alpha. Furthermore, these protective effects observed were mediated by PPARgamma activation. To the best of our knowledge, the results of the present study demonstrated for the first time that CYP2C8-derived EETs exerted antivascular inflammatory and anti-oxidative effects, at least in part, through the activation of PPARgamma. Thus, the CYP2C8 gene may be useful in the prevention and treatment of vascular inflammatory diseases. PMID- 25017039 TI - Synthetic microbial consortia: from systematic analysis to construction and applications. AB - Synthetic biology is an emerging research field that focuses on using rational engineering strategies to program biological systems, conferring on them new functions and behaviours. By developing genetic parts and devices based on transcriptional, translational, post-translational modules, many genetic circuits and metabolic pathways had been programmed in single cells. Extending engineering capabilities from single-cell behaviours to multicellular microbial consortia represents a new frontier of synthetic biology. Herein, we first reviewed binary interaction modes of microorganisms in microbial consortia and their underlying molecular mechanisms, which lay the foundation of programming cell-cell interactions in synthetic microbial consortia. Systems biology studies on cellular systems enable systematic understanding of diverse physiological processes of cells and their interactions, which in turn offer insights into the optimal design of synthetic consortia. Based on such fundamental understanding, a comprehensive array of synthetic microbial consortia constructed in the last decade were reviewed, including isogenic microbial communities programmed by quorum sensing-based cell-cell communications, sender-receiver microbial communities with one-way communications, and microbial ecosystems wired by two way (bi-directional) communications. Furthermore, many applications including using synthetic microbial consortia for distributed bio-computations, chemicals and bioenergy production, medicine and human health, and environments were reviewed. Synergistic development of systems and synthetic biology will provide both a thorough understanding of naturally occurring microbial consortia and rational engineering of these complicated consortia for novel applications. PMID- 25017041 TI - Coronary artery bypass grafting versus combined coronary artery bypass grafting and mitral valve repair in treating ischaemic mitral regurgitation: a meta analysis. AB - BACKGROUND: Ischaemic mitral regurgitation (IMR) is commonly manifested after coronary artery disease, but it is still controversial as to whether coronary artery bypass grafting (CABG) alone improves postoperative outcome. OBJECTIVES: A focussed clinical question was designed and a meta-analysis of published studies was performed to identify the impact of mitral valve repair (MVR) in patients with IMR undergoing CABG versus those undergoing CABG alone. METHODS: Using the Medline database, the Cochrane clinical trials database and online clinical trial databases, we reviewed all RCTs and observational studies examining the impact of MVR and CABG in treating patients with IMR. We searched for literature published before September 2013 and earlier. RESULTS: This analysis identified five studies which examined the impact of CABG alone versus combined CABG and MVR in treating patients with IMR, involving 1038 patients, with 423 patients undergoing CABG alone and 615 were performed combined CABG and MVR procedures. There was significant improvement in postoperative mitral regurgitation (MR) grade in combined group, comparing with CABG alone group (WMD: 1.34, 95% CI: 0.47 to 2.21, p = 0.003), but no significant differences were noted between the CABG plus MVR group and CABG alone group in terms of in-hospital mortality (OR: 0.84, 95% CI: 0.44 to 1.61, p = 0.60), MR grade improvement rate (OR: 0.19, 95% CI: 0.02 to 1.66, p = 0.13), postoperative mean NYHA functional class (WMD: 0.33, 95% CI: 0.29 to 0.94, p = 0.30) and five-year survival (OR: 0.77, 95% CI: 0.34 to 1.73, p = 0.53). CONCLUSIONS: Compared with CABG alone, patients who underwent combined CABG and MVR procedures showed a greater improvement in postoperative MR grade, but in terms of in-hospital mortality, MR grade improvement rate, postoperative mean NYHA functional class and five-year survival, adding MVR to CABG surgery lacks evidence to show its superiority. PMID- 25017040 TI - Microfluidic 3D models of cancer. AB - Despite advances in medicine and biomedical sciences, cancer still remains a major health issue. Complex interactions between tumors and their microenvironment contribute to tumor initiation and progression and also contribute to the development of drug resistant tumor cell populations. The complexity and heterogeneity of tumors and their microenvironment make it challenging to both study and treat cancer. Traditional animal cancer models and in vitro cancer models are limited in their ability to recapitulate human structures and functions, thus hindering the identification of appropriate drug targets and therapeutic strategies. The development and application of microfluidic 3D cancer models have the potential to overcome some of the limitations inherent to traditional models. This review summarizes the progress in microfluidic 3D cancer models, their benefits, and their broad application to basic cancer biology, drug screening, and drug discovery. PMID- 25017043 TI - Nine-year experience of recurrent anastomotic pseudoaneurysms after thoracoabdominal aneurysm graft replacement in a patient with Behcet disease. AB - A 47 year-old woman with Behcet disease presented with back pain. Computed tomography showed an extent IV thoracoabdominal aneurysm. Graft replacement with reconstruction of all visceral arteries was performed. At five years postoperatively, anastomotic pseudoaneurysm of the left renal artery occurred, and it was reconstructed with an 8-mm graft. Two years after the second reconstruction, anastomotic pseudoaneurysms of the abdominal aorta developed. Y shaped graft replacement was performed. There has been no recurrence for one year since the last operation. In situ graft reconstruction for recurrent pseudoaneurysms in a Behcet disease patient more than five years after graft replacement with reconstruction of all visceral arteries is rare. PMID- 25017042 TI - Comparison of the safety of right internal mammary artery versus radial artery for the second arterial conduit during coronary artery bypass grafting. AB - OBJECTIVE: To compare the safety of procedure in patients receiving right internal mammary artery (RIMA) versus radial artery (RA) as the second arterial graft during left internal mammary artery bypass surgery. METHODS: A literature search was performed, and observational studies comparing RA and RIMA as a second arterial conduit were included. The end points included in-hospital mortality, sternal wound infection (SWI), myocardial infarction (MI), reoperation for bleeding, stroke and low cardiac output syndrome. Sensitivity analysis was performed, and publication bias was assessed. RESULTS: Analysis of nine studies comprising 1,738 RIMA patients and 1,906 RA patients showed a similar risk of in hospital mortality (relative risk [RR] 1.13, 95% confidence interval [CI] 0.64 to 1.98) between two groups. The risk of SWI in RIMA patients was significantly higher than that in RA patients (RR 3.19, 95% CI 1.64 to 6.20). The risk of the rest end points did not differ. CONCLUSIONS: The postoperative risk seems to be similar between RIMA group and RA group, except the higher risk of SWI in RIMA patients. The surgeon relies on his own experience with these two arterial grafts and assessment of the patient profile to decide the choice of the second arterial conduit. PMID- 25017044 TI - Comparison of two real-time RT-PCR assays for differentiation of C-strain vaccinated from classical swine fever infected pigs and wild boars. AB - Classical swine fever is one of the most important infectious diseases for the pig industry worldwide due to its economic impact. Vaccination is an effective means to control disease, however within the EU its regular use is banned owing to the inability to differentiate infected and vaccinated animals, the so called DIVA principle. This inability complicates monitoring of disease and stops international trade thereby limiting use of the vaccine in many regions. The C strain vaccine is safe to use and gives good protection. It is licensed for emergency vaccination in the EU in event of an outbreak. Two genetic assays that can distinguish between wild type virus and C-strain vaccines have recently been developed. Here the results from a comparison of these two real-time RT-PCR assays in an interlaboratory exercise are presented. Both assays showed similar performance. PMID- 25017046 TI - Back-up strategies in drug discovery: what, how and when? AB - The management of back-up strategies in drug discovery and development is usually done on an ad hoc basis depending upon a series of external factors including overall portfolio status and resource and/or budget availability. These are however an essential component of risk management and merit a more structured and systematic conduct throughout the lifetime of a project. An approach based upon a thorough alignment of decision points and data availability as well as a tailor made progression of various types of back-up program as a function of project categorization is suggested. PMID- 25017047 TI - Estrogen receptor alpha promotes non-amyloidogenic processing of platelet amyloid precursor protein via the MAPK/ERK pathway. AB - Deposition of amyloid beta peptide (Abeta), a proteolytic product of amyloid precursor protein (APP), in senile plaques and in the walls of cerebral blood vessels is a hallmark of Alzheimer's disease (AD). Platelets contain high levels of APP and Abeta and may contribute to amyloid deposits seen in AD. However, the biochemical mechanism(s) involved in the regulation of platelet APP metabolism are largely unknown. The estrogen receptor alpha (ERalpha) is found to be expressed in platelets. It has not been elucidated whether ERalpha-mediated non genomic signaling intervenes with platelet APP processing. Using ERalpha knock out (alpha-ERKO) mice and wild type (WT) littermates, the present study demonstrated that ERalpha-specific agonist propylpyrazole triol (PPT) promoted non-amyloidogenic processing of platelet APP via the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathway. The underlying basis involves direct association of activated ERK with a disintegrin and metalloprotease domain 17 (ADAM17, an alpha-secretase candidate) and ERK dependent threonine phosphorylation of ADAM17. These results suggest that selective modulation of ERalpha in peripheral target tissues may serve as an anti amyloidogenic strategy for AD and other amyloidogenic diseases. PMID- 25017048 TI - The female human heart at rest and during exercise: a review. AB - Sexual dimorphism exists in numerous aspects of exercise physiology. One area that has long been debated is the potential of sex differences in cardiac structure and function. Anthropometric differences exist between males and females, and the relationship between absolute body size and cardiac structure dictate that men typically have larger hearts than women. However, increasing evidence suggests that males and females may also demonstrate different cardiac structure and function independent of body size, and it is likely that female sex hormones play a role in these differences. The purpose of this review is to draw together and examine the literature that has compared cardiac structure and function in men and women at rest and during exercise. We make specific reference to the influence of female sex hormones, and discuss the confounding effects of age and training status. Wherever possible, we provide conclusive remarks. Due to the paucity of data in this field, and general lack of consensus, the review concludes by making recommendations for future work. PMID- 25017049 TI - Knockdown of nuclear factor erythroid 2-related factor 2 by lentivirus induces differentiation of glioma stem-like cells. AB - Glioma stem cells (GSCs) are key in the progression and recurrence of glioblastoma. Inducing the differentiation of GSCs is an important therapeutic target for glioblastoma. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported to be important in maintaining the stem cell status of GSCs; however, its association with differentiation has not been studied. Herein, we knocked down Nrf2 from GSCs to investigate the role of Nrf2 in the differentiation of GSCs. First, Nrf2 expression was observed at different stages of differentiation; then, Nrf2 was knocked down and the association of Nrf2 with differentiation degree was observed in vitro. Finally, GSCs were planted in nude mice to study the association of Nrf2 with differentiation in vivo. The expression of Nrf2 decreased with the differentiation process. Following Nrf2 knockdown, the proportion of sphere-like colonies decreased and the dendritic cells in spheres increased; the expression of Nrf2 significantly decreased while the expression of differentiation marker glial fibrillary acidic protein (GFAP) and betaIII-tubulin increased both at the protein and the gene level. In the xenografts of nude mice, the differentiation of tumor cells was improved. These results suggest that Nrf2 is a key factor inhibiting the differentiation of GSCs, and knockdown of Nrf2 may promote the differentiation process, providing a therapy target for GSCs. PMID- 25017051 TI - Standardized measurement of quality of life after incisional hernia repair: a systematic review. AB - BACKGROUND: Recent improvements in incisional hernia repair have led to lower rates of recurrence. As a consequence, increasing attention has been paid to patient-reported outcomes after surgery. However, there is no consensus on how to measure patients' quality of life after incisional hernia repair. The aim of this systematic review was to analyze existing standardized methods to measure quality of life after incisional hernia repair. DATA SOURCES: A PubMed and Embase search was carried out together with a cross-reference search of eligible papers, giving a total of 26 included studies. CONCLUSIONS: Different standardized methods for measurement of quality of life after incisional hernia repair are available, but no consensus on the optimal method, timing, or length of follow-up exist. International guidelines could help standardization, enabling better comparison between studies. PMID- 25017050 TI - Spatial imagery in haptic shape perception. AB - We have proposed that haptic activation of the shape-selective lateral occipital complex (LOC) reflects a model of multisensory object representation in which the role of visual imagery is modulated by object familiarity. Supporting this, a previous functional magnetic resonance imaging (fMRI) study from our laboratory used inter-task correlations of blood oxygenation level-dependent (BOLD) signal magnitude and effective connectivity (EC) patterns based on the BOLD signals to show that the neural processes underlying visual object imagery (objIMG) are more similar to those mediating haptic perception of familiar (fHS) than unfamiliar (uHS) shapes. Here we employed fMRI to test a further hypothesis derived from our model, that spatial imagery (spIMG) would evoke activation and effective connectivity patterns more related to uHS than fHS. We found that few of the regions conjointly activated by spIMG and either fHS or uHS showed inter-task correlations of BOLD signal magnitudes, with parietal foci featuring in both sets of correlations. This may indicate some involvement of spIMG in HS regardless of object familiarity, contrary to our hypothesis, although we cannot rule out alternative explanations for the commonalities between the networks, such as generic imagery or spatial processes. EC analyses, based on inferred neuronal time series obtained by deconvolution of the hemodynamic response function from the measured BOLD time series, showed that spIMG shared more common paths with uHS than fHS. Re-analysis of our previous data, using the same EC methods as those used here, showed that, by contrast, objIMG shared more common paths with fHS than uHS. Thus, although our model requires some refinement, its basic architecture is supported: a stronger relationship between spIMG and uHS compared to fHS, and a stronger relationship between objIMG and fHS compared to uHS. PMID- 25017045 TI - The neurobiological link between OCD and ADHD. AB - Obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) are two of the most common neuropsychiatric diseases in paediatric populations. The high comorbidity of ADHD and OCD with each other, especially of ADHD in paediatric OCD, is well described. OCD and ADHD often follow a chronic course with persistent rates of at least 40-50 %. Family studies showed high heritability in ADHD and OCD, and some genetic findings showed similar variants for both disorders of the same pathogenetic mechanisms, whereas other genetic findings may differentiate between ADHD and OCD. Neuropsychological and neuroimaging studies suggest that partly similar executive functions are affected in both disorders. The deficits in the corresponding brain networks may be responsible for the perseverative, compulsive symptoms in OCD but also for the disinhibited and impulsive symptoms characterizing ADHD. This article reviews the current literature of neuroimaging, neurochemical circuitry, neuropsychological and genetic findings considering similarities as well as differences between OCD and ADHD. PMID- 25017052 TI - The putative Halloween gene phantom involved in ecdysteroidogenesis in the white backed planthopper Sogatella furcifera. AB - Postembryonic development of insects is highly dependent on ecdysteroid hormones ecdysone (E) and 20-hydroxyecdysone (20E). A cytochrome P450 monooxygenase CYP306A1, the product of the Halloween gene phantom (phm), is involved in the ecdysteroidogenesis in representative insects in Diptera, Lepidoptera and Orthoptera. In the present paper, Sfphm was cloned from a hemipteran insect species, the white-backed planthopper Sogatella furcifera. SfPHM has five insect conserved P450 motifs, i.e., Helix-C, Helix-I, Helix-K, PERF and heme-binding motifs. Temporal and spatial expression patterns of Sfphm were evaluated by q PCR. Sfphm showed three expression peaks in late second-, third- and fourth instar stages. In contrast, the expression levels were lower and formed three troughs in the newly-molted second-, third- and fourth-instar nymphs. The relative 20E levels exhibited similar temporal patterns to Sfphm expression levels. On day 3 of the fourth-instar nymphs, Sfphm clearly had a high transcript level in the thorax where PGs were located. Dietary introduction of double stranded RNA of Sfphm into the second instars successfully knocked down the target gene, and greatly reduced 20E level and ecdysone receptor (EcR) expression level. Moreover, knockdown of Sfphm caused lethality and slowed down ecdysis during nymphal stages. Furthermore, ingestion of 20-hydroxyecdysone did not alter Sfphm expression level, but almost completely rescued SfEcR expression level, and relieved the negative effects on nymphal survival and ecdysis in Sfphm-dsRNA exposed planthoppers. Thus, our results suggest that Sfphm plays a critical role in ecdysteroidogenesis in S. furcifera. PMID- 25017053 TI - Analysis of gene expression for studying tumor progression: the case of glucocorticoid administration. AB - BACKGROUND: Glucocorticoids are commonly used as adjuvant treatment for side effects and have anti-proliferative activity in several tumors but, on the other hand, their proliferative effect has been reported in several studies, some of them involving the spread of cancer. We shall attempt to reconcile these incongruities from the genomic and tissue-physiology perspectives with our findings. METHODS: An accurate phenotype analysis of microarray data can help to solve multiple paradoxes derived from tumor-progression models. We have developed a new strategy to facilitate the study of interdependences among the phenotypes defined by the sample clusters obtained by common clustering methods (HC, SOTA, SOM, PAM). These interdependences are obtained by the detection of non-linear expression-relationships where each fluctuation in the relationship implies a phenotype change and each relationship typology implies a specific phenotype interdependence. As a result, multiple phenotypic changes are identified together with the genes involved in the phenotype transitions. In this way, we study the phenotypic changes from microarray data that describe common phenotypes in cancer from different tissues, and we cross our results with biomedical databases to relate the glucocorticoid activity to the phenotypic changes. RESULTS: 11,244 significant non-linear expression relationships, classified into 11 different typologies, have been detected from the data matrix analyzed. From them, 415 non linear expression relationships were related to glucocorticoid activity. Studying them, we have found the possible reason for opposite effects of some stressor agents like dexamethasone on tumor progression and it has been confirmed by literature. This hidden reason has resulted in being linked with the type of tumor progression of the tissues. In the first type of tumor progression found, new cells can be stressed during proliferation and stressor agents increase tumor proliferation. In the second type, cell stress and tumor proliferation are antagonists so, therefore, stressor agents stop tumor proliferation in order to stress the cells. The non-linear expression relationships among DUSP6, FERMT2, FKBP5, EGFR, NEDD4L and CITED2 genes are used to synthesize these findings. PMID- 25017054 TI - Isolation, promoter analysis and expression profile of Dreb2 in response to drought stress in wheat ancestors. AB - Drought is one of the most important abiotic stresses, constraining crop production seriously. The dehydration responsive element binding proteins (DREBs) are important plant-specific transcription factors that respond to various abiotic stresses and consequently induce abiotic stress-related genes that impart stress endurance in plants. Wild species are naturally exposed to various abiotic stresses and potentially harbor suitable alleles through natural selection. In this study we isolated and characterized Dreb2 from Triticum urartu (GenBank: KF731664), Aegilops speltoides (GenBank: KF731665) and Aegilops tauschii (GenBank: KF731663), the A, B and D genome ancestors of bread wheat, respectively. Analysis of over 1.3 kb upstream region of the gene revealed the presence of several conserved cis-acting regulatory elements including ABA responsive elements, low temperature responsive elements, and several light and environmental signaling related motifs potentially vindicate Dreb2 responses to environmental signals. Moreover, the gene exhibited an alternative splicing, conserved among orthologous genes in grasses, and produced a non-functional isoform due to splicing in an exon resulted frame-shift creating an early stop codon before the functional domain. The expression analysis of Dreb2 under normal and different levels of dehydration stress conditions indicated that the two active spliced isoforms are upregulated when the plant exposed to drought stress whereas the non-functional isoform is downregulated in severe drought. PMID- 25017055 TI - Prevalence and spectrum of GATA4 mutations associated with sporadic dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is the most frequent type of primary myocardial disorder responsible for substantial morbidity and mortality. DCM is the third most common cause of heart failure and the most common reason for heart transplantation. A recent study has implicated GATA4 mutation in the pathogenesis of familial DCM. However, the prevalence and spectrum of GATA4 mutations associated with sporadic DCM remain unclear. In this study, the coding exons and exon-intron boundaries of the GATA4 gene, which encodes a cardiac transcription factor crucial for normal cardiogenesis, were sequenced in 220 unrelated patients with sporadic DCM. A total of 200 unrelated ethnically-matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were assayed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, 3 novel heterozygous GATA4 mutations, p.V39L, p.P226Q and p.T279S, were identified in 3 unrelated patients with sporadic DCM, with a mutational prevalence of approximately 1.36%. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional analysis showed that the GATA4 mutants were consistently associated with significantly decreased transcriptional activity and markedly reduced the synergistic activation between GATA4 and NKX2-5. This study firstly links GATA4 mutations to increased susceptibility to sporadic DCM and provides novel insight into the molecular etiology underlying DCM, suggesting the potential implications for the early prophylaxis and allele-specific treatment of this common form of cardiomyopathy. PMID- 25017056 TI - Molecular analysis of porcine TDRD10 gene: a novel member of the TDRD family. AB - Tudor domain-containing proteins (TDRDs) are characterized by various numbers of Tudor domains, which are known to recognize and bind to symmetric methylated arginine residues. These proteins affect a wide variety of processes, including differentiation, genome stability and gametogenesis. In mammals, there are 12 members (TDRD1-TDRD12) in the TDRD protein family. Among them, the information about TDRD10 is less known. Here, we analyzed the sequence and structure properties of porcine TDRD10 gene, and examined its expression profile and subcellular distribution. Our data show that porcine TDRD10 has an opening reading frame (ORF) of 1068 bp, which encodes 355 amino acids. It localizes to chromosome 4. The gene product of porcine TDRD10 contains a Tudor domain and a RNA recognition motif (RRM). Serial deletion shows that the 5'-flanking sequence of porcine TDRD10 contains several negative and positive regulatory elements and identifies a 670-bp TATA-less region as an optimal promoter. Site-directed mutagenesis reveals that the nucleotides from -451 to -445 relative to the transcriptional start site forms one of the very important positive regulatory elements. Real time PCR detects the highest expression level of porcine TDRD10 gene in heart among 12 tissues. In PK15 cells, it mainly distributed in the cell nucleus, but also exhibited localization to the cytoplasm. These results increase our knowledge of TDRD10 gene, and provide basis for further investigation of its function. PMID- 25017057 TI - Oligo-dT anchored cDNA-SCoT: a novel differential display method for analyzing differential gene expression in response to several stress treatments in mango (Mangifera indica L.). AB - Differential display is a powerful technique for analyzing differences in gene expression. Oligo-dT cDNAstart codon targeted marker (cDNA-SCoT) technique is a novel, simple, cheap, rapid, and efficient method for differential gene expression research. In the present study, the oligo-dT anchored cDNA-SCoT technique was exploited to identify differentially expressed genes during several stress treatments in mango. A total of 37 primers combined with oligo-dT anchor primers 3side amplified approximately 150 fragments of 150 bp to 1500 bp in length. Up to 100 fragments were differentially expressed among the stress treatments and control samples, among which 92 were obtained and sequenced. Out of the 92 transcript derived fragments (TDFs), 70% were highly homologous to known genes, and 30% encoded unclassified proteins with unknown functions. The expression pattern of nine genes with known functions involved in several abiotic stresses in other species was confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) under cold (4 degrees C), salinity (NaCl), polyethylene glycol (PEG, MW 6000), and heavy metal treatments in leaves and stems at different time points (0, 24, 48, and 72 h). The expression patterns of the genes (TDF4, TDF7, TDF23, TDF45, TDF49, TDF50, TDF57, TDF91 and TDF92) that had direct or indirect relationships with cold, salinity, drought and heavy metal stress response were analyzed through qRT-PCR. The possible roles of these genes are discussed. This study suggests that the oligo-dT anchored cDNA-SCoT differential display method is a useful tool to serve as an initial step for characterizing transcriptional changes induced by abiotic stresses and provide gene information for further study and application in genetic improvement and breeding in mango. PMID- 25017058 TI - Construction of an infectious clone of simian foamy virus of Japanese macaque (SFVjm) and phylogenetic analyses of SFVjm isolates. AB - Foamy viruses belong to the genus Spumavirus of the family Retroviridae and have been isolated from many mammalian species. It was reported that simian foamy viruses (SFVs) have co-evolved with host species. In this study, we isolated four strains (WK1, WK2, AR1 and AR2) of SFV (named SFVjm) from Japanese macaques (Macaca fuscata) in main island Honshu of Japan. We constructed an infectious molecular clone of SFVjm strain WK1, termed pJM356. The virus derived from the clone replicated and induced syncytia in human (human embryonic kidney 293T cells), African green monkey (Vero cells) and mouse cell lines (Mus dunni tail fibroblast cells). Phylogenetic analysis also revealed that these four SFVjm strains formed two distinct SFVjm clusters. SFVjm strains WK1 and WK2 and SFV isolated from Taiwanese macaques (Macaca cyclopis) formed one cluster, whereas strains AR1 and AR2 formed the other cluster with SFV isolated from a rhesus macaque (Macaca mulatta). PMID- 25017059 TI - Cloning, expression, and characterization of miR058 and its target PPO during the development of grapevine berry stone. AB - Polyphenol oxidases catalyzing the oxygen-dependent oxidation of phenols to quinones are ubiquitous among angiosperms. They are key enzymes playing a significant role during the synthesis of lignin. The inhibition of the synthesis of lignin in grapevine can cause seedless grapevine berry development. In this study, grapevine PPO (Vv-PPO) was predicted as the target gene of Vv-miR058 by bioinformatics analysis, and it was further cloned and its homologous conservation in various plants was analyzed. The expression profiles of miR058 and its target Vv-PPO were detected by qRT-PCR in peel, pulp and seeds of three grapevine cultivars and Vv-PPO was expressed in an opposite variation way with Vv miR058 where both of them could be detected, suggesting that Vv-miR058 can play an important role by regulating the expression of Vv-PPO. In addition, the potential target gene Vv-PPO for Vv-miR058 was verified by RLM-RACE. This result would be helpful in theoretical basis for further research and seedless grapevine berry production. PMID- 25017060 TI - Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis. AB - During bacterial sepsis, proinflammatory cytokines contribute to multiorgan failure and death in a process regulated in part by cytolytic cell granzymes. When challenged with a sublethal dose of the identified mouse pathogen Brucella microti, wild-type (WT) and granzyme A (gzmA)(-/-) mice eliminate the organism from liver and spleen in 2 or 3 weeks, whereas the bacteria persist in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells. In comparison, after a fatal challenge, only gzmA(-/-) mice exhibit increased survival, which correlated with reduced proinflammatory cytokines. Depletion of natural killer (NK) cells protects WT mice from sepsis without influencing bacterial clearance and the transfer of WT, but not gzmA(-/-) NK, cells into gzmA(-/-) recipients restores the susceptibility to sepsis. Therefore, infection related pathology, but not bacterial clearance, appears to require gzmA, suggesting the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen. PMID- 25017061 TI - Arginylation of myosin heavy chain regulates skeletal muscle strength. AB - Protein arginylation is a posttranslational modification with an emerging global role in the regulation of actin cytoskeleton. To test the role of arginylation in the skeletal muscle, we generated a mouse model with Ate1 deletion driven by the skeletal muscle-specific creatine kinase (Ckmm) promoter. Ckmm-Ate1 mice were viable and outwardly normal; however, their skeletal muscle strength was significantly reduced in comparison to controls. Mass spectrometry of isolated skeletal myofibrils showed a limited set of proteins, including myosin heavy chain, arginylated on specific sites. Atomic force microscopy measurements of contractile strength in individual myofibrils and isolated myosin filaments from these mice showed a significant reduction of contractile forces, which, in the case of myosin filaments, could be fully rescued by rearginylation with purified Ate1. Our results demonstrate that arginylation regulates force production in muscle and exerts a direct effect on muscle strength through arginylation of myosin. PMID- 25017062 TI - The role of the endocrine system in feeding-induced tissue-specific circadian entrainment. AB - The circadian clock is entrained to environmental cycles by external cue-mediated phase adjustment. Although the light input pathway has been well defined, the mechanism of feeding-induced phase resetting remains unclear. The tissue-specific sensitivity of peripheral entrainment to feeding suggests the involvement of multiple pathways, including humoral and neuronal signals. Previous in vitro studies with cultured cells indicate that endocrine factors may function as entrainment cues for peripheral clocks. However, blood-borne factors that are well characterized in actual feeding-induced resetting have yet to be identified. Here, we report that insulin may be involved in feeding-induced tissue-type dependent entrainment in vivo. In ex vivo culture experiments, insulin-induced phase shift in peripheral clocks was dependent on tissue type, which was consistent with tissue-specific insulin sensitivity, and peripheral entrainment in insulin-sensitive tissues involved PI3K- and MAPK-mediated signaling pathways. These results suggest that insulin may be an immediate early factor in feeding mediated tissue-specific entrainment. PMID- 25017063 TI - ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. AB - We generated mice deficient in Lon protease (LONP1), a major enzyme of the mitochondrial quality control machinery. Homozygous deletion of Lonp1 causes early embryonic lethality, whereas its haploinsufficiency protects against colorectal and skin tumors. Furthermore, LONP1 knockdown inhibits cellular proliferation and tumor and metastasis formation, whereas its overexpression increases tumorigenesis. Clinical studies indicate that high levels of LONP1 are a poor prognosis marker in human colorectal cancer and melanoma. Additionally, functional analyses show that LONP1 plays a key role in metabolic reprogramming by remodeling OXPHOS complexes and protecting against senescence. Our findings demonstrate the relevance of LONP1 for cellular and organismal viability and identify this protease as a central regulator of mitochondrial activity in oncogenesis. PMID- 25017064 TI - MicroRNA-mediated regulation of Dp53 in the Drosophila fat body contributes to metabolic adaptation to nutrient deprivation. AB - Multiple conserved mechanisms sense nutritional conditions and coordinate metabolic changes in the whole organism. We unravel a role for the Drosophila homolog of p53 (Dp53) in the fat body (FB; a functional analog of vertebrate adipose and hepatic tissues) in starvation adaptation. Under nutrient deprivation, FB-specific depletion of Dp53 accelerates consumption of major energy stores and reduces survival rates of adult flies. We show that Dp53 is regulated by the microRNA (miRNA) machinery and miR-305 in a nutrition-dependent manner. In well-fed animals, TOR signaling contributes to miR-305-mediated inhibition of Dp53. Nutrient deprivation reduces the levels of miRNA machinery components and leads to Dp53 derepression. Our results uncover an organism-wide role for Dp53 in nutrient sensing and metabolic adaptation and open up avenues toward understanding the molecular mechanisms underlying p53 activation under nutrient deprivation. PMID- 25017065 TI - Recruitment of circulating breast cancer cells is stimulated by radiotherapy. AB - Radiotherapy (RT) is a localized therapy that is highly effective in killing primary tumor cells located within the field of the radiation beam. We present evidence that irradiation of breast tumors can attract migrating breast cancer cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) produced by tumor cells in response to radiation stimulates the recruitment of migrating tumor cells to irradiated tumors, suggesting a mechanism of tumor recurrence after radiation facilitated by transit of unirradiated, viable circulating tumor cells to irradiated tumors. Data supporting this hypothesis are presented through in vitro invasion assays and in vivo orthotopic models of breast cancer. Our work provides a mechanism for tumor recurrence in which RT attracts cells outside the radiation field to migrate to the site of treatment. PMID- 25017066 TI - Yorkie promotes transcription by recruiting a histone methyltransferase complex. AB - Hippo signaling limits organ growth by inhibiting the transcriptional coactivator Yorkie. Despite the key role of Yorkie in both normal and oncogenic growth, the mechanism by which it activates transcription has not been defined. We report that Yorkie binding to chromatin correlates with histone H3K4 methylation and is sufficient to locally increase it. We show that Yorkie can recruit a histone methyltransferase complex through binding between WW domains of Yorkie and PPxY sequence motifs of NcoA6, a subunit of the Trithorax-related (Trr) methyltransferase complex. Cell culture and in vivo assays establish that this recruitment of NcoA6 contributes to Yorkie's ability to activate transcription. Mammalian NcoA6, a subunit of Trr-homologous methyltransferase complexes, can similarly interact with Yorkie's mammalian homolog YAP. Our results implicate direct recruitment of a histone methyltransferase complex as central to transcriptional activation by Yorkie, linking the control of cell proliferation by Hippo signaling to chromatin modification. PMID- 25017067 TI - The strength of an Ig switch region is determined by its ability to drive R loop formation and its number of WGCW sites. AB - R loops exist at the murine IgH switch regions and possibly other locations, but their functional importance is unclear. In biochemical systems, R loop initiation requires DNA sequence regions containing clusters of G nucleotides, but cellular studies have not been done. Here, we vary the G-clustering, total switch region length, and the number of target sites (WGCW sites for the activation-induced deaminase) at synthetic switch regions in a murine B cell line to determine the effect on class switch recombination (CSR). G-clusters increase CSR regardless of their immediate proximity to the WGCW sites. This increase is accompanied by an increase in R loop formation. CSR efficiency correlates better with the absolute number of WGCW sites in the switch region rather than the total switch region length or density of WGCW sites. Thus, the overall strength of the switch region depends on G-clusters, which initiate R loop formation, and on the number of WGCW sites. PMID- 25017069 TI - Neurexin dysfunction in adult neurons results in autistic-like behavior in mice. AB - Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic betaNrx1DeltaC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the betaNrx1DeltaC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of betaNrx1DeltaC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes. PMID- 25017068 TI - Looking under the lamp post: neither fruitless nor doublesex has evolved to generate divergent male courtship in Drosophila. AB - How do evolved genetic changes alter the nervous system to produce different patterns of behavior? We address this question using Drosophila male courtship behavior, which is innate, stereotyped, and evolves rapidly between species. D. melanogaster male courtship requires the male-specific isoforms of two transcription factors, fruitless and doublesex. These genes underlie genetic switches between female and male behaviors, making them excellent candidate genes for courtship behavior evolution. We tested their role in courtship evolution by transferring the entire locus for each gene from divergent species to D. melanogaster. We found that despite differences in Fru+ and Dsx+ cell numbers in wild-type species, cross-species transgenes rescued D. melanogaster courtship behavior and no species-specific behaviors were conferred. Therefore, fru and dsx are not a significant source of evolutionary variation in courtship behavior. PMID- 25017070 TI - Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo. AB - In mammals, a cell's decision to divide is thought to be under the control of the Rb/E2F pathway. We previously found that inactivation of the Rb family of cell cycle inhibitors (Rb, p107, and p130) in quiescent liver progenitors leads to uncontrolled division and cancer initiation. Here, we show that, in contrast, deletion of the entire Rb gene family in mature hepatocytes is not sufficient for their long-term proliferation. The cell cycle block in Rb family mutant hepatocytes is independent of the Arf/p53/p21 checkpoint but can be abrogated upon decreasing liver size. At the molecular level, we identify YAP, a transcriptional regulator involved in organ size control, as a factor required for the sustained expression of cell cycle genes in hepatocytes. These experiments identify a higher level of regulation of the cell cycle in vivo in which signals regulating organ size are dominant regulators of the core cell cycle machinery. PMID- 25017072 TI - Delay before implanting a port-a-cath after removing the previous one because of infection. AB - AIMS: We had for objective to assess the risk of a new Port-a-Cath (PAC) infection after re-implantation when the first one had been removed because of infection in the previous month. METHODS: We conducted a retrospective bicentric study including all patients having undergone PAC removal because of infection, followed by re-implantation of a new one in the next month, between 2004 and 2012. RESULT: One hundred and forty-nine PAC removals were followed by re implantation in the next month. The cause of removal was infection for 63 patients: 34 presented with bacteremia (13 PAC removals and simultaneous re implantation, and 21 with delayed re-implantation for a mean 14days) and 29 presented with local signs of infection (20 PAC removals and simultaneous re implantation, and with delayed re-implantation for a mean 13days). Two out of 13 PACs were re-infected in the bacteremia group, (15.4%) when the removal and re implantation were performed simultaneously, and 1 out of 21 (4.8%) when re implantation of the second PAC was delayed. The 3 re-infected PACs were successfully treated with antibiotics. CONCLUSION: The early re-implantation of a PAC after removal of the previous one because of infection is a relatively safe procedure. The risk of infection can be higher when PAC removal and re implantation are performed simultaneously in patients presenting with bacteremia; nevertheless, all reinfections were successfully treated with antibiotics. PMID- 25017073 TI - Evolving trends in liver transplantation: listing and liver donor allocation. AB - The success of liver transplantation in the past three decades as a life-saving procedure for patients with end-stage liver disease has led to the ever increasing disparity between the demands for liver transplantation and the supply of donor liver organs. Donor allocation and distribution remains a challenge and a moral issue as to how these organs can be equitably distributed. This article reviews the evolution of the liver allocation policy and discusses in detail the challenges clinicians face today in this area of medicine. PMID- 25017074 TI - Cardiac and pulmonary issues in LT assessment candidates. AB - With the incidence of liver disease increasing worldwide, a growing number of patients are being referred for assessment for liver transplant (LT). Unfortunately, the donor pool is not expanding at the same rate, which consequentially results in increasing demand on a finite resource. It is therefore imperative that the candidate who undergoes an LT gets maximal benefit with a resultant maximal increase in life expectancy. This article addresses some of the main cardiac and pulmonary issues that may occur in LT assessment candidates. PMID- 25017075 TI - Renal dysfunction in end-stage liver disease and post-liver transplant. AB - Renal dysfunction is a frequent complication in patients with end-stage liver disease awaiting orthotopic liver transplantation and in the post-liver transplant period. Although the stereotypical form of renal dysfunction is the hepatorenal syndrome, other causes of acute kidney injury in this population include prerenal azotemia and acute tubular necrosis. Renal injury in a patient with cirrhosis is associated with a poor prognosis. PMID- 25017071 TI - Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription. AB - The estrogen receptor alpha (ERalpha) controls cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to control gene transcription. A deeper understanding of these transcriptional mechanisms may uncover therapeutic targets for ERalpha-dependent cancers. We show that BRD4 regulates ERalpha-induced gene expression by affecting elongation-associated phosphorylation of RNA polymerase II (RNAPII) and histone H2B monoubiquitination. Consistently, BRD4 activity is required for proliferation of ER(+) breast and endometrial cancer cells and uterine growth in mice. Genome wide studies revealed an enrichment of BRD4 on transcriptional start sites of active genes and a requirement of BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we demonstrate that BRD4 occupancy on distal EREs enriched for H3K27ac is required for recruitment and elongation of RNAPII on EREs and the production of ERalpha-dependent enhancer RNAs. These results uncover BRD4 as a central regulator of ERalpha function and potential therapeutic target. PMID- 25017076 TI - Acute-on-chronic liver failure. AB - The Model for End-Stage Liver Disease (MELD) has been the single best predictor of outcome of the progression of cirrhosis. Acute-on-chronic liver failure (ACLF) has been proposed as an alternative path in the natural history of cirrhosis. ACLF occurs in patients with chronic liver disease and is characterized by a precipitating event, resulting in acute deterioration in liver function, multiorgan system failure, and high short-term mortality. In this review, the natural course of patients with ACLF, especially as it relates to management of cirrhotic patients on the transplant waiting list, and its impact on liver transplantation outcomes are defined. PMID- 25017077 TI - Hepatitis viruses and liver transplantation: evolving trends in antiviral management. AB - Viral hepatitis is both a leading indication for liver transplant (LT) and an important cause of posttransplant graft loss and mortality. Treatment and prevention of hepatitis B virus in LT recipients, with the observed corresponding improvement in post-LT outcomes, is among the great success stories in transplantation. By comparison, treatment of hepatitis C virus with safe and effective regimens is only just becoming a reality. Chronic hepatitis E virus infection in LT recipients represents a newly described phenomenon that can also lead to graft loss; early diagnosis and treatment may be key in the management of these patients. PMID- 25017078 TI - Liver transplant for hepatocellular cancer: very small tumors, very large tumors, and waiting time. AB - The role of liver transplant for treatment of early hepatocellular cancer (HCC) is no longer contested. However, its benefit relative to other therapies for patients with very early (<2 cm) HCC is still a matter of debate. Twenty years after the establishment of the Milan criteria, we are beginning to realize that the number and size of tumors may not be the best metric by which to prognosticate outcomes and allocate organs. A better assessment of tumor aggressiveness is clearly needed. PMID- 25017079 TI - The adolescent liver transplant patient. AB - The rapid development of new diagnostic tests and improved therapy, especially the success of liver transplantation, has changed the outcome for children with liver disease, many of whom survive into adolescence without liver transplantation. The indications for transplantation in adolescence are similar to pediatric indications and reflect the medical advances made in this specialty that allow later transplantation. These young people need a different approach to management that involves consideration of their physical and psychological stage of development. A focused approach to their eventual transition to adult care is essential for long-term survival and quality of life. PMID- 25017081 TI - Challenges in living donor liver transplantation. AB - Living donor liver transplantation is a procedure that has waned in its application over the past decade but remains a beneficial procedure for properly selected candidates. This review discusses some of the newer, relevant studies in the field, focusing on outcomes with hepatocellular carcinoma, ABO-incompatible transplant, and issues in donor complications and safety. PMID- 25017082 TI - Multivisceral transplantation: where do we stand? AB - Intestinal transplantation is the definitive therapy for patients with irreversible intestinal failure and can be combined with transplantation of other abdominal organs, such as stomach, spleen, and pancreas with or without liver. There is an increasing trend in the volume of intestinal and multivisceral transplantation in the past few decades and there is also increasing trend in patient and graft survival primarily due to improved patient selection, advances in immunosuppression, and improved perioperative management. This review summarizes the various key elements in patient selection, types of grafts, and updates in the perioperative management involved in multivisceral transplantation. PMID- 25017080 TI - Expanded criteria donors. AB - The greatest challenge facing liver transplantation today is the shortage of donor livers. Demand far exceeds supply, and this deficit has driven expansion of what is considered an acceptable organ. The evolving standard has not come without costs, however, as each new frontier of expanded donor quality (i.e., advancing donor age, donation after cardiac death, and split liver) may have traded wait-list for post-transplant morbidity and mortality. This article delineates the nature and severity of risk associated with specific deceased donor liver characteristics and recommends strategies to maximally mitigate these risks. PMID- 25017083 TI - Recurrence of nonviral liver diseases after liver transplantation. AB - Many nonviral diseases that cause liver failure may recur after liver transplantation. Although most studies have shown that a recurrent disease does not negatively affect patient and graft survival in the intermediate postoperative course, there is growing evidence that, especially in patients with primary sclerosing cholangitis and in patients with recurrent abusive alcohol drinking, disease recurrence is a significant risk factor for graft dysfunction and graft loss. Therefore, the recurrence of nonviral diseases has become a clinically important and prognostically relevant issue in the long-term management of recipients of liver transplantation. PMID- 25017084 TI - Immunosuppression: trends and tolerance? AB - Advances in pharmacologic immunosuppression are responsible for the excellent outcomes experienced by recipients of liver transplants. However, long-term follow-up of these patients reveals an increasing burden of morbidity and mortality that is attributable to these drugs. The authors summarize the agents used in contemporary liver transplantation immunosuppression protocols and discuss the emerging trend within the community to minimize or eliminate these agents from use. The authors present recently published data that may provide the foundation for immunosuppression minimization or tolerance induction in the future and review studies that have focused on the utility of biomarkers in guiding immunosuppression management. PMID- 25017085 TI - Improving long-term outcomes after liver transplantation. AB - Long-term survival following liver transplantation is profoundly affected by conditions unrelated to graft function. Many causes of mortality are contributed to by the metabolic syndrome. The approach to metabolic syndrome in liver transplant recipients requires consideration of transplant-specific factors, particularly immunosuppression. Enhancing long-term outcomes for liver transplant recipients necessitates minimizing the amount of immunosuppression required to prevent rejection. Studies to determine the optimal approach to minimize the impact of metabolic syndrome and complications of immunosuppression in transplant recipients are needed. PMID- 25017086 TI - Hepatic retransplant: what have we learned? AB - Hepatic retransplant accounts for 5% to 15% of liver transplants in most series and is associated with significantly increased hospital costs and inferior patient survival when compared with primary liver transplant. Early retransplants are usually due to primary graft nonfunction or vascular thrombosis, whereas later retransplants are most commonly necessitated by chronic rejection or recurrent primary liver disease. Hepatic retransplant remains the sole option for survival in many patients facing allograft failure after liver transplant. With improved techniques to match retransplant candidates with appropriate donor grafts, it is hoped that the outcomes of retransplant will continue to improve in future. PMID- 25017087 TI - Liver transplantation: update of concepts and practice. PMID- 25017088 TI - Sensitive detection of microRNA by chronocoulometry and rolling circle amplification on a gold electrode. AB - We developed a quantitative detection scheme for nucleic acids, combining solid phase rolling circle amplification and chronocoulometry (RCA-CC). A gold electrode was directly formed on a polystyrene substrate as a cost-effective and flexible biosensor for sensitive detection of microRNA (mir-143) in blood samples. PMID- 25017089 TI - Alcohol, marijuana, and tobacco use trajectories from age 12 to 24 years: demographic correlates and young adult substance use problems. AB - Substance use trajectories were examined from early adolescence to young adulthood among a diverse sample of 998 youths. Analysis of longitudinal data from ages 12 to 24 identified distinct trajectories for alcohol, marijuana, and tobacco use. Modeling revealed 8 alcohol, 7 marijuana, and 6 tobacco use trajectories. Analyses assessed risk for substance use problems in early adulthood within each trajectory, as well as overlap among alcohol, marijuana, and tobacco use trajectories. Findings confirmed that adolescents with early- and rapid-onset trajectories are particularly vulnerable to the development of problematic substance use in early adulthood. However, analyses also identified an escalating high school onset trajectory for alcohol and for marijuana use that was equally prognostic of problem use in adulthood. Moreover, tobacco use in early adolescence was associated with developing high-risk marijuana and alcohol use patterns. Random assignment to the Family Check-Up intervention was found to reduce risk for membership in the high-risk marijuana use trajectories, suggesting that family-based approaches delivered during adolescence can prevent escalations to problematic substance use. These findings suggest the importance of developmental heterogeneity and equifinality in considering prevention for alcohol and drug use. PMID- 25017090 TI - Hydrogen retention and diffusion in tungsten beryllide. AB - Beryllide compounds are often used in various domains because they are more resilient to oxidation than pure beryllium and at the same time they keep some of the properties of this metal. Nevertheless, the data about their properties during atomic hydrogen exposure are very scarce: numerous experiments have been conducted in the past few years on solid hydride deposition under beryllium seeded plasma action or on energetic hydrogen implantation into metallic beryllium; many others have been devoted to hydrogen retention and diffusion in tungsten. There have been fewer studies about hydrogen interaction with the alloys of these metals, although the beryllium-tungsten mixed compounds have been experimentally detected in laboratory experiments. This article reports on calculations carried out using first-principles density functional theory (DFT) on tungsten beryllide crystal (Be12W) taken as a model alloy. The formation and reactivity of atomic vacancies are investigated in the domain of temperature ranging from 0 to 500 K, together with atomic hydrogen retention and diffusivity in the bulk and in/out vacancies. PMID- 25017091 TI - Effective visualization assay for alcohol content sensing and methanol differentiation with solvent stimuli-responsive supramolecular ionic materials. AB - This study demonstrates a rapid visualization assay for on-spot sensing of alcohol content as well as for discriminating methanol-containing beverages with solvent stimuli-responsive supramolecular ionic material (SIM). The SIM is synthesized by ionic self-assembling of imidazolium-based dication C10(mim)2 and dianionic 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) in water and shows water stability, a solvent stimuli-responsive property, and adaptive encapsulation capability. The rationale for the visualization assay demonstrated here is based on the combined utilization of the unique properties of SIM, including its water stability, ethanol stimuli-responsive feature, and adaptive encapsulation capability toward optically active rhodamine 6G (Rh6G); the addition of ethanol into a stable aqueous dispersion of Rh6G-encapsulated SIM (Rh6G-SIM) destructs the Rh6G-SIM structure, resulting in the release of Rh6G from SIM into the solvent. Alcohol content can thus be visualized with the naked eyes through the color change of the dispersion caused by the addition of ethanol. Alcohol content can also be quantified by measuring the fluorescence line of Rh6G released from Rh6G-SIM on a thin-layer chromatography (TLC) plate in response to alcoholic beverages. By fixing the diffusion distance of the mobile phase, the fluorescence line of Rh6G shows a linear relationship with alcohol content (vol %) within a concentration range from 15% to 40%. We utilized this visualization assay for on-spot visualizing of the alcohol contents of three Chinese commercial spirits and discriminating methanol-containing counterfeit beverages. We found that addition of a trace amount of methanol leads to a large increase of the length of Rh6G on TLC plates, which provides a method to identify methanol adulterated beverages with labeled ethanol content. This study provides a simple yet effective assay for alcohol content sensing and methanol differentiation. PMID- 25017092 TI - Association between cardiovascular risk factors and measurements of blood pressure and cholesterol in 27 European countries in 2009. AB - OBJECTIVE: To investigate whether having multiple risk factors for cardiovascular disease is associated with having had cholesterol and blood pressure measurements in the past year. METHODS: Cross-sectional data from the 2009 Eurobarometer survey (wave 72.3), were analysed. Self-reported data on smoking, fruit consumption, alcohol consumption and physical activity were collected from 15,287 individuals aged between 40 and 75 years from 27 European countries. RESULTS: Having had a cholesterol test was inversely associated with smoking (OR=0.85; 95% CI:0.74-0.96), high alcohol (OR=0.81; 95% CI: 0.66-0.99) and low fruit consumption (OR=0.83; 95% CI: 0.73-0.93), but not with sedentary lifestyle. Having had a blood pressure test was also inversely associated with smoking (OR=0.84; 95% CI: 0.73-0.97), high alcohol (OR=0.74; 95% CI: 0.60-0.92) and low fruit consumption (OR=0.73; 95% CI: 0.64-0.84). The more risk factors reported by respondents, the less likely they were to have had a preventive test in the past year. Individuals with all four risk factors were less likely to have had their cholesterol (OR=0.42; 95% CI: 0.26-0.68) and blood pressure (OR=0.45; 95% CI: 0.27-0.75) measured compared to individuals with no risk factors. CONCLUSIONS: Screening strategies in Europe need to be revised, as Europeans at the highest risk for cardiovascular diseases were the least likely to have received cholesterol or blood pressure tests. PMID- 25017093 TI - Exploration of the patient-therapist relationship in psychotherapy. AB - Research from several domains indicates that genetic factors, childhood environment, and later interpersonal experiences are important sources of how patients relate to their therapists (transference). Transference work, a core specific technique in psychodynamic psychotherapy, focuses on exploring the patient-therapist relationship, with the idea that this may lead to improvement of the patients' relationships outside therapy. Many psychotherapy researchers hold the position that specific techniques do not contribute much to the outcome of psychotherapy. However, more than 30 studies have reported significant associations between transference work and outcome. These findings indicate that transference work interventions are indeed active ingredients (for better or worse). Naturalistic studies suggest that a high frequency of transference interventions may have negative effects. Randomized clinical trials indicate that transference-based treatments and alternative treatments work equally well with regard to symptom improvement. However, transference-based treatments appear to be much more effective with regard to interpersonal relations and other measures of personality functioning. The average between-groups effect size for the experimental studies listed in this article was large. Contrary to common clinical wisdom, transference interventions seem to be most important for (mainly female) patients with difficult interpersonal relationships and more severe personality pathology. Gain of insight may be a specific mechanism of change in dynamic psychotherapy, but only one treatment component study has linked transference work directly to gains in insight and subsequent improvement in interpersonal functioning. Research that examines how transference phenomena may be responded to in nondynamic therapies is scarce. PMID- 25017094 TI - Osteoimmunomodulatory properties of magnesium scaffolds coated with beta tricalcium phosphate. AB - The osteoimmunomodulatory property of bone biomaterials is a vital property determining the in vivo fate of the implants. Endowing bone biomaterials with favorable osteoimmunomodulatory properties is of great importance in triggering desired immune response and thus supports the bone healing process. Magnesium (Mg) has been recognized as a revolutionary metal for applications in orthopedics due to it being biodegradable, biocompatible, and having osteoconductive properties. However, Mg's high rate of degradation leads to an excessive inflammatory response and this has restricted its application in bone tissue engineering. In this study, beta-tricalcium phosphate (beta-TCP) was used to coat Mg scaffolds in an effort to modulate the detrimental osteoimmunomodulatory properties of Mg scaffolds, due to the reported favorable osteoimmunomodulatory properties of beta-TCP. It was noted that macrophages switched to the M2 extreme phenotype in response to the Mg-beta-TCP scaffolds, which could be due to the inhibition of the toll like receptor (TLR) signaling pathway. VEGF and BMP2 were significantly upregulated in the macrophages exposed to Mg-beta-TCP scaffolds, indicating pro-osteogenic properties of macrophages in beta-TCP modified Mg scaffolds. This was further demonstrated by the macrophage-mediated osteogenic differentiation of bone marrow stromal cells (BMSCs). When BMSCs were stimulated by conditioned medium from macrophages cultured on Mg-beta-TCP scaffolds, osteogenic differentiation of BMSCs was significantly enhanced; whereas osteoclastogenesis was inhibited, as indicated by the downregualtion of MCSF, TRAP and inhibition of the RANKL/RANK system. These findings suggest that beta TCP coating of Mg scaffolds can modulate the scaffold's osteoimmunomodulatory properties, shift the immune microenvironment towards one that favors osteogenesis over osteoclastogenesis. Endowing bone biomaterials with favorable osteoimmunomodulatory properties can be a highly valuable strategy for the development or modification of advanced bone biomaterials. PMID- 25017095 TI - PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment. AB - Combination cancer therapy has emerged as crucial approach for achieving superior anti-cancer efficacy. In this study, we developed a strategy by localized co delivery of PLK1shRNA/polylysine-modified polyethylenimine (PEI-Lys) complexes and doxorubicin (DOX) using biodegradable, thermosensitive PLGA-PEG-PLGA hydrogels for treatment of osteosarcoma. When incubated with osteosarcoma Saos-2 and MG-63 cells, the hydrogel containing PLK1shRNA/PEI-Lys and DOX displayed significant synergistic effects in promoting the apoptosis of osteosarcoma cells in vitro. After subcutaneous injection of the hydrogel containing PLK1shRNA/PEI Lys and DOX beside the tumors of nude mice bearing osteosarcoma Saos-2 xenografts, the hydrogels exhibited superior antitumor efficacy in vivo compared to the hydrogels loaded with PLK1shRNA/PEI-Lys or DOX alone. It is noteworthy that the combination treatment in vivo led to almost complete suppression of tumor growth up to 16 days, significantly enhanced PLK1 silencing, higher apoptosis of tumor masses, as well as increased cell cycle regulation. Additionally, ex vivo histological analysis of major organs of the mice indicated that the localized treatments showed no obvious damage to the organs, suggesting lower systemic toxicity of the treatments. Therefore, the strategy of localized, sustained co-delivery of PLK1shRNA and DOX by using the biodegradable, injectable hydrogel may have potential for efficient clinical treatment of osteosarcoma. PMID- 25017096 TI - Textile-templated electrospun anisotropic scaffolds for regenerative cardiac tissue engineering. AB - For patients with end-stage heart disease, the access to heart transplantation is limited due to the shortage of donor organs and to the potential for rejection of the donated organ. Therefore, current studies focus on bioengineering approaches for creating biomimetic cardiac patches that will assist in restoring cardiac function, by repairing and/or regenerating the intrinsically anisotropic myocardium. In this paper we present a simplified, straightforward approach for creating bioactive anisotropic cardiac patches, based on a combination of bioengineering and textile-manufacturing techniques in concert with nano biotechnology based tissue-engineering stratagems. Using knitted conventional textiles, made of cotton or polyester yarns as template targets, we successfully electrospun anisotropic three-dimensional scaffolds from poly(lactic-co-glycolic) acid (PLGA), and thermoplastic polycarbonate-urethane (PCU, Bionate((r))). The surface topography and mechanical properties of textile-templated anisotropic scaffolds significantly differed from those of scaffolds electrospun from the same materials onto conventional 2-D flat-target electrospun scaffolds. Anisotropic textile-templated scaffolds electrospun from both PLGA and PCU, supported the adhesion and proliferation of H9C2 cardiac myoblasts cell line, and guided the cardiac tissue-like anisotropic organization of these cells in vitro. All cell-seeded PCU scaffolds exhibited mechanical properties comparable to those of a human heart, but only the cells on the polyester-templated scaffolds exhibited prolonged spontaneous synchronous contractility on the entire engineered construct for 10 days in vitro at a near physiologic frequency of ~120 bpm. Taken together, the methods described here take advantage of straightforward established textile manufacturing strategies as an efficient and cost-effective approach to engineering 3D anisotropic, elastomeric PCU scaffolds that can serve as a cardiac patch. PMID- 25017097 TI - The influence of surface micro-structure on endothelialization under supraphysiological wall shear stress. AB - Interaction between platelets and artificial materials within cardiovascular devices triggers blood coagulation and represents a frequent adverse response to implant deployment. Avoidance of this interaction is obtained through the generation and sustenance under flow of a confluent and stable endothelial monolayer covering the luminal device surface, altogether defined as the process of endothelialization. Supraphysiological wall shear stress (WSS) levels generated within vascular assist devices (VADs) constitute a major challenge toward endothelialization. Here we report the experimental demonstration that stable endothelialization can be achieved at supraphysiological WSS levels by pure means of appropriate surface micro-structuring. Using a custom-designed flow bioreactor we exposed endothelial monolayers to physiological and supraphysiological WSS levels and investigated the resulting integrity of cell-to cell junctions, the cell density and the cell polarization. At physiological WSS levels, optimal endothelialization was obtained independently from surface topography. However, at higher WSS levels, only monolayers grown on appropriately micro-structured surfaces preserved optimal integrity. Under these flow conditions, endothelial cells polarized by the contact with the micro-structure and, interestingly, oriented themselves in the direction perpendicular to flow. Such endothelial layers withstood WSS levels exceeding of 100% or more the thresholds detected on flat substrates. PMID- 25017098 TI - Evaluating the cation binding strength and selectivity of calix[4]pyrroles: a computational and ESI-MS/MS study. AB - The cation binding strength of calix[4]pyrroles in the gas phase has been evaluated by computational studies and further substantiated by ESI mass spectrometry experiments. The DFT optimized geometries of [CP + X](+) complexes are found to be stable in a 1,3-alternate conformation through cation-pi interactions and interestingly CPs are found to be better cation receptor than calix[4]arenes. The binding energy values of [CP + X](+) complexes computed at B2PLYP/TZVP//M05-2X/TZVP follows the binding order, Li(+) > Na(+) > K(+) > Rb(+) > Cs(+). The diameter of Li(+) matches very well with the cavity size of CP and thus is optimally disposed to interact simultaneously with all four pyrrole rings through multiple cation-pi interactions. However, other cations, due to the increase in their size, drift away from the cavity center towards the rim of the cavity exhibiting weak cation-pi interactions. Energy decomposition analysis (EDA) reveals that the electrostatic and polarization effects act as the major driving force in these interactions. The important outcome of the current study is that the stability of precursor and product ions is found to be crucial in the experimental evaluation of binding affinity of Li(+) and Na(+) complexes of CP. The ESI-MS/MS experiments on the cation complexes of different substituted CPs revealed that the binding strength of CPs towards cations is also dependant on the substituents at the meso-position. PMID- 25017099 TI - Exploiting DNA mismatch repair deficiency as a therapeutic strategy. AB - The DNA Mismatch repair (MMR) pathway is critical for the maintenance of genomic stability. It is primarily responsible for the recognition and repair of mismatches that occur during DNA replication, but accumulating evidence suggest additional non-canonical roles for MMR proteins. MMR deficiency is a common feature of many tumor types. Germline mutations in MMR genes gives rise to the familial disorder, Lynch syndrome, which is associated with an increased predisposition to numerous cancers, including colorectal and endometrial. MMR deficiency has been associated with resistance to a wide range of standard therapeutic agents such as methylating agents, platinum compounds and fluoropyrimidine agents. Therefore, there is critical clinical need to identify new therapies for these resistant tumors. Recent studies, focussing on synthetic lethal interactions with MMR loss and emerging data identifying novel regulators of MMR may enable more successful treatment for MMR deficient patients. This review focuses on MMR loss in cancer and how exploiting both the canonical and non-canonical roles of MMR proteins may aid future therapeutic strategies. PMID- 25017100 TI - Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. AB - Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification of proteins catalysed by Poly(ADP-ribose) polymerases (PARP). A wealth of recent advances in the biochemical and functional characterization of the DNA-dependent PARP family members have highlighted their key contribution in the DNA damage response network, the best characterized being the role of PARP1 and PARP2 in the resolution of single-strand breaks as part of the BER/SSBR process. How PARylation contributes to the repair of double-strand breaks is less well defined but has become recently the subject of significant research in the field. The aim of this review is to provide an overview of the current knowledge concerning the role of the DNA-activated PARP1, PARP2 and PARP3 in cellular response to double strand breaks (DSB). In addition, we outline the biological significance of these properties in response to programmed DNA lesions formed during physiological processes such as antibody repertoire assembly and diversification. PMID- 25017101 TI - Ritonavir binds to and downregulates estrogen receptors: molecular mechanism of promoting early atherosclerosis. AB - Estrogenic actions are closely related to cardiovascular disease. Ritonavir (RTV), a human immunodeficiency virus (HIV) protease inhibitor, induces atherosclerosis in an estrogen-related manner. However, how RTV induce pathological phenotypes through estrogen pathway remains unclear. In this study, we found that RTV increases thickness of coronary artery walls of Sprague Dawley rats and plasma free fatty acids (FFA) levels. In addition, RTV could induce foam cell formation, downregulate both estrogen receptor alpha (ERalpha) and ERbeta expression, upregulate G protein-coupled estrogen receptor (GPER) expression, and all of them could be partially blocked by 17beta-estradiol (E2), suggesting RTV acts as an antagonist for E2. Computational modeling shows a similar interaction with ERalpha between RTV and 2-aryl indoles, which are highly subtype-selective ligands for ERalpha. We also found that RTV directly bound to ERalpha and selectively inhibited the nuclear localization of ERalpha, and residue Leu536 in the hydrophobic core of ligand binding domain (LBD) was essential for the interaction with RTV. In addition, RTV did not change the secondary structure of ERalpha-LBD like E2, which explained how ERalpha lost the capacity of nuclear translocation under the treatment of RTV. All of the evidences suggest that ritonavir acts as an antagonist for 17beta-estradiol in regulating alpha subtype estrogen receptor function and early events of atherosclerosis. PMID- 25017102 TI - Mutations in ZBTB20 cause Primrose syndrome. AB - Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism. PMID- 25017103 TI - Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle. AB - The 1000 bull genomes project supports the goal of accelerating the rates of genetic gain in domestic cattle while at the same time considering animal health and welfare by providing the annotated sequence variants and genotypes of key ancestor bulls. In the first phase of the 1000 bull genomes project, we sequenced the whole genomes of 234 cattle to an average of 8.3-fold coverage. This sequencing includes data for 129 individuals from the global Holstein-Friesian population, 43 individuals from the Fleckvieh breed and 15 individuals from the Jersey breed. We identified a total of 28.3 million variants, with an average of 1.44 heterozygous sites per kilobase for each individual. We demonstrate the use of this database in identifying a recessive mutation underlying embryonic death and a dominant mutation underlying lethal chrondrodysplasia. We also performed genome-wide association studies for milk production and curly coat, using imputed sequence variants, and identified variants associated with these traits in cattle. PMID- 25017105 TI - Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. AB - High-throughput DNA sequencing technology has transformed genetic research and is starting to make an impact on clinical practice. However, analyzing high throughput sequencing data remains challenging, particularly in clinical settings where accuracy and turnaround times are critical. We present a new approach to this problem, implemented in a software package called Platypus. Platypus achieves high sensitivity and specificity for SNPs, indels and complex polymorphisms by using local de novo assembly to generate candidate variants, followed by local realignment and probabilistic haplotype estimation. It is an order of magnitude faster than existing tools and generates calls from raw aligned read data without preprocessing. We demonstrate the performance of Platypus in clinically relevant experimental designs by comparing with SAMtools and GATK on whole-genome and exome-capture data, by identifying de novo variation in 15 parent-offspring trios with high sensitivity and specificity, and by estimating human leukocyte antigen genotypes directly from variant calls. PMID- 25017104 TI - Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P=1.9*10(-16)), we identified an association at 2p23 spanning CAPN14 (P=2.5*10(-10)). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8*10(-2) 0.05). Fluid retention was higher for SD than W (68.2% +/- 13.0% vs. 51.3% +/- 12.6%, p = 0.013), but not for FCW and NEW (62.5% +/- 15.4% and 65.9% +/- 15.4%, p > 0.05). All beverages were palatable and well tolerated; none maintained a positive net fluid balance after 3 h, but deficit was greater in W versus SD (p = 0.001). FCW scored higher for sweetness (p = 0.03). Thirst increased immediately after exercise but returned to baseline after drinking a small volume (p < 0.0005). In conclusion, additional potassium in FCW and NEW did not result in additional rehydration benefits over those already found in a conventional sports drink with sodium. PMID- 25017114 TI - Cold-water immersion and iced-slush ingestion are effective at cooling firefighters following a simulated search and rescue task in a hot environment. AB - Firefighters are exposed to hot environments, which results in elevated core temperatures. Rapidly reducing core temperatures will likely increase safety as firefighters are redeployed to subsequent operational tasks. This study investigated the effectiveness of cold-water immersion (CWI) and iced-slush ingestion (SLUSH) to cool firefighters post-incident. Seventy-four Australian firefighters (mean +/- SD age: 38.9 +/- 9.0 years) undertook a simulated search and rescue task in a heat chamber (105 +/- 5 degrees C). Testing involved two 20 min work cycles separated by a 10-min rest period. Ambient temperature during recovery periods was 19.3 +/- 2.7 degrees C. Participants were randomly assigned one of three 15-min cooling protocols: (i) CWI, 15 degrees C to umbilicus; (ii) SLUSH, 7 g.kg(-1) body weight; or (iii) seated rest (CONT). Core temperature and strength were measured pre- and postsimulation and directly after cooling. Mean temperatures for all groups reached 38.9 +/- 0.9 degrees C at the conclusion of the second work task. Both CWI and SLUSH delivered cooling rates in excess of CONT (0.093 and 0.092 compared with 0.058 degrees C.min(-1)) and reduced temperatures to baseline measurements within the 15-min cooling period. Grip strength was not negatively impacted by either SLUSH or CONT. CWI and SLUSH provide evidence-based alternatives to passive recovery and forearm immersion protocols currently adopted by many fire services. To maximise the likelihood of adoption, we recommend SLUSH ingestion as a practical and effective cooling strategy for post-incident cooling of firefighters in temperate regions. PMID- 25017116 TI - Exaltation in temporal lobe epilepsy: neuropsychiatric symptom or portal to the divine? AB - Religiosity is a prominent feature of the Geschwind syndrome, a behavioural pattern found in some cases of temporal lobe epilepsy. Since the 1950s, when Wilder Penfield induced spiritual feelings by experimental manipulation of the temporal lobes, development of brain imaging technology has revealed neural correlates of intense emotional states, spurring the growth of neurotheology. In their secular empiricism, psychiatry, neurology and psychology are inclined to pathologise deviant religious expression, thereby reinforcing the dualism of objective and phenomenal worlds. Considering theological perspectives and the idea of cosmic consciousness, the authors urge a holistic approach to the spiritual events of epileptic aura, potentially leading to a deeper understanding of the mind and its transcendent potential. PMID- 25017117 TI - A UK Single Centre Retrospective Analysis of the Relationship between Haemodynamic Changes and Outcome in Patients Undergoing Prolonged Left Ventricular Assist Device Support. AB - PURPOSE: Despite their efficacy, LVADs remain associated with serious complications. The relationship between haemodynamic changes during support and outcome remains inadequately characterised. This association was investigated in LVAD recipients undergoing prolonged support. METHODS: Forty patients receiving LVAD therapy for >2 years were reviewed retrospectively (mean support duration was 38.62 +/- 15.28). Pre- and on-LVAD haemodynamic data were assessed in three groups: (1) those receiving ongoing support (n = 24); (2) those who underwent cardiac transplantation (n = 4); (3) those who died during support (n = 12). RESULTS: For group 1 and 2, LVAD support achieved a decrease in mean PAP, mean PCWP, TPG, and PVR and an increase in thermodilution blood flow (TBF) with significance at <=5% level. For group 3, there were non-significant changes in TPG and PVR at the 5% level but for mean PAP, mean PCWP, and TBF the changes were similar to Groups 1 and 2 with significance at <=5% level. Aggregated data from all three groups showed a 58% increase in TBF on LVAD support. CONCLUSION: Highly significant and favourable haemodynamic changes were found. However, group 3 did not undergo decrease in TPG and PVR possibly because of suboptimal LVAD flow, right heart dysfunction and unavoidable prolongation of support. PMID- 25017118 TI - Galanin receptor 2 utilizes distinct signaling pathways to suppress cell proliferation and induce apoptosis in HNSCC. AB - Galanin and its receptors, GALR1 and GALR2, are tumor suppressors and represent therapeutic targets in head and neck squamous cell carcinoma (HNSCC). In the present study, it was demonstrated that the re-expression of GALR1 in GALR1 and GALR2-negative HNSCC cells suppresses tumor cell proliferation. This is mediated via extracellular-regulated protein kinase-1/2 (ERK1/2)-dependent effects on the cyclin-dependent kinase inhibitors (CKI) and cyclin D1. In combination with galanin, GALR2 also suppressed proliferation by increasing CKI and decreasing cyclin D1 levels. In contrast to GALR1, overexpression of GALR2 also induced caspase-3-dependent apoptosis. It was identified that in GALR2-transfected cells, galanin induced activation of ERK1/2 and suppressed cell proliferation. Galanin stimulation also decreased the expression of cyclin D1 and induced apoptotic DNA ladder formation in GALR2-transfected cells. Pretreatment with the ERK1/2 specific inhibitor U0126 and pertussis toxin prevented the suppression of cyclin D1 expression, however did not affect DNA ladder formation. In conclusion, GALR2 expression in the presence of galanin exerts antitumor effects via cell cycle arrest and apoptotic pathways, and reactivation of these pathways may have therapeutic benefits in HNSCC. PMID- 25017119 TI - Naringenin inhibits migration of bladder cancer cells through downregulation of AKT and MMP-2. AB - Bladder cancer is one of the causes of cancer-related death and has a high mortality rate due to its metastatic ability. Naringenin, a bioactive compound predominantly found in citrus fruits, exhibits several cellular functions, including anti-oxidant, -lipidemia and -cancer abilities. However, the effects of naringenin on bladder cancer cells are yet to be elucidated. The present study investigated the molecular mechanisms underlying the effects of naringenin on the migration of TSGH-8301 bladder cancer cells. Treatment with naringenin at doses ranging between 0 and 300 uM over a period of 24 h was found to reduce cell viability. Furthermore, zymography and western blot analysis revealed that naringenin reduced the expression of matrix metalloproteinase (MMP)-2 in a dose dependent manner, and repressed its activity. Naringenin also reduced TSGH-8301 cell migration in a concentration-dependent manner, as evidenced by wound healing and Transwell(r) assays. In addition, naringenin was found to inhibit AKT activity and block the nuclear translocation of nuclear factor kappa-light-chain enhancer of activated B cells. In conclusion, the findings of the present study show that naringenin is capable of inhibiting bladder cancer cell migration through the downregulation of the AKT and MMP-2 pathways. PMID- 25017120 TI - Life, cognition and metabiology. AB - At the biological level, what is innate is the result of an evolutionary process and is "programed" by natural selection. Natural selection is the "coder" (once linked to the emergence of meaning). This coupled process is indissolubly correlated with the continuous construction of new formats in accordance with the unfolding of ever-new mathematics, a mathematics that necessarily moulds coder's activity. Hence, the necessity of articulating and inventing a mathematics capable of engraving itself in an evolutionary landscape in accordance with the opening up of meaning. In this sense, for instance, the realms of non-standard models and non-standard analysis represent, today, a fruitful perspective in order to point out, in mathematical terms, some of the basic concepts concerning the articulation of an adequate intentional information theory. PMID- 25017121 TI - Trade-offs between voice and silence: a qualitative exploration of oncology staff's decisions to speak up about safety concerns. AB - BACKGROUND: Research suggests that "silence", i.e., not voicing safety concerns, is common among health care professionals (HCPs). Speaking up about patient safety is vital to avoid errors reaching the patient and thus to prevent harm and also to improve a culture of teamwork and safety. The aim of our study was to explore factors that affect oncology staff's decision to voice safety concerns or to remain silent and to describe the trade-offs they make. METHODS: In a qualitative interview study with 32 doctors and nurses from 7 oncology units we investigated motivations and barriers to speaking up towards co-workers and supervisors. An inductive thematic content analysis framework was applied to the transcripts. Based on the individual experiences of participants, we conceptualize the choice to voice concerns and the trade-offs involved. RESULTS: Preventing patients from serious harm constitutes a strong motivation to speaking up but competes with anticipated negative outcomes. Decisions whether and how to voice concerns involved complex considerations and trade-offs. Many respondents reflected on whether the level of risk for a patient "justifies" the costs of speaking up. Various barriers for voicing concerns were reported, e.g., damaging relationships. Contextual factors, such as the presence of patients and co workers in the alarming situation, affect the likelihood of anticipated negative outcomes. Speaking up to well-known co-workers was described as considerably easier whereas "not knowing the actor well" increases risks and potential costs of speaking up. CONCLUSIONS: While doctors and nurses felt strong obligation to prevent errors reaching individual patients, they were not engaged in voicing concerns beyond this immediacy. Our results offer in-depth insight into fears and conditions conducive of silence and voicing and can be used for educational interventions and leader reinforcement. PMID- 25017122 TI - Co-overexpression of HER2/HER3 is a predictor of impaired survival in breast cancer patients. AB - BACKGROUND: Recently, HER3-expression was postulated as independent risk factor for metastatic spread. Therefore, we investigated the role of HER3 expression as prognostic marker in metastatic breast cancer patients. METHODS: Patients of different breast cancer subtypes diagnosed with metastatic disease (visceral and/or brain metastases) were identified from a breast cancer database. Tissue samples of the respective primary tumors were retrieved, and immunohistochemical staining for estrogen-receptor, progesterone-receptor, HER2, and HER3 was performed. In HER2 equivocal and selected HER3 positive cases, subsequent fluorescent in situ hybridization (FISH) analysis was performed. RESULTS: Tissue specimens of 110 patients were available for this analysis. 21% had strong, complete, membranous HER3 staining of at least 10% of all tumor cells; HER3 protein expression was not associated with HER3 gene amplification. HER2/HER3 co overexpression was observed in 12/110 (11%) specimens and HER3-overexpression showed a statistically significant association with HER2-overexpression (p = 0.02). No correlation was observed for HER3-overexpression and overall survival (OS), time to diagnosis of brain metastases, and incidence of brain metastases. Still, in patients with HER3 overexpression, a higher rate of 'brain only' metastatic behavior was observed (p = 0.042). In the HER2-positive subgroup, HER3 overexpression was significantly associated with shorter OS from diagnosis of metastatic disease (median 17 vs. 35 months; p = 0.04; log rank test). CONCLUSIONS: HER2/HER3 co-overexpression is significantly associated with impaired OS from diagnosis of metastatic disease in patients with HER2-positive metastatic breast cancer. Co-inhibition of HER2 and HER3 or the inhibition of HER2/HER3 hetero-dimerization may improve clinical outcome in this subgroup. PMID- 25017123 TI - Transcription factors as master regulator for cancer stemness: remove milk from fox? AB - Some cancers display a cellular hierarchy of varying differentiation states, as if they phenocopy the normal organ development processes. Accumulating evidence suggests that the molecular signals that control carcinogenesis, at least partially, overlap with those involved in organogenesis. Cancer stem cells (CSCs) at the apex of cellular hierarchy are likely one, if not the only, critical therapeutic target in cancers. The proto-oncogene FOXM1 is a transcription factor (TF) defined as a master regulator for a broad array of genes required for CSCs and therefore FOXM1 is overexpressed in various cancers. In general, therapeutic development for TFs is a challenging task. Recently, on the other hand, novel insight has been brought by the discovery of a protein complex of FOXM1 with the mitotic kinase MELK in CSCs in brain cancers, as this protein complex appears to be cancer-specific. This editorial describes FOXM1 signaling in cancers and its potential therapeutic development. PMID- 25017124 TI - Alternative promoter activation leads to the expression of a novel human lysyl oxidase variant that functions as an amine oxidase. AB - The lysyl oxidase (LOX) family is an emerging family of amine oxidases that is responsible for lysine-mediated crosslinks found in collagen and elastin. Several novel functions, such as tumor suppression, tumor progression, cellular senescence, chemotaxis and the modification of histones have recently been attributed to the LOX family of proteins. In the search for more human LOX paralogs, in the present study, we identified several expressed sequence tag (EST) clones that showed an alternative exon-intron splice pattern from LOX. These ESTs corresponded to the LOX transcript variant 2 (LOX-v2) that was recently reported in GenBank (accession no. NM_001178102). LOX-v2 mRNA lacks exon 1 of LOX, but contains an additional 222 bp sequence from the 5'-flanking intronic region of exon 2. The deduced LOX-v2 polypeptide contains the characteristic C-terminal domains of the LOX family, but does not contain the N terminal propeptide region that has been reported to have tumor suppressor activity. In peroxidase-coupled fluorometric assays, LOX-v2 showed beta aminopropionitrile-inhibitable amine oxidase activity toward collagen and elastin. RT-PCR analysis of human tissues revealed a distinct tissue specificity of LOX-v2 expression compared to that of LOX. Promoter assays indicated that an alternative promoter element present in the exon 1 region of LOX was sufficient for the differential expression of LOX-v2. These findings indicate that the human LOX gene encodes 2 variants, LOX and LOX-v2, both of which function as amine oxidases with distinct tissue specificities. PMID- 25017125 TI - Nanogold plasmonic photocatalysis for organic synthesis and clean energy conversion. AB - This review provides the basic concepts, an overall survey and the state-of-the art of plasmon-based nanogold photocatalysis using visible light including fundamental understanding and major applications to organic reactions and clean energy-conversion systems. First, the basic concepts of localized surface plasmon resonance (LSPR) are recalled, then the major preparation methods of AuNP-based plasmonic photocatalysts are reviewed. The major part of the review is dedicated to the latest progress in the application of nanogold plasmonic photocatalysis to organic transformations and energy conversions, and the proposed mechanisms are discussed. In conclusion, new challenges and perspectives are proposed and analyzed. PMID- 25017127 TI - The Vicious Worm: a computer-based Taenia solium education tool. AB - Ignorance is a major obstacle for the effective control of diseases. To provide evidence-based knowledge about prevention and control of Taenia solium cysticercosis, we have developed a computer-based education tool: 'The Vicious Worm'. The tool targets policy makers, professionals, and laypeople, and comprises educational materials including illustrated short stories, videos, and scientific texts designed for the different target groups. We suggest that evidence-based health education is included as a specific control measure in any control programme. PMID- 25017128 TI - Chemosensory receptors in tsetse flies provide link between chemical and behavioural ecology. AB - Tsetse flies survive in a variety of environments across tropical Africa, often rising to large numbers, despite their low birth rate of one offspring every seven to nine days. They use olfactory receptors to process chemical signals in their environments to find food, escape from predators, and locate suitable larviposition sites. We discuss the identification of odorant and gustatory receptors in Glossina morsitans morsitans and the role genomics could play in management of nuisance insects. PMID- 25017126 TI - Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells. AB - Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival. PMID- 25017129 TI - Destructuration or continuity? The daily rhythm of eating in Denmark, Finland, Norway and Sweden in 1997 and 2012. AB - There is a widely shared belief that contemporary eating culture is undergoing a process of 'destructuration' in which collective norms guiding temporal, social, and spatial aspects of eating as well as cuisine will decline or disappear. From another theoretical perspective one could argue that shared and regular patterns are quite resistant to change because they are functionally necessary for the organization and maintenance of social actions in everyday life. Using questionnaire data from Denmark, Finland, Norway and Sweden from the years 1997 and 2012 we investigate whether culturally shared timing of eating rhythms has disappeared or declined. At the population-wide level, we find clear national peaks (occurring around breakfast, lunch, and to a lesser extent dinner) during which a great number, or even the majority, of people eat. These basic rhythms of eating are nationally specific and clearly identifiable in 1997 and 2012, and only small changes were found to have occurred over the period studied. Subsequent examination of within-country differences in daily eating rhythms identified a specific sub-population with very similar features in all countries. The sub-population deviates temporally from the collective peaks of eating, and in it conventional meal types such as breakfast and lunch are skipped to a higher extent, giving what we call an 'unsynchronized' eating pattern. Interestingly, the pattern has become more common in all countries. While the growth of this sub population may be a sign of a coming destructuration of meal culture, further analysis suggests this is not the case. Thus, we find clear socio-structural explanations for unsynchronized eating. It is related to the social coordination of work, and unsynchronized eating tends to be abandoned over the life course: with the establishment of a family, and old age, people tend to synchronize their eating habits with collective activities in society. Coupling this with the relatively modest growth of the unsynchronized pattern, and bearing in mind that it is a minority phenomenon, encompassing approximately one quarter of the population in 2012, we argue that an all-encompassing temporal destructuration will not develop. Additional analysis shows that the idea of a simultaneous rupture of eating culture on several dimensions (temporal, social, spatial, manners, cuisine) is doubtful. Thus, although, to a higher extent, individuals with an unsynchronized eating rhythm lack "manners" and eat more unhealthily, they do not display a higher degree of destructuration in the social and spatial dimensions of eating. Indeed, unsynchronized eating leads to fewer daily eating events, which contradicts the 'grazing' theory altogether. PMID- 25017130 TI - Young people's food practices and social relationships. A thematic synthesis. AB - Food practices are embedded in everyday life and social relationships. In youth nutrition promotion little attention is awarded to this centrality of food practices, yet it may play a pivotal role for young people's overall health and wellbeing beyond the calories food provides. Limited research is available explicitly investigating how food practices affect social relationships. The aim of this synthesis was therefore to find out how young people use everyday food practices to build, strengthen, and negotiate their social relationships. Using a thematic synthesis approach, we analysed 26 qualitative studies exploring young people's food practices. Eight themes provided insight into the ways food practices affected social relationships: caring, talking, sharing, integrating, trusting, reciprocating, negotiating, and belonging. The results showed that young people use food actively to foster connections, show their agency, and manage relationships. This synthesis provides insight into the settings of significance for young people where more research could explore the use of food in everyday life as important for their social relationships. A focus on social relationships could broaden the scope of nutrition interventions to promote health in physical and psychosocial dimensions. Areas for future research are discussed. PMID- 25017132 TI - Appropriately sized bioengineered human external anal sphincter constructs. PMID- 25017131 TI - Swedish students' interpretations of food symbols and their perceptions of healthy eating. An exploratory study. AB - This study used focus group discussions to investigate how a group of Swedish University students (24 women and five men) interpret symbols with claims about health and/or symbols with information about nutrition. The participants mostly talked about farming methods and food processes when asked about health and nutrition symbols. The Swedish Keyhole was the most familiar symbol to the participants but they had scant knowledge of its meaning. Symbols that were judged to be the most useful in guiding food choices were, according to the participants, symbols showing information about number of calories and/or nutrients. However, the most striking finding is still that the food experts' medical discourse, i.e. the focus on physical health and nutritional effects on the individual body, seems to be inconsistent with the participants' perceptions of healthy eating and risk. The participants rather used what we call an "inauthenticity discourse" where health and risks are judged in relation to farming methods, industrial food production, additives and other aspects of the food that are unknown to the individual. Despite limitations considering the number of participations and their relative homogeneity, these findings contribute to a further understanding of the gap between experts and the public when it comes to perceptions of healthy eating and risks. If this is a broader phenomenon, then we argue that this must be acknowledged if information about health and risk is to be communicated successfully. PMID- 25017133 TI - Medicare Hospital Readmission Reduction Program: what is the effect on surgery? PMID- 25017134 TI - The adverse effects of preoperative cholangitis on the outcome of portal vein embolization and subsequent major hepatectomies. AB - BACKGROUND: The presence of cholangitis has been shown to impair liver regeneration capacity after major hepatectomy in a rat cholangitis model. It is unclear, however, whether the presence of cholangitis has any impact on liver generation in clinical settings. OBJECTIVE: To determine the effects of preoperative cholangitis on hepatic regeneration rates after preoperative portal vein embolizations (PVEs) and postoperative courses after major hepatectomies in humans. METHODS: From 1991 to 2012, 450 patients underwent preoperative PVEs and subsequent major hepatectomies. Among them, 72 patients (16.0%) had preoperative cholangitis. The volume change of the nonembolized lobe after PVE and the postoperative outcomes after a major hepatectomy were compared between cholangitis and noncholangitis groups. RESULTS: The average volume increase in the nonembolized lobe after PVE was almost identical in both the cholangitis (10.0%) and noncholangitis (9.5%) groups. The average term required to acquire institutional safety criteria, however, was longer in the cholangitis group (24.3 days) compared with the noncholangitis group (18.3 days) (P < .001). The postoperative maximum serum total bilirubin levels (5.7 mg/dL vs 8.1 mg/dL, P = .035), morbidity rate (56% vs 78%, P = .001), and postoperative hospital stay (44 days vs 53 days, P = .021) were all greater in the cholangitis group compared with the noncholangitis group. With multivariate logistic regression analyses, the presence of preoperative cholangitis was identified as one of the independent risk factors for postoperative morbidity. CONCLUSION: These results indicate that patients with preoperative cholangitis should be carefully managed during their perioperative periods of PVE and after major hepatectomies. PMID- 25017136 TI - Prophylactic synthetic mesh can be safely used to close emergency laparotomies, even in peritonitis. AB - BACKGROUND: This study was conducted to determine the efficacy and safety of the use of a partially absorbable large pore synthetic prophylactic mesh in emergent midline laparotomies for the prevention of evisceration and incisional hernia. METHODS: Retrospective analysis of all patients who underwent an emergency midline laparotomy between January of 2009 and July of 2010 was performed. Patients with complicated ventral hernia repair, postoperative death, and lack of follow-up were excluded. RESULTS: A total of 266 patients were included. Laparotomies were closed with a running suture of slow-reabsorbable material in 190 patients (Group S), and 50 patients within this group (26.3%) received additional retention sutures. In 76 patients (Group M), an additional partially absorbable lightweight mesh was placed in the Supra-aponeurotic space. Both groups presented similar complication rates (71.1% Group S vs 80.3% Group M, P = .97). There were no differences regarding surgical-site infection rates (17.9% Group S vs 26.3% Group M; P = .13) or postoperative mortality (13.7% Group S vs 18.3% Group M; P = .346). A total of 150 patients completed the follow-up (99 Group S; 51 Group M) at a mean time of 16.7 months. During follow-up, 36 cases of incisional hernia (24%) were diagnosed: 33 (33%) in Group S, whereas there were only three cases (5.9%) in Group M (P = .0001). Mesh removal for chronic infection was not required in any case. CONCLUSION: The use of a partially absorbable, lightweight large pore prophylactic mesh in the closure of emergency midline laparotomies is feasible for the prevention of incisional hernia without adding a substantial rate of morbidity to the procedure, even if high contamination or infections are present. PMID- 25017135 TI - A comparison of open and minimally invasive surgery for hepatic and pancreatic resections using the Nationwide Inpatient Sample. AB - BACKGROUND: The use of minimally invasive surgery (MIS) techniques for pancreatic and liver operations remains ill defined. We sought to compare inpatient outcomes among patients undergoing open versus MIS pancreas and liver operations using a nationally representative cohort. METHODS: We queried the Nationwide Inpatient Sample database for all major pancreatic and hepatic resections performed between 2000 and 2011. Appropriate International Classification of Diseases, 9th Revision (ICD-9) coding modifiers for laparoscopy and robotic assist were used to categorize procedures as MIS. Demographics, comorbidities, and inpatient outcomes were compared between the open and MIS groups. RESULTS: A total of 65,033 resections were identified (pancreas, n = 36,195 [55.7%]; liver, n = 28,035 [43.1%]; combined pancreas and liver, n = 803 [1.2%]). The overwhelming majority of operations were performed open (n = 62,192, 95.6%), whereas 4.4% (n = 2,841) were MIS. The overall use of MIS increased from 2.3% in 2000 to 7.5% in 2011. Compared with patients undergoing an open operation, MIS patients were older and had a greater incidence of multiple comorbid conditions. After operation, the incidence of complications for MIS (pancreas, 35.4%; liver, 29.5%) was lower than for open (pancreas, 41.6%; liver, 33%) procedures (all P < .05) resulting in a shorter median length of stay (8 vs 7 days; P = .001) as well as a lower in hospital mortality (5.1% vs 2.8%; P = .001). CONCLUSION: During the last decade, the number of MIS pancreatic and hepatic operations has increased, with nearly 1 in 13 HPB cases now being performed via an MIS approach. Despite MIS patients tending to have more preoperative medical comorbidities, postoperative morbidity, mortality, and duration of stay compared favorably with open surgery. PMID- 25017137 TI - Reply to questions in response to "improved survival after adding dissection of the superior mesenteric vein lymph node (14v) to standard D2 gastrectomy for advanced distal gastric cancer". PMID- 25017138 TI - Shifting role of operative and nonoperative interventions in managing complications after pancreatoduodenectomy: what is the preferred intervention? AB - INTRODUCTION: Operative complications after pancreatoduodenectomy can be managed by nonoperative or operative interventions. The aim of this study was to analyze the shift in management of five major complications and their success rates. An algorithm was developed according to predictors for type of intervention and failure of management. METHODS: From 1992-2012, patients with pancreaticojejunostomy, hepaticojejunostomy or gastroenterostomy leakage, postpancreatectomy hemorrhage, or primary abscess after pancreatoduodenectomy were selected from a prospectively maintained database. Complications were treated by nonoperative or operative intervention Two cohorts were created according to period of index operation. Pre- and postoperative characteristics were analyzed. RESULTS: Of 1,037 patients, 263 (25%) experienced operative complications. The incidence of pancreatic fistula increased from 11 to 18%, accompanied by a shift from operative toward nonoperative management. This was also seen in the management of late hemorrhage. Success rates of interventions remained similar for all complications. The incidence of primary abscesses decreased. Early sepsis (odds ratio [OR] 17.8, 95% confidence interval [CI] 4.9 64.4) was associated with failure of nonoperative interventions in patients with pancreatic fistula. Hemodynamic instability (OR 17.2, 95% CI 1.8-160.1) and sepsis (OR 6.7, 95% CI 2.7-16.3) were predictive for operative intervention. Failure of nonoperative intervention (HR 3.95% CI 1.3-7.1) and operative intervention (HR 6.4 95% CI 3.2-12.8) were predictors for poor survival. CONCLUSION: The shift towards nonoperative interventions was notable in patients suffering from pancreaticojejunostomy leakage and late hemorrhage. Anastomotic leakage, late hemorrhage, and primary abscesses can be managed nonoperatively however; hemodynamic instability and early sepsis are strong arguments to perform surgery. PMID- 25017139 TI - G2019S LRRK2 mutant fibroblasts from Parkinson's disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy. AB - Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. It is considered as a multifactorial disease dependent on environmental and genetic factors. Deregulation in cell degradation has been related with a significant increase in cell damage, becoming a target for studies on the PD etiology. In the present study, we have characterized the parkinsonian toxin 1-methyl-4 phenylpyridinium ion (MPP(+))-induced damage in fibroblasts from Parkinson's patients with the mutation G2019S in leucine-rich repeat kinase 2 protein (LRRK2) and control individuals without this mutation. The results reveal that MPP(+) induces mTOR-dependent autophagy in fibroblasts. Moreover, the effects of caspase dependent cell death to MPP(+) were higher in cells with the G2019S LRRK2 mutation, which showed basal levels of autophagy due to the G2019S LRRK2 mutation (mTOR-independent). The inhibition of autophagy by 3-methyladenine (3-MA) treatment reduces these sensitivity differences between both cell types, however, the inhibition of autophagosome-lysosome fusion by bafilomycin A1 (Baf A1) increases these differences. This data confirm the importance of the combination of genetic and environmental factors in the PD etiology. Thereby, the sensitivity to the same damage may be different in function of a genetic predisposition, reason why individuals with certain mutations can develop some early-onset diseases, such as individuals with G2019S LRRK2 mutation and PD. PMID- 25017140 TI - DNA methylation in cardiac fibrosis: new advances and perspectives. AB - Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. More specifically, cardiac fibroblasts are activated by a variety of pathological stimuli, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of cardiac fibrosis. DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. The aberrant methylation of CpG island promoters of selected genes is the prominent epigenetic mechanism by which gene transcription can be effectively silenced. Aberrant hypermethylation of a few selected genes such as RASSF1A plays an important role in facilitating fibrotic fibroblast activation and in driving fibrosis. In this review we will discuss the mechanisms of DNA methylation and their implications for cardiac fibroblasts activation and fibrosis. Control of DNA methylation may serve as a new strategy for anti-fibrotic therapy. PMID- 25017141 TI - Variations in Medicare payments for episodes of spine surgery. AB - BACKGROUND CONTEXT: Although the high cost of spine surgery is generally recognized, there is little information on the extent to which payments vary across hospitals. PURPOSE: To examine the variation in episode payments for spine surgery in the national Medicare population. We also sought to determine the root causes for observed variations in payment at high cost hospitals. STUDY DESIGN: All patients in the national fee for service Medicare population undergoing surgery for three conditions (spinal stenosis, spondylolisthesis, and lumbar disc herniation) between 2005 and 2007 were included. PATIENT SAMPLE: Included 185,954 episodes of spine surgery performed between 2005 and 2007. OUTCOME MEASURES: Payments per episode of spine surgery. METHODS: All patients in the national fee for service Medicare population undergoing surgery for three conditions (spinal stenosis, spondylolisthesis, and lumbar disc herniation) between 2005 and 2007 were identified (n=185,954 episodes of spine surgery). Hospitals were ranked on least to most expensive and grouped into quintiles. Results were risk- and price adjusted using the empirical Bayes method. We then assessed the contributions of index hospitalization, physician services, readmissions, and postacute care to the overall variations in payment. RESULTS: Episode payments for hospitals in the highest quintile were more than twice as high as those made to hospitals in the lowest quintile ($34,171 vs. $15,997). After risk- and price-adjustment, total episode payments to hospitals in the highest quintile remained $9,210 (47%) higher. Procedure choice, including the use of fusion, was a major determinant of the total episode payment. After adjusting for procedure choice, however, hospitals in the highest quintile continued to be 28% more expensive than those in the lowest. Differences in the use of postacute care accounted for most of this residual variation in payments across hospitals. Hospital episode payments varied to a similar degree after subgroup analyses for disc herniation, spinal stenosis, and spondylolisthesis. Hospitals expensive for one condition were also found to be expensive for services provided for other spinal diagnoses. CONCLUSIONS: Medicare payments for episodes of spine surgery vary widely across hospitals. As they respond to the new financial incentives inherent in health care reform, high cost hospitals should focus on the use of spinal fusion and postacute care. PMID- 25017142 TI - Kruppel-homolog 1 mediates juvenile hormone action to promote vitellogenesis and oocyte maturation in the migratory locust. AB - Juvenile hormone (JH) prevents insect larval metamorphosis and stimulates processes for adult reproduction. Kruppel-homolog 1 (Kr-h1), a zinc finger transcription factor, is shown to mediate the anti-metamorphic effect of JH in both holometabolous and hemimetabolous insects. However, the role of Kr-h1 in JH mediated reproduction has not been determined. Using the migratory locust, Locusta migratoria, we showed here that Kr-h1 was expressed in response to JH in female adults, and Kr-h1 transcription was directly regulated by the JH-receptor complex comprised of Methoprene-tolerant (Met) and steroid receptor co-activator. We demonstrated that Kr-h1 RNAi phenocopied Met RNAi and JH-deprived condition during post-eclosion development and vitellogenesis of female locusts. Knockdown of Kr-h1 resulted in substantial reduction of Vg expression in the fat body and lipid accumulation in the primary oocytes, accompanied by blocked follicular epithelium development, oocyte maturation and ovarian growth. Our data therefore reveal a crucial role of Kr-h1 in insect vitellogenesis and egg production. This study suggests that JH-Met-Kr-h1 signaling pathway is also functional in insect reproduction. PMID- 25017143 TI - Rapid incorporation of glucosinolates as a strategy used by a herbivore to prevent activation by myrosinases. AB - Various plants have a binary defence system that consists of a substrate and a glucosidase, which is activated upon tissue disruption thereby forming reactive hydrolysis products. Insects feeding on such plants have to overcome this binary defence system or prevent the activation. In this study, we investigated the strategy used by a herbivore to deal with such binary defence. We studied, how the larvae of the sawfly Athalia rosae (Hymenoptera: Tenthredinidae) circumvent the activation of glucosinolates by myrosinase enzymes, which are found in their Brassicaceae host plants. Myrosinase activities were low in the front part of the larval gut but activities increased over the gut passage. In contrast, the glucosinolates were only highly concentrated in the first gut part and were rapidly incorporated into the haemolymph before the food reached the second half of the gut. Thus, the uptake and concentration of glucosinolates, i.e., sequestration, must occur in the front part of the gut. Using Matrix Assisted Laser Desorption Ionization-Mass Spectrometry Imaging (MALDI-MSI), we could demonstrate that the incorporated glucosinolate sinalbin circulates in the haemolymph where it accumulates around the Malpighian tubules. This study highlights the pivotal role of the gut of an adapted herbivore as a regulatory functional organ to cope with plant toxins. MALDI-MSI turned out as a highly useful technique to visualise glucosinolates in a herbivore, which has to deal with plants exhibiting a binary defence system, and may be applied to follow the fate of plant metabolites in other insect species in the future. PMID- 25017144 TI - Effects of seat structural dynamics on current ride comfort criteria. AB - The ISO 2631-1 ( 1997 ) provides methodologies for assessment of the seated human body comfort in response to vibrations. The standard covers various conditions such as frequency content, direction and location of the transmission of the vibration to the human body. However, the effects of seat structural dynamics mode shapes and corresponding resonances have not been discussed. This study provides important knowledge about the effects of vehicle seat structural vibration modes on discomfort assessment. The occupied seat resonant frequencies and corresponding vibration modes were measured and comfort test was carried out based on the paired comparison test method. The results show that the ISO 2631-1 ( 1997 ) method significantly underestimates the vibration discomfort level around the occupied seat twisting resonant frequencies. This underestimation is mainly due to the ISO suggested location of the accelerometer pad on the seatback. The centre of the seatback is a nodal point at the seat twisting mode. Therefore, it underestimates the total vibration transferred to the occupant body from the seatback. PRACTITIONER SUMMARY: The effects of the vehicle seat structural dynamics have not been discussed in the human body vibration ISO . The results of this research show that the current measurement method suggested by ISO 2631-1 (1997) can significantly underestimate the vibration discomfort level at around the seat structural vibration mode. PMID- 25017146 TI - Molecular phylogeny of short-tailed opossums (Didelphidae: Monodelphis): taxonomic implications and tests of evolutionary hypotheses. AB - Short-tailed opossums (genus Monodelphis) represent one of the most speciose clades of New World marsupials, with 26 currently recognized species that collectively range from eastern Panama to northern Argentina. Here we present the first phylogenetic analyses of the genus based on dense taxonomic sampling and multiple genes. From most sampled species we obtained >4800bp of DNA sequence from one mitochondrial gene (CYTB), two autosomal exons (IRBP exon 1, BRCA1 exon 11), one autosomal intron (SLC38 intron 7), and one X-linked intron (OGT intron 14). Maximum-parsimony, maximum-likelihood and Bayesian analyses of these data strongly support the monophyly of Monodelphis and recover six major clades within the genus. Additionally, our analyses support previous suggestions that several nominal taxa are synonyms of other species (M. "sorex" of M. dimidiata, M. "theresa" of M. scalops, M. "rubida" and M. "umbristriata" of M. americana, and M. "maraxina" of M. glirina). By contrast, four unnamed lineages recovered by our analyses may represent new species. Reconstructions of ancestral states of two discrete characters-dorsal pelage color pattern and habitat-suggest that the most recent common ancestor of Monodelphis was uniformly colored (with unpatterned dorsal pelage) and inhabited moist forest. Whereas some dorsal pelage patterns appear to have evolved homoplastically in Monodelphis, dorsal stripes may have had a unique historical origin in this genus. PMID- 25017147 TI - Advancing science for human and environmental health--The 50th EUROTOX Congress. PMID- 25017148 TI - Fe-bLf nanoformulation targets survivin to kill colon cancer stem cells and maintains absorption of iron, calcium and zinc. AB - AIM: To validate the anticancer efficacy of alginate-enclosed, chitosan conjugated, calcium phosphate, iron-saturated bovine lactoferrin (Fe-bLf) nanocarriers/nanocapsules (NCs) with improved sustained release and ability to induce apoptosis by downregulating survivin, as well as cancer stem cells. MATERIALS & METHODS: The stability, nanotoxicity of the modified nanoformulation was evaluated and their anticancer efficacy was re-examined. Their mechanism of internalization was studied and we identified the role of various miRNAs in absorption of these NCs/iron in various body parts of mice. We determined the effect of these NCs on survivin, stem cell markers, red blood cell count, iron, calcium and zinc concentration in mice, determined the antiangiogenic properties of these NCs and studied their effect on cancer stem-like cells. RESULTS: Spherical NCs (396.1 +/- 27.2 nm) exceedingly reduced viability of Caco-2 cells (32 +/- 2.83%). The NCs also showed effective internalization and reduction of cancer stem cell markers in triple-positive CD133, survivin and CD44 cancer stem like cells. Mice treated with the NCs showed no nanotoxicity and did not develop any tumors in xenograft colon cancer models. We found that the serum iron, zinc and calcium absorption were increased. DMT1, LRP, transferrin and lactoferrin receptors were responsible for internalization of the NCs. Different miRNAs were responsible for iron regulation in different organs. Interestingly, NCs inhibited survivin and its different isoforms. CONCLUSION: Our results confirmed that NCs internalized and changed the expression of selected miRNAs that further enhanced their uptake. The NCs activated both extrinsic, as well as intrinsic apoptotic pathways to induce apoptosis by targeting survivin in cancer cells and cancer stem cells, without inducing any nonspecific nanotoxicity. Apart from inhibiting angiogenesis and stem cell markers, NCs also maintained iron and calcium levels. PMID- 25017149 TI - Percutaneous ablation of bone tumors. AB - Percutaneous ablation (radiofrequency or cryotherapy) of bone tumors is most often performed for palliative purposes. Many studies have shown that percutaneous ablation of a painful bone metastasis can significantly and sustainably reduce symptoms. It is therefore an alternative to radiotherapy and to long-term opiates. Percutaneous ablation can also be performed for curative purposes. In this situation, its efficacy has however only been studied to a very small extent (apart from radiofrequency ablation of osteoid osteomas in which the success rate is almost 100%). In our experience, the success rate after radiofrequency ablation of a bone metastasis is 75% if it is less than 3cm in diameter and fall significantly over this (to 40%, P=0.04). This treatment can therefore be justified in oligometastatic patients whose disease is progressing slowly. Its benefit on survival has however not been assessed in this selected population. Whether it is performed for palliative or curative reasons, percutaneous ablation should ideally be followed by an injection of cement if the metastasis being treated is lytic and located in a bone, which is subject to mechanical forces. The aim of consolidating cementoplasty is to counterbalance the additional risk of fracture due to destruction of the percutaneously ablated bone. PMID- 25017150 TI - Standardized diagnosis and reporting of breast cancer. AB - Standardized terminology developed by the American College of Radiography (ACR) through the Breast-Imaging Reporting and Data System (BI-RADS) lexicon is used worldwide to describe the findings of the various breast-imaging techniques (mammography, ultrasound, and magnetic resonance imaging (MRI)). A 7-level positive predictive value (PPV) of malignancy classification system (from BI-RADS category 0 to category 6) has been based on this terminology, giving imaging a central role in the diagnostic strategy. This document presents the standardized, compulsory BI-RADS terminology used in breast-imaging reports in 2013 in view of the new edition that will be published at the end of the year. PMID- 25017151 TI - Post-therapeutic imaging findings. AB - Any surgical approach modifies the normal anatomical and functional arrangement of the segmental spine which is aimed, therefore image interpretation cannot ignore a correct set of knowledge in the field of anatomy, pathophysiology, drug compliance, interventional radiology and surgery. Neuroradiological imaging has an important role before surgery to direct the surgeon or interventional radiologist during the operation, both in post-surgery, where imaging examination can rightly evaluate properties and effects of the treatment and can detect potential complications as infections, abscess, bleeding, exuberant scar, mobilization and rupture of devices. The available methods of imaging are the X rays (XR) made at least in two projections, Computed Tomography (CT) with MPR (multiplanar) and VR (volume rendering) reconstruction, and Magnetic Resonance (MR), often performed before and after contrast media injection. Imaging assessment of spine after surgery is complex and depends upon several factors, including surgical procedures and disease for which it was performed; biomechanical of the underlying cortical and cancellous bone findings; conditions of muscles, intervertebral disk and ligaments; time since surgery procedures; duration and nature of the post-surgical syndrome. Depending upon several factors, one or a combination of complementary imaging modalities (X-rays, Computed Tomography, Magnetic Resonance) may be required to evaluate effectiveness of the treatment; to demonstrate any clinically relevant abnormality at the treated region and adjacent structures (complications such as inflammation, abscesses, bleeding and misplacement of the device); to assist the interventional radiologist or surgeon in deciding if is necessary intervene again, in which nature and in which vertebral level(s). PMID- 25017152 TI - Parallel-transmit-accelerated spatially-selective excitation MRI for reduced-FOV diffusion-weighted-imaging of the pancreas. AB - OBJECTIVES: To find out whether the use of accelerated 2D-selective parallel transmit excitation MRI for diffusion-weighted EPI (pTX-EPI) offers advantages over conventional single-shot EPI (c-EPI) with respect to different aspects of image quality in the MRI of the pancreas. MATERIALS AND METHODS: The MRI examinations of 33 consecutive patients were evaluated in this prospective and IRB-approved study. PTX-EPI was performed with a reduced (zoomed) FOV of 230 * 118 mm(2). The 2D-RF pulse of pTX-EPI was accelerated, i.e. shortened by a factor of 1.7 (pTX-acceleration factor). C-EPI used a full-FOV of 380 * 285 mm(2). In a qualitative analysis, two experienced readers evaluated 3 different aspects of image quality on 3- to 5-point Likert scales. Additionally, apparent diffusion coefficients (ADCs) were determined in both c-EPI and pTX-EPI in normal-appearing pancreatic tissue using regions of interests (ROIs). Mean ADC values and standard deviations were compared between the two techniques. RESULTS: The reduced-FOV pTX EPI was superior to c-EPI with respect to overall image quality (p<0.0001) and identifiability of the pancreatic ducts (p<0.01). Artifacts were significantly less severe in pTX-EPI (p<0.01). The mean ADC values of c-EPI (1.29 +/- 0.19 * 10(-3)mm(2)/s) and pTX-EPI (1.27 +/- 0.17 * 10(-3)mm(2)/s) did not differ significantly between the two techniques (p=0.44). The variation within the ROIs as measured by the standard deviation was significantly lower in pTX-EPI (0.095 * 10(-3)mm(2)/s) than in c-EPI (0.135 * 10(-3)mm(2)/s), p<0.05. CONCLUSIONS: PTX accelerated EPI with spatially-selective excitation and reduced FOV leads to substantial improvements in DWI of the pancreas with respect to different aspects of image quality without significantly influencing the ADC values. PMID- 25017154 TI - Implications of non-specific strigolactone signaling in the rhizosphere. AB - Strigolactones produced by various plant species are involved in the development of different plant parts. They are also exuded by plant roots to the rhizosphere, where they are involved in the induction of seed germination of the parasitic plants Striga and Orobanche, hyphal branching of the symbiotic arbuscular mycorrhizal fungi (AMF), and the symbiotic interaction with Rhizobium. In the present discussion paper, the essentialness of strigolactones as communication signals in these plant interactions is discussed in view of the existence of other plant-derived substances that are able to promote these plant interactions. In addition, the importance of strigolactones for determination of interaction specificity is discussed based on current knowledge on strigolactone composition, perception and delivery. The different activities of strigolactones in plant development and in the rhizosphere suggest their possible use in agriculture. However, despite efforts made in this direction, there is no current, practical implementation. Possible reasons for the encountered difficulties and suggested solutions to promote strigolactone use in agriculture are discussed. PMID- 25017155 TI - The effect of mepiquat chloride on elongation of cotton (Gossypium hirsutum L.) internode is associated with low concentration of gibberellic acid. AB - The growth regulator mepiquat chloride (MC) is globally used in cotton (Gossypium hirsutum L.) canopy manipulation to avoid excess growth and yield loss. However, little information is available as to whether the modification of plant architecture by MC is related to alterations in gibberellic acid (GA) metabolism and signaling. Here, the role of GA metabolism and signaling was investigated in cotton seedlings treated with MC. The MC significantly decreased endogenous GA3 and GA4 levels in the elongating internode, which inhibited cell elongation by downregulating GhEXP and GhXTH2, and then reducing plant height. Biosynthetic and metabolic genes of GA were markedly suppressed within 2-10d of MC treatment, which also downregulated the expression of DELLA-like genes. A remarkable feedback regulation was observed at the early stage of MC treatment when GA biosynthetic and metabolic genes expression was evidently upregulated. Mepiquat chloride action was controlled by temporal translocation and spatial accumulation which regulated GA biosynthesis and signal expression for maintaining GA homeostasis. The results suggested that MC application could reduce endogenous GA levels in cotton through controlled GA biosynthetic and metabolic genes expression, which might inhibit cell elongation, thereby shortening the internode and reducing plant height. PMID- 25017156 TI - Regulation of protein trafficking: posttranslational mechanisms and the unexplored transcriptional control. AB - Endomembrane protein trafficking assures protein location through the endocytic and secretory routes. Trafficking pathways are diverse, depending on the proteins being trafficked, the final destination as well as their itinerary. Trafficking pathways are operated by machineries composed of a set of coordinately acting factors that transport proteins between compartments. Different machineries participate in each protein trafficking pathway, providing specificity and accuracy. Changes in the activity and abundance of trafficking proteins regulate protein flux. The preponderance of one pathway over another regulates protein location and relocation. Cellular requirements change during different processes and in response to stimuli; modulation of trafficking mechanisms must relocate proteins or alternatively increase/decrease the targeting rate of certain proteins. Conventionally, protein trafficking modulation has been explained as posttranslational modification of components of the relevant trafficking machinery. However, trafficking components are also transcriptionally regulated and several reports support that this regulation can modulate protein trafficking as well. This transcriptional modulation has an impact on plant physiology, and is a critical and fundamental mechanism. This scenario suggests a determinant mechanism that must be considered in the endomembrane protein trafficking research field. PMID- 25017157 TI - Overwintering of herbaceous plants in a changing climate. Still more questions than answers. AB - The increase in surface temperature of the Earth indicates a lower risk of exposure for temperate grassland and crop to extremely low temperatures. However, the risk of low winter survival rate, especially in higher latitudes may not be smaller, due to complex interactions among different environmental factors. For example, the frequency, degree and length of extreme winter warming events, leading to snowmelt during winter increased, affecting the risks of anoxia, ice encasement and freezing of plants not covered with snow. Future climate projections suggest that cold acclimation will occur later in autumn, under shorter photoperiod and lower light intensity, which may affect the energy partitioning between the elongation growth, accumulation of organic reserves and cold acclimation. Rising CO2 levels may also disturb the cold acclimation process. Predicting problems with winter pathogens is also very complex, because climate change may greatly influence the pathogen population and because the plant resistance to these pathogens is increased by cold acclimation. All these factors, often with contradictory effects on winter survival, make plant overwintering viability under future climates an open question. Close cooperation between climatologists, ecologists, plant physiologists, geneticists and plant breeders is strongly required to predict and prevent possible problems. PMID- 25017158 TI - The polar auxin transport inhibitor TIBA inhibits endoreduplication in dark grown spinach hypocotyls. AB - We addressed the question of whether an additional round of endoreduplication in dark-grown hypocotyls is a common feature in dicotyledonous plants having endopolyploid tissues. Ploidy distributions of hypocotyl tissues derived from in vitro-grown spinach (Spinacia oleracea L. cv. Atlas) seedlings grown under different light conditions were analyzed by flow cytometry. An additional round of endoreduplication (represented by 32C cells) was found in the dark-grown hypocotyl tissues. This response was inhibited by light, the intensity of which is a crucial factor for the inhibition of endoreduplication. The higher ploidy cells in cortical tissues of the dark-grown hypocotyls had larger cell sizes, suggesting that the additional round of endoreduplication contributes to hypocotyl elongation. More importantly, a polar auxin transport inhibitor, 2,3,5 triiodobenzoic acid (TIBA), strongly inhibits endoreduplication, not only in spinach but also in Arabidopsis. Because other polar auxin transport inhibitors or an auxin antagonist show no or mild effects, TIBA may have a specific feature that inhibits endoreduplication. PMID- 25017159 TI - Zn and Fe biofortification: the right chemical environment for human bioavailability. AB - A considerable fraction of global disease burden and child mortality is attributed to Fe and Zn deficiencies. Biofortification, i.e. the development of plants with more bioavailable Zn and Fe, is widely seen as the most sustainable solution, provided suitable crops can be generated. In a cereal-dominated diet availability of Fe and Zn for absorption by the human gut is generally low and influenced by a highly complex chemistry. This complexity has mostly been attributed to the inhibitory effect of Fe and Zn binding by phytate, the principal phosphorus storage compound in cereal and legume seeds. However, phytate is only part of the answer to the multifaceted bioavailability question, albeit an important one. Recent analyses addressing elemental distribution and micronutrient speciation in seeds strongly suggest the existence of different Fe and Zn pools. Exploration of natural variation in maize showed partial separation of phytate levels and Fe bioavailability. Observations made with transgenic plants engineered for biofortification lend further support to this view. From a series of studies the metal chelator nicotianamine is emerging as a key molecule. Importantly, nicotianamine levels have been found to not only increase the loading of Fe and Zn into grains. Bioavailability assays indicate a strong activity of nicotianamine also as an enhancer of intestinal Fe and Zn absorption. PMID- 25017160 TI - Artificial transcription factor-mediated regulation of gene expression. AB - The transcriptional regulation of endogenous genes with artificial transcription factors (TFs) can offer new tools for plant biotechnology. Three systems are available for mediating site-specific DNA recognition of artificial TFs: those based on zinc fingers, TALEs, and on the CRISPR/Cas9 technology. Artificial TFs require an effector domain that controls the frequency of transcription initiation at endogenous target genes. These effector domains can be transcriptional activators or repressors, but can also have enzymatic activities involved in chromatin remodeling or epigenetic regulation. Artificial TFs are able to regulate gene expression in trans, thus allowing them to evoke dominant mutant phenotypes. Large scale changes in transcriptional activity are induced when the DNA binding domain is deliberately designed to have lower binding specificity. This technique, known as genome interrogation, is a powerful tool for generating novel mutant phenotypes. Genome interrogation has clear mechanistic and practical advantages over activation tagging, which is the technique most closely resembling it. Most notably, genome interrogation can lead to the discovery of mutant phenotypes that are unlikely to be found when using more conventional single gene-based approaches. PMID- 25017161 TI - Rice SAPs are responsive to multiple biotic stresses and overexpression of OsSAP1, an A20/AN1 zinc-finger protein, enhances the basal resistance against pathogen infection in tobacco. AB - Eukaryotic A20/AN1 zinc-finger proteins (ZFPs) play an important role in the regulation of immune and stress response. After elucidation of the role of first such protein, OsSAP1, in abiotic stress tolerance, 18 rice stress associated protein (SAP) genes have been shown to be regulated by multiple abiotic stresses. In the present study, expression pattern of all the 18 OsSAP genes have been analysed in response to different biotic stress simulators, in order to get insights into their possible involvement in biotic stress tolerance. Our results showed the upregulation of OsSAP1 and OsSAP11 by all biotic stress simulator treatments. Furthermore, the functional role of OsSAP1 in plant defence responses has been explored through overexpression in transgenic plants. Constitutive expression of OsSAP1 in transgenic tobacco resulted into enhanced disease resistance against virulent bacterial pathogen, together with the upregulation of known defence-related genes. Present investigation suggests that rice SAPs are responsive to multiple biotic stresses and OsSAP1 plays a key role in basal resistance against pathogen infection. This strongly supports the involvement of rice SAPs in cross-talk between biotic and abiotic stress signalling pathways, which makes them ideal candidate to design strategies for protecting crop plants against multiple stresses. PMID- 25017162 TI - Constitutive camalexin production and environmental stress response variation in Arabidopsis populations from the Iberian Peninsula. AB - Optimal defense theory predicts that induction of defensive secondary metabolites in plants will be inversely correlated with constitutive expression of those compounds. Here, we asked whether camalexin, an important defense against fungal and bacterial pathogens, support this prediction in structured natural populations of Arabidopsis thaliana from the Iberian Peninsula. In common garden experiments, we found that genotypes from the VIE population constitutively hyper accumulated camalexin. Camalexin concentrations were not induced significantly when plants were exposed to a temperature of 10 degrees C for 48h. However, they were induced when plants were exposed to 48h of infection by the virulent bacterial pathogen, Pseudomonas syringae pv. tomato DC3000. Genotypes from the VIE population with the hyper-accumulation of camalexin were significantly more resistant to bacterial growth. Induction of camalexin was negatively correlated with constitutive camalexin concentrations following log transformation and two different corrections for autocorrelation, thus supporting the tradeoff predicted by optimal defense theory. Constitutive overexpression of camalexin was not explained by the only known natural genetic polymorphism at the Accelerated Cell Death 6, ACD6, locus. Collectively, the results support an important role of camalexin in defense against P. syringae as well as significant structured variation in defense levels within wild populations. PMID- 25017153 TI - Identification of laticifer-specific genes and their promoter regions from a natural rubber producing plant Hevea brasiliensis. AB - Latex, the milky cytoplasm of highly differentiated cells called laticifers, from Hevea brasiliensis is a key source of commercial natural rubber production. One way to enhance natural rubber production would be to express genes involved in natural rubber biosynthesis by a laticifer-specific overexpression system. As a first step to identify promoters which could regulate the laticifer-specific expression, we identified random clones from a cDNA library of H. brasiliensis latex, resulting in 4325 expressed sequence tags (ESTs) assembled into 1308 unigenes (692 contigs and 617 singletons). Quantitative analyses of the transcription levels of high redundancy clones in the ESTs revealed genes highly and predominantly expressed in laticifers, such as Rubber Elongation Factor (REF), Small Rubber Particle Protein and putative protease inhibitor proteins. HRT1 and HRT2, cis-prenyltransferases involved in rubber biosynthesis, was also expressed predominantly in laticifers, although these transcript levels were 80 fold lower than that of REF. The 5'-upstream regions of these laticifer-specific genes were cloned and analyzed in silico, revealing seven common motifs consisting of eight bases. Furthermore, transcription factors specifically expressed in laticifers were also identified. The common motifs in the laticifer specific genes and the laticifer-specific transcription factors are potentially involved in the regulation of gene expression in laticifers. PMID- 25017164 TI - The role of brassinosteroids and abscisic acid in stomatal development. AB - Gas exchange with the atmosphere is regulated through the stomata. This process relies on both the degree and duration of stomatal opening, and the number and patterning of these structures in the plant surface. Recent work has revealed that brassinosteroids and abscisic acid (ABA), which control stomatal opening, also repress stomatal development in cotyledons and leaves of at least some plants. It is speculated that, in Arabidopsis, these phytohormones control the same steps of this developmental process, most probably, through the regulation of the same mitogen-activated protein (MAP) kinase module. The conservation, in seeds plants, of components downstream of this module with MAP kinase target domains, suggests that these proteins are also regulated by these cascades, which, in turn, may be regulated by brassinosteroids and/or ABA. PMID- 25017163 TI - Cell division interference in newly fertilized ovules induces stenospermocarpy in cross-pollinated citrus fruit. AB - Seedlessness is a highly desirable characteristic in fresh fruits. However, post fertilization seed abortion of cross-pollinated citrus fruit is uncommon. The factors regulating stenospermocarpy in citrus are unknown. In this research, we induced stenospermocarpy interfering in newly fertilized ovule cell division. The research also elucidates the most sensitive stage for ovule/seed abortion in citrus. Experiments were conducted with 'Afourer' mandarin that cross-pollinates with several cultivars and species. Cross-pollinated fruitlets were treated with maleic hydrazide (MH), a systemic growth regulator that specifically interferes in cell division. MH reduced ovule growth rate, the number of cell layers in nucella and inhibited embryo sac expansion; moreover, the treatment increased callose accumulation in nucella and surrounding the embryo sac. Fruits developed an early-aborted seed type with an immature, soft and edible seed coat. Seed number (-80%) and seed weight (-46%) were reduced in mature fruits. MH also hampered cell division in ovary walls, mesocarp and endocarp, thus reducing daily fruitlet growth and increasing fruit abscission. Stenospermocarpy could only be induced for a short period of time in the progamic phase of fertilization, specifically, when ovules are ready to be fertilized (7 days after anthesis) to early stages of embryo sac development (14 days after anthesis). PMID- 25017165 TI - Analysis of gene-disruption mutants of a sucrose phosphate synthase gene in rice, OsSPS1, shows the importance of sucrose synthesis in pollen germination. AB - The molecular function of an isoform of sucrose phosphate synthase (SPS) in rice, OsSPS1, was investigated using gene-disruption mutant lines generated by retrotransposon insertion. The progeny of the heterozygote of disrupted OsSPS1 (SPS1(+/-)) segregated into SPS1(+/+), SPS1(+/-), and SPS1(-/-) at a ratio of 1:1:0. This distorted segregation ratio, together with the expression of OsSPS1 in the developing pollen revealed by quantitative RT-PCR analysis and promoter beta-glucuronidase (GUS) fusion assay, suggested that the disruption of OsSPS1 results in sterile pollen. This hypothesis was reinforced by reciprocal crosses of SPS1(+/-) plants with wild-type plants in which the disrupted OsSPS1 was not paternally transmitted to the progeny. While the pollen grains of SPS(+/-) plants normally accumulated starch during their development, pollen germination on the artificial media was reduced to half of that observed in the wild-type control. Overall, our data suggests that sucrose synthesis via OsSPS1 is essential in pollen germination in rice. PMID- 25017166 TI - Breakthroughs spotlighting roles for extracellular nucleotides and apyrases in stress responses and growth and development. AB - Animal and plant cells release nucleotides into their extracellular matrix when touched, wounded, and when their plasma membranes are stretched during delivery of secretory vesicles and growth. These released nucleotides then function as signaling agents that induce rapid increases in the concentration of cytosolic calcium, nitric oxide and superoxide. These, in turn, are transduced into downstream physiological changes. These changes in plants include changes in the growth of diverse tissues, in gravitropism, and in the opening and closing of stomates. The concentration of extracellular nucleotides is controlled by various phosphatases, prominent among which are apyrases EC 3.6.1.5 (nucleoside triphosphate diphosphohydrolases, NTPDases). This review provides phylogenetic and pHMM analyses of plant apyrases as well as analysis of predicted post translational modifications for Arabidopsis apyrases. This review also summarizes and discusses recent advances in research on the roles of apyrases and extracellular nucleotides in controlling plant growth and development. These include new findings that document how apyrases and extracellular nucleotides control auxin transport, modulate stomatal aperture, and mediate biotic and abiotic stress responses, and on how apyrase suppression leads to growth inhibition. PMID- 25017167 TI - Endogenous hydrogen sulfide enhances salt tolerance by coupling the reestablishment of redox homeostasis and preventing salt-induced K+ loss in seedlings of Medicago sativa. AB - Despite the external application of hydrogen sulfide (H2S) conferring plant tolerance against various environmental cues, the physiological significance of l cysteine desulfhydrase (L-DES)-associated endogenous H2S production involved in salt-stress signaling was poorly understood. To address this gap, the participation of in planta changes of H2S homeostasis involved in alfalfa salt tolerance was investigated. The increasing concentration of NaCl (from 50 to 300 mM) progressively caused the induction of total l-DES activity and the increase of endogenous H2S production. NaCl-triggered toxicity symptoms (175 mM), including seedling growth inhibition and lipid peroxidation, were alleviated by sodium hydrosulfide (NaHS; 100 MUM), a H2S donor, whereas aggravated by an inhibitor of l-DES or a H2S scavenger. A weaker or negative response was observed in lower or higher dose of NaHS. Further results showed that endogenous l-DES related H2S modulated several genes/activities of antioxidant defence enzymes, and also regulated the contents of antioxidant compounds, thus counterbalancing the NaCl-induced lipid peroxidation. Moreover, H2S maintained K(+)/Na(+) homeostasis by preventing the NaCl-triggered K(+) efflux, which might be result form the impairment of SKOR expression. Together, our findings indicated that endogenous H2S homeostasis enhance salt tolerance by coupling the reestablishment of redox balance and restraining K(+) efflux in alfalfa seedlings. PMID- 25017168 TI - Challenges to develop nitrogen-fixing cereals by direct nif-gene transfer. AB - Some regions of the developing world suffer low cereal production yields due to low fertilizer inputs, among other factors. Biological N2 fixation, catalyzed by the prokaryotic enzyme nitrogenase, is an alternative to the use of synthetic N fertilizers. The molybdenum nitrogenase is an O2-labile metalloenzyme composed of the NifDK and NifH proteins, which biosyntheses require a number of nif gene products. A challenging strategy to increase cereal crop productivity in a scenario of low N fertilization is the direct transfer of nif genes into cereals. The sensitivity of nitrogenase to O2 and the apparent complexity of nitrogenase biosynthesis are the main barriers identified so far. Expression of active NifH requires the products of nifM, nifH, and possibly nifU and nifS, whereas active NifDK requires the products of nifH, nifD, nifK, nifB, nifE, nifN, and possibly nifU, nifS, nifQ, nifV, nafY, nifW and nifZ. Plastids and mitochondria are potential subcellular locations for nitrogenase. Both could provide the ATP and electrons required for nitrogenase to function but they differ in their internal O2 levels and their ability to incorporate ammonium into amino acids. PMID- 25017169 TI - RNA silencing is induced by the expression of foreign recombinant products in transgenic rice. AB - RNA silencing plays important roles in the regulation of gene expression in eukaryotes. We previously reported that RNA silencing of a linked endogenous gene and a transgene in transgenic rice seeds can be induced by the expression of foreign recombinant mGLP-1, which acts as a silencing-inducible sequence through RNA interference. In this study, we found that the induction of RNA silencing by foreign transgenes is not restricted to mGLP-1 but is observed in many other genes as a relatively general phenomenon, as several foreign genes were involved in inducing RNA silencing in the same manner as mGLP-1 in transgenic rice. We detected 21-24-nt siRNAs using both sense and antisense probes specific to the silenced genes in both the leaves and endosperm of transgenic rice plants. Moreover, read-through transcripts were consistently observed in silenced transgenic rice plants. Taken together, these results suggest that proper transcription termination was prevented in these plants, and the highly divergent 3'-end transcripts served as templates for double-stranded RNA synthesis, resulting in the degradation of the target genes via siRNA. PMID- 25017170 TI - Programmed cell death: a mechanism for the lysigenous formation of secretory cavities in leaves of Dictamnus dasycarpus. AB - The formation of secretory cavities in Rutaceae has been the subject of great interest. In this study, cytological events that are involved in the lysigenous formation of the secretory cavities in the leaves of Dictamnus dasycarpus are characterized by an interesting pattern of programmed cell death (PCD). During the developmental process, clusters of cells from a single protoepidermal cell embark on different trajectories and undergo different cell death fates: the cell walls of the secretory cells have characteristics of thinning or complete breakdown, while the sheath cells present a predominantly thick-walled feature. A DAPI assay shows deformed nuclei that are further confirmed to be TUNEL-positive. Gel electrophoresis indicates that DNA cleavage is random and does not result in ladder-like DNA fragmentation. Ultrastructurally, several remarkable features of PCD have been determined, such as misshapen nuclei with condensed chromatin and a significantly diffused membrane, degenerated mitochondria and plastids with disturbed membrane systems, multivesicular bodies, plastolysomes, vacuole disruption and lysis of the center secretory cell. Cytological evidence and Nile red stains exhibit abundant essential oils accumulated in degenerated outer secretory cells after the dissolution of the center secretory cell. In addition, explanations of taxonomic importance and the relationship between PCD and oil droplet accumulation in the secretory cavities are also discussed. PMID- 25017171 TI - Authors' response regarding 'Who should be an author on your academic paper?'. PMID- 25017172 TI - How midwives tailor health information used in antenatal care. AB - OBJECTIVE: to examine the informal approaches taken by midwives and other antenatal staff to adapt health communication to the needs of their patients, as well as their perception of the barriers faced when trying to provide tailored health promotion. DESIGN: qualitative research methods (participant observation, individual and group interviews) were utilised to gain an understanding of how media and communication resources were used in practice within the study hospital. SETTING: a major metropolitan teaching hospital located in the Northern suburbs of Adelaide, South Australia. PARTICIPANTS: individual semi-structured interviews with antenatal staff (n=8) were combined with group interviews (n=2; total number of staff=13), and observational research. FINDINGS: midwives and other antenatal staff use a range of strategies to meet the perceived health literacy level of their patients. However, their attempts to tailor health information to individual needs are frequently based on incomplete information about patients' health literacy, may be inconsistent in delivery and content and are seldom assessed to determine whether communication has been understood or led to patient behaviour change. KEY CONCLUSIONS: midwives fully recognise the need to adapt standard printed materials to meet the diverse health literacy needs of patients but lack the resources required to evaluate whether these adaptations have positive effect. IMPLICATIONS FOR PRACTICE: midwives' commitment to improving health communication provides a latent resource that institutions can build on to improve health outcomes for patients with low health literacy. This requires improvements in health communication training, willingness to use a range of validated instruments for measuring health literacy, and commitment to use of innovative approaches to health promotion where these have been shown to have a positive impact on health behaviours. PMID- 25017174 TI - Outcome measures in studies on the use of oxytocin for the treatment of delay in labour: a systematic review. AB - OBJECTIVES: to identify primary and secondary outcome measures in randomised trials, and systematic reviews of randomised trials, measuring effectiveness of oxytocin for treatment of delay in the first and second stages of labour, and to identify any positive health-focussed outcomes used. DESIGN: eight relevant citation databases were searched up to January 2013 for all randomised trials, and systematic reviews of randomised trials, measuring effectiveness of oxytocin for treatment of delay in labour. Trials of active management of labour or partogram action lines were excluded. 1918 citations were identified. Two reviewers reviewed all citations and extracted data. Twenty-six individual trials and five systematic reviews were included. Primary and secondary outcome measures were documented and analysed using frequency distributions. FINDINGS: most frequent primary outcomes were caesarean section (n=15, 46%), length of labour (n=14, 42%), measurements of uterine activity (n=13, 39%) and mode of vaginal birth (n=9, 27%). Maternal satisfaction was identified a priori by one review and included as a secondary outcome by three papers. No further positive health focussed outcomes were identified. KEY CONCLUSIONS: outcomes used to measure the effectiveness of oxytocin for treatment of delay in labour are heterogeneous and tend to focus on adverse events. IMPLICATIONS FOR PRACTICE: it is recommended that, in future randomised trials of oxytocin use for delay in labour, some women centred and health-focussed outcome measures should be used, which may instil a more salutogenic culture in childbirth. PMID- 25017173 TI - Relationship between reflection ability and clinical performance: a cross sectional and retrospective-longitudinal correlational cohort study in midwifery. AB - BACKGROUND: increasingly, reflection is highlighted as integral to core practice competencies but empirical research into the relationship between reflection and performance in the clinical workplace is scarce. AIM: this study investigated the relationship between reflection ability and clinical performance. METHODS: we designed a cross-sectional and a retrospective-longitudinal cohort study. Data from first, second and third year midwifery students were collected to study the variables 'clinical performance' and 'reflection ability'. Data were analysed with SPSS for Windows, Release 20.0. Descriptive statistics, Pearson's Product Moment Correlation Coefficients (r) and r2 values were computed to investigate associations between the research variables. FINDINGS: the results showed a moderate observed correlation between reflection ability and clinical performance scores. When adopting a cross-sectional perspective, all correlation values were significant (p<0.01) and above 0.4, with the exception of the third year correlations. Assuming perfect reliability in the measurement, the adjusted correlations, for year 2 and year 3 indicated a high association between reflection ability and clinical performance (>0.6). The results based on the retrospective-longitudinal data set explained a moderate proportion of the variance after correction for attenuation. Finally, the results indicate that 'reflection ability' scores of earlier years are significant related with 'clinical performance' scores of subsequent years. These results suggest that (1) reflection ability is linked to clinical performance; (2) that written reflections are an important, but not the sole way to assess professional competence and that (3) reflection is a contributor to clinical performance improvement. CONCLUSIONS: the data showed a moderate but significant relationship between 'reflection ability' and 'clinical performance' scores in clinical practice of midwifery students. Reflection therefore seems an important component of professional competence. PMID- 25017175 TI - An H2O2-responsive nanocarrier for dual-release of platinum anticancer drugs and O2: controlled release and enhanced cytotoxicity against cisplatin resistant cancer cells. AB - Synergistic release of platinum anticancer drugs and O2 can be achieved in an H2O2-responsive nanocarrier incorporated with catalase. Such a system combines the advantages of chemotherapy and oxygen therapy and demonstrated improved therapeutic efficacy against cisplatin resistant cell lines which often appear to be in hypoxia. PMID- 25017176 TI - Small for gestational age and poor fluid intelligence in childhood predict externalizing behaviors among young adults born at extremely low birth weight. AB - Although infants born at extremely low birth weight (ELBW; birth weight < 1000 g) are at increased risk for developing later psychopathology, the mechanisms contributing to this association are largely unknown. In the present study, we examined a putative cognitive link to psychopathology in a cohort of ELBW survivors. These individuals were followed up prospectively at age 8 and again at ages 22-26. At 8 years, participants completed measures of fluid and general intelligence. As young adults, a subset of ELBW survivors free of major neurosensory impairments provided self-reports of personality characteristics related to psychopathology. Data from 66 participants indicated that, as predicted, the association between ELBW and externalizing behaviors was moderated by fluid intelligence. Specifically, ELBW individuals with poor fluid intelligence who were born small for gestational age (birth weight < 10th percentile for gestational age) showed the highest level of externalizing behaviors. These findings provide support for a cumulative risk model and suggest that fluid intelligence might be a cognitive mechanism contributing to the development of psychopathology among nonimpaired individuals who were born at ELBW and small for gestational age. PMID- 25017177 TI - Using randomized variable practice in the treatment of childhood apraxia of speech. AB - PURPOSE: The purpose of this study was to determine if randomized variable practice, a central component of concurrent treatment, would be effective and efficient in treating childhood apraxia of speech (CAS). Concurrent treatment is a treatment program that takes the speech task hierarchy and randomizes it so that all tasks are worked on in one session. Previous studies have shown the treatment program to be effective and efficient in treating phonological and articulation disorders. The program was adapted to be used with children with CAS. METHOD: A research design of multiple baselines across participants was used. Probes of generalization to untaught words were administered every fifth session. Three children, ranging in age from 4 to 6 years old, were the participants. Data were collected as percent correct productions during baseline, treatment, and probes of generalization of target sounds to untaught words and three-word phrases. RESULTS: All participants showed an increase in correct productions during treatment and during probes. Effect sizes (standard mean difference) for treatment were 3.61-5.00, and for generalization probes, they were 3.15-8.51. CONCLUSIONS: The results obtained from this study suggest that randomized variable practice as used in concurrent treatment can be adapted for use in treating children with CAS. Replication of this study with other children presenting CAS will be needed to establish generality of the findings. PMID- 25017178 TI - Perspectives on moving ionic liquid chemistry into the solid phase. AB - Ionic liquid (IL) chemistry has evolved over the past century, such that these organic salts have impacted virtually every area of science and engineering. In the area of chemistry, initial applications of these salts were primarily the domain of chemists or chemical engineers who desired to manipulate the properties of IL solvents for a variety of applications including tuning various chemical processes. Since then, the chemistry of these organic salts has progressed such that changing an important property of a solvent (e.g., melting point or hydrophobicity) often involves simply altering the counterion of the organic salt. It is with this simplicity in mind that we have recently embarked upon the use of such chemistry to manipulate important properties of solid-phase ionic organic materials. To differentiate this chemistry from ionic liquid chemistry, we have coined the acronym GUMBOS (group of uniform materials based on organic salts). In this perspective article, we describe and demonstrate how ionic liquid chemistry can provide distinct and sometimes unique chemistry for solid-phase applications. Solid phase properties which can be manipulated via this chemistry include, but are not limited to, magnetism, melting point, hydrophobicity, fluorescence quantum yields, nanoformulations, material aggregation, viscosity, viscoelasticity, and cytotoxicity. In addition, we discuss a few examples to demonstrate how GUMBOS chemistry, until now, has been beneficial to the general area of materials chemistry and, more broadly, to the field of analytical chemistry. We also project future applications of this technology. PMID- 25017179 TI - Recovery of oil from oil-in-water emulsion using biopolymers by adsorptive method. AB - In the present study, it is aimed to identify, a low cost sorbent for the recovery of oil from oil-in-water emulsion using biopolymers such as chitin and chitosan. Chitin has the greater adsorption capacity than chitosan due to its hydrophobic nature. The characterizations of chitin and chitosan were done using FTIR, SEM, EDAX, XRD, TGA and DSC techniques. Under batch equilibrium mode, a systematic study was performed to optimize the various equilibrium parameters viz., contact time, pH, dosage, initial concentration of oil, and temperature. The adsorption process reached equilibrium at 40 min of contact time and the percentage removal of oil was found to be higher (90%) in the acidic medium. The Freundlich and Langmuir models were applied to describe the equilibrium isotherms and the isotherm constants were calculated. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees were calculated to find out the nature of the sorption mechanism. The kinetic studies were investigated with reaction-based and diffusion-based models. The suitable mechanism for the removal of oil has been established. PMID- 25017180 TI - Effect of (-)-epigallocatechin gallate on the fibrillation of human serum albumin. AB - Human serum albumin (HSA), the most abundant plasma protein in the human body is known to form fibrils under partial denaturing conditions. Natural polyphenols are known to interact with HSA and some polyphenols have been shown to be potent inhibitors of amyloid fibrillation. (-)-Epigallocatechin gallate (EGCG), the major component of green tea is known to inhibit amyloid fibrillation. In this report, we have investigated the effect of EGCG on native HSA as well as on the fibrillation process of HSA from amide III band analysis of their respective visible Raman spectra. The differential role of the tryptophan (Trp214) residue present in domain II of HSA in the absence and presence of EGCG has been pointed out using fluorescence anisotropy and visible Raman spectroscopy. PMID- 25017181 TI - Hepatitis B vaccine response among infants born to hepatitis B surface antigen positive women. PMID- 25017182 TI - Pharmacokinetic interaction between rosuvastatin and olmesartan: a randomized, open-label, 3-period, multiple-dose crossover study in healthy Korean male subjects. AB - PURPOSE: Rosuvastatin has been widely used in combination with olmesartan for the treatment of dyslipidemia accompanied by hypertension. With no information currently available on the interaction between the 2 drugs, a pharmacokinetic study was conducted to investigate the influence of rosuvastatin on olmesartan and vice versa when the 2 drugs were coadministered. The purpose of this study was to investigate the pharmacokinetic profile of coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet and the associated drug drug interaction in healthy Korean male volunteers. METHODS: This was a randomized, open-label, 3-period, multiple-dose crossover study. Eligible subjects were aged 20 to 50 years and within 20% of their ideal body weight. After being randomly assigned to 6 groups of equal number, subjects received each of the following 3 formulations once a day for 7 consecutive days with an 8-day washout period between the formulations: rosuvastatin 20-mg tablet, olmesartan 40 mg tablet, and coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet. Blood samples were collected up to 72 hours after dosing, and pharmacokinetic parameters were determined for rosuvastatin, its active metabolite (N-desmethyl rosuvastatin), and olmesartan. Adverse events were evaluated based on subject interviews and physical examinations. FINDINGS: Among the 36 enrolled subjects, 34 completed the study (mean [range] age, 28.6 [23-49] y; mean [range] weight, 66.4 [52.2-78.7] kg). The 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for the coadministration of the 2 drugs to the mono-administration of each drug were 85.14% to 96.08% for AUCtau and 81.41% to 97.48% for Css,max for rosuvastatin, and 77.55% to 89.48% for AUCtau and 75.62% to 90.12% for Css,max for N-desmethyl rosuvastatin; those values were 95.61% to 102.57% for AUCtau and 91.73% to 102.98% for Css,max for olmesartan. Dizziness was the most frequently noted adverse drug reaction, occurring in 1 subject receiving mono-administration of rosuvastatin, 1 subject receiving mono-administration of olmesartan, and 4 subjects receiving coadministration of rosuvastatin and olmesartan. All the adverse events were expected, and there was no significant difference in the incidence between the 2 formulations. IMPLICATIONS: This study suggests that rosuvastatin and olmesartan did not significantly influence each other's pharmacokinetics when coadministered. Although the pharmacokinetics of N-desmethyl rosuvastatin were influenced by olmesartan, such interactions were considered clinically insignificant. All 3 formulations were well tolerated, and no serious adverse events or drug reactions were noted. PMID- 25017184 TI - Significant evidence of C...O and C...C long-range contacts in several heterodimeric complexes of CO with CH3-X, should one refer to them as carbon and dicarbon bonds! AB - Noncovalent interactions in 18 weakly bound binary complexes formed between either of the two end-on orientations of the CO molecule and the methylated carbon positive sigma-hole associated with the hydrophobic part of the CH3-X molecules are exploited using the density functional theory to examine the physical chemistry of the recently introduced 'carbon bonds' (Phys. Chem. Chem. Phys., 2013, 15, 14377), where X = -NO2, -CN, -F, -Cl, -Br, -OH, -CF3, -CCl3, and -NH2. The two important types of interactions are identified as C...O and C...C, the latter has probably never studied before, and are found to be stabilized by charge-transfer delocalizations between the electron-acceptor and -donor natural bond orbitals of the interacting partners involved, unveiled using natural bond orbital analysis. Application of atoms in molecular theory revealed preferable quantum mechanical exchange-correlation energy channels and (3, -1) bond critical points (bcps) between the atoms of noncovalently bonded pairs in these complexes, in excellent agreement with the results of the noncovalent-interaction reduced density-gradient (NCI-RDG) theory that revealed expected isosurfaces and troughs in the low density region of the RDG vs. sign(lambda2)rho plots. The dependencies of the C...O and C...C bcp charge densities on their corresponding local energy densities, as well as on their corresponding bond electron delocalization indices are found to exhibit nontrivial roles of these topological descriptors to explain the stabilities of the investigated binary complexes. Moreover, the vibrational red- and blue-shifts in the CO bond stretching frequencies, and concomitant elongations and contractions of the corresponding bond lengths, both with respect to the monomer values, are observed upon the formation of the C...O- and C...C bonded complexes, respectively. The increase and decrease in the complex dipole moments, relative to the sum of their respective monomer values, are found to be a characteristic that separates the aforementioned red- and blue-shifted interactions. In analogy with dihydrogen bonding, as well as that with the charge and electrostatic surface potential model descriptions, we suggest the C...C interactions to be referred to as dicarbon bonds. PMID- 25017183 TI - Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. AB - PURPOSE: Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a beta-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. METHODS: All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. FINDINGS: Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. IMPLICATIONS: Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen. PMID- 25017185 TI - Role of nitric oxide synthase isoforms for ophthalmic artery reactivity in mice. AB - Nitric oxide synthases (NOS) are involved in regulation of ocular vascular tone and blood flow. While endothelial NOS (eNOS) has recently been shown to mediate endothelium-dependent vasodilation in mouse retinal arterioles, the contribution of individual NOS isoforms to vascular responses is unknown in the retrobulbar vasculature. Moreover, it is unknown whether the lack of a single NOS isoform affects neuron survival in the retina. Thus, the goal of the present study was to examine the hypothesis that the lack of individual nitric oxide synthase (NOS) isoforms affects the reactivity of mouse ophthalmic arteries and neuron density in the retinal ganglion cell (RGC) layer. Mice deficient in one of the three NOS isoforms (nNOS-/-, iNOS-/- and eNOS-/-) were compared to respective wild type controls. Intraocular pressure (IOP) was measured in conscious mice using rebound tonometry. To examine the role of each NOS isoform for mediating vascular responses, ophthalmic arteries were studied in vitro using video microscopy. Neuron density in the RGC layer was calculated from retinal wholemounts stained with cresyl blue. IOP was similar in all NOS-deficient genotypes and respective wild type controls. In ophthalmic arteries, phenylephrine, nitroprusside and acetylcholine evoked concentration-dependent responses that did not differ between individual NOS-deficient genotypes and their respective controls. In all genotypes except eNOS-/- mice, vasodilation to acetylcholine was markedly reduced after incubation with L-NAME, a non-isoform-selective inhibitor of NOS. In contrast, pharmacological inhibition of nNOS and iNOS had no effect on acetylcholine-induced vasodilation in any of the mouse genotypes. Neuron density in the RGC layer was similar in all NOS-deficient genotypes and respective controls. Our findings suggest that eNOS contributes to endothelium-dependent dilation of murine ophthalmic arteries. However, the chronic lack of eNOS is functionally compensated by NOS-independent vasodilator mechanisms. The lack of a single NOS isoform does not appear to affect IOP or neuron density in the RGC layer. PMID- 25017186 TI - Extracellular matrix remodeling during retinal development. AB - The extracellular matrix (ECM) consists of a versatile and dynamic meshwork of proteoglycans and glycoproteins and plays an important functional role in complex tissues such as the developing retina. ECM forms the milieu surrounding retinal cells, constitutes basement membranes and provides structural as well as mechanical support. In addition, ECM molecules regulate the retinal homeostasis and cellular signaling. This review discusses the current state of ECM remodeling and its function during retinal development. In addition, we illustrate how ECM components control axonal growth and guidance of retinal ganglion cells and focus on ECM modulation during de- and regeneration processes. PMID- 25017187 TI - Thumb CMC total exchange arthroplasty with the ARPE implant. AB - We present two case reports of successful total exchange arthroplasty at the carpometacarpal joint of the thumb using an ARPE implant. In one patient (62-year old female), a primary MOJE prosthesis had been implanted two years previous. In the second patient (48-year-old female), a primary ELEKTRA prosthesis had been implanted one year previous. At a follow-up of two and three years respectively, there were no changes in position of both ARPE implants and no signs of loosening. All clinical parameters (DASH score, pain through VAS, grip strength) had improved. PMID- 25017188 TI - Hydrogen storage in Pd nanocrystals covered with a metal-organic framework. AB - Hydrogen is an essential component in many industrial processes. As a result of the recent increase in the development of shale gas, steam reforming of shale gas has received considerable attention as a major source of H2, and the more efficient use of hydrogen is strongly demanded. Palladium is well known as a hydrogen-storage metal and an effective catalyst for reactions related to hydrogen in a variety of industrial processes. Here, we present remarkably enhanced capacity and speed of hydrogen storage in Pd nanocrystals covered with the metal-organic framework (MOF) HKUST-1 (copper(II) 1,3,5 benzenetricarboxylate). The Pd nanocrystals covered with the MOF have twice the storage capacity of the bare Pd nanocrystals. The significantly enhanced hydrogen storage capacity was confirmed by hydrogen pressure-composition isotherms and solid-state deuterium nuclear magnetic resonance measurements. The speed of hydrogen absorption in the Pd nanocrystals is also enhanced by the MOF coating. PMID- 25017189 TI - Automatic multigenic family annotation: risks and solutions. AB - A major challenge facing bioinformatics today is the efficient annotation of the exponential flow of genomic data. This has led to an increasing dependence on automatic annotation procedures, despite the relatively high error rates of these programs, particularly for multigenic families. We discuss here the errors and biases introduced by automatic genome annotations, focusing on issues with structural annotations of gene families, and suggest ways to overcome these limitations. PMID- 25017190 TI - Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. AB - Defects in DNA repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. However, tumors rely on residual DNA repair capacities to survive the damage induced by genotoxic stress. This dichotomy might explain why only isolated DNA repair pathways are inactivated in cancer cells. Accordingly, synergism has been observed between DNA damaging drugs and targeted inhibitors of DNA repair. DNA repair pathways are generally thought of as mutually exclusive mechanistic units handling different types of lesions in distinct cell cycle phases. Recent preclinical studies, however, provide strong evidence that multifunctional DNA repair hubs, which are involved in multiple conventional DNA repair pathways, are frequently altered in cancer. We therefore propose that targeted anticancer therapies should not only exploit synthetic lethal interactions between two single genes but also consider alterations in DNA repair hubs. Such a network-based approach considerably increases the opportunities for targeting DNA repair-defective tumors. PMID- 25017191 TI - Multimodal neuroimaging in humans at 9.4 T: a technological breakthrough towards an advanced metabolic imaging scanner. AB - The aim of this paper is twofold: firstly, to explore the potential of simultaneously acquiring multimodal MR-PET-EEG data in a human 9.4 T scanner to provide a platform for metabolic brain imaging. Secondly, to demonstrate that the three modalities are complementary, with MRI providing excellent structural and functional imaging, PET providing quantitative molecular imaging, and EEG providing superior temporal resolution. A 9.4 T MRI scanner equipped with a PET insert and a commercially available EEG device was used to acquire in vivo proton based images, spectra, and sodium- and oxygen-based images with MRI, EEG signals from a human subject in a static 9.4 T magnetic field, and demonstrate hybrid MR PET capability in a rat model. High-resolution images of the in vivo human brain with an isotropic resolution of 0.5 mm and post-mortem brain images of the cerebellum with an isotropic resolution of 320 um are presented. A (1)H spectrum was also acquired from 2 * 2 * 2 mm voxel in the brain allowing 12 metabolites to be identified. Imaging based on sodium and oxygen is demonstrated with isotropic resolutions of 2 and 5 mm, respectively. Auditory evoked potentials measured in a static field of 9.4 T are shown. Finally, hybrid MR-PET capability at 9.4 T in the human scanner is demonstrated in a rat model. Initial progress on the road to 9.4 T multimodal MR-PET-EEG is illustrated. Ultra-high resolution structural imaging, high-resolution images of the sodium distribution and proof-of-principle (17)O data are clearly demonstrated. Further, simultaneous MR-PET data are presented without artefacts and EEG data successfully corrected for the cardioballistic artefact at 9.4 T are presented. PMID- 25017192 TI - Parallel and serial processing in dual-tasking differentially involves mechanisms in the striatum and the lateral prefrontal cortex. AB - The lateral prefrontal cortex and the basal ganglia are known to be important for response selection processes, also in dual-task situations. However, response selection in dual-task situations can be achieved using different modes ranging from a parallel selection to a more serial selection of responses. Nothing is known whether differences in these processing modes during dual-tasking have distinct functional neuroanatomical correlates. In this fMRI study we analyzed performance in a psychological refractory period paradigm. In this paradigm we design a PRP task where we vary the frequency of short and long stimulus onset asynchronies between the two tasks. Using mathematical constraints we interpret the effects of this manipulation with respect to processing modes ranging from more serial to more parallel response selection. Contrastingly these blocks showed that response selection in dual-tasking under the constraint of more parallel processing is mediated by mechanisms operating at the striatal level, while response selection under the constraint of more serial processing is mediated via mechanisms operating in the lateral prefrontal cortex. The results suggest that lateral prefrontal and striatal regions are 'optimized' for a certain processing modes in dual tasking. PMID- 25017193 TI - Lower border bone onlays to augment the severely atrophic (class VI) mandible in preparation for implants: a preliminary report. AB - We present the preliminary results of a study involving a group of consecutive patients who underwent lower border onlay grafting, limited to the symphyseal area, in preparation for implant insertion. This technique allows for maximum sized implants, followed by prosthetic rehabilitation. The main advantage of this method is the minimal risk of damage to the mental nerve. Sixteen patients were followed for a period of 6 months to 4 years and all were free of neurosensory disturbances. Eight had a removable overdenture placed and were satisfied with the result. This surgical approach allows the patient to wear their dentures during the healing period. A further advantage of lower border grafting over intraoral upper border grafting is that mucosal dehiscences are not seen. PMID- 25017194 TI - Exploring luminescence-based temperature sensing using protein-passivated gold nanoclusters. AB - We explore the analytical performance and limitations of optically monitoring aqueous-phase temperature using protein-protected gold nanoclusters (AuNCs). Although not reported elsewhere, we find that these bio-passivated AuNCs show pronounced hysteresis upon thermal cycling. This unwanted behaviour can be eliminated by several strategies, including sol-gel coating and thermal denaturation of the biomolecular template, introducing protein-templated AuNC probes as viable nanothermometers. PMID- 25017195 TI - Arterial location-specific calcification at the carotid artery and aortic arch for chronic kidney disease, diabetes mellitus, hypertension, and dyslipidemia. AB - Several risk factors for arterial calcification have been reported but controversial. The aim of this study was to clarify the interactions among chronic kidney disease (CKD), diabetes mellitus (DM), hypertension, and dyslipidemia in altering the risk of arterial calcification in the three different arterial locations and the intramural location at the internal carotid artery (ICA) origins. Calcified burdens at the ICA origins, the aortic arch, and its orifices were evaluated in a retrospective fashion by using computed tomography angiography in 397 patients. The multivariate analyses were adjusted for age, gender, CKD, DM, hypertension, dyslipidemia, and current smoking status. Additionally, subgroup analyses in each variable were conducted. Our multivariate logistic regression analyses revealed that CKD was significantly associated with the outside-wall calcification at the ICA origins, whereas DM was only associated with the inside-ICA-wall calcification. Additionally, we found that DM increased the association between CKD and arterial calcification at the aortic arch and its orifices, and the outside-wall at the ICA origins. Hypertension was significantly associated with the calcification at the orifices of the aortic arch branches synergistically with CKD. Dyslipidemia did not have any significant association with calcification in any of the three vascular beds. CKD had the highest prevalence risk of calcification in common with the three different vascular beds. CKD in combination with DM, as well as hypertension in combination with CKD, were key relationships affecting the risk of arterial calcification, especially at the aortic arch and its orifices. PMID- 25017196 TI - Recent trends in nanomaterials immobilised enzymes for biofuel production. AB - Application of nanomaterials as novel supporting materials for enzyme immobilisation has generated incredible interest in the biotechnology community. These robust nanostructured forms, such as nanoparticles, nanofibres, nanotubes, nanoporous, nanosheets, and nanocomposites, possess a high surface area to volume ratios that can cause a high enzyme loading and facilitate reaction kinetics, thus improving biocatalytic efficiency for industrial applications. In this article, we discuss research opportunities of nanoscale materials in enzyme biotechnology and highlight recent developments in biofuel production using advanced material supports for enzyme immobilisation and stabilisation. Synthesis and functionalisation of nanomaterial forms using different methods are highlighted. Various simple and effective strategies designed to result in a stable, as well as functional protein-nanomaterial conjugates are also discussed. Analytical techniques confirming enzyme loading on nanomaterials and assessing post-immobilisation changes are discussed. The current status of versatile nanomaterial support for biofuel production employing cellulases and lipases is described in details. This report concludes with a discussion on the likely outcome that nanomaterials will become an integral part of sustainable bioenergy production. PMID- 25017202 TI - Marker Assisted Selection (MAS) for chickpea Fusarium oxysporum wilt resistant genotypes using PCR based molecular markers. AB - The exploration of genetically superior accessions is the key source of germplasm conservation and potential breeding material for the future. To meet the demand of better yielding chickpea cultivars in Pakistan the present study was organized to select more stable and resistant lines from indigenous as well as exotic chickpea germplasm obtained from Plant Genetic Resource Institute (PGRI), National Agricultural Research Centre, Islamabad, Pakistan. For the identification and evaluation of chickpea wilt resistant lines against Fusarium oxysporum f. sp. ciceris (Schlechtends), the germplasm was tested in the field for the selection of wilt resistant lines and the PCR based molecular markers were investigated to use Marker Assisted Selection (MAS) for selection of the desirable cultivars. In field trial, 70 % accessions were resistant to wilt disease, while the remaining 30 % have shown susceptibility to the disease. A total of 5 RAPD and 15 SSR markers were screened for molecular based characterization of wilt response. The data of molecular markers were scored by the presence (1) and absence (0) of allele and subjected to statistical analysis. The analysis was based on coefficient of molecular similarity using UPGMA and sorted the germplasm into two groups based on disease response. Among the total used RAPD/SSR primers, only TA194 SSR marker showed linkage to wilt resistant locus at 85 % probability. The linkage of a marker was reconfirmed by receiver operating characteristic curve. The use of the sorted wilt resistant genotypes through SSR marker TA194 can make available ample prospect in MAS breeding for yield improvement of the crop in Pakistan. PMID- 25017203 TI - Effects of platycodins on liver complications of type 2 diabetes. AB - The aim of the current study was to investigate the therapeutic effects and mechanism of platycodin in liver complications of type 2 diabetes. All rats were randomly divided into two groups: The control group (normal diet) and the model group (a high-fat and high-sugar diet). The model group was injected with 2% streptozocin (25 mg/kg body weight) through the tail vein following 4 weeks of dieting. After a total of 8 weeks of dieting, fasting blood glucose (FBG) and liver function were examined. The high-fat and high-sugar diet was continued in the successful model rats, which were randomly divided into four groups and treated with the following doses of platycodins: The untreated, and 50, 100 and 200 mg/kg body weight/day groups. Platycodins treatment lasted for 12 weeks. Platycodins treatment at a dose of 200 mg/kg body weight/day reduced the FBG, glutamate pyruvate transaminase (GPT), glutamic oxalacetic transaminase, triglycerides, total cholesterol (TC), low-density lipoprotein (LDL) and liver index levels compared with the untreated group (P<0.05), while the high-density lipoprotein levels increased (P<0.05). Furthermore, FBG, GPT, TC and LDL levels were returned to the normal level. This dose also increased the expression of BMP 9 mRNA and BMP-9 protein, and reduced the expression of Smad-4 mRNA and Smad-4 protein. These findings indicate that platycodins can rectify disorders of blood glucose and lipid metabolism, improve liver index and protect liver function in liver complications of type 2 diabetes. The current study suggests that this therapeutic effect is mediated through the BMP-9/Smad-4 pathway. PMID- 25017204 TI - Elevated expression of SLC34A2 inhibits the viability and invasion of A549 cells. AB - Abnormal expression of solute carrier family 34 (sodium phosphate), member 2 (SLC34A2) in the lung may induce abnormal alveolar type II (AT II) cells to transform into lung adenocarcinoma cells, and may also be important in biological process of lung adenocarcinoma. However, at present, the effects and molecular mechanisms of SLC34A2 in the initiation and progression of lung cancer remain to be elucidated. To the best of our knowledge, the present study revealed for the first time that the expression levels of SLC34A2 were downregulated in the A549 and H1299 lung adenocarcinoma cell lines. Further investigation demonstrated that the elevated expression of SLC34A2 in A549 cells was able to significantly inhibit cell viability and invasion in vitro. In addition, 10 upregulated genes between the A549-P-S cell line stably expressing SLC34A2 and the control cell line A549-P were identified by microarray analysis and quantitative polymerase chain reaction, including seven tumor suppressor genes and three complement genes. Furthermore, the upregulation of complement gene C3 and complement 4B preproprotein (C4b) in A549-P-S cells was confirmed by ELISA analysis and was identified to be correlated with recovering Pi absorption in A549 cells by the phosphomolybdic acid method by enhancing the expression of SLC34A2. Therefore, it was hypothesized that the mechanisms underlying the effect of SLC34A2 on A549 cells might be associated with the activation of the complement alternative pathway (C3 and C4b) and upregulation of the expression of selenium binding protein 1, thioredoxin-interacting protein, PDZK1-interacting protein 1 and dual specificity protein phosphatase 6. Downregulation of SLC34A2 may primarily cause abnormal AT II cells to escape from complement-associated immunosurveillance and abnormally express certain tumor-suppressor genes inducing AT II cells to develop into lung adenocarcinoma. The present study further elucidated the effects and mechanisms of SLC34A2 in the generation and development of lung cancer. PMID- 25017205 TI - Smoking and its treatment in addiction services: clients' and staff behaviour and attitudes. AB - BACKGROUND: High smoking prevalence has been observed among those misusing other substances. This study aimed to establish smoking behaviours and attitudes towards nicotine dependence treatment among clients and staff in substance abuse treatment settings. METHODS: Cross-sectional questionnaire survey of staff and clients in a convenience sample of seven community and residential addiction services in, or with links to, Europe's largest provider of mental health care, the South London and Maudsley NHS Foundation Trust. Survey items assessed smoking behaviour, motivation to quit, receipt of and attitudes towards nicotine dependence treatment. RESULTS: Eighty five percent (n = 163) and 97% (n = 145) response rates of clients and staff were achieved. A high smoking prevalence was observed in clients (88%) and staff (45%); of current smokers, nearly all clients were daily smokers, while 42% of staff were occasional smokers. Despite 79% of clients who smoked expressing a desire to quit and 46% interested in receiving advice, only 15% had been offered support to stop smoking during their current treatment episode with 56% reported never having been offered support. Staff rated smoking treatment significantly less important than treatment of other substances (p < 0.001), and only 29% of staff thought it should be addressed early in a client's primary addiction treatment, compared with 48% of clients. CONCLUSIONS: A large unmet clinical need is evident with a widespread failure to deliver smoking cessation interventions to an extraordinarily high prevalence population of smokers in addiction services. This is despite the majority of smokers reporting motivation to quit. Staff smoking and attitudes may be a contributory factor in these findings. PMID- 25017206 TI - Chimpanzee intelligence is heritable. AB - The role that genes play in human intelligence or IQ has remained a point of significant scientific debate dating back to the time of Galton [1]. It has now become increasingly clear that IQ is heritable in humans, but these effects can be modified by nongenetic mechanisms [2-4]. In contrast to human IQ, until recently, views of learning and cognition in animals have largely been dominated by the behaviorist school of thought, originally championed by Watson [5] and Skinner [6]. A large body of accumulated research now demonstrates a variety of cognitive abilities in nonhuman animals and challenges traditional behaviorist interpretations of performance [7, 8]. This, in turn, has led to a renewed interest in the role that social and biological factors might play in explaining individual and phylogenetic differences in cognition [9]. Specifically, aside from early attempts to selectively breed for learning skills in rodents [10-12], studies examining the role that genetic factors might play in individual variation in cognitive abilities in nonhuman animals, particularly nonhuman primates, are scarce. Here, we utilized a modified Primate Cognitive Test Battery [13] in conjunction with quantitative genetic analyses to examine whether cognitive performance is heritable in chimpanzees. We found that some but not all cognitive traits were significantly heritable in chimpanzees. We further found significant genetic correlations between different dimensions of cognitive functioning, suggesting that the genes that explain the variability of one cognitive trait might also explain that of other cognitive traits. PMID- 25017207 TI - Will oil palm's homecoming spell doom for Africa's great apes? AB - Expansion of oil palm plantations has led to extensive wildlife habitat conversion in Southeast Asia [1]. This expansion is driven by a global demand for palm oil for products ranging from foods to detergents [2], and more recently for biofuels [3]. The negative impacts of oil palm development on biodiversity [1, 4, 5], and on orangutans (Pongo spp.) in particular, have been well documented [6, 7] and publicized [8, 9]. Although the oil palm is of African origin, Africa's production historically lags behind that of Southeast Asia. Recently, significant investments have been made that will likely drive the expansion of Africa's oil palm industry [10]. There is concern that this will lead to biodiversity losses similar to those in Southeast Asia. Here, we analyze the potential impact of oil palm development on Africa's great apes. Current great ape distribution in Africa substantially overlaps with current oil palm concessions (by 58.7%) and areas suitable for oil palm production (by 42.3%). More importantly, 39.9% of the distribution of great ape species on unprotected lands overlaps with suitable oil palm areas. There is an urgent need to develop guidelines for the expansion of oil palm in Africa to minimize the negative effects on apes and other wildlife. There is also a need for research to support land use decisions to reconcile economic development, great ape conservation, and avoiding carbon emissions. PMID- 25017208 TI - Object-centered shifts of receptive field positions in monkey primary visual cortex. AB - Stimuli that project the same retinal visual angle can appear to occupy very different proportions of the visual field if they are perceived to be at different distances [1-8]. Previous research shows that perceived angular size alters the spatial distribution of activity in early retinotopic visual cortex [7, 9-11]. For example, a sphere superimposed on the far end of a corridor scene appears to occupy a larger visual angle and activates a larger region of primary visual cortex (V1) compared with the same sphere superimposed on the near end of the corridor [7]. These previous results, however, were obtained from human subjects using psychophysics and fMRI, a fact that fundamentally limits our understanding of the underlying neuronal mechanisms. Here, we present an animal model that allows for a finer examination of size perception at the level of single neurons. We first show that macaque monkeys perceive a size-distance illusion similarly to humans. Then, using extracellular recordings, we test the specific hypothesis [12] that neurons in V1 shift the position of their receptive fields (RFs) in response to complex monocular depth cues. Consistent with this hypothesis, we found that when ring-shaped stimuli appeared at the back of the corridor, RFs of V1 neurons shifted toward the center of the rings. When the same stimuli appeared at the front of the corridor, RFs shifted outward. Thus, our results show for the first time that V1 RFs can shift, potentially serving as the neural basis for the perception of angular size. PMID- 25017209 TI - A diverse paleobiota in early eocene Fushun amber from China. AB - Paleogene arthropod biotas have proved important for tracing the faunal turnover and intercontinental faunal interchange driven by climatic warming and geodynamic events [1-5]. Despite the large number of Paleogene fossil arthropods in Europe and North America [5-8], little is known about the typical Asian (Laurasia originated) arthropod biota. Here, we report a unique amber biota (50-53 million years ago) from the Lower Eocene of Fushun in northeastern China, which fills a large biogeographic gap in Eurasia. Fushun amber is derived from cupressaceous trees, as determined by gas chromatography-mass spectrometry, infrared spectroscopy, and paleobotanical observations. Twenty-two orders and more than 80 families of arthropods have been reported so far, making it among the most diverse amber biotas. Our results reveal that an apparent radiation of ecological keystone insects, including eusocial, phytophagous, and parasitoid lineages, occurred at least during the Early Eocene Climatic Optimum. Some insect taxa have close phylogenetic affinities to those from coeval European ambers, showing a biotic interchange between the eastern and western margins of the Eurasian landmass during the Early Paleogene. PMID- 25017210 TI - The alarming decline of Mediterranean fish stocks. AB - In recent years, fisheries management has succeeded in stabilizing and even improving the state of many global fisheries resources [1-5]. This is particularly evident in areas where stocks are exploited in compliance with scientific advice and strong institutional structures are in place [1, 5]. In Europe, the well-managed northeast (NE) Atlantic fish stocks have been recovering in response to decreasing fishing pressure over the past decade [3-6], albeit with a long way to go for a universal stock rebuild [3, 7]. Meanwhile, little is known about the temporal development of the European Mediterranean stocks, whose management relies on input controls that are often poorly enforced. Here, we perform a meta-analysis of 42 European Mediterranean stocks of nine species in 1990-2010, showing that exploitation rate has been steadily increasing, selectivity (proportional exploitation of juveniles) has been deteriorating, and stocks have been shrinking. We implement species-specific simulation models to quantify changes in exploitation rate and selectivity that would maximize long term yields and halt stock depletion. We show that stocks would be more resilient to fishing and produce higher long-term yields if harvested a few years after maturation because current selectivity is far from optimal, especially for demersal stocks. The European Common Fisheries Policy that has assisted in improving the state of NE Atlantic fish stocks in the past 10 years has failed to deliver similar results for Mediterranean stocks managed under the same policy. Limiting juvenile exploitation, advancing management plans, and strengthening compliance, control, and enforcement could promote fisheries sustainability in the Mediterranean. PMID- 25017213 TI - Thermal dewetting behavior of polystyrene composite thin films with organic modified inorganic nanoparticles. AB - The thermal dewetting of polystyrene composite thin films with oleic acid modified CeO2 nanoparticles prepared by the supercritical hydrothermal synthesis method was investigated, varying the nanoparticle concentration (0-30 wt %), film thickness (approximately 50 and 100 nm), and surface energy of silanized silicon substrates on which the composite films were coated. The dewetting behavior of the composite thin films during thermal annealing was observed by an optical microscope. The presence of nanoparticles in the films affected the morphology of dewetting holes, and moreover suppressed the dewetting itself when the concentration was relatively high. It was revealed that there was a critical value of the surface energy of the substrate at which the dewetting occurred. In addition, the spatial distributions of nanoparticles in the composite thin films before thermal annealing were investigated using AFM and TEM. As a result, we found that most of nanoparticles segregated to the surface of the film, and that such distributions of nanoparticles contribute to the stabilization of the films, by calculating the interfacial potential of the films with nanoparticles. PMID- 25017212 TI - Could valproic acid be an effective anticancer agent? The evidence so far. AB - Valproic acid is an inhibitor of class I histone deacetylases. Epigenetic therapies in cancer have been focus of a keen interest and histone deacetylase inhibitors, in particular, have been approved for certain types of hematologic malignancies. Valproic acid is an attractive candidate for cancer therapy due to its mechanism of action, its low cost and generally good clinical tolerability. In the following editorial, we will review its role as monotherapy for cancer, its place in combination epigenetic therapy, and its role as chemosensitizer, and cancer preventative agent. PMID- 25017211 TI - Cellular control of cortical actin nucleation. AB - The contractile actin cortex is a thin layer of actin, myosin, and actin-binding proteins that subtends the membrane of animal cells. The cortex is the main determinant of cell shape and plays a fundamental role in cell division [1-3], migration [4], and tissue morphogenesis [5]. For example, cortex contractility plays a crucial role in amoeboid migration of metastatic cells [6] and during division, where its misregulation can lead to aneuploidy [7]. Despite its importance, our knowledge of the cortex is poor, and even the proteins nucleating it remain unknown, though a number of candidates have been proposed based on indirect evidence [8-15]. Here, we used two independent approaches to identify cortical actin nucleators: a proteomic analysis using cortex-rich isolated blebs, and a localization/small hairpin RNA (shRNA) screen searching for phenotypes with a weakened cortex or altered contractility. This unbiased study revealed that two proteins generated the majority of cortical actin: the formin mDia1 and the Arp2/3 complex. Each nucleator contributed a similar amount of F-actin to the cortex but had very different accumulation kinetics. Electron microscopy examination revealed that each nucleator affected cortical network architecture differently. mDia1 depletion led to failure in division, but Arp2/3 depletion did not. Interestingly, despite not affecting division on its own, Arp2/3 inhibition potentiated the effect of mDia1 depletion. Our findings indicate that the bulk of the actin cortex is nucleated by mDia1 and Arp2/3 and suggest a mechanism for rapid fine-tuning of cortex structure and mechanics by adjusting the relative contribution of each nucleator. PMID- 25017214 TI - Inhibition of osteoclast bone resorption activity through osteoprotegerin-induced damage of the sealing zone. AB - Bone remodeling is dependent on the dynamic equilibrium between osteoclast mediated bone resorption and osteoblast-mediated osteogenesis. The sealing zone is an osteoclast-specific cytoskeletal structure, the integrity of which is critical for osteoclast-mediated bone resorption. To date, studies have focused mainly on the osteoprotegerin (OPG)-induced inhibition of osteoclast differentiation through the OPG/receptor activator of the nuclear factor kappa-B ligand (RANKL)/RANK system, which affects the bone resorption of osteoclasts. However, the effects of OPG on the sealing zone have not been reported to date. In this study, the formation of the sealing zone was observed by Hoffman modulation contrast (HMC) microscopy and confocal laser scanning microscopy. The effects of OPG on the existing sealing zone and osteoclast-mediated bone resorption activity, as well as the regulatory role of genes involved in the formation of the sealing zone were examined by immunofluorescence staining, HMC microscopy, quantitative reverse transcription polymerase chain reaction (RT qPCR), western blot analysis and scanning electron microscopy. The sealing zone was formed on day 5, with belt-like protuberances at the cell edge and scattered distribution of cell nuclei, but no filopodia. The sealing zone was intact in the untreated control group. However, defects in the sealing zone were observed in the OPG-treated group (20 ng/ml) and the structure was absent in the groups treated with 40 and 80 ng/ml OPG. The podosomes showed a scattered or clustered distribution between the basal surface of the osteoclasts and the well surface. Furthermore, resorption lacunae were not detected in the 20 ng/ml OPG-treated group, indicating the loss of osteoclast-mediated bone resorption activity. Treatment with OPG resulted in a significant decrease in the expression of Arhgef8/Net1 and DOCK5 Rho guanine nucleotide exchange factors (RhoGEFs), 10 of 18 RhoGTPases (RhoA, RhoB, cdc42v1, cdc42v2, RhoU/Wrch1, RhoF/Rif, Rac2, RhoG, Rnd1 and RhoBTB1), ROCK1 and ROCK2. In conclusion, podosome distribution was affected by the OPG-induced inhibition of the expression of genes in the RhoGTPase signaling pathway. This resulted in damage to or destruction of the sealing zone, thus inhibiting osteoclast-mediated bone resorption activity. PMID- 25017216 TI - [Problems in diagnosis and treatment of laryngopharyngeal reflux disease]. PMID- 25017215 TI - Structural variability, topological analysis and photocatalytic properties of neoteric Cd(II) coordination polymers based on semirigid bis(thiazolylbenzimidazole) and different types of carboxylic acid linkers. AB - A series of novel Cd(II) coordination complexes, formulated as {[Cd(btbb)0.5(p phda)].H2O}n (), [Cd(btbb)0.5(oba)]n (), {[Cd2(btbb)(m-bdc)2(H2O)].2H2O}n (), {[Cd(btbb)0.5(btec)0.5(H2O)].2H2O}n (), [Cd(btbb)0.5(o-bdc)]n () and {[Cd2(btbb)(bptc)(H2O)].4H2O}n () (btbb = 1,4-bis(2-(4-thiazolyl)benzimidazol-1 ylmethyl)benzene, H2phda = phenylenediacetic acid, H2oba = 4,4'-oxybis(benzoic acid), m-H2bdc = 1,3-benzenedicarboxylic acid, H4btec = 1,2,4,5 benzenetetracarboxylate, o-H2bdc = 1,2-benzenedicarboxylic acid, H4bptc = 3,3',4,4'-benzophenone tetracarboxylic acid), have been obtained by solvothermal/hydrothermal reactions for the exploration of efficient photocatalytic degradation of organic dye pollutants. Complex features a 6 connected 3D pcu alpha-Po primitive cubic topology net with the point symbol 4(12).6(3). Interestingly, complexes , and contain left- and right-handed helical chains (: a 2-fold interpenetrating 3D architecture with {4(12).6(3)}-pcu topology network; : a (3,6)-connected net with a vertex symbol (4(2).5(4).6(6).7.8(2))(4.6(2)); : a (3,4)-connected 3,4L83 topology net with point symbol (4(2).6)(4(2).6(3).8)). Complex exhibits a (3,4)-connected 3,4T48 topology net with point symbol (8(4).10(2))(8.10(2)), while complex possesses a (3,5)-connected 3,5L2 topology with the point symbol (4(2).6)(4(2).6(7).8). Furthermore, the photophysical studies indicate that the relatively narrow optical energy gaps of complexes (<2.30 eV) calculated from the diffuse reflectivity spectra reflect their outstanding semiconductive nature. The photocatalytic properties of complexes were studied in detail, and the results demonstrate their good photocatalytic activities in methylene blue (MB) degradation reactions, especially for complexes , and (: 91.4%, : 92.7%, : 86.7%). PMID- 25017217 TI - [Research on the association of the laryngeal carcinoma and laryngopharyngeal reflux]. AB - OBJECTIVE: The objective of this study is to investigate the association between laryngeal carcinoma and laryngopharyngeal reflux. METHODS: This was a case control study with 31 laryngeal cancer patients who had undergone 24-hour ambulatory double pH monitoring and 76 in the control group which were divided into negative group (36 patients) and positive group (40 patients) by the score of RSI (reflux symptom index) and RFI (reflux findings index) scale. The results of reflux and parameters of 24-hour ambulatory double pH monitoring among the three groups were statistically analysed. RESULTS: The smoking rate of 80.6% (25/31) in laryngeal carcinoma group was significantly higher than that of (36.1%, P < 0.0167) in the negative group while it did not vary in laryngeal carcinoma group and the positive group (65.0%, P > 0.0167). The drinking rate of 71.0% (22/31) in laryngeal carcinoma group was higher than that of (36.1%, P < 0.0167) in the negative group whereas there was no significant difference between laryngeal carcinoma group and positive group (50.0%, P > 0.0167). The positive rate of laryngopharyngeal reflux in laryngeal carcinoma group, the positive group, the negative group were 74.2% (23/31), 16.7% (6/36) and 52.5% (21/40) respectively, which was significantly different (P < 0.05). The positive rate of gastroesophageal reflux in the three groups above were 71.0% (22/31), 52.8% (19/36) and 75.0% (30/40), which had no significant difference (P > 0.05). The positive rate of laryngopharyngeal reflux differed in laryngeal carcinoma group and the negative group (P < 0.0167) while did not differ in laryngeal carcinoma group and the positive group (P > 0.0167). In the results of 24-hour ambulatory double pH monitoring, there was significant difference in the total and upright reflux number, the total reflux time, the percent times for the pH falling below 4, total reflux number which lasted more than 5 minutes and DeMeester Scores. CONCLUSIONS: The positive rate of laryngopharyngeal reflux in laryngeal carcinoma group was very high while the drinking and smoking rate were also high. Therefore whether the laryngopharyngeal reflux is a risk factor of the laryngeal carcinoma, it needs further research. PMID- 25017218 TI - [Role of laryngopharyngeal reflux on the pathogenesis of vocal cord leukoplakia and early glottic cancer]. AB - OBJECTIVE: To explore the significance of laryngopharyngeal reflux (LPR) and gastroesophageal reflux (GER) in patients with vocal cord leukoplakia and early glottic cancer. METHODS: Patients with vocal cord leukoplakia and early glottic cancer encountered in Nanfang Hospital between December 2012 to January 2014 were included in this study. Ambulatory 24 hour multichannel intraluminal impedance-pH monitoring (MII-pH) was applied to obtain LPR and GER events, as well as the reflux properties of substances. Tobacco and alcohol history was also evaluated. Sixteen healthy volunteers were recruited as normal controls. RESULTS: There were 26.3% (5/19) LPR patients in glottic cancer group, 35.3% (6/17) LPR patients in vocal cord leukoplakia group and 12.5% (2/16) LPR volunteers in normal controls. There was no statistically significant difference in the positive rate of LPR between early glottic cancer patients and normal controls as well as between vocal cord leukoplakia patients and normal controls (P > 0.05). There was statistically significance in numbers of acid reflux events, time of acid exposure, and time of acid clearance between vocal cord leukoplakia patients and normal controls as well as between glottic cancer patients and normal controls (P < 0.05). GER was found in 26.3% (5/19) patients in glottic cancer group and 23.5% (4/17) patients in vocal cord leukoplakia group and 6.3% (1/16) volunteer in normal controls. There was no statistically significant difference in the positive rate of GER between early glottic cancer patients and normal controls as well as between vocal cord leukoplakia patients and normal controls (P > 0.05). However, there was statistically significance in DeMeester scores between glottic cancer patients and normal controls (P < 0.05), while no statistically significance between vocal cord leukoplakia patients and normal controls (P > 0.05). Reflux events were dominated by acid and weakly acidic reflux in upright position. Weakly alkaline reflux events in upright position, acid reflux events in supine position, and weakly alkaline reflux events in supine position in vocal cord leukoplakia patients were significantly more than those in normal controls (P < 0.05). No statistically significant difference existed in positions and contents between early glottic cancer patients and normal controls (P > 0.05). There was also no statistically significant correlation between happening LPR and GER, smoking and drinking in patients with vocal cord leukoplakia and early glottic cancer (P > 0.05). CONCLUSIONS: Reflux events are more in vocal cord leukoplakia patients and early glottic cancer patients, however, the relationship between laryngopharyngeal reflux and canceration of the vocal cord is still needed to be investigated. The significance of mucosal injury induced by nonacid refluxes is needed to be further studies. PMID- 25017219 TI - [Observation of clinicopathological characteristics of vocal fold leukoplakia and laryngopharyngeal reflux]. AB - OBJECTIVE: To investigate the correlation between clinicopathological characteristics of vocal fold leukoplakia and laryngopharyngeal reflux (LRP). METHODS: One hundred and thirty-eight patients with vocal leukoplakia who received laryngeal microsurgeries under suspension laryngoscope were recruited in this study. Reflux symptom index (RSI) and reflux finding score (RFS) were measured. The clinical features, pathological characteristics were collected. RESULTS: There were 129 males and 9 females with a mean age of (53.4 +/- 11.5) years. The mean age of patients with severe dysplasia/carcinoma and invasive carcinoma was significantly older than that of inflammation/hyperplasia (F = 6.773, P < 0.05) . In 138 patients, 85 patients (61.6%) were pathologically diagnosed as chronic inflammation or squamous epithelium hyperplasia, 18 patients (13.0%) as mild dysplasia, 10 patients (7.2%) as moderate dysplasia, 15 patients (10.9%) as severe dysplasia/carcinoma in situ and 10 patients (7.2%) as invasive carcinoma. One hundred and twenty-nine patients (93.5%) complained of hoarseness with clinical courses between 7 days and 20 years. 68.5% vocal folds with inflammation/hyperplasia showed nearly normal mucosal waves, and 72.7% to 80.0% vocal folds with moderate or more severe dysplasia showed severe reduced mucosal waves. A correlation existed between the severity of pathological type and the decreased extent of mucosal waves (rank correlation coefficient was 0.427, P < 0.001). The prevalence of LPR diagnosed with RSI > 13 or RFS > 7 was 54.3 %, while the positive rate of RSI was 21.7% and that of RFS was 43.5%. There was no significant differences of the positive rates of RSI and RFS among different pathological types (chi2 values 3.537 and 7.619 respectively with both P > 0.05). According to RSI evaluation, the most common reflux symptoms were hoarseness (94.9%), throat clearing (68.8%) and globus sensation (62.3%). The most common RFS findings were posterior commissure hypertrophy (79.7%), thick endolaryngeal mucus (77.5%) and vocal fold edema (70.3%). CONCLUSIONS: The vocal fold leukoplakia consisted of various pathological types including benign, dysplasia and malignancy. There was a correlation between pathological types and the extent of mucosal waves. About half of the patients with vocal fold leukoplakia existed LPR using RFS and RSI evaluation, but no significant difference of LPR positive rates were observed among different pathological types. PMID- 25017220 TI - [Clinical observation of traumatic granuloma after CO2 laser cordectomy and laryngopharyngeal reflux]. AB - OBJECTIVE: Through clinical observation of granuloma after CO2 laser cordectomy under suspensive laryngoscope to discuss the effects of laryngopharyngeal reflux(LPR) to traumatic granuloma. METHODS: According to the classification of depth and range of CO2 laser cordectomy, 111 cases were divided into 5 groups, and the incidence of postoperative granuloma of each group was observed. The largest number of the 5 groups was 49 cases of type III CO2 laser cordectomy which was subdivided into 4 groups according to whether or not laryngopharyngeal reflux and whether or not proton pump inhibitor (PPI) treatment. RESULTS: In 111 cases, 56 cases (50.5%) developed granuloma after CO2 laser cordectomy. The incidence of traumatic granuloma after surgery was 10% (1/10), 26.1% (6/23), 53.1% (26/49), 78.6% (11/14), 80.0% (12/15) in I, II, III, IV, V type, respectively. It had statistical significance in chi-square test between 5 kinds of operative classification and the incidences of postoperative granuloma (chi2 = 20.32, P < 0.01) and Spearman correlation analysis showed positive correlation between classification of operation and incidences of granuloma (r = 0.44, P < 0.01). According to LPR (-), LPR (+)and PPI (+), PPI (-), the incidence of granuloma had statistical significance in these 4 group patients of 49 type III cases (chi2= 5.83, P < 0.05). The incidence of granuloma after surgery was the lowest in LPR (-) PPI (+) group (30%) and the highest in LPR (+) PPI (-) group (80%), and it showed significant difference (chi2 = 6.25, P < 0.05). CONCLUSIONS: With the increase of removal depth and the range after CO2 laser cordectomy, it appears rising trend in incidence of granuloma. Laryngopharyngeal reflux and PPI therapy on the incidence of traumatic granuloma has certain influence. PMID- 25017221 TI - [Observation the clinical curative effect of children's laryngopharyngeal reflux and sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To observe the clinical curative effect of anti-reflux treatment for obstructive sleep apnea hypopnea syndrome (OSAHS) in children. METHODS: Twenty children with sleep-disordered breathing were included in this study. There were 15 males and 5 females, aged 3-9 years old, median 6 years old. The electronic laryngoscope, polysomnography (PSG) monitoring, Reflux symptom index (RSI) questionnaire and Reflux finding score (RFS) were used to establish the initial diagnosis of OSAHS with LPRD, preclude adenoid hypertrophy and tonsil hypertrophy and nasal disorders. Oral Domperidone and Omeprazole were given for treatment. For children under 3-year-old, the dosage of Domperidone was 0.6 ml.kg-1.day 1.For children over 3-year-old, Domperidone combined with Omeprazole were given with the dosage of 0.3 mg.kg-1.day-1. RESULTS: After 4 weeks of treatment, 19 patients symptoms of OSAHS include disturbed sleep, dyspnoea and apneic attack improved. After 8 weeks of treatment, 20 cases with OSAHS symptoms improved than before treatment. Under the electronic laryngoscope, the decrease in pharyngeal lymphoid follicles, the epiglottis, aryepiglottic fold and scoop intergenic region erythema shallow, edema lessened. After treatment of 4 weeks and 8 weeks, there was statistically significant (P < 0.05). Before and after treatment, the difference of RFS was statistically significant (P < 0.05); PSG monitoring proved significant effect in 3 cases (15.0%), effective in 11 cases (55.0%) and 6 cases were ineffective (30.0%). Twenty patients with obstructive apnea index change was not obvious (P > 0.05), apnea hypopnea index and lowest artery oxygen saturation better, differences were statistically significant (Z of 2.819 and 2.733 respectively, P < 0.05). CONCLUSION: The treatment of LPRD can improve the symptoms of OSAHS, these two diseases may coexist in mutual relations. PMID- 25017222 TI - [Investigation of the reverse phase nystagmus in positioning test for benign paroxysmal positional vertigo]. AB - OBJECTIVE: To investigate the clinical significances and formation mechanism by analyzing the characteristics of the reverse phase nystagmus parameters from benign paroxysmal positional vertigo (BPPV) positioning test. METHODS: There were 183 cases with BPPV, including 108 cases (59.0%) of posterior semicircular canal canalithiasis, 55 cases (30.1%) of horizontal semicircular canal canalithiasis, and 15 cases (8.2%) of horizontal and posterior semicircular canal cupulolithiasis and 5 cases (2.7%) of anterior semicircular canalithiasis . The video-nystagmography was utilized in positioning tests to induce nystagmus. The direction, intensity, time parameters characteristic of vertical nystagmus in Dix Hallpike test and horizontal nystagmus in roll test were analyzed and compared. RESULTS: There were no reversal phase nystagmus in 15 cases of semicircular canal cupulolithiasis and 5 cases of anterior semicircular canalithiasis. After the disappearance of vertical nystagmus which induced by hanging position (the first phase nystagmus) in 108 cases of posterior semicircular canalithiasis of Dix Hallpike test, there was 54 cases(50.0%) of posterior semicircular canal canalithiasis displayed downward vertical nystagmus (reverse phase nystagmus) . The latency, duration time and intensity of the first phase nystagmus and reverse phase nystagmus were [(2.00 +/- 1.10) s, (3.54 +/- 1.42) s], [ (16.27 +/- 4.95) s, (61.65 +/- 33.69)s] and [ (51.80 +/- 25.25) degrees /s, (10.65 +/- 6.29) degrees /s] respectively; 43 cases(78.2%) of horizontal semicircular canal canalithiasis displayed the opposite to turning head (reverse phase nystagmus) after the horizontal nystagmus, similar with turning head disappeared in Roll test. The latency, duration time and intensity of the first phase of nystagmus and reverse phase nystagmus were [ (1.67 +/- 1.07) s, (3.57 +/- 1.89)s], [ (25.19 +/- 9.74) s, (70.48 +/- 40.26)s] and [ (68.47 +/- 30.18) degrees /s, (11.22 +/- 8.78) degrees /s] respectively. Comparing with the latency, duration time, intensity of first phase nystagmus and reverse phase nystagmus of posterior and horizontal semicircular canal canalithiasis, the differences had statistical significances (P < 0.05). Comparing with the first phase nystagmus of reverse phase and no reverse phase nystagmus canalithiasis, the difference of nystagmus intensity had statistical significances (P < 0.05); but the differences of latency and duration of nystagmus had no significant difference (P > 0.05). CONCLUSIONS: It is common in PSC-Can and HSC-Can patients that reverse phase nystagmus is one of the clinical features of canalithiasis. It appears in side head position of Rolling test or the hanging of Dix- Hallpike test. More power of the first phase nystagmus has, reverse phase nystagmus will be induced much easier. In comparison of the reverse phase nystagmus, the first phase nystagmus has the shorter incubation and duration, but it has more power. It is helpful to avoid interruptions of clinical statolith positioning and reset since we recognize the reverse phase nystagmus. The mechanism might be similar to the vestibular mirror image nystagmus. It is another form of the vestibular mirror image nystagmus in BPPV patients. PMID- 25017223 TI - [Imbalance between Th1 and Th2 cells in cord blood is influenced by maternal allergic rhinitis and associated with atopic dermatitis during the first two years of life]. AB - OBJECTIVE: To investigate the influence of maternal atopy on cord blood effector T cells and to identify these biologic markers as predictors of atopic dermatitis (AD). METHODS: Seventy mother-infant pairs were recruited in this prospective birth cohort study. Suspected factors for allergy, including maternal allergic history, total serum IgE, and maternal age at birth, were collected. Mother peripheral blood samples and cord blood were obtained and assayed for the percentage of interferon-gamma (IFN-gamma) and interleukin 4 (IL-4) producing T cells(Th1 and Th2 respectively) using flow cytometry. Their offspring at the age of 2 years old were evaluated by their dermatologist whether they had AD. Statistical analysis was performed using multiple logistic regression models and receiver-operating characteristic curve was employed to predict atopic dermatitis. RESULTS: Twenty-one allergic and 49 nonallergic mothers were recruited in this study. During the first two years of life, 15.7% children (n = 11) developed a physician-diagnosed AD (all children were the only child in the family). In group with maternal allergic rhinitis, a significantly increased percentage of Th2 was observed in peripheral blood of mother (7.10[1.18;16.1]% vs. 0.37[0.25;0.72]%, U = 10.0, P < 0.05) and cord blood of newborns (1.02[0.57;1.34]% vs. 0.21[0.15;0.42]%, U = 127.5, P < 0.05), respectively. Maternal atopic history did not affect the percentage of Th1 cells in cord blood (0.69[0.40;1.12]% vs.0.50[0.31;0.66]%, U = 361.0, P > 0.05). Children with reduced Th1/Th2 ratio in cord blood had a higher risk to develop AD (OR = 1.72, P = 0.001) . The model including Th1/Th2, maternal allergy, maternal age at birth and maternal total IgE showed high ability to discriminate children with and without AD. AUC was 0.907 (95% CI: 0.804-1.011, P < 0.001). CONCLUSIONS: Elevated IL-4+CD4+ T cells in cord blood were of relevance with maternal allergic history. Imbalance between Th1 cell and Th2 cell at birth are associated with maternal allergy and promoted subsequent AD development. PMID- 25017224 TI - [Diagnosis and treatment of cavernous sinus syndrome caused by fungal infection to sphenoid sinus]. AB - OBJECTIVE: To discuss the clinical diagnosis and treatment of cavernous sinus syndrome caused by fungal infection of sphenoid sinus. METHODS: The clinical manifestations, imaging examination, operation methods and complications were analyzed retrospectively in 9 patients with fungal infection of sphenoid sinus treated between January 2007 and September 2012, and the clinical experience was summarized. The treatment methods included endoscopic operation combined with antifungal drugs, and the primary disease was treated actively at the same time. RESULTS: After treatment, one patient with cavernous sinus thrombophlebitis had complications of ptosis, eyeball fixation and could only see the moving finger in the serious eye, while the contralateral eye regained normal vision. One patient with hypoproteinemia mucormycosis and diabetic remained blindness, eyeball fixation and ptosis in the left eye. In 3 patients, the vision was improved, but the eyeball movement was still limited. In another 3 patients, there was no significant recovery of vision, with one eye fixed in movement. The symptoms in 1 patient disappeared completely. All patients had no other systemic complications. CONCLUSIONS: Cavernous sinus syndrome caused by the fungal infection of sphenoid sinus is rare. It is commonly happened in patients with systemic disease or immunocompromised patients. Early detection and parallel operation and continuous antifungal therapy can reduce the damage, but the prognosis is poor. PMID- 25017225 TI - [Expression and significance of PTEN and HIF-1alpha proteins in sinonasal inverted papilloma]. AB - OBJECTIVE: To investigate the expression and clinical significance of phosphatase and tensin homology deleted on chromosome ten (PTEN) and hypoxia-inducible factor 1 alpha (HIF-1alpha) in sinonasal inverted papilloma (SNIP) of different pathological grades. METHODS: Fifty-five paraffin samples from patients with SNIP and a control group of 10 paraffin samples of patients with normal nasal cavity mucosa (NM) who underwent inferior turbinectomy were consisted in this study. Among the 55 cases of SNIP, 30 cases were without dysplasia subtypes, 11 cases were with dysplasia subtypes, and 14 cases with canceration to squamous cell carcinoma (SCC) subtypes. PTEN and HIF-1alpha expression in SNIP was detected by immunohistochemistry. The differences between NM and SNIP, and among the three subtypes were analyzed, and the relationship between PTEN, HIF-1alpha expression and SNIP recurrence and the correlation between PTEN expression and HIF-1alpha expression were also analyzed. SPSS 16.0 software was used to analyze the data. RESULTS: The positive expression rate of PTEN in NM and SNIP was 100% and 65.5%, the difference was significant (U = 147, P = 0.014), while HIF-1alpha was 0 and 30.9%, the difference was significant (U = 190, P = 0.045). The positive expression rate of PTEN in SNIP without dysplasia, SNIP with dysplasia and NSCC was 83.3%, 63.6%, 28.6%, respectively, the difference was significant (H = 12.644, P = 0.002); while HIF-1alpha was 16.7%, 45.5%, 50.0%, respectively, the difference was significant (H = 8.292, P = 0.016). A total of 22 SNIP patients recurred. PTEN had lower expression in recurrent SNIP (45.5%) than that in non recurrent SNIP (82.8%), and the difference was significant(chi2 = 7.834, P = 0.005). However, the expression of HIF-1alpha had no significant difference between recurrent SNIP and the SNIP which had no recurrence (chi2 = 0.901, P = 0.343). The expression of PTEN protein was negatively correlated with that of HIF 1alpha protein (r = -0.503, P = 0.001). CONCLUSIONS: PTEN expression decreased graduately with the severity of malignancy of SNIP, but HIF-1alpha increased. The expression of HIF-1alpha was induced by hypoxia, which may negatively effect the expression of PTEN, and both HIF-1alpha and PTEN may play critical roles in the progress of SNIP. PTEN is one of the factors responsible for the postoperative recurrence of SNIP. PMID- 25017226 TI - [Clinicopathologic features and risk factors of bilateral cervical lymph node metastasis in head and neck squamous cell carcinoma]. AB - OBJECTIVE: To investigate the clinicopathologic features and associated risk factors for bilateral neck node metastasis (BNM) in head and neck squamous cell carcinoma (HNSCC). METHODS: Two hundred eighty-six cases with HNSCC were retrospectively studied, including 83 cases of oral tongue cancers, 101 cases of hypopharyngeal cancers and 102 cases of supraglottic laryngeal cancers. All patients had unilateral or bilateral cervical lymph node metastasis confirmed by postoperative pathologic examinations. The following factors were evaluated to determine the risk for BNM in HNSCC: T staging, size, location, trans-midline condition, growth pattern, pathologic grading and infiltration of primary tumors; N staging; the size, number and extracapsular spread (ECS) of ipsilateral metastatic nodes; the number of involved levels on the ipsilateral neck. Chi square test and logistic regression test were used for statistical analysis. RESULTS: BNM was found in 86 (30.1%) of 286 patients with HNSCC, including 52 (18.2%) cases of contralateral occult neck node metastasis. The incidence of BNM was 35.6% (36/101) in hypopharyngeal cancer, 31.4% (32/102) in supraglottic laryngeal cancer and 21.7% (18/83) in oral tongue cancer, respectively. N staging, the number and ECS of ipsilateral metastatic nodes, and the number of involved levels on the ipsilateral neck were important factors contributing to BNM. Multiple logistic regression analysis revealed that midline passing of primary tumor was associated with BNM in oral tongue cancer. The midline passing and ECS of ipsilateral metastatic node were key factors for BNM in hypopharyngeal and supraglottic laryngeal cancers. T staging, size and midline passing of primary tumor were closely related to BNM in oral tongue cancer. T staging and midline passing were associated with BNM in hypopharyngeal cancer. Midline passing was an important factor related to BNM in supraglottic laryngeal cancer. CONCLUSION: Midline passing of primary tumor is the most important factor determining BNM in hypopharyngeal, supraglottic laryngeal and oral tongue cancers, whereas ECS of ipsilateral metastatic node is the most important factor impacting BNM in hypopharyngeal and supraglottic laryngeal cancers. PMID- 25017227 TI - [Facial nerve palsy secondary to blunt trauma without a temporal bone fracture case report and literature review]. PMID- 25017228 TI - [Extra-tonsillar approach to the styloid process]. PMID- 25017229 TI - [Synovial sarcoma of the neck: report of two cases]. PMID- 25017230 TI - [Maxillary sinus large metal foreign body: a case report]. PMID- 25017232 TI - [A case of ectopic tonsil in the neck and literature review]. PMID- 25017231 TI - [Combined pharynx and neck incision in treatment one case of the second branchial cleft integrity fistula]. PMID- 25017233 TI - [A case of parathyroid carcinoma presented with hyperparathyroidism]. PMID- 25017234 TI - [Hereditary medullary thyroid cancer in a family with MEN2B: clinical analysis and mutation detection of RET proto-oncogene]. PMID- 25017236 TI - [Obstructive sleep apnea hypopnea syndrome and reflux disease]. PMID- 25017235 TI - [Research development of childhood hearing screening]. PMID- 25017237 TI - [Laryngopharyngeal reflux disease]. PMID- 25017238 TI - [Pediatric laryngopharyngeal reflux]. PMID- 25017239 TI - Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. AB - Angiotensin-(1-7) is one of the most important active peptides of the renin angiotensin system (RAS) with recognized cardiovascular relevance; however several studies have shown the potential therapeutic role of Ang-(1-7) on treating and preventing metabolic disorders as well. This peptide achieves a special importance considering that in the last few decades obesity and metabolic syndrome (MS) have become a growing worldwide health problem. Angiotensin (Ang) II is the most studied component of RAS and is increased during obesity, diabetes and dyslipidemia (MS); some experimental evidence has shown that Ang II modulates appetite and metabolism as well as mechanisms that induce adipose tissue growth and metabolism in peripheral organs. Recent articles demonstrated that Ang-(1 7)/Mas axis modulates lipid and glucose metabolism and counterregulates the effects of Ang II. Based on these data, angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas pathway activation have been advocated as a new tool for treating metabolic diseases. This review summarizes the new evidence from animal and human experiments indicating the use of Ang-(1-7) in prevention and treatment of obesity and metabolic disorders. PMID- 25017240 TI - Hyperalgesic and edematogenic effects of Secapin-2, a peptide isolated from Africanized honeybee (Apis mellifera) venom. AB - Honeybee stings are a severe public health problem. Bee venom contains a series of active components, including enzymes, peptides, and biogenic amines. The local reactions observed after envenoming include a typical inflammatory response and pain. Honeybee venom contains some well-known polycationic peptides, such as Melittin, Apamin, MCD peptide, Cardiopep, and Tertiapin. Secapin in honeybee venom was described 38 years ago, yet almost nothing is known about its action. A novel, variant form of this peptide was isolated from the venom of Africanized honeybees (Apis mellifera). This novel peptide, named Secapin-2, is 25 amino acid residues long. Conformational analyses using circular dichroism and molecular dynamics simulations revealed a secondary structure rich in strands and turns, stabilized by an intramolecular disulfide bridge. Biological assays indicated that Secapin-2 did not induce hemolysis, mast cell degranulation or chemotactic activities. However, Secapin-2 caused potent dose-related hyperalgesic and edematogenic responses in experimental animals. To evaluate the roles of prostanoids and lipid mediators in the hyperalgesia and edema induced by this peptide, Indomethacin and Zileuton were used to inhibit the cyclooxygenase and lipoxygenase pathways, respectively. The results showed that Zileuton partially blocked the hyperalgesia induced by Secapin-2 and decreased the edematogenic response. In contrast, Indomethacin did not interfere with these phenomena. Zafirlukast, a leukotriene receptor antagonist, blocked the Secapin-2 induced hyperalgesia and edematogenic response. These results indicate that Secapin-2 induces inflammation and pain through the lipoxygenase pathway in both phenomena. PMID- 25017241 TI - Changes of PACAP level in cerebrospinal fluid and plasma of patients with severe traumatic brain injury. AB - PACAP has well-known neuroprotective potential including traumatic brain injury (TBI). Its level is up-regulated following various insults of the CNS in animal models. A few studies have documented alterations of PACAP levels in human serum. The time course of post-ictal PACAP levels, for example, show correlation with migraine severity. Very little is known about the course of PACAP levels following CNS injury in humans and the presence of PACAP has not yet been detected in cerebrospinal fluid (CSF) of subjects with severe TBI (sTBI). The aim of the present study was to determine whether PACAP occurs in the CSF and plasma (Pl) of patients that suffered sTBI and to establish a time course of PACAP levels in the CSF and Pl. Thirty eight subjects with sTBI were enrolled with a Glasgow Coma Scale <=8 on admission. Samples were taken daily, until the time of death or for maximum 10 days. Our results demonstrated that PACAP was detectable in the CSF, with higher concentrations in patients with TBI. PACAP concentrations markedly increased in both Pl and CSF in the majority of patients 24-48h after the injury stayed high thereafter. In cases of surviving patients, Pl and CSF levels displayed parallel patterns, which may imply the damage of the blood-brain barrier. However, in patients, who died within the first week, Pl levels were markedly higher than CSF levels, possibly indicating the prognostic value of high Pl PACAP levels. PMID- 25017242 TI - Peripheral injected cholecystokinin-8S modulates the concentration of serotonin in nerve fibers of the rat brainstem. AB - Serotonin and cholecystokinin (CCK) play a role in the short-term inhibition of food intake. It is known that peripheral injection of CCK increases c-Fos immunoreactivity (Fos-IR) in the nucleus of the solitary tract (NTS) in rats, and injection of the serotonin antagonist ondansetron decreases the number of c-Fos IR cells in the NTS. This supports the idea of serotonin contributing to the effects of CCK. The aim of the present study was to elucidate whether peripherally injected CCK-8S modulates the concentration of serotonin in brain feeding-regulatory nuclei. Ad libitum fed male Sprague-Dawley rats received 5.2 and 8.7 nmol/kg CCK-8S (n=3/group) or 0.15M NaCl (n=3-5/group) injected intraperitoneally (ip). The number of c-Fos-IR neurons, and the fluorescence intensity of serotonin in nerve fibers were assessed in the paraventricular nucleus (PVN), arcuate nucleus (ARC), NTS and dorsal motor nucleus of the vagus (DMV). CCK-8S increased the number of c-Fos-ir neurons in the NTS (mean+/-SEM: 72+/-4, and 112+/-5 neurons/section, respectively) compared to vehicle-treated rats (7+/-2 neurons/section, P<0.05), but did not modulate c-Fos expression in the DMV or ARC. Additionally, CCK-8S dose-dependently increased the number of c Fos-positive neurons in the PVN (218+/-15 and 128+/-14, respectively vs. 19+/-5, P<0.05). In the NTS and DMV we observed a decrease of serotonin-immunoreactivity 90 min after injection of CCK-8S (46+/-2 and 49+/-8 pixel/section, respectively) compared to vehicle (81+/-8 pixel/section, P<0.05). No changes of serotonin immunoreactivity were observed in the PVN and ARC. Our results suggest that serotonin is involved in the mediation of CCK-8's effects in the brainstem. PMID- 25017243 TI - Impact of molecular adsorbent recirculating system therapy on tacrolimus elimination: a case report. AB - BACKGROUND: We report a unique case which quantifies the effect of molecular adsorbent recirculating system (MARS [Gambro, Sweden]) therapy on blood concentrations of tacrolimus in a patient treated for refractory pruritus associated with recurrent hepatitis C of the liver allograft. Tacrolimus is a low molecular-weight, highly protein-bound drug with the potential to be removed during MARS therapy. CASE REPORT: Results of therapeutic drug monitoring revealed extracorporeal tacrolimus elimination accounted for only 0.3% of total drug removal during the session. CONCLUSIONS: Although no explanation can be offered as to why MARS contributed so little to overall tacrolimus elimination, the data clearly show minimal impact of MARS on tacrolimus blood level. PMID- 25017245 TI - Validity and reliability of the munsell soil color charts for assessing human skin color. AB - BACKGROUND: Skin pigmentation is a key factor for ultraviolet radiation exposure related cancers and can make a significant contribution to the patterns of other diseases. For surveys, and to appropriately target cancer control activities, valid and reliable measures of skin color are required. METHODS: Validity and reliability of the Munsell Soil Color Charts were investigated for skin color assessment. The unexposed skin color of 280 university students was measured by spectrophotometer to calculate an Individual Typology Angle (ITA) value, and categorized by two independent raters according to the Munsell system (the latter was repeated after a 7-day interval). RESULTS: Interrater and intrarater reliability for the Munsell charts was found to be acceptable [intraclass correlation coefficients (ICC) of 0.85 and 0.86, respectively]. When ITA values were converted to the six Del Bino skin color categories, weighted kappa for agreement between raters, within rater, and between Munsell chip and spectrophotometer were 0.63, 0.60, and 0.61, respectively. A tendency toward overestimation of the extremes of skin pigmentation was evident, particularly for the "brown" and "dark" skin types. CONCLUSIONS: Study findings suggest that the Munsell Soil Color Charts represent a reliable and valid measurement strategy when assessing skin type. IMPACT: The Munsell Year 2000 Soil Color Charts may provide a useful instrument for fieldwork contexts. Subsequent classification of individuals into skin cancer risk categories, rather than the use of precise ITA values, may be sufficient for targeting public health messages for skin cancer prevention and other health risks. PMID- 25017244 TI - Reduced insulin-like growth factor I receptor and altered insulin receptor isoform mRNAs in normal mucosa predict colorectal adenoma risk. AB - BACKGROUND: Hyperinsulinemia resulting from obesity and insulin resistance is associated with increased risk of many cancers, but the biology underlying this risk is unclear. We hypothesized that increased mRNA levels of the insulin-like growth factor I receptor (IGFIR) versus the insulin receptor (IR) or elevated ratio of IR-A:IR-B isoforms in normal rectal mucosa would predict adenoma risk, particularly in individuals with high body mass index (BMI) or plasma insulin. METHODS: Biopsies from normal rectal mucosa were obtained from consenting patients undergoing routine colonoscopy at University of North Carolina Hospitals (Chapel Hill, NC). Subjects with colorectal adenomas were classified as cases (n = 100) and were matched to adenoma-free controls (n = 98) based on age, sex, and BMI. IGFIR and IR mRNA levels were assessed by qRT-PCR, and IR-A:IR-B mRNA ratios by standard PCR. Plasma insulin and crypt apoptosis were measured by ELISA and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), respectively. Logistic regression models examined relationships between receptor mRNAs, BMI, plasma insulin, and adenoma risk. RESULTS: Unexpectedly, cases were significantly more likely to have lower IGFIR mRNA levels than controls. No overall differences in total IR mRNA or IR-A:IR-B ratios were observed between cases and controls. Interestingly, in patients with high plasma insulin, increased IR-A:IR-B ratio was associated with increased likelihood of having adenomas. CONCLUSIONS: Our work shows novel findings that reduced IGFIR mRNA and, during high plasma insulin, increased IR-A:IR-B ratios in normal rectal mucosa are associated with colorectal adenoma risk. IMPACT: Our work provides evidence supporting a link between IGFIR and IR isoform expression levels and colorectal adenoma risk. PMID- 25017246 TI - The use of metformin in patients with prostate cancer and the risk of death. AB - BACKGROUND: Given the conflicting results from observational studies, we assessed whether the use of metformin after a prostate cancer diagnosis is associated with a decreased risk of cancer-specific and all-cause mortality. METHODS: This study was conducted linking four databases from the United Kingdom. A cohort of men newly diagnosed with nonmetastatic prostate cancer with a history of treated type II diabetes, between April 1, 1998 and December 31, 2009, was followed until October 1, 2012. Nested case-control analyses were performed for cancer-specific mortality and all-cause mortality, in which exposure was defined as use of metformin during the time to risk-set. Conditional logistic regression was used to estimate adjusted rate ratios (RR) of each outcome with 95% confidence intervals (CI). RESULTS: The cohort consisted of 935 men with prostate cancer and a history of type II diabetes. After a mean follow-up of 3.7 years, 258 deaths occurred, including 112 from prostate cancer. Overall, the post-diagnostic use of metformin was not associated with a decreased risk of cancer-specific mortality (RR, 1.09; 95% CI, 0.51-2.33). In a secondary analysis, a cumulative duration >=938 days was associated with an increased risk (RR, 3.20; 95% CI, 1.00-10.24). The post-diagnostic use of metformin was not associated with all-cause mortality (RR, 0.79; 95% CI, 0.50-1.23). CONCLUSION: The use of metformin after a prostate cancer diagnosis was not associated with an overall decreased risk of cancer specific and all-cause mortality. IMPACT: The results of this study do not support a role for metformin in the prevention of prostate cancer outcomes. PMID- 25017247 TI - A pooled analysis of body mass index and pancreatic cancer mortality in african americans. AB - BACKGROUND: Pancreatic cancer is a leading cause of cancer-related mortality in the United States and both incidence and mortality are highest in African Americans. Obesity is also disproportionately high in African Americans, but limited data are available on the relation of obesity to pancreatic cancer in this population. METHODS: Seven large prospective cohort studies pooled data from African American participants. Body mass index (BMI) was calculated from self reported height and weight at baseline. Cox regression was used to calculate HRs and 95% confidence intervals (CI) for levels of BMI relative to BMI 18.5-24.9, with adjustment for covariates. Primary analyses were restricted to participants with >=5 years of follow-up because weight loss before diagnosis may have influenced baseline BMI in cases who died during early follow-up. RESULTS: In follow-up of 239,597 participants, 897 pancreatic cancer deaths occurred. HRs were 1.08 (95% CI, 0.90-1.31) for BMI 25.0 to 29.9, 1.25 (95% CI, 0.99-1.57) for BMI 30.0 to 34.9, and 1.31 (95% CI, 0.97-1.77) for BMI >=35.0 among those with >=5 years of follow-up (Ptrend = 0.03). The association was evident among both sexes and was independent of a history of diabetes. A stronger association was observed among never-smokers (BMI >=30 vs. referent: HR = 1.44; 95% CI, 1.02 2.03) than among smokers (HR = 1.16; 95% CI, 0.87-1.54; Pinteraction = 0.02). CONCLUSION: The findings suggest that obesity is independently associated with increased pancreatic cancer mortality in African Americans. IMPACT: Interventions to reduce obesity may also reduce risk of pancreatic cancer mortality, particularly among never-smokers. PMID- 25017248 TI - A multilevel model of postmenopausal breast cancer incidence. AB - BACKGROUND: Breast cancer has a complex etiology that includes genetic, biologic, behavioral, environmental, and social factors. Etiologic factors are frequently studied in isolation with adjustment for confounding, mediating, and moderating effects of other factors. A complex systems model approach may present a more comprehensive picture of the multifactorial etiology of breast cancer. METHODS: We took a transdisciplinary approach with experts from relevant fields to develop a conceptual model of the etiology of postmenopausal breast cancer. The model incorporated evidence of both the strength of association and the quality of the evidence. We operationalized this conceptual model through a mathematical simulation model with a subset of variables, namely, age, race/ethnicity, age at menarche, age at first birth, age at menopause, obesity, alcohol consumption, income, tobacco use, use of hormone therapy (HT), and BRCA1/2 genotype. RESULTS: In simulating incidence for California in 2000, the separate impact of individual variables was modest, but reduction in HT, increase in the age at menarche, and to a lesser extent reduction in excess BMI >30 kg/m(2) were more substantial. CONCLUSIONS: Complex systems models can yield new insights on the etiologic factors involved in postmenopausal breast cancer. Modification of factors at a population level may only modestly affect risk estimates, while still having an important impact on the absolute number of women affected. IMPACT: This novel effort highlighted the complexity of breast cancer etiology, revealed areas of challenge in the methodology of developing complex systems models, and suggested additional areas for further study. PMID- 25017249 TI - Adherence to dietary and lifestyle recommendations and prostate cancer risk in the prostate testing for cancer and treatment (ProtecT) trial. AB - BACKGROUND: The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) published eight recommendations for cancer prevention, but they are not targeted at prostate cancer prevention. We investigated whether adherence to the WCRF/AICR recommendations and a prostate cancer dietary index is associated with prostate cancer risk. METHODS: We conducted a nested case-control study of 1,806 prostate-specific antigen (PSA)-detected prostate cancer cases and 12,005 controls in the ProtecT trial. We developed a prostate cancer dietary index by incorporating three dietary factors most strongly associated with prostate cancer. Scores were computed to quantify adherence to the WCRF/AICR recommendations and the prostate cancer dietary index separately. RESULTS: The prostate cancer dietary index score was associated with decreased risk of prostate cancer [OR per 1 score increment: 0.91; 95% confidence interval (CI): 0.84-0.99; Ptrend = 0.04] but the WCRF/AICR index score was not (OR: 0.99; 95% CI: 0.94-1.05; Ptrend = 0.71). There was no heterogeneity in association by prostate cancer stage (P = 0.81) or grade (P = 0.61). Greater adherence to recommendations to increase plant foods (OR per 0.25 index score increment: 0.94; 95% CI: 0.89-0.99; Ptrend = 0.02) and tomato products (OR adherence vs. nonadherence: 0.82; 95% CI: 0.70-0.97; P = 0.02) was inversely associated with overall prostate cancer risk. CONCLUSIONS: Adherence to the prostate cancer specific dietary recommendations was associated with decreased risk of prostate cancer. High intake of plant foods and tomato products in particular may help protect against prostate cancer. IMPACT: Meeting the WCRF/AICR recommendations alone is insufficient for prostate cancer prevention. Additional dietary recommendations should be developed. PMID- 25017250 TI - Does the use of structured reporting improve usability? A comparative evaluation of the usability of two approaches for findings reporting in a large-scale telecardiology context. AB - One of the main reasons that leads to a low adoption rate of telemedicine systems is poor usability. An aspect that influences usability during the reporting of findings is the input mode, e.g., if a free-text (FT) or a structured report (SR) interface is employed. The objective of our study is to compare the usability of FT and ST telemedicine systems, specifically in terms of user satisfaction, efficiency and general usability. We comparatively evaluate the usability of these two input modes in a telecardiology system for issuing electrocardiography reports in the context of a statewide telemedicine system in Brazil with more than 350.000 performed tele-electrocardiography examinations. We adopted a multiple method research strategy, applying three different kinds of usability evaluations: user satisfaction was evaluated through interviews with seven medical professionals using the System Usability Scale (SUS) questionnaire and specific questions related to adequacy and user experience. Efficiency was evaluated by estimating execution time using the Keystroke-Level Model (KLM). General usability was assessed based on the conformity of the systems to a set of e-health specific usability heuristics. The results of this comparison provide a first indication that a structured report (SR) input mode for such a system is more satisfactory and efficient with a larger conformity to usability heuristics than free-text (FT) input. User satisfaction using the SUS questionnaire has been scored in average with 58.8 and 77.5 points for the FT and SR system, respectively, which means that the SR system was rated 18.65 points higher than the FT system. In terms of efficiency, the completion of a findings report using the SR mode is estimated to take 8.5s, 3.74 times faster than using the FT system (31.8s). The SR system also demonstrated less violations to usability heuristics (8 points) in comparison to 14 points observed in the FT system. These results provide a first indication that the usage of structured reporting as an input mode in telecardiology systems may enhance usability. This also seems to confirm the advantages of the usage of structured reporting, as already described in the literature for other areas such as teleradiology. PMID- 25017251 TI - Thoracic, abdominal and musculoskeletal involvement in Erdheim-Chester disease: CT, MR and PET imaging findings. AB - BACKGROUND: Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis with characteristic radiological and histological features. This entity is defined by a mononuclear infiltrate consisting of lipid-laden, foamy histiocytes that stain positively for CD68 and negatively for CD1a. Osseous involvement is constant and characteristic. Extra-osseous lesions may affect the retroperitoneum, lungs, skin, heart, brain and orbits. METHODS: Both radiography and technetium-99m bone scintigraphy may reveal osteosclerosis of the long bones, which is a typical finding in ECD. For visceral involvement, computed tomography (CT) is most useful, while magnetic resonance (MR) imaging is more sensitive for cardiovascular lesions; 2-[fluorine-18] fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/CT scanning is useful in assessing the extension of ECD lesions. RESULTS: The prognosis is extremely variable and is often worse when there is cardiovascular system involvement. Diagnosis is based on the combination of radiographic, CT, MR imaging and nuclear medicine features and a nearly pathognomonic immunohistochemical profile. CONCLUSION: The aims of this work are to perform a systematic review of Erdheim-Chester disease as seen on imaging of the chest, abdomen and musculoskeletal system and to discuss the diagnostic workup and differential diagnoses according to the imaging presentation. Teaching points * Bone involvement is usually present in patients, and the imaging findings are pathognomonic of ECD. * The circumferential periaortic infiltration may extend to its branches, sometimes becoming symptomatic. * Cardiac involvement the pericardium, right atrium and auriculoventricular sulcus-worsens its prognosis. * Perirenal infiltration extending to the proximal ureter is highly suggestive of this disease. PMID- 25017252 TI - Effects of mental fatigue on biomechanics of slips. AB - The objective of this study was to investigate the effects of mental fatigue on biomechanics of slips. A total of 44 healthy young participants were evenly categorised into two groups: no fatigue and mental fatigue. Mental fatigue was induced by performing an AX-continuous performance test. The participants in both groups were instructed to walk on a linear walkway, and slips were induced unexpectedly during walking. We found that mental fatigue has adverse effects in all the three phases of slips. In particular, it leads to increased likelihood of slip initiation, poorer slip detection and a more insufficient reactive recovery response to slips. Based on the findings from the present study, we can conclude that mental fatigue is a risk factor for slips and falls. In order to prevent slip-induced falls, interventions, such as providing frequent rest breaks, could be applied in the workplace to avoid prolonged exposures to cognitively demanding activities. PMID- 25017253 TI - Method for enhancement of plant redox-related protein expression and its application for in vitro reduction of chloroplastic thioredoxins. AB - Plant redox-related proteins were overexpressed using a genetic codon substitution downstream of the translation initiation codon. This method significantly improved recombinant protein expression levels of Arabidopsis chloroplastic thioredoxins and cytosolic nicotinamide adenine dinucleotide phosphate (NADPH)-dependent thioredoxin reductase (E.C. 1.8.1.9) in Escherichia coli. Using these proteins, the in vitro chloroplastic thioredoxins-reduction system was reconstituted in an NADPH-dependent manner. This system could convert the five classes of chloroplastic Arabidopsis thioredoxins and two chloroplastic Spinach thioredoxins to their reduced forms, independent of dithiothreitol and the photosynthetic electron transport system. PMID- 25017254 TI - Aberrant expression of enhancer of zeste homologue 2, correlated with HIF-1alpha, refines relapse risk and predicts poor outcome for breast cancer. AB - Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior in a variety of cancers. In vitro, hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptionally activates EZH2 and promotes the progression of breast tumor initiating cells. Here, we characterized the clinicopathological effect of EZH2 and HIF-1alpha in 410 breast cancer patients. We examined EZH2 and HIF-1alpha expression using immunohistochemistry and western blotting. We found that EZH2 and HIF-1alpha were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with lymphatic invasion (P=0.025), HER2 expression (P=0.005) and hypoxia (P<0.001). Overexpression of EZH2 predicted a poor 5-year overall survival (OS, 74.8 vs. 93.4%, P=0.001), disease-free survival (DFS, 72.2 vs. 88.6%, P=0.031), local failure-free survival (LFFS, 95.7 vs. 97.9%, P=0.045) and distant metastasis-free survival (DMFS, 75.4 vs. 90.5%, P=0.039). Multivariate analysis confirmed that EZH2 is an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was identified between EZH2 and HIF-1alpha (r=0.299, P<0.001). Importantly, tumors coexpressing HIF-1alpha and EZH2 had a poorer OS (P=0.007). In conclusion, our study demonstrated that EZH2 is an independent negative prognostic biomarker for breast cancer. Tumors overexpressing HIF-1alpha and EZH2 are more prone to disease progression. PMID- 25017255 TI - Neoplasms in the trocar site and peritoneal papillary serous cystadenocarcinoma. PMID- 25017256 TI - Major risk factors for stillbirth in different trimesters of pregnancy--a systematic review. AB - Stillbirth remains an event that has an important impact on global health issues. Different levels of health care between countries suggest that the stillbirth rate may be one of the indicators of the quality of a country's medical system. In this review, major risk factors for stillbirth will be discussed, especially in different trimesters of pregnancy. Early identification of risk factors for stillbirth and appropriate antenatal management may reduce preventable stillbirths and improve general outcomes of pregnancy. PMID- 25017257 TI - New perspectives on preimplantation genetic diagnosis and preimplantation genetic screening. AB - Preimplantation genetic diagnosis is a procedure that involves the removal of one or more nuclei from oocytes (a polar body) or embryos (blastomeres or trophectoderm cells) in order to test for problems in genome sequence or chromosomes of the embryo prior to implantation. It provides new hope of having unaffected children, as well as avoiding the necessity of terminating an affected pregnancy for genetic parents who carry an affected gene or have balanced chromosomal status. Polymerase chain reaction-based molecular techniques are the methods used to detect gene defects with a known sequence and X-linked diseases. The indication for using this approach has expanded for couples who are prevented from having babies because they carry a serious genetic disorder to couples with conditions that are not immediately life threatening, such as cancer predisposition genes and Huntington disease. In addition, fluorescent in situ hybridization (FISH) has been widely applied for the detection of chromosome abnormalities. FISH allows the evaluation of many chromosomes at the same time, up to 15 chromosome pairs in a single cell. Preimplantation genetic screening, defined as a test that screens for aneuploidy, has been most commonly used in situations of advanced maternal age, a history of recurrent miscarriage, a history of repeated implantation failure, or a severe male factor. Unfortunately, randomized controlled trials have as yet shown no benefit with respect to preimplantation genetic screening using cleavage stage biopsy, which is probably attributable to the high levels of mosaicism at early cleavage stages and the limitations of FISH. Recently, two main types of array-based technology combined with whole genome amplification have been developed for use in preimplantation genetic diagnosis; these are comparative genomic hybridization and single nucleotide polymorphism-based arrays. Both allow the analysis of all chromosomes, and the latter also allows the haplotype of the sample to be determined. The promising results of these two approaches will inspire further validation of these array platforms, even at the single-cell level. It remains to be decided which embryo stage is the best for biopsy. Moreover, if randomized controlled trials are confirmed to play a role in increasing delivery rates, this will be a major step forward for assisted reproductive technology patients around the world. PMID- 25017258 TI - Therapeutic potential of amniotic-fluid-derived stem cells on liver fibrosis model in mice. AB - OBJECTIVE: Liver fibrosis results from the wound healing response to chronic liver damage. Advanced liver fibrosis results in cirrhosis and liver failure, and liver transplantation is often the only option for effective therapy; however, the shortage of available donor livers limits this treatment. Thus, new therapies for advanced liver fibrosis are essential. MATERIALS AND METHODS: Amniotic fluid contains an abundance of stem cells, which are derived from all three germ layers of the developing fetus. These cells do not induce teratomas in vivo and do not pose any ethical concerns. To generate liver fibrosis models, male ICR mice were treated with CCl4 via oral gavage for 4 weeks, and the serum levels of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and albumin were higher than in the control group following chemical induction. To assess the potential of amniotic-fluid-derived stem cells (mAFSCs) to ameliorate liver fibrosis in vivo, mAFSCs were isolated from amniotic fluid of 13.5-day-old transgenic mice, which globally express the fluorescent protein, enhanced green fluorescent protein (EGFP), for tracing purposes (EGFP-mAFSCs). Single cells were injected via the mesentery (1 * 10(6) cells/mouse) of transplanted mice with liver fibrosis. RESULTS: Four weeks after EGFP-mAFSC transplantation, the serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and albumin levels of recipient mice in the EGFP-mAFSC-injected group were significantly decreased when compared with mice in the saline-injected group. Additionally, fibrotic tissues were evaluated using Masson's trichrome staining 4 weeks after cell transplantation. Shrinkage of the fibrotic area was observed in the EGFP mAFSC-injected group. The tissue-repair effects were also confirmed by hydroxyproline content analysis. CONCLUSION: The possible repair mechanism from our data revealed that EGFP-mAFSCs may fuse with the recipient liver cells. Overall, EGFP-mAFSCs can ameliorate liver fibrosis in mice, thus providing insight into the future development of regenerative medicine. PMID- 25017259 TI - Correlation of plasma osteopontin and neutrophil gelatinase-associated lipocalin levels with the severity and clinical outcome of pelvic inflammatory disease. AB - OBJECTIVE: To investigate the correlation of two important inflammatory biomarkers, plasma osteopontin and neutrophil gelatinase-associated lipocalin (NGAL), with the severity and outcome of pelvic inflammatory disease (PID). MATERIALS AND METHODS: Sixty-one patients with PID, including 25 patients with tubo-ovarian abscess (TOA), were consecutively recruited. Their blood samples were tested for the concentrations of plasma osteopontin and NGAL using enzyme linked immunosorbent assay. The associations of these biomarkers with TOA, length of hospitalization, and incidence of surgery were also analyzed. RESULTS: Plasma osteopontin level was significantly increased in PID patients with TOA compared to PID patients without TOA (median 107.77 ng/mL vs. 72.39 ng/mL, p = 0.004). However, there was no significant difference for plasma NGAL. If the cutoff level of plasma osteopontin was set at 81.1 ng/mL, there was a 76.0% sensitivity and a 24.0% false negative rate in predicting TOA in PID patients. Plasma osteopontin significantly correlated with length of hospital stay (r = 0.467, p < 0.001), and this correlation was better than that of NGAL. However, neither biomarker was associated with incidence of surgery. CONCLUSION: Plasma osteopontin has a better correlation with TOA and length of hospitalization compared to NGAL. If plasma osteopontin level falls below 81.1 ng/mL, PID patients will have about a 20% chance of developing TOA. Incorporating plasma osteopontin, but not NGAL, will allow for an adjuvant diagnostic biomarker for TOA and predictor of length of hospital stay. PMID- 25017260 TI - Comparisons of four dietary assessment methods during pregnancy in Taiwanese women. AB - OBJECTIVE: The purpose of this methodology study is to examine the relative validity of four dietary assessment methods during pregnancy and to understand the pros and cons of each method. MATERIALS AND METHODS: We recruited 181 healthy pregnant women with less than 20 weeks of gestation and collected information through personal and telephone interviews in Taipei, Taiwan. Dietary assessment methods including 24-hour recalls, 3-day food records, and the weekly food frequency questionnaire during the 3 trimesters and the meal-based Chinese food frequency questionnaire (CFFQ) in the 3(rd) trimester were used in this prospective study. RESULTS: The percentages of energy from protein (15%), fat (31 34%), and carbohydrate (50-54%) were similar by the recall and record methods. The energy intakes from 24-hour recalls were 1924 kcal, 1980 kcal, and 2172 kcal in the 1(st), 2(nd), and 3(rd) trimesters, respectively. The weekly food frequency questionnaire resulted in significantly higher intakes of all energy nutrients, especially for protein and fat intakes (percentages and densities) for the 3 trimesters; a further adjustment for the food list is needed. The CFFQ showed comparable results with the quantitative methods in estimating dietary patterns for the entire pregnancy. The 24-hour recalls by telephone interviews provided reasonable results in the assessment of the average nutrient intakes during the trimesters. CONCLUSION: The combinations of 24-hour recalls for the short-term dietary changes and the CFFQ for long-term dietary patterns are suggested as appropriate dietary assessment methods during pregnancy in Taiwan. PMID- 25017261 TI - A retrospective study on the course and outcome of fetal ventriculomegaly. AB - OBJECTIVE: To evaluate the outcomes associated with fetal ventriculomegaly. MATERIALS AND METHODS: Reports of women who underwent ultrasound scanning between 18 and 36 weeks of gestation during the period from January 1, 2000, to December 31, 2010, were reviewed. According to the defined severity of ventriculomegaly of affected fetuses, the women were divided into the following groups: (1) mild ventriculomegaly (Group A); (2) moderate ventriculomegaly (Group B); and (3) severe ventriculomegaly (Group C). The women were classified into the "gray zone" group if the fetal lateral ventricle measured between 7 mm and <10 mm. All cases were followed up with additional ultrasound scans. Postnatal information was obtained from the computer database or the medical charts. RESULTS: A total of 41 cases were recruited for this analysis. Four (9.8%) cases had an abnormal karyotype. Twelve women (29.3%) opted for termination of pregnancy. Of the 29 women who delivered, 56.1% (N = 23) were from Group A, 14.6% (N = 6) were from Group B, and none was from Group C. All children in Group A had normal neurological development. Three children in Group B had normal neurological development, whereas the other three had neurologic deficits. A total of 432 cases were classified into the "gray zone" group. Of these cases, 2.8% (N = 12) progressed to ventriculomegaly. CONCLUSION: Cases of isolated and mild ventriculomegaly without additional structural anomalies or chromosomal aberrations had good prognoses. However, the parents of fetuses with moderate or severe ventriculomegaly should be counseled regarding related risks. If the ventricular size of the fetus falls within the "gray zone", at least one additional exam in the third trimester should be performed, for early detection of ventriculomegaly and other related abnormalities. It is important to make the parents of these fetuses aware of these risks, from a medico-legal point of view. PMID- 25017262 TI - Clinical and biochemical characteristics of women with menstrual disturbance. AB - OBJECTIVE: Menstrual irregularity is one of the major complaints in women of reproductive age. The aim of this study was to evaluate the complications in women with different menstrual disturbances. MATERIALS AND METHODS: This is a retrospective study. A total of 576 women were screened first, and 470 women were included later [257 women with oligo/amenorrhea (149 hyperandrogenic and 108 nonhyperandrogenic women) and 213 normocyclic controls]. Endocrine and metabolic parameters and insulin resistance were compared among different menstrual patterns. RESULTS: The average duration of menstrual cycle length was positively correlated with age, levels of androgens and prolactin, lipid profiles, and the parameters of insulin resistance. Hyperandrogenic women with amenorrhea had higher levels of androgens and more lipid profiles disorders than hyperandrogenic women with oligomenorrhea. However, nonhyperandrogenic women with amenorrhea had a degree of insulin resistance and metabolic disturbance similar to that of nonhyperandrogenic women with oligomenorrhea. Interestingly, for women with normal prolactin levels, serum prolactin levels were significantly lower in amenorrhea than oligomenorrhea in both hyperandrogenic and nonhyperandrogenic groups. CONCLUSION: The degree of menstrual disturbances does not correlate with the severity of insulin resistance and metabolic disturbances in women without excess levels of androgen. For women with normal prolactin levels, amenorrheic patients had significantly lower serum prolactin levels than oligomenorrheic patients. PMID- 25017263 TI - Risk factors for urinary incontinence among women aged 60 or over with hypertension in Taiwan. AB - OBJECTIVE: To assess the associated risk factors and the prevalence of urinary incontinence (UI) among women with hypertension (H/T) aged 60 or over in Taiwan. MATERIALS AND METHODS: A total of 2410 women aged 60 or over were selected by a multistage random sampling method and a total of 1519 women completed the face-to face interviews. Only women who answered "yes" to the question "Do you have H/T?" were included in the H/T sample. The factors were assessed by frequency and Pearson's chi(2) test using a significance level of p < 0.05. Logistic regression was used to investigate the significance of dichotomous dependent variables. RESULTS: A total of 39.7% (602 women) interviewees had H/T, among which 39.9% (240 women) had UI symptoms. The prevalence of UI among women aged 60 or over with or without H/T was significantly different (p = 0.006). Risk factors were age [odds ratio (OR) = 1.043, 95% confidence interval (CI) 1.016-1.071, per year], diabetes mellitus (DM) (OR = 1.653, 95% CI 1.105-2.474), previous urinary diseases (OR = 3.462, 95% CI 2.260-5.301), and body mass index (BMI; OR = 1.060, 95% CI 1.012-1.110, per unit). There was no significant association between UI and drug allergy, smoking, hysterectomy, hormone therapy, or gynecological surgery. CONCLUSION: UI can be a frequent and annoying problem for aged women. In women with H/T, UI is significantly related to risk factors such as age, DM, BMI, and urinary diseases. In addition, BMI is considered a key risk factor for H/T. Therefore, effective control of BMI would help in controlling H/T and UI in aged women. PMID- 25017264 TI - Osteogenic differentiation of placenta-derived multipotent cells in vitro. AB - OBJECTIVE: Stem cells offer great potential for clinical therapeutic use because of their ability to rejuvenate and to differentiate into numerous types of cells. We isolated multipotent cells from the human term placenta that were capable of differentiation into cells of all three germ layers. MATERIALS AND METHODS: We examined the ability of these placenta-derived multipotent cells (PDMCs) to differentiate into osteoblasts (OBs) or OB-like cells. The PDMCs were treated with osteogenic medium (OM) consisting of dexamethasone, beta-glycerol phosphate, and ascorbic acid. At sequential time intervals (0 day, 3 days, 6 days, 9 days, and 12 days) we measured several parameters. These included alkaline phosphatase (ALP) activity, alizarin red staining (ARS) to measure calcium deposition, messenger RNA (mRNA) expressions of osteogenesis-related transcription factor (Cbfa1), and calcium coordination protein (osteocalcin). These variables were used as indicators of PDMC osteodifferentiation. RESULTS: We showed that ALP activity in the early stage of differentiation and calcium deposition were both significantly increased in PDMCs after OM induction. Moreover, the Cbfa1 and osteocalcin gene expressions were upregulated. The results suggested that OM induced an osteodifferentiation potential in PDMCs. CONCLUSION: PDMC-derived osteocytes provide a useful model to evaluate the mechanisms of key biomolecules and bioengineering processes. PMID- 25017265 TI - Umbilical artery Doppler velocimetry in normal pregnancies from 11(+0) to 13(+6) gestational weeks: a Taiwanese study. AB - OBJECTIVE: The aim of this study is to investigate the relationship between umbilical artery flow and gestational age (GA) at 11-13(+6) weeks in normal pregnancy in the Taiwanese population. MATERIALS AND METHODS: Two hundred and fifty-three normal singleton pregnancies with GA ranging from 11 to 13(+6) weeks were included in this study. The velocity of systolic, diastolic, and pulsatility index (PI) of the umbilical artery, and the mean velocity of the umbilical vein were recorded. RESULTS: One hundred and eighty-seven participants fulfilling the inclusion and exclusion criteria were analyzed. The mean maternal age was 31 (range 19-45) years, with a corresponding GA of 12(+4) (range 11-13(+6)) weeks. The absence of end-diastolic velocity of the umbilical artery was observed in most of our cases (90.1%). No significant change was found in the vascular indices with GA for the mean velocity of the umbilical vein (mean velocity = 0.923 * GA - 1.594, r = 0.1497, p = 0.115). The systolic velocity of the umbilical artery and PI, however, behaved differently from the other variables. There was a significant increase in systolic velocity with GA [systolic wave (S wave) velocity = 0.237 * GA + 2.267; r = 0.149, p = 0.041]. By contrast, the PI showed a significant decrease in relation to the GA (PI = -0.016 * GA + 4.068; r = 0.196, p = 0.007). CONCLUSION: The S-wave velocity of the umbilical artery increased with GA. By contrast, the PI of the umbilical artery showed a decreasing trend with GA. This may ensure optimal placental perfusion, which is necessary to accommodate the increased blood flow to the developing fetus. Furthermore, an absence of end-diastolic velocity in the first trimester and early second trimester was usually seen. PMID- 25017266 TI - Prenatal sonographic diagnosis of single umbilical artery: Emphasis on the absent side and its relation to associated anomalies. AB - OBJECTIVE: To determine the absent side of a single umbilical artery (SUA) and to evaluate whether associated anomalies are related to the side of the missing artery in a Taiwanese population. MATERIALS AND METHODS: We retrospectively studied SUA fetuses from our computer database of fetal ultrasound in a tertiary medical center in Southern Taiwan. All cases were diagnosed as SUA prenatally using conventional scanners of two- and three-dimensional (2D and 3D, respectively) ultrasound, as well as color, power, and high-definition Doppler. The absent side of UA and associated anomalies were analyzed. RESULTS: From September 2006 to November 2011, 31 fetuses with SUA were diagnosed prenatally by ultrasound and all were enrolled for this series. The incidence was estimated to be 1:556 (0.18% = 31/17,086). The mean maternal age was 29.2 years (range, 15-36 years) and the mean fetal age was 30.0 weeks of gestation (range 18-36 weeks). Notably, the left-absent UA was detected in 16/31 (52%) fetuses, compared with the right-absent UA in 15/31 (48%) cases. In addition, congenital anomalies were noted prenatally in 2/16 (13%) fetuses with left-absent UA and in 3/15 (20%) fetuses with right-absent UA. CONCLUSION: In SUA fetuses, the absence of UA appears to occur equally at each side. Moreover, this study showed no significant difference between either side of missing UA and associated anomalies after statistical examination. PMID- 25017267 TI - Chromosome abnormalities in embryos derived from microsurgical epididymal sperm aspiration and testicular sperm extraction. AB - OBJECTIVE: To evaluate the patterns of chromosome abnormalities in embryos derived from intracytoplasmic sperm injection (ICSI) in microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction (TESE) in comparison to embryos that are derived from naturally ejaculated (EJAC) patients. MATERIALS AND METHODS: Male partners with azoospermia who required MESA or TESE for ICSI were studied for chromosomal abnormalities. The ICSI patients with EJAC sperm served as the control group. Preimplantation genetic diagnosis (PGD) was performed by fluorescence in situ hybridization (FISH). Chromosome abnormalities were categorized as polyploidy, haploidy, aneuploidy, and complex abnormality (which involves more than two chromosomes). Fertilization, embryo development, and patterns of chromosome abnormalities were accessed and evaluated. RESULTS: There was no difference between the MESA, TESE, and EJAC patient groups in the rates of fertilization and pregnancy and the percentages of euploid embryos. In all three groups, less than one-half of the embryos for each group were normal (41 +/- 31%, 48 +/- 38%, and 48 +/- 31% in MESA, TESA, and EJAC, respectively). Complex chromosomal abnormality was significantly more frequent in the MESA group than in the EJAC group (48.3% vs. 26.5%, respectively; p < 0.001). Furthermore, the overall pattern of chromosomal aneuploidy was similar among all three studied groups. CONCLUSION: We suggest that MESA and TESE, followed by ICSI and PGD, appear to be acceptable approaches for treating men with severe spermatogenesis impairment. PMID- 25017268 TI - Improving compliance to osteoporosis workup and treatment in postmenopausal patients after a distal radius fracture. AB - OBJECTIVE: Distal radius fracture (DRF) in postmenopausal women is often the first clinical sign of osteoporosis (OP). Despite the availability of effective treatments, only a minority of patients who sustain a fragility fracture are tested for OP. The purpose of this study was to examine whether a simple intervention by the hospital staff increases rates of OP workup. MATERIALS AND METHODS: We conducted a prospective randomized clinical trial. Ninety nine patients after DRF were randomized to two groups. Both groups were contacted after their fracture and were asked to answer a questionnaire and were informed about the possible relationship between DRF and OP. In the intervention group, patients were sent an explanatory pamphlet and a letter to their primary care physician. An additional survey was conducted to establish whether the intervention improved the number of patients who undergo OP workup. RESULTS: The intervention increased the proportion of patients who turned to their primary care physician from 22.9% to 68.6%, and increased the proportion of patients undergoing OP workup from 14.3% to 40% (p < 0.001). CONCLUSION: Women with DRF who receive an explanation about possible OP implications and are sent explanatory materials are more likely to undergo OP workup. PMID- 25017269 TI - Comparison of the effect of penicillins versus erythromycin in preventing neonatal group B streptococcus infection in active carriers following preterm prelabor rupture of membranes. AB - OBJECTIVE: To compare the incidence of neonatal group B streptococcus (GBS) infection in active GBS carriers with preterm prelabor rupture of membranes (PPROMs) after penicillins and erythromycin prophylaxis. MATERIALS AND METHODS: Patients diagnosed to have PPROM between 2004 and 2009 inclusive were treated using erythromycin (erythromycin group), ampicillin, amoxicillin or co-amoxiclav (penicillin group), or no antibiotics (control group) according to department protocols depending on their gestation and their GBS status at the time of presentation. Patients receiving both erythromycin and penicillins were included in the penicillin group. The incidence of neonatal GBS infection was compared between groups categorized according to the antibiotic regime received. RESULTS: A total of 680 women were diagnosed to have PPROM of which 85 (12.5%) were active GBS carriers. GBS isolates were 100% sensitive to penicillins but only 35% were sensitive to erythromycin. There were 16, 22, and 47 patients in the penicillin, erythromycin, and control groups, respectively. The incidence of neonatal GBS infection in the three groups was 0%, 36%, and 13%, respectively, and was statistically significant (p = 0.023). CONCLUSION: Penicillins are more effective than erythromycin in preventing neonatal GBS infection in women with PPROM who were active GBS carriers. Because most women do not know their GBS status at the time of PPROM and it is practically difficult to identify the active carriers before delivery, ampicillin/amoxicillin should be used as a prophylactic antibiotic for active GBS carriers and women with unknown GBS carriage status to prevent neonatal GBS infection following PPROM. PMID- 25017270 TI - An association study of interleukin-4 gene and preeclampsia in Taiwan. AB - OBJECTIVE: To test whether the interleukin-4 (IL-4) gene polymorphisms could be used as markers of susceptibility for preeclampsia in Taiwan. MATERIALS AND METHODS: This study included 78 women with preeclampsia and 125 normal controls. A polymerase chain reaction was used to analyze the variable number of tandem repeats polymorphism for the IL-4 gene intron 3. Restriction fragment length polymorphism analysis using endonuclease BsmFI was performed for the IL-4 gene at the promoter -590 position. The association between the genotype and disease was examined using Chi-square tests. RESULTS: We found no significant differences in the genotype distributions and allele frequencies for the IL-4 gene at both promoter and intron 3 regions between the preeclampsia and control groups. CONCLUSION: Even though this is the first study investigating the association between the promoter region and intron 3 polymorphisms of IL-4 and preeclampsia worldwide, our data do not support a role of the IL-4 gene in the pathogenesis of preeclampsia in Taiwanese women. PMID- 25017271 TI - Suitable timing of surgical intervention for ruptured ovarian endometrioma. AB - OBJECTIVE: Patients with a rare rupture of endometriomas may require surgery. In this retrospective study, we assessed the outcomes of surgical interventions for ruptured ovarian endometriomas. MATERIALS AND METHODS: Forty-three patients who underwent surgical intervention for ruptured ovarian endometriomas were studied. Depending on the latency to surgery and endometrioma recurrence, patients were divided into two groups, and then compared with respect to patient profiles, intraoperative findings, and outcomes. RESULTS: Thirty-one of the 43 patients had a known ovarian endometrioma with an average diameter of 6.04 cm. Seventeen (39.5%) patients had a recurrent ovarian tumor during the postoperative follow up. Patients who underwent surgery within 72 hours or after 72 hours showed no difference in baseline characteristics and most clinical outcomes, except for the choice of surgery (p = 0.003) and future fertility (p = 0.005). CONCLUSION: Comprehensive and early surgical intervention after endometrioma rupture can assist in excluding ovarian malignancy and can reduce the effects of cyst fluids, prevent adhesions, and preserve fertility. PMID- 25017272 TI - Stages of endometriosis: does it affect in vitro fertilization outcome. AB - OBJECTIVE: Women with endometriosis often need in vitro fertilization (IVF) to conceive. There are conflicting data on the results of IVF in patients with endometriosis. The present study was undertaken to investigate whether or not the stage of endometriosis affects the IVF outcome in order to give the best patient counseling MATERIALS AND METHODS: We compared IVF outcome measures between 40 patients with surgically confirmed minimal and mild endometriosis (American Society for Reproductive Medicine Stage I/II) and 38 patients with moderate and severe endometriosis (Stage III/IV). Each group was also compared with a control group of 157 patients with tubal factor infertility. Outcome measures included number of follicles, number of oocytes, mean number of ampoules of gonadotropins, cumulative pregnancy, and live birth rates RESULTS: Higher cancelation rates, higher total gonadotropin requirements, and lower oocyte yield were found in women with endometriosis Stage III and IV compared with both the Stage I/II and control groups. The fertilization rate was higher in Stage III/IV endometriosis compared to Stage I/II. Clinical pregnancy and live birth rates were comparable between patients with endometriosis Stage I/II and control group, whereas they were significantly lower in patients with endometriosis Stage III/IV compared to other two groups. CONCLUSION: The American Society for Reproductive Medicine classification of endometriosis is useful in predicting IVF outcome. Advanced endometriosis means a worse prognosis for IVF treatment compared to milder stages or tubal factor infertility. The decreased fertilization rate in Stage I/II endometriosis might be a cause of subfertility in these women, as a result of a hostile environment caused by the disease. PMID- 25017273 TI - Adaptation of image cytometry methodology for DNA ploidy analysis of cervical epithelium samples: a pilot study. AB - OBJECTIVE: To determine DNA ploidy in the cervical specimens of patients revealing a suspicion of cancer by image analysis performed by using a combination of commercial analysis software, conventional microscopy, and certified filters. MATERIALS AND METHODS: This study followed a prospective design. Cervical samples were obtained from 20 patients undergoing routine screening in the Gynecologic-Oncology Unit of the University Hospital of the Federal University of Minas Gerais, Brazil. Three slides were prepared for each case and the DNA content was determined by image cytometry, post Feulgen staining. DNA ploidy, as well as events exceeding 5C and 9C, was assessed according to the guidelines and algorithms prescribed for diagnostic interpretation by the European Society for Analytical Cellular Pathology. RESULTS: By employing the adapted tool, identification of the lesions with euploid and aneuploid profiles was possible. Abnormal DNA content was found in 65% of the cases (13/20), with 45% (9/20) presenting nuclei with >5C content and 20% (4/20) with >9C content. In the analyses conducted in this study, the coefficient of variation with respect to DNA quantity was lower than the 5% threshold recommended by the European Society for Analytical Cellular Pathology. CONCLUSION: Image cytometry of the cervical specimens revealed DNA aneuploidy, most probably resulting from chromosomal alterations and appearing as precancerous lesions in 65% of the cases. The adaptations implemented in this study, enabled the DNA-image cytometry to become more accessible, enhancing its extended use as an adjuvant strategy for the early screening of the cervical epithelium samples during routine analyses. PMID- 25017274 TI - Potential role of circulating microRNAs as early markers of preeclampsia. AB - OBJECTIVE: To identify microRNAs (miRNAs) differentially expressed at early stages of gestation (12-14 weeks) in the serum of pregnant women, who later developed severe preeclampsia (sPE) in the third trimester of pregnancy (n = 24) compared to women with normal pregnancy (n = 24). MATERIALS AND METHODS: Sera from 12-14-week-gestation whole blood were subjected to microarray analysis with TaqMan Low Density Array chips (human microRNA panel V3.0), and to quantitative real-time polymerase chain reaction. RESULTS: By using the TaqMan Low Density Array chip technology, 19 mature miRNAs appeared differentially expressed in the group of women who later developed sPE as compared to normal women. The expression of four miRNAs (miR-1233, miR-520, miR-210, miR-144) was validated by quantitative real-time polymerase chain reaction analysis. MiR-1233 was the most overexpressed in the serum of women who later developed sPE. CONCLUSION: Circulating miRNAs deserve further investigation in order to explore their potential role in the pathogenesis of preeclampsia. In particular, miR-1233 might represent a potential marker of early sPE. PMID- 25017275 TI - Diagnostic challenges in cornual epithelioid trophoblastic tumor. AB - OBJECTIVE: We present a case of primary cornual epithelioid trophoblastic tumor (ETT) because of its rarity and diagnostic and therapeutic challenge. CASE REPORT: A 28-year-old woman, gravida 1, para 1, who missed menstruation for 3 months, had an elevated beta-human chorionic gonadotropin serum level of 2764 mIU/mL, an absence of intrauterine pregnancy, and the presence of an adnexal mass detected by transvaginal ultrasound. As an ectopic pregnancy was suspected, laparoscopic surgery was performed and showed a right corneal mass. Complete excision of the tumor was done through exploratory laparotomy. Frozen pathology favored the diagnosis of squamous cell carcinoma. Since there was no apparent tumor at other sites, no additional surgery was done. The final pathology showed ETT. Primary ETT is often misdiagnosed as an ectopic pregnancy, leading to delayed treatment, and poses a diagnostic challenge in distinguishing it from squamous cell carcinoma during pathological examination. CONCLUSION: Careful evaluation and avoidance of overtreatment are emphasized. PMID- 25017276 TI - Rare case of a paratubal cystadenoma with bilateral hydrosalpinges in an infertile woman. AB - OBJECTIVE: Serous tumors can occur on the surface of the ovaries and-rarely-as primary tumors on the peritoneal surface. However, the origin of extraovarian serous tumors is unknown. An unusual case of a serous tumor is presented here. CASE REPORT: A 34-year-old nulligravid woman presented for evaluation of her primary infertility, with acute abdominal pain. At laparoscopy, a paratubal cyst, independent of the ovaries, was found to be associated with bilateral hydrosalpinges. The final pathology diagnosis was of a benign paratubal serous cystadenoma. CONCLUSION: We present an unusual case of a paratubal serous cystadenoma with bilateral hydrosalpinges in an infertile woman, which was resected laparoscopically.. PMID- 25017277 TI - Prenatal ultrasonography and postnatal follow-up of a case of McKusick-Kaufman syndrome. AB - OBJECTIVE: McKusick-Kaufman syndrome (MKS) is a rare autosomal recessive syndrome characterized by hydrometrocolpos (HMC) and postaxial polydactyly (PAP). It is very difficult to diagnose MKS prenatally because of overlapping manifestations and associated anomalies with other syndromes. Herein, we present a case of MKS with prenatal ultrasound illustrating a fetal abdominal cystic mass. CASE REPORT: A 33-year-old woman, gravida 3 para 2, was referred to our obstetrics clinic at 34 weeks' gestation for fetal abdominal cyst detected by prenatal ultrasound. Our ultrasound illustrated a fetal abdominal cystic mass with two communicating components (suspected HMC) and polydactyly involving both hands and feet. At birth, the gross appearance revealed abdominal distention, vulva edema, and PAP. MKS was highly suspected. Abdominal computed tomography (CT) at 3 days of life showed HMC with a transverse vaginal septum. At 3 months of age, she received colpotomy and vaginal reconstruction to relieve the abdominal distension by HMC. Then she accepted corrections of PAP of both hands and feet at 8 months and 10 months. At 5 years of age, her body and mental development did not show any retardation. Pediatric ophthalmologic examination revealed no specific findings. Given the above evidences, the diagnosis of MKS was finally made at 5 years of age. CONCLUSION: Rare syndromes like MKS may need early comprehensive evaluations and consultations. Although prenatal diagnosis might be impossible for MKS, prenatal awareness by fetal ultrasound is very helpful to assist early management and maternal transfer. The final diagnosis and appropriate management of MKS requires the collaboration of obstetricians, geneticists, pediatricians, and ophthalmologists as soon as abnormal signs are detected in utero. PMID- 25017278 TI - Spontaneous pneumothorax after intensive chemotherapy in endometrial cancer: a rare complication. AB - OBJECTIVE: Endometrial cancer with hematogenous metastases can be treated with chemotherapy. We present a case of spontaneous pneumothorax that occurred when a solitary pulmonary endometrial metastatic lesion was treated with paclitaxel plus carboplatin. CASE REPORT: A 38-year-old female had stage II endometrial endometrioid adenocarcinoma. Solitary bilateral pulmonary metastases developed after primary treatment. Complete remission accompanied by a right spontaneous pneumothorax occurred during chemotherapy with paclitaxel plus carboplatin. CONCLUSION: Rapid shrinkage of a pulmonary space-occupying tumor sometimes causes rare but life-threatening spontaneous pneumothoraces. We report the first case of a spontaneous pneumothorax after using paclitaxel plus carboplatin in the treatment of endometrial cancer. PMID- 25017279 TI - Prenatal diagnosis and molecular cytogenetic characterization of chromosome 22q11.2 deletion syndrome associated with congenital heart defects. AB - OBJECTIVE: To report prenatal diagnosis of 22q11.2 deletion syndrome in a pregnancy with congenital heart defects in the fetus. CASE REPORT: A 26-year-old, primigravid woman was referred for counseling at 24 weeks of gestation because of abnormal ultrasound findings of fetal congenital heart defects. The Level II ultrasound revealed a singleton fetus with heart defects including overriding aorta, small pulmonary artery, and ventricular septal defect. Cordocentesis was performed. The DNA extracted from the cord blood was analyzed by multiplex ligation-dependent amplification (MLPA). The MLPA showed deletion in the DiGeorge syndrome (DGS) critical region of chromosome 22 low copy number repeat (LCR) 22 A~C. Conventional cytogenetic analysis revealed a normal male karyotype. Repeated amniocentesis and cordocentesis were performed. Whole-genome array comparative genomic hybridization (aCGH) on cord blood was performed. aCGH detected a 3.07-Mb deletion at 22q11.21. Conventional cytogenetic analysis of cultured amniocytes revealed a karyotype 46,XY. Metaphase fluorescence in situ hybridization (FISH) analysis on cultured amniocytes confirmed an interstitial 22q11.2 deletion. CONCLUSION: Prenatal ultrasound findings of congenital heart defects indicate that the fetuses are at increased risk for chromosome abnormalities. Studies for 22q11.2 deletion syndrome should be considered adjunct to conventional karyotyping. Although FISH has become a standard procedure for diagnosis of 22q11.2 deletion syndrome, MLPA can potentially diagnose a broader spectrum of abnormalities, and aCGH analysis has the advantage of refining the 22q11.2 deletion breakpoints and detecting uncharacterized chromosome rearrangements or genomic imbalances. PMID- 25017280 TI - Acute pancreatitis secondary to primary hyperparathyroidism in a postpartum patient: a case report and literature review. AB - OBJECTIVE: Primary hyperparathyroidism (PHPT) is a rare clinical entity in reproductive women. Unusual hypercalcemia causing pancreatitis in the peripartum period carries significant morbidity to both the fetus and the mother. CASE REPORT: A 38-year-old woman developed a morbid course of intractable intra abdominal abscess by pancreatitis, hydronephrosis by renal lithiasis, and unusual neurological presentations soon after delivery. Serial serum calcium level and imaging studies lead to the final diagnosis of PHPT due to a parathyroid adenoma. Data on 14 patients who suffered from pancreatitis due to hyperparathyroidism were collected from a MEDLINE search. The reasons for delayed diagnosis and literature review of acute pancreatitis in PHPT are discussed. CONCLUSION: Hypercalcemia can be masked during pregnancy and in severe pancreatitis, as was detected in about half of the case series. Clinicians should have a high level of suspicion of parathyroid adenoma in cases with a profound pancreatitis. Timely diagnosis and early therapeutic intervention are important to resolve complications and improve the outcomes of mothers and fetuses. PMID- 25017281 TI - Solitary primary peritoneal carcinoma arising from the omentum. AB - OBJECTIVE: To report a case of isolated omental peritoneal carcinoma without peritoneal carcinomatosis. CASE REPORT: A 60-year-old female with abdominal distention was found to have a pelvic mass. Under the impression of ovarian cancer, laparotomy was performed only to show one isolated mass over omentum. Serial examination and pathology study including immunochemical staining indicated primary peritoneal serous carcinoma. CONCLUSION: Isolated omental peritoneal carcinoma without peritoneal carcinomatosis and ascites is rare, and whether this represented a unique entity with different chemotherapy response and treatment outcome from the disseminated form of primary peritoneal carcinoma needs to be reviewed in the future. PMID- 25017282 TI - Ovarian steroid cell tumor, not otherwise specified, with virilization symptoms. PMID- 25017283 TI - The coexistence of interstitial cystitis and overactive bladder in a patient with lower urinary tract symptoms. PMID- 25017285 TI - Large-cell neuro-endocrine carcinoma associated with borderline mucinous tumor of the ovary. PMID- 25017284 TI - Rapid presentation of endometrial carcinoma after removal of an intrauterine device. PMID- 25017286 TI - Pulmonary embolism after cesarean section and successful treatment with early application of extracorporeal membrane oxygenation system and anticoagulant agents. PMID- 25017287 TI - Delayed postpartum hemorrhage secondary to idiopathic rupture of right uterine artery: a case report and literature review. PMID- 25017288 TI - Interstitial ectopic pregnancy complicated by uterine arteriovenous malformations treated with unilateral transarterial embolization. PMID- 25017289 TI - Is it possible to use cell-free fetal DNA to perform prenatal tests for multiple pregnancies? PMID- 25017290 TI - The NOVEL project update. PMID- 25017293 TI - Periodontal management in orthognathic surgery: early screening of periodontal risk and its current management for the optimization of orthodontic and surgical treatments. AB - Orthodontic preparation for orthognathic surgery requires correcting mal occlusions and coordination of arcades. In addition to improving the aesthetics, these treatments can ensure the achievement and sustainability of prosthetics and/or implants. Nevertheless, periodontal structures are easily damaged. Orthodontic displacement can only be applied in the absence of inflammation or weakened periodontal structure. An early detection of periodontal risk should be achievable by prescribers of a surgical-orthodontic treatment. Simplified periodontal examination, with easily detectable warning signs, will help to identify the periodontal risk. Although periodontal treatment follows current "non invasive" trend, some procedures remain necessary to prevent and/or remedy periodontal defects or diseases, such as mineral periodontal reinforcement corticotomy. It is essential that the patient meets all the practitioners to plan and assess the extent of the constraints necessary to optimize results, before starting orthodontic treatment combined with orthognathic surgery. Any periodontal complication (even minor) will be considered as a failure, regardless of good aesthetic and functional results. PMID- 25017291 TI - Secondhand smoke exposure, parental depressive symptoms and preschool behavioral outcomes. AB - Little is known about the association of secondhand smoke (SHS) exposure and behavioral conditions among preschoolers. A cross-sectional analysis was used to examine billing and pharmacy claims from November 2004 to June 2012 linked to medical encounter-level data for 2,441 children from four pediatric community health clinics. Exposure to SHS was associated with attention deficit hyperactivity disorder/ADHD and disruptive behavior disorder/DBD after adjusting for potential confounding factors. Assessment of exposure to SHS and parental depressive symptoms in early childhood may increase providers' ability to identify children at higher risk of behavioral issues and provide intervention at the earliest stages. PMID- 25017294 TI - Complete genomes of freshwater sulfur oxidizers Sulfuricella denitrificans skB26 and Sulfuritalea hydrogenivorans sk43H: genetic insights into the sulfur oxidation pathway of betaproteobacteria. AB - Despite detailed studies of marine sulfur-oxidizing bacteria, our knowledge concerning their counterparts in freshwater lake ecosystems is limited. Genome sequencing of the freshwater sulfur-oxidizing betaproteobacteria Sulfuricella denitrificans skB26 and Sulfuritalea hydrogenivorans sk43H have been completed. Strain skB26 possessed a circular plasmid of 86.6-kbp in addition to its chromosome, and an approximate 18-kbp region of the plasmid was occupied by an arxA-like operon, encoding a new clade of anaerobic arsenite oxidase. Multilocus sequence analysis showed that strain skB26 could not be assigned to any existing order; thus a novel order, Sulfuricellales, is proposed. The genomes of strains skB26 and sk43H were examined, focusing on the composition and the phylogeny of genes involved in the oxidation of inorganic sulfur compounds. Strains skB26 and sk43H shared a common pathway, which consisted of Sqr, SoxEF, SoxXYZAB, Dsr proteins, AprBA, Sat, and SoeABC. Comparative genomics of betaproteobacterial sulfur oxidizers showed that this pathway was also shared by the freshwater sulfur oxidizers Thiobacillus denitrificans and Sideroxydans lithotrophicus. It also revealed the presence of a conserved gene cluster, which was located immediately upstream of the betaproteobacterial dsr operon. PMID- 25017295 TI - Changes of proteolysis and angiotensin-I converting enzyme-inhibitory activity in white-brined cheese as affected by adjunct culture and ripening temperature. AB - The effects of use of adjunct cultures (Lactobacillus helveticus and Lb. casei) and ripening temperatures (6 or 12 degrees C) on proteolysis and angiotensin-I converting enzyme (ACE)-inhibitory activity in white-brined cheeses were investigated during 120 d ripening. Proteolysis was monitored by urea polyacrylamide gel electrophoresis (urea-PAGE) and reversed phase-HPLC (RP-HPLC) of water-insoluble and -soluble fractions of the cheeses, respectively. Urea-PAGE patterns of the samples revealed that the intensities of the bands representing casein fractions decreased in the experimental cheeses, being more pronounced in the cheeses made with adjunct cultures. Similarly, peptide profiles and the concentrations of individual and total free amino acids were influenced by both the adjunct cultures and ripening temperatures. The ACE-inhibitory activity of the water-soluble extracts of the cheeses were higher in the cheeses made using adjunct cultures (especially Lb. helveticus) and ripened at 12 degrees C. The ACE-inhibitory activity did not decrease during ripening. The contribution of Lb. helveticus to the development of proteolysis and ACE-inhibitory peptide activities were higher than that of Lb. casei. To conclude, the use of Lb. helveticus as adjunct culture in white-brined cheese and ripening at 12 degrees C would be recommended to obtain white-brined cheese with high ACE-I-inhibitory peptides activity and higher levels of preoteolysis. PMID- 25017296 TI - Quantitative assessment based on kinematic measures of functional impairments during upper extremity movements: A review. AB - BACKGROUND: Quantitative measures of human movement quality are important for discriminating healthy and pathological conditions and for expressing the outcomes and clinically important changes in subjects' functional state. However the most frequently used instruments for the upper extremity functional assessment are clinical scales, that previously have been standardized and validated, but have a high subjective component depending on the observer who scores the test. But they are not enough to assess motor strategies used during movements, and their use in combination with other more objective measures is necessary. The objective of the present review is to provide an overview on objective metrics found in literature with the aim of quantifying the upper extremity performance during functional tasks, regardless of the equipment or system used for registering kinematic data. METHODS: A search in Medline, Google Scholar and IEEE Xplore databases was performed following a combination of a series of keywords. The full scientific papers that fulfilled the inclusion criteria were included in the review. FINDINGS: A set of kinematic metrics was found in literature in relation to joint displacements, analysis of hand trajectories and velocity profiles. These metrics were classified into different categories according to the movement characteristic that was being measured. INTERPRETATION: These kinematic metrics provide the starting point for a proposed objective metrics for the functional assessment of the upper extremity in people with movement disorders as a consequence of neurological injuries. Potential areas of future and further research are presented in the Discussion section. PMID- 25017297 TI - Initiator-chain transfer agent combo in the RAFT polymerization of styrene. AB - The combo agent with roles of initiator and chain transfer agent was demonstrated in RAFT polymerization of styrene. Polymers with defined structures at both alpha and omega ends were obtained, which was verified by the successful synthesis of seven-block segments of PS and PMA by sequential addition of monomers in one pot. PMID- 25017298 TI - Cumulative contextual risk, maternal responsivity, and social cognition at 18 months. AB - By 18 months children demonstrate a range of social-cognitive skills that can be considered important precursors to more advanced forms of social understanding such as theory of mind. Although individual differences in social cognition have been linked to neurocognitive maturation, sociocultural models of development suggest that environmental influences operate in the development of children's social-cognitive outcomes. In the current study of 501 children and their mothers, we tested and found support for a model in which distal environmental risk, assessed when children were newborns, was indirectly associated with children's social-cognitive competency at 18 months through mothers' responsivity at 18 months. Part of this effect also operated through children's concomitant language skills, suggesting both a language-mediated and a language-independent mechanism of social-cognitive development. These findings are discussed with respect to the Vygotskian themes of internalization and semiotic mediation. PMID- 25017299 TI - Nursing leadership competencies: low-fidelity simulation as a teaching strategy. AB - Nurses must demonstrate leadership and followership competencies within complex adaptive team environments to ensure patient and staff safety, effective use of resources, and an adaptive health care system. These competencies are demonstrated through the use of communication strategies that are embedded within a relational practice. Health care professionals, regardless of formal position, need to assert their opinions and perspectives using a communication style that demonstrates value of all team members in open discussions about quality patient care, appropriate access, and stewardship. Challenges to effective communication and relational practice are the individual and organizational patterns of behavior, and the subsequent impact that these behaviors have on others. Students articulate situational awareness when they conduct a critical analysis of individual, team, and organizational functioning, and then use this information and evidence gained from a critical literature review to develop recommendations to improve individual, team, and/or organizational performance. Leadership and followership simulation exercises, inclusive of public feedback and debriefing, are used as a pedagogical/andragogical strategy in a nursing baccalaureate senior leadership course to facilitate learning of team communication skills and improve situational awareness. We view this strategy as an alternative to traditional classroom learning activities which provide little opportunity for recursive learning. PMID- 25017300 TI - Analysis of thoracic aorta hemodynamics using 3D particle tracking velocimetry and computational fluid dynamics. AB - Parallel to the massive use of image-based computational hemodynamics to study the complex flow establishing in the human aorta, the need for suitable experimental techniques and ad hoc cases for the validation and benchmarking of numerical codes has grown more and more. Here we present a study where the 3D pulsatile flow in an anatomically realistic phantom of human ascending aorta is investigated both experimentally and computationally. The experimental study uses 3D particle tracking velocimetry (PTV) to characterize the flow field in vitro, while finite volume method is applied to numerically solve the governing equations of motion in the same domain, under the same conditions. Our findings show that there is an excellent agreement between computational and measured flow fields during the forward flow phase, while the agreement is poorer during the reverse flow phase. In conclusion, here we demonstrate that 3D PTV is very suitable for a detailed study of complex unsteady flows as in aorta and for validating computational models of aortic hemodynamics. In a future step, it will be possible to take advantage from the ability of 3D PTV to evaluate velocity fluctuations and, for this reason, to gain further knowledge on the process of transition to turbulence occurring in the thoracic aorta. PMID- 25017301 TI - Viscoelastic characterisation of pig liver in unconfined compression. AB - Understanding and modelling liver biomechanics represents a significant challenge due to the complex nature of this organ. Unfortunately, there is no consensus on liver viscoelastic properties, and results are strongly dependent on sample type and status, adopted testing method, and testing conditions. Standard force triggered tests (e.g. step response or dynamic mechanical tests) necessitate an initial contact between sample and testing apparatus, which may result in significant pre-stress to very soft and highly hydrated samples. In a previous study we proposed the epsilon dot method (epsilonM): a testing and analysis framework to address the drawbacks of standard mechanical tests. Focusing on ex vivo unconfined bulk compressive tests, here we use both the epsilonM and dynamic mechanical analysis (DMA) to derive liver viscoelastic parameters in the region of small strains or the linear viscoelastic region (LVR). As liver samples were visibly deteriorated at the end of frequency sweep tests, a modified approach was adopted to reduce DMA testing times. This approach, termed step-reconstructed DMA (SRDMA), is based on dynamic measurements around specific frequencies and then reconstruction of liver behaviour in the entire frequency range of interest. The instantaneous elastic modulus obtained from SRDMA tests (2.65 +/- 0.30 kPa) was significantly higher than that obtained with the epsilonM (2.04 +/- 0.01 kPa). We show that the overestimation of stiffness is due to data acquisition in a local rather than an absolute LVR, highlighting the importance of using a rapid and zero pre-stress approach to characterise very soft and highly hydrated biological tissues. PMID- 25017302 TI - Integrating biochemiluminescence detection on smartphones: mobile chemistry platform for point-of-need analysis. AB - In this paper, we report, for the first time, the use of a smartphone to image and quantify biochemiluminescence coupled biospecific enzymatic reactions to detect analytes in biological fluids. Using low-cost three-dimensional (3D) printing technology, we fabricated a smartphone accessory and a minicartridge for hosting biospecific reactions. As a proof-of-principle, we report two assays: a bioluminescence assay for total bile acids using 3alpha-hydroxyl steroid dehydrogenase coimmobilized with bacterial luciferase system and a chemiluminescence assay for total cholesterol using cholesterol esterase/cholesterol oxidase coupled with the luminol-H2O2-horseradish peroxidase system. These assays can be performed within 3 min in a very straightforward manner and provided adequate analytical performance for the analysis of total cholesterol in serum (limit of detection (LOD) = 20 mg/dL) and total bile acid in serum and oral fluid (LOD = 0.5 MUmol/L) with a reasonable accuracy and precision. Smartphone-based biochemiluminescence detection could be thus applied to a variety of clinical chemistry assays. PMID- 25017303 TI - Influence of the nucleus area distribution on the survival fraction after charged particles broad beam irradiation. AB - It is well known that broad beam irradiation with heavy ions leads to variation in the number of hit(s) received by each cell as the distribution of particles follows the Poisson statistics. Although the nucleus area will determine the number of hit(s) received for a given dose, variation amongst its irradiated cell population is generally not considered. In this work, we investigate the effect of the nucleus area's distribution on the survival fraction. More specifically, this work aims to explain the deviation, or tail, which might be observed in the survival fraction at high irradiation doses. For this purpose, the nucleus area distribution was added to the beam Poisson statistics and the Linear-Quadratic model in order to fit the experimental data. As shown in this study, nucleus size variation, and the associated Poisson statistics, can lead to an upward survival trend after broad beam irradiation. The influence of the distribution parameters (mean area and standard deviation) was studied using a normal distribution, along with the Linear-Quadratic model parameters (alpha and beta). Finally, the model proposed here was successfully tested to the survival fraction of LN18 cells irradiated with a 85 keV um(- 1) carbon ion broad beam for which the distribution in the area of the nucleus had been determined. PMID- 25017304 TI - Role of microglia in ethanol-induced neurodegenerative disease: Pathological and behavioral dysfunction at different developmental stages. AB - Alcohol abuse can result in significant alterations to the structure of the brain and ultimately to behavioral dysfunctions. Epidemiological studies have shown that alcoholism is closely associated with impaired memory and judgment. However, the degree of deficit (brain injury) depends on factors such as the age of onset, duration of heavy drinking, continuous versus periodic (binge) drinking and the typical amount consumed per session. In recent years, neuroinflammation has been proposed as one of the alcoholism-induced neuropathological mechanisms, since increased levels of microglial markers are observed in the brains of both post mortem human alcoholics and various alcohol-treated animals, from newborn or adolescent rodents to adult rodents. Many studies have investigated how microglia modulate alcohol-induced behavioral changes such as cognitive deficits, abnormal locomotor activity, motor impairment and mood disturbance. Importantly, we try to characterize and compare the distinct features in different ethanol (EtOH) induced neurodegenerative disease (NDD) models. Moreover, mounting evidence indicates that in response to certain environmental toxins, microglia can become over-activated under oxidative stress, releasing pro-inflammatory mediators that cause central nervous system (CNS) disease. The molecular mechanisms involve free radical formation and the release of pro-inflammatory cytokines that are detrimental to neighboring neurons and interfere with the molecules regulating cell-cell interactions. The identification and understanding of the cellular and molecular mechanisms of microglial activation are described, as well as multiple downstream targets, in different alcohol-treated animal models. This review might contribute to the development of treatments and/or therapeutic agents that can reduce or eliminate the deleterious effects of alcohol-induced NDD. PMID- 25017305 TI - Structure prediction of nanoclusters; a direct or a pre-screened search on the DFT energy landscape? AB - The atomic structure of inorganic nanoclusters obtained via a search for low lying minima on energy landscapes, or hypersurfaces, is reported for inorganic binary compounds: zinc oxide (ZnO)n, magnesium oxide (MgO)n, cadmium selenide (CdSe)n, and potassium fluoride (KF)n, where n = 1-12 formula units. The computational cost of each search is dominated by the effort to evaluate each sample point on the energy landscape and the number of required sample points. The effect of changing the balance between these two factors on the success of the search is investigated. The choice of sample points will also affect the number of required data points and therefore the efficiency of the search. Monte Carlo based global optimisation routines (evolutionary and stochastic quenching algorithms) within a new software package, viz. Knowledge Led Master Code (KLMC), are employed to search both directly and after pre-screening on the DFT energy landscape. Pre-screening includes structural relaxation to minimise a cheaper energy function - based on interatomic potentials - and is found to improve significantly the search efficiency, and typically reduces the number of DFT calculations required to locate the local minima by more than an order of magnitude. Although the choice of functional form is important, the approach is robust to small changes to the interatomic potential parameters. The computational cost of initial DFT calculations of each structure is reduced by employing Gaussian smearing to the electronic energy levels. Larger (KF)n nanoclusters are predicted to form cuboid cuts from the rock-salt phase, but also share many structural motifs with (MgO)n for smaller clusters. The transition from 2D rings to 3D (bubble, or fullerene-like) structures occur at a larger cluster size for (ZnO)n and (CdSe)n. Differences between the HOMO and LUMO energies, for all the compounds apart from KF, are in the visible region of the optical spectrum (2-3 eV); KF lies deep in the UV region at 5 eV and shows little variation. Extrapolating the electron affinities found for the clusters with respect to size results in the qualitatively correct work functions for the respective bulk materials. PMID- 25017306 TI - The complement system in human cardiometabolic disease. AB - The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis. In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD. The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to disentangle which aspects of the complement system and complement activation affect the different processes in human cardiometabolic disease. PMID- 25017307 TI - The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders. AB - Interleukin-33 (IL-33) is a recently discovered cytokine that belongs to the IL-1 superfamily and acts as an important regulator in several allergic disorders. It is considered to function as an alarmin, or danger cytokine, that is released upon structural cell damage. IL-33 activates several immune cells, including Th2 cells, mast cells and basophils, following its interaction with a cell surface heterodimer consisting of an IL-1 receptor-related protein ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP). This activation leads to the production of a variety of Th2-like cytokines that mediate allergic-type immune responses. Thus, IL-33 appears to be a double-edged sword because, in addition to its important contribution to host defence, it exacerbates allergic responses, such as allergic rhinitis and asthma. A major purported mechanism of IL-33 in allergy is the activation of mast cells to produce a variety of pro-inflammatory cytokines and chemokines. In this review, we summarize the current knowledge regarding the genetics and physiology of IL-33 and IL-1RL1 and its association with different allergic diseases by focusing on its effects on mast cells and basophils. PMID- 25017308 TI - "Blind spots" in forensic autopsy: improved detection of retrobulbar hemorrhage and orbital lesions by postmortem computed tomography (PMCT). AB - OBJECTIVES: The purpose of this study was to correlate the occurrence of retrobulbar hemorrhage (RBH) with mechanism of injury, external signs and autopsy findings to postmortem computed tomography (PMCT). METHODS: Six-teen subjects presented with RBH and underwent PMCT, external inspection and conventional autopsy. External inspection was evaluated for findings of the bulbs, black eye, raccoon eyes and Battle's sign. Fractures of the viscerocranium, orbital lesions and RBH were evaluated by PMCT. Autopsy and PMCT was evaluated for orbital roof and basilar skull fracture. RESULTS: The leading manner of death was accident with central regulatory failure in cases of RBH (31.25%). Imaging showed a high sensitivity in detection of orbital roof and basilar skull fractures (100%), but was less specific compared to autopsy. Volume of RBH (0.1-2.4ml) correlated positively to the presence of Battle's sign (p<0.06) and the postmortem interval. Ecchymosis on external inspection correlated with RBH. There was a statistical significant correlation between bulbar lesion and RBH. Orbital roof fracture count weakly correlated with the total PMCT derived RBH volume. Maxillary hemosinus correlated to maxillary fractures, but not to RBH. CONCLUSIONS: RBH are a specific finding in forensically relevant head trauma. PMCT is an excellent tool in detecting and quantifying morphological trauma findings particularly in the viscerocranium, one of the most relevant "blind spots" of classic autopsy. PMCT was superior in detecting osseous lesions, scrutinizing autopsy as the gold standard. PMID- 25017309 TI - The role of the Oregon State University Endophyte Service Laboratory in diagnosing clinical cases of endophyte toxicoses. AB - The Oregon State University Colleges of Veterinary Medicine and Agricultural Sciences instituted the Endophyte Service Laboratory to aid in diagnosing toxicity problems associated with cool-season grasses in livestock. The endophyte (Neotyphodium coenophalum) present in tall fescue (Festuca arundinacea) produces ergopeptine alkaloids, of which ergovaline is the molecule used to determine exposure and toxicity thresholds for the vasoconstrictive conditions "fescue foot" and "summer slump". Another vasoconstrictive syndrome, "ergotism," is caused by a parasitic fungus, Claviceps purpurea, and its primary toxin, ergotamine. "Ryegrass staggers" is a neurological condition that affects livestock consuming endophyte (Neotyphodium lolii)-infected perennial ryegrass (Lolium perenne) with high levels of lolitrem B. HPLC-fluorescent analytical methods for these mycotoxins are described and were used to determine threshold levels of toxicity for ergovaline and lolitrem B in cattle, sheep, horses, and camels. In addition, six clinical cases in cattle are presented to illustrate diagnosis of these three diseases. PMID- 25017310 TI - Direct determination of spin-orbit interaction coefficients and realization of the persistent spin helix symmetry. AB - The spin-orbit interaction plays a crucial role in diverse fields of condensed matter, including the investigation of Majorana fermions, topological insulators, quantum information and spintronics. In III-V zinc-blende semiconductor heterostructures, two types of spin-orbit interaction--Rashba and Dresselhaus- act on the electron spin as effective magnetic fields with different directions. They are characterized by coefficients alpha and beta, respectively. When alpha is equal to beta, the so-called persistent spin helix symmetry is realized. In this condition, invariance with respect to spin rotations is achieved even in the presence of the spin-orbit interaction, implying strongly enhanced spin lifetimes for spatially periodic spin modes. Existing methods to evaluate alpha/beta require fitting analyses that often include ambiguity in the parameters used. Here, we experimentally demonstrate a simple and fitting parameter-free technique to determine alpha/beta and to deduce the absolute values of alpha and beta. The method is based on the detection of the effective magnetic field direction and the strength induced by the two spin-orbit interactions. Moreover, we observe the persistent spin helix symmetry by gate tuning. PMID- 25017311 TI - Opisthorchis felineus liver fluke invasion is an environmental factor modifying genetic risk of atopic bronchial asthma. AB - According to epidemiological observations, Opisthorchis felineus liver fluke invasion is negatively associated with the development and severity of allergic diseases in endemic regions of Russia. We hypothesized that the invasion is an important factor in gene-environmental interactions (GEI) underlying allergy. To prove this, we tested 10 single nucleotide polymorphisms of immune response modifying genes in 428 individuals stratified by atopic bronchial asthma presence and O. felineus invasion. Using regression models, a statistically significant interaction between the rs6737848 polymorphism of SOCS5 gene and O. felineus invasion was observed (pint=0.001, OR=5.66, 95% CI 1.96-16.31 for dominant model; pint=0.003; OR=4.38, 95% CI 1.68-11.45 for additive model). The interaction is based on the statistically significant association between the SOCS5 gene and atopic bronchial asthma in patients without O. felineus infection, while no such association is seen in patients infected by the helminth. These data confirm for the first time the importance of the helminth invasion as an environmental factor influencing the association between genetic factors and atopic bronchial asthma. In particular, O. felineus diminishes the risk of atopic bronchial asthma associated with the SOCS5 gene polymorphism. PMID- 25017312 TI - Trypanosoma cruzi strains cause different myocarditis patterns in infected mice. AB - AIMS: Chagas disease pathology is dependent on the infecting Trypanosoma cruzi strain. However, the relationship between the extent and type of myocarditis caused by different T. cruzi strains in the acute and chronic phases of infection has not been studied in detail. To address this, we infected mice with three genetically distant T. cruzi strains as well as infected in vitro different cell types. METHODS AND RESULTS: Parasitemia was detected in mice infected with the Y and VFRA strains, but not with the Sc43 strain; however, only the Y strain was lethal. When infected with VFRA, mice showed higher inflammation and parasitism in the heart than with Sc43 strain. Y and VFRA caused homogeneous pancarditis with inflammatory infiltrates along the epicardium, whereas Sc43 caused inflammation preferentially in the auricles in association with intracellular parasite localization. We observed intramyocardic perivasculitis in mice infected with the VFRA and Y strains, but not with Sc43, during the acute phase, which suggests that endothelial cells may be involved in heart colonization by these more virulent strains. In in vitro infection assays, the Y strain had the highest parasite-cell ratio in epithelial, macrophage and endothelial cell lines, but Y and VFRA strains were higher than Sc43 in cardiomyocytes. CONCLUSIONS: This study supports parasite variability as a cause for the diverse cardiac outcomes observed in Chagas disease, and suggests that endothelial cells could be involved in heart infection during the acute phase. PMID- 25017313 TI - Incidence of and risk factors for traumatic anterior shoulder dislocation: an epidemiologic study in high-school rugby players. AB - BACKGROUND: The incidence of reinjuries due to glenohumeral instability and the major risk factors for primary anterior shoulder dislocation in youth rugby players have been unclear. PURPOSE: The purpose of this study was to investigate the incidence, mechanisms, and intrinsic risk factors of shoulder dislocation in elite high-school rugby union teams during the 2012 season. METHODS: A total of 378 male rugby players from 7 high-school teams were investigated by use of self administered preseason and postseason questionnaires. RESULTS: The prevalence of a history of shoulder dislocation was 14.8%, and there were 21 events of primary shoulder dislocation of the 74 overall shoulder injuries that were sustained during the season (3.2 events per 1000 player-hours of match exposure). During the season, 54.3% of the shoulders with at least one episode of shoulder dislocation had reinjury. This study also indicated that the persistence of glenohumeral instability might affect the player's self-assessed condition, regardless of the incidence during the current season. By a multivariate logistic regression method, a history of shoulder dislocation on the opposite side before the season was found to be a risk factor for contralateral primary shoulder dislocation (odds ratio, 3.56; 95% confidence interval, 1.27-9.97; P = .02). CONCLUSIONS: High-school rugby players with a history of shoulder dislocation are not playing at full capacity and also have a significant rate of reinjury as well as a high risk of dislocating the other shoulder. These findings may be helpful in deciding on the proper treatment of primary anterior shoulder dislocation in young rugby players. PMID- 25017314 TI - Ultrasound elastography-based assessment of the elasticity of the supraspinatus muscle and tendon during muscle contraction. AB - BACKGROUND: Although elasticity of the supraspinatus muscle and tendon is a useful parameter to represent the conditions of the supraspinatus muscle and tendon, assessment of the elasticity in clinical settings has not been established. The purpose of this study was to determine the elasticity of the supraspinatus muscle belly and tendon under different muscle contraction conditions using ultrasound real-time tissue elastography (RTE). METHODS: Twenty three healthy individuals participated in this study. Ultrasound RTE was used for elasticity measurements of the muscle belly and tendon of the supraspinatus muscle. The elasticity was defined as the ratio of strain in the tissues to that in an acoustic coupler (reference). A greater ratio indicated that the tissue was softer. Measurements were performed with study subjects in the lateral decubitus position at 10 degrees of shoulder abduction under conditions of (1) no contraction, (2) isometric contraction without a weight, and (3) isometric contraction with a 1-kg weight. RESULTS: The intraclass correlation coefficient (ICC1,3) of 3 measurements under each condition ranged from 0.931 to 0.998, showing high intraobserver reliability. Strain ratios for both the supraspinatus muscle belly and tendon significantly decreased with increases in muscle contraction (P < .001). CONCLUSIONS: Ultrasound RTE with the acoustic coupler has the potential to noninvasively detect changes in the elasticity of the supraspinatus muscle belly and tendon that accompany varying levels of muscle contraction in clinical practice. PMID- 25017315 TI - An efficient, Schiff-base derivative for selective fluorescence sensing of Zn2+ ions: quantum chemical calculation appended by real sample application and cell imaging study. AB - Since zinc ions (Zn(2+)) are involved in numerous biological phenomena and go through subsequent interactions with zinc-binding proteins, we have attempted a sensitive fluorescence based detection of this second most abundant metal ion using an engineered and synthesized Schiff-base ligand, namely 2,4-bis((Z)-2-(1 (pyridin-2-yl)ethylidene)hydrazinyl)pyrimidine (PyHP). The ligand exhibits a zinc induced fluorescence response when investigated in a MeOH-buffer (10 mM HEPES, pH = 7) (4 : 1) solvent mixture. The presence of zinc ions (lambda(ex) = 410 nm, quantum yield, phi = 0.20) causes approximately 45 fold fluorescence enhancement at 489 nm. Formation of the metal-ligand complex was ascertained by (1)H NMR and mass spectra analysis. 1 : 1 binding affinity was ascertained according to Job's plot. Apart from this, theoretical interpretation of the experimental outcome was also obtained by applying density functional theory (DFT) to the PyHP-Zn(2+) complex formation. The practical applicability of the ligand has been tested in bacterial cells as well as in mammalian cell imaging and also by measuring and comparing the amount of Zn(2+) in some real samples such as liquid milk, tomato juice, banana stem juice and commercial fruit juice. PMID- 25017316 TI - The natural trait of the curvature of human hair is correlated with bending of the hair follicle and hair bulb by a structural disparity in the root sheath. PMID- 25017317 TI - Consumer preference, behavior and perception about meat and meat products: an overview. AB - Meat and meat products currently represent an important source of protein in the human diet, and their quality varies according to intrinsic and extrinsic parameters that can sometimes be shaped to make a product more desirable. Because consumers are the final step in the production chain, it is useful to identify which factors affect their behavioral patterns. This would allow the meat sector to better satisfy consumer expectations, demands and needs. This paper focuses on features that might influence consumer behavior, preferences and their perception of meat and meat products with respect to psychological, sensory and marketing aspects. This multidisciplinary approach includes evaluating psychological issues such as attitudes, beliefs, and expectations; sensory properties such as appearance, texture, flavor and odor; and marketing-related aspects such as price and brand. PMID- 25017318 TI - Brazilian beef produced on pastures: sustainable and healthy. AB - With a herd of 209 million cattle, Brazilian beef production estimate for 2023 is 10,935 million tons, representing an increase of 28.9% and accounting for 20% of the world trade. Beef cattle production is constantly evolving; however, there are extremes, ranging from simple existing farm ranges to intensive forage systems, strategic supplementation, updated health and genetic improvement programs for the production of quality beef. This modern production is based on scientific research carried out at universities and other research institutions. A new generation of professionals with multidisciplinary knowledge and a holistic vision of the productive chain-proposed management practices to reduce greenhouse gas emissions in the production of grass-fed beef cattle, whose meat has high omega-3 and CLA contents. Age at slaughter of steers and of heifers at first mating, significant increases in the ratio calves/100 cows, adequate traceability for pastoral systems with hundreds or thousands of animals per farm and a more intense transference of technology are required. PMID- 25017320 TI - Inflammation-induced haemostatic response in layer chickens infected with Streptococcus equi subsp. zooepidemicus as evaluated by fibrinogen, prothrombin time and thromboelastography. AB - Streptococcus zooepidemicus has recently been shown to be a severe pathogen in layer chickens, where it is able to cause serious lesions in the vascular system. To evaluate the haemostatic response, 10 layer chickens were inoculated intravenously with S. zooepidemicus. Four hypotheses were tested: that the infection-induced inflammation would increase the plasma fibrinogen (Fbg) concentration, would prolong the prothrombin time (PT) and would prompt hypercoagulability or hypocoagulability as assessed by whole-blood thromboelastography (TEG), and that a possible correlation would exist between one of the TEG values and Fbg/PT. Each parameter was measured at days 1, 3 and 6 post inoculation (p.i.), and compared with the values at day 0 from each individual bird and with values obtained from non-infected control chickens (n = 10). In the infected chickens, the mean (+/- standard error) of Fbg was higher at day 3 p.i. (9.4 +/- 1.4 g/l) and day 6 p.i. (8.0 +/- 0.7 g/l) and the PT was prolonged at day 6 p.i. (168.1 +/- 21.0 sec) compared with the day 0 standards (2.6 +/- 0.2 g/l and 104.6 +/- 2.0 sec, respectively) (P < 0.05). The majority of infected chickens demonstrated a hypercoagulable TEG result with increased mean values of the clot formation rate (alpha-angle) and maximal amplitude (MA) of TEG tracing at day 3 p.i. (83.1 +/- 0.7 degrees , 83.8 +/- 1.4 mm) and day 6 p.i. (84.0 +/- 0.4 degrees , 89.8 +/- 1.0 mm) compared with the day 0 values (75.8 +/- 2.2 degrees and 66.9 +/- 1.4 mm, respectively) (P < 0.05). In control birds, the means of Fbg (1.5 +/- 0.1 g/l), PT (79.4 +/- 6.4 sec), TEG-alpha (76.7 +/- 1.5 degrees ) and TEG-MA (64.0 +/- 2.3 mm) were lower at day 6 compared with values observed for the infected chickens (P < 0.05). A negative correlation coefficient (-0.71) was found between the clot formation time (TEG-K) and Fbg at day 1 in the control group (P = 0.02). In conclusion, infection with S. zooepidemicus following intravenous injection in layer chickens induced haemostatic alterations including hyperfibrinogenaemia, prolonged PT, and hypercoagulability as measured by increased TEG-alpha and TEG-MA. PMID- 25017319 TI - Eliminating Plasmodium falciparum in Hainan, China: a study on the use of behavioural change communication intervention to promote malaria prevention in mountain worker populations. AB - BACKGROUND: In the island of Hainan, the great majority of malaria cases occur in mountain worker populations. Using the behavioral change communication (BCC) strategy, an interventional study was conducted to promote mountain worker malaria prevention at a test site. This study found the methods and measures that are suitable for malaria prevention among mountain worker populations. METHODS: During the Plasmodium falciparum elimination stage in Hainan, a representative sampling method was used to establish testing and control sites in areas of Hainan that were both affected by malaria and had a relatively high density of mountain workers. Two different methods were used: a BCC strategy and a conventional strategy as a control. Before and after the intervention, house visits, core group discussions, and structural surveys were utilized to collect qualitative and quantitative data regarding mountain worker populations (including knowledge, attitudes, and practices [KAPs]; infection status; and serological data), and these data from the testing and control areas were compared to evaluate the effectiveness of BCC strategies in the prevention of malaria. RESULTS: In the BCC malaria prevention strategy testing areas, the accuracy rates of malaria-related KAP were significantly improved among mountain worker populations. The accuracy rates in the 3 aspects of malaria-related KAP increased from 37.73%, 37.00%, and 43.04% to 89.01%, 91.53%, and 92.25%, respectively. The changes in all 3 aspects of KAP were statistically significant (p < 0.01). In the control sites, the changes in the indices were not as marked as in the testing areas, and the change was not statistically significant (p > 0.05). Furthermore, in the testing areas, both the percentage testing positive in the serum malaria indirect fluorescent antibody test (IFAT) and the number of people inflicted decreased more significantly than in the control sites (p < 0.01). CONCLUSION: The use of the BCC strategy significantly improved the ability of mountain workers in Hainan to avoid malarial infection. Educational and promotional materials and measures were developed and selected in the process, and hands-on experience was gained that will help achieve the goal of total malaria elimination in Hainan. PMID- 25017321 TI - Berberine attenuates spontaneous action potentials in sinoatrial node cells and the currents of human HCN4 channels expressed in Xenopus laevis oocytes. AB - The present study investigated the electropharmacological effects of a traditional Chinese herbal drug, berberine, on the spontaneous activity of sinoatrial nodes (SANs) of the rabbit heart and on human hyperpolarization activated cyclic nucleotide-gated 4 (hHCN4) channels, which are heterologously expressed in xenopus oocytes, and which contribute to pacemaker currents (Ifs). A standard microelectrode technique and standard two-electrode voltage-clamp recordings were employed to examine the properties of transmembrane potentials and cloned hHCN4 subunit currents, respectively, under control conditions and berberine administration. Berberine decreased the rate of pacemaker firing and the rate of diastolic depolarization, and modified the action potential parameters. In addition, berberine suppressed the hHCN4 channel currents in a concentration- (1-300 uM) and use-dependent manner, and simultaneously decreased the activation and deactivation kinetics of the hHCN4 channels. The ability of berberine to modulate the If of cardiac pacemaker cells may contribute to its antiarrhythmic action. PMID- 25017323 TI - Synergistic skin heat shock protein expression in response to combined laser treatment with a diode laser and ablative fractional lasers. AB - BACKGROUND: Diode laser-based skin heating has been shown to minimise scars by interfering with wound healing responses through the induction of heat shock proteins (HSP). HSP are also induced after ablative fractional laser (AFXL) wound healing. AFXL itself is highly recommended for scar treatment. Therefore, the sequential combination of both modalities may produce superior outcomes. OBJECTIVES: The aim of this study was to examine the pretreatment effects of a diode laser before AFXL on wound healing responses in terms of HSP up-regulation in an in vitro model. MATERIALS AND METHODS: Immediate responses and responses on days 1, 3 or 6 post-procedure were studied in an in vitro porcine skin model (n = 240). Untreated samples served as control. Immunohistochemical investigation (Hsp70) was performed in all untreated controls, diode laser-, AFXL-, and in diode laser + AFXL-treated samples. RESULTS: Hsp70 was shown to be up-regulated by all interventions between days 1 and 6 after interventions. The largest effect was caused by the combination of a diode laser and an AFXL procedure. CONCLUSION: Diode laser exposure induces a skin HSP response that can be further enhanced by sequential AFXL treatment. Clinical studies are necessary to investigate the dose response of HSP on scar formation and refine suitable laser exposure settings. PMID- 25017324 TI - Sequential vapour ablation of adjacent segments in canine lung. AB - INTRODUCTION: Vapour ablation is used to create lung volume reduction for emphysema patients to improve lung function and quality of life. This study characterises effects of vapour ablation treatment in lung segments within a lobe that are adjacent to lung segments previously treated with vapour in a healthy canine model. Because emphysema is a progressive disease, subsequent treatments could offer continued benefit to the patient. METHOD: Six healthy canines were treated with vapour at 8.5 cal/g in one upper lobe segment. After a 4-week healing period, the adjacent segment was treated. After a second 4-week healing period, necropsy was performed and the tissue inspected. Clinical effects were monitored during each healing period. RESULTS: Each treatment was well tolerated and no significant abnormalities were observed during the healing phases, including death, pneumothorax, or major decline in health status. Animal health, oxygenation changes, pathology, and airway changes were monitored during the study. Analysis of these end points showed no difference in changes after treatment 2 as compared to changes after treatment 1. CONCLUSION: In this model, there was no evidence of increased or different clinical observations after a second adjacent vapour ablation. It was not possible to differentiate between the clinical effects of treatment 1 and the clinical effects of treatment 2. These results support investigation of sequential adjacent segmental vapour treatments in humans. PMID- 25017322 TI - Interstitial ultrasound ablation of vertebral and paraspinal tumours: parametric and patient-specific simulations. AB - PURPOSE: Theoretical parametric and patient-specific models are applied to assess the feasibility of interstitial ultrasound ablation of tumours in and near the spine and to identify potential treatment delivery strategies. METHODS: 3D patient-specific finite element models (n = 11) of interstitial ultrasound ablation of tumours associated with the spine were generated. Gaseous nerve insulation and various applicator configurations, frequencies (3 and 7 MHz), placement trajectories, and tumour locations were simulated. Parametric studies with multilayered models investigated the impacts of tumour attenuation, tumour dimension, and the thickness of bone insulating critical structures. Temperature and thermal dose were calculated to define ablation (>240 equivalent minutes at 43 degrees C (EM43 degrees C)) and safety margins (<45 degrees C and <6 EM43 degrees C), and to determine performance and required delivery parameters. RESULTS: Osteolytic tumours (<=44 mm) encapsulated by bone could be successfully ablated with 7 MHz interstitial ultrasound (8.1-16.6 W/cm(2), 120-5900 J, 0.4-15 min). Ablation of tumours (94.6-100% volumetric) 0-14.5 mm from the spinal canal was achieved within 3-15 min without damaging critical nerves. 3 MHz devices provided faster ablation (390 versus 930 s) of an 18 mm diameter osteoblastic (high bone content) volume than 7 MHz devices. Critical anatomy in proximity to the tumour could be protected by selection of appropriate applicator configurations, active sectors, and applied power schemas, and through gaseous insulation. Preferential ultrasound absorption at bone surfaces facilitated faster, more effective ablations in osteolytic tumours and provided isolation of ablative energies and temperatures. CONCLUSIONS: Parametric and patient-specific studies demonstrated the feasibility and potential advantages of interstitial ultrasound ablation treatment of paraspinal and osteolytic vertebral tumours. PMID- 25017325 TI - c-FLIPp43 induces activation of the nuclear factor-kappaB signaling pathway in a dose-dependent manner in the A375 melanoma cell line. AB - In order to investigate the role of c-FLIPp43 in the regulation of the nuclear factor (NF)-kappaB signaling pathway in melanoma cell lines, a eukaryotic expression vector for c-FLIPp43 was constructed with the pCMV-Tag2B plasmid. The monoclonal A375 cells with stable expression of c-FLIPp43 were obtained by G418 selection and were identified with western blot analysis. The protein level of NF kappaBp65 in the A375 cell line with stable expression of c-FLIPp43 was examined by western blot analysis. The translocation of NF-kappaBp65 was examined using immunofluorescence. The A375 cell lines were transfected with the pCMV-Tag2B cFLIPp43 vector at different doses and the activation of the NF-kappaB signaling pathway was examined by the dual-luciferase reporter assay system. The stable expression of c-FLIPp43 in the A375 cell lines transfected with the pCMV-Tag2B cFLIPp43 vector increased the protein level of NF-kappaBp65 compared with in the A375 cell lines transfected with the empty vector. Transfection of the cells using the pCMV-Tag2B-cFLIPp43 vector increased the amount of NF-kappaBp65 in the nucleus in a dose-dependent manner. In conclusion, the transfection of the c FLIPp43 expression vector induces the protein expression of NF-kappaBp65 and promotes the activation of the NF-kappaB signaling pathway in the A375 melanoma cell line. PMID- 25017326 TI - Using EPR spectroscopy as a unique probe of molecular-scale reorganization and solvation in self-assembled gel-phase materials. AB - We describe the synthesis of spin-labeled bis-ureas which coassemble with bis urea gelators and report on self-assembly as detected using electron paramagnetic resonance spectroscopy (EPR). Specifically, EPR detects the gel-sol transition and allows us to quantify how much spin-label is immobilized within the gel fibers and how much is present in mobile solvent pools-as controlled by temperature, gelator structure, and thermal history. EPR is also able to report on the initial self-assembly processes below the gelation threshold which are not macroscopically visible and appears to be more sensitive than NMR to intermediate sized nongelating oligomeric species. By studying dilute solutions of gelator molecules and using either single or double spin-labels, EPR allows quantification of the initial steps of the hierarchical self-assembly process in terms of cooperativity and association constant. Finally, EPR enables us to estimate the degree of gel-fiber solvation by probing the distances between spin labels. Comparison of experimental data against the predicted distances assuming the nanofibers are only composed of gelator molecules indicates a significant difference, which can be assigned to the presence of a quantifiable number of explicit solvent molecules. In summary, EPR provides unique data and yields powerful insight into how molecular-scale mobility and solvation impact on assembly of supramolecular gels. PMID- 25017327 TI - The use of regression and normalisation for the comparison of spatio-temporal gait data in children. AB - Spatio-temporal parameters (STPs) are fundamental gait measures often used to compare children of different ages or gait ability. In the first case, non dimensional normalisation (ND) of STPs using either leg-length or height is frequently conducted even though the process may not remove known inter-subject variability. STPs of children with and without disability can be compared through matched databases or using regression driven prediction. Unfortunately, database assignment is largely arbitrary and previous regressions have employed too few parameters to be successful. Therefore, the aims of this study were to test how well actual and ND STPs could be predicted from anthropometrics and speed and to assess if self-selected speed could be predicted from anthropometrics using multivariate regression in a cohort of eighty-nine typically developing children. Equations were validated on an extraneous dataset. We found that equations for actual step length, stride length, and cadence explained more than 84% of the variance compared to their ND counterparts. Moreover, only leg-length ND versions of these parameters were linearly proportional to speed. Prediction of single and double limb support times was weaker (R(2)=0.69 and 0.72, respectively) and we were unable to predict self-selected speed (R(2)<0.16) suggesting the use of anthropometrics is inappropriate for this purpose. Validation was successful for most STPs except in children lying near or outside the normal ranges and for gait speed. Clinically, regression could be used to quantify the difference between a patient's actual and theoretical STPs, allowing for monitoring of progress pre- and post intervention. PMID- 25017328 TI - Safety of Ommaya reservoirs in children with brain tumors: a 20-year experience with 5472 intraventricular drug administrations in 98 patients. AB - The Ommaya reservoir facilitates repetitive delivery of drugs into the CSF and is a pharmacologically rational system for intrathecal chemotherapy. Because previous studies have found a high rate of infection and other complications we herein studied our experience with this device. Between 1993 and 2013, 98 children with brain tumors aged 3 months to 21 years (38 <= 3 years) had an Ommaya reservoir placed. All patients received perioperative antibiotics. Only specially trained personnel that followed standardized guidelines were allowed to access the reservoir. As of April 2014, 5,472 chemotherapy instillations were performed amounting to a median of 36 deliveries (2-280) per reservoir. Ommaya reservoirs were present for 199,956 days and a median of 1,336 days per device. Median survival of the 52 patients still alive is 7.5 years. Only one patient developed an Ommaya reservoir infection (1 %) that could be temporarily sterilized but eventually required Ommaya reservoir explantation. Early complications related to Ommaya reservoir placement occurred in two patients, in one catheter malposition was corrected intraoperatively and in the other kinking of the catheter at the burr-hole required minor surgical correction. Two delayed complications requiring surgical revision included malpositioning of the catheter tip after rapid shrinkage of the ventricles and disconnection of the ventricular catheter after 24 accesses. No leucodystrophic changes occurred along the catheter track. In conclusion, Ommaya reservoirs are safe and complications infrequent providing that all personnel involved in implanting and subsequently accessing the device are specially trained and pay meticulous attention to strict aseptic conditions. PMID- 25017329 TI - Extensive vertebral scalloping in a case of giant cystic spinal schwannoma: more than just a radiological diagnosis. PMID- 25017331 TI - Transcatheter aortic valve implantation: technique, complications and perspectives. AB - Transcatheter aortic valve implantation (TAVI) has become the preferred treatment option for patients with symptomatic severe aortic stenosis who are inoperable or at high risk for surgical aortic valve replacement. TAVI has shown a clear mortality benefit compared to conservative treatment in inoperable patients, and is at least non-inferior to surgical aortic valve replacement in high-risk operable patients. Through improvements in the field of imaging, refinement in valve technologies, increasing operator and team experience and continuous valuable research, TAVI has developed rapidly in the past years and is expected to further boost in the near future. In this review, we discuss the technical and procedural aspects of TAVI, the acute and late outcomes, and highlight the current expectations and potential future development of this rapidly evolving technology. PMID- 25017333 TI - Green synthesis of Fe3O4 nanoparticles with controlled morphologies using urease and their application in dye adsorption. AB - This paper describes a simple and environmentally friendly method for the preparation of highly stable dispersions of Fe3O4 nanoparticles with controlled morphologies, in the same synthesis system for the first time. During the process, the Fe3O4 nanoparticles are formed using urease as a multifunctional reagent, including catalyst, template and dispersant, due to its enzymatic activity and special enzymatic steric structure. A possible formation mechanism for these Fe3O4 nanoparticles, which have various morphologies including nanospheres, nanosheets and nanorods, is proposed. The as-prepared nanoparticles show a larger specific surface area and a stronger magnetism, which enhances their dye adsorption capacity and increases their potential for application in wastewater treatment. PMID- 25017332 TI - The transcriptional activity of Gli1 is negatively regulated by AMPK through Hedgehog partial agonism in hepatocellular carcinoma. AB - The aberrant activation of the Hedgehog (Hh) signaling pathway has been implicated in a variety of malignancies, including hepatocellular carcinoma (HCC). The mammalian 5' adenosine monophosphate-activated protein kinase (AMPK) plays a crucial role in cellular energy homeostasis. However, the interaction between the Hh and AMPK signaling pathways has not been investigated to date. In the present study, to the best of our knowlege, we report for the first time the negative regulation of glioma-associated oncogene 1 (Gli1), an important downstream effector of Hh, by the AMPK signal transduction pathway. Immunoprecipitation and GST-pull down assay showed a direct interaction between AMPK and Gli1. The overexpression of AMPK induced the downregulation of Gli1 expression, while the knockdown of AMPK upregulated Gli1 expression in a relatively short period of time (24 h or less). Our data suggest that AMPK may function as an upstream molecule that regulates Gli1 expression. Therefore, AMPK may play a role in the Hh signaling pathway, through which it regulates tumorigenesis. PMID- 25017334 TI - [Regarding the article "Adults with Down syndrome: characterization of a Portuguese sample"]. PMID- 25017335 TI - [Regional Cancer Registry and clinical research in Portugal: challenges and opportunities]. PMID- 25017336 TI - [Analysis of the Cochrane review: Anticoagulation versus placebo for heart failure in sinus rhythm. Cochrane Database Syst Rev. 2014;3:CD003336]. AB - Thrombotic and embolic events contribute to the morbidity and mortality associated to Chronic Heart Failure (HF). Differently from patients with atrial fibrillation (AF) and HF, in which the benefit of anticoagulation is well documented, the use of these drugs in those with HF in sinus rhythm (without AF history) is controversial. In this systematic review from the Cochrane Collaboration, the authors evaluated the benefits and risks associated with oral anticoagulation (versus placebo) in this population. Only 2 randomized controlled trials were published (one with open-label design) enrolling a total of 324 patients. The results of the meta-analysis based on the best available evidence do not support the systematic use of oral anticoagulants in patients with HF and sinus rhythm for preventing death (overall or cardiovascular) or non-fatal cardiovascular events. Furthermore the major bleeding risk was significantly increased. PMID- 25017337 TI - [General practice and family medicine: challenges today and in the future]. PMID- 25017338 TI - [The challenges to good quality science journalism]. PMID- 25017339 TI - [Meningococcal disease admissions in a paediatric intensive care unit]. AB - INTRODUCTION: Meningococcal infection has a high mortality and morbidity in children. Aggressive initial shock approach, early referral, secondary transport and vaccination are potential factors with impact in reducing its mortality. Objectives were to characterize children admitted to intensive care due to invasive meningococcal disease, to evaluate their prognostic scores and mortality. MATERIAL AND METHODS: Observational study, with retrospective data collection. Two periods were created according to the year of admission (A: 2000 2005 and B: 2006-2011). Prognostic parameters, organ failure and mortality rates were compared in these groups. RESULTS: 70 children were admitted with invasive meningococcal disease. When compared with other causes of admission, a decrease in the number of admissions due to invasive meningococcal disease was observed (period A: 3.4%; period B: 1.5%; p = 0.001). The presence of meningitis was 41% in period A and 29% in period B (p = 0.461). Rapidly progressive purpura occurred in 78% in period A and 50% in period B (p = 0.032). Children from period A had multi-organ failure (80%), disseminated intravascular coagulation (76%) and coma (22%) more frequently than children from period B (29%, 29%, 0%; p < 0.05). Mortality was 26% in period A and 0% in period B (p = 0.006) and standardized mortality by PRISM was 1.3 and 0 in period A and B respectively. DISCUSSION: The decrease in the number of admissions due to invasive meningococcal disease can be explained by the introduction of anti-meningococcal C vaccine in 2006. Mortality decline can be possibly explained by an improvement in the initial patient stabilization and to secondary transport. CONCLUSION: A decrease in the number of admissions due to invasive meningococcal disease and in mortality was observed. PMID- 25017340 TI - [Allergic contact dermatitis to metals over a 20-year period in the Centre of Portugal: evaluation of the effects of the European directives]. AB - INTRODUCTION: Metals are a common cause of allergic contact dermatitis. After the introduction of the EU Nickel Directive (1994/27/CE; 2004/96/EC) and, more recently, the Cement Directive (2003/53/EC) there has been a significant decrease in sensitization to metals mainly in the Nordic countries. The applicability of these directives and their impact in the Portuguese population is unknown. MATERIAL AND METHODS: A retrospective study (1992-2011) was carried out in our patch test clinic to assess the temporal trend of metal sensitization (nickel [Ni], cobalt [Co] and chromium [Cr]) along the last 20 years, particularly considering age, sex and its relation with occupational activity. RESULTS: Out of 5 250 consecutively patch-tested patients, 1 626 (31%) were reactive to at least one metal (26.5% to Ni; 10.0% to Co and 7.9% to Cr). Women had a higher prevalence of sensitization to Ni (34.4% vs 8.9%) whereas men were more reactive to Cr (11.5% vs 5.0%). Nickel sensitization did not decrease significantly over the years, although in recent years among women sensitized to nickel the percentage of younger patients (16-30 years-old) is significantly lower (p < 0.001). Chromium sensitization significantly decreased, particularly in men (r = 0.535), and mainly in the construction workers (r = -0.639). Chromium reactivity associated with the shoe dermatitis has remained stable. DISCUSSION: We emphasize the higher and stable percentage of nickel sensitized individuals suggesting, so far, a low impact from the EU Ni directive, although a decreasing percentage in the the younger group among Ni sensitized women may suggest a beneficial effect is becoming evident is this age group. On the contrary, the impact of the directive regarding the modification of Cr in cement seems to be effective. There is now a need to regulate chromium content in leather products, namely in shoes. CONCLUSIONS: The regulation of interventional measures related either to the manufacture and trade of adornments or professional use will better protect the population of allergy to metals. PMID- 25017341 TI - Hyperplastic polyp? Look again... the impact of the new classification for serrated polyps. AB - INTRODUCTION: The World Health Organization reviewed the classification for serrated colonic polyps in 2010. A new entity, sessile serrated adenoma, was included with two variants: with and without cytological dysplasia. This lesion's malignant potential has been recognized and according to the new classification, many polyps may be reclassified. The impact of this change is yet to be assessed. OBJECTIVE: Analyze the proportion of lesions that were reclassified according to the new World Health Organization classification and the variables that influenced it. MATERIAL AND METHODS: Every patient with at least one sessile serrated adenoma diagnosed in a 5 year period was included. All polyps (regardless of type) resected during the study period were reviewed. Data concerning polyp's characteristics and patient variables were collected. Forty consecutive patients were included [13 female, mean age at 1st sessile serrated adenoma -59 yrs (34-80)]. RESULTS: Were reviewed 247 polyps: hyperplastic--42%; conventional adenomas--29%; sessile serrated adenoma--24%; serrated adenomas--5%. Sixty-three polyps were reclassified: 43 hyperplastic, 12 serrated adenomas, 7 sessile serrated adenoma and 1 conventional adenoma with low grade dysplasia. Reclassification was significantly greater for hyperplastic polyps when compared with the other subtypes. Forty-three of one hundred and four (41%) hyperplastic polyps were reclassified all as sessile serrated adenoma. In these polyps the probability of reclassification was independent from polyp location but was greater if polyp size >= 5 mm. DISCUSSION: This is a single center, rectrospective study. The fact that it was done in an Oncology Referral Institution with a Family Risk Clinic may have influenced the results. Nevertheless the impressive reclassification rate for Hyperplastic Polyps and the fact that they were reclassified mainly as Serrated Adenomas makes these results relevant to daily practice. CONCLUSION: Our results suggest that, according to the new World Health Organization classification for serrated colonic polyps, a considerable proportion of hyperplastic polyps will be reclassified. The serrated pathway of colorectal carcinogenesis has probably been underestimated and at-risk patients may have been under inappropriate surveillance. PMID- 25017342 TI - [The geography of diabetes mellitus in Portugal: how context influence the risk of dying]. AB - INTRODUCTION: Diabetes Mellitus is a public health problem that is on the increase throughout the world, including in Portugal. This paper aims to identify the changing geographic pattern of this cause of death in Portugal and its association with sociomaterial deprivation. MATERIAL AND METHODS: This is a transversal ecological study of the deaths by Diabetes Mellitus in Portuguese municipalities in three periods (1989-1993, 1999-2003 and 2006-2010). It uses a Bayesian hierarchical model in order to obtain a smooth standardized mortality ratio and the relative risk of death by Diabetes Mellitus associated to sociomaterial deprivation. RESULTS: In 1989-1993, the highest smooth standardized mortality ratio values were found in coastal urban municipalities (80% of municipalities with smooth standardized mortality ratio >= 161, of which 60% are urban); in 2006-2010, the opposite was found, with the highest smooth standardized mortality ratio values occurring in rural areas in southern inland regions (76.9% of municipalities with smooth standardized mortality ratio >= 161, of which 69.2% are rural), particularly the Alentejo. The relative risk of death by Diabetes Mellitus increases with vulnerability associated to social and economic conditions in the area of residence, and is significant in the last two periods (relative risk: 1.00; IC95%: 0.98-1.02). DISCUSSION: Diabetes Mellitus presents a geographic pattern marked by coastal-inland and urban-rural asymmetry. However, this has been altering over the last twenty years. 48% of the population reside in municipalities where the smooth standardized mortality ratio has increased in the last twenty years, particularly in the rural areas of inland Portugal. CONCLUSION: The highest smooth standardized mortality ratio are currently found in rural municipalities with the highest index of sociomaterial deprivation. PMID- 25017343 TI - Symptoms and reason for a medical visit in lung cancer patients. AB - BACKGROUND: Patients with lung cancer usually present with symptoms at the time of diagnosis, but it is common that neither the doctor nor the patient initially associate them with the possibility of a malignant tumour. OBJECTIVES: The aim of our study is to analyse the symptoms of patients with lung cancer and the relationship with the personal characteristics or the oncological disease. MATERIAL AND METHODS: A retrospective study was conducted on all patients diagnosed with lung cancer in the Pontevedra Health Area over a period of three years. The symptoms presented by the patient, the reason for the consultation and the agreement between both or any factors associated with either of the two are analysed. RESULTS: A total of 358 patients, with a mean age of 68.7 years, and of whom 87% males, were included in the study. The most common initial symptoms were, constitutional in 30.4% of the cases, cough in 20.9% of cases, and in third place was chest pain, which was referred to by 12% of the patients. The most frequent reason for the consultation was dyspnea in 22.1% of patients, an incidental finding in 15.4%, and haemoptysis in 12.8%. There was a moderate association (correlation coefficient = 0.495) between the initial symptoms and the consulting symptom. CONCLUSIONS: A high percentage of patients with lung cancer had symptoms associated with the tumour at the time of diagnosis, even in early stage disease. PMID- 25017344 TI - Breast cancer patients survival and associated factors: reported outcomes from the Southern Cancer Registry in Portugal. AB - OBJECTIVES: Although the breast cancer incidence in Portugal is lower than the European average, it is the most frequent cancer in women. Overall, mortality rates are heterogeneous throughout Portugal. Implicated factors may include demographic and socioeconomic aspects, tumor biological characteristics, and access to medical care. The aim of this study is to detect survival differences in female breast cancer and identify the main associated factors. MATERIAL AND METHODS: We have conducted a population-based, retrospective cohort study with follow-up. Incident breast cancer cases diagnosed in 2005 of residents in the southern region of Portugal were included. Data was collected from the Southern Portugal Cancer Registry (ROR-Sul) database and completed with clinical chart information. RESULTS: A total of 1 354 patients were included in this study. Observed geographical variations were as follows: for age distribution, with an aging population in Alentejo; for tumor sub-types, there was a higher incidence of HER2-positive tumors in the Algarve and a higher incidence of HER2-negative tumors in Regiao Autonoma da Madeira. Reported estimated 5-year overall survival was 80%, with significant association with tumor stage, hormone receptor and HER2 status. No survival differences were identified among women from distinct geographical regions. DISCUSSION: Although we found differences in age and tumor sub-type distribution between geographical regions, our study does not support the existence of discrepancies in breast cancer survival between these regions. Tumor biological characteristics seem to be the main associated factor with breast cancer survival in our population. CONCLUSIONS: Our study confirms the association between patient survival and tumor stage, hormone receptor and HER2 status. However, no differences in patient survival were observed among different regions of residence. PMID- 25017345 TI - [PRAdA intervention: effects on weight of dietary intervention among treated hypertensive Portuguese natives and African immigrants]. AB - INTRODUCTION: Blood pressure is significantly improved with weight loss. Behavioral interventions for weight loss seem to be less successful in African immigrants. Our main aims were to assess the effect of a dietary and lifestyle intervention on weight among hypertensive Portuguese natives and immigrants and to identify success factors for weight loss, and also to evaluate changes in knowledge and compliance with food recommendations. MATERIAL AND METHODS: Hypertensive medicated patients followed in primary care setting were randomly enrolled in a two phase study, observational (15-months) and behavioral intervention (six months). Participants were divided in two groups: immigrants from African Countries of Portuguese Official Language and Portuguese natives. Participants were given dietary and life styles recommendations in individual face-to-face and telephone sessions. RESULTS: Of 110 participants with a mean BMI of 31.6 +/- 3.7 Kg/m(2), 60 were immigrants. The number of dietary recommendations known and followed at the end was significantly greater than at baseline; however natives performed a greater number of recommendations. Weight loss during intervention was in average 1.4 +/- 2.7% in natives and 0.8 +/- 3.6% in immigrants and was greater than in the observational period. Being male and consuming more than 2 servings of low-fat dairy products/day was associated with higher weight loss, independently of age and ethnicity. DISCUSSION: In general the proposed intervention was efficacious especially in Portuguese natives, confirming other studies. CONCLUSION: The intervention increased knowledge and adherence to recommendations, highlighting the relevance of nutrition education, culturally adapted in primary care. PMID- 25017346 TI - [Successful pregnancies outcomes with the use of in vitro fertilization after Essure(r) unilateral hydrossalpinx occlusion]. AB - INTRODUCTION: Since two decades we witnessed the publication of several studies devoted to the study of the influence of the presence of hydrosalpinx on the results of embryo transfer techniques. The aim of this study is to present the results of treatment and pregnancy outcomes in women with a history of infertility associated with unilateral hydrosalpinx, visible on vaginal ultrasound, which were subjected to unilateral occlusion with Essure(r) and subsequent treatment with in vitro fertilization. MATERIAL AND METHODS: We performed a prospective analysis of a sample of 6 women, with a history of infertility and unilateral hydrosalpinx, between April 2010 to May 2013. In all cases we proceeded to unilateral hysteroscopic placement of the Essure(r) microinsert, prior to performing a cycle for in vitro fertilization. RESULTS: Of the 6 patients undergoing in vitro fertilization, 4 became pregnant (66.7%). Of these, two were uneventful pregnancies until delivery and 2 are still under surveillance, without complications. Of the patients who did not become pregnant after in vitro fertilization (n = 2, 33.3%), 1 conceived spontaneously during the subsequent monitoring. DISCUSSION: The advancement of hysteroscopy in the treatment of hydrosalpinx using the Essure(r) microinsert placement is a valid alternative to the laparoscopic approach. CONCLUSION: This study suggests the effectiveness of unilateral tubal occlusion caused by Essure(r) microinsert in improving outcomes of in vitro fertilization treatment in cases of infertility associated with unilateral hydrosalpinx, visible in the vaginal ultrasound. PMID- 25017347 TI - Traumatic brain injury in Portugal: trends in hospital admissions from 2000 to 2010. AB - INTRODUCTION: Traumatic brain injury has a considerable socio-economic impact, being a major cause of morbi-mortality, often with permanent disability. We sought to characterize health resource utilization of adult traumatic brain injury patients in Portugal between 2000 and 2010. MATERIAL AND METHODS: Retrospective study of medical records of adult patients with ICD9 diagnostic code of traumatic brain injury included in the National Diagnosis Related Groups Database from 2000-2010. Descriptive statistical analysis was performed and trends during the decade were evaluated. RESULTS: We analysed 72 865 admissions to 111 hospitals, 64.1% males, mean age 57.9 +/- 21.8 years (18-107). We found a decrease in number of traumatic brain injury in younger patients and an increase in older ones. The number of traffic accidents decreased and the number of falls increased. There was an increase of moderate to severe traumatic brain injury admissions: 47.2% in 2000 / 80% in 2010. Patients admitted in Intensive Care have nearly doubled (15.8% vs 29.5%) as well as the number submitted to neurosurgical procedures (8.2% vs 15.2%). Total mortality increased from 7.1% to 10.6%. DISCUSSION: The decrease of traumatic brain injury may be associated with the trauma prevention campaigns, road network improvement and health politics. The increase in mortality may be related to better pre-hospital care, enabling more severe cases to arrive in hospital alive, and although treated more frequently in Intensive Care and requiring more neurosurgical procedures, they end up having higher mortality. Also this may be due to an increase in patients' age and worse pre-morbid status. CONCLUSION: Traumatic brain injury in Portugal is changing. Although hospital admissions due to global traumatic brain injury have decreased, mortality rate has increased. PMID- 25017348 TI - Adults with Down syndrome: characterization of a Portuguese sample. AB - INTRODUCTION: Down syndrome or Trisomy 21 affects physical, behavioral and cognitive development. Ageing people with Down syndrome may suffer from several comorbidities that interfere with their daily life. OBJECTIVE: To analyze in a sample of adults with Down syndrome the presence of common medical diseases, regular use of medication, possible cognitive impairment and oral communication skills. MATERIAL AND METHODS: The socio-demographic and clinical data of 209 Portuguese adults (20-58 years) with Down syndrome were collected. Twenty-six subjects were assessed with the WAIS-III. Data was statistically analyzed--SPSS (v.19). RESULTS: Almost half (47.36%) of the sample suffers from comorbidities, with cardiac, psychiatric, epilepsy and hypothyroidism ranked as the most prevalent diseases. Seventy-two patients (34.45%) take medication that acts on the central nervous system. The WAIS-III results revealed IQ scores between 45-61 (mean = 49.65, SD = 4.93) and 141 individuals (67.5%) who can express themselves through basic oral language. DISCUSSION: In line with other studies, these individuals are vulnerable to various comorbidities. Most have basic oral language, but the IQ values are in the 'extremely low' range, with better performance on verbal tasks. CONCLUSION: The cognitive constraints and communication difficulties in the population with Down syndrome may difficult the early clinical recognition of comorbidities associated with ageing. The identification of new semiology, with caregiver support, is essential to ensure that appropriate care is provided to this population. PMID- 25017349 TI - [Urinary tract infections in a cohort of kidney transplant recipients]. AB - INTRODUCTION: Urinary tract infection is the most common infectious complication following renal transplantation and its frequency is insufficiently studied in Portugal. The aim of this study was to characterize the incidence of urinary tract infections and recurrent urinary tract infections in renal transplant recipients. MATERIAL AND METHODS: This was a retrospective cohort observational study, obtained from clinical files of all patients who received a renal transplant at the Hospital of Santa Cruz, from January 2004 to December 2005, with a mean follow-up period of five years or until date of graft loss, death or loss of follow-up. After a descriptive analysis of the population, we used bivariate tests to identify risk factors for urinary tract infections. RESULTS: A total of 127 patients were included, with a 593 patients.year follow-up. We detected 53 patients (41.7%) presenting with at least one episode of urinary tract infection; 21 patients (16.5%) had recurrent urinary tract infection. Female gender was the only risk factor associated with the occurrence of urinary tract infections (p < 0.001, OR = 7.08, RR = 2.95) and recurrent urinary tract infections (p < 0.001, OR = 4.66, RR = 2.83). Escherichia coli (51.6%), Klebsiella pneumoniae (15.5%) and Enterobacter spp (9.9%) were the most frequently identified pathogens. Patients did not reveal an increased mortality or allograft loss. However, urinary tract infections were the most important cause of hospital admissions. DISCUSSION: Female gender was the only risk factor for urinary tract infections in this population. Escherichia coli was the most frequent agent isolated. CONCLUSION: Despite preventive measures, urinary tract infections remain an important cause of morbidity and hospital admissions. PMID- 25017350 TI - Depression and anxiety following deep brain stimulation in Parkinson's disease: systematic review and meta-analysis. AB - INTRODUCTION: Deep brain stimulation (DBS) is effective in advanced Parkinson's disease (PD), improving motor symptoms, fluctuations and quality of life. However, adverse psychiatric outcomes have been reported, albeit variably and in an unstandardized fashion. We aimed to summarize the published evidence on the outcomes of anxiety and depressive symptoms in Parkinson's disease patients following DBS, through systematic review and meta-analysis. MATERIAL AND METHODS: PubMed was searched until May 2012 to identify studies assessing anxiety and depressive symptoms in PD patients who underwent bilateral DBS of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Random effects metaanalyses were conducted for groups of at least three studies that were homogeneous regarding the design and the instruments used. RESULTS: 63 references were selected; 98.4% provided data on depression, and 38.1% on anxiety assessment scales. Two studies did not discriminate the target; from the remaining 61 references, short-term evaluation was performed in 37 (60.7%), mid-term in 36 (59.0%) and long-term in 5 (8.2%). Data on pre to postop variation was available in 57 (93.4%) reports and 16 (26.2%) presented STNDBS versus different comparison groups: GPi-DBS (n = 4 studies, 25.0%), eligible for surgery (n = 6, 37.5%), and medical treatment (n = 7, 43.8%). DISCUSSION: Improvement of depression and anxiety is apparent after DBS, more pronounced in the short-term, an effect that seems to wane in later assessments. Concerning depression, STN-DBS shows superiority against medical treatment, but not when compared to eligible for surgery control groups. The opposite is apparent for anxiety, as results favor medical treatment over STN DBS, and STNDBS over eligible for surgery control group. Superiority of one target over the other is not evident from the results, but data slightly favors GPi for both outcomes. CONCLUSION: The pattern and course of depressive symptoms and anxiety following DBS in PD is not clear, although both seem to improve in the short-term, especially depression following STN-DBS. RESULTS are highly heterogeneous. Efforts should be carried out to standardize assessment procedures across centers. KEYWORDS: Parkinson's Disease; Deep Brain Stimulation; Anxiety; Depression; Meta-Analysis. PMID- 25017351 TI - [Pediatric anesthetic during brain immaturity and neurodevelopment disorders]. AB - INTRODUCTION: Several experimental and clinical studies suggest that drugs used in pediatric anesthesia may exert undesirable effects on the developing central nervous system. The objective of this review was to assess the results and conclusions of published studies on long lasting neurodevelopment disorders following exposure to anesthetics in children in a phase of brain immaturity. MATERIAL AND METHODS: We performed a literature search in several sources (PubMed, SciELO and Cochrane Library) using the terms 'Pediatric anesthesia OR Pediatric anesthetic OR Developing brain anesthetic OR Developing brain anesthesia AND behavior disorders'. We selected human studies, referring to long lasting neurodevelopment effects after exposure to anesthetics in the first four years of life. RESULTS: Ten retrospective studies met the inclusion criteria. Of these, seven suggest risk of neurobehavioral disorders after exposure of small children to anesthetics, as opposed to the results obtained by the other three. DISCUSSION: Although mostly using large databases, the studies found are retrospective, vary in test groups, include sometimes avoidable confounders and some present inaccuracies in the choice of the test and control populations that can compromise the reliability of the results. CONCLUSION: Because of the numerous limitations of the few studies available, the reported results are still deemed insufficient to change current clinical practice. However, although it is undisputable that anesthesia should be provided when needed, regardless of age, the warnings found in literature are worrisome, therefore whenever surgery is unavoidable in small children, alternatives that may help reduce the risks of anesthetic exposure should be sought. PMID- 25017352 TI - Large right ventricular thrombus. AB - Right ventricular thrombosis is a rare yet potentially fatal condition. It has been described in association with hypercoagulability states, autoimmune diseases and dilated cardiomyopathy. Echocardiography constitutes the election tool for diagnosis and characterization of these entities, allowing for the differentiation between the various types of thrombi. We present a case of a patient with alcoholic dilated cardiomyopathy admitted for congestive heart failure and lower respiratory infection. In the diagnostic approach, a routine echocardiography revealed a large mural right ventricular thrombus in association with severe biventricular dysfunction. The patient was proposed for anticoagulation strategy, which he refused. PMID- 25017353 TI - Secondary progression is not the only explanation. AB - Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system. Its presentation is variable and its course and prognosis are unpredictable. Approximately 85% of individuals present a relapsing-remitting form of the disease, but some patients may evolve into a progressive course, accumulating irreversible neurological disability, defining its secondary progressive phase. Despite all the advances that had been reached in terms of diagnosis, many decisions are still taken based only on pure clinical skills. We present the case of a patient that, after being diagnosed with a clinically isolated syndrome many years ago, seemed to be entering in a secondary progressive course, developing a clinical picture dominated by a progressive gait disturbance. Nevertheless, multiple sclerosis heterogeneity asks for some clinical expertise, in order to exclude all other possible causes for patients' complaints. Here we present an important red flag in the differential diagnosis of secondary progressive multiple sclerosis. PMID- 25017354 TI - [Schistosomiasis and acute appendicitis]. AB - Acute appendicitis associated to Schistosoma haematobium and S. mansoni infection has been found in patients submitted to urgent appendectomy at the Hospital Americo Boavida in Luanda. Due to the high prevalence and morbidity caused by schistosomiasis (or bilharziasis) in the country, we suspect that the involvement of Schistosoma infection on appendicular pathology could be very frequent, in particular for those individuals more exposed to the parasite transmission. We report two clinical cases of acute appendicitis whose surgical specimens of the appendix revealed S. haematobium and S. mansoni eggs in histological samples. The reported patients live in endemic areas and have been exposed to schistosome during childhood, which may explain the infection's chronicity. Information of these clinical cases could be relevant, particularly for surgery specialists and clinical pathologists, due to the possibility of finding more patients with concurrent appendicitis and schistosomiasis. PMID- 25017355 TI - [Chronic hypocalcemia due to anti-calcium sensing receptor antibodies]. AB - INTRODUCTION: Hypoparathyroidism is an entity associated with hypocalcemia, more frequently a consequence of neck surgery. An autoimmune etiology is rare and its diagnosis difficult to establish. CLINICAL REPORT: 52 year-old woman, with irrelevant past medical history and no significant familial conditions, referred because of hypocalcemia and basal ganglia calcifications, detected in the course of investigation of myalgias. Besides hypocalcemia (4.6 mg/ dL), hyperphosphatemia (8.7 mg/dL), undetectable parathyroid hormone and low urinary calcium, phosphorus and magnesium were present. Molecular analysis of CaSR gene excluded germinal mutations. Anti-calcium sensing receptor antibodies (anti-CaSR) were present. The patient is asymptomatic and normocalcemic under treatment with calcium and vitamin D. DISCUSSION: Although rare, hypocalcemia due to anti-CaSR hypoparathyroidism must be considered in the absence of previous neck surgery, hypocalcemic drugs, familial history or phenotype suggesting a genetic disorder. Low or undetectable parathyroid hormone excludes pseudohypoparathyroidism and anti-CaSR positivity establishes the diagnosis. PMID- 25017356 TI - [Syphilis diagnosis made from oral mucosal lesions]. PMID- 25017357 TI - [Ureteral stump empyema after heminephrectomy]. PMID- 25017358 TI - Concerning the article: J Pereira de Moura, M Santos Rosa, V Alves, A Mota Pinto, V Rodrigues, JM Silva, JJ Alves de Moura. Populacoes Celulares Perifericas (CD4+, CD8+ e CD19+) em individuos dislipidemicos. PMID- 25017359 TI - In reply to Viroj Wiwanitkit. Acta Med Port 2014;27(3):405. PMID- 25017360 TI - 'The last coachman', the trio of risk factors: alcohol, tobacco and traffic accidents. PMID- 25017361 TI - Evaluating the association between menthol cigarette use and the likelihood of being a former versus current smoker. AB - Menthol in cigarettes has been examined for its potential to affect smoking dependence, measured primarily as number of cigarettes smoked per day and time to first cigarette after waking; the ability to quit smoking constitutes an additional measure of dependence. Successful quitting among menthol compared to non-menthol cigarette smokers is difficult to determine from the literature, due in part to the various definitions of quitting used by researchers. Nevertheless, intervention and follow-up studies of smoking cessation treatments generally indicate no differences in quitting success among menthol compared to non-menthol smokers, while cross-sectional studies suggest some differences within race/ethnicity groups. The association between menthol cigarette use and likelihood of being a former versus current smoker was examined based on data from the National Health Interview Survey and Tobacco Use Supplement to the Current Population Survey. Analyses stratified by race/ethnicity and limited to smokers who had quit at least one year prior to survey participation provided inconsistent results with regard to menthol cigarette use and quitting, both within surveys (i.e., comparing race/ethnicity groups) and between surveys (i.e., same race/ethnicity group across surveys). Evidence suggesting the existence or direction of an association between menthol in cigarettes and quitting depended on the data source. PMID- 25017362 TI - Effect of estrogenic binary mixtures in the yeast estrogen screen (YES). AB - Endocrine disrupting compounds (EDCs) of natural or synthetic origin can interfere with the balance of the hormonal system, either by altering hormone production, secretion, transport, or their binding and consequently lead to an adverse outcome in intact animals. An important aspect is the prediction of effects of combined exposure to two or more EDCs at the same time. The yeast estrogen assay (YES) is a broadly used method to assess estrogenic potential of chemicals. Besides exhibiting good predictivity to identify compounds which interfere with the estrogen receptor, it is easy to handle, rapid and therefore allows screening of a large number of single compounds and varying mixtures. Herein, we applied the YES assay to determine the potential combination effects of binary mixtures of two estrogenic compounds, bisphenol A and genistein, as well as one classical androgen that in vitro also exhibits estrogenic activity, trenbolone. In addition to generating data from combined exposure, we fitted these to a four-parametric logistic dose-response model. As all compounds tested share the same mode of action dose additivity was expected. To assess this, the Loewe model was utilized. Deviations between the Loewe additivity model and the observed responses were always small and global tests based on the whole dose response data set indicated in general a good fit of the Loewe additivity model. At low concentrations concentration additivity was observed, while at high concentrations, the observed effect was lower than additivity, most likely reflecting receptor saturation. In conclusion, our results suggest that binary combinations of genistein, bisphenol A and trenbolone in the YES assay do not deviate from expected additivity. PMID- 25017363 TI - Determination of physicochemical properties of diacylglycerol oil at high pressure by means of ultrasonic methods. AB - The purpose of the paper is to address, using ultrasonic methods, the impact of temperature and pressure on the physicochemical properties of liquids on the example of diacylglycerol (DAG) oil. The paper presents measurements of sound velocity, density and volume of DAG oil sample in the pressure range from atmospheric pressure up to 0.6GPa and at temperatures ranging from 20 to 50 degrees C. Sound speed measurements were performed in an ultrasonic setup with a DAG oil sample located in the high-pressure chamber. An ultrasonic method that uses cross-correlation method to determine the time-of-flight of the ultrasonic pulses through the liquid was employed to measure the sound velocity in DAG oil. This method is fast and reliable tool for measuring sound velocity. The DAG oil density at high pressure was determined from the monitoring of sample volume change. The adiabatic compressibility and isothermal compressibility have been calculated on the basis of experimental data. Discontinuities in isotherms of the sound speed versus pressure point to the existence of phase transitions in DAG oil. The ultrasonic method presented in this study can be applied to investigate the physicochemical parameters of other liquids not only edible oils. PMID- 25017364 TI - An unusual case of spontaneous Riata lead tip embolization. PMID- 25017365 TI - RKIP suppresses gastric cancer cell proliferation and invasion and enhances apoptosis regulated by microRNA-224. AB - The purposes of this study were to determine the expression profile of Raf kinase inhibitor protein (RKIP) in human gastric cancer cells and its effect on the biological characteristics of SGC-7901 cell lines, to examine the modulatory effect of microRNA-224 (miR-224) on RKIP. The research will provide novel strategies for gastric cancer treatment in the future. Quantitative real-time reverse transcription PCR (qRT-PCR) was employed to determine the expression profile of RKIP in gastric cancer cell lines (SGC-7901, MGC80-3, and MKN45). A eukaryotic expression vector, pcDNA3.1-RKIP, was constructed and transfected into SGC-7901 cells. Changes in RKIP protein expression were examined by Western blot assays, and the effect of RKIP overexpression on SCG-7901 cell viability was determined by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide (MTT) assays. The effect of RKIP overexpression on SGC-7901 cell proliferation and apoptosis was analyzed by flow cytometry and that on the migration of SGC-7901 cells was investigated by Transwell migration assays. RKIP was identified to be a regulatory target gene of miR-224 using a luciferase reporter gene system, and the effect of miR-224 on intracellular RKIP protein expression was examined by Western blot assays. The regulatory effect of miR-224 on the biological characteristics of RKIP was investigated by MTT, flow cytometry, and Transwell invasion chamber assays. The expression of RKIP in gastric cancer cells was decreased significantly in comparison to that of normal gastric mucosal epithelial cells (GES-1) (p < 0.01), as demonstrated by qRT-PCR assays. Compared with the control group, the up-regulation of RKIP intracellular expression was observed in SGC-7901 cells after transfection of pcDNA3.1-RKIP for 48 h (p < 0.01). There were significant decreases in cell viability and the S-phase fraction (p < 0.05), concomitant with a significant increase in apoptosis (p < 0.01), as well as a significant reduction in cells migrating through Transwell chambers (p < 0.05), as shown by MTT, flow cytometry, and Transwell invasion chamber assays. A significant decrease in luciferase activities in cells transfected with a miR-224 mimic was observed compared with that of the control group (p < 0.05), as suggested by the luciferase reporter gene system. As shown by Western blot assays, there was a significant decrease in RKIP expression in SGC-7901 cells transfected with the miR-224 mimic for 48 h compared with the control group (p < 0.05). As shown by MTT, flow cytometry, and Transwell invasion chamber assays, the changes in biological characteristics induced by RKIP overexpression could be suppressed in SGC-7901 cells after transfection of the miR-224 mimic. In conclusion, the down-regulation of RKIP expression was observed in human gastric cell lines, and miR-224 could negatively regulate the expression and biological characteristics of RKIP, contributing to suppress the proliferation and invasion of gastric cells. PMID- 25017366 TI - Long noncoding RNA HOTAIR can serve as a common molecular marker for lymph node metastasis: a meta-analysis. AB - A number of studies have reported that HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and overexpression of HOTAIR was prone to lymph node metastasis. This meta-analysis collected all relevant articles and explored the association between HOTAIR expression levels with lymph node metastasis. A literature collection was conducted by searching electronic databases PubMed, Cochrane Library, OVID, Web of Science, and CNKI (up to March 22, 2014). The odds ratio (OR) and its corresponding 95 % confidence interval (CI) were calculated to assess the strength of the association by using RevMan5.2 software. A total of 748 patients from 8 studies were included in this meta-analysis. The results showed there was a significant difference in the incidence of lymph node metastasis between high HOTAIR expression group and low HOTAIR expression group (OR = 2.81, 95 % CI 1.38-5.70, P = 0.004 random-effects model). This meta-analysis demonstrated that the incidence of lymph node metastasis in patients detected with high HOTAIR expression was higher than that in patients with low HOTAIR expression. PMID- 25017368 TI - Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS). AB - Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. It is a neurodegenerative disorder with high genetic and phenotypic variability. In most patients, the cause of the disease is unknown. Until now, no treatment strategy has been discovered with the exception of riluzole which has a moderate effect on the disease process. While developing a new causal therapy targeting a specific disease-causing gene can have a huge effect on the disease process, only a limited number of ALS patients will benefit from such a therapy. Alternatively, pathogenic processes that are common in ALS patients with different etiology can also be targeted. The effect of such a modifying treatment will be smaller, but the target population will be larger as more ALS patients could benefit. In this review, we summarize the evidence for the involvement of different biological processes in the pathogenesis of ALS and will discuss how strategies influencing these processes can be translated into new therapeutic approaches. In order to further improve this translational step, there is an urgent need for a better understanding of the underlying mechanism(s), for new ALS animal models and for rigorous protocols to perform preclinical studies. PMID- 25017369 TI - Generic change indicators in therapeutic processes with different outcomes. AB - OBJECTIVES: This paper analyzes the relationship between ongoing change and final outcome in therapies carried out in natural settings with 39 clients. METHOD: Ongoing change was assessed through generic change indicators (GCIs), an observational method designed to label the content of change moments by selecting one specific GCI from the sequence of 19 that covers from more rudimentary and low complexity to more elaborated and complex changes. These GCIs can also be grouped into three broad stages of change, according to their level of complexity. Productivity indicators were generated to account for the number of GCIs (total and grouped by stage) adjusted by the length of therapy and the respective individual production of GCIs. Outcome, in turn, is understood as the final result of therapy and was measured by Lambert's Outcome Questionnaire (OQ 45.2). RESULTS: Using the Reliable Change Index of this measure, which qualifies the difference between initial and final scores, therapies were grouped into "good outcome" and "poor outcome" cases. Findings indicate that therapies with good final outcome show a greater presence of Stage III GCIs during the process. Furthermore, in these therapies there is a significant association between Stage I GCI productivity and the productivity of Stages II and III GCIs. This is not the case for poor outcome cases, where results show a greater productivity of initial stage GCIs, mostly in the second half of therapy and no relation of this productivity with Stage II and Stage III GCIs. CONCLUSIONS: Results support the relation of ongoing change and final outcome. Possibilities for the clinical use of GCIs, specifically for monitoring ongoing therapies, are discussed. PMID- 25017367 TI - Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice. AB - It has been widely accepted that deficits in neuronal plasticity underlie the cognitive abnormalities observed in fetal alcohol spectrum disorder (FASD). Exposure of rodents to acute ethanol on postnatal day 7 (P7), which is equivalent to the third trimester of fetal development in human, induces long-term potentiation (LTP) and memory deficits in adult animals. However, the molecular mechanisms underlying these deficits are not well understood. Recently, we found that histone H3 dimethylation (H3K9me2), which is mediated by G9a (lysine dimethyltransferase), is responsible for the neurodegeneration caused by ethanol exposure in P7 mice. In addition, pharmacological inhibition of G9a prior to ethanol treatment at P7 normalized H3K9me2 proteins to basal levels and prevented neurodegeneration in neonatal mice. Here, we tested the hypothesis that pre administration of G9a/GLP inhibitor (Bix-01294, Bix) in conditions in which ethanol induces neurodegeneration would be neuroprotective against P7 ethanol induced deficits in LTP, memory and social recognition behavior in adult mice. Ethanol treatment at P7 induces deficits in LTP, memory and social recognition in adult mice and these deficits were prevented by Bix pretreatment at P7. Together, these findings provide physiological and behavioral evidence that the long-term harmful consequences on brain function after ethanol exposure with a third trimester equivalent have an epigenetic origin. PMID- 25017370 TI - iTRAQ-based proteomic study of the effects of Spiroplasma eriocheiris on Chinese mitten crab Eriocheir sinensis hemocytes. AB - Spiroplasma eriocheiris is as a novel pathogen of Chinese mitten crab Eriocheir sinensis tremor disease. The hemocytes have been shown to be major target cells in S. eriocheiris infection. The aim of this study was to examine the hemocytes' immune response at the protein levels. The differential proteomes of the crab hemocytes were analyzed immediately prior to injection with the pathogen, and at 10 d post-injection by isobaric tags for relative and absolute quantization (iTRAQ) labeling, followed by liquid chromatography-tandem mass spectrometry (LC MS/MS). A total of 1075 proteins were identified by LC-MS/MS and de novo sequencing data. Using a 1.2-fold change in expression as a physiologically significant benchmark, 76 differentially expressed proteins (7.07%) were reliably quantified by iTRAQ analysis. Thirty-five (3.26%) proteins were up-regulated and 41 (3.81%) proteins were down-regulated resulting from a S. eriocheiris infection. Approximately 20 differential proteins in hemocytes were involved in the stress and immune responses. Up-regulated proteins included alpha-2 macroglobulin (alpha2M), prostaglandin D synthase (GST), ferritin, and heat shock protein 60. Down-regulated proteins included two lectins (mannose-binding protein and hemocytin), three kinds of serine proteinase inhibitors (two serpins and pacifastin), three different kinds of serine proteases, mitogen-activated protein kinase kinase (MAPKK), and two thioredoxins (Trx), crustin, etc. Selected bioactive factors (alpha2M, GST, ferritin, tubulin, crustin, thioredoxin, clip domain serine protease and serpin) are verified by their immune roles in the S. eriocheiris infection using Real-time PCR. The variation trend of immune gene's mRNA expression is similar with the result of iTRAQ, except the tubulin. The prophenoloxidase-activating system, antimicrobial action and antioxidant system involved in the immune responses of E. sinensis is believed to be a resistance to S. eriocheiris infection. This is the first report of the proteome response of crab hemocytes against S. eriocheiris infection. These findings contribute to our understanding of tremor disease processes in crabs, and provide the first evidence to promote a search for potential biomarkers of the disease. PMID- 25017371 TI - Over-inhibition of NADPH oxidase reduce the wound healing in liver of finfish. AB - Wound healing is a complex process involving soluble mediators, blood cells, extracellular matrix, and parenchymal cells in a response that occurs after surgical procedure or traumatic injury. The present study aims to investigate the ROS producing from the injury that involved in the wound healing using the ZFL (zebrafish liver cell) and tilapia partial hepatectomy model. In the ZFL, we observed that while over-inhibition of NADPH activity leading to reduce the wound healing moreover, experiment of the oxidative stress by the extracellular hydrogen peroxide exactly presented to increase the PCNA, BrdU and Ki-67 histopathological repair response of tilapia liver follow partial hepatectomy. We conclude that over inhibition of the NADPH oxidase by DPI may reduce the cell even the tissue in the progress of healing after the injury. PMID- 25017372 TI - Artemisinin reduces cell proliferation and induces apoptosis in neuroblastoma. AB - Artemisinin, a natural product from the Chinese medicinal plant, Artemisia annua L., is commonly used in the treatment of malaria, and has recently been reported to have potent anticancer activity in various types of human tumors. Yet, the effect of artemisinin on neuroblastoma is still unclear. In the present study, we aimed to investigate the effects of artemisinin on neuroblastoma cells. We observed that artemisinin significantly inhibited cell growth and proliferation, and caused cell cycle arrest in the G1 phase in neuroblastoma cell lines. Annexin V-FITC/PI staining assay revealed that artemisinin markedly induced apoptosis. Soft agar assays revealed that artemisinin suppressed the ability of clonogenic formation of neuroblastoma cells and a xenograft study in NOD/SCID mice showed that artemisinin inhibited tumor growth and development in vivo. Therefore, our results suggest that the Chinese medicine artemisinin could serve as a novel potential therapeutic agent in the treatment of neuroblastoma. PMID- 25017373 TI - Enzyme inhibition, antioxidant and immunomodulatory activities, and brine shrimp toxicity of extracts from the root bark, stem bark and leaves of Terminalia macroptera. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root bark, stem bark and leaves of Terminalia macroptera have been traditionally used against a variety of ailments such as wounds, hepatitis, malaria, fever, cough, and diarrhea as well as tuberculosis and skin diseases in African folk medicine. Boiling water extracts of Terminalia macroptera, administered orally, are the most common preparations of this plant used by the traditional healers in Mali. This study aimed to investigate the inhibition of the activities of alpha-glucosidase, 15-lipoxygenase and xanthine oxidase, DPPH scavenging activity, complement fixation activity and brine shrimp toxicity of different extracts obtained by boiling water extraction (BWE) and by ASE (accelerated solvent extraction) with ethanol, ethanol-water and water as extractants from different plant parts of Terminalia macroptera. MATERIALS AND METHODS: 27 different crude extracts were obtained by BWE and ASE from root bark, stem bark and leaves of Terminalia macroptera. The total phenolic and carbohydrate contents, enzyme inhibition activities (alpha-glucosidase, 15 lipoxygenase and xanthine oxidase), DPPH scavenging activity, complement fixation activity and brine shrimp toxicity of these extracts were evaluated. Principal component analysis (PCA) was applied for total biological activities evaluation. RESULTS: Several of the extracts from root bark, stem bark and leaves of Terminalia macroptera obtained by BWE and ASE showed potent enzyme inhibition activities, radical-scavenging properties and complement fixation activities. None of the extracts are toxic against brine shrimp larvae in the test concentration. Based on the results from PCA, the ASE ethanol extracts of root bark and stem bark and the low molecular weight fraction of the 50% ethanol-water extract of leaves showed the highest total biological activities. The boiling water extracts were less active, but the bark extracts showed activity as alpha glucosidase inhibitors and radical scavengers, the leaf extract being less active. CONCLUSION: The observed enzyme inhibition activities, radical scavenging properties and complement fixation activities may explain some of the traditional uses of this medicinal tree, such as in wound healing and against diabetes. PMID- 25017375 TI - Science meets regulation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The European Pharmacopoeia (Ph. Eur.) is a standard reference for both European and non-European countries and defines requirements for the qualitative and quantitative composition of medicines. Herbal drug (HD) monographs state which aspects have to be considered for quality assurance through the relevant chapters "Definition", "Characters", "Identification", "Tests", and "Assay". Identification of botanical material is achieved by macroscopic and microscopic morphology, generally examined by a trained expert. Content or assay is the most difficult area of quality control to perform, since in most herbal drugs the active constituents are unknown and markers should be used which cannot be really related to the quality. The other critical points are represented by the purity tests, in particular some tests such as heavy metals, aflatoxins and pesticides are laborious and time intensive, requiring a significant investment in equipment, materials, and maintenance. MATERIAL AND METHODS: A literature survey concerning alternative and/or complementary tools for quality control of botanicals has been performed by searching the scientific databases Pubmed, SciFinder, Scopus and Web of Science. RESULTS: Diverse analytical methods including DNA fingerprinting, Nuclear Magnetic Resonance (NMR), Near Infra Red (NIR) and (bio)sensors have been reported in the literature to evaluate the quality of botanical products. Identification of plants at the species level can be successfully based on genome based methods, using DNA barcodes, the nucleotide sequence of a short DNA fragment. NMR can provide direct NMR fingerprint determination (complete assignment of the signals by 1D and 2D experiments), quantitative NMR and chemometric analysis (the metabolite fingerprint is based on the distribution of intensity in the NMR spectrum to provide sample classification). NIR spectroscopy is a fast qualitative and quantitative analytical method, getting knowledge about plant species and/or its geographic origin. Finally, the development of chemical and biological sensors is currently one of the most active areas of analytical research. Immobilization of specific enzymes led to recognize definite class of compounds such as cysteine sulfoxides, glucosinolates, cyanogenic glycosides, and polyphenols. Other recognition elements are nucleic acids to evaluate the ability of different molecules to bind DNA. Sensors have also been developed for the detection of heavy metals in botanicals. Moreover, the analysis of mycotoxins and pesticides, could represent another field of possible application. CONCLUSIONS: These alternative/complementary analytical methods represent tools which appear to be an analyst's dream: they are able to give rapid analysis responses; to operate directly on complex matrices, in many cases; to be selective and sensitive enough for the required application; to be portable and sometimes also disposable; and to have fast analysis times. PMID- 25017374 TI - Effects of Tulbaghia violacea Harv. (Alliaceae) rhizome methanolic extract on kidney function and morphology in Dahl salt-sensitive rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tulbaghia violacea has been used traditionally for the treatment of several ailments, including hypertension. The herb has been shown to have antihypertensive properties which have been attributed to its angiotensin-converting enzymeinhibitory (ACEI) activity. It could, therefore, prove beneficial in ameliorating renal pathology associated with hypertension. To evaluate the effects of long-term administration of Tulbaghia violacea on renal function and morphology in the Dahl salt-sensitive (DSS) rat model. MATERIALS AND METHODS: Male DSS rats were treated intra-peritoneally (i.p.) as follows: methanolic extract of Tulbaghia violacea: (TVL) (50 mg/kg/b.w.), captopril: (CAP) (25 mg/kg/b.w.), or distilled water, control: (CON) (3 ml/kg/b.w.). Blood pressure (BP) was measured bi-weekly, whilst 24-h urine volumes and electrolyte concentrations were assessed weekly. Animals were sacrificed on day 49 by halothane overdose. Blood was removed for determination of plasma and serum electrolytes. Left kidney tissues were harvested for the determination of nuclear factor-kappabeta (NF-kbeta) and transforming growth factor-beta (TGF-beta) gene expressions. RESULTS: TVL significantly reduced mean arterial pressure (MAP) and diastolic blood pressure (DBP). TVL showed reduced blood urea nitrogen, serum creatinine, total protein in urine as well as increased serum total protein. TVL decreased thiobarbituric acid reactive substances (TBARS) and increased glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity and nitric oxide significantly. NF-kbeta and TGF-beta) gene expressions were significantly reduced in TVL and CAP treated rats. Moreover, renal morphology improved significantly in TVL and CAP treated animals. CONCLUSION: TVL and CAP demonstrated marked improvement in renal function and morphology. PMID- 25017376 TI - Estimated risk of radiation-induced cancer following paediatric cranio-spinal irradiation with electron, photon and proton therapy. AB - BACKGROUND: Improvement in radiotherapy during the past decades has made the risk of developing a radiation-induced secondary cancer as a result of dose to normal tissue a highly relevant survivorship issue. Important factors expected to influence secondary cancer risk include dose level and dose heterogeneity, as well as gender and type of tissue irradiated. The elevated radio-sensitivity in children calls for models particularly tailored to paediatric cancer patients. MATERIAL AND METHODS: Treatment plans of six paediatric medulloblastoma patients were analysed with respect to secondary cancer risk following cranio-spinal irradiation (CSI), using either: 1) electrons and photons combined; 2) conformal photons; 3) double-scattering (DS) protons; or 4) intensity-modulated proton therapy (IMPT). The relative organ equivalent dose (OED) concept was applied in three dose-risk scenarios: a linear response model, a plateau response and an organ specific linear-exponential response. Life attributable risk (LAR) was calculated based on the BEIR VII committee's preferred models for estimating age- and site-specific solid cancer incidence. Uncertainties in the model input parameters were evaluated by error propagation using a Monte Carlo sampling procedure. RESULTS: Both DS protons and IMPT achieved a significantly better dose conformity compared to the photon and electron irradiation techniques resulting in a six times lower overall risk of radiation-induced cancer. Secondary cancer risk in the thyroid and lungs contributed most to the overall risk in all compared modalities, while no significant difference was observed for the bones. Variations between DS protons and IMPT were small, as were differences between electrons and photons. CONCLUSION: Regardless of technique, using protons decreases the estimated risk of secondary cancer following paediatric CSI compared to conventional photon and electron techniques. Substantial uncertainties in the LAR estimates support relative risk comparisons by OED. PMID- 25017377 TI - Positron emission tomography and pharmacokinetics of 2-[18F]-fluoroethyl choline for metabolic studies in breast cancer xenografts. AB - BACKGROUND: Breast carcinomas (BC) can have abnormal choline (Cho) metabolism. Earlier studies indicated that Cho uptake can differ between different subtypes of BC. The purpose of this study was to investigate uptake of 2-[(18)F] fluoroethyl-choline ([(18)F]FECh) in three different patient-derived breast cancer xenografts (BCXs) using dynamic positron emission tomography (dPET). MATERIAL AND METHODS: Nine athymic nude mice bearing bilateral MAS98.12 (basal like), HBCx34 or MAS98.06 (both luminal B) BCXs were subjected to a 90-minute dPET scan following a bolus injection of 10 MBq of [(18)F]FECh. A Patlak Plot analysis and a well-established two-tissue compartment model were fitted to the uptake curves of the whole tumors, providing estimates of transfer rates between the vascular, non-metabolized and metabolized compartments. Patlak slope KP and intercept V, the rate constants k1, k2, k3, the intravascular fraction vb and MR[(18)F]FECh were estimated. Additionally, analyses of terminal blood samples and tumor cell suspension incubated with [(18)F]FECh were performed. RESULTS: [(18)F]FECh uptake in all BCXs was similar to surrounding normal tissue, thus creating no image contrast. The average liver uptake was 10 times higher than the tumor uptake. The uptake in MAS98.12 was higher than in the other two BCXs during the whole course of the acquisition, and was significantly higher than in HBCx34 at 10-30 minutes after injection. No significant differences were found for k1, MR[(18)F]FECh and intravascular fraction vb. Patlak slope KP, k2 and k3 were significantly lower for the MAS98.12 xenograft, in line with in vitro results. KP was correlated with both MR[(18)F]FECh and k3. CONCLUSIONS: dPET demonstrated that different subtypes of breast cancer have different uptake of [(18)F]FECh. Differences in rate constants and KP were in line with in vitro uptake in cell suspensions and earlier spectroscopy and gene expression analysis. PMID- 25017378 TI - Correction of diffusion-weighted magnetic resonance imaging for brachytherapy of locally advanced cervical cancer. AB - BACKGROUND: Geometrical distortion is a major obstacle for the use of echo planar diffusion-weighted magnetic resonance imaging (DW-MRI) in planning of radiotherapy. This study compares geometrical distortion correction methods of DW MRI at time of brachytherapy (BT) in locally advanced cervical cancer patients. MATERIAL AND METHODS: In total 21 examinations comprising DW-MRI, dual gradient echo (GRE) for B0 field map calculation and T2-weighted (T2W) fat-saturated MRI of eight patients with locally advanced cervical cancer were acquired during BT with a plastic tandem and ring applicator in situ. The ability of B0 field map correction (B0M) and deformable image registration (DIR) to correct DW-MRI geometric image distortion was compared to the non-corrected DW-MRI including evaluation of apparent diffusion coefficient (ADC) for the gross tumor volume (GTV). RESULTS: Geometrical distortion correction decreased tandem displacement from 3.3 +/- 0.9 mm (non-corrected) to 2.9 +/- 1.0 mm (B0M) and 1.9 +/- 0.6 mm (DIR), increased mean normalized cross-correlation from 0.69 +/- 0.1 (non- corrected) to 0.70 +/- 0.10 (B0M) and 0.77 +/- 0.1 (DIR), and increased the Jaccard similarity coefficient from 0.72 +/- 0.1 (non-corrected) to 0.73 +/- 0.06 (B0M) and 0.77 +/- 0.1 (DIR). For all parameters only DIR corrections were significant (p < 0.05). ADC of the GTV did not change significantly with either correction method. CONCLUSION: DIR significantly improved geometrical accuracy of DW-MRI, with remaining residual uncertainties of less than 2 mm, while no significant improvement was seen using B0 field map correction. PMID- 25017379 TI - Surrogate endpoints in second-line treatment for mCRC: a systematic literature based analysis from 23 randomised trials. AB - PURPOSE: To evaluate progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) as potential surrogate endpoints (SEP) for overall survival (OS) in second-line treatment for metastatic colorectal cancer (mCRC). METHODS: A systematic literature search of randomised trials of second-line chemotherapy for mCRC reported from January 2000 to July 2013 was performed. Correlation coefficients weighted by number of patients in the treatment arms between median PFS, ORR and DCR with median OS were estimated. RESULTS: Twenty three trials reflecting 10 800 patients met the inclusion criteria. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. PFS showed moderate correlation with OS [RPFS = 0.73; 95% confidence interval (CI) 0.61-0.82]. In contrast, ORR only weakly correlated with OS (RORR = 0.58; 95% CI 0.38-0.72, n = 22). Despite a small number of studies (n = 10) reporting on DCR, moderate correlation with OS was observed (RDCR = 0.74; 95% CI 0.56-0.86). CONCLUSION: Based on the available trial-level data, PFS may serve as an appropriate SEP in second-line chemotherapy for mCRC. A small number of studies revealed moderate correlation of DCR with OS that justifies further investigation. PMID- 25017380 TI - Paradoxes of follow-up - health professionals' views on follow-up after surgical treatment in gynecological cancer. AB - OBJECTIVE: Evidence now reveals that attending a follow-up program may not improve survival for low-stage gynecological cancer patients. The aim of this study was to explore health professionals' experiences with the follow-up programs and their views on follow-up in the future. METHODS: A qualitative approach was undertaken with semi-structured focus group interviews. Three focus group interviews were conducted at neutral ground. One group with onco gynecologists, one group with specialist nurses, and one mixed group. The main themes of the interviewguide were: Existing follow-up program, life after cancer and future follow-up. The interviews were transcribed verbatim. Patterns and themes were uncovered from the data inspired by interpretive description. RESULTS: The doctors described most advantages, such as: Quality control of their own work, detection of sequelae after surgery, and credit and appraisal from the patients. A disadvantage was the inadequate use of the nurses' main competencies. Some dilemmas were described by the nurses as well as doctors: First, both groups were aware of the existing evidence that attendance of follow-up programs may not improve survival and yet, health professionals still performed the follow-ups and most often did not address this paradox for the patients. Second, the existing follow-up program seemed to bring the patients comfort and security on one hand, but on the other hand it seemed to induce insecurity and anxiety. The health professionals agreed that future follow-up should be individualized with focus on the single patients' needs and psychological wellbeing. The health professionals identified a great challenge in communicating the evidence and the forthcoming changes in the follow-up programs to the patients. CONCLUSIONS: This study revealed that the existing follow-up regime contains several dilemmas. According to the health professionals, future follow-up must be more individualized, and a shift in focus is needed from relapse to quality of life after cancer. PMID- 25017381 TI - A case of intracranial meningioma detected by 18F-choline PET/CT and examined by PET/MRI fusion imaging. PMID- 25017382 TI - Giant thoracic ganglioneuroma in a pediatric patient: staging and restaging with 18F-FDG PET-CT. PMID- 25017384 TI - Erythromycin- and copper-resistant Enterococcus hirae from marine sediment and co transfer of erm(B) and tcrB to human Enterococcus faecalis. AB - An erythromycin-, copper- and cadmium-resistant isolate of Enterococcus hirae from marine sediment was shown to harbor the plasmid pRE25 and to co-transfer erm(B) and tcrB to Enterococcus faecalis JH2-2. These data highlight the scope for antibiotic resistance selection by the marine environment through heavy metals and its possible involvement in antibiotic-resistant enterococcal infections. PMID- 25017383 TI - Synchronous ovarian carcinoma detected on staging 18F-FDG PET/CT in a patient of esophageal carcinoma: a rare association. PMID- 25017385 TI - Aural microsuction for wax impaction: survey of efficacy and patient perception. AB - OBJECTIVE: Cerumen impaction is a common problem, and aural microsuction is a technique frequently employed for its management. This study aimed to quantify the patient perception, safety and efficacy of this procedure. METHODS: Patients were asked to complete a questionnaire following cerumen clearance by microsuction. The perceived severity of pain, noise-related discomfort and vertigo was scored on a scale of 1 to 10. Patients with mastoid cavities and those who had used a cerumenolytic agent in the preceding week were analysed separately. RESULTS: A total of 159 questionnaires were returned. Mean scores (95 per cent confidence intervals) were: pain, 2.34 (2.06-2.62); noise discomfort, 3.03 (2.71-3.35); and vertigo, 1.95 (1.66-2.25). There was successful clearance (i.e. sufficient to view the tympanic membrane) in 91 per cent of cases. Patients who had used cerumenolytics reported significantly less pain and vertigo (p = 0.008 and p < 0.001, respectively) compared with those who had not, whilst patients with mastoid cavities reported greater levels of vertigo (p < 0.001) than those without. CONCLUSION: Aural microsuction is well tolerated. Side effects are mild, and the prior use of cerumenolytics appears to further reduce their severity. PMID- 25017387 TI - Is it possible to preserve the ovaries during surgical intervention in younger women diagnosed with endometrial cancer? PMID- 25017386 TI - Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain. AB - BACKGROUND: Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. RESULTS: The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. CONCLUSION: These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity. PMID- 25017388 TI - Transparent conducting p-type thin films of c-axis self-oriented Bi2Sr2Co2O(y) with high figure of merit. AB - Transparent conducting p-type Bi2Sr2Co2O(y) thin films have been first grown on SrTiO3 substrates by a chemical solution deposition, showing c-axis self orientation. The figure of merit can reach as high as 800 MOmega(-1), which is the highest value for p-type transparent conducting thin films by solution methods. PMID- 25017389 TI - Heterogeneity in men's marijuana use in the 20s: adolescent antecedents and consequences in the 30s. AB - Adolescent psychopathology is commonly connected to marijuana use. How changes in these adolescent antecedents and in adolescent marijuana use are connected to patterns of marijuana use in the 20s is little understood. Another issue not clearly understood is psychopathology in the 30s as predicted by marijuana use in the 20s. This study sought to examine these two issues and the associations with marijuana disorder diagnoses using a longitudinal data set of 205 men with essentially annual reports. Individual psychopathology and family characteristics from the men's adolescence were used to predict their patterns of marijuana use across their 20s, and aspects of the men's psychopathology in their mid-30s were predicted from these patterns. Three patterns of marijuana use in the 20s were identified using growth mixture modeling and were associated with diagnoses of marijuana disorders at age 26 years. Parental marijuana use predicted chronic use for the men in adulthood. Patterns of marijuana use in the 20s predicted antisocial behavior and deviant peer association at age 36 years (controlling for adolescent levels of the outcomes by residualization). These findings indicate that differential patterns of marijuana use in early adulthood are associated with psychopathology toward midlife. PMID- 25017390 TI - Risk analysis for second hip fracture in patients after hip fracture surgery: a nationwide population-based study. AB - OBJECTIVES: The current treatment program for fragility hip fractures (HFx) emphasizes a combination of early surgery, rehabilitation, and tertiary prevention strategy for osteoporosis; however, the effect is unclear and little information is available on the risk factors predicting the occurrence of a second hip fracture (SHFx). The aim of this study was to explore the incidence, risk factors, and subsequent mortality of SHFx in patients after their first hip fracture surgery (HFxS). DESIGN, SETTING, AND PARTICIPANTS: We performed a nationwide population-based longitudinal observational study using the National Health Insurance Research Database (NHIRD) of Taiwan with a logistic regression model analysis. Of 87,415 patients undergoing HFxS during the period 2004 to 2007, we identified 8027 patients who had sustained an SHFx for analyses. MEASUREMENTS: Data collected included patient characteristics (demographics, comorbidities, and concurrent medication use), incidence and hazard ratios of SHFx after HFxS, and subsequent age-specific mortality. RESULTS: The overall incidence of SHFx was 9.18% and the age-specific mortality was increased 1.6- to 2.2-fold in patients with SHFx compared with those without after HFxS in this 7 year longitudinal study. The identified risk factors included age (AOR = 1.84, 95% CI: 1.24-2.89), female gender (AOR = 1.12, 95% CI: 1.03-2.30), obesity (AOR = 2.89, 95% CI: 1.81-3.01), diabetes (AOR = 3.85, 95% CI: 2.54-4.05), arterial hypertension (AOR = 2.45, 95% CI: 1.83-2.62), hyperlipidemia (AOR = 2.77, 95% CI: 1.27-3.19), stroke/TIA (AOR = 2.85, 95% CI: 2.20-3.23), blindness/low vision (AOR = 3.09, 95% CI: 2.54-3.73), and prolonged use of analgesics and anti-inflammatory medications (all AOR >= 3.05, all P values <=.012). Bisphosphonate therapy after HFxS had a significant negative risk association with the development of an SHFx (20.8% vs 32.3%, P = .023; AOR = 2.24, 95% CI: 1.38-2.90). CONCLUSION: We concluded that the occurrence of an SHFx and subsequent mortality in patients after HFxS is rather high. An understanding of the risk factors predicting the occurrence of an SHFx provides a valuable basis to improve health care for geriatric populations. PMID- 25017392 TI - Supersonically blown ultrathin thorny devil nanofibers for efficient air cooling. AB - The effect of the supersonically blown below-74 nm nanofibers on cooling of high temperature surfaces is studied experimentally and theoretically. The ultrathin supersonically blown nanofibers were deposited and then copper-plated, while their surfaces resembled those of the thorny-devil nanofibers. Here, we study for the first time the enhancement of surface cooling in gas in the cases of the forced and natural convection with the help of ultrathin thorny-devil nanofibers. These polymer core-metal shell nanofibers in nanometric scale possess a relatively high thickness of the metal shell and a high effective thermal conductivity, which facilitates heat transfer. The additional surface temperature reduction close to 5 degrees C in the case of the forced convection in the impinging air jet and close to 17 degrees C in the case of the natural convection was achieved. Correspondingly, an increase in the value of the heat transfer coefficient of about 41% in the forced convection, and about 20% in the natural convection was achieved due to the presence of the thorny devil electrospun and/or supersonically blown nanofibers. PMID- 25017391 TI - Hospice family members' perceptions of and experiences with end-of-life care in the nursing home. AB - OBJECTIVE: Even though more than 25% of Americans die in nursing homes, end-of life care has consistently been found to be less than adequate in this setting. Even for those residents on hospice, end-of-life care has been found to be problematic. This study had 2 research questions; (1) How do family members of hospice nursing home residents differ in their anxiety, depression, quality of life, social networks, perceptions of pain medication, and health compared with family members of community dwelling hospice patients? (2) What are family members' perceptions of and experiences with end-of-life care in the nursing home setting? METHODS: This study is a secondary mixed methods analysis of interviews with family members of hospice nursing home residents and a comparative statistical analysis of standard outcome measures between family members of hospice patients in the nursing home and family members of hospice patients residing in the community. RESULTS: Outcome measures for family members of nursing home residents were compared (n = 176) with family members of community dwelling hospice patients (n = 267). The family members of nursing home residents reported higher quality of life; however, levels of anxiety, depression, perceptions of pain medicine, and health were similar for hospice family members in the nursing home and in the community. Lending an understanding to the stress for hospice family members of nursing home residents, concerns were found with collaboration between the nursing home and the hospice, nursing home care that did not meet family expectations, communication problems, and resident care concerns including pain management. Some family members reported positive end-of life care experiences in the nursing home setting. CONCLUSION: These interviews identify a multitude of barriers to quality end-of-life care in the nursing home setting, and demonstrate that support for family members is an essential part of quality end-of-life care for residents. This study suggests that nursing homes should embrace the opportunity to demonstrate the value of family participation in the care-planning process. PMID- 25017393 TI - Simultaneous quantification of purine and pyrimidine bases, nucleosides and their degradation products in bovine blood plasma by high performance liquid chromatography tandem mass spectrometry. AB - Improved nitrogen utilization in cattle is important in order to secure a sustainable cattle production. As purines and pyrimidines (PP) constitute an appreciable part of rumen nitrogen, an improved understanding of the absorption and intermediary metabolism of PP is essential. The present work describes the development and validation of a sensitive and specific method for simultaneous determination of 20 purines (adenine, guanine, guanosine, inosine, 2' deoxyguanosine, 2'-deoxyinosine, xanthine, hypoxanthine), pyrimidines (cytosine, thymine, uracil, cytidine, uridine, thymidine, 2'-deoxyuridine), and their degradation products (uric acid, allantoin, beta-alanine, beta-ureidopropionic acid, beta-aminoisobutyric acid) in blood plasma of dairy cows. The high performance liquid chromatography-based technique coupled to electrospray ionization tandem mass spectrometry (LC-MS/MS) was combined with individual matrix-matched calibration standards and stable isotopically labelled reference compounds. The quantitative analysis was preceded by a novel pre-treatment procedure consisting of ethanol precipitation, filtration, evaporation and reconstitution. Parameters for separation and detection during the LC-MS/MS analysis were investigated. It was confirmed that using a log-calibration model rather than a linear calibration model resulted in lower CV% and a lack of fit test demonstrated a satisfying linear regression. The method covers concentration ranges for each metabolite according to that in actual samples, e.g. guanine: 0.10-5.0 MUmol/L, and allantoin: 120-500 MUmol/L. The CV% for the chosen quantification ranges were below 25%. The method has good repeatability (CV%<=25%) and intermediate precision (CV%<=25%) and excellent recoveries (91 107%). All metabolites demonstrated good long-term stability and good stability within-runs (CV%<=10%). Different degrees of absolute matrix effects were observed in plasma, urine and milk. The determination of relative matrix effects revealed that the method was suitable for almost all examined PP metabolites in plasma drawn from an artery and the portal hepatic, hepatic and gastrosplenic veins and, with a few exceptions, also for other species such as chicken, pig, mink, human and rat. PMID- 25017394 TI - Hydrophilic interaction chromatography versus reversed phase liquid chromatography coupled to mass spectrometry: effect of electrospray ionization source geometry on sensitivity. AB - In this study, the influence of electrospray ionization (ESI) source design on the overall sensitivity achieved in hydrophilic interaction chromatography (HILIC) and reversed phase liquid chromatography (RPLC), was investigated. State of-the-art triple quadrupole mass analyzers from AB Sciex, Agilent Technologies and Waters equipped with brand specific source geometries were tested with various mobile phase pH on 53 pharmaceutical compounds. The design of the ESI source showed to strongly influence the gain in sensitivity that can be achieved in HILIC compared to RPLC mode. The 6460 Triple Quadrupole LC/MS system from Agilent Technologies was particularly affected by mobile phase settings. Indeed, compared to RPLC conditions, 92% of the compounds had an increased signal-to noise ratio at a flow rate of 300 MUL/min in HILIC mode at pH 6, while this percentage dropped to only 7% at 1000 MUL/min and pH 3. In contrast, the influence of flow rate and mobile phase pH on the gain in sensitivity between RPLC and HILIC was found very limited with the API 5000 LC/MS/MS system from AB Sciex, as only 15 to 36% of the tested compounds showed an enhanced sensitivity in HILIC mode. With the Xevo TQ-S instrument from Waters, superior sensitivity in HILIC was noticed for 85% of the compounds with optimal conditions (i.e., pH 3 and 1000 MUL/min), whereas at sub-optimal conditions (i.e. pH 6 and 300 MUL/min), it represented less than 50%. The gain in sensitivity observed in HILIC was found less significant with the recent LC-MS platforms used in this study than for old generation instruments. Indeed, the improved ESI sources equipping the recent mass analyzers allow for enhanced evaporation efficiency, mainly for RPLC mobile phases containing high proportion of water and this even at high flow rates. PMID- 25017395 TI - Separation of 25R/S-ergostane triterpenoids in the medicinal mushroom Antrodia camphorata using analytical supercritical-fluid chromatography. AB - Ergostanes are major bioactive constituents of the medicinal mushroom Antrodia camphorata. These tetracyclic triterpenoids usually occur as 25R/S epimeric pairs, which renders their chromatographic separation difficult. In this study, we used analytical supercritical-fluid chromatography (SFC) to separate seven pairs of 25R/S-ergostanes from A. camphorata. The (R)- and (S)-forms for each of the seven pairs could be well resolved (Rs>1.3) on a Chiralcel OJ-H column (4.6*250mm, 5MUm, chiral), eluted by 10% MeOH in CO2 at 2mL/min with a back pressure of 120bar and a column temperature of 40 degrees C. Particularly, this chiral-SFC method could rapidly and efficiently separate low-polarity epimers like antcin A and antcin B, which were very difficult for RP-HPLC. A 3-min preparative-scale method was established to purify (25S)- and (25R)-antcin A for the first time. However, OJ-H column suffered from peak overlapping of different pairs of ergostanes. We found that Princeton 2-ethylpyridine column (2-EP, 4.6*250mm, 3MUm, achiral) could effectively separate different pairs, although the resolutions for 25-R/S forms of each epimeric pair were not as good as OJ-H column. Meanwhile, all the (25S)-forms showed stronger retentions than the corresponding (25R)-epimers on the 2-EP column. These results demonstrated different selectivity of chiral- and achiral-SFC in separating 25R/S-ergostane epimers. Aside from high separation efficiency, SFC also showed advantage over HPLC in short analysis time and low consumption of organic solvents. Finally, both OJ-H and 2-EP columns were used on analytical SFC to separate 25R/S ergostanes in an extract of A. camphorata. PMID- 25017396 TI - Quantitative determination of 26 steroids in eggs from various species using liquid chromatography-triple quadrupole-mass spectrometry. AB - A method for analyzing 26 types of steroids in egg matrix was developed. The method used liquid chromatography coupled with tandem mass spectrometry (LC MS/MS) in electrospray ionization mode (ESI). The procedure involved extraction with acetonitrile and removal of phospholipids by zinc chloride (ZnCl2) followed by SPE cleanup with a Plexa cartridge. The effect of ZnCl2 on phospholipid removal was directly observed using the post column infusion procedure. The SPE washing and elution conditions were optimized using a shallow gradient procedure. The free and conjugated steroids forms were determined using enzyme hydrolysis. The developed method resulted in satisfactory precision (RSD<=15%), and the limits of quantification were between 0.05 and 25 ng/g depending on the steroid types. The recoveries ranged from 63.2% to 121.5%. Finally, the developed method was successfully applied to compare the steroids in eggs from different species (i.e., hen, duck, quail and pigeon eggs) or different raising system (i.e., normal vs. organic eggs). The steroids can be clearly clustered according to species and raising system. The hierarchical clustering analysis indicated similarity of the steroids among the species. The developed method is sensitive and useful for detection and quantification of steroids in eggs and can be used for residue control programs. In addition, the observed steroid content will provide a fundamental reference for food risk assessment analysis. PMID- 25017397 TI - A novel technique for determination of two dimensional signal-to-noise ratio improvement factor of an antiscatter grid in digital radiography. AB - PURPOSE: to present a new and simplified method for pixel-wise determination of the signal-to-noise ratio improvement factor KSNR of an antiscatter grid, when used with a digital imaging system. The method was based on approximations of published formulas. The simplified estimate of K(2)SNR may be used as a decision tool for whether or not to use an antiscatter grid. METHODS: the primary transmission of the grid Tp was determined with and without a phantom present using a pattern of beam stops. The Bucky factor B was measured with and without a phantom present. Hence K(2)SNR maps were created based on Tp and B. A formula was developed to calculate K(2)SNR from the measured Bs without using the measured Tp. The formula was applied on two exposures of anthropomorphic phantoms, adult legs and baby chest, and on two homogeneous poly[methyl methacrylate] (PMMA) phantoms, 5 cm and 10 cm thick. The results from anthropomorphic phantoms were compared to those based on the beam stop method. The results for the PMMA phantoms were compared to a study that used a contrast-detail phantom. RESULTS: 2D maps of K(2)SNR over the entire adult legs and baby chest phantoms were created. The maps indicate that it is advantageous to use the antiscatter grid for imaging of the adult legs. For baby chest imaging the antiscatter grid is not recommended if only the lung regions are of interest.The K(2)SNR maps based on the new method correspond to those from the beam stop method, and the K(2)SNR from the homogenous phantoms arising from two different approaches also agreed well with each other. CONCLUSION: a method to measure 2D K(2)SNR associated with grid use in digital radiography system was developed and validated. The proposed method requires four exposures and use of a simple formula. It is fast and provides adequate estimates for K(2)SNR. PMID- 25017398 TI - Clinical experience with a novel electromyographic approach to preventing phrenic nerve injury during cryoballoon ablation in atrial fibrillation. AB - BACKGROUND: Phrenic nerve palsy remains the most frequent complication associated with cryoballoon-based pulmonary vein (PV) isolation. We sought to characterize our experience using a novel monitoring technique for the prevention of phrenic nerve palsy. METHODS AND RESULTS: Two hundred consecutive cryoballoon-based PV isolation procedures between October 2010 and October 2013 were studied. In addition to standard abdominal palpation during right phrenic nerve pacing from the superior vena cava, all patients underwent diaphragmatic electromyographic monitoring using surface electrodes. Cryoablation was terminated on any perceived reduction in diaphragmatic motion or a 30% decrease in the compound motor action potential (CMAP). During right-sided ablation, a >=30% reduction in CMAP amplitude occurred in 49 patients (24.5%). Diaphragmatic motion decreased in 30 of 49 patients and was preceded by a 30% reduction in CMAP amplitude in all. In 82% of cases, this reduction in CMAP amplitude occurred during right superior PV isolation. The baseline CMAP amplitude was 946.5+/-609.2 mV and decreased by 13.8+/-13.8% at the end of application. This decrease was more marked in the 33 PVs with a reduction in diaphragmatic motion than in those without (40.9+/-15.3% versus 11.3+/-10.5%; P<0.001). In 3 cases, phrenic nerve palsy persisted beyond the end of the procedure, with all cases recovering within 6 months. Despite the shortened application all veins were isolated. At repeat procedure the right sided PVs reconnected less frequently than the left-sided PVs in those with phrenic nerve palsy. CONCLUSIONS: Electromyographic phrenic nerve monitoring using the surface CMAP is reliable, easy to perform, and offers an early warning to impending phrenic nerve injury. PMID- 25017400 TI - Mapping of focal atrial tachycardia with an uninterpretable activation map after extensive atrial ablation: tricks and tips. AB - BACKGROUND: Atrial tachycardias (ATs) after extensive ablation are increasingly common and challenging arrhythmias. The prolonged intra-atrial conduction time (IACT) during ATs in the milieu may complicate the mapping of focal ATs. In this present study, we aim to characterize the electrophysiological features of ATs in this unique setting and to delineate an effective mapping strategy further. METHODS AND RESULTS: In total, 13 patients (average age, 59+/-7 years) in a cohort of 80 patients referred for AT ablation were selected for the study. The patients all demonstrated an undistinguishable map not ready to be interpreted the 3-dimensional mapping. A total of 13 ATs were mapped with mean tachycardia cycle length of 296+/-70 ms. Two activation patterns were identified, which were referred to as pseudo-macroreentry and chaotic activation. The former was a focal AT originating from the vicinity of an area of conduction block with the IACT less than the window of interest duration (4 cases; IACT/window of interest ratio range, 0.93-0.98). The latter refers to a focal AT exhibiting a disorderly color mapping display with IACT exceeding the window of interest duration (9 cases; IACT/window of interest ratio range, 1.02-1.29). The IACT was determined after resetting the annotation. All ATs were successfully eliminated at the originating site. CONCLUSIONS: We delineated a series of focal ATs in the setting of a significantly prolonged IACT encountered in patients after previous extensive ablation. Two activation patterns were identified, which may help facilitate the mapping of focal ATs in this setting. PMID- 25017399 TI - Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. AB - BACKGROUND: Genome-wide association studies have revealed significant association of caveolin-1 (Cav1) gene variants with increased risk of cardiac arrhythmias. Nevertheless, the mechanism for this linkage is unclear. METHODS AND RESULTS: Using adult Cav1(-/-) mice, we revealed a marked reduction in the left ventricular conduction velocity in the absence of myocardial Cav1, which is accompanied with increased inducibility of ventricular arrhythmias. Further studies demonstrated that loss of Cav1 leads to the activation of cSrc tyrosine kinase, resulting in the downregulation of connexin 43 and subsequent electric abnormalities. Pharmacological inhibition of cSrc mitigates connexin 43 downregulation, slowed conduction, and arrhythmia inducibility in Cav1(-/-) animals. Using a transgenic mouse model with cardiac-specific overexpression of angiotensin-converting enzyme (ACE8/8), we demonstrated that, on enhanced cardiac renin-angiotensin system activity, Cav1 dissociated from cSrc because of increased Cav1 S-nitrosation at Cys(156), leading to cSrc activation, connexin 43 reduction, impaired gap junction function, and subsequent increase in the propensity for ventricular arrhythmias and sudden cardiac death. Renin angiotensin system-induced Cav1 S-nitrosation was associated with increased Cav1 endothelial nitric oxide synthase binding in response to increased mitochondrial reactive oxidative species generation. CONCLUSIONS: The present studies reveal the critical role of Cav1 in modulating cSrc activation, gap junction remodeling, and ventricular arrhythmias. These data provide a mechanistic explanation for the observed genetic link between Cav1 and cardiac arrhythmias in humans and suggest that targeted regulation of Cav1 may reduce arrhythmic risk in cardiac diseases associated with renin-angiotensin system activation. PMID- 25017401 TI - Respiratory precautions for MERS-CoV: acceptable risk-benefit determination. PMID- 25017402 TI - Debate on MERS-CoV respiratory precautions: surgical mask or N95 respirators? AB - Since the emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in mid-2012, there has been controversy over the respiratory precaution recommendations in different guidelines from various international bodies. Our understanding of MERS-CoV is still evolving. Current recommendations on infection control practices are heavily influenced by the lessons learnt from severe acute respiratory syndrome. A debate on respiratory precautions for MERS-CoV was organised by Infection Control Association (Singapore) and the Society of Infectious Disease (Singapore). We herein discuss and present the evidence for surgical masks for the protection of healthcare workers from MERS-CoV. PMID- 25017403 TI - Application of legal principles and medical ethics: multifetal pregnancy and fetal reduction. AB - In the management of complex medical cases such as a multifetal pregnancy, knowledge of the ethical and legal implications is important, alongside having competent medical skills. This article reviews these principles and applies them to scenarios of multifetal pregnancy and fetal reduction. Such a discussion is not solely theoretical, but is also relevant to clinical practice. The importance of topics such as bioethical principles and informed consent are also herein addressed. PMID- 25017404 TI - Coarctation of the aorta: nonsurgical treatment using stent implantation. AB - INTRODUCTION: Coarctation of the aorta (CoA) accounts for 5%-8% of all congenital heart defects. If left untreated, most patients with significant CoA will have varying degrees of morbidity (e.g. hypertension, stroke, collateral formation and ventricular hypertrophy), possibly even mortality. Traditionally, treatment for this condition is surgical. Herein, we report stenting during catheterisation as an alternative nonsurgical treatment option for patients with CoA, and present the treatment outcomes of patients who underwent this treatment option. METHODS: We retrospectively reviewed four patients (2 men and 2 women; age range 20-41 years) who underwent CoA stenting under general anaesthesia for the treatment of native CoA or restenosis of CoA at our institution. Three patients had a 40-mm Palmaz stent inserted, while one had a 39-mm Cheatham-Platinum covered stent inserted. Angiography and measurement of pressure gradients were performed before and after stent implantation to ensure good treatment outcomes. RESULTS: The patients' treatment outcomes were good, with a significant reduction in pressure gradients across the narrowed segments. Angiography showed relief of CoA. The patients were followed up for 1-3 years, during which no complications were noted. CONCLUSION: This is the first reported series in Singapore on the nonsurgical treatment of CoAs in adult patients using stents during interventional cardiac catheterisation. This less invasive procedure may lead to a new paradigm shift with regard to the treatment of CoA. PMID- 25017405 TI - Female ageing and reproductive outcome in assisted reproduction cycles. AB - INTRODUCTION: Fertility in women declines with increasing age. With the deferment of marriage and childbearing, couples are turning to assisted reproductive technology to counteract this decline. We aimed to evaluate the results of in vitrofertilisation (IVF)/intracytoplasmic sperm injection (ICSI) in women of different age groups, and highlight the cost-effectiveness of IVF treatment in these groups while assessing its implications on the national healthcare provision model. METHODS: Retrospective analysis of 3,412 stimulated IVF/ICSI cycles in a hospital-based IVF centre was performed from January 2008 to December 2010. Patients were stratified into seven age groups: < 30 years; 30-35 years; 36 37 years; 38 years; 39 years; 40-44 years; and >= 45 years. RESULTS: Age had a significant effect on the number of cycles leading to embryo transfer (p < 0.001). The number of oocytes retrieved decreased across the various age groups (p < 0.001) and was the highest among women aged < 30 (mean 18.5 +/- 10.3) years. With increasing age, there was a trend toward a lower fertilisation rate. Age also had a significant effect on the rates of clinical pregnancy, live birth and multiple pregnancies (p < 0.001). CONCLUSION: Patients aged < 30 years had the best IVF outcomes, reflecting optimal reproductive capacity. Age-related decline in fertility starts after 30 years. Women opting for IVF should be counselled about age-specific success rates while taking into account individual risk factors. PMID- 25017406 TI - Reappraisal of twinning: epidemiology and outcome in the early neonatal period. AB - INTRODUCTION: The present study aimed to determine the epidemiology, maternal complications and adverse neonatal outcomes associated with twin births at a tertiary care hospital in India. METHODS: A prospective observational study was conducted on all successively born twin pairs (>= 23 weeks of gestation) and their mothers from January to September 2005. Main outcome measures included maternal medical/obstetric complications, labour characteristics and the morbidities/mortality observed during the early neonatal period. RESULTS: The twinning rate was 1 in 54 deliveries. Around 10% of mothers had a predisposition for twinning in the form of familial tendency or consumption of clomiphene. Anaemia (85%) was the most common maternal complication, followed by gestational hypertension (17%). Nearly one-third of births were delivered via Caesarean section. Prematurity (61%) was the most common neonatal complication followed by early-onset neonatal sepsis (21%). The risk of early neonatal death was 27%. Shorter gestation and low birth weight were significantly associated with adverse neonatal outcome (p < 0.05). Factors such as chorionicity, mode of delivery, birth order, inter-twin delivery time interval, gender and intra-pair birth weight discordance did not affect neonatal morbidity or mortality (p >= 0.05). CONCLUSION: The rates of maternal complications and early neonatal morbidities/mortality were quite high in twin gestations. Except for the prematurity and low birth weight, none of the other factors, including inter-twin delivery time interval of more than 15 mins, were found to affect neonatal outcome. PMID- 25017408 TI - Pocket-sized versus standard ultrasound machines in abdominal imaging. AB - The pocket-sized ultrasound machine has emerged as an invaluable tool for quick assessment in emergency and general practice settings. It is suitable for instant and quick assessment in cardiac imaging. However, its applicability in the imaging of other body parts has yet to be established. In this pictorial review, we compared the performance of the pocketsized ultrasound machine against the standard ultrasound machine for its image quality in common abdominal pathology. PMID- 25017407 TI - I-ROAD could be efficient in predicting severity of community-acquired pneumonia or healthcare-associated pneumonia. AB - INTRODUCTION: The ability to predict the prognosis of patients with pneumonia is critical, especially when making decisions regarding treatment regimens and sites of care. However, prognostic guidelines for healthcare-associated pneumonia (HCAP) have yet to be established. I-ROAD is the prognostic guideline of the Japanese Respiratory Society for hospital-acquired pneumonia (HAP). This study compared available prognostic guidelines to determine the usefulness of I-ROAD as a prognostic tool for patients with HCAP. METHODS: We conducted a retrospective review of all patients with pneumonia admitted to Kameda Medical Center, Japan, from January 2006 to September 2009. Patients were categorised into two groups, namely those with community acquired pneumonia (CAP) and those with HCAP. We compared the baseline characteristics, laboratory findings, identified pathogens, antibiotic regimens, clinical outcomes, pneumonic severity and prognostic accuracy of each guideline between the two patient groups. The severity of each disease was assessed on admission using the A-DROP, CURB-65, PSI and I-ROAD guidelines. RESULTS: Of the 302 patients evaluated, 228 (75.5%) were diagnosed with CAP and 74 (24.5%) with HCAP. Patients with HCAP were older and had a higher performance status than patients with CAP. The mortality rate in the CAP group tended to rise with increasing severity scores of prognostic guidelines. Although the severity scores of all prognostic guidelines could predict 30-day mortality in patients with CAP, I-ROAD exhibited a higher discriminatory power for patients with HCAP based on analysis of receiver-operating characteristic curves. CONCLUSION: I-ROAD could be more accurate than other prognostic guidelines for evaluating the severity of HCAP. PMID- 25017409 TI - Ministry of Health Clinical Practice Guidelines: Diabetes Mellitus. AB - The Ministry of Health (MOH) have updated the clinical practice guidelines on Diabetes Mellitus to provide doctors and patients in Singapore with evidence based treatment for diabetes mellitus. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Diabetes Mellitus, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guideline /cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines. PMID- 25017410 TI - Tubular duplication of the oesophagus presenting with dysphagia. AB - Duplications of the alimentary tract are rare congenital malformations, with the ileum being the most commonly affected site, followed by the oesophagus. Among oesophageal duplications, cystic duplication is the most common and the tubular variety, the rarest. Herein, we report a rare case of tubular oesophageal duplication, complicated by adenosquamous carcinoma at the lower end of the oesophagus, in a 32-year-old man who presented with progressive dysphagia. Although proton pump inhibitors may relieve dysphagia, oesophagectomy and gastric interpositioning should be the first-line treatment for patients with tubular oesophageal duplication, in order to reduce the risk of malignant transformation at the lower end of the oesophagus. PMID- 25017412 TI - Improvement of aerosol optical properties modeling over Eastern Asia with MODIS AOD assimilation in a global non-hydrostatic icosahedral aerosol transport model. AB - A new global aerosol assimilation system adopting a more complex icosahedral grid configuration is developed. Sensitivity tests for the assimilation system are performed utilizing satellite retrieved aerosol optical depth (AOD) from the Moderate Resolution Imaging Spectroradiometer (MODIS), and the results over Eastern Asia are analyzed. The assimilated results are validated through independent Aerosol Robotic Network (AERONET) observations. Our results reveal that the ensemble and local patch sizes have little effect on the assimilation performance, whereas the ensemble perturbation method has the largest effect. Assimilation leads to significantly positive effect on the simulated AOD field, improving agreement with all of the 12 AERONET sites over the Eastern Asia based on both the correlation coefficient and the root mean square difference (assimilation efficiency). Meanwhile, better agreement of the Angstrom Exponent (AE) field is achieved for 8 of the 12 sites due to the assimilation of AOD only. PMID- 25017411 TI - Precocious cervical ripening as a screening target to predict spontaneous preterm delivery among asymptomatic singleton pregnancies: a systematic review. AB - Routine second-trimester transvaginal ultrasonographic (TVU) screening for short cervical length (CL) predicts spontaneous preterm delivery (SPTD), albeit with limited sensitivity (35-40%) and a moderate positive likelihood ratio of 4-6. However, CL describes one of the multidimensional changes that are associated with precocious cervical ripening (PCCR) and that also include cervical softening, cervical funneling (CF), and dilation. PCCR, a precursor and a strong predictor for SPTD, was proposed as a potential screening target. We hypothesized that screening for composite measures of PCCR (eg, CL, CF, cervical consistency, and dilation) with the use of either digital examination or TVU would improve the prediction of SPTD compared with screening for short CL alone. We searched PubMed and EMBASE electronic databases for observational cohort studies to evaluate cervical screening in asymptomatic obstetric populations. Multidimensional composite cervical measures were assessed in 10 datasets (n = 22,050 pregnancies) and 12 publications. Appreciable heterogeneity in cervical measurements, data quality, and outcomes across studies prevented quantitative metaanalysis. Only one study reported intra- and interobserver reliability of cervical measurements. The prevalence of CF ranged from 0.7-9.1%. Five studies compared composite measures of PCCR (ie, CL and CF) with short CL alone and consistently reported improved screening performance. Among 3 TVU studies, gains in sensitivity ranged from 5-27%, and increases in positive likelihood ratio ranged from 3-16. Our findings suggest that composite measures of PCCR might serve as valuable screening targets. High-quality interdisciplinary studies that integrate epidemiologic approaches are needed to test this hypothesis and to accelerate the translation of advances in cervical pathophysiology into effective preventive interventions. PMID- 25017413 TI - EGFR CA repeat polymorphism predict clinical outcome in EGFR mutation positive NSCLC patients treated with erlotinib. AB - OBJECTIVES: Somatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). A CA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. This study evaluates the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib. MATERIALS AND METHODS: Number of CA repeats in the EGFR gene was evaluated with PCR-fragment length analysis by capillary electrophoresis in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA<=16 in any allele) or long alleles (CA>16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. RESULTS: In EGFR mutation positive patients (N=62) we demonstrate a significantly higher median progression free survival (HR=0.39 (0.22-0.70); p=0.002) and overall survival (HR=0.43 (0.23-0.78); p=0.006) in patients also harboring a short CA repeat length vs. a long (median follow-up time of 52.2 months). The result remained highly significant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. CONCLUSION: Our study demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for both longer progression free survival and overall survival. PMID- 25017414 TI - Long-term outcomes of boston type 1 keratoprosthesis implantation: a retrospective multicenter cohort. AB - PURPOSE: To study the long-term outcomes of Boston type 1 keratoprosthesis (KPro) surgery. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: A total of 158 eyes of 150 patients underwent KPro implantation at 5 participating tertiary centers in the United States between January 2003 and December 2006. Of those, 139 eyes of 133 patients were included in the analyses. METHODS: The medical records of consecutive adult patients who received KPro surgery were reviewed. All patients with at least 1 postoperative visit were retained in the outcomes analyses. In eyes in which a repeat KPro procedure was performed, only the outcomes of the initial surgery were analyzed. MAIN OUTCOME MEASURES: Visual acuity (VA) outcomes, postoperative complications, and device retention. RESULTS: The mean follow-up was 46.7 +/- 26 months with all but 4 eyes having at least 6 months of follow-up. Preoperatively, only 10.8% of the eyes had VA of >= 20/200. Postoperatively, the VA in 70% of eyes improved to >= 20/200. The probability of maintaining VA of >= 20/200 at 7 years was 50%. The device retention rate was estimated at 67% at 7 years. The 7-year cumulative incidence of complications was 49.7% for retroprosthetic membrane formation, 21.6% for glaucoma surgery, 18.6% for retinal detachment, and 15.5% for endophthalmitis. CONCLUSIONS: Although the risk for complications with longer follow-up seemed to increase, this large multicenter cohort demonstrates favorable outcomes with KPro, with a large number of patients achieving and retaining useful vision over a 7-year period. PMID- 25017416 TI - Absence of amiodarone-associated optic neuropathy. PMID- 25017417 TI - Protein-precipitable tannin in wines from Vitis vinifera and interspecific hybrid grapes (Vitis ssp.): differences in concentration, extractability, and cell wall binding. AB - Although they possess significant viticultural advantages, interspecific hybrid grapes (Vitis spp.) are reported to produce wine with lower tannin concentrations than European wine varieties (Vitis vinifera). However, extensive quantitative data on this phenomenon as well as mechanistic explanations for these differences are lacking. A survey of primarily commercial wines from the Finger Lakes American Viticultural Area (New York) using a protein precipitation method determined that hybrid-based wines had >4-fold lower tannin concentrations than vinifera wines. To elucidate factors responsible for differences in wine tannin, 24 wines were produced from both red hybrid and vinifera cultivars under identical conditions. Lower wine tannin in French-American hybrid- than vinifera based wines could be partially explained by lower grape tannin. However, experiments in which cell wall material was incubated with tannin indicated that cell wall binding may be of equal or greater importance in explaining lower wine tannin concentrations in hybrid-based wines. Subsequent characterization of cell wall material revealed that protein in flesh cell walls and, to a lesser extent, pectin in skin cell walls were correlated with cell wall binding. PMID- 25017415 TI - Periocular corticosteroid injections in uveitis: effects and complications. AB - PURPOSE: To evaluate the benefits and complications of periocular depot corticosteroid injections in patients with ocular inflammatory disorders. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: A total of 914 patients (1192 eyes) who had received >= 1 periocular corticosteroid injection at 5 tertiary uveitis clinics in the United States. METHODS: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained at every visit via medical record review by trained reviewers. MAIN OUTCOME MEASURES: Control of inflammation, improvement of visual acuity (VA) to >= 20/40, improvement of VA loss attributed to macular edema (ME), incident cataract affecting VA, cataract surgery, ocular hypertension, and glaucoma surgery. RESULTS: Among 914 patients (1192 eyes) who received >= 1 periocular injection during follow-up, 286 (31.3%) were classified as having anterior uveitis, 303 (33.3%) as intermediate uveitis, and 324 (35.4%) as posterior or panuveitis. Cumulatively by <= 6 months, 72.7% (95% CI, 69.1-76.3) of the eyes achieved complete control of inflammation and 49.7% (95% CI, 45.5-54.1) showed an improvement in VA from <20/40 to >= 20/40. Among the subset with VA <20/40 attributed to ME, 33.1% (95% CI, 25.2-42.7) improved to >= 20/40. By 12 months, the cumulative incidence of >= 1 visits with an intraocular pressure of >= 24 mmHg and >= 30 mmHg was 34.0% (95% CI, 24.8 45.4) and 15.0% (95% CI, 11.8-19.1) respectively; glaucoma surgery was performed in 2.4% of eyes (95% CI, 1.4-3.9). Within 12 months, among phakic eyes initially >= 20/40, the incidence of a reduction in VA to <20/40 attributed to cataract was 20.2% (95% CI, 15.9-25.6); cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes (95% CI, 11.1-17.2). CONCLUSIONS: Periocular injections were effective in treating active intraocular inflammation and in improving reduced VA attributed to ME in a majority of patients. The response pattern was similar across anatomic locations of uveitis. Overall, VA improved in one half of the patients at some point within 6 months. However, cataract and ocular hypertension occurred in a substantial minority. PMID- 25017419 TI - Synthesis of 3,3-disubstituted-2,3-dihydroazanaphthoquinones via simultaneous alkyne oxidation and nitrile hydration of ortho-alkynylarenenitriles. AB - o-Alkynylarenenitriles when heated with Pd(OAc)2/H2O/(+/-)-CSA in DMSO undergo simultaneous alkyne oxidation and nitrile hydration to give 3-aryl-3-hydroxy-2,3 dihydroazanaphthoquinones. Upon treatment with (+/-)-CSA, these compounds form 3 arylazanaphthoquinones in situ, which add to electron-rich aromatics and terminal alkene/alkyne to afford 3,3-disubstituted-2,3-dihydroazanaphthoquinones. PMID- 25017418 TI - ALK expression is absent in pancreatic ductal adenocarcinoma. AB - PURPOSE: It has not yet been clearly defined whether anaplastic lymphoma kinase (ALK) expression can be detected in pancreatic ductal adenocarcinoma (PDAC). METHODS: Within a retrospective study, archival PDAC surgical specimens were screened for ALK expression in tumor and normal tissue by immunohistochemistry (IHC) with the use of a specific ALK detection kit on a tissue microarray (TMA). RESULTS: PDAC tumor tissue was available from 99 resected cases: fifty-eight out of 99 patients (59 %) had nodal-positive disease, and 80 patients (81 %) had pT3 tumors. Forty-nine patients underwent R0 resection, and in 48 cases, resection status was classified R1. Regarding ALK expression, five cases showed faint immunoreactivity on TMA, which was negative on whole mount sections. All other 94 cases showed no ALK expression. CONCLUSION: In 99 PDAC cases, no ALK expression was detected by IHC; ALK thus may not serve as a relevant drug target in PDAC. PMID- 25017420 TI - Treatment with essential oil of Achyrocline satureioides in rats infected with Trypanosoma evansi: relationship between protective effect and tissue damage. AB - The aim of this study was to evaluate the effects of treatment with free and nanoencapsulated essential oil of Achyrocline satureioides on trypanosomosis and its oxidative/antioxidants variables in liver and kidney of rats infected experimentally with Trypanosoma evansi. For that, 48 rats were divided into six groups (A-F), eight animals each group. Groups A, C and D were composed of uninfected animals, while animals in groups B, E and F were inoculated intraperitoneally with T. evansi. Groups A and B were used as controls, negative and positive, respectively. Groups C and E receive oil (orally), as well as the animals in groups D and F were treated with nanoencapsulated essential oil. The treatment was not able to eliminate the parasites, but it remained the levels of parasitemia low. The carbonyl levels in liver and kidney did not differ between groups. Infected animals (group B) showed an increase in the TBARS levels and a decrease in the CAT activity and NPSH levels in liver and kidney, compared with the same parameters in the control (group A). Treatment with A. satureioides (groups C and D) did not influence the TBARS levels and CAT activity in the liver, but it increased the CAT activity in kidneys of the animals of group C. NPSH levels decreased in liver in the groups treated with nanoencapsulated essential oil (groups D and F). An interesting result observed was that the animals infected and then treated with essential oil of A. satureioides (groups E and F) did not differ from animals of group A for TBARS, CAT and NPSH, unlike what happened with the animals of group B. Therefore, the treatment with essential oil did not eliminate the parasites from the bloodstream, but it reduced the number of trypanosomes, mainly by its nanoencapsulated form. The same occurred with the lipid peroxidation in the liver. However, the treatments reduced the oxidative damage, and it led to the activation of the antioxidant enzymes. We believe that the association of this natural product with a trypanocidal drug may enhance its curative effect. PMID- 25017421 TI - Evaluation of non-polynomial equations for one-compartment correction of slope intercept GFR: theoretical prediction and experimental measurement. AB - BACKGROUND: Polynomial equations for one-compartment correction of slope intercept glomerular filtration rate (GFR) will underestimate values at high clearance rates. Non-polynomial correction equations that are independent of patient size and renal function would be advantageous and may have cross-species use. MATERIALS AND METHODS: The study explored the theoretical basis of firstly the Jodal and Brochner-Mortensen one-compartment correction equation, replacing plasma volume with extracellular fluid volume, and secondly an equation described by Peters. One-compartment correction factors (a which is related to plasma volume and v which is related to extracellular fluid volume) which avoided the need for scaling to body size were developed. Both factors were determined from the biexponential clearance curve of the markers iohexol and (51)Cr-EDTA in humans and iohexol in cats and dogs. Relationships between a and v and filtration function and body size were then determined using data from humans, cats and dogs to assess their validity and compare this with theoretical predictions. RESULTS: In all species, v was higher than a, as theoretically predicted. Both were significantly higher in humans than cats and dogs, ruling out cross-species use. Significant relationships were present between v and measures of filtration function in humans, but were weak with respect to a. Neither a nor v showed significant relationships with filtration function in animals or with body size in any species. CONCLUSIONS: a and v (which are factors independent of body size) can be used interchangeably for correcting slope-intercept clearance. However values of both for humans are higher compared to cats and dogs. Therefore a single cross-species factor cannot be used. PMID- 25017422 TI - Need for a standardized protocol for stress echocardiography in provoking subaortic and valvular gradient in various cardiac conditions. AB - (Semi) supine exercise testing has an established role in the evaluation of patients with valvular heart disease and can help clinical decision making. Stress echocardiography has the advantages of its wide availability, low cost, and versatility for the assessment of disease severity. However, exercise-induced changes in valve hemodynamics, left ventricular outflow obstruction and pulmonary artery pressure depended on load variation. Changing position from supine to upright rapidly decreases load conditions for the ventricles. Therefore several cardiac centers have proposed exercise stress echocardiography in the upright position with gradient monitoring sometimes also in post-exercise recovery. Doppler measurement of subaortic gradient has been a very helpful and informative examination in several heart diseases (especially in hypertrophic cardiomyopathy, valve heart diseases, prosthesis dysfunction). PMID- 25017423 TI - Expression of miR-224-5p is associated with the original cisplatin resistance of ovarian papillary serous carcinoma. AB - Chemoresistance is a major challenge to successful chemotherapy of ovarian cancer, which represents the leading cause of mortality from gynecologic malignancies. We demonstrated that overexpression of miR-224-5p in ovarian cancer patients is associated with platinum-based chemoresistance using miRNA microarray analysis and quantitative real-time polymerase chain reaction (qRT-PCR) validation in vivo, as well as in 4 human ovarian cancer cell lines (C13/OV2008; A2780CP/A2780S) in vitro. In the present study, we aimed to clarify the role of miR-224-5p in regulating the chemoresistance of ovarian cancer. By using the sensitive miRNA transient transfection, we demonstrated expression and bioactivity of miR-224-5p in ovarian cancer cell lines. It is of note that enforced expression of miR-224-5p enhanced chemoresistance to cisplatin in ovarian cancer cells through apoptosis reversion. We predicted and identified the PRKCD gene as one of the targets of miR-224-5p in mediating the primary chemoresistance of ovarian cancer patients. We showed reciprocal expression of miR-224-5p and PRKCD by quantitative analysis in complete response and incomplete response patients in vivo, and 2 pairs of cisplatin resistance and sensitive cell lines in vitro, after either miR-224-5p overexpression or knockdown transfection. Additionally, miR-224-5p and PRKCD can serve as novel predictors and prognostic biomarkers for ovarian papillary serous carcinoma (OPSC) patient response to overall disease-specific survival. Our findings suggest that miR-224-5p may function as an oncogene and induce platinum resistance in OPSC at least in part by downregulating PRKCD, thereby providing a biomarker for predicting chemosensitivity to cisplatin in patients with ovarian cancer. PMID- 25017424 TI - A survey of the attitudes of practitioners toward teleaudiology. AB - Abstract Objective: To survey hearing healthcare practitioners' (1) attitudes toward teleaudiology appointments, (2) willingness to conduct different clinical tasks via teleaudiology, and (3) willingness to conduct a teleaudiology appointment with different patient populations. DESIGN: All participants were asked to complete the Attitudes toward Teleaudiology Scale for Practitioners (ATS P), a 46-item online survey designed for this study. STUDY SAMPLE: The responses from 202 hearing healthcare practitioners working in Canada were collected. The sample consisted of 152 audiologists, 49 hearing instrument specialists, and one who did not specify a category. RESULTS: The majority of respondents indicated that teleaudiology is likely to have a minimal effect on the quality of hearing healthcare in audiology and the quality of client-practitioner interactions, although many respondents indicated that teleaudiology would have a positive effect on accessibility to service. Nevertheless, a small minority of respondents indicated that teleaudiology would have a negative impact on quality of care in audiology. CONCLUSIONS: Willingness to use teleaudiology depended on a combination of the clinical tasks to be performed and the patient populations to be served. These findings can help guide the successful implementation of teleaudiology services. PMID- 25017425 TI - Pre-exposure prophylaxis accessibility research and evaluation (PrEPARE Study). AB - Tenofovir-emtricitabine (TDF-FTC) has demonstrated effectiveness as HIV preexposure prophylaxis (PrEP), but it is not commonly prescribed. Our study was designed to determine the barriers preventing utilization of PrEP among men who have sex with men (MSM), the group at greatest risk for HIV infection in the United States. A population-based sample of MSM presenting for HIV testing at 'Early Test' HIV testing and counseling sites in San Diego, California were offered PrEP and education about potential efficacy. Eligible individuals reported having unprotected sex within the past 12 months and who tested negative for HIV were offered study participation. Despite offering procedures for evaluation and prescription for PrEP to 416 eligible subjects, less than 0.5 % of participants received the drug. Surveys collected from 54 of those who declined study participation revealed multiple barriers to PrEP among MSM including cost, low perceived risk of infection and concerns about taking a daily medication and potential long-term side effects. Efforts should be made to address these barriers, especially lowering the cost of TDF-FTC, education about PrEP side effects and awareness of HIV risks. PMID- 25017427 TI - Multidentate ionic surfactant mediated extraction and dispersion of gold nanoparticles in organic solvents. AB - Resorcinarenes with three different quaternary ammonium headgroups were synthesized and evaluated for their ability to stabilize gold nanoparticles in organic and aqueous medium. Aqueous dispersions of citrate stabilized gold nanoparticles of dimensions up to 29 nm could be extracted into organic solvents by resorcinarenes functionalized with tetrapyridinium tetrabromide (1), tetratrimethylammonium tetrabromide (2), and tetratributylammonium tetrabromide (3). Such nanoparticles were characterized by TEM, EDS, UV-vis, and IR. Their long-term dispersion stability varied significantly and depended on the nature of the resorcinarene headgroup, and in particular nanoparticles extracted by resorcinarene 1 were stable for several weeks. Nanoparticles passivated by resorcinarenes 1 and 2 were also stable in the presence of thiourea for several hours in both aqueous and organic medium. This is notable as thiourea is known to result in the instantaneous aggregation of citrate stabilized nanoparticles. Remarkably nanoparticles stabilized by resorcinarenes 1 and 2 could be precipitated and redispersed in chloroform without any visible aggregation. The critical parameters controlling the extraction of the nanoparticles into the organic phase have also been evaluated. The resorcinarene surfactant mediated facile phase transfer of gold nanoparticles described here can be readily applied for the stabilization of other citrate stabilized mono- and bimetallic nanoparticles, thus providing opportunities to disperse and stabilize relatively larger nanoparticles in organic solvents using ionic surfactants opening up new applications. PMID- 25017426 TI - Estrogen protects cardiomyocytes against lipopolysaccharide by inhibiting autophagy. AB - Autophagy has a significant role in myocardial injury induced by lipopolysaccharide (LPS). Estrogen (E2) has been demonstrated to protect cardiomyocytes against apoptosis; however, it remains to be determined whether it exhibits anti-autophagic effects. The aim of the present study was to investigate whether estrogen-regulated autophagy attenuates cardiomyocyte injury induced by LPS. The cardiomyocytes of neonatal rats were randomized to the control (Con), LPS and estrogen + LPS groups. The LPS group was treated with 1 ug LPS for 24 h and the estrogen + LPS group was treated with 10-8 M estrogen 30 min prior to treatment with LPS. Cardiomyocyte autophagy was quantitated by investigating the mRNA and protein level of autophagy-related genes (Atgs). The mRNA expression of Atg5 and Beclin1 were measured by quantitative polymerase chain reaction and the microtubule-associated protein light chain 3 (LC3) protein expression was measured by western blot analysis. To demonstrate the cardiomyocyte protection of estrogen, cell vitality and serum lactate dehydrogenase (LDH) levels were measured following LPS treatment. It was identified that LPS induced cardiomyocyte injury, together with the upregulation of Atg5, Beclin1 mRNA and LC3-II protein. Furthermore, estrogen attenuated the effect of LPS. The present study provides evidence that estrogen has a myocardial protective role against injury induced by LPS by regulating autophagy. PMID- 25017428 TI - Reduced automatic frontal response to auditory deviance in Huntington's disease as indexed by magnetic mismatch negativity. AB - Huntington's disease (HD) is a neurodegenerative disorder accompanied by a degradation of dopaminergic receptors. It is evident that dopaminergic dysfunction leads to attention deterioration. However, little is known about the functional integrity of involuntary attention processing in patients with HD. The present study aimed to investigate whether patients with HD exhibit a deficit in automatic deviance detection that can be indexed by magnetic mismatch responses. Magnetoencephalographic responses during a passive oddball task were recorded to examine automatic neural activation to auditory deviants in patients with symptomatic HD and age and sex-matched healthy volunteers. The mean amplitude and peak latency of magnetic mismatch responses were calculated from the waveforms in each hemisphere. Furthermore, minimum current estimate (MCE) was applied to estimate the source strength of temporal and frontal mismatch responses. Compared with healthy participants, patients with HD exhibited a decreased waveform amplitude and a prolonged peak latency of magnetic mismatch responses in the left temporal lobe. The MCE analysis also revealed significantly lower activation of the bilateral frontal mismatch responses in patients. In conclusion, the frontal underactivation to occasional auditory deviance suggests a deficit of involuntary attention switching in HD. PMID- 25017429 TI - Use of external fixators for damage-control orthopaedics in natural disasters like the 2005 Pakistan earthquake. AB - PURPOSE: In the 2005 Pakistan earthquake, the great many injured with multiple fractures and open wounds provided a unique opportunity to practice damage control orthopaedics. External fixators remain a time-tested tools for operating surgeons on such occasions. The locally manufactured, readily available Naseer Awais (NA) external fixator filled such needs of this disaster with good outcome. METHODS: This is a retrospective descriptive study of 19,700 patients that presented over seven months to the two centres established by the lead author (SMA) in Muzaffarabad and Mansehra just one night after the 2005 earthquake. A series of local and foreign orthopaedic surgeon teams operated in succession. The computerised patient data collection of 1,145 operations was retrospectively analysed. RESULTS: Of the 19,700 patients presenting to the SMA centres, 50% had limb injuries. Total fracture fixations were 1,145, of which 295 were external fixations: 185 were applied on the lower limb and 90 on upper limb, the majority were applied on tibia. CONCLUSION: External fixators are valuable damage-control tools in natural disasters and warfare injuries. The locally manufactured NA external fixator served the needs of the many limb injuries during the 2005 Pakistan earthquake. PMID- 25017430 TI - Baroreflex activation therapy for patients with drug-resistant hypertension. AB - Uncontrolled or resistant hypertension is still a major problem facing many physicians daily in the clinic. Several new therapies are being developed to help those patients whose blood pressure does not respond sufficiently to regular antihypertensive medication. One of these promising therapies is electrical activation of the carotid sinus baroreflex. In this overview, the authors predominantly summarize the background, efficacy and safety of this promising treatment with its latest achievements in patients with resistant hypertension. The authors also discuss certain issues that need further clarification before this therapy can be added to the common treatment guidelines of hypertension. PMID- 25017431 TI - Probucol plus cilostazol attenuate hypercholesterolemia-induced exacerbation in ischemic brain injury via anti-inflammatory effects. AB - Probucol, a lipid-lowering agent with anti-oxidant properties, is involved in protection against atherosclerosis, while cilostazol, an antiplatelet agent, has diverse neuroprotective properties. In this study, we investigated the anti inflammatory effects of probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high fat diet (HFD) with or without 0.3% probucol and/or 0.2% cilostazol for 10 weeks. To assess the protective effects of the combined therapy of probucol and cilostazol on ischemic injury, the mice received 40 min of middle cerebral artery occlusion (MCAO). Infarct volumes, neurobehavioral deficits and neuroinflammatory mediators were subsequently evaluated 48 h after reperfusion. Probucol alone and probucol plus cilostazol significantly decreased total- and low-density lipoprotein (LDL)-cholesterol in ApoE KO with HFD. MCAO resulted in significantly larger infarct volumes in ApoE KO mice provided with HFD compared to those fed a regular diet, although these volumes were significantly reduced in the probucol plus cilostazol group. Consistent with a smaller infarct size, probucol alone and the combined treatment of probucol and cilostazol improved neurological and motor function. In addition, probucol alone and probucol plus cilostazol decreased MCP 1 expression and CD11b and GFAP immuno-reactivity in the ischemic cortex. These findings suggested that the inhibitory effects of probucol plus cilostazol in MCP 1 expression in the ischemic brain with hypercholesterolemia allowed the identification of one of the mechanisms responsible for anti-inflammatory action. Probucol plus cilostazol may therefore serve as a therapeutic strategy for reducing the impact of stroke in hypercholesterolemic subjects. PMID- 25017432 TI - The structure and energetics of arsenic(III) oxide intercalated by ionic azides. AB - Unprecedented intercalates of arsenic(iii) oxide with potassium azide and ammonium azide have been obtained and characterized by single crystal X-ray diffraction. The compounds are built of As2O3 sheets separated by charged layers of cations and azide anions perpendicular to the sheets. The intercalates are an interesting example of hybrid materials whose structure is governed by covalent bonds in two directions and ionic bond in the third one. The obtained compounds are the first examples of As2O3 intercalates containing linear pseudohalogen anions. Periodic DFT calculations of interlayer interaction energies were carried out with the B3LYP-D* functional. The layers are held together mainly by ionic bonds, although the computations indicate that interactions between cations and As2O3 sheets also play a significant role. A comparison of cation and anion interaction energies with neutral As2O3 sheets sheds light on the crystallisation process, indicating the templating effect of potassium and ammonium cations. It consist in the formation of sandwich complexes of cations with crown-ether resembling As6O12 rings. Raman spectra of both compounds are recorded and computed ab initio and all vibrational bands are assigned. PMID- 25017433 TI - Peritoneal dialysis and in-centre haemodialysis: a cost-utility analysis from a UK payer perspective. AB - BACKGROUND: With limited healthcare resources available, cost-effective provision of dialysis to patients with end-stage renal disease (ESRD) is important. OBJECTIVES: To assess the cost-effectiveness of varying levels of peritoneal dialysis (PD) use versus current practice among incident ESRD patients requiring dialysis. METHODS: A Markov model was developed to investigate the cost effectiveness of increasing uptake of PD to 39 and 50 % versus current practice of 22 % PD from a UK National Health Service perspective for the year of 2013 2014. A scenario with 5 % PD was also considered. Sensitivity analyses were performed. RESULTS: Five- and 10-year discounted total costs and quality-adjusted life years (QALYs) per patient for the current scenario (22 % PD) were L96,307 and 2.104, and L133,339 and 3.301, respectively. Use of PD in 39 % of patients resulted in 5- and 10-year total per-patient cost savings of L3,180 and L4,102 versus current usage alongside total per-patient QALY increases of 0.017 and 0.020. Use of PD in 50 % of patients resulted in 5- and 10-year per-patient cost savings of L5,238 and L6,758 versus current usage alongside per-patient QALY increases of 0.029 and 0.033. Thus, increasing use of PD was associated with marginally better outcomes and lower costs. Cost savings were driven by lower treatment costs and reduced transport requirements for PD versus haemodialysis. Reducing PD use was associated with higher costs and a small reduction in QALYs. CONCLUSIONS: These findings suggest increasing PD use among incident dialysis patients would be cost-effective, associated with reduced costs and potential modest improvements in quality of life. PMID- 25017434 TI - Heat transfer in heterogeneous nanostructures can be described by a simple chain model. AB - We present a simple chain model for ballistic-diffusive heat transfer in heterogeneous nanostructures connected by atomistic interfaces, which are under extensive investigation for nanoscale heat transfer control. Heat transfer in typical heterogeneous nanostructures, including junctions with a single interface, multi-layered SiGe-Si systems, and nanocrystal arrays, can be well reproduced by the model. Good performance of the model in all the investigated cases shows that it captures the essential feature of interfaces connecting ballistic and diffusive thermal conducting regions. This will help to design tunable thermal transport devices and to further clarify the origin of interfacial resistance. PMID- 25017435 TI - The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma. AB - There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners. PMID- 25017436 TI - Species differences in bacterial NhaA Na+/H+ exchangers. AB - Bacteria have adapted their NhaA Na(+)/H(+) exchangers responsible for salt homeostasis to their different habitats. We present an electrophysiological and kinetic analysis of NhaA from Helicobacter pylori and compare it to the previously investigated exchangers from Escherichia coli and Salmonella typhimurium. Properties of all three transporters are described by a simple model using a single binding site for H(+) and Na(+). We show that H.pylori NhaA only has a small acidic shift of its pH-dependent activity profile compared to the other transporters and discuss why a more drastic change in its pH activity profile is not physiologically required. PMID- 25017437 TI - Expression of NYV1 encoding the negative regulator of Pmc1 is repressed by two transcriptional repressors, Nrg1 and Mig1. AB - ESCRT components function to form multivesicular bodies for sorting of proteins destined to the yeast vacuole. The calcium hypersensitivity of ESCRT mutants is mainly due to repressed expression of PMR1 through the Rim101/Nrg1 pathway in budding yeast. Here, we show that overexpression of PMC1 and its negative regulator gene NYV1 suppresses and increases calcium hypersensitivity of ESCRT mutants, respectively. Consistently, deletion of NYV1 suppresses their calcium hypersensitivity. Expression of NYV1 is dramatically reduced in ESCRT mutants. Promoter analysis demonstrates that both Nrg1 and Mig1 repress NYV1 expression. Deletion of ESCRTs increases Nrg1 binding, but not Mig1-binding, to the NYV1 promoter. Deletion of MIG1 increases calcium sensitivity of ESCRT mutants due to derepression of NYV1 expression. PMID- 25017438 TI - Catalytic role of the calcium ion in GH97 inverting glycoside hydrolase. AB - The role of calcium ion in the active site of the inverting glycoside hydrolase family 97 enzyme, BtGH97a, was investigated through structural and kinetic studies. The calcium ion was likely directly involved in the catalytic reaction. The pH dependence of kcat/Km values in the presence or absence of calcium ion indicated that the calcium ion lowered the pKa of the base catalyst. The significant decreases in kcat/Km for hydrolysis of substrates with basic leaving groups in the absence of calcium ion confirmed that the calcium ion facilitated the leaving group departure. PMID- 25017439 TI - FOXO1 3'UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity. AB - The competitive endogenous RNAs (ceRNAs) are RNA molecules that affect each other's expression through competition for their shared microRNAs (miRNAs). In this study we explored whether FOXO1 3'UTR can function as a ceRNA in repressing epithelial-to-mesenchymal transition (EMT) and metastasis of breast cancer cells via regulating miR-9 activity. We found that miR-9 binds to both the FOXO1- and E cadherin-3'UTR, indicating that the FOXO1- and E-cadherin-3'UTR can be linked through miR-9. Follow-up analyses showed that there existed a competition of miR 9 between FOXO1 and E-cadherin-3'UTR. Thus FOXO1 3'UTR inhibits the metastases of breast cancer cells via induction of E-cadherin expression. Our results suggest that FOXO1 3'UTR may function as a miRNA-inhibitor in modulating metastasis of breast cancer cells. PMID- 25017440 TI - Calcium signaling mediates the response to cadmium toxicity in Saccharomyces cerevisiae cells. AB - The involvement of Ca(2+) in the response to high Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Hg(2+) was investigated in Saccharomyces cerevisiae. The yeast cells responded through a sharp increase in cytosolic Ca(2+) when exposed to Cd(2+), and to a lesser extent to Cu(2+), but not to Mn(2+), Co(2+), Ni(2+), Zn(2+), or Hg(2+). The response to high Cd(2+) depended mainly on external Ca(2+) (transported through the Cch1p/Mid1p channel) but also on vacuolar Ca(2+) (released into the cytosol through the Yvc1p channel). The adaptation to high Cd(2+) was influenced by perturbations in Ca(2+) homeostasis. Thus, the tolerance to Cd(2+) often correlated with sharp Cd(2+)-induced cytosolic Ca(2+) pulses, while the Cd(2+) sensitivity was accompanied by the incapacity to rapidly restore the low cytosolic Ca(2+). PMID- 25017441 TI - A pan-theoretical conceptualization of client involvement in psychotherapy. AB - OBJECTIVE: The present paper attempts to differentiate client involvement from other, similar process variables and presents a pan-theoretical conceptualization of client involvement. METHOD: A modified Delphi poll was conducted with 20 experienced clinicians and researchers. In two rounds of data collection, the experts completed a questionnaire designed to elicit their feedback on whether a variety of involvement items were representative of our pan-theoretical definition of client involvement. RESULTS: The results of the survey provide insight into which types of client activities are good representations of client involvement. CONCLUSION: We propose that client involvement can be understood as being comprised of behavioral, cognitive, and emotional elements, and we provide concrete examples of these activities. PMID- 25017442 TI - What is an anti-aging treatment? AB - Key objectives of biogerontology are to understand the biology of aging and to translate scientific insight into interventions that improve late-life health - or anti-aging treatments. In this context, when considering the problem of how to effect translational research, it is useful to have a clear, consensus view on what exactly constitutes an anti-aging treatment. This essay critically assesses the understanding of this concept common among biogerontologists, and proposes a new definition. A current conception of anti-aging treatment imagines a primary cause of aging that is causally upstream of, and the cause of, all age-related pathology. Intervening in this aging process thus protects against the totality of age-related diseases. However, this underlying aging process remains an abstraction. By contrast, what is demonstrable is that interventions in model organisms can improve late-life health and extend lifespan. Furthermore, a safe deduction is that treatments that extend lifespan do so by reducing age-related pathology, both florid and subtle. What is currently identifiable about aging (i.e. senescence) is that it is a very complex disease syndrome, likely involving a number of biological mechanisms. Treatments that substantially extend lifespan must suppress multiple pathologies that otherwise limit lifespan, but whether they suppress the entire aging process remains undemonstrated. A more pragmatic and realistic definition of anti-aging treatment is any preventative approach to reduce late-life pathology, based on the understanding that senescence is a disease syndrome. This definition would encompass preventative approaches aimed at both broad and narrow spectra of age-related pathologies. Its adoption would facilitate translation, since it would shift the emphasis to medical practice, particularly the introduction of preventative approaches. Narrow spectrum anti aging treatments (e.g. the cardiovascular polypill) could establish a practice that eventually extends to broader spectrum anti-aging treatments (e.g. dietary restriction mimetics). PMID- 25017444 TI - Perspectives on clinical trial data transparency and disclosure. AB - The increased demand for transparency and disclosure of data from clinical trials sponsored by pharmaceutical companies poses considerable challenges and opportunities from a statistical perspective. A central issue is the need to protect patient privacy and adhere to Good Clinical and Statistical Practices, while ensuring access to patient-level data from clinical trials to the wider research community. This paper offers options to navigate this dilemma and balance competing priorities, with emphasis on the role of good clinical and statistical practices as proven safeguards for scientific integrity, the importance of adopting best practices for reporting of data from secondary analyses, and the need for optimal collaboration among stakeholders to facilitate data sharing. PMID- 25017445 TI - TNF-related apoptosis-inducing ligand enhances vinorelbine-induced apoptosis and antitumor activity in a preclinical model of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is relatively insensitive to chemotherapy. NP [vinorelbine (NVB) + cisplatin] is the standard chemotherapy regimen in clinical treatment; however, its side-effects are intolerable for most patients. In some reports, the TNF-related apoptosis-inducing ligand (TRAIL) can enhance the sensitivity of chemotherapy drugs by inducing apoptosis without toxicity to normal cells. In the present study, we evaluated the antitumor effects of the two drugs (TRAIL and NVB alone or in combination) by inducing apoptosis in vitro and in vivo. Using the human NSCLC cell line (A549) and a BALB/c nude mice model, we observed the cell viability (MTT assay), cell apoptosis [Hoechst staining, Annexin V/propidium iodide (PI) staining assay, immunohistochemical staining, RT PCR and western blotting] and cell proliferation (soft agar colony formation and cell cycle assay). The results showed that TRAIL and NVB alone inhibited tumor growth both in vivo and in vitro. However, the combination of the two drugs produced a more potent antitumor effect (P<0.05) and caused more severe apoptosis in tumor tissue (P<0.05). The key molecular protein level of the mitochondrial apoptotic pathway (Bax and caspase-3) was further upregulated by the combination of the two drugs (P<0.01) and either drug alone (P<0.05). The mRNA level of Bcl-2 and Bax in the combination group was downregulated and upregulated respectively, when compared with the control group (P<0.01). The combination group of A549 cells also showed lower viability compared with the one drug alone group (P<0.05). Moreover, the Hoechst staining assay and Annexin V/PI staining assay showed that the combination of the two drugs induced a more potent apoptosis than either drug alone (P<0.05, early apoptosis P<0.01, respectively). In addition, the cell colony numbers were deduced after treatment with TRAIL or NVB alone (P<0.05) and the two drug combination (P<0.01). Cell cycle analysis showed that TRAIL and NVB alone markedly increased the percentage of cells in G1 phase (P<0.05) and the combination of the two drugs decreased the percentage of cells in G2 and S phase (P<0.05). Thus, the combination of TRAIL and NVB can inhibit lung cancer cell growth by affecting the level of key signaling protein expression of the apoptosis pathway. PMID- 25017447 TI - Self-reported participation and beliefs about bowel cancer screening in New South Wales, Australia. AB - ISSUE ADDRESSED: To describe self-reported bowel cancer screening participation, beliefs and attitudes in a sample of New South Wales (NSW) adults, and to identify beliefs and demographic factors associated with self-reported bowel cancer screening participation. METHODS: This study used data from the International Cancer Benchmarking Partnership Module 2, a representative population-based telephone survey. Self-reported participation in and beliefs about bowel cancer screening were measured using the Awareness and Beliefs about Cancer survey of people aged 50 years and over living in NSW, Australia (n=2001). Logistic regression modelling was used to identify explanatory variables associated with bowel cancer screening participation. RESULTS: Half of all women (54.1%, 95% CI: 50.8-57.4%) and two-thirds of men (65.7%, 95% CI: 61.5-69.9%) reported screening for bowel cancer within the previous 5 years. Believing that screening was only necessary when experiencing symptoms was more likely to be endorsed by people aged 65 years and over (25.5%, 95% CI: 22.2-28.7%) rather than younger (50-64 years; 16.7%, 95% CI: 13.8-19.7%), non-English-speaking migrants (35.4%, 95% CI: 26.7-44.1%) versus others (18.6%, 95% CI: 16.4-20.7%), and people in metropolitan (23.3%, 95% CI: 20.4-26.1%) versus non-metropolitan areas (16.4%, 95% CI: 12.8-20%). People who disagreed that screening was only necessary when experiencing symptoms were four times more likely to report screening participation (OR 3.96, 95% CI: 3.11-5.03). CONCLUSIONS: Community education about bowel cancer screening is needed to correct misperceptions regarding screening in the absence of symptoms. Tailored strategies for older, migrant and urban communities may be beneficial. SO WHAT? Education strategies that promote the need for screening in the absence of symptoms and correct misconceptions about bowel cancer screening amongst subgroups of the NSW population may improve screening rates and decrease the burden of bowel cancer in NSW. PMID- 25017446 TI - Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. AB - The effect of extra-fiber structural and pathological components confounding diffusion tensor imaging (DTI) computation was quantitatively investigated using data generated by both Monte-Carlo simulations and tissue phantoms. Increased extent of vasogenic edema, by addition of various amount of gel to fixed normal mouse trigeminal nerves or by increasing non-restricted isotropic diffusion tensor components in Monte-Carlo simulations, significantly decreased fractional anisotropy (FA) and increased radial diffusivity, while less significantly increased axial diffusivity derived by DTI. Increased cellularity, mimicked by graded increase of the restricted isotropic diffusion tensor component in Monte Carlo simulations, significantly decreased FA and axial diffusivity with limited impact on radial diffusivity derived by DTI. The MC simulation and tissue phantom data were also analyzed by the recently developed diffusion basis spectrum imaging (DBSI) to simultaneously distinguish and quantify the axon/myelin integrity and extra-fiber diffusion components. Results showed that increased cellularity or vasogenic edema did not affect the DBSI-derived fiber FA, axial or radial diffusivity. Importantly, the extent of extra-fiber cellularity and edema estimated by DBSI correlated with experimentally added gel and Monte-Carlo simulations. We also examined the feasibility of applying 25-direction diffusion encoding scheme for DBSI analysis on coherent white matter tracts. Results from both phantom experiments and simulations suggested that the 25-direction diffusion scheme provided comparable DBSI estimation of both fiber diffusion parameters and extra-fiber cellularity/edema extent as those by 99-direction scheme. An in vivo 25-direction DBSI analysis was performed on experimental autoimmune encephalomyelitis (EAE, an animal model of human multiple sclerosis) optic nerve as an example to examine the validity of derived DBSI parameters with post-imaging immunohistochemistry verification. Results support that in vivo DBSI using 25-direction diffusion scheme correctly reflect the underlying axonal injury, demyelination, and inflammation of optic nerves in EAE mice. PMID- 25017448 TI - Treatment adherence and competency ratings among therapists, supervisors, study related raters and external raters in a clinical trial of a 12-step facilitation for stimulant users. AB - This study investigated the correspondence among four groups of raters on adherence to STAGE-12, a manualized 12-step facilitation (TSF) group and individual treatment targeting stimulant abuse. The four rater groups included the study therapists, supervisors, study-related ("TSF expert") raters, and non project related ("external") raters. Results indicated that external raters rated most critically mean adherence - the mean of all the adherence items - and global performance. External raters also demonstrated the highest degree of reliability with the designated expert. Therapists rated their own adherence lower, on average, than did supervisors and TSF expert raters, but therapist ratings also had the poorest reliability. Findings highlight the challenges in developing practical, but effective methods of fidelity monitoring for evidence based practice in clinical settings. Recommendations based on study findings are provided. PMID- 25017450 TI - Lesions of the ovary with T1-hypersignal. AB - Pelvic magnetic resonance imaging (MRI) has been used successfully to diagnose ovarian masses that cannot be adequately evaluated using pelvic ultrasound. T1 hyperintensity is a common finding in an ovarian mass and has important diagnostic implications. The aims of this review are to list the substances that may produce high signal intensity on T1-weighted MRI, to explain the physical basis for causes of the high T1 signal intensity, and to describe common and uncommon T1 hyperintense ovarian lesions. The morphological findings, the imaging features of the additional sequences, and clinical variables can help in the differential diagnosis, and in some cases, enable a specific diagnosis, leading to appropriate management of the patient. PMID- 25017449 TI - Pilot study evaluating catheter-directed contrast-enhanced ultrasound compared to catheter-directed computed tomography arteriography as adjuncts to digital subtraction angiography to guide transarterial chemoembolization. AB - AIM: To investigate the feasibility and procedural value of catheter-directed contrast-enhanced ultrasound (CCEUS) compared with catheter-directed computed tomography arteriography (CCTA) in patients undergoing transarterial chemoembolization (TACE) guided by digital subtraction angiography (DSA). MATERIALS AND METHODS: From December 2010 to December 2011, a pilot study was conducted including nine patients (mean age 66.6 years; SD 8.3 years; seven men) undergoing TACE with drug-eluting beads for unresectable hepatocellular carcinoma (HCC). Both CCEUS and CCTA were performed in addition to DSA. Alterations of treatment plan based on CCEUS were recorded and compared with CCTA. RESULTS: CCEUS provided additional information to DSA altering the treatment plan in four out of nine patients (44.4%). In these four patients, CCEUS helped to identify additional tumour feeders (n = 2) or led to a change in catheter position (n = 2). The information provided by CCEUS was similar to that provided by CCTA. CONCLUSION: CCEUS is a potentially valuable imaging tool in adjunction to DSA when performing TACE and may provide similar information to CCTA. PMID- 25017451 TI - Contrast-induced acute kidney injury after computed tomography prior to transcatheter aortic valve implantation. AB - AIM: To identify independent predictors of contrast medium-induced acute kidney injury (CI-AKI) after enhanced multidetector-row computed tomography (MDCT) prior to transcatheter aortic valve implantation (TAVI) in high-risk patients. MATERIALS AND METHODS: The present single-centre study analysed retrospectively 361 patients who were assessed using MDCT prior to TAVI. CI-AKI was defined as an increase in serum creatinine (SCr) of >= 25% or >= 0.5 mg/dl in at least one sample over baseline (24 h before MDCT) and at 24, 48, and 72 h after MDCT. RESULTS: A total of 38 patients (10.5%) experienced CI-AKI. As compared to patients without CI-AKI, they presented more frequently with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), (81.6% versus 64.4%, p = 0.045) and tended to receive higher volumes of iodinated contrast media (ICM; 55.3% versus 39%, p = 0.057). There was a significant interaction between baseline eGFR and the amount of intravenous ICM administered (pfor interaction = <0.001) identifying the amount of ICM >90 ml as independent predictive factor of CI-AKI only in patients with baseline eGFR <60 ml/min/1.73m(2) (OR 2.615; 95% CI: 1.21 5.64). CONCLUSION: One in ten elderly patients with aortic stenosis undergoing MDCT to plan a TAVI procedure experienced CI-AKI after intravenous ICM injection. Intravenous administration of <90 ml of ICM reduces this risk in patients with or without pre-existing impaired renal function. However, in the majority of patients renal function recovers before the TAVI procedure. PMID- 25017452 TI - MRI appearances of benign uterine disease. AB - Benign uterine disease is a common entity affecting women of all ages. Ultrasound has historically been the predominant imaging method used in the evaluation of benign gynaecological disease, magnetic resonance imaging (MRI) being reserved for use in the staging of malignant uterine and cervical disease. MRI is now increasingly used in the diagnosis of benign uterine disease as well as a tool for problem-solving in cases of diagnostic dilemma. It allows detailed assessment of benign conditions, such as endometrial lesions, leiomyomas, and adenomyosis, and can be helpful in the stratification of patients to different treatment modalities, including surgical resection, uterine artery embolization, and medical therapies. In this article, we review the MRI findings in the common benign uterine diseases. PMID- 25017453 TI - Tranexamic acid - a useful drug in ENT surgery? AB - BACKGROUND: Tranexamic acid is a synthetic antifibrinolytic drug. It has been widely available for over 40 years, but only recently has it started to be used routinely in many surgical disciplines. For ENT surgeons, epistaxis and post tonsillectomy bleeding contribute a significant proportion of the morbidity and emergency workload in a general ENT department. Published evidence indicates a potentially helpful role for tranexamic acid in managing epistaxis. RESULTS AND CONCLUSION: To date, the benefits of tranexamic acid as a prophylactic treatment to reduce the rate and severity of post-tonsillectomy bleeding are less certain. Two recently published pilot studies looking at primary haemorrhage in children and secondary haemorrhage in adults following tonsillectomy suggest that further large, randomised trials should explore the efficacy of tranexamic acid in routine ENT surgery. There are potential reductions in patient morbidity and cost savings if tranexamic acid is found to be efficacious in larger trials. PMID- 25017454 TI - Cu nanoclusters supported on nanocrystalline SiO2-MnO2: a bifunctional catalyst for the one-step conversion of glycerol to acrylic acid. AB - A material consisting of highly dispersed Cu nanoclusters anchored on nanocrystalline SiO2-MnO2 has been prepared, and was found to act as a bifunctional catalyst for the one-step conversion of glycerol to acrylic acid using H2O2. Under optimized conditions a glycerol conversion of 77.1%, with 74.7% selectivity for acrylic acid, was achieved after 30 h reaction time. PMID- 25017455 TI - Assessment of sleep in patients with fibromyalgia: qualitative development of the fibromyalgia sleep diary. AB - OBJECTIVES: Sleep disturbance is a common experience in fibromyalgia (FM). The field lacks a sleep specific patient reported outcome (PRO) measure developed and validated in a FM population. The study objective is to gain an in-depth understanding of sleep in FM and to develop a PRO measure of it. METHODS: Research involved the following stages: 1) A literature review conducted to identify key concepts associated with FM patient experience of sleep and PRO measures that have been used to assess this; 2) Qualitative interviews with therapeutic area experts; 3) Focus groups with FM patients who experienced sleep disturbance; 4) Development of a conceptual framework and the Fibromyalgia Sleep Diary (FMSD); and 5) Cognitive interviews with patients to explore content validity of the FMSD. RESULTS: The literature review and expert interviews supported sleep disturbance being an important aspect of the FM patient experience, and underscored the need for a new FM specific sleep PRO measure. Results from the focus groups demonstrated that FM patients experience sleep disturbances that they attribute to their FM symptoms, such as pain and stiffness, confirming the importance of understanding more about sleep changes. Aspects of sleep raised by FM patients included poor sleep quality and insufficient quantity including difficulty with falling asleep, getting comfortable, and staying asleep; restlessness; light sleep; not feeling rested upon awakening; and difficulty starting the day. Cognitive interview results showed that the 8-item FMSD, developed to reflect the concepts identified above, was relevant to FM patients with content that was interpreted as intended. CONCLUSIONS: The FMSD was developed in line with the recommendations of the FDA PRO guidance and ISPOR PRO Task Force. The qualitative evidence generated thus far strongly supports the content validity of the FMSD as a PRO measure of sleep disturbance in FM populations. Psychometric evaluation of the FMSD to demonstrate reliability, validity and sensitivity to change is recommended as a next step. PMID- 25017456 TI - Pediatric dermatology: part I. PMID- 25017457 TI - Current workup and therapy of infantile hemangiomas. AB - Many practitioners assume every vascular lesion is a hemangioma; then tell parents not to worry, because hemangiomas "go away" after they grow. In fact, over the past three decades, advances in the stratification of vascular lesions, identification of clinical associations and syndromic vascular anomalies, and the discovery of germline and somatic mutations accompanying certain vascular anomalies have broadened our understanding. Concomitantly, the evaluation and management of vascular anomalies have become more sophisticated, and a laissez faire approach is often inadequate. This paper focuses on hemangiomas of infancy and is divided into two sections, Evaluation and Management, both sections including updated references to clinical and basic research and reviews supporting the discussion. PMID- 25017458 TI - Complications of infantile hemangiomas. AB - Most infantile hemangiomas have a spontaneous and uneventful involution and, hence, may be treated expectantly. Others, however, will present some complication along their evolution that may require prompt therapeutic interventions. Ulceration is the most common complication, and amblyopia is frequently associated with periocular tumors. Airways hemangiomas may be life threatening, and disfigurement can heavily impact the patient's quality of life. PMID- 25017459 TI - An update on diaper dermatitis. AB - Diaper dermatitis leads to approximately 20% of all childhood dermatology visits. There have been several technologic advances in diaper design the last several years; however, due to the unique environment of the diaper area, many children continue to suffer from a variety of dermatologic conditions of this region. Common causes include allergic contact dermatitis, irritant contact dermatitis, infection, and psoriasis. Treatments include allergen avoidance, barrier protection, parent education, and topical therapies. PMID- 25017461 TI - Contraceptive use in acne. AB - Acne vulgaris is an inflammatory disorder of the pilosebaceous follicle. It is well established that androgen hormones play a major role in sebum production and excretion, and are vital in the pathogenesis of acne. Isotretinoin notwithstanding, hormonal therapies such as combined oral contraceptives (COCs) and spironolactone are the only treatments that can affect sebum production and the androgen component of acne. Contraceptives are also used during isotretinoin therapy for pregnancy prevention. It is important for a dermatologist to be familiar with all the available methods of contraception to provide essential counseling to patients. The aim of this paper is to review the role of hormones in acne pathogenesis, discuss the use of hormonal therapies for acne, and detail various alternative contraceptive methods in relation to isotretinoin treatment and pregnancy prevention. PMID- 25017460 TI - Autoinflammatory syndromes for the dermatologist. AB - While autoimmunity as cause of disease is well-established, other categories of immune-mediated diseases that are not produced by targeting of self-antigens by antibodies is in the process of being described. These so-called autoinflammatory diseases arise when an inappropriate activation of antigen-independent mechanisms occurs. Autoinflammatory diseases course with recurrent attacks of fever and multisystemic inflammation; however, the skin may also be affected by a variety of inflammatory manifestations that often alert the clinician about the presence of an autoinflammatory disease. Recognizing the cutaneous features of these syndromes will aid for prompt diagnosis and early treatment that is key for the quality of life and survival of the affected patients. In this paper, we focus on the skin manifestations of autoinflammatory diseases in children, which is the usual period of appearing of the first symptoms and signs. PMID- 25017462 TI - An update on pediatric cutaneous drug eruptions. AB - One of the early lessons learned in dermatology training is "any drug, any rash." This maxim quickly summarizes the vast array of cutaneous reactions that can be seen in response to systemic medications. We have reviewed common and unusual drug eruptions in pediatric patients that span the morphologic spectrum. These reactions can have an equally broad range of severity, from harmless to lethal, and by the end of this paper the reader will be better equipped to sort one from the other. PMID- 25017463 TI - Recent advances in childhood vitiligo. AB - Vitiligo is an autoimmune depigmentation disorder that is estimated to affect about .5% of the worldwide population. Half of all cases begin in childhood. A variety of advances occurred in the past two decades that have enhanced the management of childhood vitiligo. This contribution reviews recent advances in vitiligo, including a better understanding of the pathogenesis and autoimmune comorbidities, description of the psychological comorbidities, a broader range of therapeutic options. PMID- 25017464 TI - Patient safety and quality care. PMID- 25017465 TI - Oxidation of 7-dehydrocholesterol and desmosterol by human cytochrome P450 46A1. AB - Cytochrome P450 (P450 or CYP) 46A1 is expressed in brain and has been characterized by its ability to oxidize cholesterol to 24S-hydroxycholesterol. In addition, the same enzyme is known to further oxidize 24S-hydroxycholesterol to the 24,25- and 24,27-dihydroxy products, as well as to catalyze side-chain oxidations of 7alpha-hydroxycholesterol and cholestanol. As precursors in the biosynthesis of cholesterol, 7-dehydrocholesterol has not been found to be a substrate of P450 46A1 and desmosterol has not been previously tested. However, 24-hydroxy-7-dehydrocholesterol was recently identified in brain tissues, which prompted us to reexamine this enzyme and its potential substrates. Here we report that P450 46A1 oxidizes 7-dehydrocholesterol to 24-hydroxy-7-dehydrocholesterol and 25-hydroxy-7-dehydrocholesterol, as confirmed by LC-MS and GC-MS. Overall, the catalytic rates of formation increased in the order of 24-hydroxy-7 dehydrocholesterol < 24-hydroxycholesterol < 25-hydroxy-7-dehydrocholesterol from their respective precursors, with a ratio of 1:2.5:5. In the case of desmosterol, epoxidation to 24S,25-epoxycholesterol and 27-hydroxylation was observed, at roughly equal rates. The formation of these oxysterols in the brain may be of relevance in Smith-Lemli-Opitz syndrome, desmosterolosis, and other relevant diseases, as well as in signal transduction by lipids. PMID- 25017466 TI - Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. AB - Foxp3(+) T cells play a critical role for the maintenance of immune tolerance. Here we show that in mice, Foxp3(+) T cells contributed to diversification of gut microbiota, particularly of species belonging to Firmicutes. The control of indigenous bacteria by Foxp3(+) T cells involved regulatory functions both outside and inside germinal centers (GCs), consisting of suppression of inflammation and regulation of immunoglobulin A (IgA) selection in Peyer's patches, respectively. Diversified and selected IgAs contributed to maintenance of diversified and balanced microbiota, which in turn facilitated the expansion of Foxp3(+) T cells, induction of GCs, and IgA responses in the gut through a symbiotic regulatory loop. Thus, the adaptive immune system, through cellular and molecular components that are required for immune tolerance and through the diversification as well as selection of antibody repertoire, mediates host microbial symbiosis by controlling the richness and balance of bacterial communities required for homeostasis. PMID- 25017468 TI - Sarcoidosis presenting as metastatic lymphadenopathy in breast cancer. PMID- 25017467 TI - Immunoglobulin E signal inhibition during allergen ingestion leads to reversal of established food allergy and induction of regulatory T cells. AB - Immunoglobulin E (IgE) antibodies are known for triggering immediate hypersensitivity reactions such as food anaphylaxis. In this study, we tested whether they might additionally function to amplify nascent antibody and T helper 2 (Th2) cell-mediated responses to ingested proteins and whether blocking IgE would modify sensitization. By using mice harboring a disinhibited form of the IL 4 receptor, we developed an adjuvant-free model of peanut allergy. Mast cells and IgE were required for induction of antibody and Th2-cell-mediated responses to peanut ingestion and they impaired regulatory T (Treg) cell induction. Mast-cell targeted genetic deletion of the FcepsilonRI signaling kinase Syk or Syk blockade also prevented peanut sensitization. In mice with established allergy, Syk blockade facilitated desensitization and induction of Treg cells, which suppressed allergy when transferred to naive recipients. Our study suggests a key role for IgE in driving Th2 cell and IgE responses while suppressing Treg cells in food allergy. PMID- 25017469 TI - Cascading effects of interparental conflict in adolescence: Linking threat appraisals, self-efficacy, and adjustment. AB - This study examined the longitudinal implications of adolescents' exposure to interparental conflict for their developmental success. In the proposed developmental cascade model, adolescents' perceptions of parental conflict as threatening is a risk factor for diminished self-efficacy, which would account for diminished adjustment. This study presents longitudinal data for 768 sixth grade students and their families over four time points, ending in eighth grade. Analyses were conducted in three steps. First, replication of longitudinal support for threat as a mediator of the link between interparental conflict and emotional distress was found; however, findings did not support threat as a mediator of behavior problems or subjective well-being. Second, threat was found to mediate the longitudinal association between interparental conflict and self efficacy. Third, a developmental cascade model supported a risk process in which interparental conflict was related to adolescents' threat appraisals, which undermined self-efficacy beliefs, and was then linked with emotional distress, behavior problems, and subjective well-being. PMID- 25017470 TI - Analytical method for lipoperoxidation relevant reactive aldehydes in human sera by high-performance liquid chromatography-fluorescence detection. AB - A validated, simple and sensitive HPLC method was developed for the simultaneous determination of lipoperoxidation relevant reactive aldehydes: glyoxal (GO), acrolein (ACR), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) in human serum. The studied aldehydes were reacted with 2,2'-furil to form fluorescent difurylimidazole derivatives that were separated on a C18 column using gradient elution and fluorescence detection at excitation and emission wavelengths of 250 and 355nm, respectively. The method showed good linearity over the concentration ranges of 0.100-5.00, 0.200-10.0, 0.200-40.0, and 0.400-10.0nmol/mL for GO, ACR, HNE, and MDA, respectively, with detection limits ranging from 0.030 to 0.11nmol/mL. The percentage RSD of intraday and interday precision did not exceed 5.0 and 6.2%, respectively, and the accuracy (%found) ranged from 95.5 to 103%. The proposed method was applied for monitoring the four aldehydes in sera of healthy, diabetic, and rheumatic human subjects with simple pretreatment steps and without interference from endogenous components. By virtue of its high sensitivity and accuracy, our method enabled detection of differences between analytes concentrations in sera of human subjects under different clinical conditions. PMID- 25017471 TI - Nordihydroguaiaretic acid (NDGA) inhibits replication and viral morphogenesis of dengue virus. AB - Dengue is the most common mosquito borne viral disease in humans. The infection with any of the 4 dengue virus serotypes (DENV) can either be asymptomatic or manifest in two clinical forms, the mild dengue fever or the more severe dengue hemorrhagic fever that may progress into dengue shock syndrome. A DENV replicative cycle relies on host lipid metabolism; specifically, DENV infection modulates cholesterol and fatty acid synthesis, generating a lipid-enriched cellular environment necessary for viral replication. Thus, the aim of this work was to evaluate the anti-DENV effect of the Nordihydroguaiaretic acid (NDGA), a hypolipidemic agent with antioxidant and anti-inflammatory properties. A dose dependent inhibition in viral yield and NS1 secretion was observed in supernatants of infected cells treated for 24 and 48 h with different concentrations of NDGA. To evaluate the effect of NDGA in DENV replication, a DENV4 replicon transfected Vero cells were treated with different concentrations of NDGA. NDGA treatment significantly reduced DENV replication, reiterating the importance of lipids in viral replication. NDGA treatment also led to reduction in number of lipid droplets (LDs), the neutral lipid storage organelles involved in DENV morphogenesis that are known to increase in number during DENV infection. Furthermore, NDGA treatment resulted in dissociation of the C protein from LDs. Overall our results suggest that NDGA inhibits DENV infection by targeting genome replication and viral assembly. PMID- 25017472 TI - HSPA5 is an essential host factor for Ebola virus infection. AB - Development of novel strategies targeting the highly virulent ebolaviruses is urgently required. A proteomic study identified the ER chaperone HSPA5 as an ebolavirus-associated host protein. Here, we show using the HSPA5 inhibitor (-)- epigallocatechin gallate (EGCG) that the chaperone is essential for virus infection, thereby demonstrating a functional significance for the association. Furthermore, in vitro and in vivo gene targeting impaired viral replication and protected animals in a lethal infection model. These findings demonstrate that HSPA5 is vital for replication and can serve as a viable target for the design of host-based countermeasures. PMID- 25017473 TI - Rational design of a new fluorescent 'ON/OFF' xanthene dye for phosphate detection in live cells. AB - A new fluorescein derivative with ON/OFF features, 9-[1-(4-tert-butyl-2 methoxyphenyl)]-6-hydroxy-3H-xanthen-3-one (Granada Green, GG), was designed and synthesised. The new dye has spectral characteristics similar to those of other xanthenic derivatives but shows a higher pK(a) value for the equilibrium between its neutral and anionic forms. In addition, GG undergoes the same phosphate mediated excited state proton transfer (ESPT) reaction as other xanthenic derivatives, giving rise to fluorescence decay traces that are dependent on both the phosphate concentration and pH of the medium. The phosphate-mediated ESPT reaction was employed to detect changes in the phosphate concentrations in live, permeabilised MC3T3-E1 preosteoblasts at pH 7.35. Its high pK(a) value indicates that this new dye is more sensitive as an intracellular phosphate sensor than other previously tested dyes, as experimentally demonstrated by its ability to detect a wider range of phosphate concentrations in biomimetic media and by the increased ratio of the phosphate concentration/decay time. PMID- 25017474 TI - Cytokine expression and cytokine-based T cell profiling in South Indian rheumatoid arthritis. AB - Rheumatoid arthritis (RA), a chronic inflammatory disease affects up to 1% of the general population. Early diagnosis and treatment are limited by the absence of specific and reliable diagnostic/prognostic biomarkers. This study was carried out in 48 Tamil South Indian RA patients and 49 healthy controls (HC) to identify any cytokine signature(s) that could potentially serve as biomarkers. Expression profiles of Th1, Th2, Th17 and Tregs cell type-specifying cytokines and transcription factors were analyzed using real time quantitative PCR (qPCR) assay. To explore if such expression profiles mirror their steady state plasma levels, a bead-based multiplex fluorescent assay was carried out. We found that the expression of transcription factors T-bet (for Th1), GATA-3 (for Th2) and FoxP3 (for Tregs) were significantly lower in patients than in healthy controls (P<0.0001) similar to lowering of IFNgamma (P=0.004) and IL-10 (P=0.04). The transcript levels of IL-12p40 and TNF-alpha were higher among patients as compared to HC (P<0.0001 and P=0.02, respectively). Circulating levels of assessed cytokines were in general higher in RA patients as compared to controls. These alterations in the expression of transcription factors and cytokines highlight the underlying dysregulation of T cell subsets in RA that reflects a predominantly inflammatory phenotype. Despite dissecting these cellular and molecular processes, no specific signature that could be of diagnostic and/or prognostic value was identified. Additional longitudinal follow-up studies, especially on newly diagnosed treatment-naive patients are warranted to uncover clinically useful biomarkers of RA. PMID- 25017476 TI - Surface energy-mediated construction of anisotropic semiconductor wires with selective crystallographic polarity. AB - ZnO is a wide band-gap semiconductor with piezoelectric properties suitable for opto-electronics, sensors, and as an electrode material. Controlling the shape and crystallography of any semiconducting nanomaterial is a key step towards extending their use in applications. Whilst anisotropic ZnO wires have been routinely fabricated, precise control over the specific surface facets and tailoring of polar and non-polar growth directions still requires significant refinement. Manipulating the surface energy of crystal facets is a generic approach for the rational design and growth of one-dimensional (1D) building blocks. Although the surface energy is one basic factor for governing crystal nucleation and growth of anisotropic 1D structures, structural control based on surface energy minimization has not been yet demonstrated. Here, we report an electronic configuration scheme to rationally modulate surface electrostatic energies for crystallographic-selective growth of ZnO wires. The facets and orientations of ZnO wires are transformed between hexagonal and rectangular/diamond cross-sections with polar and non-polar growth directions, exhibiting different optical and piezoelectrical properties. Our novel synthetic route for ZnO wire fabrication provides new opportunities for future opto electronics, piezoelectronics, and electronics, with new topological properties. PMID- 25017475 TI - Toxic effects of xylazine on endothelial cells in combination with cocaine and 6 monoacetylmorphine. AB - The use of xylazine as a drug of abuse has emerged worldwide in the last 7 years, including Puerto Rico. Clinical findings reported that xylazine users present greater physiological deterioration, than heroin users. The aim of this study was to assess the xylazine toxicity on endothelial cells, as this is one of the first tissues impact upon administration. Human umbilical vein endothelial cells in culture were treated with xylazine, cocaine, 6-monoacetylmorphine (heroin metabolite) and its combinations, at concentrations of 0.10-400 MUM, for periods of 24, 48 and 72 h. IC50 were calculated and the Annexin V assay implemented to determine the cell death mechanism. Results indicated IC50 values at 24h as follow: xylazine 62 MUM, cocaine 210 MUM, 6-monoacetylmorphine 300 MUM. When these drugs were combined the IC50 value was 57 MUM. Annexin V results indicated cell death by an apoptosis mechanism in cells treated with xylazine or in combination. Results demonstrated that xylazine use inhibits the endothelial cell proliferation, at lower concentrations than cocaine and 6-monoacetylmorphine. These findings contribute to the understanding of the toxicity mechanisms induced by xylazine on endothelial cells. PMID- 25017478 TI - False positives in multiplex PCR-based next-generation sequencing have unique signatures. AB - Next-generation sequencing shows great promise by allowing rapid mutational analysis of multiple genes in human cancers. Recently, we implemented the multiplex PCR-based Ion AmpliSeq Cancer Hotspot Panel (>200 amplicons in 50 genes) to evaluate EGFR, KRAS, and BRAF in lung and colorectal adenocarcinomas. In 10% of samples, automated analysis identified a novel G873R substitution mutation in EGFR. By examining reads individually, we found this mutation in >5% of reads in 50 of 291 samples and also found similar events in 18 additional amplicons. These apparent mutations are present only in short reads and within 10 bases of either end of the read. We therefore hypothesized that these were from panel primers promiscuously binding to nearly complementary sequences of nontargeted amplicons. Sequences around the mutations matched primer binding sites in the panel in 18 of 19 cases, thus likely corresponding to panel primers. Furthermore, because most primers did not show this effect, we demonstrated that next-generation sequencing may be used to better design multiplex PCR primers through iterative elimination of offending primers to minimize mispriming. Our results indicate the need for careful sequence analysis to avoid false-positive mutations that can arise in multiplex PCR panels. The AmpliSeq Cancer panel is a valuable tool for clinical diagnostics, provided awareness of potential artifacts. PMID- 25017477 TI - Detection of mutations in myeloid malignancies through paired-sample analysis of microdroplet-PCR deep sequencing data. AB - Amplicon-based methods for targeted resequencing of cancer genes have gained traction in the clinic as a strategy for molecular diagnostic testing. An 847 amplicon panel was designed with the RainDance DeepSeq system, covering most exons of 28 genes relevant to acute myeloid leukemia and myeloproliferative neoplasms. We developed a paired-sample analysis pipeline for variant calling and sought to assess its sensitivity and specificity relative to a set of samples with previously identified mutations. Thirty samples with known mutations in JAK2, NPM1, DNMT3A, MPL, IDH1, IDH2, CEBPA, and FLT3, were profiled and sequenced to high depth. Variant calling using an unmatched Hapmap DNA control removed a substantial number of artifactual calls regardless of algorithm used or variant class. The removed calls were nonunique, had lower variant frequencies, and tended to recur in multiple unrelated samples. Analysis of sample replicates revealed that reproducible calls had distinctly higher variant allele depths and frequencies compared to nonreproducible calls. On the basis of these differences, filters on variant frequency were chosen to select for reproducible calls. The analysis pipeline successfully retrieved the associated known variant in all tested samples and uncovered additional mutations in some samples corresponding to well-characterized hotspot mutations in acute myeloid leukemia. We have developed a paired-sample analysis pipeline capable of robust identification of mutations from microdroplet-PCR sequencing data with high sensitivity and specificity. PMID- 25017479 TI - Coating gigaporous polystyrene microspheres with cross-linked poly(vinyl alcohol) hydrogel as a rapid protein chromatography matrix. AB - Gigaporous polystyrene (PS) microspheres were hydrophilized by in situ polymerization to give a stable cross-linked poly(vinyl alcohol) (PVA) hydrogel coating, which can shield proteins from the hydrophobic PS surface underneath. The amination of microspheres (PS-NH2) was first carried out through acetylization, oximation and reduction, and then 4,4'-azobis (4-cyanovaleric acid) (ACV), a polymerization initiator, was covalently immobilized on PS-NH2 through amide bond formation, and the cross-linked poly(vinyl acetate) (PVAc) was prepared by radical polymerization at the surfaces of ACV-immobilized PS microspheres (PS-ACV). Finally, the cross-linked PVA hydrogel coated gigaporous PS microspheres (PS-PVA) was easily achieved through alcoholysis of PVAc. Results suggested that the PS microspheres were effectively coated with cross-linked PVA hydrogel, where the gigaporrous structure remained under optimal conditions. After hydrophilic modification (PS-PVA), the protein-resistant ability of microspheres was greatly improved. The hydroxyl-rich PS-PVA surface can be easily derivatized by classical chemical methods. Performance advantages of the PS-PVA column in flow experiment include good permeability, low backpressure, and mechanical stability. These results indicated that PS-PVA should be promising in rapid protein chromatography. PMID- 25017480 TI - Salvage stereotactic body radiation therapy (SBRT) for local failure after primary lung SBRT. AB - PURPOSE: Local failure after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) is uncommon. We report the safety and efficacy of SBRT for salvage of local failure after previous SBRT with a biologically effective dose (BED) of >= 100 Gy10. METHODS AND MATERIALS: Using an institutional review board-approved lung SBRT registry, we identified all patients initially treated for early-stage NSCLC between August 2004 and January 2012 who received salvage SBRT for isolated local failure. Failure was defined radiographically and confirmed histologically unless contraindicated. All patients were treated on a Novalis/BrainLAB system using ExacTrac for image guidance, and received a BED of >= 100 Gy10 for each SBRT course. Tumor motion control involved a Bodyfix vacuum system for immobilization along with abdominal compression. RESULTS: Of 436 patients treated from August 2004 through January 2012, we identified 22 patients with isolated local failure, 10 of whom received SBRT for salvage. The median length of follow-up was 13.8 months from salvage SBRT (range 5.3-43.5 months). Median tumor size was 3.4 cm (range 1.7-4.8 cm). Two of the 10 lesions were "central" by proximity to the mediastinum, but were outside the zone of the proximal bronchial tree. Since completing salvage, 3 patients are alive and without evidence of disease. A fourth patient died of medical comorbidities without recurrence 13.0 months after salvage SBRT. Two patients developed distant disease only. Four patients had local failure. Toxicity included grade 1-2 fatigue (3 patients) and grade 1-2 chest wall pain (5 patients). There was no grade 3-5 toxicity. CONCLUSIONS: Repeat SBRT with a BED of >= 100 Gy10 after local failure in patients with early-stage medically inoperable NSCLC was well tolerated in this series and may represent a viable salvage strategy in select patients with peripheral tumors <= 5 cm. PMID- 25017481 TI - Molecularly imprinted polymer on magnetic graphene oxide for fast and selective extraction of 17beta-estradiol. AB - A novel nanosized substrate imprinted polymer (MIPs-GO-Fe3O4) was developed on a magnetic graphene oxide (GO-Fe3O4) surface for selective recognition and fast removal of 17beta-estradiol (17beta-E2). The characteristics of MIPs-GO-Fe3O4 were evaluated by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy. and vibrating sample magnetometer (VSM). Results suggested that GO had a thin single layer structure anchoring Fe3O4 nanoparticles and that the imprinted film was coated on the GO-Fe3O4 surface. MIPs-GO-Fe3O4 was sensitive to the magnetic field and could be easily separated using an external magnet. The adsorption results indicated that the kinetic value and binding capacity of MIPs-GO-Fe3O4 were 0.0062 g (mg.min)(-1) and 4.378 MUmol g(-1), respectively. The Langmuir Freundlich isotherm and pseudo-second-order kinetic models were the main adsorption mechanisms for MIPs-GO-Fe3O4. MIPs-GO-Fe3O4 showed excellent recognition selectivity, as well as enrichment and separation abilities for 17beta-E2 in complex matrices. MIPs-GO-Fe3O4 was also used to analyze 17beta-E2 in real food samples, and satisfactory recoveries such as 84.20% with relative standard deviation (RSD) of 4.67% at a spike of 0.5 MUmol L(-1) were obtained. Thus, the MIPs-GO-Fe3O4-based method provided a convenient and practical platform for the separation, enrichment, and removal of 17beta-E2 in food samples. PMID- 25017482 TI - Experimental determination of kQ factors for cylindrical ionization chambers in 10 cm * 10 cm and 3 cm * 3 cm photon beams from 4 MV to 25 MV. AB - For the ionometric determination of absorbed dose to water, Dw, in megavoltage photon beams from a linear accelerator, beam-quality-dependent correction factors, kQ, are used for the ionization chambers. By using a water calorimeter, these factors can be determined experimentally and with substantially lower standard uncertainties compared to calculated values of the kQ, which are published in various dosimetry protocols. In this investigation, kQ for different types of cylindrical ionization chambers (NE 2561, NE 2571, FC 65 G) were determined experimentally in 10 cm * 10 cm photon beams from 4 MV to 25 MV (corresponding beam quality index TPR20,10 from 0.64 to 0.80). The measurements were carried out at the linear accelerator facility of the Physikalisch Technische Bundesanstalt. It is shown that the kQ factors for a single ionization chamber in 10 cm * 10 cm photon beams can be measured with a relative standard uncertainty of 0.31%. In addition to these measurements in 10 cm * 10 cm fields, kQ factors for the NE 2561 chamber were also determined in smaller 3 cm * 3 cm photon beams between 6 MV and 25 MV. In this case, relative standard uncertainties between 0.35 % and 0.38 % are achieved for the kQ factors. It is found for this ionization chamber, that the ratio of the kQ factors in 3 cm * 3 cm and in 10 cm * 10 cm beams increases with increasing TPR20,10 to reach a value of 1.0095 at TPR20,10 = 0.8 with a relative standard uncertainty of 0.4 %. PMID- 25017483 TI - Partial harvesting technique in anterior cruciate ligament reconstruction with autologous semitendinosus tendon to prevent a postoperative decrease in deep knee flexion torque. AB - BACKGROUND: A significant decrease in deep knee flexion torque has been reported after harvesting the semitendinosus tendon for anterior cruciate ligament (ACL) reconstruction. Thus, we have developed a partial harvesting technique that leaves part of the width of the insertion of semitendinosus tendon by splitting it. Our hypothesis was that the partial harvesting technique would reduce postoperative functional deficits in deep knee flexion by achieving regeneration of harvested tendon without shortening. METHODS: A total of 36 patients who underwent ACL reconstruction with an autologous semitendinosus tendon by means of either the conventional whole harvesting technique (whole-ST group, n=16) or the partial harvesting technique (partial-ST group, n=20) were included in this study. Clinical outcome, semitendinosus muscle length, and deep knee flexion torque were assessed 2 years after surgery. RESULTS: No significant group differences were found in terms of range of motion, Lysholm score, or anterior knee laxity. Shortening of the semitendinosus muscle was significantly less in the partial-ST group (mean 8mm) than in the whole-ST group (mean 36 mm; P<0.001). The side-to-side ratio of isometric knee flexion torque in the prone position with 90 degrees of knee flexion was statistically different between the partial ST (87.0 +/- 20.4%) and whole-ST (55.3 +/- 13.9%; P<0.001) groups. CONCLUSIONS: The present partial harvesting technique not only prevented shortening of the semitendinosus muscle, but also reduced the deficit in the maximum knee flexion angle in the standing position and a decrease in the deep knee flexion torque in the prone position with the partial harvesting technique compared to the nonoperated side with good clinical outcomes. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 25017484 TI - The effect of tibial component sizing on patient reported outcome measures following uncemented total knee replacement. AB - When performing total knee replacement (TKR), surgeons are required to decide on the most appropriate size of tibial component. As implants are predominantly selected from incremental sizes of a preferred design, it may be necessary for a surgeon to slightly under or oversize the component. There are concerns that overhang could lead to pain from irritation of soft tissues, and an undersized component could lead to subsidence and failure. Patient reported outcome measures were recorded in 154 TKRs at one year postoperatively (in 100 TKRs) and five years post-operatively (in 54 TKRs) in 138 patients. The Oxford Knee Score (OKS), WOMAC and SF-12 were recorded, and a composite pain score was derived from the OKS and WOMAC pain questions. Tibial component size and position were assessed on scaled radiographs and implants were grouped into anatomic sized tibial component (78 TKRs), undersized component (48 TKRs), minor overhang one to three mm (10 TKRs) or major overhang >= 3 mm (18 TKRs). There was no statistically significant difference between the mean post-operative OKS, WOMAC, SF-12 or composite pain score of each group. Furthermore, localisation of the site of pain did not correlate with medial or lateral overhang of the tibial component. Our results suggest that tibial component overhang or undersizing is not detrimental to outcome measures or pain. LEVEL OF EVIDENCE: II. PMID- 25017485 TI - Global dynamics of the buffered chemostat for a general class of response functions. AB - We study how a particular spatial structure with a buffer impacts the number of equilibria and their stability in the chemostat model. We show that the occurrence of a buffer can allow a species to persist or on the opposite to go extinct, depending on the characteristics of the buffer. For non-monotonic response functions, we characterize the buffered configurations that make the chemostat dynamics globally asymptotically stable, while this is not possible with single, serial or parallel vessels of the same total volume and input flow. These results are illustrated with the Haldane kinetic function. PMID- 25017486 TI - Periodic oscillations of a model for membrane permeability with fluctuating environmental conditions. AB - We perform an analytical study of the dynamics of a multi-solute model for water transport across a cell membrane under periodic fluctuations of the extracellular solute molalities. Under the presence of non-permeating intracellular solute, water volume experiences periodic oscillations if and only if the extracellular non-permeating solute molality is positive in the average. On the other hand, in the absence of non-permeating intracellular solute, a sufficient condition for the existence of an infinite number of periodic solutions of the model is provided. Such sufficient condition holds automatically in the case of only one permeating solute. The proofs are based on classical tools from the qualitative theory of differential equations, namely Brouwer degree, upper and lower solutions and comparison arguments. PMID- 25017487 TI - The pharmacokinetics of everolimus in de novo kidney transplant patients receiving tacrolimus: an analysis from the randomized ASSET study. AB - BACKGROUND: Pharmacokinetic data regarding a drug-drug interaction between everolimus and tacrolimus are sparse. MATERIAL AND METHODS: In a pharmacokinetic substudy of the randomized ASSET trial, 46 de novo kidney transplant patients receiving very low (1.5-3 ng/mL) or low (4-7 ng/mL) tacrolimus exposure after month 3, both with everolimus and steroids, provided area under the curve (AUC) concentration profiles at day 5 and months 1, 3, and 12. RESULTS: At month 12, mean values for tacrolimus trough concentration (C0), peak concentration (Cmax), and AUC0-12 in the very low tacrolimus group were approximately half that in the low tacrolimus group, but everolimus dose, C0, Cmax, and AUC0-12 were virtually identical in both groups. In a cross-study comparison with data at months 1 and 3 from the pharmacokinetic substudy of the A2307 trial, in which patients received cyclosporine, mean values for everolimus C0, Cmax and AUC0-12 were similar to those in the ASSET trial but the everolimus dose needed to achieve similar exposure was 1.5- to 2-fold higher with concomitant tacrolimus versus cyclosporine. CONCLUSIONS: Everolimus exposure is unaffected when tacrolimus exposure is down-titrated within the trough concentration range of 1.5-7 ng/mL. Higher doses of everolimus are needed to achieve a given exposure when combined with tacrolimus versus cyclosporine. PMID- 25017488 TI - Alternating stereoselective self-assembly of SSSS/RRRR or RSSR isomers of tetrakisphosphines in the row of 14-, 16-, 18- and 20-membered macrocycles. AB - Novel 18- and 20-membered P,N-macrocycles have been obtained stereoselectively by covalent self-assembly of alpha,omega-bisphosphines, formaldehyde and benzylamine. Alternating SSSS/RRRR or RSSR diastereomers were formed in the row of the 14-, 16-, 18- and 20-membered macrocyclic aminomethylphosphines. For the first time it was demonstrated that the stereochemical result of the reaction depends on the even or odd number of the methylene groups between the two chiral phosphorus atoms in the initial alpha,omega-bisphosphines. PMID- 25017489 TI - Reference genes for RT-qPCR studies in Corynebacterium pseudotuberculosis identified through analysis of RNA-seq data. AB - Reference genes presenting stable expression profiles over a wide variety of conditions are required in relative expression studies of specific bacterial genes by quantitative reverse transcription PCR (RT-qPCR). High-throughput sequencing of bacterial transcriptomes using the RNA-seq methodology now provides a wealth of data that may be searched for identification of the most stably expressed genes of a given bacterium. Herein, we searched a RNA-seq dataset from various experiments with the pathogenic bacterium Corynebacterium pseudotuberculosis, grown under different stress conditions, in order to select appropriate candidate reference genes for this species. Nineteen genes involved in maintenance of basic cellular functions, so-called housekeeping genes, were chosen for study and their expression profiles in C. pseudotuberculosis were evaluated throughout all growth conditions. Eight of these genes (atpA, dnaG, efp, fusA, gyrA, gyrB, rpoB, and rpoC), mostly participating in DNA replication and transcription, matched the defined criteria to be included as candidate reference genes. Transcriptional levels of these genes were quantified by RT-qPCR assays after growth of C. pseudotuberculosis under two additional conditions. Expression stability analysis by NormFinder indicated the combination of genes encoding DNA gyrase subunit A (gyrA) and elongation factor P (fusA) as the most suitable for normalization of RT-qPCR studies in C. pseudotuberculosis. PMID- 25017490 TI - Biomimicking micropatterned surfaces and their effect on marine biofouling. AB - When synthetic materials are submerged in marine environments, dissolved matter and marine organisms attach to their surfaces by a process known as marine fouling. This phenomenon may lead to diminished material performance with detrimental consequences. Bioinspired surface patterning and chemical surface modifications present promising approaches to the design of novel functional surfaces that can prevent biofouling phenomena. In this study, we report the synergistic effects of surface patterns, inspired by the marine decapod crab Myomenippe hardwickii in combination with chemical surface modifications toward suppressing marine fouling. M. hardwickii is known to maintain a relatively clean carapace although the species occurs in biofouling communities of tropical shallow subtidal coastal waters. Following the surface analysis of selected specimens, we designed hierarchical surface microtopographies that replicate the critical features observed on the crustacean surface. The micropatterned surfaces were modified with zwitterionic polymer brushes or with layer-by-layer deposited polyelectrolyte multilayers to enhance their antifouling and/or fouling-release potential. Chemically modified and unmodified micropatterned surfaces were subjected to extensive fouling tests, including laboratory assays against barnacle settlement and algae adhesion, and field static immersion tests. The results show a statistically significant reduction in settlement on the micropatterned surfaces as well as a synergistic effect when the microtopographies are combined with grafted polymer chains. PMID- 25017491 TI - Ligustrum lucidum Ait. fruit extract induces apoptosis and cell senescence in human hepatocellular carcinoma cells through upregulation of p21. AB - Nu-zhen-zi, the fruit of Ligustrum lucidum Ait., is one of the most frequently used liver Yin tonifying Chinese herbs for the treatment of liver cancer. However, the effect of Ligustrum lucidum fruit on hepatocarcinoma cells remains unknown. In the present study, we evaluated the effects of a Ligustrum lucidum fruit extract (LLFE) on human hepatocellular carcinoma Bel-7402 cells. The results showed that LLFE inhibited the proliferation of the Bel-7402 cells in a dose- and time-dependent manner. LLFE induced apoptosis in Bel-7402 cells accompanied by activation of caspase-3, -8 and -9. LLFE-induced apoptosis was completely abrogated by a pan caspase inhibitor, Z-VAD-FMK. LLFE treatment also caused a large and flat morphologic cellular change, positive SA-beta-gal staining, and G0/G1 phase cell cycle arrest in the Bel-7402 cells, accompanied by upregulation of p21 and downregulation of RB phosphorylation. Specific knockdown of p21 expression by RNA interference partially abrogated LLFE-induced apoptosis, and significantly abrogated LLFE-induced cell senescence. These observations suggest that Nu-zhen-zi is a potential anticancer herb and support the traditional use of Nu-zhen-zi for hepatocarcinoma treatment. PMID- 25017492 TI - Romanticism and schizophrenia. First part: The recency hypothesis and the core Gestalt of the disease. AB - Descriptions of irrational, incomprehensible, or unconstrained behavior such as is common nowadays in patients suffering from severe mental disorders can be found in the Bible, in Mesopotamian scripts, in classical Greek and Roman literature, and in the writings of many non-Western cultures. However, the presence of full-blown features of schizophrenia as seen today in psychiatric settings is controversial. Typical symptoms, the expected onset, duration and outcome, the impact of the disease on psychic functioning and the associated disability of the disease are mostly absent in those texts. Torrey (1980) and Hare (1988) have claimed that the disease did not exist before the year 1800 (this is known as the recency hypothesis). This would be the consequence of biological factors such as viruses, genetic or dietary factors or environmental contaminants associated to civilization. Others have put the emphasis on industrialization and its repercussions on social conditions such as family structure and migration. After analyzing the many manifestations of insanity in literary characters, in medical texts and in key historical figures, the arguments presented in this paper tend to support the recency hypothesis. A review of the core characteristics of schizophrenia and its impact on selfhood, intersubjetivity and ipseity, topics relatively neglected in recent psychiatric literature, opens the doors to consider in a second part the relationship between the features of Romanticism, starting by the "discovery of intimacy", and its articulation with the disturbance of ipseity and selfhood characteristic of the disease. PMID- 25017493 TI - Nonsuicidal self-injury in a community sample of older children and adolescents of Mexico City. AB - INTRODUCTION: In Mexico, as in other countries, studies do not distinguish between attempted suicide and suicidal and nonsuicidal self-injury (NSSI). The aim of this study was to investigate self-injury and its prevalence using several definitions, in addition to studying the frequency of the proposed DSM-5 criteria for NSSI in adolescent girls and boys. METHODOLOGY: The study was observational, descriptive, cross-sectional, and comparative using a nonrandomized sample of adolescent girls and boys from official high schools who completed the self injury questionnaire. RESULTS: The participants were 533 older children and adolescents with a mean (SD) age of 13.37 (0.95) years, age range 11 to 17 years, and 54% female sex distribution. The prevalence of NSSI defined according to proposed DSM-5 criteria was 5.6% (N=30) and, according to a broad definition using only item 51 ("Do you hurt yourself without intending to end your life?"), 17.1% (N=140). Prevalence defined by the number of events in the last month (1-3 events) was 9.9% (N=53), in the last 6 months (1-3 events), 11.6% (N=62), and in the last year (5 events), 12.6% (N=67). The age at onset was 11.9 (1.39) years (range 6-15 years). Most DSM-5 criteria were more frequent in girls than boys. CONCLUSIONS: Suicidal and nonsuicidal self-injury are frequent in the community. Important points for decision-making in schools and medical practice are discussed. PMID- 25017494 TI - Attention-deficit/hyperactivity disorder: prevalence of risk in the scholastic scope of the Canary Islands. AB - OBJECTIVE: To obtain data of prevalence of risk of the disorder attention deficit (ADHD) in the child and adolescent population of the Canary Islands. SUBJECTS AND METHOD: The sample used is 4858 participants of whom 2553 are girls (52.55%) and 2305 boys (47.45%) with a range of age between 6 and 16 years. Also of the total sample 2500 participants belong to primary while 2358 come from. These samples detected those participants exceeding the cut-off points in the EDAH scale versions validated for the Canary Islands. RESULTS AND CONCLUSIONS: Analysis of the data gives us a global risk of 11.52% prevalence, which is why one of every seven school children could manifest this disorder. We explore the possible differences by sex and age, both in primary and secondary. PMID- 25017495 TI - Effectiveness of cognitive-behavioral group therapy for panic disorder in a specialized unit. AB - INTRODUCTION: The efficacy of cognitive-behavior therapy for panic disorder (PD) with or without agoraphobia is well established, but few data exist on its effectiveness using a group format. The goal of the present study was to assess the effectiveness of group CBT in a sample of PD patients in a specialized unit. METHODS: Treatment consisted of nine weekly group sessions. Patients with PD (n=56) were assessed at baseline, after the treatment and in one and three-months followups. RESULTS: There were significant reductions in panic/agoraphobia symptoms and related variables between baseline and post-treatment, and these reductions were maintained in three-month follow-up. No differences were observed between those patients who received only CBT and those who received pharmacological treatment as well as CBT. Only initial panic/agoraphobia symptoms were significant predictors of treatment response at the end of treatment (a greater severity was associated with a worse response to CBT). CONCLUSIONS: Our results show that group CBT in a specialized unit is effective for PD patients. PMID- 25017496 TI - Neurodevelopment or neurodegeneration: review of theories of schizophrenia. AB - Many hypothesis have tried to explain the aetiology of schizophrenia, the abnormal neurodevelopmental hypothesis is one of the most widely acknowledged and is based on the presence of both prenatal and perinatal disorders, differences in IQ or the existence of genetic abnormalities, which, with the interaction of certain environmental factors, schizophrenia could occur at some point in the development. This hypothesis provides a good account of how these factors result in an alteration in the normal development and how they can lead to a disorder of schizophrenia. On the other hand, a smaller but not insignificant number of studies based on variables such as the presence of neurotoxicity in the brains of individuals with schizophrenia, alterations at the structural and brain connectivity, suggest the existence of a degenerative process in the course of this disease. In this work, we review the different factors underlying both hypotheses, some of which are difficult to categorize in either approach given the controversy and lack of consensus in their interpretation of the available data. Finally, we discuss the need for a non-exclusive alternative model to help understand the available evidence on the origin, course and consequences of the disease. PMID- 25017497 TI - Neuropsychological functioning of a patient with organic personality disorder. PMID- 25017498 TI - Should HAS-BLED scoring be revised for better risk estimation in patients with intracerebral hemorrhage? AB - Many efforts have been made to develop decision-support tools and bleeding prediction schemes to start or resume anticoagulation after intracerebral hemorrhage, related with anticoagulation use or not, such as CHA2DS2-VASc or HAS BLED scoring. HAS-BLED is a validated scoring system to predict the risk of major bleeding in a patient with atrial fibrillation; some current scientific guidelines suggest its use in 'risk-benefit' reasoning when deciding whether to start long-term oral anticoagulation. Here the authors present a patient with atrial fibrillation and intracerebral hemorrhage, and aim to discuss the use of HAS-BLED, suggesting that some revisions may help better management of these patients for major bleeding risk. PMID- 25017499 TI - The associations among hand dexterity, functional performance, and quality of life in diabetic patients with neuropathic hand from objective- and patient perceived measurements. AB - PURPOSE: To comprehend the associations among the dexterity and functional performance of the hands and quality of life in diabetic patients with neuropathic hands, via objective- and patient-perceived measurements. METHODS: The study participants were 144 diabetes patients who received objective evaluations, including the Purdue pegboard test, electrophysiological testing in sensory amplitude of the median nerve, and self-administrated measurements, including the Michigan Hand Outcomes Questionnaire (MHQ) and Diabetes-39 (D-39). Pearson's and Spearman's correlation tests were conducted to assess the relationships among hand neuropathy, hand dexterity and functions, and quality of life. RESULTS: The results show that the amplitude of the sensory nerve action potential of the median nerve was positively correlated with hand dexterity (r = 0.28-0.43; p < 0.01) and the total score of MHQ (r = 0.24-0.33; p < 0.01). Objective hand dexterity had mild to moderate relationships with most of the MHQ results, but only weak associations with some dimensions of the D-39 results. The MHQ results were negatively correlated with the D-39 scores, with mild to moderate relationships in the domains of energy/mobility and anxiety. CONCLUSIONS: In comparison with diabetic feet, neuropathic diabetic hands are an easily neglected problem, with insufficient empirical evidence in the literature to indicate its impact on functional performance and quality of life. This study showed that lesions related to neural functioning in the diabetic hand may negatively influence dexterity and functional hand performance and thus also affect the quality of life. PMID- 25017500 TI - Identification of gene-based responses in human blood cells exposed to alpha particle radiation. AB - BACKGROUND: The threat of a terrorist-precipitated nuclear event places humans at danger for radiological exposures. Isotopes which emit alpha (alpha)-particle radiation pose the highest risk. Currently, gene expression signatures are being developed for radiation biodosimetry and triage with respect to ionizing photon radiation. This study was designed to determine if similar gene expression profiles are obtained after exposures involving alpha-particles. METHODS: Peripheral blood mononuclear cells (PBMCs) were used to identify sensitive and robust gene-based biomarkers of alpha-particle radiation exposure. Cells were isolated from healthy individuals and were irradiated at doses ranging from 0-1.5 Gy. Microarray technology was employed to identify transcripts that were differentially expressed relative to unirradiated cells 24 hours post-exposure. Statistical analysis identified modulated genes at each of the individual doses. RESULTS: Twenty-nine genes were common to all doses with expression levels ranging from 2-10 fold relative to control treatment group. This subset of genes was further assessed in independent complete white blood cell (WBC) populations exposed to either alpha-particles or X-rays using quantitative real-time PCR. This 29 gene panel was responsive in the alpha-particle exposed WBCs and was shown to exhibit differential fold-changes compared to X-irradiated cells, though no alpha-particle specific transcripts were identified. CONCLUSION: Current gene panels for photon radiation may also be applicable for use in alpha-particle radiation biodosimetry. PMID- 25017501 TI - Reestablishment of Amblyomma tenellum Koch, 1844 (Acari: Ixodidae). AB - Herein, Amblyomma tenellumKoch, 1844 (Ixodidae) is reestablished as a valid tick name and removed from the synonymy list of Amblyomma cajennense (Fabricius, 1787), while Amblyomma imitatorKohls, 1958, is relegated to a junior synonym of A. tenellum. Amblyomma tenellum is redescribed based on the examination of male type specimens collected by Deppe at the beginning of the 19th century in Mexico and described by Koch in 1844. PMID- 25017502 TI - Pupillometry reveals reduced unconscious emotional reactivity in autism. AB - Recent theoretical conceptualisations have suggested that emotion processing impairments in autism stem from disruption to the sub-cortical, rapid emotion processing system. We argue that a clear way to ascertain whether this system is affected in autism is by measuring unconscious emotional reactivity. Using backwards masking, we presented fearful expressions non-consciously (subliminally) as well as consciously (supraliminally), and measured pupillary responses as an index of emotional reactivity in 19 children with autism and 19 typically developing children, aged 2-5 years. The pupillary responses of the children with autism revealed reduced unconscious emotional reactivity, with no group differences on consciously presented emotion. Together, these results indicate a hyporesponsiveness to non-consciously presented emotion suggesting a fundamental difference in emotion processing in autism, which requires consciousness and more time. PMID- 25017504 TI - Another unique river: a consideration of some of the characteristics of the trunk tributaries of the Nile River in northwestern Ethiopia in relationship to their aquatic food resources. AB - Aquatic food resources are important components of many modern human hunter gatherer diets and yet evidence attesting to the widespread exploitation of this food type appears rather late in the archaeological record. While there are times when, for example, the capture of fish and shellfish requires sophisticated technology, there are other cases when the exact ecological attributes of an individual species and the particulars of its environment make it possible for these foods to be incorporated into the human diet with little or no tool use and only a minimal time investment. In order to better understand the full set of variables that are considered in these sorts of foraging decisions, it is necessary to detail the attributes of each particular aquatic environment. We discuss here some of the characteristics of the trunk tributaries of the Nile and Blue Rivers in the Horn of Africa. Unlike typical perennial rivers, these 'temporary' rivers flow only during a brief but intense wet season; during the much longer dry season, the rivers are reduced to a series of increasingly disconnected waterholes, and the abundant and diverse fish and mollusk populations are trapped in ever smaller evaporating pools. The local human population today utilizes a number of diverse capture methods that range from simple to complex, and vary according to the size and depth of the waterhole and the time of the year. When we view the particular characteristics of an individual river system, we find that each river is 'unique' in its individual attributes. The Horn of Africa is believed to be along the route that modern humans followed on their migration out of Africa, and it is likely that the riverine-based foraging behaviors of these populations accompanied our species on its movement into the rest of the Old World. PMID- 25017503 TI - Speed pressure in conflict situations impedes inhibitory action control in Parkinson's disease. AB - The current study investigated the effects of Parkinson's disease (PD) on the ability to resolve conflicts when performance emphasized speed vs. response accuracy. PD patients and healthy controls (HC) completed a Simon task, and a subset of participants provided movement-related potential (MRP) data to investigate motor cortex activation and inhibition associated with conflict resolution. Both groups adjusted performance strategically with speed or accuracy instructions. The groups experienced similar susceptibility to making fast errors in conflict trials, but PD patients were less proficient compared to HC at suppressing incorrect responses, especially under speed pressure. Analysis of MRPs showed attenuated inhibition of the motor cortex controlling the conflicting response in PD patients compared to HC. These results confirm the detrimental effects of PD on inhibitory control mechanisms with speed pressure and also suggest that a downstream effect of inhibitory dysfunction in PD might be due to diminished inhibition of the motor cortex. PMID- 25017505 TI - The optical phonon spectrum of CdSe colloidal quantum dots. AB - The direct coupling of excited electronic states to optical phonons in single CdSe colloidal quantum dots is explored using both photoluminescence emission and excitation spectroscopies. We find a broad optical phonon spectrum associated with a single fine structure state. Multiple peaks in the optical phonon sideband are ascribed to different optical phonon types emanating from both the core and shell layers. A mixed emission process that involves the simultaneous generation of two different types of optical phonon is also observed. In general, rather than a single mode, each designated phonon type is associated with a dispersed family of modes. Narrow optical phonon sidebands, consistent with the dominant LO mode, are observed in some nanocrystals. A linewidth analysis indicates that optical phonon lifetimes are in the 10 picosecond range. We demonstrate the ability to selectively excite a specific band-edge state by directly exciting its LO phonon sideband. PMID- 25017506 TI - Mouse models for human infectious diseases. PMID- 25017507 TI - Isolation of healthy individuals' and rheumatoid arthritis patients' peripheral blood neutrophils by the gelatin and Ficoll-Hypaque methods: comparative efficiency and impact on the neutrophil oxidative metabolism and Fcgamma receptor expression. AB - In vitro assessment of the functional responses of leukocytes sometimes requires their isolation from blood, joint and tissues. In this study, we compared the efficiency of two procedures - the gelatin method and Ficoll-Hypaque density centrifugation gradient - to isolate peripheral blood neutrophils of healthy individuals and patients with active rheumatoid arthritis (RA). We also assessed whether these procedures affect the neutrophil activation status. Both purification procedures were concluded in 90min, and yielded cell populations with similar degrees of purity (80-90%), number of neutrophils (1-2*10(6) cells per mL of blood), and viability (97-100%). In vitro neutrophil priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased the reactive oxygen species producing ability of the cells stimulated with n formyl-methionyl-leucyl-phenylalanine (n-fMLP), soluble immune complexes (s-ICs), and insoluble immune complexes (i-ICs). Isolated neutrophils not treated with GM CSF responded to n-fMLP and i-IC, but not to s-IC. Almost all of the neutrophils (98-100%) purified by both methods expressed FcgammaRII/CD32 and FcgammaRIII/CD16, but they did not express significant levels of FcgammaRI/CD64. Similar results were obtained for healthy individuals' and RA patients' neutrophils. In summary, the gelatin method was comparable to Ficoll-Hypaque gradient in terms of purity, yield, and viability of the neutrophil preparations. Both methods neither primed or activated the neutrophils, nor affected their functional responsiveness. Therefore, both methods are suitable to isolate peripheral blood neutrophils of healthy individuals and RA patients. PMID- 25017508 TI - Successful treatment of a humeral capitulum osteonecrosis with bone morphogenetic protein-7 combined with autologous bone grafting. AB - We present the case of a 27-year-old female with subcortical osteonecrosis of the humeral capitulum. Percutaneous retrograde drilling of the lesion and application of recombinant human bone morphogenetic protein (BMP)-7 were combined with autologous bone grafting. At follow-up the patient was almost pain-free, had normalized her range of motion, and radiography showed consolidation of the lesion without any heterotopic bone formation. By timing surgery prior to subchondral collapse, biomechanical stability of the subchondral bone was maintained. To our knowledge, this is the first report on the treatment of an osteonecrosis in this location with a BMP, and this strategy could potentially be applied in other locations with juxta-articular osteonecrosis. PMID- 25017509 TI - Transforming growth factor-beta1 induces epithelial-mesenchymal transition and increased expression of matrix metalloproteinase-16 via miR-200b downregulation in bladder cancer cells. AB - Transforming growth factor-beta1 (TGF-beta1) is involved in the migration and metastases of bladder cancer. The present study was designed to investigate whether TGF-beta1 is able to induce epithelial-mesenchymal transition (EMT) and the upregulation of matrix metalloproteinase-16 (MMP-16), and to identify an association between EMT and MMP-16 in bladder cancer. Following TGF-beta1 treatment, samples of HTB9 and T24 bladder cancer cells were collected at various time points. Western blotting and quantitative polymerase chain reaction (qPCR) confirmed that TGF-beta1 induced EMT in HTB9 and T24 cells at the protein and mRNA levels. The expression levels of the miR-200 family were determined by qPCR, which indicated that TGF-beta1 treatment significantly reduced the expression of miR-200b. Bioinformatic analysis indicated that MMP-16 may be the target of miR 200b. Reporter luciferase assay confirmed that MMP-16 is a direct downstream functional target of miR-200b. A Matrigel migration assay demonstrated that miR 200b overexpression inhibited the migration of bladder cancer cells. In summary, the current study demonstrated that exogenous TGF-beta1 leads to the induction of EMT and the downregulation of miR-200b in bladder cancer cells. To the best of our knowledge, this is the first evidence that MMP-16 is a direct target of miR 200b. PMID- 25017510 TI - Nucleotide substitution analyses of the glaucophyte Cyanophora suggest an ancestrally lower mutation rate in plastid vs mitochondrial DNA for the Archaeplastida. AB - A lot is known about the evolution and architecture of plastid, mitochondrial, and nuclear genomes, but surprisingly little is known about their relative rates of mutation. Most available relative-rate data come from seed plants, which, with few exceptions, have a mitochondrial mutation rate that is lower than those of the plastid and nucleus. But new findings from diverse plastid-bearing lineages have shown that for some eukaryotes the mitochondrial mutation rate is an order of magnitude greater than those of the plastid and nucleus. Here, we explore for the first time relative rates of mutation within the Glaucophyta-one of three main lineages that make up the Archaeplastida (or Plantae sensu lato). Nucleotide substitution analyses from distinct isolates of the unicellular glaucophyte Cyanophora paradoxa reveal 4-5-fold lower rates of mutation in the plastid and nucleus than the mitochondrion, which is similar to the mutational pattern observed in red algae and haptophytes, but opposite to that of seed plants. These data, together with data from previous reports, suggest that for much of the known photosynthetic eukaryotic diversity, plastid DNA mutations occur less frequently than those in mitochondrial DNA. PMID- 25017511 TI - Purity matters more than harm in moral judgments of suicide: response to Gray (2014). AB - Many people judge suicide to be immoral. We have found evidence that these moral judgments are primarily predicted by people's belief that suicide taints the soul and by independent concerns about purity. This finding is inconsistent with accounts that define morality as fundamentally based upon harm considerations. In this commentary, we respond to a critique of our finding, and we provide further support for our original conclusions. Even when applying new exclusion criteria to our data, an examination of effect sizes demonstrates that concerns about purity robustly and meaningfully explain variance in moral judgments of suicide. While harm concerns sometimes predict moral judgments of suicide alongside purity concerns, they reliably explain a much smaller proportion of the variance than do purity concerns. Therefore, data from six studies continue to suggest that the relevance of harm concerns for moral judgments of suicide is substantially overshadowed by the contribution of purity concerns. PMID- 25017512 TI - Discussion. PMID- 25017513 TI - The prevalence and impact of undiagnosed cognitive impairment in older vascular surgical patients. AB - OBJECTIVE: The objectives of this observational cohort study were to investigate the prevalence of undiagnosed cognitive impairment in older patients presenting for vascular surgery, to examine its association with adverse postoperative outcomes, and to test the feasibility of a preoperative cognitive assessment tool. METHODS: Patients aged 60 years or older were recruited by consent on admission to the vascular surgical ward of an inner-city teaching hospital with a large tertiary referral practice for proposed elective or emergency aortic or lower limb arterial intervention. Cognition was assessed preoperatively by the Montreal Cognitive Assessment (MoCA), and a score below 24/30 indicated cognitive impairment or dementia. The mean length of time taken to complete the assessment was recorded. Baseline characteristics (medical multimorbidity, frailty, and laboratory tests), hospital length of stay (LOS), and postoperative complications were documented. RESULTS: Preoperative MoCA was completed in 114 patients with a mean age of 76.3 years (standard deviation, 7.36 years); 67.5% were men, and 55.3% of procedures were elective. The MoCA was completed in 100% of patients and was quick and acceptable to patients in this setting. Cognitive impairment or dementia was found in 68% of patients (77 of 114) and was previously unrecognized in 88.3% of patients (68 of 77). Therefore, 60.5% of patients (68 of 114) aged 60 years or older presenting for vascular surgery had previously undiagnosed cognitive impairment. MoCA <24 was univariately associated with pre-existing frailty (Edmonton Frail Scale [EFS] score >=6.5) and longer LOS (>=12 days). In logistic regression modeling, MoCA <24 was strongly independently associated with frailty EFS score >=6.5 (odds ratio, 12.55; P < .001). By use of the area under the receiver operating characteristic curve (AUC), MoCA <24 was predictive of longer LOS of >=12 days (AUC, 0.621; P = .049). The strength of predictive power increased with the addition of frailty (EFS score >=6.5) to the models (AUC, 0.695; P = .002). CONCLUSIONS: The prevalence of cognitive impairment among older patients presenting for vascular surgery is high and frequently undiagnosed before admission. It is feasible to use the MoCA to identify cognitive impairment in this high-risk surgical group preoperatively. The combined assessment of frailty and cognition is predictive of adverse postoperative outcomes and longer LOS. PMID- 25017514 TI - Open bypass and endovascular procedures among diabetic foot ulcer cases in the United States from 2001 to 2010. AB - OBJECTIVE: The objective of this study was to evaluate trends in outcomes of inpatient mortality, surgical complications, charges, and length of stay stratified according to open vs endovascular revascularization and amputation status in patients admitted to the hospital with diabetic foot ulcers (DFUs). METHODS: Inpatient discharge records from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project were used in this retrospective cohort study spanning 2001 to 2010. Multivariate regression analyses were used to simultaneously control for patient demographic and socioeconomic attributes, hospital characteristics, and comorbid case-mix disease severity. RESULTS: During the study period, 2.5 million inpatient DFU cases were observed, of which 412,051 (16.5%) involved amputation (34.8% major, 61.2% minor). Overall, 211,534 (8.5%) of DFU cases underwent revascularization (43.5% open, 51.1% endovascular treatment [EVT], 5.4% both). From 2001 vs 2010, the volume of open procedures decreased 34.9%, and EVT volume increased 197.1%. The percentage of amputations for DFUs remained relatively unchanged, and a major:minor ratio of 0.534 was observed among all cases. Across specific procedure type and amputation status, multivariate analyses indicated equal or decreased inpatient mortality and lengths of stay since 2001, and inflation-adjusted charges generally increased. The presence of a surgical complication, however, was observed to increase by >50% for open procedures involving minor amputations and >30% for open procedures involving no amputations. Because of many potential factors, surgical complications were noted to exceed approximately 900% among cases of EVT involving major amputations beginning in 2007 relative to 2001. CONCLUSIONS: This nationally-representative investigation found that DFU admissions are common, long, and costly (often >$100,000 per case), with a marked shift having occurred from open bypass to EVT. Although hospital mortality and length of stay either remained the same or have decreased significantly, an increase in procedure specific surgical complications was observed across several intervention categories. PMID- 25017515 TI - Aurora kinase A is a possible target of OSU-03012 to destabilize MYC family proteins. AB - OSU-03012, a 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitor, destabilizes MYCN and MYC proteins in neuroblastoma cells. However, AKT phosphorylation is barely detectable in neuroblastoma cells under normal culture conditions whether treated with OSU-03012 or not. This observation suggests that PDK1 is not the main target of OSU-03012 to destabilize MYC and MYCN in neuroblastoma cells. In the present study, we explored one of the possible mechanisms by which OSU-03012 destabilizes MYC and MYCN. Since Aurora kinase A is reported to phosphorylate GSK3beta, leading to its inactivation, we hypothesized that one of the targets of OSU-03012 is Aurora kinase A. Comparative analysis of OSU-03012 and VX-680, a potent and specific inhibitor of Aurora kinases, showed that both inhibitors destabilized MYC and MYCN and were significantly growth suppressive to neuroblastoma cell lines. In silico molecular docking analysis further showed that the calculated interaction energy between Aurora kinase A and OSU-03012 was 109.901 kcal/mol, which was lower than that (-89.273 kcal/mol) between Aurora kinase A and FXG, an Aurora kinase-specific inhibitor. Finally, an in vitro Aurora kinase A inhibition assay using a recombinant Aurora kinase A showed that OSU-03012 significantly inhibited Aurora kinase A, although it was weaker in potency than that of VX-680. Thus, OSU-03012 has a likelihood of binding to and inhibiting Aurora kinase A in vivo. These results suggest that OSU-03012 affects multiple cellular targets, including Aurora kinase A, to exhibit its growth suppressive and MYC and MYCN-destabilizing effects on neuroblastoma and other cancer cells. PMID- 25017516 TI - Looking in amoebae as a source of mycobacteria. AB - Mycobacteria exhibit various relationships with amoebae, ranging from the killing of one partner by the other one, to amoebae hosting mycobacteria in trophozoites and cysts. This observation indicates that poorly described biological factors affect the relationships, including mycobacterial cell-wall glycolipids and the size of the mycobacteria. Experimental observations indicate that a majority of environmental, opportunistic mycobacteria but also obligate pathogens including Mycobacterium tuberculosis, Mycobacterium leprae and Mycobacterium ulcerans are inter-amoebal organisms. Amoebae may give opportunities for genetic exchanges between mycobacteria, sympatric intra-amoebal organisms and the amoebae themselves. Amoebae clearly protect opportunistic mycobacterial pathogens during their environmental life but their role for obligate mycobacterial infection remains to be established. Accordingly, water was the source for emerging, community-acquired and health care-associated infection with amoeba-resisting mycobacteria of the Mycobacterium avium, Mycobacterium abscessus and Mycobacterium fortuitum groups, among others. Amoebae are organisms where mycobacteria can be found and, accordingly, amoeba co-culture can be used for the isolation of mycobacteria from environmental and clinical specimens. Looking in amoebae may help recovering new species of mycobacteria. PMID- 25017517 TI - Traditional uses, phytochemistry and pharmacology of Ficus carica: a review. AB - CONTEXT: Ficus carica Linn (Moraceae) has been used in traditional medicine for a wide range of ailments related to digestive, endocrine, reproductive, and respiratory systems. Additionally, it is also used in gastrointestinal tract and urinary tract infection. OBJECTIVE: This review gathers the fragmented information available in the literature regarding morphology, ethnomedicinal applications, phytochemistry, pharmacology, and toxicology of Ficus carica. It also explores the therapeutic potential of Ficus carica in the field of ethnophytopharmacology. MATERIALS AND METHODS: All the available information on Ficus carica was compiled from electronic databases such as Academic Journals, Ethnobotany, Google Scholar, PubMed, Science Direct, Web of Science, and library search. RESULTS: Worldwide ethnomedical uses of Ficus carica have been recorded which have been used traditionally for more than 40 types of disorders. Phytochemical research has led to the isolation of primary as well as secondary metabolites, plant pigment, and enzymes (protease, oxidase, and amylase). Fresh plant materials, crude extracts, and isolated components of Ficus carica have shown a wide spectrum of biological (pharmacological) activities. CONCLUSION: Ficus carica has emerged as a good source of traditional medicine for the treatment of various ailments such as anemia, cancer, diabetes, leprosy, liver diseases, paralysis, skin diseases, and ulcers. It is a promising candidate in pharmaceutical biology for the development/formulation of new drugs and future clinical uses. PMID- 25017518 TI - Anticoagulant activity of isolated coumarins (suberosin and suberenol) and toxicity evaluation of Ferulago carduchorum in rats. AB - CONTEXT: Ferulago carduchorum Boiss. & Hausskn. (Apiaceae) is known as Chavil in Persian which grows in west of Iran. Local people add Chavil to dairy and oil ghee as a natural preservative to extend the expiration date. OBJECTIVE: The goal of this survey is the safety evaluation of the total extract of F. carduchorum in rats by determining both oral acute and subchronic toxicities; furthermore, the anticoagulant activity of isolated coumarins was evaluated. MATERIALS AND METHODS: The aerial parts of F. carduchorum were extracted by the percolation method. The anticoagulant activity of isolated coumarins was evaluated and the total extract was used to investigate acute and subchronic toxicity in rats. In the subchronic toxicity model, doses of 250, 500, and 1000 mg/kg of the extract were administered to treated groups for 30 consecutive days by gavage. RESULTS: According to the results of acute toxicity, the LD50 of Chavil extract was more than 2000 mg/kg. The subchronic study showed no significant difference (p > 0.05) between the groups treated with extract and control groups in hematological (erythrocyte, total and differential leukocyte, hematocrit, hemoglobin, platelet count) and biochemical parameter (glucose, albumin, cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) evaluations. The isolated coumarins (suberosin and suberenol) prolonged the prothrombin time (PT) at doses of 3 and 6 mg/kg compared with control (p < 0.05). The longest PT was for suberosin at 6 mg/kg (17.4 s). CONCLUSION: In conclusion, oral administration of the Chavil extract did not cause either acute or subchronic toxicities although the coumarins showed anticoagulant effect in rats. PMID- 25017519 TI - Reply: To PMID 24374246. PMID- 25017520 TI - Anterior-apical single-incision mesh surgery (SIMS): surgical and functional outcomes at 1 year. AB - STUDY OBJECTIVES: To study the surgical and functional outcomes of single incision mesh surgery for treatment of advanced pelvic organ prolapse (POP). DESIGN: Case series (Canadian Task Force classification II-3). SETTING: University hospital. PATIENTS: Sixty-five patients who underwent surgery to treat symptomatic POP greater than stage II according to the Pelvic Organ Prolapse Quantification System (POP-Q). INTERVENTION: All patients underwent anterior apical single-incision mesh surgery using the Elevate Anterior and Apical Prolapse Repair System. MEASUREMENTS AND MAIN RESULTS: The primary objectives were anatomical correction of anterior and apical prolapse of POP stage I or greater and absence of voiding dysfunction reported via multi-channel urodynamic study at 6 months after surgery. Subjective outcome was measured via patient feedback using questions 2 and 3 of the Pelvic Organ Prolapse Distress Inventory 6 (POPDI-6). The secondary outcome was quality of life using the following: Urogenital Distress Inventory 6 (UDI-6), Incontinence Impact Questionnaire 7 (IIQ 7), POPDI-6, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). Two-dimensional introital ultrasonography was performed in the first and third months after surgery and at 1-year follow-up. Descriptive statistics were used for demographic and perioperative data. The paired-samples t test was used for comparison of preoperative and postoperative continuous data. For all comparisons, a value of p < .05 was considered statistically significant. All statistical methods were performed using commercially available software (SPSS version 17). Postoperative data were available for 64 patients. The objective outcome was 96.9%, and the subjective outcome was 93.8%. All patients demonstrated significant improvement in anatomical outcomes after prolapse surgery (p < .05), and none experienced recurrence requiring further surgery. There was concomitant significant improvement in POPDI-6, UDI-6, IIQ-7, and PISQ 12 scores after surgery. A subanalysis of POP quantification measurements immediately after surgery and at 1-year postoperative follow-up demonstrated deepening of the C point and total vaginal length. Ultrasound evaluation demonstrated a significant increase in the length and thickness of mesh at 1-year follow-up. There has been no documented mesh extrusion to date. However, the number of patients with stress urinary incontinence has increased. Four patients received treatment, whereas in the remaining patients the condition was not severe enough to require surgical intervention. CONCLUSIONS: Single-incision mesh surgery for treatment of advanced POP results in improvement in anatomical and quality-of-life outcomes. No mesh exposure was recorded in the first year after surgery; however, new onset of stress urinary incontinence may occur. Ultrasound evaluation demonstrated an increase in mesh length and thickness over time, with concurrent calculated lengthening of the C point and total vaginal length. PMID- 25017521 TI - Measurement of the sound intensity during suction of middle-ear fluid following myringotomy. AB - OBJECTIVE: To determine noise intensity during middle-ear aspiration in order to evaluate whether levels can be potentially harmful. METHODS: In this prospective, observational study, middle-ear effusion was aspirated following myringotomy using a suction instrument with a probe tube microphone. Sound pressure levels and duration were measured, and frequency domain analysis was performed. RESULTS: Forty-four ears were analysed, consisting of 20 with mucoid effusion, 11 with serous effusion and 13 with no effusion. Maximum peak sound intensity ranged from 84 to 157 dB. Half of the ears (50 per cent) were exposed to greater than 140 dB; of these, 82 per cent were exposed for longer than 0.2 ms (range, 0.05-14 ms). There was no significant difference in sound pressure level between ears with mucoid and serous effusion; however, ears with mucoid effusion required longer suction times (p < 0.0030). In addition, peak intensity was greater for ears with mucoid effusion versus those with serous or no effusion (p < 0.0001). CONCLUSION: Middle-ear aspiration during myringotomy caused noise levels within a potentially harmful range. PMID- 25017522 TI - Clinical management of atopic dermatitis: practical highlights and updates from the atopic dermatitis practice parameter 2012. AB - Atopic dermatitis is a challenging condition for clinicians and patients. Recent advances were documented in the Atopic Dermatitis Practice Parameter 2012, and we want to provide clinicians with key points from the Atopic Dermatitis Practice Parameter 2012. In this article, we highlight the evidence-based therapy of atopic dermatitis as well as provide practical tips for clinicians and families. An updated review of immunopathology provides a firm basis for patient education and therapy. We also review clinical diagnosis and ways to improve quality of life for patients with atopic dermatitis. PMID- 25017523 TI - Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. AB - Atopic dermatitis is the most common chronic inflammatory skin disease. Its pathogenesis combines barrier defects, immune dysregulation, and increased skin infections; however, the relative contribution of each of these components is yet to be determined. Uninvolved atopic dermatitis skin also displays broad immune and barrier abnormalities, which highlights a role for proactive treatment strategy. The residual disease genomic profile that accompanies clinical resolution provides further support for proactive treatment approaches. Although intrinsic and extrinsic atopic dermatitis subtypes share a common clinical phenotype, they show some important differences in their Th22/Th17 cytokine profile, which opens the door for personalized specific therapeutics for each disease category. PMID- 25017524 TI - The role of contact dermatitis in patients with atopic dermatitis. AB - Because both atopic dermatitis (AD) and contact dermatitis (CD) are characterized by a similar morphologic appearance and similar distribution of skin involvement, the diagnosis of CD in AD has been difficult. Historically, it was thought that patients with AD were unable or less likely to develop CD due to various studies in which patients with AD stimulated with strong allergens failed to develop sensitization at rates similar to patients without AD. However, more recent evidence from the United States and Europe has shown that patients with AD have similar if not higher rates of positive patch test results to common contact allergens, including metals and fragrance, than those patients without AD. In this review, we highlight evidence for and against the role of contact allergy in patients with AD and seek to give clinically relevant management recommendations for the evaluation of CD in the patient with AD. PMID- 25017525 TI - Atopic dermatitis in children. AB - A 7-year-old girl presented with atopic dermatitis (AD) that did not respond to standard therapy. She was avoiding dairy, egg, and wheat in her diet because of a history of skin flares. Her weight gain was poor, and laboratory test results showed low iron and zinc levels. Over the previous 6 months, she had been prescribed numerous courses of antibiotics, but, despite this, she continued to have secondary skin infections as well as deep circumscribed erosions on her shins. She was awake much of the night because of scratching and displayed repetitive and habitual behavior. She also had troublesome allergic rhinoconjunctivitis with positive allergy testing results to house dust mite. Methicillin-resistant Staphylococcus aureus was isolated from her skin, which was successfully treated with appropriate antibiotics and flares controlled with topical antiseptics and better personal and caregiver hygiene. Although milk, egg, and wheat specific IgE were raised, these foods were successfully reintroduced back into her diet with improvement of her nutritional status and no flare of her AD. In view of her habitual behavior and family history of obsessive compulsive disorder, she underwent cognitive behavioral therapy, and her general well-being, sleep, and ulcers over her shins improved. Despite high house dust mite-specific IgE, house dust mite sublingual immunotherapy led to no additional improvement in her AD although it did improve her rhinitis. Although there may be no "quick fixes" in patients with AD, the clinician should be aware of antimicrobial, allergen, and educational and/or behavioral interventions, which may greatly improve eczema severity and the patient's well-being. PMID- 25017526 TI - Recurrent MRSA skin infections in atopic dermatitis. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of recurrent skin and soft tissue infections. For patients with atopic dermatitis, recurrent skin infections with MRSA often lead to eczema exacerbation. There currently is no standard practice in the prevention of recurrent MRSA soft tissue infections in the general and the atopic dermatitis populations. The current article reviews recent data on S aureus decolonization treatments for the prevention of recurrent MRSA soft tissue infections in the community setting. PMID- 25017527 TI - Wet wrap therapy in children with moderate to severe atopic dermatitis in a multidisciplinary treatment program. AB - BACKGROUND: Atopic dermatitis (AD) is the most common chronic, relapsing inflammatory skin disease of children and is a global public health problem. National and international AD guidelines address AD care in a stepwise fashion. Wet wrap therapy (WWT) is a therapeutic intervention for moderate-to-severe AD. OBJECTIVE: This cohort study evaluated the effectiveness of WWT as part of a multidisciplinary AD treatment program to improve disease severity. Patients treated in this unique outpatient program had moderate-to-severe AD and had multiple therapies that failed. METHODS: An observational cohort study was completed. The primary outcome was improvement in AD severity as measured by SCORAD (Scoring Atopic Dermatitis). Demographics; clinical management of AD, including use of antibiotics and systemic treatments; and WWT methodology were comprehensively described. RESULTS: Seventy-two children with a mean +/- SD age of 4.6 +/- 3.12 years were included. By using a paired t test, the SCORAD at admission and at discharge showed significant differences in mean +/- SD values, of 49.68 +/- 17.72 versus 14.83 +/- 7.45, respectively (t, 18.93; df, 71; P < .001). None of these patients required systemic immunosuppressive therapy during the treatment program. By using a previously published parent-administered outcomes tool, patients were shown to maintain clinical improvement of their AD 1 month after discharge. CONCLUSION: To our knowledge, this study is the largest to date of WWT for pediatric patients with moderate-to-severe AD by using a validated outcomes tool. None of the patients required systemic immunosuppressive therapy, and only 31% were treated with an oral antibiotic. This study demonstrated the benefit of incorporating WWT as an acute intervention in a supervised multidisciplinary AD treatment program with lasting benefit 1 month after discontinuing this intervention. PMID- 25017528 TI - Effect of a drug allergy educational program and antibiotic prescribing guideline on inpatient clinical providers' antibiotic prescribing knowledge. AB - BACKGROUND: Inpatient providers have varying levels of knowledge in managing patients with drug and/or penicillin (PCN) allergy. OBJECTIVES: Our objectives were (1) to survey inpatient providers to ascertain their baseline drug allergy knowledge and preparedness in caring for patients with PCN allergy, and (2) to assess the impact of an educational program paired with the implementation of a hospital-based clinical guideline. METHODS: We electronically surveyed 521 inpatient providers at a tertiary care medical center at baseline and again 6 weeks after an educational initiative paired with clinical guideline implementation. The guideline informed providers on drug allergy history taking and antibiotic prescribing for inpatients with PCN or cephalosporin allergy. RESULTS: Of 323 unique responders, 42% (95% CI, 37-48%) reported no prior education in drug allergy. When considering those who responded to both surveys (n = 213), we observed a significant increase in knowledge about PCN skin testing (35% vs 54%; P < .001) and loss of PCN allergy over time (54% vs 80%; P < .0001). Among those who reported attending an educational session (n = 62), preparedness to determine if an allergy was severe significantly improved (77% vs 92%; P = .03). Other areas, including understanding absolute contraindications to receiving a drug again and PCN cross-reactivity with other antimicrobials, did not improve significantly. CONCLUSIONS: Inpatient providers have drug allergy knowledge deficits but are interested in tools to help them care for inpatients with drug allergies. Our educational initiative and hospital guideline implementation were associated with increased PCN allergy knowledge in several crucial areas. To improve care of inpatients with drug allergy, more research is needed to evaluate hospital policies and sustainable educational tools. PMID- 25017530 TI - Growth velocity reduced with once-daily fluticasone furoate nasal spray in prepubescent children with perennial allergic rhinitis. AB - BACKGROUND: The effect of fluticasone furoate nasal spray (FFNS) on growth in prepubescent children has not been evaluated. OBJECTIVE: To characterize the difference in mean prepubescent growth velocities, as determined by stadiometry, between patients treated continuously for 1 year with FFNS 110 mcg once daily and placebo nasal spray. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 76-week safety study. Nasal symptom assessments were used as a measure of adherence. Eligible patients were ages 5 to <8.5 years at screening and had at least a 1-year clinical history and diagnosis of perennial allergic rhinitis, including a positive skin test or specific IgE to an appropriate perennial allergen within the past year. RESULTS: One hundred eighty-six patients in the FFNS group and 187 patients in the placebo group completed the entire 52-week treatment period. During treatment, the least squares mean growth velocity was 5.19 cm/y for the FFNS group and 5.46 cm/y for the placebo group; mean difference, -0.270 cm/y (95% CI, -0.48 to -0.06 cm/y). Other safety assessments, including 24-hour urinary cortisol excretion, were comparable between the treatment groups. Daily reflective total nasal symptom scores declined similarly in both the FFNS and placebo groups. CONCLUSION: Once daily treatment with FFNS over 52 weeks in prepubescent children resulted in a small reduction in growth velocity compared with placebo. Clinicians will need to balance the reduction in growth observed with FFNS to its potential for clinical benefit. PMID- 25017529 TI - Nonsteroidal anti-inflammatory drugs are major causes of drug-induced anaphylaxis. AB - BACKGROUND: Drugs are responsible for 40% to 60% of anaphylactic reactions treated in the emergency department. A global research agenda to address uncertainties in anaphylaxis includes studies that identify factors associated with morbidity and mortality. OBJECTIVE: The present study investigated drug induced anaphylaxis, etiologies, aggravating factors, and treatment. METHODS: A total of 806 patients with adverse drug reactions were screened, and those who had a clinical diagnosis of anaphylaxis were included in the study. Clinical and demographic characteristics of anaphylaxis were described, including etiologies, pathophysiologic mechanisms involved in the reactions, and a personal history of atopy and asthma. Factors associated with disease severity also were identified. RESULTS: Anaphylaxis was diagnosed in 117 patients (14.5%). The etiologies were defined in 76% of the cases, nonsteroidal anti-inflammatory drugs being the most frequent. Seventy-eight patients (66.7%) reported a previous reaction to the drug involved in the current reaction or to a drug from the same class and/or group. Epinephrine was used to treat 34.2% of patients who presented with anaphylaxis, and 40.8% of those with anaphylactic reactions with cardiovascular involvement. IgE-mediated reactions were associated with greater severity, manifested by the rates of cardiovascular dysfunction, hospitalization, and use of epinephrine. CONCLUSIONS: The prevalence of anaphylaxis is high in patients who seek medical assistance for drug reactions, but its diagnosis is missed in emergency services, and adrenaline is underused. Drugs were prescribed to many patients despite a history of previous reaction. Nonsteroidal anti-inflammatory drugs were implicated in most cases of anaphylaxis induced by drugs, and IgE-mediated reactions were less frequent but more severe. PMID- 25017531 TI - Management of hypersensitivity reactions to Carboplatin and Paclitaxel in an outpatient oncology infusion center: a 5-year review. AB - BACKGROUND: A high incidence of hypersensitivity reactions (HSR) to carboplatin and Taxol is limiting the use of carboplatin and Taxol. OBJECTIVE: We conducted a 5-year study of all patients with HSR to carboplatin or Taxol to better understand the nature of infusion HSR and success or failure of management plans after the initial HSR. METHODS: We performed a retrospective chart review of all safety reports from the Massachusetts General Hospital outpatient chemotherapy infusion center between January 2006 and February 2011. All the patients with HSRs to carboplatin or Taxol were identified and included in the final analysis. We reviewed patient characteristics, clinical symptoms, timing, and treatment of the initial HSR, and determined if the patient was rechallenged despite an initial HSR. RESULTS: We identified 152 patients with HSR to carboplatin (n = 45) or Taxol (n = 107). Carboplatin HSR was less severe than Taxol HSR. When comparing the 2 groups, the patients with carboplatin HSRs more commonly described itchy palms and feet, generalized itch, and general urticaria and/or erythema, whereas patients with Taxol HSR more commonly described facial flushing, back pain, and chest or throat tightness (all P < .05). Among 40 patients with mild-to-moderate carboplatin HSRs, only 7 were rechallenged, and 100% tolerated rechallenge without desensitization. None of the patients with severe carboplatin HSRs (n = 5) were rechallenged. Most patients (75%) with Taxol HSRs were rechallenged, and 91% tolerated rechallenge without desensitization; the patients with a severe HSR to Taxol were less likely to be rechallenged. CONCLUSION: The clinical symptoms and timing of carboplatin HSR are distinct from Taxol HSR. Most patients with carboplatin HSR were not rechallenged, whereas most patients with Taxol HSR were successfully rechallenged. PMID- 25017532 TI - Treatment of chronic urticaria in children with antihistamines and cyclosporine. AB - BACKGROUND: Chronic idiopathic urticaria, daily hives that last >6 weeks, can be resistant to antihistamines, even when higher than conventional doses are used. Other pharmacologic agents have been associated with inconsistent benefit. OBJECTIVE: We examined the relationship of clinical characteristics and the presence of autoimmune antibodies to antihistamine resistance in children. We further examined the efficacy and safety of cyclosporine in children whose urticaria was resistant to antihistamine. METHODS: Patients referred to the pediatric allergy and pulmonary specialty clinic at the University of Iowa Children's Hospital and diagnosed as having chronic idiopathic urticaria were identified during the period from August 2008 to July 2013. A retrospective examination of treatment and outcome was performed. RESULTS: Forty-six patients, 26 female patients and 20 male patients, with chronic idiopathic urticaria were identified. The ages of 16 patients who were antihistamine resistant ranged from 9 to 18 years (median, 12.5 years). Those patients who were antihistamine responsive had a median age of 6 years, significantly lower than those who were antihistamine resistant (P = .0001). There was no significant association between autoimmune antibodies and antihistamine resistance. All the patients who were antihistamine resistant were treated with cyclosporine; all experienced complete resolution of urticaria at times that ranged from 2 days to 3 months (median, 7 days). Relapses responsive to repeated cyclosporine occurred in 5 of the patients after 1 week to 15 months (median, 6 months). Adverse effects were not seen in these patients. CONCLUSION: Our data were consistent with efficacy and safety of cyclosporine for chronic urticaria in children when even high doses of antihistamines are ineffective. PMID- 25017533 TI - Penicillin skin testing is a safe and effective tool for evaluating penicillin allergy in the pediatric population. AB - BACKGROUND: Penicillin skin testing has been validated in the evaluation of adult patients with penicillin allergy. However, the commercially available benzylpenicilloyl polylysine (Pre-Pen) is not indicated in the pediatric population. Moreover, the safety and validity of penicillin skin testing in the pediatric population has not been well studied. OBJECTIVE: We describe the safety and validity of penicillin skin testing in the evaluation of children with a history of penicillin allergy. METHODS: Children (<18 years) with a history of penicillin allergy were evaluated with penicillin skin tests and were reviewed for basic demographics, penicillin skin test results, adverse drug reaction to penicillin after penicillin skin test, and adverse reaction to penicillin skin test. By using the chi(2) test, we compared the differences in the proportion of children and adults with a positive penicillin skin test. P value (<.05) was considered statistically significant. The institutional review board approved the study, and all the subjects signed written informed consents. RESULTS: A total of 778 children underwent penicillin skin testing; 703 of 778 patients had a negative penicillin skin test (90.4%), 66 had a positive test (8.5%), and 9 had an equivocal test (1.1%). Children were more likely to have a positive penicillin skin test (P < .0001) compared with adults (64 of 1759 [3.6%]); 369 of 703 patients with negative penicillin skin test (52%) were challenged with penicillin, and 14 of 369 patients (3.8%) had an adverse drug reaction. No adverse reactions to penicillin skin testing were observed. CONCLUSION: Penicillin skin testing was safe and effective in the evaluation of children with a history of penicillin allergy. PMID- 25017534 TI - Real-time asthma outreach reduces excessive short-acting beta2-agonist use: a randomized study. AB - BACKGROUND: Excessive use of short-acting beta2-agonists (SABA) indicates impaired asthma control. OBJECTIVE: To determine whether real-time outreach to excessive SABA users reduces SABA canister dispensings. METHODS: After real-time determination of a seventh SABA canister dispensing in the prior 12 months by using informational pharmacy technology, 12 to 56 year old patients with physician-coded asthma and inhaled corticosteroid dispensing were block randomized by prior asthma specialist care and medication step-care level into intervention (n = 1001) and control groups (n = 998). Intervention included real time letter notification to patients and an electronic message to their physician with management suggestions, including facilitated allergy referral for patients without prior asthma specialist care. The control group received this organization's standard asthma care management without research contact. Frequency of the seventh SABA canister dispensing in the follow-up year was the primary outcome. RESULTS: Compared with controls, intervention patients reached 7 SABA canister dispensings less frequently (50.7% vs 57.1%; risk ratio 0.89 [95% CI, 0.82-0.97]; P = .007) and later (hazard ratio 0.80 [95% CI, 0.71-0.91; P < .001). SABA canister dispensings (mean +/- SD) were less in intervention (7.5 +/- 4.9 canisters) than controls (8.6 +/- 5.3 canisters) (rate ratio 0.87 [95% CI, 0.82-0.93]; P < .001). The intervention reduced the risk of >=7 SABA canister dispensings in patients without specialist care compared with patients with specialist care in the prior 3 years (P < .001) (P = .04 for interaction by prior specialist care). Visits to allergists were more frequent for intervention patients (30.9%) than for control patients (16.8%) (risk ratio 1.83 [95% CI, 1.54 2.16]; P < .001). Asthma exacerbations were unaffected. CONCLUSIONS: A novel administrative-based asthma outreach program improves markers of asthma impairment in patients without prior asthma specialist care and is adaptable to managed care organizations with electronic medical records. PMID- 25017535 TI - Electronic health record-generated interventions to reduce asthma risk: seeing the glass half full. PMID- 25017536 TI - An unusual case of recurrent "recall urticaria" in a patient on immunotherapy. PMID- 25017537 TI - A survey of physician practice and knowledge of drug allergy at a university medical center. PMID- 25017538 TI - Predisposition to infection and SIRS in mitochondrial disorders: 8 years' experience in an academic center. PMID- 25017539 TI - Fixed drug eruption to quinine: a case report and review of the literature. PMID- 25017541 TI - Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis. PMID- 25017540 TI - Hypersensitivity to methylprednisolone sodium succinate in children with milk allergy. PMID- 25017542 TI - Anaphylaxis during skin prick testing for amoxicillin allergy. PMID- 25017544 TI - Hypersensitivity pneumonitis by Fusarium vasinfectum in a home environment. PMID- 25017543 TI - Low preparedness for food allergy as perceived by school staff: a EuroPrevall survey across Europe. PMID- 25017546 TI - Systemic contact dermatitis possibly related to metal implants. PMID- 25017545 TI - Clinical case of anaphylaxis with sublingual immunotherapy: house dust mite allergen. PMID- 25017547 TI - Non-activation ZnO array as a buffering layer to fabricate strongly adhesive metal-organic framework/PVDF hollow fiber membranes. AB - A non-activation (NA) ZnO array is directly grown on a PVDF hollow fiber membrane. The defect-free MOF layers can be synthesized easily on the NA-ZnO array without any activation procedure. The array and MOF layers are strongly adhered to the hollow fiber membrane. The prepared ZIF membranes exhibit excellent gas separation performances. PMID- 25017549 TI - Bringing new HIV infections to zero - opportunities and challenges offered by antiretroviral-based prevention in Asia, the Pacific and beyond: An overview of this special issue. AB - This editorial to the special issue of Sexual Health on antiretroviral-based prevention of HIV infection is dedicated to showcasing research and practice in this area. It aims to promote debate regarding the potential of new antiretroviral-based prevention approaches and the challenges encountered in moving prevention innovations into the community. This special issue covers the breadth of innovative HIV prevention research, including that undertaken in the fields of epidemiology, clinical research, social and behavioural science, public health and policy analysis, and with special emphasis on Asia and the Pacific region. Most importantly, it provides an indication of how the region is progressing towards embracing new prevention approaches to combat HIV epidemics across the region. PMID- 25017548 TI - The development and application of audit criteria for assessing knowledge exchange plans in health research grant applications. AB - BACKGROUND: Research funders expect evidence of end user engagement and impact plans in research proposals. Drawing upon existing frameworks, we developed audit criteria to help researchers and their institutions assess the knowledge exchange plans of health research proposals. FINDINGS: Criteria clustered around five themes: problem definition; involvement of research users; public and patient engagement; dissemination and implementation; and planning, management and evaluation of knowledge exchange. We applied these to a sample of grant applications from one research institution in the United Kingdom to demonstrate feasibility. CONCLUSION: Our criteria may be useful as a tool for researcher self assessment and for research institutions to assess the quality of knowledge exchange plans and identify areas for systematic improvement. PMID- 25017551 TI - Preface to 'Antiretroviral-based Prevention of HIV'. PMID- 25017552 TI - Relationship based care and the psychiatric mental health nurse. PMID- 25017553 TI - Nurse as athlete: an antidote for compassion fatigue. PMID- 25017554 TI - Resilience, loneliness, and psychological distress among homeless youth. AB - Extant quantitative research on loneliness among homeless youth has grouped loneliness with other elements of psychological distress. The current study seeks to determine if loneliness has a different relationship with resilience than does psychological distress among street youth. Using data from 47 participants, linear regression was conducted. Results indicate that homeless youth experiencing higher psychological distress reported lower resilience scores. However, levels of resilience are not significantly associated with feelings of loneliness when psychological distress was accounted for. This study has implications for how researchers and clinicians conceptualize and address feelings of loneliness among homeless youth. PMID- 25017555 TI - Hope, hopelessness, and anxiety: a pilot instrument comparison study. AB - BACKGROUND AND PURPOSE: Hope has a powerful influence on living. This pilot study compared three measures of hope and one hopelessness measure, and examined their associations with a measure of anxiety. METHODS: In this cross-sectional study, 23 adult mental health patients >=18 years old completed the: Herth Hope Index, Miller Hope Scale, Snyder Hope Scale, Beck Hopelessness Scale, and STAI-S, STAI T. RESULTS: Cronbach's alpha from each instrument ranged from 0.85 to 0.96. Correlations ranged from -.802 to .780. PMID- 25017556 TI - Family skills training in dialectical behaviour therapy: the experience of the significant others. AB - AIM: The aim was to describe significant others' experiences of dialectical behaviour therapy-family skills training (DBT-FST), their life situation before and after DBT-FST, and measurement of their levels of anxiety and depressive symptoms. METHODS: The study had a descriptive mixed method design. Data were collected with free text questionnaires (n=44), group interviews (n=53) and the HAD scale (n=52) and analysed by qualitative content analysis and descriptive and inferential statistics. RESULTS: The results show that life before DBT-FST was a struggle. DBT-FST gave hope for the future and provided strategies, helpful in daily life. For the subgroup without symptoms of anxiety and depression before DBT-FST, anxiety increased significantly. For the subgroup with symptoms of anxiety and depression the symptoms decreased significantly. This indicates, despite increased anxiety for one group, that DBT-FST is a beneficial intervention and most beneficial for those with the highest anxiety- and depressive symptoms. PMID- 25017557 TI - Older Hispanics' explanatory model of depression. AB - Cultural variations in the perception of depression make it difficult to recognize the disorder resulting in older Hispanics not being diagnosed and not receiving appropriate treatment. This study used a mixed-method design to explore older Hispanics' explanatory model of depression. Depression was recognized as the result of life stressors and personal weaknesses. Terms used for depressed people included "crazy, worry, bored, and nerves." These culturally coded terms may confound diagnosis among many Hispanics who find depression a shameful condition. Findings can be used to inform the adaptation of culturally relevant approaches to better serve the Hispanic community in this country. PMID- 25017558 TI - Lessons learned from implementing a pilot RCT of transitional care model for individuals with serious mental illness. AB - We adapted an evidence-based transitional care model for older adults being released from acute care hospitals for patients with serious mental illness and medical co-morbidities being discharged from two psychiatric units of an acute care hospital (TCare) and evaluated implementation issues. An advisory group (AG) of community stakeholders assessed barriers and facilitators of a 90-day T-Care intervention delivered by a psychiatric nurse practitioner (NP) in the context of conducting a pilot randomized controlled trial. Minutes of AG and case narratives by NP of 20 intervention participants were content analyzed. Patients with immediate and pressing physical health problems were most receptive and actively utilized the service. Provider barriers consisted of communication and privacy issues making it difficult to contact patients in mental health facilities. In contrast, the NP was accepted and valued in the physical health arena. Psychosocial needs and relationship issues were demanding, and we recommend a team approach for TCare with the addition of a social worker, peer provider, and consulting psychiatrist for severely mentally ill patients being released from an acute physical health hospitalization. PMID- 25017559 TI - Mental health literacy and postpartum depression: a qualitative description of views of lower income women. AB - The purpose of this study is to understand mental health literacy (MHL) (Jorm, 2000) in lower income women postpartum and share participant experiences of recognizing and seeking help for depressive symptoms. Focus group textual data were received from 25 participants who completed a weight and psychosocial health longitudinal study. Iterative content data analysis using Jorm's framework provided thematic understandings descriptive of MHL. Women recognized behavioral changes indicating mental distress, but fears prevented them from seeking help, and some resorted to risky behaviors. This framework could guide providers to identify women who may benefit from early intervention for postpartum depressive symptoms. PMID- 25017560 TI - Mental health care professionals' experiences with the discharge planning process and transitioning patients attending outpatient clinics into community care. AB - BACKGROUND: Health care reform promotes delivery of mental health care in the community. Outpatient mental healthcare professionals (HCPs) are pressured to discharge patients. This study's purpose: to understand the experience and perceptions of mental HCPs with discharge planning and transitioning patients into community care. METHODS: Twelve HCPs participated in semi-structured qualitative interviews. FINDINGS: Three main categories: engaging in the discharge planning process, making the transition smooth, and guiding values emerged. A conceptual framework was created to explain the phenomenon. CONCLUSION: HCPs valued strengthening partnerships and building relationships to ensure smooth transition. Sufficient resources and trust imperative for safe patient discharge. PMID- 25017561 TI - Frequency of involuntary admissions and its associations with demographic and clinical characteristics in China. AB - Involuntary admissions (IA) continue to be a controversial topic in psychiatry. There have been very few studies investigating the pattern of IA and contributing factors in Chinese psychiatric patients. This study examined the prevalence of IA and its relationships with demographic and clinical characteristics in a large psychiatric institution in Hunan province, China. A consecutively collected sample of 161 psychiatric inpatients was collected. The patients' basic socio demographic and clinical data including admission types were collected. The frequency of IA was 53.1% in the whole sample. In multiple logistic regression analysis, IA was independently associated with female sex, more recent aggression prior to admission and poorer social function and insight into illness. IA was common in clinical practice in China, and its demographic and clinical correlates are similar to the findings reported from western settings. PMID- 25017562 TI - Evaluation of a theory-based education program to motivate nursing students to intervene with their seriously mentally ill clients who use tobacco. AB - Tobacco dependence is a major health problem for persons with a serious mental illness (SMI). Nurses working with psychiatric clients often lack the knowledge, ability, and confidence to offer their clients meaningful, effective help to quit smoking. The purpose of this study was to evaluate the effects of a tobacco education program on the perceived competence and motivation of baccalaureate nursing students (BSN) to intervene with SMI clients who use tobacco. The education program significantly improved the competence and motivation of BSN students to deliver cessation interventions to this vulnerable population of smokers. PMID- 25017563 TI - Development and psychometric testing of the Suicide Caring Competence Scale (SCCS) for family caregivers in Taiwan. AB - Suicide caring competence is important for family caregivers to care their relatives with suicidal tendencies. The purpose of this study was to develop and test the psychometric properties of the Suicide Caring Competence Scale (SCCS) for family caregivers in Taiwan. A 20-item SCCS was tested on 165 family caregivers. Confirmatory factor analysis indicated that five subscales with 19 items best fit the data. The Cronbach's alpha and test-retest reliability of the SCCS was 0.90 and 0.81, respectively. The SCCS demonstrated acceptable construct validity and reliability. Nurses can use the SCCS to assess the suicide caring competence of family caregivers. PMID- 25017564 TI - Investigation of the effect of self-efficacy levels of caregiver family members of the individuals with schizophrenia on burden of care. AB - Sixty-two individuals with schizophrenia and their families were part of a descriptive study that investigated the effect of self-efficacy levels on the burden of care, using family member caregivers of schizophrenia patients. Data were collected using a questionnaire on the descriptive characteristics of patients and their families, the Self-Efficacy Scale, and Zarit Caregiver Burden Scale. The results for caregivers indicated a total mean self-efficacy score of 76.4+/-17.76 and a total mean of burden of care score of 68.64+/-18.60. A negative significant relation was discovered by looking at the correlation between the total mean scores (r=-.260, p<0.05). These results indicate that the burden of care decreases with the increasing level of self-efficacy in caregiver family members. PMID- 25017565 TI - The adolescent brain: an overview of recent research. PMID- 25017566 TI - Caveolin-1 functions as a key regulator of 17beta-estradiol-mediated autophagy and apoptosis in BT474 breast cancer cells. AB - Estradiol (E2) acts as a crucial regulator of cell growth by mediating autophagy and apoptosis in breast cancer cells. Caveolin-1 plays a key role in carcinogenesis through its diverse roles in membrane trafficking, cholesterol transport and cellular signal transduction. However, it remains unknown as to how caveolin-1 is associated with E2-mediated autophagy and apoptosis in breast cancer cells. To resolve this issue, in the present study, we used the human breast cancer cell line, BT474, in which caveolin-1 is abundantly expressed. We demonstrated that treatment with E2 increased the expression of caveolin-1, high mobility group box 1 protein (HMGB1) and autophagy-related proteins [Beclin-1, light chain (LC3)-II and Atg12/5] in a time-dependent manner and inhibited the apoptosis of BT474 cells. Following the knockdown of caveolin-1 expression using small interfering RNA (siRNA), the expression of HMGB1, LC3-II and Atg12/5 was decreased, autophgosome formation was inhibited and apoptosis was induced; however, Beclin-1 expression was not affected. Furthermore, we knocked down HMGB1 to validate the role of HMGB1 in E2/caveolin-1-regulated autophagy and apoptosis. Notably, the knockdown of HMGB1 decreased the expression of Beclin-1 and LC3-II and attenuated autophgosome formation and promoted apoptosis. Furthmore, caveolin 1 or HMGB1 knockdown markedly suppressed E2-induced cell growth. These results suggest that caveolin-1 is a positive regulator for E2-induced cell growth by promoting auptophagy and inhibiting apoptosis in BT474 cells. PMID- 25017567 TI - Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention. AB - Beginning in the last decade of the twentieth century, the fields of pigment cell research and melanoma have witnessed major breakthroughs in the understanding of the role of melanocortins in human pigmentation and the DNA damage response of human melanocytes to solar ultraviolet radiation (UV). This began with the cloning of the melanocortin 1 receptor (MC1R) gene from human melanocytes and the demonstration that the encoded receptor is functional. Subsequently, population studies found that the MC1R gene is highly polymorphic, and that some of its variants are associated with red hair phenotype, fair skin and poor tanning ability. Using human melanocytes cultured from donors with different MC1R genotypes revealed that the alleles associated with red hair color encode for a non-functional receptor. Epidemiological studies linked the MC1R red hair color variants to increased melanoma risk. Investigating the impact of different MC1R variants on the response of human melanocytes to UV led to the important discovery that the MC1R signaling activates antioxidant, DNA repair and survival pathways, in addition to stimulation of eumelanin synthesis. These effects of MC1R were absent in melanocytes expressing 2 MC1R red hair color variants that result in loss of function of the receptor. The importance of the MC1R in reducing UV-induced genotoxicity in melanocytes led us to design small peptide analogs of the physiological MC1R agonist alpha-melanocortin (alpha-melanocyte stimulating hormone; alpha-MSH) for the goal of utilizing them for melanoma chemoprevention. PMID- 25017568 TI - Cyclic AMP (cAMP) signaling in melanocytes and melanoma. AB - G-protein coupled receptors (GPCRs), which include melanocortin-1 receptor (MC1R), play a crucial role in melanocytes development, proliferation and differentiation. Activation of the MC1R by the alpha-melanocyte stimulating hormone (alpha-MSH) leads to the activation of the cAMP signaling pathway that is mainly associated with differentiation and pigment production. Some MC1R polymorphisms produce cAMP signaling impairment and pigmentary phenotypes such as the red head color and fair skin phenotype (RHC) that is usually associated with higher risk for melanoma development. Despite its importance in melanocyte biology, the role of cAMP signaling cutaneous melanoma is not well understood. Melanoma is primarily driven by mutations in the components of mitogen-activated protein kinases (MAPK) pathway. Increasing evidence, however, now suggests that cAMP signaling also plays an important role in melanoma even though genetic alterations in components of this pathway are note commonly found in melanoma. Here we review these new roles for cAMP in melanoma including its contribution to the notorious treatment resistance of melanoma. PMID- 25017569 TI - Effectiveness of antipsychotic drugs against hostility in patients with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study - ADDENDUM. PMID- 25017570 TI - Dissociating effects of acute photic stress on spatial, episodic-like and working memory in the rat. AB - Adaptively responding to acute stress has been of great importance for human and animal survival. However, for our species, stress-related disorders are putting an ever-increasing burden on healthcare systems. It is thus crucial to understand the basic processes and cognitive changes associated with acute stress. Here, we examined the effects of acute stress exposure on spatial (water maze) and memory (delayed match to sample and episodic-memory-like tasks) performance. We found striking performance deficits in stressed animals navigating in the water maze. We also found, in an episodic-like memory task, striking object-location deficits, but not in temporal-object association learning in stressed animals. Finally, no differences were apparent for any delay periods (up to 30s) in a delayed match to sample task. Taken together, these results show a strong differential effect of acute stress on differing memory processes. PMID- 25017572 TI - Microinjections of a dopamine D1 receptor antagonist into the ventral tegmental area block the expression of cocaine conditioned place preference in rats. AB - Stimulation of dopamine (DA) D1 receptors in the ventral tegmental area (VTA) is involved in primary rewards. In the current study we investigated whether VTA D1 receptor stimulation likewise plays a role in mediating the rewarding effects of cocaine-associated stimuli, using the cocaine conditioned place preference (CPP) paradigm. Rats were prepared with cannulae so as to allow microinjections in the VTA and later conditioned to a cocaine-associated environment using the CPP paradigm. Prior to each conditioning session rats were injected with either saline or cocaine (10mg/kg, intraperitoneally) and then placed in one of the two sides of the CPP apparatus. Sessions lasted 30min a day over a period of eight days, such that rats alternated daily between consistently experiencing cocaine in one side and saline in the other. On the test day, which was conducted one day after conditioning, rats were given bilateral microinjections of one of four doses of the D1 antagonist, SCH 23390, (0, 2, 4 or 8MUg/0.5MUl) directly into the VTA and allowed free access to both sides of the apparatus. Preference for either side was measured as time spent in each side and compared to the same measures taken before conditioning. The D1 antagonist produced a dose-related, significant reduction in the preference for the cocaine-paired side compared to vehicle. These data suggest that the expression of cocaine conditioned place preference requires stimulation of VTA D1 receptors and, as such, are the first to suggest a role for VTA dendritically released DA in cocaine-, or other reward-, related learning. PMID- 25017573 TI - C-H arylation of azaheterocycles: a direct ligand-free and Cu-catalyzed approach using diaryliodonium salts. AB - An efficient and high yielding Cu-catalyzed direct C-H arylation of azaheterocycles including oxadiazoles, thiadiazoles, benzoxazoles and benzothiazoles has been achieved by employing easily accessible diaryliodonium salts. PMID- 25017571 TI - Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors. AB - Emerging evidence indicates that adenosine is a major regulator of striatum activity, in part, through the antagonistic modulation of dopaminergic function. Exercise can influence adenosine and dopamine activity, which may subsequently promote plasticity in striatum adenosine and dopamine systems. Such changes could alter activity of medium spiny neurons and impact striatum function. The purpose of this study was twofold. The first was to characterize the effect of long-term wheel running on adenosine 1 (A1R), adenosine 2A (A2AR), dopamine 1 (D1R), and dopamine 2 (D2R) receptor mRNA expression in adult rat dorsal and ventral striatum structures using in situ hybridization. The second was to determine if changes to adenosine and dopamine receptor mRNA from running are associated with altered cfos mRNA induction in dynorphin- (direct pathway) and enkephalin- (indirect pathway) expressing neurons of the dorsal striatum following stress exposure. We report that chronic running, as well as acute uncontrollable stress, reduced A1R and A2AR mRNA levels in the dorsal and ventral striatum. Running also modestly elevated D2R mRNA levels in striatum regions. Finally, stress-induced cfos was potentiated in dynorphin and attenuated in enkephalin expressing neurons of running rats. These data suggest striatum adenosine and dopamine systems are targets for neuroplasticity from exercise, which may contribute to changes in direct and indirect pathway activity. These findings may have implications for striatum mediated motor and cognitive processes, as well as exercise facilitated stress-resistance. PMID- 25017574 TI - Chest X-ray screening examinations among French uranium miners: exposure estimation and impact on radon-associated lung cancer risk. AB - BACKGROUND: Medical surveillance of uranium miners can include periodic chest X ray examinations. This study aimed to assess the X-ray exposure due to occupational health monitoring in the French cohort of uranium miners, and to test whether consideration of this additional radiation exposure impacts the excess risk of lung cancer death associated with radon exposure. METHOD: X-ray exposure due to occupational health monitoring was estimated retrospectively based on review of a sample of miners' medical records and bibliographic data. Four exposure scenarios were designed, differing in their assumptions about the type of procedures performed, their frequency, and the lung dose delivered. Radon exposure and lung doses from exposure to alpha-particle emitters and external gamma rays have previously been individually assessed. Exposure-risk and dose risk relations were estimated by Poisson regression with a linear excess relative risk (ERR) model. RESULTS: The cohort included 5086 miners with a mean follow-up duration of 30.1 years. The mean number of chest X-ray examinations ranged from 15.1 in the lowest to 34 in the highest-exposure scenario, and produced a mean cumulative lung dose ranging from 4.6 to 34.2 mGy. The role of occupation-related imaging screening X-ray procedures in total equivalent lung dose appeared insignificant compared to alpha-emitter exposure. X-ray exposure was not associated with lung cancer mortality risk. The ERR associated with radon remained significantly positive when X-ray exposure was included in the multivariate analysis. CONCLUSIONS: X-ray exposure did not confound the exposure risk relation between radon and lung cancer. PMID- 25017575 TI - Dilution of a mepivacaine-adrenaline solution in isotonic sodium bicarbonate for reducing subcutaneous infiltration pain in ambulatory phlebectomy procedures: a randomized, double-blind, controlled trial. AB - BACKGROUND: Varicose veins are treated under local infiltration anesthesia. Literature shows that adding sodium bicarbonate reduces the pain associated with local infiltration anesthesia. Nonetheless, sodium bicarbonate is underused. OBJECTIVE: We sought to assess if the use of a solution of mepivacaine 2% plus adrenaline with sodium bicarbonate 1.4% results in less pain associated with local infiltration anesthesia preceding ambulatory phlebectomies, compared with standard preparation diluted with normal saline. METHODS: In all, 100 adult patients undergoing scheduled ambulatory phlebectomy were randomized to receive either a solution of mepivacaine chlorhydrate 2% plus adrenaline in sodium bicarbonate 1.4% or a similar solution diluted in normal saline 0.9%. RESULTS: Median pain scores associated with local infiltration anesthesia reported in the intervention and control groups were 2 (SD=1.6) and 5 (SD=2.0) (P<.0001), respectively. A general linear model with bootstrapped confidence intervals showed that using the alkalinized solution would lead to a reduction in pain rating of about 3 points. LIMITATIONS: Patients were not asked to distinguish the pain of the needle stick from the pain of the infiltration. Moreover, a complete clinical study of sensitivity on the infiltrated area was not conducted. CONCLUSIONS: Data obtained from this study may contribute to improve local infiltration anesthesia in ambulatory phlebectomy and other phlebologic procedures. PMID- 25017576 TI - Upregulation of HIF-1alpha protein induces mitochondrial autophagy in primary cortical cell cultures through the inhibition of the mTOR pathway. AB - Cerebral ischemia/reperfusion (I/R) can induce neuronal death, particularly in the hippocampal formation (HF). Molecular genetic studies have suggested that the activities of the transcription factor, hypoxia-inducible factor-1alpha (HIF 1alpha), are closely linked to ischemia-induced neuronal death. However, the mechanisms through which HIF-1alpha functions remain poorly understood. In this study, primary cortical neurons were subjected to oxygen-glucose deprivation (OGD) to establish a cell model of OGD/reperfusion (RP). HIF-1alpha mRNA and protein expression was measured by qRT-PCR and western blot analysis. Cell proliferation was detected by MTT assay. Flow cytometric analysis was used to detect cell apoptosis and changes in mitochondrial mass. The expression of LC3-I and LC3-II was examined by western blot analysis. We found that HIF-1alpha increased cell proliferation and decreased cell apoptosis in our cell model of OGD/RP using cultured neonatal rat cortical neurons. The overexpression of HIF 1alpha significantly induced changes in mitochondrial mass and mitochondrial autophagy in cortical neurons. Moreover, the inhibition of HIF-1alpha markedly suppressed cell proliferation and mitochondrial autophagy. We also demonstrated that the HIF-1alpha-induced mitochondrial autophagy was accompanied by the inhibition of the mTOR pathway. This study provides direct in vitro evidence that HIF-1alpha overexpression triggers mitochondrial autophagy, thereby increasing neuronal survival. Our results highlight a novel target molecule toward which anti-ischemic neuroprotective effects can be applied. PMID- 25017577 TI - Bioavailability of lutein from a lutein-enriched egg-yolk beverage and its dried re-suspended versions. AB - Drying a fresh lutein-enriched egg-yolk beverage would extend its shelf life, however, functional properties should not be affected. It was investigated whether consumption of a dried beverage containing lutein-enriched egg-yolk significantly increases serum lutein. One-hundred healthy young subjects participated in this 6-weeks randomized controlled study. Subjects consumed either a "plain" control beverage (n = 26), a fresh lutein-enriched egg-yolk beverage (n = 25), a dried version of this beverage (n = 25), or a beverage composed of the dried individual components of the drink (n = 24). The fresh and both dried versions of the lutein-enriched egg-yolk beverage were able to increase serum lutein levels after 6 weeks of consumption (lutein change: -38 +/- 47 nmol/L, +304 +/- 113 nmol/L, +148 +/- 79 nmol/L and +178 +/- 83 nmol/L for control, fresh, dried and combined dried group respectively; p < 0.001). No significant change in serum cholesterol level was seen in the beverages containing lutein-enriched egg-yolk compared to the control drink. PMID- 25017578 TI - Taking part: engaging knowledge on health in clinical encounters. AB - Clinical encounters are the most widely shared form of engagement of citizens with health care and medical knowledge and a major setting for the constitution of the health-aware, somatic citizen and are included in the repertoire of participation in the field of health. Following Joelle Zask's notion of participation, we propose to look at clinical encounters as an instances of "taking part" in the field of health through the mutual engagement of diverse forms of knowledge and experience. Through interviews with health professionals and patients diagnosed with asthma, we explore clinical encounters as settings where physicians and patients mutually engage in a process of contesting, sharing and appropriating medical knowledge and information, while recognizing the normative authority of medical knowledge and expertise and the status of biomedicine as a form of veridiction. Clinical encounters are described as processes where citizens qua patients appropriate biomedical knowledge and health information for coping with health problems and the disruptions they generate in their lives, even if their outcomes are uncertain concerning the binding power of medical authority. Patients' engagements with health care services and health professionals and their use of biomedical knowledge for the (self) management of their condition offers a privileged entry point into a neglected dimension of citizen participation in the field of health. PMID- 25017579 TI - Where do they go and how do they get there? Older adults' travel behaviour in a highly walkable environment. AB - Mobility-the ability to move about in one's neighbourhood and maintain independence-is essential for older adults' wellbeing. Neighbourhood environments support or hinder mobility especially as health declines and physical vulnerability increases with age. Linkages between mobility and planning and policy are key to designing age-friendly neighbourhoods with destinations that encourage older adults to get out and be physically active. We describe the mobility of older adults who live in a highly walkable neighbourhood. Specifically, we address the questions of 'where do older adults go?' (destinations) and 'how they get there?' (travel mode, physical activity). We recruited older adults (age 60+) who live in Vancouver's downtown core, an area acknowledged to be highly walkable (Walk Score((r)): 94-97/100), and who leave their houses most days of the week. Participants (n = 184) recorded travel in diaries and wore an ActiGraph GT3X + accelerometer for 7 days during September to October 2012. We classified reported destinations according to the North American Industry Classification System, and analysed mobility [trip rates (overall and walking), steps, moderate to vigorous physical activity (MVPA)] and associations between travel and physical activity-related mobility measures. Key destinations were grocery stores (13.6% of trips), restaurants (7.2%), malls/marketplaces (5.5%), and others' homes (5.4%). Participants made 4.6 (std: 2.5) one-way trips/day, took 7910.1 (3871.1) steps/day, and accrued 39.2 (32.9) minutes/day of MVPA. Two-thirds of trips were by active modes (62.8% walk, 3.2% bike) and 22.4% were by car. Trip rates were significantly associated with physical activity outcomes. Older adults living in highly walkable neighbourhoods were very mobile and frequently used active transportation. Travel destinations signify the importance of nearby commercial and social opportunities, even in a highly walkable environment. The high rates of active travel and physical activity in a walkable neighbourhood suggest that when provided compelling destinations, community dwelling older adults walk more and may achieve health benefits through daily travel. PMID- 25017580 TI - Skin color, interviewer-ascribed ethnoracial classification, racial/ethnic self identification & discrimination: commentary on Perreira and Telles (2014). PMID- 25017581 TI - Management of the symptomatic wrist following distal ulna resection. PMID- 25017582 TI - The effects of locally injected triamcinolone on entrapment neuropathy in a rat chronic constriction injury model. AB - PURPOSE: Patients with idiopathic carpal tunnel syndrome are commonly treated by steroid injections into the carpal tunnel. We administered triamcinolone (Tr) to chronic constriction injury model rats. We hypothesized that Tr administration would have both favorable behavioral effects and quantifiable immunohistological effects on compressed nerves. METHODS: Thirty-six male Wister rats were used. For rats to be treated with Tr, we loosely ligated their right sciatic nerves at 4 sites. Sham rats had their nerves exposed without ligation. On postoperative day 7, we reexposed their ligated nerves, after which we delivered either 0.1 mg of Tr (0.1-mg group), 0.5 mg of Tr (0.5-mg group), or normal saline (saline group) around the nerve fibers at the injured sites. Gait was analyzed, and allodynia was assessed with von Frey hairs, before surgery and on postoperative days 3, 7, 10, 14, and 21. The right sciatic nerve was resected and stained using hematoxylin-eosin, and the fourth and fifth lumbar dorsal root ganglia (DRG) were removed and assessed by immunohistochemistry for calcitonin gene-related peptide (CGRP) and activating transcription factor 3 (ATF3) on postoperative day 21. In addition, interleukin-1beta (IL-1beta) in sciatic nerve was quantified using enzyme-linked immunosorbent assays. RESULTS: Mechanical allodynia was significantly decreased in the 0.5-mg group compared with the saline group. In hematoxylin-eosin sections, the extent of inflammation-induced edema between the nerve fibers and infiltration of inflammatory cells was significantly reduced in the 0.5-mg group compared with the saline group. IL-1beta levels at the sciatic nerve in the 0.5-mg group were significantly lower than those in the saline group. CONCLUSIONS: Tr-treated chronic constriction injury rats exhibited significant alleviation of sensory disturbance, edema, inflammation, and pain related peptide upregulation. These phenomena suggest the validity of Tr administration as a treatment affecting the nerve itself. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 25017583 TI - Facile preparation of mussel-inspired polyurethane hydrogel and its rapid curing behavior. AB - A facile method was found to incorporate a mussel-inspired adhesive moiety into synthetic polymers, and mussel mimetic polyurethanes were developed as adhesive hydrogels. In these polymers, a urethane backbone was substituted for the polyamide chain of mussel adhesive proteins, and dopamine was appended to mimic the adhesive moiety of adhesive proteins. A series of mussel mimetic polyurethanes were created through a step-growth polymerization based on hexamethylene diisocyanate as a hard segment, PEG having different molecular weights as a soft segment, and lysine-dopamine as a chain extender. Upon a treatment with Fe(3+), the aqueous mussel mimetic polyurethane solutions can be triggered by pH adjustment to form adhesive hydrogels instantaneously; these materials can be used as injectable adhesive hydrogels. Upon a treatment with NaIO4, the mussel mimetic polyurethane solutions can be cured in a controllable period of time. The successful combination of the unique mussel-inspired adhesive moiety with a tunable polyurethane structure can result in a new kind of mussel inspired adhesive polymers. PMID- 25017584 TI - Evaluation of various active surveillance protocols in prostate cancer. AB - OBJECTIVE: This study aims to investigate whether pathology results obtained by radical retropubic prostatectomy (RRP) were correlated with active surveillance (AS) criteria defined by Klotz, Soloway and D'Amico. MATERIALS AND METHODS: In our clinic we evaluated 211 patients with diagnosis of localized prostate cancer who underwent RRP between 2007 and 2012. AS criteria defined by Soloway (cT <= T2, PSA <= 15 ng/dl, Gleason <= 6), Klotz (cT1c-T2a; if age >= 70 PSA <= 15 ng/dl, if age < 70 PSA <= 10 ng/dl; if age >= 70 Gleason <= 7(3+4), if age < 70 Gleason <= 6) and D'Amico (cT1c-T2a, PSA <= 10 ng/dl, Gleason <= 6) were used in our study. Pathological stages and Gleason scores were evaluated with coherence to AS protocols, mis-staging rates, biochemical recurrence (BC) of the mis-staged patients and death due to prostate cancer Data was analyzed using NCSS 2007 & PASS 2008 Statistical Software (Utah, USA). Chi square test and Mann-Whitney U test were applied for analyzing qualitative data. Significance was determined as p < 0.05. RESULTS: 137 (64.9%) patients were coherent with Soloway AS criteria, 118 (55.9%) with Klotz AS criteria and 108 (51.1%) with D'Amico AS criteria. Histopathological results of the patients grouped according to Soloway, Klotz and D'Amico AS protocols showed high stage prostate cancer in 40 (29.2%), 32 (27%) and 27 (24.9%) patients, respectively. High grade prostate cancer rates in Soloway, Klotz, D'Amico groups were 55 (40.2%), 46 (38%) and 39 (36.1%); respectively. Misstaging rates of Soloway, Klotz and D'Amico AS protocols were determined as 65 (47.4%), 54 (45.5%) and 46 (42.5%), respectively. In the Soloway group BC rate was 21.9% in those with high stages. Relation between BC and high stage was found to be statistically significant (p < 0.05). CONCLUSION: Misstaging rates were relatively high in the three groups and there was no difference between the three groups in BC rates. Randomized studies with adequate follow up are needed. PMID- 25017585 TI - Ureteroscopy and holmium laser lithotripsy: is this procedure safe in pregnant women with ureteral stones at different locations? AB - OBJECTIVES: The aim of this study was to assess the safety and effectiveness of ureteroscopy and Holmium: Yttrium-Aluminum-Garnet lithotripsy for the treatment of ureteral stones with different localizations in symptomatic pregnant women. METHODS: A retrospective analysis was performed on 19 pregnant patients referred to our center between January 2005 and December 2012 with symptomatic hydronephrosis requiring surgical intervention. 7.5 F and 9.5 F semirigid ureterorenoscopy with Holmium laser lithotripsy was used for treatment in all patients. Complications were stratified according to modified Clavien criteria. RESULTS: The mean age of patients was 25.4 (18-41) years, and the mean gestation duration was 24.8 (7-33) weeks. Six cases (31.5%) had a history of stone. Solitary kidney secondary to previous nephrectomy was observed in 2 patients and 1 patient had a hypoplastic kidney. Abdominal ultrasonography was used as the main diagnostic tool. Mean stone size was 9.2 mm (6-13). The location of the stones was the lower, middle, and upper ureter in 8 (42.1%), 5 (26.3%) and 6 (31.5%) cases, respectively. All stones were fragmented with Holmium laser lithotripsy. Of the 19 patients, 11 (57.8%) required double J stent insertion peroperatively. Intraoperative urological and obstetric complications were not observed. Postoperatively two complications were noted. According to Clavien criteria a complication was level 1, and the other was level 2. CONCLUSIONS: For treatment of pregnant women with symptomatic ureteral stones in every location, Holmium laser lithotripsy with a semirigid ureteroscopy can be used as judicious treatment. This approach is effective and safe with an acceptable complication rate. PMID- 25017586 TI - Comparison of the urethrovesical anastomoses with polyglecaprone (Monocryl(r)) and bidirectional barbed (V-Loc 180(r)) running sutures in laparoscopic radical prostatectomy. AB - OBJECTIVE: We compared polyglecaprone (Monocryl(r)) and bidirectional barbed (V Loc(r) 180) running sutures during urethrovesial anastomosis (UVA) in laparoscopic radical prostatectomy (LRP). MATERIALS AND METHODS: A total of 92 consecutive patients underwent extraperitoneal LRP for prostate cancer. In the first 47 patients, the running UVA was performed using 3-0 monofilament polyglecaprone (Monocryl(r)) suture (Group 1). In the subsequent 45 patients, the running UVA was performed with the 3-0 barbed suture (V-Loc(r) 180) (Group 2). Rhabdosphincter reconstruction was performed in all the patients. RESULTS: The mean prostatectomy time was 196 and 179 minutes in Group 1 and 2, respectively (p < 0.001). Moreover, the mean UVA time was 40 and 24 minutes in Group 1 and 2, respectively (p < 0.001). Also, catheterization time, lenght of hospital stay and the number of the patients with urine leakage were significantly lower in Group 2 than the other (p < 0.001). No patients in V-Loc(r) 180 suture group and 5 patients in Monocryl(r) suture group experienced postoperative drain leakage in the present study. Overall pad usage at 6th month was higher in group 1 than the other group. In group 1 and 2, 78.7% and 93.3% of the patients reported 0 to 1 pads daily, whereas 21.3% and 6.7% reported >= 2 pads daily (p = 0.002). CONCLUSIONS: We therefore consider that use of barbed suture running UVA during LRP is associated with a significantly shorter operative time maintaining a proper suturing tension compared with standard suture and it is not associated with a higher incidence of adverse events with no postoperative complications. PMID- 25017587 TI - Musculoskeletal disorders among robotic surgeons: a questionnaire analysis. AB - OBJECTIVE: Robotic surgical systems offer better workplace in order to relieve surgeons from prolonged physical efforts and improve their surgical outcomes. However, robotic surgery could produce musculoskeletal disorders due to the prolonged sitting position of the operator, the fixed position of the console viewer and the movements of the limbs. Until today, no one study has been reported concerning the association between robotics and musculoskeletal pain. The aim of this work was verify the prevalence of musculoskeletal disorders among Italian robotic surgeons. MATERIAL AND METHODS: Between July 2011 and April 2012 a modified Standardized Nordic Questionnaire was delivered to thirty-nine Italian robotic centres. Twentytwo surgeons (56%) returned the questionnaires but only seventeen questionnaires (43.5%) were evaluable. RESULTS: Seven surgeons (41.2%) reported musculoskeletal disorders, by since their first use of the robot which significantly persisted during the daily surgical activity (P < 0.001). Regarding the body parts affected, musculoskeletal disorders were mainly reported in the cervical spine (29.4%) and in the upper limbs (23.5%). Six surgeons (35.3%) defined the robotic console as less comfortable or neither comfortable/uncomfortable with a negative influence on their surgical procedures. CONCLUSIONS: In spite of some important limitations, our data showed musculoskeletal disorders due to posture discomfort with negative impact on daily surgical activity among robotic surgeons. These aspects could be due to the lack of ergonomic seat and to the fixed position of the console viewer which could have produced an inadequate spinal posture. The evaluation of these postural factors, in particular the development of an integrated and more ergonomic chair, could further improve the comfort feeling of the surgeon at the console and probably his surgical outcomes. PMID- 25017588 TI - Urolithiasis in Italy: an epidemiological study. AB - OBJECTIVES: Worldwide the urolithiasis is the third most frequent urological disease affecting both males and females. In literature there are not recent Italian epidemiological data about stone disease. The objective of this study is the evaluation of current epidemiology of urolithiasis in Italy using the Health Search/CSD Longitudinal Patient Database (HS) database. MATERIAL AND METHODS: An observational, descriptive, retrospective trial was conducted. Inclusion criteria were: family physician- assisted Italian living population member of HS database within 31 December 2012, both genders, age over 17 years, at least two years of clinical history recorded from the beginning the trial. Data were collected by HS database and elaborated by its software Millewin(r). RESULTS: In Italy prevalence of urolithiasis in 2012 was 4.14%, it was higher in males than in females (4.53% versus 3.78%) with a positive relation with increasing age. The highest prevalence rate of urolithiasis was reported in the region Campania (6.08%). The general incidence was 2.23 * 1000, with the highest incidence in the region Sicilia (3.15 * 1000). Incidence was higher in group age 65-74 years (3.18 * 1000). CONCLUSIONS: In Italy the incidence and prevalence of urolithiasis is increasing with particular distribution in relation to gender, age and regional position. PMID- 25017589 TI - Medical expulsive therapy for distal ureteric stones: tamsulosin versus silodosin. AB - OBJECTIVES: To compare the efficacy and safety of tamsulosin and silodosin in the context of medical expulsive therapy (MET) of distal ureteric stones. PATIENTS AND METHODS: Observational data were collected retrospectively from patients who received silodosin (N = 50) or tamsulosin (N = 50) as MET from January 2012 to January 2013. Inclusion criteria were: patients aged >= 18 years with a single, unilateral, symptomatic, radiopaque ureteric stone of 10 mm or smaller in the largest dimension located between the lower border of the sacroiliac joint and the vesico-ureteric junction. Stone expulsion rate, stone expulsion time, number of pain episodes, need for analgesics use, incidence of side effects were compared. RESULTS: Stone-expulsion rate in the silodosin and in the tamsulosin groups were 88% and 82%, respectively (p not significant). Mean expulsion times were 6.7 and 6.5 days in the silodosin and tamsulosin group, respectively (p not significant). Mean number of pain episodes were 1.6 and 1.7 in the silodosin and tamsulosin group, respectively (p not significant). The mean number of analgesic requirement was 0.84 and 0.9 for the silodosin and tamsulosin group, respectively (p not significant). Overall, incidence of side effects was similar in both groups. Patients taking silodosin experienced an higher incidence of retrograde ejaculation but a lower incidence of side effects related to peripheral vasodilation when compared to patients taking tamsulosin. Subgroup analysis demonstrated significantly lower mean expulsion times and pain episodes in patients with stones <= 5 mm in both groups. CONCLUSIONS: Tamsulosin and silodosin are equally effective as MET for distal ureteric stones sized 10 mm or smaller. MET with silodosin is associatd with a lower incidence of side effects related to peripheral vasodilation but an higher incidence of retrograde ejaculation when compared to tamsulosin. PMID- 25017590 TI - Management of bladder stones associated with foreign bodies following incontinence and contraception surgery. AB - AIM OF THE STUDY: To investigate success of endoscopic lithotripsy for bladder stone following stress urinary incontinance surgery and contraception surgery. MATERIALS AND METHODS: Charts of patients admitted in two centers between January 2006 and March 2013 were retrospectively reviewed and seven women were enrolled in our study. Patients demographic parameters including age, main complaint(s), previous surgery type, time to diagnosis were analyzed. Also operative time, hospitalisation lenght, perioperative and postoperative complication( s) were evaluated. RESULTS: Five patients had undergone tension free vaginal tape procedure and one patient had undergone transobturator tape procedure. Median age was 62 (50-71) years. In one patient bladder stone formed around an intrauterine device. Dysuria (85%), hematuria (57%) and recurrent urinary tract infection (57%) were the main complaints. The median diagnosis time was 44.1 months. Abdominal ultrasonography and non contrast enhanced computer tomography were performed for five and two patients respectively and diagnosis was confirmed cystoscopically. Endoscopic lithotripsy using Holmium laser lithotripter or pneumatic lithotripter was used for all cases. The mean operation time was 41.2 minutes (20-70) and success was 100%. There was no intraoperative complication. Only one patient had fever higher than 38oC postoperatively and was treated by appropriate antibiotic. The median hospitalisation time was 1.57 day. CONCLUSION: In conclusion endoscopic lithotripsy is a safe and effective approach to manage bladder stone associated with mid-urethral synthetic slings and intrauterine devices. PMID- 25017591 TI - Managing female urinary incontinence: a regional prospective analysis of cost utility ratios (curs) and effectiveness. AB - INTRODUCTION: To evaluate the cost-utility of incontinence treatments, particularly anticholinergic therapy, by examining costs and quality-adjusted life years. MATERIALS AND METHODS: A prospective cohort study of women who were consecutively referred by general practitioners (GPs) to the Urology Department because of urinary incontinence. The primary outcome was evaluation of the cost utility of incontinence treatments (surgery, medical therapy and physiotherapy) for stress and/or urgency incontinence by examining costs and quality-adjusted life years. RESULTS: 137 consecutive female patients (mean age 60.6 +/- 11.6; range 36-81) were enrolled and stratified according to pathologies: SUI and UUI. Group A: SUI grade II-III: 43 patients who underwent mid-urethral sling (MUS); Group B: SUI grade I-II 57 patients who underwent pelvic floor muscle exercise and Group C: UUI: 37 patients who underwent antimuscarinic treatment with 5 mg solifenacin daily. The cost utility ratio (CUR) was estimated as saving more than ?1200 per QALY for surgery and physiotherapy and as costing under ? 100 per QALY for drug therapy. CONCLUSIONS: This study shows that appropriate diagnosis and treatment of a patient with incontinence lowers National Health Service costs and improves the benefits of treatment and quality of life. PMID- 25017593 TI - Awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation: 5 years experience. AB - OBJECTIVES: To assess the cure rate of patients with premature ejaculation who underwent a treatment involving: 1) awareness of the pelvic floor muscles 2) learning the timing of execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase 3) pelvic floor rehabilitation (bio feed back, pelvic exercises and electrostimulation). MATERIALS AND METHODS: We recruited 78 patients with lifelong premature ejaculation who completed the training. The patients were informed of the role of the pelvic floor. They were taught to carry out the execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase to control the ejaculatory reflex. In order to improve the awareness, the tone and the endurance of the pelvic floor muscles, patients were treated with the rehabilitation of pelvic floor (RPF) consisting mainly in biofeedback, pelvic exercises and in some cases also in electro-stimulation (ES). The training was carried out for a period of about 2-6 months with an average of 2-5 visits per cycle. RESULTS: 54% of patients who completed the training were cured of premature ejaculation and learned over time to be able to postpone the ejaculation reflex. In a subgroup of 26 patients was also measured the IELT which on the average increased from < 2 minutes to >10 minutes. The best results occurred mainly in patients aged less than 35 where the cure rate was 65%. There were no side effects. CONCLUSIONS: In this study, approximately half of patients with premature ejaculation were cured after applying the above treatment.This therapy, necessitates a fairly long period of time (2-6 months) and a great commitment on the part of the patient, nevertheless it can be a valid and effective treatment for patients with premature ejaculation. This treatment makes the patient independent in that he is not bound to specific times for taking medication. Furthermore there are no side effects and this therapy is particularly effective in young males. PMID- 25017592 TI - Low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center. AB - AIM OF THE STUDY: To demonstrate how, in a center with a large number of patients, as our center is, it is possible to perform ureterolithotripsy using a limited set of instruments. METHODS: We evaluated medical charts of our center related to semirigid ureteral ureteroscopy (URS) with ureterolithotripsy using Holmium laser performed from July 2004 to July 2011. Overall, 658 URS for ureteral stones were performed in 601 patients, of which 204 in proximal ureter (31%), 86 in the mid (13.06%) and 368 (57.76%) in the distal ureter. In 504 patients (76.5%) ureterohydronephrosis (Grade II-III) was observed. In 57 patients (8.6%), we performed a bilateral approach at the same time, but most patients had a solitary distal ureteral stone. 106 patients (16.1%) had more than one stone in their distal ureter and 96 (14.8%) had a proximal ureteral stone treated in the same surgery as well. RESULTS: The overall stone-free rate for ureteral stones was 86.1% (567/658). Success rates for proximal, medial and distal ureteral stones were 68.13% (139/204 patients), 84.8% (73/86 patients) and 96.4% (355/368 patients), respectively. One hundred and twenty patients (18.3%) required additional surgical treatment for their stones beyond the initial URS, including a second URS in 97 patients (14.74%) and URS plus Retrograde Intra Renal Surgery (RIRS) in 23 patients (3.54%). The overall stonefree rate after the second treatment was 99.3%. Intra-operative complications accounted for 5.92% and consisted of ureteral perforations in 16 pts (2.4%), erosions of urothelium leading to significant bleeding in 15 pts (2.27%), severe pain in 4 pts (0.6%), fever in 3 pts (0.45%) and one case of ureteral avulsion (0.15%). CONCLUSIONS: This study demonstrates that the use of Holmium laser lithotripsy is a safe and effective means of treating ureteral stones regardless of sex, age, stone location, or stone size. The instrumentation we used was extremely limited, in order to reduce costs related to the procedure to an absolute minimum whilst maintaining the two quality indicators for the procedure, namely success rate and length of hospitalisation (86.1% and 34 hours). PMID- 25017594 TI - Painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management. AB - Interstitial cystitis or bladder pain syndrome (BPS) is often a chronic debilitating condition characterised by predominantly storage symptoms and associated frequently with pelvic pain that varies with bladder filling. The aetiology is uncertain as the condition occurs in the absence of a urinary tract infection or other obvious pathology. Resulting discomfort may vary and ranges from abdominal tenderness to intense bladder spasms. Diagnosis and management of this syndrome may be difficult and is often made by its typical cystoscopic features. This review discusses the diagnosis and management of interstitial cystitis according to the current available best evidence and advises a multimodal approach in its management. PMID- 25017595 TI - Preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: a technical modification to improve the early recovery of continence. AB - OBJECTIVE: We describe our technique for preservation of the smooth muscular internal (vesical) sphincter and proximal urethra during radical retropubic prostatectomy (RRP) and present our preliminary clinical results. MATERIALS AND METHODS: The first steps of the prostatectomy reflect the standard RRP, while for the final phases the procedure continues in an anterograde manner with incision of the fibers of the detrusor muscle at the insertion of the ventral surface of the base of the prostate. At this level, the inner circular muscle of the bladder neck forms a sphincteric ring of smooth muscle that covers the longitudinally oriented smooth muscle component of the urethral musculature that extends distally to the verumontanum. These two proximal structures represent the internal sphincter that envelopes and locks the proximal urethra. A blunt dissection is continued until the ring shaped vesical sphincter is separated from the prostate and the longitudinally oriented smooth muscle component of the urethral musculature is identified. The base of the prostate is then gently separated from the urethra and from the bladder until the maximal length of the urethral musculature is isolated and preserved. RESULTS: After 30 initial set-up procedures, 40 consecutive patients with organ confined prostate cancer were submitted to radical retropubic prostatectomy with the preservation of muscular internal sphincter and the proximal urethra and compared to 40 patients submitted to standard procedure who served as control group. The group of patients submitted to our technical modification had a faster recovery of early continence than control group at 3 and 7 days. CONCLUSIONS: The described technique is a feasible and safe method for preservation of the internal urethral sphincter and allows improving the early recovery of urinary continence. The technique does not increase the rate of positive margins and the duration of the procedure. PMID- 25017596 TI - Pseudo-capsule "coffin effect": how to prevent penile retraction after implant of three-piece inflatable prosthesis. AB - OBJECTIVE: Following three-component implantation of a penile prosthesis, some patients are dissatisfied with their penile length. This may be due to the procedure by itself or pre-existing risk factors or psychological reasons. We supposed that formation of a restricted pseudo-capsule due to a late prosthesis activation can inhibit later system expansion. We aimed to identify the presence or absence of penile retraction after implant and to prevent it by immediate prosthesis activation after implantation. MATERIAL AND METHODS: Forty-six patients operated with three-piece inflatable penile prosthesis (AMS 700 CX o LGX) were enrolled. In 27 patients prosthesis was first activated four weeks after surgery (NEA group) and in 19 patients prosthesis was activated immediately after surgery (DEA group). Length and girth of the penis was evaluated before (in DEA group) and after the surgical procedure. RESULTS: The average post implant dorsal length of the erect penis in group NEA was found 3.28 cm shorter than in group with early activation (DEA). In DEA group there was no lenght difference between pre-operative stretching (14.57 cm) and post operative erection (14.98 cm). When early activation was not performed, the clinical result was a smaller penis in erect phase. CONCLUSION: Reduced lenght of the penis after implantation can be caused by the presence of a pseudo-capsule that limits the elongation of the prosthesis and of the penis ("coffin effect"). Timing of first activation seems to be the key in order to prevent the risk of penile retraction after implantation. Early activation is identified as the best measure to maintain the length of the pre implant erect penis after the prosthetic hydraulic implant. PMID- 25017597 TI - Treatment of penile strangulation by the rotating saw and 4-needle aspiration method: two case reports. AB - INTRODUCTION: The aim of this article was to describe our experience in using rotating saw and also combination of the instrument with 4-needle aspiration. METHODS: A comprehensive review of the literature was performed using PubMed. "Penile strangulation, -constriction, -incarceration, -entrapment" were used as search terms, and a manual bibliographic review of cross referenced items was performed. RESULTS: Search results yielded nearly 70 cases of penile strangulation caused by a variety of objects. Various instruments have been described in the literature for their safe removal, each with its own pros and cons. CONCLUSIONS: Penile strangulation should be accepted as a self-induced priapism and managed as an emergency in order to preserve erectile function and to prevent penile necrosis. Surgical creativity and patience are necessary in order to have a successful outcome. PMID- 25017598 TI - A case report of urethral prolapse in a 38 year old female with 46XY karyotype. AB - A 38-year old female presented with the acute onset of a vulval mass associated with pain and vaginal bleeding. She is female phenotype but has 46XY karyotype and Complete Androgen Insensitivity Syndrome (CAIS). At 15 years old she had a laparotomy and bilateral orchidectomy. Following admission, an examination under anaesthesia and cystoscopy was performed. A diagnosis of strangulated complete urethral prolapse was made. The lesion was excised with diathermy and the meatal skin was reanastomosed to the urethra. At follow-up, the urethra was well healed. The patient now attends Menopause Clinic for oestrogen-replacement therapy. We hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. It provides further incentive for compliance with hormone replacement therapy for patients with CAIS following gonadectomy, or other women with premature menopause. PMID- 25017599 TI - Idiopathic spontaneous perforation of the upper urinary tract. A presentation of 4 cases. AB - Spontaneous perforation of the collecting system constitutes a rare entity masked by the presentation of a typical renal colic. However, it should not be forgotten when managing patients with colic, since missed diagnoses may carry significant morbidity. We herein present a series of spontaneous perforation of the collecting system without an apparent obstruction site evident in helical CT urography. Four consecutive patients who presented with typical renal colic were initially subjected to KUB and renal ultrasound imaging and were ultimately diagnosed with perforation of the collecting system via contrast enhanced- helical CT urography. Despite thorough evaluation, the cause responsible obstructive was not discovered and an exclusion diagnosis of idiopathic collecting system perforation was assigned to all patients. Due to the rarity of a spontaneous perforation traditional retrograde urography was performed in an effort to identify the possible cause but was also unrevealing. All patients were successfully treated with endourological means. Perforation of the collecting system without an evident obstructive cause is a rare entity with obscure etiology. A reasonable but yet unconfirmed speculation is that of a transient obstruction capable of a significant increase of intraluminal pressures. PMID- 25017600 TI - Giant isolated renal cyst hydatid: From diagnosis to treatment. AB - Hydatid cyst disease is a parasitic infestation caused by Echinococcus granulosus. Renal involvement is rarely seen as 2-4% of all cases. Rarely renal involvement is isolated whereas commonly it accompanies involvement of other organs. We aimed to present a 30-year-old male patient with renal involvement reaching a giant size and undiagnosed in another center. PMID- 25017601 TI - Post-renal acute renal failure due to a huge bladder stone. AB - A 63-year old male was referred to our emergency unit due to acute renal failure. The level of serum renal function tests levels, blood urea nitrogen (BUN)/creatinine, were 63 mmol/L/848 MUmol/L. CT (Computarised Tomography) scan showed a huge bladder stone (5 cm x 6 cm x 5 cm) with increased bladder wall thickness. Post-renal acute renal failure due to bilateral ureterohydronephrosis was diagnosed. The huge bladder stone was considered to be the cause of ureterohydronephrosis and renal failure. The patient was catheterised and received haemodialysis immediately. He received haemodialysis four times during ten days of hospitalization and the level of serum renal function tests levels (BUN/ creatinine) decreased 18 mmol/L/123 MUmol/L. After improvement of renal function, we performed cystoscopy that demonstrated normal prostatic urethra and bladder neck and bilaterally normal ureteral orifices. Bladder wall was roughly trabeculated and Bladder outlet was completely obstructed by a huge bladder stone. After cystoscopy open, cystolithotomy was performed to remove calcium phosphate and magnesium ammonium phosphate stone weighing 200 g removed. Four days after operation the patient was discharged uneventfully and urethral catheter was removed on the seventh day. Post-renal acute renal failure due to large bladder stones is rare in literature. According to the our knowledge; early diagnosis of the stone avoid growth to large size and prevent renal failure. PMID- 25017602 TI - A case with primary signet ring cell adenocarcinoma of the prostate and review of the literature. AB - Primary signet cell carcinoma of the prostate is a rare histological variant of prostate malignancies. It is commonly originated from the stomach, colon, pancreas, and less commonly in the bladder. Prognosis of the classical type is worse than the adenocarcinoma of the prostate. Primary signet cell adenocarcinoma is diagnosed by eliminating the adenocarcinomas of other organs such as gastrointestinal tract organs. In this case report, we present a case with primary signet cell adenocarcinoma of the prostate who received docetaxel chemotherapy because of short prostate specific antigen doubling time. PMID- 25017603 TI - Mixed primary prostatic carcinoma with acinar, neuroendocrine and ductal components. AB - Mixed tumors in the prostate gland have been described; they are primarily originate in the gland or are the product of metastatic compromise. Mixed primary epithelial carcinomas of the prostate are very rare; here we report the case of a 72-years-old man with histopathologic findings of a primary prostate mixed carcinoma, showing characteristics of acinar, ductal and neuroendocrine adenocarcinoma. We also discuss the clinical, diagnostic, and therapeutic aspects of these uncommon mixed neoplasms. PMID- 25017604 TI - Delayed-onset ureteral lesions due to thermal energy: an emerging condition. AB - OBJECTIVES: To describe the risks of ureteral damage occurring during urological and gynecological procedures utilizing energybased surgical devices (ESD) during both laparoscopic and open procedures. MATERIALS AND METHODS: During the last 20 months we observed five cases of iatrogenic ureteral lesions caused by ESD which required open surgery. There were 3 lesions of the lower ureter occurring during gynecological laparoscopic or robotic procedures, and 2 lesions of the upper ureter occurring during open enucleation of low-stage renal cell carcinomas. RESULTS: In the laparoscopic gynecological lesions the cause was attributable to monopolar cutting and bipolar coagulation: they presented with urine extravasation after 20, 15 and 15 days respectively and required ureteral reimplantation in 2 out of 3 cases. In the upper ureteral lesions the causes were bipolar coagulation and LigaSure Impact TM used for perirenal fat dissection: they presented after 2 and 4 months respectively and required uretero ureterostomy and inferior nephropexy in one case and nephrectomy in the other. In 3 out of 5 cases there was an unsuccessful attempt at placing an ureteral double J stent, and in the 2 cases where it was placed it did not prevent the formation of subsequent stricture in one. CONCLUSIONS: The widespread diffusion of ESD has the potential drawback of inadvertent thermal energy transmission to the ureter. Delayed presentation of ureteral lesions and difficulties in ureteral stent placement were the common features of the cases observed. Inadvertent ureteral damage by different thermal energy sources is an emerging condition, requiring awareness, prompt recognition and adequate treatment with the reconstructive urology principles. PMID- 25017605 TI - A rare complication of ESWL: focal metastatic multiple organ abscesses in a horseshoe kidney. AB - Extracorporeal shock wave lithotripsy (ESWL) is an effective treatment modality in the minimal invasive management of urinary system stone disease. Although the majority of the complications occuring after ESWL are minor (most common ones are gross haematuria, pain, perinephritic hematoma); bacteriuria may also occur in some cases which sometimes can lead to sepsis and even metastatic abscess formation in a very rare part of the cases treated. In this rare situation infection agent spreads quickly via hematogenous route and causes abscess formation in different parts of the body. Majority of such cases usually have an underlying systemic disease like diabetes mellitus (DM), malignancy, HIV or steroid use which lead to disruption of immune system functions. Abscess formation following ESWL is extremely rare and usually limited with some case reports published in the literature. Herein, we present a diabetic case with formation of multiple abscess foci in kidney, as well as in lungs and liver following ESWL. The patient was first admitted to our emergency department with high fever and respiratory distress and misdiagnosed as metastatic tumor foci based on radiologic findings. To the best of our knowledge, our case is the first one in the literature in whom simultanous abscess formation in multiple organ systems has been documented following an otherwise uneventful ESWL. PMID- 25017606 TI - Triorchidism: genetic and imaging evaluation in an adult male. AB - We report the results of imaging and cytogenetic studies in a case of triorchidism in a 54 years old male without any associated anomaly. A scrotal ultrasonography revealed the presence of two testes within the left hemiscrotum with complete septation and echotexture and vascular flow pattern similar to the vascular flow of the normal right testis. There was no focal abnormal echogenicity suggesting malignancy. Scrotal MRI confirmed two soft-tissue structures in the left hemiscrotum with normal signal intensity at T1w and T2w images. Both testes had a tunica albuginea with low-signal intensity. Cytogenetic analysis resulted in normal male karyotype 46XY. Array-CGH analysis detected the presence of two interstitial rearrangements: a ~120 Kb deletion of chromosome 1 and a ~140 Kb deletion of chromosome 16. Currently there are little details on the functions of both genes. PMID- 25017607 TI - Rare type of bladder cancer: malign fibrous histiocytoma. AB - Malignant fibrous histocytoma (MFH) is the most common soft tissue sarcoma in adults. Urinary tract is a very rare location for MFH. Involvement of the bladder is more common in males and at the 6th decade of life. A case of MFH of the bladder with poor prognosis is presented. Prognostic factors for MFH are tumor grade, amount of invasion, age, tumor size, and histological type. Survival rate is very low and 3-year disease specific survival is approximately 40%. PMID- 25017609 TI - An unequal burden. PMID- 25017610 TI - ZNF703 promotes tumor cell proliferation and invasion and predicts poor prognosis in patients with colorectal cancer. AB - Zinc finger protein 703 (ZNF703), identified as an oncogene in luminal B breast cancer, is a member of the NET/NlZ family of zinc finger transcription factors. However, the role of ZNF703 in colorectal cancer (CRC) is unknown. We investigated the expression of ZNF703 in paired tumor and corresponding normal tissues using reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analysis. Immunohistochemistry (IHC) was applied on paraffin embedded specimens, including 138 CRC tissues, 58 matched normal tissues and 30 paired metastatic lymph node samples. Levels of mRNA (72.72%, 16/22) and ZNF703 protein expression (65.38%, 17/26, respectively) were upregulated in CRC tissues. IHC staining revealed higher expression of ZNF703 in the CRC tissues (68/138, 49.3%) compared with that in the adjacent normal mucosal tissues (4/58, 6.9%) (p<0.001). Moreover, high ZNF703 expression was significantly correlated with tumor size, pathological grading, serosal invasion, lymph node metastasis and AJCC stage. CRC patients with relatively low ZNF703 expression had higher survival rates than those with high ZNF703 expression. In addition, we investigated ZNF703 expression in eight CRC cell lines (LS174T, SW480, HT29, SW620, DLD1, SW1116, LoVo and CaCo-2) in vitro. The highest ZNF703 expression was detected in the LoVo cell line. RNA interference was used to assess the effects of ZNF703 knockdown in LoVo cells. Knockdown of ZNF703 expression inhibited CRC cell proliferation and migration. Collectively, these results reveal that ZNF703 may act as an oncogene in CRC and could be considered as a potential therapeutic target for metastatic CRC. PMID- 25017608 TI - Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder. AB - Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n = 48) and healthy volunteers (HV, n = 35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n = 39; HV, n = 33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76 = 12.493, p = 0.001), and impulsivity (F1,65 = 5.598, p = 0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76 = 7.941, p = 0.001) and impulsivity (F1,65 = 3.485, p = 0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission. PMID- 25017611 TI - Endometrial pathology in postmenopausal women with no bleeding. AB - OBJECTIVE: The aim of this study was to determine the rate of unexpected uterine pathology in postmenopausal women admitted to a gynecology clinic with symptoms other than vaginal bleeding and who were scheduled to undergo hysterectomy. MATERIALS AND METHODS: We reviewed retrospectively the medical records of 283 postmenopausal patients who had gynecological surgery between September 2007 and January 2014. We reviewed their presenting symptoms on admission, the indications for surgery, and their transvaginal ultrasonographic findings. Postoperative histopathological results based on uterine specimens were also recorded. The results were analyzed statistically. RESULTS: Of 283 patients who had surgery, 209 had no vaginal bleeding at the time of admission. From this group, 75.6% were found to have unsuspected pathology, including endometrial hyperplasia, endometrial polyps, uterine fibroids, adenomyosis, and one case of endometrial carcinoma (0.5%). The remaining 74 patients had experienced postmenopausal bleeding and in 87.8% there were pathological findings including 13 cases (17.6%) of endometrial cancer (p = 0.0001). CONCLUSION: Vaginal bleeding in postmenopausal women is indicative of a wide array of gynecological pathologies, including endometrial carcinoma. However, uterine fibroids, pelvic masses, or even endometrial cancer may develop without co-morbid vaginal bleeding. Therefore we advocate that postmenopausal women should undergo yearly screening and consultation, without waiting for an episode of vaginal bleeding. PMID- 25017612 TI - Using quality-adjusted progression-free survival as an outcome measure to assess the benefits of cancer drugs in randomized-controlled trials: case of the BOLERO 2 trial. AB - The aim of this study is to estimate the quality-adjusted progression-free survival (QAPFS) as an effectiveness measure for the treatment arms of the BOLERO 2 trial. For each treatment arm of the trial, QAPFS was estimated by multiplying the overall health utility weights associated with progression-free survival (PFS) (accounting for utility decrements associated with the adverse events of treatments) by the corresponding mean PFS time. Health utility data were obtained from the literature, while mean PFS times were estimated through a survival analysis of the reconstructed individual patient data of the BOLERO-2 trial. PFS (robust mean, (95 % robust confidence interval)) was 44.73 weeks (41.03; 48.43) for Everolimus + Exemestane and 22.98 weeks (19.88; 26.08) for Placebo + Exemestane. The QAPFS (robust mean, (95 % robust confidence interval)) for the treatment arms of the trial was 30.09 (27.60; 32.58) for Everolimus + Exemestane and 16.27 (14.07; 18.46) for Placebo + Exemestane, respectively. Using QAPFS as an outcome measure provides a complete picture of the benefit induced by the treatment arms of the BOLERO-2 trial. The benefit of Everolimus + Exemestane over Placebo + Exemestane observed in the trial is maintained in this analysis. The approach and estimates obtained as part of our analysis can serve as a basis for cost effectiveness analyses of the treatment arms of the BOLERO-2 trial. PMID- 25017613 TI - Agreement between the spatio-temporal gait parameters from treadmill-based photoelectric cell and the instrumented treadmill system in healthy young adults and stroke patients. AB - BACKGROUND: Treadmill gait analysis was more advantageous than over-ground walking because it allowed continuous measurements of the gait parameters. The purpose of this study was to investigate the concurrent validity and the test retest reliability of the OPTOGait photoelectric cell system against the treadmill-based gait analysis system by assessing spatio-temporal gait parameters. MATERIAL AND METHODS: Twenty-six stroke patients and 18 healthy adults were asked to walk on the treadmill at their preferred speed. The concurrent validity was assessed by comparing data obtained from the 2 systems, and the test-retest reliability was determined by comparing data obtained from the 1st and the 2nd session of the OPTOGait system. RESULTS: The concurrent validity, identified by the intra-class correlation coefficients (ICC [2, 1]), coefficients of variation (CVME), and 95% limits of agreement (LOA) for the spatial-temporal gait parameters, were excellent but the temporal parameters expressed as a percentage of the gait cycle were poor. The test-retest reliability of the OPTOGait System, identified by ICC (3, 1), CVME, 95% LOA, standard error of measurement (SEM), and minimum detectable change (MDC95%) for the spatio-temporal gait parameters, was high. CONCLUSIONS: These findings indicated that the treadmill-based OPTOGait System had strong concurrent validity and test-retest reliability. This portable system could be useful for clinical assessments. PMID- 25017614 TI - Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial. AB - While statins target many of the pathways to neuroprogression in schizophrenia, the safety and efficacy of statins for treating schizophrenia has never been examined. This is an 8-week randomized double blind controlled clinical trial examining the efficacy and safety of adjunctive lovastatin (20 mg/day) treatment or placebo for people with schizophrenia. The baseline characteristics of the two groups were not different. Endpoint changes in Positive and Negative Syndrome Scale (PANSS) total and subscale scores did not differ between the two groups. However there was a significant difference between the doses of risperidone used in the two groups. The mean dose in the lovastatin and placebo groups were 4.8(1.8) and 3.4(1.4) mg/day, respectively (P<.03). No serious adverse events were reported. Slowness of movements, muscle rigidity, increased appetite, and decreased energy were the most common adverse effects, and these rates did not differ between the two groups. This study failed to demonstrate a benefit of lovastatin on symptoms of schizophrenia. This combination was well tolerated. However, a higher dosage of risperidone was used for treating the disorder in those taking concomitant lovastatin compared to placebo. PMID- 25017615 TI - The developmental course of childhood inattention symptoms uniquely predicts educational attainment: a 16-year longitudinal study. AB - In this 16-year longitudinal study, a new trajectory estimation approach was used to verify whether the developmental course of childhood inattention significantly predicted functional impairment. A rising childhood inattention trajectory significantly predicted graduation failure (OR: 1.76 [1.32-2.34]) independently of averaged inattention levels. Rising inattention is, in itself, important for prognosis. PMID- 25017616 TI - Clinical investigation of set-shifting subtypes in anorexia nervosa. AB - While evidence continues to accumulate on the relevance of cognitive inflexibility in anorexia nervosa (AN), its clinical correlates remain unclear. We aimed at examining the relationship between set-shifting and clinical variables (i.e., eating psychopathology, depression, and personality) in AN. Ninety-four individuals affected by AN and 59 healthy controls (HC) were recruited. All participants were assessed using: Eating Disorders Inventory-2 (EDI-2), Temperament and Character Inventory (TCI), Beck Depression Inventory (BDI), and Wisconsin Card Sorting Test (WCST). The AN group scored worse than HCs on set-shifting. According to their neuropsychological performances, AN patients were split into two groups corresponding to poor (N=30) and intact (N=64) set shifting subtypes. Interoceptive awareness, impulse regulation, and maturity fears on the EDI-2 and depression on the BDI differed across all groups (HC, intact, and poor set-shifting subtype). Self-directedness on the TCI differed significantly among all groups. Cooperativeness and reward dependence differed instead only between HC and AN poor set-shifting subtype. After controlling for depression, only interoceptive awareness remained significant with reward dependence showing a trend towards statistical significance. These findings suggest that multiple clinical variables may be correlated with set-shifting performances in AN. The factors contributing to impaired cognitive inflexibility could be more complex than heretofore generally considered. PMID- 25017617 TI - The relationship between family resiliency factors and caregiver-perceived duration of untreated psychosis in persons with first-episode psychosis. AB - Although the family has an important role in the early detection and intervention of first-episode psychosis (FEP), there are few findings reporting associations between family strengths and early treatment-seeking experiences. This study aimed to investigate, within the framework of the resiliency model of family stress, adjustment, and adaptation, the association between family coping strategies, resource management factors and duration of untreated psychosis (DUP) in Iranian families with one adult child with FEP. Hundred and seven individuals referred to three medical centers in Tehran and diagnosed with FEP participated in this study. Caregiver-perceived DUP was measured via semi-structured interviews administered to primary caregivers. They also completed two questionnaires regarding family resources of stress management and family coping strategies. Data analysis indicated that the Family Inventory of Resources of Management (FIRM) total scale score did not significantly explain the variance of caregiver-perceived DUP, but one of the FIRM subscales, the Extended Family Social Support, and the Family Crisis-Oriented Personal Evaluation scale (F COPES) total score and one its subscales, the Acquiring Social Support, explained a significant amount of the variance of caregiver-perceived DUP. The results suggest that higher family resiliency, especially social support, facilitates the family's appropriate adaptive reaction (i.e., treatment-seeking), with the consequent decrease of DUP. PMID- 25017618 TI - Reward bias and lateralization in gambling behavior: behavioral activation system and alpha band analysis. AB - The present research explored the main factors that can influence subjects' choices in the case of decisions. In order to elucidate the individual differences that influence the decisional processes, making their strategies more or less advantageous, we tested the effect of a reward sensitivity in the behavioral activation system (BAS-Reward) constructed on the ability to distinguish between high- and low-risk decisions. Secondly, the lateralization effect, related to increased activation of the left (BAS-related) hemisphere, was explored. Thirty-one subjects were tested using the Iowa Gambling Task, and the BAS-Reward measure was applied to distinguish between high-BAS and low-BAS groups. Behavioral responses (gain/loss options) and alpha-band modulation were considered. It was found that high-BAS group increased their tendency to opt in favor of the immediate reward (loss strategy) rather than the long-term option (win strategy). Secondly, high-BAS subjects showed an increased left-hemisphere activation in response to losing (with immediate reward) choices in comparison with low-BAS subjects. A "reward bias" effect was supposed to explain both the bad strategy and the unbalanced hemispheric activation for high-BAS and more risk taking subjects. PMID- 25017619 TI - Metacognition in psychosis: comparison of schizophrenia with bipolar disorder. AB - While deficits in metacognition have been observed in schizophrenia (SZ), it is less clear whether these are specific to the disorder. Accordingly, this study compared metacognitive abilities of patients with schizophrenia and bipolar disorder (BD) and examined the degree to which neurocognition contributed to metacognitive deficits in both groups. Participants were 30 patients with SZ and 30 with BD. Metacognitive capacity was measured using the Metacognition Assessment Scale Abbreviated (MAS-A). This scale comprises four domains: self reflectivity, understanding others' minds, decentration and mastery. Verbal memory, executive functioning and symptoms were concurrently assessed. Group comparisons revealed that SZ patients had greater deficits in metacognitive self reflectivity, which correctly classified 85.2% of patients with SZ in a logistic regression. Self-reflectivity and understanding others'minds were related to verbal memory and executive functioning in the SZ group, but not in the BD group. Furthermore, greater positive and general psychotic symptoms were associated with poorer metacognition in SZ. Results suggest SZ involves unique deficits in the ability to self-reflect and that these deficits may be uniquely linked with neurocognition. PMID- 25017620 TI - Association between dopa decarboxylase gene variants and borderline personality disorder. AB - Despite heritability estimates of 37-69%, research has identified few genetic risk variants for borderline personality disorder (BPD). The present collaborative candidate gene study of 987 BPD cases and 1110 healthy controls found an association between BPD and single nucleotide polymorphism rs12718541 in the dopa decarboxylase gene. PMID- 25017621 TI - Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis? AB - BACKGROUND: Minimal Change Disease (MCD) is associated with CD80 expression in podocytes and elevated urinary CD80 excretion during active renal disease. We have evaluated the urinary excretion of CTLA-4 and CD80 during different stages of the nephrotic syndrome in patients with MCD to test the hypothesis that persistent increased urinary CD80 excretion in patients with MCD in relapse is due to an ineffectual CTLA-4 response of the host to curtail the activation of CD80. METHODS: Thirty-two children with biopsy-proven MCD were studied during relapse and/or remission. Eleven healthy subjects served as controls. RESULTS: Urinary CD80 excretion was significantly increased in MCD patients in relapse relative to that in MCD patients in remission (p < 0.001) and controls (p < 0.001). Although urinary CTLA-4 excretion was higher in MCD patients in relapse than in MCD patients in remission (p = 0.01) and controls (p = 0.03), no significant correlation was observed between urinary CD80 excretion and urinary CTLA-4 level in MCD patients at the time of relapse (p = 0.06). At the time of remission, CD80 had decreased significantly in all patients, but CTLA-4 levels either decreased or remained unchanged in all but five patients, and no correlation was observed between urinary CD80 excretion and CTLA-4 level (p = 0.7). CONCLUSIONS: Urinary CTLA-4 levels do not correlate with urinary CD80 excretion, suggesting the possibility that the CTLA4 response may be suboptimal in this disease during relapse. PMID- 25017622 TI - Oral anticoagulant use in addition to antiplatelet therapy for secondary prevention in acute coronary syndrome: current perspectives. AB - Patients with acute coronary syndrome (ACS) are typically managed with long-term dual antiplatelet therapy of acetylsalicylic acid plus a P2Y12 platelet receptor antagonist; however, although effective, the risk of another vascular event within 12 months remains at approximately 10%. Considerable efforts have been made to find improved therapeutic approaches to secondary prevention in ACS. The ATLAS ACS 2-TIMI 51 trial demonstrated that rivaroxaban (2.5 mg twice daily) significantly reduced recurrent vascular events, increased the risk of major bleeding but not the risk of fatal bleeding, and resulted in reduced rates of death from cardiovascular causes. These results formed the basis for approval in Europe of rivaroxaban (2.5 mg twice daily) in conjunction with standard antiplatelet therapy for the secondary prevention of ACS. PMID- 25017623 TI - Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis stilbene diamines: a platform for the preparation of single-enantiomer cis imidazolines for protein-protein inhibition. AB - The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate catalyst matching. This method was used to prepare highly substituted cis-4,5 diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions. PMID- 25017624 TI - Efficacy of a family intervention program for prevention of hospitalization in patients with schizophrenia. A naturalistic multicenter controlled and randomized study in Spain. AB - BACKGROUND: According to most relevant guidelines, family psycho-educational interventions are considered to be one the most effective psychosocial treatments for people with schizophrenia. The main outcome measure in controlled and randomized studies has been prevention of relapses and admissions, and encouragement of compliance, although some questions remain about its applicability and results in clinical practice. OBJECTIVES: The aim of study was to evaluate the efficacy and implementation of a single family psychoeducational intervention in 'real' conditions for people diagnosed with schizophrenia. METHODS: A total of 88 families were randomized in two groups. The family intervention group received a 12 months psychoeducational treatment, and the other group followed normal standard treatment. Assessments were made at baseline, at 12 and at 18 months. The main outcome measure was hospitalization, and secondary outcome measures were clinical condition (BPRS-E) and social disability (DAS-II). RESULTS: A total of 71 patients finished the study (34 family intervention group and 37 control group). Patients who received family intervention reduced the risk of hospitalization by 40% (P = .4018; 95%CI: 0.1833 0.6204). Symptomatology improved significantly at 12 months (P = .4018; 95%CI: 0.1833-0.6204), but not at 18 months (P = .4018; 95%CI: 0.1833-0.6204). Social disability was significantly reduced in the family intervention group at 12 months and 18 months. CONCLUSIONS: Family psychoeducational intervention reduces hospitalization risk and improves clinical condition and social functioning of people with schizophrenia. PMID- 25017626 TI - Mechanism of foam destruction by antifoams: a molecular dynamics study. AB - In enhanced oil recovery (EOR), the micro-oil droplet heavily affected the stability of foam and prevented foam flooding. In this paper, the oil bridge stretching mechanism of foam rupture was described through molecular dynamics with the aim of providing supplements to the experiments at the molecular level. Two important phenomena for foam rupture have been pointed out by the simulation. One is about the pseudoemulsion film, representing the stability of the oil-water air three phase interface. The bound water connecting the headgroups of the surfactant through strong H-bonding interactions played a vital role in the stability of the pseudoemulsion film. These water molecules could hinder the disappearance of the water phase in the pseudoemulsion film. The additional energy barrier, which was influenced by the surfactant concentration, also played a vital role in preventing the destruction process. The other factor is about the oil bridge, which appeared after the destruction of the pseudoemulsion film. The external horizontal force stretched the bridge resulting in the destruction of the bridge. The process was decided by the properties of the oil molecules. In the simulation, the stretching force was divided into three stages including the initial increasing force, the middle equilibrium force and the final decreasing force. Especially the second equilibrium force, which stretched the middle of the oil bridge so that it became thin, was vital to the foam rupture. The concentration and properties of the oil molecules were the crucial factors for foam rupture. The simulated results offer important supplements to experiments. PMID- 25017625 TI - Synthesis and cholinesterase inhibition of cativic acid derivatives. AB - Alzheimer's disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitive deficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase (AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolic extract of Grindelia ventanensis (IC50=0.79 mg/mL). This result prompted us to isolate the active constituent, a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guided fractionation. Taking into account that 1 showed moderate inhibition of AChE (IC50=21.1 MUM), selectivity over butyrylcholinesterase (BChE) (IC50=171.1 MUM) and that it was easily obtained from the plant extract in a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoid through simple structural modifications. A set of twenty new cativic acid derivatives (3-6) was prepared from 1 through transformations on the carboxylic group at C-15, introducing a C2 C6 linker and a tertiary amine group. They were tested for their inhibitory activity against AChE and BChE and some structure-activity relationships were outlined. The most active derivative was compound 3c, with an IC50 value of 3.2 MUM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitor targeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was non-cytotoxic. PMID- 25017627 TI - High efficiency photocatalysis for pollutant degradation with MoS2/C3N4 heterostructures. AB - Porous graphitic carbon nitride was synthesized by controllable thermal polymerization of urea in air. Their textural, electrical, and optical properties were tuned by varying the heating rate. The presence of proper residual oxygen in carbon nitride matrix had enhanced light absorption and inhibited the recombination of charge carriers. Furthermore, the MoS2 nanosheets were coupled into the carbon nitride to form MoS2/C3N4 heterostructures via a facile ultrasonic chemical method. The optimized MoS2/C3N4 heterostructure with 0.05 wt % MoS2 showed a reaction rate constant as high as 0.301 min(-1), which was 3.6 times that of bare carbon nitride. As analyzed by SEM, TEM, UV-vis absorption, PL and photoelectrochemical measurements, intimate contact interface, extended light response range, enhanced separation speed of charge carriers, and high photocurrent density upon MoS2 coupling led to the photocatalytic promotion of the MoS2/C3N4 heterostructures. In this architecture, MoS2 served as electron trapper to extend the lifetime of separated electron-hole pairs. Meanwhile, the accumulated holes on the surface of carbon nitride oxidized the organic dye directly, which was a predominant process in the photodegradation of organic pollutants in water treatment. The promotional mechanisms and principles reported here would have great significance in heterogeneous photocatalysis. PMID- 25017628 TI - Flipping through the genetic code: new developments in discrimination between cognate and near-cognate tRNAs and the effect of antibiotics. PMID- 25017629 TI - Anti-tumor effects of anti-T-cell globulin. AB - In vivo T-cell depletion using anti-T-cell antibodies is a standard procedure during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Clinical data demonstrate that in vivo T-cell depletion with the anti-CD52 monoclonal antibody Alemtuzumab is associated with increased relapse rates of hematologic malignancies after allo-HSCT, underlining the importance of donor T cells for graft versus tumor activity. In contrast, recent results suggest that in vivo T cell depletion with rabbit anti-T-cell globulin (ATG) Fresenius is not associated with tumor relapse after allo-HSCT, raising the possibility that ATG mediates antitumor effects. However, data on ATG's ability to bind to tumor cells and on its effect on the induction of antibody-dependent cellular cytotoxicity (ADCC) are lacking. We used ATG Fresenius, which contains polyclonal rabbit IgG directed against the human T-lymphoma cell line Jurkat, to study relevant mechanisms of ATG-mediated antitumor effects, including ADCC, complement-dependent cytotoxicity, and induction of apoptosis. Based on the knowledge that Jurkat cells aberrantly express myeloid markers and B-cell markers, we hypothesized that rabbit ATG Fresenius binds to a variety of hematologic malignancies. We found that ATG specifically binds to a variety of hematologic malignancies including acute myeloid leukemia and B-cell lymphoma in a concentration-dependent manner. We demonstrate that ATG mediates antitumor activity, including induction of ADCC, complement-dependent cytotoxicity, and apoptosis, toward different hematologic malignancies. Our results contribute to a better understanding of the effects of ATG on posttransplant immunology in patients undergoing allo-HSCT. PMID- 25017631 TI - Estimation of lung motion fields in 4D CT data by variational non-linear intensity-based registration: A comparison and evaluation study. AB - Accurate and robust estimation of motion fields in respiration-correlated CT (4D CT) images, usually performed by non-linear registration of the temporal CT frames, is a precondition for the analysis of patient-specific breathing dynamics and subsequent image-supported diagnostics and treatment planning. In this work, we present a comprehensive comparison and evaluation study of non-linear registration variants applied to the task of lung motion estimation in thoracic 4D CT data. In contrast to existing multi-institutional comparison studies (e.g. MIDRAS and EMPIRE10), we focus on the specific but common class of variational intensity-based non-parametric registration and analyze the impact of the different main building blocks of the underlying optimization problem: the distance measure to be minimized, the regularization approach and the transformation space considered during optimization. In total, 90 different combinations of building block instances are compared. Evaluated on proprietary and publicly accessible 4D CT images, landmark-based registration errors (TRE) between 1.14 and 1.20 mm for the most accurate registration variants demonstrate competitive performance of the applied general registration framework compared to other state-of-the-art approaches for lung CT registration. Although some specific trends can be observed, effects of interchanging individual instances of the building blocks on the TRE are in general rather small (no single outstanding registration variant existing); the same level of accuracy is, however, associated with significantly different degrees of motion field smoothness and computational demands. Consequently, the building block combination of choice will depend on application-specific requirements on motion field characteristics. PMID- 25017630 TI - Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. AB - The biguanide metformin is widely prescribed for Type II diabetes and has anti neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria. PMID- 25017632 TI - Dabigatran treatment: effects on infarct size and the no-reflow phenomenon in a model of acute myocardial ischemia/reperfusion. AB - The no-reflow phenomenon occurs when an epicardial coronary artery is reopened following myocardial infarction, but portions of the intramural microvasculature fail to reperfuse. One potential mechanism for this is the presence of fibrin tactoids. In addition, some recent studies have suggested that dabigatran treatment may be associated with increased incidence of myocardial infarction. Our aim was to investigate the effect on myocardial infarct size and no-reflow in an acute model of ischemia/reperfusion. Anesthetized, open-chest rabbits were randomly assigned to receive dabigatran (Dab, 0.5 mg/kg bolus + infusion, 0.15 mg/kg/h, IV, n = 11) or vehicle (Veh, n = 11) 15 m before a 30-m coronary artery occlusion and during 2.5 h of the 3 h reperfusion procedure. At the end of the reperfusion period, infarct size (% risk zone) and no-reflow defect were measured. The ischemic risk zone (% of left ventricle) was similar in groups, 24 % in Dab and 25 % in Veh. Necrosis was neither reduced nor increased by Dab treatment; expressed as a percentage of the risk region, infarct size was 30 +/- 4 % in Dab and 28 +/- 5 % in Veh, p = 0.76. The extent of no-reflow was comparable, expressed either as a percent of the risk region (19 +/- 3 %, Dab and 18 +/- 3 %, Veh) or as a percent of the necrotic zone (67 +/- 8 % Dab and 65 +/- 10 % Veh). Dab treatment had no effect on heart rate or blood pressure. Dabigatran treatment did not prevent or ameliorate the no-reflow phenomenon, suggesting that fibrin does not play a major role in the development of microvascular obstruction. Dabigatran did not exacerbate myocardial infarct size. PMID- 25017633 TI - Effects of flow intermittency and pharmaceutical exposure on the structure and metabolism of stream biofilms. AB - Increasing concentrations of pharmaceutical compounds occur in many rivers, but their environmental risk remains poorly studied in stream biofilms. Flow intermittency shapes the structure and functions of ecosystems, and may enhance their sensitivity to toxicants. This study evaluates the effects of a long-term exposure of biofilm communities to a mixture of pharmaceutical compounds at environmental concentrations on biofilm bioaccumulation capacity, the structure and metabolic processes of algae and bacteria communities, and how their potential effects were enhanced or not by the occurrence of flow intermittency. To assess the interaction between those two stressors, an experiment with artificial streams was performed. Stream biofilms were exposed to a mixture of pharmaceuticals, as well as to a short period of flow intermittency. Results indicate that biofilms were negatively affected by pharmaceuticals. The algal biomass and taxa richness decreased and unicellular green algae relatively increased. The structure of the bacterial (based on denaturing gradient gel electrophoresis of amplified 16S rRNA genes) changed and showed a reduction of the operational taxonomic units (OTUs) richness. Exposed biofilms showed higher rates of metabolic processes, such as primary production and community respiration, attributed to pharmaceuticals stimulated an increase of green algae and heterotrophs, respectively. Flow intermittency modulated the effects of chemicals on natural communities. The algal community became more sensitive to short-term exposure of pharmaceuticals (lower EC50 value) when exposed to water intermittency, indicating cumulative effects between the two assessed stressors. In contrast to algae, the bacterial community became less sensitive to short-term exposure of pharmaceuticals (higher EC50) when exposed to water intermittency, indicating co-tolerance phenomena. According to the observed effects, the environmental risk of pharmaceuticals in nature is high, but different depending on the flow regime, as well as the target organisms (autotrophs vs heterotrophs). PMID- 25017634 TI - Interdisciplinary assessment of sea-level rise and climate change impacts on the lower Nile delta, Egypt. AB - CLImate-induced changes on WAter and SECurity (CLIWASEC) was a cluster of three complementary EC-FP7 projects assessing climate-change impacts throughout the Mediterranean on: hydrological cycles (CLIMB - CLimate-Induced changes on the hydrology of Mediterranean Basins); water security (WASSERMed - Water Availability and Security in Southern EuRope and the Mediterranean) and human security connected with possible hydro-climatic conflicts (CLICO - CLImate change hydro-COnflicts and human security). The Nile delta case study was common between the projects. CLIWASEC created an integrated forum for modelling and monitoring to understand potential impacts across sectors. This paper summarises key results from an integrated assessment of potential challenges to water-related security issues, focusing on expected sea-level rise impacts by the middle of the century. We use this common focus to illustrate the added value of project clustering. CLIWASEC pursued multidisciplinary research by adopting a single research objective: sea-level rise related water security threats, resulting in a more holistic view of problems and potential solutions. In fragmenting research, policy-makers can fail to understand how multiple issues can materialize from one driver. By combining efforts, an integrated assessment of water security threats in the lower Nile is formulated, offering policy-makers a clearer picture of inter-related issues to society and environment. The main issues identified by each project (land subsidence, saline intrusion - CLIMB; water supply overexploitation, land loss - WASSERMed; employment and housing security - CLICO), are in fact related. Water overexploitation is exacerbating land subsidence and saline intrusion, impacting on employment and placing additional pressure on remaining agricultural land and the underdeveloped housing market. All these have wider implications for regional development. This richer understanding could be critical in making better policy decisions when attempting to mitigate climate and social change impacts. The CLIWASEC clustering offers an encouraging path for the new European Commission Horizon 2020 programme to follow. PMID- 25017635 TI - Occurrence and spatial distribution of EDCs and related compounds in waters and sediments of Iberian rivers. AB - The environmental presence of chemicals capable of affecting the endocrine system has become a matter of scientific and public concern after certain endocrine disruptor compounds (EDCs) have been detected in the aquatic environment. In this work, 31 different EDCs and related compounds (suspect EDCs) belonging to different contaminant classes were studied: 10 estrogens, natural and synthetic, 8 alkylphenolic compounds, bisphenol A, triclosan and triclorocaraban, 4 parabens, 2 benzotriazoles, 3 organophosphorous flame retardants and the chemical marker caffeine, in river water and sediment of four Iberian rivers (Ebro, Llobregat, Jucar and Guadalquivir). An extensive sampling has been undertaken in two monitoring campaigns (2010 and 2011). A total of 77 samples of water and 75 sediments were collected. For this propose two different multiresidue analytical methods were applied, using the automated online EQuan/TurboFlowTM liquid chromatography coupled to mass spectrometry detection in tandem. In terms of concentrations the compounds found at the highest average concentrations were: nonylphenol monocarboxylate (NP1EC), tolyltriazole (TT), tris(chloroisopropyl)phosphate (TCPP) found at average concentrations above 100 ng/L, followed by 1H-benzotriazole and tris(butoxyethyl)phosphate (TBEP) found at average concentration higher than 50 ng/L. Natural and synthetic hormones were found at low levels not exceeding 16 ng/L and 7 ng/g for water and sediment, respectively, however they contributed to more than 80% of the total estrogenicity of the samples (expressed as the equivalents of estradiol EEQ, ng/L). Regarding the spatial distribution of these contaminants, the Llobregat river was found to be the most contaminated river basin, having sites near the mouth of the river the ones with the highest contaminant load. In the Ebro river basin several hot spots were identified and Jucar showed to be the least contaminated. Overall, the study confirmed the presence of complex mixtures of unregulated contaminants, thus raising concern about their potential interactive effects. PMID- 25017636 TI - Impact of long-term organic residue recycling in agriculture on soil solution composition and trace metal leaching in soils. AB - Recycling composted organic residues in agriculture can reduce the need of mineral fertilizers and improve the physicochemical and biological properties of cultivated soils. However, some trace elements may accumulate in soils following repeated applications and impact other compartments of the agrosystems. This study aims at evaluating the long-term impact of such practices on the composition of soil leaching water, especially on trace metal concentrations. The field experiment QualiAgro started in 1998 on typical loess Luvisol of the Paris Basin, with a maize-wheat crop succession and five modalities: spreading of three different urban waste composts, farmyard manure (FYM), and no organic amendment (CTR). Inputs of trace metals have been close to regulatory limits, but supplies of organic matter and nitrogen overpassed common practices. Soil solutions were collected from wick lysimeters at 45 and 100 cm in one plot for each modality, during two drainage periods after the last spreading. Despite wide temporal variations, a significant effect of treatments on major solutes appears at 45 cm: DOC, Ca, K, Mg, Na, nitrate, sulphate and chloride concentrations were higher in most amended plots compared to CTR. Cu concentrations were also significantly higher in leachates of amended plots compared to CTR, whereas no clear effect emerged for Zn. The influence of amendments on solute concentrations appeared weaker at 1 m than at 45 cm, but still significant and positive for major anions and DOC. Average concentrations of Cu and Zn at 1m depth lied in the ranges [2.5; 3.8] and [2.5; 10.5 MUg/L], respectively, with values slightly higher for plots amended with sewage sludge compost or FYM than for CTR. However, leaching of both metals was less than 1% of their respective inputs through organic amendments. For Cd, most values were <0.05 MUg/L. So, metals added through spreading of compost or manure during 14 years may have increased metal concentrations in leachates of amended plots, in spite of increased soil organic matter, factor of metal retention. Indeed, DOC, also increased by amendments, favours the mobility of Cu; whereas pH variations, depending on treatments, influence negatively the solubility of Zn. Generic adsorption functions of these variables partly explain the variations of trace metal concentrations and helped to unravel the numerous processes induced by regular amendments with organic waste products. PMID- 25017637 TI - Risk assessment based prioritization of 200 organic micropollutants in 4 Iberian rivers. AB - The use of chemicals is continuously growing both in total amount as well as in a number of different substances, among which organic chemicals play a major role. Owing to the growing public awareness on the need of protecting both ecosystems and human health from the risks related to chemical pollution, an increasing attention has been drowned to risk assessment and prioritization of organic pollutants. In this context, the aims of this study were (a) to perform an environmental risk assessment for 200 organic micropollutants including both regulated and emerging contaminants (pesticides, alkylphenols, pharmaceuticals, hormones, personal care products, perflourinated compounds and various industrial organic chemicals) monitored in four rivers located in the Mediterranean side of the Iberian Peninsula, namely, the Ebro, Llobregat, Jucar and Guadalquivir rivers; and (b) to prioritize them for each of the four river basins studied, taking into account their observed concentration levels together with their ecotoxicological potential. For this purpose, a prioritization approach has been developed and a resulting ranking index (RI) associated with each compound. Ranking index is based on the measured concentrations of the chemical in each river and its ecotoxicological potential (EC50 values for algae, Daphnia sp. and fish). Ten compounds were identified as most important for the studied rivers: pesticides chlorpyriphos, chlorfenvinphos, diazinon, dichlofenthion, prochloraz, ethion carbofuran and diuron and the industrial organic chemicals nonylphenol and octylphenol that result from the biodegration of polyethoxylated alkyphenol surfactants. Also, further research into chronic toxicity of emerging contaminants is advocated. PMID- 25017638 TI - Managing aquatic ecosystems and water resources under multiple stress--an introduction to the MARS project. AB - Water resources globally are affected by a complex mixture of stressors resulting from a range of drivers, including urban and agricultural land use, hydropower generation and climate change. Understanding how stressors interfere and impact upon ecological status and ecosystem services is essential for developing effective River Basin Management Plans and shaping future environmental policy. This paper details the nature of these problems for Europe's water resources and the need to find solutions at a range of spatial scales. In terms of the latter, we describe the aims and approaches of the EU-funded project MARS (Managing Aquatic ecosystems and water Resources under multiple Stress) and the conceptual and analytical framework that it is adopting to provide this knowledge, understanding and tools needed to address multiple stressors. MARS is operating at three scales: At the water body scale, the mechanistic understanding of stressor interactions and their impact upon water resources, ecological status and ecosystem services will be examined through multi-factorial experiments and the analysis of long time-series. At the river basin scale, modelling and empirical approaches will be adopted to characterise relationships between multiple stressors and ecological responses, functions, services and water resources. The effects of future land use and mitigation scenarios in 16 European river basins will be assessed. At the European scale, large-scale spatial analysis will be carried out to identify the relationships amongst stress intensity, ecological status and service provision, with a special focus on large transboundary rivers, lakes and fish. The project will support managers and policy makers in the practical implementation of the Water Framework Directive (WFD), of related legislation and of the Blueprint to Safeguard Europe's Water Resources by advising the 3rd River Basin Management Planning cycle, the revision of the WFD and by developing new tools for diagnosing and predicting multiple stressors. PMID- 25017639 TI - Physicochemical analysis and adequation of olive oil mill wastewater after advanced oxidation process for reclamation by pressure-driven membrane technology. AB - Physicochemical characterization of olive mill wastewaters (OMW) was studied after a primary and secondary treatment was implemented in an olive oil factory in Jaen (Spain), comprising natural precipitation, Fenton-like reaction, flocculation-sedimentation and olive stone filtration in series. The application of membrane technology in improving the quality of the secondary-treated OMW (OMW/ST) was examined, to reduce the hazardous electroconductivity (EC) values (2 3 mS cm(-1)). Particle size distribution on OMW/ST shows supra-micron colloids and suspended solids as well as sub-micron particles with a mean size below 1.5 MUm remaining in considerable concentration. The high organic pollutants percentage (31.7%) registered with an average diameter below 3 kDa is sensibly relevant for membrane fouling. Mesophilic aerobic bacteria growth warns of possible membrane biofouling formation. The saturation index indicates to work upon recovery factor below 90%. Finally, operating at a pressure equal to 15 bar ensured low fouling and high flux production on the selected NF membrane (69.9 L h(-1)m(-2)) and significant rejection efficiencies (55.5% and 88.5% for EC and COD). This permits obtaining an effluent with good quality according to the recommendations of the Food and Agricultural Association (FAO) with the goal of reusing the regenerated water for irrigation. PMID- 25017640 TI - Role of the N-terminal peptide of amelogenin on osteoblastic differentiation of human mesenchymal stem cells. AB - Porcine enamel matrix derivative (pEMD), a complex mixture of proteins and peptides including full-length amelogenin protein, splice variants, and proteolytic peptides, is used clinically with a carrier to regenerate supportive tissue around teeth. During application, pEMD self-assembles as nanospheres and precipitates as a three-dimensional matrix to facilitate cell migration and differentiation. Amelogenin, the primary constituent of pEMD, stimulates osteoblast differentiation, but it is unclear what specific roles other components of pEMD play in determining biological response. This study examined the potential of one constituent of pEMD, the N-terminal amelogenin peptide (NTAP), to promote osteoblastic differentiation of human mesenchymal stem cells (MSCs) and to elucidate possible signaling pathways involved. Effects of porcine NTAP on MSC cultures were compared to those of recombinant human amelogenin. While amelogenin induced MSC osteoblastic differentiation, a more robust osteoblastic response was seen after NTAP treatment. A phospho-kinase proteasome array measuring phosphorylation of 35 proteins indicated that protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2), and beta-catenin were highly phosphorylated by NTAP. This was confirmed by measuring PKC activity and levels of phospho-ERK1/2 and beta-catenin. Both amelogenin and NTAP increased PKC, but NTAP induced higher phosho-ERK1/2 and phospho-beta-catenin than amelogenin. ERK1/2 inhibition blocked both amelogenin- and NTAP-induced increases in RUNX2, ALP, OCN, COL1, and BMP2. The results demonstrate that NTAP induces osteogenic differentiation of MSCs via PKC and ERK1/2 activation and beta-catenin degradation. NTAP may be an active bone regeneration component of amelogenin, and may play this role in pEMD-stimulated periodontal regeneration. PMID- 25017641 TI - Transplantation and perfusion of microvascular fragments in a rodent model of volumetric muscle loss injury. AB - Few clinical options are available for the treatment of volumetric muscle loss (VML). An important consideration that needs to be addressed for the development of treatments for these injuries is the establishment of a vascular supply sufficient to support skeletal muscle regeneration. The objective of the current study was to evaluate the potential for microvascular fragments (MVFs) harvested from adipose tissue to support tissue perfusion for VML. Tibialis anterior muscle defects in rats were replaced with constructs that were created on the day of surgery containing either (1) collagen only (COL), (2) freshly isolated microvascular fragments in collagen (MVF), or (3) adipose tissue derived stem cells (ASCs) in collagen. Muscles were harvested 7 and 14 days after surgery. Defects treated with MVFs had a vessel density higher than the other groups at both 7 and 14 days, and those treated with ASCs had a higher vessel density than COL by day 14 (p < 0.05). Perfused vessels were observed in both the ASC and MVF treated defects at day 14, as well as at day 7 in the MVF. This study supports the use of MVFs as a platform to improve tissue perfusion to treat large VML defects. The use of freshly isolated MVFs on the day of surgery supports their clinical use and application. PMID- 25017644 TI - Effects of MDMA on olfactory memory and reversal learning in rats. AB - The effects of acute and sub-chronic MDMA were assessed using a procedure designed to test rodent working memory capacity: the odor span task (OST). Rats were trained to select an odor that they had not previously encountered within the current session, and the number of odors to remember was incremented up to 24 during the course of each session. In order to separate drug effects on the OST from more general performance impairment, a simple olfactory discrimination was also assessed in each session. In Experiment 1, acute doses of MDMA were administered prior to select sessions. MDMA impaired memory span in a dose dependent fashion, but impairment was seen only at doses (1.8 and 3.0 mg/kg) that also increased response omissions on both the simple discrimination and the OST. In Experiment 2, a sub-chronic regimen of MDMA (10.0 mg/kg, twice daily over four days) was administered after OST training. There was no evidence of reduced memory span following sub-chronic MDMA, but a temporary increase in omission errors on the OST was observed. In addition, rats exposed to sub-chronic MDMA showed delayed learning when the simple discrimination was reversed. Overall, the disruptive effects of both acute and sub-chronic MDMA appeared to be due to non mnemonic processes, rather than effects on specific memory functions. PMID- 25017646 TI - On the left anterior negativity (LAN): The case of morphosyntactic agreement: a reply to Tanner et al. PMID- 25017645 TI - Knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of the AKT pathway. AB - Octamer-binding transcription factor 4 (OCT4) is one of the factors associated with self-renewal and differentiation in cancer stem cells, and is crucial for the progression of various types of human malignancy. However, the expression and function of OCT4 in human pancreatic cancer has not been fully elucidated. The purpose of the present study was to investigate the function and molecular mechanisms of OCT4 in pancreatic cancer cells. The clinical significance of OCT4 expression was assessed by an immunohistochemical assay using a tissue microarray procedure in pancreatic cancer tissues and cells with different degrees of differentiation. A loss-of-function approach was used to examine the effects of a lentivirus-mediated OCT4 small hairpin RNA vector on biological behaviors, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of OCT4 protein in cancer tissues were significantly elevated compared with those in adjacent non-cancerous tissues (65.0 vs. 42.5%; P=0.005), which was correlated with tumor differentiation (P=0.008). The knockdown of OCT4 inhibited the proliferation and invasion of pancreatic cancer cells (Panc-1) expressing high levels of OCT4, accompanied with decreased expression of AKT, proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2). In conclusion, the present study reveals that the increased expression of OCT4 is correlated with the differentiation of pancreatic cancer, while knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of AKT pathway-mediated PCNA and MMP-2 expression, suggesting that OCT4 might serve as a potential therapeutic target for the treatment of pancreatic cancer. PMID- 25017647 TI - Selective attention modulates high-frequency activity in the face-processing network. AB - Face processing depends on the orchestrated activity of a large-scale neuronal network. Its activity can be modulated by attention as a function of task demands. However, it remains largely unknown whether voluntary, endogenous attention and reflexive, exogenous attention to facial expressions equally affect all regions of the face-processing network, and whether such effects primarily modify the strength of the neuronal response, the latency, the duration, or the spectral characteristics. We exploited the good temporal and spatial resolution of intracranial electroencephalography (iEEG) and recorded from depth electrodes to uncover the fast dynamics of emotional face processing. We investigated frequency-specific responses and event-related potentials (ERP) in the ventral occipito-temporal cortex (VOTC), ventral temporal cortex (VTC), anterior insula, orbitofrontal cortex (OFC), and amygdala when facial expressions were task relevant or task-irrelevant. All investigated regions of interest (ROI) were clearly modulated by task demands and exhibited stronger changes in stimulus induced gamma band activity (50-150 Hz) when facial expressions were task relevant. Observed latencies demonstrate that the activation is temporally coordinated across the network, rather than serially proceeding along a processing hierarchy. Early and sustained responses to task-relevant faces in VOTC and VTC corroborate their role for the core system of face processing, but they also occurred in the anterior insula. Strong attentional modulation in the OFC and amygdala (300 msec) suggests that the extended system of the face processing network is only recruited if the task demands active face processing. Contrary to our expectation, we rarely observed differences between fearful and neutral faces. Our results demonstrate that activity in the face-processing network is susceptible to the deployment of selective attention. Moreover, we show that endogenous attention operates along the whole face-processing network, and that these effects are reflected in frequency-specific changes in the gamma band. PMID- 25017648 TI - Recovery of biological motion perception and network plasticity after cerebellar tumor removal. AB - Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition. PMID- 25017649 TI - Safety measures in hip arthroscopy and their efficacy in minimizing complications: a systematic review of the evidence. AB - PURPOSE: The purpose of this systematic review was to evaluate the literature to determine complications of hip arthroscopy, with a secondary focus on how to minimize complications and risks. METHODS: Two independent reviewers performed a search of PubMed for articles that contained at least 1 of the following terms: complications and hip arthroscopy, hip impingement, femoral acetabular impingement and complications, or femoroacetabular impingement (FAI) and complications. The search was limited to articles published between 1999 and June 2013. An additional search was performed for articles evaluating techniques on how to minimize complications. RESULTS: We identified 81 studies (5,535 patients; 6,277 hips). The mean age was 35.48 years, and the mean body mass index was 25.20 kg/m(2). Of the participants, 52% were male and 48% were female. The majority of studies were Level IV Evidence (63%). A total of 285 complications were reported, for an overall rate of 4.5%. There were 26 major complications (0.41%) and a 4.1% minor complication rate. The overall reoperation rate was 4.03%. A total of 94 hips underwent revision arthroscopy. Regarding open procedures, 150 patients (93%) underwent either total hip arthroplasty or a hip resurfacing procedure. The conversion rate to total hip arthroplasty or a resurfacing procedure was 2.4%. CONCLUSIONS: Overall, primary hip arthroscopy is a successful procedure with low rates of major (0.41%) and minor (4.1%) complications. The reoperation rate was 4.03% in our review. There is admittedly a learning curve to performing hip arthroscopy, and we present a systematic review of the complications and how to minimize these complications with careful technique and planning. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to V studies. PMID- 25017650 TI - The novel bis-benzylisoquinoline PY35 reverses P-glycoprotein-mediated multidrug resistance. AB - Multidrug resistance (MDR) to chemotherapeutic drugs is the main cause of chemotherapy failure in cancer treatment, and it generally results from expression of ATP-dependent efflux pump P-glycoprotein (P-gp). MDR reversal agents typically act by inhibiting the drug efflux activity of P-gp, thereby increasing intracellular drug levels. PY35 is a novel 5-substituted tetrandrine (Tet) derivative (CN Application No. 201210238709.6). The present study was performed to investigate the ability of PY35 to reverse P-gp-mediated MDR and its mechanism in resistant K562/Adriamycin (ADM), MCF-7/ADM cells and their sensitive cell lines K562 and MCF-7. The ability of PY35 to reverse drug resistance was evaluated by MTT assay. The results showed that PY35 can reverse MDR more effectively than the drug prototype-Tet. The P-gp function was assessed by the Rhodamine 123 (Rho-123; a P-gp substrate) uptake assay with flow cytometry (FCM) and laser scanning confocal microscopes (LSCM); it showed that the MDR cells pumped Rho-123 out the cells, while their sensitive cells scarcely showed efflux. The presence of PY35 efficiently decreased the efflux of the Rho-123, showing that PY35 can reverse P-gp-mediated MDR by increasing the intracellular concentration of Rho-123. The intracellular accumulation of ADM was analyzed by FCM and showed that the coadministration of PY35 and ADM had clearer accumulation than the treatment of Tet and ADM, and was also more evident than treatment with only ADM. The effect of PY35 on the expression of P-gp was assessed by western blotting. The results indicated that PY35 does not inhibit the expression level of the P-gp. This study indicated that PY35 can effectively reverse P-gp-mediated MDR, not by inhibiting the expression of P-gp, but by the coadministration of PY35 and ADM that could increase the intracellular accumulation of drugs. Thus, PY35 may be a potential inhibitor to overcome drug resistance. PMID- 25017651 TI - Commentary in response to the letter from Farsalinos et al. regarding our publication entitled: "identification of toxicants in cinnamon-flavored electronic cigarette refill fluids". PMID- 25017652 TI - Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy. AB - CONTEXT: Polymeric nanoparticles (NPs) have been used frequently as drug delivery vehicles. Surface modification of polymeric NPs with specific ligands defines a new biological identity, which assists in targeting of the nanocarriers to specific cancers cells. OBJECTIVE: The aim of this study is to develop a kind of modified vector which could target the cancer cells through receptor-mediated pathways to increase the uptake of doxorubicin (DOX). METHODS: Folate (FA) conjugated PEG-PE (FA-PEG-PE) ligands were used to modify the polymeric NPs. The modification rate was optimized and the physical-chemical characteristics, in vitro release, and cytotoxicity of the vehicle were evaluated. The in vivo therapeutic effect of the vectors was evaluated in human nasopharyngeal carcinoma KB cells baring mice by giving each mouse 100 ul of 10 mg/kg different solutions. RESULTS: FA-PEG-PE-modified NPs/DOX (FA-NPs/DOX) have a particle size of 229 nm, and 86% of drug loading quantity. FA-NPs/DOX displayed remarkably higher cytotoxicity (812 mm(3) tumor volume after 13 d of injection) than non-modified NPs/DOX (1290 mm(3)) and free DOX solution (1832 mm(3)) in vivo. CONCLUSION: The results demonstrate that the modified drug delivery system (DDS) could function comprehensively to improve the efficacy of cancer therapy. Consequently, the system was shown to be a promising carrier for delivery of DOX, leading to the efficiency of antitumor therapy. PMID- 25017653 TI - Analgesic activity of Eugenia jambolana leave constituent: a dikaempferol rhamnopyranoside from ethyl acetate soluble fraction. AB - CONTEXT: Eugenia jambolana Lam. (Myrtaceae) is a medicinal plant used in folk medicine for the treatment of diabetes, inflammation, and pain. OBJECTIVE: We investigated the antinociceptive effect of kaempferol-7-O-alpha-l rhamnopyranoside]- 4'-O-4'-[kaempferol-7-O-alpha-l-rhamnopyranoside (EJ-01), isolated from the E. jambolana leaves. MATERIALS AND METHODS: EJ-01 (3, 10, and 30 mg kg(-1), orally) was assessed for peripheral (formalin-nociception and acetic acid-writhing) and central (hot plate and tail flick test) analgesic activity in mice and the in vitro anti-inflammatory activity (25, 50, and 100 ug mL(-1)) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. RESULTS AND DISCUSSION: EJ-01 (10 and 30 mg kg(-1)) significantly inhibited mean writhing counts (37.74 and 36.83) in acetic acid writhing and paw licking time (55.16 and 45.66 s) in the late phase of the formalin test as compared with the respective control (60.66 and 104.33 s). EJ-01 did not show analgesic activity in central pain models. Significant reduction in the tumor necrosis factor (TNF)-alpha (295.48, 51.20, and 49.47 pg mL(-1)) and interleukin (IL)-1beta (59.38, 20.08, and 15.46 pg mL(-1)) levels were observed in EJ-01-treated medium (25, 50, and 100 ug mL(-1)) as compared with vehicle-treated control values (788.67 and 161.77 pg mL(-1)), respectively. Significant reduction in total nitrite plus nitrate (NOx) levels (70.80 nmol) was observed in the EJ-01-treated medium (100 ug mL( 1)) as compared with the vehicle-treated value (110.41 nmol). CONCLUSION: EJ-01 is a valuable analgesic constituent of E. jambolana leaves and this study supports the pharmacological basis for the use of this plant in traditional medicine for curing inflammatory pain. PMID- 25017654 TI - Evolutionary and dispersal history of Triatoma infestans, main vector of Chagas disease, by chromosomal markers. AB - Chagas disease, one of the most important vector-borne diseases in the Americas, is caused by Trypanosoma cruzi and transmitted to humans by insects of the subfamily Triatominae. An effective control of this disease depends on elimination of vectors through spraying with insecticides. Genetic research can help insect control programs by identifying and characterizing vector populations. In southern Latin America, Triatoma infestans is the main vector and presents two distinct lineages, known as Andean and non-Andean chromosomal groups, that are highly differentiated by the amount of heterochromatin and genome size. Analyses with nuclear and mitochondrial sequences are not conclusive about resolving the origin and spread of T. infestans. The present paper includes the analyses of karyotypes, heterochromatin distribution and chromosomal mapping of the major ribosomal cluster (45S rDNA) to specimens throughout the distribution range of this species, including pyrethroid-resistant populations. A total of 417 specimens from seven different countries were analyzed. We show an unusual wide rDNA variability related to number and chromosomal position of the ribosomal genes, never before reported in species with holocentric chromosomes. Considering the chromosomal groups previously described, the ribosomal patterns are associated with a particular geographic distribution. Our results reveal that the differentiation process between both T. infestans chromosomal groups has involved significant genomic reorganization of essential coding sequences, besides the changes in heterochromatin and genomic size previously reported. The chromosomal markers also allowed us to detect the existence of a hybrid zone occupied by individuals derived from crosses between both chromosomal groups. Our genetic studies support the hypothesis of an Andean origin for T. infestans, and suggest that pyrethroid-resistant populations from the Argentinean-Bolivian border are most likely the result of recent secondary contact between both lineages. We suggest that vector control programs should make a greater effort in the entomological surveillance of those regions with both chromosomal groups to avoid rapid emergence of resistant individuals. PMID- 25017655 TI - Full-length genome analysis of Calovo strains of Batai orthobunyavirus (Bunyamwera serogroup): implications to taxonomy. AB - Batai virus (BATV) is a poorly studied arthropod-borne virus belonging to the genus Orthobunyavirus (Bunyamwera serogroup) within the family Bunyaviridae. It has been associated with human influenza-like febrile illness in several Asian, African, and European countries. Calovo virus (CVOV), isolated in 1960 in Slovakia, has been classified as BATV based on high antigenic similarity, and since then both CVOV and BATV were used as synonyms. In order to fully clarify the phylogenetic relationships between CVOV, BATV, and other members of the Bunyamwera serogroup, we performed whole genome sequencing of four CVOV strains isolated in Europe and phylogenetic analyses of all related viruses. The nucleocapsid protein, encoded by the S genomic segment, contains 233 amino acids, 60 of which, putatively critical for protein function, are conserved. Within the CVOV polyprotein encoded by the M genomic segment, putative cleavage sites, N glycosylation sites, and seven transmembrane regions were identified. The RNA dependent RNA polymerase, encoded by the L genome segment, exhibits conservation of the three regions known to be conserved among bunyavirus and arenavirus L proteins. Phylogenetic analyses of all three genomic segments of selected orthobunyaviruses clearly revealed that European and Asian/African strains of BATV are phylogenetically different and form two distinct lineages, indicating the existence of two different genotypes of BATV, tentatively named European genotype (with CVOV as a type strain) and Afro-Asian genotype (with BATV as a type strain) of BATV. PMID- 25017656 TI - African genetic ancestry is associated with a protective effect on Dengue severity in colombian populations. AB - The wide variation in severity displayed during Dengue Virus (DENV) infection may be influenced by host susceptibility. In several epidemiological approaches, differences in disease outcomes have been found between some ethnic groups, suggesting that human genetic background has an important role in disease severity. In the Caribbean, It has been reported that populations of African descent present considerable less frequency of severe forms compared with Mestizo and White self-reported groups. Admixed populations offer advantages for genetic epidemiology studies due to variation and distribution of alleles, such as those involved in disease susceptibility, as well to provide explanations of individual variability in clinical outcomes. The current study analysed three Colombian populations, which like most of Latin American populations, are made up of the product of complex admixture processes between European, Native American and African ancestors; having as a main goal to assess the effect of genetic ancestry, estimated with 30 Ancestry Informative Markers (AIMs), on DENV infection severity. We found that African ancestry has a protective effect against severe outcomes under several systems of clinical classification: Severe Dengue (OR: 0.963 for every 1% increase in African ancestry, 95% confidence interval (0.934-0.993), p-value: 0.016), Dengue Haemorrhagic Fever (OR: 0.969, 95% CI (0.947-0.991), p-value: 0.006), and occurrence of haemorrhages (OR: 0.971, 95% CI (0.952-0.989), p-value: 0.002). Conversely, decrease from 100% to 0% African ancestry significantly increases the chance of severe outcomes: OR is 44 fold for Severe Dengue, 24-fold for Dengue Haemorrhagic Fever, and 20-fold for occurrence of haemorrhages. Furthermore, several warning signs also showed statistically significant association given more evidences in specific stages of DENV infection. These results provide consistent evidence in order to infer statistical models providing a framework for future genetic epidemiology and clinical studies. PMID- 25017657 TI - Immunisations and antibiotics in patients with anterior skull base cerebrospinal fluid leaks. AB - OBJECTIVE: There are no UK guidelines for the use of antibiotics and/or immunisations in patients with an active anterior skull base cerebrospinal fluid leak. This study aimed to define current UK practice in this area and inform appropriate guidelines for ENT surgeons. METHOD: A web-based survey of all members of the British Rhinological Society was carried out and the literature in this area was reviewed. RESULTS: Of those who responded to the survey, 14 per cent routinely give prophylactic antibiotics to patients with cerebrospinal fluid leaks, and 34.9 per cent recommend immunisation against at least one organism, most commonly Streptococcus pneumoniae (86.7 per cent). CONCLUSION: There is no evidence to support the use of antibiotic prophylaxis in patients with a cerebrospinal fluid leak. We propose that all such patients are advised to seek immunisation against pneumococcus, meningococcus and haemophilus. PMID- 25017658 TI - Should repair of partial atrioventricular septal defect be delayed until later in childhood? AB - Surgical repair of partial atrioventricular septal defects (AVSD) has been successful for more than 60 years. However, recent data from the Pediatric Heart Network show that 31% of patients have moderate or severe left atrioventricular valve regurgitation (LAVVR) at follow-up. Previously, our institution found that only 9% of patients had more than moderate LAVVR at the last follow-up. Our objective was to determine the long-term outcomes after repair of partial AVSD in the current era. We reviewed all patients with partial AVSD who had primary biventricular repair from January 1995 to June 2011 at our institution. The Kaplan-Meier method was used to estimate the survival free of an event, and factors were evaluated for an association with each outcome using the log-rank test. All 105 patients with partial AVSD who had surgery during this period were evaluated. The median age at surgery was 7.9 years. The overall survival rate at 1 year was 97%. Median follow-up was 5.3 years (interquartile range 1.7 to 11.1). At 3 years, the survival rate free from reoperation was 89%. Thirteen patients required reoperations with the most common reason being LAVVR. A total of 10 patients developed more than moderate LAVVR with a cumulative incidence of 8% by 2 years. The discrepancy with the Pediatric Heart Network data may be due to the later age of operation for patients in our cohort suggesting that elective repair of partial AVSD should be deferred until children are somewhat older (ages 5 to 8 years). Neither patient age (p = 0.11) nor severity of preoperative LAVVR (p = 0.16) were identified as statistically significant risk factors. In conclusion, there is less morbidity and mortality after surgical repair for partial AVSD. PMID- 25017659 TI - Physiological assessment of nonculprit stenoses during acute coronary syndromes. PMID- 25017660 TI - Obesity paradox rethinking: do unequal sample sizes and racial differences matter? PMID- 25017661 TI - Modification of Penn classification and its validation for acute type A aortic dissection. PMID- 25017662 TI - Salt intake, sugar-sweetened soft drink consumption, and blood pressure. PMID- 25017663 TI - Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors: a word of comfort to younger patients? PMID- 25017664 TI - Reply: To PMID 24630786. PMID- 25017665 TI - Fast detection of nitroaromatics using phosphonate pyrene motifs as dual chemosensors. AB - A new class of dual fluorescent chemosensors for nitroaromatic compounds (NACs) based on phosphonated pyrene derivatives is reported, showing high selectivity towards trinitrotoluene (TNT). The strong intermolecular interactions (pi-pi stacking and hydrogen bonding) allow high fluorescence quenching with visual detection in short response times. PMID- 25017666 TI - Incidence of congenital toxoplasmosis among infants born to HIV-coinfected mothers: case series and literature review. AB - INTRODUCTION: There is a paucity of data on the occurrence of congenital toxoplasmosis in children born to mothers dually infected with HIV and Toxoplasma gondii. OBJECTIVE: To evaluate aspects of the mother-infant pairs associated with vertical transmission of toxoplasmosis in women co-infected with HIV in a referral center for perinatally acquired infections in Belo Horizonte, Brazil. METHODS: Descriptive study of HIV vertically exposed children, with congenital toxoplasmosis, followed at a referral center (cohort/Belo Horizonte). Prenatal and post-natal variables for the mother-infant pairs were evaluated. A literature review with no filtering for time and language was performed to identify reports of congenital toxoplasmosis in HIV vertically exposed children. RESULTS: Among 2007 HIV vertically exposed children evaluated in the period from 1998 to 2011, 10 cases of congenital toxoplasmosis were identified (incidence: 0.5%, 95% confidence interval: 0.24-0.91). In searching the literature 22 additional cases in 17 reports were found. Combining the findings of our cohort with other reported cases, 50% (16/32) of congenital toxoplasmosis in HIV vertically exposed children were from Brazil. The cases of congenital toxoplasmosis in HIV vertically exposed children identified in Brazil occurred mainly in the post Highly Active Antiretroviral Therapy era (p=0.002) and presented a lower death rate (p=0.003) than those from other countries. In the cohort/Belo Horizonte, HIV infection was identified mainly during gestation; T. gondii vertical transmission was observed in pregnant women with CD4(+)>500 cells/mm(3) and latent toxoplasmosis. High rates of ocular lesions (87.5%) and central nervous system involvement (70%) were detected. CONCLUSIONS: The risk of vertical transmission of T. gondii in HIV-infected women is low and has been usually associated with maternal immunosuppression and elevated viral load. However, our findings of congenital toxoplasmosis in children born to HIV-infected mothers with latent toxoplasmosis and not immunosuppressed emphasize the need for careful follow-up in these cases. PMID- 25017667 TI - Total knee arthroplasty in carefully selected patients aged 80 years or older. AB - BACKGROUND: The patients aged >= 80 years have been considered to have a higher risk of mortality, postoperative complications, and longer hospital stay following total knee arthroplasty (TKA) than younger patients. The purposes of this retrospective study were to review the results of TKA in patients aged >= 80 years after a preoperative consultation. METHODS: Seventy-five patients aged >= 80 years underwent TKA from January 2006 and June 2010. A control group of younger patients (65-74 years) was matched in a 1:1 ratio with the >= 80 years group for sex, diagnosis of the disease, body mass index, the American Society of Anesthesiologists' type of anesthesia, and comorbidities. Cardiologists and neurologists carefully evaluated the risk of patients for both groups before surgery. The groups were compared with regard to Knee Society Scores, Knee Society Function Score, Western Ontario and McMaster Universities Osteoarthritis Index scores, length of stay, postoperative complications, and 90-day mortality rate. RESULTS: The mean follow-up was 2.3 years (range 1-5 years). We found no difference in the functional outcomes and length of stay between the two groups. The >= 80 years group had a higher rate of blood transfusion (29.3% versus 10.7%, p = 0.006) after Bonferroni correction. There were no cardiovascular or cerebrovascular complications in the >= 80 years group. There were no mortalities within 90 days in either group. CONCLUSIONS: Despite similar functional results and pain relief of the TKA compared with the young patient group, the >= 80 years group had a higher complication rate of blood transfusion. With a preoperative consultation by cardiologists and neurologists, patients aged >= 80 years have a low cardiovascular or cerebrovascular complications and 90-day mortality after TKA. PMID- 25017668 TI - Oral phosphate binders in CKD - is calcium the (only) answer? AB - All-cause mortality and cardiovascular- related mortality have both been linked to abnormal serum phosphate concentrations in chronic kidney disease (CKD). Aberrant serum phosphate concentration in patients with CKD has also been associated with adverse cardiac and renal outcomes. Early prevention or management of rising or high serum phosphate concentrations in patients with CKD is now considered to be an important intervention to prevent downstream complications resulting from the poor management of serum calcium and parathyroid hormone (PTH). It is widely considered that starting phosphate binder therapy early, with concurrent dietary management of serum phosphate, constitutes an effective course of interventions, although normalization of serum phosphate in dialysis patients remains atypical, unless specific dialytic measures are also undertaken. Calcium- based phosphate binders are often the first type of binders prescribed due to their low cost. Evidence shows that most phosphate binders are roughly equally effective in lowering serum phosphate concentrations in adults compared to placebo, with a small probability that sevelamer hydrochloride is better than calcium acetate or lanthanum carbonate. However, not all binders are created equal in regards to their safety profiles. The potential for accumulations and toxicities does exist with very long-term continuous exposure. We discuss these issues in the course of this review. PMID- 25017669 TI - Diffuse segmental and pure diffuse global proliferative glomerulonephritis: different patterns of class IV lupus nephritis. AB - BACKGROUND: No consensus has been obtained on the differences between class IV-S and IV-G lupus nephritis (LN), especially regarding renal outcome. Our study investigated clinical-pathological features and prognosis of diffuse segmental and pure diffuse global proliferative LN. METHODS: In this retrospective study, a total of 120 patients with biopsy-proven diffuse LN were included, of which 31 patients were class IV-S and 89 were pure class IVG. Class IV-S was defined as segmental lesion involving >= 50% of all glomeruli, while pure class IV-G was defined as global lesion involving >= 50% of all glomeruli with no segmental necrosis or crescents. The clinical- pathological and prognostic features of the two classes were compared. RESULTS: There was no difference in levels of urine protein or serum creatinine between the two groups. Higher serological activity was observed in the pure IV-G group with lower complement C3 (p < 0.001) and C4 level (p < 0.001), compared to the IV-S group. Histologically, immune-complex deposits were significantly more common in the pure IV-G group, with higher prevalence of wire loop (42.7% vs. 0%, p < 0.001) and hyaline thrombi (34.8% vs. 3.2%, p < 0.001). However, the complete remission (CR) rate to intravenous cyclophosphamide (IVCY) induction was lower in the IV-S than in the pure IV-G group (16.7% vs. 53.2%, p = 0.023). After 1 year, the pure class IV-G group had a higher CR rate (71.9% vs. 48.4%, p = 0.017). The 10-year renal survival rate (without doubling of serum creatinine or end-stage renal disease) was significantly lower in patients with IV-S than pure IV-G (75.2% vs. 97.4%, p = 0.028). CONCLUSION: LN class IV-S and class IV-G without segmental lesion showed different clinical-histological features and prognosis, suggesting that different mechanisms may exist. PMID- 25017670 TI - Effect of chronic cortical stimulation on chronic severe tinnitus: a prospective randomized double-blind cross-over trial and long-term follow up. AB - BACKGROUND: Chronic severe tinnitus can be greatly detrimental to quality of life. Some authors have reported benefit of repetitive transcranial magnetic stimulation, others of electrical cortical stimulation by stimulating the Heschl's gyrus or secondary auditory areas. OBJECTIVE: To evaluate the efficacy of chronic electrical epidural stimulation of the auditory cortex on severe and disabling tinnitus. METHOD: In this double-blind randomized cross-over, patients with chronic (at least 2 years), severe (Strukturierte Tinnitus-Interview, STI score > 19), unilateral or strongly lateralized tinnitus were included. After open-phase stimulation for 4 months, patients were randomized into 2 groups for double-blind stimulation with cross-over between significant and non-significant phases and wash-out in between. Each of the 3 phases was 2 weeks in duration. Patients were chronically stimulated and followed if not explanted. A decrease of STI score >35% was considered as clinically significant. RESULTS: None of the 9 patients included achieved significant improvement during the double-blind phase. Four were explanted, 2 owing to lack of effect, one for breast cancer under the stimulator, and another for psychiatric decompensation. Five are still stimulated. Three felt slight to great subjective effectiveness, the remaining 2 reported benefits and still requested stimulation. CONCLUSIONS: This study did not find an objective efficiency of chronic cortical stimulation for severe and resistant tinnitus. The discordance between the results in double-blind and open evaluations could be related to a placebo effect of surgery, but may also be explained by a poorly defined target, a too short randomized phase, or inappropriate outcome measures. Clinical trial reference: NCT00486577. PMID- 25017672 TI - Drug allergy diagnosis. AB - Poorly documented and often self-reported drug hypersensitivity (DH) is a frequent problem in daily clinical practice and has a considerable impact on prescription choices. Little is known about the natural history of true DH. The suspicion of DH starts on clinical grounds. When assessing a patient with a presumed DH reaction in the symptomatic phase, it is mandatory to look for severity signs and, after doing so, to update the risk/benefit balance of exploring the suspected drug(s) on a case-by-case basis. With the help of allergy tests and a careful approach, a firm diagnosis is often possible. PMID- 25017671 TI - Acute changes in mood induced by subthalamic deep brain stimulation in Parkinson disease are modulated by psychiatric diagnosis. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood. OBJECTIVE: The study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS. METHODS: Thirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal. RESULTS: STN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS. CONCLUSIONS: PD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group. PMID- 25017673 TI - Management of nonimmediate hypersensitivity reactions to drugs. AB - Nonimmediate hypersensitivity to drugs has a huge diversity of clinical presentations affecting exclusively or predominantly a single organ (most often the skin) or multiple organs. The latter is the rule with drug reaction with eosinophilia and systemic symptoms, and with drug-induced vasculitis. The management includes a dozen successive steps. Finally, the patient should be provided clear information on the suspected cause of the reaction, recommendations for follow-up after severe reactions associated with a risk of sequelae, and clear recommendations for future use of medications. Pharmacovigilance networks should be informed. PMID- 25017674 TI - Antibiotic allergy. AB - Although allergy to beta-lactam and non-beta-lactam antibiotics is commonly claimed, true allergy to these drugs is often absent. Reactions to antibiotics can be classified according to the interval between the last administration of the drug and the onset of symptoms, but except for immediate reactions occurring within an hour of exposure, which are almost always either IgE-mediated or due to direct stimulation of mast cells, reactions occurring later than 1 hour probably have multiple mechanisms, including being IgE-mediated or involving cell-mediated reactions. The latter are likely caused by drug-specific T lymphocytes. The diagnosis of antibiotic allergy can be difficult. PMID- 25017675 TI - Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most commonly involved in hypersensitivity drug reactions. Such reactions can be due to the release of inflammatory mediators in the absence of specific immunologic recognition, or immunoglobulin E (IgE)- or T-cell-selective responses. The former include upper and lower airway symptoms in patients with chronic underlying respiratory disease, the exacerbation of chronic spontaneous urticaria, and the induction of cutaneous symptoms. The latter include selective responses to a single NSAID with good tolerance to strong cyclooxygenase-1 inhibitors, with a putative IgE or T-cell mechanism proposed. These reactions can be acute or delayed. PMID- 25017676 TI - Local and general anesthetics immediate hypersensitivity reactions. AB - Intraoperative anaphylaxis and hypersensitivity reactions in the setting of anesthesia contribute significantly to the morbidity and mortality of surgeries and surgical procedures. Because multiple medications and products are given in a short period of time, identifying the specific cause can be difficult. Neuromuscular blocking agents, antibiotics, and latex are the most common causes of anesthesia-related reactions, though other medications or exposures could be involved. Careful review of anesthetic charts and allergy testing can help identify the underlying cause. The identification of the cause and subsequent prevention of reactions are critical to reduce overall mortality and morbidity related to anesthesia. PMID- 25017677 TI - Hypersensitivity to contrast media and dyes. AB - This article updates current knowledge on hypersensitivity reactions to diagnostic contrast media and dyes. After application of a single iodinated radiocontrast medium (RCM), gadolinium-based contrast medium, fluorescein, or a blue dye, a hypersensitivity reaction is not a common finding; however, because of the high and still increasing frequency of those procedures, patients who have experienced severe reactions are nevertheless frequently encountered in allergy departments. Evidence on allergologic testing and management is best for iodinated RCM, limited for blue dyes, and insufficient for fluorescein. Skin tests can be helpful in the diagnosis of patients with hypersensitivity reactions to these compounds. PMID- 25017678 TI - Adverse events to nontargeted and targeted chemotherapeutic agents: emphasis on hypersensitivity responses. AB - Use of cytotoxic agents is associated with potential hypersensitivity reactions which are common with platinum compounds, L-asparaginase, taxanes, procarbazine and epipodophyllotoxins. Mechanisms underlying the reactions may involve IgE, non allergic or a number of pathogenetically unclear events. Targeted therapies produce less collateral damage but demonstrate their own unique reactions. Cytopenias occur less often and mucocutaneous reactions to EGFR inhibitors, including papulopustular rash, are common. Fifteen currently approved mAbs provoke all four types of hypersensitivities including immune cytopenias, vasculitis, serum sickness and pulmonary events. Some successful desensitization protocols have been developed. Prevention of hypersensitivity reactions is based on skin testing, premedication and/or desensitization. PMID- 25017679 TI - Vaccine allergy. AB - Overdiagnosis of vaccine allergy is considered a major public health problem. This article discusses the different types of allergic reactions after immunization based on the timing (immediate vs nonimmediate) and the extent of the reaction (local vs systemic). The vaccine components potentially responsible for an allergic reaction are discussed, as well as the management of patients with a history of reaction to a specific vaccine and those with a history of allergy to one of the vaccine components. PMID- 25017680 TI - Hypersensitivity reactions to biologic agents. AB - Biologic agents (BAs) are important therapeutic tools; their use has rapidly expanded and they are used in oncology, immunology, and inflammatory diseases. Their use may be limited, however, by adverse drug reactions. This article reviews the current literature on clinical presentation and pathogenic mechanisms of both acute and delayed reactions. In addition, procedures for management of BA induced reactions, including preventive and diagnostic work-up, are provided. Lastly, this article summarizes the current knowledge of desensitization to several widely used monoclonal antibodies. PMID- 25017681 TI - Hypersensitivity to antiepileptic drugs. AB - Adverse reactions to antiepileptic drugs (AEDs) may lead to treatment failure, morbidity, and mortality. Drug hypersensitivity reactions (DHRs) are potentially fatal. AED DHRs present with a variety of clinical manifestations. The pathogenesis of AED DHRs has not been fully elucidated. Bioactivation, detoxification, covalent adduct formation, presentation to the immune system, and consequent formation of antibody and T-cell immune effectors have been suggested. This article summarizes the epidemiology, pathogenic mechanisms, risk factors, clinical features, and management of allergic reactions to the aromatic AEDs carbamazepine, phenytoin, and lamotrigine. PMID- 25017683 TI - Allergic contact dermatitis from the vehicle components of topical pharmaceutical products. AB - The local application of pharmaceutical products may induce skin adverse reactions, including allergic contact dermatitis. Indeed, pharmaceutical products are, in general, applied on diseased or inflamed skin, the barrier function of which is often incapacitated, leading to enhanced skin penetration of the applied chemicals. Under these circumstances, even weak allergens are in such cases able to induce sensitization. The contact allergens in topical pharmaceutical products concern active principles and vehicle components, the latter of which are discussed in this article. PMID- 25017682 TI - Antiviral drug allergy. AB - Antiviral drugs used to treat HIV and hepatitis C are common causes of delayed drug hypersensitivities for which many of the more severe reactions have been recently shown to be immunogenetically mediated such as abacavir hypersensitivity where HLA-B(*)57:01 is now used routinely as a screening test to exclude patients carrying this allele from abacavir prescription. Most antiviral drug allergies consist of mild to moderate delayed rash without other serious features (eg, fever, mucosal involvement, blistering rash, organ impairment. In these cases treatment can be continued with careful observation and symptomatic management and the discontinuation rate is low. PMID- 25017684 TI - Place of excipients in systemic drug allergy. AB - Hypersensitivity reactions to excipients contained in drugs are rare but can be severe or confusing. With regard to generic versus brand drug, often the ingredients are different; for each DHR, we recommend that the physician exercises caution in considering which brand drug or generic was administered and in listing all medicine components and not only the active drug. PMID- 25017685 TI - In vitro diagnosis of immediate IgE-mediated drug hypersensitivity: warnings and (unmet) needs. AB - Immediate drug hypersensitivity reactions (DHR) constitute an important health condition, with serious consequences of inadequate diagnosis. In this article, some of the most important issues related to in vitro diagnosis of IgE-mediated allergies are discussed. In vitro diagnostics will benefit from expanded and novel insights and understandings in drug chemical reactivity, protein binding, biotransformation, degradation, identification of (cross-reactive) drug antigenic determinants, and deeper understanding of sensitization routes. Collective efforts should be undertaken to activate fundamental and clinical investigations. PMID- 25017687 TI - Hypersensitivity from intravenous iron products. AB - In the last several years, intravenous therapy with iron products has been more widely used. Although it has been a standard procedure in dialysis-associated anemia since the early 1990s, its use is expanding to a host of conditions associated with iron deficiency, especially young women with heavy uterine bleeding and pregnancy. Free iron is associated with unacceptable high toxicity inducing severe, hemodynamically significant symptoms. Subsequently, formulations that contain the iron as an iron carbohydrate nanoparticle have been designed. With newer formulations, including low-molecular-weight iron dextran, iron sucrose, ferric gluconate, ferumoxytol, iron isomaltoside, and ferric carboxymaltose, serious adverse events are rare. PMID- 25017686 TI - In vitro diagnosis of delayed-type drug hypersensitivity: mechanistic aspects and unmet needs. AB - Several laboratories use the lymphocyte transformation test for the diagnosis of delayed-type drug hypersensitivity reactions. Recently, the availability of multiple readouts has improved our ability to diagnose reactions. It is important to note that most published studies characterizing the usefulness of diagnostic tests utilize blood samples from well-defined test and control patient groups. The purpose of this article is to briefly summarize the cellular and chemical basis of delayed-type drug hypersensitivity reactions and to review in vitro assays that are available for drug hypersensitivity diagnosis. PMID- 25017688 TI - The complexity of drug hypersensitivity. Foreword. PMID- 25017689 TI - Drug hypersensitivity. Preface. PMID- 25017690 TI - Human adipose tissue-derived stem cells alleviate radiation-induced xerostomia. AB - Hyposalivation is an intractable side-effect of radiotherapy for head and neck cancer. It is caused by the irreversible loss of acinar cells and decreased saliva secretion. However, this situation severely compromises the quality of life of affected patients. Currently, there is no effective treatment for this condition. In the present study, we developed a novel approach to regenerate the function of the irradiation-damaged salivary glands using human adipose tissue derived stem cell (hADSC) intraglandular transplantation. ZsGreen-labeled hADSCs were adoptively transferred into Sprague-Dawley (SD) rat submandibular glands immediately following exposure to 18 Gy irradiation. A higher salivary flow rate (SFR) was observed in the hADSC-treated group. Tissue improvement, including angiogenesis, anti-apoptosis and anti-fibrosis, was detected in the hADSC-treated glands as compared to the untreated glands. Quantitative reverse transcription PCR (RT-qPCR) revealed a significantly higher expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) in the hADSC-treated rats. Furthermore, immunohistochemical analysis indicated that the hADSCs had differentiated into acinar and ductal cells in the rat submandibular glands. Thus, our results suggest that hADSCs are able to regenerate irradiation-damaged salivary glands through glandular transplantation. PMID- 25017691 TI - Organization in photosynthetic membranes of purple bacteria in vivo: the role of carotenoids. AB - Photosynthesis in purple bacteria is performed by pigment-protein complexes that are closely packed within specialized intracytoplasmic membranes. Here we report on the influence of carotenoid composition on the organization of RC-LH1 pigment protein complexes in intact membranes and cells of Rhodobacter sphaeroides. Mostly dimeric RC-LH1 complexes could be isolated from strains expressing native brown carotenoids when grown under illuminated/anaerobic conditions, or from strains expressing green carotenoids when grown under either illuminated/anaerobic or dark/semiaerobic conditions. However, mostly monomeric RC-LH1 complexes were isolated from strains expressing the native photoprotective red carotenoid spheroidenone, which is synthesized during phototrophic growth in the presence of oxygen. Despite this marked difference, linear dichroism (LD) and light-minus-dark LD spectra of oriented intact intracytoplasmic membranes indicated that RC-LH1 complexes are always assembled in ordered arrays, irrespective of variations in the relative amounts of isolated dimeric and monomeric RC-LH1 complexes. We propose that part of the photoprotective response to the presence of oxygen mediated by synthesis of spheroidenone may be a switch of the structure of the RC-LH1 complex from dimers to monomers, but that these monomers are still organized into the photosynthetic membrane in ordered arrays. When levels of the dimeric RC-LH1 complex were very high, and in the absence of LH2, LD and ?LD spectra from intact cells indicated an ordered arrangement of RC LH1 complexes. Such a degree of ordering implies the presence of highly elongated, tubular membranes with dimensions requiring orientation along the length of the cell and in a proportion larger than previously observed. PMID- 25017692 TI - Spatial regionalization and heterochrony in the formation of adult pallial neural stem cells. AB - Little is known on the embryonic origin and related heterogeneity of adult neural stem cells (aNSCs). We use conditional genetic tracing, activated in a global or mosaic fashion by cell type-specific promoters or focal laser uncaging, coupled with gene expression analyses and Notch invalidations, to address this issue in the zebrafish adult telencephalon. We report that the germinal zone of the adult pallium originates from two distinct subtypes of embryonic progenitors and integrates two modes of aNSC formation. Dorsomedial aNSCs derive from the amplification of actively neurogenic radial glia of the embryonic telencephalon. On the contrary, the lateral aNSC population is formed by stepwise addition at the pallial edge from a discrete neuroepithelial progenitor pool of the posterior telencephalic roof, activated at postembryonic stages and persisting lifelong. This dual origin of the pallial germinal zone allows the temporally organized building of pallial territories as a patchwork of juxtaposed compartments. PMID- 25017693 TI - SAS-6 assembly templated by the lumen of cartwheel-less centrioles precedes centriole duplication. AB - Centrioles are 9-fold symmetric structures duplicating once per cell cycle. Duplication involves self-oligomerization of the centriolar protein SAS-6, but how the 9-fold symmetry is invariantly established remains unclear. Here, we found that SAS-6 assembly can be shaped by preexisting (or mother) centrioles. During S phase, SAS-6 molecules are first recruited to the proximal lumen of the mother centriole, adopting a cartwheel-like organization through interactions with the luminal wall, rather than via their self-oligomerization activity. The removal or release of luminal SAS-6 requires Plk4 and the cartwheel protein STIL. Abolishing either the recruitment or the removal of luminal SAS-6 hinders SAS-6 (or centriole) assembly at the outside wall of mother centrioles. After duplication, the lumen of engaged mother centrioles becomes inaccessible to SAS 6, correlating with a block for reduplication. These results lead to a proposed model that centrioles may duplicate via a template-based process to preserve their geometry and copy number. PMID- 25017695 TI - Perioperative complications and oncological safety of robot-assisted (RARC) vs. open radical cystectomy (ORC). AB - OBJECTIVES: To assess the surgical and oncological outcome of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC). PATIENTS AND METHODS: Clinical data of 64 patients undergoing RARC between August 2010 and August 2013 were prospectively documented and retrospectively compared with 79 patients undergoing ORC between August 2008 and August 2013 at a single academic institution. Perioperative results, surgical margins status, and nodal yield after RARC and ORC were compared using Mann-Whitney U test (continuous variables) and chi-square test (categorical variables). Additional age-stratified analysis was performed in elderly patients (>=75 y). To avoid inference errors by multiple testing, P-values were adjusted using Bonferroni's correction. RESULTS: Baseline characteristics of both cohorts were balanced. RARC patients had significantly less blood loss (RARC: 300 [interquartile range {IQR}: 200-500]ml; perioperative transfusion rate: 0 [IQR: 0-2] red packed blood cells [RPBCs]; ORC: 800 [IQR: 500 1200]ml, P<0.01; transfusion rate: 3 [IQR: 2-4] RPBCs, P<0.01), and hospital stay of RARC patients was reduced by 20% (RARC: 13 [IQR: 9-17]d, ORC: 16 [IQR: 13 21]d, P< 0.01). A total of 55 patients who underwent RARC and 59 patients who underwent ORC were eligible for analysis of oncological surrogates "surgical margin status" and "lymph-node yield" as well as for survival data. No differences between patients undergoing RARC or ORC were observed. In elderly patients (>=75 y; RARC: 17 patients, ORC: 28 patients), decreased intraoperative blood loss (RARC: 300 [IQR: 100-475]ml; ORC: 800 [IQR: 400-1300]ml, P<0.01) and lower transfusion rate (RARC: 0 [IQR: 0-1] RPBCs; ORC: 4 [IQR: 2-5] RPBCs, P<0.01) were observed in the robotic group. Major limitations of this study are the retrospective study design and a potential selection bias. CONCLUSIONS: RARC provides significant advantages compared with ORC regarding blood loss and postoperative recovery, whereas surgical and oncological outcomes are not different. PMID- 25017694 TI - Population-based assessment of prostate-specific antigen testing for prostate cancer in the elderly. AB - OBJECTIVES: To perform a population-based analysis to characterize the effect of prostate-specific antigen (PSA) testing on oncologic outcomes in men diagnosed with prostate cancer. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare-linked data to identify 98,883 men diagnosed with prostate cancer from 1996 to 2007. We stratified frequency of PSA testing as none, 1 to 2, 3 to 5, and>=6 tests in the 5 years before prostate cancer diagnosis. We used propensity scoring methods to assess the effect of frequency of PSA testing on likelihood of (1) metastases at diagnosis and (2) overall mortality and prostate cancer-specific mortality. RESULTS: In adjusted analyses, the likelihood of being diagnosed with metastatic prostate cancer decreased with greater frequency of PSA testing (none, 10.6; 1-2, 8.3; 3-5, 3.7; and>=6, 2.5 events per 100 person years, P<0.001). Additionally, greater frequency of PSA testing was associated with improved overall survival and prostate cancer-specific survival (P<0.001 for both). CONCLUSIONS: Greater frequency of PSA testing in men 70 years of age or older in the 5 years before prostate cancer diagnosis is associated with lower likelihood of being diagnosed with metastatic prostate cancer and improved overall and prostate cancer-specific survival. PMID- 25017696 TI - Preoperative neutrophil-lymphocyte ratio predicts death among patients with localized clear cell renal carcinoma undergoing nephrectomy. AB - OBJECTIVES: The neutrophil-lymphocyte ratio (NLR) is an indicator of the systemic inflammatory response. An increased pretreatment NLR has been associated with adverse outcomes in other malignancies, but its role in localized (M0) clear cell renal cell carcinoma (ccRCC) remains unclear. As such, we evaluated the ability of preoperative NLR to predict oncologic outcomes in patients with M0 ccRCC undergoing radical nephrectomy (RN). METHODS AND MATERIALS: From 1995 to 2008, 952 patients underwent RN for M0 ccRCC. Of these, 827 (87%) had pretreatment NLR collected within 90 days before RN. Metastasis-free, cancer-specific, and overall survival was estimated using the Kaplan-Meier method and compared using the log rank test. Multivariate models were used to analyze the association of NLR with clinicopathologic outcomes. RESULTS: At a median follow-up of 9.3 years, 302, 233, and 436 patients had distant metastasis, death from ccRCC, and all-cause mortality, respectively. Higher NLR was associated with larger tumor size, higher nuclear grade, histologic tumor necrosis, and sarcomatoid differentiation (all, P < 0.001). A NLR >= 4.0 was significantly associated with worse 5-year cancer specific (66% vs. 85%) and overall survival (66% vs. 85%). Finally, after controlling for clinicopathologic features, NLR remained independently associated with risks of death from ccRCC and all-cause mortality (hazard ratio for 1-unit increase: 1.02, P < 0.01). CONCLUSIONS: Our results suggest that NLR is independently associated with increased risks of cancer-specific and all-cause mortality among patients with M0 ccRCC undergoing RN. Accordingly, NLR, an easily obtained marker of biologically aggressive ccRCC, may be useful in preoperative patient risk stratification. PMID- 25017697 TI - Shotgun proteomics to unravel the complexity of the Leishmania infantum exoproteome and the relative abundance of its constituents. AB - The exoproteome of some Leishmania species has revealed important insights into host-parasite interaction, paving the way for the proposal of novel disease oriented interventions. The focus of the present investigation constituted the molecular profile of the L. infantum exoproteome revealed by a shotgun proteomic approach. Promastigotes under logarithmic phase of growth were obtained and harvested by centrifugation at different time points. Cell integrity was evaluated through the counting of viable parasites using propidium iodide labeling, followed by flow cytometry analysis. The 6h culture supernatant, operationally defined here as exoproteome, was then conditioned to in solution digestion and the resulting peptides submitted to mass spectrometry. A total of 102 proteins were identified and categorized according to their cellular function. Their relative abundance index (emPAI) allowed inference that the L. infantum exoproteome is a complex mixture dominated by molecules particularly involved in nucleotide metabolism and antioxidant activity. Bioinformatic analyses support that approximately 60% of the identified proteins are secreted, of which, 85% possibly reach the extracellular milieu by means of non-classic pathways. At last, sera from naturally infected animals, carriers of differing clinical forms of Canine Visceral Leishmaniasis (CVL), were used to test the immunogenicity associated to the L. infantum exoproteome. Western blotting experiments revealed that this sub-proteome was useful at discriminating symptomatic animals from those exhibiting other clinical forms of the disease. Collectively, the molecular characterization of the L. infantum exoproteome and the preliminary immunoproteomic assays opened up new research avenues related to treatment, prognosis and diagnosis of CVL. PMID- 25017698 TI - Gas dissolution in antibubble dynamics. AB - Antibubbles are ephemeral objects. Their lifetime is driven by the slow drainage of the air shell from the bottom to the top of the antibubble under the action of hydrostatic pressure. We show in this paper that this argument is only valid if the water used to make the surfactant mixture is saturated in air. Otherwise, two paths are used by the air, which conduct to the thinning and the eventual collapse of the air shell: the drainage from the bottom to the top of the antibubble and the dissolution of the air into the liquid. Using degassed water dramatically shortens the lifetime of the antibubbles, as observed experimentally and rationalised by time-dependent simulations. Consequently, the antibubble lifetime is not only correlated with physical and chemical properties of the air liquid interface but also with the gas content of the liquid. We also show that pure gas dissolution does not depend on the antibubble radius, a behaviour that allows to rationalise unexplained experimental data found in literature. PMID- 25017699 TI - Working memory mediates the relationship between intellectual enrichment and long term memory in multiple sclerosis: an exploratory analysis of cognitive reserve. AB - Some individuals with multiple sclerosis (MS) show decrements in long-term memory (LTM) while other individuals do not. The theory of cognitive reserve suggests that individuals with greater pre-morbid intellectual enrichment are protected from disease-related cognitive decline. How intellectual enrichment affords this benefit remains poorly understood. The present study tested an exploratory meditational hypothesis whereby working memory (WM) capacity may mediate the relationship between intellectual enrichment and verbal LTM decline in MS. Intellectual enrichment, verbal LTM, and WM capacity were estimated with the Wechsler Test of Adult Reading and Peabody Picture Vocabulary Test, delayed recall of the Hopkins Verbal Learning Test-Revised and Logical Memory of the Wechsler Memory Scale, and Digit Span Total, respectively. Intellectual enrichment predicted LTM (B=.54; p=.003) and predicted WM capacity (B=.91; p<.001). WM capacity predicted LTM, (B=.44; p<.001) and fully mediated the relationship between intellectual enrichment (B=.24; p=.27) and LTM (B=.33, p=.03), Sobel test, Z=3.31, p<.001. These findings implicate WM capacity as an underlying mechanism of cognitive reserve and are an initial first step in understanding the relationship between intellectual enrichment, WM, and LTM in MS. PMID- 25017700 TI - A roadmap to embryo identity in plants. AB - Although plant embryogenesis is usually studied in the context of seed development, there are many alternative roads to embryo initiation. These include somatic embryogenesis in tissue culture and microspore embryogenesis, both widely used in breeding and crop propagation, but also include other modes of ectopic embryo initiation. In the past decades several genes, mostly transcription factors, were identified that can induce embryogenesis in somatic cells. Because the genetic networks in which such regulators operate to promote embryogenesis are largely unknown, a key question is how their activity relates to zygotic and alternative embryo initiation. We describe here the many roads to plant embryo initiation and discuss a framework for defining the developmental roles and mechanisms of plant embryogenesis regulators. PMID- 25017701 TI - Cytosolic glutamine synthetase: a target for improvement of crop nitrogen use efficiency? AB - Overexpression of the cytosolic enzyme glutamine synthetase 1 (GS1) has been investigated in numerous cases with the goal of improving crop nitrogen use efficiency. However, the outcome has generally been inconsistent. Here, we review possible reasons underlying the lack of success and conclude that GS1 activity may be downregulated via a chain of processes elicited by metabolic imbalances and environmental constraints. We suggest that a pivotal role of GS1 may be related to the maintenance of essential nitrogen (N) flows and internal N sensing during critical stages of plant development. A number of more refined overexpression strategies exploiting gene stacking combined with tissue and cell specific targeting to overcome metabolic bottlenecks are considered along with their potential in relation to new N management strategies. PMID- 25017702 TI - A review of the nutritional composition, organoleptic characteristics and biological effects of the high oleic peanut. AB - A growing body of literature has been published on the health benefits of peanuts, but the potential biological effects of high-oleic (HO) peanuts, along with their organoleptic characteristics have not been reviewed to date. In this paper, examination of evidence showed that HO peanuts provide a spectrum of nutrients and have improved sensory properties and technological advances, such as enhanced shelf life, beyond that of conventional peanuts. This may be attributed to their oleic to linoleic ratio (OL ratio) which is substantially (around 10 times) higher than normal peanuts. In terms of their biological effects, HO peanuts appear to be no more allergenic, and could even be less allergenic than conventional peanuts. There is also emerging evidence that HO peanuts may improve lipid profile and markers of glycemic control. Further randomized controlled human trials are now needed to build on animal and in vitro studies. PMID- 25017703 TI - Communal beverage trolleys are an infection risk. PMID- 25017704 TI - Methodological issues concerning the meta-analysis by Leroy on the risk of infectious complications after endovaginal and transrectal ultrasonography. PMID- 25017705 TI - Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/beta-catenin pathway. AB - Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma (HCC) via a network of signaling pathways. Notch pathway is a major member of the network. Notch signaling may generate opposing effect in different steps of carcinogenesis, depending on the tumor cell type and the status of other signaling pathways, such as Wnt signaling pathway. Our previous studies have shown that activated Notch1 signaling is required for HBx to promote proliferation and survival of human hepatic cell line L02. However, the exact mechanisms remain vague. Here, we used L02/HBx cell lines as a cell model to study the relationship between Notch and Wnt/beta-catenin pathways in promoting proliferation. We observed that activated Notch1 and Wnt/beta-catenin signaling pathways and L02 cell malignant transformation were induced by HBx. Inhibition of the Notch1 pathway decreased the activation of Wnt/beta-catenin pathway and cell proliferation, while inhibition of the Wnt/beta-catenin pathway impaired cell proliferation, but did not significantly affect Notch1 signaling pathway in L02/HBx cells. Furthermore, inhibition of the Wnt/beta-catenin pathway overcame the inhibition effect of knockdown Notch1 on proliferation and survival in L02/HBx cells. Additionally, the activity of Wnt/beta-catenin signaling appears to be consistent with Fzd10 expression. Therefore, we demonstrate that Wnt signaling is downstream of the Notch pathway in regulating proliferation of L02/HBx cells, and which may be related to Fzd10 instead of Fzd7. These data suggest a new model of HBx-related HCC via cooperation between Wnt and Notch pathways. PMID- 25017706 TI - A review of animal models for portal vein embolization. AB - BACKGROUND: Portal vein embolization (PVE) is a preoperative intervention to increase the future remnant liver (FRL) through regeneration of the non-embolized liver lobes. This review assesses all the relevant animal models of PVE available, to guide researchers who intend to study PVE. MATERIALS AND METHODS: We performed a systematic literature search in Medline and Pubmed, from 1993-June 2013, using search headings "PVE" and "portal vein ligation". Articles were included when meeting the selection criteria: experimental animal study on PVE or portal vein ligation and experiments described in 5 animals or more. RESULTS: Sixty-one articles were selected, describing six different animal models. Most articles reported experiments with rats, rabbits, and pigs. In rats, the increase in wet-weight ratio of the non-occluded liver or total liver weight is greatest in the first 7 d with values ranging from 75%-80.5% on day 7. The volume increase of FRL in the rabbit model is greatest in the first 7 d with values ranging from 33.6%-80% on day 7. In pigs, the largest gain in volume of the FRL was seen in the first 2 wk. CONCLUSIONS: The choice of the model depends on the specific aim of the study. Evaluating the increase in liver volume and liver function after PVE, larger animals as the pig, rabbit, or the dog is useful because of the possibility to apply computed tomography volumetry. To evaluate mechanisms of regeneration after PVE, the rat model is useful, because of the variety of antibodies commercially available. PMID- 25017707 TI - Levobupivacaine inhibits lipopolysaccharide-induced high mobility group box 1 release in vitro and in vivo. AB - BACKGROUND: The aim of the study was to investigate whether levobupivacaine (LB) suppressed lipopolysaccharide (LPS)-induced high mobility group box 1 (HMGB1) release in vitro and in vivo, and to determin its molecular mechanisms of action. MATERIALS AND METHODS: RAW264.7 cells were treated with LPS and LB for 24 h. Levels of HMGB1, nuclear factor-kappa B (NF-kappaB) and phosphorylated p38 mitogen-activated protein kinase (MAPK) were measured by Enzyme-linked immunosorbent assay and Western blotting; the levels of HMGB1 messenger RNA were measured by real-time polymerase chain reaction. In addition, cecal ligation and puncture-induced septic C57BL/6 received LB infusion, and the levels of HMGB1 and functional parameters of multiple organs determined using several detection kits. RESULTS: LB inhibited HMGB1 release in vitro and in vivo. Furthermore, LB inhibited the translocation of NF-kappaB and phosphorylation of p38 MAPK in vitro. Mice treated with LB infusion improved survival in mice and significantly reduced cecal ligation and puncture-induced dysfunction of organs. CONCLUSIONS: LB suppresses LPS-induced HMGB1 release in vitro and in vivo by partially inhibiting NF-kappaB/p38 MAPK pathways. LB can rescue mice from sepsis and protect against organ dysfunction in septic mice. PMID- 25017708 TI - Identification of T cell receptor signaling pathway proteins in a feline large granular lymphoma cell line by liquid chromatography tandem mass spectrometry. AB - Tryptic peptides of a feline large granular lymphoma cell line were analyzed by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI MS/MS). Seventeen proteins of the T cell receptor signaling pathway could be identified by this approach. So far the existence of these proteins has only been postulated in the protein databases while experimental proof of their expression is predominantly pending. This article suggests where these proteins are located within the T cell receptor signaling pathway, thereby giving a short overview of the structure and function of this cascade. PMID- 25017709 TI - Association between nucleotide oligomerisation domain two (Nod2) gene polymorphisms and canine inflammatory bowel disease. AB - The most important genetic associations that have been implicated to play a role in the etiology of Crohn's disease (CD) in humans are single nucleotide polymorphisms (SNPs) in nucleotide oligomerisation domain 2 (NOD2). The aim of this study was to investigate whether SNPs in the canine NOD2 gene are associated with inflammatory bowel disease (IBD) in German shepherd dogs (GSDs) and other canine breeds. A mutational analysis of the NOD2 gene was carried out in 10 randomly selected GSDs with IBD. The mutational analysis identified five non synonymous SNPS, of which four in exon 3 of the NOD2 gene were evaluated in a case-control study using sequence based typing. Sequencing information from 55 GSDs with IBD were compared to a control group consisting of 61 GSDs. In addition, 85 dogs of other breeds with IBD and a breed-matched control group consisting of 162 dogs were also genotyped. All four SNPs were in complete linkage and, in the GSD population, were found to be in Hardy-Weinberg equilibrium. When the GSD case population was compared to the GSD control group, the heterozygote genotype for all four SNPs was more frequently found in the IBD population (p=0.03, OR=2.30, CI=1.07-4.94). However, these results were not mirrored in other canine breeds. Our study suggests that the four SNPs in exon 3 of NOD2 are significantly associated with IBD in GSDs when analyzed in an over dominant model. However, these results were not mirrored in other canine breeds with IBD. This suggests that the etiology of this disease is complex and may involve the interaction of SNPs present in several genes or pathways to bring about the inflammatory changes seen in the intestine. PMID- 25017710 TI - Is bacteriostatic saline superior to normal saline as an echocardiographic contrast agent? AB - Objective data on the performance characteristics and physical properties of commercially available saline formulations [normal saline (NS) vs. bacteriostatic normal saline (bNS)] are sparse. This study sought to compare the in vitro physical properties and in vivo characteristics of two commonly employed echocardiographic saline contrast agents in an attempt to assess superiority. Nineteen patients undergoing transesophageal echocardiograms were each administered agitated regular NS and bNS injections in random order and in a blinded manner according to a standardized protocol. Video time-intensity (TI) curves were constructed from a representative region of interest, placed paraseptally within the right atrium, in the bicaval view. TI curves were analyzed for maximal plateau acoustic intensity (Vmax, dB) and dwell time (DT, s), defined as time duration between onset of Vmax and decay of video intensity below clinically useful levels, reflecting the duration of homogenous opacification of the right atrium. To further characterize the physical properties of the bubbles in vitro, fixed aliquots of similarly agitated saline were injected into a glass well slide-cover slip assembly and examined using an optical microscope to determine bubble diameter in microns (um) and concentration [bubble count/high power field (hpf)]. A higher acoustic intensity (a less negative dB level), higher bubble concentration and longer DT were considered properties of a superior contrast agent. For statistical analysis, a paired t test was conducted to evaluate the differences in means of Vmax and DT. Compared to NS, bNS administration was associated with superior opacification (video intensity -8.69 +/- 4.7 vs. -10.46 +/- 4.1 dB, P = 0.002), longer DT (17.3 +/- 6.1 vs. 10.2 +/- 3.7 s) in vivo and smaller mean bubble size (43.4 vs. 58.6 MUm) and higher bubble concentration (1,002 vs. 298 bubble/hpf) in vitro. bNS provides higher intensity and more sustained opacification of the right atrium compared to NS. Higher bubble concentration and stability appear to be additional desirable rheological characteristics favoring bNS as a contrast agent. PMID- 25017711 TI - [Epidemiological data for uterine fibroids in France in 2010-2012 in medical center--analysis from the French DRG-based information system (PMSI)]. AB - OBJECTIVE: Uterine fibroids are a common disorder, responsible for menorrhagia/metrorrhagia and pelvic pain and remain the leading reason for hysterectomy in France. Although it is common disorder, French epidemiological data are locking. The objective of this study was to realize an epidemiological analysis from the medicalized information system program (PMSI). MATERIALS AND METHODS: The diagnosis codes were selected from 10th version of the International Classification Disease. The medical procedures concerning uterine fibroids were selected (so called: procedures listed). A descriptive analysis was performed from hospitals stays, patients' characteristics and medical procedures (mean, standard distribution, median, range, quartile). RESULTS AND DISCUSSION: In 2012, 46,126 patients (median age: 46 years old) were admitted in hospital (public or private hospitals) due to uterine fibroid corresponding to 47,690 hospital stays (hospital stays for surgery: 32,397). Diagnosis of anemia was reported in approximately 8% of patients and 7.1% of patients hospitalized in 2012 had already been hospitalized between 2004-2012. The median length of hospital stay was 4 days. In 2012, 16,070 hospital stays were reported for total or subtotal hysterectomy, 16,384 hospitals stays for myomectomy and 1376 hospital stays for embolization. In terms of management care, among 46,126 patients with uterine fibroids (principal or related diagnosis), 31,846 patients received a procedure listed in a surgical diagnostic related groups (DRG). CONCLUSION: To conclude, the study permits to update the epidemiological data concerning uterine fibroid management between 2010-2011-2012 in final. Because the PMSI collects partially information regarding epidemiological data, a clear epidemiological study is needed either with database from health insurance or with dedicated study. PMID- 25017712 TI - [Circulating tumor cells: cornerstone of personalized medicine]. AB - Cancer treatment has evolved toward personalized medicine. It is mandatory for clinicians to ascertain tumor biological features in order to optimize patients' treatment. Identification and characterization of circulating tumor cells demonstrated a prognostic value in many solid tumors. Here, we describe the main technologies for identification and characterization of circulating tumor cells and their clinical application in gynecologic and breast cancers. PMID- 25017713 TI - Pilomatrix Carcinoma of the scalp. A case report and review of the literature. AB - INTRODUCTION: Pilomatrix Carcinoma (PC) is a rare and malignant dermo-hypodermic tumor. Only 11 cases were reported in patients younger than 18 years old and only 13 cases were reported on the scalp. CASE REPORT: We report the case of a 15-year old woman who underwent cyst excision on the vertex. Anatomopathology shed light trichilemmal cyst. Five months later, she presented a first local recurrence. The tumor was removed with wide margin. Anatomopathology shed light PC. No adjuvant therapy was performed. The patient presented a second recurrence 3 months later with a parietal bone and superior sagittal sinus invasion and a lung metastasis. She underwent a craniotomy and radiochemotherapy. A third local recurrence was detected 4 months later. Three more lines of chemotherapy were performed without success. DISCUSSION: PC is a locally aggressive tumour, with a high rate of local recurrences and metastases. PC arises de novo or through malignant transformation of a pilomatrixoma. PC were observed frequently in the white male over 50 years old. The histological diagnosis is difficult to prove. Treatment consists of a wide surgical excision. Peritumoral margins are not codified. Because of most cases are on the face and neck, Mohs Micrographic Surgery seems to be a good modality to limit margins. Radiation therapy is an adjuvant treatment. Chemotherapy can be used in metastasis case. CONCLUSION: PC is a rare malignant tumor with high rate of disease relapse. Histological diagnosis is difficult and treatment is not standardized. Surgical procedure with wide margins is recommended to avoid the large recurrence when the staging shows no metastasis. PMID- 25017714 TI - Uptake of contaminants of emerging concern by the bivalves Anodonta californiensis and Corbicula fluminea. AB - Uptake of seven contaminants regularly detected in surface waters and spanning a range of hydrophobicities (log D(ow) -1 to 5) was studied for two species of freshwater bivalves, the native mussel Anodonta californiensis and the invasive clam Corbicula fluminea. Batch systems were utilized to determine compound partitioning, and flow-through systems, comparable to environmental conditions in effluent dominated surface waters, were used to determine uptake and depuration kinetics. Uptake of compounds was independent of bivalve type. Log bioconcentration factor (BCF) values were correlated with log D(ow) for nonionized compounds with the highest BCF value obtained for triclocarban (TCC). TCC concentrations were reduced in the water column due to bivalve activity. Anionic compounds with low D(ow) values, i.e., clofibric acid and ibuprofen, were not removed from water, while the organic cation propranolol showed biouptake similar to that of TCC. Batch experiments supported compound uptake patterns observed in flow-through experiments. Contaminant removal from water was observed through accumulation in tissue or settling as excreted pseudofeces or feces. The outcomes of this study indicate the potential utility of bivalve augmentation to improve water quality by removing hydrophobic trace organic compounds found in natural systems. PMID- 25017716 TI - Establishment and characterization of a cisplatin-resistant human osteosarcoma cell line. AB - The aim of the present study was to establish a new cisplatin-resistant human osteosarcoma cell line and investigate its biological characteristics. The human osteosarcoma cell line SOSP-9607 was exposed to cisplatin by stepwisely increasing the concentrations in the medium to select for the drug-resistant subline, SOSP-9607/CDDP cells. The morphological features were observed using inverted microscopy. The growth curves of SOSP-9607 and SOSP-9607/CDDP cells were drawn to calculate the doubling time. FCM was also used to determine the distribution of the cell cycle. The MTT assay was performed to test the drug resistance of SOSP-9607 and SOSP-9607/CDDP cells. Transwell assay was used to examine the invasive capability of the SOSP-9607/CDDP and SOSP-9607 cells. RT-PCR was performed to determine the mRNA expression levels of drug resistance-related and apoptosis-related genes, MDR1, MRP1, MRP2, LRP, ABCG2, GST-pi, Bcl-2 and Bax, in both cell lines. SOSP-9607/CDDP cells exhibited changes in morphology, proliferation rate, doubling time, cell cycle distribution and invasive capability as compared with the SOSP-9607 cells. SOSP-9607/CDDP cells were 6.24 fold resistant to cisplatin in comparison with the SOSP-9607 cells and also exhibited cross-resistance to methotrexate and adriamycin. SOSP-9607/CDDP cells overexpressed MRP1, MRP2 and GST-pi. In conclusion, SOSP-9607/CDDP cells are invaluable tools with which to study the resistance of anticancer drugs and to identify the methods to overcome resistance. PMID- 25017715 TI - Effects of traditional Chinese medicine on symptom clusters during the menopausal transition. AB - AIMS: To review controlled clinical trials of traditional Chinese medicine (TCM) therapies for hot flushes and at least one other co-occurring symptom among sleep, cognitive function, mood, and pain. METHODS: An experienced reference librarian performed an extensive search of PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for randomized, controlled trials reported in English between 2004 and July 2011. Of 1193 abstracts identified, 58 trials examined effectiveness of therapies for hot flushes and at least one additional co-occurring symptom. RESULTS: Eleven trials (13 publications) examined TCM therapeutics of acupuncture, Chinese herbal medicine (CHM) or moxibustion. Acupuncture trials (eight) yielded mixed results; five trials significantly reduced hot flushes. Of those five trials, one also showed benefit for sleep and pain and two trials found benefit for mood symptoms. Of three CHM trials, three trials had significant findings: one for hot flushes and mood, one for hot flushes and pain, and one for hot flushes, sleep, mood symptoms and pain. Moxibustion and counseling (one trial) significantly reduced hot flushes, mood symptoms and pain. None of the trials reported any serious adverse events. CONCLUSIONS: TCM therapeutics of acupuncture, CHM and moxibustion show promising results for the treatment of mood and pain symptoms co-occurring with hot flushes. Although the controlled clinical trials of TCM therapeutics reviewed here measured multiple symptom outcomes, few report treatment effects in ways that allow clinicians to consider symptom clusters when prescribing therapies. Future studies need to measure and report results for individual symptoms or group like symptoms together into subscales. Controlled clinical trials with larger numbers of participants are essential to allow evaluation of these therapies on hot flushes and multiple co-occurring symptoms. PMID- 25017717 TI - Neisseria proteomics for antigen discovery and vaccine development. AB - Neisseria meningitidis (meningococcus) is a major causative organism of meningitis and sepsis and Neisseria gonorrhoeae (gonococcus) is the causative organism of the sexually transmitted disease gonorrhea. Infections caused by meningococci are vaccine-preventable, whereas gonococcal vaccine research and development has languished for decades and the correlates of protection are still largely unknown. In the past two decades, complementary 'omic' platforms have been developed to interrogate Neisseria genomes and gene products. Proteomic techniques applied to whole Neisseria bacteria, outer membranes and outer membrane vesicle vaccines have generated protein maps and also allowed the examination of environmental stresses on protein expression. In particular, immuno-proteomics has identified proteins whose expression is correlated with the development of human natural immunity to meningococcal infection and colonization and following vaccination. Neisseria proteomic techniques have produced a catalog of potential vaccine antigens and investigating the functional and biological properties of these proteins could finally provide 'universal' Neisseria vaccines. PMID- 25017718 TI - A multicellular, neuro-mimetic model to study nanoparticle uptake in cells of the central nervous system. AB - Evaluating the uptake and handling of biomedically relevant nanoparticles by cells of the nervous system critically underpins the effective use of nanoparticle platforms for neuro-regenerative therapies. The lack of biologically relevant and 'neuromimetic' models for nanomaterials testing (that can simulate the cellular complexity of neural tissue) currently represents a bottleneck. Further, propagation of individual cell types, in different neural cell-specific media (as commonly occurs in the nanotechnology field), can result in non standardised corona formation around particles, confounding analyses of intercellular differences between neural cells in nanoparticle uptake. To address these challenges, we have developed a facile multicellular model that broadly simulates the ratios of neurons, astrocytes and oligodendrocytes found in vivo. All cell types in the model are derived from a single neural stem cell source, and propagated in the same medium overcoming the issue of variant corona formation. Using a fluorescent transfection-grade magnetic particle (MP), we demonstrate dramatic differences in particle uptake and resultant gene transfer between neural cell subtypes, with astrocytes being the dominant population in terms of particle uptake and transfection. We demonstrate the compatibility of the model with a high resolution scanning electron microscopy technique, allowing for membrane features of MP stimulated cells to be examined. Using this approach, astrocytes displayed high membrane activity in line with extensive particle uptake/transfection, relative to neurons and oligodendrocytes. We consider that the stem cell based model described here can provide a simple and versatile tool to evaluate interactions of neural cells with nanoparticle systems developed for neurological applications. Models of greater complexity can be evolved from this basic system, to further enhance its neuromimetic capacity. PMID- 25017719 TI - Role of photophysics processes in thermal lens spectroscopy of fluids: a theoretical study. AB - Photophysics processes are ubiquitous in nature and difficult to be quantitatively characterized by conventional spectroscopy. Alternatively, pump probe methods have been widely applied to study these complex processes. In this context, the thermal lens technique is a precise spectroscopic tool for material characterization and presents a wide range of applications in chemical analysis. Here, we present an all numerical approach to analyze the dynamics of photophysics processes and to identify the role of individual contributions of photoreaction and mass diffusion in the thermal lens experiments. The results are essential for a proper understanding of the dominant physical mechanisms in laser induced photodegradation, which allow precise data analysis of the effects in photosensitive fluids. PMID- 25017720 TI - Kit regulates HSC engraftment across the human-mouse species barrier. AB - In-depth analysis of the cellular and molecular mechanisms regulating human HSC function will require a surrogate host that supports robust maintenance of transplanted human HSCs in vivo, but the currently available options are problematic. Previously we showed that mutations in the Kit receptor enhance engraftment of transplanted HSCs in the mouse. To generate an improved model for human HSC transplantation and analysis, we developed immune-deficient mouse strains containing Kit mutations. We found that mutation of the Kit receptor enables robust, uniform, sustained, and serially transplantable engraftment of human HSCs in adult mice without a requirement for irradiation conditioning. Using this model, we also showed that differential KIT expression identifies two functionally distinct subpopulations of human HSCs. Thus, we have found that the capacity of this Kit mutation to open up stem cell niches across species barriers has significant potential and broad applicability in human HSC research. PMID- 25017721 TI - Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment. AB - Planarians are flatworms capable of regenerating any missing body region. This capacity is mediated by neoblasts, a proliferative cell population that contains pluripotent stem cells. Although population-based studies have revealed many neoblast characteristics, whether functionally distinct classes exist within this population is unclear. Here, we used high-dimensional single-cell transcriptional profiling from over a thousand individual neoblasts to directly compare gene expression fingerprints during homeostasis and regeneration. We identified two prominent neoblast classes that we named zeta (zeta) and sigma (sigma). Zeta neoblasts encompass specified cells that give rise to an abundant postmitotic lineage, including epidermal cells, and are not required for regeneration. By contrast, sigma-neoblasts proliferate in response to injury, possess broad lineage capacity, and can give rise to zeta-neoblasts. These findings indicate that planarian neoblasts comprise two major and functionally distinct cellular compartments. PMID- 25017722 TI - Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. AB - Perivascular mesenchymal stem and progenitor cells (MSPCs) are critical for forming a healthy hematopoietic stem cell (HSC) niche. However, the interactions and influence of acute myelogenous leukemia (AML) stem cells with the microenvironment remain largely unexplored. We have unexpectedly found that neuropathy of the sympathetic nervous system (SNS) promotes leukemic bone marrow infiltration in an MLL-AF9 AML model. Development of AML disrupts SNS nerves and the quiescence of Nestin(+) niche cells, leading to an expansion of phenotypic MSPCs primed for osteoblastic differentiation at the expense of HSC-maintaining NG2(+) periarteriolar niche cells. Adrenergic signaling promoting leukemogenesis is transduced by the beta2, but not beta3, adrenergic receptor expressed on stromal cells of leukemic bone marrow. These results indicate that sympathetic neuropathy may represent a mechanism for the malignancy in order to co-opt the microenvironment and suggest separate mesenchymal niche activities for malignant and healthy hematopoietic stem cells in the bone marrow. PMID- 25017723 TI - Selenopeptide transamidation and metathesis. AB - Selenopeptides can be transamidated by cysteinyl peptides in water using mild conditions (pH 5.5, 37 degrees C) in the presence of an arylthiol catalyst. Similar conditions also catalyze the metathesis of selenopeptides. The usefulness of the selenophosphine derived from TCEP (TCEP?Se) for inhibiting the TCEP induced deselenization of selenocysteine residue is also reported. PMID- 25017724 TI - An ordinary differential equation model for full thickness wounds and the effects of diabetes. AB - Wound healing is a complex process in which a sequence of interrelated phases contributes to a reduction in wound size. For diabetic patients, many of these processes are compromised, so that wound healing slows down. In this paper we present a simple ordinary differential equation model for wound healing in which attention focusses on the dominant processes that contribute to closure of a full thickness wound. Asymptotic analysis of the resulting model reveals that normal healing occurs in stages: the initial and rapid elastic recoil of the wound is followed by a longer proliferative phase during which growth in the dermis dominates healing. At longer times, fibroblasts exert contractile forces on the dermal tissue, the resulting tension stimulating further dermal tissue growth and enhancing wound closure. By fitting the model to experimental data we find that the major difference between normal and diabetic healing is a marked reduction in the rate of dermal tissue growth for diabetic patients. The model is used to estimate the breakdown of dermal healing into two processes: tissue growth and contraction, the proportions of which provide information about the quality of the healed wound. We show further that increasing dermal tissue growth in the diabetic wound produces closure times similar to those associated with normal healing and we discuss the clinical implications of this hypothesised treatment. PMID- 25017725 TI - Total reproductive value of juvenile females is twice that of juvenile males under X-linkage and haplodiploidy. AB - Grafen (2014) has shown that, although the total reproductive value of females is not generally equal to that of males in an age-structured population under diploidy and autosomal inheritance, the total reproductive value of juvenile females is equal to that of juvenile males, provided there is a stable class distribution. It is the latter equality that is key to R.A. Fisher's famous explanation for equal investment into daughters and sons. Here, I simplify the derivation of Grafen's key result and extend the analysis to consider X-linkage and haplodiploid inheritance, i.e. scenarios in which a female receives one set of genes from her mother and one set from her father but where males receive genes only from their mother. I find that, although the total reproductive value of females need not be twice that of males, as is commonly supposed, the total reproductive value of juvenile females is twice that of juvenile males. This recovers the principle of equal maternal investment into daughters and sons in panmictic populations. PMID- 25017726 TI - Evil green beards: Tag recognition can also be used to withhold cooperation in structured populations. AB - Natural selection works against cooperation unless a specific mechanism is at work. These mechanisms are typically studied in isolation. Here we look at the interaction between two such mechanisms: tag recognition and population structure. If cooperators can recognize each other, and only cooperate among themselves, then they can invade defectors. This is known as the green beard effect. Another mechanism is assortment caused by population structure. If interactions occur predominantly between alike individuals, then indiscriminate cooperation can evolve. Here we show that these two mechanisms interact in a non trivial way. When assortment is low, tags lead to conventional green beard cycles with periods of tag based cooperation and periods of defection. However, if assortment is high, evil green beard cycles emerge. In those cycles, tags are not used to build up cooperation with others that share the tag, but to undermine cooperation with others that do not share the tag. High levels of assortment therefore do not lead to indiscriminate cooperation if tags are available. This shows that mechanisms that are known to promote cooperation in isolation can interact in counterintuitive ways. PMID- 25017727 TI - Network-based biomarkers for complex diseases. PMID- 25017728 TI - Feasibility of high-resolution MR imaging for the diagnosis of intracranial vertebrobasilar artery dissection. AB - OBJECTIVES: To evaluate the feasibility of high-resolution MRI (HR-MRI) for diagnosing intracranial vertebrobasilar artery dissection (VBD) and to identify the most useful imaging findings suggesting dissection. METHODS: We retrospectively reviewed 50 patients with suspected intracranial VBDs who underwent HR-MRI. Two neuroradiologists independently reviewed the HR-MR images. The diagnosis based on HR-MRI was compared with the final diagnosis by consensus among the neuroradiologists, neurointerventionist, and neurologist. Two neuroradiologists also sought signs of dissection (mural hematoma, dissection flap, outer-diameter enlargement on T2WI of steno-occlusive lesions). Inter- and intraobserver agreements were analysed. RESULTS: HR-MRI corroborated the final diagnosis in 47 (94%; 31 VBD and 16 non-VBD) patients. A mural haematoma was best detected on T1WI and contrast-enhanced (CE)-T1WI (54.3%). Dissection flaps were observed in almost all cases on CE-T1WI (91.4 %), and then were detected on T2WI (68.6%). Outer-diameter enlargement of the steno-occlusive lesions on angiography was detected in more than half of the cases (62.9%). The two reviewers showed almost perfect agreement for the diagnosis of VBD and detecting dissection signs on every sequence. CONCLUSIONS: HR-MRI can be a useful and non-invasive diagnostic tool for intracranial VBD, and dissection flaps on CE-T1WI are the signs with the greatest diagnostic value. KEY POINTS: Direct imaging findings of dissection were well visualised by HR-MRI. Detection of a dissection flap on CE T1WI is the most reliable diagnostic finding. HR-MRI could be a useful diagnostic tool for intracranial VBDs. PMID- 25017729 TI - Experimental consideration of the Hansen solubility parameters of as-produced multi-walled carbon nanotubes by inverse gas chromatography. AB - The Hansen solubility parameters (HSPs) of as-produced multi-walled carbon nanotubes (APMWCNTs) were determined by means of the inverse gas chromatography (IGC) technique. Due to non-homogeneous surfaces of the APMWCNTs arising from defects and impurities, it was necessary to establish adequate working conditions for determining the HSPs of the CNTs. We then obtained the HSPs of the APMWCNTs and compared these results with earlier reports as determined by using sedimentation and molecular dynamics simulation methods. It was found that the determination of the HSPs of the CNTs by IGC can give an enhanced determination range based on the adsorption thermodynamic parameters, compared to the HSPs determined using sedimentation methods. And the HSPs of the APMWCNTs, determined here, provided good guidelines for the selection of feasible solvents that can improve the dispersion of the APMWCNTs. PMID- 25017730 TI - Phosphorylation of an intrinsically disordered segment in Ets1 shifts conformational sampling toward binding-competent substates. AB - Functions of many proteins are affected by posttranslational modifications of intrinsically disordered (ID) regions, yet little is known about the underlying molecular mechanisms. By combining molecular dynamics simulations and protein docking, we demonstrate that the addition of phosphates to an ID segment adjacent to the PNT domain of Ets1 directs conformational sampling toward substates that are most compatible with high-affinity binding of the TAZ1 domain of its coactivator CBP. The phosphate charges disrupt salt bridges and thereby open a hydrophobic cleft and expose hydrophobic residues at the ID N terminus. The structure of the PNT-TAZ1 complex that we determined shows that PNT binds to TAZ1 via these hydrophobic regions in a similar manner to how it interacts with other partners. Our calculations reveal a dual effect of phosphorylation in that it changes the dynamics of PNT so that it becomes more compatible for TAZ1 binding and increases complementarity with this binding partner. PMID- 25017731 TI - NMR polypeptide backbone conformation of the E. coli outer membrane protein W. AB - The outer membrane proteins (Omps) are key factors for bacterial survival and virulence. Among the Omps that have been structurally characterized either by X ray crystallography or by NMR in solution, the crystal structure of OmpW stands out because three of its four extracellular loops are well defined, whereas long extracellular loops in other E. coli Omps are disordered in the crystals as well as in NMR structures. OmpW thus presented an opportunity for a detailed comparison of the extracellular loops in a beta-barrel membrane protein structure in crystals and in noncrystalline milieus. Here, the polypeptide backbone conformation of OmpW in 30-Fos micelles was determined. Complete backbone NMR assignments were obtained and the loops were structurally characterized. In combination with the OmpW crystal structure, NMR line shape analyses, and (15)N{(1)H}-NOE data, these results showed that intact regular secondary structures in the loops undergo slow hinge motions at the detergent-solvent interface. PMID- 25017732 TI - Genetic dissection of IGF1-dependent and -independent effects of permanent GH excess on postnatal growth and organ pathology of mice. AB - To study insulin-like growth factor 1 (IGF1)-independent effects of permanent growth hormone (GH) excess on body and organ growth and pathology in vivo, hemizygous bovine GH transgenic mice with homozygous disruption of the Igf1 gene (Igf1(-/-)/GH) were generated, and examined in comparison to Igf1(-/-), Igf1(+/ ), wild-type (WT), Igf1(+/-)/GH, and GH mice. GH mice and Igf1(+/-)/GH mice showed increased serum IGF1 levels and the well-known giant-phenotype of GH transgenic mice. In contrast, the typical dwarf-phenotype of Igf1(-/-) mice was only slightly ameliorated in Igf1(-/-)/GH mice. Similar to GH mice, Igf1(-/-)/GH mice displayed hepatocellular hypertrophy, glomerulosclerosis, and reduced volumes of acidophilic cells in the pituitary gland. However, GH excess associated skin lesions of male GH mice were not observed in Igf1(-/-)/GH mice. Therefore, development of GH excess induced liver-, kidney-, and pituitary gland alterations in GH transgenic mice is independent of IGF1 whereas GH stimulated body growth depends on IGF1. PMID- 25017733 TI - Diverse signaling systems activated by the sweet taste receptor in human GLP-1 secreting cells. AB - Sweet taste receptor regulates GLP-1 secretion in enteroendocrine L-cells. We investigated the signaling system activated by this receptor using Hutu-80 cells. We stimulated them with sucralose, saccharin, acesulfame K and glycyrrhizin. These sweeteners stimulated GLP-1 secretion, which was attenuated by lactisole. All these sweeteners elevated cytoplasmic cyclic AMP ([cAMP]c) whereas only sucralose and saccharin induced a monophasic increase in cytoplasmic Ca(2+) ([Ca(2+)]c). Removal of extracellular calcium or sodium and addition of a Gq/11 inhibitor greatly reduced the [Ca(2+)]c responses to two sweeteners. In contrast, acesulfame K induced rapid and sustained reduction of [Ca(2+)]c. In addition, glycyrrhizin first reduced [Ca(2+)]c which was followed by an elevation of [Ca(2+)]c. Reductions of [Ca(2+)]c induced by acesulfame K and glycyrrhizin were attenuated by a calmodulin inhibitor or by knockdown of the plasma membrane calcium pump. These results indicate that various sweet molecules act as biased agonists and evoke strikingly different patterns of intracellular signals. PMID- 25017734 TI - Development of potent selective competitive-antagonists of the melanocortin type 2 receptor. AB - Cushing's disease, a hypercortisolemic state induced by an ACTH overexpressing pituitary adenoma, causes increased morbidity and mortality. Selective antagonism of the melanocortin type 2 receptor (MC2R) may be a novel treatment modality. Five structurally related peptides with modified HFRW sites but intact putative MC2R binding sites were tested for antagonistic activity at MC1R, MC2R/MRAP, MC3R, MC4R and MC5R. Two of these peptides (GPS1573 and GPS1574) dose-dependently antagonized ACTH-stimulated MC2R activity (IC50s of 66+/-23 nM and 260+/-1 nM, respectively). GPS1573 and 1574 suppressed the Rmax but not EC50 of ACTH on MC2R, indicating non-competitive antagonism. These peptides did not antagonize alpha MSH stimulation of MC1R and antagonized MC3, 4 and 5R at markedly lower potency. GP1573 and GPS1574 antagonize MC4R with IC50s of 950 nM and 3.7 MUM, respectively. In conclusion, two peptide antagonists were developed with selectivity for MC2R, forming a platform for development of a medical treatment for Cushing's disease. PMID- 25017735 TI - Swedish-German contacts in the field of anatomy 1930-1950: Gosta Haggqvist and Hermann Stieve. AB - This study presents a first exploration of Swedish-German contacts in the field of anatomy between 1930 and 1950, a subject of research that has only recently come into focus. Based on the background of the general cultural and scientific exchange between Sweden and Germany and the biographies of the Swedish anatomist Gosta Haggqvist (1891-1972) and his German colleague Hermann Stieve (1886-1952), this study identifies specific areas of collaboration between anatomists of the two countries. These include mutual professional career advancement, publication of research results, the exchange of technological expertise and transfer of anatomical specimens. The investigation also examines the use of "material" from executed persons in Sweden and Germany as well as public postwar critiques of this practice. Open research questions on Swedish-German interactions in anatomy during this time period are formulated. The contacts between Haggqvist and Stieve give insight into the impact of scientific collaborations and controversial political liaisons in the relationship between Swedish and German science in recent history. The study is based on documents from German and Swedish archives, including Nobel Prize nominations and reports from the Nobel Archive for Physiology or Medicine in Stockholm. PMID- 25017736 TI - Dataset size and composition impact the reliability of performance benchmarks for peptide-MHC binding predictions. AB - BACKGROUND: It is important to accurately determine the performance of peptide:MHC binding predictions, as this enables users to compare and choose between different prediction methods and provides estimates of the expected error rate. Two common approaches to determine prediction performance are cross validation, in which all available data are iteratively split into training and testing data, and the use of blind sets generated separately from the data used to construct the predictive method. In the present study, we have compared cross validated prediction performances generated on our last benchmark dataset from 2009 with prediction performances generated on data subsequently added to the Immune Epitope Database (IEDB) which served as a blind set. RESULTS: We found that cross-validated performances systematically overestimated performance on the blind set. This was found not to be due to the presence of similar peptides in the cross-validation dataset. Rather, we found that small size and low sequence/affinity diversity of either training or blind datasets were associated with large differences in cross-validated vs. blind prediction performances. We use these findings to derive quantitative rules of how large and diverse datasets need to be to provide generalizable performance estimates. CONCLUSION: It has long been known that cross-validated prediction performance estimates often overestimate performance on independently generated blind set data. We here identify and quantify the specific factors contributing to this effect for MHC-I binding predictions. An increasing number of peptides for which MHC binding affinities are measured experimentally have been selected based on binding predictions and thus are less diverse than historic datasets sampling the entire sequence and affinity space, making them more difficult benchmark data sets. This has to be taken into account when comparing performance metrics between different benchmarks, and when deriving error estimates for predictions based on benchmark performance. PMID- 25017737 TI - Toll-like receptor 6 gene polymorphisms increase the risk of bovine tuberculosis in Chinese Holstein cattle. AB - Our present study aimed to investigate the effect of four SNPs (G1793A, C1859A, A1980G, G1934A) in toll-like receptor 6 (TLR6) on bovine tuberculosis (bTB) resistance in a case-control study. A total of 603 Chinese Holstein cattle (264 from a dairy farm of Henan province, 339 from Hubei province) were selected to analyze the genotype of TLR6 gene by PCR-RFLP. Genotype frequencies of C1859A and A1980G site differed significantly between bTB-infected and non-infected cows (chi(2)=6.062, P=0.048 and chi(2)=6.749, P=0.034, respectively). Relative risk of tuberculosis incidence result showed that genotypes of AA or CA had greater relative risk (OR=2.730, 95%CI=0.869-8.573; OR=1.547, 95CI%=0.803-2.982, respectively) than those with genotype CC at C1859A site between bTB-infected and non-infected animals. Genotypes of GG or GA had greater relative risk (OR=2.986, 95%CI=1.245-7.165; OR=1.582, 95%CI=0.734-3.409, respectively) than those with genotype AA at A1980G site. No significant association can be inferred from G1793A and G1934A polymorphism site. The present study suggests that variants in the TLR6 gene are associated with susceptibility to bTB and the TLR6 gene may be considered as a candidate gene for bTB resistance. PMID- 25017738 TI - Vascular responses in patients with and without diabetes mellitus after everolimus-eluting stent implantation. AB - BACKGROUND: Previous reports have shown potential disadvantages of limus derivative drugs for the stenting treatment of patients with diabetes mellitus (DM). METHODS AND RESULTS: We studied 159 coronary artery lesions (DM: n=72, non DM: n=87) in 123 patients treated with everolimus-eluting stent (EES) and who underwent scheduled 9-month follow-up angiography with optical coherence tomography (OCT) regardless of symptoms. In addition to standard OCT variables, neointimal unevenness score (maximum/average neointimal thickness) and stent eccentricity index (minimum/maximum stent diameter) were calculated for each cross-section. To investigate a potential baseline difference between DM and non DM lesions, pre- and post-interventional intravascular ultrasound (IVUS) images were also evaluated as an IVUS subgroup analysis. The average neointimal thickness and neointimal coverage did not differ between DM and non-DM patients. DM patients had, however, greater asymmetric stent expansion and variability of neointimal thickness than non-DM patients. There was a weak, but significant association between average stent eccentricity index and neointimal unevenness score. The IVUS substudy showed that the culprit plaque volume and plaque eccentricity in DM patients were significantly greater than in non-DM patients. CONCLUSIONS: Although EES provided a similar level of average neointimal thickness and coverage both in the presence and absence of DM, uneven neointimal suppression occurred in DM patients. A larger plaque volume of the culprit lesion may hamper symmetric stent expansion, possibly explaining the non-uniform neointimal suppression in DM patients. PMID- 25017739 TI - Latest advances in transseptal structural heart interventions-Percutaneous Mitral Valve Repair and Left Atrial Appendage Occlusion. AB - Recent advances in structural heart intervention have produced increasing demand for transseptal access, which was first introduced as a diagnostic tool to directly measure left atrial pressure. Transseptal access allows safe and adequate approach to the left atrium and surrounding structures. Percutaneous transcatheter mitral valve repair using the MitraClip device is a safe and less invasive treatment for selected patients with significant mitral regurgitation, who are at high risk for surgery. This is an echocardiographic- and fluoroscopic guided procedure requiring accurate transseptal access of the left atrium and clipping of the mitral leaflets at the precise location of their malcoaptation. Percutaneous transcatheter closure of the left atrial appendage is another novel procedure that requires transseptal access of the left atrium, followed by closure or ligation of the left atrial appendage. This catheter-based therapy has been shown to be a safe and effective alternative to long-term anticoagulant therapy for the prevention of stroke in patients with atrial fibrillation. In this article, we systematically review these novel structural heart interventions. PMID- 25017740 TI - Impact of target lesion coronary calcification on stent expansion. AB - BACKGROUND: Stent underexpansion remains a concern as a cause of drug-eluting stent (DES) failure. Although coronary calcification is considered to be a contributing factor in stent underexpansion, previous intravascular ultrasound studies have failed to demonstrate this relationship. We investigated whether stent expansion could be predicted by coronary calcification as assessed by optical coherence tomography (OCT). METHODS AND RESULTS: We enrolled 51 de novo native coronary artery lesions treated by a single 2nd-generation DES (3 types). Prior to stent deployment, the arc and area of calcium at the target lesion were measured using OCT. After successful stent implantation, OCT imaging was repeated to assess minimal stent diameter and area (MSD and MSA). Stent expansion was defined as MSD (or MSA) divided by the values predicted by the manufacturers' compliance charts. Patients were divided into 4 groups according to the median values of the arc and area of calcium. Mean stent expansion was 73.3+/-8.7% for MSD and 65.2+/-12.0% for MSA. Stent expansion defined by MSD was significantly different among the 4 groups (P=0.02). A similar trend was observed for stent expansion defined by MSA (P=0.16). CONCLUSIONS: The extent of target lesion calcification as assessed by OCT may be an important determinant of the expansion of 2nd-generation DES. PMID- 25017741 TI - Nocturnal sleep problems among university students from 26 countries. AB - BACKGROUND: The aim of this study is to estimate the prevalence of nocturnal sleeping problems and its associated factors among university students in mainly low- and middle-income countries. METHODS: A cross-sectional survey was conducted with 20,222 undergraduate university students (mean age, 20.8; SD = 2.8) from 27 universities in 26 countries across Asia, Africa and the Americas. RESULTS: Overall, 10.4% reported severe or extreme nocturnal sleeping problems (male, 10.2%; female, 10.5%) in the past month. Noctural sleeping problems differed by country, from 32.9% in Indonesia to 3.0 % in Thailand among Asian countries, from 13.7% in Mauritius to 7.5% in South Africa, and from 11.8% in Jamaica to 6.1% in Columbia in the Americas. In multivariate logistic regression analysis, coming from a poor family background, staying off campus (on their own or with parents or guardians), stress (history of child sexual abuse), poor mental health (depression and PTSD symptoms), health risk behaviour (tobacco use, heavy internet use, gambling, skipping breakfast and having sustained an injury), lack of social support and poor academic performance were associated with nocturnal sleeping problems. CONCLUSIONS: A significant prevalence of past-month nocturnal sleeping problems was found. Potential factors associated with the risk of reporting sleeping complaints were identified, which may assist in prevention strategies to promote a better quality of sleep. PMID- 25017742 TI - Breeding and preliminarily phenotyping of a congenic mouse model with alopecia areata. AB - In the current study, the alopecia areata gene was introduced into the C57BL/6 (B6) mouse through repeated backcrossing/intercrossing, and the allelic homozygosity of congenic AA(tj)mice (named B6.KM-AA) was verified using microsatellites. The gross appearance, growth characteristics, pathological changes in skin, and major organs of B6.KM-AA mice were observed. Counts and proportions of CD4+ and CD8+ T lymphocytes in peripheral blood were determined by flow cytometry. Results show that congenic B6.KM-AA mice were obtained after 10 generations of backcrossing/intercrossing. B6.KM-AA mice grew slower than B6 control mice and AA skin lesions were developed by four weeks of age. The number of hair follicles was reduced, but hair structures were normal. Loss of hair during disease progression was associated with CD4+ and CD8+ T lymphocytes infiltration peri-and intra-hair follicles. No pathological changes were found in other organs except for the skin. In the peripheral blood of B6.KM-AA mice, the percentage of CD4+ T cells was lower and percentage of CD8+ T cells higher than in control mice. These findings indicate that B6.KM-AA mice are characterized by a dysfunctional immune system, retarded development and T-cell infiltration mediated hair loss, making them a promising new animal model for human alopecia areata. PMID- 25017743 TI - Avoidance of potentially harmful food cannot be socially transmitted between rats. AB - The social transmission of food preferences (STFP) is a behavioural task of olfactory memory, in which an observer rat learns safe food odours from a demonstrator rat, and shows preference for this odour in a subsequent choice test. However, previous studies have failed to detect the transmission of information about food of potential danger and food aversion using STFP test. In this study, we tested how demonstrators' health affects the exchange of odour information and whether observers can learn danger information from an unhealthy demonstrator. As expected, the observer rat formed an odour preference after interacting with a demonstrator rat that had just eaten food containing a new odour, however, odour preference rather than aversion was also formed after interacting with a demonstrator rat injected with LiCl (used to induce gastric malaise). Furthermore, anaesthetized demonstrator rats and half-anaesthetized demonstrator rats, which showed obvious motor deficits suggesting an unhealthy state, also socially transmitted food preferences to observers. These results suggest that the social transmission of food preferences task is independent of a demonstrators' health, and that information about dangerous foods cannot be transmitted using this behavioural task. PMID- 25017744 TI - The role of leptin in striped hamsters subjected to food restriction and refeeding. AB - Food restriction (FR) and refeeding (Re) have been suggested to impair body mass regulation and thereby making it easier to regain the lost weight and develop over-weight when FR ends. However, it is unclear if this is the case in small mammals showing seasonal forging behaviors. In the present study, energy budget, body fat and serum leptin level were measured in striped hamsters that were exposed to FR-Re. The effects of leptin on food intake, body fat and genes expressions of several hypothalamus neuropeptides were determined. Body mass, fat content and serum leptin level decreased during FR and then increased during Re. Leptin supplement significantly attenuated the increase in food intake during Re, decreased genes expressions of neuropepetide Y (NPY) and agouti-related protein (AgRP) of hypothalamus and leptin of white adipose tissue (WAT). Hormone sensitive lipase (HSL) gene expression of WAT increased in leptin-treated hamsters that were fed ad libitum, but decreased in FR-Re hamsters. This indicates that the adaptive regulation of WAT HSL gene expression may be involved in the mobilization of fat storage during Re, which partly contributes to the resistance to FR-Re-induced overweight. Leptin may be involved in the down regulations of hypothalamus orexigenic peptides gene expression and consequently plays a crucial role in controlling food intake when FR ends. PMID- 25017745 TI - Acute and joint toxicity of three agrochemicals to Chinese tiger frog (Hoplobatrachus chinensis) tadpoles. AB - We studied acute and joint toxicity of three different agrochemicals (chlorantraniliprole, flubendiamide-abamectin and penoxsulam) to Chinese tiger frog (Hoplobatrachus chinensis) tadpoles with the method of stability water tests. Results showed that the three agrochemicals increased tadpole mortality. For acute toxicity, the LC50 values after 24, 48 and 72 h of chlorantraniliprole, flubendiamide-abamectin and penoxsulam exposure were 5.37, 4.90 and 4.68 mg/L; 0.035, 0.025 and 0.021 mg/L; 1.74, 1.45 and 1.29 mg/L, respectively. The safety concentrations (SC) of chlorantraniliprole, flubendiamide-abamectin and penoxsulam to the tadpoles were 1.23, 0.30 and 0.003 mg/L, respectively. Based on these findings, chlorantraniliprole and penoxsulam were moderately toxic, while flubendiamide-abamectin was highly toxic. All pairwise joint toxicity tests showed moderate toxicity. The LC50 values after 24, 48 and 72 h of exposure were 7.08, 6.61 and 6.03 mg/L for chlorantraniliprole+penoxsulam, with corresponding values of 2.455, 2.328 and 2.183 mg/L for chlorantraniliprole+flubendiamide abamectin, and 1.132, 1.084 and 1.050 mg/L for penoxsulam+flubendiamide abamectin, with safe concentrations of 1.73, 0.63 and 0.30 mg/L, respectively. For toxic evaluations of pairwise combinations of the three agrochemicals, only the joint toxicity of chlorantraniliprole and flubendiamide-abamectin after 24 h was found to be synergistic, whereas all other tests were antagonistic. Our findings provide valuable information on the toxic effects of agrochemicals on amphibians and how various types of agrochemicals can be reasonably used in agricultural areas. PMID- 25017746 TI - Metabolic rate and evaporative water loss in the silky starling (Sturnus sericeus). AB - To better understand the physiological characteristics of the silky starling (Sturnus sericeus), its body temperature (Tb), basal metabolic rate (BMR), evaporative water loss (EWL) and thermal conductance (C) elicited by different ambient temperatures (Ta) (5-30 C) were determined in the present study. Our results showed that they have a high Tb (41.6 +/- 0.1 C), a wide thermal neutral zone (TNZ) (20-27.5C) and a relatively low BMR within the TNZ (3.37 +/- 0.17 mL O2/g.h). The EWL was nearly stable below the TNZ (0.91 +/- 0.07 mg H2O/g.h) but increased remarkably within and above the TNZ. The C was constant below the TNZ, with a minimum value of 0.14 +/- 0.01 mL O2/g.h.C. These findings indicate that the BMR, Tb and EWL of the silky starling were all affected by Ta, especially when Ta was below 20 C and the EWL plays an important role in thermal regulation. PMID- 25017747 TI - Postnatal ontogenetic size and shape changes in the craniums of plateau pika and woolly hare (Mammalia: Lagomorpha). AB - In the present study, postnatal ontogenetic size and shape changes in the cranium of two lagomorph species, the plateau pika (Ochotona curzoniae) and woolly hare (Lepus oiostolus), were investigated by geometric morphometrics. The ontogenetic size and shape changes of their cranium exhibited different growth patterns in response to similar environmental pressures on the Qinghai-Tibetan Plateau. The overall size change in the cranium of the plateau pika was slower than that of the woolly hare. The percentage of ontogenetic shape variance explained by size in the woolly hare was greater than that in the plateau pika. The overall shape of the cranium was narrowed in both species, and morphological components in relation to neural maturity showed negative allometry, while those responsible for muscular development showed isometric or positive allometry. The most remarkable shape variations in the plateau pika were associated with food acquisition (temporalis development), though other remarkable shape variations in the incisive and palatal foramen in the ventral view were also observed. The most important shape change in the woolly hare was demonstrated by the elongation of the nasal bones, expansion of the supra-orbital process and shape variation of the neurocranium. PMID- 25017748 TI - Characterization and expression of sweetfish (Pleco glossus altivelis) cathepsin D. AB - Cathepsin D (CTSD) is a lysosomal acidic endoproteinase that plays an important role in immune response. In this study, we obtained sweetfish (Plecoglossus altivelis) CTSD (PaCTSD) via de-novo transcriptome sequencing of sweetfish macrophages. The full length cDNA sequence of PaCTSD was 1 955 bp encoding a propeptide of 397 amino acids. The deduced protein had a calculated molecular weight of 43.17 * 103. Multiple alignment with other known CTSD amino acid sequences revealed amino acid conservation through the teleosts. Phylogenetic tree analysis showed that PaCTSD grouped tightly with other fish CTSD, and was close to that of Atlantic salmon and rainbow trout. Subsequently, PaCTSD was prokaryotically expressed and refolded by the urea gradient method on a nickel nitrilotriacetic acid column. Enzyme activity analysis showed that PaCTSD exhibited pH-dependent proteolytic activity. Quantitative real-time PCR showed that PaCTSD mRNA was expressed in all detected tissues in healthy sweetfish. The highest expression was observed in the spleen and white blood cells, followed by liver, head-kidney, kidney, intestine, gill, and muscle. After Listonella anguillarum infection, PaCTSD transcripts were up-regulated significantly in liver, spleen, white blood cells, and head-kidney of sweetfish. In summary, PaCTSD has proteolytic activity and is closely involved in the immune response of sweetfish. PMID- 25017749 TI - Molecular cloning and function analysis of insulin-like growth factor-binding protein 1a in blunt snout bream (Megalobrama amblycephala). AB - Insulin-like growth factor-binding protein 1 (IGFBP-1), a hypoxia-induced protein, is a member of the IGFBP family that regulates vertebrate growth and development. In this study, full-length IGFBP-1a cDNA was cloned from a hypoxia sensitive Cyprinidae fish species, the blunt snout bream (Megalobrama amblycephala). IGFBP-1a was expressed in various organs of adult blunt snout bream, including strongly in the liver and weakly in the gonads. Under hypoxia, IGFBP-1a mRNA levels increased sharply in the skin, liver, kidney, spleen, intestine and heart tissues of juvenile blunt snout bream, but recovered to normal levels after 24-hour exposure to normal dissolved oxygen. In blunt snout bream embryos, IGFBP-1a mRNA was expressed at very low levels at both four and eight hours post-fertilization, and strongly at later stages. Embryonic growth and development rates decreased significantly in embryos injected with IGFBP-1a mRNA. The average body length of IGFBP-1a-overexpressed embryos was 82.4% of that of the control group, and somite numbers decreased to 85.2%. These findings suggest that hypoxia-induced IGFBP-1a may inhibit growth in this species under hypoxic conditions. PMID- 25017750 TI - cDNA clone and expression analysis of alpha-Tropomyosin during Japanese flounder (Paralichthys olivaceus) metamorphosis. AB - Tropomyosin (TM) plays a critical role in skeletal and cardiac muscle development and function. To assess the functional significance of alpha-TM in Japanese flounder (Paralichthys olivaceus) development and metamorphosis, cDNA from Japanese flounder was cloned and alpha-TM mRNA measured during development and metamorphosis. The full-length cDNA is 1 191 bp, including a 5'-untranslated region of 114 bp, a 3'-UTR of 222 bp, and an open reading frame of 855 bp encoding a polypeptide of 284 amino acids. Real-time quantitative PCR revealed that alpha-TM mRNA is initially expressed in unfertilized ovum, indicating the alpha-TM gene is maternal. Relatively low mRNA levels were observed in different embryonic stages. A higher level of alpha-TM mRNA was detected 3 days post hatching (dph), while the highest level was measured at 29 dph (metamorphic climax) after which it declined towards the end of metamorphosis. The expression of alpha-TM mRNA was up-regulated in thyroid hormone-treated larvae at 36 dph, but there was no marked difference at other stages when compared to control animals. After thiourea treatment, the expression of alpha-TM mRNA declined slightly. These data provide basic information that can be utilized in further studies into the role of alpha-TM in P. olivaceus development and metamorphosis. PMID- 25017751 TI - Molecular identification of Taenia mustelae cysts in subterranean rodent plateau zokors (Eospalax baileyi). AB - Cestode larvae spend one phase of their two-phase life cycle in the viscera of rodents, but cases of cestodes infecting subterranean rodents have only been rarely observed. To experimentally gain some insight into this phenomenon, we captured approximately 300 plateau zokors (Eospalax baileyi), a typical subterranean rodent inhabiting the Qinghai-Tibet Plateau, and examined their livers for the presence of cysts. Totally, we collected five cysts, and using a mitochondrial gene (cox1) and two nuclear genes (pepck and pold) as genetic markers, we were able to analyze the taxonomy of the cysts. Both the maximum likelihood and Bayesian methods showed that the cysts share a monophyly with Taenia mustelae, while Kimura 2-parameter distances and number of different sites between our sequences and T. mustelae were far less than those found between the examined sequences and other Taeniidae species. These results, alongside supporting paraffin section histology, imply that the cysts found in plateau zokors can be regarded as larvae of T. mustelae, illustrating that zokors are a newly discovered intermediate host record of this parasite. PMID- 25017752 TI - AVP and Glu systems interact to regulate levels of anxiety in BALB/cJ mice. AB - Whilethe roles of glutamic acid (Glu), arginine vasopressin (AVP) and their respective receptors in anxiety have been thoroughly investigated, the effects of interactions among Glu, N-methyl-D-aspartic acid (NMDA) receptor, AVP and a-amino 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor on anxiety are still unclear. In the present study, the agonist and antagonist of the NMDA receptor and AMPA receptor, as well as the antagonist of AVP V1 receptor (V1aR) were introduced into BALB/cJ mice by intracerebroventricular microinjection, and the anxiety-like behaviors of the mice were evaluated by open field and elevated plus maze tests. Compared with C57BL/6 mice, BALB/cJ mice displayed higher levels of anxiety-like behavior. Significant anxiolytic effects were found in the NMDA receptor antagonist (MK-801) and the AMPA receptor or V1aR antagonist (SSRI49415), as well as combinations of AVP/MK-801 and SSRI49415/DNQX. These results indicated that anxiety-like behaviors expressed in BALB/CJ mice may be due to a coordination disorder among glutamate, NMDA receptor, AMPA receptor, AVP and V1aR, resulting in the up-regulation of the NMDA receptor and V1aR and down regulation of the AMPA receptor. However, because the AMPA receptor can execute its anxiolytic function by suppressing AVP and V1aR, we cannot exclude the possibility of the NMDA receptor being activated by AVP acting on V1aR. PMID- 25017753 TI - Differentiations of 5-HT and GAS cells in the digestive canals of Rana chensinensis tadpoles. AB - In the current study, 5-nydroxytryptamine (5-HT) and gastrin (GAS) cells in the digestive canals of Rana chensinensis tadpoles at different developmental stages were investigated by immunohistochemistry. Results showed that the 5-HT cells were only detected in the duodenum before metamorphosis began, and were extensively distributed in the stomach, duodenum, small intestine, and rectum thereafter, with the highest counts found in the duodenum and rectum when metamorphosis was completed. The GAS cells were only distributed in the stomach and duodenum, and only rarely detected in the duodenum before metamorphosis began, but increased in the stomach during metamorphosis and showed zonal distribution in the gastric mucosa when metamorphosis was completed. Metamorphosis is a critical period for amphibians, during which structural and functional physiological adaptations are required to transition from aquatic to terrestrial environments. During metamorphosis, the differentiations of 5-HT cells in the gastrointestinal canals of tadpoles could facilitate mucus secretion regulation, improve digestive canal lubrication, and help water-shortage food digestion in terrestrial environments. Conversely, GAS cell differentiations during metamorphosis might contribute to the digestive and absorptive function transition from herbivore to omnivore. PMID- 25017754 TI - Effects of light intensity on activity in four sympatric anuran tadpoles. AB - Though light conditions are known to affect the development and anti-predation strategies of several aquatic species, relatively little is known about how different species react to light, or how light can affect these species during different points in their life-cycle. In this study, we used four sympatric anuran tadpoles (Bufo gargarizans, B. melanostictus, Pelophylax nigromaculatus and Microhyla fissipes) as animal system to examine species-specific activities of the underdoing different light intensity treatments, so as to better understand how they respond to light. We exposed four different species of tadpoles to 1660 and 14 lux light intensity treatments and then measured several parameters including development stage, body length and tail length, and as well as their basic activities. The results of this observation and analysis showed that the activities of tadpoles were significantly greater in B. gargarizans and B. melanostictus than in P. nigromaculatus and M. fissipes; and were also significantly greater during times of high light intensity as compared to during low light intensity. Moreover, the observed relationship between species and light intensity was significant. The activities of B. gargarizans and B. melanostictus tadpoles were greater in high light, while the activity of P. nigromaculatus tadpoles was greater in low light intensity, while M. fissipes tadpoles showed no differences in either low or high intensity light. Furthermore, the activities of B. gargarizans, B. melanostictus and M. fissipes tadpoles in terms of developmental stage, body size or tail length did not seem to differ with light intensity, but during early larval developmental period of P. nigromaculatus, the activity of tadpoles was negatively correlated with development stage, but irrelevant to either body size or tail length in different light intensities. These results lead us to conclude the observed activities of the four sympatric anuran tadpoles are closely correlated with their specific anti-predation strategies. PMID- 25017755 TI - Population survey and conservation assessment of the globally threatened cheer pheasant (Catreus wallichi) in Jhelum Valley, Azad Kashmir, Pakistan. AB - The cheer pheasant Catreus wallichi is a globally threatened species that inhabits the western Himalayas. Though it is well established that the species is threatened and its numbers declining, updated definitive estimates are lacking, so in 2011, we conducted a survey to assess the density, population size, and threats to the species in Jhelum valley, Azad Kashmir, which holds the largest known population of cheer pheasants in Pakistan. We conducted dawn call count surveys at 17 points clustered in three survey zones of the valley, 11 of which had earlier been used for a 2002-2003 survey of the birds. Over the course of our survey, 113 birds were recorded. Mean density of cheer pheasant in the valley was estimated at 11.8 +/- 6.47 pairs per km2, with significant differences in terms of both counts and estimated density of cheer were significantly different across the three survey zones, with the highest in the Chinari region and the lowest, that is the area with no recorded sightings of the pheasants, in Gari Doppata. The total breeding population of cheer pheasants is estimated to be some 2 490 pairs, though this does not consider the actual area of occupancy in the study area. On the whole, more cheer pheasants were recorded in this survey than from the same points in 2002-2003, indicating some success in population growth. Unfortunately, increasing human settlement, fires, livestock grazing, hunting, and the collection of non-timber forest products continue to threaten the population of cheer in the Jhelum valley. To mitigate these potential impacts, some degree of site protection should be required for the conservation of cheer pheasants in Pakistan, and more effective monitoring of the species is clearly needed. PMID- 25017756 TI - Ecological predictors of extinction risks of endemic mammals of China. AB - In this brief report, we analyzed ecological correlates of risk of extinction for mammals endemic to China using phylogenetic eigenvector methods to control for the effect of phylogenetic inertia. Extinction risks were based on the International Union for Conservation of Nature (IUCN) Red List and ecological explanatory attributes that include range size and climatic variables. When the effect of phylogenetic inertia were controlled, climate became the best predictor for quantifying and evaluating extinction risks of endemic mammals in China, accounting for 13% of the total variation. Range size seems to play a trivial role, explaining ~1% of total variation; however, when non-phylogenetic variation partitioning analysis was done, the role of range size then explained 7.4% of total variation. Consequently, phylogenetic inertia plays a substantial role in increasing the explanatory power of range size on the extinction risks of mammals endemic to China. Limitations of the present study are discussed, with a focus on under-represented sampling of endemic mammalian species. PMID- 25017757 TI - New occurrence of Sinovipera sichuanensis in Guizhou. AB - Three Asian green pit vipers were collected in August 2013 during a field trip in Fanjin Mt. National Conservation Area, Guizhou. These specimens were identified as Sinovipera sichuanensis, based on subsequent examination and comparison. This is a new record of the genus Sinovipera and S. sichuanensis in Guizhou, and the first time that male specimens have been collected in the field. PMID- 25017761 TI - Outcomes of hematopoietic cell transplantation in adult patients with acquired aplastic anemia using intermediate-dose alemtuzumab-based conditioning. AB - Graft-versus-host disease (GVHD) has no therapeutic benefit after hematopoietic cell transplantation (HCT) for patients with acquired aplastic anemia (AA), and its prevention is highly desirable. We designed a conditioning regimen using an intermediate dose of alemtuzumab (50 to 60 mg) and describe our institutional experience of 41 patients who underwent HCT for AA. The median age at HCT was 37 years (range, 17 to 59). The conditioning regimen was high-dose cyclophosphamide (n = 9) or fludarabine based (n = 32). Additional GVHD prophylaxis was with cyclosporine. With a median follow-up of 3.6 years, overall survival at 3 years was 85%. Survival in patients <40 years and >=40 years was 96% and 67%, respectively (P = .04). Graft failure occurred in 4 (10%) patients; 2 primary and 2 secondary. The cumulative incidences of acute (grades 1 to 2) and chronic GVHD were 27% and 15%, respectively. No patients developed grade 3 to 4 acute GVHD or severe chronic GVHD. The following viral complications were frequent: cytomegalovirus reactivation (79%), herpes simplex (18%), varicella zoster (25%), and BK virus hemorrhagic cystitis (8%). The majority of patients had no significant long-term health issues. This intermediate-dose alemtuzumab-based conditioning regimen results in excellent survival with a favorable impact on GVHD and long-term health outcomes, but close monitoring for viral complications is important. PMID- 25017762 TI - Impact of beta-globin mutations on outcome of matched related donor hematopoietic stem cell transplantation for patients with beta-thalassemia major. AB - The clinical outcome of hematopoietic stem cell transplantation (HSCT) for patients with beta-thalassemia major (beta-TM) can be affected by several factors. We investigated the influence of beta-globin gene mutation in patients with beta-TM on the clinical outcome of HSCT and conducted a prospective study of consecutive beta-TM patients who underwent allogeneic HSCT at our center. Among 87 included patients, 62 (71%) had homozygous and 25 (29%) had compound heterozygous beta-globin gene mutations. Intervening sequence II-1 appeared to be the most common mutation, with an occurrence rate of 33% in beta-globin alleles. With a median follow-up of 12 months, the thalassemia-free survival and overall survival probabilities were 83% (standard error, 4%) and 90% (standard error, 3%), respectively. Overall survival was not found to be associated with the beta globin gene mutation status, but thalassemia-free survival was significantly improved in patients with homozygous mutations compared with patients with compound heterozygous mutations in univariate (91.2% versus 64.0%, P = .009) and multivariable (hazard ratio, 3.83; P = .014) analyses. This is the first report on the impact of beta-globin mutation status on the outcome of beta-TM after allogeneic HSCT and helps to better illustrate the course and prognosis of beta TM after transplantation. PMID- 25017763 TI - Central nervous system relapse in adults with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. AB - Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse. PMID- 25017764 TI - Prognostic biomarkers for acute graft-versus-host disease risk after cyclophosphamide-fludarabine nonmyeloablative allotransplantation. AB - Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3alpha [REG3alpha], elafin, tumor necrosis factor receptor 1 [TNFR1], and soluble IL-2 receptor-alpha [sIL2Ralpha]) were measured at specific time points after cyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft versus-host disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21, and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset at day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-statistic = .72, P = .03), day +14 (c-statistic = .74, P = .02), and day +21 (c-statistic = .75, P = .02); elevated plasma REG3alpha concentrations at day +14 (c-statistic = .73, P = .03), day +21 (c-statistic = .76, P = .01), and day +30 (c-statistic = .73, P = .03); and elevated elafin at day +14 (c-statistic = .71, P = .04). Plasma concentrations of TNFR1 and sIL2Ralpha were not associated with aGVHD risk at any of the time points studied. This study identified ST2, REG3alpha, and elafin as prognostic biomarkers to evaluate risk of aGVHD after cyclophosphamide/fludarabine-based NMAT. These results need to be confirmed in an independent validation cohort. PMID- 25017765 TI - A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P < .001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated. PMID- 25017766 TI - Pattern of microRNA expression associated with different stages of alcoholic liver disease in rat models. AB - Emerging evidence has suggested that aberrant expression of micro (mi)RNAs contributes to the development of alcoholic liver injury (ALD). However, miRNA profiles distinguishing different stages of ALD have not yet been reported. The present study was designed to investigate the unique miRNA expression patterns at different stages of ALD in a rat model and analyze the gene functions and pathways of dysregulated miRNA-targeted genes. Using microarray and stem-loop quantitative polymerase chain reaction analyses, 16 miRNAs were identified as upregulated and 13 were identified as downregulated in an alcoholic steatohepatitis (ASH) group compared with the control group, while five miRNAs were identified to be upregulated and eight were identified to be downregulated in the alcoholic fatty liver (AFL) group as compared with the control group. Following further confirmation by Significance Analysis of Microarray and prediction by Prediction Analysis of Microarray, 8 and 12 types of miRNA were screened as molecular signatures in distinguishing AFL and ASH, respectively, from normal rat liver. In addition, several miRNA-target pairs were predicted by computer-aided algorithms (Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using the Database for Annotation, Visualization and Integrated Discovery platform) and these genes may be involved in cancer signaling pathways, the Wnt signaling pathway and other signaling pathways. These results may provide novel miRNA targets for diagnosis and therapeutic intervention at different stages of ALD. PMID- 25017767 TI - WITHDRAWN: Exploratory study comparing dysautonomia between asthmatic and non asthmatic elite swimmers. AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.05.004. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25017768 TI - Desirable and undesirable future thoughts call for different scene construction processes. AB - Despite the growing interest in the ability of foreseeing (episodic future thinking), it is still unclear how healthy people construct possible future scenarios. We suggest that different future thoughts require different processes of scene construction. Thirty-five participants were asked to imagine desirable and less desirable future events. Imagining desirable events increased the ease of scene construction, the frequency of life scripts, the number of internal details, and the clarity of sensorial and spatial temporal information. The initial description of general personal knowledge lasted longer in undesirable than in desirable anticipations. Finally, participants were more prone to explicitly indicate autobiographical memory as the main source of their simulations of undesirable episodes, whereas they equally related the simulations of desirable events to autobiographical events or semantic knowledge. These findings show that desirable and undesirable scenarios call for different mechanisms of scene construction. The present study emphasizes that future thinking cannot be considered as a monolithic entity. PMID- 25017769 TI - Ruptured and unruptured mycotic superior mesenteric artery aneurysms. AB - Aneurysms of the superior mesenteric artery (SMA) and branches thereof are uncommon but have a high rate of rupture and mortality relative to other visceral artery aneurysms. Historically, the predominant etiology has been infectious; with a renewed rise in intravenous drug abuse rates in the last decade, we hypothesize a resurgence in septic embolic complications may occur in the coming years. Here, we describe the presentation and management of 2 cases of intravenous drug users presenting with infectious endocarditis and SMA main trunk and branch aneurysms, one of which was ruptured. In addition, we review the literature on these rare clinical entities. PMID- 25017771 TI - Abdominal aortic endograft collapse due to false lumen radial force of an acute type B aortic dissection. AB - We report a case of abdominal endograft proximal collapse due to acute type B aortic dissection in a patient previously treated with endovascular repair (EVAR) for an infrarenal abdominal aortic aneurysm. Patient underwent axillobifemoral bypass grafting, in emergency. The postoperative computed tomography scan showed reexpansion of the occluded endograft. The patient died after 2 days with evidence of progression of the thrombosis of the false lumen and with involvement of renal, visceral, and medullar artery. EVAR collapse associated to acute type B aortic dissection is a challenging condition, which requires aggressive approach. PMID- 25017770 TI - C-reactive protein predicts postoperative delirium following vascular surgery. AB - BACKGROUND: The etiology of postoperative delirium (POD) following vascular surgery is generally unknown. The incidence, however, can be as high as 35%. A possible neuroinflammatory basis for delirium is likely and C-reactive protein (CRP) as a marker for inflammation can possibly play a predictive role. METHODS: Between March 2010 and September 2012, 277 consecutive elective vascular surgery patients were prospectively evaluated for the diagnosis of POD. Various potential risk factors, including postoperative CRP values, were collected. RESULTS: The mean age of the patients was 69 +/- 11 years (range 21-92). The mean hospital length of stay was 6 +/- 4 days (range 1-33). Sixteen patients (6%) developed POD during hospital stay. Univariate analysis revealed multiple comorbidities (P = 0.001), postoperative elevated CRP levels (P = 0.001), intensive care unit admittance (P = 0.01), and open aortic surgery or amputation procedures (P = 0.0001) to be significantly related to the diagnosis POD. Multivariate logistic regression analysis confirmed the relationship between an elevated CRP value and POD (odds ratio [OR] 1.01, 95% confidence interval 1.00-1.03, P = 0.04). The sensitivity analyses yielded essentially similar results. Based on OR, it can be calculated that the risk of POD is increased by approximately 35% if the CRP concentration is 50 mg/L, and by approximately 90% if the CRP concentration is 100 mg/L (compared with a CRP concentration of 5 mg/L). Thirty-one percent (5/16) of patients with POD needed a long-stay care facility after discharge (P = 0.0001). CONCLUSIONS: In this study, CRP can be used as a marker for an increased risk of POD after vascular surgery. In addition, it was found that POD was associated with a 10-fold increase in the need of long-stay care after discharge. PMID- 25017772 TI - Wandering stent within the pulmonary circulation. AB - To present a case of a wandering stent within the pulmonary circulation that was managed conservatively with the "wait-and-see" strategy. Accidental dislodgement of a left brachiocephalic vein stent into the left lower lobe pulmonary artery occurred in an 83-year-old patient suffering from end-stage renal disease during placement of a left jugular vein catheter. The following day, a second X-ray revealed migration of the stent from the left to the right lower lobe pulmonary artery. Our patient was managed conservatively with low-molecular-weight heparin and was discharged on clopidogrel. The patient remained asymptomatic with regard to the migrated stent for four and a half years and died of old age. This is the first case of a wandering stent within the pulmonary circulation reported in the literature, supporting the "wait-and-see" policy in the management of such patients. PMID- 25017773 TI - Hemobilia associated with a giant thrombosed aneurysm of the hepatic artery requiring hepatectomy. AB - Hemobilia is an unusual and potentially catastrophic cause of gastrointestinal bleeding. Although hepatic artery aneurysm is a cause of hemobilia, nontraumatic cases are infrequently reported. Herein, we describe the case of a giant hepatic artery aneurysm requiring hepatectomy because of repeated hemobilia in a patient with Marfan syndrome. A 53-year-old man presented to our hospital with sudden epigastric pain and jaundice. Abdominal computed tomography showed a giant hepatic arterial aneurysm in the porta hepatis, and emergency endoscopic retrograde cholangiography revealed hemobilia. Assuming that the aneurysm caused the hemobilia, we performed an abdominal angiogram for treatment. The study revealed a thrombosed aneurysm along with tortuous abnormal vessels in the periphery of the left hepatic artery, which appeared to surround the aneurysm. Therefore, we embolized the left hepatic artery, and immediate hemostasis was achieved. Rebleeding occurred 3 times thereafter, and each time, transarterial embolization was performed, resulting in prompt but only temporary hemostasis. Then, emergency left hemihepatectomy and resection of the aneurysm were performed. Pathologic examination of the resected specimen revealed that the aneurysm was completely thrombosed and organized; however, abnormal arterioles proliferated between the aneurysmal wall and the bile duct. The unique feature of this case was that the abnormal arterioles induced by the organized hepatic artery aneurysm, not the aneurysm itself, caused the hemobilia. PMID- 25017774 TI - Successful endovascular correction of an endograft connected with the false lumen of a type B aortic dissection. AB - Thoracic endografting is widely used in the treatment of complicated acute type B aortic dissections to redirect the entire aortic flow toward the true lumen by covering the proximal entry tear. This procedure is challenging because endovascular navigation, maintaining position in the true lumen, can be difficult as there are frequently numerous reentry tears. There is obvious potential for complications such as malpositioning of the distal part of the endograft within the false lumen. This error can promote true lumen collapse and/or aortic rupture. This report details the endovascular correction of such a complication. PMID- 25017775 TI - Endovascular treatment of ruptured abdominal aortic aneurysm with aortocaval fistula based on aortic and inferior vena cava stent-graft placement. AB - A ruptured abdominal aortic aneurysm (RAAA), complicated by an aortocaval fistula (ACF), is usually associated with high morbidity and mortality during open operative repair. We report a case of endovascular treatment of an RAAA with ACF. After accessing both common femoral arteries, a bifurcated aortic stent graft was placed. Subsequently, we accessed the fistula from the right femoral vein and a cava vein angiography showed a persistent massive flow from the cava to the excluded aneurysm sac. We proceeded by covering the fistula with an Excluder aortic stent-graft cuff to prevent pressurization of the aneurysm sac and secondary endoleaks. This procedure is feasible and may reduce the chances of posterior endoleaks. PMID- 25017777 TI - Chronic rupture of abdominal aortic aneurysm with vertebral erosion: an uncommon but important cause of back pain. AB - Chronic contained rupture of the aorta is a rare condition that may present with varied patient symptomatology. We present a case of contained rupture of an abdominal aortic aneurysm causing vertebral erosion in an elderly male patient who had chronic backache and presented to the emergency services with a recently developed throbbing epigastric mass. Early use of computed tomography enabled prompt diagnosis and the condition was managed by endovascular stenting. The clinical and imaging findings of this potentially fatal condition are described, awareness of which is important to the physicians, orthopedicians, surgeons, and radiologists. PMID- 25017778 TI - Radiotherapy for intraarticular venous malformations of the knee. AB - Intraarticular venous malformation (IAVM) of the knee is a rare vascular disease that manifests with pain, swelling, and hemarthrosis. A young man with left knee pain and swelling was admitted to our institution for the treatment of the IAVM of the left knee which was diagnosed by a local orthopedic doctor via arthroscopy. A total dose of 40 Gy of radiotherapy was delivered with a daily dose of 2.0 Gy using 6 MV X-ray beams and a linear accelerator through anteroposterior portals. Fifteen months after radiotherapy, follow-up examination using radiologic imaging showed distinct shrinkage of the venous malformations. Swelling and pain of the left knee had decreased, and range of motion of the left knee was maintained. This report describes a case involving a 38-year-old man with IAVM of the left knee in whom favorable outcomes were obtained in response to radiotherapy. PMID- 25017776 TI - Mycotic abdominal aortic aneurysm caused by Campylobacter fetus: a case report and literature review. AB - Campylobacter spp. usually cause gastrointestinal infections, but among them, Campylobacter fetus is a well-known organism causing mycotic abdominal aortic aneurysm (MAAA), which requires proper surgical intervention and antibiotic therapy. We report a 65-year-old man who was successfully treated by an in situ operation using a rifampicin (RFP)-bonded J-Graft for C. fetus-induced MAAA. We performed a review of the English literature on MAAA caused by C. fetus and summarized the results of the cases (28 cases). All but 2 of the patients (92.9%) were men. Blood culture and arterial wall culture were positive in 63% and 73.1% of the cases, respectively. Aneurysm rupture was seen in half of the patients, and approximately half of those patients died. Among the 18 patients who underwent in situ graft replacement, only 1 patient (5.6%) died after surgery. Antibiotic therapy was performed for more than 1 month in most cases, and overall mortality rate was 25.9% (7 of 27 cases, 3 deaths before the operation and 4 deaths after surgery). Although extra-anatomic bypass has been conventionally performed after complete resection of an MAAA, the utility of in situ surgery has generally been recognized. Our review suggests that the in situ operation can be a choice also in cases of C. fetus-associated MAAA. Furthermore, our case suggested the clinical utility of a newly manufactured prosthetic graft, J-Graft, for such surgical treatment. PMID- 25017779 TI - An endovascular option is the final treatment for a giant arteriovenous malformation. AB - We report the case of a 58-year-old man presented with bleeding ulcer of the left arm caused by a high-flow type-C arteriovenous malformation (AVM), feed by branches from both the subclavian arteries. He had been previously treated with AVM sclerotherapy, embolization, humeral artery endografting, and open surgery. We urgently performed coil embolization of the left vertebral artery, and we covered the huge subclavian artery by a thoracic endograft. Then, we embolized the right tyrocervical trunk. The result was an immediate interruption of bleeding. At 12 months, the patient had no neurologic complications, and the upper limb continued to decompress. PMID- 25017780 TI - Bier spots are an under-recognized cutaneous manifestation of lower extremity lymphedema: a case series and brief review of the literature. AB - Bier spots represent a benign vascular mottling characterized by multiple irregular white macules along the extensor surfaces of the arms and legs. They have been reported in a variety of diverse conditions with no consistent disease association. We have identified a novel association between these physiologic anemic macules and lower extremity lymphedema. Eleven patients between 23 and 70 years of age (5 male and 6 female) were diagnosed with Bier spots as evidenced by reversible white macules ranging from 3 to 8 mm in diameter on the extensor portions of the feet, ankles, and calves. The thighs were affected as well in 2 morbidly obese subjects. We suspect that these lesions are not uncommon in lymphedema but are simply under-recognized. PMID- 25017781 TI - Venous thromboembolism secondary to penile prosthesis. AB - We report the case of a 65-year-old male who presented with an extensive iliofemoral venous thrombosis, which computed tomography demonstrated was secondary to compression of the right common and external iliac veins by a 5-cm diameter penile prosthesis reservoir. A similar occurrence has only been reported a handful of times previously, and only in urological journals, never in vascular literature. It is a potentially serious complication of penile prosthesis surgery, the risk of which can be minimized by ready awareness of this postoperative event. PMID- 25017782 TI - Endovascular repair of an asymptomatic aortic pseudoaneurysm after penetrating injury. AB - Penetrating injuries to the aorta usually result in immediate life-threatening hemorrhage. Because these lesions are typically either fatal or identified and controlled surgically, chronic pseudoaneurysms after penetrating aortic trauma are rare. Most of these patients present with rupture or local complications, and management before the endovascular era has historically been open repair. As such, there are limited data to guide the modern management of an asymptomatic, posttraumatic aortic pseudoaneurysm. Here, we describe a 54-year-old man who was diagnosed with an incidental, supraceliac aortic pseudoaneurysm 14 years after an abdominal stab wound. He underwent successful and uncomplicated endovascular repair. PMID- 25017783 TI - Concomitant aortic leiomyosarcoma and takayasu arteritis in a 55-year-old male patient. AB - Takayasu arteritis is a form of large vessel granulomatous vasculitis affecting often young or middle-aged women, especially of Asian descent. It mainly affects the aorta and its branches. Primary malignancies, such as leiomyosarcoma of the aorta are extremely rare. This report discusses the exceptional and concomitant association of Takayasu arteritis and aortic leiomyosarcoma in a 55-year-old male. The patient suffered from systemic signs and symptoms related to arteritis together with claudication of left upper limb due to left artery subclavian stenosis. After instrumental evaluation, an infiltrating neoplasm at the level of abdominal aortic wall was detected and the patient underwent en bloc excision of the mass together with abdominal aorta and subsequent aortoaortic by pass reconstruction. Histologic findings showed an arterial leiomyosarcoma combined with elements of arterial inflammation. Patients completed therapeutic scheme with chemotherapy (doxorubicin and isosfamide) and radiotherapy for the cancer condition, as well as medical treatment (prednisone and adalimumab) for Takayasu arteritis. After 12 months, the patient showed no cancer recurrence and complete normalization of inflammatory indexes and symptoms of Takayasu arteritis. PMID- 25017784 TI - Insulin receptor substrate-1 and Golgi phosphoprotein 3 are downstream targets of miR-126 in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is a common histologic subtype in China. It has been suggested that abnormal expression of microRNAs (miRNAs) is associated with carcinogenesis. We investigated miR-126 expression and its potential targets in ESCC. The expression of miR-126 was detected in cancerous and paired paracancer tissues from 102 patients with ESCC. Target analysis of miR 126 was predicted using online tools. The effect of miR-126 expression on target proteins was assessed using miR-126 mimics or miR-126 inhibitors in ESCC cell lines. In addition, the impact of miR-126 on cell proliferation, apoptosis, migration and invasion was detected in ESCC cell lines. The expression of miR-126 was significantly lower in ESCC tissues, which was associated with tumor differentiation, lymph node metastasis, tumor in-depth and TNM stage. Insulin receptor substrate-1 (IRS-1) and Golgi phosphoprotein 3 (GOLPH3) were overexpressed in ESCC. Overexpression of IRS-1 was associated with cell differentiation, whereas GOLPH3 was related to lymph node metastasis, tumor invasion in-depth and TNM stage in ESCC patients. miR-126 mimics downregulated the expression of IRS-1 and GOLPH3 protein and suppressed the proliferation, migration and invasion of ESCC cells, whereas miR-126 inhibitors led to the opposite results. miR-126 suppressed the proliferation, migration and invasion of ESCC cells, and acted as a tumor suppressor in the carcinogenesis of ESCC. IRS-1 and GOLPH3 are downstream targets of miR-126 at the post-transcriptional level in ESCC. PMID- 25017785 TI - Novel method for conscious airway resistance and ventilation estimation in neonatal rodents using plethysmography and a mechanical lung. AB - In unrestrained whole body plethysmography, tidal volume is commonly determined using the barometric method, which assumes that temperature and humidity changes (the 'barometric component') are solely responsible for breathing-related chamber pressure fluctuations. However, in small animals chamber pressure is also influenced by a 'mechanical component' dependent on airway resistance and airflow. We devised a novel 'mechanical lung' capable of simulating neonatal mouse breathing in the absence of temperature or humidity changes. Using this device, we confirm that the chamber pressure fluctuations produced by breathing of neonatal mice are dominated by the mechanical component, precluding direct quantitative assessment of tidal volume. Recognizing the importance of airway resistance to the chamber pressure signal and the ability of our device to simulate neonatal breathing at different frequencies and tidal volumes, we invented a novel in vivo, non-invasive method for conscious airway resistance and ventilation estimation (CARVE) in neonatal rodents. This technique will allow evaluation of developmental, pathological and pharmaceutical effects on airway resistance. PMID- 25017786 TI - Use of the nine-step inflation/deflation test and resting middle-ear pressure range as predictors of middle-ear barotrauma in aircrew members. AB - OBJECTIVE: To explore the role of the nine-step inflation/deflation tympanometric test and resting middle-ear pressure range as predictors of barotrauma in aircrew members. METHODS: A prospective, non-randomised study was conducted on 100 aircrew members. Resting middle-ear pressure was measured and the nine-step inflation/deflation test performed on all subjects before flights. Subjects were allocated to two groups according to resting middle-ear pressure range (group A, within the range of +26 to +100 and -26 to -100 mmH2O; group B, -25 to +25 mmH2O). All aircrew members were assessed after flights regarding the presence and the grade of barotrauma. RESULTS: In both groups, the sensitivity and specificity values of the entire post-inflation/deflation test were close to those of the post-deflation part of the test. The post-deflation test had a higher negative predictive value than the post-inflation test. Ears with resting middle-ear pressure lower than -55 mmH2O experienced barotrauma, regardless of good or poor post-inflation or post-deflation test results. CONCLUSION: In an aircrew member, a resting middle-ear pressure within the range of -55 and +50 mmH2O, together with good post-deflation test results, are considered reliable predictors for fitness to fly. PMID- 25017787 TI - Spinal cord ischemia after aortic surgery. AB - This article discusses the etiology of spinal cord ischemia (SCI) mechanisms that may lead to paraplegia during open and endovascular repair from an anatomical and physiological perspective as well as the role of various protective measures used in prevention of this dreadful complication of aortic surgery. There are many adjuncts that must be considered to reduce the risk of spinal cord injury, such as revascularisation of intercostal arteries, maintenance of high mean blood pressure, spinal cord drainage and a few new promising models like NIRS and MISACE which usefulness is yet to be determined. These measures and techniques as well as possible etiology mechanisms of SCI are discussed, highlighting the evidence available for each method, the practical ways in which they may be used, giving some new theories and explanations. PMID- 25017788 TI - Prosthesis infection: prevention and treatment. AB - Implantation of a vascular prosthesis increases surgical site infection risk by producing a microenvironment conducive to bacterial attachment and biofilm formation, which sustains bacterial colonization and protects encased organisms from host defenses and antimicrobial therapy. Many maneuvers are used in an attempt to reduce infection in arterial reconstructions, but there are no clear guidelines on the most appropriate or effective. As well, there is no good evidence to guide management. A general principle is that indication for removal of the entire infected graft is mandatory when a suture line is involved in the infectious process, an infected anastomotic aneurism and a suture-line hemorrhage is evident, or when a graft-enteric fistula is diagnosed. Conservative, non resectional management of graft infection is still a respectable solution for selected patients, as those with significant comorbidities, or those where the implanted aortic graft is in a location that precludes excision without causing a high likelihood of morbidity and/or mortality. Anyway, definitive management depends on the patient's condition and a tailored approach should be always offered. Surgical techniques favor in terms of mortality, patency and reinfection rate the in situ reconstruction. Currently, the choice of the technique used relies on center and operator's experience. This article summarizes the incidence of graft infection, analyze the predisponding factors to graft infection, and review current strategies for prevention and treatment of prosthesis and endograft infection. PMID- 25017789 TI - Phase transfer and dispersion of reduced graphene oxide nanosheets using cluster suprasurfactants. AB - Surfactant-encapsulated polyoxometalate complexes are used as cluster suprasurfactants to transfer reduced graphene oxide (RGO) nanosheets from water to low polar organic solvents, which realizes the single-layer dispersion and the cluster-functionalization of RGO in one step. PMID- 25017790 TI - Evidence of infectivity of airborne porcine epidemic diarrhea virus and detection of airborne viral RNA at long distances from infected herds. AB - Porcine epidemic diarrhea virus (PEDV) spread rapidly after being diagnosed in the USA in April 2013. In this study we assessed whether PEDV could become airborne and if so, whether the virus was infectious. Air samples were collected both from a room containing experimentally infected pigs and at various distances from the outside of swine farms experiencing acute PEDV outbreaks. Results indicated presence of infectious PEDV in the air from experimentally infected pigs and genetic material of PEDV was detected up to 10 miles downwind from naturally infected farms. Airborne transmission should be considered as a potential route for PEDV dissemination. PMID- 25017791 TI - Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity. AB - Poorly-differentiated colorectal cancers (PD-CRC) show high metastatic potential and poor prognosis. However, molecular characteristics of PD-CRC remain unknown to date, particularly in molecular targeting therapy for patients with PD-CRC. In this study, we examined the expression of EGFR, HER2 and HER3 in PD-CRC by immunohistochemical analysis of archived clinical specimens of primary tumors and investigated the sensitivity of PD-CRC cell lines to gefitinib, a tyrosine kinase inhibitor for EGFR in vitro. We found that HER3 expression of PD-CRC among members of the HER family was significantly lower than that of well to moderately differentiated CRC (WMD-CRC) and 37% of the PD cases showed a EGFR+/HER2+/HER3- expression pattern. COLM-5 cells, a PD-CRC-derived cell line, which exhibits EGFR+/HER2+/HER3- expression pattern and recapitulates the typical histology of PD-CRC in xenografted tumors, showed high gefitinib sensitivity both in vitro and in vivo, compared with WMD-CRC cell line (COLM-2). Treatment with gefitinib resulted in the upregulation of p27Kip1 expression and induction of G1 cell cycle arrest, concomitantly associated with inactivation of PI3K/Akt signaling in COLM 5 cells and marked inhibition of xenografted tumors in nude mice, but not evident in COLM-2 cells. Treatment with sodium butyrate, an HDAC inhibitor that induces differentiation, upregulated the expression of HER3 associated with enhancement of the PI3K/Akt signaling, attenuated gefitinib-mediated p27Kip1 upregulation and reduced gefitinib sensitivity in COLM-5 cells in vitro. Furthermore, enforced expression of HER3 in COLM-5 cells resulted in significant resistance to gefitinib treatment both in vitro and in vivo. These findings suggest that deficient HER3 expression plays an important role in gefitinib sensitivity and that a malignant subset of PD with EGFR+/HER2+/HER3- phenotype is a potential candidate for a target of anti-EGFR molecular therapy such as gefitinib. PMID- 25017792 TI - Noncontinuously binding loop-out primers for avoiding problematic DNA sequences in PCR and sanger sequencing. AB - We present a method in which noncontinuously binding (loop-out) primers are used to exclude regions of DNA that typically interfere with PCR amplification and/or analysis by Sanger sequencing. Several scenarios were tested using this design principle, including M13-tagged PCR primers, non-M13-tagged PCR primers, and sequencing primers. With this technique, a single oligonucleotide is designed in two segments that flank, but do not include, a short region of problematic DNA sequence. During PCR amplification or sequencing, the problematic region is looped-out from the primer binding site, where it does not interfere with the reaction. Using this method, we successfully excluded regions of up to 46 nucleotides. Loop-out primers were longer than traditional primers (27 to 40 nucleotides) and had higher melting temperatures. This method allows the use of a standardized PCR protocol throughout an assay, keeps the number of PCRs to a minimum, reduces the chance for laboratory error, and, above all, does not interrupt the clinical laboratory workflow. PMID- 25017793 TI - Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy. AB - Numerous studies have shown that the NALP3 inflammasome plays an important role in various immune and inflammatory diseases. However, whether the NALP3 inflammasome is involved in the pathogenesis of diabetic nephropathy (DN) is unclear. In our study, we confirmed that high glucose (HG) concentrations induced NALP3 inflammasome activation both in vivo and in vitro. Blocking NALP3 inflammasome activation by NALP3/ASC shRNA and caspase-1 inhibition prevented IL 1beta production and eventually attenuated podocyte and glomerular injury under HG conditions. We also found that thioredoxin (TRX)-interacting protein (TXNIP), which is a pro-oxidative stress and pro-inflammatory factor, activated NALP3 inflammasome by interacting with NALP3 in HG-exposed podocytes. Knocking down TXNIP impeded NALP3 inflammasome activation and alleviated podocyte injury caused by HG. In summary, the NALP3 inflammasome mediates podocyte and glomerular injury in DN, moreover, TXNIP participates in the formation and activation of the NALP3 inflammasome in podocytes during DN, which represents a novel mechanism of podocyte and glomerular injury under diabetic conditions. PMID- 25017794 TI - [Autologous stem cell transplantation for autoimmune diseases: recommendations from the SFGM-TC]. AB - Autologous hematopoietic stem cell transplantation is a valid alternative to immunosuppressive treatment in patients with auto-immune disease; however, the role of this approach remains subject to debate. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. In this article we give an overview regarding the indications of autologous stem cell transplantation in auto-immune diseases as well as recommendations regarding post-transplant follow-up of patients. PMID- 25017795 TI - High bacterial loads of Ureaplasma may be associated with non-specific cervicitis. AB - BACKGROUND: Ureaplasma parvum and Ureaplasma urealyticum are commonly found in the cervix of women with non-chlamydial and non-gonococcal cervicitis or non specific cervicitis (NSC). However their contribution to the aetiology of NSC is controversial. METHODS: U. parvum and U. urealyticum were identified and quantified in cervical swabs collected from 155 women with NSC and 312 controls without NSC, using real-time PCR. The relative bacterial quantification was then calculated using the Ureaplasma copy number divided by the number of host cells; this is important for the correction of bias linked to the number of cells harvested in different swabs. RESULTS: Ureaplasma was detected in 58.7% (91/155) of NSC patients: U. parvum in 30.3%, U. urealyticum in 16.1%, and mixed infection in 12.3%. It was also detected in 54.5% (170/312) of controls: U. parvum in 33.0%, U. urealyticum in 11.5%, and mixed infection in 9.9%. There were no significant differences for U. parvum, U. urealyticum, or mixed infection between the 2 groups (p > 0.05). However, both biovars were present at higher concentrations in NSC patients than in controls (p < 0.05). Using >10 copies/1000 cells as a reference, the positive rate of U. parvum in NSC patients was 16.1%, significantly higher than that in controls at 5.1% (relative risk 3.145, p < 0.05); positive rates of U. urealyticum in NSC patients and controls were 28.4% and 8.7%, respectively, with a statistically significant difference (relative risk 3.131, p < 0.05). CONCLUSIONS: Ureaplasma can adhere to host cells, colonize, internalize, and subsequently produce pathological lesions. A high density of Ureaplasma in the cervix may be associated with the aetiology of NSC. PMID- 25017796 TI - Risk factors for infection and predictors of mortality among patients with KPC producing Klebsiella pneumoniae bloodstream infections in the intensive care unit. AB - BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections in intensive care units (ICUs) are associated with increased mortality. We aimed to determine risk factors for infection and predictors of 30-day mortality in ICU patients with KPC-Kp bloodstream infections (BSI). METHODS: During a 26-month period, patients (n = 273) who stayed more than 6 days in the ICU of the University Hospital of Patras, Greece, were divided into 2 groups, those who developed KPC-Kp BSI and those who did not. K. pneumoniae was identified by Vitek 2 technology. Antibiotic susceptibility testing was performed by agar disk diffusion method. Minimum inhibitory concentrations were determined by Etest. The presence of the blaKPC gene was confirmed by PCR. Molecular typing was performed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Epidemiological data were collected by patient chart review. RESULTS: Five patients had bacteraemia upon admission, while in 48 (17.6%) the BSI developed after 6 days of hospitalization. Risk factors for KPC-Kp BSI in the latter group were the administration of aminoglycosides, number of invasive catheters inserted after the third day, and tracheostomy. The 30-day mortality was 43.4% (23/53 patients). Multivariate analysis revealed that age, SAPS II score at onset of BSI, resistance to colistin, gentamicin, or tigecycline, and septic shock were independently associated with mortality. Treatment with at least 2 appropriate antibiotics was identified as a predictor of a good prognosis. CONCLUSIONS: Many risk factors are involved in KPC-Kp BSI among ICU patients. The high mortality in patients with KPC-KP BSI in the ICU requires the implementation of appropriate infection control measures. PMID- 25017798 TI - Cranial fasciitis of the petrous temporal bone. AB - Cranial fasciitis (CF) is a rare benign neoplastic lesion affecting the pericranium and deep fascia of the scalp. We report a case confined to the temporal bone, resembling a malignant destructive lesion. The mass was identified during myringotomy for recurrent unilateral otitis media. Biopsy was consistent with CF, which was partially resected. The patient has remained disease free for 12 months. Due to its rarity, no defined treatment algorithm for CF exists. Despite aggressive features on radiology, they may respond very well to partial resection. PMID- 25017797 TI - Metal-based 2,3-indolinedione derivatives as proteasome inhibitors and inducers of apoptosis in human cancer cells. AB - Proliferation and apoptotic pathways are tightly regulated in cells by the ubiquitin-proteasome system (UPS). Alterations in the UPS may result in cellular transformation or other pathological conditions. The proteasome is indeed often found to be overactive in cancer cells. It has been reported that 2,3 indolinedione (L), which exists in marine organisms, as well as in mammals, is a proteasome inhibitor. Studies have shown that metal-based complexes inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we synthesized six novel metal-based complexes with derivatives of 2,3-indolinedione: [Cd (C15H11O3N2) (CH3COO)] (C1), [Cd (C15H11O2N2) (CH3COO)] (C2), [Co (C15H9O4N2) (CH3COO)] (C3), [Co (C15H11O2N2) (CH3COO)] (C4), [Zn (C19H14O3N3) (CH3COO)] (C5) and [Zn (C17H13O3N2) (CH3COO)] (C6). We sought to characterize and assess the proteasome inhibitory and anti-proliferative effects of these metal-based complexes in human breast (MDA-MB-231) and prostate (LNCaP and PC-3) cancer cells, in order to determine whether specific structures contribute to the inhibition of tumor proteasome activity and the induction of apoptosis. The results revealed that the complexes, C1, C3 and C5, but not their counterparts, C2, C4 and C6, inhibited the chymotrypsin-like activity of the human cancer cellular 26S proteasome; in addition, these complexes promoted the accumulation of the proteasome target protein, Bax, inhibited cell growth and induced apoptosis in a concentration- and time-dependent manner due to their unique structures. Our data suggest that the study of metal-based complexes, including aromatic ring structures with electron-attracting groups, may be an interesting research direction for the development of anticancer drugs. PMID- 25017799 TI - Remote evaluation of video-otoscopy recordings in an unselected pediatric population with an otitis media scale. AB - BACKGROUND: A recently validated image-based grading scale for acute otitis media (OMGRADE) can be used to assess tympanic membrane (TM) status. The aim of this study was to evaluate the validity and reliability of this scale for remote assessments of TM status using video-otoscopy recordings in an unselected pediatric population. METHOD: Children 2-16 years attending a South African primary health clinic were offered an ear examination by an otologist using otomicroscopy. An ear and hearing telehealth facilitator then made video-otoscopy recordings (9-33s) of the ears and uptakes were uploaded to a secure server for remote assessments in Sweden by an otologist and general practitioner at four- and eight-weeks post onsite assessment. TM appearance was judged according to the OMGRADE scale. Concordance between onsite otomicroscopy and asynchronous assessments of video-otoscopy recordings was calculated together with intra- and inter-rater agreements. RESULTS: One hundred and eighty ears were included. Concordance of TM classifications using the OMGRADE scale was found to be substantial (weighted kappa range 0.66-0.79). Intra- and inter-rater agreement (test-retest) was found to be substantial to almost perfect (weighted kappa range 0.85-0.88 and 0.69-0.72, respectively). CONCLUSION: The OMGRADE scale can be used to accurately assess the normal TM and secretory otitis media (SOM) remotely using video-otoscopy recordings in an unselected pediatric population. PMID- 25017800 TI - Galleria mellonella native and analogue peptides Gm1 and DeltaGm1. I) biophysical characterization of the interaction mechanisms with bacterial model membranes. AB - Natural occurring antimicrobial peptides (AMPs) are important components of the innate immune system of animals and plants. They are considered to be promising alternatives to conventional antibiotics. Here we present a comparative study of two synthetic peptides: Gm1, corresponding to the natural overall uncharged peptide from Galleria mellonella (Gm) and DeltaGm1, a modified overall positively charged Gm1 variant. We have studied the interaction of the peptides with lipid membranes composed of different kinds of lipopolysaccharides (LPS) and dimyristoylphosphatidylglycerol (DMPG), in some cases also dimyristoylphosphatidylethanolamine (DMPE) as representative lipid components of Gram-negative bacterial membranes, by applying Fourier-transform infrared spectroscopy (FTIR), Forster resonance energy transfer spectroscopy (FRET), differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC). Gm1 generates a destabilizing effect on the gel to liquid crystalline phase transition of the acyl chains of the lipids, as deduced from a decrease in the phase transition temperature and enthalpy, suggesting a fluidization, whereas DeltaGm1 led to the opposite behavior. Further, FTIR analysis of the functional groups of the lipids participating in the interaction with the peptides indicated a shift in the band position and intensity of the asymmetric PO2(-) stretching vibration originating from the lipid phosphate groups, a consequence of the sterical changes in the head group region. Interestingly, FRET spectroscopy showed a similar intercalation of both peptides into the DMPG and LPS, but much less into the DMPE membrane systems. These results are discussed in the light of a possible use of the peptides as antimicrobial and anti-endotoxin drugs. PMID- 25017801 TI - Cationic liposomes formulated with DMPC and a gemini surfactant traverse the cell membrane without causing a significant bio-damage. AB - Cationic liposomes have been intensively studied both in basic and applied research because of their promising potential as non-viral molecular vehicles. This work was aimed to gain more information on the interactions between the plasmamembrane and liposomes formed by a natural phospholipid and a cationic surfactant of the gemini family. The present work was conducted with the synergistic use of diverse experimental approaches: electro-rotation measurements, atomic force microscopy, zeta-potential measurements, laser scanning confocal microscopy and biomolecular/cellular techniques. Electro rotation measurements pointed out that the interaction of cationic liposomes with the cell membrane alters significantly its dielectric and geometric parameters. This alteration, being accompanied by significant changes of the membrane surface roughness as measured by atomic force microscopy, suggests that the interaction with the liposomes causes locally substantial modifications to the structure and morphology of the cell membrane. However, the results of electrophoretic mobility (zeta-potential) experiments show that upon the interaction the electric charge exposed on the cell surface does not vary significantly, pointing out that the simple adhesion on the cell surface of the cationic liposomes or their fusion with the membrane is to be ruled out. As a matter of fact, confocal microscopy images directly demonstrated the penetration of the liposomes inside the cell and their diffusion within the cytoplasm. Electro-rotation experiments performed in the presence of endocytosis inhibitors suggest that the internalization is mediated by, at least, one specific pathway. Noteworthy, the liposome uptake by the cell does not cause a significant biological damage. PMID- 25017803 TI - Poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer. AB - OBJECTIVES: Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown single agent activity against tumors with deficiencies in the DNA repair mechanism homologous recombination including, but not limited to those harboring BRCA mutations. We hypothesized that, in the context of homologous recombination deficiency (HRD), PARPi could have an effect in head and neck cancer (HNC). MATERIALS AND METHODS: We evaluated TCGA data for evidence of HRD using a copy number data signature established for breast cancer. The comparative potency of three PARPi was evaluated using cell viability assays in a panel of HNC cell lines and response was compared to BRCA-deficient breast cancer cell lines. The change in foci formation of gammaH2AX and RAD51 was assessed with immunofluorescent staining after exposure to a PARPi. Baseline gene expression was analyzed using microarray data. RESULTS: We found a subgroup in the TCGA HNC cohort harboring genomic aberrations consistent with HRD in breast cancer. Rucaparib activity was superior to olaparib and veliparib and showed single agent activity in a subset of HNC cell lines that was comparable to BRCA-deficient breast cancer cell lines. Rucaparib-sensitive and rucaparib-resistant groups showed significant differences in gammaH2AX and RAD51 foci formation after rucaparib exposure. Expression of genes involved in chromosome structure was strongly associated with rucaparib resistance. CONCLUSION: We demonstrate that PARPi are effective in a subset of HNC cell lines and propose that HRD may be present in HNC in vivo suggesting that these compounds could play a role in the treatment of HNC. PMID- 25017802 TI - Cellular solid-state NMR investigation of a membrane protein using dynamic nuclear polarization. AB - While an increasing number of structural biology studies successfully demonstrate the power of high-resolution structures and dynamics of membrane proteins in fully understanding their function, there is considerable interest in developing NMR approaches to obtain such information in a cellular setting. As long as the proteins inside the living cell tumble rapidly in the NMR timescale, recently developed in-cell solution NMR approaches can provide 3D structural information. However, there are numerous challenges to study membrane proteins inside a cell. Research in our laboratory is focused on developing a combination of solid-state NMR and biological approaches to overcome these challenges in order to obtain high-resolution structural insights into electron transfer processes mediated by membrane-bound proteins like mammalian cytochrome-b5, cytochrome-P450 and cytochrome-P450-reductase. In this study, we demonstrate the feasibility of using dynamic nuclear polarization (DNP) magic angle spinning (MAS) NMR spectroscopy for in-cell studies on a membrane-anchored protein. Our experimental results obtained from 13C-labeled membrane-anchored cytochrome-b5 in native Escherichia coli cells show a ~16-fold DNP signal enhancement. Further, results obtained from a 2D 13C/13C chemical shift correlation MAS experiment demonstrate the feasibility of suppressing the background signals from other cellular contents for high-resolution structural studies on membrane proteins. We believe that this study would pave new avenues for high-resolution structural studies on a variety of membrane-associated proteins and their complexes in the cellular context to fully understand their functional roles in physiological processes. PMID- 25017804 TI - Nutrition impact symptoms in a population cohort of head and neck cancer patients: multivariate regression analysis of symptoms on oral intake, weight loss and survival. AB - OBJECTIVES: To evaluate the impact of 17 symptoms on reduced dietary intake, weight loss, and survival of patients with Head and Neck Cancer (HNC). METHODS: 635 Consecutive patients were screened (Patient- Generated Subjective Global Assessment(c), Head and Neck Symptom Checklist(c)) before radiation and/or chemotherapy. Multivariate regression analyses were used to relate severity of symptoms to reduced dietary intake and weight loss and identify prognostic individual symptoms impact on dietary intake. Cox proportional hazards model was used to find significant predictors of survival. RESULTS: Aggregate burden of symptoms was a significant independent predictor of reduced intake, weight loss and survival. Patients with a highest total symptom scores survived significantly less (205days, 95% CI=146-264) compared to patients with lowest total symptom score (577days, CI=429-725), log-rank P<0.001). Loss of appetite, difficulty chewing, dry mouth, thick saliva and pain were individual symptoms that significantly associated with reduced dietary intake in the entire cohort. In subgroup analyses, tumor location, disease stage, performance status, and presence of dysphagia altered the profile of individual symptoms that predict intake. However across all subgroups loss of appetite had the highest impact (OR=4.6; 95% CI=3.1-6.8), followed by difficulty chewing (OR=2.5; 95% CI=2.0 3.9). CONCLUSION: HNC patients experience significant symptom burden prior to radiation and chemotherapy. The nutritional impact of these symptoms on dietary intake is revealed by multivariate analysis and support the suggestion that unique individual symptom profiles require management to improve nutritional status. PMID- 25017805 TI - Extraordinary hydrogen evolution and oxidation reaction activity from carbon nanotubes and graphitic carbons. AB - The hydrogen evolution reaction, 2H(+) + 2e(-) -> H2, and its converse, the hydrogen oxidation reaction, H2 -> 2H(+) + 2e(-), are central to any realization of a hydrogen economy. Various forms of carbon have been used for decades as the precious metal catalyst support in these reactions. Here we report the unexpected result that single-wall carbon nanotubes and some graphitic carbons, activated by brief exposure to electrochemical potentials that induce hydrogen evolution in intercalating acids combined with extended soak times in such acids, acquire an activity for these reactions that exceeds that of known nonprecious metal catalysts. PMID- 25017806 TI - Menopause is associated with lumbar disc degeneration: a review of 4230 intervertebral discs. AB - OBJECTIVE: The main objective of this study was to investigate, in a population of normal postmenopausal women, the association between menopause and severity of lumbar disc degeneration from the first lumbar to the first sacral vertebra on magnetic resonance imaging. METHODS: Between January 2010 and May 2013, 846 normal women and 4230 intervertebral discs were retrospectively analyzed. Age, height, weight and years since menopause (YSM) were recorded. Disc degeneration was evaluated using the modified Pfirrmann grading system. RESULTS: Compared to premenopausal and perimenopausal women, postmenopausal women had more severe disc degeneration after removal of age, height and weight effects (p < 0.0001). Postmenopausal women were divided into six subgroups for every 5 YSM. When YSM was below 15 years, there was a significant difference between every two groups, i.e. groups 1-5 YSM, 6-10 YSM and 11-15 YSM (p < 0.01). A positive trend was observed between YSM and severity of disc degeneration, respectively, i.e. L1/L2 (r = 0.235), L2/L3 (r = 0.161), L3/L4 (r = 0.173), L4/L5 (r = 0.146), L5/S1 (r = 0.137) and all lumbar discs (r = 0.259) (p < 0.05 or 0.01). However, when YSM was above 15, there was no difference, i.e. groups 16-20 YSM, 21-25 YSM and 26-30 YSM (p > 0.05), and the significance correlation also disappeared (p > 0.05). CONCLUSION: Menopause is associated with disc degeneration in the lumbar spine. The association almost entirely occurred in the first 15 years since menopause, suggesting estrogen decrease may be a risk factor for lumbar disc degeneration. PMID- 25017807 TI - Family sociodemographic characteristics as correlates of children's breakfast habits and weight status in eight European countries. The ENERGY (EuropeaN Energy balance Research to prevent excessive weight Gain among Youth) project. AB - OBJECTIVE: The purpose of the present study was to investigate the associations of family sociodemographic characteristics with children's weight status and whether these potential associations are mediated by children's breakfast habits. DESIGN: A school-based survey among 10-12-year-old children was conducted in eight European countries. Children's weight and height were measured and breakfast habits and family sociodemographic characteristics were self-reported by 5444 children and their parents. International Obesity Task Force cut-off points were used to categorize children as overweight/obese or normal weight. Mediation analyses were used to test the potential mediating effect of children's breakfast consumption on the associations between family sociodemographic characteristics and children's overweight/obesity. SETTING: Schools in eight European countries participating in the ENERGY (EuropeaN Energy balance Research to prevent excessive weight Gain among Youth) project. SUBJECTS: Children aged 10 12 years and their parents (n 5444). RESULTS: Children's reported daily breakfast consumption varied from 56 % in Slovenia to 92 % in Spain on weekdays and from 79 % in Greece to 93 % in Norway on weekends. Children of native parents, with both parents employed and with at least one parent having more than 14 years of education were more likely to consume breakfast daily and less likely to be overweight/obese. Finally, mediation analyses revealed that the association of parental nationality and parental educational status with children's overweight/obesity was partially mediated by children's daily breakfast consumption. CONCLUSIONS: The study shows that the lower likelihood of being overweight/obese among 10-12-year-old children of native background and higher parental educational status was partially mediated by children's daily breakfast consumption. PMID- 25017808 TI - Insights on the molecular mechanism for the recalcitrance of biochars: interactive effects of carbon and silicon components. AB - Few studies have investigated the effects of structural heterogeneity (particularly the interactions of silicon and carbon) on the mechanisms for the recalcitrance of biochar. In this study, the molecular mechanisms for the recalcitrance of biochars derived from rice straw at 300, 500, and 700 degrees C (named RS300, RS500, and RS700, respectively) were elucidated. Short-term (24 h) and long-term (240 h) oxidation kinetics experiments were conducted under different concentrations of H2O2 to distinguish the stable carbon pools in the biochars. We discovered that the stabilities of the biochars were influenced not only by their aromaticity but also through possible protection by silicon encapsulation, which is regulated by pyrolysis temperatures. The aromatic components and recalcitrance of the biochars increased with increasing pyrolysis temperatures. The morphologies of the carbon forms in all of the biochars were also greatly associated with those of silica. Silica-encapsulation protection only occurred for RS500, not for RS300 and RS700. In RS300, carbon and silica were both amorphous, and they were easily decomposed by H2O2. The separation of crystalline silica from condensed aromatic carbon in RS700 eliminated the protective role of silicon on carbon. The effect of the biochar particle size on the stability of the biochar was greatly influenced by C-Si interactions and by the oxidation intensities. A novel silicon-and-carbon-coupled framework model was proposed to guide biochar carbon sequestration. PMID- 25017809 TI - Effect of external electric fields on the phase behavior of colloidal silica rods. AB - We examine the effect of external electric fields on the behavior of colloidal silica rods. We find that the electric fields can be used to induce para-nematic and para-smectic phases, and to reduce the number of defects in smectic phases. At high field strengths, a new crystal structure was observed that consisted of strings of rods ordered in a hexagonal pattern in which neighboring rods were shifted along their length. We also present a simple model to describe this system, which we used in computer simulations to calculate the phase diagram for rods of L/D = 6, with L the end-to-end length of the rods and D the diameter of the rods. Our theoretical predictions for the phase behavior agree well with the experimental observations. PMID- 25017810 TI - Advances in endothelial shear stress proteomics. AB - The vascular endothelium lining the luminal surface of all blood vessels is constantly exposed to shear stress exerted by the flowing blood. Blood flow with high laminar shear stress confers protection by activation of antiatherogenic, antithrombotic and anti-inflammatory proteins, whereas low or oscillatory shear stress may promote endothelial dysfunction, thereby contributing to cardiovascular disease. Despite the usefulness of proteomic techniques in medical research, however, there are relatively few reports on proteome analysis of cultured vascular endothelial cells employing conditions that mimic in vivo shear stress attributes. This review focuses on the proteome studies that have utilized cultured endothelial cells to identify molecular mediators of shear stress and the roles they play in the regulation of endothelial function, and their ensuing effect on vascular function in general. It provides an overview on current strategies in shear stress-related proteomics and the key proteins mediating its effects which have been characterized so far. PMID- 25017811 TI - Healthy young minds: the effects of a 1-hour classroom workshop on mental illness stigma in high school students. AB - This study aimed to test the effects of a 1-h classroom-based workshop, led by medical students, on mental illness stigma amongst secondary school students. Students (aged 14-17) from three public secondary schools in British Columbia participated in the workshop. A questionnaire measuring stigma (including stereotype endorsement and desire for social distance) was administered immediately before (T1), immediately after (T2), and 1-month after the workshop (T3). A total of 279 students met the study inclusion criteria. Total scores on the stigma scale decreased by 23 % between T1 and T2 (p < 0.01). This was sustained 1-month post-workshop with a 21 % stigma reduction compared to pre intervention (p < 0.01). This effect was primarily due to improvements in scores that measured desire for social distance. There were no significant changes in scores that measured stereotype endorsement. Adolescents' stigmatizing attitudes can be effectively reduced through a 1-h easily implementable and cost-effective classroom-based workshop led by medical students. PMID- 25017812 TI - Polymorphism in paracetamol: evidence of additional forms IV and V at high pressure. AB - The structural phase stability of N-(4-hydroxyphenyl) acetamide (paracetamol) has been studied at ambient temperature up to 23 GPa using Raman spectroscopy. Spectral changes have provided further evidence for a highly kinetically driven Form I -> II transition that occurs as a mixed phase from 4.8 to 6.5 GPa, and might complete as early as 7 GPa. Upon further compression to 8.1 GPa, a drastic shift in spectral signature was observed providing the first evidence for a previously undiscovered Form IV of paracetamol. Additional shifts in mode intensities were observed near 11 GPa indicating a potential restructuring of the hydrogen bonding network and/or structural modification to a potentially new Form V. Phase boundaries at 7 and 8 GPa were confirmed under hydrostatic conditions using Raman spectroscopy. Spectral changes indicate that the transition Form IV > V occurs near 11 GPa. Multiple ab initio harmonic frequency calculations at different levels of theory were performed with a B3LYP/6-31G** being used to provide a more robust mode assignment to our experimentally obtained Raman modes. High pressure X-ray diffraction (XRD) was performed up to 21 GPa, which provided further evidence for a highly kinetically driven Form I -> II transition in agreement with our Raman measurements. In addition, the XRD provided further evidence for the existence of Form IV near 8 GPa and Form V near 11 GPa with Form V persisting up to 21 GPa. PMID- 25017813 TI - Multiplexed immunoassay based on micromotors and microscale tags. AB - This work reports on the coupling of antibody-functionalized micromotors and microwire-tagged proteins for rapid and multiplexed immunoassays. While micromotor-induced mixing accelerates the immunoreaction, tagging the proteins with microscopic particles of different sizes and shapes allows for their multiplexed discrimination, alerting of the presence of a biological threat. PMID- 25017814 TI - New enhanced and effective method for staging cancer to detect lymph nodes after fat-dissociation. AB - Pathologic staging is a key factor in the treatment and outcome of cancer patients, and lymph node status plays a pivotal role in this staging process. Several methods of lymph node assessment, such as the fat clearance, Schwartz solution and GEWF solution, are unpopular as they require a significant amount of time (1-9 days) to clear the fat of the resected mesentery and to visualize the lymph nodes. In the present study, we discussed a more simple and effective method, called the fat-dissociation method, which clears the fat using enzymes and allows for easy identification of lymph nodes around vessels. This new procedure facilitates precise staging of cancer which directs the post-operative treatment plan. PMID- 25017815 TI - Imaging Findings of Isolated Bronchial Anthracofibrosis: A Computed Tomography Analysis of Patients With Bronchoscopic and Histologic Confirmation. AB - BACKGROUND: To evaluate the chest computed tomography (CT) findings of patients with isolated bronchial anthracofibrosis confirmed by bronchoscopy and histopathology. METHODOLOGY: Fifty-eight patients with isolated bronchial anthracofibrosis (29 females; mean age, 70 years) were enrolled in this study. The diagnosis of bronchial anthracofibrosis was made based on both bronchoscopy and pathology findings in all patients. The various chest CT images were retrospectively reviewed by two chest radiologists who reached decisions in consensus. RESULTS: Central peribronchial soft tissue thickening (n=37, 63.8%) causing bronchial narrowing (n=37, 63.8%) or obstruction (n=11, 19%) was identified as an important finding on imaging. Multiple bronchial stenoses with concurrent involvement of 2, 3, and 5 bronchi were seen in 12 (21%), 9 (15%), and 2 (3.4%) patients, respectively. Segmental atelectasis and lobar or multilobar collapse were detected. These findings mostly occurred in the right lung, predominantly in the right middle lobe. Mosaic attenuation patterns, scattered parenchymal nodules, nodular patterns, and calcified or non-calcified lymph nodes were also observed. CONCLUSIONS: On chest CT, isolated bronchial anthracofibrosis appeared as peribronchial soft tissue thickening, bronchial narrowing or obstruction, segmental atelectasis, and lobar or multilobar collapse. The findings were more common in the right side, with simultaneous involvement of multiple bronchi in some patients. PMID- 25017816 TI - Bronchoaspiration of Foreign Bodies. Clinical Case and Review. PMID- 25017817 TI - Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice. AB - INTRODUCTION: Emphysema has been associated with decreased VEGF and VEGFR-2 expression and the presence of high numbers of apoptotic alveolar cells. Keratinocyte growth factor stimulates VEGF synthesis which in turn confers normal lung structure maintenance via the Akt pathway. In this study the potential role of rHuKGF in the improvement of deregulated Akt mediated cell survival pathway in emphysematous mice was investigated. METHODS: Three experimental groups, i.e., emphysema, treatment and control groups, were prepared. Lungs of mice were treated on 3 occasions by oropharyngeal instillation of 10mg rHuKGF per kg body weight after induction of emphysema with porcine pancreatic elastase. Subsequently, lung tissues from mice were collected for histopathology and molecular biology studies. RESULTS AND DISCUSSION: Histopathology photomicrographs and destructive index analysis have shown that elastase-induced airspace enlargement and loss of alveoli recovered in the treatment group. rHuKGF stimulates VEGF production which in turn induces the Akt mediated cell survival pathway in emphysematous lungs. mRNA expression of VEGF, VEGFR, PI3K and Akt was significantly increased while Pten, Caspase-9 and Bad was notably decreased in treatment group when compared with emphysema group, being comparable with the control group. Moreover, VEGF protein expression was in accordance with that found for mRNA. CONCLUSION: Therapeutic rHuKGF supplementation improves the deregulated Akt pathway in emphysema, resulting in alveolar cell survival through activation of the endogenous VEGF-dependent cell survival pathway. Hence rHuKGF may prove to be a potential drug in the treatment of emphysema. PMID- 25017818 TI - Low magnification narrow band imaging by inexperienced endoscopists has a high accuracy in differentiation of colon polyp histology. AB - BACKGROUND/OBJECTIVE: Several studies have shown that NBI can predict the colorectal polyp histology with moderate to high accuracy. Most of them were conducted by highly experienced endoscopists at academic centers by using high magnification colonoscopes. We evaluated the accuracy of standard definition low magnification NBI in predicting the real time histology of colorectal polyps when used by inexperienced endoscopists and whether it can meet the thresholds recently defined for discard, resect and discard strategies of diminutive polyps by ASGE. METHODS: The study was a prospective observational trial and involved 430 patients who underwent colonoscopy. A total of 214 polyps were detected in 317 patients. Colonoscopies were performed by a gastroenterology attending physician and two fellows who had no experience in NBI. Standard definition low magnification colonoscopes were used. The endoscopists recorded the size, Paris classification, and location of polyps under white light and consecutively described the superficial mucosal architecture and vascular pattern based on NBI International Colorectal Endoscopic criteria. RESULTS: The overall accuracy of NBI in predicting adenomatous histology was 93.4%. The negative predictive value for diagnosing adenomatous histology in diminutive rectosigmoid polyps (93.3%) and the accuracy in predicting the colonoscopy surveillance interval (92.3%) were above the threshold levels defined by ASGE. CONCLUSIONS: Low magnification NBI by inexperienced endoscopists has a high accuracy in predicting in vivo colorectal polyp histology encouraging its use in routine clinical practice. PMID- 25017819 TI - Application of ultra-weak photon emission measurements in agriculture. AB - Here we report our two applications of ultra-weak photon emission (UPE) measurements in agriculture. One is to find new types of agrochemicals that potentiate plants' defense, so-called "plant activator". We first analyzed the relation between plant defense and Elicitor-Responsive Photon Emission (ERPE) using a combination of rice cells and a chitin elicitor. Pharmacological analyses clarified that ERPE was generated as a part of the chitin elicitor-responsive defense in close relation with the generation of reactive oxygen species (ROS). Then we successfully detected the activity of plant activators as the potentiation of ERPE, and developed a new screening system for plant activators based on this principle. Another UPE application is to distinguish herbicide resistant weeds from susceptible ones by measuring UPE in weeds. In our study, it was revealed that the weed biotypes resistant to sulfonylurea (SU) herbicides, one of the major herbicide groups, showed stronger UPE than susceptible ones after an SU herbicide treatment. By further analysis with a pharmacological and RNAi study, we found that the detoxifying enzyme P450s contributed to the UPE increase in SU herbicide resistant weeds. It is considered that weeds resistant to herbicides other than SU might also be able to be distinguished from susceptible ones by UPE measurement, as long as the herbicides are subject to detoxification by P450s. PMID- 25017820 TI - Ultra-weak photon emission from living systems--from mechanism to application. PMID- 25017821 TI - The opioid prescription epidemic and the role of emergency medicine. PMID- 25017822 TI - A text message alcohol intervention for young adult emergency department patients: a randomized clinical trial. AB - STUDY OBJECTIVE: Opportunistic brief in-person emergency department (ED) interventions can be effective at reducing hazardous alcohol use in young adult drinkers, but require resources frequently unavailable. Mobile telephone text messaging (short message service [SMS]) could sustainably deliver behavioral support to young adult patients, but efficacy remains unknown. We report 3-month outcome data of a randomized controlled trial testing a novel SMS-delivered intervention in hazardous-drinking young adults. METHODS: We randomized 765 young adult ED patients who screened positive for past hazardous alcohol use to one of 3 groups: SMS assessments+feedback (SA+F) intervention who were asked to respond to drinking-related queries and received real-time feedback through SMS each Thursday and Sunday for 12 weeks (n=384), SMS assessments (SA) who were asked to respond to alcohol consumption queries each Sunday but did not receive any feedback (N=196), and a control group who did not participate in any SMS (n=185). Primary outcomes were self-reported number of binge drinking days and number of drinks per drinking day in the past 30 days, collected by Web-based timeline follow-back method and analyzed with regression models. Secondary outcomes were the proportion of participants with weekend binge episodes and most drinks consumed per drinking occasion during 12 weekends, collected by SMS. RESULTS: With Web-based data, there were decreases in the number of self-reported binge drinking days from baseline to 3 months in the SA+F group (-0.51 [95% confidence interval {CI} -0.10 to -0.95]), whereas there were increases in the SA group (0.90 [95% CI 0.23 to 1.6]) and the control group (0.41 [95% CI -0.20 to 1.0]). There were also decreases in the number of self-reported drinks per drinking day from baseline to 3 months in the SA+F group (-0.31 [95% CI -0.07 to -0.55]), whereas there were increases in the SA group (0.10 [95% CI -0.27 to 0.47]) and the control group (0.39 [95% CI 0.06 to 0.72]). With SMS data, there was a lower mean proportion of SA+F participants reporting a weekend binge during 12 weeks (30.5% [95% CI 25% to 36%) compared with the SA participants (47.7% [95% CI 40% to 56%]). There was also a lower mean drinks consumed per weekend during 12 weeks in the SA+F group (3.2 [95% CI 2.6 to 3.7]) compared to the SA group (4.8 [95% CI 4.0 to 5.6]). CONCLUSION: A text message intervention can produce small reductions in self-reported binge drinking and the number of drinks consumed per drinking day in hazardous-drinking young adults after ED discharge. PMID- 25017823 TI - Should children with acute asthma exacerbation receive inhaled anticholinergics? PMID- 25017824 TI - Managing propofol-induced hypoventilation. PMID- 25017825 TI - Overexpression of mitofusin 2 inhibits reactive astrogliosis proliferation in vitro. AB - Astrocytes become activated in response to central nervous system (CNS) injury, and excessive astrogliosis is considered an impediment to axonal regeneration by forming glial scar. Mitofusin 2 (Mfn2), a key protein in mitochondrial network, has been reported to negatively regulate cell proliferation. The present study aimed to explore whether reactive astrogliosis could be suppressed by Mfn2 overexpression. Scratch injury and starvation-serum stimulation models in cultured astrocytes were combined to address this issue. In scratch model, reactive proliferation status of damaged astrocytes was implicated by migration of high ratio of EdU(+) cells into lesion region and significantly increased expression of GFAP and PCNA. At meantime, Mfn2 expression was found to exert a down-regulated trend both in gen and protein levels. Pretreatment of cells with adenoviral vector encoding Mfn2 gene increased Mfn2 expression and subsequently attenuated injury-induced astrocytes hyperplasia, activation-relevant protein synthesis, cellular proliferation, eventually delayed wound healing process. Furthermore, Mfn2 overexpression markedly inhibited astrocytes proliferation induced by serum stimulation, by arresting the transition of cell cycle from G1 to S phase. Together, these in vitro results demonstrated that reactive astrogliosis can be effectively suppressed by up-regulation of Mfn2, which might contribute to a promising therapeutic intervention in CNS disease characterized by glia-related damage. PMID- 25017826 TI - Altered structural connectivity and trait anhedonia in patients with schizophrenia. AB - This study tested association between anhedonia scores and white matter integrity in order to investigate the neural basis of trait anhedonia in schizophrenia. A total of 31 patients with schizophrenia and 33 healthy controls underwent diffusion weighted imaging and scoring of trait anhedonia using the Physical Anhedonia Scale. Using tract-based spatial statistics, we found that fractional anisotropy values of some white matter regions were differently correlated with Physical Anhedonia Scale scores between the two groups. The white matter regions that were more significantly correlated with trait anhedonia in patients than in controls included the left side of the cingulum, splenium of the corpus callosum, inferior longitudinal fasciculus, superior longitudinal fasciculus I and II, anterior thalamic radiation, and optic radiation. Of these regions, fractional anisotropy values in the cingulum and superior longitudinal fasciculus II were positively correlated with trait anhedonia in patients with schizophrenia. These findings suggest that alterations in structural connectivity within large-scale brain networks, including the default mode and central executive networks, may contribute to the development of trait anhedonia in patients with schizophrenia. PMID- 25017827 TI - Preserved white matter in unmedicated pediatric bipolar disorder. AB - White matter (WM) abnormalities have been reported in bipolar disorder (BD) patients, as well as in their non-BD relatives, both children and adults. Although it is considered an emerging vulnerability marker for BD, there are no studies investigating WM alterations in pediatric unmedicated patients and young healthy offspring. In this study, we evaluated the presence of WM alterations in 18 pediatric, non medicated BD patients, as well as in 18 healthy offspring of BD type I parents and 20 healthy controls. 3T DT-MRI data were acquired and scans were processed with tract-based spatial statistics to provide measures of fractional anisotropy and diffusivity. We found no significant differences in WM microstructure between BD patients, healthy offspring and healthy controls. Previous studies that reported WM alterations investigated older subjects, either on medication (BD patients) or with psychiatric diagnoses other than BD (unaffected offspring). Our findings highlight the importance of the understanding of disease ontogeny and brain development dynamics in the search for early vulnerability markers for psychiatric disorders. PMID- 25017829 TI - Diagnostic and Statistical Manual-5: No revolutionary road. PMID- 25017830 TI - The New ICMJE Recommendations. PMID- 25017828 TI - Distinct miRNA signatures associate with subtypes of cholangiocarcinoma from infection with the tumourigenic liver fluke Opisthorchis viverrini. AB - BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a significant public health problem in East Asia, where it is strongly associated with chronic infection by the food-borne parasite Opisthorchis viverrini (OV). We report the first comprehensive miRNA expression profiling by microarray of the most common histologic grades and subtypes of ICC: well differentiated, moderately differentiated, and papillary ICC. METHODS: MicroRNA expression profiles from FFPE were compared among the following: ICC tumour tissue (n = 16), non-tumour tissue distally macrodissected from the same ICC tumour block (n = 15), and normal tissue (n = 13) from individuals undergoing gastric bypass surgery. A panel of deregulated miRNAs was validated by qPCR. RESULTS: Each histologic grade and subtype of ICC displayed a distinct miRNA profile, with no cohort of miRNAs emerging as commonly deregulated. Moderately differentiated ICC showed the greatest miRNA deregulation in quantity and magnitude, followed by the papillary subtype, and then well differentiated ICC. Moreover, when ICC tumour tissues were compared to adjacent non-tumour tissue, similar miRNA dysregulation profiles were observed. CONCLUSIONS: We show that common histologic grades and subtypes of ICC have distinct miRNA profiles. As histological grade and subtypes are associated with ICC aggressiveness, these profiles could be used to enhance the early detection and improve the personalised treatment for ICC. These findings also suggest the involvement of specific miRNAs during ICC tumour progression and differentiation. We plan to use these insights to (a) detect these profiles in circulation and (b) conduct functional analyses to decipher the roles of miRNAs in ICC tumour differentiation. PMID- 25017831 TI - N-acetyltransferase and cytochrome P450 2E1 gene polymorphisms and susceptibility to antituberculosis drug hepatotoxicity in an Indian population. AB - Background. Antituberculosis drug hepatotoxicity (ATDH) is common in India. Isoniazid, a constituent of most anti- tuberculosis drug regimens, is metabolized by N-acetyltransferase (NAT2) and cytochrome P450 2E1 (CYP2E1) enzymes. We therefore studied the association of some single-nucleotide polymorphisms (SNPs) in these enzyme genes with ATDH. Methods. Allelic and genotypic frequencies at three SNP loci in the NAT2 gene (rs1799929, rs1799930 and rs1799931) and one locus (rs2031920) in the CYP2E1 gene were studied using restriction fragment length polymorphism in 33 patients who developed ATDH following an isoniazid- containing antituberculosis drug regimen and 173 healthy blood donors. After confirming adherence of the control data to the Hardy-Weinberg equilibrium model, genotype and allele frequencies in the two groups were compared. Results. For SNP rs1799930 in the NAT2 gene, 7 (21%), 21 (64%) and 5 (15%) patients, and 93 (54%), 62 (36%) and 18 (10%) controls had GG, GA and AA genotypes, respectively (p=0.003; odds ratio [OR] for GA v. GG=4.50 [95% CI 1.80-11.22] and for AA v. GG=3.69 [1.05-12.93]). Allele frequency for G nucleotides for this SNP was 0.53 among patients and 0.72 among controls (OR 2.24 [1.31-3.84], p=0.007). The allele and genotype frequencies of the other NAT2 SNPs and the CYP2E1 SNP showed no significant difference between cases and controls. All the 33 patients and 151 (87%) of 173 controls had mutant allele at one or more of the three NAT2 SNP loci (p=0.03). The presence of two or more mutant alleles, a marker of slow acetylator status, was more frequent in patients (23/33 [70%]) than in controls (73/173 [42%]; OR 3.23 [95% CI 1.45-7.19], p=0.004). Conclusion. In India, the risk of ATDH is increased in persons with 'A' allele at SNP rs1799930 in the NAT2 gene, but is not associated with rs2031920 polymorphism in the CYP2E1 gene. PMID- 25017832 TI - Reproducibility and validity of a quantitative food frequency questionnaire in an urban and rural area of northern India. AB - Background. Food frequency questionnaires (FFQs) have been used in epidemiological studies across the world to capture the usual food intake of individuals. As food habits vary in different population groups, FFQs should be validated before use. Hence, we determined the reproducibility and validity of FFQs designed for urban and rural populations of northern India. Methods. Separate FFQs, designed for urban and rural populations using standard methods, were administered to a sample of 200 subjects (100 urban and 100 rural) in the age group of 35-70 years in the beginning (baseline FFQ) of the study and after an interval of 1 year (1-year FFQ) to assess their reproducibility. Six 24-hour dietary-recalls, taken at an interval of 2 months over a period of 1 year, were used as a reference method to test the validity. Crude and energy- adjusted nutrient intakes estimated from FFQs and 24-hour dietary-recalls were compared using Pearson correlation coefficients. Bland and Altman plots were also used to test the agreement between the two methods. Results. Nutrient intakes were found to be similar at the baseline and 1-year FFQs in urban and rural areas. The unadjusted Pearson correlation between 24-hour dietary- recalls and 1-year FFQ ranged from 0.22 for vitamin C to 0.63 for iron in the urban area. It ranged from 0.06 for vitamin C to 0.74 for energy in the rural area. The correlations lowered after adjusting for energy and there was a minimal increase after de-attenuation. Conclusion. The FFQs were reproducible and valid for assessing nutrient intakes except for some micronutrients. PMID- 25017833 TI - Female health workers in Gujarat: Examining human resource actions and workforce objectives-an exploratory mixed methods study. AB - Background. Female health workers (FHWs), posted at subcentres, each serving a rural population of 3000 to 5000, are the final points of contact between the people and the health system. This study assesses a selected sample of FHWs using the 'managing for performance' framework. Methods. Twenty-two FHWs and their supervisors at five primary health centres near Ahmedabad were purposively selected for this mixed methods study. They were administered a semi-structured questionnaire, which also guided 12 individual interviews and four focus group discussions. Quantitative data were analysed using Epi Info and Excel. Content analysis of the qualitative data was done using Microsoft Word. Results. In spite of increased FHW strength due to recent recruitments, one-third of these FHWs were carrying out additional responsibilities of another FHW or supervisor. Planning of tasks was the most popular activity while the chief demotivating factor at work was meeting targets. Recent trainings have been useful but failed to build specific competence as required. About 37% of routine person-tasks carried out by FHWs were graded below 60 points by supervisors. They rated the FHWs highly for their collaboration with community leaders although FHWs themselves did not consider community leaders to be a helpful resource. Conclusion. Mapping age, skill levels and locations of existing FHWs and soon-to be retirees would be useful when planning future expansion of the FHW cadre. The natural elasticity of base populations due to migration as well as unpredictability of their work schedules need to be taken into account when monitoring the work performance of FHWs. District training centres need to be developed to provide a wide range of competencies. PMID- 25017834 TI - Prevalence of symptomatic and asymptomatic coronary artery disease in patients with stroke. AB - Background. Studies have shown that myocardial infarction is a leading cause of death in patients recovering from stroke or transient ischaemic attacks. We aimed to study the prevalence of symptomatic and asymptomatic coronary artery disease (CAD) in patients with stroke. Methods. Eighty-six patients with stroke were evaluated for risk factors and presence of CAD. Patients without a previous diagnosis of CAD underwent stress-rest gated technetium-99m (Tc99m) tetrofosmin myocardial perfusion SPECT (MPS) scan to estimate the presence or absence of a reversible perfusion deficit. Results. Thirty-three patients (clinically asymptomatic for CAD) did not consent for the MPS scan. Among the remaining 53 patients, 13 patients had been previously diagnosed to have CAD, 8 patients were suspected to have underlying CAD and 32 patients were asymptomatic. Among the patients with suspected CAD, 2 had abnormal MPS scans and one had triple-vessel disease on coronary angiography. Of the asymptomatic patients, 6 had CAD. The overall proportion of CAD among patients with stroke was 41.5% (22/53) and that of asymptomatic CAD 18.8% (6/32). Conclusion. A considerable number of patients with stroke may have associated CAD. An optimal management strategy in stroke patients who have silent CAD may improve clinical outcomes. PMID- 25017835 TI - Posterior reversible encephalopathy syndrome presenting with seizures. AB - Hyperperfusion syndrome, previously known as posterior reversible encephalopathy syndrome (PRES), is a clinico- radiological entity with characteristic features on neuro-imaging. It is believed to be caused by vasogenic oedema, predominantly in the posterior cerebral hemispheres. We report the case of an elderly man who presented with convulsions and was diagnosed to have PRES due to hypertension. PMID- 25017836 TI - The PROSEVA trial: Is it time to flip over the ARDS patient? PMID- 25017837 TI - Should surgical residents work shorter hours? PMID- 25017838 TI - Postgraduate medical education in Community Medicine: The AIIMS model. AB - Introduction : Community Medicine as a discipline in India is variously known as Community Medicine, Social and Preventive Medicine, and Preventive and Social Medicine. In India, 218 medical colleges offer a 3-year MD course in Community Medicine, with a total of 742 seats annually.1 Admission to this course at the All India Institute of Medical Sciences (AIIMS), New Delhi is through a competitive entrance examination held twice a year.2 The total number of seats for the course at a given time is 23. PMID- 25017839 TI - Using the Indian National Sample Survey data in public health research. AB - The National Sample Survey (NSS), instituted in 1950, was the brainchild of Professor Mahalanobis, widely regarded as the father of Indian statistics.1 His ambition was to obtain and quantify comprehensive information on an annual basis on the socio- economic, demographic, agricultural and other profiles of the country, both at the national and state levels. The NSS is a multi- stage, multi subject and multi-purpose cross-sectional survey, which is conducted annually and covers topics of current interest. PMID- 25017840 TI - Emergency care for older people in India. AB - Increasing longevity has been hailed as a triumph of medicine in recent years. With increasing life expectancy all over the world, ageing has been seen to outpace social and economic development in many countries. Declining mortality rates and total fertility rates result in an increase in the proportion of elderly individuals. The impact of the ageing population is felt less in the developed world, and it has been estimated that by the year 2050 over 80% of the elderly world population would be living in the developing world. Despite a higher life expectancy in developing nations, there has also been an increase in the risk of having chronic ailments during the increased years; a reflection of life-long accumulation of risk factors.1. PMID- 25017841 TI - Rustom A. Irani. PMID- 25017842 TI - Letter from North America. PMID- 25017843 TI - Letter from Chennai. PMID- 25017844 TI - Letter from Mumbai. PMID- 25017849 TI - Visceral leishmaniasis complicated by haemophagocytosis. PMID- 25017850 TI - Clinical problem-solving: A dying art? PMID- 25017851 TI - The quality of Indian medical journals: Then and now. PMID- 25017852 TI - Humour in medicine. PMID- 25017853 TI - Publishing articles of relevance to general practitioners. PMID- 25017854 TI - Sturge-Weber syndrome. PMID- 25017855 TI - Andhra Medical College, Visakhapatnam celebrates Granite anniversary. PMID- 25017856 TI - Pesticide residues in food. PMID- 25017857 TI - Pioglitazone flip-flop by the Indian government. PMID- 25017858 TI - Translational Cancer Research Center to be set up in Kolkata. PMID- 25017861 TI - Use of side-chain for rational design of n-type diketopyrrolopyrrole-based conjugated polymers: what did we find out? AB - The primary role of substituted side chains in organic semiconductors is to increase their solubility in common organic solvents. In the recent past, many literature reports have suggested that the side chains play a critical role in molecular packing and strongly impact the charge transport properties of conjugated polymers. In this work, we have investigated the influence of side chains on the charge transport behavior of a novel class of diketopyrrolopyrrole (DPP) based alternating copolymers. To investigate the role of side-chains, we prepared four diketopyrrolopyrrole-diketopyrrolopyrrole (DPP-DPP) conjugated polymers with varied side-chains and carried out a systematic study of thin film microstructure and charge transport properties in polymer thin-film transistors (PTFTs). Combining results obtained from grazing incidence X-ray diffraction (GIXD) and charge transport properties in PTFTs, we conclude side-chains have a strong influence on molecular packing, thin film microstructure, and the charge carrier mobility of DPP-DPP copolymers. However, the influence of side-chains on optical properties was moderate. The preferential "edge-on" packing and dominant n-channel behavior with exceptionally high field-effect electron mobility values of >1 cm(2) V(-1) s(-1) were observed by incorporating hydrophilic (triethylene glycol) and hydrophobic side-chains of alternate DPP units. In contrast, moderate electron and hole mobilities were observed by incorporation of branched hydrophobic side-chains. This work clearly demonstrates that the subtle balance between hydrophobicity and hydrophilicity induced by side-chains is a powerful strategy to alter the molecular packing and improve the ambipolar charge transport properties in DPP-DPP based conjugated polymers. Theoretical analysis supports the conclusion that the side-chains influence polymer properties through morphology changes, as there is no effect on the electronic properties in the gas phase. The exceptional electron mobility is at least partially a result of the strong intramolecular conjugation of the donor and acceptor as evidenced by the unusually wide conduction band of the polymer. PMID- 25017862 TI - Autonomic control of heart rate during orthostasis and the importance of orthostatic-tachycardia in the snake Python molurus. AB - Orthostasis dramatically influences the hemodynamics of terrestrial vertebrates, especially large and elongated animals such as snakes. When these animals assume a vertical orientation, gravity tends to reduce venous return, cardiac filling, cardiac output and blood pressure to the anterior regions of the body. The hypotension triggers physiological responses, which generally include vasomotor adjustments and tachycardia to normalize blood pressure. While some studies have focused on understanding the regulation of these vasomotor adjustments in ectothermic vertebrates, little is known about regulation and the importance of heart rate in these animals during orthostasis. We acquired heart rate and carotid pulse pressure (P PC) in pythons in their horizontal position, and during 30 and 60 degrees inclinations while the animals were either untreated (control) or upon muscarinic cholinoceptor blockade and a double autonomic blockade. Double autonomic blockade completely eradicated the orthostatic-tachycardia, and without this adjustment, the P PC reduction caused by the tilts became higher than that which was observed in untreated animals. On the other hand, post-inclinatory vasomotor adjustments appeared to be of negligible importance in counterbalancing the hemodynamic effects of gravity. Finally, calculations of cardiac autonomic tones at each position revealed that the orthostatic-tachycardia is almost completely elicited by a withdrawal of vagal drive. PMID- 25017863 TI - Pilot-scale production of lipase using palm oil mill effluent as a basal medium and its immobilization by selected materials. AB - A pilot-scale production of lipase using palm oil mill effluent (POME) as a fermentation basal medium was carried out, and parameters for immobilization of the produced lipase were optimized. Lipase production in a 300-L bioreactor was performed using two proposed strategies, constant power per volume (P/V) and constant tip speed. Moreover, lipase immobilization on different materials was also investigated. Lipase production was performed using liquid-state bioconversion of POME as the medium and Candida cylindracea as the inoculum. The fermentation medium was composed of 1% total suspended solids (TSS) of POME, 0.5% (w/v) peptone, 0.7% (v/v) Tween-80, and 2.2% inoculum. The medium composition was decided on the basis of the medium optimization results of a previous study. The fermentation was carried out for 48 h at 30 degrees C and pH 6. The maximum lipase production was 5.72U/mL and 21.34 U/mL, obtained from the scale-up strategies of constant tip speed and P/V, respectively. Four accessible support materials were screened for their potential use in immobilization. The most suitable support material was found to be activated carbon, with a maximum immobilization of 94%. PMID- 25017864 TI - Carotenoid biosynthesis regulatory mechanisms in plants. AB - Carotenoids are bioactive compounds with remarkably special properties produced by plants in response to internal and external stresses. In this review paper, we focus on the subject of carotenoid biosynthesis and several factors that have been reported to significantly enhance or reduce carotenoid accumulation in studied plant species. These factors include varietal aspects, location, growing season, and type of stress experienced by a plant. In addition, we propose that there are three stress resistance mechanisms in plants: avoidance, tolerance, and acclimation. Better understanding of the environmental factors affecting carotenoid biosynthesis will help researchers to develop methods for enhancing the production of carotenoids and other pigments to desired concentrations in plant crops. PMID- 25017865 TI - Antioxidant effects of pH-regulating agents on the thermal deterioration of vegetable oils. AB - pH-Regulating agents, such as sodium tartrate, disodium succinate, and trisodium citrate, were investigated for their antioxidant activities during the thermal deterioration of vegetable oils. Refined rapeseed and rice bran oils, supplemented with pH-regulating agents and alpha-tocopherol (0.1%) were heated at 180C. After heating, acid values (AVs), carbonyl values (CVs), polar material contents, and color (absorbance at 420 nm) of each sample were measured. All pH regulating agents gave rise to reduced AVs, CVs, and polar material contents of vegetable oils during heating relative to samples not containing a pHregulating agent. Rapeseed and rice bran oils supplemented with sodium tartrate showed the lowest AVs, CVs, polar material contents and absorbances at 420 nm after heating. Sodium tartrate not only retarded the hydrolysis, thermal oxidation, polymerization, and coloration of both oils while heating at high temperatures, but it also showed antioxidant activity at the supplementation level of 0.01%. The antioxidant activity of sodium tartrate was higher than that of alpha tocopherol during the deterioration of vegetable oils. Sodium tartrate was particularly effective retarding hydrolysis while heating at high temperatures, resulting in increase of AVs of vegetable oils. Sodium tartrate is therefore expected to be an effective antioxidant for the thermal deterioration of fats and oils during deep-fat frying. PMID- 25017866 TI - Bioactivity of essential oil of Artemisia argyi Levl. et Van. and its main compounds against Lasioderma serricorne. AB - Artemisia argyi Levl. et Van., a perennial herb with a strong volatile odor, is widely distrbuted in the world. Essential oil obtained from Artemisia argyi was analyzed by gas chromatography-mass spectrometry (GC-MS). A total of 32 components representing 91.74% of the total oil were identified and the main compounds in the oil were found to be eucalyptol (22.03%), beta-pinene (14.53%), beta-caryophyllene (9.24%) and (-)-camphor (5.45%). With a further isolation, four active constituents were obtained from the essential oil and identified as eucalyptol, beta-pinene, beta-caryophyllene and camphor. The essential oil and the four isolated compounds exhibited potential bioactivity against Lasioderma serricorne adults. In the progress of assay, it showed that the essential oil, camphor, eucalyptol, beta-caryophyllene and beta-pinene exhibited strong contact toxicity against L. serricorne adults with LD50 values of 6.42, 11.30, 15.58, 35.52, and 65.55 MUg/adult, respectively. During the fumigant toxicity test, the essential oil, eucalyptol and camphor showed stronger fumigant toxicity against L. serricorne adults than beta-pinene (LC50 = 29.03 mg/L air) with LC50 values of 8.04, 5.18 and 2.91 mg/L air. Moreover, the essential oil, eucalyptol, beta pinene and camphor also exhibited the strong repellency against L. serricorne adults, while, beta-caryophyllene exhibited attracting activity relative to the positive control, DEET. The study revealed that the bioactivity properties of the essential oil can be attributed to the synergistic effects of its diverse major and minor components. The results indicate that the essential oil of A. argyi and the isolated compounds have potential to be developed into natural insecticides, fumigants or repellents in controlling insects in stored grains and traditional Chinese medicinal materials. PMID- 25017867 TI - Contrast medium application in pediatric high-pitch cardiovascular CT angiography: manual or power injection? AB - BACKGROUND: Dual-source CT offers accurate depiction of cardiac structures in children with congenital heart disease. For cardiac CT, optimal enhancement of the cardiovascular structures is essential. There is considerable controversy about the administration of contrast medium (CM) in infants and small children, with either a power injector or a manual (hand) injection. OBJECTIVE: The aim of this study was to compare image quality with power injection of CM (study group) and manual injection (control group). METHODS: Thirty-four patients (study group, 6.8 +/- 9.6 months and control group, 4.6 +/- 8.9 months, nonrandomized) underwent dual-source CT angiography of the chest using a prospective electrocardiography-triggered high-pitch spiral mode (pitch, 3.4; 80 kV). In the study group (17 patients), a power injector was used, and in the control group (17 patients, historical group), manual CM injection had been performed. To assess image quality, both subjective and objective parameters were evaluated independently by 2 experienced radiologists. RESULTS: Subjective overall image quality, signal-to-noise ratio, and contrast-to-noise ratio were significantly higher using power injection compared with manual injection (P < .05). However, depiction of cardiovascular structures did not differ significantly between both groups in all evaluated regions except the superior vena cava and the coronary arteries. CONCLUSION: In infants and small children with congenital heart disease, both manual and power injector protocols allowed for diagnostic imaging of cardiac and extracardiac structures. However, image quality and vascular attenuation were superior using a power injector. PMID- 25017868 TI - Association of serum lead and mercury level with cardiometabolic risk factors and liver enzymes in a nationally representative sample of adolescents: the CASPIAN III study. AB - This study aims to determine the difference of serum Pb and Hg levels in adolescents with or without metabolic syndrome (MetS) and the association of serum levels of these heavy metals with cardiometabolic risk factors and liver enzymes in Iranian adolescents. The study population consisted of 320 adolescents (160 with MetS and 160 healthy controls). The relationship between serum heavy metals and cardiometabolic risk factors was assessed by linear regression. The odds ratios (OR) of having metabolic syndrome across Pb and Hg quartiles were determined by multiple logistic regression analysis. The mean (SD) of Pb and Hg concentrations were higher in adolescents with MetS than in those without it (0.83 (0.27) and 0.17 (0.01) vs. 0.65 (0.15) and 0.10 (0.08) MUg/L, P = 0.01 and 0.0001, respectively). Increase in serum Pb and Hg was associated with increase in some cardiometabolic risk factors. Among boys and girls, diastolic blood pressure (DBP), fasting blood glucose, total cholesterol (TC), triglycerides (TG), and alanine aminotransaminase increased significantly across quartiles of serum Pb. Among girls, SBP, DBP, TC, and TG had a significant increase across Hg quartiles. The corresponding figure among boys was significant for SBP, DBP, and TG. Higher quartiles of Pb increased the risk of having MetS (OR 95 % CI 3.10, 2.25-4.27), the corresponding figure was 2.03, 1.75-3.16, across Hg quartiles. Our study showed significant associations between serum Pb and Hg levels with cardiometabolic risk factors in adolescents. In future surveys, the role of potential confounders should be considered more extensively. The clinical significance of these findings needs to be confirmed in longitudinal studies. By considering the origins of chronic diseases from early life, controlling environmental pollutants should be considered as a health priority for primordial or primary prevention of noncommunicable diseases. PMID- 25017869 TI - Distribution of Co, Cu, Fe, Mn, Se, Zn, and Cd among cytosolic proteins of different molecular masses in gills of European chub (Squalius cephalus L.). AB - The distribution of essential elements Co, Cu, Fe, Mn, Se, and Zn, and nonessential element Cd among cytosolic proteins of different molecular masses in the gills of European chub (Squalius cephalus) sampled in the moderately contaminated Sutla River in September of 2009, was studied after the protein separation by size exclusion high-performance liquid chromatography (SEC-HPLC), and the metal determination in the obtained fractions by high-resolution inductively coupled plasma mass spectrometry (HR ICP-MS). The aims of the study were to characterize the distribution profiles of metals within different protein categories in gills in the conditions of low metal exposure in the river water, and to compare them with the previously published hepatic profiles. The distribution profiles of analyzed metals were mainly characterized with several peaks. However, some observations could be emphasized: both Cu and Cd were eluted near metallothionein elution time; elution time of one of Co peaks could be associated with Co-containing compound cobalamin; increasing cytosolic Fe concentrations resulted in possible Fe binding to storage protein ferritin; both Mn and Zn had poorly resolved peaks covering wide ranges of molecular masses and indicating their binding to various proteins; both Zn and Se increased in protein fractions of molecular masses <5 kDa following their concentration increase in the gill cytosol; expected clear metallothionein peak was not observed for Zn. Comparison of gill profiles with previously published hepatic profiles revealed similar and in case of some elements (e.g., Co, Fe, Mn, and Se) almost identical distributions in both organs regarding elution times. On the contrary, heights of obtained peaks were different, indicating possible metal binding to the same proteins in the gills and liver, but in different proportions. The results obtained in this study can be used as a basis for comparison in monitoring studies, for identification of changes that would occur after exposure of chub to increased metal concentrations. PMID- 25017870 TI - Mercury contamination in alligators (Melanosuchus niger) from Mamiraua Reservoir (Brazilian Amazon) and human health risk assessment. AB - Mercury (Hg) concentrations in muscles of wild alligators (Melanosuchus niger) from the Mamiraua Reservoir (a reference area in the Brazilian Amazon) and the human health risks associated with its consumption were assessed. The mean Hg concentration in alligator muscles was 0.407 +/- 0.114 MUg/g (N = 61). Close to 5 % of the muscle samples showed Hg levels above the World Health Organization guideline for fish consumption (0.5 MUg/g). A positive and significant relationship was observed between Hg concentrations in muscle and the age of the specimens. The dose-response approach suggests that close to 27.4 years is required for half of the exposed specimens to attain 0.5 MUg/g. The hazard quotient (HQ) is a risk indicator which defines the ratio of exposure level and a toxicological reference dose. HQ resulted above the unity for all the specimens when the ingestion rate for riverine communities (200 g of muscle per day) is considered, indicating the existence of hazard. When the ingestion rate for market consumers (28.57 g/day) is considered, the risks are much lower (mean HQ = 0.55), suggesting that such group is not at risk. The establishment of local and regional ingestion rates for riverine populations and market consumers is extremely recommended. PMID- 25017871 TI - Experimental study on the survival of the water hyacinth (Eichhornia crassipes (Mart.) Solms--Pontederiaceae) under different oil doses and times of exposure. AB - In the last decades, petroleum activities have increased in the Brazilian Amazon where there is oil exploration on the Urucu River, a tributary of the Amazon River, about 600 km from the city of Manaus. Particularly, transportation via the Amazon River to reach the oil refinery in Manaus may compromise the integrity of the large floodplains that flank hundreds of kilometers of this major river. In the Amazon floodplains, plant growth and nutrient cycling are related to the flood pulse. When oil spills occur, floating oil on the water surface is dispersed through wind and wave action in the littoral region, thus affecting the vegetation of terrestrial and aquatic environments. If pollutants enter the system, they are absorbed by plants and distributed in the food chain via plant consumption, mortality, and decomposition. The effect of oil on the growth and survival of vegetation in these environments is virtually unknown. The water hyacinth [Eichhornia crassipes (Mart.) Solms] has a pantropical distribution but is native to the Amazon, often growing in high-density populations in the floodplains where it plays an important role as shelter and food source for aquatic and terrestrial biota. The species is well known for its high capacity to absorb and tolerate high levels of heavy metal ions. To study the survival and response of water hyacinth under six different oil doses, ranging from 0 to 150 ml l(-1), and five exposure times (1, 5, 10, 15, and 20 days), young individuals distributed in a completely randomized design experiment composed of vessels with a single individual each were followed over a 50-day period (30-day acclimatization, 20 days under oil treatments). Growth parameters, biomass, visual changes in the plants, and pH were recorded at 1, 5, 10, 15, and 20 days. Increasing the time of oil exposure caused a decrease in biomass, ratio of live/dead biomass and length of leaves, and an increase in the number of dead leaves. Dose of oil and time of exposure are the most important factors controlling the effects of petroleum hydrocarbons on E. crassipes. Although the species is able to survive exposure to a moderate dose of oil, below 75 ml l(-1) for only 5 days, severe alterations in plant growth and high mortality were observed. Therefore, we conclude that Urucu oil heavily affects E. crassipes despite its known resistance to many pollutants. PMID- 25017876 TI - Transdermal transport pathway creation: Electroporation pulse order. AB - In this study we consider the physics underlying electroporation which is administered to skin in order to radically increase transdermal drug delivery. The method involves the application of intense electric fields to alter the structure of the impermeable outer layer, the stratum corneum. A generally held view in the field of skin electroporation is that the skin's drop in resistance (to transport) is proportional to the total power of the pulses (which may be inferred by the number of pulses administered). Contrary to this belief, experiments conducted in this study show that the application of high voltage pulses prior to the application of low voltage pulses result in lower transport than when low voltage pulses alone are applied (when less total pulse power is administered). In order to reconcile these unexpected experimental results, a computational model is used to conduct an analysis which shows that the high density distribution of very small aqueous pathways through the stratum corneum associated with high voltage pulses is detrimental to the evolution of larger pathways that are associated with low voltage pulses. PMID- 25017872 TI - Identification of tissue-enriched novel transcripts and novel exons in mice. AB - BACKGROUND: RNA sequencing (RNA-seq) has revolutionized the detection of transcriptomic signatures due to its high-throughput sequencing ability. Therefore, genomic annotations on different animal species have been rapidly updated using information from tissue-enriched novel transcripts and novel exons. RESULTS: 34 putative novel transcripts and 236 putative tissue-enriched exons were identified using RNA-Seq datasets representing six tissues available in mouse databases. RT-PCR results indicated that expression of 21 and 2 novel transcripts were enriched in testes and liver, respectively, while 31 of the 39 selected novel exons were detected in the testes or heart. The novel isoforms containing the identified novel exons exhibited more dominant expression than the known isoforms in heart and testes. We also identified an example of pathology associated exclusion of heart-enriched novel exons such as Sorbs1 and Cluh during pressure-overload cardiac hypertrophy. CONCLUSION: The present study depicted tissue-enriched novel transcripts, a tissue-specific isoform switch, and pathology-associated alternative splicing in a mouse model, suggesting tissue specific genomic diversity and plasticity. PMID- 25017877 TI - 2nd European Conference on the Biology of Hydrogen Sulfide, Exeter, England 8th 11th September 2013. PMID- 25017878 TI - Promiscuous and specific recognition among ephrins and Eph receptors. AB - Eph-ephrin interactions control the signal transduction between cells and play an important role in carcinogenesis and other diseases. The interactions between Eph receptors and ephrins of the same subclass are promiscuous; there are cross interactions between some subclasses, but not all. To understand how Eph-ephrin interactions can be both promiscuous and specific, we investigated sixteen energy landscapes of four Eph receptors (A2, A4, B2, and B4) interacting with four ephrin ligands (A1, A2, A5, and B2). We generated conformational ensembles and recognition energy landscapes starting from separated Eph and ephrin molecules and proceeding up to the formation of Eph-ephrin complexes. Analysis of the Eph ephrin recognition trajectories and the co-evolution entropy of 400 ligand binding domains of Eph receptor and 241 ephrin ligands identified conserved residues during the recognition process. Our study correctly predicted the promiscuity and specificity of the interactions and provided insights into their recognition. The dynamic conformational changes during Eph-ephrin recognition can be described by progressive conformational selection and population shift events, with two dynamic salt bridges between EphB4 and ephrin-B2 contributing to the specific recognition. EphA3 cancer-related mutations lowered the binding energies. The specificity is not only controlled by the final stage of the interaction across the protein-protein interface, but also has large contributions from binding kinetics with the help of dynamic intermediates along the pathway from the separated Eph and ephrin to the Eph-ephrin complex. PMID- 25017879 TI - Midkine and syndecan-1 levels correlate with the progression of malignant gastric cardiac adenocarcinoma. AB - The present study aimed to determine whether the expression levels of midkine (MK) and syndecan-1 correlate with the malignant progression and poor prognosis of gastric cardiac adenocarcinoma (GCA). GCA tissue samples (n=72) were obtained from the Department of Pathology of the First Affiliated Hospital of Henan University of Science and Technology (Luoyang, China). The paraffin-embedded samples had been surgically resected and pathologically diagnosed between 2007 and 2009. Normal gastric cardiac biopsy specimens (n=40) were also collected as the control. The expression levels of MK and syndecan-1 were assessed by immunohistochemistry using the high-sensitivity streptavidin-peroxidase method. Statistical analysis was performed on the data obtained using the SPSS 17.0 statistics package. MK expression was detected in 76.4% of GCA samples and 5% of normal gastric cardiac mucosa specimens. A significant positive correlation was observed between the expression levels of MK and the infiltrative depth of the tumor, the presence of lymph node metastasis and the prognosis of the patients (P<0.05). Syndecan-1 expression was detected in 38.9% of GCA samples and 100% of normal gastric cardiac mucosa samples. The expression levels of syndecan-1 were negatively correlated with the grade of differentiation, serosal membrane invasion, lymph node metastasis and the patient's prognosis (P<0.05). Notably, the expression levels of MK and syndecan-1 were inversely correlated (r=-0.352, P<0.01) in the GCA tissue samples. These results suggest that high expression levels of MK in GCA tissues may indicate a differentiation stage that is characteristic of malignancy, a late clinical stage and a poor prognosis, whereas increased syndecan-1 levels may indicate a high degree of differentiation, an early clinical stage and a favorable prognosis. MK and syndecan-1 may serve as important biomarkers for monitoring the development and progression of GCA. PMID- 25017880 TI - Extensively drug-resistant tuberculosis. The way out from the alley: "Tuberculosis ultrarresistente". PMID- 25017881 TI - Development and survival of Ascaris suum eggs in deep litter of pigs. AB - SUMMARY Indoor transmission of Ascaris suum partly depends on the physico chemical conditions in bedding material. Temperature, pH, aqueous ammonia, moisture, occurrence and development of A. suum eggs were therefore compared in different areas (resting, intermediate and latrine) of two deep litter pens on an organic farm in four seasons. There was some variation, but mean ammonia levels were generally very low (1.0-2.6 mm) and pH levels were moderate (8.04-8.88) in all three areas. Relatively, resting areas were characterized by overall moderate moisture (36%) and moderately high temperature (35.7 degrees C) levels. The area contained few eggs (50 eggs g-1 DM) of which 17% were viable, and though only 4% were larvated and 0.7% appeared infective, it was more than in the other areas. Intermediate areas had moderate moisture (43%) and high temperature (43.6 degrees C) levels. There were many eggs (523 eggs g-1 DM), but overall viability was very low (5%) and few eggs were larvated (0.004%) or even infective (0.002%). Latrines typically had high moisture (79%) and moderate temperature (30 degrees C) levels. The concentration of eggs was very high (1444 egg g-1 DM) and though 32% were viable, none had developed larval stages. The large majority of A. suum eggs appear to die and only few become infective while in the deep litter. However, a large fraction of eggs may remain viable for some time and could thus contaminate agricultural land and develop to infectivity, if the manure is not composted appropriately. PMID- 25017882 TI - Tracheostomy and invasive ventilation in Japanese ALS patients: decision-making and survival analysis: 1990-2010. AB - OBJECTIVE: To evaluate the factors related to the choice of a tracheostomy and invasive ventilation in amyotrophic lateral sclerosis patients and to determine survival time after a tracheostomy at a single institute in Japan between 1990 and 2010. METHODS: Data for survival time until death or tracheostomy were obtained from 160 patients. Fifty-two patients (33%) underwent tracheostomy/mechanical ventilation. RESULTS: Tracheostomy and invasive ventilation prolonged median survival time (74 months), as did non-invasive ventilation (48 months) when compared to a non-ventilation-supported control group (32 months; p<0.001 each). The ratio of tracheostomy/mechanical ventilation in patients >65 years old significantly increased after 1999 (27%) compared to earlier years (10%, p=0.002). Cox proportional modeling confirmed an age of <=65 years as advantageous for long-term survival after a tracheostomy. In univariate logistic regression analysis, factors related to the decision to perform a tracheostomy included an age of <=65 years, greater use of non-invasive ventilation, the presence of a spouse, interval and speed from disease onset to diagnosis/tracheostomy and preservation of motor function. In multivariate logistic regression analysis, age, shorter duration from disease onset until tracheostomy and the presence of a spouse were independently associated with the decision to perform a tracheostomy. Kaplan-Meier plots revealed longer survival times in patients who resided at home after a tracheostomy compared to patients who stayed at a hospital (p=0.007). CONCLUSIONS: Tracheostomy and invasive ventilation are frequently used in Japan. Various factors impact patients' decisions to have these procedures. This study identified factors related to the decision-making process and post-tracheostomy survival. PMID- 25017884 TI - Pleiotropic molecules in axon regeneration and neuroinflammation. AB - Neuroinflammation is the foremost defense reaction of the nervous system to most if not all insults. Injuries to the central and peripheral nervous system (CNS and PNS) are followed by immediate activation of innate immune cells and infiltration of peripheral immune cells, amid waves of upregulation of numerous inflammatory mediators. Prolonged inflammation can lead to secondary tissue damage and prohibit regeneration of the injured nervous system. The regulation of inflammation and neuroregeneration are orchestrated through a complex network of signal transduction. Interestingly, many molecules play pleiotropic roles in both processes. Growing evidence implicates a handful of axon regeneration regulators in the processes of neuroinflammation, among which are the myelin and glial scar associated axon growth inhibitors and their axonal receptors. In this article, we will review the roles of these canonical axon regeneration regulators in neuroinflammation. PMID- 25017883 TI - Pattern recognition receptors and central nervous system repair. AB - Pattern recognition receptors (PRRs) are part of the innate immune response and were originally discovered for their role in recognizing pathogens by ligating specific pathogen associated molecular patterns (PAMPs) expressed by microbes. Now the role of PRRs in sterile inflammation is also appreciated, responding to endogenous stimuli referred to as "damage associated molecular patterns" (DAMPs) instead of PAMPs. The main families of PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-like receptors (RLRs), AIM2-like receptors (ALRs), and C-type lectin receptors. Broad expression of these PRRs in the CNS and the release of DAMPs in and around sites of injury suggest an important role for these receptor families in mediating post-injury inflammation. Considerable data now show that PRRs are among the first responders to CNS injury and activation of these receptors on microglia, neurons, and astrocytes triggers an innate immune response in the brain and spinal cord. Here we discuss how the various PRR families are activated and can influence injury and repair processes following CNS injury. PMID- 25017886 TI - Complement and spinal cord injury: traditional and non-traditional aspects of complement cascade function in the injured spinal cord microenvironment. AB - The pathology associated with spinal cord injury (SCI) is caused not only by primary mechanical trauma, but also by secondary responses of the injured CNS. The inflammatory response to SCI is robust and plays an important but complex role in the progression of many secondary injury-associated pathways. Although recent studies have begun to dissect the beneficial and detrimental roles for inflammatory cells and proteins after SCI, many of these neuroimmune interactions are debated, not well understood, or completely unexplored. In this regard, the complement cascade is a key component of the inflammatory response to SCI, but is largely underappreciated, and our understanding of its diverse interactions and effects in this pathological environment is limited. In this review, we discuss complement in the context of SCI, first in relation to traditional functions for complement cascade activation, and then in relation to novel roles for complement proteins in a variety of models. PMID- 25017887 TI - Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. AB - Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain. PMID- 25017888 TI - Cytokine pathways regulating glial and leukocyte function after spinal cord and peripheral nerve injury. AB - Injury to the nervous system causes the almost immediate release of cytokines by glial cells and neurons. These cytokines orchestrate a complex array of responses leading to microgliosis, immune cell recruitment, astrogliosis, scarring, and the clearance of cellular debris, all steps that affect neuronal survival and repair. This review will focus on cytokines released after spinal cord and peripheral nerve injury and the primary signalling pathways triggered by these inflammatory mediators. Notably, the following cytokine families will be covered: IL-1, TNF, IL-6-like, TGF-beta, and IL-10. Whether interfering with cytokine signalling could lead to novel therapies will also be discussed. Finally, the review will address whether manipulating the above-mentioned cytokine families and signalling pathways could exert distinct effects in the injured spinal cord versus peripheral nerve. PMID- 25017885 TI - Extracellular matrix regulation of inflammation in the healthy and injured spinal cord. AB - Throughout the body, the extracellular matrix (ECM) provides structure and organization to tissues and also helps regulate cell migration and intercellular communication. In the injured spinal cord (or brain), changes in the composition and structure of the ECM undoubtedly contribute to regeneration failure. Less appreciated is how the native and injured ECM influences intraspinal inflammation and, conversely, how neuroinflammation affects the synthesis and deposition of ECM after CNS injury. In all tissues, inflammation can be initiated and propagated by ECM disruption. Molecules of ECM newly liberated by injury or inflammation include hyaluronan fragments, tenascins, and sulfated proteoglycans. These act as "damage-associated molecular patterns" or "alarmins", i.e., endogenous proteins that trigger and subsequently amplify inflammation. Activated inflammatory cells, in turn, further damage the ECM by releasing degradative enzymes including matrix metalloproteinases (MMPs). After spinal cord injury (SCI), destabilization or alteration of the structural and chemical compositions of the ECM affects migration, communication, and survival of all cells - neural and non-neural - that are critical for spinal cord repair. By stabilizing ECM structure or modifying their ability to trigger the degradative effects of inflammation, it may be possible to create an environment that is more conducive to tissue repair and axon plasticity after SCI. PMID- 25017889 TI - Lymphocytes and autoimmunity after spinal cord injury. AB - Over the past 15 years an immense amount of data has accumulated regarding the infiltration and activation of lymphocytes in the traumatized spinal cord. Although the impact of the intraspinal accumulation of lymphocytes is still unclear, modulation of the adaptive immune response via active and passive vaccination is being evaluated for its preclinical efficacy in improving the outcome for spinal-injured individuals. The complexity of the interaction between the nervous and the immune systems is highlighted in the contradictions that appear in response to these modulations. Current evidence regarding augmentation and inhibition of the adaptive immune response to spinal cord injury is reviewed with an aim toward reconciling conflicting data and providing consensus issues that may be exploited in future therapies. Opportunities such an approach may provide are highlighted as well as the obstacles that must be overcome before such approaches can be translated into clinical trials. PMID- 25017890 TI - Immune modulatory therapies for spinal cord injury--past, present and future. AB - Historically, the immune response after spinal cord injury was considered largely detrimental owing to the release of neurotoxic factors. While there is validity to this view, there is much greater heterogeneity of immune cells than was previously realized. Associated with this heterogeneity of immune cell subtypes, there is diversity of functions of immune cells that is still poorly understood after spinal cord injury. Modulating the immune system requires improved understanding of the major players: those immune cell subtypes that are more detrimental than beneficial and those that are important in repair. In this review we will discuss the early findings that supported the use of various anti inflammatory medications as well as the evolving concept that not all immune subtypes are detrimental and some might even be beneficial. In the last section we will highlight the need to characterize better the role of immune cell subsets in the hopes of developing potential therapeutic targets for the future. PMID- 25017891 TI - The systemic response to CNS injury. AB - Inflammation within the brain or spinal cord has the capacity to damage neurons and is known to contribute to long-term disability in a spectrum of central nervous system (CNS) pathologies. However, there is a more profound increase in the recruitment of potentially damaging populations of leukocytes to the spinal cord than to the brain after equivalent injuries. Increased levels of inflammatory cytokines and chemokines in the spinal cord underpin this dissimilarity after injury, which also appears to be very sensitive to processes that operate within organs distant from the primary injury site such as the liver, lung and spleen. Indeed, CNS injury per se can generate profound changes in gene expression and the cellularity of these organs, which, as a consequence, gives rise to secondary organ damage. Our understanding of the local inflammatory processes that can damage neurons is becoming clearer, but our understanding of how the peripheral immune system coordinates the response to CNS injury and how any concomitant infections or injury might impact on the outcome of CNS injury is not so well developed. It is clear that the orientation of the response to peripheral challenges, be it a pro- or anti-inflammatory effect, appears to be dependent on the nature and timing of events. Here, the importance of the inter relationship between inflammation in the CNS and the consequent inflammatory response in peripheral tissues is highlighted. PMID- 25017892 TI - Is neuroinflammation in the injured spinal cord different than in the brain? Examining intrinsic differences between the brain and spinal cord. AB - The field of neuroimmunology is rapidly advancing. There is a growing appreciation for heterogeneity, both in inflammatory composition and region specific inflammatory responses. This understanding underscores the importance of developing targeted immunomodulatory therapies for treating neurological disorders. Concerning neurotrauma, there is a dearth of publications directly comparing inflammatory responses in the brain and spinal cord after injury. The question therefore remains as to whether inflammatory cells responding to spinal cord vs. brain injury adopt similar functions and are therefore amenable to common therapies. In this review, we address this question while revisiting and modernizing the conclusions from publications that have directly compared inflammation across brain and spinal cord injuries. By examining molecular differences, anatomical variations, and inflammatory cell phenotypes between the injured brain and spinal cord, we provide insight into how neuroinflammation relates to neurotrauma and into fundamental differences between the brain and spinal cord. PMID- 25017893 TI - The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. AB - During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity. PMID- 25017895 TI - Differential distribution of hypoxia-inducible factor 1-beta (ARNT or ARNT2) in mouse substantia nigra and ventral tegmental area. AB - Hypoxia has been proposed as a mechanism underlying gene-environment interactions in the neurodevelopmental model of schizophrenia, and hypoxia-inducible factor 1 (HIF-1) could mediate the interactions. In the current study, we analyzed the HIF 1 beta subunit, as formed by aryl hydrocarbon receptor nuclear translocator (ARNT) or ARNT2, in the mouse substantia nigra (SN) and the ventral tegmental area (VTA). We performed immunohistochemical studies of ARNT and ARNT2 in the adult mouse brain, and colocalization analyses, with specific emphasis on dopaminergic cells, i.e. tyrosine hydroxylase (TH) immunoreactive cells. Bioinformatic analyses identified shared protein partners for ARNT and ARNT2. ARNT immunoreactivity showed widespread neuronal labeling without overt regional specificity. We observed co-localization of ARNT and TH in the SN compacta and VTA. Nuclei strongly labeled for ARNT2 were observed in the SN reticulata, while only weak immunoreactivity for ARNT2 was found in TH-immunoreactive neurons in SN compacta and VTA. Stereological analysis showed that ARNT was preferentially expressed in dopaminergic neurons in SN compacta and VTA. Nuclei strongly labeled for ARNT2 were present in neocortex and CA1 of hippocampus. Differential expression of ARNT and ARNT2 in dopaminergic neurons may relate to the vulnerability of distinct dopaminergic projections to hypoxia and to functional vulnerability in schizophrenia and other neuropsychiatric disorders. PMID- 25017896 TI - Influence of hormonal therapy in prostate cancer patients undergoing [18F]fluoromethyl choline PET/CT: a retrospective study. AB - BACKGROUND: Patients with suspected recurrence of prostate cancer undergoing [18F]fluoromethyl choline ([18F]FCH) PET/CT were retrospectively evaluated to investigate the influence of hormonal therapy (HT) in [18F]FCH uptake. METHODS: [18F]FCH PET/CT was performed in 102 surgically treated patients with suspected recurrence (PSA increase >0.2 ng/mL) of prostate cancer, divided in two groups: under HT (N.=54) and without HT (N.=48) at the time of PET scanning. PET/CT was carried out by an integrated system (Biograph 6, CTI/Siemens, Knoxville, TN, USA) intravenously by administering 4.1 MBq/kg of [18F]FCH to each patient; images were acquired 60 minutes later. RESULTS: On the total number of patients, 66 were found to be true positives (TP), 9 false positives (FP), 5 false negatives (FN) and 22 true negatives (TN), sensitivity to [18F]FCH PET/CT was 93%, specificity 71%, accuracy 86%, positive predictive value (PPV) 88%, negative predictive value (NPV) 81%. In the 54 patients under HT, 38 were TP, 6 FP, 3 FN and 7 TN, sensitivity was 93%, specificity 54%, accuracy 83%, PPV 86% and NPV was 70%. In the 48 patients receiving no HT, 28 were TP, 3 FP, 2 FN and 15 TN, sensitivity was 93%, specificity 83%, accuracy 90%, PPV 90% and NPV 88%. A chi2 test showed that sensitivity, accuracy and PPV did not differ among patients with and without HT, while specificity and NPV were significantly lower (P<0.001) in HT treated patients. CONCLUSIONS: Sensitivity, accuracy and PPV were similar in patients with and without HT. Specificity and NPV were reduced in patients under HT, but further data are necessary to support if this reduction is casual or related to therapy and it could be confirmed in a larger series of patients. PMID- 25017894 TI - Non-mammalian model systems for studying neuro-immune interactions after spinal cord injury. AB - Mammals exhibit poor recovery after injury to the spinal cord, where the loss of neurons and neuronal connections can be functionally devastating. In contrast, it has long been appreciated that many non-mammalian vertebrate species exhibit significant spontaneous functional recovery after spinal cord injury (SCI). Identifying the biological responses that support an organism's inability or ability to recover function after SCI is an important scientific and medical question. While recent advances have been made in understanding the responses to SCI in mammals, we remain without an effective clinical therapy for SCI. A comparative biological approach to understanding responses to SCI in non mammalian vertebrates will yield important insights into mechanisms that promote recovery after SCI. Presently, mechanistic studies aimed at elucidating responses, both intrinsic and extrinsic to neurons, that result in different regenerative capacities after SCI across vertebrates are just in their early stages. There are several inhibitory mechanisms proposed to impede recovery from SCI in mammals, including reactive gliosis and scarring, myelin associated proteins, and a suboptimal immune response. One hypothesis to explain the robust regenerative capacity of several non-mammalian vertebrates is a lack of some or all of these inhibitory signals. This review presents the current knowledge of immune responses to SCI in several non-mammalian species that achieve anatomical and functional recovery after SCI. This subject is of growing interest, as studies increasingly show both beneficial and detrimental roles of the immune response following SCI in mammals. A long-term goal of biomedical research in all experimental models of SCI is to understand how to promote functional recovery after SCI in humans. Therefore, understanding immune responses to SCI in non mammalian vertebrates that achieve functional recovery spontaneously may identify novel strategies to modulate immune responses in less regenerative species and promote recovery after SCI. PMID- 25017897 TI - [18F]FDG-PET scan in patients with fasting hyperglycemia. AB - BACKGROUND: It is generally accepted that a non-fasting state reduces [18F]FDG PET quality, but the significance of higher levels of fasting blood glucose has aroused some doubts over time. The aim of this work was to provide further evidence to clarify this issue and its impact on the handling of hyperglycemic patients in daily routine. METHODS: Muscle and liver standardized uptake values (SUV) and their ratio, tumor SUV and the frequency of positive PET findings were retrospectively analyzed in 116 hyperglycemic (HG) patients (>11 mmol/L), in 116 patients with slightly elevated glycemia (SEG) (5.6-7.0 mmol/L) and in 116 normoglycemic (NG) patients (4.7 mmol/L). RESULTS: No significant difference was found in the muscle to liver ratio, in muscle SUV and in the frequency of positive PET findings among HG, SEG and NG patients. HG patients exhibited ~10% higher liver SUV in comparison to SEG and NG patients; a positive correlation (r=0.2849) was found between liver SUV and blood glucose levels. Significantly higher tumor SUV was present in SEG patients. CONCLUSIONS: We did not confirm that hyperglycemia in a fasting state negatively influences the diagnostic quality of [18F]FDG-PET. The positive correlation between liver SUV and blood glucose levels is clinically negligible and might be explained by increased fasting hepatic gluconeogenesis in diabetics. Our data encourage the performance of [18F]FDG-PET investigations under fasting conditions, regardless of the mild to medium elevation of fasting blood glucose level. PMID- 25017898 TI - Stereoselective construction of a key hydroindole precursor of epidithiodiketopiperazine (ETP) natural products. AB - An asymmetric synthetic strategy for constructing the divergent-synthesis monomer of epidithiodiketopiperazine (ETP) natural products has been successfully developed. The functionalized 2,3,3a,4,7,7a-hexahydroindole scaffold was constructed by a diastereoselective inverse electron-demand Diels-Alder (IEDDA) reaction. PMID- 25017899 TI - Prevalence of voice & swallowing complaints in Pre-operative thyroidectomy patients: a prospective cohort study. AB - BACKGROUND: Compressive symptoms are common in patients with thyroid disease and are an accepted indication for thyroidectomy. The objective of this study was to evaluate the prevalence and severity of voice and swallowing complaints in pre operative thyroidectomy patients and to compare these with thyroid volume, thyroid pathology and laryngopharyngeal reflux. METHODS: A consecutive case series design was performed. All patients undergoing a thyroidectomy (partial or total) at a tertiary care centre during a 2 year period were invited to participate. Fifty nine (10 male, 49 female) aged 19-73 were enrolled (59.3% total thyroidectomy, 40.7% partial thyroidectomy). Voice and swallowing complaints were subjectively evaluated using the Voice Handicap Index (VHI) and the Modified Swallowing Impairment Score (MSIS), respectively. All patients completed the Reflux Symptom Index (RSI) and underwent videostroboscopy. Vocal function was objectively evaluated using perceptual ratings (GRBAS) and acoustic voice analysis (jitter, shimmer, maximum phonation time, maximum fundamental frequency range). The relationship between voice and swallowing symptoms was compared with thyroid volume and surgical pathology. RESULTS AND DISCUSSION: The average VHI score was 8.39, representing normal voice scores. Of the objective voice measures, only jitter and a subset of GRBAS measures were slightly elevated. Swallowing complaints were reported at least "some of the time" by 25 patients (41.7%), and "often or always" by 16 patients (26.7%). Of the patients with voice and swallowing complaints, 68.4% and 56%, respectively, had elevated RSI scores consistent with laryngopharyngeal reflux. No correlation was found with thyroid volume or thyroid pathology. CONCLUSIONS: Swallowing complaints appear to be common in pre-operative thyroidectomy patients. A large percentage, however, have associated laryngopharyngeal reflux which may in part account for these symptoms. Patients presenting with compressive thyroid symptoms should be evaluated for laryngopharyngeal reflux, and treated where appropriate. PMID- 25017900 TI - Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition. AB - Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras. PMID- 25017901 TI - Evaluation of fluorescent stains for visualizing extracellular DNA in biofilms. AB - Here we determine an optimal technique for the visualization of extracellular DNA in bacterial biofilms using the fluorescent eDNA stain TOTO-1 and the counterstain SYTO 60. This technique allows for more sensitive eDNA visualization than other fluorescent staining methods currently in use. PMID- 25017902 TI - An efficient and rapid method for the enumeration of heterotrophic prokaryotes in coastal sediments by flow cytometry. AB - Flow cytometry offers an easy and powerful way to assess multi-parametric data in different domains, notably in the environmental sciences. Because evaluating heterotrophic prokaryotic abundance is crucial to understand an ecosystem's functioning, we propose a quick and efficient protocol for (1) cell's detachment in muddy coastal sediments followed by (2) enumeration of prokaryotes by flow cytometry compared to epifluorescence microscopy and (3) a type of storage adapted for benthic samples. First, sample preparation by incubation in a detergent mix containing sodium pyrophosphate (0.01M final concentration) and Tween 80 (0.1% final concentration) drastically increased cell detachment from sediment particles (+130.40%) compared to extraction with sodium pyrophosphate only. Cell sorting allowed to control the efficiency of the extraction as few cells were found attached to sediment particles in epifluorescence microscopy after sorting. Flow cytometry gave consistent results with strong reliability by counting 1.81 times more cells compared to epifluorescence microscopy. Thirdly, results revealed that sediment samples fixed with formaldehyde and then liquid-N2 frozen and directly stored at -80 degrees C can be analyzed within 3months. In routine, our method of extraction and counting allowed to evaluate 83.67% of the real abundance in a sediment sample. Finally, this optimized technique was applied on sandy and muddy coastal and freshwater sediments and allowed us to prove the high efficiency of this new method. Flow cytometry is a fast, replicable and low-cost method for counting heterotrophic prokaryotes, even for sediment samples. The two-step method that we developed enables high frequency analyses (30 samples in less than 4h). PMID- 25017903 TI - Imaging of T-cell receptor fused to CD3zeta reveals enhanced expression and improved pairing in living cells. AB - T cell receptor (TCR) gene adoptive therapy is a promising clinical approach for the treatment of malignant tumors and viral diseases. However, the effectiveness of this strategy is hampered by the generation of mixed TCR heterodimers comprising both exogenous and endogenous TCR chains (i.e., mispairing of TCR chains). In the present study, we constructed genetically encoded reporters fused to a pair of fluorescent proteins [enhanced cyan fluorescent protein (ECFP)/enhanced yellow fluorescent protein (EYFP)] to monitor the expression of TCRalphazetabetazeta and pairing between TCRalphazeta and TCRbetazeta. We demonstrate that these reporters provide accurate images of TCRalphazetabetazeta expression, which is markedly stronger with evident microclusters accumulated at the plasma membrane compared to wild-type (wt)TCR. Using fluorescence resonance energy transfer (FRET) analysis, we demonstrate that, in addition to the improved pairing, the expression and assembly of TCRalphazetabetazeta are independent of endogenous CD3 subunits. These results suggest that the fusion genes, TCRalphazeta and TCRbetazeta, coupled to ECFP and EYFP, respectively can effectively monitor the expression and interaction in cells. Our data suggest a novel strategy with which it is possible to effectively express and pair TCRalphazetabetazeta, thus making TCR gene adoptive therapy more effective. PMID- 25017904 TI - Mean platelet volume and coronary artery disease: a systematic review and meta analysis. AB - BACKGROUND: Platelets with high hemostatic activity play an important role in the pathophysiology of coronary artery disease(CAD) and mean platelet volume(MPV) has been proposed as an indicator of platelet reactivity. Thus, MPV may emerge as a potential marker of CAD risk. The aim of this study was to conduct a systematic review and meta-analysis comparing mean difference in MPV between patients with CAD and controls and pooling the odds ratio of CAD in those with high versus low MPV. METHODS: Medline and Scopus databases were searched up to 12 March 2013. All observational studies that considered MPV as a study's factor and measured CAD as an outcome were included. Two reviewers independently selected the studies and extracted the data. RESULTS: Forty studies were included in this meta-analysis. The MPV was significantly larger in patients with CAD than controls with the unstandardized mean difference of 0.70 fL (95% CI: 0.55, 0.85). The unstandardized mean difference of MPV in patients with acute coronary event and in patients with chronic stable angina was 0.84 fL (95% CI: 0.63, 1.04) and 0.46 fL (95% CI: 0.11, 0.81) respectively. Patients with larger MPV (>=7.3 fL) also had a greater odds of having CAD than patients with smaller MPV with a pooled odds ratio of 2.28 (95% CI: 1.46, 3.58). CONCLUSION: Larger MPV was associated with CAD. Thus, it might be helpful in risk stratification, or improvement of risk prediction if combining it with other risk factors in risk prediction models. PMID- 25017905 TI - RORalpha suppresses proliferation of vascular smooth muscle cells through activation of AMP-activated protein kinase. AB - BACKGROUND: Retinoic acid-related orphan receptor alpha (RORalpha) has been implicated in the progression of atherosclerosis, but its role in the proliferation of vascular smooth muscle cells (vSMCs) has not been fully examined. We previously reported that RORalpha activates AMP-activated protein kinase (AMPK), which is associated with the suppression of vSMC proliferation. Therefore, we investigated the suppressive function of RORalpha on the proliferation of vSMCs and the molecular mechanisms involved. RESULTS: First, RORalpha and its activator, cholesterol sulfate (CS), induced the activation of AMPK in both human aortic SMCs and rat A7r5 cells, which was accompanied by the suppression of mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase 1. Second, RORalpha and CS modulated the expression of cell-cycle regulating factors, such as p53, p27, and cyclin D in vSMCs. Consistent with this, the overexpression of RORalpha or CS treatment suppressed the proliferation of human aortic SMCs and rat A7r5 cells, possibly through G1 arrest. RORalpha and CS also inhibited the migration of A7r5 cells in two-dimensional and three dimensional cell migration assays. Finally, we demonstrated that the infusion of adenovirus encoding RORalpha into arteries suppressed neointima formation after balloon injury in rats. CONCLUSION: These results demonstrate that RORalpha inhibits vSMC proliferation through AMPK-induced mTOR suppression, and suggest that RORalpha is a therapeutic target for the cardiovascular diseases associated with vSMC proliferation. PMID- 25017906 TI - Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation. AB - BACKGROUND: Oxidative stress-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Several evidences indicate that ellagic acid (EA), a phenolic compound, contributes to cardiovascular health. This study was to investigate the effects of EA on endothelial dysfunction and atherosclerosis via antioxidant-related mechanisms. METHODS: In animal studies, wild-type (WT) C57BL/6 mice and apolipoprotein E-deficient mice (ApoE(-/-)) mice were fed: a high-fat (21%) diet (HFD) or a HFD plus with EA (HFD+EA), for 14weeks. Vascular reactivity was studied in mice aortas. The effect of EA in human umbilical vein endothelial cells (HAECs) exposed to hypochlorous acid (HOCl) was also investigated. RESULTS: Compared with animals on HFD alone, EA attenuated atherosclerosis in WT mice. In aortic rings from two mice models, EA significantly improved endothelium-dependent relaxation and attenuated HOCl induced endothelial dysfunction. Besides, EA significantly improved nitric oxide synthase activity, antioxidant capacity and markers of endothelial dysfunction in plasma. Western blot analysis showed that EA increased NF-E2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) expression in the aortas (P<0.05). In a separate experiment, EA did not protect against HOCl-induced endothelial dysfunction in arteries obtained from Nrf2 gene knockout mice compared with WT mice. In HAECs, EA prevented HOCl-induced cellular damage and induced HO-1 protein expression, and these effects markedly abolished by the siRNA of Nrf2. CONCLUSIONS: Our results provide further support for the protective effects of dietary EA particularly oxidant-induced endothelial dysfunction and atherosclerosis partly via Nrf2 activation. PMID- 25017907 TI - Differential impact of five coronary devices on plaque size: insights from the ABSORB and SPIRIT trials. AB - BACKGROUND: Coronary plaque size modification, by either local (device) or systemic treatments, has been the target for many years. METHODS: From ABSORB Cohort A (Absorb BVS 1.0), ABSORB Cohort B (Absorb BVS 1.1), SPIRIT FIRST (Multi Link Vision vs. Xience V) & SPIRIT II (Xience V vs. Taxus), we calculated the total plaque area (vessel minus lumen area - thus it comprises both compartments the plaque behind struts and the neointima.) changes by IVUS. RESULTS: A total of 313 patients were included. Comparison-at-6-month follow-up: All devices induced an increase in the total plaque area. The largest increase occurred with Vision and Taxus stents as compared to other devices [Absorb BVS (1.0 and 1.1) and Xience V], (p=0.0002). Comparison-at-2-year follow-up: Absorb BVS 1.1 had a larger increase from post procedure in total plaque compared to Absorb BVS 1.0, Xience V and Taxus (p=0.0499). However, in Absorb BVS 1.1 total plaque showed a reduction of 2.2% from 1 to 3 years. Specifically, the total plaque in the sequential cohorts of Absorb BVS 1.1 increased 16.2% from baseline to 2 years (Cohort B1) while at 3 years this increase is only 5% compared to baseline (Cohort B2). CONCLUSIONS: Local devices affect coronary plaque size differently and it depends on the platform (metallic vs. polymeric) and on whether it is a bare - or drug eluting stent. Coronary scaffolds appear to be a promising alternative to metallic stents since they allow plaque regression at long-term follow-up. PMID- 25017908 TI - A subdivided molecular architecture with separate features and stepwise emergence among proinsulin C-peptides. AB - The C-peptide of proinsulin exhibits multiple activities and several of the underlying molecular interactions are known. We recently showed that human C peptide is sub-divided into a tripartite architecture and that the pattern, rather than the exact residue positions, is a characteristic feature. We have now analyzed 75 proinsulins, ranging from fish to human and find a limited co evolution with insulin, but with many marked deviations. This suggests a complex relationship, in which not only insulin affects the evolution of C-peptide. A subdivided nature, however, is a characteristic feature among all C-peptides, with the N-terminal segment the one most conserved. This segment, ascribed chaperoning charge-interactions with insulin, suggests that the insulin interactions constitute a basic function, although largely shifting from Glu to Asp residues in C-peptides of lower life forms. A second conserved feature is a mid-segment with a high content of adjacent Pro and Gly residues, in mammalian C peptides compatible with a turn structure, but with fewer and more distantly interspaced such residues in the non-mammalian forms, and even absent in several fish forms. However, this segment of coelacanth C-peptide possesses a unique Cys distribution, capable of forming a disulfide-stabilized turn. Finally, the C terminal segment of mammalian C-peptides, ascribed a possible receptor interacting function, is not really discernable in the sub-mammalian forms. Combined, these patterns suggest an evolutionary stepwise acquisition of the tripartite mammalian C-peptide molecule, with insulin-interaction being ancestral, various turn stabilizations apparently of intermediate emergence, and possible receptor-interaction the most recent addition. PMID- 25017909 TI - Activation-induced structural change in the GluN1/GluN3A excitatory glycine receptor. AB - Unlike GluN2-containing N-methyl-d-aspartate (NMDA) receptors, which require both glycine and glutamate for activation, receptors composed of GluN1 and GluN3 subunits are activated by glycine alone. Here, we used atomic force microscopy (AFM) imaging to examine the response to activation of the GluN1/GluN3A excitatory glycine receptor. GluN1 and GluN3A subunits were shown to interact intimately within transfected tsA 201 cells. Isolated GluN1/GluN3A receptors integrated into lipid bilayers responded to addition of either glycine or d serine, but not glutamate, with a ~1 nm reduction in height of the extracellular domain. The height reduction in response to glycine was abolished by the glycine antagonist 5,7-dichlorokynurenic acid. Our results represent the first demonstration of the effect of activation on the conformation of this receptor. PMID- 25017910 TI - Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis. AB - Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra membrane proteolysis at the erythrocyte stage of malaria parasite life cycle. PMID- 25017911 TI - Structural optimization of SadA, an Fe(II)- and alpha-ketoglutarate-dependent dioxygenase targeting biocatalytic synthesis of N-succinyl-L-threo-3,4 dimethoxyphenylserine. AB - L-threo-3,4-Dihydroxyphenylserine (l-DOPS, Droxidopa) is a psychoactive drug and synthetic amino acid precursor that acts as a prodrug to the neurotransmitters. SadA, a dioxygenase from Burkholderia ambifaria AMMD, is an Fe(II)- and alpha ketoglutarate (KG)-dependent enzyme that catalyzes N-substituted branched-chain or aromatic l-amino acids. SadA is able to produce N-succinyl-l-threo-3,4 dimethoxyphenylserine (NSDOPS), which is a precursor of l-DOPS, by catalyzing the hydroxylation of N-succinyl-3,4-dimethoxyphenylalanine (NSDOPA). However, the catalytic activity of SadA toward NSDOPS is much lower than that toward N succinyl branched-chain l-amino acids. Here, we report an improved biocatalytic synthesis of NSDOPS with SadA. Structure-based protein engineering was applied to improve the alpha-KG turnover activity for the synthesis of NSDOPS. The G79A, G79A/F261W or G79A/F261R mutant showed a more than 6-fold increase in activity compared to that of the wild-type enzyme. The results provide a new insight into the substrate specificity toward NSDOPA and will be useful for the rational design of SadA mutants as a target of industrial biocatalysts. PMID- 25017912 TI - Down-regulation of lipoprotein lipase increases ABCA1-mediated cholesterol efflux in THP-1 macrophages. AB - The ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of excess cholesterol from foam cells to lipid-poor apolipoprotein A-I, in a process called reverse cholesterol transport. Lipoprotein lipase (LPL) is a lipolytic enzyme expressed by macrophages within atherosclerotic lesions. Lentivirus-mediated RNA interference was used to genetically knock-down (KD) the expression of LPL in THP 1 macrophages. Silencing of the LPL gene was confirmed by end-point PCR, real time PCR, and protein analysis. Suppression of LPL expression correlated with a 1.6-fold up-regulation of ABCA1 mRNA levels, and resulted in a 4.5-fold increase in ABCA1-dependent cholesterol efflux. Replenishing LPL by addition of purified bovine LPL to the cell culture media resulted in down-regulation of ABCA1 mediated cholesterol efflux in both wild-type and LPL knockdown cells. These findings suggest an inverse correlation between macrophage LPL levels and ABCA1 cholesterol transport activity. PMID- 25017913 TI - The tomato DWD motif-containing protein DDI1 interacts with the CUL4-DDB1-based ubiquitin ligase and plays a pivotal role in abiotic stress responses. AB - CULLIN4(CUL4)-DAMAGED DNA BINDING PROTEIN1 (DDB1)-based ubiquitin ligase plays significant roles in multiple physiological processes via ubiquitination-mediated degradation of relevant target proteins. The DDB1-CUL4-associated factor (DCAF) acts as substrate receptor in the CUL4-DDB1 ubiquitin ligase complex and determines substrate specificity. In this study, we identified a tomato (Solanum lycopersicum) DDB1-interacting (DDI1) protein as a DCAF protein involved in response to abiotic stresses, including UV radiation, high salinity and osmotic stress. Co-immunoprecipitation and bimolecular fluorescence complementation assay indicated that DDI1 associates with CUL4-DDB1 in the nucleus. Quantitative RT-PCR analysis indicated the DDI1 gene is induced by salt, mannitol and UV-C treatment. Moreover, transgenic tomato plants with overexpression or knockdown of the DDI1 gene exhibited enhanced or attenuated tolerance to salt/mannitol/UV-C, respectively. Thus, our data suggest that DDI1 functions as a substrate receptor of the CUL4-DDB1 ubiquitin ligase, positively regulating abiotic stress response in tomato. PMID- 25017914 TI - Eicosapentaenoic acid promotes thermogenic and fatty acid storage capacity in mouse subcutaneous adipocytes. AB - In this study, we determined if eicosapentaenoic acid (EPA) promotes beneficial metabolic activities of subcutaneous adipocytes. Stromal-vascular (SV) cells were isolated from inguinal adipose tissue of C57BL/6 mice and induced to differentiate into adipocytes. EPA effect on thermogenic and mitochondrial gene expression and oxidative metabolism were assessed in inguinal adipocytes. When added to SV cell cultures during 8 day differentiation, EPA significantly increased the expression of thermogenic genes UCP1-3, CIDEA and VEGFalpha. Moreover, EPA increased mitochondrial DNA content and the expression of genes involved in mitochondrial biogenesis including PGC1alpha, Nrf1 and COXiv. However, this effect was not perceived when EPA was added to mature inguinal adipocytes for 24h, suggesting that EPA exerts its browning effect via recruiting brite adipocytes. Consistently, long-term EPA treatment also upregulated AMPKalpha phosphorylation and CPT1 expression and increased glucose uptake and GLUT4 mRNA expression, suggesting improved mitochondrial oxidation. Additionally, EPA-treated adipocytes had enlarged lipid droplets and increased expression of triglyceride synthesis genes GPAT1 and GPAT3, while significantly decreased glycerol release and down-regulation of HSL and ATGL gene expression. We conclude that EPA enhances energy dissipation capacity by recruiting brite adipocytes to stimulate oxidative metabolism and reduces fatty acid release by facilitating fatty acid storage in subcutaneous adipocytes. PMID- 25017915 TI - A novel membrane inlet mass spectrometer method to measure 15NH44+ for isotope enrichment experiments in aquatic ecosystems. AB - Nitrogen (N) pollution in aquatic ecosystems has attracted much attention over the past decades, but the dynamics of this bioreactive element are difficult to measure in aquatic oxygen-transition environments. Nitrogen-transformation experiments often require measurement of (15)N-ammonium ((15)NH4(+)) ratios in small-volume (15)N-enriched samples. Published methods to determine N isotope ratios of dissolved ammonium require large samples and/or costly equipment and effort. We present a novel ("OX/MIMS") method to determine N isotope ratios for (15)NH4(+) in experimental waters previously enriched with (15)N compounds. Dissolved reduced (15)N (dominated by (15)NH4(+)) is oxidized with hypobromite iodine to nitrogen gas ((29)N2 and/or (30)N2) and analyzed by membrane inlet mass spectrometry (MIMS) to quantify (15)NH4(+) concentrations. The N isotope ratios, obtained by comparing the (15)NH4(+) to total ammonium (via autoanalyzer) concentrations, are compared to the ratios of prepared standards. The OX/MIMS method requires only small sample volumes of water (ca. 12 mL) or sediment slurries and is rapid, convenient, accurate, and precise (R(2) = 0.9994, p < 0.0001) over a range of salinities and (15)N/(14)N ratios. It can provide data needed to quantify rates of ammonium regeneration, potential ammonium uptake, and dissimilatory nitrate reduction to ammonium (DNRA). Isotope ratio results agreed closely (R = 0.998, P = 0.001) with those determined independently by isotope ratio mass spectrometry for DNRA measurements or by ammonium isotope retention time shift liquid chromatography for water-column N-cycling experiments. Application of OX/MIMS should simplify experimental approaches and improve understanding of N-cycling rates and fate in a variety of freshwater and marine environments. PMID- 25017918 TI - The ten advances that have defined modern cardiology. AB - Modern cardiology was born early in the twentieth century. Here I list and review what I believe to be the ten most important advances in the twentieth century in this field. They are as follows: electrocardiography, cholesterol-induced atherosclerosis, cardiac catheterization, cardiovascular surgery, coronary angiography and percutaneous coronary angioplasty, the coronary care unit, the development of new cardiovascular drugs, preventive cardiology, cardiac imaging, and implanted cardiac pacemakers/defibrillators. PMID- 25017921 TI - My approach to detecting atrial fibrillation. PMID- 25017919 TI - Renal denervation for refractory ventricular arrhythmias. AB - The autonomic nervous system is known to play a significant role in the genesis and persistence of arrhythmias. Neuromodulation has become a new therapeutic strategy for the treatment of ventricular arrhythmias. Catheter-based renal denervation (RDN) is being studied as a treatment option for drug-refractory hypertension. Ablation within the renal arteries, by altering efferent and afferent signaling, has the potential to improve blood pressure, as well as heart failure, atrial, and ventricular tachyarrhythmias. We present a brief review of the anatomic and pathophysiological rationale for RDN as an adjunctive treatment for ventricular tachyarrhythmias. PMID- 25017922 TI - Micronucleus assay in human lymphocytes after exposure to alloxydim sodium herbicide in vitro. AB - This study evaluates the cytotoxic and genotoxic potential of alloxydim sodium using micronucleus (MN) assay, in human peripheral lymphocytes. MN assay was used to investigate the genotoxic effects of alloxydim sodium in human peripheral lymphocytes treated with 250, 500, 750, 1,000 ug/ml concentrations of alloxydim sodium for 24 and 48 h. Solvent, negative and positive controls were also used in the experiments in parallel. The obtained results were evaluated in statistical analyses by using Dunnett-t test (two sided) and p < 0.05 was accepted as significant. Alloxydim sodium significantly increased the MN formation compared with the negative control, at both 750 and 1,000 ug/ml concentrations and treatment periods. We also evaluated the nuclear division index (NDI) for cytotoxicity of this pesticide in the experiment, and finally observed a significant decrease of the NDI values at all concentrations of alloxydim sodium and at both treatment periods. PMID- 25017923 TI - Invertible vesicles and micelles formed by dually-responsive diblock random copolymers in aqueous solutions. AB - Dually responsive diblock random copolymers poly(nPA0.8-co-DEAEMA0.2)-block poly(nPA0.8-co-EA0.2) were made from N-n-propylacrylamide (nPA), 2 (diethylamino)ethyl methacrylate (DEAEMA) and N-ethylacrylamide (EA) via reversible addition-fragmentation chain transfer (RAFT) polymerization. Copolymers of different block length ratios, poly(nPA28-co-DEAEMA7)-block poly(nPA29-co-EA7) (P1) and poly(nPA28-co-DEAEMA7)-block-poly(nPA70-co-EA18) (P2), self-assemble into vesicles and micelles, responding to external stimuli in aqueous solutions, and both show "schizophrenic" inversion behavior when the pH and temperature are varied. The relative lengths of the two blocks are shown to affect the self-assembly of amphiphilic diblock copolymers. P1 has a similar length for both blocks and forms spherical vesicles with the first block poly(nPA29-co-EA7) as the membrane inner layer at pH 7 and 37 degrees C (above the cloud point of the more hydrophobic block, CP1), while spherical micelle-like aggregates are obtained at pH 10 and 25 degrees C (above CP1) with the second block poly(nPA28-co-DEAEMA7) as the core. In comparison, P2 has a different block length ratio (1 : 3, thus a much longer second block) and forms spherical micelles above CP1 at both pH 7 (the second block as the core) and pH 10 (the first block as the core). Further aggregation was observed by heating the polymer solution above the cloud point of the more hydrophilic block (CP2). The variation of the length and chemical composition of the blocks allows the tuning of the responsiveness of the block copolymers toward both pH and temperature and determines the formation of either micelles or vesicles during the aggregation. PMID- 25017924 TI - Low-dose oral or non-oral hormone therapy: effects on C-reactive protein and atrial natriuretic peptide in menopause. AB - OBJECTIVE: To assess the effects of oral low-dose and non-oral hormone therapy (HT) on ultra-sensitive C-reactive protein (CRP), atrial natriuretic peptide (ANP), and cardiovascular risk factors in postmenopause. METHODS: In this randomized, cross-over study, 44 recently postmenopausal women, with no clinical evidence of cardiovascular disease, received oral low-dose HT (estradiol 1 mg + drospirenone 2 mg/day) for 3 months. Forty-two patients received non-oral, conventional HT (1.5 mg/day percutaneous 17beta-estradiol gel or equivalent for nasal route) for 3 months followed by 200 mg/day micronized progesterone by the vaginal route (14 days during each menstrual period). After 3 months, patients were crossed over without washout. Post-HT vs. pre-HT measures were determined: lipids, glucose, body mass index, waist circumference, fibrinogen, CRP-stratified levels, and ANP levels. The study was registered at clinical trials.gov (NCT01432028). RESULTS: The mean age was 51 +/- 3 years and the mean time since the menopause was 22 +/- 10 months. CRP-stratified high levels decreased in a higher number of non-oral HT patients, who moved to intermediate and low levels (p = 0.02). No effect of HT was observed on ANP levels (baseline 67.4 (18.4 104.5), low-dose oral 43.5 (14.4-95.9), non-oral 39.8 (15.5-67.5) pg/ml). Markers of endothelial function did not worsen with either low-dose oral or non-oral HT: von Willebrand factor (baseline 118 +/- 37%, low-dose oral 119 +/- 38%, non-oral 108 +/- 3%, p < 0.01), fibrinogen (baseline 356 +/- 58 mg/dl; low-dose oral 343 +/- 77 mg/dl; non-oral 326 +/- 71 mg/dl, p < 0.01). CONCLUSIONS: Low-dose oral and non-oral HT for 6 months had neutral or beneficial effects in recently postmenopausal women with no clinical evidence of cardiovascular disease. PMID- 25017925 TI - Improved pertussis vaccines based on adjuvants that induce cell-mediated immunity. AB - Bordetella pertussis is a Gram-negative bacterium that causes the severe and sometimes lethal respiratory disease whooping cough in infants and children. There has been a recent resurgence in the number of cases of pertussis in several countries with high vaccine coverage. This has been linked with waning or ineffective immunity induced by current acellular pertussis vaccines. These acellular pertussis vaccines are formulated with alum as the adjuvant, which promotes strong antibody responses but is less effective at inducing Th1-type responses crucial for effective bacterial clearance. Studies in animal models have demonstrated that replacing alum with alternative adjuvants, such as toll like receptor agonists, can promote more robust cell-mediated immunity and confer a high level of protection against infection following respiratory challenge. PMID- 25017933 TI - Editorial overview: Novel technologies in microbiology: Recent advances in techniques in microbiology. PMID- 25017934 TI - Laser-induced vibration of a thin soap film. AB - We report on the vibration of a thin soap film based on the optical radiation pressure force. The modulated low power laser induces a counter gravity flow in a vertical free-standing draining film. The thickness of the soap film is then higher in the upper region than in the lower region of the film. Moreover, the lifetime of the film is dramatically increased by a factor of 2. Since the laser beam only acts mechanically on the film interfaces, such a film can be employed in an optofluidic diaphragm pump, the interfaces behaving like a vibrating membrane and the liquid in-between being the fluid to be pumped. Such a pump could then be used in delicate micro-equipment, in chips where temperature variations are detrimental and even in biological systems. PMID- 25017936 TI - Galium verum aqueous extract strongly inhibits the motility of head and neck cancer cell lines and protects mucosal keratinocytes against toxic DNA damage. AB - Galium verum, also known as Lady's Bedstraw, is an herbaceous plant native to Europe and Asia, and has been used in traditional medicine as an anticancer medicine applied in most cases as a decoction. The influence of a Galium verum decoction on the head and neck cancer cell lines HLaC78 and FADU was analyzed and proved to be toxic in high doses on both cell lines. Cytotoxicity appeared to be influenced by expression of p-glycoprotein (MDR-1) in the carcinoma cell lines. Mucosal keratinocytes, although void of MDR-1 expression, showed only low sensitivity against high Galium concentrations. Sublethal doses of Galium extract acted as strong inhibitors of motility, as shown by a spheroid-based invasion analysis on Matrigel-coated surfaces. Inhibition of invasion was significantly more pronounced in the invasive HLaC78 cell line. mRNA expression analysis of matrix metalloproteinases MMP-2 and MMP-9 and their inhibitors TIMP-1/-2 revealed significant TIMP-1 upregulation after an 8-h Galium exposition in FADU cells. Gelatinolytic activity, however, was not influenced by Galium extract in HLaC78, in the FADU cells MMP-2/-9 activity was slightly increased after incubation with Galium extract. In primary mucosal keratinocytes, Galium decoction protected DNA against benz[a]pyrene, one of the most DNA toxic agents in cigarette smoke. In conclusion Galium extract may be useful as a preventive and/or a concomitant therapeutic approach in head and neck cancer. PMID- 25017937 TI - HIV in (and out of) the clinic: biomedicine, traditional medicine and spiritual healing in Harare. AB - Contemporary lived experiences of the human immunodeficiency virus (HIV) are shaped by clinical and cultural encounters with illness. In sub-Saharan countries such as Zimbabwe, HIV is treated in very different ways in various therapeutic contexts including by biomedical experts, traditional medicine and faith healers. The co-existence of such expertise raises important questions around the potencies and limits of medicalisation and alternative healing practices in promoting HIV recovery. First, in this study, drawing on in-depth qualitative interviews with 60 people from poor urban areas in Harare, we explore the experiences of people living with and affected by HIV. Specifically, we sought to document, interrogate and reflect on their perceptions and experiences of biomedicine in relation to traditional medicine and spiritual healing. Their accounts indicate that traditional medicine and spiritual beliefs continue to significantly influence the way in which HIV is understood, and the forms of help and care people seek. Second, we observe the dramatic and overwhelmingly beneficial impact of Antiretroviral Therapy and conclude through Zimbabwean's own stories that limitations around delivery and wider structural inequalities impede its potential. Lastly, we explore some practical implications of the biomedical clinic (and alternative healing practices) being understood as sites of ideological and expert contestation. This paper aimed to add to our knowledge of the relationships between traditional medicine and spiritual healing in connection with biomedicine and how this may influence HIV treatment and prevention. PMID- 25017938 TI - Randomized controlled trial of the acceptability, feasibility, and preliminary effects of a cognitive behavioral skills building intervention in adolescents with chronic daily headaches: a pilot study. AB - INTRODUCTION: The treatment challenge of adolescents with chronic daily headaches (CDHs) creates an urgent need for evidence-based interventions. Therefore the purpose of this pilot study was to evaluate the acceptability, feasibility, and preliminary effects of a brief cognitive behavioral skills building intervention with 36 adolescents, 13 to 17 years of age, who had CDHs and mild to moderate depressive symptoms. METHODS: Participants were randomly assigned either to the Creating Opportunities for Personal Empowerment-Headache Education Program (COPE HEP) or to a headache education comparison group. RESULTS: Adolescents and parents found the COPE-HEP to be highly acceptable. Medium to large positive effects were demonstrated on the adolescents' depression in both groups and on anxiety and beliefs in the COPE-HEP group. COPE-HEP offered additional benefits of a larger decrease in adolescent anxiety over time and stronger beliefs in the teens' ability to manage their headaches. DISCUSSION: Adolescents with CDHs and elevated depressive/anxiety symptoms should be offered headache hygiene education plus cognitive-behavioral skills building interventions. A full-scale trial to determine the more long-term benefits of COPE-HEP is now warranted. PMID- 25017939 TI - HPV vaccine hesitancy: findings from a statewide survey of health care providers. AB - INTRODUCTION: Health care provider recommendations are critical for human papillomavirus (HPV) vaccine uptake. We sought to describe providers' HPV vaccine recommendation practices and explore their perceptions of parental hesitancy. METHOD: A statewide sample (n = 575) of Minnesota health care providers (20% pediatricians, 47% family medicine physicians, and 33% nurse practitioners) completed our online survey in April 2013. RESULTS: Only 76% of health care providers reported routinely recommending HPV vaccine for girls ages 11 to 12 years, and far fewer (46%) did so for boys (p < .001). A majority of providers reported asking questions about parents' concerns (74%), but many lacked time to probe reasons (47%) or believed that they could not change parents' minds (55%). Higher levels of self-efficacy and outcome expectations were associated with routine recommendations (p < .05). DISCUSSION: Findings suggest that providers' perceptions of hesitancy may discourage them from routinely recommending the HPV vaccine. Improving providers' self-efficacy to address hesitancy may be important for improving vaccination rates. PMID- 25017940 TI - Rural adolescents' access to adolescent friendly health services. AB - INTRODUCTION: The purpose of this study was to assess rural North Dakota adolescents' experiences in accessing adolescent-friendly health services and to examine the relationship between rural adolescents' communication with health care providers and risk behaviors. METHODS: Data are from the Rural Adolescent Health Survey (RAHS), an anonymous survey of 14- to 19-year-olds (n = 322) attending secondary schools in four frontier counties of North Dakota. Descriptive statistics were used to assess participants' access to adolescent friendly health services characterized as accessible, acceptable, and appropriate. Logistic regressions were used to examine whether participant reported risk behaviors predicted communication with health care providers about individual health risk behaviors. RESULTS: Rural adolescents reported high access to acceptable primary health care services but low levels of effective health care services. Participant report of engaging in high-risk behaviors was associated with having received information from health care providers about the leading causes of morbidity and mortality. DISCUSSIONS: These findings reveal missed opportunities for primary care providers in rural settings to provide fundamental health promotion to adolescents. PMID- 25017941 TI - A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents. AB - BACKGROUND: Anorexia nervosa (AN) is a serious disorder incurring high costs due to hospitalization. International treatments vary, with prolonged hospitalizations in Europe and shorter hospitalizations in the USA. Uncontrolled studies suggest that longer initial hospitalizations that normalize weight produce better outcomes and fewer admissions than shorter hospitalizations with lower discharge weights. This study aimed to compare the effectiveness of hospitalization for weight restoration (WR) to medical stabilization (MS) in adolescent AN. METHOD: We performed a randomized controlled trial (RCT) with 82 adolescents, aged 12-18 years, with a DSM-IV diagnosis of AN and medical instability, admitted to two pediatric units in Australia. Participants were randomized to shorter hospitalization for MS or longer hospitalization for WR to 90% expected body weight (EBW) for gender, age and height, both followed by 20 sessions of out-patient, manualized family-based treatment (FBT). RESULTS: The primary outcome was the number of hospital days, following initial admission, at the 12-month follow-up. Secondary outcomes were the total number of hospital days used up to 12 months and full remission, defined as healthy weight (>95% EBW) and a global Eating Disorder Examination (EDE) score within 1 standard deviation (s.d.) of published means. There was no significant difference between groups in hospital days following initial admission. There were significantly more total hospital days used and post-protocol FBT sessions in the WR group. There were no moderators of primary outcome but participants with higher eating psychopathology and compulsive features reported better clinical outcomes in the MS group. CONCLUSIONS: Outcomes are similar with hospitalizations for MS or WR when combined with FBT. Cost savings would result from combining shorter hospitalization with FBT. PMID- 25017943 TI - Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. AB - The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets. PMID- 25017944 TI - Up-regulation of brain cytokines and chemokines mediates neurotoxicity in early acute liver failure by a mechanism independent of microglial activation. AB - The neurological involvement in acute liver failure (ALF) is characterized by arousal impairment with progression to coma. There is a growing body of evidence that neuroinflammatory mechanisms play a role in this process, including production of inflammatory cytokines and microglial activation. However, it is still uncertain whether brain-derived cytokines and glial cells are crucial to the pathophysiology of ALF at the early stage, before coma development. Here, we investigated the influence of cytokines and microglia in ALF-induced encephalopathy in mice as soon as neurological symptoms were identifiable. Behavior was assessed at 12, 24, 36 and 48 h post-injection of thioacetamide, a hepatotoxic drug, through locomotor activity by an open field test. Brain concentration of cytokines (TNF-alpha and IL-1beta) and chemokines (CXCL1, CCL2, CCL3 and CCL5) were assessed by ELISA. Microglial activation in brain sections was investigated through immunohistochemistry, and cellular ultrastructural changes were observed by transmission electron microscopy. We found that ALF induced animals presented a significant decrease in locomotor activity at 24 h, which was accompanied by an increase in IL-1beta, CXCL1, CCL2, CCL3 and CCL5 in the brain. TNF-alpha level was significantly increased only at 36 h. Despite marked morphological changes in astrocytes and brain endothelial cells, no microglial activation was observed. These findings suggest an involvement of brain-derived chemokines and IL-1beta in early pathophysiology of ALF by a mechanism independent of microglial activation. PMID- 25017945 TI - Hypothalamic orexin-A (hypocretin-1) neuronal projections to the vestibular complex and cerebellum in the rat. AB - Immunohistochemistry combined with retrograde tract-tracing techniques were used to investigate the distribution of orexin-A (OX-A)- and OX-A receptor-like (OX1) immunoreactivity within the vestibular complex and cerebellum, and the location of hypothalamic OX-A neurons sending axonal projections to these regions in the Wistar rat. OX-A immunoreactive fibers and presumptive terminals were found throughout the medial (MVe) and lateral (LVe) vestibular nuclei. Light fiber labeling was also observed in the spinal and superior vestibular nuclei. Within the cerebellum, dense fiber and presumptive terminal labeling was observed in the medial cerebellar nucleus (Med; fastigial nucleus), with less dense labeling in the interposed (Int) and lateral cerebellar nuclei (Lat; dentate nucleus). A few scattered OX-A immunoreactive fibers were also observed throughout the cortex of the paraflocculus. OX1-like immunoreactivity was found densely concentrated within LVe, moderate in MVe, and scattered within the spinal and superior vestibular nuclei. Within the cerebellum, OX1-like immunoreactivity was also observed densely within Med and in the dorsolateral aspects of Int. Additionally, OX1 like-labeling was found in Lat, and within the granular layer of the caudal paraflocculus cerebellar cortex. Fluorogold (FG) microinjected into these vestibular and cerebellar regions resulted in retrogradely labeled neurons throughout the ipsilateral hypothalamus. Retrogradely labeled neurons containing OX-A like immunoreactivity were observed dorsal and caudal to the anterior hypothalamic nucleus and extending laterally into the lateral hypothalamic area, with the largest number clustered around the dorsal aspects of the fornix in the perifornical area. A few FG OX-A like-immunoreactive neurons were also observed scattered throughout the dorsomedial, and posterior hypothalamic nuclei. These data indicate that axons from OX-A neurons terminate within the vestibular complex and deep cerebellar nuclei of the cerebellum and although the function of these pathways is unknown, they likely represent pathways by which hypothalamic OX-A containing neurons co-ordinate vestibulo-cerebellar motor and autonomic functions associated with ingestive behaviors. PMID- 25017942 TI - Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. AB - The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes. PMID- 25017946 TI - Increased adenosine levels in mice expressing mutant glial fibrillary acidic protein in astrocytes result in failure of induction of LTP reversal (depotentiation) in hippocampal CA1 neurons. AB - Astrocytes regulate the activity of neighboring neurons by releasing chemical transmitters, including ATP. Adenosine levels in the cerebrospinal fluid of mice that express a mutant human glial fibrillary acidic protein in astrocytes are slightly elevated compared to those in wild type mice and this might result from the observed increased release by mutant astrocytes of ATP, which can be used to produce adenosine. Using hippocampal slices from these mutant mice, we examined whether the increased endogenous adenosine levels in the hippocampus modulate the reversal of long-term potentiation (LTP), i.e. depotentiation (DP), in CA1 neurons. In hippocampal slices from wild type mice, a stable LTP was induced by tetanic stimulation consisting of 100 pulses at 100 Hz, and this was reversed by a train of low frequency stimulation (LFS) of 500 pulses at 1 Hz applied 30 min later. This induction of DP was inhibited by application of either 100 nM adenosine or 0.5 nM N(6)-cyclopentyladenosine, an adenosine A1 receptor agonist, during LFS, indicating that the increase in extracellular adenosine levels attenuated DP induction by acting on adenosine A1 receptors. In contrast, although a stable LTP was also induced in hippocampal slices from mutant mice, induction of DP was inhibited, but DP could be induced by application, during LFS, of 50 nM 8-cyclopentyltheophylline, an adenosine A1 receptor antagonist. These results suggest that a small increase in extracellular adenosine levels resulting from increased ATP release by astrocytes results in attenuation of DP in hippocampal CA1 neurons in the mutant mice. PMID- 25017947 TI - Total thyroidectomy versus hemithyroidectomy for patients with follicular neoplasm. A cost-utility analysis. AB - INTRODUCTION: Thyroid nodules are a common condition. Overall, 20% of the nodules assessed with FNAB correspond to the follicular pattern. A partial thyroidectomy is the minimal procedure that should be performed to determine the nature of these nodules. Some authors have suggested performing a total thyroidectomy based on the elimination of reoperation and ultrasound follow-up. The aim of this study was to evaluate the most cost-useful surgical strategy in a patient with an undetermined nodule, assessing complications, reoperation, recurrence and costs. MATERIAL AND METHODS: A cost-utility study was designed to compare hemithyroidectomy and total thyroidectomy. The outcomes were complications (definitive RLN palsy, permanent hypoparathyroidism, reoperation for cancer, and recurrence of the disease), direct costs and utility. We used the payer perspective at 5 years. A deterministic and probabilistic sensitivity analysis was completed. RESULTS: In a deterministic analysis, the cost, utility and cost utility ratio was COP $12.981.801, 44.5 and COP $291.310 for total thyroidectomy and COP $14.309.889, 42.0 and $340.044 for partial thyroidectomy, respectively. The incremental cost-utility ratio was -$535.302 favoring total thyroidectomy. Partial thyroidectomy was more cost-effective when the risks of RLN injury and definitive hypoparathyroidism were greater than 8% and 9% in total thyroidectomy, respectively. In total, 46.8% of the simulations for partial thyroidectomy were located in the quadrant of more costly and less effective. CONCLUSION: Under a common range of complications, and considering the patient's preference and costs, total thyroidectomy should be selected as the most cost-effective treatment for patients with thyroid nodules and follicular patterns. PMID- 25017948 TI - Wound healing properties of quince seed mucilage: in vivo evaluation in rabbit full-thickness wound model. AB - OBJECTIVE: Quince seed mucilage (QSM) has been used in Iranian traditional medicine for the treatment of skin wounds and burns. Recent studies indicated that QSM accelerated wound healing. The present study was undertaken to investigate the healing efficiency of QSM formulated as 5%, 10%, and 20% creams in eucerin base with especial attention on growth factors involving in wound healing. METHODS: Full thickness wounds were created in Iranian male rabbits divided into five experimental groups (n = 6), as negative control, eucerin and treatments. Negative control group did not receive any treatment. Eucerin group received topical eucerin, twice a day. Treatment groups were treated topically by creams of QSM 5%, 10% and 20% (w/w) in eucerin base, twice daily. The efficacy of treatment was evaluated based on wound contraction, haydroxyproline content, tensile strength of wound tissue. The levels of epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) were also determined in serum and wound fluid of tested animals. RESULTS: Results showed that there were statistically significant differences in wound contraction between QSM 10 and 20% creams treatments groups and control groups (P < 0.05) in most of the days. Rabbits treated with QSM 20% cream had the best results (completed healing in 13 days, higher hydroxyproline content, higher tissue resistance and higher wound fluid levels of evaluated growth factors). CONCLUSION: We concluded tha QSM in 10 20% concentrations have a good potential for promote wound healing thus supports its traditional use. PMID- 25017949 TI - Massive hemorrhage after percutaneous nephrolithotomy: saving the kidney when angioembolization has failed or is unavailable. AB - OBJECTIVES: To describe the management protocol in cases with massive hemorrhage after percutaneous nephrolithotomy (PCNL) with a failed angioembolization or when angioembolization is not available. PATIENTS AND METHODS: Between October 2006 and December 2012, the charts of patients who had undergone PCNL and were complicated with massive post procedural bleeding unresponsive to conservative management were reviewed. Those cases in whom angioembolization had failed, or was unavailable, or could not be afforded by the patient were selected and studied. These patients underwent open surgical exploration through a midline transperitoneal or a flank retroperitoneal approach. In both approaches, kidney mobilization outside the Gerota's fascia, temporal renal pedicle clamping and partial nephrectomy or renorrhaphy were done in a stepwise manner. RESULTS: During the study period, we had 8 patients for whom angioembolization had failed (n = 4), was not available (n = 2) or the patient could not afford it (n = 2). Median patients' age was 31 years (range 16-59 years). We did a partial nephrectomy in 2 and renorrhaphy in 6 of patients with a successful outcome. Median operative time was 2.25 h and median warm ischemia time was 26 min (range 24-42 min). After a median follow up period of 21 months, the involved renal unit, in all cases, remained functional in the postoperative intravenous urography. CONCLUSION: Massive hemorrhage after PCNL when angioembolization failed or was not feasible due to any reason could be controlled by partial nephrectomy or renorrhaphy with the same principles as that used for surgical exploration in patients with high grade renal trauma. PMID- 25017950 TI - Ordered liquids and hydrogels from alkenyl succinic ester terminated bola amphiphiles for large-scale applications. AB - The present study describes an economic and scalable approach to aqueous mesophases from bola-amphiphiles (BA) obtained via nucleophilic addition of dimer fatty acid based alpha,omega-polyesterdiols (PES) on cyclic acid anhydrides and conversion of the carboxylic end groups into ammonium salts. Novel bola amphiphilic head groups are introduced using alkenyl succinic anhydrides (ASA). The additional terminal hydrophobic side chains favour the self-assembly of polymeric BA of different molecular weights into nanoscale anisotropic objects, their shape and ordering into nematic or lamellar-like phases being dependent on the length and structural uniformity of the ASA chains. Corresponding diester based on C15 (hydrogenated bisphenol-A, HBA) and C8 (1,4-cyclohexanedimethanol, CHDM) spacers have been prepared and the self-assembly of the resulting BA in water has been studied using SAXS, (2)H-NMR and optical polarization microscopy. While the rigid C8 spacer impedes any ordering, ASA capped C15 tends to form ordered hydrogels over extended regions of the phase diagram that resemble mesh phases and L(alpha)/L(3) polymorphism. Rheological and simulation results confirm the presence of elastically responding bicontinuous morphologies and biased porous assemblies resembling interconnected mesh phases. Both the use of the dimer fatty acid based spacer as well as of ASA head groups open up large-scale applications of ordered liquids (or hydrogels) as a formulation basis for e.g. films, coatings and adhesives. PMID- 25017952 TI - Will studies in individuals with systemic lupus erythematosus be the key to future HIV vaccine design? AB - The induction of HIV-1 broadly neutralizing antibodies (bnAbs) remains the primary goal of a preventive HIV-1 vaccine but no HIV-1 vaccine candidate has succeeded in inducing bnAbs. All the bnAbs isolated from chronically HIV-1 infected subjects display one or more traits associated with control by host tolerance and immunoregulatory mechanisms, including reactivity against self antigens. Recent studies on a HIV-1 patient with concurrent systemic lupus erythematosus have informed on how similar bnAbs are to typical autoantibodies controlled by immune tolerance mechanisms. Future studies aimed at elucidating the intersection between autoantibodies generated in the context of systemic lupus erythematosus and the development of HIV-1 bnAbs will further our knowledge of specific roadblocks that hamper the production of bnAbs and, ultimately, inform us on how to implement vaccine strategies to circumvent them. PMID- 25017953 TI - Epidemiological information regarding the periodic epidemics of influenza C virus in Japan (1996-2013) and the seroprevalence of antibodies to different antigenic groups. AB - BACKGROUND: Although influenza C virus is widely distributed throughout the world, epidemiological information, based on long-term surveillance, has not yet been acquired. OBJECTIVES: To clarify the epidemiological features of influenza C virus infection, and to examine whether the prevalence of the antibodies against the influenza C virus is associated with the epidemics. STUDY DESIGN: Between 1996 and 2013, 36,973 respiratory specimens were collected from two pediatric outpatient clinics in Yamagata, Japan. The specimens were examined for the presence of influenza C virus using cell culture methods. Isolated viruses were antigenically analyzed. The differences in seropositivity, with respect to the different antigenic groups, were examined using serum samples collected in 2001 and 2011 by a hemagglutination inhibition assay. RESULTS: Influenza C viruses were isolated from 190 specimens during an 18-year period. Most influenza C viruses were isolated from winter to early summer in even-numbered years, and the frequency of virus isolation per year ranged from 0.43% to 1.73%. An antigenic analysis revealed that the dominant antigenic groups were the C/Yamagata/26/81 from 1996 to 2000, the C/Kanagawa/1/76 in 2002 and 2004, and the C/Sao Paulo/378/82 from 2006 to 2012. When compared to the other antigenic groups, the seroprevalence of the C/Sao Paulo/378/82 group was lower in 2001 for individuals older than 5 years and was higher in 2011 in individuals younger than 40 years. CONCLUSIONS: The results from our study suggest that epidemics of influenza C virus infection periodically occur and the replacement of the dominant antigenic group may be caused by immune selection within older children and/or adults in the community. PMID- 25017955 TI - Formation mechanism and possible stereocontrol of bisphenol a derivatives: a computational study. AB - Density functional theoretical study elucidates two different pathways for metabolic activation of 2,2'-bis(4-hydroxyphenyl) propane (Bisphenol A; BPA) and consequential formation of 4-methyl-2,4-bis(p-hydroxyphenyl)pent-2-ene (M-1) and 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (M-2, the potential environmental estrogen). Selectivity toward M-1(nontoxic)/M-2(toxic) formation can be controlled by varying the polarity of the reaction medium. We also found the reversal of thermodynamic stability for M-1/M-2 in response to the static polarization of the medium. Moreover, stereocontrol of biologically active M-2 with static polarization as the switch (~0.005 au) might affect the receptor binding. This analysis may be useful in dictating the prevention of the harmful action of BPA and its metabolites. PMID- 25017954 TI - Evolution of an influenza pandemic in 13 countries from 5 continents monitored by protein microarray from neonatal screening bloodspots. AB - BACKGROUND: Because of lack of worldwide standardization of influenza virus surveillance, comparison between countries of impact of a pandemic is challenging. For that, other approaches to allow internationally comparative serosurveys are welcome. OBJECTIVES: Here we explore the use of neonatal screening dried blood spots to monitor the trends of the 2009 influenza A (H1N1) pdm virus by the use of a protein microarray. STUDY DESIGN: We contacted colleagues from neonatal screening laboratories and asked for their willingness to participate in a study by testing anonymized neonatal screening bloodspots collected during the course of the pandemic. In total, 7749 dried blood spots from 13 countries in 5 continents where analyzed by using a protein microarray containing HA1 recombinant proteins derived from pandemic influenza A (H1N1) 2009 as well as seasonal influenza viruses. RESULTS: Results confirm the early start of the pandemic with extensive circulation in the US and Canada, when circulation of the new virus was limited in other parts of the world. The data collected from sites in Mexico suggested limited circulation of the virus during the early pandemic phase in this country. In contrast and to our surprise, an increase in seroprevalence early in 2009 was noted in the dataset from Argentina, suggestive of much more widespread circulation of the novel virus in this country than in Mexico. CONCLUSIONS: We conclude that this uniform serological testing of samples from a highly standardized screening system offers an interesting opportunity for monitoring population level attack rates of widespread diseases outbreaks and pandemics. PMID- 25017956 TI - Plasmonic properties of triangle-shaped silver trimers selectively fabricated by near-field photo-reduction using an apertured cantilever for an atomic force microscope. AB - On an AgNO3 crystal, an equilateral or a right-angle triangle-shaped Ag trimer was selectively fabricated through near-field photo-reduction and observed in situ by using an apertured cantilever coupled with an atomic force microscope. By using the different triangle-shaped Ag trimers, irradiation wavelength and polarization dependence of surface-enhanced Raman scattering were investigated. PMID- 25017957 TI - [Comparison between two different mesh fixation methods in laparoscopic inguinal hernia repair: tacker vs. Synthetic cyanoacrylate glue.] AB - AIM: The aim of this retrospective study was to compare the results of two different mesh fixation methods in laparoscopic transabdominal preperitoneal hernioplasty (TAPP): tacker vs. synthetic cyanoacrylate glue. METHODS: The study group includes 70 patients with bilateral and monolateral recurrent inguinal hernia undergoing transabdominal preperitoneal repair (TAPP) in the period 2011 2013. A polypropylene mesh was fixed in group A (N.=35) with titanium tacks (EndoUniversal stapler, Covidien) or in group B (N.=35) with synthetic cyanoacrylate glue (Glubran-2, GEM). Patient outcome was assessed by the following variables: sex, mean age, ASA score, intra- and postoperative morbidity, hospitalization, postoperative acute and chronic pain, recurrence rate. The observation period was 24 months, with a mean follow-up of 10.5 months (range, 1-23) for Group A and 11 months (range, 2-24) for Group B. RESULTS: No difference between the two groups was observed with respect to mean operative time and hospitalization. In all cases, surgery was successfully concluded laparoscopically. Intraoperative complications occurred in 1 patient of the group A and consisted of a urinary bladder injury, which was immediately sutured. Postoperative complication rate was 5.7% (4 patients, of whom 3 in group A and 1 in group B). In each group we detected one recurrence within 6 (group A) and 18 months (group B) postsurgery; both patients were treated with a re-TAPP. Postoperative pain at 6 months from surgery, measured by visual analogue score (VAS), was reported by 4 patients in the group A and in no case of the group B (P=0.04). CONCLUSION: Data from this study demonstrate the advantages of synthetic cyanoacrylate glue for mesh fixation in laparoscopic transabdominal preperitoneal inguinal hernia repair, compared to titanium tacks. The use of this surgical glue was associated with a significantly reduced risk for developing chronic groin pain and a shortened hospital stay. Nevertheless, further studies with longer follow-up periods are needed to confirm our encouraging results. PMID- 25017958 TI - Comparison of postoperative short-term complications after laparoscopic transabdominal preperitoneal (TAPP) versus Lichtenstein tension free inguinal hernia repair: a randomized trial study. AB - AIM: The aim of this randomized trial was to compare short-term postoperative complications of laparoscopic transabdominal preperitoneal (TAPP) and Lichtenstein tension free hernia repair. METHODS: A total of 120 patients who went inguinal hernia repair at Shahid Sadoughi university training hospital from April 2011 to August 2013 were randomized into two TAPP (N.=60) and Lichtenstein (N.=60) repair group. Follow-up occurred within 6 weeks. The postoperative assessments included pain score (VAS), hematoma/seroma, urinary retention, wound infection incidence, and duration of hospital stay. RESULTS: Pain was the most common symptoms in both groups. The TAPP group patients significantly had experienced less postoperative pain than the Lichtenstein group in all moments (P<0.05). TAPP group had lower incidence of hematoma (TAPP, 6.6% vs. Lichtenstein 13.3%; P=0.67), seroma (TAPP 10% vs. Lichtenstein 13.3%; P=1.00), and infection (TAPP 0 vs. Lichtenstein 1.6%; P=0.67). However, no differences between the 2 groups were found in terms of postoperative complications. In TAPP group mean of hospital stay significantly was less than Lichtenstein group (TAPP, 8.13+/-2.19 vs. Lichtenstein, 13.15+/-1.5 days; P<0.001). CONCLUSION: The laparoscopic TAPP repair is safer and less complicated approach to inguinal hernia repair. The two main short-term advantages of the laparoscopic TAPP repair with the tension free Lichtenstein repair were less postoperative pain and earlier return to the normal life activities. No difference was seen in overall complications. PMID- 25017959 TI - The effect of glufosinate on nitrogen assimilation at the physiological, biochemical and molecular levels in Phaeodactylum tricornutum. AB - This study investigated the effects of glufosinate, a widely used herbicide, on the marine diatom Phaeodactylum tricornutum through short-term toxicity tests at the physiological and gene transcriptional levels. Glufosinate (4 mg L(-1)) decreased the amount of pigments but increased reactive oxygen species (ROS) and malondialdehyde levels. As a glutamine synthetase (GS) inhibitor, glufosinate affected the transcripts and activities of key enzymes related to nitrogen assimilation. Transcript levels of GS and nitrate reductase (NR) in P. tricornutum decreased to only 57 and 26 % of the control. However, transcript levels of nitrate transporter (NRT) and the small subunit of glutamate synthase (GltD) were 1.79 and 1.76 times higher than that of the control. The activities of NRT, GS and GOGAT were consistent with gene expression except for NR, which was regulated mainly by post-translational modification. Furthermore, the results of electron microscopy showed that chloroplast structure was disrupted in response to glufosinate exposure. These results demonstrated that glufosinate first disturbed nitrogen metabolism and caused a ROS burst, which disrupted chloroplast ultrastructure. Ultimately, the growth of P. tricornutum was greatly inhibited by glufosinate. PMID- 25017960 TI - Coal mining activities change plant community structure due to air pollution and soil degradation. AB - The aim of this study was to investigate the effects of coal mining activities on the community structures of woody and herbaceous plants. The response of individual plants of community to defilement caused by coal mining was also assessed. Air monitoring, soil physico-chemical and phytosociological analyses were carried around Jharia coalfield (JCF) and Raniganj coalfield. The importance value index of sensitive species minified and those of tolerant species enhanced with increasing pollution load and altered soil quality around coal mining areas. Although the species richness of woody and herbaceous plants decreased with higher pollution load, a large number of species acclimatized to the stress caused by the coal mining activities. Woody plant community at JCF was more affected by coal mining than herbaceous community. Canonical correspondence analysis revealed that structure of herbaceous community was mainly driven by soil total organic carbon, soil nitrogen, whereas woody layer community was influenced by sulphur dioxide in ambient air, soil sulphate and soil phosphorus. The changes in species diversity observed at mining areas indicated an increase in the proportion of resistant herbs and grasses showing a tendency towards a definite selection strategy of ecosystem in response to air pollution and altered soil characteristics. PMID- 25017961 TI - Genetic screen identifies suppressor of morphogenesis in genitalia-1 (SMG-1) as a modulator of sorafenib resistance in hepatocellular carcinoma cell lines. AB - Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis and a very complex dysregulated molecular etiology. Furthermore, conventional therapy thus far has had only limited success. A recently developed oral multikinase inhibitor, sorafenib, has been used to improve survival in HCC patients, however, follow-up studies have revealed a high rate of cancer recurrence. Therefore, identification of genes involved in sorafenib resistance is urgently required. RNA interference (RNAi) is a powerful tool for performing loss-of-function genetic screens and can facilitate the identification of components of the cellular signaling pathway. This study describes the results of an unbiased genomic screening using RNAi in an HCC cell line to elucidate genes related to sorafenib non-responsiveness or resistance. A genome-wide in vitro RNA interference screen revealed the role of suppressor of morphogenesis in genitalia 1 (SMG-1) as a determinant of sorafenib resistance. The inhibition of SMG-1 reduced sorafenib sensitivity in the studied HCC cell lines. An immunohistochemical comparison of cancerous and non-cancerous regions showed strong staining in the non-neoplastic hepatocyte regions of HCC. SMG-1 may warrant investigation as an agent to reverse sorafenib resistance. PMID- 25017962 TI - Stress task specific impairments of cardiovascular functioning in obese participants. AB - The role that excess adipose tissue plays in chronic inflammation gives rise to its importance as an independent risk factor in cardiovascular dysfunction. Operationalizing chronic stress as obesity, we sought to explore the relationship between obesity, perceived stress and cardiovascular reactivity and recovery from laboratory stressors. Cardiovascular function was assessed using blood pressure and heart rate. Two stress tasks (mental arithmetic and cold pressor) were employed to examine potential differences between type of stress and cardiovascular response. Body mass index (BMI) was able to predict dysfunction in both cardiovascular reactivity and recovery. Participants with a higher BMI exhibited blunted systolic blood pressure and heart rate reactivity to the mental arithmetic task. In contrast, BMI has an incongruent effect on blood pressure reactivity to the cold pressor task that is dependent on the level of perceived stress. This suggests that in some instances the effect of BMI on cardiovascular response to acute stress may be moderated by perceived stress. Further, we found greater adiposity was related to delayed heart rate recovery following both stress tasks. PMID- 25017963 TI - ERP adaptation provides direct evidence for early mirror neuron activation in the inferior parietal lobule. AB - Mirror neuron systems are frequently investigated by assessing overlapping brain activity during observation and execution of actions; however, distinct neuronal subpopulations may be activated that fall below the spatial resolution of magnetic resonance techniques. This shortfall can be resolved using repetition suppression paradigms that identify physiological adaptation processes caused by repeated activation of identical neuronal circuits. Here, event-related potentials were used to investigate the time course of mirror neuron circuit activation using repetition suppression within and across action observation and action execution modalities. In a lip-reading and speech production paradigm, the N170 component indexed stimulus repetition by adapting to both cross-modal and intra-modal repetitions in the left hemisphere. Neuronal source localization revealed activation of the left inferior parietal lobule during cross-modal relative to intra-modal trials. These results provide support for the position that the same neuronal circuits are activated in perceiving and performing articulatory actions. Moreover, our data strongly suggest that inferior parietal lobule mirror neurons are activated relatively early in time, which indicates partly automatic processes of linguistic perception and mirroring. Repetition suppression paradigms therefore help to elucidate neuronal correlates of different cognitive processes and may serve as a starting point for advanced electrophysiological research on mirror neurons. PMID- 25017964 TI - Malarial pigment hemozoin impairs chemotactic motility and transendothelial migration of monocytes via 4-hydroxynonenal. AB - Natural hemozoin, nHZ, is avidly phagocytosed in vivo and in vitro by human monocytes. The persistence of the undigested beta-hematin core of nHZ in the phagocyte lysosome for long periods of time modifies several cellular immune functions. Here we show that nHZ phagocytosis by human primary monocytes severely impaired their chemotactic motility toward MCP-1, TNF, and FMLP, by approximately 80% each, and their diapedesis across a confluent human umbilical vein endothelial cell layer toward MCP-1 by 45+/-5%. No inhibition was observed with latex-fed or unfed monocytes. Microscopic inspection revealed polarization defects in nHZ-fed monocytes due to irregular actin polymerization. Phagocytosed nHZ catalyzes the peroxidation of polyunsaturated fatty acids and generation of the highly reactive derivative 4-hydroxynonenal (4-HNE). Similar to nHZ phagocytosis, the exposure of monocytes to in vivo-compatible 4-HNE concentrations inhibited cell motility in both the presence and the absence of chemotactic stimuli, suggesting severe impairment of cytoskeleton dynamics. Consequently, 4-HNE conjugates with the cytoskeleton proteins beta-actin and coronin-1A were immunochemically identified in nHZ-fed monocytes and mass spectrometrically localized in domains of protein-protein interactions involved in cytoskeleton reorganization and cell motility. The molecular and functional modifications of actin and coronin by nHZ/4-HNE may also explain impaired phagocytosis, another motility-dependent process previously described in nHZ-fed monocytes. Further studies will show whether impaired monocyte motility may contribute to the immunodepression and the frequent occurrence of secondary infections observed in malaria patients. PMID- 25017965 TI - Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies. AB - Although mitochondrial dysfunction and oxidative stress have been proposed to play a crucial role in several types of muscular dystrophy (MD), whether a causal link between these two alterations exists remains an open question. We have documented that mitochondrial dysfunction through opening of the permeability transition pore plays a key role in myoblasts from patients as well as in mouse models of MD, and that oxidative stress caused by monoamine oxidases (MAO) is involved in myofiber damage. In the present study we have tested whether MAO dependent oxidative stress is a causal determinant of mitochondrial dysfunction and apoptosis in myoblasts from patients affected by collagen VI myopathies. We find that upon incubation with hydrogen peroxide or the MAO substrate tyramine myoblasts from patients upregulate MAO-B expression and display a significant rise in reactive oxygen species (ROS) levels, with concomitant mitochondrial depolarization. MAO inhibition by pargyline significantly reduced both ROS accumulation and mitochondrial dysfunction, and normalized the increased incidence of apoptosis in myoblasts from patients. Thus, MAO-dependent oxidative stress is causally related to mitochondrial dysfunction and cell death in myoblasts from patients affected by collagen VI myopathies, and inhibition of MAO should be explored as a potential treatment for these diseases. PMID- 25017966 TI - Plasma selenium levels and oxidative stress biomarkers: a gene-environment interaction population-based study. AB - The role of selenium exposure in preventing chronic disease is controversial, especially in selenium-repleted populations. At high concentrations, selenium exposure may increase oxidative stress. Studies evaluating the interaction of genetic variation in genes involved in oxidative stress pathways and selenium are scarce. We evaluated the cross-sectional association of plasma selenium concentrations with oxidative stress levels, measured as oxidized to reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), and 8-oxo-7,8-dihydroguanine (8-oxo-dG) in urine, and the interacting role of genetic variation in oxidative stress candidate genes, in a representative sample of 1445 men and women aged 18 85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.76 ug/L. In fully adjusted models the geometric mean ratios for oxidative stress biomarker levels comparing the highest to the lowest quintiles of plasma selenium levels were 0.61 (0.50-0.76) for GSSG/GSH, 0.89 (0.79-1.00) for MDA, and 1.06 (0.96-1.18) for 8-oxo-dG. We observed nonlinear dose-responses of selenium exposure and oxidative stress biomarkers, with plasma selenium concentrations above ~110 MUg/L being positively associated with 8-oxo-dG, but inversely associated with GSSG/GSH and MDA. In addition, we identified potential risk genotypes associated with increased levels of oxidative stress markers with high selenium levels. Our findings support that high selenium levels increase oxidative stress in some biological processes. More studies are needed to disentangle the complexity of selenium biology and the relevance of potential gene-selenium interactions in relation to health outcomes in human populations. PMID- 25017968 TI - Cancer cachexia: towards integrated therapeutic interventions. AB - Biological treatments represent a novel approach to counteract cancer cachexia. Monoclonal antibodies targeting cytokines and molecules responsible for muscle wasting, with an anti-inflammatory effect, however, still have several limitations and need further clinical investigation. New research in this field will contribute to the better understanding of the multifactorial pathogenesis of cancer cachexia, while favoring the consolidation of multimodal preventive and therapeutic strategies encompassing nutritional and pharmacological treatments. New pharmacological therapies and conventional nutritional treatments will soon integrate in the 'parallel pathway', aimed at early recognition, prevention and treatment of the metabolic and nutritional derangements occurring in cancer. This will likely produce improvement in quality of life, tolerance to treatments and survival. PMID- 25017967 TI - Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury. AB - NADPH oxidase plays a central role in mediating oxidative stress during heart, liver, and lung ischemia/reperfusion injury, but limited information is available about NADPH oxidase in renal ischemia/reperfusion injury. Our aim was to investigate the activation of NADPH oxidase in a swine model of renal ischemia/reperfusion damage. We induced renal ischemia/reperfusion in 10 pigs, treating 5 of them with human recombinant C1 inhibitor, and we collected kidney biopsies before ischemia and 15, 30, and 60 min after reperfusion. Ischemia/reperfusion induced a significant increase in NADPH oxidase 4 (NOX-4) expression at the tubular level, an upregulation of NOX-2 expression in infiltrating monocytes and myeloid dendritic cells, and 8-oxo-7,8-dihydro-2' deoxyguanosine synthesis along with a marked upregulation of NADPH-dependent superoxide generation. This burden of oxidative stress was associated with an increase in tubular and interstitial expression of the myofibroblast marker alpha smooth muscle actin (alpha-SMA). Interestingly, NOX-4 and NOX-2 expression and the overall NADPH oxidase activity as well as alpha-SMA expression and 8-oxo-7,8 dihydro-2'-deoxyguanosine synthesis were strongly reduced in C1-inhibitor-treated animals. In vitro, when we incubated tubular cells with the anaphylotoxin C3a, we observed an enhanced NADPH oxidase activity and alpha-SMA protein expression, which were both abolished by NOX-4 silencing. In conclusion, our findings suggest that NADPH oxidase is activated during ischemia/reperfusion in a complement dependent manner and may play a potential role in the pathogenesis of progressive renal damage in this setting. PMID- 25017969 TI - Crossbreeding effects on pig growth and carcass traits from two Iberian strains. AB - An experiment of a 2*2 full diallelic cross between two contemporary Iberian pig strains (Retinto: RR, and Torbiscal: TT) was conducted to estimate the crossbreeding effects for growth and carcass traits. Phenotypic records were obtained under intensive management and consisted of two different data sets. The first set comprised growth traits until weaning and was collected at two different farms (6236 and 1208 records, respectively). Specific data included individual piglet weight at birth and at weaning at 28 days and average daily gain from birth to weaning at 28 days (ADG28) for both RR and TT and their reciprocal crosses. The second set comprised growth data from birth to slaughter (~340 days and ~160 kg) and carcass traits from 349 individuals (randomly) sampled at weaning from the first dataset. Data were analyzed through a Bayesian analysis by using a reparameterization of Dickerson's model that allowed estimation of the posterior distributions of the following crossbreeding effects: average maternal breed effect (gM), average paternal breed effect (gP) and individual heterosis (hI). Results showed that the relative magnitude of crossbreeding effects depends on the trait analyzed. Crosses where Torbiscal strain was used as mother (RT and TT) achieved the greatest performance for all growth traits at weaning, leading to remarkable gM effects. The most outstanding example is the case of ADG28 where the probability of relevance was one. In contrast, TR cross showed the greatest differences from RR cross for all growth at slaughter and carcass traits. These differences were mainly due to hI and gP crossbreeding parameters. In particular, the posterior mean of hI was more noticeable for live weight at slaughter, average daily gain at slaughter and carcass length, while gP was more relevant for hams (kg) and loins (kg) representing from 3% to10% of average performance of traits. Hence, growth traits at weaning did not reveal any notable advantage of the crossbreeding scheme because of the superiority of the Torbiscal strain with respect to its mothering ability and the small hI. However, results from growth and carcass traits at slaughter would support the implementation of a TR crossbred system. It would allow exploitation of both the gP of the Torbiscal strain and the hI between these two Iberian pig strains. Additionally, gP estimates and phenotypic differences between reciprocal crosses might suggest signs of the presence of paternal genetic imprinting in primal cuts traits. PMID- 25017970 TI - Interleukin-1beta promotes the induction of retinal autoimmune disease. AB - Interleukin-1beta (IL-1beta) is a potent proinflammatory cytokine that plays a critical role in initiating immunoinflammatory responses. In this study, we generated recombinant mouse IL-1beta and anti-mouse IL-1beta polyclonal antibodies to examine the effect of IL-1beta on experimental autoimmune uveoretinitis (EAU), a mouse model for T cell-mediated eye autoimmune disease. Administration of mouse IL-1beta by i.p. in the priming phase, but not in the effector phase, of immune response of EAU enhanced disease scores and its related immune responses including DTH, Ag-specific T cell proliferation and the production of IL-17 and IFN-gamma. Furthermore, administration of anti-IL-1beta antibody in the priming phase reduced EAU scores. These results suggest that IL 1beta is an important mediator in the pathogenesis of autoimmune diseases such as uveitis. PMID- 25017971 TI - Borrelia miyamotoi in host-seeking Ixodes ricinus ticks in England. AB - This paper reports the first detection of Borrelia miyamotoi in UK Ixodes ricinus ticks. It also reports on the presence and infection rates of I. ricinus for a number of other tick-borne pathogens of public health importance. Ticks from seven regions in southern England were screened for B. miyamotoi, Borrelia burgdorferi sensu lato (s.l.), Anaplasma phagocytophilum and Neoehrlichia mikurensis using qPCR. A total of 954 I. ricinus ticks were tested, 40 were positive for B. burgdorferi s.l., 22 positive for A. phagocytophilum and three positive for B. miyamotoi, with no N. mikurensis detected. The three positive B. miyamotoi ticks came from three geographically distinct areas, suggesting a widespread distribution, and from two separate years, suggesting some degree of endemicity. Understanding the prevalence of Borrelia and other tick-borne pathogens in ticks is crucial for locating high-risk areas of disease transmission. PMID- 25017972 TI - Role of p40 and cytokeratin 5/6 in the differential diagnosis of sinonasal undifferentiated carcinoma. AB - Sinonasal undifferentiated carcinoma (SNUC) is an epithelial neoplasm of sinonasal region which does not exhibit a squamous or glandular differentiation. The challenge in diagnosis of this entity is the rarity of the disease, the varying morphology of the tumor which leads to gamut of differential diagnosis and the paucity of consistent immunohistochemical markers except pancytokeratin. Forty-one cases of sinonasal epithelial neoplasm consisting of 11 cases of SNUC and 10 cases each of high-grade (grade 3 and 4) esthesioneuroblastoma, undifferentiated nasopharyngeal carcinoma, and poorly differentiated squamous cell carcinoma of the sinonasal region were analyzed for morphology and immunoexpression of CK5/6 and p40. It was found that SNUC did not exhibit immunohistochemical expression of p40 and CK 5/6, suggesting that these could be useful negative immune markers for diagnosis of SNUC. PMID- 25017973 TI - Metrics for identifying errors related to pre-analytical sample handling. PMID- 25017974 TI - CCT327 enhances TRAIL-induced apoptosis through the induction of death receptors and downregulation of cell survival proteins in TRAIL-resistant human leukemia cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has potential application in cancer therapy and it has the ability to selectively kill cancer cells without affecting normal cells. However, the development of resistance to TRAIL in cancer cells cannot be avoided. This study investigated the effects of 2 (5-methylselenophen-2-yl)-6,7-methylenedioxyquinolin-4-one (CCT327), an analogue of quinolin-4-one, on the sensitization of cancer cells to TRAIL and on TRAIL induced apoptosis in TRAIL-resistance human leukemia cells (HL60-TR). We found that CCT327 enhanced TRAIL-induced apoptosis through upregulation of death receptors DR4 and DR5. In addition to upregulating DRs (death receptors), CCT327 suppressed the expression of decoy receptor DcR1 and DcR2. CCT327 significantly downregulated the expression of FLICE inhibitory protein (cFLIP) and other antiapoptotic proteins. We also demonstrated that CCT327 could activate p38 and JNK. Moreover, CCT327-induced induction of DR5 and DR4 was mediated by reactive oxygen species (ROS), and N-acetylcysteine (NAC) blocked the induction of DRs by CCT327. Taken together, these results showed that CCT327 combined with TRAIL treatment may provide an effective therapeutic strategy for cancer. PMID- 25017975 TI - Suitability of faeces and tissue samples as a basis for non-invasive sampling for African swine fever in wild boar. AB - A challenging aspect of ASFV control in wild boar populations is the design and implementation of effective surveillance and monitoring programmes, both for early warning, and to determine the ongoing epidemiological situation in an infected population. Testing blood samples requires invasive sampling strategies like hunting or capture of wild boar. Besides being biased towards healthy animals, such strategies are also linked to further spread of the virus. Non invasive sampling strategies would increase the reliability of surveillance of ASFV in wild boar populations, without the negative side effects. This study evaluates the potential of faeces and tissue samples as a basis for non-invasive sampling strategies for ASFV in wild boar. In the acute phase (0-21 days after infection), in comparison with virus detection in blood, virus can be detected in faeces 50-80% of the time. This percentage decreases to below 10% for the subacute/chronic phase. ASFV DNA is quite stable in faeces. Half-lives range from more than 2 years at temperature up to 12 degrees C, to roughly 15 days at temperatures of 30 degrees C. In tissue samples, stored at 20 degrees C, half lives mostly range from 1.7 to 7.4 days. The sample of preference is the spleen, where the highest titres and highest half-life of ASFV DNA are observed. The level and duration of excretion of ASFV in the faeces, combined with the stability of the DNA, suggest that sampling of faeces could be the basis for a non-invasive sampling strategy to monitor ASFV in wild boar. PMID- 25017977 TI - [Advantages of midwife-led continuity model of care]. AB - In the Dutch maternity care system women at low risk of complications in pregnancy and birth are distinguished from women at an increased risk. Primary care midwives are responsible for the care in the low-risk group, whereas obstetricians are responsible for care when the risk is increased. Most professionals and stakeholders agree that more continuity of care is warranted but there is no consensus on the ideal organization of care. A midwife-led continuity model of care has been shown to offer several health benefits compared with other models, such as 'shared care'. We argue that this model would be appropriate for the Netherlands. Midwives should provide care where possible and obstetricians where necessary in order to use the expertise of both professions most effectively. This requires an extension of the scope of practice for primary care midwives. This model requires good cooperation between midwives and obstetricians. PMID- 25017976 TI - Prevalence of hoarseness in school-aged children. AB - OBJECTIVES: The purpose of this cross-sectional study was to determine the prevalence of hoarseness in children attending the first or second grade of primary school and to explore possible background factors for hoarseness in children. METHODS: The participants were 217 children, aged 6-10 years, from 10 different schools. Questionnaires were filled in by the parents and the teachers of the children and voice samples were recorded. The voice samples from the children were perceptually evaluated by eight trained listeners and intra- and inter-rater reliability was calculated. Additionally, the parents and teachers were in the questionnaires asked to rate the children's voices. Connections between background factors and voice quality were explored. RESULTS: Both the intra- and inter-rater reliability for the trained listeners were relatively high and significant. The prevalence of hoarseness for the whole group was 12.0% as judged by the trained listeners. For girls, the prevalence of hoarseness was 7.8% and for boys 15.8%. A lower teacher rating of degree of maturity correlated significantly with the voice quality. Additionally, there was a significant negative correlation between the amount of talking at home and voice quality. For girls, heavy voice use as an infant correlated significantly with voice quality. For boys, being the youngest sibling correlated significantly with voice quality. CONCLUSIONS: The results from the present study indicate that more attention should be paid to hoarseness in children and that background factors should be further explored. PMID- 25017978 TI - [Dutch Preventive Youth Health Care Service guideline on children born too early and/or too small for gestational age]. AB - In children who are born prematurely or whose birth weight is too low for gestational age (small for gestational age (SGA)) intensive care and follow up are desirable.However, obstacles include the shared care of children born very preterm (< 32 weeks of gestation) by paediatricians, general practitioners, youth health care service (and other professionals) and the identification of possible late onset health problems in children born late preterm (32-37 weeks of gestation). This guideline is multidisciplinary and evidence based and is relevant to all professionals involved in the care of this group of children. The main recommendations are: (a) timely and complete transfer of information after discharge from hospital; (b) structured exchange of information in aftercare; (c) assigning a case manager to each child; (d) monitoring growth and development by adjusting age for preterm birth, and (e) using special growth charts for children born preterm to evaluate growth and development. PMID- 25017979 TI - [Neuroscience in the courtroom? We first need a protocol]. AB - Neuroscientific evidence is prominently present in courts of law and may come in many forms. For example, it may consist of neuroradiological and/or neuropsychological results that are brought to courts to make the point that the claimant is suffering from dementia, ruling out his legal capacity to sign contracts. Neuroscientific evidence has an aura of solidity and objectivity and has been found to have a strong influence on the sentencing decisions of professional judges. In this article, we address one often overlooked issue, namely the biasability of neuroscientific evidence. We argue that neuroscientific evidence is sensitive to pathology bias, allegiance effects, and malingering (by claimants and defendants). In our view, neuroscientific evidence requires a protocol protecting expert witnesses against the biasing effects that are often inherent to the legal context. Such a protocol could, for example, emphasize blinding of procedures. PMID- 25017980 TI - [Meningitis after a mouse bite]. AB - BACKGROUND: Infection with the lymphocytic choriomeningitis virus is a human zoonosis caused by a rodent-borne arenavirus and is often seen in autumn and winter when mice retreat into houses. Infection in humans is acquired after inhalation of aerosols or direct contact with excreta of an infected rodent. CASE DESCRIPTION: A 37-year-old woman was referred to St. Elisabeth hospital in Tilburg, Netherlands, complaining of severe progressive headache, nausea and vomiting. Three weeks before presentation a mouse had bitten her finger. On neurological examination there were no abnormalities. Cerebrospinal fluid investigations indicated viral meningitis. Immunofluorescence serological testing confirmed the diagnosis of lymphocytic choriomeningitis. CONCLUSION: Infection by lymphocytic choriomeningitis virus after contact with rodents can cause viral meningitis. The acquired form of the disease is known to be self-limiting in immunocompetent patients. PMID- 25017981 TI - [Occupational physicians should play a more active role; multidisciplinary practice guidelines pay attention to work]. AB - The practice guideline 'Diagnosis and treatment of the subacromial pain syndrome' provides a thorough overview of the treatment possibilities that a doctor has when a patient with a painful shoulder presents. This guideline recognizes the importance of occupational exposure and functioning in the development, maintenance and treatment of health problems too. As is the case with so many multidisciplinary guidelines, it can be seen as an appeal to doctors to inquire about work and an appeal to occupational physicians to become active in the functional recovery of patients with a subacromial pain syndrome. PMID- 25017982 TI - [Optimal timing of antibiotic prophylaxis: effect on surgical site infection is overrated]. AB - Surgical site infection (SSI) is a common complication of surgery and a major cause of morbidity, mortality and health care costs. Several patient and perioperative care related factors play a role in SSI, which above all is the result of a complex process. Timing of antibiotic prophylaxis (AP) is a process indicator that has been described extensively. However, the optimal timing remains controversial. A large SSI reduction was initially shown for administration of AP within two hours before incision. Later the optimal timing seemed to be 30-60 minutes or the final 30 minutes before incision. Recently, it has been shown that there is no significant association between timing and SSI. This controversy is reflected in several guidelines with dissimilar advice. If there is no optimal AP timing, it should not be a process indicator. Other SSI risk factors that are presently not the focus of attention may be more important process indicators. PMID- 25017983 TI - [Inguinal hernia in children: examine thoroughly, treat rapidly]. AB - An inguinal hernia is a protrusion of the intra-abdominal contents (in most cases the small bowel) via the inguinal canal towards the labium or the scrotum and is possible due to the fact that the processus vaginalis has not obliterated. It occurs in 1-2% of children. If surgical repair is not performed within a short period of time, the consequences can be far-reaching. Incarceration may occur, with the risk of ischaemia and necrosis. Morbidity and mortality due to inguinal hernias can be prevented by well-timed surgical interventions. The diagnosis can be made by the patient's history, and examination and palpation. Ultrasonography or other radiological tests are not indicated, although often performed. In this clinical lesson the Dutch guideline on inguinal hernias in children will be explicated with reference to three cases. PMID- 25017984 TI - [A boy with an eschar and a rash]. AB - An 8-year-old boy presented with a fever, headache, maculopapular rash and painful joints after a vacation in Morocco. He had an eschar on his arm. Under the presumed diagnosis of rickettsiosis he was treated with doxycycline after which his fever subsided. Serology became positive for Rickettsia conorii 2 weeks later. PMID- 25017985 TI - [Appropriate use of antibiotics shortens length of hospital stay]. AB - Antimicrobial resistance is an increasing health care problem, both abroad and in the Netherlands, and its main driving force is antibiotic use. In patients with pneumonia or sepsis, appropriate antibiotic use has been associated with improved clinical outcome, shorter length of hospital stay, decreased bacterial resistance and reduced costs. In a recent study in 19 hospitals in the Netherlands, we found that appropriate antibiotic use in patients with another common type of infection, i.e. urinary tract infection, was also associated with a reduction in length of hospital stay, thus improving patient outcome and healthcare costs. A social and behavioural scientific approach with different intervention strategies - restrictive and persuasive - is required if antibiotic prescription in hospitals is to be improved. As a part of this antimicrobial stewardship programme, antibiotic teams (A-teams) must be introduced in all hospitals in 2014. PMID- 25017986 TI - In silico analysis of all point mutations on the 2B domain of K5/K14 causing epidermolysis bullosa simplex: a genotype-phenotype correlation. AB - Epidermolysis bullosa simplex (EBS) is a genodermatosis caused by mutations in keratins 5 and 14 (K5 and K14), which leads to fragility of basal keratinocytes and eventually epidermal cytolysis and blistering. Depending upon the severity of symptoms, EBS is classified into three major subtypes. In order of increasing severity these classes are EBS, localized (EBS-loc), EBS, other generalized (EBS, gen-nonDM), and EBS, Dowling-Meara (EBS-DM). We have searched and assembled 36 previously reported point mutations located on the 2B domain of K5/K14 in order to investigate the effects of point mutations. By performing a comprehensive in silico analysis we determine the underlying relationship between the mutation and its phenotypic effects. Our result showed that all pathogenic point mutations exert their dominant negative effect on the K5/K14 coiled-coil heterodimer complex by altering interchain interaction, leading to the changes in stability and assembly competence of the heterodimer complex. The physico-chemical properties of substituted amino acid and location of the mutation are also deeply correlated with disease severity. In addition, we found a SNP previously reported as non-pathogenic (K14 p.M338R) that likely affects the stability of the dimer structure due to the loss of interchain interaction and steric clashes. Overall, our finding demonstrates the significance of in silico characterization of EBS severity and would allow for accurate genetic counseling and prenatal diagnosis. PMID- 25017987 TI - Comment on: Three years durability of the improvements in health-related quality of life (HR-QoL) observed after gastric banding. PMID- 25017988 TI - Characterizing IGR IRES-mediated translation initiation for use in yeast cell free protein synthesis. AB - Eukaryotic cell-free protein synthesis (CFPS) systems are limited, in part, by inefficient translation initiation. Here, we report three internal ribosome entry site (IRES) sequences from the Dicistroviridae family that are highly active in yeast CFPS. These include the intergenic region (IGR) IRES from cricket paralysis virus (CrPV), plautia stali intestine virus (PSIV) and Solenopsis invicta virus 1 (SINV1). Optimization of combined transcription and translation (Tx/Tl) CFPS reactions primed with linear DNA containing the CrPV IGR IRES resulted in batch synthesis yields of 0.92 +/- 0.17 MUg/mL luciferase. Further template engineering, such as including the first 12 nt of native CrPV gene, increased yields to 2.33 +/- 0.11 MUg/mL. We next observed that the inclusion of a 50 nt poly(A) to the 3' end of the IGR IRES-mediated message increased yields an additional 81% to 4.33 +/- 0.37 MUg/mL, without any effect on mRNA stability or copy number. This was surprising because the CrPV IGR IRES requires no known translation initiation factors. Lastly, we investigated a method to inhibit background expression through competitive inhibition by supplying the reaction with 5' cap structure analog. This study highlights the crucial role translation initiation plays in yeast CFPS and offers a simple platform to study IRES sequences. PMID- 25017989 TI - The effect of substituted 1,2,4-triazole moiety on the emission, phosphorescent properties of the blue emitting heteroleptic iridium(III) complexes and the OLED performance: a theoretical study. AB - A series of neutral heteroleptic mononuclear iridium(III) complexes was investigated using the density functional theory/time-dependent density functional theory approach to determine the effect of the substituted 1,2,4 triazole moiety on the electronic structures, emission, and phosphorescent properties and the organic light emitting diode (OLED) performance. The results reveal that substitution of the free position in the triazole ring by -PhOCH3 (2) provides a higher emission energy and a lower oscillator strength, leading to longer radiative lifetime values mainly due to the ligand-to-ligand charge transfer transition character. The evaluation, based on one-center spin-orbit coupling, results in higher kr values for the substituent -F5Ph (5) and a lower DeltaE(S-T) value. Furthermore, we also investigated the performance of the OLED device, including the charge injection/transport/balance ability, increases in the Forster energy transfer rate and triplet exciton confinement for host and guest materials of blue emitting Ir(III) complexes. Finally, we hope that our investigations will help in the design of highly efficient phosphorescent materials. PMID- 25017990 TI - Determination of heavy metal contents in water, sediments, and fish tissues of Shizothorax plagiostomus in river Panjkora at Lower Dir, Khyber Pakhtunkhwa, Pakistan. AB - The present study was conducted to investigate the contamination of water, sediments, and fish tissues with heavy metals in river Panjkora at Lower Dir, Khyber Pakhtunkhwa, Pakistan. Water, sediments, and fish (Shizothorax plagiostomus) samples were collected from September 2012 to January 2013 at three different sites (upstream site at Sharigut, sewage site at Timergara, and downstream site at Sadoo) of river Panjkora. The concentrations of heavy metals in water were in the order Zn > Cu ~ Pb > Ni ~ Cd with mean values of 0.30, 0.01, 0.01, 0.0 and 0.0 mg/l, respectively, which were below the maximum permissible limits of WHO for drinking water. In sediments, heavy metals were found in the order Cu > Zn > Ni > Pb > Cd with mean concentrations of 50.6, 38.7, 9.3, 8, and 0.4 mg/kg, respectively. Ni and Cd were not found in any fish tissues, but Zn, Cu, and Pb were detected with the mean concentration ranges of 0.04-1.19, 0.03 0.12, and 0.01-0.09 MUg/g, respectively. The present study demonstrates that disposal of waste effluents causes a slight increase in the concentration of heavy metals in river Panjkora as revealed by variation in metal concentrations from upstream to downstream site. Sewage disposal was also found to change physicochemical characteristics of Panjkora water. At present, water and fish of river Panjkora are safe for human consumption, but the continuous sewage disposal may create problems in the future. PMID- 25017991 TI - Mercury proxies and mercury dynamics in a forested watershed of the US Northeast. AB - Although many studies focus on mercury (Hg) and methylmercury (MeHg) dynamics in streams, challenges remain in identifying the relative importance of land cover and seasonality at regulating Hg and MeHg dynamics at the watershed scale. Developing robust proxies for Hg and/or MeHg determination also remains a challenge. Our study used Hg, MeHg, and dissolved organic carbon (DOC) concentration measurements and various DOC fluorescence indices to characterize Hg and DOC dynamics in a forested watershed of the US Northeast. Principal component analysis indicated that land cover/landscape position (i.e., headwater vs. wetland-influenced area vs. lake-influenced area) explained 44 % of the variance in Hg, MeHg, DOC concentrations, and DOC quality during the snow-free season, while seasonality (i.e., air temperature and discharge) explained only 21 % of the variance in the results. Furthermore, finding a good proxy for Hg that is valid across a range of landscape positions remains a challenge; however, regression analysis indicated that the fluorescence peak Humic C (excitation = 350 nm; emission = max (420-480)), which corresponds to the presence of melanoidins in water, explained 21 % of the variability in MeHg concentrations across both space and time (p = 0.001), and thus appears to be a possible proxy for MeHg determination in our study watershed. From a management perspective, land cover modifications (lake, reservoir, and wetland) are likely to play more important roles at regulating Hg, MeHg, and DOC exports at the watershed scale than long-term changes in the climate of this region. PMID- 25017992 TI - Developmental shaping of dendritic arbors in Drosophila relies on tightly regulated intra-neuronal activity of protein kinase A (PKA). AB - Dendrites develop morphologies characterized by multiple levels of complexity that involve neuron type specific dendritic length and particular spatial distribution. How this is developmentally regulated and in particular which signaling molecules are crucial in the process is still not understood. Using Drosophila class IV dendritic arborization (da) neurons we test in vivo the effects of cell-autonomous dose-dependent changes in the activity levels of the cAMP-dependent Protein Kinase A (PKA) on the formation of complex dendritic arbors. We find that genetic manipulations of the PKA activity levels affect profoundly the arbor complexity with strongest impact on distal branches. Both decreasing and increasing PKA activity result in a reduced complexity of the arbors, as reflected in decreased dendritic length and number of branching points, suggesting an inverted U-shape response to PKA. The phenotypes are accompanied by changes in organelle distribution: Golgi outposts and early endosomes in distal dendritic branches are reduced in PKA mutants. By using Rab5 dominant negative we find that PKA interacts genetically with the early endosomal pathway. We test if the possible relationship between PKA and organelles may be the result of phosphorylation of the microtubule motor dynein components or Rab5. We find that Drosophila cytoplasmic dynein components are direct PKA phosphorylation targets in vitro, but not in vivo, thus pointing to a different putative in vivo target. Our data argue that tightly controlled dose-dependent intra-neuronal PKA activity levels are critical in determining the dendritic arbor complexity, one of the possible ways being through the regulation of organelle distribution. PMID- 25017993 TI - Considerations for the rapid deployment of vaccines against H7N9 influenza. AB - The threat of an outbreak of avian-origin influenza H7N9 and the devastating consequences that a pandemic could have on global population health and economies has mobilized programs of constant surveillance and the implementation of preemptive plans. Central to these plans is the production of prepandemic vaccines that can be rapidly deployed to minimize disease severity and deaths resulting from such an occurrence. In this article, we review current H7N9 vaccine strategies in place and the available technologies and options that can help accelerate vaccine production and increase dose-sparing capabilities to provide enough vaccines to cover the population. We also present possible means of reducing disease impact during the critical period after an outbreak occurs before a strain matched vaccine becomes available and consider the use of existing stockpiles and seed strains of phylogenetically related subtypes, alternate vaccination regimes and vaccine forms that induce cross-reactive immunity. PMID- 25017994 TI - The case for transmissible antivirals to control population-wide infectious disease. AB - Infectious disease control faces significant challenges including: how to therapeutically target the highest-risk populations, circumvent behavioral barriers, and overcome pathogen persistence and resistance mechanisms. We review a recently proposed solution to overcome these challenges: antivirals that transmit by 'piggybacking' on viral replication. These proposed antivirals, termed 'therapeutic interfering particles' (TIPs), are engineered molecular parasites of viruses that are designed to steal replication resources from the wild type virus. Depriving viruses of crucial replication machinery, TIPs would reduce viral loads. As obligate parasites, TIPs would transmit via the same risk factors and transmission routes as wild type viruses, automatically reaching high risk populations, and thereby substantially limiting viral transmission even in resource-poor settings. Design issues and ethical/safety considerations of this proposed intervention are discussed. PMID- 25017995 TI - Autoregulatory feedback loop of EZH2/miR-200c/E2F3 as a driving force for prostate cancer development. AB - The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has recently attracted considerable attention because of its dysregulation in prostate cancer (PCa) and its important function in PCa development. To date, little is known about the underlying cellular function and regulatory networks of EZH2 in PCa. This study aims to determine whether or not the autoregulatory feedback loop of EZH2/miR-200c/E2F3 serves key functions in PCa development. Bioinformatics and integrative analytical approaches were employed to identify the relationships of EZH2 to specific cancer-related gene sets. Results indicated that the enrichment of gene sets about cell cycle progression was associated with EZH2 expression. The depletion of EZH2 in cell experiments inhibited PCa cell growth and blocked cell cycle accompanying the downregulation of E2F3 expression. Furthermore, miR 200c served as an important mediator between EZH2 and E2F3. Compared with scrambled control cells, sh-EZH2 cells showed lower H3K27me3 expression and higher miR-200c expression. Western blot and luciferase reporter assays showed that miR-200c inversely modulated E2F3 by directly targeting the binding site within 3'UTR. Moreover, decreased miR-200c expression largely abrogated the effect of sh-EZH2 on E2F3 expression and E2F3-induced cell cycle progression. EZH2 was positively regulated by E2F3 at the transcriptional level. Immunohistochemistry and in situ hybridization revealed a significant correlation among EZH2, miR-200c, and E2F3 expression in human PCa tissues. In conclusion, the autoregulatory feedback loop of EZH2/miR-200c/E2F3 served an important function in PCa development. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy against PCa. PMID- 25017996 TI - miR-128 and miR-149 enhance the chemosensitivity of temozolomide by Rap1B mediated cytoskeletal remodeling in glioblastoma. AB - Glioblastoma multiforme (GBM) is one of the most deadly diseases affecting humans, and is often characterized by poor survival and by high resistance to chemotherapy and radiotherapy. Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of GBM following surgery. Although TMZ may restrain GBM growth, TMZ resistance is also common and accounts for numerous cases of treatment failure. Studies indicate that aberrant miRNA expression is associated with hallmark malignant properties of GBM. Thus, miRNA-based anticancer therapeutic approaches have been exploited, either alone or in combination with standard targeted therapies to enhance the efficacy of chemotherapy agents. In the present study, we demonstrated that the expression of miR-128 and miR-149 was downregulated in glioblastoma, and their overexpression inhibited the invasion of glioblastoma cells by targeting Rap1B-mediated cytoskeletal and related molecular alterations. Moreover, miR-128 and miR-149 enhanced the chemosensitivity of glioblastoma cells to TMZ. PMID- 25017997 TI - High-speed imaging using rigid laryngoscopy for the analysis of register transitions in professional operatic tenors. AB - INTRODUCTION: Vocal fold oscillation patterns in tenors singing at high pitches (stage voice above the passaggio) are not yet understood in detail. MATERIALS AND METHODS: Nine professional opera tenors performed a transition from modal register (220 Hz) to falsetto or stage voice above the passaggio (440 Hz) on an /i/ vowel. High-speed digital imaging was performed using a rigid laryngoscopic system with a frame rate of 4,000 frames per second. RESULTS: During the transition to stage voice above the passaggio seven out of nine tenors exhibited a strong retraction of the epiglottis with rising F0, which prevented further analysis of vocal fold oscillations. During transitions to falsetto many supraglottic modifications were also observed. CONCLUSION: Tenor stage voice above the passaggio seems to be typically associated with retraction of the epiglottis for the vowel /i/ thus preventing examination of vocal fold oscillations using rigid laryngoscopy. PMID- 25017998 TI - Ni(2+)-sensitive T-type Ca(2+) channel currents are regulated in parallel with synaptic and visual response plasticity in visual cortex. AB - Visual cortical neurons undergo depression and potentiation of their visual responses to stimulation of the deprived and non-deprived eyes, respectively, after monocular deprivation. This modification occurs predominantly during an early postnatal period in normal development, and this critical period is postponed until adulthood in animals reared in darkness from birth. We have proposed that Ni(2+)-sensitive T-type Ca(2+) channel-dependent long-term potentiation (T-LTP) mediates the potentiation of non-deprived eye responses. In this study, to investigate the development of Ni(2+)-sensitive T-type Ca(2+) channels, presumed CaV3.2 channels, we performed whole-cell recordings from layer 2/3 pyramidal neurons in rat visual cortical slices. T-type Ca(2+) channel currents were activated by voltage steps from -100mV to -40mV under a pharmacological blockade of Na(+) and K(+) channels. We estimated presumed CaV3.2 currents from the currents obtained after subtraction of the currents in the presence of Ni(2+) (50MUM) from those in control solution. The estimated currents were very small before eye opening, peaked during the critical period and then returned to a small value by adulthood. Dark rearing prevented the developmental decline in these currents until adulthood. These results suggest that the regulation of CaV3.2 currents underlies the developmental changes in T-LTP and ocular dominance plasticity. PMID- 25017999 TI - Increasing cardiac 18F-fluorodeoxyglucose (FDG) uptake on PET-CT as a biomarker for cardiotoxicity of chemo-radiotherapy in cancer: a myth or a reality? PMID- 25018001 TI - Who wins the race of predicting chemoradiation-induced esophagitis? Is there anyone else to join the competition? In response to Tang et al. PMID- 25018000 TI - Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: a near pathologic complete response does not translate into good clinical outcome. AB - BACKGROUND: After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum. AIM: The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients. METHODS: Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 * 2 Gy with capecitabine) and TME 6-8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators. RESULTS: The 3-year distant metastasis-free interval, disease free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators. CONCLUSION: The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that "watch-and-wait" in LARC patients should be applied with care. PMID- 25018002 TI - High-dose-rate brachytherapy with two or three fractions as monotherapy in the treatment of locally advanced prostate cancer. AB - BACKGROUND: To evaluate late urinary (GU) and gastrointestinal (GI) adverse events (AEs) and biochemical control of disease after high-dose rate brachytherapy (HDR-BT) in locally advanced prostate cancer. PATIENTS AND METHODS: 227 consecutive patients were treated with 3 * 10.5 Gy (n = 109) or 2 * 13 Gy (n = 118) HDR-BT alone. Biochemical failure was assessed using the Phoenix definition of PSA nadir + 2 MUg/l and late AEs using the RTOG scoring system and the International Prostate Symptom Score (IPSS). RESULTS: Kaplan-Meier estimates and prevalence of late events indicate that urinary, bowel and IPSS symptoms are higher after 31.5 Gy than after 26 Gy, however differences are significant only for Grade 1 and 2 urinary toxicity. Kaplan-Meier estimates of morbidity are consistently and considerably higher than time-point estimates of prevalence; which reflects the transient nature of most symptoms. At 3 years 93% and 97% of patients treated with 26 and 31.5 Gy, respectively, were free from biochemical relapse (p = 0.5) and 91% for the latter regimen at 5 years. In univariate and multivariate analysis risk-category was the only significant predictor of relapse (p < 0.03). CONCLUSION: These HDR-BT schedules achieved high levels of biochemical control of disease in patients with advanced prostate cancer with few severe complications seen throughout the first 3 years. PMID- 25018003 TI - Metal-free oxidative direct C(sp3)-H bond functionalization of ethers with alpha,alpha-diaryl allylic alcohols. AB - A metal-free method for direct C(sp(3))-H bond functionalization of simple ethers with alpha,alpha-diaryl allylic alcohols is described. The established protocol provides facile access to alpha-aryl-beta-oxyalkylated carbonyl ketones via radical addition and a 1,2-aryl migration cascade process. An application of the product has been demonstrated in the synthesis of a serotonin antagonist. PMID- 25018004 TI - Chemistry of free radicals produced by oxidation of endogenous alpha aminoketones. A study of 5-aminolevulinic acid and alpha-aminoacetone by fast kinetics spectroscopy. AB - BACKGROUND: Excess 5-aminolevulinic acid (ALA) and alpha-aminoacetone (AA) are implicated in ketosis, porphyrinpathies and diabetes. Pathologic manifestations involve O2-, H2O2, OH, enoyl radicals (ALA and AA) and their oxidation end products. METHODS: To characterize enoyl radicals resulting from reaction of OH radicals with ALA and AA, micromolar OH concentrations were produced by pulse radiolysis of ALA and AA in aqueous solutions. RESULTS: ALA and AA react with OH at k=1.5 * 109 M-1s-1. At pH7.4, the ALA absorbance spectrum has a maximum at 330 nm (epsilon=750 M-1cm-1). This band appears as a shoulder at pH8.3 where two ALA species are present: (NH3)+-CH2-CO-CH2-CH2-COO- and NH2-CH2-CO-CH2-CH2-COO- (pKa=8.3). At pH8.3, ALA reacts with oxygen (k=1.4 * 108 M-1s-1) but not with O2 . At pH8.3, AA oxidation produces two AA species characterized by an absorbance spectrum with maxima at 330 and 450 nm. ALA and AA are repaired by antioxidants (quercetin (QH), catechin, trolox, ascorbate) which are semi-oxidized (k>10(8)M 1s-1). QH bound to HSA or to apoferritin and ferritin repairs ALA and AA. In O2 saturated apoferritin solutions, Q, O2-, AA and reaction product(s) react with QH. CONCLUSIONS: The optical absorption properties and the time evolution of ALA and AA were established for the first time. These radicals and their reaction products may be neutralized by antioxidants free in solution or bound to proteins. GENERAL SIGNIFICANCE: Adjuvant antioxidant administration may be of interest in pathologies related to excess ALA or AA production. PMID- 25018005 TI - A Fourier transform infrared spectroscopy study of cell membrane domain modifications induced by docosahexaenoic acid. AB - BACKGROUND: Detergent resistant membranes (DRMs) are a useful model system for the in vitro characterization of cell membrane domains. Indeed, DRMs provide a simple model to study the mechanisms underlying several key cell processes based on the interplay between specific cell membrane domains on one hand, and specific proteins and/or lipids on the other. Considering therefore their biological relevance, the development of methods capable to provide information on the composition and structure of membrane domains and to detect their modifications is highly desirable. In particular, Fourier transform infrared (FTIR) spectroscopy is a vibrational tool widely used for the study not only of isolated and purified biomolecules but also of complex biological systems, including intact cells and tissues. One of the main advantages of this non-invasive approach is that it allows obtaining a molecular fingerprint of the sample under investigation in a rapid and label-free way. METHODS: Here we present an FTIR characterization of DRM fractions purified from the human breast cancer cells MCF 7, before and after treatment with the omega 3 fatty acid docosahexaenoic acid (DHA), which was found to promote membrane microdomain reorganization. RESULTS AND CONCLUSIONS: We will show that FTIR spectroscopy coupled with multivariate analysis enables to monitor changes in the composition of DRMs, induced in particular by the incorporation of DHA in cell membrane phospholipids. GENERAL SIGNIFICANCE: This study paves the way for a new label-free characterization of specific membrane domains within intact cells, which could provide complementary information to the fluorescence approaches presently used. PMID- 25018006 TI - Mechanistic studies on the anticancer activity of 2,4-disubstituted quinazoline derivative. AB - BACKGROUND: Accelerated proliferation of solid tumor and hematologic cancer cells is related to accelerated transcription of ribosomal DNA by the RNA polymerase I to produce elevated level of ribosomal RNA. Therefore, down-regulation of RNA polymerase I transcription in cancer cells is an important anticancer therapeutic strategy. METHODS: A variety of methods were used, including cloning, expression and purification of protein, electrophoretic mobility shift assay (EMSA), circular dichroic (CD) spectroscopy, CD-melting, isothermal titration calorimetry (ITC), chromatin immunoprecipitation (Ch-IP), RNA interference, RT-PCR, Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell assay. RESULTS: Our results showed that 2,4-disubstituted quinazoline derivative Sysu12d could down-regulate c-myc through stabilization of c-myc promoter G-quadruplex, resulting in down-regulation of nucleolin expression. Sysu12d could also disrupt nucleolin/G-quadruplex complex. Both of the above contributed to the down-regulation of ribosomal RNA synthesis, followed by activation of p53 and then cancer cell apoptosis. CONCLUSIONS: These mechanistic studies set up the basis for further development of Sysu12d as a new type of lead compound for cancer treatment. GENERAL SIGNIFICANCE: 2,4-Disubstituted quinazoline derivatives may have multi-functional effect for cancer treatment. PMID- 25018007 TI - Loss of HuR leads to senescence-like cytokine induction in rodent fibroblasts by activating NF-kappaB. AB - BACKGROUND: HuR (human antigen R) is a ubiquitously expressed member of the Hu/ELAV family of proteins that is involved in diverse biological processes. HuR has also been shown to play an important role in cell cycle arrest during replicative senescence in both human and mouse cells. Senescent cells not only halt their proliferation, but also activate the secretion of proinflammatory cytokines. A persistent DNA damage response is essential for the senescence associated secretory phenotype (SASP), and increasing evidence has suggested that the SASP is associated with malignancy. METHODS: Senescence-associated phenotypes were analyzed in MEFs and other cell line in which HuR expression is inhibited by sh-RNA-mediated knockdown. RESULTS: RNAi-mediated HuR inhibition resulted in an increase in SASP-related cytokines. The induction of SASP factors did not depend on ARF-p53 pathway-mediated cell cycle arrest, but required NF-kappaB activity. In the absence of HuR, cells were defective in the DNA-damage response, and single strand DNA breaks accumulated, which may have caused the activation of NF kappaB and subsequent cytokine induction. CONCLUSIONS: In the absence of HuR, cells exhibit multiple senescence-associated phenotypes. Our findings suggest that HuR regulates not only the replicative lifespan, but also the expression of SASP-related cytokines in mouse fibroblasts. GENERAL SIGNIFICANCE: RNA-binding protein HuR protects cells from undergoing senescence. Senescence-associated phenotypes are accelerated in HuR-deficient cells. PMID- 25018008 TI - The geographical co-distribution and socio-ecological drivers of childhood pneumonia and diarrhoea in Queensland, Australia. AB - SUMMARY This study aimed to explore the spatio-temporal patterns, geographical co distribution, and socio-ecological drivers of childhood pneumonia and diarrhoea in Queensland. A Bayesian conditional autoregressive model was used to quantify the impacts of socio-ecological factors on both childhood pneumonia and diarrhoea at a postal area level. A distinct seasonality of childhood pneumonia and diarrhoea was found. Childhood pneumonia and diarrhoea were mainly distributed in the northwest of Queensland. Mount Isa city was the high-risk cluster where childhood pneumonia and diarrhoea co-distributed. Emergency department visits (EDVs) for pneumonia increased by 3% per 10-mm increase in monthly average rainfall in wet seasons. By comparison, a 10-mm increase in monthly average rainfall may cause an increase of 4% in EDVs for diarrhoea. Monthly average temperature was negatively associated with EDVs for childhood diarrhoea in wet seasons. Low socioeconomic index for areas (SEIFA) was associated with high EDVs for childhood pneumonia. Future pneumonia and diarrhoea prevention and control measures in Queensland should focus more on Mount Isa. PMID- 25018009 TI - Neurophysiological correlates of dysregulated emotional arousal in severe traumatic brain injury. AB - OBJECTIVE: This study aimed to elucidate relationships between dysregulated emotional arousal after severe traumatic brain injury (TBI), alpha power and skin conductance levels (SCL), and brain atrophy. METHODS: Nineteen adults with severe TBI and 19 age-, education-, and gender-matched controls (all p's>0.05) participated. Magnetic resonance imaging (MRI) scan established bilateral insulae and amygdale volumes. Mean EEG alpha power and SCLs were recorded simultaneously across four, 2 min conditions: eyes-closed pre-task baseline, view neutral face, happy face and angry face. RESULTS: Scalp-wide alpha suppression occurred from pre-task baseline to the face-viewing conditions (p<.001), but was diminished in TBI (p=.04). TBI participants exhibited marginally significantly lower SCL (p=.051), and elevated alpha power hemispherically, contrasting with controls' midline dominance (p<.01). Significant atrophy was observed in most structures in TBI participants (p's=.004-0.04). Larger left insula, left amygdala and right amygdala correlated positively with alpha power and alpha suppression, and SCLs; all structures uniquely contributed to variance in arousal. CONCLUSIONS: Findings suggest that alpha power provides a sensitive measure of dysregulated emotional arousal post-TBI. Atrophy in pertinent brain structures may contribute to these disturbances. SIGNIFICANCE: These findings have potential implications for the assessment and remediation of TBI-related arousal deficits, by directing more targeted remediation, and better assessing post-TBI recovery. PMID- 25018010 TI - Altered event-related potentials in adults with ADHD during emotional faces processing. AB - OBJECTIVE: This study investigated behavioral and neural correlates of emotional processing in adults with ADHD using scalp-recorded event-related potentials (ERPs). METHODS: We used a visual-emotional oddball paradigm, in which subjects were confronted with neutral and emotional faces (happy and angry). Responses to target and non-target stimuli were compared across groups of 17 adults with ADHD and 20 control subjects. RESULTS: Participants with ADHD had slower RTs than controls in response to happy but not to angry faces. ADHD participants, but not controls, responded faster to angry than to happy faces. ERP results indicated that group significantly interacted with the type of facial expression. P1 was significantly increased for the ADHD group compared with controls, but only to emotional (and not to neutral) faces. In the ADHD group, but not in controls, P1 was greater in response to emotional compared with neutral faces. N170 was more pronounced to angry than to happy faces in the ADHD group, while in the control group N170 was more pronounced to happy than to angry faces. Participants with ADHD showed a pronounced reduction in P3 to both emotional and neutral faces. CONCLUSIONS: The current results provide indication of altered behavioral responses as well as altered P1, N170 and P3 to emotional faces in adults with ADHD compared with healthy controls. SIGNIFICANCE: Behavioral and brain function measures of emotion processing may provide valuable additional tools for clinical assessment of ADHD in adulthood. PMID- 25018011 TI - Small worlds. PMID- 25018012 TI - Remembering K. S. Krishnan (1946-2014). AB - Dr. K. S. Krishnan was on the faculty of the Division of Biological Sciences at the Tata Institute of Fundamental Research (TIFR) in Mumbai, India, and later emeritus professor at the National Center for Biological Sciences (NCBS) in Bangalore, India. His research using fruit flies has contributed richly to our understanding of synaptic function and mechanisms of anesthetic action. Dr. Krishnan passed away suddenly of a heart attack on the 24th of May, 2014. Below a few of his students fondly recall how it was to work in his group. PMID- 25018013 TI - Loss of 11p11 is a frequent and early event in sporadic nonfunctioning pancreatic neuroendocrine neoplasms. AB - The pathogenesis of sporadic pancreatic neuroendocrine neoplasms (PNENs) is poorly understood. To gain insight into the genetic mechanisms underlying this tumor entity, we performed genome-wide screening of 16 surgical specimens from 15 patients with sporadic PNEN, combining G-band karyotyping and high resolution comparative genomic hybridization (HR-CGH). G-banding revealed abnormal karyotypes in 2 of 10 tumor samples analyzed. DNA copy number changes were detected in 13 samples, whereas three tumors showed a balanced genome. Gains were more frequent than losses in the nonfunctioning tumors (n=13). Common gains were scored at 5p12-13, 4q13-24, 5p15, 5q11-31, and 9q21-22. Common losses were scored at 11p11, 11p14-15, 11q23, 11p12-13, and 11q22. The average number of copy aberrations (ANCA index) was 12 for 13 nonfunctioning primary tumors, 4.8 for the nonfunctioning tumors with low Ki-67 (>=5%), 21.2 for the tumors with high Ki-67 (<5%), 2.5 for small tumors (<3.5 cm), and 17.8 for large tumors (>=3.5 cm). There was a statistically significant difference in the ANCA index between the groups defined by Ki-67 and tumor size. Nonfunctioning tumors with low Ki-67, no distant metastasis and small size had few aberrations detected by HR-CGH, but frequent loss of material from chromosomal band 11p11. The present study indicates the existence of distinct cytogenetic patterns in sporadic nonfunctioning PNEN. Loss of chromosomal band 11p11 might indicate a primary pathogenetic event in these tumors. PMID- 25018014 TI - MicroRNA-10a enhances the metastatic potential of cervical cancer cells by targeting phosphatase and tensin homologue. AB - Cervical cancer is one of the leading causes of cancer-related mortality worldwide. Previously, the upregulation of microRNA (miR)-10a has been identified in human cervical cancer. The present study firstly demonstrated that miR-10a was markedly upregulated in primary tumor tissues in patients with positive lymph node metastasis (LN+) compared with negative (LN-) by quantitative polymerase chain reaction. miR-10a mimics markedly enhanced cervical cancer cell migration and invasion abilities, and accordingly the miR-10a inhibitor suppressed those functions. Furthermore, these data suggested that the phosphatase and tensin homologue (PTEN) was inhibited by miR-10a through an miR-10a binding site within the 3'-untranslated region of PTEN at the posttranscriptional level, and that miR 10a mimics promoted nuclear translocation of beta-catenin. Therefore, it was concluded that the overexpression of miR-10a contributes to metastasis in cervical cancer by targeting PTEN. miR-10a may therefore be used clinically as a molecular marker for patients with cervical cancer lymph node metastasis. PMID- 25018015 TI - Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma. AB - Leukotriene B4 (LTB4) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model. In this double-blind, 3-period crossover study, 22 patients with mild, atopic asthma were randomized to one of three treatments per period: 100 mg/day JNJ-40929837 for 6 days followed by 50 mg/day on day 7; 10 mg/day montelukast for 6 days; and matched placebo. The BAC was performed on day 6 of each treatment period. Primary outcome was BAC-induced late asthmatic response (LAR) measured by maximal percent reduction in forced expiratory volume (FEV1) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV1, EAR and LAR evaluated by area under the FEV1/time curve (AUC0-2, AUC3-10, respectively), change in baseline FEV1 after 5 day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB4 levels and sputum basal LTB4 levels. No significant differences were observed in the primary or secondary FEV1 endpoints with JNJ-40929837 versus placebo. Compared with placebo (n = 17, LS mean = 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV1 with JNJ-40929837 (n = 16, LS mean = 28.6, P = 0.63) but montelukast (n = 17, LS mean = 22.6, P = 0.01) significantly attenuated the LAR. JNJ-40929837 substantially inhibited LTB4 production in whole blood, decreased sputum LTB4 levels and was well-tolerated. The number of adverse events leading to study withdrawal was the same in JNJ-40929837 and placebo groups. In conclusion, JNJ-40929837 demonstrated target engagement in blood and sputum. No significant impact in response to allergen inhalation was observed with JNJ 40929837 versus placebo. REGISTRATION: This study is registered at ClinicalTrials.gov: NCT01241422. PMID- 25018016 TI - Clinical experience with ramucirumab : outcomes in breast cancer. AB - INTRODUCTION: Monoclonal antibodies and small molecules targeting the VEGF pathway are part of the arsenal to treat malignant tumors. Antiangiogenesis therapies has been studied in breast cancer with partial success, reflected by the approval of bevacizumab in Europe but not in United States, for metastatic breast cancer (mBC). Ramucirumab is a mAb against VEGFR-2 interfering with the normal activation of this receptor by its natural ligand VEGF. AREAS COVERED: This article will review the preclinical data available to date for ramucirumab, as well as survey the main clinical trials of antiangiogenic agents reported in breast cancer, focusing on Phase III clinical trials. It will also review the clinical trial data for ramucirumab in mBC, including the design of the Phase II trials, and report on the preliminary results of the TRIO-012 trial. This trial did not meet its primary end point in progression-free survival and has to be considered as a negative trial. EXPERT OPINION: Despite preliminary positive data with ramucirumab in other metastatic solid tumors reported to date, the results of TRIO-012 discourage pursuing more efforts with ramucirumab in mBC unless predictive and reproducible biomarkers can be established to select those patients who are most likely to benefit from it. PMID- 25018017 TI - A synthetic multifunctional mammalian pH sensor and CO2 transgene-control device. AB - All metabolic activities operate within a narrow pH range that is controlled by the CO2-bicarbonate buffering system. We hypothesized that pH could serve as surrogate signal to monitor and respond to the physiological state. By functionally rewiring the human proton-activated cell-surface receptor TDAG8 to chimeric promoters, we created a synthetic signaling cascade that precisely monitors extracellular pH within the physiological range. The synthetic pH sensor could be adjusted by organic acids as well as gaseous CO2 that shifts the CO2 bicarbonate balance toward hydrogen ions. This enabled the design of gas programmable logic gates, provided remote control of cellular behavior inside microfluidic devices, and allowed for CO2-triggered production of biopharmaceuticals in standard bioreactors. When implanting cells containing the synthetic pH sensor linked to production of insulin into type 1 diabetic mice developing diabetic ketoacidosis, the prosthetic network automatically scored acidic pH and coordinated an insulin expression response that corrected ketoacidosis. PMID- 25018018 TI - Mechanism of DNA methylation-directed histone methylation by KRYPTONITE. AB - In Arabidopsis, CHG DNA methylation is controlled by the H3K9 methylation mark through a self-reinforcing loop between DNA methyltransferase CHROMOMETHYLASE3 (CMT3) and H3K9 histone methyltransferase KRYPTONITE/SUVH4 (KYP). We report on the structure of KYP in complex with methylated DNA, substrate H3 peptide, and cofactor SAH, thereby defining the spatial positioning of the SRA domain relative to the SET domain. The methylated DNA is bound by the SRA domain with the 5mC flipped out of the DNA, while the H3(1-15) peptide substrate binds between the SET and post-SET domains, with the epsilon-ammonium of K9 positioned adjacent to bound SAH. These structural insights, complemented by functional data on key mutants of residues lining the 5mC and H3K9-binding pockets within KYP, establish how methylated DNA recruits KYP to the histone substrate. Together, the structures of KYP and previously reported CMT3 complexes provide insights into molecular mechanisms linking DNA and histone methylation. PMID- 25018019 TI - Noncoding transcription by alternative RNA polymerases dynamically regulates an auxin-driven chromatin loop. AB - The eukaryotic epigenome is shaped by the genome topology in three-dimensional space. Dynamic reversible variations in this epigenome structure directly influence the transcriptional responses to developmental cues. Here, we show that the Arabidopsis long intergenic noncoding RNA (lincRNA) APOLO is transcribed by RNA polymerases II and V in response to auxin, a phytohormone controlling numerous facets of plant development. This dual APOLO transcription regulates the formation of a chromatin loop encompassing the promoter of its neighboring gene PID, a key regulator of polar auxin transport. Altering APOLO expression affects chromatin loop formation, whereas RNA-dependent DNA methylation, active DNA demethylation, and Polycomb complexes control loop dynamics. This dynamic chromatin topology determines PID expression patterns. Hence, the dual transcription of a lincRNA influences local chromatin topology and directs dynamic auxin-controlled developmental outputs on neighboring genes. This mechanism likely underscores the adaptive success of plants in diverse environments and may be widespread in eukaryotes. PMID- 25018020 TI - Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development. AB - Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade 2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2 mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons. PMID- 25018021 TI - Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG I. AB - RIG-I activates interferon signaling pathways by promoting filament formation of the adaptor molecule, MAVS. Assembly of the MAVS filament is mediated by its CARD domain (CARD(MAVS)), and requires its interaction with the tandem CARDs of RIG-I (2CARD(RIG-I)). However, the precise nature of the interaction between 2CARD(RIG I) and CARD(MAVS), and how this interaction leads to CARD(MAVS) filament assembly, has been unclear. Here we report a 3.6 A electron microscopy structure of the CARD(MAVS) filament and a 3.4 A crystal structure of the 2CARD(RIG I):CARD(MAVS) complex, representing 2CARD(RIG-I) "caught in the act" of nucleating the CARD(MAVS) filament. These structures, together with functional analyses, show that 2CARD(RIG-I) acts as a template for the CARD(MAVS) filament assembly, by forming a helical tetrameric structure and recruiting CARD(MAVS) along its helical trajectory. Our work thus reveals that signal activation by RIG I occurs by imprinting its helical assembly architecture on MAVS, a previously uncharacterized mechanism of signal transmission. PMID- 25018023 TI - Human herpesvirus 8 glycoprotein B binds the entry receptor DC-SIGN. AB - We have previously shown that human herpesvirus 8 (HHV-8) uses DC-SIGN as an entry receptor for dendritic cells, macrophages and B cells. The viral attachment protein for DC-SIGN is unknown. HHV-8 virions contain five conserved herpesvirus glycoproteins, a single unique glycoprotein, and two predicted glycoproteins. Previous studies have shown that DC-SIGN binds highly mannosylated glycoproteins. The HHV-8 glycoprotein B (gB) has been reported to be highly mannosylated, and therefore we hypothesized that gB will bind to DC-SIGN. In this report we confirm that gB has a high mannose carbohydrate structure and demonstrate for the first time that it binds DC-SIGN in a dose-dependent manner. We also identify key amino acids in the DC-SIGN carbohydrate recognition domain that are required for HHV-8 infection and compare these results with published binding regions for ICAM-2/3 and HIV-1 gp120. These results clarify some of the initial events in HHV-8 entry and can be used for the design of targeted preventive therapies. PMID- 25018024 TI - Poor sleep quality measured by polysomnography in non-obese asthmatic children with or without moderate to severe obstructive sleep apnea. AB - BACKGROUND: The co-effect of asthma and obstructive sleep apnea (OSA) on sleep quality among children remained unclear. OBJECTIVE: To compare sleep quality and emotional/behavioral problems among asthmatic and non-asthmatic children with or without moderate to severe obstructive sleep apnea. METHOD: An AHI-range-matched BMI-range-matched cross-sectional design was used to examine polysomnographic evaluation and emotional/behavioral problems in 102 non-obese children aged between 6 and 12 years old, categorized as with or without asthma and sleep disordered breathing. RESULTS: Asthmatic children in AHI <= 5/h group revealed a significantly longer sleep latency, a greater leg movement index (LMI), and a lower ratio of slow wave sleep compared with non-asthmatic AHI <= 5/h group. Compared with non-asthmatic AHI > 5/h group, asthmatic children displayed a higher ratio of REM sleep, sleep stage 1 and 2, a lower ratio of slow wave sleep, as well as a greater respiratory arousal index and LMI. There was no significant difference in emotional/behavior problems among groups. CONCLUSION: Sleep disturbance exists in asthmatic children with or without moderate to severe obstructive sleep apnea. Non-obese asthmatic children had less slow wave sleep compared with non-asthmatic children. We might recommend that sleep quality could be noticed and evaluated in children with asthma. PMID- 25018022 TI - Antiretroviral restriction factors in mice. AB - One of the most exciting areas in contemporary retrovirus research is the discovery of "restriction factors". These are cellular proteins that act after virus entry to inhibit infection by or replication of retroviruses (and other viruses and intracellular pathogens). We briefly discuss here three antiretroviral restriction factors in mice: Fv1, APOBEC3, and tetherin, touching on both biological and molecular aspects of these restriction systems. PMID- 25018025 TI - Agreement of different methods for assessing sleep characteristics: a comparison of two actigraphs, wrist and hip placement, and self-report with polysomnography. AB - OBJECTIVE: To assess the agreement of sleep parameters measured by two actigraphs (SOMNOwatch plus, ActiGraph GT3X+) at two different placements (wrist, hip) and of self-reported sleep with polysomnography (PSG). METHODS: We estimated agreement with PSG for total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), number of awakenings after sleep onset (NASO), and sleep efficiency (SE%) for 100 participants of the general population, aged 18-75 years by judging mean differences to PSG and intervals of agreement using Bland Altman plots. RESULTS: Mean difference to PSG for TST was 8.3 min (95% confidence intervals [CI] -7.4; 24.1) for SOMNOwatch plus (wrist), 39.8 min (95% CI 24.3; 55.3) for self-report, -79.0 min (95% CI -89.0; -68.9) for SOMNOwatch plus (hip), and -81.1 min (95% CI -91.9; -70.4) for GT3X+ (hip), respectively. The width of intervals of agreement differed with the placement of the devices. Mean differences to PSG were higher for hip-based measurements compared with wrist placement for most parameters. CONCLUSIONS: Agreement of sleep parameters assessed by actigraphy with PSG differs with the placement of the device and is limited for hip-based measurements. Agreement of self-report with PSG is comparable to that of actigraphy for some parameters. PMID- 25018026 TI - A new method of measurement of cerebral circulation time: contrast-enhanced ultrasonography in healthy adults and patients with intracranial shunts. AB - Alterations in the cerebral circulation time (CCT) are observed in several cerebrovascular diseases. We designed a new method of global CCT measurement using gray-scale contrast-enhanced ultrasound and studied healthy Chinese adults and patients with intracranial shunts. Eighty-one healthy volunteers and eight patients with intracranial shunt disease were enrolled. The contrast agent Sonovue was used. Perfusion in the carotid artery and internal jugular vein bilaterally was recorded. Start and peak filling CCTs were calculated and analyzed. Imaging of carotid vessels was uncomplicated in all patients. The bilateral start CCT was 6.23 +/- 1.39 s in healthy patients. There were no significant differences within subgroups and contrast-dosage groups. In the patient group, the mean start CCT was 3.0 +/- 0.56 s. There was a significant difference between the control and patient groups (p < 0.001). This new method using gray-scale contrast imaging can measure CCT and cerebral blood volume accurately. It can be used to visualize blood flow differences in real time and is less dependent on the training of the operator. PMID- 25018027 TI - Harmonic imaging with fresnel beamforming in the presence of phase aberration. AB - Fresnel beamforming is a beamforming method with a delay profile similar in shape to a physical Fresnel lens. The advantage of Fresnel beamforming is the reduced channel count, which consists of four to eight transmit and two analog-to-digital receive channels. Fresnel beamforming was found to perform comparably to conventional delay-and-sum beamforming. However, the performance of Fresnel beamforming is highly dependent on focal errors. These focal errors result in high side-lobe levels and further reduce the performance of Fresnel beamforming in the presence of phase aberration. With the advantages of lower side-lobe levels and suppression of aberration effects, harmonic imaging offers an effective solution to the limitations of Fresnel beamforming. We describe the implementation of tissue harmonic imaging and pulse inversion harmonic imaging in Fresnel beamforming, followed by dual apodization with cross-correlation, to improve image quality. Compared with conventional delay-and-sum beamforming, experimental results indicated contrast-to-noise ratio improvements of 10%, 49% and 264% for Fresnel beamforming using tissue harmonic imaging in the cases of no aberrator, 5-mm pork aberrator and 12-mm pork aberrator, respectively. These improvements were 22%, 57% and 352% for Fresnel beamforming using pulse inversion harmonic imaging. Moreover, dual apodization with cross-correlation was found to further improve the contrast-to-noise ratios in all cases. Harmonic imaging was also found to narrow the lateral beamwidth and shorten the axial pulse length by at least 25% and 21%, respectively, for Fresnel beamforming at different aberration levels. These results suggest the effectiveness of harmonic imaging in improving image quality for Fresnel beamforming, especially in the presence of phase aberration. Even though this combination of Fresnel beamforming and harmonic imaging does not outperform delay-and-sum beamforming combined with harmonic imaging, it provides the benefits of reduced channel count and potentially reduced cost and size of ultrasound systems. PMID- 25018028 TI - Evaluation of statin therapy on endothelial function in hypercholesterolemic rabbits by automatic measurement of arterial wall movement using ultrasound images. AB - The aim of this study was to evaluate arterial endothelial function, assessed as acetylcholine-mediated dilation (AMD), in a hypercholesterolemic atherosclerotic rabbit model to investigate the effects of atorvastatin in the atherosclerotic process, using a new computerized analysis model and ultrasound images. Twenty seven rabbits were fed a high-cholesterol (2%) diet for 6 wk and then divided into three groups for an additional 9 wk: Group A received regular chow food, group B received a 2% cholesterol-rich diet plus atorvastatin drug, and group C received regular chow food plus atorvastatin. Ultrasound examinations of endothelial function of the rabbit abdominal aorta artery were performed immediately after the 6 weeks (0 wk) and then 3, 6 and 9 wk after that. For off line analysis, a computerized analysis method for evaluating instantaneous changes in the wall of the rabbit abdominal aorta was used. As parameters of improvement resulting from treatment, endothelium-dependent acetylcholine-induced dilation and endothelium-independent nitroglycerin-induced dilation were evaluated in treated rabbits. Differences among groups were tested using analysis of variance. On histopathology, intima-media thickness decreased after treatment in all groups. There were no significant differences in arterial diameter and blood velocity changes among treated rabbits at 0, 3, 6 and 9 wk of treatment in all groups, except in end-diastolic velocity, radial strain percentage, pulse index and resistance index in group C. In group A, AMD did not significantly improve after 3, 6 and 9 wk, as compared with 0 wk. Atorvastatin treatment significantly increased AMD (18%) at 3 wk in group B, compared with week 0. AMD significantly increased after 3 (26%), 6 (124%) and 9 (182%) wk in group C, compared with 0 wk. It is concluded that the new automatic method enables accurate and repeated evaluation of endothelial function during the progression and regression of atherosclerosis. Also, the results obtained in this study indicate that short-term administration of atorvastatin can improve endothelial function in cholesterol-fed rabbits. PMID- 25018029 TI - Hepatic filling rate of a microbubble agent: a novel predictor of long-term outcomes in patients with cirrhosis. AB - The aim of the study described here was to evaluate the significance of the hepatic filling rate of a perflubutane microbubble agent in predicting long-term outcomes and prognoses in 32 patients with cirrhosis (37-76 y, 20 females, Child Pugh A16, B16). The time from delivery of the contrast agent to the hepatic artery to maximum enhancement of the liver parenchyma on the sonogram was defined as the hepatic filling rate (mean = 18.6 s). Hepatic filling rate did not correlate significantly with the Child-Pugh score or the model for end-stage liver disease score. However, the survival rate was lower (93.3% at 1 y, 60.2% at 3 y) and the rate of occurrence of hepatocellular carcinoma (HCC) was higher (13.3% at 1 y, 33.3% at 3 y) in the group with the slow filling rate (>=18 s) than in the group with the rapid filling rate (<18 s) (93.3% at 1 and 3 y for survival, 6.3% at 1 and 3 y for HCC occurrence). Hepatic filling rate may constitute a non-invasive marker for the occurrence of HCC and prognosis of cirrhosis. PMID- 25018030 TI - Dietary glycemic index, glycemic load and risk of age-related cataract extraction: a case-control study in Italy. AB - PURPOSE: Although a role of glycemic index (GI) and glycemic load (GL) in age related cataract development is plausible, a few studies, all conducted in USA or Australia, provided results on this issue. The aim of the present study was to provide new original data from a Mediterranean population. METHODS: We analyzed data from an Italian case-control study including 761 cases with cataract extraction and 1,522 hospital controls, frequency-matched with cases by center, sex, and age. Multivariate odds ratios (ORs) for GI and GL intakes were obtained from logistic regression models after allowance for major confounding factors, including non carbohydrate energy intake, smoking, and diabetes. RESULTS: The ORs of cataract extraction for the highest versus the lowest tertile were 1.20 (95% confidence interval, CI 0.91-1.57) for GI and 1.57 (95% CI 1.16-2.13) for GL, with a statistically significant trend in risk for GL (p < 0.01). Results were materially unchanged when diabetics were excluded from the analysis. No heterogeneity emerged across strata of sex, age, education, smoking habits and body mass index. CONCLUSIONS: The present study supports a positive association between dietary GL and the risk of cataract extraction, independently from diabetes, and a lack of association for GI. PMID- 25018031 TI - Whey peptide ingestion suppresses body fat accumulation in senescence-accelerated mouse prone 6 (SAMP6). AB - PURPOSE: Body weight in young growing and young adult animals was reduced by a high dietary density of whey protein concentrate; however, it is unclear whether dietary proteins similarly affect body weight in aging animals. Here, we examined whether whey protein or whey peptide ingestion suppressed body fat accumulation and affected protein expression and phosphorylation in skeletal muscle in aging mice. METHODS: Twenty-six male senescence-accelerated mouse prone 6 (SAMP6) mice were assigned randomly to three dietary treatment groups: 18.7% casein control (CON), 18.7% whey protein (WPR), and 18.7% whey peptide (WPE). After 28 weeks of treatment, skeletal tissues were dissected and weighed for analysis. Western blotting was performed to examine the expression of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and adipose triglyceride lipase (ATGL) in quadriceps muscles. RESULTS: Body (CON: 47.6 +/- 2.2 g, WPR: 48.2 +/- 2.7 g, WPE: 38.3 +/- 2.0 g) and relative white adipose tissue (CON: 38.5 +/- 3.5 mg/g, WPR: 43.8 +/- 4.0 mg/g, WPE: 21.1 +/- 4.4 mg/g) weights were lower in the WPE group compared with the other two groups (p < 0.05), and no significant differences were observed between the CON and WPR groups. The relative weights of tibialis anterior muscle (CON: 1.04 +/- 0.04 mg/g, WPR: 0.97 +/- 0.03 mg/g, 1.23 +/- 0.05 mg/g) and gastrocnemius muscle (CON: 3.02 +/- 0.12 mg/g, WPR: 2.92 +/- 0.15 mg/g, WPE: 3.65 +/- 0.18 mg/g) were higher in the WPE group compared with the other groups (p < 0.05). The phosphorylation of AMPK (WPR: 1.03 +/- 0.11, WPE: 1.36 +/- 0.12; fold change from control) and ACC (WPR: 1.08 +/- 0.07, WPE: 1.18 +/- 0.05; fold change from control) in WPE was higher than in CON (p < 0.05). There were no significant differences in the expression levels of ATGL among the three groups. CONCLUSIONS: These data suggest that a normal (or moderate excess) dietary density of whey peptide attenuates body fat accumulation via upregulation of fatty acid oxidation in skeletal muscle in aging mice. PMID- 25018032 TI - The comparison of instrumented and non-instrumented fusion in the treatment of lumbar spondylolisthesis: a meta-analysis. AB - PURPOSE: This meta-analysis compared whether fusion with or without instrumentation to treat this disease differed with respect to patient-centered outcomes. METHODS: Medline, Cochrane, EMBASE, Google Scholar data bases were searched for randomized control trials that investigated patients with severe chronic lower back pain resulting from localized lumbar or lumbosacral instability caused by either isthmic spondylolisthesis or degenerative spondylolisthesis. Included randomized studies reported quantitative outcomes for low back pain and functional recovery. The primary outcome was the improvement of function and the secondary outcomes were the improvement of pain, patients' satisfactory level, and the fusion rate. RESULTS: A significantly lower function change in patients with instrumented compared with non-instrumented from baseline (pooled standardized mean difference; -1.02 (95% CI -1.76 to -0.27); Z -2.67; (P = 0.008)]. There was no significant pain change for patients with instrumented compared with that of non-instrumented from baseline [pooled standardized mean difference; -0.07 (95% CI -1.25 to 1.12); Z -0.11; (P = 0.913)]. There was no significant difference in satisfactory level for patients with instrumented compared with that of non-instrumented [pooled OR; 2.36 (95% CI 0.91-6.11); Z 1.76; (P = 0.078)]. There was significantly higher fusion rate for patients with instrumented compared with that of non-instrumented [pooled OR; 3.28 (95% CI 2.22 4.85); Z 5.96; (P < 0.001)]. CONCLUSIONS: This meta-analysis found that inclusion of fusion surgery with instrumentation provided no benefit as evaluated by patient-reported outcomes in patients with lumbar spondylolisthesis. LEVEL OF EVIDENCE: Not applicable. PMID- 25018033 TI - Pelvic incidence-lumbar lordosis mismatch predisposes to adjacent segment disease after lumbar spinal fusion. AB - PURPOSE: Several risk factors and causes of adjacent segment disease have been debated; however, no quantitative relationship to spino-pelvic parameters has been established so far. A retrospective case-control study was carried out to investigate spino-pelvic alignment in patients with adjacent segment disease compared to a control group. METHODS: 45 patients (ASDis) were identified that underwent revision surgery for adjacent segment disease after on average 49 months (7-125), 39 patients were selected as control group (CTRL) similar in the distribution of the matching variables, such as age, gender, preoperative degenerative changes, and numbers of segments fused with a mean follow-up of 84 months (61-142) (total n = 84). Several radiographic parameters were measured on pre- and postoperative radiographs, including lumbar lordosis measured (LL), sacral slope, pelvic incidence (PI), and tilt. RESULTS: Significant differences between ASDis and CTRL groups on preoperative radiographs were seen for PI (60.9 +/- 10.0 degrees vs. 51.7 +/- 10.4 degrees , p = 0.001) and LL (48.1 +/- 12.5 degrees vs. 53.8 +/- 10.8 degrees , p = 0.012). Pelvic incidence was put into relation to lumbar lordosis by calculating the difference between pelvic incidence and lumbar lordosis (?PILL = PI-LL, ASDis 12.5 +/- 16.7 degrees vs. CTRL 3.4 +/- 12.1 degrees , p = 0.001). A cutoff value of 9.8 degrees was determined by logistic regression and ROC analysis and patients classified into a type A (?PILL <10 degrees ) and a type B (?PILL >=10 degrees ) alignment according to pelvic incidence-lumbar lordosis mismatch. In type A spino-pelvic alignment, 25.5 % of patients underwent revision surgery for adjacent segment disease, whereas 78.3 % of patients classified as type B alignment had revision surgery. Classification of patients into type A and B alignments yields a sensitivity for predicting adjacent segment disease of 71 %, a specificity of 81 % and an odds ratio of 10.6. CONCLUSION: In degenerative disease of the lumbar spine a high pelvic incidence with diminished lumbar lordosis seems to predispose to adjacent segment disease. Patients with such pelvic incidence-lumbar lordosis mismatch exhibit a 10-times higher risk for undergoing revision surgery than controls if sagittal malalignment is maintained after lumbar fusion surgery. PMID- 25018034 TI - Surgical strategies for removal of intra- and extraforaminal dumbbell-shaped schwannomas in the subaxial cervical spine. AB - PURPOSE: Spinal dumbbell-shaped schwannoma is common neoplasm, usually occurring in the cervical spine. Posterior or anterolateral approaches are frequently used to remove this benign tumor. We analyzed how much amount of tumor could be possible to be totally removed with posterior approach. METHOD: Surgery was performed on 41 cases of cervical, dumbbell-shaped subaxial schwannomas with both intra- and extraforaminal involvement. The same surgeon performed all the procedures. Mean follow-up was 42.5 months (24-108 months). A combined anterolateral and posterior approach was used if the extraforaminal tumor was larger than 10 mm. A posterior approach and unilateral facet removal were used if it was smaller than 10 mm. We performed MRI and serial dynamic X-rays for postoperative 2 years. RESULTS: We used the posterior approach with facetectomy in 35 cases and the combined approach in six. Complete removal was achieved with the combined approach in all six, and with the posterior approach in 28 of 35 cases. With the posterior approach, the extraforaminal dimension of totally resected tumors ranged from 3 to 5.4 mm. Subtotal resection was limited to extraforaminal tumors larger than 5.7 mm. On follow-up, instability on dynamic X ray was not observed before 24 months in any patient after unilateral facetectomy. CONCLUSION: Total removal of intra- and extraforaminal cervical subaxial schwannomas could be possible using a posterior approach with facet removal if the size of extraforaminal tumor was less than 5.4 mm. PMID- 25018035 TI - Reducing prostate cancer deaths: unsupported speculation about the androgen deprivation hypothesis. AB - The reduction in prostate cancer deaths in the European Randomized Study of Screening for Prostate Cancer is best explained by a stage migration in the intervention arm, resulting in earlier effective treatment of localized prostate cancer compared with controls. PMID- 25018036 TI - A multigene assay identifying distinct prognostic subtypes of clear cell renal cell carcinoma with differential response to tyrosine kinase inhibition. AB - Patients with clear cell renal cell carcinoma (ccRCC) have divergent survival outcomes and therapeutic responses, which may be determined by underlying molecular diversity. We aimed to develop a practical molecular assay that can identify subtypes with differential prognosis and response to targeted therapy. Whole-genome expression analysis of formalin-fixed paraffin-embedded (FFPE) material from 55 ccRCC patients was performed and two molecular subtypes with differential clinical outcomes were identified by hierarchical clustering. An eight-gene quantitative polymerase chain reaction assay for classification into two subtypes was developed for FFPE material. The primary objective was to assess assay performance by correlating ccRCC prognostic subtypes to cancer-specific survival (CSS) and, for patients receiving targeted therapy, radiologic response. In three validation cohorts, patients could be distinguished into prognostic subtypes with differential CSS (Singapore General Hospital FFPE cohort: n = 224; p = 1.48 * 10(-8); the Cancer Genome Atlas RNA-Sequencing cohort: n = 419; p = 3.06 * 10(-7); Van Andel Research Institute microarray cohort: n=174; p=0.00743). For 48 patients receiving tyrosine kinase inhibitor (TKI) treatment, the prognostic classification was associated with radiologic response to treatment (p = 5.96 * 10(-4)) and prolonged survival on TKI treatment (p=0.019). The multigene assay can classify ccRCCs into clinical prognostic subtypes, which may be predictive of response in patients receiving TKI therapy. PMID- 25018038 TI - Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. AB - BACKGROUND: The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To compare the activity of enzalutamide after abiraterone in docetaxel-experienced and docetaxel-naive mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate specific antigen (PSA) response rates (PSA decline >= 50% confirmed >= 3 wk later), and survival data were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chi-square for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. RESULTS AND LIMITATIONS: A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p=0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p=0.6), and median OS (10.6 mo vs 8.6 mo; p=0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide. CONCLUSIONS: Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future research. PATIENT SUMMARY: We looked at the effectiveness of enzalutamide after abiraterone acetate for treatment of advanced prostate cancer. We found that patients who had received docetaxel chemotherapy before abiraterone gained similar benefit from enzalutamide compared with patients who had not received docetaxel. These results suggest that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone. PMID- 25018037 TI - Impact of baseline corticosteroids on survival and steroid androgens in metastatic castration-resistant prostate cancer: exploratory analysis from COU-AA 301. AB - BACKGROUND: Corticosteroids have been used to mitigate mineralocorticoid-related effects and restore sensitivity to abiraterone acetate. Corticosteroids may also mediate glucocorticoid receptor or mutated androgen receptor activation and adversely influence outcome. OBJECTIVE: This post hoc exploratory analysis investigated whether baseline corticosteroids were an independent prognostic factor and its level of contribution in the presence of other prognostic factors for overall survival (OS) in study COU-AA-301. DESIGN, SETTING, AND PARTICIPANTS: COU-AA-301 was a randomised study of abiraterone plus prednisone versus prednisone in metastatic castration-resistant prostate cancer patients after docetaxel. INTERVENTION: Patients were randomised 2:1 to abiraterone 1000 mg plus prednisone 5mg by mouth twice daily versus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of OS with baseline corticosteroids was determined by univariate and multivariate Cox models. RESULTS AND LIMITATIONS: At study entry, 33% of patients received corticosteroids, had worse disease characteristics (p<0.05 except liver metastases), and were more likely to have testosterone levels below the median (odds ratio: 2.92; chi-square p<0.0001). Associations between prostate-specific antigen response as well as circulating tumour cell decline and higher baseline androgen levels were demonstrated. Patients taking baseline corticosteroids had inferior OS in univariate analysis (hazard ratio: 1.48; p<0.0001); however, in multivariate stepwise selection modelling, baseline corticosteroids did not add substantially to the model. This analysis is limited as a retrospective analysis and restricted to patients after docetaxel. CONCLUSIONS: In the COU-AA-301 study, baseline corticosteroids were associated with adverse prognostic features, inferior OS, and lower baseline androgen levels but did not add substantial information to the final prognostic model. Thus in these data from study COU-AA-301, concurrent baseline corticosteroids did not have an independent impact on OS. PATIENT SUMMARY: Baseline corticosteroids did not adversely affect abiraterone clinical benefit in metastatic castration-resistant prostate cancer. Their use was associated with patients having worse disease characteristics. PMID- 25018039 TI - Active surveillance: protocol makes perfect. PMID- 25018041 TI - Structural plasticity of the brain to psychostimulant use. AB - Over the past years it has become evident that repeated exposure to a variety of psychoactive stimulants, like amphetamine, cocaine, MDMA (3,4-methylenedioxy-N methylamphetamine), methylphenidate and nicotine may produce profound behavioral changes as well as structural and neurochemical alterations in the brain that may persist long after drug administration has ceased. These stimulants have been shown to produce long-lasting enhanced embranchments of dendrites and increasing spine density in brain regions linked to behavioral sensitization and compulsive patterns characteristic of drug seeking and drug addiction. In this regard, addiction to stimulant drugs represents a compulsory behavior that includes drug seeking, drug use and drug craving, but is also characterized as a cognitive disorder. In this article, recent findings regarding the impact of central stimulants on plasticity in brain regions of relevance for addictive behavior will be highlighted. A particular focus will be given to changes in neuroplasticity that occur in areas related to memory and cognition. Possible routes for the reversal of altered brain plasticity will also be discussed. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID- 25018040 TI - Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an alpha1 adrenergic receptor-dependent manner. AB - Dopaminergic innervation of the extended amygdala regulates anxiety-like behavior and stress responsivity. A portion of this dopamine input arises from dopamine neurons located in the ventral lateral periaqueductal gray (vlPAG) and rostral (RLi) and caudal linear nuclei of the raphe (CLi). These neurons receive substantial norepinephrine input, which may prime them for involvement in stress responses. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase promoter, we explored the physiology and responsiveness to norepinephrine of these neurons. We find that RLi dopamine neurons differ from VTA dopamine neurons with respect to membrane resistance, capacitance and the hyperpolarization-activated current, Ih. Further, we found that norepinephrine increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) on RLi dopamine neurons. This effect was mediated through the alpha1 adrenergic receptor (AR), as the actions of norepinephrine were mimicked by the alpha1-AR agonist methoxamine and blocked by the alpha1-AR antagonist prazosin. This action of norepinephrine on sEPSCs was transient, as it did not persist in the presence of prazosin. Methoxamine also increased the frequency of miniature EPSCs, indicating that the alpha1-AR action on glutamatergic transmission likely has a presynaptic mechanism. There was also a modest decrease in sEPSC frequency with the application of the alpha2-AR agonist UK-14,304. These studies illustrate a potential mechanism through which norepinephrine could recruit the activity of this population of dopaminergic neurons. PMID- 25018042 TI - Chronic periadolescent alcohol consumption produces persistent cognitive deficits in rhesus macaques. AB - Although human alcoholics exhibit lasting cognitive deficits, it can be difficult to definitively rule out pre-alcohol performance differences. For example, individuals with a family history of alcoholism are at increased risk for alcoholism and are also behaviorally impaired. Animal models of controlled alcohol exposure permit balanced group assignment, thereby ruling out the effects of pre-existing differences. Periadolescent male rhesus macaques (N = 5) consumed alcohol during 200 drinking sessions (M-F) across a 10-month period (mean daily alcohol consumption: 1.38 g/kg/day). A control group (N = 5) consumed a fruit flavored vehicle during the same period. Spatial working memory, visual discrimination learning and retention and response time behavioral domains were assessed with subtests of the Monkey CANTAB (CAmbridge Neuropsychological Test Automated Battery). Spatial working memory performance was impaired in the alcohol group after 120 drinking sessions (6 mo) in a manner that depended on retention interval. The chronic alcohol animals were also impaired in retaining a visual discrimination over 24 hrs when assessed 6-8 weeks after cessation of alcohol drinking. Finally, the presentation of distractors in the response time task impaired the response time and accuracy of the chronic alcohol group more than controls after 6 months of alcohol cessation. Chronic alcohol consumption over as little as 6 months produces cognitive deficits, with some domains still affected after acute (6-8 wks) and lasting (6 mo) discontinuation from drinking. Animals were matched on alcohol preference and behavioral performance prior to exposure, thus providing strong evidence for the causal role of chronic alcohol in these deficits. PMID- 25018044 TI - Toward building the cow folliculome. AB - One of the goals of the EmbryoGENE network was to gather information on the conditions leading to competent oocytes. Using a combination of transcriptomic analyses we are building the foundation of the folliculome, which will take the form of a virtual follicle with gene expression profiling data spanning small to ovulatory or atretic follicles. The different models currently being established not only provide information on the follicular conditions leading to good outcome but also intermediary steps, including evolution towards atresia. The physiology of very few species has been covered to the extent of our database, which is the only one for mono-ovulatory species. The first interesting observation extracted from our data is related to the plateau phase of follicular development, which is not a linear intermediate between growth and ovulation but rather an important modification step of tissue ontogenesis during which growth switches to differentiation or atresia. The markers of cell division, matrix rearrangement, mesenchymal differentiation, oxidation, steroidogenesis and ovulatory changes identified confirm known changes but also several others are now hinting to a more complex picture of this dynamic tissue. In addition to biomarkers, we have insight into the multiple pathways involved during the last few days before ovulation. Our new ability to validate these networks in vitro using primary granulosa cells culture also contributes to the construction of a follicular blueprint. The amazing list of gene responding to FSH alone is a good start but a complete meta-analysis will provide the foundation of the bovine folliculome. PMID- 25018043 TI - Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: the role of inhibition of Drp1 in ischemic brain damage. AB - Mitochondria dysfunction is implicated in diverse conditions, including metabolic and neurodegenerative disorders. Mitochondrial dynamics has attracted increasing attention as to its relationship with mitochondria autophagy, also known as mitophagy, which is critical for degradation of dysfunctional mitochondria maintaining mitochondrial homeostasis. Mitochondrial fission and its role in clearance of injured mitochondria in acute ischemic injury, however, have not been elucidated yet. Here we showed that hypoxic/ischemic conditions led to fragmentation of mitochondria and induction of mitophagy in permanent middle cerebral artery occlusion (pMCAO) rats and oxygen-glucose deprivation (OGD) PC12 cells. Inhibition of Drp1 by pharmacologic inhibitor or siRNA resulted in accumulation of damaged mitochondria mainly through selectively blocking mitophagy without affecting mitochondrial biogenesis and non-selective autophagy. Drp1 inhibitors increased the infarct volume and aggravated the neurological deficits in a rat model of pMCAO. We demonstrated that the devastating role of disturbed mitochondrial fission by inhibiting Drp1 contributed to the damaged mitochondria-mediated injury such as ROS generation, cyt-c release and activation of caspase-3. Taken together, we proved that under hypoxic/ischemic stress a Drp1 dependent mitophagy was triggered which was involved in the removal of damaged mitochondria and cellular survival at the early stage of hypoxic/ischemic injury. Thus, Drp1 related pathway involved in selective removal of dysfunctional mitochondria is proposed as an efficient target for treatment of cerebral ischemia. PMID- 25018045 TI - Heavy ion radiation can promote greater motility and enolase protein expression in ram sperm in in vitro liquid storage. AB - The aim of the study was to determine the effects of heavy ion radiation (HIR) on ram sperm quality during 24h of in vitro liquid storage at 15 degrees C, and identify the most appropriate dose which did not injure, but actually improved sperm quality and confirmed the relationship between highly expressed enolase and ram sperm quality during storage in vitro. Six Dorset ram (Ovis aries) semen pools from five mature and healthy rams were each divided into seven experimental groups with different doses of HIR (0, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5Gy) under the same experimental conditions. Sperm motility, viability, ATP content, and the gene and protein expression of enolase were measured at 24h of storage. Irradiated semen which had been stored for 24h, retained not only greater sperm motility, viability, and ATP content, but had greater enolase protein expression. This was evidenced by increased amounts of mRNA for this enzyme and amount of enolase protein as compared with semen from control rams, especially for the 0.1Gy group (P<0.001). These results indicate that HIR can promote enhanced motility and viability during in vitro liquid storage, and the 0.1Gy may be a suitable dose for improving sperm quality. Greater amounts of enolase and ATP content may results from enhanced sperm glycolysis by HIR. HIR enhances sperm glycolysis to generate sufficient ATP for maintaining sperm motility during storage. PMID- 25018046 TI - Molecular cloning, expression profile and transcriptional modulation of two splice variants of very low density lipoprotein receptor during ovarian follicle development in geese (Anser cygnoide). AB - Very low density lipoprotein receptor (VLDLR)-mediated endocytosis of plasma lipoproteins into the ovary is essential for ovarian follicle development. Two splice variants of VLDLR have been identified in several species, yet little is known about their distinctive roles in ovarian developing follicles. In the present study, the full-length cDNAs of two splice isoforms of VLDLR were obtained from geese (Anser cygnoide) ovaries using the RACE method. The longer isoform (TypeI VLDLR) is 3141bp and contains five conserved structural domains, while the other (TypeII VLDLR) lacks 90bp encoding for the O-linked sugar domain. TypeII VLDLR was predominantly expressed in the ovary, with greater amounts of mRNA in theca and granulosa cells from early stages of follicle development but decreased during vitellogenesis. However, there was minimal expression of the TypeI VLDLR gene in theca cells and expression was almost undetectable in granulosa cells throughout follicle development. Yolk VLDL concentrations decreased as stage of development advanced while yolk triglyceride and cholesterol concentrations increased in a follicular size-dependent manner. The significant correlations between transcripts of TypeII VLDLR and yolk lipids supported its important role on yolk lipid deposition. In addition, in vitro experiments suggested that exogenous cholesterol, 25-hydroxycholesterol and mevinolin (a highly potent competitive inhibitor of HMG-CoA) treatment could significantly alter TypeII VLDLR gene expression in granulosa cells from both pre hierarchical and pre-ovulatory follicles. Collectively, data from the present study indicate that TypeII VLDLR is more important for the transport of plasma lipoproteins into developing follicles than TypeI VLDLR, and provide new evidence about the influence of steroids in modulating VLDLR gene expression in ovarian cells. PMID- 25018047 TI - Variation in Sp1 binding sites correlates with expression of survivin in breast cancer. AB - Survivin is the smallest member of the inhibitor of apoptosis (IAP) family and is deregulated in breast cancer, where it is associated with a poor overall prognosis. It is well established that survivin overexpression predominately occurs at the transcriptional level. Numerous transcription factors bind to specific sequences in the promoter regions of genes and are involved in transcriptional regulation. Specificity protein (Sp) 1 binding sites have been found in the promoter region of the survivin gene. The present study aimed to investigate whether variations in Sp1 binding sites affect survivin expression. Nested polymerase chain reaction followed by DNA sequencing were performed to analyze the survivin gene promoter region in 42 breast cancer tissue samples. Furthermore, survivin expression was assessed using immunohistochemistry. High survivin protein expression was found in 66.7% (28/42) of breast cancer tissue samples. In addition, 15 variations in seven Sp1 binding sites were detected in 12 samples and Sp1 binding site variation was found to be associated with low survivin expression in the 42 samples. These findings suggested that variations in Sp1 binding sites may be associated with survivin expression. PMID- 25018048 TI - An oligonucleotide-tagged microarray for routine diagnostics of colon cancer by genotyping KRAS mutations. AB - Colorectal cancer (CRC) is one of the most prevalent types of cancer, causing significant morbidity and mortality worldwide. CRC is curable if diagnosed at an early stage. Mutations in the oncogene KRAS play a critical role in early development of CRC. Detection of activated KRAS is of diagnostic and therapeutic importance. In this study, KRAS gene fragments containing mutations in codon 12 were amplified by multiplex PCR using a 5'-Cy5-labeled reverse primer in combination with 3'-mutation-specific forward primers that were linked with four unique nucleotide-sequence tags at the 5'-end. The Cy5-labeled reverse primer was extended under PCR amplification to the 5'-end of the mutation-specific forward primers and thus included the complimentary sequence of the tag. PCR products were hybridized to tag-probes immobilized on various substrates and detected by a scanner. Our results indicate that all mutations at codon 12 of KRAS derived from cancer cells and clinical samples could be unambiguously detected. KRAS mutations were accurately detected when the mutant DNA was present only in 10% of the starting mixed materials including wild-type genomic DNA, which was isolated from either cancer cells or spiked fecal samples. The immobilized tag-probes were stable under multiple thermal cycling treatments, allowing re-use of the tag microarray and further optimization to solid PCR. Our results demonstrated that a novel oligonucleotide-tagged microarray system has been developed which would be suitable to be used for detection of KRAS mutations and clinical diagnosis of CRC. PMID- 25018049 TI - Automated voxel-by-voxel tissue classification for hippocampal segmentation: methods and validation. AB - The hippocampus is an important structural biomarker for Alzheimer's disease (AD) and has a primary role in the pathogenesis of other neurological and psychiatric diseases. This study presents a fully automated pattern recognition system for an accurate and reproducible segmentation of the hippocampus in structural Magnetic Resonance Imaging (MRI). The method was validated on a mixed cohort of 56 T1 weighted structural brain images, and consists of three processing levels: (a) Linear registration: all brain images were registered to a standard template and an automated method was applied to capture the global shape of the hippocampus. (b) Feature extraction: all voxels included in the previously selected volume were characterized by 315 features computed from local information. (c) Voxel classification: a Random Forest algorithm was used to classify voxels as belonging or not belonging to the hippocampus. In order to improve the classification performance, an adaptive learning method based on the use of the Pearson's correlation coefficient was developed. The segmentation results (Dice similarity index = 0.81 +/- 0.03) compare well with other state-of-the art approaches. A validation study was conducted on an independent dataset of 100 T1 weighted brain images, achieving significantly better results than those obtained with FreeSurfer. PMID- 25018050 TI - Gafchromic film dosimetry: four years experience using FilmQA Pro software and Epson flatbed scanners. AB - PURPOSE: s: To assess performance of FilmQA Pro software for pre-treatment patient-specific quality assurance (QA), using radiochromic films and two commercial flatbed scanners. To evaluate a novel multichannel approach compared to the classical red channel evaluation. MATERIAL AND METHODS: Patient films (mostly EBT2 films, one box of EBT3) were digitalized using successively two flatbed scanners: the A4-size Epson V750 and the A3-size Epson 10000XL. Prior to patient dose verification, basic characteristics of films and scanners were investigated. Patient films were analyzed using FilmQA Pro software, which enables to use the signal from all three colour channels (Red, Green, Blue). RESULTS: Compared to the red channel evaluation, multichannel evaluation presents better passing rates with regard to local gamma index. As expected, we obtained better results using A3-size scanner compared to A4-size scanner, especially when considering large region of interest. An observation of great interest was made for both scanners: after intensive use, a tilting in the blue transmittance profiles appeared in the lamp direction, making multichannel analysis unsuitable for accurate dose evaluation. PMID- 25018051 TI - The development of Wilms tumor: from WT1 and microRNA to animal models. AB - Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/beta-catenin pathway-related WT1, beta-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor. PMID- 25018052 TI - 6-iodolactone, key mediator of antitumoral properties of iodine. AB - An iodinated derivative of arachidonic acid, 5-hydroxy-6-iodo-8,11,14 eicosatrienoic acid, delta-lactone (6-IL) has been implicated as a possible intermediate in the autoregulation of the thyroid gland by iodine. In addition to antiproliferative and apoptotic effects observed in thyrocytes, this iodolipid could also exert similar actions in cells derived from extrathyroidal tissues like mammary gland, prostate, colon, or the nervous system. In mammary cancer (solid tumors or tumor cell lines), 6-IL has been detected after molecular iodine (I2) supplement, and is a potent activator of peroxisome proliferator-activated receptor type gamma (PPARgamma). These observations led us to propose I2 supplement as a novel coadjutant therapy which, by inducing differentiation mechanisms, decreases tumor progression and prevents chemoresistance. Some kinds of tumoral cells, in contrast to normal cells, contain high concentrations of arachidonic acid, making the I2 supplement a potential "magic bullet" that enables local, specific production of 6-IL, which then exerts antineoplastic actions with minimal deleterious effects on normal tissues. PMID- 25018053 TI - Alternative stable states and alternative endstates of community assembly through intra- and interspecific positive and negative interactions. AB - Positive and negative interactions within and between species may occur simultaneously, with the net effect depending on population densities. For instance, at low densities plants may ameliorate stress, while competition for resources dominates at higher densities. Here, we propose a simple two-species model in which con- and heterospecifics have a positive effect on per capita growth rate at low densities, while negative interactions dominate at high densities. The model thus includes both Allee effects (intraspecific positive effects) and mutualism (interspecific positive effects), as well as intra- and interspecific competition. Using graphical methods we derive conditions for alternative stable states and species coexistence. We show that mutual non invasibility (i.e. the inability of each species to invade a population of the other) is more likely when species have a strong positive effect on the own species or a strong negative effect on the other species. Mutual non-invasibility implies alternative stable states, however, there may also be alternative stable states at which species coexist. In the case of species symmetry (i.e. when species are indistinguishable), such alternative coexistence states require that if the positive effect exerted at low densities at the own species is stronger than on the other species, the negative effect at higher densities is also stronger on the own species than on the other species, or, vice versa, if the interspecific positive effects at low densities are stronger than the intraspecific effects, the negative effects at higher densities are also stronger between species than within species. However, the reachability of alternative stable states is restricted by the frequency and density at which species are introduced during community assembly, so that alternative stable states do not always represent alternative endstates of community assembly. PMID- 25018054 TI - A SNaPshot assay for the rapid and simple detection of hepatitis B virus genotypes. AB - A simple technique for the identification of common genotypes of the hepatitis B virus (HBV) remains to be identified. The present study was conducted to establish such a methodology. Four plasmids of genotypes A-D and 123 clinical serum specimens of HBV-infected patients were genotyped. HBV genotypes would be detected successfully when the HBV genotype reached a viral load of 1 x 103 copies/ml or the BC genotype mixed samples reached a 5% level. The lower limit of detection of HBV DNA in serum specimens was determined to be 2.14x102 IU/ml. The assay sensitivity and specificity were 100% and the consistency was demonstrated to reach as high as 90.24 and 100% compared with that of the DNA sequencing and cloning. The frequencies of the genotypes B, C, BC, BD and BCD were found to be 65.0, 23.6, 7.3, 3.3 and 0.8%, respectively. The accuracy of detection of the mixed infections was also higher using the rapid and simple SNaPshot method compared with that achieved with the DNA sequencing methods. The results of the present study indicated that the SNaPshot technique accurately distinguishes the HBV genotypes A-D and is able to be readily applied as a monitoring tool in HBV prognosis and treatment. PMID- 25018055 TI - Serum Th17 cytokines in leprosy: correlation with circulating CD4(+) CD25 (high)FoxP3 (+) T-regs cells, as well as down regulatory cytokines. AB - Leprosy is not only a bacteriological disease but also an immunological disease, in which T helper17 and CD4(+) CD25(high)FoxP3(+) regulatory T cells (T-regs), among others, may play a role. We aimed to evaluate serum levels of interleukin (IL)-17, IL-22 (Th17 cytokines), IL-10 and transforming growth factor (TGF)-beta (down regulatory cytokines) in 43 untreated leprosy patients and 40 controls by enzyme-linked immunosorbent assay, and to assess circulating CD4(+) CD25(high)FoxP3(+)T-regs in patients using flow cytometry. Patients were grouped into tuberculoid, pure neural, borderline, lepromatous, type 1 reactional leprosy, and erythema nodosum leprosum. IL-10 and TGF-beta were significantly higher in patients as compared to controls (p < 0.001), while IL-17, but not IL 22, was significantly lower (p < 0.001), with no significant difference comparing patients' subgroups. Significantly higher CD4(+) CD25(high)FoxP3(+)T-regs levels was detected in tuberculoid, type 1 reaction and pure neural leprosy, while the lowest levels in erythema nodosum leprosum (p < 0.001). TregsFoxP3 expression% was significantly lower in pure neural leprosy than other patients' subgroups (p < 0.05). T-regs/T-effs was lowest in erythema nodosum leprosum (p < 0.05). TGF beta correlated negatively with TregsFoxP3 expression% and T-effs% (p = 0.009 and 0.018 respectively). Leprosy is associated with defective IL-17 and overproduction of IL-10 and TGF-beta. Tuberculoid, type 1 reaction and pure neural leprosy express significantly higher circulating T-regs, consistent with effector immune mechanisms activation, but with lower TregsFoxP3 expression (in pure neural leprosy). Erythema nodosum leprosum is characterized by deficient T regs and increased TregsFoxP3 expression%. The present study pinpointed a potential role of Th17, CD4(+) CD25(high)FoxP3(+)T-regs, and probably CD4(+) CD25(+)IL-10(+) T regulatory cells 1 (Tr1), and Th3 in leprosy. PMID- 25018056 TI - The role of contact media at the skin-electrode interface during transcranial direct current stimulation (tDCS). PMID- 25018057 TI - Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. AB - OBJECTIVE: Preclinical studies have shown that low-dose methylene blue increases mitochondrial cytochrome oxidase activity in the brain and improves memory retention after learning tasks, including fear extinction. The authors report on the first controlled experiment to examine the memory-enhancing effects of posttraining methylene blue administration on retention of fear extinction and contextual memory following fear extinction training. METHOD: Adult participants displaying marked claustrophobic fear were randomly assigned to double-blind administration of 260 mg of methylene blue (N=23) or administration of placebo (N=19) immediately following six 5-minute extinction trials in an enclosed chamber. Retesting occurred 1 month later to assess fear renewal as indexed by peak fear during exposure to a nontraining chamber, with the prediction that the effects of methylene blue would vary as a function of fear reduction achieved during extinction training. Incidental contextual memory was assessed 1 and 30 days after training to assess the cognitive-enhancing effects of methylene blue independent of its effects on fear attenuation. RESULTS: Consistent with predictions, participants displaying low end fear posttraining showed significantly less fear at the 1-month follow-up if they received methylene blue posttraining compared with placebo. In contrast, participants displaying moderate to high levels of posttraining fear tended to fare worse at the follow-up if they received methylene blue posttraining. Methylene blue's enhancement of contextual memory was unrelated to initial or posttraining claustrophobic fear. CONCLUSIONS: Methylene blue enhances memory and the retention of fear extinction when administered after a successful exposure session but may have a deleterious effect on extinction when administered after an unsuccessful exposure session. PMID- 25018058 TI - XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma. AB - The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03-2.75) and 0.66 (0.48-0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas. PMID- 25018059 TI - Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS mediated mitochondrial and p53-related apoptotic pathways. AB - Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100 MUM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways. PMID- 25018060 TI - Transoral surgery using a novel single-port flexible endoscope system. AB - The transoral resection of pharyngeal and laryngeal tumors is challenging due to their location in a narrow anatomic space. In this study, the visualization and resection in the area of the pharynx and larynx using a novel computer-assisted flexible endoscopic robotic system are evaluated. The Medrobotics((r)) Flex((r)) System (Medrobotics Corp., Raynham, MA, USA) is an operator-controlled flexible endoscope robotic system that includes a flexible endoscope and computer-assisted controllers, with two accessory channels for the use of compatible, 3.5 mm flexible instruments. In six human cadavers, four basic procedures (tonsillectomy, base of tongue resection, hemi-epiglottectomy and resection of false vocal cords) were performed bilaterally by two surgeons. Success in appropriate visualization of the target structure and resection was documented. The driving and resection time was determined for each procedure. An appropriate exposure and resection within the pharynx and larynx was achieved in all cases. Both surgeons experienced a learning curve in driving the system and performing the procedures. The Medrobotics Flex((r)) system is a promising tool for transoral resections within the pharynx and larynx. Good visualization, access, and resectability are hereby clear advantages of the system compared to commonly used systems. PMID- 25018061 TI - Modified application of superficial temporal artery flap in hypopharyngeal reconstruction. PMID- 25018062 TI - Thrombosis and hemostatic abnormalities in hematological malignancies. AB - There is a paucity of data that pertain to thrombosis in patients with hematological malignancies. Recent studies showed that patients with lymphoma, multiple myeloma, and acute leukemia have an increased thrombotic risk, particularly at the time of diagnosis and during chemotherapy. We searched the PubMed database for articles on thromboembolic complications in patients with hematological malignancies published between 1996 and 2013. The incidence of thrombotic events is variable, and is influenced by the type and the stage of hematological malignancy, the antitumor therapy, and the use of central venous devices. The pathogenesis of thromboembolic disease in hematological malignancies is multifactorial. Tumor cell-derived procoagulant, fibrinolytic, or proteolytic factors, and inflammatory cytokines affect clotting activation, and chemotherapy and immunomodulatory drugs increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. Infections might also contribute to the pathogenesis of the thromboembolic complications: endotoxins from gram negative bacteria induce the release of tissue factor, tumor necrosis factor and interleukin-1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. In the setting of plasma cell dyscrasias, hyperviscosity, decreased fibrinolysis, procoagulant autoantibody production, inflammatory cytokines, acquired activated protein C resistance, and the prothrombotic effects of antimyeloma agents might be the cause of thromboembolic complications. Anticoagulant therapy is very complicated because of high risk of hemorrhage. Therefore, an accurate estimate of a patient's thrombotic risk is essential to allow physicians to target thromboprophylaxis in high-risk patients. PMID- 25018063 TI - Hepatic extramedullary disease in multiple myeloma with 17p deletion. PMID- 25018064 TI - Potent proapoptotic actions of dihydroartemisinin in gemcitabine-resistant A549 cells. AB - Our recent studies have demonstrated the key roles of reactive oxygen species (ROS)-mediated caspase-8- and Bax-dependent apoptotic pathways in dihydroartemisinin (DHA)-induced apoptosis of A549 cells. This report is designed to investigate the proapoptotic mechanisms of DHA in gemcitabine (Gem)-resistant A549 (A549GR) cells. A549GR cells exhibited lower basal antioxidant capacity, higher level of basal ROS and intracellular Fe(2+) than Gem-sensitive A549 (A549) cells. In contrast to the sluggish ROS generation induced by Gem, DHA induced a rapid ROS generation within 30min. Moreover, Gem induced similar ROS generation in both cell lines, while DHA induced more ROS generation in A549GR cells than in A549 cells. More importantly, after treatment with DHA, A549GR cells showed more potent induction in Bax activation, loss of mitochondrial membrane potential (DeltaPsim), caspase activation and apoptosis than A549 cells. Furthermore, NAC pretreatment potently prevented DHA-induced ROS generation and loss of DeltaPsim as well as apoptosis, and silencing Bax by shRNA or inhibition of one of caspase 3, -8 and -9 also significantly prevented DHA-induced apoptosis in both cell lines, indicating the key roles of ROS and Bax as well as the caspases. Collectively, DHA presents more potent proapoptotic actions in A549GR cells preferentially over normal A549 cells via ROS-dependent apoptotic pathway, in which Bax and caspases are involved. PMID- 25018065 TI - In memoriam: Prof. Dr. Jose Roberto Giglio and his contributions to toxinology. AB - Prof. Dr. Jose R. Giglio (1934-2014) made a highly significant contribution to the field of Toxinology. During 48 years devoted to research and teaching Prof Giglio published more than 160 articles, with more than 4400 citations, in international journals, trained a vast amount of graduate and undergraduate students, and developed an international network of collaborators. Throughout these years, he worked with dedication and deep commitment to science, leaving an immortalized legacy. During his professional career he contributed mostly in the isolation, and biochemical and functional characterization of various protein toxins derived from animal venoms such as snakes, scorpions and spiders, in addition to his studies searching for alternative therapies for poisoning. Even after his departure, his presence and influence remains among his former students and in the outstanding legacy of his scientific contributions. PMID- 25018066 TI - Tumor response assessment using volumetric doubling time: better than RECIST? PMID- 25018068 TI - Improving detection of siderotic nodules in patients with liver disease using 2D ESWAN technique. AB - RATIONALE AND OBJECTIVES: To conduct a preliminary evaluation of the use of two dimensional (2D) enhanced multiecho T2*-weighted angiography (ESWAN) sequence for detection and quantification of siderotic nodules (SNs) in patients with liver disease. MATERIALS AND METHODS: Seventy-four patients with liver cirrhosis SNs confirmed by pathology were imaged using conventional T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2*-weighted imaging (T2*WI), and 2D ESWAN. The signal intensity ratio (SIR) and the lesion-to-liver contrast-to-noise ratio (CNR) were calculated. The quality of SNs identification of the ESWAN images was evaluated. RESULTS: The SIR of SNs on ESWAN was lower than those in any other sequence, whereas the CNR of SNs on ESWAN was significantly greater than those in the other sequences (P < .05). The conspicuity of SNs was shown to be significantly different between every pair of techniques (P < .05). The nodules had the better conspicuity in ESWAN images than in the T1WI, T2WI, and T2*WI. Almost all (97.3%, 72 of 74) patients were considered to have excellent grade 3 conspicuity on ESWAN imaging, compared to 40.5% (30 of 74) for T2*WI. The signal intensity of small hepatic cancer on ESWAN was greater than those of SNs. CONCLUSIONS: The detection and conspicuity of SNs is substantially improved using breath-hold 2D ESWAN. Therefore, 2D ESWAN imaging may be an alternative for the accurate detection of hepatic SNs in the future. PMID- 25018067 TI - Automated Percentage of Breast Density Measurements for Full-field Digital Mammography Applications. AB - RATIONALE AND OBJECTIVES: Increased mammographic breast density is a significant risk factor for breast cancer. A reproducible, accurate, and automated breast density measurement is required for full-field digital mammography (FFDM) to support clinical applications. We evaluated a novel automated percentage of breast density measure (PDa) and made comparisons with the standard operator assisted measure (PD) using FFDM data. METHODS: We used a nested breast cancer case-control study matched on age, year of mammogram and diagnosis with images acquired from a specific direct x-ray conversion FFDM technology. PDa was applied to the raw and clinical display (or processed) representation images. We evaluated the transformation (pixel mapping) of the raw image, giving a third representation (raw-transformed), to improve the PDa performance using differential evolution optimization. We applied PD to the raw and clinical display images as a standard for measurement comparison. Conditional logistic regression was used to estimate the odd ratios (ORs) for breast cancer with 95% confidence intervals (CI) for all measurements; analyses were adjusted for body mass index. PDa operates by evaluating signal-dependent noise (SDN), captured as local signal variation. Therefore, we characterized the SDN relationship to understand the PDa performance as a function of data representation and investigated a variation analysis of the transformation. RESULTS: The associations of the quartiles of operator-assisted PD with breast cancer were similar for the raw (OR: 1.00 [ref.]; 1.59 [95% CI, 0.93-2.70]; 1.70 [95% CI, 0.95-3.04]; 2.04 [95% CI, 1.13-3.67]) and clinical display (OR: 1.00 [ref.]; 1.31 [95% CI, 0.79-2.18]; 1.14 [95% CI, 0.65-1.98]; 1.95 [95% CI, 1.09-3.47]) images. PDa could not be assessed on the raw images without preprocessing. However, PDa had similar associations with breast cancer when assessed on 1) raw-transformed (OR: 1.00 [ref.]; 1.27 [95% CI, 0.74-2.19]; 1.86 [95% CI, 1.05-3.28]; 3.00 [95% CI, 1.67-5.38]) and 2) clinical display (OR: 1.00 [ref.]; 1.79 [95% CI, 1.04 3.11]; 1.61 [95% CI, 0.90-2.88]; 2.94 [95% CI, 1.66-5.19]) images. The SDN analysis showed that a nonlinear relationship between the mammographic signal and its variation (ie, the biomarker for the breast density) is required for PDa. Although variability in the transform influenced the respective PDa distribution, it did not affect the measurement's association with breast cancer. CONCLUSIONS: PDa assessed on either raw-transformed or clinical display images is a valid automated breast density measurement for a specific FFDM technology and compares well against PD. Further work is required for measurement generalization. PMID- 25018069 TI - Optimal Pancreatic Phase Delay with 64-Detector CT Scanner and Bolus-tracking Technique. AB - RATIONALE AND OBJECTIVES: To assess the optimal pancreatic phase delay in terms of parenchymal enhancement and tumor-to-pancreas contrast with a bolus-tracking method. MATERIALS AND METHODS: Patients referred for suspicion of pancreatic tumor and undergoing 64-detector computed tomography scanner were randomized to an individualized scan delay of 10, 20, or 30 seconds of nonionic contrast material (370 mg I/mL) after aortic enhancement above 150 Hounsfield units. The volume of contrast was adjusted to patient weight. Pancreatic and tumor enhancements were measured. Statistical analysis included analysis of variance and post hoc Tukey tests. RESULTS: One hundred and fifty patients were randomized to individualized scan delays of 10, 20, or 30 seconds. Pancreatic parenchymal enhancement in all patients (n = 150) was significantly higher with a delay of 20 or 30 seconds than that with 10 seconds (P < .001 for both). Tumor-to-pancreas contrast for solid tumors (n = 59) was significantly higher with a delay of 30 seconds than that with 10 seconds (P = .015). Adenocarcinoma-to-pancreas contrast during pancreatic phase was significantly higher for a 20- or 30-second delay than for a 10-second delay (P = .027 and .011, respectively) for one reader. CONCLUSIONS: With a flow rate of 4 mL/s and weight-adjusted contrast volume, an individualized scan delay of 30 seconds after aortic transit time revealed higher pancreatic enhancement and tumor-to-pancreas contrast than that with a delay of 10 seconds. PMID- 25018071 TI - Phase-contrast MRI for detection of mild systemic hemodynamic response after segmental allergen challenge in asthmatic patients. AB - RATIONALE AND OBJECTIVES: Detection of a systemic hemodynamic response in patients suffering from allergic asthma after segmental endobronchial allergen challenge using phase-contrast magnetic resonance imaging (MRI). MATERIALS AND METHODS: Nine asthma patients and four healthy volunteers were examined using MRI (1.5T) before (0 hour), 6 hours, and 24 hours after segmental allergen challenge. Two-dimensional phase-contrast MRI measurements were performed in the aorta (AO) and in the pulmonary artery (PA). In addition, short-axis balanced steady state free precession cardiac cine MRI was performed. Maximum systolic flow, maximum flow acceleration, acceleration volume, acceleration time, distensibility, ejection fraction, stroke volume, end-systolic/diastolic volume, cardiac mass, heart rate (HR), and cardiac output (CO) were determined. Spirometry and bronchoalveolar lavage were also performed. RESULTS: In patients with asthma, maximal systolic flow and maximal flow acceleration increased 6 hours after provocation in the AO (112.3% and 118.9%, respectively) and PA (113.9% and 116.0%, respectively) compared to baseline (100%, P < .05). HR and CO increased significantly at 6 hours (115% and 118%, respectively) compared to baseline (100%, P = .003). In healthy subjects, almost all MRI-derived hemodynamic parameters did not significantly change at 6 hours and were significantly lower than baseline values at 24 hours (P < .02). Twenty-four hours after allergen challenge, all MRI-derived flow parameters were significantly lower in the control group compared to the asthma group (P < .05). HR, CO, and cardiac function parameters measured at 24 hours showed no significant difference comparing the two groups (P > .05). CONCLUSIONS: In asthmatic patients, MRI derived hemodynamic parameters using phase-contrast MRI are slightly altered after segmental allergen provocation compared to normal controls indicating a mild systemic reaction to local allergen challenge. PMID- 25018070 TI - Longitudinal changes in airway remodeling and air trapping in severe asthma. AB - RATIONALE AND OBJECTIVES: Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aimed to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma. MATERIALS AND METHODS: Phenotypic characterization and quantitative multidetector-row computed tomography (MDCT) of the chest were performed at baseline and ~2.6 years later in 38 participants with asthma (severe n = 24 and mild-to-moderate n = 14) and nine normal controls from the Severe Asthma Research Program. RESULTS: Subjects with severe asthma had a significant decline in postbronchodilator forced expiratory volume in 1 second percent (FEV1%) predicted over time (P < .001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent [WA%]: P < .05) and normals (P < .05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness percent (WT%) in all subjects (P = .030 and .009, respectively) with no change in emphysema-like lung or air trapping. Baseline prebronchodilator FEV1% inversely correlated with WA% and WT% (both P < .05). In a multivariable regression model, baseline WA%, race, and health care utilization were predictors of subsequent airway remodeling. CONCLUSIONS: Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling. PMID- 25018072 TI - Magnetic resonance assessment of pulmonary (QP) to systemic (QS) flows using 4D phase-contrast imaging: pilot study comparison with standard through-plane 2D phase-contrast imaging. AB - RATIONALE AND OBJECTIVES: To investigate four-dimensional (4D) phase-contrast (PC) magnetic resonance (MR) in the evaluation of intracardiac shunts by simultaneous assessment of pulmonary (QP) and systemic (QS) flows in a pilot study and to compare results to through-plane two-dimensional (2D) PC MR. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Nineteen patients with suspected intracardiac shunts underwent cardiac MR at 1.5T. Assessments of QP and QS were performed using free breathing retrospectively gated 2D PC gradient recalled echo (GRE; 1.6 * 1.6 * 5 mm(3)) imaging with one-dimensional through-plane velocity encoding gradient (venc = 150 cm/s) in consecutive measurements for the main pulmonary artery (MPA) and ascending aorta (AA), respectively. A prospectively triggered 4D PC GRE technique (2.4 * 1.8 * 3 mm(3)) with three orthogonal venc directions was also used with volume coverage of both MPA and AA. RESULTS: QP and QS assessed by 4D PC correlated with 2D PC acquisitions (r = 0.92 and r = 0.67 respectively; P < .0001 for both) but demonstrated significant underestimation of individual flow volumes (-21.9 +/- 12.2 mL; P < .0001 and -10.7 +/- 13.1 mL; P = .0023, respectively). Calculated QP:QS ratios demonstrated high correlation (r = 0.78; P < .0001) and no significant differences between 4D PC and 2D PC acquisitions ( 0.09 +/- 0.24, P = .14). Image acquisition times for 2D PC assessment of QP and QS were 2.98 +/- 0.52 and 2.84 +/- 0.50 minutes, respectively (P = .038), whereas time to acquire 4D PC images was significantly longer, 18.75 +/- 4.58 minutes (P < .001). CONCLUSIONS: Four-dimensional PC MR imaging allows for accurate assessment of QP:QS ratios in the evaluation of intracardiac shunts while absolute flow volumes demonstrate offsets. Further refinement of the technique with improvement in acquisition times may be required before widespread clinical implementation. PMID- 25018073 TI - A Workflow to Improve the Alignment of Prostate Imaging with Whole-mount Histopathology. AB - RATIONALE AND OBJECTIVES: Evaluation of prostate imaging tests against whole mount histology specimens requires accurate alignment between radiologic and histologic data sets. Misalignment results in false-positive and -negative zones as assessed by imaging. We describe a workflow for three-dimensional alignment of prostate imaging data against whole-mount prostatectomy reference specimens and assess its performance against a standard workflow. MATERIALS AND METHODS: Ethical approval was granted. Patients underwent motorized transrectal ultrasound (Prostate Histoscanning) to generate a three-dimensional image of the prostate before radical prostatectomy. The test workflow incorporated steps for axial alignment between imaging and histology, size adjustments following formalin fixation, and use of custom-made parallel cutters and digital caliper instruments. The control workflow comprised freehand cutting and assumed homogeneous block thicknesses at the same relative angles between pathology and imaging sections. RESULTS: Thirty radical prostatectomy specimens were histologically and radiologically processed, either by an alignment-optimized workflow (n = 20) or a control workflow (n = 10). The optimized workflow generated tissue blocks of heterogeneous thicknesses but with no significant drifting in the cutting plane. The control workflow resulted in significantly nonparallel blocks, accurately matching only one out of four histology blocks to their respective imaging data. The image-to-histology alignment accuracy was 20% greater in the optimized workflow (P < .0001), with higher sensitivity (85% vs. 69%) and specificity (94% vs. 73%) for margin prediction in a 5 * 5-mm grid analysis. CONCLUSIONS: A significantly better alignment was observed in the optimized workflow. Evaluation of prostate imaging biomarkers using whole-mount histology references should include a test-to-reference spatial alignment workflow. PMID- 25018074 TI - Feasibility and preliminary experience of quantitative T2* mapping at 3.0 T for detection and assessment of aggressiveness of prostate cancer. AB - RATIONALE AND OBJECTIVES: To assess the feasibility of quantitative T2* mapping at 3.0 T for prostate cancer detection and to investigate the use of T2* values to characterize tumor aggressiveness, with whole-mount step-section pathologic analysis as the reference standard. MATERIALS AND METHODS: Prostate multiecho T2* was performed in 55 consecutive patients with prostate cancer using a multishot fast-field echo sequence at 3.0 T magnetic resonance imaging. T2* mapping was obtained by exponentially fitting the multiecho T2* images pixel by pixel with different echo times for each slice. Generalized estimating equations were used to test the T2* value difference between normal and malignant prostate regions and the association between T2* value and tumor Gleason scores. RESULTS: The T2* values of the cancerous prostatic regions (mean: 42.51 +/- 0.65 milliseconds) were significantly lower (P < .001) than those of the normal prostatic regions (mean: 74.87 +/- 0.99 milliseconds). Adopting a threshold value of 59.27 milliseconds, T2* mapping resulted in 94.8% sensitivity and 77.3% specificity in the identification of prostate cancer. A lower mean T2* value was significantly associated with a higher tumor Gleason score (mean T2* values of 53.53, 43.75, 33.66, and 22.95 milliseconds were associated with Gleason score of 3 + 3, 3 + 4, 4 + 3, and >=8, respectively P < .05). CONCLUSIONS: From these preliminary data, quantitative T2* mapping seems to be a potential method in the characterization of prostate cancer. T2* mapping may provide additional quantitative information that significantly correlated with prostate cancer aggressiveness. PMID- 25018075 TI - Dual-energy KUB radiographic examination for the detection of renal calculus. AB - RATIONALE AND OBJECTIVES: The dual-energy radiographic technique has been proved to be clinically useful in the thorax. Herein, we attempt to apply this technique to the abdomen and pelvis in the context of renal colic. MATERIALS AND METHODS: The visibility of renal calculi were assessed using various dual energy peak kilovoltage combination radiographs applied to standard phantoms. RESULTS: This technique demonstrates a higher than acceptable radiation dosage required to optimize the image quality and the optimized diagnostic quality is inferior to that of the standard Kidneys, Ureters, and Bladder radiograph. CONCLUSIONS: The dual-energy radiographic technique could not better identify the radiopaque renal calculi. Limiting technical considerations include the increased subcutaneous and peritoneal adipose tissue and the limited contrast between the soft tissue and underlying calculi. PMID- 25018077 TI - Three-dimensional MRI assessments of patchy and large myocardial infarction in beating and nonbeating swine hearts: validation with microscopy. AB - RATIONALE AND OBJECTIVES: To measure and validate patchy and large myocardial infarction (MI) at 3 days and 5 weeks in beating and nonbeating hearts using contrast-enhanced three-dimensional (3D) inversion-recovery gradient echo (IR GRE) magnetic resonance imaging (MRI) and microscopy. MATERIALS AND METHODS: Pigs (n = 28) were subjected to 1) patchy MI (group I), 2) large MI (group II), or 3) combined (patchy and large) MI (groups III and IV) using microemboli and/or 90 minute left anterior descending (LAD) occlusion and imaged at 3 days and 5 weeks after interventions. Gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) enhanced 3D and two-dimensional (2D) IR-GRE were performed for comparison in beating and nonbeating hearts. Macroscopic histochemical and microscopic histopathologic measurements were used for validation. RESULTS: Three-dimensional images demonstrated hyperenhanced patchy microinfarction, large MI, hypoenhanced/hyperenhanced microvascular obstruction, and infarct resorption. Acute and chronic combined MI on 3D was underestimated compared to microscopy (bias: -1.8 +/- 3.8%) but overestimated acute large infarction. In beating and nonbeating hearts, close correlations/agreements were found between 3D/2D acquisitions in all groups (beating hearts: r = 0.70-0.99; bias: group I 0.47 +/- 2.0%, II 0.33 +/- 1.2%, III 0.54 +/- 1.5%, and IV 0.28 +/- 1.0%). CONCLUSIONS: The 3D IR-GRE underestimated the extent of acute and chronic combined MI compared to microscopic measurements. This sequence may have the potential to differentiate patchy from large MI and demonstrate MI healing after coronary interventions. PMID- 25018076 TI - A multiobserver study of the effects of including point-of-care patient photographs with portable radiography: a means to detect wrong-patient errors. AB - RATIONALE AND OBJECTIVES: To evaluate whether the presence of facial photographs obtained at the point-of-care of portable radiography leads to increased detection of wrong-patient errors. MATERIALS AND METHODS: In this institutional review board-approved study, 166 radiograph-photograph combinations were obtained from 30 patients. Consecutive radiographs from the same patients resulted in 83 unique pairs (ie, a new radiograph and prior, comparison radiograph) for interpretation. To simulate wrong-patient errors, mismatched pairs were generated by pairing radiographs from different patients chosen randomly from the sample. Ninety radiologists each interpreted a unique randomly chosen set of 10 radiographic pairs, containing up to 10% mismatches (ie, error pairs). Radiologists were randomly assigned to interpret radiographs with or without photographs. The number of mismatches was identified, and interpretation times were recorded. RESULTS: Ninety radiologists with 21 +/- 10 (mean +/- standard deviation) years of experience were recruited to participate in this observer study. With the introduction of photographs, the proportion of errors detected increased from 31% (9 of 29) to 77% (23 of 30; P = .006). The odds ratio for detection of error with photographs to detection without photographs was 7.3 (95% confidence interval: 2.29-23.18). Observer qualifications, training, or practice in cardiothoracic radiology did not influence sensitivity for error detection. There is no significant difference in interpretation time for studies without photographs and those with photographs (60 +/- 22 vs. 61 +/- 25 seconds; P = .77). CONCLUSIONS: In this observer study, facial photographs obtained simultaneously with portable chest radiographs increased the identification of any wrong-patient errors, without substantial increase in interpretation time. This technique offers a potential means to increase patient safety through correct patient identification. PMID- 25018078 TI - Work and retirement preferences of practicing radiologists as a predictor of workforce needs. AB - RATIONALE AND OBJECTIVES: The radiology job market has been described as highly variable, and recent practice hiring surveys predict that the number of available jobs will remain flat. Radiologists may be working more hours and retiring later than desired, activities that influence overall job availability. A national survey was performed to determine the desired work rate and retirement preferences of practicing radiologists, and the responses are used to estimate current and potential future work output and future workforce needs. MATERIALS AND METHODS: Practicing radiologists were surveyed regarding current and preferred work level and desired and expected retirement age. A model incorporating these preferences and stratified by age was developed using survey responses and American Medical Association full-time equivalent (FTE) estimates. Available FTE radiologists are estimated under four scenarios from 2016 to 2031 in 5-year intervals. RESULTS: The model predicts a total of 26,362 FTE radiologists available in 2011, which corresponds to previous estimates. Participants reported working more hours and expecting to retire later than desired, with younger radiologists and women reporting the greatest desired decrease in FTE hours worked. Under each scenario, there is an initial FTE availability in 2016 ranging from 21,156 to 24,537, which increases to between 27,753 and 31,435 FTE by 2031 depending on work rate and retirement patterns. CONCLUSIONS: Practicing radiologists report that they currently work more hours than desired and expect to retire later than they would prefer. If radiologists changed current personal work rate and expected retirement age to meet these preferences, there would be an immediate shortage of FTE radiologists continuing until at least 2020 assuming no other workforce needs changes. PMID- 25018079 TI - Neurochemical changes observed by in vivo proton magnetic resonance spectroscopy in the mouse brain postadministration of scopolamine. AB - RATIONALE AND OBJECTIVES: This study is aimed at investigating neurochemical changes in scopolamine (SCP)-induced memory impairment using spatially localized in vivo magnetic resonance spectroscopy (MRS) of the hippocampus. MATERIALS AND METHODS: Four groups of mice (eight mice per group) were scanned after the injection of different SCP doses: 0, 1, 3, and 5 mg/kg (intraperitoneally). All the animals received (1)H MRS of their hippocampus at two time intervals: 30 minutes and 72 hours after SCP injection. RESULTS: This work demonstrated that the doses of 3 mg/kg SCP or higher reduce the concentration of total choline containing compounds, and these levels returned to baseline after 72 hours. These results are consistent with observations made by others using more invasive brain dialysis approaches. The levels of glutamate and glutamic compounds (glutamate + glutamine) were slightly changed at 3 and 5 mg/kg SCP dose, but the differences were not statistically significant (P > .05). These findings suggest that SCP produces transient, in vivo measurable alterations in the cholinergic system in the hippocampus. CONCLUSIONS: On this basis, we conclude that in vivo MRS is a feasible noninvasive method to probe aspects of the alterations induced by SCP in the cholinergic neurotransmission pathways in both animal models and human studies of memory impairment. PMID- 25018080 TI - The golden rule of education. PMID- 25018081 TI - Treatment of varicocele with transfemoral retrograde sclero-embolization in pediatric patients under local anesthesia. AB - AIM: Varicocele treatment in pediatric age is still under discussion. The aim of this study was to present our experience with transfemoral retrograde sclero embolization in pediatric patients and varicocele under local anesthesia METHODS: Between December 2008 and December 2011, 184 patients aged between 10 to 14 years with left varicocele were treated. Study inclusion criteria were: grade II or III left varicocele; previous inguinal surgeries and contraindications to general anesthesia. Sclero-embolization included the following procedures: right femoral access under local sedation (carbocaine). Mean time of intervention, recurrence and persistence rates as well as early and late complications were also considered. RESULTS: During the study period 184 cases were treated with the radiological technique, 172 of which proved to be successful. In 10 cases a continent valve was found and it was therefore impossible to use this technique (5.4%); two cases had rupture of the vein with consequent spillage of the contrast agent. Twelve cases (6.5%) showed recurrence after 3 months. No patient reported postoperative pain. CONCLUSION: This technique proved to be efficient and reliable. It can be performed under local sedation and it involves fewer complications than traditional techniques. The use of such technique allows preservation of the spermatic artery and is free from complications like testicular atrophy and hydrocele. PMID- 25018082 TI - Clinicopathological correlation of biopsy proven Lupus Nephritis in children and treatment response with mycophenolate moefetil. PMID- 25018083 TI - Pilot guidelines for the use of bidirectional webcams with children suffering from advanced-stage oncological diseases. AB - This paper presents guidelines for school staff on the use of bidirectional webcams for the sake of school continuity with school children suffering from malignant tumors. These guidelines are designed to inform school staff about the interests of the main actors involved in the interaction (sick child, classmates, teachers). Repeated clinical observations were conducted after virtual school attendance (requested by parents) of children treated at the Pediatric Oncology Unit. During virtual school attendance, the school staff requested counseling from the psychological team of the National Cancer Institute and Foundation for Scientific Research regarding some difficulties which had arisen, namely: 1) the sick patient's difficulties due to functional impairment and fear of possible shame experiences resulting from physical changes; 2) classmates' difficulties due to emotional ties with the sick child and dynamics of identification; 3) professional and personal difficulties of teachers. This paper aims at introducing some guidelines to guide the principal and teachers at school in the adoption and use of webcams for children suffering from malignant tumors. The importance of acquiring information on the opinion of the sick child (to adopt the webcam) and of the classmates is highlighted. Another important point is the teachers' need to consider their own and other actors' emotional reactions, and the possible involvement and/or support of a clinical psychologist. PMID- 25018084 TI - Enhanced spin-crossover behavior mediated by supramolecular cooperative interactions. AB - Three one-dimensional (1D) hetereobimetallic coordination polymers [Fe(II)(L)2(AgCN)2].Solv (L = bpt(-), 1; L = Mebpt(-), Solv = 1.75EtOH, 2; L = bpzt(-), 3) with in situ generated AgCN species were synthesized by solvothermal reactions of Fe(II) salt, K[Ag(CN)2], and the corresponding ligands [bptH = 3,5 bis(pyridin-2-yl)-1,2,4-triazole, MebptH = 3-(3-methyl-2-pyridyl)-5-(2-pyridyl) 1,2,4-triazole, and bpztH = 3,5-bis(pyrazin-2-yl)-1,2,4-triazole]. They were further characterized by X-ray crystallography, magnetic and photomagnetic measurements, and differential scanning calorimetry. Single-crystal X-ray analyses show that they are isostructural with 1D zigzag chain structures with rhombus {Fe2Ag2} units, in which the substituted bpt(-) ligand connects the Fe(II) ion and AgCN species in a cis bridging mode. Then the zigzag chains are packed into three-dimensional supramolecular structures by pi...pi interactions. Most importantly, weak Ag...N interactions (2.750 A at 150 K) between the pi stacked neighboring chains present in complex 3. Magnetic susceptibility measurements exhibit that complex 1 displays characteristic paramagnetic behavior in the temperature range investigated. Complex 2 undergoes a gradual spin crossover (SCO) with critical temperatures T(1/2)? = 232 K and T(1/2)? = 235 K, whereas 3 exhibits an abrupt SCO with critical temperatures T(1/2)? = 286 K and T(1/2)? = 292 K. The magnetostructural relationships suggest that the magnetic behaviors can be modulated from paramagnetic behavior to abrupt and hysteretic SCO near room temperature through adjustment of the electronic substituent effect and intermolecular interactions. PMID- 25018085 TI - Interaction of gold nanoclusters with IR light emitting cyanine dyes: a systematic fluorescence quenching study. AB - This paper describes the intermolecular interactions of gold nanoclusters (Au NCs) with cyanine dyes, namely HITC P, DTTC I, and IR 144. All the cyanine dyes quenched the fluorescence of Au NCs effectively. Steady-state and time-resolved measurements were performed to understand the competition between electron transfer and energy transfer in the Au NCs and cyanine dye system. A significant spectral overlap between the emission spectrum of the Au NCs and the absorption spectrum of cyanine dyes was observed, making both ideal for studying FRET interactions. However, after careful inspection of the steady state spectra and time resolved decays we concluded that photoinduced electron transfer (PET) could be the major pathway to quench the fluorescence intensity of Au NCs. To elucidate the interaction mechanism between Au NCs and cyanine dyes, docking studies were also performed. The docking studies reveal that the quencher molecules, i.e. cyanine dyes, come in close proximity with the 34-cysteine (Cys) in BSA where the Au clusters are located to enable the electron transfer process. PMID- 25018086 TI - The timing and directional connectivity of human frontoparietal and ventral visual attention networks in emotional scene perception. AB - Electrocortical and hemodynamic measures reliably identify enhanced activity in the ventral and dorsal visual cortices during the perception of emotionally arousing versus neutral images, an effect that may reflect directive feedback from the subcortical amygdala. However, other brain regions strongly modulate visual attention, such as frontal eye fields (FEF) and intraparietal sulcus (IPS). Here we employ rapid sampling of BOLD signal (4 Hz) in the amygdala, fusiform gyrus (FG), FEF and IPS in 42 human participants as they viewed a series of emotional and neutral natural scene photographs balanced for luminosity and complexity, to test whether emotional discrimination is evident in dorsal structures prior to such discrimination in the amygdala and FG. Granger causality analyses were used to assess directional connectivity within dorsal and ventral networks. Results demonstrate emotionally-enhanced peak BOLD signal in the amygdala, FG, FEF, and IPS, with the onset of BOLD signal discrimination occurring between 2 and 3s after stimulus onset in ventral structures, and between 4 and 5s in FEF and IPS. Granger causality estimates yield stronger directional connectivity from IPS to FEF than the reverse in this emotional picture paradigm. Consistent with a reentrant perspective of emotional scene perception, greater directional connectivity was found from the amygdala to FG compared to the reverse. These data support a perspective in which the registration of emotional scene content is orchestrated by the amygdala and rostral inferotemporal visual cortex. PMID- 25018087 TI - Deletion of protein tyrosine phosphatase 1B rescues against myocardial anomalies in high fat diet-induced obesity: Role of AMPK-dependent autophagy. AB - Obesity-induced cardiomyopathy may be mediated by alterations in multiple signaling cascades involved in glucose and lipid metabolism. Protein tyrosine phosphatase-1B (PTP1B) is an important negative regulator of insulin signaling. This study was designed to evaluate the role of PTP1B in high fat diet-induced cardiac contractile anomalies. Wild-type and PTP1B knockout mice were fed normal (10%) or high (45%) fat diet for 5months prior to evaluation of cardiac function. Myocardial function was assessed using echocardiography and an Ion-Optix MyoCam system. Western blot analysis was employed to evaluate levels of AMPK, mTOR, raptor, Beclin-1, p62 and LC3-II. RT-PCR technique was employed to assess genes involved in hypertrophy and lipid metabolism. Our data revealed increased LV thickness and LV chamber size as well as decreased fractional shortening following high fat diet intake, the effect was nullified by PTP1B knockout. High fat diet intake compromised cardiomyocyte contractile function as evidenced by decreased peak shortening, maximal velocity of shortening/relengthening, intracellular Ca2+ release as well as prolonged duration of relengthening and intracellular Ca2+ decay, the effects of which were alleviated by PTP1B knockout. High fat diet resulted in enlarged cardiomyocyte area and increased lipid accumulation, which were attenuated by PTP1B knockout. High fat diet intake dampened myocardial autophagy as evidenced by decreased LC3-II conversion and Beclin-1, increased p62 levels as well as decreased phosphorylation of AMPK and raptor, the effects of which were significantly alleviated by PTP1B knockout. Pharmacological inhibition of AMPK using compound C disengaged PTP1B knockout conferred protection against fatty acid-induced cardiomyocyte contractile anomalies. Taken together, our results suggest that PTP1B knockout offers cardioprotection against high fat diet intake through activation of AMPK. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. PMID- 25018088 TI - Changes in glutathione-dependent redox status and mitochondrial energetic strategies are part of the adaptive response during the filamentation process in Candida albicans. AB - Candida albicans is an opportunist pathogen responsible for a large spectrum of infections, from superficial mycosis to systemic diseases called candidiasis. Its ability to grow in various morphological forms, such as unicellular budding yeast, filamentous pseudohyphae and hyphae, contributes to its survival in the diverse microenvironments it encounters in the host. During infection in vivo, C. albicans is faced with high levels of reactive oxygen species (ROS) generated by phagocytes, and the thiol-dependent redox status of the cells reflects their levels of oxidative stress. We investigated the role of glutathione during the transition between the yeast and hyphal forms of the pathogen, in relation to possible changes in mitochondrial bioenergetic pathways. Using various growth media and selective mutations affecting the filamentation process, we showed that C. albicans filamentation was always associated with a depletion of intracellular glutathione levels. Moreover, the induction of hypha formation resulted in general changes in thiol metabolism, including the oxidation of cell surface -SH groups and glutathione excretion. Metabolic adaptation involved tricarboxylic acid (TCA) cycle activation, acceleration of mitochondrial respiration and a redistribution of electron transfer pathways, with an increase in the contribution of the alternative oxidase and rotenone-insensitive dehydrogenase. Changes in redox status and apparent oxidative stress may be necessary to the shift to adaptive metabolic pathways, ensuring normal mitochondrial function and adenosine triphosphate (ATP) levels. The consumption of intracellular glutathione levels during the filamentation process may thus be the price paid by C. albicans for survival in the conditions encountered in the host. PMID- 25018089 TI - A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition. AB - The naked mole-rat maintains robust proteostasis and high levels of proteasome mediated proteolysis for most of its exceptional (~31years) life span. Here, we report that the highly active proteasome from the naked mole-rat liver resists attenuation by a diverse suite of proteasome-specific small molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked mole-rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity. Gel filtration coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although Heat shock protein 72 kDa (HSP72) and Heat shock protein 40 kDa (Homolog of bacterial DNAJ1) (HSP40(Hdj1)) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked mole rat and allow it to successfully defy aging. PMID- 25018090 TI - Clinical and microbiological characteristics of cryptococcosis in Singapore: predominance of Cryptococcus neoformans compared with Cryptococcus gattii. AB - OBJECTIVES: To describe the clinical features, treatments, outcomes, and subtype prevalence of cryptococcosis in Singapore. METHODS: All patients with laboratory confirmed cryptococcal infections admitted from 1999 to 2007 to a teaching hospital in Singapore were reviewed retrospectively. Identification and molecular types of Cryptococcus neoformans variants and Cryptococcus gattii were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serotypes were inferred with a multiplex PCR method. RESULTS: Of 62 patients with cryptococcosis, C. neoformans var. grubii was the predominant subtype (in 95%), affecting mainly immunocompromised hosts (91%) with HIV infection (80%). Patients with HIV were younger (median age 36.5 vs. 49.5 years, p=0.006) and less likely to present with an altered mental status (14% vs. 50%, p=0.013). In contrast, delayed treatment (median 7 days vs. 2 days, p=0.03), pulmonary involvement (58% vs. 14%, p=0.03), and initial treatment with fluconazole (25% vs. 2%, p=0.02) were more common in HIV-negative patients. C. gattii was uncommon, affecting only three patients, all of whom were immunocompetent and had disseminated disease with pulmonary and neurological involvement. All C. gattii were RFLP type VG II, serotype B and all C. neoformans var. grubii were RFLP type VN I, serotype A, except for one that was RFLP type VN II. CONCLUSION: C. neoformans var. grubii, subtype VN I, was the predominant subtype in Singapore, infecting younger, mainly immunocompromised hosts with HIV. C. gattii was uncommon, causing pulmonary manifestations in older, immunocompetent patients and were RFLP type VG II. PMID- 25018091 TI - Persistent detection of avian influenza A/H7N9 virus among poultry in Huzhou City, China, in the summer of 2013. AB - In eastern China, live poultry markets were successively re-opened in the summer of 2013 following their closure in April 2013. We detected influenza A/H7N9 RNA with positive rates from 4% to 22.2% among poultry samples in targeted markets in Huzhou City, China, from August 6 to September 24, 2013. Phylogenetic analyses of hemagglutinin and neuraminidase genes confirmed that the strain prevalent among poultry in Huzhou City in the summer of 2013 belonged to the same genotype as those capable of infecting humans. These results raise concern for a further outbreak of H7N9 in the cooler season. PMID- 25018092 TI - Selection and characterization of single-chain recombinant antibodies against phosphoprotein of Newcastle disease virus. AB - Phosphoprotein (P), involved in virus RNA replication and transcription, had become a new target for the research on treating Newcastle disease virus (NDV). Here we described the cloning and expression of phosphoprotein from NDV, and then screened the anti-P antibodies from the chicken single chain fragment variable (scFv) library, which were generated from chickens immunized with the ND vaccines. As a first step, the recombinant expression vector pET28a-P was successfully constructed. In a following step, two anti-P positive scFv clones from the scFv library were selected by indirect enzyme-linked immunosorbent assay (ELISA) method. The sequence analysis of two positive clones showed that there were more variation in complementary determine region (CDR) of VH and VL, and the CDR3 in VH exhibited a significant change in amino acid number and type. In another experiment, the purified scFv antibodies used in the assay was shown to be specific for NDV-P by western blot. The results indicated that the strategy we used in this experiment proved to be convenient way for screening scFv antibody, which paved a new way for the immunization diagnosis and the exploration of integrated control of NDV. PMID- 25018093 TI - The effect of dietary carbohydrate composition on apparent total tract digestibility, feed mean retention time, nitrogen and water balance in horses. AB - A total of four diets with different carbohydrate composition were investigated in a 4*4 Latin square design experiment with four Norwegian Coldblooded trotter horses. The objective of the present study was to increase the fermentable fibre content and reduce the starch intake of the total ration obtained by partly substituting mature hay and barley with sugar beet pulp (SBP), a soluble fibre source. The diets investigated were hay only (HAY), hay (85% of dry matter intake (DMI)) and molassed SBP (15% of DMI) (SBP), hay (68% of DMI) and barley (32% of DMI) (BAR), and hay (68% of DMI), barley (26% of DMI) and SBP (6% of DMI) (BAR+SBP). The feeding level was 18.5, 17.3, 15.7 and 15.7 g DM/kg BW per day for the HAY, SBP, BAR and BAR+SBP diets, respectively. Each diet was fed for 18 days followed by 10 days of data collection, where apparent total tract digestibility (ATTD), total mean retention time (TMRT) of ytterbium-labelled hay, water balance, digestible energy (DE) intake and nitrogen balance were measured. An enzymatic chemical dietary fibre (DF) method was used to get detailed information on the composition and ATTD of the fibre fraction. Inclusion of SBP in the diet increased the ATTD of the constituent sugars galactose and arabinose (P<0.01). Feeding the HAY and SBP diets resulted in a lower TMRT owing to a higher DF intake than the BAR and BAR+SBP diets (P<0.01). There was no difference in water intake between HAY and SBP, but faecal dry matter was lower for HAY than the other diets (P=0.017), indicating that water was more tightly bound to fibre in the HAY diet. The diets were iso-energetic and provided enough DE and protein for light to moderate exercise for a 550 kg horse. In conclusion, this study showed that the DF intake had a larger effect on TMRT than partly substituting hay or barley with SBP, and that highly fermentable pectin-rich soluble DF from SBP maintains high nutrient utilization in horses. PMID- 25018094 TI - Update on advance directives. PMID- 25018095 TI - Induction of remission of idiopathic anaphylaxis with rituximab. PMID- 25018096 TI - Disruption of the basal body protein POC1B results in autosomal-recessive cone rod dystrophy. AB - Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.Gln67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.Gln67del variant forms of POC1B. Morpholino-oligonucleotide induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.Gln67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors. PMID- 25018098 TI - [An approach to care indicators benchmarking. Learning to improve patient safety]. AB - Improvements in clinical safety can be achieved by promoting a safety culture, professional training, and learning through benchmarking. The aim of this study was to identify areas for improvement after analysing the safety indicators in two public Hospitals in North-West Madrid Region. MATERIAL AND METHODS: Descriptive study performed during 2011 in Hospital Universitario Puerta de Hierro Majadahonda (HUPHM) and Hospital de Guadarrama (HG). The variables under study were 40 indicators on nursing care related to patient safety. Nineteen of them were defined in the SENECA project as care quality standards in order to improve patient safety in the hospitals. The data collected were clinical history, Madrid Health Service assessment reports, care procedures, and direct observation RESULTS: Within the 40 indicators: 22 of them were structured (procedures), HUPHM had 86%, and HG 95% 14 process indicators (training and protocols compliance) with similar results in both hospitals, apart from the care continuity reports and training in hand hygiene. The 4 results indicators (pressure ulcer, falls and pain) showed different results. CONCLUSIONS: The analysis of the indicators allowed the following actions to be taken: to identify improvements to be made in each hospital, to develop joint safety recommendations in nursing care protocols in prevention and treatment of chronic wound, to establish systematic pain assessments, and to prepare continuity care reports on all patients transferred from HUPHM to HG. PMID- 25018097 TI - Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial. AB - BACKGROUND: A community-based randomized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine (NCT00128661). The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease (CIN2+) associated with incident HPV-16/18 cervical infections. Secondary objectives were to evaluate efficacy against CIN2+ associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18. Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated. METHODS: We randomized (3727 HPV arm; 3739 control arm), vaccinated (HPV-16/18 or Hepatitis A) and followed (median 53.8 months) 7466 healthy women aged 18-25 years. 5312 women (2635 HPV arm; 2677 control arm) were included in the according to protocol analysis for efficacy. The full cohort was evaluated for safety. Immunogenicity was considered on a subset of 354 (HPV 16) and 379 (HPV-18) women. HPV type was assessed by PCR on cervical specimens. Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays. Disease outcomes were histologically confirmed. Vaccine efficacy and 95% confidence intervals (95%CI) were computed. RESULTS: Vaccine efficacy was 89.8% (95% CI: 39.5-99.5; N=11 events total) against HPV-16/18 associated CIN2+, 59.9% (95% CI: 20.7-80.8; N=39 events total) against CIN2+ associated with non-HPV 16/18 oncogenic HPVs and 61.4% (95% CI: 29.5-79.8; N=51 events total) against CIN2+ irrespective of HPV type. The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses. CONCLUSIONS: Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types. These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial. TRIAL REGISTRATION: Registered with clinicaltrials.gov: NCT00128661. PMID- 25018099 TI - Three-dimensional interconnected network of nanoporous CoP nanowires as an efficient hydrogen evolution cathode. AB - For the first time we demonstrate the topotactic synthesis of a three-dimensional (3D) interconnected network of nanoporous CoP nanowires directly on a Ti substrate (np-CoP NWs/Ti) via low-temperature phosphidation of a Co2(OH)2(CO3)2/Ti precursor and its further use as a highly efficient hydrogen evolution cathode. PMID- 25018101 TI - Epistatic interactions among metabolic genes depend upon environmental conditions. AB - When the effect of the state of one gene is dependent on the state of another gene in more than an additive or a neutral way, the phenomenon is termed epistasis. In particular, positive epistasis signifies that the impact of the double deletion is less severe than the neutral combination, while negative epistasis signifies that the double deletion is more severe. Epistatic interactions between genes affect the fitness landscape of an organism in its environment and are believed to be important for the evolution of sex and the evolution of recombination. Here we use large-scale computational metabolic models of microorganisms to study epistasis computationally using Flux Balance Analysis (FBA). We study what the effects of the environment are on epistatic interactions between metabolic genes in three different microorganisms: the model bacterium E. coli, the cyanobacteria Synechocystis PCC6803 and the model green algae, C. reinhardtii. Prior studies have shown that under standard laboratory conditions epistatic interactions between metabolic genes are dominated by positive epistasis. We show here that epistatic interactions depend strongly upon environmental conditions, i.e. the source of carbon, the carbon/oxygen ratio, and for photosynthetic organisms, the intensity of light. By a comparative analysis of flux distributions under different conditions, we show that whether epistatic interactions are positive or negative depends upon the topology of the carbon flow between the reactions affected by the pair of genes being considered. Thus complex metabolic networks can show epistasis even without explicit interactions between genes, and the direction and the scale of epistasis are dependent on network flows. Our results suggest that the path of evolutionary adaptation in fluctuating environments is likely to be very history dependent because of the strong effect of the environment on epistasis. PMID- 25018100 TI - IGF expression in HPV-related and HPV-unrelated human cancer cells. AB - The human Igf-1 gene not only produces insulin-like growth factor-I (IGF-I), but also different carboxy-terminal extensions, known as E peptides, through alternative splicing. We and others have shown that human Eb peptide (hEb) derived from Igf-1 has intrinsic biological activity and is localized to nuclei of transfected cells. Since hEb actions can complement the activity of IGF-I itself, the aim of the present study was to compare IGF-I isoforms at the endogenous protein and transcript level in cancer cell lines, including HeLa, U2OS, HepG2 and K562 cells. Quantitative real-time PCR (qRT-PCR) using Igf-1 isoform specific primers was performed to determine expression patterns, using beta-actin as a reference gene. The overall relative Igf-1 transcript level was different across the cell lines, with ~80-fold higher expression in K562 (130.2+/ 31.2) than in U2OS cells (1.7+/-1.1). The relative copy number of Igf-1b was the highest in HepG2 (69.9+/-28.6) and K562 cells (28.3+/-6.7), whereas the relative copy numbers of Igf-1a and Igf-1c were significantly higher in K562 cells compared to all other cell lines. Immunoblotting using total cell lysates, cytoplasmic and nuclear fractions were carried out to determine the level and distribution of IGF-I proteins. K562 cells exhibited the highest level of hEb in total cell lysates and nuclear fractions and no cell lines displayed hEb in the cytoplasmic fractions. In contrast, IGF-IA was the highest in HeLa cells and was enriched only in the cytoplasmic fraction. Since relatively low IGF-1A transcript level but relatively high pro-IGF-1A protein level is plausible, we hypothesized that these transcripts could be processed with higher efficiency and/or the protein product may be stabilized by viral HPV oncogenes in HeLa cells. We assert that while it is important to analyze Igf-1 transcript level, it may be more relevant to determine the IGF isoforms at the protein level. PMID- 25018102 TI - Common flaws exist in published cost-effectiveness models of pharmacologic stroke prevention in atrial fibrillation. AB - OBJECTIVES: Decision makers use models to assist in evaluating the cost effectiveness of pharmacologic stroke prevention in atrial fibrillation (SPAF). STUDY DESIGN AND SETTING: We performed a search of databases through October 3, 2012 to identify pharmacologic SPAF cost-effectiveness models. RESULTS: Of 30 identified models, 28 included warfarin, but only 60% assessed the impact of warfarin control on conclusions. Aspirin, dual antiplatelet, and newer anticoagulants were included in 41%, 10%, and 63% of models, respectively. Models used similar structures but included varying health states and made varying assumptions. They rarely reported performing a literature search to identify anticoagulant-specific inputs and used similar and older sources. Sixteen models used a lone randomized trial to reflect the efficacy and safety of main comparisons. One-third of models claimed a societal perspective; however, none included indirect costs. Patients typically initiated anticoagulation in the sixth or seventh decade of life and are followed for their lifetimes. Almost 70% of incremental cost-effectiveness ratios were below reported willingness-to-pay thresholds. All used deterministic sensitivity analyses and 77% conducted Monte Carlo simulation. Less than half of the models were rated "high quality," yet were frequently published in high-impact journals. CONCLUSION: Pharmacologic SPAF cost-effectiveness models have been extensively reported, but many may have flaws giving reason for decision makers to use caution. We provide 10 recommendations to avoid common flaws in SPAF cost-effectiveness models. PMID- 25018103 TI - Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. AB - Myelin sheaths provide critical functional and trophic support for axons in white matter tracts of the brain. Oligodendrocyte precursor cells (OPCs) have extraordinary metabolic requirements during development as they differentiate to produce multiple myelin segments, implying that they must first secure adequate access to blood supply. However, mechanisms that coordinate myelination and angiogenesis are unclear. Here, we show that oxygen tension, mediated by OPC encoded hypoxia-inducible factor (HIF) function, is an essential regulator of postnatal myelination. Constitutive HIF1/2alpha stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7a/7b. Surprisingly, such OPCs also show paracrine activity that induces excessive postnatal white matter angiogenesis in vivo and directly stimulates endothelial cell proliferation in vitro. Conversely, OPC-specific HIF1/2alpha loss of function leads to insufficient angiogenesis in corpus callosum and catastrophic axon loss. These findings indicate that OPC-intrinsic HIF signaling couples postnatal white matter angiogenesis, axon integrity, and the onset of myelination in mammalian forebrain. PMID- 25018104 TI - Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. AB - Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multidomain protein IRE1alpha promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1alpha lumenal domain homo-oligomerization, inducing trans autophosphorylation that further drives homo-oligomerization of its cytosolic kinase/endoribonuclease (RNase) domains to activate mRNA splicing of adaptive XBP1 transcription factor. However, under high/chronic ER stress, IRE1alpha surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis. To modulate these effects, we developed ATP-competitive IRE1alpha Kinase-Inhibiting RNase Attenuators-KIRAs that allosterically inhibit IRE1alpha's RNase by breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1alpha in vivo and promotes cell survival under ER stress. Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. Systemically, KIRA6 preserves pancreatic beta cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. Thus, IRE1alpha powerfully controls cell fate but can itself be controlled with small molecules to reduce cell degeneration. PMID- 25018105 TI - Starvation-induced transgenerational inheritance of small RNAs in C. elegans. AB - Evidence from animal studies and human famines suggests that starvation may affect the health of the progeny of famished individuals. However, it is not clear whether starvation affects only immediate offspring or has lasting effects; it is also unclear how such epigenetic information is inherited. Small RNA induced gene silencing can persist over several generations via transgenerationally inherited small RNA molecules in C. elegans, but all known transgenerational silencing responses are directed against foreign DNA introduced into the organism. We found that starvation-induced developmental arrest, a natural and drastic environmental change, leads to the generation of small RNAs that are inherited through at least three consecutive generations. These small, endogenous, transgenerationally transmitted RNAs target genes with roles in nutrition. We defined genes that are essential for this multigenerational effect. Moreover, we show that the F3 offspring of starved animals show an increased lifespan, corroborating the notion of a transgenerational memory of past conditions. PMID- 25018106 TI - Brain volume and white matter hyperintensities as determinants of cerebral blood flow in Alzheimer's disease. AB - To better understand whether decreased cerebral blood flow (CBF) in patients with Alzheimer's disease (AD) reflects neurodegeneration or cerebral small vessel disease, we investigated the associations of normalized brain volume (NBV) and white matter hyperintensity (WMH) volume with CBF. We included 129 patients with AD (66 +/- 7 years, 53% female) and 61 age-matched controls (64 +/- 5 years, 43% female). CBF was measured with pseudocontinuous arterial spin labeling at 3T in the whole brain and in partial volume corrected cortical maps. When NBV and WMH were simultaneously entered in age and sex adjusted models, smaller NBV was associated with lower whole brain (Stbeta: 0.29; p < 0.01) and cortical CBF (Stbeta: 0.28; p < 0.01) in patients with AD. Larger WMH volume was also associated with lower whole brain (Stbeta: -0.22; p < 0.05) and cortical CBF (Stbeta: -0.24; p < 0.05) in AD. Additional adjustments did not change these results. In controls, neither NBV nor WMH was associated with CBF. Our results indicate that in AD, lower CBF as measured using pseudocontinuous arterial spin labeling, reflects the combined disease burden of both neurodegeneration and small vessel disease. PMID- 25018107 TI - Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice. AB - Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [(18)F]MK-9470 and [(18)F]JNJ42259152 small-animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in presymptomatic, early symptomatic, and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([(18)F]FDG PET), brain morphology (magnetic resonance imaging) and motor function. Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxelwise. Volumetric microMRI imaging was performed to assess HD pathology. In R6/2 mice, CB1 receptor binding was decreased in comparison with WT in a cluster comprising the bilateral caudate-putamen, globus pallidus, and thalamic nucleus at week 5 (-8.1% +/- 2.6%, p = 1.7 * 10(-5)). Longitudinal follow-up showed further progressive decline compared with controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus, and cerebellum (late vs. presymptomatic age: -13.7% +/- 3.1% for R6/2 and +1.5% +/- 4.0% for WT, p = 1.9 * 10(-5)). In R6/2 mice, PDE10A binding potential also decreased over time to reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1% +/- 1.9% for R6/2 and +2.1% +/- 2.7% for WT, p = 1.5 * 10(-4)). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, whereas no correlation was found with magnetic resonance imaging based striatal volume. Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, which may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide evidence of subtle motor deficits at earlier stages than previously described. PMID- 25018108 TI - Novel APP K724M mutation causes Chinese early-onset familial Alzheimer's disease and increases amyloid-beta42 to amyloid-beta40 ratio. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly individuals. Although there are several million cases of AD estimated in China with the most population in the world, no Chinese early-onset familial AD caused by new APP gene mutation has ever been reported. Here, we first described a Chinese family with early-onset AD that was inherited in autosomal dominant manner, and the age of onset was 46.6 +/- 7.7 years (n = 5; range, 40-58 years). By using genetic analysis of 3 collected patients' DNA samples, we identified a heterozygous APP gene mutation (g.275363A>T, K724M according to APP770). Finally, when APP695 with K724M mutation was ectopically expressed in HEK293 cell, the ratio of amyloid-beta42 to amyloid-beta40 was 2.23-fold higher than that of wild type control. Together, our data suggest that APP K724M gene mutation may contribute to the cause of this Chinese early-onset familial AD. PMID- 25018110 TI - Neuregulin-1 induces cancer stem cell characteristics in breast cancer cell lines. AB - In breast cancer, neuregulin-1 (NRG1) is known as a ligand for the HER3 receptor, which has no intrinsic tyrosine kinase activity. When activated by NRG1 binding, the HER3 receptor forms a heterodimer with other HER family receptors and mediates downstream signaling pathways, leading to multiple effects including growth, proliferation, decreased apoptosis, cellular migration and angiogenesis. Cancer stem cells (CSCs), a subgroup of cancer cells, are considered to have features of stem cells such as self-renewal ability and pluripotent differentiation into other types of mature cells. This study showed that NRG1 treatment induced CSC characteristics in breast cancer cell lines. Using breast cancer cell lines, MCF-7, SKBr-3 and MDA-MB 468, changes related to CSC characteristics were analyzed. Flow cytometry was used to analyze changes in CSC fractions in multiple cell lines after NRG1 treatment. Western blot analysis and immunofluorescence staining demonstrated the expression of CSC markers. To confirm that NRG1 treatment acts through the HER3 receptor, inhibition studies using small interfering RNA (siRNA) were performed. In MCF-7 and SKBr-3 cells, increases in the CSC fraction and expression of CSC markers were observed after NRG1 treatment. However, MDA-MB 468 cells showed high intrinsic expression of CSC markers and a high cellular fraction of CSCs, and in these cells, NRG1 treatment caused no significant change in CSC characteristics. Inhibition of the HER3 receptor blocked the NRG1-induced CSC characteristics, indicating that NRG1 functions through the HER3 receptor. The results imply the presence of a mechanism by which the HER receptors, activated by NRG1, contribute to the acquisition of CSC-like characteristics in some types of breast cancer. PMID- 25018109 TI - Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model. AB - Alzheimer's disease (AD) is a complicated, neurodegenerative disorder involving multifactorial pathogeneses and still lacks effective clinical treatment. Recent studies show that lithium exerts disease-modifying effects against AD. However, the intolerant side effects at conventional effective dosage limit the clinical use of lithium in treating AD. To explore a novel AD treatment strategy with microdose lithium, we designed and synthesized a new chemical, tri-lithium pyrroloquinoline quinone (Li3PQQ), to study the synergistic effects of low-dose lithium and pyrroloquinoline quinone, a native compound with powerful antioxidation and mitochondrial amelioration. The results showed that Li3PQQ at a relative low dose (6 and 12 mg/kg) exhibited more powerful effects in restoring the impairment of learning and memory, facilitating hippocampal long-term potentiation, and reducing cerebral amyloid deposition and phosphorylated tau level in APP/PS1 transgenic mice than that of lithium chloride at both low and high dose (5 and 100 mg/kg). We further found that Li3PQQ inhibited the activity of glycogen synthase kinase-3 and increased the activity of beta-amyloid-binding alcohol dehydrogenase, which might underlie the beneficial effects of Li3PQQ on APP/PS1 transgenic mice. Our study demonstrated the efficacy of a novel AD therapeutic strategy targeting at multiple disease-causing mechanisms through the synergistic effects of microdose lithium and pyrroloquinoline quinone. PMID- 25018111 TI - Long-term prognosis of patients presenting first-ever vestibular symptoms in a community-based study. AB - BACKGROUND: Vestibular symptoms (VSs) are frequent complaints in patients attending ambulatory care and the emergency room. They may represent a peripheral vestibular disorder or a stroke/transient ischemic attack (TIA), yet many patients have VSs that cannot be clearly classified at presentation. This study aims to characterize and determine the long-term prognosis of these patients. METHODS: In a prospective community-based study involving 104,700 individuals registered at 4 health centers of Northern Portugal, patients with a first-ever in-lifetime focal neurologic symptom (FNS) were ascertained using comprehensive methods, including referrals from physicians working in the study area and data retrieved from emergency/discharge records. Physicians were encouraged to report/notify any patient who might have experienced an FNS, including those with vertigo or vertigo-like symptoms, imbalance, presyncope, or nonspecific dizziness. After neurologic assessment patients were classified as having a peripheral vestibular symptom (pVS), a stroke/TIA, or an unclassified vestibular symptom (uVS). They were followed up 7 years after the index event at the outpatient clinic; predictors of survival free from stroke or vascular events were determined using Cox proportional hazards models. RESULTS: Of the 1163 patients with an FNS, 360 (31.0%) were included, 16.7% had a stroke/TIA, 57.8% had pVS, and 25.6% had uVS. Most patients presented only isolated VSs (62.8%); 63% were women and mean age was 60.1 years (standard deviation = 16); hypertension (47.8%), hypercholesterolemia (41.9%), and diabetes (19.2%) were the most prevalent vascular risk factors (VRFs). Cranial computed tomography (CT) scan was performed in 63.3%. Adjusting for age, sex, VRFs, and diagnosis (TIA, pVS and uVS), the long-term risk of stroke was higher when CT showed silent infarctions (hazard rate [HR] = 3.96; 95% confidence interval [CI], 1.63-9.60) and the risk of vascular events (stroke, myocardial infarction, or vascular death) was higher in patients with 2 or more VRFs (HR = 2.70; 95% CI, 1.25-5.86). Identical results were obtained when restricting the model to patients with pVS or uVS. CONCLUSIONS: First-ever-in-lifetime VSs are common in patients with FNS and may represent a good opportunity for preventing a serious vascular event, particularly in patients with vascular comorbidity (silent infarctions and VRFs). PMID- 25018112 TI - Effect of intravenous thrombolysis on stroke associated with atrial fibrillation. AB - BACKGROUND: Data based on randomized clinical trials regarding the efficacy and safety of intravenous thrombolysis (IVT) versus placebo or any other antithrombotic agent in the treatment of stroke associated with atrial fibrillation (AF) are unavailable. METHODS: Prospectively collected data on AF associated stroke patients treated in a 3-year period were analyzed to assess the effect of IVT treatment. Outcome measures were modified Rankin Scale (mRS) score for functional outcome, death, and symptomatic intracerebral hemorrhage (sICH). RESULTS: Of 787 patients diagnosed with an acute ischemic stroke in the observed period, 131 (16.6%) had AF. Multivariate logistic regression analysis after adjustment for confounders demonstrated that independent predictors of excellent outcome (mRS 0-1) in patients with AF-associated stroke were lower baseline National Institutes of Health Stroke Scale [NIHSS] score (adjusted odds ratio [(adj)OR], .87; 95% confidence interval [CI], 0.81-.94; P = .000) and the use of IVT ((adj)OR, 5.31; 95% CI, 1.90-14.82; P = .001), whereas independent predictors of death were higher baseline NIHSS score ((adj)OR, 1.07; 95% CI, 1.02-1.12; P = .003), previous stroke ((adj)OR, 4.11; 95% CI, 1.49-11.35; P = .006), absence of IVT use ((adj)OR, .19; 95% CI, .05-.77; P = .021), sICH ((adj)OR, 18.52; 95% CI, 1.59-215.37; P = .020), and higher serum glucose levels ((adj)OR, 1.26; 95% CI, 1.06-1.50; P = .008). Thrombolyzed patients with AF were less severe at baseline and were less likely to have NIHSS >18. They were more likely to have excellent and good functional outcome (mRS 0-2) whereas less likely to have death as outcome at 3 months. Thrombolyzed AF patients had constantly lower probability of death regardless of the baseline NIHSS score values. CONCLUSIONS: These results should encourage the use of IVT in AF-associated strokes. PMID- 25018113 TI - Recanalization therapy for internal carotid artery occlusion presenting as acute ischemic stroke. AB - BACKGROUND: We aimed to describe the current status and clinical outcomes of recanalization therapy for internal carotid artery occlusion (ICAO) presenting as acute ischemic stroke. METHODS: Using a nationwide stroke registry database in Korea, we identified consecutive ischemic stroke patients with ICAO hospitalized within 12 hours of onset between March 2010 and November 2011. RESULTS: ICAO accounted for 10.6% (322 of 3028) of acute ischemic strokes within 12 hours of onset. Among the 322 ICAO patients, 53% underwent recanalization therapy, 41% intravenous thrombolysis (IVT) alone, and 59% endovascular treatment (EVT). Twenty-two percent of those with mild deficits (National Institutes of Health Stroke Scale <4) and 50% of those 80 years of age or more received recanalization therapy. Compared with no treatment, recanalization therapy was not significantly associated with a favorable outcome (3-month modified Rankin scale, 0-2) (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], .80-3.91; P = .16). However, compared with IVT, EVT significantly improved the odds of favorable outcome (OR, 2.86; 95% CI, 1.19-6.88; P = .02) without significant increase of symptomatic intracranial hemorrhage (OR, 2.18; 95% CI, .42-11.43; P = .36) and 3-month mortality (OR, .53; 95% CI, .23-1.18; P = .12). Successful recanalization rate (Thrombolysis in Cerebral Infarction >=2a) by EVT was 76%. CONCLUSIONS: In Korea, one tenth of acute ischemic stroke was caused by ICAO, and about 50% were treated by recanalization therapy. EVT was widely used as a recanalization modality (about 60% of cases) despite lack of evidence. However, its effectiveness and safety were acceptable. PMID- 25018114 TI - The L-arginine pathway in acute ischemic stroke and severe carotid stenosis: temporal profiles and association with biomarkers and outcome. AB - BACKGROUND: Endothelial dysfunction is associated with increased levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) resulting in a decreased production of nitric oxide, which regulates the vascular tone. METHODS: Patients with acute ischemic stroke (AIS, n = 55) and asymptomatic significant carotid stenosis (AsCS, n = 44) were prospectively investigated. L arginine, ADMA, SDMA, S100 B, and high-sensitivity C-reactive protein (hsCRP) were serially measured within 6 hours after the onset of stroke, at 24 and 72 poststroke hours. All markers were compared with healthy subjects (n = 45). The severity of AIS was daily assessed by National Institute of Health Stroke Scale scoring. RESULTS: Even within 6 hours after the onset of stroke, L-arginine, ADMA, and SDMA were significantly higher in patients with AIS compared with both AsCS and healthy subjects. S100 B reflecting infarct size, positively correlated with the level of SDMA at 72 poststroke hours; changes in concentration of S100 B positively correlated with changes in the concentration of ADMA by 72 hours. Change in concentration of both ADMA and SDMA correlated with the change in concentration of hsCRP. Concentrations of L-arginine and hsCRP at 72 poststroke hours, respectively, were independent predictors of poststroke infection. S100 B level measured within 6 hours after the onset of AIS and hsCRP at 72 poststroke hours were independent predictors of death. CONCLUSIONS: Metabolites of the L arginine pathway were elevated in the very acute phase of ischemic stroke indicating a more pronounced endothelial dysfunction compared with AsCS. An increased basal L-arginine level in patients with AIS might be an adaptive mechanism; such transient elevation of the L-arginine/ADMA ratio at 24 poststroke hours may suggest that a temporary increase of L-arginine along with decrease of ADMA might be related to the protective role of L-arginine. Changes in the L arginine pathway are predictive of poststroke infections. PMID- 25018115 TI - SIPL1 enhances the proliferation, attachment, and migration of CHO cells by inhibiting PTEN function. AB - The PTEN tumour suppressor plays critical roles in inhibiting cell proliferation, adhesion and migration through downregulation of the PI3K-AKT pathway. SIPL1 is a novel PTEN-negative regulator (PTEN-NR) that contributes to PTEN inactivation during tumorigenesis. However, whether SIPL1 plays a role in inhibiting PTEN function in the process of cell adhesion and migration remains unclear. The aim of this study was to investigate this possibility using CHO-K1 cells, and western blotting, qPCR analyses and microscopy. Results showed that the overexpression of SIPL1 in CHO-K1 cells decreased the amount of PTEN protein. The downregulation was not caused by an obvious reduction in PTEN mRNA levels or ubiquitin-dependent protein degradation. Nonetheless, the reduction was functional, as SIPL1 overexpression increased the activation of AKT under serum-starved conditions, promoting CHO-K1 cell proliferation in an AKT-dependent manner. Furthermore, SIPL1 increased the migration and attachment of CHO-K1 cells. Taken together, the evidence suggested that SIPL1 promotes AKT activation by decreasing the amount of PTEN protein in CHO-K1 cells, thereby promoting cell proliferation and migration. PMID- 25018116 TI - Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. AB - BACKGROUND: An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children. METHODS: We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2-14 years were randomly assigned (2:1), by computer generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratified by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective efficacy against symptomatic, virologically confirmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281. FINDINGS: We randomly assigned 10,275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confirmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 56.5% (95% CI 43.8-66.4) efficacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries. INTERPRETATION: Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2-14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit. FUNDING: Sanofi Pasteur. PMID- 25018117 TI - Which incretin-based therapy for type 2 diabetes? PMID- 25018118 TI - The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities. PMID- 25018119 TI - Dengue vaccines: dawning at last? PMID- 25018120 TI - Effect of a single inactivated poliovirus vaccine dose on intestinal immunity against poliovirus in children previously given oral vaccine: an open-label, randomised controlled trial. AB - BACKGROUND: Intestinal immunity induced by oral poliovirus vaccine (OPV) is imperfect and wanes with time, permitting transmission of infection by immunised children. Inactivated poliovirus vaccine (IPV) does not induce an intestinal mucosal immune response, but could boost protection in children who are mucosally primed through previous exposure to OPV. We aimed to assess the effect of IPV on intestinal immunity in children previously vaccinated with OPV. METHODS: We did an open-label, randomised controlled trial in children aged 1-4 years from Chinnallapuram, Vellore, India, who were healthy, had not received IPV before, and had had their last dose of OPV at least 6 months before enrolment. Children were randomly assigned (1:1) to receive 0.5 mL IPV intramuscularly (containing 40, 8, and 32 D antigen units for serotypes 1, 2, and 3) or no vaccine. The randomisation sequence was computer generated with a blocked randomisation procedure with block sizes of ten by an independent statistician. The laboratory staff did blinded assessments. The primary outcome was the proportion of children shedding poliovirus 7 days after a challenge dose of serotype 1 and 3 bivalent OPV (bOPV). A second dose of bOPV was given to children in the no vaccine group to assess intestinal immunity resulting from the first dose. A per-protocol analysis was planned for all children who provided a stool sample at 7 days after bOPV challenge. This trial is registered with Clinical Trials Registry of India, number CTRI/2012/09/003005. FINDINGS: Between Aug 19, 2013, and Sept 13, 2013, 450 children were enrolled and randomly assigned into study groups. 225 children received IPV and 225 no vaccine. 222 children in the no vaccine group and 224 children in the IPV group had stool samples available for primary analysis 7 days after bOPV challenge. In the IPV group, 27 (12%) children shed serotype 1 poliovirus and 17 (8%) shed serotype 3 poliovirus compared with 43 (19%) and 57 (26%) in the no vaccine group (risk ratio 0.62, 95% CI 0.40-0.97, p=0.0375; 0.30, 0.18-0.49, p<0.0001). No adverse events were related to the study interventions. INTERPRETATION: The substantial boost in intestinal immunity conferred by a supplementary dose of IPV given to children younger than 5 years who had previously received OPV shows a potential role for this vaccine in immunisation activities to accelerate eradication and prevent outbreaks of poliomyelitis. FUNDING: Bill & Melinda Gates Foundation. PMID- 25018121 TI - Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non inferiority trial. AB - BACKGROUND: Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. METHODS: We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (>=1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7.0% or greater (>=53 mmol/mol) and 10.0% or lower (<=86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1.5 mg) or once-daily liraglutide (1.8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0.4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. FINDINGS: We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1.42% (SE 0.05) in the dulaglutide group and -1.36% (0.05) in the liraglutide group. Mean treatment difference in HbA1c was -0.06% (95% CI -0.19 to 0.07, pnon-inferiority<0.0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0.34 (SE 1.44) and 0.52 (3.01) events per patient per year, respectively, and no severe hypoglycaemia was reported. INTERPRETATION: Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least squares mean reduction in HbA1c, with a similar safety and tolerability profile. FUNDING: Eli Lilly and Company. PMID- 25018122 TI - Keeping pace with population growth. PMID- 25018123 TI - Polio endgame management: focusing on performance with or without inactivated poliovirus vaccine. PMID- 25018124 TI - Social isolation as a risk factor for inadequate diet of older Eastern Europeans. AB - OBJECTIVES: Social isolation has been shown to be a risk factor for inadequate diet among older adults living in Western Europe and North America. This article investigates whether socially isolated older adults (65+) living in Eastern Europe also experience an increased risk of dietary inadequacy. METHODS: The study used SHARE IV survey data collected in the Czech Republic (n = 2,867), Poland (n = 772), and Hungary (n = 1,353). Logistic regression models were estimated for each country separately to predict the likelihood of two proxies for dietary adequacy, having three meals a day and/or a serving of fruits or vegetables, by social isolation. RESULTS: Social isolation was associated with lower likelihood of having three meals a day among Czech older adults (OR 0.39) and with lower likelihood of having a daily serving of fruits or vegetables among Czech (OR 0.62) and Polish older adults (OR 0.35). No association between social isolation and either one of the outcomes was found in Hungary. CONCLUSIONS: Socially isolated Eastern European older adults may be at a higher risk of dietary inadequacy, particularly in the Czech Republic and Poland. PMID- 25018125 TI - The copy number and integration site analysis of IGF-1 transgenic goat. AB - Transgenic animals have been used previously to study gene function, produce important proteins, and generate models for the study of human diseases. As the number of transgenic species increases, reliable detection and molecular characterization of integration sites and copy number are crucial for confirming transgene expression and genetic stability, as well as for safety evaluation and to meet commercial demands. In this study, we generated four transgenic goats by somatic cell nuclear transfer (SCNT). After birth, the cloned goat contained transferred insulin-like growth factor I (IGF-1) gene was initially confirmed using a polymerase chain reaction (PCR)-based method. The four cloned goats were identified as IGF-1 transgenic goats by southern blotting. The number of copies of the IGF-1 gene in each of the transgenic goats was determined. Additionally, four integration sites of the transgene in the transgenic goats with a modified thermal asymmetric interlaced (TAIL)-PCR method were identified. The four different integration sites were located on chromosomes 2, 11, 16 and 18. The present study identified the copy number and integration sites using quantitative PCR (qPCR) and TAIL-PCR, enabling the bio-safety evaluation of the transgenic goats. PMID- 25018126 TI - Compassionate care and Schwartz Rounds: the nature of the work--acknowledging it is hard. PMID- 25018127 TI - The experience of living with a traumatic hand injury in a rural and remote location: an interpretive phenomenological study. AB - INTRODUCTION: The aim of this research study was to gain an understanding of how rural and remote residents in North Queensland, Australia, engaged in work, activities of daily living tasks and social activities following a traumatic hand injury. Findings from a previous retrospective survey with these participants revealed that patients experienced difficulties such as pain for many years after their injury; however, because of the survey methodology, the voices of participants were not heard. This study contributes to a larger project that seeks to propose a model of service delivery to rural and remote residents who have sustained a traumatic injury. METHODS: Utilising an interpretive phenomenological research design, data were gathered through in-depth, semistructured interviews. Fifteen participants were recruited into this study and questions were designed to explore the experience of having a traumatic hand injury in rural and remote areas of North Queensland. RESULTS: The thematic analysis indicated five major themes: injury and impairment, pain, occupation and activity, and resilience. Participants reported that having a hand injury often caused further injury due to the impairment. The pain experienced could be 'all consuming' yet participants reported 'pushing through' this pain to complete daily tasks. Participants reported that they would 'go mad' if they did not work and highlighted the importance of activity in their recovery. Participants felt grateful at having their hand and thought towards the future. Being self-reliant was important but they were willing to accept support from others when needed. CONCLUSIONS: Incorporating activity and occupation in rehabilitation programs as opposed to focusing on strict protocols is an important consideration in the recovery process of rural and remote residents. In particular, engaging in activity and occupation was an important part of managing the pain associated with the hand trauma. This research also found that participants demonstrated resilient qualities while recovering from a traumatic hand injury. Health professionals who work with people from a rural and remote location with a traumatic hand injury should consider a treatment model that encourages active patient participation, identifying collaborative treatment goals that align with the values of people living in rural and remote locations. Education regarding the high risk of further injury due to the nature of, and exposure to, the type of work and activity in rural and remote locations is also recommended. PMID- 25018128 TI - Malignant rhabdoid tumor of the bladder and ganglioglioma in a 14 year-old male with a germline 22q11.2 deletion. AB - Malignant rhabdoid tumors (MRTs) are rare pediatric malignancies characterized by clinically aggressive lesions that typically show loss of SMARCB1 expression. We herein describe a case of a malignant rhabdoid tumor of the bladder in a 14-year old male with an autism spectrum disorder and a de novo 3 Mb germline deletion in chromosome band 22q11.2 that included the SMARCB1 gene. The malignancy developed in the setting of chronic hematuria (>2 years) following the occurrence of two other lesions: a central nervous system ganglioglioma and an intraoral dermoid cyst. MRTs of the bladder are exceedingly rare, and this patient is the oldest child reported with this tumor to date. This case adds to the growing body of literature regarding the recently described, phenotypically diverse, distal 22q11.2 syndrome. Furthermore, this is the first reported case in which an MRT of the bladder appears to have developed from a pre-existing bladder lesion. Finally, this case further supports a rhabdoid tumorigenesis model in which heterozygous loss of SMARCB1 predisposes to initial tumor formation with intact SMARCB1 expression, with subsequent inactivation of the other SMARCB1 allele, which results in transformation into more malignant lesions. PMID- 25018129 TI - Geographical and seasonal barriers to mammography services and breast cancer stage at diagnosis. AB - INTRODUCTION: Routine mammography screening and early detection are important prognostic indicators for breast cancer. Geographical and seasonal barriers to mammography services and relationship to breast cancer stage at diagnosis were examined. METHODS: Travel time to mammography center, seasonal distribution of mammogram use, mammography frequency, and stage of cancer were retrospectively examined in 1428 female patients diagnosed with primary breast cancer at a tertiary care clinic system in Wisconsin, USA, from 2002 to 2008. RESULTS: Women with no missed mammograms before diagnosis lived a median of 15 minutes from the nearest facility, while those who missed five of their past five annual mammograms lived nearly twice as far, with a median travel time of 27 minutes (p<0.0001). There was a direct relationship between travel time to nearest mammogram facility and stage of breast cancer at diagnosis, with travel time increasing from 17 to 24 minutes for stage 0 and stage 4 breast cancers, respectively (p=0.0586). Women were less likely to undergo mammography screening during the winter months (p<0.0001), especially women with greater than 30 mi (48.3 km) to travel to the nearest mammogram facility (p=0.0448). CONCLUSIONS: In the studied service area, travel time to nearest mammogram center appears inversely related to regular mammography screening and breast cancer stage at diagnosis. Mammograms are less common in the winter, especially in women with further to travel. This is the first study to demonstrate that inclement winter weather may impact on screening behaviors in rural areas and demonstrates the importance of considering climate as part of geographical access to preventative care. PMID- 25018130 TI - Hoffa's disease: a report on 5 cases. AB - We report the case of five patients referred to our department with Hoffa's disease: three patients were at the initial stage of the disease and the two others had reached the chronic stage. This condition is one of the less well documented causes of pain in the anterior compartment of the knee. The pathophysiological mechanism is still unclear. It is probably caused by repetitive micro trauma resulting in inflammatory, haemorrhagic and fibrous changes to Hoffa's fat pad. The final outcome of the disease is an osteochondroma. The diagnosis is established by MRI, which demonstrates inflammation of the fat pat. At the chronic stage, a standard X-ray is sufficient to demonstrate ossification of the fat pad. PMID- 25018131 TI - ANCA-negative associated vasculitis initially presenting with pulmonary embolism. AB - Antineutrophil-cytoplasm antibodies (ANCA)-associated vasculitis are severe inflammatory pathologies that, although rare, may induce significant morbidity or death. Their impact on multiple organ systems implies an important variability in their clinical presentation, which might delay the diagnosis. In this setting we report on a case of ANCA-negative-associated vasculitis, initially presenting as pulmonary embolism with severe pulmonary infarction and digestive involvement. Literature is then discussed on these complications and their implications for therapy. PMID- 25018132 TI - Tuberculin skin test versus interferon-gamma release assays for the diagnosis of tuberculosis infection. AB - OBJECTIVE: Accurate detection of latent tuberculosis infection (LTBI) is becoming increasingly important due to the increasing use of immunosuppressive medications and the human immunodeficiency epidemic, which have increased the risk for reactivation to active tuberculosis (TB) infection. LTBI is detected by tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). The latter include T-SPOT((r)).TB (Oxford Immunotec) and QuantiFERON((r))-TB Gold In Tube (QFT-GIT; Cellestis). We examined the value of TST versus IGRAs in the diagnosis of TB infection by meta-analysis based on data derived from a systematic literature review. METHODS: PubMed was searched for articles in English published between January 2010 and July 2012 in which TST and IGRA were performed simultaneously in individuals with and without active TB infection. A random effect model meta-analysis was performed to determine pooled sensitivity and specificity values for TST, T-SPOT.TB, and QFT-GIT. Owing to the absence of a gold standard for the diagnosis of LTBI, active TB infection was used as a surrogate for LTBI. RESULTS: Nineteen studies were included. T-SPOT.TB was significantly more sensitive [90% (95% confidence interval: 85-95) versus 64% (46 81)] than TST. The specificity of T-SPOT.TB was higher than the specificity of TST, but there was overlap between confidence intervals [77% (68-85) versus 57% (41-72)]. QFT-GIT seemed to be more sensitive than TST [75% (61-86) versus 64% (48-78)] but similarly specific [71% (62-86) versus 70% (57-81)]. CONCLUSIONS: IGRAs, especially T-SPOT.TB, are more effective at detecting TB infection than TST. Despite their higher cost, they have added value and can be requested in addition to TST. PMID- 25018133 TI - Intramural haematoma of the esophagus: multimodality imaging findings and clinical triad. AB - Intramural haematoma of the esophagus (IHE) is an uncommon clinical condition, which can mimic other cardiothoracic emergencies in both clinical and imaging perspectives. We presented the case of a 54-year-old female who presented to the emergency department with a clinical triad of retrosternal chest pain, odynophagia, and haematemesis for 3 days. Multi-detector computed tomography (MDCT) revealed long-segmental, well-defined, isodense mass in postero-lateral wall of esophagus with smooth arc-shaped indentation into the lumen and no obvious enhancement after IV contrast administration. The preserved fat plane between the thickened esophagus and the aorta allows exclusion of aortic dissection. Subsequent esophagogram and endoscopy confirmed the finding of IHE and thus, patient was successfully treated with conservative treatment and discharged uneventfully. Owing to the presence of clinical and image mimickers of IHE, the recognition of clinical triad of retrosternal pain, odynophagia, and haematemesis, and the typical MDCT and esophagographic presentation of submucosal haematoma are important in avoiding misdiagnosis with inappropriate treatment. PMID- 25018134 TI - Metastatic small cell neuroendocrine carcinoma of the pyriform sinus evaluated by 18F-FDG PET/CT. PMID- 25018135 TI - Standardized uptake value and metabolic tumor volume measured by 18F FDG PET/CT are sensitive biomarkers for the presence of lymph node metastasis in patients with cervical carcinoma. AB - The aim of this study was to evaluate whether tumor standardized uptake value (SUVmax) and metabolic tumor volume (MTV) associate with the presence of PET positive pelvic/para-aortic lymph nodes (LN) in cervical cancer patients. METHOD: Seventy-four patients with stage IB-IVB cervical cancer (squamous [n:66], nonsquamous [n:8]), who were referred to FDG-PET/CT department for initial staging, were enrolled in this study. RESULTS: Patients were staged according to International Federation of Gynecology and Obstetrics [FIGO] criteria as; stage I (n:5), stage II (n:25), stage III (n:15) and stage IV (n:29). PET/CT detected 53 patients with hypermetabolic LN (average SUVmax: 7.5 +/- 4.1, range: 4.1-22.8, pelvic LN: 29 patients, para-aortic LN:5 patients, pelvic and para-aortic LN:19 patients). SUVmax and MTV were significantly higher in patients with PET-positive LN compared to others (18.4 and 88.8 cm(3) vs. 13.9 and 39.9 cm(3) respectively, p = 0.007 for SUVmax, p = 0.0001 for MTV). Cut-off values in association with PET positive LN were 15.2 for SUVmax and 35 cm(3) for MTV on ROC curve analysis. There was no correlation between SUVmax and MTV (correlation coefficient (R(2)) = 0.07). MTV differed significantly with FIGO stages (41, 98 and 107 cm(3), in stage II, III and IV respectively, p = 0.015). CONCLUSION: Presence of PET positive LN correlates with tumor SUVmax and MTV of cervical tumor. These findings support the use of PET/CT in the pretreatment evaluation of cervical cancer patients in order to identify cases with high risk of lymphatic involvement. PMID- 25018136 TI - 1-O-tigloyl-1-O-deacetyl-nimbolinin B inhibits LPS-stimulated inflammatory responses by suppressing NF-kappaB and JNK activation in microglia cells. AB - Overactivation of microglia may contribute to the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and HIV dementia. Thus, regulating microglial activation has been an important therapeutic strategy for treating neurodegenerative diseases. In this research, we compared three limonoids compounds extracted from Melia toosendan by a cell based assay to investigate their anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated microglia cells. Our study indicated that 1-O-tigloyl-1-O deacetyl-nimbolinin B (TNB) markedly suppressed the production of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha in LPS-stimulated microglia cells. TNB also inhibited the gene expression of inducible nitric oxide synthase (iNOS), TNF alpha, cyclooxygenase (COX-2), and interleukin (IL)-1beta. In addition, TNB inhibited generation of intracellular reactive oxygen species (ROS). We found that TNB significantly attenuated the nuclear translocation of NF-kappaB, inhibiting the activation of c-jun N-terminal kinase (JNK) in LPS-stimulated BV-2 cells. Furthermore, TNB reduced cytotoxicity of activated microglia toward HT-22 hippocampal cells in a co-culture system. Taken together, our experimental results reveal, for the first time, that TNB is a potent inhibitor of microglia mediated inflammation, and it might be a potential candidate for the treatment of neurodegenerative diseases. PMID- 25018137 TI - Changes of body composition in patients with BMI 23-50 after tailored one anastomosis gastric bypass (BAGUA): influence of diabetes and metabolic syndrome. AB - BACKGROUND: The use of bariatric surgery to treat diabetes mellitus (DM) requires procedures developed for morbid obese in patients with normal and over-weight. Therefore, we started tailoring one anastomosis gastric bypass (BAGUA) adapted to each patient. This study analyzes changes in body composition (BC) of patients with BMI 23-50 after BAGUA as well as influence of DM and MS. METHODS: We studied 79 (37 diabetic and 42 non-diabetic) patients (BMI 23-50) who completed all evaluation appointment (preoperative, 10 days, 1, 3, 6, and 12 months) after tailored BAGUA for obesity, diabetes, or diabesity. Patients were classified according to BMI (23-29, 30-34, 35-50) and bearing or not diabetes. Variables are components of BC as well as DM and MS. RESULTS: Preoperatively, mean values of weight varied 37 kg (78-115 kg), muscle mass (MM) 8 kg (54-62 kg), while fat mass (FM) 30 kg (22-53 kg). Basal metabolism (BM) was higher in diabetic. After surgery, percentage (%) of excess weight loss (%EWL) ranged from 76 % (BMI 35-50) to 128 % (BMI 23-29), FM 56 % (BMI 23-29) to 65 % (BMI 35-50), without differences bearing DM. MM 12 % (non-diabetics BMI 30-34) to 17 % (diabetics BMI 35-50) and visceral fat (VF) 50 % (diabetics BMI 30-34) to 56 % (non-diabetics BMI 35-50). CONCLUSIONS: After tailored BAGUA, MM maintains steady while FM is highly reduced and variable. BM is reduced in all groups. Diabetics lose less weight and VF but more MM than non-diabetic patients. Preoperative presence of MS influences the changes in BC. PMID- 25018138 TI - Parent and family impact of raising a child with perinatal stroke. AB - BACKGROUND: Perinatal stroke is a leading cause of early brain injury, cerebral palsy, and lifelong neurological morbidity. No study to date has examined the impact of raising a child with perinatal stroke on parents and families. However, a large breadth of research suggests that parents, especially mothers, may be at increased risk for psychological concerns. The primary aim of this study was to examine the impact of raising a child with perinatal stroke on mothers' wellbeing. A secondary aim was to examine how caring for a child with perinatal stroke differentially affects mothers and fathers. METHODS: In Study I, a matched case-control design was used to compare the wellbeing of mothers of children with perinatal stroke and mothers of children with typical development. In Study II, a matched case-control design was used to compare mother-father dyads. Participants completed validated measures of anxiety and depression, stress, quality of life and family functioning, marital satisfaction, and marital distress. Parents of children with perinatal stroke also completed a recently validated measure of the psychosocial impact of perinatal stroke including guilt and blame outcomes. Disease severity was categorized by parents, validated by the Pediatric Stroke Outcome Measure (PSOM), and compared across the above outcomes in Study I. RESULTS: A total of 112 mothers participated in Study I (n = 56 per group; mean child age = 7.42 years), and 56 parents participated in Study II (n = 28 per group; mean child age = 8.25 years). In Study I, parent assessment of disease severity was correlated with PSOM scores (gamma = 0.75, p < .001) and associated with parent outcomes. Mothers of children with mild conditions were indistinguishable from controls on the outcome measures. However, mothers of children with moderate/severe conditions had poorer outcomes on measures of depression, marital satisfaction, quality of life, and family functioning. In Study II, mothers and fathers had similar outcomes except mothers demonstrated a greater burden of guilt and higher levels of anxiety. CONCLUSIONS: Although most mothers of children with perinatal stroke adapt well, mothers of children with moderate/severe conditions appear to be at higher risk for psychological concerns. PMID- 25018140 TI - What's the difference? PMID- 25018141 TI - Flashcard: a 57-year-old woman with pleural effusion following percutaneous nephrolithotripsy. PMID- 25018142 TI - Prospective randomized trial: endoscopic follow up 3 vs 6 months after esophageal variceal eradication by band ligation in cirrhosis. AB - BACKGROUND AND OBJECTIVES: Endoscopic variceal ligation (EVL) is recommended to treat esophageal varices (EV) in cirrhosis and portal hypertension. A program of endoscopic surveillance is not clearly established. The aim of this prospective randomized trial was to assess the most effective timing of endoscopic monitoring after variceal eradication and its impact on the patient's outcome and on the costs. METHODS: A hundred and two cirrhotic patients with esophageal varices treated by EVL were evaluated. After variceal eradication patients were randomized to receive first endoscopic control at 3 (Group 1) and 6 (Group 2) months respectively. RESULTS: Variceal obliteration was achieved in all patients. Variceal recurrence was observed in 28 cases at the first control (29.1%) without difference between the two groups (32% vs 29% in group 1 and 2 respectively, p=0.75). The incidence of large varices is similar in the two groups (33% vs 38% respectively). Using a multivariate analysis, medical therapy with B blockers was the only independent predictor of lowest risk of variceal recurrence [OR 2.30, 95% CI (1.68-3.26)]. Bleeding related to recurrent varices occurred in 3.1% of cases and was associated with portal thrombosis. Child Pugh score >=8 was the only predictor of mortality (p=0.0002). CONCLUSIONS: Recurrence of varices after banding ligation is not rare but it is associated with a low risk of variceal progression and bleeding. Accordingly, a first endoscopic control at 6 months after variceal eradication associated with a good risk stratification might be a cost-effective strategy of monitoring. PMID- 25018143 TI - Does a craniotomy for treatment of unruptured aneurysm affect cognitive function? AB - The surgical procedure used to treat an unruptured intracranial aneurysm (UIA) has controversial effects on cognitive function. From January 2010 through December 2012, we enrolled patients who underwent surgical clipping for a UIA. Patients were tested within one week prior to surgery and again postoperatively (6.8 +/- 2.3 days) using a neuropsychological battery comprising the Mini-Mental State Examination, the Trail Making Test (TMT), the Frontal Assessment Battery (FAB), and Raven's colored progressive matrices (RCPM). Differences between preoperative and postoperative test scores for each examination were analyzed across individuals. In an additional subgroup analysis, patients were grouped according to age (< 65 or >= 65 years), the largest dimension of the aneurysm, the location of the aneurysm (i.e., anterior communicating artery, internal carotid artery, or middle cerebral artery) and operation duration. Paired student's t-tests were used to examine potential differences between groups. Two tailed P-values < 0.05 were considered significant. Seventy-one patients were included in the analysis. The surgical procedure used to correct a UIA resulted in significant changes in neuropsychological scores. After the procedure, the TMT A score declined significantly, whereas the FAB and RCPM scores were significantly improved. In the subgroup analysis, a significant deterioration in TMT-A score was observed in older patients and those with larger aneurysms, anterior communicating artery aneurysms and longer surgeries. Our findings, therefore, indicate that the surgical procedure to correct a UIA affects cognitive function. Older patients and those with large aneurysms, anterior communicating aneurysms, and long operations represent the high-risk groups. PMID- 25018144 TI - Mental health professionals and information sharing: carer perspectives. AB - BACKGROUND: The important role played by carers of those with mental health problems is frequently undervalued among healthcare professionals. AIMS: To identify the difficulties encountered by carers in relation to obtaining information from mental health teams. METHODS: Participants in the study included carers or family members of persons with mental illness who were affiliated with a support group in Ireland. Information was gathered using an 18-item self-report questionnaire. This is an amended version of the Carer Well-Being and Support Questionnaire for carers of people with a mental health problem or dementia. RESULTS: One-hundred and fifty-nine carers complete the questionnaire. On average respondents stated that they have been in the role of a carer for someone with a mental health problem for 14.4 years, spending a median of 20-h caring each week. Despite most carers maintaining that they are generally satisfied with the support offered to them from medical and/or care staff, the majority (56.3%) of respondents stated that they have specifically encountered difficulties accessing information from the treating mental health team. The main reasons given to them by the mental health team for withholding information include: lack of patient consent (46.2%) and unavailability of a team member (46.2%). From a carer perspective, respondents stated that the main reason they feel there is difficulty in accessing information is a lack of concern for their role as a carer in the patient's management (60.5%). More than 75% of all respondents are afraid of negative consequences for them or for the person in their care as a result of information being withheld by the treating team. CONCLUSIONS: Carer involvement is essential for the complete and effective management of individuals with mental illness. Confidentiality should not be used as a reason for completely excluding carers. PMID- 25018145 TI - Strong association between earlier abuse and revictimization in youth. AB - BACKGROUND: Violence victimization among youth is recognized as a public health problem. The objective was to analyze the risk pattern of emotional, physical, and sexual abuse during the past 12 months by gender, sociodemographic factors, health risk behaviors, and exposure to abuse before the age of 15, among young men and women attending youth health centers in Sweden. METHODS: A cross sectional survey was conducted using a nationally representative sample of youth health centers. A total of 2,250 young women and 920 young men aged 15-23 completed a self-administered questionnaire. Odds ratios (OR) and adjusted odds ratios (AOR) with 95% CI were calculated. RESULTS: A consistent and strong association was noted between exposure to all types of violence during the past year and victimization before the age of 15 for all types of violence for both women and men. The only exceptions were childhood sexual victimization and sexual violence during the past year for men. Younger age was associated with all violence exposure for the women and with emotional violence for the men. For the women, drug use was associated with all types of violence, while the association with hazardous alcohol use and not living with parents was restricted to physical and sexual violence exposure, present smoking was restricted to emotional and physical violence exposure, and partnership and living in urban areas were restricted to sexual violence. For men, not being partnered, hazardous alcohol consumption, and drug use meant increased risk for physical violence, while smoking and living in urban areas were associated with sexual violence. After adjustment, immigration had no association with violence exposure. CONCLUSIONS: Violence victimization in young men and women is often not a single experience. Findings underline the importance of early interventions among previously abused youth. PMID- 25018147 TI - Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences. AB - Dietary interventions like gluten-free and casein-free diets have been reported to improve intestinal, autoimmune and neurological symptoms in patients with a variety of conditions; however, the underlying mechanism of benefit for such diets remains unclear. Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be modulated by nutritional factors such as milk and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat derived protein) releases peptides with opioid activity, and in the present study, we demonstrate that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine. Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis was also observed. These results illustrate the potential of milk- and wheat-derived peptides to exert antioxidant and epigenetic changes that may be particularly important during the postnatal transition from placental to GI nutrition. Differences between peptides derived from human and bovine milk may contribute to developmental differences between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by wheat- and milk-derived opioid peptides, may predispose susceptible individuals to inflammation and systemic oxidation, partly explaining the benefits of gluten-free or casein-free diets. PMID- 25018148 TI - Life course approach in social epidemiology: an overview, application and future implications. AB - The application of the life course approach to social epidemiology has helped epidemiologists theoretically examine social gradients in population health. Longitudinal data with rich contextual information collected repeatedly and advanced statistical approaches have made this challenging task easier. This review paper provides an overview of the life course approach in epidemiology, its research application, and future challenges. In summary, a systematic approach to methods, including theoretically guided measurement of socioeconomic position, would assist researchers in gathering evidence for reducing social gradients in health, and collaboration across individual disciplines will make this task achievable. PMID- 25018149 TI - Utilization of extracorporeal membrane oxygenation alleviates intestinal ischemia reperfusion injury in prolonged hemorrhagic shock animal model. AB - Intestinal ischemia-reperfusion injury is one of the main factors leading to multiple organ failure after resuscitation of prolonged hemorrhagic shock; however, the current conventional fluid resuscitation still cannot effectively reduce intestinal injury caused by prolonged hemorrhagic shock. To investigate the effect of ECMO resuscitation on alleviating intestinal ischemia-reperfusion injury in a prolonged hemorrhagic shock rabbit model. Thirty New Zealand white rabbits were randomly divided into three groups: control group, conventional fluid resuscitation group, and ECMO resuscitation group. The prolonged hemorrhagic shock model was established by keeping the arterial blood pressure from 31 to 40 mmHg for 3 h through the femoral artery bleeding, and performing the resuscitation for 2 h by conventional fluid resuscitation and ECMO resuscitation, respectively. Chiu's score of intestinal injury, serum lactate and TNF-alpha levels, intestinal mucosamyeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM-1), and Claudin-1expression were detected. The mean arterial blood pressure in Group 2 was significantly higher after resuscitation than in Group 1, but serum lactate and inflammatory cytokines TNF-alpha level were significantly lower. And Chiu's score of intestinal injury and myeloperoxidase (MPO) activity level and ICAM-1 expression were significantly lower in the ECMO resuscitation group, in which the Claudin-1 levels were significantly increased. ECMO resuscitation for the prolonged hemorrhagic shock improves tissue perfusion and reduces the systemic inflammation, and thus alleviates intestinal damage caused by prolonged hemorrhagic shock. PMID- 25018150 TI - Posterior fossa decompression combined with resection of the cerebellomedullary fissure membrane and expansile duraplasty: a radical and rational surgical treatment for Arnold-Chiari type I malformation. AB - This study aims to introduce a new surgical procedure for the treatment of Arnold Chiari type I malformation (ACM-1) and to compare its effectiveness with the techniques described in previous studies. We performed the following procedures: foramen magnum decompression combined with the removal of both the atlanto occipital membrane, extended resection of the cerebellomedullary fissure arachnoid membrane, and artificial duraplasty to enlarge the membranic posterior fossa without resecting the cerebellar tonsils and syringosubarachnoid shunting. There were 21 ACM-1 patients: 12 cases had osteo-compression on the cerebellar hemisphere, 18 cases had thickened adhered fabric ring that stretched from arachnoid membrane to cerebellar hemisphere, and 15 cases with syringomyelia. The patients were followed up for 6 months to 3 years after the surgery. All patients showed a remarkable recovery of syringomyelia. There were no morbidity or death related to the surgery. Most of ACM-1 patients, the osteo- and membrane compression on cerebellar hemisphere and tonsil were observed during the operation. Therefore, decompression of foramen magnum and posterior craniocervical combined with the removal of cerebellomedullary fissure arachnoid membrane and placement of an artificial dural graft should be considered as a comprehensive option of minimally invasive surgery and rational and radical treatment of ACM-1. Our experience showed that, by using our procedure, shunting becomes no longer necessary in the treatment of ACM-1-associated syringomyelia. PMID- 25018151 TI - Lower health literacy predicts smoking relapse among racially/ethnically diverse smokers with low socioeconomic status. AB - BACKGROUND: Nearly half of U.S. adults have difficulties with health literacy (HL), which is defined as the ability to adequately obtain, process, and understand basic health information. Lower HL is associated with negative health behaviors and poor health outcomes. Racial/ethnic minorities and those with low socioeconomic status (SES) are disproportionately affected by poor HL. They also have higher smoking prevalence and more difficulty quitting smoking. Thus, lower HL may be uniquely associated with poorer cessation outcomes in this population. METHODS: This study investigated the association between HL and smoking cessation outcomes among 200, low-SES, racially/ethnically diverse smokers enrolled in smoking cessation treatment. Logistic regression analyses adjusted for demographics (i.e., age, gender, race/ethnicity, relationship status), SES related characteristics (i.e., education, income), and nicotine dependence were conducted to investigate associations between HL and smoking relapse at the end of treatment (3 weeks post quit day). RESULTS: Results indicated that smokers with lower HL (score of < 64.5 on the Rapid Estimate of Adult Literacy in Medicine [REALM]) were significantly more likely than those with higher HL (score of >= 64.5 on the REALM) to relapse by the end of treatment, even after controlling for established predictors of cessation including demographics, SES, and nicotine dependence (OR = 3.26; 95% CI = 1.14, 9.26). CONCLUSIONS: Findings suggest that lower HL may serve as an independent risk factor for smoking relapse among low-SES, racially/ethnically diverse smokers enrolled in treatment. Future research is needed to investigate longitudinal relations between HL and cessation outcomes and potential mechanisms of this relationship. PMID- 25018152 TI - The politics of harm reduction in federal prisons. AB - BACKGROUND: We need to understand better the political barriers to prison-based harm reduction programs. In this paper, I examine the situation in the Correctional Service of Canada (CSC), a federal prison agency with a zero tolerance drug policy and general opposition to prison needle and syringe programs (PNSPs) and safer tattooing initiatives. METHODS: This study draws on 16 interviews with former CSC senior officials, former frontline staff, and external stakeholders; CSC policy and practice documents; and testimony from a House of Commons Standing Committee public study. Thematic coding and comparison of texts were used to examine emergent themes of interest. RESULTS: Four interrelated issues were central for understanding the political barriers: a narrower definition of harm reduction used in corrections, both in principle and practice; the Conservative government's tough-on-crime agenda; strong union opposition; and stakeholder perceptions that political constraints will likely persist, including the view that litigation may offer the only way to introduce PNSPs. CONCLUSION: The system is at an impasse and key questions remain about the importability of harm reduction services into federal prisons. Despite a highly challenging policy environment, moving forward will demand asking new, critical questions and devising more strategic ways of entering the political-operational dialogue that opposes evidence-based programs. PMID- 25018153 TI - Somadril and edgework in South Sulawesi. AB - The use of psychoactive prescription drugs (PPDs) by young people is part of a broader worldwide trend towards the consumption of pharmaceuticals to improve social, emotional, and sexual performance. Few studies have examined how young people use PPDs in developing countries, where off-label use is likely to be greater due to weaker market controls. This study presents our findings on PPD use among sex workers in Makassar, Indonesia. We focus on one potent painkiller, Somadril, which is freely available over the counter in pharmacies. The sex workers we studied used most of their earnings to purchase Somadril pills, which they used to feel more confident and to make their work more palatable. This paper also traces the history of the active component in Somadril, carisoprodol. This was developed in the United States, where it was soon used recreationally. We found that knowledge of its effects seeped from health professionals into youth networks, where it was spread by word of mouth. The flow of information on carisoprodol's harmful effects, however, was less evident. PMID- 25018155 TI - Collection of recyclables does not need demagoguery. PMID- 25018154 TI - Urinary 8-hydroxydeoxyguanosine is a potential indicator for estimating pulmonary rehabilitation-induced oxidative stress in COPD patients. AB - Chronic obstructive pulmonary disease (COPD) is the most common chronic lung disease and is an important cause of morbidity worldwide. The aim of this study was to evaluate whether pulmonary rehabilitation (PR) improves the oxidant/antioxidant imbalance, exercise capacity and health-related quality of life (HRQL) in patients with different stages of COPD. Eighteen stable COPD patients participated in 8-week PR; the exercise intensity was set at 70% of the VO2 peak. Subjects were divided into 2 groups: moderate to severe (stages II/III: n = 12) and very severe COPD with FEV1 < 30% predicted (stage IV: n = 6). In patients at stages II/III, PR improved exercise capacity (6-minute walking test: 431.2 +/- 26.6 vs. 489.1 +/- 26.5 m, P < 0.01 and shuttle walking test: 329.2 +/- 41.4 vs. 378.2 +/- 41.5 m, P < 0.01) and HRQL, whereas no significant change was observed in erythrocyte lipid peroxidation and urinary 8-hydroxydeoxyguanosine, a marker for DNA damage. In contrast, PR for stage IV patients did not improve exercise capacity and HRQL, but significantly increased urinary 8 hydroxydeoxyguanosine (14.5 +/- 1.7 vs. 24.3 +/- 2.6 ng/mg Cr, P < 0.05). In both groups, erythrocyte antioxidants (superoxide dismutase, glutathione peroxidase, and catalase) did not change significantly after PR. Thus, urinary 8 hydroxydeoxyguanosine is a useful indicator for the PR-induced oxidative stress in COPD patients. In conclusion, appropriate exercise program in COPD patients can improve exercise capacity and HRQL without further increase of oxidative stress. However, PR for very severe COPD patients enhanced exercise-induced oxidative stress. PMID- 25018156 TI - Acute type A aortic dissection extending beyond ascending aorta: Limited or extensive distal repair. AB - OBJECTIVE: The aim of our study was to delineate the effect of aortic arch surgery extension on the outcomes in acute type A dissection extending beyond the ascending aorta. METHODS: From 2001 to 2013, of 197 patients with type A dissection, 153 (78%) with dissection extending beyond the ascending aorta (age, 61 years; first quartile, 50; third quartile, 69; 67% men) were identified. Aortic repair involved isolated ascending replacement (n = 102), hemiarch (n = 37), and total arch replacement (n = 14). The median follow-up period was 4.9 years (first quartile, 2.5; third quartile, 7.6; 733 patient-years). RESULTS: In hospital mortality was 9.8%, 21.6%, and 28.6% (P = .122) for patients with no, hemiarch, and total arch replacement. Age > 80 years (odds ratio [OR], 9.37; P = .006), malperfusion syndrome (OR, 4.74; P = .004), and total arch replacement (OR, 6.47; P = .016) were independent predictors of perioperative mortality. Freedom from distal reintervention was 93% +/- 3%, 97% +/- 3%, and 100% at 1 year and 89% +/- 3%, 97% +/- 3%, and 100% at 5 years for the no, hemiarch, and total arch replacement groups, respectively (log-rank, P = .440). Marfan syndrome (OR, 12.40; P = .038) and dissection of all aortic segments (OR, 10.68; P = .007) predicted distal aortic reintervention. In-hospital mortality for elective reintervention was 0%. CONCLUSIONS: Limiting the extent of surgery for type A aortic dissection to ascending aortic replacement was associated with low perioperative mortality. Thus, aortic arch repair can be deferred, because it can be performed electively with a lower mortality risk. PMID- 25018158 TI - When does transapical aortic valve replacement become a futile procedure? An analysis from a national registry. AB - OBJECTIVES: Patient selection is crucial to achieve good outcomes and to avoid futile procedures in patients undergoing transcatheter aortic valve replacement. The aim of this multicenter retrospective study was to identify independent predictors of 1-year mortality in patients surviving after transapical transcatheter aortic valve replacement. METHODS: We analyzed data from the Italian registry of transapical transcatheter aortic valve replacement that includes patients undergoing operation in 21 centers from 2007 to 2012. Futility was defined as mortality within 1 year after transapical transcatheter aortic valve replacement in patients surviving at 30 days. Thirty-day survivors were divided in 2 groups: futility (group F) and nonfutility (group NF). Cox proportional hazard regression analysis was performed to identify independent predictors of futility. RESULTS: We analyzed data from 645 patients with survival of 30 days or more after transapical transcatheter aortic valve replacement. Groups F and NF included 60 patients (10.8%) and 585 patients (89.2%), respectively. Patients in group F were more likely to have insulin-dependent diabetes (15% vs 7.2%, P = .03), creatinine 2.0 mg/dL or greater or dialysis (18.3% vs 8.2%, P = .01), logistic European System for Cardiac Operative Risk Evaluation greater than 20% (66.7% vs 50.3%, P = .02), preoperative rhythm disorders (40% vs 25.3%, P = .03), critical preoperative state (8.3% vs 1.8%, P = .002), and left ventricular ejection fraction less than 30% (15% vs 2.9%, P < .001). The multivariate analysis identified the following as independent predictors of futility: insulin-dependent diabetes (odds ratio, 3.1; P = .003), creatinine 2.0 mg/dL or greater or dialysis (odds ratio, 2.52; P = .012), preoperative rhythm disorders (odds ratio, 1.88; P = .04), and left ventricular ejection fraction less than 30% (odds ratio, 4.34; P = .001). CONCLUSIONS: According to our data, among patients undergoing transapical transcatheter aortic valve replacement, those with insulin-dependent diabetes, advanced chronic kidney disease, rhythm disorders, and low left ventricular ejection fraction have a higher risk to undergo futile procedures. PMID- 25018554 TI - Edge states of a three-dimensional topological insulator. AB - We use the bulk Hamiltonian for a three-dimensional topological insulator such as Bi(2) Se(3) to study the states which appear on its various surfaces and along the edge between two surfaces. We use both analytical methods based on the surface Hamiltonians (which are derived from the bulk Hamiltonian) and numerical methods based on a lattice discretization of the bulk Hamiltonian. We find that the application of a potential barrier along an edge can give rise to states localized at that edge. These states have an unusual energy-momentum dispersion which can be controlled by applying a potential along the edge; in particular, the velocity of these states can be tuned to zero. The scattering and conductance across the edge is studied as a function of the edge potential. We show that a magnetic field in a particular direction can also give rise to zero energy states on certain edges. We point out possible experimental ways of looking for the various edge states. PMID- 25018457 TI - 0084 A Case-Control Study of Occupational Exposure to Metalworking Fluids and Bladder Cancer Risk among Men. AB - OBJECTIVES: Metalworking has been associated with bladder cancer risk in many studies. Metalworking fluids (MWFs) are suspected as the putative exposure, but epidemiologic data are limited. Based on state-of-the-art, quantitative exposure assessment, we examined MWF exposure and bladder cancer risk in the New England Bladder Cancer Study. METHOD: Male cases (n = 895) and population controls (n = 1031) provided occupational histories and information on use of each of three MWF types: (1) straight (mineral oil, additives), (2) soluble (mineral oil, water, additives), and (3) synthetic (water, organics, additives) or semi-synthetic (soluble/synthetic hybrid), in response to exposure-oriented modules administered during personal interviews. We estimated the probability, frequency, and intensity of exposure to each MWF type and, if probability exceeded 50%, cumulative exposure. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors. RESULTS: Risk was increased for men reporting use of straight MWFs (OR=1.7, 95% CI=1.1-2.8), with a significant trend with increasing cumulative exposure (p = 0.024). Use of soluble MWFs conferred a 50% elevated risk (95% CI=0.96-2.5). ORs were nonsignificantly elevated for synthetic MWFs, based on small numbers. Men who were never metalworkers, but held jobs with possible exposure to mineral oil, had a 40% increased risk (95% CI=1.1-1.8). CONCLUSIONS: In the most comprehensive assessment of MWF exposure in a bladder cancer case-control study, exposure to straight MWFs significantly increased bladder cancer risk, as did employment in non-metalworking jobs with possible mineral oil exposure. Our results strengthen prior evidence for mineral oil as a bladder carcinogen. PMID- 25018555 TI - Electric field for tuning quantum entanglement in supported clusters. AB - We show that quantum entanglement, nowadays so widely observed and used in a multitude of systems, can be traced in the atomic spins of metal clusters supported on metal surfaces. Most importantly, we show that it can be voluntarily altered with external electric fields. We use a combination of ab initio and model Heisenberg-Dirac-Van Vleck quantum spin Hamiltonian calculations to show, with the example of a prototype system (Mn dimers on Ag(0 0 1) surface), that, in an inherently unentangled system an electric field can 'switch on' the entanglement and significantly change its critical temperature parameter. The physical mechanism allowing such rigorous control of entanglement by an electric field is the field-induced change in the internal magnetic coupling of the supported nanostructure. PMID- 25018556 TI - Economic Effects of Childhood Exposure To Tropical Disease. AB - To what extent do tropical diseases contribute to the poverty characteristic of tropical countries? Estimates of the impact of health on income are difficult to obtain because health is a normal good-countries with higher income will buy more of it-and third factors such as remoteness and bad government might impede both productivity and public health. In the Abuja Declaration of 2005, African heads of states claim that malaria has depressed income growth in Subsaharan Africa since the 1960s, so much so that GDP in the region today is 40% lower because of malaria. Estimates of this magnitude have been mocked at cocktail parties and clambakes. But how ridiculous is this number? PMID- 25018557 TI - Reply to Correspondence: Interpretation of Outer Retina Appearance in High Resolution OCT. PMID- 25018558 TI - Individual variation in exploratory behaviour improves speed and accuracy of collective nest selection by Argentine ants. AB - Collective behaviours are influenced by the behavioural composition of the group. For example, a collective behaviour may emerge from the average behaviour of the group's constituents, or be driven by a few key individuals that catalyse the behaviour of others in the group. When ant colonies collectively relocate to a new nest site, there is an inherent trade-off between the speed and accuracy of their decision of where to move due to the time it takes to gather information. Thus, variation among workers in exploratory behaviour, which allows gathering information about potential new nest sites, may impact the ability of a colony to move quickly into a suitable new nest. The invasive Argentine ant, Linepithema humile, expands its range locally through the dispersal and establishment of propagules: groups of ants and queens. We examine whether the success of these groups in rapidly finding a suitable nest site is affected by their behavioural composition. We compared nest choice speed and accuracy among groups of all exploratory, all-nonexploratory and half-exploratory-half-nonexploratory individuals. We show that exploratory individuals improve both the speed and accuracy of collective nest choice, and that exploratory individuals have additive, not synergistic, effects on nest site selection. By integrating an examination of behaviour into the study of invasive species we shed light on the mechanisms that impact the progression of invasion. PMID- 25018559 TI - Multiple paternity does not depend on male genetic diversity. AB - Polyandry is common in many species and it has been suggested that females engage in multiple mating to increase the genetic diversity of their offspring (genetic diversity hypothesis). Multiple paternity occurs in 30% of litters in wild populations of house mice, Mus musculus musculus, and multiple-sired litters are genetically more diverse than single-sired ones. Here, we aimed to test whether female house mice produce multiple-sired litters when they have the opportunity to produce genetically diverse litters. We assessed the rates of multiple paternity when females could choose to mate with two males that were genetically dissimilar to each other (i.e. nonsiblings and MHC dissimilar) compared with when females could choose to mate with two males that were genetically similar to each other (i.e. siblings and shared MHC alleles). Multiple mating may depend upon a female's own condition, and, therefore, we also tested whether inbred (from full sibling matings) females were more likely to produce multiple-sired progeny than outbred controls. Overall we found that 29% of litters had multiple sires, but we found no evidence that females were more likely to produce multiple-sired litters when they had the opportunity to mate with genetically dissimilar males compared with controls, regardless of whether females were inbred or outbred. Thus, our findings do not support the idea that female mice increase multiple paternity when they have the opportunity to increase the genetic diversity of their offspring, as expected from the genetic diversity hypothesis. PMID- 25018560 TI - Explosive thermal reduction of graphene oxide-based materials: mechanism and safety implications. AB - Thermal reduction of graphene oxide or graphite oxide (GO) is an important processing step in the fabrication of many graphene-based materials and devices. Here we show that some bulk solid GO samples can undergo explosive decomposition when small samples are heated slowly in inert gas environments, while others do not. These micro-explosions can occur for samples as small as few milligrams and are sufficiently energetic to cause laboratory equipment damage. Thermochemical analysis methods are used to understand the factors that lead to the explosive reduction mode. The studies show that the explosive mode of reduction is caused by the exothermicity of GO reduction coupled with a threshold sample mass/size that causes heat and mass transfer limitations leading to local temperature rise and a thermal runaway reaction. The explosive mode of reduction is not caused or promoted by interstitial water, and its onset temperature can be lowered by immersion in potassium hydroxide solution. By allowing early release of internal gas pressure, the explosive mode reduces the extent of surface area development in GO exfoliation from an optimum value of 1470 m2g-1 obtained under non explosive reduction conditions. Explosive reduction of bulk GO poses industrial safety hazards during large-scale storage, handling, and processing. PMID- 25018561 TI - Ancestry, Temporality, and Potentiality: Engaging Cancer Genetics in Southern Brazil. AB - In this paper I examine the variety of ways potential is articulated, entailed, and produced in how the field of cancer genetics is being constituted as a domain of transnational research and an emerging site of health-care intervention in southern Brazil. Drawing on analysis of fieldwork in Brazilian cancer-genetics clinics, I explore how different expressions of potential come to inform dynamically the pursuit of prevention, care, and research as diversely scaled investments for those working and living with cancer-genetics knowledge and technologies. It illustrates how specific temporalities help to constitute and "abductively" frame the meaning of these different potentials particularly as this relates to a focus on ancestry. Colonial histories of migration, the embodied effects of dietary habits, or the moral failings of near and distant ancestors as well as promissory futures and the contingency of lived lives become at different times templates for identifying, materializing, and transforming how the potential of cancer genetics in Brazil is articulated. Potential is also expressed through an idiom of "choice" in different efforts to situate participation in cancer-genetics research as prevention or to negotiate access to basic public health. I explore how these expressions of cancer genetics as potential powerfully yet unevenly work to sustain knowledge practices as well as propel patients and their families into fledgling domains of clinical practice and scientific research. At the same time there is always an "excess of meaning" in these endeavors that make visible lines of fracture and disjuncture in collective efforts to make future histories of and from the pursuit of cancer genetics in southern Brazil. PMID- 25018562 TI - Immigration and Language Diversity in the United States. PMID- 25018563 TI - Functional Segregation of the Entopallium in Pigeons. AB - In birds, the entopallium is the primary telencephalic target of the major visual ascending route called the tectofugal pathway. Often functionally compared to the primate geniculo-striate pathway and its subsequent telencephalic (cortical) regions, the latter processes visual information in a parallel fashion in terms of anatomy, physiology, and function. Little is known, however, about the exact mechanism of whether or how information is segregated or integrated in the avian tectofugal pathway including the telencephalon. Testing four pigeons, we examined whether or not color, form, and motion information is selectively processed by different portions of the entopallium. Each learned three distinct visual tasks requiring discrimination of different combinations of color, form and motion cues. After learning and pre-lesion testing, two pigeons received lesions to the anterior portion of the entopallium and two received lesions to the posterior entopallium. During post-lesion testing the pigeons with anterior lesions exhibited significant deficits in those tasks most dependent on color and form discrimination, but showed no deficit on a task that had involved discriminating among forms that were moving. Pigeons with posterior lesions showed a different pattern of deficits, exhibiting significant reductions in discriminating both moving and static forms, but little or no deficits in color discrimination. These divergent profiles of effects for each lesion suggest there is a functional segregation of visual information processing in the pigeon telencephalon. This indicates a convergence between birds and primates regarding the parallel processing and separation of information within their phylogenetically distinct major visual pathways. PMID- 25018564 TI - MEASURING BELIEFS AND REWARDS: A NEUROECONOMIC APPROACH. AB - The neurotransmitter dopamine is central to the emerging discipline of neuroeconomics; it is hypothesized to encode the difference between expected and realized rewards and thereby to mediate belief formation and choice. We develop the first formal test of this theory of dopaminergic function, based on a recent axiomatization by Caplin and Dean [2008A]. These tests are satisfied by neural activity in the nucleus accumbens, an area rich in dopamine receptors. We find evidence for separate positive and negative reward prediction error signals, suggesting that behavioral asymmetries in response to losses and gains may parallel asymmetries in nucleus accumbens activity. PMID- 25018565 TI - The Neurobiological Toll of Early Human Deprivation. AB - Children raised in institutions frequently suffer from a variety of behavioral, emotional, and neuropsychological sequelae, including deficits in attention, executive functions, disorders of attachment and in some cases a syndrome that mimics autism. The extent and severity of these disorders appears to be mediated, in part, by the age at which the child entered and, in some cases, left the institution. Here we review the neurobiological literature on early institutionalization that may account for the psychological and neurological sequelae discussed in other chapters in this volume. PMID- 25018567 TI - Intramolecular Rearrangement of alpha-Amino Acid Amide Derivatives of 2 Aminobenzothiazoles. AB - We have found that alpha-amino acid amide derivatives of 2-aminobenzothiazoles undergo a time-dependent, thermal rearrangement in which the amine group attacks the 2-position carbon of the thiazole ring to form a 5,5-spiro ring system. This is followed by sulfur leaving and air oxidation to the corresponding symmetrical disulfide. The isolated yields of such products are quite high (>70%) if there is conformational bias to further promote the intramolecular reaction such as for the 2-aminobenzothiazole amides derived from proline or 4-aminopiperidine-4 carboxylic acid. This rearrangement has not been described previously for alpha amino acid amide derivatives of 2-aminobenzothiazoles. However, a related reaction involving 2-semicarbazido benzothiazoles has been recently reported. PMID- 25018566 TI - Research, Practice, and Policy Perspectives on Issues of Children without Permanent Parental Care. AB - This chapter presents conclusions, trends, conceptual analyses, hypotheses, and speculations regarding some fundamental issues of research, practice, and policy that are largely unsettled or controversial. As such, the chapter is not a summary of Chapters 1-8, but rather contains interpretations and opinions of the author intended to elevate the priority of certain issues, suggest hypotheses to be studied, and propose practice and policy steps to be considered. PMID- 25018568 TI - POWER-ENHANCED MULTIPLE DECISION FUNCTIONS CONTROLLING FAMILY-WISE ERROR AND FALSE DISCOVERY RATES. AB - Improved procedures, in terms of smaller missed discovery rates (MDR), for performing multiple hypotheses testing with weak and strong control of the family wise error rate (FWER) or the false discovery rate (FDR) are developed and studied. The improvement over existing procedures such as the Sidak procedure for FWER control and the Benjamini-Hochberg (BH) procedure for FDR control is achieved by exploiting possible differences in the powers of the individual tests. Results signal the need to take into account the powers of the individual tests and to have multiple hypotheses decision functions which are not limited to simply using the individual p-values, as is the case, for example, with the Sidak, Bonferroni, or BH procedures. They also enhance understanding of the role of the powers of individual tests, or more precisely the receiver operating characteristic (ROC) functions of decision processes, in the search for better multiple hypotheses testing procedures. A decision-theoretic framework is utilized, and through auxiliary randomizers the procedures could be used with discrete or mixed-type data or with rank-based nonparametric tests. This is in contrast to existing p-value based procedures whose theoretical validity is contingent on each of these p-value statistics being stochastically equal to or greater than a standard uniform variable under the null hypothesis. Proposed procedures are relevant in the analysis of high-dimensional "large M, small n" data sets arising in the natural, physical, medical, economic and social sciences, whose generation and creation is accelerated by advances in high throughput technology, notably, but not limited to, microarray technology. PMID- 25018569 TI - Stability analysis of 4-species Abeta aggregation model: A novel approach to obtaining physically meaningful rate constants. AB - Protein misfolding and concomitant aggregation towards amyloid formation is the underlying biochemical commonality among a wide range of human pathologies. Amyloid formation involves the conversion of proteins from their native monomeric states (intrinsically disordered or globular) to well-organized, fibrillar aggregates in a nucleation-dependent manner. Understanding the mechanism of aggregation is important not only to gain better insight into amyloid pathology but also to simulate and predict molecular pathways. One of the main impediments in doing so is the stochastic nature of interactions that impedes thorough experimental characterization and the development of meaningful insights. In this study, we have utilized a well-known intermediate state along the amyloid-beta peptide aggregation pathway called protofibrils as a model system to investigate the molecular mechanisms by which they form fibrils using stability and perturbation analysis. Investigation of protofibril aggregation mechanism limits both the number of species to be modeled (monomers, and protofibrils), as well as the reactions to two (elongation by monomer addition, and protofibril-protofibril lateral association). Our new model is a reduced order four species model grounded in mass action kinetics. Our prior study required 3200 reactions, which makes determining the reaction parameters prohibitively difficult. Using this model, along with a linear perturbation argument, we rigorously determine stable ranges of rate constants for the reactions and ensure they are physically meaningful. This was accomplished by finding the ranges in which the perturbations dieout in a five-parameter sweep, which includes the monomer and protofibril equilibrium concentrations and three of the rate constants. The results presented are a proof-of-concept method in determining meaningful rate constants that can be used as a bonafide way for determining accurate rate constants for other models involving complex biological reactions such as amyloid aggregation. PMID- 25018570 TI - Period-Based Mortality Change: Turning Points in Trends since 1950. PMID- 25018571 TI - Robust rankings: Review of multivariate assessments illustrated by the Shanghai rankings. AB - Defined errors are entered into data collections in order to test their influence on the reliability of multivariate rankings. Random numbers and real ranking data serve as data origins. In the course of data collection small random errors often lead to a switch in ranking, which can influence the general ranking picture considerably. For stabilisation an objective weighting method is evaluated. The robustness of these rankings is then compared to the original forms. Robust forms of the published Shanghai top 100 rankings are calculated and compared to each other. As a result, the possibilities and restrictions of this type of weighting become recognisable. PMID- 25018572 TI - NON-PARAMETRIC ESTIMATION UNDER STRONG DEPENDENCE. AB - We study non-parametric regression function estimation for models with strong dependence. Compared with short-range dependent models, long-range dependent models often result in slower convergence rates. We propose a simple differencing sequence based non-parametric estimator that achieves the same convergence rate as if the data were independent. Simulation studies show that the proposed method has good finite sample performance. PMID- 25018573 TI - Data Collection Strategies and Measurement Tools for Assessing Academic and Therapeutic Outcomes in Recovery Schools. AB - Accurate evaluation and documentation of the efficacy of recovery schools can be vital to the continuation and expansion of these beneficial resources. A very limited data set currently exists that examines the value of specific schools established to support adolescents and young adults in recovery; additional research is necessary. The following article outlines the methodology utilized in a current quasi-experimental study evaluating both academic and therapeutic outcomes of adolescents attending recovery high schools as compared to traditional (non-recovery-based) high schools. The developmental considerations in assessing adolescents in recovery and their parents is delineated in this article, which underscores the need for extensive knowledge of adolescent substance abuse and other mental health issues. In addition, sensitivity around privacy among adolescents, parents, schools, and health providers is highlighted, as well as the validity of assessment. Key assessment strategies, including protocol of recruitment and interviewing techniques, are also presented along with a list of parent and adolescent assessment instruments and their corresponding interpretive variables. Protocol recommendations for future research are also outlined. PMID- 25018574 TI - Estimating Risk with Time-to-Event Data: An Application to the Women's Health Initiative. AB - Accurate and individualized risk prediction is critical for population control of chronic diseases such as cancer and cardiovascular disease. Large cohort studies provide valuable resources for building risk prediction models, as the risk factors are collected at the baseline and subjects are followed over time until disease occurrence or termination of the study. However, for rare diseases the baseline risk may not be estimated reliably based on cohort data only, due to sparse events. In this paper, we propose to make use of external information to improve efficiency for estimating time-dependent absolute risk. We derive the relationship between external disease incidence rates and the baseline risk, and incorporate the external disease incidence information into estimation of absolute risks, while allowing for potential difference of disease incidence rates between cohort and external sources. The asymptotic properties, namely, uniform consistency and weak convergence, of the proposed estimators are established. Simulation results show that the proposed estimator for absolute risk is more efficient than that based on the Breslow estimator, which does not utilize external disease incidence rates. A large cohort study, the Women's Health Initiative Observational Study, is used to illustrate the proposed method. PMID- 25018575 TI - Child Well-Being in Same-Sex Parent Families: Review of Research Prepared for American Sociological Association Amicus Brief. AB - Recent legal cases before the Supreme Court of the United States were challenging federal definitions of marriage created by the Defense of Marriage Act and California's voter approved Proposition 8 which limited marriage to different-sex couples only. Social science literature regarding child well-being was being used within these cases, and the American Sociological Association sought to provide a concise evaluation of the literature through an amicus curiae brief. The authors were tasked in the assistance of this legal brief by reviewing literature regarding the well-being of children raised within same-sex parent families. This article includes our assessment of the literature, focusing on those studies, reviews and books published within the past decade. We conclude that there is a clear consensus in the social science literature indicating that American children living within same-sex parent households fare just, as well as those children residing within different-sex parent households over a wide array of well-being measures: academic performance, cognitive development, social development, psychological health, early sexual activity, and substance abuse. Our assessment of the literature is based on credible and methodologically sound studies that compare well-being outcomes of children residing within same-sex and different-sex parent families. Differences that exist in child well-being are largely due to socioeconomic circumstances and family stability. We discuss challenges and opportunities for new research on the well-being of children in same-sex parent families. PMID- 25018576 TI - Synthetic Brainbows. AB - Brainbow is a genetic engineering technique that randomly colorizes cells. Biological samples processed with this technique and imaged with confocal microscopy have distinctive colors for individual cells. Complex cellular structures can then be easily visualized. However, the complexity of the Brainbow technique limits its applications. In practice, most confocal microscopy scans use different florescence staining with typically at most three distinct cellular structures. These structures are often packed and obscure each other in rendered images making analysis difficult. In this paper, we leverage a process known as GPU framebuffer feedback loops to synthesize Brainbow-like images. In addition, we incorporate ID shuffing and Monte-Carlo sampling into our technique, so that it can be applied to single-channel confocal microscopy data. The synthesized Brainbow images are presented to domain experts with positive feedback. A user survey demonstrates that our synthetic Brainbow technique improves visualizations of volume data with complex structures for biologists. PMID- 25018577 TI - Visual speech segmentation: using facial cues to locate word boundaries in continuous speech. AB - Speech is typically a multimodal phenomenon, yet few studies have focused on the exclusive contributions of visual cues to language acquisition. To address this gap, we investigated whether visual prosodic information can facilitate speech segmentation. Previous research has demonstrated that language learners can use lexical stress and pitch cues to segment speech and that learners can extract this information from talking faces. Thus, we created an artificial speech stream that contained minimal segmentation cues and paired it with two synchronous facial displays in which visual prosody was either informative or uninformative for identifying word boundaries. Across three familiarisation conditions (audio stream alone, facial streams alone, and paired audiovisual), learning occurred only when the facial displays were informative to word boundaries, suggesting that facial cues can help learners solve the early challenges of language acquisition. PMID- 25018579 TI - On the Modeling of Polar Component of Solvation Energy using Smooth Gaussian Based Dielectric Function. AB - Traditional implicit methods for modeling electrostatics in biomolecules use a two-dielectric approach: a biomolecule is assigned low dielectric constant while the water phase is considered as a high dielectric constant medium. However, such an approach treats the biomolecule-water interface as a sharp dielectric border between two homogeneous dielectric media and does not account for inhomogeneous dielectric properties of the macromolecule as well. Recently we reported a new development, a smooth Gaussian-based dielectric function which treats the entire system, the solute and the water phase, as inhomogeneous dielectric medium (J Chem Theory Comput. 2013 Apr 9; 9(4): 2126-2136.). Here we examine various aspects of the modeling of polar solvation energy in such inhomogeneous systems in terms of the solute-water boundary and the inhomogeneity of the solute in the absence of water surrounding. The smooth Gaussian-based dielectric function is implemented in the DelPhi finite-difference program, and therefore the sensitivity of the results with respect to the grid parameters is investigated, and it is shown that the calculated polar solvation energy is almost grid independent. Furthermore, the results are compared with the standard two-media model and it is demonstrated that on average, the standard method overestimates the magnitude of the polar solvation energy by a factor 2.5. Lastly, the possibility of the solute to have local dielectric constant larger than of a bulk water is investigated in a benchmarking test against experimentally determined set of pKa's and it is speculated that side chain rearrangements could result in local dielectric constant larger than 80. PMID- 25018578 TI - Association between Maternal sensitivity and Externalizing Behavior from Preschool to Preadolescence. AB - Using data from the longitudinal NICHD Study of Early Child Care and Youth Development (N=1364), this study examined the association between mothers' sensitivity and children's externalizing behavior from preschool to preadolescence. Externalizing behavior declined on average across this period with a slowing of this decline around middle childhood. Maternal sensitivity remained relatively stable on average, and there was significant variation across mothers. A decrease in maternal sensitivity from ages 3 to 11 was related to an increase in externalizing behavior from ages 4 to 12. A model-based test of the direction of the effect suggested that the association between changes in maternal sensitivity and externalizing behavior from ages 4 to 11 was driven by child effects on mothers and not vice-versa. Between late preschool age and preadolescence, the behavior problems of children appear to strongly influence the sensitive support of mothers. Practical implications were discussed in light of these findings. PMID- 25018580 TI - Life Domain Satisfactions as Predictors of Overall Life Satisfaction Among Workers: Evidence from Chile. AB - This article examines the subjective antecedents of life satisfaction of workers. Adopting a 'bottom-up' perspective, we assessed the unique influence that satisfaction with multiple life domains have on evaluative judgments of overall life satisfaction. Based on a nationwide sample of 530 Chilean workers, we simultaneously tested the effects of seven life domain satisfactions that have been consistently included in extant models of life satisfaction and subjective well-being. These were satisfaction with health, financial situation, social relationships, one's self-worth, leisure-time, family, and work. Having controlled for age and gender, results showed that satisfaction with one's financial situation was the dominant predictor of overall life satisfaction of workers, with a weight of .36. Satisfaction with family, work, and health had effects of .25, .14, and .14, respectively. Interestingly, satisfaction with one's self-worth, leisure-time, and social relationships did not have statistically significant effects on life satisfaction, although the first two showed t values near the critical value. PMID- 25018581 TI - The Interplay of Reader Goals, Working Memory, and Text Structure During Reading. AB - In the current study we examined the complex interactions of instructional context, text properties, and reader characteristics during comprehension. College students were tasked with the goal of reading for study versus entertainment (instructional context) while thinking-aloud about four different expository text structures (text properties). Working memory also was assessed (reader characteristics). Reading goals and working memory interacted to influence paraphrasing and non-coherence processes when thinking aloud. Reading goals, working memory, and text structure all interacted to influence text-based inferences. Text structure also influenced knowledge-based inferences. Post reading recall was highest for those with the instructional goal of reading for study (compared to entertainment), as well as for problem-response and compare contrast texts (compared to descriptive and chronological texts). Implications of the findings are discussed. PMID- 25018582 TI - Empirical Assessment of Spatial Prediction Methods for Location Cost Adjustment Factors. AB - In the feasibility stage, the correct prediction of construction costs ensures that budget requirements are met from the start of a project's lifecycle. A very common approach for performing quick-order-of-magnitude estimates is based on using Location Cost Adjustment Factors (LCAFs) that compute historically based costs by project location. Nowadays, numerous LCAF datasets are commercially available in North America, but, obviously, they do not include all locations. Hence, LCAFs for un-sampled locations need to be inferred through spatial interpolation or prediction methods. Currently, practitioners tend to select the value for a location using only one variable, namely the nearest linear-distance between two sites. However, construction costs could be affected by socio economic variables as suggested by macroeconomic theories. Using a commonly used set of LCAFs, the City Cost Indexes (CCI) by RSMeans, and the socio-economic variables included in the ESRI Community Sourcebook, this article provides several contributions to the body of knowledge. First, the accuracy of various spatial prediction methods in estimating LCAF values for un-sampled locations was evaluated and assessed in respect to spatial interpolation methods. Two Regression-based prediction models were selected, a Global Regression Analysis and a Geographically-weighted regression analysis (GWR). Once these models were compared against interpolation methods, the results showed that GWR is the most appropriate way to model CCI as a function of multiple covariates. The outcome of GWR, for each covariate, was studied for all the 48 states in the contiguous US. As a direct consequence of spatial non-stationarity, it was possible to discuss the influence of each single covariate differently from state to state. In addition, the article includes a first attempt to determine if the observed variability in cost index values could be, at least partially explained by independent socio-economic variables. PMID- 25018583 TI - All varieties of encoding variability are not created equal: Separating variable processing from variable tasks. AB - Whether encoding variability facilitates memory is shown to depend on whether item-specific and relational processing are both performed across study blocks, and whether study items are weakly versus strongly related. Variable-processing groups studied a word list once using an item-specific task and once using a relational task. Variable-task groups' two different study tasks recruited the same type of processing each block. Repeated-task groups performed the same study task each block. Recall and recognition were greatest in the variable-processing group, but only with weakly related lists. A variable-processing benefit was also found when task-based processing and list-type processing were complementary (e.g., item-specific processing of a related list) rather than redundant (e.g., relational processing of a related list). That performing both item-specific and relational processing across trials, or within a trial, yields encoding variability benefits may help reconcile decades of contradictory findings in this area. PMID- 25018585 TI - The Role of Access to Head Start and Quality Ratings for Spanish-Speaking Dual Language Learners' (DLLs) Participation in Early Childhood Education. AB - Data from the Head Start Impact Study (N = 4,442) were used to test for differences between Spanish-speaking Dual Language Learners (DLLs) and monolingual English-speaking children in: (1) Head Start attendance rates when randomly assigned admission; and (2) quality ratings of other early childhood education (ECE) programs attended when not randomly assigned admission to Head Start. Logistic regressions showed that Spanish-speaking DLL children randomly assigned a spot in Head Start were more likely than monolingual-English learners to attend. Further, Spanish-speaking DLLs not randomly assigned a spot in Head Start were more likely to attend higher-quality ECE centers than non-DLL children. Policy implications are discussed, suggesting that, if given access, Spanish-speaking DLL families will take advantage of quality ECE programs. PMID- 25018584 TI - Biological interactions and safety of graphene materials. AB - As graphene technologies progress to commercialization and large-scale manufacturing, issues of material and processing safety will need to be more seriously considered. The single word "graphene" actually represents a family of related materials with large variations in number of layers, surface area, lateral dimensions, stiffness, and surface chemistry. Many of these materials have aerodynamic diameters below 5 MUm and can potentially be inhaled into the human lung. Graphene materials show several unique modes of interaction with biological molecules, tissues, and cells. The limited literature suggests that graphene materials can be either benign or harmful and that the biological response varies according to a material's physicochemical properties and biologically effective dose. The present article reviews the current literature on the graphene-biological interface with an emphasis on the mechanisms and fundamental biological responses relevant to material safety and also to potential biomedical applications. PMID- 25018586 TI - You can't always want what you get: Children's intuitions about ownership and desire. AB - Ownership is a central element of human experience. The present experiments were designed to examine the influence of psychological state on ownership judgments. In three experiments, 4-year-olds were asked to make ownership attributions about owners and non-owners who either desired or did not desire a gift. Despite exhibiting a clear sensitivity to the desires of others, children made accurate ownership attributions independent of individuals' desires. At the same time, there are subtle influences of desires on children's ownership judgments, as well as subtle influences of ownership on children's desire judgments. Thus, the two factors are largely but not wholly distinct in young children's thinking. PMID- 25018587 TI - Ex Situ Integration of Multifunctional Porous Polymer Monoliths into Thermoplastic Microfluidic Chips. AB - A unique method for incorporating functional porous polymer monolith elements into thermoplastic microfluidic chips is described. Monolith elements are formed in a microfabricated mold, rather than within the microchannels, and chemically functionalized off chip before insertion into solvent-softened thermoplastic microchannels during chip assembly. Because monoliths may be trimmed prior to final placement, control of their size, shape, and uniformity is greatly improved over in-situ photopolymerization methods. A characteristic trapezoidal profile facilitates rapid insertion and enables complete mechanical anchoring of the monolith periphery, eliminating the need for chemical attachment to the microchannel walls. Off-chip processing allows the parallel preparation of monoliths of differing compositions and surface chemistries in large batches. Multifunctional flow-through arrays of multiple monolith elements are demonstrated using this approach through the creation of a fluorescent immunosensor with integrated controls, and a microfluidic bubble separator comprising a combination of integrated hydrophobic and hydrophilic monolith elements. PMID- 25018588 TI - Insulin blocks glutamate-induced neurotoxicity in differentiated SH-SY5Y neuronal cells. AB - Insulin is a cytokine which promotes cell growth. Recently, a few published reports on insulin in different cell lines support the antiapoptotic effect of insulin. But the reports fail to explain the role of insulin in modulating glutamate-mediated neuronal cell death through excitotoxicity. Thus, we examined the neuroprotective effect of insulin on glutamate-induced toxicity on differentiated SH-SY5Y neuronal cells. Changes in cell viability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) based assay, while apoptotic damage was detected by acridine orange/ethidium bromide and Hoechst staining. Intracellular reactive oxygen species (ROS) accumulation and morphological alterations were also measured. Treatment with glutamate induced apoptosis, elevated ROS levels and caused damage to neurons. Insulin was able to attenuate the glutamate-induced excitotoxic damage to neuronal cells. PMID- 25018590 TI - The migration response to the Legal Arizona Workers Act. AB - The 2008 Legal Arizona Workers Act (LAWA) requires all public and private employers to authenticate the legal status of their workers using the federal employment verification system known as E-Verify. With LAWA, Arizona became the first state to have a universal mandate for employment verification. While LAWA targets unauthorized workers, most of whom are Latino immigrants, other groups could experience LAWA's effects, such as those who share households with undocumented workers. In addition, employers may seek to minimize their risk of LAWA penalties by not hiring those who appear to them as more likely to be unauthorized, such as naturalized Latino immigrants and US-born Latinos. Existing research has found a reduction in foreign-born Latino employment and population in response to LAWA. This paper asks a different question: have groups that are most likely to be affected by the law migrated to other states? We find a significant and sustained increase in the internal outmigration rate from Arizona of foreign-born, noncitizen Latinos - the group most likely to include the unauthorized - after the passage of LAWA. There was no significant LAWA internal migration response by foreign-born Latino citizens. US-born Latinos showed some signs of a LAWA-induced internal migration response after the law went into effect, but it is not sustained. The results indicate that local and state immigration policy can alter the settlement geography of the foreign born. This leads us to speculate about how immigrant settlement may adjust in the coming years to the intersecting geographies of post-recession economic opportunity and tiered immigration policies. PMID- 25018589 TI - Toddler Inhibitory Control, Bold Response to Novelty, and Positive Affect Predict Externalizing Symptoms in Kindergarten. AB - Poor inhibitory control and bold-approach have been found to predict the development of externalizing behavior problems in young children. Less research has examined how positive affect may influence the development of externalizing behavior in the context of low inhibitory control and high approach. We used a multimethod approach to examine how observed toddler inhibitory control, bold approach, and positive affect predicted externalizing outcomes (observed, adult- and self-reported) in additive and interactive ways at the beginning of kindergarten. 24-month-olds (N = 110) participated in a laboratory visit and 84 were followed up in kindergarten for externalizing behaviors. Overall, children who were low in inhibitory control, high in bold-approach, and low in positive affect at 24-months of age were at greater risk for externalizing behaviors during kindergarten. PMID- 25018591 TI - Vocational Training and Employment Attainment among Substance Abuse Recovering Individuals within a Communal Living Environment. AB - PURPOSE: The present study explored the effects of length of stay in an Oxford House (a sober living environment) with the number of days attended school/vocational training and days worked in the past 90 days with 292 women and 604 men. DESIGN/METHODOLOGY/APPROACH: This paper presents quantitative data. FINDINGS: Results indicated that number of days residing in these recovery homes was related to number of days attending school/vocational training and days worked. ORIGINALITY/VALUE: The present study suggested that in addition to staying abstinent from alcohol and drugs, Oxford House residents may gain useful life skills through vocational education, training, and employment. This is an area of further exploration for the substance abuse recovery community. PMID- 25018592 TI - Alexandrium fundyense cysts in the Gulf of Maine: long-term time series of abundance and distribution, and linkages to past and future blooms. AB - Here we document Alexandrium fundyense cyst abundance and distribution patterns over nine years (1997 and 2004-2011) in the coastal waters of the Gulf of Maine (GOM) and identify linkages between those patterns and several metrics of the severity or magnitude of blooms occurring before and after each autumn cyst survey. We also explore the relative utility of two measures of cyst abundance and demonstrate that GOM cyst counts can be normalized to sediment volume, revealing meaningful patterns equivalent to those determined with dry weight normalization. Cyst concentrations were highly variable spatially. Two distinct seedbeds (defined here as accumulation zones with > 300 cysts cm-3) are evident, one in the Bay of Fundy (BOF) and one in mid-coast Maine. Overall, seedbed locations remained relatively constant through time, but their area varied 3-4 fold, and total cyst abundance more than 10 fold among years. A major expansion of the mid-coast Maine seedbed occurred in 2009 following an unusually intense A. fundyense bloom with visible red-water conditions, but that feature disappeared by late 2010. The regional system thus has only two seedbeds with the bathymetry, sediment characteristics, currents, biology, and environmental conditions necessary to persist for decades or longer. Strong positive correlations were confirmed between the abundance of cysts in both the 0-1 and the 0-3 cm layers of sediments in autumn and geographic measures of the extent of the bloom that occurred the next year (i.e., cysts -> blooms), such as the length of coastline closed due to shellfish toxicity or the southernmost latitude of shellfish closures. In general, these metrics of bloom geographic extent did not correlate with the number of cysts in sediments following the blooms (blooms -> cysts). There are, however, significant positive correlations between 0-3 cm cyst abundances and metrics of the preceding bloom that are indicative of bloom intensity or vegetative cell abundance (e.g., cumulative shellfish toxicity, duration of detectable toxicity in shellfish, and bloom termination date). These data suggest that it may be possible to use cyst abundance to empirically forecast the geographic extent of the forthcoming bloom and, conversely, to use other metrics from bloom and toxicity events to forecast the size of the subsequent cyst population as the inoculum for the next year's bloom. This is an important step towards understanding the excystment/encystment cycle in A. fundyense bloom dynamics while also augmenting our predictive capability for this HAB-forming species in the GOM. PMID- 25018593 TI - Efficacy and feasibility of frontozygomatic angle approach for extra oral maxillary nerve block in oral surgery: a descriptive clinical trial. AB - BACKGROUND: Pain control is an integral part of minor oral surgery and maxillary/mandibular nerve blocks have proved promising in achieving the same. Although intra oral techniques of maxillary nerve block are common and are widely used, there are certain inherent disadvantages and potential complications. Less commonly described in the literature, the extra oral techniques have a wide spectrum of indications as well as can be more advantageous than the intra oral approach. This prospective clinical trial is an attempt to evaluate the feasibility and the efficacy of the extra oral frontozygomatic approach to the foramen rotundum to block the maxillary nerve. MATERIALS AND METHODS: Sample size was 100 patients and the inclusion criteria were patients of ASA I or II category who needed extraction of a minimum of 4 maxillary teeth in the same quadrant in a single sitting while exclusion criteria were patients with a history of allergy to local anesthesia, medically compromised patients in whom dental extraction was contraindicated. Mean age was 71.9 years and 56 patients were males while 44 were females. Only a single quadrant (first or second) was chosen as the operative site in each patient and local anaesthesia was secured using a 21 gauge 89 mm long spinal needle with frontozygomatic angle approach and the parameters used were pain experienced during the injection, onset of subjective symptoms, time required for the peak effect (objective symptoms), pain during extraction and the duration of anesthesia. All the parameters were expressed as mean values with standard deviations. RESULTS: A successful anesthesia was secured in first attempt in 98 patients while in 2 patients, the procedure had to be repeated owing to the difficulty in reaching the target site. A majority of the patients i.e., 71 % scored 0-2 (no pain) on visual analogue scale (VAS) while only 2 patients experienced a moderate degree of pain. Subjective symptoms were reported in 27.24 s (mean value) and 12.93 s (mean value) in the palate and the infraorbital fossa respectively. Peak effect of anesthesia was noted in 66.7, 37.38 and 31.71 s (all values expressed as mean) in palate, infraorbital fossa and posterior superior alveolar areas respectively. CONCLUSION: Although with only dental extraction as the procedure of choice, the present study has favoured the frontozygomatic angle approach for the maxillary nerve block as simple, safe, efficacious and associated with minimum and clinically mild complications. PMID- 25018594 TI - On factors influencing the absorption capacity of surgical sponges. AB - BACKGROUND: Cotton balls and surgical gauzes (CSG) have been routinely used for mopping fluids and blood in surgeries. Polyurethane sheets (PUS) are increasingly used instead of CSG. The factors influencing the absorption of fluids by CSG and PUS have not been studied in detail. There are a variety of factors that could be modified by the manufacturer while a limited number of them could be manipulated by the operator. MATERIALS AND METHODS: Mathematical models and equations have been employed in this study. The impact of absorbency was performed by modulating various factors. RESULTS AND DISCUSSION: A variety of factors such as thickness, density of the web, radius of fiber, temperature, surface tension and viscosity of fluid, all influenced the absorption rate and capacity to varying degrees. The optimal variation by which the PUS can be effectively used is discussed. The suggested mathematical model will help the operator to choose the appropriate type of PUS based on the individual's needs. CONCLUSION: In an area of rapidly developing technology and change in biomaterials, where the choice of such materials are overwhelming, hopefully this basic knowledge will help the clinician to make a more educated and rational decision. PMID- 25018595 TI - Efficacy of Temporomandibular Joint Arthrocentesis on Mouth Opening and Pain in the Treatment of Internal Derangement of TMJ-A Clinical Study. AB - PURPOSE: This study was designed to investigate the efficacy of arthrocentesis on mouth opening and pain in the treatment of temporomandibular joint (TMJ) internal derangement patients. MATERIALS AND METHODS: Fifteen males and 25 females aged between 18 and 37 years comprised the study material in the department of oral and maxillofacial surgery at Govt Dental College Srinagar (India). The patients' complaints were limited mouth opening and TMJ pain. Arthrocentesis was performed under aseptic conditions. Clinical evaluation of the patients was done before the procedure, and 1 week and 4 months post-operatively. Intensity of TMJ pain and maximal mouth opening were recorded at each follow-up visit. RESULTS: There was significant improvement in mouth opening and reduction in pain scores in the post operative period. CONCLUSIONS: Arthrocentesis is a simple and safe procedure for patients of internal derangement with closed lock for improving mouth opening and decreasing pain. PMID- 25018596 TI - Practices and Perceptions of Doctors for Patients on Anti-platelets During Dental Surgery: A National Survey. AB - PURPOSE: Marked variations are noticed in the practices about anti-platelet therapy during dental surgery due to fear of thrombotic events versus bleeding. The main aim of this survey was to study the prevalent practices and perceptions amongst dentists, physicians and cardiologists for stopping anti-platelet agents (APA) in patients undergoing dental extractions. MATERIALS AND METHODS: A questionnaire consisting of 5 questions was distributed to 800 doctors. Questions were related to their perception about increased bleeding complications versus thrombotic risks in cardiac patient on anti-platelet agents undergoing dental surgery. The data was analyzed using Chi-square test and Z-test. RESULTS: Total number of responders was 428 from a total of 800 doctors. It consisted of two groups, group I (325) included physicians and group II (103) included dentists. 82.5 % of dentists believed that bleeding increased if APA are continued whereas 42.77 % of physicians felt the opposite (p = 0.0000035). When asked about stopping APA in patients of stable angina and stroke, both groups had similar answers (63.1 vs. 60.92 %). For patients with medicated stents 70.76 % of physicians were not in favor of stopping APA but 49.51 % dentists believed that it should be stopped (p = 0.0001). However, regarding their attitude towards stopping APA in patients with bare metal stents or post CABG, most of the doctors felt that it should be stopped (48.61 vs. 42.71 %). Discrepancy regarding the number of days for which APA should be withdrawn was found among both the groups. CONCLUSION: Marked variation was found amongst participants in this survey despite international guidelines on APA being used during dental surgery. There is a need for national guidelines to be laid on this issue and dissemination of knowledge among the practicing doctors. PMID- 25018597 TI - Computerized cephalometric study of the pharyngeal airway space in patients submitted to orthognathic surgery. AB - INTRODUCTION: Pharynx is a muscular organ with is sustained by craniofacial bones. It is divided into nasal, oral and hipopharynx, and can be considered as a tube that serves both respiratory and digestive systems. Its anatomical morphology permits that factors facilitate its obstruction, leading to the sleep apnea syndrome. One of the treatment consists of surgical mandibular advancement, increasing pharyngeal dimensions. The aim of this study was evaluate the cephalometric changes in the pharyngeal airway space after orthognathic surgery procedures for correction of mandibular prognathism. MATERIALS AND METHODS: Pre and post-operative cephalometric analysis was performed on 19 patients submitted to mandibular setback by mandibular bilateral sagittal split osteotomy associated with maxillary advancement by Le Fort I osteotomy, using the Dolphin Imaging 10.0 software. RESULTS: Results did not reveal statistically significant changes in the upper (nasopharyngeal), middle (oropharyngeal) and lower (hypopharyngeal) airway spaces, but showed increase in the nasal pharynx due the maxillary advancement and a lower position of the hyoid bone due the mandibular setback. DISCUSSION: Maxillomandibular orthognathic surgery for correction of mandibular prognathism does not seem to statistically significantly change the pharyngeal airway space, but it increases the maxillary airway. CONCLUSION: It seems to be important to consider the double jaw surgery in cases of mandibular prognathism, aiming prevention of a possible reduction of whole upper airway. PMID- 25018598 TI - Retrospective Clinical Study of Marginal Bone Level Changes with Two Different Screw-Implant Types: Comparison Between Tissue Level (TE) and Bone Level (BL) Implant. AB - AIM: The objective of this retrospective cohort study was to compare the amount of marginal bone loss (MBL) in a bone-level and a soft-tissue-level implant system, both of which have similar intra-bony shape and surface composition. A subgroup analysis was done to compare the amount of MBL of each implant type in relation to the different vertical placement within the respective groups of implants. MATERIALS AND METHODS: Records of all patients who underwent implantation for replacement of teeth using comparable bone level (BL) and soft tissue level implants (TE) from 1st January 2006 to 31st December 2009 were scrutinized. Initial depth of implant placement (IDIP) was measured for all implants. Marginal bone loss was measured in patients whose records were available at time point corresponding to 12, 24 and 36 months post insertion. RESULTS: Out of a total of 384 implants, 337 implants were included for study. The mean MBL for the BL implants were 0.3, 0.38, 0.48 and for TE implant were 0.6, 0.54 and 0.93 for time periods 12, 24 and 36 months respectively. Although there was no statistically significant difference between the two groups at time periods at 6-12 months, in later time periods, there was a slightly greater amount of MBL around TE implants as compared to BL implants (p < 0.001). When comparing the IDIP and MBL in the same implant type, there was a statistically significant (p < 0.001) positive correlation between the depth of implant placement and the amount of MBL, with deeper placed implants having more bone loss. CONCLUSION: Within the limitations of this retrospective cohort study design, one can conclude that BL implants had statistically significant lesser MBL as compared to TE in time periods above 12 months. Although the difference is statistically significant, the difference may not be clinically significant. The IDIP had an influence on the amount of MBL, with deeper placed implants and screw structure of the implant placed below the bone, having more MBL in the period of study. PMID- 25018599 TI - Demographic study of prevalence of systemic diseases in oral maxillofacial surgery patients of central India. AB - SUMMARY: An evaluation and consideration of health status of patient prior to any surgical treatment forms an essential part of comprehensive health care. Apparently well but in fact medically compromised patients usually present with unacceptable possibility of complications; whereas adequate pretreatment utilization of many techniques available to diagnose and treat underlying systemic disease significantly decreases morbidity and mortality associated with it. AIMS AND OBJECTIVES: Purpose of this study was to evaluate, prospectively, prevalence of various systemic diseases in oral surgery patients. MATERIALS AND METHODS: For analyzing prevalence of systemic diseases in oral surgery patients, the patients reporting to oral surgery department for various treatments were prospectively evaluated for a period of 6 months and were grouped according to a system involved and findings analyzed to get prevalence in central India. RESULT: Of the 12,487 patients who reported to the department 506 (4.055 %) were medically compromised with a highest prevalence of cardiovascular diseases (35.57 %), and least prevalence of infectious diseases (3.55 %). These results are statistically significant (by Chi-square test) at p < 0.01 (chi(2) = 342.752). CONCLUSION: The aim of study was to evaluate prevalence of systemic disease in oral surgery patients of central India which is 4.055 % with highest population showing involvement of cardiovascular disease and minimum population undergoing oral surgical procedures are compromised by various infectious diseases. PMID- 25018600 TI - Sinus elevation with an alloplastic material and simultaneous implant placement: a 1-stage procedure in severely atrophic maxillae. AB - AIMS AND OBJECTIVE: The aim of the study is to evaluate clinically and radiographically the long term success of one-stage direct (lateral) sinus lift procedure using alloplastic bone graft material and bio-absorbable membrane in conjunction with two stage implant placement in atrophic partially edentulous posterior maxilla. MATERIALS AND METHODS: One stage direct maxillary sinus lift in conjunction with two stage implant placement was carried out in 12 patients at 13 sites. All the patients were partially edentulous with posterior maxillary alveolar ridge height of >5 mm and were in the age group of 20-50 years. Bioactive glass putty, bio-absorbable collagen membrane and 3.75 * 11.5 mm implants were used. Loading of implants was done 6 months after placement of implants. Patients were evaluated clinically and radio-graphically 6, 18, 30 months after placement of implants to assess increase in residual ridge height, peri-implant condition (marginal bone loss, plaque and gingival index) and implant stability. RESULTS: Maxillary first molar was the most common site (69.23 %) for sinus lift and implant placement. Caries was the most common cause (76.92 %) for loss of tooth. Increase in residual ridge height ranged from (71.43 to 133.33 %) as measured by Denta-Scan. Implant survival rate was 100 %. Marginal bone loss ranged from 0.68 to 1.22 mm. Implant stability was measured by periotest (-2.7 to -3.6). Only one patient had perforation of sinus membrane, but it was sealed satisfactorily by bio-absorbable membrane. CONCLUSION: One stage lateral sinus lift procedure with alloplastic bone graft material in combination with 2 stage implant placement has a predictable outcome in patients with severe resorption of posterior maxilla. PMID- 25018601 TI - Matrix metalloproteinase-9 (mmp-9) expression in different subtypes of ameloblastoma. AB - BACKGROUND: Ameloblastoma is a common benign odontogenic tumor of the jaw with a local invasive and highly destructive behavior and can develop in any age, with peak prevalence in 3rd-4th decade. Ameloblastoma can be divided into six histological types: follicular, plexiform, acanthomatous, desmoplastic, granular, and basal cell. Matrix metalloproteinase-9 (MMP-9) (92-kD gelatinase/type IV collagenases = gelatinase B) is involved in bone resorption by degradation of extracellular matrix and osteoclasts recruitment. Recent studies have found that MMP-9 is expressed by ameloblastoma and has a role in ameloblastoma local invasiveness. OBJECTIVE: To analyze MMP-9 expression between different histological types of ameloblastoma. MATERIAL AND METHOD: Forty samples of ameloblastoma were collected through consecutive sampling and the MMP-9 expression was detected using immunohistochemistry. RESULT: All samples showed positive MMP-9 expression with moderate to strong intensity. 82.4 % plexiform type and 83.3 % mixed type have strong immunoexpression, significantly different with follicular type with only 36.4 % (P < 0.05). CONCLUSION: Ameloblastoma plexiform and mixed type have higher MMP-9 expression than ameloblastoma follicular type. Different MMP-9 expression may contribute in different ameloblastoma biological behavior. PMID- 25018602 TI - The Efficacy of ErCr:YSGG Laser Fibrotomy in Management of Moderate Oral Submucous Fibrosis: A Preliminary Study. AB - INTRODUCTION: Oral submucous fibrosis (OSMF) is a chronic insidious disease mainly associated with fibroelastic change of the oral mucous membrane, leading to progressive trismus and oral burning sensation. The management of OSMF is empirical, depends on staging of the condition and is combination of conservative/medical/surgical interventions. Management of moderate OSMF is more challenging as conservative and medical treatments are not effective while surgical techniques involving fibrotomy and reconstruction of resultant defect are excessive. Lasers can provide an alternative and better means for surgical fibrotomy in moderate OSMF as they are minimally invasive and have the advantage of short operating time, less hemorrhage, faster healing, less morbidity, less surgical-site scarring and relapse. Laser fibrotomy in moderate OSMF have been done under general anesthesia. MATERIALS AND METHODS: A case series of 16 cases of moderate OSMF treated with Erbium Chromium Yttrium Scandium Gallium Garnet (ErCr:YSGG) laser fibrotomy under local anesthesia in combination with cessation of habits, topical steroids, lycopene and oral physiotherapy is presented. RESULTS: The mean increase in mouth opening achieved at 1 year was 17.5 mm. The mean difference in the preoperative and 1 year mouth opening was found to be statistically significant. The mean difference in the preoperative and six-month Visual Analogue Scale scores for oral burning sensation and Oral Health Impact Profile-14 scores for assessment of oral health-related quality of life was statistically significant implying improvement. CONCLUSIONS: ErCr:YSGG laser fibrotomy under local anesthesia is a minimally invasive, cost effective, chair side procedure and an useful adjunct in management of moderate OSMF. PMID- 25018603 TI - Peripheral neurectomy: minimally invasive surgical modality for trigeminal neuralgia in Indian population: a retrospective analysis of 20 cases. AB - OBJECTIVE: To evaluate the efficacy of peripheral neurectomy in 20 cases of trigeminal neuralgia as minimally invasive surgical treatment modality. MATERIALS AND METHODS: Twenty (12 males and 8 females) patients with trigeminal neuralgia aged between 35 and 68 years (mean 48 years), who had undergone peripheral neurectomy, were retrospectively analyzed for relief of pain, complications, recurrence of pain, and any additional procedure required to treat recurrence, in a follow-up period of 36 months postoperatively. RESULTS: There was no significant intra-operative and post-operative complications. There was recurrence of pain in two patients (10 %) in 24 and 28 months post-operative follow-up respectively, whereas, rest of the 18 patients were symptom free during 36 months follow-up. CONCLUSION: Peripheral neurectomy is one of the minimally invasive and expeditious forms of surgical modality for the treatment of trigeminal neuralgia. This treatment option is cost effective and provides long term relief from neuralgic pain. PMID- 25018604 TI - A discrete swelling of the upper lip: a diagnostic and clinical stepladder. AB - An upper lip swelling can be attributed to multiple etiologies. The clinical presentation and differential diagnosis of an upper lip swelling is described. Histologic examination revealed the presence of a Schwannoma. This rare entity in the upper lip must be considered by the clinician during the evaluation of an upper lip swelling. PMID- 25018605 TI - Palatal fistulae: a comprehensive classification and difficulty index. AB - INTRODUCTION: Palatal fistula formation is a known complication of palatoplasty. Numerous classifications have been proposed that help in identifying the location of fistula and systematically arrange data for record keeping. They do not assess the difficulty level of the fistula. Management of fistulae can be very tricky and a definitive success cannot be guaranteed even in the best of hands. Hence we devised a classification system and a difficulty index to help evaluate the difficulty level and plan the treatment accordingly to predict the prognosis prior to surgery. MATERIALS AND METHODS: We reviewed 610 cases of palatal fistula operated at our center with a minimum follow-up of 6 months from May 2003 to May 2010. They were classified according to our classification. Difficulty index was also assessed. The data was tabulated and analysed. RESULTS: Longitudinal fistulae showed a recurrence rate of 7.87 % whereas transverse fistulae showed a recurrence rate of 19.66 %. Total recurrence rate was 11.31 %. Unilateral clefts with fistulae showed a recurrence of 6.55 % whereas bilateral clefts with fistulae showed a recurrence of 14.17 %. A total of 220 Grade 1 and 390 Grade 2 fistulae were managed. Out of these, 7 (3.18 %) Grade 1 and 62 (15.90 %) Grade 2 fistulae recurred. 90 % of failed fistulae showed decrease in the size of the fistula. CONCLUSION: Classification and evaluation of difficulty of palatal fistula is essential to plan the surgical treatment so as to give better results. Bidimensional fistulae in the anterior hard palate are associated with higher recurrence rate. Also, fistulae in bilateral clefts are more difficult to close than those in unilateral clefts. Classification of fistulae according to the difficulty index helps in pre-operative judgment of the outcome. PMID- 25018606 TI - Comparison of Stability of Fracture Segments in Mandible Fracture Treated with Different Designs of Mini-Plates Using FEM Analysis. AB - AIM: To compare the displacement gap of mandible fracture segments treated with different designs of mini-plates under various loading conditions. MATERIALS AND METHODS: Fracture in the body of mandible was bridged with 15 different designs and configuration of titanium mini-plates. Bite forces were applied at 3 locations, ipsilateral fractured side, contra lateral side and incisor site. 3D finite element methods (FEM) model of mandible was generated using 10 nodal tetrahedral elements. A commercial FE solver was used to solve bone inter fragmentary displacement during loading. RESULTS: Superior position of mini plates produced better stability than inferior position. Positive bending moments can be reduced by larger plate in lower border in 2 plate system. Results of X mini-plate are comparable to 2 plate configuration. If length of middle portion of plate increased, stability decreased. Number of screws did not affect fracture stability. CONCLUSION: Finite element methods analysis is used to determine the gap between mandible fragments which is otherwise impossible to measure clinically. The results obtained from this study offered us a choice of mini plate design and configuration for clinical application. PMID- 25018607 TI - Excision of Oral Leukoplakia by CO2 Lasers Versus Traditional Scalpel: A Comparative Study. AB - PURPOSE: Laser surgery has shown to exhibit several advantages over scalpel for many procedures. Some of these advantages include hemostasis, decreased scarring, and ability to perform certain procedures without anaesthesia. It has been postulated that laser surgery results in less post-operative pain. However this can be a difficult parameter to measure. This study sought to determine if there was a difference in the intensity and frequency of pain following excision with scalpel when compared to excision done with a CO2 laser. AIMS AND OBJECTIVE: (1) Hemostasis intra operatively and (2) pain, swelling and scarring post operatively. MATERIALS AND METHODS: Thirty patients with bilateral (60 lesions) were selected for the entire proposed research. Group A: carbon dioxide laser excision (experimental group). Group B: scalpel excision (control group). RESULT: (1) Intra operative bleeding is significantly higher in scalpel side compared to laser side treatment. (2) Percentage change (gained) in facial edema is significantly higher in scalpel side compared to laser side treatment. (3) Distribution of level of pain is approximately similar in both the treatments. (4) Distribution of scarring after 1 month post-operative pain is significantly higher in scalpel side compared to laser side treatment. CONCLUSION: Through this study we can infer that CO2 laser supersedes conventional scalpel in terms of better intra-operative and reduced scarring. Post-operative pain and swelling after laser excision did not show any significant difference from that of scalpel. PMID- 25018608 TI - Lipoma of the floor of the mouth: report of an unusually large lesion. AB - Lipomas are among the most common benign tumors affecting the human body. However, they are relatively uncommon in the oral cavity. Oral lipomas are likely to affect cheek, tongue, lips, gingiva and rarely the floor of the mouth. We report a case of huge lipoma of the floor of the mouth, associated with difficulty in speech and mastication in a 72-year-old male. The tumor was completely excised and sent for histopathological examination, which confirmed the tumor to be a simple classical lipoma. PMID- 25018609 TI - Small central odontogenic fibroma mimicking hyperplastic dental follicle and dentigerous cyst. AB - Central odontogenic fibroma has been defined as a benign odontogenic tumor, representing the intraosseous counterpart of a peripheral odontogenic fibroma. The odontogenic fibroma is a rare tumor. Differential diagnosis of radiolucent lesions in the molar-premolar region of mandible which involve impacted tooth may include central odontogenic fibroma, hyperplastic dental follicle, dentigerous cyst, unicystic ameloblastoma, and keratocystic odontogenic tumor. We describe an example of a small central odontogenic fibroma mimicking hyperplastic dental follicle and dentigerous cyst, resulting in uneruption of a primary tooth. PMID- 25018610 TI - Huge ossifying fibroma of the maxilla. AB - Ossifying fibroma of bone is a central neoplasm of bone. It is more common in young adult with marked predilection for mandible. It is more common in females. Lesion is generally asymptomatic until growth produces a noticeable swelling and deformity. It presents an extremely variable roentographic appearance depending upon stage of development. This lesion is composed basically of many delicate interlacing collagen fibres, seldom arranged in discrete bundle, interspersed by large numbers of active, proliferating fibroblasts. The lesion should be excised conservatively. We present a case of huge ossifying fibroma arising from maxilla. PMID- 25018611 TI - Bilateral odontogenic keratocyst of the mandible. AB - Odontogenic keratocyst (OKC) is a cyst of dental origin with an aggressive clinical behavior, having high recurrence rate. Multiple cysts are associated with bifid-rib basal cell nevus syndrome (Gorlin syndrome). We present a case of bilateral odontogenic keratocyst in a cleft lip patient. PMID- 25018612 TI - Oral verrucous hyperplasia: a case report. AB - Oral verrucous hyperplasia is a whitish or pinkinsh elevated pre malignant lesion which occurs rarely. Its is also considered to be an early form of verrucous carcinoma. We have reported a case of verrucous hyperplasia which was diagnosed and treated with buccal fat pad as graft. PMID- 25018613 TI - Modification of MacFee Incision: A Balance Between Cosmesis and Accessibility. AB - Incision design is a critical element of operative planning. Incisions are chosen with the aim of optimizing exposure of relevant neck levels and minimizing morbidity. Various incisions have been proposed over the years but none fulfilled the criterias of ideal incisions. We propose a modification of MacFee s incision which is the balance between cosmesis and exposure. PMID- 25018614 TI - Foreign body granuloma. AB - Foreign bodies can penetrate soft tissues through open wounds, lacerations or through accidents iatrogenically. Among the commonly encountered foreign bodies encountered due to trauma are of glass, metal and wood in nature. We report a case of a 32 year old male who reported to our clinic, complaining of a small wound in the right upper cheek region intraorally since 1 month. Patient had a history of road traffic accident (RTA) 6 months back. PMID- 25018615 TI - Efficacy of the Getting Ready Intervention and the Role of Parental Depression. AB - This study reports the results of a randomized trial of a parent engagement intervention (the Getting Ready Project) on directly observed learning-related social behaviors of children from families of low-income in the context of parent child interactions. The study explored the moderating effect of parental depression on intervention outcomes. Participants were 204 children and their parents, and 29 Head Start teachers. Semi-structured parent-child interaction tasks were videotaped two times annually over the course of two academic years. Observational codes of child behaviors included agency, persistence, activity level, positive affect, distractibility, and verbalizations. Controlling for gender and disability concerns, relative to children in the control group, those in the treatment condition experienced a significant decline in activity level. Furthermore, compared to children of non-depressed mothers and to control children, those in the experimental condition whose parent reported elevated levels of depression showed greater gains in positive affect and in verbalizations. PMID- 25018616 TI - Why Virginity Pledges Succeed or Fail: The Moderating Effect of Religious Commitment Versus Religious Participation. AB - Over the past two decades, virginity pledges have proliferated in the US, despite mixed results regarding their effectiveness. Few studies have examined possible mechanisms that may shed light on why pledges work for some individuals but not others. Using a sample of emerging-adults aged 18-24 years old (n = 1,380),we examine the influence of religiosity on pledge signing and adherence, specifically whether the effectiveness of pledges is moderated by religiosity. Findings show that while religious participation is positively associated with signing a pledge, there is amoderating effect of religious commitment. That is, when religious commitment is high, adherence to the pledge is greater. However, for pledge signers with low religious commitment, there are unintended negative consequences with regard to increased participation in risky sexual behaviors, whether compared to other people who signed the pledge who are equally committed to their religion or to individuals who have never taken such a pledge. Implications for research and policy are discussed. PMID- 25018617 TI - Associations of Sexual Victimization, Depression, and Sexual Assertiveness with Unprotected Sex: A Test of the Multifaceted Model of HIV Risk Across Gender. AB - This study examined whether the Multifaceted Model of HIV Risk (MMOHR) would predict unprotected sex based on predictors including gender, childhood sexual abuse (CSA), sexual victimization (SV), depression, and sexual assertiveness for condom use. A community-based sample of 473 heterosexually active men and women, aged 18-46 years completed survey measures of model variables. Gender predicted several variables significantly. A separate model for women demonstrated excellent fit, while the model for men demonstrated reasonable fit. Multiple sample model testing supported the use of MMOHR in both men and women, while simultaneously highlighting areas of gender difference. Prevention interventions should focus on sexual assertiveness, especially for CSA and SV survivors, as well as targeting depression, especially among men. PMID- 25018618 TI - Orthodontics at a Pivotal Point of Transformation. AB - The profession of orthodontics is projected to face a multitude of challenges. Do cyclic forces accelerate the rate of tooth movement and hence the speed of orthodontic treatment? Would bioengineered cementum and dentine be a solution to root resorption? What would orthodontics be like when bioengineered periodontal ligament and alveolar bone become clinical practice, or one day, entire teeth are bioengineered? Would it be possible to selectively differentiate stem cells into osteoblasts or osteoclasts by either static or cyclic forces? What is the new demand on orthodontic expertise with increasingly automated appliances? What will be the impact of the next generation of dental implants or rapid prototyped crowns on orthodontics? A century ago, Edward Angle's practice of fixed appliances, along with other seminal contributions, such as functional appliances, established the profession of orthodontics. Today, the biophysical principles of orthodontics remain largely unchanged from Angle's era, despite incremental refinements of brackets and wires. The paucity of fundamental innovations in orthodontics for decades presents intrinsic risks for the profession. This review will identify challenges for contemporary orthodontics and delineate strategies for the profession to evolve in an era of unprecedented scientific and technological advances, and serve as a call to action for the orthodontic profession. PMID- 25018619 TI - Aqueous humor erythropoietin levels in open-angle glaucoma patients with and without TTR V30M familial amyloid polyneuropathy. AB - PURPOSE: Glaucoma is the leading cause of irreversible blindness in familial amyloidotic polyneuropathy (FAP) patients. Erythropoietin (EPO) is a cytokine that has been shown to play a role in neuroprotection and is endogenously produced in the eye. EPO levels in the aqueous humor are increased in eyes with glaucoma. In this study, we evaluated the EPO concentration in the aqueous humor of FAP and non-FAP patients, with and without glaucoma. METHODS: Undiluted aqueous humor samples were obtained from 42 eyes that underwent glaucoma surgery, phacoemulsification, or vitrectomy. EPO concentration in the aqueous humor and blood were measured using the Immulite 2000 Xpi using an automatic analyzer (Siemens Healthcare Diagnostics). RESULTS: The mean EPO concentration in the aqueous humor of non-FAP glaucoma eyes group 2 (75.73+/-13.25 mU/ml) was significantly higher than non-FAP cataract eyes (17.22+/-5.33 mU/ml; p<0.001), FAP glaucoma eyes (18.82+/-10.16 mU/ml; p<0.001), and FAP nonglaucoma eyes (20.62+/-6.22 mU/ml; p<0.001). There was no statistically significant difference between FAP nonglaucoma eyes versus non-FAP cataract eyes (p = 0.23) and FAP glaucoma eyes versus FAP nonglaucoma eyes (p = 0.29). In the glaucoma groups, there was no correlation between the aqueous humor EPO concentration and the ocular pressure (p = 0.95) and mean deviation (p = 0.41). There was no correlation between the EPO serum concentration and EPO aqueous humor concentration in our patients (p = 0.77). CONCLUSIONS: Unlike other glaucomatous patients, FAP patients with glaucoma do not show increased and potentially neuroprotective endocular EPO production in the aqueous humor and may need more aggressive glaucoma management. PMID- 25018620 TI - Upregulation of regulator of G-protein signaling 2 in the sclera of a form deprivation myopic animal model. AB - PURPOSE: Scleral remodeling is an important mechanism underlying the development of myopia. Atropine, an antagonist of G protein-coupled muscarinic receptors, is currently used as an off-label treatment for myopia. Regulator of G-protein signaling 2 (RGS2) functions as an intracellular selective inhibitor of muscarinic receptors. In this study we measured scleral RGS2 expression and scleral remodeling in an animal model of myopia in the presence or absence of atropine treatment. METHODS: GUINEA PIGS WERE ASSIGNED TO FOUR GROUPS: normal (free of form deprivation), form deprivation myopia (FDM) for 4 weeks, FDM treated with saline, and FDM treated with atropine. Biometric measurements were then performed. RGS2 expression levels and scleral remodeling, including scleral thickness and collagen type I expression, were compared among the four groups. RESULTS: Compared with normal eyes and contralateral control eyes, the FDM eyes had the most prominent changes in refraction, axial length, and scleral remodeling, indicating myopia. There was no significant difference between control and normal eyes. Hematoxylin and eosin staining showed that the scleral thickness was significantly thinner in the posterior pole region of FDM eyes compared to normal eyes. Real-time PCR and western blot analysis showed a significant decrease in posterior scleral collagen type I mRNA and protein expression in the FDM eyes compared to the normal eyes. The FDM eyes also had increased levels of RGS2 mRNA and protein expression in the sclera. Atropine treatment attenuated the FDM-induced changes in refraction, axial length, and scleral remodeling. Interestingly, atropine treatment significantly increased collagen type I mRNA expression but decreased RGS2 mRNA and protein expression in the sclera of the FDM eyes. CONCLUSIONS: We identified a significant RGS2 upregulation and collagen type I downregulation in the sclera of FDM eyes, which could be partially attenuated by atropine treatment. Our data suggest that targeting dysregulated RGS2 may provide a novel strategy for development of therapeutic agents to suppress myopia progression. PMID- 25018621 TI - Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: novel variants and genotype-phenotype correlations. AB - PURPOSE: This study aimed to investigate the role of CYP1B1 mutations in primary congenital glaucoma (PCG) in Pakistani patients. METHODS: After consent was received, 20 families with at least more than one member affected with primary congenital glaucoma were enrolled in the study. The disease was confirmed with standard ophthalmological investigations. Genomic DNA was extracted from whole blood for localization of linkage and sequencing. Bioinformatics tools were used to assess the predicted pathological role of novel variants. RESULTS: Ten out of 20 families (50%, 10/20) showed homozygosity with CYP1B1-linked short tandem repeat (STR) markers. On direct sequencing of the CYP1B1 gene in the linked families, six mutations, including two novel pathogenic variants, were identified. p. R390H was the most frequently found mutation in five families (50%, 5/10), whereas c.868_869insC, p.E229K, and p.A115P were found once in three families. Two novel mutations, a missense mutation (p.G36D) and an in-frame deletion mutation (p.G67-A70del), were segregated with disease phenotype in two families. Age of disease onset was congenital in all mutations; however, disease severity and response to clinical interventions varied among the mutations and families. Haplotype analysis using five polymorphisms revealed a distinct haplotype for a common mutation. CONCLUSIONS: This is the largest cohort of Pakistani patients with PCG to be genetically screened for CYP1B1 mutations. Identifying common mutation and genotype-phenotype correlations may help in genetic testing and better prognosis for the disease. Novel mutations identified in the study may help in better understanding the pathophysiology of CYP1B1 associated glaucoma. PMID- 25018623 TI - Evaluation and improvement of doctor-patient communication competence for emergency neurosurgeons: a standardized family model. AB - Disease treatments have been significantly influenced by the communications between patients, their families, and doctors the lack of which may lead to malpractice allegations and complaints. In particular, inadequate communication may delay diagnosis and treatment. Therefore, for doctors communication and interpersonal skills, are as important as clinical skills and medical knowledge. In this study we intended to develop two detailed communication content checklists and a modified interpersonal skills inventory, aiming to evaluate their integrity in the midst of communication skills assessments, to provide feedback for some participants, and to observe their communication competence in both aspects. PMID- 25018622 TI - Comparison of effect of gamma ray irradiation on wild-type and N-terminal mutants of alphaA-crystallin. AB - PURPOSE: To study the comparative structural and functional changes between wild type (wt) and N-terminal congenital cataract causing alphaA-crystallin mutants (R12C, R21L, R49C, and R54C) upon exposure to different dosages of gamma rays. METHODS: Alpha A crystallin N-terminal mutants were created with the site directed mutagenesis method. The recombinantly overexpressed and purified wt and mutant proteins were used for further studies. A (60)Co source was used to generate gamma rays to irradiate wild and mutant proteins at dosages of 0.5, 1.0, and 2.0 kGy. The biophysical property of the gamma irradiated (GI) and non-gamma irradiated (NGI) alphaA-crystallin wt and N-terminal mutants were determined. Oligomeric size was determined by size exclusion high-performance liquid chromatography (HPLC), the secondary structure with circular dichroism (CD) spectrometry, conformation of proteins with surface hydrophobicity, and the functional characterization were determined regarding chaperone activity using the alcohol dehydrogenase (ADH) aggregation assay. RESULTS: alphaA-crystallin N terminal mutants formed high molecular weight (HMW) cross-linked products as well as aggregates when exposed to GI compared to the NGI wt counterparts. Furthermore, all mutants exhibited changed beta-sheet and random coil structure. The GI mutants demonstrated decreased surface hydrophobicity when compared to alphaA-crystallin wt at 0, 1.0, and 1.5 kGy; however, at 2.0 kGy a drastic increase in hydrophobicity was observed only in the mutant R54C, not the wt. In contrast, chaperone activity toward ADH was gradually elevated at the minimum level in all GI mutants, and significant elevation was observed in the R12C mutant. CONCLUSIONS: Our findings suggest that the N-terminal mutants of alphaA crystallin are structurally and functionally more sensitive to GI when compared to their NGI counterparts and wt. Protein oxidation as a result of gamma irradiation drives the protein to cross-link and aggregate culminating in cataract formation. PMID- 25018624 TI - A prospective randomized comparison of left and right radial approach for percutaneous coronary angiography in Asian populations. AB - BACKGROUND: The efficacy of coronary angiography may be different in the right radial approach (RRA) and the left radial approach (LRA) due to more common vascular tortuosity in the RRA. The aim of the study was to determine whether LRA is a valid alternative for coronary angiography compared with RRA in Asian populations. METHODS: This is a single-center, prospective, randomized controlled study. A total of 1,400 consecutive patients undergoing diagnostic coronary angiography were recruited and randomized to the RRA (number [n]=700) or LRA (n=700) group. The primary end point was total procedural duration. Secondary end points included fluoroscopy time, dose of radiation including cumulative air kerma and dose area product, contrast volume, and the incidence of vascular complications. RESULTS: Coronary procedural success was achieved in 682 of 700 (97.4%) patients in the RRA and 680 of 700 (97.1%) in the LRA. The total procedural time (RRA 14.1+/-6.3 minutes versus LRA 13.2+/-6.0 minutes; P=0.006) and fluoroscopy time (RRA 3.8+/-3.3 minutes versus LRA 3.4+/-2.8 minutes; P=0.046) were significantly shorter via LRA in comparison to RRA. The percentage of hydrophilic wire use was also lower in the LRA group (14% [RRA] versus 10% [LRA]; P=0.016). The dose of radiation and contrast volume were not different between the two approaches. No cases of major bleeding and vascular complications requiring surgical intervention were reported, other than with one patient who experienced a symptomatic stroke and died in the RRA group compared with none in the LRA group. CONCLUSION: The LRA seems to be a feasible alternative for coronary angiography in Asian patients due to shorter procedural duration and fluoroscopy time, as well as less hydrophilic wire use in comparison to RRA. PMID- 25018625 TI - Sleep disturbance in older ICU patients. AB - Maintaining a stable and adequate sleeping pattern is associated with good health and disease prevention. As a restorative process, sleep is important for supporting immune function and aiding the body in healing and recovery. Aging is associated with characteristic changes to sleep quantity and quality, which make it more difficult to adjust sleep-wake rhythms to changing environmental conditions. Sleep disturbance and abnormal sleep-wake cycles are commonly reported in seriously ill older patients in the intensive care unit (ICU). A combination of intrinsic and extrinsic factors appears to contribute to these disruptions. Little is known regarding the effect that sleep disturbance has on health status in the oldest of old (80+), a group, who with diminishing physiological reserve and increasing prevalence of frailty, is at a greater risk of adverse health outcomes, such as cognitive decline and mortality. Here we review how sleep is altered in the ICU, with particular attention to older patients, especially those aged >=80 years. Further work is required to understand what impact sleep disturbance has on frailty levels and poor outcomes in older critically ill patients. PMID- 25018628 TI - Surveillance of chronic obstructive pulmonary disease in high-risk individuals by using regional lung cancer mass screening. AB - BACKGROUND AND OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) are at risk for lung cancer; the diseases have common etiologies, including cigarette smoking. We aimed to clarify the effectiveness of COPD detection using a regional mass-screening program for lung cancer. MATERIALS AND METHODS: A total of 7,067 residents of Togane, Chiba, Japan received lung cancer screening between May and July, 2011. We defined four groups of possible COPD candidates: group A (n=358), positive smoking history, positive chronic respiratory symptoms; group B (n=766), positive smoking history, positive lifestyle-related disease; group C (n=75), passive smoking history, positive chronic respiratory symptoms; and group D (n=301), passive smoking history, positive lifestyle-related disease. Candidates underwent on-site pulmonary function testing (PFT). RESULTS: The criteria for COPD candidates were fulfilled in 1,686 of 7,067 individuals (23.9%); 1,500 participants underwent PFT (89%), and 171 (11.4%) were diagnosed with COPD. The overall COPD detection rate was 2.4%. The frequency of COPD was significantly higher in groups A and B than in groups C and D (P=0.048); however, the distribution of COPD grades was similar among the groups (P=0.372). Multiple logistic regression analysis identified male sex, age 60 years or greater, and positive smoking history as risk factors for COPD. CONCLUSION: COPD screening using a community-based lung cancer-screening program may be effective for disease detection. Individuals who are 60 years of age or older with a positive smoking history should undergo PFT to detect COPD. PMID- 25018627 TI - Long-term dynamics of death rates of emphysema, asthma, and pneumonia and improving air quality. AB - BACKGROUND: The respiratory tract is a major target of exposure to air pollutants, and respiratory diseases are associated with both short- and long term exposures. We hypothesized that improved air quality in North Carolina was associated with reduced rates of death from respiratory diseases in local populations. MATERIALS AND METHODS: We analyzed the trends of emphysema, asthma, and pneumonia mortality and changes of the levels of ozone, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and particulate matters (PM2.5 and PM10) using monthly data measurements from air-monitoring stations in North Carolina in 1993-2010. The log-linear model was used to evaluate associations between air-pollutant levels and age-adjusted death rates (per 100,000 of population) calculated for 5-year age-groups and for standard 2000 North Carolina population. The studied associations were adjusted by age group-specific smoking prevalence and seasonal fluctuations of disease-specific respiratory deaths. RESULTS: Decline in emphysema deaths was associated with decreasing levels of SO2 and CO in the air, decline in asthma deaths-with lower SO2, CO, and PM10 levels, and decline in pneumonia deaths-with lower levels of SO2. Sensitivity analyses were performed to study potential effects of the change from International Classification of Diseases (ICD)-9 to ICD-10 codes, the effects of air pollutants on mortality during summer and winter, the impact of approach when only the underlying causes of deaths were used, and when mortality and air-quality data were analyzed on the county level. In each case, the results of sensitivity analyses demonstrated stability. The importance of analysis of pneumonia as an underlying cause of death was also highlighted. CONCLUSION: Significant associations were observed between decreasing death rates of emphysema, asthma, and pneumonia and decreases in levels of ambient air pollutants in North Carolina. PMID- 25018629 TI - Roflumilast and dyspnea in patients with moderate to very severe chronic obstructive pulmonary disease: a pooled analysis of four clinical trials. AB - PURPOSE: Breathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit. The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD. PATIENTS AND METHODS: To provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1 year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted. RESULTS: In this pooled analysis (N=5,595), roflumilast significantly improved TDI focal scores versus placebo at week 52 (treatment difference, 0.327; P<0.0001). Roflumilast was associated with significantly greater TDI responders and significantly fewer TDI deteriorators (>=1-unit increase or decrease from baseline, respectively) versus placebo at week 52 (P<0.01, both); these significant differences were apparent by week 8 and maintained until study end (P<0.05, all). At study end, the postbronchodilator forced expiratory volume in 1 second improvement in TDI responders was significantly greater with roflumilast versus placebo (P<0.05). Similar to the overall population, improvements in TDI focal scores at week 52 were small but consistently significant over placebo in patients with chronic bronchitis, regardless of exacerbation history, concomitant treatment with short-acting muscarinic antagonists or long-acting beta2-agonists, or pretreatment with inhaled corticosteroids. CONCLUSION: This analysis shows that patients treated with roflumilast to reduce exacerbation risk may also experience small but significant improvements in dyspnea, with accompanying improvements in lung function. PMID- 25018630 TI - Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood-brain barrier. AB - PURPOSE: The present study examines the use of an external magnetic field in combination with the disruption of tight junctions to enhance the permeability of iron oxide nanoparticles (IONPs) across an in vitro model of the blood-brain barrier (BBB). The feasibility of such an approach, termed magnetic field enhanced convective diffusion (MFECD), along with the effect of IONP surface charge on permeability, was examined. METHODS: The effect of magnetic field on the permeability of positively (aminosilane-coated [AmS]-IONPs) and negatively (N (trimethoxysilylpropyl)ethylenediaminetriacetate [EDT]-IONPs) charged IONPs was evaluated in confluent monolayers of mouse brain endothelial cells under normal and osmotically disrupted conditions. RESULTS: Neither IONP formulation was permeable across an intact cell monolayer. However, when tight junctions were disrupted using D-mannitol, flux of EDT-IONPs across the bEnd.3 monolayers was 28%, increasing to 44% when a magnetic field was present. In contrast, the permeability of AmS-IONPs after osmotic disruption was less than 5%. The cellular uptake profile of both IONPs was not altered by the presence of mannitol. CONCLUSIONS: MFECD improved the permeability of EDT-IONPs through the paracellular route. The MFECD approach favors negatively charged IONPs that have low affinity for the brain endothelial cells and high colloidal stability. This suggests that MFECD may improve IONP-based drug delivery to the brain. PMID- 25018631 TI - Long-term functional improvements in the 2-year treatment of schizophrenia outpatients with olanzapine long-acting injection. AB - BACKGROUND: Little is known about the long-term changes in the functioning of schizophrenia patients receiving maintenance therapy with olanzapine long-acting injection (LAI), and whether observed changes differ from those seen with oral olanzapine. METHODS: This study describes changes in the levels of functioning among outpatients with schizophrenia treated with olanzapine-LAI compared with oral olanzapine over 2 years. This was a secondary analysis of data from a multicenter, randomized, open-label, 2-year study comparing the long-term treatment effectiveness of monthly olanzapine-LAI (405 mg/4 weeks; n=264) with daily oral olanzapine (10 mg/day; n=260). Levels of functioning were assessed with the Heinrichs-Carpenter Quality of Life Scale. Functional status was also classified as "good", "moderate", or "poor", using a previous data-driven approach. Changes in functional levels were assessed with McNemar's test and comparisons between olanzapine-LAI and oral olanzapine employed the Student's t test. RESULTS: Over the 2-year study, the patients treated with olanzapine-LAI improved their level of functioning (per Quality of Life total score) from 64.0 70.8 (P<0.001). Patients on oral olanzapine also increased their level of functioning from 62.1-70.1 (P<0.001). At baseline, 19.2% of the olanzapine-LAI treated patients had a "good" level of functioning, which increased to 27.5% (P<0.05). The figures for oral olanzapine were 14.2% and 24.5%, respectively (P<0.001). Results did not significantly differ between olanzapine-LAI and oral olanzapine. CONCLUSION: In this 2-year, open-label, randomized study of olanzapine-LAI, outpatients with schizophrenia maintained or improved their favorable baseline level of functioning over time. Results did not significantly differ between olanzapine-LAI and oral olanzapine. PMID- 25018632 TI - Association of dopamine D1 receptor gene polymorphism with schizophrenia: a meta analysis. AB - To date, the role of dopamine D1 receptor (DRD1) polymorphism in schizophrenia remains controversial. We carried out a meta-analysis to determine whether DRD1 polymorphism influences the risk of schizophrenia. We examined whether rs4532 and rs5326 genetic variants are related to the etiology of schizophrenia, using a meta-analysis. Relevant case-control studies were retrieved by database searching and selected according to established inclusion criteria. A total of ten studies were identified and included in our meta-analysis, nine for rs4532, with 1,941 cases and 2,480 controls, and four for rs5326, with 1,285 cases and 1,195 controls. No significant association was found between the rs4532 locus and schizophrenia. For the rs5326 locus, the guanine-adenine (GA) genotype was associated with schizophrenia as a risk factor (for GA vs guanine-guanine [GG], odds ratio [OR] =1.36, 95% confidence interval [CI]: 1.15-1.61, P<0.001). The GA genotype of rs5326 increased the risk of schizophrenia, but there was no association between rs4532 and schizophrenia. These data may provide references for case-control studies in schizophrenia in future. PMID- 25018634 TI - The King VisionTM video laryngoscope for awake intubation: series of cases and literature review. AB - Intubation of patients with a supraglottic mass causing obstruction of the glottis remains a difficult problem for the experienced anesthesiologist. Awake fiberscopic endotracheal intubation is the recommended approach in such cases; however, use of a video laryngoscope for awake intubation can be an alternative to a fiberscope. Here we present two cases of awake intubation using a King VisionTM video laryngoscope in patients with a supraglottic mass, and a literature review on use of video laryngoscopes for awake intubation. After topical anesthesia and sedation with opioids, the patients were successfully intubated. PMID- 25018633 TI - Role of the latest endovascular technology in the treatment of intermittent claudication. AB - Intermittent claudication is a serious symptom in patients with peripheral arterial disease, and severely limits activities of daily living. Conservative treatment (optimal medical therapy and exercise rehabilitation programs) and revascularization procedures (endovascular treatment [EVT] or open bypass surgery) can relieve intermittent claudication. Among these treatment options, EVT has developed dramatically during the past decade, and has enabled physicians to offer less invasive treatment options with increasing durability. EVT for aortoiliac lesions has matured, and its long-term patency now approaches that of open bypass surgery. The latest EVT technologies include drug-eluting stents, stent grafts, drug-coated balloons, and bioresorbable stents. The recently reported patency of stent grafts in the femoropopliteal lesions was comparable with that of the prosthetic bypass graft. In the course of the paradigm shift from bypass surgery to EVT, evidence of any long-term benefit of EVT compared with supervised exercise is still inconclusive. EVT could improve walking performance in the short-term, while supervised exercise could improve walking performance more efficiently in the long-term. Combined treatment with EVT and exercise may offer the most sustainable and effective symptom relief. This paper reviews the relevant literature on the treatment of intermittent claudication, focusing on the latest EVT technologies, and outlines a strategy for achieving long-term benefits. PMID- 25018635 TI - The triple line pattern on carotid intima media thickness imaging and its relationship to cardiovascular risk factors in patients on lipid lowering therapy. AB - BACKGROUND: Carotid intima media thickness (CIMT) infrequently identifies a triple line pattern (TLP) in the visualization of the internal elastic lamina. We examined the prevalence and predictors of the TLP among a consecutive series of subjects enrolled in a CIMT clinical trial, and also the effects of lipid lowering therapy. METHODS: Baseline CIMT studies of subjects with known heart disease, or high risk for heart disease, were evaluated from a single site of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis trial (N=120). One sonographer obtained four views of the right and left far wall common CIMT, using a 13 MHz ultrasound probe. Images were blindly reviewed for the presence of the TLP. The TLP was defined as absent (0), possible (1), or definite (2). A composite score from all four views was calculated. A patient was defined as having the TLP if the composite score was >=4. Univariate predictors of the TLP were explored. Follow-up ultrasounds at 14 months were also reviewed for presence of the TLP. RESULTS: The prevalence of the TLP at baseline was 22.5%. Among cardiovascular risk variables, systolic blood pressure was significantly higher in subjects displaying the TLP (141.3+/-15.6 mmHg versus 133.1+/-18.4 mmHg; P=0.036). There were no differences among those with, and without, the TLP, with respect to other cardiovascular risk variables (age, sex, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein, glucose, weight, waist girth, tobacco use, medications, quantitative CIMT), or image quality. During ongoing lipid lowering therapy, the prevalence of the TLP increased to 54.2% (P<0.001). However, it was unrelated to changes in lipid concentrations or cardiovascular risk variables. CONCLUSION: The TLP in CIMT imaging is commonly identifiable using high-frequency ultrasound, and appears to be associated with higher systolic blood pressure. Its prevalence and incidence is unrelated to lipid parameters. PMID- 25018637 TI - Principles to guide sustainable implementation of extended-scope-of-practice physiotherapy workforce redesign initiatives in Australia: stakeholder perspectives, barriers, supports, and incentives. AB - Sustainable implementation of new workforce redesign initiatives requires strategies that minimize barriers and optimize supports. Such strategies could be provided by a set of guiding principles. A broad understanding of the concerns of all the key stakeholder groups is required before effective strategies and initiatives are developed. Many new workforce redesign initiatives are not underpinned by prior planning, and this threatens their uptake and sustainability. This study reports on a cross-sectional qualitative study that sought the perspectives of representatives of key stakeholders in a new workforce redesign initiative (extended-scope-of-practice physiotherapy) in one Australian tertiary hospital. The key stakeholder groups were those that had been involved in some way in the development, management, training, funding, and/or delivery of the initiative. Data were collected using semistructured questions, answered individually by interview or in writing. Responses were themed collaboratively, using descriptive analysis. Key identified themes comprised: the importance of service marketing; proactively addressing barriers; using readily understood nomenclature; demonstrating service quality and safety, monitoring adverse events, measuring health and cost outcomes; legislative issues; registration; promoting viable career pathways; developing, accrediting, and delivering a curriculum supporting physiotherapists to work outside of the usual scope; and progression from "a good idea" to established service. Health care facilities planning to implement new workforce initiatives that extend scope of usual practice should consider these issues before instigating workforce/model of care changes. PMID- 25018636 TI - Defining risks and predicting adverse events after lower extremity bypass for critical limb ischemia. AB - Successful treatment of patients with critical limb ischemia (CLI), hinges on the adequacy of revascularization. However, CLI is associated with a severe burden of systemic atherosclerosis, and patients often suffer from multiple cardiovascular comorbidities. Therefore, CLI patients in general represent a cohort at increased risk for procedural complications and adverse events. Although endovascular therapy represents a minimally invasive alternative to open surgical bypass, the durability of surgical reconstruction is superior, and it remains the "gold standard" approach to revascularization in CLI. Therefore, selection of the optimal treatment modality for individual patients requires careful consideration of the procedural risks and likelihood of adverse events associated with surgery. Individualized decision-making with regard to revascularization strategy requires a comprehensive understanding of the likelihood of adverse outcomes after major surgery. Here we review the risks of surgical bypass in patients with CLI, with particular emphasis on the identification of preoperative variables that predict poor outcome. PMID- 25018638 TI - Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma. AB - Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK positive ALCL. Phase I/II studies will be required for safety and efficacy analysis. PMID- 25018639 TI - Stemness and plasticity of lung cancer cells: paving the road for better therapy. AB - Lung cancer is a devastating disease that is responsible for around 160,000 deaths each year in United States. The discovery that lung cancer, like most other solid tumors, contains a subpopulation of cancer stem cells or cancer stem like cells (CSCs/CS-LCs) that if eliminated could lead to a cure has brought new hope. However, the exact nature of the putative lung CSCs/CS-LCs is not known and therefore therapies to eliminate this subpopulation have been elusive. A limited knowledge and understanding of cancer stem cell properties and tumor biology may be responsible for the limited clinical success. In this review we discuss the stemness and plasticity properties of lung cancer cells that are critical aspects in terms of developing effective therapies. We suggest that the available experimental evidence obtained from lung cancer cell lines and patients' derived primary cultures does not support a tumor model consistent with the classical CSC model. Instead, all lung cancer cells may be extremely versatile and new models of cancer stem cells may be better working models. PMID- 25018640 TI - Clinical analysis of 13 males with primary choriocarcinoma and review of the literature. AB - OBJECTIVE: To analyze the management and prognosis of primary choriocarcinoma (PCC) in male patients. METHODS: The clinical records of males with PCC who were treated at Peking Union Medical College Hospital between 1990 and 2012 were analyzed retrospectively. The literature regarding this clinical condition was also reviewed. RESULTS: The median survival interval of the 13 patients treated at Peking Union Medical College Hospital was 54 months (range, 6-115 months), and the 1- and 3-year survival rates were 53.8% and 43.1%, respectively. All patients were treated with surgery; 12 were treated with combined chemotherapy. After including 100 cases found in the literature, for a total of 113 patients, the median survival interval was 10 months (range, 6.4-13.6 months). The testis was the most common primary site (36.2%). Most patients (70.9%) had metastatic lesions at diagnosis. Univariate and multivariate analyses revealed that longer median overall survival was significantly associated with patient age <34 years old (48 months vs 10 months, odds ratio [OR] =0.47, P=0.029), the presence of other histological components (54 months vs 11 months, OR =0.54, P=0.011), and combined chemotherapy and surgical treatments (14 months vs 2.5 months, OR =0.18, P=0.002). CONCLUSION: PCC is an extremely rare disease among men, and its prognosis is much worse than that of gestational choriocarcinoma. The complete resection of the primary site and metastases followed by chemotherapy seems to provide patients with the best chance at survival. Furthermore, additional chemotherapy cycles might facilitate better progress. PMID- 25018641 TI - Horizontal gene transfer in the human gastrointestinal tract: potential spread of antibiotic resistance genes. AB - Bacterial infections are becoming increasingly difficult to treat due to widespread antibiotic resistance among pathogens. This review aims to give an overview of the major horizontal transfer mechanisms and their evolution and then demonstrate the human lower gastrointestinal tract as an environment in which horizontal gene transfer of resistance determinants occurs. Finally, implications for antibiotic usage and the development of resistant infections and persistence of antibiotic resistance genes in populations as a result of horizontal gene transfer in the large intestine will be discussed. PMID- 25018642 TI - Cost of opioid intravenous patient-controlled analgesia: results from a hospital database analysis and literature assessment. AB - BACKGROUND: Intravenous patient-controlled analgesia (PCA) equipment and opioid cost analyses on specific procedures are lacking. This study estimates the intravenous PCA hospital cost for the first 48 postoperative hours for three inpatient surgeries. METHODS: Descriptive analyses using the Premier database (2010-2012) of more than 500 US hospitals were conducted on cost (direct acquisition and indirect cost for the hospital, such as overhead, labor, pharmacy services) of intravenous PCA after total knee/hip arthroplasty (TKA/THA) or open abdominal surgery. Weighted average cost of equipment and opioid drug and the literature-based cost of adverse events and complications were aggregated for total costs. RESULTS: Of 11,805,513 patients, 272,443 (2.3%), 139,275 (1.2%), and 195,062 (1.7%) had TKA, THA, and abdominal surgery, respectively, with approximately 20% of orthopedic and 29% of abdominal patients having specific intravenous PCA database cost entries. Morphine (57%) and hydromorphone (44%) were the most frequently used PCA drugs, with a mean cost per 30 cc syringe of $16 (30 mg) and $21 (6 mg), respectively. The mean number of syringes used for morphine and hydromorphone in the first 48 hours were 1.9 and 3.2 (TKA), 2.0 and 4.2 (THA), and 2.5 and 3.9 (abdominal surgery), respectively. Average costs of PCA pump, intravenous tubing set, and drug ranged from $46 to $48, from $20 to $22, and from $33 to $46, respectively. Pump, tubing, and saline required to maintain patency of the intravenous PCA catheter over 48 hours ranged from $9 to $13, from $8 to $9, and from $20 to $22, respectively. Supplemental non-PCA opioid use ranged from $56 for THA to $87 for abdominal surgery. Aggregated mean intravenous PCA equipment and opioid cost per patient were $196 (THA), $204 (TKA), and $243 (abdominal surgery). Total costs, including for adverse events, complications, and intravenous PCA errors, ranged from $647 to $694. CONCLUSION: Although there is variation between different types of surgery, the hospital cost of intravenous PCA after major surgery is substantial. Novel technology should demonstrate cost-effectiveness in addition to clinical superiority. PMID- 25018643 TI - Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. AB - Islet transplantation is a well-established therapeutic treatment for a subset of patients with complicated type I diabetes mellitus. Prior to the Edmonton Protocol, only 9% of the 267 islet transplant recipients since 1999 were insulin independent for >1 year. In 2000, the Edmonton group reported the achievement of insulin independence in seven consecutive patients, which in a collaborative team effort propagated expansion of clinical islet transplantation centers worldwide in an effort to ameliorate the consequences of this disease. To date, clinical islet transplantation has established improved success with insulin independence rates up to 5 years post-transplant with minimal complications. In spite of marked clinical success, donor availability and selection, engraftment, and side effects of immunosuppression remain as existing obstacles to be addressed to further improve this therapy. Clinical trials to improve engraftment, the availability of insulin-producing cell sources, as well as alternative transplant sites are currently under investigation to expand treatment. With ongoing experimental and clinical studies, islet transplantation continues to be an exciting and attractive therapy to treat type I diabetes mellitus with the prospect of shifting from a treatment for some to a cure for all. PMID- 25018644 TI - Exenatide extended-release: a once weekly treatment for patients with type 2 diabetes. AB - BACKGROUND: This article reviews the clinical efficacy, safety, and patient outcomes literature on the first once weekly treatment for type 2 diabetes mellitus (T2DM), exenatide extended-release (ER). METHODS: Relevant literature on exenatide ER and T2DM was identified through PubMed database searches from inception until April 2014. RESULTS: Exenatide ER is the first medication for the treatment of T2DM dosed on a weekly schedule. Exenatide ER is a glucagon-like peptide-1 (GLP-1) receptor agonist, the third to be approved in the US, and is associated with a low risk of hypoglycemia, may result in weight loss, and has proven to be a safe and effective treatment for T2DM. Exenatide ER reduces A1c levels by decreasing fasting and postprandial hyperglycemia. The most common adverse events are gastrointestinal in nature, which are lesser in frequency than those observed with short-acting exenatide. Exenatide ER has been shown to be more effective than exenatide twice daily and slightly less efficacious than liraglutide. Exenatide ER is useful as monotherapy and in combination with other oral antidiabetic drugs. CONCLUSION: Once weekly treatment options for diabetes such as exenatide ER have the potential to offer substantial convenience for patients who have high medication burden and poor medication adherence. PMID- 25018646 TI - Do you know where your fillers go? An ultrastructural investigation of the lips. AB - AIM: To investigate the exact location and position of hyaluronic acid fillers in the perioral region by ultrasound and optical coherence tomography. INTRODUCTION: To date, there are few in vivo investigations in humans on the exact positioning of injectable hyaluronic acid fillers, and severe complications such as hematoma and thromboembolism are rarely addressed. MATERIALS AND METHODS: There were nine female patients investigated in this pilot study. All of them were periorally injected with hyaluronic acid. The exact product, amount, and locations, as well as the injection techniques, were recorded and compared. Before, immediately after, and 18 days after injection, photo documentation as well as high resolution ultrasonography and optical coherence tomography of the lip surface were performed. RESULTS: Minor bruising occurred, which resolved within 7 to 9 days. On day 18, no more hemorrhage could be detected. Injected material distributed well in the tissue, and no embolism or thrombosis occurred. However, the injected material came close (up to 1 mm) to important structures such as blood vessels. Lip wrinkles improved, and the lip surface was smoother and more even. CONCLUSION: Hyaluronic acid injections can improve aesthetics and reduce fine wrinkles of the lips. In the patients investigated in this study, compression of structures such as vessels and nerve fibers did not occur, nor did any severe complications result from injection. However, one must be aware of serious complications (eg, hematoma, thromboembolism) and the important anatomic structures (eg, orbicularis oris muscle, vessels, and nerves), and injecting physicians should always have hyaluronidase as a rescue medication at hand. SUMMARY: Hyaluronic acid is a suitable tool for lip augmentation and reduction of fine lines; however, one must be aware of anatomic structures when injecting filler material into the lips and perioral area, and be familiar with the injection techniques. PMID- 25018645 TI - AMPK activation: a therapeutic target for type 2 diabetes? AB - Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance, beta-cell dysfunction, and elevated hepatic glucose output. Over 350 million people worldwide have T2D, and the International Diabetes Federation projects that this number will increase to nearly 600 million by 2035. There is a great need for more effective treatments for maintaining glucose homeostasis and improving insulin sensitivity. AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase whose activation elicits insulin sensitizing effects, making it an ideal therapeutic target for T2D. AMPK is an energy-sensing enzyme that is activated when cellular energy levels are low, and it signals to stimulate glucose uptake in skeletal muscles, fatty acid oxidation in adipose (and other) tissues, and reduces hepatic glucose production. There is substantial evidence suggesting that AMPK is dysregulated in animals and humans with metabolic syndrome or T2D, and that AMPK activation (physiological or pharmacological) can improve insulin sensitivity and metabolic health. Numerous pharmacological agents, natural compounds, and hormones are known to activate AMPK, either directly or indirectly - some of which (for example, metformin and thiazolidinediones) are currently used to treat T2D. This paper will review the regulation of the AMPK pathway and its role in T2D, some of the known AMPK activators and their mechanisms of action, and the potential for future improvements in targeting AMPK for the treatment of T2D. PMID- 25018647 TI - Hereditary leiomyomatosis and renal cell carcinoma. AB - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant hereditary syndrome, which is caused by germline mutations in the FH gene that encodes the tricarboxylic acid cycle enzyme fumarate hydratase (FH). HLRCC patients are predisposed to develop cutaneous leiomyomas, multiple, symptomatic uterine fibroids in young women resulting in early hysterectomies, and early onset renal tumors with a type 2 papillary morphology that can progress and metastasize, even when small. Since HLRCC-associated renal tumors can be more aggressive than renal tumors in other hereditary renal cancer syndromes, caution is warranted, and surgical intervention is recommended rather than active surveillance. At-risk members of an HLRCC family who test positive for the familial germline FH mutation should undergo surveillance by annual magnetic resonance imaging from the age of 8 years. Biochemical studies have shown that FH deficient kidney cancer is characterized by a metabolic shift to aerobic glycolysis. It is hoped that through ongoing clinical trials evaluating targeted molecular therapies, an effective form of treatment for HLRCC-associated kidney cancer will be developed that will offer an improved prognosis for individuals affected with HLRCC-associated kidney cancer. PMID- 25018648 TI - Clinical experience with desvenlafaxine in treatment of pain associated with diabetic peripheral neuropathy. AB - PURPOSE: To assess the safety and efficacy of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine in adults with painful diabetic peripheral neuropathy (DPN). CLINICALTRIALSGOV IDENTIFIERS: NCT00283842, NCT01050218. PATIENTS AND METHODS: This was a 13-week, randomized, double-blind, placebo controlled, fixed-dose study of desvenlafaxine in adults with painful DPN. The primary efficacy endpoint was change from baseline in numeric rating scale (NRS) score. Patients who completed the 13-week trial could continue in a 9-month open label, flexible-dose extension study. RESULTS: A total of 412 patients were randomized to treatment with placebo or desvenlafaxine 50, 100, 200, or 400 mg/day. Of those, 240 patients continued in the extension study. After a planned interim analysis, conducted when the first 225 patients had completed 6 weeks of treatment in the short-term study, randomization to the 50 mg or 400 mg doses was stopped. At week 13, the mean change from baseline in NRS score was significantly greater compared with placebo in the desvenlafaxine 200 mg (difference [95% confidence interval {CI}]: 1.10 [0.50 to 1.70]; P<0.001) and 400 mg groups (0.91 [95% CI: 0.23 to 1.59]; P=0.027); differences from placebo were not statistically significant for the 50 mg (0.58 [95% CI: -0.08 to 1.25]) and 100 mg (0.59 [95% CI: -0.03 to 1.21]) groups. Nausea and dizziness were the most common treatment emergent adverse events reported in the short-term study, and the most common adverse events leading to discontinuation in the short-term study and the extension. Adverse events rates were dose-dependent in the short-term studies. CONCLUSION: Desvenlafaxine was effective in relieving pain associated with DPN at doses of 200 and 400 mg/day, and improved activity impairment at all doses assessed. Desvenlafaxine was generally well-tolerated in the short-term and long term studies. PMID- 25018649 TI - Reduction of painful area as new possible therapeutic target in post-herpetic neuropathic pain treated with 5% lidocaine medicated plaster: a case series. AB - Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient's quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as "a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain". Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a "protective" function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38+/ 140.34 cm(2) to 128.80+/-95.7 cm(2)) and a 66% reduction after 3 months (81.38+/ 59.19 cm(2)). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug-drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials. PMID- 25018650 TI - Liposome bupivacaine for improvement in economic outcomes and opioid burden in GI surgery: IMPROVE Study pooled analysis. AB - Postsurgical pain management remains a significant challenge. Liposome bupivacaine, as part of a multimodal analgesic regimen, has been shown to significantly reduce postsurgical opioid consumption, hospital length of stay (LOS), and hospitalization costs in gastrointestinal (GI) surgery, compared with intravenous (IV) opioid-based patient-controlled analgesia (PCA). Pooled results from open-label studies comparing a liposome bupivacaine-based multimodal analgesic regimen with IV opioid PCA were analyzed. Patients (n=191) who underwent planned surgery and received study drug (IV opioid PCA, n=105; multimodal analgesia, n=86) were included. Liposome bupivacaine-based multimodal analgesia compared with IV opioid PCA significantly reduced mean (standard deviation [SD]) postsurgical opioid consumption (38 [55] mg versus [vs] 96 [85] mg; P<0.0001), postsurgical LOS (median 2.9 vs 4.3 days; P<0.0001), and mean hospitalization costs (US$8,271 vs US$10,726; P=0.0109). The multimodal analgesia group reported significantly fewer patients with opioid-related adverse events (AEs) than the IV opioid PCA group (P=0.0027); there were no significant between group differences in patient satisfaction scores at 30 days. A liposome bupivacaine-based multimodal analgesic regimen was associated with significantly less opioid consumption, opioid-related AEs, and better health economic outcomes compared with an IV opioid PCA-based regimen in patients undergoing GI surgery. STUDY REGISTRATION: This pooled analysis is based on data from Phase IV clinical trials registered on the US National Institutes of Health www.ClinicalTrials.gov database under study identifiers NCT01460485, NCT01507220, NCT01507233, NCT01509638, NCT01509807, NCT01509820, NCT01461122, NCT01461135, NCT01534988, and NCT01507246. PMID- 25018651 TI - Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape. AB - Malignant melanoma is on the rise. There have been recent advances in targeted agents and immunotherapies that have improved the management and treatment of patients with advanced melanoma. This review discusses the clinical efficacy and unique side effects of targeted immunotherapy and the role of predictive biomarkers in better selection of patients who would derive most benefit from specific treatments. Additionally, this review addresses concerns about the best sequencing algorithms for the currently available targeted agents. By thoroughly and extensively researching through PubMed and the American Society of Clinical Oncology, 69 published articles and abstracts were identified as addressing topics related to malignant melanoma and immunotherapy. The research was divided into subcategories discussing cytokine-based therapy, immunotherapy, molecularly targeted agents, other novel targeted agents, and combination regimens for malignant melanoma. New immune checkpoint inhibitors and targeted agents are able to improve immune-mediated regulatory effects against tumors and, specifically in advanced melanoma, are associated with improvement in overall survival. These new agents have distinct side effects that are often controlled and reversed with dose reductions and/or use of corticosteroids. Currently, there are clinical trials underway to assess the role of combination therapy, whereas other trials are focusing on devising algorithms to delineate how best to sequentially administer these drugs. Although there has been tremendous progress in the management of advanced melanoma with immunotherapy and targeted agents, there is still much to be learned about clinically useful predictive biomarkers and combination therapies as well as how to administer these agents safely. PMID- 25018652 TI - New developments in the treatment of metastatic melanoma - role of dabrafenib trametinib combination therapy. AB - Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant melanoma. The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway. Combining selective BRAF and MEK inhibition, such as the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced melanoma while significantly alleviating the paradoxical activation of mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia and gastrointestinal or ocular toxicity. While combined BRAF-MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1 antibodies. Here we review the development of the dabrafenib plus trametinib combination, the characteristics of each drug and the combination, and the role of this combination in the management of patients with BRAF-mutant melanoma. PMID- 25018653 TI - Embolization of uterine fibroids from the point of view of the gynecologist: pros and cons. AB - Uterine artery embolization (UAE) is a minimally invasive procedure with large symptomatic potential in treatment of women with uterine leiomyomas. Due to specificities of this method and possible complications the appropriate indication is crucial. Patient' symptoms, age, plans for pregnancy, and surgical and reproductive history play a major role in decision-making regarding appropriate subjects for UAE. Close cooperation between the gynecologist and the interventional radiologist is necessary. UAE is usually offered as an alternative to surgical treatment. In patients with no fertility plans, it is a less invasive option than abdominal hysterectomy, with a comparable effect on fibroid-related symptoms and quality of life. The need for reintervention is markedly greater in patients after UAE (up to 35% within 5 years) than after hysterectomy. Women with large symptomatic fibroids wishing to retain the uterus and ineligible for minimally invasive (laparoscopic or vaginal) hysterectomy are good candidates for UAE. However, studies comparing UAE with minimally invasive hysterectomy are lacking. Use of UAE in younger women desiring pregnancy is more controversial, mainly because of the significant risk of miscarriage (as high as 64% in some studies) as well as the increased risk of other complications of pregnancy, such as preterm delivery, abnormal placentation, and post-partum hemorrhage. The risk of infertility or subfertility following UAE is unknown. Even poor candidates for myomectomy should be carefully selected for UAE after counseling about all possible adverse effects on fertility. Good prospective studies focused on fertility comparing UAE with no treatment or with myomectomy are needed but would be ethically questionable. This review summarizes the current knowledge regarding the benefits and potential risks of UAE from the point of view of the gynecologist, who should be responsible for proper indication of this treatment. PMID- 25018654 TI - Menstrual suppression: current perspectives. AB - Menstrual suppression to provide relief of menstrual-related symptoms or to manage medical conditions associated with menstrual morbidity or menstrual exacerbation has been used clinically since the development of steroid hormonal therapies. Options range from the extended or continuous use of combined hormonal oral contraceptives, to the use of combined hormonal patches and rings, progestins given in a variety of formulations from intramuscular injection to oral therapies to intrauterine devices, and other agents such as gonadotropin releasing hormone (GnRH) antagonists. The agents used for menstrual suppression have variable rates of success in inducing amenorrhea, but typically have increasing rates of amenorrhea over time. Therapy may be limited by side effects, most commonly irregular, unscheduled bleeding. These therapies can benefit women's quality of life, and by stabilizing the hormonal milieu, potentially improve the course of underlying medical conditions such as diabetes or a seizure disorder. This review addresses situations in which menstrual suppression may be of benefit, and lists options which have been successful in inducing medical amenorrhea. PMID- 25018655 TI - 18F-fluorodeoxyglucose positron emission tomography might be useful for diagnosis of hepatic amyloidosis. AB - We report on a woman with hepatic involvement of primary systemic (immunoglobulin light chain, AL) amyloidosis. Her diagnosis was confirmed by liver biopsy. Clinical symptoms of hepatic amyloidosis are generally mild at its first stage, with most frequent findings being hepatomegaly and alkaline phosphatase elevation. Recent advances in the understanding of the pathophysiology of systemic amyloidosis have made several treatments available. However, its prognosis is occasionally poor. Because liver biopsy is not always safe, other modalities for the diagnosis are needed. Of interest was that fluorodeoxyglucose (FDG) uptake into the liver was observed, compared with that into the spleen, in this patient, indicating that FDG positron emission tomography and computed tomography might be useful for the diagnosis of hepatic amyloidosis with mild liver dysfunction. PMID- 25018656 TI - A case of anxiety associated with miliary tuberculosis. AB - Miliary tuberculosis (TB) is a serious infection with various presentations that can perplex even the most experienced clinicians. To our knowledge, there is a lack of published reports that link psychiatric symptoms directly with miliary TB (either alone or co-occurring with other medical symptoms). Mental health workers may, therefore, not consider, and consequently miss, this important diagnosis. Here we are reporting a case of cyclical anxiety occurring in a 67-year-old patient. For 3 years prior to admission, the patient failed to respond to multiple courses of different antianxiety medications. The patient required hospital admission as he deteriorated and had a reduced level of consciousness. A chest X-ray revealed bilateral nodules and a magnetic resonance imaging scan showed multiple enhancing tuberculous lesions in the cerebral white matter, brain stem, and cerebellum. A diagnosis of miliary TB was finally made. Several characteristics of this case suggest that the diagnosed anxiety disorder was due to miliary TB. However, we cannot exclude the possibility that generalized anxiety disorder preceded the onset of miliary TB or that both diseases were coincidental. The report serves as a reminder that organic causes for psychiatric symptoms always need to be considered, particularly if they follow an atypical pattern or fail to improve with usual psychiatric medications. PMID- 25018657 TI - Investigation of biofilm formation on a charged intravenous catheter relative to that on a similar but uncharged catheter. AB - Catheter-related blood stream infections increase morbidity, mortality, and costs. This study investigated whether Certofix((r)) protect antimicrobial catheters carry a surface charge and whether this inhibits biofilm formation. The capacitance of the catheter surfaces was measured and, to determine if the catheters released ions, distilled water was passed through and current measured as a function of voltage. With probes touching the inner and outer surfaces, capacitance was not voltage-dependent, indicating surfaces were uncharged or carried a similar charge. When one probe penetrated the catheter wall, capacitance was weakly voltage-dependent, indicating the presence of a surface charge. Standard and charged catheters were also exposed to phosphate buffered saline as controls or 2*10(6) colony forming units/mL (in phosphate buffered saline) of six different microorganisms for 60 or 120 minutes. When the growth of detached bacteria was measured, biofilm formation was significantly reduced, (P<0.05), for charged catheters for all organisms. PMID- 25018658 TI - Association between dentures and the rate of falls in dementia. AB - BACKGROUND: Poor oral health, chronic diseases, functional decline, and low cognitive ability can increase the risk of falls in the elderly. OBJECTIVES: The current study aimed to show the effects of oral health, diabetes mellitus (DM), hypertension (HT), heart disease, functional status, and sociodemographic factors on the risk of falls in elderly with dementia. MATERIALS AND METHODS: The sample comprised 1,210 Malaysian elderly who were demented and noninstitutionalized. This study was a national cross-sectional survey entitled "Determinants of Health Status among Older Malaysians". The effects of age, ethnicity, sex differences, marital status, educational level, oral health, DM, HT, heart disease, and functional status on the risk of falls were evaluated. The multiple logistic regression model was used to estimate the effects of contributing variables on the risk of falls in samples. RESULTS: The prevalence of falls was approximately 17% in subjects. It was found that age (odds ratio [OR] 1.02), non-Malay ethnicity (OR 1.66), heart disease (OR 1.92), and functional decline (OR 1.58) significantly increased the risk of falls in respondents (P<0.05). Furthermore, having teeth (OR 0.59) and dentures (OR 0.66) significantly decreased the rate of falls (P<0.05). CONCLUSION: It was concluded that age, non-Malay ethnicity, functional decline, heart disease, and oral health significantly affected falls in dementia. PMID- 25018659 TI - Causes and consequences of sleepiness among college students. AB - Daytime sleepiness, sleep deprivation, and irregular sleep schedules are highly prevalent among college students, as 50% report daytime sleepiness and 70% attain insufficient sleep. The consequences of sleep deprivation and daytime sleepiness are especially problematic to college students and can result in lower grade point averages, increased risk of academic failure, compromised learning, impaired mood, and increased risk of motor vehicle accidents. This article reviews the current prevalence of sleepiness and sleep deprivation among college students, contributing factors for sleep deprivation, and the role of sleep in learning and memory. The impact of sleep and sleep disorders on academics, grade point average, driving, and mood will be examined. Most importantly, effective and viable interventions to decrease sleepiness and sleep deprivation through sleep education classes, online programs, encouragement of naps, and adjustment of class time will be reviewed. This paper highlights that addressing sleep issues, which are not often considered as a risk factor for depression and academic failure, should be encouraged. Promotion of university and college policies and class schedules that encourage healthy and adequate sleep could have a significant impact on the sleep, learning, and health of college students. Future research to investigate effective and feasible interventions, which disseminate both sleep knowledge and encouragement of healthy sleep habits to college students in a time and cost effective manner, is a priority. PMID- 25018660 TI - Establishing a clinical pharmacology fellowship program for physicians, pharmacists, and pharmacologists: a newly accredited interdisciplinary training program at the Ohio State University. AB - Studying the effect of drugs on humans, clinical pharmacologists play an essential role in many academic medical and research teams, within the pharmaceutical industry and as members of government regulatory entities. Clinical pharmacology fellowship training programs should be multidisciplinary and adaptable, and should combine didactics, applied learning, independent study, and one-on-one instruction. This article describes a recently developed 2 year clinical pharmacology fellowship program - one of only nine accredited by the American Board of Clinical Pharmacology - that is an integrative, multi faceted, adaptable method for training physicians, pharmacists, and scientists for leadership roles in the pharmaceutical industry, in academia, or with regulatory or accreditation agencies. The purpose of this article is to provide information for academic clinicians and researchers interested in designing a similar program, for professionals in the field of clinical pharmacology who are already affiliated with a fellowship program and may benefit from supplemental information, and for clinical researchers interested in clinical pharmacology who may not be aware that such training opportunities exist. This article provides the details of a recently accredited program, including design, implementation, accreditation, trainee success, and future directions. PMID- 25018662 TI - Effects of Oral Stimulus Frequency Spectra on the Development of Non-nutritive Suck in Preterm Infants with Respiratory Distress Syndrome or Chronic Lung Disease, and Preterm Infants of Diabetic Mothers. AB - The precocial nature of orofacial sensorimotor control underscores the biological importance of establishing ororythmic activity in human infants. The purpose of this study was to assess the effects of comparable doses of three forms of orosensory experience, including a low-velocity spectrally reduced orocutaneous stimulus (NT1), a high-velocity broad spectrum orocutaneous stimulus (NT2), and a SHAM stimulus consisting of a blind pacifier. Each orosensory experience condition was paired with gavage feedings 3x/day for 10 days in the neonatal intensive care unit (NICU). Four groups of preterm infants (N=214), including those with respiratory distress syndrome (RDS), chronic lung disease (CLD), infants of diabetic mothers (IDM), and healthy controls (HI) were randomized to the type of orosensory condition. Mixed modeling, adjusted for gender, gestational age, postmenstrual age, and birth weight, demonstrated the most significant gains in non-nutritive suck (NNS) development among CLD infants who were treated with the NT2 stimulus, with smaller gains realized among RDS and IDM infants. The broader spectrum of the NT2 stimulus maps closely to known response properties of mechanoreceptors in lip, tongue, and oral mucosa and is more effective in promoting NNS development among preterm infants with impaired oromotor function compared to the low-velocity, spectrally reduced NT1 orosensory stimulus. PMID- 25018661 TI - Carboxylesterases: Dual roles in lipid and pesticide metabolism. AB - Carboxylesterases (CES, EC 3.1.1.1) are members of a superfamily of serine hydrolases that hydrolyze ester, amide, and carbamate bonds. Several different CES genes exist in mammalian species with evidence of multiple gene duplication events occurring throughout evolutionary history. There are five CES genes reported in the Human Genome Organization database, although CES1 and CES2 are the two best characterized human genes. An emerging picture of the CES family suggests that these enzymes have dual roles in the metabolism of xenobiotic and endobiotic compounds. Pesticides, such as the pyrethroids, are important xenobiotic substrates that are metabolized by CES, whereas cholesteryl esters, triacylglycerols, and 2-arachidonoylglycerol are examples of endobiotics known to be substrates for CES. Functional studies using selective chemical inhibitors, siRNA, and gene knockout models are providing valuable insights into the physiological functions of CES, and suggest that CES may be a novel target for the treatment of diseases such as diabetes and atherosclerosis. This review will examine the known physiological functions of CES, the interactions between xenobiotics (primarily pesticides) and lipids that occur with CES enzymes, and where possible the implications that these findings may have in terms of health and disease. PMID- 25018663 TI - Identifying Regions Based on Flexible User Defined Constraints. AB - The identification of regions is both a computational and conceptual challenge. Even with growing computational power, regionalization algorithms must rely on heuristic approaches in order to find solutions. Therefore, the constraints and evaluation criteria that define a region must be translated into an algorithm that can efficiently and effectively navigate the solution space to find the best solution. One limitation of many existing regionalization algorithms is a requirement that the number of regions be selected a priori. The max-p algorithm, introduced in Duque et al. (2012), does not have this requirement, and thus the number of regions is an output of, not an input to, the algorithm. In this paper we extend the max-p algorithm to allow for greater flexibility in the constraints available to define a feasible region, placing the focus squarely on the multidimensional characteristics of region. We also modify technical aspects of the algorithm to provide greater flexibility in its ability to search the solution space. Using synthetic spatial and attribute data we are able to show the algorithm's broad ability to identify regions in maps of varying complexity. We also conduct a large scale computational experiment to identify parameter settings that result in the greatest solution accuracy under various scenarios. The rules of thumb identified from the experiment produce maps that correctly assign areas to their "true" region with 94% average accuracy, with nearly 50 percent of the simulations reaching 100 percent accuracy. PMID- 25018664 TI - Engineered drug-protein nanoparticle complexes for folate receptor targeting. AB - Nanomaterials that are used in therapeutic applications need a high degree of uniformity and functionality which can be difficult to attain. One strategy for fabrication is to utilize the biological precision afforded by recombinant synthesis. Through protein engineering, we have produced ~27-nm dodecahedral protein nanoparticles using the thermostable E2 subunit of pyruvate dehydrogenase as a scaffold and added optical imaging, drug delivery, and tumor targeting capabilities. Cysteines in the internal cavity of the engineered caged protein scaffold (E2 variant D381C) were conjugated with maleimide-bearing Alexa Fluor 532 (AF532) and doxorubicin (DOX). The external surface was functionalized with polyethylene glycol (PEG) alone or with the tumor-targeting ligand folic acid (FA) through a PEG linker. The resulting bi-functional nanoparticles remained intact and correctly assembled. The uptake of FA-displaying nanoparticles (D381C AF532-PEG-FA) by cells overexpressing the folate receptor was approximately six times greater than of non-targeting nanoparticles (D381C-AF532-PEG) and was confirmed to be FA-specific. Nanoparticles containing DOX were all cytotoxic in the low micromolar range. To our knowledge, this work is the first time that acid labile drug release and folate receptor targeting have been simultaneously integrated onto recombinant protein nanoparticles, and it demonstrates the potential of using biofabrication strategies to generate functional nanomaterials. PMID- 25018665 TI - Complex formation of fenchone with alpha-cyclodextrin: NMR titrations. AB - 13C NMR titration studies of inclusion complexes of bicyclic terpenoid, fenchone enantiomers with alpha-cyclodextrin revealed their 1:2 guest-host stoichiometry. Sequential binding constants were determined indicating a strong binding cooperativity of two alpha-cyclodextrin to fenchone. The overall association constants were used to calculate the Gibbs free energies of diastereomeric complex formation, which might be used as a measure of chiral recognition of fenchone by alpha-cyclodextrin. These results were compared with corresponding data derived for camphor, which is an isomeric bicyclic terpenoid. PMID- 25018666 TI - Electrochemical and spectral studies of auto-assembled arrays of calix[4]arenequinhydrone charge-transfer complex on indium-tin oxide (ITO) glass. AB - A sensing materiel based on calix[4]arene molecules is electrochemically deposited on ITO electrode coated. A brown film was electrodeposited at a potential Eimp = -1.00 V versus SCE in acetonitrile solvent, however in dichloromethane solvent, a bluish film auto-assembled on the ITO electrode coated at a potential Eimp = -0.65 V versus SCE. Both films are subsequently analyzed by cyclic voltammetry and UV-Vis spectroscopy. This investigation shows that in acetonitrile solvent, the charge-transfer complex, calix[4]arenequinhydrone was formed in electrolytic solution and it was not self-assembled on the ITO electrode. The related UV-Vis spectrum shows a single absorption band towards a wavelength about 350 nm. The optical behaviour of the blue film shows two absorption bands: the first one appears on the first absorption band of the acceptor at 305 nm and the second one in the visible range at 502 nm. The band situated in the visible range correspond to a well-defined charge-transfer band indicating the presence of the charge-transfer complex, the calix[4]arenequinhydrone. PMID- 25018667 TI - Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis. AB - A single set of conditions consisting of a palladium catalyst, a commercially available ligand, and a base, allow for several types of C-N bond constructions to be conducted in water with the aid of a commercially available "designer" surfactant (TPGS-750-M). Products containing a protected NH2 group in the form of a carbamate, sulfonamide, or urea can be fashioned starting with aryl or heteroaryl bromides, iodides, and in some cases, chlorides, as substrates. Reaction temperatures are in the range of room temperature to, at most, 50 degrees C, and result in essentially full conversion and good isolated yields. PMID- 25018668 TI - Electrical impedance tomography during major open upper abdominal surgery: a pilot-study. AB - BACKGROUND: Electrical impedance tomography (EIT) of the lungs facilitates visualization of ventilation distribution during mechanical ventilation. Its intraoperative use could provide the basis for individual optimization of ventilator settings, especially in patients at risk for ventilation-perfusion mismatch and impaired gas exchange, such as patients undergoing major open upper abdominal surgery. EIT throughout major open upper abdominal surgery could encounter difficulties in belt positioning and signal quality. Thus, we conducted a pilot-study and tested whether EIT is feasible in patients undergoing major open upper abdominal surgery. METHODS: Following institutional review board's approval and written informed consent, we included patients scheduled for major open upper abdominal surgery of at least 3 hours duration. EIT measurements were conducted prior to intubation, at the time of skin incision, then hourly during surgery until shortly prior to extubation and after extubation. Number of successful intraoperative EIT measurements and reasons for failures were documented. From the valid measurements, a functional EIT image of changes in tidal impedance was generated for every time point. Regions of interest were defined as horizontal halves of the picture. Monitoring of ventilation distribution was assessed using the center of ventilation index, and also using the total and dorsal ventilated lung area. All parameter values prior to and post intubation as well as extubation were compared. A p < 0.05 was considered statistically significant. RESULTS: A total of 120 intraoperative EIT measurements during major abdominal surgery lasting 4-13 hours were planned in 14 patients. The electrode belt was attached between the 2(nd) and 4(th) intercostal space. Consecutive valid measurements could be acquired in 13 patients (93%). 111 intraoperative measurements could be retrieved as planned (93%). Main obstacle was the contact of skin electrodes. Despite the high belt position, distribution of tidal volume showed a significant shift of ventilation towards ventral lung regions after intubation. This was reversed after weaning from mechanical ventilation. CONCLUSIONS: Despite a high belt position, monitoring of ventilation distribution is feasible in patients undergoing major open upper abdominal surgery lasting from 4 to 13 hours. Therefore, further interventional trials in order to optimize ventilatory management should be initiated. PMID- 25018670 TI - Racial and Ethnic Disparities in Education-Occupation Mismatch Status Among Immigrants in South Africa and the United States. AB - In this study, a comparative-international approach is used to examine race ethnic disparities in education-occupation mismatch status among immigrants. Using data from the USA and South Africa, this study finds that immigrants are most likely to be undereducated, or have less schooling for their jobs, when their racial characteristics are similar to those of the local racial majority. Black immigrants in South Africa and White immigrants in the USA are the most likely to be undereducated. Having racial characteristics similar to those of the local racial majority is associated with a lower likelihood of overeducation among immigrants. PMID- 25018669 TI - The Lottia gigantea shell matrix proteome: re-analysis including MaxQuant iBAQ quantitation and phosphoproteome analysis. AB - BACKGROUND: Although the importance of proteins of the biomineral organic matrix and their posttranslational modifications for biomineralization is generally recognized, the number of published matrix proteomes is still small. This is mostly due to the lack of comprehensive sequence databases, usually derived from genomic sequencing projects. However, in-depth mass spectrometry-based proteomic analysis, which critically depends on high-quality sequence databases, is a very fast tool to identify candidates for functional biomineral matrix proteins and their posttranslational modifications. Identification of such candidate proteins is facilitated by at least approximate quantitation of the identified proteins, because the most abundant ones may also be the most interesting candidates for further functional analysis. RESULTS: Re-quantification of previously identified Lottia shell matrix proteins using the intensity-based absolute quantification (iBAQ) method as implemented in the MaxQuant identification and quantitation software showed that only 57 of the 382 accepted identifications constituted 98% of the total identified matrix proteome. This group of proteins did not contain obvious intracellular proteins, such as cytoskeletal components or ribosomal proteins, invariably identified as minor components of high-throughput biomineral matrix proteomes. Fourteen of these major proteins were phosphorylated to a variable extent. All together we identified 52 phospho sites in 20 of the 382 accepted proteins with high confidence. CONCLUSIONS: We show that iBAQ quantitation may be a useful tool to narrow down the group of functional biomineral matrix protein candidates for further research in cell biology, genetics or materials research. Knowledge of posttranslational modifications in these major proteins could be a valuable addition to previously published proteomes. This is true especially for phosphorylation, because this modification was already shown to modify mineralization processes in some instances. PMID- 25018671 TI - OTITIS MEDIA VOCABULARY AND GRAMMAR. AB - We propose an automated algorithm for classifying diagnostic categories of otitis media (middle ear inflammation); acute otitis media, otitis media with effusion and no effusion. Acute otitis media represents a bacterial superinfection of the middle ear fluid and otitis media with effusion a sterile effusion that tends to subside spontaneously. Diagnosing children with acute otitis media is hard, leading to overprescription of antibiotics that are beneficial only for children with acute otitis media, prompting a need for an accurate and automated algorithm. To that end, we design a feature set understood by both otoscopists and engineers based on the actual visual cues used by otoscopists; we term this otitis media vocabulary. We also design a process to combine the vocabulary terms based on the decision process used by otoscopists; we term this otitis media grammar. The algorithm achieves 84% classification accuracy, in the range or outperforming clinicians who did not receive special training, as well as state of-the-art classifiers. PMID- 25018672 TI - Theory of Adaptive Optimization for Umbrella Sampling. AB - We present a theory of adaptive optimization for umbrella sampling. With the analytical bias force constant obtained from the constrained thermodynamic length along the reaction coordinate, the windows are distributed to optimize the overlap between neighbors. Combining with the replica exchange method, we propose a method of adaptive window exchange umbrella sampling. The efficiency gain in sampling by the present method originates from the optimal window distribution, in which windows are concentrated to the region where the free energy is steep, as well as consequently improved random walk. PMID- 25018673 TI - Thermodynamics of Water in an Enzyme Active Site: Grid-Based Hydration Analysis of Coagulation Factor Xa. AB - Water molecules in the active site of an enzyme occupy a complex, heterogeneous environment, and the thermodynamic properties of active-site water are functions of position. As a consequence, it is thought that an enzyme inhibitor can gain affinity by extending into a region occupied by unfavorable water or lose affinity by displacing water from a region where it was relatively stable. Recent advances in the characterization of binding-site water, based on the analysis of molecular simulations with explicit water molecules, have focused largely on simplified representations of water as occupying well-defined hydration sites. Our grid-based treatment of hydration, GIST, offers a more complete picture of the complex distributions of water properties, but it has not yet been applied to proteins. This first application of GIST to protein-ligand modeling, for the case of Coagulation Factor Xa, shows that ligand scoring functions based on GIST perform at least as well as scoring functions based on a hydration-site approach (HSA), when applied to exactly the same simulation data. Interestingly, the displacement of energetically unfavorable water emerges as the dominant factor in the fitted scoring functions, for both GIST and HSA methods, while water entropy plays a secondary role, at least in the present context. PMID- 25018674 TI - Hydration Free Energy from Orthogonal Space Random Walk and Polarizable Force Field. AB - The orthogonal space random walk (OSRW) method has shown enhanced sampling efficiency in free energy calculations from previous studies. In this study, the implementation of OSRW in accordance with the polarizable AMOEBA force field in TINKER molecular modeling software package is discussed and subsequently applied to the hydration free energy calculation of 20 small organic molecules, among which 15 are positively charged and five are neutral. The calculated hydration free energies of these molecules are compared with the results obtained from the Bennett acceptance ratio method using the same force field, and overall an excellent agreement is obtained. The convergence and the efficiency of the OSRW are also discussed and compared with BAR. Combining enhanced sampling techniques such as OSRW with polarizable force fields is very promising for achieving both accuracy and efficiency in general free energy calculations. PMID- 25018675 TI - Computational Recipe for Efficient Description of Large-Scale Conformational Changes in Biomolecular Systems. AB - Characterizing large-scale structural transitions in biomolecular systems poses major technical challenges to both experimental and computational approaches. On the computational side, efficient sampling of the configuration space along the transition pathway remains the most daunting challenge. Recognizing this issue, we introduce a knowledge-based computational approach toward describing large scale conformational transitions using (i) nonequilibrium, driven simulations combined with work measurements and (ii) free energy calculations using empirically optimized biasing protocols. The first part is based on designing mechanistically relevant, system-specific reaction coordinates whose usefulness and applicability in inducing the transition of interest are examined using knowledge-based, qualitative assessments along with nonequilirbrium work measurements which provide an empirical framework for optimizing the biasing protocol. The second part employs the optimized biasing protocol resulting from the first part to initiate free energy calculations and characterize the transition quantitatively. Using a biasing protocol fine-tuned to a particular transition not only improves the accuracy of the resulting free energies but also speeds up the convergence. The efficiency of the sampling will be assessed by employing dimensionality reduction techniques to help detect possible flaws and provide potential improvements in the design of the biasing protocol. Structural transition of a membrane transporter will be used as an example to illustrate the workings of the proposed approach. PMID- 25018676 TI - The relevance of the procedures related to the physiotherapy in the interventions in patients with prostate cancer: short review with practice approach. AB - Advances in medical science procedures and their utilization in the field of oncology improved the survival of patients. In consequence, these advances have influenced the practice of physiotherapy. Physiotherapists utilize physical agents with the objective to enhance the health, welfare and quality of life and thus they can play important role in the management and rehabilitation of patients with prostate cancer (PCa). Urinary incontinence (UI) and erectile dysfunction (ED) are effects normally associated with the radical prostatectomy and radiotherapy due to the damage of the muscles of the pelvic floor (MPV). The aim of this work is to present findings related to the PCa and how the physiotherapist can guide the patient in relation to the knowledge and understanding of the anatomic structures related directly with the pelvic floor, the correct breathing and the perception of the MPV, as other muscles of the pelvis. Interventions of the physiotherapy will re-train the muscles of the pelvis by improving the active retention strength of the MPV in order to overcome the insufficiency (mainly the UI and ED) of the injured muscles. In conclusion, it is suggested to consider and to offer to the PCa patients the techniques related to the physiotherapy before and after the treatment. PMID- 25018678 TI - Spinal anaesthesia for caesarean section in pregnant women with fetal distress: time for reappraisal. AB - Residents' competency-based training and multidisciplinary cooperation are needed for rapid sequence spinal anaesthesia for fetal distress. Multiple standard but 'crash' spinal anaesthesia for non-obstetric procedures is imperative for acquisition of experienced hands. The purpose of this review is to share our modest experiences in the use of rapid spinal anaesthesia for emergency Caesarean delivery in pregnant women complicated with fetal distress. Fetal distress diagnosis is made promtly, intravenous line put in place in labour ward. Pre loading or not, one-touch, non-touch spinal technique prevents unnecessary delay and further fetal hypoxic injury. Spinal pack is on stand by in the operating room at all time. Preloading is possible during the waiting period for other care providers otherwise coloading is used. A single wipe of the back with chlorhexidine lotion is frequently used for scrubbing. Lidocaine infiltration or spay is essential and does not waste time but opioid as adjuvant to bupivacaine wastes a lot of time to constitute and measure. So, opioid should be avoided. Average of 2.5 ml of 0.5% hyperbaric bupivacaine is frequently used in our centres. Surgery starts almost immediately after cleaning and drapping of the patient by the obstetrician. Ephedrine is made handy and constituted in case there is hypotension which fluid alone cannot treat. PMID- 25018677 TI - Brain Na(+), K(+)-ATPase Activity In Aging and Disease. AB - Na(+)/K(+) pump or sodium- and potassium-activated adenosine 5'-triphosphatase (Na(+), K(+)-ATPase), its enzymatic version, is a crucial protein responsible for the electrochemical gradient across the cell membranes. It is an ion transporter, which in addition to exchange cations, is the ligand for cardenolides. This enzyme regulates the entry of K(+) with the exit of Na(+) from cells, being the responsible for Na(+)/K(+) equilibrium maintenance through neuronal membranes. This transport system couples the hydrolysis of one molecule of ATP to exchange three sodium ions for two potassium ions, thus maintaining the normal gradient of these cations in animal cells. Oxidative metabolism is very active in brain, where large amounts of chemical energy as ATP molecules are consumed, mostly required for the maintenance of the ionic gradients that underlie resting and action potentials which are involved in nerve impulse propagation, neurotransmitter release and cation homeostasis. Protein phosphorylation is a key process in biological regulation. At nervous system level, protein phosphorylation is the major molecular mechanism through which the function of neural proteins is modulted in response to extracellular signals, including the response to neurotransmitter stimuli. It is the major mechanism of neural plasticity, including memory processing. The phosphorylation of Na(+), K(+) ATPase catalytic subunit inhibits enzyme activity whereas the inhibition of protein kinase C restores the enzyme activity. The dephosphorylation of neuronal Na(+), K(+)-ATPase is mediated by calcineurin, a serine / threonine phosphatase. The latter enzyme is involved in a wide range of cellular responses to Ca(2+) mobilizing signals, in the regulation of neuronal excitability by controlling the activity of ion channels, in the release of neurotransmitters and hormones, as well as in synaptic plasticity and gene transcription. In the present article evidence showing Na(+), K(+)-ATPase involvement in signaling pathways, enzyme changes in diverse neurological diseases as well as during aging, have been summarized. Issues refer mainly to Na(+), K(+)-ATPase studies in ischemia, brain injury, depression and mood disorders, mania, stress, Alzheimer's disease, learning and memory, and neuronal hyperexcitability and epilepsy. PMID- 25018679 TI - Topical "soft candle" applications for infected diabetic foot wounds: a cause for concern? AB - AIMS: There is a cultural barrier to early medical intervention for diabetic foot infections in Trinidad & Tobago, stemming from the strong cultural belief in "soft candle" as effective treatment. We carried out a case-control study to evaluate the outcomes of "soft candle" to treat diabetic foot infections. METHODS: ALL CONSECUTIVE PATIENTS ADMITTED WITH DIABETIC FOOT INFECTIONS WERE INTERVIEWED TO COLLECT DATA ON: demographics, medical history, unhealthy lifestyle markers (exposure to risk factors for chronic diseases), chosen treatment and details of "soft candle" use. The hospital records were accessed on discharge to records the main outcome measures: HbA1c readings, duration of hospitalization, amputation and in-hospital mortality. Two groups were defined: The control group included patients who sought medical attention after detecting a foot infection. The study group included patients who recognized their infection but voluntarily chose to utilize "soft candle" regimens. We excluded patients who voluntarily chose to use other forms of non-traditional treatment or sought no treatment at all. Outcomes were compared using SPSS ver 19. A two tailed P value was calculated for variables of interest in each group using Fisher's exact test. The duration of hospitalization between the groups was compared using paired T-Test. A P value <0.05 was considered statistically significant. RESULTS: There were 442 patients who met inclusion criteria: There were 60 patients in the study group at an average age of 55.2 years (SD +/- 11.4; range 43-88): 63% had HBA1c readings >7.0% at presentation and 95% had unhealthy lifestyle habits. There were 382 patients in the control group at an average age of 59.1 years (SD +/- 12.6, Range 37-89): 74% with HBA1c readings >7.0% at presentation and 48% with unhealthy lifestyle habits. Patients who used "soft candle" had significantly longer duration of hospitalization (15.5 +/- 10.2 vs 9.2 +/- 3.9 days; P<0.001) and major amputations (13.3% vs 5.6%; P=0.048) that was considered clinically significant. There was no difference in minor amputations (31.7% vs 34.3%; P=0.770) or in-hospital mortality (1.7% vs 0.52%; P=0.355) between the groups. CONCLUSION: In its current form, the traditional practice of topical "soft candle" application to diabetic foot wounds may be potentially harmful. Persons with diabetes should be warned about these effects. We have identified the target population for educational campaigns. PMID- 25018680 TI - Association of inflammatory sialoproteins, lipid peroxides and serum magnesium levels with cardiometabolic risk factors in obese children of South Indian population. AB - The Incidence of childhood obesity and metabolic syndrome is increasing even in rural and semi-urban regions of India. Adipose tissue mass secretes several inflammatory proteins, which could potentially alter the metabolic processes, leading to several complications at the later stages of life. With limited studies on protein bound sialic acid (PBSA) as a marker of oxidative stress mediated inflammation in obese children, this study was aimed to assess and correlate PBSA with lipid peroxidation and other cardiometabolic risk factors like Insulin Resistance (IR), serum magnesium, and high sensitive C reactive Protein (hsCRP) levels in order to provide an insight into the degree of systemic inflammation and oxidative stress. This study included 62 obese children (>=95% percentile of the CDC chart) and 60 non obese controls. This study documents significant higher levels of PBSA, IR, Malondialdehyde (MDA), hsCRP and uric acid in obese children (p<0.001). PBSA was associated with IR, hsCRP, uric acid, hypomagnesaemia. Higher degrees of oxidative stress, Insulin resistance and low serum magnesium levels were noted in obese children. PBSA and hsCRP levels were elevated and were associated with Insulin resistance in obese children of South Indian population. PMID- 25018681 TI - A Comparative Study of Serum Uric Acid levels and Lipid Ratios in Coronary Artery Disease Patients. AB - INTRODUCTION: Coronary Artery Disease (CAD) appears to be common in the Indian population of different geographical origins, religions and languages. Measurement of lipid fractions and ratios are widely recommended for risk assessment. A few studies have shown that serum uric acid plays a role in the development of cardiovascular morbidity. Very few reports are cited linking serum uric acid with the lipid fraction in CAD. OBJECTIVES: To find the significance of non-HDL cholesterol, LDL-c/HDL-c ratio, TC/HDL ratio and serum uric acid level in CAD patients. SUBJECTS AND METHODOLOGY: In this study, we included fifty CAD patients as subjects and an equal number of controls. Both subjects and controls were assessed for anthropometric, physiological and biochemical parameters. RESULTS: The present study showed significant increased levels of total cholesterol (p=0.002), TAGs (p<0.001), HDL (p=0.005), LDL (p<0.006) and non-HDL cholesterol (p<0.001). LDL-c/HDL-c ratio (p<0.001) and TC/HDL ratio (p<0.001) in CAD patients (subjects) were also significant when compared to controls. Uric acid level in CAD patients was increased (p<0.001). CONCLUSION: Serum Uric Acid, TC/HDL and LDL/HDL ratios could be regarded as objective markers, in association with existing atherogenic dyslipidemia in patients with CAD. PMID- 25018682 TI - Is cervical inlet patch important clinical problem? AB - AIM: In this study we aim to determine the frequency of Inlet Patch (IP) and its association to clinical symptoms and draw attention to be aware of this heterotopic gastric mucosa. METHODS: This study was a prospective case series that IP was detected in the upper gastrointestinal endoscopy. Patients with laringopharyngeal reflux symptoms underwent endoscopy between March 2009 and July 2012 in two different institutions. All the biopsies were obtained from if there is the IP lesion and antral or/and gastric mucosa. The data was prospectively evaluated. The prevalence was compared with those of patients that did not determine IP in the study period. RESULTS: 3907 upper gastrointestinal system endoscopy was performed while 123 patients consist of 51 male and 72 female was determined as IP. The prevalence of IP in patiens who underwent upper gastrointestinal endoscopy was 3.14% in our study. The majority of symptoms of those who had IP were laringopharyngeal reflux symptoms. Heterotopic gastric mucosa was fixed in 114 cases while 28 chronic inflammation, 9 esophagitis, 5 intestinal metaplasia, 4 glicogenic acanthosis were obtained as additional findings in pathological examinations. CONCLUSION: Heterotopic gastric mucosa in the proximal esophagus is a frequent finding if the endoscopist is aware of this entity. The importance of IP is the increasing number of cases of neoplastic transformation. Symptomatic patients should be treated and should be considered of the complications of heterotopic gastric mucosa. PMID- 25018683 TI - Comparative radiographic assessment of root canal obturation quality: manual verses rotary canal preparation technique. AB - OBJECTIVE: To compare the technical quality of root canal obturation in relation to rotary and manual root canal preparation techniques. STUDY DESIGN: Cross sectional, analytical study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital Karachi from January till December 2011. METHODOLOGY: Data was retrospectively retrieved by periapical radiographs of 60 root canal treated molars for assessment of obturation quality. Data was divided into two groups, 30 radiographs in each group. Group 1 and 2 teeth were prepared with rotary and manual canal preparation technique respectively followed by obturartion with cold lateral condensation technique. Postobturation radiographs were assessed to evaluate technical quality of obturation in term of length, density and taper of root filling. Mann Whitney-U and Chi- square test was applied to compare the difference in technical quality of obturation between two canal preparation techniques. RESULTS: Amongst Thirty molar prepared with rotary instruments, 27 had achieved acceptable length, 25 had adequate density and 27 had achieved adequate taper. Amongst 30 molars prepared manually, 18 had achieved acceptable length, 14 had adequate density and 12 had adequate taper. CONCLUSION: Radiographic technical quality of the obturation (length, density and taper) was better with rotary technique as compared to manual canal preparation technique. PMID- 25018684 TI - Vulval fibroadenoma - a report of two cases with review of literature. AB - Vulval fibroadenoma is rare benign tumours arising from ectopic breast tissue or mammary like anogenital glands tissue. Only a few cases are reported in medical literature. It is usually seen between 20 - 80 years of age. Excision usually has good prognosis and rarely recurs. We present two cases of vulval fibroadenoma, one in a 26 years woman as a well defined soft tissue mass in right labia major and other in a 45 years woman as a pedunculated soft tissue mass in left labia major. PMID- 25018685 TI - Clinical utility of treprostinil in the treatment of pulmonary arterial hypertension: an evidence-based review. AB - Pulmonary arterial hypertension (PAH) remains a progressive disease without a cure, despite the development of several treatment options over the past several decades. Its management strategy consists of the endothelin receptor antagonists (ambrisentan, bosentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), and prostacyclin analogs (epoprostenol, treprostinil, iloprost). Treprostinil, a stable prostacyclin analog, displays vasodilatory effects in the pulmonary vasculature, as well as antiplatelet aggregation properties. Clinical practice guidelines recommend oral endothelin receptor antagonist or phosphodiesterase inhibitor therapy in mild to moderate PAH. Epoprostenol is specifically suggested as first-line therapy in moderate to severe PAH patients (ie, World Health Organization/New York Heart Association functional class III-IV). However, treprostinil may be an alternative option in these severe PAH patients. The longer half-life and stability at room temperature with treprostinil may be associated with lower risk of pulmonary hemodynamic worsening as a result of abrupt infusion discontinuation and less frequent drug preparation. These characteristics make treprostinil an attractive alternative to continuous infusion of epoprostenol, due to convenience and patient safety. The purpose of this review is to evaluate the safety and efficacy of continuous infusion of treprostinil as well as the inhaled and oral routes of administration in PAH. PMID- 25018686 TI - Graphene-Induced Adsorptive and Optical Artifacts During In Vitro Toxicology Assays. PMID- 25018687 TI - A DNA-Device that Mediates Selective Endosomal Escape and Intracellular Delivery of Drugs and Biologicals. AB - Design of materials to aid intracellular delivery of agents can greatly improve medical treatments. While DNA is a molecule difficult to introduce into cells, DNA can be engineered into devices capable of intracellular delivery. Yet, transport mediated by DNA-devices void of other structural material, with size greater than that associated with non-specific penetration, and with targeting capacity enough to overcome non-specific pathways has not been achived. This study demonstrates that this is possible. Submicrometer (200-nm) dendrimers built of DNA (nucleodendrimers (NDs)) are coupled to antibodies against selected cell surface receptors and compared to polymer nanoparticles (NPs). NDs and NPs bind specifically to cells expressing these targets and efficiently enter cells via the pathway associated with the selected receptor. While NPs traffic to perinuclear endo-lysosomes, NDs remain scattered throughout the cell, suggesting endosomal escape. This is confirmed in vitro, where NDs disrupt membranous vesicles at endosomal-like pH and in cell culture, where they: provide endosomal escape of model drugs, sugars, proteins, and nucleic acids; allow access to other intracellular compartments; result in measurable effects of cargoes; and do not cause cytotoxicity. Therefore, these DNA-nanodevices can be used to selectively overcome intracellular barriers, underscoring the growing range of applications of DNA materials. PMID- 25018688 TI - Dietary patterns and changes in body composition in children between 9 and 11 years. AB - OBJECTIVE: Childhood obesity is rising and dietary intake is a potentially modifiable factor that plays an important role in its development. We aim to investigate the association between dietary patterns, obtained through principal components analysis and gains in fat and lean mass in childhood. DESIGN: Diet diaries at 10 years of age collected from children taking part in the Avon Longitudinal Study of Parents and Children. Body composition was assessed using dual-energy X-ray absorptiometry at 9 and 11. SETTING: Longitudinal birth cohort. SUBJECTS: 3911 children with complete data. RESULTS: There was an association between the Health Aware (positive loadings on high-fiber bread, and fruits and vegetables; negative loadings on chips, crisps, processed meat, and soft drinks) pattern score and decreased fat mass gain in girls. After adjusting for confounders, an increase of 1 standard deviation (sd) in this score led to an estimated 1.2% decrease in fat mass gain in valid-reporters and 2.1% in under reporters. A similar decrease was found only in under-reporting boys. There was also an association between the Packed Lunch (high consumption of white bread, sandwich fillings, and snacks) pattern score and decreased fat mass gain (1.1% per sd) in valid-reporting but not under-reporting girls. The main association with lean mass gain was an increase with Packed Lunch pattern score in valid reporting boys only. CONCLUSIONS: There is a small association between dietary patterns and change in fat mass in mid-childhood. Differences between under- and valid-reporters emphasize the need to consider valid-reporters separately in such studies. PMID- 25018689 TI - NG2 cells (polydendrocytes) in brain physiology and repair. AB - NG2 cells, also referred to as oligodendrocyte precursor cells (OPCs) or polydendrocytes, represent a major resident glial cell population that is distinct from mature astrocytes, oligodendrocytes, microglia, and neural stem cells and exist throughout the gray and white matter of the developing and mature central nervous system (CNS). While their most established fate is the oligodendrocyte, they retain lineage plasticity in an age- and region-specific manner. During development, they contribute to 36% of protoplasmic astrocytes in the ventral forebrain. Despite intense investigation on the neuronal fate of NG2 cells, there is no definitive evidence that they contribute substantially to the neuronal population. NG2 cells have attributes that suggest that they have functions other than to generate oligodendrocytes, but their exact role in the neural network remains unknown. Under pathological states, NG2 cells not only contribute to myelin repair, but they become activated in response to a wide variety of insults and could play a primary role in pathogenesis. PMID- 25018690 TI - Whole brain functional connectivity using phase locking measures of resting state magnetoencephalography. AB - The analysis of spontaneous functional connectivity (sFC) reveals the statistical connections between regions of the brain consistent with underlying functional communication networks within the brain. In this work, we describe the implementation of a complete all-to-all network analysis of resting state neuronal activity from magnetoencephalography (MEG). Using graph theory to define networks at the dipole level, we established functionally defined regions by k means clustering cortical surface locations using Eigenvector centrality (EVC) scores from the all-to-all adjacency model. Permutation testing was used to estimate regions with statistically significant connections compared to empty room data, which adjusts for spatial dependencies introduced by the MEG inverse problem. In order to test this model, we performed a series of numerical simulations investigating the effects of the MEG reconstruction on connectivity estimates. We subsequently applied the approach to subject data to investigate the effectiveness of our method in obtaining whole brain networks. Our findings indicated that our model provides statistically robust estimates of functional region networks. Application of our phase locking network methodology to real data produced networks with similar connectivity to previously published findings, specifically, we found connections between contralateral areas of the arcuate fasciculus that have been previously investigated. The use of data-driven methods for neuroscientific investigations provides a new tool for researchers in identifying and characterizing whole brain functional connectivity networks. PMID- 25018691 TI - Brain state-dependent abnormal LFP activity in the auditory cortex of a schizophrenia mouse model. AB - In schizophrenia, evoked 40-Hz auditory steady-state responses (ASSRs) are impaired, which reflects the sensory deficits in this disorder, and baseline spontaneous oscillatory activity also appears to be abnormal. It has been debated whether the evoked ASSR impairments are due to the possible increase in baseline power. GABAergic interneuron-specific NMDA receptor (NMDAR) hypofunction mutant mice mimic some behavioral and pathophysiological aspects of schizophrenia. To determine the presence and extent of sensory deficits in these mutant mice, we recorded spontaneous local field potential (LFP) activity and its click-train evoked ASSRs from primary auditory cortex of awake, head-restrained mice. Baseline spontaneous LFP power in the pre-stimulus period before application of the first click trains was augmented at a wide range of frequencies. However, when repetitive ASSR stimuli were presented every 20 s, averaged spontaneous LFP power amplitudes during the inter-ASSR stimulus intervals in the mutant mice became indistinguishable from the levels of control mice. Nonetheless, the evoked 40-Hz ASSR power and their phase locking to click trains were robustly impaired in the mutants, although the evoked 20-Hz ASSRs were also somewhat diminished. These results suggested that NMDAR hypofunction in cortical GABAergic neurons confers two brain state-dependent LFP abnormalities in the auditory cortex; (1) a broadband increase in spontaneous LFP power in the absence of external inputs, and (2) a robust deficit in the evoked ASSR power and its phase-locking despite of normal baseline LFP power magnitude during the repetitive auditory stimuli. The "paradoxically" high spontaneous LFP activity of the primary auditory cortex in the absence of external stimuli may possibly contribute to the emergence of schizophrenia-related aberrant auditory perception. PMID- 25018693 TI - Novel roles of non-coding brain RNAs in health and disease. PMID- 25018694 TI - Pea3 transcription factor promotes neurite outgrowth. AB - Pea3 subfamily of E-twenty six transcription factors consist of three major exhibit branching morphogenesis, the function of Pea3 family in nervous system development and regeneration is only beginning to unfold. In this study, we provide evidence that Pea3 can directs neurite extension and axonal outgrowth in different model systems, and that Serine 90 is important for this function. We have also identified neurofilament-L and neurofilament-M as two putative novel targets for Pea3. PMID- 25018692 TI - A lifetime of neurogenesis in the olfactory system. AB - Neurogenesis continues well beyond embryonic and early postnatal ages in three areas of the nervous system. The subgranular zone supplies new neurons to the dentate gyrus of the hippocampus. The subventricular zone supplies new interneurons to the olfactory bulb, and the olfactory neuroepithelia generate new excitatory sensory neurons that send their axons to the olfactory bulb. The latter two areas are of particular interest as they contribute new neurons to both ends of a first-level circuit governing olfactory perception. The vomeronasal organ and the main olfactory epithelium comprise the primary peripheral olfactory epithelia. These anatomically distinct areas share common features, as each exhibits extensive neurogenesis well beyond the juvenile phase of development. Here we will discuss the effect of age on the structural and functional significance of neurogenesis in the vomeronasal and olfactory epithelia, from juvenile to advanced adult ages, in several common model systems. We will next discuss how age affects the regenerative capacity of these neural stem cells in response to injury. Finally, we will consider the integration of newborn neurons into an existing circuit as it is modified by the age of the animal. PMID- 25018695 TI - PDE9A is expressed in the inner retina and contributes to the normal shape of the photopic ERG waveform. AB - The ubiquitous second messenger cGMP is synthesized by guanylyl cyclase and hydrolyzed by phosphodiesterase (PDE). cGMP mediates numerous signaling pathways in multiple tissues. In the retina, cGMP regulates signaling in nearly every cell class including photoreceptors, bipolar cells, amacrine cells, and ganglion cells. In order to understand the specific role of cGMP and its regulating enzymes in different cell types, it is first necessary to localize these components and dissect their influence on the circuits. Here we tested the contribution of PDE9A to retinal processing by recording the electroretinograms (ERG) of PDE9A (TM/TM) (KO) mice and by localizing the enzyme. We found that while the scotopic ERG of KO was the same as that of wild type (WT) in both amplitude and kinetics, the photopic ERG was greatly affected. The greatest effect was on the recovery of the b-wave; the falling phase and the b-wave duration were significantly longer in the KO mice for all photopic stimuli (UV, green, or saturating white flashes). The rising phase was slower in KO than in WT for UV and green stimuli. For certain stimuli, amplitudes of both the a- and b waves were smaller than in WT. Using Lac-Z expression in KO retinas as a reporter for PDE9A expression pattern, we found that PDE9A is localized to GABA-positive and GABA-negative amacrine cells, and likely also to certain types of ganglion cells. Our results indicate that PDE9A, by controlling the level of cGMP, modulates inhibitory processes within the cone pathway. We speculate that these circuits involve NO/cGMP signaling pathways. PMID- 25018696 TI - Protein degradation and protein synthesis in long-term memory formation. AB - Long-term memory (LTM) formation requires transient changes in the activity of intracellular signaling cascades that are thought to regulate new gene transcription and de novo protein synthesis in the brain. Consistent with this, protein synthesis inhibitors impair LTM for a variety of behavioral tasks when infused into the brain around the time of training or following memory retrieval, suggesting that protein synthesis is a critical step in LTM storage in the brain. However, evidence suggests that protein degradation mediated by the ubiquitin proteasome system (UPS) may also be a critical regulator of LTM formation and stability following retrieval. This requirement for increased protein degradation has been shown in the same brain regions in which protein synthesis is required for LTM storage. Additionally, increases in the phosphorylation of proteins involved in translational control parallel increases in protein polyubiquitination and the increased demand for protein degradation is regulated by intracellular signaling molecules thought to regulate protein synthesis during LTM formation. In some cases inhibiting proteasome activity can rescue memory impairments that result from pharmacological blockade of protein synthesis, suggesting that protein degradation may control the requirement for protein synthesis during the memory storage process. Results such as these suggest that protein degradation and synthesis are both critical for LTM formation and may interact to properly "consolidate" and store memories in the brain. Here, we review the evidence implicating protein synthesis and degradation in LTM storage and highlight the areas of overlap between these two opposing processes. We also discuss evidence suggesting these two processes may interact to properly form and store memories. LTM storage likely requires a coordinated regulation between protein degradation and synthesis at multiple sites in the mammalian brain. PMID- 25018698 TI - CIIA prevents SOD1(G93A)-induced cytotoxicity by blocking ASK1-mediated signaling. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with higher selectivity in degeneration of motor neurons. However, the molecular mechanism by which the ALS-linked mutants of human superoxide dismutase 1 (SOD1) gene induce neurotoxicity remains obscure yet. Here, we show that depletion of CIIA expression by RNA interference (RNAi) promoted cytotoxicity caused by ALS linked G93A mutant of the SOD1 gene. The RNAi-mediated knockdown of CIIA also enhanced the SOD1(G93A)-induced interaction between ASK1 and TRAF2 as well as ASK1 activity. Furthermore, endogenous silencing of CIIA by RNAi augmented the effects of SOD1(G93A) on reduction of mitochondria membrane potential (Deltapsim), release of cytochrome c into the cytoplasm, and caspase activation. Together, our results suggest that CIIA negatively modulates ASK1-mediated cytotoxic signaling processes in a SOD1(G93A)-expressing cellular model of ALS. PMID- 25018697 TI - Exocytosis of serotonin from the neuronal soma is sustained by a serotonin and calcium-dependent feedback loop. AB - The soma of many neurons releases large amounts of transmitter molecules through an exocytosis process that continues for hundreds of seconds after the end of the triggering stimulus. Transmitters released in this way modulate the activity of neurons, glia and blood vessels over vast volumes of the nervous system. Here we studied how somatic exocytosis is maintained for such long periods in the absence of electrical stimulation and transmembrane Ca(2+) entry. Somatic exocytosis of serotonin from dense core vesicles could be triggered by a train of 10 action potentials at 20 Hz in Retzius neurons of the leech. However, the same number of action potentials produced at 1 Hz failed to evoke any exocytosis. The 20-Hz train evoked exocytosis through a sequence of intracellular Ca(2+) transients, with each transient having a different origin, timing and intracellular distribution. Upon electrical stimulation, transmembrane Ca(2+) entry through L type channels activated Ca(2+)-induced Ca(2+) release. A resulting fast Ca(2+) transient evoked an early exocytosis of serotonin from sparse vesicles resting close to the plasma membrane. This Ca(2+) transient also triggered the transport of distant clusters of vesicles toward the plasma membrane. Upon exocytosis, the released serotonin activated autoreceptors coupled to phospholipase C, which in turn produced an intracellular Ca(2+) increase in the submembrane shell. This localized Ca(2+) increase evoked new exocytosis as the vesicles in the clusters arrived gradually at the plasma membrane. In this way, the extracellular serotonin elevated the intracellular Ca(2+) and this Ca(2+) evoked more exocytosis. The resulting positive feedback loop maintained exocytosis for the following hundreds of seconds until the last vesicles in the clusters fused. Since somatic exocytosis displays similar kinetics in neurons releasing different types of transmitters, the data presented here contributes to understand the cellular basis of paracrine neurotransmission. PMID- 25018699 TI - The self-regulation of neurotransmitter release. PMID- 25018701 TI - Imaging ATUM ultrathin section libraries with WaferMapper: a multi-scale approach to EM reconstruction of neural circuits. AB - The automated tape-collecting ultramicrotome (ATUM) makes it possible to collect large numbers of ultrathin sections quickly-the equivalent of a petabyte of high resolution images each day. However, even high throughput image acquisition strategies generate images far more slowly (at present ~1 terabyte per day). We therefore developed WaferMapper, a software package that takes a multi-resolution approach to mapping and imaging select regions within a library of ultrathin sections. This automated method selects and directs imaging of corresponding regions within each section of an ultrathin section library (UTSL) that may contain many thousands of sections. Using WaferMapper, it is possible to map thousands of tissue sections at low resolution and target multiple points of interest for high resolution imaging based on anatomical landmarks. The program can also be used to expand previously imaged regions, acquire data under different imaging conditions, or re-image after additional tissue treatments. PMID- 25018700 TI - Abundance of gap junctions at glutamatergic mixed synapses in adult Mosquitofish spinal cord neurons. AB - "Dye-coupling", whole-mount immunohistochemistry for gap junction channel protein connexin 35 (Cx35), and freeze-fracture replica immunogold labeling (FRIL) reveal an abundance of electrical synapses/gap junctions at glutamatergic mixed synapses in the 14th spinal segment that innervates the adult male gonopodium of Western Mosquitofish, Gambusia affinis (Mosquitofish). To study gap junctions' role in fast motor behavior, we used a minimally-invasive neural-tract-tracing technique to introduce gap junction-permeant or -impermeant dyes into deep muscles controlling the gonopodium of the adult male Mosquitofish, a teleost fish that rapidly transfers (complete in <20 mS) spermatozeugmata into the female reproductive tract. Dye-coupling in the 14th spinal segment controlling the gonopodium reveals coupling between motor neurons and a commissural primary ascending interneuron (CoPA IN) and shows that the 14th segment has an extensive and elaborate dendritic arbor and more gap junctions than do other segments. Whole-mount immunohistochemistry for Cx35 results confirm dye-coupling and show it occurs via gap junctions. Finally, FRIL shows that gap junctions are at mixed synapses and reveals that >50 of the 62 gap junctions at mixed synapses are in the 14th spinal segment. Our results support and extend studies showing gap junctions at mixed synapses in spinal cord segments involved in control of genital reflexes in rodents, and they suggest a link between mixed synapses and fast motor behavior. The findings provide a basis for studies of specific roles of spinal neurons in the generation/regulation of sex-specific behavior and for studies of gap junctions' role in regulating fast motor behavior. Finally, the CoPA IN provides a novel candidate neuron for future studies of gap junctions and neural control of fast motor behaviors. PMID- 25018703 TI - Localization of the cannabinoid CB1 receptor and the 2-AG synthesizing (DAGLalpha) and degrading (MAGL, FAAH) enzymes in cells expressing the Ca(2+) binding proteins calbindin, calretinin, and parvalbumin in the adult rat hippocampus. AB - The retrograde suppression of the synaptic transmission by the endocannabinoid sn 2-arachidonoylglycerol (2-AG) is mediated by the cannabinoid CB1 receptors and requires the elevation of intracellular Ca(2+) and the activation of specific 2 AG synthesizing (i.e., DAGLalpha) enzymes. However, the anatomical organization of the neuronal substrates that express 2-AG/CB1 signaling system-related molecules associated with selective Ca(2+)-binding proteins (CaBPs) is still unknown. For this purpose, we used double-label immunofluorescence and confocal laser scanning microscopy for the characterization of the expression of the 2 AG/CB1 signaling system (CB1 receptor, DAGLalpha, MAGL, and FAAH) and the CaBPs calbindin D28k, calretinin, and parvalbumin in the rat hippocampus. CB1, DAGLalpha, and MAGL labeling was mainly localized in fibers and neuropil, which were differentially organized depending on the hippocampal CaBPs-expressing cells. CB(+) 1 fiber terminals localized in all hippocampal principal cell layers were tightly attached to calbindin(+) cells (granular and pyramidal neurons), and calretinin(+) and parvalbumin(+) interneurons. DAGLalpha neuropil labeling was selectively found surrounding calbindin(+) principal cells in the dentate gyrus and CA1, and in the calretinin(+) and parvalbumin(+) interneurons in the pyramidal cell layers of the CA1/3 fields. MAGL(+) terminals were only observed around CA1 calbindin(+) pyramidal cells, CA1/3 calretinin(+) interneurons and CA3 parvalbumin(+) interneurons localized in the pyramidal cell layers. Interestingly, calbindin(+) pyramidal cells expressed FAAH specifically in the CA1 field. The identification of anatomically related-neuronal substrates that expressed 2-AG/CB1 signaling system and selective CaBPs should be considered when analyzing the cannabinoid signaling associated with hippocampal functions. PMID- 25018702 TI - Spatio-temporal extension in site of origin for cortical calretinin neurons in primates. AB - The vast majority of cortical GABAergic neurons can be defined by parvalbumin, somatostatin or calretinin expression. In most mammalians, parvalbumin and somatostatin interneurons have constant proportions, each representing 5-7% of the total neuron number. In contrast, there is a threefold increase in the proportion of calretinin interneurons, which do not exceed 4% in rodents and reach 12% in higher order areas of primate cerebral cortex. In rodents, almost all parvalbumin and somatostatin interneurons originate from the medial part of the subpallial proliferative structure, the ganglionic eminence (GE), while almost all calretinin interneurons originate from its caudal part. The spatial pattern of cortical GABAergic neurons origin from the GE is preserved in the monkey and human brain. However, it could be expected that the evolution is changing developmental rules to enable considerable expansion of calretinin interneuron population. During the early fetal period in primates, cortical GABAergic neurons are almost entirely generated in the subpallium, as in rodents. Already at that time, the primate caudal ganglionic eminence (CGE) shows a relative increase in size and production of calretinin interneurons. During the second trimester of gestation, that is the main neurogenetic stage in primates without clear correlates found in rodents, the pallial production of cortical GABAergic neurons together with the extended persistence of the GE is observed. We propose that the CGE could be the main source of calretinin interneurons for the posterior and lateral cortical regions, but not for the frontal cortex. The associative granular frontal cortex represents around one third of the cortical surface and contains almost half of cortical calretinin interneurons. The majority of calretinin interneurons destined for the frontal cortex could be generated in the pallium, especially in the newly evolved outer subventricular zone that becomes the main pool of cortical progenitors. PMID- 25018704 TI - Preserving subject variability in group fMRI analysis: performance evaluation of GICA vs. IVA. AB - Independent component analysis (ICA) is a widely applied technique to derive functionally connected brain networks from fMRI data. Group ICA (GICA) and Independent Vector Analysis (IVA) are extensions of ICA that enable users to perform group fMRI analyses; however a full comparison of the performance limits of GICA and IVA has not been investigated. Recent interest in resting state fMRI data with potentially higher degree of subject variability makes the evaluation of the above techniques important. In this paper we compare component estimation accuracies of GICA and an improved version of IVA using simulated fMRI datasets. We systematically change the degree of inter-subject spatial variability of components and evaluate estimation accuracy over all spatial maps (SMs) and time courses (TCs) of the decomposition. Our results indicate the following: (1) at low levels of SM variability or when just one SM is varied, both GICA and IVA perform well, (2) at higher levels of SM variability or when more than one SMs are varied, IVA continues to perform well but GICA yields SM estimates that are composites of other SMs with errors in TCs, (3) both GICA and IVA remove spatial correlations of overlapping SMs and introduce artificial correlations in their TCs, (4) if number of SMs is over estimated, IVA continues to perform well but GICA introduces artifacts in the varying and extra SMs with artificial correlations in the TCs of extra components, and (5) in the absence or presence of SMs unique to one subject, GICA produces errors in TCs and IVA estimates are accurate. In summary, our simulation experiments (both simplistic and realistic) and our holistic analyses approach indicate that IVA produces results that are closer to ground truth and thereby better preserves subject variability. The improved version of IVA is now packaged into the GIFT toolbox (http://mialab.mrn.org/software/gift). PMID- 25018705 TI - Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice. AB - Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (Mecp2) cause most cases of Rett syndrome (RTT). Currently there is no cure for RTT. Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep dysfunction, the cause of which is not well understood. Mice deficient in MeCP2 protein have been studied and characterized for their neuropathological and behavioral deficits to better understand RTT. With the goal to study the non ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2(tm1.1Bird/y)), and determine novel EEG biomarkers of their reported progressive neurodegeneration, we used 24 h video-EEG/EMG with synchronous in-vivo cortical glutamate biosensor in the frontal cortex. We scored the EEG for activity states and spectral analysis was performed to evaluate correlations to the synchronous extracellular glutamate fluctuations underlying Mecp2 inactivation as compared to WT. Significant alterations in sleep structure due to dark cycle-specific long wake states and poor quality of slow-wave sleep were associated with a significant increase in glutamate loads per activity cycle. The dynamics of the activity state-dependent physiological rise and fall of glutamate indicative of glutamate homeostasis were significantly altered in the KO mice. Colorimetric quantitation of absolute glutamate levels in frontal cortex also indicated the presence of significantly higher levels in KO. This study for the first time found evidence of uncompensated sleep deprivation-like EEG biomarkers that were associated with glutamate homeostatic dysfunction in the Mecp2 KO mice. PMID- 25018707 TI - BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice. AB - The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14/10 h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence of time-of-day on electrical seizure threshold in mice and suggest that this effect is under the control of genes that are known to regulate circadian behaviors. Furthermore, low seizure thresholds in BMAL1 KO mice suggest that BMAL1 itself is directly involved in controlling neuronal excitability. PMID- 25018709 TI - Is neural hyperpolarization by cathodal stimulation always detrimental at the behavioral level? AB - Cathodal transcranial direct current stimulation (c-tDCS) is usually considered an inhibitory stimulation. From a physiological perspective, c-tDCS induces hyperpolarization at the neural level. However, from a behavioral perspective, c tDCS application does not always result in performance deterioration. In this work, we investigated the role of several important stimulation parameters (i.e., timing, presence of pauses, duration, and intensity) in shaping the behavioral effects of c-tDCS over the primary visual cortex. In Experiment 1, we applied c tDCS at two different times (before or during an orientation discrimination task). We also studied the effects of pauses during the stimulation. In Experiments 2 and 3, we compared different durations (9 vs. 22 min) and intensities (0.75 vs. 1.5 mA) of stimulation. c-tDCS applied before task execution induced an improvement of performance, highlighting the importance of the activation state of the cortex. However, this result depended on the duration and intensity of stimulation. We suggest that the application of c-tDCS induces depression of cortical activity over a specific stimulated area; but to keep reactivity within given limits, the brain react in order to restore the equilibrium and this might result in increased sensitivity in visual performance. This is a further example of how the nervous system dynamically maintains a condition that permits adequate performance in different environments. PMID- 25018708 TI - Mechanisms underlying the antidepressant response and treatment resistance. AB - Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance. PMID- 25018706 TI - Hypothesis-driven methods to augment human cognition by optimizing cortical oscillations. AB - Cortical oscillations have been shown to represent fundamental functions of a working brain, e.g., communication, stimulus binding, error monitoring, and inhibition, and are directly linked to behavior. Recent studies intervening with these oscillations have demonstrated effective modulation of both the oscillations and behavior. In this review, we collect evidence in favor of how hypothesis-driven methods can be used to augment cognition by optimizing cortical oscillations. We elaborate their potential usefulness for three target groups: healthy elderly, patients with attention deficit/hyperactivity disorder, and healthy young adults. We discuss the relevance of neuronal oscillations in each group and show how each of them can benefit from the manipulation of functionally related oscillations. Further, we describe methods for manipulation of neuronal oscillations including direct brain stimulation as well as indirect task alterations. We also discuss practical considerations about the proposed techniques. In conclusion, we propose that insights from neuroscience should guide techniques to augment human cognition, which in turn can provide a better understanding of how the human brain works. PMID- 25018710 TI - Seeing what you want to see: priors for one's own actions represent exaggerated expectations of success. AB - People perceive the consequences of their own actions differently to how they perceive other sensory events. A large body of psychology research has shown that people also consistently overrate their own performance relative to others, yet little is known about how these "illusions of superiority" are normally maintained. Here we examined the visual perception of the sensory consequences of self-generated and observed goal-directed actions. Across a series of visuomotor tasks, we found that the perception of the sensory consequences of one's own actions is more biased toward success relative to the perception of observed actions. Using Bayesian models, we show that this bias could be explained by priors that represent exaggerated predictions of success. The degree of exaggeration of priors was unaffected by learning, but was correlated with individual differences in trait optimism. In contrast, when observing these actions, priors represented more accurate predictions of the actual performance. The results suggest that the brain internally represents optimistic predictions for one's own actions. Such exaggerated predictions bind the sensory consequences of our own actions with our intended goal, explaining how it is that when acting we tend to see what we want to see. PMID- 25018712 TI - The contribution of a central pattern generator in a reflex-based neuromuscular model. AB - Although the concept of central pattern generators (CPGs) controlling locomotion in vertebrates is widely accepted, the presence of specialized CPGs in human locomotion is still a matter of debate. An interesting numerical model developed in the 90s' demonstrated the important role CPGs could play in human locomotion, both in terms of stability against perturbations, and in terms of speed control. Recently, a reflex-based neuro-musculo-skeletal model has been proposed, showing a level of stability to perturbations similar to the previous model, without any CPG components. Although exhibiting striking similarities with human gaits, the lack of CPG makes the control of speed/step length in the model difficult. In this paper, we hypothesize that a CPG component will offer a meaningful way of controlling the locomotion speed. After introducing the CPG component in the reflex model, and taking advantage of the resulting properties, a simple model for gait modulation is presented. The results highlight the advantages of a CPG as feedforward component in terms of gait modulation. PMID- 25018711 TI - Lithium ameliorates autistic-like behaviors induced by neonatal isolation in rats. AB - Neonatal isolation is a widely accepted model to study the long-term behavioral changes produced by the early life events. However, it remains unknown whether neonatal isolation can induce autistic-like behaviors, and if so, whether pharmacological treatment can overcome it. Here, we reported that newborn rats subjected to individual isolations from their mother and nest for 1 h per day from postnatal days 1-9 displayed apparent autistic-like symptoms including social deficits, excessive repetitive self-grooming behavior, and increased anxiety- and depressive-like behaviors tested in young adult (postnatal days 42 56) compared to normal reared controls. Furthermore, these behavioral changes were accompanied by impaired adult hippocampal neurogenesis and reduced the ratio of excitatory/inhibitory synaptic transmissions, as reflected by an increase in spontaneous inhibitory postsynaptic current (sIPSC) and normal spontaneous excitatory postsynaptic current (sEPSC) in the hippocampal CA1 pyramidal neuron. More importantly, chronic administration of lithium, a clinically used mood stabilizer, completely overcame neonatal isolation-induced autistic-like behaviors, and restored adult hippocampal neurogenesis as well as the balance between excitatory and inhibitory activities to physiological levels. These findings indicate that neonatal isolation may produce autistic-like behaviors, and lithium may be a potential therapeutic agent against autism spectrum disorders (ASD) during development. PMID- 25018713 TI - Harnessing the power of neuroplasticity for intervention. AB - A fundamental property of the brain is its capacity to change with a wide variety of experiences, including injury. Although there are spontaneous reparative changes following injury, these changes are rarely sufficient to support significant functional recovery. Research on the basic principles of brain plasticity is leading to new approaches to treating the injured brain. We review factors that affect synaptic organization in the normal brain, evidence of spontaneous neuroplasticity after injury, and the evidence that factors including postinjury experience, pharmacotherapy, and cell-based therapies, can form the basis of rehabilitation strategies after brain injuries early in life and in adulthood. PMID- 25018714 TI - Non-invasive brain stimulation in neurorehabilitation: local and distant effects for motor recovery. AB - Non-invasive brain stimulation (NIBS) may enhance motor recovery after neurological injury through the causal induction of plasticity processes. Neurological injury, such as stroke, often results in serious long-term physical disabilities, and despite intensive therapy, a large majority of brain injury survivors fail to regain full motor function. Emerging research suggests that NIBS techniques, such as transcranial magnetic (TMS) and direct current (tDCS) stimulation, in association with customarily used neurorehabilitative treatments, may enhance motor recovery. This paper provides a general review on TMS and tDCS paradigms, the mechanisms by which they operate and the stimulation techniques used in neurorehabilitation, specifically stroke. TMS and tDCS influence regional neural activity underlying the stimulation location and also distant interconnected network activity throughout the brain. We discuss recent studies that document NIBS effects on global brain activity measured with various neuroimaging techniques, which help to characterize better strategies for more accurate NIBS stimulation. These rapidly growing areas of inquiry may hold potential for improving the effectiveness of NIBS-based interventions for clinical rehabilitation. PMID- 25018715 TI - Use it and/or lose it-experience effects on brain remodeling across time after stroke. AB - The process of brain remodeling after stroke is time- and neural activity dependent, and the latter makes it inherently sensitive to behavioral experiences. This generally supports targeting early dynamic periods of post stroke neural remodeling with rehabilitative training (RT). However, the specific neural events that optimize RT effects are unclear and, as such, cannot be precisely targeted. Here we review evidence for, potential mechanisms of, and ongoing knowledge gaps surrounding time-sensitivities in RT efficacy, with a focus on findings from animal models of upper extremity RT. The reorganization of neural connectivity after stroke is a complex multiphasic process interacting with glial and vascular changes. Behavioral manipulations can impact numerous elements of this process to affect function. RT efficacy varies both with onset time and its timing relative to the development of compensatory strategies with the less-affected (nonparetic) hand. Earlier RT may not only capitalize on a dynamic period of brain remodeling but also counter a tendency for compensatory strategies to stamp-in suboptimal reorganization patterns. However, there is considerable variability across injuries and individuals in brain remodeling responses, and some early behavioral manipulations worsen function. The optimal timing of RT may remain unpredictable without clarification of the cellular events underlying time-sensitivities in its effects. PMID- 25018716 TI - Computational anatomy for studying use-dependant brain plasticity. AB - In this article we provide a comprehensive literature review on the in vivo assessment of use-dependant brain structure changes in humans using magnetic resonance imaging (MRI) and computational anatomy. We highlight the recent findings in this field that allow the uncovering of the basic principles behind brain plasticity in light of the existing theoretical models at various scales of observation. Given the current lack of in-depth understanding of the neurobiological basis of brain structure changes we emphasize the necessity of a paradigm shift in the investigation and interpretation of use-dependent brain plasticity. Novel quantitative MRI acquisition techniques provide access to brain tissue microstructural properties (e.g., myelin, iron, and water content) in vivo, thereby allowing unprecedented specific insights into the mechanisms underlying brain plasticity. These quantitative MRI techniques require novel methods for image processing and analysis of longitudinal data allowing for straightforward interpretation and causality inferences. PMID- 25018717 TI - Finding an optimal rehabilitation paradigm after stroke: enhancing fiber growth and training of the brain at the right moment. AB - After stroke the central nervous system reveals a spectrum of intrinsic capacities to react as a highly dynamic system which can change the properties of its circuits, form new contacts, erase others, and remap related cortical and spinal cord regions. This plasticity can lead to a surprising degree of spontaneous recovery. It includes the activation of neuronal molecular mechanisms of growth and of extrinsic growth promoting factors and guidance signals in the tissue. Rehabilitative training and pharmacological interventions may modify and boost these neuronal processes, but almost nothing is known on the optimal timing of the different processes and therapeutic interventions and on their detailed interactions. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the therapeutic interventions in accordance with defined plastic time windows. In this review we summarize the mechanisms of spontaneous plasticity after stroke and experimental interventions to enhance growth and plasticity, with an emphasis on anti-Nogo-A immunotherapy. We highlight critical time windows of growth and of rehabilitative training and consider different approaches of combinatorial rehabilitative schedules. Finally, we discuss potential future strategies for designing repair and rehabilitation paradigms by introducing a "3 step model": determination of the metabolic and plastic status of the brain, pharmacological enhancement of its plastic mechanisms, and stabilization of newly formed functional connections by rehabilitative training. PMID- 25018718 TI - Neurorestorative therapy for stroke. AB - Ischemic stroke is responsible for many deaths and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review will discuss some of the latest findings on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells, and off-label use of some pharmacological agents, to promote recovery processes in the sub-acute and chronic phases following stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes, which enhance angiogenesis, arteriogenesis, neurogenesis, and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke are described. PMID- 25018721 TI - The role of the frontal cortex in memory: an investigation of the Von Restorff effect. AB - Evidence from neuropsychology and neuroimaging indicate that the pre-frontal cortex (PFC) plays an important role in human memory. Although frontal patients are able to form new memories, these memories appear qualitatively different from those of controls by lacking distinctiveness. Neuroimaging studies of memory indicate activation in the PFC under deep encoding conditions, and under conditions of semantic elaboration. Based on these results, we hypothesize that the PFC enhances memory by extracting differences and commonalities in the studied material. To test this hypothesis, we carried out an experimental investigation to test the relationship between the PFC-dependent factors and semantic factors associated with common and specific features of words. These experiments were performed using Free-Recall of word lists with healthy adults, exploiting the correlation between PFC function and fluid intelligence. As predicted, a correlation was found between fluid intelligence and the Von Restorff effect (better memory for semantic isolates, e.g., isolate "cat" within category members of "fruit"). Moreover, memory for the semantic isolate was found to depend on the isolate's serial position. The isolate item tends to be recalled first, in comparison to non-isolates, suggesting that the process interacts with short term memory. These results are captured within a computational model of free recall, which includes a PFC mechanism that is sensitive to both commonality and distinctiveness, sustaining a trade-off between the two. PMID- 25018719 TI - Brain plasticity-based therapeutics. AB - The primary objective of this review article is to summarize how the neuroscience of brain plasticity, exploiting new findings in fundamental, integrative and cognitive neuroscience, is changing the therapeutic landscape for professional communities addressing brain-based disorders and disease. After considering the neurological bases of training-driven neuroplasticity, we shall describe how this neuroscience-guided perspective distinguishes this new approach from (a) the more behavioral, traditional clinical strategies of professional therapy practitioners, and (b) an even more widely applied pharmaceutical treatment model for neurological and psychiatric treatment domains. With that background, we shall argue that neuroplasticity-based treatments will be an important part of future best-treatment practices in neurological and psychiatric medicine. PMID- 25018720 TI - The functional significance of cortical reorganization and the parallel development of CI therapy. AB - For the nineteenth and the better part of the twentieth centuries two correlative beliefs were strongly held by almost all neuroscientists and practitioners in the field of neurorehabilitation. The first was that after maturity the adult CNS was hardwired and fixed, and second that in the chronic phase after CNS injury no substantial recovery of function could take place no matter what intervention was employed. However, in the last part of the twentieth century evidence began to accumulate that neither belief was correct. First, in the 1960s and 1970s, in research with primates given a surgical abolition of somatic sensation from a single forelimb, which rendered the extremity useless, it was found that behavioral techniques could convert the limb into an extremity that could be used extensively. Beginning in the late 1980s, the techniques employed with deafferented monkeys were translated into a rehabilitation treatment, termed Constraint Induced Movement therapy or CI therapy, for substantially improving the motor deficit in humans of the upper and lower extremities in the chronic phase after stroke. CI therapy has been applied successfully to other types of damage to the CNS such as traumatic brain injury, cerebral palsy, multiple sclerosis, and spinal cord injury, and it has also been used to improve function in focal hand dystonia and for aphasia after stroke. As this work was proceeding, it was being shown during the 1980s and 1990s that sustained modulation of afferent input could alter the structure of the CNS and that this topographic reorganization could have relevance to the function of the individual. The alteration in these once fundamental beliefs has given rise to important recent developments in neuroscience and neurorehabilitation and holds promise for further increasing our understanding of CNS function and extending the boundaries of what is possible in neurorehabilitation. PMID- 25018722 TI - Visual memory in musicians and non-musicians. AB - Many investigations have reported structural, functional, and cognitive changes in the brains of musicians, which occur as a result of many years of musical practice. We aimed to investigate if intensive, long-term musical practice is associated with improved visual memory ability. Musicians and non-musicians, who were comparable in age, gender, and education, were submitted to a visual memory test. The test consisted of the presentation of four sets of stimuli, each one containing eight figures to be memorized. Each set was followed by individual figures and the subject was required to indicate if each figure was or was not present in the memorized set, by pressing the corresponding keys. We divided the test in two parts, in which the stimuli had greater or reduced semantic coding. Overall, musicians showed better performance on reaction times, but not on accuracy. An additional analysis revealed no significant interaction between group and any part of the test in the prediction of the outcomes. When simple reaction time was included as covariate, no significant difference between groups was found on reaction times. In the group of musicians, we found some significant correlations between variables related to musical practice and performance in the visual memory test. In summary, our data provide no evidence of enhanced visual memory ability in musicians, since there was no difference in accuracy between groups. Our results suggest that performance of musicians in the visual memory test may be associated with better sensorimotor integration, since although they have presented shorter reaction times, such effect disappeared when taken in consideration the simple reaction time test. However, given existing evidence of associations between simple reaction time and cognitive function, their performance in the visual memory test could also be related to enhanced visual attention ability, as has been suggested by previous studies, but this hypothesis deserves more investigation. PMID- 25018725 TI - Brain and art. PMID- 25018723 TI - What does the brain of children with developmental dyslexia tell us about reading improvement? ERP evidence from an intervention study. AB - Intervention is key to managing developmental dyslexia (DD), but not all children with DD benefit from treatment. Some children improve (improvers, IMP), whereas others do not improve (non-improvers, NIMP). Neurobiological differences between IMP and NIMP have been suggested, but studies comparing IMP and NIMP in childhood are missing. The present study examined whether ERP patterns change with treatment and differ between IMP and NIMP. We investigated the ERPs of 28 children with DD and 25 control children (CON) while performing a phonological lexical decision (PLD) task before and after a 6-month intervention. After intervention children with DD were divided into IMP (n = 11) and NIMP (n = 17). In the PLD-task children were visually presented with words, pseudohomophones, pseudowords, and false fonts and had to decide whether the presented stimulus sounded like an existing German word or not. Prior to intervention IMP showed higher N300 amplitudes over fronto-temporal electrodes compared to NIMP and CON and N400 amplitudes were attenuated in both IMP and NIMP compared to CON. After intervention N300 amplitudes of IMP were comparable to those of CON and NIMP. This suggests that the N300, which has been related to phonological access of orthographic stimuli and integration of orthographic and phonological representations, might index a compensatory mechanism or precursor that facilitates reading improvement. The N400, which is thought to reflect grapheme phoneme conversion or the access to the orthographic lexicon increased in IMP from pre to post and was comparable to CON after intervention. Correlations between N300 amplitudes pre, growth in reading ability and N400 amplitudes post indicated that higher N300 amplitudes might be important for reading improvement and increase in N400 amplitudes. The results suggest that children with DD, showing the same cognitive profile might differ regarding their neuronal profile which could further influence reading improvement. PMID- 25018724 TI - Model averaging, optimal inference, and habit formation. AB - Postulating that the brain performs approximate Bayesian inference generates principled and empirically testable models of neuronal function-the subject of much current interest in neuroscience and related disciplines. Current formulations address inference and learning under some assumed and particular model. In reality, organisms are often faced with an additional challenge-that of determining which model or models of their environment are the best for guiding behavior. Bayesian model averaging-which says that an agent should weight the predictions of different models according to their evidence-provides a principled way to solve this problem. Importantly, because model evidence is determined by both the accuracy and complexity of the model, optimal inference requires that these be traded off against one another. This means an agent's behavior should show an equivalent balance. We hypothesize that Bayesian model averaging plays an important role in cognition, given that it is both optimal and realizable within a plausible neuronal architecture. We outline model averaging and how it might be implemented, and then explore a number of implications for brain and behavior. In particular, we propose that model averaging can explain a number of apparently suboptimal phenomena within the framework of approximate (bounded) Bayesian inference, focusing particularly upon the relationship between goal-directed and habitual behavior. PMID- 25018726 TI - Understanding what is visible in a mirror or through a window before and after updating the position of an object. AB - In the Venus effect observers assume that Venus is admiring her own reflection in the mirror (Bertamini et al., 2003a). However, since the observer sees her face in the mirror, Venus is actually looking at the reflection of the painter. This effect is general because it is not specific to paintings or to images of people. This study tests whether people have difficulties in estimating what is visible from a given viewpoint using a paper and pencil task. Participants (N = 80) judged what is visible in a scene that could include a mirror or an aperture. The object in the scene (a train) was already located in front of the mirror or behind the aperture, or the same object had to be imagined to move to that location. The hypothesis was that this extra step (spatial transformation) is always part of how people reason about mirrors because they have to imagine the location of the reflection based on the location of the physical object. If so, this manipulation would equate the difficulty of the mirror and of the aperture conditions. Results show that performance on the paper and pencil task was better than expected, probably because of the asymmetric nature of the object used. However, an additional cost in reasoning about mirrors was confirmed. PMID- 25018727 TI - A critical role of holistic processing in face gender perception. AB - Whether face gender perception is processed by encoding holistic (whole) or featural (parts) information is a controversial issue. Although neuroimaging studies have identified brain regions related to face gender perception, the temporal dynamics of this process remain under debate. Here, we identified the mechanism and temporal dynamics of face gender perception. We used stereoscopic depth manipulation to create two conditions: the front and behind condition. In the front condition, facial patches were presented stereoscopically in front of the occluder and participants perceived them as disjoint parts (featural cues). In the behind condition, facial patches were presented stereoscopically behind the occluder and were amodally completed and unified in a coherent face (holistic cues). We performed three behavioral experiments and one electroencephalography experiment, and compared the results of the front and behind conditions. We found faster reaction times (RTs) in the behind condition compared with the front, and observed priming effects and aftereffects only in the behind condition. Moreover, the EEG experiment revealed that face gender perception is processed in the relatively late phase of visual recognition (200-285 ms). Our results indicate that holistic information is critical for face gender perception, and that this process occurs with a relatively late latency. PMID- 25018728 TI - Extending the NIF DISCO framework to automate complex workflow: coordinating the harvest and integration of data from diverse neuroscience information resources. AB - This paper describes how DISCO, the data aggregator that supports the Neuroscience Information Framework (NIF), has been extended to play a central role in automating the complex workflow required to support and coordinate the NIF's data integration capabilities. The NIF is an NIH Neuroscience Blueprint initiative designed to help researchers access the wealth of data related to the neurosciences available via the Internet. A central component is the NIF Federation, a searchable database that currently contains data from 231 data and information resources regularly harvested, updated, and warehoused in the DISCO system. In the past several years, DISCO has greatly extended its functionality and has evolved to play a central role in automating the complex, ongoing process of harvesting, validating, integrating, and displaying neuroscience data from a growing set of participating resources. This paper provides an overview of DISCO's current capabilities and discusses a number of the challenges and future directions related to the process of coordinating the integration of neuroscience data within the NIF Federation. PMID- 25018729 TI - Slow gait speed - an indicator of lower cerebral vasoreactivity in type 2 diabetes mellitus. AB - OBJECTIVE: Gait speed is an important predictor of health that is negatively affected by aging and type 2 diabetes. Diabetes has been linked to reduced vasoreactivity, i.e., the capacity to regulate cerebral blood flow in response to CO2 challenges. This study aimed to determine the relationship between cerebral vasoreactivity and gait speed in older adults with and without diabetes. RESEARCH DESIGN AND METHODS: We studied 61 adults with diabetes (65 +/- 8 years) and 67 without diabetes (67 +/- 9 years) but with similar distribution of cardiovascular risk factors. Preferred gait speed was calculated from a 75 m walk. Global and regional perfusion, vasoreactivity and vasodilation reserve were measured using 3 D continuous arterial spin labeling MRI at 3 Tesla during normo-, hyper- and hypocapnia and normalized for end-tidal CO2. RESULTS: Diabetic participants had slower gait speed as compared to non-diabetic participants (1.05 +/- 0.15 m/s vs. 1.14 +/- 0.14 m/s, p < 0.001). Lower global vasoreactivity (r (2) adj = 0.13, p = 0.007), or lower global vasodilation reserve (r (2) adj = 0.33, p < 0.001), was associated with slower walking in the diabetic group independently of age, BMI and hematocrit concentration. For every 1 mL/100 g/min/mmHg less vasodilation reserve, for example, gait speed was 0.05 m/s slower. Similar relationships between vasodilation reserve and gait speed were also observed regionally within the cerebellum, frontal, temporal, parietal, and occipital lobes (r (2) adj = 0.27-0.33, p < 0.0001). In contrast, vasoreactivity outcomes were not associated with walking speed in non-diabetic participants, despite similar vasoreactivity ranges across groups. CONCLUSION: In the diabetic group only, lower global vasoreactivity was associated with slower walking speed. Slower walking in older diabetic adults may thus hallmark reduced vasomotor reserve and thus the inability to increase perfusion in response to greater metabolic demands during walking. PMID- 25018730 TI - Axonal degeneration in an Alzheimer mouse model is PS1 gene dose dependent and linked to intraneuronal Abeta accumulation. AB - Abnormalities and impairments in axonal transport are suggested to strongly contribute to the pathological alterations underlying AD. The exact mechanisms leading to axonopathy are currently unclear, but it was recently suggested that APP expression itself triggers axonal degeneration. We used APP transgenic mice and crossed them on a hemi- or homozygous PS1 knock-in background (APP/PS1KI). Depending on the mutant PS1 dosage, we demonstrate a clear aggravation in both plaque-associated and plaque-distant axonal degeneration, despite of an unchanged APP expression level. Amyloid-beta (Abeta) peptides were found to accumulate in axonal swellings as well as in axons and apical dendrites proximate to neurons accumulating intraneuronal Abeta in their cell bodies. This suggests that Abeta can be transported within neurites thereby contributing to axonal deficits. In addition, diffuse extracellular Abeta deposits were observed in the close vicinity of axonal spheroids accumulating intracellular Abeta, which might be indicative of a local Abeta release from sites of axonal damage. PMID- 25018731 TI - Aging induced loss of complexity and dedifferentiation: consequences for coordination dynamics within and between brain, muscular and behavioral levels. AB - Growing evidence demonstrates that aging not only leads to structural and functional alterations of individual components of the neuro-musculo-skeletal system (NMSS) but also results in a systemic re-organization of interactions within and between the different levels and functional domains. Understanding the principles that drive the dynamics of these re-organizations is an important challenge for aging research. The present Hypothesis and Theory paper is a contribution in this direction. We propose that age-related declines in brain and behavior that have been characterized in the literature as dedifferentiation and the loss of complexity (LOC) are: (i) synonymous; and (ii) integrated. We argue that a causal link between the aforementioned phenomena exists, evident in the dynamic changes occurring in the aging NMSS. Through models and methods provided by a dynamical systems approach to coordination processes in complex living systems, we: (i) formalize operational hypotheses about the general principles of changes in cross-level and cross-domain interactions during aging; and (ii) develop a theory of the aging NMSS based on the combination of the frameworks of coordination dynamics (CD), dedifferentiation, and LOC. Finally, we provide operational predictions in the study of aging at neural, muscular, and behavioral levels, which lead to testable hypotheses and an experimental agenda to explore the link between CD, LOC and dedifferentiation within and between these different levels. PMID- 25018734 TI - Cricket antennae shorten when bending (Acheta domesticus L.). AB - Insect antennae are important mechanosensory and chemosensory organs. Insect appendages, such as antennae, are encased in a cuticular exoskeleton and are thought to bend only between segments or subsegments where the cuticle is thinner, more flexible, or bent into a fold. There is a growing appreciation of the dominating influence of folds in the mechanical behavior of a structure, and the bending of cricket antennae was considered in this context. Antennae will bend or deflect in response to forces, and the resulting bending behavior will affect the sensory input of the antennae. In some cricket antennae, such as in those of Acheta domesticus, there are a large number (>100) of subsegments (flagellomeres) that vary in their length. We evaluated whether these antennae bend only at the joints between flagellomeres, which has always been assumed but not tested. In addition we questioned whether an antenna undergoes a length change as it bends, which would result from some patterns of joint deformation. Measurements using light microscopy and SEM were conducted on both male and female adult crickets (Acheta domesticus) with bending in four different directions: dorsal, ventral, medial, and lateral. Bending occurred only at the joints between flagellomeres, and antennae shortened a comparable amount during bending, regardless of sex or bending direction. The cuticular folds separating antennal flagellomeres are not very deep, and therefore as an antenna bends, the convex side (in tension) does not have a lot of slack cuticle to "unfold" and does not lengthen during bending. Simultaneously on the other side of the antenna, on the concave side in compression, there is an increasing overlap in the folded cuticle of the joints during bending. Antennal shortening during bending would prevent stretching of antennal nerves and may promote hemolymph exchange between the antenna and head. PMID- 25018733 TI - Mega roles of microRNAs in regulation of skeletal muscle health and disease. AB - Skeletal muscle is a dynamic tissue with remarkable plasticity. Skeletal muscle growth and regeneration are highly organized processes thus it is not surprising that a high degree of complexity exists in the regulation of these processes. Recent discovery of non-coding microRNAs (miRNAs) has prompted extensive research in understanding the roles of these molecules in skeletal muscle. Research so far shows that miRNAs play a very significant role at every aspect of muscle biology. Besides muscle growth, development, and regeneration miRNAs are also involved in the pathology of muscle diseases and metabolism. In this review, recent advancements in miRNA function during myogenesis, exercise, atrophy, aging, and dystrophy are discussed. PMID- 25018735 TI - The early origins of human charity: developmental changes in preschoolers' sharing with poor and wealthy individuals. AB - Recent studies have provided evidence that young children already engage in sharing behavior. The underlying social-cognitive mechanisms, however, are still under debate. In particular, it is unclear whether or not young children's sharing is motivated by an appreciation of others' wealth. Manipulating the material needs of recipients in a sharing task (Experiment 1) and a resource allocation task (Experiment 2), we show that 5- but not 3-year-old children share more with poor than wealthy individuals. The 3-year-old children even showed a tendency to behave less selfishly towards the rich, yet not the poor recipient. This suggests that very early instances of sharing behavior are not motivated by a consideration of others' material needs. Moreover, the results show that 5-year old children were rather inclined to give more to the poor individual than distributing the resources equally, demonstrating that their wish to support the poor overruled the otherwise very prominent inclination to share resources equally. This indicates that charity has strong developmental roots in preschool children. PMID- 25018732 TI - Possible role of hemichannels in cancer. AB - In humans, connexins (Cxs) and pannexins (Panxs) are the building blocks of hemichannels. These proteins are frequently altered in neoplastic cells and have traditionally been considered as tumor suppressors. Alteration of Cxs and Panxs in cancer cells can be due to genetic, epigenetic and post-transcriptional/post translational events. Activated hemichannels mediate the diffusional membrane transport of ions and small signaling molecules. In the last decade hemichannels have been shown to participate in diverse cell processes including the modulation of cell proliferation and survival. However, their possible role in tumor growth and expansion remains largely unexplored. Herein, we hypothesize about the possible role of hemichannels in carcinogenesis and tumor progression. To support this theory, we summarize the evidence regarding the involvement of hemichannels in cell proliferation and migration, as well as their possible role in the anti tumor immune responses. In addition, we discuss the evidence linking hemichannels with cancer in diverse models and comment on the current technical limitations for their study. PMID- 25018736 TI - Cross-recurrence quantification analysis of categorical and continuous time series: an R package. AB - This paper describes the R package crqa to perform cross-recurrence quantification analysis of two time series of either a categorical or continuous nature. Streams of behavioral information, from eye movements to linguistic elements, unfold over time. When two people interact, such as in conversation, they often adapt to each other, leading these behavioral levels to exhibit recurrent states. In dialog, for example, interlocutors adapt to each other by exchanging interactive cues: smiles, nods, gestures, choice of words, and so on. In order for us to capture closely the goings-on of dynamic interaction, and uncover the extent of coupling between two individuals, we need to quantify how much recurrence is taking place at these levels. Methods available in crqa would allow researchers in cognitive science to pose such questions as how much are two people recurrent at some level of analysis, what is the characteristic lag time for one person to maximally match another, or whether one person is leading another. First, we set the theoretical ground to understand the difference between "correlation" and "co-visitation" when comparing two time series, using an aggregative or cross-recurrence approach. Then, we describe more formally the principles of cross-recurrence, and show with the current package how to carry out analyses applying them. We end the paper by comparing computational efficiency, and results' consistency, of crqa R package, with the benchmark MATLAB toolbox crptoolbox (Marwan, 2013). We show perfect comparability between the two libraries on both levels. PMID- 25018738 TI - Syntax, action, comparative cognitive science, and Darwinian thinking. PMID- 25018737 TI - Neural correlates of suspiciousness and interactions with anxiety during emotional and neutral word processing. AB - Suspiciousness is usually classified as a symptom of psychosis, but it also occurs in depression and anxiety disorders. Though how suspiciousness overlaps with depression is not obvious, suspiciousness does seem to overlap with anxious apprehension and anxious arousal (e.g., verbal iterative processes and vigilance about environmental threat). However, suspiciousness also has unique characteristics (e.g., concern about harm from others and vigilance about social threat). Given that both anxiety and suspiciousness have been associated with abnormalities in emotion processing, it is unclear whether it is the unique characteristics of suspiciousness or the overlap with anxiety that drive abnormalities in emotion processing. Event-related brain potentials were obtained during an emotion-word Stroop task. Results indicated that suspiciousness interacts with anxious apprehension to modulate initial stimulus perception processes. Suspiciousness is associated with attention to all stimuli regardless of emotion content. In contrast, anxious arousal is associated with a later response to emotion stimuli only. These results suggest that suspiciousness and anxious apprehension share overlapping processes, but suspiciousness alone is associated with a hyperactive early vigilance response. Depression did not interact with suspiciousness to predict response to emotion stimuli. These findings suggest that it may be informative to assess suspiciousness in conjunction with anxiety in order to better understand how these symptoms interact and contribute to dysfunctional emotion processing. PMID- 25018739 TI - Immediate sensitivity to structural constraints in pronoun resolution. AB - Real-time interpretation of pronouns is sometimes sensitive to the presence of grammatically-illicit antecedents and sometimes not. This occasional sensitivity has been taken as evidence that structural constraints do not immediately impact the initial antecedent retrieval for pronoun interpretation. We argue that it is important to separate effects that reflect the initial antecedent retrieval process from those that reflect later processes. We present results from five reading comprehension experiments. Both the current results and previous evidence support the hypothesis that agreement features and structural constraints immediately constrain the antecedent retrieval process for pronoun interpretation. Occasional sensitivity to grammatically-illicit antecedents may be due to repair processes triggered when the initial retrieval fails to return a grammatical antecedent. PMID- 25018740 TI - A note on age differences in mood-congruent vs. mood-incongruent emotion processing in faces. AB - THIS ARTICLE ADDRESSES FOUR INTERRELATED RESEARCH QUESTIONS: (1) Does experienced mood affect emotion perception in faces and is this perception mood-congruent or mood-incongruent?(2) Are there age-group differences in the interplay between experienced mood and emotion perception? (3) Does emotion perception in faces change as a function of the temporal sequence of study sessions and stimuli presentation, and (4) does emotion perception in faces serve a mood-regulatory function? One hundred fifty-four adults of three different age groups (younger: 20-31 years; middle-aged: 44-55 years; older adults: 70-81 years) were asked to provide multidimensional emotion ratings of a total of 1026 face pictures of younger, middle-aged, and older men and women, each displaying six different prototypical (primary) emotional expressions. By analyzing the likelihood of ascribing an additional emotional expression to a face whose primary emotion had been correctly recognized, the multidimensional rating approach permits the study of emotion perception while controlling for emotion recognition. Following up on previous research on mood responses to recurring unpleasant situations using the same dataset (Voelkle et al., 2013), crossed random effects analyses supported a mood-congruent relationship between experienced mood and perceived emotions in faces. In particular older adults were more likely to perceive happiness in faces when being in a positive mood and less likely to do so when being in a negative mood. This did not apply to younger adults. Temporal sequence of study sessions and stimuli presentation had a strong effect on the likelihood of ascribing an additional emotional expression. In contrast to previous findings, however, there was neither evidence for a change from mood-congruent to mood-incongruent responses over time nor evidence for a mood-regulatory effect. PMID- 25018741 TI - Using a multinomial tree model for detecting mixtures in perceptual detection. AB - In the area of memory research there have been two rival approaches for memory measurement-signal detection theory (SDT) and multinomial processing trees (MPT). Both approaches provide measures for the quality of the memory representation, and both approaches provide for corrections for response bias. In recent years there has been a strong case advanced for the MPT approach because of the finding of stochastic mixtures on both target-present and target-absent tests. In this paper a case is made that perceptual detection, like memory recognition, involves a mixture of processes that are readily represented as a MPT model. The Chechile (2004) 6P memory measurement model is modified in order to apply to the case of perceptual detection. This new MPT model is called the Perceptual Detection (PD) model. The properties of the PD model are developed, and the model is applied to some existing data of a radiologist examining CT scans. The PD model brings out novel features that were absent from a standard SDT analysis. Also the topic of optimal parameter estimation on an individual-observer basis is explored with Monte Carlo simulations. These simulations reveal that the mean of the Bayesian posterior distribution is a more accurate estimator than the corresponding maximum likelihood estimator (MLE). Monte Carlo simulations also indicate that model estimates based on only the data from an individual observer can be improved upon (in the sense of being more accurate) by an adjustment that takes into account the parameter estimate based on the data pooled across all the observers. The adjustment of the estimate for an individual is discussed as an analogous statistical effect to the improvement over the individual MLE demonstrated by the James-Stein shrinkage estimator in the case of the multiple group normal model. PMID- 25018742 TI - The influence of deliberate practice on musical achievement: a meta-analysis. AB - Deliberate practice (DP) is a task-specific structured training activity that plays a key role in understanding skill acquisition and explaining individual differences in expert performance. Relevant activities that qualify as DP have to be identified in every domain. For example, for training in classical music, solitary practice is a typical training activity during skill acquisition. To date, no meta-analysis on the quantifiable effect size of deliberate practice on attained performance in music has been conducted. Yet the identification of a quantifiable effect size could be relevant for the current discussion on the role of various factors on individual difference in musical achievement. Furthermore, a research synthesis might enable new computational approaches to musical development. Here we present the first meta-analysis on the role of deliberate practice in the domain of musical performance. A final sample size of 13 studies (total N = 788) was carefully extracted to satisfy the following criteria: reported durations of task-specific accumulated practice as predictor variables and objectively assessed musical achievement as the target variable. We identified an aggregated effect size of r c = 0.61; 95% CI [0.54, 0.67] for the relationship between task-relevant practice (which by definition includes DP) and musical achievement. Our results corroborate the central role of long-term (deliberate) practice for explaining expert performance in music. PMID- 25018743 TI - How important is importance for prospective memory? A review. AB - Forgetting to carry out an intention as planned can have serious consequences in everyday life. People sometimes even forget intentions that they consider as very important. Here, we review the literature on the impact of importance on prospective memory performance. We highlight different methods used to manipulate the importance of a prospective memory task such as providing rewards, importance relative to other ongoing activities, absolute importance, and providing social motives. Moreover, we address the relationship between importance and other factors known to affect prospective memory and ongoing task performance such as type of prospective memory task (time-, event-, or activity-based), cognitive loads, and processing overlaps. Finally, we provide a connection to motivation, we summarize the effects of task importance and we identify important venues for future research. PMID- 25018745 TI - The neural mechanisms for the recognition of face identity in humans. AB - Every day we encounter dozens of people, and in order to interact with them appropriately we need to recognize their identity. The face is a crucial source of information to recognize a person's identity. However, recognizing the identity of a face is challenging because it requires distinguishing between very similar images (e.g., the front views of two different faces) while categorizing very different images (e.g., a front view and a profile) as the same person. Neuroimaging has the whole-brain coverage needed to investigate where representations of face identity are encoded, but it is limited in terms of spatial and temporal resolution. In this article, we review recent neuroimaging research that attempted to investigate the representation of face identity, the challenges it faces, and the proposed solutions, to conclude that given the current state of the evidence the right anterior temporal lobe is the most promising candidate region for the representation of face identity. PMID- 25018744 TI - The genetic basis of music ability. AB - Music is an integral part of the cultural heritage of all known human societies, with the capacity for music perception and production present in most people. Researchers generally agree that both genetic and environmental factors contribute to the broader realization of music ability, with the degree of music aptitude varying, not only from individual to individual, but across various components of music ability within the same individual. While environmental factors influencing music development and expertise have been well investigated in the psychological and music literature, the interrogation of possible genetic influences has not progressed at the same rate. Recent advances in genetic research offer fertile ground for exploring the genetic basis of music ability. This paper begins with a brief overview of behavioral and molecular genetic approaches commonly used in human genetic analyses, and then critically reviews the key findings of genetic investigations of the components of music ability. Some promising and converging findings have emerged, with several loci on chromosome 4 implicated in singing and music perception, and certain loci on chromosome 8q implicated in absolute pitch and music perception. The gene AVPR1A on chromosome 12q has also been implicated in music perception, music memory, and music listening, whereas SLC6A4 on chromosome 17q has been associated with music memory and choir participation. Replication of these results in alternate populations and with larger samples is warranted to confirm the findings. Through increased research efforts, a clearer picture of the genetic mechanisms underpinning music ability will hopefully emerge. PMID- 25018746 TI - Development of magnitude processing in children with developmental dyscalculia: space, time, and number. AB - Developmental dyscalculia (DD) is a learning disorder associated with impairments in a preverbal non-symbolic approximate number system (ANS) pertaining to areas in and around the intraparietal sulcus (IPS). The current study sought to enhance our understanding of the developmental trajectory of the ANS and symbolic number processing skills, thereby getting insight into whether a deficit in the ANS precedes or is preceded by impaired symbolic and exact number processing. Recent work has also suggested that humans are endowed with a shared magnitude system (beyond the number domain) in the brain. We therefore investigated whether children with DD demonstrated a general magnitude deficit, stemming from the proposed magnitude system, rather than a specific one limited to numerical quantity. Fourth graders with DD were compared to age-matched controls and a group of ability-matched second graders, on a range of magnitude processing tasks pertaining to space, time, and number. Children with DD displayed difficulties across all magnitude dimensions compared to age-matched peers and showed impaired ANS acuity compared to the younger, ability-matched control group, while exhibiting intact symbolic number processing. We conclude that (1) children with DD suffer from a general magnitude-processing deficit, (2) a shared magnitude system likely exists, and (3) a symbolic number-processing deficit in DD tends to be preceded by an ANS deficit. PMID- 25018748 TI - Role of intravenous levetiracetam in acute seizure management. PMID- 25018747 TI - How implementation of systems biology into clinical trials accelerates understanding of diseases. AB - Systems biology comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances. The goal of systems biology is to re-integrate putatively critical elements extracted from multi-modality datasets in order to understand how interactions among multiple components form functional networks at the organism/patient-level, and how dysfunction of these networks underlies a particular disease. Due to the genetic and environmental diversity of human subjects, identification of critical elements related to a particular disease process from cross-sectional studies requires prohibitively large cohorts. Alternatively, implementation of systems biology principles to interventional clinical trials represents a unique opportunity to gain predictive understanding of complex diseases in comparatively small cohorts of patients. This paper reviews systems biology principles applicable to translational research, focusing on lessons from systems approaches to inflammation applied to multiple sclerosis. We suggest that employing systems biology methods in the design and execution of biomarker-supported, proof-of-principle clinical trials provides a singular opportunity to merge therapeutic development with a basic understanding of disease processes. The ultimate goal is to develop predictive computational models of the disease, which will revolutionize diagnostic process and provide mechanistic understanding necessary for personalized therapeutic approaches. Added, biologically meaningful information can be derived from diagnostic tests, if they are interpreted in functional relationships, rather than as independent measurements. Such systems biology based diagnostics will transform disease taxonomies from phenotypical to molecular and will allow physicians to select optimal therapeutic regimens for individual patients. PMID- 25018749 TI - An optimized method for the extraction of bacterial mRNA from plant roots infected with Escherichia coli O157:H7. AB - Analysis of microbial gene expression during host colonization provides valuable information on the nature of interaction, beneficial or pathogenic, and the adaptive processes involved. Isolation of bacterial mRNA for in planta analysis can be challenging where host nucleic acid may dominate the preparation, or inhibitory compounds affect downstream analysis, e.g., quantitative reverse transcriptase PCR (qPCR), microarray, or RNA-seq. The goal of this work was to optimize the isolation of bacterial mRNA of food-borne pathogens from living plants. Reported methods for recovery of phytopathogen-infected plant material, using hot phenol extraction and high concentration of bacterial inoculation or large amounts of infected tissues, were found to be inappropriate for plant roots inoculated with Escherichia coli O157:H7. The bacterial RNA yields were too low and increased plant material resulted in a dominance of plant RNA in the sample. To improve the yield of bacterial RNA and reduce the number of plants required, an optimized method was developed which combines bead beating with directed bacterial lysis using SDS and lysozyme. Inhibitory plant compounds, such as phenolics and polysaccharides, were counteracted with the addition of high molecular-weight polyethylene glycol and hexadecyltrimethyl ammonium bromide. The new method increased the total yield of bacterial mRNA substantially and allowed assessment of gene expression by qPCR. This method can be applied to other bacterial species associated with plant roots, and also in the wider context of food safety. PMID- 25018750 TI - Inteins as indicators of gene flow in the halobacteria. AB - This research uses inteins, a type of mobile genetic element, to infer patterns of gene transfer within the Halobacteria. We surveyed 118 genomes representing 26 genera of Halobacteria for intein sequences. We then used the presence-absence profile, sequence similarity and phylogenies from the inteins recovered to explore how intein distribution can provide insight on the dynamics of gene flow between closely related and divergent organisms. We identified 24 proteins in the Halobacteria that have been invaded by inteins at some point in their evolutionary history, including two proteins not previously reported to contain an intein. Furthermore, the size of an intein is used as a heuristic for the phase of the intein's life cycle. Larger size inteins are assumed to be the canonical two domain inteins, consisting of self-splicing and homing endonuclease domains (HEN); smaller sizes are assumed to have lost the HEN domain. For many halobacterial groups the consensus phylogenetic signal derived from intein sequences is compatible with vertical inheritance or with a strong gene transfer bias creating these clusters. Regardless, the coexistence of intein-free and intein-containing alleles reveal ongoing transfer and loss of inteins within these groups. Inteins were frequently shared with other Euryarchaeota and among the Bacteria, with members of the Cyanobacteria (Cyanothece, Anabaena), Bacteriodetes (Salinibacter), Betaproteobacteria (Delftia, Acidovorax), Firmicutes (Halanaerobium), Actinobacteria (Longispora), and Deinococcus-Thermus group. PMID- 25018751 TI - Application of calcifying bacteria for remediation of stones and cultural heritages. AB - Since ages, architects and artists worldwide have focused on usage of durable stones as marble and limestone for construction of beautiful and magnificent historic monuments as European Cathedrals, Roman, and Greek temples, Taj Mahal etc. But survival of these irreplaceable cultural and historical assets is in question these days due to their degradation and deterioration caused by number of biotic and abiotic factors. These causative agents have affected not only the esthetic appearance of these structures, but also lead to deterioration of their strength and durability. The present review emphasizes about different causative agents leading to deterioration and application of microbially induced calcium carbonate precipitation as a novel and potential technology for dealing with these problems. The study also sheds light on benefits of microbial carbonate binders over the traditional agents and future directions. PMID- 25018753 TI - Exploring the molecular mechanisms of electron shuttling across the microbe/metal space. AB - Dissimilatory metal reducing organisms play key roles in the biogeochemical cycle of metals as well as in the durability of submerged and buried metallic structures. The molecular mechanisms that support electron transfer across the microbe-metal interface in these organisms remain poorly explored. It is known that outer membrane proteins, in particular multiheme cytochromes, are essential for this type of metabolism, being responsible for direct and indirect, via electron shuttles, interaction with the insoluble electron acceptors. Soluble electron shuttles such as flavins, phenazines, and humic acids are known to enhance extracellular electron transfer. In this work, this phenomenon was explored. All known outer membrane decaheme cytochromes from Shewanella oneidensis MR-1 with known metal terminal reductase activity and a undecaheme cytochrome from Shewanella sp. HRCR-6 were expressed and purified. Their interactions with soluble electron shuttles were studied using stopped-flow kinetics, NMR spectroscopy, and molecular simulations. The results show that despite the structural similarities, expected from the available structural data and sequence homology, the detailed characteristics of their interactions with soluble electron shuttles are different. MtrC and OmcA appear to interact with a variety of different electron shuttles in the close vicinity of some of their hemes, and with affinities that are biologically relevant for the concentrations typical found in the medium for this type of compounds. All data support a view of a distant interaction between the hemes of MtrF and the electron shuttles. For UndA a clear structural characterization was achieved for the interaction with AQDS a humic acid analog. These results provide guidance for future work of the manipulation of these proteins toward modulation of their role in metal attachment and reduction. PMID- 25018752 TI - Development of "-omics" research in Schistosoma spp. and -omics-based new diagnostic tools for schistosomiasis. AB - Schistosomiasis, caused by dioecious flatworms in the genus Schistosoma, is torturing people from many developing countries nowadays and frequently leads to severe morbidity and mortality of the patients. Praziquantel based chemotherapy and morbidity control for this disease adopted currently necessitate viable and efficient diagnostic technologies. Fortunately, those "-omics" researches, which rely on high-throughput experimental technologies to produce massive amounts of informative data, have substantially contributed to the exploitation and innovation of diagnostic tools of schistosomiasis. In its first section, this review provides a concise conclusion on the progresses pertaining to schistosomal "-omics" researches to date, followed by a comprehensive section on the diagnostic methods of schistosomiasis, especially those innovative ones based on the detection of antibodies, antigens, nucleic acids, and metabolites with a focus on those achievements inspired by "-omics" researches. Finally, suggestions about the design of future diagnostic tools of schistosomiasis are proposed, in order to better harness those data produced by "-omics" studies. PMID- 25018754 TI - Monocyte Expressed Macromolecular C1 and C1q Receptors as Molecular Sensors of Danger: Implications in SLE. AB - The ability of circulating blood monocytes to express C1q receptors (cC1qR and gC1qR) as well as to synthesize and secrete the classical pathway proteins C1q, C1r, and C1s and their regulator, C1-INH is very well established. What is intriguing, however, is that, in addition to secretion of the individual C1 proteins monocytes are also able to display macromolecular C1 on their surface in a manner that is stable and functional. The cell surface C1 complex is presumably formed by a Ca(2+)-dependent association of the C1r2?C1s2 tetramer to C1q, which in turn is anchored via a membrane-binding domain located in the N-terminus of its A-chain as shown previously. Monocytes, which circulate in the blood for 1-3 days before they move into tissues throughout the body, not only serve as precursors of macrophages and dendritic cells (DCs), but also fulfill three main functions in the immune system: phagocytosis, antigen presentation, and cytokine production. Since the globular heads of C1q within the membrane associated C1 are displayed outwardly, we hypothesize that their main function - especially in circulating monocytes - is to recognize and capture circulating immune complexes or pathogen-associated molecular patterns in the blood. This in turn may give crucial signal, which drives the monocytes to migrate into tissues, differentiate into macrophages or DCs, and initiate the process of antigen elimination. Unoccupied C1q on the other hand may serve to keep monocytes in a pre-dendritic phenotype by silencing key molecular players thus ensuring that unwarranted DC driven immune response does not occur. In this paper, we will discuss the role of monocyte/DC-associated C1q receptors, macromolecular C1 as well as secreted C1q in both innate and acquired immune responses. PMID- 25018755 TI - The splicing fate of plant SPO11 genes. AB - Toward the global understanding of plant meiosis, it seems to be essential to decipher why all as yet sequenced plants need or at least encode for two different meiotic SPO11 genes. This is in contrast to mammals and fungi, where only one SPO11 is present. Both SPO11 in Arabidopsis thaliana are essential for the initiation of double strand breaks (DSBs) during the meiotic prophase. In nearly all eukaryotic organisms DSB induction during prophase I by SPO11 leads to meiotic DSB repair, thereby ensuring the formation of a necessary number of crossovers (CO) as physical connections between the homologous chromosomes. We aim to investigate the specific functions and evolution of both SPO11 genes in land plants. Therefore, we identified and cloned the respective orthologous genes from Brassica rapa, Carica papaya, Oryza sativa, and Physcomitrella patens. In parallel we determined the full length cDNA sequences of SPO11-1 and -2 from all of these plants by RT-PCR. During these experiments we observed that the analyzed plants exhibit a pattern of alternative splicing products of both SPO11 mRNAs. Such an aberrant splicing has previously been described for Arabidopsis and therefore seems to be conserved throughout evolution. Most of the splicing forms of SPO11-1 and -2 seem to be non-functional as they either showed intron retention (IR) or shortened exons. However, the positional distribution and number of alternative splicing events vary strongly between the different plants. The cDNAs showed in most cases premature termination codons (PTCs) due to frameshift. Nevertheless, in some cases we found alternatively spliced but functional cDNAs. These findings let us suggest that alternative splicing of SPO11 depends on the respective gene sequence and on the plant species. Therefore, this conserved mechanism might play a role concerning regulation of SPO11. PMID- 25018757 TI - Interploidy hybridization barrier of endosperm as a dosage interaction. AB - Crosses between plants at different ploidy levels will often result in failure of endosperm development. The basis of this phenomenon has been attributed to parental gene imprinting of genes involved with endosperm development but a review of the data from maize indicates a dosage interaction between the contributions of the female gametophyte and the primary endosperm nucleus to early endosperm development. However, it is noted that parental imprinting is a non-mutational means that can alter dosage sensitive factors and therefore can contribute to this effect. Operationally, the genes determining ploidy hybridization barrier would qualify for Dobzhansky-Muller incompatibilities that prevent gene flow between species. PMID- 25018756 TI - An overview of the gene regulatory network controlling trichome development in the model plant, Arabidopsis. AB - Trichomes are specialized epidermal cells located on aerial parts of plants and are associated with a wide array of biological processes. Trichomes protect plants from adverse conditions including UV light and herbivore attack and are also an important source of a number of phytochemicals. The simple unicellular trichomes of Arabidopsis serve as an excellent model to study molecular mechanism of cell differentiation and pattern formation in plants. The emerging picture suggests that the developmental process is controlled by a transcriptional network involving three major groups of transcription factors (TFs): the R2R3 MYB, basic helix-loop-helix (bHLH), and WD40 repeat (WDR) protein. These regulatory proteins form a trimeric activator complex that positively regulates trichome development. The single repeat R3 MYBs act as negative regulators of trichome development. They compete with the R2R3 MYBs to bind the bHLH factor and form a repressor complex. In addition to activator-repressor mechanism, a depletion mechanism may operate in parallel during trichome development. In this mechanism, the bHLH factor traps the WDR protein which results in depletion of WDR protein in neighboring cells. Consequently, the cells with high levels of bHLH and WDR proteins are developed into trichomes. A group of C2H2 zinc finger TFs has also been implicated in trichome development. Phytohormones, including gibberellins and jasmonic acid, play significant roles in this developmental process. Recently, microRNAs have been shown to be involved in trichome development. Furthermore, it has been demonstrated that the activities of the key regulatory proteins involved in trichome development are controlled by the 26S/ubiquitin proteasome system (UPS), highlighting the complexity of the regulatory network controlling this developmental process. To complement several excellent recent relevant reviews, this review focuses on the transcriptional network and hormonal interplay controlling trichome development in Arabidopsis. PMID- 25018758 TI - Management practices impact vine carbohydrate status to a greater extent than vine productivity. AB - Light pruning and deficit irrigation regimes are practices which are widely used in high yielding commercial vineyards in the warm climate regions of Australia. Little information is available on their impacts on carbohydrate dynamics in vegetative organs within and between seasons, and on the resulting plant capacity to maintain productivity and ripen fruits. This study was conducted to address this gap in knowledge over five vintages on Vitis vinifera L. cv. Cabernet Franc, Shiraz, and Cabernet Sauvignon in the Sunraysia region of Victoria, Australia. Lighter pruning did not change the total carbohydrates concentration and composition in wood and roots within seasons in Cabernet Franc and Shiraz. However, the total carbohydrate pool (starch and soluble sugars) at the end of dormancy increased under lighter pruning, due to higher vine size, associated with retention and growth of old-wood (trunk and cordons). Water deficit negatively impacted trunk and leaf starch concentrations, over the day and within seasons in Cabernet Sauvignon. Soluble sugars concentrations in these tissues tended to be higher under limited water supply, possibly due to higher sugar mobilization as photosynthesis decreased. Trunk carbohydrate concentrations markedly varied within and between seasons, highlighting the importance of interactive factors such as crop load and climate on carbon status. The period between fruit-set and veraison was shown to be critical for its impact on the balance between carbon accretion and depletion, especially under water deficit. The lower leaf and trunk starch concentration under water deficit resulted in a decrease of yield components at harvest, while similar yields were reached for all pruning systems. The sugar allocated to berries at harvest remained remarkably stable for all practices and seasons, irrespective of vine yield and carbohydrate status in vegetative organs in Shiraz and Cabernet Sauvignon. PMID- 25018759 TI - Forest response and recovery following disturbance in upland forests of the Atlantic Coastal Plain. AB - Carbon and water cycling of forests contribute significantly to the Earth's overall biogeochemical cycling and may be affected by disturbance and climate change. As a larger body of research becomes available about leaf-level, ecosystem and regional scale effects of disturbances on forest ecosystems, a more mechanistic understanding is developing which can improve modeling efforts. Here, we summarize some of the major effects of physical and biogenic disturbances, such as drought, prescribed fire, and insect defoliation, on leaf and ecosystem scale physiological responses as well as impacts on carbon and water cycling in an Atlantic Coastal Plain upland oak/pine and upland pine forest. During drought, stomatal conductance and canopy stomatal conductance were reduced, however, defoliation increased conductance on both leaf-level and canopy scale. Furthermore, after prescribed fire, leaf-level stomatal conductance was unchanged for pines but decreased for oaks, while canopy stomatal conductance decreased temporarily, but then rebounded the following growing season, thus exhibiting transient responses. This study suggests that forest response to disturbance varies from the leaf to ecosystem level as well as species level and thus, these differential responses interplay to determine the fate of forest structure and functioning post disturbance. PMID- 25018760 TI - A novel phylogeny and morphological reconstruction of the PIN genes and first phylogeny of the ACC-oxidases (ACOs). AB - The PIN and ACO gene families present interesting questions about the evolution of plant physiology, including testing hypotheses about the ecological drivers of their diversification and whether unrelated genes have been recruited for similar functions. The PIN-formed proteins contribute to the polar transport of auxin, a hormone which regulates plant growth and development. PIN loci are categorized into groups according to their protein length and structure, as well as subcellular localization. An interesting question with PIN genes is the nature of the ancestral form and location. ACOs are members of a superfamily of oxygenases and oxidases that catalyze the last step of ethylene synthesis, which regulates many aspects of the plant life cycle. We used publicly available PIN and ACO sequences to conduct phylogenetic analyses. Third codon positions of these genes in monocots have a high GC content, which could be historical but is more likely due to a mutational bias. Thus, we developed methods to extract phylogenetic information from nucleotide sequences while avoiding this convergent feature. One method consisted in using only A-T transformations, and another used only the first and second codon positions for serine, which can only take A or T and G or C, respectively. We also conducted tree-searches for both gene families using unaligned amino acid sequences and dynamic homology. PIN genes appear to have diversified earlier than ACOs, with monocot and dicot copies more mixed in the phylogeny. However, gymnosperm PINs appear to be derived and not closely related to those from primitive plants. We find strong support for a long PIN gene ancestor with short forms subsequently evolving one or more times. ACO genes appear to have diversified mostly since the dicot-monocot split, as most genes cluster into a small number of monocot and dicot clades when the tree is rooted by genes from mosses. Gymnosperm ACOs were recovered as closely related and derived. PMID- 25018761 TI - Role of plastoglobules in metabolite repair in the tocopherol redox cycle. AB - Plants are exposed to ever changing light environments and continuously forced to adapt. Excessive light intensity leads to the production of reactive oxygen species that can have deleterious effects on photosystems and thylakoid membranes. To limit damage, plants increase the production of membrane soluble antioxidants such as tocopherols. Here, untargeted lipidomics after high light treatment showed that among hundreds of lipid compounds alpha-tocopherol is the most strongly induced, underscoring its importance as an antioxidant. As part of the antioxidant mechanism, alpha-tocopherol undergoes a redox cycle involving oxidative opening of the chromanol ring. The only enzyme currently known to participate in the cycle is tocopherol cyclase (VTE1, At4g32770), that re introduces the chromanol ring of alpha-tocopherol. By mutant analysis, we identified the NAD(P)H-dependent quinone oxidoreductase (NDC1, At5g08740) as a second enzyme implicated in this cycle. NDC1 presumably acts through the reduction of quinone intermediates preceding cyclization by VTE1. Exposure to high light also triggered far-ranging changes in prenylquinone composition that we dissect herein using null mutants and lines overexpressing the VTE1 and NDC1 enzymes. PMID- 25018762 TI - Duplications and losses in gene families of rust pathogens highlight putative effectors. AB - Rust fungi are a group of fungal pathogens that cause some of the world's most destructive diseases of trees and crops. A shared characteristic among rust fungi is obligate biotrophy, the inability to complete a lifecycle without a host. This dependence on a host species likely affects patterns of gene expansion, contraction, and innovation within rust pathogen genomes. The establishment of disease by biotrophic pathogens is reliant upon effector proteins that are encoded in the fungal genome and secreted from the pathogen into the host's cell apoplast or within the cells. This study uses a comparative genomic approach to elucidate putative effectors and determine their evolutionary histories. We used OrthoMCL to identify nearly 20,000 gene families in proteomes of 16 diverse fungal species, which include 15 basidiomycetes and one ascomycete. We inferred patterns of duplication and loss for each gene family and identified families with distinctive patterns of expansion/contraction associated with the evolution of rust fungal genomes. To recognize potential contributors for the unique features of rust pathogens, we identified families harboring secreted proteins that: (i) arose or expanded in rust pathogens relative to other fungi, or (ii) contracted or were lost in rust fungal genomes. While the origin of rust fungi appears to be associated with considerable gene loss, there are many gene duplications associated with each sampled rust fungal genome. We also highlight two putative effector gene families that have expanded in Cqf that we hypothesize have roles in pathogenicity. PMID- 25018763 TI - Evolution of fruit development genes in flowering plants. AB - The genetic mechanisms regulating dry fruit development and opercular dehiscence have been identified in Arabidopsis thaliana. In the bicarpellate silique, valve elongation and differentiation is controlled by FRUITFULL (FUL) that antagonizes SHATTERPROOF1-2 (SHP1/SHP2) and INDEHISCENT (IND) at the dehiscence zone where they control normal lignification. SHP1/2 are also repressed by REPLUMLESS (RPL), responsible for replum formation. Similarly, FUL indirectly controls two other factors ALCATRAZ (ALC) and SPATULA (SPT) that function in the proper formation of the separation layer. FUL and SHP1/2 belong to the MADS-box family, IND and ALC belong to the bHLH family and RPL belongs to the homeodomain family, all of which are large transcription factor families. These families have undergone numerous duplications and losses in plants, likely accompanied by functional changes. Functional analyses of homologous genes suggest that this network is fairly conserved in Brassicaceae and less conserved in other core eudicots. Only the MADS box genes have been functionally characterized in basal eudicots and suggest partial conservation of the functions recorded for Brassicaceae. Here we do a comprehensive search of SHP, IND, ALC, SPT, and RPL homologs across core eudicots, basal eudicots, monocots and basal angiosperms. Based on gene-tree analyses we hypothesize what parts of the network for fruit development in Brassicaceae, in particular regarding direct and indirect targets of FUL, might be conserved across angiosperms. PMID- 25018764 TI - Identification of "safe harbor" loci in indica rice genome by harnessing the property of zinc-finger nucleases to induce DNA damage and repair. AB - Zinc-finger nucleases (ZFNs) have proved to be successful tools for targeted genome manipulation in several organisms. Their main property is the induction of double-strand breaks (DSBs) at specific sites, which are further repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). However, for the appropriate integration of genes at specific chromosomal locations, proper sites for gene integration need to be identified. These regions, hereby named safe harbor loci, must be localized in non-coding regions and possess high gene expression. In the present study, three different ZFN constructs (pZFN1, pZFN2, pZFN3), harboring beta-glucuronidase (GUS) as a reporter gene, were used to identify safe harbor loci on rice chromosomes. The constructs were delivered into IR64 rice by using an improved Agrobacterium-mediated transformation protocol, based on the use of immature embryos. Gene expression was measured by histochemical GUS activity and the flanking regions were determined through thermal-asymmetric interlaced polymerase chain reaction (TAIL PCR). Following sequencing, 28 regions were identified as putative sites for safe integration, but only one was localized in a non-coding region and also possessed high GUS expression. These findings have significant applicability to create crops with new and valuable traits, since the site can be subsequently used to stably introduce one or more genes in a targeted manner. PMID- 25018766 TI - Quorum sensing communication between bacteria and human cells: signals, targets, and functions. AB - Both direct and long-range interactions between pathogenic Pseudomonas aeruginosa bacteria and their eukaryotic hosts are important in the outcome of infections. For cell-to-cell communication, these bacteria employ the quorum sensing (QS) system to pass on information of the density of the bacterial population and collectively switch on virulence factor production, biofilm formation, and resistance development. Thus, QS allows bacteria to behave as a community to perform tasks which would be impossible for individual cells, e.g., to overcome defense and immune systems and establish infections in higher organisms. This review highlights these aspects of QS and our own recent research on how P. aeruginosa communicates with human cells using the small QS signal molecules N acyl homoserine lactones (AHL). We focus on how this conversation changes the behavior and function of neutrophils, macrophages, and epithelial cells and on how the signaling machinery in human cells responsible for the recognition of AHL. Understanding the bacteria-host relationships at both cellular and molecular levels is essential for the identification of new targets and for the development of novel strategies to fight bacterial infections in the future. PMID- 25018767 TI - Stent selection for endoscopic ultrasound-guided drainage of pancreatic fluid collections: a multicenter study in china. AB - Aims. We attempted to establish some guidelines for the selection of transmural stents during endoscopic drainage of PFCs by retrospective review of the clinical data obtained from three tertiary hospitals. Patients and Methods. Clinical data of 93 patients with attempted endoscopic drainage of symptomatic PFCs were obtained through chart review and prospective follow-up. Results. Treatment success for acute pseudocyst (n = 67), chronic pseudocyst (n = 9), and WOPN (n = 17) was 95.3%, 100%, and 88.2%, respectively (P = 0.309). Clinical success for single-stent drainage was 93.9% (46/49) versus 97.4% (37/38) for multiple-stent drainage (P = 0.799). Secondary infection for single-stent drainage was 18.4% (9/49) versus 5.3% (2/38) for multiple-stent drainage (P = 0.134). Secondary infection for stent diameter less than or equal to 8.5 F was 3.4% (1/29) versus 17.2% (10/58) for stent diameter larger than or equal to 10 F (P = 0.138). Conclusion. EUS-guided transmural drainage is an effective therapy for PFCs. Single-stent transmural drainage of PFCs is enough and does not seem to influence clinical success. The number or diameter of stents does not seem to be associated with secondary infection. PMID- 25018765 TI - Dominant resistance against plant viruses. AB - To establish a successful infection plant viruses have to overcome a defense system composed of several layers. This review will overview the various strategies plants employ to combat viral infections with main emphasis on the current status of single dominant resistance (R) genes identified against plant viruses and the corresponding avirulence (Avr) genes identified so far. The most common models to explain the mode of action of dominant R genes will be presented. Finally, in brief the hypersensitive response (HR) and extreme resistance (ER), and the functional and structural similarity of R genes to sensors of innate immunity in mammalian cell systems will be described. PMID- 25018768 TI - Adipose tissue and adrenal glands: novel pathophysiological mechanisms and clinical applications. AB - Hormones produced by the adrenal glands and adipose tissues have important roles in normal physiology and are altered in many disease states. Obesity is associated with changes in adrenal function, including increase in adrenal medullary catecholamine output, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, elevations in circulating aldosterone together with changes in adipose tissue glucocorticoid metabolism, and enhanced adipocyte mineralocorticoid receptor activity. It is unknown whether these changes in adrenal endocrine function are in part responsible for the pathogenesis of obesity and related comorbidities or represent an adaptive response. In turn, adipose tissue hormones or "adipokines" have direct effects on the adrenal glands and interact with adrenal hormones at several levels. Here we review the emerging evidence supporting the existence of "cross talk" between the adrenal gland and adipose tissue, focusing on the relevance and roles of their respective hormones in health and disease states including obesity, metabolic syndrome, and primary disorders of the adrenals. PMID- 25018769 TI - Imaging findings of bisphosphonate-related osteonecrosis of the jaws: a critical review of the quantitative studies. AB - Objectives. This paper offers a critical review of published information on the imaging strategies used for diagnosing bisphosphonate-associated osteonecrosis of the jaw (BRONJ) in patients taking intravenous bisphosphonates, pointing at the different methodologies and results of existing literature. Methods. Electronic literature search was performed in order to identify as many quantitative studies that discussed the imaging findings of BRONJ up to February 2014. Initially, the search for articles was based on the following four types of imaging modalities for evaluating BRONJ: computed tomography, plain film radiographs, magnetic resonance imaging, and nuclear bone scanning. Results. Eleven out of the 79 initially selected articles met the inclusion criteria. Most of the selected articles were cross-sectional studies. Regarding the selected studies, 54.5% have used plain films radiographs and 54.5% were based on computed tomography findings. All of the selected studies showed a small number of patients and none of the selected studies have tested the accuracy of the imaging examination for evaluating BRONJ. Conclusions. This critical review showed a scarcity of quantitative studies that analyzed the typical imaging findings related to BRONJ. Further studies are necessary in order to analyze the role of different imaging techniques in the assessment of BRONJ. PMID- 25018770 TI - Comparison of maxillary molar distalization with an implant-supported distal jet and a traditional tooth-supported distal jet appliance. AB - Aim. To investigate and compare the efficiency of two appliances for molar distalization: the bone-anchored distal screw (DS) and the traditional tooth supported distal jet (DJ) for molar distalization and anchorage loss. Methods. Tests (18 subjects) were treated with a DS and controls (18 subjects) were treated with a DJ. Lateral cephalograms were obtained before and at the end of molar distalization and were analysed. Shapiro Wilk test, unpaired t-test, and Wilcoxon rank-sum test were applied according to values distribution. The alpha level was fixed at 0.05. Results. Maxillary first molars were successfully distalized into a Class I relationship in all patients. The mean molar distalization and treatment time were similar in both groups. The DS group exhibited a spontaneous distalization (2.1 +/- 0.9 mm) of the first premolar with control of anchorage loss, distal tipping, extrusion, and skeletal changes. Conclusions. The DS is an adequate compliance-free distalizing appliance that can be used safely for the correction of Class II malocclusions. In comparison to the traditional DJ, the DS enables not only a good rate of molar distalization, but also a spontaneous distalization of the first premolars. PMID- 25018772 TI - Intermolecular Interactions between Eosin Y and Caffeine Using 1H-NMR Spectroscopy. AB - DETECHIP has been used in testing analytes including caffeine, cocaine, and tetrahydrocannabinol (THC) from marijuana, as well as date rape and club drugs such as flunitrazepam, gamma-hydroxybutyric acid (GHB), and methamphetamine. This study investigates the intermolecular interaction between DETECHIP sensor eosin Y (DC1) and the analyte (caffeine) that is responsible for the fluorescence and color changes observed in the actual array. Using 1H-NMR, 1H-COSY, and 1H-DOSY NMR methods, a proton exchange from C-8 of caffeine to eosin Y is proposed. PMID- 25018771 TI - Future directions for the management of pain in osteoarthritis. AB - Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future. PMID- 25018774 TI - A new kind of auxiliary heart in insects: functional morphology and neuronal control of the accessory pulsatile organs of the cricket ovipositor. AB - INTRODUCTION: In insects, the pumping of the dorsal heart causes circulation of hemolymph throughout the central body cavity, but not within the interior of long body appendages. Hemolymph exchange in these dead-end structures is accomplished by special flow-guiding structures and/or autonomous pulsatile organs ("auxiliary hearts"). In this paper accessory pulsatile organs for an insect ovipositor are described for the first time. We studied these organs in females of the cricket Acheta domesticus by analyzing their functional morphology, neuroanatomy and physiological control. RESULTS: The lumen of the four long ovipositor valves is subdivided by longitudinal septa of connective tissue into efferent and afferent hemolymph sinuses which are confluent distally. The countercurrent flow in these sinuses is effected by pulsatile organs which are located at the bases of the ovipositor valves. Each of the four organs consists of a pumping chamber which is compressed by rhythmically contracting muscles. The morphology of the paired organs is laterally mirrored, and there are differences in some details between the dorsal and ventral organs. The compression of the pumping chambers of each valve pair occurs with a left-right alternating rhythm with a frequency of 0.2 to 0.5 Hz and is synchronized between the dorsal and ventral organs. The more anteriorly located genital chamber shows rhythmical lateral movements simultaneous to those of the ovipositor pulsatile organs and probably supports the hemolymph exchange in the abdominal apex region. The left-right alternating rhythm is produced by a central pattern generator located in the terminal ganglion. It requires no sensory feedback for its output since it persists in the completely isolated ganglion. Rhythm-modulating and rhythm-resetting interneurons are identified in the terminal ganglion. CONCLUSION: The circulatory organs of the cricket ovipositor have a unique functional morphology. The pumping apparatus at the base of each ovipositor valve operates like a bellow. It forces hemolymph via sinuses delimited by thin septa of connective tissue in a countercurrent flow through the valve lumen. The pumping activity is based on neurogenic control by a central pattern generator in the terminal ganglion. PMID- 25018773 TI - MicroRNAs are potential therapeutic targets in fibrosing kidney disease: lessons from animal models. AB - Chronic disease of the kidneys has reached epidemic proportions in industrialized nations. New therapies are urgently sought. Using a combination of animal models of kidney disease and human biopsy samples, a pattern of dysregulated microRNA expression has emerged which is common to chronic diseases. A number of these dysregulated microRNA have recently been shown to have functional consequences for the disease process and therefore may be potential therapeutic targets. We highlight microRNA-21, the most comprehensively studied microRNA in the kidney so far. MicroRNA-21 is expressed widely in healthy kidney but studies from knockout mice indicate it is largely inert. Although microRNA-21 is upregulated in many cell compartments including leukocytes, epithelial cells and myofibroblasts, the inert microRNA-21 also appears to become activated, by unclear mechanisms. Mice lacking microRNA-21 are protected from kidney injury and fibrosis in several distinct models of kidney disease, and systemically administered oligonucleotides that specifically bind to the active site in microRNA-21, inhibiting its function, recapitulate the genetic deletion of microRNA-21, suggesting inhibitory oligonucleotides may have therapeutic potential. Recent studies of microRNA-21 targets in kidney indicate that it normally functions to silence metabolic pathways including fatty acid metabolism and pathways that prevent Reactive Oxygen Species generation in peroxisomes and mitochondria in epithelial cells and myofibroblasts. Targeting specific pathogenic microRNAs in a specific manner is feasible in vivo and may be a new therapeutic target in disease of the kidney. PMID- 25018775 TI - Tuberculosis screening at the Sainte-Anne Hospital in Paris - results of first and second IGRA. AB - INTRODUCTION: Healthcare workers (HCWs) are exposed to Mycobacterium tuberculosis (MTB) and therefore are screened for tuberculosis (TB). Results of TB screenings with the Interferon-gamma Release Assay (IGRA) in a French psychiatric hospital without a TB ward are described. METHODS: At the Sainte-Anne Hospital, a referral centre for psychiatric patients throughout the municipal region of Paris, IGRA screening is performed during pre-employment and general health examination or after potential contact to MTB. The QuantiFERON Gold in tube (QFT) is used and data on TB history are assessed in a standardized manner. RESULTS: Between August 2008 und August 2013 in total 1.192 HCWs were tested and the QFT was positive in 265 (22.2%). Probability of a positive QFT increased with age. A second QFT was performed in 144 HCWs with a positive QFT and 53 (36.8%) HCWs had a reversion. With a positive QFT close to the cut-off (e.g. 0.35-0.7 IU/ml) the odds ratio for a reversion was 4.6 compared to an INF-gamma concentration of >=3.0 IU/ml. Probability of reversion was not influenced by preventive chemotherapy, which was completed by 28 (19.4%) HCWs with a positive QFT. No active TB was detected. CONCLUSION: Prevalence of positive IGRA is high in French HCWs as is the number of reversions in IGRA. Reversion rate is particularly high around the cut-off of the IGRA. A borderline zone will therefore reduce the influence of test variability. PMID- 25018776 TI - Breastfeeding policy and practices at the general paediatric outpatient clinic of a teaching hospital in Lagos, Nigeria. AB - BACKGROUND: Hospitals have a role to play in supporting, protecting and promoting breastfeeding. The aim of this study was to describe hospital breastfeeding policy and practices and breastfeeding rates among mothers attending General Paediatric Outpatient Clinic at a tertiary hospital in Lagos, Nigeria. METHODS: This was a cross-sectional study involving paediatric nurses and doctors, as well as the mothers who brought their child to the General Paediatric Outpatient Clinic. Two sets of questionnaires, different in content, were administered to doctors and nurses, and to mothers of children aged 6-24 months, to assess hospital policy and breastfeeding rates, respectively. Stepwise multiple logistic regression analysis was used to examine factors associated with duration of breastfeeding. RESULTS: Although the hospital had a written breastfeeding policy copies of the policy were not clearly displayed in any of the units in the Paediatric department. Almost half the staff (48%; 60/125) were not aware of the policy. The hospital had no breastfeeding support group. Nearly three quarters (92/125) of the staff had received lactation management training. 36% (112/311) of mothers exclusively breastfed for six months, 42% (129/311) had stopped breastfeeding at the time of the survey. 67% (207/311) of babies were given infant formula, 85% (175/207) before 6 months. Women who had antenatal care in private hospitals and were Christian were more likely to breastfeed exclusively for 6 months. Low maternal education was the only factor associated with breastfeeding longer than 12 months. CONCLUSION: Breastfeeding practices and policy implementation at this outpatient clinic were suboptimal. We have identified a need for interventions to increase knowledge of the benefits of breastfeeding and to provide support for its longer term duration. We suggest that BFHI be considered across all facilities concerned with infant and early child health to disseminate appropriate information and promote an increase in exclusive breastfeeding for six months as well as the duration of breastfeeding. PMID- 25018777 TI - Optimization, evaluation, and comparison of standard algorithms for image reconstruction with the VIP-PET. AB - A novel positron emission tomography (PET) scanner design based on a room temperature pixelated CdTe solid-state detector is being developed within the framework of the Voxel Imaging PET (VIP) Pathfinder project [1]. The simulation results show a great potential of the VIP to produce high-resolution images even in extremely challenging conditions such as the screening of a human head [2]. With unprecedented high channel density (450 channels/cm3) image reconstruction is a challenge. Therefore optimization is needed to find the best algorithm in order to exploit correctly the promising detector potential. The following reconstruction algorithms are evaluated: 2-D Filtered Backprojection (FBP), Ordered Subset Expectation Maximization (OSEM), List-Mode OSEM (LM-OSEM), and the Origin Ensemble (OE) algorithm. The evaluation is based on the comparison of a true image phantom with a set of reconstructed images obtained by each algorithm. This is achieved by calculation of image quality merit parameters such as the bias, the variance and the mean square error (MSE). A systematic optimization of each algorithm is performed by varying the reconstruction parameters, such as the cutoff frequency of the noise filters and the number of iterations. The region of interest (ROI) analysis of the reconstructed phantom is also performed for each algorithm and the results are compared. Additionally, the performance of the image reconstruction methods is compared by calculating the modulation transfer function (MTF). The reconstruction time is also taken into account to choose the optimal algorithm. The analysis is based on GAMOS [3] simulation including the expected CdTe and electronic specifics. PMID- 25018778 TI - Complex systems models in biology and medicine: generic properties and applications. PMID- 25018779 TI - Impact of density of schistosomal antigen expression in urinary bladder tissue on the stratification, cell type, and staging, and prognosis of carcinoma of the bladder in Egyptian patients. AB - BACKGROUND: Infection with urinary schistosomiasis and its severity are oncogenic factors for developing carcinoma of the bladder, whether it is urothelial carcinoma (UC) of a transitional cell type (TCC) or non-urothelial of squamous cell carcinoma (SCC). In UC it is not defined whether it is schistosomal or not. This led to controversial results in expression of tumour markers, tumour prognosis, and response to therapy. OBJECTIVES: We assessed the application by immunohistochemistry method (IHC) for detection of schistosomal antigen in bladder cancer tissue samples to differentiate UC associated with or without schistosomiasis. Urothelial carcinoma stage, grade, and progression were correlated with the density, intensity, and index of schistosomal antigen expression. Follow up was done for 2-5 years. DESIGN AND PARTICIPANTS: Archival tissue samples of 575 patients were studied: 515 urothelial carcinoma, 30 patients with SCC associated with schistosomiasis, and a control group of 30 patients without schistosomiasis. MEASUREMENTS: Expression of schistosomal antigen in tissue was done by IHC using monoclonal antibodies (MAbs) against schistosomal antigens (SA). Correlation of intensity of antigen expression to clinical and pathological data was analysed. RESULTS AND LIMITATIONS: We identified 3 parameters of antigen expression: density, intensity and index with 4 grades for each. SCC-group was 100% positive. UC was positive in 61.4% distributed as follows: Ta: 37.5%, T1: 62%, and muscle invasive T2-4 were 64%. Upstaging, metastases and recurrence were correlated with high index in T1 and T2 4 tumours. CONCLUSION: Urothelial carcinoma associated with schistosomiasis was defined by the positive expression of schistosomal antigens in tissues detected by lHC using MAbs against schistosomal haematobium. Upstaging and progression of T1 and T2-4 were correlated with high density, intensity, and index of antigen expression. Non-schistosomal UC had negative expression for schistosomal antigen, which was detected in 36.5% of cases. These results would be of significance in differentiating schistosomal from non-schistosomal bladder cancer of UC and would predict the prognosis in T1, T2-3 tumours. Implementation of IHC using MAbs against SA in UC would help in planning the proper therapy. Schistosomiasis should be considered as an oncogene for UC in endemic areas. PMID- 25018780 TI - Alteration of leaf shape, improved metal tolerance, and productivity of seed by overexpression of CsHMA3 in Camelina sativa. AB - BACKGROUND: Camelina sativa (L.) Crantz, known by such popular names as "gold-of pleasure" and "false flax," is an alternative oilseed crop for biofuel production and can be grown in harsh environments. Considerable interest is now being given to the new concept of the development of a fusion plant which can be used as a soil remediation plant for ground contaminated by heavy metals as well as a bioenergy crop. However, knowledge of the transport processes for heavy metals across Camelina plant membranes is still rudimentary. RESULTS: Firstly, to investigate whether Camelina HMA (heavy metal P1B-ATPase) genes could be used in such a plant, we analyzed the expression patterns of eight HMA genes in Camelina (taken from the root, leaf, stem, flower, and silique). CsHMA3 genes were expressed in all organs. In addition, CsHMA3 was induced in roots and leaves especially after Pb treatment. Heterogeneous expression of CsHMA3 complemented the Pb- or Zn-sensitive phenotype of Deltaycf1 or Deltazrc1 yeast mutant strains. Subsequently, we cloned and overexpressed CsHMA3 in Camelina. The root growth of transgenic lines was better than that in the wild-type plant under heavy metal stress (for Cd, Pb, and Zn). In particular, the transgenic lines showed enhanced Pb tolerance in a wide range of Pb concentrations. Furthermore, the Pb and Zn content in the shoots of the transgenic lines were higher than those in the wild type plant. These results suggest that overexpression of CsHMA3 might enhance Pb and Zn tolerance and translocation. Also, the transgenic lines displayed a wider leaf shape compared with the wild-type plant due to an induction of genes related to leaf width growth and showed a greater total seed yield compared to the wild type under heavy metal stress. CONCLUSIONS: Our data obtained from physiological and functional analyses using CsHMA3 overexpression plants will be useful to develop a multifunctional plant that can improve the productivity of a bioenergy crop and simultaneously be used to purify an area contaminated by various heavy metals. PMID- 25018781 TI - Changes in full blood count parameters in leptospirosis: a prospective study. AB - BACKGROUND: Leptospirosis presents diagnostic challenges to clinicians, in settings where other acute febrile illness are prevalent. The patterns of serial changes in haematological parameters in leptospirosis has not been evaluated previously. METHODS: Clinical and laboratory data were collected prospectively from patients with leptospirosis in two hospitals in Sri Lanka. Leptospirosis was diagnosed based on WHO clinical criteria with confirmation using Microscopic Agglutination Test titre > 400 or 4 fold rise between acute and convalescent samples. Full blood count parameters were analysed up to the 14(th) day of illness. RESULTS: Data from 201 patients with leptospirosis were available. Leukocyte counts and absolute neutrophil counts showed a decline over the first 5 days of illness, then rose until the end of the second week. On day 3 of fever, the majority (75%) had normal leukocyte counts, and by day 5, leukocytosis was seen only in 38.1%; leucopenia was an uncommon finding. Lymphopenia was seen in over half on day 5, declining to just under a quarter of patients by day 10. Platelets declined over the first 6 days and then gradually rose. Thrombocytopenia was seen in nearly three-fourths of patients by day 5. Haemoglobin and haematocrit levels declined over the course of illness. Total white cell and neutrophil counts were higher, and haemoglobin and haematorcrit were significantly lower, in patients with severe disease. CONCLUSIONS: Neither leukocytosis nor lymphopenia were prominent features, while thrombocytopenia was seen during the 3(rd) to 5(th) day of illness, with dropping haemoglobin levels. Neutrophilia and low haemoglobin levels appear to predict severe disease. These findings may be of use to clinicians in differentiating leptospirosis from other acute infections like dengue, and could help in predicting severe leptospirosis. PMID- 25018782 TI - Serum HE4, CA125, YKL-40, bcl-2, cathepsin-L and prediction optimal debulking surgery, response to chemotherapy in ovarian cancer. AB - BACKGROUND: The most important prognostic factor in the ovarian cancer is optimal cytoreduction. The neoadjuvant chemotherapy, an only optional method of treatment in this case and is still the subject of debate. The object of this study was to evaluate the usefulness of markers: CA 125, HE4, YKL-40 and bcl-2 as well as cathepsin L in predicting optimal cytoreduction and response to chemotherapy. METHODS: Sera were secured preoperatively. The division into groups was performed retrospectively depending on the method of treatment (surgery vs neoadjuvant chemotherapy) as well as on response to chemotherapy (sensitive vs resistant vs refractory). Comparisons were made between groups, and the diagnostic usefulness of tested proteins was examined. RESULTS: We found that statistically significant differences between primary operated patients and patients undergoing neoadjuvant chemotherapy were applicable only to the tumour markers (CA125 1206.79 vs 2432.38, p=0.000191; HE4 78.87 vs 602.45, p=0.000004; YKL-40 108.13 vs 203.96, p=0.003991). Cathepsin-L and Bcl-2 were statistically insignificant. The cut-off point values were determined for the CA 125 (345 mIU/ml), HE4 (218.43 pmol/L) and YKL-40 (140.9 ng/ml). The sensitivity, specificity, PPV and NPV were as follows: CA125 (83.3%; 75%; 80.6%; 78.3%), HE4 (86.6%; 91.3%; 92.9%; 84%) and YKL-40 (75%; 83.3%; 84%; 74.1%). CONCLUSION: Among the tested proteins the HE4 marker appears to be helpful in forecasting of optimal cytoreduction and possibly also of the prediction of response to platinum analogues used in first-line treatment of ovarian cancer. PMID- 25018783 TI - Ovarian adult stem cells: hope or pitfall? AB - For many years, ovarian biology has been based on the dogma that oocytes reserve in female mammals included a finite number, established before or at birth and it is determined by the number and quality of primordial follicles developed during the neonatal period. The restricted supply of oocytes in adult female mammals has been disputed in recent years by supporters of postnatal neo-oogenesis. Recent experimental data showed that ovarian surface epithelium and cortical tissue from both mouse and human were proved to contain very low proportion of cells able to propagate themselves, but also to generate immature oocytes in vitro or in vivo, when transplanted into immunodeficient mice ovaries. By mentioning several landmarks of ovarian stem cell reserve and addressing the exciting perspective of translation into clinical practice as treatment for infertility pathologies, the purpose of this article is to review the knowledge about adult mammalian ovarian stem cells, a topic that, since the first approach quickly attracted the attention of both the scientific media and patients. PMID- 25018784 TI - Characterization of bacterial community shift in human Ulcerative Colitis patients revealed by Illumina based 16S rRNA gene amplicon sequencing. AB - BACKGROUND: The healthy human intestine is represented by the presence of bacterial communities predominantly belonging to obligate anaerobes; however disparity and dysanaerobiosis in intestinal microflora may lead to the progression of ulcerative colitis (UC). The foremost aim of this study is to consider and compare the gut microbiota composition in patients suffering from different stages of UC. METHODS: This study represents data from the biopsy samples of six individuals suffering from UC. The samples were collected by colonoscopy and were processed immediately for isolation of DNA. Mucosal microbiota was analyzed by means of 16S rRNA gene-based Illumina high throughput sequencing. Quantitative real-time PCR (qPCR) was performed to determine total bacterial abundances. RESULTS: Analysis of 23,927 OTUs demonstrated a significant reduction of bacterial diversity consistently from phylum to species level (p < 0.05) for individuals suffering from severe stage of UC. Significant increase in abundance of unusual aerobes and facultative anaerobes, including members from the phylum Proteobacteria (p- = 0.031) was also observed. A 10 fold increase in the total bacterial count was detected in patients suffering from severe inflammatory stage (2.98 +/-0.49 E + 09/ml) when compared with patients with moderate (1.03+/-0.29 E + 08/ml) and mild (1.76 +/-0.34 E + 08/ml) stages of inflammation. CONCLUSION: The reduction of bacterial diversity with an increase in the total bacterial count indicates a shift of bacterial communities which signifies dysbiosis and dysanaerobiosis at the mucosal level for patients suffering from UC. PMID- 25018785 TI - Mammalian-wide interspersed repeat (MIR)-derived enhancers and the regulation of human gene expression. AB - BACKGROUND: Mammalian-wide interspersed repeats (MIRs) are the most ancient family of transposable elements (TEs) in the human genome. The deep conservation of MIRs initially suggested the possibility that they had been exapted to play functional roles for their host genomes. MIRs also happen to be the only TEs whose presence in-and-around human genes is positively correlated to tissue specific gene expression. Similar associations of enhancer prevalence within genes and tissue-specific expression, along with MIRs' previous implication as providing regulatory sequences, suggested a possible link between MIRs and enhancers. RESULTS: To test the possibility that MIRs contribute functional enhancers to the human genome, we evaluated the relationship between MIRs and human tissue-specific enhancers in terms of genomic location, chromatin environment, regulatory function, and mechanistic attributes. This analysis revealed MIRs to be highly concentrated in enhancers of the K562 and HeLa human cell-types. Significantly more enhancers were found to be linked to MIRs than would be expected by chance, and putative MIR-derived enhancers are characterized by a chromatin environment highly similar to that of canonical enhancers. MIR derived enhancers show strong associations with gene expression levels, tissue specific gene expression and tissue-specific cellular functions, including a number of biological processes related to erythropoiesis. MIR-derived enhancers were found to be a rich source of transcription factor binding sites, underscoring one possible mechanistic route for the element sequences co-option as enhancers. There is also tentative evidence to suggest that MIR-enhancer function is related to the transcriptional activity of non-coding RNAs. CONCLUSIONS: Taken together, these data reveal enhancers to be an important cis regulatory platform from which MIRs can exercise a regulatory function in the human genome and help to resolve a long-standing conundrum as to the reason for MIRs' deep evolutionary conservation. PMID- 25018787 TI - Roles for the High Affinity IgE Receptor, FcepsilonRI, of Human Basophils in the Pathogenesis and Therapy of Allergic Asthma: Disease Promotion, Protection or Both? AB - The role of basophils, the rarest of blood granulocytes, in the pathophysiology of allergic asthma is still incompletely understood. Indirect evidence generated over many decades is consistent with a role for basophils in disease promotion. Recent improvements in procedures to purify and analyze very small numbers of human cells have generally supported this view, but have also revealed new complexities. This chapter focuses on our analyses of Fcepsilon R1 function in basophils in the context of understanding and treating human allergic asthma. In long-term studies, we demonstrated that asthmatic subjects have higher circulating numbers of basophils than non-atopic non-asthmatic subjects and that their basophils show higher rates of both basal and anti-IgE or antigen stimulated histamine release. These results hint at a direct role for basophils in promoting asthma. Supporting this interpretation, the non-releaser phenotype that we linked to the excessive proteolysis of Syk via the ubiquitin/proteasomal pathway is less common in basophils from asthmatic than non-asthmatic donors. The discovery of a basophil-specific pathway regulating Syk levels presents a clear opportunity for therapy. Another route to therapy was revealed by evidence that basophil FcepsilonRI signaling can be downregulated by co-crosslinking the ITAM containing IgE receptor, FcgammaRI, to the ITIM-containing IgG receptor, FcgammaRIIB. Based on this discovery, hybrid co-crosslinking fusion proteins are being engineered as potential therapies targeting basophils. A third distinguishing property of human basophils is their high dependence on IgE binding to stabilize membrane FcepsilonRI. The circulating IgE scavenging mAb, Omalizumab, reduces FcepsilonRI expression in basophils from asthmatics by over 95% and produces a substantial impairment of IL-4, IL-8 and IL-13 production in response to the crosslinking of residual cell surface IgE-FcepsilonRI. A search for small molecule inhibitors that similarly impair high affinity IgE binding to basophils may yield reagents that mimic Omalizumab's therapeutic benefits without the potential for immune side effects. Although studies on allergen and FcepsilonRI-mediated basophil activation all point to a role in promoting disease, a case can also be made for an alternative or additional role of basophil FcepsilonRI in protection against allergic asthma. Human basophils have high affinities for IgE, they upregulate receptor levels over a >100-fold range as circulating IgE levels increase and they have short half-lives in the circulation. Thus, when allergen is absent, basophil FcepsilonRI could serve as scavengers of serum IgE and therefore protectors against mast cell IgE-mediated inflammatory responses. Further studies are clearly needed to determine if FcepsilonR-expressing basophils play pathogenic or protective roles - or both - in human allergic asthma and other IgE-mediated inflammatory disorders. PMID- 25018788 TI - GENE-LEVEL PHARMACOGENETIC ANALYSIS ON SURVIVAL OUTCOMES USING GENE-TRAIT SIMILARITY REGRESSION. AB - Gene/pathway-based methods are drawing significant attention due to their usefulness in detecting rare and common variants that affect disease susceptibility. The biological mechanism of drug responses indicates that a gene based analysis has even greater potential in pharmacogenetics. Motivated by a study from the Vitamin Intervention for Stroke Prevention (VISP) trial, we develop a gene-trait similarity regression for survival analysis to assess the effect of a gene or pathway on time-to-event outcomes. The similarity regression has a general framework that covers a range of survival models, such as the proportional hazards model and the proportional odds model. The inference procedure developed under the proportional hazards model is robust against model misspecification. We derive the equivalence between the similarity survival regression and a random effects model, which further unifies the current variance component based methods. We demonstrate the effectiveness of the proposed method through simulation studies. In addition, we apply the method to the VISP trial data to identify the genes that exhibit an association with the risk of a recurrent stroke. TCN2 gene was found to be associated with the recurrent stroke risk in the low-dose arm. This gene may impact recurrent stroke risk in response to cofactor therapy. PMID- 25018786 TI - Control of cellular motility by neuropilin-mediated physical interactions. AB - The neuropilin (Nrp) family consists of multifunctional cell surface receptors with critical roles in a number of different cell and tissue types. A core aspect of Nrp function is in ligand-dependent cellular migration, where it controls the multistep process of cellular motility through integration of ligand binding and receptor signaling. At a molecular level, the role of Nrp in migration is intimately connected to the control of adhesive interactions and cytoskeletal reorganization. Here, we review the physiological role of Nrp in cellular adhesion and motility in the cardiovascular and nervous systems. We also discuss the emerging pathological role of Nrp in tumor cell migration and metastasis, providing motivation for continued efforts toward developing Nrp inhibitors. PMID- 25018789 TI - Factors Controlling the Spectroscopic Properties and Supramolecular Chemistry of an Electron Deficient 5,5-Dimethylphlorin Architecture. AB - A new 5,5-dimethylphlorin derivative (3H(PhlCF3 )) was prepared and studied through a combination of redox, photophysical, and computational experiments. The phlorin macrocycle is significantly distorted from planarity compared to more traditional tetrapyrrole architectures and displays solvatochroism in the soret region of the UV-vis spectrum (~370-420 nm). DFT calculations indicate that this solvatochromic behavior stems from the polarized nature of the frontier orbital (LUMO+1) that is most heavily involved in these transitions. Compound 3H(PhlCF3 ) also displays an intriguing supramolecular chemistry with certain anions; this phlorin can cooperatively hydrogen-bond two equivalents of fluoride to form 3H(PhlCF3 ).2F- but does not bind larger halides such as Cl- or Br-. Analogous studies revealed that the phlorin can hydrogen-bond with carboxylate anions such as acetate to form 1:1 complexes such as 3H(PhlCF3 ).OAc- . These supramolecular assemblies are robust and form even in relatively polar solvents such as MeCN. Hydrogen-bonding of fluoride and acetate anions to the phlorin N-H residues significantly attenuates the redox and photophysical properties of the phlorin. Moreover, The ability to independently vary the size and pKa of a series of carboxylate hydrogen-bond acceptors has allowed us to probe how phlorin-anion association is controlled by the anion's size and/or basicity. These studies elucidate the physical properties and the electronic effects that shape the supramolecular chemistry displayed by the phlorin platform. PMID- 25018790 TI - Mechanistic Insights into the Formation of Dodecanethiolate-Stabilized Magnetic Iridium Nanoparticles: Thiosulfate vs Thiol Ligands. AB - The synthesis of stable and isolable iridium nanoparticles with an average core size of ~1.2 +/- 0.3 nm was achieved by employing sodium S-dodecylthiosulfate as a ligand precursor during the modified Brust-Schiffrin reaction. Transmission electron microscopy (TEM) of the isolated Ir nanoparticles revealed a high degree of monodispersity. Further characterizations with 1H NMR, FT-IR, UV-vis spectroscopy, thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS) confirmed that the synthesized Ir nanoparticles are stabilized by dodecanethiolate ligands produced upon the adsorption/cleavage of S dodecylthiosulfate on the growing Ir nanoparticle surface. By comparison, synthetic attempts employing dodecanethiol as a stabilizing ligand led to the formation of Ir-thiolate species (Ir(SR)3) as an intermediate and Ir-hydroxide species at the completion of reaction. Mechanistic investigations of these two reactions using S-dodecylthiosulfate and dodecanethiol provided deeper understandings on the novelty of thiosulfate ligands, which allow the successful formation of stable thiolate-capped Ir nanoparticles. Moreover, these Ir nanoparticles were shown to have strong magnetic properties. PMID- 25018791 TI - Preoperative diagnosis of bicipitoradial bursitis: a case report. AB - Inflammation of the bicipitoradial bursa is a rare condition and only few reports can be found in literature. Several causes for a cubital bursitis have been suggested in the past. The need to include a malignant lesion in the differential diagnosis has only been mentioned in one of these reports. May main objective in reporting this case is to make this pathological entity better known. PMID- 25018792 TI - [Epidemiology of gastric cancer: experience of a Moroccan hospital]. PMID- 25018793 TI - [A rare cause of respiratory distress in infants: subglottic hemangioma]. PMID- 25018795 TI - [Bilateral axillary supernumerary breasts]. PMID- 25018794 TI - Adherence to antiepileptic drugs among children attending a tertiary health unit in a low resource setting. AB - INTRODUCTION: Epilepsy is one of the neglected and highly stigmatised diseases, yet it is very common affecting about 70 million people worldwide. In Uganda, the estimated prevalence of epilepsy is 13% with about 156 new cases per 100,000 people per year. Adherence to antiepileptic drugs is crucial in achieving seizure control yet in Uganda; there is lack of information on adherence to antiepileptic drugs and the factors that affect this among children. This study was therefore designed to determine the level of adherence to antiepileptic drugs and the factors that are associated with non adherence. METHODS: In a cross sectional study, 122 children who met the inclusion criteria were enrolled and interviewed using a pretested questionnaire. Assessment of adherence to antiepileptic drugs was done by self report and assay of serum drug levels of the antiepileptic drugs. Focus group discussions were held to further evaluate the factors that affect adherence. RESULTS: Age range was 6 months - 16 years, male to female ratio 1.3:1 and majority had generalised seizures 76 (62.3%). Adherence to antiepileptic drugs by self report was 79.5% and 22.1% by drug levels. Majority of the children in both adherent and non adherent groups by self report had inadequate drug doses (95/122). Children were found to be more non-adherent if the caregiver had an occupation (p-value 0.030, 95%CI 1.18-28.78). CONCLUSION: Majority of children had good adherence levels when estimated by self report. The caregiver having an occupation was found to increase the likelihood of non adherence in a child. PMID- 25018796 TI - [Study of anemia in HIV positive children naive to antiretroviral treatment in Lubumbashi, Democratic Republic of Congo]. PMID- 25018797 TI - [Superior mesenteric artery syndrome: rare, but think about it]. PMID- 25018798 TI - [Cystic lymphangioma of the lesser sac]. PMID- 25018799 TI - Vancomycin resistant enterococcus bacteremia in a patient with Pneumocystis jiroveci pneumonia, granulocystic sarcoma and acute respiratory distress syndrome. AB - In this case report we aimed to present a patient with granulocytic sarcomaa, neutropenic fever, ARDS and Pneumocystis jirovecii pneumoniae that was hospitalized in our intensive care unit. The patient recovered and then developed vancomycin resistant enterococci (VRE) bacteremia due to port catheter during follow up. The patient had risk factors for VRE bacteremia and he was administered linezolide without removing the catheter. He was discharged with recovery. PMID- 25018800 TI - [Neurofibromatosis type I]. PMID- 25018801 TI - [Giant cells angiofibroma of the eye-socket: report of a case]. PMID- 25018802 TI - Bilateral fracture of the olecranon in a young footballer. PMID- 25018803 TI - The prevalence of hepatitis B virus E antigen among Ghanaian blood donors. AB - Hepatitis B viral infection is an important clinical problem due to its worldwide distribution and potential of adverse sequelae, including hepatocellular carcinoma (HCC). We studied the prevalence of hepatitis B virus 'e' antigen (HBeAg) among individuals determined to be hepatitis B virus (HBV) surface antigen-positive and analyzed the gender/age category associated with more active HBV infection and whether alteration in the levels of alanine aminotransferase could be associated with HBeAg positivity. A total of 150 prospective blood donors who tested positive for hepatitis B surface antigen (HBsAg) at the blood transfusion center of the Komfo Anokye Teaching Hosptital (KATH), Kumasi were randomly selected for the study. The serum samples were further tested for HBsAg and HBeAg using a lateral flow immunochromatographic assay. Twenty (20) individuals were found to be HBeAg-positive giving an overall prevalence of 13.3%, of which 18 (15.5%) were males and 2 (5.9%) were females. Our results also revealed that the prevalence of HBeAg was higher in patients between the age group of 10-20 years and appeared to decrease with increase in age. There was no statistical difference between the HBeAg positive and negative individuals with respect to alanine aminotransferase (ALT) levels. We show for the first time that approximately 1/10 of HBV-infected individuals are HBeAg positive in the Ashanti Region of Ghana, suggestive of active viral replication and liver-cell infectivity thereby contributing to an increased HBV-transmission pool within the Ghanaian population. PMID- 25018804 TI - The role of magnetic resonance imaging and visual evoked potential in management of optic neuritis. AB - INTRODUCTION: To report our experience in management of patients with optic neuritis. The effects of brain magnetic resonance imaging and visual evoked potential on management were investigated. METHODS: This is a four years clinical trial that included patients presenting with first attack of optic neuritis older than 16 years with visual acuity of less than 6/60 and presentation within first week of illness. Brain magnetic resonance imaging and visual evoked potentials were done for all patients. Patients were classified into three groups. First group received placebo, second received oral steroids and third received intravenous and oral steroids. Primary outcome measure was improvement in visual acuity. RESULTS: A total number of 150 patients were enrolled in the study. Ocular pain was seen 127 patients Relative afferent pupillary defect in 142 patients and color vision impairment in 131 patients. Abnormal MRI findings were seen in 84 patients. Pattern reversal VEP was abnormal in all patients. Using oral or intravenous steroid resulted in faster recovery but did not affect the final visual outcome. Recurrence rate was higher in patients with multiple MRI lesions and diminished VEP amplitude. Using intravenous steroids decreased recurrence rate in patients with three and more MRI lesions and non recordable VEP response. CONCLUSION: MRI and pattern reversal VEP are recommended to be done in all patients presenting with optic neuritis. We advise to give intravenous methyl prednisolone in patients with multiple MRI white matter lesions and non recordable VEP at presentation. PMID- 25018805 TI - The Gorlin-Goltz syndrome: a sporadic case. PMID- 25018806 TI - A case of dysphagia. PMID- 25018807 TI - [Prevalence and risk factors of overweight and obesity in a population of school children in urban areas Sfax, Tunisia]. PMID- 25018808 TI - Yellow card or red card: airport tribulations and new developments on yellow fever vaccination. PMID- 25018809 TI - [Destructive chronic arthritis revealing a relapsing polychondritis]. PMID- 25018810 TI - Right upper quadrant pain: a case where diagnosis was made from the chest X-Ray. PMID- 25018811 TI - Unusual actinomycosis of the chest wall. PMID- 25018812 TI - [Hospital-based morbidity and mortality from cardiovascular diseases in tropical areas: example of a hospital in Lome (Togo)]. PMID- 25018813 TI - Malignant infantile osteopetrosis: case report with review of literature. AB - Malignant Infantile Osteopetrosis (MIOP) is a rare genetic disorder due to osteoclast abnormal activity. We report a thirteen month-old male patient, diagnosed as MIOP while investigating the cause of hepatosplenomegaly associated with hydrocephalus. His medical history revealed non consanguineous parents and one brother's death at the same age of unknown etiology (similar symptoms). Systemic examination showed hepatosplenomegaly, growth failure, developmental milestones delay, and rickets features. Ophthalmic exam yielded bilateral optic atrophy. Skeleton radiographs detected generalized dense bone and rickets. Cerebral CT scan revealed hydrocephalus. Histological examination showed hypoplastic bone marrow and extra-medullary hematopoeisis. Diagnosis was confirmed by genetic testing that showed two heterozygote mutations within the TCIRG1 gene. The patient received supportive treatment. He died from an acute respiratory distress. MIOP should be kept in mind as a rare cause of hepatosplenomegaly. Early diagnosis and timely Hematopoietic stem cell transplantation are the only curative approach for an otherwise fatal disease. PMID- 25018814 TI - [Orbital tuberculosis: about a case]. PMID- 25018815 TI - No need to wait for the blood tests: the clinical diagnosis of hypocalcemia. PMID- 25018816 TI - [Using color Doppler ultrasonography in the localization of the insertion of the umbilical cord and maternal-fetal outcome at the maternity ward of Yaounde Central Hospital of: a descriptive and analytical study]. PMID- 25018817 TI - Multiple massive neurofibromas of lumbosacral plexus with intraspinal and pelvic extension. PMID- 25018818 TI - [Lymphangioma circumscriptum]. PMID- 25018819 TI - Intraosseous extradural meningioma of the frontal bone. PMID- 25018820 TI - [Clinical and epidemiological profile of tuberculosis in the health area of Lubumbashi (DR Congo)]. PMID- 25018821 TI - [Ocular toxocariasis: report of two cases and review of the literature]. PMID- 25018822 TI - 2013, a very good year. PMID- 25018823 TI - [Painful bruising syndrome: an entity rare not to ignore]. PMID- 25018824 TI - [Corneal dystrophy: Granular dystrophy or Groenouw dystrophy Type 1]. PMID- 25018825 TI - Lipid profile frequency and the prevalence of dyslipidaemia from biochemical tests at Saint Louis University Hospital in Senegal. AB - INTRODUCTION: The aim of this study was to evaluate the frequency of lipid profile requests and the prevalence of dyslipidemia in patients at the biochemistry laboratory of St. Louis University Hospital, as well as their correlation with sex and age. METHODS: This was a retrospective study reviewing 14,116 laboratory results of patients of both sexes, over a period of six months (January-June 2013) regardless of the indication for the request. The lipid parameters included were: Total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides with normal values defined as follows: Total cholesterol (<2g/l), HDL- cholesterol (>0,40g/l), LDL- cholesterol (<1,30g/l) and Triglycerides (<1,50g/l). RESULTS: The average age of our study population was 55.15 years with a female predorminance (M/F = 0.60). The age group most represented was that between 55-64 years. The frequency of lipid profile request in our sample was 9.41% (or 1,329). The overall prevalence of isolated hypercholesterolemia, hyperLDLaemia, hypoHDLaemia, hypertriglyceridaemia, and mixed hyperlipidemia were respectively 60.91%, 66.27%, 26.58%, 4.57% and 2.75%. Hypercholesterolemia, hyperLDLaemia, hypertriglyceridaemia and mixed hyperlipidaemia were higher in women with respectively 66.22%, 67.98%, 4.58%, 2.89% than in men (52.01%, 62.81%, 4.44% and 2.40% respectively). On the other hand, the prevalence of hypoHDLaemia was higher in males (32.19%) compared to females (23.76%). Hypercholesterolemia correlated significantly with age and sex. CONCLUSION: Our study showed a relatively low request rate for lipid profile and a high prevalence of dyslipidaemia hence the importance of conducting a major study on the prevalence of dyslipidaemia and associated factors in the Senegalese population. PMID- 25018826 TI - Assessment of client satisfaction in labor and delivery services at a maternity referral hospital in Ethiopia. AB - INTRODUCTION: Patients perception about service quality shapes their confidence with regard to use of the available health care facility. This study is aimed to assess the client's satisfaction in a maternal health care setting. METHODS: This is an institution based cross sectional descriptive study. A total of 423 postpartum women were interviewed. Data was analyzed using SPSS version 20 statistical package. RESULTS: The proportion of mothers who are completely satisfied with health care ranges between 2.4 to 21%. Pain control was the poorest source of satisfaction with 82% reporting dissatisfaction. Provider's communication with clients yielded complete satisfaction rates ranging between 0.7 to 26%. Inadequate information about the drug prescribed and explanation of procedures to be done to the client were found to be major causes of dissatisfaction. The complete satisfaction rate with environmental factor of the hospital was between 3.3 to 40.2%. Age of the client, educational status, income of the client and client's address away from Addis Ababa were found to be the predictors of client satisfaction. Provider's attitude and communication, as well as longer duration of stay in the ward were independent predictors of client satisfaction. CONCLUSION: Pain management, client privacy and client provider communication need to be addressed to ensure the satisfaction of maternity clients. The clients need to be involved in the management of their own health problems. PMID- 25018827 TI - Impact of heavy load activity on cardiovascular system: echocardiographic assessment of informal construction workers heart in Cameroon. AB - INTRODUCTION: Physiological cardiac hypertrophy and dilation are common findings in heavy physical load activity. We carried out this study to investigate the relationship between construction work and cardiac parameters adaptations, by comparing healthy masons to office workers on heart ultrasound. METHODS: The study was carried out on, 50 construction workers and 50 office workers matched for their weight, height and age. Systolic and Diastolic blood pressures, Left Ventricular diameter and thickness, Septum wall thickness and Left ventricular mass index were measured and calculated. RESULTS: Heart rate, systolic and diastolic blood pressures were lower in construction workers, as compared to office workers: respectively 63+/-7 bpm vs. 75+/-6 bpm (p = 0.000); 120.1+/-7 mmHg vs. 130.5+/-9 mmHg (p = 0.000) and 68.5+/-7 mmHg vs. 77.0 +/-9 mmHg (p = 0.000). Construction workers had a thicker septum and posterior wall: respectively 10.3 +/- 1.1 mm vs. 8.9 +/- 0.9 mm (p = 0.000); and 9.0 +/- 1.2 mm vs. 8.1 +/- 0.8 mm (p = 0.000). CONCLUSION: Conclusion We deducted that heavy load work has an impact on the heart mensuration. The past occupational history has to be taken into consideration during initial medical assessing of a worker in for a new job so as to avoid erroneous conclusions. PMID- 25018828 TI - [Ankle arthrodesis: technic and results: about 10 cases]. PMID- 25018829 TI - Musculoskeletal disorders among nursing staff: a comparison of five hospitals in Uganda. AB - INTRODUCTION: Low and middle income countries have severe nursing staff shortages which is associated with risk of poor quality of patient care and increased patient exposure to adverse events. This is accompanied with increased risk of musculoskeletal disorders to the nursing staff. This paper sets out to identify and compare factors associated with musculoskeletal disorders among nursing staff in 5 different hospitals in Uganda. METHODS: This was a cross sectional study on nurses from 5 different hospitals in Uganda. The study used a 12 month recall of reported Musculoskeletal disorders (MSD) among nurses. Ethical approval was obtained. Logistic regression analysis and ANOVA were used. The level of significance was set at 0.05 for all statistical tests. RESULTS: There were 755 respondents of whom 433 (58.4%) were nurses. The prevalence of MSD at anybody site was 80.8%. There were significant differences in reported MSD among nursing staff across different hospital settings which were worse in the public hospitals as compared to the private and private not for profit hospitals (p <0.001). Age (adjusted OR 1.03, 95% CI 1.01-1.06), self reported poor general health status (adj OR 4.5, 95% CI 2.8-7.24) and stress as suggested by waking up tired in the morning (adj OR 3.4, 95% CI 2.17-5.32) were significant associated factors for MSD in this population. CONCLUSION: Reported MSD among nursing staff across 5 different hospitals is worse in public as compared to private hospitals. Age, self reported poor general health status and stress were important factors for MSD in this population. PMID- 25018830 TI - [Chronic necrotizing pulmonary Aspergillus niger aspergillosis in a smoker and former TB patient]. PMID- 25018831 TI - Possible macrophage activation syndrome following initiation of adalimumab in a patient with adult-onset Still's disease. AB - Macrophage activation syndrome (MAS) has been rarely reported in the course of adult-onset Still's disease (AOSD) and in the majority of cases, it was triggered by an infection. Here, we report, to our knowledge, the first case of MAS occurring after adalimumab treatment initiation and not triggered by an infection. A 26-yearold woman with classical features of AOSD developed persistent fever, severe bicytopenia associated with extreme hyperferritinemia, hyponatremia and abnormal liver function tow months after the initiation of adalimumab treatment. The diagnosis of MAS was made without histological proof. The patient was treated with methylprednisolone pulse therapy and her condition improved. During the disease course, extensive studies could not identify any viral infection or other known underlying etiology for the reactive MAS. The adalimumab was incriminated in this complication. Currently, the patient is in remission on tocilizumab and low-dose prednisolone. PMID- 25018832 TI - Neglected painless wounds in a child with congenital insensitivity to pain. PMID- 25018833 TI - Vertebral artery dissection due to an esophageal foreign body migration: a case report. AB - Unintentional foreign bodies' swallowing is a fairly common occurrence in ENT consultation especially among children. They usually pass through the gastrointestinal tract without complications. Migration of a foreign body through the esophageal wall is rare. It represents about 1% to 4% of all cases of foreign bodies' ingestion. A 16 year's old female patient has presented to ENT emergency with a painful dysphagia following an accidental ingestion of a metallic pin. Cervical X ray confirmed the presence of the pin while endoscopic investigations have shown no foreign body. Cervical CT scan revealed the migration of the foreign body through the esophageal wall with left vertebral artery dissection. Endoscopic management has been sufficient with an uneventful post operative follow up. Esophageal foreign bodies are very diverse mainly dominated by fish bones (60%) and chicken bones (16%). Metallic pins are rare. The major risks of migration of those foreign bodies are cervical abscess, mediastinitis and oeso vascular fistulae. Cases of self extrusion through the skin have been reported. Migration of a foreign body through the esophageal wall is rare. Endoscopic management has been sufficient. PMID- 25018834 TI - Myelinated retinal nerve fibers. PMID- 25018835 TI - [A peri-liver abscess complicating duodenal perforation taken for a subcapsular liver abscess]. PMID- 25018836 TI - [Ovarian cyst and pregnancy]. PMID- 25018837 TI - [Etiologic profile of severe and profound sensorineural hearing loss in children in the region of north-central Morocco]. PMID- 25018838 TI - [Choroidal white spots and sarcoidosis]. PMID- 25018839 TI - [Hidradenocarcinoma of the scalp: report of a case]. PMID- 25018840 TI - [A painful hip bone revealing multifocal histiocytosis]. PMID- 25018842 TI - [Early acute coagulopathy of severe head injuries: mortality and prognostic factors]. PMID- 25018841 TI - Strictly-posterior thoracotomy: a minimal-access approach for construction of the modified Blalock-Taussig shunt in West African children. AB - INTRODUCTION: In resource-poor settings, the modified Blalock-Taussig shunt (MBTS) is often performed for symptomatic relief of Fallot's tetralogy. From September 2011, we adopted the strictly posterior thoracotomy (SPOT), a minimal access technique for the MBTS and report the cosmetic advantages in this communication. METHODS: We retrospectively analyzed the records of consecutive patients in whom the SPOT approach was used to construct the MBTS. Study end points were early mortality, improvement in peripheral oxygenation, morbidity, and the cosmetic appeal. RESULTS: Between September 2011 and January 2013, 15 males and 8 females, median age 4 years (1.3 - 17 years) and weight 13 kg (11 - 54 kg) underwent the MBTS through the SPOT approach. The polytetrafluoroethylene grafts used ranged from sizes 4 - 6mm (median 5mm). The median preoperative SpO2 was 74% (55% - 78%), increasing to a postoperative median value of 84% (80% - 92%). Shunts were right-sided in 22 patients and left-sided in one. There were no shunt failures. Hospital stay ranged from 7 - 10 days. There was one early death (4.3%), and two postoperative complications (re-exploration for bleeding and readmission for drainage of pleural effusion). The surgical scars had excellent cosmetic appeal: they ranged from 5-10 cm in length; all were entirely posterior and imperceptible to the patient. CONCLUSION: The SPOT approach represents a safe and cosmetically superior alternative to the standard posterolateral thoracotomy, the scar being imperceptible to the patient. The excellent cosmetic appeal and preservation of body image makes this approach particularly attractive in children and young adults. PMID- 25018843 TI - Successfully treated unusual case of primary adrenal and spinal tuberculosis with three years follow up. AB - The global increase in incidence of Tuberculosis (TB) is returning to be a major health issue grabbing a universal concern. Although extrapulmonary tuberculosis (EPTB) has a broad spectrum of clinical manifestations, primary involvement of the adrenal glands along with spine without pulmonary affection has been rarely reported. We report a case of successfully treated adult Asian male patient presented with primary adrenal TB, complicated with chronic adrenal insufficiency accompanied with upper lumber spinal TB. We also present the follow up of our patient after three years. PMID- 25018844 TI - [Clinical profile of post-cerebrovascular depression: descriptive cross-sectional study in the rehabilitation center for people with disabilities of Kinshasa (DR Congo)]. PMID- 25018845 TI - [Type 7 spinocerebellar ataxia (SCA) dignosed by the appearance of the fundus]. PMID- 25018846 TI - Cardiac Masses on Cardiac CT: A Review. AB - Cardiac masses are rare entities that can be broadly categorized as either neoplastic or non-neoplastic. Neoplastic masses include benign and malignant tumors. In the heart, metastatic tumors are more common than primary malignant tumors. Whether incidentally found or diagnosed as a result of patients' symptoms, cardiac masses can be identified and further characterized by a range of cardiovascular imaging options. While echocardiography remains the first-line imaging modality, cardiac computed tomography (cardiac CT) has become an increasingly utilized modality for the assessment of cardiac masses, especially when other imaging modalities are non-diagnostic or contraindicated. With high isotropic spatial and temporal resolution, fast acquisition times, and multiplanar image reconstruction capabilities, cardiac CT offers an alternative to cardiovascular magnetic resonance imaging in many patients. Additionally, cardiac masses may be incidentally discovered during cardiac CT for other reasons, requiring imagers to understand the unique features of a diverse range of cardiac masses. Herein, we define the characteristic imaging features of commonly encountered and selected cardiac masses and define the role of cardiac CT among noninvasive imaging options. PMID- 25018847 TI - Primary prevention of bleeding from esophageal varices in patients with liver cirrhosis. AB - Variceal bleeding is a life threatening situation with mortality rates of at least 20%. Prophylactic treatment with non-selective beta blockers (NSBBs) is recommended for patients with small varices that have not bled but with increased risk for bleeding. The recommended treatment strategies on primary prevention of variceal bleeding in patients with medium and large-sized varices are NSBBs or endoscopic band ligation. Nitrates, shunt surgery and sclerotherapy are not recommended in this setting. In this review, the most recent data on prevention of esophageal variceal bleeding are presented. Available data derived from randomized-controlled trials suggest both treatment strategies, and according to Baveno V consensus in portal hypertension "the choice of treatment should be based on local resources and expertise, patient preference and characteristics, side-effects and contra-indications". PMID- 25018848 TI - Management of cytomegalovirus infection and disease in liver transplant recipients. AB - Cytomegalovirus (CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and such occurrence of late-onset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach (antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation. PMID- 25018849 TI - Clinical impact of occult hepatitis B virus infection in immunosuppressed patients. AB - Occult hepatitis B infection (OBI), is characterized by low level hepatitis B virus (HBV) DNA in circulating blood and/or liver tissue. In clinical practice the presence of antibody to hepatitis B core antigen in hepatitis B surface antigen (HBsAg)-/anti-HBs-negative subjects is considered indicative of OBI. OBI is mostly observed in the window period of acute HBV infection in blood donors and in recipients of blood and blood products, in hepatitis C virus chronic carriers, in patients under pharmacological immunosuppression, and in those with immunodepression due to HIV infection or cancer. Reactivation of OBI mostly occurs in anti-HIV-positive subjects, in patients treated with immunosuppressive therapy in onco-hematological settings, in patients who undergo hematopoietic stem cell transplantation, in those treated with anti-CD20 or anti-CD52 monoclonal antibody, or anti-tumor necrosis factors antibody for rheumatological diseases, or chemotherapy for solid tumors. Under these conditions the mortality rate for hepatic failure or progression of the underlying disease due to discontinuation of specific treatment can reach 20%. For patients with OBI, prophylaxis with nucleot(s)ide analogues should be based on the HBV serological markers, the underlying diseases and the type of immunosuppressive treatment. Lamivudine prophylaxis is indicated in hemopoietic stem cell transplantation and in onco-hematological diseases when high dose corticosteroids and rituximab are used; monitoring may be indicated when rituximab-sparing schedules are used, but early treatment should be applied as soon as HBsAg becomes detectable. This review article presents an up-to-date evaluation of the current knowledge on OBI. PMID- 25018850 TI - Challenge of liver disease in systemic lupus erythematosus: Clues for diagnosis and hints for pathogenesis. AB - Systemic lupus erythematosus (SLE) encompass a broad spectrum of liver diseases. We propose here to classify them as follows: (1) immunological comorbilities (overlap syndromes); (2) non-immunological comorbilities associated to SLE; and (3) a putative liver damage induced by SLE itself, referred to as "lupus hepatitis". In the first group, liver injury can be ascribed to overlapping hepatopathies triggered by autoimmune mechanisms other than SLE occurring with higher incidence in the context of lupus (e.g., autoimmune hepatitis, primary biliary cirrhosis). The second group includes non-autoimmune liver diseases, such as esteatosis, hepatitis C, hypercoagulation state-related liver lesions, hyperplasic parenchymal and vascular lesions, porphyria cutanea tarda, and drug induced hepatotoxicity. Finally, the data in the literature to support the existence of a hepatic disease produced by SLE itself, or the occurrence of a SLE associated prone condition that increases susceptibility to acquire other liver diseases, is critically discussed. The pathological mechanisms underlying each of these liver disorders are also reviewed. Despite the high heterogeneity in the literature regarding the prevalence of SLE-associated liver diseases and, in most cases, lack of histopathological evidence or clinical studies large enough to support their existence, it is becoming increasingly apparent that liver is an important target of SLE. Consequently, biochemical liver tests should be routinely carried out in SLE patients to discard liver disorders, particularly in those patients chronically exposed to potentially hepatotoxic drugs. Diagnosing liver disease in SLE patients is always challenging, and the systematization of the current information carried out in this review is expected to be of help both to attain a better understanding of pathogenesis and to build an appropriate work up for diagnosis. PMID- 25018851 TI - Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids. AB - In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use but it can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers. PMID- 25018852 TI - Management of hepatitis C virus infection in hemodialysis patients. AB - The prevalence of hepatitis C virus (HCV) infection in patients on maintenance hemodialysis (MHD) is relatively higher than those without MHD. Chronic HCV infection detrimentally affects the life quality and expectancy, leads to renal transplant rejection, and increases the mortality of MHD patients. With the application of erythropoietin to improve uremic anemia and avoid blood transfusion, the new HCV infections during MHD in recent years are mainly caused by the lack of stringent universal precautions. Strict implementation of universal precautions for HCV transmission has led to markedly decreased HCV infections in many hemodialysis units, but physicians still should be alert for the anti-HCV negative HCV infection and occult HCV infection in MHD patients. Standard interferon alpha and pegylated interferon alpha monotherapies at a reduced dose are currently the main treatment strategies for MHD patients with active HCV replication, but how to increase the sustained virological response and decrease the side effects is the key problem. IFNalpha-free treatments with two or three direct-acting antivirals without ribavirin in MHD patients are waiting for future investigations. PMID- 25018853 TI - Hepatitis E virus in patients with acute severe liver injury. AB - AIM: To examine the incidence of hepatitis E (HepE) in individuals with acute liver injury severe enough to warrant treatment at a transplant unit. METHODS: Hepatitis E virus (HEV) is an emerging pathogen in developed countries causing severe illness, particularly in immunocompromised patients or those with underlying chronic liver disease. HepE infection is often under diagnosed, as clinicians can be reluctant to test patients who have not travelled to regions traditionally considered hyperendemic for HepE. There are few data regarding the significance of HEV in patients with very severe acute liver injury in developed countries. Eighty patients with acute severe liver injury attending the Scottish Liver Transplant unit were tested for HEV and anti-HEV IgG and IgM. Severe acute liver injury was defined as a sudden deterioration in liver function confirmed by abnormal liver function tests and coagulopathy or presence of hepatic encephalopathy. Eighty percent of these patients were diagnosed with paracetomol overdose. No patients had a history of chronic or decompensated chronic liver disease at time of sampling. IgG positive samples were quantified against the World Health Organization anti-HEV IgG standard. Samples were screened for HEV viral RNA by quantitative reverse transcription polymerase chain reaction. RESULTS: Four cases of hepatitis E were identified. Three of the four cases were only diagnosed on retrospective testing and were initially erroneously ascribed to drug-induced liver injury and decompensated chronic liver disease, with the cause of the decompensation uncertain. One case was caused by HEV genotype 1 in a traveller returning from Asia, the other three were autochthonous and diagnosed on retrospective testing. In two of these cases (where RNA was detected) HEV was found to be genotype 3, the most prevalent genotype in developed countries. Three patients survived, two of whom had been misdiagnosed as having drug induced liver injury. The fourth patient died from sepsis and liver failure precipitated as a result of hepatitis E infection and previously undiagnosed cirrhosis. Histopathology data to date is limited to mainly that seen for endemic HepE. All patients, with the exception of patient 1, demonstrated characteristics of HepE infection, as seen in previously described locally acquired cases. CONCLUSION: In patients with acute severe liver injury, HEV testing should be part of the initial diagnostic investigation algorithm irrespective of suspected initial diagnosis, age or travel history. PMID- 25018854 TI - Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects: A pilot study. AB - AIM: To investigate genetic susceptibility in Indian subjects with non-alcoholic fatty liver disease (NAFLD) by performing a pooled genetic study. METHODS: Study subjects (n = 306) were recruited and categorized into NAFLD and control groups based on ultrasound findings of fatty infiltration. Of the 306 individuals, 156 individuals had fatty infiltration and thus comprised the NAFLD group. One hundred and fifty (n = 150) individuals were normal, without fatty infiltration of the liver, comprising the control group. Blood samples, demographic and anthropometric data from the individuals were collected after obtaining informed consent. Anthropometric data, blood glucose, lipids and liver function tests were estimated using standard methods. Genome wide association studies done to date on NAFLD were identified, 19 single nucleotide polymorphisms (SNPs) were selected from these studies that were reported to be significantly associated with NAFLD and genotyping was performed on the Sequenom platform. Student's t test for continuous variables and chi(2) test was applied to variant carriers from both groups. Required corrections were applied as multiple testing was done. RESULTS The mean age of the control group was 39.78 +/- 10.83 and the NAFLD group was 36.63 +/- 8.20 years. The waist circumference of males and females in the control and NAFLD groups were 80.13 +/- 10.35; 81.77 +/- 13.65 and 94.09 +/- 10.53; 92.53 +/- 8.27 cms respectively. The mean triglyceride and alanine transaminase (ALT) levels in the control and NAFLD groups were 135.18 +/- 7.77 mg/dL; 25.39 +/- 14.73 IU/L and 184.40 +/- 84.31 mg/dL; 110.20 +/- 67.05 IU/L respectively. When chi(2) test was applied to the number of individuals carrying the variant risk alleles between the control and NAFLD group, a significant association was seen between rs738409 of the patatin-like phospholipase domain containing 3 (PNPLA3) gene (P = 0.001), rs2073080 of the PARVB gene (P = 0.02), rs2143571 of SAMM50 gene (P = 0.05) and rs6487679 of the pregnancy zone protein (PZP) gene (P = 0.01) with the disease. Variant single nucleotide polymorphisms (SNPs) in NCAN and PNPLA3 gene were associated with higher levels of ALT, whereas variant SNPs in APOC3, PNPLA3, EFCAB4B and COL13A1 were associated with high triglyceride levels. Apart from the above associations, rs2073080, rs343062 and rs6591182 were significantly associated with high BMI; rs2854117 and rs738409 with high triglyceride levels; and rs2073080, rs2143571, rs2228603, rs6487679 and rs738409 with high ALT levels. CONCLUSION: Pooled genetic analysis revealed an association of SNPs in PNPLA3, PARVB, SAMM50 and PZP genes with NAFLD. SNPs in NCAN and PNPLA3 gene were associated with higher levels of ALT, whereas variant SNPs in APOC3, PNPLA3, EFCAB4B and COL13A1 were associated with high triglyceride levels. PMID- 25018855 TI - Reuse of liver grafts following the brain death of the initial recipient. AB - AIM: To determine if there is a reasonable prospect of success of a re-use liver transplantation. METHODS: We systematically searched for reports of liver graft re-use using electronic searches of PubMed and Web of Knowledge. We performed hand searches of references lists of articles reporting re-use of grafts. RESULTS: A systematic review of the literature reveals 28 liver transplantations using previously transplanted grafts. First and second recipients ranged in age from 4 to 72 years and 29 to 62 years respectively. Liver disease in the first recipient was varied including 5 (18%) patients with fulminant liver failure who died subsequently of cerebral edema. The second transplantation was performed after a median interval of 5 d (one day-13 years). Viral hepatitis was present in 3 (11%) of the initial recipients and in 8 (29%) of final recipients. Hepatocellular carcinoma was present in 6 (21%) of the final recipients. Early survival after the final transplantation was 93%, whereas long-term survival was 78% with a mean follow-up of 23.3 (3-120) mo. CONCLUSION: Outcomes of transplantation using previously transplanted grafts in this select population are similar to those seen with conventional grafts. PMID- 25018856 TI - Grade 4 febrile neutropenia and Fournier's Syndrome associated with triple therapy for hepatitis C virus: A case report. AB - The use of triple therapy for hepatitis C not only increases the rate of sustained virological responses compared with the use of only interferon and ribavirin (RBV) but also leads to an increased number of side effects. The subject of this study was a 53-year-old male who was cirrhotic with hepatitis C virus genotype 1 A and was a previous null non-responder. We initially attempted retreatment with boceprevir (BOC), Peg-interferon and RBV, and a decrease in viral load was observed in the 8(th) week. In week 12, he presented with disorientation, flapping, fever, tachypnea, arterial hypotension and tachycardia. He also exhibited leucopenia with neutropenia. Cefepime and filgrastim were initiated, and treatment for hepatitis C was suspended. A myelogram revealed hypoplasia, cytotoxicity and maturational retardation. After 48 h, he developed bilateral inguinal erythema that evolved throughout the perineal area to the root of the thighs, with exulcerations and an outflow of seropurulent secretions. Because we hypothesized that he was suffering from Fournier's Syndrome, treatment was replaced with the antibiotics imipenem, linezolid and clindamycin. After this new treatment paradigm was initiated, his lesions regressed without requiring surgical debridement. Triple therapy requires knowledge regarding the management of adverse effects and drug interactions; it also requires an understanding of the importance of respecting the guidelines for the withdrawal of treatment. In this case report, we observed an adverse event that had not been previously reported in the literature with the use of BOC. PMID- 25018857 TI - Experiences from coordinating research after the 2011 terrorist attacks in Norway. AB - This brief report presents some of the lessons learned from coordinating research in which people directly affected by terrorist attacks in Norway in 2011 are taking part. After the terrorist attacks, it was decided to establish a national coordinating function in order to protect those who were affected when they participate in research. By gathering key stakeholders, it is possible to avoid duplication of research through practical measures such as information sharing, facilitating cooperation, and working toward sharing of data. In addition, a coordinating function provides a platform for working to increase the impact of the research among practitioners and policy makers, and inform the general public. The conclusions are that coordination should be interdisciplinary, that it is important to plan for the sharing and reuse of data, and that both the research community and the research infrastructure should take steps to improve preparedness when disaster inevitably strikes again. PMID- 25018859 TI - Explaining the unexplainable: designing a national strategy on classroom communication concerning the 22 July terror attack in Norway. AB - BACKGROUND: In the context of crisis and disasters, school-aged children are a vulnerable group with fewer coping resources than adults. The school is a key arena for preventive interventions; teachers can be given a key role in large scale school-based interventions following a man-made or natural disaster. OBJECTIVES: This paper describes a practical example of designing a school-based population-level intervention. METHODS: The preventive measures were delivered as a national communication strategy between teachers and pupils aged 6-19 concerning the terror attack on 22 July 2011 in Norway. The strategy is based on principles from international research. RESULTS: The presentation contributes to the discussion of defining the teacher's role in school-based crisis interventions and dealing with high-intensity media coverage of war, terror, and catastrophes. CONCLUSIONS: THE PRESENTATION PROVIDES EDUCATIONAL AND PSYCHOLOGICAL PERSPECTIVES ON HOW TEACHERS CAN TAKE AN ACTIVE ROLE IN HELPING PUPILS TO DEAL WITH SUCH EVENTS THROUGH TWO APPROACHES: the therapeutic approach, to restore calm and feelings of safety; and the educational approach, to foster reflection and deeper understanding. PMID- 25018858 TI - Early outreach to survivors of the shootings in Norway on the 22nd of July 2011. AB - BACKGROUND: Under-treatment and unmet needs among survivors have been documented years after terror attacks. Improved early and proactive outreach strategies, including targeted interventions for individuals in need, are required. After the terrorist attacks in Norway on 22 July 2011, a national, proactive outreach strategy was developed and implemented to help those who were directly affected. OBJECTIVES: THE AIMS OF THIS STUDY WERE THREEFOLD: (1) to investigate whether the survivors at the island of Utoya had received proactive outreach from the municipalities, (2) to examine the relationships between received health services and the survivors' level of exposure and post-trauma health problems, and (3) to explore the level of unmet needs among survivors 5 months post-terror. METHODS: Three hundred and twenty five survivors (M age=19.4, SD=4.6, 47.1% females, response rate 66%) of the 2011 massacre on Utoya Island, Norway, were interviewed face-to-face 4-5 months post-terror. The survivors were asked if they had received proactive outreach from their municipality, and what type of health services they had received. Survivors' level of peri-trauma exposure, loss and injury, posttraumatic stress reactions, symptoms of anxiety and depression, somatic health problems, and sick leave, were assessed. RESULTS: Most participants (87%) reported that they had received early and proactive outreach, and most (84%) had a contact person. In addition a majority of the survivors has received support from their general practitioner (63%), or other municipal help services (66%). Specialized mental health services by psychiatrists or psychologists had been provided to 73.1% of the survivors. Survivors who had been referred to specialized mental health services reported higher levels of exposure to trauma, posttraumatic stress reactions, depression and anxiety, and somatic health problems, compared to non-receivers of such services. Forty-three survivors (14%) reported unmet needs for services. CONCLUSION: In accordance with the national strategy, the vast majority of the participants in this study had received an early and proactive outreach and targeted responses from specialized mental health services had been provided to survivors in need of more extensive help. However, an important minority of the participants had not been reached as planned. The knowledge from this study may guide professionals and decision makers in planning for future disasters and improve the levels of care. PMID- 25018861 TI - The role of attachment in recovery after a school-shooting trauma. AB - BACKGROUND: Survivors of life-endangering trauma use varying resources that help them to recover. Attachment system activates in the times of distress, and is expected to associate with stress responses, arousal regulation, and mental health. OBJECTIVE: We examined the associations of attachment style with posttraumatic stress disorders (PTSD) symptoms and dissociative symptoms, and posttraumatic growth (PTG) among students exposed to a school shooting in Finland in a three-wave follow-up setting. METHOD: Participants were students (M age=24.9 years; 95% female) who were followed 4 (T1, N=236), 16 (T2, N=180), and 28 months (T3, N=137) after the shooting. The assessments included the Attachment Style Questionnaire, the Impact of Event Scale, part of the Adolescent Dissociative Experiences Scale and the Posttraumatic Growth Inventory. RESULTS: Securely attached survivors had lower levels of posttraumatic stress and dissociative symptoms than preoccupied at T1 and T2 as hypothesized. At T3 survivors with avoidant attachment style had higher levels of intrusive and hyperarousal symptoms than those with secure style. Concerning PTG, survivors with avoidant attachment style scored lower in PTG at T3 than survivors with both secure and preoccupied style. CONCLUSION: Secure attachment style was beneficial in trauma recovery. A challenge to the health care systems is to acknowledge that survivors with preoccupied and avoidant attachment styles react uniquely to trauma, and thus need help in different doses, modalities, and timings. PMID- 25018860 TI - Design, delivery, and evaluation of early interventions for children exposed to acute trauma. AB - BACKGROUND: Exposure to acute, potentially traumatic events is an unfortunately common experience for children and adolescents. Posttraumatic stress (PTS) responses following acute trauma can have an ongoing impact on child development and well-being. Early intervention to prevent or reduce PTS responses holds promise but requires careful development and empirical evaluation. OBJECTIVES: The aims of this review paper are to present a framework for thinking about the design, delivery, and evaluation of early interventions for children who have been exposed to acute trauma; highlight targets for early intervention; and describe next steps for research and practice. RESULTS AND CONCLUSIONS: Proposed early intervention methods must (1) have a firm theoretical grounding that guides the design of intervention components; (2) be practical for delivery in peri trauma or early post-trauma contexts, which may require creative models that go outside of traditional means of providing services to children; and (3) be ready for evaluation of both outcomes and mechanisms of action. This paper describes three potential targets for early intervention-maladaptive trauma-related appraisals, excessive early avoidance, and social/interpersonal processes-for which there is theory and evidence suggesting an etiological role in the development or persistence of PTS symptoms in children. PMID- 25018862 TI - Framework of the outreach after a school shooting and the students perceptions of the provided support. AB - BACKGROUND: A large number of bereaved family members, surviving students, and their relatives as well as school staff and the wider community were in need of psychosocial support as a result of a school shooting in Kauhajoki, Finland, 2008. A multilevel outreach project provided psychosocial care to the trauma affected families, students, schools staff, and wider community for 2 years and 4 months. OBJECTIVE: This article is twofold. First, it presents the theoretical rationale behind the psychosocial support and describes the multimodal elements of the services. Second, it analyzes the trauma-exposed students' help-seeking behavior and perceptions of the usefulness of the support they were offered in different phases of recovery. METHOD: Information of students' help-seeking and perceptions of support is based on a follow-up data from 4 months (T1, N=236), 16 months (T2, N=180), and 28 months (T3, N=137) after the shootings. Mean age of students was 24.9 (SD=10.2; 95% women). Their perceptions of the offered psychosocial support were collected with structured and open questions constructed for the study. RESULTS: The results confirmed the importance of enhancing the natural networks after a major trauma and offering additional professional support for those in greatest need. The students' perceptions of the provided care confirmed that the model of the acute and long-term outreach can be used after major tragedies in diverse situations and in other countries as well. PMID- 25018863 TI - Understanding terror and violence in the lives of children and adolescents. PMID- 25018864 TI - Cavin-1/PTRF alters prostate cancer cell-derived extracellular vesicle content and internalization to attenuate extracellular vesicle-mediated osteoclastogenesis and osteoblast proliferation. AB - BACKGROUND: Tumour-derived extracellular vesicles (EVs) play a role in tumour progression; however, the spectrum of molecular mechanisms regulating EV secretion and cargo selection remain to be fully elucidated. We have reported that cavin-1 expression in prostate cancer PC3 cells reduced the abundance of a subset of EV proteins, concomitant with reduced xenograft tumour growth and metastasis. METHODS: We examined the functional outcomes and mechanisms of cavin 1 expression on PC3-derived EVs (PC3-EVs). RESULTS: PC3-EVs were internalized by osteoclast precursor RAW264.7 cells and primary human osteoblasts (hOBs) in vitro, stimulating osteoclastogenesis 37-fold and hOB proliferation 1.5-fold, respectively. Strikin gly, EVs derived from cavin-1-expressing PC3 cells (cavin-1 PC3-EVs) failed to induce multinucleate osteoblasts or hOB proliferation. Cavin-1 was not detected in EVs, indicating an indirect mechanism of action. EV morphology, size and quantity were also not affected by cavin-1 expression, suggesting that cavin-1 modulated EV cargo recruitment rather than release. While cavin-1-EVs had no osteoclastogenic function, they were internalized by RAW264.7 cells but at a reduced efficiency compared to control EVs. EV surface proteins are required for internalization of PC3-EVs by RAW264.7 cells, as proteinase K treatment abolished uptake of both control and cavin-1-PC3-EVs. Removal of sialic acid modifications by neuraminidase treatment increased the amount of control PC3 EVs internalized by RAW264.7 cells, without affecting cavin-1-PC3-EVs. This suggests that cavin-1 expression altered the glycosylation modifications on PC3 EV surface. Finally, cavin-1 expression did not affect EV in vivo tissue targeting as both control and cavin-1-PC3-EVs were predominantly retained in the lung and bone 24 hours after injection into mice. DISCUSSION: Taken together, our results reveal a novel pathway for EV cargo sorting, and highlight the potential of utilizing cavin-1-mediated pathways to attenuate metastatic prostate cancer. PMID- 25018865 TI - Co-isolation of extracellular vesicles and high-density lipoproteins using density gradient ultracentrifugation. AB - Extracellular vesicles (EVs) facilitate intercellular communication by carrying bioactive molecules such as proteins, messenger RNA, and micro (mi)RNAs. Recently, high-density lipoproteins (HDL) isolated from human plasma were also reported to transport miRNA to other cells. HDL, when isolated from human plasma, ranges in density between 1.063 and 1.21 g/mL, which grossly overlap with the reported density of EVs. Consequently, HDL and EV will be co-isolated when using density gradient ultracentrifugation. Thus, more stringent isolation/separation procedures of EV and HDL are essential to know their relative contribution to the pool of circulating bioactive molecules. PMID- 25018866 TI - Facing the challenge of teaching emotions to individuals with low- and high functioning autism using a new Serious game: a pilot study. AB - BACKGROUND: It is widely accepted that emotion processing difficulties are involved in Autism Spectrum Conditions (ASC). An increasing number of studies have focused on the development of training programs and have shown promising results. However, most of these programs are appropriate for individuals with high-functioning ASC (HFA) but exclude individuals with low-functioning ASC (LFA). We have developed a computer-based game called JeStiMulE based on logical skills to teach emotions to individuals with ASC, independently of their age, intellectual, verbal and academic level. The aim of the present study was to verify the usability of JeStiMulE (which is its adaptability, effectiveness and efficiency) on a heterogeneous ASC group. We hypothesized that after JeStiMulE training, a performance improvement would be found in emotion recognition tasks. METHODS: A heterogeneous group of thirty-three children and adolescents with ASC received two one-hour JeStiMulE sessions per week over four weeks. In order to verify the usability of JeStiMulE, game data were collected for each participant. Furthermore, all participants were presented before and after training with five emotion recognition tasks, two including pictures of game avatars (faces and gestures) and three including pictures of real-life characters (faces, gestures and social scenes). RESULTS: Descriptive data showed suitable adaptability, effectiveness and efficiency of JeStiMulE. Results revealed a significant main effect of Session on avatars (ANOVA: F (1,32) = 98.48, P < .001) and on pictures of real-life characters (ANOVA: F (1,32) = 49.09, P < .001). A significant Session * Task * Emotion interaction was also found for avatars (ANOVA: F (6,192) = 2.84, P = .01). This triple interaction was close to significance for pictures of real-life characters (ANOVA: F (12,384) = 1.73, P = .057). Post-hoc analyses revealed that 30 out of 35 conditions found a significant increase after training. CONCLUSIONS: JeStiMulE appears to be a promising tool to teach emotion recognition not only to individuals with HFA but also those with LFA. JeStiMulE is thus based on ASC-specific skills, offering a model of logical processing of social information to compensate for difficulties with intuitive social processing. TRIAL REGISTRATION: Comite de Protection des Personnes Sud Mediterranee V (CPP): reference number 11.046 (https://cpp-sud-mediterranee v.fr/). PMID- 25018868 TI - Treatment of hormone positive uterine leiomyosarcoma with aromatase inhibitors. AB - BACKGROUND: Aromatase inhibitors (AIs) have not been used consistently as part of the management of hormone receptor positive uterine leiomyosarcomas (ULMS). As a result, the published data regarding the efficacy of AIs in this subtype of ULMS are sparse. METHODS: We performed a retrospective electronic medical record review of patients with ULMS treated with an AI, in the 1st or the 2nd line setting, at the Sarcoma Unit of the Royal Marsden Hospital between 2001 and 2012. We assessed progression-free survival (PFS), objective response and toxicities and explored the correlation of the intensity of the hormone receptor status, as well as of the grade with PFS. RESULTS: Sixteen patients with measurable advanced ULMS were treated with an AI in our unit. All of them were oestrogen receptor (ER) and progesterone receptor (PgR) positive. Letrozole was used in all patients as 1st line endocrine therapy, while exemestane was mainly prescribed as 2nd line (83%). Median PFS in 1st line was 14 months (95% CI: 0 - 30 months), and prolonged PFS was more likely to be observed in patients with low grade compared to high grade ULMS (20 months vs. 11 months), and in moderately/strongly ER positive compared to weakly ER positive ULMS (20 months vs. 12 months). Best response was partial response (PR) in 2/16 patients (12.5%) and clinical benefit (CB), defined as complete response (CR) + PR + stable disease >=6 months, was observed in 10/16 patients (CB rate (CBR) 62.5%). Median duration of 2nd line was 3 months and median PFS was not reached. The 1-year progression-free rate for the 2nd line AI was 80%. Best response was PR in one patient and CBR was 50%. AIs were well tolerated in both lines of treatment. CONCLUSIONS: In this population of patients with hormone positive ULMS, AIs achieved a significant CBR (62.5%) in 1st line, which was retained in 2nd line (CBR: 50%). The relatively prolonged median PFS (14 months), along with the favourable toxicity profile could place AIs among the first choices of systemic treatment in hormone positive ULMS, preferably in strongly positive (>90%), and/ or low grade and low volume disease. PMID- 25018867 TI - Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. AB - Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of abnormal liver function tests (LFTs) in the UK with approximately a third of the population being affected. The exact prevalence is not known, but population studies from the USA and China using magnetic resonance spectroscopy estimate that approximately 30% of the general population have steatosis. It is a spectrum of disease ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH), through to advanced fibrosis and cirrhosis. The majority have simple steatosis, but approximately 10-30% develop NASH and the development of NASH cirrhosis is associated with a poor long-term prognosis. Patients with NASH have increased liver-related and cardiovascular mortality. Many patients with NAFLD remain undiagnosed, and recognising those at risk is the first step. Clinicians overly rely on abnormal liver enzymes to identify patients with NAFLD, so patients with significant liver disease can be overlooked, potentially missing opportunities for intervention. Although liver biopsy is the gold standard method for diagnosing and staging NAFLD, the majority of patients can be effectively diagnosed non-invasively with tests that are routinely available in the clinic today. This review discusses a pragmatic approach to diagnosis and staging of NAFLD so that patients at the highest risk of liver-related complications can be identified. PMID- 25018869 TI - Filling the treatment gap in the weight management of overweight and obese patients. AB - Approximately two out of three adult Americans are overweight or obese. Despite widespread recognition of this disorder, there has been little progress in the past 20 years in finding effective noninvasive treatments for weight loss. The consequences of obesity are increasingly well recognized and include increases in blood pressure, plasma lipids, the onset of type 2 diabetes, sleep apnea, asthma, osteoarthritis and a variety of cancers. Obesity can increase the rate of pregnancy complications and fetal malformations in normoglycemic women. Current medical approaches to obesity, including intensive lifestyle interventions and drug therapies, have been successful in achieving modest weight loss of 4-7%, less than the 1998 NIH Guidelines target of 10%. Surgical approaches, including laparoscopic adjustable gastric banding, vertical banded gastroplasty and Roux-en Y gastric bypass, are much more successful, achieving weight loss of 15-50%. A treatment gap therefore exists in the management of obese and overweight patients, because many patients desire and would receive great health benefits by achieving weight loss of 7-15%. This review will discuss the dilemma of the treatment gap and explore possible ways by which it may be filled in the future by the use of innovative approaches. PMID- 25018870 TI - Conceptual basis and clinical rationale for the development of a multidisciplinary weight management center. AB - Overweight (body mass index (BMI) 25 kg m-2) or obesity (BMI 30>kg m-2) affects more than two-thirds of Americans. Overweight and obesity are commonly associated with multiple coexisting conditions, such as hypertension, diabetes, dyslipidemia, cardiovascular disease, obstructive sleep apnea and cancer. Lifestyle modification can induce a modest weight loss, which is associated with the prevention or improvement of many of these comorbidities. A combination of diet, exercise and behavioral therapy is considered the cornerstone of treatment for all overweight and obese individuals. As the etiology and therapy of obesity is complex, what is needed for these patients is a multidisciplinary clinic where specialists from different disciplines share their knowledge and participate in the treatment of the obese patient. PMID- 25018871 TI - Weighing in on bariatric surgery: who and when? AB - Over two-thirds of the United States is overweight or obese, and over 5% of the country is morbidly obese. Numerous public health preventative measures have been established to help battle this public health epidemic. Surgical obesity treatment, although now gaining popularity, has been an underutilized treatment option for obesity. Patients with a body mass index (BMI) of >40 or >35 kg m-2 with two or more comorbid conditions are eligible for bariatric surgery. Currently, the three most popular bariatric surgeries are Roux-en-y gastric bypass, sleeve gastrectomy and gastric banding procedures, all overwhelmingly performed laparoscopically. The purpose of this article is to discuss the heterogeneity of bariatric surgery. In our practice, among 834 patients operated over a 4-year period (2006-2010), patients were of an average age of 45 years (16 73 years), 80.4% were female patients, 82.5% had private insurance, 61% were White, 17% were Hispanic and 9% were Black. Patients had an average BMI of 46.2 kg m-2 (30.1-75.3 kg m-2), waist circumference of 133.6 cm (68.6-207.8 cm) and four preoperative comorbidities (0-11 comorbidities). Variation exists in surgeon practice patterns for preoperative weight-loss recommendations and complication rates based on surgery case volume. Despite variation in patient, surgeon and hospital characteristics, bariatric surgery outcomes are generally highly safe and effective. PMID- 25018872 TI - Maternal diet: a modulator for epigenomic regulation during development in nonhuman primates and humans. AB - The importance of diet in health and disease has been well characterized in the past decades. Although the earlier focus of diet research was in the context of undernutrition and the importance of adequate nutrient intake to prevent malnutrition, in the current era of epidemic obesity the focus of our efforts has evolved toward understanding the effects of excess caloric intake. The current surge in childhood obesity rates suggests a correlation of maternal metabolic syndrome and obesity with programming of the fetal epigenome for metabolic diseases later in life. Alterations of the fetal genome, epigenome and metabolome have been well documented in cases of maternal malnutrition, including both overnutrition and undernutrition. It is of great interest and importance to understand how these divergent maternal factors regulate/program the fetus for metabolic diseases, and we and others have observed that epigenetic modifications to the fetal and placental epigenome accompany these reprogramming events. The following review summarizes recent studies on the effects of maternal diet and obesity on fetal epigenetics contributing to adult diseases later in life by taking advantage of state-of-the-art genomic, epigenomic and metagenomic techniques in nonhuman primate model systems. PMID- 25018873 TI - Inflammation, ectopic fat and lipid metabolism: view from the chair. AB - How meals containing large amounts of lipids induce insulin resistance in the short and long term remains a topic of intense research. Speakers of the afternoon session showed recent findings on the modulation of mitochondria induced oxidative stress by energy substrates, both in chronic and acute (single high-fat intake) contexts, which have enabled a better understanding of insulin action at the molecular and cellular levels. These advances are highly amenable to being combined with innovative, elegant imaging techniques to look at the fate of these energy substrates at the in vivo level within optimally defined experimental protocols, both in human and nonhuman models. PMID- 25018874 TI - Education for childhood obesity prevention across the life-course: workshop conclusions. AB - The objectives of this paper are to present the conclusions from the workshop 'Education for childhood obesity prevention: a life-course approach', coordinated by the Pan-American Health Organization and the Pan-American Health and Education Foundation, and held on 14 June 2012 in Aruba, as part of the II Pan-American Conference on Childhood Obesity (http://www.paco.aw/). This workshop focused on the need to recognize the life-course framework and education as a social determinant of health to address the childhood obesity epidemic through diverse education-based initiatives. Workshop participants agreed that both education per se and the education sector are key for obesity prevention and must form part of multidisciplinary interventions and collaboration between schools, families and the entire society. Capacity building in obesity prevention is required and should include the entire learning community, teachers, leaders, health-care providers, related services personnel, university professors and other interested community members. Obesity prevention initiatives should also engage key community institutions outside the formal education system, including early childhood centers, churches, pediatric/family medicine clinics, among others, to support family nutrition education, healthy food access and daily physical activity-all of which are key to promote a child's 'healthy weight'. PMID- 25018875 TI - Childhood obesity prevention: a life-course framework. AB - Overweight/obese women are more likely to deliver newborns that also have a predisposition to store excessive amounts of fat since the early infancy period. Two evidence-based cycles are considered on the explanation of the maternal-child life-course approach for obesity prevention. The 'maternal' cycle indicates that pre-pregnancy overweight primiparous women are more likely to gain excessive weight during gestation and to retain excessive weight postpartum. The 'offspring' cycle indicates that newborns of pre-pregnancy overweight/obese women are more likely themselves to store excessive body fat starting very early on in life. The social ecological model (SEM) has been adopted as the framework needed to guide obesity prevention initiatives. The SEM considers the complex interrelationship among highly interconnected systems embedded within each other and having the individual on its inner most. Recommendations to women should include prevention of overweight/obesity prenatally, to attain adequate gestational weight and to lose the weight normally gained as part of the physiological response to pregnancy in the postpartum period. For the 'offspring' the aims should be to promote optimal breastfeeding and complementary feeding practices, and to foster physical activity and adequate dietary habits. Well coordinated inter-sectorial national obesity prevention programs built upon the life-course framework foundation requires in-depth early life systems analyses driven by the SEM. PMID- 25018876 TI - Identification of conserved, centrosome-targeting ASH domains in TRAPPII complex subunits and TRAPPC8. AB - BACKGROUND: Assembly of primary cilia relies on vesicular trafficking towards the cilium base and intraflagellar transport (IFT) between the base and distal tip of the cilium. Recent studies have identified several key regulators of these processes, including Rab GTPases such as Rab8 and Rab11, the Rab8 guanine nucleotide exchange factor Rabin8, and the transport protein particle (TRAPP) components TRAPPC3, -C9, and -C10, which physically interact with each other and function together with Bardet Biedl syndrome (BBS) proteins in ciliary membrane biogenesis. However, despite recent advances, the exact molecular mechanisms by which these proteins interact and target to the basal body to promote ciliogenesis are not fully understood. RESULTS: We surveyed the human proteome for novel ASPM, SPD-2, Hydin (ASH) domain-containing proteins. We identified the TRAPP complex subunits TRAPPC8, -9, -10, -11, and -13 as novel ASH domain containing proteins. In addition to a C-terminal ASH domain region, we predict that the N-terminus of TRAPPC8, -9, -10, and -11, as well as their yeast counterparts, consists of an alpha-solenoid bearing stretches of multiple tetratricopeptide (TPR) repeats. Immunofluorescence microscopy analysis of cultured mammalian cells revealed that exogenously expressed ASH domains, as well as endogenous TRAPPC8, localize to the centrosome/basal body. Further, depletion of TRAPPC8 impaired ciliogenesis and GFP-Rabin8 centrosome targeting. CONCLUSIONS: Our results suggest that ASH domains confer targeting to the centrosome and cilia, and that TRAPPC8 has cilia-related functions. Further, we propose that the yeast TRAPPII complex and its mammalian counterpart are evolutionarily related to the bacterial periplasmic trafficking chaperone PapD of the usher pili assembly machinery. PMID- 25018877 TI - Successful recovery after major surgery: moving beyond length of stay. AB - There is strong evidence that Enhanced Recovery Pathways improve length of hospital stay, readmission rates, and complications after major surgery. However, recovery is a complex process that only finishes when the patient returns to normal function. Future studies should also address the patient experience, as well as functional recovery and quality of life after major surgery. PMID- 25018878 TI - Linearised and non-linearised isotherm models optimization analysis by error functions and statistical means. AB - In adsorption study, to describe sorption process and evaluation of best-fitting isotherm model is a key analysis to investigate the theoretical hypothesis. Hence, numerous statistically analysis have been extensively used to estimate validity of the experimental equilibrium adsorption values with the predicted equilibrium values. Several statistical error analysis were carried out. In the present study, the following statistical analysis were carried out to evaluate the adsorption isotherm model fitness, like the Pearson correlation, the coefficient of determination and the Chi-square test, have been used. The ANOVA test was carried out for evaluating significance of various error functions and also coefficient of dispersion were evaluated for linearised and non-linearised models. The adsorption of phenol onto natural soil (Local name Kalathur soil) was carried out, in batch mode at 30 +/- 20 C. For estimating the isotherm parameters, to get a holistic view of the analysis the models were compared between linear and non-linear isotherm models. The result reveled that, among above mentioned error functions and statistical functions were designed to determine the best fitting isotherm. PMID- 25018879 TI - Pentachlorophenol removal from aqueous solutions by microwave/persulfate and microwave/H2O2: a comparative kinetic study. AB - Pentachlorophenol (PCP) is one of the most fungicides and pesticides used in wood protection. Poisoning from PCP may be happened in dermal absorption, and respiration or ingestion. With regard to health and environmental effects of PCP, many methods were studied for its removal. Microwave assisted other methods are environmental friendly, safety, and economical method, therefore, in this study; a modified domestic microwave assisted hydrogen peroxide (MW/H2O2) and sodium persulfate (MW/SPS) was used for PCP removal from aqueous solutions. PCP removal rate was measured under different factors such as pH, energy intensity, SPS, H2O2 concentration, Tert- butyl alcohol (TBA) and chemical oxygen demand (COD). The concentration changes of PCP were determined using spectrophotometer and HPLC spectra, respectively. The best removal PCP rate obtained in condition of pH of 11, 0.02 mol L(-1) of SPS, 0.2 mol L(-1) of H2O2 and energy intensity of 600 W. Moreover, COD removals in MW/H2O2 and MW/SPS process were 83% and 94%, respectively, also TBA test decreased 15% and 3% of PCP removal in MW/SPS and MW/H2O2 processes respectively. Experimental results indicated that sulfate radical was stronger than hydroxyl radical and examinations order reaction was in first order. In this study, was cleared that MW/SPS process was more effective than MW/H2O2 process in PCP removal. PMID- 25018880 TI - Clinical, radiological, microbiological, and histopathological aspects of acquired dacryocystoceles. AB - Purpose. The aim of this study is to investigate the etiology and the clinical, microbiological, histopathological, and radiological findings of acquired dacryocystoceles. Methods. In this retrospective study, we reviewed the clinical records of 10 eyes of 8 patients with dacryocystoceles who underwent external dacryocystorhinostomy (DCR) surgery. Etiology, presenting symptoms and radiological findings as well as microbiological and histopathological assessment results and outcome were analyzed. Results. The records of 8 patients with dacryocystoceles were included in this study. In the histopathological evaluations of the samples collected from the lacrimal sac wall, chronic inflammation was found in all biopsied samples and fibrosis was observed in two histopathological evaluations. Computerized tomography (CT) imaging showed fluid collection separated from adjacent tissues by a thin rim, corresponding to dacryocystoceles in the sac. In the microbiological culture examination of samples collected from the fluid within the cyst, no bacterial growth in 5 eyes, gram-negative bacillus growth in 3 eyes, and gram-positive cocci growth in 2 eyes were found. Conclusions. Acquired dacryocystoceles were observed extremely rarely and a definite pathogenic agent could not be identified in any of the cases, either microbiologically or histologically, whereas chronic inflammation was detected in all cases in our study. PMID- 25018881 TI - Prediction of spontaneous regression of cervical intraepithelial neoplasia lesions grades 2 and 3 by proteomic analysis. AB - Regression of cervical intraepithelial neoplasia (CIN) 2-3 to CIN 1 or less is associated with immune response as demonstrated by immunohistochemistry in formaldehyde-fixed paraffin-embedded (FFPE) biopsies. Proteomic analysis of water soluble proteins in supernatants of biopsy samples with LC-MS (LTQ-Orbitrap) was used to identify proteins predictive of CIN2-3 lesions regression. CIN2-3 in the biopsies and persistence (CIN2-3) or regression (<=CIN1) in follow-up cone biopsies was validated histologically by two experienced pathologists. In a learning set of 20 CIN2-3 (10 regressions and 10 persistence cases), supernatants were depleted of seven high abundance proteins prior to unidimensional LC-MS/MS protein analysis. Mean protein concentration was 0.81 mg/mL (range: 0.55-1.14). Multivariate statistical methods were used to identify proteins that were able to discriminate between regressive and persistent CIN2-3. The findings were validated in an independent test set of 20 CIN2-3 (10 regressions and 10 persistence cases). Multistep identification criteria identified 165 proteins. In the learning set, zinc finger protein 441 and phospholipase D6 independently discriminated between regressive and persistent CIN2-3 lesions and correctly classified all 20 patients. Nine regression and all persistence cases were correctly classified in the validation set. Zinc finger protein 441 and phospholipase D6 in supernatant samples detected by LTQ-Orbitrap can predict regression of CIN2-3. PMID- 25018883 TI - Successful advanced maternal age pregnancy with mosaic turner syndrome conceived after ovulation induction with clomiphene citrate: a case report. AB - Turner women typically experience gonadal dysfunction that results in amenorrhea and sterility. We encountered a case of mosaic Turner syndrome where conception was possible after ovulation induction with clomiphene citrate (CC). The patient's ovaries were overresponsive to induction with CC. The challenges and successful outcome are reported. PMID- 25018884 TI - Fetal tachycardia treated successfully with maternally administered propylthiouracil. AB - Background. Fetal tachycardia may result from the transplacental passage of thyroid stimulating immunoglobulins in a patient with hypothyroidism secondary to ablation of Graves' disease. Case. A 32-year-old woman, gravida 4, para 2, and abortus 1, with hypothyroidism and a history of Graves' disease, presented at 23 6/7 weeks of gestation with a persistent fetal tachycardia. The treatment of the fetal tachycardia with maternally administered digoxin and Sotalol was unsuccessful. Maternal thyroid stimulating immunoglobulins were elevated, and treatment with maternally administered propylthiouracil (PTU) resulted in a normal sinus rhythm for the remainder of the pregnancy. An induction of labor was performed at 37 weeks. Four to five days after delivery, the neonate exhibited clinical signs of hyperthyroidism necessitating treatment. Conclusion. Fetal tachycardia resulting from the transplacental passage of thyroid stimulating immunoglobulins can be successfully treated with maternally administered PTU. The neonate needs to be followed up closely as clinical signs of hyperthyroidism may occur as thyroid stimulating immunoglobulins continue to circulate in the neonate, while the serum levels of PTU decline. PMID- 25018885 TI - Guillain-Barre Syndrome following Treatment with Sunitinib Malate. AB - Sunitinib malate (Sutent, SU011248) is an oral multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of metastatic renal cell carcinoma and imatinib (Gleevec)-resistant gastrointestinal stromal tumor (GIST) with few reported side effects including asthenia, myelosuppression, diarrhea, and mucositis. Scarce literature exists regarding the rare but often serious toxicities of sunitinib. Autoimmune and neurological side effects have been linked to sunitinib's inhibition of VEGF receptors with a corresponding increase in VEGF levels, which is associated with development of different neuropathies. We hereby report an interesting case of Guillain-Barre syndrome in a middle-aged patient with metastatic renal cell carcinoma following sunitinib treatment. PMID- 25018882 TI - A brain centred view of psychiatric comorbidity in tinnitus: from otology to hodology. AB - Introduction. Comorbid psychiatric disorders are frequent among patients affected by tinnitus. There are mutual clinical influences between tinnitus and psychiatric disorders, as well as neurobiological relations based on partially overlapping hodological and neuroplastic phenomena. The aim of the present paper is to review the evidence of alterations in brain networks underlying tinnitus physiopathology and to discuss them in light of the current knowledge of the neurobiology of psychiatric disorders. Methods. Relevant literature was identified through a search on Medline and PubMed; search terms included tinnitus, brain, plasticity, cortex, network, and pathways. Results. Tinnitus phenomenon results from systemic-neurootological triggers followed by neuronal remapping within several auditory and nonauditory pathways. Plastic reorganization and white matter alterations within limbic system, arcuate fasciculus, insula, salience network, dorsolateral prefrontal cortex, auditory pathways, ffrontocortical, and thalamocortical networks are discussed. Discussion. Several overlapping brain network alterations do exist between tinnitus and psychiatric disorders. Tinnitus, initially related to a clinicoanatomical approach based on a cortical localizationism, could be better explained by an holistic or associationist approach considering psychic functions and tinnitus as emergent properties of partially overlapping large-scale neural networks. PMID- 25018886 TI - Isolated liver metastasis of sacrococcygeal chordoma: case report and review of the literature. AB - Chordomas are rare neoplasms arising from notochordal remnants and may develop anywhere in the body while the most common anatomic site is the sacrococcygeal area. The most effective treatment of chordoma is surgery. Chordomas rarely metastasize to lung, bone, soft tissue, liver, lymph nodes, and skin. However, there is currently no standard systemic treatment for advanced stage chordoma. Here, we reported a rare presentation of chordoma patient with liver only metastases and poor prognosis. PMID- 25018887 TI - Gouty panniculitis with ulcerations in a patient with multiple organ dysfunctions. AB - Gouty panniculitis is a rare manifestation of gout. Clinically, it is characterized by indurated subcutaneous nodules in nonjoint areas. Pathologically, typical characteristic gouty tophi can be seen in subcutaneous tissue. It is postulated that gouty panniculitis develops as a consequence of uric acid accumulation in the body and localized inflammatory changes in subcutaneous tissue. We report a case of a 46-year-old man with 20-year history of gout, who developed multiple subcutaneous nodules over the abdomen and right groin/thigh area over a 2-year period. After a recent episode of congestive heart failure and acute renal failure, the nodules increased in size and the overlying skin became erythematous and ulcerated. Pathologic examination demonstrated typical tophi in the dermis and subcutaneous tissue. A review of the literature yielded fifteen similar cases that had been previously reported. We conclude that gouty panniculitis may be a manifestation of undertreated gout and may be exacerbated by the deterioration of other systemic functions. PMID- 25018888 TI - Jejunal Cancer with WRN Mutation Identified from Next-Generation Sequencing: A Case Study and Minireview. AB - Small bowel cancer is a rare, gastrointestinal cancer originating from the small intestines. Carcinogenesis in the jejunum, the middle segment of the small intestines, occurs less commonly than in the duodenum and ileum. Despite the increasing incidences globally, the cancer is still poorly understood, which includes lack of pathological understanding and etiological reasoning, as it seems to exhibit both similarities and differences with other types of cancers. A 76-year-old Asian man was presented with abdominal pain, which was later attributed to an adenocarcinoma in the jejunum. Initial immunoreactive staining results found no connections to colorectal cancer. The microsatellite instability test was further examined by immunohistochemistry which revealed them to be wild type. From our exome-capture sequencing results, mutations of WRN may be important as they represent the only genetic defect in this jejunal cancer. The patient has since undergone surgical resection of his cancer and is currently being treated with chemotherapy. The pathology, genomic markers, and treatments are described along with literature review. PMID- 25018889 TI - A Short Bowel (Small Intestine = 40 cm), No Ileocecal Valve, and Colonic Inertia Patient Works Well with Oral Intake Alone without Parenteral Nutrition. AB - We present a 50-year-old male who suffered from ischemic bowel disease, having undergone massive resection of small intestine and ileocecal valve. He had to cope with 40 cm proximal jejunum and 70 cm distal colon remaining. In the postoperative period parenteral nutrition (PN) was used immediately for nutrition support and electrolyte imbalance correction. We gave him home PN as regular recommendation for the short bowel status after discharge from hospital. This patient has tolerated regular oral intake 2 months later and did not develop significant short bowel syndrome. There were several episodes of venous access infection which troubled this patient and admitted him for treatment during home PN. Therefore, we changed home PN to cyclic tapering pattern. The patient could maintain his nutrition and hydration with oral intake alone after tapering home PN 15 months later. He has survived more than one year without PN support and still maintained 80% ideal body weight with average albumin of 3.5 +/- 0.2 mg/dL. Although patient was hospitalized every two months to supplement nutrients, however, this has greatly improved the quality of life. PMID- 25018890 TI - Prophylactic antioxidant potential of gallic Acid in murine model of sepsis. AB - Present study is to investigate the effect of Gallic acid pretreatment on survival of septic animals and oxidative stress in different organs like lungs, liver, kidney, spleen, and vascular dysfunction of mice. Sepsis was induced by cecal ligation and puncture (CLP) in healthy adult male albino mice (25-30 g) and was divided into 3 groups each consisting of 6 animals, that is, sham-operated (SO group (Group I), SO + sepsis (Group II), and Gallic acid + sepsis (Group III)). Group III animals were pretreated with Gallic acid at the dose rate of 20 mg/kg body weight for 2 days before induction of sepsis. Animals were sacrificed on 8th day and the tissue samples were obtained for further investigation on lipid peroxidation (LPO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH). Gallic acid pretreatment significant (P < 0.05) reduces kidney, spleen, liver, and lungs' malondialdehyde level in septic mice. However, it fails to improve reduced glutathione level in all given organs, while, Gallic acid pretreated mice showed significant improvement in SOD activity of kidney and spleen when compared to septic mice. Finally, the beneficial effects of Gallic acid pretreatment in sepsis are evident from the observations that Gallic acid partially restored SOD and catalase activity and completely reversed lipid peroxidation. Further studies are required to find out the possible mechanisms underlying the beneficial effects of Gallic acid on large population. PMID- 25018891 TI - Molecular and Morphological Characterization of Fasciola spp. Isolated from Different Host Species in a Newly Emerging Focus of Human Fascioliasis in Iran. AB - The current study aimed to find out the morphometric and genotypic divergences of the flukes isolated from different hosts in a newly emerging focus of human fascioliasis in Iran. Adult Fasciola spp. were collected from 34 cattle, 13 sheep, and 11 goats from Kohgiluyeh and Boyer-Ahmad province, southwest of Iran. Genomic DNA was extracted from the flukes and PCR-RFLP was used to characterize the isolates. The ITS1, ITS2, and mitochondrial genes (mtDNA) of NDI and COI from individual liver flukes were amplified and the amplicons were sequenced. Genetic variation within and between the species was evaluated by comparing the sequences. Moreover, morphometric characteristics of flukes were measured through a computer image analysis system. Based on RFLP profile, from the total of 58 isolates, 41 isolates (from cattle, sheep, and goat) were identified as Fasciola hepatica, while 17 isolates from cattle were identified as Fasciola gigantica. Comparison of the ITS1 and ITS2 sequences showed six and seven single-base substitutions, resulting in segregation of the specimens into two different genotypes. The sequences of COI markers showed seven DNA polymorphic sites for F. hepatica and 35 DNA polymorphic sites for F. gigantica. Morphological diversity of the two species was observed in linear, ratios, and areas measurements. The findings have implications for studying the population genetics, epidemiology, and control of the disease. PMID- 25018892 TI - Radiosensitivity and Induction of Apoptosis by High LET Carbon Ion Beam and Low LET Gamma Radiation: A Comparative Study. AB - Cancer treatment with high LET heavy ion beam, especially, carbon ion beam ((12)C), is becoming very popular over conventional radiotherapy like low LET gamma or X-ray. Combination of Poly(ADP-ribose) polymerase (PARP) inhibitor with xenotoxic drugs or conventional radiation (gamma or X-ray) is the newer approach for cancer therapy. The aim of our study was to compare the radiosensitivity and induction of apoptosis by high LET (12)C and low LET gamma radiation in HeLa and PARP-1 knocked down cells. We did comet assay to detect DNA breaks, clonogenic survival assay, and cell cycle analysis to measure recovery after DNA damage. We measured apoptotic parameters like nuclear fragmentation and caspase-3 activation. DNA damage, cell killing, and induction of apoptosis were significantly higher for (12)C than gamma radiation in HeLa. Cell killing and apoptosis were further elevated upon knocking down of PARP-1. Both (12)C and gamma induced G2/M arrest although the (12)C had greater effect. Unlike the gamma, (12)C irradiation affects DNA replication as detected by S-phase delay in cell cycle analysis. So, we conclude that high LET (12)C has greater potential over low LET gamma radiation in killing cells and radiosensitization upon PARP-1 inhibition was several folds greater for (12)C than gamma. PMID- 25018893 TI - Experience Developing a Community Pharmacy Practice-based Research Network. AB - In 2010, the Purdue University College of Pharmacy established the Medication Safety Research Network of Indiana (Rx-SafeNet), the first practice-based research network (PBRN) in Indiana comprised solely of community pharmacies. In the development of Rx-SafeNet and through our early project experiences, we identified several "lessons learned." We share our story and what we learned in an effort to further advance the work of the greater PBRN community. We have formed the infrastructure for Rx-SafeNet, including an Executive Committee, Advisory Board, member pharmacies/site coordinators, and Project Review Team. To date, 22 community pharmacies have joined and we have recently completed data collection for the network's first project. Lessons learned during the development of Rx-SafeNet may benefit PBRNs nationally. Although community pharmacy PBRNs are not yet commonplace in the U.S., we believe their development and subsequent research efforts serve as an important avenue for investigating medication use issues. PMID- 25018894 TI - Stressor-dependent Alterations in Glycoprotein 130: Implications for Glial Cell Reactivity, Cytokine Signaling and Ganglion Cell Health in Glaucoma. AB - OBJECTIVE: The interleukin-6 (IL-6) family of cytokines is associated with retinal ganglion cell (RGC) survival and glial reactivity in glaucoma. The purpose of this study was to evaluate glaucoma-related changes in glycoprotein 130 (gp130), the common signal transducer of the IL-6 family of cytokines, as they relate to RGC health, glial reactivity and expression of IL-6 cytokine family members. METHODS: For all experiments, we examined healthy retina (young C57), aged retina (aged C57), retina predisposed to glaucoma (young DBA/2) and retina with IOP-induced glaucoma (aged DBA/2). We determined retinal gene expression of gp130 and IL-6 family members, using quantitative PCR, and protein expression of gp130, using multiplex ELISA. For protein localization and cell specific expression, we performed co-immunolabeling for gp130 and cell type specific markers. We used quantitative microscopy to measure layer-specific expression of gp130 and its relationships to astrocyte and Muller glia reactivity and RGC axonal transport, as determined by uptake and transport of cholera toxin beta-subunit (CTB). RESULTS: Gene expression of gp130 was elevated with all glaucoma-related stressors, but only normal aging increased protein levels. In healthy retina, gp130 localized primarily to the inner retina, where it was expressed by astrocytes, Muller cells and RGCs. Layer-specific analysis of gp130 expression revealed increased expression in aging retina and decreased expression in glaucomatous retina that was eccentricity-dependent. These glaucoma-related changes in gp130 expression correlated with the level of GFAP and glutamine synthetase expression, as well as axonal transport in RGCs. The relationships between gp130, glial reactivity and RGC health could impact signaling by many IL 6 family cytokines, which exhibited overall increased expression in a stressor dependent manner. CONCLUSIONS: Glaucoma-related stressors, including normal aging, glaucoma predisposition and IOP-induced glaucoma, differentially alter expression of gp130 and these alterations have direct implications for astrocyte and Muller glia reactivity, RGC health and cytokine signaling. PMID- 25018895 TI - The dysfunctional endothelium in CKD and in cardiovascular disease: mapping the origin(s) of cardiovascular problems in CKD and of kidney disease in cardiovascular conditions for a research agenda. AB - Endothelial dysfunction resulting in disintegration of vascular structure and function is a key element in the progression of chronic kidney disease (CKD). Many risk factors-traditional and non-traditional-are thought to have a role in the progression and development of cardiovascular disease (CVD) in patients with CKD. However, many risk factors await definitive confirmation of their clinical relevance obtained from intervention trials. Moreover, the investigation of the relative contribution of these factors to the twin-risk problem of CVD and progression in patients with CKD is one of the most important future challenges for nephrologists. PMID- 25018896 TI - Arterial aging and arterial disease: interplay between central hemodynamics, cardiac work, and organ flow-implications for CKD and cardiovascular disease. AB - Cardiovascular disease is an important cause of morbidity and mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). All epidemiological studies have clearly shown that accelerated arterial and cardiac aging is characteristic of these populations. Arterial premature aging is heterogeneous. It principally involves the aorta and central capacitive arteries, and is characterized by preferential aortic stiffening and disappearance of stiffness/impedance gradients between the central and peripheral arteries. These changes have a double impact: on the heart, upstream, with left ventricular hypertrophy and decreased coronary perfusion; and, downstream, on renal and brain microcirculation (decrease in glomerular filtration and cognitive functions). Multifactorial at origin, the pathophysiology of aortic 'progeria' and microvascular disorders in CKD/ESRD is not well understood and should be the focus of interest in future studies. PMID- 25018897 TI - Major pathways of the reno-cardiovascular link: the sympathetic and renin angiotensin systems. AB - Chronic kidney disease is often characterized by enhanced activity of the renin angiotensin system (RAS) and the sympathetic nervous system. Independent of their effect on blood pressure, these systems also contribute to the pathogenesis of both structural and functional cardiovascular abnormalities and contribute importantly to clinical outcome. There is much evidence that the diseased kidneys are of central importance in the pathogenesis of both abnormalities. Inhibitors of the RAS also reduce sympathetic overactivity. Future research should be aimed at addressing the pathophysiological mechanisms causing the enhanced activities. Given the fact that even a small kidney lesion can cause enhanced activity of the RAS and the sympathetic nervous system, it is likely that these pathophysiological mechanisms are operational in more disease conditions, including essential hypertension, heart failure, and obesity/metabolic syndrome. PMID- 25018898 TI - The lingering dilemma of arterial pressure in CKD: what do we know, where do we go? AB - Despite many advances in the management of hypertensive chronic kidney disease (CKD) patients, both on and off dialysis, there exist several gaps in our knowledge. Although the modern techniques to measure blood pressure (BP) indirectly have been available for a long time, among those with CKD, how to best assess hypertension and the level to which it should be lowered are mired in controversy. Other controversial areas relate to a lack of a consensus definition of hypertension among hemodialysis patients, uncertainty in the definition and assessment of volume excess, and the lack of adequately powered randomized trials to evaluate the level to which BP can be lowered in those on dialysis. This review discusses the limitations of the available evidence base and suggests areas for future research. Suggestions include evaluation of techniques to assess volume, randomized trials to target different levels of BP among hypertensive hemodialysis patients, evaluation of ambulatory BP monitoring, and non pharmacological means to lower BP in CKD. It is hoped that among patients with CKD these data will improve the dismal cardiovascular outcomes. PMID- 25018899 TI - T-cell co-stimulatory blockade in kidney transplantation: back to the bench. AB - It is believed that blocking positive T-cell co-stimulatory pathways should lead to long-term graft acceptance. Despite the exciting initial achievements in experimental animal models, targeting co-stimulatory pathways has shown to be much more complex in the clinic. In addition to multiple binding partners, some co-stimulatory interactions have been found to be inhibitory in nature, whereas others were demonstrated to be important in the development of regulatory T cells. Moreover, memory T cells have been shown to be resistant to co-stimulation blockade. Herein we focus on the B7:CD28 pathway and describe the evolution of targeting this pathway with cytotoxic T-lymphocyte antigen-4-Ig from bench to clinic. We also attempt to address possible causes for the unexpected high rejection rate observed in the phase III clinical trials with belatacept, using experimental data obtained from basic science research. PMID- 25018900 TI - Changes in the number of circulating TCM and TEM subsets in renal transplantation: relationship with acute rejection and induction therapy. AB - Effector (TEM) and central memory (TCM) T cells have been recently described as the main memory T-cell subsets generated after primary immune response, with a potential role in graft rejection after rechallenge with alloantigen. Because of their effector function, they could be involved in driving the response against the allograft, leading to rejection. In this study, we sought to investigate the different memory T-cell subpopulations in peripheral blood from a cohort of 90 patients who underwent consecutive renal transplant, and their association with acute rejection (AR) episodes and induction therapy. Twenty-one of them were monitored in the short term during the first 2 months after transplantation. Three of them suffered an AR but no changes in the circulating levels of either CD4+ or CD8+ TEM were observed as compared with rejection-free renal transplant patients. In total, 69 patients out of 90 were monitored in the long term. Even 2 years after transplantation, maintained increased numbers of peripheral blood CD4+ TEM were observed in patients suffering with AR. Interestingly, induction therapy with thymoglobulin, but not with basiliximab, produced an increase in circulating CD4+ TEM cells at 6 months after transplantation. In conclusion, our data suggest that AR episodes favor the induction of TEM cells in the periphery of renal transplant patients in the long term. It remains to be determined whether such an effect has any impact on long-term renal transplantation. PMID- 25018901 TI - Subclinical rejection in renal transplants is associated with low serum mannose binding lectin levels. AB - Surveillance biopsies have contributed to the understanding of the natural history of renal allograft lesions. Subclinical rejection, defined as the presence of histological lesions, indistinguishable from acute rejection in stable grafts, is associated with progression of interstitial fibrosis and tubular atrophy. The prevalence of subclinical rejection has decreased as more powerful immunosuppressive treatments have been introduced, suggesting that subclinical rejection represents the degree of control of the alloimmune response. However, non-immune factors such as donor age are also associated with the prevalence of subclinical rejection, suggesting that kidneys from older donors are more susceptible to insult and have a reduced capacity for tissue regeneration. Innate immunity has a crucial role in the modulation of the inflammatory response during infection and tissue damage. Mannose-binding lectin (MBL) is an innate immune protein, the polymorphisms of which are associated with infection, low-grade inflammation, diabetes, and cardiovascular disease. However, the relationship between MBL and disease is complex. For example, low MBL level is associated with higher risk for diabetes, whereas in patients with diabetes, high MBL level is associated with more severe renal damage. In renal transplant patients, low MBL levels are associated with an increased prevalence of infection and diabetes, whereas high MBL levels are associated with shortened graft survival. Although MBL is not clearly associated with prevalence of acute rejection, surveillance biopsy studies have shown that low MBL levels are associated with subclinical rejection in kidney and the heart, suggesting that MBL modulates the injury-repair process of the allograft. PMID- 25018902 TI - Biomarkers of tolerance: searching for the hidden phenotype. AB - Induction of transplantation tolerance remains the ideal long-term clinical and logistic solution to the current challenges facing the management of renal allograft recipients. In this review, we describe the recent studies and advances made in identifying biomarkers of renal transplant tolerance, from study inceptions, to the lessons learned and their implications for current and future studies with the same goal. With the age of biomarker discovery entering a new dimension of high-throughput technologies, here we also review the current approaches, developments, and pitfalls faced in the subsequent statistical analysis required to identify valid biomarker candidates. PMID- 25018903 TI - NKG2D and its ligands: active factors in the outcome of solid organ transplantation? AB - The role of natural killer (NK) cells in solid organ transplantation is not well established, although several recent reports highlight the importance of the activating receptor NKG2D and its ligands in the development of rejection during transplantation. The human NKG2D ligands (MICA and MICB) are induced in allografts during acute and chronic rejection, and the presence of anti-MICA antibodies is correlated with a higher incidence of rejection. The binding of these ligands to its receptor NKG2D activates NK cells, enhances the functions of effectors, and allows NK cells to function as a bridge between innate and adaptive immunity associated with the transplantation. In fact, blockage of NKG2D with the anti-NKG2D monoclonal antibodies prolongs graft survival and prevents CD28-independent rejection in heart and skin allograft mouse models. Furthermore, the current immunosuppressive therapies can modulate the expression of NK cell receptors and consequently the effector functions of NK cells. That is particularly important during the first few months after transplantation, when the susceptibility to opportunistic viral infections is higher and NKG2D has an essential role. In this review, we analyze in detail the potential role of the NKG2D-activating receptor and its ligands in the immune responses during the outcome of solid organ transplantation. These findings open a new pathway for therapeutic intervention that can contribute to tolerance in solid organ transplantation. PMID- 25018905 TI - Mesenchymal stromal cells: main factor or helper in regenerative medicine? AB - Mesenchymal stromal cells (mSCs) are presently studied for the prophylaxis and therapy of a variety of diseases such as acute graft-versus-host disease after allogeneic stem cell transplantation, cardiac indications, bone degeneration, Crohn's disease, and organ rejection, as well as prevention of acute renal failure in high-risk situations. mSCs appear to function through paracrine mechanisms that exert immunosuppressive, anti-inflammatory, anti-apoptotic, mitogenic, and other organ-protective and repair-stimulating actions. mSCs are either cultured in the presence of fetal calf serum (FCS) or platelet lysate (PL). PL lysate-generated mSCs exhibit faster doubling times, different gene expression profiles, and more potent immunosuppressive activity compared with FSC generated mSCs. The utility of mSCs in the treatment of chronic inflammatory diseases is being evaluated in prospective studies. PMID- 25018904 TI - Mesenchymal stem cells as a therapeutic approach to glomerular diseases: benefits and risks. AB - Most studies using adult stem cells (ASCs) and progenitor cells as potential therapeutics for kidney disorders have been conducted in models of acute kidney injury, where the damage mainly affects the tubulointerstitium. The results are promising, whereas the underlying mechanisms are still being discussed controversially. Glomerular diseases have not received as much attention. Likely reasons include the often insidious onset, rendering the choice of optimal treatment timing difficult, and the fact that chronic diseases may require long term therapy. In this mini review, we summarize current strategies in adult stem cell-based therapies for glomerular diseases. In addition, we focus on possible side effects of stem cell administration that have been reported recently, that is, profibrotic actions and maldifferentiation of mesenchymal stem cells. PMID- 25018906 TI - Genetic tracing of the epithelial lineage during mammalian kidney repair. AB - Developing new therapeutic approaches to treat acute kidney injury requires a detailed understanding of endogenous cellular repair. Genetic fate mapping defines cellular hierarchies in vivo and we used this technique to assess a possible contribution of non-epithelial stem cells to renal repair after ischemic injury. Mice with efficient labeling of renal epithelial cells, but not non epithelial interstitial cells, were subjected to a single cycle or sequential cycles of kidney injury and repair. No dilution of the epithelial cell fate marker was observed despite robust epithelial cell proliferation. Thus, non tubular cells do not have the ability to migrate across the basement membrane and differentiate into epithelial cells in this model. Instead, surviving tubular epithelial cells are responsible for repair of the damaged nephron. Future studies will need to distinguish between uniform dedifferentiation and proliferation of all epithelial cells after injury versus selective expansion of an intratubular epithelial stem cell. PMID- 25018907 TI - Role of SDF-1 as a regulatory chemokine in renal regeneration after acute kidney injury. AB - Both the homing of hematopoietic stem cells (HSCs) to the bone marrow and their engraftment in recipients of bone marrow transplants are primarily mediated by the chemokine stromal-derived factor-1 (SDF-1) or CXCL12, which activates CXCR4, its cognate receptor on HSCs. We showed that the recruitment and temporary attachment of CXCR4-expressing cells, such as HSCs and a fraction of mesenchymal stem cells (MSCs), to the kidney, following ischemia/reperfusion acute kidney injury, are similarly mediated by robustly upregulated SDF-1 in the kidney, indicating that such organ injury appears to lead to the transient expression of a facultative stem cell niche. This SDF-1 response of the injured kidney facilitates both the mobilization from the bone marrow and homing of precursor cells, and other CXCR4-expressing cells such as administered MSCs, to the kidney, where they aid in its protection and repair. Similar responses have been observed subsequent to the injury of other solid organs such as the heart, liver, and brain. PMID- 25018908 TI - Stem cell therapy for diabetes mellitus. AB - In this review, we present (1) a brief discussion of hematopoietic stem cell transplantation (HSCT) for severe and refractory autoimmune diseases (AIDs) from its beginning in 1996 through recently initiated prospective randomized clinical trials; (2) an update (up to July 2009) of clinical and laboratory outcomes of 23 patients with newly diagnosed type 1 diabetes mellitus (T1DM), who underwent autologous HSCT at the Bone Marrow Transplantation Unit of the Ribeirao Preto Medical School, University of Sao Paulo, Brazil; (3) a discussion of possible mechanisms of action of HSCT in AIDs, including preliminary laboratory data obtained from our patients; and (4) a discussion of future perspectives of stem cell therapy for T1DM and type 2 DM, including the use of stem cell sources other than adult bone marrow and the combination of cell therapy with regenerative compounds. PMID- 25018909 TI - Cardiac and renal cell therapies: similarities and differences. AB - Patients with terminal cardiac or renal disease have few therapeutic options besides organ transplantation. Optimally, cell therapies would be used both in acute and chronic stages of such diseases. In the injured myocardium, the main therapeutic goal is reestablishment of adequate perfusion and cardiac output. This can be achieved by stem cell (SC) infusions, and currently several clinical trials have provided promising results. Considering the heart's low intrinsic capacity for regeneration and its paucity of resident cardiac SCs, we believe that induction of angiogenesis must be the primary goal, thereby promoting activation of resident SCs as well as mobilization of perivascular mesenchymal SCs that can mediate myocardial regeneration. Renal tissue, in contrast to the myocardium, has a high intrinsic capacity to respond to injuries and thus repair itself. Infusion of bone marrow (BM) cells or of their sub-populations protects the injured renal tissue and elicits immediate activation and proliferation of resident cells, which are able to undertake repair and regeneration of structures of both mesenchymal and epithelial origin. Experimental evidence indicates that infused cells function essentially through paracrine pathways, decreasing inflammation and fibrosis. In both severe cardiac and renal disorders, cell therapies appear to be a promising therapeutic option. PMID- 25018910 TI - Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials. AB - Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their administration into the suprarenal aorta after reflow significantly protected renal function and hastened repair, mediated by complex antiapoptotic, mitogenic, anti-inflammatory, and immune modulating actions that were not elicited by isogeneic fibroblasts. Infused mesenchymal stem cells, recruited to renal sites of injury, did not significantly differentiate into target cells but rather disappeared from kidneys and other organs within 72 h. Furthermore, at 3 months, compared with vehicle-treated controls, renal function was well preserved and interstitial fibrosis was absent. These preclinical data served as the scientific basis for a recently completed Phase I Clinical Trial (http://www.clinicaltrials.gov; # NCT00733876), in which patients at high risk for cardiac surgery-associated AKI were treated with allogeneic mesenchymal stem cells. Until now, MSC therapy in the study subjects has been safe, and none of the patients has developed postoperative AKI or subsequent loss of renal function, suggesting that this novel form of therapy may have promise in this group of high-risk patients, which will be further investigated in a Phase II Trial. PMID- 25018913 TI - Reference Keys. PMID- 25018911 TI - Mineral and bone disorders in chronic kidney disease and end-stage renal disease patients: new insights into vitamin D receptor activation. AB - Progressive loss of kidney function leads to reduced production of calcitriol (1,25-dihydroxyvitamin D; active vitamin D) and an imbalance in serum calcium (Ca) and phosphorus (P) levels, which are associated with progression of renal failure as well as increased rates of cardiovascular (CV) events and mortality. In addition, multifactorial hypocalcemia and resistance to parathyroid hormone (PTH) can lead to prolonged and excessive synthesis and secretion of PTH, eventually leading to development of secondary hyperparathyroidism and renal osteodystrophy. These changes associated with chronic kidney disease (CKD), extending beyond bone and related biochemical abnormalities, have prompted the development of the term CKD-mineral and bone disorder to describe its systemic nature. Excessive P loading, among other factors, will promote vascular calcification (VC), and PTH production will affect bone remodeling. Although administration of calcitriol increases serum Ca levels and decreases PTH, it is also associated with elevated Ca * P product. Therefore, compounds that selectively activate vitamin D receptors (VDR activators), potentially reducing Ca-P toxicity and distinctly affecting pathogenic mechanisms of VC, might enhance CV and renal protection, increase the vitamin D therapeutic window, and thus provide a significant clinical benefit. Moreover, selective VDR activators have been associated with improvement in survival, at least among dialysis patients. Thus, selective VDR activators should be considered a novel and interesting approach to enhance the standard of care in CKD patients. PMID- 25018912 TI - Kidney disease and vitamin D levels: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and VDR activation. AB - A normal vitamin D status is essential for human health. Vitamin D deficiency is a recognized risk factor for all-cause mortality in normal individuals and in chronic kidney disease (CKD) patients. The link between vitamin D deficiency and death is a defective activation of the vitamin D receptor (VDR) by 1,25 dihydroxyvitamin D (calcitriol, the vitamin D hormone) to induce/repress genes that maintain mineral homeostasis and skeletal integrity, and prevent secondary hyperparathyroidism, hypertension, immune disorders, and renal and cardiovascular (CV) damage. The kidney is the main site for the conversion of 25-hydroxyvitamin D (25D) to circulating calcitriol, and therefore essential for the health benefits of endocrine VDR activation. The kidney is also essential for the uptake of 25D from the glomerular ultrafiltrate for its recycling to the circulation to maintain serum 25D levels, extrarenal calcitriol synthesis, and the prosurvival benefits of autocrine/paracrine VDR activation. Indeed, both calcitriol and vitamin D deficiency increase progressively in the course of CKD, and associate directly with accelerated disease progression and death. Therefore, the safe correction of calcitriol and vitamin D deficiency/insufficiency is becoming a high priority among nephrologists. This review updates the pathophysiology behind 25D and calcitriol deficiency and impaired VDR activation in CKD, the adequacy of current recommendations for vitamin D supplementation, and potential markers of the efficacy of therapy to prevent or slow the development of renal and CV lesions unrelated to parathyroid hormone suppression, a knowledge required for the design of trials to obtain evidence-based recommendations for vitamin D and calcitriol replacement at all stages of CKD. PMID- 25018914 TI - Abbreviations and Acronyms. PMID- 25018916 TI - Summary of Recommendation Statements. PMID- 25018917 TI - Section 1: Introduction and Methodology. PMID- 25018918 TI - Section 2: AKI Definition. PMID- 25018922 TI - Biographic and Disclosure Information. PMID- 25018924 TI - Foreword. PMID- 25018919 TI - Section 3: Prevention and Treatment of AKI. PMID- 25018920 TI - Section 4: Contrast-induced AKI. PMID- 25018925 TI - Work Group Membership. PMID- 25018927 TI - Summary of Recommendation Statements. PMID- 25018928 TI - Chapter 2: General principles in the management of glomerular disease. PMID- 25018921 TI - Section 5: Dialysis Interventions for Treatment of AKI. PMID- 25018929 TI - Chapter 4: Steroid-resistant nephrotic syndrome in children. PMID- 25018930 TI - Chapter 5: Minimal-change disease in adults. PMID- 25018931 TI - Chapter 6: Idiopathic focal segmental glomerulosclerosis in adults. PMID- 25018932 TI - Chapter 7: Idiopathic membranous nephropathy. PMID- 25018933 TI - Chapter 8: Idiopathic membranoproliferative glomerulonephritis. PMID- 25018934 TI - Chapter 9: Infection-related glomerulonephritis. PMID- 25018936 TI - Chapter 11: Henoch-Schonlein purpura nephritis. PMID- 25018935 TI - Chapter 10: Immunoglobulin A nephropathy. PMID- 25018938 TI - Chapter 13: Pauci-immune focal and segmental necrotizing glomerulonephritis. PMID- 25018940 TI - Biographic and Disclosure Information. PMID- 25018937 TI - Chapter 12: Lupus nephritis. PMID- 25018939 TI - Chapter 14: Anti-glomerular basement membrane antibody glomerulonephritis. PMID- 25018942 TI - Training nephrologists from developing countries: does it have a positive impact? AB - In the past 25 years the International Society of Nephrology has sponsored 545 physicians from 83 developing countries to undertake nephrology training in renal units in the developed world. Data collected biennially from past fellows have demonstrated a very positive impact of the program on individual trainees and their home institutions. Many of the trainees have gone on to leadership positions in their home institutions, countries, and regions. Increasingly, fellowships are undertaken in selected developed centers within the fellow's own region, which increases the relevance and utility of the training to the fellow and the fellow's home institution, and lessens the risk of 'brain drain'. PMID- 25018944 TI - Foreword. PMID- 25018947 TI - Summary of Recommendation Statements. PMID- 25018945 TI - Work Group Membership. PMID- 25018948 TI - Chapter 1: Diagnosis and evaluation of anemia in CKD. PMID- 25018949 TI - Chapter 2: Use of iron to treat anemia in CKD. PMID- 25018950 TI - Chapter 3: Use of ESAs and other agents to treat anemia in CKD. PMID- 25018952 TI - Methods for guideline development. PMID- 25018951 TI - Chapter 4: Red cell transfusion to treat anemia in CKD. PMID- 25018953 TI - Biographic and Disclosure Information. PMID- 25018956 TI - Foreword. PMID- 25018959 TI - Summary of Recommendation Statements. PMID- 25018957 TI - Work Group Membership. PMID- 25018960 TI - Chapter 1: Introduction. PMID- 25018961 TI - Chapter 2: Lifestyle and pharmacological treatments for lowering blood pressure in CKD ND patients. PMID- 25018962 TI - Chapter 3: Blood pressure management in CKD ND patients without diabetes mellitus. PMID- 25018964 TI - Chapter 5: Blood pressure management in kidney transplant recipients (CKD T). PMID- 25018963 TI - Chapter 4: Blood pressure management in CKD ND patients with diabetes mellitus. PMID- 25018965 TI - Chapter 6: Blood pressure management in children with CKD ND. PMID- 25018968 TI - Biographic and disclosure information. PMID- 25018966 TI - Chapter 8: Future directions and controversies. PMID- 25018967 TI - Methods for guideline development. PMID- 25018972 TI - Work Group Membership. PMID- 25018971 TI - Foreword. PMID- 25018974 TI - Introduction: The case for updating and context. PMID- 25018976 TI - Chapter 2: Definition, identification, and prediction of CKD progression. PMID- 25018978 TI - Biographic and Disclosure Information. PMID- 25018977 TI - Methods for guideline development. PMID- 25018975 TI - Chapter 1: Definition and classification of CKD. PMID- 25018980 TI - Latin American Dialysis and Transplant Registry: 2008 prevalence and incidence of end-stage renal disease and correlation with socioeconomic indexes. AB - In 2008, 563,294,000 people were living in Latin America (LA), of which 6.6% were older than 65. The region is going through a fast demographic and epidemiologic transition process, in the context of an improvement in socio-economic indices. The Latin American Dialysis and Renal Transplant Registry has collected data since 1991, through an annual survey completed by 20 affiliated National Societies. Renal replacement treatment (RRT) prevalence and incidence showed an increase year by year. The prevalence rate (in all modalities) correlated with the World Bank country classification by income and the epidemiologic transition stage the countries were experiencing. RRT prevalence and kidney transplantation rates correlated significantly with gross national income (GNI), health expenditure in constant dollars (HeExp), % older than 65, life expectancy at birth, and % of the population living in urban settings. Kidney transplantation increased also, year by year, with more than 50% of transplants performed using kidneys from deceased donors. Double transplants were performed in six countries. RRT prevalence and incidence increased in LA, and are associated with indexes reflecting higher and more evenly distributed national wealth (GNI and HeExp), and the stage of demographic and epidemiological transition. PMID- 25018981 TI - Burden of chronic kidney disease: North Africa. AB - North Africa (NAF) is composed of six countries located in the African Sahara, namely the Western Sahara, Morocco, Algeria, Tunisia, Libya, and Egypt. Common features between these countries include similar climate, ecology, population genetics, and the socioeconomic environment. This commonality reflects on the chronic kidney disease (CKD) profile in these countries. While there are some estimates on the epidemiology of end-stage kidney disease, that of earlier stages is unknown. Several national screening programs are currently addressing this issue, such as the EGIPT-CKD project in Egypt and the MAREMAR study in Morocco. Preliminary results from the former suggest a prevalence of proteinuria in 10.6% of the relatives of patients on regular dialysis treatment. Despite the lack of reliable registries, it was possible to gather information on the etiology of CKD by direct contact with leading nephrologists in those countries. It turns out that glomerulonephritis (GN) accounts for 9-20%, diabetes 11-18%, hypertensive nephrosclerosis 10-35%, chronic interstitial nephritis 7-17%, and polycystic disease 2-3%. Compared to two decades earlier, diabetes has become more common at the expense of GN, proliferative GN, and amyloidosis regressed in favor of IgA and membranous nephropathies in Tunisian adults. Conventional schistosomal nephropathies are regressing in favor of hepatitis C viral (HCV) nephropathy in Egyptians. Focal segmental glomerulosclerosis is increasing at the expense of proliferative GNs in the region at large. Access to regular dialysis has been optimized during the past decade, with favorable outcomes despite the high incidence of HCV infection, tuberculosis, and protein-calorie malnutrition. Kidney transplantation is available in all NAF countries except the Western Sahara. About 650 transplants are performed annually from live donors, the majority in Egypt, where data from the largest center in Mansoura display a 10 year graft survival of 62%. Many transplants are performed from living unrelated donors, particularly in Egypt, which creates an ethical debate. Legislation for deceased-donor transplantation has been passed successively over the past two decades in Tunisia, Morocco, Algeria, and Egypt, which is expected to reflect quantitatively and qualitatively on the transplantation activity in the near future. PMID- 25018982 TI - Current status of maintenance hemodialysis in Beijing, China. AB - The Beijing Hemodialysis Quality Control and Improvement Center started patient data collection from 2007. We report here the trends in incidence, prevalence, and mortality of end-stage renal disease (ESRD) patients on maintenance hemodialysis (MHD). The incidence increased from 94 per million population in 2007 to 147.3 per million population in 2010. The leading cause of ESRD changed from chronic glomerulonephritis (32.1%) to diabetes (40.1%). The point prevalence of MHD at the end of 2006 was 269 per million population, and gradually increased to 509 per million population in the end of 2010. The leading cause of ESRD in 2010 prevalent patients was chronic nephritis (33.9%), followed by diabetes (29.5%). The annual mortality varied from 7.4 to 9.0%. Old or diabetic patients suffered a higher mortality. The 2010 prevalent MHD patients achieved KDOQI hemoglobin, calcium, phosphate, and intact parathyroid hormone guidelines, which was comparable to other DOPPS (Dialysis Outcome and Practice Pattern Study) countries; Beijing MHD patients had a relatively higher albumin level. PMID- 25018983 TI - End-stage kidney disease among indigenous peoples of Australia and New Zealand. AB - Although possessing different anthropological origins, there are similarities in the epidemiology of end-stage kidney disease (ESKD) among the indigenous peoples of Australia (the Australian Aborigines and Torres Strait Islanders) and New Zealand (Maori and Pacific Peoples). In both countries there is a substantially increased rate of ESKD among these groups. This is more marked in Australia than in New Zealand, but in both countries the relative rate (in comparison to non indigenous rates) as well as absolute rate have nearly stabilized in recent years. The excess risk affects females particularly-in contrast to the non indigenous picture. Among Aboriginal and Torres Strait Islander people in Australia, there is a strong age interaction, with the most marked risk being among those aged 25 to 45 years. Indigenous peoples are less likely to be treated with home dialysis, and much less likely to receive a kidney transplant. In particular, rates of living donation are very low among indigenous groups in both countries. Outcomes during dialysis treatment and during transplantation are inferior to those of nonindigenous ones, even after adjustment for the higher prevalence of comorbidities. The underlying causes for these differences are complex, but the slowing and possible stabilization of incident rate changes is heartening. PMID- 25018984 TI - Multidisciplinary care for poor patients with chronic kidney disease in Mexico. AB - Coordinated multidisciplinary care (MDC) could improve management and outcomes of patients with chronic kidney disease (CKD). We opened a nurse-led, MDC CKD clinic in Guadalajara, Mexico. We report the clinic's results between March 2008 and July 2011. The records of 353 patients with CKD stage 3 and 4 were reviewed. Data were collected prospectively. Mean age was 59.1+/-15.5 years; 54.4% were female and 63.7% were diabetic. We observed significant changes in the quality of care between baseline and follow-up. Compliance with practice guidelines for angiotensin II receptor blockers (ARB) and beta blockers increased from 30.6% to 46.6%, and from 11% to 19%, respectively; for statins from 41.4% to 80.3% for erythropoietin and calcium binders from 10.5% to 23.4%, and from 41.9 to 82.6%, respectively. At last visit, 90% of patients were on ACE inhibitors/ARB. Blood pressure <130/80 mm Hg increased from 23% to 38%. Serum glucose ?130 mg/dl increased from 54.4% to 67.7%. Serum cholesterol >160 mg/dl decreased from 64.8% to 60.3%. At last visit, 70% of the patients had a serum Hgb ?11.0 g/dl, and 80.1% and 65.1% had a normal serum calcium and serum phosphate, respectively. In conclusion, we observed a trend in the improvement of quality of care of CKD patients similar to those reported by other MDC programs in the developed world. Our study demonstrated that a nurse-led MDC program could be successfully implemented in developing countries. PMID- 25018985 TI - Empowerment of young nephrologists in developing countries: the role of the ISN Young Nephrologists Committee. AB - The International Society of Nephrology (ISN) established the Young Nephrologists Committee (YNC) in 2007 to increase the awareness of the ISN mission and activities among younger nephrologists and thus increase their involvement. One of the primary aims of the YNC is to empower young nephrologists from developing countries by providing education and mentoring support. This is being achieved by establishing ISN YN workshops in the developing world for junior medical staff and nephrology trainees, with local younger nephrologists supervising the workshops. Mentoring is important for young nephrologists, and the ISN YNC have established a mentoring program through the ISN where mentors and the mentored are matched, and also meet-the professor sessions at ISN Nexus conferences. Research is being encouraged by establishing the World Congress of Nephrology Young Nephrology awards in basic and clinical science from the developing and developed world, allowing young nephrologists the opportunity to attend the WCN and present their work in plenary sessions. Another important focus of the ISN YNC has been to raise the awareness of ISN activities and their relevance to young nephrologists in the developing world. In conclusion, the ISN YNC is hoping to empower young nephrologists from developing countries and this will improve the prevention, diagnosis, and treatment of kidney disease worldwide. PMID- 25018986 TI - Comparison of primary health-care models in the management of chronic kidney disease. AB - Negative lifestyle habits (potential risks for chronic kidney disease, CKD) are rarely modified by physicians in a conventional health-care model (CHCM). Multidisciplinary strategies may have better results; however, there is no information on their application in the early stages of CKD. Thus, the aim of this study was to compare a multiple intervention model versus CHCM on lifestyle and renal function in patients with type 2 diabetes mellitus and CKD stage 1-2. In a prospective cohort study, a family medicine unit (FMU) was assigned a multiple intervention model (MIM) and another continued with conventional health care model (CHCM). MIM patients received an educational intervention guided by a multidisciplinary team (family physician (FP), social worker, dietitian, physical trainer); self-help groups functioned with free activities throughout the study. CHCM patients were managed only by the FP, who decided if patients needed referral to other professionals. Thirty-nine patients were studied in each cohort. According to a lifestyle questionnaire, no baseline differences were found between cohorts, but results reflected an unhealthy lifestyle. After 6 months of follow-up, both cohorts showed significant improvement in their dietary habits. Compared to CHCM diet, exercise, emotional management, knowledge of disease, and adherence to treatment showed greater improvement in the MIM. Blood pressure decreased in both cohorts, but body mass index, waist circumference, and HbA1C significantly decreased only in MIM. Glomerular filtration rate (GFR) was maintained equally in both cohorts, but albuminuria significantly decreased only in MIM. In conclusion, MIM achieves better control of lifestyle-related variables and CKD risk factors in type 2 diabetes mellitus (DM2) patients with CKD stage 1 2. Broadly, implementation of a MIM in primary health care may produce superior results that might assist in preventing the progression of CKD. PMID- 25018987 TI - Quality of life of chronic kidney disease patients in developing countries. AB - In the developing world, the emphasis of care for the patient with chronic kidney disease is, in general, focused on the basics of care and patient survival; attention is not primarily focused on quality of life assessments. However, this arena is beginning to attract more attention. It is important to determine if standardized instruments are valid in the developing world and which unique assessments need to be utilized in individual cultural settings. PMID- 25018988 TI - Management of chronic kidney disease and dialysis in homeless persons. AB - End-stage renal disease and dialysis are complicated illnesses to manage in homeless persons, who often suffer medical comorbidities, psychiatric disease, cognitive impairment and addictions; descriptions of this population and management strategies are lacking. A retrospective review of dialysis patients who were homeless or unstably housed was undertaken at an urban academic Canadian center from 2001 to 2011. Electronic hospital records were analyzed for demographic, housing, medical, and psychiatric history, dialysis history, adherence to treatment, and outcomes. Two detailed cases of homeless patients with chronic kidney disease are presented. Eleven homeless dialysis patients with a mean age of 52.7+/-12.3 years, mostly men and mostly from minority groups were dialyzed for 41.1+/-29.2 months. Most resided permanently in shelters, eventually obtained fistula access, and were adherent to dialysis schedules. Patients were often nonadherent to pre-dialysis management, resulting in emergency starts. Many barriers to care for homeless persons with end-stage kidney disease and on dialysis are identified, and management strategies are highlighted. Adherence is optimized with shelter-based health care and intensive team-oriented case management. PMID- 25018989 TI - A kidney transplantation model in a low-resource country: an experience from Pakistan. AB - Pakistan is a low-resource country with a population of 185 million where expenditure on health is 1.3% of the gross national product. The estimated incidence of end-stage renal disease (ESRD) is 100 per million of the population. The paucity and high costs of renal replacement therapy render more than 90% of the ESRD population disenfranchised from replacement therapy. Our center, which is a government sector organization, established as an integrated dialysis and living related renal transplant program in the 1980s, where all services were provided free of cost to all patients with life-long follow-up care including medications. The model was based on a concept of community/government partnership where the contributions to funds vary between 40% and 60% for each partner. The model has been self sustaining for 25 years, with an annual budget of $28 million in 2010. Presently, over 600 patients are dialyzed each day and each week, 7-10 patients have received live related transplants. The overall 1- and 5-year graft survival rate of 3150 transplants is 92% and 85%, respectively. Free dialysis and transplantation established our institute as a focus of transplantation in the country. This model therefore allowed the institute to have a vital role in the campaign against transplant tourism and in the promulgation of the transplant law. It shows that in low-resource countries, specialized centers in the government sector can, with community support, provide high-quality ESRD care to the disenfranchised population. PMID- 25018990 TI - Kidney transplantation in a low-resource setting: Nigeria experience. AB - The incidence and prevalence of chronic kidney disease and end-stage renal disease (ESRD) have continued to increase exponentially all over the world in both developed and developing countries. While the majority of patients in developed countries benefit from various modalities of renal replacement therapies, those from developing economies suffer untimely deaths from uremia and cardiovascular disease. Kidney transplantation (KT) leads to improvement in both the quantity and quality of life. Unfortunately, it is not exploited to its full potential in most countries and this is particularly the case in developing economies. Only a very small fraction of the ESRD population in emerging countries ever gets transplanted because of the many constraints. This review focuses on KT in Nigeria between 2000 and 2010 and assessed particular challenges that need be addressed for KT potential to be fully harnessed in such resource constrained settings. A total of 143 KTs were performed in 5 transplant centers, some of which have only recently opened. One-year graft and patient survival was 83.2% and 90.2%, respectively, while the 5-year graft and patient survival was 58.7% and 73.4%, respectively. Mortality was reported in 38 (27%) of recipients. The complications recorded included acute rejection episodes in 15-30%, chronic allograft nephropathy in 21(14.7%) and malignancies, particularly Kaposi Sarcoma, which was reported in 8 (5.6%) recipients. It was concluded that KT has led to an improved survival but is bedevilled with unaffordability, inaccessibility, a shortage of donor organs and poor legislative support. Enactment of relevant organ transplant legislation, subsidization of renal care, and further development of local capacities would improve KT utilization and thus lead to better outcomes. PMID- 25018991 TI - Renal replacement therapy: can we separate the effects of social deprivation and ethnicity? AB - Britain's current ethnic mix is largely a consequence of legislation introduced following the Second World War to allow people from the British Empire and Commonwealth unhindered access to enter Britain to help revive the economy. British minority ethnic populations tend to live in more socially deprived areas, making differentiation between the effects of social deprivation and ethnicity difficult to distinguish. Free-at-the-point-of-use health care should minimize finance-related difficulty accessing treatment, and issues of geographical access to treatment will certainly differ from those of larger, more sparsely populated countries. To examine this, the UK Renal Registry has adopted an approach of studying social deprivation separately in the white-only population before studying the effect of ethnicity and social deprivation in the general population. Using this approach, rates of renal replacement therapy have been shown to be higher in individuals from socially deprived areas and, to varying extents, in those from ethnic minority groups. Attainment of standards on RRT, however, tended not to differ. Survival on RRT is lower for individuals from socially deprived areas but higher for South Asian and black patients. Inequalities have been identified in access to transplantation, with reduced access to the transplant waiting list for socially deprived patients and reduced access to transplantation, once on the waiting list, for ethnic minority patients. The reasons for these inequalities, including any contribution from underlying inequities, are the subject of ongoing research. PMID- 25018992 TI - Chronic kidney disease in homeless persons in Mexico. AB - Little is known about the prevalence of chronic kidney disease (CKD) among the homeless in Mexico. The role of substance abuse, alcoholism, and homelessness in CKD has not been properly evaluated. We screened 260 homeless individuals in the state of Jalisco, Mexico, for the presence of CKD and its risk factors, and compared their characteristics with those from a separate cohort of poor Jalisco residents and with a survey of the general Mexican population. CKD was more prevalent among the homeless than among the poor Jalisco population (22% vs. 15.8%, P=0.0001); 16.5% had stage 3, 4.3% stage 4, and 1.2% stage 5. All were unaware of having CKD. Only 5.8% knew they had diabetes, but 19% had fasting blood sugar >126 mg/dl; 3.5% knew they were hypertensive but 31% had systolic blood pressure ?140 mm Hg or diastolic blood pressure ?90 mm Hg. Alcoholism was less common than in the poor Jalisco population (23.5% vs. 32.3%, P=0.002), but tobacco smoking (34.6% vs. 21.5%, P=0.0001) and substance abuse (18% vs. 1.1%, P=0.0001) were more prevalent among the homeless. Likewise, chronic viral infections such as HIV (4.5% vs. 0.3%, P=0.0001) and HCV (7.7% vs. 1.4%, P=0.0001) were also significantly higher among the homeless than in the general population. In conclusion, CKD and its risk factors are highly prevalent among the homeless individuals in Jalisco, Mexico. Lack of awareness of having diabetes and hypertension is highly common, as is substance abuse. Programs aiming to prevent CKD and its risk factors in Mexico should specifically target this high risk population. PMID- 25018995 TI - Foreword. PMID- 25018993 TI - A population-based study on care and clinical outcomes in remote dwellers with heavy proteinuria. AB - Patients with proteinuria are at high risk of cardiovascular and renal complications. Since this risk can be reduced by appropriate interventions, we hypothesized that remote dwellers, who are known to have lower access to health care, might have a higher risk of complications. Using a database of all adults with at least one measure of urine protein between May 2002 and March 2009, we examined the frequency of heavy proteinuria, quality of care delivery, and rates of adverse clinical outcomes across travel distance categories to the nearest nephrologist. Heavy proteinuria was defined by an albumin:creatinine ratio ?60 mg/mmol, protein:creatinine ratio ?100 mg/mmol, or protein ?2+ on dipstick urinalysis. Of 1,359,330 subjects in the study, 262,209 were remote dwellers. The overall prevalence of proteinuria was 2.3%, 2.9%, and 2.5% in those who live >200, 100.1-200, and 50.1-100 km, respectively, as compared to 1.5% in those who live within 50 km of the nearest nephrologist (P<0.001). Similarly, the prevalence of heavy proteinuria was increased among remote dwellers compared to urban dwellers (P=0.001 for trend). There were no differences in markers of good quality care or the rate of adverse outcomes (all-cause mortality, heart failure, and renal outcomes) across distance categories. However, the rates of hospitalizations and stroke were significantly higher with increased distance from the nearest nephrologist (P<0.001and 0.02, respectively). In conclusion, heavy proteinuria was common in Alberta residents, especially in remote dwellers. Care seemed similar across distance categories of travel, but with higher risk of hospitalizations and stroke among remote dwellers. Further work is needed to understand the basis for the increased risk of hospitalizations and stroke. PMID- 25018996 TI - Work Group Membership. PMID- 25018998 TI - Summary of Recommendation Statements. PMID- 25018999 TI - Introduction: The case for updating and context. PMID- 25019000 TI - Chapter 1: Assessment of lipid status in adults with CKD. PMID- 25019001 TI - Chapter 2: Pharmacological cholesterol-lowering treatment in adults. PMID- 25019002 TI - Chapter 4: Pharmacological cholesterol-lowering treatment in children. PMID- 25019003 TI - Chapter 5: Triglyceride-lowering treatment in adults. PMID- 25019004 TI - Chapter 6: Triglyceride-lowering treatment in children. PMID- 25019006 TI - Biographic and disclosure information. PMID- 25019005 TI - Methods for guideline development. PMID- 25019008 TI - Fifteenth national congress of the Turkish Society of Hypertension and Renal Diseases. PMID- 25019009 TI - Hypertension and chronic kidney disease in Turkey. AB - Worldwide, both hypertension and chronic kidney disease are major public health problems, due to their epidemic proportions and their association with high cardiovascular mortality. In 2003, the first Prevalence, awareness, treatment, and control of hypertension in Turkey (the PatenT) study was conducted in a nationally representative population (n=4910) by the Turkish Society of Hypertension and Renal Diseases, and showed that overall age- and sex-adjusted prevalence of hypertension in Turkey was 31.8%. The PatenT study also reported that overall awareness (40.7%), treatment (31.1%), and control rates (8.1%) of hypertension were strikingly low. Only 20.7% of the patients who were aware of their hypertension and receiving treatment had their blood pressure controlled to <140/90 mm Hg. In the Chronic Renal Disease in Turkey (CREDIT) study (n=10,748), the overall prevalence of chronic kidney (including all stages) disease was 15.7% and increased with advancing age. In the same population, the prevalence of hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome were reported as 32.7%, 12.7%, 76.3%, 20.1%, and 31.3%, respectively. The prevalence and awareness of hypertension in CREDIT population was 32.7% and 48.6%, respectively. According to the data obtained from national surveys, the prevalence of hypertension and chronic kidney disease in Turkey is alarmingly high. To improve prevention, early diagnosis, and treatment of these major public health problems, appropriate health strategies should be implemented by the government, together with medical societies, non-governmental organizations, industry, health-care providers, and academia. PMID- 25019010 TI - Cardiovascular and other effects of salt consumption. AB - Salt is one of the most important determinants of high blood pressure and increased cardiovascular risk worldwide. However, a high salt intake has other adverse effects beyond those involving the cardiovascular system, so that there is renewed interest in the relationships between high salt intake and other diseases. PMID- 25019011 TI - Salt and hypertension: why is there still a debate? AB - More than a quarter of human populations now suffer from hypertension paralleling the marked increase in the dietary intake of salt during the recent several decades. Despite overwhelming experimental and epidemiological evidence, some still debate the relation between salt and hypertension. Pointing to some conflicting data in a few flawed studies, they argue that policy interventions to reduce the dietary intake of salt are premature and maybe unsafe without further studies. A brief review of data relating salt intake to hypertension, along with an overview of the history of the introduction of salt to human diet on an historic and evolutionary time scale, should help dispel doubts on the effectiveness and safety of low-salt diet. The recorded history confirms how rare and inaccessible salt has been until recent times. Like all other terrestrial life forms, humans evolved in a salt-free environment under intense evolutionary pressure for the selection of salt-conserving genes. Hypertension is a prototypical evolutionary maladaptation disorder of the modern man-a species exquisitely well adapted to low salt conditions suddenly confronted with salt excess. The World Health Organization and many governments have finally taken action to reduce dietary intake of salt, which already has started to reduce the burden of hypertension and the associated cardiovascular morbidity and mortality. This brief review is to broadly look at the evidence linking salt to hypertension from a historic and evolutionary perspective as well as touching upon some of the epidemiological and experimental data. PMID- 25019012 TI - Translational studies on augmentation of intratubular renin-angiotensin system in hypertension. AB - Various models of experimental hypertension and clinical examples of increased renin formation from a stenotic kidney or a juxtaglomerular cell tumor have shown that increased circulating angiotensin II (Ang II) stimulates the intrarenal/intratubular renin-angiotensin system (RAS) that elicits renal vasoconstriction, enhanced tubular sodium reabsorption, and progressive development of hypertension and renal injury. The enhanced intrarenal Ang II activity is due to both receptor-mediated Ang II uptake and Ang II type 1 (AT1) receptor-mediated stimulation of renal angiotensinogen (AGT) mRNA and protein by proximal tubule cells. The increased AGT secretion leads to local formation of Ang II and spillover of AGT into the distal nephron segments as reflected by increased AGT excretion in the urine, which provides an index of intrarenal RAS activity. In clinical studies, increased urinary excretion of AGT has been demonstrated in hypertension, type 1 and type 2 diabetes mellitus, and several types of chronic kidney diseases. In addition, renin secretion from principal cells of the collecting ducts is increased by AT1 receptor activation and acts on AGT from the proximal tubule to form more Ang I. Renin and/or (pro)renin activity is enhanced by binding to the (pro)renin receptor (PRR) on intercalated cells or secreted as soluble PRR contributing further to AGT cleavage, thus making more substrate available for Ang II conversion by local angiotensin-converting enzyme. The augmented intratubular Ang II concentrations together with elevated renal interstitial Ang II concentrations contribute to sustained stimulation of sodium reabsorption, vasoconstriction, development of hypertension, and progressive renal injury and fibrosis. PMID- 25019014 TI - Early diagnosis saves lives: focus on patients with hypertension. AB - It is estimated that one out of three adults has hypertension and that more than 50% of them are unaware of this condition. Blood pressure screening can facilitate early diagnosis and reduce the risk of further complications associated with hypertension. However, disagreement between credible guidelines on major topics like diagnosis of hypertension and the threshold blood pressure values for treatment initiations caused confusion and inaction among physicians. PMID- 25019013 TI - Controlling hypertension in Turkey: not a hopeless dream. AB - Despite major progress in prevention, diagnosis, and treatment during the recent decades, hypertension remains the leading risk factor for cardiovascular disease and mortality throughout the world. The prevalence of hypertension in developing countries continues to rise reaching alarming rates. Several risk factors of hypertension appear to be more common in developing countries than in developed countries. In Turkey, hypertension is a prevalent condition affecting approximately 22.5 million individuals. Hypertension control (defined as blood pressure <140/90 mm Hg) rate increased from 8.1% in 2003 (first Prevalence, awareness, treatment, and control of hypertension in Turkey (PatenT) study) to 28.7% in 2012 (PatenT 2 study). Meanwhile, rates of cardiovascular morbidity and mortality remained high in Turkey. Controlling risk factors such as hypertension, tobacco use, unhealthy diet, obesity, diabetes, hyperlipidemia, and physical inactivity can prevent most of the deaths from cardiovascular disease. It is also crucial for the public health system to have a hypertension education program aimed at reducing cardiovascular disease and prevention and control of hypertension promoting a healthy lifestyle in Turkey. Such a program could positively affect other lifestyle-related diseases as well. Importantly, cooperation among the components of the health system could contribute to improved outcomes in hypertensive populations. PMID- 25019015 TI - Early diagnosis saves lives: focus on patients with chronic kidney disease. AB - Chronic kidney disease is a global public health problem. Patients with chronic kidney disease have an increased risk of developing end-stage kidney disease and its complications. Early identification and management of patients with chronic kidney disease is important in order to decrease the morbidity and mortality. Early detection of chronic kidney disease is possible with screening programs targeting high-risk patients, such as patients with diabetes mellitus, hypertension, elderly patients, and patients having a family history of chronic kidney disease. PMID- 25019016 TI - Home and ambulatory blood pressure monitoring: when? who? AB - Blood pressure measurement in the diagnosis and management of hypertension, including the technique required for ambulatory blood pressure monitoring and home blood pressure monitoring, will be reviewed in this article. Home and ambulatory measurements are widely used, both to confirm the diagnosis and to improve adherence to therapy. The major advantage of out-of-office blood pressure monitoring is that it provides a large number of blood pressure measurements away from the medical environment, which represents a more reliable assessment of actual blood pressure than office blood pressure. The advantage of ambulatory blood pressure monitoring is its unique ability to measure nocturnal blood pressure. Although not fully validated in large-scale clinical trials, ambulatory blood pressure monitoring appears to correlate best with prognosis. Ambulatory blood pressure monitoring and home blood pressure monitoring provide somewhat different information on the subject's blood pressure status, and the two methods should thus be regarded as complementary, rather than competitive or alternative. PMID- 25019017 TI - Assessment of cardiovascular risk in hypertensive patients: a comparison of commonly used risk scoring programs. AB - Several calculation modalities are used today for cardiovascular risk assessment. Cardiovascular risk assessment should be performed in all hypertensive patients. Risk assessment methods being based on the population in which the patient lives and the inclusion of factors such as ethnicity variations, socioeconomic status, and medication use will contribute to improvements in risk assessments. The results should be shared with the patient, and modifiable risk factors must be effectively treated. PMID- 25019018 TI - Rational approaches to the treatment of hypertension: diet. AB - Hypertension affects one in three adults in Turkey and the United States. Only half are treated for this condition and only 10-20% is controlled. Dietary modifications such as salt restriction, moderation of alcohol drinking, and a diet rich in fruits, vegetables, and legumes and low in snacks, sweets, meat, and saturated fat are helpful in the treatment of hypertension. Consumption of dark chocolate is also associated with a drop in systolic blood pressure. Individual dietary factors that may reduce blood pressure include increased intakes of potassium, calcium, fish oil, fiber, and milk-based and vegetable-based protein. PMID- 25019019 TI - Rational approaches to the treatment of hypertension: modification of lifestyle measures. AB - Hypertension is an important health problem. Informative counseling is required for patients to completely understand the importance of non-pharmacologic treatments. Lifestyle changes such as restriction of salt intake, exercise, restriction of alcohol intake, diet, and weight loss are included in all hypertension treatment guidelines. However, serious motivation is required from the patient and the physician to succeed in this. Although the decrease in blood pressure may be limited with these measures, lifestyle modifications should be continued. PMID- 25019020 TI - Cell-based therapies in kidney disease. AB - Cell-based therapy is an emerging field but one that has shown early promise for the treatment of human kidney diseases. The most widely used cell is the mesenchymal stem cell (MSC) given its ability to be harvested from bone marrow, expanded in culture, and used in allogeneic protocols. The beneficial effects of MSCs occur through differentiation-independent pathways that include increased cell survival and proliferation, decreased inflammation, and suppression of immune function. Acute kidney injury and kidney transplantation are the two conditions most frequently treated with MSC infusion. Although initial studies are promising, the long-term efficacy and safety of MSC infusion awaits further study. PMID- 25019021 TI - Risk factors for chronic kidney disease: an update. AB - Chronic kidney disease has become a serious public health issue. There are currently over 1.4 million patients receiving renal replacement therapy worldwide. One way to reduce the economic burden of chronic kidney disease would be early intervention. In order to achieve this, we should be able to identify individuals with increased risk of renal disease. An individual's genetic and phenotypic make-up puts him/her at risk for kidney disease. Factors such as race, gender, age, and family history are highly important. For instance, being of African-American decent, older age, low birth weight and family history of kidney disease are considered to be strong risk factors for chronic kidney disease. Moreover, smoking, obesity, hypertension, and diabetes mellitus can also lead to kidney disease. An uncontrolled diabetic and/or hypertensive patient can easily and quickly progress to an end-stage kidney disease patient. Exposure to heavy metals, excessive alcohol consumption, smoking, and the use of analgesic medications also constitute risks. Experiencing acute kidney injury, a history of cardiovascular disease, hyperlipidemia, metabolic syndrome, hepatitis C virus, HIV infection, and malignancy are further risk factors. Determination of serum creatinine levels and urinalysis in patients with chronic kidney disease risk will usually be sufficient for initial screening. PMID- 25019022 TI - Slowing progression of chronic kidney disease. AB - Early identification of chronic kidney disease (CKD) provides an opportunity to implement therapies to improve kidney function and slow progression. The goal of this article is to review established and developing clinical therapies directed at slowing progression. The importance of controlling blood pressure will be discussed along with the target blood pressure that should be achieved in CKD patients. Therapy directed at inhibiting the renin-angiotensin-aldosterone system remains the mainstay of treatment with single-agent inhibition of this system being as good as dual blockade with fewer adverse effects. Other therapies that may be used include correction of metabolic acidosis, dietary protein restriction, and new models for delivering care to patients with CKD. Emerging therapies targeting endothelin, uric acid, kidney fibrosis, and oxidant stress hold promise for the future. PMID- 25019023 TI - Introduction: expanding concepts of chronic kidney disease-mineral and bone disorder (CKD-MBD). PMID- 25019024 TI - A phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease. AB - Extracellular phosphate is toxic to the cell at high concentrations. When the phosphate level is increased in the blood by impaired urinary phosphate excretion, premature aging ensues. When the phosphate level is increased in the urine by dietary phosphate overload, this may lead to kidney damage (tubular injury and interstitial fibrosis). Extracellular phosphate exerts its cytotoxicity when it forms insoluble nanoparticles with calcium and fetuin-A, referred to as calciprotein particles (CPPs). CPPs are highly bioactive ligands that can induce various cellular responses, including osteogenic transformation of vascular smooth muscle cells and cell death in vascular endothelium and renal tubular epithelium. CPPs are detected in the blood of animal models and patients with chronic kidney disease (CKD) and associated with adaptation of the endocrine axes mediated by fibroblast growth factor-23 (FGF23) and Klotho that regulate mineral metabolism and aging. These observations have raised the possibility that CPPs may contribute to the pathophysiology of CKD. This notion, if validated, is expected to provide new diagnostic and therapeutic targets for CKD. PMID- 25019025 TI - Vitamin D receptor activation: cardiovascular and renal implications. AB - The effects of vitamin D receptor activation on cardiovascular diseases, especially hypertension and cardiac dysfunction, are areas of active investigation. This article reviews the current state of knowledge about vitamin D receptor activation with respect to blood pressure, heart, and vascular health, as well as to chronic kidney disease and end-stage renal disease. Potential biological mechanisms, the role of vitamin D-binding protein, and data from observational and randomized controlled trials on this topic are summarized. PMID- 25019026 TI - Impact of cinacalcet introduction on MBD management: the MBD-5D study in Japan. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) has recently attracted attention in light of its association with clinical outcomes, such as fracture, cardiovascular disease, and mortality. Management of CKD-MBD has therefore come to have a central role in dialysis practice. Cinacalcet, a newly developed drug, has changed prescription patterns in many centers based on different changes in MBD markers than those observed with active vitamin D derivatives. As physicians require real-world evidence to guide their treatment decisions with respect to MBD management, we conducted the Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D), a 3-year observational study involving prevalent hemodialysis patients with secondary hyperparathyroidism (SHPT). Here, we review the results from the MBD-5D and discuss issues of MBD management in the cinacalcet era. Three years since the introduction of cinacalcet, 40% of hemodialysis patients with SHPT have come to use cinacalcet, enjoying marked improvement in management of circulating MBD markers, such as intact parathyroid hormone (PTH), phosphorus, and calcium. Combination therapy with cinacalcet and a vitamin D receptor activator (VDRA) may allow physicians to choose more suitable prescription patterns based on patient characteristics and therapeutic purposes. We observed an additive association between 'starting cinacalcet' and 'increased VDRA dose,' with marked improvement in the control of intact PTH levels. Further, the combination pattern of 'starting cinacalcet' and 'decreased VDRA dose' was associated with better achievement of target serum phosphorus and calcium levels. Future studies should examine the effect of different prescription patterns for SHPT treatment on clinical outcomes. PMID- 25019027 TI - Mechanisms of arterial calcifications and consequences for cardiovascular function. AB - Cardiovascular complications are the leading cause of mortality in chronic (CKD) and end-stage renal disease (ESRD). The risk of developing cardiovascular complications is associated with changes in the structure and function of the arterial system, which are in many aspects similar to those occurring with aging. The presence of traditional risk factors does not fully explain the extension and severity of arterial disease. Therefore, other factors associated with CKD and ESRD must also be involved. Arterial calcification (AC) is a common complication of CKD and ESRD, and the extent of AC in general population as well as in patients with CKD is predictive of subsequent cardiovascular mortality beyond established conventional risk factors. AC is an active process similar to bone formation that implicates a variety of proteins involved in bone and mineral metabolism and is considered part of a systemic dysfunction defined as CKD associated mineral and bone disorder (CKD-MBD). PMID- 25019028 TI - Uremic osteoporosis. AB - Abnormalities in bone turnover, mineralization, and volume represent one of the three components of chronic kidney disease-related mineral and bone disorder (CKD MBD). The risk of hip fracture is considerably high, while the risk of spinal compression fracture may not be more elevated among CKD patients than in general population. The relationship between bone fracture and bone mineral density in CKD patients is more complex than in those without kidney disease. An increase in the rate of falls has been reported to be a major cause of high hip fracture risk among CKD patients; however, it certainly is not the only underlying mechanism. Abnormal parathyroid function is not likely to be a major cause of hip fracture among CKD patients. In experimental CKD animals, mechanical elasticity properties of long bones showed an inverse correlation with kidney function. The deterioration of bone elasticity showed a significant correlation with bone biochemical changes. Of note, administration of the oral absorbent AST-120 was capable of preventing both changes. These findings suggest that uremic toxins cause a deterioration of bone material properties, and changes in material properties disturb bone elasticity. This disease concept cannot be considered to be a direct consequence of CKD-MBD. We therefore would like to call it 'uremic osteoporosis'. This entity may be a major cause of increased hip fracture risk among CKD patients. PMID- 25019029 TI - A Japanese approach for CKD-MBD. AB - Disturbances in mineral and bone metabolism have a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). The term 'renal osteodystrophy' has recently been replaced by 'CKD mineral and bone disorder (CKD-MBD)', which includes abnormalities in bone and mineral metabolism and vascular calcification. The Japanese Society for Dialysis Therapy clinical practice guideline for the management of secondary hyperparathyroidism in chronic dialysis patients was originally published in Japanese in 2006, then in English in 2008. During the past 5 years, this first guideline has contributed to a considerably better understanding and control of secondary hyperparathyroidism in CKD patients by physicians, other medical professionals, and the patients themselves. However, since its publication several new therapeutic modalities have become available for Japanese dialysis patients, which added more evidence to this area. Thus, we revised the guideline to include several new policies, and the new guideline was published in Japanese in 2012. This article contains the new guideline text, and clinical significance of CKD-MBD in Japan. PMID- 25019030 TI - Optimizing the cost-effectiveness of treatment for chronic kidney disease-mineral and bone disorder. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is an important risk factor in patients with CKD, and some medications for treating CKD-MBD have been recently marketed. Because assessment of health-care cost-effectiveness is growing in importance with increases in health expenditures, several cost effectiveness analyses for new medications such as sevelamer, lanthanum carbonate, cinacalcet hydrochloride, and paricalcitol have been conducted. The results of these analyses have stimulated discussion on the efficient use of these medications and, in some cases, have affected treatment recommendation. However, most of these studies had methodological problems, one of them being that the effectiveness of medications was estimated based on changes of surrogate parameters, such as vascular calcification or serum biochemistry values. Furthermore, even if cost-effectiveness analyses were based on a given clinical trial, the results might differ from country to country. To provide greater health benefits under limited health expenditures based on the results of cost effectiveness analyses, it is necessary to confirm the effectiveness of medications through well-designed clinical trials having mortality as the primary end point. In addition, cost-effectiveness analyses need to be performed separately for each country. PMID- 25019031 TI - Hyperphosphatemia is a combined function of high serum PTH and high dietary protein intake in dialysis patients. AB - Elevated serum phosphorus is associated with higher death risk in hemodialysis patients. Previous studies have suggested that both higher serum parathyroid hormone (PTH) level and higher dietary protein intake may contribute to higher serum phosphorus levels. However, it is not well known how these two factors simultaneously contribute to the combined risk of hyperphosphatemia in real patient-care scenarios. We hypothesized that the likelihood of hyperphosphatemia increases across higher serum PTH and higher normalized protein catabolic rate (nPCR) levels, a surrogate of protein intake. Over an 8-year period (July 2001 June 2009), we identified 69,355 maintenance hemodialysis patients with PTH, nPCR, and phosphorus data in a large dialysis provider. Logistic regression models were examined to assess the association between likelihood of hyperphosphatemia (serum phosphorus >5.5 mg/dl) and serum PTH and nPCR increments. Patients were 61+/-15 years old and included 46% women, 33% blacks, and 57% diabetics. Both higher serum PTH level and higher protein intake were associated with higher risk of hyperphosphatemia in dialysis patients. Compared with patients with PTH level 150-<300 pg/ml and nPCR level 1.0-<1.2 g/kg/day, patients with iPTH>600 pg/ml and nPCR>1.2 g/kg/day had a threefold higher risk of hyperphosphatemia (OR: 3.17, 95% CI: 2.69-3.75). Hyperphosphatemia is associated with both higher dietary protein intake and higher serum PTH level in maintenance hemodialysis patients. Worsening or resistant hyperphosphatemia may be an under appreciated consequence of secondary hyperparathyroidism independent of dietary phosphorus load. Management of hyperphosphatemia should include diligent correction of hyper-parathyroidism while maintaining adequate intake of high protein foods with low phosphorus content. PMID- 25019032 TI - Fibroblast growth factor 23 and 25-hydroxyvitamin D levels are associated with estimated glomerular filtration rate decline. AB - The combination of serum 25-hydroxyvitamin D (25D) and fibroblast growth factor 23 (FGF23) levels predict hard renal outcomes in patients with chronic kidney disease (CKD), independent of classical markers of mineral and bone disorders, including serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D levels, and active vitamin D therapy. In a prospective cohort study of 738 Japanese pre dialysis outpatients with CKD, we examined potentially non-linear associations between 25D and FGF23 levels and estimated glomerular filtration rate (eGFR) changes in 727 patients with at least a 6-month observation period and no history of admission by acute kidney injury. We used multiple regression analyses with restricted cubic spline functions using annualized eGFR decline as a dependent variable. A significantly non-linear positive relationship between 25D and eGFR changes was observed. The annualized eGFR decline was greater in patients with 25D concentrations <25 and 23 ng/ml in univariate and multivariate analyses, respectively. Above this threshold, the eGFR decline plateaued. FGF23 showed a linear negative association with eGFR changes. After dividing the patients into four groups according to median 25D and FGF23 levels, the annualized eGFR changes in the Low FGF23-Low 25D, High FGF23-High 25D, and High FGF23-Low 25D groups were 0.49 (95% confidence intervals: -2.83 to 3.81), -1.24 (-5.00 to 2.52), -4.77 ( 8.85 to -0.69), respectively, relative to the Low FGF23-High 25D group (P for trend, 0.02). Thus, combined use of FGF23 and 25D is useful to predict eGFR change in patients with CKD as well as hard renal outcomes. PMID- 25019033 TI - Computer-Automated Static, Dynamic and Cellular Bone Histomorphometry. AB - Dynamic and cellular histomorphometry of trabeculae is the most biologically relevant way of assessing steady state bone health. Traditional measurement involves manual visual feature identification by a trained and qualified professional. Inherent with this methodology is the time and cost expenditure, as well as the subjectivity that naturally arises under human visual inspection. In this work, we propose a rapidly deployable, automated, and objective method for dynamic histomorphometry. We demonstrate that our method is highly effective in assessing cellular activities in distal femur and vertebra of mice which are injected with calcein and alizarin complexone 7 and 2 days prior to sacrifice. The mineralized bone tissues of mice are cryosectioned using a tape transfer protocol. A sequential workflow is implemented in which endogenous fluorescent signals (bone mineral, green and red mineralization lines), tartrate resistant acid phosphatase identified by ELF-97 and alkaline phosphatase identified by Fast Red are captured as individual tiled images of the section for each fluorescent color. All the images are then submitted to an image analysis pipeline that automates identification of the mineralized regions of bone and selection of a region of interest. The TRAP and AP stained images are aligned to the mineralized image using strategically placed fluorescent registration beads. Fluorescent signals are identified and are related to the trabecular surface within the ROI. Subsequently, the pipelined method computes static measurements, dynamic measurements, and cellular activities of osteoclast and osteoblast related to the trabecular surface. Our method has been applied to the distal femurs and vertebrae of 8 and 16 week old male and female C57Bl/6J mice. The histomorphometric results reveal a significantly greater bone turnover rate in female in contrast to male irrespective of age, validating similar outcomes reported by other studies. PMID- 25019034 TI - Reactive Arrays of Colorimetric Sensors for Metabolite and Steroid Identification. AB - The work described herein examines a rapid mix-and-measure method called DETECHIP suitable for screening of steroids and metabolites. The addition of steroids and metabolites to reactive arrays of colorimetric sensors generated characteristic color "fingerprints" that were used to identify the analyte. A color analysis tool was used to identify the analyte pool that now includes biologically relevant analytes. The mix-and-measure arrays allowed the detection of disease metabolites, orotic acid and argininosuccinic acid; and the steroids androsterone, 1,4-androstadiene, testosterone, stanozolol, and estrone. The steroid 1,4-androstadiene was also detected by this method while dissolved in synthetic urine. Some of the steroids, such as androstadiene, stanozolol, and androsterone were co-dissolved with (2-hydroxypropyl)-beta-cyclodextrin in order to increase solubility in aqueous buffered solutions. The colorimetric arrays do not intend to eliminate ELISA or mass spectroscopy based screening, but to possibly provide an alternative analytical detection method for steroids and metabolites. PMID- 25019035 TI - TNF-alpha Antagonist and Infection in Rheumatoid Arthritis. AB - BACKGROUND: Anti-TNF treatment may increase infection risk, although this has been difficult to study because the timing of anti-TNF treatment is driven by disease activity, which may influence infection susceptibility leading to confounding that varies over time. We evaluated the association between anti-TNF initiation in rheumatoid arthritis (RA) patients on disease modifying anti rheumatic drugs (DMARD) and infection using multiple approaches adjusting for time-varying confounding. METHODS: 383 anti-TNF-naive RA patients on >=1 non biologic-DMARD at enrollment from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) were followed up to two years. Pooled logistic regressions estimated the association between anti-TNF and infection by including time-varying covariates in the adjusted models and inverse probability treatment weighting (IPTW). RESULTS: Adjustment for time-varying disease activity and other suspected confounders yielded non-statistically significant positive associations between anti-TNF start and infection regardless of analytic approach (RRmvar_adj = 2.1, 95% CI: 0.8 - 5.8). CONCLUSIONS: Incorporating changing clinical status, and treatment indications and consequences, yielded consistently (though not significantly) elevated relative risks of infection associated with anti-TNF initiation. Due to limited statistical power, we cannot draw firm conclusions. However, we have illustrated multiple approaches adjusting for potential time varying confounding in longitudinal studies and hope to replicate the approaches in larger studies. PMID- 25019036 TI - Emerging Adults with Type 1 Diabetes during the First Year Post-High School: Perceptions of Parental Behaviors. AB - Among 182 emerging adults with type 1 diabetes (93% White and 57% female), changes during the year post-high school were examined in perceptions of diabetes specific conflict with parents, parent-youth shared responsibility, parental tangible aid, and parental autonomy support, as well as the moderating effects of living situation, gender, years with diabetes, and glycemic control. A linear mixed effects model, controlling for baseline values, tested the changes in and relationships among these variables over time. Changes over time in parent-youth conflict were moderated by living independently of parents; autonomy support and shared responsibility were moderated by years with diabetes; and tangible aid was moderated by glycemic control. Future longitudinal research needs to examine whether changes in parental behaviors lead to positive or negative diabetes outcomes among these emerging adults with diabetes. PMID- 25019037 TI - A structured approach to design-for-frequency problems using the Cayley-Hamilton theorem. AB - An inverse eigenvalue problem approach to system design is considered. The Cayley Hamilton theorem is developed for the general case involving the generalized eigenvalue vibration problem. Since many solutions exist for a desired frequency spectrum, a discussion of the required design information and suggestions for including structural constraints are given. An algorithm for solving the inverse eigenvalue design problem using the generalized Cayley-Hamilton theorem is proposed. A method for solving partially described systems is also specified. The Cayley-Hamilton theorem algorithm is shown to be a good design tool for solving inverse eigenvalue problems of mechanical and structural systems. PMID- 25019038 TI - Synchronous tuberculosis, Epstein-Barr virus-associated lymphoproliferative disorder and cytomegalovirus infection in an allogeneic transplant recipient: a case report. AB - BACKGROUND: Allogeneic stem cell transplant recipients are prone to infections by various organisms. Tuberculosis (TB) represents a rare infectious complication, especially in countries non-endemic for TB. CASE REPORT: Here, we report the case of a German patient with exposure to TB decades before he was diagnosed with disseminated TB as well as synchronous Epstein-Barr virus associated lymphoproliferative disorder and cytomegalovirus infection after allogeneic stem cell transplantation for refractory acute myeloid leukemia. Tuberculostatic and virostatic therapy was administered and the patient could be discharged with no apparent signs of infection two weeks after initiation of therapy. CONCLUSION: This case illustrates the need for awareness of mycobacterial infections in patients from non-endemic regions undergoing stem cell transplantation even if other reasons for fever are present. PMID- 25019039 TI - In vivo interactions of continuous flucloxacillin infusion and high-dose oral rifampicin in the serum of 15 patients with bone and soft tissue infections due to Staphylococcus aureus - a methodological and pilot study. AB - BACKGROUND: Increased antibiotic resistance against Staphylococcus aureus and low penetration into bone requires regimen optimization of available drugs. METHODS: We evaluate pharmoacokinetic and pharmacodynamic parameters (PK/PD) as well as in vivo interactions of continuous flucloxacillin 12 g/d administration combined with high dose oral rifampicin 600 mg bid in the serum of 15 adult patients with bone and soft tissue infections. We use the patient's own serum directed against his own isolated S. aureus strain to reproduce in vivo conditions as closely as possible. RESULTS: The continuous flucloxacillin infusion constantly generated plasma free drug levels largely exceeding the serum minimal inhibitory concentrations (mean 74-fold). Combination with rifampicin significantly increased flucloxacillin levels by 44.5%. Such an increase following rifampicin introduction was documented in 10/15 patients, whereas a decrease was observed in 1/15 patients. Finally, all infections were cured and the combination was well tolerated. CONCLUSIONS: In this in vivo methodological pilot study among adult patients with orthopaedic infections due to S. aureus, we describe a new method and reveal substantial but inconsistent interactions between flucloxacillin and rifampicin, of which the clinical significance remains unclear. PMID- 25019040 TI - Determination of abnormally expressed microRNAs in bone marrow smears from patients with follicular lymphomas. AB - The abnormal expression of microRNAs (miRNAs) is implicated in various human diseases, including cancers. Accordingly, miRNA expressions have been examined in many cancer tissues and blood, but there have been few studies examining smear samples from bone marrow (BM) or peripheral blood. Here we successfully isolated small RNAs from BM smears using a mirVana miRNA Isolation Kit with our original modifications. The isolated small RNAs were then used to measure the levels of representative miRNAs such as miR-155, let-7a, and U6 via real-time PCR with a specific TaqMan probe, although peaks for the ribosomal RNAs (18S, and 28S) were not identified. The PCR curves of the miRNAs were indistinguishable from those from BM living cells from the same donor. Finally, our method for BM smears identified numerous abnormally altered miRNAs (significantly decreased, 39 miRNAs; significantly increased, 27 miRNAs) in follicular lymphomas (FL) compared with normal donors via TaqMan real-time PCR miRNA array. The array indicated that miR-451 showed the greatest decrease in FL (a 345-fold decrease), while miR-338 5p showed the greatest increase in FL (172-fold) relative to normal donors. The miRNAs identified by our study might serve as markers to predict the invasion of FL cells into BM without biopsy. Furthermore, our method will provide a new avenue for the analysis of miRNAs in BM smear samples from various hematologic diseases. PMID- 25019041 TI - Concurrent congenital peritoneopericardial diaphragmatic hernia and bochdalek hernia in a neonate. AB - We present the first report of a neonate with, concurrent left sided Bochdalek hernia and peritoneopericardial diaphragmatic hernia. PMID- 25019042 TI - Comparison between leached metakaolin and leached diatomaceous earth as raw materials for the synthesis of ZSM-5. AB - Inexpensive raw materials have been used to prepare ZSM-5 zeolites with SiO2/Al2O3 molar ratios in the range 20 - 40. Kaolin or Bolivian diatomaceous earth was used as aluminosilicate raw materials and sodium hydroxide and n butylamine were used as mineralizing agents and template. Dealumination of the raw materials by acid leaching made it possible to reach appropriate SiO2/Al2O3 ratios and to reduce the amount of iron and other impurities. After mixing the components and aging, hydrothermal treatment was carried out and the products were recovered The results clearly show for the first time that well-crystallized ZSM-5 can be directly prepared from leached metakaolin or leached diatomaceous earth using sodium hydroxide and n-butylamine as mineralizing agents and template under appropriate synthesis conditions. A longer induction time prior to crystallization was observed for reaction mixtures prepared from leached diatomaceous earth, probably due to slower digestion of the fossilized diatom skeletons as compared with that for microporous leached metakaolin. The use of leached diatomaceous earth allowed higher yield of ZSM-5 crystals within comparable synthesis times. However, low amounts of Mordenite formed, which was related to the high calcium content of diatomaceous earth. Another considerable advantage of diatomaceous earth over kaolin is that diatomaceous earth does not require heat treatment at high temperature for metakaolinization. PMID- 25019043 TI - The measurement of stiffness of uterine smooth muscle tumor by elastography. AB - Leiomyoma shows various diagnostic images, often making it difficult to differentiate from leiomyosarcoma. Recently, the utility of elastography has been reported for the differentiation of superficial tumors. We attempted to diagnose two cases of uterine smooth muscle tumors by elastography. One case was strongly suspected of leiomyosarcoma, and the other case had been diagnosed with leiomyoma. We preoperatively performed virtual tissue imaging (VTI) and virtual tissue quantification (VTQ). In VTQ, we measured shear wave velocity (Vs) five times at each point that ROI was placed. In case of suspected leiomyosarcoma, we attached the tip of convex probe 2 cm below the navel, perpendicular to the floor and measured Vs. In case of leiomyoma, we placed four ROIs randomly in leiomyomas for VTQ. For the case of suspected leiomyosarcoma, Vs and pathological findings from the VTQ were comparably examined. Significant differences were observed in the Vs in the leiomyosarcoma case, whereas not in the leiomyoma case. The comparison of VTQ and pathological findings for the case of leiomyosarcoma indicated high viability in the region where the highest Vs was measured, and strong necrosis in the region with the lowest Vs. These findings suggest that VTQ is useful for diagnosing uterine smooth muscle tumors. PMID- 25019044 TI - Methods and protocol of a mixed method quasi-experiment to evaluate the effects of a structural economic and food security intervention on HIV vulnerability in rural Malawi: The SAGE4Health Study. AB - BACKGROUND: Poverty and lack of a predictable, stable source of food are two fundamental determinants of ill health, including HIV/AIDS. Conversely, episodes of poor health and death from HIV can disrupt the ability to maintain economic stability in affected households, especially those that rely on subsistence farming. However, little empirical research has examined if, and how, improvements in people's economic status and food security translate into changes in HIV vulnerability. METHODS: In this paper, we describe in detail the methods and protocol of an academic-NGO collaboration on a quasi-experimental, longitudinal study of the mechanisms and magnitude of the impact of a multilevel economic and food security program (Support to Able-Bodied Vulnerable Groups to Achieve Food Security; SAFE), as implemented by CARE. Primary outcomes include HIV vulnerability (i.e., HIV risk behaviors, HIV infection), economic status (i.e., income, household assets) and food security (including anthropometric measures). We recruited participants from two types of areas of rural central Malawi: traditional authorities (TA) selected by CARE to receive the SAFE program (intervention group) and TAs receiving other unrelated CARE programming (controls). In the intervention TAs, we recruited 598 program participants (398 women, 200 men) and interviewed them at baseline and 18- and 36-month follow-ups; we interviewed 301 control households. In addition, we conducted random surveys (n = 1002) in the intervention and control areas with a 36-month assessment interval, prior to and after implementation of SAFE. Thus, we are examining intervention outcomes both in direct SAFE program participants and their larger communities. We are using multilevel modeling to examine mediators and moderators of the effects of SAFE on HIV outcomes at the individual and community levels and determine the ways in which changes in HIV outcomes feed back into economic outcomes and food security at later interviews. Finally, we are conducting a qualitative end-of-program evaluation consisting of in-depth interviews with 90 SAFE participants. DISCUSSION: In addition to examining pathways linking structural factors to HIV vulnerability, this research will yield important information for understanding the impact of a multilevel environmental/structural intervention on HIV, with the potential for other sustainable long-term public health benefits. PMID- 25019045 TI - Ganoderma formosanum polysaccharides attenuate Th2 inflammation and airway hyperresponsiveness in a murine model of allergic asthma. AB - Allergic asthma is an inflammatory disease of the airways mediated by Th2 immune responses and characterized by airway hyperresponsiveness (AHR). Fungi of the genus Ganoderma are basidiomycetes that have been used in traditional Asian medicine for centuries. We recently found that PS-F2, a polysaccharide fraction purified from the submerged culture broth of Ganoderma formosanum, stimulates the activation of dendritic cells and primes a T helper 1 (Th1)-polarized adaptive immune response. This study was designed to investigate whether the Th1 adjuvant properties of PS-F2 could suppress the development of allergic asthma in a mouse model. BALB/c mice were sensitized by repeated immunization with chicken ovalbumin (OVA) and alum, followed by intranasal challenge of OVA to induce acute asthma. PS-F2 administration during the course of OVA sensitization and challenge effectively prevented AHR development, OVA-specific IgE and IgG1 production, bronchial inflammation, and Th2 cytokine production. Our data indicate that PS-F2 has a potential to be used for the prevention of allergic asthma. PMID- 25019047 TI - Early childhood development: the role of community based childcare centres in Malawi. AB - BACKGROUND: Somatic changes including growth and development of the brain of a human being occur very early in life. Programmes that enhance early childhood development (ECD) therefore should be part of the national agenda. Cognizant of this fact, the Malawi Government together with development partners facilitated the establishment of community-based child care centres (CBCCs) which are owned and managed by community members. This study was aimed at understanding how CBCCs operated and their core functions. METHODS: Using information from databases kept by the District Social Welfare Officers from all the 28 districts in Malawi, coupled with snowballing, all functioning CBCCs were enumerated. A questionnaire was administered to the head of the CBCC or a care giver. Highly trained Research Assistants also carried our observations of the structures around the centres and the activities that actually happened. Data was analysed using a Statistical Package for Social Sciences. RESULTS: Communities provide structures, support for care givers, food, utensils, labour and play materials for the children in CBCCs. The first ECD centre was established in 1966 but the real surge in establishing these happened towards the end of the 1990s and by 2007 there were 5,665 CBCCs in Malawi caring for 407,468 children aged between 3 and 5 years. CBCCs were established to provide pre-primary school learning, and in some cases provide special care to orphans and other vulnerable. CONCLUSIONS: Despite the fact that most CBCC premises and structures fell short of the standards laid down by the CBCC profile, the activities and services provided were mostly to the book. Children were provided with nutritious foods and subjected to play that stimulated their cognitive and mental development. Despite the fact that some members of the community do not realize the value of the CBCCs, the existence of these institutions is an opportunity for the community to take care of their children communally, a task that has become imperative as a result of the upsurge in the number of orphans as a result of the HIV and AIDS epidemic. The study recommends that Malawi should take investments in ECD programmes as a priority. PMID- 25019046 TI - Cytotoxic effects of the compound cis-tetraammine(oxalato)ruthenium(III) dithionate on K-562 human chronic myelogenous leukemia cells. AB - Chemotherapy is a common treatment for leukemia. Ruthenium complexes have shown potential utility in chemotherapy and photodynamic therapy. The identification of new chemotherapeutics agents is critical for further progress in the treatment of leukemia. Ruthenium complexes generally have lower toxicities compared to cisplatin attributed to their specific accumulation in cancer tissues. Based on these evidences, in the present work we studied the cytotoxic activity of the ruthenium(III) compound cis-tetraammine(oxalato)ruthenium(III) dithionate - {cis [Ru(C2O4)(NH3)4]2(S2O6)} against human chronic myelogenous leukemia cells (K-562) tumor cell line. The tested compound induces cell death in a dose and time dependent manner on K-562 cells. It is found that the effect was improved linearly while prolonging the incubation time. Compared to the cell cycle profiles of untreated cells, flow cytometric analysis indicated the sub-G1 arresting effect of ruthenium compound on K-562 cells. In our study, {cis [Ru(C2O4)(NH3)4]2(S2O6)} shows a significant increase in tailed cells in any of the concentrations tested compared with negative control. Consequently, the concentration of {cis-[Ru(C2O4)(NH3)4]2(S2O6)} might be associated cytotoxicity with direct effect on K-562 cells DNA. Thus, it can be deducted that ruthenium based compounds present selectivity to enter both tumor and normal cells. Additional studies are needed to determine the molecular mechanisms of the active components and to evaluate the potential in vivo anticancer activity of the cis tetraammine(oxalato)ruthenium(III) dithionate. PMID- 25019048 TI - Spatial analysis of cattle and shoat population in Ethiopia: growth trend, distribution and market access. AB - The livestock subsector has an enormous contribution to Ethiopia's national economy and livelihoods of many Ethiopians. The subsector contributes about 16.5% of the national Gross Domestic Product (GDP) and 35.6% of the agricultural GDP. It also contributes 15% of export earnings and 30% of agricultural employment. The livestock subsector currently support and sustain livelihoods for 80% of all rural population. The GDP of livestock related activities valued at 59 billion birr. Ethiopian livestock population trends, distribution and marketing vary considerably across space and time due to a variety of reasons. This study was aimed to assess cattle and shoat population growth trend, distribution and their access to market. Regression analysis was used to assess the cattle and shoat population growth trend and Geographic Information Systems (GIS) techniques were used to determine the spatial distribution of cattle and shoats, and their relative access to market. The data sets used are agricultural census (2001/02) and annual CSA agricultural sample survey (1995/96 to 2012/13). In the past eighteen years, the livestock population namely cattle, sheep and goat grew from 54.5 million to over 103.5 million with average annual increment of 3.4 million. The current average national cattle, sheep and goat population per km(2) are estimated to be 71, 33 and 29 respectively (excluding Addis Ababa, Afar and Somali regions). From the total livestock population the country owns about 46% cattle, 43% sheep and 40% goats are reared within 10 km radius from major livestock market centres and all-weather roads. On the other hand, three fourth of the country's land mass which comprises 15% of the cattle, 20% of the sheep and 21% of goat population is not accessible to market (greater than 30 km from major livestock market centres). It is found that the central highland regions account for the largest share of livestock population and also more accessible to market. Defining the spatial and temporal variations of livestock population is crucial in order to develop a sound and geographically targeted livestock development policy. PMID- 25019049 TI - Evaluation of the nutritive value of muiumba (Baikiaea plurijuga) seeds: chemical composition, in vitro organic matter digestibility and in vitro gas production. AB - One of the main constraints hindering the increase of animal production in semi arid regions of Africa is the inadequate supply of nutrients during the dry season. Incorporation of alternative feed resources in ruminant diets during this period could be a viable approach to overcome these limitations. The objective of this study was to evaluate the nutritive value of muiumba (Baikiaea plurijuga) tree seeds as an alternative nutrient source for ruminants. Muiumba seeds were compared to other eight feedstuffs including two cereal grains (corn and oat), two wheat by-products (wheat bran and distilled wheat) and four protein meals (coconut meal, sunflower meal, soybean meal and rapeseed meal) as to its chemical composition, in vitro organic matter digestibility (IVOMD) and in vitro gas production. The moderate crude protein concentrations (145 g/kg DM) of muiumba seeds indicate that this feedstuff could not be used as a protein supplement, contrarily to the majority of multipurpose tree seeds. Although the starch content was scarce (15 g/kg DM), the low neutral detergent fibre (235 g/kg DM), low molecular weight sugar (76.1 g/kg DM) and non-starch polysaccharide (510.5 g/kg DM) contents indicate that this feedstuff has potential feeding value. This was confirmed by the IVOMD (0.770) and by the data provided by the in vitro gas production showing that muiumba seeds had high (P < 0.05) maximum gas production and fractional fermentation rates, suggesting that these seeds are characterized by a highly fermentable fraction. PMID- 25019050 TI - Interim analysis for binary outcome trials with a long fixed follow-up time and repeated outcome assessments at pre-specified times. AB - In trials with binary outcomes, assessed repeatedly at pre-specified times and where the subject is considered to have experienced a failure at the first occurrence of the outcome, interim analyses are performed, generally, after half or more of the subjects have completed follow-up. Depending on the duration of accrual relative to the length of follow-up, this may be inefficient, since there is a possibility that the trial will have completed accrual prior to the interim analysis. An alternative is to plan the interim analysis after subjects have completed follow-up to a time that is less than the fixed full follow-up duration. Using simulations, we evaluated three methods to estimate the event proportion for the interim analysis in terms of type I and II errors and the probability of early stopping. We considered: 1) estimation of the event proportion based on subjects who have been followed for a pre-specified time (less than the full follow-up duration) or who experienced the outcome; 2) estimation of the event proportion based on data from all subjects that have been randomized by the time of the interim analysis; and 3) the Kaplan-Meier approach to estimate the event proportion at the time of the interim analysis. Our results show that all methods preserve and have comparable type I and II errors in certain scenarios. In these cases, we recommend using the Kaplan-Meier method because it incorporates all the available data and has greater probability of early stopping when the treatment effect exists. PMID- 25019051 TI - Social construction of disability and its potential impacts to welfare practice in Vietnamese contexts. AB - From the survey responses and the policy analysis, the initial findings on this paper present some aspects of knowledge, attitude and practice (KAP) on disability which are presented as following: Firstly, there is a significant changes in legal documents and social policies related to disability in Vietnam, especially from 2006, in terms of its name and contents for improving the life of PWD with inclusive approach, however the meaning of disability is not clear in policies. Secondly, the understanding on disability is mainly based on medical/individual model which focuses on the disability's causes in words of health or individual problem rather than viewing the social causes in aspects of the social barriers and restriction, in addition almost policies focus on the problems of PWD rather than the social aspects. Thirdly, social attitude toward disability and PWD seems to be very empathetic, however it is less regard to CWD's ability as well as there are more attitudes on charity giving and supporting than helping them to be independent in their life. Finally, in spite of positive knowledge and attitudes on disability, there is still limitation on practical activities towards CWD/PWD from society in daily life. PMID- 25019053 TI - Diagnosis of ALG12-CDG by exome sequencing in a case of severe skeletal dysplasia. AB - Congenital Disorder of Glycosylation type Ig (ALG12-CDG) is part of a group of autosomal recessive conditions caused by deficiency of proteins involved in the assembly of dolichol-oligosaccharides used for protein N-glycosylation. In ALG12 CDG, the enzyme affected is encoded by the ALG12 gene. Affected individuals present clinically with neurodevelopmental delay, growth retardation, immune deficiency, male genital hypoplasia, and cardiomyopathy. A total of six individuals have been reported in the literature. Here, we present an infant with rhizomelic short stature, talipes equinovarus, platyspondyly, and joint dislocations. The infant had marked underossification of the pubic bones. Exome sequencing was performed and two deletions, each resulting in frameshifts, were found in ALG12. A review of the literature revealed two infants with ALG12-CDG and a severe skeletal dysplasia, including under-ossification of cervical vertebrae, pubic bones, and knees; in addition to talipes equinovarus and rhizomelic short stature. The phenotype of the individual we describe resembles pseudodiastrophic dysplasia and we discuss similarities and differences between ALG12-CDG and pseudodiastrophic dysplasia. The differential diagnosis in selected undiagnosed skeletal dysplasias should include CDGs. PMID- 25019052 TI - Circulating microRNAs as biomarkers for inflammatory diseases. AB - MicroRNAs (miRNAs), a class of small, non-coding RNA molecules with gene regulatory functions, have emerged to play a critical role in the pathogenesis of a variety of diseases. Current technological advances allow accurate, high throughput profiling of miRNA abundance in different tissues. More recently, extracellular, circulating miRNAs have begun to be demonstrated as highly stable, blood-based biomarkers for diseases. Understanding the interactions between circulating miRNAs and clinical phenotypes can enhance our knowledge of complex diseases and traits. On the other hand, given the advantages of utilizing blood based biomarkers (e.g., convenience in collecting samples), circulating miRNAs as biomarkers may improve both disease diagnosis and management. Particularly, we reviewed recent progress in identifying circulating miRNAs as biomarkers for several common inflammatory diseases including asthma, inflammatory bowel disease, and rheumatoid arthritis. Current studies showed a promising future of using circulating miRNAs in the care of inflammatory diseases. PMID- 25019054 TI - What's in a name? Compliance, adherence and concordance in chronic psychiatric disorders. AB - About half or more of the patients with chronic psychiatric illnesses, either do not take their medications correctly, or completely stop taking them. The problem of poor initial compliance or adherence is often compounded by a continued decline in compliance/adherence over time. The failure to take medicines, adversely affects the outcome of treatment, and places a huge burden of wasted resources on the society. Three terms have been used to describe medication taking among patients with chronic psychiatric disorders. Compliance is defined as "the extent to which the patient's behaviour matches the prescriber's recommendations". Though compliance has been frequently employed to describe medication-taking behaviour, it has proved problematic because it refers to a process where the clinician decides on a suitable treatment, which the patient is expected to comply with unquestioningly. Studies over the past few decades have emphasized the importance of patients' perspectives in medication-taking, based on their own beliefs, their personal circumstances, the information and resources available for them. Adherence has been used as a replacement for compliance in an effort to place the clinician-patient relationship in its proper perspective. Adherence refers to a process, in which the appropriate treatment is decided after a proper discussion with the patient. It also implies that the patient is under no compulsion to accept a particular treatment, and is not to be held solely responsible for the occurrence of non-adherence. Adherence has been defined as "the extent to which a person's behaviour, taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider". To overcome certain problems in the concept of adherence, a third term concordance has been used. The concept of concordance has evolved from a narrower view, emphasizing an agreement between the clinician and the patient, which takes into account each other's perspective on medication-taking, to a broader process consisting of open discussions with the patient regarding medication-taking, imparting information and supporting patients on long-term medication. It is a process, which entertains patients' views on medication-taking, and acknowledges that patients' views have to be respected even if they make choices, which appear to be in conflict with the clinician's views. Although none of these terms are ideal solutions to understanding the complex process of medication-taking behaviour of patients, the move from compliance to adherence and concordance represents genuine progress in this field, which puts the patient's perceptions at the centre of the whole process. PMID- 25019055 TI - Melancholia in medieval Persian literature: The view of Hidayat of Al-Akhawayni. AB - "Melancholia" seems to be the oldest term used to describe the manifestations of depression. Throughout the history of medicine, melancholia has been the focus of consideration of many scholars who have provided varying definitions of this disorder and its manifestations. This continual process has resulted in the gradual development of the concept of melancholia over time. Persian scholars were among the scientists who have studied the melancholia and contributed to its concept. One figure, Al-Akhawayni Bukhari (?-983 AD), a Persian physician whose reputation was based on the treatment of patients with mental problems, investigated this disorder. He described Melancholia and explained its clinical manifestations and treatment methods. Al-Akhawayni provided an early classification of the patients suffering from this disorder. Since the medieval Persian concept of melancholia is not well-known, this paper aims to review Al Akhawayni's 10(th) century knowledge on melancholia which can represent the early concept of this disorder in the Near East. PMID- 25019056 TI - Cognitive inflexibility in Japanese adolescents and adults with autism spectrum disorders. AB - AIM: To investigate executive function in Japanese adolescents and adults with autism spectrum disorders (ASD) compared to Japanese controls. METHODS: Thirty three individuals with ASD and 33 controls participated. The ASD and control groups' demographic variables were matched for gender (male/female: 20/13 vs 20/13), age (26.1 +/- 11.5 vs 26.8 +/- 9.6), years of education (13.2 +/- 2.9 vs 14.2 +/- 1.9), full-scale intelligence quotient (IQ) (103.0 +/- 16.7 vs 103.7 +/- 14.7), performance IQ (96.2 +/- 16.1 vs 97.8 +/- 15.0), and verbal IQ (107.9 +/- 16.3 vs 107.7 +/- 14.4). Participants performed the Wisconsin Card Sorting Test (WCST), which assesses the executive processes involved in problem solving and cognitive flexibility, and the Continuous Performance Test (CPT), which assesses attention and impulsivity. Symptoms were assessed by the Autism-Spectrum Quotient Japanese version (AQ-J). First, we compared the scores of the WCST between the groups using a Mann-Whitney U-test and conducted an analysis of covariance for the variables with the scores of category archives and CPT scores as covariates. Second, we analyzed the correlation between the scores of the WCST and the AQ-J in the ASD group using Pearson's r. RESULTS: The total errors (TE) and the percentages of perseverative errors of the Milner type (%PEM) and Nelson type (%PEN) among the TE in the ASD group were significantly worse compared with the control group (ASD vs Control, respectively: TE: 16.0 +/- 6.2 vs 12.6 +/- 3.5, P = 0.012; %PEM: 11.7 +/- 10.7 vs 6.6 +/- 8.9, P = 0.037; %PEN: 20.1 +/- 14.5 vs 8.7 +/- 10.4, P = 0.0011). In contrast, no significant difference was observed between the two groups in the scores of categories achieved on the WCST or the CPT. An analysis of covariance revealed significant differences between the groups in the %PEN scores (P = 0.0062) but not in the TE or the %PEM scores. These results suggest that Japanese adolescents and adults with ASD have cognitive inflexibility. Furthermore, our results suggest that Japanese adolescents and adults with ASD may have difficulties using negative feedback because perseverative errors of the Nelson type indicate persistence in choosing the incorrect reaction. By contrast, there was no significant correlation between the WCST and AQ-J scores. CONCLUSION: We confirmed the presence of cognitive inflexibility in Japanese adolescents and adults with ASD. Our results also indicated that subjects with ASD may not use negative feedback effectively. PMID- 25019057 TI - Semen lactoferrin promotes CCL20 production by epithelial cells: Involvement in HIV transmission. AB - AIM: To study the effect of seminal plasma on Chemokine (C-C motif) ligand 20 (CCL20) production by epithelial cells and its relationship with lactoferrin. METHODS: HEC-1A cells, a cell line derived from a monostratified endocervical epithelium, were incubated with samples of seminal plasma (diluted 1:10 in culture medium) recovered from human immunodeficiency virus (HIV) seronegative (HIV-) or HIV seropositive (HIV+) subjects. Recombinant human interleukin 1 beta (IL-1beta) was used as positive control, and culture medium only as negative control. The measurement of CCL20 production in the supernatants of HEC-1A cells and of lactoferrin in seminal plasma was determined by enzyme-linked immunosorbent assay techniques. A fractionation of seminal plasma proteins was performed by ion exchange chromatography on a pool of seminal plasma specimens from HIV- subjects. Each fraction was tested for its ability to stimulate the production of CCL20 by HEC-1A cells and for its lactoferrin concentration. The HIV viral load in seminal plasma samples from HIV+ patients was measured using the HIV-Monitor kit (Roche Diagnostic Systems, Branchburg, NJ, United States). RESULTS: The positive control IL-1beta was responsible for an increase of 11.36 +/- 3.36 times in the production of CCL20. Stimulation of HEC-1A cells was performed in 34 seminal plasma samples (22 from HIV+ subjects and 12 from HIV- subjects). The mean production of CCL20 by HEC-1A in presence of seminal plasma from HIV- and HIV+ subjects was respectively 5.38 +/- 0.91 and 7.57 +/- 3.26 times higher than that obtained with the untreated cells (P < 0.05 between the two groups). Using the same 34 specimens of seminal plasma, no correlation was observed between the concentration of total proteins in seminal plasma and their ability to stimulate the secretion of CCL20 by HEC-1 cells. In contrast, the ability to produce CCL20 by HEC-1A cells correlated to the concentration of lactoferrin in the seminal plasma samples (r coefficient = 0.56; CI: 0.26-0.76; P < 0.001). After fractionation by ion exchange chromatography, the seminal plasma fractions exhibiting the highest concentrations of lactoferrin were responsible for the greatest stimulation of CCL20 production by HEC-1A cells (r coefficient = 0.89; CI: 0.78-0.95; P < 0.0001). CONCLUSION: Lactoferrin present in seminal plasma correlated with an increased production of CCL20 by HEC-1A cells and therefore could facilitate HIV entry through the genital mucosa. PMID- 25019058 TI - Treatment paradigms for patients with metastatic non-small cell lung cancer, squamous lung cancer: first, second, and third-line. AB - Historically, the treatment algorithm applied to non-small cell lung cancer (NSCLC) was the same for all histologic subtypes. However, recent advances in our understanding of the molecular profiles of squamous and non-squamous NSCLC have changed this perspective. Histologic subtype and the presence of specific molecular abnormalities have predictive value for response to and toxicity from therapy, as well as overall survival. For patients with squamous NSCLC, a platinum agent plus gemcitabine, or paclitaxel is recommended as first-line therapy. The role of epidermal growth factor receptor monoclonal antibodies is uncertain. Maintenance therapy is not widely recommended, although data exist for the use of erlotinib. The standard recommendation for second-line therapy is docetaxel and erlotinib should be considered as second or third-line therapy. There is ongoing research identifying molecular targets in squamous NSCLC and many agents are in early phase clinical trials. Immunotherapeutic approaches targeting programed death-1 receptor and its ligand (PD-L1) appear promising. PMID- 25019059 TI - Putative role of adipose tissue in growth and metabolism of colon cancer cells. AB - Newly emerging data highlight obesity as an important risk factor for developing certain types of cancer, including colorectal cancer. Although evidence supports a link between the two, the mechanisms responsible for this relationship have not yet been fully elucidated. Hypertrophied and dysfunctional adipose tissue of the obese state is characterized by low-grade inflammation. Adipokines and cytokines secreted from adipocytes, together with the abundant availability of lipids from adipocytes in the tumor microenvironment, promote adhesion, migration, and invasion of tumor cells and support tumor progression and uncontrolled growth. One of the predisposed targets of the deleterious effects exerted by secretions from adipose tissue in obesity is the activities associated with the cellular mitochondria. Mitochondrial oxidative metabolism plays a key role in meeting cells' energetic demands by oxidative phosphorylation (OxPhos). Here we discuss: (a) the dynamic relationship between glycolysis, the tricarboxylic acid cycle, and OxPhos; (b) the evidence for impaired OxPhos (i.e., mitochondrial dysfunction) in colon cancer; (c) the mechanisms by which mitochondrial dysfunction can predispose to cancer. We propose that impaired OxPhos increases susceptibility to colon cancer since OxPhos is sensitive to a large number of factors that are intrinsic to the host (e.g., inflammation). Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes should reveal new therapeutic possibilities. PMID- 25019060 TI - External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma. AB - PURPOSE: Pheochromocytomas (PCCs) are neuroendocrine tumors arising from the adrenal medulla or as paraganglioma (PGL) from extra-adrenal sites. While usually benign, a small fraction is malignant. Multi-modality therapy is used in treating malignant disease; however, little data exist on the role of external beam radiation therapy (EBRT). In this retrospective review, we assessed response to EBRT in malignant PCCs or PGLs. METHODS AND MATERIALS: Records of patients treated at the National Institutes of Health who received EBRT between 1990 and 2012 were studied. Patients were assessed for symptomatic control, biochemical response, local and distant control by response evaluation criteria in solid tumors v1.1 or stable disease on imaging reports, toxicity by radiation therapy oncology group (RTOG) criteria, and survival. RESULTS: There were 24 patients treated who received EBRT to lesions of the abdomen (n = 3), central nervous system (n = 4), and bone (n = 40). Lesions were treated with 3D conformal EBRT to a mean dose of 31.8 Gy in 3.3 Gy fractions, or fractionated stereotactic radiosurgery to 21.9 Gy in 13.6 Gy fractions. Patients experienced acute (n = 15) and late (n = 2) RTOG toxicities; no patient experienced acute toxicity >=4 or late toxicity >=2. Symptomatic control was achieved in 81.1% of lesions. Stable radiographic response was achieved in 86.7% of lesions with progression in 13%. Distant progression was observed overall in 75% of patients and average survival was 52.4 months. CONCLUSION: Malignant PCC and PGL often do not respond well to current systemic therapies. In these cases, EBRT can be considered in patients with symptomatic, localized disease progression. PMID- 25019062 TI - Aberrant Proliferation of Differentiating Alveolar Cells Induces Hyperplasia in Resting Mammary Glands of SV40-TAg Transgenic Mice. AB - WAP-T1 transgenic mice express SV40-TAg under control of the whey acidic protein (WAP) promoter, which directs activity of this strong viral oncogene to luminal cells of the mammary gland. Resting uniparous WAP-T1 glands develop hyperplasia composed of TAg positive cells prior to appearance of advanced tumor stages. We show that cells in hyperplasia display markers of alveolar differentiation, suggesting that TAg targets differentiating cells of the alveolar compartment. The glands show significant expression of Elf5 and milk genes (Lalba, Csn2, and Wap). TAg expressing cells largely co-stain with antibodies to Elf5, lack the epithelial marker Sca1, and are hormone receptor negative. High expression levels of Elf5 but not of milk genes are also seen in resting glands of normal BALB/c mice. This indicates that expression of Elf5 in resting WAP-T1 glands is not specifically induced by TAg. CK6a positive luminal cells lack TAg. These cells co express the markers prominin-1, CK6a, and Sca1, and are positive for hormone receptors. These hormone sensitive cells localize to ducts and seem not to be targeted by TAg. Despite reaching an advanced stage in alveolar differentiation, the cells in hyperplasia do not exit the cell cycle. Thus, expression of TAg in conjunction with regular morphogenetic processes of alveologenesis seem to provide the basis for a hormone independent, unscheduled proliferation of differentiating cells in resting glands of WAP-T1 transgenic mice, leading to the formation of hyperplastic lesions. PMID- 25019061 TI - Activated ras signaling pathways and reovirus oncolysis: an update on the mechanism of preferential reovirus replication in cancer cells. AB - The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrated the preferential replication of reovirus in transformed cell lines but not in normal cells. Later investigations have revealed the involvement of activated Ras signaling pathways (both upstream and downstream) and key steps of the reovirus infectious cycle in promoting preferential replication in cancer cells with reovirus-induced cancer cell death occurring through necrotic, apoptotic, and autophagic pathways. There is increasing evidence that reovirus-induced antitumor immunity involving both innate and adaptive responses also contributes to therapeutic efficacy though this discussion is beyond the scope of this article. Here, we review our current understanding of the mechanism of oncolysis contributing to the broad anticancer activity of reovirus. Further understanding of reovirus oncolysis is critical in enhancing the clinical development and efficacy of reovirus. PMID- 25019063 TI - Nestin(+) tissue-resident multipotent stem cells contribute to tumor progression by differentiating into pericytes and smooth muscle cells resulting in blood vessel remodeling. AB - Tumor vessels with resistance to anti-angiogenic therapy are characterized by the normalization of the vascular structures through integration of mature pericytes and smooth muscle cells (SMC) into the vessel wall, a process termed vessel stabilization. Unfortunately, stabilization-associated vascular remodeling can result in reduced sensitivity to subsequent anti-angiogenic therapy. We show here that blockade of VEGF by bevacizumab induces stabilization of angiogenic tumor blood vessels in human tumor specimen by recruiting Nestin-positive cells, whereas mature vessels down-regulated Nestin-expression. Using xenograft tumors growing on bone-marrow (BM) chimera of C57Bl/6 wildtype and Nestin-GFP transgenic mice, we show for first time that Nestin(+) cells inducing the maturation of tumor vessels do not originate from the BM but presumably reside within the adventitia of adult blood vessels. Complementary ex vivo experiments using explants of murine aortas revealed that Nestin(+) multipotent stem cells (MPSCs) are mobilized from their niche and differentiated into pericytes and SMC through the influence of tumor-cell-secreted factors. We conclude that tissue-resident Nestin(+) cells are more relevant than BM-derived cells for vessel stabilization and therefore have to be considered in future strategies for anti-angiogenic therapy. The identification of proteins mediating recruitment or differentiation of local Nestin(+) cells with potential stem cell character to angiogenic blood vessels may allow the definition of new therapeutic targets to reduce tumor resistance against anti-angiogenic drugs. PMID- 25019064 TI - Acquiring and maintaining a normal oral microbiome: current perspective. AB - The oral microbiota survives daily physical and chemical perturbations from the intake of food and personal hygiene measures, resulting in a long-term stable microbiome. Biological properties that confer stability in the microbiome are important for the prevention of dysbiosis-a microbial shift toward a disease, e.g., periodontitis or caries. Although processes that underlie oral diseases have been studied extensively, processes involved in maintaining of a normal, healthy microbiome are poorly understood. In this review we present our hypothesis on how a healthy oral microbiome is acquired and maintained. We introduce our view on the prenatal development of tolerance for the normal oral microbiome: we propose that development of fetal tolerance toward the microbiome of the mother during pregnancy is the major factor for a successful acquisition of a normal microbiome. We describe the processes that influence the establishment of such microbiome, followed by our perspective on the process of sustaining a healthy oral microbiome. We divide microbiome-maintenance factors into host-derived and microbe-derived, while focusing on the host. Finally, we highlight the need and directions for future research. PMID- 25019066 TI - Emerging technologies to promote and evaluate physical activity: cutting-edge research and future directions. PMID- 25019065 TI - Treatments for biomedical abnormalities associated with autism spectrum disorder. AB - Recent studies point to the effectiveness of novel treatments that address physiological abnormalities associated with autism spectrum disorder (ASD). This is significant because safe and effective treatments for ASD remain limited. These physiological abnormalities as well as studies addressing treatments of these abnormalities are reviewed in this article. Treatments commonly used to treat mitochondrial disease have been found to improve both core and associated ASD symptoms. Double-blind, placebo-controlled (DBPC) studies have investigated l carnitine and a multivitamin containing B vitamins, antioxidants, vitamin E, and co-enzyme Q10 while non-blinded studies have investigated ubiquinol. Controlled and uncontrolled studies using folinic acid, a reduced form of folate, have reported marked improvements in core and associated ASD symptoms in some children with ASD and folate related pathway abnormities. Treatments that could address redox metabolism abnormalities include methylcobalamin with and without folinic acid in open-label studies and vitamin C and N-acetyl-l-cysteine in DBPC studies. These studies have reported improved core and associated ASD symptoms with these treatments. Lastly, both open-label and DBPC studies have reported improvements in core and associated ASD symptoms with tetrahydrobiopterin. Overall, these treatments were generally well-tolerated without significant adverse effects for most children, although we review the reported adverse effects in detail. This review provides evidence for potentially safe and effective treatments for core and associated symptoms of ASD that target underlying known physiological abnormalities associated with ASD. Further research is needed to define subgroups of children with ASD in which these treatments may be most effective as well as confirm their efficacy in DBPC, large-scale multicenter studies. PMID- 25019067 TI - Aptamer based electrochemical sensors for emerging environmental pollutants. AB - Environmental contaminants monitoring is one of the key issues in understanding and managing hazards to human health and ecosystems. In this context, aptamer based electrochemical sensors have achieved intense significance because of their capability to resolve a potentially large number of problems and challenges in environmental contamination. An aptasensor is a compact analytical device incorporating an aptamer (oligonulceotide) as the sensing element either integrated within or intimately associated with a physiochemical transducer surface. Nucleic acid is well known for the function of carrying and passing genetic information, however, it has found a key role in analytical monitoring during recent years. Aptamer based sensors represent a novelty in environmental analytical science and there are great expectations for their promising performance as alternative to conventional analytical tools. This review paper focuses on the recent advances in the development of aptamer based electrochemical sensors for environmental applications with special emphasis on emerging pollutants. PMID- 25019068 TI - Gbeta1gamma2 activates phospholipase A2-dependent Golgi membrane tubule formation. AB - Heterotrimeric G proteins transduce the ligand binding of transmembrane G protein coupled receptors into a variety of intracellular signaling pathways. Recently, heterotrimeric Gbetagamma subunit signaling at the Golgi complex has been shown to regulate the formation of vesicular transport carriers that deliver cargo from the Golgi to the plasma membrane. In addition to vesicles, membrane tubules have also been shown to mediate export from the Golgi complex, which requires the activity of cytoplasmic phospholipase A2 (PLA2) enzyme activity. Through the use of an in vitro reconstitution assay with isolated Golgi complexes, we provide evidence that Gbeta1gamma2 signaling also stimulates Golgi membrane tubule formation. In addition, we show that an inhibitor of Gbetagamma activation of PLA2 enzymes inhibits in vitro Golgi membrane tubule formation. Additionally, purified Gbetagamma protein stimulates membrane tubules in the presence of low (sub-threshold) cytosol concentrations. Importantly, this Gbetagamma stimulation of Golgi membrane tubule formation was inhibited by treatment with the PLA2 antagonist ONO-RS-082. These studies indicate that Gbeta1gamma2 signaling activates PLA2 enzymes required for Golgi membrane tubule formation, thus establishing a new layer of regulation for this process. PMID- 25019069 TI - NCOA5, a molecular link between type 2 diabetes and liver cancer. AB - It is reported that nuclear receptor co-activator 5 (NCOA5) is a possible susceptibility gene to both type 2 diabetes (T2D) and hepatocellular carcinoma (HCC). The link between these two diseases is an important area of study with the growing prevalence of T2D. Thus, discovery of a genetic link may have great impact on the field. The group used NCOA5 (+/-) mice to observe the effects of the gene's haploinsufficiency on the symptoms of T2D and HCC and claimed NCOA5's regulation of IL-6 in the pathogenesis of the diseases. PMID- 25019070 TI - Shall we take a second thought before applying radiofrequency ablation for resectable HCC <=2 cm? AB - Hepatocellular carcinoma (HCC), a disease with poor survival rates unless recognized and treated early, ranks as the fifth most common cancer worldwide. Previous researches has led some authors to choose radiofrequency ablation (RFA) as the primary treatment even the tumor is resectable. Dr. Roayaie's study retrospectively analyzed the surgical outcome of HCC <=2 cm. The results obtained in the studies indicate that anatomic resection may achieve better survival for patients with well-preserved liver function, and without liver cirrhosis. This research also revealed the presence of satellite lesions and microvascular invasion were evident in such early tumors, as the benefit of anatomic resection is unique and cannot be duplicated by ablation. Further RCTs with large sample sizes and long-term follow-up are still required to clarify which should be the best treatment of choice. PMID- 25019071 TI - OPN sesame. AB - Osteopontin (OPN) is a growth regulatory protein for hepatocellular carcinoma (HCC) and a potent chemoattractant for macrophages. Zhu and colleagues recently reported significant clinical associations between poor postoperative prognosis and the concurrent detection of tumoral OPN expression and peritumoral macrophage (PTM) infiltration. An in-depth understanding on the complex interaction between tumoral OPN and macrophage-infiltrated microenvironment opens new doors to novel anticancer treatments. PMID- 25019072 TI - Hidden secret in hepatitis B viral X protein mutation and hypoxia-inducible factor-1alpha in hepatocarcinoma cancer. AB - Hepatitis B type virus (HBV) is an old hepato oncogenic and hepatitis agent. Hepatitis B viral X protein (HBx)-induced malignant transformation requires the excess amounts of ATP level, inducing the extremely oxygen-deprived condition in the cancer tissues and vessels. To adapt, cells go to shift the hypoxic responsive state by altered hypoxia-responsive molecules such as HIF-1. In addition, tumors avoid or suppress immune recognition in the energy-deprived condition. The hypoxia-inducible factor-1alpha (HIF-1alpha) regulates MAP1, histone deacetylase and MAPK pathway. In the hypoxia, the HIF-1alpha interacts with HIF-1beta, allowing DNA binding at the hypoxia response elements (HREs), while HBx binds with the nHLH/PAS domain of HIF-1alpha, preventing pVHL and HIF 1alpha binding capacity and degradation of HIF-1alpha protein. Recent work of Liu et al. [2013] demonstrated that HBx in hepatocellular carcinoma (HCC) tissues contained mutations, affecting the HBx transactivation capacity and C-terminal HBx mutation. In the HCC tissues, the HBx C-terminal mutation and HIF-1alpha expression were related and the different C-terminal mutations of HBx exhibit the different functionality of HIF-1alpha. The C-terminal region of amino acids 119 140 was important for the stability and transactivation, and the point mutations K130M/V131I enhance the functionality of HIF-1alpha, while C-terminal truncation diminish the HIF-1alpha function. PMID- 25019073 TI - Prolonged administration of secretin to normal rats increases biliary proliferation and secretin-induced ductal secretory activity. AB - BACKGROUND AND AIM: Cholangiocyte proliferation is coordinately regulated by a number of gastrointestinal hormones/peptides, some of which display stimulatory effects and some have inhibitory actions on cholangiocyte proliferation. Enhanced biliary proliferation [for example after bile duct ligation (BDL) and partial hepatectomy] is associated with increased expression of secretin receptor (SR), cystic fibrosis transmembrane conductance regulator (CFTR) and Cl(-)/HCO3 (-) anion exchanger 2 and secretin-stimulated ductal secretion, whereas loss/damage of bile ducts [for example after acute carbon tetrachloride (CCl4) administration] is associated with reduced secretin-stimulated ductal secretory activity. There is growing information regarding the role of gastrointestinal hormones the regulation of biliary growth. For example, while gastrin, somatostatin and serotonin inhibit bile duct hyperplasia of cholestatic rats by downregulation of cAMP signaling, secretin has been shown to stimulate the proliferation of normal mice by activation of cyclic adenosine 3',5' monophosphate (cAMP)-dependent signaling. However, no information exists regarding the stimulatory effects of secretin on biliary proliferation of normal rats. Thus, we evaluated the in vivo and in vitro effect of secretin on biliary proliferation, the expression of markers key of ductal secretion and secretin stimulated ductal secretion. METHODS: Normal male rats were treated with saline or secretin (2.5 nmoles/kg BW/day by osmotic minipumps for one week). We evaluated: (I) intrahepatic bile duct mass (IBDM) in liver sections and PCNA expression in purified cholangiocytes; (II) SR and CFTR mRNA expression and secretin-stimulated cAMP levels in purified cholangiocytes; and (III) secretin stimulated bile and bicarbonate secretion in bile fistula rats. In vitro, normal rat intrahepatic cholangiocyte lines (NRIC) were treated with BSA (basal) or secretin (100 nM) for 24 to 72 hours in the absence/presence of a PKA or a MEK inhibitor before evaluating proliferation by MTS assays. RESULTS: Prolonged administration of secretin to normal rats increased IBDM and PCNA expression in purified cholangiocytes compared to saline-treated normal rats. Also, secretin increased the expression of proteins (SR and CFTR) that are key in the regulating ductal secretion and enhanced secretin-stimulated cAMP levels and bile and bicarbonate secretion. In vitro, secretin increased the proliferation of NRIC, increase that was prevented by PKA and MAPK inhibitors. CONCLUSIONS: We have demonstrated that secretin stimulates both in vivo and in vitro biliary proliferation and secretin-stimulated ductal secretory activity in normal rats. We suggest that the stimulatory effect of secretin on biliary proliferation and secretion may be important for preventing biliary dysfunction during ductopenic disorders. PMID- 25019075 TI - Perioperative nutritional support and fluid therapy in patients with liver diseases. AB - The prevalence of liver dysfunction and malnutrition is common among patients with obstructive jaundice or cirrhosis, the poor nutrition status in patients with indications for hepatic resection increases the risk of postoperative complications and/or mortality. Hepatic surgery significantly affects body's metabolism and environment. Therefore, it is very important for patients with liver diseases undergoing hepatic surgery to receive essential nutritional support and fluid therapy during perioperative period. There are several principles in nutritional support and fluid therapy that surgeons need to pay attention to, for example, time, nutritional approach, fluid volume, choice of fat emulsions and amino acids. Some issues, such as albumin and plasma application, choice of crystalloid and colloid, liver protective therapy, also need further attention. PMID- 25019074 TI - The multifaceted nature of retinoid transport and metabolism. AB - Since their discovery over a century ago, retinoids have been the most studied of the fat-soluble vitamins. Unlike most vitamins, retinoids are stored at relatively high concentrations in the body to buffer against nutritional insufficiency. Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water soluble beta-glucuronides of retinol and retinoic acid, and provitamin A carotenoids. This review will focus on explaining this evolving understanding of retinoid metabolism and transport within the body. PMID- 25019076 TI - Liver resection using total vascular exclusion of the liver preserving the caval flow, in situ hypothermic portal perfusion and temporary porta-caval shunt: a new technique for central tumors. AB - Standard total vascular exclusion (TVE) of the liver is indicated for resection of tumors involving or adjacent to the vena cava and/or the confluence of the hepatic veins. The duration of liver ischemia can be prolonged by combined portal hypothermic perfusion of the liver (in or ex situ). The use of a venovenous bypass (VVB) during standard TVE maintains stable hemodynamics as well as optimal renal and splanchnic venous drainage. When the hepatic veins can be controlled, TVE preserving the caval flow negates the need for VVB. However this technique remains limited in duration as it is performed under warm ischemia (so-called normothermia) of the liver. To prolong the ischemia time, we have designed a modification of TVE with preservation of the caval flow including the use of temporary porta-caval shunt (PCS) and hypothermic perfusion of the liver. We describe here the first two cases of this new technique. Two patients underwent left hepatectomy extended to segments 5 and 8 (also called extended left hepatectomy) for large centrally located tumors. TVE lasted seventy-two and seventy-nine minutes, respectively. The postoperative course was uneventful and both patients were discharged on day ten and day twenty-five respectively. Both are alive without recurrence at ten and seven months following surgery. Provided the roots of the hepatic veins can be controlled, this technique combines the advantages of standard TVE with in situ hypothermic perfusion and VVB and obviates the need and the subsequent risks of the latter. PMID- 25019077 TI - Double carcinomas simultaneously identified in biliary system. PMID- 25019079 TI - Professor Carlos Eduardo R. Santos: my experiences with liver metastases of sarcoma. PMID- 25019078 TI - Liver hilar abscesses secondary to gastrointestinal perforation by ingested fish bones: surgical management of two cases. AB - Several hepatobiliary complications secondary to gastrointestinal perforation after ingestion of a fish bone have been described in the literature, the most common being liver abscess, which can be potentially fatal. Treatment involves removal of the foreign body if possible (endoscopically or surgically), drainage of the abscess (radiologically or surgically), and appropriate antibiotic therapy. To our knowledge, no cases of hepatic hilar abscesses secondary to gastrointestinal perforation by a fish bone have been described in the literature. We report surgical management of two cases of abscess localized in the hepatic hilum secondary to the ingestion of fish bones. PMID- 25019081 TI - High expression of polo-like kinase 1 is associated with early development of hepatocellular carcinoma. AB - Polo-like kinase 1 (PLK1), one of serine/threonine-protein kinase, has been demonstrated to play pivotal roles in malignant transformation. Here we illustrated the clinicopathological significance of PLK1 expression in hepatocellular carcinoma (HCC) in more detail. Immunohistochemistry was performed to detect the expression of PLK1 in 67 HCC patients as well as corresponding noncancerous liver tissues. In addition, the correlation of PLK1 expression with clinicopathological factors or prognosis of HCC was analyzed. Results showed that the expression of PLK1 was increased significantly in HCC tissues than that of corresponding normal liver tissues. The correlation between PLK1 and HCC cell differentiation or capsule invasion was also revealed. We found that PLK1 inhibition promoted cell arrest in G2/M phase of cell cycle and cell apoptosis. Our results also indicated that the potential mechanisms of PLK1 inhibition regulating cell growth involved enhancing expression of caspase3, caspase8, and Bax and decreasing expression of Bcl-2. Furthermore, we also found that PLK1 downregulation inducing inhibition of cell growth was associated with enhancing expression of p53. Thus, we presume that the status of PLK1 expression might be an independent prognostic factor for HCC and targeting PLK1 might be a useful strategy for diagnosis and treatment of human HCC. PMID- 25019082 TI - Novelties in the anatomy of the central nervous system and related disorders. PMID- 25019083 TI - Phylogenetic analysis of H7N9 avian influenza virus based on a novel mathematical descriptor. AB - A new mathematical descriptor was proposed based on 3D graphical representation. Using the method, we construct the phylogenetic trees of nine proteins of H7N9 influenza virus to analyze the originated source of H7N9. The results show that the evolution route of H7N9 avian influenza is from America through Europe to Asia. Furthermore, two samples collected from environment in Nanjing and Zhejiang and one sample collected from chicken are the sources of H7N9 influenza virus that infected human in China. PMID- 25019085 TI - Chondrogenic differentiation of human adipose-derived stem cells: a new path in articular cartilage defect management? AB - According to data published by the Centers for Disease Control and Prevention, over 6 million people undergo a variety of medical procedures for the repair of articular cartilage defects in the U.S. each year. Trauma, tumor, and age-related degeneration can cause major defects in articular cartilage, which has a poor intrinsic capacity for healing. Therefore, there is substantial interest in the development of novel cartilage tissue engineering strategies to restore articular cartilage defects to a normal or prediseased state. Special attention has been paid to the expansion of chondrocytes, which produce and maintain the cartilaginous matrix in healthy cartilage. This review summarizes the current efforts to generate chondrocytes from adipose-derived stem cells (ASCs) and provides an outlook on promising future strategies. PMID- 25019084 TI - Docosahexaenoic acid supplementation early in pregnancy may prevent deep placentation disorders. AB - Uteroplacental ischemia may cause preterm birth, either due to preterm labor, preterm premature rupture of membranes, or medical indication (in the presence of preeclampsia or fetal growth restriction). Uteroplacental ischemia is the product of defective deep placentation, a failure of invasion, and transformation of the spiral arteries by the trophoblast. The failure of normal placentation generates a series of clinical abnormalities nowadays called "deep placentation disorders"; they include preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, in utero fetal death, and placental abruption. Early reports suggested that a LC-PUFAs (long chain polyunsaturated fatty acids) rich diet reduces the incidence of deep placentation disorders. Recent randomized controlled trials are inconsistent to show the benefit of docosahexaenoic acid (DHA) supplementation during pregnancy to prevent deep placentation disorders, but most of them showed that DHA supplementation was associated with lower risk of early preterm birth. We postulate that DHA supplementation, early in pregnancy, may reduce the incidence of deep placentation disorders. If our hypothesis is correct, DHA supplementation, early in pregnancy, will become a safe and effective strategy for primary prevention of highly relevant pregnancy diseases, such as preterm birth, preeclampsia, and fetal growth restriction. PMID- 25019086 TI - Ibuprofen protects ventilator-induced lung injury by downregulating Rho-kinase activity in rats. AB - BACKGROUND: Ventilator-induced lung injury-(VILI-) induced endothelial permeability is regulated through the Rho-dependent signaling pathway. Ibuprofen inhibits Rho activation in animal models of spinal-cord injury and Alzheimer's disease. The study aims to investigate ibuprofen effects on high tidal volume associated VILI. METHODS: Twenty-eight adult male Sprague-Dawley rats were randomized to receive a ventilation strategy with three different interventions for 2 h: (1) a high-volume zero-positive end-expiratory pressure (PEEP) (HVZP) group; (2) an HVZP + ibuprofen 15 mg/kg group; and (3) an HVZP + ibuprofen 30 mg/kg group. A fourth group without ventilation served as the control group. Rho kinase activity was determined by ratio of phosphorylated ezrin, radixin, and moesin (p-ERM), substrates of Rho-kinase, to total ERM. VILI was characterized by increased pulmonary protein leak, wet-to-dry weight ratio, cytokines level, and Rho guanine nucleotide exchange factor (GEF-H1), RhoA activity, p-ERM/total ERM, and p-myosin light chain (MLC) protein expression. RESULTS: Ibuprofen pretreatment significantly reduced the HVZP ventilation-induced increase in pulmonary protein leak, wet-to-dry weight ratio, bronchoalveolar lavage fluid interleukin-6 and RANTES levels, and lung GEF-H1, RhoA activity, p-ERM/total ERM, and p-MLC protein expression. CONCLUSION: Ibuprofen attenuated high tidal volume induced pulmonary endothelial hyperpermeability. This protective effect was associated with a reduced Rho-kinase activity. PMID- 25019087 TI - Immobilized lentivirus vector on chondroitin sulfate-hyaluronate acid-silk fibroin hybrid scaffold for tissue-engineered ligament-bone junction. AB - The lack of a fibrocartilage layer between graft and bone remains the leading cause of graft failure after anterior cruciate ligament (ACL) reconstruction. The objective of this study was to develop a gene-modified silk cable-reinforced chondroitin sulfate-hyaluronate acid-silk fibroin (CHS) hybrid scaffold for reconstructing the fibrocartilage layer. The scaffold was fabricated by lyophilizing the CHS mixture with braided silk cables. The scanning electronic microscopy (SEM) showed that microporous CHS sponges were formed around silk cables. Each end of scaffold was modified with lentiviral-mediated transforming growth factor- beta 3 (TGF- beta 3) gene. The cells on scaffold were transfected by bonded lentivirus. In vitro culture demonstrated that mesenchymal stem cells (MSCs) on scaffolds proliferated vigorously and produced abundant collagen. The transcription levels of cartilage-specific genes also increased with culture time. After 2 weeks, the MSCs were distributed uniformly throughout scaffold. Deposited collagen was also found to increase. The chondral differentiation of MSCs was verified by expressions of collagen II and TGF- beta 3 genes in mRNA and protein level. Histology also confirmed the production of cartilage extracellular matrix (ECM) components. The results demonstrated that gene-modified silk cable reinforced CHS scaffold was capable of supporting cell proliferation and differentiation to reconstruct the cartilage layer of interface. PMID- 25019088 TI - Preliminary characterization of mitochondrial genome of Melipona scutellaris, a Brazilian stingless bee. AB - Bees are manufacturers of relevant economical products and have a pollinator role fundamental to ecosystems. Traditionally, studies focused on the genus Melipona have been mostly based on behavioral, and social organization and ecological aspects. Only recently the evolutionary history of this genus has been assessed using molecular markers, including mitochondrial genes. Even though these studies have shed light on the evolutionary history of the Melipona genus, a more accurate picture may emerge when full nuclear and mitochondrial genomes of Melipona species become available. Here we present the assembly, annotation, and characterization of a draft mitochondrial genome of the Brazilian stingless bee Melipona scutellaris using Melipona bicolor as a reference organism. Using Illumina MiSeq data, we achieved the annotation of all protein coding genes, as well as the genes for the two ribosomal subunits (16S and 12S) and transfer RNA genes as well. Using the COI sequence as a DNA barcode, we found that M. cramptoni is the closest species to M. scutellaris. PMID- 25019089 TI - Development of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking. AB - Alzheimer's (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression. beta-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BACE-1 and AChE. The GQSAR model provides site-specific clues about the molecules where certain modifications can result in increased biological activity. This information could be of high value for design and development of multifunctional drugs for combating AD. PMID- 25019090 TI - Ethanol at low concentration attenuates diabetes induced lung injury in rats model. AB - To observe the changes of lung injury when diabetic rats were treated with low concentration of ethanol (EtOH) and analyze the related mechanisms, male Sprague Dawley (SD) rats were divided into control, diabetic (DM), and EtOH+DM groups. Diabetic rat was mimicked by injection of streptozotocin intraperitoneally. Fasting blood glucose (FBG) level, lung weight (LW), body weight (BW), and LW/BW were measured. The changes of lung tissue and Type II alveolar cell were detected. Pulmonary malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured; meanwhile, ALDH2 mRNA and protein expressions were detected by RT-PCR and western blotting, respectively. Compared with control group, in DM group, SOD activity was decreased; FBG level, LW/BW, MDA content, ALDH2 mRNA, and protein expressions were decreased. Compared with DM group, in EtOH+DM group, SOD activity, ALDH2 mRNA, and protein expressions were increased; LW/BW and MDA content were decreased. The structures of lung tissue and lamellar bodies were collapsed in DM group; the injury was attenuated in EtOH+DM group. Our findings suggested that, in diabetic rat, pulmonary ALDH2 expression was decreased accompanying lung injury. EtOH at low concentration decreased diabetes induced lung injury through activating ALDH2 expression. PMID- 25019092 TI - Ventral prostate fibrosis in the Akita mouse is associated with macrophage and fibrocyte infiltration. AB - A higher incidence of lower urinary tract symptoms (LUTS) among diabetic men is unexplained. Recently, prostate inflammation and fibrosis have been implicated as major contributing factors to bladder outlet obstruction and LUTS. We characterized the inflammatory cell infiltrate and collagen content of the anterior, dorsal, and ventral lobes of 18-week-old DBA2J.Ins2-Akita mice (Akita) and age-matched control mice. We performed hematoxylin and eosin staining to score tissue injury and inflammation, picrosirius red staining to quantitate collagen content, and immunostaining to identify monocytes/macrophages and infiltrating fibrocytes. We observed significantly greater numbers of monocytes/macrophages and fibrocytes specifically in the ventral prostate of the Akita mice and found that this was associated with significant greater collagen content specifically in the ventral prostate of the Akita mice. These observations support the inference that diabetes elicits monocyte/macrophage infiltration and collagen accumulation in the prostate and suggest that further study of Akita mice may inform translational studies of diabetes in the genesis prostatic inflammation, prostatic fibrosis, and LUTS. PMID- 25019093 TI - Link Clustering to Explore Brain Dynamics Using Resting State Functional MRI. AB - Quantitative network analysis of brain networks has been an important tool for characterizing brain function. Cognitive abilities emerge from coordinated activity of distributed brain regions that may participate in multiple networks at different times. However, neuroimaging has few available tools to model and quantify networks with spatially overlapping nodes that are active at different times. The dynamics of network reconfiguration may yield important insight into networks that are damaged with neurodegenerative disease. We describe here an approach that uses a graph analytic technique called link clustering, which identifies communities that have overlapping functional nodes, demonstrating its ability to highlight differences in the dynamic reorganization of networks between subjects with Alzheimer's dementia and normal controls. PMID- 25019091 TI - Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. AB - Chronic overnutrition creates chronic hyperglycemia that can gradually induce insulin resistance and insulin secretion impairment. These disorders, if not intervened, will eventually be followed by appearance of frank diabetes. The mechanisms of this chronic pathogenic process are complex but have been suggested to involve production of reactive oxygen species (ROS) and oxidative stress. In this review, I highlight evidence that reductive stress imposed by overflux of NADH through the mitochondrial electron transport chain is the source of oxidative stress, which is based on establishments that more NADH recycling by mitochondrial complex I leads to more electron leakage and thus more ROS production. The elevated levels of both NADH and ROS can inhibit and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH), respectively, resulting in blockage of the glycolytic pathway and accumulation of glycerol 3-phospate and its prior metabolites along the pathway. This accumulation then initiates all those alternative glucose metabolic pathways such as the polyol pathway and the advanced glycation pathways that otherwise are minor and insignificant under euglycemic conditions. Importantly, all these alternative pathways lead to ROS production, thus aggravating cellular oxidative stress. Therefore, reductive stress followed by oxidative stress comprises a major mechanism of hyperglycemia induced metabolic syndrome. PMID- 25019094 TI - A functional system for high-content screening of neuromuscular junctions in vitro. AB - High-content phenotypic screening systems are the logical extension of the current efficient, yet low information content, pre-clinical screens for drug discovery. A physiologically accurate in vitro neuromuscular junction (NMJ) screening system would therefore be of tremendous benefit to the study of peripheral neuropathies as well as for basic and applied neuromuscular research. To date, no fully-defined, selective assay system has been developed which would allow investigators to determine the functional output of cultured muscle fibers (myotubes) when stimulated via the NMJ in real time for both acute and chronic applications. Here we present the development of such a phenotypic screening model, along with evidence of NMJ formation and motoneuron initiated neuromuscular transmission in an automated system. Myotubes assembled on silicon cantilevers allowed for measurement of substrate deflection in response to contraction and provided the basis for monitoring the effect of controlled motoneuron stimulation on the contractile behavior. The effect was blocked by treatment with D-tubocurarine, confirming NMJ functionality in this highly multiplexed assay system. PMID- 25019095 TI - Functional trait trade-offs for the tropical montane rain forest species responding to light from simulating experiments. AB - Differences among tropical tree species in survival and growth to light play a key role in plant competition and community composition. Two canopy species with contrasting functional traits dominating early and late successional stages, respectively, in a tropical montane rain forest of Hainan Island, China, were selected in a pot experiment under 4 levels of light intensity (full, 50%, 30%, and 10%) in order to explore the adaptive strategies of tropical trees to light conditions. Under each light intensity level, the pioneer species, Endospermum chinense (Euphorbiaceae), had higher relative growth rate (RGR), stem mass ratio (SMR), specific leaf area (SLA), and morphological plasticity while the shade tolerant climax species, Parakmeria lotungensis (Magnoliaceae), had higher root mass ratio (RMR) and leaf mass ratio (LMR). RGR of both species was positively related to SMR and SLA under each light level but was negatively correlated with RMR under lower light (30% and 10% full light). The climax species increased its survival by a conservative resource use strategy through increasing leaf defense and root biomass investment at the expense of growth rate in low light. In contrast, the pioneer increased its growth by an exploitative resource use strategy through increasing leaf photosynthetic capacity and stem biomass investment at the expense of survival under low light. There was a trade-off between growth and survival for species under different light conditions. Our study suggests that tree species in the tropical rainforest adopt different strategies in stands of different successional stages. Species in the earlier successional stages have functional traits more advantageous to grow faster in the high light conditions, whereas species in the late successional stages have traits more favorable to survive in the low light conditions. PMID- 25019096 TI - Fast transient thermal analysis of non-Fourier heat conduction using Tikhonov well-conditioned asymptotic waveform evaluation. AB - Non-Fourier heat conduction model with dual phase lag wave-diffusion model was analyzed by using well-conditioned asymptotic wave evaluation (WCAWE) and finite element method (FEM). The non-Fourier heat conduction has been investigated where the maximum likelihood (ML) and Tikhonov regularization technique were used successfully to predict the accurate and stable temperature responses without the loss of initial nonlinear/high frequency response. To reduce the increased computational time by Tikhonov WCAWE using ML (TWCAWE-ML), another well conditioned scheme, called mass effect (ME) T-WCAWE, is introduced. TWCAWE with ME (TWCAWE-ME) showed more stable and accurate temperature spectrum in comparison to asymptotic wave evaluation (AWE) and also partial Pade AWE without sacrificing the computational time. However, the TWCAWE-ML remains as the most stable and hence accurate model to analyze the fast transient thermal analysis of non Fourier heat conduction model. PMID- 25019097 TI - Biodegradation of palm kernel cake by cellulolytic and hemicellulolytic bacterial cultures through solid state fermentation. AB - Four cellulolytic and hemicellulolytic bacterial cultures were purchased from the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Culture (DSMZ) and the American Type Culture Collection (ATCC). Two experiments were conducted; the objective of the first experiment was to determine the optimum time period required for solid state fermentation (SSF) of palm kernel cake (PKC), whereas the objective of the second experiment was to investigate the effect of combinations of these cellulolytic and hemicellulolytic bacteria on the nutritive quality of the PKC. In the first experiment, the SSF was lasted for 12 days with inoculum size of 10% (v/w) on different PKC to moisture ratios. In the second experiment, fifteen combinations were created among the four microbes with one untreated PKC as a control. The SSF lasted for 9 days, and the samples were autoclaved, dried, and analyzed for proximate analysis. Results showed that bacterial cultures produced high enzymes activities at the 4th day of SSF, whereas their abilities to produce enzymes tended to be decreased to reach zero at the 8th day of SSF. Findings in the second experiment showed that hemicellulose and cellulose was significantly (P < 0.05) decreased, whereas the amount of reducing sugars were significantly (P < 0.05) increased in the fermented PKC (FPKC) compared with untreated PKC. PMID- 25019098 TI - Microstrip triband bandstop filter with sharp stop band skirts and independently controllable second stop band response. AB - This paper presents a compact planar triband bandstop filter (TBBSF) with compact size and high selectivity. The structure of the filter incorporates two folded trisection stepped-impedance resonators (TSSIRs). One of these resonators is designed to operate at the first and third center frequencies and the other resonator is designed to operate at the second center frequency of the proposed filter. To achieve a compact size filter, alternating impedance lines of the resonators are folded widthwise and also one resonator is embedded within another. Theoretical analysis and design procedures are described, including the synthesis equations for each resonator. The main advantage of the proposed method is that the filter provides flexibility to tune the second center frequency and control the corresponding bandwidth without changing the first and third stop band response. Additionally, several reflection zeros (RZs) are introduced in the pass band to improve its flatness. To demonstrate the feasibility of the proposed design method, both the first and second order TBBSFs were designed, simulated, and fabricated, with center frequencies of 1.92 GHz, 3.55 GHz, and 5.5 GHz. PMID- 25019099 TI - Estimation of hypertension risk from lifestyle factors and health profile: a case study. AB - Hypertension is a highly prevalent risk factor for cardiovascular disease and it can also lead to other diseases which seriously harm the human health. Screening the risks and finding a clinical model for estimating the risk of onset, maintenance, or the prognosis of hypertension are of great importance to the prevention or treatment of the disease, especially if the indicator can be derived from simple health profile. In this study, we investigate a chronic disease questionnaire data set of 6563 rural citizens in East China and find out a clinical signature that can assess the risk of hypertension easily and accurately. The signature achieves an accuracy of about 83% on the external test dataset, with an AUC of 0.91. Our study demonstrates that a combination of simple lifestyle features can sufficiently reflect the risk of hypertension onset. This finding provides potential guidance for disease prevention and control as well as development of home care and home-care technologies. PMID- 25019100 TI - Effect of flow rate of side-type orifice intake on withdrawn water temperature. AB - Side-type orifice intake is a type of selective withdrawal facility used in managing reservoirs to mitigate the negative effects of low-temperature water. Based on the temperature data of a thermal stratified reservoir in China, an experiment was conducted in flume to study the influence of intake flow rate on withdrawn water temperature with different temperature distributions. Results indicated that withdrawn water temperature changed with different flow rates. The temperature change was determined by the water temperature gradients above and below the intake, whereas the change trend of temperature depended on the difference between the water temperature gradient above and below the intake. We likewise proposed a new equation with which the withdrawn water temperature of a thermal stratified reservoir using a side-type orifice could be calculated. These findings could be directly applied to the design and operation of side-type orifice intake in thermal stratified reservoirs. PMID- 25019101 TI - SOA-based model for value-added ITS services delivery. AB - Integration is currently a key factor in intelligent transportation systems (ITS), especially because of the ever increasing service demands originating from the ITS industry and ITS users. The current ITS landscape is made up of multiple technologies that are tightly coupled, and its interoperability is extremely low, which limits ITS services generation. Given this fact, novel information technologies (IT) based on the service-oriented architecture (SOA) paradigm have begun to introduce new ways to address this problem. The SOA paradigm allows the construction of loosely coupled distributed systems that can help to integrate the heterogeneous systems that are part of ITS. In this paper, we focus on developing an SOA-based model for integrating information technologies (IT) into ITS to achieve ITS service delivery. To develop our model, the ITS technologies and services involved were identified, catalogued, and decoupled. In doing so, we applied our SOA-based model to integrate all of the ITS technologies and services, ranging from the lowest-level technical components, such as roadside unit as a service (RSUAAS), to the most abstract ITS services that will be offered to ITS users (value-added services). To validate our model, a functionality case study that included all of the components of our model was designed. PMID- 25019102 TI - Malocclusion and related quality of life among 13- to 19-year-old students in Mysore City - a cross-sectional study. AB - PURPOSE: To assess malocclusion and related quality of life among 13- to 19-year old students in Mysore City. MATERIALS AND METHODS: A total of 900 students aged 13-19 years selected based on multistage stratified random sampling were included in this cross-sectional study. A pre-designed format was used to record the sociodemographic details, oral hygiene practices, personal habits, malocclusion and oral health related quality of life. Malocclusion was assessed using Dental Aesthetic Index (DAI ) and quality of life using Oral Health Impact Profile-14 (OHIP-14). Further, the association between malocclusion and related quality of life was assessed. RESULTS: Normal or slight malocclusion was seen in 79.2% (n = 713). Definite malocclusion was seen in 12.8%, severe malocclusion in 5.7% and handicapping malocclusion in 2.3% of the subjects. The overall prevalence of malocclusion was found to be 20.8%. Out of the 900 study subjects 46.6% (n = 419) reported that malocclusion had some impact on their oral health related quality of life. The results of logistic regression demonstrated that those with malocclusion experienced a significant impact on quality of life (OR = 16.07, CI = 9.17-28.17). CONCLUSION: Malocclusion has an impact on the oral health related quality of life among 13- to 19-year-old students in Mysore City. PMID- 25019103 TI - Patient-related evaluation after systematic periodontal therapy - a clinical study on periodontal health-related quality of life (PHQoL). AB - PURPOSE: To evaluate how periodontitis patients perceive the outcome after long term supportive therapy. MATERIALS AND METHODS: 281 patients (150 women/131 men) with a mean age of 55 years (range: 45-86 years) were randomly selected and consecutively interviewed using a questionnaire designed for laypersons. All patients had shown high compliance with the recommended supportive periodontal therapy (SPT) for up to 16 years (mean observation period: 12.5 years). Statistical evaluation was performed using the 2-sided t-test. RESULTS: A very high degree of confidence in the periodontal treatment (mean: 9.24, range 0-10) was found. Women noticed a higher positive impact on their social environment (P < 0.05). Patients who underwent SPT < 3 years showed a higher positive perception of treatment success than patients with SPT > 3 years (P < 0.01) and reported a greater impact on appearance (P < 0.01). Regenerative treatment demonstrated advantages over resective open flap debridement (OFD) procedures (P < 0.05) and scaling and root planing (SRP) (P < 0.05). However, treatment costs (P < 0.001) and time required (P < 0.01) for regenerative procedures were perceived as a burden. Periodontal treatment by a specialised team led to a significant reduction in the patients' complaints (P < 0.01). The SPT interval did not influence patients' perception of treatment success. CONCLUSIONS: Systematic periodontal therapy with subsequent SPT met the patients' demand to preserve oral health. Regenerative procedures prompt the perception in patients of better remission of periodontitis symptoms. Further trials should investigate clinical results of periodontal therapy regarding patient expectations. PMID- 25019104 TI - Diagnosis and prescribing pattern of antibiotics and painkillers among dentists. AB - PURPOSE: To examine the pattern of antibiotic and painkiller prescriptions per diagnosis by dentists. MATERIALS AND METHODS: A cross-sectional study was conducted in Karachi, Pakistan. Dentists in the outpatient departments of the Dr. Isharat-ul-Ebad Khan Institute of Oral Health Sciences (DIKIOHS) filled out a form for each patient visiting during a two-week period. The form included: personal history of the patient, i.e. name, age, sex and education, patient's complaint(s), medical history, dental history, full examination of the teeth and oral cavity, treatment need as far as different specialties are concerned, investigations, provisional diagnosis and treatment given. The WHO ATC system for drug classification was used. The number of prescriptions and defined daily doses (DDD) were recorded. RESULTS: A total of 709 patient forms (355 for male patients and 354 for female patients) were collected and included in the analysis. Of these, 123 (17%) included antibiotics and 455 (64%) painkillers. Caries/pulpitis was the most common diagnosis (n = 222; 31% of cases), of which 48 (21%) were prescribed antibiotics. Amoxicillin and metronidazole were the most common antibiotics prescribed for this diagnosis (n = 25); for caries/pulpitis diagnosis, 44 DDD/100 patients were prescribed. This was also the diagnosis for which painkiller prescription was most common (n = 191; 86%), with 102 DDD/100 patients. CONCLUSION: Our study shows the prescription pattern of antibiotics and painkillers by dentists in Pakistan for the first time. There is a clear need to emphasise correct diagnostic methods and develop contextualised prescription guidelines and educational initiatives, so that the optimum effect of antibiotics and painkillers will be achieved without compromising patients' health. PMID- 25019105 TI - Dissemination and use of the children's dental pass in Germany. AB - PURPOSE: Children's Dental Passes (CDP) are widely used in Germany for documentation and motivation of oral health in children, but have not been evaluated at all. The purpose of this cross-sectional study was to analyse the distribution, use and acceptance of the CDP in Mecklenburg-Western Pomerania (MWP), Germany. MATERIALS AND METHODS: Data were collected with a self administered mail questionnaire sent to all registered dental offices in MWP. RESULTS: The effective response rate to the survey was 18%, representing 21% of all dentists in the state. Almost all dentists (91%) considered the information contained in the CDP important. Additionally, 81% of dentists provided their patients with a CDP and 78% recorded the oral health status of their patients in it. 54% confirmed that the CDP's implementation has improved the consultation behaviour of young children's parents. 71% of dentists felt that the behaviour of their young patients during treatment has improved after the implementation of the CDP. Likewise, 61% of the respondents thought that oral health among children has improved after the introduction of the CDP. CONCLUSION: The CDP can be considered an important element for health promotion that offers a comprehensive approach to early prevention of oral health diseases of young children in Mecklenburg-Western Pomerania. PMID- 25019106 TI - Oral health status of elderly chinese with dementia in Hong Kong. AB - PURPOSE: To compare toothbrushing habits, unstimulated salivary flow rates and oral health status of elderly Hong Kong Chinese with and without dementia. MATERIALS AND METHODS: A sample size calculation was performed and a sample of 82 elderly Chinese with dementia were invited who were aged 60 or above, fit for periodontal assessment with probing and attended day-care centres. Age- and gender-matched generally healthy people without dementia were recruited as controls. Toothbrushing practices were recorded using a questionnaire. Additionally, unstimulated salivary flow rate was measured. Caries experience and periodontal status were assessed through clinical examination by the DMFT index and Community Periodontal Index (CPI), respectively. RESULTS: Fifty-nine people with dementia and 59 age- and gender-matched generally healthy controls were recruited. Their mean age was 80 (SD = 7). Compared with the individuals in the control group, fewer people with dementia performed toothbrushing twice daily (31% vs 5%; P < 0.001). Furthermore, their unstimulated salivary flow rate was lower than that of the control group (0.30 ml/min vs 0.41 ml/min; P = 0.043). Their caries experience in mean DMFT (+/- SD) was similar to the control group (22.3 +/- 8.2 vs 21.5 +/- 8.2, P = 0.59). There was also no significant difference in the prevalence of periodontal pockets (CPI >= 3) between the two groups (78% vs 74%, P = 0.64). CONCLUSION: Compared to those without dementia, fewer elderly Chinese with dementia practiced toothbrushing twice daily. Although their resting salivary secretion was reduced, their caries experience and prevalence of advanced periodontal disease were not significantly different from those without dementia. PMID- 25019107 TI - Gingivitis, Psychological Factors and Quality of Life in Children. AB - PURPOSE: To evaluate the associations between gingivitis, emotional status and quality of life in children. MATERIALS AND METHODS: Sixty-four Brazilian students (11 to 12 years old) were examined for clinical and self-reported gingivitis. The participants were divided into two groups: those with gingivitis (n = 21) and controls (n = 43). Quality of life, anxiety and depression were measured using self-administered questionnaires. Saliva was collected 30 min after waking and at bedtime to measure the diurnal decline in salivary cortisol. The results were analysed using bivariate and multivariate analyses. RESULTS: There were significantly more female participants in the control group. Approximately 90% of the children with gingivitis had good oral hygiene and 10.5% had satisfactory oral hygiene. There was a significant positive correlation between anxiety and depression in both clinical groups. Anxiety was negatively correlated with quality of life in the control group. Depression was negatively correlated with quality of life and cortisol concentrations in the group with gingivitis, and with quality of life in the control group. Children with gingivitis were more likely to be older and males. CONCLUSIONS: Older children are more likely to experience gingival bleeding. The presence of gingivitis in children may be associated with worse psychological well-being, possibly compromising the quality of life. PMID- 25019108 TI - Demographic profile, plaque index and DMFT scores of young individuals with dental anxiety and exaggerated gag reflex. AB - PURPOSE: To characterise demographic and clinical parameters among individuals with dental anxiety and exaggerated gag reflex compared to a control group and to analyse the associations between the various parameters. MATERIALS AND METHODS: Sixty-eight patients with dental anxiety and 54 patients with exaggerated gag reflex were compared to a control group of 200 individuals undergoing dental treatment. The collected data included demographic parameters, health status, smoking habits, Decayed, Missing and Filled Teeth (DMFT) and plaque index (PI) scores. RESULTS: PI was significantly higher among patients with exaggerated gag reflex (1.91 +/- 0.95) and dental anxiety patients (1.82 +/- 0.89) compared to the control group (1.27 +/- 0.74; P < 0.001). DMFT was significantly higher among patients with dental anxiety (13.64 +/- 7.57) compared to patients with exaggerated gag reflex (10.52 +/- 5.42; P = 0.033), and between both groups compared to the control group (4.09 +/- 4.034; P < 0.001). Multivariate logistic regression analysis revealed that PI, DMFT and age were positively associated with exaggerated gag reflex and that DMFT and educational level were positively associated with dental anxiety compared to the control group. DMFT was the only significant parameter positively associated with dental anxiety compared to exaggerated gag reflex. CONCLUSION: DMFT and PI scores were higher among patients with dental anxiety and exaggerated gag reflex. Clinicians should consider additional oral hygiene measures and education, maintenance meetings and recall visits in those patients, as well as using supplementary aids, such as fluoride mouthwash and fluoride varnish applications, to maintain oral hygiene without triggering the exaggerated gag reflex. PMID- 25019109 TI - Susceptibility of methacrylate-based root canal filling to degradation by bacteria found in endodontic infections. AB - OBJECTIVES: To present a case of endodontic failure obturated with a methacrylate based root filling material, Resilon/RealSeal (RS). To determine if RS is susceptible to biodegradation by endodontically relevant microbes by a method known to show RS degradation. METHOD AND MATERIALS: Emulsions of RS were dispersed in agar with minimal bacterial nutrients in culture plates. Lipase PS served as a positive control. Pseudomonas aeruginosa, Fusobacterium nucleatum, Prevotella intermedia, Porphyromonas gingivalis, Porphyromonas asaccharolytica, Enterococcus faecalis, Streptococcus sanguis, Streptococcus mutans, Staphylococcus aureus, and Staphylococcus epidermidis were tested for their ability to biodegrade RS. The bacteria were inoculated in the plates and examined daily for RS degradation for 7 days. RESULTS: Degradation of the emulsified RS manifested in the formation of clear zones around P aeruginosa, P intermedia, P asaccharolytica, S aureus, and S epidermidis. No degradation was seen with the other tested bacteria or in plates that did not contain RS emulsion. CONCLUSION: Endodontic pathogenic bacteria can degrade RS. These findings complement other work and suggest that the seal and integrity of root canal fillings obturated with RS may be impaired by a microbial insult. PMID- 25019110 TI - Effect of mini-implant-supported mandibular overdentures on electromyographic activity of the masseter muscle during chewing of hard and soft food. AB - OBJECTIVE: To objectively evaluate the effect of mini-implant- supported mandibular overdentures on electromyographic activity (EMG) of the masseter muscle during chewing of hard and soft foods. METHOD AND MATERIALS: Twelve completely edentulous patients (4 females and 8 males) with maladaptive experience of wearing mandibular dentures received new maxillary and mandibular dentures. After 3 months of adaptation, four mini dental implants (MDIs) were inserted in the interforaminal region of the mandible, and the new mandibular dentures were connected to the implants immediately with O/ring attachments. The activity of masseter muscle (EMG) and the duration of chewing cycle were measured during chewing hard (carrot) and soft (gum) foods. The measurements were made 3 months after wearing each of the following prostheses: the new conventional dentures; and the MDI-retained mandibular overdentures. RESULTS: The EMG of masseter muscle increased and the DC decreased with MDI-retained mandibular overdentures when compared to conventional dentures. Hard food (carrot) was associated with increased EMG and decreased DC when compared to soft food (gum) for both conventional dentures and MDI-retained mandibular overdentures. CONCLUSION: Mini-implant-supported mandibular overdentures are associated with increased activity of masseter muscle and decreased duration of chewing cycle for both hard and soft foods when compared to conventional dentures. PMID- 25019111 TI - Therapeutic efficacy of bromelain in impacted third molar surgery: a randomized controlled clinical study. AB - OBJECTIVE: Bromelain is the name given to a family of proteolytic enzymes obtained from Ananas comosus, the pineapple plant. It is considered a potent anti inflammatory and antiedematous substance. Surgery of impacted third molars in the outpatient setting is one of the procedures most often associated with postoperative pain and swelling. The aim of this study was to evaluate the efficacy of bromelain in reducing postoperative pain and swelling. METHOD AND MATERIALS: 80 patients were recruited to the study from patients attending the Maxillofacial Surgery Unit of the Istituto Stomatologico Italiano, Milan, Italy, for impacted third molar surgery. At time 0 when surgery was performed, patients started simultaneous antibiotic and analgesic therapy. On the following day, patients were divided into two groups. Patients in group 1 were prescribed bromelain. Patients in group 2 were prescribed only the analgesic if required. Three parameters were evaluated: pain, edema, and erythema. The first evaluation visit was performed 3 hours after surgery, the second 48 hours after surgery, and the final evaluation 7 days after surgery. RESULTS: Postoperative pain, edema, and erythema were significantly lower in the study group than in the control group. Analgesic consumption, both in terms of days of treatment and number of tablets taken, was slightly lower in the study group. Only one adverse event was recorded, which occurred in a patient in the control group. CONCLUSION: The present study demonstrates an important anti-inflammatory and anti-edematous effect of bromelain. Statistical analysis shows that in the group treated with bromelain the inflammatory response was significantly less than in the control group. PMID- 25019112 TI - Vertical brushing versus horizontal brushing: a randomized split-mouth clinical trial. AB - OBJECTIVE: The aim of this randomized, single-blind, splitmouth design, clinical trial was to evaluate the effectiveness in plaque removal of two brushing methods, the vertical and the horizontal, in a sample of healthy young adults. METHOD AND MATERIALS: Forty-nine subjects were enrolled and 43 completed the study. All subjects abstained from oral hygiene practices for 48 hours. Plaque and gingival abrasions were recorded according to the Rustogi Modified Navy Plaque Index (RMNPI) and the van der Weijden method by one calibrated examiner before and immediately after the brushing session. A dental hygienist performed the two brushing methods using a randomized split-mouth design. The average plaque scores from the whole mouth, interproximal surfaces, and gingival margin were obtained before and after brushing, and the differences were evaluated using one-way analysis of variance. RESULTS: The differences in mean plaque scores between pre- and postbrushing were statistically significant for both methods. Considering the interbrushing differences, the vertical method produced lower plaque scores compared to the horizontal for the whole mouth (P=.02). In the interproximal surfaces, the vertical method removed more plaque compared to the horizontal one (P<.01). In the gingival margin no statistically significant differences in plaque scores were recorded. Only 10 gingival abrasions were registered, mainly produced by the horizontal method. CONCLUSION: RESULTS suggest that both toothbrushing methods are effective in plaque removal; nevertheless, the vertical brushing method has demonstrated to remove more plaque from the interproximal surfaces than the horizontal method. PMID- 25019113 TI - Verification of posterior superior alveolar artery distribution in lateral wall of maxillary sinus by location and defect pattern. AB - OBJECTIVE: Maxillary sinus augmentation is used when performing implant treatment in the maxillary molar region with inadequate bone height. Posterior superior alveolar artery (PSAA) is the branch of the maxillary artery that supplies the lateral sinus wall and sinus membrane. When performing an osteotomy via lateral approach, however, damage to the PSAA can occur, because it runs inside the lateral wall of the maxillary sinus, causing hemorrhage and hampering surgery. The objective of the present study was to compare the defect patterns with the distances from the alveolar crest and sinus floor to the PSAA. METHOD AND MATERIALS: 280 lateral regions in 235 patients with at least three missing consecutive posterior teeth were measured. Measurement locations were the 1st premolar (P1), the 2nd premolar (P2), the 1st molar (M1), and the 2nd molar (M2). RESULTS: The detection rate was 29% to 59%, and the longest diameter was between 1.1 mm and 1.3 mm. The average distances between the PSAA and the alveolar crest were 24.1 mm, 21.3 mm, 15.4 mm, and 15.3 mm (P1-M2), with statistically significant differences in all locations except M1 and M2. The average distances between the PSAA and the maxillary sinus floor were 10.4 mm, 10.4 mm, 9.0 mm, and 8.5 mm (P1-M2), with no significant differences. There were no significant differences between different defect patterns in the distance between the PSAA and either the alveolar crest or the maxillary sinus floor. PSAA detection rate and the longest diameter were related to the spatial resolution of the computed tomography (CT) scan. CONCLUSION: Although the distance between the PSAA and the alveolar crest was significantly shorter in the molar region than in the premolar region, it did not affect the defect pattern. PMID- 25019114 TI - Effectiveness of nano-hydroxyapatite toothpaste in reducing dentin hypersensitivity: a double-blind randomized controlled trial. AB - OBJECTIVE: The present double-blind randomized clinical trial aimed to compare the efficacy in reducing dentin hypersensitivity of a dentifrice formulation containing nano-hydroxyapatite with a fluoride dentifrice and a placebo. METHOD AND MATERIALS: 105 subjects were recruited to participate in the study. A computer-generated random table with blocking to one of the three study treatments was used in order to have 35 subjects per group: 1) nano hydroxyapatite 15% toothpaste, fluoride-free; 2) fluoride toothpaste; 3) placebo. Groups 1, 2, and 3 were instructed to brush their teeth for 2 minutes twice a day with the provided toothpaste. The participant's dentin hypersensitivity was evaluated at baseline and after 2 and 4 weeks using airblast and tactile tests. In addition, a subjective evaluation using a visual analog scale (VAS) was used. RESULTS: Significantly lower values of cold air sensitivity and tactile sensitivity (P<.001) were found for the test group at 2 weeks and 4 weeks. In addition, statistically significantly (P<.001) lower values of sensitivity were reported for group 1 compared to groups 2 and 3, at 2 and 4 weeks respectively. The VAS scores were significantly lower (P<.001) in the test group at 2 and 4 weeks compared to baseline and to the control groups. CONCLUSION: The findings of the present study encourage the application of nano-hydroxyapatite in fluoride free toothpaste as an effective desensitizing agent providing quick relief from symptoms after 2 and 4 weeks. PMID- 25019115 TI - Efficacy of honey in comparison to topical corticosteroid for treatment of recurrent minor aphthous ulceration: a randomized, blind, controlled, parallel, double-center clinical trial. AB - BACKGROUND: Recurrent aphthous ulceration represents a very common mucosal disorder that general dentists may encounter on a daily basis, and for which there is no curative treatment. The best treatment that can be achieved is to avoid local traumatic precipitants, lessen the pain and duration of ulceration by suppressing the local immune response, and prevent secondary infection. OBJECTIVE: The objective of this study was to clinically determine the efficacy of honey as a topical treatment of recurrent minor aphthous ulceration in a Saudi cohort. METHOD AND MATERIALS: A randomized, blind, controlled, parallel, double center clinical trial was carried out. Honey was applied by patients four times a day for 5 days. Clinical parameters (ulcer size, pain scale, and degree of erythema and healing) were recorded both at baseline and during the follow-up period. RESULTS: There were 94 subjects, with 180 minor recurrent aphthous ulcerations. The ulcers were distributed as 67, 57, and 56 ulcers for honey, topical corticosteroid, and Orabase treatment, respectively. There was a statistically significant difference between the honey group and the other two groups in terms of reduction of ulcer size, days of pain, and degree of erythema. No side effects were reported in any group. CONCLUSION: Honey was found to be effective and safe in reducing minor aphthous ulcer pain, size, and erythema in a Saudi cohort. PMID- 25019116 TI - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) associated with a once yearly IV infusion of zoledronic acid (Reclast) 5 mg: two cases and review of the literature. AB - The use of a once-yearly IV infusion of 5 mg zoledronic acid has become more common, as the drug is being reported as safe, with few to minimal adverse reactions. This one-time annual administration has a favorable outcome for patients with osteoporosis and spares the burden of taking daily oral bisphosphonates. The present literature search found 10 well-documented cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) associated with annual administration of 5 mg zoledronic acid for the treatment of osteoporosis. Two new cases are also described, with underlying risk factors similar to previous reports. These include prior dental surgical procedures, the presence of diabetes, autoimmune conditions, past use of bisphosphonate and steroids, and concomitant immunosuppression. Although the reported incidence of BRONJ related to once-a-year IV administered zoledronic acid is low, it may be plausible. Both medical and dental clinicians should be aware of its manifestation. PMID- 25019117 TI - Risk of developing BRONJ among patients exposed to intravenous bisphosphonates following tooth extraction. AB - OBJECTIVE: A study was designed to measure of the incidence of bisphosphonate related osteonecrosis of the jaws (BRONJ) following tooth extraction in patients receiving or who have received intravenous bisphosphonates (Zometa, zoledronic acid). METHOD AND MATERIALS: A prospective cohort study was made of 36 patients subjected to 62 tooth extractions. All these 36 patients had been treated or were receiving treatment with zoledronic acid. RESULTS: The incidence of BRONJ following 62 tooth extractions in patients treated with zoledronic acid 4 months after extraction was 14.5%. CONCLUSION: No statistically significant associations were found with patient age, sex, hygiene index, total treatment time, surgical difficulty, or extraction site. However, the factors that significantly influenced the final presence of osteonecrosis were related to tooth extractions in the absence of periodontal disease, and if sockets remained unhealed at the month of extraction. PMID- 25019118 TI - In-vitro evaluation of the accuracy of conventional and digital methods of obtaining full-arch dental impressions. AB - OBJECTIVE: To investigate the accuracy of conventional and digital impression methods used to obtain full-arch impressions by using an in-vitro reference model. METHOD AND MATERIALS: Eight different conventional (polyether, POE; vinylsiloxanether, VSE; direct scannable vinylsiloxanether, VSES; and irreversible hydrocolloid, ALG) and digital (CEREC Bluecam, CER; CEREC Omnicam, OC; Cadent iTero, ITE; and Lava COS, LAV) full-arch impressions were obtained from a reference model with a known morphology, using a highly accurate reference scanner. The impressions obtained were then compared with the original geometry of the reference model and within each test group. RESULTS: A point-to-point measurement of the surface of the model using the signed nearest neighbour method resulted in a mean (10%-90%)/2 percentile value for the difference between the impression and original model (trueness) as well as the difference between impressions within a test group (precision). Trueness values ranged from 11.5 MUm (VSE) to 60.2 MUm (POE), and precision ranged from 12.3 MUm (VSE) to 66.7 MUm (POE). Among the test groups, VSE, VSES, and CER showed the highest trueness and precision. The deviation pattern varied with the impression method. Conventional impressions showed high accuracy across the full dental arch in all groups, except POE and ALG. CONCLUSIONS: Conventional and digital impression methods show differences regarding full-arch accuracy. Digital impression systems reveal higher local deviations of the full-arch model. Digital intraoral impression systems do not show superior accuracy compared to highly accurate conventional impression techniques. However, they provide excellent clinical results within their indications applying the correct scanning technique. PMID- 25019119 TI - A comparison of conservative and invasive dental approaches in the treatment of tension-type headache. AB - OBJECTIVE: To investigate the efficacy of conservative dental treatment (occlusal splint and pharmacologic therapy) and invasive therapy (prosthetic restorations) in the treatment of tension-type headache (TTH). METHOD AND MATERIALS: The study sample was composed of 70 patients who presented with symptomatic TTH and were assigned to three treatment groups according to their treatment needs. Group A (30 patients): a conservative treatment protocol with a combination of an occlusal splint and analgesic and muscle relaxant medication. Group B (10 patients): invasive prosthodontic procedures. Group C (30 patients): patients who refused any type of treatment but consented to the study served as a control group. Pain quality was measured with the Headache Impact Test (HIT-6). The statistical analysis was performed with the Wilcoxon rank test (P<=.05). RESULTS: Conservative treatment with splints and analgesic medication and invasive treatment by prosthetic rehabilitation relieved the TTH symptoms. The patients who received treatment experienced a significant reduction in their discomfort after 6 months (P<=.01), whereas the patients who refused therapy remained, on average, at the same pain level (P<=.117). In group A, the HIT-6 score was reduced for 26 patients, and in group B for 8 patients. In group C a reduction of HIT-6 scores was observed in 10 patients. CONCLUSION: Conservative or invasive occlusal adjustments may serve as a useful tool in the treatment of TTH. PMID- 25019120 TI - Analysis of spontaneous repositioning of pathologically migrated teeth: a clinical and radiographic study. AB - OBJECTIVE: Pathologic migration is defined as a change in tooth position, resulting from a disruption of forces that maintain the teeth in the normal position with reference to the skull. Clinical evidence is limited that pathologically migrated teeth may reposition themselves after periodontal therapy. The current study was carried out to determine the frequency of spontaneous repositioning of pathologically migrated teeth after periodontal therapy, and to study the relation between the severity of migration and the degree of repositioning following treatment. METHOD AND MATERIALS: Twenty-five patients aged 20 to 45 years with moderate to severe form of periodontitis presenting 52 diastema sites secondary to pathologic migration involving maxillary anterior teeth participated in the study. After conventional periodontal treatment had been performed, reactive repositioning was assessed by measuring the space between pathologically migrated teeth and adjacent teeth on study models and radiographs obtained at baseline, reevaluation at 4 weeks after scaling and root planing (SRP), 3 months after periodontal surgery, and 6 months from baseline. RESULTS: No changes were noted after SRP. On study models, 88.46% of all sites (46 of 52 sites) demonstrated various degrees of repositioning (both partial closure and complete closure) after periodontal therapy 6 months after baseline. Of these 46 sites, all exhibited improvement after surgical therapy. Labiopalatal repositioning was seen in 32 out of 51 teeth (62.74%). On radiographs, 77.27% of all sites (34 of 44 sites) demonstrated various degrees of repositioning (both partial closure and complete closure) after periodontal therapy 6 months after baseline. Of these 34 sites, all exhibited improvement after surgical therapy. Complete repositioning occurred in 34.61% and partial closure was seen in 53.80%. CONCLUSION: The findings suggest that spontaneous repositioning after periodontal therapy is likely, particularly when light to moderate degrees of pathologic migration are considered. PMID- 25019123 TI - Epidemiology: The complexities of epilepsy. PMID- 25019122 TI - Epilepsy. PMID- 25019121 TI - Impact of the 2008 economic and financial crisis on child health: a systematic review. AB - The aim of this study was to provide an overview of studies in which the impact of the 2008 economic crisis on child health was reported. Structured searches of PubMed, and ISI Web of Knowledge, were conducted. Quantitative and qualitative studies reporting health outcomes on children, published since 2007 and related to the 2008 economic crisis were included. Two reviewers independently assessed studies for inclusion. Data were synthesised as a narrative review. Five hundred and six titles and abstracts were reviewed, from which 22 studies were included. The risk of bias for quantitative studies was mixed while qualitative studies showed low risk of bias. An excess of 28,000-50,000 infant deaths in 2009 was estimated in sub-Saharan African countries, and increased infant mortality in Greece was reported. Increased price of foods was related to worsening nutrition habits in disadvantaged families worldwide. An increase in violence against children was reported in the U.S., and inequalities in health-related quality of life appeared in some countries. Most studies suggest that the economic crisis has harmed children's health, and disproportionately affected the most vulnerable groups. There is an urgent need for further studies to monitor the child health effects of the global recession and to inform appropriate public policy responses. PMID- 25019124 TI - [It is time for the inevitable farewell ...]. PMID- 25019125 TI - Neurobiology: Unrestrained excitement. PMID- 25019126 TI - Perspective: The surgical solution. PMID- 25019127 TI - Genetics: Complex expressions. PMID- 25019128 TI - Sociology: Shedding the shame. PMID- 25019129 TI - Drug development: Illuminated targets. PMID- 25019130 TI - Food science: Fat chance. PMID- 25019131 TI - Technology: Dressed to detect. PMID- 25019132 TI - [In memoriam F. J. Sole Balcells]. PMID- 25019133 TI - In memoriam Ralf Kohnen, PhD, professor of clinical psychology. PMID- 25019134 TI - Automatic extraction of property norm-like data from large text corpora. AB - Traditional methods for deriving property-based representations of concepts from text have focused on either extracting only a subset of possible relation types, such as hyponymy/hypernymy (e.g., car is-a vehicle) or meronymy/metonymy (e.g., car has wheels), or unspecified relations (e.g., car--petrol). We propose a system for the challenging task of automatic, large-scale acquisition of unconstrained, human-like property norms from large text corpora, and discuss the theoretical implications of such a system. We employ syntactic, semantic, and encyclopedic information to guide our extraction, yielding concept-relation feature triples (e.g., car be fast, car require petrol, car cause pollution), which approximate property-based conceptual representations. Our novel method extracts candidate triples from parsed corpora (Wikipedia and the British National Corpus) using syntactically and grammatically motivated rules, then reweights triples with a linear combination of their frequency and four statistical metrics. We assess our system output in three ways: lexical comparison with norms derived from human-generated property norm data, direct evaluation by four human judges, and a semantic distance comparison with both WordNet similarity data and human-judged concept similarity ratings. Our system offers a viable and performant method of plausible triple extraction: Our lexical comparison shows comparable performance to the current state-of-the-art, while subsequent evaluations exhibit the human-like character of our generated properties. PMID- 25019135 TI - [The importance of the human intestinal microbiota]. PMID- 25019136 TI - Sample size calculation in cost-effectiveness cluster randomized trials: optimal and maximin approaches. AB - In this paper, the optimal sample sizes at the cluster and person levels for each of two treatment arms are obtained for cluster randomized trials where the cost effectiveness of treatments on a continuous scale is studied. The optimal sample sizes maximize the efficiency or power for a given budget or minimize the budget for a given efficiency or power. Optimal sample sizes require information on the intra-cluster correlations (ICCs) for effects and costs, the correlations between costs and effects at individual and cluster levels, the ratio of the variance of effects translated into costs to the variance of the costs (the variance ratio), sampling and measuring costs, and the budget. When planning, a study information on the model parameters usually is not available. To overcome this local optimality problem, the current paper also presents maximin sample sizes. The maximin sample sizes turn out to be rather robust against misspecifying the correlation between costs and effects at the cluster and individual levels but may lose much efficiency when misspecifying the variance ratio. The robustness of the maximin sample sizes against misspecifying the ICCs depends on the variance ratio. The maximin sample sizes are robust under misspecification of the ICC for costs for realistic values of the variance ratio greater than one but not robust under misspecification of the ICC for effects. Finally, we show how to calculate optimal or maximin sample sizes that yield sufficient power for a test on the cost-effectiveness of an intervention. PMID- 25019137 TI - Acute cardiovascular events: anger mounts the checklist. PMID- 25019138 TI - Brain responses to stress and their effects on the cardiovascular system. PMID- 25019139 TI - Motivation and prevention of cardiovascular disease. PMID- 25019140 TI - Common analgesics 'pose cardiac risk'. PMID- 25019141 TI - Special section on the 2013 IEEE Conference on Bioinformatics and Biomedicine (BIBM). PMID- 25019143 TI - A bittersweet celebration of crystallography. PMID- 25019142 TI - Inhibitors of microsomal prostaglandin E2 synthase-1 enzyme as emerging anti inflammatory candidates. AB - Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid (AA) into PGH2 that is further metabolized by terminal prostaglandin (PG) synthases into biologically active PGs, for example, prostaglandin E2 (PGE2), prostacyclin I2 (PGI2), thromboxane A2 (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 alpha (PGF2alpha). Among them, PGE2 is a widely distributed PG in the human body, and an important mediator of inflammatory processes. The successful modulation of this PG provides a beneficial strategy for the potential anti-inflammatory therapy. For instance, nonsteroidal anti-inflammatory agents (NSAIDs), both classical nonselective (cNSAIDs) and the selective COX-2 inhibitors (coxibs) attenuate the generation of PGH2 from AA that in turn reduces the synthesis of PGE2 and modifies the inflammatory conditions. However, the long term use of these agents causes severe side effects due to the nonselective inhibition of other PGs, such as PGI2 and TXA2, etc. Microsomal prostaglandin E2 synthase-1 (mPGES-1), a downstream PG synthase, specifically catalyzes the biosynthesis of COX-2-derived PGE2 from PGH2, and describes itself as a valuable therapeutic target for the treatment of acute and chronic inflammatory disease conditions. Therefore, the small molecule inhibitors of mPGES-1 would serve as a beneficial anti-inflammatory therapy, with reduced side effects that are usually associated with the nonselective inhibition of PG biosynthesis. PMID- 25019144 TI - The author file: Dmitriy Chudakov. PMID- 25019145 TI - Points of view: designing comparative experiments. PMID- 25019146 TI - [The main repair pathways of double-strand breaks in the genomic DNA and interactions between them]. AB - Double-strand DNA breaks (DSBs) resulting from cellular metabolic processes and external factors are a serious threat to the stability of the genome. Therefore, the cells have different molecular mechanisms for the efficient repair of this type of da-mage. In this review we consider two main biochemical pathways of double-strand DNA breaks repair in eukaryotic cells--DNA strands nonhomologous end joining and homologous recombination between sister chromatids or chromatids of homologous chromosomes. Numerous data obtained recently for various eukaryotic cells suggest that complex interplay between the major DSB repair pathways normally facilitate the efficient repair and maintenance of the structural and functional genome integrity, but at the same time, under conditions ofgenotoxic factors exposure may induce increased genomic instability. PMID- 25019147 TI - Pipeline full of new diabetes drugs presents challenge to health plans. PMID- 25019148 TI - NCCN endorses PSA testing in absence of better alternatives. PMID- 25019149 TI - By the numbers. Largest national healthcare associations. Organizations ranked by 2012 revenue, based on Modern Healthcare's review of IRS 990 filings. PMID- 25019151 TI - Utilizing FMR1 gene mutations as predictors of treatment success in human in vitro fertilization. AB - CONTEXT: Mutations of the fragile X mental retardation 1 (FMR1) gene are associated with distinct ovarian aging patterns. OBJECTIVE: To confirm in human in vitro fertilization (IVF) that FMR1 affects outcomes, and to determine whether this reflects differences in ovarian aging between FMR1 mutations, egg/embryo quality or an effect on implantation. DESIGN, SETTING, PATIENTS: IVF outcomes were investigated in a private infertility center in reference to patients' FMR1 mutations based on a normal range of CGG(n = 26-34) and sub-genotypes high (CGG(n>34)) and low (CGG(<26)). The study included 3 distinct sections and study populations: (i) A generalized mixed-effects model of morphology (777 embryos, 168 IVF cycles, 125 infertile women at all ages) investigated whether embryo quality is associated with FMR1; (ii) 1041 embryos in 149 IVF cycles in presumed fertile women assessed whether the FMR1 gene is associated with aneuploidy; (iii) 352 infertile patients (< age 38; in 1st IVF cycles) and 179 donor-recipient cycles, assessed whether the FMR1 gene affects IVF pregnancy chances via oocyte/embryo quality or non-oocyte maternal factors. INTERVENTIONS: Standardized IVF protocols. MAIN OUTCOME MEASURES: Morphologic embryo quality, ploidy and pregnancy rates. RESULTS: (i) Embryo morphology was reduced in presence of a low FMR1 allele (P = 0.032). In absence of a low allele, the odds ratio (OR) of chance of good (vs. fair/poor) embryos was 1.637. (ii) FMR1 was not associated with aneuploidy, though aneuploidy increased with female age. (iii) Recipient pregnancy rates were neither associated with donor age or donor FMR1. In absence of a low FMR1 allele, OR of clinical pregnancy (vs. chemical or no pregnancy) was 2.244 in middle-aged infertility patients. CONCLUSIONS: A low FMR1 allele (CGG(<26)) is associated with significantly poorer morphologic embryo quality and pregnancy chance. As women age, low FMR1 alleles affect IVF pregnancy chances by reducing egg/embryo quality by mechanisms other than embryo aneuploidy. PMID- 25019152 TI - Formation of worm-like micelles in mixed N-hexadecyl-N-methylpyrrolidinium bromide-based cationic surfactant and anionic surfactant systems. AB - Through the descriptive and rheological characterization of worm-like micelles formed by N-hexadecyl-N-methylpyrrolidinium bromide and sodium laurate, the formation and properties of the worm-like micelles were affected by the concentrations of sodium laurate and temperature. Additionally, cryogenic transmission electron microscopy images further validated the formation of worm like micelles. PMID- 25019154 TI - Multilocus sequence analysis for the assessment of phylogenetic diversity and biogeography in hyphomonas bacteria from diverse marine environments. AB - Hyphomonas, a genus of budding, prosthecate bacteria, are primarily found in the marine environment. Seven type strains, and 35 strains from our collections of Hyphomonas, isolated from the Pacific Ocean, Atlantic Ocean, Arctic Ocean, South China Sea and the Baltic Sea, were investigated in this study using multilocus sequence analysis (MLSA). The phylogenetic structure of these bacteria was evaluated using the 16S rRNA gene, and five housekeeping genes (leuA, clpA, pyrH, gatA and rpoD) as well as their concatenated sequences. Our results showed that each housekeeping gene and the concatenated gene sequence all yield a higher taxonomic resolution than the 16S rRNA gene. The 42 strains assorted into 12 groups. Each group represents an independent species, which was confirmed by virtual DNA-DNA hybridization (DDH) estimated from draft genome sequences. Hyphomonas MLSA interspecies and intraspecies boundaries ranged from 93.3% to 96.3%, similarity calculated using a combined DDH and MLSA approach. Furthermore, six novel species (groups I, II, III, IV, V and XII) of the genus Hyphomonas exist, based on sequence similarities of the MLSA and DDH values. Additionally, we propose that the leuA gene (93.0% sequence similarity across our dataset) alone could be used as a fast and practical means for identifying species within Hyphomonas. Finally, Hyphomonas' geographic distribution shows that strains from the same area tend to cluster together as discrete species. This study provides a framework for the discrimination and phylogenetic analysis of the genus Hyphomonas for the first time, and will contribute to a more thorough understanding of the biological and ecological roles of this genus. PMID- 25019155 TI - RANK rs1805034 T>C polymorphism is associated with susceptibility of esophageal cancer in a Chinese population. AB - Esophageal cancer remains the sixth leading cause of cancer associated death and eighth most common cancer worldwide. Genetic factors, such as single nucleotide polymorphisms (SNPs), may contribute to the carcinogenesis of esophageal cancer. Here, we conducted a hospital based case-control study to evaluate the genetic susceptibility of functional SNPs on the development of esophageal cancer. A total of 629 esophageal squamous cell carcinoma (ESCC) cases and 686 controls were enrolled for this study. The OPG rs3102735 T>C, rs2073618 G>C, RANK rs1805034 T>C, RANKL rs9533156 T>C and rs2277438 A>G were determined by ligation detection reaction method. Our findings suggested that RANK rs1805034 T>C is associated with the susceptibility of ESCC, which is more evident in male and elder (>=63) patients. Our study provides the first evidence that functional polymorphisms RANK rs1805034 T>C may be an indicator for individual susceptibility to ESCC. However, further larger studies among different ethnic populations are warranted to verify our conclusion. PMID- 25019156 TI - How listeners weight acoustic cues to intonational phrase boundaries. AB - The presence of an intonational phrase boundary is often marked by three major acoustic cues: pause, final lengthening, and pitch reset. The present study investigates how these three acoustic cues are weighted in the perception of intonational phrase boundaries in two experiments. Sentences that contained two intonational phrases with a critical boundary between them were used as the experimental stimuli. The roles of the three acoustic cues at the critical boundary were manipulated in five conditions. The first condition featured none of the acoustic cues. The following three conditions featured only one cue each: pause, final lengthening, and pitch reset, respectively. The fifth condition featured both pause duration and pre-final lengthening. A baseline condition was also included in which all three acoustic cues were preserved intact. Listeners were asked to detect the presence of the critical boundaries in Experiment 1 and judge the strength of the critical boundaries in Experiment 2. The results of both experiments showed that listeners used all three acoustic cues in the perception of prosodic boundaries. More importantly, these acoustic cues were weighted differently across the two experiments: Pause was a more powerful perceptual cue than both final lengthening and pitch reset, with the latter two cues perceptually equivalent; the effect of pause and the effects of the other two acoustic cues were not additive. These results suggest that the weighting of acoustic cues contributes significantly to the perceptual differences of intonational phrase boundary. PMID- 25019157 TI - ACE and ACE2 in inflammation: a tale of two enzymes. AB - The renin-angiotensin system (RAS) conceived as a coordinated hormonal cascade plays an important role in controlling multiple functions in many organs and is much more complex than previously thought. The RAS has continued to expand, with the identification of new components, functions and subsystems. Angiotensin converting enzyme (ACE) and its novel homolog angiotensin converting enzyme 2 (ACE2) are two key enzymes involved in the synthesis of bioactive components of the RAS. The main active peptides of the RAS include angiotensin II (Ang II), Ang III, Ang IV, and angiotensin-(1-7) [Ang-(1-7)] among which Ang II and Ang-(1-7) are much more important in health and disease. The axis formed by ACE2 represents an endogenous counter-regulatory pathway within the RAS, and its actions are opposite to those of the ACE axis. Conventionally the RAS has been considered to be important in the cardiovascular system, metabolism, cell growth and homeostasis. In recent years, a key role of ACE and ACE2 and their peptides has been recognized in the inflammatory process in conditions such as cardiac hypertrophy, pulmonary hypertension, glomerulonephritis, lung injury, sepsis, and acute pancreatitis. Investigations are ongoing to better understand the role of the RAS in inflammation. A comprehensive understanding of the RAS components in inflammation can provide new possibilities for therapeutic approaches against inflammatory diseases. In this review, we discuss our current understanding of the subject, based on recent findings, on the role of ACE and ACE2 in inflammation. PMID- 25019158 TI - Effects of meteorological factors on daily hospital admissions for asthma in adults: a time-series analysis. AB - BACKGROUND: There is limited evidence for the impacts of meteorological changes on asthma hospital admissions in adults in Shanghai, China. OBJECTIVES: To quantitatively evaluate the short-term effects of daily mean temperature on asthma hospital admissions. METHODS: Daily hospital admissions for asthma and daily mean temperatures between January 2005 and December 2012 were analyzed. After controlling for secular and seasonal trends, weather, air pollution and other confounding factors, a Poisson generalized additive model (GAM) combined with a distributed lag non-linear model were used to explore the associations between temperature and hospital admissions for asthma. RESULTS: During the study periods, there were 15,678 hospital admissions for asthma by residents of Shanghai, an average 5.6 per day. Pearson correlation analysis found a significant negative correlation (r = -0.174, P<0.001) between asthma hospitalizations and daily mean temperature (DMT). The DMT effect on asthma increased below the median DMT, with lower temperatures associated with a higher risk of hospital admission for asthma. Generally, the cold effect appeared to be relatively acute, with duration lasting several weeks, while the hot effect was short-term. The relative risk of asthma hospital admissions associated with cold temperature (the 25th percentile of temperature relative to the median temperature) was 1.20 (95% confidence interval [CI], 1.01~1.41) at lag0-14. However, warmer temperatures were not associated with asthma hospital admissions. CONCLUSIONS: Cold temperatures may trigger asthmatic attacks. Effective strategies are needed to protect populations at risk from the effects of cold. PMID- 25019159 TI - Morphological change to birds over 120 years is not explained by thermal adaptation to climate change. AB - Changes in morphology have been postulated as one of the responses of animals to global warming, with increasing ambient temperatures leading to decreasing body size. However, the results of previous studies are inconsistent. Problems related to the analyses of trends in body size may be related to the short-term nature of data sets, to the selection of surrogates for body size, to the appropriate models for data analyses, and to the interpretation as morphology may change in response to ecological drivers other than climate and irrespective of size. Using generalized additive models, we analysed trends in three morphological traits of 4529 specimens of eleven bird species collected between 1889 and 2010 in southern Germany and adjacent areas. Changes and trends in morphology over time were not consistent when all species and traits were considered. Six of the eleven species displayed a significant association of tarsus length with time but the direction of the association varied. Wing length decreased in the majority of species but there were few significant trends in wing pointedness. Few of the traits were significantly associated with mean ambient temperatures. We argue that although there are significant changes in morphology over time there is no consistent trend for decreasing body size and therefore no support for the hypothesis of decreasing body size because of climate change. Non-consistent trends of change in surrogates for size within species indicate that fluctuations are influenced by factors other than temperature, and that not all surrogates may represent size appropriately. Future analyses should carefully select measures of body size and consider alternative hypotheses for change. PMID- 25019160 TI - Wireless monitoring of liver hemodynamics in vivo. AB - Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics. PMID- 25019161 TI - Intracellular targeting of CD44+ cells with self-assembling, protein only nanoparticles. AB - CD44 is a multifunctional cell surface protein involved in proliferation and differentiation, angiogenesis and signaling. The expression of CD44 is up regulated in several types of human tumors and particularly in cancer stem cells, representing an appealing target for drug delivery in the treatment of cancer. We have explored here several protein ligands of CD44 for the construction of self assembling modular proteins designed to bind and internalize target cells. Among five tested ligands, two of them (A5G27 and FNI/II/V) drive the formation of protein-only, ring-shaped nanoparticles of about 14 nm that efficiently bind and penetrate CD44(+) cells by an endosomal route. The potential of these newly designed nanoparticles is evaluated regarding the need of biocompatible nanostructured materials for drug delivery in CD44-linked conditions. PMID- 25019162 TI - Autologous bone marrow mononuclear cell transplant and surgical decompression in a dog with chronic spinal cord injury. AB - OBJECTIVES: In dogs with deep analgesia caused by acute spinal cord injury from thoracolumbar disk herniation, autologous bone marrow mononuclear cell transplant may improve recovery. The purpose of the present study was to evaluate autologous bone marrow mononuclear cell transplant in a dog that had paraplegia and deep analgesia caused by chronic spinal cord injury. MATERIALS AND METHODS: Autologous bone marrow mononuclear cell transplant was performed in a dog having paraplegia and analgesia for 3 years that was caused by a chronic spinal cord injury secondary to Hansen type I thoracolumbar disk herniation. Functional recovery was evaluated with electrophysiologic studies and the Texas Spinal Cord Injury Scale. RESULTS: Somatosensory evoked potentials were absent before transplant but were detected after transplant. Functional improvement was noted (Texas Spinal Cord Injury Scale: before transplant, 0; after transplant, 6). No adverse events were observed. CONCLUSIONS: Autologous bone marrow mononuclear cell transplant into the subarachnoid space may be a safe and beneficial treatment for chronic spinal cord injury in dogs. PMID- 25019164 TI - Complex-to-predict generational shift between nested and clustered organization of individual prey networks in digger wasps. AB - Although diet has traditionally been considered to be a property of the species or populations as a whole, there is nowadays extensive knowledge that individual specialization is widespread among animal populations. Nevertheless, the factors determining the shape of interactions within food webs remain largely undiscovered, especially in predatory insects. We used an aggregation of the digger wasp Bembix merceti to 1) analyse patterns of individual prey use across three flying seasons in a network-based context; and 2) test the effect of four potential factors that might explain network topologies (wasp mass, nest spatial distribution, simultaneous nest-provisioning, prey availability). Inter individual diet variation was found in all three years, under different predator prey network topologies: Individuals arranged in dietary clusters and displayed a checkerboard pattern in 2009, but showed nestedness in 2008 and 2010. Network topologies were not fully explained by the tested factors. Larger females consumed a higher proportion of the total number of prey species captured by the population as a whole, in such a way that nested patterns may arise from mass dependent prey spectrum width. Conversely, individuals with similar body mass didn't form clusters. Nested patterns seemed to be associated with a greater availability of the main prey species (a proxy for reduced intra-specific competition). Thus, according with theory, clusters seemed to appear when competition increased. On the other hand, the nests of the individuals belonging to a given cluster were not more closely located, and neither did individuals within a cluster provision their nests simultaneously. Thus, a female-female copying behaviour during foraging was unlikely. In conclusion, wasp populations can maintain a considerable individual variation across years under different food web organizations. The tested factors only partially accounted for the shift in network properties, and new analyses should be carried out to elucidate how diet network topologies arise in wasp populations. PMID- 25019163 TI - Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies. AB - BACKGROUND: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk. PMID- 25019166 TI - Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation. AB - Abstract Objective: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films. Methods: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters. Results: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher Cmax and almost doubled AUC compared with raw SMV-loaded films. Conclusion: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters. PMID- 25019165 TI - TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy. AB - BACKGROUND: Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN. METHODS & RESULTS: Genomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n = 26, renal failure n = 46, persistent proteinuria n = 29, follow-up median 80 months {range 51-166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors. CONCLUSIONS: Our data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN. PMID- 25019167 TI - High-throughput and sensitive next-generation droplet digital PCR assay for the quantitation of the hepatitis C virus mutation at core amino acid 70. AB - The next-generation droplet digital polymerase chain reaction (ddPCR) assay employs an emulsion-based endpoint to quantitate the amount of target DNA and is more robust than real-time PCR when analyzing sequence variations. However, no studies have applied this technique to quantitate mutations in polymorphic viral genomes. To develop this approach, a ddPCR-based assay was designed to quantitate with high-throughput and sensitivity mutations and their frequencies in codon 70 of the hepatitis C virus (HCV) gene that encodes the Core protein. The assay was linear from 2.5 to 10(5) copies per assay, and the limit of detection of mutants in the presence of a 20,000-fold excess of wild type was 0.005%. The results correlated well with those obtained using the COBAS((r)) TaqMan((r)) HCV Test, which is a real-time PCR assay for the quantitative detection of HCV RNA in human serum (n=87; range, 2.3-7.7log10IU/mL; Pearson's R(2)=0.9120; p<0.0001). The median frequencies of mutations by ddPCR were 0.262% (n=55; range, 0-37.951%) and 99.687% (n=32; range, 52.191-100%) for the wild-type and mutant sequences, respectively, by direct sequencing. The ddPCR assay should be useful for quantitating mutations in other polymorphic viral genomes. PMID- 25019168 TI - Effects of storage time on Cytomegalovirus DNA stability in plasma determined by quantitative real-time PCR. AB - Quantitative real-time PCR (QRT-PCR) assays are faster, more precise, and more sensitive quantitative laboratory methods for monitoring serial CMV DNA viral load in patients undergoing organ or hematopoietic stem cell transplantation. Clinical laboratories often face practical concerns about the storage of specimens from these patients to ensure the accuracy and reproducibility of CMV viral load test results. Different studies that have assessed CMV DNA stability have shown mixed results. Therefore, we analyzed CMV DNA stability of 30 EDTA plasma samples in samples containing between 300 and 100,000copies/ml over a 21 day period. The concentration of CMV DNA in all samples stored at 4 degrees C for 21 days did not differ significantly from the baseline viral load (t=0.242, p=0.810), and no trend was evident to indicate continued degradation over a 2 week period. PMID- 25019169 TI - Development and evaluation of a duplex real-time RT-PCR for detection and differentiation of virulent and variant strains of porcine epidemic diarrhea viruses from the United States. AB - Porcine epidemic diarrhea virus (PEDV) has caused significant economic losses in the US swine industry since May 2013. A new variant strain of PEDV emerged in the US in the late December, 2013. This variant strain of PEDV differs from the virulent strain of PEDV currently circulating in the US in 1170nt of the 5'end of the S1 domain in the spike gene. Importantly, the variant PEDV caused significantly less mortality in piglets than the virulent PEDV, based on clinical observations. This suggests it may be a potential vaccine candidate for PED. Variant PEDV has been detected in samples from multiple states by our laboratory as well as other laboratories in the US. It is critical to detect and differentiate variant PEDV from the virulent PEDV during outbreaks to enhance control and to prevent PED associated disease. In this study, the development and validation of a duplex real-time RT-PCR assay for detection and differentiation of the variant and the virulent strains of PEDV currently circulating in the US was reported. PMID- 25019170 TI - Comparison of conventional RT-PCR, reverse-transcription loop-mediated isothermal amplification, and SYBR green I-based real-time RT-PCR in the rapid detection of bovine viral diarrhea virus nucleotide in contaminated commercial bovine sera batches. AB - Bovine viral diarrhea virus (BVDV) can contaminate biological products produced in bovine or porcine cells or manufactured using bovine sera. A rapid, specific, sensitive, and practical method of detecting BVDV in bio-products is needed. The purpose of this study was to compare three assays with respect to their ability to accurately detect BVDV in biological samples, namely reverse-transcription loop-mediated isothermal amplification (RT-LAMP), SYBR green I-based real-time RT PCR, and conventional RT-PCR. All assays detected BVDV nucleotide and differentiated between BVDV-free and -contaminated bovine sera successfully. In addition, the results were specific to BVDV: the amplification of samples containing the closely related classical swine fever virus or other pathogenic bovine viruses yielded negative results. The lowest detection threshold, 10(1) copies, was displayed by the SYBR green I-based real-time RT-PCR and RT-LAMP assay. This assay was also the most effective in the detection of BVDV contamination in a set of commercially available bovine sera. The field conditions suggest that RT-LAMP is specific and sensitive to detecting BVDV in biological samples and may be used for quality control of biomaterials. PMID- 25019171 TI - Copper-mediated aromatic amination reaction and its application to the total synthesis of natural products. AB - Herein, we review copper-mediated aromatic amination reactions including the classical Ullmann coupling and the recently developed mild aryl amination with an effective ligand as well as the C-H amination reaction. Several applications of intramolecular aryl amination to the syntheses of natural products demonstrate the general applicability of the reaction. PMID- 25019172 TI - Dual-transmission line modeling of electrochemical processes in polyaniline cellulose ester composite porous membranes. AB - The charge transport processes in polyaniline (PANI) composite porous membranes have been elaborated in this study using dual-transmission line impedance model conventionally used for macroscopically homogeneous (nanoporous) membranes. Mixed cellulose ester (ME)-PANI porous membranes were prepared using various in situ chemical polymerization techniques including solution- and vapor-phase polymerizations, and two-compartment cell diaphragmatic polymerization. Each technique yielded different PANI deposition site and content in the membranes. As a result, the modeling of electrochemical impedance spectroscopy (EIS) data yielded different model parameters that have been correlated with the PANI content and deposition site (i.e., surface layering versus in-bulk deposition) in the membranes. The modeling results showed that PANI deposition enhanced charge transport by shifting the interfacial transfer mechanism at pore walls from simple double layer charging to the charge transfer involving oxidation of PANI molecular chains deposited at the pore walls of the composite membranes. In addition, in-bulk PANI deposition in the membranes by means of two-compartment cell polymerization showed several orders of magnitude faster charge transport as compared to the membranes where PANI deposited only at the surface. This study shows that pore-controlled diffusion in PANI composite porous membranes can be satisfactorily modeled using dual-transmission line model and correlated with PANI deposition site in the membranes. PMID- 25019173 TI - Global emissions of trace gases, particulate matter, and hazardous air pollutants from open burning of domestic waste. AB - The open burning of waste, whether at individual residences, businesses, or dump sites, is a large source of air pollutants. These emissions, however, are not included in many current emission inventories used for chemistry and climate modeling applications. This paper presents the first comprehensive and consistent estimates of the global emissions of greenhouse gases, particulate matter, reactive trace gases, and toxic compounds from open waste burning. Global emissions of CO2 from open waste burning are relatively small compared to total anthropogenic CO2; however, regional CO2 emissions, particularly in many developing countries in Asia and Africa, are substantial. Further, emissions of reactive trace gases and particulate matter from open waste burning are more significant on regional scales. For example, the emissions of PM10 from open domestic waste burning in China is equivalent to 22% of China's total reported anthropogenic PM10 emissions. The results of the emissions model presented here suggest that emissions of many air pollutants are significantly underestimated in current inventories because open waste burning is not included, consistent with studies that compare model results with available observations. PMID- 25019174 TI - Early menarche, depressive symptoms, and coping strategies. AB - During the time around menarche, young women must make many emotional and social adjustments to adapt to a new life stage. We compared depressive symptomatology and coping strategies between early and average maturer Mexican adolescents girls. The relationships between elapsed time since menarche and both depressive symptomatology and coping strategies were also studied. Three hundred eighty post menarcheal students from 11 to 15 years completed the Children's Depression Scale and the Children's Situational Coping Scale. Early maturers showed more depressive symptoms than their peers, but they reported having used fewer non productive coping strategies. Early maturers who experienced menarche one to three years previously reported more non-productive coping strategies than those who had experienced menarche four to six years ago. However, no differences were found in the results of the average maturers depending on the time elapsed since menarche. These findings are discussed in light of the psychosocial context of early maturers. PMID- 25019175 TI - Occurrence of spontaneous periodontal disease in the SAMP1/YitFc murine model of Crohn disease. AB - BACKGROUND: Oral involvement is often associated with inflammatory bowel disease (IBD). Recent evidence suggests a high incidence of periodontal disease in patients with Crohn disease (CD). To the best of the authors' knowledge, no animal model of IBD that displays associated periodontal disease was reported previously. The aim of this study is to investigate the occurrence and progression of periodontal disease in SAMP1/YitFc (SAMP) mice that spontaneously develop a CD-like ileitis. In addition, the temporal correlation between the onset and progression of periodontal disease and the onset of ileitis in SAMP mice was studied. METHODS: At different time points, SAMP and parental AKR/J (AKR) control mice were sacrificed, and mandibles were prepared for stereomicroscopy and histology. Terminal ilea were collected for histologic assessment of inflammation score. Periodontal status, i.e., alveolar bone loss (ABL) and alveolar bone crest, was examined by stereomicroscopy and histomorphometry, respectively. RESULTS: ABL increased in both strains with age. SAMP mice showed greater ABL compared with AKR mice by 12 weeks of age, with maximal differences observed at 27 weeks of age. AKR control mice did not show the same severity of periodontal disease. Interestingly, a strong positive correlation was found between ileitis severity and ABL in SAMP mice, independent of age. CONCLUSIONS: The present results demonstrate the occurrence of periodontal disease in a mouse model of progressive CD-like ileitis. In addition, the severity of periodontitis strongly correlated with the severity of ileitis, independent of age, suggesting that common pathogenic mechanisms, such as abnormal immune response and dysbiosis, may be shared between these two phenotypes. PMID- 25019176 TI - Severe chronic periodontitis is associated with endothelial and microvascular dysfunctions: a pilot study. AB - BACKGROUND: Periodontitis is an inflammatory chronic disease that has been implicated as a risk factor for cardiovascular disease (CVD). Endothelium has a central role in CVD pathogenesis, and chronic inflammation can make it dysfunctional, contributing to CVD emergence. Thus, the aim of this study is to investigate the existence of an association between severe chronic periodontitis (CP) and nailfold microvascular, gingival microvascular, and endothelial functions. METHODS: Twenty-three patients were included, 13 with severe periodontitis (median age, 46 years; interquartile range, 9.5 years) and 10 healthy control patients (median age, 35.5 years; interquartile range, 12.5 years). Clinical and laboratorial variables were gathered, and patients were examined by the following: 1) nailfold videocapillaroscopy to assess functional capillary density (FCD), capillary diameters, red blood cell velocity at rest (RBCV) and after 1-minute arterial occlusion (RBCVmax), and time taken to reach RBCVmax (TRBCVmax); 2) side-stream dark-field imaging to determine gingival capillary density (GCD); and 3) venous occlusion plethysmography to assess endothelium-dependent (% Hyper) and endothelium-independent vasodilatation (% Nitro). RESULTS: Patients with CP have smaller values for FCD, RBCV, RBCVmax, and % Hyper and higher values for TRBCVmax and GCD compared with controls (P <0.05). There were significant correlations between periodontal parameters with FCD, RBCV, RBCVmax, TRBCVmax, GCD, and % Hyper. There was also a negative correlation between FCD and GCD (r = -0.7; P <0.01). Associations between periodontitis and FCD, RBCVmax, TRBCVmax, GCD, and % Hyper remained significant after adjustments for age and systolic blood pressure. CONCLUSION: Severe CP was directly associated with endothelial and microvascular dysfunctions. PMID- 25019177 TI - The effects of the microbiota on the host immune system. AB - The human gastrointestinal track harbors hundreds of species of commensal organisms, collectively known as microbiota. The composition of the intestinal microbiota is changeable by various factors, such as host genotype, diet, antibiotics, pathogen infections, among others. Changes in these factors can cause microbiome disruption known as dysbiosis, leading to the outgrowth of potential pathogenic bacteria or decrease in the number of beneficial bacteria. Dysbiosis has been implicated in numerous inflammatory and autoimmune diseases. This review is focused on host-microbiota interactions, specifically on influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory and autoimmune diseases. PMID- 25019178 TI - Word informativity influences acoustic duration: effects of contextual predictability on lexical representation. AB - Language-users reduce words in predictable contexts. Previous research indicates that reduction may be stored in lexical representation if a word is often reduced. Because representation influences production regardless of context, production should be biased by how often each word has been reduced in the speaker's prior experience. This study investigates whether speakers have a context-independent bias to reduce low-informativity words, which are usually predictable and therefore usually reduced. Content word durations were extracted from the Buckeye and Switchboard speech corpora, and analyzed for probabilistic reduction effects using a language model based on spontaneous speech in the Fisher corpus. The analysis supported the hypothesis: low-informativity words have shorter durations, even when the effects of local contextual predictability, frequency, speech rate, and several other variables are controlled for. Additional models that compared word types against only other words of the same segmental length further supported this conclusion. Words that usually appear in predictable contexts are reduced in all contexts, even those in which they are unpredictable. The result supports representational models in which reduction is stored, and where sufficiently frequent reduction biases later production. The finding provides new evidence that probabilistic reduction interacts with lexical representation. PMID- 25019180 TI - Stable 7,14-disubstituted-5,12-dithiapentacenes with quinoidal conjugation. AB - Two 7,14-disubstituted-5,12-dithiapentacenes (1 and 2) with quinoidal conjugation were synthesized. Their ground-state quinoidal structures were proven by X-ray crystallographic analysis. They showed very different electronic and optical properties from those of the corresponding pentacene derivatives with diene conjugation, and their stability was significantly improved. Organic field effect transistors based on solution processed thin films of 1 and 2 exhibited a hole mobility of up to 0.032 cm(-2) V(-1) s(-1). PMID- 25019179 TI - Axial chiral bisbenzophenazines: solid-state self-assembly via halide hydrogen bonds triggered by linear alkanes. AB - An axial chiral tetrachlorinated bisbenzo[a]phenazine has been discovered that undergoes an alkane-induced shift in the solid state from a disordered amorphous form to an ordered polycrystalline form. This phase transition is caused by the formation of pores that accommodate linear alkanes of varying lengths with a very strong affinity as judged by differential scanning calorimetry. Single crystal X ray structure analysis revealed that a series of weak phenolic OH...Cl hydrogen bonds dictates the pore structure. These weak interactions can be disrupted mechanically, causing the material to revert to the amorphous form. Notably, the interchange between the amorphous and crystalline forms is readily reversible and is easily observed by characteristic colorimetric changes. Measurements via photoimage processing reveal that the degree of color change is dictated by the type of alkane employed. PMID- 25019181 TI - Preactivated thiolated poly(methacrylic acid-co-ethyl acrylate): synthesis and evaluation of mucoadhesive potential. AB - The study was aimed to developed and investigate a novel polymer for intestinal drug delivery with improved mucoadhesive properties. Therefore Eudragit(r) L 100 55 (poly(methacrylic acid-co-ethyl acrylate)) was thiolated by covalent attachment of L-cysteine. The immobilized thiol groups were preactivated by disulfide bond formation with 2-mercaptonicotinic acid. Resulting derivative (Eu S-MNA) was investigated in terms of mucoadhesion via three different methods: tensile studies, rotating cylinder studies and rheological synergism method, as well as water-uptake capacity and cytotoxicity. Different derivatives were obtained with increasing amount of bound L-cysteine (60, 140 and 266 MUmol/g polymer) and degree of preactivation (33, 45 and 51 MUmol/g polymer). Tensile studies revealed a 30.5-, 35.3- and 52.2-fold rise of total work of adhesion for the preactivated polymers compared to the unmodified Eudragit. The adhesion time on the rotating cylinder was prolonged up to 17-fold in case of thiolated polymer and up to 34-fold prolonged in case of the preactivated polymer. Rheological synergism revealed remarkable interaction of all investigated modified derivatives with mucus. Further, water-uptake studies showed an over 7h continuing weight gain for the modified polymers whereat disintegration took place for the unmodified polymer within the first hour. Cell viability studies revealed no impact of modification. Accordingly, the novel preactivated thiolated Eudragit-derivative seems to be a promising excipient for intestinal drug delivery. PMID- 25019182 TI - Calcium-sensing receptor gene polymorphisms in patients with calcium urolithiasis: a systematic review. AB - BACKGROUND: Calcium-sensing receptor gene (CaSR) might be a strong component of the complex genetic background regulating calcium excretion and stone formation in kidney. The polymorphisms in different parts of the gene could be associated with calcium stone formation. OBJECTIVE: The individual studies indicate a correlation between CaSR gene polymorphisms and urolithiasis but not sufficient to draw a precise result. We aimed to search literature to come to a reliable conclusion through a systematic review. MATERIALS AND METHODS: We have serached individiual studies regarding the issue and high quality reviews. We assessed all the studies to draw a conclusion. CONCLUSION: The genetic background of the neprolithiasis is an interesting issue deserving to be disscussed on. Regading genes of which, CaSR gene polymorphisms is the leading one, are studied in many individual studies but they are not sufficient to have a precise conclusion. Well oriented and documented, phenotypically homogenous large cohort studies are needed for further evaluation. PMID- 25019184 TI - Herpes zoster meningoencephalitis complicated with peripheral vascular disease: an uncommon presentation of a common disease. AB - Herpes zoster is reactivation of the varicella zoster virus that has remained dormant in the dorsal root ganglia since an earlier episode of chickenpox. Herpes zoster has variable clinical presentations, but meningo-encephalitis is not frequently encountered. There is growing evidence of both large and small vessel involvement in immunocompetent and immunocompromised patients, in contrast with the previous opinion that immunocompetent patients have vasculopathy in the large vessels while immunosuppressed patients have vasculopathy in the small vessels. We present the case of a patient in whom herpes zoster meningoencephalitis was complicated with multifocal vasculopathy with peripheral vascular disease; this is an unusual co-occurrence. PMID- 25019183 TI - Progesterone-targeted magnetic resonance imaging probes. AB - Determination of progesterone receptor (PR) status in hormone-dependent diseases is essential in ascertaining disease prognosis and monitoring treatment response. The development of a noninvasive means of monitoring these processes would have significant impact on early detection, cost, repeated measurements, and personalized treatment options. Magnetic resonance imaging (MRI) is widely recognized as a technique that can produce longitudinal studies, and PR-targeted MR probes may address a clinical problem by providing contrast enhancement that reports on PR status without biopsy. Commercially available MR contrast agents are typically delivered via intravenous injection, whereas steroids are administered subcutaneously. Whether the route of delivery is important for tissue accumulation of steroid-modified MRI contrast agents to PR-rich tissues is not known. To address this question, modification of the chemistry linking progesterone with the gadolinium chelate led to MR probes with increased water solubility and lower cellular toxicity and enabled administration through the blood. This attribute came at a cost through lower affinity for PR and decreased ability to cross the cell membrane, and ultimately it did not improve delivery of the PR-targeted MR probe to PR-rich tissues or tumors in vivo. Overall, these studies are important, as they demonstrate that targeted contrast agents require optimization of delivery and receptor binding of the steroid and the gadolinium chelate for optimal translation in vivo. PMID- 25019185 TI - Gender specific issues in hereditary ocular disorders. AB - This review is intended to summarize the current knowledge from basic science and clinical medical literature cited within PubMed that pertain to gender-related factors and affect those individuals with hereditary ocular disorders. We consider gender-related biological factors that (a) affect disease onset and progression, (b) gender differences for major X-linked ocular disorders, (c) gender-specific conditions, (d) medications that may influence genetic eye disorders, and finally, (e) gender-related issues that influence the management and quality of life of these patients. Several studies have demonstrated the manner in which sex-related hormones in animal models are capable of influencing cell pathway and survival that are likely to affect hereditary eye disorders. There are very few clinical studies that provide compelling evidence for gender differences in human ocular conditions, other than for a number of X-linked disorders. Disease expression for X-linked disorders may be impacted by genetic mechanisms such as lyonization or uniparental disomy. Clinical evidence regarding the impact of gender-related medical conditions and therapies on eye conditions is extremely limited and primarily based on anecdotal evidence. Gender-specific factors may play a major role in the underlying biological pathways that influence the onset, rate of progression, and clinical findings associated with ocular genetic conditions. Clinicians need to be aware of the variable phenotypes observed in female carriers of X-linked disorders of gender specific issues, many of which are inadequately addressed in the current literature. Clinicians need to be sensitive to gender differences in social, cultural, and religious systems and they should also be aware of how their own gender biases may influence how they counsel patients. Finally, it is clear that the lack of effective clinical studies in this area creates an opportunity for future research that will have real benefits for these patients. PMID- 25019186 TI - Paternal age and genetic load. AB - The incidence of base substitutions in humans increases with the age of the father, which shows up as an increased incidence of mutational disorders in the children of older fathers. There is a less obvious implication: an extended period of high average paternal age in a population will lead to increased genetic load. We mention some societies that have had high average paternal age for many generations. This may explain some surprising regional differences in recent measurements of deleterious mutations. High average paternal age also influences life history evolution, strengthening selection against mortality in late life while weakening selection against child mortality. PMID- 25019187 TI - The human environment and the vitamin D compromise: Scotland as a case study in human biocultural adaptation and disease susceptibility. AB - Year-round human habitation of environments with highly seasonal regimes of ultraviolet B radiation (UVB) depended on adaptive complexes of biological and cultural traits to ensure adequacy of vitamin D. Perturbations of such adaptive complexes resulting from changes in the physical environment, human behavior and culture, or both have had unexpected and untoward consequences for health. Scotland is an excellent case study of the changing nature of human biocultural adaptation to low-UVB environments. Occupation of Scotland after the last Pleistocene glaciation event about 14,000 YBP was made possible by maximally depigmented skin, which facilitated cutaneous biosynthesis of vitamin D3, and by a diet that emphasized foods rich in vitamin D. Changes in human subsistence and diet began with the introduction of agriculture and grazing about 5,000 YBP and accelerated greatly in the last 200 years through industrialization and urbanization. The resulting changes in domiciles, patterns of daily activity and behavior, and diet have led to reduced exposure to UVB and reduced consumption of vitamin D-rich foods. This has perturbed the "vitamin D compromise," an adaptive complex established in Scotland during the Mesolithic and Neolithic. We describe the UVB environment of Scotland from remotely sensed data and combine these data with information from the archaeological record to describe the vitamin D compromise in Scotland. Changes in human exposure to UVB and vitamin D consumption, which occurred as the result of urbanization and the dietary shift away from the consumption of oily fish, are traced. Vitamin D deficiency contributes to increased disease prevalence in Scotland, including that of the autoimmune disease multiple sclerosis, a debilitating neurodegenerative disease caused by demyelination of the central nervous system. These conditions have created an "imperfect storm" of poor health that should command the attention of public health experts and policy makers. PMID- 25019188 TI - Evaluation of the Bayesian method to derive migration patterns from changes in surname distributions over time. AB - Known migration in The Netherlands between the periods 1950-1969 and 2007, for 4.5 million individuals, was used to estimate the origin of migration by means of a Bayesian method on the basis of surname distributions in these two periods. Results of the method depend on the geographic specificity of the surnames and tend to be positioned between population density and actual probability of migration origin. An optimum in the correlation between estimated and actual percentages of origin of migration, and their differentiation as expressed by the correlation between the estimated and actual entropy across 40 distinguished areas, was found after a few iterations. The optimal correlation was 0.806 (Spearman), which shows that the Bayesian method provides a reasonable proxy of the rank order of a migrant's origin. PMID- 25019189 TI - Selection variability for Arg48His in alcohol dehydrogenase ADH1B among Asian populations. AB - The variant His at codon 48 of the alcohol dehydrogenase gene (ADH1B) results in more efficient ethanol metabolism than with the "typical" codon 48Arg. In this study we introduced selection properties of Arg48His genotypes of ADH1B and estimated fitness in four ethnic-geographical clusters in Asia. Population genetics models were employed that derive observed gene frequencies from fitness relationships among genotypes, to infer the selection pattern of polymorphisms in an indirect manner. The data were analyzed using the model of "complete stationary distribution" by Wright that takes into account random genetic drift, pressure of migrations, mutations, and selection as influential factors of gene frequency. We found that the different population groups showed some variation in the types of selection for Arg48His. Han Chinese from eastern and southeastern China and the Japanese and Korean populations showed stabilizing selection, while the groups from Central Asian and Indochina showed divergent selection. However, all the groups demonstrated a strong positive selection for Arg48His. PMID- 25019190 TI - A Review of the ischium-pubis index: accuracy,reliability, and common errors. AB - This article examines the utility of the ischium-pubic index (IPI), a sexing technique that compares the lengths of pubis and ischium. The ratio was adapted by Washburn from a primate index devised by Schultz and was tested by Washburn on documented remains from the Hamann-Todd Human Osteological Collection. The IPI is used by forensic investigators, and indeed, the method is found in standard forensic textbooks and thus appears to be valid to early-stage researchers. However, its reliability has been questioned by physical anthropologists almost from its inception due to the intrinsic subjectivity of locating the base point from which both lengths are taken. In addition, at least one variation of the original technique is found in the literature, which alters the base point profoundly. To explore both the original method and the ramifications of altering the base point, in this article the IPI is calculated from os coxae recovered from the Mary Rose, a 16th-century English warship lost in a documented disaster; the sample is assumed to be from males. Using the original index, 20.4% of individuals (11 of 54) or, viewing the remains as commingled, 15.5% of individual pelves (15 of 97) were misclassified. Results with the base point shifted were disastrous: 95.5% (21 of 22) individuals and 91.4% (32 of 35) pelves were misclassified. Accuracy may be influenced by the technician's expertise; however, when the original methodology is altered, the results become meaningless. This article aims to promote more careful reading of our sources and to suggest that the IPI is not appropriate as a tool for sexing forensic remains. PMID- 25019192 TI - Sibling composition and household room sharing are associated with menarcheal status among rural Bengalee girls of West Bengal, India. AB - Menarche, the first menstruation, is one of the most important events in a woman's reproductive life. The timing of menarche varies across populations and depends upon social interaction and family environment. It is also associated with several biological as well as social factors. The objective of this study was to explore the relationship between sibling composition and age at menarche (AAM) and to assess the association between the pattern of room sharing with family members of different sexes and menarcheal occurrence among rural Bengalee girls from West Bengal, India. The total sample comprised 577 Bengalee girls, 6 17 years of age, from various schools and madrasas in two blocks of the Nadia District of West Bengal State in India. The effects of room sharing on the occurrence of menarche, and of sibling composition on the menarcheal age, were assessed by analyses of covariance. The room-sharing pattern had a significant effect on menarcheal status (yes/no): a significantly higher percentage of girls who shared a room with the mother and/or sisters were postmenarcheal compared with those who shared a room with male family members. AAM did not differ significantly between girls having brothers or sisters. However, sibling order had a significant impact on AAM. Girls who had a younger sibling only (brother or sister) had a higher mean AAM, and girls who had both younger brothers and younger sisters had significantly higher mean AAM, than did the girls who had no younger sibling (singletons or having only elder siblings). There was no difference in AAM between the girls who had younger sister(s) and those who had younger brother(s). These differences were also independent of body mass index. In conclusion, the room sharing characteristics and the sibling sex composition, particularly their order, had significant effect on menarche in adolescent rural Bengalee girls. PMID- 25019191 TI - Reevaluating a model of gender-biased gene flow among Sub-Saharan Hunter gatherers and farmers. AB - In a previous study, we proposed a model for genetic admixture between African hunter-gatherers and food producers, in which we integrated demographic and genetic aspects together with ethnographic knowledge (Destro-Bisol et al. 2004b). In that study it was possible to test the model only using genetic information from widely dispersed and genetically heterogeneous populations. Here we reevaluate the congruence between the model and patterns of genetic variation using an anthropologically and geographically more homogeneous data set that includes Pygmies and farmers from Cameroon, Congo, and the Central African Republic. As implied by the model, the ratios of mtDNA to Y chromosome Nm estimates (effective population size, N, times the migration rate, m; 0.154 in Pygmies and 6.759 in farmers), support an asymmetric gene flow, with a higher Bantu-to-Pygmy gene flow for paternal than for maternal lineages, and vice versa for farmers. Analyses of intra- and interpopulation genetic variation further support the above observation, showing a prevailing effect of genetic drift on maternal lineages and gene flow on paternal lineages among Pygmies, and an opposite pattern among farmers. We also detected differences between patterns for classical and molecular measures of Y chromosome intrapopulation variation, which likely represent signatures of the introgression of Bantu lineages into the gene pool of Pygmy populations. On the whole, our results seem to reflect differences in the demographic history and the degree of patrilocality and polygyny between the two population groups, thus providing further support to our microevolutionary model in an anthropologically coherent framework. PMID- 25019193 TI - Spousal choice by height in an urban middle-class Japanese population. PMID- 25019194 TI - A longitudinal study of digit ratio (2D:4D) and its relationships with adult running speed in Jamaicans. PMID- 25019197 TI - Thylakoid direct photobioelectrocatalysis: utilizing stroma thylakoids to improve bio-solar cell performance. AB - Thylakoid membranes from spinach were separated into grana and stroma thylakoid fractions which were characterized by several methods (pigment content, protein gel electrophoresis, photosystem activities, and electron microscopy analysis) to confirm that the intact thylakoids were differentiated into the two domains. The results of photoelectrochemical experiments showed that stroma thylakoid electrodes generate photocurrents more than four times larger than grana thylakoids (51 +/- 4 nA cm(-2) compared to 11 +/- 1 nA cm(-2)). A similar trend was seen in a bio-solar cell configuration with stroma thylakoids giving almost twice the current (19 +/- 3 MUA cm(-2)) as grana thylakoids (11 +/- 2 MUA cm(-2)) with no change in open circuit voltage. PMID- 25019196 TI - Gamma-retroviral vector design for the co-expression of artificial microRNAs and therapeutic proteins. AB - To generate gamma-retroviral vectors for stable conjoint expression of artificial microRNAs (amiR) and therapeutic genes in primary human lymphocytes, and to identify the design parameters that are key for successful vector generation. Gamma-retroviral vectors were designed to co-express both amiRs and a linked reporter gene, truncated CD34 (tCD34). Artificial miRs based on microRNAs miR-16, miR-142, miR-146b, miR-150, miR155, and miR-223 were inserted into sites within the intron of the vector and tested for tCD34 expression by flow cytometry (FACS). Different constructs were assembled with amiRs targeted to knockdown expression of suppressor of cytokine signaling 1 (SOCS1) or programmed cell death 1 (PDCD1, PD-1). Three of the six amiRs maintained tCD34 expression. Expansion of primary human T cells transduced with these amiR vectors, as well as transgene expression, were equivalent to control engineered T cells over a 40-day period. Knockdown of SOCS1 RNA and PD-1 expression by FACS was shown to vary between constructs, dependent on either the specific short interfering RNA sequence used in the amiR, or the microRNA backbone and location in the vector intron. Gamma retroviral vectors that both efficiently knockdown endogenous gene expression and maintain linked transgene production can be produced, but empirical vector evaluations were best suited for optimal construct analysis. PMID- 25019198 TI - Asymmetric aneuploidy in mesenchymal stromal cells detected by in situ karyotyping and fluorescence in situ hybridization: suggestions for reference values for stem cells. AB - Cytogenetic testing is important to ensure patient safety before therapeutic application of mesenchymal stromal cells (MSCs). However, the standardized methods and criteria for the screening of chromosomal abnormalities of MSCs have not yet been determined. We investigated the frequency of cytogenetic aberrations in MSCs using G-banding and fluorescence in situ hybridization (FISH) and suggest reference values for aneuploidy in MSCs. Cytogenetic analysis was performed on 103 consecutive cultures from 68 MSCs (25 adipose-origin, 20 bone marrow-origin, 18 cord blood-origin, and 5 neural stem cells; 8 from adipose tissue of patients with breast cancer and 60 from healthy donors). We compared the MSC aneuploidy patterns with those of hematological malignancies and benign hematological diseases. Interphase FISH showed variable aneuploid clone proportions (1%-20%) in 68 MSCs. The aneuploidy patterns were asymmetric, and aneuploidy of chromosomes 16, 17, 18, and X occurred most frequently. Clones with polysomy were significantly more abundant than those with monosomy. The cutoff value of maximum polysomy rates (upper 95th percentile value) was 13.0%. By G-banding, 5 of the 61 MSCs presented clonal chromosomal aberrations. Aneuploidy was asymmetric in the malignant hematological diseases, while it was symmetric in the benign hematological diseases. We suggest an aneuploidy cutoff value of 13%, and FISH for aneuploidy of chromosomes 16, 17, 18, and X would be informative to evaluate the genetic stability of MSCs. Although it is unclear whether the aneuploid clones might represent the senescent cell population or transformed cells, more attention should be focused on the safety of MSCs, and G-banding combined with FISH should be performed. PMID- 25019199 TI - Application of solubility parameters in 1,3:2,4-bis(3,4 dimethylbenzylidene)sorbitol organogel in binary organic mixtures. AB - The gelation behavior of 1,3:2,4-bis(3,4-dimethylbenzylidene)sorbitol (DMDBS) in binary solvents has been systematically investigated. DMDBS is soluble in DMSO and insoluble in toluene (apolar) or 1-propanol (polar). When DMSO is added to a poor solvent at a certain volume fraction, DMDBS forms an organogel in the mixed solvent. With increasing DMSO content, the minimum gelation concentration increases and the gel-to-sol transition temperature decreases in both systems. However, compared with those in toluene-DMSO mixtures, the gelation ability and thermal stability are better in 1-propanol-DMSO mixtures. Scanning electron microscopy images reveal that the gelators aggregate to form three-dimensional networks. X-ray diffraction shows that the gel has a lamellar structure, which is different from the structure of the precipitate. Fourier transform infrared results reveal H-bonding is the main driving force for self-aggregation and indicate that stronger H-bonding interactions exist between gelators in 1 propanol-DMSO mixtures in contrast with toluene-DMSO mixtures. Attempts have been taken to correlate solvent parameters to gelation behavior in binary solvents. A Teas plot exhibits distinctly different solvent zones in the studied mixed solvents. The polar parameter (deltap) indicates a narrow favorable domain for gel formation in the range of 1.64-7.99 MPa(1/2) for some apolar solvent-DMSO mixtures. The hydrogen-bonding parameter (deltah) predicts that gelation occurs for values of 14.00-16.50 MPa(1/2) for some polar solvent-DMSO mixtures. The result may have potential applications in predicting the gelation behavior of 1,3:2,4-di-O-benzylidene-d-sorbitol derivatives in mixed solvents. PMID- 25019201 TI - A pharmacokinetic evaluation of oral edivoxetine hydrochloride for the treatment of attention deficit-hyperactivity disorder. AB - INTRODUCTION: The majority of available therapeutics to treat attention deficit/hyperactivity disorder (ADHD) are formulations of either methylphenidate or amphetamine. However, psychostimulants may not be suitable options for many patients. The availability of novel pharmacological agents to treat ADHD is highly desirable. Edivoxetine hydrochloride (LY2216684) is a highly selective and potent norepinephrine reuptake inhibitor under clinical development for ADHD. AREAS COVERED: This paper provides an overview of what is presently known of the pharmacokinetics (PK) of edivoxetine based on available studies in healthy volunteers, in subjects with compromised renal and hepatic functioning and in children and adolescents. EXPERT OPINION: Available data suggest edivoxetine is safe and well tolerated. Edivoxetine is readily absorbed with metabolism proceeding through the CYP hepatic enzyme pathway, with CYP2D6 and CYP3A4 playing the most prominent roles. The tmax is ~ 2 h post-dose, and the plasma t1/2 is ~ 4 - 6 h irrespective of the dose. Pharmacokinetic parameters are not substantially different between children and adults. Edivoxetine may be a promising non stimulant therapeutic agent. However, at present, there is insufficient data available to permit a thorough analysis of its potential place in ADHD pharmacotherapy, or how its PK and pharmacodynamics may differ in clinically meaningful ways from existing agents. PMID- 25019202 TI - Risk of cerebral palsy among the offspring of immigrants. AB - BACKGROUND: Cerebral palsy (CP) has a multifactorial etiology, and placental vascular disease may be one major risk factor. The risk of placental vascular disease may be lower among some immigrant groups. We studied the association between immigrant status and the risk of CP. METHODS: We conducted a population based retrospective cohort study of all singleton and twin livebirths in Ontario between 2002-2008, and who survived >=28 days after birth. Each child was assessed for CP up to age 4 years, based on either a single inpatient or >=2 outpatient pediatric diagnoses of CP. Relative to non-immigrants (n = 566,668), the risk of CP was assessed for all immigrants (n = 177,390), and further evaluated by World region of origin. Cox proportional hazard ratios (aHR) were adjusted for maternal age, income, diabetes mellitus, obesity, tobacco use, Caesarean delivery, year of delivery, physician visits, twin pregnancy, preterm delivery, as well as small- and large-for-gestational age birthweight. RESULTS: There were 1346 cases of CP, with a lower rate among immigrants (1.45 per 1000) than non-immigrants (1.92 per 1000) (aHR 0.77, 95% confidence interval [CI] 0.67 to 0.88). Mothers from East Asia and the Pacific (aHR 0.54, 95% CI 0.39 to 0.77) and the Caribbean (aHR 0.58, 95% CI 0.37 to 0.93) were at a significantly lower risk of having a child with CP. Whether further adjusting for preeclampsia, gestational hypertension, placental abruption or placental infraction, or upon using a competing risk analysis that further accounted for stillbirth and neonatal death, these results did not change. CONCLUSIONS: Immigration and ethnicity appear to attenuate the risk of CP, and this effect is not fully explained by known risk factors. PMID- 25019204 TI - Photophysical properties of trans-platinum acetylide complexes featuring N heterocyclic carbene ligands. AB - A series of trans-N-heterocyclic carbene (NHC) platinum(ii) acetylide complexes of the form (ICy)2Pt(R)2 (where ICy = 1,3-bis-(cyclohexyl)imidazol-2-ylidene and R = 1-Ethynyl-4-(phenylethynyl)benzene (PE2), 2-(9,9-Diethyl-9H-fluoren-7 yl)benzo[d]thiazole (BTF), and 9,9-Diethyl-7-ethynyl-N,N-diphenyl-9H-fluoren-2 amine (DPAF), respectively), were synthesized via Hagihara reaction of the unprotected aryl-acetylide ligands with trans-(ICy)2PtCl2 () in 47-73% yield. Precursor was generated in a one-pot synthesis via formation of a silver carbene precursor followed by transmetallation, and was obtained in high yield (95%). The single-crystal X-ray structures of , were determined and analyzed. The photophysical properties of were compared to their respective tributyl phosphine (PBu3) analogues. The optical properties of the series were studied by UV-Vis spectroscopy, photoluminescence spectroscopy, nanosecond transient absorption spectroscopy, and open aperture nanosecond z-scan. Coupling of the organic chromophores to the platinum center affords efficient intersystem crossing as concluded by the complexes' low fluorescence quantum yields, efficient phosphorescence and intense T1 - Tn absorption. Open aperture z-scan with 606 nm, 10 ns laser pulses showed comparable optical attenuation relative to a standard sample of (PBu3)2Pt(DPAF)2 (). Pulse limiting was achieved via a dual-mechanism of two-photon absorption (2PA) coupled with excited-state absorption (ESA). TD DFT Computations were also employed for to give greater insight into the nature of the singlet-singlet electronic transitions. PMID- 25019203 TI - MiR-20a inhibits cutaneous squamous cell carcinoma metastasis and proliferation by directly targeting LIMK1. AB - BACKGROUND: MicroRNA-20a (miR-20a) plays a key role in tumorigenesis and progression. But its function is reverse in different kinds of malignant tumor, and its role and mechanism in cutaneous squamous cell carcinoma (CSCC) remains unclear. OBJECT: To determine the miR-20a's roles in CSCC and confirm whether LIMK1 is a direct target gene of miR-20a. METHODS: First miR-20a and LIMK1 expression levels were detected in six pairs of CSCC tissues and corresponding normal skin by qRT-PCR. Then MTT assays and colony formation assays were performed to evaluate the impact of miR-20a on cell proliferation. In addition, scratch migration assays and transwell invasion assays were performed to check miR-20a's effect on cell metastasis. Since LIMK1 (LIM kinase-1) was predicted as a target gene of miR-20a, the changes of LIMK1 protein and mRNA were measured by western blot and qRT-RCR methods after miR-20a overexpression. Moreover the dual reporter gene assay was performed to confirm whether LIMK1 is a direct target gene of miR-20a. Finally LIMK1 mRNA and miR-20a in other 30 cases of CSCC pathological specimens were determined and a correlation analysis was evaluated. RESULTS: The miR-20a significantly low-expressed in CSCC tissues compared with that in matched normal tissues while LIMK1 has a relative higher expression. MiR 20a inhibited A431 and SCL-1 proliferation and metastasis. Both of LIMK1 protein and mRNA levels were downregulated after miR-20a overexpression. The dual reporter gene assays revealed that LIMK1 is a direct target gene of miR-20a. Furthermore, qRT-PCR results of LIMK1 mRNA and miR-20a in 30 cases of CSCC pathological specimens showed miR-20a is inversely correlated with LIMK1 expression. CONCLUSION: Our study demonstrated that miR-20a is involved in the tumor inhibition of CSCC by directly targeting LIMK1 gene. This finding provides potential novel strategies for therapeutic interventions of CSCC. PMID- 25019205 TI - Controls on the entrainment of juvenile Chinook Salmon (Oncorhynchus tshawytscha) into large water diversions and estimates of population-level loss. AB - Diversion of freshwater can cause significant changes in hydrologic dynamics and this can have negative consequences for fish populations. Additionally, fishes can be directly entrained into diversion infrastructure (e.g. canals, reservoirs, pumps) where they may become lost to the population. However, the effect of diversion losses on fish population dynamics remains unclear. We used 15 years of release and recovery data from coded-wire-tagged juvenile Chinook Salmon (Oncorhynchus tshawytscha) to model the physical, hydrological and biological predictors of salvage at two large water diversions in the San Francisco Estuary. Additionally, entrainment rates were combined with estimates of mortality during migration to quantify the proportion of total mortality that could be attributed to diversions. Statistical modeling revealed a strong positive relationship between diversion rate and fish entrainment at both diversions and all release locations. Other significant relationships were specific to the rivers where the fish were released, and the specific diversion facility. Although significant relationships were identified in statistical models, entrainment loss and the mean contribution of entrainment to total migration mortality were low. The greatest entrainment mortality occurred for fish released along routes that passed closest to the diversions and certain runs of Chinook Salmon released in the Sacramento River suffered greater mortality but only at the highest diversion rates observed during the study. These results suggest losses at diversions should be put into a population context in order to best inform effective management of Chinook Salmon populations. PMID- 25019206 TI - Chronic caffeine treatment protects against experimental autoimmune encephalomyelitis in mice: therapeutic window and receptor subtype mechanism. AB - Chronic treatment with caffeine, the most widely consumed psychoactive drug and a non-selective antagonist of adenosine receptors, can protection against myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In this study, we investigated the mechanism underlying caffeine-mediated neuroprotection against EAE by determining the effective therapeutic time-window of caffeine and the involvement of adenosine A2A and A1 receptor. We found that administration of caffeine during the effector phase (10 -> 20 days post-immunization, d.p.i., corresponding to appearance of neurological deficits) but not the induction phase (0 -> 10 d.p.i., before the appearance of ascending flaccid paralysis) significantly ameliorated EAE-induced neurobehavioral deficits, reduced the infiltration of inflammatory cells into the spinal cord and reduced the demyelination of spinal cord. Furthermore, genetic deletion of the A2AR exacerbated MOG-induced brain damage and caffeine administering to A2AR knockout mice reversed this EAE pathology by acting at non-A2AR target. The protective effect of chronic caffeine treatment was associated with up-regulation of brain A1R (but not A2AR). The identification of the effective therapeutic window of caffeine at the effector phase and clarification of non-A2AR target (likely A1R) in caffeine action in EAE models advance the therapeutic prospective that chronic caffeine consumption may attenuate brain damage in MS. PMID- 25019207 TI - The cinnamyl alcohol dehydrogenase gene family in melon (Cucumis melo L.): bioinformatic analysis and expression patterns. AB - Cinnamyl alcohol dehydrogenase (CAD) is a key enzyme in lignin biosynthesis. However, little was known about CADs in melon. Five CAD-like genes were identified in the genome of melons, namely CmCAD1 to CmCAD5. The signal peptides analysis and CAD proteins prediction showed no typical signal peptides were found in all CmCADs and CmCAD proteins may locate in the cytoplasm. Multiple alignments implied that some motifs may be responsible for the high specificity of these CAD proteins, and may be one of the key residues in the catalytic mechanism. The phylogenetic tree revealed seven groups of CAD and melon CAD genes fell into four main groups. CmCAD1 and CmCAD2 belonged to the bona fide CAD group, in which these CAD genes, as representative from angiosperms, were involved in lignin synthesis. Other CmCADs were distributed in group II, V and VII, respectively. Semi-quantitative PCR and real time qPCR revealed differential expression of CmCADs, and CmCAD5 was expressed in different vegetative tissues except mature leaves, with the highest expression in flower, while CmCAD2 and CmCAD5 were strongly expressed in flesh during development. Promoter analysis revealed several motifs of CAD genes involved in the gene expression modulated by various hormones. Treatment of abscisic acid (ABA) elevated the expression of CmCADs in flesh, whereas the transcript levels of CmCAD1 and CmCAD5 were induced by auxin (IAA); Ethylene induced the expression of CmCADs, while 1-MCP repressed the effect, apart from CmCAD4. Taken together, these data suggested that CmCAD4 may be a pseudogene and that all other CmCADs may be involved in the lignin biosynthesis induced by both abiotic and biotic stresses and in tissue-specific developmental lignification through a CAD genes family network, and CmCAD2 may be the main CAD enzymes for lignification of melon flesh and CmCAD5 may also function in flower development. PMID- 25019208 TI - Tautomerisation of thymine acts against the Huckel 4N + 2 rule. The effect of metal ions and H-bond complexations on the electronic structure of thymine. AB - The stability and aromaticity of thirteen known thymine tautomers were studied in the gas phase at the B3LYP/6-311++G(2d,2p) computational level. It was found that they do not follow the Huckel 4N + 2 rule when the energetic criterion is considered, but they follow it when aromaticity indices, such as NICS, HOMA and the sum of the Wiberg bond indices, are applied. It was shown that the stability of a given tautomer is strongly dependent on the number of C[double bond, length as m-dash]O groups attached to the ring. The most stable tautomer i.e. with two carbonyl groups exhibits low pi-electron delocalization (HOMA = 0.490, NICS(0) = 1.5). Its stability results from specific interactions between N(delta-)H(delta+) and C(delta+)O(delta-) bond dipoles. A qualitative rule, which implies an increase in stability and a loss of aromaticity with increasing number of C[double bond, length as m-dash]O groups, holds in the case of thymine tautomers. Effects of intermolecular interactions (H-bonding and metal ion complexation) on the geometry and pi-electron structure were analyzed for the five most stable tautomers with the following partners: HF/F(-) and Li(+)/Na(+)/K(+). The magnitude of these effects strongly depends on the site and type of intermolecular interaction. The electronic structure of the most aromatic tautomers is more weakly influenced by external perturbations such as H-bonding and is almost entirely resistant to metal complexation. PMID- 25019209 TI - An examination of resveratrol's mechanisms of action in human tissue: impact of a single dose in vivo and dose responses in skeletal muscle ex vivo. AB - The current study tested the hypothesis that a single, moderate dose of RSV would activate the AMPK/SIRT1 axis in human skeletal muscle and adipose tissue. Additionally, the effects of RSV on mitochondrial respiration in PmFBs were examined. Eight sedentary men (23.8+/-2.4 yrs; BMI: 32.7+/-7.1) reported to the lab on two occasions where they were provided a meal supplemented with 300 mg of RSV or a placebo. Blood samples, and a muscle biopsy were obtained in the fasted state and again, with the addition of an adipose tissue biopsy, two hours post prandial. The effect of RSV on mitochondrial respiration was examined in PmFBs taken from muscle biopsies from an additional eight men (23.4+/-5.4 yrs; BMI: 24.4+/-2.8). No effect of RSV was observed on nuclear SIRT1 activity, acetylation of p53, or phosphorylation of AMPK, ACC or PKA in either skeletal muscle or adipose tissue. A decrease in post absorptive insulin levels was accompanied by elevated skeletal muscle phosphorylation of p38 MAPK, but no change in either skeletal muscle or adipose tissue insulin signalling. Mitochondrial respiration in PmFBs was rapidly inhibited by RSV at 100-300 uM depending on the substrate examined. These results question the efficacy of a single dose of RSV at altering skeletal muscle and adipose tissue AMPK/SIRT1 activity in humans and suggest that RSV mechanisms of action in humans may be associated with altered cellular energetics resulting from impaired mitochondrial ATP production. PMID- 25019210 TI - High-grade cervical lesions among women attending a reference clinic in Brazil: associated factors and comparison among screening methods. AB - BACKGROUND: Although screening for cervical cancer is recommended for women in most countries, the incidence of cervical cancer is greater in developing countries. Our goal was to determine the prevalence and factors associated with high-grade lesions/cervical cancer among women attending a reference clinic in Brazil and evaluate the correlation of histology with cytology, colposcopy and the high-risk HPV (HR-HPV) tests. METHODS: A cross-sectional study of women attending a colposcopy clinic was carried out. The patients were interviewed to collect demographic, epidemiological and clinical data. Specimens were collected for cervical cytology, Chlamydia trachomatis and HPV testing using the Hybrid Capture (HC) and PCR tests. Colposcopy was performed for all patients and biopsy for histology when cell abnormalities or cervical intraepithelial neoplasia (CIN) were present. RESULTS: A total of 291 women participated in the study. The median age was 38 years (DIQ: 30-48 years). The prevalence of histologically confirmed high-grade lesions/cervical cancer was 18.2% (95%, CI: 13.8%-22.6%), with 48 (16.5%) cases of CIN-2/CIN-3 and 5 (1.7%) cases of invasive carcinoma. In the final logistic regression model, for ages between 30 and 49 years old [OR = 4.4 (95%: 1.01-19.04), history of smoking [OR = 2.4 (95%, CI: 1.14-5.18)], practice of anal intercourse [OR = 2.4 (95%, CI: 1.10-5.03)] and having positive HC test for HR-HPV [OR = 11.23 (95%, CI: 4 0.79-26, 36)] remained independently associated with high-grade lesions/cervical cancer. A total of 64.7% of the cases CIN-3?Ca in situ were related to HPV-16. Non-oncogenic HPV were only found in CIN 1 biopsy results. Compared to histology, the sensitivity of cytology was 31.8%, the specificity 95.5%; the sensitivity of colposcopy for high-grade lesions/cervical cancer was 51.0%, specificity was 91.4% and the concordance with HPV testing was high. CONCLUSIONS: The results confirm an association of HR-HPV with precursor lesions for cervical cancer. These data emphasize that cytological screening to detect precursor lesions is still important in some regions and that HR-HPV should be included for screening. PMID- 25019211 TI - TGF beta1 mediates epithelial mesenchymal transition via beta6 integrin signaling pathway in breast cancer. AB - BACKGROUND: To understand the function of beta6 integrin and elucidate its signaling pathways in TGF-beta-induced EMT in breast cancer. METHODS: The interactions between TGF-beta1 and beta6 integrin were measured by coimmunoprecipitation. The EMT responses, phospherlation of PI3K/Akt and COX-2 expression were determined by real-time PCR, transwell assay, and western blot after the blockage of beta6 integrin. RESULTS: TGF-beta1 and beta6 integrin could bind with each other. Blockage of beta6 integrin rescued TGF-beta1-induced EMT phenotype and reduced expression of COX-2 via dephosphorylation of PI3K/Akt. CONCLUSIONS: beta6 integrin plays a critical role in TGF-beta1-induced EMT and overexpression of COX-2 in breast cancer. PMID- 25019212 TI - Betulinic acid-induced cytotoxicity in human breast tumor cell lines MCF-7 and T47D and its modification by tocopherol. AB - Betulinic acid (BA) has been shown to cause apoptosis in neuroblastoma and melanoma cell lines. We evaluated the cytotoxicity of BA in two breast cancer cell lines MCF-7 and T47D differing in their p53 status. Treatment with BA resulted in a dose dependent inhibition of cell proliferation and induction of apoptosis. This indicates p53-independent apoptotic pathway, because response of both p53 mutant and wild type cell line were found unaffected after treatment with pifithrin-alpha, an inhibitor of p53. Cells were significantly protected when treated by tocopherol suggesting involvement of membrane centered lipid peroxidation-mediated mechanism in BA-induced apoptosis. PMID- 25019214 TI - MKK6 is upregulated in human esophageal, stomach, and colon cancers. AB - Expression analysis of MKK6 protein in solid tumors has never been investigated. Here, we report systematic analysis of MKK6 protein in different types of human tumor samples using western blotting and immunofluorescence techniques. We observed significant increase in the expression of MKK6 in Esophageal, Stomach, and Colon cancers as compared to controls. Results were alternately confirmed by Immunofluorescence studies. Upregulation of MKK6 protein is indicative of its role in human cancers and could possibly be used as a novel diagnostic or prognostic marker in these cancers. PMID- 25019213 TI - Evaluation of eight plasma proteins as candidate blood-based biomarkers for malignant gliomas. AB - Eight brain-derived proteins were evaluated regarding their potential for further development as a blood-based biomarker for malignant gliomas. Plasma levels for glial fibrillary acidic protein, neurogranin, brain-derived neurotrophic factor, intracellular adhesion molecule 5, metallothionein-3, beta-synuclein, S100 and neuron specific enolase were tested in plasma of 23 patients with high-grade gliomas (WHO grade IV), 11 low-grade gliomas (WHO grade II), and 15 healthy subjects. Compared to the healthy controls, none of the proteins appeared to be specific for glioblastomas. However, the data are suggestive of higher protein levels in gliosarcomas (n = 2), which may deserve further exploration. PMID- 25019215 TI - Comparative computational study of interaction of C60-fullerene and tris-malonyl C60-fullerene isomers with lipid bilayer: relation to their antioxidant effect. AB - Oxidative stress induced by excessive production of reactive oxygen species (ROS) has been implicated in the etiology of many human diseases. It has been reported that fullerenes and some of their derivatives-carboxyfullerenes-exhibits a strong free radical scavenging capacity. The permeation of C60-fullerene and its amphiphilic derivatives-C3-tris-malonic-C60-fullerene (C3) and D3-tris-malonyl C60-fullerene (D3)-through a lipid bilayer mimicking the eukaryotic cell membrane was studied using molecular dynamics (MD) simulations. The free energy profiles along the normal to the bilayer composed of 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) for C60, C3 and D3 were calculated. We found that C60 molecules alone or in clusters spontaneously translocate to the hydrophobic core of the membrane and stay inside the bilayer during the whole period of simulation time. The incorporation of cluster of fullerenes inside the bilayer changes properties of the bilayer and leads to its deformation. In simulations of the tris-malonic fullerenes we discovered that both isomers, C3 and D3, adsorb at the surface of the bilayer but only C3 tends to be buried in the area of the lipid headgroups forming hydrophobic contacts with the lipid tails. We hypothesize that such position has implications for ROS scavenging mechanism in the specific cell compartments. PMID- 25019216 TI - Temperature-activated layer-breathing vibrations in few-layer graphene. AB - We investigated the low-frequency Raman spectra of freestanding few-layer graphene (FLG) at varying temperatures (400-900 K) controlled by laser heating. At high temperature, we observed the fundamental Raman mode for the lowest frequency branch of rigid-plane layer-breathing mode (LBM) vibration. The mode frequency redshifts dramatically from 81 cm(-1) for bilayer to 23 cm(-1) for 8 layer. The thickness dependence is well described by a simple model of coupled oscillators. Notably, the LBM Raman response is unobservable at room temperature, and it is turned on at higher temperature (>600 K) with a steep increase of Raman intensity. The observation suggests that the LBM vibration is strongly suppressed by molecules adsorbed on the graphene surface but is activated as desorption occurs at high temperature. PMID- 25019217 TI - Platelet Janus particles with hairy polymer shells for multifunctional materials. AB - A novel approach is developed for the large-scale synthesis of Janus particles with platelet geometry and dense polymer shells by employing simultaneous "grafting from" of hydrophilic and hydrophobic polymers using surface-induced ATRP in emulsion. The method is based on the fabrication of an emulsion consisting of a water solution of a hydrophilic monomer and a solution of a hydrophobic monomer in an organic solvent, which is stabilized by initiator modified kaolinite particles. Two polymers are grafted simultaneously on the opposite faces of the kaolinite particle during polymerization. The synthesized particles have a clear Janus character and are highly efficient for the stabilization of emulsions. Because of its simplicity, the method can readily be upscaled for the synthesis of large amounts of Janus particles, up to several grams. PMID- 25019219 TI - Rosmarinic acid improves function and in vitro fertilising ability of boar sperm after cryopreservation. AB - During cryopreservation, oxidative stress exerts physical and chemical changes on sperm functionality. In the present study we investigated the antioxidant effect of rosmarinic acid (RA) on quality and fertilising ability of frozen-thawed boar spermatozoa. Ejaculates collected from mature boar were cryopreserved in lactose egg yolk buffer supplemented with different concentrations of RA (0 MUM, 26.25 MUM, 52.5 MUM and 105 MUM). Motion parameters, acrosome and plasma membrane integrity, lipoperoxidation levels, DNA oxidative damage (8-hydroxy-2 deoxyguanosine base lesion) and in vitro fertilisation ability were evaluated. Total and progressive motility were significantly higher in experimental extenders with RA than in the control (P<0.05) at 0 and 120 min post-thawing. The plasma and acrosomal membrane integrity were improved by supplementation with 105 MUMRA (P<0.05). Negative correlation between RA and malondialdehyde (MDA) concentration were determined (P<0.05). After thawing, the percentage of spermatozoa with oxidised DNA did not differ between extenders, however, at 120 and 240 min post-thawing, the samples supplemented with 105 MUMRA showed the lowest DNA oxidation rate (P<0.05). The penetration rate was significantly higher on spermatozoa cryopreserved with 105 MUMRA (P<0.05). The results suggest that RA provides a protection for boar spermatozoa against oxidative stress during cryopreservation by their antioxidant properties. PMID- 25019218 TI - Antileukemic activity of sulforaphane in primary blasts from patients affected by myelo- and lympho-proliferative disorders and in hypoxic conditions. AB - Sulforaphane is a dietary isothiocyanate found in cruciferous vegetables showing antileukemic activity. With the purpose of extending the potential clinical impact of sulforaphane in the oncological field, we investigated the antileukemic effect of sulforaphane on blasts from patients affected by different types of leukemia and, taking into account the intrinsically hypoxic nature of bone marrow, on a leukemia cell line (REH) maintained in hypoxic conditions. In particular, we tested sulforaphane on patients with chronic lymphocytic leukemia, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, and blastic NK cell leukemia. Sulforaphane caused a dose dependent induction of apoptosis in blasts from patients diagnosed with acute lymphoblastic or myeloid leukemia. Moreover, it was able to cause apoptosis and to inhibit proliferation in hypoxic conditions on REH cells. As to its cytotoxic mechanism, we found that sulforaphane creates an oxidative cellular environment that induces DNA damage and Bax and p53 gene activation, which in turn helps trigger apoptosis. On the whole, our results raise hopes that sulforaphane might set the stage for a novel therapeutic principle complementing our growing armature against malignancies and advocate the exploration of sulforaphane in a broader population of leukemic patients. PMID- 25019220 TI - Effect of niloticin, a protolimonoid isolated from Limonia acidissima L. (Rutaceae) on the immature stages of dengue vector Aedes aegypti L. (Diptera: Culicidae). AB - The aim of the present study was to evaluate the mosquitocidal activity of fractions and a compound niloticin from the hexane extract of Limonia acidissima L. leaves on eggs, larvae and pupae of Aedes aegypti L. (Diptera: Culicidae). In these bioassays, the eggs, larvae and pupae were exposed to concentrations of 2.5, 5.0, 7.5 and 10.0ppm for fractions and 0.5, 1.0, 1.5 and 2.0ppm for compound. After 24h, the mortality was assessed and the LC50 and LC90 values were calculated for larvae and pupae. Per cent ovicidal activity was calculated for eggs after 120h post treatment. Among the sixteen fractions screened, fraction 8 from the hexane extract of L. acidissima generated good mosquitocidal activity against Ae. aegypti. The LC50 and LC90 values of fraction 8 were 4.11, 8.04ppm against Ae. aegypti larvae and 4.19, 8.10ppm against Ae. aegypti pupae, respectively. Further, the isolated compound, niloticin recorded strong larvicidal and pupicidal activities. The 2ppm concentration of niloticin showed 100% larvicidal and pupicidal activities in 24h. The LC50 and LC90 values of niloticin on Ae. aegypti larvae were 0.44, 1.17ppm and on pupae were 0.62, 1.45ppm, respectively. Niloticin presented 83.2% ovicidal activity at 2ppm concentration after 120h post treatment and niloticin exhibited significant growth disruption and morphological deformities at sub lethal concentrations against Ae. aegypti. The structure of the isolated compound was identified on the basis of single XRD and spectral data ((1)H NMR and (13)C NMR) and compared with literature spectral data. The results indicate that niloticin could be used as a potential natural mosquitocide. PMID- 25019222 TI - Arylation and heteroarylation of thienylsulfonamides with organotrifluoroborates. AB - A mild, practical protocol has been developed for the Suzuki cross-coupling of unprotected thienylsulfonamides from air- and bench-stable organotrifluoroborates in the absence of a protecting group on the sulfonamide nitrogen. The developed synthetic method can be applied to the preparation of various arylated and heteroarylated thienylsulfonamides under conditions that are tolerant of a broad range of functional groups. PMID- 25019223 TI - Proton dynamics of two-dimensional oxalate-bridged coordination polymers. AB - A two-dimensional porous coordination polymer (NH4)2{HOOC(CH2)4COOH}[Zn2(C2O4)3] (abbreviated as (NH4)2(adp)[Zn2(ox)3] (adp = adipic acid, ox = oxalate)), which accommodates water molecules between the [Zn2(ox)3] layers, is highly remarked as a new type of crystalline proton conductor. In order to investigate its phase behavior and the proton conducting mechanism, we have performed adiabatic calorimetry, neutron diffraction, and quasi-elastic neutron scattering experiments on a fully hydrated sample (NH4)2(adp)[Zn2(ox)3].3H2O with the highest proton conductivity (8 * 10(-3) S cm(-1), 25 degrees C, 98% RH). Its isostructural derivative K2(adp)[Zn2(ox)3].3H2O was also measured to investigate the role of ammonium ions. (NH4)2(adp)[Zn2(ox)3].3H2O and K2(adp)[Zn2(ox)3].3H2O exhibit higher order transitions at 86 K and 138 K, respectively. From the magnitude of the transition entropy, the former is of an order-disorder type while the latter is of a displacive type. (NH4)2(adp)[Zn2(ox)3].3H2O has four Debye-type relaxations and K2(adp)[Zn2(ox)3].3H2O has two similar relaxations above each transition temperature. The two relaxations of (NH4)2(adp)[Zn2(ox)3].3H2O with very small activation energies (DeltaEa < 5 kJ mol(-1)) are due to the rotational motions of ammonium ions and play important roles in the proton conduction mechanism. It was also found that the protons in (NH4)2(adp)[Zn2(ox)3].3H2O are carried through a Grotthuss mechanism. We present a discussion on the proton conducting mechanism based on the present structural and dynamical information. PMID- 25019221 TI - omega-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer. AB - Epidemiological and pre-clinical studies support the anti-tumor effects of omega 3 PUFAs; however, the results from human trials are mixed, making it difficult to provide dietary guidelines or recommendations of omega-3 PUFAs for disease prevention or treatment. Understanding the molecular mechanisms by which omega-3 PUFAs inhibit cancer could lead to better nutritional paradigms and human trials to clarify their health effects. The omega-3 PUFAs exert their biological activities mainly through the formation of bioactive lipid metabolites. Here we discuss the biology of cyclooxygenase, lipoxygenase and cytochrome P450 enzymes derived omega-3-series lipid metabolites on angiogenesis, inflammation and cancer. PMID- 25019224 TI - Selective reduction of aromatic ketones in aqueous medium mediated by Ti(III)/Mn: a revised mechanism. AB - An experimental study on the role played by each of the reagents involved in the selective reduction of aromatic ketones in aqueous medium is reported. In this reaction, the reduction of aromatic ketones is mediated by Cp2TiCl. Moreover, the presence of Mn in the reaction medium is mandatory. To account for these findings, a substantially revised mechanism is proposed. PMID- 25019225 TI - Memory concerns, memory performance and risk of dementia in patients with mild cognitive impairment. AB - BACKGROUND: Concerns about worsening memory ("memory concerns"; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI). METHODS: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models. RESULTS: Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33 4.89), lower memory performance (HR = 0.63, 95%CI: 0.56-0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18-3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment. CONCLUSIONS: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI. PMID- 25019226 TI - Differences in TCR-Vbeta repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age. AB - Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-Vbeta repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-Vbeta subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-Vbeta repertoire in TIL but not in PBL, and the dispersion degree of the differences of TCR-Vbeta subfamilies between TIL and PBL correlated positively with age (P = 0.007). Utilizing immunoscope analysis, we identified the age-related reduction in TCR-Vbeta diversity, but polyclonal pattern was predominant in significantly expanded TCR-Vbeta subfamilies. In addition, we found that older patients possessed a decreased ratio of CD8+CD62L+ non-effector cells in TIL compared to PBL, implying age-related increase of CD8+CD62L- effector cells in TIL. The colocalization analysis of CD8 and CD3, however, suggested the suppressed activity of these effector cells in tumor microenvironment. These findings further elucidate the properties of TIL, showing an increasing difference between TIL and PBL with age, which may provide insight for the development of effective immunotherapies for cancer patients of different ages. PMID- 25019228 TI - A prospective longitudinal evaluation and affecting factors of health related quality of life after appendectomy. AB - BACKGROUND: The aim of the present study was to longitudinally evaluate the pattern of Health-Related Quality of Life (HRQoL) alterations, as an indirect convalescence index after appendectomy, to assess the timing of its restoration to the healthy population levels and to attempt a profound investigation into factors determining HRQoL outcomes. METHODS: Uncomplicated cases of histologically verified acute appendicitis (AA) were enrolled in a prospective cohort study. HRQoL indices were collected at baseline, 15 days, 1 and 3 months using EQ-5D, SF-36 and, GIQLI questionnaires. Data were processed with non parametric tests and logistic regression analysis. RESULTS: For the 147 patients eventually included, significant improvements compared to baseline at EQ-5D and SF-36 general health and physical function domains were noted at 15 days, while bodily pain was worse. The majority HRQoL parameters were significantly better at the 1st and the 3rd-month compared to baseline and the 15th-day assessments. General health, physical and emotional function were restored at the general population levels between 15 days and 1 month, while bodily pain, social function and EQ-5D indices between the 1st and 3rd month. Logistic regression analysis indicated that high Alvarado score was the most powerful predictor of HRQoL impairment with older age coming second. CONCLUSIONS: Post-appendectomy HRQoL disturbances predominate and the burden of AA should not be underestimated. Convalescence period as translated by HRQoL restoration may be extended beyond the second week and up to the first month. Degree of inflammation and patient's age emerged as key mediators of HRQoL outcomes. PMID- 25019229 TI - Surgical care in low and middle-income countries: burden and barriers. AB - Surgically correctable pathology accounts for a sizeable proportion of the overall global burden of disease. Over the last decade the role of surgery in the public health agenda has increased in prominence and attempts to quantify surgical capacity suggest that it is a significant public health issue, with a great disparity between high-income, and low- and middle-income countries (LMICs). Although barriers such as accessibility, availability, affordability and acceptability of surgical care hinder improvements in LMICs, evidence suggests that interventions to improve surgical care in these settings can be cost effective. Currently, efforts to improve surgical care are mainly coordinated by academia and intuitions with strong surgical and global health interests. However, with the involvement of various international organisations, policy makers, healthcare managers and other stakeholders, a collaborative approach can be achieved in order to accelerate progress towards improved and sustainable surgical care. In this article, we discuss the current burden of global surgical disease and explore some of the barriers that may be encountered in improving surgical capacity in LMICs. We go on to consider the role that international organisations can have in improving surgical care globally. We conclude by discussing surgery as a global health priority and possible solutions to improving surgical care globally. PMID- 25019227 TI - Complement regulatory protein CD46 protects against choroidal neovascularization in mice. AB - Dysregulation of the complement system is increasingly recognized as a contributing factor in age-related macular degeneration. Although the complement regulator CD46 is expressed ubiquitously in humans, in mouse it was previously thought to be expressed only on spermatozoa. We detected CD46 mRNA and protein in the posterior ocular segment (neuronal retina, retinal pigment epithelium, and choroid) of wild-type (WT) C57BL/6J mice. Cd46(-/-) knockout mice exhibited increased levels of the membrane attack complex and of vascular endothelial growth factor (VEGF) in the retina and choroid. The Cd46(-/-) mice were also more susceptible to laser-induced choroidal neovascularization (CNV). In Cd46(-/-) mice, 19% of laser spots were positive for CNV at day 2 after treatment, but no positive spots were detected in WT mice. At day 3, 42% of laser spots were positive in Cd46(-/-) mice, but only 11% in WT mice. A fully developed CNV complex was noted in both Cd46(-/-) and WT mice at day 7; however, lesion size was significantly (P < 0.05) increased in Cd46(-/-) mice. Our findings provide evidence for expression of CD46 in the mouse eye and a role for CD46 in protection against laser-induced CNV. We propose that the Cd46(-/-) mouse has a greater susceptibility to experimental CNV because of insufficient complement inhibition, which leads to increased membrane attack complex deposition and VEGF expression. PMID- 25019230 TI - The outcome of antibiotic therapy for uncomplicated appendicitis with diameters <= 10 mm. AB - PURPOSE: Although many patients receive antibiotic therapy for uncomplicated appendicitis, the relatively high treatment failure and recurrence rates are problematic. We assumed that patients with appendicitis and appendiceal diameters <= 10 mm, have better outcomes. The purpose of this prospective non-randomized study was to assess the outcomes of antibiotic therapy in patients with uncomplicated appendicitis and appendiceal diameters <= 10 mm. METHODS: Over 2 years, we enrolled 119 patients who initially received antibiotic therapy. The failure of antibiotic therapy was defined as the need for appendectomy and true appendicitis. Peritonitis was defined as either complicated appendicitis or intra abdominal abscess postoperatively. We evaluated the rates of treatment failure, peritonitis, and recurrence. RESULTS: Nine patients (7.6%) failed to respond to initial antibiotic therapy, and 6 had true appendicitis after subsequent surgery. Two patients had complicated appendicitis (peritonitis), but no patient displayed intra-abdominal abscess postoperatively. During a median follow-up period months of 14 months, 14 patients (12.7%) experienced recurrence. CONCLUSIONS: Antibiotic therapy without surgery may be a safe treatment for uncomplicated appendicitis in select patients with appendiceal diameters <= 10 mm. PMID- 25019231 TI - Mortality from Herpes Simplex Virus (HSV) Infection in Australian Children, 1999 2011 Using National Datasets. AB - BACKGROUND: This study examines national childhood HSV mortality data in Australia from 1999-2011. This information is important to better understand the disease burden of HSV in early life and to formulate public health interventions. METHODS: Retrospective analysis of Australian Bureau of Statistics (ABS) national mortality data from 1999- 2011 in children aged <15 years who died with specific ICD-10 codes for HSV infection listed as an underlying or contributing cause. RESULTS: Twenty nine HSV-associated deaths in children aged <15 years from 1999 2011 were identified (0.05 per 100,000 children; 95% CI 0.04-0.06), 16 in the first month of life (0.45 per 100,000 live births; 95% CI 0.23- 0.67). Among those, 20 were males and 9 were females (p=0.04). The majority of deaths (69%) occurred in infants aged <12 months and most in infants aged <1 month (55%). HSV associated death in infants aged < 1 month of age accounted for 0.15% of all neonatal deaths for 1999-2011 in Australia. A downward trend in HSV-associated neonatal mortality was observed between 1999 and 2011 (p=0.52). During the study period, mortality from HSV infections in Australian children resulted in an estimated 2,275 age-adjusted years of potential life lost. CONCLUSIONS: This data confirms reported findings from active surveillance of a downward trend in mortality rate from HSV infection in infants aged < 1 month in Australia over this period. Ongoing surveillance is required to confirm this observation. PMID- 25019232 TI - Mycobacterium fortuitum Complex Skin Infection in a Healthy Adolescent. AB - Mycobacterium fortuitum complex skin infection is described in a previously healthy adolescent girl in Sydney, Australia. Mycobacterium fortuitum typically causes superficial skin infections following trauma to the skin and in our patient may have been related to prior leg "waxing". This case highlights common causes for a delay in diagnosis: lack of clinician awareness and inadequate microbiological and histopathological investigations of tissue samples. Due to the size and number of lesions, surgical excision was felt to be a less desirable therapeutic option due to the potential risk of poor cosmetic outcome for our patient. The standard chemotherapeutic approach to M. fortuitum infections involves the use of a combination of at least two antimicrobial agents to which the isolate is susceptible. Despite in vitro susceptibility testing that suggested that the isolate from our patient was resistant to most oral anti microbial agents, our patient was treated successfully with a 10-week course of oral trimethoprim-sulfamethoxazole and moxifloxacin. PMID- 25019233 TI - Knowledge, Attitude and Practice (KAP) Survey Concerning Antimicrobial Use among Australian Hajj Pilgrims. AB - Resistance to antimicrobial agents has increased for reasons relating to the use and misuse of antimicrobials in human, agriculture and aquaculture. Antimicrobial use is quite high during mass gatherings such as the Hajj pilgrimage. To reduce non-prescription use and inappropriate prescribing of antimicrobials, a more thorough understanding of their use and the motives behind why patients request, even demand, antimicrobials, fail to adhere to the prescription is important. Therefore, we conducted a knowledge, attitude and practice (KAP) survey among Australian Hajj pilgrims in Mecca during Hajj 2013 using an anonymous, self administered questionnaire concerning antimicrobial use. Our sample consisted of 229 adult Australian subjects. Mean age was 42.4 (SD+/-12.7) years, 178 (77.9%) were male and 80 (34.9%) used antimicrobials during their stay in Saudi Arabia. Twenty one (26.3%) obtained these in Saudi Arabia without prescription, and about half (38, 47.5%) brought them from Australia. Of the respondents, 55.8% believed that antibiotics are effective against viruses, 53.6% thought that antibiotics are effective against common cold and flu, 78.6 % that humans themselves can become resistant to antibiotics and 75.9% knew that overuse or unnecessary use of antibiotics can cause them to lose effectiveness. This study has revealed that Hajj pilgrims have inappropriate access to antimicrobials in Saudi Arabia as well as in Australia. A large scale education campaign and tighter control on prescribing and dispensing of antimicrobials could improve the appropriate antimicrobial use among Hajj pilgrims. PMID- 25019234 TI - Vaccination of Older Adults with Dementia Against Respiratory Infections. AB - People with dementia are at a greater risk of complications from respiratory infections therefore can benefit from vaccinations against influenza, pneumococcal disease and pertussis. This review aimed to evaluate the uptake and impact of vaccination in older adults with dementia against respiratory infections and identify knowledge gaps. Key databases were explored, search results were assessed, relevant studies identified, and data were synthesised and summarised. Most available data suggest that older adults with dementia are less likely to receive influenza or pneumococcal vaccine while a few studies indicate an increase in vaccination uptake but poor immunogenicity. Among dementia patients, community dwellers have a lower vaccination rate than home care residents. However, vaccinations against influenza and pneumococcal disease can benefit individuals with dementia by reducing both mortality and morbidity. Health professionals caring for patients with dementia could play a role in fostering vaccination of these individuals. PMID- 25019235 TI - Recent advances in molecular biology of parasitic viruses. AB - The numerous protozoa that can inhabit the human gastro-intestinal tract are known, yet little is understood of the viruses which infect these protozoa. The discovery, morphologic details, purification methods of virus-like particles, genome and proteome of the parasitic viruses, Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, and the Eimeria sp. are described in this review. The protozoan viruses share many common features: most of them are RNA or double stranded RNA viruses, ranging between 5 and 8 kilobases, and are spherical or icosahedral in shape with an average diameter of 30-40 nm. These viruses may influence the function and pathogenicity of the protozoa which they infect, and may be important to investigate from a clinical perspective. The viruses may be used as specific genetic transfection vectors for the parasites and may represent a research tool. This review provides an overview on recent advances in the field of protozoan viruses. PMID- 25019236 TI - Foot Injuries Among Hajj Pilgrims with and Without Diabetes Mellitus: Implications for Infection Management. AB - Pilgrims attending Hajj in Makkah are at high risk of suffering from trauma and foot injury as they are required to make circuits barefooted on scorching marbles around the Holy Mosque, and march between two hillocks for hours. No study has systematically described the pattern of foot wounds among them. This observational study aimed to determine the spectrum of foot injuries among diabetic and non-diabetic Hajj pilgrims and the preventive measures adopted by them. Pilgrims who attended the Hajj 2013 and sought medical care for foot wounds at mobile podiatric clinics in Mina during the peak days of Hajj were invited to participate in the study and fill out a questionnaire while they were serviced. Podiatric carers noted down the significant signs of foot injuries. Out of 197 pilgrims from 21 different countries who participated in this study, 60 (31%) were diabetic. The two most common injuries observed were blisters (34%) and erythema (25%). Both diabetic and non-diabetic Hajj pilgrims were at high risk of developing infectious wounds, however a significantly higher proportion of diabetic pilgrims had callosities. Use of appropriately fitting protective footwear, and regularity in diets and drugs are highly recommended for pilgrims' optimum foot care. Tailored educational advice on foot hygiene before and during travel could be beneficial for Hajj pilgrims. PMID- 25019238 TI - Sensitivity of SARS/MERS CoV to interferons and other drugs based on achievable serum concentrations in humans. AB - A novel coronavirus (MERS-CoV) related to SARS-CoV recently emerged in the Middle East causing more than 400 deaths with a mortality rate of about 30%, much higher than SARS-CoV. Both viruses target epithelial cells in the respiratory tract, although utilizing different cellular receptors. Because of the sporadic nature of the MERS outbreak and difficulty in collecting randomized, controlled clinical data, the objective of this review was to focus on published in vitro and in vivo drug sensitivity data using both cell lines and available animal models of SARS/MERS CoV infection. Determination of drug activity was based on achievable serum levels in humans relative to in vitro IC50 (50% inhibitory concentration) or EC50 (50% effective concentration) drug concentrations. The most active drugs against SARS/MERS CoV at clinically achievable serum levels were type I interferons and a TLR3 agonist, interferon inducer/activator. PMID- 25019239 TI - Arginine kinase: a potential pharmacological target in trypanosomiasis. AB - Trypanosomatids parasites have complex life cycles which involve a wide diversity of milieus with very different physicochemical properties. Arginine kinase is one of the key enzymes, responsible for the parasites' metabolic plasticity, which maintains the cell energy homeostasis during environment changes. Arginine kinase catalyzes the reversible phosphorylation between phosphoarginine and ADP. The phosphagen phosphoarginine sustains high levels of cellular activity until metabolic events, such as glycolysis and oxidative phosphorylation, are switched on. In different unicellular and multicellular organisms including trypanosomatids, it was demonstrated that arginine kinase is an important component in resistance mechanisms to different stress factors, such as reactive oxygen species, trypanocidal drugs, pH and starvation. In addition, few arginine kinase inhibitors were identified during the lasts years, some of them with trypanocidal activity, such as polyphenolic compounds. All these unique features, in addition to the fact that arginine kinase is completely absent in mammals, make this pathway a favorable start point for rational drug design for the treatment of human trypanosomamiases. PMID- 25019237 TI - Pneumococcal Vaccine Uptake Among Australian Hajj Pilgrims in 2011-13. AB - The uptake of the pneumococcal vaccine is suboptimal in Australia and remains unknown among Australian Hajj pilgrims, many of whom are eligible because of age or underlying disease and at particular risk because of travel and activities at Hajj. Pneumococcal vaccination uptake was examined over three consecutive years (2011 to 2013) through anonymous self-administered cross sectional surveys among Australian pilgrims who assembled in Mina valley, Mecca, Saudi Arabia. Respectively, 158, 513 and 219 pilgrims were recruited in 2011, 2012 and 2013; their mean ages were 43.8 (SD+/-13), 43 (SD+/-13.5) and 42.6 (SD+/-12.3) years; males accounted for 67 (42.4%), 325 (63.4%) and 172 (78.5%). Pneumococcal vaccine uptake rates were 28.5% (45/158), 28.7% (147/513) and 14.2% (31/219); among the pilgrims with 'at risk' conditions the pneumococcal vaccine uptake rates were 15 (30.6%), 43 (45.3%) and 9 (29%) respectively. According to our surveys, the pneumococcal vaccine uptake among Australian pilgrims is low. Further research is needed to explore the reasons through a validated study. PMID- 25019242 TI - Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs. AB - Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel beta,beta-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs. PMID- 25019241 TI - PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. AB - Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high-mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1alpha (HIF1alpha) and activates the HIF-1alpha dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1alpha and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases. PMID- 25019243 TI - N-Phenethyl caffeamide and photodamage: protecting skin by inhibiting type I procollagen degradation and stimulating collagen synthesis. AB - Skin is mainly damaged by genetic and environmental factors such as ultraviolet (UV) light and pollutants. UV light is a well-known factor that causes various types of skin damage and premature aging. Reactive oxygen species (ROS) are commonly involved in the pathogenesis of skin damage by activating the metalloproteinases that break down type I collagen. This study investigated the antioxidant and antiphotodamage activity and mechanisms of N-phenethyl caffeamide (K36) in human skin fibroblasts. The results indicated that K36 demonstrated strong 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activity, which dose-dependently reduced the production of UVB-induced intracellular ROS in human dermal fibroblasts. K36 prevented UVB-irradiation-induced type I collagen degradation by inhibiting the expression of matrix metalloproteins-1, -3, and -9 and the phosphorylation of mitogen-activated protein (MAP) kinases. Furthermore, K36 elevated collagen synthesis in skin fibroblasts by inhibiting UVB-induced Smad7 overexpression. K36 downregulated the expression of the transcription factor, activator protein-1 (AP-1). Our results indicated that K36 exhibited antioxidant properties and prevented skin collagen degradation caused by UV exposure and the stimulation of collagen synthesis, which suggests the potential use of K36 in preventing photodamage. PMID- 25019244 TI - Platycodon grandiflorum polysaccharide induces dendritic cell maturation via TLR4 signaling. AB - Dendritic cell (DC) maturation is critical for initiation of the adoptive immune response. DC maturation is often attenuated in several pathological conditions including cancer. In this study, we report the effect of Platycodon grandiflorum polysaccharide (PG) on DC maturation. PG induced phenotypic maturation of DCs, as proved by the increase in the expression of CD40, CD80, CD86, and major histocompatibility complex (MHC)-I/II on the cell surface. PG also induced functional maturation of DCs, as proved by elevated production of interleukin (IL)-12, tumor necrosis factor-alpha, IL-1beta, IL-6, IL-10, and interferon-beta, and by enhanced allogeneic T cell stimulation ability of PG-treated DCs. PG efficiently induced maturation of DCs from C3H/HeN mice, which have normal Toll like receptor-4 (TLR4), but not that of DCs from C3H/HeJ mice, which have mutated TLR4, suggesting that TLR4 might be one of the PG receptors in DCs. In line with TLR4 activation, PG increased the phosphorylation of ERK, p38, and JNK, and the nuclear translocation of p-c-Jun, p-CREB, and c-Fos. PG also activated NF-kappaB signaling, as evidenced by degradation of IkappaBalpha/beta and nuclear translocation of p65 and p50. In summary, our data suggest that PG induces DC maturation by activating MAPK and NF-kappaB signaling downstream of TLR4. PMID- 25019245 TI - A 3-week dietary safety study of octenyl succinic anhydride (OSA)-modified starch in neonatal farm piglets. AB - Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2 days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20 g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with AmiocaTM Powder to balance the nutritional profiles of all formulations. There were no test article related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20 g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. PMID- 25019246 TI - A retrospective, quality improvement review of maggot debridement therapy outcomes in a foot and leg ulcer clinic. AB - Maggot debridement is the deliberate use of larvae known to consume only necrotic tissue. A retrospective quality improvement analysis of maggot debridement therapy (MDT) was conducted among patients with devitalized tissue or gangrene attending a Canadian foot and leg ulcer clinic who received MDT between January 2001 and June 2006. MDT was applied every 48 hours until >90% of necrotic tissue was debrided. The authors identified MDT patients in the clinic database and reviewed their medical records for age, gender, presence of diabetes or peripheral arterial disease (PAD), type of wound, number of maggot applications required, wound outcomes, and nursing visit costs (week before, during, and after MDT) and noted patient experiences. Records of 68 patients (average age 71, range 22 to 95, years) were identified and abstracted. Of those, 44% had leg ulcers and 67% had both diabetes and PAD. The majority (39, 58%) of wounds required three debridement sessions. All but one patient achieved debridement of >90% of necrotic tissue in 2 to 10 days. Most wounds (56) healed with follow-up moist wound care. Only one patient withdrew from MDT. No other patient or safety concerns were documented. Total nursing visits for all patients the week before and then after MDT were 307 and 102, respectively. These findings confirm results of previous reports about the effectiveness of MDT for wound debridement. Randomized, controlled clinical studies are needed to confirm the efficacy and cost-effectiveness of MDT compared to other debridement modalities. PMID- 25019247 TI - Extracorporeal shock wave therapy as an adjunct wound treatment: a systematic review of the literature. AB - Standard care procedures for complex wounds are sometimes supported and reinforced by physical treatment modalities such as extracorporeal shock wave therapy (ESWT). To evaluate available evidence of ESWT effectiveness in humans, a systematic review of the literature was conducted using MEDLINE, PubMed, Scopus, EBSCOhost, and PEDro databases. Of the 393 articles found, 13 met the publication date (year 2000-2013), study type (clinical study), language (English only), and abstract availability (yes) criteria. The 13 studies (n = 919 patients with wounds of varying etiologies) included seven randomized controlled trials that were evaluated using Cochrane Collaboration Group standards. Only studies with randomization, well prepared inclusion/exclusion criteria protocol, written in English, and full version available were analyzed. An additional six publications reporting results of other clinical studies including a total of 523patients were identified and summarized. ESWT was most commonly applied once or twice a week using used low or medium energy, focused or defocused generator heads (energy range 0.03 to 0.25 mJ/mm2; usually 0.1 mJ/mm2), and electrohydraulic or electromagnetic sources. Few safety concerns were reported, and in the controlled clinical studies statistically significant differences in rates of wound closure were reported compared to a variety of standard topical treatment modalities, sham ESWT treatment, and hyperbaric oxygen therapy. Based on this analysis, ESWT can be characterized as noninvasive, mostly painless, and safe. Controlled, randomized, multicenter, blind clinical trials still are required to evaluate the efficacy and cost-effectiveness of ESWT compared to sham control, other adjunctive treatments, and commonly used moisture-retentive dressings. In the future, ESWT may play an important role in wound care once evidence-based practice guidelines are developed. PMID- 25019248 TI - Transcutaenous electrical nerve stimulation to manage a lower extremity wound complicated by peripheral arterial disease: a case report. AB - Transcutaneous electrical nerve stimulation (TENS) is used to alleviate muscle pain, and there is some evidence it may affect healing in chronic wounds. An 80 year-old male patient with a chronic left lower extremity wound and a history of peripheral arterial disease, type 2 diabetes, hypertension, chronic obstructive pulmonary disease, and lung cancer presented for treatment. Previous protocols of care, mainly consisting of sharp debridement and daily dressing changes, had not resulted in a decrease in wound size. The patient had right and left iliac artery stenosis - not amenable to surgical intervention - and an ankle brachial index (ABI) of 0.63 on the left and 0.59 on the right lower extremities. On presentation, the wound measured 3.0 cm x 2.0 cm with a depth of 0.3 cm and a 0.5 cm tract at the 5 o'clock position. Treatment was changed to application of an ionic silver-containing HydrofiberTM dressing and low-frequency TENS. Electrodes were applied 2 cm superior and inferior to the wound margin at a frequency of 2 Hz with a pulse width of 250 microseconds and amplitude of 33 mA. Treatment time was 45 minutes, twice daily, for 3 months, performed at home by the patient and his caregiver. After 4 weeks, wound dimensions decreased by 1.51% per day, and the wound was completely healed (100% epithelialized) after 12 weeks. At that time, the ABI of the left (treated) leg had increased to 0.71. Research is needed to determine the efficacy and effectiveness of low-frequency TENS to help clinicians provide evidenced-based treatment for wounds complicated by decreased blood flow. PMID- 25019249 TI - L-Ascorbic acid metabolism during fruit development in an ascorbate-rich fruit crop chestnut rose (Rosa roxburghii Tratt). AB - Chestnut rose (Rosa roxburghii Tratt) is a fruit crop that contains unusually high levels of l-ascorbic acid (AsA; ~1300 mg 100g(-1) FW). To explore the mechanisms underlying AsA metabolism, we investigated the distribution and abundance of AsA during fruit development. We also analyzed gene expression patterns, enzyme activities, and content of metabolites related to AsA biosynthesis and recycling. AsA first accumulated during late fruit development and continued to accumulate during ripening, with the highest accumulation rate near fruit maturity. The redox state of AsA in fruit was also enhanced during late fruit development, while leaf and other tissues had much lower levels of AsA and the redox state of AsA was lower. In mature fruit, AsA was mainly distributed in the cytoplasm of the mesocarp. Correlation analysis suggested that the gene expression patterns, enzyme activities, and related metabolite concentrations involved in the l-galactose pathway showed relatively high correlations with the accumulation rate of AsA. The gene expression pattern and activity of dehydroascorbate reductase (DHAR, EC 1.8.5.1) correlated strongly with AsA concentration, possibly indicating the crucial role of DHAR in the accumulation of high levels of AsA in chestnut rose fruit. Over expression of DHAR in Arabidopsis significantly increased the reduced AsA content and redox state. This was more effective than over expression of the l-galactose pathway gene GDP-d mannose-3,5-epimerase (EC 5.1.3.18). These findings will enhance understanding of the molecular mechanisms regulating accumulation of AsA in chestnut rose. PMID- 25019250 TI - The effect of donor-recipient body surface area ratio on donor age and donor glomerular filtration rate in Chinese patients undergoing a living-donor kidney transplant. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of donor recipient body surface area ratio on donor age and donor glomerular filtration rate in living-donor kidney transplant. MATERIALS AND METHODS: This retrospective study included 254 rejection-free patients who underwent their first living-donor kidney transplant at our center between April 2007 and April 2011. We performed multivariate linear regression and receiver operating characteristic curve analyses to determine independent associations and the cumulative effects on posttransplant graft function and outcomes in persons in China who had a living donor kidney transplant. RESULTS: In multivariate linear regression, donor age, donor estimated glomerular filtration rate, and donor-recipient body surface area ratio were independent predictors of 1-year graft function. Linear regression showed that correcting donor age by donor-recipient body surface area ratio increased the strength of the correlation between donor age and 1-year graft function. In the older group (donor age >= 45 y), the effect of donor-recipient body surface area ratio on graft function was stronger. By considering the 1-year donor estimated glomerular filtration rate in 2 groups (< 60 or >= 60 mL/min/1.73 m(2)), the cutoff values for corrected donor age was 55 years and donor estimated glomerular filtration rate before surgery was 113 mL/min/1.73 m(2). CONCLUSIONS: By correcting for donor-recipient body surface area ratio, donor age accurately predicted and correlated better with 1 year graft function. During preoperative evaluation donor and recipient body surface area matching may be useful. PMID- 25019251 TI - Asymmetric clustering index in a case study of 5-HT1A receptor ligands. AB - The automatic clustering of chemical compounds is an important branch of chemoinformatics. In this paper the Asymmetric Clustering Index (Aci) is proposed to assess how well an automatically created partition reflects the reference. The asymmetry allows for a distinction between the fixed reference and the numerically constructed partition. The introduced index is applied to evaluate the quality of hierarchical clustering procedures for 5-HT1A receptor ligands. We find that the most appropriate combination of parameters for the hierarchical clustering of compounds with a determined activity for this biological target is the Klekota Roth fingerprint combined with the complete linkage function and the Buser similarity metric. PMID- 25019252 TI - Chelator-free (64)Cu-integrated gold nanomaterials for positron emission tomography imaging guided photothermal cancer therapy. AB - Using positron emission tomography (PET) imaging to monitor and quantitatively analyze the delivery and localization of Au nanomaterials (NMs), a widely used photothermal agent, is essential to optimize therapeutic protocols to achieve individualized medicine and avoid side effects. Coupling radiometals to Au NMs via a chelator faces the challenges of possible detachment of the radiometals as well as surface property changes of the NMs. In this study, we reported a simple and general chelator-free (64)Cu radiolabeling method by chemically reducing (64)Cu on the surface of polyethylene glycol (PEG)-stabilized Au NMs regardless of their shape and size. Our (64)Cu-integrated NMs are proved to be radiochemically stable and can provide an accurate and sensitive localization of NMs through noninvasive PET imaging. We further integrated (64)Cu onto arginine glycine-aspartic acid (RGD) peptide modified Au nanorods (NRs) for tumor theranostic application. These NRs showed high tumor targeting ability in a U87MG glioblastoma xenograft model and were successfully used for PET image-guided photothermal therapy. PMID- 25019253 TI - Educational intervention to increase detection of metabolic syndrome in patients at community mental health centers. AB - The prevalence of metabolic syndrome and associated illness is approximately double in individuals with mental illness compared with the general public. An educational intervention on metabolic syndrome was provided to mental health counselors, who performed intake assessments of patients newly admitted to two outpatient mental health facilities. Researchers of the current study first measured mastery of metabolic syndrome content following the educational intervention; they then conducted a chart audit on new admissions to measure changes in clinician behavior. Prior to the intervention, neither facility screened for metabolic syndrome at intake or referred patients with a body mass index (BMI) >25 for medical evaluation. A paired t test showed no significant difference in the educational pre-posttest scores; however, following the intervention, 53 of 132 patients had a documented BMI >25, and 47 of 53 patients were referred to a primary care provider for evaluation. The current study's findings suggest that mental health counselors who screen for metabolic syndrome and associated illnesses will increase the rate of detection of these chronic conditions. PMID- 25019254 TI - Personality and prosocial behavior: linking basic traits and social value orientations. AB - Concerning the dispositional determinants of prosocial behavior and cooperation, work based on the classic 5 personality factors, and especially Agreeableness, has turned out somewhat inconsistent. A clearer picture has emerged from consideration of the HEXACO model of personality--though supported entirely by hypothetical behavior as criterion, so far. Thus, in 2 studies and a reanalysis, we investigated "actual behavior" in the form of individually and socially consequential distribution decisions. As expected, HEXACO Honesty-Humility consistently predicted prosocial behavior, including a theory-consistent pattern on the facet level. Importantly, this pattern might explain why five-factor Agreeableness has only sometimes been found to account for prosocial behavior. Indeed, further results indicate that five-factor Agreeableness comprises some aspects that are predictive of prosocial behavior--aspects well covered by HEXACO Honesty-Humility--but also others that play no role for this criterion. As such, the links between five-factor Agreeableness and prosocial behavior are well covered by HEXACO Honesty-Humility, but not vice versa. Taken together, these findings hint that especially HEXACO Honesty-Humility (and certain aspects of five-factor Agreeableness) account for prosocial behavior--thus explaining previous inconsistencies and providing a more nuanced understanding of the links between basic personality and prosocial or cooperative behavior. PMID- 25019255 TI - Examination of the Teaching Styles of Nursing Professional Development Specialists, Part II: Correlational Study on Teaching Styles and Use of Adult Learning Theory. AB - This article, the second in a two-part series, details a correlational study that examined the effects of four variables (graduate degrees in nursing education, professional development training in adult learning theory, nursing professional development [NPD] certification, and NPD specialist experience) on the use of adult learning theory to guide curriculum development. Using the Principles of Adult Learning Scale, 114 NPD specialists tested the hypothesis that NPD specialists with graduate degrees in nursing education, professional development training in adult learning theory, NPD certification, and NPD experience would use higher levels of adult learning theory in their teaching practices to guide curriculum development than those without these attributes. This hypothesis was rejected as regression analysis revealed only one statistically significant predictor variable, NPD certification, influenced the use of adult learning theory. In addition, analysis revealed NPD specialists tended to support a teacher-centered rather than a learner-centered teaching style, indicating NPD educators are not using adult learning theory to guide teaching practices and curriculum development. J Contin Educ Nurs. 2014;45(8):xxx-xxx. PMID- 25019256 TI - Promoting continuing competence and confidence in nurses through high-fidelity simulation-based learning. AB - In many health care settings, nurses are challenged with higher acuity patients in technical and evolving environments. Practicing nurses are expected to adapt by independently acquiring new clinical knowledge through experience and independent study. However, health care institutions have struggled with providing quality patient care and supporting nurses' learning through experience at the same time. High-fidelity simulation-based learning addresses this need by providing no-risk experiential learning that expands skills without jeopardizing patient safety. There is limited literature discussing the use of high-fidelity simulation-based learning in continuing competency and staff development for practicing nurses. This article identifies opportunities for employers to use high-fidelity simulation-based learning programs that promote continued competency and confidence in practicing nurses. PMID- 25019257 TI - Expanding nurse of the future nursing core competencies across the academic practice transition: a pilot study. AB - BACKGROUND: A regional state university and three health care organizations formed a regional education- service partnership to expand the implementation of the Massachusetts Nurse of the Future Nursing Core Competencies (NOFNCC) across the academic-practice transition. METHOD: Using a conveienience sample in a one- group preteos-posttest design, the study examined the extent to which transitioning new licensed nurses and their preceptors were knowledgeable regarding NOFNCC as a basis for practice, and assessed changes following an educational intervention. A newly developed instrument based on NOFNCC, the Nurse Competency Assessment Tool (NCAT), served as the measurement: tool. RESULTS: Findings indicate knowledge gaps in system- based practice, quality improvement, and evidence- based practice among both transitioning newly licensed nurses and preceptor groups in need of improvement. CONCLUSION: NOFNCC identify essential knowledge, attitudes, and skills integral to providing safe quality nursing care not only in Massachusetts but also nationally and globally. Need for continued refinement of the NCAT was also apparent. PMID- 25019261 TI - Ordered mesoporous carbons obtained by a simple soft template method as sulfur immobilizers for lithium-sulfur cells. AB - Carbon materials with ordered mesoporous structures were synthesized using soft template methods and then activated by CO2 treatment. Sulfur was incorporated in these carbons via a simple chemical deposition method in aqueous solutions and the resulting composites were tested as electrodes in Li-S cells. The electrochemical results showed that well-ordered mesoporous carbons perform better than those with a random mesopore arrangement (wormhole-like mesoporous structure). The mesopore ordering yields a framework of well-connected empty sites that results in an enhancement of both the charge carrier mobility and the reversibility of the electrochemical reaction. Although the activation with CO2 partially destroys the mesopore arrangement, which adversely affects the electrode performance, it notably increases the surface area and the micropore content which improves the connectivity between the mesopores. The final observation was an irrelevant effect of the activation process at low current densities. However, at higher rates the activated carbon composite delivered higher capacities. The hierarchical pore structure formed by micro- and mesopores should guarantee the required fast mobility of the Li(+). PMID- 25019262 TI - Helicity inversion and redox chemistry of chiral manganese(II) cubanes. AB - The chiral ligand S-1,2-bis(1H-benzimidazol-2-yl)ethanol, 1, reacts with manganese(II) salts to form cubanes which readily undergo oxidation reactions leading either to a tetranuclear manganese(II,III) mixed valence complex 4 or to a tetranuclear complex of ligand 5 where the secondary alcohol has been oxidised to an enolate. N-methylation of ligand 1 slows the oxidation reaction and stable manganese(II) cubanes may be isolated. The fully methylated ligand 2 gives a cubane of opposite helicity to that found previously for 1 with cobalt. The inversion may be explained by conformational analysis. Cyclic voltammetry suggests that the manganese cubanes reported here are insufficiently robust to store oxidising equivalents as in the oxygen evolving system of photosystem II. PMID- 25019263 TI - An activatable, polarity dependent, dual-luminescent imaging agent with a long luminescence lifetime. AB - In this proof-of-concept study, a new activatable imaging agent based on two luminophores and two different quenching mechanisms is reported. Both partial and total activation of the luminescence signal can be achieved, either in solution or in vitro. Bond cleavage makes the compound suitable for luminescence lifetime imaging. PMID- 25019264 TI - Tobacco smoking status and perception of health among a sample of Jordanian students. AB - Limited data are available from Jordan examining patterns of tobacco use among adolescents, or how use is related to health perceptions. This study aims to estimate the prevalence of tobacco use and to assess the relationship between use and health-related perceptions. A cross-sectional survey was conducted among a sample of 11-18 year old school students from a major governorate in Jordan. Using a multistage random sampling 1050 students were selected. Students were categorized as non-smokers, cigarette-only smokers, waterpipe-only smokers, or dual smokers. Rates of waterpipe-only and cigarette-only smoking were 7% and 3%, respectively, and were similar for boys and girls. In contrast, the rate of dual use was much higher than for single product use and was double in girls compared to boys (34% vs. 17%). Dual-smokers were significantly more likely to think that it is safe to smoke as long as the person intends to quit within two years compared to non-smokers, and had lower self-rated health status than other groups. This is the first study among Arab adolescents to document high rates of dual tobacco use, especially pronounced among girls. The study findings have significant implications for designing tobacco smoking prevention programs for school health settings. PMID- 25019266 TI - Environmental consequences of rapid urbanization in zhejiang province, East china. AB - Since reforms carried out in the late 1970s, China has experienced unprecedented rates of urban growth. Remote sensing data and surface observational data are used to investigate the urbanization process and related environmental consequences, focusing on extreme heat events and air pollution, in Zhejiang Province (ZJP, East China). Examination of satellite-measured nighttime light data indicates rapid urbanization in ZJP during the past decade, initially forming three urban clusters. With rapid urban sprawl, a significant Urban Heat Island (UHI) effect has emerged. During extreme heat events in summer, the UHI effect significantly exacerbates nocturnal heat stress in highly urbanized areas. Taking a long-term view, urbanization also causes additional hot days and hot degree days in urban areas. Urbanization also imposes a heavy burden on local and regional air quality in ZJP. Degraded visibility and an increase in haze days are observed at most meteorological stations, especially in the three urban clusters. The results show that urbanization has led to serious environmental problems in ZJP, not only on the city scale, but also on the regional scale. Maintaining a balance between the continuing process of urbanization and environmental sustainability is a major issue facing the local government. PMID- 25019265 TI - Reliability of urinary excretion rate adjustment in measurements of hippuric acid in urine. AB - The urinary excretion rate is calculated based on short-term, defined time sample collections with a known sample mass, and this measurement can be used to remove the variability in urine concentrations due to urine dilution. Adjustment to the urinary excretion rate of hippuric acid was evaluated in 31 healthy volunteers (14 males and 17 females). Urine was collected as short-term or spot samples and tested for specific gravity, creatinine and hippuric acid. Hippuric acid values were unadjusted or adjusted to measurements of specific gravity, creatinine or urinary excretion rate. Hippuric acid levels were partially independent of urinary volume and urinary flow rate, in contrast to specific gravity and creatinine, which were both highly dependent on the hippuric acid level. Accordingly, hippuric acid was independent on urinary specific gravity and creatinine excretion. Unadjusted and adjusted values for specific gravity or creatinine were generally closely correlated, especially in spot samples. Values adjusted to the urinary excretion rate appeared well correlated to those unadjusted and adjusted to specific gravity or creatinine values. Thus, adjustment of crude hippuric acid values to the urinary excretion rate is a valid procedure but is difficult to apply in the field of occupational medicine and does not improve the information derived from values determined in spot urine samples, either unadjusted or adjusted to specific gravity and creatinine. PMID- 25019267 TI - Home and health in the third age - methodological background and descriptive findings. AB - BACKGROUND: The understanding of the complex relationship between the home environment, well-being and daily functioning in the third age is currently weak. The aim of this paper is to present the methodological background of the Home and Health in the Third Age Study, and describe a sample of men and women in relation to their home and health situation. METHODS AND DESIGN: The study sample included 371 people aged 67-70, living in ordinary housing in the south of Sweden. Structured interviews and observations were conducted to collect data about objective and perceived aspects of home and health. RESULTS: The majority of the participants were in good health and had few functional limitations. Women had more functional limitations and reported more symptoms than men. Environmental barriers were found in every home investigated; the most were found in the kitchen and hygiene area. Environmental barriers were more common in multi-family than in one-family dwellings. DISCUSSION: This study will increase our knowledge on home and health dynamics among people in the third age. The results have potential to contribute to societal planning related to housing provision, home care and social services for senior citizens. PMID- 25019269 TI - Ranibizumab versus mitomycin C in primary trabeculectomy--a pilot study. AB - PURPOSE: The current standard adjunctive agent used in primary trabeculectomy is mitomycin C (MMC), but it is associated with well known complications. The objective of this study is to test the feasibility of the anti-vascular endothelial growth factor (anti-VEGF) agent ranibizumab for adjunctive use instead of MMC (0.4 mg/ml). MATERIALS AND METHODS: A prospective, randomized open label study of 24 consecutive patients undergoing primary trabeculectomy at the Wills Eye Institute Glaucoma Service from March 2008 through February 2010 was conducted. Twenty-four eyes were included in the study and clinical outcomes were examined. RESULTS: There were no significant differences in baseline demographic or clinical characteristics between the ranibizumab and MMC groups. Nine of the 12 ranibizumab patients completed the 1 year study. Three subjects required tube shunt surgery and were removed from the study. Eleven of 12 MMC patients completed the study (one underwent hip surgery and was lost to follow-up). Mean intra-ocular pressure (IOP) was significantly higher in the ranibizumab arm at 1 month (p = 0.002). Bleb extent was significantly less in the ranibizumab arm at 6 months (p = 0.006). Patients in the ranibizumab arm required more hypotensive medication at month 3 (p = 0.011). CONCLUSIONS: Although there was no IOP difference or difference in medication use between the two treatment groups at one year, more patients in the ranibizumab group required additional glaucoma surgery during the study period. PMID- 25019268 TI - Indoor air quality in Brazilian universities. AB - This study evaluated the indoor air quality in Brazilian universities by comparing thirty air-conditioned (AC) (n = 15) and naturally ventilated (NV) (n = 15) classrooms. The parameters of interest were indoor carbon dioxide (CO2), temperature, relative humidity (RH), wind speed, viable mold, and airborne dust levels. The NV rooms had larger concentration of mold than the AC rooms (1001.30 +/- 125.16 and 367.00 +/- 88.13 cfu/m3, respectively). The average indoor airborne dust concentration exceeded the Brazilian standards (<80 ug/m3) in both NV and AC classrooms. The levels of CO2 in the AC rooms were significantly different from the NV rooms (1433.62 +/- 252.80 and 520.12 +/- 37.25 ppm, respectively). The indoor air quality in Brazilian university classrooms affects the health of students. Therefore, indoor air pollution needs to be considered as an important public health problem. PMID- 25019270 TI - The defective bone marrow-derived mesenchymal stem cells in patients with chronic immune thrombocytopenia. AB - Chronic immune thrombocytopenia (ITP) is characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. Mesenchymal stem cells (MSCs) are proposed to exhibit immune modulatory functions in self-tolerance maintenance. In this study, we aimed to characterize phenotypically and functionally bone marrow (BM)-derived MSCs from adult chronic ITP patients. Our results showed that BM-MSCs from patients with chronic ITP exhibited impaired proliferation, abnormal morphology and excessive apoptosis, and these defects could be ameliorated by modifying the culture environment. BM-MSCs from chronic ITP patients were shown to have similar immunophenotype and capacities to differentiate along adipogenic and osteogenic lineages as those from normal controls. However, the immune-inhibiting potential and the regulatory T cell inducing ability of BM-MSCs from patients were defective compared to that of normal BM-MSCs. These findings suggest that the BM-MSCs were defective in chronic ITP patients. Whether the defective BM-MSCs are relevant to the pathogenesis of chronic ITP remains to be determined. PMID- 25019271 TI - Self-reflections on mortality among hospice patients? PMID- 25019273 TI - Visual word learning in skilled readers of English. AB - Three experiments are reported analysing the processes by which adult readers of English learn new written words. Visual word learning was simulated by presenting short (four-letter) and longer (seven-letter) nonwords repeatedly and observing the reduction in naming latencies and the convergence in reaction times (RTs) to shorter and longer items that are the hallmarks of visual word learning. Experiment 1 presented nonwords in ten consecutive blocks. Naming latencies reduced over the first four or five presentations. The effect of length on naming RTs was large in block 1 but non-significant after four or five presentations. Experiment 2 demonstrated some reduction in RTs to untrained nonwords following practice on a trained set, but the reduction was less than for the trained items and RTs to shorter and longer nonwords did not converge. Experiment 3 included a retest after seven days which showed some slowing of RTs compared with the end of the first session but also considerable retention of learning. We conclude that four to six exposures to novel words (nonwords) are sufficient to establish durable lexical representations that permit parallel processing of newly-learned words. The results are discussed in terms of theoretical models of reading and word learning. PMID- 25019272 TI - Regulation of cell transformation by Rb-controlled redox homeostasis. AB - Rb is a tumor suppressor, and regulates various biological progresses, such as cell proliferation, development, metabolism and cell death. In the current study, we show that Rb knockout in 3T3 cells leads to oxidative redox state and low mitochondrial membrane potential by regulating mitochondrial activity. Our results indicate that Rb plays an important role in controlling redox homeostasis. More importantly, the functions of Rb in modulating cell proliferation, death and transformation are, at least in part, mediated by its controlling cellular redox state. In addition, our results also suggest that the cellular redox state possibly determines various biological activities, including cell survival, death and transformation, where Rb is functioning as a regulator of redox homeostasis. PMID- 25019274 TI - Evaluation of a clinical fMRI cueing system utilizing complex scene and auditory stimuli for neurosurgical treatment planning of patients with cognitive and physical deficits. AB - PURPOSE: The adoption of functional MRI for presurgical planning in neuro oncology has been limited by the high degree of patient compliance required to generate accurate activation maps. The purpose of this work was to evaluate the brain activation properties and patient head motion associated with a presurgical fMRI cueing system utilizing complex scene and auditory commands to enhance compliance in patients with cognitive and physical deficits. MATERIALS AND METHODS: An fMRI cueing system which delivered simultaneous audio and video task instructions was compared to a simple visual cueing system across 10 healthy volunteers, each performing two different motor tasks (40 total fMRI acquisitions). Statistical differences between the complex and simple cueing systems were evaluated using a mixed effects modeling method which was able to carry up variances from the individual analyses to the group analysis. Differences in relative head motion between the systems were evaluated using a paired t-test. RESULTS: Both cueing systems demonstrated typical somatotopic activity distributions in the pre- and postcentral gyrus of the left hemisphere. No significant differences were found between the systems in target brain regions. Furthermore, relative head motion using the complex system was found to not differ statistically from the simple method. CONCLUSION: The fMRI cueing system using complex scene stimuli produced results comparable to a simple cueing system in target regions of the brain. In patients presenting with deficits that lead to noncompliance with fMRI procedures, the use of complex scene stimuli may provide a good alternative to conventional cueing methods. PMID- 25019275 TI - Lack of association of a genetic variant in the long intergenic noncoding RNA (linc01080) with Alzheimer's disease and amnestic mild cognitive impairment in Han Chinese. AB - Alzheimer's disease (AD) is a complex neurodegenerative disorder that is the most common form of dementia in the elderly and is characterized by progressive memory loss and cognitive dysfunction. Although the pathogenetic mechanism of AD is still unknown, genetic variants play a critical role in the pathogenesis of AD. Increasing evidence has suggested that noncoding RNAs (ncRNAs) may be associated with the development of AD. A previous study analyzing human single-nucleotide polymorphisms (SNPs) of long intergenic noncoding RNA (lincRNA) at the genome level indicated that a genetic variant, rs7990916, in the lincRNA 01080 (linc01080) may play an important role in the physiology and pathophysiology of the human brain. To determine whether this SNP alters the risk for sporadic AD (SAD) or amnestic mild cognitive impairment (aMCI) susceptibility, we conducted a case-control study in a Han Chinese population with 106 SAD patients, 67 aMCI patients, and 179 healthy controls. Using the LDR-PCR genotyping method, we found no significant difference in allele or genotype frequency in the SNP rs7990916 between patients and controls (p > 0.05). Our results do not support previous findings, suggesting that further studies by using large-scale association analyses are warranted in Han Chinese populations. PMID- 25019276 TI - Meta-analysis of 5-hydroxytryptamine type 2A receptor polymorphisms and migraine susceptibility. AB - Epidemiologic studies have investigated the association of polymorphisms in 5 hydroxytryptamine type 2A receptor (5HT2A) gene and migraine susceptibility, but the results of those studies are inconclusive. To obtain a more systematic estimation of the association, we conducted a comprehensive search to examine all the eligible studies of 5HT2A polymorphisms and migraine risk. The odd ratios (ORs) with 95% confidence intervals (CIs) were used to determine the strength of the association. Publication bias was analyzed by Begg's funnel plots. Seven eligible studies regarding 5HT2A T102C and A-1438G polymorphisms with 721 cases and 713 controls were included in this meta-analysis. Overall, no significant associations were found between 5HT2A T102C (for T vs. C: OR = 1.029, 95% CI = 0.870-1.217, p = 0.739; for TT vs. CC: OR = 1.083, 95% CI = 0.760-1.544, p = 0.657; for TT + TC vs. CC: OR = 1.066, 95% CI = 0.802-1.416, p = 0.662; for TT vs. TC + CC: OR = 1.017, 95% CI = 0.774-1.336, p = 0.904) or A-1438G (for T vs. C: OR = 0.996, 95% CI = 0.726-1.365, p = 0.979; for TT vs. CC: OR = 0.983, 95% CI = 0.511-1.891, p = 0.960; for TT + TC vs. CC: OR = 1.118, 95% CI = 0.654-1.910, p = 0.684; for TT vs. TC + CC: OR = 0.890, 95% CI = 0.528-1.499, p = 0.661) polymorphisms and migraine risk. The further subgroup analysis by ethnicity, assay and disease type also found no significant association using four genetic models. Meanwhile, the publication bias analysis suggests that there is no publication bias in these studies. In conclusion, our current meta-analysis implies that 5HT2A T102C and A-1438G polymorphisms may be not risk factors in the pathogenesis of migraine. PMID- 25019277 TI - A "click" chemistry constructed affinity system for 2-oxoglutaric acid receptors and binding proteins. AB - An ingenious and specific affinity resin designed to capture the 2-oxoglutaric acid (2-OG) binding proteins was constructed by appending a 2-OG tag to the solid resin via a Cu-catalyzed Huisgen "click" reaction. The so-obtained affinity resin was able to recognize, retain and separate the established 2-OG binding protein NtcA in both the pure form and crude cellular extract, thus constituting a valuable means of searching for novel 2-OG receptors with a view to exploring the signalling pathways of 2-OG, a key Krebs cycle intermediate with unprecedented signalling functions. PMID- 25019279 TI - Investigating the economic burden of ALS in Greece: a cost-of-illness approach. AB - The present study aims to investigate the economic burden of ALS per patient in Greece. A sample of 33 patients who were monitored in Aeginition University Hospital in Athens, a reference centre for ALS in Greece, was used for the calculations. According to the findings of this study the total annual cost per ALS patient in Greece was ?7450. The direct cost was estimated at ?4305 (or 57.8% of the total cost), while the indirect cost was ?3145 (or 42.2% of the total cost). Medications, professional home help and cost due to work absenteeism were the leading components of total cost. In general, the aforementioned amount is considered substantial, albeit lower than the corresponding amount of other countries. PMID- 25019278 TI - mTOR signaling in T cell immunity and autoimmunity. AB - The mammalian target of rapamycin (mTOR), a phosphoinositide-3-kinase-related protein kinase, acts as a rheostat capable of integrating a variety of environmental cues in the form of nutrients, energy, and growth factors to modulate organismal processes and homeostasis. Recently, there is a growing appreciation of mTOR in adaptive immunity for its crucial roles in keeping a proper balance between T cell quiescence and activation. Under steady-state circumstances, mTOR is subtly inhibited by multiple mechanisms to maintain normal T cell homeostasis. Antigen recognition by naive T cells leads to mTOR activation, which subsequently promotes the differentiation of these cells into distinct effector T cell subsets. This review focuses primarily on the recent literature with respect to the regulatory effects and mechanisms of mTOR signaling in dictating T cell fate, and discusses the therapeutic implications of mTOR modulation in T-cell-mediated autoimmunity. PMID- 25019280 TI - Bioassay-guided isolation and identification of anti-platelet-active compounds from the root of Ashitaba (Angelica keiskei Koidz.). AB - Platelet aggregation is fundamental to a wide range of physiological and pathological processes, including the induction of thrombosis and arteriosclerosis. Anti-platelet activity of a crude methanol extract and solvent fractions of Ashitaba roots (Angelica keiskei Koidz.) was evaluated using a turbidimetric method using washed rabbit platelets. We identified the anti platelet activities of two chalcones, 4-hydroxyderricin and xanthoangelol, isolated from the ethyl acetate-soluble fraction of Ashitaba roots by using a bioassay-guided isolation method. 4-Hydroxyderricin and xanthoangelol effectively inhibited platelet aggregation induced by collagen (IC50 of 41.9 and 35.9 MUM, respectively), platelet-activating factor (IC50 of 46.1 and 42.3 MUM, respectively) and phorbol 12-myristate 13-acetate (IC50 of 16.5 and 45.9 MUM, respectively). These compounds did not inhibit thrombin-induced platelet aggregation (IC50 of>80 MUM). The results suggest that the chalcones 4 hydroxyderricin and xanthoangelol may be potent anti-thrombotic components of A. keiskei Koidz. PMID- 25019281 TI - Fast-proliferating adipose tissue mesenchymal-stromal-like cells for therapy. AB - Human mesenchymal stromal cells, whether from the bone marrow or adipose tissue (hASCs), are promising cell therapy agents. However, generation of abundant cells for therapy remains to be a challenge, due to the need of lengthy expansion and the risk of accumulating genomic defects during the process. We show that hASCs can be easily induced to a reversible fast-proliferating phenotype (FP-ASCs) that allows rapid generation of a clinically useful quantity of cells in <2 weeks of culture. Expanded FP-ASCs retain their finite expansion capacity and pluripotent properties. Despite the high proliferation rate, FP-ASCs show genomic stability by array-comparative genomic hybridization, and did not generate tumors when implanted for a long time in an SCID mouse model. Comparative analysis of gene expression patterns revealed a set of genes that can be used to characterize FP ASCs and distinguish them from hASCs. As potential candidate therapeutic agents, FP-ASCs displayed high vasculogenic capacity in Matrigel assays. Moreover, application of hASCs and FP-ASCs in a fibrin scaffold over a myocardium infarct model in SCID mice showed that both cell types can differentiate to endothelial and myocardium lineages, although FP-ASCs were more potent angiogenesis inducers than hASCs, at promoting myocardium revascularization. PMID- 25019282 TI - Effects of a novel pesticide-particle conjugate on viability and reactive oxygen species generation in neuronal (PC12) cells. AB - Development of new methods and compounds to eradicate insect vectors are desperately needed. To that end, our team has previously described the synthesis and characterization of a conjugate comprised of a silver nanoparticle core encapsulated by the pyrethroid pesticide, deltamethrin (pesticide encapsulated silver nanoparticle termed "PENS"). For this current work, the PENS conjugate was tested in neuronal cultured cells to compare the cytotoxic responses to the unconjugated pesticide deltamethrin - a known neurotoxic agent and pristine silver nanoparticles. The PC12 (pheochromocytoma of the rat adrenal medulla) cell line was chosen as a model neuronal culture system. Cells were exposed to known concentrations of PENS, deltamethrin or silver nanoparticle suspensions to assess the degree of toxicity in vitro. After 24 hours of incubation, cell viability and intracellular reactive oxygen species (ROS) were measured. Bright field images of high dose exposures to dosing solutions were also acquired to evaluate cell morphology. Exposure to PENS resulted in a 17% decline in viability at the highest concentration of 45 uM while exposure to deltamethrin caused a 47% decrease. These results suggest that cellular viability was less adversely affected by PENS than by the deltamethrin. Also, ROS production following PENS exposure indicated that the newly developed conjugate was responding in a similar manner as that of cells treated with deltamethrin only. PMID- 25019283 TI - Annexin5 plays a vital role in Arabidopsis pollen development via Ca2+-dependent membrane trafficking. AB - The regulation of pollen development and pollen tube growth is a complicated biological process that is crucial for sexual reproduction in flowering plants. Annexins are widely distributed from protists to higher eukaryotes and play multiple roles in numerous cellular events by acting as a putative "linker" between Ca2+ signaling, the actin cytoskeleton and the membrane, which are required for pollen development and pollen tube growth. Our recent report suggested that downregulation of the function of Arabidopsis annexin 5 (Ann5) in transgenic Ann5-RNAi lines caused severely sterile pollen grains. However, little is known about the underlying mechanisms of the function of Ann5 in pollen. This study demonstrated that Ann5 associates with phospholipid membrane and this association is stimulated by Ca2+ in vitro. Brefeldin A (BFA) interferes with endomembrane trafficking and inhibits pollen germination and pollen tube growth. Both pollen germination and pollen tube growth of Ann5-overexpressing plants showed increased resistance to BFA treatment, and this effect was regulated by calcium. Overexpression of Ann5 promoted Ca2+-dependent cytoplasmic streaming in pollen tubes in vivo in response to BFA. Lactrunculin (LatB) significantly prohibited pollen germination and tube growth by binding with high affinity to monomeric actin and preferentially targeting dynamic actin filament arrays and preventing actin polymerization. Overexpression of Ann5 did not affect pollen germination or pollen tube growth in response to LatB compared with wild-type, although Ann5 interacts with actin filaments in a manner similar to some animal annexins. In addition, the sterile pollen phenotype could be only partially rescued by Ann5 mutants at Ca2+-binding sites when compared to the complete recovery by wild-type Ann5. These data demonstrated that Ann5 is involved in pollen development, germination and pollen tube growth through the promotion of endomembrane trafficking modulated by calcium. Our results provide reliable molecular mechanisms that underlie the function of Ann5 in pollen. PMID- 25019284 TI - A novel, simplified technique to amplify Eimeria (Coccidia: Apicomplexa) DNA from oocysts. AB - A new method to amplify coccidia DNA by polymerase chain reaction (PCR) was developed by placing freeze-thawed oocysts in Ready-to-Go PCR bead tubes and using a 5-min initial heat denaturation step. Positive PCR reactions were found in 3 of 3 samples containing 20 or 50 oocysts; when <=5 oocysts were used, 1 of 3 samples was positive. This technique shows potential for effectively and efficiently detecting and identifying oocysts from soil, feces, and other matter. PMID- 25019286 TI - Radial scars and subsequent breast cancer risk: a meta-analysis. AB - BACKGROUND: The relationship between radial scars and breast cancer is unclear, as the results of different studies are inconsistent. We aim to solve the controversy and assess the breast cancer risk of radial scars. METHODS: Case control or cohort studies about radial scars and breast cancer risk published in PubMed, Web of Science and the Cochrane Library from 2000 to 2013 were searched. Heterogeneity for the eligible data was assessed and a pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. RESULTS: Five observational studies involving 2521 cases and 20290 controls were included in our study. From pooled analysis, radial scars were found to have a 1.33 fold increased risk of breast cancer, but which was not significant (P = 0.138). Sample size contributed to heterogeneity. In subgroup analysis, the results pooled from studies with sample size >2000 show that presence of radial scars was associated with 1.6 times breast cancer risk compared to absence of radial scars. Radial scars increased the risk of breast cancer among women with proliferative disease without atypia, but no significant association between radial scars and carcinoma was noted among women with atypical hyperplasia. CONCLUSIONS: Radial scars tend to be associated with an increased breast cancer risk. Radial scars should be considered among women with proliferative disease without atypia, while atypical hyperplasia is still the primary concern among women with both radial scars and atypical hyperplasia. PMID- 25019287 TI - Insight into insulator-to-metal transition of sulfur-doped silicon by DFT calculations. AB - Using density functional theory calculations, the mechanism of insulator-to-metal transition of S-doped Si has been systematically investigated. The calculated crystal structure indicates that the gentle lattice distortion is caused by sulfur doping, and this doping effect is gradually weakened with the increase of sulfur concentration. Two distinct impurity energy levels in the band gap are induced by sulfur doping, and their position and width are linearly varying along with the increase of sulfur concentration. Owing to the overlap and dispersion of these impurity energy levels, the insulator-to-metal transition occurs at the sulfur concentration of 2.095 * 10(20) cm(-3), which is consistent with the experimental measurement. Moreover, the defect states related with sulfur doping show delocalization features and are more outstanding at the higher sulfur concentration. The calculated results suggest that S-hyperdoped Si is a suitable candidate for intermediate band solar cells. PMID- 25019288 TI - Identification of a cytotoxic form of dimeric interleukin-2 in murine tissues. AB - Interleukin-2 (IL-2) is a multi-faceted cytokine, known for promoting proliferation, survival, and cell death depending on the cell type and state. For example, IL-2 facilitates cell death only in activated T cells when antigen and IL-2 are abundant. The availability of IL-2 clearly impacts this process. Our laboratory recently demonstrated that IL-2 is retained in blood vessels by heparan sulfate, and that biologically active IL-2 is released from vessel tissue by heparanase. We now demonstrate that heparanase digestion also releases a dimeric form of IL-2 that is highly cytotoxic to cells expressing the IL-2 receptor. These cells include "traditional" IL-2 receptor-bearing cells such as lymphocytes, as well as those less well known for IL-2 receptor expression, such as epithelial and smooth muscle cells. The morphologic changes and rapid cell death induced by dimeric IL-2 imply that cell death is mediated by disruption of membrane permeability and subsequent necrosis. These findings suggest that IL-2 has a direct and unexpectedly broad influence on cellular homeostatic mechanisms in both immune and non-immune systems. PMID- 25019289 TI - Pharmacokinetic evaluation of esomeprazole for the treatment of gastroesophageal reflux disease. AB - INTRODUCTION: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD). They are recommended by the American College of Gastroenterology for healing erosive esophagitis (EO) and as long-term treatment in patients with healed EO. The available PPIs differ somewhat in their pharmacokinetics and clinical properties, but whether these differences are of clinical relevance is a matter of debate. Some safety concerns have been raised with the use of PPIs, mostly an increased incidence of infectious diseases such as community-acquired pneumonia or Clostridium difficile diarrhea. AREAS COVERED: This article explores the results of clinical studies on the pharmacokinetics and pharmacodynamics of esomeprazole , as well as on its clinical efficacy to manage patients with GERD. EXPERT OPINION: GERD is a public health concern as its worldwide incidence and associated complications are increasing alongside the exponentially increasing problem of obesity. PPIs are the first pharmacological option because of their efficacy and overall positive risk-to-benefit ratio. Improved efficacy with the use of stereospecific isomers of PPIs, such as esomeprazole, has not yet been convincingly demonstrated. Nevertheless, because of individual experience with former treatment, some patients may report better symptom control when treated with a specific PPI rather than with others. PMID- 25019290 TI - Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis. AB - Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis. PMID- 25019292 TI - WITHDRAWN: Drugs for preventing migraine headaches in children. PMID- 25019291 TI - Epigenetic inheritance, epimutation, and the response to selection. AB - There has been minimal theoretical exploration of the role of epigenetic variation in the response to natural selection. Using a population genetic model, I derive formulae that characterize the response of epigenetic variation to selection over multiple generations. Unlike genetic models in which mutation rates are assumed to be low relative to the strength of selection, the response to selection decays quickly due to a rapid lowering of parent-offspring epiallelic correlation. This effect is separate from the slowing response caused by a reduction in epigenetic variation. These results suggest that epigenetic variation may be less responsive to natural selection than is genetic variation, even in cases where levels of heritability appear similar. PMID- 25019293 TI - Drug therapies for reducing gastric acidity in people with cystic fibrosis. AB - BACKGROUND: Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. OBJECTIVES: To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 17 March 2014. SELECTION CRITERIA: All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS: The searches identified 39 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta analyses. The included trials were generally not reported adequately enough to allow judgements on risk of bias.However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS: Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions. PMID- 25019294 TI - WITHDRAWN: Dipyrone for acute primary headaches. PMID- 25019295 TI - Phototherapy for treating pressure ulcers. AB - BACKGROUND: A pressure ulcer is defined as "an area of localized injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure, or pressure in combination with shear". The use of phototherapy - that is, light (or laser) used as an adjuvant, non-surgical intervention, with the aim of having a therapeutic effect on healing - has increased recently. OBJECTIVES: To determine the effects of phototherapy on the healing of pressure ulcers. SEARCH METHODS: In January 2014, we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid EMBASE; Ovid MEDLINE (In-Process & Other Non Indexed Citations); and EBSCO CINAHL. We did not restrict the search by language or publication date. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of phototherapy (in addition to standard treatment) with sham phototherapy (in addition to standard treatment), another type of phototherapy (in addition to standard treatment) or standard or conventional treatment alone. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies for relevance and design according to the selection criteria, extracted data and evaluated study quality. The authors made attempts to obtain missing data by contacting study authors. Disagreement was resolved by consensus and discussion with a third review author. MAIN RESULTS: We identified seven RCTs involving 403 participants. All the trials were at unclear risk of bias. Trials compared the use of phototherapy with standard care only (six trials) or sham phototherapy (one trial). Only one of the trials included a third arm in which another type of phototherapy was applied. Overall, there was insufficient evidence to determine the relative effects of phototherapy for healing pressure ulcers. Time to complete healing was reported in three studies. Two studies showed the ultraviolet (UV) treated group had a shorter mean time to complete healing than the control group (mean difference -2.13 weeks (95% CI -3.53 to 0.72, P value 0.003)). One study reported that the laser group had a longer mean time to complete healing than the control group (mean difference 5.77 weeks; 95% CI -0.25 to 11.79). However, this result should be interpreted with caution, as these were small studies and the findings may have been due to chance. Three studies reported proportions of ulcers healed with a variety of results. One study reported a different outcome measure, and the other two studies had different treatment durations. These variations did not allow us to pool the studies and draw any conclusions as to whether phototherapy is effective or not. Adverse effects were reported in only two studies that compared phototherapy with control; the risk ratio for adverse events was imprecise. One study reported risk ratio (RR) 0.72 (95%CI 0.18 to 2.80). However, another study reported RR 0.89 (95% CI: 0.71 to 1.12) based on the number of events in each group, rather than the number of people with events. Among five studies reporting the rate of change in ulcer area, three studies found no statistically significant difference between the two groups. Pooling was not undertaken because of differences in outcome measures reported. The results were based on data from trials with unclear risk of bias for which generation of the randomisation sequence, concealment allocation and blinding of outcome assessors were unclear. No studies reported on quality of life, length of hospital stay, pain or cost. AUTHORS' CONCLUSIONS: We are very uncertain as to the effects of phototherapy in treating pressure ulcers. The quality of evidence is very low due to the unclear risk of bias and small number of trials available for analysis. The possibility of benefit or harm of this treatment cannot be ruled out. Further research is recommended. PMID- 25019296 TI - Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy. AB - BACKGROUND: Patients with brain tumour usually suffer from increased pressure in the skull due to swelling of brain tissue. A swollen brain renders surgical removal of the brain tumour difficult. To ease surgical tumour removal, measures are taken to reduce brain swelling, often referred to as brain relaxation. Brain relaxation can be achieved with intravenous fluids such as mannitol or hypertonic saline. This review was conducted to find out which of the two fluids may have a greater impact on brain relaxation. OBJECTIVES: The objective of this review was to compare the effects of mannitol versus those of hypertonic saline on intraoperative brain relaxation in patients undergoing craniotomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), MEDLINE via Ovid SP (1966 to October 2013) and EMBASE via Ovid SP (1980 to October 2013). We also searched specific websites, such as www.indmed.nic.in, www.cochrane-sadcct.org and www.Clinicaltrials.gov. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the use of hypertonic saline versus mannitol for brain relaxation. We also included studies in which any other method used for intraoperative brain relaxation was compared with mannitol or hypertonic saline. Primary outcomes were longest follow up mortality, Glasgow Outcome Scale score at three months and any adverse events related to mannitol or hypertonic saline. Secondary outcomes were intraoperative brain relaxation, intensive care unit (ICU) stay, hospital stay and quality of life. DATA COLLECTION AND ANALYSIS: We used standardized methods for conducting a systematic review, as described by the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis. We used a fixed effect model when no evidence was found of significant heterogeneity between studies, and a random-effects model when heterogeneity was likely. MAIN RESULTS: We included six RCTs with 527 participants. Only one RCT was judged to be at low risk of bias. The remaining five RCTs were at unclear or high risk of bias. No trial mentioned the primary outcomes of longest follow-up mortality, Glasgow Outcome Scale score at three months or any adverse events related to mannitol or hypertonic saline. Three trials mentioned the secondary outcomes of intraoperative brain relaxation, hospital stay and ICU stay; quality of life was not reported in any of the trials. Brain relaxation was inadequate in 42 of 197 participants in the hypertonic saline group and in 68 of 190 participants in the mannitol group. The risk ratio for brain bulge or tense brain in the hypertonic saline group was 0.60 (95% confidence interval (CI) 0.44 to 0.83, low-quality evidence). One trial reported ICU and hospital stay. The mean (standard deviation (SD)) duration of ICU stay in the mannitol and hypertonic saline groups was 1.28 (0.5) and 1.25 (0.5) days (P value 0.64), respectively; the mean (SD) duration of hospital stay in the mannitol and hypertonic saline groups was 5.7 (0.7) and 5.7 (0.8) days (P value 1.00), respectively AUTHORS' CONCLUSIONS: From the limited data available on the use of mannitol and hypertonic saline for brain relaxation during craniotomy, it is suggested that hypertonic saline significantly reduces the risk of tense brain during craniotomy. A single trial suggests that ICU stay and hospital stay are comparable with the use of mannitol or hypertonic saline. However, focus on other related important issues such as long-term mortality, long-term outcome, adverse events and quality of life is needed. PMID- 25019297 TI - Interventions to improve hearing aid use in adult auditory rehabilitation. AB - BACKGROUND: Acquired adult-onset hearing loss is a common long-term condition for which the most common intervention is hearing aid fitting. However, up to 40% of people fitted with a hearing aid either fail to use it or may not gain optimal benefit from it. OBJECTIVES: To assess the long-term effectiveness of interventions to promote the use of hearing aids in adults with acquired hearing loss fitted with at least one hearing aid. SEARCH METHODS: We searched the Cochrane ENT Disorders Group Trials Register; CENTRAL; PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 6 November 2013. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions designed to improve or promote hearing aid use in adults with acquired hearing loss compared with usual care or another intervention. We excluded interventions that compared hearing aid technology. We classified interventions according to the 'chronic care model' (CCM). The primary outcomes were hearing aid use (measured as adherence or daily hours of use) and adverse effects (inappropriate advice or clinical practice, or patient complaints). Secondary patient-reported outcomes included quality of life, hearing handicap, hearing aid benefit and communication. Outcomes were measured over the short ( 12 to < 52 weeks) and long term (one year plus). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 32 studies involving a total of 2072 participants. The risk of bias across the included studies was variable. We judged the GRADE quality of evidence to be very low or low for the primary outcomes where data were available.The majority of participants were over 65 years of age with mild to moderate adult-onset hearing loss. There was a mix of new and experienced hearing aid users. Six of the studies (1018 participants) were conducted in a military veteran population. Six of the studies (287 participants) assessed long-term outcomes.All 32 studies tested interventions that could be classified as self management support (ways to help someone to manage their hearing loss and hearing aid(s) better by giving information, practice and experience at listening/communicating or by asking people to practise tasks at home) and/or delivery system design interventions (just changing how the service was delivered) according to the CCM. Self management support interventions We found no studies that investigated the effect of these interventions on adherence, adverse effects or hearing aid benefit. Two studies reported daily hours of hearing aid use but we were unable to combine these in a meta-analysis. There was no evidence of a statistically significant effect on quality of life over the medium term. Self management support reduced short- to medium-term hearing handicap (two studies, 87 participants; mean difference (MD) 12.80, 95% confidence interval (CI) -23.11 to -2.48 (0 to 100 scale)) and increased the use of verbal communication strategies in the short to medium term (one study, 52 participants; MD 0.72, 95% CI 0.21 to 1.23 (0 to 5 scale)). The clinical significance of these statistical findings is uncertain but it is likely that the outcomes were clinically significant for some, but not all, participants. Our confidence in the quality of this evidence was very low. No self management support studies reported long-term outcomes. Delivery system design interventions These interventions did not significantly affect adherence or daily hours of hearing aid use in the short to medium term, or adverse effects in the long term. We found no studies that investigated the effect of these interventions on quality of life. There was no evidence of a statistically or clinically significant effect on hearing handicap, hearing aid benefit or the use of verbal communication strategies in the short to medium term. Our confidence in the quality of this evidence was low or very low. Long-term outcome measurement was rare. Combined self management support/delivery system design interventions We found no studies that investigated the effect of complex interventions combining components of self management support and delivery system design on adherence or adverse effects. There was no evidence of a statistically or clinically significant effect on daily hours of hearing aid use over the long term, or the short to medium term. Similarly, there was no evidence of an effect on quality of life over the long term, or short to medium term. These combined interventions reduced hearing handicap in the short to medium term (13 studies, 485 participants, standardised mean difference (SMD) -0.27, 95% CI -0.49 to 0.06). This represents a small-moderate effect size but there is no evidence of a statistically significant effect over the long term. There was evidence of a statistically, but not clinically, significant effect on long-term hearing aid benefit (two studies, 69 participants, MD 0.30, 95% CI 0.02 to 0.58 (1 to 5 scale)), but no evidence of effect over the short to medium term. There was evidence of a statistically, but not clinically, significant effect on the use of verbal communication strategies in the short term (four studies, 223 participants, MD 0.45, 95% CI 0.15 to 0.74 (0 to 5 scale)), but not the long term. Our confidence in the quality of this evidence was low or very low.We found no studies that assessed the effect of other CCM interventions (decision support, the clinical information system, community resources or health system changes). AUTHORS' CONCLUSIONS: There is some low to very low quality evidence to support the use of self management support and complex interventions combining self management support and delivery system design in adult auditory rehabilitation. However, effect sizes are small and the range of interventions that have been tested is relatively limited. Priorities for future research should be assessment of long-term outcome a year or more after the intervention, development of a core outcome set for adult auditory rehabilitation and development of study designs and outcome measures that are powered to detect incremental effects of rehabilitative healthcare system changes over and above the provision of a hearing aid. PMID- 25019298 TI - Physician anaesthetists versus non-physician providers of anaesthesia for surgical patients. AB - BACKGROUND: With increasing demand for surgery, pressure on healthcare providers to reduce costs, and a predicted shortfall in the number of medically qualified anaesthetists it is important to consider whether non-physician anaesthetists (NPAs), who do not have a medical qualification, are able to provide equivalent anaesthetic services to medically qualified anaesthesia providers. OBJECTIVES: To assess the safety and effectiveness of different anaesthetic providers for patients undergoing surgical procedures under general, regional or epidural anaesthesia. We planned to consider results from studies across countries worldwide (including developed and developing countries). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL on 13 February 2014. Our search terms were relevant to the review question and not limited by study design or outcomes. We also carried out searches of clinical trials registers, forward and backward citation tracking and grey literature searching. SELECTION CRITERIA: We considered all randomized controlled trials (RCTs), non-randomized studies (NRS), non-randomized cluster trials and observational study designs which had a comparison group. We included studies which compared an anaesthetic administered by a NPA working independently with an anaesthetic administered by either a physician anaesthetist working independently or by a NPA working in a team supervised or directed by a physician anaesthetist. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial quality and extracted data, contacting study authors for additional information where required. In addition to the standard methodological procedures, we based our risk of bias assessment for NRS on the specific NRS risk of bias tool presented at the UK Cochrane Contributors' Meeting in March 2012. We considered case-mix and type of surgical procedure, patient co-morbidity, type of anaesthetic given, and hospital characteristics as possible confounders in the studies, and judged how well the authors had adjusted for these confounders. MAIN RESULTS: We included six NRS with 1,563,820 participants. Five were large retrospective cohort studies using routinely collected hospital or administrative data from the United States (US). The sixth was a smaller cohort study based on emergency medical care in Haiti. Two were restricted to obstetric patients whilst the others included a range of surgical procedures. It was not possible to combine data as there was a degree of heterogeneity between the included studies.Two studies failed to find a difference in the risk of death in women undergoing caesarean section when given anaesthesia by NPAs compared with physician anaesthetists, both working independently. One study reported there was no difference in mortality between independently working provider groups. One compared mortality risks between US states that had, or had not, 'opted-out' of federal insurance requirements for physician anaesthetists to supervise or direct NPAs. This study reported a lower mortality risk for NPAs working independently compared with physician anaesthetists working independently in both 'opt-out' and 'non-opt out' states.One study reported a lower mortality risk for NPAs working independently compared with supervised or directed NPAs. One reported a higher mortality risk for NPAs working independently than in a supervised or directed NPA group but no statistical testing was presented. One reported a lower mortality risk in the NPA group working independently compared with the supervised or directed NPA group in both 'opt-out' and 'non-opt out' states before the 'opt-out' rule was introduced, but a higher mortality risk in 'opt out' states after the 'opt-out' rule was introduced. One reported only one death and was unable to detect a risk in mortality. One reported that the risk of mortality and failure to rescue was higher for NPAs who were categorized as undirected than for directed NPAs.Three studies reported the risk of anaesthesia related complications for NPAs working independently compared to physician anaesthetists working independently. Two failed to find a difference in the risk of complications in women undergoing caesarean section. One failed to find a difference in risk of complications between groups in 'non-opt out' states. This study reported a lower risk of complications for NPAs working independently than for physician anaesthetists working independently in 'opt-out' states before the 'opt-out' rule was introduced, but a higher risk after, although these differences were not tested statistically.Two studies reported that the risk of complications was generally lower for NPAs working independently than in the NPA supervised or team group but no statistical testing was reported. One reported no evidence of increased risk of postoperative complications in an undirected NPA group versus a directed NPA group.The risk of bias and assessment of confounders was particularly important for this review. We were concerned about the use of routine data for research and the likely accuracy of such databases to determine the intervention and control groups, thus judging four studies at medium risk of inaccuracy, one at low and one, for which there was insufficient detail, at an unclear risk. Whilst we expected that mortality would have been accurately reported in record systems, we thought reporting may not be as accurate for complications, which relied on the use of codes. Studies were therefore judged as at high risk or an unclear risk of bias for the reporting of complications data. Four of the six studies received funding, which could have influenced the reporting and interpretation of study results. Studies considered confounders of case-mix, co-morbidity and hospital characteristics with varying degrees of detail and again we were concerned about the accuracy of the coding of data in records and the variables considered during assessment. Five of the studies used multivariate logistic regression models to account for these confounders. We judged three as being at low risk, one at medium risk and one at high risk of incomplete adjustment in analysis. AUTHORS' CONCLUSIONS: No definitive statement can be made about the possible superiority of one type of anaesthesia care over another. The complexity of perioperative care, the low intrinsic rate of complications relating directly to anaesthesia, and the potential confounding effects within the studies reviewed, all of which were non-randomized, make it impossible to provide a definitive answer to the review question. PMID- 25019300 TI - Local mapping of detector response for reliable quantum state estimation. AB - Improved measurement techniques are central to technological development and foundational scientific exploration. Quantum physics relies on detectors sensitive to non-classical features of systems, enabling precise tests of physical laws and quantum-enhanced technologies including precision measurement and secure communications. Accurate detector response calibration for quantum scale inputs is key to future research and development in these cognate areas. To address this requirement, quantum detector tomography has been recently introduced. However, this technique becomes increasingly challenging as the complexity of the detector response and input space grow in a number of measurement outcomes and required probe states, leading to further demands on experiments and data analysis. Here we present an experimental implementation of a versatile, alternative characterization technique to address many-outcome quantum detectors that limits the input calibration region and does not involve numerical post processing. To demonstrate the applicability of this approach, the calibrated detector is subsequently used to estimate non-classical photon number states. PMID- 25019299 TI - Up-regulation of microRNA-145 associates with lymph node metastasis in colorectal cancer. AB - Metastasis is the main cause of mortality in patients with solid tumours. Identifying the exact molecules associated with CRC metastasis may be crucial to understand the process, which might also be translated to the diagnosis and treatment of CRC. In this study, we investigate the association of microRNA expression patterns with the lymph node metastasis of colorectal cancer. Among these candidate miRNAs, the expression of miRNA-145 was significantly related to lymph node metastasis of CRC. Both in vitro and in vivo study demonstrated that up-regulation of miR-145 could improve the ability of migration and invasion of colorectal cancer cell, while no effect on proliferation was observed. The mechanism of this promotion is associated with the stabilization of Hsp-27, a protein which plays an important role in the promotion of metastasis. These results may be crucial to understanding CRC metastasis and may be translated to the diagnosis and treatment of CRC. PMID- 25019303 TI - Screening and referral to identify children at risk for FASD: Search for new methods 2006-2013. AB - As part of the Canadian Association of Paediatric Health Centres Taskforce on FASD Screening commitment to further pilot, validate and evaluate the multiple components of the Canadian FASD Screening Tool Kit, it was deemed necessary that recent developments and/or improvements in FASD screening were identified and considered. In 2008 a literature review of methods for screening for FASD was published until 2006 and identified five tools which met pre-set criteria. A review of all new papers was published from the period January 2006 until July 1, 2013. Out of 1392 papers, two new screening methods met the inclusion criteria: Clarren et al's new norms for palpebral fissure length by age in Canada; and Breiner et al's extension of the Neurobehavioral Screening Test (NST) to age 4 years. Further work is needed to validate these methods in other settings. PMID- 25019302 TI - Qualitative and quantitative comparison of the proteome of erythroid cells differentiated from human iPSCs and adult erythroid cells by multiplex TMT labelling and nanoLC-MS/MS. AB - Induced pluripotent stem cells (iPSC) are an attractive progenitor source for the generation of in vitro blood products. However, before iPSC-derived erythroid cells can be considered for therapeutic use their similarity to adult erythroid cells must be confirmed. We have analysed the proteome of erythroid cells differentiated from the iPSC fibroblast derived line (C19) and showed they express hallmark RBC proteins, including all those of the ankyrin and 4.1R complex. We next compared the proteome of erythroid cells differentiated from three iPSC lines (C19, OCE1, OPM2) with that of adult and cord blood progenitors. Of the 1989 proteins quantified <3% differed in level by 2-fold or more between the different iPSC-derived erythroid cells. When compared to adult cells, 11% of proteins differed in level by 2-fold or more, falling to 1.9% if a 5-fold threshold was imposed to accommodate slight inter-cell line erythropoietic developmental variation. Notably, the level of >30 hallmark erythroid proteins was consistent between the iPSC lines and adult cells. In addition, a sub population (10-15%) of iPSC erythroid cells in each of the iPSC lines completed enucleation. Aberrant expression of some cytoskeleton proteins may contribute to the failure of the majority of the cells to enucleate since we detected some alterations in cytoskeletal protein abundance. In conclusion, the proteome of erythroid cells differentiated from iPSC lines is very similar to that of normal adult erythroid cells, but further work to improve the induction of erythroid cells in existing iPSC lines or to generate novel erythroid cell lines is required before iPSC-derived red cells can be considered suitable for transfusion therapy. PMID- 25019301 TI - Hydrogen sulfide (H2S) releasing agents: chemistry and biological applications. AB - Hydrogen sulfide (H2S) is a newly recognized signaling molecule with very potent cytoprotective actions. The fields of H2S physiology and pharmacology have been rapidly growing in recent years, but a number of fundamental issues must be addressed to advance our understanding of the biology and clinical potential of H2S in the future. Hydrogen sulfide releasing agents (also known as H2S donors) have been widely used in these fields. These compounds are not only useful research tools, but also potential therapeutic agents. It is therefore important to study the chemistry and pharmacology of exogenous H2S and to be aware of the limitations associated with the choice of donors used to generate H2S in vitro and in vivo. In this review we summarized the developments and limitations of currently available donors including H2S gas, sulfide salts, garlic-derived sulfur compounds, Lawesson's reagent/analogs, 1,2-dithiole-3-thiones, thiol activated donors, photo-caged donors, and thioamino acids. Some biological applications of these donors were also discussed. PMID- 25019305 TI - Unmet expectations of adjustment and depressive symptoms among people with chronic traumatic spinal cord injury. AB - OBJECTIVE: We attempted to gain a better understanding of overall adjustment among people with chronic traumatic spinal cord injury (TSCI) by identifying participants who experienced unmet expectations of adjustment to TSCI. We also examined the relationship between unmet expectations and depressive symptoms. METHOD: This was a prospective cohort study. Participants who survived at least 1 year postinjury (N = 863) were assessed at 2 time points separated by 10 years. Using a 10-point ladder (1 = worst and 10 = best adjustment), self-predicted future adjustment was measured at Time 1. At Time 2, current adjustment was reassessed using the same scale to evaluate differences between predicted and actual adjustment. Adjustment expectations were considered unmet when actual adjustment ratings at Time 2 were lower than predicted adjustment at Time 1. We measured depressive symptoms by using the Older Adult Health and Mood Questionnaire at both time points. RESULTS: More than half of our participants experienced unmet expectations of adjustment over a 10-year period, and having unmet expectations was positively associated with depressive symptoms. CONCLUSION: Unmet expectations of adjustment after TSCI are common among those injured, and they are important predictors of depressive symptoms. PMID- 25019304 TI - Icam-1 targeted nanogels loaded with dexamethasone alleviate pulmonary inflammation. AB - Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with "stealth" properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (~120% ID/g vs ~15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation. PMID- 25019306 TI - The role of resilience in adjustment and coping with chronic pain. AB - PURPOSE: In clinical practice, it is often noted that some individuals struggle with chronic pain, while others find effective means to cope. The purpose of this study was to better understand how resilience fits into coping with persistent pain problems. Of interest was whether measures of resilience add to the prediction of adjustment to chronic pain over and above measures of pain coping as typically used with this patient group. METHOD: Individuals (N = 101) with chronic pain who attended an initial assessment at a pain clinic completed self report measures of resilience and coping. Pain related outcome data were also collected. RESULTS: Bivariate correlations indicated that higher resilience was associated with significantly less fear avoidance, less pain-related disability, and lower reported pain intensity. Consistent with theoretical propositions, bivariate analyses also indicated that more resilient individuals with chronic pain reported better social support, and were more likely to be working. Higher resilience was also positively correlated with greater pain self-efficacy. However, when hierarchical regression analyses were performed, resilience did not add significantly to the prediction of depression scores and disability scores, over and above the contribution made by existing measures of pain coping. CONCLUSION: These findings suggest that, although the construct of resilience appears to have important relationships with various dimensions of chronic pain, as currently operationalized, it does not add significantly to the understanding of chronic-pain adjustment. Rather than abandoning the resilience construct, our findings suggest that resilience as applied to the problem of chronic pain may require a refinement in measurement with this population. PMID- 25019307 TI - Factors associated with alcohol-related problems following moderate to severe traumatic brain injury. AB - PURPOSE/OBJECTIVE: Postinjury alcohol use is a common problem within the traumatic brain injury (TBI) population. Given the association between heavy drinking and the development of alcohol-related consequences, we attempted to understand the contribution of postinjury coping strategies and other risk factors to alcohol-related problems following moderate to severe TBI. RESEARCH METHOD/DESIGN: Participants were enrolled in a longitudinal study and followed up to 15 years following TBI; only persons with moderate to severe TBI (N = 278) were recruited. Participants completed questionnaires assessing preinjury alcohol use, demographic variables, postinjury alcohol-related problems (Short Michigan Alcohol Screening Test; SMAST; Selzer, Vinokus, & Van Rooijan, 1975), and postinjury coping strategies (Coping Inventory for Stressful Situations; CISS; Endler & Parker, 1990). Only those who completed the SMAST were included in this investigation. RESULTS: The overall regression model, with time to follow commands, age at the time of TBI, education, time since injury, and task-oriented coping style, was statistically significant. After accounting for other factors, specific postinjury coping strategies were not associated with post-TBI alcohol related problems. Time to follow commands, education, and time since injury independently explained a unique portion of the variance in SMAST score. A second multiple regression analysis was conducted for a subset of the sample that provided information about premorbid binge drinking (n = 95). The overall model was not significant, likely due to the reduced power to detect an effect, but premorbid binge drinking explained 4% of the variance in SMAST scores. CONCLUSION/IMPLICATIONS: Injury severity, education, and time since injury should be assessed, and at-risk patients should be informed of the consequences of alcohol use among those with TBI. PMID- 25019308 TI - Health care worry is associated with worse outcomes in multiple sclerosis. AB - PURPOSE/OBJECTIVE: People with multiple sclerosis (MS) experience higher levels of depression and anxiety than the general population. This is the first study to examine the relationship of worry about affording health care and symptoms in MS. RESEARCH METHOD/DESIGN: People with MS (n = 405) were recruited for a needs assessment study. Participants completed a structured telephone interview measuring depression, anxiety, fatigue, sleep disturbance, pain interference, social function, and perceived cognitive functioning, and rated their worry about the following: premiums increasing, income decreasing, affording health care services, insurance dropping coverage, and affording prescriptions. Multiple regression analyses controlled for age, gender, disability status, education, income, and health insurance coverage. RESULTS: The highest rated worry was inability to afford health care services. Higher health care worry was reported by women, younger participants, participants with lower incomes, and those with only private (vs. public) insurance. Total level of health care worry was significantly related to depression, anxiety, fatigue, sleep disturbance, pain interference, social function, and perceived cognitive functioning. CONCLUSIONS/IMPLICATIONS: Health care worry was significantly related to psychological, physical, and cognitive symptoms. Future research should compare health care worry in MS with other populations (i.e., healthy adults) and should examine changes in health care worry over time. PMID- 25019309 TI - Health care transition services for youth with autism spectrum disorders. AB - OBJECTIVE: Little is known about accessibility to health care transition (HCT) services (HCT) for youth with autism spectrum disorders (ASD). This study examined how often youth with ASD receive HCT services and how access varied by individual, family, and health system characteristics. METHOD: Questionnaires were completed by 101 parents of youth with ASD (ages 12-17 years) enrolled in a national online autism registry. Descriptive statistics and bivariate analysis were used to examine a composite HCT variable and its components. RESULTS: Fewer than 15% of youth received HCT services. Although 41% received at least 1 HCT discussion, only 3% received all 3. One-quarter had a discussion with their health care provider about transitioning to an adult provider, adult health care needs, or insurance retention, and 31% of providers encouraged youth to take on more responsibilities. Most caregivers reported not needing 1 or more of the discussions. RESULTS varied significantly when the sample was divided by age, with older youth more likely to have received transition services than younger adolescents. CONCLUSIONS: These findings indicate a significant disparity in access to HCT services for youth with ASD. Further research is needed to understand this disparity and develop interventions to improve HCT both for youth with ASD and those with other disabling health conditions. Additionally, many caregivers do not recognize the importance of HCT services. Education and training for caregivers, youth, and providers is essential to ensure all parties are working together to address transition issues early and often. PMID- 25019310 TI - Using the social cognitive theory to understand physical activity among dialysis patients. AB - PURPOSE/OBJECTIVE: The purpose of this study was to use the social cognitive theory (SCT) constructs self-efficacy, outcome expectations, and self-regulation to better understand associations of physical activity (PA) behaviors among dialysis patients after controlling for demographic and health-related factors. RESEARCH METHOD/DESIGN: This study was cross-sectional in design. Participants (N = 115; mean age = 61.51 years, SD = 14.01) completed self-report questionnaires during a regularly scheduled dialysis treatment session. Bivariate and hierarchical linear regression analyses were conducted to examine relationships among SCT constructs and PA. RESULTS: Significant relationships between PA and self-efficacy (r = .336), self-regulation (r = .280), and outcome expectations (r = .265) were detected among people on dialysis in bivariate analyses. Hierarchical linear regression revealed significant increases in variance explained for the addition of self-efficacy, self-regulation, and covariates (p < .01). Younger age, self-efficacy, and self-regulation were associated (p < .10) with greater participation in physical activity in the final model (R2 = .272). Conclusion/Implication: This research supports the use of SCT in understanding PA among people undergoing dialysis treatment. The findings of this study can help health educators and health care practitioners better understand PA and how to promote it among this population. Future research should further investigate which activities dialysis patients participate in across the life span of their disease. Future PA programs should focus on increasing a patient's self-efficacy and self-regulation. PMID- 25019311 TI - Reinjury anxiety, coping, and return-to-sport outcomes: a multiple mediation analysis. AB - PURPOSE/OBJECTIVE: This study aimed to examine whether the dimensions of reinjury anxiety (i.e., intensity, frequency, and direction) predicted perceived return-to sport outcomes and whether coping mediated this relationship. RESEARCH METHOD/DESIGN: Using a cross-sectional research design, 335 participants (M age = 23.5; SD = 6.6) who had sustained a sports-related injury preventing participation in training and competition for a minimum of 4 weeks (M time loss = 98 days; SD = 96.8) completed measures of reinjury anxiety (RIA-RE subscale of the Reinjury Anxiety Inventory (RIAI); Walker, Thatcher, & Lavallee, 2010), coping (MCOPE; Crocker & Graham, 1995), and perceived return-to-sport outcomes (RSSIQ; Podlog & Eklund, 2005). Pearson product-moment correlation and Preacher and Hayes's (2008) bootstrapping procedure were used to analyze the data. RESULTS: Consistent with our hypotheses, results indicated a positive relationship between reinjury anxiety (intensity and frequency) and heightened return concerns, whereas reinjury anxiety interpreted as facilitative toward postinjury performance was associated with a positive renewed perspective on sport participation. Significant indirect effects for coping were found for wishful thinking, venting of emotions, denial, and behavioral disengagement. CONCLUSIONS/IMPLICATIONS: Future avenues of research that aim to provide a greater knowledge and understanding of the relationship between reinjury anxiety and return-to-sport outcomes are discussed, including the need for alternative theoretical perspectives and diverse methodologies. PMID- 25019313 TI - N-tetradecylcarbamyl lipopeptides as novel agonists for Toll-like receptor 2. AB - New analogues (UPam) of triacylated lipopeptide Pam3CysSK4, a popular agonist of Toll-like receptor 2 (TLR2), were designed making use of the cocrystal structure of a TLR2 heterodimer (with TLR1) with Pam3CysSK4. Twenty-two UPam derivatives that feature an N-tetradecylcarbamyl chain to mimic the native N-palmitoyl moiety and various small amino acids residues at the penultimate N-terminal position were prepared via solid-phase synthesis. In vitro evaluation of immunostimulatory properties revealed new potent TLR2 ligands. PMID- 25019312 TI - Psychosocial outcomes after traumatic brain injury: life satisfaction, community integration, and distress. AB - OBJECTIVE: To examine the relationship between life satisfaction, community integration, and emotional distress in adults with traumatic brain injury (TBI). METHOD: This was an archival study of a longitudinal data set on the outcome and recovery process of persons with TBI. Participants were 253 consecutive adults with mild complicated, moderate, and severe TBI who were enrolled in a large, longitudinal study of persons with TBI. Main measures included the Satisfaction with Life Scale, the Positive Affective and Negative Affective Schedule, the Craig Hospital Assessment and Reporting Technique Short-Form, the Community Integration Measure, and the Brief Symptom Inventory-18. RESULTS: The three factor model adequately fit the data, and a higher-order model did not necessarily improve model fit but revealed significant relationships with first order constructs and one second-order construct. CONCLUSIONS: Life satisfaction, community integration, and emotional distress were found to be related yet unique concepts in persons with TBI. Life satisfaction was positively related to community involvement and inversely related to emotional distress. Community integration was inversely related to emotional distress. In addition, these concepts are related to a higher-order concept of psychosocial status, a global representation of subjective and objective functioning. These findings demonstrate the interrelated and dynamic nature of psychosocial well-being after brain injury and highlight the need for integrative and holistic treatment plans. PMID- 25019315 TI - Synthesis, in vitro biological screening and molecular docking studies of novel camphor-based thiazoles. AB - Synthesis, characterization and investigation of antibacterial and antifungal activities of twelve camphor based 2,4-disubstituted 1,3-thiazoles is presented. Their structures were determined using NMR, IR, FAB MS and HRMS analyses. Among the derivatives, 3i and 5 were found to exhibit antifungal and antibacterial activities comparable to that of fluconazole and ciprofloxacin against yeast belonging to Candida spp., MIC 0.12-0.98 MUg/ml and Gram-positive bacteria including both pathogenic S. aureus and opportunistic S. epidermidis, MIC 0.98 7.81 MUg/ml, B. subtilis and B. cereus, MIC 3.91-31.25 MUg/ml, and M. luteus, MIC 0.98 MUg/ml species, respectively. Molecular docking studies of all compounds into the active sites of microbial enzymes indicated a possible targets SAP and NMT, thiazoles 3a-j, 4, 5 showed more favourable affinity than the native ligand. PMID- 25019314 TI - Glycocalyx remodeling with proteoglycan mimetics promotes neural specification in embryonic stem cells. AB - Growth factor (GF) signaling is a key determinant of stem cell fate. Interactions of GFs with their receptors are often mediated by heparan sulfate proteoglycans (HSPGs). Here, we report a cell surface engineering strategy that exploits the function of HSPGs to promote differentiation in embryonic stem cells (ESCs). We have generated synthetic neoproteoglycans (neoPGs) with affinity for the fibroblast growth factor 2 (FGF2) and introduced them into plasma membranes of ESCs deficient in HS biosynthesis. There, the neoPGs assumed the function of native HSPGs, rescued FGF2-mediated kinase activity, and promoted neural specification. This glycocalyx remodeling strategy is versatile and may be applicable to other types of differentiation. PMID- 25019316 TI - Role of local structure and dynamics of small ligand migration in proteins: a study of a mutated truncated hemoprotein from Thermobifida fusca by time resolved MIR spectroscopy. AB - Carbon monoxide recombination dynamics in a mutant of the truncated hemoglobin from Thermobida fusca (3F-Tf-trHb) has been analyzed by means of ultrafast Visible-pump/MidIR-probe spectroscopy and compared with that of the wild-type protein. In 3F-Tf-trHb, three topologically relevant amino acids, responsible for the ligand stabilization through the formation of a H-bond network (TyrB10 TyrCD1 and TrpG8), have been replaced by Phe residues. X-ray diffraction data show that Phe residues in positions B10 and G8 maintain the same rotameric arrangements as Tyr and Trp in the wild-type protein, while Phe in position CD1 displays significant rotameric heterogeneity. Photodissociation of the ligand has been induced by exciting the sample with 550 nm pump pulses and the CO rebinding has been monitored in two mid-IR regions respectively corresponding to the nu(CO) stretching vibration of the iron-bound CO (1880-1980 cm(-1)) and of the dissociated free CO (2050-2200 cm(-1)). In both the mutant and wild-type protein, a significant amount of geminate CO rebinding is observed on a subnanosecond time scale. Despite the absence of the distal pocket hydrogen-bonding network, the kinetics of geminate rebinding in 3F-Tf-trHb is very similar to the wild-type, showing how the reactivity of dissociated CO toward the heme is primarily regulated by the effective volume and flexibility of the distal pocket and by caging effects exerted on the free CO on the analyzed time scale. PMID- 25019317 TI - Effect of prophylactic versus preemptive lamivudine treatment and tenofovir on HBsAg+ kidney transplant recipients. AB - OBJECTIVES: Chronic hepatitis B virus infection remains a clinical problem for HBsAg (+) kidney transplant recipients. Lamivudine is the approved treatment; however, there are contrary views about optimal initiation. In case of resistance, novel nucleoside analogs should be considered but experience is limited. MATERIALS AND METHODS: The study was a retrospective cohort study that included 58 HBsAg (+) kidney transplant recipients. Medical records were reviewed for nucleoside analogs, viral replication, and graft/hepatic functions. Prophylactic and preemptive lamivudine modalities were compared to reveal optimal initiation. Additionally, novel nucleoside analogs were evaluated for safety and efficacy. RESULTS: The graft/patient survival rates for HBsAg (+) recipients were the same as those of hepatitis-free recipients (P = .18). Prophylactic group had 24 and the preemptive had 34 patients. In the prophylactic group, there were fewer hepatic dysfunctions (12.5% vs. 30%, P = .12), viral breakthroughs (16% vs. 32%, P = .17) and elevated alanine aminotransferase concentrations (37% vs. 52%, P = .24), however these did not reach statistical significance. Progressive hepatic dysfunction was observed in 5 patients. Treatment was altered to tenofovir (n = 4) and adefovir (n = 1), and adequate virologic/biochemical response was achieved. These nucleoside analogs were almost as safe as lamivudine, as there were no significant differences among proteinuria (4740 +/- 9480 vs 1250 +/- 430 mg/L; P = .60) and estimated glomerular filtration rate (1.23 +/- 0.37 vs 1.10 +/- 0.35 mL/s; P = .33) CONCLUSIONS: Lamivudine is an efficient means of providing comparable graft/patient survival with hepatitis free kidney transplant recipients. The prophylactic initiation of lamivudine may be better in preventing hepatic dysfunction. Tenofovir can be an effective and safe treatment for lamivudine-resistant kidney transplant recipients. PMID- 25019318 TI - Spatial trends, sources, and air-water exchange of organochlorine pesticides in the Great Lakes basin using low density polyethylene passive samplers. AB - Polyethylene passive samplers were deployed during summer and fall of 2011 in the lower Great Lakes to assess the spatial distribution and sources of gaseous and freely dissolved organochlorine pesticides (OCPs) and their air-water exchange. Average gaseous OCP concentrations ranged from nondetect to 133 pg/m(3). Gaseous concentrations of hexachlorobenzene, dieldrin, and chlordanes were significantly greater (Mann-Whitney test, p < 0.05) at Lake Erie than Lake Ontario. A multiple linear regression implied that both cropland and urban areas within 50 and 10 km buffer zones, respectively, were critical parameters to explain the total variability in atmospheric concentrations. Freely dissolved OCP concentrations (nondetect to 114 pg/L) were lower than previously reported. Aqueous half-lives generally ranged from 1.7 to 6.7 years. Nonetheless, concentrations of p,p'-DDE and chlordanes were higher than New York State Ambient Water Quality Standards for the protection of human health from the consumption of fish. Spatial distributions of freely dissolved OCPs in both lakes were influenced by loadings from areas of concern and the water circulation patterns. Flux calculations indicated net deposition of gamma-hexachlorocyclohexane, heptachlor-epoxide, and alpha- and beta-endosulfan (-0.02 to -33 ng/m(2)/day) and net volatilization of heptachlor, aldrin, trans-chlordane, and trans-nonachlor (0.0 to 9.0 ng/m(2)/day) in most samples. PMID- 25019320 TI - Stability and toxicity of heteroleptic organometallic Bi(V) complexes towards Leishmania major. AB - Eleven heteroleptic Bi(V) complexes of the form [BiPh3(O2CR)2] have been synthesised and fully characterised. The carboxylate ligands are derived from a series of simple substituted benzoic acids, four of which are common non steroidal anti-inflammatories (NSAIDs). The solid-state structures of eight of the complexes were determined by single crystal X-ray diffraction, and all were shown to adopt a typical trigonal bipyramidal geometry with chelating carboxylate ligands. Nine of the complexes were assessed for their anti-parasitic activity against Leishmania major promastigotes and their cytotoxicity towards human fibroblasts. The assays indicated that while the complexes showed good anti leishmanial activity with IC50 values ranging from 0.6 to 2.5 MUM they were also non-selectively toxic towards the fibroblasts at similar or slightly higher concentrations. Using (1)H NMR, the stability of one of the complexes, [Bi(C6H5)3(O2CC6H3(m-OH)2)2] was studied in water, DMSO and in the DMEM culture medium. This showed that while the Bi(v) complex was stable in D2O and DMSO, the complex slowly decomposed in the culture medium undergoing reduction to give BiPh3 and the free acid. Since the acids and BiPh3 were not toxic to either the parasites or fibroblasts at the concentrations studied, the implication is that the Bi(v) complexes are stable enough for long enough to have significant in vitro anti-parasitic activity. PMID- 25019319 TI - Axl tyrosine kinase protects against tubulo-interstitial apoptosis and progression of renal failure in a murine model of chronic kidney disease and hyperphosphataemia. AB - Chronic kidney disease (CKD) is defined as the progressive loss of renal function often involving glomerular, tubulo-interstitial and vascular pathology. CKD is associated with vascular calcification; the extent of which predicts morbidity and mortality. However, the molecular regulation of these events and the progression of chronic kidney disease are not fully elucidated. To investigate the function of Axl receptor tyrosine kinase in CKD we performed a sub-total nephrectomy and fed high phosphate (1%) diet to Axl+/+ and Axl-/- mice. Plasma Gas6 (Axl' ligand), renal Axl expression and downstream Akt signalling were all significantly up-regulated in Axl+/+ mice following renal mass reduction and high phosphate diet, compared to age-matched controls. Axl-/- mice had significantly enhanced uraemia, reduced bodyweight and significantly reduced survival following sub-total nephrectomy and high phosphate diet compared to Axl+/+ mice; only 45% of Axl-/- mice survived to 14 weeks post-surgery compared to 87% of Axl+/+ mice. Histological analysis of kidney remnants revealed no effect of loss of Axl on glomerular hypertrophy, calcification or renal sclerosis but identified significantly increased tubulo-interstitial apoptosis in Axl-/- mice. Vascular calcification was not induced in Axl+/+ or Axl-/- mice in the time frame we were able to examine. In conclusion, we identify the up-regulation of Gas6/Axl signalling as a protective mechanism which reduces tubulo-interstitial apoptosis and slows progression to end-stage renal failure in the murine nephrectomy and high phosphate diet model of CKD. PMID- 25019321 TI - Prevention of thermally induced aggregation of IgG antibodies by noncovalent interaction with poly(acrylate) derivatives. AB - Prevention of thermal aggregation of antibodies in aqueous solutions was achieved by noncovalent association with hydrophobically modified poly(acrylate) copolymers. Using a polyclonal immunoglobin G (IgG) as a model system for antibodies, we have studied the mechanisms by which this multidomain protein interacts with polyanions when incubated at physiological pH and at temperatures below and above the protein unfolding/denaturation temperature, in salt-free solutions and in 0.1 M NaCl solutions. The polyanions selected were sodium poly(acrylates), random copolymers of sodium acrylate and N-n-octadecylacrylamide (3 mol %), and a random copolymer of sodium acrylate, N-n-octylacrylamide (25 mol %), and N-isopropylacrylamide (40 mol %). They were derived from two poly(acrylic acid) parent chains of Mw 5000 and 150000 g.mol(-1). The IgG/polyanion interactions were monitored by static and dynamic light scattering, fluorescence correlation spectroscopy, capillary zone electrophoresis, and high sensitivity differential scanning calorimetry. In salt-free solutions, the hydrophilic PAA chains form complexes with IgG upon thermal unfolding of the protein (1:1 w/w IgG/PAA), but they do not interact with native IgG. The complexes exhibit a remarkable protective effect against IgG aggregation and maintain low aggregation numbers (average degree of oligomerization <12 at a temperature up to 85 degrees C). These interactions are screened in 0.1 M NaCl and, consequently, PAAs lose their protective effect. Amphiphilic PAA derivatives (1:1 w/w IgG/polymer) are able to prevent thermal aggregation (preserving IgG monomers) or retard aggregation of IgG (formation of oligomers and slow growth), revealing the importance of both hydrophobic interactions and modulation of the Coulomb interactions with or without NaCl present. This study leads the way toward the design of new formulations of therapeutic proteins using noncovalent 1:1 polymer/protein association that are transient and require a markedly lower additive concentration compared to conventional osmolyte protecting agents. They do not modify IgG permanently, which is an asset for applications in therapeutic protein formulations since the in vivo efficacy of the protein should not be affected. PMID- 25019322 TI - Branch-selective, iridium-catalyzed hydroarylation of monosubstituted alkenes via a cooperative destabilization strategy. AB - Highly branch-selective, carbonyl-directed hydroarylations of monosubstituted alkenes are described. The chemistry relies upon a cationic Ir(I) catalyst modified with an electron deficient, wide bite angle bisphosphine ligand. This work provides a regioisomeric alternative to the Murai hydroarylation protocol. PMID- 25019323 TI - Sandwich-type Au-PEI/DNA/PEI-Dexa nanocomplex for nucleus-targeted gene delivery in vitro and in vivo. AB - Many synthetic Au-based cationic nanoparticles (AuNPs) for nonviral gene delivery show high efficiency in vitro, but their excessive charge density, harsh reducing conditions, and nontarget delivery prevent their application in vivo. Herein, we constructed a sandwich-type layered polyethylenimine (PEI)-coated gold nanocomposite outerlaid with a nucleus-targeted Dexamethasone (Dexa), namely, Au PEI/DNA/PEI-Dexa nanocomplex, for DNA delivery system using a low molecular weight PEI as a mild reducing agent. The nucleus-targeting Au-PEI/DNA/PEI-Dexa nanocomplex with low positive charge and low cytotoxicity condensed DNA and protected from enzymatic degradation. In vitro transfection studies demonstrated that Au-PEI/DNA/PEI-Dexa nanocomplex exhibited much more efficient nucleus transfection than Au-PEI/DNA/PEI without nucleus-targeted residues and commercially available PEI 25 kDa due to the Dexa targeting of the nucleus. Furthermore, the nanocomplex markedly transfected pTRAIL (TRAIL = tumor-necrosis factor-related apoptosis-inducing ligand) to tumors in vivo and subsequently inhibited the tumor growth with minimal side effects. These findings suggest that nucleus-targeting Au-PEI/DNA/PEI-Dexa ternary complexes have promising potential in gene delivery. PMID- 25019324 TI - Interaction of amphotericin B with lipid monolayers. AB - Langmuir isotherm, neutron reflectivity, and Brewster angle microscopy experiments have been performed to study the interaction of amphotericin B (AmB) with monolayers prepared from 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and mixtures of this lipid with cholesterol or ergosterol to mimic mammalian and fungal cell membranes, respectively. Isotherm data show that AmB causes a more pronounced change in surface pressure in the POPC/ergosterol system than in the POPC and POPC/cholesterol systems, and its interaction with the POPC/ergosterol monolayer is also more rapid than with the POPC and POPC/cholesterol monolayers. Brewster angle microscopy shows that, in interaction with POPC monolayers, AmB causes the formation of small domains which shrink and disappear within a few minutes. The drug also causes domain formation in the POPC/cholesterol and POPC/ergosterol monolayers; in the former case, these are formed more slowly than is seen with the POPC monolayers and are ultimately much smaller; in the latter case, they are formed rather more quickly and are more heterogeneous in size. Neutron reflectivity data show that the changes in monolayer structure following interaction with AmB are the same for all three systems studied: the data are consistent with the drug inserting into the monolayers with its macrocyclic ring intercalated among the lipid acyl chains and sterol ring systems, with its mycosamine moiety colocalizing with the sterol hydroxyl and POPC head groups. On the basis of these studies, it is concluded that AmB inserts in a similar manner into POPC, POPC/cholesterol, and POPC/ergosterol monolayers but does so with differing kinetics and with the formation of quite different in-plane structures. The more rapid time scale for interaction of the drug with the POPC/ergosterol monolayer, its more pronounced effect on monolayer surface pressure, and its more marked changes as regards domain formation are all consistent with the drug's selectivity for fungal vs mammalian cell membranes. PMID- 25019325 TI - An efficient ruthenium(IV) catalyst for the selective hydration of nitriles to amides in water under mild conditions. AB - A Ru(IV) catalyst able to promote the selective hydration of nitriles to amides in water, at low metal loadings and under mild conditions, is presented. PMID- 25019331 TI - Selective conversion of alcohols in water to carboxylic acids by in situ generated ruthenium trans dihydrido carbonyl PNP complexes. AB - In this work, we present a mild method for direct conversion of primary alcohols into carboxylic acids with the use of water as an oxygen source. Applying a ruthenium dihydrogen based dehydrogenation catalyst for this cause, we investigated the effect of water on the catalytic dehydrogenation process of alcohols. Using 1 mol% of the catalyst we report up to high yields. Moreover, we isolated key intermediates which most likely play a role in the catalytic cycle. One of the intermediates was identified as a trans dihydrido carbonyl complex which is generated in situ in the catalytic process. PMID- 25019330 TI - A versatile PDMS/paper hybrid microfluidic platform for sensitive infectious disease diagnosis. AB - Bacterial meningitis is a serious health concern worldwide. Given that meningitis can be fatal and many meningitis cases occurred in high-poverty areas, a simple, low-cost, highly sensitive method is in great need for immediate and early diagnosis of meningitis. Herein, we report a versatile and cost-effective polydimethylsiloxane (PDMS)/paper hybrid microfluidic device integrated with loop mediated isothermal amplification (LAMP) for the rapid, sensitive, and instrument free detection of the main meningitis-causing bacteria, Neisseria meningitidis (N. meningitidis). The introduction of paper into the microfluidic device for LAMP reactions enables stable test results over a much longer period of time than a paper-free microfluidic system. This hybrid system also offers versatile functions, by providing not only on-site qualitative diagnostic analysis (i.e., a yes or no answer), but also confirmatory testing and quantitative analysis in laboratory settings. The limit of detection of N. meningitidis is about 3 copies per LAMP zone within 45 min, close to single-bacterium detection sensitivity. In addition, we have achieved simple pathogenic microorganism detection without a laborious sample preparation process and without the use of centrifuges. This low cost hybrid microfluidic system provides a simple and highly sensitive approach for fast instrument-free diagnosis of N. meningitidis in resource-limited settings. This versatile PDMS/paper microfluidic platform has great potential for the point of care (POC) diagnosis of a wide range of infectious diseases, especially for developing nations. PMID- 25019332 TI - Enediyne polyketide synthases stereoselectively reduce the beta-ketoacyl intermediates to beta-D-hydroxyacyl intermediates in enediyne core biosynthesis. AB - PKSE biosynthesizes an enediyne core precursor from decarboxylative condensation of eight malonyl-CoAs. The KR domain of PKSE is responsible for iterative beta ketoreduction in each round of polyketide chain elongation. KRs from selected PKSEs were investigated in vitro with beta-ketoacyl-SNACs as substrate mimics. Each of the KRs reduced the beta-ketoacyl-SNACs stereoselectively, all affording the corresponding beta-D-hydroxyacyl-SNACs, and the catalytic efficiencies (k(cat)/K(M)) of the KRs increased significantly as the chain length of the beta ketoacyl-SNAC substrate increases. PMID- 25019334 TI - Mesoscale imperfections in MoS2 atomic layers grown by a vapor transport technique. AB - The success of isolating small flakes of atomically thin layers through mechanical exfoliation has triggered enormous research interest in graphene and other two-dimensional materials. For device applications, however, controlled large-area synthesis of highly crystalline monolayers with a low density of electronically active defects is imperative. Here, we demonstrate the electrical imaging of dendritic ad-layers and grain boundaries in monolayer molybdenum disulfide (MoS2) grown by a vapor transport technique using microwave impedance microscopy. The micrometer-sized precipitates in our films, which appear as a second layer of MoS2 in conventional height and optical measurements, show ~ 2 orders of magnitude higher conductivity than that of the single layer. The zigzag grain boundaries, on the other hand, are shown to be more resistive than the crystalline grains, consistent with previous studies. Our ability to map the local electrical properties in a rapid and nondestructive manner is highly desirable for optimizing the growth process of large-scale MoS2 atomic layers. PMID- 25019333 TI - On guanidinium and cellular uptake. AB - Guanidinium-rich scaffolds facilitate cellular translocation and delivery of bioactive cargos through biological barriers. Although impressive uptake has been demonstrated for nonoligomeric and nonpept(o)idic guanidinylated scaffolds in cell cultures and animal models, the fundamental understanding of these processes is lacking. Charge pairing and hydrogen bonding with cell surface counterparts have been proposed, but their exact role remains putative. The impact of the number and spatial relationships of the guanidinium groups on delivery and organelle/organ localization is yet to be established. PMID- 25019335 TI - Impalement brain injury from steel rod causing injury to jugular bulb: case report and review of the literature. AB - BACKGROUND: The management of impalement penetrating brain injuries (IPBI) from non-missile objects is extremely challenging, especially when vascular structures are involved. Cerebral angiography is a crucial tool in initial evaluation to assess for vascular injury as standard non-invasive imaging modalities are limited by foreign body artifact, especially for metallic objects. CASE STUDY: This study reports a case of an IPBI caused by a segment of steel rebar resulting in injury to the left jugular bulb and posterior temporal lobe. It describes the initial presentation, radiology, management and outcome in this patient and reviews the literature of similar injuries. PMID- 25019337 TI - Antioxidant and anti-inflammatory active dihydrobenzofuran neolignans from the seeds of Prunus tomentosa. AB - Prunus tomentosa seeds were researched for antioxidant and anti-inflammatory constituents. By activity-guided fractionation of P. tomentosa seed extract, six new dihydrobenzofuran neolignans, prunustosanans AI-IV (1-4) and prunustosanansides AI and AII (5 and 6), together with 10 known compounds (7-16) were isolated from bioactive fraction. The structures were determined by spectroscopic analyses, especially NMR, HRESIMS, and CD spectra. The antioxidant activity was greatest for 5, 10, and 12 against DPPH radical and for 8, 9, and 13 against ABTS radical. Moreover, compounds 7 and 11 exhibited much stronger inhibitory activity on nitric oxide (NO) production in murine microglia BV-2 compared with positive control minocycline (IC50 = 19.7 +/- 1.5 MUM). The results show that P. tomentosa seeds can be regarded as a potential source of antioxidants and inflammation inhibitors. PMID- 25019336 TI - Trends in obesity prevalence and disparities among low-income children in Oklahoma, 2005-2010. AB - BACKGROUND: National WIC (the Special Supplemental Nutrition Program for Women, Infants, and Children) data indicate a decrease in obesity prevalence among most low-income preschool-aged children. Though racial/ethnic disparities exist, studies examining obesity trends among various racial/ethnic groups are lacking. The aims of this study were to identify racial/ethnic disparities in obesity among low-income preschool children in Oklahoma and describe trends in obesity prevalence among four major racial/ethnic groups. METHODS: Subjects included 218,486 children 2-4 years of age who participated in WIC in Oklahoma from 2005 to 2010. Logistic regression was performed to identify disparities and trends in obesity among American Indian, Hispanic, White, and African American children. RESULTS: Racial/ethnic disparities in obesity were evident, with prevalence highest in Hispanics and lowest in African Americans. Obesity increased among girls for all racial/ethnic groups from 2005 to 2010 (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01, 1.03). Among boys, obesity increased in African Americans (OR, 1.04; 95% CI, 1.01, 1.07), but remained stable in other racial/ethnic groups. CONCLUSIONS: In Oklahoma, in contrast to recent national studies, obesity is increasing among certain groups of low-income preschool children. These findings suggest geographic diversity in obesity and that state specific obesity surveillance is important to help target interventions to those at highest risk. PMID- 25019338 TI - Photon energy upconverting nanopaper: a bioinspired oxygen protection strategy. AB - The development of solid materials which are able to upconvert optical radiation into photons of higher energy is attractive for many applications such as photocatalytic cells and photovoltaic devices. However, to fully exploit triplet triplet annihilation photon energy upconversion (TTA-UC), oxygen protection is imperative because molecular oxygen is an ultimate quencher of the photon upconversion process. So far, reported solid TTA-UC materials have focused mainly on elastomeric matrices with low barrier properties because the TTA-UC efficiency generally drops significantly in glassy and semicrystalline matrices. To overcome this limit, for example, combine effective and sustainable annihilation upconversion with exhaustive oxygen protection of dyes, we prepare a sustainable solid-state-like material based on nanocellulose. Inspired by the structural buildup of leaves in Nature, we compartmentalize the dyes in the liquid core of nanocellulose-based capsules which are then further embedded in a cellulose nanofibers (NFC) matrix. Using pristine cellulose nanofibers, a sustainable and environmentally friendly functional nanomaterial with ultrahigh barrier properties is achieved. Also, an ensemble of sensitizers and emitter compounds are encapsulated, which allow harvesting of the energy of the whole deep-red sunlight region. The films demonstrate excellent lifetime in synthetic air (20.5/79.5, O2/N2)-even after 1 h operation, the intensity of the TTA-UC signal decreased only 7.8% for the film with 8.8 MUm thick NFC coating. The lifetime can be further modulated by the thickness of the protective NFC coating. For comparison, the lifetime of TTA-UC in liquids exposed to air is on the level of seconds to minutes due to fast oxygen quenching. PMID- 25019339 TI - Modular microfluidic valve structures based on reversible thermoresponsive ionogel actuators. AB - This paper reports for the first time the use of a cross-linked poly(N isopropylacrylamide) ionogel encapsulating the ionic liquid 1-ethyl-3 methylimidazolium ethyl sulphate as a thermoresponsive and modular microfluidic valve. The ionogel presents superior actuation behaviour to its equivalent hydrogel. Ionogel swelling and shrinking mechanisms and kinetics are investigated as well as the performance of the ionogel when integrated as a valve in a microfluidic device. The modular microfluidic valve demonstrates fully a reversible on-off behaviour without failure for up to eight actuation cycles and a pressure resistance of 1100 mbar. PMID- 25019340 TI - Facile access to amides and hydroxamic acids directly from nitroarenes. AB - A new method for synthesis of amides and hydroxamic acids from nitroarenes and aldehydes is described. The MnO2 catalyzed thermal deoxygenation of nitrobenzene resulted in formation of a reactive nitroso intermediate which on reaction with aldehydes provided amides and hydroxamic acids. The thermal neat reaction in the presence of 0.01 mmol KOH predominantly led to formation of hydroxamic acid whereas reaction in the presence of 1 mmol acetic acid produced amides as the only product. PMID- 25019341 TI - Six weeks in Soweto: an Australian experience of palliative medicine in South Africa. PMID- 25019342 TI - Association between STAT4 gene polymorphisms and autoimmune thyroid diseases in a Chinese population. AB - The STAT4 gene encodes a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. The aim of this study was to explore the association of STAT4 polymorphism with Graves' disease (GD) and Hashimoto's thyroiditis (HT). A total of 1048 autoimmune thyroid diseases (AITDs) patients (693 with GD and 355 with HT) and 909 age- and gender-matched controls were examined. STAT4 polymorphisms (rs7574865/rs10181656/ rs7572482) were genotyped by multiplex polymerase chain reaction (PCR) and ligase detection reaction (LDR). The results indicated that the frequencies of rs7574865 genotypes in patients with GD differed significantly from the controls (p=0.028), the T allele frequency of GD patients was also significantly higher than the controls (p=0.020). The genotypes of rs10181656 differed significantly in GD patients from controls (p=0.012); G allele frequencies were significantly higher in AITD patients than the controls (p=0.014 and 0.031, respectively). The frequencies of haplotype GC with GD and HT patients were significantly lower than their controls (p=0.015 and 0.030, respectively). In contrast, the frequencies of haplotype TG with GD and HT patients were significantly higher than their controls (p=0.016 and 0.048, respectively). These findings strongly suggest that STAT4 rs7574865/rs10181656 polymorphisms increase the risk of AITD in a Chinese population. PMID- 25019343 TI - Novel bioactive antimicrobial lignin containing coatings on titanium obtained by electrophoretic deposition. AB - Hydroxyapatite (HAP) is the most suitable biocompatible material for bone implant coatings; its brittleness, however, is a major obstacle, and the reason why research focuses on creating composites with biopolymers. Organosolv lignin (Lig) is used for the production of composite coatings, and these composites were examined in this study. Titanium substrate is a key biomedical material due to its well-known properties, but infections of the implantation site still impose a serious threat. One approach to prevent infection is to improve antimicrobial properties of the coating material. Silver doped hydroxyapatite (Ag/HAP) and HAP coatings on titanium were obtained by an electrophoretic deposition method in order to control deposited coating mass and morphology by varying applied voltage and deposition time. The effect of lignin on microstructure, morphology and thermal behavior of biocomposite coatings was investigated. The results showed that higher lignin concentrations protect the HAP lattice during sintering, improving coating stability. The corrosion stability was evaluated in simulated body fluid (SBF) at 37 degrees C. Newly formed plate-shaped carbonate-HAP was detected, indicating enhanced bioactive performance. The antimicrobial efficiency of Ag/HAP/Lig was confirmed by its higher reduction of bacteria Staphylococcus aureus TL (S. aureus TL) than of HAP/Lig coating. Cytotoxicity assay revealed that both coatings can be classified as non-toxic against healthy immunocompetent peripheral blood mononuclear cells (PBMC). PMID- 25019345 TI - Revising the fasting glucose threshold for detection of cardiovascular risk factors: analysing two representative population-based studies of more than 50,000 Iranians in 3 years: The National Survey of Risk Factors for Non Communicable Diseases of Iran. AB - OBJECTIVES: To study the prevalence of cardiovascular risk factors across different glycaemia strata and to assess the optimal cut-off value of fasting plasma glucose (FPG) to identify the constellation of cardiovascular risk factors. METHODS: Data of the National Survey of Risk Factors for Non Communicable Diseases of Iran (SURFNCD 2005-2007) were analysed. Prevalence rates of obesity, central obesity, hypertension and hypercholesterolemia of individuals with Impaired Fasting Glucose (IFG) were compared with those of individuals with normal fasting glycaemia and newly diagnosed diabetes. Optimal FPG cut-point to diagnose subjects with cardiovascular risk factors was assessed. RESULTS: Prevalence of each and combinations of cardiovascular risk factors were higher among subjects with IFG compared to those with normal fasting glycaemia. The areas under the curve (AUC) for detecting cardiovascular risk were highest at FPG values of 90 mg/dL. FPG of 90 mg/dL was the optimal cut-off and, in comparison to 100 mg/dL, corresponds to correct detection of 26-29% of obese, 22-27% of centrally obese, 26-29% of hypertensive and 25-30% of hypercholesterolemic individuals. CONCLUSIONS: IFG and even lower levels of FPG are associated with high prevalence of cardiovascular risk factors in Iranian adults. This study suggests the FPG cut-off to be revised at 90 mg/dL to identify people with increased cardiovascular risk. PMID- 25019344 TI - Oleocanthal, a phenolic derived from virgin olive oil: a review of the beneficial effects on inflammatory disease. AB - Virgin olive oil (VOO) is credited as being one of many healthful components of the Mediterranean diet. Mediterranean populations experience reduced incidence of chronic inflammatory disease states and VOO is readily consumed as part of an everyday dietary pattern. A phenolic compound contained in VOO, named oleocanthal, shares unique perceptual and anti-inflammatory characteristics with Ibuprofen. Over recent years oleocanthal has become a compound of interest in the search for naturally occurring compounds with pharmacological qualities. Subsequent to its discovery and identification, oleocanthal has been reported to exhibit various modes of action in reducing inflammatory related disease, including joint-degenerative disease, neuro-degenerative disease and specific cancers. Therefore, it is postulated that long term consumption of VOO containing oleocanthal may contribute to the health benefits associated with the Mediterranean dietary pattern. The following paper summarizes the current literature on oleocanthal, in terms of its sensory and pharmacological properties, and also discusses the beneficial, health promoting activities of oleocanthal, in the context of the molecular mechanisms within various models of disease. PMID- 25019346 TI - Knockdown of EpCAM enhances the chemosensitivity of breast cancer cells to 5 fluorouracil by downregulating the antiapoptotic factor Bcl-2. AB - Resistance to fluoropyrimidine-based chemotherapy is the main reason for the failure of cancer treatment, and drug resistance is associated with an inability of tumor cells to undergo apoptosis in response to treatment. Alterations in the expression of epithelial cell adhesion molecule (EpCAM) affect the sensitivity or resistance of tumor cells to anticancer treatment and the activity of intracellular signaling pathways. However, the role of EpCAM in the induction of apoptosis in breast cancer cells remains unclear. Here, we investigated the effect of EpCAM gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in MCF-7 cells and explored the underlying mechanisms. Our results showed that knockdown of EpCAM promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest. EpCAM knockdown enhanced the cytotoxic effect of 5-FU, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax, and caspase3 via the ERK1/2 and JNK MAPK signaling pathways in MCF-7 cells. These results indicate that knockdown of EpCAM may have a tumor suppressor effect and suggest EpCAM as a potential target for the treatment of breast cancer. PMID- 25019347 TI - Whisker-related circuitry in the trigeminal nucleus principalis: Topographic precision. AB - Single whiskers are topographically represented in the trigeminal (V) nucleus principalis (PrV) by a set of cylindrical aggregates of primary afferent terminals and somata (barrelettes). This isomorphic pattern is transmitted to the thalamus and barrel cortex. However, it is not known if terminals in PrV from neighboring whiskers interdigitate so as to violate rules of spatial parcellation predicted by barrelette borders; nor is it known the extent to which higher order inputs are topographic. The existence of inter-whisker arbor overlap or diffuse higher order inputs would demand additional theoretical principles to account for single whisker dominance in PrV cell responses. In adult rats, first, primary afferent pairs responding to the same or neighboring whiskers and injected with Neurobiotin or horseradish peroxidase were rendered brown or black to color-code their terminal boutons. When collaterals from both fibers appeared in the same topographic plane through PrV, the percentage of the summed area of the two arbor envelopes that overlapped was computed. For same-whisker pairs, overlap was 5 +/- 6% (mean +/- SD). For within-row neighbors, overlap was 2 +/- 5%. For between-row neighbors, overlap was 1 +/- 4%. Second, the areas of whisker primary afferent arbors and their corresponding barrelettes in the PrV were compared. In the transverse plane, arbor envelopes significantly exceeded the areas of cytochrome oxidase-stained barrelettes; arbors often extended into neighboring barrelettes. Third, bulk tracing of the projections from the spinal V subnucleus interpolaris (SpVi) to the PrV revealed strict topography such that they connect same-whisker barrelettes in the SpVi and PrV. Thus, whisker primary afferents do not exclusively project to their corresponding PrV barrelette, whereas higher order SpVi inputs to the PrV are precisely topographic. PMID- 25019348 TI - The effects of non-calcium-based phosphate binders versus calcium-based phosphate binders on cardiovascular calcification and bone remodeling among dialysis patients: a meta-analysis of randomized trials. AB - BACKGROUND: Vascular calcification significantly increases the rates of cardiovascular mortality in hemodialysis (HD) patients. Abnormalities in mineral metabolism may play a role in the pathogenesis of arterial calcification. Whether patients treated with non-calcium-based phosphate binders had reduced aortic vascular calcification compared to those treated with calcium-based phosphate binders is still unclear. METHODS: We searched multiple databases for studies published through August 2013 that evaluated the effects of non-calcium-based phosphate binders (NCBP) versus calcium-based phosphate binders (CBP) on cardiovascular calcification and bone remodeling among dialysis patients. We summarized test performance characteristics with the use of forest plots, fixed and random effects models, and Egger regression test. RESULTS: Eighteen eligible randomized controlled trials totaling 3676 patients were included. Meta-analysis results showed NCBP could significantly attenuate the progression of coronary artery calcification than CBP (WMD: -144.62, 95% CI: -285.62 to -3.63). The serum calcium levels significant lower in NCPB group than in CPB groups (WMD: -0.26, 95% CI: -0.37 to -0.14), but the serum iPTH levels were significantly higher in NCPB groups (WMD: 57.1, 95% CI: 13.42 to 100.78). The osteoid volume and osteoblast numbers were significant higher in NCPB group than in CPB group (WMD: 1.75, 95% CI: 0.78 to 2.73 for osteoid volume; WMD: 4.49, 95% CI: 1.83 to 7.15 for osteoblast numbers). The Egger regression test also showed no potential publication bias (p = 0.725). CONCLUSIONS: Based on available data, NCBPs have equally effective with CBPs for serum phosphate control. But there was significantly lower incidence of coronary artery calcification and a significant higher bone formatting rate in NCBP groups than in CBP groups. So we recommend NCBPs as phosphate binders for HD patients. PMID- 25019350 TI - Continuous terbutaline infusion in severe asthma in adults: a retrospective study of long-term efficacy and safety. AB - BACKGROUND: Long-term subcutaneous or intravenous infusion of terbutaline has been used to stabilize asthma in patients enduring frequent hospital admissions due to severe asthma despite maximum therapy. However, this treatment is not supported by significant body of evidence. AIM: To study long-term efficacy and safety of using continuous infusions of terbutaline in unstable severe asthma. METHODS: The available medical records of all patients received terbutaline infusions at a severe asthma unit between 1982 and 2008 were retrospectively studied. We retrieved data on treatment indication, asthma subtype, patient demographics, pre-treatment terbutaline trial outcome, duration of treatment, effect on lung function, hospital admissions, oral corticosteroids (OCSs) requirement, safety and side effects. RESULTS: Forty-two patients with adequate medical information were studied (31 females, mean age 43.6 years, 88% had type 1 brittle asthma and 12% had other severe asthma). This group of patients had a mean body mass index of 30.8 kg/m2, mean oral prednisolone or equivalent of 26.6 mg and mean predicted FEV1 of 66.8%. The mean treatment duration was 86.7 months (range 7-216). Long-term continuous terbutaline infusion significantly reduced hospital admissions (mean pre-treatment = 6.7 (95% CI 0.96-12.4) per annum, and mean annualized on-treatment admission = 3.3 (95% CI 0.63-6.9, p = 0.045). We observed overall reduction in OCSs use in 59% of patients with available data, but there was no significant change in lung function. Side effects related to terbutaline or the method of its infusion were common and some were serious especially when central venous access device were used. CONCLUSION: Continuous terbutaline infusion could be a treatment option for severe unstable asthma and may reduce hospital admissions. However, the treatment was associated with significant side effects and its use should be limited to centers possessing necessary expertise. PMID- 25019349 TI - Findings from a community-based asthma education fair for Latino caregivers. AB - OBJECTIVE: To assess limited English proficiency (LEP) asthma caregiver quality of life (QoL), skills retention and healthcare utilization after an asthma education fair (AEF). METHODS: A language concordant AEF was conducted at a Latino community center. LEP caregivers of children 1-12 years old and an established asthma diagnosis participated in three skill stations: (a) medication recognition and administration, (b) peak flow use (if child >= 5 years) and (c) action plan dissemination. Spacers, peak flow meters and individualized action plans were distributed. A validated, pediatric asthma caregiver quality of life questionnaire (PACQLQ-Spanish version) was administered. Baseline data was compared to follow-up interview data at three and six months after the AEF. Mean PACQLQ scores were analyzed with Wilcoxon signed-rank test and nominal paired data with McNemar's test. RESULTS: We analyzed data from 18 caregivers able to speak English well (22%), not well (28%) or not at all (50%). After three months, improved caregiver QoL was experienced (51 vs. 72, p<0.01). No differences were observed in medication recognition, spacer and peak flow use or peak flow interpretation. After six months, mean school days missed due to asthma decreased (4.1 vs. 0.4, p<0.01). Mean clinic visits, emergency department visits and hospitalizations remained unchanged. CONCLUSIONS: Implementation of a community based AEF with action plan administration can be beneficial for LEP caregivers and their children. QoL improvements to emotional wellbeing and activity limitations were observed, and lower rates of school absenteeism were reported. Caregiver ability to accurately identify medications was not enhanced. PMID- 25019351 TI - Effects of cigarette smoke on methacholine- and AMP-induced air trapping in asthmatics. AB - Abstract Objective: No information is available on the effect of cigarette smoke on bronchoconstrictor-induced air trapping in asthma. The aim of this study was to evaluate the additional influence of smoking on methacholine- and adenosine 5' monophosphate (AMP)-induced air trapping in subjects with asthma. METHODS: Airway responsiveness to methacholine and AMP, bronchial (J'awNO) and alveolar (CANO) nitric oxide (NO) and exhaled breath condensate pH were measured in 68 adults (23 current smokers with asthma, 23 non-smokers with asthma and 22 current or former smokers with chronic obstructive pulmonary disease; COPD). The degree of air trapping induced by each bronchoconstrictor agent was expressed by the percent fall in forced vital capacity (FVC) at a 20% fall in forced expiratory volume in 1 s relative to FVC after saline inhalation (DeltaFVC%). RESULTS: The DeltaFVC% for AMP was higher in both smokers with asthma and patients with COPD than in non smokers with asthma (p<0.001). By contrast, DeltaFVC% for methacholine was similar in the three groups of subjects (p=0.69). In smokers with asthma, but not in the other two groups, there was a correlation between the residual volume/total lung capacity at baseline and the DeltaFVC% induced by each bronchoconstrictor agent. Mean values for J'awNO were higher in non-smokers with asthma than in the other two groups (p<0.05). CONCLUSIONS: The results of this study suggest that factors underlying bronchoconstriction induced by indirect agonists are different in smokers and non-smokers with asthma. These observations might be clinically relevant, because triggers that frequently induce bronchial obstruction in the real world act by an indirect mechanism. PMID- 25019352 TI - Serum mannose-binding lectin and C-reactive protein are potential biomarkers for patients with community-acquired pneumonia. AB - AIM: The aim of this study was to identify whether mannose-binding lectin (MBL) and C-reactive protein (CRP) may be used as clinical biomarkers for predicting outcome of community-acquired pneumonia (CAP) by tracking serum MBL and CRP level changes during a time course. METHODS: One hundred four patients with CAP and 100 healthy individuals were enrolled in this study. The patients were further divided into Survivor and Death groups based on 30-day mortality. The MBL and CRP levels in these patients at pre- and post-treatments at days 4 and 7 were determined using an immunoturbidimetric assay and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to the control group, the MBL and CRP levels in the CAP group were significantly higher. CRP levels in the CAP group significantly reduced within 1 week following anti-infection and other supporting therapies including anti-phlegm and liquidation. MBL levels were significantly higher in the Survivor group than in the Death group (p<0.05). On the contrary, CRP levels were significantly higher in the Death group than in the Survivor group (p<0.05). There was a negative correlation between the serum MBL and CRP levels in all patients following the treatments. CONCLUSION: Both the MBL and CRP can serve as inflammatory markers in predicting the outcome of patients with CAP. PMID- 25019353 TI - Changes to corneal aberrations and vision after Presbylasik refractive surgery using the MEL 80 platform. AB - PURPOSE: To investigate changes to corneal surface aberrations and vision between PresbyLASIK and LASIK for correction of presbyopia using the MEL 80 platform (Carl Zeiss Meditec, Jena, Germany). METHODS: The retrospective data of 31 patients who underwent PresbyLASIK (the PresbyLASIK group) between January 2009 and November 2011 and 20 matched patients who underwent LASIK (the LASIK group) were analyzed for changes to refraction, corrected distance visual acuity, and corneal surface wavefront aberrations calculated over 4- and 6-mm pupils. Outcomes at the 3-month follow-up visit were compared to data collected immediately prior to surgery and between PresbyLASIK and LASIK correction. Associations between induced corneal aberrations and best spherical equivalent refraction were explored. RESULTS: PresbyLASIK and LASIK significantly reduced refractive error in both myopes and hyperopes. Residual refractive error was not significantly different between treatment groups, except for spherical equivalent refraction, which was significantly more myopic following LASIK treatment compared to PresbyLASIK in myopes. There was no significant difference in postoperative corrected distance visual acuity between groups. LASIK and PresbyLASIK induced positive spherical aberration in myopes and negative spherical aberration in hyperopes, with significant differences between treatments only apparent in myopes when analyzed over a 4-mm pupil (PresbyLASIK group: 0.07 +/- 0.06 um; LASIK group: 0.03 +/- 0.04 um, P < .05). In hyperopes, induced spherical aberration was more highly associated with refractive change after LASIK (r = 0.82, P < .05) than PresbyLASIK (r = 0.64, P < .001); instead PresbyLASIK led to a more consistent shift of approximately 0.3 um independent of induced change to refraction. CONCLUSIONS: PresbyLASIK using the MEL 80 platform induced significant changes in spherical aberration in myopes and hyperopes. PresbyLASIK appears to offer an improved response over LASIK when correcting myopes due to an apparent increase in depth of focus resulting from changes in spherical aberration. For hyperopes, PresbyLASIK provides a more consistent spherical aberration effect independent of refractive change. PMID- 25019354 TI - Nurses and physicians in a medical admission unit can accurately predict mortality of acutely admitted patients: a prospective cohort study. AB - BACKGROUND: There exist several risk stratification systems for predicting mortality of emergency patients. However, some are complex in clinical use and others have been developed using suboptimal methodology. The objective was to evaluate the capability of the staff at a medical admission unit (MAU) to use clinical intuition to predict in-hospital mortality of acutely admitted patients. METHODS: This is an observational prospective cohort study of adult patients (15 years or older) admitted to a MAU at a regional teaching hospital. The nursing staff and physicians predicted in-hospital mortality upon the patients' arrival. We calculated discriminatory power as the area under the receiver-operating characteristic curve (AUROC) and accuracy of prediction (calibration) by Hosmer Lemeshow goodness-of-fit test. RESULTS: We had a total of 2,848 admissions (2,463 patients). 89 (3.1%) died while admitted. The nursing staff assessed 2,404 admissions and predicted mortality in 1,820 (63.9%). AUROC was 0.823 (95% CI: 0.762-0.884) and calibration poor. Physicians assessed 738 admissions and predicted mortality in 734 (25.8% of all admissions). AUROC was 0.761 (95% CI: 0.657-0.864) and calibration poor. AUROC and calibration increased with experience. When nursing staff and physicians were in agreement (+/-5%), discriminatory power was very high, 0.898 (95% CI: 0.773-1.000), and calibration almost perfect. Combining an objective risk prediction score with staff predictions added very little. CONCLUSIONS: Using only clinical intuition, staff in a medical admission unit has a good ability to identify patients at increased risk of dying while admitted. When nursing staff and physicians agreed on their prediction, discriminatory power and calibration were excellent. PMID- 25019356 TI - T'ain't the way you say it, it's what you say--perceptual continuity of voice and top-down restoration of speech. AB - Phonemic restoration, or top-down repair of speech, is the ability of the brain to perceptually reconstruct missing speech sounds, using remaining speech features, linguistic knowledge and context. This usually occurs in conditions where the interrupted speech is perceived as continuous. The main goal of this study was to investigate whether voice continuity was necessary for phonemic restoration. Restoration benefit was measured by the improvement in intelligibility of meaningful sentences interrupted with periodic silent gaps, after the gaps were filled with noise bursts. A discontinuity was induced on the voice characteristics. The fundamental frequency, the vocal tract length, or both of the original vocal characteristics were changed using STRAIGHT to make a talker sound like a different talker from one speech segment to another. Voice discontinuity reduced the global intelligibility of interrupted sentences, confirming the importance of vocal cues for perceptually constructing a speech stream. However, phonemic restoration benefit persisted through all conditions despite the weaker voice continuity. This finding suggests that participants may have relied more on other cues, such as pitch contours or perhaps even linguistic context, when the vocal continuity was disrupted. PMID- 25019357 TI - Determination and quantification of Schistosoma mansoni cercarial emergence from Biomphalaria glabrata snails. AB - Living and fixed samples of Schistosoma mansoni -infected Biomphalaria glabrata snails were used to determine the relative contributions of different snail tissues to cercarial emergence (shedding). Three methods of observations were employed: (1) direct microscopical observations of shedding snails; (2) microscopic analysis of 5 MUm serial sections (H&E stained) of actively shedding snails; and (3) scanning electron microscopic (SEM) observations of snails that were fixed while actively shedding. For this investigation, there were advantages and disadvantages to using each method. We confirmed the results of others that there were 3 tissues of the snail that contributed most prominently to cercarial release (mantle collar, pseudobranch, and headfoot). Based on histological analysis of cercarial accumulations in presumed shedding sites in these 3 tissues, 57% of the cercariae could be seen in the mantle collar, 30.6% in the pseudobranch, and 12.5% in the headfoot. Other anterior structures were involved to a much lesser extent. SEM observations clearly showed cercariae emerging either body first, tail first, or likely emerging en masse from blebs, especially from the mantle collar. These studies provide a more quantitative appraisal of the role the different anterior snail tissues play in cercarial emergence. PMID- 25019355 TI - Peak I of the human auditory brainstem response results from the somatic regions of type I spiral ganglion cells: evidence from computer modeling. AB - Early neural responses to acoustic signals can be electrically recorded as a series of waves, termed the auditory brainstem response (ABR). The latencies of the ABR waves are important for clinical and neurophysiological evaluations. Using a biophysical model of transmembrane currents along spiral ganglion cells, we show that in human (i) the non-myelinated somatic regions of type I cells, which innervate inner hair cells, predominantly contribute to peak I, (ii) the supra-strong postsynaptic stimulating current (400 pA) and transmembrane currents of the myelinated peripheral axons of type I cells are an order smaller; such postsynaptic currents correspond to the short latencies of a small recordable ABR peak I', (iii) the ABR signal involvement of the central axon of bipolar type I cells is more effective than their peripheral counterpart as the doubled diameter causes larger transmembrane currents and a larger spike dipole-length, (iv) non myelinated fibers of type II cells which innervate the outer hair cells generate essentially larger transmembrane currents but their ABR contribution is small because of the small ratio type II/type I cells, low firing rates and a short dipole length of spikes propagating slowly in non-myelinated fibers. Using a finite element model of a simplified head, peaks In and II (where In is the negative peak after peak I) are found to be stationary potentials when volleys of spikes cross the external electrical conductivity barrier at the bone&dura/CSF and at the CSF/brainstem interface whereas peaks I' and I may be generated by strong local transmembrane currents as postsynaptic events at the distal ending and the soma region of type I cells, respectively. All simulated human inter-peak times (I-I', II-I, In-I) are close to published data. PMID- 25019358 TI - Reconstruction of the biomechanical transfer path of femoral head necrosis: a subject-specific finite element investigation. AB - According to Wolff's law, the structure and function of bone are interdependent. The disruption of trabeculae in the necrotic femoral head destroys the biomechanical transfer path, increasing the risk of a collapse in the cortical bone. Hence, biomaterials are needed to promote osteogenesis to aid in the reconstruction of a similar biomechanical transfer path that can provide structural and biomechanical support to prevent and delay bone deterioration. Fibular allograft combined with impaction bone grafting (FAIBG) is a hip preservation method that provides both biological repair materials and biomechanical support. This method has been used successfully in the clinical setting, but it still lacks biomechanical insight. In this paper, we aim to provide a biomechanical basis for treatment using FAIBG, we used subject-specific finite element (FE) methods to analyse the biomechanical transfer characteristics of hip models: physiological, pathological and postoperative. The physiological model provided insight into the biomechanical transfer characteristics of the proximal femur. The pathological model showed an abnormal stress distribution that destroyed stress transfer capability. The postoperative model showed that FAIBG can reconstruct the biomechanical transfer path of the femoral head and reduce the risk of a collapse in the cortical bone. In conclusion, FAIBG seems to treat necrosis of the femoral head. PMID- 25019359 TI - I do not even remember what I smoked! A case of marijuana-induced transient global amnesia. PMID- 25019360 TI - Patient fraud: a tale of two tales. PMID- 25019361 TI - Thrombolytic therapy for acute pulmonary embolism: when do the benefits exceed the risks? PMID- 25019362 TI - Surface-based morphometry of the cortical architecture of autism spectrum disorders: volume, thickness, area, and gyrification. AB - Structural neuroimaging studies of autism spectrum disorder (ASD) have uncovered widespread neuroanatomical abnormalities, which may have a significant impact on brain function, connectivity, and on behavioral symptoms of autism. The findings of previous structural MRI studies have largely been distributed across several brain areas, with limited consistency. The current study examined neuroanatomical abnormalities by comparing surface-based measures of cortical morphology (CT: cortical thickness, CSA: cortical surface area, CV: cortical volume, and GI: gyrification index) in 55 high-functioning children and adults with ASD to 60 age and-IQ-matched typically developing (TD) peers. A few brain areas, the fusiform gyrus (FG), middle temporal gyrus (MTG), and inferior frontal gyrus (IFG), emerged to be primarily different in their morphology between the two groups. Compared to TD participants, ASD participants had significantly smaller CV in left MTG, reduced CSA in bilateral MTG and FG, reduced GI in left supramarginal gyrus, and significantly increased CT in the pars opercularis of the IFG. As a function of age, ASD participants had significant reductions in: CT in the pars opercularis, CSA of the left rostral middle frontal gyrus, and GI for left supramarginal gyrus. Thus, alterations in cortical morphology in ASD were seen primarily in regions that are considered part of the social brain. Overall, these findings point to: neuroanatomical alterations in social brain areas, developmental differences in neuroanatomy, and the need to study neuroanatomy at multiple levels in order to better characterize the cortical architecture of ASD. PMID- 25019363 TI - Resin composites: Modulus of elasticity and marginal quality. AB - OBJECTIVE: To investigate how the modulus of elasticity of resin composites influences marginal quality in restorations submitted to thermocyclic and mechanical loading. METHODS: Charisma, Filtek Supreme XTE and Grandio were selected as they were found to possess different moduli of elasticity but quite similar polymerization contraction. MOD cavities (n=30) were prepared in extracted premolars, restored and then subjected to thermocyclic and mechanical loading. Marginal quality of the restorations before and after loading was analyzed on epoxy replicas under a scanning electron microscope. The percentage of gap-free margins and occurrence of paramarginal fractures were registered. Modulus of elasticity and polymerization contraction were analyzed with parametric and margins with nonparametric ANOVA and post hoc Tukey HSD or Wilcoxon rank-sum tests, respectively. The number of paramarginal fractures was analyzed with exact Fisher tests (alpha=0.05). RESULTS: Grandio demonstrated significantly more gap-free enamel margins than Charisma and Filtek Supreme XTE, before and after loading (p<0.01), whereas there was no difference between Charisma and Filtek Supreme XTE (p>0.05). No significant effect of resin composite (p=0.81) on the quality of dentine margins was observed, before or after loading. Deterioration of all margins was evident after loading (p<0.0001). More paramarginal enamel fractures were observed after loading in teeth restored with Grandio when compared to Charisma (p=0.008). CONCLUSIONS: The resin composite with the highest modulus of elasticity resulted in the highest number of gap-free enamel margins but with an increased incidence of paramarginal enamel fractures. CLINICAL SIGNIFICANCE: The results from this study suggest that the marginal quality of restorations can be improved by the selection of a resin composite with modulus of elasticity close to that of dentine, although an increase in paramarginal enamel fractures can result as a consequence. PMID- 25019364 TI - Optical properties of CAD-CAM ceramic systems. AB - OBJECTIVES: To evaluate the direct transmittance (T%), translucency, opacity and opalescence of CAD-CAM ceramic systems and the correlation between the translucency parameter (TP) and the contrast ratio (CR). METHODS: Specimens of shades A1, A2 and A3 (n=5) were fabricated from CAD-CAM ceramic blocks (IPS e.max((r)) CAD HT and LT, IPS Empress((r)) CAD HT and LT, ParadigmTM C, and VITABLOCS((r)) Mark II) and polished to 1.0+/-0.01mm in thickness. A spectrophotometer (Lambda 20) was used to measure T% on the wavelength range of 400-780nm. Another spectrophotometer (VITA Easyshade((r)) Advance) was used to measure the CIE L(*)a(*)b(*) coordinates and the reflectance value (Y) of samples on white and black backgrounds. TP, CR and the opalescence parameter (OP) were calculated. Data were statistically analysed using VAF (variance accounting for) coefficient with Cauchy-Schwarz inequality, one-way ANOVA, Tukey's test, Bonferroni correction and Pearson's correlation. RESULTS: T% of some ceramic systems is dependent on the wavelength. The spectral behaviour showed a slight and constant increase in T% up to approximately 550nm, then some ceramics changed the behaviour as the wavelength gets longer. TP and CR values ranged, respectively, from 16.79 to 21.69 and from 0.52 to 0.64 (r(2)=-0.97). OP values ranged from 3.01 to 7.64. CONCLUSIONS: The microstructure of CAD-CAM ceramic systems influenced the optical properties. TP and CR showed a strong correlation for all ceramic systems evaluated. Yet, all ceramics showed some degree of light transmittance. SIGNIFICANCE: In addition to shade, this study showed that other optical properties influence on the natural appearance of dental ceramics. PMID- 25019365 TI - Density dependent mechanical properties and structures of a freeze dried biopharmaceutical excipient--sucrose. AB - Knowledge of the mechanical behaviour of freeze dried biopharmaceutical products is essential for designing of products with physical robustness that will not to crack, crumble or collapse during processing or transportation. The compressive mechanical deformation behaviour for freeze-dried sucrose cakes has been experimentally studied from a relative density (rhof/rhos) of 0.01-0.30 using a novel in-vial indentation test. Cakes exhibited more open like structures at lower densities and more closed structures at higher densities with some faces being present at all densities, as confirmed by SEM. The reduced elastic modulus Ef/Es=0.0044(rhof/rhos)(1) for all cake densities, indicating that face stretching was the dominant deformation mode assuming Gibson and Ashby's closed cell model. This linear scaling for the reduced elastic modulus is in line with various theoretical treatments based on tetrakaidecahedral cells and other experimental studies. Consistently, the wall thickness to cell diameter ratio scaled rhof/rhos with a power constant of 1.05. The maximum crushing stress was given by sigmamax=3800(rhof/rhos)(1.48) which agrees with a strut bending failure stress, assuming Gibson and Ashby's open cell model. Overall, the freeze dried cakes behaved as neither classic closed cell nor open cell materials, with their compressive elastic moduli reflecting a closed cell elastic response whilst their failure stresses reflecting an open cell failure mode. It was concluded that the mechanical response of freeze dried cellular materials depends upon their complex cellular structures and morphologies, and they cannot be rationalised using simple limiting case models of open or closed cell solids. PMID- 25019366 TI - Non-adiabatic molecular dynamics investigation of photoionization state formation and lifetime in Mn2+-doped ZnO quantum dots. AB - The unique electronic structure of Mn(2+)-doped ZnO quantum dots gives rise to photoionization states that can be used to manipulate the magnetic state of the material and to generate zero-reabsorption luminescence. Fast formation and long non-radiative decay of this photoionization state is a necessary requirement for these important applications. In this work, surface hopping based non-adiabatic molecular dynamics are used to demonstrate the fast formation of a metal-to ligand charge transfer state in a Mn(2+)-doped ZnO quantum dot. The formation occurs on an ultrafast timescale and is aided by the large density of states and significant mixing of the dopant Mn(2+) 3dt2 levels with the valence-band levels of the ZnO lattice. The non-radiative lifetime of the photoionization states is also investigated. PMID- 25019367 TI - Histone deacetylase 8 suppresses osteogenic differentiation of bone marrow stromal cells by inhibiting histone H3K9 acetylation and RUNX2 activity. AB - Bone marrow stromal cells (BMSCs) are multipotent progenitor cells with capacities to differentiate into the various cell types and hold great promise in regenerative medicine. The regulatory roles of histone deacetylases (HDACs) in osteoblast differentiation process have been increasingly recognized; however, little is known about the precise roles of HDAC8 in the osteogenic differentiation of BMSCs. Herein we aimed to investigate the roles of HDAC8 in the osteogenic differentiation of rat BMSCs by pharmacological and genetic manipulations in vitro. During osteogenic differentiation of BMSCs, pharmacological inhibition of HDAC8 by HDAC inhibitor valproic acid (VPA) promoted the level of histone H3 lysine 9 acetylation (H3K9Ac) and significantly enhanced the expression of osteogenesis-related genes Runx2, Osterix, osteocalcin (OCN), osteopontin (OPN) and alkaline phosphatase (ALP). Similarly, knockdown of HDAC8 using short interfering RNA triggered H3K9Ac and enhanced osteogenic differentiation of BMSCs, largely phenocopied the effects of VPA-mediated HDAC8 depletion. However, enforced expression of HDAC8 significantly reduced the level of H3K9Ac and inhibited osteogenic differentiation of BMSCs, which can be attenuated by VPA addition. Mechanistically, HDAC8 suppressed osteogenesis related genes expression by removing the acetylation of histone H3K9, thus leading to transcriptional inhibition during osteogenic differentiation of BMSCs. Importantly, we found that HDAC8 physically associated with Runx2 to repress its transcriptional activity and this association decreased when BMSCs underwent osteogenic differentiation. Taken together, these results indicate that epigenetic regulation of Runx2 by HDAC8-mediated histone H3K9 acetylation is required for the proper osteogenic differentiation of BMSCs. PMID- 25019368 TI - CCR7: roles in cancer cell dissemination, migration and metastasis formation. AB - The CC-chemokine receptor 7 (CCR7) coordinates the migration of cancer cells as well as immune cells towards lymphatic organs where its two ligands CCL19 and CCL21 are constitutively expressed. Here we provide a topological model of CCR7, which belongs to the class A of G-protein coupled, seven-transmembrane spanning receptors, and describe how CCR7 expression is regulated. We focus on its role in cancer cell migration and metastasis formation and discuss how cancer cells can utilize CCR7 or its ligands to escape from immune surveillance. PMID- 25019371 TI - Genetics of gastrointestinal atresias. AB - Gastrointestinal atresias are a common and serious feature within the spectrum of gastrointestinal malformations. Atresias tend to be lethal, although, now-days surgery and appropriate care can restore function to the affected organs. In spite of their frequency, their life threatening condition and report history gastrointestinal atresias' etiology remains mostly unclarified. Gastrointestinal atresias can occur as sporadic but they are more commonly seen in association with other anomalies. For the syndromic cases there is mounting evidence of a strong genetic component. Sporadic cases are generally thought to originate from mechanical or vascular incidents in utero, especially for the atresias of the lower intestinal tract. However, recent data show that a genetic component may be present also in these cases. Embryological and genetic studies are starting to uncover the mechanism of gastrointestinal development and their genetic components. Here we present an overview of the current knowledge of gastrointestinal atresias, their syndromic forms and the genetic pathways involved in gastrointestinal malformation. PMID- 25019369 TI - Direct induction of haematoendothelial programs in human pluripotent stem cells by transcriptional regulators. AB - Advancing pluripotent stem cell technologies for modelling haematopoietic stem cell development and blood therapies requires identifying key regulators of haematopoietic commitment from human pluripotent stem cells (hPSCs). Here, by screening the effect of 27 candidate factors, we reveal two groups of transcriptional regulators capable of inducing distinct haematopoietic programs from hPSCs: pan-myeloid (ETV2 and GATA2) and erythro-megakaryocytic (GATA2 and TAL1). In both cases, these transcription factors directly convert hPSCs to endothelium, which subsequently transform into blood cells with pan-myeloid or erythro-megakaryocytic potential. These data demonstrate that two distinct genetic programs regulate the haematopoietic development from hPSCs and that both of these programs specify hPSCs directly to haemogenic endothelial cells. In addition, this study provides a novel method for the efficient induction of blood and endothelial cells from hPSCs via the overexpression of modified mRNA for the selected transcription factors. PMID- 25019370 TI - GRAF1 promotes ferlin-dependent myoblast fusion. AB - Myoblast fusion (a critical process by which muscles grow) occurs in a multi-step fashion that requires actin and membrane remodeling; but important questions remain regarding the spatial/temporal regulation of and interrelationship between these processes. We recently reported that the Rho-GAP, GRAF1, was particularly abundant in muscles undergoing fusion to form multinucleated fibers and that enforced expression of GRAF1 in cultured myoblasts induced robust fusion by a process that required GAP-dependent actin remodeling and BAR domain-dependent membrane sculpting. Herein we developed a novel line of GRAF1-deficient mice to explore a role for this protein in the formation/maturation of myotubes in vivo. Post-natal muscles from GRAF1-depleted mice exhibited a significant and persistent reduction in cross-sectional area, impaired regenerative capacity and a significant decrease in force production indicative of lack of efficient myoblast fusion. A significant fusion defect was recapitulated in isolated myoblasts depleted of GRAF1 or its closely related family member GRAF2. Mechanistically, we show that GRAF1 and 2 facilitate myoblast fusion, at least in part, by promoting vesicle-mediated translocation of fusogenic ferlin proteins to the plasma membrane. PMID- 25019372 TI - Raine syndrome: an overview. AB - Raine syndrome (RS) is a bone dysplasia characterised by generalised osteosclerosis with periosteal bone formation, characteristic face, and brain abnormalities [MIM # 259775]. Its prevalence is estimated to be < 1/1,000,000. Although it was originally thought always to be lethal, there have now been six reports of patients surviving into childhood and this phenotype is still being defined. The skeletal dysplasia predominantly affects craniofacial development explaining the severe proptosis, underdeveloped midface, depressed nasal bridge and short nose. The main radiological manifestation is a diffuse, marked osteosclerosis of the base of skull and long bones. Raine syndrome is caused by biallelic mutations in FAM20C, located on chromosome 7p22.3. This gene encodes a Golgi casein kinase, which phosphorylates serine residues of extracellular proteins involved in biomineralisation. Facial appearance and radiological findings allow the clinical diagnosis, and molecular testing of FAM20C can confirm this. Desmosterolosis and congenital cytomegalovirus infection may resemble Raine syndrome. If Raine syndrome is suspected prenatally the newborn should be admitted at a neonatal intensive care unit as significant respiratory distress is often present immediately after birth. We present here a review of the pertinent literature in clinical manifestations, molecular background, diagnosis and management. PMID- 25019373 TI - NIR-triggered drug release from switchable rotaxane-functionalized silica-covered Au nanorods. AB - An NIR-triggered drug delivery system was developed by capping photo-switchable azobenzene-based rotaxane onto Au nanorod-mesoporous silica core-shell hybrids. Drug release from the nanocarrier in zebrafish embryo models could be controlled remotely under NIR irradiation, showing significant drug spreading to the adjacent tissues. PMID- 25019374 TI - Human immunodeficiency virus and hepatitis C virus/hepatitis B virus co-infection in Southern Brazil: clinical and epidemiological evaluation. AB - Hepatitis B virus, hepatitis C virus and human immunodeficiency virus share a similar transmission pathway and are often diagnosed in the same patient. These patients tend to have a faster progression of hepatic fibrosis. This cross sectional study describes the demographic features and clinical profile of human immunodeficiency virus/hepatitis co-infected patients in Parana, Southern Brazil. A total of 93 human immunodeficiency virus-infected patients attending a tertiary care academic hospital in Southern Brazil were included. Clinical, demographic and epidemiological data were evaluated. Hepatitis B virus and/or hepatitis C virus positive serology was found in 6.6% of patients. The anti-hepatitis C virus serum test was positive in 85% (79/93) of patients, and the infection was confirmed in 72% of the cases. Eighteen patients (19%) were human immunodeficiency virus/hepatitis B virus positive (detectable HBsAg). Among co infected patients, there was a high frequency of drug use, and investigations for the detection of co-infection were conducted late. A low number of patients were eligible for treatment and, although the response to antiretroviral therapy was good, there was a very poor response to hepatitis therapy. Our preliminary findings indicate the need for protocols aimed at systematic investigation of hepatitis B virus and hepatitis C virus in human immunodeficiency virus-infected patients, thus allowing for early detection and treatment of co-infected patients. PMID- 25019375 TI - Patient experiences and preferences with ureteral stent removal. AB - PURPOSE: Ureteral stent removal is a source of patient morbidity. We surveyed 599 patients to evaluate their experiences and identify the preferred method of stent removal. MATERIALS AND METHODS: Visitors to a kidney stone website were invited to participate. Respondents were asked how their ureteral stent was removed? Pain during and after the procedure, patient experiences, and preferences regarding stent removal were queried. Chi-square and ANOVA tests were used to identify significant differences among removal methods. RESULTS: Five hundred seventy-one respondents were included in the study. The majority of stents (44%) were removed by office cystoscopy while 39% had their stents removed by string. Mean pain during stent removal was 4.8 out of 10 with 57% reporting moderate-to-severe pain levels of 4 or more. Removal by office cystoscopy resulted in the highest experienced pain (5.3). Thirty-two percent reported delayed severe pain after stent removal, including 9% who returned for emergency care. Removal by string resulted in more emergency room visits when compared to cystoscopy. Willingness to undergo the same removal technique was lowest for those who underwent office cystoscopy and highest for operating room cystoscopy. Being informed of why a stent was placed and the removal process was of high priority for respondents. CONCLUSIONS: The majority of patients report moderate-to-severe pain with stent removal and a third report delayed significant pain after stent removal. Variations exist in the patient experience with stent removal based on the method used. More research is needed to identify effective ways to prevent or manage stent-removal-related adverse events. PMID- 25019376 TI - Use of a population pharmacokinetic approach for the clinical development of a fixed-dose subcutaneous formulation of trastuzumab. AB - A new subcutaneous (s.c.) trastuzumab formulation provides savings in terms of time and is preferred by patients and health care professionals relative to standard intravenous (i.v.) administration due to simpler and more rapid administration (2-5 minutes). Selection of the s.c. dose was based on a pharmacokinetic bridging approach that aimed to achieve noninferior trastuzumab serum trough concentrations (Ctrough) vs. reference i.v. administration. Using population modeling and simulation, we showed that a fixed 600-mg trastuzumab s.c. dose, administered thrice-weekly (Q3W) without a loading dose, would provide Ctrough (predose Cycle 8) and area under the time-concentration curve (AUC0-21 days, Cycle 7) at least as high as Q3W i.v. administration. The model was retrospectively validated using observed pharmacokinetic data from an independent phase III study of (neo)adjuvant trastuzumab (HannaH). These results provide a strong pharmacokinetic rationale for the trastuzumab s.c. 600-mg fixed dose, supported by the noninferior efficacy of this regimen vs. reference i.v. administration.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e87; doi:10.1038/psp.2013.63; advance online publication 2 January 2014. PMID- 25019377 TI - Strain differences in fitness of Escherichia coli O157:H7 to resist protozoan predation and survival in soil. AB - Escherichia coli O157:H7 (EcO157) associated with the 2006 spinach outbreak appears to have persisted as the organism was isolated, three months after the outbreak, from environmental samples in the produce production areas of the central coast of California. Survival in harsh environments may be linked to the inherent fitness characteristics of EcO157. This study evaluated the comparative fitness of outbreak-related clinical and environmental strains to resist protozoan predation and survive in soil from a spinach field in the general vicinity of isolation of strains genetically indistinguishable from the 2006 outbreak strains. Environmental strains from soil and feral pig feces survived longer (11 to 35 days for 90% decreases, D-value) with Vorticella microstoma and Colpoda aspera, isolated previously from dairy wastewater; these D-values correlated (P<0.05) negatively with protozoan growth. Similarly, strains from cow feces, feral pig feces, and bagged spinach survived significantly longer in soil compared to clinical isolates indistinguishable by 11-loci multi-locus variable number tandem-repeat analysis. The curli-positive (C+) phenotype, a fitness trait linked with attachment in ruminant and human gut, decreased after exposure to protozoa, and in soils only C- cells remained after 7 days. The C+ phenotype correlated negatively with D-values of EcO157 exposed to soil (rs = -0.683; P = 0.036), Vorticella (rs = -0.465; P = 0.05) or Colpoda (rs = -0.750; P = 0.0001). In contrast, protozoan growth correlated positively with C+ phenotype (Vorticella, rs = 0.730, P = 0.0004; Colpoda, rs = 0.625, P = 0.006) suggesting a preference for consumption of C+ cells, although they grew on C- strains also. We speculate that the C- phenotype is a selective trait for survival and possibly transport of the pathogen in soil and water environments. PMID- 25019378 TI - Exogenous Oct-4 inhibits lens transdifferentiation in the newt Notophthalmus viridescens. AB - From the cocktail of four factors that were able to induce pluripotent stem cells from differentiated cells, Oct-4, c-Myc, Sox-2 and Klf4, only Oct-4 was not expressed during regeneration in newts. To explore the possible action of this stemness factor we developed an assay where we introduced exogenous Oct-4 protein to an in vitro system for lens regeneration in newts. We found that exogenous Oct 4 inhibits differentiation of iris pigmented epithelial cells into lens cells and also regulates Sox-2 and Pax-6, both important players during lens development. Thus, presence of Oct-4 hinders transdifferentiation of iris cells. PMID- 25019379 TI - Conservation of endangered Lupinus mariae-josephae in its natural habitat by inoculation with selected, native Bradyrhizobium strains. AB - Lupinus mariae-josephae is a recently discovered endemism that is only found in alkaline-limed soils, a unique habitat for lupines, from a small area in Valencia region (Spain). In these soils, L. mariae-josephae grows in just a few defined patches, and previous conservation efforts directed towards controlled plant reproduction have been unsuccessful. We have previously shown that L. mariae josephae plants establish a specific root nodule symbiosis with bradyrhizobia present in those soils, and we reasoned that the paucity of these bacteria in soils might contribute to the lack of success in reproducing plants for conservation purposes. Greenhouse experiments using L. mariae-josephae trap plants showed the absence or near absence of L. mariae-josephae-nodulating bacteria in "terra rossa" soils of Valencia outside of L. mariae-josephae plant patches, and in other "terra rossa" or alkaline red soils of the Iberian Peninsula and Balearic Islands outside of the Valencia L. mariae-josephae endemism region. Among the bradyrhizobia able to establish an efficient symbiosis with L. mariae-josephae plants, two strains, LmjC and LmjM3 were selected as inoculum for seed coating. Two planting experiments were carried out in consecutive years under natural conditions in areas with edapho-climatic characteristics identical to those sustaining natural L. mariae-josephae populations, and successful reproduction of the plant was achieved. Interestingly, the successful reproductive cycle was absolutely dependent on seedling inoculation with effective bradyrhizobia, and optimal performance was observed in plants inoculated with LmjC, a strain that had previously shown the most efficient behavior under controlled conditions. Our results define conditions for L. mariae-josephae conservation and for extension to alkaline limed soil habitats, where no other known lupine can thrive. PMID- 25019380 TI - The anti-apoptotic and cardioprotective effects of salvianolic acid a on rat cardiomyocytes following ischemia/reperfusion by DUSP-mediated regulation of the ERK1/2/JNK pathway. AB - The purpose of this study was to observe the effects of salvianolic acid A (SAA) pretreatment on the myocardium during ischemia/reperfusion (I/R) and to illuminate the interrelationships among dual specificity protein phosphatase (DUSP) 2/4/16, ERK1/2 and JNK pathways during myocardial I/R, with the ultimate goal of elucidating how SAA exerts cardioprotection against I/R injury (IRI). Wistar rats were divided into the following six groups: control group (CON), I/R group, SAA+I/R group, ERK1/2 inhibitor PD098059+I/R group (PD+I/R), PD+SAA+I/R group, and JNK inhibitor SP600125+I/R group (SP+I/R). The cardioprotective effects of SAA on the myocardium during I/R were investigated with a Langendorff device. Heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximum rate of ventricular pressure rise and fall (+/-dp/dtmax), myocardial infarction areas (MIA), lactate dehydrogenase (LDH), and cardiomyocytes apoptosis were monitored. To determine the crosstalk betwee JNK and ERK1/2 via DUSP2/4/16 with SAA pretreatment, siRNA DUSP2/4/16 were performed. The expression levels of Bcl-2, Bax, caspase 3, p-JNK, p-ERK1/2 and DUSP2/4/16 in cardiomyocytes were assayed by Western blot. Our results showed that LDH, MIA and cell apoptosis were decreased, and various parameters of heart function were improved by SAA pretreatment and SP application. In the I/R group, the expression levels of p-ERK1/2 and DUSP4/16 were not significantly different compared with the CON group, however, the protein expression levels of p-ERK1/2, Bcl-2 and DUSP4/16 were higher, while p JNK, Bax, caspase 3 and DUSP2 levels were reduced among the SAA+I/R, PD+SAA+I/R and SP+I/R groups. The above indices were not significantly different between the SAA+I/R and SP+I/R groups. Compared with the SAA+I/R group, p-ERK1/2 was increased and p-JNK was decreased in the SAA+si-DUSP2+I/R, however, p-ERK was downregulated and p-JNK was upregulated in SAA+si-DUSP4+I/R group. SAA exerts an anti-apoptotic role against myocardial IRI by inhibiting DUSP2-mediated JNK dephosphorylation and activating DUSP4/16-mediated ERK1/2 phosphorylation. PMID- 25019381 TI - Mistakenly seeking solitude. AB - Connecting with others increases happiness, but strangers in close proximity routinely ignore each other. Why? Two reasons seem likely: Either solitude is a more positive experience than interacting with strangers, or people misunderstand the consequences of distant social connections. To examine the experience of connecting to strangers, we instructed commuters on trains and buses to connect with a stranger near them, to remain disconnected, or to commute as normal (Experiments 1a and 2a). In both contexts, participants reported a more positive (and no less productive) experience when they connected than when they did not. Separate participants in each context, however, expected precisely the opposite outcome, predicting a more positive experience in solitude (Experiments 1b and 2b). This mistaken preference for solitude stems partly from underestimating others' interest in connecting (Experiments 3a and 3b), which in turn keeps people from learning the actual consequences of social interaction (Experiments 4a and 4b). The pleasure of connection seems contagious: In a laboratory waiting room, participants who were talked to had equally positive experiences as those instructed to talk (Experiment 5). Human beings are social animals. Those who misunderstand the consequences of social interactions may not, in at least some contexts, be social enough for their own well-being. PMID- 25019382 TI - HIF-1alpha-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion. AB - PTK6/Brk is a non-receptor tyrosine kinase overexpressed in cancer. Here we demonstrate that cytosolic PTK6 is rapidly and robustly induced in response to hypoxic conditions in a HIF-1-independent manner. Furthermore, a proportion of hypoxic PTK6 subsequently re-localized to the cell membrane. We observed that the rapid stabilization of PTK6 is associated with a decrease in PTK6 ubiquitylation and we have identified c-Cbl as a putative PTK6 E3 ligase in normoxia. The consequences of hypoxia-induced PTK6 stabilization and subcellular re localization to the plasma membrane include increased cell motility and invasion, suggesting PTK6 targeting as a therapeutic approach to reduce hypoxia-regulated metastatic potential. This could have particular significance for breast cancer patients with triple negative disease. PMID- 25019383 TI - AHR over-expression in papillary thyroid carcinoma: clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow up. AB - AIM: Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3-7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. METHODS: Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. RESULTS: 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. CONCLUSIONS: The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma. PMID- 25019385 TI - Environmental drivers of the Canadian Arctic megabenthic communities. AB - Environmental gradients and their influence on benthic community structure vary over different spatial scales; yet, few studies in the Arctic have attempted to study the influence of environmental gradients of differing spatial scales on megabenthic communities across continental-scales. The current project studied for the first time how megabenthic community structure is related to several environmental factors over 2000 km of the Canadian Arctic, from the Beaufort Sea to northern Baffin Bay. Faunal trawl samples were collected between 2007 and 2011 at 78 stations from 30 to 1000 m depth and patterns in biomass, density, richness, diversity, and taxonomic composition were examined in relation to indirect/spatial gradients (e.g., depth), direct gradients (e.g., bottom oceanographic variables), and resource gradients (e.g., food supply proxies). Six benthic community types were defined based on their biomass-based taxonomic composition. Their distribution was significantly, but moderately, associated with large-scale (100-1000 km) environmental gradients defined by depth, physical water properties (e.g., bottom salinity), and meso-scale (10-100 km) environmental gradients defined by substrate type (hard vs. soft) and sediment organic carbon content. We did not observe a strong decline of bulk biomass, density and richness with depth or a strong increase of those community characteristics with food supply proxies, contrary to our hypothesis. We discuss how local- to meso-scale environmental conditions, such as bottom current regimes and polynyas, sustain biomass-rich communities at specific locations in oligotrophic and in deep regions of the Canadian Arctic. This study demonstrates the value of considering the scales of variability of environmental gradients when interpreting their relevance in structuring of communities. PMID- 25019384 TI - The regulation and role of c-FLIP in human Th cell differentiation. AB - The early differentiation of T helper (Th) cells is a tightly controlled and finely balanced process, which involves several factors including cytokines, transcription factors and co-stimulatory molecules. Recent studies have shown that in addition to the regulation of apoptosis, caspase activity is also needed for Th cell proliferation and activation and it might play a role in Th cell differentiation. The isoforms of the cellular FLICE inhibitory protein (c-FLIP) are regulators of CASPASE-8 activity and the short isoform, c-FLIPS, has been shown to be up-regulated by IL-4, the Th2 driving cytokine. In this work, we have studied the expression and functional role of three c-FLIP isoforms during the early Th cell differentiation. Only two of the isoforms, c-FLIPS and c-FLIPL, were detected at the protein level although c-FLIPR was expressed at the mRNA level. The knockdown of c-FLIPL led to enhanced Th1 differentiation and elevated IL-4 production by Th2 cells, whereas the knockdown of c-FLIPS diminished GATA3 expression and IL-4 production by Th2 cells. In summary, our results provide new insight into the role of c-FLIP proteins in the early differentiation of human Th cells. PMID- 25019386 TI - Probing the in vitro cytotoxicity of the veterinary drug oxytetracycline. AB - The study investigated the effect of oxytetracycline (OTC) on the anti-oxidative defense system, the structure (hemolysis rate and morphology) and function (ATP enzyme activity) of human red blood cells (hRBCs) to investigate the possible toxic mechanism of OTC to hRBCs. The experimental results indicate that OTC can cause a decline in the function of the antioxidant defense system of hRBCs, resulting in oxidative stress. OTC can bring about morphological changes to hRBCs, and further leads to hemolysis, when the concentration of OTC is over 8*10(-5) M (about 164 ug/ml). At a low OTC concentration, below 4*10(-5) M (82 ug/ml), OTC can enhance the activity of ATP enzyme of hRBCs, known as hormesis. However, at a high concentration, above 4*10(-5) M (about 82 ug/ml), the ATP enzymatic activity was inhibited, affecting the function of hRBCs. The estalished mechanism of toxicity of OTC to hRBCs can facilitate a deeper understanding of the toxicity of OTC in vivo. PMID- 25019387 TI - Urinary neutrophil gelatinase-associated lipocalin and the occurrence of delayed graft function after kidney transplant. AB - OBJECTIVES: To investigate the predictive value of urinary neutrophil gelatinase associated lipocalin in the occurrence of delayed graft function after kidney transplant. MATERIALS AND METHODS: In this prospective cohort study of 67 consecutive patients who received a living-related (40 patients [61%]) or deceased-donor kidney transplant (27 patients [39%]), urinary neutrophil gelatinase-associated lipocalin was determined in the first 100 mL perfusate of the donor kidney and in urine at 6 hours after transplant. Patients were followed (11 +/- 7 mo) for changes in estimated glomerular filtration rate and delayed graft function. RESULTS: The mean urinary neutrophil gelatinase-associated lipocalin level at 6 hours after transplant was significantly higher after deceased-donor (781 +/- 452 ng/mL) than living-donor transplant (229 +/- 223 ng/mL; P <= 0.001). The decrease in estimated glomerular filtration rate from 6 to 12 months after transplant was positively correlated with the urinary neutrophil gelatinase-associated lipocalin levels in the perfusate in living donor transplant. A significant correlation was noted between the occurrence of delayed graft function and the urinary neutrophil gelatinase-associated lipocalin level at 6 hours after living-donor transplant. In the deceased-donor group, the occurrence of delayed graft function was correlated with urinary neutrophil gelatinase-associated lipocalin levels in the perfusate. In deceased-donor kidney transplant, the mean urinary neutrophil gelatinase-associated lipocalin level in the perfusion fluid was significantly greater from donors who had terminal serum creatinine > 150 MUmol/L, and urinary neutrophil gelatinase-associated lipocalin level at 6 hours after transplant was significantly greater in transplants with longer cold ischemia time and donors who had hypertension. CONCLUSIONS: Urinary neutrophil gelatinase-associated lipocalin levels in the donor kidney perfusate and 6 hours after transplant may be a useful predictor of delayed graft function and decreased graft function from 6 to 12 months after transplant. PMID- 25019388 TI - Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX 787) of influenza PB2. AB - In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window. PMID- 25019389 TI - Current status of anti-tuberculosis therapy: a patent analysis. AB - Affecting more than one third of the world population, tuberculosis remains one of the world's most dreadful diseases, with no easy cures. Mycobacterial infestation and the evasion of host immune response are significantly responsible for the emergence of pulmonary tuberculosis. Mycobacterium tuberculosis, a weak gram positive, facultative aerobe colonizes in respiratory regions rich in oxygen reserves. Up regulation of CR and MR expression and function due to signaling by LAM results in electing immuno regulatory cytokines IL-4, IL-8 and Th2. Binding of NF-kappaB complex with mRNA prevention, due to mutation of leucine zipper domain of IK, inhibits the activation of cytokines and receptor molecules. Mechanism of energy generation by conversion of ADP to ATP, initiated by utilizing intermediary and/or end products of carbohydrate, amino acid or fatty acid catabolism is essential in approximating potential drug targets for elimination of the bacterium. A few improved diagnostic techniques have been evaluated over the last few years like Interferon Gamma Relese Assays, Nucleic Acid Amplification tests etc. of which most have certainly proven to facilitate specific detection of TB. Drugs like Rifampicin, Isoniazid etc. have also shown great curing effects on TB patients. Further research is required for better understanding of mechanism of pathogenesis and multiple drug resistance issues for developing the effective therapeutics and diagnostics against TB. The paper focuses on the effective diagnostics and therapeutics applications for tuberculosis prevention and cure based on recent patents and their analysis. PMID- 25019391 TI - [Metabolic profiling of human blood]. AB - Metabolomics is a novel "omics" branch of science intended for studying a comprehensive set of low molecular weight substances (metabolites) of various biological objects. Metabolite profiles represent a molecular phenotype of biological systems and reflect information encoded at the genome level and realized at the transcriptome and proteome levels. Analysis of human blood metabolic profile is universal and promising tool for clinical applications because it is a sensitive measure of both endogenous and exogenous (environmental) factors affected on the patient's organism. Technical implementation of metabolic profiling of blood and statistic analysis of metabolite profiles for effective diagnostics and risk assessments of diseases are discussed in this review. PMID- 25019392 TI - [Lecture: prospects of hormone analyses in saliva]. PMID- 25019390 TI - Zinc regulates meiotic resumption in porcine oocytes via a protein kinase C related pathway. AB - Zinc is an extremely important trace element that plays important roles in several biological processes. However, the function of zinc in meiotic division of porcine oocytes is unknown. In this study, we investigated the role of zinc during meiotic resumption in in vitro matured porcine oocytes. During meiotic division, a massive release of zinc was observed. The level of free zinc in the cytoplasm significantly increased during maturation. Depletion of zinc using N, N, N', N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+ chelator, blocked meiotic resumption in a dose dependent manner. The level of phosphorylated mitogen activated protein kinase (MAPK) and p34cdc2 kinase activity were reduced when zinc was depleted. Moreover, zinc depletion reduced the levels of phosphorylated protein kinase C (PKC) substrates in a dose dependent manner. Real-time PCR analysis showed that expression of the MAPK- and maturation promoting factor related genes C-mos, CyclinB1, and Cdc2 was downregulated following zinc depletion. Treatment with the PKC agonist phorbol 12 myristate 13-acetate (PMA) increased phosphorylation of PKC substrates and MAPK and increased p34cdc2 kinase activity. This rescued the meiotic arrest, even in the presence of TPEN. Activation of PKC by PMA increased the level of zinc in the cytoplasm. These data demonstrate that zinc is required for meiotic resumption in porcine oocytes, and this appears to be regulated via a PKC related pathway. PMID- 25019393 TI - [Development of barcode and proteome profiling of glioblastoma]. AB - High grade glioma (glioblastoma) is the most common brain tumor. Its malignancy makes it the fourth biggest cause of cancer death. In our experiments we used several glioblastoma cell lines generated in our laboratory to obtain proteomics information specific for this disease. This study starts our developing the complete 2DE map of glioblastoma proteins. 2DE separation with following imaging, immunochemistry, spot picking, and mass-spectrometry allowed us detecting and identifying more than 100 proteins. Several of them have prominent differences in their level between norm and cancer. Among them are alpha-enolase (ENOA_HUMAN), pyruvate kinase isozymes M1/M2 (KPYM_HUMAN), cofilin 1 (COF1_HUMAN), translationally-controlled tumor protein TCTP_HUMAN, annexin 1 (ANXA1_HUMAN), PCNA (PCNA_HUMAN), p53 (TP53_HUMAN) and others. Most interesting results were obtained with protein p53. In all glioblastoma cell lines, its level was dramatically up regulated and enriched by multiple additional isoforms. This distribution is well correlated with presence of these proteins inside of cells themselves. At this initial step we suggest the panel of specific brain tumor markers (signature) to help creating noninvasive techniques to diagnose disease. These preliminary data point to these proteins as promising markers of glioblastoma. PMID- 25019394 TI - [The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer]. AB - The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21 activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER) positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors. PMID- 25019395 TI - [Highly active fractions of the medicinal leech recombinant destabilase lysozyme]. AB - From the highly purified but lowly active recombinant protein Destabilas-Lysozyme (Dest-Lys) by use cation-exchange column TSK CM 3-SW chromatography, it was separated non-active fraction IV, contained 90% of protein. Fractions I, II and III, represented proteins with lysozyme and isopeptidase activities. Their lysozyme activity correlates with the activity of natural Des-Lys. The ratio of the activities in fractions I - III is such, that maximal lysozyme activity is concentrated in fraction III, isopeptidase - in fraction I. It is discussed the possibility of Dest-Lys different functions regulation is depended on the formation of protein complex forms. PMID- 25019396 TI - [Perspectives of disodium salt 2.4-di(1-metoxyethyl)-deuteroporphyrin - IX ("Dimegin") application for photodynamic therapy in non-oncologic cases]. AB - Effects of disodium salt 2,4-di(1-metoxyethyl)-deuteroporphyrine-IX (Dimegin) and the light from Soret band ("395-405 nm) at the viability of microbial cells and at their potential to form microbial biofilms have been compared with traditional antiseptics. Irradiation of microbial cells of S. aureus, E. coli, C. albicans and others with diode light (power density 0.05 Wt/cm2) caused a bactericidial effect similar to that obtained with standard anticeptics (chlorhexidine and dioxidine). A comparative study of the effectiveness of Dimegin and Photoditazine (a soluble salt of chlorine e6) as photosensitizers have been performed using the test system of erythrocyte hemolysis in vitro under irradiation with light from the Sore band. Results have shown insignificant difference in the photodynamic effect with similar doses of absorbed light and preparation concentration. PMID- 25019397 TI - [Interaction of rifampicin embedded in phospholipid nanoparticles with blood plasma lipoproteins]. AB - The drug formulations of antituberculous remedy rifampicin in nanoparticles less than 30 nm based on soy phosphatidylcholine and sodium oleate was elaborated in Institute of Biomedical Chemistry. The distribution of rifampicin in blood plasma fractions after incubation with this formulation and with free rifampicin was studied. This goal was stimulated by the literature data about activation of macrophages LDL receptors in cases of M. tuberculosis infection. Plasma was incubated 30 min with free rifampicin or rifampicin encapsulated into the nanoformulation followed by ultracentrifugation and subsequent rifampicin determination by HPLC in lipoprotein fractions. In the case of free rifampicin it appeared mainly in the plasma protein fraction and in HDL (41% and 38%, correspondentely). But after incubation of rifampicin in nanoparticles the drug redistribution was observed. Its proportion in these factions decreased 2-3-fold, and it was found mainly in LDL (60% as compared with 21% for free rifampicin). The increased association of rifampicin encapsulated into phospholipid nanoparticles with LDL is considered as facilitating factor for macrophages delivery and thus for antituberculosis efficiency as well. PMID- 25019398 TI - [Study into molecular targets of a neuroprotective compound dimebon using a transgenic mice line]. AB - In the present study we have used a transgenic mice overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of dimebon on proteinopathy progression. Neuroprotective effect of chronic dimebon administration in these mice at organismal level was confirmed by the increased lifespan. Using histological and biochemical approaches we have demonstrated that dimebon reduced the number of amyloid inclusions in spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in detergent-insoluble fractions. These effects are likely to occur at the level of aggregated protein species, since transgene expression was not altered. Thus, pathological protein aggregation serves as one of dimebon targets in neurodegeneration. PMID- 25019399 TI - [Effect of hyperbaric oxygenation on metabolism of glutamine in the liver]. AB - The effect of three-day course of hyperbaric oxygenation (HBO; 3 atm, 50 min, 1 session per day) on glutamine metabolism in the liver has been investigated in 72 adult albino rats. The content of ammonia, glutamate, glutamine, activity of glutamine synthetase (GS), phosphate-dependent glutaminase (PDG), and glutamate dehydrogenase (GDH) were studied in left (LLL) and median (MLL) lobes of the liver. The course of HBO had an inhibitory effect on all the enzymes studied. Inhibitory effect of hyperoxia on GDH activity persisted up to day 11 after the course of HBO in both lobes of the liver, while decreased glutamate normalized in both lobes. Reduced glutamine concentration normalized to day 4, and the concentration of ammonia and remained elevated for 11 days after the end of hyperoxic exposure. Inhibitory effect of hyperoxia on GS activity in LLL and MLL disappeared on day 4 and day 11 day after the end of the HBO course. PDG activity reduced by HBO in both lobes normalized to the day 4 day after oxygenation; however, on day 11 it selectively decreased in LLL, where simultaneous stimulation of GS activity was also observed. The results demonstrate different sensitivity of liver GS, PDG and GDH of normal rats to the inhibitory effect of HBO. Different dynamics of GS and PDG activity in LLL and MLL of oxygenated rats suggests functional heterogeneity of the glutamine cycle in hepatocytes of liver lobes after HBO. PMID- 25019400 TI - [The use of real time PCR for quantitative determination of some propionic bacteria residing on human skin]. AB - A test system has been developed for determination of propionic bacterial species residing on human skin. This system developed in the real time PCR format is applicable for quantitative determination and also detection of genomes of the following Propionibacterium species: P. acnes, P. granulosum and P. avidum. This system was used for analysis of wash samples from the skin of 17 pentathlon sportsmen and 16 students. All three species of propionic bacteria were found in all skin wash samples. However, contamination with P. acnes was two times higher in control group than in the group of pentathlon sportsmen. PMID- 25019401 TI - [Determination of Al, Be, Cd, Co, Cr, Mn, Ni, Pb, Se and Tl in whole blood by atomic absorption spectrometry without preliminary sample digestion]. AB - Methods of whole blood trace element determination by Graphite furnace atomic absorption spectrometry (in the variant of Zeeman's modulation polarization spectrometry) have been proposed. They do not require preliminary sample digestion. Furnace programs, modifiers and blood dilution factors were optimized. SeronormTM human whole blood reference materials were used for validation. Dynamic ranges (for undiluted blood samples) were: Al 8 210 mg/L; Be 0.3 50 mg/L; Cd 0.2 75 mg/L; So 5 350 mg/L; Cr 10 100 mg/L; Mn 6 250 mg/L; Ni 10 350 mg/L; Pb 3 240 mg/L; Se 10 500 mg/L; Tl 2 600 mg/L. Precision (RSD) for the middle of dynamic range ranged from 5% for Mn to 11 for Se. PMID- 25019402 TI - [Proteolytic activity of fetoplacental complex in norm and pathology]. AB - The activity of angiotensin converting enzyme (ACE), carboxypeptidase N (CPN), and leucine aminopeptidase (LAP) has been investigated in the fetoplacental complex (FPC) in normal and placental insufficiency (FPI). ACE and LAP activities were significantly higher in the placental tissue than in maternal serum and umbilical vein serum. CPN activity was significantly lower in umbilical vein serum as compared to that of women in childbirth. Probably, the studied enzymes are involved in formation of reduced sensitivity of FPC of blood vessels during physiological pregnancy. In cases of placental insufficiency a significant increase of LAP activity was found in the placental tissue and umbilical vein serum. In addition, the pathological course of pregnancy caused a significant increase of CPN activity in serum of pregnant women in comparison to the norm. The obtained data suggest that during FPI proteolytic enzymes participate in the formation of compensatoty-adaptive reactions in the FPC. Results of this study are interesting in context of development of methods for prevention and correction of metabolic disorders in pathologies of pregnancy. PMID- 25019403 TI - Divergent kinetic and thermodynamic hydration of a porous Cu(II) coordination polymer with exclusive CO2 sorption selectivity. AB - Selective adsorption and separation of CO2 are of great importance for different target applications. Metal-organic frameworks (MOFs) represent a promising class of porous materials for this purpose. Here we present a unique MOF material, [Cu(tba)2]n (tba = 4-(1H-1,2,4-triazol-1-yl)benzoate), which shows high CO2 adsorption selectivity over CH4/H2/O2/Ar/N2 gases (with IAST selectivity of 41-68 at 273 K and 33-51 at 293 K). By using a critical point dryer, the CO2 molecules can be well sealed in the 1D channels of [Cu(tba)2]n to allow a single-crystal X ray analysis, which reveals the presence of not only C(delta+)-H...O(delta-) bonds between the host framework and CO2 but also quadrupole-quadrupole (CO2(delta-)...(delta+)CO2) interactions between the CO2 molecules. Furthermore, [Cu(tba)2]n will suffer divergent kinetic and thermodynamic hydration processes to form its isostructural hydrate {[Cu(tba)2](H2O)}n and a mononuclear complex [Cu(tba)2(H2O)4] via single-crystal to single-crystal transformations. PMID- 25019405 TI - Contact mechanics and induced hysteresis at oscillatory contacts with adhesion. AB - In this article, we develop a phenomenological model for the contact mechanics and the dissipation mechanism at an oscillatory contact with adhesion. We consider an inflated spherical membrane held between two large rigid static/oscillating parallel flat plates. For the contact problem, the critical energy release rate is used to determine the detachment of the membrane from the plate surface. An analytical relation between the adhesion energy and the adhesive bond force is established. For the geometry considered, we obtain a relation between the adhesive bond force (and hence also the energy release rate) and the displacement of the plate at equilibrium without any external force. An interesting and counterintuitive stretch-induced softening phenomenon (in terms of the equilibrium displacement) is observed in certain material models. In the oscillatory contact problem, the plates are assumed to provide a kinematic oscillating boundary condition. The effective energy dissipated through hysteresis during a period of oscillation of the plate against the membrane is determined. The effect of initial inflation on energy dissipation is studied. PMID- 25019404 TI - Children's Hospital Association consensus statements for comorbidities of childhood obesity. AB - BACKGROUND: Childhood obesity and overweight affect approximately 30% of US children. Many of these children have obesity-related comorbidities, such as hypertension, dyslipidemia, fatty liver disease, diabetes, polycystic ovary syndrome (PCOS), sleep apnea, psychosocial problems, and others. These children need routine screening and, in many cases, treatment for these conditions. However, because primary care pediatric providers (PCPs) often are underequipped to deal with these comorbidities, they frequently refer these patients to subspecialists. However, as a result of the US pediatric subspecialist shortage and considering that 12.5 million children are obese, access to care by subspecialists is limited. The aim of this article is to provide accessible, user friendly clinical consensus statements to facilitate the screening, interpretation of results, and early treatment for some of the most common childhood obesity comorbidities. METHODS: Members of the Children's Hospital Association (formerly NACHRI) FOCUS on a Fitter Future II (FFFII), a collaboration of 25 US pediatric obesity centers, used a combination of the best available evidence and collective clinical experience to develop consensus statements for pediatric obesity-related comorbidities. FFFII also surveyed the participating pediatric obesity centers regarding their current practices. RESULTS: The work group developed consensus statements for use in the evaluation and treatment of lipids, liver enzymes, and blood pressure abnormalities and PCOS in the child with overweight and obesity. The results of the FFFII survey illustrated the variability in the approach for initial evaluation and treatment as well as pattern of referrals to subspecialists among programs. CONCLUSIONS: The consensus statements presented in this article can be a useful tool for PCPs in the management and overall care of children with overweight and obesity. PMID- 25019406 TI - Benzhydrylpiperazine compounds inhibit cholesterol-dependent cellular entry of hepatitis C virus. AB - Hepatitis C virus (HCV) remains a serious global health problem that lacks an effective cure. Although the introduction of protease inhibitors to the current standard-of-care interferon/ribavirin therapy for HCV infection has improved sustained virological response of genotype 1-infected patients, these inhibitors exacerbate already problematic side effects. Thus, new HCV antivirals are urgently needed. Using a cell-protection screen previously developed in our laboratory, we evaluated 30,426 compounds for inhibitors of potentially any stage of the HCV life cycle and identified 49 new HCV inhibitors. The two most potent hits, hydroxyzine and chlorcyclizine, belong to the family of benzhydrylpiperazines and were found to inhibit the entry of cell culture produced HCV with IC50 values of 19 and 2.3 nM, respectively, and therapeutic indices of >500 and >6500. Both compounds block HCV entry at a late stage of entry prior to viral fusion and their inhibitory activities are highly dependent on the host's cholesterol content. Both compounds are currently used in the clinic for treating allergy-related disorders and the reported peak plasma level (160 nM) and estimated liver concentration (1.7 MUM) of hydroxyzine in humans are much higher than the molecule's anti-HCV IC90 in cell culture (64 nM). Further studies are therefore justified to evaluate the use of these molecules in an anti HCV therapeutic regimen. PMID- 25019407 TI - Three-dimensional graphene networks as a new substrate for immobilization of laccase and dopamine and its application in glucose/O2 biofuel cell. AB - We report here three-dimensional graphene networks (3D-GNs) as a novel substrate for the immobilization of laccase (Lac) and dopamine (DA) and its application in glucose/O2 biofuel cell. 3D-GNs were synthesized with an Ni(2+)-exchange/KOH activation combination method using a 732-type sulfonic acid ion-exchange resin as the carbon precursor. The 3D-GNs exhibited an interconnected network structure and a high specific surface area. DA was noncovalently functionalized on the surface of 3D-GNs with 3,4,9,10-perylene tetracarboxylic acid (PTCA) as a bridge and used as a novel immobilized mediating system for Lac-based bioelectrocatalytic reduction of oxygen. The 3D-GNs-PTCA-DA nanocomposite modified glassy carbon electrode (GCE) showed stable and well-defined redox current peaks for the catechol/o-quinone redox couple. Due to the mediated electron transfer by the 3D-GNs-PTCA-DA nanocomposite, the Nafion/Lac/3D-GNs-PTCA DA/GCE exhibited high catalytic activity for oxygen reduction. The 3D-GNs are proven to be a better substrate for Lac and its mediator immobilization than 2D graphene nanosheets (2D-GNs) due to the interconnected network structure and high specific surface area of 3D-GNs. A glucose/O2 fuel cell using Nafion/Lac/3D-GNs PTCA-DA/GCE as the cathode and Nafion/glucose oxidase/ferrocence/3D-GNs/GCE as the anode can output a maximum power density of 112 MUW cm(-2) and a short circuit current density of 0.96 mA cm(-2). This work may be helpful for exploiting the popular 3D-GNs as an efficient electrode material for many other biotechnology applications. PMID- 25019408 TI - Evaluating habitat suitability for the establishment of Monochamus spp. through climate-based niche modeling. AB - Pine sawyer beetle species of the genus Monochamus are vectors of the nematode pest Bursaphelenchus xylophilus. The introduction of these species into new habitats is a constant threat for those regions where the forestry industry depends on conifers, and especially on species of Pinus. To obtain information about the potential risk of establishment of these insects in Chile, we performed climate-based niche modeling using data for five North American and four Eurasian Monochamus species using a Maxent approach. The most important variables that account for current distribution of these species are total annual precipitation and annual and seasonal average temperatures, with some differences between North American and Eurasian species. Projections of potential geographic distribution in Chile show that all species could occupy at least 37% of the area between 30 degrees and 53 degrees S, where industrial plantations of P. radiata are concentrated. Our results indicated that Chile seems more suitable for Eurasian than for North American species. PMID- 25019409 TI - Dependence of purple membrane bump curvature on pH and ionic strength analyzed using atomic force microscopy combined with solvent exchange. AB - Purple membrane (PM), which is a membrane patch formed by the self-assembly of the membrane protein bacteriorhodopsin (bR) with archaeal lipids, is a good subject for studying the mechanism for the supramolecular structural formation of membrane proteins. Several studies have suggested that PM is not simply planar but that it has a curvature. Atomic force microscopy (AFM) studies also indicate the presence of dome-like structures (bumps) on the cytoplasmic surface of PM. PM must have a curvature to form the bump structures; therefore, bump formations will be related to a mechanism for supramolecular structural formation via self assembly. To elucidate the effect of an asymmetric distribution of charged residues between two aqueous domains on the bump curvature, AFM topography of identical PM sheets were examined with variation of the solvent ionic strength and pH using a newly constructed solvent circulation system. The radius and height distributions of the bumps on the identical PM sheets indicated a linear correlation. The bump curvature, which was simply estimated by the slope of the distribution, became smaller with increasing KCl concentration, which suggests that tension at the cytoplasmic surface caused by electrostatic repulsive force between negatively charged amino acid residues becomes weaker by the electrostatic shielding effect. AFM observations revealed that the bump curvature remained even at high KCl concentration where the Debye length is within a few Angstroms; therefore, the contribution of the intrinsic difference between the domain sizes of bR between two sides was confirmed. Interestingly, the bump curvature was significantly increased by the addition of CaCl2 and then decreased with a similar dependency to KCl at higher CaCl2 concentration. The effect of pH on the bump curvature was also examined, where the curvature increased and reached a maximum at pH 9, while it decreased above pH 10, at which point the two dimensional crystalline lattice of bR began to disassemble. These experimental results indicate that the bump curvature is strongly influenced by electrostatic interactions. A plausible model for bump structure formation by electrostatic repulsive force is presented based on these results. PMID- 25019410 TI - Multidimensional assessment of strongly irregular voices such as in substitution voicing and spasmodic dysphonia: a compilation of own research. AB - This article is a compilation of own research performed during the European COoperation in Science and Technology (COST) action 2103: 'Advance Voice Function Assessment', an initiative of voice and speech processing teams consisting of physicists, engineers, and clinicians. This manuscript concerns analyzing largely irregular voicing types, namely substitution voicing (SV) and adductor spasmodic dysphonia (AdSD). A specific perceptual rating scale (IINFVo) was developed, and the Auditory Model Based Pitch Extractor (AMPEX), a piece of software that automatically analyses running speech and generates pitch values in background noise, was applied. The IINFVo perceptual rating scale has been shown to be useful in evaluating SV. The analysis of strongly irregular voices stimulated a modification of the European Laryngological Society's assessment protocol which was originally designed for the common types of (less severe) dysphonia. Acoustic analysis with AMPEX demonstrates that the most informative features are, for SV, the voicing-related acoustic features and, for AdSD, the perturbation measures. Poor correlations between self-assessment and acoustic and perceptual dimensions in the assessment of highly irregular voices argue for a multidimensional approach. PMID- 25019411 TI - The Cu2+ binding properties of branched peptides based on L-2,3-diaminopropionic acid. AB - Three new branched peptides, namely, H-Gly-Dap(H-Gly)-Gly-NH2 (3G), H-His-Dap(H His)-Gly-NH2 (2HG), and H-Gly-Dap(H-Gly)-His-NH2 (2GH), where Dap stands for the 2,3-diaminopropionic acid residue, were synthesized by solid phase procedures. Because of the junction at Dap these peptides have three available pending arms for metal chelation. The complex formation between these peptides and 1 equiv of Cu(2+) was investigated as a function of pH by potentiometry ultraviolet-visible absorption, circular dichroism, and X-band electron paramagnetic resonance spectroscopy in aqueous medium. Our results clearly demonstrate that cooperation between all three peptide arms essentially contributes to the stability of copper(II) complexes. PMID- 25019412 TI - Highly efficient degradation of dye pollutants by Ce-doped MoO3 catalyst at room temperature. AB - In order to efficiently degrade organic pollutants via an easily operated method, Ce-doped MoO3 (Ce(x)/MoO3) samples are synthesized by a simple impregnation method. The samples are characterized by scanning electron microscopy (SEM), X ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED), nitrogen sorption isotherms and UV-vis diffused reflectance spectra (UV-DRS), total organic carbon (TOC), infrared spectroscopy (IR) and mass spectrometry (MS) analyses. Furthermore, we have mainly investigated the degradation of different dye pollutants by the Ce(x)/MoO3 samples, including cationic methylene blue (MB), anionic methyl orange (MO), neutral phenol, and a MB-MO mixture dye. For the single-component MB and MO dyes, the highest degradation efficiencies are achieved by Ce(5)/MoO3 and Ce(10)/MoO3 samples. For the MB-MO mixture dyes, the highest degradation efficiency for MB is achieved by a Ce(10)/MoO3 sample. It is surprising that the degradation efficiency of MB in the MB-MO mixture dye solution is higher than that in the single-component MB dye solution, which has been mainly ascribed to the promoting effect of MO. Moreover, a plausible degradation mechanism of the dyes has been proposed and discussed. It should be noted that the degradation reaction is carried out at room temperature and normal atmospheric pressure, and without light irradiation. As a result, this degradation reaction is obviously different from the conventional thermally activated heterogeneous catalysis (or photocatalysis), in which thermal energy (or light irradiation) is indispensable; also different from a sorption technology, in which the pollutants cannot be degraded, but only transformed from one phase to another one. Thus, the reported degradation reaction is a quite promising environmental cleaning technology, which could be widely practically applied. PMID- 25019414 TI - Palladium-catalyzed cross-coupling reaction of diazo compounds and vinyl boronic acids: an approach to 1,3-diene compounds. AB - A palladium-catalyzed oxidative cross-coupling of vinyl boronic acids and cyclic alpha-diazocarbonyl compounds has been reported. The reaction constitutes an efficient method for the synthesis of 1,3-diene compounds bearing a ring structure. Mechanistically, the reaction involves migratory insertion of palladium carbene as the key step. PMID- 25019413 TI - Characterization of antibacterial and hemolytic activity of synthetic pandinin 2 variants and their inhibition against Mycobacterium tuberculosis. AB - The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural "kink" linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 uM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti tuberculosis agents with reduced hemolytic effects. PMID- 25019415 TI - Postpolymerization modification using less cytotoxic activated ester polymers for the synthesis of biological active polymers. AB - Activated ester polymers, pioneered by Ferruti and Ringsdorf in the 1970s, are attractive polymeric materials because they can easily be converted into functional polymers by reacting with amine nucleophiles. In the present study, methyl salicylate acrylate, salicyl acrylate, and tert-butyl salicylate acrylate monomers were polymerized yielding three novel reactive precursors suitable for the postpolymerization modification with primary and secondary amines. The reactivities of poly(pentafluorophenyl acrylate), poly(methyl salicylate acrylic ester), and poly(salicyl acrylate) toward amines were compared by kinetic studies and revealed the practical applicability of salicylic acid based derivatives for efficient postpolymerization modifications. In addition, in vitro cytotoxicity of water-soluble leaving groups, pentafluorophenol and salicylic acid, as well as water-soluble polymers containing the respective activated ester groups were investigated using HeLa cells. In short, compared to the frequently used poly(pentafluorophenyl acrylate), poly(salicyl acrylate) activated ester feature a lower reactivity, but exhibit less cytotoxicity. In this respect, poly(salicyl acrylate) as reactive precursor polymers may become alternative routes for the synthesis of functional polyacrylamides when it comes to advanced applications in vivo. PMID- 25019417 TI - Formation of stable phosphorus-carbon bond for enhanced performance in black phosphorus nanoparticle-graphite composite battery anodes. AB - High specific capacity battery electrode materials have attracted great research attention. Phosphorus as a low-cost abundant material has a high theoretical specific capacity of 2596 mAh/g with most of its capacity at the discharge potential range of 0.4-1.2 V, suitable as anodes. Although numerous research progress have shown other high capacity anodes such as Si, Ge, Sn, and SnO2, there are only a few studies on phosphorus anodes despite its high theoretical capacity. Successful applications of phosphorus anodes have been impeded by rapid capacity fading, mainly caused by large volume change (around 300%) upon lithiation and thus loss of electrical contact. Using the conducting allotrope of phosphorus, "black phosphorus" as starting materials, here we fabricated composites of black phosphorus nanoparticle-graphite by mechanochemical reaction in a high energy mechanical milling process. This process produces phosphorus carbon bonds, which are stable during lithium insertion/extraction, maintaining excellent electrical connection between phosphorus and carbon. We demonstrated high initial discharge capacity of 2786 mAh.g(-1) at 0.2 C and an excellent cycle life of 100 cycles with 80% capacity retention. High specific discharge capacities are maintained at fast C rates (2270, 1750, 1500, and 1240 mAh.g(-1) at C/5, 1, 2, and 4.5 C, respectively). PMID- 25019416 TI - Gold-nanoparticle-decorated silica nanorods for sensitive visual detection of proteins. AB - We report a rapid and highly sensitive approach based on gold-nanoparticle decorated silica nanorods (GNP-SiNRs) label and lateral-flow strip biosensor (LFSB) for visually detecting proteins. Owing to its biocompatibility and convenient surface modification, SiNRs were used as carriers to load numerous GNPs, and the GNP-SiNRs were used as labels for the lateral-flow assay. The LFSB detection limit was lowered 50 times compared to the traditional GNP-based lateral-flow assay. Rabbit IgG was used as a model target to demonstrate the proof-of-concept. Sandwich-type immunoreactions were performed on the immunochromatographic strips, and the accumulation of GNP-SiNRs on the test zone produced the characteristic colored bands, enabling visual detection of proteins without instrumentation. The quantitative detection was performed by reading the intensities of the colored bands with a portable strip reader. The response of the optimized device was highly linear for the range of 0.05-2 ng mL(-1), and the detection limit was estimated to be 0.01 ng mL(-1). The GNP-SiNR-based LFSB, thus, offered an ultrasensitive method for rapidly detecting trace amounts of proteins. This method has a potential application with point-of-care screening for clinical diagnostics and biomedical research. PMID- 25019418 TI - Validation of caffeine dehydrogenase from Pseudomonas sp. strain CBB1 as a suitable enzyme for a rapid caffeine detection and potential diagnostic test. AB - Excess consumption of caffeine (>400 mg/day/adult) can lead to adverse health effects. Recent introduction of caffeinated products (gums, jelly beans, energy drinks) might lead to excessive consumption, especially among children and nursing mothers, hence attracting the Food and Drug Administration's attention and product withdrawals. An "in-home" test will aid vigilant consumers in detecting caffeine in beverages and milk easily and quickly, thereby restricting its consumption. Known diagnostic methods lack speed and sensitivity. We report a caffeine dehydrogenase (Cdh)-based test which is highly sensitive (1-5 ppm) and detects caffeine in beverages and mother's milk in 1 min. Other components in these complex test samples do not interfere with the detection. Caffeine dependent reduction of the dye iodonitrotetrazolium chloride results in shades of pink proportional to the levels in test samples. This test also estimates caffeine levels in pharmaceuticals, comparable to high-performance liquid chromatography. The Cdh-based test is the first with the desired attributes of a rapid and robust caffeine diagnostic kit. PMID- 25019419 TI - Short-term and long-term within-person variability in performance: an integrative model. AB - Previous research on within-person variability in performance has largely examined short-term fluctuations and long-term changes in performance separately. The present study proposes a model-based on the cognitive-affective personality system meta--theory (Mischel & Shoda, 1995)--that integrates short-term and long term performance variability within the 1 framework. Key propositions of the model include that short-term performance fluctuations are contingent on variability in situational cues and that situational cue-performance contingencies change over time. To test the propositions, performance data for 393 professional male tennis players were analyzed using hierarchical linear modeling. The results showed that 2 types of situational cues--resource allocation cues and task complexity--interact in complex ways to account for short-term performance variability. Moreover, as predicted, the contingency of performance on the situational cues changed over time, highlighting the importance of an integrated approach to short-term and long-term performance variability. The implications of these findings are discussed for studies of performance at work and practical applications that managers can employ to increase work performance. Furthermore, parallels are drawn with previous studies from the broader literature on dynamic job performance. PMID- 25019420 TI - All-printed paper memory. AB - We report the memory device on paper by means of an all-printing approach. Using a sequence of inkjet and screen-printing techniques, a simple metal-insulator metal device structure is fabricated on paper as a resistive random access memory with a potential to reach gigabyte capacities on an A4 paper. The printed-paper based memory devices (PPMDs) exhibit reproducible switching endurance, reliable retention, tunable memory window, and the capability to operate under extreme bending conditions. In addition, the PBMD can be labeled on electronics or living objects for multifunctional, wearable, on-skin, and biocompatible applications. The disposability and the high-security data storage of the paper-based memory are also demonstrated to show the ease of data handling, which are not achievable for regular silicon-based electronic devices. We envision that the PPMDs manufactured by this cost-effective and time-efficient all-printing approach would be a key electronic component to fully activate a paper-based circuit and can be directly implemented in medical biosensors, multifunctional devices, and self-powered systems. PMID- 25019421 TI - Neuropathology of 22q11 deletion syndrome in an infant. AB - The 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and one of the chromosomal conditions most associated with psychosis and autism spectrum disorder. To date, only 2 neuropathologic studies of 22q11DS have been reported. Findings included polymicrogyria, neuronal heterotopias, excess subcortical white-matter (interstitial) neurons, significant white-matter gliosis/hypomyelination, and microvasculopathy. Here, we report on a 3-month-old infant with documented 22q11DS, tetralogy of Fallot, and pulmonary atresia. The brain exhibited tortuous cerebral vessels and proportionately smaller occipital lobes. Histologic examination revealed cerebral white-matter pathology and subtle differences in cortical lamination, including an excess of interstitial white matter neurons compared with a sample of age-matched controls. There was a 15% increase in DARPP-32+ medium spiny neurons in the anterior-superior caudate. In this first neuropathologic report of an infant with 22q11DS, the findings were similar to previously reported manifestations and are likely secondary to perfusion issues, developmental microvasculopathy, and abnormal frontal cortical development. PMID- 25019422 TI - Close relationship between serum hyaluronan levels and vascular function in patients with type 2 diabetes. AB - OBJECTIVE: To clarify the relationship between serum hyaluronan levels and vascular function in type 2 diabetic patients. METHODS: A cross-sectional cohort study. RESULTS: In multivariate regression analysis, endothelium-dependent flow mediated dilation was associated with age and duration of diabetes, but not with serum hyaluronan level, while endothelium-independent nitroglycerine-mediated dilation (NMD) was only associated with serum hyaluronan level (standardized estimate = -0.401, p = 0.003). NMD in the lowest tertile of hyaluronan level was significantly higher than the other tertiles (15.9% versus 12.5% and 10.4%, p = 0.047 and p = 0.002, respectively). CONCLUSIONS: Serum hyaluronan level may be useful as a surrogate marker for early changes in the vascular function, which often occurs in patients with diabetes mellitus. PMID- 25019423 TI - The diagnostic efficacy of nectin 4 expression in ovarian cancer patients. AB - CONTEXT: Nectin 4 plays a significant role in cancer cell growth and invasion. OBJECTIVE: To explore its diagnostic role in ovarian cancer. MATERIALS AND METHODS: Evaluation of nectin 4 expression in ovarian biopsies by real-time PCR and serum nectin 4 and CA-125 by ELISA in 39 ovarian cancer patients, 21 females with benign ovarian neoplasms and 25 control females. RESULTS: Nectin 4 expression was significantly higher in ovarian cancer patients and it was significantly correlated to serum nectin 4 and CA-125. CONCLUSIONS: Ovarian tissue expression and serum nectin 4 appear to be potential markers in ovarian cancer. PMID- 25019424 TI - Exhaled nitric oxide and nasal tryptase are associated with wheeze, rhinitis and nasal allergy in primary school children. AB - Rhinitis and asthma are the most common respiratory diseases in children. We assessed whether airway inflammation markers were associated with nasal allergies and self-reported symptoms of wheeze and rhinitis in 130 children 6-12 year old in an epidemiological context. Independent of sex and age, the fraction of exhaled nitric oxide (FeNO) and nasal mast cell (MC) activation (tryptase >= 5 ng/mL) were positively associated with wheeze, rhinitis and with nasal allergy. Nasal eosinophil cationic protein (ECP) and exhaled breath condensate (EBC) markers (pH, 8-isoprostane, interleukin-1beta) were not associated with symptoms or with nasal allergy. In conclusion, FeNO and nasal tryptase reflect allergic inflammation in the respiratory system. PMID- 25019427 TI - Experimental and theoretical understanding of the gas phase oxidation of atmospheric amides with OH radicals: kinetics, products, and mechanisms. AB - Atmospheric amides have primary and secondary sources and are present in ambient air at low pptv levels. To better assess the fate of amides in the atmosphere, the room temperature (298 +/- 3 K) rate coefficients of five different amides with OH radicals were determined in a 1 m(3) smog chamber using online proton transfer-reaction mass spectrometry (PTR-MS). Formamide, the simplest amide, has a rate coefficient of (4.44 +/- 0.46) * 10(-12) cm(3) molec(-1) s(-1) against OH, translating to an atmospheric lifetime of ~1 day. N-methylformamide, N methylacetamide and propanamide, alkyl versions of formamide, have rate coefficients of (10.1 +/- 0.6) * 10(-12), (5.42 +/- 0.19) * 10(-12), and (1.78 +/ 0.43) * 10(-12) cm(3) molec(-1) s(-1), respectively. Acetamide was also investigated, but due to its slow oxidation kinetics, we report a range of (0.4 1.1) * 10(-12) cm(3) molec(-1) s(-1) for its rate coefficient with OH radicals. Oxidation products were monitored and quantified and their time traces were fitted using a simple kinetic box model. To further probe the mechanism, ab initio calculations are used to identify the initial radical products of the amide reactions with OH. Our results indicate that N-H abstractions are negligible in all cases, in contrast to what is predicted by structure-activity relationships. Instead, the reactions proceed via C-H abstraction from alkyl groups and from formyl C(O)-H bonds when available. The latter process leads to radicals that can readily react with O2 to form isocyanates, explaining the detection of toxic compounds such as isocyanic acid (HNCO) and methyl isocyanate (CH3NCO). These contaminants of significant interest are primary oxidation products in the photochemical oxidation of formamide and N-methylformamide, respectively. PMID- 25019425 TI - The endocytic receptor megalin and its associated proteins in proximal tubule epithelial cells. AB - Receptor-mediated endocytosis in renal proximal tubule epithelial cells (PTECs) is important for the reabsorption and metabolization of proteins and other substances, including carrier-bound vitamins and trace elements, in glomerular filtrates. Impairment of this endocytic process results in the loss of such substances and development of proteinuria, which is an important clinical indicator of kidney diseases and is also a risk marker for cardiovascular disease. Megalin, a member of the low-density lipoprotein receptor gene family, is a multiligand receptor expressed in the apical membrane of PTECs and plays a central role in the endocytic process. Megalin interacts with various intracellular adaptor proteins for intracellular trafficking and cooperatively functions with other membrane molecules, including the cubilin-amnionless complex. Evidence suggests that megalin and the cubilin-amnionless complex are involved in the uptake of toxic substances into PTECs, which leads to the development of kidney disease. Studies of megalin and its associated molecules will be useful for future development of novel strategies for the diagnosis and treatment of kidney diseases. PMID- 25019426 TI - Endocytic trafficking of membrane-bound cargo: a flotillin point of view. AB - The ubiquitous and highly conserved flotillin proteins, flotillin-1 and flotillin 2, have been shown to be involved in various cellular processes such as cell adhesion, signal transduction through receptor tyrosine kinases as well as in cellular trafficking pathways. Due to the fact that flotillins are acylated and form hetero-oligomers, they constitutively associate with cholesterol-enriched lipid microdomains. In recent years, such microdomains have been appreciated as platforms that participate in endocytosis and other cellular trafficking steps. This review summarizes the current findings on the role of flotillins in membrane bound cargo endocytosis and endosomal trafficking events. We will discuss the proposed function of flotillins in endocytosis in the light of recent findings that point towards a role for flotillins in a step that precedes the actual endocytic uptake of cargo molecules. Recent findings have also revealed that flotillins may be important for endosomal sorting and recycling of specific cargo molecules. In addition to these aspects, the cellular trafficking pathway of flotillins themselves as potential cargo in the context of growth factor signaling will be discussed. PMID- 25019428 TI - Methods for clinical evaluation of noise reduction techniques in abdominopelvic CT. AB - Most noise reduction methods involve nonlinear processes, and objective evaluation of image quality can be challenging, since image noise cannot be fully characterized on the sole basis of the noise level at computed tomography (CT). Noise spatial correlation (or noise texture) is closely related to the detection and characterization of low-contrast objects and may be quantified by analyzing the noise power spectrum. High-contrast spatial resolution can be measured using the modulation transfer function and section sensitivity profile and is generally unaffected by noise reduction. Detectability of low-contrast lesions can be evaluated subjectively at varying dose levels using phantoms containing low contrast objects. Clinical applications with inherent high-contrast abnormalities (eg, CT for renal calculi, CT enterography) permit larger dose reductions with denoising techniques. In low-contrast tasks such as detection of metastases in solid organs, dose reduction is substantially more limited by loss of lesion conspicuity due to loss of low-contrast spatial resolution and coarsening of noise texture. Existing noise reduction strategies for dose reduction have a substantial impact on lowering the radiation dose at CT. To preserve the diagnostic benefit of CT examination, thoughtful utilization of these strategies must be based on the inherent lesion-to-background contrast and the anatomy of interest. The authors provide an overview of existing noise reduction strategies for low-dose abdominopelvic CT, including analytic reconstruction, image and projection space denoising, and iterative reconstruction; review qualitative and quantitative tools for evaluating these strategies; and discuss the strengths and limitations of individual noise reduction methods. PMID- 25019429 TI - Imaging spectrum of CNS vasculitis. AB - Cerebral vasculitis is characterized by inflammation of the walls of blood vessels and may affect vessels of any size. The pathogenesis of vasculitis remains poorly understood. Vasculitis may affect large vessels (Takayasu arteritis, giant cell arteritis), medium-sized vessels (Kawasaki disease, polyarteritis nodosa), small vessels (immunoglobulin A vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis), or variable-sized vessels (Behcet disease, Cogan syndrome). Primary angiitis of the central nervous system (CNS) is an idiopathic disorder with no evidence of generalized inflammation that may simulate reversible cerebral vasoconstriction syndromes. Vasculitis may be secondary to systemic disease, infection, malignancy, drug use, or radiation therapy. Imaging findings vary from small ischemic changes to frank infarction, hemorrhage, and white matter edema and may show contrast material enhancement. The cerebral arteries may demonstrate a beaded appearance with variable degrees of stenosis, occlusion, and contrast enhancement of the vessel wall. Correlation of imaging findings with clinical presentation and laboratory test results helps establish the diagnosis of CNS vasculitis. PMID- 25019431 TI - Pulmonary coccidioidomycosis: pictorial review of chest radiographic and CT findings. AB - Pulmonary coccidioidomycosis is a fungal disease endemic to the desert regions of the southwestern United States, Mexico, Central America, and South America. The incidence of reported disease increased substantially between 1998 and 2011, and the infection is encountered beyond the endemic areas because of a mobile society. The disease is caused by inhalation of spores of Coccidioides species. Individuals at high risk are those exposed to frequent soil aerosolization. The diagnosis is established by direct visualization of mature spherules by using special stains or cultures from biologic specimens. Serologic testing of anticoccidioidal antibodies is used for diagnosis and treatment monitoring. The infection is self-limited in 60% of cases. When the disease is symptomatic, the lung is the primary site of involvement. On the basis of clinical presentation and imaging abnormalities, pulmonary involvement is categorized into acute, disseminated, and chronic forms, each with a spectrum of imaging findings. In patients with acute disease, the most common findings are lobar or segmental consolidation, multifocal consolidation, and nodules. Adenopathy and pleural effusions are also seen, usually in association with parenchymal disease. Disseminated disease is rare and occurs in less than 1% of patients. Pulmonary findings are miliary nodules and confluent parenchymal opacities. Acute respiratory distress syndrome is an infrequent complication of disseminated disease. The acute findings resolve in most patients, with chronic changes developing in approximately 5% of patients. Manifestations of chronic disease include residual nodules, chronic cavities, persistent pneumonia with or without adenopathy, pleural effusion, and regressive changes. Unusual complications of chronic disease are mycetoma, abscess formation, and bronchopleural fistula. Patients in an immunocompromised state, those with diabetes mellitus, pregnant women, and those belonging to certain ethnic groups may show severe, progressive, or disseminated disease. PMID- 25019432 TI - Interpreting one-view mammographic findings: minimizing callbacks while maximizing cancer detection. AB - Overlap of breast tissue is a frequent consequence of the necessary positioning and compression of the three-dimensional breast to obtain two-dimensional mammograms. The mammary glands contain fewer anatomically fixed landmarks than solid organs do; thus, variability in positioning can have an even greater effect on mammography than it has on other imaging examinations. Most often, areas of overlapping fibroglandular tissue, also known as summation shadows, are seen on only one of the two standard mammographic views. While striving to detect breast cancer as early as possible, radiologists must learn to visually compensate for apparent abnormalities in the breast that are produced by such tissue overlap. Mammographic interpretation in this setting is made even more challenging by the fact that the only manifestation of breast cancer might be a subtle change on a single mammographic view. Breast cancer might be obscured on one of the two standard views because of the density of surrounding breast tissue, mammographic technique, lesion size or location within the breast, histopathologic characteristics of the tumor, or lack of effect by the tumor on the appearance of surrounding tissues. To heighten awareness of the factors that can lead to either unnecessary recalls or failure to identify breast cancer, cases are reviewed in which false-positive findings and breast cancers were visible on only one mammographic view. Strategies for interpreting screening mammograms and determining which findings merit diagnostic evaluation are outlined so as to help minimize false-positive findings and aid in cancer detection. PMID- 25019430 TI - Thoracic diseases associated with HIV infection in the era of antiretroviral therapy: clinical and imaging findings. AB - The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) pandemic has entered its 4th decade. Since the introduction of combination antiretroviral therapy (ART) in 1996, the number of AIDS-related deaths has plateaued worldwide. Today, owing to the effectiveness of ART, the HIV-infected population is aging and HIV infection has become a chronic illness. Non-AIDS comorbidities are increasing, and the spectrum of HIV-related thoracic diseases is evolving. In developed countries, bacterial pneumonia has become more common than Pneumocystis pneumonia. Its imaging appearance depends on the responsible organism, most commonly Streptococcus pneumoniae. Mycobacterium tuberculosis continues to be a major threat. Its imaging patterns vary depending on CD4 count. Primary lung cancer and Hodgkin lymphoma are two important non-AIDS-defining malignancies that are increasingly encountered at chest imaging. Human herpesvirus 8, also known as Kaposi sarcoma-associated herpesvirus (KSHV), is strongly linked to HIV-related diseases, including Kaposi sarcoma, multicentric Castleman disease, KSHV inflammatory cytokine syndrome, and primary effusion lymphoma. Immune reconstitution inflammatory syndrome is a direct complication of ART whose manifestations vary with the underlying disease. Given the high rate of smoking among HIV-infected patients, chronic obstructive pulmonary disease is another important cause of morbidity and mortality. A high degree of suspicion is required for the early diagnosis of pulmonary arterial hypertension and lymphocytic interstitial pneumonia, given their nonspecific manifestations. Finally, multilocular thymic cyst manifests as a cystic anterior mediastinal mass. Recognition of the clinical and radiologic manifestations of these less traditional HIV-related diseases can expedite diagnosis and treatment in the ART era. PMID- 25019433 TI - Abdominal and pelvic complications of nonoperative oncologic therapy. AB - Oncologic patients are treated with a combination of chemotherapy, radiation therapy, and surgery. Advances in therapeutic options have greatly improved the survival of patients with cancer. Examples of these advances are newer chemotherapeutic agents that target the cell receptors and advanced radiation therapy delivery systems. It is imperative that radiologists be aware of the variety of imaging findings seen after therapy in patients with cancer. Complications may occur with classic cytotoxic therapies (eg, 5-fluorouracil), usually at higher or prolonged doses or when administered to radiosensitive areas. Newer targeted systemic agents, such as bevacizumab and imatinib, have associated characteristic toxicities because their effects on cells do not depend on dose. Radiation may induce early and late effects in local normal tissues that may be seen at imaging. Imaging findings after chemotherapy include fatty liver, pseudocirrhosis, hepatic veno-occlusive disease, and splenic rupture. Complications of radiation therapy include large and small bowel strictures and radiation-induced hepatitis and tumors. Awareness of the various therapeutic options and knowledge of the spectrum of posttherapeutic complications allows radiologists to provide a comprehensive report that may impact patient management. PMID- 25019434 TI - Resident and fellow education feature: imaging evaluation of peritoneal disease: overview of anatomy and differential diagnosis. PMID- 25019435 TI - Soft-tissue myxomatous lesions: review of salient imaging features with pathologic comparison. AB - Myxoid soft-tissue lesions are a heterogeneous group of benign and malignant mesenchymal tumors with an abundance of extracellular mucoid material. These lesions may mimic cysts on radiologic evaluation because of the high water content, and histopathologic features also overlap. Benign myxoid lesions include intramuscular myxoma, synovial cyst, bursa, ganglion, and benign peripheral nerve sheath tumor, including neurofibroma and schwannoma. Malignant entities include myxoid liposarcoma, myxoid leiomyosarcoma, myxoid chondrosarcoma, ossifying fibromyxoid tumor, and myxofibrosarcoma. Some syndromes are associated with myxoid soft-tissue lesions, such as Mazabraud syndrome in patients with soft tissue myxomas and fibrous dysplasia. Certain discriminating features, such as intralesional fat in a myxoid liposarcoma, perilesional edema and a rim of fat in soft-tissue myxoma, and the swirled T2-weighted signal intensity and enhancement pattern of aggressive angiomyxoma, assist the radiologist in differentiating these lesions. The presence of an internal chondroid matrix or incomplete peripheral ossification may suggest myxoid chondrosarcoma or ossifying fibromyxoid tumor, respectively. The entering-and-exiting-nerve sign is suggestive of a peripheral nerve sheath tumor. Communication with a joint or tendon sheath and peripheral enhancement may indicate a ganglion or synovial cyst. This article (a) reviews the magnetic resonance, computed tomographic, and ultrasonographic imaging characteristics of soft-tissue myxomatous lesions, emphasizing imaging findings that can help differentiate benign and malignant lesions; (b) presents differential diagnoses; and (c) provides pathologic correlation. PMID- 25019436 TI - MR imaging-based diagnosis and classification of meniscal tears. AB - Magnetic resonance (MR) imaging is currently the modality of choice for detecting meniscal injuries and planning subsequent treatment. A thorough understanding of the imaging protocols, normal meniscal anatomy, surrounding anatomic structures, and anatomic variants and pitfalls is critical to ensure diagnostic accuracy and prevent unnecessary surgery. High-spatial-resolution imaging of the meniscus can be performed using fast spin-echo and three-dimensional MR imaging sequences. Normal anatomic structures that can mimic a tear include the meniscal ligament, meniscofemoral ligaments, popliteomeniscal fascicles, and meniscomeniscal ligament. Anatomic variants and pitfalls that can mimic a tear include discoid meniscus, meniscal flounce, a meniscal ossicle, and chondrocalcinosis. When a meniscal tear is identified, accurate description and classification of the tear pattern can guide the referring clinician in patient education and surgical planning. For example, longitudinal tears are often amenable to repair, whereas horizontal and radial tears may require partial meniscectomy. Tear patterns include horizontal, longitudinal, radial, root, complex, displaced, and bucket handle tears. Occasionally, meniscal tears can be difficult to detect at imaging; however, secondary indirect signs, such as a parameniscal cyst, meniscal extrusion, or linear subchondral bone marrow edema, should increase the radiologist's suspicion for an underlying tear. Awareness of common diagnostic errors can ensure accurate diagnosis of meniscal tears. Online supplemental material is available for this article. PMID- 25019437 TI - Patterns of osteonecrosis in the femur. PMID- 25019438 TI - From the radiologic pathology archives imaging of osteonecrosis: radiologic pathologic correlation. AB - Osteonecrosis is common and represents loss of blood supply to a region of bone. Common sites affected include the femoral head, humeral head, knee, femoral/tibial metadiaphysis, scaphoid, lunate, and talus. Symptomatic femoral head osteonecrosis accounts for 10,000-20,000 new cases annually in the United States. In contradistinction, metadiaphyseal osteonecrosis is often occult and asymptomatic. There are numerous causes of osteonecrosis most commonly related to trauma, corticosteroids, and idiopathic. Imaging of osteonecrosis is frequently diagnostic with a serpentine rim of sclerosis on radiographs, photopenia in early disease at bone scintigraphy, and maintained yellow marrow at MR imaging with a serpentine rim of high signal intensity (double-line sign) on images obtained with long repetition time sequences. These radiologic features correspond to the underlying pathology of osseous response to wall off the osteonecrotic process and attempts at repair with vascularized granulation tissue at the reactive interface. The long-term clinical importance of epiphyseal osteonecrosis is almost exclusively based on the likelihood of overlying articular collapse. MR imaging is generally considered the most sensitive and specific imaging modality both for early diagnosis and identifying features that increase the possibility of this complication. Treatment subsequent to articular collapse and development of secondary osteoarthritis typically requires reconstructive surgery. Malignant transformation of osteonecrosis is rare and almost exclusively associated with metadiaphyseal lesions. Imaging features of this dire sequela include aggressive bone destruction about the lesion margin, cortical involvement, and an associated soft-tissue mass. Recognizing the appearance of osteonecrosis, which reflects the underlying pathology, improves radiologic assessment and is important to guide optimal patient management. PMID- 25019440 TI - Pediatric cardiac tumors: clinical and imaging features. AB - Cardiac tumors in children are rare, are more commonly benign, and differ in types when compared with those in adults. Rhabdomyoma, teratoma, and fibroma are the most common cardiac tumors in fetuses and neonates. In infants and children, the most common cardiac tumors are rhabdomyoma and fibroma, which are benign primary cardiac tumors, whereas in adults, thrombus is the most common cardiac mass and myxoma is the most common primary cardiac tumor. Sarcomas are the most common primary malignant cardiac tumors in both children and adults. Metastatic cardiac tumors are less common in children than in adults and include sarcoma, lymphoma, testicular cancer, and Wilms tumor. Patients with cardiac tumors can be asymptomatic or may present with murmur, arrhythmia, heart failure, or sudden death. Echocardiography is the primary modality for initial evaluation of symptomatic patients. Cardiac magnetic resonance imaging provides further characterization of cardiac masses and tumors for diagnostic purposes and can be used to assess cardiac and extracardiac involvement for treatment planning. Treatment varies from conservative management or surgical resection to transplantation, depending on the diagnosis and the patient's symptoms. Rhabdomyoma typically regresses spontaneously during early childhood and does not require surgical intervention if asymptomatic. However, fibroma is generally resected because it does not regress. An understanding of the types of cardiac tumors that occur in infants and children, their clinical implications and associations, and their imaging appearances will facilitate patient management. PMID- 25019439 TI - Practice corner: can we find flow when reading imaging studies? PMID- 25019441 TI - MR imaging of hypoxic-ischemic injury in term neonates: pearls and pitfalls. AB - Hypoxic-ischemic injury (HII) continues to be an important cause of neonatal mortality and morbidity. In recent years, the role of magnetic resonance (MR) imaging has increased by providing early detection to initiate preventive measures and assess the severity of tissue injury, and it often serves as a prognostic indicator. However, because of the subtle findings and temporal variability of signal abnormalities, the imaging diagnosis often remains troublesome, particularly for trainees and general radiologists who do not often encounter these findings. The imaging manifestations between term and preterm infants differ significantly; the imaging findings in term neonates are discussed. Two main patterns of HII have been described in term neonates: peripheral and basal ganglia-thalamus, with the predominant pattern in an affected infant dependent on the duration and severity of the insult. The peripheral pattern occurs in the setting of mild hypoxia or ischemia of prolonged duration, with predominant findings in the cerebral cortex and subcortical white matter along the intervascular boundary zones. The basal ganglia-thalamus pattern is most often secondary to a more severe hypoxic or ischemic event of short duration and manifests with abnormal hyperintensity on T1-weighted images and hypointensity on T2-weighted images in the posterolateral putamen and ventrolateral thalamus. Associated loss of normal hyperintensity on T1-weighted images and hypointensity on T2-weighted images in the posterior limb of the internal capsule may be present. Restricted diffusion and evolution of imaging findings may be seen in each of these regions, depending on when images are obtained. Advanced imaging techniques, including MR spectroscopy, may add valuable information and specificity, with an abnormal lactate peak often serving as an indicator of HII in term neonates. PMID- 25019442 TI - Imaging across the life span: innovations in imaging and therapy for gynecologic cancer. AB - The focus of this article is radiation therapy for gynecologic cancers, with emphasis on imaging-based treatment planning and delivery. For the various gynecologic cancers, radiation oncologists rely on essential clinical information to triage treatment options, and various imaging studies are performed for treatment planning and radiation therapy delivery. A practical approach is provided to help radiologists tailor their reports for the needs of their radiation oncology and gynecologic oncology colleagues, to optimize multidisciplinary care for patients with gynecologic cancer. Template radiology reports are proposed to address the specific information needs of oncologists at each phase-before, during, and after treatment. Fueled by the rapid progress in engineering and computer sciences during the past 2 decades, remarkable advances have been made in anatomic, functional, and molecular imaging and in radiation treatment planning and delivery in patients with gynecologic cancer. Radiation therapy has evolved from a nontargeted approach to a precisely targeted, highly conformal treatment modality, to further improve treatment outcomes and reduce morbidity. High-quality imaging has become essential for staging of the disease, delineation of tumor extent for treatment planning and delivery, and monitoring therapy response. Anatomic and functional imaging has also been shown to provide prognostic information that allows clinicians to tailor therapy on the basis of personalized patient information. This field is an area of active research, and future clinical trials are warranted to validate preliminary results in the field. PMID- 25019444 TI - Early cervical carcinoma and fertility-sparing treatment options: MR imaging as a tool in patient selection and a follow-up modality. AB - Because of the widespread use of cytologic screening programs in industrialized nations, cervical carcinoma is being diagnosed in younger patients and at an earlier stage. The traditional therapy for early-stage disease is radical hysterectomy with pelvic lymphadenectomy, which leads to infertility. In the past 20 years, fertility-sparing therapies, such as cervical conization and radical trachelectomy, have emerged and show good oncologic and obstetric outcomes. The selection criteria for vaginal radical trachelectomy include stages IA2 and IB1, a tumor that is smaller than 2 cm, distance from the internal os of at least 1 cm, limited stromal invasion, and no nodal or extracervical extension. Magnetic resonance (MR) imaging accurately depicts these criteria and is a necessary tool in the preoperative evaluation of patients with cervical carcinoma who are eligible for fertility-sparing surgery. The MR imaging report must provide the following pieces of information for adequate surgical planning: tridimensional diameters of the lesion, uterine and cervical lengths, the degree of stromal invasion, distance from the internal os, and the presence of extracervical or nodal involvement. Because patients also undergo follow-up MR imaging, radiologists must be familiar with the postoperative imaging appearance of the cervix. After trachelectomy, the uterovaginal anastomosis may appear end-to-end or with a neoposterior vaginal fornix. Vaginal wall thickening, hematomas, lymphoceles, and hematometra secondary to isthmic stenosis may be seen. The normal postoperative appearance must be differentiated from recurrent disease, which is seen as a mass with intermediate to high signal intensity in the vaginal vault or parametrium on T2-weighted images. Functional imaging, including diffusion-weighted and dynamic contrast-enhanced imaging, may help characterize recurrence. PMID- 25019443 TI - Optimization of MR imaging for pretreatment evaluation of patients with endometrial and cervical cancer. AB - Endometrial and cervical cancer are the most common gynecologic malignancies in the world. Accurate staging of cervical and endometrial cancer is essential to determine the correct treatment approach. The current International Federation of Gynecology and Obstetrics (FIGO) staging system does not include modern imaging modalities. However, magnetic resonance (MR) imaging has proved to be the most accurate noninvasive modality for staging endometrial and cervical carcinomas and often helps with risk stratification and making treatment decisions. Multiparametric MR imaging is increasingly being used to evaluate the female pelvis, an approach that combines anatomic T2-weighted imaging with functional imaging (ie, dynamic contrast material-enhanced and diffusion-weighted imaging). MR imaging helps guide treatment decisions by depicting the depth of myometrial invasion and cervical stromal involvement in patients with endometrial cancer and tumor size and parametrial invasion in those with cervical cancer. However, its accuracy for local staging depends on technique and image quality, namely thin section high-resolution multiplanar T2-weighted imaging with simple modifications, such as double oblique T2-weighting supplemented by diffusion weighting and contrast enhancement. PMID- 25019445 TI - Historical perspective: eponyms of vascular radiology. AB - Eponyms are ubiquitous throughout the medical literature, especially the radiology lexicon. In particular, vascular radiology is replete with dozens of eponyms named after pathologic and anatomic features and various medical devices. Several disease processes are known exclusively by their eponyms or by both their eponyms and their descriptive names. Although some authors advocate abandoning eponyms in favor of more descriptive terms, the established history and common use of eponyms make it unlikely that they will disappear from the vocabulary. Radiologists should be familiar with both the eponymous and descriptive names of disease processes to ensure effective communication and prevent erroneous identification. Study of these eponyms provides information about these disease processes and other medical knowledge for use in daily practice. In addition, biographic information about the pertinent physicians can yield insights into the sometimes surprising origins of these eponyms. The authors provide biographic sketches of these physicians and discuss the clinical relevance of the anatomic features, malformations, and syndromes that bear their names. PMID- 25019446 TI - Radial Imaging of the Hip Also for Properly Measuring the alpha Angle. PMID- 25019447 TI - Touchless user interface for intraoperative image control: almost there. PMID- 25019449 TI - Invited commentary: digital breast tomosynthesis-the road ahead. PMID- 25019450 TI - MR imaging of hip arthroplasty implants. AB - Hip arthroplasty has become the standard treatment for end-stage hip disease, allowing pain relief and restoration of mobility in large numbers of patients; however, pain after hip arthroplasty occurs in as many as 40% of cases, and despite improved longevity, all implants eventually fail with time. Owing to the increasing numbers of hip arthroplasty procedures performed, the demographic factors, and the metal-on-metal arthroplasty systems with their associated risk for the development of adverse local tissue reactions to metal products, there is a growing demand for an accurate diagnosis of symptoms related to hip arthroplasty implants and for a way to monitor patients at risk. Magnetic resonance (MR) imaging has evolved into a powerful diagnostic tool for the evaluation of hip arthroplasty implants. Optimized conventional pulse sequences and metal artifact reduction techniques afford improved depiction of bone, implant-tissue interfaces, and periprosthetic soft tissue for the diagnosis of arthroplasty-related complications. Strategies for MR imaging of hip arthroplasty implants are presented, as well as the imaging appearances of common causes of painful and dysfunctional hip arthroplasty systems, including stress reactions and fractures; bone resorption and aseptic loosening; polyethylene wear-induced synovitis and osteolysis; adverse local tissue reactions to metal products; infection; heterotopic ossification; tendinopathy; neuropathy; and periprosthetic neoplasms. A checklist is provided for systematic evaluation of MR images of hip arthroplasty implants. MR imaging with optimized conventional pulse sequences and metal artifact reduction techniques is a comprehensive imaging modality for the evaluation of the hip after arthroplasty, contributing important information for diagnosis, prognosis, risk stratification, and surgical planning. PMID- 25019451 TI - Digital breast tomosynthesis: lessons learned from early clinical implementation. AB - The limitations of mammography are well known and are partly related to the fact that with conventional imaging, the three-dimensional volume of the breast is imaged and presented in a two-dimensional format. Because normal breast tissue is similar in x-ray attenuation to some breast cancers, clinically relevant malignancies may be obscured by normal overlapping tissue. In addition, complex areas of normal tissue may be perceived as suspicious. The limitations of two dimensional breast imaging lead to low sensitivity in detecting some cancers and high false-positive recall rates. Although mammographic screening has been shown to reduce breast cancer deaths by approximately 30%, controversy exists over when and how often screening mammography should occur. Digital breast tomosynthesis (DBT) is rapidly being implemented in breast imaging clinics around the world as early clinical data demonstrate that it may address some of the limitations of conventional mammography. With DBT, multiple low-dose x-ray images are acquired in an arc and reconstructed to create a three-dimensional image, thus minimizing the impact of overlapping breast tissue and improving lesion conspicuity. Early studies of screening DBT have shown decreased false-positive callback rates and increased rates of cancer detection (particularly for invasive cancers), resulting in increased sensitivity and specificity. In our clinical practice, we have completed more than 2 years of using two-view digital mammography combined with two-view DBT for all screening and select diagnostic imaging examinations (over 25,000 patients). Our experience, combined with previously published data, demonstrates that the combined use of DBT and digital mammography is associated with improved outcomes for screening and diagnostic imaging. Online supplemental material is available for this article. PMID- 25019452 TI - Strabismus, visual acuity, and uncorrected refractive error in portuguese children aged 6 to 11 years. AB - INTRODUCTION: Visual anomalies that affect school-age children represent an important public health problem. Data on the prevalence are lacking in Portugal but is needed for planning vision services. This study was conducted to determine the prevalence of strabismus, decreased visual acuity, and uncorrected refractive error in Portuguese children aged 6 to 11 years. METHODS AND MATERIALS: A cross sectional study was carried out on a sample of 672 school-age children (7.69+/ 1.19 years). Children received an orthoptic assessment (visual acuity, ocular alignment, and ocular movements) and non-cycloplegic autorefraction. RESULTS: After orthoptic assessment, 13.8% of children were considered abnormal (n=93). Manifest strabismus was found in 4% of the children. Rates of esotropia (2.1%) were slightly higher than exotropia (1.8%). Strabismus rates were not statistically significant different per sex (p=0.681) and grade (p=0.228). Decreased visual acuity at distance was present in 11.3% of children. Visual acuity<=20/66 (0.5 logMAR) was found in 1.3% of the children. We also found that 10.3% of children had an uncorrected refractive error. CONCLUSIONS: Strabismus affects a small proportion of the Portuguese school-age children. Decreased visual acuity and uncorrected refractive error affected a significant proportion of school-age children. New policies need to be developed to address this public health problem. PMID- 25019453 TI - Multiplexed determination of human growth hormone and prolactin at a label free electrochemical immunosensor using dual carbon nanotube-screen printed electrodes modified with gold and PEDOT nanoparticles. AB - A label-free dual electrochemical immunosensor was constructed for the multiplexed determination of human growth (hGH) and prolactin (PRL) hormones. The immunosensor used an electrochemical platform composed of carbon nanotube-screen printed carbon electrodes (CNT/SPCEs) modified with poly(ethylene-dioxythiophene) (PEDOT) and gold nanoparticles, on which the corresponding hGH and PRL antibodies were immobilized. The affinity reactions were monitored by measuring the decrease in the differential pulse voltammetric oxidation response of the redox probe dopamine. The experimental variables involved in the preparation of both AuNP/PEDOT/CNT/SPC modified electrodes and the dual immunosensor were optimized. The immunosensor exhibited an improved analytical performance for hGH and PRL with respect to other electrochemical immunosensor designs, showing wide ranges of linearity and low detection limits of 4.4 and 0.22 pg mL(-1), respectively. An excellent selectivity against other hormones and in the presence of ascorbic and uric acids was found. The usefulness of the dual immunosensor for the simultaneous analysis of hGH and PRL was demonstrated by analyzing human serum and saliva samples spiked with the hormones at different concentration levels. PMID- 25019454 TI - Experiences of people living with HIV and people living close to them of a comprehensive HIV stigma reduction community intervention in an urban and a rural setting. AB - HIV stigma remains high globally. Although there is a selection of HIV stigma reduction interventions discussed in the literature, there is a paucity of research about the effectiveness of these interventions. This study aimed at gaining a deeper understanding of the experiences of people living with HIV (PLWH) and people living close to them from six designated groups during and after having undergone a comprehensive HIV stigma reduction community intervention in both an urban and a rural setting. Attention was focused on their expressed experiences of the workshop and projects executed. A qualitative interpretive description approach was used. PLWH as participants were selected through purposive voluntary sampling and through snowball sampling for the people living close to them. Recruitment was from both urban and rural settings in the North West Province, South Africa. Data collection was via in-depth interviews with 23 PLWH and 60 people living close to them from specific designated groups. The data were thematically analysed through manual open coding. The results from the urban and rural settings were pooled, as there were no noteworthy differences in the themes between them. The results indicated that there was an increase in knowledge in all the groups, as well as experiences of enhanced relationships and of being equipped with leadership skills in order to go out into the community and being part of HIV stigma reduction actions. The intervention in its comprehensive nature was found to have been successful and promising for future use in reducing HIV stigma. PMID- 25019455 TI - Pituitary abscess following transsphenoidal surgery: the experience of 12 cases from a single institution. AB - OBJECTIVE: To explore possible reasons for the incidence of a pituitary abscess following transsphenoidal surgery and determine the most effective treatment. METHODS: A series of 12 patients who had undergone transsphenoidal surgery in other hospitals before being treated at Peking Union Medical College Hospital were reviewed. The presence of a pituitary abscess was confirmed when pus was intraoperatively observed within the sella turcica. All patients were treated with debridement of the abscess, nine among whom through a transsphenoidal approach and the other three via a craniotomy, followed by antibiotic treatment and hormone replacement therapy. The mean follow-up time was 27.0 months (range from 3.0 to 79.0 months). RESULTS: Headache (92%), panhypopituitarism (58%) and visual disturbance (50%) were the most common clinical indicators of a pituitary abscess. Imaging tests demonstrated a pituitary mass in all patients, with seven (58%) manifested with typical magnetic resonance features of an abscess. Ten patients (83%) were correctly diagnosed preoperatively. During surgical exploration, six presented with severe inflammation or an abscess within the sphenoidal sinus. Causative organisms were identified in five patients (42%). After surgical and antibiotic therapies, all patients fully recovered except for two presenting with severe visual impairment. Six patients (50%) required hormone replacement therapy. CONCLUSION: Retrograde infection from the sphenoid sinus may be a vital mechanism underlying the formation of a pituitary abscess following transsphenoidal surgery. Debridement of the abscess through surgical approaches combined with antibiotic treatment has been found to yield positive outcomes. PMID- 25019456 TI - Surgical outcomes after classifying Grade III arteriovenous malformations according to Lawton's modified Spetzler-Martin grading system. AB - OBJECTIVE: We aimed to evaluate microsurgical outcomes after classifying Grade III arteriovenous malformations (AVMs) according to Lawton's modified Spetzler Martin grading system. METHODS: Of 131 patients with Grade III AVMs, 55 had undergone microsurgery between 1995 and 2010. The 55 AVMs were classified as follows: Grade III-/S1E1V1, Grade III/S2E0V1, Grade III+/S2E1V0, or Grade III*/S3E0V0. The surgical obliteration rate, morbidity rate, and functional outcomes for each subtype were compared before surgery and after follow-up. Additionally, factors related with morbidity were investigated from demographic and morphological characteristics. RESULTS: We observed 18 Grade III-, 16 Grade III, 20 Grade III+, and 1 Grade III* AVMs. Complete resection was achieved in 49 patients (obliteration rate, 89.1%). Incomplete resection rates were higher for Grade III (12.5%) and III+ (15.0%) AVMs than that for Grade III- (5.6%) AVMs. Seven patients (12.7%) presented postoperative deficits, of which 3 (5.4%) experienced disabilities. Patients with Grade III+ (25.0%) had higher morbidity rates than those with other subtypes. Modified Rankin scale scores at the last follow-up indicated unfavorable outcomes for Grades III (18.8%) and III+ (25.0%) AVMs. AVM size (>=3 cm) and non-hemorrhagic type were associated with the occurrence of postoperative deficits (p<0.05). CONCLUSION: The modified classification of Grade III AVMs was useful to predict surgical morbidity and clinical outcomes. We recommend that microsurgery should be used to treat Grade III- AVMs, but should be considered carefully for the treatment of Grades III and III+. PMID- 25019457 TI - Cryopreservation versus subcutaneous preservation of autologous bone flaps for cranioplasty: comparison of the surgical site infection and bone resorption rates. AB - OBJECTIVE: Decompressive craniectomy is performed to treat malignant brain hypertension. Surgical site infection (SSI) and bone resorption are common complications following cranioplasty, and the storage method that minimizes such complication has yet to be identified. METHODS: Over a 10-year period, the details of 290 decompressive craniectomy procedures performed at our trauma and stroke center were recorded. Bone flaps from 110 patients were preserved in subcutaneous pockets (SPs), and 180 were preserved via cryopreservation (CP). RESULTS: SSIs occurred in 20 cases (18.2%) in the SP group and 20 cases (11.1%) in the CP group (P=0.129). After dividing each group according to the traumatic brain injury (TBI) etiologies, we found that in the SP group, the SSI rates in the TBI and non-TBI patients were 17.3% and. 20.7% (P=0.899), respectively, and in the TBI- and non-TBI CP-group patients, the SSI rates were 11.9% and. 9.7% (P=0.864), respectively. The average decrease in bone flap thicknesses were 1.14 mm in the SP group (n=34) and 1.89 mm in the CP group (n=57), and this difference was significant (P=0.039). CONCLUSIONS: In this series, the SSI rates were similar in the SP and CP groups. There was no significant difference when the patients were grouped by TBI etiology. The incidence of bone flap resorption in the CP group was higher than that in the SP group. However, identifying of the method that yields superior results might depend on the individual surgeon's preference and the available equipment. PMID- 25019458 TI - Minimally invasive lateral transpsoas interbody fusion using a stand-alone construct for the treatment of adjacent segment disease of the lumbar spine: review of the literature and report of three cases. AB - We describe 3 patients who presented with radiographic signs and clinical symptoms of adjacent segment disease several years after undergoing L4-S1 posterior pedicle screw fusion. All patients underwent successful lateral lumbar interbody fusion (LLIF) at 1-2 levels above their previous constructs, using stand-alone cages, with complete resolution of radiculopathy and a significant improvement in low-back pain. In addition to a thorough analysis of these cases, we review the pertinent literature regarding treatment options for adjacent segment disease and the applications of the lateral lumbar interbody technique. PMID- 25019459 TI - Protective effect of external ventricular drainage on cerebral vasospasm. A retrospective study on aneurysmal SAH treated endovascularly. AB - OBJECTIVE: Cerebral vasospasm (VS) is one of the factors that can most significantly worsen the prognosis after aneurysmal subarachnoid hemorrhage (SAH). A substantial body of evidence supports the idea that CSF diversion could prevent VS, even if this issue is still much debated. External ventricular drainage (EVD) is the recommended procedure for post-hemorrhagic hydrocephalus. In this study we analyzed whether EVD, placed for acute hydrocephalus, is effective in reducing the incidence of clinical and radiological cerebral vasospasm in patients who underwent endovascular treatment for aneurysmal SAH. PATIENTS AND METHODS: We retrospectively studied the incidence of radiologically confirmed VS in 141 patients treated endovascularly for aneurysmal SAH: 80 underwent EVD for hydrocephalus, 61 did not undergo EVD. RESULTS: VS occurred in 8.75% of cases (7 patients) in the first groups, while in 22.95% (14 patients) in the second group. In addition, patients not treated with EVD display a prevalence of VS in lower Fisher grades compared to the other group. CONCLUSION: Our data indicate that CSF drainage reduces the risk of vasospasms in patients with endovascular treatment for aneurysmal SAH. PMID- 25019460 TI - Isolated cerebral mucormycosis of the basal ganglia. PMID- 25019461 TI - Additive and synergistic antiandrogenic activities of mixtures of azol fungicides and vinclozolin. AB - OBJECTIVE: Many pesticides including pyrethroids and azole fungicides are suspected to have an endocrine disrupting property. At present, the joint activity of compound mixtures is only marginally known. Here we tested the hypothesis that the antiandrogenic activity of mixtures of azole fungicides can be predicted by the concentration addition (CA) model. METHODS: The antiandrogenic activity was assessed in MDA-kb2 cells. Following assessing single compounds activities mixtures of azole fungicides and vinclozolin were investigated. Interactions were analyzed by direct comparison between experimental and estimated dose-response curves assuming CA, followed by an analysis by the isobole method and the toxic unit approach. RESULTS: The antiandrogenic activity of pyrethroids deltamethrin, cypermethrin, fenvalerate and permethrin was weak, while the azole fungicides tebuconazole, propiconazole, epoxiconazole, econazole and vinclozolin exhibited strong antiandrogenic activity. Ten binary and one ternary mixture combinations of five antiandrogenic fungicides were assessed at equi-effective concentrations of EC25 and EC50. Isoboles indicated that about 50% of the binary mixtures were additive and 50% synergistic. Synergism was even more frequently indicated by the toxic unit approach. CONCLUSION: Our data lead to the conclusion that interactions in mixtures follow the CA model. However, a surprisingly high percentage of synergistic interactions occurred. Therefore, the mixture activity of antiandrogenic azole fungicides is at least additive. PRACTICE: Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment. IMPLICATIONS: Our evaluation provides an appropriate "proof of concept", but whether it equally translates to in vivo effects should further be investigated. PMID- 25019462 TI - Synthesis and properties of oligonucleotides modified with 2'-O-(2 carboxyethyl)nucleotides and their carbamoyl derivatives. AB - 2'-O-Methyl oligoribonucleotides with four kinds of 2'-O-modified uridine derivatives were synthesised. Their duplex stability, hydration behavior and exonuclease resistance were studied by spectroscopic analyses and molecular dynamics simulations. Consequently, 2'-O-modification of the uridine residue with 2-carbamoylethyl or 2-(N-methylcarbamoyl)ethyl groups resulted in a significant improvement of the exonuclease resistance without the loss of duplex stability. PMID- 25019463 TI - "Suspended" Pt nanoparticles over TiO2 nanotubes for enhanced photocatalytic H2 evolution. AB - In the present work we introduce a technique to form a photocatalyst based on Pt nanoparticles suspended over the mouth of anodic TiO2 nanotubes. These structures are obtained by decorating the top end of highly ordered TiO2 nanotubes with a web of TiO2 nanofibrils, followed by sputter deposition of a minimum amount of Pt. A subsequent thermal dewetting step forms 3-6 nm-sized Pt nanoparticles along the nanofibrils. These structures, when compared to conventional Pt decoration techniques of TiO2 nanotubes, show strongly enhanced photocatalytic H2 evolution efficiency. PMID- 25019464 TI - Localization of molecular orbitals: from fragments to molecule. AB - Conspectus Localized molecular orbitals (LMO) not only serve as an important bridge between chemical intuition and molecular wave functions but also can be employed to reduce the computational cost of many-body methods for electron correlation and excitation. Therefore, how to localize the usually completely delocalized canonical molecular orbitals (CMO) into confined physical spaces has long been an important topic: It has a long history but still remains active to date. While the known LMOs can be classified into (exact) orthonormal and nonorthogonal, as well as (approximate) absolutely localized MOs, the ways for achieving these can be classified into two categories, a posteriori top-down and a priori bottom-up, depending on whether they invoke the global CMOs (or equivalently the molecular density matrix). While the top-down approaches have to face heavy tasks of minimizing or maximizing a given localization functional typically of many adjacent local extrema, the bottom-up ones have to invoke some tedious procedures for first generating a local basis composed of well-defined occupied and unoccupied subsets and then maintaining or resuming the locality when solving the Hartree-Fock/Kohn-Sham (HF/KS) optimization condition. It is shown here that the good of these kinds of approaches can be combined together to form a very efficient hybrid approach that can generate the desired LMOs for any kind of gapped molecules. Specifically, a top-down localization functional, applied to individual small subsystems only, is minimized to generate an orthonormal local basis composed of functions centered on the preset chemical fragments. The familiar notion for atomic cores, lone pairs, and chemical bonds emerges here automatically. Such a local basis is then employed in the global HF/KS calculation, after which a least action is taken toward the final orthonormal localized molecular orbitals (LMO), both occupied and virtual. This last step is very cheap, implying that, after the CMOs, the LMOs can be obtained essentially for free. Because molecular fragments are taken as the basic elements, the approach is in the spirit of "from fragments to molecule". Two representatives of highly conjugated molecules, that is, C12H2 and C60, are taken as showcases for demonstrating the success of the proposed approach. The use of the so-obtained LMOs will lead naturally to low-order scaling post-HF/KS methods for electron correlation or excitation. In addition, the underlying fragment picture allows for easy and pictorial interpretations of the correlation/excitation dynamics. PMID- 25019465 TI - Exposure of breast cancer cells to a subcytotoxic dose of apigenin causes growth inhibition, oxidative stress, and hypophosphorylation of Akt. AB - Epidemiological studies show that fruit- and vegetable-rich diets are associated with a reduced risk of developing certain forms of cancer, including breast cancer. In this study we demonstrate that a subcytotoxic concentration of apigenin, which is a flavone found at high concentrations in parsley, onions, grapefruit, oranges, and chamomile tea, inhibited DNA synthesis in a panel of human breast cancer cell lines (MDA-MB-231, MBA-MB-468, MCF-7, SK-BR-3). Decreased proliferation of MDA-MB-468 cells in the presence of apigenin was associated with G2/M phase cell cycle arrest and the production of reactive oxygen species. Apigenin-treated MDA-MB-468 cells also showed reduced phosphorylation of Akt (protein kinase B), which is an essential effector serine/threonine kinase in the phosphatidylinositide 3-kinase pathway that promotes tumor growth and progression. However, exposure to the antioxidant reduced glutathione failed to reverse apigenin-mediated inhibition of Akt phosphorylation and cell proliferation, indicating that these effects were not due to oxidative stress. Taken together, these findings suggest that low-dose apigenin has the potential to slow or prevent breast cancer progression. PMID- 25019466 TI - Interprofessional Education and Practice Guide No. 1: developing faculty to effectively facilitate interprofessional education. AB - With the growth of interprofessional education (IPE) and practice in health professional schools, faculty members are being asked to assume new roles in leading or delivering interprofessional curriculum. Many existing faculty members feel ill-prepared to face the challenges of this curricular innovation. From 2012 2013, University of Missouri - Columbia and University of Washington partnered with six additional academic health centers to pilot a faculty development course to prepare faculty leaders for IPE. Using a variety of techniques, including didactic teaching, small group exercises, immersion participation in interprofessional education, local implementation of new IPE projects, and peer learning, the program positioned each site to successfully introduce an interprofessional innovation. Participating faculty confirmed the value of the program, and suggested that more widespread similar efforts were worthwhile. This guide briefly describes this faculty development program and identifies key lessons learned from the initiative. Peer learning arising from a faculty development community, adaptation of curricula to fit local context, experiential learning, and ongoing coaching/mentoring, especially as it related to actual participation in IPE activities, were among the key elements of this successful faculty development activity. PMID- 25019468 TI - Associations of prenatal maternal blood mercury concentrations with early and mid childhood blood pressure: a prospective study. AB - BACKGROUND: Childhood blood pressure (BP) is an important determinant of adult cardiovascular disease. Prenatal exposure to methylmercury through maternal fish consumption has been reported to increase the BP of children years later. METHODS: Mother-child pairs were enrolled from Project Viva, a prospective cohort study in Massachusetts. From second trimester maternal blood samples, we measured erythrocyte mercury concentration. Systolic BP in children, measured up to 5 times per visit in early and mid-childhood (median ages 3.2 and 7.7 years), was the primary outcome. We used mixed-effect regression models to account for variation in the number of BP measurements and to average effects over both time points. RESULTS: Among 1103 mother-child pairs, mean (SD) second trimester total erythrocyte mercury concentration was 4.0 (3.9)ng/g among mothers whose children were assessed in early childhood and 4.0 (4.0)ng/g for children assessed in mid childhood. Mean (SD) offspring systolic BP was 92.1 (10.4)mm Hg in early childhood and 94.3 (8.4)mm Hg in mid-childhood. After adjusting for mother and infant characteristics, mean second trimester blood mercury concentration was not associated with child systolic BP (regression coefficient, 0.1mm Hg; 95% CI, -1.3 to 1.5 for quartile 4 vs. quartile 1) at either time period. Further adjusting for second trimester maternal fish consumption, as well as docosahexaenoic acid and eicosapentaenoic acid consumption, did not substantially change the estimates. CONCLUSIONS: The results of this study demonstrate an absence of association between childhood blood pressure and low-level mercury exposure typical of the general US population. PMID- 25019469 TI - Toxic metals in seminal plasma and in vitro fertilization (IVF) outcomes. AB - We measured toxic metals in seminal plasma collected from 30 men using vitro fertilization (IVF), to evaluate associations with semen quality and IVF outcomes. A doubling in Hg-adjusted Pb concentration was associated with 47% lower total motile sperm. Positive associations were suggested for Hg with pregnancy and live birth, adjusted for Cd or Pb. A negative association was suggested for Hg-adjusted Cd with pregnancy. These data add to evidence indicating that toxic metals impact IVF. PMID- 25019467 TI - A comparison of glycosaminoglycan distributions, keratan sulphate sulphation patterns and collagen fibril architecture from central to peripheral regions of the bovine cornea. AB - This study investigated changes in collagen fibril architecture and the sulphation status of keratan sulphate (KS) glycosaminoglycan (GAG) epitopes from central to peripheral corneal regions. Freshly excised adult bovine corneal tissue was examined as a function of radial position from the centre of the cornea outwards. Corneal thickness, tissue hydration, hydroxyproline content, and the total amount of sulphated GAG were all measured. High and low-sulphated epitopes of keratan sulphate were studied by immunohistochemistry and quantified by ELISA. Chondroitin sulphate (CS) and dermatan sulphate (DS) distributions were observed by immunohistochemistry following specific enzyme digestions. Electron microscopy and X-ray fibre diffraction were used to ascertain collagen fibril architecture. The bovine cornea was 1021+/-5.42 MUm thick at its outer periphery, defined as 9-12 mm from the corneal centre, compared to 844+/-8.10 MUm at the centre. The outer periphery of the cornea was marginally, but not significantly, more hydrated than the centre (H=4.3 vs. H=3.7), and was more abundant in hydroxyproline (0.12 vs. 0.06 mg/mg dry weight of cornea). DMMB assays indicated no change in the total amount of sulphated GAG across the cornea. Immunohistochemistry revealed the presence of both high- and low-sulphated epitopes of KS, as well as DS, throughout the cornea, and CS only in the peripheral cornea before the limbus. Quantification by ELISA, disclosed that although both high- and low-sulphated KS remained constant throughout stromal depth at different radial positions, high-sulphated epitopes remained constant from the corneal centre to outer-periphery, whereas low-sulphated epitopes increased significantly. Both small angle X-ray diffraction and TEM analysis revealed that collagen fibril diameter remained relatively constant until the outer periphery was reached, after which fibrils became more widely spaced (from small angle x-ray diffraction analysis) and of larger diameter as they approached the sclera. Depth-profiled synchrotron microbeam analyses showed that, at different radial positions from the corneal centre outwards, fibril diameter was greater superficially than in deeper stromal regions. The interfibrillar spacing was also higher at mid-depth in the stroma than it was in anterior and posterior stromal regions. Collagen fibrils in the bovine cornea exhibited a fairly consistent spacing and diameter from the corneal centre to the 12 mm radial position, after which a significant increase was seen. While the constancy of the overall sulphation levels of proteoglycans in the cornea may correlate with the fibrillar architecture, there was no correlation between the latter and the distribution of low-sulphated KS. PMID- 25019470 TI - Associations between perfluoroalkyl acids (PFASs) and maternal thyroid hormones in early pregnancy: a population-based cohort study. AB - BACKGROUND: Associations between perfluoroalkyl acids (PFASs) and human thyroid hormone levels remain unclear, especially during early pregnancy when small changes in maternal thyroid hormones can affect fetal brain development. OBJECTIVES: To examine associations between maternal serum PFAS levels and maternal thyroid hormone levels in the early 2nd trimester of pregnancy. METHODS: Participants were euthyroid pregnant women (n=152) enrolled in the Chemicals, Health and Pregnancy (CHirP) study based in Vancouver, Canada. Associations between maternal serum PFASs, including perfluorohexanesulfonate (PFHxS), perfluorononanoate (PFNA), perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) and repeated measures of maternal thyroid hormones, including free thyroxine (fT4), total thyroxine (TT4) and thyroid stimulating home (TSH) were examined using mixed effects linear models. Associations were considered in all women, then separately in women with high (>= 9 IU/mL) vs normal (<9 IU/mL) levels of thyroid peroxidase antibody (TPOAb), a marker of autoimmune hypothyroidism (Hashimoto's disease). RESULTS: Median PFAS concentrations (ng/mL) in maternal sera were 1.0 (PFHxS), 0.6 (PFNA), 1.7 (PFOA) and 4.8 (PFOS). PFASs were not associated with fT4, TT4 or TSH among women with normal TPOAb. However, among the 9% of women with high TPOAb (n=14), interquartile range (IQR) increases of PFASs were associated with a 46-69% increase in maternal TSH (95% CIs ranging from 8% to 123%) (PFNA, PFOA and PFOS only), and with a 3% to 7% decrease in maternal fT4 (95% CIs ranging from -18% to 5%) (all 4 PFASs). PFNA was also associated with higher maternal TSH in the whole sample. CONCLUSIONS: PFASs were positively associated with TSH, and weakly negatively associated with fT4 in the subset of pregnant women with high TPOAb, which occurs in 6-10% of pregnancies. PFASs may exacerbate the already high TSH and low fT4 levels in these women during early pregnancy, which is a critical time of thyroid hormone-mediated fetal brain development. The clinical significance of these findings is not clear. We propose a "multiple hit hypothesis" to explain these findings; this hypothesis deserves evaluation in larger, more representative study samples. PMID- 25019471 TI - Reliability and relationships among handgrip strength, leg extensor strength and power, and balance in older men. AB - PURPOSE: To quantify the reliability of isometric leg extension torque (LEMVC), rate of torque development (LERTD), isometric handgrip force (HGMVC) and RFD (HGRFD), isokinetic leg extension torque and power at 1.05rad.s(-1) and 3.14rad.s(-1); and explore relationships among strength, power, and balance in older men. METHODS: Sixteen older men completed 3 isometric handgrips, 3 isometric leg extensions, and 3 isokinetic leg extensions at 1.05rad.s(-1) and 3.14rad.s(-1) during two visits. Intraclass correlation coefficients (ICCs), ICC confidence intervals (95% CI), coefficients of variation (CVs), and Pearson correlation coefficients were calculated. RESULTS: LERTD demonstrated no reliability. The CVs for LERTD and HGRFD were <=23.26%. HGMVC wasn't related to leg extension torque or power, or balance (r=0.14-0.47; p>0.05). However, moderate to strong relationships were found among isokinetic leg extension torque at 1.05rad.s(-1) and 3.14rad.s(-1), leg extension mean power at 1.05rad.s(-1), and functional reach (r=0.51-0.95; p<=0.05). CONCLUSIONS: LERTD and HGRFD weren't reliable and shouldn't be used as outcome variables in older men. Handgrip strength may not be an appropriate surrogate for lower body strength, power, or balance. Instead, perhaps handgrip strength should only be used to describe upper body strength or functionality, which may compliment isokinetic assessments of lower body strength, which were reliable and related to balance. PMID- 25019472 TI - Circulating oxidative stress parameters in pre- and post-menopausal healthy women and in women suffering from breast cancer treated or not with neoadjuvant chemotherapy. AB - We evaluate here the redox status in pre- and post-menopausal healthy women and in women with breast cancer in order to understand the consequences of the hormonal alterations of menopause for the oxidative stress status, its modifications with breast cancer and the influence of neoadjuvant chemotherapy (NC). To that, serum oxidative stress parameters (total antioxidant capacity, lipid peroxidation and protein oxidation), non-enzyme antioxidant defenses (total glutathione, uric acid and bilirubin) and enzyme antioxidant defenses (superoxide dismutase, catalase and glutathione peroxidase activities) were measured in healthy women and in women with breast cancer divided according to their menopausal status and that received or not NC. Circulating estradiol, progesterone, FSH and LH were also analyzed. We found that menopause itself modifies the redox status of healthy women, being most of these differences also reflected in women with breast cancer. However, several changes occur as a consequence of the disease. Furthermore, NC increases oxidative damage, decreases antioxidant defenses and eliminates the differences found in menopause. We conclude that the normal redox balance is disrupted by breast cancer but is also affected by the hormonal status promoted by menopause. In fact, NC nullifies the differences found between pre- and postmenopausal women in several antioxidant defense systems. PMID- 25019473 TI - Age related changes of cAMP and MAPK signaling in Leydig cells of Wistar rats. AB - Here, we chronologically analyzed age-associated changes of cAMP- and MAPK signaling in Leydig cells (LCs) in relation with decreased testosterone (T) production. In Wistar rats, decreased serum T observed in 12 to 24-month-old rats was not related to decreased serum LH concentration but to reduced luteinizing hormone receptor (Lhr/LHR) and time-coordinated reduction of steroidogenic gene expression (decreased Cyp11a1, Cyp17a1 in 12-month-old rats followed by decreased Star/StAR, Hsd3b/HSD3B, Hsd17b4, and increased Cyp19a1 later in life). The predecessors of age-related changes noted in LCs from 6 to 12-month-old rats were increased level of soluble adenylate cyclase (Adcy/AC) 10, increased JNK phosphorylation but suppressed P38 MAPK. At approximately the same time changed mRNA abundance for transcription factors important for steroidogenesis was detected (increased Nur77 and decreased Sf1, Dax1). Aging caused biphasic expression pattern of ERK1/2 and Nur77: increased in 12-month but decreased in LCs from 24-month-old rats. Further, decreased basal cAMP level observed from 12 to 24th month coincidence with increased expression of cAMP-specific phosphodiesterase (Pde)4a, Pde4b and regulatory subunit of protein kinase A (Prkar/PKAR). Exposing of senescent LCs to permeable cAMP-analog improved transcription of Sf1, Nur77, Star, Cyp11a1,Cyp17a1, but without effect on aging pattern of Dax1, Pde4a/b, Prkar2a, Lhr and MAPK genes. Collectively, results indicated that age-related LC dysfunction is accompanied with changes in MAPK and cAMP signaling and coordinated reduction in the expression of many of the genes that participate in T synthesis. The predecessors of aged-related changes are increased ratio of pJNK/JNK, AC10 and decreased P38 level in LCs from 6-month-old rats. PMID- 25019474 TI - Lower lean mass and higher percent fat mass in patients with Alzheimer's disease. AB - In this study we analyzed body composition in relation to cognitive and functional status, in a cross-sectional sample of patients with Alzheimer's disease (AD). Seventy individuals (27 men, 78.1+/-6.5years; 43 women, 80.4+/ 5.6years) with mild-moderate stages of AD (clinical dementia ratings 1 and 2) were selected from the Alzheimer Center, SS. Trinita Hospital, ASL 8 of Cagliari (Italy). Cognitive and psycho-functional status was evaluated using mini-mental state examination (MMSE), activities of daily living (ADL) scale, and geriatric depression scale (GDS). Mini-nutritional assessment (MNA) was applied. Anthropometric measurements were taken and body mass index (BMI) was calculated. Body composition was assessed by means of specific bioelectrical impedance vector analysis (BIVA), using the references for the elderly. In comparison with the reference group, patients with AD showed similar BMI and MNA, but peculiar bioelectrical characteristics: lower phase angles and longer vectors (p<0.05). According to specific BIVA, this bioelectrical pattern is indicative of a reduction of lean tissue mass and an increase of percent fat mass (FM%). A more accentuated lean mass reduction (p < 0.05) was observed in women with worse cognitive status and a FM% increase (p < 0.01) in women with worse functional status. In conclusion, patients with AD had lower lean tissue mass and higher percent fat mass than healthy elderly individuals. In women, this pattern was associated with cognitive and functional decline, as indicated by MMSE and ADL values. Specific BIVA showed to be a suitable technique in the elderly, that could enhance BMI and MNA information in the evaluation of nutritional status. PMID- 25019475 TI - IMA and IMAR in serum and saliva of preeclampsia--a preliminary study. AB - INTRODUCTION: Oxidative stress could play a role in the development of preeclampsia. Ischemia modified albumin (IMA) is a oxidatively modified form of albumin. OBJECTIVE: To evaluate the levels of salivary and serum IMA and IMA: albumin ratio (IMAR) in preeclampsia and with its severity and investigate their correlation with the fetal birth weight. METHODS: This case control study was conducted on 50 preeclamptic (32 mild and 18 severe cases) and 50 normal pregnant controls. Blood and saliva were obtained to measure albumin, IMA and IMAR was calculated. RESULTS: serum and salivary IMA and IMAR were significantly increased in preeclampsia. Although the increase in serum was in accordance with the severity, it was not so in the saliva. Yet, salivary IMAR showed significant difference between controls and mild preeclampsia. There was a negative correlation between IMA and albumin in both serum and saliva. A weak negative correlation was seen between the serum IMAR and fetal birth weight (r = -0.293; p < 0.05), but not with salivary IMAR. CONCLUSION: This study is an evidence for involvement of oxidative stress in the pathogenesis of preeclampsia, which is reflected in serum and saliva. Salivary IMAR could be a better marker for early prediction of preeclampsia. PMID- 25019476 TI - Synthesis of novel thiadiazolotriazin-4-ones and study of their mosquito larvicidal and antibacterial properties. AB - A series of novel 3-tert-butyl-7-(aryloxymethyl)-4H-[1,3,4]thiadiazolo[2,3 c][1,2,4]triazin-4-ones (5a-5n) were synthesized by refluxing 3,3-dimethyl-2 oxobutanoic acid (trimethyl pyruvic acid) (1) and thiocarbohydrazide (2) in ethanol as solvent for 12 h, to yield 3-mercapto-4-amino-6-tert-butyl-1,2,4 triazine-5(4H)-one (3) (Scheme 1), then the compound (3) was condensed with different substituted aryloxyacetic acids (4) in POCl3 at 90 degrees C for 8 h (Scheme 2). The structures of the newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR, elemental analyses and mass spectroscopic studies. Few of the synthesized compounds exhibited moderate mosquito-larvicidal and antibacterial activities. Among the novel derivatives, the compound (5f) showed relatively high larvicidal activity against a malaria vector. Compounds (5i) and (5m) exhibited a broad spectrum antibacterial activity against Gram positive and Gram negative species and hence they may be considered as drug candidates for bacterial pathogens. PMID- 25019477 TI - Investigations of amide bond variation and biaryl modification in analogues of alpha7 nAChR agonist SEN12333. AB - Several lines of experimental evidence support the involvement of the alpha7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the alpha7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel alpha7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at alpha7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted. PMID- 25019478 TI - Flavones: an important scaffold for medicinal chemistry. AB - Flavones have antioxidant, anti-proliferative, anti-tumor, anti-microbial, estrogenic, acetyl cholinesterase, anti-inflammatory activities and are also used in cancer, cardiovascular disease, neurodegenerative disorders, etc. Also, flavonoids are found to have an effect on several mammalian enzymes like protein kinases that regulate multiple cell signaling pathways and alterations in multiple cellular signaling pathways are frequently found in many diseases. Flavones have been an indispensable anchor for the development of new therapeutic agents. The majority of metabolic diseases are speculated to originate from oxidative stress, and it is therefore significant that recent studies have shown the positive effect of flavones on diseases related to oxidative stress. Due to the wide range of biological activities of flavones, their structure-activity relationships have generated interest among medicinal chemists. The outstanding development of flavones derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research. The present review gives detail about the structural requirement of flavone derivatives for various pharmacological activities. This information may provide an opportunity to scientists of medicinal chemistry discipline to design selective, optimize as well as poly-functional flavone derivatives for the treatment of multi-factorial diseases. PMID- 25019479 TI - Cyclic tertiary sulfamates: selective inhibition of the tumor-associated carbonic anhydrases IX and XII by N- and O-substituted acesulfame derivatives. AB - Carbonic anhydrase (hCA) IX and XII isoforms are over-expressed both in primary and in metastatic cell lines of hypoxic tumors and are innovative targets for cancer diagnosis and treatment. On the basis of the importance of the pharmacophoric sulfamate moiety (bioisostere of the sulfonamide group) present in the structure of recent human CA inhibitors, we designed N-alkylated and O alkylated derivatives of acesulfame, a cyclic tertiary sulfamate, assessing the inhibitory activity against the ubiquitous isoforms hCA I and II and the cancer related isoforms hCA IX and XII. All derivatives were nanomolar inhibitors, with some of them possessing an outstanding selectivity towards the tumor-associated hCA IX and/or hCA XII isoforms. PMID- 25019480 TI - Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives. AB - A series of 2-substituted amino-3-chloro-1,4-naphthoquinone derivatives (3-12) were synthesized as anticancer agents and tested against four cancer cell lines including HepG2, HuCCA-1, A549 and MOLT-3. The most potent cytotoxic activity against the HepG2, HuCCA-1 and A549 cell lines was found to be m acetylphenylamino-1,4-naphthoquinone (8) affording IC50 values of 4.758, 2.364 and 12.279 MUM, respectively. On the other hand, p-acetylphenylamino-1,4 naphthoquinone (9) exhibited the most potent cytotoxic activity against the MOLT 3 cell line with an IC50 of 2.118 MUM. Quantitative structure-activity relationship (QSAR) investigations provided good predictive performance as observed from cross-validated R of 0.9177-0.9753 and RMSE of 0.0614-0.1881. The effects of substituents at the 2-amino position on the naphthoquinone core structure and its corresponding influence on the cytotoxic activity were investigated by virtually constructing additional 1,4-naphthoquinone compounds (13-36) for which cytotoxic activities were predicted using equations obtained from the previously constructed QSAR models. Interpretation of informative descriptors from QSAR models revealed pertinent knowledge on physicochemical properties governing the cytotoxic activities of tested cancer cell lines. It is anticipated that the QSAR models developed herein could provide guidelines for further development of novel and potent anticancer agents. PMID- 25019482 TI - Anatomic relationships of psoas muscle: clinical applications to psoas hitch ureteral reimplantation. AB - OBJECTIVE: The objective of the study was to examine the anatomic relationship of the genitofemoral and femoral nerves to the psoas major muscle. STUDY DESIGN: Dissections were performed in 17 unembalmed female cadavers. Point A was used as the approximate location for placement of psoas hitch sutures and as the reference point from which all measurements were taken. Measurements included the width of the psoas major muscle, psoas minor tendon, genitofemoral nerve branches, and femoral nerve. The relative location of the genitofemoral and femoral nerves to point A and the presence or absence of a psoas minor tendon were documented. RESULTS: The psoas minor tendon was absent on at least 1 side in 11 specimens (64.7%). The median width of the psoas minor tendon was 7 mm (range, 3-11.5 mm). The median width and depth of the psoas major muscle was 21.5 mm (range, 10-35 mm) and 20.0 mm (range, 11.5-32 mm), respectively. The median width of the genitofemoral nerve was 2 mm (range, 1-4.5 mm) and that of the femoral nerve was 6.3 mm (range, 5-10.5 mm). Overall, 54 genitofemoral nerve branches were identified in 17 cadavers, 30 medial (55.5%), 22 lateral (40.7%), and 2 directly overlying point A (3.7%). CONCLUSION: The exact location for the placement of the psoas hitch sutures will vary, depending on the location of the ureteral injury and the anatomy of the psoas muscle and surrounding structures. A thorough understanding of this regional anatomy should optimize the placement of psoas hitch sutures during ureteral reimplantation procedures and help avoid nerve and vessel injury. PMID- 25019483 TI - Reply: To PMID 24560557. PMID- 25019481 TI - MiR-9 promotes microglial activation by targeting MCPIP1. AB - Microglia participate in innate inflammatory responses within the central nervous system. The highly conserved microRNA-9 (miR-9) plays critical roles in neurogenesis as well as axonal extension. Its role in microglial inflammatory responses, however, remains poorly understood. Here we identify a unique role of miR-9 in mediating the microglial inflammatory response via distinct signalling pathways. MiR-9-mediated regulation of cellular activation involved downregulated expression of the target protein, monocyte chemotactic protein-induced protein 1 (MCPIP1) that is crucial for controlling inflammation. Results indicate that miR 9-mediated cellular activation involved signalling via the NF-kappaB pathway, but not the beta-catenin pathway. PMID- 25019484 TI - Does a postpartum hemorrhage patient safety program result in sustained changes in management and outcomes? AB - We sought to determine whether the introduction of a postpartum hemorrhage (PPH) safety program was associated with changes in clinical practice and outcomes, and to examine whether these changes were sustained over time. In August 2008, a multidisciplinary PPH patient safety program was implemented at our single tertiary care hospital. We performed a cohort study of all women with PPH from August 2007 through December 2011. Changes in clinical practice and outcomes were compared before and after the intervention. Shewhart charts were used to examine sustainability of these changes over time. During the study period 52,819 women delivered, and 3105 (5.9%) experienced PPH. After the introduction of the program there was a significant increase in the use of uterotonic medications (P < .001), intrauterine balloon tamponade (P = .002), B-Lynch suture placement (P = .042), uterine artery embolization (P = .050), and cryoprecipitate use (P = .0222). Concomitantly, the number of days between admissions to the intensive care unit for PPH increased. PMID- 25019485 TI - A cost-effectiveness analysis of conservative versus surgical management for the initial treatment of stress urinary incontinence. AB - OBJECTIVE: We sought to determine whether conservative or surgical therapy is more cost effective for the initial treatment of stress urinary incontinence (SUI). STUDY DESIGN: We created a decision tree model to compare costs and cost effectiveness of 3 strategies for the initial treatment of SUI: (1) continence pessary, (2) pelvic floor muscle therapy (PFMT), and (3) midurethral sling (MUS). We identified probabilities of SUI after 12 months of use of a pessary, PFMT, or MUS using published data. Parameter estimates included Health Utility Indices of no incontinence (.93) and persistent incontinence (0.7) after treatment. Morbidities associated with MUS included mesh erosion, retention, de novo urge incontinence, and recurrent SUI. Cost data were derived from Medicare in 2012 US dollars. One- and 2-way sensitivity analysis was used to examine the effect of varying rates of pursuing surgery if conservative management failed and rates of SUI cure with pessaries and PFMT. The primary outcome was an incremental cost effectiveness ratio threshold <$50,000. RESULTS: Compared to PFMT, initial treatment of SUI with MUS was the more cost-effective strategy with an incremental cost-effectiveness ratio of $32,132/quality-adjusted life year. Initial treatment with PFMT was also acceptable as long as subjective cure was >35%. In 3-way sensitivity analysis, subjective cure would need to be >40.5% for PFMT and 43.5% for a continence pessary for the MUS scenario to not be the preferred strategy. CONCLUSION: At 1 year, MUS is more cost effective than a continence pessary or PFMT for the initial treatment for SUI. PMID- 25019486 TI - Sacral nerve stimulation reduces elevated urinary nerve growth factor levels in women with symptomatic detrusor overactivity. AB - OBJECTIVES: To investigate changes in urinary nerve growth factor (uNGF) in women with symptomatic detrusor overactivity (DO) following peripheral nerve evaluation (PNE) for sacral neuromodulation vs controls. STUDY DESIGN: There were 23 subjects with overactive bladder symptoms and DO who failed management with anticholinergics and 22 controls consented to participate in this prospective pilot study. Urine specimens were collected from controls at baseline for evaluation of uNGF and creatinine. Subjects were evaluated at baseline and 5 days after a trial of sacral nerve stimulation referred to as a PNE. Each visit included urine collection for uNGF and, Incontinence Quality of Life Questionnaire, Urinary Distress Inventory Questionnaire, postvoid residual volume, and a 3-day voiding diary. uNGF levels were measured by enzyme-linked immunosorbent assay and expressed as uNGF pg/creatinine mg. RESULTS: Subjects with DO had significantly higher baseline uNGF levels (corrected for creatinine) compared with controls (19.82 pg/mg vs 7.88 pg/mg, P < .002). Seventeen DO subjects underwent PNE and were evaluated at the end of the testing period. There was a significant improvement in quality of life scores for subjects after PNE compared with baseline (Urinary Distress Inventory Questionnaire: 7.0 vs 13.7, P < .001; Incontinence Quality of Life Questionnaire: 87.3 vs 52.8, P < .0001). Concordantly, uNGF levels significantly decreased from 17.23 pg/mg to 9.24 pg/mg (P < .02) after PNE. CONCLUSION: uNGF levels decrease with symptomatic response in DO subjects undergoing PNE. DO subjects had significantly higher uNGF at baseline vs controls, and uNGF levels significantly decreased after only 5 days of sacral nerve stimulation. These findings support a larger study to validate the use of uNGF as an objective tool to assess therapeutic outcome in patients undergoing PNE for sacral neuromodulation. PMID- 25019488 TI - Preoperative uterine bleeding pattern and risk of endometrial ablation failure. AB - OBJECTIVE: The objectives of the study were to compare among women who had an endometrial ablation the risks of treatment failure and subsequent gynecological procedures between women with regular and irregular heavy uterine bleeding and to determine other characteristics associated with the risk of treatment failure. STUDY DESIGN: This study was a retrospective cohort of 968 women who underwent endometrial ablation between January 2007 and July 2009. Preoperative bleeding pattern was categorized as regular or irregular. Treatment failure was defined as reablation or hysterectomy. Subsequent gynecological procedures included endometrial biopsy, dilation and curettage, hysteroscopy, reablation, or hysterectomy. We calculated the odds of treatment failure and gynecological procedures using multiple logistic regression. RESULTS: Bleeding pattern prior to ablation was heavy and regular in 30% (n = 293), heavy and irregular in 36% (n = 352), and unspecified in 30% (n = 286). We found no differences in treatment failure (13% vs 12%, P = .9) or subsequent procedures (16% vs 18%, P = .7) between women with regular and irregular bleeding. Compared with the women with regular bleeding, the women with irregular bleeding were not at increased odds of treatment failure or subsequent procedures (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.65-1.74 and OR, 1.17; 95% CI, 0.76-1.80, respectively). Factors associated with an increased odds of treatment failure and subsequent procedures included tubal ligation (OR, 1.94; 95% CI, 1.30-2.91 and OR, 1.71; 95% CI, 1.20 2.43, respectively); dysmenorrhea (OR, 2.42; 95% CI, 1.44-4.06 and OR, 1.93; 95% CI, 1.20-3.13, respectively); and obesity (OR, 1.82; 95% CI, 1.21-2.73 and OR, 1.75; 95% CI, 1.22-2.50, respectively). CONCLUSION: Preoperative bleeding pattern did not appear to affect failure rates or the need for gynecological procedures after endometrial ablation. Other risk factors for ablation failure identified included preoperative dysmenorrhea, prior tubal ligation, and obesity. PMID- 25019487 TI - Effectiveness of blinding: sham suprapubic incisions in a randomized trial of retropubic midurethral sling in women undergoing vaginal prolapse surgery. AB - OBJECTIVE: This planned secondary analysis of the Outcomes Following Vaginal Prolapse Repairs and Midurethral Sling trial assessed whether treatment knowledge differed between randomized groups at 12 months and whether treatment success was affected by treatment perception. STUDY DESIGN: Sham suprapubic tension-free vaginal tape (TVT) incisions were made in the Outcomes Following Vaginal Prolapse Repairs and Midurethral Sling trial participants randomized to no-TVT. Primary surgical outcomes and maintenance of blinding was assessed at 12 months. Knowledge of treatment assignment was compared between groups, and the relationship with treatment success rates was assessed. RESULTS: Prior to the 12 month postoperative visit, only 4% of treated participants (13 of 336) formally reported unmasking. At 12 months, 94% of the randomized participants (315 of 336) provided treatment knowledge data. Sixteen TVT participants (10%) reported treatment knowledge; most (n = 15, 94%) were correct; 17 of the sham participants (11%) reported treatment knowledge; half (n = 8, 47%) were correct. Similar proportions of unmasked participants who reported no treatment knowledge correctly guessed/perceived treatment assignment (sham, 46 [33%] vs TVT, 44 [33%]). We did not detect significant differences in treatment success rates based on perception within and across received treatment groups (perceived sham vs TVT overall [P = .76]). Of those receiving TVT, more participants perceiving TVT had treatment success compared with those who perceived sham (84% vs 74%; P = .29). Among sham participants, more participants perceiving sham had success compared with those who perceived receiving TVT (65% vs 56%; P = .42). CONCLUSION: Sham surgical incisions effectively mask TVT randomization. These findings may help to inform future surgical trial designs. PMID- 25019489 TI - Self-assembly of supramolecularly engineered polymers and their biomedical applications. AB - Noncovalent interactions provide a flexible method of engineering various chemical entities with tailored properties. Specific noncovalent interactions between functionalized small molecules, macromolecules or both of them bearing complementary binding sites can be used to engineer supramolecular complexes that display unique structure and properties of polymers, which can be defined as supramolecularly engineered polymers. Due to their dynamic tunable structures and interesting physical/chemical properties, supramolecularly engineered polymers have recently received more and more attention from both academia and industry. In this feature article, we summarize the recent progress in the self-assembly of supramolecularly engineered polymers as well as their biomedical applications. In view of different molecular building units, the supramolecularly engineered polymers can be classified into the following three major types: supramolecularly engineered polymers built by small molecules, supramolecularly engineered polymers built by small molecules and macromolecules, and supramolecularly engineered polymers built by macromolecules, which possess distinct morphologies, definite architectures and specific functions. Owing to the reversible nature of the noncovalent interactions, the supramolecularly engineered polymers have exhibited unique features or advantages in molecular self-assembly, for example, facile preparation and functionalization, controllable morphologies and structures, dynamic self-assembly processes, adjustable performance, and so on. Furthermore, the self-assembled supramolecular structures hold great potential as promising candidates in various biomedical fields, including bioimaging, drug delivery, gene transfection, protein delivery, regenerative medicine and tissue engineering. Such developments in the self-assembly of supramolecularly engineered polymers and their biomedical applications greatly promote the interdiscipline research among supramolecular chemistry, polymer materials, biomedicine, nano-science and technology. PMID- 25019490 TI - Hevea brasiliensis REF (Hev b 1) and SRPP (Hev b 3): An overview on rubber particle proteins. AB - This review article aims to gather all the knowledge on two important proteins associated with Hevea brasiliensis rubber particles: namely the rubber elongation factor (REF) and the small rubber particle protein (SRPP). It covers more then three decades of research on these two proteins and their homologues in plants, and particularly emphasizes on the different possible properties or functions of these various proteins found in plants. PMID- 25019491 TI - Novel hybrid nanocomposites of polyhedral Cu2O nanoparticles-CuO nanowires with enhanced photoactivity. AB - Novel hybrid nanocomposites of Cu2O nanoparticles (NPs) partially embedded in CuO nanowires (NWs) were produced by simple thermal reduction of CuO NWs in a vacuum. It is found that most Cu2O NPs adopt two regular shapes, one being cubic and the other being octahedral. The shape selection of the Cu2O nanocrystals is governed by the orientation relationship between Cu2O NPs and CuO NWs. The formation of such hierarchical hybrid nanostructures is induced by the topotactic reduction of CuO NWs. Compared with pure CuO NWs, the polyhedral Cu2O NP-CuO NW hierarchical hybrid nanostructures exhibit enhanced ability to photodegrade methyl orange under visible light, which is attributed to the synergic effects of CuO NWs and Cu2O NPs. PMID- 25019492 TI - Headache after traumatic brain injury: a national survey of clinical practices and treatment approaches. AB - BACKGROUND: Individuals with headache after traumatic brain injury (TBI) receive care in a wide variety of clinical locations by physicians trained in multiple specialties. OBJECTIVE: To understand current practice patterns and perceptions of treatment issues among clinicians managing headache after TBI. DESIGN: National survey of current clinical practice using a 20-item questionnaire developed by the authors. PARTICIPANTS: Survey respondents were members of the Central Nervous System Council list survey of the American Academy of Physical Medicine and Rehabilitation (N = 1782) and the American Headache Society membership (N = 1260). METHODS: The survey was sent electronically to potential participants and was followed by 2 biweekly reminders. The survey queried the physicians' clinical setting; their use of headache classification systems, headache diaries, checklists, and diagnostic procedures; the pharmacologic and nonpharmacologic treatments prescribed; and headache chronicity and associated symptoms and disorders among their patients with TBI. RESULTS: Completed surveys were received from 193 respondents. The use of standardized classification systems and checklists was commonly reported. Respondents used nonpharmacologic and pharmacologic treatment approaches with similar frequency and modest perceived success rates. A high frequency of headache-associated new sleep and mood disorders was reported. When response differences occurred between practice settings, they reflected a focus on headache diagnosis, classification, and pharmacologic treatment among neurology and specialty headache clinics, whereas a nonpharmacologic approach to management among TBI specialty and general rehabilitation clinicians was more commonly reported. CONCLUSION: Management strategies for treating headache after TBI vary widely among general and specialty clinical practices. This suggests that additional research is needed that would lead to an increase in the use of established headache classification and the development of standardized management approaches so that all practitioners who care for patients after TBI can provide consistent effective care. PMID- 25019493 TI - P22 mediated recombination of frt-sites. AB - Flp mediated site specific recombination of frt-sites is frequently used in genetic engineering to excise, insert or invert DNA-cassettes in the chromosome. While constructs flanked by frt-sites are generally considered to be stable in the absence of the Flp enzyme, we observed that P22 chromosomes exceeding wild type length tend to lose frt-flanked insertions via Flp independent recombination of frt-sites during phage propagation. This spontaneous recombination should be considered when engineering the chromosome of P22 and perhaps of other phages as well. PMID- 25019494 TI - MiR-221 accentuates IFN's anti-HCV effect by downregulating SOCS1 and SOCS3. AB - MiR-221 was reported to be upregulated and play roles in tumorigenesis of hepatitis C virus (HCV) associated hepatocellular carcinoma (HCC). However, the role of miR-221 in HCV infection remains unknown. In this study, it was found that miR-221 was upregulated in serum of HCV chronic hepatitis patients and Huh7.5.1 cells infected with HCVcc. Further studies indicated that miR-221 mimic could accentuate anti-HCV effect of IFN-alpha in HCVcc model, miR-221 mimic could further repressed 10% HCV RNA expression and 35-42% HCV core or NS5A protein expression in HCVcc infected Huh7.5.1 cells treated with 100IU/mL IFN-alpha, and miR-221 inhibitor resulted in the reverse effects. Furthermore, two members of suppressor of cytokine signaling (SOCS) family, SOCS1 and SOCS3, which are well established inhibitory factors on IFN/JAK/STAT pathway, were identified as the targets of miR-221 and were involved in the effect of miR-221. In conclusion, miR 221 could accentuate IFN's anti-HCV effect by targeting SOCS1 and SOCS3. PMID- 25019495 TI - The impact of hospital volume on postoperative complications following robot assisted partial nephrectomy. AB - PURPOSE: We sought to evaluate the relationship between hospital volume and postoperative complications following robot-assisted partial nephrectomy (RAPN) using the Nationwide Inpatient Sample. MATERIALS AND METHODS: We identified patients undergoing RAPN between 2009 and 2011. Hospitals were divided into volume-based tertiles for each year (high, medium, low). Descriptive analyses were performed using Pearson's chi-squared and Student's t-test. Multivariable logistic regression assessed the association between hospital volume and postoperative complications, adjusting for age, gender, hospital region, type of hospital, primary payer, comorbidities, and kidney cancer. RESULTS: We identified 17,583 cases from 323 hospitals, of which 112 were low volume, 112 medium volume, and 99 high volume. 13,645 (78%) cases were performed at high-volume institutions. Eleven percent of patients developed an in-hospital postoperative complication, with 15% at low-volume, 12% at medium-volume, and 10% at high volume hospitals (p=0.071). In addition, blood transfusion was less common at high-volume hospitals (p=0.015). On multivariable logistic regression, high volume hospitals had 42% decreased odds of postoperative in-hospital complications (95% confidence interval 0.37-0.90; p=0.016). Complications were associated with a $4500 increase in hospital costs. CONCLUSIONS: High-volume hospitals are associated with decreased blood transfusions and complications. With the recognition that high-volume RAPN hospitals are independently associated with improved clinical outcomes, further studies should be performed to determine the role of the hospital and surgeon volume thresholds in the performance of RAPN. PMID- 25019496 TI - New perspectives and lessons learned in the identification of impurities in drug development. AB - Within the pharmaceutical industry, the rapid identification, elucidation and characterization of synthetic or process impurities or degradants form an intense and a comprehensive undertaking. Advances in laboratory hardware and software are changing the way in which scientists work together to help resolve impurities in a quick and efficient manner. Although the industry trend toward externalization and outsourcing of development tasks provides a cost-effective method, the demand for improved productivity in laboratory workflows in drug development continues to be a high priority. This brings a need for new approaches for communication, collaboration and data management. PMID- 25019497 TI - Structural and functional analyses of bovine and porcine intestinal heparins confirm they are different drugs. AB - Anticoagulant heparins are mostly obtained from porcine intestine. Occasionally they are also obtained from bovine intestine. Structural and functional analyses of pharmaceutical-grade heparins from these two sources using multiple methods such as NMR spectroscopy, in vitro and in vivo assays of the anticoagulant, antithrombotic and bleeding effects, complemented by fractionation on anion exchange chromatography, confirm they are different drugs. Although bovine heparin is more heterogeneous and less sulfated, heparins from both sources are overall made of a similar mixture of fractions, however with different proportions. Therefore, high-anticoagulant composites from bovine origin, similar to porcine counterparts, can be properly obtained. PMID- 25019498 TI - Influence of stimulus velocity profile on rhythmic visuomotor coordination. AB - Every day, we visually coordinate our movements with environmental rhythms. Despite its ubiquity, it largely remains unclear why certain visual rhythms or stimuli facilitate such visuomotor coordination. The goal of the current study was to investigate whether the velocity profile of a rhythmic stimulus modulated the emergence and stability of this coordination. We examined both intended (Experiment 1) and unintended or spontaneous coordination (Experiment 2) between the rhythmic limb movements of participants and stimuli exhibiting different velocity profiles. Specifically, the stimuli oscillated with either a sinusoidal (harmonic), nonlinear Rayleigh, or nonlinear Van der Pol velocity profile, all of which are typical of human or biological rhythmic movement. The results demonstrated that the dynamics of both intended and unintended visuomotor coordination were modulated by the stimulus velocity profile, and that the Rayleigh velocity profile facilitated the coordination, suggesting a crucial role of the slowness to the endpoints or turning points of the stimulus trajectory for stable coordination. More generally, these findings open promising research directions to better understand and improve coordination with artificial agents and people with social deficits. PMID- 25019499 TI - Comparison of cytotoxicity in vitro and irritation in vivo for aqueous and oily solutions of surfactants. AB - The in vivo model on rabbit eyes and the in vitro cytotoxicity on fibroblasts were used to compare irritation effect of aqueous and oily (Miglyol 812) solutions of surfactants. Tween 20, Tween 80 and Cremophor EL were tested in different concentrations (0.1, 1 or 5%) and the in vitro test demonstrated that surfactants in oil are less cytotoxic than in aqueous solutions. In the in vivo study, the aqueous solutions of surfactants were characterized as non-irritant while small changes in conjunctiva were observed after application the oily solutions of surfactants and the preparations were classified as slightly irritant, however this effect was similar when Miglyol was applied alone. In conclusion, it is reported that the MTT assay does not correlate well with the Draize scores. PMID- 25019501 TI - Elastic liposomes-in-vehicle formulations destined for skin therapy: the synergy between type of liposomes and vehicle. AB - OBJECTIVE: The present study is focused on optimization of elastic liposomes-in vehicle formulations in respect to drug release and formulation properties. By combining penetration potential of elastic liposomes containing high ratio of entrapped drug and physicochemical properties of vehicles, both affecting the release and texture properties, optimal formulation could be achieved. MATERIALS AND METHODS: Deformable, propylene glycol-containing or conventional liposomes with hydrophilic model drug (diclofenac sodium) were incorporated into the following vehicles appropriate for skin application: a hydrogel, a cream base and derma membrane structure base cream (DMS base). Each formulation was assessed for in vitro drug release and mechanical properties. RESULTS AND DISCUSSION: The composition and type of both liposomes and the vehicle affected the rate and amount of the released drug. The cream base exhibited the slowest release, followed by the hydrogel and DMS base. Similar release profiles were achieved with both types of elastic vesicles (deformable and propylene glycol liposomes); the slowest release was observed for conventional liposomes, regardless of the vehicle used. The drug release profiles from different liposomes-in-vehicle formulations were in agreement with the physicochemical properties of the formulations. All of the liposomes were found to be compatible with the hydrogel preserving its original textures, whereas a significant decrease in all texture parameters was observed for liposomes-in-DMS base, regardless of liposome type. CONCLUSION: Propylene glycol liposomes-in-hydrogel is considered as the optimal formulation for improving skin delivery of hydrophilic drug. Further investigations involving in vivo animal studies are necessary to confirm its applicability in skin therapy. PMID- 25019500 TI - Solid self microemulsification of Atorvastatin using hydrophilic carriers: a design. AB - CONTEXT: Atorvastatin has a limited advantage to formulate oral dosage forms. OBJECTIVE: To enhance the solubility of Atorvastatin and to design the suitable solid self-microemulsifying drug delivery systems (S-SMEDDS) Materials and methods: The clear and transparent self-microemulsifying drug delivery system (SMEDDS) were formulated using coconut oil and isopropyl myristate as lipid phases; Tween 80 as surfactant; PEG 400 and glycerin as co-surfactant at 2:1, 3:1, 1:2 and 1:3 ratio. The pseudo ternary phase diagrams were constructed to identify the microemulsion region. The SMEDDS were evaluated for zeta potential, poly dispersity index, globule size, pH, viscosity and drug release. The solid SMEDDS were developed by employing adsorption and melt granulation methods. The S SMEDDS were evaluated for micromeritics, morphology, solid state property, reconstitution ability, drug release and stability. RESULTS: The micro formulations formed with particle size of 25 nm had shown a 3-folds rise in drug release. The solid SMEDDS had reconstituted to a good microemulsion rapidly in 1 3 min, with a release of 94.62% at the end of 30 min and behaved as immediate releasing capsules. Their shelf-life was found to be 1.3 years. DISCUSSION: The 1:3 ratio SMEDDS had shown more drug release owing to their less particle size. The solid SMEDDS had shown an increased dissolution profiles than atorvastatin. The solid state of the drug had changed in formulation inferring their enhanced solubility. CONCLUSION: The solid form of atorvastatin liquid SMEDDS had been formulated successfully with enhanced shelf life and solubility. PMID- 25019502 TI - Co-delivery of paclitaxel and alpha-tocopherol succinate by novel chitosan-based polymeric micelles for improving micellar stability and efficacious combination therapy. AB - The aim of this study was to develop chitosan derivative polymeric micelles for co-delivery of paclitaxel (PTX) and alpha-tocopherol succinate (alpha-TS) to the cancer cells to improve the therapeutic efficiency and reduce side effects of PTX. In this study, amphiphilic tocopheryl succinate-grafted chitosan oligosaccharide was synthesized and physically loaded by PTX and alpha-TS with entrapment efficiency of 67.9% and 73.2%, respectively. Physical incorporation of alpha-TS into the micelles increased the hydrophobic interaction between PTX and the micelles core, which improved micelle stability, reduced the micelle size and also sustained the PTX release from the micelles. The mean particle size and zeta potential of alphaTS/PTX-loaded micelles were about 133 nm and +25.2 mV, respectively, and PTX release was completed during 6-9 d from the micelles. Furthermore, the cytotoxicity of alpha-TS/PTX-loaded micelles against human ovarian cancer cell line cancer cell in vitro was higher than that of PTX-loaded micelles and the free drug solution. Half maximal inhibitory concentration values of PTX after 48-h exposure of the cells to the PTX-loaded micelles modified and unmodified with alpha-TS were 110 and 188 ng/ml, respectively. PMID- 25019503 TI - Influence of association state and DNA binding on the O2-reactivity of [4Fe-4S] fumarate and nitrate reduction (FNR) regulator. AB - The fumarate and nitrate reduction (FNR) regulator is the master switch for the transition between anaerobic and aerobic respiration in Escherichia coli. Reaction of dimeric [4Fe-4S] FNR with O2 results in conversion of the cluster into a [2Fe-2S] form, via a [3Fe-4S] intermediate, leading to the loss of DNA binding through dissociation of the dimer into monomers. In the present paper, we report studies of two previously identified variants of FNR, D154A and I151A, in which the form of the cluster is decoupled from the association state. In vivo studies of permanently dimeric D154A FNR show that DNA binding does not affect the rate of cluster incorporation into the apoprotein or the rate of O2-mediated cluster loss. In vitro studies show that O2-mediated cluster conversion for D154A and the permanent monomer I151A FNR is the same as in wild-type FNR, but with altered kinetics. Decoupling leads to an increase in the rate of the [3Fe-4S]1+ into [2Fe-2S]2+ conversion step, consistent with the suggestion that this step drives association state changes in the wild-type protein. We have also shown that DNA-bound FNR reacts more rapidly with O2 than FNR free in solution, implying that transcriptionally active FNR is the preferred target for reaction with O2. PMID- 25019504 TI - Graphene-enhanced infrared near-field microscopy. AB - Graphene is a promising two-dimensional platform for widespread nanophotonic applications. Recent theories have predicted that graphene can also enhance evanescent fields for subdiffraction-limited imaging. Here, for the first time we experimentally demonstrate that monolayer graphene offers a 7-fold enhancement of evanescent information, improving conventional infrared near-field microscopy to resolve buried structures at a 500 nm depth with lambda/11-resolution. PMID- 25019507 TI - Increased gut permeability and bacterial translocation after chronic chlorpyrifos exposure in rats. AB - The epithelium's barrier function is crucial for maintaining homeostasis and preventing the passage of food antigens and luminal bacteria. This function is essentially subserved by tight junctions (TJs), multiprotein complexes located in the most apical part of the lateral membrane. Some gastrointestinal disease states are associated with elevated intestinal permeability to macromolecules. In a study on rats, we determined the influence of chronic, daily ingestion of chlorpyrifos (CPF, a pesticide that crosses the placental barrier) during pre- and postnatal periods on intestinal permeability and TJ characteristics in the pups. Fluorescein isothiocyanate (FITC)-dextran was used as a marker of paracellular transport and mucosal barrier dysfunction. Pups were gavaged with FITC-dextran solution and blood samples were collected every 30 min for 400 min and analyzed spectrofluorimetrically. At sacrifice, different intestinal segments were resected and prepared for analysis of the transcripts (qPCR) and localization (using immunofluorescence) of ZO-1, occludin and claudins (scaffolding proteins that have a role in the constitution of TJs). In rats that had been exposed to CPF in utero and after birth, we observed a progressive increase in FITC-dextran passage across the epithelial barrier from 210 to 325 min at day 21 after birth (weaning) but not at day 60 (adulthood). At both ages, there were significant changes in intestinal TJ gene expression, with downregulation of ZO-1 and occludin and upregulation of claudins 1 and 4. In some intestinal segments, there were changes in the cellular localization of ZO-1 and claudin 4 immunostaining. Lastly, bacterial translocation to the spleen was also observed. The presence of CPF residues in food may disturb epithelial homeostasis in rats. Changes in TJ protein expression and localization may be involved in gut barrier dysfunction in this model. Uncontrolled passage of macromolecules and bacteria across the intestinal epithelium may be a risk factor for digestive inflammatory diseases. PMID- 25019508 TI - Efficient removal of formaldehyde by nanosized gold on well-defined CeO2 nanorods at room temperature. AB - Gold (Au) nanoparticles (NPs) supported on well-defined ceria (CeO2) nanorods with exposed {110} and {100} facets were prepared by a deposition-precipitation method and characterized by powder X-ray diffraction, micro-Raman spectroscopy, X ray photoelectron spectroscopy, nitrogen adsorption-desorption, transmission electron microscopy, high-resolution transmission electron microscopy, and high angle annular dark-field scanning transmission electron microscopy. Both nanometer and subnanometer gold particles were found to coexist on ceria supports with various Au contents (0.01-5.4 wt %). The catalytic performance of Au/CeO2 catalysts was examined for formaldehyde (HCHO) oxidation into CO2 and H2O at room temperature and shown to be Au content dependent, with 1.8 wt % Au/CeO2 displaying the best performance. On the basis of the results from hydrogen temperature-programmed reduction and in situ Fourier transform infrared spectroscopy observations, the high reactivity and stability of Au/CeO2 catalysts is mainly attributed to the well-defined ceria nanorods with {110} and {100} facets which present a relatively low energy for oxygen vacancy formation. Furthermore, gold NPs could induce the weakened Ce-O bond which in turn promotes HCHO oxidation. PMID- 25019509 TI - Design of surfactant-substrate interactions for roll-to-roll assembly of carbon nanotubes for thin-film transistors. AB - Controlled assembly of single-walled carbon nanotube (SWCNT) networks with high density and deposition rate is critical for many practical applications, including large-area electronics. In this regard, surfactant chemistry plays a critical role as it facilitates the substrate-nanotube interactions. Despite its importance, detailed understanding of the subject up until now has been lacking, especially toward tuning the controllability of SWCNT assembly for thin-film transistors. Here, we explore SWCNT assembly with steroid- and alkyl-based surfactants. While steroid-based surfactants yield highly dense nanotube thin films, alkyl surfactants are found to prohibit nanotube assembly. The latter is attributed to the formation of packed alkyl layers of residual surfactants on the substrate surface, which subsequently repel surfactant encapsulated SWCNTs. In addition, temperature is found to enhance the nanotube deposition rate and density. Using this knowledge, we demonstrate highly dense and rapid assembly with an effective SWCNT surface coverage of ~99% as characterized by capacitance voltage measurements. The scalability of the process is demonstrated through a roll-to-roll assembly of SWCNTs on plastic substrates for large-area thin-film transistors. The work presents an important process scheme for nanomanufacturing of SWCNT-based electronics. PMID- 25019505 TI - Prognostic value of miR-21 in various cancers: an updating meta-analysis. AB - BACKGROUND: Recently, more and more studies investigated the value of microRNA (miRNA) as a diagnostic or prognostic biomarker in various cancers. MiR-21 was found dysregulated in almost all types of cancers. While the prognostic role of miR-21 in many cancers has been studied, the results were not consistent. METHODS: We performed a meta-analysis to investigate the correlation between miR 21 and survival of general cancers by calculating pooled hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: The pooled results of 63 published studies showed that elevated miR-21 was a predictor for poor survival of general carcinomas, with pooled HR of 1.91 (95%CI: 1.66-2.19) for OS, 1.42 (95% CI: 1.16 1.74) for DFS and 2.2 (95% CI: 1.64-2.96) for RFS/CSS. MiR-21 was also a prognostic biomarker in the patients who received adjuvant therapy, with pooled HR of 2.4 (95%CI: 1.18-4.9) for OS. CONCLUSIONS: Our results showed that miR-21 could act as a significant biomarker in the prognosis of various cancers. Further studies are warranted before the application of the useful biomarker in the clinical. PMID- 25019510 TI - Bridging the Gap between Family-Based Treatment and Family-Based Research in Childhood Obesity. PMID- 25019511 TI - Visualization and analysis of hepatitis C virus structural proteins at lipid droplets by super-resolution microscopy. AB - Cytosolic lipid droplets are central organelles in the Hepatitis C Virus (HCV) life cycle. The viral capsid protein core localizes to lipid droplets and initiates the production of viral particles at lipid droplet-associated ER membranes. Core is thought to encapsidate newly synthesized viral RNA and, through interaction with the two envelope proteins E1 and E2, bud into the ER lumen. Here, we visualized the spatial distribution of HCV structural proteins core and E2 in vicinity of small lipid droplets by three-color 3D super resolution microscopy. We observed and analyzed small areas of colocalization between the two structural proteins in HCV-infected cells with a diameter of approximately 100 nm that might represent putative viral assembly sites. PMID- 25019512 TI - Changes in liver cell DNA methylation status in diabetic mice affect its FT-IR characteristics. AB - BACKGROUND: Lower levels of cytosine methylation have been found in the liver cell DNA from non-obese diabetic (NOD) mice under hyperglycemic conditions. Because the Fourier transform-infrared (FT-IR) profiles of dry DNA samples are differently affected by DNA base composition, single-stranded form and histone binding, it is expected that the methylation status in the DNA could also affect its FT-IR profile. METHODOLOGY/PRINCIPAL FINDINGS: The DNA FT-IR signatures obtained from the liver cell nuclei of hyperglycemic and normoglycemic NOD mice of the same age were compared. Dried DNA samples were examined in an IR microspectroscope equipped with an all-reflecting objective (ARO) and adequate software. CONCLUSIONS/SIGNIFICANCE: Changes in DNA cytosine methylation levels induced by hyperglycemia in mouse liver cells produced changes in the respective DNA FT-IR profiles, revealing modifications to the vibrational intensities and frequencies of several chemical markers, including nuas -CH3 stretching vibrations in the 5-methylcytosine methyl group. A smaller band area reflecting lower energy absorbed in the DNA was found in the hyperglycemic mice and assumed to be related to the lower levels of -CH3 groups. Other spectral differences were found at 1700-1500 cm(-1) and in the fingerprint region, and a slight change in the DNA conformation at the lower DNA methylation levels was suggested for the hyperglycemic mice. The changes that affect cytosine methylation levels certainly affect the DNA-protein interactions and, consequently, gene expression in liver cells from the hyperglycemic NOD mice. PMID- 25019513 TI - CRE promoter sites modulate alternative splicing via p300-mediated histone acetylation. AB - Histone acetylation modulates alternative splicing of several hundred genes. Here, we tested the role of the histone acetyltransferase p300 in alternative splicing and showed that knockdown of p300 promotes inclusion of the fibronectin (FN1) alternative EDB exon. p300 associates with CRE sites in the promoter via the CREB transcription factor. We created mini-gene reporters driven by an artificial promoter containing CRE sites. Both deletion and mutation of the CRE site affected EDB alternative splicing in the same manner as p300 knockdown. Next we showed that p300 controls histone H4 acetylation along the FN1 gene. Consistently, p300 depletion and CRE deletion/mutation both reduced histone H4 acetylation on mini-gene reporters. Finally, we provide evidence that the effect of CRE inactivation on H4 acetylation and alternative splicing is counteracted by the inhibition of histone deacetylases. Together, these data suggest that histone acetylation could be one of the mechanisms how promoter and promoter binding proteins influence alternative splicing. PMID- 25019514 TI - Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity. AB - Oxidative stress is generated by reactive oxygen species (ROS) produced in response to metabolic activity and environmental factors. Increased oxidative stress is associated with the pathophysiology of a broad spectrum of inflammatory diseases. Cellular response to excess ROS involves the induction of antioxidant response element (ARE) genes under control of the transcriptional activator Nrf2 and the transcriptional repressor Bach1. The development of synthetic small molecules that activate the protective anti-oxidant response network is of major therapeutic interest. Traditional small molecules targeting ARE-regulated gene activation (e.g., bardoxolone, dimethyl fumarate) function by alkylating numerous proteins including Keap1, the controlling protein of Nrf2. An alternative is to target the repressor Bach1. Bach1 has an endogenous ligand, heme, that inhibits Bach1 binding to ARE, thus allowing Nrf2-mediated gene expression including that of heme-oxygenase-1 (HMOX1), a well described target of Bach1 repression. In this report, normal human lung fibroblasts were used to screen a collection of synthetic small molecules for their ability to induce HMOX1. A class of HMOX1 inducing compounds, represented by HPP-4382, was discovered. These compounds are not reactive electrophiles, are not suppressed by N-acetyl cysteine, and do not perturb either ROS or cellular glutathione. Using RNAi, we further demonstrate that HPP-4382 induces HMOX1 in an Nrf2-dependent manner. Chromatin immunoprecipitation verified that HPP-4382 treatment of NHLF cells reciprocally coordinated a decrease in binding of Bach1 and an increase of Nrf2 binding to the HMOX1 E2 enhancer. Finally we show that HPP-4382 can inhibit Bach1 activity in a reporter assay that measures transcription driven by the human HMOX1 E2 enhancer. Our results suggest that HPP-4382 is a novel activator of the antioxidant response through the modulation of Bach1 binding to the ARE binding site of target genes. PMID- 25019515 TI - Role of global and local topology in the regulation of gene expression in Streptococcus pneumoniae. AB - The most basic level of transcription regulation in Streptococcus pneumoniae is the organization of its chromosome in topological domains. In response to drugs that caused DNA-relaxation, a global transcriptional response was observed. Several chromosomal domains were identified based on the transcriptional response of their genes: up-regulated (U), down-regulated (D), non-regulated (N), and flanking (F). We show that these distinct domains have different expression and conservation characteristics. Microarray fluorescence units under non-relaxation conditions were used as a measure of gene transcriptional level. Fluorescence units were significantly lower in F genes than in the other domains with a similar AT content. The transcriptional level of the domains categorized them was D>U>F. In addition, a comparison of 12 S. pneumoniae genome sequences showed a conservation of gene composition within U and D domains, and an extensive gene interchange in F domains. We tested the organization of chromosomal domains by measuring the relaxation-mediated transcription of eight insertions of a heterologous Ptccat cassette, two in each type of domain, showing that transcription depended on their chromosomal location. Moreover, transcription from the four promoters directing the five genes involved in supercoiling homeostasis, located either in U (gyrB), D (topA), or N (gyrA and parEC) domains was analyzed both in their chromosomal locations and in a replicating plasmid. Although expression from the chromosomal PgyrB and PtopA showed the expected domain regulation, their expression was down-regulated in the plasmid, which behaved as a D domain. However, both PparE and PgyrA carried their own regulatory signals, their topology-dependent expression being equivalent in the plasmid or in the chromosome. In PgyrA a DNA bend acted as a DNA supercoiling sensor. These results revealed that DNA topology functions as a general transcriptional regulator, superimposed upon other more specific regulatory mechanisms. PMID- 25019517 TI - Electrospray ionization-tandem mass spectrometry analysis of phospholipid molecular species from Antarctic and non-Antarctic yeasts. AB - High performance liquid chromatography-electrospray ionization tandem mass spectrometry was applied to the comprehensive analysis of phospholipids from seven Antarctic and seven non-Antarctic yeasts. Identification of specific fatty acyl moieties to the sn-1 and sn-2 positions of phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylinositol (PI) were determined by relative abundance of fragment ions associated with formation of carboxylate anions and loss of fragment ions as free fatty carboxylic acid and ketene. Modulations with growth temperature in fatty acyl moieties in the sn-1 and sn-2 positions were characterized. Principal component analysis demonstrated that PE, PC and to a lesser extent PS, but not PI, were grouped into three distinct clusters consisting of seven Antarctic yeasts (Cryptococcus victoriae, Holtermanniella wattica, H. nyarrowii, Candida psychrophila, Leucosporidium fellii, Glaciozyma antarctica, Rhodotorula mucilaginosa), four non-Antarctic yeasts (C. albicans, Zygosaccharomyces rouxii, Cr. humicolus, R. mucilaginosa) and three strains of Saccharomyces cerevisiae. PMID- 25019516 TI - Surface roughness mediated adhesion forces between borosilicate glass and gram positive bacteria. AB - It is well-known that a number of surface characteristics affect the extent of adhesion between two adjacent materials. One of such parameters is the surface roughness as surface asperities at the nanoscale level govern the overall adhesive forces. For example, the extent of bacterial adhesion is determined by the surface topography; also, once a bacteria colonizes a surface, proliferation of that species will take place and a biofilm may form, increasing the resistance of bacterial cells to removal. In this study, borosilicate glass was employed with varying surface roughness and coated with bovine serum albumin (BSA) in order to replicate the protein layer that covers orthopedic devices on implantation. As roughness is a scale-dependent process, relevant scan areas were analyzed using atomic force microscope (AFM) to determine Ra; furthermore, appropriate bacterial species were attached to the tip to measure the adhesion forces between cells and substrates. The bacterial species chosen (Staphylococci and Streptococci) are common pathogens associated with a number of implant related infections that are detrimental to the biomedical devices and patients. Correlation between adhesion forces and surface roughness (Ra) was generally better when the surface roughness was measured through scanned areas with size (2 * 2 MUm) comparable to bacteria cells. Furthermore, the BSA coating altered the surface roughness without correlation with the initial values of such parameter; therefore, better correlations were found between adhesion forces and BSA-coated surfaces when actual surface roughness was used instead of the initial (nominal) values. It was also found that BSA induced a more hydrophilic and electron donor characteristic to the surfaces; in agreement with increasing adhesion forces of hydrophilic bacteria (as determined through microbial adhesion to solvents test) on BSA-coated substrates. PMID- 25019518 TI - Semi-automated protocol for purification of Mycobacterium leprae from tissues using the gentleMACSTM Octo Dissociator. AB - Mycobacterium leprae, etiologic agent of leprosy, is propagated in athymic nude mouse footpads (FPs). The current purification protocol is tedious and physically demanding. A simpler, semi-automated protocol was developed using gentleMACSTM Octo Dissociator. The gentleMACS protocol provided a very effective means for purification of highly viable M. leprae from tissue. PMID- 25019519 TI - Effects of broth composition and light condition on antimicrobial susceptibility testing of ionic silver. AB - In this study, the minimum inhibitory concentrations (MICs) of AgNO3 against bacteria were investigated in a variety of microorganism culture broths. Broth- and light-dependent MIC values were observed and correlated negatively with nano Ag speciation development. We advocate here the importance of broth and light standardization in Ag antimicrobial test. PMID- 25019520 TI - A quick and accurate screening method for fungal gene-deletion mutants by direct, priority-based, and inverse PCRs. AB - Using two-step-PCR screening which consists of direct and priority-based PCR and inverse PCR, fungal gene-deletion mutants were selected quickly and accurately. It omits genomic DNA extraction and Southern blotting steps and prevents misinterpretations caused by PCR failure. It is anticipated to facilitate large scale reverse genetic studies in fungi. PMID- 25019521 TI - A new chemically defined medium for the growth and sporulation of Bacillus cereus strains in anaerobiosis. AB - A new chemically defined liquid medium, MODS, was developed for the aerobic growth and anaerobic growth and sporulation of Bacillus cereus strains. The comparison of sporulation capacity of 18 strains of B. cereus has shown effective growth and spore production in anaerobiosis.. PMID- 25019522 TI - Hydrogel nanomembranes as templates for patterned deposition of nanoparticles on arbitrary substrates. AB - Patterns of nanoparticles (NPs) on solid supports are usually restricted to a particular substrate or a class of substrates. Here we present a procedure that decouples the patterning step from the target substrate, enabling the fabrication of custom designed NP assemblies on nearly any solid support, including nonflat ones. The procedure relies on a hydrogel template prepared on the primary, conductive substrate and transferred to the target support as a sacrificial nanomembrane. The template is structured by electron beam lithography (EBL) which seals predefined areas of poly(ethylene glycol) based hydrogel film, making them inert to NP deposition in contrast to pristine areas that adsorb NPs in high densities. The deposition of NPs, occurring from an aqueous solution into the transferred membrane, follows EBL generated structure, delivering the desired NP pattern on the target support after removal of the organic matrix. Efficiency and flexibility of the procedure is illustrated by creating a variety of representative submicrometer patterns of densely packed gold and silver NPs on glass, including a useful pattern of a miniaturized quick-response code. The arrangement of NPs in these patterns corresponds to the negative image of EBL generated template. This significantly reduces the exposure time for designs where large areas covered with NPs are separated by thin, NP-free stripes. PMID- 25019523 TI - Continuous infusions of meropenem in ambulatory care: clinical efficacy, safety and stability. AB - OBJECTIVES: Concerns regarding the clinical impact of meropenem instability in continuous infusion (CI) devices may contribute to inconsistent uptake of this method of administration across outpatient parenteral antimicrobial therapy (OPAT) services. METHODS: We retrospectively reviewed the clinical efficacy and safety of CIs of meropenem in two Australian tertiary hospitals and assessed its stability under simulated OPAT conditions including in elastomeric infusion devices containing 1% (2.4 g) or 2% (4.8 g) concentrations at either 'room temperature' or 'cooled' conditions. Infusate aliquots were assayed at different time-points over 24 hours. RESULTS: Forty-one (82%) of 50 patients had clinical improvement or were cured. Adverse patient outcomes including hemato-, hepato- and nephrotoxicity were infrequent. Cooled infusers with 1% meropenem had a mean 24-hour recovery of 90.3%. Recoveries of 1% and 2% meropenem at room temperature and 2% under cooled conditions were 88%, 83% and 87%, respectively. Patients receiving 1% meropenem are likely to receive >95% of the maximum deliverable dose (MDD) over a 24-hour period whilst patients receiving 2% meropenem should receive 93% and 87% of the MDD under cooled and room temperature conditions, respectively. CONCLUSIONS: Meropenem infusers are likely to deliver ~95% MDD and maintain effective plasma concentrations throughout the dosing period. These data reflect our local favourable clinical experience with meropenem CIs. PMID- 25019524 TI - Late-Onset Cytomegalovirus Gastritis in Low-Risk Renal Allograft Recipients. AB - OBJECTIVES: Skin grafting has been evolving as an important application in reconstructive surgery. Mixed reports about the survival of allogeneic and xenogeneic keratinocytes require further substantiation to determine the role of these cells in wound healing. MATERIALS AND METHODS: Rabbit and rat skins were recovered and cultured in vitro. Full-thickness wounds were created on the dorsum of rabbits (2 cm * 2 cm; n = 4). Cultured epithelial autograft, allograft, and xenograft cells were sprayed onto 3 freshly created wounds, with 1 wound acting as a control. The wounds were monitored every 2 days for 4 weeks. After 4 weeks, the rabbits were killed; skin biopsies were taken from each healed wound and stained with hematoxylin and eosin, and epidermal thickness was measured. RESULTS: All examined grafts showed favorable healing outcomes because the wounds appeared similar to normal skin upon healing. The only observed significant difference was the thickness of the epidermis layer, which was thinner in the xenograft (P = .002) than the autograft or allograft. Morphologic evaluation of the skin surface showed that the rat skin was thinner than the rabbit skin. The graft that achieved the best result was the autograft because the thickness was similar to and mimicked normal skin. CONCLUSIONS: All 3 grafts (autograft, allograft, and xenograft) have the potential to reconstitute epithelial defects. This approach can overcome the limitation of autologous skin donor sites, especially in burn cases. PMID- 25019526 TI - Congruency sequence effects without feature integration or contingency learning confounds. AB - The congruency effect in distracter interference (e.g., Stroop) tasks is often reduced after incongruent trials, relative to congruent trials. It has been proposed that this congruency sequence effect (CSE) results from trial-by-trial adjustments of attention, which are triggered by changes in response conflict, expectancy, or negative affect. Hence, a large literature has developed to investigate the source(s) of attention adaptation in distracter interference tasks. Recent work, however, suggests that CSEs may stem from feature integration and/or contingency learning processes that are confounded with congruency sequence in the vast majority of distracter interference tasks. By combining an established method for measuring CSEs in the absence of these learning and memory confounds with a prime-probe task, we observed robust CSEs in two experiments. These findings provide strong evidence of CSEs independent of learning and memory confounds, which might be explainable by trial-by-trial adjustments of attention. They also reveal a highly effective approach for observing CSEs independent of the typical confounds, which will facilitate future studies of how people adapt to distraction. PMID- 25019525 TI - Davis-Beirut reaction: route to thiazolo-, thiazino-, and thiazepino-2H indazoles. AB - Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitrobenzaldehydes or o-nitrobenzyl bromides and S-trityl-protected 1 degrees -aminothioalkanes are reported. The process consists of formation of the requisite N-(2-nitrobenzyl)(tritylthio)alkylamine, subsequent deprotection of the trityl moiety with TFA, and immediate treatment with aq. KOH in methanol under Davis-Beirut reaction conditions to deliver the target thiazolo-, thiazino-, or thiazepino-2H-indazole in good overall yield. Subsequent S-oxidation gives the corresponding sulfone. PMID- 25019527 TI - Liquid oil that flows in spaces of aqueous foam without defoaming. AB - A very interesting phenomenon has been observed in which foam formed from an aqueous fatty acid potassium salt solution spontaneously absorbs liquid oil immediately upon contact without defoaming. Although this phenomenon initially appeared to be based on capillary action, it was clarified that the liquid oil that flows in foam film did not wet the air/water interface. In this study, it is discussed why aqueous foam can spontaneously soak up liquid oil without defoaming using equilibrium surface tension, dynamic oil/water interfacial tension, and image analysis techniques. The penetration of oil was attributed both to the dynamic decrease in the surface tension at the oil/water interface and to Laplace pressure, depending on the curvature of the plateau border. Therefore, the foam does not absorb the oil, but the oil spontaneously penetrates the foam. This interesting behavior can be expected to be applied to aqueous detergents for liquid oil removal. PMID- 25019528 TI - Lack of association of body composition and functionality variables with metabolic syndrome in the elderly. AB - BACKGROUND: The aging process causes alterations in body composition (decrease in lean mass and increase in fat mass), diminution of functionality (strength, mobility, and physical performance), and an increased prevalence of chronic diseases such as metabolic syndrome and obesity. The aim of this study was to investigate the association of body composition and functionality with metabolic syndrome in the elderly. METHODS: A cross-sectional study was conducted in the Outpatient Clinic of the Geriatric Service of Hospital Sao Lucas of Pontifical Catholic University of Rio Grande do Sul (PUCRS) involving 74 patients (14 males and 60 females). The patients were separated into two groups: Group 1=elderly with metabolic syndrome [through the National Cholesterol Education Program Adult Treatment Panel III (NECP ATP III) criteria; n=34], group 2=elderly without metabolic syndrome (n=40). The variables evaluated included age, gender, body composition (circumferences, skinfold thickness, BMI, muscle and fat thickness and muscle mass), functional variables [hand grip strength, Timed Up and Go Test (TUGT), and Sit-to-Stand Test]. RESULTS: The results showed that elderly individuals with metabolic syndrome had a higher mean of the anthropometric measures (except abdominal skinfold thickness) compared to subjects without metabolic syndrome (P<0.005). We observed significant differences for muscle mass index (higher, P=0.029), TUGT (longer time, P=0.008), and hand grip strength (lower, P=0.015) in elderly with metabolic syndrome compared with subjects without metabolic syndrome. However, when these variables were adjusted for gender, age, and body mass index (BMI), none showed a significant association with metabolic syndrome. CONCLUSION: We did not observe associations among metabolic syndrome, body composition, and functionality variables. PMID- 25019529 TI - Retrosynthetic approach to the design of molybdenum-magnesium oxoalkoxides. AB - The reaction of MoCl5 methanolysis in the presence of magnesium ions was shown to produce an extensive row of heterobimetallic Mg-Mo(V, VI) oxomethoxides of different nuclearity ranging from 4 for [Mg2(CH3OH)4Mo2O2(OCH3)10] (1) to 26 for [Mg(DMF)3(CH3OH)3]2[Mo22Mg4O48(OCH3)28(DMF)6] (2) with the latter possessing a ring morphology. Examination of [Mo6O12(OCH3)16Mg4(CH3OH)6] (3), [Mo6O12(OCH3)12Mg2(DMF)4] (4a), and [Mo6O16(OCH3)4Mg2(DMF)8] (5a) X-ray structures revealed the presence of the well known tetranuclear core {Mo4O8(OCH3)2}(2+) thus similar reactivity patterns leading to their formation were assumed. For convenient synthesis of such heterobimetallic oxoalkoxides, the retrosynthetic approach based on speculative deconstruction of a target molecule onto simpler fragments was suggested and successfully employed. Namely, the reaction of the stoichiometric amounts of appropriately chosen Mo(V), Mo(VI) and Mg(2+) synthons led to their assembling resulting in the formation of heterometallic clusters 3, 5a and [Mo6O12(OCH3)12Mg2(CH3OH)4].2CH3OH (4b) characterized by means of elemental analysis, UV-Vis, IR spectroscopy, and X-ray crystallography. PMID- 25019530 TI - Systematic comparison of sets of (13)C NMR spectra that are potentially identical. Confirmation of the configuration of a cuticular hydrocarbon from the cane beetle Antitrogus parvulus. AB - A systematic process is introduced to compare (13)C NMR spectra of two (or more) candidate samples of known structure to a natural product sample of unknown structure. The process is designed for the case where the spectra involved can reasonably be expected to be very similar, perhaps even identical. It is first validated by using published (13)C NMR data sets for the natural product 4,6,8,10,16,18-hexamethyldocosane. Then the stereoselective total syntheses of two candidate isomers of the related 4,6,8,10,16-pentamethyldocosane natural product are described, and the process is applied to confidently assign the configuration of the natural product as (4S,6R,8R,10S,16S). This is accomplished even though the chemical shift differences between this isomer and its (16R) epimer are only +/-5-10 ppb (+/-0.005-0.01 ppm). PMID- 25019532 TI - Nondestructive characterization of the structural quality and thickness of large area graphene on various substrates. AB - We demonstrate an inspection technique, based on only one ellipsometric parameter, Psi, of spectroscopic ellipsometry (SE), for the rapid, simultaneous identification of both the structural quality and thicknesses of large-area graphene films. The measured Psi spectra are strongly affected by changes in the out-of-plane absorption coefficients (alphaTM); they are also correlated to the ratio of the intensities of the D and G bands in Raman spectra of graphene films. In addition, the electronic transition state of graphene within the UV regime assists the characterization of the structural quality. We also demonstrated that the intensities and shifts of the signals in Psi spectra allow clear identification of the structural qualities and thicknesses, respectively, of graphene films. Moreover, this Psi-based method can be further applied to graphene films coated on various substrates. In addition, mapping of the values of Psi is a very convenient and useful means of rapidly characterizing both the structural quality and thickness of 2D materials at local areas. Therefore, this Psi-based characterization method has great potential for application in the mass production of devices based on large-area graphene. PMID- 25019531 TI - Epistatic interaction of ERAP1 and HLA-B in Behcet disease: a replication study in the Spanish population. AB - Behcet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population. PMID- 25019533 TI - Four flavonoid compounds from Phyllostachys edulis leaf extract retard the digestion of starch and its working mechanisms. AB - Bamboo leaf extract as a food additive has been used for preventing the oxidation of food. In the present study, we investigated the influence of Phyllostachys edulis leaf extract on starch digestion. Orientin, isoorientin, vitexin, and isovitexin were determined as its alpha-amylase inhibitory constituents. An inhibitory kinetics experiment demonstrated that they competitively inhibit alpha amylase with Ki values of respectively 152.6, 11.5, 569.6, and 75.8 MUg/mL. Molecular docking showed the four flavones can interact with the active site of alpha-amylase, and their inhibitory activity was greatly influenced by the glucoside linking position and 3'-hydroxyl. Moreover, the results of starch iodine complex spectroscopy, X-ray diffraction, and scanning electron microscopy indicated that P. edulis flavonoids retard the digestion of starch not only through interaction with digestive enzymes, but also through interaction with starch. Thus, P. edulis leaf extract can be potentially used as a starch-based food additive for adjusting postprandial hyperglycemia. PMID- 25019534 TI - Black phosphorus-monolayer MoS2 van der Waals heterojunction p-n diode. AB - Phosphorene, a elemental 2D material, which is the monolayer of black phosphorus, has been mechanically exfoliated recently. In its bulk form, black phosphorus shows high carrier mobility (~10,000 cm(2)/V.s) and a ~0.3 eV direct band gap. Well-behaved p-type field-effect transistors with mobilities of up to 1000 cm(2)/V.s, as well as phototransistors, have been demonstrated on few-layer black phosphorus, showing its promise for electronics and optoelectronics applications due to its high hole mobility and thickness-dependent direct band gap. However, p n junctions, the basic building blocks of modern electronic and optoelectronic devices, have not yet been realized based on black phosphorus. In this paper, we demonstrate a gate-tunable p-n diode based on a p-type black phosphorus/n-type monolayer MoS2 van der Waals p-n heterojunction. Upon illumination, these ultrathin p-n diodes show a maximum photodetection responsivity of 418 mA/W at the wavelength of 633 nm and photovoltaic energy conversion with an external quantum efficiency of 0.3%. These p-n diodes show promise for broad-band photodetection and solar energy harvesting. PMID- 25019535 TI - Orienting patient to affect, sense of self, and the activation of affect over the course of psychotherapy with cluster C patients. AB - This article investigates whether patients' sense of self and therapists' interventions aimed at orienting patients toward affect produce an affective activation in the patient. Both the independent contribution of sense of self and therapist intervention, as well as sense of self's moderating effect on therapist interventions, were investigated. Fifty cluster C patients were analyzed using 2 psychotherapy process measures and multilevel modeling. The results indicate that patients' affect experience increases over time. Both the therapist orienting the patient toward affect and the patient's sense of self predicted affect activation for the within-person effect (i.e., the patient's or therapist's standing in any given session relative to his or her baseline), but only sense of self was significant for the between-person effect (i.e., the patient's standing relative to all other patients). The relationship between a therapist orienting the patient toward affect and the patient's affective response was moderated by the patient's sense of self. The results have implications for therapists who want their patients to experience affect in a session. PMID- 25019536 TI - Is it the unexpected experience that keeps them coming back? Group climate and session attendance examined between groups, between members, and between sessions. AB - Attending group therapy sessions is necessary for a group member to have a chance at receiving benefit from the intervention. Group members' perceptions of their group's climate has been linked with important group member outcomes, including session attendance. On the basis of the writings of Curran and Bauer (2011), the current study examined group members' longitudinal ratings of session engagement and decomposed them into between-groups, between-members, and between-sessions components. These components were then used to examine the relationship between group members' ratings of an engaged group climate in the previous session and their attendance the following session. Session attendance in 573 group sessions for 91 group members in 14 Taiwanese counseling groups was modeled in a 3-level hierarchical model (sessions within group members, within groups). Contrary to our hypotheses, between-groups, between-members, and between-sessions components of engagement were not related to session attendance. However, there was a significant interaction between the between-members and between-sessions components of session engagement and group size in predicting session attendance. The likelihood of attendance increased when group members who, on average, rated sessions as being low in engagement uncharacteristically rated a previous session as high in engagement. The likelihood of attendance also increased when group members who, on average, rated sessions as high in engagement uncharacteristically rated the previous session as low in engagement. Larger group sizes amplified these effects. Expectancy (dis)confirmation theory is used to explain these results. Theoretical, research, and clinical implications are discussed. PMID- 25019537 TI - Whose perceptions matter more: mine or my group's? An actor-partner interdependence analysis disaggregating between-person and between-session effects of group climate perceptions on intimate behaviors. AB - Group climate refers to the atmosphere that is both created and experienced by a group of people. Theoretically, the "climate" of a group should therefore be related to the behaviors of its members during group sessions; however, this has not been empirically tested. A longitudinal design was used to examine the relationship between group member perceptions of engagement and conflict and group member intimate behaviors during the group session. Data came from 73 incarcerated women participating in 6 manualized (Trauma Recovery and Empowerment Model) therapy groups. At each session, group members completed measures of their perceptions of the group's engagement and conflict (the Group Climate Questionnaire), and the group leader completed a behavioral count of each member's intimate behaviors. Group climate was examined both for the group member (actor) and aggregated across the other group members, excluding the actor (partner). In addition, these actor and partner scores were decomposed into between-member and within-member components. None of the between-member differences in engaged or conflict perceptions were significantly related to intimate behaviors. There was a significant positive relationship between actor's and partner's engagement ratings and partner's conflict ratings in a session and the actor's intimate behaviors in that session. Study results highlight the importance of examining changes that may be occurring from session to session in group climate perceptions and the need to examine partner's perceptions in order to best understand how an individual group member will behave. PMID- 25019538 TI - AAPI college students' willingness to seek counseling: the role of culture, stigma, and attitudes. AB - This study tested 4 theoretically and empirically derived structural equation models of Asian, Asian American, and Pacific Islanders' willingness to seek counseling with a sample of 278 college students. The models represented competing hypotheses regarding the manner in which Asian cultural values, European American cultural values, public stigma, stigma by close others, self stigma, and attitudes toward seeking professional help related to willingness to seek counseling. We found that Asian and European American cultural values differentially related to willingness to seek counseling indirectly through specific indirect pathways (public stigma, stigma by close others, self-stigma, and attitudes toward seeking professional help). Our results also showed that the magnitude of model-implied relationships did not vary as a function of generational status. Study limitations, future directions for research, and implications for counseling are discussed. PMID- 25019540 TI - Self-critical perfectionism and binge eating symptoms: a longitudinal test of the intervening role of psychological need frustration. AB - Although abundant research has shown that self-critical perfectionism relates to binge eating symptoms, fewer studies have addressed the role of intervening processes that might explain why this is the case. Grounded in self-determination theory, we hypothesized that self-critical perfectionism would relate to an increased risk for binge eating symptoms because it engenders frustration of the psychological needs for autonomy, competence, and relatedness. This hypothesis was tested in a sample of 566 adolescents (72% female; mean age = 13.3 years) using a 3-wave longitudinal study with a 6-month interval. Structural equation modeling analyses showed that self-critical perfectionism related to increases in psychological need frustration which, in turn, predicted increases in binge eating symptoms. Structural relations were found to be equivalent for males and females. Theoretical and clinical implications of these findings are discussed. PMID- 25019539 TI - Social resources mediate the relations between attachment dimensions and distress following potentially traumatic events. AB - Insecure adult attachment dimensions are consistently related to poorer posttrauma adjustment, but these relations have rarely been examined prospectively or across a wide range of potentially traumatic events. In addition, the factors mediating these relations are not yet fully understood. Therefore, the first aim of this study was to assess whether anxious and avoidant attachment dimensions assessed preevent would predict changes in adjustment (e.g., distress) following a broad range of potentially traumatic events. The second aim was to determine whether postevent social resources mediated the relations between attachment dimensions and postevent adjustment. Undergraduate students (N = 1,084) completed preevent measures of attachment dimensions and psychological distress at Time 1 (T1); 73% (n = 789) completed a follow-up survey 2 months later assessing exposure to potentially traumatic events and social resources (Time 2; T2). Those who reported experiencing a potentially traumatic event between T1 and T2 and who completed a final follow-up survey assessing distress 2 months after T2 (Time 3) constituted the sample for the present analyses (n = 174). Individuals with more attachment avoidance and anxiety had greater increases in posttraumatic stress disorder symptoms and general psychological distress. These relations were mediated by social resources (i.e., positive and negative support, social withdrawal) at T2 such that anxious and avoidant attachment dimensions were associated with having fewer social resources following a potentially traumatic event, which in turn was associated with reporting more distress. Implications for research and practice with individuals exposed to potentially traumatic events are discussed. PMID- 25019542 TI - Stigma-related stressors, coping self-efficacy, and physical health in lesbian, gay, and bisexual individuals. AB - Understanding and intervening to address health disparities is part of the expanding role of psychologists (Johnson, 2013). We drew on Hatzenbuehler's (2009) psychological mediation framework and Lick, Durso, and Johnson's (2013) conceptual pathways to lesbian, gay, and bisexual (LGB) physical health disparities to test a serial mediation model in which 2 types of cognitive appraisals (proximal minority stressors and coping self-efficacy) partially account for the association between perceived discrimination and prejudice (distal minority stressor) and self-reported physical health symptoms in a nationally recruited sample of 564 LGB individuals (270 women, 294 men) who participated in a web-based survey. Results indicated that perceived experiences of discrimination and prejudice were associated with expectations of rejection and internalized homonegativity. These 2 proximal stressors were associated with lower coping self-efficacy, and the combined cognitive appraisal pathways were associated with higher levels of self-reported physical symptom severity. The pathway through emotion-focused coping self-efficacy was particularly salient in accounting for the overall mediation. Interventions to address distal and proximal minority stressors and improve emotion-focused coping self-efficacy may be particularly helpful in reducing the negative effects of stigma on physical health. PMID- 25019541 TI - Emotional awareness as a pathway linking adult attachment to subsequent depression. AB - Although research links insecure adult attachment with depression, the emotional processes accounting for this association over time remain relatively unexplored. To address this gap, this study investigated whether deficits in emotional awareness serve as one explanatory process. Adult female caregivers (N = 417, Mage = 37.83) completed questionnaires annually for 3 years. As anticipated, attachment avoidance exerted an indirect effect on depression via emotional awareness. Attachment anxiety directly predicted subsequent depression, but the indirect effect through emotional awareness was nonsignificant. These results suggest that an avoidant attachment style interferes with the effective processing of emotions, thereby placing women at risk for depression. This research implicates emotional awareness as a potential target for interventions aimed at reducing depressive symptoms in mothers with avoidant attachment styles. PMID- 25019543 TI - Trauma, posttraumatic stress disorder, and depression among sexual minority and heterosexual women veterans. AB - This study examined the impact of various traumas across the life span on screening positive for current posttraumatic stress disorder (PTSD) and depression among heterosexual and sexual minority women veterans. Women veterans were recruited over the Internet (N = 706, 37% lesbian or bisexual) to participate in an anonymous, online survey. We assessed childhood trauma; adult sexual assault and adult physical victimization before, during, and after the military; combat exposure; perceived sexist discrimination during military service; sexual minority military stressors; past-year sexist events; and whether participants screened positive for PTSD or depression. Binary logistic regressions were used to generate odds ratios and 95% confidence intervals for PTSD and depression, stratified by sexual orientation and controlling for demographic characteristics. Lesbian and bisexual women reported higher rates of trauma across the life span, although in some instances (e.g., sexual assault during and after military service, combat exposure), they did not differ from their heterosexual counterparts. Childhood trauma and traumas that occurred during military service added the most variance to both PTSD and depression models. Sexual assault during military service appeared to be especially harmful with respect to screening positive for PTSD for both sexual orientation groups. Results revealed a number of other predictors of mental health status for women veterans, some of which differed by sexual orientation. Findings indicate a significant burden of interpersonal trauma for both heterosexual and lesbian/bisexual women veterans and provide information on the distinct association of various traumas with current PTSD and depression by sexual orientation. PMID- 25019544 TI - Coping with discrimination among Mexican American college students. AB - There is limited research directly examining the process of how Mexican American college students cope with unique experiences of racial discrimination. The present study used a multiple mediation model to collectively examine the indirect effects of engagement (i.e., problem solving, cognitive restructuring, expression of emotion, and social support) and disengagement (i.e., social withdrawal, self-criticism, problem avoidance, and wishful thinking) coping strategies on the relationship between perceived racial discrimination and subjective well-being of 302 Mexican American college students. Results suggested that perceived racial discrimination was negatively correlated with subjective well-being. Moreover, of the engagement coping strategies examined, only problem solving had a significant mediating effect that was associated with elevations in subjective well-being. Specifically, perceptions of racial discrimination were positively related to problem solving, which, in turn, was positively related to subjective well-being. Of the disengagement coping strategies examined, self criticism, wishful thinking, and social withdrawal had a significant mediating effect that was negatively associated with subjective well-being. Specifically, perceptions of racial discrimination were positively related to self-criticism, wishful thinking, and social withdrawal, which, in turn, were negatively related to subjective well-being. Ultimately, these findings highlight the indirect and complex ways in which multiple coping strategies are used to effectively, and sometimes not effectively, deal with racism experienced by Mexican Americans college students. PMID- 25019545 TI - Dimensions of belonging as an aspect of racial-ethnic-cultural identity: an exploration of indigenous Australians. AB - Sense of belonging is a key aspect of racial and ethnic identity. Interestingly, there is little exploration of the multiple characteristics of belongingness within the racial and ethnic identity literature. Through individual interviews and a focus group, we explored the sense of racial-ethnic-cultural (REC) belonging among 19 self-identified Black Indigenous Australians (Aborigines and Torres Strait Islanders). Using dimensional analysis, we uncovered 5 core interrelated dimensions of REC belonging: History/Memory, Place, and Peoplehood; Sense of Community; Acceptance and Pride; Shared Language and Culture; and Interconnections. We also uncovered 3 main barriers undermining participants' sense of REC belonging: phenotype, social identity, and history of colonization. PMID- 25019546 TI - Bicultural competence, acculturative family distancing, and future depression in Latino/a college students: a moderated mediation model. AB - In his acculturative family distancing (AFD) theory, Hwang (2006b) argued that acculturation gaps among parents and youth may lead to psychological and emotional distancing. AFD includes 2 dimensions: incongruent cultural values and breakdowns in communication. This study examined whether bicultural competence (BC) served as a mediator and moderator for the relationship between AFD and depression using structural equation modeling. Two hundred and forty-one Latino/a college students attending predominantly White, midwestern universities completed an online survey at 2 time points. For mediation, results indicated that BC at Time 2 (T2) mediated the relationship between AFD at Time 1 (T1) and depression at T2 above and beyond the effects of depression, acculturation, and enculturation at T1. A bootstrap method estimated the significance of the indirect effect. Moreover, 16% of the variance in BC at T2 was explained by acculturation, enculturation, and AFD at T1; 30% of the variance in depression at T2 was explained by BC at T2 and depression at T1. Post hoc analyses of the AFD and BC dimensions suggested that (a) positive attitudes toward both groups, communication ability, and social groundedness were significant mediators for the incongruent cultural values-depression link and (b) communication ability and social groundedness were significant mediators for the communication breakdown depression link. For moderation, the AFD * BC interaction did not significantly predict depression at T2. Limitations, future research directions, and counseling implications are discussed. PMID- 25019547 TI - Well-being of Taiwanese and Singaporean college students: cross-cultural validity of a modified social cognitive model. AB - This study tested the cross-cultural validity of a modified version of Lent's (2004) normative well-being model. Data of 317 Taiwanese and 259 Singaporean college students were collected using the Mandarin and English versions of the survey and were analyzed using structural equation modeling techniques. Satisfactory fit showed that the modified model offered a reasonable representation of the relations among the constructs and accounted for substantial amounts of the variances in academic well-being and life satisfaction for both samples. Results of the bootstrapping procedure revealed that indirect effects of personality traits and self-construal variables on well-being outcomes were mediated mostly by pathways that involved academic self-efficacy, academic goal progress, and/or academic supports. Academic well-being also filtered the effects of other predictors on life satisfaction. Multigroup structural equation modeling analyses indicated the presence of measurement equivalence across these 2 groups. However, several structural paths differed significantly between the Taiwanese and the Singaporean samples. Overall, this study provides evidence for the applicability of the modified well-being model to college students in Taiwan and Singapore and suggests that students in these 2 Asian countries might pursue and maintain their well-being through different psychological mechanisms. Practical implications for interventions and outreach programs as well as directions for future research are discussed. PMID- 25019548 TI - Work, family, support, and depression: employed mothers in Israel, Korea, and the United States. AB - Our research revealed differences in work-family constructs for employed mothers in 3 countries, Israel (N = 105), Korea (N = 298), and the United States (N = 305). Although levels of work-family conflict were comparable, the Korean women had the lowest levels of work-family enrichment compared with the Israeli and American mothers. Moreover, Korean women reported the most depression and the least support from both spouses and employers. Spousal support mediated the relationship between work-family conflict and depression for employed mothers in Israel, Korea, and the United States. As hypothesized by conservation of resources theory (Hobfoll, 1989, 1998, 2001), threat of resource loss (operationalized as work-family conflict) was related to depression more strongly than was resource gain (i.e., work-family enrichment). PMID- 25019549 TI - Tests of the theory of work adjustment with economically distressed African Americans. AB - The present study tested 2 competing, extended models of the theory of work adjustment (TWA) with a sample of 100 economically distressed working African Americans receiving services at a nonprofit community center. Model 1 depicted a mediated model consistent with postulations of the TWA's original theorists. Model 2 depicted a moderated mediation model consistent with cultural critiques of the TWA. Bivariate correlations indicated that perceptions of person organization (P-O) fit were positively related to job satisfaction and negatively related to turnover intentions, and job satisfaction was negatively related to turnover intentions. Furthermore, perceptions of racial climate were positively related to perceptions of P-O fit and job satisfaction and negatively related to turnover intentions. Moreover, results of the path analyses indicated stronger support for Model 2, the moderated mediation model, in which the indirect link of P-O fit with turnover intentions through job satisfaction was conditional on levels of racial climate. Specifically, when racial climate was perceived as less supportive, the indirect link of P-O fit with turnover intentions was nonsignificant, but when employees reported moderate and more supportive levels of racial climates, this indirect relation was significant. Research and career counseling implications of the present study's findings for financially distressed African American employees are discussed. PMID- 25019550 TI - You speak English well! Asian Americans' reactions to an exceptionalizing stereotype. AB - This study examined a specific type of racial microaggression known as an exceptionalizing stereotype, in which an action is framed as interpersonally complimentary but perpetuates negative stereotypical views of a racial/ethnic group. Asian American participants (N = 68) were assigned to 1 of 3 brief semistructured interview conditions that highlight an exceptionalizing stereotype of Asian Americans to varying degrees. In the low racially loaded condition, participants were told, "You speak English well" by a White confederate. In the high racially loaded condition, they were told, "You speak English well for an Asian." In the control condition, the confederate said, "Nice talking to you." Only participants in the high racially loaded condition rated their partner, the interaction, and future interactions less favorably than participants in the control condition. They also evaluated their partner and interaction less positively than participants in the low racial loading condition. The results suggest exceptionalizing stereotypes can be interpersonally damaging for Asian Americans. PMID- 25019551 TI - The secret ingredient in mindfulness interventions? A case for practice quality over quantity. AB - As mindfulness-based interventions become increasingly widespread, interest has grown in better understanding which features of these treatments produce beneficial effects. The present study examined the relative contribution of mindfulness practice time and practice quality in predicting psychological functioning (negative affect, emotion regulation, quality of life, mindfulness). Data were drawn from a randomized clinical trial of mindfulness training for smokers and assessed outcomes at posttreatment (n = 43) and 5-month follow-up (n = 38). The intervention included instruction in mindfulness techniques targeted to smoking cessation and relapse prevention and was composed of 10 group meetings over 8 weeks. Data from 8 treatment groups were used. Mindfulness practice quality was measured weekly over the course of treatment, and multilevel modeling was used to estimate trajectories of change in practice quality. The measure of practice quality was shown to be valid and reliable, with change in practice quality predicting change in psychological functioning at both posttreatment (beta = .31, 95% CI = [0.04, 0.56], p = .022) and follow-up (beta = .45 [0.16, 0.73], p = .002), even when controlling for practice time. Practice time predicted outcomes at posttreatment (beta = .31 [0.05, 0.57], p = .019) but not at follow-up (beta = .16 [-0.14, 0.47], p = .293). Neither practice time nor change in practice quality predicted smoking abstinence at 1 month or 6 months postquit. Results support the importance of practice quality as a relevant aspect of mindfulness interventions. PMID- 25019552 TI - Authenticity, life satisfaction, and distress: a longitudinal analysis. AB - The purpose of the present study was to examine the reciprocal relationships between authenticity and measures of life satisfaction and distress using a 2 wave panel study design. Data were collected from 232 college students attending 2 public universities. Structural equation modeling was used to analyze the data. The results of the cross-lagged panel analysis indicated that after controlling for temporal stability, initial authenticity (Time 1) predicted later distress and life satisfaction (Time 2). Specifically, higher levels of authenticity at Time 1 were associated with increased life satisfaction and decreased distress at Time 2. Neither distress nor life satisfaction at Time 1 significantly predicted authenticity at Time 2. However, the relationship between Time 1 distress and Time 2 authenticity was not significantly different from the relationship between Time 1 authenticity and Time 2 distress. Results are discussed in light of humanistic-existential theories and the empirical research on well-being. PMID- 25019553 TI - Hematogones in the peripheral blood of a 51/2-month-old boy with cyclic neutropenia due to heterozygous, novel ELANE gene mutation p.Q97P, c.290 A>C. AB - We have identified a novel point mutation in the ELANE gene of a 5.5-month-old boy with severe cyclic neutropenia, and we are reporting for the first time, to our knowledge, the presence of hematogones in the peripheral blood of an infant. The novel point mutation occurred at base number 290 in codon 97, where adenine was replaced with cytosine. The mutation caused the replacement of amino acid glutamine with amino acid proline in the activation domain of the elastase 2 enzyme. The heterozygous mutation generated severe cyclic neutropenia, granulocytic maturation arrest, an increased number of hematogones (26% of marrow cells) in the bone marrow, an absence of neutrophils, and the presence of stage 3 (mature) hematogones in the peripheral blood. The percentage of hematogones in the peripheral blood was inversely proportional to the absolute number of neutrophils. Leukemic number of blast-like cells (hematogones) in the bone marrow, blast-like cells in the peripheral blood, marked neutropenia, and the arrest of granulopoiesis might suggest an acute leukemia. However, the finding of characteristic flow cytometric features of hematogones should help to avoid a wrong diagnosis. PMID- 25019555 TI - MicroRNAs and bone metastasis: a new challenge. AB - The development of bone metastases requires multistep and multicellular machinery consisting not only of processes shared with any type of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to the particular bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). MiRNAs are highly conserved, small RNAs molecules that regulate gene expression. The functional consequence of miRNA deregulation lies in the mRNA targets whose expression is altered. MiRNA networks acting as upstream regulators of these genes interfere with the initial steps of tumor local invasion and cancer cell intravasation, mainly by regulating the epithelial-mesenchymal transition, the motility, invasiveness and survival abilities of these cells. The miRNA-mediated regulation on the steps of bone tropism, anchorage, homing and finally bone colonization is more tissue specific, being dependent on the expression pattern of target miRNAs in bone marrow sinusoids, bone cells and microenvironment. In that, miRNA specific expression signatures that can distinguish between primary tumors from their corresponding bone metastases might be determinants of clinical aggressiveness. In this review, we focus on the current advances on functions and molecular mechanisms by which miRNAs exert their biological roles in regulating bone metastases development. PMID- 25019556 TI - Computer aided screening of secreted frizzled-related protein 4 (SFRP4): a potential control for diabetes mellitus. AB - Diabetes mellitus is a life threatening disease and scientists are doing their best to find a cost effective and permanent treatment of this malady. The recent trend is to control the disease by target base inhibiting of enzymes or proteins. Secreted frizzled-related protein 4 (SFRP4) is found to cause five times more risk of diabetes when expressed above average levels. This study was therefore designed to analyze the SFRP4 and to find its potential inhibitors. SFRP4 was analyzed by bio-informatics tools of sequence tool and structure tool. A total of three potential inhibitors of SFRP4 were found, namely cyclothiazide, clopamide and perindopril. These inhibitors showed significant interactions with SFRP4 as compared to other inhibitors as well as control (acetohexamide). The findings suggest the possible treatment of diabetes mellitus type 2 by inhibiting the SFRP4 using the inhibitors cyclothiazide, clopamide and perindopril. PMID- 25019554 TI - Household ventilation may reduce effects of indoor air pollutants for prevention of lung cancer: a case-control study in a Chinese population. AB - BACKGROUND: Although the International Agency for Research on Cancer (IARC) has classified various indoor air pollutants as carcinogenic to humans, few studies evaluated the role of household ventilation in reducing the impact of indoor air pollutants on lung cancer risk. OBJECTIVES: To explore the association between household ventilation and lung cancer. METHODS: A population-based case-control study was conducted in a Chinese population from 2003 to 2010. Epidemiologic and household ventilation data were collected using a standardized questionnaire. Unconditional logistic regression was employed to estimate adjusted odds ratios (ORadj) and their 95% confidence intervals (CI). RESULTS: Among 1,424 lung cancer cases and 4,543 healthy controls, inverse associations were observed for good ventilation in the kitchen (ORadj = 0.86, 95% CI: 0.75, 0.98), bedroom (ORadj = 0.90, 95% CI: 0.79, 1.03), and both kitchen and bedroom (ORadj = 0.87, 95% CI: 0.75, 1.00). Stratified analyses showed lung cancer inversely associated with good ventilation among active smokers (ORadj = 0.85, 95% CI: 0.72, 1.00), secondhand smokers at home (ORadj = 0.77, 95% CI: 0.63, 0.94), and those exposed to high-temperature cooking oil fumes (ORadj = 0.82, 95% CI: 0.68, 0.99). Additive interactions were found between household ventilation and secondhand smoke at home as well as number of household pollutant sources. CONCLUSIONS: A protective association was observed between good ventilation of households and lung cancer, most likely through the reduction of exposure to indoor air pollutants, indicating ventilation may serve as one of the preventive measures for lung cancer, in addition to tobacco cessation. PMID- 25019557 TI - First order temperature dependent phase transition in a monoclinic polymorph crystal of 1,6-hexanedioic Acid: an interpretation based on the landau theory approach. AB - Crystals of 1,6-hexanedioic acid (I) undergo a temperature-dependent reversible phase transition from monoclinic P21/c at a temperature higher than the critical temperature (Tc) 130 K to another monoclinic P21/c at temperature lower than Tc. The phase transition is of first order, involving a discontinuity and a tripling of the b-axis at Tc whereas the other unit cell parameters vary continuously. The transition is described by the phenomenological Landau theory. The crystal structure analyses for data collected at 297(2) K and 120.0(1) K show that there is half of a molecule of (I) in the asymmetric unit at 297(2) K whereas there are one and a half molecules of (I) in the asymmetric unit at 120.0(1) K. At both temperatures, 297(2) and 120.0(1) K, intermolecular O-H...O hydrogen bonds link the molecules of I into infinite 1D chains along [101] direction. However there are significantly more O-H...O hydrogen bonds presented in the 120.0(1) K polymorph, thereby indicating this phase transition is negotiated via hydrogen bonds. The relationship of the conformational changes and hydrogen bonding for these two polymorphs are explained in detail. PMID- 25019559 TI - Unraveling the polymorphism of [(p-cymene)Ru(kappaN-INA)Cl2] through dispersion corrected DFT and NMR GIPAW calculations. AB - The structural and (13)C/(1)H NMR parameters of the four crystal forms (1alpha, 1.H2O, 1beta, and 1gamma) of the solid wheel-and-axle (WAA) metal-organic compound [(p-cymene)Ru(kappaN-INA)Cl2] have been studied by means of periodic DFT calculations. The quality of the results obtained strongly depends on a correct description of long-range interactions; thus, in the geometry refinement protocol used, the pure DFT functionals need to be coupled with a dispersion-correction term (B3LYP-D2, B3LYP-D*). The solid-state (13)C/(1)H NMR delta(iso) parameters and (13)C MAS NMR spectra, calculated by means of the PBE-GIPAW method, agree well with the experimental data for the four crystal forms (mean absolute deviations of the (13)C and (1)H delta(iso) data values lie in the ranges 1.3-2.9 and 0.3-1.0 ppm, respectively). In this context, some revisions in the experimental assignment of the (13)C/(1)H NMR delta(iso) parameters of the 1.H2O, 1beta, and 1gamma crystal forms can be suggested. The mismatch in the assignment seems to be due to the rotation of the -COOH moiety, which occurs at the 1alpha 1.H2O transition and was not considered in the experiments. Finally, the results obtained suggest the presence of two COOH...Cl hydrogen bonds of comparable strength established by the two molecules in the asymmetric unit of the 1gamma polymorph, in partial disagreement with previous findings. PMID- 25019558 TI - Challenges, applications, and recent advances of protein-ligand docking in structure-based drug design. AB - The docking methods used in structure-based virtual database screening offer the ability to quickly and cheaply estimate the affinity and binding mode of a ligand for the protein receptor of interest, such as a drug target. These methods can be used to enrich a database of compounds, so that more compounds that are subsequently experimentally tested are found to be pharmaceutically interesting. In addition, like all virtual screening methods used for drug design, structure based virtual screening can focus on curated libraries of synthesizable compounds, helping to reduce the expense of subsequent experimental verification. In this review, we introduce the protein-ligand docking methods used for structure-based drug design and other biological applications. We discuss the fundamental challenges facing these methods and some of the current methodological topics of interest. We also discuss the main approaches for applying protein-ligand docking methods. We end with a discussion of the challenging aspects of evaluating or benchmarking the accuracy of docking methods for their improvement, and discuss future directions. PMID- 25019560 TI - Electronic properties of FC(O)SCH2CH3. a combined helium(I) photoelectron spectroscopy and synchrotron radiation study. AB - The valence electronic properties of S-ethyl flouromethanethioate (S-ethyl fluoromethsanethioate), FC(O)SCH2CH3, were investigated by means of He(I) photoelectron spectroscopy in conjunction with the analysis of the photofragmentation products determined by PEPICO (phtoelectron-photoion coincidence) by using synchrotron radiation in the 11.1-21.6 eV photon energy range. The first band observed at 10.28 eV in the HeI photoelectron spectrum can be assigned with confidence to the ionization process from the HOMO [npi(S) orbital], which is described as a lone pair formally localized on the sulfur atom, in agreement with quantum chemical calculations using the outer valence Green function method [OVGF/6-311++G (d,p)]. One of the most important fragmentation channels also observed in the valence region corresponds to the decarbonylation process yielding the [M-CO](.+) ion, which is clearly observed at m/z = 80. Moreover, S 2p and S 2s absorption edges have been examined by measuring the total ion yield spectra in the 160-240 eV region using variable synchrotron radiation. The dynamic of ionic fragmentation following the Auger electronic decay has been evaluated with the help of the PEPIPICO (photoion photoion-photoelectron-coincidence spectra) technique. PMID- 25019561 TI - Electricity resonance-induced fast transport of water through nanochannels. AB - We performed molecular dynamics simulations to study water permeation through a single-walled carbon nanotube with electrical interference. It was found that the water net flux across the nanochannel is greatly affected by the external electrical interference, with the maximal net flux occurred at an electrical interference frequency of 16670 GHz being about nine times as high as the net flux at the low or high frequency range of (<1000 GHz or >80,000 GHz). The above phenomena can be attributed to the breakage of hydrogen bonds as the electrical interference frequency approaches to the inherent resonant frequency of hydrogen bonds. The new mechanism of regulating water flux across nanochannels revealed in this study provides an insight into the water transportation through biological water channels and has tremendous potential in the design of high-flux nanofluidic systems. PMID- 25019563 TI - Electroconvulsive therapy for catatonia in an 18-year-old patient presenting with mixed features of schizophrenia and obsessive-compulsive disorder. PMID- 25019562 TI - Multi-ethnic study of atherosclerosis: association between left atrial function using tissue tracking from cine MR imaging and myocardial fibrosis. AB - PURPOSE: To investigate the association between left atrial ( LA left atrium ) function and left ventricular myocardial fibrosis using cardiac magnetic resonance (MR) imaging in a multi-ethnic population. MATERIALS AND METHODS: For this HIPAA-compliant study, the institutional review board at each participating center approved the study protocol, and all participants provided informed consent. Of 2839 participants who had undergone cardiac MR in 2010-2012, 143 participants with myocardial scar determined with late gadolinium enhancement and 286 age-, sex-, and ethnicity-matched control participants were identified. LA left atrium volume, strain, and strain rate were analyzed by using multimodality tissue tracking from cine MR imaging. T1 mapping was applied to assess diffuse myocardial fibrosis. The association between LA left atrium parameters and myocardial fibrosis was evaluated with the Student t test and multivariable regression analysis. RESULTS: The scar group had significantly higher minimum LA left atrium volume than the control group (mean, 22.0 +/- 10.5 [standard deviation] vs 19.0 +/- 7.8, P = .002) and lower LA left atrium ejection fraction (45.9 +/- 10.7 vs 51.3 +/- 8.7, P < .001), maximal LA left atrium strain ( Smax maximum LA strain ) (25.4 +/- 10.7 vs 30.6 +/- 10.6, P < .001) and maximum LA left atrium strain rate ( SRmax maximum LA strain rate ) (1.08 +/- 0.45 vs 1.29 +/- 0.51, P < .001), and lower absolute LA left atrium strain rate at early diastolic peak ( SRE LA strain rate at early diastolic peak ) (-0.77 +/- 0.42 vs 1.01 +/- 0.48, P < .001) and LA left atrium strain rate at atrial contraction peak ( SRA LA strain rate at atrial contraction peak ) (-1.50 +/- 0.62 vs -1.78 +/- 0.69, P < .001) than the control group. T1 time 12 minutes after contrast material injection was significantly associated with Smax maximum LA strain (beta coefficient = 0.043, P = .013), SRmax maximum LA strain rate (beta coefficient = 0.0025, P = .001), SRE LA strain rate at early diastolic peak (beta coefficient = -0.0016, P = .027), and SRA LA strain rate at atrial contraction peak LA strain rate at atrial contraction peak (beta coefficient -0.0028, P = .01) in the regression model. T1 time 25 minutes after contrast material injection was significantly associated with SRmax maximum LA strain rate (beta coefficient = 0.0019, P = .016) and SRA LA strain rate at atrial contraction peak (beta coefficient = -0.0022, P = .034). CONCLUSION: Reduced LA left atrium regional and global function are related to both replacement and diffuse myocardial fibrosis processes. Clinical trial registration no.: NCT00005487 PMID- 25019564 TI - Capacity of the aquatic fern (Salvinia minima Baker) to accumulate high concentrations of nickel in its tissues, and its effect on plant physiological processes. AB - An experiment was designed to assess the capacity of Salvinia minima Baker to uptake and accumulate nickel in its tissues and to evaluate whether or not this uptake can affect its physiology. Our results suggest that S. minima plants are able to take up high amounts of nickel in its tissues, particularly in roots. In fact, our results support the idea that S. minima might be considered a hyper accumulator of nickel, as it is able to accumulate 16.3 mg g(-1) (whole plant DW basis). Our results also showed a two-steps uptake pattern of nickel, with a fast uptake of nickel at the first 6 to 12h of being expose to the metal, followed by a slow take up phase until the end of the experiment at 144 h. S. minima thus, may be considered as a fern useful in the phytoremediation of residual water bodies contaminated with this metal. Also from our results, S. minima can tolerate fair concentrations of the metal; however, at concentrations higher than 80 MUM Ni (1.5 mg g(-1) internal nickel concentration), its physiological performance can be affected. For instance, the integrity of cell membranes was affected as the metal concentration and exposure time increased. The accumulation of high concentrations of internal nickel did also affect photosynthesis, the efficiency of PSII, and the concentration of photosynthetic pigments, although at a lower extent. PMID- 25019565 TI - Signaling pathways in anchoring junctions of epithelial cells: cell-to-cell and cell-to-extracellular matrix interactions. AB - Epithelial cells form the epithelium, one of the basic tissues of the human body. These cells present specializations from tissue to tissue, determining different structures and functions. Tissues formed by epithelial cells are characterized by the few extracellular matrix found between adjacent cells. In this way, to preserve tissue integrity, cells have to stick to each other and have to maintain a strict communication with the environment via cell junctions. Signal transduction is the main way of cell communication, being vital for the regulation of cell survival and proliferation. In cell junctions, this communication occurs through cell adhesion molecules that promote cell-to-cell and cell-to-extracellular matrix adhesion, as well as, enable the flow of information to the inside and to the outside of the cell. These molecules include integrins and cadherins, among others. The impairment of cell signaling in epithelial junctions has been involved in several pathological processes that underlie the development of, for example, colorectal cancer. Thus, epithelial cell signaling mediators have been explored as potential therapeutic targets and efforts have been made to achieve a deeper understanding of molecular events that occur at cell junctions. In this review, we address the current knowledge on the main signaling events that take place in anchoring junctions of epithelial cells, focusing both on cell-to-cell and cell-to-matrix interactions. To conclude, we explore some relevant consequences from epithelial cell signaling impairment and demonstrate that the molecular mediators of the pathways analyzed may be putative therapeutic targets. PMID- 25019566 TI - Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy. AB - Active pulmonary tuberculosis (APTB) is associated with a failure of the host immune system to control the invading Mycobacterium tuberculosis (Mtb). The objective of this study was to quantify and assess the role of serum inflammatory cytokines in active pulmonary tuberculosis patients following anti-tuberculosis drug (ATD) therapy. Blood samples were collected from APTB patients and normal healthy subjects (NHS) (total n=204) at baseline and 2, 4 and 6 months post therapy and the abundance of serum inflammatory cytokines were measured by cytokine specific ELISA. Compared to NHS, APTB patients at baseline had higher levels of serum pro-inflammatory cytokines IL-12p40 (P<0.001), IFN-gamma (P<0.001), TNF-alpha (P<0.01), IL-1beta (P<0.001) and IL-6 (P<0.001) and anti inflammatory cytokines IL-10 (P<0.001) and TGF-beta1 (P<0.001) while there was no change in the level of IL-4. In APTB patients, the serum levels of IFN-gamma, TNF alpha, IL-6 and TGF-beta1 directly relate to the bacterial load while the TNF alpha, IL-1beta, IL-6 and TGF-beta1 relate to radiological severity. At baseline, the IL-6 level in NHS and APTB patients differed most and following ATD therapy, this level rapidly decreased and stabilized by 4-month in APTB patients. It is concluded that a subtle reduction in the serum level of IL-6 of the APTB patients following ATD therapy might play a vital role in immune-protection of the host against Mtb infection and hence the serum IL-6 level can be a useful marker to diagnose the effectiveness of therapy in the patients. PMID- 25019567 TI - Recombinant TB10.4 of Mycobacterium bovis induces cytokine production in RAW264.7 macrophages through activation of the MAPK and NF-kappaB pathways via TLR2. AB - The TB10.4 antigen of Mycobacterium bovis/Mycobacterium tuberculosis induces a strong Th1 CD4+ T-cell response. Thus, it is currently under intensive study as a possible vaccine candidate. However, how TB10.4 activates innate immune cells is unclear. How TB10.4 interacts with toll-like receptors (TLRs) and signaling pathways responsible for active inflammation have also not been fully elucidated. Here, as stimulated RAW264.7 cells with recombinant TB10.4 (rTB10.4), derived from M. bovis, increased TNF-alpha, IL-6 and IL-12 p40 secretin in a dose dependent manner. Blocking assays showed that TLR2-, but not TLR4-neutralizing antibody reduced expression of TNF-alpha, IL-6 and IL-12 p40 in RAW264.7 cells. rTB10.4 stimulation activated p38 kinase (p38) and extracellular-regulated kinase (ERK) was TLR2-dependent, whereas inhibition of p38 and ERK activity significantly reduced TNF-alpha, IL-6 and IL-12 p40 production. Furthermore, rTB10.4 stimulation of RAW264.7 cells resulted in TLR2-mediated activation of NF kappaB and induced translocation of NF-kappaB p65 from the cytoplasm to the nucleus via IkappaBalpha degradation. rTB10.4-induced TNF-alpha, IL-6 and IL-12 p40 release was attenuated by the specific IkappaB phosphorylation inhibitor, BAY 11-7082. These findings indicate that the M. bovis-derived rTB10.4 induced production of TNF-alpha, IL-6 and IL-12 p40 involves p38, ERK and NF-kappaB via the TLR2 pathway. PMID- 25019569 TI - A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. AB - OBJECTIVE: To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum resistant or partially platinum-sensitive ovarian cancer. METHODS: In this open label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti trebananib antibodies, and pharmacokinetics (secondary). RESULTS: 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. CONCLUSIONS: Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts. PMID- 25019568 TI - A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer. AB - OBJECTIVE: To assess the ability of preoperative computed tomography (CT) scan of the abdomen/pelvis and serum CA-125 to predict suboptimal (>1cm residual disease) primary cytoreduction in advanced ovarian, fallopian tube, and peritoneal cancer. METHODS: This was a prospective, non-randomized, multicenter trial of patients who underwent primary cytoreduction for stage III-IV ovarian, fallopian tube, and peritoneal cancer. A CT scan of the abdomen/pelvis and serum CA-125 were obtained within 35 and 14 days before surgery, respectively. Four clinical and 20 radiologic criteria were assessed. RESULTS: From 7/2001 to 12/2012, 669 patients were enrolled; 350 met eligibility criteria. The optimal debulking rate was 75%. On multivariate analysis, three clinical and six radiologic criteria were significantly associated with suboptimal debulking: age >= 60 years (p=0.01); CA 125 >= 500 U/mL (p<0.001); ASA 3-4 (p<0.001); suprarenal retroperitoneal lymph nodes >1cm (p<0.001); diffuse small bowel adhesions/thickening (p<0.001); and lesions >1cm in the small bowel mesentery (p=0.03), root of the superior mesenteric artery (p=0.003), perisplenic area (p<0.001), and lesser sac (p<0.001). A 'predictive value score' was assigned for each criterion, and the suboptimal debulking rates of patients who had a total score of 0, 1-2, 3-4, 5-6, 7-8, and >= 9 were 5%, 10%, 17%, 34%, 52%, and 74%, respectively. A prognostic model combining these nine factors had a predictive accuracy of 0.758. CONCLUSIONS: We identified nine criteria associated with suboptimal cytoreduction, and developed a predictive model in which the suboptimal rate was directly proportional to a predictive value score. These results may be helpful in pretreatment patient assessment. PMID- 25019570 TI - Prognostic factors and treatment outcomes for patients with surgically staged uterine clear cell carcinoma focusing on the early stage: A Taiwanese Gynecologic Oncology Group study. AB - OBJECTIVE: The aim of this study was to investigate the clinical and pathological characteristics of uterine clear cell carcinoma (UCCC) and the treatment of this disease in relation to patient outcomes. METHODS: The clinicopathological data for and the management of all patients with UCCC who presented between 1991 and 2010 at 11 member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed. RESULTS: There were no significant differences in 5-year overall survival (OS) rates between patients with pure UCCC (n=100) and non-pure UCCC (n=53) at the same surgical stage, with OS rates of 92.6%, and 87.7% for stage I; 83.3% and 83.3% for stage II; 64.0% and 67.8% for stage III; and 16.7% and 0% for stage IV (n=1), respectively. Tumor stage and age independently influenced the OS rate of UCCC. For the patients with early stage UCCC, the adjuvant therapy modality was the only significant prognostic factor for recurrence-free survival. The patients with early stage UCCC who received adjuvant therapy had excellent 5-year recurrence-free survival and OS rates compared to those who received radiotherapy (100% vs. 74%, p=0.01; 100% vs. 72%, p=0.03). CONCLUSIONS: The 5-year survival rates of patients with pure UCCC and non-pure UCCC were similar. The prognosis for surgical staging of patients with stage I/II UCCC was encouraging. Postoperative adjuvant platinum-based chemotherapy is recommended for patients with early stage UCCC who are at a high risk of recurrence. PMID- 25019572 TI - Fuzzy electron density fragments in macromolecular quantum chemistry, combinatorial quantum chemistry, functional group analysis, and shape-activity relations. AB - Conspectus Just as complete molecules have no boundaries and have "fuzzy" electron density clouds approaching zero density exponentially at large distances from the nearest nucleus, a physically justified choice for electron density fragments exhibits similar behavior. Whereas fuzzy electron densities, just as any fuzzy object, such as a thicker cloud on a foggy day, do not lend themselves to easy visualization, one may partially overcome this by using isocontours. Whereas a faithful representation of the complete fuzzy density would need infinitely many such isocontours, nevertheless, by choosing a selected few, one can still obtain a limited pictorial representation. Clearly, such images are of limited value, and one better relies on more complete mathematical representations, using, for example, density matrices of fuzzy fragment densities. A fuzzy density fragmentation can be obtained in an exactly additive way, using the output from any of the common quantum chemical computational techniques, such as Hartree-Fock, MP2, and various density functional approaches. Such "fuzzy" electron density fragments properly represented have proven to be useful in a rather wide range of applications, for example, (a) using them as additive building blocks leading to efficient linear scaling macromolecular quantum chemistry computational techniques, (b) the study of quantum chemical functional groups, (c) using approximate fuzzy fragment information as allowed by the holographic electron density theorem, (d) the study of correlations between local shape and activity, including through-bond and through-space components of interactions between parts of molecules and relations between local molecular shape and substituent effects, (e) using them as tools of density matrix extrapolation in conformational changes, (f) physically valid averaging and statistical distribution of several local electron densities of common stoichiometry, useful in electron density databank mining, for example, in medicinal drug design, and (g) tools for combinatorial quantum chemistry approaches using fuzzy fragment databanks and rapid construction of a large number of approximate electron densities for large sets of related molecules, relevant in theoretical molecular and nanostructure design. PMID- 25019571 TI - A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. AB - PURPOSE: Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS: Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of <=2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. RESULTS: Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1-24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%-31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%-43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-alpha (ER) expression was positively correlated with OS. CONCLUSION: Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC. PMID- 25019573 TI - Pancreatic polypeptide inhibits somatostatin secretion. AB - Pancreatic polypeptide (PP) is a major agonist for neuropeptide Y4 receptors (NPY4R). While NPY4R has been identified in various tissues, the cells on which it is expressed and its function in those cells has not been clearly delineated. Here we report that NPY4R is present in all somatostatin-containing cells of tissues that we tested, including pancreatic islets, duodenum, hippocampus, and hypothalamus. Its agonism by PP decreases somatostatin secretion from human islets. Mouse embryonic hippocampal (mHippo E18) cells expressed NPY4Rs and their activation by PP consistently decreased somatostatin secretion. Furthermore, central injection of PP in mice induced c-Fos immunoreactivity in somatostatin containing cells in the hippocampus compared with PBS-injected mice. In sum, our results identify PP as a pivotal modulator of somatostatin secretion. PMID- 25019574 TI - Nitric oxide increases the invasion of pancreatic cancer cells via activation of the PI3K-AKT and RhoA pathways after carbon ion irradiation. AB - Previous studies have shown that serine proteases and Rho-associated kinase contribute to carbon ion radiation-enhanced invasion of the human pancreatic cancer cell line PANC-1. The results presented here show that nitric oxide synthase (NOS) also plays a critical role in this process. Irradiation of PANC-1 cells promoted invasion and production of nitric oxide (NO), which activated the PI3K-AKT signaling pathway, while independently activating RhoA. Inhibition of PI3K, Rho-associated kinase, and serine protease alone or in conjunction with NOS suppressed the radiation-enhanced invasion of PANC-1 cells, suggesting that they could serve as possible targets for the management of tumor metastasis. PMID- 25019575 TI - Enoyl acyl carrier protein reductase (FabI) catalyzed asymmetric reduction of the C=C double bond of alpha,beta-unsaturated ketones: preparation of (R)-2-alkyl cyclopentanones. AB - Enoyl-ACP reductase (FabI) was identified as a non-OYE 'ene'-reductase for asymmetric reduction of the C=C double bond of alpha, beta-unsaturated ketones. Reduction of several 2-alkylidenecyclopentanones with A-FabI and E-FabI gave (R) 2-alkylcyclopentanones in 95-90% and 70-81% ee, respectively. The product ee was improved to 99-98% in high yield by subsequent one-pot biooxidation. PMID- 25019576 TI - Stabilizing poly(vinyl chloride) using its blends with poly(methyl methacarylate): pyrolysis GC/MS studies. AB - Binary blends of poly(vinyl chloride) (PVC) with poly(methyl methacarylate) (PMMA) of various compositions were prepared through solution blending. Thermogravimetric and pyrolysis studies of these blends were carried out and the volatile products were separated and quantitatively analyzed by GC/MS. Harmful pyrolysis products from PVC like HCl and different aromatic hydrocarbons are significantly suppressed in presence of a small amount of PMMA. The stabilization effect on PVC was found to be the most significant with 10 wt.%. PMMA contents in the matrix. Mechanism of the stabilization has been explained by the interaction of micro- and macro-radicals resulting from PMMA with PVC, which stabilize the unzipping of polymer chains by a reversible blocking mechanism and increase the amount of cross-linked residue retained above 500 degrees C. PMID- 25019577 TI - Nonionic surfactant greatly enhances the reductive debromination of polybrominated diphenyl ethers by nanoscale zero-valent iron: mechanism and kinetics. AB - Nanoscale zero-valent iron (nZVI) has been considered as an effective agent for reductive debromination of polybrominated diphenyl ethers (PBDEs). But the high lipophilicity of PBDEs will hinder their debromination owing to the inefficient contact of PBDEs with nZVI. In this study, different ionic forms of surfactants were investigated aiming to promote PBDE debromination, and the beneficial effects of surfactant were found to be: nonionic polyethylene glycol octylphenol ether (Triton X-100, TX)>cationic cetylpyridinium chloride (CPC)>anionic sodium dodecyl benzenesulfonate (SDDBS). Except for with SDDBS, the promotion effect for PBDE debromination was positively related to the surfactant concentrations until a critical micelle concentration (CMC). The debromination process of octa-BDE and its intermediates could be described as a consecutive reaction. The corresponding rate constants (k) for the debromination of parent octa-BDE (including nona- to hepta-BDEs), the intermediates hexa-, penta-, and tetra-BDEs are 1.24 * 10(-1) h( 1), 8.97 * 10(-2) h(-1), 6.50 * 10(-2) h(-1) and 2.37 * 10(-3) h(-1), respectively. PMID- 25019578 TI - Sunlight mediated diesel degradation under saline conditions using ionic silver coated sand via nanoreduction: use of impregnated form of thiourea modified chitosan membranes for ex situ application. AB - The present research investigates the use of ionic silver coated sand dust (ISSD) for the sunlight mediated degradation of diesel under saline conditions. Sand dust was used as a template for reduction of silver ions by effective removal of chloride ions. Diesel degradation was estimated in terms of degradation (%), chloride removal, volume reduction and nanoparticle synthesis, respectively. The process was optimized using a 7-level Box-Behnken design. Among several factors, time (B), Tween 80 (C), ISSD dosage (D) and silver(I) concentration (F) were found to be most significant. Maximum diesel degradation 99.8% was obtained in a period of 14 h which was analyzed by gas chromatography. XPS analysis confirmed silver reduction as the underlying phenomena. TEM analysis and albeit first approximation method confirmed that enhanced degradation occurred due to physical contact between diesel components and ISSD. First order kinetic model exhibited the best fit. Light microscopy results showed the various stages in diesel degradation by a reduction in bubble size. Ex situ application was carried out using ISSD impregnated thiourea modified chitosan/PVA membranes by surface floatation technique for the remediation of diesel contaminated sea water. Complete diesel degradation was noted after 48 h of sunlight exposure. PMID- 25019579 TI - Quantitative lobar cerebral blood flow for outcome prediction after traumatic brain injury. AB - The aim of this study was to examine cortical cerebral blood flow (CBF) in patients with traumatic brain injury (TBI) and determine whether lobar cortical CBF is a better predictor of long-term neurological outcome assessed by the Glasgow Outcome Scale (GOS) than global cortical CBF. Ninety-eight patients with TBI had a stable xenon computed tomography scan (Xe/CT-CBF study) performed at various time points after their initial injury. Spearman's correlation coefficients and Kruskall-Wallis' test were used to examine the relationship between patient age, emergency room Glasgow Coma Scale (GCS), Injury Severity Score, prehospital hypotension, prehospital hypoxia, mechanism of injury, type of injury, side of injury, global average CBF, lobar CBF, number of lobes with CBF below normal, and GOS (discharge, 3 and 6 months). Univariate ordinal regression was performed using these same variables and in combination with principle component analysis (PCA) to determine independent variables for multi-variate ordinal regression. Significant correlation between age, GCS, prehospital hypotension, type of injury, global average CBF, lobar CBF, number of lobes below normal CBF, and GOS was found. Individual lobar CBF was highly correlated with global CBF and the number of lobes below normal CBF. PCA found one principle component among these three CBF variables; therefore, average global CBF and number of lobes with CBF below normal were each chosen as independent variables for multiple ordinal regression, which found age, GCS, and prehospital hypotension, global average CBF, and number of lobes below normal CBF significantly associated with GOS. This study found global average CBF and lobar CBF significantly correlated with GOS at follow-up. There was, however, no individual cerebral lobe that was more predictive than any other, which puts into question the value of calculating lobar CBF versus global CBF in predicting GOS. PMID- 25019580 TI - Modeling economic implications of alternative treatment strategies for acute bacterial skin and skin structure infections. AB - OBJECTIVE: The economic implications from the US Medicare perspective of adopting alternative treatment strategies for acute bacterial skin and skin structure infections (ABSSSIs) are substantial. The objective of this study is to describe a modeling framework that explores the impact of decisions related to both the location of care and switching to different antibiotics at discharge. METHODS: A discrete event simulation (DES) was developed to model the treatment pathway of each patient through various locations (emergency department [ED], inpatient, and outpatient) and the treatments prescribed (empiric antibiotic, switching to a different antibiotic at discharge, or a second antibiotic). Costs are reported in 2012 USD. RESULTS: The mean number of days on antibiotic in a cohort assigned to a full course of vancomycin was 11.2 days, with 64% of the treatment course being administered in the outpatient setting. Mean total costs per patient were $8671, with inpatient care accounting for 58% of the costs accrued. The majority of outpatient costs were associated with parenteral administration rather than drug acquisition or monitoring. Scenarios modifying the treatment pathway to increase the proportion of patients receiving the first dose in the ED, and then managing them in the outpatient setting or prescribing an oral antibiotic at discharge to avoid the cost associated with administering parenteral therapy, therefore have a major impact and lower the typical cost per patient by 11-20%. Since vancomycin is commonly used as empiric therapy in clinical practice, based on these analyses, a shift in treatment practice could result in substantial savings from the Medicare perspective. CONCLUSIONS: The choice of antibiotic and location of care influence the costs and resource use associated with the management of ABSSSIs. The DES framework presented here can provide insight into the potential economic implications of decisions that modify the treatment pathway. PMID- 25019581 TI - Persistence with and adherence to fingolimod compared with other disease modifying therapies for the treatment of multiple sclerosis: a retrospective US claims database analysis. AB - OBJECTIVE: Achieving therapeutic goals in multiple sclerosis (MS) requires strict adherence to treatment schedules. This retrospective study analyzed persistence with, and adherence to, fingolimod compared with injectable/infusible disease modifying therapies (DMTs) in patients with MS. METHODS: Patients in the PharMetrics PlusTM US administrative claims database with at least one prescription for, or administration of, fingolimod, glatiramer acetate (GA), interferon (IFN), or natalizumab (index DMT) between October 1, 2010 and September 30, 2011 were included. Patients were naive to index DMT (no claim in the previous 360 days) and had an MS diagnosis code within 360 days of the first index DMT prescription. Outcomes were persistence, risk of discontinuing index DMT (evaluated by a Cox proportional hazards model), adherence (measured using the medication possession ratio [MPR] and proportion of days covered [PDC] in patients with at least two index DMT prescriptions), and the risk of being non adherent (MPR <80% and PDC <80%, assessed using a logistic regression model). RESULTS: The study included 3750 patients (fingolimod, n = 889; GA, n = 1233; any IFN, n = 1341; natalizumab, n = 287). Discontinuation rates (fingolimod, 27.9%; GA, 39.5%; IFN, 43.7%; natalizumab, 39.5%; all p < 0.001) and risk of discontinuation were significantly higher (hazard ratios vs fingolimod [95% confidence interval]: GA, 1.75 [1.49-2.07]; IFN, 2.01 [1.71-2.37]; natalizumab, 1.53 [1.22-1.91]) for patients receiving other DMTs compared with fingolimod. The risk of being non-adherent was also lower for patients in the fingolimod cohort than the other treatment cohorts, irrespective of whether non-adherence was defined as MPR <80% (p < 0.05 for all) or PDC <80% (p < 0.05 for GA and IFN). LIMITATIONS: As with all studies assessing real-world treatment patterns it is unclear if medications were used as prescribed. CONCLUSIONS: In a real-world setting, persistence with, and adherence to, oral fingolimod was higher than for injectable and infusible DMTs. PMID- 25019583 TI - The role of microglia activation in the development of sepsis-induced long-term cognitive impairment. AB - Oxidative stress and inflammation is likely to be a major step in the development of sepsis-associated encephalopathy (SAE) and long-term cognitive impairment. To date, it is not known whether brain inflammation and oxidative damage are a direct consequence of systemic inflammation or whether these events are driven by brain resident cells, such as microglia. Therefore, the aim of this study is to evaluate the effect of minocycline on behavioral and neuroinflammatory parameters in rats submitted to sepsis. Male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP). The animals were divided into sham-operated (Sham+control), sham-operated plus minocycline (sham+MIN), CLP (CLP+control) and CLP plus minocycline (CLP+MIN) (100 MUg/kg, administered as a single intracerebroventricular (ICV) injection). Some animals were killed 24h after surgery to assess the breakdown of the blood brain barrier, cytokine levels, oxidative damage to lipids (TBARS) and proteins in the hippocampus. Some animals were allowed to recover for 10 days when step-down inhibitory avoidance and open field tasks were performed. Treatment with minocycline prevented an increase in markers of oxidative damage and inflammation in the hippocampus after sepsis. This was associated with an improvement in long-term cognitive performance. In conclusion, we demonstrated that the inhibition of the microglia by an ICV injection of minocycline was able to decrease acute brain oxidative damage and inflammation as well as long-term cognitive impairment in sepsis survivors. PMID- 25019582 TI - Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells. AB - Myelin loss is a widespread neuropathological hallmark of the atypical parkinsonian disorder multiple system atrophy (MSA). On a cellular level, MSA is characterized by alpha-synuclein (aSyn)-positive glial cytoplasmic inclusions (GCIs) within mature oligodendrocytes leading to demyelination as well as axonal and neuronal loss. Oligodendrocyte progenitor cells (OPCs) represent a proliferative cell population distributed throughout the adult mammalian central nervous system. During remyelination, OPCs are recruited to sites of demyelination, differentiate, and finally replace dysfunctional mature oligodendrocytes. However, comprehensive studies investigating OPCs and remyelination processes in MSA are lacking. In the present study, we therefore investigate the effect of human aSyn (h-aSyn) on early primary rat OPC maturation. Upon lentiviral transduction, h-aSyn expressing OPCs exhibit fewer and shorter primary processes at the initiation of differentiation. Until day 4 of a 6day differentiation paradigm, h-aSyn expressing OPCs further show a severely delayed maturation evidenced by reduced myelin gene expression and increased levels of the progenitor marker platelet derived growth factor receptor alpha (PDGFRalpha). Matching these results, OPCs that take up extracellular recombinant h-aSyn exhibit a similar delayed differentiation. In both experimental setups however, myelin gene expression is restored at day 6 of differentiation paralleled by decreased intracellular h-aSyn levels indicating a reverse correlation of h-aSyn and the differentiation potential of OPCs. Taken together, these findings suggest a tight link between the intracellular level of h-aSyn and maturation capacity of primary OPCs. PMID- 25019584 TI - The serum level of transforming growth factor beta1 and its association with Foxp3 gene polymorphism in Iranian women with recurrent spontaneous abortion. AB - The aim of the study was to determine the role of transforming growth factor beta1 (TGF-beta1) and Foxp3 (rs3761548) promoter polymorphisms in Iranian women with recurrent spontaneous abortion (RSA). Eighty women with RSA were compared with eighty in a control group. Serum levels of TGF-beta1 were measured using ELISA and Foxp3 (rs3761548) promoter polymorphisms using a PCR-RFLP technique. In addition, serum levels of TGF-beta1 were compared in different genotypes in the two groups. The women's ages in the two groups were similar (30.15 +/- 4.42 years [RSA] vs. 29.97 +/- 4.51 [control]) as were serum TGF-beta1 concentrations in case and control groups (53.42 +/- 2.08 ng/ml in control and 56.31 +/- 2.58 ng/ml in the RSA group; p = 0.4). Furthermore, there was no significant difference in the genotype frequencies of the rs3761548 Foxp3 gene between the two groups (p = 0.3) and the levels of TGF-beta1 were similar in different genotypes. In conclusion, the data indicate that serum TGF-beta1 levels and Foxp3 (rs3761548) promoter polymorphism is not a risk factor for RSA and that there is no association between the polymorphism and serum TGF-beta1 levels. PMID- 25019585 TI - Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury. AB - To investigate the role of oxidative stress and/or mitochondrial impairment in the occurrence of acute kidney injury (AKI) during sepsis, we developed a sepsis induced in vitro model using proximal tubular epithelial cells exposed to a bacterial endotoxin (lipopolysaccharide, LPS). This investigation has provided key features on the relationship between oxidative stress and mitochondrial respiratory chain activity defects. LPS treatment resulted in an increase in the expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase 4 (NOX-4), suggesting the cytosolic overexpression of nitric oxide and superoxide anion, the primary reactive nitrogen species (RNS) and reactive oxygen species (ROS). This oxidant state seemed to interrupt mitochondrial oxidative phosphorylation by reducing cytochrome c oxidase activity. As a consequence, disruptions in the electron transport and the proton pumping across the mitochondrial inner membrane occurred, leading to a decrease of the mitochondrial membrane potential, a release of apoptotic-inducing factors and a depletion of adenosine triphosphate. Interestingly, after being targeted by RNS and ROS, mitochondria became in turn producer of ROS, thus contributing to increase the mitochondrial dysfunction. The role of oxidants in mitochondrial dysfunction was further confirmed by the use of iNOS inhibitors or antioxidants that preserve cytochrome c oxidase activity and prevent mitochondrial membrane potential dissipation. These results suggest that sepsis-induced AKI should not only be regarded as failure of energy status but also as an integrated response, including transcriptional events, ROS signaling, mitochondrial activity and metabolic orientation such as apoptosis. PMID- 25019586 TI - An electromagnetic field disrupts negative geotaxis in Drosophila via a CRY dependent pathway. AB - Many higher animals have evolved the ability to use the Earth's magnetic field, particularly for orientation. Drosophila melanogaster also respond to electromagnetic fields (EMFs), although the reported effects are quite modest. Here we report that negative geotaxis in flies, scored as climbing, is disrupted by a static EMF, and this is mediated by cryptochrome (CRY), the blue-light circadian photoreceptor. CRYs may sense EMFs via formation of radical pairs of electrons requiring photoactivation of flavin adenine dinucleotide (FAD) bound near a triad of Trp residues, but mutation of the terminal Trp in the triad maintains EMF responsiveness in climbing. In contrast, deletion of the CRY C terminus disrupts EMF responses, indicating that it plays an important signalling role. CRY expression in a subset of clock neurons, or the photoreceptors, or the antennae, is sufficient to mediate negative geotaxis and EMF sensitivity. Climbing therefore provides a robust and reliable phenotype for studying EMF responses in Drosophila. PMID- 25019587 TI - Mercury bioaccumulation in estuarine wetland fishes: evaluating habitats and risk to coastal wildlife. AB - Estuaries are globally important areas for methylmercury bioaccumulation because of high methylmercury production rates and use by fish and wildlife. We measured total mercury (THg) concentrations in ten fish species from 32 wetland and open bay sites in San Francisco Bay Estuary (2005-2008). Fish THg concentrations (MUg/g dry weight +/- standard error) differed by up to 7.4* among estuary habitats. Concentrations were lowest in open bay (0.17 +/- 0.02) and tidal wetlands (0.42 +/- 0.02), and highest in managed seasonal saline wetlands (1.27 +/- 0.05) and decommissioned high salinity salt ponds (1.14 +/- 0.07). Mercury also differed among fishes, with Mississippi silversides (0.87 +/- 0.03) having the highest and longjaw mudsuckers (0.37 +/- 0.01) the lowest concentrations. Overall, 26% and 12% of fish exceeded toxicity benchmarks for fish (0.20 MUg/g wet weight) and piscivorous bird (0.30 MUg/g wet weight) health, respectively. Our results suggest that despite managed wetlands' limited abundance within estuaries, they may be disproportionately important habitats of Hg risk to coastal wildlife. PMID- 25019588 TI - Formation of a hetero[3]rotaxane by a dynamic component-swapping strategy. AB - Acid-catalysed scrambling of the mechanically interlocked components between two different homo[3]rotaxanes, constituted of dumbbells containing two secondary dialkylammonium ion recognition sites encircled by two [24]crown-8 rings, each containing a couple of imine bonds, affords a statistical mixture of a hetero[3]rotaxane along with the two homo[3]rotaxanes, indicating that neither selectivity nor cooperativity is operating during the assembly process. PMID- 25019589 TI - Blue absorption and red emission of Bi2+ in solids: strongly spin-orbit coupled 6p levels in low symmetry fields. AB - Wave function embedded cluster ab initio calculations on a (BiO8)(14-) cluster under the effects of a high symmetry Oh confinement potential are used to study the energies of the (2)P1/2, (2)P3/2(1), and (2)P3/2(2) spin-orbit coupling levels of the 6s(2)6p configuration of Bi(2+) in Oh, D4h, D2h, D4, D2d, D2, S4, C4v, C4, C3v, C2v, C2, Cs, and C1 fields, together with the (2)P1/2->(2)P3/2(1) and (2)P1/2->(2)P3/2(2) absorption oscillator strengths and the (2)P3/2(1) radiative lifetime. These levels are responsible for the blue absorptions and the red-orange emissions produced when Bi(2+) is doped in borates, phosphates, sulphates, and other hosts. It is found that the splitting of (2)P3/2 is mainly due to the tetragonal D4h and orthorhombic D2h components of the actual field. It is enhanced by Bi going towards two or four ligands. The intensities of the (2)P1/2->(2)P3/2(1) and (2)P1/2->(2)P3/2(2) absorptions are mostly induced by the Bi displacements and by tetragonal scalenoidal D2d fields. The most favorable fields for a large splitting of the (2)P3/2 level that can drive a red shift of the (2)P3/2(1) ->(2)P1/2 emission are the C2v and Cs fields resulting from the combination of D2h orthorhombic fields and Bi approaching two or four ligands on the main orthorhombic planes. PMID- 25019590 TI - Suppression of the N1 auditory evoked potential for sounds generated by the upper and lower limbs. AB - Sensory attenuation is typically observed for self-generated compared to externally generated action effects. In the present study we investigated whether auditory sensory suppression is modulated as a function of sounds being generated by the upper or lower limbs. We report sensory attenuation, as reflected in a reduced auditory N1 component, which was comparable for sounds generated by the lower and the upper limbs. Increasing temporal delays between actions and sounds did not modulate suppression of the N1 component, but did have an effect on the latency of the N1 component. In contrast, for the P2 component sensory suppression was only observed for sounds generated by the hands and presented at short latencies. These findings provide new insight into the functional and neural dynamics of sensory suppression and suggest the existence of comparable agency mechanisms for both the upper and the lower limbs. PMID- 25019591 TI - Trait hostility is associated with systemic inflammation in married couples: an actor-partner analysis. AB - Trait anger and hostility predict the development of coronary heart disease, and systemic inflammation may partly mediate this association. In a sample of 94 middle-aged and older married couples, we replicate research showing a within individuals (i.e., actor effect) association of trait hostility with high sensitivity C-reactive protein (hsCRP). As a novel extension of that research, the present study also examined the association of individuals' trait hostility with their partners' hsCRP (i.e., partner effect). Controlling for potential confounds, trait hostility, measured with the Buss-Perry Aggression Questionnaire, was significantly associated with both participants' own hsCRP, b=.0528 (SE=.0196), p=.008 and their partners' levels b=.0473 (SE=.0194), p=.016. Hence, the inflammatory correlates of trait hostility occur not only within individuals but between them, as well. The effects of unhealthy personality traits may extend to intimate partners and possibly other social network members. PMID- 25019592 TI - Electrostatic stabilization of beta-lactoglobulin fibrils at increased pH with cationic polymers. AB - In order to improve the stability of beta-lactoglobulin fibrils formed in acidic conditions to increased pH values (pH 3-7), formation of electrostatic complexes between fibrils and cationic polymers chitosan (CH), amine-terminated poly(ethylene glycol) (APEG), low molecular weight poly(ethylenimine) (LPEI), and high molecular weight poly(ethylenimine) (HPEI) was investigated by electrophoretic mobility, turbidimetry, and atomic force microscopy. Except for suspensions with APEG, addition of polycations increased zeta-potential values of the fibrils at pH 5, 6, and 7, verifying their interactions with fibrils. Maximal increase in zeta-potential at pH 7, indicating optimal electrostatic interactivity, occurred at concentrations (w/w) of 0.05, 0.01, and 0.01% (corresponding to 6.9, 50, and 4 MUmol.kg(-1)) for CH, LPEI, and HPEI, respectively. Turbidity of fibril solutions at pH 5, indicating isoelectric instability, was decreased significantly with increasing concentration of CH, LPEI, and BPEI, but not with added APEG. Turbidity was increased at pH 7 with added polycation, except for suspensions containing >=0.02% HPEI. Fibril length and resistance to aggregation, as observed by atomic force microscopy, were increased at pH 5 with increasing concentration of CH and LPEI, yet only HPEI was capable of maintaining the morphology of fibrils at pH 7. Calculated persistence lengths of the fibrils, as compared to pure fibrils at pH 3 (~4 MUm), were only slightly reduced at pH 5 with CH and at pH 7 with HPEI, but increased at pH 5 with LPEI and HPEI. Improvement in the stability of beta-lactoglobulin fibrils at higher pH conditions with the addition of polycations will contribute to their potential utilization in packaging, food, and pharmaceutical applications. PMID- 25019593 TI - A novel microRNA regulates osteoclast differentiation via targeting protein inhibitor of activated STAT3 (PIAS3). AB - MicroRNAs (miRNAs) involve in the regulation of a wide range of physiological processes. Recent studies suggested that miRNAs might play a role in osteoclast differentiation. Here, we identify a new miRNA (miR-9718) in primary mouse osteoclasts that promotes osteoclast differentiation by repressing protein inhibitor of activated STAT3 (PIAS3) at the post-transcriptional level. MiR-9718 was found to be transcribed during osteoclastogenesis, which was induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL). Overexpression of miR-9718 in RAW 264.7 cells promoted M-CSF and RANKL-induced osteoclastogenesis, whereas inhibition of miR 9718 attenuated it. PIAS3 was predicted to be a target of miR-9718. Luciferase reporter gene validated the prediction. Transfection of pre-miR-9718 in RAW 264.7 cells induced by both M-CSF and RANKL inhibited expression of PIAS3 protein, while the mRNA levels of PIAS3 were not attenuated. In vivo, our study showed that silencing of miR-9718 using a specific antagomir inhibited bone resorption and increased bone mass in mice receiving ovariectomy (OVX) and in sham-operated control mice. Thus, our study showed that miR-9718 played an important role in osteoclast differentiation via targeting PIAS3 both in vitro and in vivo. PMID- 25019594 TI - Does collagen trigger the recruitment of osteoblasts into vacated bone resorption lacunae during bone remodeling? AB - Osteoblast recruitment during bone remodeling is obligatory to re-construct the bone resorbed by the osteoclast. This recruitment is believed to be triggered by osteoclast products and is therefore likely to start early during the remodeling cycle. Several osteoclast products with osteoblast recruitment potential are already known. Here we draw the attention on the osteoblast recruitment potential of the collagen that is freshly demineralized by the osteoclast. Our evidence is based on observations on adult human cancellous bone, combined with in vitro assays. First, freshly eroded surfaces where osteoblasts have to be recruited show the presence of non-degraded demineralized collagen and close cell-collagen interactions, as revealed by electron microscopy, while surface-bound collagen strongly attracts osteoblast lineage cells in a transmembrane migration assay. Compared with other extracellular matrix molecules, collagen's potency was superior and only equaled by fibronectin. Next, the majority of the newly recruited osteoblast lineage cells positioned immediately next to the osteoclasts exhibit uPARAP/Endo180, an endocytic collagen receptor reported to be involved in collagen internalization and cell migration in various cell types, and whose inactivation is reported to lead to lack of bone formation and skeletal deformities. In the present study, an antibody directed against this receptor inhibits collagen internalization in osteoblast lineage cells and decreases to some extent their migration to surface-bound collagen in the transmembrane migration assay. These complementary observations lead to a model where collagen demineralized by osteoclasts attracts surrounding osteoprogenitors onto eroded surfaces, and where the endocytic collagen receptor uPARAP/Endo180 contributes to this migration, probably together with other collagen receptors. This model fits recent knowledge on the position of osteoprogenitor cells immediately next to remodeling sites in adult human cancellous bone. PMID- 25019595 TI - gamma-Tocotrienol protects against ovariectomy-induced bone loss via mevalonate pathway as HMG-CoA reductase inhibitor. AB - gamma-Tocotrienol (GT3), an analogue of vitamin E, has gained increasing scientific interest recently as it provides significant health benefits. GT3 exerts its biological effects not only by virtue of antioxidant properties but also by inhibiting hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Studies have reported that the mevalonate pathway is relevant for bone metabolism and HMG-CoA reductase inhibitors can increase bone mass and are useful in osteoporosis therapy. However, whether it is involved in the bone anabolic activity of GT3 is not clear. This study was conducted to investigate the ability of GT3 to protect against ovariectomy-induced bone loss, as well as the correlation between the protections and mevalonate pathway. Results showed that mice supplemented with 100mg/kg emulsified GT3 via subcutaneous injection once per month for three months were significantly protected from ovariectomy-induced bone loss as evaluated by various bone structural parameters, bone metabolic gene expression levels and serum levels of biochemical markers for bone resorption and bone formation. Importantly, the effect of GT3 on preventing against ovariectomy induced bone loss could be reversed by daily supplementation with mevalonate, indicating that GT3 may via an HMG-CoA reductase-dependent mechanism to protect against ovariectomy-induced bone loss. Our results suggest that GT3 is suitable as dietary supplement and has potential as an alternative drug to treat or prevent osteoporosis. PMID- 25019596 TI - Quinolone-based HDAC inhibitors. AB - HDAC inhibitors emerged as promising drug candidates in combating wide variety of cancers. At present, two of the compounds SAHA and Romidepsin were approved by FDA for cutaneous T-cell lymphoma and many are in various clinical phases. A new quinolone cap structure was explored with hydroxamic acid as zinc-binding group (ZBG). The pan HDAC inhibitory and antiproliferative activities against three human cancer cell lines HCT-116 (colon), NCI-H460 (lung) and U251 (glioblastoma) of the compounds (4a-4w) were evaluated. Introduction of heterocyclic amines in CAP region increased the enzyme inhibitory and antiproliferative activities and few of the compounds tested are metabolically stable in both MLM and HLM. PMID- 25019597 TI - Ethanol-based in situ bioremediation of acidified, nitrate-contaminated groundwater. AB - A novel approach for the in situ bioremediation of acidified, nitrate contaminated groundwater was developed. Ethanol was introduced into the groundwater to enhance the activity of intrinsic denitrifying micro-organisms. Infiltration of the carbon source was made via an infiltration gallery constructed in the unsaturated zone to avoid clogging problems and to allow wider distribution of ethanol in the groundwater. The changes in the groundwater geochemistry and soil gas composition were monitored at the site to evaluate the efficiencies of the infiltration system and nitrate removal. Moreover, the impact of pH and ethanol addition on the denitrification rate was studied in laboratory. A reduction of 95% was achieved in the groundwater nitrate concentrations during the study. Neither clogging problems nor inefficient introduction of ethanol into the saturated zone were observed. Most crucial to the denitrifying communities was pH, values above 6 were required for efficient denitrification. PMID- 25019598 TI - Contrasting effects of arachidonic acid and docosahexaenoic acid membrane incorporation into cardiomyocytes on free cholesterol turnover. AB - The preservation of a constant pool of free cholesterol (FC) is critical to ensure several functions of cardiomyocytes. We investigated the impact of the membrane incorporation of arachidonic acid (C20:4 omega6, AA) or docosahexaenoic acid (C22:6 omega3, DHA) as omega6 or omega3 polyunsaturated fatty acids (PUFAs) on cholesterol homeostasis in primary cultures of neonatal rat cardiac myocytes. We measured significant alterations to the phospholipid FA profiles, which had markedly different omega6/omega3 ratios between the AA and DHA cells (13 vs. 1). The AA cells showed a 2.7-fold lower cholesterol biosynthesis than the DHA cells. Overall, the AA cells showed 2-fold lower FC masses and 2-fold higher cholesteryl ester masses than the DHA cells. The AA cells had a lower FC to phospholipid ratio and higher triglyceride levels than the DHA cells. Moreover, the AA cells showed a 40% decrease in ATP binding cassette transporter A1 (ABCA1)-mediated and a 19% decrease in ABCG1-mediated cholesterol efflux than the DHA cells. The differences in cholesterol efflux pathways induced by AA or DHA incorporation were not caused by variations in ABCs transporter expression and were reduced when ABC transporters were overexpressed by exposure to LXR/RXR agonists. These results show that AA incorporation into cardiomyocyte membranes decreased the FC turnover by markedly decreasing the endogenous cholesterol synthesis and by decreasing the ABCA1- and ABCG1-cholesterol efflux pathways, whereas DHA had the opposite effects. We propose that these observations may partially contribute to the beneficial effects on the heart of a diet containing a high omega3/omega6 PUFA ratio. PMID- 25019599 TI - Are metacognitive processes associated with posttraumatic stress symptom severity following acquired brain injury? AB - PURPOSE: Although posttraumatic stress disorder (PTSD) after acquired brain injury (ABI) is relatively common, its causal mechanisms remain speculative and little research has considered psychological perspectives. The current study aimed to examine whether metacognitive variables were associated with posttraumatic stress symptom (PTSS) severity in individuals with an ABI. METHODS: Participants who had a traumatic brain injury (n = 47) or subarachnoid haemorrhage (n = 93) completed questionnaires related to demographic, clinical, social support and metacognitive variables. Correlation analyses and a hierarchical multiple regression analysis, with total PTSS severity used as the outcome variable, were conducted. RESULTS: Results demonstrated that metacognitive factors were correlated with PTSS severity and were able to explain an additional and significant amount of variance in PTSS severity within the regression analysis. CONCLUSIONS: The results provide preliminary support that metacognitive variables are associated with PTSS after ABI. Clinical implications within rehabilitative settings are discussed, as well as theoretical and research implications in the context of the study's limitations. IMPLICATIONS FOR REHABILITATION: Posttraumatic stress disorder (PTSD) can impede quality of life after brain injury. Clinical, social and metacognitive processes all influence the development of PTSD after brain injury and should be considered within rehabilitative care plans. Rehabilitative care plans should incorporate interventions for PTSD when appropriate, and metacognitive interventions could prove beneficial. PMID- 25019600 TI - Cost-effectiveness of a one-year coaching program for healthy physical activity in early rheumatoid arthritis. AB - PURPOSE: To describe cost-effectiveness of the Physical Activity in Rheumatoid Arthritis (PARA) study intervention. METHOD: Costs were collected and estimated retrospectively. Cost-effectiveness was calculated based on the intervention cost per patient with respect to change in health status (EuroQol global visual analog scale--EQ-VAS and EuroQol--EQ-5D) and activity limitation (Health assessment questionnaire - HAQ) using cost-effectiveness- and cost-minimization analyses. RESULTS: Total cost of the one-year intervention program was estimated to be ?67 317 or ?716 per participant. Estimated difference in total societal cost between the intervention (IG) and control (CG) was ?580 per participant. Incremental cost effectiveness ratio (ICER) for one point (1/100) of improvement in EQ-VAS was estimated to be ?116. By offering the intervention to more affected participants in the IG compared to less affected participants, 15.5 extra points of improvement in EQ-VAS and 0.13 points of improvement on HAQ were gained at the same cost. "Ordinary physiotherapy" was most cost-effective with regard to EQ-5D. CONCLUSIONS: The intervention resulted in improved effect in health status for the IG with a cost of ?116 per extra point in VAS. The intervention was cost effective if targeted towards a subgroup of more affected patients when evaluating the effect using VAS and HAQ. IMPLICATIONS FOR REHABILITATION: The physical activity coaching intervention resulted in an improved effect on VAS for the intervention group, to a higher cost. In order to maximize cost effectiveness, this type of physical activity coaching intervention should be targeted towards patients largely affected by their RA. The intervention is cost effective from the patients' point of view, but not from that of the general population. PMID- 25019601 TI - Reasoning about intentions: counterexamples to reasons for actions. AB - Four experiments tested the idea that people distinguish between biconditional, conditional, and enabling intention conditionals by thinking about counterexamples. The experiments examined intention conditionals that contain different types of reasons for actions, such as beliefs, goals, obligations, and social norms, based on a corpus of 48 intention conditionals established through an extensive materials test (n = 136). Experiment 1 (n = 19) showed that retrieved alternative reasons suppress the affirmation of the consequent and denial of the antecedent inferences from conditional intentions, whereas retrieved disabling reasons suppress the modus ponens and modus tollens inferences from enabling intentions. Experiment 2 (n = 61) showed that the suppression effects also occur for explicitly provided alternatives and disablers, for a large corpus of 80 intention conditionals. Experiment 3 (n = 60) showed that the suppression effects also occur for unfamiliar content, for which participants cannot rely on prior knowledge or beliefs about probabilities. Experiment 4 (n = 26) showed that participants retrieve alternatives and disablers readily for intentions just as they do for causal conditionals. The implications of the results for alternative accounts based on possibilities and probabilities are discussed. PMID- 25019602 TI - Strategic flexibility in computational estimation for Chinese- and Canadian educated adults. AB - The purpose of the present study was to examine factors that influence strategic flexibility in computational estimation for Chinese- and Canadian-educated adults. Strategic flexibility was operationalized as the percentage of trials on which participants chose the problem-based procedure that best balanced proximity to the correct answer with simplification of the required calculation. For example, on 42 * 57, the optimal problem-based solution is 40 * 60 because 2,400 is closer to the exact answer 2,394 than is 40 * 50 or 50 * 60. In Experiment 1 (n = 50), where participants had free choice of estimation procedures, Chinese educated participants were more likely to choose the optimal problem-based procedure (80% of trials) than Canadian-educated participants (50%). In Experiment 2 (n = 48), participants had to choose 1 of 3 solution procedures. They showed moderate strategic flexibility that was equal across groups (60%). In Experiment 3 (n = 50), participants were given the same 3 procedure choices as in Experiment 2 but different instructions and explicit feedback. When instructed to respond quickly, both groups showed moderate strategic flexibility as in Experiment 2 (60%). When instructed to respond as accurately as possible or to balance speed and accuracy, they showed very high strategic flexibility (greater than 90%). These findings suggest that solvers will show very different levels of strategic flexibility in response to instructions, feedback, and problem characteristics and that these factors interact with individual differences (e.g., arithmetic skills, nationality) to produce variable response patterns. PMID- 25019603 TI - Vectorial nanoscale mapping of optical antenna fields by single molecule dipoles. AB - Optical nanoantennas confine light on the nanoscale, enabling strong light-matter interactions and ultracompact optical devices. Such confined nanovolumes of light have nonzero field components in all directions (x, y, and z). Unfortunately mapping of the actual nanoscale field vectors has so far remained elusive, though antenna hotspots have been explored by several techniques. In this paper, we present a novel method to probe all three components of the local antenna field. To this end a resonant nanoantenna is fabricated at the vertex of a scanning tip. Next, the nanoantenna is deterministically scanned in close proximity to single fluorescent molecules, whose fixed excitation dipole moment reads out the local field vector. With nanometer molecular resolution, we distinctly map x-, y-, and z-field components of the dipole antenna, i.e. a full vectorial mode map, and show good agreement with full 3D FDTD simulations. Moreover, the fluorescence polarization maps the localized coupling, with emission through the longitudinal antenna mode. Finally, the resonant antenna probe is used for single molecule imaging with 40 nm fwhm response function. The total fluorescence enhancement is 7.6 times, while out-of-plane molecules, almost undetectable in far-field, are made visible by the strong antenna z-field with a fluorescence enhancement up to 100 times. Interestingly, the apparent position of molecules shifts up to 20 nm depending on their orientation. The capability to resolve orientational information on the single molecule level makes the scanning resonant antenna an ideal tool for extreme resolution bioimaging. PMID- 25019604 TI - Evaluation of PCR in the diagnosis of canine leishmaniasis in two different epidemiological regions: Campinas (SP) and Teresina (PI), Brazil. AB - SUMMARY Using the polymerase chain reaction (PCR) test for diagnosis of canine leishmaniasis has greater sensitivity and specificity than culture and visualization of the parasite. This study compares PCR for the diagnosis of the genus and species of Leishmania with serological techniques used for the control of canine visceral leishmaniasis (CVL) in Brazil, considering two regions. We analysed peripheral blood samples collected from 195 dogs in the Campinas (SP) and Teresina (PI) regions. ELISA was performed as a serological method and PCR was performed using specific primers for the genus Leishmania spp. and the species Leishmania chagasi. In Campinas, a greater sensitivity of PCR (88.24%) (P = 0.0455) compared to Teresina (14.71%) (P < 0.0001) was observed, and an agreement was observed for Cohen's kappa index (0.9096). Both PCR and ELISA showed discordance for sensitivity (Campinas 100%, Teresina 21.74%), specificity (Campinas 30.77%, Teresina 100%), positive predictive value (Campinas 68.97%, Teresina 100%), negative predictive value (Campinas 100%, Teresina 37.94%) and Cohen's kappa index (0.1238). This study confirms the importance of PCR in analysis of the canine reservoir, and as an effective method for the detection of active and recent infection. PMID- 25019605 TI - Anti-fouling behavior of hyperbranched polyglycerol-grafted poly(ether sulfone) hollow fiber membranes for osmotic power generation. AB - To sustain high performance of osmotic power generation by pressure-retarded osmosis (PRO) processes, fouling on PRO membranes must be mitigated. This is especially true for the porous support of PRO membranes because its porous structure is very prone to fouling by feeding river water. For the first time, we have successfully designed antifouling PRO thin-film composite (TFC) membranes by synthesizing a dendritic hydrophilic polymer with well-controlled grafting sites, hyperbranched polyglycerol (HPG), and then grafting it on poly(ether sulfone) (PES) hollow fiber membrane supports. Compared to the pristine PES membranes, polydopamine modified membranes, and conventional poly(ethylene glycol) (PEG) grafted membranes, the HPG grafted membranes show much superior fouling resistance against bovine serum albumin (BSA) adsorption, E. coli adhesion, and S. aureus attachment. In high-pressure PRO tests, the PES TFC membranes are badly fouled by model protein foulants, causing a water flux decline of 31%. In comparison, the PES TFC membrane grafted by HPG not only has an inherently higher water flux and a higher power density but also exhibits better flux recovery up to 94% after cleaning and hydraulic pressure impulsion. Clearly, by grafting the properly designed dendritic polymers to the membrane support, one may substantially sustain PRO hollow fiber membranes for power generation. PMID- 25019606 TI - Electrolessly deposited electrospun metal nanowire transparent electrodes. AB - Metal nanowire (MNW) transparent electrodes have been widely developed for their promising sheet resistance (R(s))-transmittance (T) performance, excellent mechanical flexibility, and facile synthesis. How to lower the junction resistance without compromising optical transmittance has become the key issue in enhancing their performance. Here we combine electrospinning and electroless deposition to synthesize interconnected, ultralong MNW networks. For both silver and copper nanowire networks, the R(s) and T values reach around 10 Omega/sq and 90%, respectively. This process is scalable and takes place at ambient temperature and pressure, which opens new opportunities for flexible electronics and roll-to-roll large-scale manufacturing. PMID- 25019607 TI - Effect of blockade of mGluR5 on stress hormone release and its gene expression in the adrenal gland. AB - The aim of this study was to verify the presence of metabotropic glutamate receptor subtype 5 (mGluR5) in the adrenal gland of male rats of 2 different strains, and to test the hypothesis that treatment with mGluR5 antagonist 2 methyl-6-(phenylethynyl)-pyridine (MPEP) affects hormone release and adrenal gene expression of mGluR5 under conditions of stress. The results clearly show the gene expression of mGluR5 in the adrenal gland in both the adrenal cortex and medulla. Treatment with the glutamate release inhibitor riluzole (4 mg.(kg body mass)(-1).day(-1) for 2 weeks) failed to modify mRNA levels of either the mGluR5 or NR1 subunit of the NMDA receptor in the adrenal glands, as measured by real time PCR. Blockade of mGluR5 with MPEP (1 mg.kg(-1) for 4 days) increased corticosterone but not catecholamine release during restraint stress (20 min). Treatment with MPEP had no effect on mRNA levels coding for steroidogenic factors StAR and SF-1, and decreased mGluR5 gene expression in the adrenal gland. In conclusion, mGluR5 is not likely to play a significant role in stress-induced catecholamine release. Pharmacological blockade of mGluR5 has a modest influence on the hypothalamic-pituitary-adrenocortical axis, as reflected in adrenal hypertrophy and increased corticosterone concentrations. PMID- 25019608 TI - The road to gold: training and peaking characteristics in the year prior to a gold medal endurance performance. AB - PURPOSE: To describe training variations across the annual cycle in Olympic and World Champion endurance athletes, and determine whether these athletes used tapering strategies in line with recommendations in the literature. METHODS: Eleven elite XC skiers and biathletes (4 male; 28+/-1 yr, 85+/-5 mL x min(-1) x kg(-1) VO2max, 7 female, 25+/-4 yr, 73+/-3 mL x min(-1) x kg(-1) VO2max) reported one year of day-to-day training leading up to the most successful competition of their career. Training data were divided into periodization and peaking phases and distributed into training forms, intensity zones and endurance activity forms. RESULTS: Athletes trained ~800 h/500 sessions x year(-1), including ~500 h x year(-1) of sport-specific training. Ninety-four percent of all training was executed as aerobic endurance training. Of this, ~90% was low intensity training (LIT, below the first lactate threshold) and 10% high intensity training (HIT, above the first lactate threshold) by time. Categorically, 23% of training sessions were characterized as HIT with primary portions executed at or above the first lactate turn point. Training volume and specificity distribution conformed to a traditional periodization model, but absolute volume of HIT remained stable across phases. However, HIT training patterns tended to become more polarized in the competition phase. Training volume, frequency and intensity remained unchanged from pre-peaking to peaking period, but there was a 32+/-15% (P<.01) volume reduction from the preparation period to peaking phase. CONCLUSIONS: The annual training data for these Olympic and World champion XC skiers and biathletes conforms to previously reported training patterns of elite endurance athletes. During the competition phase, training became more sport-specific, with 92% performed as XC skiing. However, they did not follow suggested tapering practice derived from short-term experimental studies. Only three out of 11 athletes took a rest day during the final 5 days prior to their most successful competition. PMID- 25019609 TI - Selective hydrogen production from formic acid decomposition on Pd-Au bimetallic surfaces. AB - Pd-Au catalysts have shown exceptional performance for selective hydrogen production via HCOOH decomposition, a promising alternative to solve issues associated with hydrogen storage and distribution. In this study, we utilized temperature-programmed desorption (TPD) and reactive molecular beam scattering (RMBS) in an attempt to unravel the factors governing the catalytic properties of Pd-Au bimetallic surfaces for HCOOH decomposition. Our results show that Pd atoms at the Pd-Au surface are responsible for activating HCOOH molecules; however, the selectivity of the reaction is dictated by the identity of the surface metal atoms adjacent to the Pd atoms. Pd atoms that reside at Pd-Au interface sites tend to favor dehydrogenation of HCOOH, whereas Pd atoms in Pd(111)-like sites, which lack neighboring Au atoms, favor dehydration of HCOOH. These observations suggest that the reactivity and selectivity of HCOOH decomposition on Pd-Au catalysts can be tailored by controlling the arrangement of surface Pd and Au atoms. The findings in this study may prove informative for rational design of Pd Au catalysts for associated reactions including selective HCOOH decomposition for hydrogen production and electro-oxidation of HCOOH in the direct formic acid fuel cell. PMID- 25019610 TI - Luminescent CePO4:Tb colloids for H2O2 and glucose sensing. AB - Hydrogen peroxide (H2O2) is an essential molecule in intracellular signaling transduction and normal cell functions. It is critical to be able to detect H2O2 quantitatively in cellular processes for getting useful physiological information. Herein, we developed a novel fluorescent probe for H2O2 sensing, CePO4:Tb colloidal solution. Upon addition of H2O2, the luminescence of the colloidal CePO4:Tb solution responds linearly in a wide H2O2 concentration range of 0-200 MUM, allowing for quantitative detection of H2O2. The H2O2 sensing by this method exhibits a rapid response within several minutes, a detection limit of 1.03 MUM H2O2, and a relative standard deviation lower than 3.1%. This sensing material for H2O2 is also suitable for the detection of glucose since H2O2 is generated via the catalytic oxidation of glucose by oxidase enzymes. In addition to a wide linear response, a low detection limit and a high reproducibility, our present method for glucose sensing shows a highly specific response to glucose in a mixed carbohydrate solution due to the specificity of glucose oxidase to glucose. This lanthanide-based fluorescent sensing material might have potential for detecting H2O2 and glucose in biological applications. PMID- 25019611 TI - Neuronal subtype specification in establishing mammalian neocortical circuits. AB - The functional integrity of the neocortical circuit relies on the precise production of diverse neuron populations and their assembly during development. In recent years, extensive progress has been made in the understanding of the mechanisms that control differentiation of each neuronal type within the neocortex. In this review, we address how the elaborate neocortical cytoarchitecture is established from a simple neuroepithelium based on recent studies examining the spatiotemporal mechanisms of neuronal subtype specification. We further discuss the critical events that underlie the conversion of the stem amniotes cerebrum to a mammalian-type neocortex, and extend these key findings in the light of mammalian evolution to understand how the neocortex in humans evolved from common ancestral mammals. PMID- 25019612 TI - Phase winding of a nematic liquid crystal by dynamic localized reorientation of an azo-based self-assembled monolayer. AB - Azobenzene-based molecules forming a self-assembled monolayer (SAM) tethered to a glass surface are highly photosensitive and readily reorient liquid crystals in contact with them when illuminated with polarized actinic light. We probe the coupling of such monolayers to nematic liquid crystal in a hybrid cell by studying the dynamics of liquid crystal reorientation in response to local orientational changes of the monolayer induced by a focused actinic laser with a rotating polarization. The steady increase in the azimuth of the mean molecular orientation of the SAM around the laser beam locally reorients the nematic, winding up an extended set of nested rings of splay-bend nematic director reorientation until the cumulative elastic torque exceeds that of the surface coupling within the beam, after which the nematic director starts to slip. Quantitative analyses of the ring dynamics allow measurements of the anchoring strength of the azo-SAM and its interaction with the nematic liquid crystal. PMID- 25019614 TI - Self-assembled monolayers of thiols adsorbed on Au/ZnO-functionalized silica nanosprings: photoelectron spectroscopy-analysis and detection of vaporized explosives. AB - Self-assembled monolayers (SAMs) of thiols of L-cysteine, 6-mercaptohexanol, 4 mercaptobenzoic acid, DL-thioctic acid and 11-(1-pyrenyl)-1-undecathiol, which have been selected for their propensity to interact with vaporized explosives, have been attached from solution onto gold decorated ZnO-coated nanosprings. X ray and ultraviolet photoelectron spectroscopies (XPS and UPS) have been used to investigate the surface electronic structure of the SAMs coated nanosprings. On the basis of XPS analysis, it has been determined that the packing densities of L cysteine, 6-mercaptohexanol, 4-mercaptobenzoic acid, DL-thioctic acid and 11-(1 pyrenyl)-1-undecathiol on gold (zinc oxide) are 5.42 * 10(14) (2.83 * 10(14)), 3.26 * 10(14) (2.54 * 10(14)), 9.50 * 10(13), 2.55 * 10(14) (1.12 * 10(14)), and 5.23 * 10(13) molecules/cm(2), respectively. A single S 2p core level doublet is observed for 4-mercaptobenzoic acid and 11-(1-pyrenyl)-1-undecathiol, which is assigned to the S-Au bond. The S 2p core level for L-cysteine, 6-mercaptohexanol, and DL-thioctic acid consist of two doublets, where one is S-Au bond and the other is the S-Zn bond. Analysis of the C/S ratios agrees well with the stoichiometry of the respective thiols. UPS analysis shows that the hybridization of S 3p states and Au d-bands produces antibonding and bonding states, above and below the Au d-bands, which is characteristic of molecular chemisorption on Au nanoparticles. Gas sensors were constructed with thiolated nanosprings and their responsiveness to ammonium nitrate at 100-150 degrees C was tested. Nanosprings sensors functionalized with 4-mercaptobenzoic acid and 6-mercaptohexanol showed the strongest responses by a factor of 4 to 5 relative to the less responsive thiols. The response to ammonium nitrate can be correlated to the packing density and ordering of the SAMs. PMID- 25019613 TI - Substitution at aspartic acid 1128 in the SARS coronavirus spike glycoprotein mediates escape from a S2 domain-targeting neutralizing monoclonal antibody. AB - The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is the etiological agent for the infectious disease, SARS, which first emerged 10 years ago. SARS CoV is a zoonotic virus that has crossed the species barriers to infect humans. Bats, which harbour a diverse pool of SARS-like CoVs (SL-CoVs), are believed to be the natural reservoir. The SARS-CoV surface Spike (S) protein is a major antigenic determinant in eliciting neutralizing antibody production during SARS CoV infection. In our previous work, we showed that a panel of murine monoclonal antibodies (mAbs) that target the S2 subunit of the S protein are capable of neutralizing SARS-CoV infection in vitro (Lip KM et al, J Virol. 2006 Jan; 80(2): 941-50). In this study, we report our findings on the characterization of one of these mAbs, known as 1A9, which binds to the S protein at a novel epitope within the S2 subunit at amino acids 1111-1130. MAb 1A9 is a broadly neutralizing mAb that prevents viral entry mediated by the S proteins of human and civet SARS-CoVs as well as bat SL-CoVs. By generating mutant SARS-CoV that escapes the neutralization by mAb 1A9, the residue D1128 in S was found to be crucial for its interaction with mAb 1A9. S protein containing the substitution of D1128 with alanine (D1128A) exhibited a significant decrease in binding capability to mAb 1A9 compared to wild-type S protein. By using a pseudotyped viral entry assay, it was shown that the D1128A substitution in the escape virus allows it to overcome the viral entry blockage by mAb 1A9. In addition, the D1128A mutation was found to exert no effects on the S protein cell surface expression and incorporation into virion particles, suggesting that the escape virus retains the same viral entry property as the wild-type virus. PMID- 25019615 TI - Stereoselective total synthesis of the putative structure of nitraraine. AB - After the structure originally proposed for nitraraine was shown to be incorrect by total synthesis, the alternative structure 5 was recently suggested for the alkaloid on biosynthetic grounds and by comparison with the (1)H NMR data of tangutorine. The unambiguous synthesis of 5 is reported from tryptophanol and ketodiester 6, via oxazoloquinolone lactam 7. However, the melting point and (1)H NMR data of 5 did not match those reported for the natural product. PMID- 25019616 TI - Molecular detection of Chlamydia trachomatis and other sexually transmitted bacteria in semen of male partners of infertile couples in Tunisia: the effect on semen parameters and spermatozoa apoptosis markers. AB - This study was undertaken to determine the prevalence of Chlamydia trachomatis, Mycoplasmas, and Ureaplasmas in semen samples of the male partners of infertile couples and to investigate whether Chlamydia trachomatis could initiate apoptosis in human spermatozoa. A total of 85 males partners of infertile couples undergoing routine semen analysis according to World Health Organization guidelines were included. Specimens were examined for the presence of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum and Ureaplasma parvum by Real time PCR (qPCR). Semen specimens were analysed for the appearance of apoptotic markers (sperm DNA fragmentation, activated caspase 3 levels, mitochondrial membrane potential (DeltaPsim)) using flow cytometry. C. trachomatis, N. gonorrhoeae, U. urealyticum, M genitalium were detected in semen samples of 13 (15.2%), 5 (5.8%), 5 (5.8%) and 3 (3.5%) male partners of infertile couples, respectively. M. hominis and U. parvum were detected in semen sample of only one patient (1.1%). The semen of infertile men positive for C. trachomatis showed lower mean of semen count and lower rapid progressive motility (category [a]) of spermatozoa compared to uninfected men with statistically significances (p = 0.02 and p = 0.04, respectively). Flow cytometry analyses demonstrated a significant increase of the mean rate of semen with low DeltaPsim and caspase 3 activation of infertile men positive for C. trachomatis compared to uninfected men (p = 0.006 and p = 0.001, respectively). DNA fragmentation was also increased in sperm of infertile men positive for C. trachomatis compared to uninfected men but without statistical significances (p = 0.62). Chlamydial infection was associated to loss of DeltaPsim and caspase 3activation. Thus, C. trachomatis infection could be incriminated in apoptosis induction of spermatozoa. These effects may explain the negative direct impact of C. trachomatis infection on sperm fertilizing ability. PMID- 25019617 TI - Identification of functional amino acid residues involved in polyamine and agmatine transport by human organic cation transporter 2. AB - Polyamine (putrescine, spermidine and spermine) and agmatine uptake by the human organic cation transporter 2 (hOCT2) was studied using HEK293 cells transfected with pCMV6-XL4/hOCT2. The Km values for putrescine and spermidine were 7.50 and 6.76 mM, and the Vmax values were 4.71 and 2.34 nmol/min/mg protein, respectively. Spermine uptake by hOCT2 was not observed at pH 7.4, although it inhibited both putrescine and spermidine uptake. Agmatine was also taken up by hOCT2, with Km value: 3.27 mM and a Vmax value of 3.14 nmol/min/mg protein. Amino acid residues involved in putrescine, agmatine and spermidine uptake by hOCT2 were Asp427, Glu448, Glu456, Asp475, and Glu516. In addition, Glu524 and Glu530 were involved in putrescine and spermidine uptake activity, and Glu528 and Glu540 were weakly involved in putrescine uptake activity. Furthermore, Asp551 was also involved in the recognition of spermidine. These results indicate that the recognition sites for putrescine, agmatine and spermidine on hOCT2 strongly overlap, consistent with the observation that the three amines are transported with similar affinity and velocity. A model of spermidine binding to hOCT2 was constructed based on the functional amino acid residues. PMID- 25019618 TI - Solubility and aggregation of Gly(5) in water. AB - Experimentally, the solubility of oligoglycines in water decreases as its length increases. Computationally, the free energy of solvation becomes more favorable with chain length for short (n = 1-5) oligoglycines. We present results of large scale simulations with over 600 pentaglycines at varying concentrations in explicit solvent to consider the mechanism of aggregation. The solubility limit of Gly5 for the force field used was calculated and compared with experimental values. We find that intermolecular interactions between pentaglycines are favored over interactions between glycine and water, leading to their aggregation. However, the interaction driving peptide associations, liquid-liquid phase separation, are not predominantly hydrogen bonding. Instead, non-hydrogen bonding interactions between partially charged atoms on the peptide backbone allow the formation of dipole-dipole and charge layering correlations that mechanistically stabilize the formation of large, stable peptide clusters. PMID- 25019620 TI - Chinese wild-growing Vitis amurensis ICE1 and ICE2 encode MYC-type bHLH transcription activators that regulate cold tolerance in Arabidopsis. AB - Winter hardiness is an important trait for grapevine breeders and producers, so identification of the regulatory mechanisms involved in cold acclimation is of great potential value. The work presented here involves the identification of two grapevine ICE gene homologs, VaICE1 and VaICE2, from an extremely cold-tolerant accession of Chinese wild-growing Vitis amurnensis, which are phylogenetically related to other plant ICE1 genes. These two structurally different ICE proteins contain previously reported ICE-specific amino acid motifs, the bHLH-ZIP domain and the S-rich motif. Expression analysis revealed that VaICE1 is constitutively expressed but affected by cold stress, unlike VaICE2 that shows not such changed expression as a consequence of cold treatment. Both genes serve as transcription factors, potentiating the transactivation activities in yeasts and the corresponding proteins localized to the nucleus following transient expression in onion epidermal cells. Overexpression of either VaICE1 or VaICE2 in Arabidopsis increase freezing tolerance in nonacclimated plants. Moreover, we show that they result in multiple biochemical changes that were associated with cold acclimation: VaICE1/2-overexpressing plants had evaluated levels of proline, reduced contents of malondialdehyde (MDA) and decreased levels of electrolyte leakage. The expression of downstream cold responsive genes of CBF1, COR15A, and COR47 were significantly induced in Arabidopsis transgenically overexpressing VaICE1 or VaICE2 upon cold stress. VaICE2, but not VaICE1 overexpression induced KIN1 expression under cold-acclimation conditions. Our results suggest that VaICE1 and VaICE2 act as key regulators at an early step in the transcriptional cascade controlling freezing tolerance, and modulate the expression levels of various low-temperature associated genes involved in the C-repeat binding factor (CBF) pathway. PMID- 25019621 TI - An iterative and targeted sampling design informed by habitat suitability models for detecting focal plant species over extensive areas. AB - Prioritizing areas for management of non-native invasive plants is critical, as invasive plants can negatively impact plant community structure. Extensive and multi-jurisdictional inventories are essential to prioritize actions aimed at mitigating the impact of invasions and changes in disturbance regimes. However, previous work devoted little effort to devising sampling methods sufficient to assess the scope of multi-jurisdictional invasion over extensive areas. Here we describe a large-scale sampling design that used species occurrence data, habitat suitability models, and iterative and targeted sampling efforts to sample five species and satisfy two key management objectives: 1) detecting non-native invasive plants across previously unsampled gradients, and 2) characterizing the distribution of non-native invasive plants at landscape to regional scales. Habitat suitability models of five species were based on occurrence records and predictor variables derived from topography, precipitation, and remotely sensed data. We stratified and established field sampling locations according to predicted habitat suitability and phenological, substrate, and logistical constraints. Across previously unvisited areas, we detected at least one of our focal species on 77% of plots. In turn, we used detections from 2011 to improve habitat suitability models and sampling efforts in 2012, as well as additional spatial constraints to increase detections. These modifications resulted in a 96% detection rate at plots. The range of habitat suitability values that identified highly and less suitable habitats and their environmental conditions corresponded to field detections with mixed levels of agreement. Our study demonstrated that an iterative and targeted sampling framework can address sampling bias, reduce time costs, and increase detections. Other studies can extend the sampling framework to develop methods in other ecosystems to provide detection data. The sampling methods implemented here provide a meaningful tool when understanding the potential distribution and habitat of species over multi-jurisdictional and extensive areas is needed for achieving management objectives. PMID- 25019622 TI - Simple signaling molecules for inductive bone regenerative engineering. AB - With greater than 500,000 orthopaedic procedures performed in the United States each year requiring a bone graft, the development of novel graft materials is necessary. We report that some porous polymer/ceramic composite scaffolds possess intrinsic osteoinductivity as shown through their capacity to induce in vivo host osteoid mineralization and in vitro stem cell osteogenesis making them attractive synthetic bone graft substitutes. It was discovered that certain low crystallinity ceramics partially dissociate into simple signaling molecules (i.e., calcium and phosphate ions) that induce stem cells to endogenously produce their own osteoinductive proteins. Review of the literature has uncovered a variety of simple signaling molecules (i.e., gases, ions, and redox reagents) capable of inducing other desirable stem cell differentiation through endogenous growth factor production. Inductive simple signaling molecules, which we have termed inducerons, represent a paradigm shift in the field of regenerative engineering where they can be utilized in place of recombinant protein growth factors. PMID- 25019624 TI - Long-term outcome of 114 adult JIA patients in a non-pediatric rheumatology institute in Japan. AB - OBJECTIVE: To evaluate the long-term outcome of patients with juvenile idiopathic arthritis (JIA) using data from a large cohort database, Institute of Rheumatology, Rheumatoid Arthritis, managed by the Tokyo Women's Medical University. METHODS: Of 182 patients identified from the database from 2000 to 2013, 114 were verified as having JIA. The transition of medical care and the contributions of biological DMARDs were evaluated. RESULTS: The mean age of the patients (93 females, 81.6%) at the latest examination was 36.6 +/- 13.3 years. The mean age at disease onset and mean disease duration were 11.6 +/- 3.4 and 25.0 +/- 13.3 years, respectively. Of the 114 patients, 106 (93.0%) had poly- or oligoarthritis. Only one-fourth transferred from general pediatricians or pediatric rheumatologists. More patients with recent disease onset were treated with biological DMARDs (16.7% in the 1970s, vs. 80.0% in the 2000s). Disease activity assessed with DAS28 was significantly lower when disease onset was more recent (3.9 +/- 1.3 for onset in the 1960s vs. 2.2 +/- 1.1 for onset in the 2000s, p = 0.04). The percentage of patients requiring orthopedic surgery has decreased (53.8% before the 1970s vs. 10.0% in the 2000s). CONCLUSION: Patients with more recent disease onset showed an improved outcome. Establishing and sharing a transition program among pediatric and non-pediatric rheumatologists is desirable. PMID- 25019623 TI - Spinal cord transection-induced allodynia in rats--behavioral, physiopathological and pharmacological characterization. AB - In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2*4, P2*7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1beta, IL 6 and TNF-alpha were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3-10 mg/kg s.c.) and tapentadol (10-20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain. PMID- 25019625 TI - Current status of cancer care for young patients with nasopharyngeal carcinoma in Jakarta, Indonesia. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is endemic in Indonesia and 20% of the patients are diagnosed before the age of 31. This study evaluates presentation and treatment outcome of young patients in Jakarta, in a tertiary referral centre. METHODS: Forty-nine patients under the age of 31, diagnosed with NPC between July 2004 and January 2007, were evaluated. Baseline data included histological type, stage of disease and presenting symptoms. We intended to follow all patients after diagnosis to reveal treatment outcome and overall survival (OS). RESULTS: All but two patients had advanced stage disease (94%), 7 (14%) had distant metastasis. The median interval between start of complaints and diagnosis was 9 months. Forty-two patients were planned for curative intent treatment. Eleven patients (26%) never started treatment, 2 patients did not complete treatment and 3 patients did not return after finishing treatment. Four patients died before radiation could start. Three patients died within 4 months after treatment. Nine patients (21%) had a complete response. Due to the high number of patients who were lost to follow-up (LFU), OS was analyzed as follows: a best-case (patients censored at last contact) and a worst-case scenario (assuming that patients who did not finish treatment or had disease at last contact would have died). The 2-year OS for patients without distant metastases was 39-71%. CONCLUSION: Treatment outcome for young patients with NPC in this institute was poor. Improvement can be achieved when NPC is diagnosed at an earlier stage and when there is better treatment compliance. PMID- 25019627 TI - Plant coumestans: recent advances and future perspectives in cancer therapy. AB - Natural products are often used in drug development due to their ability to form unique and diverse chemical structures. Coumestans are polycyclic aromatic plant secondary metabolites containing a coumestan moiety, which consists of a benzoxole fused to a chromen-2-one to form 1-Benzoxolo[3,2-c]chromen-6-one. These natural compounds are known for large number of biological activities. Many of their biological effects can be attributed to their action as phytoestrogens and polyphenols. In the last decade, anticancer effects of these compounds have been described in vitro but there is only limited number of studies based on models in vivo. More information concerning their in vivo bioavailability, stability, metabolism, toxicity, estrogenicity, cellular targets and drug interactions is therefore needed to proceed further to clinical studies. This review focuses on coumestans exhibiting anticancer properties and summarizes mechanisms of their toxicity to cancer cells. Moreover, the possible role of coumestans in cancer prevention is discussed. PMID- 25019626 TI - Cell-permeable parkin proteins suppress Parkinson disease-associated phenotypes in cultured cells and animals. AB - Parkinson's disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM13 and PM10) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo. PMID- 25019628 TI - Benign triton tumor: multidisciplinary approach to diagnosis and treatment. AB - Benign Triton tumor (neuromuscular choristoma) is a rare mass that most commonly occurs as a multinodular expansion of tissue in or around large nerves. Intracranial occurrence is uncommon. We report on a 4-year-old girl presenting with a right-sided facial mass and trismus. Imaging revealed a large, complex mass extending from the ventral aspect of the pons, along the trigeminal nerve, through the foramen ovale, and into the right infratemporal fossa. The lesion was partially enhancing, invaded adjacent infratemporal musculature, was associated with marked overgrowth of the right coronoid process, and induced bony erosion of the middle cranial fossa. After needle biopsy, a multidisciplinary team, including plastic surgery, otolaryngology, and neurosurgery, performed a combined, multistep, single-day surgical approach for resection. Unique to this case was the resection of the coronoid process, a modified middle fossa intradural and extradural approach, coupled with a transfacial infratemporal approach. Microscopically, the resected tissue showed skeletal muscle, fibrous tissue, and nerve in a disorganized arrangement characteristic of a benign Triton tumor. We present this case to illustrate diagnostic clues and pitfalls in the preoperative evaluation of a benign Triton tumor. We also highlight the pathologist's role as a partner in a multidisciplinary approach to diagnosis and treatment of this rare pediatric mass, potentially the largest Triton tumor in the head reported to date. PMID- 25019629 TI - Tandem mass spectrometry assays of palmitoyl protein thioesterase 1 and tripeptidyl peptidase activity in dried blood spots for the detection of neuronal ceroid lipofuscinoses in newborns. AB - We report new substrates for quantitative enzyme activity measurements of human palmitoyl protein thioesterase (PPT1) and tripeptidyl peptidase (TPP1) in dried blood spots from newborns using tandem mass spectrometry. Deficiencies in these enzyme activities due to inborn errors of metabolism cause neuronal ceroid lipofuscinoses. The assays use synthetic compounds that were designed to mimic the natural substrates. Incubation produces nanomole quantities of enzymatic products per a blood spot that are quantified by tandem mass spectrometry using synthetic internal standards and selected reaction monitoring. The assays utilize a minimum steps for sample workup and can be run in a duplex format for the detection of neuronal ceroid lipofuscinoses or potentially multiplexed with other mass spectrometry-based assays for newborn screening of lysosomal storage disorders. PMID- 25019630 TI - Paramagnetic and theoretical study of Y2@C81N: an endohedral azafullerene radical. AB - A metallofullerene radical Y2@C81N was synthesized and characterized by ESR spectroscopy and ab initio calculations. It was revealed that the molecule adopts an unique azafullerene C81N cage derived from C82-C(2v)(9), and two yttrium ions are entrapped to form the endohedral structure. The unpaired electron of Y2@C81N radical was calculated to mainly localize on the Y2 dimer, leading to large hyperfine coupling constants of 75.7 and 69.8 G for the two yttrium nuclei. PMID- 25019631 TI - Highly sensitive nuclease assays based on chemically modified DNA or RNA. AB - Nucleolytic enzymes are associated with various diseases, and several methods have been developed for their detection. DNase expression is modulated in such diseases as acute myocardial infarction, transient myocardial ischemia, oral cancer, stomach cancer, and malignant lymphoma, and DNase I is used in cystic fibroma therapy. RNase is used to treat mesothelial cancer because of its antiproliferative, cytotoxic, and antineoplastic activities. Angiogenin, an angiogenic factor, is a member of the RNase A family. Angiogenin inhibitors are being developed as anticancer drugs. In this review, we describe fluorometric and electrochemical techniques for detecting DNase and RNase in disease. Oligonucleotides having fluorescence resonance energy transfer (FRET)-causing chromophores are non-fluorescent by themselves, yet become fluorescent upon cleavage by DNase or RNase. These oligonucleotides serve as a powerful tool to detect activities of these enzymes and provide a basis for drug discovery. In electrochemical techniques, ferrocenyl oligonucleotides with or without a ribonucleoside unit are used for the detection of RNase or DNase. This technique has been used to monitor blood or serum samples in several diseases associated with DNase and RNase and is unaffected by interferents in these sample types. PMID- 25019633 TI - Solution to the SLAM problem in low dynamic environments using a pose graph and an RGB-D sensor. AB - In this study, we propose a solution to the simultaneous localization and mapping (SLAM) problem in low dynamic environments by using a pose graph and an RGB-D (red-green-blue depth) sensor. The low dynamic environments refer to situations in which the positions of objects change over long intervals. Therefore, in the low dynamic environments, robots have difficulty recognizing the repositioning of objects unlike in highly dynamic environments in which relatively fast-moving objects can be detected using a variety of moving object detection algorithms. The changes in the environments then cause groups of false loop closing when the same moved objects are observed for a while, which means that conventional SLAM algorithms produce incorrect results. To address this problem, we propose a novel SLAM method that handles low dynamic environments. The proposed method uses a pose graph structure and an RGB-D sensor. First, to prune the falsely grouped constraints efficiently, nodes of the graph, that represent robot poses, are grouped according to the grouping rules with noise covariances. Next, false constraints of the pose graph are pruned according to an error metric based on the grouped nodes. The pose graph structure is reoptimized after eliminating the false information, and the corrected localization and mapping results are obtained. The performance of the method was validated in real experiments using a mobile robot system. PMID- 25019632 TI - Bidirectional and multi-user telerehabilitation system: clinical effect on balance, functional activity, and satisfaction in patients with chronic stroke living in long-term care facilities. AB - BACKGROUND: The application of internet technology for telerehabilitation in patients with stroke has developed rapidly. OBJECTIVE: The current study aimed to evaluate the effect of a bidirectional and multi-user telerehabilitation system on balance and satisfaction in patients with chronic stroke living in long-term care facilities (LTCFs). METHOD: This pilot study used a multi-site, blocked randomization design. Twenty-four participants from three LTCFs were recruited, and the participants were randomly assigned into the telerehabilitation (Tele) and conventional therapy (Conv) groups within each LTCF. Tele group received telerehabilitation but the Conv group received conventional therapy with two persons in each group for three sessions per week and for four weeks. The outcome measures included Berg Balance Scale (BBS), Barthel Index (BI), and the telerehabilitation satisfaction of the participants. SETTING: A telerehabilitation system included "therapist end" in a laboratory, and the "client end" in LTCFs. The conventional therapy was conducted in LTCFs. RESULTS: Training programs conducted for both the Tele and Conv groups showed significant effects within groups on the participant BBS as well as the total and self-care scores of BI. No significant difference between groups could be demonstrated. The satisfaction of participants between the Tele and the Conv groups also did not show significant difference. CONCLUSIONS: This pilot study indicated that the multi-user telerehabilitation program is feasible for improving the balance and functional activity similar to conventional therapy in patients with chronic stroke living in LTCFs. PMID- 25019634 TI - A shoe-embedded piezoelectric energy harvester for wearable sensors. AB - Harvesting mechanical energy from human motion is an attractive approach for obtaining clean and sustainable electric energy to power wearable sensors, which are widely used for health monitoring, activity recognition, gait analysis and so on. This paper studies a piezoelectric energy harvester for the parasitic mechanical energy in shoes originated from human motion. The harvester is based on a specially designed sandwich structure with a thin thickness, which makes it readily compatible with a shoe. Besides, consideration is given to both high performance and excellent durability. The harvester provides an average output power of 1 mW during a walk at a frequency of roughly 1 Hz. Furthermore, a direct current (DC) power supply is built through integrating the harvester with a power management circuit. The DC power supply is tested by driving a simulated wireless transmitter, which can be activated once every 2-3 steps with an active period lasting 5 ms and a mean power of 50 mW. This work demonstrates the feasibility of applying piezoelectric energy harvesters to power wearable sensors. PMID- 25019635 TI - Detection of quorum sensing activity in the multidrug-resistant clinical isolate Pseudomonas aeruginosa strain GB11. AB - A multidrug-resistant clinical bacteria strain GB11 was isolated from a wound swab on the leg of a patient. Identity of stain GB11 as Pseudomonas aeruginosa was validated by using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Detection of the production of signaling molecules, N-acylhomoserine lactones (AHLs), was conducted using three different bacterial biosensors. A total of four different AHLs were found to be produced by strain GB11, namely N-butyryl homoserine lactone (C4-HSL), N-hexanoylhomoserine lactone (C6-HSL), N-octanoyl homoserine lactone (C8-HSL) and N-3-oxo dodecanoylhomoserine lactone (3-oxo-C12-HSL) using high resolution liquid chromatography tandem mass spectrometry (LC-MS/MS). Of these detected AHLs, 3-oxo C12-HSL was found to be the most abundant AHL produced by P. aeruginosa GB11. PMID- 25019636 TI - A study on the clustering technology of underwater isomorphic sensor networks based on energy balance. AB - Nowadays, there is a greater need for energy efficient and stable underwater sensor networks (UWSNs). Underwater sensors usually do not have enough power, so the goal of underwater sensor networks is to make the network have a long lifetime. An underwater heterogeneous sensor network (UWHSN) is one way to cluster the sensors, and the application of UWHSNs is simple and fast, but robots, lifetime and energy-partition are all drawbacks of UWHSNs. In this paper we propose the underwater isomorphic sensor network (UWISN) clustering technology. By analyzing the characteristics of UWISNs, we determine that an UWISN has strong expansibility, mobility, energy-efficiency and long lifetime. An UWISN adopts normal sensor nodes to be cluster heads, and these cluster heads communicate with each other. This paper seeks the optimal number of clusters and uses FCM to elect cluster heads and establish the network. In addition, an idea of real cluster heads and the method to elect them have been proposed. Finally, the simulation results show that the solution is effective and UWISNs can improve the energy consumption of an UWSN. PMID- 25019637 TI - Augmented switching linear dynamical system model for gas concentration estimation with MOX sensors in an open sampling system. AB - In this paper, we introduce a Bayesian time series model approach for gas concentration estimation using Metal Oxide (MOX) sensors in Open Sampling System (OSS). Our approach focuses on the compensation of the slow response of MOX sensors, while concurrently solving the problem of estimating the gas concentration in OSS. The proposed Augmented Switching Linear System model allows to include all the sources of uncertainty arising at each step of the problem in a single coherent probabilistic formulation. In particular, the problem of detecting on-line the current sensor dynamical regime and estimating the underlying gas concentration under environmental disturbances and noisy measurements is formulated and solved as a statistical inference problem. Our model improves, with respect to the state of the art, where system modeling approaches have been already introduced, but only provided an indirect relative measures proportional to the gas concentration and the problem of modeling uncertainty was ignored. Our approach is validated experimentally and the performances in terms of speed of and quality of the gas concentration estimation are compared with the ones obtained using a photo-ionization detector. PMID- 25019638 TI - Synthesis and characterization of a Mg2+-selective fluorescent probe. AB - A new Mg2+-selective fluorescent probe P was synthesized and characterized. With optimal conditions, the proposed probe P showed good selectivity to Mg2+ compared to other common metal ions, and worked in a wide linear range of 5.0 * 10(-7)-6.0 * 10(-6) M with a detection limit of 1.7 * 10(-7) M Mg2+ in ethanol-water solution (9:1, v/v, 20 mM HEPES, pH = 10.0). PMID- 25019639 TI - A universal decision support system. Addressing the decision-making needs of patients, families, and clinicians in the setting of critical illness. AB - In the setting of a complex critical illness, preference-sensitive decision making-choosing between two or more reasonable treatment options-can be difficult for patients, families, and clinicians alike. A common challenge to making high quality decisions in this setting is a lack of critical information access and sharing among participants. Decision aids-brochures, web applications, and videos are a major focus of current research because mounting evidence suggests they can improve decision-making quality and enhance collaborative shared decision making. However, many decision aids have important limitations, including a relatively narrow capacity for personalization, an inability to gather and generate clinical data, a focus on only a single disease or treatment, and high developmental costs. To address these issues and to help guide future research, we propose a model of "universal" electronic decision support that can be easily adapted by clinicians and patients/families for whatever decision is at hand. In this scalable web-based platform, a general shared decision-making core structure would accommodate simple, interchangeable disease and treatment information modules. The format and content of the system could be adapted to decisional participants' unique characteristics, abilities, and needs. Universal decision support can better standardize a decisional approach and also allow a unique degree of personalization within a framework of shared decision making. We also discuss potential criticisms of this approach as well as strategies that can overcome them in a critical illness setting. PMID- 25019641 TI - Scavenging and characterization of short-lived radicals using a novel stable nitroxide radical with a characteristic UV-vis absorption spectrum. AB - A stable tert-butyl(10-phenyl-9-anthryl)nitroxide (BPAN) radical was newly synthesized and used for the capture/characterization of reactive radicals. Adducts obtained from the reactions of BPAN with in situ generated reactive radicals showed excellent stability, assuring complete isolation and purification. The structures of the adducts were established by LC-MS and NMR analyses. PMID- 25019640 TI - DNA repair biomarkers XPF and phospho-MAPKAP kinase 2 correlate with clinical outcome in advanced head and neck cancer. AB - BACKGROUND: Induction chemotherapy is a common therapeutic option for patients with locoregionally-advanced head and neck cancer (HNC), but it remains unclear which patients will benefit. In this study, we searched for biomarkers predicting the response of patients with locoregionally-advanced HNC to induction chemotherapy by evaluating the expression pattern of DNA repair proteins. METHODS: Expression of a panel of DNA-repair proteins in formalin-fixed paraffin embedded specimens from a cohort of 37 HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation were analyzed using quantitative immunohistochemistry. RESULTS: We found that XPF (an ERCC1 binding partner) and phospho-MAPKAP Kinase 2 (pMK2) are novel biomarkers for HNSCC patients undergoing platinum-based induction chemotherapy. Low XPF expression in HNSCC patients is associated with better response to induction chemoradiotherapy, while high XPF expression correlates with a worse response (p = 0.02). Furthermore, low pMK2 expression was found to correlate significantly with overall survival after induction plus chemoradiation therapy (p = 0.01), suggesting that pMK2 may relate to chemoradiation therapy. CONCLUSIONS: We identified XPF and pMK2 as novel DNA-repair biomarkers for locoregionally advanced HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation. Our study provides insights for the use of DNA repair biomarkers in personalized diagnostics strategies. Further validation in a larger cohort is indicated. PMID- 25019642 TI - A new method for computer-assisted detection, definition and differentiation of the urinary calculi. AB - PURPOSE: Urinary stones are common and can be diagnosed with computed tomography (CT) easily. In this study, we aimed to specify the opacity characteristics of various types of calcified foci that develop through the urinary system by using an image analysis program. With this method, we try to differentiate the calculi from the non-calculous opacities and also we aimed to present how to identify the characteristic features of renal and ureteral calcules. MATERIALS AND METHODS: We obtained the CT studies of the subjects (n = 48, mean age = 41 years) by using a dual source CT imaging system. We grouped the calculi detected in the dual-energy CT sections as renal (n = 40) or ureteric (n = 45) based on their locations. Other radio-opaque structures that were identified outside but within close proximity of the urinary tract were recorded as calculi "mimickers". We used ImageJ program for morphological analysis. All the acquired data were analyzed statistically. RESULTS: According to thorough morphological parameters, there were statistically significant differences in the angle and Feret angle values between calculi and mimickers (p < 0.001). Multivariate logistical regression analysis showed that Minor Axis and Feret angle parameters can be used to distinguish between ureteric (p = 0.003) and kidney (p = 0.001) stones. CONCLUSIONS: Computer-based morphologic parameters can be used simply to differentiate between calcular and noncalcular densities on CT and also between renal and ureteric stones. PMID- 25019644 TI - Supercritical fluid extraction (SFE) of cranberries does not extract oligomeric proanthocyanidins (PAC) but does alter the chromatography and bioactivity of PAC fractions extracted from SFE residues. AB - Supercritical fluid extraction (SFE) removed lipophilic compounds and low molecular weight flavonoids from cranberries. However, SFE did not extract proanthocyanidins (PAC). The SFE PAC-enriched residue was submitted to fractionation on Sephadex LH-20 using ethanol, ethanol/methanol, and 80% acetone. PAC degree of polymerization (DP) and ratios of "A-type" to "B-type" interflavan bonds were compared with those of PAC fractions without SFE. Mass spectrometry showed that when SFE was used, PAC distribution was shifted toward higher DP and contained higher amounts of two and three "A-type" bonds compared to PAC fractions without SFE. The 80% acetone fraction with SFE had significantly greater extraintestinal pathogenic Escherichia coli (ExPEC) agglutination and significantly lower ExPEC invasion of enterocytes than the fraction without SFE. Cranberry PAC with higher numbers of "A-type" interflavan bonds are more bioactive in agglutinating ExPEC and inhibiting ExPEC enterocyte invasion. PMID- 25019643 TI - The effects of local and general hypothermia on temperature profiles of the central nervous system following spinal cord injury in rats. AB - Local and general hypothermia are used to treat spinal cord injury (SCI), as well as other neurological traumas. While hypothermia is known to provide significant therapeutic benefits due to its neuroprotective nature, it is unclear how the treatment may affect healthy tissues or whether it may cause undesired temperature changes in areas of the body that are not the targets of treatment. We performed 2-hour moderate general hypothermia (32 degrees C core) or local hypothermia (30 degrees C spinal cord) on rats that had received either a moderate contusive SCI or laminectomy (control) while monitoring temperatures at three sites: the core, spinal cord, and cortex. First, we identified that injured rats that received general hypothermia exhibited larger temperature drops at the spinal cord (-3.65 degrees C, 95% confidence intervals [CIs] -3.72, -3.58) and cortex (-3.64 degrees C, CIs -3.73, -3.55) than uninjured rats (spinal cord: 3.17 degrees C, CIs -3.24, -3.10; cortex: -3.26 degrees C, CIs -3.34, -3.17). This was found due to elevated baseline temperatures in the injured group, which could be due to inflammation. Second, both general hypothermia and local hypothermia caused a significant reduction in the cortical temperature (-3.64 degrees C and -1.18 degrees C, respectively), although local hypothermia caused a significantly lower drop in cortical temperature than general hypothermia (p<0.001). Lastly, the rates of rewarming of the cord were not significantly different among the methods or injury groups that were tested; the mean rate of rewarming was 0.13+/-0.1 degrees C/min. In conclusion, local hypothermia may be more suitable for longer durations of hypothermia treatment for SCI to reduce temperature changes in healthy tissues, including the cortex. PMID- 25019645 TI - Enhanced near-infrared to visible upconversion nanoparticles of Ho3+-Yb3+-F- tri doped TiO2 and its application in dye-sensitized solar cells with 37% improvement in power conversion efficiency. AB - New near-infrared (NIR)-to-green upconversion nanoparticles of Ho(3+)-Yb(3+)-F(-) tridoped TiO2 (UC-F-TiO2) were designed and fabricated via the hydrosol hydrothermal method. Under 980 nm NIR excitation, UC-F-TiO2 emit strong green upconversion fluorescence with three emission bands at 543, 644, and 751 nm and convert the NIR light in situ to the dye-sensitive visible light that could effectively reduce the distance between upconversion materials and sensitizers; thus, they minimize the loss of the converted light. Our results show that this UC-F-TiO2 offers excellent opportunities for the other types of solar cells applications, such as organic solar cells, c-Si solar cells, multijunction solar cells, and so on. When integrating the UC-F-TiO2 into dye-sensitized solar cells (DSSCs), superior total energy conversion efficiency was achieved. Under AM1.5G light, open-circuit voltage reached 0.77 +/- 0.01 V, short-circuit current density reached 21.00 +/- 0.69 mA cm(-2), which resulted in an impressive overall energy conversion efficiency of 9.91 +/- 0.30%, a 37% enhancement compared to DSSCs with pristine TiO2 photoanode. PMID- 25019646 TI - A modified delta-shaped gastroduodenostomy in totally laparoscopic distal gastrectomy for gastric cancer: a safe and feasible technique. AB - BACKGROUND: The present study introduced a modified delta-shaped gastroduodenostomy (DSG) technique and assessed the safety, feasibility and clinical results of this procedure in patients undergoing totally laparoscopic distal gastrectomy (TLDG) for gastric cancer (GC). MATERIALS AND METHODS: A total of 102 patients with distal GC undergoing TLDG with modified DSG between January 2013 and December 2013 were enrolled. A retrospective study was performed using a prospectively maintained comprehensive database to evaluate the results of the procedure. Univariate and multivariate analyses were performed to estimate the predictive factors for postoperative morbidity. RESULTS: The mean operation time was 150.6+/-30.2 min, the mean anastomosis time was 12.2+/-4.2 min, the mean blood loss was 48.2+/-33.2 ml, and the mean times to first flatus, fluid diet, soft diet and postoperative hospital stay were 3.8+/-1.3 days, 5.0+/-1.0 days, 7.4+/-2.1 days and 12.0+/-6.5 days, respectively. Two patients with minor anastomotic leakage after surgery were managed conservatively; no patient experienced any complications around the anastomosis, such as anastomotic stricture or anastomotic hemorrhage. Univariate analysis showed that age, gastric cancer with hemorrhage and cardiovascular disease combined were significant factors that affected postoperative morbidity (P<0.05). Multivariate analysis found that gastric cancer with hemorrhage was the independent risk factor for the postoperative morbidity (P = 0.042). At a median follow-up of 7 months, no patients had died or experienced recurrent or metastatic disease. CONCLUSIONS: The modified DSG was technically safe and feasible, with acceptable surgical outcomes, in patients undergoing TLDG for GC, and this procedure may be promising in these patients. PMID- 25019648 TI - Ultrafast spectroscopic signature of charge transfer between single-walled carbon nanotubes and C60. AB - The time scales for interfacial charge separation and recombination play crucial roles in determining efficiencies of excitonic photovoltaics. Near-infrared photons are harvested efficiently by semiconducting single-walled carbon nanotubes (SWCNTs) paired with appropriate electron acceptors, such as fullerenes (e.g., C60). However, little is known about crucial photochemical events that occur on femtosecond to nanosecond time scales at such heterojunctions. Here, we present transient absorbance measurements that utilize a distinct spectroscopic signature of charges within SWCNTs, the absorbance of a trion quasiparticle, to measure both the ultrafast photoinduced electron transfer time (taupet) and yield (phipet) in photoexcited SWCNT-C60 bilayer films. The rise time of the trion induced absorbance enables the determination of the photoinduced electron transfer (PET) time of taupet <= 120 fs, while an experimentally determined trion absorbance cross section reveals the yield of charge transfer (phipet ~ 38 +/- 3%). The extremely fast electron transfer times observed here are on par with some of the best donor:acceptor pairs in excitonic photovoltaics and underscore the potential for efficient energy harvesting in SWCNT-based devices. PMID- 25019647 TI - Meta-analysis of suicide-related behavior or ideation in child, adolescent, and adult patients treated with atomoxetine. AB - OBJECTIVE: This meta-analysis examined suicide-related events in the acute phases of double-blind, placebo-controlled atomoxetine trials in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 3883 pediatric and 3365 adult patients were included. Potential events were identified from the adverse events database using a text-string search. Mantel Haenszel risk ratios (MHRR) were calculated for potential suicide-related events categorized according to United States Food and Drug Administration defined codes. RESULTS: In this data set, no completed suicides were reported in the pediatric or adult populations. One pediatric (attempted suicide) (and no adult patient events) was categorized as suicidal behavior in the atomoxetine group. The frequency of combined suicidal behavior or ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo) and the risk compared with placebo was not statistically significant (MHRR=1.57; p=0.42 and MHRR=0.96; p=0.96, respectively). In pediatric patients, suicidal ideation only was reported more frequently compared with placebo (MHRR=1.63; p=0.41). CONCLUSIONS: Overall in this data set, no completed suicides and 1 pediatric patient suicidal behavior event were reported in atomoxetine-treated pediatric and adult patients. Suicidal ideation was uncommon among atomoxetine-treated pediatric and adult patients, although it was reported more frequently in atomoxetine-treated pediatric patients compared with placebo; the reporting rate difference was not statistically significant. The MHRR of suicidal ideation was consistent with a previous meta-analysis of similar design. There was no evidence of increased risk for suicidal behavior in atomoxetine-treated pediatric or adult patients. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov . The data reported are from an analysis of 23 pediatric and 9 adult clinical trials completed between 1998 and 2011. Ten pediatric (Studies HFBD, HFBK, LYAC, LYAS, LYAT, LYAW, LYAX, LYBG, LYBI, and LYBP) and two adult trials (Studies LYAA and LYAO) were conducted before the requirement to post trials at initiation (ongoing as of July 1, 2005) and, therefore, do not have a registration number. The registration numbers for the 13 pediatric trials meeting this requirement are: NCT00191698 (LYBX), NCT00486122 (LYCC), NCT00386581 (LYCZ), NCT00485459 (S010), NCT00191542 (LY15), NCT00191295 (LYBC), NCT00191906 (LYCK), NCT00192023 (LYCY), NCT00191945 (LYDM), NCT00546910 (LYDV), NCT00406354 (LYDW), NCT00380692 (S017), and NCT00607919 (LYEB). For the seven adult trials, the registration numbers are: NCT00190931 (LYBV), NCT00190957 (LYBY), NCT00190736 (LYCU), NCT00190775 (LYCW), NCT00190879 (LYDQ), NCT00510276 (LYDZ), and NCT00962104 (LYEE). PMID- 25019649 TI - Glycogen storage disease type I: clinical and laboratory profile. AB - OBJECTIVES: To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. METHODS: This was a cross-sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow-up were assessed. RESULTS: Twenty-one patients were included (median age 10 years, range 1-25 years), all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1-132 months), and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height-for-age and BMI for-age Z-scores (r=0.561; p=0.008). CONCLUSIONS: Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients. PMID- 25019650 TI - Insulin resistance in obese children and adolescents. AB - OBJECTIVE: To evaluate the presence of insulin resistance and its association with other metabolic abnormalities in obese children and adolescents. METHODS: Retrospective study of 220 children and adolescents aged 5-14 years. Anthropometric measurements were performed (weight, height, and waist circumference) and clinical (gender, age, pubertal stage, and degree of obesity) and biochemical (glucose, insulin, total cholesterol, and fractions, triglycerides) data were analyzed. Insulin resistance was identified by the homeostasis model assessment for insulin resistance (HOMA-IR) index. The analysis of the differences between the variables of interest and the HOMA-IR quartiles was performed by ANOVA or Kruskal-Wallis tests. RESULTS: Insulin resistance was diagnosed in 33.20% of the sample. It was associated with low levels of high density lipoprotein cholesterol (HDL-C; p=0.044), waist circumference measurement (p=0.030), and the set of clinical and metabolic (p=0.000) alterations. Insulin resistant individuals had higher mean age (p=0.000), body mass index (BMI; p=0.000), abdominal circumference (p=0.000), median triglycerides (p=0.001), total cholesterol (p<=0.042), and low-density lipoprotein cholesterol (LDL-C; p<=0.027); and lower HDL-C levels (p=0.005). There was an increase in mean BMI (p=0.000), abdominal circumference (p=0.000), and median triglycerides (p=0.002) as the values of HOMA -IR increased, with the exception of HDL-C, which decreased (p=0.001). Those with the highest number of simultaneous alterations were between the second and third quartiles of the HOMA-IR index (p=0.000). CONCLUSION: The results confirmed that insulin resistance is present in many obese children and adolescents, and that this condition is associated with alterations that represent an increased risk for developing metabolic disorders in adulthood. PMID- 25019651 TI - Influence of neonatal tactile stimulation on amphetamine preference in young rats: parameters of addiction and oxidative stress. AB - This study investigated the influence of neonatal handling on amphetamine-induced conditioned place preference (CPP), as well as the consequent anxiety-like symptoms and oxidative status related to drug abstinence in young rats. Male pups were exposed to tactile stimulation (TS) or neonatal isolation (NI) for 10 min every day from postnatal day one (PND1) to PND21. After being weaned (PND22), pups were separated by handling type until PND40, when treatment with amphetamine (AMPH-4 mg/kg/mL ip, for 8 days) or vehicle (NaCl 0.9% ip, 1 mL/Kg) in CPP started. AMPH-conditioning evoked drug-preference (in 24h and 96 h) and abstinence symptoms in unhandled (UH) animals, followed by oxidative damage in the cortex, hippocampus and striatum. TS showed beneficial influence, as observed by the decreased drug-preference (24 and 96 h) in relation to UH and NI, showing no abstinence symptoms in this last period, as observed by the reduced anxiety like symptoms. The oxidative status indicated a protective influence of TS on brain tissues: lower lipid peroxidation (LP) and reduced protein carbonylation (PC) in the cortex, hippocampus and striatum. Furthermore, TS also increased antioxidant defenses in brain tissues and blood: i) increased plasma levels of vitamin C; ii) increased activity of catalase (CAT) and iii) higher levels of glutathione (GSH) in red blood cells (RBC). Moreover, there were positive correlations of AMPH-CPP with PC and LP levels in all the brain areas assessed. In summary, TS modifies AMPH-preference in the CPP paradigm, reducing drug abstinence behaviors, and stimulating the antioxidant defense system, thus protecting the brain areas closely related to addiction in young rats. Studies about TS and addiction in animal models should be extended to the molecular level. PMID- 25019652 TI - Fluoxetine and WAY 100,635 dissociate increases in scototaxis and analgesia induced by conspecific alarm substance in zebrafish (Danio rerio Hamilton 1822). AB - Alarm reactions to a substance secreted by the damaged skin of conspecifics and closely-related species are increasingly being recognized as fear-like responses in fish. The neurochemical underpinnings of these effects are so far unknown; however, given the role of the serotonergic system on defensive behavior, it is possible that the alarm reaction is mediated by this monoamine. Exposure to conspecific alarm substance (CAS) increased anxiety-like behavior in the light/dark test in zebrafish and decreased nocifensive behavior. These effects were accompanied by increases in blood glucose, hemoglobin, epinephrine and norepinephrine levels, as well as extracellular levels of serotonin in the brain. Pretreatment with fluoxetine blocked the anxiogenic effects of CAS on the light/dark test as well as all physiological parameters and the increase in extracellular brain 5-HT, but not the reduction in nocifensive behavior. Conversely, pretreatment with the 5-HT1AR antagonist WAY 100635 blocked the effects on nocifensive behavior, but not the effects on anxiety-like behavior nor on physiological parameters. These results point to an important and complex role of the serotonergic system in the mediation of fear-potentiated behavior in the light/dark test and in fear-induced analgesia in zebrafish. PMID- 25019653 TI - Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine. AB - Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-alpha in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-alpha levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-alpha levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect. PMID- 25019654 TI - The effect of recombinant adeno-associated virus-adiponectin (rAAV2/1-Acrp30) on glycolipid dysmetabolism and liver morphology in diabetic rats. AB - Adiponectin is an adipocytokine derived from adipocytes with insulin resistance improving and anti-inflammatory activities. The level of Adiponectin is decreased in obesity, insulin resistance and Type 2 diabetes mellitus. The administration of recombinant adiponectin has been shown to improve hyperglycemia and insulin resistance in diabetic mice. Therefore, we investigated the effects of recombinant adeno-associated virus-adiponectin (rAAV2/1-Acrp30) on the glycolipid profile and liver morphology in streptozotocin-induced diabetic rats. Animals were fed a high-fat/high-glucose diet for 4weeks and diabetes induced by intraperitoneal administration of streptozotocin. The animals were divided randomly into four groups: diabetes control group, rAAV2/1-Acrp30 treatment group, vacuity virus group, and normal control group. Compared with diabetic rats and those in the vacuity virus group, animals treated with rAAV2/1-Acrp30 exhibited significantly lower values for glycaemic and lipidic profiles, and significantly higher levels of HDL. Although APN expression increased in the liver tissue, serum levels were not significantly increased. However, the rAAV2/1 Acrp30 treated animals showed amelioration of hepatic disease, accompanied by marked reduction in the expression of NF-kappaBp65 and IkappaBalpha. The results suggest that rAAV2/1-Acrp30 ameliorates glycolipid dysmetabolism and hepatic disease in streptozotocin-induced diabetic rats. These observations indicate that the function of rAAV2/1-Acrp30 is mediated by downregulated expression of NF kappaBp65 and IkappaBalpha. PMID- 25019655 TI - Stress response of wild bottlenose dolphins (Tursiops truncatus) during capture release health assessment studies. AB - There is a growing concern about the impacts of stress in marine mammals as they face a greater array of threats. The stress response of free-ranging dolphins (Tursiops truncatus) was examined by measuring their physiologic response to capture and handling. Samples were collected from 168 dolphins during capture release health assessments 2003-2007 at two study sites: Charleston, SC (CHS) and the Indian River Lagoon, FL (IRL). Adrenocorticotropic hormone (ACTH), cortisol, aldosterone (ALD) and catecholamines (epinephrine (EPI), norepinephrine (NOR), dopamine (DA)), were measured in blood and cortisol in urine. Mean time to collect pre-examination samples after netting the animals was 22min; post examination samples were taken prior to release (mean 1h 37min). EPI and DA concentrations decreased significantly with increased time to blood sampling. ACTH and cortisol levels increased from the initial capture event to the post examination sample. EPI concentrations increased significantly with increasing time to the pre-examination sample and decreased significantly with time between the pre- and post-examination sample. Cortisol concentrations increased between the pre- and post-examination in CHS dolphins. Age- and sex-adjusted mean pre examination values of catecholamines were significantly higher in CHS dolphins; ALD was higher in IRL dolphins. Significant differences related to age or sex included higher NOR concentrations in males; higher ALD and urine cortisol levels in juveniles than adults. Wild dolphins exhibited a typical mammalian response to acute stress of capture and restraint. Further studies that relate hormone levels to biological and health endpoints are warranted. PMID- 25019656 TI - Temperature has species-specific effects on corticosterone in alligator lizards. AB - In response to conditions that threaten homeostasis and/or life, vertebrates generally increase production of glucocorticoid hormones, such as corticosterone (CORT), which induces an emergency physiological state referred to as the stress response. Given that extreme temperatures pose a threat to performance and survival, glucocorticoid upregulation might be an important component of a vertebrate ectotherm's response to extreme thermal conditions. To address this hypothesis, we experimentally examined the effects of body temperature (10, 20, 28, and 35 degrees C; 5-h exposure) on CORT in two congeneric species of lizard naturally exposed to different thermal environments, northern and southern alligator lizards (Elgaria coerulea and Elgaria multicarinata, respectively). In both species, CORT was similarly elevated at medium and high temperatures (28 and 35 degrees C, respectively), but CORT was only elevated at low temperatures (10 degrees C) in southern alligator lizards. We also examined CORT before and after adrenocorticotrophic hormone (ACTH) challenge. In both species, ACTH induced higher CORT levels than any temperature, suggesting that these animals could respond to further stressors at all experimental temperatures. Finally, we compared our laboratory results to measurements of CORT in field-active southern alligator lizards. Plasma CORT concentrations from our laboratory experiment had the same mean and less variance than the field lizards, suggesting that our laboratory lizards displayed CORT within natural levels. Our results demonstrate that body temperature directly affects CORT in alligator lizards. Moreover, the CORT response of these lizards appears to be adapted to their respective thermal environments. Species-specific differences in the thermal CORT response might be common in vertebrate ectotherms and have implications for species' biogeography and responses to climate change. PMID- 25019657 TI - Bioinspired one-dimensional materials for directional liquid transport. AB - One-dimensional materials (1D) capable of transporting liquid droplets directionally, such as spider silks and cactus spines, have recently been gathering scientists' attention due to their potential applications in microfluidics, textile dyeing, filtration, and smog removal. This remarkable property comes from the arrangement of the micro- and nanostructures on these organisms' surfaces, which have inspired chemists to develop methods to prepare surfaces with similar directional liquid transport ability. In this Account, we report our recent progress in understanding how this directional transport works, as well our advances in the design and fabrication of bioinspired 1D materials capable of transporting liquid droplets directionally. To begin, we first discuss some basic theories on droplet directional movement. Then, we discuss the mechanism of directional transport of water droplets on natural spider silks. Upon contact with water droplets, the spider silk undergoes what is known as a wet-rebuilt, which forms periodic spindle-knots and joints. We found that the resulting gradient of Laplace pressure and surface free energy between the spindle-knots and joints account for the cooperative driving forces to transport water droplets directionally. Next, we discuss the directional transport of water droplets on desert cactus. The integration of multilevel structures of the cactus and the resulting integration of multiple functions together allow the cactus spine to transport water droplets continuously from tip to base. Based on our studies of natural spider silks and cactus spines, we have prepared a series of artificial spider silks (A-SSs) and artificial cactus spines (A-CSs) with various methods. By changing the surface roughness and chemical compositions of the artificial spider silks' spindle-knots, or by introducing stimulus-responsive molecules, such as thermal-responsive and photoresponsive molecules, onto the spindle-knots, we can reversibly manipulate the direction of water droplet's movement on the prepared A-SSs. In addition, the A-SSs with nonuniform spindle knots, such as multilevel sized spindle-knots and gradient spindle-knots, further demonstrate integrated directional transport ability for water droplets. Through mimicking the main principle of cactus spines in transporting water droplets, we were able to fabricate both single and array A-CSs, which are able to transport liquid droplets directionally both in air and under water. Lastly, we demonstrated some applications of this directional liquid transport, from aspects of efficient fog collection to oil/water separation. In addition, we showed some potential applications in smart catalysis, tracer substance enrichment, smog removal, and drug delivery. PMID- 25019658 TI - Systematic review of timed stair tests. AB - Functional testing is particularly useful in the clinic and for making research translatable; however, finding measures relevant across ages and different conditions can be difficult. A systematic review was conducted to investigate timed stair tests as an objective measure of functional abilities and musculoskeletal integrity. Data were analyzed for their ability to differentiate between controls and patient groups and between different patient groups. Literature was reviewed using the Medline, CINAHL, and PubMed databases until February 2012. Data were grouped according to methodology, ages, and medical conditions. Time per step was calculated to allow comparison between studies. Eighty-eight studies were included in this review. Methodologies varied considerably with stair ascent, stair descent, or a combination of the two being used across a wide range of ages and medical conditions. Times increased with age for ascent, descent, and combined and for a variety of medical problems. Timed stair tests appear to be sensitive to medical conditions but further data are required to obtain normative values for this test. We suggest that timed stair tests should follow a more standardized methodology using a combination of ascent and descent and asking participants to complete the stairs as quickly and safely as possible. PMID- 25019659 TI - Self-reported and performance-based outcomes using DEKA Arm. AB - Mechanical properties of the DEKA Arm and associated engineering innovations are easy to observe. What is less clear is how these advances translate into functional benefits for the user with amputation. Study aims were to (1) quantify outcomes including dexterity, performance of daily activities, and prosthetic skill and spontaneity of users of the DEKA Arm and (2) compare outcomes when using the DEKA Arm with scores using the existing prosthesis. This was a quasi experimental study. Descriptive analyses examined outcomes by DEKA Arm configuration level. Of the 39 subjects fit with a DEKA Arm, 32 were trained in use and completed end-of-study testing. Data from 26 prosthetic users were used to compare outcomes using existing prostheses with outcomes with the DEKA Arm. Dexterity and activity performance with the DEKA Arm varied by amputation level (p < 0.01). Self-reported function and number of activities performed using the prosthesis were similar across levels. Comparisons with existing prostheses showed the effect on dexterity varied by level. Activity performance and spontaneity of prosthetic use improved for users of the shoulder configuration level, while use of the prosthesis to perform activities and perceived difficulty performing self-selected tasks improved for all levels. PMID- 25019660 TI - Concordance of clinician judgment of mild traumatic brain injury history with a diagnostic standard. AB - The concordance of Department of Veterans Affairs (VA) clinician judgment of mild traumatic brain injury (mTBI) history with American Congress of Rehabilitation Medicine (ACRM)-based criteria was examined for Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) Veterans. In order to understand inconsistencies in agreement, we also examined the associations between evaluation outcomes and conceptually relevant patient characteristics, deployment-related events, current self-reported health symptoms, and suspected psychiatric conditions. The Veteran sample comprised 14,026 OIF/OEF VA patients with deployment-related mTBI history (n = 9,858) or no history of mTBI (n = 4,168) as defined by ACRM-based criteria. In the majority of cases (76.0%), clinician judgment was in agreement with the ACRM-based criteria. The most common inconsistency was between clinician judgment (no) and ACRM-based criteria (yes) for 21.3% of the patients. Injury etiology, current self-reported health symptoms, and suspected psychiatric conditions were additional factors associated with clinician diagnosis and ACRM-based criteria disagreement. Adherence to established diagnostic guidelines is essential for accurate determination of mTBI history and for understanding the extent to which mTBI symptoms resolve or persist over time in OIF/OEF Veterans. PMID- 25019661 TI - Pilot study: Computer-based virtual anatomical interactivity for rehabilitation of individuals with chronic acquired brain injury. AB - Deficiencies in upper-limb motor function and executive functioning can compromise an affected individual's ability to complete everyday activities. Impaired motor and executive functioning therefore pose a risk to increasing numbers of veterans who have been diagnosed with acquired brain injury. This article reports on changes in upper-limb motor function and executive functioning of 12 adult participants with chronic acquired brain injury using a novel, computer-based, motor and cognitive rehabilitation program called PreMotor Exercise Games (PEGs). Manual muscle, goniometric range of motion, and dynamometer assessments were used to determine motor functioning while the Executive Function Performance Test measured cognitive functioning. A three-level repeated measures design was conducted to determine changes pre- and postintervention. Participants demonstrated significant improvement in shoulder (p = 0.01) and wrist (p = 0.01) range of motion and clinically relevant improvement for elbow range of motion. Participants demonstrated clinically relevant improvement in shoulder, elbow, and wrist strength. Finally, participants demonstrated significant improvement in executive functioning (p < 0.05). Using PEGs as a modality for both motor and cognitive intervention is a potentially beneficial adjunct to rehabilitation and warrants further study. PMID- 25019662 TI - Anomia treatment platform as behavioral engine for use in research on physiological adjuvants to neurorehabilitation. AB - The purpose of this study was to create a "behavioral treatment engine" for future use in research on physiological adjuvants in aphasia rehabilitation. We chose the behavioral target anomia, which is a feature displayed by many persons who have aphasia. Further, we wished to saturate the treatment approach with many strategies and cues that have been empirically reported to have a positive influence on aphasia outcome, with the goal being to optimize the potential for positive response in most participants. A single-subject multiple baseline design with replication across eight participants was employed. Four men and four women, with an average age of 62 yr and an average of 63.13 mo poststroke onset, served as participants. Word-retrieval treatment was administered 3 d/wk, 1 h/d for a total of 20 treatment hours (6-7 wk). Positive acquisition effects were evident in all eight participants (d effect size [ES] = 5.40). Treatment effects were maintained 3 mo after treatment termination for five participants (d ES = 2.94). Within and across semantic category, generalization was minimal (d ES = 0.43 within and 1.09 across). This study demonstrates that this behavioral treatment engine provides a solid platform on which to base future studies whereby various treatment conditions are manipulated and pharmacologic support is added. PMID- 25019663 TI - Receipt of employment services among Veterans Health Administration users with psychiatric diagnoses. AB - This study examined the population-based reach of Veterans Health Administration (VHA) employment services to VHA patients with psychiatric diagnoses. Reach of services includes the percentage and characteristics of people who accessed services compared with those who did not. Using clinical administrative data, we identified patients with a psychiatric diagnosis among a random sample of all patients who received VHA services in 1 yr. Among VHA patients with psychiatric diagnoses, we examined their likelihood of receiving any VHA employment services and specific types of employment services, including supported employment, transitional work, incentive therapy, and vocational assistance. We identified clinical and demographic characteristics associated with receiving employment services. Results indicated that 4.2% of VHA patients with a psychiatric diagnosis received employment services. After adjusting for clinical and demographic characteristics, VHA patients with schizophrenia and bipolar disorder were more likely to receive any employment services and to receive supported employment than were patients with depression, PTSD, or other anxiety disorders. VHA patients with depression and PTSD were more likely to receive transitional work and vocational assistance than patients with schizophrenia. Future studies should examine system-level barriers to receiving employment services and identify types of employment services most appropriate for Veterans with different psychiatric diagnoses. PMID- 25019664 TI - Prospective prediction of functional difficulties among recently separated veterans. AB - Reports of functional problems are common among Veterans who served post-9/11 (more than 25% report functional difficulties in at least one domain). However, little prospective work has examined the risk and protective factors for functional difficulties among Veterans. In a sample of recently separated Marines, we used stepwise logistic and multiple regressions to identify predictors of functional impairment, including work-related problems, financial problems, unlawful behavior, activity limitations due to mental health symptoms, and perceived difficulty reintegrating into civilian life. Posttraumatic stress disorder symptoms assessed both before and after military separation significantly predicted functional difficulties across all domains except unlawful behavior. Certain outcomes, such as unlawful behavior and activity limitations due to mental health symptoms, were predicted by other or additional predictors. Although several forms of functioning were examined, the list was not exhaustive. The results highlight a number of areas where targeted interventions may facilitate the reintegration of military servicemembers into civilian life. PMID- 25019665 TI - Toe clearance when walking in people with unilateral transtibial amputation: effects of passive hydraulic ankle. AB - Most clinically available prosthetic feet have a rigid attachment or incorporate an "ankle" device allowing elastic articulation during stance, with the foot returning to a "neutral" position at toe-off. We investigated whether using a foot with a hydraulically controlled articulating ankle that allows the foot to be relatively dorsiflexed at toe-off and throughout swing would increase minimum toe clearance (MTC). Twenty-one people with unilateral transtibial amputation completed overground walking trials using their habitual prosthetic foot with rigid or elastic articulating attachment and a foot with a hydraulic ankle attachment (hyA-F). MTC and other kinematic variables were assessed across multiple trials. When using the hyA-F, mean MTC increased on both limbs (p = 0.03). On the prosthetic limb this was partly due to the device being in its fully dorsiflexed position at toe-off, which reduced the "toes down" foot angle throughout swing (p = 0.01). Walking speed also increased when using the hyA-F (p = 0.001) and was associated with greater swing-limb hip flexion on the prosthetic side (p = 0.04), which may have contributed to the increase in mean MTC. Variability in MTC increased on the prosthetic side when using the hyA-F (p = 0.03), but this did not increase risk of tripping. PMID- 25019666 TI - Development of inexpensive prosthetic feet for high-heeled shoes using simple shoe insole model. AB - The large majority of prosthetic feet are aimed at low-heeled shoes, with a few models allowing a heel height of up to 5 cm. However, a survey by the American Podiatric Medical Association indicates that most women wear heels over 5 cm; thus, current prosthetic feet limit most female prosthesis users in their choice. Some prosthetic foot components are heel-height adjustable; however, their plantar surface shapes do not change to match the insole shapes of the shoes with different heel heights. The aims of the study were therefore (1) to develop a model that allows prediction of insole shape for various heel height shoes in combination with different shoe sizes and (2) to develop and field-test low-cost prototypes of prosthetic feet whose insole shapes were based on the new model. An equation was developed to calculate insole shapes independent of shoe size. Field testing of prototype prosthetic feet fabricated based on the equation was successful and demonstrated the utility of the equation. PMID- 25019667 TI - Qualitative assessment of tongue drive system by people with high-level spinal cord injury. AB - The Tongue Drive System (TDS) is a minimally invasive, wireless, and wearable assistive technology (AT) that enables people with severe disabilities to control their environments using tongue motion. TDS translates specific tongue gestures into commands by sensing the magnetic field created by a small magnetic tracer applied to the user's tongue. We have previously quantitatively evaluated the TDS for accessing computers and powered wheelchairs, demonstrating its usability. In this study, we focused on its qualitative evaluation by people with high-level spinal cord injury who each received a magnetic tongue piercing and used the TDS for 6 wk. We used two questionnaires, an after-scenario and a poststudy, designed to evaluate the tongue-piercing experience and the TDS usability compared with that of the sip-and-puff and the users' current ATs. After study completion, 73% of the participants were positive about keeping the magnetic tongue-barbell in order to use the TDS. All were satisfied with the TDS performance and most said that they were able to do more things using TDS than their current ATs (4.22/5). PMID- 25019668 TI - Effect of dynamic keyboard and word-prediction systems on text input speed in persons with functional tetraplegia. AB - Information technology plays a very important role in society. People with disabilities are often limited by slow text input speed despite the use of assistive devices. This study aimed to evaluate the effect of a dynamic on-screen keyboard (Custom Virtual Keyboard) and a word-prediction system (Sibylle) on text input speed in participants with functional tetraplegia. Ten participants tested four modes at home (static on-screen keyboard with and without word prediction and dynamic on-screen keyboard with and without word prediction) for 1 mo before choosing one mode and then using it for another month. Initial mean text input speed was around 23 characters per minute with the static keyboard and 12 characters per minute with the dynamic keyboard. The results showed that the dynamic keyboard reduced text input speed by 37% compared with the standard keyboard and that the addition of word prediction had no effect on text input speed. We suggest that current forms of dynamic keyboards and word prediction may not be suitable for increasing text input speed, particularly for subjects who use pointing devices. Future studies should evaluate the optimal ergonomic design of dynamic keyboards and the number and position of words that should be predicted. PMID- 25019669 TI - Posture-dependent control of stimulation in standing neuroprosthesis: simulation feasibility study. AB - We used a three-dimensional biomechanical model of human standing to test the feasibility of feed-forward control systems that vary stimulation to paralyzed muscles based on the user's posture and desire to effect a postural change. The controllers examined were (1) constant baseline stimulation, which represented muscle activation required to maintain erect standing, and (2) posture follower, which varied muscle activation as a function of the location of the projection of whole-body center of mass on the base of support. Posture-dependent control of stimulation demonstrated significant benefits over open-loop stimulation. Posture follower reduced upper-limb (UL) effort by an average of 50% compared with UL effort alone and by an average of 34% compared with baseline stimulation. On the other hand, reduction in UL effort was an average of 32% when using baseline stimulation. Compared with using UL effort alone, both controllers result in more than a 50% reduction in effort. The results of this study indicate that control systems that facilitate user-driven, task-dependent postures can be more effective and efficient than conventional open-loop stimulation. Also, they obviate the need for complicated posture-setting devices such as switches and joysticks. Functional implications include the potential to expand reachable workspace and better preparation for anticipated disturbances that could challenge balance over existing neuroprostheses for standing. PMID- 25019670 TI - Management of multijoint stiffness of bilateral upper limbs secondary to heterotopic ossification: case report and literature review. AB - The management of heterotopic ossification (HO) is controversial. Although some reports have investigated assessment and surgical resection techniques for HO affecting one or more joints, the cases of multijoint stiffness secondary to HO are rare. This article describes a rare case of HO affecting both upper limbs of a 32-year-old man that severely interfered with activities of daily living. We present the rehabilitation management of this case and the functional outcome 1 to 2 yr after excision of the ossific masses. PMID- 25019671 TI - Mixed-method approach to veteran satisfaction with pain education. AB - Patient education is a central component in high-quality integrated care of patients with chronic pain. The current study assessed patients' satisfaction with a 12 wk "Pain Education School" program within the initial 2 yr phase of implementation. A mixed-method treatment outcome design was used. A sample of 219 veterans between November 6, 2009, and January 20, 2012, was evaluated. Quantitative findings suggest that patients reported learning "new and useful" information (mean = 4.62 +/- 0.82), perceived the program as "easy to understand" (4.62 +/- 0.70), used the learned information (4.58 +/- 0.77), and recommended the program to others (4.71 +/- 0.74). Four thematic maps emerged from the qualitative data. Response percentages were calculated in order to illustrate the relative magnitude of emerging themes and subthemes corresponding to participant extracts. PMID- 25019672 TI - Toward a veteran-centric view on community (re)integration. PMID- 25019673 TI - Lewis base mediated halogenation/semipinacol rearrangement of diazo compounds: new access to alpha-halo-quaternary ketones. AB - A novel halogenation/semipinacol rearrangement of alpha-diazo alcohol catalyzed by Lewis base has been developed through a carbene-free mechanism. This semipinacol transposition, initiated by an electrophilic halogenation (X = Cl(+), Br(+), and I(+)) of diazo carbon event, furnished a convenient synthetic route for the efficient synthesis of alpha-halo-quaternary ketones under mild conditions. PMID- 25019674 TI - Brain microdialysis as a tool to explore the ionic profile of the brain extracellular space in neurocritical patients: a methodological approach and feasibility study. AB - Our aim is to determine whether the ionic concentration in brain microdialysate enables calculations of the actual Na(+), K(+), and Cl(-) concentrations in vitro and whether this method can be applied to determine the ionic concentrations in the brain extracellular fluid. We designed an experiment using CMA-71 probes (M Dialysis, Stockholm, Sweden) and the standard conditions used in a clinical setting. Nine CMA-71 probes were inserted in different matrices and perfused with mock cerebrospinal fluid containing 3% albumin at the standard infusion rate used in the clinical setting (0.3 MUL/min). Microvials were replaced every 12 h, and the ionic concentrations, both in the dialysate and the matrix, were analyzed. For each ion, scatter plots were built, with [Na(+)], [K(+)], and [Cl(-)] in the dialysate as the predictor variables and the matrix concentrations as the outcome variables. A linear regression model allowed us to calculate the true ionic concentrations in the matrix. To demonstrate the feasibility of the method, we present the calculated ionic profile of one patient with a malignant infarction and a second with a severe traumatic brain injury. Our results confirm that the ionic concentration in microdialysate can be used to calculate the true concentrations of ions in a matrix and the actual concentrations in the extracellular fluid. Microdialysis offers the unique possibility of monitoring the dynamic changes of ions in the brain over time and opens a new avenue to explore the brain's ionic profile, its changes in brain edema, and how this profile can be modified with different therapies. PMID- 25019675 TI - Coriander leaf extract exerts antioxidant activity and protects against UVB induced photoaging of skin by regulation of procollagen type I and MMP-1 expression. AB - Ultraviolet (UV) radiation causes photodamage to the skin, which, in turn, leads to depletion of the dermal extracellular matrix and chronic alterations in skin structure. Skin wrinkles are associated with collagen synthesis and matrix metalloproteinase-1 (MMP-1) activity. Coriandrum sativum L. (coriander leaf, cilantro; CS) has been used as a herbal medicine for the treatment of diabetes, hyperlipidemia, liver disease, and cancer. In this study, we examined whether CS ethanol extract (CSE) has protective effects against UVB-induced skin photoaging in normal human dermal fibroblasts (NHDF) in vitro and in the skin of hairless mice in vivo. The main component of CSE, linolenic acid, was determined by gas chromatography-mass spectroscopy. We measured the cellular levels of procollagen type I and MMP-1 using ELISA in NHDF cells after UVB irradiation. NHDF cells that were treated with CSE after UVB irradiation exhibited higher procollagen type I production and lower levels of MMP-1 than untreated cells. We found that the activity of transcription factor activator protein-1 (AP-1) was also inhibited by CSE treatment. We measured the epidermal thickness, dermal collagen fiber density, and procollagen type I and MMP-1 levels in photo-aged mouse skin in vivo using histological staining and western blot analysis. Our results showed that CSE-treated mice had thinner epidermal layers and denser dermal collagen fibers than untreated mice. On a molecular level, it was further confirmed that CSE treated mice had lower MMP-1 levels and higher procollagen type I levels than untreated mice. Our results support the potential of C. sativum L. to prevent skin photoaging. PMID- 25019677 TI - Surface-based mixed effects multilevel analysis of grouped human electrocorticography. AB - Electrocorticography (ECoG) in humans yields data with unmatched spatio-temporal resolution that provides novel insights into cognitive operations. However, the broader application of ECoG has been confounded by difficulties in accurately depicting individual data and performing statistically valid population-level analyses. To overcome these limitations, we developed methods for accurately registering ECoG data to individual cortical topology. We integrated this technique with surface-based co-registration and a mixed-effects multilevel analysis (MEMA) to control for variable cortical surface anatomy and sparse coverage across patients, as well as intra- and inter-subject variability. We applied this surface-based MEMA (SB-MEMA) technique to a face-recognition task dataset (n=22). Compared against existing techniques, SB-MEMA yielded results much more consistent with individual data and with meta-analyses of face-specific activation studies. We anticipate that SB-MEMA will greatly expand the role of ECoG in studies of human cognition, and will enable the generation of population level brain activity maps and accurate multimodal comparisons. PMID- 25019678 TI - Inhibitory repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex modulates early affective processing. AB - The dorsolateral prefrontal cortex (dlPFC) has often been suggested as a key modulator of emotional stimulus appraisal and regulation. Therefore, in clinical trials, it is one of the most frequently targeted regions for non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). In spite of various encouraging reports that demonstrate beneficial effects of rTMS in anxiety disorders, psychophysiological studies exploring the underlying neural mechanisms are sparse. Here we investigated how inhibitory rTMS influences early affective processing when applied over the right dlPFC. Before and after rTMS or sham stimulation, subjects viewed faces with fearful or neutral expressions while whole-head magnetoencephalography (MEG) was recorded. Due to the disrupted functioning of the right dlPFC, visual processing in bilateral parietal, temporal, and occipital areas was amplified starting at around 90 ms after stimulus onset. Moreover, increased fear-specific activation was found in the right TPJ area in a time-interval between 110 and 170 ms. These neurophysiological effects were reflected in slowed reaction times for fearful, but not for neutral faces in a facial expression identification task while there was no such effect on a gender discrimination control task. Our study confirms the specific and important role of the dlPFC in regulation of early emotional attention and encourages future clinical research to use minimal invasive methods such as transcranial magnetic (TMS) or direct current stimulation (tDCS). PMID- 25019676 TI - Brain representations for acquiring and recalling visual-motor adaptations. AB - Humans readily learn and remember new motor skills, a process that likely underlies adaptation to changing environments. During adaptation, the brain develops new sensory-motor relationships, and if consolidation occurs, a memory of the adaptation can be retained for extended periods. Considerable evidence exists that multiple brain circuits participate in acquiring new sensory-motor memories, though the networks engaged in recalling these and whether the same brain circuits participate in their formation and recall have less clarity. To address these issues, we assessed brain activation with functional MRI while young healthy adults learned and recalled new sensory-motor skills by adapting to world-view rotations of visual feedback that guided hand movements. We found cerebellar activation related to adaptation rate, likely reflecting changes related to overall adjustments to the visual rotation. A set of parietal and frontal regions, including inferior and superior parietal lobules, premotor area, supplementary motor area and primary somatosensory cortex, exhibited non-linear learning-related activation that peaked in the middle of the adaptation phase. Activation in some of these areas, including the inferior parietal lobule, intra parietal sulcus and somatosensory cortex, likely reflected actual learning, since the activation correlated with learning after-effects. Lastly, we identified several structures having recall-related activation, including the anterior cingulate and the posterior putamen, since the activation correlated with recall efficacy. These findings demonstrate dynamic aspects of brain activation patterns related to formation and recall of a sensory-motor skill, such that non overlapping brain regions participate in distinctive behavioral events. PMID- 25019679 TI - Functional organization for musical consonance and tonal pitch hierarchy in human auditory cortex. AB - Pitch relationships in music are characterized by their degree of consonance, a hierarchical perceptual quality that distinguishes how pleasant musical chords/intervals sound to the ear. The origins of consonance have been debated since the ancient Greeks. To elucidate the neurobiological mechanisms underlying these musical fundamentals, we recorded neuroelectric brain activity while participants listened passively to various chromatic musical intervals (simultaneously sounding pitches) varying in their perceptual pleasantness (i.e., consonance/dissonance). Dichotic presentation eliminated acoustic and peripheral contributions that often confound explanations of consonance. We found that neural representations for pitch in early human auditory cortex code perceptual features of musical consonance and follow a hierarchical organization according to music-theoretic principles. These neural correlates emerge pre-attentively within ~ 150 ms after the onset of pitch, are segregated topographically in superior temporal gyrus with a rightward hemispheric bias, and closely mirror listeners' behavioral valence preferences for the chromatic tone combinations inherent to music. A perceptual-based organization implies that parallel to the phonetic code for speech, elements of music are mapped within early cerebral structures according to higher-order, perceptual principles and the rules of Western harmony rather than simple acoustic attributes. PMID- 25019681 TI - Temporal unpredictability of a stimulus sequence affects brain activation differently depending on cognitive task demands. AB - Within cognitive neuroscience, in nearly every experimental setting, subjects are presented with stimuli that appear at either constant or variable points in time, referred to as interstimulus intervals (ISIs). These temporal patterns differ in the degree to which an exact stimulus onset may be predicted. We investigated whether this experimental feature affects brain and behavior, and whether the impact is modulated by the cognitive demands of a task. Subjects (N=26) were assessed via fMRI while solving three different tasks under either temporally predictable (constant ISI) or unpredictable (variable ISI) conditions. The tasks differed with regard to demands on working memory and response uncertainty. Compared to constant ISIs, variable (i.e., less predictable) ISIs led to a general increase in reaction time and in right amygdala activation. Depending on the cognitive demands required by the specific task, the left amygdala, the parietal cortex, the supplementary motor area, and the dorsolateral prefrontal cortex were engaged as well. The results indicate that the temporal structure in a stimulus sequence affects both overt and covert behaviors. Implicit temporal uncertainty increases activation in several brain regions depending on cognitive demands. Thus, an often-overlooked basic design feature, the application of constant or variable ISIs, may contribute to heterogeneity in cognitive neuroscience findings. PMID- 25019680 TI - Functional organization of human auditory cortex: investigation of response latencies through direct recordings. AB - The model for functional organization of human auditory cortex is in part based on findings in non-human primates, where the auditory cortex is hierarchically delineated into core, belt and parabelt fields. This model envisions that core cortex directly projects to belt, but not to parabelt, whereas belt regions are a major source of direct input for auditory parabelt. In humans, the posteromedial portion of Heschl's gyrus (HG) represents core auditory cortex, whereas the anterolateral portion of HG and the posterolateral superior temporal gyrus (PLST) are generally interpreted as belt and parabelt, respectively. In this scheme, response latencies can be hypothesized to progress in serial fashion from posteromedial to anterolateral HG to PLST. We examined this hypothesis by comparing response latencies to multiple stimuli, measured across these regions using simultaneous intracranial recordings in neurosurgical patients. Stimuli were 100 Hz click trains and the speech syllable /da/. Response latencies were determined by examining event-related band power in the high gamma frequency range. The earliest responses in auditory cortex occurred in posteromedial HG. Responses elicited from sites in anterolateral HG were neither earlier in latency from sites on PLST, nor more robust. Anterolateral HG and PLST exhibited some preference for speech syllable stimuli compared to click trains. These findings are not supportive of a strict serial model envisioning principal flow of information along HG to PLST. In contrast, data suggest that a portion of PLST may represent a relatively early stage in the auditory cortical hierarchy. PMID- 25019682 TI - Compliance with surgical follow-up does not influence fistula maturation in a county hospital population. AB - BACKGROUND: The purpose of this study is to examine follow-up rates and maturation rates after dialysis access surgery using a fistula-first approach in a county hospital with an indigent population. METHODS: A prospectively maintained dialysis access database was queried for cases performed between August 1, 2009 and September 30, 2011. The follow-up period ended on December 31, 2011. An attempt was made to contact patients who did not have complete follow-up data recorded to the point of fistula maturation for arteriovenous fistulas (AVF). Patients were contacted directly or through their dialysis center. Maturation was defined by successful use of the AVF for hemodialysis for at least 2 weeks for patients who are dialysis dependent or by the clinical assessment of an attending vascular surgeon for those not on dialysis. RESULTS: Two hundred three dialysis access cases were performed. The mean age was 51.4 years. One hundred twenty-six (62%) were male and 175 (86%) were Hispanic. Of these, 194 (95.6%) were AVF. Three AVF were ligated in the postoperative period for steal. Of the remaining 191 AVF, 94 (49%) patients completed their scheduled follow-up appointments. Sixty-six (35%) patients did not come to clinic but were contacted. Twenty-six (14%) patients were completely lost to follow-up and 5 (2.6%) died. Maturation data was obtained on 160 AVF. Of those, 123 (77%) reached maturation with a mean maturation time of 112 +/- 99 days (range, 21-483). Twenty patients who completed follow-up underwent at least 1 additional surgical or endovascular procedure in an attempt to achieve maturation. Seventeen (85%) patients who underwent a secondary procedure went on to achieve maturation. There was no significant difference in maturation between the group that completed follow-up and those who were contacted by phone (69 [73%] vs. 54 [81%], P = not significant). CONCLUSIONS: In this indigent population, follow-up does not influence maturation rates of AVF. Despite poor compliance with follow-up in the setting of a public hospital, the maturation rate of an aggressive fistula-first approach is acceptable. PMID- 25019683 TI - Lost in transition: women experiencing infertility. AB - This paper illustrates key findings from a qualitative doctoral research project exploring women's experience of infertility. Six women maintained treatment diaries, reflecting on their experiences prior to, during and beyond infertility treatment. The following key themes are identified: hopefulness, adaptation, transitioning and shifting focus. The data suggest that treatment, clinic experience and living a life 'on hold' act as turning points within the individual life course. It is at the intersection between treatment and outcome that difficulties negotiating the expected and anticipated life course become illuminated, revealing limited connectivity and transitioning through and beyond the treatment process. This is a critical focus area and one that sets the scene for effective future adaptation. The data suggest that the accessibility of supportive care moving through and beyond treatment is limited. This paper argues that the infertility clinic is a critical space and place and one where effective supportive care may enable effective transitioning beyond the experience of infertility as an unanticipated life course disruption. PMID- 25019684 TI - Specific interaction to PIP2 increases the kinetic rate of membrane binding of VILIPs, a subfamily of Neuronal Calcium Sensors (NCS) proteins. AB - VIsinin-LIke Proteins (VILIPs) are a subfamily of the Neuronal Calcium Sensor (NCS) proteins, which possess both N-myristoylation and EF-hand motifs allowing for a putative 'calcium-myristoyl switch' regulation mechanism. It has previously been established that myristoyl conjugation increases the affinity of proteins for membranes, but, in many cases, a second feature such as a cluster of positively-charged residues is needed for stable membrane binding. The interaction of two members of this family, VILIP-1 and VILIP-3, with Langmuir monolayers as membrane models has been investigated in order to study the effects of both myristoylation and the highly basic region containing conserved poly lysine residues on membrane association kinetics and binding properties. Results show that in the presence of calcium, N-myristoylation significantly increases the kinetic rate of VILIP adsorption to the membrane. Additionally, the proteins bind to negatively charged phospholipids independently of the conjugated myristate moiety. Besides the regulatory effect of calcium on the rate of binding presumably due to exposure of the myristoyl moiety ascribed to their putative 'calcium-myristoyl switch', VILIP-1 and -3 also engage specific interactions with biomimetic membranes containing phosphatidylinositol 4,5-bisphosphate (PIP2). The presence of PIP2 increases the membrane association rates of both VILIPs. Taken together, these results show the major kinetic role of N-myristoylation for membrane binding, and highlight the critical role of specific phosphoinositide interactions for membrane association of members of the VILIP family. PMID- 25019686 TI - Engineering light-inducible nuclear localization signals for precise spatiotemporal control of protein dynamics in living cells. AB - The function of many eukaryotic proteins is regulated by highly dynamic changes in their nucleocytoplasmic distribution. The ability to precisely and reversibly control nuclear translocation would, therefore, allow dissecting and engineering cellular networks. Here we develop a genetically encoded, light-inducible nuclear localization signal (LINuS) based on the LOV2 domain of Avena sativa phototropin 1. LINuS is a small, versatile tag, customizable for different proteins and cell types. LINuS-mediated nuclear import is fast and reversible, and can be tuned at different levels, for instance, by introducing mutations that alter AsLOV2 domain photo-caging properties or by selecting nuclear localization signals (NLSs) of various strengths. We demonstrate the utility of LINuS in mammalian cells by controlling gene expression and entry into mitosis with blue light. PMID- 25019687 TI - Diastereoselective synthesis of novel aza-diketopiperazines via a domino cyclohydrocarbonylation/addition process. AB - Herein, we report an unprecedented, short and diastereo-selective synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds starting from amino acids. The strategy is based on a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation of allyl-substituted aza-DKP, followed by a diastereoselective functionalization of the platform. This methodology allows the synthesis of novel bicyclic and tricyclic aza-DKP scaffolds incorporating six- or seven-membered rings, with potential applications in medicinal chemistry. PMID- 25019685 TI - HIV-1 antibodies and vaccine antigen selectively interact with lipid domains. AB - The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a required first-step in HIV-1 neutralization. HIV-1 virions have high concentration of cholesterol and sphingomyelin, which are able to organize into liquid-ordered domains (i.e., lipid rafts), and could influence the interaction of neutralizing antibodies with epitopes proximal to the membrane. The objective of this research is to understand how these lipid domains contribute to 2F5/4E10 membrane interactions and to antigen presentation in liposomal form of HIV-1 vaccines. To this end we have engineered biomimetic supported lipid bilayers and are able to use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions. Our results demonstrate that 2F5/4E10 do not interact with highly ordered gel and liquid-ordered domains and exclusively bind to a liquid-disordered lipid phase. This suggests that vaccine liposomes that contain key viral membrane components, such as high cholesterol content, may not be advantageous for 2F5/4E10 vaccine strategies. Rather, vaccine liposomes that primarily contain a liquid-disordered phase may be more likely to elicit production of lipid reactive, 2F5- and 4E10-like antibodies. PMID- 25019688 TI - Intracerebral interleukin-10 injection modulates post-ischemic neuroinflammation: an experimental microarray study. AB - Stroke induces a profound neuroinflammatory reaction that leads to secondary cerebral tissue injury. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that is endogenously produced by immune cells and limits this inflammatory reaction. Previously, therapeutic administration of IL-10 has been shown to be neuroprotective in experimental stroke. However, the signaling pathways affected by this approach are largely unknown. The aim of this study was to verify the neuroprotective effects of IL-10 in an experimental mouse stroke model and to analyze the pathways modulated by this approach. Therefore, we performed a whole genome microarray analysis comparing the cerebral gene expression profile at two time points after cortical stroke in IL-10-treated and control C57Bl/6J mice. We administered IL-10 locally by intracerebroventricular injection. We were able to validate a reduction of infarct volume by IL-10 administration and characterized the kinetics of endogenous cerebral IL-10 expression after stroke. The microarray analysis revealed that IL-10 treatment effectively downregulated pro-inflammatory signaling cascades which were upregulated by the ischemic lesion in the acute phase after the stroke. This is the first study characterizing the global gene regulation profile of IL-10 immunotherapy for ischemic stroke. Our results emphasize the key role of IL-10 as a neuroprotective cytokine and suggest several novel downstream pathways for further investigation to better understand the mechanisms of post-stroke neuroinflammation. PMID- 25019689 TI - No association of SLC6A3 and SLC6A4 gene polymorphisms with schizophrenia in the Han Chinese population. AB - The SLC6A3 and SLC6A4 genes are members of a class of neurotransmitter transporters for the release, re-uptake and recycling of neurotransmitters in synapses. SLC6A3 and SLC6A4 encode a dopamine transporter and serotonin transporter, respectively. Abnormal expression and genetic polymorphism of SLC6A3 and SLC6A4 genes may increase the risk of developing mental illness, such as schizophrenia, bipolar disorder, ADHD, and aggressive behavior in Alzheimer disease, etc. Nevertheless, association between SLC6A3, SLC6A4 genes polymorphism and schizophrenia patients have not been well studied in Han Chinese people. In this study, we examined whether single nucleotide polymorphisms (SNPs) in SLC6A3, SLC6A4 were associated with schizophrenia in Han Chinese people (893 schizophrenia patients and 611 healthy controls). No significant difference in allelic or genotypic frequency was found between schizophrenia patients and healthy controls. No positive linkage disequilibrium (LD) was detected either. No haplotypic distributions were positive. Accordingly, our study suggests that the 10 SNPs within both genes we examined do not play a major role in schizophrenia in the Han Chinese population. PMID- 25019690 TI - Interaction between socio-demographic characteristics: traffic rule violations and traffic crash history for young drivers. AB - Young drivers' high traffic violation involvement rate and significant contribution to traffic crashes compared to older drivers creates the need for detailed analyses of factors affecting young drivers' behaviors. This study is based on survey data collected from 2,057 18-29 year old young adults. Data were collected via face-to-face questionnaire surveys in four different cities in Turkey. The main objective of this study is to identify the relationship between socio-demographic characteristics, traffic rule violations, and traffic crashes among young drivers. Four main traffic rule violations are examined: red light violations, seat belt violations, speeding, and driving under the influence of alcohol, which are decisive in determining driving behavior and traffic crashes. The survey investigates the socio-demographic characteristics, traffic rule violation behavior and traffic crash histories of young adults. Four hypothetical scenarios were prepared for each traffic rule violation and data from the scenarios were modeled using the ordered probit model. Significant variables affecting each traffic rule violation are stated. Finally, significant variables that interact with crash involvements were investigated with binary logit models. According to the data analysis, 23.9% of drivers stated that they were involved in at least one traffic crash within the last three years. This crash rate increases to 38.3% for those who received at least one traffic citation/violation in last three years and peaks to 47.4% for those who were fined for seat belt violations in last three years. PMID- 25019691 TI - Mechanical circulatory support for the right ventricle in the setting of a left ventricular assist device. AB - Right ventricular failure is a difficult problem to manage and typically carries a dismal prognosis. In the setting of post-left ventricular assist device implantation (LVAD), right ventricular dysfunction both in the early and late stages is of particularly high incidence and concern. There are currently no agreed upon preoperative algorithms to predict patients at risk for this problem, thus adding another level of complexity to treatment. Furthermore, there is no current technology available for chronic right ventricular support and the devices currently in use are LVADS modified to adapt to the right circulatory system. This review provides an overview of right ventricular failure, particularly after LVAD implantation, and describes the survival outcomes and continued challenges in this area. PMID- 25019692 TI - Synthetic racemates of abyssinone I and II induces apoptosis through mitochondrial pathway in human cervix carcinoma cells. AB - Abyssinones I and II are prenylated flavanones existing in plant Erythrina abyssinica showing diverse biological activities including anticancer activities. We synthesized racemic mixtures of these flavanones from corresponding chalcones and herein we report for the first time the molecular mechanisms of cell death, anti-proliferative effect and ability to induce apoptosis in human cervical carcinoma (HeLa) cells. Cytotoxicity was assessed by MTT assay to determine LD50 for prenylated chalcones and their corresponding flavones. Abyssinones promoted apoptosis by up regulation of p53 and Bax, along with down regulation of Bcl-2. Apoptosis induction was mediated through mitochondrial pathway releasing cytochrome c and Apaf-1 into cytosol; associated with activation of caspase-3. Further they were able to decrease the expression of cell proliferation markers PCNA and cyclin D1 indicating anti proliferative activity. These observations demonstrate that abyssinones trigger apoptosis via mitochondrial pathway by activation of caspase-3 and disrupts cell cycle. PMID- 25019693 TI - Thermal spin filtering, thermal spin switching and negative-differential resistance in thermal spin currents in zigzag SiC nanoribbons. AB - Spin caloritronics with a combination of spintronics and thermoelectrics has potential applications in future information science and opens a new direction in the development of multi-functional materials. Based on density functional theory and the nonequilibrium Green's function method, we calculate thermal spin dependent transport through a zigzag silicon carbide nanoribbon (ZSiCNR), which is a heterojunction consisting of a left electrode (ZSiC-2H1H) and right electrode terminated (ZSiC-1H1H) by hydrogen. Our results show that when the temperature in the left contact increases over a critical value, the thermal spin down current increases remarkably from zero, while the thermal spin-up current remains zero in the total-temperature region, indicating that a perfect thermal spin filter together with a perfect spin switcher is obtained. Furthermore, the thermal spin current shows a negative differential resistance effect and quantum oscillation behaviors. These results suggest that the zigzag SiC nanoribbon proposed by us can be designed as a highly-efficient spin caloritronics device with multiple functionalities. PMID- 25019694 TI - Practice patterns and attitudes of primary care providers and barriers to surveillance of hepatocellular carcinoma in patients with cirrhosis. AB - BACKGROUND & AIMS: Fewer than 20% of patients with cirrhosis undergo surveillance for hepatocellular carcinoma (HCC), therefore these tumors often are detected at late stages. Although primary care providers (PCPs) care for 60% of patients with cirrhosis in the United States, little is known about their practice patterns for HCC surveillance. We investigated factors associated with adherence to guidelines for HCC surveillance by PCPs. METHODS: We conducted a web-based survey of all 131 PCPs at a large urban hospital. The survey was derived from validated surveys and pretested among providers; it included questions about provider and practice characteristics, self-reported rates of surveillance, surveillance test and frequency preference, and attitudes and barriers to HCC surveillance. RESULTS: We obtained a clinic-level response rate of 100% and a provider-level response rate of 60%. Only 65% of respondents reported annual surveillance and 15% reported biannual surveillance of patients for HCC. Barriers to HCC surveillance included not being up-to-date with HCC guidelines (68% of PCPs), difficulties in communicating effectively with patients about HCC surveillance (56%), and more important issues to manage in the clinic (52%). Approximately half of PCPs (52%) reported using ultrasound or measurements of alpha-fetoprotein in surveillance; 96% said that this combination was effective in reducing HCC-related mortality. However, many providers incorrectly believed that clinical examination (45%) or levels of liver enzymes (59%) or alpha-fetoprotein alone (89%) were effective surveillance tools. CONCLUSIONS: PCPs have misconceptions about tests to detect HCC that contribute to ineffective surveillance. Reported barriers to surveillance include suboptimal knowledge about guidelines, indicating a need for interventions, including provider education, to increase HCC surveillance effectiveness. PMID- 25019695 TI - Esophageal anastomotic strictures: outcomes of endoscopic dilation, risk of recurrence and refractory stenosis, and effect of foreign body removal. AB - BACKGROUND & AIMS: Esophageal anastomotic strictures often require repeat dilation to relieve dysphagia. Little is known about factors that affect their remediation. We investigated long-term success and rates of recurrence or refractoriness after dilation and factors associated with refractory stenosis. METHODS: We performed a retrospective study of 74 patients with an anastomotic stricture that had been dilated during a 5-year period (564 dilations; median follow-up period, 8 months). A stricture was refractory if luminal patency could not be maintained after >=5 dilation sessions during 10 weeks. RESULTS: Of the 74 patients, 93% had initial relief of dysphagia. The stricture recurred in 43% of patients, and 69% were considered refractory. Removal of sutures/staples protruding into the lumen did not accelerate time to initial patency (median, 37 days; interquartile range [IQR], 20-82 days) or lengthen the dysphagia-free interval (37.4 days; IQR, 8-41 weeks), compared with patients who did not undergo removal (initial patency, median 55 days; IQR, 14-109 days; P = .66 and median dysphagia-free interval, 21.7 days; IQR, 9-64 weeks; P = .8). Use of fluoroscopy during dilation (odds ratio, 8.92; 95% confidence interval, 1.98-40.14) was positively associated with development of refractory strictures, whereas neoadjuvant chemotherapy (odds ratio, 0.28; 95% confidence interval, 0.07-0.97) was inversely associated. Female sex and distal location of strictures increased risk of refractoriness as effect modifiers in multivariate analysis. CONCLUSIONS: Endoscopic dilation is highly successful in achieving luminal remediation, yet anastomotic strictures are often refractory and frequently recur. Removal of sutures/staples within the lumen does not help achieve patency. Need for fluoroscopic guidance indicates a high likelihood of refractoriness to dilation, whereas prior neoadjuvant chemotherapy indicates a lower risk. PMID- 25019696 TI - Reply: To PMID 24161350. PMID- 25019697 TI - Use of visible light spectroscopy to diagnose chronic gastrointestinal ischemia and predict response to treatment. AB - BACKGROUND & AIMS: Chronic gastrointestinal ischemia (CGI) is more common than previously thought. Visible light spectroscopy (VLS) allows for noninvasive measurements of mucosal capillary hemoglobin oxygen saturation during endoscopy. We evaluated the response of patients with occlusive CGI to treatment after evaluation by radiologic imaging of the vasculature and VLS. We also identified factors associated with response to treatment in these patients. METHODS: In a prospective study, we collected data from 212 patients referred for evaluation of suspected CGI from November 2008 through January 2011. Patients underwent an extensive evaluation that included visualization of gastrointestinal arteries and assessments of mucosal perfusion by means of VLS. Treatment response was evaluated in patients with occlusive CGI. Factors associated with response to therapy were assessed by using multivariate logistic regression analysis. RESULTS: Occlusive CGI was diagnosed in 107 patients (50%); 96 were offered treatment (90%). After median follow-up period of 13 months, data on treatment response were available from 89 patients (93%); 62 patients had a sustained response (70%). Weight loss before treatment (odds ratio [OR], 1.93), presence of an abdominal bruit (OR, 2.36), and corpus mucosal saturation level <56% (OR, 4.84) were the strongest predictors of a positive response to treatment. CONCLUSIONS: Treatment of CGI, diagnosed by a multimodal approach, provides a substantial long-term rate of response (70% in 13 months). Weight loss, abdominal bruit, and low corpus mucosal saturation identify patients most likely to respond to treatment. Multiple techniques should therefore be used to assess patients with CGI, including VLS measurements, to detect mucosal hypoxia. PMID- 25019699 TI - Reply: To PMID 24316103. PMID- 25019698 TI - Performance of endoscopic ultrasound in staging rectal adenocarcinoma appropriate for primary surgical resection. AB - BACKGROUND & AIMS: Endoscopic ultrasound (EUS) often is used to stage rectal cancer and thereby guide treatment. Prior assessments of its accuracy have been limited by small sets of data collected from tumors of varying stages. We aimed to characterize the diagnostic performance of EUS analysis of rectal cancer, paying particular attention to determining whether patients should undergo primary surgical resection. METHODS: We performed a retrospective observational study using procedural databases and electronic medical records from 4 academic tertiary-care hospitals, collecting data on EUS analyses from 2000 through 2012. Data were analyzed from 86 patients with rectal cancer initially staged as T2N0 by EUS. The negative predictive value (NPV) was calculated by comparing initial stages determined by EUS with those determined by pathology analysis of surgical samples. Logistic regression models were used to assess variation in diagnostic performance with case attributes. RESULTS: EUS excluded advanced tumor depth with an NPV of 0.837 (95% confidence interval [CI], 0.742-0.908), nodal metastasis with an NPV of 0.872 (95% CI, 0.783-0.934), and both together with an NPV of 0.767 (95% CI, 0.664-0.852) compared with pathology analysis. Incorrect staging by EUS affected treatment decision making for 20 of 86 patients (23.3%). Patient age at time of the procedure correlated with the NPV for metastasis to lymph node, but no other patient features were associated significantly with diagnostic performance. CONCLUSIONS: Based on a multicenter retrospective study, EUS staging of rectal cancer as T2N0 excludes advanced tumor depth and nodal metastasis, respectively, with an approximate NPV of 85%, similar to that of other modalities. EUS has an error rate of approximately 23% in identifying disease appropriate for surgical resection, which is lower than previously reported. PMID- 25019700 TI - Risk factors and outcomes of acute kidney injury in patients with acute liver failure. AB - BACKGROUND & AIMS: Patients with acute liver failure (ALF) frequently develop renal dysfunction, yet its overall incidence and outcomes have not been fully assessed. We investigated the incidence of acute kidney injury (AKI) among patients with ALF, using defined criteria to identify risk factors and to evaluate its effect on overall outcomes. METHODS: We performed a retrospective review of data from 1604 patients enrolled in the Acute Liver Failure Study Group, from 1998 through 2010. Patients were classified by the Acute Kidney Injury Network criteria, as well as for etiology of liver failure (acetaminophen based, ischemic, and all others). RESULTS: Seventy percent of patients with ALF developed AKI, and 30% received renal replacement therapy (RRT). Patients with severe AKI had higher international normalized ratio values than those without renal dysfunction (P < .001), and a higher proportion had advanced-grade coma (coma grades 3 or 4; P < .001) or presented with hypotension requiring vasopressor therapy (P < .001). A greater proportion of patients with acetaminophen-induced ALF had severe kidney injury than of patients with other etiologies of ALF; 34% required RRT, compared with 25% of patients with ALF not associated with acetaminophen or ischemia (P < .002). Of the patients with ALF who were alive at 3 weeks after study entry, significantly fewer with AKI survived for 1 year. Although AKI reduced the overall survival time, more than 50% of patients with acetaminophen-associated or ischemic ALF survived without liver transplantation (even with RRT), compared with 19% of patients with ALF attribute to other causes (P < .001). Only 4% of patients requiring RRT became dependent on dialysis. CONCLUSIONS: Based on a retrospective analysis of data from more than 1600 patients, AKI is common in patients with ALF and affects short- and long-term outcomes, but rarely results in chronic kidney disease. Acetaminophen-induced kidney injury is frequent, but patients have better outcomes than those with other forms of ALF. PMID- 25019701 TI - 3-Methyladenine can depress drug efflux transporters via blocking the PI3K-AKT mTOR pathway thus sensitizing MDR cancer to chemotherapy. AB - Multi-drug resistance (MDR) cancer is an intractable problem. Over-expression of drug efflux transporters such as ABCB1, ABCC1 and ABCG2 contributes to it, by which they pump drugs out of cells, and result in the decrease in the efficacy of chemotherapy. To reverse the cancer MDR, we used 3-methyladenine (3-MA) treatment on taxol or doxorubicin stressed MDR cell lines A2780DX5 and SGC7091R and xeno tumor implanted mice. The results indicate that ABCB1, ABCC1 and ABCG2 were depressed, and the PI3K-AKT-mTOR pathway was blocked. Moreover, using FITC labeled taxol as the indicator, we observed that the drug accumulation was enhanced in MDR cells and more cells were killed after 3-MA administration. Thus suggesting that 3-MA can reverse cancer MDR via depressing agent-efflux transporters. PMID- 25019702 TI - Tunable phonon-induced transparency in bilayer graphene nanoribbons. AB - In the phenomenon of plasmon-induced transparency, which is a classical analogue of electromagnetically induced transparency (EIT) in atomic gases, the coherent interference between two plasmon modes results in an optical transparency window in a broad absorption spectrum. With the requirement of contrasting lifetimes, typically one of the plasmon modes involved is a dark mode that has limited coupling to the electromagnetic radiation and possesses relatively longer lifetime. Plasmon-induced transparency not only leads to light transmission at otherwise opaque frequency regions but also results in the slowing of light group velocity and enhanced optical nonlinearity. In this article, we report an analogous behavior, denoted as phonon-induced transparency (PIT), in AB-stacked bilayer graphene nanoribbons. Here, light absorption due to the plasmon excitation is suppressed in a narrow window due to the coupling with the infrared active Gamma-point optical phonon, whose function here is similar to that of the dark plasmon mode in the plasmon-induced transparency. We further show that PIT in bilayer graphene is actively tunable by electrostatic gating and estimate a maximum slow light factor of around 500 at the phonon frequency of 1580 cm(-1), based on the measured spectra. Our demonstration opens an avenue for the exploration of few-photon nonlinear optics and slow light in this novel two dimensional material. PMID- 25019703 TI - Announcement: in memory of Irwin Oppenheim. PMID- 25019704 TI - Universality class of the conserved Manna model in one dimension. AB - The nonequilibrium absorbing phase transition of the discrete conserved Manna model was studied via Monte Carlo simulations on a one-dimensional chain, using the natural initial states with a sequential update. The critical density of the particles was found to be smaller than the recently reported value, and the order parameter exponent was considerably different from the directed percolation (DP) value. The influence of quenched disorder was also studied on a diluted strip of L_{x}*L_{y} lattice sites with L_{x}?L_{y}, and the results were compared with those of the contact process (CP). It was found that the Manna model and the CP exhibited distinctly different behaviors; the CP exhibited nonuniversal power-law decreases of active-site densities in the Griffith phase, whereas the Manna model showed a standard critical behavior. These results consistently suggest that the Manna model belongs to a universality class that is different from the DP class. PMID- 25019705 TI - Indirect measurement of interfacial melting from macroscopic ice observations. AB - Premelted water that is adsorbed to particle surfaces and confined to capillary regions remains in the liquid state well below the bulk melting temperature and can supply the segregated growth of ice lenses. Using macroscopic measurements of ice-lens initiation position in step-freezing experiments, we infer how the nanometer-scale thicknesses of premelted films depend on temperature depression below bulk melting. The interfacial interactions between ice, liquid, and soda lime glass particles exhibit a power-law behavior that suggests premelting in our system is dominated by short-range electrostatic forces. Using our inferred film thicknesses as inputs to a simple force-balance model with no adjustable parameters, we obtain good quantitative agreement between numerical predictions and observed ice-lens thickness. Macroscopic observations of lensing behavior have the potential as probes of premelting behavior in other systems. PMID- 25019706 TI - Achieving realistic interface kinetics in phase-field models with a diffusional contrast. AB - Phase-field models are powerful tools to tackle free-boundary problems. For phase transformations involving diffusion, the evolution of the nonconserved phase field is coupled to the evolution of the conserved diffusion field. Introducing the kinetic cross coupling between these two fields [E. A. Brener and G. Boussinot, Phys. Rev. E 86, 060601(R) (2012)], we solve the long-standing problem of a realistic description of interface kinetics when a diffusional contrast between the phases is taken into account. Using the case of the solidification of a pure substance, we show how to eliminate the temperature jump at the interface and to recover full equilibrium boundary conditions. We confirm our results by numerical simulations. PMID- 25019707 TI - Twist-bend nematic liquid crystals in high magnetic fields. AB - We present magneto-optic measurements on two materials that form the recently discovered twist-bend nematic (N_{tb}) phase. This intriguing state of matter represents a fluid phase that is orientationally anisotropic in three directions and also exhibits translational order with periodicity several times larger than the molecular size. N_{tb} materials may also spontaneously form a visible, macroscopic stripe texture. We show that the optical stripe texture can be persistently inhibited by a magnetic field, and a 25T external magnetic field depresses the N-N_{tb} phase transition temperature by almost 1{?}C. We propose a quantitative mechanism to account for this shift and suggest a Helfrich-Hurault type mechanism for the optical stripe formation. PMID- 25019709 TI - Optimal swimming of a sheet. AB - Propulsion at microscopic scales is often achieved through propagating traveling waves along hairlike organelles called flagella. Taylor's two-dimensional swimming sheet model is frequently used to provide insight into problems of flagellar propulsion. We derive numerically the large-amplitude wave form of the two-dimensional swimming sheet that yields optimum hydrodynamic efficiency: the ratio of the squared swimming speed to the rate-of-working of the sheet against the fluid. Using the boundary element method, we show that the optimal wave form is a front-back symmetric regularized cusp that is 25% more efficient than the optimal sine wave. This optimal two-dimensional shape is smooth, qualitatively different from the kinked form of Lighthill's optimal three-dimensional flagellum, not predicted by small-amplitude theory, and different from the smooth circular-arc-like shape of active elastic filaments. PMID- 25019708 TI - Self-assembly of skyrmion-dressed chiral nematic colloids with tangential anchoring. AB - We describe dipolar nematic colloids comprising mutually bound solid microspheres, three-dimensional skyrmions, and point defects in a molecular alignment field of chiral nematic liquid crystals. Nonlinear optical imaging and numerical modeling based on minimization of Landau-de Gennes free energy reveal that the particle-induced skyrmions resemble torons and hopfions, while matching surface boundary conditions at the interfaces of liquid crystal and colloidal spheres. Laser tweezers and videomicroscopy reveal that the skyrmion-colloidal hybrids exhibit purely repulsive elastic pair interactions in the case of parallel dipoles and an unexpected reversal of interaction forces from repulsive to attractive as the center-to-center distance decreases for antiparallel dipoles. The ensuing elastic self-assembly gives rise to colloidal chains of antiparallel dipoles with particles entangled by skyrmions. PMID- 25019710 TI - Solitary state at the edge of synchrony in ensembles with attractive and repulsive interactions. AB - We discuss the desynchronization transition in networks of globally coupled identical oscillators with attractive and repulsive interactions. We show that, if attractive and repulsive groups act in antiphase or close to that, a solitary state emerges with a single repulsive oscillator split up from the others fully synchronized. With further increase of the repulsing strength, the synchronized cluster becomes fuzzy and the dynamics is given by a variety of stationary states with zero common forcing. Intriguingly, solitary states represent the natural link between coherence and incoherence. The phenomenon is described analytically for phase oscillators with sine coupling and demonstrated numerically for more general amplitude models. PMID- 25019711 TI - Rapid geometrical chaotization in slow-fast Hamiltonian systems. AB - In this Rapid Communication we demonstrate effects of a new mechanism of adiabaticity destruction in Hamiltonian systems with a separatrix in the phase space. In contrast to the slow diffusive-like destruction typical for many systems, this new mechanism is responsible for very fast chaotization in a large phase volume. To investigate this mechanism we consider a Hamiltonian system with two degrees of freedom and with a separatrix in the phase plane of fast variables. The fast chaotization is due to an asymmetry of the separatrix and corresponding geometrical jumps of an adiabatic invariant. This system describes the motion of charged particles in a inhomogeneous electromagnetic field with a specific configuration. We show that geometrical jumps of the adiabatic invariant result in a very fast chaotization of particle motion. PMID- 25019712 TI - Multiplicative-cascade dynamics in pole balancing. AB - Pole balancing is a key task for probing the prospective control that organisms must engage in for purposeful action. The temporal structure of pole-balancing behaviors will reflect the on-line operation of control mechanisms needed to maintain an upright posture. In this study, signatures of multifractality are sought and found in time series of the vertical angle of a pole balanced on the fingertip. Comparisons to surrogate time series reveal multiplicative-cascade dynamics and interactivity across scales. In addition, simulations of a pole balancing model generating on-off intermittency [J. L. Cabrera and J. G. Milton, Phys. Rev. Lett. 89, 158702 (2002)] were analyzed. Evidence of multifractality is also evident in simulations, though comparing simulated and participant series reveals a significantly greater contribution of cross-scale interactivity for the latter. These findings suggest that multiplicative-cascade dynamics are an extension of on-off intermittency and play a role in prospective coordination. PMID- 25019713 TI - Consecutive turbulence transition delay with reinforced passive control. AB - Miniature vortex generators (MVGs) are able to delay the transition to turbulence in a flat plate boundary layer if properly designed. Unfortunately, the natural recovery of the modulated laminar base flow in the streamwise direction is of exponential space scale and hence the passive laminar control fades away fairly rapidly. Here we show that by placing a second array of MVGs downstream of the first one it is possible to nourish the counter-rotating streamwise vortices responsible for the modulation, which results in a prolonged streamwise extent of the control. With this control strategy it is possible to delay the transition to turbulence, consecutively, by reinforcing the control effect and with the ultimate implication of obtaining a net skin-friction drag reduction of at least 65%. PMID- 25019714 TI - Response function of turbulence computed via fluctuation-response relation of a Langevin system with vanishing noise. AB - For a shell model of the fully developed turbulence and the incompressible Navier Stokes equations in the Fourier space, when a Gaussian white noise is artificially added to the equation of each mode, an expression of the mean linear response function in terms of the velocity correlation functions is derived by applying the method developed for nonequilibrium Langevin systems [Harada and Sasa, Phys. Rev. Lett. 95, 130602 (2005)]. We verify numerically for the shell model case that the derived expression of the response function, as the noise tends to zero, converges to the response function of the noiseless shell model. PMID- 25019715 TI - Selection of the Taylor-Saffman bubble does not require surface tension. AB - A new general class of exact solutions is presented for the time evolution of a bubble of arbitrary initial shape in a Hele-Shaw cell when surface tension effects are neglected. These solutions are obtained by conformal mapping the viscous flow domain to an annulus in an auxiliary complex plane. It is then demonstrated that the only stable fixed point (attractor) of the nonsingular bubble dynamics corresponds precisely to the selected pattern. This thus shows that, contrary to the established theory, bubble selection in a Hele-Shaw cell does not require surface tension. The solutions reported here significantly extend previous results for a simply connected geometry (finger) to a doubly connected one (bubble). We conjecture that the same selection rule without surface tension holds for Hele-Shaw flows of arbitrary connectivity. PMID- 25019716 TI - Gravity-driven clustering of inertial particles in turbulence. AB - We report a different kind of particle clustering caused purely by gravity, discovered in our simulation of particle-laden turbulence. Clustering in a vertical strip pattern forms when strong gravity acts on heavy particles. This phenomenon is explained by the skewness of the flow velocity gradient in the gravitational direction experienced by particles, which causes horizontal convergence of particles. PMID- 25019717 TI - Comparisons of dense-plasma-focus kinetic simulations with experimental measurements. AB - Dense-plasma-focus (DPF) Z-pinch devices are sources of copious high-energy electrons and ions, x rays, and neutrons. The mechanisms through which these physically simple devices generate such high-energy beams in a relatively short distance are not fully understood and past optimization efforts of these devices have been largely empirical. Previously we reported on fully kinetic simulations of a DPF and compared them with hybrid and fluid simulations of the same device. Here we present detailed comparisons between fully kinetic simulations and experimental data on a 1.2 kJ DPF with two electrode geometries, including neutron yield and ion beam energy distributions. A more intensive third calculation is presented which examines the effects of a fully detailed pulsed power driver model. We also compare simulated electromagnetic fluctuations with direct measurement of radiofrequency electromagnetic fluctuations in a DPF plasma. These comparisons indicate that the fully kinetic model captures the essential physics of these plasmas with high fidelity, and provide further evidence that anomalous resistivity in the plasma arises due to a kinetic instability near the lower hybrid frequency. PMID- 25019718 TI - Symplectic integrators for spin systems. AB - We present a symplectic integrator, based on the implicit midpoint method, for classical spin systems where each spin is a unit vector in R{3}. Unlike splitting methods, it is defined for all Hamiltonians and is O(3)-equivariant, i.e., coordinate-independent. It is a rare example of a generating function for symplectic maps of a noncanonical phase space. It yields a new integrable discretization of the spinning top. PMID- 25019719 TI - Loop-erased random walk on a percolation cluster: crossover from Euclidean to fractal geometry. AB - We study loop-erased random walk (LERW) on the percolation cluster, with occupation probability p >= p_{c}, in two and three dimensions. We find that the fractal dimensions of LERW_{p} are close to normal LERW in a Euclidean lattice, for all p>p_{c}. However, our results reveal that LERW on critical incipient percolation clusters is fractal with d_{f}=1.217 +/- 0.002 for d=2 and 1.43 +/- 0.02 for d=3, independent of the coordination number of the lattice. These values are consistent with the known values for optimal path exponents in strongly disordered media. We investigate how the behavior of the LERW_{p} crosses over from Euclidean to fractal geometry by gradually decreasing the value of the parameter p from 1 to p_{c}. For finite systems, two crossover exponents and a scaling relation can be derived. This work opens up a theoretical window regarding the diffusion process on fractal and random landscapes. PMID- 25019720 TI - Effective field theory of thermal Casimir interactions between anisotropic particles. AB - We employ an effective field theory (EFT) approach to study thermal Casimir interactions between objects bound to a fluctuating fluid surface or interface dominated by surface tension, with a focus on the effects of particle anisotropy. The EFT prescription disentangles the constraints imposed by the particles' boundaries from the calculation of the interaction free energy by constructing an equivalent point particle description. The finite-size information is captured in a derivative expansion that encodes the particles' response to external fields. The coefficients of the expansion terms correspond to generalized tensorial polarizabilities and are found by matching the results of a linear response boundary value problem computed in both the full and effective theories. We demonstrate the versatility of the EFT approach by constructing the general effective Hamiltonian for a collection of particles of arbitrary shapes. Taking advantage of the conformal symmetry of the Hamiltonian, we discuss a straightforward conformal mapping procedure to systematically determine the polarizabilities and derive a complete description for elliptical particles. We compute the pairwise interaction energies to several orders for nonidentical ellipses as well as their leading-order triplet interactions and discuss the resulting preferred pair and multibody configurations. Furthermore, we elaborate on the complications that arise with pinned particle boundary conditions and show that the powerlike corrections expected from dimensional analysis are exponentially suppressed by the leading-order interaction energies. PMID- 25019721 TI - Work and quantum phase transitions: quantum latency. AB - We study the physics of quantum phase transitions from the perspective of nonequilibrium thermodynamics. For first-order quantum phase transitions, we find that the average work done per quench in crossing the critical point is discontinuous. This leads us to introduce the quantum latent work in analogy with the classical latent heat of first order classical phase transitions. For second order quantum phase transitions the irreversible work is closely related to the fidelity susceptibility for weak sudden quenches of the system Hamiltonian. We demonstrate our ideas with numerical simulations of first, second, and infinite order phase transitions in various spin chain models. PMID- 25019722 TI - Multicritical behavior of two coupled Ising models in the presence of a random field. AB - A system defined by two coupled Ising models, with a bimodal random field acting in one of them, is investigated. The interactions among variables of each Ising system are infinite ranged, a limit where mean field becomes exact. This model is studied at zero temperature, as well as for finite temperatures, representing physical situations which are appropriate for describing real systems, such as plastic crystals. A very rich critical behavior is found, depending directly on the particular choices of the temperature, couplings, and random-field strengths. Phase diagrams exhibiting ordered, partially ordered, and disordered phases are analyzed, showing the sequence of transitions through all these phases, similarly to what occurs in plastic crystals. Due to the wide variety of critical phenomena presented by the model, its usefulness for describing critical behavior in other substances is also expected. PMID- 25019723 TI - Scaling analysis of stationary probability distributions of random walks on one dimensional lattices with aperiodic disorder. AB - Stationary probability distributions of one-dimensional random walks on lattices with aperiodic disorder are investigated. The pattern of the distribution is closely related to the diffusional behavior, which depends on the wandering exponent Omega of the background aperiodic sequence: If Omega<0, the diffusion is normal and the distribution is extended. If Omega>0, the diffusion is ultraslow and the distribution is localized. If Omega=0, the diffusion is anomalous and the distribution is singular, which shows its complex and hierarchical structure. Multifractal analyses are performed in order to characterize these distributions. Extended, localized, and singular distributions are clearly distinguished only by the finite-size scaling behavior of alpha_{min} and f(alpha_{min}). The multifractal spectrum of the singular distribution agrees well with that of a simple partitioning process. PMID- 25019724 TI - Generalized extensive entropies for studying dynamical systems in highly anisotropic phase spaces. AB - Starting from the geometrical interpretation of the Renyi entropy, we introduce further extensive generalizations and study their properties. In particular, we found the probability distribution function obtained by the MaxEnt principle with generalized entropies. We prove that for a large class of dynamical systems subject to random perturbations, including particle transport in random media, these entropies play the role of Liapunov functionals. Some physical examples, which can be treated by the generalized Renyi entropies, are also illustrated. PMID- 25019725 TI - Grassmannian representation of the two-dimensional monomer-dimer model. AB - We present an application of the Grassmann algebra to the problem of the monomer dimer statistics on a two-dimensional square lattice. The exact partition function, or total number of possible configurations, of a system of dimers with a finite set of n monomers at fixed positions can be expressed via a quadratic fermionic theory. We give an answer in terms of a product of two pfaffians and the solution is closely related to the Kasteleyn result of the pure dimer problem. Correlation functions are in agreement with previous results, both for monomers on the boundary, where a simple exact expression is available in the discrete and continuous case, and in the bulk where the expression is evaluated numerically. PMID- 25019726 TI - Dynamic phase transitions in simple driven kinetic networks. AB - We analyze the probability distribution for entropy production rates of trajectories evolving on a class of out-of-equilibrium kinetic networks. These networks can serve as simple models for driven dynamical systems, where energy fluxes typically result in nonequilibrium dynamics. By analyzing the fluctuations in the entropy production, we demonstrate the emergence, in a large system size limit, of a dynamic phase transition between two distinct dynamical regimes. PMID- 25019727 TI - Optimal rectification in the ultrastrong coupling regime. AB - We study the effect of ultrastrong coupling on the transport of heat. In particular, we present a condition for optimal rectification, i.e., flow of heat in one direction and complete isolation in the opposite direction. We show that the strong-coupling formalism is necessary for correctly describing heat flow in a wide range of parameters, including moderate to low couplings. We present a situation in which the strong-coupling formalism predicts optimal rectification whereas the phenomenological approach predicts no heat flow in any direction, for the same parameter values. PMID- 25019728 TI - Local quenches with global effects in interacting quantum systems. AB - We study one-dimensional lattices of interacting spins-1/2 and show that the effects of quenching the amplitude of a local magnetic field applied to a single site of the lattice can be comparable to the effects of a global perturbation applied instantaneously to the entire system. Both quenches take the system to the chaotic domain, the energy distribution of the initial states approaches a Breit-Wigner shape, the fidelity (Loschmidt echo) decays exponentially, and thermalization becomes viable. PMID- 25019729 TI - Boltzmann distribution in a nonequilibrium steady state: measuring local potential by granular Brownian particles. AB - We investigate experimentally the steady state motion of a millimeter-sized granular polyhedral object on vertically vibrating platforms of flat, conical, and parabolic surfaces. We find that the position distribution of the granular object is related to the shape of the platform, just like that of a Brownian particle trapped in a potential at equilibrium, even though the granular object is intrinsically not at equilibrium due to inelastic collisions with the platform. From the collision dynamics, we derive the Langevin equation which describes the motion of the object under an effective potential that equals the gravitational potential along the platform surface. The potential energy is found to agree with the equilibrium equipartition theorem while the kinetic energy does not. Furthermore, the granular temperature is found to be higher than the effective temperature associated with the average potential energy, suggesting the presence of heat transfer from the kinetic part to the potential part of the granular object. PMID- 25019730 TI - Nonequilibrium work relation beyond the Boltzmann-Gibbs distribution. AB - The presence of multiplicative noise can alter measurements of forces acting on nanoscopic objects. Taking into account of multiplicative noise, we derive a series of nonequilibrium thermodynamical equalities as generalization of the Jarzynski equality, the detailed fluctuation theorem and the Hatano-Sasa relation. Our result demonstrates that the Jarzynski equality and the detailed fluctuation theorem remains valid only for systems with the Boltzmann-Gibbs distribution at the equilibrium state, but the Hatano-Sasa relation is robust with respect to different stochastic interpretations of multiplicative noise. PMID- 25019731 TI - Emergence of patterns in random processes. II. Stochastic structure in random events. AB - Random events can present what appears to be a pattern in the length of peak-to peak sequences in time series and other point processes. Previously, we showed that this was the case in both individual and independently distributed processes as well as for Brownian walks. In addition, we introduced the use of the discrete form of the Langevin equation of statistical mechanics as a device for connecting the two limiting sets of behaviors, which we then compared with a variety of observations from the physical and social sciences. Here, we establish a probabilistic framework via the Smoluchowski equation for exploring the Langevin equation and its expected peak-to-peak sequence lengths, and we introduce a concept we call "stochastic structure in random events," or SSRE. We extend the Brownian model to include antipersistent processes via autoregressive (AR) models. We relate the latter to describe the behavior of Old Faithful Geyser in Yellowstone National Park, and we devise a further test for the validity of the Langevin and AR models. Given our analytic results, we show how the Langevin equation can be adapted to describe population cycles of three to four years observed among many mammalian species in biology. PMID- 25019732 TI - Universality classes for unstable crystal growth. AB - Universality has been a key concept for the classification of equilibrium critical phenomena, allowing associations among different physical processes and models. When dealing with nonequilibrium problems, however, the distinction in universality classes is not as clear and few are the examples, such as phase separation and kinetic roughening, for which universality has allowed to classify results in a general spirit. Here we focus on an out-of-equilibrium case, unstable crystal growth, lying in between phase ordering and pattern formation. We consider a well-established 2+1-dimensional family of continuum nonlinear equations for the local height h(x,t) of a crystal surface having the general form ?_{t}h(x,t)=-?.[j(?h)+?(?^{2}h)]: j(?h) is an arbitrary function, which is linear for small ?h, and whose structure expresses instabilities which lead to the formation of pyramidlike structures of planar size L and height H. Our task is the choice and calculation of the quantities that can operate as critical exponents, together with the discussion of what is relevant or not to the definition of our universality class. These aims are achieved by means of a perturbative, multiscale analysis of our model, leading to phase diffusion equations whose diffusion coefficients encapsulate all relevant information on dynamics. We identify two critical exponents: (i) the coarsening exponent, n, controlling the increase in time of the typical size of the pattern, L~t^{n}; (ii) the exponent beta, controlling the increase in time of the typical slope of the pattern, M~t^{beta}, where M~H/L. Our study reveals that there are only two different universality classes, according to the presence (n=1/3, beta=0) or the absence (n=1/4, beta>0) of faceting. The symmetry of the pattern, as well as the symmetry of the surface mass current j(?h) and its precise functional form, is irrelevant. Our analysis seems to support the idea that also space dimensionality is irrelevant. PMID- 25019733 TI - Giant negative mobility of Janus particles in a corrugated channel. AB - We numerically simulate the transport of elliptic Janus particles along narrow two-dimensional channels with reflecting walls. The self-propulsion velocity of the particle is oriented along either its major (prolate) or minor axis (oblate). In smooth channels, we observe long diffusion transients: ballistic for prolate particles and zero diffusion for oblate particles. Placed in a rough channel, prolate particles tend to drift against an applied drive by tumbling over the wall protrusions; for appropriate aspect ratios, the modulus of their negative mobility grows exceedingly large (giant negative mobility). This suggests that a small external drive suffices to efficiently direct self-propulsion of rod-like Janus particles in rough channels. PMID- 25019734 TI - Control of quantum thermodynamic behavior of a charged magneto-oscillator with momentum dissipation. AB - In this work we expose the role of environment, confinement, and external magnetic field B in determining the low-temperature thermodynamic behavior in the context of cyclotron motion of a charged oscillator with anomalous dissipative coupling involving momentum instead of the much studied coordinate coupling. Explicit expressions for different quantum thermodynamic functions (QTFs) are obtained at low temperatures for different quantum heat baths characterized by the spectral density function MU(omega). The power-law fall of different QTFs is in conformity with the third law of thermodynamics; however, the sensitivity of decay, i.e., the power of the power-law decay, explicitly depends on MU(omega). We also discuss separately the influence of confinement and magnetic field on the low-temperature behavior of different QTFs. In this process we demonstrate how to control the low-temperature behavior of anomalous dissipative quantum systems by varying the confining length a, B, and the temperature T. Momentum dissipation reduces the effective mass of the system and we also discuss its effect on different QTFs at low temperatures. PMID- 25019735 TI - Correlated cluster mean-field theory for spin-glass systems. AB - The competition between cluster spin glass (CSG) and ferromagnetism or antiferromagnetism is studied in this work. The model considers clusters of spins with short-range ferromagnetic or antiferromagnetic (FE-AF) interactions (J_{0}) and long-range disordered couplings (J) between clusters. The problem is treated by adapting the correlated cluster mean-field theory of D. Yamamoto [Phys. Rev. B 79, 144427 (2009)]. Phase diagrams T/J*J_{0}/J are obtained for different cluster sizes n_{s}. The results show that the CSG phase is found below the freezing temperature T_{f} for lower intensities of J_{0}/J. The increase of short-range FE interaction can favor the CSG phase, while the AF one reduces the CSG region by decreasing the T_{f}. However, there are always critical values of J_{0} where AF or FE orders become stable. The results also indicate a strong influence of the cluster size in the competition of magnetic phases. For AF cluster, the increase of n_{s} diminishes T_{f} reducing the CSG phase region, which indicates that the cluster surface spins can play an important role in the CSG arising. PMID- 25019737 TI - Performance optimization of minimally nonlinear irreversible heat engines and refrigerators under a trade-off figure of merit. AB - A performance optimization for minimally nonlinear heat engines and refrigerators is conducted under an optimization criterion of Omega. The results show that under tight-coupling conditions, the efficiency and coefficient of performance (COP) bounds in asymmetric dissipation limits are the same as those obtained by de Tomas et al. [Phys. Rev. E 87, 012105 (2013)] for low dissipation heat devices. The efficiency bounds for heat engines under nontight-coupling conditions are also analyzed and the experimental results lie between theoretical results obtained under different coupling strengths. For refrigerators, the theoretical results are also in good agreement with some observed results. The efficiency and COP bounds under the Omega criterion are refined, which are closer to real heat engines and refrigerators. PMID- 25019736 TI - Efficiency at maximum power of motor traffic on networks. AB - We study motor traffic on Bethe networks subject to hard-core exclusion for both tightly coupled one-state machines and loosely coupled two-state machines that perform work against a constant load. In both cases we find an interaction induced enhancement of the efficiency at maximum power (EMP) as compared to noninteracting motors. The EMP enhancement occurs for a wide range of network and single-motor parameters and is due to a change in the characteristic load velocity relation caused by phase transitions in the system. Using a quantitative measure of the trade-off between the EMP enhancement and the corresponding loss in the maximum output power we identify parameter regimes where motor traffic systems operate efficiently at maximum power without a significant decrease in the maximum power output due to jamming effects. PMID- 25019738 TI - Relations between short-range and long-range Ising models. AB - We perform a numerical study of the long-range (LR) ferromagnetic Ising model with power law decaying interactions (J?r{-d-sigma}) on both a one-dimensional chain (d=1) and a square lattice (d=2). We use advanced cluster algorithms to avoid the critical slowing down. We first check the validity of the relation connecting the critical behavior of the LR model with parameters (d,sigma) to that of a short-range (SR) model in an equivalent dimension D. We then study the critical behavior of the d=2 LR model close to the lower critical sigma, uncovering that the spatial correlation function decays with two different power laws: The effect of the subdominant power law is much stronger than finite-size effects and actually makes the estimate of critical exponents very subtle. By including this subdominant power law, the numerical data are consistent with the standard renormalization group (RG) prediction by Sak [Phys. Rev. B 8, 281 (1973)], thus making not necessary (and unlikely, according to Occam's razor) the recent proposal by Picco [arXiv:1207.1018] of having a new set of RG fixed points in addition to the mean-field one and the SR one. PMID- 25019739 TI - Model to interpret pulsed-field-gradient NMR data including memory and superdispersion effects. AB - We propose a versatile model specifically designed for the quantitative interpretation of NMR velocimetry data. We use the concept of mobile or immobile tracer particles applied in dispersion theory in its Lagrangian form, adding two mechanisms: (i) independent random arrests of finite average representing intermittent periods of very low velocity zones in the mean flow direction and (ii) the possibility of unexpectedly long (but rare) displacements simulating the occurrence of very high velocities in the porous medium. Based on mathematical properties related to subordinated Levy processes, we give analytical expressions of the signals recorded in pulsed-field-gradient NMR experiments. We illustrate how to use the model for quantifying dispersion from NMR data recorded for water flowing through a homogeneous grain pack column in single- and two-phase flow conditions. PMID- 25019740 TI - Tagged-particle motion in a dense confined liquid. AB - We investigate the dynamics of a tagged particle embedded in a strongly interacting confined liquid enclosed between two opposing flat walls. Using the Zwanzig-Mori projection operator formalism we obtain an equation of motion for the incoherent scattering function suitably generalized to account for the lack of translational symmetry. We close the equations of motion by a self-consistent mode-coupling ansatz. The interaction of the tracer with the surrounding liquid is encoded in generalized direct correlation functions. We extract the in-plane dynamics and provide a microscopic expression for the diffusion coefficient parallel to the walls. The solute particle may differ in size or interaction from the surrounding host-liquid constituents offering the possibility of a systematic analysis of dynamic effects on the tagged-particle motion in confinement. PMID- 25019741 TI - Large-n approach to thermodynamic Casimir effects in slabs with free surfaces. AB - The classical n-vector phi{4} model with O(n) symmetrical Hamiltonian H is considered in a infinity{2}*L slab geometry bounded by a pair of parallel free surface planes at separation L. Standard quadratic boundary terms implying Robin boundary conditions are included in H. The temperature-dependent scaling functions of the excess free energy and the thermodynamic Casimir force are computed in the large-n limit for temperatures T at, above, and below the bulk critical temperature T_{c}. Their n=infinity limits can be expressed exactly in terms of the spectrum and eigenfunctions of a self-consistent one-dimensional Schrodinger equation. This equation is solved by numerical means for two distinct discretized versions of the model: in the first ("model A"), only the coordinate z across the slab is discretized and the integrations over momenta conjugate to the lateral coordinates are regularized dimensionally; in the second ("model B"), a simple cubic lattice with periodic boundary conditions along the lateral directions is used. Renormalization-group ideas are invoked to show that, in addition to corrections to scaling ?L{-1}, anomalous ones ?L{-1}lnL should occur. They can be considerably decreased by taking an appropriate g->infinity (T_{c} >infinity) limit of the phi{4} interaction constant g. Depending on the model A or B, they can be absorbed completely or to a large extent in an effective thickness L_{eff}=L+deltaL. Excellent data collapses and consistent high precision results for both models are obtained. The approach to the low temperature Goldstone values of the scaling functions is shown to involve logarithmic anomalies. The scaling functions exhibit all qualitative features seen in experiments on the thinning of wetting layers of {4}He and Monte Carlo simulations of XY models, including a pronounced minimum of the Casimir force below T_{c}. The results are in conformity with various analytically known exact properties of the scaling functions. PMID- 25019742 TI - Stochastic functionals and fluctuation theorem for multikangaroo processes. AB - We introduce multikangaroo Markov processes and provide a general procedure for evaluating a certain type of stochastic functional. We calculate analytically the large deviation properties. We apply our results to zero-crossing statistics and to stochastic thermodynamics, including the derivation of the fluctuation theorem and the large deviation properties for the stochastic entropy production in a typical solid state device. PMID- 25019743 TI - From pairwise to group interactions in games of cyclic dominance. AB - We study the rock-paper-scissors game in structured populations, where the invasion rates determine individual payoffs that govern the process of strategy change. The traditional version of the game is recovered if the payoffs for each potential invasion stem from a single pairwise interaction. However, the transformation of invasion rates to payoffs also allows the usage of larger interaction ranges. In addition to the traditional pairwise interaction, we therefore consider simultaneous interactions with all nearest neighbors, as well as with all nearest and next-nearest neighbors, thus effectively going from single pair to group interactions in games of cyclic dominance. We show that differences in the interaction range affect not only the stationary fractions of strategies but also their relations of dominance. The transition from pairwise to group interactions can thus decelerate and even revert the direction of the invasion between the competing strategies. Like in evolutionary social dilemmas, in games of cyclic dominance, too, the indirect multipoint interactions that are due to group interactions hence play a pivotal role. Our results indicate that, in addition to the invasion rates, the interaction range is at least as important for the maintenance of biodiversity among cyclically competing strategies. PMID- 25019744 TI - Crossover from anomalous to normal diffusion in porous media. AB - Random walks (RW) of particles adsorbed in the internal walls of porous deposits produced by ballistic-type growth models are studied. The particles start at the external surface of the deposits and enter their pores in order to simulate an external flux of a species towards a porous solid. For short times, the walker concentration decays as a stretched exponential of the depth z, but a crossover to long-time normal diffusion is observed in most samples. The anomalous concentration profile remains at long times in very porous solids if the walker steps are restricted to nearest neighbors and is accompanied with subdiffusion features. These findings are correlated with a decay of the explored area with z. The study of RW of tracer particles left at the internal part of the solid rules out an interpretation by diffusion equations with position-dependent coefficients. A model of RW in a tube of decreasing cross section explains those results by showing long crossovers from an effective subdiffusion regime to an asymptotic normal diffusion. The crossover position and density are analytically calculated for a tube with area decreasing exponentially with z and show good agreement with numerical data. The anomalous decay of the concentration profile is interpreted as a templating effect of the tube shape on the total number of diffusing particles at each depth, while the volumetric concentration in the actually explored porous region may not have significant decay. These results may explain the anomalous diffusion of metal atoms in porous deposits observed in recent works. They also confirm the difficulty in interpreting experimental or computational data on anomalous transport reported in recent works, particularly if only the concentration profiles are measured. PMID- 25019745 TI - Effects of intrinsic noise on a cubic autocatalytic reaction-diffusion system. AB - Starting from our recent chemical master equation derivation of the model of an autocatalytic reaction-diffusion chemical system with reactions U+2V->[over lambda_{0}]3V and V->[over MU]P, U->[over nu]Q, we determine the effects of intrinsic noise on the momentum-space behavior of its kinetic parameters and chemical concentrations. We demonstrate that the intrinsic noise induces n->n molecular interaction processes with n>=4, where n is the number of participating molecules of type U or V. The momentum dependences of the reaction rates are driven by the fact that the autocatalytic reaction (inelastic scattering) is renormalized through the existence of an arbitrary number of intermediate elastic scatterings, which can also be interpreted as the creation and subsequent decay of a three body composite state sigma=phi_{u}phi_{v}^{2}, where phi_{i} corresponds to the fields representing the densities of U and V. Finally, we discuss the difference between representing sigma as a composite or an elementary particle (molecule) with its own kinetic parameters. In one dimension, we find that while they show markedly different behavior in the short spatiotemporal scale, high-momentum (UV) limit, they are formally equivalent in the large spatiotemporal scale, low momentum (IR) regime. On the other hand, in two dimensions and greater, due to the effects of fluctuations, there is no way to experimentally distinguish between a fundamental and composite sigma. Thus, in this regime, sigma behaves as an entity unto itself, suggesting that it can be effectively treated as an independent chemical species. PMID- 25019746 TI - Mean cover time of one-dimensional persistent random walks. AB - The cover time is defined as the time needed for a random walker to visit every site of a confined domain. Here, we focus on persistent random walks, which provide a minimal model of random walks with short-range memory. We derive the exact expression of the mean cover time of a one-dimensional lattice by such a persistent random walk, both for periodic and reflecting boundary conditions. PMID- 25019747 TI - Planck radiation law and Einstein coefficients reexamined in Kaniadakis kappa statistics. AB - Blackbody radiation is reconsidered using the counterpart of the Bose-Einstein distribution in the kappa statistics arising from the Kaniadakis entropy. The generalized Planck radiation law is presented and compared to the usual law, to which it reduces in the limiting case kappa->0. Effective Einstein's coefficients of emission and absorption are defined in terms of the Kaniadakis parameter kappa. It is shown that the Kaniadakis statistics keeps unchanged the first Einstein coefficient A while the second coefficient B admits a generalized form within the present theoretical framework. PMID- 25019748 TI - Exchange symmetry, fluctuation-compressibility relation, and thermodynamic potentials of quantum liquids. AB - Liquid helium does not obey the Gibbs fluctuation-compressibility relation, which was noted more than six decades ago. However, still missing is a clear explanation of the reason for the deviation or the correct fluctuation compressibility relation for the quantum liquid. Here we present the fluctuation compressibility relation valid for any grand canonical system. Our result shows that the deviation from the Gibbs formula arises from a nonextensive part of thermodynamic potentials. The particle-exchange symmetry of many-body wave function of a strongly degenerate quantum gas is related to the thermodynamic extensivity of the system; a Bose gas does not always obey the Gibbs formula, while a Fermi gas does. Our fluctuation-compressibility relation works for classical systems as well as quantum systems. This work demonstrates that the application range of the Gibbs-Boltzmann statistical thermodynamics can be extended to encompass nonextensive open systems without introducing any postulate other than the principle of equal a priori probability. PMID- 25019749 TI - Universal scaling effects of a temperature gradient at first-order transitions. AB - We study the effects of smooth inhomogeneities at first-order transitions. We show that a temperature gradient at a thermally driven first-order transition gives rise to nontrivial universal scaling behaviors with respect to the length scale l_{t} of the variation of the local temperature T_{x}. We propose a scaling ansatz to describe the crossover region at the surface where T_{x}=T_{c}, where the typical discontinuities of a first-order transition are smoothed out. The predictions of this scaling theory are checked, and get strongly supported, by numerical results for the two-dimensional (2D) Potts models, for a sufficiently large number of states to have first-order transitions. Comparing with analogous results at the 2D Ising transition, we note that the scaling behaviors induced by a smooth inhomogeneity appear quite similar in first-order and continuous transitions. PMID- 25019751 TI - Maximum efficiency of ideal heat engines based on a small system: correction to the Carnot efficiency at the nanoscale. AB - We study the maximum efficiency of a heat engine based on a small system. It is revealed that due to the finiteness of the system, irreversibility may arise when the working substance contacts with a heat reservoir. As a result, there is a working-substance-dependent correction to the Carnot efficiency. We derive a general and simple expression for the maximum efficiency of a Carnot cycle heat engine in terms of the relative entropy. This maximum efficiency approaches the Carnot efficiency asymptotically when the size of the working substance increases to the thermodynamic limit. Our study extends Carnot's result of the maximum efficiency to an arbitrary working substance and elucidates the subtlety of thermodynamic laws in small systems. PMID- 25019750 TI - Critical behavior of absorbing phase transitions for models in the Manna class with natural initial states. AB - The critical behavior of absorbing phase transitions for two typical models in the Manna universality class, the conserved Manna model and the conserved lattice gas model, both on a square lattice, was investigated using the natural initial states. Various critical exponents were estimated using the static and dynamic simulations. The exponents characterizing dynamics of active particles differ considerably from the known exponents obtained using the random initial states, whereas those associated with the steady-state quantities remain the same. The critical exponents for both models were consistent with errors of less than 1% and satisfied the known scaling relations; thus, the known violation of scaling relations for models with a conserved field was resolved using the natural initial states. The results differed by 7%~12% from the directed percolation values. PMID- 25019752 TI - Estimation of quenched random fields in the inverse Ising problem using a diagonal matching method. AB - We consider a method for the accurate estimation of quenched random fields in the inverse Ising problem. Approximations such as the mean-field or Bethe methods are applied to estimate quenched random coupling parameters and external fields. A diagonal matching method is introduced to ensure consistency of the diagonal part of the susceptibility, and the method yields an accurate estimation of the external fields. We introduce the diagonal matching method into the mean-field, Thouless-Anderson-Palmer, and Bethe approximations, and we investigate the effect of the diagonal matching method on the accuracy of estimation of the external fields. PMID- 25019753 TI - Baxter-Wu model in a transverse magnetic field. AB - We investigate the low-energy properties as well as quantum and thermal phase transitions of the Baxter-Wu model in a transverse magnetic field. Our study relies on stochastic series expansion quantum Monte Carlo and on series expansions about the low- and high-field limits at zero temperature using the quantum finite-lattice method on the triangular lattice. The phase boundary consists of a second-order critical line in the four-state Potts model universality class starting from the pure Baxter-Wu limit meeting a first-order line connected to the zero-temperature transition point (h~2.4, T=0). Both lines merge at a tricritical point approximately located at (h~2.3J, T~J). PMID- 25019754 TI - Bethe free-energy approximations for disordered quantum systems. AB - Given a locally consistent set of reduced density matrices, we construct approximate density matrices which are globally consistent with the local density matrices we started from when the trial density matrix has a tree structure. We employ the cavity method of statistical physics to find the optimal density matrix representation by slowly decreasing the temperature in an annealing algorithm, or by minimizing an approximate Bethe free energy depending on the reduced density matrices and some cavity messages originated from the Bethe approximation of the entropy. We obtain the classical Bethe expression for the entropy within a naive (mean-field) approximation of the cavity messages, which is expected to work well at high temperatures. In the next order of the approximation, we obtain another expression for the Bethe entropy depending only on the diagonal elements of the reduced density matrices. In principle, we can improve the entropy approximation by considering more accurate cavity messages in the Bethe approximation of the entropy. We compare the annealing algorithm and the naive approximation of the Bethe entropy with exact and approximate numerical simulations for small and large samples of the random transverse Ising model on random regular graphs. PMID- 25019755 TI - Binding polynomial in molecular self-assembly. AB - In the present work the concept of a binding polynomial is revisited for the most widely used case of self-assembly of identical molecular units and results in the re-construction of a link to the grand partition function of such a system. It is found that if the self-assembly process is not pronounced (i.e., the product of the equilibrium constant and the monomer concentration is close to zero), the binding polynomial has the meaning of a molecular partition function that is given by the summation over energy levels of any molecule in the system. In other cases the concept of a binding polynomial may be misleading. PMID- 25019756 TI - Minimum vertex cover problems on random hypergraphs: replica symmetric solution and a leaf removal algorithm. AB - The minimum vertex-cover problems on random alpha-uniform hypergraphs are studied using two different approaches, a replica method in statistical mechanics of random systems and a leaf removal algorithm. It is found that there exists a phase transition at the critical average degree e/(alpha-1), below which a replica symmetric ansatz in the replica method holds and the algorithm estimates exactly the same solution of the problem as that by the replica method. In contrast, above the critical degree, the replica symmetric solution becomes unstable and the leaf-removal algorithm fails to estimate the optimal solution because of the emergence of a large size core. These results strongly suggest a close relation between the replica symmetry and the performance of an approximation algorithm. Critical properties of the core percolation are also examined numerically by a finite-size scaling. PMID- 25019758 TI - Retention capacity of correlated surfaces. AB - We extend the water retention model [C. L. Knecht et al., Phys. Rev. Lett. 108, 045703 (2012)] to correlated random surfaces. We find that the retention capacity of discrete random landscapes is strongly affected by spatial correlations among the heights. This phenomenon is related to the emergence of power-law scaling in the lake volume distribution. We also solve the uncorrelated case exactly for a small lattice and present bounds on the retention of uncorrelated landscapes. PMID- 25019757 TI - Thermodynamic description of the Ising antiferromagnet on a triangular lattice with selective dilution by a modified pair-approximation method. AB - The pair-approximation method is modified in order to describe systems with geometrical frustration. The Ising antiferromagnet on a triangular lattice with selective dilution (Kaya-Berker model) is considered and a self-consistent thermodynamic description of this model is obtained. For this purpose, the Gibbs free energy as a function of temperature, concentration of magnetic atoms on the selected sublattice, and external magnetic field is derived. In particular, the phase diagram is constructed and a comparison of different methods is presented. The thermodynamic quantities are discussed in the context of their physical validity, and the improvement in the description introduced by the modified method is emphasized. PMID- 25019759 TI - Degenerate ground states and multiple bifurcations in a two-dimensional q-state quantum Potts model. AB - We numerically investigate the two-dimensional q-state quantum Potts model on the infinite square lattice by using the infinite projected entangled-pair state (iPEPS) algorithm. We show that the quantum fidelity, defined as an overlap measurement between an arbitrary reference state and the iPEPS ground state of the system, can detect q-fold degenerate ground states for the Z_{q} broken symmetry phase. Accordingly, a multiple bifurcation of the quantum ground-state fidelity is shown to occur as the transverse magnetic field varies from the symmetry phase to the broken-symmetry phase, which means that a multiple bifurcation point corresponds to a critical point. A (dis)continuous behavior of quantum fidelity at phase transition points characterizes a (dis)continuous phase transition. Similar to the characteristic behavior of the quantum fidelity, the magnetizations, as order parameters, obtained from the degenerate ground states exhibit multiple bifurcation at critical points. Each order parameter is also explicitly demonstrated to transform under the Z_{q} subgroup of the symmetry group of the Hamiltonian. We find that the q-state quantum Potts model on the square lattice undergoes a discontinuous (first-order) phase transition for q=3 and q=4 and a continuous phase transition for q=2 (the two-dimensional quantum transverse Ising model). PMID- 25019760 TI - Gas-liquid phase coexistence and crossover behavior of binary ionic fluids with screened Coulomb interactions. AB - We study the effects of an interaction range on the gas-liquid phase diagram and the crossover behavior of a simple model of ionic fluids: an equimolar binary mixture of equisized hard spheres interacting through screened Coulomb potentials which are repulsive between particles of the same species and attractive between particles of different species. Using the collective variables theory, we find explicit expressions for the relevant coefficients of the effective phi{4} Ginzburg-Landau Hamiltonian in a one-loop approximation. Within the framework of this approximation, we calculate the critical parameters and gas-liquid phase diagrams for varying inverse screening length z. Both the critical temperature scaled by the Yukawa potential contact value and the critical density rapidly decrease with an increase of the interaction range (a decrease of z) and then for z<0.05 they slowly approach the values found for a restricted primitive model (RPM). We find that gas-liquid coexistence region reduces with an increase of z and completely vanishes at z?2.78. Our results clearly show that an increase in the interaction range leads to a decrease of the crossover temperature. For z?0.01, the crossover temperature is the same as for the RPM. PMID- 25019761 TI - Correntropy-based partial directed coherence for testing multivariate Granger causality in nonlinear processes. AB - Identification of directional influences in multivariate systems is of prime importance in several applications of engineering and sciences such as plant topology reconstruction, fault detection and diagnosis, and neurosciences. A spectrum of related directionality measures, ranging from linear measures such as partial directed coherence (PDC) to nonlinear measures such as transfer entropy, have emerged over the past two decades. The PDC-based technique is simple and effective, but being a linear directionality measure has limited applicability. On the other hand, transfer entropy, despite being a robust nonlinear measure, is computationally intensive and practically implementable only for bivariate processes. The objective of this work is to develop a nonlinear directionality measure, termed as KPDC, that possesses the simplicity of PDC but is still applicable to nonlinear processes. The technique is founded on a nonlinear measure called correntropy, a recently proposed generalized correlation measure. The proposed method is equivalent to constructing PDC in a kernel space where the PDC is estimated using a vector autoregressive model built on correntropy. A consistent estimator of the KPDC is developed and important theoretical results are established. A permutation scheme combined with the sequential Bonferroni procedure is proposed for testing hypothesis on absence of causality. It is demonstrated through several case studies that the proposed methodology effectively detects Granger causality in nonlinear processes. PMID- 25019762 TI - Driven surface diffusion with detailed balance and elastic phase transitions. AB - Driven surface diffusion occurs, for example, in molecular beam epitaxy when particles are deposited under an oblique angle. Elastic phase transitions happen when normal modes in crystals become soft due to the vanishing of certain elastic constants. We show that these seemingly entirely disparate systems fall under appropriate conditions into the same universality class. We derive the field theoretic Hamiltonian for this universality class, and we use renormalized field theory to calculate critical exponents and logarithmic corrections for several experimentally relevant quantities. PMID- 25019763 TI - Singular-potential random-matrix model arising in mean-field glassy systems. AB - We consider an invariant random matrix ensemble where the standard Gaussian potential is distorted by an additional single pole of arbitrary fixed order. Potentials with first- and second-order poles have been considered previously and found applications in quantum chaos and number theory. Here we present an application to mean-field glassy systems. We derive and solve the loop equation in the planar limit for the corresponding class of potentials. We find that the resulting mean or macroscopic spectral density is generally supported on two disconnected intervals lying on the two sides of the repulsive pole, whose edge points can be completely determined imposing the additional constraint of traceless matrices on average. For an unbounded potential with an attractive pole, we also find a possible one-cut solution for certain values of the couplings, which is ruled out when the traceless condition is imposed. Motivated by the calculation of the distribution of the spin-glass susceptibility in the Sherrington-Kirkpatrick spin-glass model, we consider in detail a second-order pole for a zero-trace model and provide the most explicit solution in this case. In the limit of a vanishing pole, we recover the standard semicircle. Working in the planar limit, our results apply to matrices with orthogonal, unitary, and symplectic invariance. Numerical simulations and an independent analytical Coulomb fluid calculation for symmetric potentials provide an excellent confirmation of our results. PMID- 25019764 TI - Higher-order effects on orientational correlation and relaxation dynamics in homogeneous cooling of a rough granular gas. AB - The orientational or angular correlation between the directions of the translational and rotational motions is analyzed theoretically for the homogeneous cooling state of a rough granular gas. The dynamical equations are derived using an approximate form of the single-particle distribution function that incorporates angular correlations. The goal is to assess the effects of higher-order angular corrections for which both quadratic- and quartic-order terms (in translational and rotational velocities of particles) are retained in the perturbation expansion of the distribution function. We show that higher order corrections can markedly affect the steady-state orientational correlation when the normal restitution coefficient is moderate or small, and this effect is more prominent for nearly smooth particles. The transient evolution of orientational correlation is found to be significantly affected by higher-order terms. In particular the higher-order orientational correlations can dominate over the leading-order contribution during short times even in the quasi-elastic limit, although the steady correlation remains unaffected by such corrections in the same limit. The buildup of correlations during the transient stage seems to be closely tied to the evolution of the ratio between the rotational and translational temperatures. It is demonstrated that the transient dynamics of the temperature ratio and its steady state remain insensitive to higher-order angular correlation. PMID- 25019765 TI - Stress-dependent normal-mode frequencies from the effective mass of granular matter. AB - A zero-temperature critical point has been invoked to control the anomalous behavior of granular matter as it approaches jamming or mechanical arrest. Criticality manifests itself in an anomalous spectrum of low-frequency normal modes and scaling behavior near the jamming transition. The critical point may explain the peculiar mechanical properties of dissimilar systems such as glasses and granular materials. Here we study the critical scenario via an experimental measurement of the normal modes frequencies of granular matter under stress from a pole decomposition analysis of the effective mass. We extract a complex-valued characteristic frequency which displays scaling |omega (sigma)| ~ sigmaOmega' with vanishing stress sigma for a variety of granular systems. The critical exponent is smaller than that predicted by mean-field theory opening new challenges to explain the exponent for frictional and dissipative granular matter. Our results shed light on the anomalous behavior of stress-dependent acoustics and attenuation in granular materials near the jamming transition. PMID- 25019766 TI - Hypocoordinated solids in particulate media. AB - We propose a "phase diagram" for particulate systems with purely repulsive contact forces, such as granular media and colloids. We characterize two classes of behavior as a function of the input kinetic energy per degree of freedom T_{0} and packing fraction deviation from jamming onset Deltaphi=phi-phi_{J} using simulations of frictionless disks. Isocoordinated solids (ICS) exist above jamming; they possess an average contact number equal to the isostatic value z_{iso}. ICS display "strict" harmonic response, where the density of vibrational modes from the Fourier transform of the velocity autocorrelation function is a set of sharp peaks at eigenfrequencies omega_{k}{d} of the dynamical matrix. In contrast, hypocoordinated solids (HCS) occur above and below jamming and possess fluctuating networks of interparticle contacts but do not undergo cage-breaking particle rearrangements. The density of vibrational frequencies for the HCS is not a collection of sharp peaks at omega_{k}{d}, but it does possess a common form over a range of Deltaphi and T_{0}. PMID- 25019767 TI - Density-driven spontaneous streak segregation patterns in a thin rotating drum. AB - Granular mixtures may segregate because of external driving forces, which play an important role in industry and geophysics. We investigate experimentally the mechanism of density-driven spontaneous streak segregation patterns in a thin rotating drum. We find that a spontaneous streak segregation pattern can occur in such a system, which we call a D-system. A phase diagram identifies three segregation pattern regimes in this study: the mixing regime, the core segregation regime, and the streak segregation regime. PMID- 25019768 TI - Interstitial gas effect on vibrated granular columns. AB - Vibrated granular materials have been intensively used to investigate particle segregation, convection, and heaping. We report on the behavior of a column of heavy grains bouncing on an oscillating solid surface. Measurements indicate that, for weak effects of the interstitial gas, the temporal variations of the pressure at the base of the column are satisfactorily described by considering that the column, despite the observed dilation, behaves like a porous solid. In addition, direct observation of the column dynamics shows that the grains of the upper and lower surfaces are in free fall in the gravitational field and that the dilation is due to a small delay between their takeoff times. PMID- 25019769 TI - Center of mass scaling in three-dimensional binary granular systems. AB - Using a combination of experimental results acquired through positron emission particle tracking and simulational results obtained via the discrete particle method, we determine a scaling relationship for the center of mass height of a vibrofluidized three-dimensional, bidisperse granular system. We find the scaling to be dependent on the characteristic velocity with which the system is driven, the depth of the granular bed, and the elasticities of the particles involved, as well as the degree of segregation exhibited by the system and the ratio of masses between particle species. The scaling is observed to be robust over a significant range of system parameters. PMID- 25019770 TI - Clustering and heterogeneous dynamics in a kinetic Monte Carlo model of self propelled hard disks. AB - We introduce a kinetic Monte Carlo model for self-propelled hard disks to capture with minimal ingredients the interplay between thermal fluctuations, excluded volume, and self-propulsion in large assemblies of active particles. We analyze in detail the resulting (density, self-propulsion) nonequilibrium phase diagram over a broad range of parameters. We find that purely repulsive hard disks spontaneously aggregate into fractal clusters as self-propulsion is increased and rationalize the evolution of the average cluster size by developing a kinetic model of reversible aggregation. As density is increased, the nonequilibrium clusters percolate to form a ramified structure reminiscent of a physical gel. We show that the addition of a finite amount of noise is needed to trigger a nonequilibrium phase separation, showing that demixing in active Brownian particles results from a delicate balance between noise, interparticle interactions, and self-propulsion. We show that self-propulsion has a profound influence on the dynamics of the active fluid. We find that the diffusion constant has a nonmonotonic behavior as self-propulsion is increased at finite density and that activity produces strong deviations from Fickian diffusion that persist over large time scales and length scales, suggesting that systems of active particles generically behave as dynamically heterogeneous systems. PMID- 25019771 TI - Numerical study of density functional theory with mean spherical approximation for ionic condensation in highly charged confined electrolytes. AB - We investigate numerically a density functional theory (DFT) for strongly confined ionic solutions in the canonical ensemble by comparing predictions of ionic concentration profiles and pressure for the double-layer configuration to those obtained with Monte Carlo (MC) simulations and the simpler Poisson Boltzmann (PB) approach. The DFT consists of a bulk (ion-ion) and an ion-solid part. The bulk part includes nonideal terms accounting for long-range electrostatic and short-range steric correlations between ions and is evaluated with the mean spherical approximation and the local density approximation. The ion-solid part treats the ion-solid interactions at the mean-field level through the solution of a Poisson problem. The main findings are that ionic concentration profiles are generally better described by PB than by DFT, although DFT captures the nonmonotone co-ion profile missed by PB. Instead, DFT yields more accurate pressure predictions than PB, showing in particular that nonideal effects are important to describe highly confined ionic solutions. Finally, we present a numerical methodology capable of handling nonconvex minimization problems so as to explore DFT predictions when the reduced temperature falls below the critical temperature. PMID- 25019772 TI - Phase-field-crystal modeling of glass-forming liquids: spanning time scales during vitrification, aging, and deformation. AB - Two essential elements required to generate a glass transition within phase-field crystal (PFC) models are outlined based on observed freezing behaviors in various models of this class. The central dynamic features of glass formation in simple binary liquids are qualitatively reproduced across 12 orders of magnitude in time by applying a physically motivated time scaling to previous PFC simulation results. New aspects of the equilibrium phase behavior of the same binary model system are also outlined, aging behavior is explored in the moderate and deeply supercooled regimes, and aging exponents are extracted. General features of the elastic and plastic responses of amorphous and crystalline PFC solids under deformation are also compared and contrasted. PMID- 25019774 TI - Anisotropic diffusion of spherical particles in closely confining microchannels. AB - We present here the measurement of the diffusivity of spherical particles closely confined by narrow microchannels. Our experiments yield a two-dimensional map of the position-dependent diffusion coefficients parallel and perpendicular to the channel axis with a resolution down to 129 nm. The diffusivity was measured simultaneously in the channel interior, the bulk reservoirs, as well as the channel entrance region. In the channel interior we found strongly anisotropic diffusion. While the perpendicular diffusion coefficient close to the confining walls decreased down to approximately 25% of the value on the channel axis, the parallel diffusion coefficient remained constant throughout the entire channel width. In addition to the experiment, we performed finite element simulations for the diffusivity in the channel interior and found good agreement with the measurements. Our results reveal the distinctive influence of strong confinement on Brownian motion, which is of significance to microfluidics as well as quantitative models of facilitated membrane transport. PMID- 25019773 TI - Kinematic matrix theory and universalities in self-propellers and active swimmers. AB - We describe an efficient and parsimonious matrix-based theory for studying the ensemble behavior of self-propellers and active swimmers, such as nanomotors or motile bacteria, that are typically studied by differential-equation-based Langevin or Fokker-Planck formalisms. The kinematic effects for elementary processes of motion are incorporated into a matrix, called the "kinematrix," from which we immediately obtain correlators and the mean and variance of angular and position variables (and thus effective diffusivity) by simple matrix algebra. The kinematrix formalism enables us recast the behaviors of a diverse range of self propellers into a unified form, revealing universalities in their ensemble behavior in terms of new emergent time scales. Active fluctuations and hydrodynamic interactions can be expressed as an additive composition of separate self-propellers. PMID- 25019775 TI - Electro-orientation of a metal nanowire counterbalanced by thermal torques. AB - The rotational diffusion of electrically polarized metal nanowires suspended in an electrolyte is studied. The alignment of a Brownian nanowire in an ac field with a given direction is not complete due to thermal (fluctuating) torques. The orientation distribution allows us to examine the electrokinetic torques acting on the nanowire for smaller voltages than in previous deterministic experiments. In addition, the torques are obtained without recurring to the rotational friction coefficient as in dynamic deterministic experiments. The present results are in accordance with previous deterministic results of electro-orientation of metal nanowires. Nanowire rotation is originated by both the electrical torque on the induced dipole and by induced-charge electro-osmotic flow around the particle. At low frequencies of the applied ac field, induced-charge electro osmotic orientation dominates while induced dipole torque orientation dominates at high frequencies. The angular standard deviation and the rotational rate are calculated from the measured fluctuating angle as a function of time, and good agreement with theoretical predictions is found. The experiments at high frequency indicate that the electrical torque on a nanowire near an insulating wall is reduced with respect to the bulk. PMID- 25019776 TI - Variable-amplitude oscillatory shear response of amorphous materials. AB - Variable-amplitude oscillatory shear tests are emerging as powerful tools to investigate and quantify the nonlinear rheology of amorphous solids, complex fluids, and biological materials. Quite a few recent experimental and atomistic simulation studies demonstrated that at low shear amplitudes, an amorphous solid settles into an amplitude- and initial-conditions-dependent dissipative limit cycle, in which back-and-forth localized particle rearrangements periodically bring the system to the same state. At sufficiently large shear amplitudes, the amorphous system loses memory of the initial conditions, exhibits chaotic particle motions accompanied by diffusive behavior, and settles into a stochastic steady state. The two regimes are separated by a transition amplitude, possibly characterized by some critical-like features. Here we argue that these observations support some of the physical assumptions embodied in the nonequilibrium thermodynamic, internal-variables based, shear-transformation-zone model of amorphous viscoplasticity; most notably that "flow defects" in amorphous solids are characterized by internal states between which they can make transitions, and that structural evolution is driven by dissipation associated with plastic deformation. We present a rather extensive theoretical analysis of the thermodynamic shear-transformation-zone model for a variable-amplitude oscillatory shear protocol, highlighting its success in accounting for various experimental and simulational observations, as well as its limitations. Our results offer a continuum-level theoretical framework for interpreting the variable-amplitude oscillatory shear response of amorphous solids and may promote additional developments. PMID- 25019777 TI - Experimental signatures of a nonequilibrium phase transition governing the yielding of a soft glass. AB - We present direct experimental signatures of a nonequilibrium phase transition associated with the yield point of a prototypical soft solid-a binary colloidal glass. By simultaneously quantifying single-particle dynamics and bulk mechanical response, we identified the threshold for the onset of irreversibility with the yield strain. We extracted the relaxation time from the transient behavior of the loss modulus and found that it diverges in the vicinity of the yield strain. This critical slowing down is accompanied by a growing correlation length associated with the size of regions of high Debye-Waller factor, which are precursors to yield events in glasses. Our results affirm that the paradigm of nonequilibrium critical phenomena is instrumental in achieving a holistic understanding of yielding in soft solids. PMID- 25019778 TI - Statistical mechanics of two-dimensional shuffled foams: geometry-topology correlation in small or large disorder limits. AB - Bubble monolayers are model systems for experiments and simulations of two dimensional packing problems of deformable objects. We explore the relation between the distributions of the number of bubble sides (topology) and the bubble areas (geometry) in the low liquid fraction limit. We use a statistical model [M. Durand, Europhys. Lett. 90, 60002 (2010)] which takes into account Plateau laws. We predict the correlation between geometrical disorder (bubble size dispersity) and topological disorder (width of bubble side number distribution) over an extended range of bubble size dispersities. Extensive data sets arising from shuffled foam experiments, surface evolver simulations, and cellular Potts model simulations all collapse surprisingly well and coincide with the model predictions, even at extremely high size dispersity. At moderate size dispersity, we recover our earlier approximate predictions [M. Durand, J. Kafer, C. Quilliet, S. Cox, S. A. Talebi, and F. Graner, Phys. Rev. Lett. 107, 168304 (2011)]. At extremely low dispersity, when approaching the perfectly regular honeycomb pattern, we study how both geometrical and topological disorders vanish. We identify a crystallization mechanism and explore it quantitatively in the case of bidisperse foams. Due to the deformability of the bubbles, foams can crystallize over a larger range of size dispersities than hard disks. The model predicts that the crystallization transition occurs when the ratio of largest to smallest bubble radii is 1.4. PMID- 25019779 TI - Mesoscopic simulation of phase behaviors and structures in an amphiphile-solvent system. AB - We have performed a three-dimensional simulation of mesoscopic structures in a mixture of AB amphiphilic molecule and C solvent by employing the density functional theory under the conditions that (i) the size of the AB is much larger than C and (ii) the affinity between A and B is much larger than the affinity between B and C. First, we have calculated the free energy of five periodic structures, i.e., the lamellar phase, hexagonally packed cylinders, body-centered cubic spheres, face-centered-cubic spheres, and gyroid phase for different sets of the concentration of AB (phi[over -]_{AB}) and the chi parameter (chi_{AC}). By comparing the free energies for these structures, the chi_{AC}-phi[over ]_{AB} phase diagram has been obtained. In addition to these periodic structures, it has been shown that nonperiodic structures such as spherical and rodlike micelles can be obtained although they might be metastable phase. PMID- 25019780 TI - Short-time diffusivity of dicolloids. AB - The short-time diffusivity of dicolloid particles as a function of particle volume fraction phi from 0.01 <= phi <= 0.6 is measured using diffusing wave spectroscopy. The diffusivities of symmetric and asymmetric dicolloids are compared with similarly sized spheres. The short-time diffusivity is independent of salt concentration and decreases with increasing volume fraction for both spheres and asymmetric dicolloids. Symmetric dicolloids have a higher diffusivity than spheres at similar volume fractions. This difference is accounted for by rescaling the dicolloid volume fraction based on the ratio of the random close packing volume fractions of spheres and dicolloids. Finally, a useful method is provided for calculating the diffusivity of symmetric dicolloid particles of arbitrary aspect ratio based on the calculated hydrodynamic resistance of Zabarankin [Proc. R. Soc. A 463, 2329 (2007)]. PMID- 25019781 TI - Characterization of sheared colloidal aggregation using Langevin dynamics simulation. AB - Aggregation of colloidal particles under shear is studied in model systems using a Langevin dynamics model with an improved interparticle interaction potential. In the absence of shear, aggregates that form are characterized by compact structure at small scales and ramified structure at larger scales. This confirms the structural crossover mechanism previously suggested by Sorensen and coworkers, that colloidal aggregation occurs due to monomer addition at small scales and due to cluster-cluster aggregation at large scales. The fractal dimension of nonsheared aggregates is scale-dependent. Smaller aggregates have a higher fractal dimension than larger ones, but the radius of gyration where this crossover occurs is independent of potential well depth for sufficiently deep wells. When these aggregates are subjected to shear they become anisotropic and form extended cigar-like structures. The size of sheared anisotropic aggregates in the direction perpendicular to the shear flow is limited by shear-induced breakage because the shear force dominates interparticle attraction for sufficiently large aggregates. Anisotropic aggregates are not completely characterized by a single radius of gyration, but rather by an inertia ellipsoid. Consequently the fractal dimension is no longer an adequate metric to properly characterize them, and to identify changes in their structure from their nonsheared isotropic counterparts. We introduce a new compactness-anisotropy analysis that characterizes the structure of anisotropic aggregates and allows us to distinguish between aggregates from sheared and nonsheared systems. Finally, using the ratio of interparticle force to the shear force f_{pot,sh} we are able to characterize different outcomes of sheared aggregation as a function of dimensionless well depth and Peclet number. PMID- 25019782 TI - Evolution of elastic heterogeneity during aging in metallic glasses. AB - The properties of glasses vary widely depending on the way they are prepared, even though their structures appear similar. We show that the local potential energy landscape (PEL) sensitively reflects the stability differences through simulation of local structural excitation in a model metallic glass. It is observed that the spectrum of local structural excitation develops a pseudogap at low energies as the glass becomes more stable. We also demonstrate that the spatial variation of the atomic level shear modulus, rather than the distribution of the magnitude of the single atom shear modulus, is more closely related to the nature of the PEL and the stabilities of glasses. In particular, local aggregation of atoms with low shear modulus greatly contributes to instability of the system. PMID- 25019783 TI - Nonlinear viscoelasticity of entangled wormlike micellar fluid under large amplitude oscillatory shear: role of elastic Taylor-Couette instability. AB - The role of elastic Taylor-Couette flow instabilities in the dynamic nonlinear viscoelastic response of an entangled wormlike micellar fluid is studied by large amplitude oscillatory shear (LAOS) rheology and in situ polarized light scattering over a wide range of strain and angular frequency values, both above and below the linear crossover point. Well inside the nonlinear regime, higher harmonic decomposition of the resulting stress signal reveals that the normalized third harmonic I_{3}/I_{1} shows a power-law behavior with strain amplitude. In addition, I_{3}/I_{1} and the elastic component of stress amplitude sigma_{0}{E} show a very prominent maximum at the strain value where the number density (n_{v}) of the Taylor vortices is maximum. A subsequent increase in applied strain (gamma) results in the distortions of the vortices and a concomitant decrease in n_{v}, accompanied by a sharp drop in I_{3} and sigma_{0}{E}. The peak position of the spatial correlation function of the scattered intensity along the vorticity direction also captures the crossover. Lissajous plots indicate an intracycle strain hardening for the values of gamma corresponding to the peak of I_{3}, similar to that observed for hard-sphere glasses. PMID- 25019784 TI - Structural evolution in the aging process of supercooled colloidal liquids. AB - When a liquid is rapidly quenched to a temperature below the glass-transition point, it is driven out of equilibrium; it then slowly relaxes to a (quasi)equilibrium state. This slow relaxation process is called aging. By definition, any glasses are inevitably in the process of aging and actually slowly evolving with time. Thus the study of aging phenomena is of fundamental importance for understanding not only the nonequilibrium nature of the glass transition, but also the stability of glassy materials. Here we consider aging after a rather shallow quench, for which a system is still able to reach (metastable) equilibrium. By using polydisperse colloidal liquids as a model, we show the validity of dynamical scaling that there is only one relevant length scale not only for a quasiequilibrium supercooled state but also for a nonequilibrium process of aging, which is reminiscent of dynamical critical phenomena. Our finding indicates that the aging toward (metastable) equilibrium may be regarded as the growth process of critical-like fluctuations of static order associated with low-free-energy configurations, further suggesting that this ordering is the origin of cooperative slow dynamics in the systems studied. The generality of this statement for other glass-forming systems remains for a future study. PMID- 25019785 TI - Clusters, asters, and collective oscillations in chemotactic colloids. AB - The creation of synthetic systems that emulate the defining properties of living matter, such as motility, gradient-sensing, signaling, and replication, is a grand challenge of biomimetics. Such imitations of life crucially contain active components that transform chemical energy into directed motion. These artificial realizations of motility point in the direction of a new paradigm in engineering, through the design of emergent behavior by manipulating properties at the scale of the individual components. Catalytic colloidal swimmers are a particularly promising example of such systems. Here we present a comprehensive theoretical description of gradient-sensing of an individual swimmer, leading controllably to chemotactic or anti-chemotactic behavior, and use it to construct a framework for studying their collective behavior. We find that both the positional and the orientational degrees of freedom of the active colloids can exhibit condensation, signaling formation of clusters and asters. The kinetics of catalysis introduces a natural control parameter for the range of the interaction mediated by the diffusing chemical species. For various regimes in parameter space in the long ranged limit our system displays precise analogs to gravitational collapse, plasma oscillations, and electrostatic screening. We present prescriptions for how to tune the surface properties of the colloids during fabrication to achieve each type of behavior. PMID- 25019786 TI - Dynamic electrophoresis of charged colloids in an oscillating electric field. AB - The dynamics of charged colloids in an electrolyte solution is studied using direct numerical simulations via the smoothed profile method. We calculated the complex electrophoretic mobility MU(omega) of the charged colloids under an oscillating electric field of frequency omega. We show the existence of three dynamically distinct regimes, determined by the momentum diffusion and ionic diffusion time scales. The present results agree well with approximate theories based on the cell model in dilute suspensions; however, systematic deviations between the simulation results and theoretical predictions are observed as the volume fraction of colloids is increased, similar to the case of constant electric fields. PMID- 25019787 TI - Structural properties of anisotropically confined binary Coulomb balls. AB - We investigate the structural properties of a small binary system of dusty plasma subjected to an anisotropic external confinement. We have found that the ground state can form various symmetrical configurations, which generally correspond to variations of a multiple-ring structure. The presence of such structures is given through a detailed phase diagram constructed for the systems with N=18 and 24 particles. Furthermore, we show that the configurations of multiple rings can present a persistent behavior for the case in which the number of less-charged particles is equal to a multiple of the number of particles per ring. Finally, we discuss the main characteristics of the transitions of first and second orders since these are related to the main configurational changes of the ground states. PMID- 25019788 TI - Metastable states and activated dynamics in thin-film adhesion to patterned surfaces. AB - We consider adhesion due to London-van der Waals attraction between a thin film and a patterned surface with nanometer asperities. Depending on the surface topography and the stiffness of the film, three regimes of adhesion are identified: complete contact adhesion, partial contact adhesion, and glassy adhesion. For complete contact adhesion, the film conforms to the undulations of the surface, whereas for partial contact and glassy adhesion, the adhesive interface breaks down into microscopic areas of contact. When a film in the glassy regime is peeled off the surface, metastable states develop at which the crack front becomes arrested, analogously to the frustrated motion of the three phase contact line across a heterogeneous surface. For this glassy regime, we use transition state theory to model the thermally activated progression of the crack front. This theoretical treatment suggests that the rate of the adhesive failure increases exponentially with the applied force. PMID- 25019789 TI - Capillary adhesion at the nanometer scale. AB - Molecular dynamics simulations are used to study the capillary adhesion from a nonvolatile liquid meniscus between a spherical tip and a flat substrate. The atomic structure of the tip, the tip radius, the contact angles of the liquid on the two surfaces, and the volume of the liquid bridge are varied. The capillary force between the tip and substrate is calculated as a function of their separation h. The force agrees with continuum predictions based on macroscopic theory for h down to ~5 to 10 nm. At smaller h, the force tends to be less attractive than predicted and has strong oscillations. This oscillatory component of the capillary force is completely missed in the macroscopic theory, which only includes contributions from the surface tension around the circumference of the meniscus and the pressure difference over the cross section of the meniscus. The oscillation is found to be due to molecular layering of the liquid confined in the narrow gap between the tip and substrate. This effect is most pronounced for large tip radii and/or smooth surfaces. The other two components considered by the macroscopic theory are also identified. The surface tension term, as well as the meniscus shape, is accurately described by the macroscopic theory for h down to ~1 nm, but the capillary pressure term is always more positive than the corresponding continuum result. This shift in the capillary pressure reduces the average adhesion by a factor as large as 2 from its continuum value and is found to be due to an anisotropy in the pressure tensor. The component in the plane of the substrate is consistent with the capillary pressure predicted by the macroscopic theory (i.e., the Young-Laplace equation), but the normal pressure that determines the capillary force is always more positive than the continuum counterpart. PMID- 25019790 TI - Dynamic evolution of initial instability during non-steady-state growth. AB - Dynamic evolution of initial instability is investigated by an analytic model obtained by modifying the theory of Warren and Langer [Phys. Rev. E 47, 2702 (1993)] and the quantitative phase-field model in directional solidification under transient conditions for realistic parameters of a dilute alloy. The evolutions of tip velocity and concentration in the liquid side of the interface predicted by the analytic model agree very well with that from the phase-field simulation in the linear growth stage of the non-steady-state growth, indicating that the model could be used as a convenient method to study the initial instability during non-steady-state growth. The influences of non-steady-state conditions which include the increasing rate of pulling speed and temperature gradient at the onset of initial instability are investigated, and we find that, the initial instability seems to depend strongly on the non-steady-state conditions and the non-steady-state history, and thus, it should be primarily considered in the study of the transient growth. PMID- 25019791 TI - Reorientation of a dipolar monolayer and dipolar solvent. AB - The reliable persistence of an adhered monolayer film on a substrate is critical for film function. The process by which monolayers degrade or disperse remains unclear. Our study investigates the properties and dynamics of a solute of dipolar molecules initially adhered as a monolayer on a substrate in a water-like Stockmayer solvent. We find that for a rigid solute, both the solute and solvent show qualitatively different dynamics than for a flexible solute and its solvent. For the rigid solute, spreading is hindered and solvent orientation is more pronounced. We formulate a simple kinetic model that shows qualitatively similar results to the molecular dynamics simulations of the time evolution of the monolayer. Simple kinetics of molecules on substrates is a starting point for understanding important industrial monolayer applications and complex interactions on membranes. PMID- 25019792 TI - Relaxation after a change in the interface growth dynamics. AB - The global effects of sudden changes in the interface growth dynamics are studied using models of the Edwards-Wilkinson (EW) and Kardar-Parisi-Zhang (KPZ) classes during their growth regimes in dimensions d=1 and d=2. Scaling arguments and simulation results are combined to predict the relaxation of the difference in the roughness of the perturbed and the unperturbed interfaces, DeltaW^{2}~s{c}t{ gamma}, where s is the time of the change and t>s is the observation time after that event. The previous analytical solution for the EW-EW changes is reviewed and numerically discussed in the context of lattice models, with possible decays with gamma=3/2 and gamma=1/2. Assuming the dominant contribution to DeltaW{2} to be predicted from a time shift in the final growth dynamics, the scaling of KPZ KPZ changes with gamma=1-2beta and c=2beta is predicted, where beta is the growth exponent. Good agreement with simulation results in d=1 and d=2 is observed. A relation with the relaxation of a local autoresponse function in d=1 cannot be discarded, but very different exponents are shown in d=2. We also consider changes between different dynamics, with the KPZ-EW as a special case in which a faster growth, with dynamical exponent z_{i}, changes to a slower one, with exponent z. A scaling approach predicts a crossover time t_{c}~s{z/z_{i}}?s and DeltaW{2}~s{c}F(t/t_{c}), with the decay exponent gamma=1/2 of the EW class. This rules out the simplified time shift hypothesis in d=2 dimensions. These results help to understand the remarkable differences in EW smoothing of correlated and uncorrelated surfaces, and the approach may be extended to sudden changes between other growth dynamics. PMID- 25019793 TI - Influence of adsorption or desorption and surface diffusion on the formation kinetics of open half-monolayer coverage. AB - The formation kinetics of open half-monolayer films on solid substrates is studied by the deposition of particles from a gaseous (vapor) phase to a cold substrate (room temperature) provided the lateral interaction between the particles of adsorbed layer (adlayer) is attractive. A detailed analysis of two limiting cases is presented: when the half-monolayer film formation rate is limited by the adsorption of particles from the gas phase and when the formation of the half-monolayer film surface is determined by the rate of surface diffusion of the adsorbed particles. The asymptotic analysis of the coverage dispersion evolution and the characteristic spatial scale of coverage inhomogeneities at the early and late stages of relaxation of a submonolayer film after quenching under the spinodal is carried out. It is found that separation of the adlayer occurs, so inhomogeneities of submonolayer films at the later stages of the process tend to equilibrium values of coverage in any case. However, asymptotic and numerical analysis shows that in the second case for some relationship between the kinetic and thermodynamic parameters of the adlayer an intermediate asymptotic relaxation process can be observed. It testifies to a kinetic slowdown of the separation process at the spinodal values of coverages. This fact manifests as the appearance of the intermediate plateau in the evolution curves for the coverage dispersion and nonmonotonic change of the characteristic spatial scale of coverage inhomogeneities. Moreover, at the early stages of the coverage evolution, the incubation period is revealed in the development of its inhomogeneities. It is shown that at the later stages of the separation of the half-monolayer film, the characteristic spatial scale of coverage inhomogeneities increases with time according to the law tau {1/2} and the width of the transition region between enriched and depleted regions of adlayer decreases as 1/tau {1/2}. PMID- 25019794 TI - Thermal slip for liquids at rough solid surfaces. AB - Molecular dynamics simulation is used to examine the thermal slip of liquids at rough solid surfaces as characterized by fractal Cantor structures. The temperature profiles, potential energy distributions, thermal slip, and interfacial thermal resistance are investigated and evaluated for a variety of surface topographies. In addition, the effects of liquid-solid interaction, surface stiffness, and boundary condition on thermal slip length are presented. Our results indicate that the presence of roughness expands the low potential energy regions in adjacent liquids, enhances the energy transfer at liquid-solid interface, and decreases the thermal slip. Interestingly, the thermal slip length and thermal resistance for liquids in contact with solid surfaces depends not only on the statistical roughness height, but also on the fractal dimension (i.e., topographical spectrum). PMID- 25019795 TI - Role of chemical potential in relaxation of faceted crystal structure. AB - Below the roughening transition, crystal surfaces have macroscopic plateaus, facets, whose evolution is driven by the microscale dynamics of steps. A long standing puzzle was how to reconcile discrete effects in facet motion with fully continuum approaches. We propose a resolution of this issue via connecting, through a jump condition, the continuum-scale surface chemical potential away from the facet, characterized by variations of the continuum surface free energy, with a chemical potential originating from the decay of atomic steps on top of the facet. The proposed condition accounts for step flow inside a discrete boundary layer near the facet. To validate this approach, we implement in a radial geometry a hybrid discrete-continuum scheme in which the continuum theory is coupled with only a few, minimally three, steps in diffusion-limited kinetics with conical initial data. PMID- 25019796 TI - Thickness-dependent attraction or repulsion between defects on a thin elastic film. AB - We examine elastic interaction between two defects on one side or two sides of an isotropic thin film. We show that the tangential and normal forces contribute to the interaction in a coupled manner. Our finding is that the attraction or repulsion between two defects exhibiting twofold symmetry is dependent on the film thickness. The result is of particular importance for probing elastic interaction between adherent cells which have been commonly treated as twofold surface defects. PMID- 25019797 TI - Freezing of Lennard-Jones fluid on a patterned substrate. AB - Using molecular dynamics simulations, we study freezing of Lennard-Jones particles at commensurate substrate with triangular pattern. Throughout the box particles freeze onto the substrate and form close-packed layers. For the moderately attractive substrates, an intermediate hexatic phase between liquid and crystal is detected in the first two layers where the hexatic-solid freezing process is continuous while, counterintuitively, the liquid-hexatic process is of first order. Moreover, we observe that liquid-hexatic and hexatic-solid transitions shift towards higher temperatures with the attraction strength increasing. By contrast, the liquid-hexatic transition shifts faster than the hexatic-solid process, significantly widening the temperature range of the hexatic phase. When this phenomenon appears, freezing in the bulk always proceeds through a first-order transition at the same temperature. In addition, changes in the average structural order (three-dimensional) of the layers indicate that freezing processes in layers near substrates seem to cost the structural order of the bulk particles in their vicinity, and an intermediate prestructural cloud of medium-ordered particles is always observed before the layering freezing. PMID- 25019798 TI - Cooperative sequential-adsorption model in two dimensions with experimental applications for ionic self-assembly of nanoparticles. AB - Self-assembly of nanoparticles is an important tool in nanotechnology, with numerous applications, including thin films, electronics, and drug delivery. We study the deposition of ionic nanoparticles on a glass substrate both experimentally and theoretically. Our theoretical model consists of a stochastic cooperative adsorption and evaporation process on a two-dimensional lattice. By exploring the relationship between the initial concentration of nanoparticles in the colloidal solution and the density of particles deposited on the substrate, we relate the deposition rate of our theoretical model to the concentration. PMID- 25019799 TI - Paranematic-to-nematic ordering of a binary mixture of rodlike liquid crystals confined in cylindrical nanochannels. AB - We explore the optical birefringence of the nematic binary mixtures 6CB_{1 x}7CB_{x} (0 <= x <= 1) embedded into parallel-aligned nanochannels of mesoporous alumina and silica membranes for channel radii of 3.4 <= R <= 21.0 nm. The results are compared with the bulk behavior and analyzed with a Landau-de Gennes model. Depending on the channel radius the nematic ordering in the cylindrical nanochannels evolves either discontinuously (subcritical regime, nematic ordering field sigma<1/2) or continuously (overcritical regime, sigma>1/2), but in both cases with a characteristic paranematic precursor behavior. The strength of the ordering field, imposed by the channel walls, and the magnitude of quenched disorder varies linearly with the mole fraction x and scales inversely proportionally with R for channel radii larger than 4 nm. The critical pore radius, R_{c}, separating a continuous from a discontinuous paranematic-to nematic evolution varies linearly with x and differs negligibly between the silica and alumina membranes. We find no hints of preferred adsorption of one species at the channels walls. By contrast, a linear variation of the nematic-to paranematic transition point T_{PN} and of the nematic ordering field sigma versus x suggests that the binary mixtures of cyanobiphenyls 6CB and 7CB keep their homogeneous bulk stoichiometry also in nanoconfinement, at least for channel diameters larger than ~7 nm. PMID- 25019800 TI - Chiral bipolar colloids from nonchiral chromonic liquid crystals. AB - We demonstrate that high anisotropy of elastic constants of chromonic liquid crystals leads to a number of spontaneously twisted nematic director fields around colloidal particles in these non-chiral fluids. For spherical colloidal particles with surface inducing degenerate planar nematic ordering we observe that boojum defects at the particles' poles acquire twisted internal structure, extending up to three particle diameters along the rubbing direction of the cell. The twist handedness of the two boojum defects at the poles of the particle can be either the same or opposite, and we can switch the defects handedness by localized thermal microquenching. Numerical simulations confirm that the transitions into the distorted states are induced by lowering of the twist elastic constant, which results in two (meta)stable chiral configurations of the boojums, separated by an energy barrier much higher than the thermal energy. We show that boojum handedness can change the pairwise elastic interaction between the two particles positioned along the rubbing direction from repulsive to attractive. PMID- 25019801 TI - Model of hard spheroplatelets near a hard wall. AB - A system of hard spheroplatelets near an impenetrable wall is studied in the low density Onsager approximation. Spheroplatelets have optimal shape between rods and plates, and the direct transition from the isotropic to biaxial nematic phase is present. A simple local approximation for the one-particle distribution function is used. Analytical results for the surface tension and the entropy contributions are derived. The density and the order-parameter profiles near the wall are calculated. The preferred orientation of the short molecule axes is perpendicular to the wall. Biaxiality close to the wall can appear only if the phase is biaxial in the bulk. PMID- 25019802 TI - Columnar molecular aggregation in the aqueous solutions of disodium cromoglycate. AB - Stack, chimneylike, and threadlike assemblies have previously been proposed for the structure of disodium cromoglycate (DSCG) aggregates in aqueous solutions. The results of the synchrotron x-ray scattering investigations reported here reveal the formation of simple columnar assemblies with pi-pi stacking at a separation of 3.4 A between the DSCG molecules. Lateral separation between the assemblies is concentration and temperature dependent, varying from ~35 to 42 A in the orientationally ordered nematic (N) phase and from 27 to 32 A in the columnar or middle (M) phase having long range lateral positional order. The assemblies' length depends on concentration and consists of ~23 molecules in the N phase, becoming three to ten times larger in the M phase. The scission energy is concentration dependent in the N phase with values ~7.19 +/- 0.14 k_{B}T (15 wt %), 2.73 +/- 0.4 k_{B}T (20 wt %), and 3.05 +/- 0.2 k_{B}T (25 wt %). Solutions of all concentrations undergo a spinodal decomposition at temperatures above ~40 degrees C, resulting in DSCG-rich regions with the M phase and water rich regions in the N and isotropic phases. PMID- 25019803 TI - Tilt orientationally disordered hexagonal columnar phase of phthalocyanine discotic liquid crystals. AB - The structures of the discotic liquid crystalline (LC) phase of metal-free octa substituted phthalocyanine (Pc) derivatives were investigated using molecular dynamics (MD) simulations. Special attention was paid to the LC phase structure of the non-peripheral octa-hexyl substituted Pc-derivatives that were recently found to show very high carrier mobilities for the discotic LCs. We obtained spontaneous transition to the columnar hexagonal (Col_{h}) LC phase in a melting simulation from the crystal structure obtained using an x-ray diffraction study. In this simulated Col_{h} structure, the Pc-core normal vectors were tilted 47{?} from the column axis in parallel within each column, but the tilting directions are disordered between columns. We also found that the inter-core distance was not as large as previously suggested (0.4-0.5 nm) but similar to the common value (0.36 nm). This may resolve the contradiction between the high carrier mobility of the non-peripheral substituted Pcs, because larger inter-core separations degrade the mobilities. PMID- 25019804 TI - Interacting elastic lattice polymers: a study of the free energy of globular rings. AB - We introduce and implement a Monte Carlo scheme to study the equilibrium statistics of polymers in the globular phase. It is based on a model of "interacting elastic lattice polymers" and allows a sufficiently good sampling of long and compact configurations, an essential prerequisite to study the scaling behavior of free energies. By simulating interacting self-avoiding rings at several temperatures in the collapsed phase, we estimate both the bulk and the surface free energy. Moreover from the corresponding estimate of the entropic exponent alpha-2 we provide evidence that, unlike for swollen and Theta-point rings, the hyperscaling relation is not satisfied for globular rings. PMID- 25019805 TI - Designing highly tunable semiflexible filament networks. AB - Semiflexible polymers can generate a range of filamentous networks significantly different in structure from those seen in conventional polymer solutions. Our coarse-grained simulations with an implicit cross-linker potential show that networks of branching bundles, knotted morphologies, and structural chirality can be generated by a generalized approach independent of specific cross-linkers. Network structure depends primarily on filament flexibility and separation, with significant connectivity increase after percolation. Results should guide the design of engineered semiflexible polymers. PMID- 25019806 TI - Lateral phase separation in polymer-blend thin films: surface bifurcation. AB - We use simulations of a binary polymer blend confined between selectively attracting walls to identify and explain the mechanism of lateral phase separation via a transient wetting layer. We first show that equilibrium phases in the film are described by one-dimensional phase equilibria in the vertical (depth) dimension, and demonstrate that effective boundary conditions imposed by the film walls pin the film profile at the walls. We then show that, prior to lateral phase separation, distortion of the interface in a transient wetting layer is coupled to lateral phase separation at the walls. Using Hamiltonian phase portraits, we explain a "surface bifurcation mechanism" whereby the volume fraction at the walls evolves and controls the dynamics of the phase separation. We suggest how solvent evaporation may assist our mechanism. PMID- 25019807 TI - Intrinsic viscoelasticity in thin high-molecular-weight polymer films. AB - The rheology of 44-75-nm-thick polystyrene films were probed by destabilization in an electric field. The non-cross-linked films showed the hallmark of viscoelasiticy; they exhibited elastic behavior at high shear rates and viscous rheology at low shear rates for stationary applied fields. These results are interpreted in terms of surface adhesion of chain segments in contact with the substrate surface, which substantially reduces reptative molecular motion of nearly all chains within the film. PMID- 25019808 TI - Sisyphus effect in pulse-coupled excitatory neural networks with spike-timing dependent plasticity. AB - The collective dynamics of excitatory pulse-coupled neural networks with spike timing-dependent plasticity (STDP) is studied. Depending on the model parameters stationary states characterized by high or low synchronization can be observed. In particular, at the transition between these two regimes, persistent irregular low frequency oscillations between strongly and weakly synchronized states are observable, which can be identified as infraslow oscillations with frequencies ?0.02-0.03 Hz. Their emergence can be explained in terms of the Sisyphus effect, a mechanism caused by a continuous feedback between the evolution of the coherent population activity and of the average synaptic weight. Due to this effect, the synaptic weights have oscillating equilibrium values, which prevents the neuronal population from relaxing into a stationary macroscopic state. PMID- 25019809 TI - Evolution dynamics of a model for gene duplication under adaptive conflict. AB - We present and solve the dynamics of a model for gene duplication showing escape from adaptive conflict. We use a Crow-Kimura quasispecies model of evolution where the fitness landscape is a function of Hamming distances from two reference sequences, which are assumed to optimize two different gene functions, to describe the dynamics of a mixed population of individuals with single and double copies of a pleiotropic gene. The evolution equations are solved through a spin coherent state path integral, and we find two phases: one is an escape from an adaptive conflict phase, where each copy of a duplicated gene evolves toward subfunctionalization, and the other is a duplication loss of function phase, where one copy maintains its pleiotropic form and the other copy undergoes neutral mutation. The phase is determined by a competition between the fitness benefits of subfunctionalization and the greater mutational load associated with maintaining two gene copies. In the escape phase, we find a dynamics of an initial population of single gene sequences only which escape adaptive conflict through gene duplication and find that there are two time regimes: until a time t single gene sequences dominate, and after t double gene sequences outgrow single gene sequences. The time t is identified as the time necessary for subfunctionalization to evolve and spread throughout the double gene sequences, and we show that there is an optimum mutation rate which minimizes this time scale. PMID- 25019810 TI - Suppression and enhancement of transcriptional noise by DNA looping. AB - DNA looping has been observed to enhance and suppress transcriptional noise but it is uncertain which of these two opposite effects is to be expected for given conditions. Here, we derive analytical expressions for the main quantifiers of transcriptional noise in terms of the molecular parameters and elucidate the role of DNA looping. Our results rationalize paradoxical experimental observations and provide the first quantitative explanation of landmark individual-cell measurements at the single molecule level on the classical lac operon genetic system [Choi, L. Cai, K. Frieda, and X. S. Xie, Science 322, 442 (2008)]. PMID- 25019811 TI - Relaxation and curvature-induced molecular flows within multicomponent membranes. AB - The quantitative understanding of membranes is still rooted in work performed in the 1970s by Helfrich and others, concerning amphiphilic bilayers. However, most biological membranes contain a wide variety of nonamphiphilic molecules too. Drawing analogy with the physics of nematic-non-nematic mixtures, we present a dynamical (out-of-equilibrium) description of such multicomponent membranes. The approach combines nematohydrodynamics in the linear regime and a proper use of (differential-) geometry. The main result is to demonstrate that one can obtain equations describing a cross-diffusion effect (similar to the Soret and Dufour effects) between curvature and the (in-membrane) flow of amphiphilic molecules relative to nonamphiphilic ones. Surprisingly, the shape of a membrane relaxes according to a simple heat equation in the mean curvature, a process that is accompanied by a simultaneous boost to the diffusion of amphiphiles away from regions of high curvature. The model also predicts the inverse process, by which the forced bending of a membrane induces a flow of amphiphilic molecules towards areas of high curvature. In principle, numerical values for the relevant diffusion coefficients should be verifiable by experiment. PMID- 25019812 TI - Velocity alignment leads to high persistence in confined cells. AB - Many cell types display random motility on two-dimensional substrates but crawl persistently in a single direction when confined in a microchannel or on an adhesive micropattern. Does this imply that the motility mechanism of confined cells is fundamentally different from that of unconfined cells? We argue that both free- and confined-cell migration may be described by a generic model of cells as "velocity-aligning" active Brownian particles previously proposed to solve a completely separate problem in collective cell migration. Our model can be mapped to a diffusive escape over a barrier and analytically solved to determine the cell's orientation distribution and repolarization rate. In quasi one-dimensional confinement, velocity-aligning cells maintain their direction for times that can be exponentially larger than their persistence time in the absence of confinement. Our results suggest an important connection between single- and collective-cell migration: high persistence in confined cells corresponds with fast alignment of velocity to cell-cell forces. PMID- 25019813 TI - Torque correlation length and stochastic twist dynamics of DNA. AB - We introduce a short correlation length for torque in twisting-stiff biomolecules, which is necessary for the physical property that torque fluctuations be finite in amplitude. We develop a nonequilibrium theory of dynamics of DNA twisting which predicts two crossover time scales for temporal torque correlations in single-molecule experiments. Bending fluctuations can be included, and at linear order we find that they do not affect the twist dynamics. However, twist fluctuations affect bending, and we predict the spatial inhomogeneity of twist, torque, and buckling arising in nonequilibrium "rotor bead" experiments. PMID- 25019814 TI - Influence of molecular motors on the motion of particles in viscoelastic media. AB - We study theoretically and by numerical simulations the motion of particles driven by molecular motors in a viscoelastic medium representing the cell cytoplasm. For this, we consider a generalized Langevin equation coupled to a stochastic stepping dynamics for the motors that takes into account the action of each motor separately. In the absence of motors, the model produces subdiffusive motion of particles characterized by a power-law scaling of the mean square displacement versus the lag time as t^{alpha}, with 0+infinity. The second moment of the associated probability distribution grows with time as a power law ? t^{alpha}, with the exponent alpha=1/3 exactly. Also we find for superquadratic nonlinearity that the analog pseudochaotic regime at the edge of chaos is self-controlling in that it has feedback on the topology of the structure on which the transport processes concentrate. Then the system automatically (without tuning of parameters) develops its percolation point. We classify this type of behavior in terms of self-organized criticality dynamics in Hilbert space. For subquadratic nonlinearities, the behavior is shown to be sensitive to the details of definition of the nonlinear term. A transport model is proposed based on modified nonlinearity, using the idea of "stripes" propagating the wave process to large distances. Theoretical investigations, presented here, are the basis for consistency analysis of the different localization-delocalization patterns in systems with many coupled degrees of freedom in association with the asymptotic properties of the transport. PMID- 25019866 TI - Regular transport dynamics produce chaotic travel times. AB - In the hope of making passenger travel times shorter and more reliable, many cities are introducing dedicated bus lanes (e.g., Bogota, London, Miami). Here we show that chaotic travel times are actually a natural consequence of individual bus function, and hence of public transport systems more generally, i.e., chaotic dynamics emerge even when the route is empty and straight, stops and lights are equidistant and regular, and loading times are negligible. More generally, our findings provide a novel example of chaotic dynamics emerging from a single object following Newton's laws of motion in a regularized one-dimensional system. PMID- 25019867 TI - Synchronization and amplitude death in hypernetworks. AB - We study dynamical systems on a hypernetwork, namely by coupling them through several variables. For the case when the coupling(s) are all linear, a comprehensive analysis of the master stability function (MSF) for synchronized dynamics is presented and, through application to a number of paradigmatic examples, the typical forms of the MSF are discussed. The MSF formalism for hypernetworks also provides a framework to study synchronization in systems that are diffusively coupled through dissimilar variables-the so-called conjugate coupling that can lead to amplitude or oscillation death. PMID- 25019868 TI - Periodic synchronization and chimera in conformist and contrarian oscillators. AB - We consider a system of phase oscillators that couple with both attractive and repulsive interaction under a pinning force and explore collective behavior of the system. The oscillators can be divided into two subpopulations of "conformist" oscillators with attractive interaction and "contrarian" ones with repulsive interaction. We find that the interplay between the pinning force and the opposite relationship of the conformist and contrarian oscillators induce peculiar dynamic states: periodic synchronization, breathing chimera, and fully pinned state depending on the fraction of the conformists. Using the Watanabe Strogatz transformation, we reduce the dynamics into a low-dimensional one and find that the above dynamic states are generated from the reduced dynamics. PMID- 25019869 TI - Role of dissipation in flexural wave turbulence: from experimental spectrum to Kolmogorov-Zakharov spectrum. AB - The weak turbulence theory has been applied to waves in thin elastic plates obeying the Foppl-Von Karman dynamical equations. Subsequent experiments have shown a strong discrepancy between the theoretical predictions and the measurements. Both the dynamical equations and the weak turbulence theory treatment require some restrictive hypotheses. Here a direct numerical simulation of the Foppl-Von Karman equations is performed and reproduces qualitatively and quantitatively the experimental results when the experimentally measured damping rate of waves gamma_{k}=a+bk{2} is used. This confirms that the Foppl-Von Karman equations are a valid theoretical framework to describe our experiments. When we progressively tune the dissipation so that to localize it at the smallest scales, we observe a gradual transition between the experimental spectrum and the Kolmogorov-Zakharov prediction. Thus, it is shown that dissipation has a major influence on the scaling properties of stationary solutions of weakly nonlinear wave turbulence. PMID- 25019870 TI - Multisoliton Newton's cradles and supersolitons in regular and parity-time symmetric nonlinear couplers. AB - We demonstrate the existence of stable collective excitation in the form of "supersolitons" propagating through chains of solitons with alternating signs (i.e., Newton's cradles built of solitons) in nonlinear optical couplers, including the parity-time-symmetric (PT-symmetric) version thereof. In the regular coupler, stable supersolitons are created in the cradles composed of both symmetric solitons and asymmetric ones with alternating polarities. Collisions between moving supersolitons are investigated too, by means of direct simulations in both the regular and PT-symmetric couplers. PMID- 25019871 TI - Statistical properties of one-dimensional parametrically kicked Hamilton systems. AB - We study the one-dimensional Hamiltonian systems and their statistical behavior, assuming the initial microcanonical distribution and describing its change under a parametric kick, which by definition means a discontinuous jump of a control parameter of the system. Following a previous work by Papamikos and Robnik [J. Phys. A: Math. Theor. 44, 315102 (2011)], we specifically analyze the change of the adiabatic invariant (the action) of the system under a parametric kick: A conjecture has been put forward that the change of the action at the mean energy always increases, which means, for the given statistical ensemble, that the Gibbs entropy in the mean increases. By means of a detailed analysis of a great number of case studies, we show that the conjecture largely is satisfied, except if either the potential is not smooth enough or if the energy is too close to a stationary point of the potential (separatrix in the phase space). Very fast changes in a time-dependent system quite generally can be well described by such a picture and by the approximation of a parametric kick, if the change of the parameter is sufficiently fast and takes place on the time scale of less than one oscillation period. We discuss our work in the context of the statistical mechanics in the sense of Gibbs. PMID- 25019872 TI - Mechanism of unpinning spirals by a series of stimuli. AB - Antitachycardia pacing (ATP) is widely used to terminate tachycardia before it proceeds to lethal fibrillation. The important prerequisite for successful ATP is unpinning of the spirals anchored to the obstacle by a series of stimuli. Here, to understand the mechanism of unpinning spirals by ATP, we propose a theoretical explanation based on a nonlinear eikonal relation and a kinematical model. The theoretical results are quantitatively consistent with the numerical simulations in both weak and high excitabilities. PMID- 25019873 TI - Shapes and speeds of steady forced premixed flames. AB - Steady premixed flames subjected to space-periodic steady forcing are studied via inhomogeneous Michelson-Sivashinsky (MS) and then Burgers equations. For both, the flame slope is posited to comprise contributions from complex poles to locate, and from a base-slope profile chosen in three classes (pairs of cotangents, single-sine functions or sums thereof). Base-slope-dependent equations for the pole locations, along with formal expressions for the wrinkling induced flame-speed increment and the forcing function, are obtained on excluding movable singularities from the latter. Besides exact few-pole cases, integral equations that rule the pole density for large wrinkles are solved analytically. Closed-form flame-slope and forcing-function profiles ensue, along with flame speed increment vs forcing-intensity curves; numerical checks are provided. The Darrieus-Landau instability mechanism allows MS flame speeds to initially grow with forcing intensity much faster than those of identically forced Burgers fronts; only the fractional difference in speed increments slowly decays at intense forcing, which numerical (spectral) timewise integrations also confirm. Generalizations and open problems are evoked. PMID- 25019874 TI - Single-bubble dynamics in pool boiling of one-component fluids. AB - We numerically investigate the pool boiling of one-component fluids with a focus on the effects of surface wettability on the single-bubble dynamics. We employed the dynamic van der Waals theory [Phys. Rev. E 75, 036304 (2007)], a diffuse interface model for liquid-vapor flows involving liquid-vapor transition in nonuniform temperature fields. We first perform simulations for bubbles on homogeneous surfaces. We find that an increase in either the contact angle or the surface superheating can enhance the bubble spreading over the heating surface and increase the bubble departure diameter as well and therefore facilitate the transition into film boiling. We then examine the dynamics of bubbles on patterned surfaces, which incorporate the advantages of both hydrophobic and hydrophilic surfaces. The central hydrophobic region increases the thermodynamic probability of bubble nucleation while the surrounding hydrophilic region hinders the continuous bubble spreading by pinning the contact line at the hydrophobic hydrophilic intersection. This leads to a small bubble departure diameter and therefore prevents the transition from nucleate boiling into film boiling. With the bubble nucleation probability increased and the bubble departure facilitated, the efficiency of heat transfer on such patterned surfaces is highly enhanced, as observed experimentally [Int. J. Heat Mass Transfer 57, 733 (2013)]. In addition, the stick-slip motion of contact line on patterned surfaces is demonstrated in one-component fluids, with the effect weakened by surface superheating. PMID- 25019875 TI - Dynamic equilibrium under vibrations of H2 liquid-vapor interface at various gravity levels. AB - Horizontal vibration applied to the support of a simple pendulum can deviate from the equilibrium position of the pendulum to a nonvertical position. A similar phenomenon is expected when a liquid-vapor interface is subjected to strong horizontal vibration. Beyond a threshold value of vibrational velocity the interface should attain an equilibrium position at an angle to the initial horizontal position. In the present paper experimental investigation of this phenomenon is carried out in a magnetic levitation device to study the effect of the vibration parameters, gravity acceleration, and the liquid-vapor density on the interface position. The results compare well with the theoretical expression derived by Wolf [G. H. Wolf, Z. Phys. B 227, 291 (1969)]. PMID- 25019876 TI - Scaling of far-field wake angle of nonaxisymmetric pressure disturbance. AB - It has been recently emphasized that the angle of maximum wave amplitude alpha in the wake of a disturbance of finite size can be significantly narrower than the maximum value alpha_{K}=sin^{-1}(1/3)?19.47^{?} predicted by the classical analysis of Kelvin. For axisymmetric disturbance, a simple argument based on the Cauchy-Poisson initial-value problem suggests that the wake angle decreases following a Mach-like law at large velocity, alpha?Fr_{L}^{-1}, where Fr_{L}=U/sqrt[gL] is the Froude number based on the disturbance velocity U, its size L, and gravity g. In this paper we extend this analysis to the case of nonaxisymmetric disturbances, relevant to real ships. We find that, for intermediate Froude numbers, the wake angle follows an intermediate scaling law alpha?Fr_{L}^{-2}, in agreement with the recent prediction of Noblesse et al. [Eur. J. Mech. B/Fluids 46, 164 (2014)]. We show that beyond a critical Froude number, which scales as A^{1/2} (where A is the length-to-width aspect ratio of the disturbance), the asymptotic scaling alpha?Fr_{B}^{-1} holds, where now Fr_{B}=A^{1/2}Fr_{L} is the Froude number based on the disturbance width. We propose a simple model for this transition, and provide a regime diagram of the scaling of the wake angle as a function of parameters (A,Fr_{L}). PMID- 25019877 TI - Electro-osmotic flow along superhydrophobic surfaces with embedded electrodes. AB - The effect of the secondary fluid enclosed in the indentations of a superhydrophobic surface on electro-osmotic flow is investigated. We derive analytical expressions for the net electro-osmotic flow over periodically structured surfaces, accounting for the influence of dissipation within the secondary fluid as well as for the role of charges at the fluid-fluid interfaces that are generated by auxiliary electrodes. Specifically, for a surface with rectangular grooves, the electro-osmotic flow velocity is related to the geometric parameters of the surface and the viscosity of an arbitrary secondary fluid filling the grooves. The results suggest that on specific superhydrophobic surfaces a flow enhancement by more than two orders of magnitude compared to unstructured surfaces can be expected. PMID- 25019878 TI - Comparison of splashing in high- and low-viscosity liquids. AB - We explore the evolution of a splash when a liquid drop impacts a smooth dry surface. There are two splashing regimes that occur when the liquid viscosity is varied as is evidenced by its dependence on ambient gas pressure. A high viscosity drop splashes by emitting a thin sheet of liquid from a spreading liquid lamella long after the drop has first contacted the solid. Likewise, we find that there is also a delay in the ejection of a thin sheet when a low viscosity drop splashes. We show how the ejection time of the thin sheet depends on liquid viscosity and ambient gas pressure. PMID- 25019879 TI - Dynamical pattern formation in two-dimensional fluids and Landau pole bifurcation. AB - A phenomenological theory is proposed to analyze the asymptotic dynamics of perturbed inviscid Kolmogorov shear flows in two dimensions. The phase diagram provided by the theory is in qualitative agreement with numerical observations, which include three phases depending on the aspect ratio of the domain and the size of the perturbation: a steady shear flow, a stationary dipole, and four traveling vortices. The theory is based on a precise study of the inviscid damping of the linearized equation and on an analysis of nonlinear effects. In particular, we show that the dominant Landau pole controlling the inviscid damping undergoes a bifurcation, which has important consequences on the asymptotic fate of the perturbation. PMID- 25019880 TI - Dynamics of liquid drops coalescing in the inertial regime. AB - We examine the dynamics of two coalescing liquid drops in the "inertial regime," where the effects of viscosity are negligible and the propagation of the front of the bridge connecting the drops can be considered as "local." The solution fully computed in the framework of classical fluid mechanics allows this regime to be identified, and the accuracy of the approximating scaling laws proposed to describe the propagation of the bridge to be established. It is shown that the scaling law known for this regime has a very limited region of accuracy, and, as a result, in describing experimental data it has frequently been applied outside its limits of applicability. The origin of the scaling law's shortcoming appears to be the fact that it accounts for the capillary pressure due only to the longitudinal curvature of the free surface as the driving force for the process. To address this deficiency, the scaling law is extended to account for both the longitudinal and azimuthal curvatures at the bridge front, which, fortuitously, still results in an explicit analytic expression for the front's propagation speed. This expression is shown to offer an excellent approximation for both the fully computed solution and for experimental data from a range of flow configurations for a remarkably large proportion of the coalescence process. The derived formula allows one to predict the speed at which drops coalesce for the duration of the inertial regime, which should be useful for the analysis of experimental data. PMID- 25019881 TI - Ultrafast magnetic-resonance-imaging velocimetry of liquid-liquid systems: overcoming chemical-shift artifacts using compressed sensing. AB - We present simultaneous measurement of dispersed and continuous phase flow fields for liquid-liquid systems obtained using ultrafast magnetic resonance imaging. Chemical-shift artifacts, which are otherwise highly problematic for this type of measurement, are overcome using a compressed sensing based image reconstruction algorithm that accounts for off-resonant signal components. This scheme is combined with high-temporal-resolution spiral imaging (188 frames per second), which is noted for its robustness to flow. It is demonstrated that both quantitative signal intensity and phase preconditioning are preserved throughout the image reconstruction algorithm. Measurements are acquired of oil droplets of varying viscosity rising through stagnant water. From these data it is apparent that the internal droplet flow fields are heavily influenced by the droplet shape oscillations, and that the accurate modeling of droplet shape is of critical importance in the modeling of droplet-side hydrodynamics. The application of the technique to three-component systems is also demonstrated, as is the measurement of local concentration maps of a mutually soluble species (acetone in polydimethylsiloxane-water). PMID- 25019882 TI - Boundary streaming with Navier boundary condition. AB - In microfluidic applications involving high-frequency acoustic waves over a solid boundary, the Stokes boundary-layer thickness delta is so small that some non negligible slip may occur at the fluid-solid interface. This paper assesses the impact of this slip by revisiting the classical problem of steady acoustic streaming over a flat boundary, replacing the no-slip boundary condition with the Navier condition u|_{y=0}=L_{s}?_{y}u|_{y=0}, where u is the velocity tangent to the boundary y=0, and the parameter L_{s} is the slip length. A general expression is obtained for the streaming velocity across the boundary layer as a function of the dimensionless parameter L_{s}/delta. The limit outside the boundary layer provides an effective slip velocity satisfied by the interior mean flow. Particularizing to traveling and standing waves shows that the boundary slip respectively increases and decreases the streaming velocity. PMID- 25019883 TI - Vortex-mediated bouncing drops on an oscillating liquid. AB - We have investigated the behavior of bouncing drops on a liquid surface by using particle image velocimetry analysis. A drop on an oscillating liquid surface is observed to not coalesce with the liquid and to travel along the surface if the oscillation is strong enough. A streaming vortex pair, induced by the alternatively distorted liquid surface, shows up below a bouncing drop. The time averaged flow fields of the vortices are measured. In our quasi-one-dimensional setup, there are three stable distances for the drops, which can be characterized by the Faraday wavelength. The interactions of the vortex-mediated bouncing drops are deduced from the streamlines in the liquid bulk. We further show that a three dimensional vortex ring is induced by a bouncing drop in a square cell. PMID- 25019884 TI - Production of microbubbles from axisymmetric flow focusing in the jetting regime for moderate Reynolds numbers. AB - We analyze both experimentally and numerically the formation of microbubbles in the jetting regime reached when a moderately viscous liquid stream focuses a gaseous meniscus inside a converging micronozzle. If the total (stagnation) pressure of the injected gas current is fixed upstream, then there are certain conditions on which a quasisteady gas meniscus forms. The meniscus tip is sharpened by the liquid stream down to the gas molecular scale. On the other side, monodisperse collections of microbubbles can be steadily produced in the jetting regime if the feeding capillary is appropriately located inside the nozzle. In this case, the microbubble size depends on the feeding capillary position. The numerical simulations for an imposed gas flow rate show that a recirculation cell appears in the gaseous meniscus for low enough values of that parameter. The experiments allow one to conclude that the bubble pinch-off comprises two phases: (i) a stretching motion of the precursor jet where the neck radius versus the time before the pinch essentially follows a potential law, and (ii) a final stage where a very thin and slender gaseous thread forms and eventually breaks apart into a number of micron-sized bubbles. Because of the difference between the free surface and core velocities, the gaseous jet breakage differs substantially from that of liquid capillary jets and gives rise to bubbles with diameters much larger than those expected from the Rayleigh-type capillary instability. The dependency of the bubble diameter upon the flow-rate ratio agrees with the scaling law derived by A. M. Ganan-Calvo [Phys. Rev. E 69, 027301 (2004)], although a slight influence of the Reynolds number can be observed in our experiments. PMID- 25019885 TI - Geometry effects on Rayleigh-Benard convection in rotating annular layers. AB - Rayleigh-Benard convection is investigated in rotating annular cavities at a moderate dimensionless rotation rate Omega=60. The onset of convection is in the form of azimuthal traveling waves that set in at the sidewalls and at values of the Rayleigh number significantly below the value of the onset of convection in an infinitely extended layer. The present study addresses the effects of curvature and confinement on the onset of sidewall convection by using three dimensional spectral solutions of the Oberbeck-Boussinesq equations. Such solutions demonstrate that the curvature of the outer boundary promotes the onset of the wall mode, while the opposite curvature of the inner boundary tends to delay the onset of the wall mode. An inner sidewall with a radius as low as one tenth of its height is sufficient, however, to support the onset of a sidewall mode. When radial confinement is increased the two independent traveling waves interact and eventually merge to form a nearly steady pattern of convection. PMID- 25019886 TI - Trapping and instability of directional gravity waves in localized water currents. AB - The influence of localized water currents on the nonlinear dynamics and stability of large amplitude, statistically distributed gravity waves is investigated theoretically and numerically by means of an evolution equation for a Wigner function governing the spectrum of waves. It is shown that water waves propagating in the opposite direction of a localized current channel can be trapped in the channel, which can lead to the amplification of the wave intensity. Under certain conditions the wave intensity can be further localized due to a self-focusing (Benjamin-Feir) instability. The localized amplification of the wave intensity may increase the probability of extreme events in the form of freak waves, which have been observed in connection with ocean currents. PMID- 25019887 TI - Subfilter scalar-flux vector orientation in homogeneous isotropic turbulence. AB - The geometric orientation of the subfilter-scale scalar-flux vector is examined in homogeneous isotropic turbulence. Vector orientation is determined using the eigenframe of the resolved strain-rate tensor. The Schmidt number is kept sufficiently large so as to leave the velocity field, and hence the strain-rate tensor, unaltered by filtering in the viscous-convective subrange. Strong preferential alignment is observed for the case of Gaussian and box filters, whereas the sharp-spectral filter leads to close to a random orientation. The orientation angle obtained with the Gaussian and box filters is largely independent of the filter width and the Schmidt number. It is shown that the alignment direction observed numerically using these two filters is predicted very well by the tensor-diffusivity model. Moreover, preferred alignment of the scalar gradient vector in the eigenframe is shown to mitigate any probable issues of negative diffusivity in the tensor-diffusivity model. Consequentially, the model might not suffer from solution instability when used for large eddy simulations of scalar transport in homogeneous isotropic turbulence. Further a priori tests indicate poor alignment of the Smagorinsky and stretched vortex model predictions with the exact subfilter flux. Finally, strong filter dependence of subfilter scalar-flux orientation suggests that explicit filtering may be preferable to implicit filtering in large eddy simulations. PMID- 25019888 TI - Saturation of nonaxisymmetric instabilities of magnetized spherical Couette flow. AB - We numerically investigate the saturation of the hydromagnetic instabilities of a magnetized spherical Couette flow. Previous simulations demonstrated a region where the axisymmetric flow, calculated from a 2D simulation, was linearly unstable to nonaxisymmetric perturbations. Full, nonlinear, 3d simulations showed that the saturated state would consist only of harmonics of one azimuthal wave number, though there were bifurcations and transitions as nondimensional parameters (Re, Ha) were varied. Here, the energy transfer between different azimuthal modes is formulated as a network. This demonstrates a mechanism for the saturation of one mode and for the suppression of other unstable modes. A given mode grows by extracting energy from the axisymmetric flow, and then saturates as the energy transfer to its second harmonic equals this inflow. At the same time, this mode suppresses other unstable modes by facilitating an energy transfer to linearly stable modes. PMID- 25019889 TI - Capillary filling under electro-osmotic effects in the presence of electromagneto hydrodynamic effects. AB - We report various regimes of capillary filling dynamics under electromagneto hydrodynamic interactions, in the presence of electrical double layer effects. Our chosen configuration considers an axial electric field and transverse magnetic field acting on an electrolyte. We demonstrate that for positive interfacial potential, the movement of the capillary front resembles capillary rise in a vertical channel under the action of gravity. We also evaluate the time taken by the capillary front to reach the final equilibrium position for positive interfacial potential and show that the presence of a transverse magnetic field delays the time of travel of the liquid front, thereby sustaining the capillary motion for a longer time. Our scaling estimates reveal that the initial linear regime starts, as well as ends, much earlier in the presence of electrical and magnetic body forces, as compared to the corresponding transients observed under pure surface tension driven flow. We further obtain a long time solution for the capillary imbibition for positive interfacial potential, and derive a scaling estimate of the capillary stopping time as a function of the applied magnetic field and an intrinsic length scale delineating electromechanical influences of the electrical double layer. Our findings are likely to offer alternative strategies of controlling dynamical features of capillary imbibition, by modulating the interplay between electromagnetic interactions, electrical double layer phenomena, and hydrodynamics over interfacial scales. PMID- 25019890 TI - Breakage of non-Newtonian character in flow through a porous medium: evidence from numerical simulation. AB - We study the flow, through a model two-dimensional porous medium, of Newtonian fluids, power-law fluids, and viscoplastic fluids in the laminar regime and with moderate or dominant effects of the yielding term. A numerical technique able to take properly into account yielding effects in viscoplastic flows without any regularization is used to determine the detailed flow characteristics. We show that as soon as the distance between the disks forming the porous medium is sufficiently small, the velocity field and in particular the distribution function of the velocity of these different fluids in a wide range of flow regimes are similar. Moreover, the volume fraction of fluid at rest is negligible even at low flow rate. Thus the non-Newtonian character of a fluid flowing through such a complex geometry tends to be broken. We suggest that this is due to the fact that in a flow through a channel of rapidly varying cross section, the deformation, and thus the flow field, is imposed on the fluid, a situation that is encountered almost everywhere in a porous medium. These results make it possible to deduce a general expression for Darcy's law of these fluid types and estimate the parameters appearing in this expression. PMID- 25019891 TI - Length effects of a built-in flapping flat plate on the flow over a traveling wavy foil. AB - Flow over the traveling wavy foil with a built-in rigid flapping plate at its trailing edge has been numerically studied using the multi-relaxation-time lattice Boltzmann method and immersed boundary method. The effect of the plate length on the propulsive performance such as the thrust force, energy consumption, and propeller efficiency has been investigated. Three modes (body force dominated, body and tail force competing and tail force dominated modes) have been identified that are associated with different hydrodynamics and flow structures. It is revealed that there exists a better performance plate length region and, within this region, a high propeller efficiency (close to its maximum value) is achieved due to a great increase in propulsive force at a cost of a slight increase in energy consumption. Furthermore, a weak stabilizing effect on locomotion movement is indicated by the slight decrease in the root-mean-square (rms) values of drag and lateral forces. PMID- 25019892 TI - Linearized-moment analysis of the temperature jump and temperature defect in the Knudsen layer of a rarefied gas. AB - Understanding the thermal behavior of a rarefied gas remains a fundamental problem. In the present study, we investigate the predictive capabilities of the regularized 13 and 26 moment equations. In this paper, we consider low-speed problems with small gradients, and to simplify the analysis, a linearized set of moment equations is derived to explore a classic temperature problem. Analytical solutions obtained for the linearized 26 moment equations are compared with available kinetic models and can reliably capture all qualitative trends for the temperature-jump coefficient and the associated temperature defect in the thermal Knudsen layer. In contrast, the linearized 13 moment equations lack the necessary physics to capture these effects and consistently underpredict kinetic theory. The deviation from kinetic theory for the 13 moment equations increases significantly for specular reflection of gas molecules, whereas the 26 moment equations compare well with results from kinetic theory. To improve engineering analyses, expressions for the effective thermal conductivity and Prandtl number in the Knudsen layer are derived with the linearized 26 moment equations. PMID- 25019893 TI - Anomalous diffusion for inertial particles under gravity in parallel flows. AB - We investigate the bounds between normal or anomalous effective diffusion for inertial particles transported by parallel flows. The infrared behavior of the fluid kinetic-energy spectrum, i.e., the possible presence of long-range spatiotemporal correlations, is modeled as a power law by means of two parameters, and the problem is studied as a function of these latter. Our results, obtained in the limit of weak relative inertia, extend well-known results for tracers and apply to particles of any mass density, subject to gravity and Brownian diffusion. We consider both steady and time-dependent flows, and cases of both vanishing and finite particle sedimentation. PMID- 25019894 TI - Rayleigh-Taylor linear growth at an interface between an elastoplastic solid and a viscous liquid. AB - A previously developed model for the Rayleigh-Taylor instability at an interface between an elastoplastic solid and a viscous fluid [Piriz, Sun, and Tahir, Phys. Rev. E 88, 023026 (2013)] has been used for calculating the time evolution of the perturbations in terms of the mechanical properties of the solid and the liquid, as well as of the initial amplitude xi_{0} and the wavelength lambda of the perturbation. Four kinds of possible evolution are found: two stable and two unstable, depending on their positions in the space of parameters (xi_{0},lambda). All of them present some features that are independent of the solid properties and that are determined only by the liquid viscosity. PMID- 25019895 TI - Dynamo efficiency controlled by hydrodynamic bistability. AB - Hydrodynamic and magnetic behaviors in a modified experimental setup of the von Karman sodium flow-where one disk has been replaced by a propeller-are investigated. When the rotation frequencies of the disk and the propeller are different, we show that the fully turbulent hydrodynamic flow undergoes a global bifurcation between two configurations. The bistability of these flow configurations is associated with the dynamics of the central shear layer. The bistable flows are shown to have different dynamo efficiencies; thus for a given rotation rate of the soft-iron disk, two distinct magnetic behaviors are observed depending on the flow configuration. The hydrodynamic transition controls the magnetic field behavior, and bifurcations between high and low magnetic field branches are investigated. PMID- 25019896 TI - Mass flux in extended and classical hydrodynamics. AB - In classical hydrodynamics, the mass flux is universally chosen to be the momentum field. In extended hydrodynamics, the mass flux acquires different terms. The extended hydrodynamics introduced and investigated in this paper uses a one-particle distribution function as the extra state variable chosen to characterize the microstructure. We prove that the extended hydrodynamics is fully autonomous in the sense that it is compatible with thermodynamics (i.e., the entropy does not decrease during the time evolution) and with mechanics (i.e., the part of the time evolution that leaves the entropy unchanged is Hamiltonian). Subsequently, we investigate its possible reductions. In some situations the emerging reduced dynamical theory is the classical hydrodynamics that is fully autonomous (i.e., all the structure that makes the extended theory fully autonomous is kept in the reduced theory). In other situations (for example, when the fluids under investigation have large density gradients) the reduced theories are not fully autonomous. In such a case the reduced theories constitute a family of mutually related dynamical theories (each of them involving a different amount of detail) that we consider to be a mathematical formulation of multiscale (or multilevel) hydrodynamics. It is in the reduced theories belonging to the multiscale hydrodynamics where the terms that emerge in the mass flux take the form of self-diffusion. PMID- 25019897 TI - Wave turbulence in shallow water models. AB - We study wave turbulence in shallow water flows in numerical simulations using two different approximations: the shallow water model and the Boussinesq model with weak dispersion. The equations for both models were solved using periodic grids with up to 2048{2} points. In all simulations, the Froude number varies between 0.015 and 0.05, while the Reynolds number and level of dispersion are varied in a broader range to span different regimes. In all cases, most of the energy in the system remains in the waves, even after integrating the system for very long times. For shallow flows, nonlinear waves are nondispersive and the spectrum of potential energy is compatible with ~k{-2} scaling. For deeper (Boussinesq) flows, the nonlinear dispersion relation as directly measured from the wave and frequency spectrum (calculated independently) shows signatures of dispersion, and the spectrum of potential energy is compatible with predictions of weak turbulence theory, ~k{-4/3}. In this latter case, the nonlinear dispersion relation differs from the linear one and has two branches, which we explain with a simple qualitative argument. Finally, we study probability density functions of the surface height and find that in all cases the distributions are asymmetric. The probability density function can be approximated by a skewed normal distribution as well as by a Tayfun distribution. PMID- 25019898 TI - Collision of counterpropagating laser-excited wake bubbles. AB - The collision of wake bubbles behind two counterpropagating laser pulses in rarefied plasma is investigated using particle-in-cell simulation. Special attention is paid to the highly nonlinear dynamics of the electrons in the interaction region. It is found that, as the two bubbles approach each other and collide, the electrons in the interaction region first oscillate in a periodic fashion, forming a quasistationary dense electron density ripple with fairly regular spatial structure. At longer times, the electron motion becomes chaotic, and the density grating is gradually smeared. The electrons escape in the transverse direction, and eventually the two bubbles merge to form a single one. The transition of the electron motion from regular to chaotic is confirmed by analytical modeling using test electrons moving in counterpropagating planar electromagnetic waves. The findings shed light on the dynamics of wake-bubble collisions and the complex behavior induced by multiple laser pulses in plasmas. PMID- 25019899 TI - Ab initio transport coefficients of Ar+ ions in Ar for cold plasma jet modeling. AB - Collision cross sections and transport coefficients are calculated for Ar{+} ions, in the ground state {2}P_{3/2} and in the metastable state {2}P_{1/2}, colliding with their parent gas. Differential and integral collision cross sections are obtained using a numerical integration of the nuclear Schrodinger equation for several published interaction potentials. The Cohen-Schneider semi empirical model is used for the inclusion of the spin-orbit interaction. The corresponding differential collision cross sections are then used in an optimized Monte Carlo code to calculate the ion transport coefficients for each initial ion state over a wide range of reduced electric field. Ion swarm data results are then compared with available experimental data for different proportions of ions in each state. This allows us to identify the most reliable interaction potential which reproduces ion transport coefficients falling within the experimental error bars. Such ion transport data will be used in electrohydrodynamic and chemical kinetic models of the low temperature plasma jet to quantify and to tune the active species production for a better use in biomedical applications. PMID- 25019900 TI - Measurement of the laser-pulse group velocity in plasma waveguides. AB - Electrically discharged plasma channels can guide laser pulses, extending the laser-plasma interaction length to many Rayleigh ranges. In applications such as the laser-plasma accelerator, the laser group velocity in the channel plays a critical role. The laser travel time (and thus the averaged group velocity) was measured through two-pulse frequency-domain interferometry and was found to depend on the on-axis plasma density and laser spot size. The data is in agreement with theory. PMID- 25019901 TI - Properties of warm dense polystyrene plasmas along the principal Hugoniot. AB - Polystyrene (CH) is often chosen as the ablator material for inertial confinement fusion (ICF) targets. Its static, dynamical, and optical properties in warm, dense conditions (due to shock compression) are important for ICF designs. Using the first-principles quantum molecular dynamics (QMD) method, we have investigated the equation of state (EOS) and optical reflectivity of shock compressed CH up to an unprecedentedly high pressure of 62 Mbar along the principal Hugoniot. The QMD results are compared with existing experimental measurements as well as the SESAME EOS model. Although the Hugoniot pressure and/or temperature from QMD calculations agrees with experiments and the SESAME EOS model at low pressures below 10 Mbar, we have identified for the first time a stiffer behavior of shocked CH at higher pressures (>10 Mbar). Such a stiffer behavior of warm, dense CH can affect the ablation pressure (shock strength), shock coalescence dynamics, and nonuniformity growth in ICF implosions. In addition, we corrected the mistake made in literature for calculating the reflectivity of shocked CH and obtained good agreements with experimental measurements, which should lend credence to future opacity calculations in a first-principles fashion. PMID- 25019902 TI - Glass-transition properties of Yukawa potentials: from charged point particles to hard spheres. AB - The glass transition is investigated in three dimensions for single and double Yukawa potentials for the full range of control parameters. For vanishing screening parameter, the limit of the one-component plasma is obtained; for large screening parameters and high coupling strengths, the glass-transition properties cross over to the hard-sphere system. Between the two limits, the entire transition diagram can be described by analytical functions. Unlike other potentials, the glass-transition and melting lines for Yukawa potentials are found to follow shifted but otherwise identical curves in control-parameter space. PMID- 25019903 TI - Soliton interactions between multivalued localized waveguide channels within ferrites. AB - In this paper, we investigate both analytically and numerically the localized multivalued waveguide channels-the loop solitons-dynamics within a ferrite slab. In the starting point of the work, we solve in detail the initial value problem of the system while unveiling the existence of multivalued waveguide channels solutions. Paying particular interest to the nonlinear scattering among these excitations, we study extensively the different kinds of interacting features between these localized waves alongside the depiction of their energy densities. As a result, we find that the interactions can be attractive or repulsive depending strongly on the ratio of the amplitudes of the interacting structures. In the wake of these results, we address some physical implications, accordingly. PMID- 25019904 TI - Anisotropic diffusive transport: connecting microscopic scattering and macroscopic transport properties. AB - This work concerns the modeling of radiative transfer in anisotropic turbid media using diffusion theory. A theory for the relationship between microscopic scattering properties (i.e., an arbitrary differential scattering cross-section) and the macroscopic diffusion tensor, in the limit of independent scatterers, is presented. The theory is accompanied by a numerical method capable of performing the calculations. In addition, a boundary condition appropriate for modeling systems with anisotropic radiance is derived. It is shown that anisotropic diffusion theory, when based on these developments, indeed can describe radiative transfer in anisotropic turbid media. More specifically, it is reported that solutions to the anisotropic diffusion equation are in excellent agreement with Monte Carlo simulations, both in steady-state and time-domain. This stands in contrast to previous work on the topic, where inadequate boundary conditions and/or incorrect relations between microscopic scattering properties and the diffusion tensor have caused disagreement between simulations and diffusion theory. The present work thus falsify previous claims that anisotropic diffusion theory cannot describe anisotropic radiative transfer, and instead open for accurate quantitative diffusion-based modeling of anisotropic turbid materials. PMID- 25019905 TI - Thermoelastic damping in optical waveguide resonators with the bolometric effect. AB - Incorporating the bolometric effect, the thermoelastic damping in a nanowaveguide resonator driven by an optical gradient force is investigated in this paper. Based on the Euler-Bernoulli beam theory, the governing equation of the optowaveguide resonator is derived by considering the complex distribution of injected optical power, which has significant influence on the thermoelastic damping. By solving the heat diffusion equation, the theoretical model of the thermoelastic damping is presented. In this model, the effects of injected optical power, representative temperatures, waveguide material, and geometries on the thermoelastic damping are studied and discussed respectively. The results show that the peak value of thermoelastic damping increases as the injected optical power is increasing within a low range. Hardly any changes exist for the intrinsic energy dissipation of different materials at higher injected optical power. When the environmental temperature falls in the range of 293-500 K, the thermoelastic damping increases slowly, and then drops down quickly as a function of the dimensionless frequency. However, the thermoelastic damping monotonically decreases when the representative temperature drops to lower than 293 K. In addition, the thermoelastic damping is found to be scale dependent, particularly with the effect of injected optical power. PMID- 25019906 TI - Linked-cluster expansion for the Green's function of the infinite-U Hubbard model. AB - We implement a highly efficient strong-coupling expansion for the Green's function of the Hubbard model. In the limit of extreme correlations, where the onsite interaction is infinite, the evaluation of diagrams simplifies dramatically enabling us to carry out the expansion to the eighth order in powers of the hopping amplitude. We compute the finite-temperature Green's function analytically in the momentum and Matsubara frequency space as a function of the electron density. Employing Pade approximations, we study the equation of state, Kelvin thermopower, momentum distribution function, quasiparticle fraction, and quasiparticle lifetime of the system at temperatures lower than, or of the order of, the hopping amplitude. We also discuss several different approaches for obtaining the spectral functions through analytic continuation of the imaginary frequency Green's function, and show results for the system near half filling. We benchmark our results for the equation of state against those obtained from a numerical linked-cluster expansion carried out to the eleventh order. PMID- 25019907 TI - Higher-order dielectrophoresis of nonspherical particles. AB - Higher-order terms of dielectrophoretic (DEP) force are commonly ignored by invoking the simplifying dipole approximation. Concurrently, the trend towards micro- and nano-electrode structures in DEP design is bringing about an increasing number of instances where the approximation is expected to lose reliability. The case is severe for nonspherical particles (the shape of many biological particles) due to the shape-dependent nature of dielectric polarization. However, there is a lack of analytical means to determine multipole moments of nonspherical particles, numerical calculations of the same are regarded as unreliable, and there is a prevalence for higher-order force considerations to be ignored. As a result, the dipole approximation is used and/or nonspherical particles are approximated as spheres. This work proves the inefficacy of current qualitative criteria for the reliability of the dipole approximation and presents a quantitative substitute, with verified accuracy, that enables precise determination of the extent to which the dipole approximation would be reliable, and if found unreliable, corrects the approximation by adding second- and third-order terms of the DEP force. The effects of field nonuniformity, electrode design, and particle shape and aspect ratio on the significance of higher-order DEP forces is quantitatively analyzed. The results show that higher-order DEP forces are indeed of substantially increased significance for nonspherical particles; in the cases examined in this work, multipolar terms are seen to constitute more than 40% of the total force on ellipsoidal and cylindrical particles. It is further shown that approximating nonspherical particles as spheres of similar dimensions is subject to substantial error. Last, the substantial importance of the electrode design in influencing higher-order forces is shown. PMID- 25019908 TI - Pattern formation in liquid-vapor systems under periodic potential and shear. AB - In this paper the phase behavior and pattern formation in a sheared nonideal fluid under a periodic potential is studied. An isothermal two-dimensional formulation of a lattice Boltzmann scheme for a liquid-vapor system with the van der Waals equation of state is presented and validated. Shear is applied by moving walls and the periodic potential varies along the flow direction. A region of the parameter space, where in the absence of flow a striped phase with oscillating density is stable, will be considered. At low shear rates the periodic patterns are preserved and slightly distorted by the flow. At high shear rates the striped phase loses its stability and traveling waves on the interface between the liquid and vapor regions are observed. These waves spread over the whole system with wavelength only depending on the length of the system. Velocity field patterns, characterized by a single vortex, will also be shown. PMID- 25019909 TI - Mass-conserved volumetric lattice Boltzmann method for complex flows with willfully moving boundaries. AB - In this paper, we develop a mass-conserved volumetric lattice Boltzmann method (MCVLBM) for numerically solving fluid dynamics with willfully moving arbitrary boundaries. In MCVLBM, fluid particles are uniformly distributed in lattice cells and the lattice Boltzmann equations deal with the time evolution of the particle distribution function. By introducing a volumetric parameter P(x,y,z,t) defined as the occupation of solid volume in the cell, we distinguish three types of lattice cells in the simulation domain: solid cell (pure solid occupation, P=1), fluid cell (pure fluid occupation, P=0), and boundary cell (partial solid and partial fluid, 0=80 nmol/L). Three infants had fractures. Growth plate histology was abnormal in 10 cases with vitamin D deficiency (59%), but radiology was abnormal in only 3 of those cases. Eight infants (33%) with vitamin D insufficiency had abnormal histology, but radiology was normal in all cases. In 3 children hypocalcemia due to vitamin D deficiency was considered accountable for death; they all showed radiological and histological rickets: 2 babies had cardiomyopathy and a 3-year-old had hypocalcemic seizures. Children from all ethnic groups had a high proportion of low vitamin D levels. Vitamin D deficiency (the most common form of pediatric metabolic bone disease) is preventable and treatable. Profound hypocalcemia due to severe vitamin D deficiency can cause unexpected death in babies and young children. Measuring serum vitamin D levels postmortem may provide invaluable information on sudden unexplained death in 'at risk' children. Vitamin D deficiency may be relevant in childhood asthma and in children with multiple infections and babies with bone fractures. Postmortem vitamin D levels are stable and easy to measure. PMID- 25019938 TI - Strategy revealing phenotypic differences among synthetic oscillator designs. AB - Considerable progress has been made in identifying and characterizing the component parts of genetic oscillators, which play central roles in all organisms. Nonlinear interaction among components is sufficiently complex that mathematical models are required to elucidate their elusive integrated behavior. Although natural and synthetic oscillators exhibit common architectures, there are numerous differences that are poorly understood. Utilizing synthetic biology to uncover basic principles of simpler circuits is a way to advance understanding of natural circadian clocks and rhythms. Following this strategy, we address the following questions: What are the implications of different architectures and molecular modes of transcriptional control for the phenotypic repertoire of genetic oscillators? Are there designs that are more realizable or robust? We compare synthetic oscillators involving one of three architectures and various combinations of the two modes of transcriptional control using a methodology that provides three innovations: a rigorous definition of phenotype, a procedure for deconstructing complex systems into qualitatively distinct phenotypes, and a graphical representation for illuminating the relationship between genotype, environment, and the qualitatively distinct phenotypes of a system. These methods provide a global perspective on the behavioral repertoire, facilitate comparisons of alternatives, and assist the rational design of synthetic gene circuitry. In particular, the results of their application here reveal distinctive phenotypes for several designs that have been studied experimentally as well as a best design among the alternatives that has yet to be constructed and tested. PMID- 25019939 TI - One-pot hydrothermal synthesis of mesoporous Zn(x)Cd(1-x)S/reduced graphene oxide hybrid material and its enhanced photocatalytic activity. AB - We successfully synthesized mesoporous Zn(x)Cd(1-x)S/reduced graphene oxide (Z(x)CSG) hybrid materials as photocatalysts using a facile one-pot hydrothermal reaction, in which graphene oxide (GO) was easily reduced (RGO), and simultaneously Zn(x)Cd(1-x)S (Z(x)CS) nanoparticles (NPs) with a mesoporous structure were uniformly dispersed on the RGO sheets. By well tuning the band gap from 3.42 to 2.21 eV by changing the molar ratio of Zn/Cd (or Zn content), Z(x)CSG with an optimal zinc content has been found to have a significant absorption in the visible light (VL) region. In addition, under VL irradiation (lambda > 420 nm), Z(x)CSG also showed zinc content-dependent photocatalytic efficiencies for the degradation of methylene blue (MB). Our findings are that, among Z(x)CSG, Z(0.4)CSG displayed not only a superior photodegradation efficiency of MB (98%), but also good removal efficiency of total organic carbon (TOC) (67%). Furthermore, Z(0.4)CSG had a high photocatalytic stability, and could be used repeatedly. The enhanced photocatalytic activity for Z(0.4)CSG could be attributed to a synergistic effect between mesoporous Z(x)CS NPs and RGO, including the optimal band gap and the moderate conduction band position for ZxCS (compared to CdS), efficient separation and transfer ability of photogenerated electron/hole pairs in the presence of RGO sheets, and relatively high surface area for both mesoporous Z(x)CS NPs and RGO. PMID- 25019940 TI - Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells. AB - Oncolytic viruses have recently received widespread attention for their potential in innovative cancer therapy. Many telomerase promoter-regulated oncolytic adenoviral vectors retain E1A and E1B. However, the functions of E1A and E1B proteins in the oncolytic role of replication-competent adenovirus (RCAd) and RCAd enhanced transduction of replication defective adenoviruses (RDAd) have not been addressed well. In this study, we constructed viruses expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa. We then tested their roles in oncolysis and replication of RCAd as well as their roles in RCAd enhanced transfection rate and transgene expression of RDAd in various cancer cells in vitro and in xenografted human NCI-H460 tumors in nude mice. We demonstrated that RCAds expressing E1A alone and plus E1B-19 kDa exhibited an obvious ability in replication and oncolytic effects as well as enhanced RDAd replication and transgene expression, with the former showed more effective oncolysis, while the latter exhibited superior viral replication and transgene promotion activity. However, RCAd expressing both E1A and E1B-19 kDa/55 kDa was clearly worst in all these abilities. The effects of E1A and E1B observed through using RCAd were further validated by using plasmids expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa proteins. Our study provided evidence that E1A was essential for inducing replication and oncolytic effects of RCAd as well as RCAd enhanced RDAd transduction, and expression of E1B-19 kDa other than E1B-55 kDa could promote these effects. E1B-55 kDa is not necessary for the oncolytic effects of adenoviruses and somehow inhibits RCAd-mediated RDAd replication and transgene expression. PMID- 25019941 TI - Carbonic anhydrase II mediates malignant behavior of pulmonary neuroendocrine tumors. AB - In normal lung, the predominant cytoplasmic carbonic anhydrase (CA) isozyme (CAII) is highly expressed in amine- and peptide-producing pulmonary neuroendocrine cells where its role involves CO2 sensing. Here, we report robust cytoplasmic expression of CAII by immunohistochemistry in the tumor cells of different native neuroendocrine tumor (NET) types, including typical and atypical carcinoids and small-cell lung carcinomas, and in NET and non-NET tumor cell lines. Because, in both pulmonary neuroendocrine cell and related NETs, the hypercapnia-induced secretion of bioactive serotonin (5-hydroxytryptamine) is mediated by CAII, we investigated the role of CAII in the biological behavior of carcinoid cell line H727 and the type II cell-derived A549 using both in vitro clonogenicity and in vivo xenograft model. We show that short hairpin RNA mediated down-regulation of CAII resulted in significant reduction in clonogenicity of H727 and A549 cells in vitro, and marked suppression of tumor growth in vivo. CAII-short hairpin RNA cell-derived xenografts showed significantly reduced mitosis (phosphohistone H3 marker) and proliferation associated antigen Ki-67 (Ki67 marker), and significantly increased apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Using an apoptosis gene array, we found no association with caspases 3 and 8, but with a novel association of CAII-mediated apoptosis with specific mitochondrial apoptosis-associated proteins. Furthermore, these xenografts showed a significantly reduced vascularization (CD31 marker). Thus, CAII may play a critical role in NET lung tumor growth, angiogenesis, and survival, possibly via 5-hydroxytryptamine, known to drive autocrine tumor growth. As such, CAII is a potential therapeutic target for the difficult-to-treat lung NETs. PMID- 25019942 TI - Large outbreaks of ciguatera after consumption of brown marbled grouper. AB - Brown marbled grouper (Epinephelus fuscoguttatus) is an apex predator from coral reefs of the Indo-Pacific region. All five published case series of ciguatera after consumption of brown marbled grouper were reviewed to characterize the types, severity and chronicity of ciguatera symptoms associated with its consumption. Three of these case series were from large outbreaks affecting over 100-200 subjects who had eaten this reef fish served at banquets. Affected subjects generally developed a combination of gastrointestinal, neurological and, less commonly, cardiovascular symptoms. Gastrointestinal symptoms occurred early and generally subsided in 1-2 days. Some neurological symptoms (e.g., paresthesia of four limbs) could last for weeks or months. Sinus bradycardia and hypotension occurred early, but could be severe and prolonged, necessitating the timely use of intravenous fluids, atropine and dopamine. Other cardiovascular and neurological features included atrial ectopics, ventricular ectopics, dyspnea, chest tightness, PR interval >0.2 s, ST segment changes, polymyositis and coma. Concomitant alcohol consumption was associated with a much higher risk of developing bradycardia, hypotension and altered skin sensation. The public should realize that consumption of the high-risk fish (especially the ciguatoxin-rich parts and together with alcohol use) and repeated ciguatoxin exposures will result in more severe and chronic illness. PMID- 25019943 TI - Reliability of contractile properties of the knee extensor muscles in individuals with post-polio syndrome. AB - OBJECTIVE: To assess the reliability of contractile properties of the knee extensor muscles in 23 individuals with post-polio syndrome (PPS) and 18 age matched healthy individuals. METHODS: Contractile properties of the knee extensors were assessed from repeated electrically evoked contractions on 2 separate days, with the use of a fixed dynamometer. Reliability was determined for fatigue resistance, rate of torque development (MRTD), and early and late relaxation time (RT50 and RT25), using the intraclass correlation coefficient (ICC) and standard error of measurement (SEM, expressed as % of the mean). RESULTS: In both groups, reliability for fatigue resistance was good, with high ICCs (>0.90) and small SEM values (PPS: 7.1%, healthy individuals: 7.0%). Reliability for contractile speed indices varied, with the best values found for RT50 (ICCs>0.82, SEM values <2.8%). We found no systematic differences between test and retest occasions, except for RT50 in healthy subjects (p = 0.016). CONCLUSIONS: In PPS and healthy individuals, the reliability of fatigue resistance, as obtained from electrically evoked contractions is high. The reliability of contractile speed is only moderate, except for RT50 in PPS, demonstrating high reliability. SIGNIFICANCE: This was the first study to examine the reliability of electrically evoked contractile properties in individuals with PPS. Our results demonstrate its potential to study mechanisms underlying muscle fatigue in PPS and to evaluate changes in contractile properties over time in response to interventions or from natural course. PMID- 25019944 TI - Effect of parietal transcranial magnetic stimulation on spatial working memory in healthy elderly persons--comparison of near infrared spectroscopy for young and elderly. AB - In a previous study, we succeeded in improving the spatial working memory (WM) performance in healthy young persons by applying transcranial magnetic stimulation (TMS) to the parietal cortex and simultaneously measuring the oxygenated hemoglobin (oxy-Hb) level using near-infrared spectroscopy (NIRS). Since an improvement in WM was observed when TMS was applied to the right parietal cortex, the oxy-Hb distribution seemed to support a model of hemispheric asymmetry (HA). In the present study, we used the same study design to evaluate healthy elderly persons and investigated the effect of TMS on WM performance in the elderly, comparing the results with those previously obtained from young persons. The application of TMS did not affect WM performance (both reaction time and accuracy) of 38 elderly participants (mean age = 72.5 years old). To investigate the reason for this result, we conducted a three-way ANOVA examining oxy-Hb in both young and elderly participants. For the right parietal TMS site in the elderly, TMS significantly decreased the oxy-Hb level during WM performance; this result was the opposite of that observed in young participants. An additional three-way ANOVA was conducted for each of the 52 channels, and a P value distribution map was created. The P value maps for the young participants showed a clearly localized TMS effect for both the WM and control task, whereas the P map for the elderly participants showed less significant channels and localization. Further analysis following the time course revealed that right-side parietal TMS had almost no effect on the frontal cortex in the elderly participants. This result can most likely be explained by age-related differences in HA arising from the over-recruitment of oxy-Hb, differentiation in the parietal cortex, and age-related alterations of the frontal-parietal networks. PMID- 25019946 TI - Younger adults show long-term effects of cognitive training on broad cognitive abilities over 2 years. AB - In the COGITO study (Schmiedek, Lovden, & Lindenberger, 2010), 101 younger adults practiced 12 tests of perceptual speed, working memory, and episodic memory for over 100 daily 1-hr sessions. The intervention resulted in positive transfer to broad cognitive abilities, including reasoning and episodic memory. Here, we examine whether these ability-based transfer effects are maintained over time. Two years after the end of the training, 80 participants returned for follow-up assessments of the comprehensive battery of transfer tasks. We found reliable positive long-term transfer effects for reasoning and episodic memory, controlling for retest effects by including participants from the original control group. This shows, for the first time, that intensive cognitive training interventions can have long-term broad transfer at the level of cognitive abilities. PMID- 25019945 TI - Conserved arginines of bovine adenovirus-3 33K protein are important for transportin-3 mediated transport and virus replication. AB - The L6 region of bovine adenovirus (BAdV)-3 encodes a spliced protein designated 33K. The 33K specific sera detected five major proteins and three minor proteins in transfected or virus infected cells, which could arise by internal initiation of translation and alternative splicing. The 33K protein is predominantly localized to the nucleus of BAdV-3 infected cells. The 33K nuclear transport utilizes both classical importin-alpha/-beta and importin-beta dependent nuclear import pathways and preferentially binds to importin-alpha5 and transportin-3 receptors, respectively. Analysis of mutant 33K proteins demonstrated that amino acids 201-240 of the conserved C-terminus of 33K containing RS repeat are required for nuclear localization and, binding to both importin-alpha5 and transportin-3 receptors. Interestingly, the arginine residues of conserved RS repeat are required for binding to transportin-3 receptor but not to importin alpha5 receptor. Moreover, mutation of arginines residues of RS repeat proved lethal for production of progeny virus. Our results suggest that arginines of RS repeat are required for efficient nuclear transport of 33K mediated by transportin-3, which appears to be essential for replication and production of infectious virion. PMID- 25019947 TI - Individual and sex differences in the consequences of victimization: Moderation by approach and avoidance motivation. AB - Peer victimization is a known risk factor for various forms of maladjustment; however, the specific type of maladjustment may depend on individual differences in youth. This 2-wave longitudinal study examined the hypothesis that social approach-avoidance motivation, together with sex, would moderate the contribution of 3rd-grade victimization to 4th-grade maladjustment. Children (N = 574, M age = 8.94, SD = 0.37) reported on their victimization exposure, social approach avoidance motivation, and depressive symptoms. Teachers reported on students' victimization exposure and aggressive behavior. Victimization predicted aggressive behavior only in boys with moderate to high approach motivation; victimization predicted depressive symptoms only in girls with moderate to high avoidance motivation. This research elucidates the diverse consequences associated with peer victimization and informs efforts to address these consequences in a targeted manner. PMID- 25019948 TI - Amine-selective bioconjugation using arene diazonium salts. AB - A novel bioconjugation strategy is presented that relies on the coupling of diazonium terephthalates with amines in proteins. The diazonium captures the amine while the vicinal ester locks it through cyclization, ensuring no reversibility. The reaction is highly efficient and proceeds under mild conditions and short reaction times. Densely functionalized, complex natural products were directly coupled to proteins using low concentrations of coupling partners. PMID- 25019949 TI - Validation of a pre-coded food diary used among 60-80 year old men: comparison of self-reported energy intake with objectively recorded energy expenditure. AB - OBJECTIVE: To validate energy intake (EI) estimated from a pre-coded food diary (PFD) against energy expenditure (EE) measured with a valid physical activity monitor (SenseWear Pro3 Armband) and to evaluate whether misreporting was associated with overweight/obesity in a group of elderly men. METHODS: Forty seven healthy Norwegian men, 60-80 years old, completed the study. As this study was part of a larger intervention study, cross-sectional data were collected at both baseline and post-test. Participants recorded their food intake for four consecutive days using food diaries and wore SenseWear Pro3 Armband (SWA) during the same period. Only participants with complete data sets at both baseline and post-test were included in the study. RESULTS: The group average EI was 17% lower at baseline and 18% lower at post-test compared to measured EE. Mean difference from Bland-Altman plot for EI and EE was -1.5 MJ/day (+/-1.96 SD: -7.0, 4.0 MJ/day) at baseline and -1.6 MJ/day (-6.6, 3.4 MJ/day) at post-test. The intraclass correlation coefficient (ICC) was 0.30 (95% CI: 0.02, 0.54, p = 0.018) at baseline and 0.34 (0.06, 0.57, p = 0.009) at post-test. Higher values of underreporting was shown among overweight/obese compared to normal weight participants at both baseline and post-test (p<= 0.001), respectively. CONCLUSIONS: The results indicate that the PFD could be a useful tool for estimating energy intake in normal weight elderly men. On the other hand, the PFD seems to be less suitable for estimating energy intake in overweight/obese elderly men. PMID- 25019950 TI - Apelin and nutritional status in children on dialysis. AB - BACKGROUND: We aimed to evaluate whether serum apelin could reflect the nutritional status of children on dialysis. METHODS: Twelve patients on peritoneal dialysis (PD) and 20 patients on hemodialysis (HD) were enrolled. Patients received individualized diet for six months. Anthropometric and laboratory indices were measured at onset and the end of the study. RESULTS: The anthropometric indices were all significantly lower in patients than in controls whereas similar in PD and HD patients. The protein catabolic rate (nPCR), height, mid-arm circumference (MAC), triceps skinfold thickness (TSF), arm muscle area (AMA) and arm fat area (AFA) z scores were significantly increased in dialysis patients after nutritional intervention. Weight z scores statistically increased in HD group whereas did not statistically change in PD group. Serum albumin levels were significantly improved in PD and HD patients. Apelin levels were similar in PD, HD and control groups. Post nutritional apelin values did not differ in each dialysis groups. On multivariate analysis, apelin was independently associated with age, weight, ESR and TG. CONCLUSIONS: Apelin seems to be not a useful indicator for monitoring the nutritional status in children on dialysis. However, the close link of apelin with inflammatory and lipid parameters suggested that apelin might be a novel target for slowing the atherogenic process in pediatric dialysis patients. PMID- 25019951 TI - Shape-dependent hydrogen-storage properties in Pd nanocrystals: which does hydrogen prefer, octahedron (111) or cube (100)? AB - Pd octahedrons and cubes enclosed by {111} and {100} facets, respectively, have been synthesized for investigation of the shape effect on hydrogen-absorption properties. Hydrogen-storage properties were investigated using in situ powder X ray diffraction, in situ solid-state (2)H NMR and hydrogen pressure-composition isotherm measurements. With these measurements, it was found that the exposed facets do not affect hydrogen-storage capacity; however, they significantly affect the absorption speed, with octahedral nanocrystals showing the faster response. The heat of adsorption of hydrogen and the hydrogen diffusion pathway were suggested to be dominant factors for hydrogen-absorption speed. Furthermore, in situ solid-state (2)H NMR detected for the first time the state of (2)H in a solid-solution (Pd + H) phase of Pd nanocrystals at rt. PMID- 25019952 TI - Lactose-hydrolyzed milk is more prone to chemical changes during storage than conventional ultra-high-temperature (UHT) milk. AB - The enzymatic hydrolysis of lactose to glucose and galactose gives rise to reactions that change the chemistry and quality of ambient-stored lactose hydrolyzed ultra-high-temperature (UHT) milk. The aim of the present study was to investigate and compare chemical changes in lactose-hydrolyzed and conventional UHT milk during a 9 month ambient storage period. Several complementary analyses of volatiles, free amino acids, acetate, furosine, and level of free amino terminals were concluded. The analyses revealed an increased level of free amino acids and an increased formation rate of specific compounds such as furosine and 2-methylbutanal in lactose-hydrolyzed UHT milk compared to conventional UHT milk during storage. These observations indicate more favorable conditions for Maillard and subsequent reactions in lactose-hydrolyzed milk compared to conventional UHT milk stored at ambient temperature. Furthermore, it is postulated that proteolytic activity from the lactase-enzyme preparation may be responsible for the observed higher levels of free amino acids in lactose hydrolyzed UHT milk. PMID- 25019953 TI - Alteration of sexual reproduction and genetic diversity in the kelp species Laminaria digitata at the southern limit of its range. AB - Adaptation to marginal habitats at species range-limits has often been associated with parthenogenetic reproduction in terrestrial animals and plants. Laboratory observations have shown that brown algae exhibit a high propensity for parthenogenesis by various mechanisms. The kelp Laminaria digitata is an important component of the ecosystem in Northern European rocky intertidal habitats. We studied four L. digitata populations for the effects of marginality on genetic diversity and sexual reproduction. Two populations were marginal: One (Locquirec, in Northern Brittany) was well within the geographic range, but was genetically isolated from other populations by large stretches of sandy beaches. Another population was at the range limits of the species (Quiberon, in Southern Brittany) and was exposed to much higher seasonal temperature changes. Microsatellite analyses confirmed that these populations showed decreased genetic and allelic diversity, consistent with marginality and genetic isolation. Sporophytes from both marginal populations showed greatly diminished spore production compared to central populations, but only the southern-limit population (Quiberon) showed a high propensity for producing unreduced (2N) spores. Unreduced 2N spores formed phenotypically normal gametophytes with nuclear area consistent with >=2N DNA contents, and microsatellite studies suggested these were produced at least in part by automixis. However, despite this being the dominant path of spore production in Quiberon sporophyte individuals, the genetic evidence indicated the population was maintained mostly by sexual reproduction. Thus, although spore production and development showed the expected tendency of geographical parthenogenesis in marginal populations, this appeared to be a consequence of maladaptation, rather than an adaptation to, life in a marginal habitat. PMID- 25019954 TI - A multicompartment approach--diatoms, macrophytes, benthic macroinvertebrates and fish--to assess the impact of toxic industrial releases on a small French river. AB - The River Luzou flows through a sandy substrate in the South West of France. According to the results of two assessment surveys, the Water Agency appraised that this river may not achieve the good ecological status by 2015 as required by the Water Framework Directive (2000/60/EC). This ecosystem is impacted by industrial effluents (organic matter, metals and aromatic compounds). In order to assess and characterize the impact, this study aimed to combine a set of taxonomic and non-taxonomic metrics for diatoms, macrophytes, macroinvertebrates and fish along the up- to downstream gradient of the river. Diversity metrics, biological indices, biological and ecological traits were determined for the four biological quality elements (BQE). Various quantitative metrics (biomass estimates) were also calculated for diatom communities. The results were compared to physicochemical analysis. Biological measurements were more informative than physicochemical analysis, in the context of the study. Biological responses indicated both the contamination of water and its intensity. Diversity metrics and biological indices strongly decreased with pollution for all BQE but diatoms. Convergent trait selection with pollution was observed among BQE: reproduction, colonization strategies, or trophic regime were clearly modified at impaired sites. Taxon size and relation to the substrate diverged among biological compartments. Multiple anthropogenic pollution calls for alternate assessment methods of rivers' health. Our study exemplifies the fact that, in the case of complex contaminations, biological indicators can be more informative for environmental risk, than a wide screening of contaminants by chemical analysis alone. The combination of diverse biological compartments provided a refined diagnostic about the nature (general mode of action) and intensity of the contamination. PMID- 25019955 TI - Looking for childhood-onset schizophrenia: diagnostic algorithms for classifying children and adolescents with psychosis. AB - OBJECTIVE: Among children <13 years of age with persistent psychosis and contemporaneous decline in functioning, it is often difficult to determine if the diagnosis of childhood onset schizophrenia (COS) is warranted. Despite decades of experience, we have up to a 44% false positive screening diagnosis rate among patients identified as having probable or possible COS; final diagnoses are made following inpatient hospitalization and medication washout. Because our lengthy medication-free observation is not feasible in clinical practice, we constructed diagnostic classifiers using screening data to assist clinicians practicing in the community or academic centers. METHODS: We used cross-validation, logistic regression, receiver operating characteristic (ROC) analysis, and random forest to determine the best algorithm for classifying COS (n=85) versus histories of psychosis and impaired functioning in children and adolescents who, at screening, were considered likely to have COS, but who did not meet diagnostic criteria for schizophrenia after medication washout and inpatient observation (n=53). We used demographics, clinical history measures, intelligence quotient (IQ) and screening rating scales, and number of typical and atypical antipsychotic medications as our predictors. RESULTS: Logistic regression models using nine, four, and two predictors performed well with positive predictive values>90%, overall accuracy>77%, and areas under the curve (AUCs)>86%. CONCLUSIONS: COS can be distinguished from alternate disorders with psychosis in children and adolescents; greater levels of positive and negative symptoms and lower levels of depression combine to make COS more likely. We include a worksheet so that clinicians in the community and academic centers can predict the probability that a young patient may be schizophrenic, using only two ratings. PMID- 25019956 TI - Foreign nurse importation and the supply of native nurses. AB - The importation of foreign registered nurses has been used as a strategy to ease nursing shortages in the United States. The effectiveness of this policy depends critically on the long-run response of native nurses. We examine the effects of immigration of foreign-born registered nurses on the long-run employment and occupational choice of native nurses. Using a variety of empirical strategies that exploit the geographical distribution of immigrant nurses across US cities, we find evidence of large displacement effects - over a ten-year period, for every foreign nurse that migrates to a city, between 1 and 2 fewer native nurses are employed in the city. We find similar results using data on nursing board exam-takers at the state level - an increase in the flow of foreign nurses significantly reduces the number of natives sitting for licensure exams in more dependent states relative to less dependent states. Using data on self-reported workplace satisfaction among a sample of California nurses, we find suggestive evidence that part of the displacement effects could be driven by a decline in the perceived quality of the workplace environment. PMID- 25019957 TI - HIV, wages, and the skill premium. AB - The HIV epidemic has dramatically decreased labor supply among prime-age adults in Sub-Saharan Africa. Using within-country variation in regional HIV prevalence and a synthetic panel, I find that HIV significantly increases the capital-labor ratio in urban manufacturing firms. The impact of HIV on average wages is positive but imprecisely estimated. In contrast, HIV has a large positive impact on the skill premium. The impact of HIV on the wages of low skilled workers is insignificantly different from 0, and is strongly dampened by competition from rural migrants. The HIV epidemic disproportionately increases the incomes of high skilled survivors, thus increasing inequality. PMID- 25019958 TI - Staff compliance with protocols to improve the management of behavioral and psychological symptoms of dementia. AB - Using data from a larger study investigating the effectiveness of a structured clinical protocol to manage individuals in residential facilities who experience behavioral and psychological symptoms of dementia (BPSD), the current study investigated whether external clinical support in using the protocol with specific residents increased compliance in its use, over and above only providing a generic workshop about the protocol and management of BPSD. Results indicated that provision of the workshop, in addition to clinical support, was associated with significantly higher compliance. However, compliance was only found to be related to positive outcomes when staff received the generic workshop and not clinical support. When clinical support was provided, compliance was not related to outcomes or worse outcomes. These findings, when considered in the context of the results of the larger trial, suggest that the relationship among clinical support, compliance with BPSD protocols, and clinical outcomes for residents and staff is complex and needs further investigation. PMID- 25019959 TI - Tolerance for and potential indicators of second-hand smoke exposure among nonsmokers: a comparison of self-reported and cotinine verified second-hand smoke exposure based on nationally representative data. AB - OBJECTIVE: We assessed the extent to which self-reported exposure to SHS underestimates the actual exposure to SHS and what factors are associated with a tolerance for SHS exposure in the Korean setting where the smoke-free policy is incomplete. METHODS: Information on socio-demographic characteristics, alcohol drinking and smoking was collected for 7948 nonsmokers aged >= 19 years from the fourth Korea National Health and Nutrition Examination Survey, 2008-2009. Self reported and cotinine verified SHS exposures were compared. Potential factors associated with cotinine verified but not self-reported SHS exposures were assessed using a logistic regression model. RESULTS: Self-reported SHS exposure significantly underestimated the actual SHS exposure as determined by cotinine verification (kappa coefficient: 0.1066). At younger age, frequent alcohol drinking in females and a longer smoking duration in males were positively associated with cotinine verified exposure but not with the self-reported SHS exposure; they were also positively associated with cotinine verified exposure irrespective of self-reported SHS exposure. CONCLUSIONS: Our findings show a tolerance for smoking in Korea. The current partial ban on smoking does not fully protect people from exposure to SHS. Smoking should be banned in all public places. In addition, efforts to de-normalize smoking in the Korean culture need to be strengthened. PMID- 25019960 TI - Crystallinity and morphology effects on a solvent-processed solar cell using a triarylamine-substituted squaraine. AB - 2,4-Bis[4'-(N,N-di(4"-hydroxyphenyl)amino)-2',6'-dihydroxyphenyl]squaraine (Sq TAA-OH, optical bandgap 1.4 eV, HOMO level -5.3 eV by ultraviolet photoelectron spectroscopy) is used as an active layer material in solution processed, bulk heterojunction organic photovoltaic cells with configuration ITO/PEDOT:PSS/Sq-TAA OH:PC71BM/LiF/Al. Power conversion efficiencies (PCEs) up to 4.8% are obtained by a well-reproducible procedure using a mixture of good and poor Sq-TAA-OH solubilizing organic solvents, with diiodooctane (DIO) additive to make a bulk heterojunction layer, followed by thermal annealing, to give optimized V(OC) = 0.84-0.86 V, J(SC) = 10 mA cm(-2), and FF = 0.53. X-ray diffraction and scattering studies of pristine, pure Sq-TAA-OH solution-cast films show d-spacing features similar to single-crystal packing and spacing. The DIO additive in a good solvent/poor solvent mixture apparently broadens the size distribution of Sq TAA-OH crystallites in pristine films, but thermal annealing provides a narrower size distribution. Direct X-ray diffraction and scattering morphological studies of "as-fabricated" active layers show improved Sq-TAA-OH/PC71BM phase separation and formation of crystallites, ~48 nm in size, under conditions that give the best PCE. PMID- 25019961 TI - Impact of immune response on the use of iPSCs in disease modeling. AB - It has been demonstrated that mouse and human somatic cells can be reprogrammed into an embryonic stem cell-like state by introducing combinations of the transcription factors. The generation of such induced pluripotent stem cells (iPSCs) has enabled the derivation of disease-specific pluripotent cells which opens up new avenues of disease modeling and provides valuable experimental platforms. Moreover, technologies for creating humanized animal models by human iPSCs will be available as well, which will increase the utility of humanized mice for research. Emerging evidences suggest, however, that immunogenicity of iPSCs seems to be a vital and controversial issue surrounding potential of iPSCs. Recent studies on induced multipotent progenitor cells (iMPCs) extend the applications of iPSC technology and provide promising candidates for disease modeling. In this review, we introduce a wide range of applications of iPSCs in disease modeling and discuss the immune response on the use of iPSCs as well as a promising alternative for future directions of disease modeling. PMID- 25019962 TI - Urban land use decouples plant-herbivore-parasitoid interactions at multiple spatial scales. AB - Intense urban and agricultural development alters habitats, increases fragmentation, and may decouple trophic interactions if plants or animals cannot disperse to needed resources. Specialist insects represent a substantial proportion of global biodiversity and their fidelity to discrete microhabitats provides a powerful framework for investigating organismal responses to human land use. We sampled site occupancy and densities for two plant-herbivore parasitoid systems from 250 sites across a 360 km2 urban/agricultural landscape to ask whether and how human development decouples interactions between trophic levels. We compared patterns of site occupancy, host plant density, herbivory and parasitism rates of insects at two trophic levels with respect to landcover at multiple spatial scales. Geospatial analyses were used to identify landcover characters predictive of insect distributions. We found that herbivorous insect densities were decoupled from host tree densities in urban landcover types at several spatial scales. This effect was amplified for the third trophic level in one of the two insect systems: despite being abundant regionally, a parasitoid species was absent from all urban/suburban landcover even where its herbivore host was common. Our results indicate that human land use patterns limit distributions of specialist insects. Dispersal constraints associated with urban built development are specifically implicated as a limiting factor. PMID- 25019963 TI - 8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper mediated Abeta peptide aggregation. AB - One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-beta (Abeta) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Abeta peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Abeta plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8 H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8 hydroxyquinoline. The three compounds are shown to be neutral at pH7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Abeta1-40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of Cu(II). Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Abeta aggregation using the more neurotoxic Abeta1-42 in the presence and absence of Cu(II), 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu(II). However, in the presence of ligands and Cu(II), the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu(II) and limiting oligomer formation in this assay. PMID- 25019965 TI - Direct enantioselective vinylogous aldol-cyclization cascade reaction of allyl pyrazoleamides with isatins: asymmetric construction of spirocyclic oxindole dihydropyranones. AB - The first enantioselective vinylogous aldol-cyclization cascade reaction of allyl pyrazoleamides with isatins is reported. With 1 mol% of Takemoto catalyst, optically active spirocyclic oxindole-dihydropyranones were obtained in excellent yields (93-99%) and good-to-excellent enantioselectivities (82-97% ee). PMID- 25019964 TI - Effortful control and context interact in shaping neuroendocrine stress responses during childhood. AB - Trait and contextual factors can shape individual and group differences in hypothalamic-pituitary-adrenal (HPA) response to stress; but the ways in which these factors may interact with each other to modulate stress activity have rarely been examined. Here, we investigated whether the association between a temperamental self-regulatory trait - Effortful Control (EC) - and HPA axis stress response is moderated by type of laboratory stress in sixty-five children (35 boys). EC was measured at ages 3 and 6 using age-appropriate laboratory batteries as well as mother reports. HPA axis responses were measured at age 7 by randomly assigning children to one of two laboratory stress tasks (frustration vs. fear). Results indicated that EC interacted with stress context in predicting cortisol response. Specifically, lower EC was associated with greater cortisol response (steeper reactivity slopes) in the context of a frustration stressor but this was reversed in a fear context where lower EC was associated with flatter, more gradual activation. It is likely that different components of EC, such as emotion regulation and attention, differentially interact with the stress context. These types of effects and interactions need to be more thoroughly understood in order to meaningfully interpret cortisol reactivity data and better characterize the role of the HPA axis in human psychopathology. PMID- 25019966 TI - Kilohertz rotation of nanorods propelled by ultrasound, traced by microvortex advection of nanoparticles. AB - We measure the microvortical flows around gold nanorods propelled by ultrasound in water using polystyrene nanoparticles as optical tracers. We infer the rotational frequencies of such nanomotors assuming a hydrodynamic model of this interaction. In this way, we find that nanomotors rotate around their longitudinal axes at frequencies of up to ~ 2.5 kHz, or ~ 150 000 rpm, in the planar pressure node of a half-wavelength layered acoustic resonator driven at ~ 3 MHz with an acoustic energy density of <10 J.m(-3). The corresponding tangential speeds of up to ~ 2.5 mm.s(-1) at a nanomotor radius of ~ 160 nm are 2 orders of magnitude faster than the translational speeds of up to ~ 20 MUm.s(-1). We also find that rotation and translation are independent modes of motion within experimental uncertainty. Our study is an important step toward understanding the behavior and fulfilling the potential of this dynamic nanotechnology for hydrodynamically interacting with biological media, as well as other applications involving nanoscale transport, mixing, drilling, assembly, and rheology. Our results also establish the fastest reported rotation of a nanomotor in aqueous solution. PMID- 25019968 TI - Endoscopic flushing with pronase improves the quantity and quality of gastric biopsy: a prospective study. AB - BACKGROUND AND STUDY AIMS: Pronase, a proteolytic enzyme, is known to improve mucosal visibility during esophagogastroduodenoscopy (EGD), but little is known about its effects on gastric biopsy. This study assessed whether endoscopic flushing with pronase improves the quality of gastric biopsy. PATIENTS AND METHODS: Consecutive patients who underwent EGD were randomly assigned to either the control group or the pronase group in a prospective setting. The first biopsy of the identified lesion was performed during endoscopy. Endoscopic flushing with either 50 mL of water and dimethylpolysiloxane (DMPS; control group) or 50 mL of water, pronase, sodium bicarbonate, and DMPS (pronase group) was then applied to the lesion. After 5 minutes, the second biopsy was performed 2 - 3 mm away from the first biopsy site. The thickness of mucus, depth of the specimen, overall diagnostic adequacy, anatomical orientation, and crush artifact were measured to assess the quality of the biopsy. RESULTS: Of the 208 patients, 10 were not analyzed due to the absence of an identifiable lesion. Compared with the control group, the pronase group showed significantly decreased thickness of mucus (P < 0.001), increased depth of biopsy (P < 0.001), improved anatomical orientation (P = 0.010), and improved overall diagnostic assessment (P = 0.011) in the second biopsied specimen following endoscopic flushing. The crush artifact and hemorrhage did not differ between the groups. CONCLUSIONS: Endoscopic flushing with pronase not only improved the depth of biopsy but also the anatomical orientation and overall diagnostic adequacy. Pronase can be recommended for flushing during EGD to improve the quantity and quality of biopsy. PMID- 25019967 TI - Predicting local dengue transmission in Guangzhou, China, through the influence of imported cases, mosquito density and climate variability. AB - INTRODUCTION: Each year there are approximately 390 million dengue infections worldwide. Weather variables have a significant impact on the transmission of Dengue Fever (DF), a mosquito borne viral disease. DF in mainland China is characterized as an imported disease. Hence it is necessary to explore the roles of imported cases, mosquito density and climate variability in dengue transmission in China. The study was to identify the relationship between dengue occurrence and possible risk factors and to develop a predicting model for dengue's control and prevention purpose. METHODOLOGY AND PRINCIPAL FINDINGS: Three traditional suburbs and one district with an international airport in Guangzhou city were selected as the study areas. Autocorrelation and cross correlation analysis were used to perform univariate analysis to identify possible risk factors, with relevant lagged effects, associated with local dengue cases. Principal component analysis (PCA) was applied to extract principal components and PCA score was used to represent the original variables to reduce multi-collinearity. Combining the univariate analysis and prior knowledge, time series Poisson regression analysis was conducted to quantify the relationship between weather variables, Breteau Index, imported DF cases and the local dengue transmission in Guangzhou, China. The goodness-of-fit of the constructed model was determined by pseudo-R2, Akaike information criterion (AIC) and residual test. There were a total of 707 notified local DF cases from March 2006 to December 2012, with a seasonal distribution from August to November. There were a total of 65 notified imported DF cases from 20 countries, with forty-six cases (70.8%) imported from Southeast Asia. The model showed that local DF cases were positively associated with mosquito density, imported cases, temperature, precipitation, vapour pressure and minimum relative humidity, whilst being negatively associated with air pressure, with different time lags. CONCLUSIONS: Imported DF cases and mosquito density play a critical role in local DF transmission, together with weather variables. The establishment of an early warning system, using existing surveillance datasets will help to control and prevent dengue in Guangzhou, China. PMID- 25019969 TI - Randomized controlled trial comparing efficacy and acceptability of split- and standard-dose sodium picosulfate plus magnesium citrate for bowel cleansing prior to colonoscopy. AB - BACKGROUND AND STUDY AIM: Sodium picosulfate plus magnesium citrate (PMC) is a very effective, safe, and tolerated low-volume preparation for colon cleansing. This study evaluates whether split dosing is associated with a further increase in efficacy and acceptability compared with the standard dosing regimen. PATIENTS AND METHODS: This was a multicenter, randomized, single-blind study. Adult outpatients undergoing colonoscopy received PMC either in the standard dosing (two sachets taken the day before endoscopy) or in split dosing (the second sachet taken on the morning of colonoscopy). Bowel cleansing was assessed using the Boston Bowel Preparation Scale (BBPS) and was rated as adequate when BBPS was >= 2 in each segment. Patient acceptance, satisfaction, and related symptoms were recorded. RESULTS: A total of 862 patients were included in the study (577 in the standard group and 285 in the split-dose group). Preparation was adequate in only 69.8 % of patients in the standard group compared with 85.8 % of those in the split-dose group (P = 0.0001). Mean BBPS scores for the whole colon and the right colon were also statistically significantly higher in the split-dose group (P = 0.0001). Both regimens were well tolerated, and only 8.0 % of patients reported discomfort. Compliance was better with the split regimen (0.7 % vs. 7.1 % unable to take 75 % of the preparation; P < 0.0001), and willingness to repeat the preparation was similar. Performing colonoscopy within 6 hours after preparation was associated with better colon cleansing. Other predictors of poor cleansing at multivariate analysis were constipation, obesity, and discomfort during preparation. CONCLUSIONS: The split-dose regimen of PMC was superior to the standard regimen in terms of effective colon cleansing and compliance.ClinicalTrial.gov (NCT01909219). PMID- 25019970 TI - Long-term follow-up after endoscopic resection of gastric superficial neoplastic lesions in Portugal. AB - BACKGROUND AND STUDY AIMS: Although endoscopic resection for the treatment of gastric superficial neoplastic lesions is an established first-line treatment in Eastern countries, its role has yet to be considered in Western guidelines, mostly due to a lack of long-term studies. The aim of this study was to describe long-term outcomes for endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in the treatment of gastric neoplasias in Portugal. PATIENTS AND METHODS: This was a single-center, retrospective, cohort study between March 2003 and April 2013. A total of 162 consecutive patients with 195 gastric superficial neoplasias underwent EMR (n = 54) or ESD (n = 141) and were followed up for a median of 3.2 years. RESULTS: Resection was feasible in 97 %, with en bloc and R0 resection rates of 85 % (94 % ESD vs. 61 % EMR; P = 0.001) and 81 % (91 % ESD vs. 54 % EMR; P < 0.001), respectively. The recurrence rate was 7 %, and recurrence was associated with Rx/R1 resection irrespective of resection technique (OR 5.8; 95 % confidence interval 3.9 - 8.8). The long-term curative resection rate was 86 % after one procedure and 91 % after two procedures. Adverse events were observed in 13 % of cases: 8 % bleeding and 2 % of perforations (EMR = ESD). Surgery was performed in 7 %: 6 % after noncurative endoscopic resection and 1 % due to complications. Metachronous lesion detection rate was 1 % - 1.5 % per patient year. Cancer-specific survival rate was 100 % at follow-up. CONCLUSIONS: For the first time in a Western country, results are reported to be similar to those in Eastern countries. Endoscopic resection, particularly ESD, is a highly effective treatment for gastric superficial lesions, without compromising cancer survival. Endoscopic resection should also be considered as first-line treatment for gastric neoplasias in Western countries. PMID- 25019971 TI - Gastrojejunal anastomosis using a tissue-apposing stent: a safety and feasibility study in live pigs. AB - BACKGROUND AND STUDY AIMS: Various techniques using surgical and natural orifice transluminal endoscopic surgery (NOTES) have been evaluated to create a gastrojejunal bypass. The aim of the current study was to determine the safety, feasibility, and efficacy of a new technique using a pure endoscopic approach and tissue-apposing stent placement for gastrojejunal anastomosis (GJA). MATERIALS AND METHODS: This was a prospective, experimental study on six live pigs weighing 20 - 45 kg. Endoscopies were performed using a double-channel gastroscope, and included the creation of a GJA using a tissue-apposing, fully covered, self expanding metallic stent. Antibiotic therapy was continued for 7 days after the procedure, and food was gradually reintroduced from Day 3. Changes in weight following the procedure were compared with a control group of age-matched animals. Anastomosis functionality was confirmed by endoscopy at 3 weeks (before the animals were euthanized), and during histopathological analysis. The primary outcomes were morbidity and mortality at 3 weeks. Secondary outcomes were technical feasibility, procedure time, and patency of the GJA. RESULTS: The procedures were performed successfully in all animals. The mean procedure time was 26 +/- 6.7 minutes (range 15 - 32 minutes). One case of stent migration occurred during the procedure; the stent was successfully replaced using the same procedure. All animals were alive after 3 weeks. The mean weight gain during follow-up was 0.85 +/- 2.56 kg (range - 2 to + 2 kg) compared with 5.2 +/- 1.6 kg (range 3 - 7 kg) in control animals (P = 0.007). At necropsy, the stents were still in place in all animals, without evidence of peritonitis. Histopathology confirmed permeable anastomoses with continuity of the mucosa and mucosa muscle layers. CONCLUSIONS: GJA with a tissue-apposing stent is safe, feasible, and reproducible without anastomotic leakage in a porcine model using a pure endoscopic approach and standard endoscopic equipment. PMID- 25019972 TI - Purtscher-like Retinopathy Associated with Systemic Lupus Erythematosus. AB - PURPOSE: To report on clinical manifestations of Purtscher-like retinopathy (PLR) associated with systemic lupus erythematosus (SLE) and visual outcomes. METHODS: We performed a retrospective cohort study of 11 patients (21 affected eyes) with PLR in SLE. RESULTS: All patients were treated with systemic corticosteroids +/- immunosuppressive agents. Ocular therapy included intravitreal injections with bevacizumab in 18/21 eyes and posterior sub-Tenon injections with triamcinolone acetonide 13/21 eyes. Panretinal photocoagulation (PRP) was performed in 19/21 eyes and pars plana vitrectomy was required in 5/21 eyes. Visual improvement was found at follow-up of 3 and 6 months (p = 0.05). Poor visual outcome was associated with presence of neovascularizations at onset (p = 0.009), development of vitreous hemorrhage during PRP (p = 0.015), and active status of SLE after onset of PLR (p = 0.029). CONCLUSIONS: PLR might manifest as a devastating complication of SLE. We recommend treating any systemic activity of SLE and starting an early ocular treatment. PMID- 25019974 TI - Sex-specific associations between Neutrophil Gelatinase-Associated Lipocalin (NGAL) and cognitive domains in late-life depression. AB - BACKGROUND: Although it is well established that late-life depression is associated with both systemic low-graded inflammation and cognitive impairment, the relation between inflammation and cognition in depressed older persons is still equivocal. The objective of this study is to examine the association between plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentrations and cognitive functioning in late-life depression, including the potentially moderating role of sex. METHODS: A total of 369 depressed older persons (>=60 years) from The Netherlands study of Depression in Older persons (NESDO) were included. Four cognitive domains, i.e. verbal memory, processing speed, interference control and attention were assessed with three cognitive tests (Stroop test, Wais Digit span test, and Rey's verbal learning test). Multiple linear regression analyses were applied with the four cognitive domains as dependent variables adjusted for confounders. RESULTS: The association between NGAL levels and specific cognitive domains were sex-specific. In women, higher NGAL levels were associated with impaired verbal memory and lower processing speed. In men, higher NGAL levels were associated with worse interference control. Higher NGAL levels were not associated with attention. No sex-specific associations of either high sensitivity C-reactive protein (hsCRP) or interleukin 6 (IL-6) with cognitive functioning were found. CONCLUSION: This study shows sex specific association of NGAL with cognitive functioning in late-life depression. PMID- 25019973 TI - Lack of consensus in the diagnosis and treatment for ocular tuberculosis among uveitis specialists. AB - PURPOSE: To assess the approach of specialists to ocular tuberculosis (TB). METHODS: The American Uveitis Society (AUS) Listserv was surveyed using two clinical cases and general questions. RESULTS: Of 196 members, 87 responded (44.4%), of whom 64 were affiliated with practices in North America, while 23 were outside of North America. The survey provided normative data on how physicians evaluate patients with uveitis as well as opinions about ocular TB. Responses varied widely on such issues as (1) the pretest probability that a patient with granulomatous panuveitis had TB uveitis (range 1-75%) or that a patient with a risk factor for TB had ocular TB (range 0-90%); (2) the optimal duration of anti-TB therapy; and (3) whether therapy should be discontinued after 2 months in nonresponders. CONCLUSIONS: Consensus is lacking among uveitis specialists for the diagnosis or management of ocular TB. PMID- 25019975 TI - Artemia biodiversity in Asia with the focus on the phylogeography of the introduced American species Artemia franciscana Kellogg, 1906. AB - Asia harbors a diverse group of sexual and asexual Artemia species, including the invasive Artemia franciscana, which is native to the Americas. The phylogeny of Asian Artemia species and the phylogeography of the introduced A. franciscana from 81 sampling localities in Eurasia, Africa and America were elucidated using mitochondrial (COI) and nuclear DNA (ITS1) sequences. According to a COI phylogeny, 6 distinctive genetic groups were recognized, with a complex phylogeographic structure among Asian Artemia. A haplotype complex which includes parthenogenetic lineages is distributed in 39 inland geographical localities in Asia, illustrating a wide distribution with a narrow genetic structure on this continent. The invasive A. franciscana was discovered in 31 geographical localities along the southern and eastern coastal regions of Asia. Three sexual species (A. sinica, A. tibetiana and A. urmiana) have a restricted distribution in certain geographical localities in Asia. In contrast to COI phylogeny reconstruction, ITS1 sequences showed inconsistency with the COI tree, indicating incomplete lineage sorting which provided the low genetic divergence in the Asian clade. Asian A. franciscana showed higher haplotype diversity as compared to the source population from the Great Salt Lake (USA), which could be attributed to multiple introductions by mass dispersal in Asia via human activities. The invasive success of A. franciscana in Asia could lead to a long-term biodiversity disturbance of the autochthonous Artemia species on the continent. PMID- 25019976 TI - Editorial: 10th Special Issue of Reproductive Toxicology. PMID- 25019977 TI - Evaluation of the maternal-fetal transfer of granisetron in an ex vivo placenta perfusion model. AB - The objective of this study was to estimate maternal-fetal transplacental passage of granisetron in an ex vivo placental perfusion model. Term human placentas (N=8) were collected immediately after delivery. A single cotyledon from each placenta was perfused granisetron concentration to mimic systemic maternal peak plasma concentrations following either IV (50ng/mL) or transdermal administration (5ng/mL). To assess drug transfer and accumulation, samples were collected from maternal and fetal compartments. In the 50ng/mL open model, the mean transport fraction was 0.21+/-0.08 with clearance index of 0.53+/-0.66. Fetal peak concentrations achieved was 5.6+/-6.6ng/mL with mean accumulation of 5.35+/ 6.4ng/mL. No drug was detected in the fetal compartment with the 5ng/mL models. Transplacental passage of granisetron was inconsistent at the 50ng/mL concentration that achieved with IV dosing. However, there consistently was no detectable passage in all the placentas evaluated of the granisetron at 5ng/mL concentration that would be achieved after transdermal patch administration. PMID- 25019978 TI - Electrical transport properties of polycrystalline monolayer molybdenum disulfide. AB - Semiconducting MoS2 monolayers have shown many promising electrical properties, and the inevitable polycrystallinity in synthetic, large-area films renders understanding the effect of structural defects, such as grain boundaries (GBs, or line-defects in two-dimensional materials), essential. In this work, we first examine the role of GBs in the electrical-transport properties of MoS2 monolayers with varying line-defect densities. We reveal a systematic degradation of electrical characteristics as the line-defect density increases. The two common MoS2 GB types and their specific roles are further examined, and we find that only tilt GBs have a considerable effect on the MoS2 electrical properties. By examining the electronic states and sources of disorder using temperature dependent transport studies, we adopt the Anderson model for disordered systems to explain the observed transport behaviors in different temperature regimes. Our results elucidate the roles played by GBs in different scenarios and give insights into their underlying scattering mechanisms. PMID- 25019979 TI - Effect of dried pomegranate (Punica granatum) peel powder (DPPP) on textural, organoleptic and nutritional characteristics of biscuits. AB - Pomegranate (Punica granatum) peel is rich source of dietary fiber and bioactive compounds, hence could be used in the development of functional food formulations. Attempt was made to see the effect of dried pomegranate peel powder (DPPP) and emulsifiers on the rheological, nutritional and quality characteristics of biscuits. Incorporation of DPPP from 0 to 10% increased farinograph water absorption, decreased dough stability, increased amylograph pasting temperature and peak viscosity of wheat flour; increased hardness and decreased cohesiveness of biscuit dough; decreased spread ratio and increased breaking strength of biscuits. Sensory evaluation showed that biscuits incorporated with 7.5% DPPP were acceptable. Among emulsifiers, sodium stearoyl lactylate significantly improved the quality characteristics of 7.5% DPPP incorporated biscuits. Addition of 7.5% DPPP increased the protein, dietary fibre, minerals, anti-oxidant activity and beta-carotene contents of biscuits. The studies indicated the possibility of utilizing DPPP to improve the nutritional characteristics of biscuits. PMID- 25019980 TI - Stromal cell-derived factor-1alpha attenuates oleate-induced acute lung injury in rabbits. AB - The stromal cell-derived factor-1alpha/C-X-C chemokine receptor 4 (SDF-1/CXCR4) axis is involved in various aspects of tissue repair, regeneration and development. However, the role of SDF-1/CXCR4 in acute lung injury (ALI) remains largely unknown. The aim of the present investigation is to examine pathological changes in a rabbit model with ALI induced by oleic acid (OA) and to explore the protective effect of SDF-1alpha on ALI. Intravenous application (i.v.) of oleic acid (0.1 ml/kg/h for 2h) provoked pulmonary hemorrhage, edema, and protein leakage, resulting in severe ALI. When the rabbit received an infusion of SDF 1alpha (20 MUg/kg/24h) for 30 min before OA treatment, SDF-1alpha seemed to significantly improve the pathologies associated with OA-induced ALI. While dissecting the molecular mechanisms underlying the beneficial effects of SDF 1alpha, we found that SDF-1/CXCR4 is expressed in uninjured lung tissues but is greatly reduced after OA treatment. Interestingly, intravenous delivery of SDF 1alpha could target an injured lung and rescue expression of CXCR4, which in turn activates anti-apoptotic proteins, Bcl-1 and Bcl-xl, but does not affect pro apoptotic proteins, such as Bad and Bax. These data suggested that SDF-1alpha could protect rabbit lungs from AIL. The molecular mechanism might be associated with upregulating anti-apoptosis family expression through CXCR4. Thus, SDF 1/CXCR4 signaling pathway may be a promising target for treatment of patients with ALI. PMID- 25019981 TI - Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae. AB - Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. PMID- 25019982 TI - Colorimetric estimation of human glucose level using gamma-Fe2O3 nanoparticles: an easily recoverable effective mimic peroxidase. AB - This article reports simple, green and efficient synthesis of gamma-Fe2O3 nanoparticles (NPs) (maghemite) through single-source precursor approach for colorimetric estimation of human glucose level. The gamma-Fe2O3 NPs, having cubic morphology with an average particle size of 30 nm, exhibited effective peroxidase like activity through the catalytic oxidation of peroxidase substrate 3,3',5,5' tetramethylbenzidine (TMB) in the presence of H2O2 producing a blue-colored solution. On the basis of this colored-reaction, we have developed a simple, cheap, highly sensitive and selective colorimetric method for estimation of glucose using gamma-Fe2O3/TMB/glucose-glucose oxidase (GOx) system in the linear range from 1 to 80 MUM with detection limit of 0.21 MUM. The proposed glucose sensor displays faster response, good stability, reproducibility and anti interference ability. Based on this simple reaction process, human blood and urine glucose level can be monitored conveniently. PMID- 25019983 TI - Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro. AB - Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-alpha, IL-1beta, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state. PMID- 25019985 TI - Mechanisms behind signet ring cell carcinoma formation. AB - Signet ring cell carcinomas are highly malignant dedifferentiated adenocarcinomas. There are no cell-cell interactions between these round-shaped cells. They contain huge numbers of vacuoles, filled with mucins, which are secreted from the cells. The mechanism behind this phenotype has recently begun to be elucidated. In highly differentiated adenocarcinomas the ErbB2/ErbB3 complex is activated, which is followed by phosphatidylinositol 3-kinase (PI3K) activation. p38 MAP kinase is activated downstream of PI3K and adherens junctions are disrupted via Rac1 activation. Loss of adherens junctions leads to the disappearance of tight junctions, which results in a loss of cell-cell interactions. Secretion of mucin is enhanced by activation of PI3K. One of the mucins - Muc4 - can activate ErbB2. Under normal conditions Muc4 and ErbB2 are separated by adherens and tight junctions, however in signet ring cells they are able to interact, since these junctions have been lost. Therefore, an activation loop is formed, consisting of ERbB2/ErbB3-Muc4-ErbB2/ErbB3. As a result, the ErbB2/ErbB3 signaling pathway becomes constitutively activated, cell-cell interactions are lost, and signet ring carcinomas are formed. As a result of constitutive activation of the ErbB2/ErbB3 complex, cell growth is continuously enhanced. Some signet ring cell carcinomas have been found to have mutations in the E-cadherin gene, which fits the above hypothesis. PMID- 25019984 TI - Coordinated regulation of transcription and alternative splicing by the thyroid hormone receptor and its associating coregulators. AB - Emerging evidence has indicated that the transcription and processing of precursor mRNA (pre-mRNA) are functionally coupled to modulate gene expression. In collaboration with coregulators, several steroid hormone receptors have previously been shown to directly affect alternative pre-mRNA splicing coupled to hormone-induced gene transcription; however, the roles of the thyroid hormone receptor (TR) and its coregulators in alternative splicing coordinated with transcription remain unknown. In the present study, we constructed a luciferase reporter and CD44 alternative splicing (AS) minigene driven by a minimal promoter carrying 2 copies of the palindromic thyroid hormone-response element. We then examined whether TR could modulate pre-mRNA processing coupled to triiodothyronine (T3)-induced gene transcription using luciferase reporter and splicing minigene assays in HeLa cells. In the presence of cotransfected TRbeta1, T3 increased luciferase activities along with the inclusion of the CD44 variable exons 4 and 5 in a dose- and time-dependent manner. In contrast, cotransfected TRbeta1 did not affect the exon-inclusion of the CD44 minigene driven by the cytomegalovirus promoter. T3-induced two-exon inclusion was significantly increased by the cotransfection of the TR-associated protein, 150-kDa, a subunit of the TRAP/Mediator complex that has recently been shown to function as a splicing factor. In contrast, T3-induced two-exon inclusion was significantly decreased by cotransfection of the polypyrimidine tract-binding protein associated splicing factor, which was previously shown to function as a corepressor of TR. These results demonstrated that liganded TR in cooperation with its associating cofactors could modulate alternative pre-mRNA splicing coupled to gene transcription. PMID- 25019986 TI - Blockade of PDE4B limits lung vascular permeability and lung inflammation in LPS induced acute lung injury. AB - Acute lung injury (ALI), acute respiratory distress syndrome (ARDS), is actually involved in an ongoing and uncontrolled inflammatory response in lung tissues. Although extensive studies suggested that phospodiesterase type 4B (PDE4B) may be related to inflammation, the underlying cell biological mechanism of ALI remains unclear. To further investigate the mechanism how PDE4B take part in inflammatory response and the maintenance of vascular integrity, we established the experimental model of ALI in vitro and in vivo. In vitro, we found that Cilomilast, Diazepam and PDE4B knockout could potently inhibit the LPS-induced NF kappaB activation and inflammatory response in multiple cell types, including lung epithelial cells (A549), pulmonary microvascular endothelial cells (PMVECs) and vascular smooth muscle cells (VSMCs). Besides, PDE4B deletion attenuated the LPS-induced ROS generation. In vivo, PDE4B deletion could attenuate the lung water content, histological signs of pulmonary injury and elevate the ratio of partial pressure of arterial O2 to fraction of inspired O2 (PaO2/FIO2 ratio). Additionally, PDE4B deletion reduced LPS-induced vascular permeability. Collectively, our results strongly indicates that PDE4B is a valid target for anti-ALI. PMID- 25019987 TI - Beta-carotene inhibits neuroblastoma tumorigenesis by regulating cell differentiation and cancer cell stemness. AB - Neuroblastoma (NB) is the most common extracranial solid cancer in young children and malignant NB cells have been shown to possess cancer stem cell (CSC) characteristics. Thus, the successful elimination of CSCs represents a strategy for developing an effective preventive and chemotherapeutic agent. CSCs are characterized by differentiation and tumorigenicity. beta-Carotene (BC) has been associated with many anticancer mechanisms, although the efficacy of BC on CSCs remains unclear. In the present study, the effects of BC on tumor cell differentiation and tumorigenicity was investigated using a xenograft model. Mice were pretreated with BC for 21 days, then received a subcutaneous injection of SK N-BE(2)C cells. Both tumor incidence and tumor growth were significantly inhibited for mice that received BC supplementation compared to the control group. Treatment with BC has also been shown to induce tumor cell differentiation by up-regulating differentiation markers, such as vimentin, peripherin, and neurofilament. Conversely, BC treatment has been shown to significantly suppress tumor stemness by down-regulating CSC markers such as Oct 3/4 and DLK1. BC treatment also significantly down-regulated HIF1-alpha expression and its downstream target, vascular endothelial growth factor (VEGF). Taken together, these results suggest that BC is a potential chemotherapeutic reagent for the treatment of NB, and mediates this effect by regulating the differentiation and stemness of CSCs, respectively. PMID- 25019988 TI - HBx affects CUL4-DDB1 function in both positive and negative manners. AB - Hepatitis B virus (HBV) infection is a major public health problem by affecting 350 million people worldwide. The mechanisms that regulate HBV gene expression and viral replication remain poorly understood. HBx is known as the central regulator for HBV replication and is associated with the CUL4-DDB1 ubiquitin ligase through H-box motif. Here, we show that blocking the activity of DDB1 by RNA interfering inhibited viral production and gene expression of HBV, and direct association of HBx with DDB1 promoted viral activities, indicating that DDB1 function is required for viral production. On the other hand, HBx interfered with DDB1-dependent polyubiquitination of PRMT1, arginine methyltransferase 1, suggesting that HBx can also block the function of a subset of CUL4-DDB1 E3 ligases. Thus, we conclude that HBx regulates the function of DDB1 in both positive and negative manners in the context of distinct CUL4-DDB1 complexes and plays different roles in HBV replication cycle. PMID- 25019989 TI - Dengue virus disrupts Daxx and NF-kappaB interaction to induce CD137-mediated apoptosis. AB - Dengue virus (DENV) is a positive-strand RNA virus of the Flavivirus family with 4 different serotypes. Clinical manifestations of DENV infection include dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Following DENV infection, apoptosis of hepatic cells is observed both in vitro and in vivo. However, the molecular mechanisms revealing how viral components affect cellular apoptosis remain unclear. In the present study, the role of death domain associated protein 6 (Daxx) in DENV-mediated apoptosis was characterized by RNA interference and overexpression studies, and the anti-apoptotic function of Daxx during DENV infection was identified. Furthermore, the viral component, DENV capsid protein (DENV C), interacted with Daxx to disrupt interaction between Daxx and NF-kappaB. The liberated NF-kappaB activated the promoter of CD137, which is a member of the TNF family, and is previously shown to induce apoptosis during DENV infection. In summary, DENV C disrupts Daxx and NF-kappaB interaction to induce CD137-mediated apoptosis during DENV infection. PMID- 25019990 TI - Expression of high mobility group box 1 in inflamed dental pulp and its chemotactic effect on dental pulp cells. AB - High mobility group box 1 protein (HMGB1) is a chromatin protein which can be released extracellularly, eliciting a pro-inflammatory response and promoting tissue repair process. This study aimed to examine the expression and distribution of HMGB1 and its receptor RAGE in inflamed dental pulp tissues, and to assess its effects on proliferation, migration and cytoskeleton of cultured human dental pulp cells (DPCs). Our data demonstrated that cytoplasmic expression of HMGB1 was observed in inflamed pulp tissues, while HMGB1 expression was confined in the nuclei in healthy dental pulp. The mRNA expression of HMGB1 and RAGE were significantly increased in inflamed pulps. In in vitro cultured DPCs, expression of HMGB1 in both protein and mRNA level was up-regulated after treated with lipopolysaccharide (LPS). Exogenous HMGB1 enhanced DPCs migration in a dose dependent manner and induced the reorganization of f-actin in DPCs. Our results suggests that HMGB1 are not only involved in the process of dental pulp inflammation, but also play an important role in the recruitment of dental pulp stem cells, promoting pulp repair and regeneration. PMID- 25019991 TI - A single amino acid gates the KcsA channel. AB - The KcsA channel is a proton-activated potassium channel. We have previously shown that the cytoplasmic domain (CPD) acts as a pH-sensor, and the charged states of certain negatively charged amino acids in the CPD play an important role in regulating the pH-dependent gating. Here, we demonstrate the KcsA channel is constitutively open independent of pH upon mutating E146 to a neutrally charged amino acid. In addition, we found that rearrangement of the CPD following this mutation was not large. Our results indicate that minimal rearrangement of the CPD, particularly around E146, is sufficient for opening of the KcsA channel. PMID- 25019992 TI - Inhibition of cell proliferation, migration and invasion of B16-F10 melanoma cells by alpha-mangostin. AB - In this study, we have evaluated the potential antineoplastic effects of alpha mangostin (alpha-M), the most representative xanthone in Garcinia mangostana pericarp, on melanoma cell lines. This xanthone markedly inhibits the proliferation of high-metastatic B16-F10 melanoma cells. Furthermore, by deeply analyzing which steps in the metastatic process are influenced by xanthone it was observed that alpha-M strongly interferes with homotypic aggregation, adhesion, plasticity and invasion ability of B16-F10 cells, probably by the observed reduction of metalloproteinase-9 activity. The antiproliferative and antimetastatic properties of alpha-M have been established in human SK-MEL-28 and A375 melanoma cells. In order to identify pathways potentially involved in the antineoplastic properties of alpha-M, a comparative mass spectrometry proteomic approach was employed. These findings may improve our understanding of the molecular mechanisms underlying the anti-cancer effects of alpha-M on melanoma. PMID- 25019993 TI - Epigenetic regulation leading to induced pluripotency drives cancer development in vivo. AB - Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo. PMID- 25019994 TI - Unconventional secretion of the mutated 19 kDa protein of Oplophorus luciferase (nanoKAZ) in mammalian cells. AB - The putative amino-terminal signal peptide of the catalytic 19 kDa protein (KAZ) of Oplophorus luciferase was found to be a functional secretory peptide in mammalian cells. A 16 amino acid substituted mutant of KAZ (nanoKAZ) could be secreted from mammalian cells using the amino-terminal signal peptide of KAZ, but KAZ could not be secreted at all. Notably, nanoKAZ lacking the amino-terminal signal peptide could be secreted from mammalian cells, and the distribution of nanoKAZ on the cell membrane was confirmed by video-rate bioluminescence imaging. Thus, nanoKAZ lacking the amino-terminal signal peptide was expressed in the cytoplasm, translocated to the cell membrane, and released into the culture medium through an endoplasmic reticulum-Golgi-independent pathway. PMID- 25019995 TI - Sargahydroquinoic acid inhibits TNFalpha-induced AP-1 and NF-kappaB signaling in HaCaT cells through PPARalpha activation. AB - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors and expressed in various cell types in the skin, including keratinocytes, fibroblasts and infiltrating immune cells. Thus, their ligands are targets for the treatment of various skin disorders, such as photo-aging and chronological aging of skin. Intensive studies have revealed that PPARalpha/gamma functions in photo-aging and age-related inflammation by regulating matrix metalloproteinases (MMPs) via activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB). However, the detailed mechanism of PPARalpha/gamma's role in skin aging has not yet been elucidated. In this study, we confirmed that sargahydroquinoic acid (SHQA) as a PPARalpha/gamma ligand significantly decreased Tumor Necrosis Factor-alpha (TNFalpha)-induced MMP-2/-9 expression by downregulating TNFalpha-induced transcription factors, subsequently reducing IkappaBalpha degradation and blocking NF-kappaB p65 nuclear translocation in HaCaT human epidermal keratinocyte cells. Treatment of cells with SHQA and GW6471 (PPARalpha antagonist) not bisphenol A diglycidyl ether (PPARgamma antagonists), reversed the effect on TNFalpha-induced inflammatory signaling pathway activation. Taken together, our data suggest that SHQA inhibit TNFalpha-induced MMP-2/-9 expression and age-related inflammation by suppressing AP-1 and NF-kappaB pathway via PPARalpha. PMID- 25019996 TI - An unconventional BST-2 function: down-regulation of transient protein expression. AB - While viral inhibition by tethering of budding virions to host cell membranes has been focused upon as one of the main functions of BST-2/tetherin, BST-2 is thought to possess other functions as well. Overexpression of BST-2 was found here to down-regulate transient protein expression. Removal of the N- and C terminal regions of BST-2, previously described to be involved in signal transduction, reduced the impact of BST-2. These results suggest that BST-2 mediated signaling may play a role in regulating the levels of transiently expressed proteins, highlighting a new function for BST-2 that may also have implications for viral inhibition. PMID- 25019997 TI - Inhibition of Hepatitis B virus replication by SAMHD1. AB - Sterile alpha motif and HD-domain containing protein 1 (SAMHD1) is a newly identified intracellular antiviral factor. By depleting the dNTPs pool of host cells to a low level that cannot support the efficient synthesis of viral cDNA, it restricts replication of some retroviruses. As a DNA virus, Hepatitis B virus (HBV) experiences a process of reverse transcription in its life cycle akin to that of retroviruses. However, whether SAMHD1 can restrict HBV replication in liver cells is unknown. Here, we reported that SAMHD1 expression was detectable in four liver cell lines. Exogenous expression of SAMHD1 in SMMC-7721 cells restrained HBV replication. Similarly, SAMHD1 impeded HBV replication in another liver cell line, BEL-7402. Remarkably, the catalytically inactive mutant, SAMHD1 HD/AA also hampered HBV replication. Additionally, HBV replication reduced SAMHD1 expression in HepG2 cells. Moreover, it was found that IFN-alpha induced expression of SAMHD1 in liver cells. Together, these findings suggested that IFN alpha-inducible SAMHD1 inhibited HBV replication in liver cells. PMID- 25019998 TI - Super switching and control of in-plane ferroelectric nanodomains in strained thin films. AB - With shrinking device sizes, controlling domain formation in nanoferroelectrics becomes crucial. Periodic nanodomains that self-organize into so-called 'superdomains' have been recently observed, mainly at crystal edges or in laterally confined nanoobjects. Here we show that in extended, strain-engineered thin films, superdomains with purely in-plane polarization form to mimic the single-domain ground state, a new insight that allows a priori design of these hierarchical domain architectures. Importantly, superdomains behave like strain neutral entities whose resultant polarization can be reversibly switched by 90 degrees , offering promising perspectives for novel device geometries. PMID- 25020000 TI - Ultrasensitive aptamer-based SERS detection of PSAs by heterogeneous satellite nanoassemblies. AB - An ultrasensitive method for surface enhanced Raman scattering (SERS) detection of prostate-specific antigens (PSAs) was established based on the aptamer directed core-satellite nanostructures. A limit of detection (LOD) of 4.8 aM for PSA was obtained. PMID- 25019999 TI - Developmental plateau in visual object processing from adolescence to adulthood in autism. AB - A lack of typical age-related improvement from adolescence to adulthood contributes to face recognition deficits in adults with autism on the Cambridge Face Memory Test (CFMT). The current studies examine if this atypical developmental trajectory generalizes to other tasks and objects, including parts of the face. The CFMT tests recognition of whole faces, often with a substantial delay. The current studies used the immediate memory (IM) task and the parts whole face task from the Let's Face It! battery, which examines whole faces, face parts, and cars, without a delay between memorization and test trials. In the IM task, participants memorize a face or car. Immediately after the target disappears, participants identify the target from two similar distractors. In the part-whole task, participants memorize a whole face. Immediately after the face disappears, participants identify the target from a distractor with different eyes or mouth, either as a face part or a whole face. Results indicate that recognition deficits in autism become more robust by adulthood, consistent with previous work, and also become more general, including cars. In the IM task, deficits in autism were specific to faces in childhood, but included cars by adulthood. In the part-whole task, deficits in autism became more robust by adulthood, including both eyes and mouths as parts and in whole faces. Across tasks, the deficit in autism increased between adolescence and adulthood, reflecting a lack of typical improvement, leading to deficits with non-face stimuli and on a task without a memory delay. These results suggest that brain maturation continues to be affected into adulthood in autism, and that the transition from adolescence to adulthood is a vulnerable stage for those with autism. PMID- 25020001 TI - Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. AB - Near-daily intake of acute symptomatic medication for frequent headache increases the risk for medication-overuse headache (MOH). Chronic headache (CH) and MOH prevalences are inversely related to socioeconomic position (SEP). It is not known how SEP influences the health status of people with these headaches. This cross-sectional study examined the prevalence of CH in Denmark; possible associations between CH and education, work status, and income; and the health status of people with CH across socioeconomic strata. A total of 129,150 individuals aged ? 16 years were invited to the 2010 Danish National Health Survey. Data on SEP indicators and purchases of prescription drugs in 2009 were retrieved from national registers. Respondents with headache ? 15 days per month over 3 months were classified as having CH. Those with concurrent over-the counter analgesic intake of ? 15 days per month or prescription medication overuse (? 20 or ? 30 defined daily doses per month depending on the drug or drugs) were classified as having MOH. Associations between headache and SEP were analyzed by logistic regression, and associations between headache and health status scores, by linear regression. Physical and mental health composite scores (SF-12) were summarized per headache group, stratified by SEP, and compared to the sample mean. Analyses were adjusted for stratified sampling and nonresponse. The response rate was 53.1%. CH prevalence was 3.3% with 53.0% of cases having concurrent medication overuse (MOH prevalence 1.8%). CH was more prevalent among those individuals with low SEP. Health status scores were significantly lower among persons with CH in all SEP categories. The burden of CH can be reduced by preventing and treating MOH. PMID- 25020002 TI - Chronic pain, opioid prescriptions, and mortality in Denmark: A population-based cohort study. AB - This study aimed to investigate the risk of death, development of cancer, and hospital inpatient admissions resulting from injuries and toxicity/poisoning among opioid users with chronic noncancer pain. A population-based cohort of 13,127 adults, who have participated in the Danish Health Interview Surveys in 2000 or 2005 and have been followed up prospectively by registers until the end of 2011, were classified according to the absence or presence of chronic pain (ie, pain lasting ? 6 months) and long-term or short-term opioid use (individuals using at least 1 prescription per month for 6 months in the previous year and at least 1 prescription in the previous year, respectively). The risk of all-cause mortality was 1.72 (95% confidence interval [CI]=1.23-2.41) times higher among long-term opioid users than among individuals without chronic pain. The risk of death was lower, but still significantly higher in short-term (1.36, 95% CI=1.07 1.72) and non-opioid users with chronic pain (1.39, 95% CI=1.22-1.59) than in the background population. There was no statistically significant association between long-term opioid use and cardiovascular and cancer mortality. No deaths among opioid users were caused by accidents or suicides, although opioid users had higher risks of injuries and toxicity/poisoning resulting in hospital inpatient admissions than individuals without chronic pain. The risk of all-cause mortality was significantly higher among long-term opioid users, but no obvious associations between long-term opioid use and cause-specific mortality were observed. However, opioid use increased the risk of injuries and toxicity/poisoning resulting in hospital inpatient admissions. PMID- 25020003 TI - Human models of pain for the prediction of clinical analgesia. AB - Human experimental pain models are widely used to study drug effects under controlled conditions. However, efforts to improve both animal and human experimental model selection, on the basis of increased understanding of the underlying pathophysiological pain mechanisms, have been disappointing, with poor translation of results to clinical analgesia. We have developed an alternative approach to the selection of suitable pain models that can correctly predict drug efficacy in particular clinical settings. This is based on the analysis of successful or unsuccessful empirical prediction of clinical analgesia using experimental pain models. We analyzed statistically the distribution of published mutual agreements or disagreements between drug efficacy in experimental and clinical pain settings. Significance limits were derived by random permutations of agreements. We found that a limited subset of pain models predicts a large number of clinically relevant pain settings, including efficacy against neuropathic pain for which novel analgesics are particularly needed. Thus, based on empirical evidence of agreement between drugs for their efficacy in experimental and clinical pain settings, it is possible to identify pain models that reliably predict clinical analgesic drug efficacy in cost-effective experimental settings. PMID- 25020004 TI - Estimating the burden of disease in chronic pain with and without neuropathic characteristics: does the choice between the EQ-5D and SF-6D matter? AB - The EQ-5D and Short Form (SF)12 are widely used generic health-related quality of life (HRQoL) questionnaires. They can be used to derive health utility index scores, on a scale where 0 is equivalent to death and 1 represents full health, with scores less than zero representing states "worse than death." We compared EQ 5D or SF-6D health utility index scores in patients with no chronic pain, and chronic pain with and without neuropathic characteristics (NC), and to explore their discriminant ability for pain severity. Self-reported health and chronic pain status was collected as part of a UK general population survey (n=4451). We found moderate agreement between individual dimensions of EQ-5D and SF-6D, with most highly correlated dimensions found for mental health and anxiety/depression, role limitations and usual activities, and pain and pain/discomfort. Overall 43% reported full health on the EQ-5D, compared with only 4.2% on the SF-6D. There were significant differences in mean utilities for chronic pain with NC (EQ-5D 0.47 vs SF-6D 0.62) and especially for severe pain (EQ-5D 0.33 vs SF-6D 0.58). On the EQ-5D, 17% of those with chronic pain with NC and 3% without NC scored "worse than death," a state which is not possible using the SF-6D. Health utilities derived from EQ-5D and SF-12/36 can discriminate between group differences for chronic pain with and without NC and greater pain severity. However, the instruments generate widely differing HRQoL scores for the same patient groups. The choice between using the EQ-5D or SF-6D matters greatly when estimating the burden of disease. PMID- 25020005 TI - Modeling of heavy nitrate corrosion in anaerobe aquifer injection water biofilm: a case study in a flow rig. AB - Heavy carbon steel corrosion developed during nitrate mitigation of a flow rig connected to a water injection pipeline flowing anaerobe saline aquifer water. Genera-specific QPCR primers quantified 74% of the microbial biofilm community, and further 87% of the community of the nonamended parallel rig. The nonamended biofilm hosted 6.3 * 10(6) SRB cells/cm(2) and the S(35)-sulfate-reduction rate was 1.1 MUmol SO4(2-)/cm(2)/day, being congruent with the estimated SRB biomass formation and the sulfate areal flux. Nitrate amendment caused an 18-fold smaller SRB population, but up to 44 times higher sulfate reduction rates. This H2S formation was insufficient to form the observed Fe3S4 layer. Additional H2S was provided by microbial disproportionation of sulfur, also explaining the increased accessibility of sulfate. The reduced nitrate specie nitrite inhibited the dominating H2-scavenging Desulfovibrio population, and sustained the formation of polysulfide and Fe3S4, herby also dissolved sulfur. This terminated the availability of acetate in the inner biofilm and caused cell starvation that initiated growth upon metallic electrons, probably by the sulfur-reducing Desulfuromonas population. On the basis of these observations we propose a model of heavy nitrate corrosion where three microbiological processes of nitrate reduction, disproportionation of sulfur, and metallic electron growth are nicely woven into each other. PMID- 25020006 TI - Advancement in the clinical management of intestinal pseudo-obstruction. AB - Intestinal pseudo-obstruction is more commonly known in its chronic form (CIPO), a cluster of rare diseases characterized by gastrointestinal muscle and nerve impairment, so severe to result in a markedly compromised peristalsis mimicking an intestinal occlusion. The management of CIPO requires the cooperation of a group of specialists: the disease has to be confirmed by a number of tests to avoid mistakes in the differential diagnosis. The treatment should be aimed at relieving symptoms arising from gut dysmotility (ideally using prokinetic agents), controlling abdominal pain (possibly with non-opioid antinociceptive drugs) and optimizing nutritional support. Furthermore, a thorough diagnostic work-up is mandatory to avoid unnecessary (potentially harmful) surgery and to select patients with clear indication to intestinal or multivisceral transplantation. PMID- 25020007 TI - Computational assignment of redox states to Coulomb blockade diamonds. AB - With the advent of molecular transistors, electrochemistry can now be studied at the single-molecule level. Experimentally, the redox chemistry of the molecule manifests itself as features in the observed Coulomb blockade diamonds. We present a simple theoretical method for explicit construction of the Coulomb blockade diamonds of a molecule. A combined quantum mechanical/molecular mechanical method is invoked to calculate redox energies and polarizabilities of the molecules, including the screening effect of the metal leads. This direct approach circumvents the need for explicit modelling of the gate electrode. From the calculated parameters the Coulomb blockade diamonds are constructed using simple theory. We offer a theoretical tool for assignment of Coulomb blockade diamonds to specific redox states in particular, and a study of chemical details in the diamonds in general. With the ongoing experimental developments in molecular transistor experiments, our tool could find use in molecular electronics, electrochemistry, and electrocatalysis. PMID- 25020008 TI - Safety Planning for Military (SAFE MIL): rationale, design, and safety considerations of a randomized controlled trial to reduce suicide risk among psychiatric inpatients. AB - Mental health related hospitalizations and suicide are both significant public health problems within the United States Department of Defense (DoD). To date, few evidence-based suicide prevention programs have been developed for delivery to military personnel and family members admitted for psychiatric inpatient care due to suicidal self-directed violence. This paper describes the rationale and detailed methodology for a study called Safety Planning for Military (SAFE MIL) which involves a randomized controlled trial (RCT) at the largest military treatment facility in the United States. The purpose of this study is to test the efficacy of a brief, readily accessible, and personalized treatment called the Safety Planning Intervention (Stanley and Brown, 2012). Primary outcomes, measured by blinded assessors at one and six months following psychiatric discharge, include suicide ideation, suicide-related coping, and attitudes toward help seeking. Additionally, given the study's focus on a highly vulnerable patient population, a description of safety considerations for human subjects' participation is provided. Based on this research team's experience, the implementation of an infrastructure in support of RCT research within DoD settings and the processing of regulatory approvals for a clinical trial with high risk suicidal patients are expected to take up to 18-24 months. Recommendations for expediting the advancement of clinical trials research within the DoD are provided in order to maximize cost efficacy and minimize the research to practice gap. PMID- 25020009 TI - Lorentz force in water: evidence that hydronium cyclotron resonance enhances polymorphism. AB - There is an ongoing question regarding the structure forming capabilities of water at ambient temperatures. To probe for different structures, we studied effects in pure water following magnetic field exposures corresponding to the ion cyclotron resonance of H3O(+). Included were measurements of conductivity and pH. We find that under ion cyclotron resonance (ICR) stimulation, water undergoes a transition to a form that is hydroxonium-like, with the subsequent emission of a transient 48.5 Hz magnetic signal, in the absence of any other measurable field. Our results indicate that hydronium resonance stimulation alters the structure of water, enhancing the concentration of EZ-water. These results are not only consistent with Del Giudice's model of electromagnetically coherent domains, but they can also be interpreted to show that these domains exist in quantized spin states. PMID- 25020010 TI - High-resolution 3-D T1*-mapping and quantitative image analysis of GRAY ZONE in chronic fibrosis. AB - The substrate of potentially lethal cardiac arrhythmias often resides in the gray zone (GZ), a mixture of viable myocytes and collagen strands found between healthy myocardium and infarct core (IC). The specific aims of this paper are to demonstrate correspondence between regions delineated in T1* (apparent T1) maps and tissue characteristics seen in histopathology and to determine the MR imaging resolution needed to adequately identify GZ-associated substrate in chronic infarct. For this, a novel 3-D multicontrast late enhancement (MCLE) MR method was used to image ex vivo swine hearts with chronic infarction, at high resolution ( 0.6*0.6*1.25 mm). Pixel-wise classified tissue maps were calculated using steady-state and T1* images as input to a fuzzy-clustering algorithm. Quantitative histology based on collagen stains was performed in n = 10 selected slabs and showed very good correlations between histologically-determined areas of heterogeneous and dense fibrosis, and the corresponding GZ ( R2 = 0.96) and IC ( R2 = 0.97 ) in tissue classified maps. Furthermore, in n = 24 slabs, we performed volumetric measurements of GZ and IC, at the original and decreased image resolutions. Our results demonstrated that the IC volume remained relatively unchanged across all resolutions, whereas the GZ volume progressively increased with diminished image resolution, with changes reaching significance at 1*1*5 mm resolution (p < 0.05 ) but not at 1*1*2.5 mm, suggesting that this resolution may be sufficient to adequately identify the GZ from MCLE images, enabling an effective MR probing of remodeled myocardium in late infarct. Future work will focus on translating these findings to optimizing the current in vivo MCLE imaging of the GZ. PMID- 25020011 TI - Three-dimensional reconstruction of a cardiac outline by magnetocardiography. AB - A 3-D cardiac visualization is significantly helpful toward clinical applications of magnetocardiography (MCG), but the cardiac reconstruction requires a segmentation process using additional image modalities. This paper proposes a 3-D cardiac outline reconstruction method using only MCG measurement data without further imaging techniques. The cardiac outline was reconstructed by a combination of both spatial filtering and coherence mapping method. The strength of cardiac activities was first estimated by the array-gain constraint minimum norm spatial filter with recursively updated gram matrix (AGMN-RUG). Then, waveforms were reconstructed at whole source grids, and the maximum source points of an atrium and ventricle were selected as a reference, respectively. Next, the coherence between each maximum source point and whole source points was compared by the coherence mapping method. A reconstructed cardiac outline was validated by comparing with an overlapped volume ratio when the reconstructed volume was identically matched with the original volume. The results obtained by the AGMN RUG were compared to the results by other spatial filters. The accuracy of numerical simulation and phantom experiment by the AGMN-RUG was superior 10% and 8%, respectively, than the accuracy by the standardized low-resolution electromagnetic tomography. This accuracy demonstrated the efficacy of the proposed 3-D cardiac reconstruction method. PMID- 25020012 TI - An analysis of contrast agent flow patterns from sequential ultrasound images using a motion estimation algorithm based on optical flow patterns. AB - This study estimates flow patterns of contrast agents from successive ultrasound image sequences by using an anisotropic diffusion-based optical flow algorithm. Before flow fields were recovered, the test sequences were reconstructed using relative composition of structural and textural parts from the original image. To improve estimation performance, an anisotropic diffusion filtering model was embedded into a spline-based slightly nonconvex total variation-L1 minimization algorithm. In addition, an incremental coarse-to-fine warping framework was employed with a linear minimization scheme to account for a large displacement. After each warping iteration, the implementation used intermediate bilateral filtering to prevent oversmoothing across motion boundaries. The performance of the proposed algorithm was tested using three different sequences obtained from two simulated datasets and phantom ultrasound sequences. The results indicate the robust performance of the proposed method under different noise environments. The results of the phantom study also demonstrate reliable performance according to different injection conditions of contrast agents. These experimental results suggest the potential clinical applicability of the proposed algorithm to ultrasonographic diagnosis based on contrast agents. PMID- 25020013 TI - Reducing risks in type 1 diabetes using Hinfinity control. AB - A control scheme was designed in order to reduce the risks of hyperglycemia and hypoglycemia in type 1 diabetes mellitus (T1DM). This structure is composed of three main components: an Hinfinity robust controller, an insulin feedback loop (IFL), and a safety mechanism (SM). A control-relevant model that is employed to design the robust controller is identified. The identification procedure is based on the distribution version of the UVA/Padova metabolic simulator using the simulation adult cohort. The SM prevents dangerous scenarios by acting upon a prediction of future glucose levels, and the IFL modifies the loop gain in order to reduce postprandial hypoglycemia risks. The procedure is tested on the complete alic>in silico adult cohort of the UVA/Padova metabolic simulator, which has been accepted by the Food and Drug Administration (FDA) in lieu of animal trials. PMID- 25020014 TI - Light-controlled biphasic current stimulator IC using CMOS image sensors for high resolution retinal prosthesis and in vitro experimental results with rd1 mouse. AB - Retinal prosthetic devices stimulate retinal nerve cells with electrical signals proportional to the incident light intensities. For a high-resolution retinal prosthesis, it is necessary to reduce the size of the stimulator pixels as much as possible, because the retinal nerve cells are concentrated in a small area of approximately 5 mm * 5 mm. In this paper, a miniaturized biphasic current stimulator integrated circuit is developed for subretinal stimulation and tested in vitro. The stimulator pixel is miniaturized by using a complementary metal oxide-semiconductor (CMOS) image sensor composed of three transistors. Compared to a pixel that uses a four-transistor CMOS image sensor, this new design reduces the pixel size by 8.3%. The pixel size is further reduced by simplifying the stimulation-current generating circuit, which provides a 43.9% size reduction when compared to the design reported to be the most advanced version to date for subretinal stimulation. The proposed design is fabricated using a 0.35 MUm bipolar-CMOS-DMOS process. Each pixel is designed to fit in a 50 MU m * 55 MUm area, which theoretically allows implementing more than 5000 pixels in the 5 mm * 5 mm area. Experimental results show that a biphasic current in the range of 0 to 300 MUA at 12 V can be generated as a function of incident light intensities. Results from in vitro experiments with rd1 mice indicate that the proposed method can be effectively used for retinal prosthesis with a high resolution. PMID- 25020015 TI - Analysing surnames as geographic data. AB - With most surname research undertaken within the fields of anthropology and population genetics, geographers have overlooked surnames as a credible data source. In addition to providing a review of recent developments in surname analysis, this paper highlights areas where geographers can make important contributions to advancing surname research, both in terms of its quality and also its applications. The review discusses the emerging applications for surname research, not least in the mining of online data, and ends by suggesting three future research themes to ensure the building momentum of surname research continues to grow across disciplines. PMID- 25020016 TI - A multi-disciplinary approach to the origins of music: perspectives from anthropology, archaeology, cognition and behaviour. AB - Archaeological evidence for musical activities pre-dates even the earliest-known cave art and it remains the case that no human culture has yet been encountered that does not practise some recognisably musical activity. Yet the human abilities to make and appreciate music have been described as "amongst the most mysterious with which [we are] endowed" (Charles Darwin, 1872) and music itself as "the supreme mystery of the science of man" (Claude Levi-Strauss, 1970). Like language, music has been the subject of keen investigation across a great diversity of fields, from neuroscience and psychology, to ethnography, to studies of its structures in its own dedicated field, musicology; unlike the evolution of human language abilities, it is only recently that the origins of musical capacities have begun to receive dedicated attention. It is increasingly clear that human musical abilities are fundamentally related to other important human abilities, yet much remains mysterious about this ubiquitous human phenomenon, not least its prehistoric origins. It is evident that no single field of investigation can address the wide range of issues relevant to answering the question of music's origins. This review brings together evidence from a wide range of anthropological and human sciences, including palaeoanthropology, archaeology, neuroscience, primatology and developmental psychology, in an attempt to elucidate the nature of the foundations of music, how they have evolved, and how they are related to capabilities underlying other important human behaviours. It is proposed that at their most fundamental level musical behaviours (including both vocalisation and dance) are forms of deliberate metrically-organised gesture, and constitute a specialised use of systems dedicated to the expression and comprehension of social and emotional information between individuals. The abilities underlying these behaviours are selectively advantageous themselves; in addition, various mechanisms by which the practice of musical activities themselves could be advantageous are outlined. PMID- 25020017 TI - Perspectives on Open Science and scientific data sharing:an interdisciplinary workshop. AB - Looking at Open Science and Open Data from a broad perspective. This is the idea behind "Scientific data sharing: an interdisciplinary workshop", an initiative designed to foster dialogue between scholars from different scientific domains which was organized by the Istituto Italiano di Antropologia in Anagni, Italy, 2 4 September 2013.We here report summaries of the presentations and discussions at the meeting. They deal with four sets of issues: (i) setting a common framework, a general discussion of open data principles, values and opportunities; (ii) insights into scientific practices, a view of the way in which the open data movement is developing in a variety of scientific domains (biology, psychology, epidemiology and archaeology); (iii) a case study of human genomics, which was a trail-blazer in data sharing, and which encapsulates the tension that can occur between large-scale data sharing and one of the boundaries of openness, the protection of individual data; (iv) open science and the public, based on a round table discussion about the public communication of science and the societal implications of open science. There were three proposals for the planning of further interdisciplinary initiatives on open science. Firstly, there is a need to integrate top-down initiatives by governments, institutions and journals with bottom-up approaches from the scientific community. Secondly, more should be done to popularize the societal benefits of open science, not only in providing the evidence needed by citizens to draw their own conclusions on scientific issues that are of concern to them, but also explaining the direct benefits of data sharing in areas such as the control of infectious disease. Finally, introducing arguments from social sciences and humanities in the educational dissemination of open data may help students become more profoundly engaged with Open Science and look at science from a broader perspective. PMID- 25020018 TI - Symbolic or utilitarian? Juggling interpretations of Neanderthal behavior: new inferences from the study of engraved stone surfaces. AB - Different categories of finds reveal how Neanderthals have manifested at different moments behaviors not ascribable to the utilitarian sphere, but to the aesthetic or symbolic. When the majority of this evidence dates to the few millennia that preceded the spread of Anatomically Modern Humans in Europe, these are grounds to continue the debate regarding the emergence of complex behavior, seen as an autonomous phenomenon of Neanderthal man or as the result of contact with immigrant populations. Re-examination of pebbles or flaked stones, a large part of such evidence, using a rigorous technological and taphonomic approach integrated with experimental tests, has already revealed these materials to be insignificant or natural, rather than anthropic, in origin. The following work seeks to shed light on the uncertainty existing around those stones and lithic artefacts bearing surface lines and scratches; these are of doubtful anthropic origin, but have not, as yet, been definitively interpreted. Generally, these findings are occasional in Mousterian sites, and when they are recovered with an excellent degree of preservation, different methods and levels of observation can be used for investigating them. The case studies taken into account are three sites in north Italy, where the surfaces of pebbles and flakes reveal a variety of signs and modifications attributable to various utilitarian acts. Of these, preventive cleaning of flint nodules has not been excluded, even if the traces on some tools reveal intentionality and repetition of gestures applied to the construction of a curated artifact. PMID- 25020019 TI - Evidence of rickets and/or scurvy in a complete Chalcolithic child skeleton from the El Portalon site (Sierra de Atapuerca, Spain). AB - A case of what are most likely metabolic diseases is identified in a child buried during Chalcolithic times in the El Portalon site (Sierra de Atapuerca, Burgos, Spain). The skeleton has been directly dated by C14 to between 5030 to 5020 Cal BP. Macroscopic analysis and a CT scan reveal a set of lesions both in the skull and the long bones, which indicate that this individual probably suffered from rickets and scurvy at different stages of his/her life. The lesions are bilateral and are characterized by abnormal porosity, new bone formation and deformation of long bones. The presence of non-specific stress indicators, such as enamel hypoplasias and Harris lines, allow us to establish two times of stress associated with these pathologies: one crisis during infancy (1-3 yrs) and subsequently a second crisis at the beginning of childhood (3-5 yrs). The etiology of both metabolic diseases could be associated with abnormal feeding during these stages of life and/or the living conditions of these populations, e.g., the preparation of food and/ or the existence of infections caused by the transmission of pathogens and unhealthy hygiene. Evidence of metabolic diseases during the recent European Prehistory is rather unknown and very few cases have been reported. Thus, the child from El Portalon can add relevant information about the life and health conditions of these prehistoric populations. PMID- 25020020 TI - Extended mind and visuo-spatial integration: three hands for the Neandertal lineage. PMID- 25020027 TI - Open data, Science and Society: launching Oasis, the flagship initiative of the Istituto Italiano di Antropologia. PMID- 25020029 TI - Control of radiative processes using tunable plasmonic nanopatch antennas. AB - The radiative processes associated with fluorophores and other radiating systems can be profoundly modified by their interaction with nanoplasmonic structures. Extreme electromagnetic environments can be created in plasmonic nanostructures or nanocavities, such as within the nanoscale gap region between two plasmonic nanoparticles, where the illuminating optical fields and the density of radiating modes are dramatically enhanced relative to vacuum. Unraveling the various mechanisms present in such coupled systems, and their impact on spontaneous emission and other radiative phenomena, however, requires a suitably reliable and precise means of tuning the plasmon resonance of the nanostructure while simultaneously preserving the electromagnetic characteristics of the enhancement region. Here, we achieve this control using a plasmonic platform consisting of colloidally synthesized nanocubes electromagnetically coupled to a metallic film. Each nanocube resembles a nanoscale patch antenna (or nanopatch) whose plasmon resonance can be changed independent of its local field enhancement. By varying the size of the nanopatch, we tune the plasmonic resonance by ~ 200 nm, encompassing the excitation, absorption, and emission spectra corresponding to Cy5 fluorophores embedded within the gap region between nanopatch and film. By sweeping the plasmon resonance but keeping the field enhancements roughly fixed, we demonstrate fluorescence enhancements exceeding a factor of 30,000 with detector-limited enhancements of the spontaneous emission rate by a factor of 74. The experiments are supported by finite-element simulations that reveal design rules for optimized fluorescence enhancement or large Purcell factors. PMID- 25020028 TI - Haptic simulation for acupuncture needle manipulation. AB - BACKGROUND: Stimulation degree, biomechanical force, and de qi sensation are the three major components of needle manipulation. To date, it has been difficult to measure all three components quantitatively. OBJECTIVES: To (1) measure and compare biomechanical forces of six human acupoints in vivo during haptic manipulation, (2) develop phantom acupoints with biomechanical forces similar to those of human acupoints, and (3) validate the newly developed phantom acupoints based on assessment by doctors of Korean medicine. METHODS: The biomechanical force and needle grasp sensation (i.e., the practitioner's de qi sensation) of six human acupoints (LI4, LI11, LR3, ST36, ST25, and BL25) were assessed in 16 participants upon stimulation with the twisting manipulation technique. On the basis of biomechanical data from these human acupoints, phantom acupoints that generated similar biomechanical forces were developed by using 1%-7% agarose gel. RESULTS: In humans, the mean torque amplitudes of the six acupoints differed significantly. In the phantom, the biomechanical force was dose-dependently greater in higher-concentration agarose gel phantom acupoints. Biomechanical force and the needle grasp sensation were significantly correlated in both human and phantom acupoints. Importantly, practitioners could not discriminate between human and phantom acupoints, suggesting that the validity and credibility of the phantom acupoints are sufficient for applications in education and research. CONCLUSIONS: Application of force-validated phantom acupoints based on human data will be a helpful tool for training and will contribute to a more comprehensive understanding of the characteristics of acupuncture manipulation. PMID- 25020030 TI - Release of colloids from primary minimum contact under unfavorable conditions by perturbations in ionic strength and flow rate. AB - Colloid release from surfaces in response to ionic strength and flow perturbations has been mechanistically simulated. However, these models do not address the mechanism by which colloid attachment occurs, at least in the presence of bulk colloid-collector repulsion (unfavorable conditions), which is a prevalent environmental condition. We test whether a mechanistic model that predicts colloid attachment under unfavorable conditions also predicts colloid release in response to reduced ionic strength (IS) and increased fluid velocity (conditions thought prevalent for mobilization of environmental colloids). The model trades in mean-field colloid-collector interaction for discrete representation of surface heterogeneity, which accounts for a combination of attractive and repulsive interactions simultaneously, and results in an attached colloid population (in primary minimum contact with the surface) having a distribution of strengths of attraction. The model moderates equilibrium separation distance by inclusion of steric interactions. By using the same model parameters to quantitatively predict attachment under unfavorable conditions, simulated release of colloids (for all three sizes) from primary minimum attachment in response to perturbations qualitatively matched experimental results, demonstrating that both attachment and detachment were mechanistically simulated. PMID- 25020031 TI - Perturbing the general base residue Glu166 in the active site of class A beta lactamase leads to enhanced carbapenem binding and acylation. AB - Most class A beta-lactamases cannot hydrolyze carbapenem antibiotics effectively. The molecular mechanism of this catalytic inefficiency has been attributed to the unique stereochemistry of carbapenems, including their 6-alpha-hydroxyethyl side chain and the transition between two tautomeric states when bound at the active site. Previous studies have shown that the 6-alpha-hydroxyethyl side chain of carbapenems can interfere with catalysis by forming hydrogen bonds with the deacylation water molecule to reduce its nucleophilicity. Here our studies of a class A noncarbapenemase PenP demonstrate that substituting the general base residue Glu166 with Ser or other residues leads to a significant enhancement of the acylation kinetics by ~100-500 times toward carbapenems like meropenem. The structures of PenP and Glu166Ser both in apo form and in complex with meropenem reveal that Glu166 is critical for the formation of a hydrogen bonding network within the active site that locks Asn170 in an orientation to impose steric clash with the 6-alpha-hydroxyethyl side chain of meropenem. The Glu166Ser substitution weakens this network and enables Asn170 to adopt an alternative conformation to avoid steric clash and accommodate faster acylation kinetics. Furthermore, the weakened hydrogen bonding network caused by the Glu166Ser substitution allows the 6-alpha-hydroxyethyl moiety to adopt a catalytically favorable orientation as seen in class A carbapenemases. In summary, our data identify a previously unreported role of the universally conserved general base residue Glu166 in impeding the proper binding of carbapenems by restricting their 6-alpha hydroxyethyl group. PMID- 25020032 TI - Twelve tips for asking and responding to difficult questions during a challenging clinical encounter. AB - BACKGROUND: Teaching healthcare providers (HCPs) effective communication skills can be challenging, but is crucial for managing complex patient encounters. AIM: To provide medical trainees strategies for recognizing and understanding problematic interactions. METHODS: The Twelve Tips are based on a study of communication skills teaching with family medicine trainees (n = 26) who received controlled exposure to common clinical difficulties simulated by standardized patients (SPs). The following tips were derived from a thematic analysis of a subset of the transcribed coaching sessions. RESULTS: These tips demonstrate that doctor-patient communication difficulties can arise from any of three sources: the patient's issues, the HCP's misunderstanding or inaccurate responsiveness to an issue, and/or the interaction between the HCP and the patient. These tips are heuristically grouped into two themes: (1) guiding principles to hold in mind and (2) behaviors that can be used to apply these principles. CONCLUSION: We believe that these strategies will help trainees to remain attentive to the patient, the interaction, and their own reactions, to improve the overall clinical encounter. PMID- 25020033 TI - Multifunctional cationic lipid-based nanoparticles facilitate endosomal escape and reduction-triggered cytosolic siRNA release. AB - Small interfering RNA (siRNA) has garnered much attention in recent years as a promising avenue for cancer gene therapy due to its ability to silence disease related genes. Effective gene silencing is contingent upon the delivery of siRNA into the cytosol of target cells and requires the implementation of delivery systems possessing multiple functionalities to overcome delivery barriers. The present work explores the multifunctional properties and biological activity of a recently developed cationic lipid carrier, (1-aminoethyl)iminobis[N (oleicylcysteinyl-1-amino-ethyl)propionamide]) (ECO). The physicochemical properties and biological activity of ECO/siRNA nanoparticles were assessed over a range of N/P ratios to optimize the formulation. Potent and sustained luciferase silencing in a U87 glioblastoma cell line was observed, even in the presence of serum proteins. ECO/siRNA nanoparticles exhibited pH-dependent membrane disruption at pH levels corresponding to various stages of the intracellular trafficking pathway. It was found that disulfide linkages created during nanoparticle formation enhanced the protection of siRNA from degradation and facilitated site-specific siRNA release in the cytosol by glutathione mediated reduction. Confocal microscopy confirmed that ECO/siRNA nanoparticles readily escaped from late endosomes prior to cytosolic release of the siRNA cargo. These results demonstrate that the rationally designed multifunctionality of ECO/siRNA nanoparticles is critical for intracellular siRNA delivery and the continuing development of safe and effective delivery systems. PMID- 25020034 TI - Graphene quantum-dot-supported platinum nanoparticles: defect-mediated electrocatalytic activity in oxygen reduction. AB - Graphene quantum dot (GQD)-supported platinum (Pt/G) nanoparticles were prepared by a simple hydrothermal procedure at controlled temperatures. Transmission electron microscopic measurements showed that the platinum nanoparticles exhibited a rather consistent core size within the narrow range of 2.5-3.5 nm in diameter (average core diameters slightly lower than 3.0 nm) when the hydrothermal temperatures were varied between 140 and 180 degrees C, whereas at higher temperatures (200 degrees C) the nanoparticle core size was markedly larger, as a result of weakened anchoring and passivation of the metal nanoparticles by the diminishment of the GQD structural defects. Spectroscopic measurements based on Fourier-transformed infrared, Raman, and X-ray photoelectron spectroscopies confirmed the formation of various oxygenated structural defects on GQDs and the variation of their concentrations with the hydrothermal conditions. Interestingly, electrochemical studies showed that the electrocatalytic activity of the series exhibited a volcano-shaped variation with the GQD structural defects, with the best identified as the samples prepared at 160 degrees C for 12 h and at 180 degrees C for 6 h where the mass activity was found to meet the DOE target for 2017. This remarkable performance was accounted for by the deliberate manipulation of the adsorption of oxygen and reaction intermediates on platinum by the GQD structural defects through partial charge transfer. The strategy presented herein may offer a new paradigm in the design and engineering of nanoparticle catalysts for fuel cell electrochemistry. PMID- 25020035 TI - Lithium compound deposition on mesocarbon microbead anode of lithium ion batteries after long-term cycling. AB - Lithium compound deposition on mesocarbon microbead (MCMB) anode after long-term cycling was studied in LiCoO2/MCMB battery. Lithium compound deposition did not generate on the activated MCMB anode, but it generated unevenly on the long-term cycled anode. Gray deposition composed of dendrites and particles was formed on the lower surface of the MCMB layer first, then on the upper surface. The deposition and MCMB layer peeled off from the current collector, and a bump was formed in the cycled anode. The exfoliation and thick deposition increased the ohmic resistance, film resistance, and charge transfer resistance of the cell and decreased the capacity significantly. Metallic lithium did not exist in either the upper or the lower deposition layer according to the results of X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), the discharge curve, and anode potential. The outer region of both the lower and the upper deposition layers consisted of Li2CO3, LiOH, ROCO2Li, and ROLi. The inner region of the etched lower deposition layer mainly consisted of Li2O, LiF, and Li2CO3, and that of the etched upper deposition layer mainly consisted of Li2CO3, ROCO2Li, ROLi, and LiF. Solid electrolyte interphase (SEI) film hindering the intercalation of lithium ions into carbon layers and LiCoO2 cathode providing lithium source for the deposition were the two reasons leading to the formation of lithium compound deposition during long-term cycles. Because SEI film on the lower surface of MCMB layer was thicker than that on the upper surface, lithium compound deposition generated on the lower surface first. PMID- 25020036 TI - Aerobic carbon-carbon bond cleavage of alkenes to aldehydes catalyzed by first row transition-metal-substituted polyoxometalates in the presence of nitrogen dioxide. AB - A new aerobic carbon-carbon bond cleavage reaction of linear di-substituted alkenes, to yield the corresponding aldehydes/ketones in high selectivity under mild reaction conditions, is described using copper(II)-substituted polyoxometalates, such as {alpha2-Cu(L)P2W17O61}(8-) or {[(Cu(L)]2WZn(ZnW9O34)2}(12-), as catalysts, where L = NO2. A biorenewable-based substrate, methyl oleate, gave methyl 8-formyloctanoate and nonanal in >90% yield. Interestingly, cylcoalkenes yield the corresponding epoxides as products. These catalysts either can be prepared by pretreatment of the aqua-coordinated polyoxometalates (L = H2O) with NO2 or are formed in situ when the reactions are carried with nitroalkanes (for example, nitroethane) as solvents or cosolvents. Nitroethane was shown to release NO2 under reaction conditions. (31)P NMR shows that the Cu-NO2-substituted polyoxometalates act as oxygen donors to the C-C double bond, yielding a Cu-NO product that is reoxidized to Cu-NO2 under reaction conditions to complete a catalytic cycle. Stoichiometric reactions and kinetic measurements using {alpha2-Co(NO2)P2W17O61}(8-) as oxidant and trans-stilbene derivatives as substrates point toward a reaction mechanism for C-C bond cleavage involving two molecules of {alpha2-Co(NO2)P2W17O61}(8-) and one molecule of trans stilbene that is sufficiently stable at room temperature to be observed by (31)P NMR. PMID- 25020037 TI - Asymmetric total synthesis of (+)-didemniserinolipid B via Achmatowicz rearrangement/bicycloketalization. AB - A new synthetic strategy was developed for the asymmetric total synthesis of (+) didemniserinolipid B in 19 linear steps, featuring a highly efficient and enantioselective construction of 6,8-dioxabicyclo[3.2.1]octane (6,8-DOBCO) framework via a rarely explored Achmatowicz rearrangement/bicycloketalization strategy. In addition, the first total synthesis of the proposed (+) didemniserinolipid C was accomplished with 41.6% yield in 4 steps from a common advanced intermediate 18, and a possible revised structure of (+) didemniserinolipid C was proposed. The new convergent synthetic strategy greatly expedites the entry to the didemniserinolipids and their analogues for biological activity evaluation. PMID- 25020038 TI - Potential use of fucose-appended dendrimer/alpha-cyclodextrin conjugates as NF kappaB decoy carriers for the treatment of lipopolysaccharide-induced fulminant hepatitis in mice. AB - The purpose of the present study is to treat lipopolysaccharide (LPS)-induced fulminant hepatitis by NF-kappaB decoy complex with fucose-appended dendrimer (generation 2; G2) conjugate with alpha-cyclodextrin (Fuc-S-alpha-CDE (G2)). Fuc S-alpha-CDE (G2, average degree of substitution of fucose (DSF2))/NF-kappaB decoy complex significantly suppressed nitric oxide and tumor necrosis factor-alpha (TNF-alpha) production from LPS-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and fucose receptor mediated cellular uptake. Intravenous injection of Fuc-S-alpha-CDE (G2, DSF2)/NF kappaB decoy complex extended the survival of LPS-induced fulminant hepatitis model mice. In addition, Fuc-S-alpha-CDE (G2, DSF2)/NF-kappaB decoy complex administered intravenously highly accumulated in the liver, compared to naked NF kappaB decoy alone. Furthermore, the liver accumulation of Fuc-S-alpha-CDE (G2, DSF2)/NF-kappaB decoy complex was inhibited by the pretreatment with GdCl3, a specific inhibitor of Kupffer cell uptake. Also, the serum aspartate aminotransferase, alanine aminotransferase and TNF-alpha levels in LPS-induced fulminant hepatitis model mice were significantly attenuated by the treatment with Fuc-S-alpha-CDE (G2, DSF2)/NF-kappaB decoy complex, compared with naked NF kappaB decoy alone. Taken together, these results suggest that Fuc-S-alpha-CDE (G2, DSF2) has the potential for a novel Kupffer cell-selective NF-kappaB decoy carrier for the treatment of LPS-induced fulminant hepatitis in mice. PMID- 25020039 TI - 3-dimensional (3D) fabricated polymer based drug delivery systems. AB - Drug delivery from 3-dimensional (3D) structures is a rapidly growing area of research. It is essential to achieve structures wherein drug stability is ensured, the drug loading capacity is appropriate and the desired controlled release profile can be attained. Attention must also be paid to the development of appropriate fabrication machinery that allows 3D drug delivery systems (DDS) to be produced in a simple, reliable and reproducible manner. The range of fabrication methods currently being used to form 3D DDSs include electrospinning (solution and melt), wet-spinning and printing (3-dimensional). The use of these techniques enables production of DDSs from the macro-scale down to the nano scale. This article reviews progress in these fabrication techniques to form DDSs that possess desirable drug delivery kinetics for a wide range of applications. PMID- 25020040 TI - UV transition moments of tyrosine. AB - To assist polarized-light spectroscopy for protein-structure analysis, the UV spectrum of p-cresol, the chromophore of tyrosine, was studied with respect to transition moment directions and perturbation by solvent environment. From linear dichroism (LD) spectra of p-cresol aligned in stretched matrices of poly(vinyl alcohol) and polyethylene, the lowest pi-pi* transition (Lb) is found to have pure polarization over its entire absorption (250-300 nm) with a transition moment perpendicular to the symmetry axis (C1-C4), both in polar and nonpolar environments. For the second transition (La), polarized parallel with the symmetry axis, a certain admixture of intensity with orthogonal polarization is noticed, depending on the environment. While the Lb spectrum in cyclohexane shows a pronounced vibrational structure, it is blurred in methanol, which can be modeled as due to many microscopic polar environments. With the use of quantum mechanical (QM) calculations, the transition moments and solvent effects were analyzed with the B3LYP and omegaB97X-D functionals in cyclohexane, water, and methanol using a combination of implicit and explicit solvent models. The blurred Lb band is explained by solvent hydrogen bonds, where both accepting and donating a hydrogen causes energy shifts. The inhomogeneous solvent-shift sensitivity in combination with robust polarization can be exploited for analyzing tyrosine orientation distributions in protein complexes using LD spectroscopy. PMID- 25020041 TI - Liquid marbles supported by monodisperse poly(methylsilsesquioxane) particles. AB - The preparation of model, well-controlled colloidal assemblies has been a central approach to understanding and optimizing the characteristics and functionality of complex colloidal dispersion systems. This approach, which has created a significant literature and rather deep understanding for emulsions and foams, has yet to be established for the liquid marble (water-in-air) motif. In this article we report the preparation of well-controlled liquid marbles using monodisperse micron-size particles of poly(methylsilsesquioxane) (PMSQ). The low cohesive nature of the stabilizing particles, their narrow size distribution, and their hydrophobicity permit the formation of liquid marbles containing a particulate monolayer with a hexagonally close-packed (HCP) structure. The "cleaning process" by rolling of liquid marbles under a flow of air on a hydrophobic substrate was useful to obtain the monolayer structure. Moreover, the monolayer structure was only obtained from liquids with high surface energy, whereas the others were not useful even though multilayered structure was formed from liquids that have intermediate surface energy. PMID- 25020042 TI - Improved and robust detection of cell nuclei from four dimensional fluorescence images. AB - Segmentation-free direct methods are quite efficient for automated nuclei extraction from high dimensional images. A few such methods do exist but most of them do not ensure algorithmic robustness to parameter and noise variations. In this research, we propose a method based on multiscale adaptive filtering for efficient and robust detection of nuclei centroids from four dimensional (4D) fluorescence images. A temporal feedback mechanism is employed between the enhancement and the initial detection steps of a typical direct method. We estimate the minimum and maximum nuclei diameters from the previous frame and feed back them as filter lengths for multiscale enhancement of the current frame. A radial intensity-gradient function is optimized at positions of initial centroids to estimate all nuclei diameters. This procedure continues for processing subsequent images in the sequence. Above mechanism thus ensures proper enhancement by automated estimation of major parameters. This brings robustness and safeguards the system against additive noises and effects from wrong parameters. Later, the method and its single-scale variant are simplified for further reduction of parameters. The proposed method is then extended for nuclei volume segmentation. The same optimization technique is applied to final centroid positions of the enhanced image and the estimated diameters are projected onto the binary candidate regions to segment nuclei volumes.Our method is finally integrated with a simple sequential tracking approach to establish nuclear trajectories in the 4D space. Experimental evaluations with five image-sequences (each having 271 3D sequential images) corresponding to five different mouse embryos show promising performances of our methods in terms of nuclear detection, segmentation, and tracking. A detail analysis with a sub-sequence of 101 3D images from an embryo reveals that the proposed method can improve the nuclei detection accuracy by 9% over the previous methods, which used inappropriate large valued parameters. Results also confirm that the proposed method and its variants achieve high detection accuracies (> 98% mean F-measure) irrespective of the large variations of filter parameters and noise levels. PMID- 25020043 TI - Another lesson from plants: the forward osmosis-based actuator. AB - Osmotic actuation is a ubiquitous plant-inspired actuation strategy that has a very low power consumption but is capable of generating effective movements in a wide variety of environmental conditions. In light of these features, we aimed to develop a novel, low-power-consumption actuator that is capable of generating suitable forces during a characteristic actuation time on the order of a few minutes. Based on the analysis of plant movements and on osmotic actuation modeling, we designed and fabricated a forward osmosis-based actuator with a typical size of 10 mm and a characteristic time of 2-5 minutes. To the best of our knowledge, this is the fastest osmotic actuator developed so far. Moreover, the achieved timescale can be compared to that of a typical plant cell, thanks to the integrated strategy that we pursued by concurrently addressing and solving design and material issues, as paradigmatically explained by the bioinspired approach. Our osmotic actuator produces forces above 20 N, while containing the power consumption (on the order of 1 mW). Furthermore, based on the agreement between model predictions and experimental observations, we also discuss the actuator performance (including power consumption, maximum force, energy density and thermodynamic efficiency) in relation to existing actuation technologies. In light of the achievements of the present study, the proposed osmotic actuator holds potential for effective exploitation in bioinspired robotics systems. PMID- 25020044 TI - Pediatric gastrointestinal PEComas: a diagnostic challenge. AB - Perivascular epithelioid cell tumors (PEComas) in the pediatric population are very rare and frequently arise in the gastrointestinal tract. These tumors are characterized by variable morphological and immunohistochemical features, which may pose significant problems in differential diagnosis with other gastrointestinal mesenchymal tumors in pediatric patients. In presenting an unusual pediatric case of gastrointestinal PEComa, we also discuss the possible differential diagnosis of this rare entity. PMID- 25020045 TI - Long-term health effects of neutering dogs: comparison of Labrador Retrievers with Golden Retrievers. AB - Our recent study on the effects of neutering (including spaying) in Golden Retrievers in markedly increasing the incidence of two joint disorders and three cancers prompted this study and a comparison of Golden and Labrador Retrievers. Veterinary hospital records were examined over a 13-year period for the effects of neutering during specified age ranges: before 6 mo., and during 6-11 mo., year 1 or years 2 through 8. The joint disorders examined were hip dysplasia, cranial cruciate ligament tear and elbow dysplasia. The cancers examined were lymphosarcoma, hemangiosarcoma, mast cell tumor, and mammary cancer. The results for the Golden Retriever were similar to the previous study, but there were notable differences between breeds. In Labrador Retrievers, where about 5 percent of gonadally intact males and females had one or more joint disorders, neutering at <6 mo. doubled the incidence of one or more joint disorders in both sexes. In male and female Golden Retrievers, with the same 5 percent rate of joint disorders in intact dogs, neutering at <6 mo. increased the incidence of a joint disorder to 4-5 times that of intact dogs. The incidence of one or more cancers in female Labrador Retrievers increased slightly above the 3 percent level of intact females with neutering. In contrast, in female Golden Retrievers, with the same 3 percent rate of one or more cancers in intact females, neutering at all periods through 8 years of age increased the rate of at least one of the cancers by 3-4 times. In male Golden and Labrador Retrievers neutering had relatively minor effects in increasing the occurrence of cancers. Comparisons of cancers in the two breeds suggest that the occurrence of cancers in female Golden Retrievers is a reflection of particular vulnerability to gonadal hormone removal. PMID- 25020047 TI - Structural insights for the design of new borate-phosphates: synthesis, crystal structure and optical properties of Pb4O(BO3)(PO4) and Bi4O3(BO3)(PO4). AB - Two new metal borate-phosphates, Pb4O(BO3)(PO4) (1) and Bi4O3(BO3)(PO4) (2), have been successfully designed and synthesized. The structures of the title compounds were determined by single-crystal X-ray diffraction. The title compounds have similar crystal structures consisting of oxygen-centered (OPb4) or (OBi4) tetrahedra as well as isolated BO3 and PO4 groups. Structural comparison and the Madelung energy calculation indicate that the title compounds also exhibit a strong correlation with the known metal borates and phosphates. In addition, a strategy of BO3-PO4 substitution is proposed for designing new borate-phosphates. Thermal analyses, IR spectroscopy and UV-vis-NIR diffuse reflectance spectroscopy have also been performed. PMID- 25020046 TI - Avian SERPINB12 expression in the avian oviduct is regulated by estrogen and up regulated in epithelial cell-derived ovarian carcinomas of laying hens. AB - Serine protease inhibitors (SERPINs) are involved in a variety of biological processes such as blood clotting, angiogenesis, immune system, and embryogenesis. Although, of these, SERPINB12 is identified as the latest member of clade B in humans, little is known of it in chickens. Thus, in this study, we investigated SERPINB12 expression profiles in various tissues of chickens and focused on effects of steroid hormone regulation of its expression. In the chicken oviduct, SERPINB12 mRNA and protein are abundant in the luminal (LE) and glandular (GE) epithelia of the magnum in response to endogenous or exogenous estrogen. Furthermore, SERPINB12 mRNA and protein increase significantly in GE of cancerous ovaries of laying hens with epithelia-derived ovarian cancer. Collectively, these results indicate that SERPINB12 is a novel estrogen-stimulated gene that is up regulated by estrogen in epithelial cells of the chicken oviduct and that it is a potential biomarker for early detection of ovarian carcinomas in laying hens and women. PMID- 25020048 TI - Design of lipid nanocapsule delivery vehicles for multivalent display of recombinant Env trimers in HIV vaccination. AB - Immunization strategies that elicit antibodies capable of neutralizing diverse virus strains will likely be an important part of a successful vaccine against HIV. However, strategies to promote robust humoral responses against the native intact HIV envelope trimer structure are lacking. We recently developed chemically cross-linked lipid nanocapsules as carriers of molecular adjuvants and encapsulated or surface-displayed antigens, which promoted follicular helper T cell responses and elicited high-avidity, durable antibody responses to a candidate malaria antigen. To apply this system to the delivery of HIV antigens, Env gp140 trimers with terminal his-tags (gp140T-his) were anchored to the surface of lipid nanocapsules via Ni-NTA-functionalized lipids. Initial experiments revealed that the large (409 kDa), heavily glycosylated trimers were capable of extracting fluid phase lipids from the membranes of nanocapsules. Thus, liquid-ordered and/or gel-phase lipid compositions were required to stably anchor trimers to the particle membranes. Trimer-loaded nanocapsules combined with the clinically relevant adjuvant monophosphoryl lipid A primed high-titer antibody responses in mice at antigen doses ranging from 5 MUg to as low as 100 ng, whereas titers dropped more than 50-fold over the same dose range when soluble trimer was mixed with a strong oil-in-water adjuvant comparator. Nanocapsule immunization also broadened the number of distinct epitopes on the HIV trimer recognized by the antibody response. These results suggest that nanocapsules displaying HIV trimers in an oriented, multivalent presentation can promote key aspects of the humoral response against Env immunogens. PMID- 25020049 TI - Gene silencing effect of SiRNA-magnetic modified with biodegradable copolymer nanoparticles on hTERT gene expression in lung cancer cell line. AB - BACKGROUND: Telomerase is expressed in most of malignant cells, including lung cancer cells. The success of small interfering RNA (siRNA) in silencing of the telomerase catalytic subunit depends upon carriers ability to efficiently deliver therapeutic agent to cells with minimal toxicity and most biocompatibility. In this study, a potential carrier for efficient delivery was assessed by siRNA encapsulating into Iron MNPs modified with biodegradable polyester nanoparticles consisting of PLGA and PEG. RESULTS: Data analysis shows that the self-assemble diblock copolymers were synthesized, and then the siRNA designed against hTERT catalytic subunit was encapsulated. Also, the rate of telomerase gene expression in equivalent with magnetic copolymers/siRNA was lower than that of free siRNA (P = 0.001). CONCLUSIONS: In conclusion, regarding the enhancing of siRNA stability by magnetic copolymer, the expression of telomerase gene was significantly lower in the cells treated with siRNA-magnetic copolymers than those treated with free siRNA. PMID- 25020050 TI - Evaluation of the induction of immune memory following infant immunisation with serogroup C Neisseria meningitidis conjugate vaccines--exploratory analyses within a randomised controlled trial. AB - AIM: We measured meningococcal serogroup C (MenC)-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot) following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory. METHODS: Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM197 at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib)-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age. RESULTS: Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12 month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001) or 2-dose (p<0.0001) MenC-CRM197. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM197 in infancy and un-primed children. CONCLUSIONS: MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM197 and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody. TRIAL REGISTRATION: EU Clinical Trials Register 2009-016579 31 ClinicalTrials.gov NCT01129518. PMID- 25020051 TI - Rectal swabs for analysis of the intestinal microbiota. AB - The composition of the gut microbiota is associated with various disease states, most notably inflammatory bowel disease, obesity and malnutrition. This underlines that analysis of intestinal microbiota is potentially an interesting target for clinical diagnostics. Currently, the most commonly used sample types are feces and mucosal biopsy specimens. Because sampling method, storage and processing of samples impact microbiota analysis, each sample type has its own limitations. An ideal sample type for use in routine diagnostics should be easy to obtain in a standardized fashion without perturbation of the microbiota. Rectal swabs may satisfy these criteria, but little is known about microbiota analysis on these sample types. In this study we investigated the characteristics and applicability of rectal swabs for gut microbiota profiling in a clinical routine setting in patients presenting with various gastro-intestinal disorders. We found that rectal swabs appeared to be a convenient means of sampling the human gut microbiota. Swabs can be performed on demand, whenever a patient presents; swab-derived microbiota profiles are reproducible, whether they are gathered at home by patients or by medical professionals in an outpatient setting and may be ideally suited for clinical diagnostics and large-scale studies. PMID- 25020052 TI - The value of transvaginal sonography in detecting endometrial pathologies in postmenopausal women with or without bleeding. AB - AIM: The aim of this study was to estimate the incidence of endometrial pathologies and compare the findings in postmenopausal women with or without bleeding who had endometrial thickness >=5 mm. METHODS: Between January 2010 and December 2012 medical records of postmenopausal patients who underwent endometrial biopsy were reviewed retrospectively. 91 patients who presented with postmenopausal bleeding (Group A) with an endometrial thickness equal to or greater than 5 mm and 44 patients with an incidental finding of increased endometrial thickness (>=5 mm) on ultrasound without bleeding (Group B) were included in the study. RESULTS: The mean endometrial thickness of patients in group A (9.3+/-4.6) was significantly lower than women in group B (11+/-4.6). Seven (7.7%) cases of endometrial hyperplasia and 6 (6.6%) cases of endometrial carcinoma were detected in women with bleeding, 2 (4.5%) cases of endometrial hyperplasia and no cases of endometrial carcinoma were diagnosed in group B women. The prevalence of endometrial carcinoma associated with endometrial thickness in group A women whereas we cannot see this relation in group B women. The mean endometrial thickness was highest in women with the histopathologic diagnosis of polyps in this group. CONCLUSION: In postmenopausal women with bleeding, the risk of endometrial carcinoma increases with increasing endometrial thickness; however, the use of endometrial thickness as a screening test for endometrial carcinoma may not be effective in women without bleeding. 6.5 mm cut off seems to be acceptable thickness for polyp detection in postmenopausal women with bleeding. PMID- 25020053 TI - Comparison of follitropin alfa and urinary gonadotropins in IVF cycles. AB - AIM: The aim of this study was to compare human menopausal gonadotropins with recombinant follicle stimulating hormone-follitropin alpha following a long down regulation protocol in intra cytoplasmic sperm injection cycles in our clinic, and to review the outcomes in the light of preceding studies. METHODS: This was a retrospective study. Among a total number of 2798 patients who had undergone IVF/ICSI applications, 579 eligible patients were included, and their data were evaluated retrospectively. Three hundred eighteen patients were treated with follitropin alpha and 255 patients were treated with hMG. Total units of follitropin alpha preparations used in ovulation induction, total number of meiois-2 phase oocytes, total number of used oocytes in ICSI cycle, fertilization rate and clinical pregnancy rates of both groups were analyzed. RESULTS: Mean duration of stimulation was longer in the group of patients treated with rFSH alpha compared to the second group of patients treated with hMG (8.88 days and 8.55 days, respectively; P<0.05). The number of transferred embryos were 3.08 and 2.68 for patients treated with follitropin alpha and hMG, respectively (P<0.05). Clinical pregnancy rates were %28 and %33 in the groups of patients treated with follitropin alpha and hMG, respectively. Even though a greater clinical pregnancy rate was noted in the hMG group, there was no statistically significant difference between the two groups (P>0.05). CONCLUSION: Our results indicate that there is no statistically significant difference between follitropin alpha and human menopausal gonadotropin in terms of the clinical pregnancy rates. PMID- 25020054 TI - Comparison of home-based and outpatient clinic-based intravaginal electrical stimulation for the treatment of urinary incontinence. AB - AIM: Aim of the study was to compare the effects of outpatient clinic-based versus home-based intravaginal electrical stimulation (ES) for the treatment of urinary incontinence. METHODS: Women applying with the complaint of urinary incontinence and offered ES treatment were divided into outpatient clinic-based or home-based ES. Patients were instructed about home-based ES at the outpatient clinic by certified physiotherapy nurses. Bladder diary, 1-hour pad test, and King's-Health-Questionnaire (KHQ) were performed before and after treatment. ES was applied for 20 minutes, 6-8 weeks with pulses of 10-50 Hz square waves at a 300 MUs or 1 ms pulse duration and a maximal output current of 24 to 60 mA with 5 10 Hz frequency, three times/week. RESULTS: Twenty-four patients received outpatient clinic-based, 22 patients received home-based ES. Pad test, bladder diary and pelvic floor muscle strength parameters in both groups improved significantly after treatment, with no significant difference between the two groups. Seven patients (31.8%) were cured, six patients (27.3%) were much improved, and seven patients (31.8%) were improved in the home-based ES group. Nine patients (37.5%) were cured, six patients (25%) were much improved, and six patients (25%) were improved and in the outpatient clinic-based ES group. There was an improvement in quality of life in all domains in both groups when the pretreatment and post-treatment KHQ results were compared, with no significant difference between the two groups. CONCLUSION: Home-based ES is as effective in the treatment of urinary incontinence as outpatient clinic-based ES with significant improvement in objective and subjective parameters. PMID- 25020055 TI - Premenstrual syndrome and beyond: lifestyle, nutrition, and personal facts. AB - AIM: The aim was to study prevalence of menstrual symptoms and their presenting patterns, and to assess nutrition and behaviours correlates. METHODS: The study enrolled 108 women, who were prospectively assessed for menstrual symptoms; a 212 items questionnaire about lifestyle and nutrition was administered. Diagnosis and intensity of symptoms were separately compared for dietary and other factors. The chi2 test or Fisher exact test as required and a multivariate analysis were performed. RESULTS: Seventeen percent of the sample reported no symptoms; core PMD was diagnosed in 14%, and related to symptoms of moderate intensity, to late menarche, irregular, long cycles, dysmenorrhoea, and to lower intake of complex carbohydrates, fibers, calcium; non-cyclical pattern in 27%, and related to symptoms of severe intensity, to young age, unemployed, to poor health, stress, traumatic events, abnormal BMI, to long, heavy menses, to lower intake of fibers, magnesium, vitamin B6, and to higher intake of fat, proteins, sodium, caffeine; variant PMD-premenstrual exacerbation in 42%, and related to symptoms of severe - moderate intensity, to young age, students, unemployed, sedentary work, abnormal BMI, stress, to cycle irregularities, heavy menses, to higher intake of simple sugars and sodium, and to lower intake of calcium, magnesium, and vitamin B6. Regardless of diagnosis, severe intensity of symptoms was associated with young age /students (P<0.001), lower education, unemployed, smoke, sedentary work, poor health, stress, heavy menses (P<0.01), dysmenorrhea, more unfavorable and less favorable nutrients. CONCLUSION: Lifestyle, nutrition, and general health considerations seem to be important issues in the management of menstrual symptoms, prospective symptoms chart being mandatory for diagnosis. PMID- 25020056 TI - An alternative approach for the treatment of vaginal atrophy. AB - AIM: The aim of this study was to determine the efficacy of a new topic non hormonal treatment for postmenopausal women complaining of symptoms of vaginal atrophy. METHODS: Patients included in the study were prescribed Sinecol gel (AM PHARMA Srl, Vimercate, Monza and Brianza, Italy) application once a day for 20 consecutive days. Sinecol gel is a topic compound for vaginal atrophy containing hyaluronic acid, that is known to improve vaginal elasticity, lactoperoxidase, Xantham gum and glucose oxidase, which have protective and antibacterial action. We evaluated each patient before and after treatment, both subjectively with the "Visual Analogical Scale" (VAS) and objectively with the "Vaginal Health Index" (VHI). RESULTS: We observed a significant clinical improvement of the subjective and objective assessment of symptoms severity with a p value <0.001 at the end of the treatment compared to baseline. CONCLUSION: Sinecol gel appears to be an effective and valid non-hormonal alternative to the estrogen therapy for vaginal atrophy. PMID- 25020057 TI - Management of high-risk pregnancy. AB - Today, 88% of pregnancies has a physiological course during which just basic care, while in 12% of cases there is a high-risk pregnancy that requires additional assistance and specific. The approach that should be used is that of supervision in all pregnant women considering their potential to have a normal pregnancy until there is no clear evidence to the contrary. Pregnancy is considered at risk if there are medical conditions that may affect maternal or fetal health or life of the mother, fetus or both. Among the risk factors for pregnancy there is first the woman's age, in fact the increase in high-risk pregnancies in the last 20 years is attributable to the increase in the average age of women who face pregnancy. In addition, the diet is very important during pregnancy and diabetes or autoimmune diseases often lead to the failure of a pregnancy. Risk factors for pregnancy, also, are the complications that occur during its course as hypertension during pregnancy, and infectious diseases. Fears and anxieties typical of a high-risk pregnancy prevent the couple to live happily in the months of gestation. Effective communication, control and early detection are important tools that doctors must be able to ensure that women in order to plan the best treatment strategies and to minimize the risks of maternal and / or fetal. PMID- 25020058 TI - The role of cytokines in postmenopausal osteoporosis. AB - Postmenopausal osteoporosis is a silent systemic progressive disease characterised by a decrease in bone mass per unit volume. This condition compromises the physical strength of the skeleton and increases the susceptibility to fractures on minor trauma. The imbalance between bone formation and bone resorption is known to be responsible for postmenopausal bone loss. Estrogen deficiency contributes to bone loss by increasing the production of pro inflammatory cytokines by bone marrow and bone cells. Clinical and molecular evidence indicates that estrogen-regulated cytokines exert regulatory effects on bone turnover implicating their role as being the primary mediators of the accelerated bone loss at menopause. The current perspective on the role and interaction of cytokines such as IL-1, IL-4, IL-6, IL-17, TNF, IFN-gamma and TGF beta in bone loss linked with estrogen deficiency is reviewed. Current treatment options and emerging drug therapies in the management of postmenopausal osteoporosis are also evaluated. PMID- 25020059 TI - Significance of egg's zona pellucida glycoproteins in sperm-egg interaction and fertilization. AB - Mammalian fertilization is a highly programmed process by which sperm and egg unite to form a zygote, a cell with somatic chromosome numbers. To fertilize an egg, the capacitated (acrosome-intact) spermatozoa recognize and bind to the egg's extracellular glycocalyx coat, the zona pellucida (ZP). The tight and irreversible binding of the opposite gametes in the mouse and many other species studied, including man, results in the opening of Ca2+ channels on sperm plasma membrane (PM) and influx of Ca2+. The transient rise in Ca2+ and other second messengers, such as cAMP and IP3, initiates a cascade of signaling events that elevate sperm pH and triggers the fusion of the sperm PM and underlying outer acrosomal membrane at multiple sites (induction of the acrosomal reaction). The fusion of the two membranes results in the exocytosis of acrosomal contents at the site of sperm-egg adhesion. The hydrolytic action of the acrosomal enzymes (glycohydrolases, proteinases, esterases, sulfatases etc), released at the site of sperm-egg adhesion, along with the enhanced thrust generated by the hyperactivated spermatozoon, are important factors that regulate the penetration of the ZP and the fusion of the acrosome-reacted spermatozoon with the egg. Evidence accumulated over the past two decades strongly suggests that glycan units of the ZP have a significant role in the recognition and adhesion of the opposite gametes and induction of the AR. In this review article, we intend to highlight well programmed molecular events that results in the sperm-egg adhesion and fertilization. Our intention is also to discuss the increasing controversy on the role of ZP glycan chains in sperm-egg interactions. PMID- 25020060 TI - Quantifying the effect of ribosomal density on mRNA stability. AB - Gene expression is a fundamental cellular process by which proteins are eventually synthesized based on the information coded in the genes. This process includes four major steps: transcription of the DNA segment corresponding to a gene to mRNA molecules, the degradation of the mRNA molecules, the translation of mRNA molecules to proteins by the ribosome and the degradation of the proteins. We present an innovative quantitative study of the interaction between the gene translation stage and the mRNA degradation stage using large scale genomic data of S. cerevisiae, which include measurements of mRNA levels, mRNA half-lives, ribosomal densities and protein abundances, for thousands of genes. The reported results support the conjecture that transcripts with higher ribosomal density, which is related to the translation stage, tend to have elevated half-lives, and we suggest a novel quantitative estimation of the strength of this relation. Specifically, we show that on average, an increase of 78% in ribosomal density yields an increase of 25% in mRNA half-life, and that this relation between ribosomal density and mRNA half-life is not function specific. In addition, our analyses demonstrate that ribosomal density along the entire ORF, and not in specific locations, has a significant effect on the transcript half-life. Finally, we show that the reported relation cannot be explained by different expression levels among genes. A plausible explanation for the reported results is that ribosomes tend to protect the mRNA molecules from the exosome complexes degrading them; however, additional non-mutually exclusive possible explanations for the reported relation and experiments for their verifications are discussed in the paper. PMID- 25020063 TI - Patent perspectives for corticosteroids based ophthalmic therapeutics. AB - Eye inflammation, if untreated at right time poses the risk of vision loss. Several categories of drugs are available in the global market, but corticosteroids are still used for the treatment of ocular inflammation including anterior/ posterior uveitis, age related macular degeneration (AMD) and post cataract surgery inflammation. Although corticosteroids have well-documented side effects as compared to non steroidal anti-inflammatory drugs (NSAIDs), but they are still regarded as better anti-inflammatory agents for treating ocular inflammations. The prime concern with conventional formulations such as (ophthalmic solutions, suspensions, ointments) is low drug bioavailability due to precorneal barrier of the eye, tear turnover and rapid drainage of drug via nasolacrimal drainage and drug induced systemic toxicity. To overcome these limitations, various novel formulations of corticosteroids have been explored. These include nanoparticles, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanomicelles, in-situ gels, iontophoresis, liposomes, nanoemulsions, microemulsions and ocular implants for the effective ophthalmic delivery of the corticosteroids. Topical nanocarriers have also been demonstrated to be promising vectors with potential application in the ophthalmic therapeutics. This review summarizes the clinical findings and patents on various corticosteroids as ocular pharmacotherapeutics. PMID- 25020062 TI - Expansion of human mesenchymal stromal cells from fresh bone marrow in a 3D scaffold-based system under direct perfusion. AB - Mesenchymal stromal/stem cell (MSC) expansion in conventional monolayer culture on plastic dishes (2D) leads to progressive loss of functionality and thus challenges fundamental studies on the physiology of skeletal progenitors, as well as translational applications for cellular therapy and molecular medicine. Here we demonstrate that 2D MSC expansion can be entirely bypassed by culturing freshly isolated bone marrow nucleated cells within 3D porous scaffolds in a perfusion-based bioreactor system. The 3D-perfusion system generated a stromal tissue that could be enzymatically treated to yield CD45- MSC. As compared to 2D expanded MSC (control), those derived from 3D-perfusion culture after the same time (3 weeks) or a similar extent of proliferation (7-8 doublings) better maintained their progenitor properties, as assessed by a 4.3-fold higher clonogenicity and the superior differentiation capacity towards all typical mesenchymal lineages. Transcriptomic analysis of MSC from 5 donors validated the robustness of the process and indicated a reduced inter-donor variability and a significant upregulation of multipotency-related gene clusters following 3D perfusion--as compared to 2D-expansion. Interestingly, the differences in functionality and transcriptomics between MSC expanded in 2D or under 3D perfusion were only partially captured by cytofluorimetric analysis using conventional surface markers. The described system offers a multidisciplinary approach to study how factors of a 3D engineered niche regulate MSC function and, by streamlining conventional labor-intensive processes, is prone to automation and scalability within closed bioreactor systems. PMID- 25020061 TI - Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling. AB - AIM: Fasting is characterised by profound changes in energy metabolism including progressive loss of body proteins. The underlying mechanisms are however unknown and we therefore determined the effects of a 72-hour-fast on human skeletal muscle protein metabolism and activation of mammalian target of rapamycin (mTOR), a key regulator of cell growth. METHODS: Eight healthy male volunteers were studied twice: in the postabsorptive state and following 72 hours of fasting. Regional muscle amino acid kinetics was measured in the forearm using amino acid tracers. Signaling to protein synthesis and breakdown were assessed in skeletal muscle biopsies obtained during non-insulin and insulin stimulated conditions on both examination days. RESULTS: Fasting significantly increased forearm net phenylalanine release and tended to decrease phenylalanine rate of disappearance. mTOR phosphorylation was decreased by ~50% following fasting, together with reduced downstream phosphorylation of 4EBP1, ULK1 and rpS6. In addition, the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and fasting increased expression of the autophagic marker LC3B-II by ~30%. p62 is degraded during autophagy but was increased by ~10% during fasting making interpretation of autophagic flux problematic. MAFbx and MURF1 ubiquitin ligases remained unaltered after fasting indicating no change in protesomal protein degradation. CONCLUSIONS: Our results show that during fasting increased net phenylalanine release in skeletal muscle is associated to reduced mTOR activation and concomitant decreased downstream signaling to cell growth. PMID- 25020064 TI - Vitamin D receptor gene polymorphisms are associated with obesity and inflammosome activity. AB - To explore the mechanisms underlying the suggested role of the vitamin D/vitamin D receptor (VDR) complex in the pathogenesis of obesity we performed genetic and immunologic analyses in obese and non-obese Saudi individuals without other concomitant chronic diseases. Genomic DNA was genotyped for gene single nucleotide polymorphisms (SNPs) of VDR by allelic discrimination in 402 obese (body mass index -BMI>=30 kg/m2) and 489 non-obese (BMI<30 kg/m2) Saudis. Q-PCR analyses were performed using an ABI Prism 7000 Sequence Detection System. The inflammosome pathway was analysed by PCR, cytokines and plasma lipopolysaccaride (LPS) concentrations with ELISA assays. Results showed that the VDR SNPs rs731236 (G) (TaqI) and rs1544410 (T) (Bsm-I) minor allele polymorphisms are significantly more frequent in obese individuals (p = 0.009, beta = 0.086 and p = 0.028, beta = 0.072, respectively). VDR haplotypes identified are positively (GTA) (p = 0.008, beta = 1.560); or negatively (ACC) (p = 0.044, beta = 0.766) associated with obesity and higher BMI scores. The GTA "risk" haplotype was characterized by an up-regulation of inflammosome components, a higher production of proinflammatory cytokines (p<0.05) and a lower VDR expression. Plasma LPS concentration was also increased in GTA obese individuals (p<0.05), suggesting an alteration of gut permeability leading to microbial translocation. Data herein indicate that polymorphisms affecting the vitamin D/VDR axis play a role in obesity that is associated with an ongoing degree of inflammation, possibly resulting from alterations of gut permeability and microbial translocation. These results could help the definition of VDR fingerprints that predict an increased risk of developing obesity and might contribute to the identification of novel therapeutic strategies for this metabolic condition. PMID- 25020067 TI - Multi-surface and multi-field co-segmentation of 3-D retinal optical coherence tomography. AB - When segmenting intraretinal layers from multiple optical coherence tomography (OCT) images forming a mosaic or a set of repeated scans, it is attractive to exploit the additional information from the overlapping areas rather than discarding it as redundant, especially in low contrast and noisy images. However, it is currently not clear how to effectively combine the multiple information sources available in the areas of overlap. In this paper, we propose a novel graph-theoretic method for multi-surface multi-field co-segmentation of intraretinal layers, assuring consistent segmentation of the fields across the overlapped areas. After 2-D en-face alignment, all the fields are segmented simultaneously, imposing a priori soft interfield-intrasurface constraints for each pair of overlapping fields. The constraints penalize deviations from the expected surface height differences, taken to be the depth-axis shifts that produce the maximum cross-correlation of pairwise-overlapped areas. The method's accuracy and reproducibility are evaluated qualitatively and quantitatively on 212 OCT images (20 nine-field, 32 single-field acquisitions) from 26 patients with glaucoma. Qualitatively, the obtained thickness maps show no stitching artifacts, compared to pronounced stitches when the fields are segmented independently. Quantitatively, two ophthalmologists manually traced four intraretinal layers on 10 patients, and the average error ( 4.58 +/-1.46 MUm) was comparable to the average difference between the observers ( 5.86+/-1.72 MUm). Furthermore, we show the benefit of the proposed approach in co-segmenting longitudinal scans. As opposed to segmenting layers in each of the fields independently, the proposed co-segmentation method obtains consistent segmentations across the overlapped areas, producing accurate, reproducible, and artifact-free results. PMID- 25020066 TI - External vibration multi-directional ultrasound shearwave elastography (EVMUSE): application in liver fibrosis staging. AB - Shear wave speed can be used to assess tissue elasticity, which is associated with tissue health. Ultrasound shear wave elastography techniques based on measuring the propagation speed of the shear waves induced by acoustic radiation force are becoming promising alternatives to biopsy in liver fibrosis staging. However, shear waves generated by such methods are typically very weak. Therefore, the penetration may become problematic, especially for overweight or obese patients. In this study, we developed a new method called external vibration multi-directional ultrasound shearwave elastography (EVMUSE), in which external vibration from a loudspeaker was used to generate a multi-directional shear wave field. A directional filter was then applied to separate the complex shear wave field into several shear wave fields propagating in different directions. A 2-D shear wave speed map was reconstructed from each individual shear wave field, and a final 2-D shear wave speed map was constructed by compounding these individual wave speed maps. The method was validated using two homogeneous phantoms and one multi-purpose tissue-mimicking phantom. Ten patients undergoing liver magnetic resonance elastography (MRE) were also studied with EVMUSE to compare results between the two methods. Phantom results showed EVMUSE was able to quantify tissue elasticity accurately with good penetration. In vivo EVMUSE results were well correlated with MRE results, indicating the promise of using EVMUSE for liver fibrosis staging. PMID- 25020068 TI - In silico modeling of magnetic resonance flow imaging in complex vascular networks. AB - The paper presents a computational model of magnetic resonance (MR) flow imaging. The model consists of three components. The first component is used to generate complex vascular structures, while the second one provides blood flow characteristics in the generated vascular structures by the lattice Boltzmann method. The third component makes use of the generated vascular structures and flow characteristics to simulate MR flow imaging. To meet computational demands, parallel algorithms are applied in all the components. The proposed approach is verified in three stages. In the first stage, experimental validation is performed by an in vitro phantom. Then, the simulation possibilities of the model are shown. Flow and MR flow imaging in complex vascular structures are presented and evaluated. Finally, the computational performance is tested. Results show that the model is able to reproduce flow behavior in large vascular networks in a relatively short time. Moreover, simulated MR flow images are in accordance with the theoretical considerations and experimental images. The proposed approach is the first such an integrative solution in literature. Moreover, compared to previous works on flow and MR flow imaging, this approach distinguishes itself by its computational efficiency. Such a connection of anatomy, physiology and image formation in a single computer tool could provide an in silico solution to improving our understanding of the processes involved, either considered together or separately. PMID- 25020069 TI - A generic approach to pathological lung segmentation. AB - In this study, we propose a novel pathological lung segmentation method that takes into account neighbor prior constraints and a novel pathology recognition system. Our proposed framework has two stages; during stage one, we adapted the fuzzy connectedness (FC) image segmentation algorithm to perform initial lung parenchyma extraction. In parallel, we estimate the lung volume using rib-cage information without explicitly delineating lungs. This rudimentary, but intelligent lung volume estimation system allows comparison of volume differences between rib cage and FC based lung volume measurements. Significant volume difference indicates the presence of pathology, which invokes the second stage of the proposed framework for the refinement of segmented lung. In stage two, texture-based features are utilized to detect abnormal imaging patterns (consolidations, ground glass, interstitial thickening, tree-inbud, honeycombing, nodules, and micro-nodules) that might have been missed during the first stage of the algorithm. This refinement stage is further completed by a novel neighboring anatomy-guided segmentation approach to include abnormalities with weak textures, and pleura regions. We evaluated the accuracy and efficiency of the proposed method on more than 400 CT scans with the presence of a wide spectrum of abnormalities. To our best of knowledge, this is the first study to evaluate all abnormal imaging patterns in a single segmentation framework. The quantitative results show that our pathological lung segmentation method improves on current standards because of its high sensitivity and specificity and may have considerable potential to enhance the performance of routine clinical tasks. PMID- 25020070 TI - Normal mesenteric lymph ameliorates acute kidney injury following lipopolysaccharide challenge in mice. AB - BACKGROUND: The kidney is one of the prior damaged organs subjected to severe infection and sepsis shock. Our previous studies have shown that the normal mesenteric lymph (NML) obtained from healthy dogs could alleviate multiple organ injuries following endotoxic shock. In the current study, we further investigated the beneficial effect of NML from healthy mice on acute kidney injury (AKI) induced by lipopolysaccharide (LPS) in mice. METHODS: The mice in LPS and LPS + NML groups received an intraperitoneal injection of LPS (35 mg/kg). One hour later, the treatment of NML was performed and kept for 6 h. Then, the renal function indices, renal morphology, the levels of phosphorylation mitogen activated protein kinases (MAPKs), markers of sensitization to LPS, as well as pro-inflammatory mediators in renal tissue were observed. RESULTS: Intraperitoneal injection of LPS induced an increased level of urea in plasma, lipopolysaccharide-binding protein (LBP), cluster of differentiation 14 (CD14), tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), but no obvious changes in the MAPKs in renal tissue. NML treatment decreased the levels of urea, CD14, TNF-alpha and IL-6 in mice after LPS injection. CONCLUSION: The current results indicate that NML alleviates LPS-induced AKI through its attenuation of sensitization to LPS. PMID- 25020071 TI - Outlining the scope of behavioral health practice in integrated primary care: dispelling the myth of the one-trick mental health pony. AB - Patient presentation in primary care ranges from psychosocial considerations to physical and mental health concerns including serious mental illness. To best prepare for addressing all aspects of health, integrated primary care practices should be equipped with the expertise and resources to appropriately treat the range of presentations. We conducted a literature review of research articles to determine the span of service types provided by behavioral health providers in primary care settings. Among 675 articles retrieved, only 17 addressed health behaviors, 64 examined both health behaviors and mental health, and 160 included only mental health topics. Within these groups, depression was the dominant screening, assessment, and treatment target, and only 42% of all studies included Method and Results sections. Literature supports that integrating behavioral health providers and services into primary care settings benefits patients, primary care providers, and the practice at large, resulting in improved care experiences. However, primary care practices appear to not use the full range of services behavioral health providers can offer. Increased health policy efforts and payment reform are needed to enable a more expansive view of what behavioral health providers could do in a primary care context. PMID- 25020072 TI - Atomoxetine-induced mania with auditory hallucination in an 8-year-old boy with attention-deficit/hyperactivity disorder and tic disorder. PMID- 25020073 TI - Identification of antitumor lignans from the seeds of morning glory (Pharbitis nil). AB - In the search for antitumor compounds from Korean natural resources, activity guided fractionation and purification processes were used on seeds of morning glory (Pharbitis nil). Air-dried P. nil seeds were extracted with ethanol and separated into n-hexane, chloroform, ethyl acetate, and n-butanol. Four new lignans, pharbilignans A-D (1-4) were isolated from the most active ethyl acetate fraction of the ethanol extract. Their structures were characterized on the basis of spectroscopic methods, including one- and two-dimensional nuclear magnetic resonance (NMR) techniques, high resolution mass spectrometry (HRMS), and circular dichroism (CD) spectroscopy. The cytotoxic activities of the isolates (1 4) were evaluated by determining their inhibitory effects on four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15) using a sulforhodamine B (SRB) bioassay. Pharbilignan C (3) showed potent cytotoxicity against A549, SK-OV-3, SK MEL-2, and HCT-15 cell lines with IC50 values of 1.42, 0.16, 0.20, and 0.14 MUM, respectively. On the basis of the expanded understanding that inflammation is a crucial cause in tumor progress, we also evaluated anti-inflammatory activity of the isolates (1-4). Pharbilignan C (3) strongly inhibited nitric oxide (NO) production in the lipopolysaccharide (LPS)-activated BV-2 microglia cell line with an IC50 value of 12.8 MUM. PMID- 25020075 TI - Coherent anti-Stokes Raman scattering with single-molecule sensitivity using a plasmonic Fano resonance. AB - Plasmonic nanostructures are of particular interest as substrates for the spectroscopic detection and identification of individual molecules. Single molecule sensitivity Raman detection has been achieved by combining resonant molecular excitation with large electromagnetic field enhancements experienced by a molecule associated with an interparticle junction. Detection of molecules with extremely small Raman cross-sections (~10(-30) cm(2) sr(-1)), however, has remained elusive. Here we show that coherent anti-Stokes Raman spectroscopy (CARS), a nonlinear spectroscopy of great utility and potential for molecular sensing, can be used to obtain single-molecule detection sensitivity, by exploiting the unique light harvesting properties of plasmonic Fano resonances. The CARS signal is enhanced by ~11 orders of magnitude relative to spontaneous Raman scattering, enabling the detection of single molecules, which is verified using a statistically rigorous bi-analyte method. This approach combines unprecedented single-molecule spectral sensitivity with plasmonic substrates that can be fabricated using top-down lithographic strategies. PMID- 25020076 TI - Detoxified pneumolysin derivative Plym2 directly protects against pneumococcal infection via induction of inflammatory cytokines. AB - Streptococcus pneumoniae is a major cause of infectious disease and complications worldwide, such as pneumonia, otitis media, bacteremia and meningitis. New generation protein-based pneumococcal vaccines are recognized as alternative vaccine candidates. Pneumolysin (Ply) is a cholesterol-dependent cytolysin produced by all clinical isolates of S. pneumoniae. Our research group previously developed a highly detoxified Ply mutant designated Plym2 by replacement of two animo acids (C428G and W433F). Exhibiting undetectable levels of cytotoxicity, Plym2 could still elicit high titer neutralizing antibodies against the native toxin. However, evaluation of the active immunoprotective effects of Plym2 by subcutaneous immunization and lethal challenge with S. pneumoniae in mice did not yield favorable results. In the present work, we confirmed the previous observations by using passive immunization and systemic challenge. Results of the passive immunization were consistent with those of active immunization. Further experiments were conducted to explain the inability of high titer neutralizing antibodies against Ply to protect mice from S. pneumoniae challenge. Pneumococcal Ply is known to be the major factor responsible for the induction of inflammation that benefits the host. Proinflammatory cytokines facilitate the clearance of invaders by the recruitment and activation of leukocytes at the early infection stage. We demonstrated that Plym2 could induce proinflammatory cytokines similarly to wild-type Ply. A systemic infection model was used to clarify that Plym2 lacking cytolytic activity could protect mice from intraperitoneal challenge directly, while antibodies to the mutant had no effect. Therefore, the protective function of Plym2 may be due to its induction of proinflammatory cytokines. When used in the systemic infection model, Plym2 antibodies may block the induction of proinflammatory cytokines by Ply. These findings demonstrate that a Ply-based vaccine would not be an effective primary vaccine component, but it may be beneficial as an adjuvant to stimulate cytokine production. PMID- 25020077 TI - A novel adjuvant, the mixture of alum and naltrexone, augments vaccine-induced immunity against Plasmodium berghei. AB - We previously showed that the mixture of naltrexone (NLT), a general opioid antagonist, and alum, acts as an effective adjuvant in enhancing vaccine-induced T helper 1 (TH1) humoral immune responses against Toxoplasma gondii. Here, we tested the efficacy of the mixture of NLT and alum in the induction of immunity in response to blood stages of Plasmodium berghei (BSPb) as a model vaccine. BALB/c mice were divided into five vaccination groups. Mice in the experimental groups received the BSPb vaccine alone or in combination with the adjuvant alum, NLT or the alum-NLT mixture. Mice in the control group received PBS. All mice were immunized on days 0, 7 and 14. Two weeks after the last immunization, immune responses to Plasmodium berghei were assessed. Our results indicated that including the alum-NLT mixture as an adjuvant during vaccination increased the ability of the BSPb vaccine to enhance lymphocyte proliferation, shifted the immune response towards a TH1 profile and increased Plasmodium berghei-specific IgG2a. This resulted in improved protective immunity against Plasmodium berghei. In conclusion, administering alum-NLT mixture in combination with the BSPb vaccine enhanced the vaccine-induced immunity, and shifted the immune response toward TH1 pattern. PMID- 25020078 TI - Editorial. PMID- 25020079 TI - Novel evidence that attributing affectively salient signal to random noise is associated with psychosis. AB - We wished to replicate evidence that an experimental paradigm of speech illusions is associated with psychotic experiences. Fifty-four patients with a first episode of psychosis (FEP) and 150 healthy subjects were examined in an experimental paradigm assessing the presence of speech illusion in neutral white noise. Socio-demographic, cognitive function and family history data were collected. The Positive and Negative Syndrome Scale (PANSS) was administered in the patient group and the Structured Interview for Schizotypy-Revised (SIS-R), and the Community Assessment of Psychic Experiences (CAPE) in the control group. Patients had a much higher rate of speech illusions (33.3% versus 8.7%, ORadjusted: 5.1, 95% CI: 2.3-11.5), which was only partly explained by differences in IQ (ORadjusted: 3.4, 95% CI: 1.4-8.3). Differences were particularly marked for signals in random noise that were perceived as affectively salient (ORadjusted: 9.7, 95% CI: 1.8-53.9). Speech illusion tended to be associated with positive symptoms in patients (ORadjusted: 3.3, 95% CI: 0.9 11.6), particularly affectively salient illusions (ORadjusted: 8.3, 95% CI: 0.7 100.3). In controls, speech illusions were not associated with positive schizotypy (ORadjusted: 1.1, 95% CI: 0.3-3.4) or self-reported psychotic experiences (ORadjusted: 1.4, 95% CI: 0.4-4.6). Experimental paradigms indexing the tendency to detect affectively salient signals in noise may be used to identify liability to psychosis. PMID- 25020080 TI - Extraction of palm tree cellulose and its functionalization via graft copolymerization. AB - The work in this paper was planned with the aim of extracting the cellulosic component of palm tree waste and functionalizing this cellulose through graft copolymerization with acrylic acid. The cellulose extraction included hot alkali treatment with aqueous sodium hydroxide to remove the non-cellulosic binding materials. The alkali treatment was followed by an oxidative bleaching using peracid/hydrogen peroxide mixture with the aim of removing the rest of non cellulosic materials to improve the fiber hydrophilicity and accessibility towards further grafting reaction. Optimum conditions for cellulose extraction are boiling in 5% (W/V) NaOH in a material to liquor ratio of 1:20 for 1 h then bleaching with 60 ml/l bleaching mixture at initial pH value of 6.5 for 30 min. The pH of the bleaching medium is turned to the alkaline range 11 and bleaching continues for extra 30 min. Graft copolymerization reaction was initiated by potassium bromate/thiourea dioxide redox system. Optimum conditions for grafting are 30 mmol of potassium bromate, 30 mmol of thiourea dioxide and 150 g of acrylic acid (each per 100 g of cellulose). The polymerization reaction was carried out for 120 min at 50 degrees C using a material to liquor ratio of 1:20. PMID- 25020081 TI - The atmospheric and room-temperature plasma (ARTP) method on the dextranase activity and structure. AB - A novel atmospheric and room-temperature plasma (ARTP) method was used to breed high-yielding mutations of Arthrobacter KQ11. Mutagenesis produced two mutations, 4-1 and 4-13, which increased enzyme activity by 19 and 30%, respectively. Dents on the cell envelope were observed under scanning electron microscopy (SEM). The optimal temperature and pH of the wild strain were 45 degrees C and 5.5 and those of the mutant strains were 45 degrees C, pH 6.0 (4-1) and 50 degrees C, pH 6.0 (4 13). Under optimal enzyme production conditions of the wild and mutant strains, the dextranase activity of 4-13 was 50% higher than that of the wild strain. Through amino acid alignment, several nucleotides of the mutant strains were found to have changed. Experiments performed in vitro suggested that this endo dextranase may inhibit biofilm formation by Streptococcus mutans. PMID- 25020082 TI - Alginate composites for bone tissue engineering: a review. AB - Bone is a complex and hierarchical tissue consisting of nano hydroxyapatite and collagen as major portion. Several attempts have been made to prepare the artificial bone so as to replace the autograft and allograft treatment. Tissue engineering is a promising approach to solve the several issues and is also useful in the construction of artificial bone with materials including polymer, ceramics, metals, cells and growth factors. Composites consisting of polymer ceramics, best mimic the natural functions of bone. Alginate, an anionic polymer owing enormous biomedical applications, is gaining importance particularly in bone tissue engineering due to its biocompatibility and gel forming properties. Several composites such as alginate-polymer (PLGA, PEG and chitosan), alginate protein (collagen and gelatin), alginate-ceramic, alginate-bioglass, alginate biosilica, alginate-bone morphogenetic protein-2 and RGD peptides composite have been investigated till date. These alginate composites show enhanced biochemical significance in terms of porosity, mechanical strength, cell adhesion, biocompatibility, cell proliferation, alkaline phosphatase increase, excellent mineralization and osteogenic differentiation. Hence, alginate based composite biomaterials will be promising for bone tissue regeneration. This review will provide a broad overview of alginate preparation and its applications towards bone tissue engineering. PMID- 25020083 TI - A novel method for the determination of the degree of deacetylation of chitosan by coulometric titration. AB - A novel method to determine the degree of deacetylation of chitosan is described. In this method, the coulometric titrant OH- is generated by the electrolysis of water. The OH- reacted with the residual hydrochloric acid in chitosan solution and the degree of deacetylation was obtained by Faraday's law. The optimized experimental parameters in this study were 1.0 mol/L KCl as supporting electrolyte, 15.00 mA as the intensity of constant current, composite glass electrode as indicating electrode couples, double platinum generated electrode platinum wire auxiliary electrode as working electrode pairs, pH 3.80 as the titration end-point. The degree of deacetylation in the four samples, which varied from 70 to 95% were measured. The results were similar to those from 1H NMR and the standard deviations were lower than 0.5%. With merit of simplicity, convenience, quickness, high accuracy and precision, automatic detection of titration end-point and low-cost, the proposed method will be very useful in the industrial production. PMID- 25020084 TI - Effect of poly(E-caprolactone-co-L-lactide) on thermal and functional properties of poly(L-lactide). AB - A blend of poly(L-lactide) (PLLA) with star-shaped poly(E-caprolactone-co-L lactide) (s-PCLA) at different contents (PLLA/s-PCLA=100/0, 90/10, 80/20, and 70/30, w/w) were prepared by torque rheometer. Thermal and functional properties of the blends were investigated by FTIR, SEM, DSC, TGA, DMA, tensile, optical, and water vapor permeability tests. FTIR results showed that intermolecular hydrogen bonds existed between two components in the blends. SEM indicated that PLLA and s-PCLA showed limited miscibility. DSC showed that Tg occurred at lower temperatures in the PLLA/s-PCLA blends than in neat PLLA, and the crystallinity of PLLA phase increased by the presence of s-PCLA in the PLLA/s-PCLA blends. TGA indicated that s-PCLA improved the thermal stability of the PLLA/s-PCLA blends. DMA results revealed that the storage modulus of the composites decreased with respect to the pure polymer. The result of tensile tests suggested that the PLLA/s-PCLA blends showed better elongation at break than neat PLLA. The effect of s-PCLA on the color and opacity of films could be considered as negligible. The WVP of PLLA/s-PCLA blend films increased with the increase in s-PCLA, and they were still lower than that of commercial LDPE films. PMID- 25020085 TI - Minimally invasive insufflation technique is and should not be a "black box" principle. PMID- 25020086 TI - The accuracy of surgeons' provided estimates for the duration of hysterectomies: a pilot study. AB - STUDY OBJECTIVE: To determine the accuracy of gynecologic surgeons' estimate of operative times for hysterectomies and to compare these with the existing computer-generated estimate at our institution. DESIGN: Pilot prospective cohort study (Canadian Task Force classification II-2). SETTING: Academic tertiary women's hospital in the Northeast United States. PARTICIPANTS: Thirty gynecologic surgeons including 23 general gynecologists, 4 gynecologic oncologists, and 3 urogynecologists. INTERVENTION: Via a 6-question survey, surgeons were asked to predict the operative time for a hysterectomy they were about to perform. The surgeons' predictions were then compared with the time predicted by the scheduling system at our institution and with the actual operative time, to determine accuracy and differences between actual and predicted times. Patient and surgery data were collected to perform a secondary analysis to determine factors that may have significantly affected the prediction. MEASUREMENTS AND MAIN RESULTS: Of 75 hysterectomies analyzed, 36 were performed abdominally, 18 vaginally, and 21 laparoscopically. Accuracy was established if the actual procedure time was within the 15-minute increment predicted by either the surgeons or the scheduling system. The surgeons accurately predicted the duration of 20 hysterectomies (26.7%), whereas the accuracy of the scheduling system was only 9.3%. The scheduling system accuracy was significantly less precise than the surgeons, primarily due to overestimation (p = .01); operative time was overestimated on average 34 minutes. The scheduling system overestimated the time required to a greater extent than the surgeons for nearly all data examined, including patient body mass index, surgical approach, indication for surgery, surgeon experience, uterine size, and previous abdominal surgery. CONCLUSION: Although surgeons' accuracy in predicting operative time was poor, it was significantly better than that of the computerized scheduling system, which was more likely to overestimate operative time. PMID- 25020087 TI - Trends in reported resident surgical experience in hysterectomy. PMID- 25020088 TI - The role of microneedles for drug and vaccine delivery. AB - INTRODUCTION: Transdermal drug delivery offers a number of advantages for the patient, not only due to its non-invasive and convenient nature, but also due to factors such as avoidance of first-pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedles (MNs) can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum, and creating a pathway for drug permeation to the dermal tissue below. AREAS COVERED: MNs have been extensively investigated for drug and vaccine delivery. The different types of MN arrays and their delivery capabilities are discussed in terms of drugs, including biopharmaceutics and vaccines. Patient usage and effects on the skin are also considered. EXPERT OPINION: MN research and development is now at the stage where commercialisation is a viable possibility. There are a number of long term safety questions relating to patient usage which will need to be addressed moving forward. Regulatory guidance is awaited to direct the scale-up of the manufacturing process alongside provision of clearer patient instruction for safe and effective use of MN devices. PMID- 25020090 TI - Shape vocabulary: a robust and efficient shape representation for shape matching. AB - In this paper, a learning-based shape descriptor for shape matching is demonstrated. Formulated in a bag-of-words like framework, the proposed method summarizes the local features extracted from certain shape to generate a integrated representation. It contributes to the speed-up of shape matching, since the distance metric in the vector space analysis can be directly applied to compare the constructed global descriptors, eliminating the time consuming stage of local feature matching. Similar to the philosophy in spatial pyramid matching, a strategy for feature division is applied in the phase of encoded feature pooling and vocabulary learning, which helps to construct a more discriminative descriptor incorporating both global and local information. Also, a local contour based feature extraction method is designed for 2D shapes, while significant properties of the local contours are inspected for the design of feature division rules. The designed local feature extraction method and the feature division rules manage to reduce the variances of shape representation due to the changes in rotation. In addition to 2D shape, we also present a simple and natural method to extend the proposed method to the scenario of 3D shape representation. The proposed shape descriptor is validated on several benchmark data sets for evaluating 2D and 3D shape matching algorithms, and it is observed that the investigated shape descriptor maintains superior discriminative power as well as high time efficiency. PMID- 25020089 TI - Efficacy of auriculotherapy for constipation in adults: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: To assess the clinical evidence of auriculotherapy for constipation treatment and to identify the efficacy of groups using Semen vaccariae or magnetic pellets as taped objects in managing constipation. METHODS: Databases were searched, including five English-language databases (the Cochrane Library, PubMed, Embase, CINAHL, and AMED) and four Chinese medical databases. Only randomized controlled trials were included in the review process. Critical appraisal was conducted using the Cochrane risk of bias tool. RESULTS: Seventeen randomized, controlled trials (RCTs) met the inclusion criteria, of which 2 had low risk of bias. The primary outcome measures were the improvement rate and total effective rate. A meta-analysis of 15 RCTs showed a moderate, significant effect of auriculotherapy in managing constipation compared with controls (relative risk [RR], 2.06; 95% confidence interval [CI], 1.52- 2.79; p<0.00001). The 15 RCTs also showed a moderate, significant effect of auriculotherapy in relieving constipation (RR, 1.28; 95% CI, 1.13-1.44; p<0.0001). For other symptoms associated with constipation, such as abdominal distension or anorexia, results of the meta-analyses showed no statistical significance. Subgroup analysis revealed that use of S. vaccariae and use of magnetic pellets were both statistically favored over the control in relieving constipation. CONCLUSIONS: Current evidence illustrated that auriculotherapy, a relatively safe strategy, is probably beneficial in managing constipation. However, most of the eligible RCTs had a high risk of bias, and all were conducted in China. No definitive conclusion can be made because of cultural and geographic differences. Further rigorous RCTs from around the world are warranted to confirm the effect and safety of auriculotherapy for constipation. PMID- 25020091 TI - Passive Synthetic Aperture Hitchhiker Imaging of Ground Moving Targets - Part 2: Performance Analysis. AB - In Part 1 of this work, we present a passive synthetic aperture imaging and velocity estimation method for ground moving targets using a network of passive receivers. The method involves inversion of a Radon transform type forward model via a novel filtered backprojection approach combined with entropy optimization. The method is applicable to noncooperative transmitters of opportunity where the transmitter locations and transmitted waveforms are unknown. Furthermore, it can image multiple targets moving at different velocities in arbitrary imaging geometries. In this paper, we present a detailed analysis of the performance of our method. First the resolution analysis in position and velocity spaces is presented. The analysis identifies several factors that contribute positively or negativity towards position and velocity resolution. Next, we present a novel theory to analyze and predict smearing artifacts in position images due to error in velocity estimation of moving targets. Specifically, we show that small errors in the velocity estimation result in small positioning errors. We present extensive numerical simulations to demonstrate the theoretical results. While our primary interest lies in radar, the theory, methods and algorithms introduced in our work are also applicable to passive acoustic, seismic, and microwave imaging. PMID- 25020092 TI - Spatio-temporal video segmentation with shape growth or shrinkage constraint. AB - We propose a new method for joint segmentation of monotonously growing or shrinking shapes in a time sequence of noisy images. The task of segmenting the image time series is expressed as an optimization problem using the spatio temporal graph of pixels, in which we are able to impose the constraint of shape growth or of shrinkage by introducing monodirectional infinite links connecting pixels at the same spatial locations in successive image frames. The globally optimal solution is computed with a graph cut. The performance of the proposed method is validated on three applications: segmentation of melting sea ice floes and of growing burned areas from time series of 2D satellite images, and segmentation of a growing brain tumor from sequences of 3D medical scans. In the latter application, we impose an additional intersequences inclusion constraint by adding directed infinite links between pixels of dependent image structures. PMID- 25020093 TI - Bi-modal Non-rigid Registration of Brain MRI Data with Deconvolution of Joint Statistics. AB - A brain MRI protocol typically includes several imaging contrasts that can provide complementary information by highlighting different tissue properties. The acquired datasets often need to be co-registered or placed in a standard anatomic space before any further processing. Current registration methods particularly for multicontrast data are computationally very intensive, their resolution is lower than that of the images, and their distance metric and its optimization can be limiting. In this work a novel and effective non-rigid registration method is proposed that is based on the restoration of the joint statistics of pairs of such images. The registration is performed with the deconvolution of the joint statistics with an adaptive Wiener filter. The deconvolved statistics are forced back to the spatial domain to estimate a preliminary registration. The spatial transformation is also regularized with Gaussian spatial smoothing. The registration method has been compared with the B Splines method implemented in 3DSlicer and with the SyN method implemented in the ANTs toolkit. The validation has been performed with a simulated Shepp-Logan phantom, a BrainWeb phantom, the real data of the NIREP database, and real multi contrast datasets of healthy volunteers. The proposed method has shown improved comparative accuracy as well as analytical efficiency. PMID- 25020094 TI - Robust optical flow integration. AB - We analyze the problem of how to correctly construct dense point trajectories from optical flow fields. First, we show that simple Euler integration is unavoidably inaccurate, no matter how good is the optical flow estimator. Then, an inverse integration scheme is analyzed which is more robust to bias and input noise and shows better stability properties. Our contribution is threefold: 1) a theoretical analysis that demonstrates why and in what sense inverse integration is more accurate; 2) a rich experimental validation both on synthetic and real (image) data; and 3) an algorithm for approximate online inverse integration. This new technique is precious whether one is trying to propagate information densely available on a reference frame to the other frames in the sequence or, conversely, to assign information densely over each frame by pulling it from the reference. PMID- 25020095 TI - Partial difference operators on weighted graphs for image processing on surfaces and point clouds. AB - Partial difference equations (PDEs) and variational methods for image processing on Euclidean domains spaces are very well established because they permit to solve a large range of real computer vision problems. With the recent advent of many 3D sensors, there is a growing interest in transposing and solving PDEs on surfaces and point clouds. In this paper, we propose a simple method to solve such PDEs using the framework of PDEs on graphs. This latter approach enables us to transcribe, for surfaces and point clouds, many models and algorithms designed for image processing. To illustrate our proposal, three problems are considered: (1) p -Laplacian restoration and inpainting; (2) PDEs mathematical morphology; and (3) active contours segmentation. PMID- 25020096 TI - lambda domain rate control algorithm for high efficiency video coding. AB - Rate control is a useful tool for video coding, especially in real-time communication applications. Most of existing rate control algorithms are based on the R-Q model, which characterizes the relationship between bitrate R and quantization Q , under the assumption that Q is the critical factor on rate control. However, with the video coding schemes becoming more and more flexible, it is very difficult to accurately model the R-Q relationship. In fact, we find that there exists a more robust correspondence between R and the Lagrange multiplier lambda . Therefore, in this paper, we propose a novel lambda -domain rate control algorithm based on the R-lambda model, and implement it in the newest video coding standard high efficiency video coding (HEVC). Experimental results show that the proposed lambda -domain rate control can achieve the target bitrates more accurately than the original rate control algorithm in the HEVC reference software as well as obtain significant R-D performance gain. Thanks to the high accurate rate control algorithm, hierarchical bit allocation can be enabled in the implemented video coding scheme, which can bring additional R-D performance gain. Experimental results demonstrate that the proposed lambda domain rate control algorithm is effective for HEVC, which outperforms the R-Q model based rate control in HM-8.0 (HEVC reference software) by 0.55 dB on average and up to 1.81 dB for low delay coding structure, and 1.08 dB on average and up to 3.77 dB for random access coding structure. The proposed lambda -domain rate control algorithm has already been adopted by Joint Collaborative Team on Video Coding and integrated into the HEVC reference software. PMID- 25020097 TI - A comparative review of component tree computation algorithms. AB - Connected operators are morphological tools that have the property of filtering images without creating new contours and without moving the contours that are preserved. Those operators are related to the max-tree and min-tree representations of images, and many algorithms have been proposed to compute those trees. However, no exhaustive comparison of these algorithms has been proposed so far, and the choice of an algorithm over another depends on many parameters. Since the need for fast algorithms is obvious for production code, we present an in-depth comparison of the existing algorithms in a unique framework, as well as variations of some of them that improve their efficiency. This comparison involves both sequential and parallel algorithms, and execution times are given with respect to the number of threads, the input image size, and the pixel value quantization. Eventually, a decision tree is given to help the user choose the most appropriate algorithm with respect to the user requirements. To favor reproducible research, an online demo allows the user to upload an image and bench the different algorithms, and the source code of every algorithms has been made available. PMID- 25020098 TI - A mini-review on the impacts of climate change on wastewater reclamation and reuse. AB - To tackle current water insecurity concerns, wastewater reclamation and reuse have appeared as a promising candidate to conserve the valuable fresh water sources while increasing the efficiency of material utilization. Climate change, nevertheless, poses both opportunities and threats to the wastewater reclamation industry. Whereas it elevates the social perception on water-related issues and fosters an emerging water-reuse market, climate change simultaneously presents adverse impacts on the water reclamation scheme, either directly or indirectly. These effects were studied fragmentally in separate realms. Hence, this paper aims to link these studies for providing a thorough understanding about the consequences of the climate change on the wastewater reclamation and reuse. It initially summarizes contemporary treatment processes and their reuse purposes before carrying out a systematic analysis of available findings. PMID- 25020100 TI - Pretransplantation therapy with hypomethylating agents in patients with myelodysplastic syndromes receiving reduced-intensity conditioning regimens. PMID- 25020099 TI - Persistent toxic substances in Mediterranean aquatic species. AB - Fish and fishery products may represent one of the main sources of dietary exposure to persistent toxic substances (PTSs) such as polychlorinated dibenzodioxins, dibenzofurans, and biphenyls; polybromodiphenyl ethers; organochlorine pesticides; perfluorooctanoic acid and perfluorooctane sulfonate; and inorganic mercury and methyl mercury. In this study, PTS contamination of Mediterranean fish and crustaceans caught in Italian coastal waters was investigated in order to increase the representativeness of the occurrence database for wild species. The objectives were to verify the suitability of regulatory limits for PTSs, identify background concentrations values, if any, and examine the possible sources of variability when assessing the chemical body burdens of aquatic species. Twelve wild species of commercial interest and two farmed fish species were chosen. Excluding methyl mercury, chemical concentrations found in wild species fell generally towards the low ends of the concentration ranges found in Europe according to EFSA database and were quite lower than the tolerable maximum levels established in the European Union; farmed fish always showed contamination levels quite lower than those detected in wild species. The data obtained for wild species seemed to confirm the absence of local sources of contamination in the chosen sampling areas; however, species contamination could exceed regulatory levels even in the absence of specific local sources of contamination as a result of the position in the food web and natural variability in species' lifestyle. A species-specific approach to the management of contamination in aquatic organisms is therefore suggested as an alternative to a general approach based only on contaminant body burden. A chemical-specific analysis performed according to organism position in the food chain strengthened the need to develop this approach. PMID- 25020102 TI - Optimal benefits for hematopoietic stem cell transplantation: a consensus opinion. AB - Variability in transplantation benefits may directly affect outcomes of individuals undergoing autologous or allogeneic hematopoietic stem cell transplantation procedures. The Financial Working Group of the National Marrow Donor Program-sponsored System Capacity Initiative addressed the issue of variable benefits and reviewed multiple transplantation benefit packages from both public and private payer organizations. On completion of the review, a consensus was obtained on defining a recipient benefit package that avoids major coverage gaps that could negatively influence patient outcomes. The recommendation was to encourage adoption of these benefits at a national level by payers, benefit brokers/consultants, and sales teams. PMID- 25020101 TI - Bacterial foodborne infections after hematopoietic cell transplantation. AB - Diarrhea, abdominal pain, and fever are common among patients undergoing hematopoietic cell transplantation (HCT), but such symptoms are also typical with foodborne infections. The burden of disease caused by foodborne infections in patients undergoing HCT is unknown. We sought to describe bacterial foodborne infection incidence after transplantation within a single-center population of HCT recipients. All HCT recipients who underwent transplantation from 2001 through 2011 at the Fred Hutchinson Cancer Research Center in Seattle, Washington were followed for 1 year after transplantation. Data were collected retrospectively using center databases, which include information from transplantation, on-site examinations, outside records, and collected laboratory data. Patients were considered to have a bacterial foodborne infection if Campylobacter jejuni/coli, Listeria monocytogenes, E. coli O157:H7, Salmonella species, Shigella species, Vibrio species, or Yersinia species were isolated in culture within 1 year after transplantation. Nonfoodborne infections with these agents and patients with pre-existing bacterial foodborne infection (within 30 days of transplantation) were excluded from analyses. A total of 12 of 4069 (.3%) patients developed a bacterial foodborne infection within 1 year after transplantation. Patients with infections had a median age at transplantation of 50.5 years (interquartile range [IQR], 35 to 57), and the majority were adults >=18 years of age (9 of 12 [75%]), male gender (8 of 12 [67%]) and had allogeneic transplantation (8 of 12 [67%]). Infectious episodes occurred at an incidence rate of 1.0 per 100,000 patient-days (95% confidence interval, .5 to 1.7) and at a median of 50.5 days after transplantation (IQR, 26 to 58.5). The most frequent pathogen detected was C. jejuni/coli (5 of 12 [42%]) followed by Yersinia (3 of 12 [25%]), although Salmonella (2 of 12 [17%]) and Listeria (2 of 12 [17%]) showed equal frequencies; no cases of Shigella, Vibrio, or E. coli O157:H7 were detected. Most patients were diagnosed via stool (8 of 12 [67%]), fewer through blood (2 of 12 [17%]), 1 via both stool and blood simultaneously, and 1 through urine. Mortality due to bacterial foodborne infection was not observed during follow-up. Our large single-center study indicates that common bacterial foodborne infections were a rare complication after HCT, and the few cases that did occur resolved without complications. These data provide important baseline incidence for future studies evaluating dietary interventions for HCT patients. PMID- 25020103 TI - Coccidia of turkey: from isolation, characterisation and comparison to molecular phylogeny and molecular diagnostics. AB - Coccidiosis is a disease caused by apicomplexan parasites of the genus Eimeria, which has a significant economic impact on poultry production. Multiple species infecting the turkey have been described; however, due to the general lack of unambiguous description, their identification and taxonomy is debatable. In this work, a systematic approach was taken to isolate, characterise and compare coccidian species in the turkey. Individual species were tracked according to their unique 18S ribosomal DNA sequence. The single-oocyst isolation technique and passaging of mixed species field isolates in selectively immunised birds enabled the derivation of pure species. Six distinct strains representing five eimerian species that infect the turkey were obtained. It appears highly probable that these species represent all species described in the past with the exception of Eimeria subrotunda. The species were analysed using both traditional methods and DNA sequencing. For each strain the oocyst morphology, prepatent period, gross pathology, pathogenicity, host specificity and endogenous cycle were studied. Antigenic similarity was investigated in multiple cross-immunity experiments. For identification and quantification of each individual species or strain, quantitative real-time PCR markers were also developed. Parallel characterisation of pure strains allowed comprehensive comparison with the original descriptions and assignment of correct species names. The species Eimeria meleagridis, Eimeria dispersa, Eimeria gallopavonis, Eimeria meleagrimitis and Eimeria innocua were identified. Comparison of our data with those of previous studies indicates that Eimeria adenoeides is most probably a synonym for either E. meleagridis or E. gallopavonis, or a description based on a mixture of these species, and thus nomen dubium. The species E. dispersa and E. innocua were also found to infect Bobwhite Quail. Phylogenetic reconstruction based on 18S rDNA and cytochrome c oxidase subunit I gene (COI) sequences showed that these two species form a distinct clade unrelated to other turkey coccidia and point to a polyphyletic origin of the species infecting the turkey. PMID- 25020104 TI - The Effect of Pistacia atlantica Var. mutica Mouthwash on Dental Plaque Bacteria and Subgingival Microorganisms: a Randomized and Controlled Triple-blind Study. AB - Dental plaque is a well-documented etiologic factor for periodontal diseases. While chlorhexidine (CHX) is the gold-standard agent for treating dental plaques, undesirable side effects are often found after continuous use of the mouthwash. Therefore, this single-center, randomized, triple-blinded and clinical trial was undertaken to evaluate the efficacy of Pistacia atlantica Var. mutica extract mouthwash on de novo dental plaque bacteria and subgingival microorganisms compared to CHX on a total of 28 patients. The mean aerobic plaque bacterial count of patients at baseline was 2.17 * 10(6). After 4 days of treatment, there were statistically significant decreases in the mean aerobic bacteria in the patients who received P. atlantica and/or CHX (7.25 * 10(4), p = 0.006) and (9.91 * 10(3), p = 0.002), respectively, compared to the patients who received the placebo (6.26 * 10(5)). This study showed that P. atlantica mouthwash is effective against gingival microorganisms. Because of its reduced side effects, P. atlantica mouthwash may be a good alternative choice for patients. PMID- 25020105 TI - Utility of a Liquid Formulation of Levo-thyroxine in Differentiated Thyroid Cancer Patients. AB - The goal of levo-thyroxine (L-T4) administration in differentiated thyroid cancer (DTC) is to suppress thyroid stimulating hormone (TSH) levels. The tolerability and efficacy of a new formulation of liquid L-T4 vs. the previous tablet formulation was evaluated in a cohort of 59 patients with cured DTC. The correlation between breakfast modality and therapy was also monitored. Hormonal and clinical evaluations were performed before and 70 days after patients were switched from tablet to liquid L-T4 formulation, without changes in daily dose. Breakfast habits were evaluated. The interval between L-T4 therapy and breakfast was recorded. Patient approval of L-T4 formulations was evaluated. 8% of patients dropped out owing to adverse events. The modality of L-T4 administration proved adequate under tablet and liquid formulation in 64% and 68% of patients who fully complied with the protocol. While significantly more patients found the tablet formulation more agreeable, at the end of the protocol subjective symptoms had diminished significantly and 73% requested to remain on the liquid formulation. No change in TSH, thyroid hormones or thyroglobulin was noted during the study. A balanced breakfast containing less than 4 g of alimentary fibre did not interfere with L-T4 therapy. Liquid L-T4 seems to be a valid alternative formulation in DTC patients, its initial dislike being outweighed by a significant reduction in subjective symptoms. Both tablet and liquid L-T4 therapy require monitoring over time. A continental breakfast containing less than 4 g of alimentary fibres seems to favour the absorption of L-T4, whether in tablet or liquid formulation. PMID- 25020106 TI - Bradycardia is associated with future cardiovascular diseases and death in men from the general population. AB - BACKGROUND: Although a higher heart rate is known to be a risk factor for cardiovascular disease (CVD) events, there have been no reports concerning bradycardia. Whether lower and higher resting pulse rates (RPRs) are associated with cardiovascular risk was investigated in subjects from a community-based, prospective cohort study. METHODS: After subjects with atrial fibrillation, subjects with a history of CVD, and subjects receiving antihypertensive treatment were excluded, 17,766 subjects (5958 men), aged 40-79 (mean 61.5) years, were analyzed. The RPR at baseline was categorized into four groups (RPR<60, 60-69.5, 70-79.5, >=80 beats per minute (bpm)) using the average value of two consecutive measurements. The endpoint was set as the composite outcome of myocardial infarction, stroke, or sudden death. RESULTS: During a mean follow-up of 5.6 years, there were 213 events in men and 186 events in women. In Cox regression models, increased risks of CVD were found in the men group with RPR<60 bpm, as well as the group with RPR>=80 bpm, compared with the reference group with RPR 60 69.5 bpm (hazard ratio [HR] = 1.73, p = 0.005 and HR = 2.01, p < 0.001). These increased risks were found even when adjusted for age and other CVD risk factors (HR = 1.55, p = 0.026 with RPR<60 bpm and HR = 1.72, p = 0.009 with RPR>=80 bpm). In women, there were no significant associations between RPR and CVD risk. CONCLUSION: Bradycardia, as well as a higher pulse rate, may be an independent risk factor for future cardiovascular events in apparently healthy men. PMID- 25020107 TI - The emerging multiple metal nanostructures for enhancing the light trapping of thin film organic photovoltaic cells. AB - Recently, various metal nanostructures have been introduced into organic solar cells (OSCs) for performance enhancement. Here, we review the recent progress in OSCs incorporated with multiple metal nanostructures including various metal nanopatterns and metal nanomaterials. Multiple physical effects arise from these incorporated nanostructures, which require careful distinction. Changes induced by the metal nanostructures are examined in detail from the optical and electrical aspects. With the comprehensive understanding of the physical mechanisms for various metal nanostructures, further improvement in device performance and emerging applications can be expected for the new class of nanostructure-incorporated OSCs. PMID- 25020109 TI - Hierarchical assembly of plasmonic nanostructures using virus capsid scaffolds on DNA origami templates. AB - Building plasmonic nanostructures using biomolecules as scaffolds has shown great potential for attaining tunable light absorption and emission via precise spatial organization of optical species and antennae. Here we report bottom-up assembly of hierarchical plasmonic nanostructures using DNA origami templates and MS2 virus capsids. These serve as programmable scaffolds that provide molecular level control over the distribution of fluorophores and nanometer-scale control over their distance from a gold nanoparticle antenna. While previous research using DNA origami to assemble plasmonic nanostructures focused on determining the distance-dependent response of single fluorophores, here we address the challenge of constructing hybrid nanostructures that present an organized ensemble of fluorophores and then investigate the plasmonic response. By combining finite difference time-domain numerical simulations with atomic force microscopy and correlated scanning confocal fluorescence microscopy, we find that the use of the scaffold keeps the majority of the fluorophores out of the quenching zone, leading to increased fluorescence intensity and mild levels of enhancement. The results show that the degree of enhancement can be controlled by exploiting capsid scaffolds of different sizes and tuning capsid-AuNP distances. These bioinspired plasmonic nanostructures provide a flexible design for manipulating photonic excitation and photoemission. PMID- 25020108 TI - Effect of chromosome tethering on nuclear organization in yeast. AB - Interphase chromosomes in Saccharomyces cerevisiae are tethered to the nuclear envelope at their telomeres and to the spindle pole body (SPB) at their centromeres. Using a polymer model of yeast chromosomes that includes these interactions, we show theoretically that telomere attachment to the nuclear envelope is a major determinant of gene positioning within the nucleus only for genes within 10 kb of the telomeres. We test this prediction by measuring the distance between the SPB and the silent mating locus (HML) on chromosome III in wild-type and mutant yeast strains that contain altered chromosome-tethering interactions. In wild-type yeast cells we find that disruption of the telomere tether does not dramatically change the position of HML with respect to the SPB, in agreement with theoretical predictions. Alternatively, using a mutant strain with a synthetic tether that localizes an HML-proximal site to the nuclear envelope, we find a significant change in the SPB-HML distance, again as predicted by theory. Our study quantifies the importance of tethering at telomeres on the organization of interphase chromosomes in yeast, which has been shown to play a significant role in determining chromosome function such as gene expression and recombination. PMID- 25020110 TI - Gold(III)-catalyzed glycosidations for 1,2-trans and 1,2-cis furanosides. AB - Stereoselective synthesis of furanosides is still a daunting task, unlike the pyranosides, for which several methods exist. Herein, a unified stereoselective strategy for the synthesis of 1,2-trans and 1,2-cis furanosides is revealed for seven out of eight possible isomers of pentoses. The identified protocol gives access to diastereoselective synthesis of alpha- and beta-araf, ribf, lyxf, and alpha-xylf furanosides. 1,2-trans glycosides were synthesized by the use of propargyl 1,2-orthoesters under gold-catalyzed glycosidation conditions, and subsequently, they are converted into 1,2-cis glycosides through oxidation reduction as the key functional group transformation. All the reactions are found to be fully diastereoselective, mild, and high yielding. PMID- 25020111 TI - A new cobalt-salen catalyst for asymmetric cyclopropanation. Synthesis of the serotonin-norepinephrine repuptake inhibitor (+)-synosutine. AB - A new C2 symmetric cobalt(II)-salen catalyst based on cis-2,5 diaminobicyclo[2.2.2]octane as the chiral scaffold was prepared which, in the presence of potassium thioacetate as the promoter, catalyzed the formation of cyclopropanes from 1,1-disubstituted ethylenes and ethyl diazoacetate in high yield and with excellent diastereo- and enantioselectivity. Asymmetric cyclopropanation with the catalyst was used in a short, efficient synthesis of the dual serotonin-epinephrine reuptake inhibitor (+)-synosutine. PMID- 25020113 TI - Extremely large nuchal translucency measurement predicts adverse pregnancy outcome. AB - A prospective study was conducted to determine the outcome of pregnancies with 1st trimester nuchal translucency measurement of >= 6.5 mm. The risk of fetal abnormalities increases with enlarging nuchal translucency, being around 45% with a measurement of >= 6.5 mm. A total of 27,144 women with singleton pregnancies participated in the combined Down syndrome screening within the public healthcare system in Northern Finland. The study period was 1 May 2002 to 31 May 2009. The nuchal translucency measurement was >= 6.5 mm in 16 cases (0.06%). Pregnancy outcome was normal in one case (6.3%). The risk of abnormality was higher in our study than reported in the literature. According to our study, immediate diagnostic tests should be offered after an nuchal translucency measurement of >= 6.5 mm. We should also consider analysis of fetal micro-deletions associated with certain syndromes. PMID- 25020114 TI - The increasing number of surgical procedures for female genital fistula in England: analysis of Hospital Episode Statistics (HES) data. AB - The aim of this study was to describe the number and trend of surgical procedures for female genital fistula in England. An online search of Hospital Episode Statistics (HES) data was carried out. Data were available for the 4-year period from 2002-03 until 2005-06. The total number of surgical procedures carried out for female genital fistula steadily increased by 28.7% from 616 in 2002-03 to 793 in 2005-06. The number of surgical procedures performed for rectovaginal fistula exceeded the total number of surgical procedures carried out for vesicovaginal and urethrovaginal fistula in each year of the study period. This pattern needs to be monitored and investigated further. PMID- 25020112 TI - Mothers who are securely attached in pregnancy show more attuned infant mirroring 7 months postpartum. AB - This study contrasted two forms of mother-infant mirroring: the mother's imitation of the infant's facial, gestural, or vocal behavior (i.e., "direct mirroring") and the mother's ostensive verbalization of the infant's internal state, marked as distinct from the infant's own experience (i.e., "intention mirroring"). Fifty mothers completed the Adult Attachment Interview (Dynamic Maturational Model) during the third trimester of pregnancy. Mothers returned with their infants 7 months postpartum and completed a modified still-face procedure. While direct mirroring did not distinguish between secure and insecure/dismissing mothers, secure mothers were observed to engage in intention mirroring more than twice as frequently as did insecure/dismissing mothers. Infants of the two mother groups also demonstrated differences, with infants of secure mothers directing their attention toward their mothers at a higher frequency than did infants of insecure/dismissing mothers. The findings underscore marked and ostensive verbalization as a distinguishing feature of secure mothers' well-attuned, affect-mirroring communication with their infants. PMID- 25020115 TI - Rapid recurrence of a corpus luteum cyst after laparoscopic surgery in a young woman with a levonorgestrel releasing coil. PMID- 25020116 TI - Massive lower extremity lymphoedema caused by a giant myoma. PMID- 25020119 TI - Carbonylative enantioselective meso-desymmetrization of cis-epoxides to trans beta-lactones: effect of salen-ligand electronic variation on enantioselectivity. AB - Carbonylation catalysts for the desymmetrization of meso-epoxides yielding enantioenriched trans-beta-lactones are reported. Fine-tuning the electronic properties of the ligand further improved enantioselectivity. The sterics of the substrate dictated whether a given electronic variation decreased or increased enantioenrichment, revealing an unexpected relationship between the substrate's steric environment and the electronic nature of the optimal catalyst. PMID- 25020118 TI - Selective cognitive deficits in adult rats after prenatal exposure to inhaled ethanol. AB - Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by inhalation, the most likely route of exposure from gasoline-ethanol fuel blends. We evaluated the potential cognitive consequences of ethanol inhalation by exposing pregnant Long Evans rats to clean air or ethanol vapor from gestational days 9-20, a critical period of neuronal development. Concentrations of inhaled ethanol (5000, 10,000, or 21,000 ppm for 6.5h/day) produced modeled peak blood ethanol concentrations (BECs) in exposed dams of 2.3, 6.8, and 192 mg/dL, respectively. In offspring, no dose related impairments were observed on spatial learning or working memory in the Morris water maze or in operant delayed match-to-position tests. Two measures showed significant effects in female offspring at all ethanol doses: 1) impaired cue learning after trace fear conditioning, and 2) an absence of bias for the correct quadrant after place training during a reference memory probe in the Morris water maze. In choice reaction time tests, male offspring (females were not tested) from the 5000 and 10,000 ppm groups showed a transient increase in decision times. Also, male offspring from the 21,000 ppm group made more anticipatory responses during a preparatory hold period, suggesting a deficit in response inhibition. The increase in anticipatory responding during the choice reaction time test shows that inhaled ethanol yielding a peak BEC of ~200mg/dL can produce lasting effects in the offspring. The lack of a dose-related decrement in the effects observed in females on cue learning and a reference memory probe may reflect confounding influences in the exposed offspring possibly related to maternal care or altered anxiety levels in females. The surprising lack of more pervasive cognitive deficits, as reported by others at BECs in the 200mg/dL range, may reflect route-dependent differences in the kinetics of ethanol. These data show that response inhibition was impaired in the offspring of pregnant rats that inhaled ethanol at concentrations at least 5 orders of magnitude higher than concentrations observed during normal automotive transport and fueling operations, which rarely exceed 100 ppb. PMID- 25020117 TI - PKC-dependent phosphorylation of eNOS at T495 regulates eNOS coupling and endothelial barrier function in response to G+ -toxins. AB - Gram positive (G+) infections make up ~50% of all acute lung injury cases which are characterized by extensive permeability edema secondary to disruption of endothelial cell (EC) barrier integrity. A primary cause of increased permeability are cholesterol-dependent cytolysins (CDCs) of G+-bacteria, such as pneumolysin (PLY) and listeriolysin-O (LLO) which create plasma membrane pores, promoting Ca2+-influx and activation of PKCalpha. In human lung microvascular endothelial cells (HLMVEC), pretreatment with the nitric oxide synthase (NOS) inhibitor, ETU reduced the ability of LLO to increase microvascular cell permeability suggesting an endothelial nitric oxide synthase (eNOS)-dependent mechanism. LLO stimulated superoxide production from HLMVEC and this was prevented by silencing PKCalpha or NOS inhibition suggesting a link between these pathways. Both LLO and PLY stimulated eNOS T495 phosphorylation in a PKC dependent manner. Expression of a phosphomimetic T495D eNOS (human isoform) resulted in increased superoxide and diminished nitric oxide (NO) production. Transduction of HLMVEC with an active form of PKCalpha resulted in the robust phosphorylation of T495 and increased peroxynitrite production, indicative of eNOS uncoupling. To determine the mechanisms underlying eNOS uncoupling, HLMVEC were stimulated with LLO and the amount of hsp90 and caveolin-1 bound to eNOS determined. LLO stimulated the dissociation of hsp90, and in particular, caveolin 1 from eNOS. Both hsp90 and caveolin-1 have been shown to influence eNOS uncoupling and a peptide mimicking the scaffolding domain of caveolin-1 blocked the ability of PKCalpha to stimulate eNOS-derived superoxide. Collectively, these results suggest that the G+ pore-forming toxins promote increased EC permeability via activation of PKCalpha, phosphorylation of eNOS-T495, loss of hsp90 and caveolin-1 binding which collectively promote eNOS uncoupling and the production of barrier disruptive superoxide. PMID- 25020120 TI - Treatment with a hybrid between the synapsin ABC domains and the B subunit of E. coli heat-labile toxin reduces frequency of proinflammatory cells and cytokines in the central nervous system of rats with EAE. AB - Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are crucially dependent on the invasion of activated autoreactive lymphocytes and blood macrophages into the central nervous system (CNS). Proinflammatory mononuclear cells and activated local microglia mediate inflammation, demyelination and axonal damage at the target organ. Previously, we observed that the administration of a hybrid between the synapsin ABC domains and the B subunit of Escherichia coli heat labile-enterotoxin (LTBABC) to rats with EAE ameliorated disease by modulating the peripheral Th1 response to myelin basic protein (MBP). In the present study, we investigated the effect of LTBABC administration on proinflammatory cell frequency in the CNS of rats with EAE. Treatment with the hybrid in the inductive phase of EAE attenuated disease severity and diminished histological inflammatory infiltrates and demyelination in the spinal cord of rats with acute EAE. Lower frequencies of infiltrating and local macrophages as well as CD4+ T cells that produce the proinflammatory cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-17 were found at the target organ. Concomitantly, low levels of INF-gamma and IL-17 and increased levels of IL-10 were measured in cultures of CNS infiltrating cells and spinal cord tissue. An increased frequency of CD4+CD25+Foxp3 cells was observed at the disease peak and at the beginning of the recovery stage. These results provide further evidence for the immunomodulatory properties of the fusion protein LTBABC in autoimmune demyelinating disease affecting the central nervous system. PMID- 25020122 TI - Do fibromyalgia patients benefit from cognitive restructuring and acceptance? An experimental study. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to clarify mechanisms of psychological fibromyalgia treatment by experimentally examining the effectiveness of its core elements. We assessed the effects of cognitive restructuring and acceptance on experimentally-induced heat and cold pain tolerance and pain intensity in fibromyalgia patients. METHODS: Cold and heat pain were induced in a sample of 60 fibromyalgia patients using a thermode. We conducted ANCOVAs to examine group differences in posttest scores, co-varying for pretest scores. The between-groups factor was the type of instruction provided (acceptance, cognitive restructuring, and a control condition). In addition, we controlled for pain sensitivity, age, and depression. RESULTS: We found that acceptance and cognitive restructuring were superior to the control condition in increasing heat pain tolerance, but did not differ from one another. With respect to cold pain tolerance, cognitive restructuring was associated with increases in cold pain tolerance compared to the control condition, while acceptance did not differ either from the control condition or from cognitive restructuring. LIMITATIONS: Further experimental research on chronic pain treatment mechanisms is needed, particularly research on individually tailoring treatment strategies according to patients characteristics. CONCLUSION: Results show that both, cognitive restructuring and acceptance instructions, enhance pain tolerance in fibromyalgia patients. PMID- 25020121 TI - Bidirectional modulation of deep cerebellar nuclear cells revealed by optogenetic manipulation of inhibitory inputs from Purkinje cells. AB - In the mammalian cerebellum, deep cerebellar nuclear (DCN) cells convey all information from cortical Purkinje cells (PCs) to premotor nuclei and other brain regions. However, how DCN cells integrate inhibitory input from PCs with excitatory inputs from other sources has been difficult to assess, in part due to the large spatial separation between cortical PCs and their target cells in the nuclei. To circumvent this problem we have used a Cre-mediated genetic approach to generate mice in which channelrhodopsin-2 (ChR2), fused with a fluorescent reporter, is selectively expressed by GABAergic neurons, including PCs. In recordings from brain slice preparations from this model, mammalian PCs can be robustly depolarized and discharged by brief photostimulation. In recordings of postsynaptic DCN cells, photostimulation of PC axons induces a strong inhibition that resembles these cells' responses to focal electrical stimulation, but without a requirement for the glutamate receptor blockers typically applied in such experiments. In this optogenetic model, laser pulses as brief as 1 ms can reliably induce an inhibition that shuts down the spontaneous spiking of a DCN cell for ~50 ms. If bursts of such brief light pulses are delivered, a fixed pattern of bistable bursting emerges. If these pulses are delivered continuously to a spontaneously bistable cell, the immediate response to such photostimulation is inhibitory in the cell's depolarized state and excitatory when the membrane has repolarized; a less regular burst pattern then persists after stimulation has been terminated. These results indicate that the spiking activity of DCN cells can be bidirectionally modulated by the optically activated synaptic inhibition of cortical PCs. PMID- 25020123 TI - Irradiation-induced hippocampal neurogenesis impairment is associated with epigenetic regulation of bdnf gene transcription. AB - Radiotherapy is often employed for the treatment of head and neck cancer. Unfortunately, its neurotoxic effects on normal brain tissue often compromise the quality of life (QOL) for survivors. Particularly, acute cognitive deficit (ACD), which can occur several days to one month after irradiation, limits its therapeutic use. Impairment of neurogenesis in the hippocampus plays a key role in the development of radiation-induced cognitive deficit, and brain-derived neurotrophic factor (BDNF) may be involved. In the present study, we re-evaluated the effects of different doses of radiation on the development of ACD in Sprague Dawley rats. Our results showed that 30 Gy, but not 2 Gy or 10 Gy of whole brain radiation (WBI), led to significant deficits in cognitive functions at one month post-irradiation. At 7 and 30 days post-irradiation, immunofluorescence showed WBI had seriously impeded the production of new neurons and shortened their survival time. Additionally, decreased bdnf mRNA and protein expression were also observed. A significant decrease in histone deacetylase 1 (HDAC1)-dependent H3 acetylation was observed at bdnf promoters by ChIP analysis. TSA, an HDAC inhibitor, triggered bdnf transcription and rescued neurogenesis impairment following WBI. In summary, our results suggest that a single-dose exposure to 30 Gy WBI induced acute cognitive dysfunction in rats. Additionally, radiation induced persistent inhibition of bdnf gene transcription resulting from lowered rates of HDAC1-dependent H3 acetylation was associated with long-term impairment of neurogenesis in the denate gyrus (DG). Triggering of BDNF-TrkB signaling by inhibition of HDAC-1 may be used to stimulate neurogenesis. PMID- 25020124 TI - Semantic processing during morphological priming: an ERP study. AB - Previous research has yielded conflicting results regarding the onset of semantic processing during morphological priming. The present study was designed to further explore the time-course of morphological processing using event-related potentials (ERPs). We conducted a primed lexical decision study comparing a morphological (LAVAGE - laver [washing - wash]), a semantic (LINGE - laver [laundry - wash]), an orthographic (LAVANDE - laver [lavender - wash]), and an unrelated control condition (HOSPICE - laver [nursing home - wash]), using the same targets across the four priming conditions. The behavioral data showed significant effects of morphological and semantic priming, with the magnitude of morphological priming being significantly larger than the magnitude of semantic priming. The ERP data revealed significant morphological but no semantic priming at 100-250 ms. Furthermore, a reduction of the N400 amplitude in the morphological condition compared to the semantic and orthographic condition demonstrates that the morphological priming effect was not entirely due to the semantic or orthographic overlap between the prime and the target. The present data reflect an early process of semantically blind morphological decomposition, and a later process of morpho-semantic decomposition, which we discuss in the context of recent morphological processing theories. PMID- 25020125 TI - Significance of neuronal cytochrome P450 activity in opioid-mediated stress induced analgesia. AB - Stressful environmental changes can suppress nociceptive transmission, a phenomenon known as "stress-induced analgesia". Depending on the stressor and the subject, opioid or non-opioid mechanisms are activated. Brain MU opioid receptors mediate analgesia evoked either by exogenous agents (e.g. morphine), or by the release of endogenous opioids following stressful procedures. Recent work with morphine and neuronal cytochrome P450 (P450)-deficient mice proposed a signal transduction role for P450 enzymes in u analgesia. Since u opioid receptors also mediate some forms of stress-induced analgesia, the present studies assessed the significance of brain P450 activity in opioid-mediated stress-induced analgesia. Two widely-used models of opioid stress-induced analgesia (restraint and warm water swim) were studied in both sexes of wild-type control and P450-deficient (Null) mice. In control mice, both stressors evoked moderate analgesic responses which were blocked by pretreatment with the opioid antagonist naltrexone, confirming the opioid nature of these responses. Consistent with literature, sex differences (control female>control male) were seen in swim-induced, but not restraint-induced, analgesia. Null mice showed differential responses to the two stress paradigms. As compared with control subjects, Null mice showed highly attenuated restraint-induced analgesia, showing a critical role for neuronal P450s in this response. However, warm water swim-induced analgesia was unchanged in Null vs. control mice. Additional control experiments confirmed the absence of morphine analgesia in Null mice. These results are the first to show that some forms of opioid-mediated stress-induced analgesia require brain neuronal P450 activity. PMID- 25020126 TI - WO3 nanoparticle-based conformable pH sensor. AB - pH is a vital physiological parameter that can be used for disease diagnosis and treatment as well as in monitoring other biological processes. Metal/metal oxide based pH sensors have several advantages regarding their reliability, miniaturization, and cost-effectiveness, which are critical characteristics for in vivo applications. In this work, WO3 nanoparticles were electrodeposited on flexible substrates over metal electrodes with a sensing area of 1 mm(2). These sensors show a sensitivity of -56.7 +/- 1.3 mV/pH, in a wide pH range of 9 to 5. A proof of concept is also demonstrated using a flexible reference electrode in solid electrolyte with a curved surface. A good balance between the performance parameters (sensitivity), the production costs, and simplicity of the sensors was accomplished, as required for wearable biomedical devices. PMID- 25020128 TI - Molecular phylogeny of weakfish species of the Stellifer group (Sciaenidae, Perciformes) of the western South Atlantic based on mitochondrial and nuclear data. AB - The phylogenetic relationships within the Stellifer group of weakfishes (Stellifer, Odontoscion, Ophioscion, and Bairdiella) were evaluated using 2723 base pairs comprising sequences of nuclear (rhodopsin, TMO-4C4, RAG-1) and mitochondrial (16S rRNA and COI) markers obtained from specimens of nine species. Our results indicate a close relationship between Bairdiella and Odontoscion, and also that the genus Stellifer is not monophyletic, but rather that it consists of two distinct lineages, one clade containing S. microps/S. naso/S. brasiliensis and the other, S. rastrifer/S. stellifer/Stellifer sp. B, which is closer to Ophioscion than the former clade. The O. punctatissimus populations from the northern and southern Brazilian coast were also highly divergent in both nuclear (0.8% for rhodopsin and 0.9% for RAG-1) and mitochondrial sequences (2.2% for 16S rRNA and 7.3% for COI), which we conclude is consistent with the presence of two distinct species. The morphological similarities of the members of the Stellifer group is reinforced by the molecular data from both the present study and previous analyses, which have questioned the taxonomic status of the Stellifer group. If, on the one hand, the group is in fact composed of four genera (Stellifer, Ophioscion, Odontoscion, and Bairdiella), one of the two Stellifer clades should be reclassified as a new genus. However, if the close relationship and the reduced genetic divergence found within the group is confirmed in a more extensive study, including representatives of additional taxa, this, together with the morphological evidence, would support downgrading the whole group to a single genus. Obviously, these contradictory findings reinforce the need for a more systematic taxonomic revision of the Stellifer group as a whole. PMID- 25020129 TI - Number of published randomized controlled multi center trials testing pharmacological interventions or devices is increasing in both medical and surgical specialties. AB - BACKGROUND: In general, there is a need for testing new interventions in large randomized controlled trials. Depending on the research question it may be advantageous to establish multicenter studies as a way of organizing clinical trials in order to increase study power. MAIN OBJECTIVES: The object of this study was to investigate the development in the organization of multicenter studies, the distribution of studies within different clinical specialties, across continents, and investigate the differences related to testing various interventions. METHODS AND MATERIALS: A literature search was done in MEDLINE for multicenter studies published in 1995, 2000, 2005, and 2010, respectively. Data extraction identified data related to clinical specialties, interventions, participating patients, departments, countries, and continents. RESULTS: The number of multicenter studies increased from 112 in 1995 to 1,273 in 2010, with a larger share of multicenter studies being performed in Europe and North America. The pharmacological interventions were primarily being tested in medical studies followed by the device tests predominantly in surgical studies. The number of included patients as well as the number of participating departments increased during the time span, though the increase in studies was most evident in Europe and North America compared with the rest of the world. PMID- 25020130 TI - Exploring the association of hemoglobin level and adverse events in children with cancer presenting with fever in neutropenia. AB - BACKGROUND: In children and adolescents with fever in neutropenia (FN) during chemotherapy for cancer, hemoglobin >=90 g/L at presentation with FN had been associated with adverse events (AE). This analysis explored three hypothetical pathophysiological mechanisms potentially explaining this counterintuitive finding, and further analyzed the statistical association between hemoglobin and AE. METHODS: Two of 8 centers, reporting on 311 of 421 FN episodes in 138 of 215 patients participated in this retrospective analysis based on prospectively collected data from three databases (SPOG 2003 FN, transfusion and hematology laboratories). Associations with AE were analyzed using mixed logistic regression. RESULTS: Hemoglobin was >=90 g/L in 141 (45%) of 311 FN episodes, specifically in 59/103 (57%) episodes with AE, and in 82/208 (39%) without (OR, 2.3; 99%CI, 1.1-4.9; P = 0.004). In FN with AE, hemoglobin was bimodally distributed with a dip around 85 g/L. There were no significant interactions for center, age and sex. In multivariate mixed logistic regression, AE was significantly and independently associated with leukopenia (leukocytes <0.3 G/L; OR, 3.3; 99%CI, 1.1-99; P = 0.004), dehydration (hemoglobinPresentation/hemoglobin8-72 hours >=1.10 in untransfused patients; OR, 3.5; 99%CI, 1.1-11.4; P = 0.006) and non-moderate anemia (difference from 85 g/L; 1.6 per 10 g/L; 1.0-2.6; P = 0.005), but not with recent transfusion of packed red blood cells (pRBC), very recent transfusion of pRBC or platelets, or with hemoglobin >=90 g/L as such. CONCLUSIONS: Non-moderate anemia and dehydration were significantly and relevantly associated with the risk of AE in children with cancer and FN. These results need validation in prospective cohorts before clinical implementation. PMID- 25020131 TI - Pertussis vaccination and whooping cough: and now what? AB - Pertussis or whooping cough is a respiratory disease caused by Bordetella pertussis or Bordetella parapertussis that are only known to infect humans. This severe and acute respiratory disease presents epidemic cycles and became a vaccine-preventable disease in the 1940s/1950s when developed countries introduced vaccination. The first type of vaccine developed against this disease was a whole-cell pertussis (wP) vaccine containing inactivated B. pertussis bacteria. Most developed countries produced their own vaccine and given the pediatric nature of the disease at the time of licensure, infants and toddlers were the primary targets and were thus massively vaccinated. The characterization of few virulence factors produced by B. pertussis enabled the development of second-generation pertussis vaccines called the acellular pertussis (aP) vaccines. These only contain 1-5 purified, detoxified B. pertussis proteins and were first introduced in Japan around 30 years ago. Australia, Europe and North America introduced aP vaccines approximately 15 years later, which replaced wP vaccines since then. PMID- 25020132 TI - Scaling-up access to family planning may improve linear growth and child development in low and middle income countries. AB - BACKGROUND: A large literature has indicated a robust association between birth spacing and child survival, but evidence on the association of birth timing with physical growth in low and middle income countries (LMICs) remains limited. METHODS AND RESULTS: Data from 153 cross-sectional Demographic and Health Surveys (DHS) across 61 LMICs conducted between 1990 and 2011 were combined to assess the association of birth timing with child stunting (height-for-age z-score <-2). A total of 623,789 children of birth order 1-5 contributed to the maternal age analysis, while the birth spacing dataset consisted of 584,226 children of birth order 2 and higher. Compared to 27-34 year old mothers, maternal age under 18 years was associated with a relative stunting risk of 1.35 (95% CI: 1.29-1.40) for firstborn children, whereas the relative risk was 1.24 (95% CI: 1.19-1.29) for mothers aged 18-19 years. The association of young maternal age with stunting was significantly greater for urban residents and those in the top 50% of household wealth. Birth intervals less than 12 months and 12-23 months had relative risks for stunting of 1.09 (95% CI: 1.06-1.12) and 1.06 (95% CI: 1.05 1.06) as compared to a 24-35 month inter-pregnancy interval, respectively. The strength of both teenage pregnancy and short birth interval associations showed substantial variation across WHO region. We estimate that 8.6% (6.9-10.3%) of stunted cases in the South Asian DHS sample would have been averted by jointly eliminating teen pregnancies and birth intervals less than 24 months, while only 3.6% (1.5-5.7%) of stunting cases would have prevented in the Middle East and North Africa sample. CONCLUSIONS: Postponing the age of first birth and increasing inter-pregnancy intervals has the potential to significantly reduce the prevalence of stunting and improve child development in LMICs. PMID- 25020135 TI - Tailoring surface hydrophilicity of porous electrospun nanofibers to enhance capillary and push-pull effects for moisture wicking. AB - In this article, liquid moisture transport behaviors of dual-layer electrospun nanofibrous mats are reported for the first time. The dual-layer mats consist of a thick layer of hydrophilic polyacrylonitrile (PAN) nanofibers with a thin layer of hydrophobic polystyrene (PS) nanofibers with and without interpenetrating nanopores, respectively. The mats are coated with polydopamine (PDOPA) to different extents to tailor the water wettability of the PS layer. It is found that with a large quantity of nanochannels, the porous PS nanofibers exhibit a stronger capillary effect than the solid PS nanofibers. The capillary motion in the porous PS nanofibers can be further enhanced by slight surface modification with PDOPA while retaining the large hydrophobicity difference between the two layers, inducing a strong push-pull effect to transport water from the PS to the PAN layer. PMID- 25020134 TI - Ultra-pH-sensitive nanoprobe library with broad pH tunability and fluorescence emissions. AB - pH is an important physiological parameter that plays a critical role in cellular and tissue homeostasis. Conventional small molecular pH sensors (e.g., fluorescein, Lysosensor) are limited by broad pH response and restricted fluorescent emissions. Previously, we reported the development of ultra-pH sensitive (UPS) nanoprobes with sharp pH response using fluorophores with small Stokes shifts (<40 nm). In this study, we expand the UPS design to a library of nanoprobes with operator-predetermined pH transitions and wide fluorescent emissions (400-820 nm). A copolymer strategy was employed to fine tune the hydrophobicity of the ionizable hydrophobic block, which led to a desired transition pH based on standard curves. Interestingly, matching the hydrophobicity of the monomers was critical to achieve a sharp pH transition. To overcome the fluorophore limitations, we introduced copolymers conjugated with fluorescence quenchers (FQs). In the micelle state, the FQs effectively suppressed the emission of fluorophores regardless of their Stokes shifts and further increased the fluorescence activation ratios. As a proof of concept, we generated a library of 10 nanoprobes each encoded with a unique fluorophore. The nanoprobes cover the entire physiologic range of pH (4-7.4) with 0.3 pH increments. Each nanoprobe maintained a sharp pH transition (on/off < 0.25 pH) and high fluorescence activation ratio (>50-fold between on and off states). The UPS library provides a useful toolkit to study pH regulation in many pathophysiological indications (e.g., cancer, lysosome catabolism) as well as establishing tumor-activatable systems for cancer imaging and drug delivery. PMID- 25020133 TI - Chronic ingestion of H1-antihistamines increase progression of atherosclerosis in apolipoprotein E-/- mice. AB - Although increased serum histamine levels and H1R expression in the plaque are seen in atherosclerosis, it is not known whether H1R activation is a causative factor in the development of the disease, or is a host defense response to atherogenic signals. In order to elucidate how pharmacological inhibition of histamine receptor 1 (H1R) signaling affects atherogenesis, we administered either cetirizine (1 and 4 mg/kg. b.w) or fexofenadine (10 and 40 mg/kg. b.w) to ApoE-/- mice maintained on a high fat diet for three months. Mice ingesting a low dose of cetirizine or fexofenadine had significantly higher plaque coverage in the aorta and cross-sectional lesion area at the aortic root. Surprisingly, the higher doses of cetirizine or fexofenadine did not enhance atherosclerotic lesion coverage over the controls. The low dose of fexofenadine, but not cetirizine, increased serum LDL cholesterol. Interestingly, the expression of iNOS and eNOS mRNA was increased in aortas of mice on high doses of cetirizine or fexofenadine. This may be a compensatory nitric oxide (NO)-mediated vasodilatory mechanism that accounts for the lack of increase in the progression of atherosclerosis. Although the administration of cetirizine did not alter blood pressure between the groups, there was a positive correlation between blood pressure and lesion/media ratio at the aortic root in mice receiving the low dose of cetirizine. However, this association was not observed in mice treated with the high dose of cetirizine or either doses of fexofenadine. The macrophages or T lymphocytes densities were not altered by low doses of H1-antihistamines, whereas, high doses decreased the number of macrophages but not T lymphocytes. The number of mast cells was decreased only in mice treated with low dose of fexofenadine. These results demonstrate that chronic ingestion of low therapeutic doses of cetirizine or fexofenadine enhance progression of atherosclerosis. PMID- 25020136 TI - Hierarchical genetic analysis of German cockroach (Blattella germanica) populations from within buildings to across continents. AB - Understanding the population structure of species that disperse primarily by human transport is essential to predicting and controlling human-mediated spread of invasive species. The German cockroach (Blattella germanica) is a widespread urban invader that can actively disperse within buildings but is spread solely by human-mediated dispersal over longer distances; however, its population structure is poorly understood. Using microsatellite markers we investigated population structure at several spatial scales, from populations within single apartment buildings to populations from several cities across the U.S. and Eurasia. Both traditional measures of genetic differentiation and Bayesian clustering methods revealed increasing levels of genetic differentiation at greater geographic scales. Our results are consistent with active dispersal of cockroaches largely limited to movement within a building. Their low levels of genetic differentiation, yet limited active spread between buildings, suggests a greater likelihood of human-mediated dispersal at more local scales (within a city) than at larger spatial scales (within and between continents). About half the populations from across the U.S. clustered together with other U.S. populations, and isolation by distance was evident across the U.S. Levels of genetic differentiation among Eurasian cities were greater than those in the U.S. and greater than those between the U.S. and Eurasia, but no clear pattern of structure at the continent level was detected. MtDNA sequence variation was low and failed to reveal any geographical structure. The weak genetic structure detected here is likely due to a combination of historical admixture among populations and periodic population bottlenecks and founder events, but more extensive studies are needed to determine whether signatures of global movement may be present in this species. PMID- 25020138 TI - Running with a powered knee and ankle prosthesis. AB - This paper presents a running control architecture for a powered knee and ankle prosthesis that enables a transfemoral amputee to run with a biomechanically appropriate running gait and to intentionally transition between a walking and running gait. The control architecture consists firstly of a coordination level controller, which provides gait biomechanics representative of healthy running, and secondly of a gait selection controller that enables the user to intentionally transition between a running and walking gait. The running control architecture was implemented on a transfemoral prosthesis with powered knee and ankle joints, and the efficacy of the controller was assessed in a series of running trials with a transfemoral amputee subject. Specifically, treadmill trials were conducted to assess the extent to which the coordination controller provided a biomechanically appropriate running gait. Separate trials were conducted to assess the ability of the user to consistently and reliably transition between walking and running gaits. PMID- 25020137 TI - Spatio-temporal expression and functional involvement of transient receptor potential vanilloid 1 in diabetic mechanical allodynia in rats. AB - Diabetic neuropathic pain (DNP) is one of the most common clinical manifestations of diabetes mellitus (DM), which is characterized by prominent mechanical allodynia (DMA). However, the molecular mechanism underlying it has not fully been elucidated. In this study, we examined the spatio-temporal expression of a major nociceptive channel protein transient receptor potential vanilloid 1 (TRPV1) and analyzed its functional involvement by intrathecal (i.t.) application of TRPV1 antagonists in streptozocin (STZ)-induced DMA rat models. Western blot and immunofluorescent staining results showed that TRPV1 protein level was significantly increased in the soma of the dorsal root ganglion (DRG) neurons on 14 days after STZ treatment (DMA 14 d), whereas those in spinal cord and skin (mainly from the central and peripheral processes of DRG neurons) had already been enhanced on DMA 7 d to peak on DMA 14 d. qRT-PCR experiments confirmed that TRPV1 mRNA level was significantly up-regulated in the DRG on DMA 7 d, indicating a preceding translation of TRPV1 protein in the soma but preferential distribution of this protein to the processes under the DMA conditions. Cell counting assay based on double immunostaining suggested that increased TRPV1 immunoreactive neurons were likely to be small-sized and CGRP-ergic. Finally, single or multiple intrathecal applications of non-specific or specific TRPV1 antagonists, ruthenium red and capsazepine, at varying doses, effectively alleviated DMA, although the effect of the former was more prominent and long lasting. These results collectively indicate that TRPV1 expression dynamically changes during the development of DMA and this protein may play important roles in mechanical nociception in DRG neurons, presumably through facilitating the release of CGRP. PMID- 25020139 TI - Peer-assisted learning--beyond teaching: How can medical students contribute to the undergraduate curriculum? AB - INTRODUCTION: Peer-assisted learning (PAL) has become increasingly popular over recent years with many medical schools now formally incorporating peer-teaching programs into the curriculum. PAL has a sound evidence base with benefit to both peer-teacher and peer-learner. Aside from in teaching delivery, empowering students to develop education in its broadest sense has been much less extensively documented. CASE STUDIES: Five case studies with supportive evaluation evidence illustrate the success of a broad range of peer-led projects in the undergraduate medical curriculum, particularly where these have been embedded into formal teaching practices. DISCUSSION: These case studies identify five domains of teaching and support of learning where PAL works well: teaching and learning, resource development, peer-assessment, education research and evaluation and mentoring and support. Each case offers ways of engaging students in each domain. CONCLUSIONS: Medical students can contribute significantly to the design and delivery of the undergraduate medical program above and beyond the simple delivery of peer-assisted "teaching". In particular, they are in a prime position to develop resources and conduct research and evaluation within the program. Their participation in all stages enables them to feel involved in course development and education of their peers and ultimately leads to an increase in student satisfaction. PMID- 25020141 TI - Nanophotonic enhancement of the Forster resonance energy-transfer rate with single nanoapertures. AB - Tailoring the light-matter interaction and the local density of optical states (LDOS) with nanophotonics provides accurate control over the luminescence properties of a single quantum emitter. This paradigm is also highly attractive to enhance the near-field Forster resonance energy transfer (FRET) between two fluorescent emitters. Despite the wide applications of FRET in nanosciences, using nanophotonics to enhance FRET has remained a debated and complex challenge. Here we demonstrate enhanced energy transfer within single donor-acceptor fluorophore pairs confined in single gold nanoapertures. Experiments monitoring both the donor and the acceptor emission photodynamics clearly establish a linear dependence of the FRET rate on the LDOS in nanoapertures, demonstrating that nanophotonics can be used to intensify the near-field energy transfer. Strikingly, we observe a significant six-fold increase in the FRET rate for large donor-acceptor separations exceeding 13 nm. Exciting opportunities are opened to investigate biochemical structures with donor-acceptor distances much beyond the classical Forster radius. Importantly, our approach is fully compatible with the detection of single biomolecules freely diffusing in water solution under physiological conditions. PMID- 25020142 TI - Mechanistic insights into Mg2+-independent prenylation by CloQ from classical molecular mechanics and hybrid quantum mechanics/molecular mechanics molecular dynamics simulations. AB - Understanding the mechanism of prenyltransferases is important to the design of engineered proteins capable of synthesizing derivatives of naturally occurring therapeutic agents. CloQ is a Mg(2+)-independent aromatic prenyltransferase (APTase) that transfers a dimethylallyl group to 4-hydroxyphenylpyruvate in the biosynthetic pathway for clorobiocin. APTases consist of a common ABBA fold that defines a beta-barrel containing the reaction cavity. Positively charged basic residues line the inside of the beta-barrel of CloQ to activate the pyrophosphate leaving group to replace the function of the Mg(2+) cofactor in other APTases. Classical molecular dynamics simulations of CloQ, its E281G and F68S mutants, and the related NovQ were used to explore the binding of the 4-hydroxyphenylpyruvate (4HPP) and dimethylallyl diphosphate substrates in the reactive cavity and the role of various conserved residues. Hybrid quantum mechanics/molecular mechanics potential of mean force (PMF) calculations show that the effect of the replacement of the Mg(2+) cofactor with basic residues yields a similar activation barrier for prenylation to Mg(2+)-dependent APTases like NphB. The topology of the binding pocket for 4HPP is important for selective prenylation at the ortho position of the ring. Methylation at this position alters the conformation of the substrate for O-prenylation at the phenol group. Further, a two-dimensional PMF scan shows that a "reverse" prenylation product may be a possible target for protein engineering. PMID- 25020143 TI - Carbohydrate structure generalization scheme for database-driven simulation of experimental observables, such as NMR chemical shifts. AB - Carbohydrates play an immense role in different aspects of life. NMR spectroscopy is the most powerful tool for investigation of these compounds. Nowadays, progress in computational procedures has opened up novel opportunities giving an impulse to the development of new instruments intended to make the research simpler and more efficient. In this paper, we present a new approach for simulating (13)C NMR chemical shifts of carbohydrates. The approach is suitable for any atomic observables, which could be stored in a database. The method is based on sequential generalization of the chemical surroundings of the atom under prediction and heuristic averaging of database data. Unlike existing applications, the generalization scheme is tuned for carbohydrates, including those containing phosphates, amino acids, alditols, and other non-carbohydrate constituents. It was implemented in the Glycan-Optimized Dual Empirical Spectrum Simulation (GODESS) software, which is freely available on the Internet. In the field of carbohydrates, our approach was shown to outperform all other existing methods of NMR spectrum prediction (including quantum-mechanical calculations) in accuracy. Only this approach supports NMR spectrum simulation for a number of structural features in polymeric structures. PMID- 25020144 TI - Reversible addition of the OH radical to p-cymene in the gas phase: multiple adduct formation. Part 2. AB - A flash photolysis-resonance fluorescence (FP-RF) system was used to study the p cymene (PC) + OH reaction at temperatures between 299 and 349 K in helium. Triexponential functions were fitted to groups of observed OH decay curves according to a model considering a reversible addition to form two adducts as thermolabile reservoirs of OH. Compared to Part 1 of this paper, consideration of a second adduct strongly improved the fits to our measurements, and the rate constants for the major pathways were optimized between 299 and 349 K. The Arrhenius expression for the rate constant of the sum of OH addition and H-atom abstraction pathways was found to be kOH = 1.9 * 10(-12) exp[(610 +/- 210) K/T] cm(3) s(-1). Rate constants of unimolecular decomposition reactions of the adducts were similar to other aromatic compounds with the following Arrhenius expressions: 1 * 10(12) exp[(-7600 +/- 800) K/T] s(-1) for adduct 1 and 4 * 10(11) exp[(-8000 +/- 300) K/T] s(-1) for adduct 2. Adduct yields increased and decreased with temperature for adduct 1 and 2, respectively, but were similar (~0.4) around room temperature. Equilibrium constants yielded values for reaction enthalpies and entropies of adduct formations. While for one adduct reasonable agreement was obtained with theoretical predictions, there were significant deviations for the other adduct. This indicates the presence of more than two adduct isomers that were not accounted for in the reaction model. Quantum chemical calculations (DFT M06-2X/6-31G(d,p)) and RRKM kinetics were employed with the aim of clarifying the mechanism of the OH addition to PC. These calculations show that formation of adducts with OH in ortho positions to the isopropyl and methyl substituents is predominant (55% and 24%) to those with OH in ipso positions (21% and 3%). A large fraction (>90%) of the ipso-C3H7 adduct is predicted to react by dealkylation forming p-cresol (in the absence of oxygen) and isopropyl radicals. These theoretical results agree well with the interpretation of the experimental results showing that the two ortho adducts (which appeared as OH reservoirs in the experiment) have been observed. PMID- 25020145 TI - Case report of a ureteral obstruction by Candida albicans fungus balls detected by magnetic resonance imaging in kidney transplant recipient. AB - In kidney transplant recipients, acute renal failure resulting from a ureteral obstruction by fungus balls is uncommon. We report a 60-year-old man diagnosed with ureteral obstruction caused by Candida albicans fungus balls early after transplant. Diagnosis was made by a T2-weighted magnetic resonance image, which demonstrated fungus balls as a low-intensity mass in the pelvis and microscopic examination findings in the urine. The patient was treated successfully with an antifungal agent and direct irrigation. It should be noted that fungus balls may cause ureteral obstruction of transplanted kidneys, possibly resulting in graft failure. Imaging of the kidneys and collecting system and aggressive debridement that adds to systemic therapy are necessary for early diagnosis and are central to a successful outcome. PMID- 25020146 TI - Feasibility of automated speech sample collection with stuttering children using interactive voice response (IVR) technology. AB - PURPOSE: To investigate the feasibility of adopting automated interactive voice response (IVR) technology for remotely capturing standardized speech samples from stuttering children. METHOD: Participants were 10 6-year-old stuttering children. Their parents called a toll-free number from their homes and were prompted to elicit speech from their children using a standard protocol involving conversation, picture description and games. The automated IVR system was implemented using an off-the-shelf telephony software program and delivered by a standard desktop computer. The software infrastructure utilizes voice over internet protocol. Speech samples were automatically recorded during the calls. Video recordings were simultaneously acquired in the home at the time of the call to evaluate the fidelity of the telephone collected samples. Key outcome measures included syllables spoken, percentage of syllables stuttered and an overall rating of stuttering severity using a 10-point scale. RESULT: Data revealed a high level of relative reliability in terms of intra-class correlation between the video and telephone acquired samples on all outcome measures during the conversation task. Findings were less consistent for speech samples during picture description and games. CONCLUSION: Results suggest that IVR technology can be used successfully to automate remote capture of child speech samples. PMID- 25020147 TI - Cascade biocatalysis by multienzyme-nanoparticle assemblies. AB - Multienzyme complexes are of paramount importance in biosynthesis in cells. Yet, how sequential enzymes of cascade catalytic reactions synergize their activities through spatial organization remains elusive. Recent development of site-specific protein-nanoparticle conjugation techniques enables us to construct multienzyme assemblies using nanoparticles as the template. Sequential enzymes in menaquinone biosynthetic pathway were conjugated to CdSe-ZnS quantum dots (QDs, a nanosized particulate material) through metal-affinity driven self-assembly. The assemblies were characterized by electrophoretic methods, the catalytic activities were monitored by reverse-phase chromatography, and the composition of the multienzyme QD assemblies was optimized through a progressive approach to achieve highly efficient catalytic conversion. Shorter enzyme-enzyme distance was discovered to facilitate intermediate transfer, and a fine control on the stoichiometric ratio of the assembly was found to be critical for the maximal synergy between the enzymes. Multienzyme-QD assemblies thereby provide an effective model to scrutinize the synergy of cascade enzymes in multienzyme complexes. PMID- 25020148 TI - Cysteine on TiO2(110): a theoretical study by reactive dynamics and photoemission spectra simulation. AB - Owing to the importance of bioinorganic interface properties for the biocompatibility of implants and for biosensing technology, it has become indispensable to gain understanding of their crucial structure-property relations at the atomistic level. Motivated by this fact, we use cysteine amino acid on perfect and defective TiO2(110) surfaces as model systems and study adsorption by means of classical all-atom reactive molecular dynamics and ab initio O 1s, N 1s, and S 2p photoemission spectra (XPS) simulations of the most relevant adsorbate structures. By analysis of the dynamics results and a detailed comparison with spectra recently collected for this adsorbate, we obtain conclusions of both general and particular character. It is shown that the interaction of cysteine with the TiO2(110) surface has multipoint character involving the carboxylic group as well as the amino and sulfur groups. The proton-transfer reactivity of cysteine is enhanced by the presence of the surface, and different forms of cysteines are confirmed to be present in the adsorbate. A general conclusion is that reactive force field dynamics combined with selected spectroscopy provides a viable path to understanding bioinorganic surfaces with ramifications for the design of such surfaces for future technological applications. PMID- 25020149 TI - Potential of fluorescence imaging techniques to monitor mutagenic PAH uptake by microalga. AB - Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is one of the major environmental pollutants that causes mutagenesis and cancer. BaP has been shown to accumulate in phytoplankton and zooplankton. We have studied the localization and aggregation of BaP in Chlorella sp., a microalga that is one of the primary producers in the food chain, using fluorescence confocal microscopy and fluorescence lifetime imaging microscopy with the phasor approach to characterize the location and the aggregation of BaP in the cell. Our results show that BaP accumulates in the lipid bodies of Chlorella sp. and that there is Forster resonance energy transfer between BaP and photosystems of Chlorella sp., indicating the close proximity of the two molecular systems. The lifetime of BaP fluorescence was measured to be 14 ns in N,N-dimethylformamide, an average of 7 ns in Bold's basal medium, and 8 ns in Chlorella cells. Number and brightness analysis suggests that BaP does not aggregate inside Chlorella sp. (average brightness = 5.330), while it aggregates in the supernatant. In Chlorella grown in sediments spiked with BaP, in 12 h the BaP uptake could be visualized using fluorescence microscopy. PMID- 25020150 TI - Transcriptional regionalization of the fruit fly's airway epithelium. AB - Although airway epithelia are primarily devoted to gas exchange, they have to fulfil a number of different tasks including organ maintenance and the epithelial immune response to fight airborne pathogens. These different tasks are at least partially accomplished by specialized cell types in the epithelium. In addition, a proximal to distal gradient mirroring the transition from airflow conduction to real gas exchange, is also operative. We analysed the airway system of larval Drosophila melanogaster with respect to region-specific expression in the proximal to distal axis. The larval airway system is made of epithelial cells only. We found differential expression between major trunks of the airways and more distal ones comprising primary, secondary and terminal ones. A more detailed analysis was performed using DNA-microarray analysis to identify cohorts of genes that are either predominantly expressed in the dorsal trunks or in the primary/secondary/terminal branches of the airways. Among these differentially expressed genes are especially those involved in signal transduction. Wnt signalling associated genes for example are predominantly found in secondary/terminal airways. In addition, some G-protein coupled receptors are differentially expressed between both regions of the airways, exemplified by those activated by octopamine or tyramine, the invertebrate counterparts of epinephrine and norepinephrine. Whereas the OAMB is predominantly found in terminal airway regions, the oct3betaR has higher expression levels in dorsal trunks. In addition, we observed a significant association of both, genes predominantly expressed in dorsal trunks or in primary to terminal branches branches with those regulated by hypoxia. Taken together, this observed differential expression is indicative for a proximal to distal transcriptional regionalization presumably reflecting functional differences in these parts of the fly's airway system. PMID- 25020151 TI - Relationship between momentary affect states and self-efficacy in adolescent smokers. AB - OBJECTIVE: Relapse to smoking after making a quit attempt is both common and rapid in adolescent smokers. Momentary self-efficacy (SE)-that is, momentary shifts in one's confidence in the ability to abstain from smoking-predicts the occurrence and timing of relapse among adolescent smokers. Therefore, it is important to identify factors that are associated with changes in momentary SE early in a quit attempt. This study examined the relationship between affect states (including positive, negative, and nicotine withdrawal states) and momentary SE at various stages of a quit attempt. METHOD: Adolescent daily smokers interested in making a quit attempt (n = 202) completed ecological momentary assessments (EMA) each day for 1 week leading up to and 2 weeks after a quit attempt. In each assessment, they reported current SE and affect state. RESULTS: RESULTS of linear mixed models indicated that most of the examined affect states were related to momentary SE. Contrary to expectation, they were related to momentary SE both immediately before and after the quit attempt. Moderation effects were observed for select affect states, where higher baseline SE was related to lower momentary SE in the presence of increasing negative high activation, boredom, and difficulty concentrating. CONCLUSIONS: Our findings suggest that both positive and negative affect states are related to SE, and that thereby positive affect enhancement may be a promising, underutilized treatment target. PMID- 25020152 TI - Effects of a prototype Internet dissonance-based eating disorder prevention program at 1- and 2-year follow-up. AB - OBJECTIVE: A group-based eating disorder prevention program wherein young women explore the costs of pursuing the thin ideal reduces eating disorder risk factors and symptoms. However, it can be challenging to identify school clinicians to effectively deliver the intervention. The present study compares the effects of a new Internet-based version of this prevention program, which could facilitate dissemination, to the group-based program and to educational video and educational brochure control conditions at 1- and 2-year follow-up. METHOD: Female college students with body dissatisfaction (n = 107; M age = 21.6, SD = 6.6) were randomized to these 4 conditions. RESULTS: Internet participants showed reductions in eating disorder risk factors and symptoms relative to the 2 control conditions at 1- and 2-year follow-up (M -d = .34 and .17, respectively), but the effects were smaller than parallel comparisons for the group participants (M -d = .48 and .43, respectively). Yet the Internet intervention produced large weight gain prevention effects relative to the 2 control conditions at 1- and 2-year follow-up (M -d = .80 and .73, respectively), which were larger than the parallel effects for the group intervention (M -d = .19 and .47, respectively). CONCLUSIONS: Although the effects for the Internet versus group intervention were similar at posttest, results suggest that the effects faded more quickly for the Internet intervention. However, the Internet intervention produced large weight gain prevention effects, implying that it might be useful for simultaneously preventing eating disordered behavior and unhealthy weight gain. PMID- 25020153 TI - Message framing for health: moderation by perceived susceptibility and motivational orientation in a diverse sample of Americans. AB - OBJECTIVE: The present study examined how gain- and loss-framed informational videos about oral health influence self-reported flossing behavior over a 6-month period, as well as the roles of perceived susceptibility to oral health problems and approach/avoidance motivational orientation in moderating these effects. METHOD: An age and ethnically diverse sample of 855 American adults were randomized to receive no health message, or either a gain-framed or loss-framed video presented on the Internet. Self-reported flossing was assessed longitudinally at 2 and 6 months. RESULTS: Among the entire sample, susceptibility interacted with frame to predict flossing. Participants who watched a video where the frame (gain/loss) matched perceived susceptibility (low/high) had significantly greater likelihood of flossing at recommended levels at the 6-month follow-up, compared with those who viewed a mismatched video or no video at all. However, young adults (18-24) showed stronger moderation by motivational orientation than by perceived susceptibility, in line with previous work largely conducted with young adult samples. CONCLUSION: Brief informational interventions can influence long-term health behavior, particularly when the gain or loss-frame of the information matches the recipient's beliefs about their health outcome risks. PMID- 25020154 TI - Deployment stressors and physical health among OEF/OIF veterans: the role of PTSD. AB - OBJECTIVE: There is a large body of literature documenting the relationship between traumatic stress and deleterious physical health outcomes. Although posttraumatic stress disorder (PTSD) symptoms have been proposed to explain this relationship, previous research has produced inconsistent results when moderating variables such as gender or type of traumatic stressor are considered. Within a large sample of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans, the current study examined if deployment stressors (i.e., combat stress, harassment stress) contributed unique variance to the prediction of physical health symptoms (i.e., pain, nonpain) beyond the effects of PTSD symptoms. METHODS: A total of 2,332 OEF/OIF Veterans, with equal representation of women and men, completed a series of self-report measures assessing deployment stressors, PTSD symptoms, and physical health symptoms. RESULTS: RESULTS revealed that harassment, but not combat stress, added unique variance in the prediction of pain and nonpain symptoms after accounting for PTSD symptoms. CONCLUSIONS: This study extends the existing literature by demonstrating the unique influence of harassment stress on physical health outcomes. Specifically, the relationship between combat stress and physical health symptoms appears to be explained mainly by an individual's experience of PTSD symptoms, whereas the relationship between harassment stress and physical health symptoms is not fully explained by PTSD symptoms, suggesting that other variables may be involved in the pathway from harassment stress to physical health symptoms. PMID- 25020155 TI - Improving medication adherence in stroke survivors: mediators and moderators of treatment effects. AB - OBJECTIVE: The purpose of the current study was to test theory-based predictions of mediators and moderators of treatment effects of a pilot randomized controlled trial, which aimed to increase adherence to preventive medication in stroke survivors via addressing both automatic (i.e., habitual responses) and reflective (i.e., beliefs and value systems) aspects of medication-taking behavior. METHOD: Sixty-two stroke survivors were randomly allocated to either an intervention or control group. Intervention participants received a brief 2-session intervention aimed at increasing adherence via (a) helping patients establish better medication-taking routines using implementation intentions plans (automatic), and (b) eliciting and modifying any mistaken patient beliefs regarding medication and/or stroke (reflective). The control group received similar levels of non medication-related contact. Primary outcome was adherence to antihypertensive medicine measured objectively over 3 months using an electronic pill bottle. Secondary outcome measures included self-reported adherence (including forgetting) and beliefs about medication. RESULTS: Intervention participants had 10% greater adherence on doses taken on schedule (intervention, 97%; control, 87%; 95% CI [0.2, 16.2], p = .048), as well as significantly greater increases in self-reported adherence and reductions in concerns about medication. Treatment effects were mediated by reductions in both forgetting and concerns about medication, and moderated by the presence of preexisting medication-taking routines. CONCLUSIONS: Addressing both automatic and reflective aspects of behavior via helping stroke survivors develop planned regular routines for medication-taking, and addressing any concerns or misconceptions about their medication, can improve adherence and thus potentially patient outcomes. PMID- 25020157 TI - Prophylaxis of bacterial infections in cirrhosis: is an optimal 25-OH vitamin D level required? PMID- 25020156 TI - Sleep complaints predict increases in resting blood pressure following marital separation. AB - OBJECTIVE: Although marital separation and divorce are associated with many negative health outcomes, few studies examine the psychophysiological mechanisms that may give rise to these outcomes. This study examined changes in resting blood pressure (BP) as a function of sleep complaints in recently divorced adults. METHOD: Recently separated adults (n = 138; 38 men) completed a self report measure of sleep complaints and a resting blood pressure (BP) assessment in the laboratory at three occasions across 7.5 months. RESULTS: Multilevel analyses revealed that although sleep complaints were not associated with concurrent BP, sleep complaints predicted significant increases in both systolic and diastolic BP at the subsequent laboratory visit. In addition, time since the separation from an ex-partner moderated the association between sleep complaints at baseline and resting systolic blood pressure (SBP) 3 months later. People who reported high sleep complaints 10 weeks or more after their separation demonstrated greater increases in SBP. CONCLUSIONS: In recently separated adults, greater sleep complaints may index increased risk for future increases in BP. This work helps pinpoint one potential mechanistic pathway linking marital separation with an important, health-relevant biological outcome. PMID- 25020158 TI - Pyridyl-1,2,4-triazole diphenyl boron complexes as efficient tuneable blue emitters. AB - The detection of nuclear radiation necessitates the availability of new generations of tunable blue emitting fluorophores with high emission quantum yields. Here we show that pyridyl-1,2,4-triazole based diphenyl boron complexes can provide highly tuneable emission through facile modification of the C5 position of the 1,2,4-triazolato ring. The series of complexes prepared show a wide range of emission from near-UV to green, enabling fine control over the spectral overlap with detectors used in scintillator technology. PMID- 25020160 TI - Fetal craniopharyngioma: management, postmortem diagnosis, and literature review of an intracranial tumor detected in utero. PMID- 25020159 TI - The emerging role of exosomes in survivin secretion. AB - The tumor microenvironment plays an integral part in the biology of cancer, participating in tumor initiation, progression, and response to therapy. Factors released by tumor cells themselves contribute in creating an environment mostly favorable but sometimes detrimental to the tumor. Survivin, one of the key members of the inhibitor of apoptosis (IAP) family of proteins, has been shown in the cytoplasm, mitochondria, nucleus, and most recently in the extracellular space, transported via small membrane bound vesicles called exosomes. Exosomes are secreted from hematopoietic, non-hematopoietic, tumor, and non-tumor cells, shuttling essential molecules such as proteins, RNAs, and microRNAs, all believed to be important for cell-cell and cell-extracellular communication. In this review, we discuss exosomal Survivin and its role in modifying the tumor microenvironment. PMID- 25020161 TI - Comparison of the tuberculin skin test and interferon gamma release assay for the screening of tuberculosis in adolescents in close contact with tuberculosis TB patients. AB - BACKGROUND: The tuberculin skin test (TST) frequently yields false positive results among BCG-vaccinated persons thereby limiting its diagnostic value particularly in settings with high BCG vaccination rate. We determined the agreement between IGRA and TST using 2 cutoff values and identified possible relationships between the results of these tests and the development of active tuberculosis. METHODOLOGY: Adolescents aged 11-19 years in close contact with smear-positive tuberculosis cases and with normal chest radiographs were recruited from middle and high schools in South Korea. The TST was conducted by trained nurses, and blood was drawn for the QuantiFERON-TB Gold In-Tube (QFT GIT). Participants were followed up for 2 years to check for incidence tuberculosis. RESULTS: A total of 2,982 subjects were included in the study, the average age was 15.1 years (SD 1.3), 61% had BCG vaccination scars. The agreement of QFT-GIT and the TST was low (kappa = 0.38, 95% CI 0.32 to 0.42) using 10 mm cutoff; however, when the 15 mm cutoff was used, the agreement was intermediate (kappa = 0.56, 95% CI 0.50 to 0.61). The odds ratio (OR) for the development of active tuberculosis was 7.9 (95% CI 3.46 to 18.06) for QFT-GIT positive patients, 7.96 (95% CI 3.14-20.22) for TST/QFT-GIT+ and the OR 4.62 (95% CI 2.02 to 10.58) and 16.35 (95% CI 7.09 to 37.71) for TST 10 mm and 15 mm cutoff respectively. CONCLUSIONS: The results of this study suggest that the TST cutoff point for patients aged 11-17 years would be 15 mm in other study. The OR of QFT-GIT for the development of active tuberculosis and its intermediate agreement with TST using 15 mm cutoff demonstrates its role as an adjunct diagnostic tool to current clinical practice. Positive responders to both TST and QFT-GIT at the outset may benefit from chemoprophylaxis. PMID- 25020162 TI - Tactics of surgical treatment at traumatic injuries of maxillo-zygomatic-orbital complex and the lower edge of the orbit. AB - The maxilla-facial traumatic injuries, zygomatic - orbital complex and orbit lower edge injuries are characterized by dislocation of bone fragments, causing not only the anatomo-functional disorders but well-expressed deformity/ abnormality of the patient. 28 patients with traumatic fractures of zygomatic - alveolar complex and orbit lower edge have been studied and got surgical treatment by the authors. At admission to the hospitals, all the patients were the subjects to a classic comprehensive / complex examination including a Spiral Computed Tomography, with 3D reconstruction (three-dimensional) (in 3 projections). All the patients underwent surgical treatment under endotracheal anesthesia that included osteosynthesis of zygomatic bone body and arch and plasty of orbit lower edge. Osteosynthesis of zygomatic bone body and arch was conducted with titanium plates and screws (hanging zygomatic arch by steel wires), restoration of bony wall was carried out by prosthesis of titanium (net) plate made individually (auto-graft, taken from calvaria bone was used for restoration of orbit lower edge defect in 2 cases). According to the study materials no complications of transplanted grafts like purulency, removal reaction, or dislocation were observed. The obtained data have proved over again, that endoprothesis made of medical titasnium are effective for treatment of the patients with middle third facial traumatic injuries. PMID- 25020164 TI - Laparoscopic surgery of hiatal hernia and gastro-esophageal reflux disease. AB - About 10% (per cent) of world population have Hiatal hernia and gastro-esophageal reflux diseases of different forms. From this amount of people 1/5 need required surgical treatment. The goal of the thesis is to show the results and effectiveness of laparoscopic surgical treatment of this disease. In 2005-2013. at out clinics (Thoracoabdominal clinic and Caraps Medline) had been performed 145 laparoscopic fundoplications. Were used as Nissen Method with its modifications (Floppy Nissen, Classic Nissen and Nissen Rosset), as well as "Toupet" and "Dor" methods of fundoplication. From 145 cases were 84 - female, 61 - male. Age ranged from 24 to 76. From performed 145 operations in 97 cases was done Floppy Nissen Fundoplication, 23 cases - Nissen-Rosset modification, 5 cases - Classic Nissen. Toupet method Partial Fundoplication was done in 17 cases and anterior Fundopexia - Dor method - was done in 3 cases. Using various methods of laparoscopic fundoplication, due to the analysis of our results, the perfect positive result was achieved in 93.2% (per cent). PMID- 25020163 TI - Role of the bacterial vaccine Solco-Urovac(r) in treatment and prevention of recurrent urinary tract infections of bacterial origin. AB - Urinary Tract Infections (UTI) represent a serious medical problem with considerably high rate of morbidity. Recurrent episodes of urinary tract infection (rUTI) may commonly develop in the way of relapse or reinfection. For patients, rUTI is always associated with costs, discomfort and decreased quality of life. Standard treatment of rUTI is through antibiotics and usually such treatment is required repeatedly. Repeat course of antibiotics leads to increase of resistance of uropathogenic strains. According to the European Association of Urology, "the present state of microbial resistance development is alarming". Our post-marketing trial was designed to demonstrate the substantial effect of the bacterial vaccine Solco-Urovac(r) both with independent administration and in conjunction with standard antibacterial medication within therapy and prevention of rUTI. Total of 115 patients (men and non-pregnant women) were enrolled in our open-label post-marketing trial. Each patient had more than one year history of rUTI and in the past had already taken appropriate course of standard therapy. The trial group included 50 patients: 32 men, 18 women (average age +/- 32.5). 32 patients (men) of the trial group received vaccination with Solco-Urovac(r) together with the standard antibacterial medication. According to bacteriologic tests, in 62% cases infection was caused by Escherichia coli, and in 38% cases by Morganella morganii, Proteus mirabilis, Klebsiella pneumoniae, Enterococcus faecalis. 18 patients within the trial group were women with no recurrence episode at the start and during the trial period. Each woman was involved as the intercourse partner of the respective man within the trial group. The women received only vaccination with Solco-Urovac(r). 65 patients of the control group had more than one year history of rUTI and had been treated earlier, too. Patients of the control group received appropriate antibacterial medication without Solco-Urovac(r). After therapy and follow-up examination, results in the both groups were classified, also in consideration of the pathogen-specified subgroups, and then summarized and compared respectively. During the follow-up period no case of rUTI was noticed in women. In total, analysis of the medical records of 50 patients of the trial group demonstrated no case of rUTI in 46 patients during the follow-up period. Altogether, the rate of improvement of symptoms was as follows: the trial group - 92%, the control group - 74%. Through comparison with the past medical histories of patients, the higher rate of improvement and longer absence of rUTI episodes after treatment were certainly associated with the effect of Solco-Urovac(r). The results of our post-marketing trial allow recommending Solco-Urovac(r) for appropriate reference within the Georgian National Guideline on Urologic Infections. PMID- 25020165 TI - [The severity of menopausal symptoms and cardiovascular risk in women]. AB - Menopause is a crucial time in the life of any women. Perhaps the severity of menopausal symptoms defines further state of female health. The aim of the study is to assess changes of cardiovascular system during perimenopause and the connection between this changes and severity of menopausal symptoms. The data of 155 premenopausal women without coronary heart disease were analyzed. To assess women hormonal state follicle stimulating hormone was measured. The severity of menopausal symptoms was evaluated with the help of Kupperman questionnaire form in Uvarova modification. All women were divided into two groups according to follicle stimulating hormone. Women with follicle stimulating hormone higher 30 MU/l were classified as postmenopausal. It was shown that groups of pre - and postmenopausal women significantly differ in age, progesterone, follicle stimulating hormone level, and SCORE. The severity of menopausal symptoms was the same in studied groups. Regression analysis revealed that severity of menopausal symptoms depended on systolic blood pressure, follicle stimulating hormone level, progesterone level. The link between cardiovascular risk (SCORE) and follicle stimulating hormone, NO2, ApoA1, and severity of menopausal symptoms was found. PMID- 25020166 TI - State of integral remodeling parameters of target organs in patients with essential hypertension and obesity. AB - Arterial hypertension combined with obesity is a very common form of comorbid disease in most countries all over the world. The combination of these diseases is characterized by mutual burdening of remodelling processes in important target organs, what greatly increases the risk of cardiovascular complications and death. The mechanisms of injury progression to vital organs in essential hypertension (EH) and obesity have some common features. The most important risk factors of target organs damage are hemodynamic and neurohumoral: inflammatory, effectors of the renin- angiotensin-aldosterone system, insulin resistance and others. Polyethiologic remodelling, lack of knowledge concerning violations in structural and functional status of important target organs and mechanisms of the interactions of their progression with this comorbidity require further study of these issues. The objective of the study was the comparative study of the state of integral indicators of structural and functional state of the heart, blood vessels and liver in patients with EH second stage with normal body weight and with concomitant obesity I and II degrees. This study found that the presence of obesity I and II in patients with EH stage II is associated with the concentric type of left ventricular hypertrophy, saved by its ejection fraction and impaired diastolic filling processes. For the patients with EH in the early stages of obesity the following characteristics are quite typical: considerable increase of intima media thickness in the carotid arteries, increasing the stiffness in the main arteries and liver parenchyma, impaired of the functional state of endothelial. PMID- 25020167 TI - [Apelin activity in patients with essential hypertension nd accompanied prediabetes and type 2 diabetes mellitus]. AB - Studying of apelin's activity corresponding to pronunciation of carbohydrate disorders was provided in 136 patients with essential hypertension. General clinical and laboratory investigations were used. In (34,46%) patients with essential hypertension comorbid type 2 diabetes was revealed, in 37 (31,92%) patients - pre diabetes. Significant increasing of apelin levels were estimated in the whole group of hypertensive patients with marked expression in patients with comorbid type 2 diabetes. Significant correlations of apelin with components of carbohydrate pool dedicate that apelin takes part in the development of gluco metabolic disorders in essential hypertension. PMID- 25020168 TI - [Polymorphism of gene of IL-8 (A-251T) in patients with acute pancreatitis]. AB - The research aims to investigate the IL-8 A-251T (rs 4073) gene polymorphism in patients with acute pancreatitis. The frequency of allelic variants of cytokine gene in 100 patients was determined. Genotype A/T was found in 47.0% of cases (47 patients) of acute pancreatitis, T/T alleles - in 37% of cases (37 patients), A/A alleles in 16% of cases (16 patients). In 73.3% of non-operated patients with destructive forms of acute pancreatitis the reliable (r<0,05) increase of heterozygous carriers of genotype A/T were detected. In patients with edematous form of acute pancreatitis frequency of A/T was detected in 42.2% of cases, In control group frequency of A/T was detected in 46% of cases, The possible association between genotype A/T and the destruction of the pancreas was determined. PMID- 25020170 TI - Monocyte chemo attractant protein-1 in patients with chronic heart failure of different functional class with type 2 diabetes. AB - The aim of the study was to assess the dynamics of monocyte chemoattractant protein-1 in patients with chronic heart failure of different functional classes depending on the presence or absence of concomitant type 2 diabetes. 95 patients with chronic heart failure II - III FC were examined due to coronary heart disease who were treated at the cardiological department of the Kharkiv City Clinical Hospital No 27 (mean age 65,13+/-8,66 years). The first group included 52 patients with CHF with type 2 diabetes, the second - 43 CHF patients without type 2 diabetes. Research was excluded patients with acute coronary syndrome, acute myocardial infarction. 71 patients of patients had II NYHA FC, 24 patients III FC. Among the patients of first group 40 patients were diagnosed in CHF FC II, 12 - III FC. In II group 31 patients were with CHF class II, 12 patients - with III FC. Concentration of proinflammatory cytokine interleukin-1beta and fibrosis factor monocyte chemoattractant protein-1 were determined by ELISA (enzyme-linked immunosorbent assay). In patients with chronic heart failure in presence or absence of type 2 diabetes increase in the profibrotic parameter monocyte chemoattractant protein-1 and proinflammatory cytokine interleukin-1beta were increasing in parallel with NYHA FC increasing. Presence of type 2 diabetes negatively affects the work of cytokines and markers of fibrosis, as evidenced by higher levels of interleukin-1beta and monocyte chemoattractant protein-1, compared with patients without diabetes in the presence of the same NYHA FC of chronic heart failure. PMID- 25020169 TI - [Features of the humoral immune response in patients with chronic hepatitis C, spontaneous clearance of hepatitis C virus and false-positive reactions of anti HCV]. AB - Among the patients residing in the territory of Ukraine false-positive reaction of anti-HCV was determined in 5.4% of anti-HCVpositive patients with low frequency of antibodies and low reactivity of sera to a structural viral protein or nonstructural viral proteins (by SIA or RIBA). Cases of spontaneous clearance of hepatitis C virus (HCV) were detected in 16.1% of anti-HCV positive patients and based on the detection of antibodies to the core-protein and one or several of nonstructural viral proteins on condition negativation of RNA-HCV twice with an interval of 6-12 months. Chronic hepatitis C with the presence of specific RNA HCV in blood serum was confirmed in 83.9% of patients. The group of examinees with spontaneous clearance of HCV was characterized by low humoral immune response compared to chronic persistent infection. PMID- 25020171 TI - The association of some genetic factors with pulmonary tuberculosis in Georgian and Azeri ethno groups. AB - Pulmonary Tuberculosis (TB) is still one of the major public health problems. Over the last half decade the significant problem is an increased ratio of drug resistant TB cases. TB is as well the most significant infectious disease in the country of Georgia. Pulmonary tuberculosis is assessed as a complex infectious disease affected by both, environmental and genetic factors. Present study was undertaken to find out the correlation between pulmonary tuberculosis and erythrocyte blood groups antigens determinant alleles (ABO - r, p, q; Rh D+, Rh D and MN - p, q) in two different, Georgian and Azeri, ethno groups. Immune serological methods, direct reaction of universal monoclonal antibodies were used. Materials processed by biostatistician methods. The study had shown different correlation of pulmonary tuberculosis to erythrocyte blood groups determinant alleles in Georgian and Azeri ethno groups. In Georgian ethno group pulmonary TB correlates with ABO-r and p, Rh-D,+' and MN-p alleles, whether ABO q, Rh-D,-' and MN-p in Azeri ethno group. PMID- 25020172 TI - [The analysis of changes bioelectrical activity of the muscles of the upper extremities in patients with traumatic deformation of the cervical spine]. AB - The analysis of changes in bioelectrical activity of the muscles of the upper extremities was held with the help of electromyography in 37 patients with traumatic deformation of the cervical spine in order to identify its dependence on the nature of the initial damage, the amount of deformation and the terms of its existence. It was revealed that in the instrumental evaluation of patients with uncomplicated traumatic deformation of the cervical spine in 33.3 % of cases determined subclinical signs of neurological disorders in the form of changes in the bioelectric activity of the muscles of the upper extremities, most often in the DF and CF types. Frequency of manifestation of peripheral neurologic symptoms is possible with all types of traumatic deformation equally. Violation of bioelectric activity of the muscles of the upper extremities may occur at any value of the angular deformation in the sagittal plane and at different terms of its existence. PMID- 25020173 TI - [The vitamin D sufficiency in children with recurrent bronchitis]. AB - Currently in the world there is no consensus on the provision of sufficient vitamin D and its optimum serum levels of both healthy children and patients with various pathological conditions. THE OBJECTIVE: investigation of vitamin D sufficiency in children with recurrent bronchitis (RB), living in Zaporozhye, by examining of 25(OH)D and parathormone serum level. The study involved 120 children aged 4 to 10 years, divided into 2 groups (60 children each): 1) children, occasionally ill with acute respiratory infections, 2) children with RB. Investigation of serum 25(OH)D was conducted between November and February. Decrease of vitamin D3 below 30 ng/ml in serum was observed in 85% (r<0,05) patients with RB (insufficiency), below 20 ng/ml - in 15% (deficit). The children aged 4-10 years with RB, who living in Zaporozhye, have decrease of serum 25(OH)D that characterizes their vitamin D3 supply as insufficient. PMID- 25020174 TI - Etiology as a predictor of morbidity after convulsive status epilepticus in children. AB - CSE is the most common childhood neurological emergency in developed countries, which can lead to neuro cognitive sequel and death with different hazards and outcome. The majority of authors'agreed that etiology is the main determinant of morbidity, but different studies reported different etiology groups as predictors of the poor outcome. Present study was conducted to evaluate predictive value of etiology in post CSE morbidity. Prospective, hospital-based study was performed in Tbilisi. Patients, aged from one month to 18 years with CSE, admitted to the emergency department of M. Iashvili Children's Central Hospital from March 2007 to March 2012 were included. The short-term outcome of CSE was evaluated after 30 days from admission and it was classified into three categories: unchanged neurologic status, neurological consequences (new neurologic deficit compared to the condition before CSE), and lethal outcome. 48 children aged one month- 18 years were analyzed. In our study acute symptomatic, remote symptomatic and progressive encephalopathy were associated with higher morbidity. Progressive encephalopathy is the most frequent etiology group which led to develop new neurological sequel after CSE and long duration of CSE. According to our data we conclude that children with idiopathic or febrile CSE have a favorable outcome. While acute symptomatic etiology group mostly was associated and statistical significant association were found with progressive encephalopathy and development morbidity after CSE. According to our data we conclude that children with idiopathic or febrile CSE have a favorable outcome. While progressive encephalopathy lead to develop morbidity after CSE. PMID- 25020175 TI - Effect of treatment of convulsive status epilepticus on outcome in children. AB - Convulsive Status Epilepticus (CSE) is most common neurological emergency in childhood. Condition has been defined as a convulsion lasting at least 30 min or recurrent convulsions occurring over a 30-min period without recovery of consciousness. It is generally accepted that early intervention for terminating seizures is beneficial for outcome. The aim of our study was to evaluate influences of pre-hospital and hospital treatment strategies on the outcome of CSE. Our prospective, hospital-based study was performed in Tbilisi and included 48 Patients with CSE, admitted to the emergency department of M. Iashvili Children's Central Hospital from March 2007 to March 2012. The cases were reviewed according to pre-hospital and hospital treatment strategies and outcome. "North Central London Epilepsy Network for Children & Young People" Guideline "The Management of Convulsive Status Epilepticus" was adapted for the Georgian reality. Our study identified statistically significant increase of incidence of artificial ventilation in patients receiving more than one dose of BZD in pre hospital as in hospital setting; additionally we found a statistically strong relationship between timely initiation of treatment and appropriate pre-hospital treatment with a short duration of CSE. From our data the number of doses of benzodiazepine and a long period before admission are the main determinants of seizure prolongation. Lack of Standardized pre hospital treatment of pediatric CSE had statistically significant negative influence on outcome of CSE. PMID- 25020176 TI - Isolation of dentin tissue by usinga new liner biodentine at management of simulated experimental caries. AB - The aim of our study was the use of different types of isolation systems in the treatment of experimentally simulated dental caries that will allow to present additional comparative characteristic for morphological responses of the pulp.For realization of this purpose, 3 systems have been selected: UltraBlend (Ultradent), Biodentine (Septodont) and adhesive system Prime&Bond NT (Dentsply). The study was conducted at the laboratory of Alexander Natishvili Institute of Morphology. For this experiment, 12 male, 6 months of age rabbits were selected. There were created 3 experimental groups, each of which included 4 rabbits. Restoration of the teeth in experimental rabbits with Biodentine revealed sufficient physical properties enabling the operator most comfortably conduct his/her clinical activities: kneading, bringing into caries cavity, condensing and filling dental defect. Isolation of dentin by Biodentine doesn't contradict and/or reduce application of adhesive systems, which is also important for teeth restorations. Biodentine has optimal working time (final curing 10-12 minutes) enabling the operator to conduct maximal formation of material at the bottom of caries cavity. PMID- 25020177 TI - [The morphological features of the uterine body adenocarcinoma]. AB - The anthors studied the morphological features of uterine adenocarcinoma using immunohistochemical methods. The endometrial tissue was studed resulting from surgery - hysterectomy with oophorectomy in 103 patients aged 45-76 years with a clinical diagnosis of endometrial cancer. To exclude false-positive and false negative results, we carry out same investigation on 12 patients with morphological diagnosis easy-glandular hyperplasia of the endometrium. The results showed that the endometrioid adenocarcinomas exhibit the high and moderate expression of estrogen and progesterone receptors and low rate of the proliferation marker Ki-67. For serous-paapillary andenocarcionoma of the uterine body the negative ER-PR-receptor over expression phenotype and proliferation marker Ki-67 superexpression are characteristic. The results showed that in a simple-glandular endometrial hyperplasia is determined a moderate expression of estrogen and progesterone receptors, as for the Ki-67 proliferation marker an expression was found only in the single arears with an average of 5-8% of findings. Based at shis study it may be concluded thate the use of immunohistochemical studies particularly a detection of negative estrogen and progesterone resceptor phenotype and high expression of the proliferation marker Ki-67 is an additional defferential diagnostic eriterion for the diagnosis of serous papillary adenocarcinoma of the uterine body thet will ensure adepuate therapeutis approach to patients suffering from this disorder. Given he fact that serous papillary carcinoma of the endometrium is the most common neoplesm of the rarer forms of endometrial cancer with an extremely peculiar aggressive coures a ssurgical treatment as in overian cancer is recommended for this parthology, including a hysterectomy with bilateral oophorectomy, lymphadenectomy, omentektomy, cytological examination of the abdomend and biopsy of suspicious areas of the abdominal cavity, with adjuvant treatment including chemotherapy and radiation therapy. The absence of estrogen and progesterone receptors on serous papilary adenocarcinoma of the uterine body justifies the inadvisability of hormone therapy in these patients. Since the patients with serous-papillary adenocarcinoma of the uterine body need a larger voluve surgical treatment the patients with endometrioid adenocarcinoma of the uterine body. We consider that this morphological type of uterine cancer should be diagnosed preoperatively. PMID- 25020178 TI - [Influence of radiation on survivability, behavior and neurochemical correlates of rats]. AB - The aim of the work was to study the dependence of individual radiosensitivity of white and black rats on radiation. The rats under study were derived from a cross between black and white rats and called Ratus Ratus-Georgia. Comparative radiosensitivity of white (Wistar) and black rats was studied at a total exposure with sublethal and lethal doses (5, 7 and 9 Gy). Cumulative survival functions of rats, a spectrum of changes in some ethological parameters and content of serotonin and catecholamines in their brain structures were given as criteria of radiosensitivity. Survival rate of black and white rats is connected with changes in the composition and distribution of biogenic amines in the various brain structures, as well as with a decrease of locomotor and orienting-exploratory activity, on the one hand, and with increase of emotionality, stereotyped activity, passive defensive behavior of the rats, on another. Regression coefficients of dependence of survival functions on irradiation doses of black rats were rather higher than those of white rats after irradiation with doses in 5, 7 and 9 Gy. A change in the intensity of mortality with changes in radiation dose per unit depends on the synthesis of serotonin and on the number of sulfhydryl groups, deficiency of which is one of the important factors for white rats. Results of the study allow us to suppose that changes in the radiation sensitivity of rats after irradiation with sublethal and lethal doses are caused by consequences of radiation damage and by activation of the serotonergic system at the process of restitution after radiation injury. On the other hand, a higher radiation sensitivity of white rats in comparison with that of black rats is caused by low content of serotonin, thiols, melanin and other biologically active substances which are endogenous radioprotectors defining individual radioresistance. PMID- 25020179 TI - The possible use of V. parahaemolyticus - specific bacteriophages for prevention and therapy of infections caused by V. parahaemolyticus. AB - Vibrio parahaemolyticus is the most common halophilic Vibrio species causing serious gastroenteritis in humans. The main source of infection is consumption of undercooked or raw seafood or exposure to contaminated water. The monitoring conducted in 2006-2008 demonstrated that warm, subtropical climate and low- to moderate salinity of water in the Black Sea coastal zone provides a favorable environment for growth and spread of V. parahaemolyticus bacteria. Antibiotics are commonly applied for control V.parahaemolyticus infections in humans. However, with the growing problem with bacterial antibiotic-resistance search for alternative biological anti-infectives, such as bacteriophages, becomes more actual. The aim of the presented work was characterization of V. parahamolyticus- specific bacteriophages in relation with their possible use for treatment and prevention of food and waterborne gastroenteritis in humans infected with V.parahaemolyticus. 69 bacteriophages specific to V.parahaemolyticus were isolated from different water sources and 5 of them were characterized according to their virion morphology, host-range, temperature and pH dependence. Stability of phages in different media and solutions, also susceptibility to action of a number of protolithic enzymes was studied as well. Obtained results showed that studied bacteriophages can be used for preparation of phage mixture as a potential therapeutic preparation against V.parahaemolyticus associated infections. PMID- 25020180 TI - [Chemical composition and microstructural peculiarities of overground and underground vegetative organs of field restharrow (Ononis arvensis L.)]. AB - The paper presents the results of the study of anatomy and chemical composition of Field Restharrow (Ononis arvensis L.). The existence of triterpene alcohol alpha-onocerin and isoflavons in the overground organs of the plant is established by chemical analysis. Oxycumarines - scopoletin and scopolin are isolated and identified. Morphological characterization of the whole plant is given. Anatomy of the vegetative organs of the species is examined. Among the main microstructural characteristics multilayer integumentary tissues, active periderm and sclerenchyma cells were specified in roots; and complex radial rays and structural units of wood, located radially, were observed in the central cylinder. Shoots are characterized with intensive pubescence. Mechanical tissues of different structures exist in the parenchime of crust and central cylinder of shoots. Vessels with spiral and spiro-annular thickened walls are located in the libriforms of wood. Leaves of Ononis arvensis are bifacial, mesophile is of dorsiventral structure; central conductive bunch is complex-collateral. Basal cells of upper and lower epidermis belong to of bent-walled type, where paracytal and anisocytal cells of stomatal apparatus are scattered chaotically. PMID- 25020181 TI - Dietary fiber's benefit for gallstone disease prevention during rapid weight loss in obese patients. AB - The aim of present study was to compare the effects of very low calorie diets - protein rich and dietary fiber rich food based - on gallstones formation during rapid weight loss. 68 patients were involved into the study. The body weight index in all cases exceeding normal value and equaled to 35+/-4,7 kg/m2. For weight correction purposes during 5 weeks the patients in first group were kept on a 520-800 kcal diet of "Margi" food products, prepared according our technology, and in the second group on a protein rich diet of the same calorie content. The body weight and changes in the gall-bladder wall and content were assessed by sonography before starting the diet, after three weeks from the commencement of the diet and upon its completion. The measurement of the body weight after completion of the 5 week diet revealed decrease by 10.9+/-1,5kg in the first group and by 11,2+/-1,1kg in the second group. Sonography disclosed growth in the amount of biliary sludge in 3 cases in the first group and in 9 cases in the second group. The statistical analyses of results indicate successful and nearly equal reduction of body weight by means of dietary fiber rich and protein rich diet, but high fiber consumption showed statistically significant benefits for prevention of biliary slug accumulation. The study showed that, in the respect to weight loss, diets based on fiber rich and protein rich food are equal, but fiber rich diet has considerable privilege in prevention of gallstone disease. Our findings support the presence of known association between increased dietary fiber consumption and reduction of gallstone formation. Obesity and rapid weight loss are risk factors for development of gallstones. Taking in an account the beneficial effect of dietary fiber, the food rich with this nutrient, particularly low-calorie fiber rich food "Margi", can be recommended for rapid weight loss in obese patients. PMID- 25020182 TI - Exploring robust diagnostic signatures for cutaneous melanoma utilizing genetic and imaging data. AB - Multimodal data combined in an integrated dataset can be used to aim the identification of instrumental biological actions that trigger the development of a disease. In this paper, we use an integrated dataset related to cutaneous melanoma that fuses two separate sets providing complementary information (gene expression profiling and imaging). Our first goal is to select a subset of genes that comprise candidate genetic biomarkers. The derived gene signature is then utilized in order to select imaging features, which characterize disease at a macroscopic level, presenting the highest, mutual information content to the selected genes. Using information gain ratio measurements and exploration of the gene ontology tree, we identified a set of 32 uncorrelated genes with a pivotal role as regards molecular regulation of melanoma, which expression across samples correlates highly with the different pathological states. These genes steered the selection of a subset of uncorrelated imaging features based on their ranking according to mutual information measurements to the selected gene expression values. Selected genes and imaging features were used to train various classifiers that could generalize well when discriminating malignant from benign melanoma samples. Results on the selection on imaging features and classification were compared to feature selection based on a straight forward statistical selection and a stochastic-based methodology. Genes in the backstage of low-level biological processes showed to carry higher information content than the macroscopic imaging features. PMID- 25020183 TI - A Bayesian Estimation Framework for Pharmacogenomics Driven Warfarin Dosing: A Comparative Study. AB - The incorporation of pharmacogenomics information into the drug dosing estimation formulations has been shown to increase the accuracy in drug dosing and decrease the frequency of adverse drug effects in many studies in the literature. In this paper, an estimation framework based on the Bayesian structural equation modeling, which is driven by pharmacogenomics, is proposed. The results show that the model compares favorably with the linear models in terms of prediction and explaining the variations in warfarin dosing. PMID- 25020184 TI - Enantioselective synthesis of polycyclic nitrogen heterocycles by Rh-catalyzed alkene hydroacylation: constructing six-membered rings in the absence of chelation assistance. AB - Catalytic, enantioselective hydroacylations of N-allylindole-2-carboxaldehydes and N-allylpyrrole-2-carboxaldehydes are reported. In contrast to many alkene hydroacylations that form six-membered rings, these annulative processes occur in the absence of ancillary functionality to stabilize the acylrhodium(III) hydride intermediate. The intramolecular hydroacylation reactions generate 7,8 dihydropyrido[1,2-a]indol-9(6H)ones and 6,7-dihydroindolizin-8(5H)-ones in moderate to high yields with excellent enantioselectivities. PMID- 25020185 TI - Relationship between glycemic control, microalbuminuria and cognitive functions in elderly type 2 diabetic patients. AB - AIM: The prevalence of diabetes is increasing in elderly populations, and is thought to be an important risk factor for cognitive dysfunction in this age group. METHODS: The study included 104 patients aged over 60 years who were followed-up for type 2 diabetes for at least 6 months, in addition to 44 controls. Glycemic parameters, microangiopathic complications, microalbumin elimination, and the Standardized Mini Mental State Examination (SMMSE) scores were used as indicators of cognitive function. RESULTS: The SMMSE scores of diabetic patients were significantly lower than the control group (p < 0.05). The average SMMSE score for normoalbuminuric diabetic patients was 22.36 +/- 4.66, compared with 22.61 +/- 4.90 for the microalbuminuria patients (p = 0.84). A positive correlation was found between SMMSE scores and patients' hemoglobin values and education levels, whereas a negative correlation was noted between SMMSE scores and systolic and diastolic blood pressures and hemoglobin A1c levels (p < 0.05). Patients with diabetic neuropathy, a microvascular complication of diabetes, were found to have significantly lower SMMSE scores (p = 0.011). CONCLUSION: Elderly diabetic patients showed decreased cognitive function compared to volunteers. No relationship was established between microalbuminuria and cognitive functions, although diabetic neuropathy was found to be related to decreased cognitive function. PMID- 25020186 TI - Reflex sympathetic dystrophy-like syndrome, possibly caused by aripiprazole, in an adolescent patient. PMID- 25020188 TI - Flexible binder-free metal fibril mat-supported silicon anode for high performance lithium-ion batteries. AB - We report the fabrication of a flexible and binder-free metal fibril mat supported Si anode (Si@SFM) by a simple process. The fabricated Si@SFM anode showed a high discharge capacity, ~3000 mAh g(-1) at a current rate of 300 mA g( 1), and exhibited stable capacity retention, 90% at a 1 C rate (2000 mA g(-1)) after 200 cycles. The rate capability of the electrode was still high even when both the charge and the discharge current rates were markedly increased at the same time (1234 mAh g(-1) for charge-discharge time of ~12 min). Moreover, owing to its mechanical flexibility, the Si@SFM can be adopted as a key component of flexible lithium-ion batteries (LIBs). After cell packaging, the rechargeable flexible battery under bending stress showed only a little capacity fading (86% of initial capacity) at 1000 mA g(-1) over 150 cycles. These results suggest that the Si@SFM electrode is readily suitable for use in rechargeable flexible LIBs. PMID- 25020189 TI - Reconfigurable nanoantennas using electron-beam manipulation. AB - Plasmonic nanoantennas have been of increasing interest due to their ability to confine and enhance electric fields in deep sub-wavelength volumes, leading to large near-field optical forces and high refractive index sensitivity. Recently, to enhance the response for sensor applications, metal nanoantennas have been fabricated on pillars. An overlooked consequence of this elevated geometry is the introduction of the mechanical properties, for example, stiffness, as a tunable degree of freedom. Here we demonstrate pillar-bowtie nanoantenna arrays, fabricated on optically transparent SiO2, as a candidate system that couples intrinsic mechanical and electromagnetic degrees of freedom via gradient forces. We show that using a standard scanning electron microscope, individual nanoantenna gap sizes can be controllably tuned down to 5 nm, a factor of ~4 * smaller than what is currently achievable using conventional electron-beam lithography. This approach opens new avenues for fabricating reconfigurable nanoantennas that can inform exciting photonic applications. PMID- 25020190 TI - Fluorescent supramolecular metal assemblies as 'no quenching' probes for detection of threonine in the nanomolar range. AB - A highly sensitive detection of threonine is realized using a supramolecular ensemble of aggregates of hetero-oligophenylene derivative and Zn(2+) ions. On the basis of fluorogenic response of aggregates of toward Zn(2+) ions and threonine, we have constructed a 2-input, 3-output sequential logic circuit at the molecular level. PMID- 25020191 TI - Open bis(triazolium) structural motifs as a benchmark to study combined hydrogen- and halogen-bonding interactions in oxoanion recognition processes. AB - We have designed a series of triazolium-pyrene-based dyads to probe their potential as fluorescent chemosensors for anion recognition through combinations of hydrogen and halogen bonding. Cooperation between the two distinct noncovalent interactions leads to an unusual effect on receptor affinity, as a result of fundamental differences in the interactions of halogen and hydrogen bond donor groups with anions. Absorption, emission spectrophotometries and proton and phosphorus NMR spectroscopies indicate that the two interactions act in concert to achieve the selective binding of the hydrogen pyrophosphate anion, a conclusion supported by computational studies. Hence, as clearly demonstrated with respective halogen- and hydrogen-bonding triazolium receptors, the integration of a halogen atom into the anion receptor at the expense of one hydrogen-bonding receptor greatly influences the anion recognition affinity of the receptor. The association constant values of the halogen-bonding complexes are larger than the hydrogen-bonding counterpart. Thus, halogen bonding has been exploited for the selective fluorescent sensing of hydrogen pyrophosphate anion. Halogen bonding has been demonstrated to increase the strength of hydrogen pyrophosphate binding, as compared to the hydrogen-bonded analogue. Grimme's PBE D functional, which adequately reproduces the pyrene stacking energies, has been successfully applied to model the affinity for anions, especially hydrogen pyrophosphate, of the new receptors. PMID- 25020192 TI - In vitro immunomodulatory properties of a sesquiterpene lactone-bearing fraction from Artemisia khorassanica. AB - Artemisia species are important medicinal plants throughout the world. The present in vitro study, using a sesquiterpene lactone-bearing fraction prepared from Artemisia khorassanica (SLAK), sought to investigate immunomodulatory/anti inflammatory properties of this plant and elucidate potential underlying mechanisms for the actions. Effects of the SLAK on mitogen-induced murine splenocyte proliferation and interleukin (IL)-4 and interferon (IFN)-gamma secretion were evaluated. To assess anti-inflammatory activities, levels of inducible of nitric oxide (NO) and prostaglandin E2 (PGE2), as well as expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in peritoneal macrophages was examined. The results showed that SLAK noticeably was capable of suppressing PHA/LPS-stimulated splenocyte proliferation and of up regulating production of the T-helper (TH)-2 cell cytokine IL-4 while down regulating formation of TH1 IFNgamma. In addition, while SLAK caused negligible proliferation inhibition, peritoneal macrophages displayed considerable decrease in NO and PGE2 production along with iNOS and COX-2 expression. The current experiment shows Artemisia khorasanica - a traditionally used herb - may have immunomodulatory and anti-inflammatory effects. It is anticipated that the ingredients may be employed as therapeutic candidates in the regulation of some immune responses implicated in various conditions and ailments. PMID- 25020194 TI - Development and characterisation of monoclonal antibodies reactive with porcine CSF1R (CD115). AB - Macrophage colony-stimulating factor (CSF1) controls the proliferation and differentiation of cells of the mononuclear phagocyte system. CSF1, alongside a second ligand, interleukin-34 (IL-34), acts by binding to a cell surface receptor (CSF1R). We previously cloned and expressed pig CSF1 and IL-34. Here we produced a pig CSF1R-Ig+pFUSE Fc fusion protein and used it as an immunogen to produce three monoclonal antibodies (ROS8G11, ROS3A5 and ROS3B10) targeted against porcine CSF1R. Specific binding of each monoclonal antibody was confirmed by ELISA, Western blot, flow cytometry and immunocytochemistry. The antibodies did not block CSF1 signalling. The surface expression of CSF1R in pig peripheral blood was restricted to CD14-positive monocytes and was also detected on lung macrophages. These antibodies provided an opportunity to investigate the increase of available CSF1R during pig BMDM differentiation. The new monoclonal antibodies provide useful reagents to support the study of monocyte and macrophage biology in the pig. PMID- 25020193 TI - Replacement of two aminoacids in the bovine Toll-like receptor 5 TIR domain with their human counterparts partially restores functional response to flagellin. AB - Flagellin potently induces inflammatory responses in mammalian cells by activating Toll-like receptor (TLR) 5. Recently, we were able to show that stimulation of bovine TLR5 resulted in neither NFkappaB signalling nor CXCL8 production. Like other TLRs, TLR5 recruits signalling molecules to its intracellular TIR domain, leading to inflammatory responses. Analysis of available TLR5 sequences revealed substitutions in all artiodactyl sequences at amo acid (AA) position 798 and 799. Interestingly, a putative binding site for PI3K was identified at tyrosine 798 in the human TLR5 TIR domain, analogous to the PI3K recruitment domain in the IL-1 receptor. Mutation of the artiodactyl residues at position 798, 799 or both with their corresponding human counterparts partially restored the response of bovine (bo)TLR5 to flagellin as well as phosphorylation of PI3K. Together, our results suggest a potential lack of phosphorylation of F798 and H799 in boTLR5 partially explains the lack in observed response. PMID- 25020195 TI - Flagellin from Marinobacter algicola and Vibrio vulnificus activates the innate immune response of gilthead seabream. AB - Adjuvants have emerged as the best tools to enhance the efficacy of vaccination. However, the traditional adjuvants used in aquaculture may cause adverse alterations in fish making necessary the development of new adjuvants able to stimulate the immune system and offer strong protection against infectious pathogens with minimal undesirable effects. In this respect, flagellin seems an attractive candidate due to its ability to strongly stimulate the immune response of fish. In the present study, we have evaluated the ability of recombinant flagellin from Marinobacter algicola (MA) and Vibrio vulnificus (Vvul), a non pathogenic and a pathogenic bacteria, respectively, to stimulate the innate immune system of gilthead seabream (Sparus aurata L.) and compare the effect with that of the classical flagellin from Salmonella enterica serovar Typhimurium (Salmonella Typhimurium, STF). Intraperitoneal injection of MA and Vvul resulted in a strong inflammatory response characterized by increased reactive oxygen species production and the infiltration of acidophilic granulocytes at the injection site. Interestingly, however, only flagellin from MA consistently induced the expression of the gene encoding pro-inflammatory interleukin-1beta. These effects were further confirmed in vitro, where a dose-dependent activation of macrophages and acidophilic granulocytes by MA and Vvul flagellins was observed. In contrast, STF flagellin was found to be less potent in both in vivo and in vitro experiments. Our results suggest the potential use of MA and Vvul flagellins as immunostimulants and adjuvants for fish vaccination. PMID- 25020196 TI - Uptake of yeast cells in the Atlantic salmon (Salmo salar L.) intestine. AB - The intestinal mucosa is an important port of entry for many pathogens. Information of antigen uptake mechanisms is essential to understand and to possibly prevent infections. In teleosts, several studies have aimed at investigating particulate uptake in the gastrointestinal system that seems to vary dependent on fish species and antigen. In the present study, particulate uptake in the Atlantic salmon intestine by anal intubation of yeast cells has been investigated. In the anal intubated fish, yeast were found in the epithelium close to nuclei of macrophage-like cells and inside large mononuclear cells in the intestinal lumen, indicating uptake and possible transport of large antigen particles over the epithelium by macrophage-like cells. PMID- 25020198 TI - CH3NH3PbI(3-x)(BF4)x: molecular ion substituted hybrid perovskite. AB - A molecular ion (BF4(-)) substituted hybrid perovskite CH3NH3PbI(3-x)(BF4)x is synthesized. The substituted perovskite shows significant enhancement in electrical conductivity at low frequencies and improved photoresponse under AM1.5 illumination as compared to the perovskite (CH3NH3PbI3). PMID- 25020197 TI - Molecular profile and functional characterization of the ferritin H subunit from rock bream (Oplegnathus fasciatus), revealing its putative role in host antioxidant and immune defense. AB - Ferritins are iron binding proteins made out of 24 subunits, involved in iron homeostasis and metabolism in cellular environments. Here, we sought to identify and functionally characterize a one type of subunits of ferritin (ferritin H-like subunit) from rock bream (Oplegnathus fasciatus; RbFerH). The complete coding sequence of RbFerH was 531 bp in length, encoding a 177-amino acid protein with a predicted molecular mass of 20.8 kDa. The deduced protein structure possessed the domain architecture characteristic of known ferritin H subunits, including metal ligands for iron binding, a ferroxidase center, and two iron-binding region signatures. As expected, the 5' untranslated region of the RbFerH cDNA sequence contained a putative iron response element region, a characteristic regulatory element involved in its translation. The RbFerH gene comprised 5 exons and 4 introns spanning a 4195 bp region. Overexpressed recombinant RbFerH protein demonstrated prominent Fe(II) ion depriving activity, bacteriostatic properties, and protective effects against oxidative double-stranded DNA damage. Using quantitative polymerase chain reaction (qPCR), we found that RbFerH was expressed ubiquitously in the majority of physiologically important tissues in rock bream. A greater abundance of the mRNA transcripts were detected in blood and liver tissues. Upon administering different microbial pathogens and pathogen-derived mitogens, RbFerH transcription was markedly elevated in the blood of rock bream. Taken together, our findings suggest that RbFerH acts as a potent iron sequestrator in rock bream and may actively participate in antimicrobial as well as antioxidative defense. PMID- 25020199 TI - Antithrombotic activities of wogonin and wogonoside via inhibiting platelet aggregation. AB - Wogonin (WGN), a flavonoid extracted from Scutellaria baicalensis Georgi, has several biological effects including antioxidant, anti-inflammatory, antiviral, neuroprotective, anxiolytic, and anticancer activities, and the flavonoid wogonoside (WGNS) can be derived from S. baicalensis, as it is a metabolite of wogonin. Here, the anticoagulant activities of WGN(S) were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin (factor IIa, FIIa) and activated factor X (FXa), and the effects of WGN(S) on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor (TNF)-alpha activated human umbilical vein endothelial cells (HUVECs). Treatment with WGN(S) resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, WGN(S) inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. WGN(S) also elicited anticoagulant effects in mice. In addition, treatment with WGN(S) resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, WGN(S) possesses antithrombotic activities and offers a basis for development of a novel anticoagulant. PMID- 25020200 TI - Sizing it up: the mechanical feedback hypothesis of organ growth regulation. AB - The question of how the physical dimensions of animal organs are specified has long fascinated both experimentalists and computational scientists working in the field of developmental biology. Research over the last few decades has identified many of the genes and signaling pathways involved in organizing the emergent multi-scale features of growth and homeostasis. However, an integrated model of organ growth regulation is still unrealized due to the numerous feedback control loops found within and between intercellular signaling pathways as well as a lack of understanding of the exact role of mechanotransduction. Here, we review several computational and experimental studies that have investigated the mechanical feedback hypothesis of organ growth control, which postulates that mechanical forces are important for regulating the termination of growth and hence the final physical dimensions of organs. In particular, we highlight selected computational studies that have focused on the regulation of growth of the Drosophila wing imaginal disc. In many ways, these computational and theoretical approaches continue to guide experimental inquiry. We demonstrate using several examples how future progress in dissecting the crosstalk between the genetic and biophysical mechanisms controlling organ growth might depend on the close coupling between computational and experimental approaches, as well as comparison of growth control mechanisms in other systems. PMID- 25020201 TI - Map transfer from the thalamus to the neocortex: inputs from the barrel field. AB - Sensory perception relies on the formation of stereotyped maps inside the brain. This feature is particularly well illustrated in the mammalian neocortex, which is subdivided into distinct cortical sensory areas that comprise topological maps, such as the somatosensory homunculus in humans or the barrel field of the large whiskers in rodents. How somatosensory maps are formed and relayed into the neocortex remain essential questions in developmental neuroscience. Here, we will present our current knowledge on whisker map transfer in the mouse model, with the goal of linking embryonic and postnatal studies into a comprehensive framework. PMID- 25020202 TI - Photocurrent enhancement of HgTe quantum dot photodiodes by plasmonic gold nanorod structures. AB - The near-field effects of noble metal nanoparticles can be utilized to enhance the performance of inorganic/organic photosensing devices, such as solar cells and photodetectors. In this work, we developed a well-controlled fabrication strategy to incorporate Au nanostructures into HgTe quantum dot (QD)/ZnO heterojunction photodiode photodetectors. Through an electrostatic immobilization and dry transfer protocol, a layer of Au nanorods with uniform distribution and controllable density is embedded at different depths in the ZnO layer for systematic comparison. More than 80 and 240% increments of average short-circuit current density (Jsc) are observed in the devices with Au nanorods covered by ~7.5 and ~4.5 nm ZnO layers, respectively. A periodic finite-difference time domain (FDTD) simulation model is developed to analyze the depth-dependent property and confirm the mechanism of plasmon-enhanced light absorption in the QD layer. The wavelength-dependent external quantum efficiency spectra suggest that the exciton dissociation and charge extraction efficiencies are also enhanced by the Au nanorods, likely due to local electric field effects. The photodetection performance of the photodiodes is characterized, and the results show that the plasmonic structure improves the overall infrared detectivity of the HgTe QD photodetectors without affecting their temporal response. Our fabrication strategy and theoretical and experimental findings provide useful insight into the applications of metal nanostructures to enhance the performance of organic/inorganic hybrid optoelectronic devices. PMID- 25020204 TI - Bilateral catamenial pneumothorax and pulmonary emboli. PMID- 25020205 TI - Congenital heart disease and adverse perinatal outcome in fetuses with confirmed isolated single functioning umbilical artery. AB - To examine the association between isolated single umbilical artery (SUA) and congenital heart disease/adverse perinatal outcome in an Australian tertiary centre. The study population was comprised of fetuses diagnosed with SUA at the mid-trimester scan between May 2003 and March 2009 during detailed ultrasound examination at The Royal Women's Hospital Melbourne, Australia. Colour Doppler was used to visualise the umbilical arteries adjacent to the fetal bladder and in a section of a free loop of cord. The diagnosis of SUA was confirmed on histopathology examination of the placenta and umbilical cord. Monochorionic twins, fetuses with chromosomal abnormalities or concurrent extracardiac anomalies were excluded from the study. A total of 261 fetuses with SUA were identified in the study period and 146 (59%) cases were isolated; no chromosomal or extracardiac abnormalities were present. Complete data were available in 104/146 pregnancies (71.2%). The mean gestational age at diagnosis was 21 weeks. A cardiac anomaly was detected in 19 of these fetuses (13.0%): six hypoplastic left heart syndromes; three coarctations of the aorta; two tetralogies of Fallot; two hypoplastic right heart syndromes; two pulmonary atresia/stenosis; one absent ductus venosus with cardiomegaly; one left isomerism; one right isomerism and one transposition of the great arteries. Fetal growth restriction was present in 9.8% (10) and preterm delivery before 34 weeks occurred in nine cases (8.7%). Our study has shown that isolated SUA is associated with cardiac anomalies, but is not associated with increased frequency of FGR and preterm delivery before 34 weeks. PMID- 25020203 TI - Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection. AB - BACKGROUND: Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity. PATIENTS AND METHODS: We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (>=60 mg/m2) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%). RESULTS: Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012). CONCLUSIONS: A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial. PMID- 25020206 TI - Feasibility and efficacy of intraperitoneal docetaxel administration as salvage chemotherapy for malignant gynaecological ascites. AB - Ovarian and endometrial cancers diagnosed at advanced stages are often associated with malignant ascites. This study aimed to determine the safety, feasibility and efficacy of intraperitoneal (IP) docetaxel (TXT) for the treatment of ascites. A phase I study, including nine patients, was undertaken to determine the maximum tolerable dose. Efficacy was retrospectively assessed in 18 patients treated with 40-70 mg/m(2) IP TXT between 2005 and 2012. In a phase I study, the dose was safely escalated to a maximum of 70 mg/m(2), at which level no patients had grade -3 haematological adverse events. In a retrospective study of 18 patients, seven had an Eastern Cooperative Oncology Group performance status of 3; 16 had prior paclitaxel administration and two, with doses of 40 and 70 mg/m(2), experienced a serological response and a decrease in paracentesis. Thus, palliative treatment of recurrent OC should be further studied with 40 mg/m(2) among more patients, and 70 mg/m(2) could be evaluated for first-line IP chemotherapy. PMID- 25020207 TI - A rare cause of anaemia in pregnancy. PMID- 25020208 TI - Two successful sequential pregnancies in the same woman following aortic valvotomy with coarctation repair and subsequent Ross procedure for bicuspid aortic valve and aortic coarctation. PMID- 25020209 TI - Dermatofibrosarcoma protuberans of the vulva. PMID- 25020210 TI - Pulmonary embolism presenting as a seizure in the immediate postpartum period. PMID- 25020211 TI - Mortality of breast cancer in Taiwan, 1971-2010: temporal changes and an age period-cohort analysis. AB - The current paper describes the age, period and cohort effects on breast cancer mortality in Taiwan. Female breast cancer mortality data were collected from the Taiwan death registries for 1971-2010. The annual percentage changes, age- standardised mortality rates (ASMR) and age-period-cohort model were calculated. The mortality rates increased with advancing age groups when fixing the period. The percentage change in the breast cancer mortality rate increased from 54.79% at aged 20-44 years, to 149.78% in those aged 45-64 years (between 1971-75 and 2006-10). The mortality rates in the 45-64 age group increased steadily from 1971 to 1975 and 2006-10. The 1951 birth cohorts (actual birth cohort; 1947-55) showed peak mortalities in both the 50-54 and 45-49 age groups. We found that the 1951 birth cohorts had the greatest mortality risk from breast cancer. This might be attributed to the DDT that was used in large amounts to prevent deaths from malaria in Taiwan. However, future researches require DDT data to evaluate the association between breast cancer and DDT use. PMID- 25020212 TI - Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway. AB - The upper airway is often modeled as a Starling resistor, which predicts that flow is independent of inspiratory effort during flow limitation. However, while some obstructive sleep apnea (OSA) patients exhibit flat, Starling resistor-like flow limitation, others demonstrate considerable negative effort dependence (NED), defined as the percent reduction in flow from peak to mid-inspiration. We hypothesized that the variability in NED could be due to differences in phasic pharyngeal muscle activation between individuals. Therefore, we induced topical pharyngeal anesthesia to reduce phasic pharyngeal muscle activation to see if it increased NED. Twelve subjects aged 50+/-10 years with a BMI of 35+/-6 kg/m(2) and severe OSA (apnea-hypopnea index=52+/-28 events/h) were studied. NED and phasic genioglossus muscle activity (EMG(GG)) of flow limited breaths were determined before and after pharyngeal anesthesia with lidocaine. Pharyngeal anesthesia led to a 33% reduction in EMG(GG) activity (p<0.001), but NED worsened only by 3.6+/-5.8% (p=0.056). In conclusion, phasic EMG(GG) had little effect on NED. This finding suggests that individual differences in phasic EMG(GG) activation do not likely explain the variability in NED found among OSA patients. PMID- 25020213 TI - Hyperventilation with and without maintenance of isocapnia: a comparison of selected gasometric and respiratory parameters. AB - The aims of this study were to examine selected respiratory and gasometric parameters during hyperventilation with and without isocapnia and to identify the possible mechanism by which isocapnic hyperventilation might be useful in the elimination of volatile substances, including CO. Ten healthy non-smoking volunteers were studied, and each underwent two procedures. During one session, CO2 was added to the respiratory circuit, and during the other session, only 100% O2 was used. The volunteers were coached to hyperventilate until the appearance of side effects. Isocapnic hyperventilation significantly increased alveolar minute ventilation and partial pressure of oxygen in arterialized capillary blood (paO2); to the best of our knowledge, these findings have not previously been reported. Isocapnic hyperventilation was associated with only mild side effects, such as dyspnea, increased respiratory effort and headache, in 30% of subjects. Side effects, including vertigo, paresthesias and muscle tremor, were present in 70% of the volunteers during hyperventilation with 100% O2, and these side effects forced them to limit their respiratory rates and tidal volumes. These increases in alveolar ventilation and the partial pressure of oxygen in the blood may play crucial roles in decreasing the half-time of carboxyhemoglobin, which is the primary goal of the treatment of CO poisoning. PMID- 25020215 TI - Upcoming enhancements to the publishing process. PMID- 25020214 TI - The pearl necklace sign: a novel spectral domain optical coherence tomography finding in exudative macular disease. AB - PURPOSE: To report a novel spectral domain optical coherence tomography finding in exudative macular disease, called the pearl necklace sign. METHODS: A retrospective case series of 21 eyes (20 patients) with chronic exudative maculopathy resulting from age-related macular degeneration, diabetic macular edema, branch retinal vein occlusion, retinal arterial macroaneurysm, and Coats disease. Spectral domain optical coherence tomography images were carefully evaluated and correlated with color fundus photography, near-infrared reflectance, and fluorescein angiography. RESULTS: A unique spectral domain optical coherence tomography macular finding of hyperreflective dots in a contiguous ring around the inner wall of cystoid spaces in the outer plexiform layer of the retina that the authors refer to as the pearl necklace sign was seen in all patients. Visual acuity ranged from 20/30 to hand motions. The cystoid spaces and the hyperreflective dots resolved in certain cases after anti-vascular endothelial growth factor therapy and/or focal macular laser, but tended to recur. CONCLUSION: Because the pearl necklace configuration can be found adjacent to hard exudates in the outer plexiform layer, the authors speculate that the hyperreflective material is composed of lipoproteins or lipid-laden macrophages. This novel spectral domain optical coherence tomography sign gives further insight into the development and progression of hard lipoprotein exudates in exudative maculopathy. PMID- 25020216 TI - Enhanced osteoblast proliferation and corrosion resistance of commercially pure titanium through surface nanostructuring by ultrasonic shot peening and stress relieving. AB - This investigation was carried out to study the effect of a novel process of surface modification, surface nanostructuring by ultrasonic shot peening, on osteoblast proliferation and corrosion behavior of commercially pure titanium (c p-Ti) in simulated body fluid. A mechanically polished disc of c p-Ti was subjected to ultrasonic shot peening with stainless steel balls to create nanostructure at the surface. A nanostructure (<20 nm) with inhomogeneous distribution was revealed by atomic force and scanning electron microscopy. There was an increase of approximately 10% in cell proliferation, but there was drastic fall in corrosion resistance. Corrosion rate was increased by 327% in the shot peened condition. In order to examine the role of residual stresses associated with the shot peened surface on these aspects, a part of the shot peened specimen was annealed at 400 degrees C for 1 hour. A marked influence of annealing treatment was observed on surface structure, cell proliferation, and corrosion resistance. Surface nanostructure was much more prominent, with increased number density and sharper grain boundaries; cell proliferation was enhanced to approximately 50% and corrosion rate was reduced by 86.2% and 41% as compared with that of the shot peened and the as received conditions, respectively. The highly significant improvement in cell proliferation, resulting from annealing of the shot peened specimen, was attributed to increased volume fraction of stabilized nanostructure, stress recovery, and crystallization of the oxide film. Increase in corrosion resistance from annealing of shot peened material was related to more effective passivation. Thus, the surface of c p-Ti, modified by this novel process, possessed a unique quality of enhancing cell proliferation as well as the corrosion resistance and could be highly effective in reducing treatment time of patients adopting dental and orthopedic implants of titanium and its alloys. PMID- 25020217 TI - An interocclusal recording method for the fabrication of full-arch implant retained restorations. AB - The prosthetic rehabilitation of full arches with implants requires exact impression and bite registration. In this report, we describe the application of a simple method that uses a duplicate of the full denture as a mounting guide, which allows the accurate recording of the maxillomandibular relationship and bite registration while expediting this process for the treating dentist. Case reports of 2 patient are used to illustrate this method, which is independent of the implant system used, can be applied for both fixed and removable restorations, and reduces chair time. PMID- 25020218 TI - Repair of a multiple implant-supported fixed superstructure with a metal-ceramic resin-bonded fixed partial denture: a clinical report. AB - Even in the case of implant loss, replacement of the implant and refabrication of the superstructure are often sufficient, as long as the bone and soft tissue are in good condition. However, if implant loss accompanied by serious bone resorption occurs with a fixed implant superstructure supported by multiple implants, it is very difficult to treat. This clinical report describes the process by which multiple implant-supported fixed metal ceramic restorations were repaired with a metal ceramic resin-bonded fixed partial denture without complete refabrication after removal of one of the implants due to severe bone resorption. The 3-year follow-up indicated excellent serviceability and a well-satisfied patient. PMID- 25020219 TI - Postoperative perforation of the Schneiderian membrane in maxillary sinus augmentation: a case report. AB - Perforation of the Schneiderian membrane constitutes a major intraoperative complication of maxillary sinus floor elevation with graft materials, but postoperative perforation of the sinus membrane is very rare. This case report demonstrates that conservative treatment involving drainage and the administration of systemic antibiotics can be used to successfully treat postoperative sinus membrane perforation with infection of the graft material. PMID- 25020220 TI - The "washing line" suture technique for securing the Subepithelial Connective Tissue Graft. AB - Following tooth extraction, resorption of the buccal wall of the socket will occur; this will be true for both the maxilla and the mandible. Where the extraction site is surrounded by natural dentition, the loss of the buccal alveolar plate can degrade the visual aesthetics of an implant-supported prosthetic rehabilitation. To aid the harmonization of the hard and soft tissue morphology, both hard and soft tissue augmentation can be carried out either consecutively with an extraction/immediate implant placement or prior to an implant placement in the delayed scenario. The contemporary method of increasing soft tissue volume is to use the Subepithelial Connective Tissue (auto) Graft (the SCTG). The graft requires fixation, otherwise it can be extruded from the recipient site. This article presents a novel suturing technique which can confidently secure the SCTG, thus resisting its dislodgement. PMID- 25020221 TI - Second harvest of mandibular ramus blocks in bone augmentation procedures: a case letter. PMID- 25020222 TI - Piezosurgery applied to implant dentistry: clinical and biological aspects. AB - Piezosurgery is a new and modern technique of bone surgery in implantology. Selective cutting is possible for different ultrasonic frequencies acting only in hard tissues (mineralized), saving vital anatomical structures. With the piezoelectric osteotomy technique, receptor site preparation for implants, autogenous bone graft acquistition (particles and blocks), osteotomy for alveolar bone crest expansion, maxillary sinus lifting, and dental implant removal can be performed accurately and safely, providing excellent clinical and biological results, especially for osteocyte viability. The aim of this review was, through literature review, to present clinical applications of piezosurgery in implant dentistry and outline their advantages and disadvantages over conventional surgical systems. Moreover, this study addressed the biological aspects related to piezosurgery that differentiate it from those of bone tissue approaches. Overall, piezosurgery enables critical operations in simple and fully executable procedures; and effectively, areas that are difficult to access have less risk of soft tissue and neurovascular tissue damage via piezosurgery. PMID- 25020223 TI - Learning locality preserving graph from data. AB - Machine learning based on graph representation, or manifold learning, has attracted great interest in recent years. As the discrete approximation of data manifold, the graph plays a crucial role in these kinds of learning approaches. In this paper, we propose a novel learning method for graph construction, which is distinct from previous methods in that it solves an optimization problem with the aim of directly preserving the local information of the original data set. We show that the proposed objective has close connections with the popular Laplacian Eigenmap problem, and is hence well justified. The optimization turns out to be a quadratic programming problem with n(n-1)/2 variables (n is the number of data points). Exploiting the sparsity of the graph, we further propose a more efficient cutting plane algorithm to solve the problem, making the method better scalable in practice. In the context of clustering and semi-supervised learning, we demonstrated the advantages of our proposed method by experiments. PMID- 25020224 TI - Fuzzy forecasting based on two-factors second-order fuzzy-trend logical relationship groups and the probabilities of trends of fuzzy logical relationships. AB - In this paper, we present a new method for fuzzy forecasting based on two-factors second-order fuzzy-trend logical relationship groups and the probabilities of trends of fuzzy-trend logical relationships. Firstly, the proposed method fuzzifies the historical training data of the main factor and the secondary factor into fuzzy sets, respectively, to form two-factors second-order fuzzy logical relationships. Then, it groups the obtained two-factors second-order fuzzy logical relationships into two-factors second-order fuzzy-trend logical relationship groups. Then, it calculates the probability of the "down-trend," the probability of the "equal-trend" and the probability of the "up-trend" of the two factors second-order fuzzy-trend logical relationships in each two-factors second order fuzzy-trend logical relationship group, respectively. Finally, it performs the forecasting based on the probabilities of the down-trend, the equal-trend, and the up-trend of the two-factors second-order fuzzy-trend logical relationships in each two-factors second-order fuzzy-trend logical relationship group. We also apply the proposed method to forecast the Taiwan Stock Exchange Capitalization Weighted Stock Index (TAIEX) and the NTD/USD exchange rates. The experimental results show that the proposed method outperforms the existing methods. PMID- 25020225 TI - Exponential Hinfinity filtering for discrete-time switched neural networks with random delays. AB - This paper addresses the exponential Hinfinity filtering problem for a class of discrete-time switched neural networks with random time-varying delays. The involved delays are assumed to be randomly time-varying which are characterized by introducing a Bernoulli stochastic variable. Effects of both variation range and distribution probability of the time delays are considered. The nonlinear activation functions are assumed to satisfy the sector conditions. Our aim is to estimate the state by designing a full order filter such that the filter error system is globally exponentially stable with an expected decay rate and a Hinfinity performance attenuation level. The filter is designed by using a piecewise Lyapunov-Krasovskii functional together with linear matrix inequality (LMI) approach and average dwell time method. First, a set of sufficient LMI conditions are established to guarantee the exponential mean-square stability of the augmented system and then the parameters of full-order filter are expressed in terms of solutions to a set of LMI conditions. The proposed LMI conditions can be easily solved by using standard software packages. Finally, numerical examples by means of practical problems are provided to illustrate the effectiveness of the proposed filter design. PMID- 25020226 TI - Structure of a C. perfringens enterotoxin mutant in complex with a modified Claudin-2 extracellular loop 2. AB - CPE (Clostridium perfringens enterotoxin) is the major virulence determinant for C. perfringens type-A food poisoning, the second most common bacterial food-borne illness in the UK and USA. After binding to its receptors, which include particular human claudins, the toxin forms pores in the cell membrane. The mature pore apparently contains a hexamer of CPE, claudin and, possibly, occludin. The combination of high binding specificity with cytotoxicity has resulted in CPE being investigated, with some success, as a targeted cytotoxic agent for oncotherapy. In this paper, we present the X-ray crystallographic structure of CPE in complex with a peptide derived from extracellular loop 2 of a modified, CPE-binding Claudin-2, together with high-resolution native and pore-formation mutant structures. Our structure provides the first atomic-resolution data on any part of a claudin molecule and reveals that claudin's CPE-binding fingerprint (NPLVP) is in a tight turn conformation and binds, as expected, in CPE's C terminal claudin-binding groove. The leucine and valine residues insert into the binding groove while the first residue, asparagine, tethers the peptide via an interaction with CPE's aspartate 225 and the two prolines are required to maintain the tight turn conformation. Understanding the structural basis of the contribution these residues make to binding will aid in engineering CPE to target tumor cells. PMID- 25020227 TI - Sorting nexin 31 binds multiple beta integrin cytoplasmic domains and regulates beta1 integrin surface levels and stability. AB - Trafficking of alpha5beta1 integrin to lysosomes and its subsequent degradation is influenced by ligand occupancy and the binding of SNX17 via its protein 4.1, ezrin, radixin, moesin (FERM) domain to the membrane-distal NPxY motif in the cytoplasmic domain of beta1 integrin in early endosomes. Two other sorting nexin (SNX) family members, namely SNX27 and SNX31, share with SNX17 next to their obligate phox domain a FERM domain, which may enable them to bind beta integrin tails. Here we report that, in addition to SNX17, SNX31 but not SNX27 binds several beta integrin tails in early endosomes in a PI3 (phosphatidylinositide 3) kinase-dependent manner. Similarly like SNX17, binding of SNX31 with beta1 integrin tails in early endosomes occurs between the FERM domain and the membrane distal NPxY motif in the beta1 integrin cytoplasmic domain. Furthermore, expression of SNX31 rescues beta1 integrin surface levels and stability in SNX17 depleted cells. In contrast to SNX17, expression of SNX31 is restricted and found highly expressed in bladder and melanoma tissue. Altogether, these results demonstrate that SNX31 is an endosomal regulator of beta integrins with a restricted expression pattern. PMID- 25020228 TI - Molecular bases and role of viruses in the human microbiome. AB - Viruses are dependent biological entities that interact with the genetic material of most cells on the planet, including the trillions within the human microbiome. Their tremendous diversity renders analysis of human viral communities ("viromes") to be highly complex. Because many of the viruses in humans are bacteriophage, their dynamic interactions with their cellular hosts add greatly to the complexities observed in examining human microbial ecosystems. We are only beginning to be able to study human viral communities on a large scale, mostly as a result of recent and continued advancements in sequencing and bioinformatic technologies. Bacteriophage community diversity in humans not only is inexorably linked to the diversity of their cellular hosts but also is due to their rapid evolution, horizontal gene transfers, and intimate interactions with host nucleic acids. There are vast numbers of observed viral genotypes on many body surfaces studied, including the oral, gastrointestinal, and respiratory tracts, and even in the human bloodstream, which previously was considered a purely sterile environment. The presence of viruses in blood suggests that virome members can traverse mucosal barriers, as indeed these communities are substantially altered when mucosal defenses are weakened. Perhaps the most interesting aspect of human viral communities is the extent to which they can carry gene functions involved in the pathogenesis of their hosts, particularly antibiotic resistance. Persons in close contact with each other have been shown to share a fraction of oral virobiota, which could potentially have important implications for the spread of antibiotic resistance to healthy individuals. Because viruses can have a large impact on ecosystem dynamics through mechanisms such as the transfers of beneficial gene functions or the lysis of certain populations of cellular hosts, they may have both beneficial and detrimental roles that affect human health, including improvements in microbial resilience to disturbances, immune evasion, maintenance of physiologic processes, and altering the microbial community in ways that promote or prevent pathogen colonization. PMID- 25020229 TI - A conserved noncoding sequence can function as a spermatocyte-specific enhancer and a bidirectional promoter for a ubiquitously expressed gene and a testis specific long noncoding RNA. AB - Tissue-specific gene expression is tightly regulated by various elements such as promoters, enhancers, and long noncoding RNAs (lncRNAs). In the present study, we identified a conserved noncoding sequence (CNS1) as a novel enhancer for the spermatocyte-specific mouse testicular cell adhesion molecule 1 (Tcam1) gene. CNS1 was located 3.4kb upstream of the Tcam1 gene and associated with histone H3K4 mono-methylation in testicular germ cells. By the in vitro reporter gene assay, CNS1 could enhance Tcam1 promoter activity only in GC-2spd(ts) cells, which were derived from mouse spermatocytes. When we integrated the 6.9-kb 5' flanking sequence of Tcam1 with or without a deletion of CNS1 linked to the enhanced green fluorescent protein gene into the chromatin of GC-2spd(ts) cells, CNS1 significantly enhanced Tcam1 promoter activity. These results indicate that CNS1 could function as a spermatocyte-specific enhancer. Interestingly, CNS1 also showed high bidirectional promoter activity in the reporter assay, and consistent with this, the Smarcd2 gene and lncRNA, designated lncRNA-Tcam1, were transcribed from adjacent regions of CNS1. While Smarcd2 was ubiquitously expressed, lncRNA Tcam1 expression was restricted to testicular germ cells, although this lncRNA did not participate in Tcam1 activation. Ubiquitous Smarcd2 expression was correlated to CpG hypo-methylation of CNS1 and partially controlled by Sp1. However, for lncRNA-Tcam1 transcription, the strong association with histone acetylation and histone H3K4 tri-methylation also appeared to be required. The present data suggest that CNS1 is a spermatocyte-specific enhancer for the Tcam1 gene and a bidirectional promoter of Smarcd2 and lncRNA-Tcam1. PMID- 25020230 TI - Direct interaction of 14-3-3zeta with ezrin promotes cell migration by regulating the formation of membrane ruffle. AB - 14-3-3 proteins have been shown to regulate the actin cytoskeleton remodeling, cell adhesion and migration. In this study, we identified ezrin, a cross-linker between plasma membrane and actin cytoskeleton, as a novel 14-3-3zeta interacting partner. The direct interaction between 14-3-3zeta and ezrin was validated in the cells and by in vitro assays. We showed that the 14-3-3zeta binding region in ezrin was located within the N-terminal and central alpha-helical domains and that the alphaG-to-alphaI helices of 14-3-3zeta are responsible for the binding to ezrin. Functional analyses revealed that the regulation of cell migration and membrane ruffling by 14-3-3zeta is ezrin dependent, for which the integrity of ezrin protein was required. Conversely, the knockdown of 14-3-3zeta abrogates also the stimulatory effect of ezrin on cell migration and membrane ruffling. Moreover, we found that the phosphorylation of Thr567 in ezrin facilitates the 14 3-3zeta-ezrin interaction and the formation of membrane ruffles. Taken together, these results suggest strongly that the functions of these two proteins in cell migration are linked and might be mediated by their direct physical interaction, which is important for the formation of membrane ruffles. PMID- 25020231 TI - Structural basis for the specific recognition of the major antigenic peptide from the Japanese cedar pollen allergen Cry j 1 by HLA-DP5. AB - The major allergen, Cry j 1, was isolated from Japanese cedar Cryptomeria japonica (Cry j) pollen and was shown to react with immunoglobulin E antibodies in the sera from pollinosis patients. We previously reported that the frequency of HLA-DP5 was significantly higher in pollinosis patients and the immunodominant peptides from Cry j 1 bound to HLA-DP5 to activate Th2 cells. In the present study, we determined the crystal structure of the HLA-DP5 heterodimer in complex with a Cry j 1-derived nine-residue peptide, at 2.4A resolution. The peptide binding groove recognizes the minimal peptide with 10 hydrogen bonds, including those between the negatively charged P1 pocket and the Lys side chain at the first position in the peptide sequence. We confirmed that HLA-DP5 exhibits the same Cry j 1-binding mode in solution, through pull-down experiments using structure-based mutations of Cry j 1. We also identified the characteristic residues of HLA-DP5 that are responsible for the distinct properties of the groove, by comparing the structure of HLA-DP5 and the previously reported structures of HLA-DP2 in complexes with pDRA of the self-antigen. The comparison revealed that the HLA-DP5.pCry j 1 complex forms several hydrogen bond/salt bridge networks between the receptor and the antigen that were not observed in the HLA-DP2.pDRA complex. Evolutionary considerations have led us to conclude that HLA-DP5 and HLA-DP2 represent two major groups of the HLA-DP family, in which the properties of the P1 and P4 pockets have evolved and acquired the present ranges of epitope peptide-binding specificities. PMID- 25020232 TI - Structural insights into the substrate specificity of (s)-ureidoglycolate amidohydrolase and its comparison with allantoate amidohydrolase. AB - In plants, the ureide pathway is a metabolic route that converts the ring nitrogen atoms of purine into ammonia via sequential enzymatic reactions, playing an important role in nitrogen recovery. In the final step of the pathway, (S) ureidoglycolate amidohydrolase (UAH) catalyzes the conversion of (S) ureidoglycolate into glyoxylate and releases two molecules of ammonia as by products. UAH is homologous in structure and sequence with allantoate amidohydrolase (AAH), an upstream enzyme in the pathway with a similar function as that of an amidase but with a different substrate. Both enzymes exhibit strict substrate specificity and catalyze reactions in a concerted manner, resulting in purine degradation. Here, we report three crystal structures of Arabidopsis thaliana UAH (bound with substrate, reaction intermediate, and product) and a structure of Escherichia coli AAH complexed with allantoate. Structural analyses of UAH revealed a distinct binding mode for each ligand in a bimetal reaction center with the active site in a closed conformation. The ligand directly participates in the coordination shell of two metal ions and is stabilized by the surrounding residues. In contrast, AAH, which exhibits a substrate-binding site similar to that of UAH, requires a larger active site due to the additional ureido group in allantoate. Structural analyses and mutagenesis revealed that both enzymes undergo an open-to-closed conformational transition in response to ligand binding and that the active-site size and the interaction environment in UAH and AAH are determinants of the substrate specificities of these two structurally homologous enzymes. PMID- 25020233 TI - Cardiac concerns associated with strontium ranelate. AB - INTRODUCTION: Strontium ranelate is proven to reduce vertebral and non-vertebral fracture risk in osteoporosis. Concerns about cardiac safety have led to a new contraindication to strontium ranelate in patients with uncontrolled hypertension and/or current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. AREAS COVERED: A literature search was performed; data were also collected from the European Medicines Agency website. Randomised controlled trial (RCT) data indicate a higher incidence of non adjudicated myocardial infarction (MI) with strontium ranelate versus placebo (1.7 vs 1.1%; odds ratio [OR]: 1.6; 95% CI: 1.07 - 2.38; p = 0.020) (Mantel Haenzel estimate of the OR). There was no increase in cardiovascular mortality. MI risk was mitigated by excluding patients with cardiovascular contraindications (OR: 0.99; 95% CI: 0.48 - 2.04; p = 0.988). Three observational studies performed in the context of real-life medical practice in the UK and Denmark did not report a signal. EXPERT OPINION: The increased risk for cardiac events with strontium ranelate has been detected in RCTs but not in real life. Excluding patients with cardiovascular contraindications appears to be an effective measure for controlling the risk of MI. Strontium ranelate remains a useful therapeutic alternative in patients with severe osteoporosis without cardiovascular contraindications who are unable to take another osteoporosis treatment. PMID- 25020234 TI - Current applications of capnography in non-intubated patients. AB - Current clinical guidelines recommend capnography as one of the best non-invasive methods to assess adequacy of ventilation in the non-intubated patient. Alveolar hypoventilation or respiratory depression is a serious event that occurs in a variety of clinical settings where patients receive sedatives and opioids. With the large number of procedures performed outside the operating room under the effects of sedatives and the increased use of patient-controlled analgesia, the need for capnography for monitoring has dramatically increased. Despite the succesful use of capnography to monitor ventilation in the operating room over several decades, other clinical areas have been very slow adapters of the technology and still rely heavily upon pulse oximetry to detect hypoventilation. This article reviews the most current evidence for using capnography in the non intubated patient and summarizes the results of outcome measures reported in recent clinical trials. Capnography should be routinely used for non-intubated patients at risk for respiratory depression, in particular those receiving supplemental oxygen. PMID- 25020235 TI - Critical care and vitamin D status assessment: what about immunoassays and calculated free 25OH-D? AB - BACKGROUND: Interpretation of 25OH-D measurement during critical care (CC) may be problematic due to variations of binding protein concentrations (albumin, ALB, and vitamin D binding protein, VDBP). Determination of free 25OH-D concentration may thus be relevant in CC patients. The aim of this observational study was to evaluate effects of an acute hemodilution on vitamin D (VD) status. METHODS: Blood samples were obtained before (T1) and after a crystalloid load (T2) administered at anesthesia induction for minor surgery. 25OH-D was measured with LC-MS/MS and with 3 immunoassays (IA): DiaSorin Liaison, IDS iSYS and bioMerieux Vidas. VDBP was measured with the R&D Elisa and ALB on Cobas. Free 25OH-D was calculated using published formula. Accuracy of each 25OH-D IA was calculated as the percentage of IA values within 20% of their respective LC-MS/MS values. Performances of the three AI were compared with LC-MC/MS using Bland-Altman analysis. RESULTS: Twenty adults were included. Compared to T1 values, VDBP, ALB and LC-MS/MS values decreased in parallel by a mean of 23% at T2. IA values decreased less significantly (12, 14 and 15% for Liaison, iSYS and Vidas, respectively). IA-based calculated free 25OH-D significantly increased after dilution, while LC-MS/MS-based free values remained stable. At T1 and T2, bias were demonstrable for all IA. After hemodilution, bias would lead to overestimation for the three IA. Accuracy of IA decreased after dilution. CONCLUSIONS: Due to matrix effects, compared to LC-MS/MS, IA results were impacted by hemodilution. In CC patients, LC-MS/MS seems to be the best option to measure 25OH-D. Specific LC-MS/MS method should be developed to measure free 25OH D. PMID- 25020236 TI - Autophagy inhibition suppresses the tumorigenic potential of cancer stem cell enriched side population in bladder cancer. AB - The mechanisms that underlie tumor formation and progression have not been elucidated in detail in cancer biology. Recently, the identification of a tumor cell subset defined as cancer stem cells (CSCs), which is enriched for tumor initiating capacity, has engendered new perspectives towards selective targeting of tumors. In this study, we isolated the side population (SP) cells which share characteristics of CSCs from bladder cancer cell lines, T24 and UM-UC-3 by fluorescence activated cell sorting. The cells were cultured in serum free medium and expression profile of stem cell like markers (SOX-2, NANOG, KLF-4 and OCT-4), drug resistant genes (ABCG2 and MDR1) and spheroid forming capability were examined in SP, non-side population (NSP) and bulk T24 and UM-UC-3 cells. We observed that SP cells possessed a higher mRNA expression of SOX-2, NANOG, KLF-4, OCT-4, ABCG2, and MDR1 as well as a higher spheroid forming ability as compared to other bulk cells or NSP cells. The SP cells had low ROS levels and high GSH/GSSG ratio which may contribute to radio-resistance. The SP cells also showed substantial resistance to gemcitabine, mitomycin and cisplatin compared with the NSP counterpart. A high autophagic flux was observed in the SP cells. Both pharmacological and siRNA mediated inhibition of autophagy potentiated the chemotherapeutic effects of gemcitabine, mitomycin and cisplatin in these cells. We concluded that the ABCG2 expressing SP cells show autophagy associated cell survival and may be a potent target for developing more effective treatment in bladder carcinoma to enhance patient survival. PMID- 25020237 TI - Atomistic insight into orthoborate-based ionic liquids: force field development and evaluation. AB - We have developed an all-atomistic force field for a new class of halogen-free chelated orthoborate-phosphonium ionic liquids. The force field is based on an AMBER framework with determination of force field parameters for phosphorus and boron atoms, as well as refinement of several available parameters. The bond and angle force constants were adjusted to fit vibration frequency data derived from both experimental measurements and ab initio calculations. The force field parameters for several dihedral angles were obtained by fitting torsion energy profiles deduced from ab initio calculations. To validate the proposed force field parameters, atomistic simulations were performed for 12 ionic liquids consisting of tetraalkylphosphonium cations and chelated orthoborate anions. The predicted densities for neat ionic liquids and the [P6,6,6,14][BOB] sample, with a water content of approximately 2.3-2.5 wt %, are in excellent agreement with available experimental data. The potential energy components of 12 ionic liquids were discussed in detail. The radial distribution functions and spatial distribution functions were analyzed and visualized to probe the microscopic ionic structures of these ionic liquids. There are mainly four high-probability regions of chelated orthoborate anions distributed around tetraalkylphosphonium cations in the first solvation shell, and such probability distribution functions are strongly influenced by the size of anions. PMID- 25020238 TI - Aptamer-functionalized hybrid carbon nanofiber FET-type electrode for a highly sensitive and selective platelet-derived growth factor biosensor. AB - Precise selectivity and rapid responses to target biomolecules are important in the development of biosensors. In particular, highly sensitive and selective biosensors have been used in clinical treatment to detect factors such as cancer oncoproteins and endocrine disruptors. Herein, highly sensitive liquid electrolyte field-effect transistor (FET) system biosensors were fabricated to detect platelet-derived growth factor (PDGF) using a PDGF-B binding aptamer conjugated with carboxylic polypyrrole-coated metal oxide-decorated carbon nanofibers (CPMCNFs) as the signal transducer. First, CPMCNFs were fabricated using vapor deposition polymerization (VDP) of the carboxylic pryrrole monomer (CPy) on metal oxide-decorated carbon nanofiber (MCNF) surfaces with no treatment for carbon surface functionalization. Furthermore, a 3 nm thick uniformly coated carboxylic polypyrrole (CPPy) layer was formed without aggregation. The CPMCNFs were integrated with the PDGF-B binding aptamer and immobilized on the interdigitated array substrate by covalent anchoring to produce a FET-type biosensor transducer. The PDGF-B binding aptamer conjugated CPMCNF (CPB-Apt) FET sensor was highly sensitive (5 fM) and extremely selective for isoforms of PDGFs. Additionally, the CPB-Apt FET sensor could be reused over a few weeks. PMID- 25020239 TI - Re: Prevalence and management of lower urinary tract symptoms in methamphetamine abusers: an under-recognized clinical identity: K. C. Koo, D. H. Lee, J. H. Kim, K. H. Rha, B. H. Chung, S. J. Hong and S. Y. Mah. J Urol 2014; 191: 722-726. PMID- 25020240 TI - Re: Tumor target volume for focal therapy of prostate cancer--does multiparametric magnetic resonance imaging allow for a reliable estimation?: F. Cornud, G. Khoury, N. Bouazza, F. Beuvon, M. Peyromaure, T. Flam, M. Zerbib, P. Legmann and N. B. Delongchamps. J Urol 2014; 191: 1272-1279. PMID- 25020241 TI - Large-area ordered P-type Si nanowire arrays as photocathode for highly efficient photoelectrochemical hydrogen generation. AB - In this Article, we report the successful fabrication of large-area ordered Si nanowire arrays (NWAs) by a cost-effective and scalable wet-etching process in combination with nanospheres lithography technique. The periodical Si NWAs are further investigated as photocathode for water splitting, with excellent hydrogen evolution performances with a maximum photocurrent density of 27 mA cm(-2) achieved, which is ~2.5 times that of planar Si and random Si nanowires electrode. The greatly improved PEC performance can be attributed to the patterned and ordered NWs structure as a result of enhancement of the light harvesting as well as charge transportation and collection efficiency. PMID- 25020242 TI - Multifunctional plasmonic film for recording near-field optical intensity. AB - We demonstrate the plasmonic equivalent of photographic film for recording optical intensity in the near field. The plasmonic structure is based on gold bowtie nanoantenna arrays fabricated on SiO2 pillars. We show that it can be employed for direct laser writing of image data or recording the polarization structure of optical vector beams. Scanning electron micrographs reveal a careful sculpting of the radius of curvature and height of the triangles composing the illuminated nanoantennas, as a result of plasmonic heating, that permits spatial tunability of the resonance response of the nanoantennas without sacrificing their geometric integrity. In contrast to other memory-dedicated approaches using Au nanorods embedded in a matrix medium, plasmonic film can be used in multiple application domains. To demonstrate this functionality, we utilize the structures as plasmonic optical tweezers and show sequestering of SiO2 microparticles into optically written channels formed between exposed sections of the film. The plasmonic film offers interesting possibilities for photonic applications including optofluidic channels "without walls," in situ tailorable biochemical sensing assays, and near-field particle manipulation and sorting. PMID- 25020243 TI - Evaluation of solid fuel char briquettes from human waste. AB - The developing world faces dual crises of escalating energy demand and lack of urban sanitation infrastructure that pose significant burdens on the environment. This article presents results of a study evaluating the feasibility of using human feces-derived char as a solid fuel for heating and cooking and a potential way to address both crises. The study determined the energy content and the elemental composition of chars pyrolyzed at 300, 450, and 750 degrees C. Fecal chars made at 300 degrees C were found to be similar in energy content to wood chars and bituminous coal, having a heating value of 25.6 +/- 0.08 MJ/kg, while fecal chars made at 750 degrees C had an energy content of 13.8 +/- 0.48 MJ/kg. The higher heating values of the studied chars were evaluated using their elemental composition and a published predictive model; results found good agreement between the measured and predicted values. Fecal chars made at low temperatures were briquetted with molasses/lime and starch binders. Briquettes made with 10% starch had an average impact resistance index of 79 and a higher heating value of 25 MJ/kg. These values are comparable to those of commercial charcoal briquettes, making fecal char briquettes a potential substitute that also contributes to the preservation of the environment. PMID- 25020244 TI - Solution and solid-state photoreductive elimination of chlorine by irradiation of a [PtSb](VII) complex. AB - In our search for novel main-group-based redox-active platforms for solar fuel production, we have synthesized Cl2Sb(IV)Pt(III)Cl3(o-dppp)2 (2, o-dppp = o (Ph2P)C6H4)), a complex featuring a highly oxidized [PtSb](VII) core. This thermally stable complex quickly evolves chlorine upon irradiation with a Xe lamp, leading to [Cl2Sb(IV)Pt(I)Cl(o-dppp)2] (1) as the photoproduct. This photoreduction is very efficient, with a maximum quantum yield of 13.8% when carried out in a 4.4 M solution of 2,3-dimethyl-1,3-butadiene in CH2Cl2. Remarkably, 2 also evolves chlorine when irradiated in the solid state under ambient conditions in the absence of a trap. PMID- 25020245 TI - Focus on caregivers to prevent dental caries in young children. PMID- 25020246 TI - The significance of abdominal obesity in youth. PMID- 25020247 TI - Species differences in alternative substrate utilization by the antibacterial target undecaprenyl pyrophosphate synthase. AB - Undecaprenyl pyrophosphate synthase (UPPS) is a critical enzyme required for the biosynthesis of polysaccharides essential for bacterial survival. In this report, we have tested the substrate selectivity of UPPS derived from the mammalian symbiont Bacteroides fragilis, the human pathogen Vibrio vulnificus, and the typically benign but opportunistic pathogen Escherichia coli. An anthranilamide containing substrate, 2-amideanilinogeranyl diphosphate (2AA-GPP), was an effective substrate for only the B. fragilis UPPS protein, yet replacing the amide with a nitrile [2-nitrileanilinogeranyl diphosphate (2CNA-GPP)] led to a compound that was fully functional for UPPS from all three target organisms. These fluorescent substrate analogues were also found to undergo increases in fluorescence upon isoprenoid chain elongation, and this increase in fluorescence can be utilized to monitor the activity and inhibition of UPPS in 96-well plate assays. The fluorescence of 2CNA-GPP increased by a factor of 2.5-fold upon chain elongation, while that of 2AA-GPP increased only 1.2-fold. The 2CNA-GPP compound was therefore more versatile for screening the activity of UPPS from multiple species of bacteria and underwent a larger increase in fluorescence that improved its ability to detect increases in chain length. Overall, this work describes the development of new assay methods for UPPS and demonstrates the difference in substrate utilization between forms of UPPS from different species, which has major implications for UPPS inhibitor development, assay construction, and the development of polysaccharide biosynthesis probes. PMID- 25020248 TI - Identification of novel dipeptidyl peptidase-IV and angiotensin-I-converting enzyme inhibitory peptides from meat proteins using in silico analysis. AB - Angiotensin-I-converting enzyme (ACE-I, EC 3.4.15.1), renin (EC 3.4.23.15), and dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) play key roles in the control of hypertension and the development of type-2 diabetes and other diseases associated with metabolic syndrome. The aim of this work was to utilize known in silico methodologies, peptide databases and software including ProtParam (http://web.expasy.org/protparam/), Basic Local Alignment Tool (BLAST), ExPASy PeptideCutter (http://web.expasy.org/peptide_cutter/) and BIOPEP (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep) to assess the release of potentially bioactive DPP-IV, renin and ACE-I inhibitory peptides from bovine and porcine meat proteins including hemoglobin, collagen and serum albumin. These proteins were chosen as they are found commonly in meat by-products such as bone, blood and low-value meat cuts. In addition, the bioactivities of identified peptides were confirmed using chemical synthesis and in vitro bioassays. The concentration of peptide required to inhibit the activity of ACE-I and DPP-IV by 50% was determined for selected, active peptides. Novel ACE-I and DPP-IV inhibitory peptides were identified in this study using both in silico analysis and a literature search to streamline enzyme selection for peptide production. These novel peptides included the ACE-I inhibitory tri-peptide Ile-Ile-Tyr and the DPP-IV inhibitory tri-peptide Pro-Pro-Leu corresponding to sequences f (182 184) and f (326-328) of both porcine and bovine serum albumin which can be released following hydrolysis with the enzymes papain and pepsin, respectively. This work demonstrates that meat proteins are a suitable resource for the generation of bioactive peptides and further demonstrates the usefulness of in silico methodologies to streamline identification and generation of bioactive peptides. PMID- 25020249 TI - Errors in knee alignment using fixed femoral resection angles. AB - This study describes the variance within a representative population of total knee arthroplasty (TKA) patients to provide guidance in improving coronal alignment. The authors retrospectively reviewed 250 preoperative full-length standing radiographs in a consecutive series of TKAs performed by one surgeon. The distal femoral resection was templated on each radiograph to establish a femoral mechanical anatomical (FMA) angle to guide resection. Mean FMA angle was 5.35 degrees , with a wide variation in FMA angle ranging from 1 degrees to 10 degrees . Slightly more than half (56%) of patients had either a 5 degrees or 6 degrees FMA angle, which is concerning for surgeons using a fixed resection angle. Ninety percent of patients measured within the 5 degrees +/-2 degrees window. Similarly, 90.7% of patients measured within the 6 degrees +/-2 degrees window. However, nearly 10% of patients (9.75%) had measurements greater than 7 degrees or less than 3 degrees . This study reports a wide variance in the angle of resection required to establish proper femoral mechanical alignment in TKA. Surgeons should be cognizant of the numerous variables that play a role in TKA and influence overall coronal alignment. Many of these variables can be fully assessed by evaluating full-length standing leg radiographs preoperatively. With experience, templating long-leg films can be reproducible and informative in preparing for each surgical procedure. Routine reliance on a single fixed resection angle could result in malalignment in 10% of patients. PMID- 25020250 TI - Dramatic increase in total knee replacement utilization rates cannot be fully explained by a disproportionate increase among younger patients. AB - The incidence of total knee replacement in the United States more than doubled between 1999 and 2008, increasing from approximately 263,000 to 616,000 cases. The purpose of this study is to evaluate the claim that there has been a disproportionate increase in knee replacements among younger patients owing to expanding indications for the procedure in this group. Data on the US population for individuals 18 to 44 years old, 45 to 64 years old, and 65 years and older were obtained from census data; the number of total knee replacements performed annually in each age group was acquired from the Agency for Healthcare Research and Quality and per-capita incidence rates were calculated. Applying the 1999 rates to the 2008 population, the number of knee replacements anticipated on the basis of population growth for each cohort was determined and compared with the number observed, yielding the unexplained growth. The data revealed that in 2008, approximately 305,000 knee replacements were performed beyond the number predicted by population growth alone. The largest segment of growth (151,000 cases) was among patients 65 years and older; the per-capita growth rate was highest in this cohort as well, increasing from 5.2 to 9.1 procedures per 1,000 individuals. The data show conclusively that a disproportionate increase in knee replacements among younger patients is not a full explanation for the growth in utilization. In fact, it is not even the best among alternative explanations. The main locus of growth was among traditional patients 65 years and older. PMID- 25020251 TI - Bombesin peptide conjugated gold nanocages internalize via clathrin mediated endocytosis. AB - The nature of interaction and mechanism of internalization of receptor-avid peptide nanoparticles with cells is not yet completely understood. This article describes the cellular internalization mechanism and intracellular trafficking of peptide conjugated receptor targeted porous Gold nanocages (AuNCs) in cancer cells. We synthesized and characterized a library of AuNCs conjugated with bombesin (BBN) peptide. Evidence of selective affinity of AuNC-BBN toward gastrin releasing peptide receptors (GRPR) was obtained using radiolabeled competitive cell binding assay. Endocytic mechanism was investigated using cell inhibitor studies and monitored using optical and transmission electron microscopy (TEM). Results show AuNC-BBN uptake in PC3 cells is mediated by clathrin mediated endocytosis (CME). Indeed, in the presence of CME inhibitors, AuNC-BBN uptake in cells is reduced up to 84%. TEM images further confirm CME characteristic clathrin coated pits and lysosomal release of AuNCs. These results demonstrate that peptide ligands conjugated to the surface of nanoparticles maintain their target specificity. This bolsters the case for peptide robustness and its persisting functionality in intracellular vehicular delivery systems. PMID- 25020252 TI - Gender, psychopathy factors, and intimate partner violence. AB - The present study sheds light on relationships between distinct psychopathic traits and perpetration of intimate partner violence (IPV) in women versus men. Men and women with recent drug and/or violence histories (N = 250) were assessed for psychopathic traits using the Psychopathy Checklist: Screening Version and for their and their partner's use of IPV with the Revised Conflict Tactics Scale. The first goal was to examine the moderating role of gender in psychopathy factor relationships to IPV. Although both the interpersonal-affective traits (Factor1) and the impulsive-antisocial traits (Factor 2) of psychopathy were related to higher frequency of IPV perpetration, the relationship between Factor 1 and IPV was stronger in men. Our second goal examined the moderating role of psychopathy traits in the relationship between partner's perpetration of IPV and participant perpetration (mutual violence) in the 2 genders. Relationships between partner- and self-IPV were similar at both low and high levels of Factor 1 in men, although the partner- and self-IPV relationship was significantly stronger among women at low relative to high levels of Factor 1. The relationship between partner- and self-IPV was stronger at high levels of Factor 2 in men, whereas Factor 2 did not moderate mutual violence in women. These results indicate that relationships between psychopathy factors and IPV differ by gender, with psychopathy generally exacerbating IPV perpetration in men and Factor 1 traits playing a unique role in mutual violence in women. These findings add to the literature on female psychopathy and have important implications for future research on gender and IPV. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25020253 TI - Automated phenotyping and advanced data mining exemplified in rats transgenic for Huntington's disease. AB - BACKGROUND: The need for improving throughput, validity, and reliability in the behavioral characterization of rodents may benefit from integrating automated intra-home-cage-screening systems allowing the simultaneous detection of multiple behavioral and physiological parameters in parallel. NEW METHOD: To test this hypothesis, transgenic Huntington's disease (tgHD) rats were repeatedly screened within phenotyping home-cages (PhenoMaster and IntelliCage for rats), where spontaneous activity, feeding, drinking, temperature, and metabolic performance were continuously measured. Cognition and emotionality were evaluated within the same environment by means of operant learning procedures and refined analysis of the behavioral display under conditions of novelty. This investigator-independent approach was further correlated with behavioral display of the animals in classical behavioral assays. Multivariate analysis (MVA) including Principle Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) was used to explore correlation patterns of variables within and across the two genotypes. RESULTS: The automated systems traced previously undetected aspects in the phenotype of tgHD rats (circadian activity, energy metabolism, rearing), and out of those spontaneous free rearing correlated with individual performance in the accelerod test. PCA revealed a segregation by genotype in juvenile tgHD rats that differed from adult animals, being further resolved by PLS-DA detecting "temperature" (juvenile) and "rearing" (adult) as phenotypic key variables in the tgHD model. CONCLUSIONS: Intra-home-cage phenotyping in combination with MVA, is capable of characterizing a complex phenotype by detecting novel physiological and behavioral markers with high sensitivity and standardization using fewer human resources. A broader application of automated systems for large-scale screening is encouraged. PMID- 25020254 TI - Superior performance of decloaking chamber-based heat-induced epitope retrieval method improves the quantification of Olig2 cells in paraffin-embedded section of embryonic mouse brain. AB - BACKGROUND: Immunohistochemistry (IHC) studies in paraffin-embedded sections can be challenging due to epitope masking. To counteract this problem the microwave oven is widely used for heat-induced epitope retrieval (HIER). However, with this method important parameters cannot be specifically controlled, such as the intensity and duration of heating. NEW METHOD: We describe here a consistent and sensitive HIER method that uses a device for epitope retrieval in tissue sections, the decloaking chamber NxGen. With this method, heat temperature and time can be accurately set. Both qualitative (sensitivity and specificity of positive immunostaining) and quantitative (amount of positive-stained cells) analyses were compared between the microwave oven approach and the decloaking chamber, in paraffin-embedded sections from embryonic mouse brain. RESULTS: We found that the decloaking chamber-based HIER method was preferable to the commonly used microwave oven for the immunodetection and discrimination in mouse brain sections of single Olig2-positive cells, a marker of oligodendrocyte precursor cells. Both automated (ICY software) and manual counting (Adobe Photoshop software) showed a significant underestimation of Olig2-positive cells in microwave oven-treated sections compared to decloaking chamber-treatment. COMPARISON WITH EXISTING METHODS: Compared to other IHC procedures for cell automated quantification, the presently established protocol is easy to use, fast, and effective for the immunodetection and quantification of Olig2 in the developing mouse telencephalon. CONCLUSIONS: We conclude that the combination of decloaking chamber-based HIER method and spot detector in ICY software is a reliable and valuable tool, suited to basic research and clinical studies. PMID- 25020255 TI - From two-dimension to one-dimension: the curvature effect of silicon-doped graphene and carbon nanotubes for oxygen reduction reaction. AB - For the goal of practical industrial development of fuel cells, inexpensive, sustainable, and highly efficient electrocatalysts for oxygen reduction reactions (ORR) are highly desirable alternatives to platinum (Pt) and other rare metals. In this work, based on density functional theory, silicon (Si)-doped carbon nanotubes (CNTs) and graphene as metal-free, low cost, and high-performance electrocatalysts for ORR are studied systematically. It is found that the curvature effect plays an important role in the adsorption and reduction of oxygen. The adsorption of O2 becomes weaker as the curvature varies from positive values (outside CNTs) to negative values (inside CNTs). The free energy change of the rate-determining step of ORR on the concave inner surface of Si-doped CNTs is smaller than that on the counterpart of Si-doped graphene, while that on the convex outer surface of Si-doped CNTs is larger than that on Si-doped graphene. Uncovering this new ORR mechanism on silicon-doped carbon electrodes is significant as the same principle could be applied to the development of various other metal-free efficient ORR catalysts for fuel cell applications. PMID- 25020256 TI - Agelamadins A and B, dimeric bromopyrrole alkaloids from a marine sponge Agelas sp. AB - Two structurally unique dimeric bromopyrrole alkaloids, agelamadins A (1) and B (2), were isolated from a marine sponge Agelas sp. Agelamadins A (1) and B (2) have a structure consisting of an agelastatin-like tetracyclic moiety and an oroidin-like linear moiety in common. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis. The antimicrobial activity and cytotoxicity of agelamadins A (1) and B (2) were evaluated. PMID- 25020257 TI - Electroosmosis in a finite cylindrical pore: simple models of end effects. AB - A theoretical model of electroosmosis through a circular pore of radius a that traverses a membrane of thickness h is investigated. Both the cylindrical surface of the pore and the outer surfaces of the membrane are charged. When h ? a, end effects are negligible, and the results of full numerical computations of electroosmosis in an infinite pore agree with theory. When h = 0, end effects dominate, and computations again agree with analysis. For intermediate values of h/a, an approximate analysis that combines these two limiting cases captures the main features of computational results when the Debye length kappa(-1) is small compared with the pore radius a. However, the approximate analysis fails when kappa(-1) ? a, when the charge cloud due to the charged cylindrical walls of the pore spills out of the ends of the pore, and the electroosmotic flow is reduced. When this spilling out is included in the analysis, agreement with computation is restored. PMID- 25020258 TI - Molecular characterization and expression of CD2BP2 in Nile tilapia (Oreochromis niloticus) in response to Streptococcus agalactiae stimulus. AB - CD2BP2 (CD2 cytoplasmic tail binding protein 2), one of several proteins interacting with the cytoplasmic tail of CD2, plays a crucial role in CD2 triggered T cell activation and nuclear splicing. The studies on CD2BP2 have tended to be confined to a few mammals, and little information is available to date regarding fish CD2BP2. In this paper, a CD2BP2 gene (On-CD2BP2) was cloned from Nile tilapia, Oreochromis niloticus. Sequence analysis showed that the full length of On-CD2BP2 cDNA was 1429 bp, containing a 5'untranslated region (UTR) of 111 bp, a 3'-UTR of 193 bp and an open reading frame of 1125 bp which is encoding 374 amino acids. Two important structural features, a GYF domain and a consensus motif GPFXXXXMXXWXXXGYF were detected in the deduced amino acid sequence of On CD2BP2, and the deduced genomic structure of On-CD2BP2 was similar to the known CD2BP2. The mRNA expression of On-CD2BP2 in various tissues of Nile tilapia was analyzed by fluorescent quantitative real-time PCR. In healthy Nile tilapia, the On-CD2BP2 transcripts were mainly detected in the head kidney and spleen. While vaccinated with inactivated Streptococcus agalactiae, the On-CD2BP2 mRNA expression was significantly up-regulated in the head kidney, spleen and brain 48 h post immunization. Moreover, there was a clear time-dependent expression pattern of On-CD2BP2 after immunization and the expression reached the highest level at 24h in the brain and 48 h in the head kidney and spleen. This is the first report of proving the presence of a CD2BP2 ortholog in fish, and investigating its tissue distribution and expression profile in response to bacterial stimulus. These findings indicated that On-CD2BP2 may play an important role in the immune response to bacteria in Nile tilapia. PMID- 25020259 TI - Cloning, expression, and purification of a new antimicrobial peptide gene from Musca domestica larva. AB - Musca domestica (Diptera: Muscidae), the housefly, exhibits unique immune defences and can produce antimicrobial peptides upon stimulation with bacteria. Based on the cDNA library constructed using the suppression subtractive hybridization (SSH) method, a 198-bp antimicrobial peptide gene, which we named MDAP-2, was amplified by rapid amplification of cDNA ends (RACE) from M. domestica larvae stimulated with Salmonella pullorum (Enterobacteriaceae: Salmonella). In the present study, the full-length MDAP-2 gene was cloned and inserted into a His-tagged Escherichia coli prokaryotic expression system to enable production of the recombinant peptide. The recombinant MDAP-2 peptide was purified using Ni-NTA HisTrap FF crude column chromatography. The bacteriostatic activity of the recombinant purified MDAP-2 protein was assessed. The results indicated that MDAP-2 had in vitro antibacterial activity against all of the tested Gram- bacteria from clinical isolates, including E. coli (Enterobacteriaceae: Escherichia), one strain of S. pullorum (Enterobacteriaceae: Salmonella), and one strain of Pasteurella multocida. DNA sequencing and BLAST analysis showed that the MDAP-2 antimicrobial peptide gene was not homologous to any other antimicrobial peptide genes in GenBank. The antibacterial mechanisms of the newly discovered MDAP-2 peptide warrant further study. PMID- 25020260 TI - Expression characterization of testicular DMRT1 in both Sertoli cells and spermatogenic cells of polyploid gibel carp. AB - Dmrt1 has been suggested to play significant roles in sex determination and differentiation, but various expression patterns and cell types have been observed in the testis of vertebrates. Polyploid gibel carp, because of the multiple modes of unisexual gynogenesis and sexual reproduction, has become a unique case to explore the evolution of sex determination and differentiation. However, the sex-determination related genes in gibel carp have remained unknown. In this study, we identified and characterized 4 cDNAs of Dmrt1 genes. Subsequently, a polyclonal antibody specific to CagDMRT1 was prepared to examine its expression and distribution patterns at protein level. Significantly, both relative real-time PCR and Western blot detection confirmed predominant expression of CagDmrt1 in the adult testis of gibel carp. Moreover, the intensive expression of CagDMRT1 around spermatogenic cysts was revealed during spermatogenesis. And, following immunofluorescence co-localization of CagDMRT1 and CagVASA, a prominent CagDMRT1 expression in Sertoli cells and a mild CagDMRT1 expression in spermatogenic cells including spermatogonia and primary spermatocytes were clearly characterized. The CagDMRT1 signal in Sertoli cells is extensively distributed in both nuclei and cytoplasm, while the CagDMRT1 in spermatogonia and primary spermatocytes is mainly expressed in nuclei, and there is only the remained CagDMRT1 signal in the cytoplasm of secondary spermatocytes. These findings suggest that DMRT1 should be related to testis differentiation and spermatogenesis in gibel carp. PMID- 25020261 TI - Expression pattern of immunoglobulin superfamily members in the silkworm, Bombyx mori. AB - Immunoglobulin superfamily (IgSF) proteins are involved in cell adhesion, cell communication and immune functions. In this study, 152 IgSF genes containing at least one immunoglobulin (Ig) domain were predicted in the Bombyx mori silkworm genome. Of these, 145 were distributed on 25 chromosomes with no genes on chromosomes 16, 18 and 26. Multiple sequence alignments and phylogenetic evolution analysis indicated that IgSFs evolved rapidly. Gene ontology (GO) annotation indicated that IgSF members functioned as cellular components and in molecular functions and biological processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that IgSF proteins were involved in signal transduction, signaling molecules and interaction, and cell communication. Microarray-based expression data showed tissue expression for 136 genes in anterior silkgland, middle silkgland, posterior silkgland, testis, ovary, fat body, midgut, integument, hemocyte, malpighian tubule and head. Expression pattern of IgSF genes in the silkworm ovary and midgut was analyzed by RNA-Seq. Expression of 105 genes was detected in the ovary in strain Dazao. Expression in the midgut was detected for 74 genes in strain Lan5 and 75 genes in strain Ou17. Expression of 34 IgSF genes in the midgut relative to the actin A3 gene was significantly different between strains Lan5 and Ou17. Furthermore, 1 IgSF gene was upregulated and 1 IgSF gene was downregulated in strain Lan5, and 4 IgSF genes were upregulated and 2 IgSF genes were downregulated in strain Ou17 after silkworms were challenged with B. mori cypovirus (BmCPV), indicating potential involvement in the response to BmCPV-infection. These results provide an overview of IgSF family members in silkworms, and lay the foundation for further functional studies. PMID- 25020262 TI - Selenium adjuvant therapy in septic patients selected according to Carrico index. AB - OBJECTIVES: The objective of this paper is to highlight the selected group of patients in which adjuvant therapy seems to have a more pronounced positive effect. DESIGN AND METHODS: 65 septic patients from the prospective observational study Se-AOX (2008-2012) (ClinicalTrials.gov Identifier: NCT02026856) were divided into a Se group, receiving sodium selenite in a continual infusion of 750MUg/24h for 6 days, and a placebo group. They were subsequently divided into subgroups according to the initial Carrico index (CI) on the day of admission: CI>200 and CI<200. Dynamical changes in glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase activities were recorded at two day intervals. Clinical parameters and mortality were compared. RESULTS: The CI increased in subgroup Se-CI<200 with negative correlation against subgroup Placebo-CI<200 during the last measuring period (p<0.02). GPx activity increased in selenium subgroups with negative correlation against placebo subgroups (p<0.01). SOD activity was elevated in all subgroups in comparison with values of healthy subjects. CONCLUSIONS: Adjuvant selenium therapy seems to be beneficial for a selected group of patients with acute lung injury. However, as is clear from the results discussed, this is not the case with persistent renal failure, as this leads to an inability to maintain synthetic renal function and ensure GPx synthesis. PMID- 25020263 TI - Quality assurance in the laboratory testing process: indirect estimation of the reference intervals for platelet parameters in neonates. AB - OBJECTIVES: One of the most powerful tools that laboratory medicine uses to help the clinical decision-making process is the reference interval (RI). By establishing their own RIs in accordance with the analytical method they apply, the laboratories contribute to the quality assurance in the laboratory testing process. DESIGN AND METHODS: This study estimates the RIs of the platelet parameters in neonates for Nihon Celltac F hematology automatic analyzer. A database of 1058 venous complete blood counts in neonates in their first day of life has been processed through two different statistical methods: the simple non parametric method and the bootstrap method. RESULTS: The results give the mean+/ SE(RI) for: platelet count (PLT)=270.39+/-0.68 (156-387*10(9)/L); plateletcrit (PCT)=0.151+/-0.0072 (0.10-0.23%); mean platelet volume (MPV)=5.72+/-0.0085 (4.0 8.0fL): platelet distribution width (PDW)=17.67+/-3.03 (16.3-18.9%). CONCLUSIONS: These values are in agreement with the RI for platelet count reported in literature, but the estimated RIs of the platelet indices are different. This justifies the need for laboratories to determine their own RIs. PMID- 25020264 TI - Highly flexible, electrically driven, top-emitting, quantum dot light-emitting stickers. AB - Flexible information displays are key elements in future optoelectronic devices. Quantum dot light-emitting diodes (QLEDs) with advantages in color quality, stability, and cost-effectiveness are emerging as a candidate for single material, full color light sources. Despite the recent advances in QLED technology, making high-performance flexible QLEDs still remains a big challenge due to limited choices of proper materials and device architectures as well as poor mechanical stability. Here, we show highly efficient, large-area QLED tapes emitting in red, green, and blue (RGB) colors with top-emitting design and polyimide tapes as flexible substrates. The brightness and quantum efficiency are 20,000 cd/m(2) and 4.03%, respectively, the highest values reported for flexible QLEDs. Besides the excellent electroluminescence performance, these QLED films are highly flexible and mechanically robust to use as electrically driven light emitting stickers by placing on or removing from any curved surface, facilitating versatile LED applications. Our QLED tapes present a step toward practical quantum dot based platforms for high-performance flexible displays and solid state lighting. PMID- 25020265 TI - Alleviation of capsular formations on silicone implants in rats using biomembrane mimicking coatings. AB - Despite their popular use in breast augmentation and reconstruction surgeries, the limited biocompatibility of silicone implants can induce severe side effects, including capsular contracture - an excessive foreign body reaction that forms a tight and hard fibrous capsule around the implant. This study examines the effects of using biomembrane-mimicking surface coatings to prevent capsular formations on silicone implants. The covalently attached biomembrane-mimicking polymer, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), prevented nonspecific protein adsorption and fibroblast adhesion on the silicone surface. More importantly, in vivo capsule formations around PMPC-grafted silicone implants in rats were significantly thinner and exhibited lower collagen densities and more regular collagen alignments than bare silicone implants. The observed decrease in alpha-smooth muscle actin also supported the alleviation of capsular formations by the biomembrane-mimicking coating. Decreases in inflammation-related cells, myeloperoxidase and transforming growth factor-beta resulted in reduced inflammation in the capsular tissue. The biomembrane mimicking coatings used on these silicone implants demonstrate great potential for preventing capsular contracture and developing biocompatible materials for various biomedical applications. PMID- 25020266 TI - Lymphatic collecting vessel maturation and valve morphogenesis. AB - The lymphatic vasculature plays an essential role in the maintenance of tissue interstitial fluid balance and in the immune response. After capture of fluids, proteins and antigens by lymphatic capillaries, lymphatic collecting vessels ensure lymph transport. An important component to avoid lymph backflow and to allow a unidirectional flow is the presence of intraluminal valves. Defects in the function of collecting vessels lead to lymphedema. Several important factors and signaling pathways involved in lymphatic collecting vessel maturation and valve morphogenesis have now been discovered. The present review summarizes the current knowledge about the key steps of lymphatic collecting vessel development and maturation and focuses on the regulatory mechanisms involved in lymphatic valve formation. PMID- 25020267 TI - Deletion of the chemokine receptor CCR2 attenuates foreign body reaction to implants in mice. AB - Subcutaneous implantation of synthetic materials and biomedical devices often induces abnormal tissue healing - the foreign body reaction - which impairs their function. Here we investigated the role of the chemokine receptor CCR2 in this reaction to subcutaneous implants in mice. We measured angiogenesis, inflammation and fibrogenesis induced by implantation, for 1, 4, 7 and 14days, of polyether polyurethane sponges in mice with genetic deletion of CCR2 (KO) and WT mice. Blood flow was determined by dye diffusion and laser Doppler perfusion techniques. Cytokines (VEGF, TNF-alpha, CCL2, TGF-beta1) were measured by ELISA. Histochemical methods were used to assess collagen deposition and macrophage derived giant cells in the implants. Skin and implant blood flow was lower in CCR2 KO than in WT mice, as were other aspects of neo-vascularization of the implants. Neutrophil accumulation was increased in KO implants but macrophage accumulation was decreased. Implant content of CCL2 was higher in KO implants, but TGF-beta1, collagen deposition and the number of foreign body giant cells were lower than in WT implants. Deletion of CCR2 decreased blood flow in normal skin and inhibited neo-vascularization, chronic inflammation and fibrogenesis in subcutaneous implants. The chemokine receptor CCR2 plays an important role in both normal skin and in the reaction elicited by subcutaneous implantation of a foreign body. PMID- 25020268 TI - A systematic review of fMRI studies in generalized anxiety disorder: evaluating its neural and cognitive basis. AB - BACKGROUND: Generalized anxiety disorder (GAD) is a prevalent anxiety disorder, but its neurobiological basis has been poorly studied. A few cognitive models have been proposed for understanding GAD development and maintenance. The aim of this study is to review functional Magnetic Resonance Image (fMRI) studies conducted with GAD patients and evaluate if they support and underpin the theoretical cognitive models proposed for this anxiety disorder. METHODS: A literature systematic review was undertaken in PubMed and ISI databases with no time limits. RESULTS: From the studies included in this review, 10 explored the "emotional dysregulation model", showing, prefrontal cortex (PFC) and anterior cingulate cortex (ACC) hypofunction and deficient top-down control system during emotion regulation tasks, despite conflicting techniques and results. Only one study explored the "conditioned fear overgeneralization theory", other the "intolerance of uncertainty model" and two studies were unspecific (worry induction tasks). Between those, there were 4 studies evaluating pre- and post treatment with antidepressants or "mindfulness". LIMITATIONS: The studies' methodologies differ between one another making it difficult to identify a common finding. CONCLUSION: Emotion dysregulation seems to be an important cognitive dysfunction in GAD patients and fMRI studies suggest that it is related to PFC and ACC hypofunction as well as a deficient cortex-amygdala functional connectivity. PMID- 25020270 TI - Gender differences in depression severity and symptoms across depressive sub types. AB - BACKGROUND: Lifetime rates of depression are distinctly higher in women reflecting both real and artefactual influences. Most prevalence studies quantifying a female preponderance have examined severity-based diagnostic groups such as major depression or dysthymia. We examined gender differences across three depressive sub-type conditions using four differing measures to determine whether any gender differences emerge more from severity or symptom prevalence, reflect nuances of the particular measure, or whether depressive sub-type is influential. METHODS: A large clinical sample was recruited. Patients completed two severity-weighted depression measures: the Depression in the Medically Ill 10 (DMI-10) and Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR) and two measures weighting symptoms and illness correlates of melancholic and non melancholic depressive disorders - the Severity of Depressive Symptoms (SDS) and Sydney Melancholia Prototype Index (SMPI). Analyses were undertaken of three diagnostic groups comprising those with unipolar melancholic, unipolar non melancholic and bipolar depressive conditions. RESULTS: Women in the two unipolar groups scored only marginally (and non-significantly) higher than men on the depression severity measures. Women in the bipolar depression group, did however, score significantly higher than men on depression severity. On measures weighted to assessing melancholic and non-melancholic symptoms, there were relatively few gender differences identified in the melancholic and non-melancholic sub-sets, while more gender differences were quantified in the bipolar sub-set. The symptoms most commonly and consistently differentiating by gender were those assessing appetite/weight change and psychomotor disturbance. CONCLUSION: Our analyses of several measures and the minimal differentiation of depressive symptoms and symptom severity argues against any female preponderance in unipolar depression being contributed to distinctly by these depression rating measures. Our analyses indicated that gender had minimal if any impact on depression severity estimates. Gender differences in depressive symptoms and severity were more distinctive in bipolar patients, a finding seemingly not previously identified or reported. LIMITATIONS: The study had considerable power reflecting large sample sizes and thus risks assigning significant differences where none truly exist, although we repeated analyses after controlling for the type I error rate. PMID- 25020269 TI - Increased alpha2- and beta1-adrenoceptor densities in postmortem brain of subjects with depression: differential effect of antidepressant treatment. AB - BACKGROUND: Brain alpha2- and beta-adrenoceptor alterations have been suggested in suicide and major depressive disorder. METHODS: The densities of alpha2-, beta1- and beta2-adrenoceptors in postmortem prefrontal cortex of 26 subjects with depression were compared with those of age-, gender- and postmortem delay matched controls. The effect of antidepressant treatment on alpha2- and beta adrenoceptor densities was also evaluated. alpha2- and beta-adrenoceptor densities were measured by saturation experiments with respective radioligands [(3)H]UK14304 and [(3)H]CGP12177. beta1- and beta2-adrenoceptor subtype densities were dissected by means of beta1-adrenoceptor selective antagonist CGP20712A. RESULTS: Both, alpha2- and beta1-adrenoceptors densities were higher in antidepressant-free depressed subjects (n=14) than those in matched controls (Delta~24%, p=0.013 and Delta~20%, p=0.044, respectively). In antidepressant treated subjects (n=12), alpha2-adrenoceptor density remained increased over that in controls (Delta~20%), suggesting a resistance of alpha2-adrenoceptors to the down-regulatory effect of antidepressants. By contrast, beta1-adrenoceptor density in antidepressant-treated depressed subjects was not different from controls, suggesting a possible down-regulation by antidepressants. The down regulation of beta1-adrenoceptor density in antidepressant-treated depressed subjects differs from the unaltered beta1-adrenoceptor density observed in citalopram-treated rats and in a group of non-depressed subjects also treated with antidepressants (n=6). beta2-adrenoceptor density was not altered in depressed subjects independently of treatment. LIMITATIONS: Antidepressant treated subjects had been treated with a heterogeneous variety of antidepressant drugs. The results should be understood in the context of suicide victims with depression. CONCLUSIONS: These results show the up-regulation of brain alpha2- and beta1-adrenoceptors in depression and suggest that the regulation induced by chronic antidepressant treatment would be altered in these subjects. PMID- 25020271 TI - One size does not fit all: psychometric properties of the Shona Symptom Questionnaire (SSQ) among adolescents and young adults in Zimbabwe. AB - BACKGROUND: Depression is a major contributor to the global burden of disease. Onset commonly occurs during the adolescent period. Understanding how depression tools are functioning among adolescents has been relatively overlooked. METHODS: Using cross-sectional survey data among a sample of 2768 adolescents (aged 15-19) and 2027 young adults (aged 20-24) living in Zimbabwe this paper calibrated the Shona Symptom Questionnaire (SSQ) against the Self Report Questionnaire (SRQ-20) and examined the performance indices of the SSQ based on various cut points for classification. Using a multivariate logistic regression model we isolated particular characteristics to test their association with the odds of being misclassified as non-depressed by the SSQ. RESULTS: A modified cut point of five or more substantially increases the depression estimates for both age groups. The prevalence of depression increased from 3.5% to 13.2% among adolescents and from 5.1% to 16.2% among young adults based on these revisions. Adolescents who were orphaned or ever had sex had significantly a greater odd of being misclassified. When retested using the modified cut point of five or greater, associations with misclassification disappeared. LIMITATIONS: Scales were not administered separately or in their entirety but rather overlapping items were only asked once, utilizing exclusively SRQ-20 phrasing rather than the culturally-emic language in the SSQ. CONCLUSIONS: Not all depression scales are appropriate for use among adolescents given their unique developmental stage. An alternative cut point for depression classification could improve detection of depression among Zimbabwean adolescents. PMID- 25020272 TI - Carbon dynamics of Florida Bay: spatiotemporal patterns and biological control. AB - Carbon dynamics of Florida Bay is manifested by wide ranges of pH (7.65-8.61), dissolved inorganic carbon (DIC, 929-3223 MUM) and partial pressure of CO2 (pCO2, 50-1313 MUatm) observed over seven years. Despite the seasonal variation, a decline of -0.0066 pH per year was observed as a result of ocean acidification and the spatiotemporal patterns were consistent with known biological processes in the bay. Microbial respiration of organic matter produced high pCO2, resulting in Florida Bay being a CO2 source to the atmosphere during winter and spring. In summer, cyanobacteria blooms developed in the north central bay drew down pCO2, causing bloom waters to become a CO2 sink while the nonbloom waters shrunk but remained a CO2 source. The maxima local CO2 fluxes were 36.4 +/- 10.5 and -14.0 +/- 5.6 mmol m(-2) d(-1) for the source and sink region, respectively. Cyanobacteria blooms modulated the interannual variation in bay-wide CO2 net flux, which averaged 7.96 * 10(9) +/- 1.84 * 10(9) mol yr(-1). Extensive cyanobacteria blooms in 2009 resulted in a 50% reduction in the net CO2 flux as compared with 2010 when a minimal cyanobacteria bloom occurred. PMID- 25020273 TI - A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. AB - INTRODUCTION: The long-acting muscarinic antagonist umeclidinium (UMEC) and the combination of UMEC with the long-acting beta2 agonist vilanterol (VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. OBJECTIVES: This study investigated the effect of UMEC and UMEC/VI on the QT interval corrected using Fridericia's correction (QTcF) following a 10-day treatment period. METHODS: Randomized, placebo- and moxifloxacin-controlled, 4 period incomplete block crossover study of healthy non-smokers (n = 103). All treatments were double blind, except for moxifloxacin/moxifloxacin placebo controls which were single blinded. Subjects were randomized to a treatment sequence which consisted of 4 of 5 regimens. Each regimen consisted of once-daily doses on Days 1-10 via the ELLIPTATM dry powder inhaler and a single tablet on Day 10 of the following: placebo + placebo; placebo + moxifloxacin; UMEC 500 MUg + placebo; UMEC/VI 125/25 MUg (delivered dose: 113/22 MUg) + placebo; UMEC/VI 500/100 MUg + placebo. QT interval, additional cardiac parameters, pharmacokinetics, pharmacodynamics and safety were assessed. RESULTS: No clinically significant changes from baseline in QTcF occurred with UMEC 500 MUg and UMEC/VI 125/25 MUg compared with placebo, however, there was a change in QTcF from baseline of 6.4 ms (90% confidence interval [CI]: 4.3, 8.5) at 10 min and 8.2 ms (90%: 6.2, 10.2) at 30 min post dose following UMEC/VI 500/100 MUg compared with placebo. On Day 10, categorical analysis demonstrated absolute QTcF values >450-480 ms for UMEC/VI 125/25 MUg (1 subject) and moxifloxacin (3 subjects), and a change from baseline QTcF of >30-60 ms for UMEC/VI 125/25 MUg, UMEC 500/100 MUg and placebo (1 subject each) and moxifloxacin (2 subjects). On Day 10, the mean change from baseline in heart rate was increased with UMEC/VI 125/25 MUg and UMEC 500/100 MUg compared with placebo with the maximum increase occurring at 10 min post dose (8.4 bpm [90% CI: 7.0, 9.8] for UMEC/VI 125/25 MUg; 20.3 bpm [90% CI: 18.9, 21.7] for UMEC/VI 500/100 MUg); after this timepoint, heart rate rapidly returned to normal levels. UMEC and VI systemic exposures following UMEC/VI 500/100 MUg were >4-fold higher than those following UMEC/VI 125/25 MUg. All treatments were generally well tolerated in terms of adverse events, laboratory, vital signs and electrocardiogram data; the proportion of subjects with any adverse event was similar across treatments arms (39-59%).. CONCLUSION: There was no clinically significant effect on QTcF observed following 10-days' treatment with inhaled UMEC/VI 125/25 MUg or UMEC 500 MUg compared with placebo. The supratherapeutic dose of UMEC/VI 500/100 MUg prolonged QTcF by 6.4 ms (90% CI: 4.3, 8.5) at 10 min and 8.2 ms (90% CI: 6.2, 10.2) at 30 min compared with placebo, following which QTcF interval difference from placebo declined rapidly.. PMID- 25020274 TI - Health assessment of gasoline and fuel oxygenate vapors: subchronic inhalation toxicity. AB - Sprague Dawley rats were exposed via inhalation to vapor condensates of either gasoline or gasoline combined with various fuel oxygenates to assess whether their use in gasoline influences the hazard of evaporative emissions. Test substances included vapor condensates prepared from an EPA described "baseline gasoline" (BGVC), or gasoline combined with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA). Target concentrations were 0, 2000, 10,000 or 20,000mg/m(3) and exposures were for 6h/day, 5days/week for 13weeks. A portion of the animals were maintained for a four week recovery period to determine the reversibility of potential adverse effects. Increased kidney weight and light hydrocarbon nephropathy (LHN) were observed in treated male rats in all studies which were reversible or nearly reversible after 4weeks recovery. LHN is unique to male rats and is not relevant to human toxicity. The no observed effect level (NOAEL) in all studies was 10,000mg/m(3), except for G/MTBE (<2000) and G/TBA (2000). The results provide evidence that use of the studied oxygenates are unlikely to increase the hazard of evaporative emissions during refueling, compared to those from gasoline alone. PMID- 25020275 TI - Target organ profiles in toxicity studies supporting human dosing: an assessment of recovery and chronic dosing. AB - We have previously reported the profile of toxic effects with respect to target organs (defined as organs showing histopathological changes) observed in rodent and non-rodent toxicity studies conducted prior to first time in man (FTIM) for 77 AstraZeneca candidate drugs (CDs) across a range of therapy areas. The main objectives of the current study were twofold; to determine which target organs observed in the FTIM studies recovered after a dose free recovery period and to determine which additional target organs were observed in subsequent chronic (?3month) studies required to support longer term clinical dosing. The analysis showed that ?86% of findings in studies supporting FTIM either fully or partially resolved at the end of the recovery period, with profiles of recovery that were similar whether the CD progressed into man or not and across different therapy areas. Compared to observations in FTIM studies, chronic studies identified toxicities in an additional 39% of target organs. Overall these data demonstrate that chronic studies in both rodents and non-rodents provide valuable information for the risk assessment for longer term dosing in humans. In addition, the high levels of recovery demonstrated in this analysis suggest that inclusion of recovery assessments on FTIM studies should be on a case-by-case basis driven by a positive indication of need. This is in line with ICH non-clinical guidance that states that reversibility of severe nonclinical toxicities of potential clinic relevance should be assessed 'when appropriate', but that the evaluation can be based on a study of reversibility or on a scientific assessment. PMID- 25020276 TI - Metastin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. AB - OBJECTIVE: The aim of the present study was to evaluate serum concentrations of metastin in relation with hormonal and metabolic profile in patients with and without polycystic ovary syndrome (PCOS). STUDY DESIGN: The study was a clinical study. Eighty-three women with PCOS and 66 body mass index (BMI) matched controls were divided into two groups, based on BMI: overweight and obese (BMI>=25 kg/m(2)) and normal weight. (BMI<25 kg/m(2)) Hirsutism scores, hormonal and metabolic profile as well as metastin levels were evaluated in each subject. Blood samples were collected in the early follicular phase (between day 2 and day 5 of the menstrual cycle) at 9:00 AM, after an overnight fast. Circulating levels of LH, FSH, PRL, TSH, T, fT, DHEAS, 17-OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, lipid profile and metastin were measured. RESULTS: Metastin levels were significantly higher in the PCOS group compared to controls (2.02 ng/ml versus 1.16 ng/ml, p<0.001). Metastin levels correlated significantly positively with luteinizing hormone (LH), total testosterone (T), dehydroepiandrosteronesulphate (DHEA-SO4) levels, modified Ferriman-Gallwey (mFG) scores and free androgen index (FAI); however, correlated negatively with sex hormone binding globulin (SHBG) levels (p<0.05). When overweight or obese (BMI>=25 kg/m(2)) and normal weight (BMI<25 kg/m(2)) women with PCOS were compared to body mass index (BMI) matched controls, higher metastin levels were also found in PCOS groups (1.94 ng/ml versus 1.18 ng/ml, and 2.06 ng/ml versus 1.08 ng/ml, p<0.05, respectively). CONCLUSIONS: These findings suggest that metastin levels were higher in women with PCOS as compared to controls regardless of BMI. Furthermore, metastin levels can be used as a specific marker for androgenic profile and this marker might play a role in the pathogenesis of PCOS. PMID- 25020277 TI - Variations in the reporting of outcomes used in systematic reviews of treatment effectiveness research in bladder pain syndrome. AB - This paper investigates the quality of outcomes reported in systematic reviews and randomised controlled trials (RCTs) of bladder pain syndrome and its relationship with study quality and journal impact factor. We searched until August 2013 the Cochrane Library, EMBASE, Medline, CINAHL, LILACS and SIGLE, without language restrictions. Quality of outcome reporting in systematic reviews and constituent RCTs was assessed using a 6-point scale. Overall study quality was assessed using the AMSTAR and Jadad scoring systems, and impact factor in the year of publication was noted. Spearman's rank correlation was calculated. There were 8 systematic reviews, with a total of 28 RCTs (1732 patients), reporting 5 outcomes using 19 different measurement scales. The outcomes reported in individual RCTs were urinary symptoms (100%), pain (64%), quality of life (39%), general wellbeing (36%) and bladder capacity (36%). The mean quality of outcomes reported was 1.63 (95% CI 0.29-2.96) for systematic reviews and 3.25 (95% CI 2.80 3.70) for RCTs. The quality of outcomes reported showed correlation with overall study quality (0.90, 95% CI 0.79-0.95, p<0.0001) but not with journal impact factor (0.07, 95% CI -0.31-0.43, p=0.35). Multivariable linear regression showed a relationship between quality of outcome reporting and study quality (beta=0.05, p<0.0001), adjusting for effects of study type, impact factor and journal type. There is a need to generate consensus over a set of core outcomes in bladder pain syndrome using standardised reporting tools and to disseminate these through good publication practice. PMID- 25020278 TI - SRF is essential for mesodermal cell migration during elongation of the embryonic body axis. AB - Mesoderm formation in the mouse embryo initiates around E6.5 at the primitive streak and continues until the end of axis extension at E12.5. It requires the process of epithelial-to-mesenchymal transition (EMT), wherein cells detach from the epithelium, adopt mesenchymal cell morphology, and gain competence to migrate. It was shown previously that, prior to mesoderm formation, the transcription factor SRF (Serum Response Factor) is essential for the formation of the primitive streak. To elucidate the role of murine Srf in mesoderm formation during axis extension we conditionally inactivated Srf in nascent mesoderm using the T(s)::Cre driver mouse. Defects in mutant embryos became apparent at E8.75 in the heart and in the allantois. From E9.0 onwards body axis elongation was arrested. Using genome-wide expression analysis, combined with SRF occupancy data from ChIP-seq analysis, we identified a set of direct SRF target genes acting in posterior nascent mesoderm which are enriched for transcripts associated with migratory function. We further show that cell migration is impaired in Srf mutant embryos. Thus, the primary role for SRF in the nascent mesoderm during elongation of the embryonic body axis is the activation of a migratory program, which is a prerequisite for axis extension. PMID- 25020279 TI - Feasibility of retinal screening in a pediatric population with type 1 diabetes mellitus. AB - PURPOSE: To study the feasibility of using a nonmydriatic camera to screen children with type 1 diabetes mellitus (DM1) as young as 2 years for diabetic retinopathy. METHODS: Prospective pilot imaging study involving children with DM1 aged 2 to 17 years. The screening consisted of: (1) intake form; (2) measurement of blood pressure, pulse, and oximetry; (3) assessment of visual acuity (SIMAV, Padova, Italy); and (4) nonmydriatic color imaging (Canon CX-1 45 degrees 15.1 megapixel camera; Canon Corp., Tokyo, Japan). Images were assessed for signs of diabetic retinopathy and graded for quality on a scale of 1 to 5 by two clinicians. Kappa coefficient was calculated to determine inter-observer agreement. RESULTS: One hundred four of 106 (98%) children underwent imaging (mean age: 11.1 years, 51% male, 88% white). One (1%) child had nonproliferative diabetic retinopathy and 2 (1.9%) had incidental findings. Only 62% of children had an eye examination within the past year, with children with DM1 for more than 5 years significantly more likely to have done so (P = .03). Children who had an eye examination within the past year were significantly older than their counterparts (P = .01). Images of high quality (grades 4 and 5) were acquired in 178 (86%) eyes, and images of some clinical value (grades >= 2) were obtained in 207 (99.5%) eyes. Inter-observer agreement for image quality was 0.896. CONCLUSIONS: The feasibility of using a nonmydriatic camera to screen children as young as 2 years for changes related to diabetic eye disease was demonstrated. Nonmydriatic imaging may supplement standard dilated clinical ophthalmology examinations for select patient populations. PMID- 25020280 TI - Surgical outcome of strabismus surgery in patients with unilateral vision loss and horizontal strabismus. AB - PURPOSE: To report on the surgical outcome of horizontal strabismus surgery in patients diagnosed as having unilateral vision loss. METHODS: Medical records of all patients with unilateral vision loss who underwent surgical repair of horizontal strabismus between 2008 and 2013 at three medical centers were reviewed. Data collected included age at time of surgery, type of strabismus, preoperative and postoperative deviation, procedure performed, and length of follow-up. Surgical success was defined as final alignment of 10 prism diopters (PD) or less unless more than one surgery was required to realign the eyes. RESULTS: Twenty-one patients (9 children) were reviewed. Mean age at time of surgery was 28.3 years (range: 3 to 64 years) and mean follow-up was 20 months (range: 6 months to 5 years). Mean preoperative logMAR visual acuity in the deviating eyes (14 right eyes) was 1.4 +/- 0.7 (range: 1.0 to 2.8) and mean deviation was 33 PD (range: 15 to 90 PD). All procedures were performed only on the deviating eye (13 recessions and 8 recession-resection procedures). Mean postoperative deviation was 6.4 PD (range: 0 to 25 PD) and 81% of patients had a manifest ocular deviation of 10 PD or less. Surgical success was comparable in children versus adults (P = .603), in patients with esotropia versus exotropia (P = 1.000), in patients with preoperative deviations larger than 30 PD compared to patients with smaller deviations (P = .521), and in patients in whom one muscle was operated on compared to all other patients (P = .617). CONCLUSIONS: Strabismus surgery in patients with unilateral vision loss is often successful in correcting ocular misalignment. PMID- 25020281 TI - Frontiers in cardiovascular biology. Abstracts of the Third Congress of the ESC Council on Basic Cardiovascular Science. July 4-6, 2014. Barcelona, Spain. PMID- 25020912 TI - Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury. AB - AIMS: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice. METHODS AND RESULTS: MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin alpha5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin alpha5 and sirtuin1. CONCLUSION: Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury. PMID- 25020913 TI - Delayed phospholamban phosphorylation in post-conditioned heart favours Ca2+ normalization and contributes to protection. AB - AIMS: It has been shown that sarcoplasmic reticulum calcium ATPase (SERCA) plays a critical role in reperfusion injury. Moreover, ischaemic post-conditioning (PoCo) results in protein kinase G (PKG) activation which has been proposed to modulate phospholamban (PLB) and SERCA. We assessed whether PLB phosphorylation contributes to the cardioprotective effects of PoCo. METHODS AND RESULTS: Isolated Sprague-Dawley rat hearts were submitted to 40 min of ischaemia and reperfusion with and without a PoCo protocol that reduced infarct size by 48%. Reperfusion caused a rapid phosphorylation in PLB at Ser16 and Thr17 that was delayed by PoCo. NO-independent activation of soluble guanylate cyclase (sGC) (ataciguat) and cAMP-dependent protein kinase (PKA) inhibition (KT5720) mimicked the reduction in Ser16 phosphorylation in reperfused control hearts, while in PoCo hearts the inhibitors of PKG (KT5823) and phosphodiesterase 2 (BAY-60-7550) reverted it. CaMKII activity measured by Thr287 phosphorylation was reduced in PoCo. In reperfused control hearts, inhibition of PLB phosphorylation or SERCA (thapsigargin) simulated the cardioprotective effects of PoCo. Ataciguat reduced cytosolic Ca(2+) oscillations and improved Ca(2+) recovery in cardiomyocytes subjected to anoxia-reoxygenation and infarct size by 32% in rats with 30 min of the left anterior descending coronary artery occlusion and 2 h of reperfusion. Blockade of Na(+)/Ca(2+)-exchanger (NCX; KB-R7943) impaired Ca(2+) control in cardiomyocytes and abolished cardioprotection in PoCo hearts. CONCLUSIONS: PoCo reduces SERCA activity at the onset of reperfusion by delaying PLB phosphorylation through activation of PKG and inhibition of PKA and CaMKII. This effect contributes to PoCo protection by favouring cytosolic Ca(2+) extrusion through NCX, and it may be mimicked by pharmacological stimulation of sGC. PMID- 25020914 TI - Abstracts of the Perinatal Medicine 2014 Congress, 9-11 June 2014, Harrogate, UK. PMID- 25021421 TI - Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. AB - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features. METHODS: Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied. RESULTS: HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1). CONCLUSIONS: Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients. PMID- 25021422 TI - The gut microbiota, dietary extremes and exercise. PMID- 25022015 TI - Abstracts of the British Society of Gastroenterology Annual General Meeting. June 16-19, 2014. PMID- 25022021 TI - ICD-10 will probably be the biggest change to your work environment. PMID- 25021423 TI - Exercise and associated dietary extremes impact on gut microbial diversity. AB - OBJECTIVE: The commensal microbiota, host immunity and metabolism participate in a signalling network, with diet influencing each component of this triad. In addition to diet, many elements of a modern lifestyle influence the gut microbiota but the degree to which exercise affects this population is unclear. Therefore, we explored exercise and diet for their impact on the gut microbiota. DESIGN: Since extremes of exercise often accompany extremes of diet, we addressed the issue by studying professional athletes from an international rugby union squad. Two groups were included to control for physical size, age and gender. Compositional analysis of the microbiota was explored by 16S rRNA amplicon sequencing. Each participant completed a detailed food frequency questionnaire. RESULTS: As expected, athletes and controls differed significantly with respect to plasma creatine kinase (a marker of extreme exercise), and inflammatory and metabolic markers. More importantly, athletes had a higher diversity of gut micro organisms, representing 22 distinct phyla, which in turn positively correlated with protein consumption and creatine kinase. CONCLUSIONS: The results provide evidence for a beneficial impact of exercise on gut microbiota diversity but also indicate that the relationship is complex and is related to accompanying dietary extremes. PMID- 25022022 TI - Not only getting personal. PMID- 25022023 TI - Overdiagnosis: a necessary part of the learning curve towards excellence. PMID- 25022024 TI - New collaboration aims to aid target validation and drive drug discovery. PMID- 25022025 TI - New high-risk gene mutation for hereditary melanoma development identified. PMID- 25022026 TI - Regulatory gene linked to progression and relapse of triple-negative breast cancer. PMID- 25022027 TI - Effect of antidepressant drug on semicarbazide-sensitive amine oxidase (SSAO) in dog brain. AB - The present study examined whether or not other cyclic antidepressants, such as the dicyclic drug zimeldine, the tricyclic drug imipramine, and tetracyclic drug maprotiline, and the noncyclic drug nomifensine, inhibit semicarbazide-sensitive amine oxidase (SSAO) activity in dog brain. After treatment with 100 nM clorgyline and 100 nM deprenyl, all four antidepressant drugs inhibit SSAO activity in dog brain. The most potent of inhibition was observed by imipramine, followed by maprotiline, zimeldine and nomifensine. All four drugs are noncompetitive inhibitor of SSAO in dog brain. We found the tricyclic antidepressant drug imipramine to be the most selective inhibitors of SSAO activity in dog brain, as compared with other type of antidepressant drugs. PMID- 25022028 TI - The properties of B-form monoamine oxidase in mitochondria from monkey platelet. AB - The present study was examined the effect of the properties of monkey platelet monoamine oxidase (MAO) based on inhibitor sensitivity. Monkey platelet showed a high MAO activity with beta-phenylethylamine (beta-PEA) as substrate and a very low A-form MAO activity with 5 hydroxytryptamine (5-HT) as substrate. Moreover, monkey platelet MAO was sensitive to the drugs deprenyl as B-form MAO inhibitor and less sensitive to clorgyline and harmaline as A form MAO inhibitor with beta PEA as the B-form MAO substrate. B-form MAO from monkey platelet was more stable against heat treatment at 55 degrees C than B-form MAO in brain. After digestion with trypsin at 37 degrees C for 4 hrs, it was found that MAO from platelet was inhibited about 70% with beta-PEA as substrate with brain. The tricyclic antidepressant imipramine and nortriptyline inhibited B-form MAO activity more potency than B-form MAO in brain. However, when the noncyclic antidepressant nomifensine was used, monkey platelet B-form MAO activities were less potently inhibited. All these reagents were noncompetitive inhibitors of B form MAO in monkey platelet. The present studies demonstrated that monkey platelet MAO is a single of B-form MAO and sensitive to tricyclic antidepressants. PMID- 25022029 TI - Effects of 5-ethyl-1-phenyl-2-(1H) pyridone on serum biomarkers of multiorgan dysfunction and mortality in lipopolysaccharide/galactosamine and cecal ligation and puncture models of septic shock in mice. AB - Septic shock results from a systemic host response to infection, in particular, and is associated with multiorgan dysfunction (MOD). Effective preventive measures against organ failure are essential as it is the cumulative burden of MOD that invariably leads to death. The aim of this study was to determine if a novel compound, 5-ethyl-1-phenyl-2-(1H) pyridone (5-EPP), could decrease the increased serum levels of various biomarkers of MOD in LPS/D-Galactosamine (LPS/D GalN) and cecal ligation and puncture (CLP) models of septic shock in mice. Treatment with 5-EPP minimized the liver dysfunction as assessed by its ability to decrease the increased serum levels of aminotransferases. It also reduced proinflammatory cytokines such as TNF-alpha, IL-6 and IL-12, and offered complete protection against mortality in LPS/D-GalN model. 5-EPP treatment also offered a significant protection against LPS alone- induced mortality. Pretreatment with 5 EPP minimized the kidney, heart and muscle damage as assessed by its ability to decrease the CLP-induced increases in the serum levels of blood urea nitrogen, creatine kinase, glucose and mortality. Several possible mechanisms for the beneficial effects of 5-EPP in the LPS/D-GalN, LPS alone, and CLP models of septic shock have been discussed. It was concluded from the findings of this study that 5-EPP, a novel pyridone, is a promising candidate for the management of septic shock by offering protection against MOD and mortality clinically seen in septic patients. PMID- 25022030 TI - Changes in monoamine oxidase activity in hepatic injury: a review. AB - This review focuses on multiplicity of monoamine oxidase (MAO) activity in rat hepatic injury. MAO play a major role in the metabolism of biogenic amines. Stress such as immobilization stress (IMMO) or cold stress changes the multiple forms of MAO activity in rat liver. Thyroid hormone-inducible MAO inhibitor may play some role in regulating the MAO activity in rat liver. Carcinogen such as dimethylnitrosamine (DEN) might change the proportions of the forms of MAO activity in tumor cells. This compound is selective to and an irreversible inhibitor of MAO-B. These changes may account for the multiplicity of MAO by hepatic injury. PMID- 25022031 TI - Protective effect of tamoxifen, a synthetic non-steroidal antiestrogen, on phenelzine and 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical generation in rat striatum. AB - The present study examined whether tamoxifen could suppress antidepressant drug phenelzine can increase an active dopaminergic neurotoxin, 1-methyl-4 phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the extracellular fluid of rat striatum, using in vivo microdialysis system. Rats were anesthetized, and sodium salicylate (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Infusion of phenelzine (0.1 mM or 0.1 nmol/microl/min) into the striatum drastically increased dopamine (DA) efflux and the *OH formation, trapped as 2,3 DHBA by the possible increased production of MPP+. However, tamoxifen (100 microM) significantly suppressed phenelzine enhanced DA efflux and *OH formation by MPP+. These results in the pressent study is the first demonstration showing the protective effect of tamoxifen on *OH generation induced by phenelzine enhanced MPP+ by suppressing DA efflux. PMID- 25022032 TI - Attenuation of bromobenzene-induced hepatotoxicity by poly(ADP-ribose) polymerase inhibitors. AB - Inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) have been demonstrated to attenuate pathophysiological conditions associated with toxicant induced oxidative stress. This investigation evaluates Nicotinamide (NIC), a non specific PARP inhibitor, and 6(5)-Phenanthridinone (Phen), a specific PARP-1 inhibitor, for their efficacy in blocking or attenuating bromobenzene (BB) induced hepatocellular toxicity. Male ICR mice were treated with an intraperitoneal injection of bromobenzene, followed by concomitant treatment with NIC or with NIC at 0.5, 1 and 2 hours after BB treatment, or with concomitant treatment of Phen at 10 mg/ml, 20 mg/ml, or 40 mg/ml solution concentration. Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3.5 fold increase in serum alanine transferase (ALT) compared to controls. Mice treated with 3 injections of NIC (at 0.5, 1 and 2 hours) after BB treatment demonstrated a 90% reduction in serum ALT at 24 hours after BB treatment (p < 0.05). Mice with concomitant BB and Phen treatment demonstrated a 75% reduction in ALT at 24 hours after treatment (p < 0.05). Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups. Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups. The PARP-1 inhibitors evaluated in this investigation produce clinically significant attenuation of BB-induced liver injury in male ICR mice. PMID- 25022033 TI - Editor's desk. PMID- 25022035 TI - Education is a path, not a destination. PMID- 25022034 TI - The "season of giving" is timeless. PMID- 25022036 TI - CAD/CAM implant provisional use reshapes gingival tissues while improving esthetics and hygiene. PMID- 25022037 TI - Changing of the Guard. PMID- 25022038 TI - Enlisted dental specialist career progression within the United States Army. PMID- 25022039 TI - Spring is in the air and for many dental assisting students, this means that graduation is approaching. PMID- 25022040 TI - Legislative infonotes. PMID- 25022042 TI - [Is the primary dentition getting worse?]. PMID- 25022043 TI - [Treatment of a patient with psychogenic non-epileptic seizures]. AB - A 36-year old man is referred to a centre for special dental care due to problems with treatability in the general dental practice and a deteriorated oral state. His behaviour is unpredictable due to the possible development of sudden changes in the patient's consciousness which are accompanied by severe aggression. The patient suffers from a conversion disorder, a serious mental disorder which expresses itself in his case with the occurrence of psychogenic non-epileptic seizures. The patient fears that dental treatment will provoke a seizure and that he will react aggressively to his surroundings. He therefore requests that he undergoes dental treatment using general anaesthesia and patient fixation measures. This case study provides an example for the discussion of the problems and the rights of patients with severe mental disorders and the use of measures of physical restraint in dentistry. PMID- 25022044 TI - [The use of temporary implants in prosthetic dentistry]. AB - Temporary implants can offer a worthwhile contribution to a patient's comfort during the integration of conventional implants or during the maturation of bone grafts. Although temporary implants are not intended for osseointegration, survival rates are sufficiently high for them to be functional during several months. Fixed prostheses which are attached to temporary implants perform better than removable prostheses which more quickly lead to the loosening and loss of these temporary implants. PMID- 25022045 TI - [Microfat transfer in cosmetic facial procedures]. AB - Loss of volume in the soft tissues of the face is considered to be an important cause of facial ageing. This volume loss can be compensated by microfattransfer. This technique offers a natural and long-lasting effect. Fat is harvested with liposuction and after centrifugation it is injected into the target areas in the face using small blunt cannulas. The goal is to place the fat in the desired place in such a way that the fat will survive and become integrated in the acceptor tissue. Microfattransfer can be combined with other cosmetic facial procedures such as blepharoplasties and facelifts. Although fatgrafting is a safe technique, complications may occur. These are mostly related to technique and amount of fat injected. Microfattransfer is a useful adjunctive procedure in maxillofacial surgery. Because only 40-50% of the result of microfattransfer is permanent touching up is often necessary. Microfattransfer should be considered as a staged treatment modality. PMID- 25022046 TI - [The dentists' image. Is history repeating itself?]. AB - Each generation likes to see itself as unique and thinks that the conditions under which people live and work are also unique. This position does not, for the most part, apply to dentists. Two questions which are now under discussion were also under discussion in the past. In the first case, this has to do with whether dentistry should be seen especially as a profession in which skill and competence are central, or as a medical discipline in which science (too) is central. The second question which was posed in the past as it is now is whether the dentist is seen especially as a salesman, albeit as a healthcare provider. Both questions are of the greatest significance for the image of dentists and also perhaps indirectly for the future of the professional group. Indeed, the answer to these questions has determined in the past as well as now the image of dentists and the degree to which the government has believed that dentists could be replaced by less highly educated non-dentists. For that reason, a clear answer to these questions ought to be formulated. It is possible that the answers given to these same questions in the past will be helpful in formulating answers now. PMID- 25022047 TI - [The Data Stations project: a monitor of dental practice in The Netherlands]. AB - Since 1995 the Dutch Dental Association (NMT) has carried out research on, in particular, the non-clinical aspects of dental practice with the Data Stations project. At present, within this research project 5 studies are conducted on a regular basis: the Dental Consumption Study, the Dental Practice Study, the Omnibus Survey, the Young Dentist Study and the Quality of Oral Care Study. From the results of this research project it appears that during the last decades dentists have increasingly been working cooperatively. This is expressed in dental practices with more dentists and more staff workers, with more dental chairs and more patients. The length of the working week, however, has changed very little over the years. Among both young people and adults gradual changes have taken place in dental consumption during the period 1997-2011. By intensifying the collaboration with clinical dental researchers the scope of the research within this project can be expanded to include the quality of oral care and the effects of care which has been provided on oral health in The Netherlands. PMID- 25022048 TI - [The development of the dental instrumentarium]. AB - The University Museum of the University of Utrecht houses within its walls a dentistry collection. A range of dental instruments is on display here which have been used through the ages to deliver people from toothaches. A long time passed, however, before instruments for tooth extraction had been developed which, with the benefit of anatomical knowledge, could effectively grasp teeth. In the middle of the 19th century, general anaesthetics were (re) discovered and that represented an enormous breakthrough. The 'tooth operator' was finally able to treat the patient in a relaxed manner. That opened up a world of medical possibilities. Musclemen who could restrain the patient were no longer necessary and in surgical treatments time became a much less pressing factor. From the beginning of the 20th century, the increase in medical knowledge also made huge advances possible, and the possibilities for dental treatment multiplied. PMID- 25022049 TI - Not so fast! Congress delays ICD-10-CM/PCS. Examining how the delay happen, its industry impact, and how best to proceed. PMID- 25022050 TI - Don't deny the denials. Experts recommend implementing a strong claims denial strategy to offset ICD-10-based coder productivity loss. PMID- 25022051 TI - Bird's eye view of ICD-10 documentation gap. Vendor analysis offers big picture look at nationwide: documentation holes--and how to fill them. PMID- 25022052 TI - Trust but verify. Safetyguards in contracting for outsourced coding services. PMID- 25022053 TI - Tighten the bolts of your ROI processes. PMID- 25022054 TI - Nonsensical data input produces undesired output for data analysis. PMID- 25022055 TI - Setting the norm. HIM increasingly involved in developing and using standards. PMID- 25022056 TI - Overcoming the risks of copy and paste in EHRs. PMID- 25022057 TI - Navigating a compliant breach management process. PMID- 25022058 TI - Traumatic brain injury coding in ICD-10-CM. PMID- 25022059 TI - Coding ICD-10-PCS medical and surgical-related sections. Understanding osteopathic, other procedures, and chiropractic. PMID- 25022060 TI - [Performance and clinical evaluation of antinuclear antibody test based on fluorescence enzyme immunoassay]. AB - BACKGROUND: The measurement of antinuclear antibodies (ANA) is used for screening of connective tissue diseases (CTD) in the laboratory. ANA detection is performed by indirect immunofluorescence (IF) assay on HEp-2 cells from human larynx carcinoma. However, it lacks specificity for the identification of specific diseases and antigen reactivity. The aim of the present study was to evaluate the EliA CTD Screen (EliA), a new enzyme fluoroimmunoassay (Phadia AB, Uppsala, Sweden) for detection of ANA in human serum. PATIENTS AND METHODS: The study involved a total of 732 serum samples, 200 from healthy donors, 297 from patients with CTD and 235 from patients with rheumatoid arthritis, vasculitis syndrome and relative disease of CTD. For all sera, ANA was measured by IF, commercial assay (MESACUP) and EliA. RESULT: The sensitivity and specificity of EliA were 73.7% and 78.7%, respectively, whereas those of MESACUP were 80.8% and 64.7%, respectively. Area under the receiver operating curves for EliA, MESACUP and IF were 0.821, 0.786 and 0.730, respectively. The concordance rate between EliA and MESACUP was 84.2%. These discrepancies between those 2 assays were found in 84 sera. Further investigation were done by each ANA antigen tests for the discrepant results of EliA in 83 sera. The discrepancies might be occurred by antigen difference or non-specific response. CONCLUSION: AUC results showed that the diagnostic performance of EliA was superior to MESACUP and IF. EliA had a good performance as method for screening of CTD. PMID- 25022061 TI - [Comparison of tests for SS-A/Ro, Ro52 and Ro60 in predicting congenital heart block]. AB - Neonatal lupus erythematosus (NLE) is a rare syndrome caused by the transplacental passage of maternal autoantibodies. Anti SS-A antibodies of a mother with Sjogren syndrome are associated with congenital heart block (CHB) in the newborns with NLE. The purpose of this study was to investigate the utility of maternal antibody titers for SS-A, Ro52 and Ro60 in mothers of newborns with CHB. The study involved a total of 304 cases, 25 from mothers of newborns with CHB, 104 from mothers of newborns without and 175 from mothers suspected to have connective tissue diseases. All sera were tested with the EliA SS-A, EliA Ro52, EliA Ro60, MESACUP Ro52 and MESACUP Ro60. The concordance rate of Ro52 assays was 93.4%, whereas Ro60 assays showed a lower concordance rate (74.7%). The areas under the curve (AUC) of the EliA assays were higher than those of the MESACUP assays. The optimal cut-off values for EliA SS-A/Ro and EliA Ro60 as derived from the ROC analysis were 2027 U/mL and 2446 U/mL, respectively. The sensitivity and specificity for EliA SS-A using optimal cut-off values were 96.0% and 92.3%, respectively. A titer of 90% positive predictive value for EliA SS-A was reached at a cut-off of 9897.1 U/mL, corresponding to sensitivity and specificity values of 36.0% and 100%, respectively. In conclusion, the optimal cut-off value for EliA SS-A is likely to be useful for application in clinical practice for the EliA SS-A measurements in mothers to evaluate the risk of NLE for their newborns. PMID- 25022062 TI - [Trends for the etiology of infective endocarditis at our hospital these 5 years]. AB - The aim of this study is to evaluate characteristics of infective endocarditis for 5 years at Kanazawa University Hospital. Retrospectively, we investigated 39 patients diagnosed as infective endocarditis at our hospital from 2006 to 2010 based on blood culture and/or rejected cardiac specimens. Of 39 patients with infective endocarditis, 27 were male and 12 were female. Mean age was 55.4 years and 69% patients were older than 50 years. The frequent underlying presumed diseases were cardiac diseases. Vegetation was mainly observed at mitral valve and aortic valve. Streptococcus species [14 cases (36%)] and Staphylococcus species [12 cases (31%)] were common pathogens. In Streptococcus species, the critical cause was mostly presumed to be associated with dental procedure and oral cavity. In Staphylococcus species, intravascular device and soft tissue infection were also frequently presumed. Frequency of chronic kidney disease and infection around valve were higher in Staphylococcus species than those observed in Streptococcus species [12 cases (100%) vs. 7 cases (50%); p < 0.05, 6 cases (50%) vs. 1 case (7%); p < 0.05]. Our results suggested that the etiology of patients with Staphylococcus species infection increased in number among patients suffering from infective endocarditis at our hospital. PMID- 25022063 TI - [New treatment and diagnostic test for multiple myeloma]. AB - Multiple myeloma (MM) is a malignancy of plasma cells of the final maturation stage of B cells, characterized by atypical plasma cell proliferation in bone marrow and the production of monoclonal immunoglobulin. The history of chemotherapy for MM began in the early 1960s, when the efficacy of alkylating agents, particularly melphalan, was shown. High-dose therapy (HDT) has been the standard treatment for patients younger than 65 years since the superiority in terms of OS as well as PFS of HDT supported by autologous stem cell transplantation (ASCT) was reported. From the 2000s, the emergence of novel agents involving proteasome inhibitors such as bortezomib, and IMiDs such as thalidomide and lenalidomide, has been markedly changing MM treatment and improving the prognosis. As initial treatment, novel agents are frequently used since high response rates have been reported. For MM patients who are not candidates for HDT ASCT because of aging and/or organ dysfunction, combined therapies that consist of conventional chemotherapy and novel agents are usually recommended. The chromosomal aberrations frequently found in MM are 'hyperdiploid' or 'non-hyperdiploid' and immunoglobulin gene (Ig) translocation of chromosomes. It is known that the chromosomal aberration is associated with the treatment response and prognosis of MM patients, and this information is indispensable. Because chromosomal translocation is not readily detected by G banding, the FISH method is essential. In recent years, molecular mechanisms of MM have been revealed by microarrays (Gene Expression Profiles) and whole genome sequencing using next-generation sequencers. Furthermore, in-depth sequencing by such next-generation sequencers has revealed that MM is monoclonal, but shows intra-clonal heterogeneity at the onset of the disease from the viewpoint of genetic abnormality. PMID- 25022064 TI - [Antibody therapy for hematopoietic malignancies and cell surface antigen testing]. AB - In recent years, the diagnostic and therapeutic approaches for malignant neoplasms have significantly improved. With the development of molecular targeted diagnosis or therapeutic drugs, marked progress has been achieved in predicting the therapeutic effect and the prognosis. In this context, progress in molecular biology and immunological cellular antigen-searching techniques has played an important role. Hematopoietic malignancies are not an exception, and also depend on these analytical techniques. For therapeutic approaches using these techniques, it is necessary to accurately determine the responsible gene or target cellular surface antigen. It is now becoming possible to determine these genes or cancer cell specific antigens with high-level accuracy. It is evident that accurate laboratory test results of features of cancer cells are essential for the implementation of appropriate therapeutic approaches. In this chapter, an overview of antibody therapy for hematopoietic malignancies and laboratory testing will be presented. PMID- 25022065 TI - [Classification and clinical findings of myelodysplastic syndromes]. AB - Myelodysplastic syndromes (MDS) are a group of related disorders in which bone marrow stem cells malfunction, while the type is diagnosed based on the WHO classification revised in 2008. Although the diagnosis largely depends on the cytomorphology, it is difficult to diagnose MDS based on the morphology alone, particularly in patients with < 5% blasts in the bone marrow and a normal karyotype. In Japan, a grading system for the diagnostic accuracy of MDS was proposed in 2007, and evaluation of dysplasia (high, intermediate, low, minimal) is a characteristic part. Morphologic dysplastic changes are classified into highly specific category A (pseudo-Pelger-Huet anomaly, degranulation of neutrophils, micro-megakaryocytes, ringed sideroblasts) and less specific category B (dysplasia other than category A). With the use of this grading system, diagnostic problems should be reduced. Flow cytometry has also been proposed as a tool to improve the evaluation of marrow dysplasia, because immunophenotyping is an accurate method for quantitative and qualitative evaluations of hematopoietic cells, and MDS specimens have been found to exhibit abnormal expressions of several cellular antigens. In addition, the molecular classification of MDS has received marked attention in recent years. New molecular markers including RPS14, TET2, IDH1/2, SF3B1, ASXL1, RUNX1, TP53, EZH2, JAK2, and WT1 have been revealed to be important for the prognosis, as well as diagnosis and classification. In this report, we review MDS diagnostic approaches from the viewpoints of cytomorphology, immunophenotyping, and cytogenetics. PMID- 25022066 TI - [The current status of genetic testing for leukemia]. AB - The pathogenic chromosome translocations present in various hematological malignancies result in the formation of fusion genes, which are detected by a reverse transcription-polymerase chain reaction method. Furthermore, with this method, it is possible to sensitively detect minimal residual disease (MRD), which is difficult by a morphological testing. It has now been established that the detection of MRD is important for the diagnosis, treatment policy, evaluation of the prognosis, and monitoring of leukemia. In particular, quantitative analysis of MRD is important for evaluation of the curative effect and prediction of recurrence. In addition, mutation analysis is valuable to decide on the therapeutic protocol for imatinib-resistant patients, and the stratification of treatment for acute myeloid leukemia. At present, however, there is no standard laboratory procedure for genetic testing for leukemia. Here, the problems related to external precision management and analytical error are discussed. PMID- 25022068 TI - [Current issues regarding companion diagnostics and future prospects]. AB - On July 1st, 2013, about two years after the FDA's drafting of the guidance for companion diagnostics (CoDx), the Ministry of Health, Labour, and Welfare in Japan issued an official notification regarding the co-development of CoDx with a drug which requires dedicated diagnostic tests or medical devices to predict the efficacy of or adverse reactions to the drug. Both recommend to co-develop CoDx and drugs as well as indicate the approved tests and devices on the package insert of the drug. However, since many useful predictive biomarkers may be discovered after the commercial launch of a drug, the more effective use of laboratory developed tests (LDT) should be considered in order to avoid a biomarker test lag. Due to an increase of clinical needs for multiple biomarker assays using sequence and/or microarray technologies, on November 19th, 2013, the FDA approved 510K clearance for the next-generation sequencer and its universal kit. This strategically new regulatory framework may allow clinical laboratories certified under the CLIA Act to more easily perform LDT for genetic markers. Unfortunately, no act like the CLIA exits in Japan to promote LDT well validated for clinical practice, and it may be necessary to reform the regulatory classification and requirements and also quality management system for in-vitro diagnostics tests and devices for reimbursement in the future. PMID- 25022067 TI - [Companion diagnostics in the era of personalized medicine--chairmen's introductory remarks]. AB - Personalized medicine is a medical model that proposes the customization of treatment for individual patients. In this model, diagnostic tests are essential for selecting safer and more efficacious treatments. The term "companion diagnostics" has been used to describe these tests, whereby molecular assays that measure the levels of proteins or specific gene mutations are used to provide a specific therapy for an individual by stratifying the disease status, selecting the proper medication, and tailoring dosages. Examples of companion diagnostics in the field of cancer medicine for molecular targeted therapy include tests for the ALK-fusion gene in non-small cell lung cancer and expression of CCR4 in adult T-cell leukemia. For breast cancer, the expression of HER2 protein is evaluated by immunohistochemistry (IHC), and gene amplification of HER2 is tested by fluorescence in situ hybridization (FISH); both tests consist of pre-analysis, analysis, and post-analysis processes that require quality control to ensure the reliability of the results. This symposium includes: 1) future aspects of companion diagnostics addressing many of the problems that must be overcome, 2) companion diagnostics using FISH focusing on HER2 amplification and ALK alteration, 3) newly developed diagnostic tests using tumor specimens and cell free DNA in serum, and 4) CCR4 expression detected by IHC and flow cytometry. PMID- 25022069 TI - [Companion diagnostics with FISH assay (HER2, ALK)]. AB - In recent anti-cancer drug treatment, personalized medicine has become popular with the development of many molecularly-targeted drugs. Companion Diagnostics (CDx) identify and detect biomarkers to predict whether a drug will work or have adverse effects on patients. We developed two CDx with FISH assays, the PathVysion HER-2 DNA Probe Kit and Vysis ALK Break Apart FISH Probe Kit. The PathVysion HER-2 DNA Probe Kit is a test to detect amplification of the HER2 gene in tissue samples from breast cancer patients to aid in determining and identifying patients eligible for treatment with Trastuzumab. The Vysis ALK Break Apart FISH Probe Kit is a test to detect rearrangements involving the ALK gene in tissue samples from non-small cell lung cancer (NSCLC) patients to aid in identifying patients eligible for treatment with Crizotinib. In this article, we review the CDx, focusing on HER2 gene and ALK fusion testing. PMID- 25022070 TI - [A novel approach to techniques in genetic testing for cancer]. AB - In molecular targeted drug therapy, genetic screening is carried out to identify the existence of target genes that are specifically expressed in cancer cells. Conventional methods for detecting the mutation of genes in cancer cells through the use of purified DNA is time consuming, especially in the case of the enzymatic treatment of pathological specimens, and it is difficult to finish all these protocols on the same day. Also, depending on the condition of the patients, it may be difficult to perform surgery or biopsy, and pathological specimens are not always obtainable. Thus, sometimes genetic screening using purified DNA and the enzymatic treatment of pathological specimens cannot be performed. We have successfully solved these problems using i-densy, a genetic analysis device, and two different methods of genetic testing for cancer. The first is a method which, without extracting DNA, uses simply pretreated pathological specimens for genetic screening. Using deparaffinized specimens that have only been heat-treated for a short period of time, we were able to obtain the exact same results as if we had extracted DNA. The second is the highly specific genetic screening technique, the MBP-QP method. Using this method, we were able to confirm the detection of genetic mutation from the DNA of blood plasma. It is now possible to screen for the mutation of genes in cancer cells using just a blood sample from patients without using tissue or cells, which also has little burden on the patient. PMID- 25022071 TI - [Another smile of the mitral valve]. PMID- 25022072 TI - [Good news ahead of the German National Soccer Team game. Watching Germany is not fatal ]. PMID- 25022073 TI - [Cooperation with non-medical health professions. The therapist: friend or enemy]. PMID- 25022074 TI - [Surprising declaration of love]. PMID- 25022075 TI - [New EBM chronic disease fee schedules lead to a financial reimbursement deficit]. PMID- 25022076 TI - [Ancient GOA compels justified rate increase]. PMID- 25022077 TI - [MFA magazine "info practice team". Telemedicine establishes itself in rural areas]. PMID- 25022078 TI - [Drug prescribing. Aut idem check tag can also be useful and necessary with generic drugs]. PMID- 25022079 TI - [Good information and high quality are essential. Early detection is helpful but can also cause damage]. PMID- 25022080 TI - [Physicians under indictment. From general practice to court appearance - and now what? ]. PMID- 25022081 TI - [Medicine in film and literature. The physician in the indictment court - and action!]. PMID- 25022082 TI - [Physicians in film and literature. The partnership also will be profoundly shaken]. PMID- 25022083 TI - [Totally atypical symptoms. Patient with pulmonary embolism almost referred to psychiatry]. PMID- 25022084 TI - [Couple problems in the physicians office. How to talk about sex without blushing]. PMID- 25022085 TI - [Analgesic-induced headache. Only a medication holiday will help here]. PMID- 25022086 TI - [No alcohol and no gallstones. Finding the cause of pancreatitis]. PMID- 25022087 TI - [Asthma therapy in transition. "For the physician it becomes ever more complicated" (interview by Dr. Elke Oberhofer)]. PMID- 25022088 TI - [Writer's cramp amd Raynaud phenomenon. How do they go together?]. PMID- 25022089 TI - [Triptans make the patient tired. May he still drive?]. PMID- 25022090 TI - [Expectation is one half of therapy]. PMID- 25022091 TI - [Herpes labialis and facial paralysis]. PMID- 25022092 TI - [Who pays the piper....]. PMID- 25022093 TI - [Sleep deprivation can trigger diabetes]. PMID- 25022094 TI - [It is itchy and sticky. Vernal keratoconjunctivitis]. PMID- 25022095 TI - [Vitamin E delays Alzheimer disease progression only slightly]. PMID- 25022096 TI - [Opportunity makes eaters]. PMID- 25022097 TI - [Hernia in the sternum]. PMID- 25022098 TI - [The confused patient]. PMID- 25022099 TI - ["Tender finger joints"]. PMID- 25022100 TI - [Terrible bloating. Meteorism in a new relationship]. PMID- 25022101 TI - [Odontogenic keratocyst of the maxillary sinus--a case report]. PMID- 25022102 TI - [Emergency checklist drowning]. PMID- 25022103 TI - [Diverticular disease]. PMID- 25022104 TI - [Diabetes and travelling]. PMID- 25022105 TI - [Symptomatic coronary heart disease. Therapy with a beta blocker and ivabradine combination]. PMID- 25022106 TI - [Effects of scalp acupuncture combined with auricular point sticking on cognitive behavior ability in patients with vascular dementia]. AB - OBJECTIVE: To compare the therapeutic differences among scalp acupuncture combined with auricular point sticking, body acupuncture and western medication for treatment of vascular dementia (VD). METHODS: Ninety cases were randomly divided into a combined therapy group (31 cases), a body acupuncture group (29 cases) and a western medication group (30 cases). The combined therapy group was treated with scalp acupuncture at forehead middle line, parieral middle line, temporal front line and temporal rear line as well as auricular point sticking at naogan (AT3,41), shen (CO10), shenmen (TF4), zhen (AT3), once a day; the body acupuncture group was treated with acupuncture at Baihui (GV 20), Fengchi (GB 20), Zusanli (ST 36) and so on, once a day; the western medication group was treated with oral administration of aniracetam tablets, 0.2 g per time, twice a day. Fourteen days were considered as a treatment course, and totally 3 courses were required. The mini-mental state examination (MMSE) and activities of daily living (ADL) were applied to assess the changes of cognitive behavior ability before and after treatment among three groups. Also the efficacy among three groups were compared. RESULTS: One case dropped out in the body acupuncture group and western medication group, respectively. The total effective rate was 90.334 (28/31) in the combined therapy group, which was superior to 85.734 (24/28) in the body acupuncture group and 79.3% (23/29) in the western medication group (both P < 0.05). After the treatment, the scores of MMSE and ADL were all improved among three groups, which was the most significant in the combined therapy group (MMSE: 23.32 +/- 4.45 vs 21.23 +/- 4.13, P < 0.05; 23.32 +/- 4.45 vs 20.41 +/- 4. 01, P < 0.01; ADL: 53.18 +/- 21.55 vs 51.92 +/- 20.42, P < 0.05; 53.18 +/- 21.55 vs 49.42 +/- 19.43, P < 0.01). CONCLUSION: The scalp acupuncture combined with auricular point sticking could improve the clinical symptoms and cognitive behavior ability in patients with vascular dementia, which has superior total efficacy to body acupuncture and western medication aniracetam tablets. PMID- 25022107 TI - [Vegetative state treated with acupoint injection combined with plum-blossom needle in children: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy difference on vegetative state in children between acupoint injection combined with plum-blossom needle and western medication based on basic treatment. METHODS: Forty-eight children of vegetative state were randomized into an observation group and a control group, 24 cases in each one. On the basis of the treatment of transcranial magnetic stimulation apparatus, balancing treatment apparatus and massage, the acupoint injection and tapping method with plum-blossom needle were adopted in the observation group, in which Xingnaojing injection, mouse nerve growth factor (mNGF) injection, monosialotetrahexosylganglioside sodium injection (MSI), compound Danshen injection were divided in 6 pairs and were injected respectively in Baihui (GV 20), Yongquan (KI 1), Fengfu (GV 16), Yamen (GV 15) and the others, 0.5 mL in each acupoint, once a day for continuous 10 days. Additionally, the tapping method with plum-blossom needle was used on the Governor Vessel and Jiaji (EX-B 2) on the back. In the control group, the intravenous infusion was adopted with citicoline sodium injection, mannitol injection and dexamethasone injection. The treatment was given once a day, 20 days of treatment made one session and totally 3 sessions were required in the two groups. The clinical efficacy, the vegetative state score and the mean curing time were observed after 20 days, 40 days and 60 days of treatment between the two groups. RESULTS: The effective rates were 58.3% (14/24), 70.8% (17/24) and 79.2% (19/24) in 20 days, 40 days and 60 days of treatment in the observation group and 20.8% (5/24), 45.8% (11/24) and 58.3% (14/24) in the control group respectively. The efficacy in the observation group was superior to those in the control group (P < 0.01, P < 0.05). The vegetative state score was improved apparently after 20 days, 40 days and 60 days of treatment as compared with those before treatment separately (all P < 0.05). It was improved obviously at the each time point after treatment in the observation group as compared with that in the control group (3.34 +/- 2.41 vs 2.64 +/- 11.56, 6.20 +/- 1.46 vs 4.34 +/- 1.64, 11.26 +/- 2.63 vs 8.75 +/- 2.18, all P < 0.05). The mean curing time was (45.67 +/- 16.24) days in the observation group, which was shorter apparently than that of (55.34 +/- 4.57) days in the control group (P < 0.05). CONCLUSION: Based on basic treatment acupoint injection combined with tapping method of plum-blossom needle achieve the reliable efficacy on vegetative state in children. PMID- 25022108 TI - [Impacts of acupuncture on blood pressure and hematoma in patients of cerebral hemorrhage at the early stage]. AB - OBJECTIVE: To explore the therapeutic effect of acupuncture for hypertensive cerebral hemorrhage at the early stage. METHODS: Fifty-four cases of small-amount cerebral hemorrhage were randomized into an acupuncture group and a conventional treatment group, 27 cases in each one. In the conventional treatment group, special care, oxygen therapy, nerve nutrition and symptomatic support were applied. In necessary, dehydrant and hypotensive drugs were prescribed for antihypertension, or surgery was given. In the acupuncture group, on the basis of the treatment as the control group, acupuncture was applied at Quchi (LI 11), Neiguan (PC 6), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3). Acupuncture was given at the admission, 4 h, 6 h and 12 h after disease onset respectively. Blood pressure was monitored in the whole procedure. 6 h and 24 h after disease onset, the cranial CT was re-examined. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), hematoma volume and neurological deficit score were compared at different time points between the two groups. RESULTS: (1) Blood pressure: from the admission to 12 h after disease onset, SBP, DBP and MAP were increased apparently in the conventional treatment group and increased slightly in the acupuncture group. The differences in SBP [(164.3 +/- 21.6) mmHg vs (158.6 +/- 21.5) mmHg] and MAP [(113.4 +/- 4.9) mmHg vs (106.7 +/- 6.1) mmHg] were significant between the two groups (both P < 0.05). From 12 h to 24 h after disease onset, compared with the conventional treatment group, SBP and MAP were decreased apparently in the acupuncture group [(147.3 +/- 21.6) mmHg vs (158.4 +/- 23.5) mmHg, (97.2 +/- 5.3) mmHg vs (106.6 +/- 5.1) mmHg, both P < 0.05)]. (2) Hematoma volume: from the admission to 6 h after disease onset, the volume was increased by (4.15 +/- 0.73) mL in the convertional treatment group and (2.67 +/- 0.33) mL in the acupuncture group, indicating the significant difference in comparison (P < 0.05). From the admission to 24 h after disease onset, it was increased by (5.57 +/- 1.26) mL in the convertional treatment group and (3.14 +/- 1.18) mL in the acupuncture group, indicating the significant difference in comparison (P < 0.05). (3) Neurological deficit score: the score was increasing gradually in first 3 days after disease onset in the two groups. The score (38.39 +/- 6.84) in the acupuncture group on the first day was different significantly as compared with that (42.37 +/- 7.46) in the conventional treatment group (P < 0.05). On the 10th days, the score (24.68 +/- 5.42) in the acupuncture group was different significantly from that (29.74 +/- 7.36) in the convertional treatment group (P < 0.05). CONCLUSION: There is no peak of blood pressure rising, and the continuous hemorrhagic volume is less in 24 h and neurological deficit score is improved in the acupuncture group. Acupuncture brings the positive significance in the treatment of cerebral hemorrhage at the early stage. PMID- 25022109 TI - [Clinical evaluation study on long-term effect of acupuncture with pattern/syndrome differentiation on functional dyspepsia]. AB - OBJECTIVE: To compare the efficacy difference in the treatment of functional dyspepsia between acupuncture at the acupoints selected by pattern/syndrome differentiation and domperidone. METHODS: Seventy cases were randomized into an acupuncture group (35 cases) and a western medication group (35 cases). In the acupuncture group, Zusanli (ST 36) and Neiguan (PC 6) were selected. Taichong (LR 3) and Neiting (ST 44) were added for excess syndrome while Gongsun (SP 4) and Yinlingquan (SP 9) were added for deficiency syndrome. A pair of electrodes was attached to one acupoint and an assistant point (2 mm next to the acupoint centripetally) and stimulated with disperse-dense wave at 2 Hz/100 Hz, once a day. In the western medication group, domperidone was prescribed for oral administration, 10 mg each time, three times a day. In the two groups, the treatment of 5 days made one session and 4 sessions were required totally. Nepean dyspepsia index (NDI) was compared after treatment, 1, 2, 3, 4 and 5 months after treatment between the two groups respectively. RESULTS: The score of symptom and score of life quality in NDI after treatment and at each follow-up time point were improved obviously in the acupuncture group as compared with those before treatment (all P < 0.01). In the western mediation group, the score of symptom and the score of life quality in NDI after treatment and in follow-up of 1, 2 and 3 months were improved obviously as compared with those before treatment (all P < 0.01), but the differences were not significant in follow-up of 4 and 5 months (both P > 0.05). Compared with the western medication group, the symptom score of NDI was reduced obviously after treatment and in each time point of follow-up in the acupuncture group (P < 0.05, P < 0.01), and the score of life quality was increased obviously (P < 0.05, P < 0.01). CONCLUSION: Acupuncture at the acupoints selected by pattern/syndrome differentiation and domperidone are effective in the treatment of functional dyspepsia. Domperidone is unsatisfactory in the long-term effect, but acupuncture achieves the positive short-term and long-term effects on functional dyspepsia. PMID- 25022110 TI - [Observation on effect characteristics of electroacupuncture for different types of functional constipation]. AB - OBJECTIVE: To explore the differences of electroacupuncture (EA) on onset time and symptom improvement for treatment of different types of functional constipation. METHODS: Thirty-eight cases of constipation were selected, including 9 cases of constipation-predominant irritable bowel syndrome (IBS-C), 10 cases of slow transit constipation (STC), 10 cases of pelvic floor dyssynergia (PFD) and 9 cases of inadequate defecatory propulsion (IDP). The electroacupuncture was applied at Tianshu (ST 25), Fujie (SP 14), Shenshu (BL 23), Dachangshu (BL 25) and so on in abdominal and lumbosacral area, 5 times per week, 10 times as a treatment course. The onset time, score of clinical symptoms of constipation and improvement of every symptom in each group were compared. RESULTS: (1) The onset time was (1.78 +/- 0.83) days in IBS-C type, (3.11 +/- 1.90) days in IDP type, (4.10 +/- 1.85) days in STC type and (4.30 +/- 2.00) days in PFD type, indicating statistical differences between IBS-C type and STC type, IBS-C type and PFD type (both P < 0.05). (2) Compared before the treatment, the total scores of symptoms on the onset day in each group were all improved (P < 0.05, P < 0.01), and score of IBS-C type was superior to the rest 3 types (P < 0.05, P < 0.01). (3) EA improved desire to defecate or frequency of defecation in each type (P < 0.05, P < 0.01), in which both were improved in STC type and PFD type, and the improvement of defecation frequency was more significant in STC type (P < 0.01). EA relieved unsmooth defecation or pendant-expansion feeling in each type (all P < 0.05), in which both were improved in IBS-C type (both P < 0.05). EA relieved abdominal distension and pain in IBS-C type, STC type and PFD type (all P < 0.05), while its effects were not obvious on defecation difficulty, defecation time and defecation texture (all P > 0.05). CONCLUSION: The electroacupuncture for treatment of 4 types of constipation is characterized by rapid onset; the improved symptoms are not identical in the electroacupuncture treatment plan for each type of defecation; the main improvement of symptoms are lied on desire to defecate and frequency of defecation, unsmooth defecation or pendant-expansion feeling and abdominal distension and pain. Meanwhile the improvements of defecation texture, defecation difficulty and defecation time were not signi-ficant. PMID- 25022111 TI - [Observation of long-term efficacy and life quality in allergic rhinitis treated with acupoint catgut embedding therapy combined with acupuncture-moxibustion therapy]. AB - OBJECTIVE: To observe the impacts of acupoint catgut embedding therapy and acupuncture-moxibustion therapy on the long-term efficacy and patient's life quality in the treatment of allergic rhinitis. METHODS: Sixty-nine patients were randomized into the combined acupuncture-moxibustion and acupoint catgut embedding therapy group (combined therapy group, 36 cases) and an acupuncture moxibustion group (33 cases). In the acupuncture-moxibustion group, acupuncture was applied at Yingxiang (LI 20), Shangyingxiang (EX-HN 8), Yintang (GV 29), Shangxing (GV 23), Tongtian (BL 7) and Zusanli (ST 36). Moxibustion was applied at Zusanli (ST 36), Feishu (BL 13), Dazhui (GV 14) and Fengmen (BL 12). In the combined therapy group, on the basis of the treatment as acupuncture-moxibustion group, the catgut embedding therapy was applied at Feishu (BL 13), Fengmen (BL 12), Pishu (BL 20), Shenshu (BL 23), Zhongwan (CV 12) and Qihai (CV 6). The treatment duration was 4 weeks in the two groups. The clinical efficacy of allergic rhinitis and rhinoconjunctivitis quality of life questionnaire (RQLQ) score were observed before and after treatment as well as in the 4-weeks follow up after the end of treatment respectively. RESULTS: The markedly effective rate was 72.7% (24/33) in the combined therapy group and 48.4% (15/31) in the acupuncture-moxibustion group after treatment. The efficacy was similar between the two groups (P > 0.05). It was 57.6% (19/33) in the combined therapy group and was 22. 6% (7/31) in the 4-week follow-up after treatment, indicating the long term efficacy in the combined therapy group was superior to that in the acupuncture-moxibustion group (P<0. 05). Scores of RQLO after treatment and in 4 week follow-up after treatment in both groups were improved as compared with those before treatment (all P < 0.05). In 4-week follow-up, the improvements in sleep and affection in the combined therapy group were superior to the acupuncture-moxibustion group (3.27 +/- 3.23 vs 4.61 +/- 3.56, 3.48 +/- 3.67 vs 5.81 +/- 4.15, both P < 0.05). CONCLUSION: The acupoint catgut embedding therapy combined with acupuncture-moxibustion therapy are safe and effective in the treatment of allergic rhinitis and display the more roles in the long-term efficacy. PMID- 25022112 TI - [Articular needling combined with muscular needling for 23 cases of sartorius injury]. PMID- 25022113 TI - [Efficacy observation on Jin's three-needle therapy for allergic rhinitis of lung qi deficiency and cold syndrome]. AB - OBJECTIVE: To compare the clinical efficacy in the treatment of allergic rhinitis (AR) of lung qi deficiency and cold syndrome between Jin's three-needle therapy and western medication. METHODS: Sixty-six patients were randomized into an acupuncture group and a western medication group, 33 cases in each one. In the acupuncture group, acupuncture was applied at three-nose points [Yingxiang (LI 20), Shangyingxiang (EX-HN 8) and Yintang (GV 29); Cuanzhu (BL 2) was added for frontal headache] and three-back points [Dazhu (BL 11), Fengmen (BL 12) and Feishu (BL 13)], once every day. Ten treatments made one session. Two sessions of treatment were required. In the western medication group, desloratadine oral suspension was prescribed, 5 mg each time, once a day, for 20 days. The scores of the symptoms and physical signs in AR patients as well as the clinical efficacy were observed between the two groups. RESULTS: The total effective rate was 93.9% (31/33) in the acupuncture group, which was better than 72.7% (24/33) in the western medication group (P < 0.05). After treatment, the scores of AR symptoms and physical signs as well as the total score were all reduced compared with those before treatment in the two groups (all P < 0.01). The score of every item in the acupuncture group was lower than that in the western medication group after treatment (score of symptoms: 4.70 +/- 2.07 vs 6.55 +/- 2. 69, score of physical signs: 0.85 +/- 0.67 vs 1.45 +/- +0.62, total score: 5.36 +/- 2.70 vs 8.00 +/- 2.91, all P < 0.01). CONCLUSION: Jin's three-needle therapy achieves superior efficacy on AR of lung-qi deficiency and cold syndrome, which is better than desloratadine oral suspension. PMID- 25022114 TI - [Acupuncture combined with auricle cutting method for blood stasis-type psoriasis: a randomized controlled trial]. AB - OBJECTIVE: To verify the clinical efficacy of acupuncture combined with auricle cutting method for treatment of blood stasis-type psoriasis. METHODS: Fifty-six cases of blood stasis-type psoriasis were randomly divided into a combined therapy group, a auricle cutting group, an acupuncture group and a control group, 14 cases in each one. Based on regular treatment of TCM decoction in four groups, the combined therapy group was treated with acupuncture and auricle cutting method, and the auricle cutting group was treated with sham-acupuncture and auricle cutting, and the acupuncture group was treated with acupuncture and sham auricle cutting, and the control group was treated with sham-acupuncture and sham auricle cutting. The acupuncture was applied at Dazhui (GV 14), Feishu (BL 13), Ganshu (BL 18) and Geshu (BL 17), etc., and manipulated with routine technique; in the sham acupuncture, the needle was inserted into dermis layer so that the needles could be swung without being dropped out. In the auricle cutting, erbeixin (P1) of unilateral auricle was selected and cut by Chan needle to perform bloodletting; in the sham auricle cutting, the neighborhood approximately 0.5 cm next to erbeixin (P) of auricle was selected as cutting area. The treatment was given once a day, seven days as a treatment session for totally two sessions. Psoriasis area and severity index (PASI) before and after treatment was observed and efficacy of each group was compared. RESULTS: The effective rate was 57.1% (8/14) in the combined therapy group, which was superior to 14.3% (2/14) in the auricle cutting group, 7.1% (1/14) in the acupuncture group and 0.0% (0/14) in the control group (all P < 0.05). The scores of PASI were all decreased in each group after the treatment (all P < 0.05), which was the most significant in the combined therapy group (all P < 0.05). After factorial analysis, the main effect was P < 0.05 in the auricle cutting, P < 0.05 in the acupuncture and P < 0.05 in interaction effect of combined therapy. CONCLUSION: The scores of PASI of blood stasis-type psoriasis could be effectively reduced by acupuncture, auricle cutting method and TCM decoction, among which the interaction effect of auricle cutting and acupuncture combined with TCM decoction is the most significant. PMID- 25022115 TI - [Case of craniocerebral trauma-induced optic nerve injury]. PMID- 25022116 TI - [Efficacy comparison of menopausal irritability between acupuncture and medication: a randomized controlled trial]. AB - OBJECTIVE: To observe the differences in the clinical efficacy on menopausal irritability between acupuncture and medication. METHODS: Sixty cases of menopausal irritability were randomized into an acupuncture group (31 cases) and a medication group (29 cases). In the acupuncture group, the warming needling manipulation was applied at the key acupoints such as Hegu (LI 4) and Taichong (LR 3), once a day, 10 treatments made one session. Totally, 2 sessions were required. In the medication group, 2.5 mg diazepam tablets were prescribed, three times a day, for 23 days totally. The clinical efficacy, the modified Kupperman score and self-rated health measurement scale (SRHMS) were compared before and after treatment in the two groups. RESULTS The total effective rate was 87. 1% (27/31) in the acupuncture group and 82.8% (24/29) in the medication group. The difference in the clinical efficacy was not significant between the two groups (P > 0.05). The modified Kupperman score and SRHMS score were both reduced obviously after treatment in the two groups, indicating the significant difference (all P < 0.05). The reduction of two scores in the acupuncture group was more obvious than those in the medication group (Kupperman: 15.23 +/- 6.19 vs 18.45 +/- 5.37; SRHMS: 116.29 +/- 38.24 vs 140.34 +/- 42.15, both P < 0.05). CONCLUSION: The acupuncture and medication are effective in the treatment of menopausal irritability, but the efficacy of warming needling manipulation is better than that of diazepam tablets. PMID- 25022117 TI - [Acupuncture at muscle belly for 32 cases of external humeral epicondylitis]. PMID- 25022118 TI - [Pronunciation analsis on Jiexi (ST 41)]. PMID- 25022119 TI - [Cervical spondylosis of vertebral artery treated with thermosensitive moxibustion with different dosages: a randomized controlled trial]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on cervical spondylosis of vertebral artery type (CSA) treated with thermosensitive moxibustion at different dosages. METHODS: Sixty cases of CSA were randomized into a saturated moxa dosage group and a regular moxa dosage group, 30 cases in each one. The thermosensitive moxibustion was adopted in the two groups. The mild suspended moxibustion was applied at two acupoints with the strongest thermosensitization. In the saturated moxa dosage group, the moxibustion time was determined by the disappearance of thermosensitization. In the regular moxa dosage group, 15 min was required on each acupoint. The treatment was given twice a day for first 4 days in the two groups. Since the 5th day, the treatment was given once a day, continuously for 10 times, and totally 14 days were required. The score of symptoms and function and clinical efficacy were compared between the two groups before and after treatment as well as 6-month follow-up after treatment. RESULTS: The curative and effective rate was 56.7% (17/30) after treatment and 60.0% (18/30) in 6-month follow-up after treatment in the saturated moxa dosage group, which were superior to 26.7% (8/30) and 30.0% (9/30) in the regular moxa dosage group respectively (P < 0.01, P < 0.05). The scores of clinical symptoms and function after treatment and in follow-up were improved apparently as compared with those before treatment in both groups (all P < 0.01). The scores of clinical symptoms and function after treatment and in follow-up in the saturated moxa dosage group were increased much more apparently than those in the regular moxa dosage group (after treatment: 22.32 +/- 4.64 vs 17.43 +/- 3.21; in follow-up: 23.01 +/- 4.76 vs 18.32 +/- 2.13, both P < 0.01). CONCLUSION: The thermosensitization moxibustion of saturated dosage achieves the superior short term and long-term efficacies in the treatment of CSA as compared with the regular moxibustion dosage. PMID- 25022120 TI - [Impacts of rotating or lifting-thrusting manipulation on distant vision of naked eye in patients of juvenile myopia: a randomized controlled trial]. AB - OBJECTIVE: To compare the differences in the efficacy on distant version of naked eye in the patients of juvenile myopia between rotating manipulation and lifting thrusting manipulation of acupuncture. METHODS: One hundred and twenty cases (240 eyes) were randomized into a rotating manipulation group and a lifting-thrusting manipulation group, 60 cases (120 eyes) in each group. Additionally, a corrective lenses group, 60 cases (120 eyes), was set up as the control. In both manipulation groups, Cuanzhu (BL 2),Yuyao (EX-HN 4), Sizhukong (TE 23), Taiyang (EX-HN 5), Fengchi (GB 20), Zusanli (ST 36), Guangming (GB 37) and Sanyinjiao (SP 6) were punctured, but stimulated with rotating manipulation and lifting thrusting manipulation respectively three times per week, 10 times as a treatment session and totally one session was required. In the corrective lenses group, the glasses were applied at daytime. The clinical efficacy and the changes in distant vision of naked eye before and after treatment were compared among the three groups. RESULTS: The total effective rate was 87.5% (105/120) in the rotating manipulation group, which was better than 69.2% (83/120) in the lifting-thrusting manipulation group (P < 0.05). The distant vision of naked eye was improved apparently in the rotating manipulation group and the lifting-thrusting manipulation group after treatment (both P < 0.05). But it was not improved in the corrective lenses group (P > 0.05). The distant vision of naked eye was improved more apparently after treatment in the rotating manipulation group as compared with that in the lifting-thrusting manipulation group (0.75 +/- 0.23 vs 0.68 +/- 0.24, P < 0.05). For 96 cases (192 eyes) with acupuncture treatment, in 3-month follow-up, 87.0% (167/192) of the cases maintained the stable vision as the original level and 13.0% (25/192) of them were reduced in the vision In the acupuncture groups, it was found that the improvement of distant vision of naked eye was more obvious after treatment with younger age, better basic vision and shorter duration of sickness (all P < 0.05). CONCLUSION: Acupuncture achieves the positive and sustainable clinical effect on juvenile myopia, and the results of rotating manipulation are superior to that of lifting-thrusting manipulation. Age, basic vision and duration of sickness impact the clinical efficacy. PMID- 25022121 TI - [Effects of acupuncture at "Tianshu" (ST 25) on electro-activity and mechanical motility of migrating motor complex during jejunal digestion period in rats with detached jejunum]. AB - OBJECTIVE: To observe the effects of acupuncture at "Tianshu" (ST 25) on electro activity and mechanical motility at different phases of migrating motor complex (MMC) during jejunal digestion period in rats with detached jejunum, so as to explore the effect and mechanism of acupuncture on regulating intestinal movement. METHODS: Sixteen adult SD rats were selected. Electrodes were implanted in the serous membrane of intestinal smooth muscl.e and high-sensitivity sensors of strain gauge were sutured on serosal surface, and then the rat was anesthetized and its jejunum was detached. Electro-acriviry and mechanical motility of jejunal smooth muscle were recorded simultaneously. Acupuncture was applied at "Tianshu" (ST 25) at MMC I , MMCII and MMC III, respectively, to observe its influence on electro-activity and mechanical motility. RESULTS: At phase of MMC I, there was no obvious change of the fast wave before and after the acupuncture, while the frequency and amplitude of slow wave and mechanical motility were both significantly decreased compared with baseline (P < 0.01). At MMCII-Ill, the frequency and amplitude of fast wave, slow wave and motility were all significantly decreased compared with baseline (P < 0.01). Acupuncture at "Tianshu" (ST 25) had prohibited effects on electro-activity and mechanical motility of jejunal smooth muscle in rats with detached jejunum. CONCLUSION: Acupuncture at "Tianshu" (ST 25) has obvious prohibited effects on electro acrivity and mechanical motility at MMC I , MMC II and MMC III time phases in rats with detached jejunum. The possible mechanism is that acupuncture at "Tianshu" (ST 25) could prohibit jejunum movement through reflex path of skin sympathetic. PMID- 25022122 TI - [Effects of electroacupuncture at "Fenglong" (ST 40) on formation of macrophage derived foam cell and efflux of cholesterol in hyperlipidemia rats]. AB - OBJECTIVE: To explore action mechanism of electroacupuncture (EA) at "Fenglong" (ST 40) for treatment of hyperlipidemia. METHODS: Forty SPF-grade SD rats were randomly divided into a normal group (group A), a model group (group B), a model diet-control group (group C), a model + EA group (group D) and model diet-control + EA group (group E), 8 cases in each one. The rats in group A were fed with normal diet continuously while those in the rest 4 groups were fed with high-fat diet to establish hyperlipidemia model. Afterwards, the rats in group C and group E were fed with normal diet, while EA at "Fenglong" (ST 40) was applied in group D and group E, 30 min per time, once a day. After 28 days of treatment, macrophage was collected in each group. Oil red O-staining was applied to detect the formation of foam cells, and enzyme-linked immunosorbent assay (ELISE) was adopted to measure the contents of total cholesterol (TC) in macrophage and analyze the rate of cholesterol efflux. RESULTS: The counts of positive cells of oil red O-staining and the contents of TC in the group B, group C and group D were significantly increased compared with those in the group A (all P < 0.01). The counts of positive cells and contents of TC in the group C, group D and group E were significantly clecreased compared with those in the group B (all P < 0.01), and the decline in group D was more obvious than that in the group C (all P < 0.01). Compared with group C and group D, the counts of positive cells and contents of TC in the group E was obviously decreased (all P < 0.01), which was not statistically different from group A (P > 0.05). In the meantime, compared with group C, the rate of cholesterol efflux in group D and group E was significantly increased (both P < 0.01), and the rise in group E was more obvious than that in the group D. CONCLUSION: The electroacupuncture at "Fenglong" (ST 40) could significantly prohibit the transformation of macrophage into foam cell and increase rate of cholesterol efflux in macrophage, which could prevent and reverse the formation of foam cell and play an essential role in treating hyperlipidemia and stopping it from developing into a further level. PMID- 25022123 TI - [Acupuncture-moxibustion combined with bloodletting therapy for 52 cases of numbness]. PMID- 25022124 TI - [Acupuncture, massage combined with herbal penetration therapy for 25 cases of acute mastitis in lactation period]. PMID- 25022125 TI - [Application of transcutaneous electrical acupoint stimulation combined with infusion of propofol in anodynia bronchoscopy]. AB - OBJECTIVE: To explore the effectiveness and safety of transcutaneous electrical acupoint stimulation (TEAS) combined with infusion of propofol in anodynia bronchoscopy. METHODS: Ninety patients who received selective bronchoscopy were randomized into a group of compound TEAS with infusion of propofol (group A), a group of compound fentanyl with propofol (group B) and a group of simple propofol (group C). In group A, the plaster electrode stimulation was applied at bilateral Hegu (LI 4), Laogong (PC 8), Neiguan (PC 6) and Waiguan (TE 5). The anesthesia was induced after 20 min of stimulation till the end of examination. In group B and group C, the electric stimulation was not adopted. In group B, before anesthesia, fentanyl 1 microg/kg was injected intravenously. Afterwards, the intravenous infusion of propofol was used in the the three groups for anesthesia. The mean arterial pressure (MAP), heart rate (HR), saturation of pulse oximetry (SpO2) and respiratory rate (RR) were recorded at different time points. The induced dosage and total dosage of propofol, examination time, the awakening time and adverse reactions were observed in the patients of each group. RESULTS: The difference in examination time was not significant among the three groups (P > 0.05). The postoperative awakening time in group A was earlier than that in group B and group C [(220.3 +/- 110.5) s vs (285.6 +/- 109.4) s, (290.1 +/- 105.1) s, both P < 0.05]. The total dosage of propofol in group C was larger than those in group A and group B [(288.5 +/- 26.7) mg vs (225.1 +/- 30.2) mg, (230.4 +/- 29.3) mg, both P < 0.05]. The induced dosage in group C was larger than those in group A and group B [(193.7 +/- 42.3) mg vs (152.3 +/- 36.1) mg, (155.4 +/- 40.5) mg, both P < 0.05]. Every life physical sign in group A during examination was more stable as compared with that in group B and group C. The incidence of hypotension and bradycardia in group A were lower than those in group C [3.3% (1/30) vs 26.7% (8/30), 0% (0/30) vs 20.0% (6/30), both P < 0.05]. The adverse incidence of oxygen supply in group A was lower than that in group B [6.7% (2/30) vs 33.3% (10/30), P < 0.05]. Intraoperative awareness and improper memory did not happen in postoperative investigation. CONCLUSION: In the transcutaneous electrical acupoint stimulation combined with infusion of propofol in anodynia bronchoscopy, the physical sign of patient is stable with less adverse reactions. This method reduces anesthetic dosage and shortens the postoperative awakening time, which can be effectively applied in bronchoscopy. PMID- 25022126 TI - [The essence of Professor Wu Lian-Zhong's acupuncture manipulation]. AB - The painless needle insertion technique, summarized by Professor WU Lian-zhong during his decades of acupuncture clinical practice is introduced in this article, which is characterized as soft, flexible, fast, plucking and activating antipathogenic qi. The Sancai (three layers) lifting and thrusting manipulation technique is adopted by Professor WU for getting the qi sensation. And features of 10 kinds of needling sensation such as soreness, numbness, heaviness, distension, pain, cold, hot, radiation, jumping and contracture are summarized. Finger force, amplitude, speed and time length are also taken as the basis of reinforcing and reducing manipulations. Moreover, examples are also given to explain the needling technique on some specific points which further embodies Professor WU's unique experiences and understandings on acupuncture. PMID- 25022127 TI - [Case of glossopharyngeal neuralgia]. PMID- 25022128 TI - [Clinical experience of Qin's eight scalp needles for treatment of Parkinson's disease]. AB - The eight scalp needles, founded by Professor QIN Liang-fu, and its clinical experience for treatment of Parkinson's disease (PD) are introduced. Based on his years of clinical experience, it is proposed by Professor QIN that the Governor Vessel is mainly for miscellaneous disease and disease of limbs. Combined with distribution of cephalic motor region and meridian, an acupuncture treatment plan that is full of innovativeness is proposed, which is called Qin's eight scalp needles. It includes bilateral Fengchi (GB 20), Shuaigu (GB 8), Toulinqi (GB 15) as well as Yintang (GV 29) and Baihui (GV 20), mainly for treatment of nervous system diseases, such as PD and multiple sclerosis and so on. Besides, some outpatient cases are introduced to explain that eight scalp needle could alleviate the progression of PD, improve patients' motor, cognitive and affective disorders, reduce the suffering of patients, and improve the patient's quality of life. PMID- 25022129 TI - [Case of loss of sense of smell]. PMID- 25022130 TI - [Efficacy observation on navel-warming therapy combined with western medication for yang-deficiency tympanites]. AB - OBJECTIVE: To observe the effects of navel-warming therapy on clinical efficacy in patients with yang-deficiency tympanites based on regular treatment of western medication. METHODS: One hundred and twenty cases of yang-deficiency tympanites were randomly divided into a navel-warming therapy group and a western medication group, sixty cases in each one. The regular treatment of western medicine was applied in the western medication group, including oral administration of antiviral drug and diuretics as well as intravenous drip of hepatic protector. Based on western medicine treatment, the navel-warming therapy was applied in the navel-warming group. A medical cake was laid on Shenque (CV 8), and then a medical cylinder was placed above the medical cake and ignited. The treatment was given once daily. One month was considered as a treatment session in both groups and totally one session was required. The TCM symptom score, B-ultrasound ascites and temporary use of diuretics before and after treatment were observed in both groups; also the efficacy was evaluated. RESULTS: The total effective rate was 81.7% (49/60) in the navel-warming therapy group, which was superior to 56.7% (34/60) in the western medication group (P < 0.05). After the treatment, the TCM symptom score and ascites were improved in both groups (all P < 0.05), which was more significant in the navel-warming therapy group (all P < 0.05). The temporary use of diuretics was statistically different between the two groups (P < 0.05), indicating the navel-warming therapy group could obviously reduce or stop the use of diuretics. CONCLUSION: Based on regular treatment of western medication, the navel-warming therapy could significantly improve therapeutic efficacy, effectively relieve clinical symptoms and ease ascites. PMID- 25022131 TI - [Efficacy comparison between needle-knife therapy and acupuncture-cupping for cervical spondylosis of cervical type]. AB - OBJECTIVE: To compare the efficacy differences between needle-knife therapy and acupuncture-cupping for treatment of cervical spondylosis (CS) of cervical type. METHODS: Sixty cases of CS were randomly divided into a needle-knife group (30 cases) and an acupuncture-cupping group (30 cases). The needle-knife therapy was applied at points among superior nuchal line of occipital bone, bilateral neck muscle, neck centerline, trapezius and medial border scapula for only once. In the acupuncture-cupping group, acupuncture was applied at Fengchi (GB 20), Fengfu (GV 16), Tianzhu (BL 10), Dazhui (GV 14), Jianjing (GB 21), Jiaji (Ex-B2, from C4 to C6), Houxi (SI 3) and Ashi point, followed by cupping on local skin, once every other day for totally six times. The score of neck stiffness and visual analogue scale (VAS) were observed before and after treatment, in follow-up of 1, 3 and 6 months after treatment in the two groups, and the efficacy was compared. RESULTS: In the needle-knife group, 9 cases were cured, 12 cases were markedly effective, 8 cases were effective and 1 case was failed; the total effective rate was 96.7% (29/30) and the cured and markedly effective rate was 70.0% (21/30). In the acupuncture-cupping group, 8 cases were cured, 9 cases were markedly effective, 11 cases were effective and 2 cases were failed; the total effective rate was 93.3% (28/30) and the cured and markedly effective rate was 56.7% (17/30). The difference of total effective rate in the two groups was not statistically significant (P > 0.05), but the cured and markedly effective rate of needle-knife group was significantly superior to that of acupuncture-cupping group (P < 0.05). The needle-knife therapy was significantly superior to acupuncture-cupping on improvement of neck stiffness in the follow-up of 1, 3, 6 months after treatment (P < 0.05, P < 0.001); both treatments were effective on relief of neck pain, but the needle-knife group had better effects in the follow up of 3 and 6 months after treatment compared with acupuncture-cupping group (both P < 0.01). CONCLUSION: The needle-knife therapy has better effects on neck stiffness and pain relief than acupuncture-cupping, and it is more treatment time saving. PMID- 25022132 TI - [Application and development of translational medicine in modern acupuncture and moxibustion]. AB - In recent years, translational medicine, which is characterized by advanced concepts and methods, developes rapidly and playes a strategic role in the development of TCM acupuncture and moxibustion. Therefore, it is worth studying by acupuncturists. Through the background, development, features and research model of translational medicine, the present situation and problems of TCM acupuncture research are analyzed. Several cases of translational Chinese medicine and acupuncture are listed with the consideration of the concept of translational medicine. Studies and thoughts on translational acupuncture are expounded as well. Thus, it is suggested that combined with characteristics of acupuncture, the concept of translational medicine should be utilized to instruct the clinical treatment and research of acupuncture, foster researchers of translational medicine as well as establish the related research teams. PMID- 25022133 TI - [WU Xiao-ren: an outstanding physician of acupuncture and moxibustion]. AB - WU Xiao-ren devoted his whole life into acupuncture practice and education. During his 50 years clinical practice, teaching and researching, he focused on standardization and application of acupuncture manipulations. Through the integration of western and Chinese medicine as well as technique innovation, he developed new therapies for hypertension, stroke and various pain syndromes with the combination of acupuncture and materia medica and various acupoint prescription. He was against parochial prejudice by advocating absorption of others successful experiences and integration of different schools. Moreover, being conscientious and meticulous, WU Xiao-ren was always strict with his followers. He set up examples for his students with both precept and practice, and made great contribution to the inheritance of both acupuncture theory and practice. PMID- 25022134 TI - [Characteristics of acupoint selection of acupuncture-moxibustion for vertigo in history: a data mining research]. AB - The data mining technique is adopted to analyze characteristics and rules of acupoint and meridian selection of acupuncture-moxibustion for treatment of vertigo at different time periods in the ancient. The data is collected from literature regarding acupuncture-moxibustion from the pre-Qin period to the end of Qing Dynasty, so as to establish a clinical literature database of ancient acupuncture-moxibustion for treatment of vertigo. Data mining method is applied to analyze the commonly used meridians, acupoints and special acupoints in different dynasties, also possible rules are explored. Totally 82 pieces of prescription of acupuncture-moxibustion for treatment of vertigo are included. In the history the leading selection of acupoitns are Fengchi (GB 20), Hegu (LI 4), Shangxing (GV 23) and Jiexi (ST 41) while that of meridians are mainly three yang meridians of foot and the Governor Vessel, especially the acupoints on the Bladder Meridian of foot yangming had the highest utilization rate, accounting for 23.04%. The acupoint selection is characterized by special acupoint, accounting for 80.6%, among which the crossing points are the most common choice. Distal-proximal acupoints combination is the most frequent method. The results indicate that the ancient acupuncture-moxibustion for treatment of vertigo focused on acupoints in the yang meridians, and the specific acupoints play an essential role in prescription; also the principle of syndrome differentiation and selecting acupoints along the meridians could be seen. PMID- 25022135 TI - [Case of multiple system atrophy]. PMID- 25022136 TI - [Application of functional magnetic resonance imaging in acupoint functional significance of encephalic region]. AB - Literatures of study on acupoint functional effect of encephalic region with functional magnetic resonance imaging (fMRI) are collected from the database of China National Knowledge Information (CNKI) and Wan fang database. Analysis and comments are made respectively from the status quo of studies on combination of single acupoint, two acupoints and multiple acupoints under both physiological and pathological conditions. The results show that the corresponding encephalic regions can be specifically activated by acupuncture. And different regions can be activated by different acupoints. However, studies on single acupoint, two acupoints and three acupoints are the major researches carried out at present. It is still lack of observation on effect of commonly-used combinations in clinic. Moreover, the reliability of the research results are also affected by disunity of operations protocol, reinforcing or reducing manipulations, intensity or depth of stimulation and duration of needling retention. Therefore, it is necessary to establish a unified and standard operation protocol to strictly control the bias factors which may affect the result of research in the future, and take patients as the study target as much as possible, so as to further explore the central effect mechanism. PMID- 25022137 TI - Revamping the reproductive health agenda in Africa after 2014. PMID- 25022138 TI - Family planning needs of women experiencing severe maternal morbidity in Accra, Ghana: another missed opportunity? AB - Women with severe maternal morbidity represent an important group to target for increasing contraceptive uptake. Our objective was to explore the future fertility intentions, use of family planning including methods and reasons for not wanting to use contraception among a group of women who had traumatic delivery experience at a tertiary teaching hospital in Accra, Ghana. Our results show that despite higher educational attainment, longer hospital stays and intention to limit or stop childbearing among women, there is a missed opportunity for family planning among women with severe maternal morbidity in this urban African hospital setting. Integrating postpartum family planning consultations by linking available services such as reproductive health clinics at the facilities rather than including additional tasks for the midwives and the doctors in the wards could be a sustainable solution in such urban, high-volume settings. PMID- 25022139 TI - Reflections on female circumcision discourse in Hargeysa, Somaliland: purified or mutilated? AB - In communities where female circumcision is carried out, increasingly large segments of the population have been exposed to strong arguments against the practice. This study aimed to explore diverse discourses on female circumcision and the relationship between discourses and practice among informants who have been exposed both to local and global discourses on female circumcision. A qualitative study was carried out in 2009/10 in Hargeysa, Somaliland, employing interviews and informal discussion. The main categories of informants were nurses, nursing students, returned exile Somalis and development workers. The study findings suggest that substantial change has taken place about perceptions and practice related to female circumcision; the topic is today openly discussed, albeit more in the public than in the private arena. An important transformation moreover seems to be taking place primarily from the severe forms (pharaoni) to the less extensive forms (Sunna). PMID- 25022140 TI - "I don't know anything about their culture": the disconnect between allopathic and traditional maternity care providers in rural northern Ghana. AB - The provision of maternal and neonatal health care in rural northern Ghana is pluralistic, consisting of traditional and allopathic providers. Although women often use these providers interchangeably, important differences exist. This study explored the differences in approaches to maternal and neonatal care provision by these two different types of providers. This research was part of the Stillbirth and Neonatal Death Study (SANDS), conducted in northern Ghana in 2010. Trained field staff of the Navrongo Health Research Centre conducted in depth interviews with 13 allopathic and 8 traditional providers. Interviews were audio-recorded, transcribed, and analyzed using in vivo coding and discussion amongst the research team. Three overarching themes resulted: 1) many allopathic providers were isolated from the culture of the communities in which they practiced, while traditional providers were much more aware of the local cultural beliefs and practices. 2) Allopathic and traditional healthcare providers have different frameworks for understanding health and disease, with allopathic providers relying heavily on their biomedical knowledge, and traditional providers drawing on their knowledge of natural remedies. 3) All providers agreed that education directed at pregnant women, providers (both allopathic and traditional), and the community at large is needed to improve maternal and neonatal outcomes. Our findings suggest that, among other things, programmatic efforts need to be placed on the cultural education of allopathic providers. PMID- 25022141 TI - Dating violence and self-efficacy for delayed sex among adolescents in Cape Town, South Africa. AB - In South Africa, dating violence is known to be widespread among adolescents, and is therefore a major public health issue because of its association with sexual risk behaviours. The objective of the study was to examine the relationship between dating violence and self-efficacy for delayed sex among school-going adolescents in Cape Town, South Africa. The study is based on analyses of data from a school-based health education programme targeting sexual and reproductive health issues.The study involved 3,655 school-going adolescents aged between 12 and 17 in Cape Town, South Africa. The data was collected by means of a self administered questionnaire composed of 153 items on sexual and reproductive health, dating violence as well as sociodemographic characteristics. The results indicated that males showed a higher percentage of both dating violence victimization and perpetration, as compared to females. It was also found that adolescents from lower socio-economic backgrounds were more likely to be the victims of dating violence as compared to those from a higher socio-economic background. Female learners showed higher levels of self-efficacy for delayed sex than their male counterparts. Although the result revealed that there was a significant association between self-efficacy for delayed sex and socio-economic status, this link decreased with age. It is concluded that educational programmes aimed solely at improving self-efficacy for delayed sex is insufficient. Such programmes must also aim at preventing dating violence and equipping adolescents with the skills to negotiate their way out of dating violence. PMID- 25022142 TI - Factors associated with unmet need for modern contraception in post-conflict Liberia. AB - We examined the association between intimate partner violence and unmet need for modern contraception in post-conflict Liberia. This is a secondary analysis of data collected using the Priorities for Local AIDS Control Efforts (PLACE) method. Data from 499 sexually experienced young women (aged 14-25) in Montserrado County, Liberia were examined. Intimate partner violence (55.7%), unintended pregnancy (83.2%), and abortion (45.3%) were pervasive in the study population. An estimated 35.9% of respondents had an unmet need for modern contraception. However, multivariate logistic regression results did not reveal an association between intimate partner violence and unmet need (OR 1.11; 95% CI 0.70-1.75). Among covariates examined, only contraceptive use at sexual debut (26.1%) was significantly associated with unmet need (OR 0.27; 95% CI 0.14-0.52). Liberian youth need information about and access to modern contraceptive methods besides condoms. Interventions to identify and treat victims of violence are also needed. PMID- 25022143 TI - Evaluation of a reproductive health program to support married adolescent girls in rural Ethiopia. AB - Few reproductive health programs are targeted to married adolescent girls. This study measures changes associated with a program for married adolescent girls and a parallel husbands' program, in rural Ethiopia. The married girls' program provided information on communication, self-esteem, reproductive health and gender through girls' groups. The husbands' program focused on non-violence, support to families, and reproductive health. Population-based surveys were undertaken among married girls, at midterm and end line. Outcomes of interest were husbands' assistance with domestic work, accompaniment to the clinic, family planning use, voluntary counseling and testing (VCT), and domestic violence. Overall, 1,010 married girls were interviewed. Participation in the girls' groups was associated with improvements in help with domestic work, accompaniment to the clinic, family planning and VCT. Further improvements were recorded when both partners participated. For example, participating girls were nearly 8 times more likely to receive VCT (OR 7.7) than nonparticipants, and more than 18 times more likely if both partners participated (OR 18.3). While these results are promising, there were indications of selectivity bias that could have contributed to the positive results. Programs engaging both wives and husbands can result in incremental improvements to the health and well-being of girls married early. PMID- 25022144 TI - Potential for revitalisation of the diaphragm for family planning in Uganda: a rapid assessment of the feasibility of introducing the SILCS Diaphragm. AB - This health systems assessment evaluated the feasibility of introducing a new contraceptive device, the SILCS single-size diaphragm, into the existing family planning method mix in Uganda. A total of 26 focus group discussions with 201 female and 77 male potential users and 98 key informant interviews with policymakers and providers were conducted between June and August 2010. Potential users, providers, and policymakers recognised that the SILCS Diaphragm could fill a gap in the method mix and expressed eagerness to make the SILCS Diaphragm available, particularly because it is nonhormonal and woman initiated. The diaphragm was viewed by all stakeholders as a method that would increase choice and could improve women's reproductive health in Uganda. Like many countries, Uganda's family planning programme is financially stretched, and clear support for the SILCS Diaphragm by end-users will need to be demonstrated before the product will be considered for public-sector introduction. PMID- 25022145 TI - Awareness and use of modern contraceptives among physically challenged in-school adolescents in Osun State, Nigeria. AB - This study assessed awareness and use of modern contraceptives among physically challenged in-school adolescents in Osun State, Nigeria. A cross-sectional study was carried out among 215 adolescents in the special schools in the state. A pretested semi-structured questionnaire was administered by trained interviewers. Data analysis was done using SPSS 17 and statistical level of significance was set at p < 0.05. The mean age of the respondents was 15.5 years and more than half of them (56%) were males. Only about two fifths of them (38%) had ever heard about modern contraceptives. More males, older adolescents and visually impaired respondents had significantly heard about modern contraceptives compared with females, younger ones and those with other challenges at p-values of 0.026, 0.001 and 0.003 respectively. Only 34% of sexually experienced respondents had used a modern contraceptive method. The male condom was the most commonly used method. PMID- 25022146 TI - Assessment of peer-based and structural strategies for increasing male participation in an antenatal setting in Lilongwe, Malawi. AB - In sub-Saharan Africa, although male involvement in antenatal care is associated with positive outcomes for HIV-infected women and their infants, men rarely accompany female partners. We implemented a project to increase the number of male partners attending an antenatal clinic at Bwaila Hospital in Lilongwe, Malawi. We evaluated changes in the proportion of women who came with a partner over three periods. During period 1 (January 2007 - June 2008) there was didactic peer education. During period 2 (July 2008 - September 2009) a peer-led male involvement drama was introduced into patient waiting areas. During period 3 (October 2009 - December 2009) changes to clinical infrastructure were introduced to make the clinic more male-friendly. The proportion of women attending ANC with a male partner increased from 0.7% to 5.7%, to 10.7% over the three periods. Peer education through drama and male-friendly hospital infrastructure coincided with substantially greater male participation, although further gains are necessary. PMID- 25022147 TI - Performance needs assessment of maternal and newborn health service delivery in urban and rural areas of Osun State, South-West, Nigeria. AB - The study aimed to determine performance and compare gaps in maternal and newborn health (MNH) services in urban and rural areas of Osun State, Nigeria, to inform decisions for improved services. This study involved 14 urban and 10 rural-based randomly selected PHC facilities. Using a Performance Needs Assessment framework, desired performances were determined by key stakeholders and actual performances measured by conducting facility survey. Questionnaire interview of 143 health workers and 153 antenatal clients were done. Performance gaps were determined for the urban and rural areas and compared using Chi-square tests with SPSS version 17. PHC facilities and health workers in Osun State, Nigeria, were found to have significant gaps in MNH service performance and this was worse in the rural areas. Root cause of most of the performance gaps was poor political will of local government authorities. Improved government commitment to MNH is needful to address most of the gaps. PMID- 25022148 TI - Physical activity and energy expenditure: findings from the Ibadan Pregnant Women's Survey. AB - Physical activity, if there are no medical caveats, is beneficial to all people including pregnant women. This study examined the level of physical activity in a group of pregnant Nigerian women. Pregnancy Physical Activity Questionnaire was used to assess the physical activity of 453 pregnant women. The mean age of participants was 30.89 +/- 4.44 years, 222 (49.0%) were sedentary, and only 46 (10.2%) presented with moderate activity level. The highest amount of energy (75.9 MET-h x wk(-1)) was expended on household activities. Women in the third trimester of pregnancy had more than three times the risk of being sedentary (OR = 3.26, 95% CI = 2.11-4.56) but the risk reduced by 58% in gravid > or = 5 women. Most of the pregnant women recorded physical activity that was lower than the recommended level, which could lead to unfavourable health outcomes for mother and child. Efforts to promote physical activity in pregnant women in this environment are desirable. PMID- 25022149 TI - In-vitro fertilization, gamete donation and surrogacy: perceptions of women attending an infertility clinic in Ibadan, Nigeria. AB - Infertility affects 20% of couples in Nigeria. Assisted reproductive techniques (ART) offered in Nigeria include in-vitro fertilization (IVF), gamete donation and surrogacy. This cross-sectional questionnaire study aimed at assessing the acceptability of ART to women seeking infertility treatment at the University College Hospital, Ibadan, Nigeria. Of the 307 respondents, 58.3% were aware of IVF and 59.3% would accept it as treatment; 35.2% would accept donor eggs and 24.7% would accept donor sperms-a smaller proportion anticipated acceptability by their husbands. Thirty five percent were aware of surrogacy, 37.8% would accept it as treatment; most preferring a stranger as a surrogate. Most felt surrogates should not be paid. Acceptance of ART was associated with older age, longer duration of infertility, previous failed treatment and women without other children. As chances of successful pregnancy are improved in younger individuals, counselling towards overcome barriers to accepting gamete donation and surrogacy should be instituted early. PMID- 25022150 TI - Unmet need for contraception among clients of FP/HIV integrated services in Nigeria: the role of partner opposition. AB - While women are aware of family planning (FP) methods in Nigeria, the unmet need for modern contraception remains high. We assessed the association between male partner opposition to FP and unmet need for modern contraception among women seeking anti-retroviral therapy (ART), HIV counseling and testing (HCT) and prevention-of-mother-to-child-transmission of HIV (PMTCT) services in Cross-River State, Nigeria. This secondary analysis used data from a facility-based FP/HIV integration study. Logistic regression was used to model the association of interest. Unmet need for modern contraception was high among all clients--ART (49%), HCT (75%), and PMTCT (32%). Perceived partner opposition to FP was widespread (> or = 70%); however, multivariate analysis showed no significant association with unmet need for modern contraception. Significant covariates were woman's age, marital status, parity, and previous use of modern contraception. Efforts to improve modern contraceptive use among women at risk of HIV infection in Nigeria should contemplate involving their male partners. PMID- 25022151 TI - Tubal ectopic gestation associated with genital schistosomiasis: a case report. AB - Schistosoma are trematode blood flukes of the family Schistosomidae affecting the urinary and gastro-intestinal tracts. Riverine areas of the world such as in Africa, Eastern Mediterranean, Central American and East Asia are endemic for the disease, with S. haematobium accounting for most of the symptomatic genital infection. A case of a 25-year-old woman with 8 weeks amenorrhoea, lower abdominal pain and per vaginal bleeding was managed for ruptured ectopic pregnancy and discovered to have tubal infection by Schistosoma on histological examination is presented. PMID- 25022152 TI - Do abnormal findings on hystero-salphingographic examination correlate with intensity of procedure associated pain? AB - The aim of this study is to determine if the intensity and nature of pain during Hystero-Salphingography could give a clue to the presence of abnormal finding/s. Eighty-two patients were recruited over a six-month period. Procedural pain was assessed using the numeric rating scale. Mean age was 33.2 +/- 4.9 years. The median pain score in patients with normal findings was 6.0 but 7.0, 8.0, and 8.5 in those with right tubal blockade, uterine fibroids and left tubal blockade respectively. No statistical difference in the absolute pain score between patients with normal and abnormal findings. Pain scores in patients with 1 and 2 abnormalities were 7.0 and 7.5, and the number of abnormalities did not affect pain score (P = 0.3). The presence or absence of pain during HSG may not be a suitable way of determining the presence or absence of abnormal HSG finding/s. PMID- 25022153 TI - Factors associated with alcohol consumption: a survey of women childbearing at a national referral hospital in Accra, Ghana. AB - A hospital based cross-sectional study was conducted to identify the factors associated with alcohol consumption in Ghanaian women of childbearing age. The sample consisted of 394 women of reproductive age, of which 234 were pregnant. Systematic random sampling was used to select respondents from the clinics of the Department of Obstetrics and Gynecology outpatient at the Korle Bu Teaching Hospital in Accra, Ghana. Data were collected using structured questionnaires and analyzed using SPSS for Windows version 17.0. In the three months preceding the survey, 37.6% imbibed alcoholic drinks, while 24.4% had ever imbibed an alcoholic herbal brew. Non-Islamic religion, not being in marital union, consuming an alcoholic herbal brew and considering alcohol was beneficial to health were strong predictors of alcohol consumption. We conclude that the prevalence of alcohol consumption is high among this cohort of Ghanaian women. Women should be screened for alcohol consumption and informed about the dangers of heavy alcohol consumption during pregnancy. PMID- 25022154 TI - Community-level distribution of misoprostol to prevent postpartum hemorrhage at home births in northern Nigeria. AB - In Nigeria, most deaths due to postpartum hemorrhage (PPH) occur in the absence of skilled birth attendants. A study using community mobilization and the training of community drug keepers to increase access to misoprostol for PPH prevention was conducted in five communities around Zaria in Kaduna State, Nigeria. Community-oriented resource persons (CORPs) and traditional birth attendants (TBAs) recruited and counseled pregnant women on bleeding after delivery, the importance of delivery at a health facility, and the role of misoprostol. Drug keepers stored and dispensed misoprostol during a woman's third trimester of pregnancy. TBAs and CORPs enrolled 1,875 women from January through December 2009. These results are based on 1,577 completed postpartum interviews. Almost all women delivered at home (95%) and skilled attendance at delivery was low (7%). The availability of misoprostol protected 83% of women who delivered at home against PPH who otherwise would not have been protected. Policymakers working in similar contexts should consider utilizing commuity-level distribution models to reach women with this life-saving intervention. PMID- 25022155 TI - Three methods of manual external chest compressions during microgravity simulation. AB - INTRODUCTION: Cardiopulmonary resuscitation (CPR) in microgravity is challenging. There are three single-person CPR techniques that can be performed in microgravity: the Evetts-Russomano (ER), Handstand (HS), and Reverse Bear Hug (RBH). All three methods have been evaluated in parabolic flights, but only the ER method has been shown to be effective in prolonged microgravity simulation. All three methods of CPR have yet to be evaluated using the current 2010 guidelines. METHODS: There were 23 male subjects who were recruited to perform simulated terrestrial CPR (+1 G(z)) and the three microgravity CPR methods for four sets of external chest compressions (ECC). To simulate microgravity, the subjects used a body suspension device (BSD) and trolley system. True depth (D(T)), ECC rate, and oxygen consumption (Vo2) were measured. RESULTS: The mean (+/- SD) D(T) for the ER (37.4 +/- 1.5 mm) and RBH methods (23.9 +/- 1.4 mm) were significantly lower than +1 G(z) CPR. However, both methods attained an ECC rate that met the guidelines (105.6 +/- 0.8; 101.3 +/- 1.5 compressions/min). The HS method achieved a superior D(T) (49.3 +/- 1.2 mm), but a poor ECC rate (91.9 +/- 2.2 compressions/min). Vo2 for ER and HS was higher than +1 Gz; however, the RBH was not. CONCLUSION: All three methods have merit in performing ECC in simulated microgravity; the ER and RBH have adequate ECC rates, and the HS method has adequate D(T). However, all methods failed to meet all criteria for the 2010 guidelines. Further research to evaluate the most effective method of CPR in microgravity is needed. PMID- 25022157 TI - Acute hypoxic hypoxia and isocapnic hypoxia effects on oculometric features. AB - INTRODUCTION: Visual performance impairment after hypoxia is well recognized in military and civilian aviation. The aims of this study were: 1) to assess oculometric features such as blink metrics, pupillary dynamics, fixations, and saccades as cognitive indicators of early signs of hypoxia; and 2) to analyze the impact of different hypoxic conditions ["hypoxic hypoxia" (HH) and "isocapnic hypoxia" (IH)] on specified oculometrics during mental workloads. METHODS: Oculometric data were collected on 25 subjects under 3 conditions: normoxia, HH (8% O2 + balance N2), and IH (7% O2 + 5% CO2 + balance N2). The mental workload task consisted of reading aloud linear arrays of numbers after exposure to gas mixtures. RESULTS: Blink rates were significantly increased under hypoxic conditions (by +100.7% in HH and by +92.8% in IH compared to normoxia). A faster recovery of blink rate was observed in transitioning from IH (23.6% vs. 76.3%) to normoxia. The percentage change in pupil size fluctuation was increased under HH more than under IH (29% vs. 4.4%). Under HH average fixation time and target area size were significantly higher than under IH. Total saccadic times under hypoxic conditions were significantly increased compared with normoxia. CONCLUSIONS: These results suggest that oculometric changes are indicators of hypoxia, which can be monitored using compact, portable, noninvasive eye-tracking devices in a cockpit analogous environment to detect hypoxia-induced physiological changes in aircrew. Comparative results between HH and IH support the potential role of carbon dioxide in augmenting cerebral perfusion and hence improved tissue oxygen delivery. PMID- 25022156 TI - Flywheel resistance exercise to maintain muscle oxidative potential during unloading. AB - BACKGROUND: As spaceflight compromises skeletal muscle oxidative and aerobic work capacity, this study assessed the efficacy of resistance exercise (RE) to counteract muscle metabolic perturbations induced by 5 wk unilateral lower limb unloading (UL). METHODS: There were 21 men and women (30-56 yr) who were randomly assigned to either UL with (Group, Grp; UL+RE; N = 10) or without (Grp UL; N = 11) concurrent RE. Iso-inertial RE comprised four sets of seven maximal coupled concentric-eccentric knee extensions executed 2-3 times per week. Percutaneous biopsies were obtained from m. vastus lateralis before and after either intervention. Levels of mRNA expression of factors regulating skeletal muscle oxidative capacity i.e., peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1alpha) and vascular endothelial growth factor (VEGF), and glycolytic capacity, i.e., phosphofructokinase (PFK), glycogen phosphorylase and synthase, hexokinase, and phosphorylase kinase alpha1, were subsequently analyzed. RESULTS: Grp UL showed decreased (36%) PGC-1alpha expression, increased (1.5-fold) PFK expression, and a trend toward decreased VEGF post-intervention. Grp UL+RE showed no changes. DISCUSSION: These results suggest that 5 wk unloading reduces skeletal muscle oxidative capacity and increases glycolytic enzyme activity. More importantly, only 12 bouts of high-force, low-volume resistance exercise attenuated these responses. Thus, the current resistance exercise paradigm emphasizing eccentric overload effectively counteracts unwarranted metabolic alterations induced by 5 wk unloading and may, therefore, aid in maintaining skeletal muscle integrity and endurance, and hence astronaut health and fitness during spaceflight. PMID- 25022158 TI - Pilots' visual scan patterns and situation awareness in flight operations. AB - INTRODUCTION: Situation awareness (SA) is considered an essential prerequisite for safe flying. If the impact of visual scanning patterns on a pilot's situation awareness could be identified in flight operations, then eye-tracking tools could be integrated with flight simulators to improve training efficiency. METHOD: Participating in this research were 18 qualified, mission-ready fighter pilots. The equipment included high-fidelity and fixed-base type flight simulators and mobile head-mounted eye-tracking devices to record a subject's eye movements and SA while performing air-to-surface tasks. RESULTS: There were significant differences in pilots' percentage of fixation in three operating phases: preparation (M = 46.09, SD = 14.79), aiming (M = 24.24, SD = 11.03), and release and break-away (M = 33.98, SD = 14.46). Also, there were significant differences in pilots' pupil sizes, which were largest in the aiming phase (M = 27,621, SD = 6390.8), followed by release and break-away (M = 27,173, SD = 5830.46), then preparation (M = 25,710, SD = 6078.79), which was the smallest. Furthermore, pilots with better SA performance showed lower perceived workload (M = 30.60, SD = 17.86), and pilots with poor SA performance showed higher perceived workload (M = 60.77, SD = 12.72). Pilots' percentage of fixation and average fixation duration among five different areas of interest showed significant differences as well. DISCUSSION: Eye-tracking devices can aid in capturing pilots' visual scan patterns and SA performance, unlike traditional flight simulators. Therefore, integrating eye-tracking devices into the simulator may be a useful method for promoting SA training in flight operations, and can provide in-depth understanding of the mechanism of visual scan patterns and information processing to improve training effectiveness in aviation. PMID- 25022159 TI - Establishment of exposure guidelines for lead in spacecraft drinking water. AB - BACKGROUND: Setting Spacecraft Water Exposure Guidelines (SWEGs) for lead (Pb) in spacecraft drinking water has special challenges related to estimating the increase in blood lead levels (PbB) due to the release of lead to systemic circulation via microgravity-induced bone loss. METHODS: The effects on the PbB of lead in drinking water (PbW) and lead released from bones, and changes in lead exposure before, during, and after spaceflight, were evaluated using a physiologically based pharmacokinetic model that incorporated environmental lead exposure on Earth and in flight and included temporarily increased rates of osteoporosis during spaceflight. RESULTS: The model predicts that in 2030 (the earliest potential launch date for a long-duration mission), the average American astronaut would have a PbB of 1.7 microg x dl(-1) at launch and that, while in microgravity, PbB levels would decrease at PbW values less than about 9 microg L( 1) because of reduced exposure within the spacecraft to environmental lead. Astronauts with high concentrations of lead stored in bones could experience increases in PbB due to microgravity-accelerated release of lead from bones. While the resultant in-flight PbB would depend on their preflight bone lead levels, their PbB will not be significantly further elevated (< 1 microg x dl( 1)) by consuming water with a PbW of < or = 9 microg x dl(-1). Selection of a SWEG that would not result in an increase in blood lead is prudent given uncertainties about health effects at low exposures. CONCLUSION: A SWEG of 9 microg x L(-1) would protect astronauts on long-duration spaceflights by ensuring that PbB values will not exceed prelaunch levels. PMID- 25022160 TI - Tolerance of centrifuge-simulated suborbital spaceflight by medical condition. AB - INTRODUCTION: We examined responses of volunteers with known medical disease to G forces in a centrifuge to evaluate how potential commercial spaceflight participants (SFPs) might tolerate the forces of spaceflight despite significant medical history. METHODS: Volunteers were recruited based upon suitability for each of five disease categories (hypertension, cardiovascular disease, diabetes, lung disease, back or neck problems) or a control group. Subjects underwent seven centrifuge runs over 2 d. Day 1 consisted of two +G(z) runs (peak = +3.5 G(z), Run 2) and two +G(x), runs (peak = +6.0 G(x), Run 4). Day 2 consisted of three runs approximating suborbital spaceflight profiles (combined +G(x) and +G(z), peak = +6.0 G(x)/+4.0 G(z)). Data collected included blood pressure, electrocardiogram, pulse oximetry, neurovestibular exams, and post-run questionnaires regarding motion sickness, disorientation, grayout, and other symptoms. RESULTS: A total of 335 subjects registered for participation, of which 86 (63 men, 23 women, age 20-78 yr) participated in centrifuge trials. The most common causes for disqualification were weight and severe and uncontrolled medical or psychiatric disease. Five subjects voluntarily withdrew from the second day of testing: three for anxiety reasons, one for back strain, and one for time constraints. Maximum hemodynamic values recorded included HR of 192 bpm, systolic BP of 217 mmHg, and diastolic BP of 144 mmHg. Common subjective complaints included grayout (69%), nausea (20%), and chest discomfort (6%). Despite their medical history, no subject experienced significant adverse physiological responses to centrifuge profiles. DISCUSSION: These results suggest that most individuals with well-controlled medical conditions can withstand acceleration forces of launch and re-entry profiles of current commercial spaceflight vehicles. PMID- 25022161 TI - Point-of-care ultrasound in aerospace medicine: known and potential applications. AB - Since its initial introduction into the bedside assessment of the trauma patient via the Focused Assessment with Sonography for Trauma (FAST) exam, the use of point-of-care ultrasound has expanded rapidly. A growing body of literature demonstrates ultrasound can be used by nonradiologists as an extension of the physical exam to accurately diagnose or exclude a variety of conditions. These conditions include, but are not limited to, hemoperitoneum, pneumothorax, pulmonary edema, long-bone fracture, deep vein thrombosis, and elevated intracranial pressure. As ultrasound machines have become more compact and portable, their use has extended outside of hospitals to places where the physical exam and diagnostic capabilities may be limited, including the aviation environment. A number of studies using focused sonography have been performed to meet the diagnostic challenges of space medicine. The following article reviews the available literature on portable ultrasound use in aerospace medicine and highlights both known and potential applications of point-of-care ultrasound for the aeromedical clinician. PMID- 25022162 TI - Helicopter pilot scan techniques during low-altitude high-speed flight. AB - INTRODUCTION: This study examined pilots' visual scan patterns during a simulated high-speed, low-level flight and how their scan rates related to flight performance. As helicopters become faster and more agile, pilots are expected to navigate at low altitudes while traveling at high speeds. A pilot's ability to interpret information from a combination of visual sources determines not only mission success, but also aircraft and crew survival. METHODS: In a fixed-base helicopter simulator modeled after the U.S. Navy's MH-60S, 17 active-duty Navy helicopter pilots with varying total flight times flew and navigated through a simulated southern Californian desert course. Pilots' scan rate and fixation locations were monitored using an eye-tracking system while they flew through the course. Flight parameters, including altitude, were recorded using the simulator's recording system. RESULTS: Experienced pilots with more than 1000 total flight hours better maintained a constant altitude (mean altitude deviation = 48.52 ft, SD = 31.78) than less experienced pilots (mean altitude deviation = 73.03 ft, SD = 10.61) and differed in some aspects of their visual scans. They spent more time looking at the instrument display and less time looking out the window (OTW) than less experienced pilots. Looking OTW was associated with less consistency in maintaining altitude. DISCUSSION: Results may aid training effectiveness specific to helicopter aviation, particularly in high-speed low level flight conditions. PMID- 25022163 TI - Exerted pressure by an in-flight oxygen mask. AB - BACKGROUND: F-16 pilots wear an in-flight oxygen mask to prevent hypoxemia. In the contact area with the mask, the pilots experience nasal discomfort and pain, and may even develop nasal deformities. A likely cause is the pressure exerted by the mask. In this study the hypothesis was that the change in pressure exerted on the nose would be higher than on the chin, an area free of symptoms. METHODS: Six F-16 pilots and five healthy former F-16 pilots volunteered to participate in this observational pilot study. At baseline the pilots donned mask and helmet. The median delta pressure (deltap) recordings at baseline were compared to the exerted deltap during the experimental head movements. RESULTS: At baseline, there was no significant difference between the median deltap on the nose and chin (2 vs. 1.6 mmHg, T = 2). Head movements increased the median deltap on the nose by 50 mmHg (T = 0) and on the chin by 31 mmHg (T = 0) when compared to baseline. Head movements also decreased the pressure by -20 mmHg (T = 1.75) on the nose and -11 mmHg (T = 0) on the chin. CONCLUSIONS: The data show that the baseline deltap is higher on the nose than on the chin. The head movements both increased and decreased the exerted pressure on the nose and the chin. These observations suggest that further evaluation of the effect of flight conditions on the exerted pressure is worthwhile to understand its contribution to the nasal symptoms. PMID- 25022164 TI - Mortality among Soviet and Russian cosmonauts: 1960-2013. AB - INTRODUCTION: Though the mortality of U.S. astronauts has been studied repeatedly in the last 20 yr, little is known about the long-term mortality trends of Soviet and Russian cosmonauts. METHODS: Using data from 266 cosmonauts accepted into cosmonaut training from 1960 to 2013, we document the causes of death and crude death rates among cosmonauts. Using standardized mortality ratios (SMR), we compared cosmonauts to the general populations of Russia and Ukraine, and to 330 U.S. astronauts. RESULTS: Cosmonauts experienced significantly lower all-cause mortality risk compared to the general population. However, cosmonauts were at almost double the risk of all-cause mortality in comparison to U.S. astronauts (SMR = 190, 95% C.I. 154-239). Cosmonauts were also at greater risk of circulatory disease (SMR = 364, 95% C.I. 225-557) and cancer (SMR = 177, 95% C.I. 108-274) compared to U.S. astronauts. Though not statistically significant, cosmonauts experienced fewer fatal accidents (SMR = 88, 95% C.I. = 54-136) than their U.S. counterparts. DISCUSSION: Cosmonauts are at much lower risk of all cause mortality than the general populations of Russia and Ukraine, yet are at greater risk for death by cardiovascular disease and cancer than are U.S. astronauts. This disparity may have common roots with decreases in life expectancy in Russia in recent decades. Further research is needed to understand these trends fully. PMID- 25022165 TI - On-site implantation of a ventricular assist device to facilitate aeromedical transport. AB - BACKGROUND: Experiencing an acute coronary event in a remote or community hospital can be fatal, particularly if the event is complicated by cardiogenic shock. Many remote and community hospitals do not have adequate resources to support such a compromised patient. Extrapolating from the domestic hub-and-spoke model, presently used between academic tertiary care facilities and community hospitals, we outline the implementation of such an ad hoc arrangement between Panama (spoke) and South Florida (hub). CASE REPORT: We transported a team of cardiovascular experts from Florida to Panama, in tandem air ambulances (to limit mandatory crew rest time), to implant a left ventricular assist device (LVAD) in a patient in cardiogenic shock refractory to mechanical/pharmacological support. The low profile LVAD inserted percutaneously by the American team stabilized the patient (a U.S. citizen on assignment in Panama), enabling his air ambulance transport back to South Florida. DISCUSSION: In this first-of-a-kind report, we outline the challenges and logistics involved in the planning, resuscitation, and aeromedical transport of a patient who was discharged from the hub hospital in Florida after just 30 d. PMID- 25022166 TI - 3D printing of surgical instruments for long-duration space missions. AB - INTRODUCTION: The first off-Earth fused deposition modeling (FDM) 3D printer will explore thermoplastic manufacturing capabilities in microgravity. This study evaluated the feasibility of FDM 3D printing 10 acrylonitrile butadiene styrene (ABS) thermoplastic surgical instruments on Earth. METHODS: Three-point bending tests compared stiffness and yield strength between FDM 3D printed and conventionally manufactured ABS thermoplastic. To evaluate the relative speed of using four printed instruments compared to conventional instruments, 13 surgeons completed simulated prepping, draping, incising, and suturing tasks. Each surgeon ranked the performance of six printed instruments using a 5-point Likert scale. RESULTS: At a thickness of 5.75 mm or more, the FDM printing process had a less than 10% detrimental effect on the tested yield strength and stiffness of horizontally printed ABS thermoplastic relative to conventional ABS thermoplastic. Significant weakness was observed when a bending load was applied transversely to a 3D printed layer. All timed tasks were successfully performed using a printed sponge stick, towel clamp, scalpel handle, and toothed forceps. There was no substantial difference in time to completion of simulated surgical tasks with control vs. 3D printed instruments. Of the surgeons, 100%, 92%, 85%, 77%, 77%, and 69% agreed that the printed smooth and tissue forceps, curved and straight hemostats, tissue and right angle clamps, respectively, would perform adequately. DISCUSSION: It is feasible to 3D print ABS thermoplastic surgical instruments on Earth. Loadbearing structures were designed to be thicker, when possible. Printing orientations were selected so that the printing layering direction of critical structures would not be transverse to bending loads. PMID- 25022168 TI - Reference management with open source tools. PMID- 25022167 TI - Post space mission lumbo-pelvic neuromuscular reconditioning: a European perspective. AB - Long-duration exposure to the space environment causes physical adaptations that are deleterious to optimal functioning on Earth. Post-mission rehabilitation traditionally concentrates on regaining general muscle strength, neuromuscular control, and lumbo-pelvic stability. A particular problem is muscle imbalance caused by the hypertrophy of the flexor and atrophy of the extensor and local lumbo-pelvic muscles, increasing the risk of post-mission injury. A method currently used in European human spaceflight to aid post-mission recovery involves a motor control approach, focusing initially on teaching voluntary contraction of specific lumbo-pelvic muscles and optimizing spinal position, progressing to functional retraining in weight bearing positions. An alternative approach would be to use a Functional Readaptive Exercise Device to appropriately recruit this musculature, thus complementing current rehabilitation programs. Advances in post-mission recovery of this nature may both improve astronaut healthcare and aid terrestrial healthcare through more effective treatment of low back pain and accelerated post bed rest rehabilitation. PMID- 25022169 TI - You're the flight surgeon: hemochromatosis. PMID- 25022170 TI - You're the flight surgeon: skin cancer. PMID- 25022171 TI - This month in aerospace medicine history. PMID- 25022173 TI - FAA's first postmortem aviation toxicology colloquium held. PMID- 25022174 TI - NASA, NSBRI select 26 proposals to support crew health on deep space missions. PMID- 25022176 TI - NIOSH presents 2014 awards for significant scientific contributions. PMID- 25022175 TI - ALPA responds to DOT regarding airfare transparency. PMID- 25022177 TI - Cobham introduces new class of safety system. PMID- 25022179 TI - United wins Sustainability Outstanding Achievement Award. PMID- 25022180 TI - Piedmont partners with Wellstreet to launch urgent care. PMID- 25022178 TI - HeartSine wins two management awards. PMID- 25022181 TI - Foreword. Substance use and abuse among adolescents. PMID- 25022182 TI - Preface. Substance use and abuse among adolescents. PMID- 25022183 TI - Adolescent substance use: the role of the medical home. AB - Given the continued high rates of substance use by adolescents and young adults, it should be among the topics addressed at every health care visit in the medical home. Primary care physicians should counsel and refer parents for substance use assessment, counseling, and cessation management when pediatric or adolescent patients are environmentally exposed to substances and substance use. The role of the medical home includes providing parents, children, and adolescents with anticipatory guidance, drug use screening, health advice, brief intervention, and referral for further assessment and treatment when an SUD is suspected. Clinical and technical reports, policy statements, and educational materials provided by national institutes and health professional societies assist those caring for children and adolescents by assuring best practices in detailed guidance and developmentally appropriate strategies related to alcohol, tobacco, and other substance use across the pediatric age range. PMID- 25022185 TI - "The new cigs on the block": an update on conventional and novel tobacco products. PMID- 25022186 TI - Young people and alcohol use: contextualizing and responding to the challenge of problematic drinking. PMID- 25022187 TI - Marijuana. AB - Marijuana use in pediatric populations remains an ongoing concern, and marijuana use by adolescents had known medical, psychological, and cognitive side effects. Marijuana alters brain development and has detrimental effects on brain structure and function in ways that are incompletely understood at this point in time. Furthermore, marijuana smoke contains tar and other harmful chemicals, so marijuana cannot be recommended by physicians. At this time, no studies suggest a benefit of marijuana use by children and adolescents. In the context of limited but clear evidence showing harm or potential harm from marijuana use by adolescents, any recommendations for medical marijuana use by adolescents are based on research studies with adults and on anecdotal evidence. Criminal prosecution for marijuana possession adversely affects hundreds of thousands of youth yearly in the United States, particularly minority youth. Current evidence does not support a focus on punishment for youth who use marijuana. Rather, drug education and treatment programs should be encouraged to better help youth who are experimenting with or are dependent on marijuana. Decriminalization of recreational use of marijuana by adults has not led to an increase in youth use rates of recreational marijuana. Thus, decriminalization may be a reasonable alternative to outright criminalization, as long as it is coupled with drug education and treatment programs. The effect of outright legalization of adult recreational use of marijuana on youth use is unknown. PMID- 25022184 TI - Neurobiology of adolescent substance use and addictive behaviors: treatment implications. PMID- 25022188 TI - Nonmedical use of prescription stimulants by adolescents. PMID- 25022190 TI - Performance-enhancing substances. PMID- 25022189 TI - Responding to the prescription opioid epidemic: practical information for pediatricians. PMID- 25022191 TI - Screening and brief intervention for alcohol and other abuse. AB - Substance use is the most common health risk behavior among adolescents and is one of the greatest threats to their current and future health. Universal screening of adolescents in general medical settings can be instrumental in identifying substance use early, before further problems develop and when BIs are more likely to be effective. Screening in and of itself may have some therapeutic effect. Brief screening tools feasible for use by busy medical offices to quickly and reliably assess adolescent risk for a substance use disorder now are available. A recent study found that a physician-conducted CRAFFT screen interview required an average of 74 seconds to complete, whereas a computer self administered version took an average of 49 seconds. The CRAFFT and AUDIT tools currently have the most evidence for validity among adolescents, whereas the validity of other widely used tools such as DAST-10, NIDA-modified ASSIST (Alcohol, Smoking and Substance Involvement Screening Test), and ultra-brief screens (AUDIT-C, single-item screens) has yet to be established for adolescents. Studies are needed to identify effective strategies to promote universal adolescent screening and the use of valid screening tools in general medical settings. One statewide (Massachusetts) study found that although most (86%) primary care physicians seeing adolescents reported screening adolescents for substance use annually, only 1 in 3 reported using a validated tool (the CRAFFT). The remaining physicians reporting using informal screening procedures, their own questionnaire, or the CAGE. Computerization of screening and integration into the electronic health record appear to be promising strategies to promote universal screening and standardized use of valid screening tools. Increasing adolescent screening rates necessitates supporting physicians' ability to respond effectively to the screen results. To that end, recent evidence-informed practice guides from the AAP and NIAAA provide a structured algorithm for specific recommended responses based on level of risk. Adolescents who are at low or moderate risk for a substance use disorder, who constitute most of those seen in general medical settings, may be effectively counseled with a few minutes of brief advice, particularly after being primed with screening, feedback, and education before seeing their physician. High-risk patients (screen-positives) should receive a brief follow-up assessment to determine the appropriate level of care needed and a BI, using MI principles, to enhance motivation for behavioral change and help-seeking. Indications of acute danger or addiction may necessitate breaking confidentiality to protect patient safety and begin RT. Our review shows a small but growing body of research on the effectiveness of opportunistic BIs following screening of adolescents in clinical settings. Studies to date have largely tested brief alcohol-focused MI-based interventions with adolescents in the ED or trauma care settings; however, the number of studies conducted in primary health care settings is increasing. The strongest BI effects found in these studies tend to be related to harm reduction, such as reduction of substance-related driving/riding, alcohol-related injuries, unplanned sex, and other negative consequences of use. Effects on substance use have been more modest and tend to be stronger at shorter (< or = 6 months) rather than longer follow-up (> or = 12 months). However, many of these studies compared BI to active control conditions, which often included elements of BI (eg, assessment, brief advice, informational handouts). Significant reductions in substance use and related harms were also seen in these control groups, likely making detection ofa BI effect more difficult. A few studies have shown initial support for a prevention effect of BI among abstinent adolescents. At the opposite end of the spectrum, little is known about the effects of BI for adolescents with dependence and needing RT because of a lack of studies. Other areas needing additional research are the effect of BI on adolescent drug use, particularly on use of drugs other than cannabis; the mediators and moderators of BI effects; ways to reinforce and sustain effects over time; and how best to increase SBI implementation in general medical settings and to effectively train physicians. The effect of efforts such as the Substance Abuse and Mental Health Services Administration-funded physician residency SBIRT training programs remain to be determined. There has been increasing investigation into the potential of interactive computer technologies to aid SBIRT delivery to adolescents and young adults. A more detailed review of this area of research is beyond the scope of this article, but computer technology is proving to be an acceptable and effective tool in the delivery of BIs to young people, both as physician "extenders" in clinical settings and in the form of stand-alone self-guided programs. Computer technologies likely will play a critical role in promoting the expansion of SBIRT implementation for youth in general medical settings. PMID- 25022192 TI - Treatment of adolescent substance use disorders. PMID- 25022193 TI - Substance abuse among culturally diverse youth. PMID- 25022194 TI - Evolving array of substances used by adolescents. PMID- 25022195 TI - Assessment and treatment of substance abuse in the juvenile justice population. PMID- 25022196 TI - Tyrosine phosphorylation in Toll-like receptor signaling. AB - There is a wealth of knowledge about how different Ser/Thr protein kinases participate in Toll-like receptor (TLR) signaling. In many cases, we know the identities of the Ser/Thr residues of various components of the TLR-signaling pathways that are phosphorylated, the functional consequences of the phosphorylation and the responsible protein kinases. In contrast, the analysis of Tyr-phosphorylation of TLRs and their signaling proteins is currently incomplete, because several existing analyses are not systematic or they do not rely on robust experimental data. Nevertheless, it is clear that many TLRs require, for signaling, ligand-dependent phosphorylation of specific Tyr residues in their cytoplasmic domains; the list includes TLR2, TLR3, TLR4, TLR5, TLR8 and TLR9. In this article, we discuss the current status of knowledge of the effect of Tyr phosphorylation of TLRs and their signaling proteins on their biochemical and biological functions, the possible identities of the relevant protein tyrosine kinases (PTKs) and the nature of regulations of PTK-mediated activation of TLR signaling pathways. PMID- 25022197 TI - In-vitro assessment of antioxidant and antimicrobial activities of methanol extracts and essential oil of Thymus hirtus sp. algeriensis. AB - BACKGROUND: Owing to the complexity of the antioxidant materials and their mechanism of actions, it is obvious that no single testing method is capable of providing a comprehensive picture of the antioxidant profile. The essential oil of the Thymus specie may still possess other important activities in traditional medicine, it can be used in the treatment of fever and cough. This essential oil may also have an anticancer activity. METHODS: The essential oils aerial parts hydrodistilled from Thymus hirtus sp. algeriensis, were characterised by GC/MS analysis and the methanolic extracts were chemically characterized by HPLC method. The essence of thyme was evaluated for its antioxidant and antibacterial activity. RESULT: The Terpinen-4-ol are the principal class of metabolites (33.34%) among which 1.8-cineole (19.96%) and camphor (19.20%) predominate. In this study, quantitative values of antioxidant activity of crude methanolic extracts of Thymus hirtus sp. algeriensis were investigated. The essential oils was screened for their antibacterial activity against six common pathogenic microorganisms (Escherichia coli, Pseudomonas aeruginosa, Salmonella enteridis, Staphylococcus aureus, Bacillus subtilis and Listeria monocytogenes) by well diffusion method and agar dilution method (MIC). All the essences were found to inhibit the growth of both gram (+) and gram (-) bacteria organisms tested. These activities were correlated with the presence of phenolic compounds in active fractions. HPLC confirmed presence of phenolic compounds in methanol extracts. CONCLUSION: Methanol extracts and essential oils from aerial parts of Thymus hirtus sp. algeriensis, were examined for their potential as antioxidants. The technique for measuring antioxidant activity, which was developed using DPPH, ABTS and beta-carotene bleaching, produced results as found in established literatures. The present results indicate clearly that methanol extracts and essential oils from Thymus hirtus sp. algeriensis possess antioxidant properties and could serve as free radical inhibitors or scavengers, acting possibly as primary antioxidants, also their essential oil have an antibacterial effect. PMID- 25022198 TI - Commercial lubricant use among HIV-negative men who have sex with men in Los Angeles: implications for the development of rectal microbicides for HIV prevention. AB - To inform the development and assess potential use of rectal microbicide gels for HIV prevention among men who have sex with men (MSM), we examined the dynamics and contexts of commercial lubricant use during receptive anal intercourse (RAI) within this population. From 2007 to 2010, 168 HIV-negative MSM living in Los Angeles who practice RAI completed computer-assisted self-interviews, which collected information on their last sexual event with <=3 recent partners, at baseline, three months, and one-year study visits. Logistic generalized linear mixed models were used to identify individual- and sexual event-level characteristics associated with commercial lubricant use during RAI at the last sexual event within 421 partnerships reported by participants over the course of follow-up. During RAI at their last sexual event, 57% of partnerships used a condom and 69% used commercial lubricant. Among partnerships that used commercial lubricant, 56% reported lubricant application by both members of the partnership, 66% first applied lubricant during sex, but before penetration, and 98% applied lubricant at multiple locations. The relationship between substance use and commercial lubricant use varied by condom use (interaction p-value = 0.01). Substance use was positively associated with commercial lubricant use within partnerships that did not use condoms during RAI at their last sexual event (AOR = 4.47, 95% [corrected] [CI]: 1.63-12.28), but no association was observed within partnerships that did use condoms (AOR = 0.66, 95% CI: 0.23-1.85). Commercial lubricant use during RAI was also positively associated with reporting more sexual partners (AOR = 1.18, 95% CI: 1.05-1.31), while older age (units = 5 years; AOR = 0.75, 95% CI: 0.61-0.94), homelessness (past year; AOR = 0.32, 95% CI: 0.13-0.76), and having sex with an older (>10 years) partner (AOR = 0.37, 95% CI: 0.14-0.95) were negatively associated with commercial lubricant use. These factors should be considered in the development of rectal microbicide gels to enhance their acceptability and use among MSM. PMID- 25022199 TI - Muscle pre-activation strategies play a role in modulating Kvert for change of direction manoeuvres: an observational study. AB - The aim of the study presented in this paper was to establish if a relationship existed between lower limb muscle pre-activation strategies and vertical stiffness (Kvert). Participants from a professional rugby union club all performed a multidirectional hopping task on a force platform which measured Kvert. Muscle activity was concurrently measured for the gluteus maximus, vastus lateralis, vastus medialis, biceps femoris, semimembranosus, and medial gastrocnemius using electromyography and the activity of those muscles in the 100ms prior to foot contact (pre-activation) was analysed. Moderate to strong positive relationships were typically seen for Kvert and muscle pre-activation for each muscle when normalized to maximum voluntary contraction. Pre-activation cocontraction of the muscles surrounding the knee joint also showed a typically moderate relationship with Kvert and peak muscle activation of antagonist muscles at the knee joint were typically similar. Results suggest that muscle pre activation strategies play a role in modulating Kvert for change of direction manoeuvre. PMID- 25022201 TI - The Australian journal of physiotherapy oration: "go west, young man". AB - Years ago, I, and many of my colleagues, were lured to a lecture to be given by a former President of the Australian Physiotherapy Association, Sir Frank Kingsley Norris, mainly because it bore the engaging title of "Why Shoot a Butler". It was in fact, until "The Man that Never Was", the greatest hoax of our time. Sir Kingsley merely introduced the real speaker of the evening, a senior police officer, who proceeded to entertain us with an enthralling account of the methods used to identify and correlate bullets and shells to particular pistols. The general theme of the evening was, that if you must murder someone, don't shoot them because the bullets and shells, if recovered, can be just as incriminating as fingerprints. To this day, I cannot remember whether it was the butler, the parlour maid or the young master who was shot - in any event it didn't matter. As on that occasion, the title of this address, like the "Flowers that Bloom in the Spring", has nothing to do with the case - or hardly anything. PMID- 25022200 TI - A focus on recent cases of suicides among Italian children and adolescents and a review of literature. AB - Suicidal behaviors are among the leading causes of death worldwide. The large spread of suicide suggests that educational programs and literature to parents or guardians should include information about the potential risks and potential consequences of the onset of the idea of suicide in children. We identified 55 cases of suicide among children and young adults <18-year-old occurring in Italy between 1st January, 2011 and 31st December, 2013. The results point to the need to increase our understanding of the dramatic rise in suicidal behaviors during childhood/adolescence and of the causal pathways linking these behaviors to child adolescent mental disorders. During routine care visits, pediatricians should be skilled to recognize risk factors for adolescent suicide in order to intervene appropriately. PMID- 25022202 TI - Recent experience in the treatment of some acute sporting injuries. AB - At Lewisham Hospital we have found the three joints most commonly injured during sport to be the ankle, the knee and the acromio-clavicular joints. PMID- 25022203 TI - The effect of breathing techniques on the end-tidal percentage of carbon dioxide and its importance during labour. AB - This experiment was undertaken to determine the connection between the breathing techniques practised in some methods of training for childbirth and the presence of certain undesirable side effects during labour. These symptoms, viz., dizziness, exhaustion, shortness of breath, "pins and needles", tremors and tetany, may be the result of hyperventilation and the ensuing hypocapnia (deficiency of CO2 in the blood) (Christophers, 1961). PMID- 25022204 TI - Discovery of (7-aryl-1,5-naphthyridin-2-yl)ureas as dual inhibitors of ERK2 and Aurora B kinases with antiproliferative activity against cancer cells. AB - A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed. PMID- 25022205 TI - A methodology for evaluating change and impact of illness perceptions among patients with memory complaints and their next of kin during the diagnosis process. PMID- 25022206 TI - Chemical composition of Propolis Extract ACF(r) and activity against herpes simplex virus. AB - Propolis Extract ACF((r)) (PPE) is a purified extract manufactured from propolis collected in a Canadian region rich in poplar trees, and it is the active substance of a topical ointment used against herpes labialis (cold sores or fever blisters). Aim of this study was to analyze the chemical composition of PPE in order to understand the plant origin and possible relations between compounds and antiviral activity, and to characterize the antiviral activity of the extract against herpes simplex virus in vitro. MATERIAL AND METHODS: The analysis of the propolis extract samples was conducted by Gas Chromatography-Mass Spectrometry (GC-MS). The antiviral activity was tested against herpes simplex viruses type 1 and type 2 in MDBK cell cultures by treating the cells with PPE at the time of virus adsorption, and by incubating the virus with the extract before infection (virucidal assay). RESULTS: Results from the GC-MS analyses revealed a dual plant origin of PPE, with components derived from resins of two different species of poplar. The chemical composition appeared standardized between extract samples and was also reproduced in the sample of topical ointment. The antiviral studies showed that PPE had a pronounced virucidal effect against herpes simplex viruses type 1 and type 2, and also interfered with virus adsorption. PMID- 25022207 TI - Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target? AB - BACKGROUND: Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasite Trypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world's 17 neglected tropical diseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment, however they cause severe adverse effects and their efficacy is still controversial. It is then important to explore for new drugs. PURPOSE: Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim of this work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs), dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx. MATERIAL AND METHODS: Hln and DhL were isolated from aerial parts of Gaillardia megapotamica and Artemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by (13)C-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruzi epimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine exposure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidal activity of natural and synthetic compounds was assayed by measuring parasite viability using the MTT method. RESULTS: The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epimastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventional antichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and either Bz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasite viability. CONCLUSION: DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infective trypomastigote forms, which is a different mechanism of action than the conventional drugs to kill the parasite. Therefore DhL and Hln may offer an interesting option for the treatment of Chagas disease, alone or in combination with conventional drugs. PMID- 25022208 TI - A multi-component herbal preparation, STW 5, shows anti-apoptotic effects in radiation induced intestinal mucositis in rats. AB - PURPOSE: Intestinal mucositis is a common adverse effect in patients undergoing radiotherapy and constitutes a treatment-limiting condition. Since no agents are yet known that can adequately guard against its development, the search continues to find safe and effective measures. The present study was intended to investigate whether the herbal preparation, STW 5, could offer a potentially effective agent in this respect. METHODS: Intestinal mucositis was induced in rats by exposing them to whole body gamma-irradiation (6 Gy). Rats were treated orally with STW 5 (5 or 10 ml/kg) for five days before and two days after irradiation. One day later, rats were sacrificed and segments of small intestine were examined histologically. Intestinal homogenates and serum samples were used to assess relevant parameters for apoptosis and different markers for inflammation and oxidative stress. RESULTS: Exposure to radiation produced dose dependent extents of intestinal injury associated with apoptotic changes with high radiation levels. Apoptosis was associated with an increase in cytosolic calcium, depletion of mitochondrial cytochrome c, B-cell lymphoma-2 and complex I. Oxidative stress parameters (reduced glutathione, thiobarbituric acid reactive substance and total nitrate/nitrite) were deranged. Inflammation markers (tumor necrosis factor and myeloperoxidase) and indices of intestinal damage (serum diamine oxidase) were increased. STW 5 protected to a large extent against histological changes and counteracted the deranged parameters. CONCLUSION: The findings provide experimental evidence for the potential beneficial use of STW5 in protecting against the development of radiation-induced intestinal mucositis and associated changes in tissue biomarkers. PMID- 25022209 TI - Neuroprotective effect of yokukansan against cytotoxicity induced by corticosterone on mouse hippocampal neurons. AB - Yokukansan, a traditional Japanese herbal medicine, has been used for the management of neurodegenerative disorders and for the treatment of neurosis, insomnia, and behavioral and psychological symptoms of dementia. Recently, several studies have shown that yokukansan has a neuroprotective effect. The aim of this study was to examine the neuroprotective effect of yokukansan on hippocampal neurons from embryonic mouse brain against the effects of corticosterone, which is considered to be a stress hormone and to be cytotoxic toward neurons. The cell survival rates were measured by the WST-8 assay and LDH assay. Twenty-four hours after treatment with corticosterone, cell numbers were significantly decreased compared with the control or treatment with vehicle in a dose-dependent manner. When cells were treated with 30 MUM corticosterone, the decrease in the number of cells was significantly recovered by treatment with yokukansan (100-1,000 MUg/ml) in a dose-dependent manner. However, yokukansan did not suppress the decrease in cell numbers that was induced by treatment with 100 MUM corticosterone. In the LDH assay, treatment with yokukansan at a high concentration (500-1,000 MUg/ml) suppressed the LDH concentration induced by treatment with both 30 MUM and 100 MUM corticosterone compared to treatment with corticosterone alone, respectively. These results suggest that yokukansan protects against the cytotoxic effect of a low concentration of corticosterone on hippocampal neurons. PMID- 25022210 TI - Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice. AB - INTRODUCTION: It was the aim of the present experiments to examine potential antidiabetic effects of the Cimicifuga racemosa extract Ze 450. METHODS: Ze 450 and some of its components (23-epi-26-deoxyactein, protopine and cimiracemoside C) were investigated in vitro for their effects on AMP-activated protein kinase (AMPK) compared to metformin in HepaRG cells. Ze 450 (given orally (PO) and intraperitonally (IP)), metformin (PO) and controls were given over 7 days to 68 male ob/ob mice. Glucose and insulin concentrations were measured at baseline and during an oral glucose tolerance test (OGTT). RESULTS: Ze 450 and its components activated AMPK to the same extent as metformin. In mice, Ze 450 (PO/IP) decreased significantly average daily and cumulative weight gain, average daily food and water intake, while metformin had no effect. In contrast to metformin, PO Ze 450 virtually did not change maximum glucose levels during OGTT, however, prolonged elimination. Ze 450 administered PO and IP decreased significantly post stimulated insulin, whereas metformin did not. HOMA-IR index of insulin resistance improved significantly after IP and PO Ze 450 and slightly after metformin. In summary, the results demonstrate that Ze 450 reduced significantly body weight, plasma glucose, improved glucose metabolism and insulin sensitivity in diabetic ob/ob mice. In vitro experiments suggest that part of the effects may be related to AMPK activation. CONCLUSIONS: Ze 450 may have utility in the treatment of type 2 diabetes. However, longer term studies in additional animal models or patients with disturbed glucose tolerance or diabetes may be of use to investigate this further. PMID- 25022211 TI - Pharmacological investigation of a HPLC/MS standardized three herbal extracts containing formulae (Bu-Shen-Yi-Qi-Tang) on airway inflammation and hypothalamic pituitary-adrenal axis activity in asthmatic mice. AB - Bu-Shen-Yi-Qi-Tang (BSYQT) which is prescribed on the basis of clinical experience is commonly used in clinic of traditional Chinese medicine (TCM) for asthma treatment. The components of BSYQT include Radix Astragali (RA), Herba Epimedii (HE) and Radix Rehmanniae (RR). The aim of this study was to screen extracts of BSYQT with best anti-inflammatory activity in asthmatic mice, and separate and identify the chemical compounds in them. Our results suggested that 60% ethanol extract of herbs (H60) and granules (G60) of BSYQT were the two extracts with best anti-inflammatory activity and effects of H60 were a little better than that of G60. High-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC-ESI Q-TOF-MS/MS) analysis of the major chemical compounds of H60 and G60 revealed that 56 and 42 peaks were identified separately in H60 and G60. Further analysis revealed that 38 compounds were identified shared by H60 and G60, and 18 compounds were only in H60. There were 25 compounds in HE, 6 compounds in RR and 7 compounds in RA in the 38 compounds shared by G60 and H60. These 38 chemical components were tentatively considered the material basis of the anti inflammatory activity of G60 and H60. The differences in the amount of the 38 chemical components as well as the 18 chemical components only in H60 were tentatively considered responsible for the activity differences between H60 and G60. In conclusion, these results suggested that extracts of BSYQT had inhibitory effects on airway inflammation in asthmatic mice, and H60 and G60 demonstrated the best anti-inflammatory activity. The 38 chemical compounds shared by H60 and G60 were responsible for their anti-inflammatory activity in asthmatic mice, and the differences in chemical compounds contents and amounts between H60 and G60 were responsible for this activity differences. This work would provide support for further pharmacodynamic material basis study of BSYQT. PMID- 25022212 TI - [Quality of life in patients with knee and hip osteoarthritis]. AB - OBJECTIVE: To evaluate the quality of life in patients with knee and hip osteoarthritis through self-assessment and those made by the physician. MATERIALS AND METHODS: An observational and cross-sectional multicenter study in which 628 traumatologists or rheumatologists evaluated 1,849 patients with knee and/or hip osteoarthritis, aged >= 50 years old, and representative of 49 Spanish provinces. Each researcher evaluated three patients and also completed the SF-12v2 health questionnaire. The patients completed the WOMAC and SF-12v2 questionnaires. RESULTS: The patients were 68.5 +/- 9.5 years old, 61.5% had knee osteoarthritis, 19% had hip osteoarthritis, and 19.5% in both locations. Older patients and those who had both knee and hip osteoarthritis had a poorer quality of life, according to patients and researchers. Physical health perceived by the researchers was better than patients reported (36.74 +/- 8.6 and 35.21 +/- 8.53; respectively, p<0.001), and the mental health score was similar between physicians and patients. Kellgren/Lawrence scale and test Timed Up & Go predict better the quality of life, assessed by WOMAC and SF-12v2 questionnaires. DISCUSSION: This is the Spanish study on quality of life in osteoarthritis of the knee and hip of larger amplitude and number of patients. CONCLUSION: These results could be considered as reference values of Spanish population aged >= 50 years with knee or hip osteoarthritis. PMID- 25022213 TI - [Radiation safety in orthopaedic operating theatres. What is the current situation?]. AB - OBJECTIVE: To analyse the exposure of two Orthopaedic Surgeons to ionizing radiations in their daily work, and to review the main national and international recommendations on this subject. MATERIAL AND METHODS: A retrospective study was conducted on the surgical treatments that use fluoroscopy performed by two Orthopaedic Surgeons during a one year period. An evaluation was made of the radiation received, based on measurements of the processes published in the bibliography section. A literature review of international recommendations and regulations is also presented. RESULTS: The radiation received by the two Orthopaedic Surgeons during one year did not exceed the limits of present-day legislation or the new European and international recommendations. The exposure was asymmetrical, with the hands being the most radiated part. The new recommendations reduce the permitted level of radiation on eyes. DISCUSSION: The evaluation of the radiation received demonstrates the need for radiation protection, paying particular attention to the hands and eyes. Good knowledge of operating a fluoroscope and radiation safety measures are also essential. PMID- 25022214 TI - Different neural correlates of facing pain with mindfulness: contributions of strategy and skill. Comment on "Facing the experience of pain: a neuropsychological perspective" by Fabbro and Crescentini. PMID- 25022215 TI - Keeping parasitology under the One Health umbrella. AB - The One Health concept is no longer new, but remains an accepted concept in modern disease control - where the interactions between animal health, human health, and the environment in which we live are recognised as being of importance. However, emerging infectious diseases often garner the greatest attention and resources. Parasitic infections, many of which are zoonotic but cannot truly be considered as emerging, must ensure that they retain their place under the One Health umbrella. PMID- 25022216 TI - A Systems Engineering Perspective on Homeostasis and Disease. AB - Engineered systems are coupled networks of interacting sub-systems, whose dynamics are constrained to requirements of robustness and flexibility. They have evolved by design to optimize function in a changing environment and maintain responses within ranges. Analysis, synthesis, and design of complex supply chains aim to identify and explore the laws governing optimally integrated systems. Optimality expresses balance between conflicting objectives while resiliency results from dynamic interactions among elements. Our increasing understanding of life's multi-scale architecture suggests that living systems share similar characteristics with much to be learned about biological complexity from engineered systems. If health reflects a dynamically stable integration of molecules, cell, tissues, and organs; disease indicates displacement compensated for and corrected by activation and combination of feedback mechanisms through interconnected networks. In this article, we draw analogies between concepts in systems engineering and conceptual models of health and disease; establish connections between these concepts and physiologic modeling; and describe how these mirror onto the physiological counterparts of engineered systems. PMID- 25022217 TI - Advances in pediatric celiac disease. AB - PURPOSE OF REVIEW: To summarize the recent advances in celiac disease in children. RECENT FINDINGS: New clues to the pathogenesis of celiac disease continue to emerge that may implicate the role of microbiome changes, antirotavirus VP7 antibodies, and the Parkinson's disease seven gene in celiac disease. Updated guidelines in pediatrics no longer support biopsies in all patients with celiac disease who have been identified by serology, clinical signs, and genetics. Serology screening of total immunoglobulin A in all patients may not be necessary in select patients. Prevalence and additional diseases associated with celiac disease continue to be elucidated. SUMMARY: Our knowledge of celiac disease continues to grow with increasing evidence of the pathogenesis, genetics, diagnosis, and risk factors of the disease. Major changes have been made with respect to the guidelines for pediatric celiac disease, and potential improvements to simplify the algorithms for diagnosis and elimination of unessential testing have been proposed by new studies. PMID- 25022218 TI - Liquiritigenin alleviates mechanical and cold hyperalgesia in a rat neuropathic pain model. AB - This study assessed the potential antinociceptive effects of liquiritigenin, a plant-derived compound with transient receptor potential melastatin 3 blocking activity in a rat model of persistent neuropathic pain. Chronic constriction injury (CCI) to the sciatic nerve was induced in male Sprague-Dawley rats to model human peripheral neuropathic pain. Liquiritigenin (1, 3, or 9 mg/kg) was administered intraperitoneally to examine the effects on mechanical, thermal, and cold hyperalgesia using the von Frey test, plantar test, and cold plate test, respectively. A rotarod test was also conducted to examine motor function. Liquiritigenin dose dependently alleviated mechanical, thermal and cold hyperalgesia. In addition, daily repeated treatment with liquiritigenin did not demonstrate significant antinociceptive tolerance in the measures of hyperalgesia. Within the doses studied, liquiritigenin did not significantly affect motor performance. These results suggest that liquiritigenin may be potentially useful novel treatments for neuropathic pain. PMID- 25022219 TI - Elastic and ultrasonic properties of single crystalline nickel nanowires. AB - In the present paper, we have theoretically calculated the non linear elastic constants of single crystalline Ni NWs at very broad temperature range 20-300K validating simple interaction potential model. The temperature dependent ultrasonic attenuation and other related properties are determined using their second and third order elastic constants (SOECs/TOECs). Where possible, the results are compared with experiments from literature. There is a correlation between the thermal conductivity and ultrasonic attenuation in the temperature range 100-300K. Also, a correlation between the resistivity and ultrasonic attenuation in the temperature range 40-100K has been established validating the theoretical approach. PMID- 25022220 TI - Differential inflammatory responses of bovine foot skin fibroblasts and keratinocytes to digital dermatitis treponemes. AB - Bovine digital dermatitis (BDD) is a serious infectious inflammatory lameness causing pain and suffering to many cattle worldwide and which has severe economic implications. This study set out to investigate relationships between the treponemes considered causal of BDD and the local inflammatory response of the bovine host. Here we describe, for the first time, the isolation of bovine foot skin keratinocytes and fibroblasts as separate cell lineages. These cell lines were then exposed to treponeme whole-cell sonicates, and the gene expression of selected host inflammatory mediators investigated using quantitative reverse transcriptase PCR. Several genes, including those encoding RANTES/CCL5, MMP12, TNFalpha, TGFbeta and TIMP3 were significantly upregulated in fibroblasts exposed to whole-cell sonicates derived from BDD treponeme phylotypes. For each of the above genes there were similar fibroblast expression increases for all three BDD treponeme phylotypes tested, suggesting common virulence mechanisms. With bovine foot skin keratinocytes, we were unable to detect expression of RANTES/CCL5 and after incubation with BDD treponeme constituents we were unable to observe any significant changes in expression of inflammatory mediators tested. These contrasting results suggest fibroblasts rather than keratinocytes may be an important shared target of pathogenesis for BDD treponemes. PMID- 25022221 TI - Stakeholders' opinions on a future in-vehicle alcohol detection system for prevention of drunk driving. AB - INTRODUCTION: There is a common understanding that driving under the influence of alcohol is associated with higher risk of being involved in crashes with injuries and possible fatalities as the outcome. Various countermeasures have therefore from time to time been taken by the authorities to prevent drunk driving. One of them has been the alcohol interlock. Up to now, interlocks have mainly been used by previously convicted drunk drivers and in the commercial road transport sector, but not in private cars. OBJECTIVE AND METHOD: New technology has today reached a level where broader implementation might be possible. To our knowledge, however, little is known about different stakeholders' opinions of a broader implementation of such systems. In order to increase that knowledge, we conducted a focus group study to collect in-depth thoughts from different stakeholders on this topic. Eight focus groups representing a broad societal span were recruited and conducted for the purpose. RESULTS AND CONCLUSIONS: The results show that most stakeholders thought that an integrated system for alcohol detection in vehicles might be beneficial in lowering the number of drunk driving crashes. They said that the system would probably mainly prevent driving by people who unintentionally and unknowingly drive under the influence of alcohol. The groups did, however, not regard the system as a final solution to the drunk driving problem, and believed that certain groups, such as criminals and alcoholics, would most likely find a way around the system. Concerns were raised about the risk of increased sleepy driving and driving just under the legal blood alcohol concentration (BAC) limit. The results also indicate that stakeholders preferred a system that provides information on the BAC up to the legal limit, but not for levels above the limit; for those, the system should simply prevent the car from starting. Acceptance of the system depended on the reliability of the system, on its ability to perform fast sampling, and on the analytical process, as well as the system's more or less inconspicuous placement and user-friendliness. The stakeholders thought that drivers would probably not voluntarily demand the system. So if broad implementation was desired, it would have to be made compulsory by legislation. As an incentive to increase demand, lower taxes and insurance premiums were suggested. PMID- 25022223 TI - Impact of residues remote from the catalytic centre on enzyme catalysis of copper nitrite reductase. AB - Enzyme mechanisms are often probed by structure-informed point mutations and measurement of their effects on enzymatic properties to test mechanistic hypotheses. In many cases, the challenge is to report on complex, often inter linked elements of catalysis. Evidence for long-range effects on enzyme mechanism resulting from mutations remains sparse, limiting the design/redesign of synthetic catalysts in a predictable way. Here we show that improving the accessibility of the active site pocket of copper nitrite reductase by mutation of a surface-exposed phenylalanine residue (Phe306), located 12 A away from the catalytic site type-2 Cu (T2Cu), profoundly affects intra-molecular electron transfer, substrate-binding and catalytic activity. Structures and kinetic studies provide an explanation for the lower affinity for the substrate and the alteration of the rate-limiting step in the reaction. Our results demonstrate that distant residues remote from the active site can have marked effects on enzyme catalysis, by driving mechanistic change through relatively minor structural perturbations. PMID- 25022224 TI - A multicentre, comparative study of Cera septal occluder versus AMPLATZER Septal Occluder in transcatheter closure of secundum atrial septal defects. AB - AIMS: To evaluate the safety and efficacy of the new Cera septal occluder (CSO) for atrial septal defect (ASD) closure as compared to the AMPLATZER Septal Occluder (ASO). METHODS AND RESULTS: A total of 405 ASD patients receiving CSO or ASO were studied. The ASDs were classified into simple defects (isolated defects <26 mm) or complex defects (isolated defects >=26 mm, large defects with a deficient rim, double or multi-fenestrated defects). Clinical and echocardiographic findings were collected before discharge, at one month, and every six months after implantation. Two hundred and five (133 females, aged 30+/ 13 years) and 200 (135 females, aged 28+/-14 years) patients received CSO and ASO implants, respectively. The CSO group had similar ASD and device sizes, prevalence of complex lesions, procedural times and success rates as compared to the ASO group. Echocardiographic follow-up at one and six months showed similar residual shunts between devices. Both groups had similar rates for device embolisation and atrial arrhythmia. The average equipment cost per patient was lower in the CSO group than in the ASO group (US $3,500 vs. US$5,600, p<0.001). CONCLUSIONS: Transcatheter ASD closure with CSO is safe and effective. It appears to be an attractive alternative to ASO because of its relatively low cost. PMID- 25022222 TI - Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. AB - Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases. PMID- 25022225 TI - MitraClip repair of a "trileaflet" regurgitant mitral valve. PMID- 25022226 TI - Incidence, predictors, and impact of neurological events in non-ST-segment elevation acute coronary syndromes: the ACUITY trial. AB - AIMS: We sought to describe the incidence, predictors, and impact of adverse neurological events (NE) in a non-ST-segment elevation acute coronary syndromes (NSTEACS) population undergoing percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or medical therapy (MT). METHODS AND RESULTS: 13,819 patients with moderate and high-risk NSTEACS were enrolled in the prospective ACUITY trial. Angiography was performed within 72 hours of presentation, after which 7,789 patients (56.4%) underwent PCI, 1,539 (11.1%) underwent CABG, and 4,491 (32.5%) received MT. The rate of NE (stroke or transient ischaemic attack) at 30 days and one year and its relationship to adverse ischaemic events, including death, were assessed. Thirty-day rates of NE were 1.1% with CABG, 0.3% with PCI, and 0.5% with MT (p<0.001). One-year rates of NE were 1.1% with CABG, 0.3% with PCI, and 0.6% with MT (p<0.001). Independent predictors of NE at 30 days and one year included age, renal insufficiency, baseline troponin elevation, and initial treatment with CABG. The occurrence of NE was a strong independent predictor of death at 30 days and one year (HR 4.07, 95% CI [1.49, 11.11], p=0.006, and HR 4.25, 95% CI [2.37, 7.62], p<0.001, respectively). CONCLUSIONS: In the large-scale ACUITY trial, CABG was associated with a higher risk of NE at 30 days and one year compared to PCI and MT. The occurrence of NE in patients with NSTEACS was strongly associated with increased early and late mortality. Clinical Trials.gov Identifier NCT00093158. PMID- 25022227 TI - Percutaneous extraction of pacing leads from the left coronary artery and left ventricle. PMID- 25022228 TI - TRINITY heart valve prosthesis: a novel repositionable and retrievable transapical transcatheter aortic valve system. AB - AIMS: Transcatheter aortic valve implantation (TAVI) has become a viable option for selected high-risk patients with severe and symptomatic aortic stenosis. First- and second-generation TAVI devices are either self- or balloon-expandable, and are often not repositionable or not fully retrievable, leading to suboptimal positioning in some cases. This may result in paravalvular regurgitation, AV conduction delay, or compromise of coronary perfusion. A broader application of TAVI requires advances in both valve and delivery systems. Therefore, in order to facilitate accurate positioning, to minimise paravalvular leakage, possibly to reduce the risk of AV conduction delay, and possibly to be able to abort the procedure, a "next-generation" TAVI system has been developed which is repositionable and retrievable, the TRINITY heart valve system. METHODS AND RESULTS: The TRINITY heart valve system was implanted in a first-in-human study using the transapical approach to demonstrate feasibility and procedural success. All endpoints were adjudicated according to VARC definitions at seven and 30 days. The TRINITY heart valve system was implanted in a 74-year-old patient with severe symptomatic aortic valve stenosis. In this case, repositioning of the TRINITY resulted in optimal position without paravalvular leakage and with perfect function. CONCLUSIONS: The TRINITY heart valve is a repositionable and retrievable TAVI system. Both the implantation result and short-term clinical and haemodynamic outcome were excellent. PMID- 25022229 TI - Preserved endothelial vasomotor function after everolimus-eluting stent implantation. AB - AIMS: To compare the degree of endothelial dysfunction (ED) in patients treated with everolimus-eluting stent (EES) versus bare metal stent (BMS) implantation. METHODS AND RESULTS: This is an observational study. A total of 30 elective patients (15 treated with EES and 15 with BMS) were recruited. All patients underwent coronary angiography and intracoronary acetylcholine (Ach) test at different doses at six months after stent implantation. Quantitative coronary angiography analysis was performed to evaluate the changes in mean luminal diameter (MLD) of the segments distal to the distal stent edge after increasing doses of Ach. Both EES and BMS groups had similar baseline characteristics except for stent length (18.6+/-2.5 vs. 16.5+/-2.5 mm; p=0.033) and diameter (3.1+/-0.2 vs. 3.4+/-0.3 mm; p=0.007). The vasomotion test showed that EES had 3.14% of MLD decrease after Ach infusion and BMS had 2.35% of vasoconstriction (p=0.62). After adjustment for baseline characteristics, no statistical difference was observed between groups. CONCLUSIONS: In our study EES implantation was associated with a low degree of ED and had a similar vasomotion response as compared to BMS. Prospective randomised investigations are warranted to confirm these findings. PMID- 25022230 TI - Balloon kyphoplasty for osteoporotic spinal fractures with middle column compromise. AB - BACKGROUND: Balloon kyphoplasty (BKP) is an effective method for osteoporotic vertebral compression fractures. However osteoporotic spinal fractures with middle column compromise are mentioned as a relative contraindication to BKP. Thus we investigated the safety and efficacy of BKP in the treatment of osteoporotic spinal fractures with middle column compromise but without neurological deficit. METHODS: In this retrospective study, 45 patients who suffered osteoporotic fractures with middle column compromise but without neurological deficits were treated by BKP from May 2007 to December 2010. The final follow-ups were finished during the time of July 2011-September 2011. The mean follow-up period was 20.2 months. The height of the compromised vertebral body, the kyphotic angle and spinal canal compromise were measured before surgery, one day after surgery, and at the final follow-up. A visual analogue scale (VAS) and the Oswestry disability index (ODI) were chosen to evaluate pain and functional activity. RESULTS: The mean VAS and ODI scores improved significantly from pre- to post-operation (p<0.05), and this improvement was sustained at the final follow-up. The mean anterior vertebral body height ratio improved from 57.6%+/- 11.8% preoperatively to 86.2%+/- 12.2% postoperatively (p<0.05), so did the mean middle vertebral body height ratio. The kyphotic angle improved from 16.3 degrees +/- 3.7 degrees preoperatively to 9.3 degrees +/- 2.6 degrees postoperatively (p<0.05). At final follow-up, BKP stabilised vertebral height and prevented further kyphotic deformity. While there were no differences in spinal canal compromise between pre-operation and one day after surgery (p>0.05), there was a significant difference from the measurement at the final follow-up (p<0.05). CONCLUSION: BKP is a safe and effective method for osteoporotic spinal fractures with middle column compromise but without neurological deficit. Spontaneous remodelling of the spinal canal also occurs after BKP. PMID- 25022231 TI - Transition overtime in household latrine use in rural Bangladesh: a longitudinal cohort study. AB - BACKGROUND: In a low-income country like Bangladesh, where the poverty rate is higher in rural compared to urban areas, the consistent use of sanitary latrines over time is a challenge. To address this issue, the Water, Sanitation, and Hygiene (WASH) program of the Bangladesh Rural Advancement Committee (BRAC) was devised to improve health of the rural poor through enhanced sanitation services, such as by providing loans or education. Sanitary latrine use in households and changes over time were assessed in this study. METHODS: This was a longitudinal cohort study of the baseline, midline, and end line status of the WASH project. Households assessed in all three rounds of surveys (26,404 in each survey) were included in the analysis. Thirty thousand households from 50 upazilas (sub districts) were selected in two stages: i) thirty villages were selected from each of the 50 upazilas by cluster sampling, and ii) twenty households were chosen systematically from each selected village. A female member capable of providing household-level information was interviewed from each house using the pre-tested questionnaire. Spot observations of some components were made to assess the quality of sanitary latrine use. The adjusted log-binomial regression was performed and risk ratios with 95% confidence intervals were estimated for sanitary latrine use. Data were analyzed using Statistical Package for the Social Sciences (SPSS) and Stata software. RESULTS: The use of sanitary latrines by households increased significantly from the baseline (31.7%) to midline (41.5%) and end line (57.4%) assessment points. The proportion of physically verified clean latrines increased significantly from 33.4% at baseline to 50.8% at the midline and 53.3% at the end line. Analysis of changes in latrine-use showed that 73.3% of the baseline latrine-using households continued to do so at the end line, while the rest switched to unsanitary practices. Households with better socioeconomic status were more likely to use sanitary latrines. CONCLUSION: There are improvements in ownership and use of sanitary latrines by households over the years in WASH intervention areas. However, switching of some households from sanitary to unsanitary latrines remains a matter of concern regarding sustainability. PMID- 25022232 TI - Simulation of the tensile properties of silica aerogels: the effects of cluster structure and primary particle size. AB - A new two-level model is proposed to investigate the relationship between the mechanical properties and microstructure of silica aerogels. This two-level model consists of the particle-particle interaction model and the cluster structure model. The particle-particle interaction model is proposed to describe interactions between primary particles, in which the polymerization reaction between primary particles is considered. The cluster structure model represents the geometrical structure of silica aerogels, and it is established using a modified diffusion-limited colloid aggregation (DLCA) algorithm. This two-level model is used to investigate the tensile behavior of silica aerogels based on the discrete element method (DEM). The numerical results show that the primary particle size has significant effects on the elastic modulus and tensile strength of silica aerogels. Moreover, the power-law relationships between tensile properties and aerogel density are dependent on the variation of the primary particle radius with density. The present results can explain the difference among different experimental exponents to a certain extent. In comparison with experimental data within a wide density range, this two-level model provides good quantitative estimations of the elastic modulus and tensile strength of silica aerogels after the size effects of the primary particle are considered. This paper provides a fundamental understanding of the relationship between the mechanical properties and microstructure of silica aerogels. The two-level model can be extended to study the mechanical properties of other aerogels and aerogel composites. PMID- 25022235 TI - Liver transplantation in case of acetaminophen poisoning: importance of assessment of the colon if arterial lactate increases despite appropriate care. PMID- 25022236 TI - Increased levels of rivaroxaban in patients after liver transplantation treated with cyclosporine A. PMID- 25022237 TI - Relationship between conventional coagulation tests and bleeding for 600 consecutive liver transplantations. PMID- 25022238 TI - Risk for BK viremia and nephropathy after desensitization. PMID- 25022239 TI - The authors' reply. PMID- 25022240 TI - Noncoding RNAs as emerging regulators of Plasmodium falciparum virulence gene expression. AB - The eukaryotic unicellular pathogen Plasmodium falciparum tightly regulates gene expression, both during development and in adaptation to dynamic host environments. This regulation is evident in the mutually exclusive expression of members of clonally variant virulence multigene families. While epigenetic regulators have been selectively identified at active or repressed virulence genes, their specific recruitment remains a mystery. In recent years, noncoding RNAs (ncRNAs) have emerged as lynchpins of eukaryotic gene regulation; by binding to epigenetic regulators, they provide target specificity to otherwise non specific enzyme complexes. Not surprisingly, there is great interest in understanding the role of ncRNA in P. falciparum, in particular, their contribution to the mutually exclusive expression of virulence genes. The current repertoire of P. falciparum ncRNAs includes, but is not limited to, subtelomeric ncRNAs, virulence gene-associated ncRNAs and natural antisense RNA transcripts. Continued improvement in high-throughput sequencing methods is sure to expand this repertoire. Here, we summarize recent advances in P. falciparum ncRNA biology, with an emphasis on ncRNA-mediated epigenetic modes of gene regulation. PMID- 25022242 TI - A case of bacterial meningitis complicated by venous sinus thrombosis. PMID- 25022241 TI - Leptomeningeal metastasis from solid tumors: a diagnostic and therapeutic challenge. AB - Leptomeningeal metastasis (LM) is a severe complication in the natural history of malignancies that occurs in 4-15 % of patients (pts) with solid tumors. Clinical presentation, cerebrospinal fluid cytology (CSF), and gadolinium magnetic resonance imaging (gdMRI) of the brain and spine are the methods routinely used to diagnose LM. Treatment encompasses involved-field radiotherapy of bulky or symptomatic disease sites and chemotherapy; however, no standard therapy has been established yet. We collected and reviewed retrospectively the clinical, pathological, radiological findings as well as the outcomes of 50 consecutive patients with LM from solid tumors to determine whether the diagnostic modalities and therapeutic procedures affected the outcomes. The results of this study confirm the role of gdMRI in the diagnosis of LM in clinical practice and suggest that an aggressive treatment may improve survival in patients with this debilitating and increasingly frequent neurological complication. PMID- 25022243 TI - Effects of spray application of lanthanum and cerium on yield and quality of Chinese cabbage (Brassica chinensis L) based on different seasons. AB - The use of single light rare earth elements in agriculture was studied using the application of single rare earth elements (La and Ce) to Chinese cabbage (Brassica chinensis L.) in field plot experiments where the soil conditions remained the same but the season (spring or autumn) in which application occurred was altered. The results showed that the Chinese cabbage's nutrition quality between the two seasons had obvious differences. When planted in the autumn, the soluble sugar and vitamin C content was higher, the titratable acid and nitrate content was lower, and the ratio of sugar to acid was higher, while when planted in spring, the situation was opposite. La or Ce treatments in spring and autumn promoted the growth of the Chinese cabbage, the fresh and dry weight of the stems and leaves increased, the ratio of dry to fresh weight increased, and the observed effects were greater in the Ce treatments than the La treatments. Moreover, the soluble sugar content increased and the titratable acid content decreased, which meant that the ratio of sugar to acid increased. There was an increase in the vitamin C and nitrate content in the spring Chinese cabbage, while there was a decrease in the vitamin C and nitrate content in the autumn. The levels of the heavy metals Cu, Zn, Cd, Pb, and Ni decreased. The La treatment had greater effects on the spring Chinese cabbage, while the Ce affected the autumn Chinese cabbage more. PMID- 25022244 TI - Moderate zinc supplementation during prolonged steroid therapy exacerbates bone loss in rats. AB - The present study was conducted to understand the influence of zinc on bone mineral metabolism in prednisolone-treated rats. Disturbance in bone mineral metabolism was induced in rats by subjecting them to prednisolone treatment for a period of 8 weeks. Female rats aged 6-8 weeks weighing 150 to 200 g were divided into four treatment groups, viz., normal control, prednisolone-treated (40 mg/kg body weight orally, thrice a week), zinc-treated (227 mg/L in drinking water, daily), and combined prednisolone + zinc-treated groups. Parameters such as changes in mineral levels in the bone and serum, bone mineral density (BMD), bone mineral content (BMC), and bone 99m-technetium-labeled methylene diphosphonate ((99m)Tc-MDP) uptake were studied in various treatment groups. Prednisolone treatment caused an appreciable decrease in calcium levels both in the bone and serum and also in bone dry weight, BMC, and BMD in rats. Prednisolone-treated rats when supplemented with zinc showed further reduction in calcium levels, bone dry weight, BMD, and BMC. The study therefore revealed that moderate intake of zinc as a nutritional supplement during steroid therapy could enhance calcium deficiency in the body and accelerate bone loss. PMID- 25022245 TI - Evaluation of lactobacilli from human sources for uptake and accumulation of selenium. AB - The trace mineral selenium (Se) is currently in demand for health supplements for human and animal nutrition. In the present study, 25 isolates of Lactobacillus species of human origin from Indian population were screened for their ability to uptake and accumulate Se in a more bioavailable form. Total Se accumulated by cells was measured by inductively coupled plasma emission spectrometry (ICPES) after wet digestion of Se-enriched cultures. Ten out of 25 isolates grew luxuriantly, as red pigmented colonies, on medium amended with different concentrations of sodium selenite. All the strains when grown in a culture medium supplemented with 10 MUg/mL sodium selenite (corresponding to 4.5 MUg/mL Se) resulted in Se accumulation in the range of 129.5 to 820.0 MUg/g of dry weight (d.w.) as measured using the ICPES method. Elemental Se produced due to reduction of sodium selenite by bacteria was seen as irregular globules under the scanning electron microscope (SEM). Out of all the tested cultures, Lactobacillus reuteri NCDC77 was found to have the greatest ability to uptake Se (28.8% of inorganic Se in medium) and total Se accumulated was up to 820 MUg/g d.w., significantly higher than that of control (742.5 MUg/g d.w.). The findings of present study indicate that lactobacilli from human sources have the ability for uptake and accumulation of Se, and the prolific strain has the potential to be explored as an alternative source of organic dietary Se. PMID- 25022247 TI - Hepatoprotective effects of Solanum nigrum Linn fruits against cadmium chloride toxicity in albino rats. AB - The present work is aimed to investigate the toxicity of 1/20 LD50 of cadmium chloride (CdCl2) on male albino rats by oral ingestion and to determine the hepatoprotective effect of Solanum nigrum Linn (SN) dried fruits and their ethanolic extract against CdCl2 toxicity using biochemical parameters. Rats were divided into six groups; the first group is control, second group is CdCl2 intoxicated rats, third group is fed with a semi-modified diet with S. nigrum fruits, fourth group rats ingested with dried extract, and intoxicated rats (groups 5 and 6) were treated with fruits and ethanolic extract of S. nigrum, respectively. The results showed that rats exposed to CdCl2 induced remarkable decrease in body weight gain, feed efficiency, and Hb, Hct, RBC, and WBC count and MCHC, but increase in MCV and MCH values. In the case of plasma enzymes, there were significant stimulations observed in ALT and AST, acid phosphatase, alkaline phosphatase, and LDH activities of CdCl2-intoxicated rats (group 2) compared to control (group 1). Plasma protein profile showed decreases in total soluble protein and albumin; also globulin content was decreased by CdCl2 ingestion. Under the same condition, plasma total bilirubin and glucose levels were increased in group 2. In addition, lipid peroxidation and antioxidative system (GSH, catalase, and SOD) of liver were harmed by CdCl2 ingestion. Whereas, normal rats treated with SN showed insignificant changes in groups 3 and 4 as compared to control (group 1). The treatment with dried fruits and their ethanolic extract in CdCl2-intoxicated rats (groups 5 and 6) ameliorated and improved these harmful effects in all above parameters either for blood or liver. The results of this study suggest the protective effect of S. nigrum against liver injury happened by CdCl2 which may be attributed to its hepatoprotective activity and thereby. PMID- 25022246 TI - The protective effect of Physalis peruviana L. against cadmium-induced neurotoxicity in rats. AB - The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p < 0.05) reduction in dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in cerebellum, hippocampus, and cerebral cortex and enhanced significantly (p < 0.05) the levels of lipid peroxidation and nitric oxide in the brain. Cadmium treatment also decreased the amount of nonenzymatic and enzymatic antioxidants significantly (p < 0.05). Pretreatment with MEPh resulted in significant (p < 0.05) decreases in lipid peroxidation and nitric oxide levels and restored the amount of glutathione successfully. Although, preadministration of MEPh also brought the activities of cellular antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase significantly (p < 0.05) to the control levels, as well as the levels of Ca(2+), Cl(-), DA, 5-HT, and serotonin metabolite, 5-HIAA. These data indicated that Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats. PMID- 25022248 TI - Evidence for diminished multisensory integration in autism spectrum disorders. AB - Individuals with autism spectrum disorders (ASD) exhibit alterations in sensory processing, including changes in the integration of information across the different sensory modalities. In the current study, we used the sound-induced flash illusion to assess multisensory integration in children with ASD and typically-developing (TD) controls. Thirty-one children with ASD and 31 age and IQ matched TD children (average age = 12 years) were presented with simple visual (i.e., flash) and auditory (i.e., beep) stimuli of varying number. In illusory conditions, a single flash was presented with 2-4 beeps. In TD children, these conditions generally result in the perception of multiple flashes, implying a perceptual fusion across vision and audition. In the present study, children with ASD were significantly less likely to perceive the illusion relative to TD controls, suggesting that multisensory integration and cross-modal binding may be weaker in some children with ASD. These results are discussed in the context of previous findings for multisensory integration in ASD and future directions for research. PMID- 25022249 TI - Observation of Spontaneous Expressive Language (OSEL): a new measure for spontaneous and expressive language of children with autism spectrum disorders and other communication disorders. AB - A new language measure, the Observation of Spontaneous Expressive Language (OSEL), is intended to document spontaneous use of syntax, pragmatics, and semantics in 2-12-year-old children with Autism Spectrum Disorder (ASD) and other communication disorders with expressive language levels comparable to typical 2-5 year olds. Because the purpose of the OSEL is to provide developmental norms for use of language, the first step involves assessment of the scale's feasibility, validity, and reliability using a sample of 180 2-5 year-old typically developing children. Pilot data from the OSEL shows strong internal consistency, high reliabilities and validity. Once replicated with a large population-based sample and in special populations, the scale should be helpful in designing appropriate interventions for children with ASD and other communication disorders. PMID- 25022250 TI - Personality Pathology of Adults With Autism Spectrum Disorder Without Accompanying Intellectual Impairment in Comparison to Adults With Personality Disorders. AB - Differentiating autism spectrum disorders (ASDs) without accompanying intellectual impairment from personality disorders is often challenging. Identifying personality traits and personality pathology specific to ASD might facilitate diagnostic procedure. We recruited a sample of 59 adults with ASD without accompanying intellectual impairment, 62 individuals with narcissistic personality disorder, 80 individuals with borderline personality disorder, and 106 nonclinical controls. Personality traits, measured with the neo-personality inventory-revised (NEO-PI-R), and personality pathology, measured with the dimensional assessment of personality pathology (DAPP-BQ), were assessed. Personality traits and personality pathology specific to ASD could be identified. ASD individuals scored significantly lower on the NEO-PI-R scales extraversion and openness to experience and significantly higher on the DAPP-BQ scales inhibitedness and compulsivity relative to all other groups. Diagnostic implications are discussed. PMID- 25022251 TI - Brief report: independent validation of autism spectrum disorder case status in the Utah Autism and Developmental Disabilities Monitoring (ADDM) Network Site. AB - An independent validation was conducted of the Utah Autism and Developmental Disabilities Monitoring Network's (UT-ADDM) classification of children with autism spectrum disorder (ASD). UT-ADDM final case status (n = 90) was compared with final case status as determined by independent external expert reviewers (EERs). Inter-rater reliability (ICC = 0.84), specificity [0.83 (95 % CI 0.74 0.90)], and sensitivity [0.99 (95 % CI 0.96-1.00)] were high for ASD case versus non-case classification between UT-ADDM and EER. At least one EER disagreed with UT-ADDM on ASD final case status on nine out of 30 records; however, all three EERs disagreed with UT-ADDM for only one record. Findings based on limited data suggest that children with ASD as identified by UT-ADDM are consistently classified as ASD cases by independent autism experts. PMID- 25022252 TI - Visuo-spatial performance in autism: a meta-analysis. AB - Visuo-spatial skills are believed to be enhanced in autism spectrum disorders (ASDs). This meta-analysis tests the current state of evidence for Figure Disembedding, Block Design, Mental Rotation and Navon tasks in ASD and neurotypicals. Block Design (d = 0.32) and Figure Disembedding (d = 0.26) showed superior performance for ASD with large heterogeneity that is unaccounted for. No clear differences were found for Mental Rotation. ASD samples showed a stronger local processing preference for Navon tasks (d = 0.35); less clear evidence for performance differences of a similar magnitude emerged. We discuss the meta analysis results together with other findings relating to visuo-spatial processing and three cognitive theories of ASD: Weak Central Coherence, Enhanced Perceptual Functioning and Extreme Male Brain theory. PMID- 25022253 TI - The factors predicting stress, anxiety and depression in the parents of children with autism. AB - The factors predicting stress, anxiety and depression in the parents of children with autism remain poorly understood. In this study, a cohort of 250 mothers and 229 fathers of one or more children with autism completed a questionnaire assessing reported parental mental health problems, locus of control, social support, perceived parent-child attachment, as well as autism symptom severity and perceived externalizing behaviours in the child with autism. Variables assessing parental cognitions and socioeconomic support were found to be more significant predictors of parental mental health problems than child-centric variables. A path model, describing the relationship between the dependent and independent variables, was found to be a good fit with the observed data for both mothers and fathers. PMID- 25022254 TI - Impact of comorbidity on survival after palliative radiotherapy. AB - PURPOSE: To evaluate prognostic factors for survival after palliative radiotherapy (PRT) with consideration of different comorbidities and the Charlson comorbidity index (CCI). PATIENTS AND METHODS: Between 2007 and 2012, 525 consecutive patients were treated with PRT and included in this retrospective study. Most patients received PRT for bone metastases, for brain metastases, or in order to improve thoracic symptoms from lung cancer. Median age was 69 years. Uni- and multivariate analyses were performed. RESULTS: Only 7% of patients had no comorbidity. A CCI of 1-2 was present in 49%, a CCI of 3-4, in 36%, and a higher CCI in 9% of patients. Younger patients, female patients, and patients who had not been smokers had significantly less comorbidity. Patients without comorbidity had significantly better median performance status (PS) and were more likely to receive palliative systemic therapy. Both lower CCI and absence of more than one cancer diagnosis independently predicted longer survival. Further significant parameters in multivariate analysis were PS and number of organs with metastatic involvement. Exploratory analyses suggested that the impact of CCI was largest in patients older than 60 years and was absent in those with brain metastases. CONCLUSION: We recommend assessment of comorbidity when prescribing PRT and selecting the optimal fractionation regimen, because most patients with severe comorbidities had limited survival. One of the possible explanations could be that only a minority of these patients are fit for systemic therapy, which plays an important role in the overall treatment concept. PMID- 25022255 TI - Diverse and dynamic sources and sinks in gradient formation and directed migration. AB - The traditional view of directional cell migration within a tissue is that it requires a gradient of a soluble attractive chemical that is stable in space and time due to the presence of a source and a sink. However, advances in live imaging technology and the ability to study cell migration in vivo have revealed that endogenous sources and sinks are typically far more varied and complex. Both sources and sinks can be made up of multiple tissues. During long-range migrations, cells tend to divide up their trajectories and follow different source signals in each segment. When a single source signal is used repeatedly in each segment, its expression is dynamically controlled. Source signals can also originate locally from neighboring migrating cells. Sinks are important in some cases but not all, to sculpt a permissive migratory path or allow cells to move from one intermediate target to another. Migrating cells themselves can function as sinks to create a gradient out of an initially uniform chemoattractant. These diverse ways of building sources and sinks allow different cell types to navigate distinct trajectories through the same embryo even as the whole embryo undergoes the dramatic changes in cell number, position, arrangement and fate that are the essence of development. PMID- 25022256 TI - What is the risk of clinical anastomotic leak in the diverted colorectal anastomosis? AB - OBJECTIVE: The objective of this study was to identify clinical leak in diverted colorectal anastomoses. DESIGN: Cohort analysis. SETTING: The study was conducted in a subspecialty practice at a tertiary care facility. PATIENTS: Consecutive subjects undergoing colorectal anastomosis and proximal fecal diversion between July 16, 2007 and June, 31 2012. INTERVENTIONS: No intervention was applied. MAIN OUTCOME MEASURES: Clinical anastomotic leak. RESULTS: Two hundred forty-five patients underwent a colorectal anastomosis with proximal fecal diversion. A total of 34 (14%) clinical leaks were identified at a median of 43 days. Clinical leaks were identified in 13 (5%) patients within 30 days of surgery (early leaks) and in 21 (9%) patients after 30 days of surgery (late leaks). Age, sex, use of neoadjuvant chemoradiotherapy, and method of anastomotic construction were similar in patients with clinical leaks as compared to those with no evidence of leak. However, clinical leaks were more likely to develop in patients with a diagnosis of inflammatory bowel disease or other diagnoses, i.e., radiation enteritis, ischemia, and injury/enterotomy. Patients with clinical leak were not more likely to have air leaks on intraoperative air leak testing. CONCLUSIONS: In diverted anastomoses, most leaks become clinically apparent beyond 30 days. The standard practice of censoring outcomes that occur beyond postoperative day 30 will fail to identify a substantial fraction of leaks in diverted colorectal anastomoses. PMID- 25022257 TI - Mitochondrial neuro-gastrointestinal encephalomyopathy presenting with recurrent bowel perforations and intra-abdominal abscesses. AB - INTRODUCTION: Mitochondrial neuro-gastrointestinal encephalomyopathy syndrome (MNGIE syndrome) is a rare genetic disorder that is defined clinically by severe gastrointestinal dysmotility, cachexia, peripheral neuropathy, ptosis and/or ophthalmoparesis, and leukoencephalopathy. CASE REPORT: We report a case of a 26 year-old man with MNGIE syndrome with a unique clinical picture consisting of recurrent episodes of spontaneous bowel perforation and multiple intra-abdominal abscesses. The patient was admitted to our hospital several times in the past few years and underwent urgent laparotomies due to perforations in the small bowel. CONCLUSION: Case reports regarding bowel perforations in MNGIE syndrome are scarce and mostly relate to a single perforation and attributed to chronic pseudo obstruction of the small bowel. To the best of our knowledge, there are no case reports regarding recurrent perforations and abscesses. Surgical management of these cases is challenging as there is no curative option for this genetic disorder. Primary care physicians and treating gastroenterologists should be aware of the potential surgical emergencies associated with this disorder. PMID- 25022258 TI - Metabolic changes of Vitis vinifera berries and leaves exposed to Bordeaux mixture. AB - Since the development of Bordeaux mixture in the late 1800's, copper-based fungicides have been widely used against grapevine (Vitis vinifera L.) diseases, mainly in organic but also in conventional viticulture; however their intensive use has raised phytotoxicity concerns. In this study, the composition of grape berries and leaves upon Bordeaux mixture treatment was investigated during the fructification season by a metabolomic approach. Four applications of Bordeaux mixture till 3 weeks before harvest were performed following the regular management practices of organic viticulture. Results showed that the copper-based treatment affected the content in sugars, organic acids, lipids and flavan-3-ols of grapes and leaves at specific developmental stages. Nonetheless, the levels of sucrose, glucose and fructose, and of tartaric and malic acids were not significantly affected in mature grapes. In contrast, a sharp decrease in free natural amino acids was observed, together with a reduction in protein content and in mineral nitrogen forms. The treatment with Bordeaux mixture increased by 7 fold the copper levels in tissue extracts from surface-washed mature berries. PMID- 25022259 TI - Soft Robotics: New Perspectives for Robot Bodyware and Control. AB - The remarkable advances of robotics in the last 50 years, which represent an incredible wealth of knowledge, are based on the fundamental assumption that robots are chains of rigid links. The use of soft materials in robotics, driven not only by new scientific paradigms (biomimetics, morphological computation, and others), but also by many applications (biomedical, service, rescue robots, and many more), is going to overcome these basic assumptions and makes the well-known theories and techniques poorly applicable, opening new perspectives for robot design and control. The current examples of soft robots represent a variety of solutions for actuation and control. Though very first steps, they have the potential for a radical technological change. Soft robotics is not just a new direction of technological development, but a novel approach to robotics, unhinging its fundamentals, with the potential to produce a new generation of robots, in the support of humans in our natural environments. PMID- 25022260 TI - Engineering a better health care system: a report from the President's Council of Advisors on Science and Technology. PMID- 25022262 TI - Increased oxidative DNA damage seen in renal biopsies adjacent stones in patients with nephrolithiasis. AB - Urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, is significantly higher in nephrolithiasis patients than in healthy individuals, indicating that these patients have higher degree of oxidative stress. In the present study, we investigated 8-OHdG expression in renal biopsies of patients with nephrolithiasis and in renal tubular cells (HK-2 cells) exposed to calcium oxalate monohydrate (COM). We performed immunohistochemical staining for 8-OHdG in renal biopsies adjacent stones obtained from 28 patients with nephrolithiasis. Controls were noncancerous renal tissues from nephrectomies of patients with renal cancer. 8-OHdG was overexpressed in the nucleus of renal tubular cells in patients with nephrolithiasis compared with controls. Only one nephrolithiasis biopsy was negative for 8-OHdG, whereas in 19 cases 8-OHdG was highly expressed. The level of expression of 8-OHdG among patients with calcium oxalate (mostly mixed with calcium phosphate) and uric acid stones was not significantly different. Increased leukocyte infiltration was observed in renal tissues from patients with nephrolithiasis. Exposure of HK-2 cells to COM caused increased intracellular reactive oxygen species and nuclear expression of 8-OHdG. To our knowledge, this is the first report of increased 8-OHdG expression in renal tubular cells of patients with nephrolithiasis. In vitro, COM crystals were capable of inducing oxidative damage of DNA in the proximal renal tubular cells. PMID- 25022261 TI - Germ-line and somatic DICER1 mutations in pineoblastoma. AB - Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours. PMID- 25022263 TI - Pediatric urolithiasis: metabolic risk factors and follow-up results in a Turkish region with endemic stone disease. AB - The goal of this study was to investigate the metabolic etiology, clinical findings and medical treatment of children with urolithiasis in an endemic region of Turkey. We retrospectively analyzed the medical records of 742 (437 males, 305 females) children with urolithiasis. Physical examination results, serum biochemistry and urine metabolic evaluation, including urinary citrate, oxalate, calcium, uric acid, cystine and magnesium levels were recorded. We obtained follow-up records in 316 patients to evaluate the association between stone recurrence and metabolic risk factors. The mean age at diagnosis was 2.6 +/- 3.4 (0.1-17.0) years. Male-to-female ratio was 1.4:1. A family history of stone disease was found in 76.5 % of patients and 41 % of parents had consanguineous marriage. The most common presenting symptoms were urinary tract infection (UTI, 23.9 %) and hematuria (23.6 %). Metabolic abnormalities were found in 588 (79.2 %) patients, including hypercalciuria in 31.5 %, hypocitraturia in 24.2 %, hyperoxaluria in 11.4 %, hyperuricosuria in 9.1 %, hypomagnesuria in 3.9 %, and cystinuria in 3.1 % of patients. The frequency of hyperoxaluria and hypocitraturia were significantly higher in patients with new stone formation. Follow-up records of 316 (42.6 %) patients (192 males, 124 females) were available. Urolithiasis was shown in 135 (42.7 %) of the patients on control ultrasonography, and 61.5 % of these patients had a stone size <= 3 mm. Hyperoxaluria and cystinuria were significantly higher in patients with stone persistence. The main goal of management for children with urolithiasis should be identification of risk factors. PMID- 25022264 TI - Occurrence and characterization of Candida nivariensis from a culture collection of Candida glabrata clinical isolates in Malaysia. AB - BACKGROUND: Candida nivariensis and C. bracarensis have been recently identified as emerging yeast pathogens which are phenotypically indistinguishable from C. glabrata. However, there is little data on the prevalence and antifungal susceptibilities of these species. OBJECTIVE: This study investigated the occurrence of C. nivariensis and C. bracarensis in a culture collection of 185 C. glabrata isolates at a Malaysian teaching hospital. METHODS: C. nivariensis was discriminated from C. glabrata using a PCR assay as described by Enache Angoulvant et al. (J Clin Microbiol 49:3375-9, 2011). The identity of the isolates was confirmed by sequence analysis of the D1D2 domain and internal transcribed spacer region of the yeasts. The isolates were cultured on Chromogenic CHROMagar Candida ((r)) agar (Difco, USA), and their biochemical and enzymic profiles were determined. Antifungal susceptibilities of the isolates against amphotericin B, fluconazole, voriconazole and caspofungin were determined using E tests. Clotrimazole MICs were determined using a microbroth dilution method. RESULTS: There was a low prevalence (1.1 %) of C. nivariensis in our culture collection of C. glabrata. C. nivariensis was isolated from a blood culture and vaginal swab of two patients. C. nivariensis grew as white colonies on Chromogenic agar and demonstrated few positive reactions using biochemical tests. Enzymatic profiles of the C. nivariensis isolates were similar to that of C. glabrata. The isolates were susceptible to amphotericin B, fluconazole, voriconazole and caspofungin. Clotrimazole resistance is suspected in one isolate. CONCLUSION: This study reports for the first time the emergence of C. nivariensis in our clinical setting. PMID- 25022265 TI - The Japanese Breast Cancer Society clinical practice guideline for radiotherapy of breast cancer. PMID- 25022266 TI - The Japanese Breast Cancer Society Clinical Practice Guideline for pathological diagnosis of breast cancer. PMID- 25022267 TI - "They think surgery is just a quick fix". AB - BACKGROUND: To prevent weight regain, patients undergoing weight loss surgery are encouraged to change their exercise and dietary habits. Building on previous research, the aim of this study was to explore women's experiences of changing exercise habits - focusing on women participating in a group based rehabilitation program including surgical as well as non-surgical participants. FINDINGS: Based on interviews with the 11 women included in this study, as well as participant observation, two themes were identified; 1) Pushing ones tolerance limits, and 2) Rebutting the "quick fix" fallacy. Taken together, the findings showcase how being a part of this mixed group involved having to relate to social stigmas, as well as notions regarding successful and non-successful surgical outcomes. Although such notions may be useful in identifying potential challenges related to changing exercise habits, they do not illuminate the complexity of undergoing such changes following weight loss surgery. CONCLUSION: The findings point to the need of acknowledging patients' own exceriences to determine how successful they are after surgery. Given the findings, I argue for the need to reconsider the notion of success in relation to group based interventions. PMID- 25022268 TI - A shifting sense of being: a secondary analysis and comparison of two qualitative studies on young-onset dementia. AB - The aim of the present study was to investigate and interpret metaphorical expressions of the lived experiences of everyday life in people with young-onset dementia (YOD) and to compare these findings with findings from an analysis via grounded theory to see if the second analysis adds more knowledge to the topic. In this secondary analysis of data, metaphors from 20 Norwegian men and women living with YOD were investigated. Using Steger's anthropological three-step method, three categories were identified: Sliding away, leaving traces, and all alone in the world. Comprehensively, we understood the metaphors as representing the participants' shifting sense of being. The main findings of the study show that by analysing the data by combining and using both methods, more knowledge to the topic was added. Acknowledging metaphorical expressions as a source of knowledge, this study reflects on how metaphors can be used in therapeutic dialogue. We conclude that metaphors add to the understanding of descriptions of daily life in a more existential way, beyond the results gained from the grounded theory analysis. However, the findings from the analysis via grounded theory included aspects that we did not find when analysing the metaphors. PMID- 25022269 TI - Isotretinoin use and celiac disease: a population-based cross-sectional study. AB - BACKGROUND AND AIM: Isotretinoin, a vitamin A analogue, can promote a pro inflammatory milieu in the small intestine in response to dietary antigens. We hypothesized that oral isotretinoin exposure would increase the risk of celiac disease (CD). METHODS: We contacted all 28 pathology departments in Sweden, and through biopsy reports identified 26,739 individuals with CD. We then compared the prevalence of ever using oral isotretinoin to the prevalence in 134,277 matched controls through conditional logistic regression. Data on isotretinoin exposure were obtained from the national Swedish Prescribed Drug Registry. As the only indication for isotretinoin use in Sweden is acne, we also examined its relationship to CD. Data on acne were obtained from the Swedish Patient Registry. RESULTS: Ninety-three individuals with CD (0.35 %) and 378 matched controls (0.28 %) had a prescription of isotretinoin. This corresponded to an odds ratio (OR) of 1.22 [95 % confidence interval (CI) 0.97-1.54]. Risk estimates were similar in men and women, and when we restricted our data to individuals diagnosed after the start of the Prescribed Drug Registry. Restricting our analyses to individuals diagnosed aged 12-45 years did not influence the risk estimates (OR 1.38, 95 % CI 0.97-1.97). Meanwhile, having a diagnosis of acne was positively associated with CD (OR 1.34, 95 % CI 1.20-1.51). CONCLUSIONS: This study found no association between isotretinoin use and CD, but a small excess risk of CD in patients with a diagnosis of acne. PMID- 25022270 TI - Biotechnological potential of sponge-associated bacteria. AB - As sessile and filter-feeding metazoans, marine sponges represent an ecologically important and highly diverse component of marine benthic communities throughout the world. It has been suggested that marine sponges are hosts to many microorganisms which can constitute up to 40-60% of its biomass. Recently, sponges have attracted a high interest from scientific community because two important factors. First there is the fact that sponges have a wide range of associated bacteria; and, second, they are a rich source of bioactive substances. Since 1950, a number of bioactive substances with various pharmacological functions have been isolated from marine sponges. However, many of these substances were subsequently shown to be actually synthesized by sponge associated bacteria. Bacteria associated with marine sponges constitute an interesting source of novel bioactive compounds with biotechnological potential such as antimicrobial substances, enzymes and surfactants. In addition, these bacteria may be biofilm forming and can act as bioindicators in bioremediation processes of environmental pollution caused by oil and heavy metals. This review focuses on the biotechnological applications of these microorganisms. PMID- 25022272 TI - microRNAs as new targets of dietary polyphenols. AB - In the lasts years it has become evident that polyphenols modify cell functionality through epigenetic mechanisms, such as modulating microRNA (miRNA) levels. miRNAs are small non-coding RNAs of about 22 nucleotides in length, that modulate gene expression at the post-transcriptional level. miRNAs are involved in almost all biological processes, affect most metabolic pathways and recent evidence suggests their dysregulation in a number of metabolic disorders and diseases. In this sense, miRNAs are emerging as potential biomarkers of numerous pathologies and therefore as new therapeutic targets. Polyphenolic modulation of miRNAs is very attractive as a strategy to target numerous cell processes and potentially reduce the risk of chronic diseases. PMID- 25022271 TI - Resveratrol as a gene regulator in the vasculature. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) possesses multiple protective properties in the vasculature, including anti-oxidative and anti-inflammatory effects and improvement of endothelial function. A substantial part of these effects is attributable to gene expression changes induced by the compound. Resveratrol can activate the NAD-dependent deacetylase sirtuin 1 (SIRT1), leading to deacetylation of SIRT1 target molecules such as NF-kB and forkhead box O (FOXO) transcription factors. The inhibition of NF-kB by resveratrol reduces the expression of inflammation mediators. FOXO factors are implicated in the upregulation of antioxidant enzymes and the endothelial-type nitric oxide synthase. In addition, resveratrol upregulates a number of antioxidant enzymes by activating nuclear factor-E2-related factor-2 (Nrf2) and downregulates NADPH oxidases through yet known mechanisms. PMID- 25022273 TI - Inquiry is launched into deaths at Gosport hospital where use of opiates was "almost routine". PMID- 25022275 TI - Decreased facial expression variability in patients with serious cardiopulmonary disease in the emergency care setting. AB - BACKGROUND AND OBJECTIVE: The hypothesis of the present work derives from clinical experience that suggests that patients who are more ill have less facial expression variability in response to emotional cues. METHODS: Prospective study of diagnostic accuracy from a convenience sample of adult patients with dyspnoea and chest pain in an emergency department. Patients viewed three stimulus slides on a laptop computer that were intended to evoke a change in facial affect. The computer simultaneously video recorded patients' facial expressions. Videos were examined by two independent blinded observers who analysed patients' facial expressions using the Facial Action Coding System (FACS). Patients were followed for predefined serious cardiopulmonary diagnosis (Disease+) within 14 days (acute coronary syndrome, pulmonary embolism, pneumonia, aortic or oesophageal disasters or new cancer). The main analysis compared total FACS scores, and action units of smile, surprise and frown between Disease+ and Disease-. RESULTS: Of 50 patients, 8 (16%) were Disease+. The two observers had 92% exact agreement on the FACS score from the first stimulus slide. During stimulus slide 1, the median of all FACS values from Disease+ patients was 3.4 (1st-3rd quartiles 1-6), significantly less than the median of 7 (3-14) from D-patients (p=0.019, Mann-Whitney U). Expression of surprise had the largest difference between Disease+ and Disease (area under the receiver operating characteristic curve 0.75, 95% CI 0.52 to 0.87). CONCLUSIONS: With a single visual stimulus, patients with serious cardiopulmonary diseases lacked facial expression variability and surprise affect. Our preliminary findings suggest that stimulus-evoked facial expressions from emergency department patients with cardiopulmonary symptoms might be a useful component of gestalt pretest probability assessment. PMID- 25022274 TI - Cohort Profile: The Nicotine Dependence in Teens (NDIT) Study. AB - The Nicotine Dependence in Teens (NDIT) study is a prospective cohort investigation of 1294 students recruited in 1999-2000 from all grade 7 classes in a convenience sample of 10 high schools in Montreal, Canada. Its primary objectives were to study the natural course and determinants of cigarette smoking and nicotine dependence in novice smokers. The main source of data was self report questionnaires administered in class at school every 3 months from grade 7 to grade 11 (1999-2005), for a total of 20 survey cycles during high school education. Questionnaires were also completed after graduation from high school in 2007-08 and 2011-12 (survey cycles 21 and 22, respectively) when participants were aged 20 and 24 years on average, respectively. In addition to its primary objectives, NDIT has embedded studies on obesity, blood pressure, physical activity, team sports, sedentary behaviour, diet, genetics, alcohol use, use of illicit drugs, second-hand smoke, gambling, sleep and mental health. Results to date are described in 58 publications, 20 manuscripts in preparation, 13 MSc and PhD theses and 111 conference presentations. Access to NDIT data is open to university-appointed or affiliated investigators and to masters, doctoral and postdoctoral students, through their primary supervisor (www.nditstudy.ca). PMID- 25022276 TI - The latent structure of loneliness: testing competing factor models of the UCLA Loneliness Scale in a large adolescent sample. AB - This study assessed the dimensional structure of the UCLA Loneliness Scale ([UCLA LS], UCLA-3). Data from the Northern Ireland Young Life and Times Survey (2011), a survey of 1,434 16-year-olds, was used to examine the underlying factor structure of the scale. Confirmatory factor analysis was employed to compare alternative factor analytical models that can inform the scoring of the measure and determine the degree to which different factors provided unique predictive utility. Fit statistics indicated that the best fitting model comprised three correlated factors: Isolation, Related Connectedness, and Collective Connectedness. These findings were consistent with previous findings that identified the multidimensional nature of the UCLA-LS. The study also found evidence that the subscales were differentially associated with psychiatric morbidity as measured by the General Health Questionnaire (GHQ-12) and provides a more reliable and comprehensive framework to assess the clinical significance of loneliness. PMID- 25022277 TI - Infants track the reliability of potential informants. AB - Across two eye-tracking experiments, we showed that infants are sensitive to the statistical reliability of informative cues and selective in their use of information generated by such cues. We familiarized 8-month-olds with faces (Experiment 1) or arrows (Experiment 2) that cued the locations of animated animals with different degrees of reliability. The reliable cue always cued a box containing an animation, whereas the unreliable cue cued a box that contained an animation only 25% of the time. At test, infants searched longer in the boxes that were reliably cued, but did not search longer in the boxes that were unreliably cued. At generalization, when boxes were cued that never contained animations before, only infants in the face experiment followed the reliable cue. These results provide the first evidence that even young infants can track the reliability of potential informants and use this information judiciously to modify their future behavior. PMID- 25022278 TI - Great apes generate goal-based action predictions: an eye-tracking study. AB - To examine great apes' on-line prediction of other individuals' actions, we used an eye-tracking technique and an experimental paradigm previously used to test human infants. Twenty-two great apes, including bonobos, chimpanzees, and orangutans, were familiarized to movie clips of a human hand reaching to grasp one of two objects. Then the objects' locations were swapped, and in the test event, the hand made an incomplete reach between the objects. In a control condition, a mechanical claw performed the same actions. The apes predictively looked at the familiarized goal object rather than the familiarized location when viewing the hand action in the test event. However, they made no prediction when viewing the claw action. These results are similar to those reported previously for human infants, and predictive looking did not differ among the three species of great apes. Thus, great apes make on-line goal-based predictions about the actions of other individuals; this skill is not unique to humans but is shared more widely among primates. PMID- 25022279 TI - Workaholism: are physicians at risk? AB - BACKGROUND: Work addiction (WA), often called 'workaholism', is a relatively recent concept that has not yet been clearly defined. Ongoing studies have found prevalence rates that are highly variable due to the diversity of the models used and the populations studied. AIMS: To assess the characteristics of WA among hospital medical staff. METHODS: All physicians practising at a French university hospital were invited to participate in a survey based on two questionnaires: the Work Addiction Risk Test (WART) for WA and the Job Contents Questionnaire (JCQ) to assess psychosocial constraints at work. RESULTS: There were 444 responding physicians. The response rate was 45%. Thirteen per cent of respondents were considered to be highly work addicted and a further 35% were considered mildly work addicted. Professors had the highest average WART score, but neither age nor sex was associated with WA. Furthermore, all 3D scores obtained using the JCQ correlated with the WART score; the highest correlation coefficient being obtained between the WART score and the job demands score, indicating that workaholics experienced high job demands. CONCLUSIONS: WA especially affects professors, who have the highest status amongst doctors in the hospital hierarchy. This study highlights the importance of constraints and workload, which are consistent with individual vulnerability factors. These factors may help identify ways of preventing and managing this type of addiction, through improvement of working conditions and organizational structures. PMID- 25022280 TI - Fitness, obesity and risk of heat illness among army trainees. AB - BACKGROUND: Exertional heat illness (EHI) affects military personnel, athletes and occupational groups such as agricultural workers, despite knowledge of preventive measures. AIMS: To evaluate EHI diagnoses during US Army basic training and its associations with fitness and body fat on entering military service. METHODS: From February 2005 to September 2006, US Army recruits at six different military entrance stations took a pre-accession fitness test, including a 5-min step test scored as pass or fail. Subsequent EHI incidence and incidence rate ratios were analysed with reference to subjects' fitness (step test performance) and whether they met (weight qualified [WQ]) or exceeded body fat (EBF) standards. RESULTS: Among the 8621 WQ and 834 EBF male subjects, there were 67 incidents of EHI within 180 days of entering military service. Among WQ subjects, step test failure was significantly associated with EHI (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.13, 3.53). For those passing the step test, the risk of EHI was significantly higher in EBF than in WQ subjects (OR 3.98, 95% CI 2.17, 7.29). Expected ORs for the joint effects of step test failure and EBF classification under additive and multiplicative models were 4.98 and 7.96, respectively. There were too few women to evaluate their data in detail. CONCLUSIONS: This study demonstrated that fitness and body fat are independently associated with incident EHI, and the effect of both was substantially higher. Those with low fitness levels and/or obesity should be evaluated further before engaging in intense physical activity, especially in warmer months. PMID- 25022281 TI - Psychosocial work conditions associated with sickness absence among hospital employees. AB - BACKGROUND: Meaningfulness of the job, collaboration among colleagues, trustworthiness of the closest superior and bullying have previously been shown to be major covariates of intention to quit the job. AIMS: To test if these elements of the psychosocial work environment are also the most essential covariates of sickness absence. METHODS: A cross-sectional questionnaire study of hospital employees which sought information on elements of the psychosocial work environment, general health status, life style, age, gender and profession. Data on sickness absence were obtained from the employer's salary database. RESULTS: A total of 1809 hospital employees took part with a response rate of 65%. The mean age was 43 (range: 20-69) and 75% were female. Totally, 363 study participants (20%) had at least 14 days sickness absence (defined as high absence) during the preceding year. Associations between high sickness absence and 29 psychosocial work elements were analysed, adjusting for relevant confounders. Following multiple logistic regression analysis, three elements had an independent statistically significant association with high sickness absence: no exposure to bullying (odds ratio (95% confidence interval) 0.50 (0.33-0.77)), high meaningfulness of the job (0.71 (0.52-0.97)) and high trustworthiness of the closest superior (0.70 (0.54-0.92)). CONCLUSIONS: Elements of the psychosocial work environment which have previously been shown to have a significant independent association with intention to quit the job were also the most essential covariates of high sickness absence. PMID- 25022282 TI - Biochemical parameters in the blood of Holstein calves given immunoglobulin Y supplemented colostrums. AB - BACKGROUND: In any calf rearing system it is desirable to obtain healthy animals, and reduce morbidity, mortality, and economic losses. Bovine syndesmochorial placentation prevents the direct transfer of bovine immunoglobulins to the fetus, and calves are born hypogammaglobulinemic. These calves therefore require colostrum immediately after birth. Colostrum is rich in immunoglobulins (Ig) and its consumption results in the transfer of passive immunity to calves. The Ig absorption occurs within the first 12 h after birth. Immunoglobulin Y (IgY), derived from chicken egg yolk, has been used in the prevention and control of diseases affecting calves because it is very similar in structure and function to immunoglobulin G (IgG). In the current study, we sought to establish whether administration routes of colostrum supplemented with avian IgY affected passive immunity in calves. RESULTS: No significant differences were observed with respect to route of administration for colostrum. However, we did observe some differences in certain interactions between the various treatments. Calves fed colostrum containing egg yolk had higher levels of TP, ALB, and IgG, along with increased GGT activity. CONCLUSIONS: Our results suggest that supplementing colostrum with egg yolk has a beneficial effect when given to calves, regardless of administration route. PMID- 25022284 TI - Antinociceptive effect of some extracts from Ajuga chamaecistus Ging. ssp. tomentella (Boiss.) Rech. f. aerial parts. AB - BACKGROUND: The genus Ajuga is used for the treatment of joint pain, gout, and jaundice in traditional Iranian medicine (TIM). Ajuga chamaecistus ssp. tomentella is an exclusive subspecies of Ajuga chamaecistus in the flora of Iran. The aim of this study was to evaluate antinociceptive properties of some extracts from aerial parts of A. chamaecistus ssp. tomentella. METHODS: Antinociceptive activities of total water and 80% methanol extracts, hexane, diethyl ether and n butanolic partition fractions of the methanolic extract were analyzed using the formalin test in mice. Indomethacin (10 mg/kg) and normal saline were employed as positive and negative controls, respectively. RESULTS: Oral administration of all extracts (200, 400 and 600 mg/kg) 30 min before formalin injection had no effect against the acute phase (0-5 min after formalin injection) of the formalin induced licking time, but hexane fraction (200 mg/kg) caused a significant effect (p < 0.001) on the chronic phase (15-60 min after formalin injection). Total water and diethyl ether extracts at a dose of 400 mg/kg showed a very significant analgesic activity on the chronic phase (p < 0.001 and p < 0.01, respectively). CONCLUSIONS: The results of this study suggest that the extracts of A. chamaecistus ssp. tomentella have an analgesic property that supports traditional use of Ajuga genus for joint pain and other inflammatory diseases. PMID- 25022283 TI - Laparoscopic versus open resection for gastric gastrointestinal stromal tumors: an updated systematic review and meta-analysis. AB - BACKGROUND: In past decades, laparoscopic surgery has been introduced for the treatment of gastrointestinal stromal tumors (GISTs). Recently, additional studies comparing laparoscopic versus open surgery for gastric GISTs have been published, and an updated meta-analysis of this subject is necessary. METHODS: A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. Comparative studies of laparoscopic and open surgery for gastric GISTs published before June 2014 were identified from databases. The Newcastle-Ottawa Quality Assessment Scale was used to perform quality assessment and original data were extracted. The statistical software STATA (version 12.0) was used for the meta-analysis. RESULTS: Finally, 22 studies, including a total of 1,166 cases, meet the inclusion criteria for meta-analysis. The operation time was similar between laparoscopic and open surgery. Compared to open surgery, laparoscopic resection was associated withless blood loss (WMD = -58.91 ml; 95% CI, -84.60 to 33.22 ml; P <0.01); earlier time to flatus (WMD = -1.31 d; 95% CI, -1.56 to 1.06, P <0.01) and oral diet (WMD = -1.75 d; 95% CI, -2.12 to -1.39; P <0.01); shorter hospital stay (WMD = -3.68 d; 95% CI, -4.47 to -2.88; P <0.01); and decreased overall complications (relative risk = 0.57; 95% CI, 0.37 to 0.89; P = 0.01). For long-term outcomes, there were no significant differences between two surgical procedures on recurrence. CONCLUSION: Laparoscopic surgery for gastric GISTs is acceptable for selective patients with better short-term outcomes compared with open surgery. The long-term survival situation of patients mainly depends on the nature of tumor itself, and laparoscopic surgery was not associated with worse oncological outcomes. PMID- 25022285 TI - Early decrease in carotid plaque lipid content as assessed by magnetic resonance imaging during treatment of rosuvastatin. AB - BACKGROUND: Statin therapy has shown to deplete atherosclerotic plaque lipid content and induce plaque regression. However, how early the plaque lipid depletion can occur with low-density lipoprotein cholesterol (LDL-C) lowering in humans in vivo has not been fully described. METHODS: We enrolled 43 lipid treatment naive subjects with asymptomatic carotid atherosclerosis and LDL-C >= 100 and <= 250 mg/dl. Rosuvastatin 5-20 mg/day was used to lower LDL-C levels to < 80 mg/dl. Lipid profile and carotid MRI scans were obtained at baseline, 3, 12, and 24 months. Carotid plaque lipid-rich necrotic core (LRNC) and plaque burden were measured and compared between baseline and during treatment. RESULTS: Among the 32 subjects who completed the study, at 3 months, an average dose of rosuvastatin of 11 mg/day lowered LDL-C levels by 47% (125.2 +/- 24.4 mg/dl vs. 66.7 +/- 17.3 mg/dl, p < 0.001). There were no statistically significant changes in total wall volume, percent wall volume or lumen volume. However, LRNC volume was significantly decreased by 7.9 mm3, a reduction of 7.3% (111.5 +/- 104.2 mm3 vs. 103.6 +/- 95.8 mm3, p = 0.044). Similarly, % LRNC was also significantly decreased from 18.9 +/- 11.9% to 17.9 +/- 11.5% (p = 0.02) at 3 months. Both LRNC volume and % LRNC continued to decrease moderately at 12 and 24 months, although this trend was not significant. CONCLUSIONS: Among a small number of lipid treatment naive subjects, rosuvastatin therapy may induce a rapid and lasting decrease in carotid plaque lipid content as assessed by MRI. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00885872. PMID- 25022286 TI - How are decisions on care services for people with dementia made and experienced? A systematic review and qualitative synthesis of recent empirical findings. AB - BACKGROUND: During recent decades, there has been a growing recognition that people cannot be assumed incapable of making decisions about their own care solely on the basis of a dementia diagnosis and international agreements and legislative changes have strengthened the formal right for people with dementia to participate in decisions on care services. This raises important questions about how these decisions are currently made and experienced in practice. In this review, we address this question and highlight directions for further research. METHODS: We searched CINAHL, PsycINFO, ASSIA, Social Services Abstracts, Science Direct, Academic Search Premier, and PubMed. Twenty-four pertinent articles were identified, all representing qualitative studies. Relevant findings were extracted and synthesized along dimensions of involvement of the person with dementia in decisions on care services, using an integrative approach to qualitative synthesis. RESULTS: We identified three overarching ways in which people with dementia are involved, primarily, in the informal part of a process of decisions: excluded, prior preferences taken into account, and current preferences respected. Several (10) articles seemed to be based on the assumption that decisions on care services are invariably and solely made within the family and without participation of the person with dementia. CONCLUSIONS: The review emphasizes the need for more updated research about international debates and agreements concerning capabilities and rights of people with dementia and about the (potential) formal contexts of care decisions in the country concerned. This, we argue, is vital for future knowledge production in the area. PMID- 25022287 TI - Opportunities for technology-based HIV prevention programming among high school students in Cape Town, South Africa. AB - One in three new cases of HIV in South Africa is among adolescents. Given that adolescents are particularly affected, scalable, and cost-effective prevention programs are urgently needed. This study aims to identify opportunities to integrate technology into youth HIV prevention efforts. In 2012, 1107 8th-11th graders completed a paper-and-pencil survey. Respondents were enrolled in one of three public high schools in Langa, a lower income community in Cape Town, South Africa. Eighty-nine percent of respondents have used text messaging (SMS) and 86% have gone online. If an HIV prevention program was offered online, 66% of youth would be somewhat or extremely likely to access it; slightly fewer (55%) felt the same about SMS-based programming. In comparison, 85% said they would be somewhat or extremely likely to access a school-based HIV prevention program. Interest in Internet- (60%) and SMS-based (54%) HIV prevention programming was similar for youth who had a self-appraised risk of HIV compared to youth who appraised their risk to be lower, as it was for youth who were tired of hearing messages about HIV prevention. Technology use is common - even among high school students who live in lower income communities. At the same time, these data reveal that it is not uncommon for youth to be tired of hearing messages about HIV prevention, and many of the typical topics key to HIV prevention have low interest levels among youth. HIV prevention researchers need to be mindful of the extent of existing programming that youth are exposed to. Technology-based programming may be especially amenable to meeting these requirements because of its novelty especially in developing countries, and because interactive functionality can be easily integrated into the program design. Given the preference for school- and Internet-based programming, it seems that a hybrid approach is likely feasible and acceptable. PMID- 25022288 TI - Antiviral innate immune response of RNA interference. AB - RNA interference (RNAi) is an ancient, natural process conserved among species from different kingdoms. RNAi is a transcriptional and post-transcriptional gene silencing mechanism in which, double-stranded RNA or hairpin RNA is cleaved by an RNase III-type enzyme called Dicer into small interfering RNA duplex. This subsequently directs sequence-specific, homology dependent, Watson-Crick base pairing post-transcriptional gene silencing by binding to its complementary RNA and initiating its elimination through degradation or by persuading translational inhibition. In plants, worms, and insects, RNAi is the main and strong antiviral defense mechanism. It is clear that RNAi silencing, contributes in restriction of viral infection in vertebrates. In a short period, RNAi has progressed to become a significant experimental tool for the analysis of gene function and target validation in mammalian systems. In addition, RNA silencing has then been found to be involved in translational repression, transcriptional inhibition, and DNA degradation. RNAi machinery required for robust RNAi-mediated antiviral response are conserved throughout evolution in mammals and plays a crucial role in antiviral defense of invertebrates, but despite these important functions RNAi contribution to mammalian antiviral innate immune defense has been underestimated and disputed. In this article, we review the literature concerning the roles of RNAi as components of innate immune system in mammals and how, the RNAi is currently one of the most hopeful new advances toward disease therapy. This review highlights the potential of RNAi as a therapeutic strategy for viral infection and gene regulation to modulate host immune response to viral infection. PMID- 25022289 TI - Salmonella serotypes, resistance patterns, and food vehicles of salmonellosis in southern Brazil between 2007 and 2012. AB - INTRODUCTION: Previous studies have identified Salmonella as the main causative agent of foodborne diseases in the state of Rio Grande do Sul (RS), southern Brazil, between 1997 and 2006. This study aimed to describe the Salmonella serotypes, antimicrobial patterns, and food vehicles of salmonellosis that occurred in RS between 2007 and 2012. METHODOLOGY: Information about Salmonella isolates and salmonellosis outbreaks registered in the official records of the Central Laboratory of RS (FEEPS/IPB-LACEN/RS) was analyzed. RESULTS: Among the 163 isolates investigated, 138 (84.7%) were identified as S. Enteritidis. The second and third most frequent serovars identified were S. Schwarzengrund (5.5%) and S. Typhimurium (3.7%). Homemade mayonnaise was the food vehicle most frequently identified (17.39%), followed by pastry products (15.94%) and beef (12.32%). Antimicrobial resistance was analyzed; 12 drugs were tested. Higher percentages of resistance were observed to nitrofurantoin (94.2%) and nalidixic acid (89.1%). The resistance to these two drugs was verified in 80.43% of the isolates. Multi-resistance to three and five drugs was verified in four and two isolates, respectively. CONCLUSIONS: Comparing the results of the present study with results of previous reports, it was possible to conclude that S. Enteritidis and homemade mayonnaise are still the main serotype and food vehicle of salmonellosis in RS and that antimicrobial resistance has been increasing among S. Enteritidis responsible for foodborne outbreaks in southern Brazil. PMID- 25022291 TI - The epidemiology of bacterial meningitis in Kosovo. AB - INTRODUCTION: The purpose of this study was to present the epidemiologic features of bacterial meningitis in the developing country of Kosovo. METHODOLOGY: Data were collected from active surveillance of bacterial meningitis cases treated at the University Clinical Center of Kosovo in the years 2000 (first post-war year) and 2010. RESULTS: Meningitis cases in 2000 compared with 2010 showed a 35.5% decline in incidence (from 4.8 to 3.1 cases per 100,000 population) and a decrease in the case fatality rate from 10% to 5%. In children, there was a lower mortality rate (5% versus 2%) and a lower incidence of neurological complications (13% versus 16%) as compared to adults (32% versus 10% and 16% versus 35%, respectively). Neisseria meningitidis was the most common pathogen of bacterial meningitis in both study periods. Bacterial meningitis was most prevalent in the pediatric population, and showed an increase in the median age, from three years in 2000 to seven years in 2010. A steady number of bacterial meningitis cases in adults throughout last decade (around 20 cases per year) was recorded. CONCLUSIONS: During the last decade, gradual changes have been observed in the epidemiology of bacterial meningitis that are unrelated to the introduction of new vaccines, but are partly due to the improvement of living conditions. PMID- 25022290 TI - Detection of plasmid-mediated qnr genes among the quinolone-resistant Escherichia coli isolates in Iran. AB - INTRODUCTION: Plasmid-mediated quinolone resistance, which complicates treatment, has been increasingly identified in Escherichia coli isolates worldwide. The purpose of this study was to identify the plasmid-mediated qnrA and qnrB genes among the quinolone-resistant Escherichia coli isolated from urinary tract infections in Iran. METHODOLOGY: A total of 140 Escherichia coli isolates were collected between March and October 2012 from urinary tract infections in Khorram Abad, Iran. All isolates were tested for quinoloe resistance using the disk diffusion method. Also, all quinolone-resistant isolates were screened for the presence of the qnrA and qnrB genes by polymerase chain reaction. Minimum inhibitory concentrations (MICs) of ciprofloxacin for the qnr-positive isolates were determined. RESULTS: One hundred sixteen (82.8%) of 140 Escherichia coli isolates were nalidixic acid-resistant; among them, 14 (12.1%) and 9 (7.8%) were qnrA and qnrB-positive, respectively. Two quinolone-resistant isolates harbored both qnrA and qnrB. Among 63 ciprofloxacin-resistant isolates, 14 (22.2%) and 9 (14.3%) were found to carry qnrA and qnrB genes, respectively. The ciprofloxacin MIC range was 0.25-512 ug/mL for 23 qnr-positive Escherichia coli isolates, 18 of which had MICs values of 4-512 ug/mL. CONCLUSION: Our study shows that the frequency of plasmid-mediated quinolone resistance genes among E. coli isolates in Iran is high. PMID- 25022292 TI - Extra-intestinal salmonellosis in a tertiary care center in South India. AB - INTRODUCTION: The present study is a retrospective analysis of a total of 36 cases of bacteriologically proven extra-intestinal salmonellosis, managed at Nizam's Institute of Medical Sciences, between 1987 and 2012 (25 years). The extra-intestinal sites involved were the skin, cerebrum, spleen, ovary, synovium, and the skeletal muscle. METHODOLOGY: The extra-intestinal specimens were first processed using standard methods. Colonies suspected as Salmonella were identified by standard laboratory methods, initially by manual biochemical reactions and later by the API system (bioMerieux, Marcy l'Etoile- France) and the Vitek-2 system (bioMerieux). All the Salmonella isolates were sent to Central Research Institute, Kasauli, for serotyping. RESULTS: The predominant serotype isolated was Salmonella Typhi (S. Typhi) in 27 (75%) patients, followed by Salmonella Senftenberg (S. Senftenberg) in 5 (14%), Salmonella Paratyphi A (S. Paratyphi A) in 3 (8%), and Salmonella Typhimurium (S. Typhimurium) in 1 (3%). There was an increasing resistance to ampicillin, chloramphenicol, cephalosporins (third generation), and quinolones over the 25 years. CONCLUSIONS: The diagnosis of extra-intestinal salmonellosis requires a high degree of clinical suspicion and should be included in the differential diagnosis in patients with deep-seated abscesses. PMID- 25022293 TI - Phytochemical-induced reduction of pulmonary inflammation during Klebsiella pneumoniae lung infection in mice. AB - INTRODUCTION: Curcumin, a polyphenol derived from the herb Curcuma longa, has number of antioxidant, anti-inflammatory, antimicrobial, and anti-carcinogenic activities. Its anti-inflammatory property was here studied alone and in combination with clarithromycin in a mouse model of acute inflammation. METHODOLOGY: A total of 80 mice divided into four groups were used. Mice receiving curcumin and/or clarithromycin were fed orally with curcumin (150 mg/kg/day) for 15 days prior to infection, whereas clarithromycin was administered orally (30 mg/kg/day) 12 hours post infection. Simultaneously, the control group receiving only infection but no treatment was also set up. Bacterial load estimation, histopathological examination and analysis of inflammatory parameters was performed on various days for all groups. RESULTS: Intranasal inoculation of bacteria resulted in significant increase in neutrophil infiltration along with increased production of various inflammatory mediators (malondialdehyde, myeloperoxidase, nitric oxide, TNFalpha) in lung tissue. Clarithromycin treatment significantly decreased the bacterial load and other inflammatory components in infected mice, but animals receiving curcumin alone or in combination with clarithromycin showed a much more significant (p < 0.05) reduction in neutrophil influx along with reduced levels of various inflammatory parameters. Though treatment with curcumin did not reduce the bacterial load, in combination with clarithromycin, both bacterial proliferation and lung tissue damage were checked. CONCLUSIONS: Though clarithromycin, because of its associated side effects, may not be the preferred treatment, it can be used in conjunction with curcumin. The latter as an adjunct therapy will help to down regulate the exaggerated state of immune response during acute lung infection. PMID- 25022294 TI - Clinical and virological response to antiretroviral drugs among HIV patients on first-line treatment in Dar-es-Salaam, Tanzania. AB - INTRODUCTION: In Tanzania, the follow-up on antiretroviral therapy (ART) response is based on clinical outcomes. We investigated virological response and ARV resistance mutations in relation to clinical response in ARV-treated patients. METHODOLOGY: A cross-sectional study of a cohort of 150 patients taking first line ART in Dar-es-Salaam was conducted. Data were collected using standardized questionnaires and patients' blood samples. HIV viral load testing and genotyping was performed on all viremic samples. Statistical analyses compared clinical responders and non-responders. RESULTS: The median time on ART was 20 months; 71 (47%) patients were ART clinical responders. Clinical non-responders were more likely to have started ART with advanced disease with significantly lower median percentage weight gain (6% versus 20%) with respect to pre-treatment levels. Sixty-one (86%) and 64 (81%) of clinical responders and non-responders, respectively, had undetectable viral loads. Genotyping was successful in 24 (96%) virologically failing patients, among whom 83% had resistance mutations; 67% had dual nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI (NNRTI) resistance mutations. Seventeen (71%) and 19 (79%) patients had NRTI and NNRTI resistance mutations, respectively, which were related to the ART in use, with no difference between clinical responders and non-responders. The most prevalent subtypes were A and C, found in 9 (38%) and 7 (29%) patients, respectively. CONCLUSIONS: The observed virological response was high and did not correlate with clinical response. The prevalence of ARV resistance mutations was high in viraemic patients and was related to the ARV prescribed. We recommend use of viral load monitoring during ART in Tanzania. PMID- 25022295 TI - Antiretroviral therapy adherence and predictors to adherence in Albania: a cross sectional study. AB - INTRODUCTION: The possibility of an HIV/AIDS epidemic in southeastern Europe (SEE) is not improbable. Thus, an understanding of the current issues surrounding HIV/AIDS care, specifically antiretroviral therapy (ART) adherence, in countries within SEE is critical. This study was conducted to determine the ART adherence characteristics of Albania's HIV-positive population. METHODOLOGY: This cross sectional study reports initial demographic and adherence characteristics of patients receiving HIV/AIDS treatment in Albania. Retrospective review of pharmacy medications dispensed supplemented reported adherence behavior. Further, an adherence index was utilized to explore adherence more thoroughly. RESULTS: Patient-reported adherence and pharmacy review showed adherence levels of 98.9+/ 4.4% and 97.7+/-4.7%, respectively. Assessment by adherence index revealed an index level of 91.7+/-6.7. Factors associated with a score of < 95 on the adherence index were: being partnered (OR = 0.29, 95% CI = 0.09 - 0.98), history of depression (OR = 0.24, 95% CI = 0.08 - 0.76), increased number of barriers to care (OR = 0.80, 95% CI = 0.66 - 0.97), and increased number of current social and medical needs (OR = 0.72, 95% CI = 0.58 - 0.91). CONCLUSIONS: Interventions aimed at reducing barriers to care, addressing current medical and social needs, and treating mental health issues may help improve adherence to ART in patients with HIV/AIDS in Albania. With little known about HIV/AIDS in SEE, this study provides guidance on how SEE countries can help prevent a possible rise in the prevalence of HIV given the close link of ART adherence and spread of HIV. PMID- 25022296 TI - HIV-1 and GBV-C co-infection in Venezuela. AB - INTRODUCTION: Co-infection with GB virus C (GBV-C) in patients infected with human immunodeficiency virus 1 (HIV-1) has been associated with prolonged survival. The aim of this study was to evaluate the prevalence of GBV-C infection among HIV-1-infected patients in Venezuela, and to determine the effects of the co-infection on the levels of relevant cytokines. METHODOLOGY: Plasma samples were collected from 270 HIV-1-seronegative and 255 HIV-1-seropositive individuals. GBV-C infection was determined by RT-PCR of the NS5 region and genotyped by sequence analysis of the 5'UTR region. HIV-1 strains were characterized by sequence analysis of pol, vif, env, and nef genes. Selected cytokines were evaluated by ELISA. RESULTS: Ninety-seven of 525 (18.5%) plasma samples tested positive for GBV-C RNA. A significantly higher prevalence of GBV-C was found among HIV-1 patients compared to HIV-1-seronegative individuals (67/255, 26% versus 30/270, 11%; p < 0.001). Statistical difference was observed in the viral load between HIV-1+GBV-C+ and HIV-1+GBV-C- (p = 0.014), although no differences in CD4+ cell counts were found between both groups. TNFalpha concentration was higher in HIV-1+GBV-C- than in HIV-1+GBV-C+ patients (25.9 pg/mL versus 17.3 pg/mL; p = 0.02); RANTES expression levels were more variable in GBV-C co-infected patients and more frequently elevated in HIV-1 mono-infected patients compared to patients co-infected with GBV-C. CONCLUSIONS: The previously observed beneficial effect of co-infection with HIV-1 and GBV-C on disease progression is complex and might be due in part to a change in the cytokine environment. More studies are required to understand the interaction between both viruses. PMID- 25022297 TI - An evaluation of the World Health Organization's 1997 and 2009 dengue classifications in hospitalized dengue patients in Malaysia. AB - INTRODUCTION: The latest revised version of the World Health Organization's dengue classification was released in 2009. A handful of studies have taken initiatives to evaluate the old and revised guidelines to determine early signs and symptoms of severe dengue. This retrospective study aimed to compare the classification of dengue using both the 1997 and 2009 guidelines in a selected cohort of dengue patients from Peninsular Malaysia between 2008 and 2012. METHODOLOGY: Adult dengue patients were recruited from tertiary hospitals in two different states, Selangor and Kelantan, in Peninsular Malaysia. Their clinical manifestations were assessed. RESULTS: A total of 281 confirmed dengue patients were enrolled; the mean duration of illness at admission was five days. Of these, 88.6%, 10.7%, and 0.7% were classified according to the 1997 guidelines as having dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), respectively. When the WHO 2009 guidelines were applied, 17.1%, 78.3%, and 4.6% were classified as dengue without warning signs, dengue with warning signs, and severe dengue, respectively. CONCLUSIONS: Our data suggests that the revised WHO 2009 guidelines stratify a much larger proportion of patients into a category that requires a higher level of medical and nursing care. PMID- 25022298 TI - Differential replication of dengue virus serotypes 2 and 3 in coinfections of C6/36 cells and Aedes aegypti mosquitoes. AB - INTRODUCTION: Different dengue virus (DENV) serotypes have been associated with greater epidemic potential. In turn, the increased frequency in cases of severe forms of dengue has been associated with the cocirculation of several serotypes. Because Colombia is a country with an endemic presence of all four DENV serotypes, the aim of this study was to evaluate the in vivo and in vitro replication of the DENV-2 and DENV-3 strains under individual infection and coinfection conditions. METHODOLOGY: C6/36HT cells were infected with the two strains individually or simultaneously (coinfection). Replication capacity was evaluated by RT-qPCR, and the effects on cell viability were assessed with an MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Additionally, Aedes aegypti mosquitoes were artificially fed the two strains of each serotype individually or simultaneously. The viral genomes were quantified by RT-qPCR and the survival of the infected mosquitoes was compared to that of uninfected controls. RESULTS: In single infections, three strains significantly affected C6/36HT cell viability, but no significant differences were found in the replication capacities of the strains of the same serotype. In the in vivo infections, mosquito survival was not affected, and no significant differences in replication between strains of the same serotype were found. Finally, in coinfections, serotype 2 replicated with a thousandfold greater efficiency than serotype 3 did both in vitro and in vivo. CONCLUSIONS: Due to the cocirculation of serotypes in endemic regions, further studies of coinfections in a natural environment would further an understanding of the transmission dynamics that affect DENV infection epidemiology. PMID- 25022299 TI - Comparison of two different skin preparation strategies for open cardiac surgery. AB - INTRODUCTION: Surgical site infection (SSI) is a serious complication after cardiac surgery; skin preparation is an important step in the prevention of wound contamination with skin flora. In this study, two different skin preparation strategies (standard povidine iodine cleaning plus plain adhesive drape and microbial sealant (InteguSeal, Kimberly-Clark Health Care, Roswell, GA, USA) were compared in cardiac surgery patients. METHODOLOGY: This prospective study included 96 cardiac surgery patients randomized to either a standard plain adhesive drape (28 patients, control group) or a microbial sealant (68 patients, study group). Bacterial isolates were obtained from the wounds in the operating room before the skin incision and after the surgical procedure had ended. RESULTS: Microorganisms were isolated from 38 patients (39.6%) in the study population. Twenty-seven of these patients were from the microbial sealant group and 11 were from the plain adhesive drape group. No postoperative wound infection was encountered in either group. No statistically significant differences between the two groups regarding the number of patients with microorganism isolation (p = 0.974) or postoperative leukocyte counts and neutrophil granulocyte percentages were observed. CONCLUSIONS: Regarding SSI after cardiac surgery, microbial sealant is equivalent to the standard skin preparation strategy applied with povidine iodine cleaning and a plain adhesive drape. PMID- 25022300 TI - Ascaris lumbricoides infection and parasite load are associated with asthma in children. AB - INTRODUCTION: Association between Ascaris lumbricoides infection and asthma is a controversial subject that has been studied by several authors based on the hygiene theory. This work contributes to better understanding this issue. METHODOLOGY: This was a cross-sectional study involving 1,004 children from a neighborhood of low socioeconomic status in Campina Grande, Paraiba, northeastern Brazil. Asthma was diagnosed using the International Study of Asthma and Allergy in Childhood (ISAAC) questionnaire. Intestinal parasitosis was diagnosed by parasitological examination (the Ritchie technique), and parasite load determined by the Kato-Katz technique. The statistical analysis was descriptive, and hypotheses were tested according to odds ratios. RESULTS: A total of 260 children were infected with A. lumbricoides, and 233 had asthma. Light parasite loads were significantly associated with asthma (wheezing more than three times per year); p = 0.003, OR = 0.41(IC 0.22 - 0.75), while the heavy parasite loads were not; p = 0.002, OR = 2.37(IC 1.35 - 4.18). Similar results were observed in almost all the symptoms of asthma. No association was found with maternal educational level. CONCLUSION: In children living in urban areas of low socioeconomic status, a light parasite load of A. lumbricoides is a protective factor against asthma and its symptoms. Meanwhile, heavy parasite load is a risk factor and contributes to the high prevalence of asthma and its symptoms among these children. PMID- 25022302 TI - An eight-year study of Shigella species in Beijing, China: serodiversity, virulence genes, and antimicrobial resistance. AB - INTRODUCTION: This study was conducted to determine the prevalence of serotypes, virulence factors, and antimicrobial resistance patterns of Shigella spp. in Beijing, China, from 2004 to 2011. METHODOLOGY: Real-time PCR assays were used to detect virulent genes, and the Kirby-Bauer disk diffusion method was used to evaluate antimicrobial resistance. RESULTS: Among the total of 1,652 Shigella isolates, S. sonnei (57.1%) was the predominant species, followed by S. flexneri (42.3%), S. dysenteriae (0.4%), and S. boydii (0.2%). Nineteen serotypes were discovered among S. flexneri strains. The virulence gene ipaH was the most frequent, followed by sen and set. The presence of set showed significant difference in two dominant serogroups, S. flexneri and S. sonnei. Over 90% of Shigella isolates showed resistance to at least three drugs with widened spectrum. High-level antimicrobial resistance to single and multiple antibiotics was more common among S. sonnei than S. flexneri. CONCLUSION: There was an obvious serotype change and a dramatic increase of antibiotic resistance in Shigella prevalence in Beijing. PMID- 25022301 TI - Performance of the Abbott Real Time CT/NG assay in urines and cervico-vaginal samples from Senegal. AB - INTRODUCTION: Chlamydia trachomatis and Neisseria gonorrhoeae are the most common causes of sexually transmitted disease in Senegal and worldwide. Molecular techniques have become the standard for their detection, and due to the frequency of co-infections, these tests can detect both agents and can be used on urine samples, vaginal swabs, or endocervical samples. In developing countries, the use of these molecular techniques is very limited and there is a need for evaluations of these techniques to be done. METHODOLOGY: A total of 181 samples were tested with the Abbott RealTime CT/NG assay and compared with the Roche Cobas Amplicor CT/NG assay. Specimens were collected from the key population of men having sex with men (urine, n = 60), female sex workers (genital swabs, n = 60) and from women visiting the laboratory for a gynecological checkup (urine, n = 60 and endocervical samples, n = 61). RESULTS: The agreement between the two techniques was 98.90% with a Kappa coefficient of 0.98. A sensitivity of 93.3%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 93.3% were found for both Chlamydia trachomatis and Neisseria gonorrhoeae. CONCLUSION: These results showed that both methods are similar and suitable for the detection of CT/NG in all types of samples examined in this study. PMID- 25022303 TI - Subclinical pulmonary pathogenic infection in camels slaughtered in Cairo, Egypt. AB - INTRODUCTION: Camels migrate between the open boundaries of Sudan and Egypt either for grazing or for slaughtering. Bad hygiene and stress is often related to pulmonary diseases in camels. This study investigated whether camels slaughtered in Cairo carried pulmonary infections. METHODOLOGY: Five hundred lung tissues of slaughtered camels were examined and 100 samples suspected for pulmonary infection were subjected to microbial identification and histopathology. RESULTS: A total of 70 lung tissues revealed 97 bacterial isolates of 8 species, including Staphylococcus aureus (37.14%), Escherichia coli (27.14%), Klebsiella pneumoniae (26.71%), Bacillus spp. (25.72%), Streptococcus pyogenes (10%), Corynebacterium spp. (8.85 %), Pasteurella spp. (2.85%), and Arcanobacterium pyogenes (1.4%). Some of these species were earlier reported to be associated with pulmonary infection. Histopathology revealed different types of pneumonia in 50% of the investigated lungs. CONCLUSIONS: A considerable number of apparently healthy camels carry pathogenic agents in their lower respiratory tracts. Immunosuppression and stressful conditions might influence these pathogens to induce respiratory diseases in camels. Thus, the infected camels might act as reservoir of these infections agents. If adequate care is not taken, this might be a threat to abattoir workers and may spread infections to humans. PMID- 25022304 TI - Serological evidence of West Nile virus infection in the horse population of northern Serbia. AB - INTRODUCTION: This study was conducted to evaluate the seroprevalence of West Nile virus (WNV) in the horse population of northern Serbia. Furthermore, it aimed to provide insight and an updated overview on the circulation of this re emerging pathogen in this part of southeastern Europe. At the time of manuscript preparation, no clinical cases of WNV infection in horses were reported in this area. METHODOLOGY: Between 2007 and 2011, a total of 252 equine serum samples were collected from seven different locations in northern Serbia. The presence of WNV-reactive IgG antibodies was examined by using commercial and in-house ELISAs. Selected ELISA-positive samples were re-tested by a WNV lineage 2 plaque reduction neutralization test 90% (PRNT-90). RESULTS: In 28.6% of the 252 tested equine serum samples antibodies against WNV were detected. The results obtained with the in-house ELISA corresponded to the outcome of the commercial kit in 90% of the samples. All selected WNV antibody ELISA-positive samples were confirmed by PRNT-90 with neutralizing antibody titers of 1:23 to > 1:512. CONCLUSION: This study confirms the circulation of WNV in northern Serbia. No striking regional differences in seroprevalences were identified suggesting WNV circulation also in other parts of Serbia. Distances between wetlands or forests and stud farms do not appear to have an influence on WNV seroprevalence. PMID- 25022305 TI - An unusual cause of peritonitis in peritoneal dialysis patients: Pantoea agglomerans. AB - Peritonitis is a serious infection and early diagnosis and treatment is mandatory. A variety of microorganisms are identified in these cases and during recent years a new one was included, Pantoea agglomerans. In this case report, a female patient on continuous ambulatory peritoneal dialysis therapy with a peritonitis episode caused by this organism is described. The source of infection was thought to be due to contact of catheter with non-sterile surfaces. In microbiologic culture, this organism was identified and the patient successfully treated with a three week course of gentamicin therapy. The number of reported cases with this organism has increased in last years and various infection localizations and clinical progress patterns have been identified. In peritoneal dialysis patients presenting with peritonitis, this organism must be kept in mind. PMID- 25022306 TI - Ramsay Hunt syndrome with facial vesicular rash: a unique clinical presentation in a kidney transplant patient. AB - Ramsay Hunt Syndrome (RHS) is the result of herpes zoster virus reactivation producing hearing loss, pain and vesicles in the ear or mouth, along with ipsilateral facial palsy due to the 7th cranial nerve geniculate ganglion infectious involvement. This condition has not been previously described, particularly in transplant patients. A 38-year old man underwent kidney transplantation and two years later experienced an ache on the left side of the face and hearing loss in the ear, also exhibiting vesicular lesions and concomitant facial peripheral palsy. Acyclovir IV was initiated, and the prednisone dose was increased. The patient was discharged 15 days later, feeling better but still exhibiting dark spots on his face. At three months follow-up he was asymptomatic, showing notable palsy improvement. Until this case, herpes zoster facial lesions causing typical RHS have never been reported in literature, particularly in kidney transplant patients. PMID- 25022307 TI - Human external ophthalmomyiasis caused by Lucilia sericata Meigen (Diptera: Calliphoridae)--a green bottle fly. AB - Ophthalmomyiasis externa is the result of infestation of the conjunctiva by the larval form or maggots of flies from the order Diptera. If not recognized and managed appropriately, it can be complicated by the potentially fatal condition ophthalmomyiasis interna. Ophthalmomyiasis externa is mainly caused by the sheep bot fly (Oestrus ovis). We present the first case, to our knowledge, of ophthalmomyiasis externa in an elderly woman from Belgrade caused by Lucilia sericata Meigen--a green bottle fly. PMID- 25022308 TI - Molecular characterization of influenza A viruses circulating in Cuba between April 2009 and August 2010. PMID- 25022309 TI - Establishing an enteric bacteria reference laboratory in Sierra Leone. AB - In 2012, Sierra Leone experienced its worst cholera outbreak in over 15 years affecting 12 of the country's 13 districts. With limited diagnostic capability, particularly in bacterial culture, the cholera outbreak was initially confirmed by microbiological testing of clinical specimens outside of Sierra Leone. During 2012 - 2013, in direct response to the lack of diagnostic microbiology facilities, and to assist in investigating and monitoring the cholera outbreak, diagnostic and reference services were established in Sierra Leone at the Central Public Health Reference Laboratory focusing specifically on isolating and identifying Vibrio cholerae and other enteric bacterial pathogens. Sierra Leone is now capable of confirming cholera cases by reference laboratory testing. PMID- 25022310 TI - Safety impacts of red light cameras at signalized intersections based on cellular automata models. AB - OBJECTIVE: This study applies a simulation technique to evaluate the hypothesis that red light cameras (RLCs) exert important effects on accident risks. Conflict occurrences are generated by simulation and compared at intersections with and without RLCs to assess the impact of RLCs on several conflict types under various traffic conditions. METHOD: Conflict occurrences are generated through simulating vehicular interactions based on an improved cellular automata (CA) model. The CA model is calibrated and validated against field observations at approaches with and without RLCs. Simulation experiments are conducted for RLC and non-RLC intersections with different geometric layouts and traffic demands to generate conflict occurrences that are analyzed to evaluate the hypothesis that RLCs exert important effects on road safety. RESULTS: The comparison of simulated conflict occurrences show favorable safety impacts of RLCs on crossing conflicts and unfavorable impacts for rear-end conflicts during red/amber phases. Corroborative results are found from broad analysis of accident occurrence. CONCLUSIONS: RLCs are found to have a mixed effect on accident risk at signalized intersections: crossing collisions are reduced, whereas rear-end collisions may increase. The specially developed CA model is found to be a feasible safety assessment tool. PMID- 25022312 TI - Atom manipulation on an insulating surface at room temperature. AB - Atomic manipulation enables us to fabricate a unique structure at the atomic scale. So far, many atomic manipulations have been reported on conductive surfaces, mainly at low temperature with scanning tunnelling microscopy, but atomic manipulation on an insulator at room temperature is still a long-standing challenge. Here we present a systematic atomic manipulation on an insulating surface by advanced atomic force microscopy, enabling construction of complex patterns such as a 'Swiss cross' of substitutional bromine ions in the sodium chloride surface. PMID- 25022311 TI - Cyanobacteria as a Platform for Biofuel Production. AB - Cyanobacteria have great potential as a platform for biofuel production because of their fast growth, ability to fix carbon dioxide gas, and their genetic tractability. Furthermore they do not require fermentable sugars or arable land for growth and so competition with cropland would be greatly reduced. In this perspective we discuss the challenges and areas for improvement most pertinent for advancing cyanobacterial fuel production, including: improving genetic parts, carbon fixation, metabolic flux, nutrient requirements on a large scale, and photosynthetic efficiency using natural light. PMID- 25022313 TI - Ups and downs in western Crete (Hellenic subduction zone). AB - Studies of past sea-level markers are commonly used to unveil the tectonic history and seismic behavior of subduction zones. We present new evidence on vertical motions of the Hellenic subduction zone as resulting from a suite of Late Pleistocene - Holocene shorelines in western Crete (Greece). Shoreline ages obtained by AMS radiocarbon dating of seashells, together with the reappraisal of shoreline ages from previous works, testify a long-term uplift rate of 2.5-2.7 mm/y. This average value, however, includes periods in which the vertical motions vary significantly: 2.6-3.2 mm/y subsidence rate from 42 ka to 23 ka, followed by ~7.7 mm/y sustained uplift rate from 23 ka to present. The last ~5 ky shows a relatively slower uplift rate of 3.0-3.3 mm/y, yet slightly higher than the long term average. A preliminary tectonic model attempts at explaining these up and down motions by across-strike partitioning of fault activity in the subduction zone. PMID- 25022314 TI - The role of early life factors in the development of ethnic differences in growth and overweight in preschool children: a prospective birth cohort. AB - BACKGROUND: Ethnic differences in childhood and adulthood are known, but ethnic differences in preschool overweight and associated factors are less studied. We assessed ethnic differences in pre-school age overweight, and studied the mediating role of early life factors in this association. Furthermore, we assessed body mass index (BMI) z-score development from birth to age 4 years to study ethnic-specific differences in BMI z-score trajectory. METHODS: We used data on 4581 children participating in a birth cohort who were born between 2002 and 2006 in Rotterdam, the Netherlands. Child's ethnicity was defined according to country of birth of the parents. Weight and length/height was repeatedly measured between 1 and 45 months of age. Overweight at age 4 years was defined according to cut-off points for BMI from the international obesity task force. We performed logistic regression to obtain independent estimates of the association between ethnicity and preschool-age overweight, and to assess the mediating role of early life risk factors. Mixed models were used to describe BMI-z development for each ethnic group from birth to preschool age. RESULTS: Relative to native Dutch children, non-Dutch children were more likely to be overweight at age 4 years, except for Surinamese-Hindustani children. Socio-demographic factors, parental BMI, and infant weight change in the first 6 months after birth reduced associations. After full adjustment, Turkish (OR: 2.02, 95% CI: 1.34-3.04) and Antillean/Surinamese Creole (OR: 1.78, 95% CI: 1.06-3.02) children were still more likely to be overweight at age 4 years. CONCLUSION: Ethnic differences on the prevalence of overweight in preschool children can be partially explained by maternal educational level, parental overweight and early infant weight change. These may be possible targets to reduce ethnic inequalities in preschool age overweight. PMID- 25022315 TI - IPF clinical trial design and endpoints. AB - PURPOSE OF REVIEW: There remains a dire need for therapies that impact the clinical course of patients with idiopathic pulmonary fibrosis (IPF). Indeed, there is a surge of interest in IPF therapeutics, with many candidate agents in various stages of development. Optimal design and implementation of the appropriate prospective clinical trials are essential to demonstrate clinical efficacy of promising drugs for the treatment of IPF. A key element in the success of such clinical trials is the choice of the best endpoint(s) to match the design of the study. RECENT FINDINGS: Although the results of many IPF clinical trials have been disappointing, these trials have provided valuable insights into the epidemiology and natural history of the disease and have sparked debate into the best clinical trial designs and endpoints. SUMMARY: This review will discuss the various clinical trial endpoints that have been used or proposed with a focus on their potential utility, as well as possible pitfalls that investigators should consider in the design of such studies. VIDEO ABSTRACT: http://links.lww.com/COPM/A13. PMID- 25022316 TI - Worsening of pulmonary sarcoidosis. AB - PURPOSE OF REVIEW: Despite the frequent occurrence of worsening pulmonary symptoms in pulmonary sarcoidosis patients, there is little available information concerning this topic. RECENT FINDINGS: In this review, we outline the various causes for these symptoms. We propose to partition the various causes for these symptoms into specific categories. SUMMARY: We believe that these categories will provide the clinician a framework to evaluate pulmonary sarcoidosis patients with such symptoms in a rigorous way that may be useful in optimizing their care. PMID- 25022317 TI - Current approach to connective tissue disease-associated interstitial lung disease. AB - PURPOSE OF REVIEW: To review current approaches to the complex intersection of interstitial lung disease (ILD) with the spectrum of connective tissue disease (CTD). RECENT FINDINGS: There is a growing appreciation that the approach to CTD associated ILD (CTD-ILD) can be enhanced by a multidisciplinary evaluation that often incorporates the rheumatologist. Determining that ILD is associated with an established CTD requires the exclusion of alternative causes and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with presumed 'idiopathic' disease requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiologic, and histopathologic features. A comprehensive treatment program for CTD-ILD should address comorbid conditions and consider implementation of adjunctive therapeutic strategies. Pharmacologic intervention for CTD-ILD is reserved for those with progressive, clinically significant disease and typically involves use of immunosuppressive therapies. SUMMARY: A multidisciplinary approach can be helpful for CTD-ILD. Further research and controlled trials are needed to determine how to best manage the diverse spectrum of CTD-ILD. PMID- 25022318 TI - Genetic susceptibility and pulmonary fibrosis. AB - PURPOSE OF REVIEW: Recent genetic findings have identified new targets of investigation in the field of pulmonary fibrosis and have the potential to change clinical care. RECENT FINDINGS: These findings implicate alterations in host defense, cell-to-cell adhesion, and aging and senescence in the pathophysiology of pulmonary fibrosis. At least one common genetic variant strongly associated with pulmonary fibrosis appears to have prognostic implications for patients. SUMMARY: The inherited risk for pulmonary fibrosis is substantial, and recent data suggest that genetic risk for familial and sporadic forms of the disease are similar. Further characterizing this genetic risk will influence clinical practice in terms of categorization, diagnosis, and screening of individuals for this disease. PMID- 25022319 TI - Goal-oriented treatment of pulmonary arterial hypertension. AB - PURPOSE OF REVIEW: To understand the rational of establishing a goal-oriented therapy for pulmonary arterial hypertension management. RECENT FINDINGS: During the last decades, the development of targeted therapies and the recognition of prognostic markers represented a major step for improving pulmonary arterial hypertension survival. Now, changing the strategy on using these compounds therapies might represent the best way to optimize treatment response. SUMMARY: Prespecified goals with regular reassessment should be incorporated as the routine practice for pulmonary arterial hypertension management to provide the best available treatment, aiming to improve or maintain every patient in a clinical and functional status that reflects better long-term survival. PMID- 25022320 TI - Defunctioning polymorphism in the immunoglobulin G inhibitory receptor (FcgammaRIIB-T/T232) does not impact on kidney transplant or recipient survival. AB - BACKGROUND: There is an increasing appreciation of the deleterious effects of antibody and B cells on acute and chronic transplant outcomes. Many effector functions of antibody are mediated by a family of receptors (FcgammaRs) that are expressed on most immune cells, including neutrophils, natural killer cells, and B cells. Most FcgammaRs are activating and controlled by a single inhibitory receptor, FcgammaRIIB (CD32B), which also regulates some aspects of B-cell activation and antibody production. FcgammaRIIB-deficient mice develop severe chronic arteriopathy in a murine cardiac allograft model. A single nucleotide polymorphism in human FcgammaRIIB (rs1050501) results in profound receptor dysfunction and is associated with systemic lupus erythematosus. The frequency of this FcgammaRIIB-I/T232 polymorphism also shows significant racial variation. METHODS: In the present study, we sought to determine whether the FcgammaRIIB I/T232 single nucleotide polymorphism rs1050501 affected susceptibility to renal allograft rejection or loss and transplant recipient survival. FcgammaRIIB-I/T232 genotype was determined in 2,851 Caucasian and 570 Afro-Caribbean renal transplant recipients, and in 236 transplant recipients with a primary diagnosis of systemic lupus erythematosus, all of whom were enrolled into the Collaborative Transplant Study. RESULTS: We found no significant difference in pretransplant panel reactive antibodies, acute rejection at 1-year nor in 10-year transplant or patient survival in individuals with differing FcgammaRIIB-I/T232 genotype. CONCLUSION: This negative result is surprising, given the importance of this receptor in modulating antibody effector function. PMID- 25022321 TI - Why Most Traumatic Brain Injuries are Not Caused by Linear Acceleration but Skull Fractures are. AB - Injury statistics have found the most common accident situation to be an oblique impact. An oblique impact will give rise to both linear and rotational head kinematics. The human brain is most sensitive to rotational motion. The bulk modulus of brain tissue is roughly five to six orders of magnitude larger than the shear modulus so that for a given impact it tends to deform predominantly in shear. This gives a large sensitivity of the strain in the brain to rotational loading and a small sensitivity to linear kinematics. Therefore, rotational kinematics should be a better indicator of traumatic brain injury risk than linear acceleration. To illustrate the difference between radial and oblique impacts, perpendicular impacts through the center of gravity of the head and 45 degrees oblique impacts were simulated. It is obvious that substantially higher strain levels in the brain are obtained for an oblique impact, compared to a corresponding perpendicular one, when impacted into the same padding using an identical impact velocity. It was also clearly illustrated that the radial impact causes substantially higher stresses in the skull with an associated higher risk of skull fractures, and traumatic brain injuries secondary to those. PMID- 25022322 TI - Semantically-based priors and nuanced knowledge core for Big Data, Social AI, and language understanding. AB - Noise-resistant and nuanced, COGBASE makes 10 million pieces of commonsense data and a host of novel reasoning algorithms available via a family of semantically driven prior probability distributions. Machine learning, Big Data, natural language understanding/processing, and social AI can draw on COGBASE to determine lexical semantics, infer goals and interests, simulate emotion and affect, calculate document gists and topic models, and link commonsense knowledge to domain models and social, spatial, cultural, and psychological data. COGBASE is especially ideal for social Big Data, which tends to involve highly implicit contexts, cognitive artifacts, difficult-to-parse texts, and deep domain knowledge dependencies. PMID- 25022323 TI - Professional networks and EBM use: a study of inter-physician interaction across levels of care. AB - Physicians around the globe are increasingly encouraged to adopt guidelines, protocols and other scientific material when making clinical decisions. Extant research suggests that the clinicians' propensity to use evidence-based medicine (EBM) is strongly associated with the professional collaborative networks they establish and maintain with peers. In this paper we explore whether and how the connectedness of primary care physicians with colleagues working in hospital settings is related to their frequency of EBM use in clinical practice. We used survey data from 104 pediatricians working in five local health authorities in the Italian NHS. Social network and attributional data concerning single physicians, as well as their self-reported frequency of EBM use, were collected for three major pathologies in pediatric care: asthmatic, gastro-enteric and urinary pathologies. Ordered regression analysis was employed. Our findings documented a positive association between the number of physicians' relationships with hospital colleagues and the frequency of use EBM. Results also indicated that physicians' organizational affiliations influence the frequency of EBM use. Finally, contrary to our expectations, it was found that clinicians' affiliation to formal collaborative arrangements is at odds with the likelihood of reporting higher frequency of EBM use. PMID- 25022324 TI - Continuing education. AB - Is continuing education really necessary? It is popular at the present time to say that it is. But in fact many professional workers go through their life without participating very much in continuing education and we must therefore suppose that there is a solid, although mainly silent, body of opinion which does not consider it necessary. Let us dissect this subject and find out whether continuing education is really essential and why it is not more popular. PMID- 25022325 TI - Evaluation of the objectives of teaching -an introduction to the techniques of examining. AB - Let me state at the outset that what I Know about physiotherapy or the teaching of physiotherapy is confined to what I have gleaned from a quick reading of the Physiotherapy Handbook and a look at a few samples of examination papers set in the subject. PMID- 25022326 TI - Assisting undergraduates develop study skills and habits. AB - Much has been written both in Australia and overseas about factors affecting the educational adjustment of tertiary students and about the gap which must be bridged by the student proceeding from secondary school to university (Schonell, 1963). The present article is concerned not with the development of teaching methods for use in bridging this gap, but with the student's task and with ways in which the lecturer or instructor can assist the student to perform that task effectively. PMID- 25022327 TI - Developing understanding of normal movement in the new physiotherapy undergraduate. AB - This paper discusses some observations on teaching movement to the new physiotherapy undergraduate at the University of Queensland. Its contents focus on aims of teaching early movement and certain aspects of realizing such aims in practice. PMID- 25022328 TI - Research in a laboratory situation. AB - In the postgraduate course on "Education of the Physiotherapist", Professor R. W. Hawker, Professor of Physiology at the University of Queensland, gave a lecture on "Research in a Laboratory Situation". A summary of part of his lecture is set out. In his lecture he asked the question-How do I become a researcher? He discussed the education for research given in the Department of Physiology where there are eight units of research. In each unit a team of investigators applies itself to a project of research. PMID- 25022329 TI - A novel technique for oviduct occlusion to generate live births from cryopreserved rabbit oocytes after in vivo fertilisation. AB - Intraoviductal transfer technique in combination with in vivo fertilisation has arisen as an effective technique to assess live births after transfer of slow frozen oocytes in the rabbit. Nevertheless, the great disadvantage of this method is the accumulation of tubal fluid in a large number of females after clamping the oviducts. In this study, we develop an alternative method to minimise damage to the oviduct and increase the birth rate. The aims of this study were (1) to evaluate the ability of cyanoacrylate tissue adhesive to occlude the oviduct for female sterilisation; (2) to evaluate the effect of oviduct occlusion immediately after transferring fresh oocytes on in vivo fertilisation; and (3) to assess this technique to generate live births from fresh and slow-frozen oocytes. In all the experiments, recipients were artificially inseminated 9h prior to occluding the oviducts. In the first experiment, the left oviduct was blocked with cyanoacrylate tissue adhesive, while the right one was used as a control. Six days later, oviducts and uterine horns were flushed to assess embryo recovery rates. While the embryo recovery rate was 79.2% in the intact oviduct, no embryos were recovered in the blocked one. In the second experiment, fresh oocytes were transferred into both oviducts, which were immediately occluded. Six days later, the in vivo fertilisation success rate was 33.7%. Finally, in the last experiment, slow-frozen oocytes were transferred and the rate of live births was 13.2+/-4.5%. The study shows that when using this method the generation of live births from slow-frozen oocytes increases significantly. In addition, our results suggest that in vivo environment could help improve the results of oocyte cryopreservation. PMID- 25022330 TI - Determination of selected parameters for non-specific and specific immunity in cows with subclinical endometritis. AB - Endometritis in dairy cow herds is a serious economic problem all over the world due to the large economic losses. The aim of the study was a comparative evaluation of selected indicators of non-specific and specific immunity in cows with subclinical endometritis and in cows without inflammation of the uterus. The study was performed on 40 cows on day 65 after delivery. Based on the results of cytological tests, the cows were divided into two groups: experimental (subclinical endometritis) and control (20 cows in each group). A flow cytometric analysis was performed for the leukocyte surface molecules CD4, CD8, CD14, CD21, CD25. Moreover the phagocytic activity of granulocytes and monocytes/macrophages in peripheral blood and uterine washings was determined. It has been demonstrated that the percentage of phagocytic granulocytes and monocytes/macrophages in both the peripheral blood and uterine washings was significantly lower for cows with subclinical endometritis when compared to cows undergoing a normal puerperal period (p<0.001). A significant (p<=0.001) decrease in the percentage of CD4+, CD14+, CD25+ and CD4+CD25+ leukocytes was also observed in peripheral blood of the cows from the experimental group. In uterine washings a significant decrease (p<0.001) in CD21+ and increase in CD8+ lymphocytes was detected. The results indicate that dysfunction of cell immunity coexisting with subclinical endometritis may be the main factor causing advanced inflammation of the uterus. Knowledge of immunological mechanisms observed in cows with subclinical endometritis could aid in choosing the right adjuvant therapy using immunomodulating agents. PMID- 25022332 TI - Zinc homeostasis and immunosenescence. AB - For more than 50 years, zinc is known to be an essential trace element, having a regulatory role in the immune system. Deficiency in zinc thus compromises proper immune function, like it is observed in the elderly population. Here mild zinc deficiency is a common condition, documented by a decline of serum or plasma zinc levels with age. This leads to a dysregulation mainly in the adaptive immunity that can result in an increased production of pro-inflammatory cytokines, known as a status called inflamm-aging. T cell activation as well as polarization of T helper (Th) cells into their different subpopulations (Th1, Th2, Th17, regulatory T cells (Treg)) is highly influenced by zinc homeostasis. In the elderly a shift of the Th cell balance towards Th2 response is observed, a non-specific pre activation of T cells is displayed, as well as a decreased response to vaccination is seen. Moreover, an impaired function of innate immune cells indicate a predominance of zinc deficiency in the elderly that may contribute to immunosenescence. This review summarizes current findings about zinc deficiency and supplementation in elderly individuals. PMID- 25022331 TI - Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phytoestrogen genistein on the activity and the presence of steroidogenic enzyme proteins in cultured granulosa cells of pigs. AB - Environmental estrogens such as dioxins (e.g. 2,3,7,8-tetrachlorodibenzo-p dioxin; TCDD) and phytoestrogens (e.g. genistein; G) are known to influence endocrine and reproductive processes in humans and animals. Because living organisms are usually exposed to small, non toxic, doses of dioxins and phytoestrogens, the aims of the study were to determine the effects of small, environmentally relevant doses of TCDD (100pM) and/or genistein (500nM) on: (1) the activity of steroidogenic enzymes (cholesterol side-chain cleavage enzyme, P450scc; 3beta-hydroxysteroid dehydrogenase, 3beta-HSD and aromatase, P450arom) and (2) amount of protein of the enzymes in granulosa cells isolated from medium and large ovarian follicles of pigs. To determine the activity of the enzymes, the incubation medium was supplemented with specific steroid substrates (25 hydroxycholesterol; pregnenolone; testosterone) of particular steroidogenic enzymes (P450scc, 3beta-HSD and P450arom, respectively). Subsequently, the production of progesterone (P450scc and 3beta-HSD) or estradiol (P450arom) was compared in the presence and absence of the appropriate steroid precursor. Neither genistein nor genistein combined with TCDD affected activity of P450arom and relative amounts of steroidogenic enzyme proteins in the examined granulosa cells of pigs. In contrast, genistein alone and in combination with TCDD decreased P450scc and 3beta-HSD activity as well as progesterone production in granulosa cells isolated from medium and large follicles of pigs. Because TCDD alone did not affect steroid hormone production or enzyme activity, the above effects should be ascribed solely to genistein. It appears that the effects of the examined doses of TCDD and genistein on granulosal cell functions were not additive. PMID- 25022333 TI - Gregorius Agricola memorial lecture: Lung cancer-A work-related disease for 500 years, as predicted by Agricola. AB - In the early 16th century Gregorius Agricola reported on Bergsucht (miner's consumption) in mine workers in the Erzgebirge. About 350 years later, Harting and Hesse reported on large numbers of lung cancers among the mine-workers in the same mine district, thus confirming that Bergsucht primarily was lung cancer, but could also have been pnumoconiosis or tuberculosis or a combination of both. Mining for bismuth continued another 75 years--through World War II. Bismuth mining was replaced by large scale uranium mining from the late 1940 through 1989, employing some 400-450,000 workers, resulting in the major local epidemic of work-related cancer larger than anywhere in the world, so far amounting to +/- 14-15,000 cases. Had the mine developers listened to the warnings by Agricola and Harting and Hesse, the epidemic could have been prevented. PMID- 25022334 TI - A study of dose response and organ susceptibility of copper toxicity in a rat model. AB - Copper (Cu) in higher concentration is toxic and results in various organ dysfunction. We report Cu concentration in liver, brain and kidney in the rat model following chronic exposure of oral copper sulphate at different subtoxic doses and correlate the tissue Cu concentrations with respective organ dysfunction. Fifty-four male wistar rats divided in 3 groups, the control group received saline water and the experimental group (Group-IIA and IIB) received oral copper sulphate in dose of 100 and 200mg/kg Body Weight. At the end of 30 days, 60 days and 90 days of exposure, six rats were sacrificed from each group. The maximum peak force in grip strength, latency to fall in rotarod and percentage attention score in Y-maze were significantly reduced in the copper sulphate exposed rats compared to the controls at all time points and these were more marked in Group-IIB compared to Group-IIA. Cu concentration was significantly higher in liver, kidney and brain in the Group-II compared to the Group-I. The Cu concentration was highest in the liver (29 folds) followed by kidney (3 folds) and brain (1.5 folds). Serum ALT, AST and bilirubin correlated with liver Cu, BUN with kidney Cu, and grip strength, rotarod and Y-maze findings correlated with brain Cu level. In rats, chronic oral copper sulphate exposure at subtoxic level results in neurobehavioral abnormality and liver and kidney dysfunctions due to increased Cu concentration in the respective organs. Liver is the most vulnerable organ and copper toxicity increases with increasing dose and duration of exposure. PMID- 25022335 TI - Beta-amyloid auto-antibodies are reduced in Alzheimer's disease. AB - Accumulation and cytotoxicity of amyloid beta (Abeta) are understood as the major cause of Alzheimer's disease (AD). There is evidence that naturally occurring antibodies against amyloid beta (Abeta) protein play a role in Abeta-clearance, and such a mechanism appears to be impaired in AD. In the present study, the anti Abeta antibodies in the serum from individuals with and without late onset AD were measured using ELISA and dot-blot methods. Abeta auto-antibodies in serum were mainly targeted to Abeta1-15 epitope and its titer was significantly lower in AD patients than elderly non-AD controls (NC). The dot-blot analysis further demonstrated that auto-antibodies against fibrillar Abeta42, Abeta1-15 and Abeta16-30 epitopes were all in a lower level in AD than in NC. The isotypes of the auto-antibodies were mainly non-inflammatory IgG2 type. We also analyzed the relationship of auto-Abeta antibody levels with the genotypes of apolipoprotein E (ApoE) and ANKK1/DRD2 gene. PMID- 25022337 TI - Endoscopic haemostasis: an overview of procedures and clinical scenarios. AB - Acute gastrointestinal bleeding is among the most urgent situations in daily gastroenterological practise. Endoscopy plays a key role in the diagnosis and treatment of such cases. Endoscopic haemostasis is probably the most important technical challenge that must be mastered by gastroenterologists. It is essential for both the management of acute gastrointestinal haemorrhage and the prevention of bleeding during high-risk endoscopic procedures. During the last decade, endoscopic haemostasis techniques and tools have grown in parallel with the number of devices available for endotherapy. Haemostatic powders, over-the-scope clips, haemostatic forceps, and other emerging technologies have changed daily practise and complement the standard available armamentarium (injectable, thermal, and mechanical therapy). Although there is a lack of strong evidence based information on these procedures because of the difficulty in designing statistically powerful trials on this topic, physicians must be aware of all available devices to be able to choose the best haemostatic tool for the most effective procedure. We herein present an overview of procedures and clinical scenarios to optimise the management of gastrointestinal bleeding in daily practise. PMID- 25022336 TI - Immunizations with unmodified tumor cells and simultaneous COX-2 inhibition eradicate malignant rat brain tumors and induce a long-lasting CD8(+) T cell memory. AB - Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon gamma levels and CD8(+) T cells systemically and intratumorally. In conclusion, we demonstrate that cyclooxygenase-2 inhibition is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors. PMID- 25022338 TI - The liver protective effect of methylprednisolone on a new experimental acute-on chronic liver failure model in rats. AB - BACKGROUND: Acute-on-chronic liver failure is a severe, life-threatening entity and the comprehension of this disease is incomplete. Currently, a reasonable surgical model of acute-on-chronic liver failure is still lacking. The aim of this study was to establish a new model of acute-on-chronic liver failure in rats and to investigate the protective effects of methylprednisolone on this model. METHODS: An obstructive jaundice model in rats was established. Two weeks later, the animals were subjected to a choledochoduodenostomy and a reduced-size hepatic ischaemia/reperfusion injury. Animals were randomly divided into a control group, a methylprednisolone injected via the tail vein group and a methylprednisolone injected via the portal vein group. The survival rates and serum levels of alanine transaminase, aspartate aminotransferase, total bilirubin, tumour necrosis factor alpha, and interferon gamma of the rats were measured and the pathological changes in liver tissues were observed. RESULTS: The survival rate was significantly improved in the methylprednisolone treatment groups. Serum levels of the biochemical indexes were the lowest in the portal vein injection group. Liver tissues under microscopy presented severe pathological injury in the control group. CONCLUSION: This model could be useful for further research into acute-on-chronic liver failure and methylprednisolone may be a potential therapeutic agent for this disease. PMID- 25022340 TI - Behavioral assessment of language brain processing in the first year of life. AB - An up-to-date review of the behavioral assessments of language development in the first year of life is reported. After recalling the anatomical bases of the early development of the auditory system, the different stages of language development during the first year of life are considered: discrimination, transition and perception. The different kinds of behavioral assessment during the course of the first year are then described by stressing their indications and limitations. PMID- 25022339 TI - Segmental kidney volumes measured by dynamic contrast-enhanced magnetic resonance imaging and their association with CKD in older people. AB - BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a potentially powerful tool for analysis of kidney structure and function. The ability to measure functional and hypofunctional tissues could provide important information in groups at risk for chronic kidney disease (CKD), such as the elderly. STUDY DESIGN: Observational study with a cross-sectional design. SETTING & PARTICIPANTS: 493 volunteers (aged 72-94 years; 278 women; mean estimated glomerular filtration rate [eGFR], 67+/-15mL/min/1.73m(2); 40% with CKD) in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. PREDICTOR: DCE-MRI kidney segmentation data. OUTCOMES & MEASUREMENTS: eGFR, urine albumin-creatinine ratio (ACR), and risk factors for and complications of CKD. RESULTS: After adjustment for age, sex, and height, eGFR was related to kidney volume (DeltaR2=0.19; P<0.001), cortex volume (DeltaR2=0.14; P<0.001), medulla volume (DeltaR2=0.18; P<0.001), and volume percentages of fibrosis (DeltaR2=0.03; P<0.001) and fat (DeltaR2=0.01; P=0.03). In similarly adjusted models, log(ACR) was related to kidney volume (DeltaR2=0.02; P<0.001) and fibrosis volume percentage (DeltaR2=0.03; P<0.001). Using multivariable regression models adjusted for eGFR, ACR, age, sex, and height, kidney volume was related positively to body mass index (B=29.9+/-2.1[SE]mL; P<0.001), smoking (B=19.7+/ 7.7mL; P=0.01), and diabetes mellitus (B=14.8+/-7.1mL; P=0.04) and negatively to hematocrit (B=-4.4+/-2.1mL; P=0.04 [model R2=0.72; P<0.001]); relations were per 1-SD greater value of the variable. Fibrosis volume percentage was associated positively with body mass index (B=0.28+/-0.03; P<0.001), cardiac output (B=0.15+/-0.03; P<0.001), and heart rate (B=0.08+/-0.03; P=0.01) and negatively with hematocrit (B=-0.07+/-0.3; P=0.02) and augmentation index (B=-0.06+/-0.03; P=0.04 [model R2=0.49; P<0.001]); again, relations are per 1-SD greater value of the variable. LIMITATIONS: Automatic segmentations were not validated by histology. The limited age range prevented meaningful interpretation of age effects on measured data or the automatic segmentation procedure. CONCLUSIONS: Kidney volume, cortex volume, and hypofunctional volume fraction assessed by DCE MRI may provide information about CKD risk and prognosis beyond that provided by eGFR and urine ACR. PMID- 25022341 TI - Responsiveness of the MD-childhood rating scale in dyskinetic cerebral palsy patients undergoing anticholinergic treatment. AB - BACKGROUND: Movement Disorder-Childhood Rating Scale (MD-CRS) is a new tool for assessment of movement disorders during developmental age. AIM: In this study we evaluated a cohort of 47 patients affected by dyskinetic cerebral palsy and treated with anticholinergic drug (trihexyphenidyl) over one year in order to verify the responsiveness of the new scale. METHODS: The participants were divided into two groups according to their age (0-3 years; 4-18 years) and were evaluated using MD-CRS 0-3 or MD-CRS 4-18 at baseline, i.e., before starting pharmacological treatment (T0), after 6 (T1) and 12 months (T2) of treatment. Univariate repeated measures ANOVA with a Greenhouse-Geisser correction was performed to analyse the scale responsiveness for the three indexes (e.g., Index I, Index II and Global Index) in each group with time (T0, T1 and T2). In addition, Bonferroni test was performed to identify the source of significant differences among means. RESULTS: Significant differences were found between time points (T1 vs T0, T2 vs. T0 and T2 vs. T1) in both scales for all indexes with the exception for T2 vs. T1 for Index II in both scales and for T2 vs. T1 for the Global Index in the older age group. There was not significant correlation between observed changes in the scores and age of children, either for MD-CRS 0-3 or MD-CRS 4-18. CONCLUSIONS: Our results suggest that MD-CRS is a suitable tool to detect changes and could be used as outcome measure for clinical trials. Further studies will be necessary to prove the efficacy of trihexyphenidyl for dyskinetic cerebral palsy. PMID- 25022342 TI - Analysis of a pilot program to implement physical therapy for women with gynecologic fistula in the Democratic Republic of Congo. AB - OBJECTIVE: To describe components of a physical therapy pilot program for women with gynecologic fistula, and to report prospective data from the first 2 years of program implementation. METHODS: A single-cohort observational study with repeated measures was conducted at HEAL Africa Hospital, Goma, Democratic Republic of Congo. Hospital staff received training in pelvic floor physical therapy. Guidelines for exercise, functional training, and reproductive health education were integrated into the existing program. Demographics, clinical findings, and functional outcomes were recorded. Key stakeholders were interviewed to understand the perceived strengths and limitations of the program. RESULTS: A total of 205 women were followed up; 161 participated in physical therapy, with an average of 9.45 sessions. Of 161 women examined postoperatively, 102 (63.4%) reported no incontinence; they remained continent at discharge. Of 21 who indicated a change in level of incontinence during postoperative physical therapy, 15 (71.4%) improved. The program was feasible and well received by staff and patients. CONCLUSION: Pelvic floor physical therapy could have significant results in women with gynecologic fistula, may be an important adjunctive treatment in comprehensive fistula care, and warrants further investigation. PMID- 25022343 TI - Access to transport for women with hypovolemic shock differs according to weeks of pregnancy. AB - OBJECTIVE: To examine whether women with hypovolemic shock secondary to obstetric hemorrhage are transported to referral hospitals differently depending on weeks of pregnancy in Zambia. METHODS: In a retrospective study, transport type, wait time, and transit time were assessed for women with obstetric hemorrhage and hypovolemic shock transported from 26 primary health centers to three referral hospitals during 2007-2012. A mean arterial pressure of less than 60 mm Hg was used to indicate severe shock. Women were split into two categories on the basis of the number of weeks of pregnancy (<24 weeks vs >=24 weeks). RESULTS: Overall, 616 women were included. Mode of transport differed significantly by group (P<0.001). 414 (93.0%) of 445 women at 24 weeks of pregnancy or more were transported by ambulance versus 114 (66.7%) of 171 women at less than 24 weeks. Among those in severe shock, 106 (93.0%) of 114 women at 24 weeks of pregnancy or more were transported in ambulances versus 26 (52.0%) of 50 women at less than 24 weeks (P<0.001). CONCLUSION: Women at 24 weeks of pregnancy or more were given preference for ambulance transport even when signs of shock were equivalent. Policy-makers aiming to lower maternal mortality need to address transport issues regardless of the etiology of hemorrhage or week of pregnancy. PMID- 25022344 TI - Association of housing first implementation and key outcomes among homeless persons with problematic substance use. AB - OBJECTIVES: Housing First is a supportive housing model for persons with histories of chronic homelessness that emphasizes client-centered services, provides immediate housing, and does not require treatment for mental illness or substance abuse as a condition of participation. Previous studies of Housing First have found reduced governmental costs and improved personal well-being among participants. However, variations in real-world program implementation require better understanding of the relationship between implementation and outcomes. This study investigated the effects of Housing First implementation on housing and substance use outcomes. METHODS: Study participants were 358 individuals with histories of chronic homelessness and problematic substance use. Clients were housed in nine scatter-site Housing First programs in New York City. Program fidelity was judged across a set of core Housing First components. Client interviews at baseline and 12 months were used to assess substance use. RESULTS: Clients in programs with greater fidelity to consumer participation components of Housing First were more likely to be retained in housing and were less likely to report using stimulants or opiates at follow-up. CONCLUSIONS: Consistently implemented Housing First principles related to consumer participation were associated with superior housing and substance use outcomes among chronically homeless individuals with a history of substance use problems. The study findings suggest that program implementation is central to understanding the potential of Housing First to help clients achieve positive housing and substance use outcomes. PMID- 25022345 TI - Microwave-assisted radiosynthesis of the hypoxia marker 1-alpha-D-(5- deoxy-5 [18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA). AB - The routine manufacture of most short-lived positron-emitting radiopharmaceuticals (PERs) involves conventional heating to accelerate the radiolabeling process. Nucleophilic radiofluorination reactions are generally slow at lower temperatures, and are accompanied by thermal decomposition of both precursor and product at higher temperatures. This necessitates HPLC purification and results in lower recovered radiochemical yields (rRCYs). [(18)F]FAZA, a PER for clinical imaging of focal tissue hypoxia, is routinely manufactured in-house in 3-12% rRCY using a Health Canada approved conventional heating procedure. The microwave-assisted (MW) radiosynthesis of [(18)F]FAZA is now reported. METHODS: Manual (MRDS) and automated (ASU) reagent delivery systems coupled to a commercial MW unit were built in-house. The MW unit controlled power, irradiation time and monitored reaction temperature (Tmax control), while the acetylAZA tosylate precursor and QMA Accel(TM) cartridge eluent reagents (K2CO3, K2.2.2) were dispensed by the MRDS or ASU. The radiofluorination yields (RFYs) and the chemical and radiochemical TLC profiles of the post-labeling reaction mixtures were compared to those obtained using the conventional heating production method and to those reported for optimized literature methods. RESULTS: MW RFYs for [(18)F]FAZA reached >76% (n=3) in 3 min. Post-labeling analysis of the MW assisted reaction mixtures demonstrated cleaner UV and radiochemical TLC profiles than those obtained from conventional heating in routine production runs; the relatively clean MW reactions allowed rapid HPLC isolation of [(18)F]FAZA in overall rRCYs of 55+/-4%. CONCLUSIONS: In practical terms, the MW process provided only small gains in reaction time and RFY, but produced only a few secondary impurities, thereby improving the rRCY in comparison to conventional heating methods. These findings provide a rationale for adaptation of the MW assisted method for the routine production of clinical [(18)F]FAZA. PMID- 25022347 TI - Multiscale BerEp4 molecular imaging of microtumor phantoms: toward theranostics for basal cell carcinoma. AB - Basal cell carcinoma (BCC), the most common cancer in humans, appears macroscopically and microscopically similar to many other skin lesions, which makes differential diagnosis difficult. We are developing an approach for quantitative molecular imaging of BerEP4, a transmembrane biomarker for BCC, with the goal of increasing the precision and accuracy of diagnosis. This pilot study was conducted to assess the affinity and selectivity of BerEp4 antibody and assess its possible use in designing theranostic probes for BCC. We provide evidence that our photon-counting fluorescence macrodetection system can recover specific signal increases from a film/pellet phantom. Additionally, we show that a two-photon excited fluorescence /backscatter confocal microscopy system can image BerEP4 antibody/antigen complex on the surface of BerEP4-expressing cancer cells in three dimensions. Based on the initial results, BerEP4 seems to be a promising biomarker for molecular imaging of BCC. To prepare BerEP4 for eventual theranostic use, we examined the feasibility of a combined macro-/micro-optical approach to imaging BCC with various histologies. These optical methods, endowed with the ability to monitor treatment in real time, may open an opportunity for noninvasive diagnosis, treatments, and follow-up. PMID- 25022346 TI - Biologic activity of the novel orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 against canine melanoma cell lines. AB - BACKGROUND: Exportin 1 (XPO1, also known as CRM1), is a chaperone protein responsible for the export of over 200 target proteins out of the nucleus. The expression and activity of XPO1 is upregulated in several human cancers and its expression is also linked to the development of chemotherapy resistance. Recent studies using both human and murine cancer cell lines have demonstrated that XPO1 is a relevant target for therapeutic intervention. The present study sought to characterize the biologic activity of an orally bioavailable selective inhibitor of nuclear export (SINE), KPT-335, against canine melanoma cell lines as a prelude to future clinical trials in dogs with melanoma. RESULTS: We evaluated the effects of KPT-335 on 4 canine malignant melanoma cell lines and found that KPT-335 inhibited proliferation, blocked colony formation, and induced apoptosis of treated cells at biologically relevant concentrations of drug. Additionally, KPT-335 downregulated XPO1 protein while inducing a concomitant increase in XPO1 messenger RNA. Lastly, KPT-335 treatment of cell lines upregulated the expression of both protein and mRNA for the tumor suppressor proteins p53 and p21, and promoted their nuclear localization. CONCLUSIONS: KPT-335 demonstrates biologic activity against canine melanoma cell lines at physiologically relevant doses, suggesting that KPT-335 may represent a viable treatment option for dogs with malignant melanoma. PMID- 25022348 TI - Focal neurological deficits after trauma. PMID- 25022349 TI - Commentary: Dennis D. Drotar Distinguished Research Award: Innovations in pediatric chronic pain research. PMID- 25022350 TI - Gender and performance of community treatment assistants in Tanzania. AB - OBJECTIVE: To examine the effects of gender and demographics of community treatment assistants (CTAs) on their performance of assigned tasks and quantity of speech during mass drug administration of azithromycin for trachoma in rural Tanzania. DESIGN: Surveys of CTAs and audio recordings of interactions between CTAs and villagers during drug distribution. SETTING: Mass drug administration program in rural Kongwa district. PARTICIPANTS: Fifty-seven randomly selected CTAs, and 3122 residents of villages receiving azithromycin as part of the Kongwa Trachoma Project. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Speech quantity graded by Roter interaction analysis system, presence of culturally appropriate greeting and education on facial hygiene for trachoma prevention from coded analysis of audio-recorded interactions. RESULTS: At sites with all female CTAs, each CTA spent more time and spoke more in each interaction in comparison with CTAs at sites with only male CTAs and CTAs at 'mixed gender' sites (sites with both male and female CTAs). At 'mixed gender' sites, males spoke significantly more than females. Female CTAs mentioned trachoma prevention with facial cleanliness more than twice as often as male CTAs; however, both genders mentioned hygiene in <10% of interactions. Both genders had culturally appropriate greetings in <25% of interactions. CONCLUSIONS: Gender dynamics affect the amount of time that CTAs spend with villagers during drug distribution, and the relative amount of speech when both genders work together. Both genders are not meeting expectations for trachoma prevention education and greeting villagers, and novel training methods are necessary. PMID- 25022351 TI - Resource development in otolaryngology-head and neck surgery: an analysis on patient education resource development. AB - BACKGROUND: There is a need for educational tools in the consenting process of otolaryngology-head and neck procedures. A development strategy for the creation of educational tools in otolaryngology-head and neck surgery, particularly pamphlets on the peri-operative period in an adenotonsillectomy, is described. METHODS: A participatory design approach, which engages key stakeholders in the development of an educational tool, is used. Pamphlets were created through a review of traditional and grey literature and then reviewed by a community expert in the field. The pamphlets were then reviewed by an interdisciplinary team including educational experts, and finally by less vulnerable members of the target population. Questionnaires evaluating the pamphlets' content, layout, style, and general qualitative features were included. RESULTS: The pamphlets yielded high ratings across all domains regardless of patient population. General feedback was provided by a non-vulnerable patient population and final pamphlets were drafted. CONCLUSIONS: By using a participatory design model, the pamphlets are written at an appropriate educational level to incorporate a broad audience. Furthermore, this methodology can be used in future resource development of educational tools. PMID- 25022352 TI - Norcantharidin induces growth inhibition and apoptosis of glioma cells by blocking the Raf/MEK/ERK pathway. AB - BACKGROUND: Malignant gliomas represent the most common primary brain tumors. The prognosis of patients with malignant gliomas is poor in spite of current intensive therapy and novel therapeutic modalities are needed. Here we report that norcantharidin is effective in growth inhibition of glioma cell lines in vitro. METHODS: Glioma cell lines (U87 and C6) were treated with norcantharidin. The effects of norcantharidin on the proliferation and apoptosis of glioma cells were measured by 3-[4,5-dimethylthiazol-2-thiazolyl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry. Western blotting was employed to determine the signaling pathway changes. RESULTS: The results showed that norcantharidin effectively inhibited cell growth and induced apoptosis in glioma cells, which was concurrent with inhibition of the expression of phospho-MEK and phospho-ERK. Furthermore, the expression anti-apoptotic proteins Bcl-2 and Mcl-1 significantly reduced, but no changes in Bcl-xL and Bax. CONCLUSIONS: Our findings demonstrate that norcantharidin is effective for growth inhibition of glioma cell lines and suggest that norcantharidin may be a new therapeutic option for patients with glioma. PMID- 25022353 TI - Nutrient transfer in plant-fungal symbioses. AB - Almost all plant species form symbioses with soil fungi, and nutrient transfer to plants is largely mediated through this partnership. Studies of fungal nutrient transfer to plants have largely focused on the transfer of limiting soil nutrients, such as nitrogen and phosphorous, by mycorrhizal fungi. However, certain fungal endophytes, such as Metarhizium and Beauveria, are also able to transfer nitrogen to their plant hosts. Here, we review recent studies that have identified genes and their encoded transporters involved in the movement of nitrogen, phosphorous, and nonlimiting soil nutrients between symbionts. These recent advances in our understanding could lead to applications in agricultural and horticultural settings, and to the development of model fungal systems that could further elucidate the role of fungi in these symbioses. PMID- 25022354 TI - Common variations in BMP4 confer genetic susceptibility to sporadic congenital heart disease in a Han Chinese population. AB - Congenital heart disease (CHD) is the most common birth defect in humans. The genetic causes of sporadic CHD remain largely unknown. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor-beta (TGF-beta) family, is required for normal heart development. Loss of BMP4 gene expression in mice is associated with septal defects, defective endocardial cushion remodeling, and abnormal semilunar valve formation. This study evaluated the contribution of single nucleotide polymorphisms (SNPs) in BMP4 to CHD susceptibility in a case control study of 575 patients with CHD and 844 non-CHD control subjects in a Chinese population. The BMP4 SNP rs762642 was associated with CHD in an additive model (odds ratio [OR]add 1.22; 95 % confidence interval [CI] 1.04-1.43; P add = 0.02). Stratified analysis by CHD subtypes showed a significant association only between rs762642 and atrial septal defect (ORadd 1.33; 95 % CI 1.04-1.72; P add = 0.03) in the additive model. This study was the first to indicate that a common variant of BMP4 may contribute to susceptibility to sporadic CHD in a Chinese population. PMID- 25022355 TI - Antioxidant effects of the sarsaparilla via scavenging of reactive oxygen species and induction of antioxidant enzymes in human dermal fibroblasts. AB - Ultraviolet (UV) radiation from sunlight causes distinct changes in collagenous skin tissues as a result of the breakdown of collagen, a major component of the extracellular matrix. UV irradiation downregulates reactive oxygen species (ROS) elimination pathways, thereby promoting the production of ROS, which are implicated in skin aging. Smilax glabra Roxb (sarsaparilla) has been used in folk medicine because of its many effects. However, no study on the protective effects of sarsaparilla root (SR) on human dermal fibroblasts has been reported previously. Here, we investigated the protective effect of SR against oxidative stress in dermal fibroblasts. SR significantly inhibited oxidative damage and skin-aging factor via mitogen-activated protein kinase signaling pathways. Also, SR decreased Ca(2+) and ROS, mitochondrial membrane potential, dysfunction, and increased glutathione, NAD(P)H dehydrogenase and heme oxygenase-1. These results demonstrate that SR can protect dermal fibroblasts against UVB-induced skin aging via antioxidant effects. PMID- 25022356 TI - Darwin's multicellularity: from neurotrophic theories and cell competition to fitness fingerprints. AB - Metazoans have evolved ways to engage only the most appropriate cells for long term tissue development and homeostasis. In many cases, competitive interactions have been shown to guide such cell selection events. In Drosophila, a process termed cell competition eliminates slow proliferating cells from growing epithelia. Recent studies show that cell competition is conserved in mammals with crucial functions like the elimination of suboptimal stem cells from the early embryo and the replacement of old T-cell progenitors in the thymus to prevent tumor formation. Moreover, new data in Drosophila has revealed that fitness indicator proteins, required for cell competition, are also involved in the culling of retinal neurons suggesting that 'fitness fingerprints' may play a general role in cell selection. PMID- 25022357 TI - Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. AB - PURPOSE OF REVIEW: Macrophage activation syndrome is the rheumatic disease associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm. In this review, we highlight recent publications related to the pathoetiology of hyperinflammatory syndromes with an emphasis on how this new knowledge will guide our diagnosis, treatment, and future research efforts to better understand these deadly conditions. RECENT FINDINGS: The heterogeneity of clinical manifestations seen in patients with hyperinflammatory syndromes continues to grow as novel genetic and immunotherapeutic triggers of cytokine storm have been identified. Recent studies characterize unique cytokine and gene expression profiles from patients with different hyperinflammatory syndromes, whereas novel murine models begin to define networks of immune dysregulation thought to drive excessive inflammation in cytokine storm. SUMMARY: Emerging evidence suggests hypercytokinemia is the driving cause of immunopathology and morbidity/mortality in hyperinflammatory syndromes. Therefore, approaches to block cytokine function may be fruitful in treating hyperinflammatory syndromes with less toxicity than current therapies. However, not all hyperinflammatory syndromes result in the same pathogenic cytokine profile, implying that a personalized approach will be required for effective use of anticytokine therapies in the treatment of hyperinflammatory syndromes. PMID- 25022358 TI - Update on infections and vaccinations in systemic lupus erythematosus and Sjogren's syndrome. AB - PURPOSE OF REVIEW: To provide an update on infections in systemic lupus erythematosus (SLE) and Sjogren's syndrome, particularly addressing their role as triggers of autoimmunity, their impact on mortality, the main microorganisms, the approaches to differential diagnosis with disease flares and recommendations for vaccination. RECENT FINDINGS: New mechanisms for autoimmunity triggered by Epstein-Barr virus and human commensal microbiota have been described. The increased risk for tuberculosis was recently demonstrated for the first time in Sjogren's syndrome. C-reactive protein was reported to be a more sensitive and specific marker for bacterial infections in SLE than procalcitonin and phagocyte specific S100A8/A9 protein. Inactivated vaccines are well tolerated and efficacy was demonstrated for influenza vaccine. Immunogenicity is generally reduced but adequate in SLE. Prednisone or immunosuppressants are associated with decreased vaccine serological response, whereas hydroxicloroquine seems to improve vaccine immunogenicity. Other infection-preventive measures for these diseases include antimalarials and prophylaxis for tuberculosis or Pneumocystis jirovecii. SUMMARY: Advances in the role of infectious agents as triggers for SLE and Sjogren's syndrome have provided new insights into disease development. Knowledge on vaccine immunogenicity, safety and efficacy has improved with evidence of a generally reduced but adequate response for inactivated vaccines in SLE. Other preventive measures comprise infection prophylaxis and antimalarials. PMID- 25022359 TI - Detection of non-Hodgkin's lymphoma in ovarian cortex pieces during the process of cryopreservation. PMID- 25022360 TI - Using claims data to generate clinical flags predicting short-term risk of continued psychiatric hospitalizations. AB - OBJECTIVE: As health information technology advances, efforts to use administrative data to inform real-time treatment planning for individuals are increasing, despite few empirical studies demonstrating that such administrative data predict subsequent clinical events. Medicaid claims for individuals with frequent psychiatric hospitalizations were examined to test how well patterns of service use predict subsequent high short-term risk of continued psychiatric hospitalizations. METHODS: Medicaid claims files from New York and Pennsylvania were used to identify Medicaid recipients ages 18-64 with two or more inpatient psychiatric admissions during a target year ending March 31, 2009. Definitions from a quality-improvement initiative were used to identify patterns of inpatient and outpatient service use and prescription fills suggestive of clinical concerns. Generalized estimating equations and Markov models were applied to examine claims through March 2011, to see what patterns of service use were sufficiently predictive of additional hospitalizations to be clinically useful. RESULTS: A total of 11,801 individuals in New York and 1,859 in Pennsylvania identified met the cohort definition. In both Pennsylvania and New York, multiple recent hospitalizations, but not failure to use outpatient services or failure to fill medication prescriptions, were significant predictors of high risk of continued frequent hospitalizations, with odds ratios greater than 4.0. CONCLUSIONS: Administrative data can be used to identify individuals at high risk of continued frequent hospitalizations. Payers and system administrators could use such information to authorize special services (such as mobile outreach) for such individuals to promote service engagement and prevent rapid rehospitalizations. PMID- 25022362 TI - Novel Hydrogen Bioreactor and Detection Apparatus. AB - In vitro hydrogen generation represents a clear opportunity for novel bioreactor and system design. Hydrogen, already a globally important commodity chemical, has the potential to become the dominant transportation fuel of the future. Technologies such as in vitro synthetic pathway biotransformation (SyPaB)-the use of more than 10 purified enzymes to catalyze unnatural catabolic pathways-enable the storage of hydrogen in the form of carbohydrates. Biohydrogen production from local carbohydrate resources offers a solution to the most pressing challenges to vehicular and bioenergy uses: small-size distributed production, minimization of CO2 emissions, and potential low cost, driven by high yield and volumetric productivity. In this study, we introduce a novel bioreactor that provides the oxygen-free gas phase necessary for enzymatic hydrogen generation while regulating temperature and reactor volume. A variety of techniques are currently used for laboratory detection of biohydrogen, but the most information is provided by a continuous low-cost hydrogen sensor. Most such systems currently use electrolysis for calibration; here an alternative method, flow calibration, is introduced. This system is further demonstrated here with the conversion of glucose to hydrogen at a high rate, and the production of hydrogen from glucose 6 phosphate at a greatly increased reaction rate, 157 mmol/L/h at 60 degrees C. PMID- 25022361 TI - Cardioprotection afforded by exercise training prior to myocardial infarction is associated with autonomic function improvement. AB - BACKGROUND: It has been suggested that exercise training (ET) protects against the pathological remodeling and ventricular dysfunction induced by myocardial infarction (MI). However, it remains unclear whether the positive adjustments on baroreflex and cardiac autonomic modulations promoted by ET may afford a cardioprotective mechanism. The aim of this study was to evaluate the effects of aerobic ET, prior to MI, on cardiac remodeling and function, as well as on baroreflex sensitivity and autonomic modulation in rats. METHODS: Male Wistar rats were divided into 4 groups: sedentary rats submitted to Sham surgery (C); trained rats submitted to Sham surgery (TC); sedentary rats submitted to MI (I), trained rats submitted to MI (TI). Sham and MI were performed after ET period. After surgeries, echocardiographic, hemodynamic and autonomic (baroreflex sensitivity, cardiovascular autonomic modulation) evaluations were conducted. RESULTS: Prior ET prevented an additional decline in exercise capacity in TI group in comparison with I. MI area was not modified by previous ET. ET was able to increase the survival and prevent additional left ventricle dysfunction in TI rats. Although changes in hemodynamic evaluations were not observed, ET prevented the decrease of baroreflex sensitivity, and autonomic dysfunction in TI animals when compared with I animals. Importantly, cardiac improvement was associated with the prevention of cardiac autonomic impairment in studied groups. CONCLUSIONS: Prior ET was effective in changing aerobic capacity, left ventricular morphology and function in rats undergoing MI. Furthermore, these cardioprotective effects were associated with attenuated cardiac autonomic dysfunction observed in trained rats. Although these cause-effect relationships can only be inferred, rather than confirmed, our study suggests that positive adaptations of autonomic function by ET can play a vital role in preventing changes associated with cardiovascular disease, particularly in relation to MI. PMID- 25022363 TI - Inverse magnetorheological fluids. AB - We report a new kind of field-responsive fluid consisting of suspensions of diamagnetic (DM) and ferromagnetic (FM) microparticles in ferrofluids. We designate them as inverse magnetorheological (IMR) fluids for analogy with inverse ferrofluids (IFFs). Observations on the particle self-assembly in IMR fluids upon magnetic field application showed that DM and FM microparticles were assembled into alternating chains oriented along the field direction. We explain such assembly on the basis of the dipolar interaction energy between particles. We also present results on the rheological properties of IMR fluids and, for comparison, those of IFFs and bidispersed magnetorheological (MR) fluids. Interestingly, we found that upon magnetic field application, the rheological properties of IMR fluids were enhanced with respect to bidispersed MR fluids with the same FM particle concentration, by an amount greater than the sum of the isolated contribution of DM particles. Furthermore, the field-induced yield stress was moderately increased when up to 30% of the total FM particle content was replaced with DM particles. Beyond this point, the dependence of the yield stress on the DM content was non-monotonic, as expected for FM concentrations decreasing to zero. We explain these synergistic results by two separate phenomena: the formation of exclusion areas for FM particles due to the perturbation of the magnetic field by DM particles and the dipole-dipole interaction between DM and FM particles, which enhances the field-induced structures. Based on the second phenomenon, we present a theoretical model for the yield stress that semi-quantitatively predicts the experimental results. PMID- 25022364 TI - Review of family therapy and dementia: twenty-five years on. AB - BACKGROUND: We reviewed the literature on family therapy and dementia to investigate the following: what is known about the use of family therapy in the context of living with dementia; what are the challenges of working in this context; and what guidelines/models are available to guide family therapists working with families living with dementia. METHODS: We searched English language literature from 1992 onwards, classified the resulting papers into broad categories of theoretical, expository, or research (descriptive, quantitative, or qualitative), and conducted a narrative review to draw learning points from the identified papers. RESULTS: In total 31 papers were identified: five theoretical, 11 expository; and 15 research papers. Several papers described methodologies; psychotherapeutic interventions applied to family members; or complex intervention packages in which the role of family therapy could not be separately identified, rather than family therapy. A range of outcomes were investigated, often involving the caregiver. Several authors suggest areas in dementia care where family therapy is likely to be beneficial. CONCLUSIONS: Although the literature on family therapy and dementia has grown over the past 25 years and suggests potentially useful roles for therapy, a number of challenges exist in terms of context, family, and therapy itself. There is a need for further research, particularly into the following fields: How to evaluate the success of therapy; how to ensure treatment integrity; how to make techniques from family therapy available more widely; and how to train the health and social care workforce in working with families. PMID- 25022365 TI - Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling. AB - Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS) to mount innate immune responses. The TLR4-induced release of pro- and anti inflammatory cytokines generates robust inflammatory responses, which must then be restrained to avoid disease. New mechanisms for the critical regulation of TLR induced cytokine responses are still emerging. Here we find TLR4 complexes localized in LPS-induced dorsal ruffles on the surface of macrophages. We discover that the small GTPase Rab8a is enriched in these ruffles and recruits phosphatidylinositol 3-kinase (PI3Kgamma) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3Kgamma function to regulate Akt signalling generated by surface TLR4. Rab8a and PI3Kgamma do not affect TLR4 endocytosis, but instead regulate mammalian target of rapamycin signalling as a mechanism for biasing the cytokine profile to constrain inflammation in innate immunity. PMID- 25022366 TI - 11C-mHED for PET / CT: principles of synthesis, methodology and first clinical applications. AB - Alterations of the cardiac autonomic nervous system play an important role in the pathway of many heart diseases. Nuclear imaging tools have been demonstrated to be useful for global and regional assessment of myocardial innervation. We used (11)C-meta-hydroxy-ephedrine ((11)C-mHED), a catecholamine analogue, as a radiotracer usable with a PET/CT scanner to study the cardiac sympathetic system. After a fast and automatic synthesis of mHED and its labeling with (11)C, we acquired cardiac images by using a PET/ CT scanner. In this paper we present our preliminary results showing the radiotracer bio-distribution in humans 10 minutes post injection. The present study assesses the feasibility of PET/CT with the radiolabeled catecholamine analogue ((11)C-mHED) in order to determine sympathetic innervation in the human heart. PMID- 25022367 TI - Sensitivity of spatiotemporal gait parameters in measuring disease severity in Friedreich ataxia. AB - Friedreich ataxia (FRDA) is an autosomal recessive disease with gait ataxia being the main source of morbidity. Mobility progressively declines, from initial symptom onset at approximately 10-15 years of age to being unable to ambulate 10 15 years later. Here, we sought to investigate the relationship between spatiotemporal gait parameters and clinical markers of disease severity. Thirteen people with FRDA walked along an 8.3-m GAITRite(r) mat six times each at their preferred fast and slow speeds. Relationships between spatiotemporal gait parameters and a range of clinical and disease characteristics were examined. Significant correlations were found between spatiotemporal gait characteristics at each of the walking speeds and Friedreich Ataxia Rating Scale (FARS) score and disease duration. During the fast-walking condition, gait speed and cadence decreased with an increase in disease duration and the FARS score. GAA1 repeat expansion negatively correlated with double-support percentage of the gait cycle in all speed conditions demonstrating a relationship between the genetic mutation and compensatory strategies for impaired dynamic balance. In all speed conditions, there were correlations between a range of spatiotemporal gait characteristics and the timed 25-ft walk test, a well-established measure of gait mobility. These findings suggest that spatiotemporal gait parameters are a sensitive measure of gait decline in individuals with FRDA and should be considered for inclusion in intervention studies whilst participants are still ambulant. PMID- 25022368 TI - A Quixotic journey with a fairy tale ending? A brief history of hyperthermia. PMID- 25022369 TI - Concurrent chemoradiation for carcinoma of cervix: what lies beyond? PMID- 25022370 TI - Art in the time of disease. PMID- 25022371 TI - Clinical correlative study on early detection of oral cancer and precancerous lesions by modified oral brush biopsy and cytology followed by histopathology. AB - BACKGROUND: Oral cancer accounts for 5% of all malignant tumors and 60% of these lesions are well advanced at the time of diagnosis. The early diagnosis could prevent a large number of deaths due to this disease. AIMS: This study aims to evaluate and compare the clinical usefulness of exfoliative cytology, modified brush biopsy (without computer assisted analysis), and biopsy in early detection of oral premalignant and malignant lesions. MATERIALS AND METHODS: Modified oral brush biopsy (using baby toothbrush) and exfoliative cytology was performed on 225 clinically diagnosed oral precancerous lesions (suspected) selected from among 1099 lesions in 877 patients. Scalpel or punch biopsy was performed based on clinic-cytological evidence (test result and/or clinical judgment) on only 117 lesions. All the specimens were analyzed manually in a double-blinded fashion. STATISTICAL ANALYSIS USED: RESULTS were analyzed using Statistical package for Social Sciences version 12 (SPSS Inc., Chicago, IL, USA) and subjected to Fischer exact test. RESULTS: Of 117 lesions that underwent all the three tests, modified oral brush biopsy showed a reasonably higher specificity (68.42%) and sensitivity (81.69%) when compared with specificity (86.48%) and sensitivity (48.57%) of cytology. CONCLUSION: The results demonstrate that modified oral brush biopsy has higher efficacy than routine cytology and can be used as a potentially practical oral cancer screening tool in resource challenged settings. However, clinical judgment is of prime importance. Immediate biopsy is mandatory in highly suspicious lesions proposed under the diagnostic criteria of "clinically diagnosed carcinoma in situ". PMID- 25022372 TI - The role of serum carcinoembryonic antigen in predicting responses to chemotherapy and survival in patients with non-small cell lung cancer. AB - BACKGROUND: Previous studies indicated that carcinoembryonic antigen (CEA) could predict the therapeutic objective response (OR) and overall survival (OS) of patients with cancers, including non-small cell lung cancer (NSCLC). However, the role it could play in evaluating therapeutic responses and OS in patients with NSCLC requires further elucidation. Herein, we investigated the potential role of CEA in predicting OR and OS in patients with NSCLC. MATERIALS AND METHODS: For this retrospective study, the medical records of 689 patients with NSCLC who were treated at Nanjing Jinling Hospital between January 2000 and August 2011 were reviewed. Serum levels of CEA of these patients were measured before and after chemotherapy. The relatedness between CEA levels and OR, and between CEA and OS were investigated for correlations via a series of statistical analyses. RESULTS: The baseline serum CEA level of 689 patients was 54.18 +/- 143.45 ng/mL. Serum CEA significantly decreased after two cycles of chemotherapy (t = 2.196, P = 0.031). The receiver operator characteristic (ROC) curve analysis showed that a 5.28% reduction in CEA level was an appropriate cut-off value for predicting the OR to chemotherapy, with a sensitivity of 61.3% and a specificity of 62.4%. The Kaplan-Meier survival analysis indicated no significant correlation between baseline CEA and OS (P = 0.079). CONCLUSION: Our study shows that while the baseline level of CEA was not a prognostic factor, the post-treatment reduction of CEA can predict the OR in patients with NSCLC. PMID- 25022373 TI - Do tobacco stimulate the production of nitric oxide by up regulation of inducible nitric oxide synthesis in cancer: Immunohistochemical determination of inducible nitric oxide synthesis in oral squamous cell carcinoma--a comparative study in tobacco habituers and non-habituers. AB - BACKGROUND: Oral cancer accounts for 6% of all cancers. The most prevalent form of oral cancer is oral squamous cell carcinoma (OSCC), which accounts for 90% of the oral cancer cases. The major risk factor for development of OSCC is the use of tobacco in various forms. NO has been studied widely over the years due to its role in various physiological and pathophysiological processes, including its complex role in carcinogenesis. MATERIALS AND METHODS: A total of 20 cases of OSCC in tobacco habituers and tobacco non-habituers were retrieved respectively from the archival biopsy specimens. Immunohistochemistry was done to assess the inducible nitric oxide synthase (iNOS) protein. RESULTS: This study was performed to assess the correlation between tobacco and nitric oxide in OSCC in order to know the association of these two in the process of carcinogenesis. The results showed the enhanced expression of iNOS in tobacco habituers in comparison with tobacco non-habituers. Though the increased expression of iNOS is found, significant difference is not obtained with scores, but significant difference was found with intensity of staining. CONCLUSIONS: The results of the present study indicate the enhanced expression in OSCC of tobacco habituers when compared to OSCC of tobacco non-habituers indicating the effect of tobacco on nitric oxide. Carcinogenic chemical compounds in Tobacco induce nitric oxide production by iNOS, by its tumor-promoting effects which may enhance the process of carcinogenesis. PMID- 25022374 TI - Treatment outcome of docetaxel plus prednisolone for metastatic castration resistant prostate cancer in Korea. AB - AIM: We retrospectively reviewed the treatment outcomes of docetaxel plus prednisolone chemotherapy in Korean men with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This Study included 106 consecutive Korean patients with mCRPC who were treated with a 3-weekly regimen of docetaxel plus prednisolone chemotherapy between 2005 and 2011. The oncologic results and treatment-related adverse events were analyzed. RESULTS: The mean patient age was 66 years. Of the 106 patients, 70 (66.0%) received docetaxel as the first-line chemotherapy. A 50% reduction in prostate-specific antigen and objective response in measurable lesion were observed in 45 (48.9%) and 14 (17.9%) patients respectively. Fifteen (14.4%) patients experienced grade 3 or higher neutropenic fever. One patient had a treatment-related death. median follow-up time was 26.5 months. The median progression-free survival and overall survival (OS) were 6.0 and 16.0 months respectively. Of several factors examined, multivariate analysis Identified good performance status and first-line setting predict longer OS. The median OS of the patients in the first- and second-line setting was 23.0 versus 11.0 months (Hazard ratio 2.485, 95% confidence interval 1.558-3.966, P < 0.001). The survival rates in the first-line at 12 and 24 months were 73.8% and 47.2% respectively. CONCLUSION: Korean castration-resistant prostate cancer patients that receive docetaxel chemotherapy have a relatively longer survival outcome compared with western countries in the first-line setting. In addition, good performance status and first-line setting predicts longer survival. A prospective study including genetic background associated with the prognosis of mCRPC patients might be required. PMID- 25022375 TI - Prognostics of Cyclin-D1 expression with chemoradiation response in patients of locally advanced oral squamous cell carcinoma. AB - OBJECTIVE: Cyclin-D1 has been strongly implicated in cell cycle proliferation particularly in the G1/S checkpoint in the cell cycle, and prognosis in many human malignancies. The present study evaluates its prognostic significance with chemoradiation response in patients of locally advanced oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: A total of 97 OSCC patients (females = 19 and males = 78), aged 20-67 years and stage III/IV were recruited. Treatment response was assessed according to World Health Organization criteria. Cyclin-D1 expression in tumor tissue was estimated by immunohistochemical method and quantified as percentage positive nuclei. RESULTS: The Cyclin-D1 expression showed significant (P < 0.01 or P < 0.001) association with tumor size, lymph node status, and clinical stage. After chemoradiation, there were 53.6% complete response (CR) and 34.0% partial response (PR) in primary tumor, and 49.5% CR and 39.2% PR in lymph node; giving an overall response rate of 85.6%. Further, the mean Cyclin-D1 expression showed significant (P < 0.05 or P < 0.001) and inverse association with chemoradiation responses (tumor size, lymph node status and overall treatment response). The 2-year progression-free and overall survival (OS) was 95.89% and 83.31% respectively. Multivariate Cox regression analysis found site of primary tumor, clinical stage, and Cyclin-D1 expression the significant (P < 0.05 or P < 0.01) and independent prognostic markers of OS and among these Cyclin-D1 expression showed the worst prognosis. The high Cyclin-D1 expression (>50%) also showed significantly lower survival in OSCC patients when compared with those had low (<10%) and moderate expressions (10-50%) (Logrank test: chi(2) = 44.42, P < 0.001). CONCLUSION: The high Cyclin-D1 expression may serve as a poor prognostic marker in OSCC. PMID- 25022376 TI - Construction, expression and characterisation of a single chain variable fragment in the Escherichia coli periplasmic that recognise MCF-7 breast cancer cell line. AB - BACKGROUND: A functional single-chain fragment variable (scFv) recognizing the MCF-7 breast cancer carcinoma cell line was constructed from the C3A8 hybridoma using phage display technology. AIM OF STUDY: This study was conducted to evaluate the binding activity of scFv antibody recognise MCF-7 breast cancer cells carcinoma, the scfv antibody constructed and expressed in Escherichia coli periplasmic. MATERIALS AND METHODS: The scFv coding sequence was cloned in frame with the pIII phage coat protein. The signal sequence included in the C terminus directed the expression of the scFv in the Escherichia coli periplasm. Following several rounds of biopanning, colonies that expressed a scFv that recognized MCF 7 cells in Western blots, ELISAs, and flow cytometry test were isolated. RESULTS: A 750-bp scFv gene was successfully isolated. Cloning and two rounds of biopanning isolated the candidate with the highest activity (clone B7), as screened by ELISA. Following poly-acrylamide gel electrophoresis (SDS-PAGE) of the purified product, a 32-kDa band was observed. A similar-sized band was observed following Western blot analysis with an E tag-specific antibody. Binding reactivity of scFv antibody with MCF cells was determined using indirect ELISA and compared with monoclonal antibodies' reactivity. Also, flow cytometry was useful in further characterization to the binding reactivity of scFv antibody with MCF-7 cells. CONCLUSIONS: The recombinant antibody technology used in this study is a rapid and effective approach that will aid in the development of the next generation of immunodiagnostic reagents. PMID- 25022377 TI - Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. AB - OBJECTIVES: This work is aimed on the study of doxorubicin cardiotoxicity and hepatotoxicity in rats and the evaluation of protective effect of trimetazidine administrated concomitantly with doxorubicin for 3 days. MATERIALS AND METHODS: Male Wistar rats used were subjected to different types of treatment (3 days); A: Control, B: Doxorubicin treatment and C: Trimetazidine and doxorubicin treatment. After sacrifice, tissular distribution of doxorubicin, cardiac scintigraphy, histological examination of the myocardium, and evaluation of liver function were assessed. RESULTS: Obtained results show that doxorubicin has a high affinity to tissues especially the heart. It causes hepatotoxicity and cardiotoxicity marked by a significant increase of aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) levels and drop of the left ventricular ejection fraction (EF LV ) by scintigraphy. Histological examination showed general alteration of myocardium structure. Concomitant administration of trimetazidine attenuates significantly the cardiotoxicity and hepatotoxity induced by doxorubicin. CONCLUSION: We have evaluated the protective effect of trimetazidine on an animal model of doxorubicin-induced cardiotoxicity and hepatotoxicity. The evaluation of these effects were assessed by several means; tissular distribution of doxorubicin, histological examination, assessment of liver function, and EF LV by scintigraphy that characterizes the originality of this study. PMID- 25022378 TI - Post-mastectomy radiation beyond chest wall in patients with N1 breast cancer: is there a benefit? AB - INTRODUCTION: Nodal stage is the most important prognostic factor and one of the indicators for loco-regional radiation in patients with breast cancer. N1 (patients with 1-3 lymph node metastases in axilla) nodal stage is a controversial area as far as axillary and supraclavicular fossa (SCF) irradiation is concerned. We conducted a retrospective analysis at our institute to assess the impact of post-mastectomy radiotherapy (PMRT) beyond chest wall (CW) in N1- nodal stage breast cancer patients. MATERIALS AND METHODS: Since January 2004 to December 2007, 293 post-mastectomy patients with N1 nodal stage breast cancer were analyzed for patient-related characteristics such as age, menopausal status, pathological stage/tumour size, tumour location, histology, oestrogen/progesterone receptor status, histological grade, extra capsular extension, lymph vascular invasion and treatment-related factors, PMRT and systemic therapy. Outcome studied were locoregional recurrence rate (LRR), disease free survival (DFS) and overall survival (OS). RESULTS: At a median follow up of 55m, 260 patients received radiotherapy; 212 to CW+SCF, 48 to the CW only; and 33 patients did not receive radiotherapy. LRR was 5% in patients who received radiotherapy to CW+SCF and 8% in CW only (P = 0.34). There was no difference in the DFS between the two groups. OS at 5 year was 88% in CW+SCF group and 76% in CW only group respectively (P < 0.001). CONCLUSION: In N1 nodal stage patients with breast cancer LRR was not significantly different after radiation to CW+SCF or to the CW only but OS was significantly better. PMID- 25022379 TI - Correlation of Computerized Tomography density patterns of lymph nodes with treatment results and outcome in head and neck cancer patients treated by 2 different chemoradiotherapy schedules. AB - AIMS/BACKGROUND: Tumor necrosis is visualized on CT scan as non enhancing hypodense area. Necrotic areas contain less oxygen and results in poor response of chemo-radiotherapy. Literature review (1) has shown that for hypodense lesions in head and neck cancer the complete response rate is lower than the isodense lesions. Locally advanced head and neck cancer require the addition of surgery but after a radical dose of radiation that is, 7000 cGy, surgery become difficult but there is no tool initially that can be used for selection of patients after delivery of 4500 cGy, that is the dose after which surgery can be performed without much difficulty. The hypothesis is that, hypodense lymph nodes even when they are small will show less response to various schedules of chemoradiotherapy so hypodensity of lymph nodes can be used as a tool to select patient, who will go for surgery after initial 4500 cGy of radiotherapy. Surgery is usually performed 2 to 3 weeks after radiotherapy, so primary can be treated to full dose while the skin in region of lymph nodes radiation field will recover from acute radiation reaction. Correlation of C T density patterns of lymph nodes in head and neck cancer patients with treatment results when two different chemoradiotherapy schedules are used is studied. MATERIALS AND METHODS: Eighty three patients with locally advanced head and neck cancer were treated with two schedules of concurrent chemoradiotherapy prospectively from August 2010 to July 2011. CT Scans of the entire neck region including primary were performed. An iodine based contrast material (150 ml) was injected intravenously starting with a bolus of 50 ml (3 ml/s), followed by a slow (1 ml/s) infusion of the remaining dose. The total tumor volume of the primary and involved neck nodes was calculated as a cuboid volume using maximum dimension in each plane: Vc= (a x b x c). Nodal density was graded. RESULTS AND CONCLUSION: No statistically significant association between recovery and CT density was found (X 2 = 0.306; P > 0.05). PMID- 25022380 TI - Orbital alveolar soft-part sarcoma: clinico-pathological profiles, management and outcomes. AB - AIM: To study the clinico-radiological and clinic-pathological features of orbital alveolar soft-part sarcomas (ASPS). MATERIALS AND METHODS: We retrieved 9 cases of orbital ASPS. Histopathological and immunohistochemical features and clinico-radiological findings were evaluated. RESULTS: Age at presentation varied from 1 to 31 years. Both, children and adults were affected. Proptosis was the most common clinical presentation. PAS-positive diastase-resistant crystals and granules were found in all cases. All patients received adjuvant radiotherapy. Two cases had positive surgical margins and were treated with additional adjuvant chemotherapy. None of the patients had recurrence or metastases till the last follow up. CONCLUSION: Early diagnosis with a multidisciplinary, multimodal approach of treatment is quintessential in achieving a long disease-free survival in patients with ASPS. PMID- 25022381 TI - HMGN2 protein inhibits the growth of infected T24 cells in vitro. AB - AIMS OF STUDY: Natural killer (NK) cells and cytolytic T lymphocytes (CTL) have been implicated as important effectors of antitumor defense. High mobility group nucleosomal-binding domain 2 (HMGN2) may be one of the effector molecules of CTL and NK cells. The antitumor effect and mechanism of HMGN2 was investigated in this study. MATERIALS AND METHODS: HMGN2 was isolated and purified from the human monocyte cell line THP-1 and then characterized by Tricine-SDS-PAGE, western blot, and mass spectrum determination. Confluent T24 cells were incubated with Klebsiella pneumoniae for 2 h, after which the extracellular bacteria were killed by the addition of gentamicin. The cells then were treated with a variety of concentrations of HMGN2. The effect of HMGN2 on the proliferation of T24 cells was analyzed with MTT, Hoechst and flow cytometry assays. RESULTS: Cell growth assay results demonstrated that HMGN2 significantly inhibited the growth of T24 bladder cancer cell lines infected by K. pneumoniae. Furthermore, results of the Hoechst and flow cytometry assays indicated that HMGN2 may promote apoptosis in this experimental model. These results suggest HMGN2 could inhibit the growth of the infected human bladder cancer cells in vitro. CONCLUSION: HMGN2 protein could inhibit the growth of infected T24 cells in vitro, and the anti-tumor action of HMGN2 was due to induce apoptosis. PMID- 25022382 TI - Utility of the trough plasma imatinib level monitoring at two time points in patients with the chronic myeloid leukemia-chronic phase. AB - INTRODUCTION: Plasma imatinib levels vary widely in patients with the chronic myeloid leukemia-chronic phase, and studies have shown improved hematological, cytogenetic, and molecular responses in patients with the higher trough imatinib levels. MATERIALS AND METHODS: We analyzed 50 consecutive patients with the chronic myeloid leukemia-chronic phase and performed plasma imatinib levels at 1 month and 12 months and correlated them with complete hematological response at 3 months and molecular response at 12 months, respectively. RESULTS: Trough plasma imatinib levels at 1 month correlated well with complete hematological response at 3 months (P = 0.007) and levels at 12 months correlated with molecular response at 12 months (P = 0.04). Compliance to imatinib also significantly correlated with imatinib levels at 1 month (P = 0.0008) and imatinib levels at 12 months (P = 0.0002). CONCLUSION: Plasma imatinib levels may be of benefit in patients not achieving desired response at defined time intervals. The plasma level monitoring also helps in the assessment of drug compliance. PMID- 25022383 TI - Micronuclei in breast aspirates. Is scoring them helpful? AB - BACKGROUND: Micronuclei scoring can be used as a biomarker of genotoxic and chromosomal damage. AIMS: 1. To score the spontaneously occurring micronuclei in the baseline population (fibroadenomas) and infiltrating ductal carcinoma, 2. Compare micronuclei frequency in benign tumors and various grades of infiltrating ductal carcinomas. MATERIALS AND METHODS: Study was done at a tertiary hospital where 40 cases of fibroadenoma and 40 cases of infiltrating ductal carcinoma were taken up. May Grunwald Giemsa stained smears were analyzed for micronuclei scoring. STATISTICAL ANALYSIS: Independent sample test (Student t test) was done to look for significant difference occurring between the controls among all grades of infiltrating ductal carcinoma. RESULTS: Mean micronuclei range in fibroadenoma was 1.8 +/- 1.9. It was 12.1 +/- 9.2, 27.4 +/- 27.2 and 100 +/- 36.5 in grade I, grade II and grade III carcinomas respectively. CONCLUSION: An increase in micronuclei values was seen from fibroadenoma to infiltrating ductal carcinoma. Micronuclei scoring can be used as a biomarker on fine needle aspiration cytology smears of breast carcinoma. PMID- 25022384 TI - Detection of survivin 2alpha gene expression in thyroid nodules. AB - CONTEXT: Functional studies of the survivin splice variants have been performed almost exclusively in various types of cancer and produced remarkable advances in our understanding of cancer biology and cancer genetics. AIM: To observation the expression of survivin 2alpha in thyroid nodules and estimate its potential as a new molecular marker in thyroid nodules screening and malignant thyroid, as well. SETTING AND DESIGN: We detected the expression of a splice variant of survivin, survivin 2alpha, in thyroid nodules. MATERIALS AND METHODS: Expression of survivin 2alpha mRNA was evaluated with specific primers by Hemi-Nested RT-PCR in 77 thyroid nodules including malignant and benign tumors, non-tumoral (goiter and thyroiditis) as well as surgical margin, non-neoplastic normal tissues adjacent to the malignant lesions. RESULT: Our data revealed for the first time the expression of survivin 2alpha in thyroid nodules. It was detected in 85.7% of non neoplastic surgical margin tissues, 71.4% of non tumoral, 63.2% of tumoral samples. Also, the expression of survivin 2alpha in benign tumor samples (64.2%) is more than malignant groups (62.8%). CONCLUSION: Survivin 2alpha expression is the highest in non-neoplastic surgical margin rather than other samples and the lowest expression was that of malignancy. According to the results, it can be concluded that survivin 2alpha protein may be has a vital protective effect throw survivin quenching due to the high expression in normal tissue compared with lesions. PMID- 25022385 TI - Analysis of the chromosomal aneuploidy by interphase fluorescence in situ hybridization (FISH) in Squamous cell carcinoma of the cervix in Jammu region of J and K state. AB - AIM: The present study was aimed to analyze the chromosomal changes obtained by using FISH. Fluorescence in situ hybridization (FISH) is a powerful technique used in the detection of chromosomal abnormalities. MATERIALS AND METHODS: During the present study, FISH technique was carried out in 26 cases of Squamous cell carcinoma of the cervix using Centromere Enumeration Probes, CEP for chromosome 3 and 17. Statistical tests including ANOVA and Chi square tests were used to analyze the numerical chromosome aberration data obtained by FISH analysis. FISH technique was also carried out in 10 healthy samples (control) by using both CEP 3 and CEP 17 probe. RESULTS AND DISCUSSION: FISH results of CEP 3 in the present study showed the frequent gains of chromosome 3 in Squamous cell carcinoma over the chromosome 17. ANOVA results were found to be significant for both CEP 3 and CEP-17 in Squamous cell carcinoma of the cervix. Chi square test (disease v/s control) was also used to study the significant difference between the patients and the controls and it was found to be significant for both chromosomes 3 and 17. PMID- 25022386 TI - Resveratrol successfully treats experimental endometriosis through modulation of oxidative stress and lipid peroxidation. AB - BACKGROUND AND AIMS: The purpose of this study was to investigate the potential therapeutic efficiency of resveratrol in the treatment of experimental endometriosis in rats. SETTINGS AND DESIGN: Experimental study was carried out in a University hospital. MATERIALS AND METHODS: Endometriosis was surgically induced in 24 female rats. Four weeks after this procedure, the viability and dimensions of the endometriosis foci were recorded. Rats were then randomly divided into three groups: (1) Control group (n = 8); (2) low dose (10 mg/kg) resveratrol group (n = 8); (3) high dose (100 mg/kg) resveratrol group (n = 8). At the end of the 7-day treatment, blood samples were taken and laparotomy was performed. The endometrial implants were processed for biochemical, histological and immunohistochemical studies. STATISTICAL ANALYSIS USED: The Kruskal-Wallis H test and one-way ANOVA test were used. RESULTS: Resveratrol-treated rats showed significantly reduced endometriotic implant volumes (P = 0.004). After treatment, a significant and dose-dependent increase in activities of superoxide dismutase and glutathione peroxidase in serum and tissue of the rats in Group 2 and Group 3 was detected. Similarly, serum and tissue malonyl dialdehyde levels and tissue catalase levels were significantly higher in Group 3 than that of control animals. Histological scores and proliferating cell nuclear antigen expression levels were also significantly reduced in Group 2 and Group 3 than that of control group. CONCLUSION: In a rat endometriosis model, resveratrol showed potential ameliorative effects on endometriotic implants probably due to its potent antioxidative properties. PMID- 25022387 TI - Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: a phase II study. AB - BACKGROUND: Cervical cancer is the most common gynecological cancer in Indian women. This study was initiated to assess whether the combination of paclitaxel and cisplatin with radiation was feasible in Indian women. AIMS AND OBJECTIVES: The aim of this study was to assess the immediate tumor response and toxicity of weekly cisplatin and paclitaxel along with radiotherapy in the treatment of cervical cancer. MATERIALS AND METHODS: Women with primary untreated squamous cell carcinoma of the cervix with FIGO stages IB2 to IIIB were treated with weekly injections of cisplatin 30 mg/m2 and paclitaxel 40 mg/m2 for 4 weeks along with radiotherapy. A total of 25 patients were enrolled in this study. Disease was assessed prior to treatment by pelvic examination and contrast enhanced computed tomography scan of the abdomen and pelvis. Response was assessed 6 weeks after completion of treatment using the same parameters. Clinical and radiological response was documented. The toxicity was assessed and was graded using the common toxicity criteria Version 3.0. Intention to treat analysis was used when reporting results. RESULTS: A total of 23 patients completed the intended treatment. There was a complete response rate of 88%, 12% were not available for response assessment. The major toxicity was Grade 3 diarrhea (48%). The mean duration of treatment was 58 days. CONCLUSIONS: Combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of cervix had a high incidence of acute toxicity. There was no increase in immediate tumor response and progression free survival with this treatment regimen. Hence, this regimen offers no added benefit when compared to the chemo radiation with cisplatin alone. PMID- 25022388 TI - Treatment outcomes after intraluminal brachytherapy following definitive chemoradiotherapy in patients with esophageal cancer. AB - AIMS AND OBJECTIVES: To report the results of treatment with intraluminal brachytherapy (ILRT) after concurrent chemoradiotherapy for esophageal carcinoma with respect to disease free survival (DFS), dysphagia free interval (DFI), and complications of treatment. MATERIALS AND METHODS: The study retrospectively analyzed the records of 26 eligible patients with nonmetastatic carcinoma of the esophagus treated with definitive chemoradiotherapy followed by ILRT between 2008 and 2011. The DFS and DFI were estimated and factors likely to influence them were analyzed. RESULTS: Nineteen (73%) patients were males. The mean age at presentation was 60 years (range: 47-90 years). All the patients had squamous cell carcinomas. Following treatment, the median DFS was 12.7 months (range: 0-27 months). Sixteen patients (61.5%) had local control of their disease, while one had residual disease at completion of treatment. Other than three patients who were not evaluated for recurrent dysphagia, six (23.1%) had proven local recurrence on follow-up. The estimated mean DFI was 13.8 months (range: 0-27 months). One patient died of tracheoesophageal fistula following treatment. On statistical analysis, only the location of tumor was prognostically significant, with lower third tumors performing worse. Other probable predictors of poor outcome included large volume (> 40 cc), tumor length (> 6 cm), and eccentric location. CONCLUSION: ILRT boost following concurrent chemoradiotherapy is well tolerated and potentially improves outcomes. It might be beneficial in selected patients with esophageal carcinoma. Further studies are required to identify its role in definitive treatment. PMID- 25022389 TI - To analyze the impact of intracavitary brachytherapy as boost radiation after external beam radiotherapy in carcinoma of the external auditory canal and middle ear: a retrospective analysis. AB - PURPOSE: The purpose of this study was to analyze the impact of intra-cavitary brachytherapy (ICBT) as boost radiation after external beam radiotherapy (EBRT) in carcinoma of the external auditory canal and middle ear (EACMA): A retrospective analysis. MATERIALS AND METHODS: A retrospective study of 18 patients with carcinoma of the EACMA who were treated with a curative intent from the year 1998 to 2010 was carried out. The age of the patients ranged from 25 years to 67 years. There were 11 male patients (61.1%) and 7 female patients (38.9%). A total of 15 (88.2%) patients were treated with curative radiation alone after a biopsy and two patients received post-operative radiation therapy. The patients were initially treated with EBRT with cobalt 60 machine up to 60-64 Gy. In our department, all the patients who were technically suitable for ICBT received an ICBT boost. RESULTS: The overall survival (OS) in these patients ranged from 7 months to 151 months (9 out of 17 patients, no evidence of disease 53%). The OS in patients treated with a combination of EBRT with ICBT was (8 out of 11) 72.7%, P value statistically significant (P value: 0.0024). The multivariate analysis shows statistically significant difference only for patients who got an ICBT boost (P Value: 0.020). CONCLUSION: ICBT as a boost after EBRT has got a positive impact on the OS. In conclusion, our results demonstrate that radical radiation therapy (EBRT and ICBT) is the treatment of choice for stage T2, carcinoma of EACMA. PMID- 25022390 TI - Clinical significance of adiponectin expression in colon cancer patients. AB - PURPOSE: Surgery is the definitive treatment for early colon cancers. Adjuvant therapies are used with the aim of eradicating micrometastases and improving cure rates. Recent studies have proposed that adiponectin might be responsible for obesity-related malignancies. We investigated the prognostic value of this cytokine. MATERIALS AND METHODS: Patients who underwent surgical removal of stage II or III (TNM staging) primary tumors and were followed for at least three years were included in the study given adequate specimen for immunohistochemical evaluation. Based on these criteria, 53 patients were included. RESULTS: Mean age was 58.3 +/- 10.1 years (35-78 years). The mean follow-up time was 41 months (10 96 months). Immunohistochemical evaluation identified 21 patients (39.6%) with cytoplasmic adiponectin present in their specimens. The rates of recurrence were 42.9% (9/21) and 34.4% (11/32) in patients with and without adiponectin expression, respectively. In cases with adiponectin expression, mean disease - free survival was 60.3 +/- 9.03 months, and in cases without adiponectin expression, mean disease - free survival was 68.7 +/- 6.67 months (P = 0.414). Mean overall survival of patients with adiponectin expression was 65 months compared to 67 months for patients without (P = 0.786). CONCLUSION: Adiponectin, which is secreted by adipose tissue, may have a role in the development and progression of cancer via its pro-apoptotic and/or anti-proliferative effects. Adiponectin expression in tumor tissues is likely to have a negative effect on disease - free survival in patients with stage II/III colon cancer; however, no statistically significant effect was demonstrated. PMID- 25022391 TI - Malignant lymphoma in Eastern India: a retrospective analysis of 455 cases according to World Health Organisation classification. AB - BACKGROUND: Malignant lymphoma (ML) is one of the most common cancers and is most prevalent in developed countries. The distribution of different subtypes of ML varies in the different geographical locations according to World Health Organization (WHO) classification. AIMS AND OBJECTIVES: The study was aimed to analyze different patterns of ML in Eastern India and to compare it with other geographical locations. MATERIALS AND METHODS: Four hundred and fifty five patients of two large hospitals in Eastern India were included over a period of four years and were categorized according to WHO classification, using morphology and immunohistochemistry (IHC). RESULTS: There were 347 (76.3%) non Hodgkin lymphomas (NHL), and 108 (23.7%) Hodgkin lymphomas (HL). Diffuse large B cell lymphoma (DLBCL) was the most common of the NHL type (35.2%) followed by the follicular lymphoma (19.3%). B cell lymphoblastic lymphoma was the least common type of NHL (1.4%). Mixed cellularity (33.3%) and nodular sclerosis (26.9%) were the two most common type of HL. Childhood lymphoma comprised of 12.5% of all ML. T cell NHL and HL were the common lymphomas in this age group. CONCLUSION: Incidence of follicular lymphoma is lower compared to western studies and mixed cellularity is most common subtype of HL unlike nodular sclerosis subtype in western world. Burkitt's type NHL though is the most common subtype of childhood ML in many studies but in our study T cell NHL is the most common type of childhood ML. PMID- 25022393 TI - An unusual case of cavernous haemangioma of the Fallopian tube. AB - Fallopian tubes are one of the uncommon sites for neoplastic lesions in the female genital tract. Haemangiomas of the fallopian tubes are rare benign neoplasms that are documented as isolated case reports only. We present a rare case of incidentally detected cavernous haemangioma of the fallopian tube in a post menopausal female who underwent hysterectomy and bilateral salphingoopherectomy for dysfunctional uterine bleeding. PMID- 25022392 TI - A comprehensive intervention program on the long-term placement of peripherally inserted central venous catheters. AB - BACKGROUND: Peripherally inserted central venous catheters (PICCs) have been increasingly utilized in treating patients in intensive care. The purpose of this study is to analyze the related complications and to evaluate effect of a comprehensive intervention on long-term PICCs. MATERIALS AND METHODS: We selected 217 and 243 cases before and after comprehensive intervention respectively from the department of radiotherapy in our hospital. Various possible factors affecting PICCs insertions and maintenance were analyzed. A quality control circle was formed for nursing care. The comprehensive intervention was performed both on catheter insertion and post-PICCs care. Complication rates were compared before and after the intervention. RESULTS: The duration for PICCs was 90 days. In the control group (before intervention), the complications were as follows: Tube feeding difficulties (23.5%), catheter dislodgment (23.5%), infection (17.6%), catheter obstruction (17.6%), puncture failure (5.9%), allergy (5.9%), and pain (5.9%). The incidence of unplanned extubations was 7.8%. The incidence of complications was significantly decreased in the test group (after intervention). Moreover, one episode of catheter obstruction (5.9%) and one episode of allergy (5.9%) were found (P < 0.01) in this study. CONCLUSION: Comprehensive intervention programs effectively reduce the incidence of complications in long-term PICCs lines. PMID- 25022394 TI - Generalized vitiligo post radiotherapy in a breast cancer patient. AB - Vitiligo is a common depigmentation disorder of skin, etiology of which is poorly understood. It has been rarely reported as a consequence of radiation at the site of irradiation, more so in patients with prior history of vitiligo. We report a rare clinical vignette that documents radiation-induced skin depigmentation, which started at the irradiated site and later manifested as generalized vitiligo, in a breast cancer patient with no family history of vitiligo. Studies describing the relationship between skin depigmentation and radiotherapeutic dose are scanty. The possible etiopathological mechanisms of vitiligo and radiation as a potential triggering factor for its development, which has been described in the literature, have been highlighted in this article. PMID- 25022395 TI - Retroperitoneal ancient schwannoma: two cases and review of literature. AB - Ancient Schwannomas are rare variants of tumors which arise from the peri-neural Schwann cells. These tumors are termed "ancient" because of the degenerative features acquired with increasing age in these tumors. They are benign, slow growing and usually detected only incidentally or due to local symptoms. Some tumors may demonstrate nuclear atypia, and may be mistakenly termed malignant. Malignant change is usually associated with von Recklinghausen's syndrome in 5% to 18% of cases. Retroperitoneal schwannomas account for only 0.5% to 5% of all cases and are extremely uncommon. They are well encapsulated and recurrences following complete surgical excision are uncommon. PMID- 25022396 TI - Aggressive angiomyxoma of greater omentum with pleural effusion in a young male. AB - Aggressive angiomyxoma is a rare, locally aggressive, myxoid mesenchymal neoplasm, preferentially arising in the pelvic and perineal regions of young adult females. It may also occur in males, in the inguinoscrotal area. Here we report a case of a young male, who presented with a firm, diffuse, nontender swelling in the abdomen and right-sided pleural effusion. Contrast-enhanced computed tomography (CT) of the abdomen showed the presence of a large, cystic mass, almost filling the entire abdominal cavity. On laparotomy, a huge mass, approximately 25 cm * 20 cm * 4 cm in size, arising from the greater omentum, with increased vascularity, and occupying the entire abdomen, was excised. Histopathological examination along with immunohistochemistry established the diagnosis of an aggressive angiomyxoma. Here, we report the case of an aggressive angiomyxoma, originating from the greater omentum, in a young male, associated with right-sided pleural effusion. PMID- 25022397 TI - Vimentin positive acantholytic penile squamous cell carcinoma with rhabdoid features. AB - Acantholytic variant of penile squamous cell carcinoma (SCC) is an exceedingly rare and associated with bad prognosis. Histologically it mimics angiosarcoma due to pseudovascular spaces. Vimentin immunopositivity in such cases represent epithelial to mesenchymal transition manifested by cellular discohesion. We describe a case of vimentin positive acantholytic penile SCC in a 55-year-old patient. PMID- 25022398 TI - Primary Ewing's sarcoma of the cranium: case series and review of literature. AB - Primary Ewing's sarcoma (EWS) of the cranium is extremely rare. It accounts for <1% of cases. We retrospectively analyzed our EWS cases to determine those which had a primary cranial involvement. Out of a total of 332 cases of EWS registered between the years 2000 and 2011, 7 were of the primary cranial involvement. Treatment modalities included surgery, chemotherapy, and radiotherapy (RT), as indicated. The follow-up ranged from 8 months to 7.5 years. In our study, parieto occipital region was the commonest site. Most patients presented with localized disease and swelling of the scalp. Excision followed by chemotherapy or RT appears to have good survival rates. At a median follow-up of 32.2 months, only one patient had a recurrence, and was successfully salvaged with second line chemotherapy. These cases illustrate that a multi-disciplinary approach in patients with EWS of the cranium results in a good outcome. PMID- 25022399 TI - Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: case report and review of literature. AB - Acute promyelocytic leukemia (APL) is an uncommon malignancy in the pediatric population, accounting for only 5-10% of pediatric acute myeloid leukemias, and for this disease to present with bone lesions at diagnosis is extremely unusual. We wish to convey that very rarely, in a pediatric cancer patient presenting with multiple extensive lytic bone lesions, the diagnosis can be APL. The treatment protocol and prognostic implications are vastly different. Histopathology is the gold standard in arriving at a correct diagnosis and delivering proper treatment in such cases. This patient had excellent response to chemotherapy. PMID- 25022400 TI - A rarely seen mucoepidermoid carcinoma of the left main bronchus. AB - Mucoepidermoid carcinomas (MEC) are rare malignant tumors that originate in the submucosal bronchial glands, and complete resection usually correlates with favorable prognosis. A 54-year-old male patient was diagnosed with high-grade MEC in the left main bronchus via bronchoscopy. After the patient was diagnosed with metastatic lung cancer, chemotherapy was started. Two years after the diagnosis, the patient is still alive. PMID- 25022401 TI - An atypical meningioma demystified and advanced magnetic resonance imaging techniques. AB - A 40-year-old male presented with visuospatial processing disturbances. Family history was free. Conventional and advanced magnetic resonance imaging (MRI) studies were performed. On T2 and fluid attenuation inversion recovery images, an increased signal intensity extra-axial lesion was demonstrated. Post-contrast scans depicted homogeneous intense contrast medium enhancement. T2* star sequence was negative for hemorrhagic or calcification foci. Diffusion-weighted imaging findings were indicative of malignant behavior and magnetic resonance venography confirmed superior sagittal sinus infiltration. Increased cerebral blood volume values were observed and peri-lesional oedema on perfusion-weighted imaging was also demonstrated. The signal intensity-time curve depicted the characteristic meningioma pattern. Spectroscopy showed increased choline and alanine levels, but decreased N-acetyl-aspartate levels. Conventional MRI is adequate for typical types of meningiomas. However, the more atypical ones, in which even the histopathologic specimen may demonstrate characteristics of typical meningioma, could be easier diagnosed with advanced MRI techniques. PMID- 25022402 TI - Primary cutaneous sweat gland carcinoma. AB - Primary cutaneous sweat gland carcinoma is a rare neoplasm of malignant sweat gland lesions. It is characterized clinically with non-symptomatic, slow-growing nodules. We report the case of a patient with cutaneous sweat gland carcinoma with local recurrence and metastasis to the lung that was treated with surgical resection therapy and chemotherapy. The initial neoplasm was excised but biopsy was not performed. The tumor then recurred 7 years later, was re-excised, biopsy was performed, and diagnosed as a low-grade hidradenocarcinoma. We presented a very good result of chemotherapy in the treatment of this rare malignant disease. It demonstrates that adjunct chemotherapy is effective to control the condition of malignant sweat-gland carcinomas patient. PMID- 25022403 TI - Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!! AB - Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiological syndrome characterized by seizures, altered level of consciousness, visual disturbance, and hyperintense lesions on magnetic resonance imaging most commonly in the posterior regions. PRES is typically associated with a number of complex clinical conditions including: Preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases, and high-dose anti-neoplastic therapy. We herein describe a case of recurrent PRES in a 29-year old lady of refractory anaplastic large-cell lymphoma who was on second-line chemotherapy with Ifosfamide-Carboplatin-etoposide regimen. We have also tried to illustrate the pathogenesis, radiological features, and management of PRES. Although reversible in most cases, PRES may be recurrent even in chemotherapy- induced cases and result in fatal outcomes despite appropriate intervention. This is the first--reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy. PMID- 25022405 TI - Merkel cell carcinoma: a rare presentation. AB - A 33-year-old man presented with a lump at the right side of chest wall of 4 months duration which started bleeding suddenly from an ulcer at its center. Examination revealed a globular ulcerated mass 2 cm in diameter, on the anterior axillary fold, with adherent clot at its center. No regional lymphadenopathy was noted. Wide local excision with 2 cm margin was done. Biopsy report revealed malignant small round-cell tumor. Immunohistochemistry showed it to be cytokeratin-20-positive and S100-negative, suggesting the diagnosis of Merkel cell carcinoma. The patient did not receive any other adjuvant therapy. He is being followed-up for the last 4 years and has shown no features of recurrence so far. PMID- 25022404 TI - Unusual presentation of metastatic gall bladder cancer. AB - To report the first case of rare isolated breast metastasis from carcinoma gall bladder. Single patient case report. A 35-year-old pre-menopausal female presented with 2 * 2 cm right upper outer quadrant breast lump. Post-mastectomy, histology confirmed it to be metastatic adenocarcinoma positive for both Cytokeratin (CK) 7 and CK20. Past history as told by the patient revealed that 2 years back, cholecystectomy was performed for gall stones, of which no histology reports were present; she had a port site scar recurrence which showed it to be adenocarcinoma. Adjuvant chemotherapy and radiotherapy was advised which the patient did not complete. This is probably the first case reported of isolated breast metastasis from gall bladder carcinoma, diagnosed retrospectively. It also highlights the importance of adjuvant treatment in gall bladder malignancy. PMID- 25022406 TI - An acute unusual presentation of hepatocellular carcinoma. AB - Hepatocellular Carcinoma (HCC) is a growing cause of mortality world over. The common risk factors include cirrhosis, viral infections, aflatoxin amongst others. Alpha Fetoprotein (AFP) levels and Ultrasonography (USG) are the preferred surveillance tools in early diagnosis of HCC. Here we present an unusual case of a young female with no known risk factors, no cirrhosis, no viral markers, and normal AFP levels who had a Acute hepatic failure eventually diagnosed as Primary Hepatocellular carcinoma. PMID- 25022407 TI - Pure epitheliod perivascular epitheloid cell tumor (epitheliod angiomyolipoma) of kidney: case report and literature review. AB - Malignant kidney tumors are rare neoplasms accounting for 3% of adult malignancies. Majority of these arises in the renal parenchyma and are adenocarcinomas. Malignant mesenchymal tumors of kidney are extremely rare. We report on the clinical behavior, the radiological and histopathological details of one such case of malignant mesenchymal tumor, we encountered. PMID- 25022408 TI - MALT lymphoma at the base of tongue of a 29-year-old woman treated with radiation therapy alone. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma is frequently reported in the gastrointestinal tract (GIT), but the incidence is low in the upper aerodigestive tract. In particular, MALT lymphoma of the tongue is very rare. Only four cases have been reported in the English literature to date. We report a case of 29-year old woman who had a past history of peripheral T cell lymphoma of the head and neck and a new mass at the right base of tongue 3 years later. An incisional biopsy of the base of tongue revealed a new pathology, one that of extranodal marginal zone B cell lymphoma (MALT lymphoma). After staging work-up, she was diagnosed to be at the Ann Arbor stage IE. She was treated with 30.6 Gy of radiation therapy alone and there was no recurrence after 3 years follow-up. PMID- 25022409 TI - Adult acute lymphoblastic leukemia mimicking renal cell carcinoma with wide spread bone metastasis. AB - A few cases with bilateral renal enlargement in acute lymphoblastic leukemia (ALL) are reported in literature. In this article, we report an unusual case of ALL in an adult presenting as multiple lesions in both kidneys and multiple bone lesions. PMID- 25022410 TI - Bone metastasis. AB - Rectal cancers may rarely metastasize in bone and when it occurs, is usually preceded by lung and/or liver metastasis. However, whether it may ever bypasses other organs, particularly lung and liver and metastasizes directly to bone or not, is debatable. Some authors have described the presence of isolated bone metastasis from colo-rectal cancers, whereas others have questioned its' existence in the absence of lung or liver metastasis. A case of isolated bone metastasis from rectal cancer in the absence of lung or liver metastasis is reported here. PMID- 25022411 TI - Primary mucosal malignant melanoma of nasopharynx: a rare case report. AB - Mucosal malignant melanoma (MMM) of the nasopharynx is extremely rare. We report a case of MMM of the nasopharynx in a 56-year-old male patient presenting with a polypoidal mass in the nasopharynx. It was increasing gradually and obstructing breathing. Computed tomography scan was suggestive of a malignant neoplasm in the nasopharynx. A biopsy of the lesion was done with a clinical suspicion of carcinoma. Microscopy revealed features suggestive of malignant melanoma with focal melanin pigmentation. Subsequently, wide local excision was done. PMID- 25022412 TI - Well-differentiated fetal adenocarcinoma of the lung in an adult male: report of an unusual tumor with a brief review of literature. AB - We report a case of a well-differentiated fetal adenocarcinoma (WDFA) of the lung in a 50-year-old male smoker. The literature regarding this uncommon tumor is limited. This rare variant of adenocarcinoma is more common in females, in the third and fourth decades. Microscopically it is composed of neoplastic glands and tubules that resemble the fetal lung. Well-differentiated fetal adenocarcinoma is a low-grade malignancy and surgery is the preferred mode of therapy. This uncommon case of a well-differentiated fetal adenocarcinoma in an adult male patient is reported, with relevant immunohistochemical findings, along with a discussion of the current literature. PMID- 25022413 TI - Malignant fibrous histiocytoma of maxillary alveolar ridge extending to the hard palate. AB - Malignant fibrous histiocytoma (MFH) is the most common soft-tissue sarcoma occurring in adults. This entity was first described by O'Brian and Stout in 1964. Apart from the soft-tissues, this tumor has been reported to occur in all other parts of the body including bone. It has male predilection and is usually noticed in the fifth to seventh decades of life. It commonly affects extremities and retroperitoneum, whereas involvement of the head and neck region is comparatively rare. However, when the head and neck region is affected, the most common sites are the maxillary sinus and the nasal cavity, in which case, later involvement of the maxillary alveolar bone can happen. The oral cavity is a relatively less common site for MFH. This article describes clinical, computed tomographic and microscopic features of a MFH of the maxillary alveolar ridge extending to the hard palate in a 46-year-old female patient. Histogenesis, advanced imaging features, differential diagnosis, and management of MFH are also discussed. PMID- 25022414 TI - Management of rectal inflammatory myofibroblastic tumor recurrence. AB - Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm of intermediate malignant potential. It may occur in various anatomic locations, but rarely in the rectum. This is a case discussion of a 36-year-old male patient with IMT of the rectum. After the patient underwent radical surgery, recurrence was seen after 18 months. Because the tumor was very close to the surrounding tissue, palliative tumor resection was performed followed by concurrent chemo radiation and non-steroidal anti-inflammatory drugs (NSAID). After 2-year follow up, the patient has no evidence of recurrence or metastasis. Surgical resection is very important for patient with rectal IMT, even in relapse cases. And adjuvant chemoradiotherapy and NSAID are in favor of the incompletely resected tumors as our case. But perhaps, the adjuvant treatments could be helpful after radical resection of rectal tumor. PMID- 25022415 TI - Idiopathic renal replacement lipomatosis: a rare renal pseudo tumor. AB - Renal replacement lipomatosis (RRL) is a rare condition that occurs as an end result of renal atrophy or destruction of renal parenchyma by excessive lipomatous tissue in renal sinus and perinephric space. We report a case of RRL presenting as a right renal mass clinically. Intra-venous pyelography and renal scan revealed a left non-functioning kidney. A left nephrectomy was performed. After histopathological examination and extensive literature search, a diagnosis of RRL was given. In majority of cases, it is associated with renal calculi. Idiopathic variety is not common. It is a rare entity and the diagnosis may be missed due to lack of experience. It has to be differentiated from other fat containing tumors such as renal lipoma, xanthogranulomatous pyelonephritis, angiomyolipoma and liposarcoma. PMID- 25022416 TI - A rare case of solitary subcutaneous scalp metastasis from follicular thyroid carcinoma revealed with positron emission tomography/computed tomography: a case report and review. AB - Differentiated thyroid cancer frequently metastasizes to regional cervical lymph nodes and in advanced cases metastases can be seen in the lungs and skeleton. Metastases to the skin or subcutaneous tissue are rare. Here we present a 49-year old female patient with solitary scalp metastasis from follicular thyroid carcinoma FTC which was revealed with positron emission tomography (PET)/computed tomography (CT) imaging. PET showed flourodeoxiglucose avid lesion in the left vertex scalp. Scalp lesion was removed totally and histopathological examination revealed well-differentiated thyroid cancer metastasis. PMID- 25022417 TI - Lipoleiomyoma of uterus and lipoma of broad ligament--a rare entity. AB - Lipoleiomyoma of uterus are a rare variant of uterine leiomyoma. Clinically the symptoms are indistinguishable from an ordinary leiomyoma. It is diagnosed pre operatively as leiomyoma or mature ovarian teratoma. Majority of them are post operative chance finding. Solid tumors of broad ligament are also rare. Most of them are lateral extensions from the uterine tumors. Primary lipomas of broad ligament are rare. They are asymptomatic in majority of cases and are incidental post-operative finding. We report this case because of the rarity of individual lesions and rarity of the combination and also speculate their histogenesis as adipose tissue is rare absent at both locations. PMID- 25022418 TI - Merkel cell carcinoma-A rare primary neuroendocrine skin tumor: case report and discussion. AB - Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous primary small cell carcinoma with an unfavorable prognosis. It is a disease of the sun exposed skin of the elderly commonly involving the head, neck, and extremities. Though most cases present as localized disease, treatment should be definitive with wide excision of the primary lesion (2-3 cm margin) and prophylactic lymphadenectomy followed by irradiation to the primary site. Even when locoregional control is achieved, close surveillance is required due to high rates of local and systemic relapses. Chemotherapy is preserved for systemic disease, though the success of this treatment is limited and no chemotherapy protocol has been shown to improve survival. PMID- 25022419 TI - Caecal amebic colitis mimicking obstructing right sided colonic carcinoma with liver metastases: a rare case. AB - Intestinal Entamoeba Histolytica infection can lead to colitis, abscess formation, colonic perforation and rarely amoeboma. We report a case of colonic amoebiasis, in which the presenting symptoms and radiological findings closely resembled an obstructing right-sided colonic carcinoma, with liver metastases. PMID- 25022420 TI - An esophageal gastrointestinal stromal tumor in a patient with MEN1-related pancreatic gastrinoma: an unusual association and review of the literature. AB - Both multiple endocrine neoplasia type 1 (MEN1)-related gastrinomas and gastrointestinal stromal tumors (GISTs) are rare neoplasms, and their association has been rarely reported. We describe an unusual association between a GIST and a MEN1-related gastrinoma. A 44-year-old man had undergone surgical removal of a pancreatic gastrinoma in 2004 and was then administered long-term somatostatin analogs, and diagnosed as having MEN1 syndrome. Following an uneventful follow up, in April 2009, an upper gastrointestinal tract endoscopy showed esophageal narrowing, with evidence of a 2-cm solid mass on endoscopic ultrasonography. Histology revealed a tumor composed of elongated cells with plump cytoplasm arranged in a storiform pattern. The immunophenotype of the lesion was CD117 and Platelet Derived Growth Factor (PDGF) positive, whereas alpha-1 muscle actin and S-100 protein were negative. Due to morphological and immunohistochemical results, a final diagnosis of esophageal GIST was made. The association between GISTs and MEN1 could be casual, although a single case of the coexistence of a GIST and a MEN1-related gastrinoma has already been reported. A role of the MEN1 gene in the pathogenesis of GISTs could be hypothesized. PMID- 25022421 TI - Multiple myeloma presenting as mediastinal mass. AB - Plasmacytomas can be classified as osseous (medullary) or non-osseous (extramedullary). Extramedullary plasmacytomas (EMP) are uncommon and may be primary or associated with multiple myeloma (MM). EMP arising from the mediastinum is extremely rare. We report two patients who presented with symptomatic mediastinal masses. On evaluation, these turned out to be EMP with coexisting MM.These two cases are being presented for their rarity and to highlight the unusual presentations of MM. PMID- 25022422 TI - Microfibrillar-associated protein 4: a potential biomarker of chronic obstructive pulmonary disease. AB - BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is a matricellular glycoprotein that co-localises with elastic fibres and is highly expressed in the lungs. The aim of this study was to test the hypothesis that plasma MFAP4 (pMFAP4) reflects clinical outcomes in chronic obstructive pulmonary disease (COPD). METHODS: pMFAP4 was measured by an AlphaLISA immunoassay in stable COPD (n = 69) at baseline and at follow-up until 24 months after inclusion and in acute exacerbations of COPD (AECOPD) (n = 14) at baseline and until 6 months after inclusion. RESULTS: The majority of patients (89%) were in GOLD II and III. Multiple linear regressions showed positive associations between pMFAP4 and the Global initiative for Obstructive Lung Disease (GOLD) grade (p = 0.01), modified Medical Research Council score (p < 0.0001) and BODE index (p = 0.04). Negative associations were found with 6-min walking distance (p = 0.04) and bronchodilator induced reversibility (p = 0.02). The pMFAP4 levels varied less than 25% between the baseline and a 3 month follow-up in 83% of the patients. The pMFAP4 levels appeared unaffected in the acute phase of severe AECOPD but rose to an increased stable level within one month after hospitalization. CONCLUSION: Increased pMFAP4 was associated to the severity in COPD and has the potential to serve as a stable disease biomarker. This observation warrants confirmation in a larger longitudinal COPD population. PMID- 25022423 TI - Laryngotracheal reconstruction for pediatric glotto-subglottic stenosis. AB - BACKGROUND: The management of pediatric laryngotracheal stenosis (LTS) can be challenging, and laryngotracheal reconstruction (LTR) with cartilage interposition grafting remains the mainstay of surgical treatment for pediatric LTS in most experienced centers. The purpose of this study was to report the results of this procedure in a center where primary cricotracheal resection is frequently performed. METHODS: A retrospective chart review was performed on 45 patients who underwent LTR in our hospital between October 1997 and July 2012. Demographic characteristics and information on the preoperative status, stenosis, and operation were collected. Primary outcomes were measured as overall (ODR) and operation-specific (OSDR) decannulation rates and secondary outcomes as morbidity, mortality, and postoperative functional results. RESULTS: ODR and OSDR were 86.7% (39/45) and 66.7% (30/45), respectively. Re-stenosis was observed in 11/45 (24%) patients, all of whom were endoscopically or surgically treated. Revision surgery was performed in 10 patients, 6 for re-stenosis and 2 for peristomial tracheomalacia. Two children died of mucous obstruction of tracheostomy tube at 3 and 6 months postoperatively (4.4%). Respiratory, voice, and swallowing functions were excellent or good in 86, 75, and 84% of patients, respectively. CONCLUSIONS: LTR for pediatric LTS has high decannulation rates with acceptable morbidity and mortality in selected patients. Most LTR procedures were double-stage for lower grade subglottic stenoses associated with glottic involvement that required stenting. Careful preoperative evaluation and adequate surgical indications are extremely important to achieve high decannulation rates. PMID- 25022424 TI - Rational design of magnetic nanorattles as contrast agents for ultrasound/magnetic resonance dual-modality imaging. AB - Nanorattles, as promising functional hollow nanomaterials, show considerable advantages in a variety of applications for drug delivery, biosensors, and biomedical imaging because of their tailored ability in both the movable core and shell. In this study, we formulate a facile controllable route to synthesize a monodisperse magnetic nanorattle with an Fe3O4 superparticle as the core and poly(vinylsilane) (PVS) as the outer shell (Fe3O4@air@PVS) using the polymer backbone-transition strategy. In the process of synthesis, besides acting as the precursor for the PVS shells of nanorattles, organosilica (o-SiO2) plays the role of template for the middle cavities. The structures of nanorattles can be easily formed via etching treatment of NaOH solution. Through encapsulating sensitive perfluorohexane (PFH) in the cavities of Fe3O4@air@PVS, the biocompatible magnetic nanosystem shows a relatively stable ultrasound signal intensity and a high r2 value of 62.19 mM(-1) s(-1) for magnetic resonance imaging (MRI). After intravenous administration of nanorattles to a healthy rat, dramatically positively enhanced ultrasound imaging and negatively enhanced T2-weighted MRI are detected in the liver. Furthermore, when the Fe3O4@PFH@PVS nanorattles are administered to tumor-bearing mice, a significant passive accumulation in the tumor via an electron paramagnetic resonance effect is detected by both ultrasound imaging and MRI. In vivo experiments indicate that the obtained Fe3O4@PFH@PVS nanorattles can be used as dual-modality contrast agents for simultaneous ultrasound and MRI detection. PMID- 25022426 TI - Radiology primer: A novel radiology course for undecided medical students. PMID- 25022427 TI - Alkane Biosynthesis Genes in Cyanobacteria and Their Transcriptional Organization. AB - In cyanobacteria, alkanes are synthesized from a fatty acyl-ACP by two enzymes, acyl-acyl carrier protein reductase and aldehyde deformylating oxygenase. Despite the great interest in the exploitation for biofuel production, nothing is known about the transcriptional organization of their genes or the physiological function of alkane synthesis. The comparison of 115 microarray datasets indicates the relatively constitutive expression of aar and ado genes. The analysis of 181 available genomes showed that in 90% of the genomes both genes are present, likely indicating their physiological relevance. In 61% of them they cluster together with genes encoding acetyl-CoA carboxyl transferase and a short-chain dehydrogenase, strengthening the link to fatty acid metabolism and in 76% of the genomes they are located in tandem, suggesting constraints on the gene arrangement. However, contrary to the expectations for an operon, we found in Synechocystis sp. PCC 6803 specific promoters for the two genes, sll0208 (ado) and sll0209 (aar), which give rise to monocistronic transcripts. Moreover, the upstream located ado gene is driven by a proximal as well as a second, distal, promoter, from which a third transcript, the ~160 nt sRNA SyR9 is transcribed. Thus, the transcriptional organization of the alkane biosynthesis genes in Synechocystis sp. PCC 6803 is of substantial complexity. We verified all three promoters to function independently from each other and show a similar promoter arrangement also in the more distant Nodularia spumigena, Trichodesmium erythraeum, Anabaena sp. PCC 7120, Prochlorococcus MIT9313, and MED4. The presence of separate regulatory elements and the dominance of monocistronic mRNAs suggest the possible autonomous regulation of ado and aar. The complex transcriptional organization of the alkane synthesis gene cluster has possible metabolic implications and should be considered when manipulating the expression of these genes in cyanobacteria. PMID- 25022428 TI - Occupation-focused interventions for well older people: an exploratory randomized controlled trial. AB - OBJECTIVE: The aim of this exploratory randomised controlled trial (RCT) was to evaluate three different occupation-focused interventions for well older people by estimating effect sizes for leisure engagement and ability in activities of daily living (ADL) and thereby identifying the most effective interventions. METHODS: One hundred and seventy seven persons, 77-82 years old, living alone and without home help, were randomized to a control group (CG), an individual intervention (IG), an activity group (AG), and a one-meeting discussion group (DG). All interventions focused on occupational engagement and how persons can cope with age-related activity restrictions in order to enhance occupational engagement. Data were collected by blinded research assistants at baseline, three, and 12 months. Ordinal outcome data were converted, using Rasch measurement methods, to linear measures of leisure engagement and ADL ability. Standardized between-group effect sizes, Cohen's d, were calculated. RESULTS: While all groups showed a decline in leisure engagement and ADL over time, the IG and the DG were somewhat effective in minimizing the decline at both three and 12 months. However, the effect sizes were small. CONCLUSIONS: The findings indicate that occupation-focused interventions intended to minimize a decline in leisure engagement and ADL were sufficiently promising to warrant their further research. PMID- 25022429 TI - Global endocardial area change rate for the assessment of left ventricular relaxation and filling pressure: using 3-dimensional speckle-tracking study. AB - Early diastolic mitral inflow and annulus velocities ratio (E/e') is the parameter used to estimate left ventricular (LV) filling pressure, but their use for patients with reduced ejection fraction (EF) (<50 %) is controversial. LV endocardial area change rate with 3-dimensional (3-D) speckle-tracking can be used to evaluate the entire LV diastolic function, we tested the hypothesis that the early diastolic area change rate (E-ACR) represents LV relaxation, and E and E-ACR ratio (E/E-ACR) can accurately predict LV filling pressure in patients with reduced and preserved EF (>=50 %). We studied 125 patients with EF of 40 +/- 17 %. E-ACR of all patients was measured using the global area change rate, and LV relaxation time constant (tau, n = 53) and pulmonary capillary wedge pressure (PCWP, n = 125) were measured by cardiac catheterization. E-ACR significantly correlated with tau (r = -0.60, p < 0.001). In the retrospective group (n = 101), E/E-ACR correlated with PCWP for patients with reduced EF as well as those with preserved EF (n = 79 and 22, r = 0.62 and 0.81, both p < 0.001). In overall patients, E/E-ACR >=94 cm was a better predictor of elevated mean PCWP (>12 mmHg) (sensitivity: 69 %, specificity: 87 %, areas under the curves = 0.82; p < 0.001) and was a more accurate predictor than E/e' (p = 0.001) for the retrospective group. For the validation group (n = 24), E/E-ACR >=94 cm was similarly predictive for elevated mean PCWP (sensitivity: 60 %, specificity: 100 %, positive predictive value: 100 %, negative predictive value: 78 %). In conclusions, global E-ACR by 3-D speckle-tracking proved to be dependent on LV relaxation. Moreover, E/E-ACR was found to be a powerful predictor of LV filling pressure regardless of EF. PMID- 25022430 TI - Evaluation of extracellular volume fraction thresholds corresponding to myocardial late-gadolinium enhancement using cardiac magnetic resonance. AB - To establish extracellular volume fraction (ECV) thresholds corresponding to myocardial lesion detected by late-gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging. Fifty-six patients with myocardial infarction or hypertrophic cardiomyopathy underwent LGE, pre- and post-contrast modified Look Locker inversion recovery (MOLLI) sequences on a 3-T CMR system. Short-axis MOLLI images generated ECV maps of left ventricular (LV) walls. The LGE areas were semi automatically determined by different signal threshold techniques. The areas of elevated ECV were measured using ECV thresholds of 28-48%. The LGE areas were compared with the areas of elevated ECV at the corresponding LV levels. The myocardial areas of LGE and elevated ECVs showed a strong and positive correlation (P < 0.01). The LGE threshold, set at two standard deviations above the mean signal from the remote myocardium, corresponded well with the area of ECV >32%. When using the full width at half-maximum (FWHM) technique, the LGE area corresponded well with the area of ECV >42 or 44%. By applying particular ECV thresholds, myocardial ECV maps can define myocardial status equivalent to LGE, and definite ECV thresholds may be useful for the straightforward evaluation of myocardial phenotypes. PMID- 25022431 TI - Strain-promoted cycloadditions involving nitrones and alkynes--rapid tunable reactions for bioorthogonal labeling. AB - The development and applications of strain-promoted alkyne-nitrone cycloaddition (SPANC) reactions have brought about new tools for rapid and specific functionalization of biomolecules in different settings. While a number of strain promoted reactions have been successfully developed, SPANC reactions offer high reactivity with bimolecular rate constants of k2 that are as fast as 60M(-1)s( 1). SPANC reactions also offer stability of starting materials, particularly in the case of endocyclic nitrones, as well as stereoelectronic tunability of the nitrone moiety to optimize reactivity towards different alkyne reaction partners. Herein we discuss recent advances in the development of SPANC reactions and their applications in bioorthogonal labeling. PMID- 25022432 TI - Photoclick chemistry: a fluorogenic light-triggered in vivo ligation reaction. AB - The ability to use chemical reactivity to monitor and control biomolecular processes with a spatial and temporal precision motivated the development of light-triggered in vivo chemistries. To this end, the photoinduced tetrazole alkene cycloaddition, also termed 'photoclick chemistry' offers a very rapid chemical ligation platform for the manipulation of biomolecules and matrices in vivo. Here we outline the recent developments in the optimization of this chemistry, ranging from the search for substrates that offer two-photon photoactivatability, superior reaction kinetics, and/or genetic encodability, to the study of the reaction mechanism. The applications of the photoclick chemistry in protein labeling in vitro and in vivo as well as in preparing 'smart' hydrogels for 3D cell culture are highlighted. PMID- 25022433 TI - Capsule commentary on Ryan et al., does it get easier to use an EHR? Report from an urban regional extension center. PMID- 25022434 TI - Development and assessment of molecular diagnostic tests for 15 enteropathogens causing childhood diarrhoea: a multicentre study. AB - BACKGROUND: Childhood diarrhoea can be caused by many pathogens that are difficult to assay in the laboratory. Molecular diagnostic techniques provide a uniform method to detect and quantify candidate enteropathogens. We aimed to develop and assess molecular tests for identification of enteropathogens and their association with disease. METHODS: We developed and assessed molecular diagnostic tests for 15 enteropathogens across three platforms-PCR-Luminex, multiplex real-time PCR, and TaqMan array card-at five laboratories worldwide. We judged the analytical and clinical performance of these molecular techniques against comparator methods (bacterial culture, ELISA, and PCR) using 867 diarrhoeal and 619 non-diarrhoeal stool specimens. We also measured molecular quantities of pathogens to predict the association with diarrhoea, by univariate logistic regression analysis. FINDINGS: The molecular tests showed very good analytical and clinical performance at all five laboratories. Comparator methods had limited sensitivity compared with the molecular techniques (20-85% depending on the target) but good specificity (median 97.3%, IQR 96.5-98.9; mean 95.2%, SD 9.1). Positive samples by comparator methods usually had higher molecular quantities of pathogens than did negative samples, across almost all platforms and for most pathogens (p<0.05). The odds ratio for diarrhoea at a given quantity (measured by quantification cycle, Cq) showed that for most pathogens associated with diarrhoea-including Campylobacter jejuni and Campylobacter coli, Cryptosporidium spp, enteropathogenic Escherichia coli, heat-stable enterotoxigenic E coli, rotavirus, Shigella spp and enteroinvasive E coli, and Vibrio cholerae-the strength of association with diarrhoea increased at higher pathogen loads. For example, Shigella spp at a Cq range of 15-20 had an odds ratio of 8.0 (p<0.0001), but at a Cq range of 25-30 the odds ratio fell to 1.7 (p=0.043). INTERPRETATION: Molecular diagnostic tests can be implemented successfully and with fidelity across laboratories around the world. In the case of diarrhoea, these techniques can detect pathogens with high sensitivity and ascribe diarrhoeal associations based on quantification, including in mixed infections, providing rich and unprecedented measurements of infectious causes. FUNDING: Bill & Melinda Gates Foundation Next Generation Molecular Diagnostics Project. PMID- 25022435 TI - Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. AB - BACKGROUND: Antibiotic drug consumption is a major driver of antibiotic resistance. Variations in antibiotic resistance across countries are attributable, in part, to different volumes and patterns for antibiotic consumption. We aimed to assess variations in consumption to assist monitoring of the rise of resistance and development of rational-use policies and to provide a baseline for future assessment. METHODS: With use of sales data for retail and hospital pharmacies from the IMS Health MIDAS database, we reviewed trends for consumption of standard units of antibiotics between 2000 and 2010 for 71 countries. We used compound annual growth rates to assess temporal differences in consumption for each country and Fourier series and regression methods to assess seasonal differences in consumption in 63 of the countries. FINDINGS: Between 2000 and 2010, consumption of antibiotic drugs increased by 36% (from 54 083 964 813 standard units to 73 620 748 816 standard units). Brazil, Russia, India, China, and South Africa accounted for 76% of this increase. In most countries, antibiotic consumption varied significantly with season. There was increased consumption of carbapenems (45%) and polymixins (13%), two last-resort classes of antibiotic drugs. INTERPRETATION: The rise of antibiotic consumption and the increase in use of last-resort antibiotic drugs raises serious concerns for public health. Appropriate use of antibiotics in developing countries should be encouraged. However, to prevent a striking rise in resistance in low-income and middle-income countries with large populations and to preserve antibiotic efficacy worldwide, programmes that promote rational use through coordinated efforts by the international community should be a priority. FUNDING: US Department of Homeland Security, Bill & Melinda Gates Foundation, US National Institutes of Health, Princeton Grand Challenges Program. PMID- 25022436 TI - Multiplex testing of diarrhoea breaks down microbial barriers. PMID- 25022437 TI - Let the games begin: the race to optimise antibiotic use. PMID- 25022438 TI - Soft tissue laxity should be considered to achieve a constant polyethylene thickness during total knee arthroplasty. AB - INTRODUCTION: In total knee arthroplasty (TKA), the gap expansion effect by soft tissue laxity and bone resection amount influence directly on the proper gap size and ideal polyethylene insert thickness. In this study, we hypothesized if bone resection level could be controlled lesser as gap expansion effect resulted in the effects on gap expansion of the collateral release and lax lateral structure, appropriate gap size would be attained without extensive medial soft tissue release even in severe varus deformed knee. The purpose of this study was to show the usefulness of preoperative calculation of soft tissue laxity for determining the appropriate gap size for the targeted PE thickness in TKA. METHODS: The preoperative varus stress view was used to estimate the effect of soft tissue release on extension gap expansion after primary bone resection. The amount of bone resection was determined with a parallel bone resection device used in our institution. Lateral laxity amount was applied into the device. This study was a retrospective review of 850 TKAs [451 with <10o varus deformity of the mechanical femoro-tibial angle (group 1); 399 with >=10o varus deformity (group 2)] with a minimum follow-up of 1 year. We compared the range of motion (ROM), the knee society score (KSS), and the incidence of surgical complications at postoperative 1 year between the two groups. RESULTS: The mean PE thickness was 10.8 +/- 1.1 in group 1 and 10.9 +/- 1.1 in group 2. The proportion of patients with appropriate PE thickness (i.e., 10-12 mm) was 97.6 % in group 1 and 97.2 % in group 2. The ROM and KSS did not differ significantly between groups. CONCLUSION: This study showed the usefulness of preoperative calculation of soft tissue laxity for appropriate gap size for targeted polyethylene thickness and possibility to attain constant extension gap regardless of preoperative varus deformity. PMID- 25022439 TI - Comparative study on the chemical constituents of essential oils from different organs of the Sicilian Kundmannia (Kundmannia sicula L.) DC. (Apiaceae) growing spontaneously in Tunisia. AB - Essential oils from odorous and volatile compounds possessing several therapeutic benefits are considered of a paramount importance in everyday human life. This study deals with a comparative study of essential oils from different parts of an aromatic plant Kundmannia sicula (L.) DC. (Apiaceae) growing in Tunisia. The hydro-distilled essential oils of the leaves and inflorescences with mature seeds (IMS) of K. sicula were analysed for the first time by gas chromatography equipped with flame ionisation detector and gas chromatography coupled with mass spectrometry. Fifty leaves and 47 IMS constituents were identified, accounting for 97.9% and 98.2% of the total oil, respectively. The major compounds identified from the leaves and IMS oils were isocurcumenol (9.9-10.1%), hexadecanoic acid (9.5-10.9%), spathulenol (6.9-3.4%), 10-epi-gamma-eudesmol (6.3 5.5%), alpha-cubebene (5.9-6.1%) and trans-dihydro occidentalol (52-6.6%). The essential oil consists mainly of oxygenated monoterpenes (50.7-53.2%). PMID- 25022440 TI - Quantifying travel behavior for infectious disease research: a comparison of data from surveys and mobile phones. AB - Human travel impacts the spread of infectious diseases across spatial and temporal scales, with broad implications for the biological and social sciences. Individual data on travel patterns have been difficult to obtain, particularly in low-income countries. Travel survey data provide detailed demographic information, but sample sizes are often small and travel histories are hard to validate. Mobile phone records can provide vast quantities of spatio-temporal travel data but vary in spatial resolution and explicitly do not include individual information in order to protect the privacy of subscribers. Here we compare and contrast both sources of data over the same time period in a rural area of Kenya. Although both data sets are able to quantify broad travel patterns and distinguish regional differences in travel, each provides different insights that can be combined to form a more detailed picture of travel in low-income settings to understand the spread of infectious diseases. PMID- 25022441 TI - Clinical composite measures of disease activity and damage used to evaluate patients with systemic lupus erythematosus: A systematic literature review. AB - OBJECTIVES: To determine the most appropriate indices to evaluate the disease activity and damage in patients with sytemic lupus erythematosus (SLE). METHODS: A systematic literature search was performed to identify validation studies of indices used to evaluate disease activity and damage. We collected information for each instrument on every aspect of validation including feasibility, reliability, validity and sensitivity to change using ad hoc forms. RESULTS: A total of 38 articles were included addressing the validation of 6 composite indices to evaluate disease activity (BILAG, ECLAM, SLAM, SLEDAI, LAI and SLAQ); and 3 indices to evaluate damage (SLICC/ACE-DI, LDIQ and BILD). Only the SLAQ, LIDIQ and the BILD were self-administered. Feasibility and internal consistency was only studied in 3 indices (BILAG, SLAQ and SDI) with a Cronbach's alpha ranging from 0.35 to 0.87. The intra-observer reliability was examined by the intraclass correlation coefficient for BILAG with a result of 0.48 (95%CI: 0,23 0,81) and using analysis of variance for SLAM-R (0,78), SLEDAI (0,33) and the LAI (0,81). The inter-observer feasibility was evaluated using the correlation coefficient for ECLAM (0,90-0,93), the SLAM (0,86) and MEX-SLEDAI (0,97-0,89). The construct validity was examined by means of convergence with other instruments, specifically with global assessment by the physician, with similar results between indices (0,48-0,75). Lastly, responsiveness was tested in all indices except LAI, SDI and LDIQ, with a standardized response mean ranging from 0.12 to 0.75. CONCLUSIONS: Although multiple instruments have been validated for use in SLE it was not possible to find direct evidence of which is the most appropriate. BILAG and SLEDAI, with moderate feasibility and low responsiveness, are the 2 indices with a most complete validation and more extensively used. PMID- 25022442 TI - Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs in rheumatoid arthritis: results of the GO-MORE study in Spain. AB - OBJECTIVES: To assess the efficacy and safety of golimumab in the 140 patients included in Spain as the first part of the GO-MORE trial, a multinational study involving patients with active rheumatoid arthritis (RA) despite treatment with different disease-modifying antirheumatic drugs (DMARDs). PATIENTS AND METHODS: The patients received subcutaneous golimumab 50mg once a month during 6 months. The primary endpoint was the percentage of individuals with a good or moderate EULAR DAS28-ESR response after 6 months of treatment. RESULTS: A total of 140 patients were included. Of these, 76.4% had very active disease (DAS28-ESR>5.1). 76.4% were taking methotrexate, 40.0% other DMARDs in monotherapy or combined, and 65.0% received corticosteroids. After 6 months, 82.9% of the patients showed a good or moderate EULAR response, 41.4% had low disease activity, and 30.7% were in remission. The percentage of responders one month after the first dose was 69.3%. The efficacy was similar in patients treated with methotrexate or other DMARDs, with different methotrexate doses, with or without corticosteroids, or in subjects who had failed one or more DMARDs. The response to golimumab was observed from the first dose. Golimumab was well tolerated and its safety profile was consistent with the findings of previous studies. Serious adverse events were reported in 11 patients (7.9%). CONCLUSION: The addition of subcutaneous golimumab 50 mg once a month to different DMARDs in patients with active RA yielded a moderate or good response after 6 months in 82.9% of the cases. The response was observed early, from the start of the second month, after a single dose of golimumab. PMID- 25022443 TI - Managing Epileptic Seizures by Controlling the Brain Driver Nodes: A Complex Network View. PMID- 25022444 TI - Substantial cultures of Propionibacterium can be found in apparently aseptic shoulders revised three years or more after the index arthroplasty. AB - BACKGROUND: Revisions of apparently "aseptic" shoulder arthroplasties are not infrequently culture positive for Propionibacterium, organisms that may be introduced at the time of the index surgery when the dermal sebaceous glands are transected. This report seeks to answer the question, Do surgeons performing revision shoulder arthroplasty years after the index procedure need to be concerned about the persistence of Propionibacterium? METHODS: We reviewed the medical records of 148 revision arthroplasties performed between July 2008 and June 2013 to find those revisions performed at least 3 years after the index procedure and at which intraoperative cultures were strongly positive for Propionibacterium. RESULTS: We identified 14 cases of revision surgery performed 8 +/- 4 years after the original arthroplasty for which deep cultures were strongly positive for Propionibacterium. A total of 109 specimens were obtained, 84 of which were positive. All 14 patients were male. CONCLUSION: Shoulder arthroplasties revised for the mechanical problems of loosening or stiffness can be substantially culture positive for Propionibacterium, even if the revision is performed many years after the index procedure. Therefore, even in shoulder arthroplasties revised for mechanical problems years after the index procedures, surgeons should consider submitting multiple deep specimens for specific Propionibacterium culture. In the presence of persistent Propionibacterium, surgeons should consider the need for directed surgical and medical treatment in their management of a failed arthroplasty. PMID- 25022446 TI - Characterization of the emerging clinically-relevant multidrug-resistant Salmonella enterica serotype 4,[5],12:i:- (monophasic variant of S. Typhimurium) clones. AB - To better understand the recent success/emergence of Salmonella enterica serotype 4,[5],12:i:- we characterized the population diversity, fljAB deletion patterns, antibiotic resistance features and associated genetic elements of a comprehensive collection obtained in the last decade from Portugal (2002-2010). One hundred thirty-one isolates from human clinical specimens, food, environment and piggeries, verified by PCR as S. 4,[5],12:i:-, were studied for clonality (Pulsed Field Gel Electrophoresis and Multilocus Sequence Typing), antibiotic resistance by phenotypic (disk diffusion and/or agar dilution) and genotypic (PCR/Restriction Fragment Length Polymorphism and sequencing, genomic location) methods and fljAB-deletions (PCR). Plasmid analysis included determination of size, content and characterization of the incompatibility group (PCR-Based Replicon Typing and I-CeuI/S1-hybridization). Results showed three multidrug resistant (MDR) clones circulating and causing infections, associated with particular phenotypic and genotypic features. Most of the isolates belonged to the widespread European (ASSuT phenotype, RR1-RR2 resistance regions, ST34) and Spanish (carrying a sul3-type III integron within IncA/C plasmids, ST19) clones circulating in Europe. A third clone, here designated Southern European clone (carrying a sul3-type I integron within IncR plasmids, ST19), presents a fljAB region different from the previous clones and similar to the US strains, despite differences in the MDR mobile genetic platforms. The success of S. 4,[5],12:i:- might be related to the selective advantage offered by MDR profiles associated with stable genetic elements, also carrying virulence features, along with well adapted clones to the animal food production and causing human infections. PMID- 25022445 TI - Short-term glutamine supplementation decreases lung inflammation and the receptor for advanced glycation end-products expression in direct acute lung injury in mice. AB - BACKGROUND: Glutamine (GLN) has been reported to improve clinical and experimental sepsis outcomes. However, the mechanisms underlying the actions of GLN remain unclear, and may depend upon the route of GLN administration and the model of acute lung injury (ALI) used. The aim of this study was to investigate whether short-term GLN supplementation had an ameliorative effect on the inflammation induced by direct acid and lipopolysaccharide (LPS) challenge in mice. METHODS: Female BALB/c mice were divided into two groups, a control group and a GLN group (4.17% GLN supplementation). After a 10-day feeding period, ALI was induced by intratracheal administration of hydrochloric acid (pH 1.0; 2 mL/kg of body weight [BW]) and LPS (5 mg/kg BW). Mice were sacrificed 3 h after ALI challenge. In this early phase of ALI, serum, lungs, and bronchoalveolar lavage fluid (BALF) from the mice were collected for further analysis. RESULTS: The results of this study showed that ALI-challenged mice had a significant increase in myeloperoxidase activity and expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in the lung compared with unchallenged mice. Compared with the control group, GLN pretreatment in ALI-challenged mice reduced the levels of receptor for advanced glycation end-products (RAGE) and IL-1beta production in BALF, with a corresponding decrease in their mRNA expression. The GLN group also had markedly lower in mRNA expression of cyclooxygenase-2 and NADPH oxidase-1. CONCLUSIONS: These results suggest that the benefit of dietary GLN may be partly contributed to an inhibitory effect on RAGE expression and pro inflammatory cytokines production at an early stage in direct acid and LPS induced ALI in mice. PMID- 25022447 TI - A controlled trial of sputum induction and routine collection methods for TB diagnosis in a South African community. AB - The diagnostic yield of pulmonary tuberculosis (TB) by sputum induction (SI) at the first point of contact with health services, conducted in all patients with suspected TB regardless of the ability to expectorate spontaneously, has not been evaluated. We compared the diagnostic yield of SI to routine sputum collection in a South African community setting. Ambulatory patients with suspected TB provided a 'spot' expectorated sputum sample, an SI sample by hypertonic (5 %) saline nebulization, and early morning expectorated sputum sample. The diagnostic yield of sputum smear microscopy and liquid culture (denominator all subjects with any positive Mycobacterium tuberculosis culture), and time-to-positivity of culture were compared between SI and expectorated samples. A total of 555 subjects completed the SI procedure, of whom 132 (24 %) were human immunodeficiency virus (HIV)-infected. One hundred and twenty-nine samples (129, 23 %) were M. tuberculosis culture-positive. The time-to-positivity of Mycobacteria Growth Indicator Tube (MGIT) culture was shorter for SI (median difference 2 days, p = 0.63) and for early morning expectorated sputum (median difference 2 days, p = 0.02) compared to spot expectorated sputum. However, there was no difference in the culture-positive diagnostic yield between SI and spot expectorated sputum [difference +0.7 %; confidence interval (CI) -7.0 to +8.5 %, p = 0.82] or SI and early morning expectorated sputum (difference +4.7 %; CI -3.2 to +12.5 %, p = 0.20) for all subjects or for HIV-infected subjects. SI reduces the time to positive M. tuberculosis culture, but does not increase the rate of positive culture compared to routine expectorated sputum collection. SI cannot be recommended as the routine collection method at first contact among ambulatory patients with suspected TB in high-burden communities. PMID- 25022448 TI - Polymorphisms in cytokine genes IL6, TNF, IL10, IL17A and IFNG influence susceptibility to complicated skin and skin structure infections. AB - Complicated skin and skin structure infections (cSSSIs) are caused by Gram positive and Gram-negative, aerobic and anaerobic pathogens, with a polymicrobial aetiology being frequent. Recognition of invading pathogens by the immune system results in the production of pro- and anti-inflammatory cytokines, which are extremely important for intercellular communication and control of infection. This study assessed whether genetic variation in genes encoding cytokines influences the susceptibility to cSSSIs. For the association study, 318 patients with cSSSI and 328 healthy controls were genotyped for single nucleotide polymorphisms (SNPs) in cytokine genes IL1A, IL1B, IL1RN, TNF, IL10, IL17A, IL17F and IFNG. For immunological validation, peripheral blood mononuclear cells (PBMCs) from 74 healthy individuals, genotyped for SNPs of interest, were stimulated with Staphylococcus aureus or Escherichia coli and corresponding cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA). Polymorphisms IL6 rs1800797, TNF rs1800629, IL10 rs1800871, IL17A rs8193036 and IFNG rs2069705 influenced susceptibility to cSSSIs. No differences in cytokine responses, stratified for genotype, were detected after PBMC stimulation. No association with cSSSIs was observed for polymorphisms IL1A rs17561 and rs1800587, IL1B rs16944 and rs1143627, IL1RN rs4251961, TNF rs361525, IL10 rs1800896, IL17A rs2275913 and IL17F rs763780. In conclusion, polymorphisms in IL6, TNF, IL10, IL17A and IFNG are associated with susceptibility to cSSSIs. PMID- 25022449 TI - In vivo surface dose measurement using GafChromic film dosimetry in breast cancer radiotherapy: comparison of 7-field IMRT, tangential IMRT and tangential 3D-CRT. AB - PURPOSE: The purpose of this study was to compare the surface dose of 7-field IMRT (7 F-IMRT), tangential beam IMRT (TB-IMRT), and tangential beam 3D-CRT (3D CRT) of breast cancer patients receiving adjuvant radiotherapy by means of in vivo GafChromic film dosimetry. MATERIAL AND METHODS: Breast cancer patients receiving adjuvant radiotherapy of the whole breast or the chest wall were eligible for the study. Study patients were treated with a treatment plan using two different radiotherapy techniques (first patient series, 3D-CRT followed by TB-IMRT; second patient series, TB-IMRT followed by 7 F-IMRT). The surface dose was evaluated on three consecutive treatment fractions per radiotherapy technique using in vivo GafChromic film dosimetry. The paired t-test was used to assess the difference of in vivo GafChromic film readings or calculated plan parameters of the compared pairs of radiation techniques for statistical significance. RESULTS: Forty-five unselected breast cancer patients were analysed in this study. 7 F IMRT significantly reduced the surface dose compared to TB-IMRT. Differences were greatest in the central and lateral breast or chest wall region and amounted to a dose reduction of -11.8% to -18.8%. No significant difference of the surface dose was observed between TB-IMRT and 3D-CRT. A corresponding observation was obtained for the calculated skin dose derived from dose-volume histograms. CONCLUSIONS: In adjuvant breast cancer radiotherapy, 7 F-IMRT offers a significantly reduced surface dose compared to TB-IMRT or 3D-CRT. PMID- 25022450 TI - The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study. AB - NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH's Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48% rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5%) and only 16 completed it (50%), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80% completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73-1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54-0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial. PMID- 25022451 TI - Systematic review of the cost effectiveness of radiation therapy for prostate cancer from 2003 to 2013. AB - BACKGROUND: Prostate cancer remains a prevalent diagnosis with a spectrum of treatment choices that offer similar oncologic outcomes but differing side effect profiles and associated costs. As the technology for prostate radiation therapy has advanced, its associated costs have escalated, thus making cost-effectiveness analyses critical to assess the value of competing treatment options, including watchful waiting, surgery, brachytherapy, intensity-modulated radiation therapy (IMRT), 3D-conformal radiation therapy (3D-CRT), proton beam therapy (PBT), and stereotactic body radiation therapy (SBRT). OBJECTIVE: The aim of this systematic review was to identify articles that performed a cost-effectiveness analysis on different radiation treatment options for localized prostate cancer, summarize their findings, and highlight the main drivers of cost effectiveness. METHODS: A literature search was performed on two databases, PubMed and the Cost Effectiveness Analysis Registry ( https://research.tufts-nemc.org/cear4 ), using search terms that included 'prostate', 'cost effectiveness prostate radiation' and 'cost analysis comparative effectiveness prostate radiation'. Studies were included in this review if the cost data were from 2002 or later, and outcomes reported both cost and effectiveness, preferably including a cost-utility analysis with the outcome of an incremental cost-effectiveness ratio with quality adjusted life-year (QALY) as the effectiveness measure. RESULTS: There were 14 articles between 2003 and 2013 that discussed cost effectiveness of prostate radiotherapy in men over the age of 65. All but four of the papers were from the US; the others were from Canada and the UK. The majority of the papers used Markov decision analysis and estimated cost from a payer's perspective, usually from Medicare reimbursement data. Assumptions for the model and utilities to calculate QALYs were estimated using published literature at the time of the analysis. Each analysis had a sensitivity analysis to compensate for the uncertainty of the model inputs. The main drivers of cost effectiveness were the cost of the radiation treatment and the differential QALYs accrued because of different treatment-related morbidities. Brachytherapy was consistently found to be more cost effective when compared with surgery and other radiation treatment options. IMRT was cost effective when compared with 3D-CRT. PBT was not found to be cost effective in any of the analyses, mostly due to the high costs of PBT. SBRT was the newest technology that was analyzed, and it was also found to be cost effective compared with IMRT and PBT. CONCLUSIONS: Cost-effectiveness research of prostate radiation treatments allows patients, providers, and payers to better understand the true value of each treatment choice. Due to the variation in each of these analyses (e.g., costing, and disease and complication assumptions, etc.), it is difficult to generalize the results. One must be careful in drawing conclusions from these studies and extrapolating to individual patients, particularly with the clear utility dependence seen in the majority of these studies. PMID- 25022452 TI - Non-rigid registration of serial dedicated breast CT, longitudinal dedicated breast CT and PET/CT images using the diffeomorphic demons method. AB - RATIONALE AND OBJECTIVES: Dedicated breast CT and PET/CT scanners provide detailed 3D anatomical and functional imaging data sets and are currently being investigated for applications in breast cancer management such as diagnosis, monitoring response to therapy and radiation therapy planning. Our objective was to evaluate the performance of the diffeomorphic demons (DD) non-rigid image registration method to spatially align 3D serial (pre- and post-contrast) dedicated breast computed tomography (CT), and longitudinally-acquired dedicated 3D breast CT and positron emission tomography (PET)/CT images. METHODS: The algorithmic parameters of the DD method were optimized for the alignment of dedicated breast CT images using training data and fixed. The performance of the method for image alignment was quantitatively evaluated using three separate data sets; (1) serial breast CT pre- and post-contrast images of 20 women, (2) breast CT images of 20 women acquired before and after repositioning the subject on the scanner, and (3) dedicated breast PET/CT images of 7 women undergoing neo adjuvant chemotherapy acquired pre-treatment and after 1 cycle of therapy. RESULTS: The DD registration method outperformed no registration (p < 0.001) and conventional affine registration (p <= 0.002) for serial and longitudinal breast CT and PET/CT image alignment. In spite of the large size of the imaging data, the computational cost of the DD method was found to be reasonable (3-5 min). CONCLUSIONS: Co-registration of dedicated breast CT and PET/CT images can be performed rapidly and reliably using the DD method. This is the first study evaluating the DD registration method for the alignment of dedicated breast CT and PET/CT images. PMID- 25022453 TI - Evaluation of testicular dose and associated risk from common pelvis radiation therapy in Iran. AB - This study aimed to investigate testicular dose (TD) and the associated risk of heritable disease from common pelvis radiotherapy of male patients in Iran. In this work, the relation between TD and changes in beam energy, pelvis size, source to skin distance (SSD) and beam directions (anterior or posterior) was also evaluated. The values of TDs were measured on 67 randomly selected male patients during common pelvis radiotherapy using 1.17 and 1.33 MeV, Theratron Cobalt-60 unit at SSD of 80 cm and 9 MV, Neptun 10 PC and 18 MV, GE Saturne 20 at SSD of 100 cm at Seyed-Al Shohada Hospital, Isfahan, Iran. Results showed that, the maximum TD was up to 12% of the tumor dose. Considering the risk factor for radiation-induced heritable disorders of 0.1% per Sv, an excess risk of hereditary disorders of 72 per 10,000 births was conservatively calculated. There was a significant difference in the measured TD using different treatment machines and energies (P < 0.001). The Pearson Correlation test showed that, as expected, there was a correlation between TD and patient's pelvis size (r = 0.275, P < 0.001). Using the student's t-tests, it was found that, there was not a significant difference between TD and beam direction (P = 0.231). Iranian male patients undergoing pelvic radiotherapy have the potential of receiving a TD of more than 1 Gy which might result in temporary azoospermia. The risk for induction of hereditary disorders in future generations should be considered as low but not negligible in comparison with the correspondent nominal risk. PMID- 25022454 TI - Disease-specific target gene expression profiling of molecular imaging probes: database development and clinical validation. AB - Molecular imaging probes can target abnormal gene expression patterns in patients and allow early diagnosis of disease. For selecting a suitable imaging probe, the current Molecular Imaging and Contrast Agent Database (MICAD) provides descriptive and qualitative information on imaging probe characteristics and properties. However, MICAD does not support linkage with the expression profiles of target genes. The proposed Disease-specific Imaging Probe Profiling (DIPP) database quantitatively archives and presents the gene expression profiles of targets across different diseases, anatomic regions, and subcellular locations, providing an objective reference for selecting imaging probes. The DIPP database was validated with a clinical positron emission tomography (PET) study on lung cancer and an in vitro study on neuroendocrine cancer. The retrieved records show that choline kinase beta and glucose transporters were positively and significantly associated with lung cancer among the targets of 11C-choline and [18F]fluoro-2-deoxy-2-d-glucose (FDG), respectively. Their significant overexpressions corresponded to the findings that the uptake rate of FDG increased with tumor size but that of 11C-choline remained constant. Validated with the in vitro study, the expression profiles of disease-associated targets can indicate the eligibility of patients for clinical trials of the treatment probe. A Web search tool of the DIPP database is available at http://www.polyu.edu.hk/bmi/dipp/. PMID- 25022455 TI - Electrodiagnostic techniques. AB - The first application of electricity to the study of excitability of nerve and muscle was at the latter half of the 19th Century when Erb (1883) described the galvanic-faradic test. Lord Adrian was the first to demonstrate the clinical application of strength-duration curves, and they became widely used in the assessment of peripheral nerve injuries during the 1939-45 War. Electromyography, or the study of the electrical activity of muscles by means of needle electrodes, was first employed about forty years ago in animal research work but soon afterwards was also applied to the study of clinical problems. PMID- 25022456 TI - Treatment of lateral epicondylitis. AB - Of the total number of injuries treated at the Lewisham Hospital Sports Medicine Clinic (Sydney), over a period of eighteen months, lateral epicondylitis constitutes approximately 1.4%. The 36 patients this figure represents received varying treatments, which are listed below. The overall results were as follows. PMID- 25022457 TI - Economy or humanity. AB - This title is chosen to be provocative and not because it is the burning issue in the question of physiotherapy treatment for the psychiatrically afflicted. It is one way, however, of considering the problem. PMID- 25022458 TI - Some principles of treatment in children with cerebral palsy and mental retardation. AB - Cerebral Palsy is a comparatively common condition in this community. It presents the patient, parents and medical team with a lifelong problem. PMID- 25022459 TI - Preventing Loss of Independence through Exercise (PLIE): qualitative analysis of a clinical trial in older adults with dementia. AB - OBJECTIVES: Preventing Loss of Independence through Exercise (PLIE) is a novel, integrative exercise program for individuals with dementia that combines elements of different conventional and complementary exercise modalities (e.g. tai-chi, yoga, Feldenkrais, and dance movement therapy) and focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection. This study presents analyses of qualitative data collected during a 36-week cross-over pilot clinical trial in 11 individuals. METHODS: Qualitative data included exercise instructors' written notes, which were prepared after each class and also following biweekly telephone calls with caregivers and monthly home visits; three video-recorded classes; and written summaries prepared by research assistants following pre- and post-intervention quantitative assessments. Data were extracted for each study participant and placed onto a timeline for month of observation. Data were coded and analyzed to identify themes that were confirmed and refined through an iterative, collaborative process by the entire team including a qualitative researcher (SA) and the exercise instructors. RESULTS: Three overarching themes emerged: (1) Functional changes included increasing body awareness, movement memory and functional skill. (2) Emotional changes included greater acceptance of resting, sharing of personal stories and feelings, and positive attitude toward exercise. (3) Social changes included more coherent social interactions and making friends. CONCLUSIONS: These qualitative results suggest that the PLIE program may be associated with beneficial functional, emotional, and social changes for individuals with mild to moderate dementia. Further study of the PLIE program in individuals with dementia is warranted. PMID- 25022460 TI - Genotoxicity test of self-renovated ceramics in primary human peripheral lymphocytes. AB - Zirconia-based ceramics is widely used in dentistry. Different compositions of ceramics have different features. Our self-renovated ceramics become more machinable without scarifying its dental restoration properties after adjusting ratio of lanthanum phosphate (LaPO4)/yttrium oxide (Y2O3). In order to evaluate its safety, here, we tested its genotoxicity in primary human peripheral lymphocytes. The human lymphocytes cultured on three groups of different ratios of LaPO4/Y2O3 diphase ceramics for 6 days showed little effect of growth inhibition and similar effect of growth trend to the negative control. Furthermore, single-cell gel electrophoresis (comet assay) indicated that there was no significant difference of the value of tail moment between the tested ceramics and negative control, the IPS Empress II (P > 0.05). Our findings implicate that our self-renovated ceramics do not induce DNA damages in human peripheral lymphocytes and support their future clinic application. PMID- 25022461 TI - Quantitative and multiplexed study of endothelial cell inflammation. AB - Endothelial inflammation plays major roles in all phases of the atherosclerotic process, the leading cause of death by cardiovascular disease. Both innate immunity and endothelial adhesion molecules contribute to endothelial inflammation. In this work, we applied multiple antibodies (Abs) to measure changes in expression levels of six proteins in response to inflammatory stimulation. These six proteins include toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) representing innate immunity and four endothelial adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin. We observed two different types of dynamic behaviors among these proteins upon inflammatory stimulation. Increased expression of toll-like receptor 2 (TLR2), P-selectin, E selectin, and TLR4 peaked relatively early (after 4 h of stimulation) while VCAM 1, and ICAM-1 showed a more gradual and consistent increase in expression with stimulatory time. The magnitude of this increase was significantly greater for VCAM-1 and ICAM-1. The multiplexed detection developed in this study using fluorophore-conjugated primary Abs provides an approach for live cell and in vivo imaging of endothelium inflammation for quantitative characterization of multiple proteins within a network. PMID- 25022462 TI - Cerebral hemorrhage increases plasma concentrations of noradrenalin and creatine kinase MB fraction with induction of cardiomyocyte damage in rats. AB - The incidence of cardiac damage is high during acute cerebral hemorrhage. The animal data on the relationship between cerebral apoplexy and cardiac damage are lacking. Thus, the aim of the study was to evaluate the effects of cerebral hemorrhage on plasma concentrations of monoamine transmitter noradrenalin (NA), creatine kinase muscle and brain (CK-MB) isoenzyme fraction, and cardiomyocyte changes in the rat model. In this study, 140 Wistar rats were randomly and equally divided into experimental and control groups, and collagenase was injected into the right caudate nucleus to induce cerebral hemorrhage in the experimental group. Plasma NA was analyzed using high-performance liquid chromatography with electrochemical detection and serum CK-MB was measured by enzyme reaction rate method. We found that both NA and CK-MB were elevated (p < 0.05) at 6 h after cerebral hematoma formation; the levels were 2.46 +/- 0.05 MUg/L and 3.51 +/- 0.23 MUkat/L, respectively. NA and CK-MB concentrations reached peak levels at 24 h which were found to be 3.52 +/- 0.06 MUg/L and 5.47 +/- 0.49 MUkat/L, respectively. Thereafter, NA and CK-MB concentrations decreased gradually. Plasma NA declined to the preoperative level (1.66 +/- 0.03 MUg/L) at 72 h, while CK-MB level (2.71 +/- 0.17 MUkat/L) was found to be still higher than its preoperative level. It was, therefore, concluded that plasma NA might be involved in the induction and development of cardiomyocytes damage during cerebral hemorrhage. PMID- 25022463 TI - Reconstruction of major scrotal defects by anterolateral thigh flap. AB - To summarize the indications and applications of anterolateral thigh flaps (ALTP) in reparation and reconstruction of acute scrotum skin deficiency. We report our experience of treating three patients for scrotal reconstruction using the ALTP method from May of 2007 to December of 2010. The flap was completely islanded, tunneled beneath the fascial septa below the rectus femoris, and placed into the defect. The resulting reconstruction provided a tension-free, cosmetically appealing scrotum with complete testicular coverage. There were no perioperative or postoperative complications. Spermatogenesis (sperm count levels), and sexual function (IIEF) were not changed significantly. ALTP represent an excellent reconstruction option for patients with contaminated perineum. ALTP is available for replacement of the avulsed portion of the scrotal skin resulting in satisfactory shape and color of the penis and scrotum. PMID- 25022464 TI - Photocatalytic action of AgCl nanoparticles and its antibacterial activity. AB - The scientific community is searching for biosynthetic methods for the production of metallic nanoparticles. Biogenic pathway has now become a vast developing area of research. A novel route biological synthesis of silver chloride nanoparticles (AgCI-NPs) using aqueous leaf extract of Morindacitrifolia under ambient conditions were evaluated. Synthesized nanoparticles were confirmed by UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and transmission electron microscopy (TEM). The effects of pH on biosynthesis of AgCI-NPs were investigated using UV-vis spectroscopy. TEM images showed that the diameter of stable AgCI-NPs were approximately 12 nm. FTIR spectra provide the evidence for the presence of protein as possible biomolecules responsible for reduction and capping of nanoparticles. The synthesized AgCI-NPs were observed to have a good catalytic activity on the reduction of methylene blue (MB) dye by M.citrifolia extract which has been confirmed by decrease in absorbance maximum values of methylene blue with respect to time using UV-vis spectroscopy and was attributed to the electron relay effect. PMID- 25022465 TI - Impact of UV-A radiation on the performance of aphids and whiteflies and on the leaf chemistry of their host plants. AB - Ultraviolet (UV) radiation directly regulates a multitude of herbivore life processes, in addition to indirectly affecting insect success via changes in plant chemistry and morphogenesis. Here we looked at plant and insect (aphid and whitefly) exposure to supplemental UV-A radiation in the glasshouse environment and investigated effects on insect population growth. Glasshouse grown peppers and eggplants were grown from seed inside cages covered by novel plastic filters, one transparent and the other opaque to UV-A radiation. At a 10-true leaf stage for peppers (53 days) and 4-true leaf stage for eggplants (34 days), plants were harvested for chemical analysis and infested by aphids and whiteflies, respectively. Clip-cages were used to introduce and monitor the insect fitness and populations of the pests studied. Insect pre-reproductive period, fecundity, fertility and intrinsic rate of natural increase were assessed. Crop growth was monitored weekly for 7 and 12 weeks throughout the crop cycle of peppers and eggplants, respectively. At the end of the insect fitness experiment, plants were harvested (68 days and 18-true leaf stage for peppers, and 104 days and 12-true leaf stage for eggplants) and leaves analysed for secondary metabolites, soluble carbohydrates, amino acids, total proteins and photosynthetic pigments. Our results demonstrate for the first time, that UV-A modulates plant chemistry with implications for insect pests. Both plant species responded directly to UV-A by producing shorter stems but this effect was only significant in pepper whilst UV A did not affect the leaf area of either species. Importantly, in pepper, the UV A treated plants contained higher contents of secondary metabolites, leaf soluble carbohydrates, free amino acids and total content of protein. Such changes in tissue chemistry may have indirectly promoted aphid performance. For eggplants, chlorophylls a and b, and carotenoid levels decreased with supplemental UV-A over the entire crop cycle but UV-A exposure did not affect leaf secondary metabolites. However, exposure to supplemental UV-A had a detrimental effect on whitefly development, fecundity and fertility presumably not mediated by plant cues as compounds implied in pest nutrition - proteins and sugars - were unaltered. PMID- 25022466 TI - Physiological roles of long noncoding RNAs: insight from knockout mice. AB - Long noncoding RNAs (lncRNAs) are a pervasive and recently recognized class of genes. lncRNAs have been proposed to modulate gene expression and nuclear architecture, but their physiological functions are still largely unclear. Several recent efforts to inactivate lncRNA genes in mouse models have shed light on their functions. Different genetic strategies have yielded specific lessons about the roles of lncRNA transcription, the lncRNA transcript itself, and underlying sequence elements. Current results indicate important functions for lncRNAs in organ development, immunity, organismal viability, and in human diseases. PMID- 25022467 TI - Infection risk in patients with rheumatoid arthritis treated with etanercept or adalimumab. AB - OBJECTIVES: To compare the risk of infection for rheumatoid arthritis (RA) patients who took etanercept or adalimumab medication in a nationwide population. METHODS: RA patients who took etanercept or adalimumab were identified in the Taiwan's National Health Insurance Research Database. The composite outcome of serious infections, including hospitalization for infection, reception of an antimicrobial injection, and tuberculosis were followed for 365 days. A Kaplan Meier survival curve with a log-rank test and Cox proportional hazards regression were used to compare risks of infection between the two cohorts of tumor necrosis factor (TNF)-alpha antagonists users. Hazard ratios (HRs) were obtained and adjusted with propensity scores and clinical factors. Sensitivity analyses and subgroup analyses were also performed. RESULTS: In total, 1660 incident etanercept users and 484 incident adalimumab users were eligible for the analysis. The unadjusted HR for infection of the etanercept users was significantly higher than that of the adalimumab users (HR: 1.93; 95% confidence interval (CI): 1.09-3.42; p=0.024). The HRs were 2.04 (95% CI: 1.14-3.65; p=0.016) and 2.02 (95% CI: 1.13-3.61; p=0.018) after adjusting for propensity scores and for propensity scores in addition to clinical factors, respectively. The subgroup analyses revealed that HRs for composite infection was significantly higher in patient subgroups of older age, female, as well as patients who did not have DM, COPD, and hospitalization history at the baseline. CONCLUSION: In this head-to-head cohort study involving a nationwide population of patients with RA, etanercept users demonstrated a higher risk of infection than adalimumab users. Results of this study suggest the possible existence of an intra-class difference in infection risk among TNF-alpha antagonists. PMID- 25022468 TI - Risk for losing physical independence in older adults: the role of sedentary time, light, and moderate to vigorous physical activity. AB - This study examined the association of a range of physical activity intensities and sedentary behavior with the risk of losing physical independence later in life in community-dwelling older adults. A total of 131 males and 240 females, aged 65-103 years, were enrolled. Physical activity (PA) and sedentary time were assessed with accelerometers and the risk for losing physical independence in later years was assessed with the self-reported composite physical function (CPF) scale adjusted for age. Participants were divided in two groups - high risk group (HRG) and low risk group (LRG), according current CPF. According to the multiple logistic regression analyses, sedentary time was not a significant predictor. The odds of a male participant being in the LRG were 12.19 times higher than those of a female (95% CI 5.06-29.39). Both, light PA (OR=1.01; 95% CI 1.01-1.02) and MVPA (OR=1.432; 95% CI 1.21-1.69) had a significant main effect on the risk of losing physical independence. Age and gender interacted with moderate to vigorous PA (MVPA) to predict the risk of losing physical independence. Thus, as age increases, participants that are more physically active became less likely (OR=0.997; 95% CI 0.995-0.999) to be in the HRG than younger participants. Similarly, the odds of a physically active women being physical independent in later life are higher (OR=0.94; 95% CI 0.91-0.96) than those of a physically active men. These new findings suggest that light PA, and MVPA are significantly associated with the risk of losing physical independence later in life, and age and gender combined with MVPA have an interaction effect on physical independence of older adults. PMID- 25022469 TI - Autonomic dysfunction and arterial stiffness in female overactive bladder patients and antimuscarinics related effects. AB - OBJECTIVES: To investigate the characteristics of autonomic function and arterial stiffness of OAB women, their relations with urodynamic parameters, and the impact of antimuscarinics on the above parameters. STUDY DESIGN: A total of 85 OAB women and another 65 women without OAB were selected. Forty-two OAB women who enrolled before March 2009 were treated with tolterodine for 12 weeks, and another 43 OAB women who enrolled thereafter were treated with solifenacin. MAIN OUTCOME MEASURES: The differences of the heart rate variability, cardio-ankle vascular index (CAVI) and ankle-brachial pressure index (ABI) between OAB and asymptomatic women, and their changes after 12 weeks' antimuscarinics for OAB women. RESULTS: OAB women had higher low frequency/high frequency ratios (LF/HF) (OAB: 1.5+/-1.1 vs. the control: 1.1+/-0.7, P=0.04). Nonetheless, CAVI and ABI did not differ between OAB and the control group. The square root of the mean squared differences of successive NN intervals (RMSSD) is associated with nocturia (Spearman's rho=0.23, P=0.049), LF is associated with urgency episodes (Spearman's rho=0.28, P=0.01), and maximum urethral closure pressure is negatively associated with CAVI (Spearman's rho=-0.26, P=0.02). After 12 weeks' treatment, a decrease of RMSSD, HF, CAVI and an increase of LF/HF were found in the tolterodine group but not in the solifenacin group. CONCLUSIONS: OAB women have higher severity of autonomic dysfunction with sympathetic predominance. Tolterodine may improve arterial stiffness but may deteriorate autonomic dysfunction to more sympathetic predominance. Thus, tolteridine should be used for OAB with caution in women with preexisting symptoms of autonomic dysfunction. PMID- 25022470 TI - More than one world, more than one health: re-configuring interspecies health. AB - 'One World One Health' (OWOH), 'One Medicine' and 'One Health' are all injunctions to work across the domains of veterinary, human and environmental health. In large part they are institutional responses to growing concerns regarding shared health risks at the human, animal and environmental interfaces. Although these efforts to work across disciplinary boundaries are welcome, there are also risks in seeking unity, not least the tendency of one health visions to reduce diversity and to under-value the local, contingent and practical engagements that make health possible. This paper uses insights from Geography and Science and Technology Studies along with multi-sited and multi-species qualitative fieldwork on animal livestock and zoonotic influenzas in the UK, to highlight the importance of those practical engagements. After an introduction to one health, I argue that there is a tendency in OWOH visions to focus on contamination and transmission of pathogens rather than the socio-economic configuration of disease and health, and this tendency conforms to or performs what sociologist John Law calls a one world metaphysics. Following this, three related field cases are used to demonstrate that health is dependent upon a patchwork of practices, and is configured in practice by skilled people, animals, micro-organisms and their social relations. From surveillance for influenza viruses to tending animals, good health it turns out is dependent on an ability to construct common sense from a complex of signs, responses and actions. It takes, in other words, more than one world to make healthy outcomes. In light of this, the paper aims to, first, loosen any association between OWOH and a one world-ist metaphysics, and, second, to radicalize the inter-disciplinary foundations of OWOH by both widening the scope of disciplinarity as well as attending to how different knowledges are brought together. PMID- 25022471 TI - On the origin of scalp responses - a comment on the letter of Polak et al. PMID- 25022472 TI - Broca's area damage is necessary but not sufficient to induce after-effects of cathodal tDCS on the unaffected hemisphere in post-stroke aphasia. AB - BACKGROUND: The inter-individual variability of behavioral effects after tDCS applied to the unaffected right hemisphere in stroke may be related to factors such as the lesion location. OBJECTIVE/HYPOTHESIS: We investigated the effect of left Broca's area (BA) damage on picture naming in aphasic patients after cathodal tDCS applied over the right BA. METHODS: We conducted a study using pre interventional diffusion and resting state functional MRI (rsfMRI) and two cross over tDCS sessions (TYPE: sham and cathodal) over the right homologous BA in aphasic stroke patients with ischemic lesions involving the left BA (BA+) or other left brain areas (BA-). Picture naming accuracy was assessed after each session. Inter-hemispheric (IH) functional balance was investigated via rsfMRI connectivity maps using the right BA as a seed. Probabilistic tractography was used to study the integrity of language white matter pathways. RESULTS: tDCS had different effects on picture naming accuracy in BA+ and BA- patients (TYPE * GROUP interaction, F(1,19): 4.6, P: 0.04). All BA- patients except one did not respond to tDCS and demonstrated normal IH balance between the right and left BA when compared to healthy subjects. BA+ patients were improved by tDCS in 36% and had decreased level of functional IH balance. Improvement in picture naming after cathodal tDCS was associated with the integrity of the arcuate fasciculus in BA+ patients. CONCLUSIONS: Behavioral effects of cathodal tDCS on the unaffected right hemisphere differ depending on whether BA and the arcuate fasciculus are damaged. Therefore, IH imbalance could be a direct consequence of anatomical lesions. PMID- 25022473 TI - Dynamic hinged orthosis following a surgical reattachment and therapy protocol of a distal triceps tendon avulsion. AB - Triceps avulsion injuries are not very common injuries. These authors describe an orthosis and protocol they utilized to successfully treat a client following a triceps avulsion injury. - Victoria Priganc, PhD., OTR, CHT, CLT, Practice Forum Editor. PMID- 25022474 TI - Tissue specific uptake and elimination of perfluoroalkyl acids (PFAAs) in adult rainbow trout (Oncorhynchus mykiss) after dietary exposure. AB - Tissue specific uptake and elimination of perfluoroalkyl acids (PFAAs) were studied in rainbow trout (Oncorhynchus mykiss). Adult trout were exposed to perfluorobutane sulfonic acid (PFBS), perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) via food over a time period of 28d. In the following 28-d depuration period the fish were fed PFAA-free food. At defined sampling times four animals were removed from the experimental tank, euthanized and dissected. Muscle, liver, kidneys, gills, blood, skin and carcass were examined individually. At the end of the accumulation phase between 0.63% (PFOA) and 15.5% (PFOS) of the absolute, applied quantity of PFAAs was recovered in the whole fish. The main target organ was the liver with recovery rates between 0.11% (PFBS) and 4.01% (PFOS) of the total amount of ingested PFAAs. Perfluoroalkyl sulfonic acids were taken up more readily and had longer estimated elimination half-lives than perfluoroalkyl carboxylic acids of the same chain length. The longest estimated elimination half-lives were found to be for PFOS between 8.4d in muscle tissue and 20.4d in the liver and for PFNA between 8.2d in the blood and 11.6d in the liver. PMID- 25022475 TI - Estimating the physicochemical properties of polyhalogenated aromatic and aliphatic compounds using UPPER: part 1. Boiling point and melting point. AB - The UPPER (Unified Physicochemical Property Estimation Relationships) model uses enthalpic and entropic parameters to estimate 20 biologically relevant properties of organic compounds. The model has been validated by Lian and Yalkowsky on a data set of 700 hydrocarbons. The aim of this work is to expand the UPPER model to estimate the boiling and melting points of polyhalogenated compounds. In this work, 19 new group descriptors are defined and used to predict the transition temperatures of an additional 1288 compounds. The boiling points of 808 and the melting points of 742 polyhalogenated compounds are predicted with average absolute errors of 13.56 K and 25.85 K, respectively. PMID- 25022476 TI - NHS England is criticised for failing to robustly oversee out of hours care. PMID- 25022477 TI - Strategies to reduce aspecific adsorption of peptides and proteins in liquid chromatography-mass spectrometry based bioanalyses: an overview. AB - In the drug-discovery setting, the development of new peptide and protein-based biopharmaceuticals attracts increased attention from the pharmaceutical industry and consequently demands the development of high-throughput LC-MS methods. Regulatory guidelines require bioanalytical methods to be validated not only in terms of linearity, sensitivity, accuracy, precision, selectivity and stability, but also in terms of carryover. Carryover results from the aspecific adsorption of analyte(s) to parts of the analytical system and thus introduces bias in both identification and quantification assays. Moreover, nonspecific binding occurs at the surface of materials used during sample preparation, such as pipette tips, sample tubes and LC-vials. Hence, linearity, sensitivity and repeatability of the analyses are negatively affected. Due to the great diversity in physicochemical properties of biomolecules, there is no general approach available to minimize adsorption phenomena. Therefore, we aim to present different strategies which can be generically applied to reduce nonspecific binding of peptides and proteins. In the first part of this review, a systematic approach is proposed to guide the reader through the different solvents which can be used to dissolve the analyte of interest. Indeed, proper solubilization is one of the most important factors for a successful analysis. In addition, alternative approaches are described to improve analyte recovery from the sample vial. The second part focuses on strategies to efficiently reduce adsorption at components of the autosampler, column and mass spectrometer. Thereby carryover is reduced while maintaining a sufficiently wide dynamic range of the assay. PMID- 25022478 TI - Determination of sterols using liquid chromatography with off-line surface assisted laser desorption/ionization mass spectrometry. AB - A new method, reversed phase liquid chromatography with off-line surface-assisted laser desorption/ionization mass spectrometry (RPLC-SALDI MS) for the determination of brassicasterol (BR), cholesterol (CH), stigmasterol (ST), campesterol (CA) and beta-sitosterol (SI) in oil samples has been developed. The sample preparation consisted of alkaline saponification followed by extraction of the unsaponificable fraction with diethyl ether. The recovery of the sterols ranged from 91 to 95% with RSD less than 4%. Separation of the five major sterols on a C18 column using methanol-water gradient was achieved in about 10min. An on line UV detector was employed for the initial sterol detection prior to effluent deposition using a laboratory-built spotter with 1:73 splitter. Off-line SALDI MS was then applied for mass determination/identification and quantification of the separated sterols. Ionization of the nonpolar analytes was achieved by silver ion cationization with silver nanoparticles used as the SALDI matrix providing limits of detection 12, 6 and 11fmol for CH, ST and SI, respectively. Because of the incorporated splitter, the effective limits of detection of the RPLC-SALDI MS analysis were 4, 3 and 4pmol (or 0.08, 0.06 and 0.08MUg/mL) for CH, ST and SI, respectively. For quantification, 6-ketocholestanol (KE) was used as the internal standard. The method has been applied for the identification and quantification of sterols in olive, linseed and sunflower oil samples. The described off-line coupling of RPLC to SALDI MS represents an alternative to GC-MS for analysis of nonpolar compounds. PMID- 25022479 TI - Identification and analysis of gastrodin and its five metabolites using ultra fast liquid chromatography electrospray ionization tandem mass spectrometry to investigate influence of multiple-dose and food. AB - A reliable and highly sensitive ultra performance liquid chromatography electrospray ionization tandem mass spectrometry (UFLC-ESI-MS/MS) analytical method was developed for identification and quantification of gastrodin (GAS) and its metabolites in rat plasma. Five metabolites were identified: p-formylphenyl beta-d-glucopyranoside (M1), p-hydroxybenzonic acid (M2), p-hydroxybenzyl alcohol (M3), p-formaldehydephenyl-beta-d-glucopyranoside (M4), p-hydroxybenzaldehyde (M5). The molecular structures of metabolites were proposed based on the characters of their precursor ions, product ions and chromatographic retention time. Four of them were reported firstly in rat plasma. This method involved the addition of bergeninum as the internal standard (IS), UFLC separation, and quantification by MS/MS system using negative electrospray ionization in the multiple reaction monitoring (MRM) mode. The lower limit of quantification of gastrodin and five metabolites were all 1ng/mL. The method was linear in the concentration range of 0.001-10MUg/mL. The intra- and inter-day precisions (R.S.D %) were within 15.0% for all analytes. No interference was noted due to endogenous substances. All analytes were stable in rat plasma stored at room temperature and 4 degrees C for at least 4h, -20 degrees C combined with three freeze-thaw cycles for at least 1 month. By this method, the influence of multiple-dose and food on the pharmacokinetics behaviors of GAS and its metabolites were studied for the first time. We hope pharmacokinetic data of present study may inspire rational clinical usage of GAS. PMID- 25022480 TI - Stepwise elusion method in micellar electrokinetic chromatography via sequential use of lithium perfluorooctadecyl sulfonate and lithium dodecyl sulfate. AB - An effective stepwise micellar electrokinetic chromatography (MEKC) elution method was developed using lithium perfluorooctadecyl sulfonate (LPFOS) and lithium dodecyl sulfate (LDS). The hydrogen-bonding property of LPFOS micelles differs from that of LDS micelles, which leads to remarkably different selectivity in the transfer of solutes to the micelles. The present stepwise method is performed by replacing the inlet reservoir of a first running solution containing LPFOS with that of a second running solution containing LDS during a single separation run in the absence of electroosmotic flow under acidic conditions, where LPFOS micelles work as carriers in first and then LDS micelles turn over. Effective separation of 15 nonionic aromatic compounds was controlled well by adjusting the time in the inlet reservoir, which could not be accomplished with systems using only LPFOS or only LDS, with significant changes in the elution order where necessary. Furthermore, separations with the present stepwise method were easily simulated, and the replacement time was optimized for 3.1min from a 70.0mM LPFOS solution to a 67.5mM LDS solution with nearly complete separation within 15min using the simulated parameters. PMID- 25022481 TI - Kafirin adsorption on ion-exchange resins: isotherm and kinetic studies. AB - Kafirin is a natural, hydrophobic and celiac safe prolamin protein obtained from sorghum seeds. Today kafirin is found to be useful in designing delayed delivery systems and coatings of pharmaceuticals and nutraceuticals where its purity is important and this can be obtained by adsorptive chromatography. This study is the first scientific insight into the isotherm and kinetic studies of kafirin adsorption on anion- and cation-exchange resins for practical applications in preparative scale chromatography. Adsorption isotherms of kafirin were determined for five anion- and two cation-exchange resins in batch systems. Isotherm parameters such as maximum binding capacity and dissociation constant were determined from Langmuir isotherm, and adsorptive capacity and affinity constant from Freundlich isotherm. Langmuir isotherm was found to fit the adsorption equilibrium data well. Batch uptake kinetics for kafirin adsorption on these resins was also carried out and critical parameters including the diffusion coefficient, film mass transfer coefficient, and Biot number for film-pore diffusion model were calculated. Both the isotherm and the kinetic parameters were considered for selection of appropriate resin for kafirin purification. UNOsphere Q (78.26 mg/ml) and Toyopearl SP-650M (57.4 mg/ml) were found to offer better kafirin binding capacities and interaction strength with excellent uptake kinetics under moderate operating conditions. With these adsorbents, film diffusion resistance was found to be major governing factor for adsorption (Bi<10 and delta<1). Based on designer objective function, UNOsphere Q was found be best adsorbent for binding of kafirin. The data presented is valuable for designing large scale preparative adsorptive chromatographic kafirin purification systems. PMID- 25022482 TI - Poly(ionic liquid) immobilized magnetic nanoparticles as new adsorbent for extraction and enrichment of organophosphorus pesticides from tea drinks. AB - New poly(ionic liquid) immobilized magnetic nanoparticles (PIL-MNPs) were synthesized via co-polymerization of 1-vinyl-3-hexylimidazolium-based ionic liquid and vinyl-modified magnetic particles and were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, and magnetic measurements. The PIL-MNPs were utilized as adsorbent phases in magnetic solid-phase extraction (MSPE). The extraction and enrichment efficiency were evaluated by using four organophosphorus pesticides (parathion, fenthion, phoxim and temephos) as test analytes. Various parameters, such as amount of adsorbent, adsorption time, desorption solvent and time, and ionic strength were investigated. The proposed method showed good linearity for the analytes in the concentration range of 1-200MUgL(-1) with a correlation coefficient (R)>0.9963. Low limit of detection of 0.01MUgL(-1) and high enrichment factors ranging from 84 to 161 were achieved. The proposed method has been successfully used to determine organophosphorus pesticides from three tea drink samples with satisfactory recovery of 81.4-112.6% and RSDs of 4.5-11.3%. The PIL-MNP adsorbent can be reused for 20 times without a noticeable decrease in extraction efficiency. PMID- 25022483 TI - Quantification of target analytes in various biofluids using a postcolumn infused internal standard method combined with matrix normalization factors in liquid chromatography-electrospray ionization mass spectrometry. AB - Liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) has become one of the most widely used methods in pharmaceutical laboratories. Although LC-ESI-MS provides high sensitivity and high specificity for quantifying target analytes in complicated biofluids, the associated severe matrix effects (MEs) generally result in large quantification errors. Here, we propose a novel strategy for correcting MEs in various biofluids using a postcolumn infused internal standard (PCI-IS) method in combination with matrix normalization factors (MNFs). We used the MNFs to normalize the encountered MEs in various biofluids to the MEs encountered in standard solutions. The use of a postcolumn infused-internal standard also corrects the MEs for individual samples. When using the PCI-IS method in combination with MNFs, the calibration curve generated from standard solutions can be applied to quantify the target analytes in various biofluids. We applied this new approach to quantify etoposide and etoposide catechol in plasma and CSF. The accuracy of the test results showed that over 93% of the data have quantification errors less than 20% and that 99% of the data have quantification errors less than 30%. The successful application of this method to evaluate real clinical samples revealed that our proposed MNFs in combination with the PCI-IS method largely simplifies the entire method development and validation processes, saves a great deal of time and cost without sacrificing quantification accuracy, and provides a simple means of quantifying target analytes in various biofluids. This method will be particularly useful in fields in which the same target analytes need to be quantified in various types of matrices, including bioanalysis, forensic toxicology, environmental studies, and food safety control. PMID- 25022484 TI - Varying the porous structure of polystyrene/divinylbenzene beads prepared by Ugelstads activated swelling technique and examining its reversed phase HPLC properties. AB - Monodisperse unfunctionalized polystyrene/divinylbenzene beads were prepared via Ugelstads two-step activated swelling procedure. The modification of the porous structure was achieved in two different ways, by either changing the kind and amount of diluent or the concentration of crosslinker. Overall 10 different types of diluents, both solvent and nonsolvent types, were utilized. In all cases divinylbenzene was used as crosslinking agent in concentrations of 55% and 80%, which are commercially available, and 100%, which had to be synthesized. The size and morphology of these particles were examined with scanning electron microscopy. For the analysis of the internal porous structure inverse size exclusion chromatography was conducted. Depending on the monomer and diluent composition beads in the range of 3.4-4.5MUm having a specific surface area from 90 to 1898m(2)/g were synthesized. Separation performance was then also investigated using RP-HPLC with benzene and propylbenzene as analytes. Porous and reversed-phase properties were subsequently linked to explain the observed shift in retention and efficiency. Polymers having the highest specific surface area and the smallest mean pore diameter exhibited the best performance with reduced plate height of 3.1. PMID- 25022485 TI - Comprehensive two dimensional gas chromatography with fast-quadrupole mass spectrometry detector analysis of polar compounds extracted from the bio-oil from the pyrolysis of sawdust. AB - In this paper it is studied the most polar fractions of bio-oil produced by fast pyrolysis of Lignocel BK40-90 (sawdust from forest timber). The biomass was submitted to the pyrolysis in an existing FCC pilot plant that was adapted for this procedure. The equipment consists of a fluidized bed reactor with nitrogen injection. The unit operates with continuous biomass feeding and continuous solids circulation. The produced bio-oil was submitted to an aqueous alkaline extraction, isolating the acidic compounds that were analyzed by one-dimensional gas chromatography and comprehensive two-dimensional gas chromatography with quadrupole mass spectrometry detection (qMS). One hundred and thirty compounds (mainly phenols and ketones) were tentatively identified in the extract, some of them by the use of retention indexes. The main differences between chromatographic techniques were the substantial increasing in the peak capacity of GC*GC and the resolution of some co-elutions that occurred in GC/qMS. It is also possible to conclude that this extract is rich in important raw materials for the chemical industry and can be used for this end. PMID- 25022487 TI - Inflammatory myofibroblastic tumor of the thigh without bone involvement: a case report. AB - Inflammatory myofibroblastic tumors are rare, and those located in the extremities without bone involvement are even rarer. We present the case of a 61 year-old Chinese male patient with an inflammatory myofibroblastic tumor of the right thigh. It was excised and a histopathologic examination revealed an inflammatory myofibroblastic tumor. This case is presented by virtue of its rare location. PMID- 25022486 TI - Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age. AB - INTRODUCTION: In the human demyelinating central nervous system (CNS) disease multiple sclerosis, remyelination promotes recovery and limits neurodegeneration, but this is inefficient and always ultimately fails. Furthermore, these regenerated myelin sheaths are thinner and shorter than the original, leaving the underlying axons potentially vulnerable. In rodent models, CNS remyelination is more efficient, so that in young animals (but not old) the number of myelinated axons is efficiently restored to normal, but in both young and old rodents, regenerated myelin sheaths are still short and thin. The reasons for these differences in remyelination efficiency, the thinner remyelinated myelin sheaths compared to developmental myelin and the subsequent effect on the underlying axon are unclear. We studied CNS remyelination in the highly regenerative adult zebrafish (Danio rerio), to better understand mechanisms of what we hypothesised would be highly efficient remyelination, and to identify differences to mammalian CNS remyelination, as larval zebrafish are increasingly used for high throughput screens to identify potential drug targets to improve myelination and remyelination. RESULTS: We developed a novel method to induce a focal demyelinating lesion in adult zebrafish optic nerve with no discernible axonal damage, and describe the cellular changes over time. Remyelination is indeed efficient in both young and old adult zebrafish optic nerves, and at 4 weeks after demyelination, the number of myelinated axons is restored to normal, but internode lengths are short. However, unlike in rodents or in humans, in young zebrafish these regenerated myelin sheaths were of normal thickness, whereas in aged zebrafish, they were thin, and remained so even 3 months later. This inability to restore normal myelin thickness in remyelination with age was associated with a reduced macrophage/microglial response. CONCLUSION: Zebrafish are able to efficiently restore normal thickness myelin around optic nerve axons after demyelination, unlike in mammals. However, this fails with age, when only thin myelin is achieved. This gives us a novel model to try and dissect the mechanism for restoring myelin thickness in CNS remyelination. PMID- 25022488 TI - Indigenous populations in Mexico: medical anthropology in the work of Ruben Lisker in the 1960s. AB - Ruben Lisker's research on the genetic hematological traits of Mexican indigenous populations illustrates the intersection of international health policies and the local modernizing nationalism of the Mexican post-revolution period. Lisker's surveys of blood group types, and of G6PD (glucose-6-phosphodehydrogenase) and hemoglobin variants in indigenous populations, incorporated linguistic criteria in the sampling methods, and historical and cultural anthropological accounts in the interpretation of results. In doing so, Lisker heavily relied on the discourse and the infrastructure created by the indigenista program and its institutions. Simultaneously, Lisker's research was thoroughly supported by international and bilateral agencies and programs, including the malaria eradication campaign of the 1950s and 1960s. As a member of the scientific elite he was able to make original contributions to the postwar field of human population genetics. His systematic research illustrates the complex entanglement of local and international contexts that explains the co-construction of global knowledge on human variation after WWII.(1.) PMID- 25022490 TI - Intraarticular fractures of calcaneus - current concepts of treatment. AB - Fractures of calcaneus are the most common among all tarsal bone fractures. Such injuries are most often produced by large forces, while accompanying soft tissue trauma makes them complicated and difficult to treat. Due to complex structure of the foot and talocalcaneal joint all injuries to this area constitute an important orthopedic problem, as improper treatment or lack thereof leads to gait impairment, particularly with regard to moving on uneven surface. In this work we presented the problem of intraarticular calcaneal fractures with particular consideration paid to methods of its treatment. We also mentioned the problem of complications after conservative and surgical treatment as well as methods of their prevention. PMID- 25022489 TI - Evaluation of the impact of organ-specific dose reduction on image quality in pediatric chest computed tomography. AB - BACKGROUND: Organ-specific dose reduction significantly reduces the radiation exposure of radiosensitive organs. OBJECTIVE: The purpose of this study was to assess the impact of a novel organ-specific dose reduction algorithm on image quality of pediatric chest CT. MATERIALS AND METHODS: We included 28 children (mean age 10.9 +/- 4.8 years, range 3-18 years) who had contrast-enhanced chest CT on a 128-row scanner. CT was performed at 100 kV using automated tube current modulation and a novel organ-specific dose-reduction algorithm (XCareTM; Siemens, Forchheim, Germany). Seven children had a previous chest CT performed on a 64-row scanner at 100 kV without organ-specific dose reduction. Subjective image quality was assessed using a five-point scale (1-not diagnostic; 5-excellent). Contrast to-noise ratio (CNR) and signal-to-noise ratio (SNR) were assessed in the descending aorta. RESULTS: Overall mean subjective image quality was 4.1 +/- 0.6. In the subgroup of the seven children examined both with and without organ specific dose reduction, subjective image quality was comparable (score 4.4 +/- 0.5 with organ-specific dose reduction vs. 4.4 +/- 0.7 without it; P > 0.05). There was no significant difference in mean signal-to-noise ratio and contrast-to noise ratio with organ-specific dose reduction (38.3 +/- 10.1 and 28.5 +/- 8.7, respectively) and without the reduction (35.5 +/- 8.5 and 26.5 +/- 7.8, respectively) (P > 0.05). Volume computed tomography dose index (CTDIvol) and size-specific dose estimates did not differ significantly between acquisitions with the organ-specific dose reduction (1.7 +/- 0.8 mGy) and without the reduction (1.7 +/- 0.8 mGy) (P > 0.05). CONCLUSION: Organ-specific dose reduction does not have an impact on image quality of pediatric chest CT and can therefore be used in clinical practice to reduce radiation dose of radiosensitive organs such as breast and thyroid gland. PMID- 25022491 TI - HIV risk behaviors in the U.S. transgender population: prevalence and predictors in a large internet sample. AB - To study the influence of gender on HIV risk, a sample of the U.S. transgender population (N = 1,229) was recruited via the Internet. HIV risk and prevalence were lower than reported in prior studies of localized, urban samples but higher than the overall U.S. population. Findings suggest that gender nonconformity alone does not itself result in markedly higher HIV risk. Sex with nontransgender men emerged as the strongest independent predictor of unsafe sex for both male-to female (MtF) and female-to-male (FtM) participants. These sexual relationships constitute a process that may either affirm or problematize gender identity and sexual orientation, with different emphases for MtFs and FtMs, respectively. PMID- 25022492 TI - Outcomes and limitations of laparoscopic and robotic partial nephrectomy. AB - PURPOSE OF REVIEW: The objective of this review article is to summarize and critically analyze the studies published in the previous year and report perioperative, functional, and oncologic outcomes after laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN). RECENT FINDINGS: Recent case series studies evaluating LPN confirmed the good oncologic results of this approach at intermediate and long-term follow-ups. Recent studies investigating RAPN confirmed the promising perioperative outcomes reported in the initial case series. Many studies tested and demonstrated the feasibility of both procedures in the treatment of very complex cases represented by tumors larger than 4 cm, hilar/central tumors, endophytic tumors, or tumors located in solitary kidney. Comparative studies confirm advantages in favor of RAPN in comparison with LPN, mainly in terms of warm ischemia time and perioperative outcomes. A recent matched pair analysis showed equivalent perioperative and functional outcomes between RAPN and open partial nephrectomy (OPN). SUMMARY: LPN and above all RAPN represent valid alternatives to OPN in the conservative treatment of renal tumors. Both procedures can be proposed also for the treatment of complex cases. Further, well conducted, comparative studies between RAPN and OPN are needed to test the ability of RAPN as an alternative to OPN in the treatment of more complex cases. PMID- 25022493 TI - Enhancement of electrogenerated chemiluminescence of luminol by ascorbic acid at gold nanoparticle/graphene modified glassy carbon electrode. AB - Gold nanoparticle/graphene (GNP/GR) nanocomposite was one-pot synthesized from water soluble graphene and HAuCl4 by hydrothermal method and characterized by TEM, Raman spectroscopy, XRD, XPS, UV-vis spectroscopy, and electrochemical impedance spectroscopy (EIS). Electrogenerated chemiluminescence (ECL) of luminol was investigated at the GNP/GR modified glassy carbon electrode (GNP/GR/GCE) and the GNP modified glassy carbon electrode (GNP/GCE) in aqueous solution respectively. The results revealed that one strong anodic ECL peak could be observed at ~0.8 V at two modified electrodes compared with that at the bare electrode. The intensity of the anodic ECL at the GNP/GR/GCE is weaker than that at the GNP/GCE, which should be due to the synergic effect of the enhancing effect of gold nanoparticles and the inhibiting effect of graphene on anodic luminol ECL. One strong cathodic ECL peak located at ~-0.8 V could be observed at the GNP/GR/GCE but not at the GNP/GCE, which should be result from the adsorbed oxygen at the graphene film. In the presence of ascorbic acid, the anodic ECL at the GNP/GR/GCE was enhanced more than 8-times, which is more apparent than that at the GNP/GCE. Whereas, the cathodic ECL peak was seriously inhibited at the GNP/GR/GCE. The enhanced ECL intensity at the GNP/GR/GCE varied linearly with the logarithm of ascorbic acid concentration in the range of 1.0 * 10(-8) to 1.0 * 10(-6)mol L(-1) with a detection limit of 1.0 * 10(-9) mol L(-1). The possible ECL mechanism was also discussed. PMID- 25022494 TI - Synthesis, an experimental and quantum chemical computational study: proton sharing in 4-Morpholinium bis(hydrogen squarate). AB - The experimental and theoretical investigation results of a novel organic squarate salt of 4-Morpholinium bis(hydrogen squarate) (1), C6H14ON(+).C8H3O8(-), were reported in this study. The crystal structure of the title compound was found to crystallize in the triclinic P-1 space group. In the crystals of 1 the morpholine ring adopts the chair conformation with the ethyl group in the equatorial and hydrogen atoms in axial positions. The hydrogen squarate anions are linked into a homoconjugated anion, [(HSQ)2H], by a short symmetric, nonlinear O8?H2?O2 hydrogen bond of 2.444 (2)A. The structural and vibrational properties of the compound were also studied by computational methods of ab initio performed on the compound at DFT/B3LYP/6-31++G(d,p) (2) and HF/6 31++G(d,p) (3) level of theory. The obtained calculation results on the basis of two models for both the optimized molecular structure and vibrational properties for the 1 obtained are presented and compared with the X-ray analysis result. On the other hand the molecular electrostatic potential (MEP), electronic absorption spectra, frontier molecular orbitals (FMOs), conformational flexibility and non linear optical properties (NLO) of the title compound were also studied at the 2 level and the results are reported. In order to evaluate the suitability for NLO applications thermal analysis (TG, DTA and DTG) data of 1 were also obtained. PMID- 25022495 TI - Synthesis, spectroscopic characterization, crystal structure, DNA interaction study and invitro biological screenings of 4-(5-chloro-2-hydroxyphenylamino)-4 oxobut-2-enoic acid. AB - The titled compound, 4-(5-chloro-2-hydroxyphenylamino)-4-oxobut-2-enoic acid was synthesized and characterized by various techniques like elemental analyses, FT IR, NMR ((1)H, and (13)C) and single crystal X-ray structural analysis. The appearance of the OH peak of the carboxylic acid in the FT-IR and NMR spectra conform the formation of the compound. A good agreement was found between the calculated values of C, H, N and found values in elemental analysis that show the purity of the compound. Protons H2 and H3 are in cis conformation with each other as conformed both from (1)H NMR as well as from single crystal X-ray analysis. The molecular structure of the title compound, C10H10NO3Cl, is stabilized by short intramolecular OH---O hydrogen bonds within the molecule. In the crystal structure, intermolecular NH---O hydrogen bonds link molecules into zigzag chains resulting in a dendrimer like structure. The title compound was screened for biological activities like interaction with DNA, cytotoxicity, antitumor and antioxidant activities. DNA interaction study reveals that the binding mode of interaction of the compound with SS-DNA is intercalative as it results in hypochromism along with significant red shift of 5 nm. It was also found to be effective antioxidant of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and show almost comparable antioxidant activity to that of the standard and known antioxidant, ascorbic acid, at higher concentration. The antitumor activity data of the compound shows that it can be used as potent antitumor agent. PMID- 25022496 TI - Interaction of the CLPFFD peptide with gold nanospheres. A Raman, surface enhanced Raman scattering and theoretical study. AB - In a previous work we demonstrated that toxic aggregates of the protein beta amyloid (ATAbeta) involved in the Alzheimer's disease (AD) can be destabilized upon electromagnetic irradiation of the peptide Cys-Leu-Pro-Phe-Phe-Asp (CLPFFD) adsorbed on gold nanospheres (AuNSs). For a selective recognition of the therapeutic target (i.e. ATAbeta) of AD by the conjugates peptide-nanoparticle it is relevant to understand how the interaction between attached ligands and nanoparticles occurs. In this work a surface enhanced Raman scattering spectroscopy (SERS) study of the interactions of CLPFFD with AuNSs of 10nm average diameter was carried out. The SERS data suggest that phenylalanine displays its aromatic ring coplanar to the surface which is supported by theoretical data obtained from molecular mechanics (MM) and Extended Huckel Theory (EHT) calculations. PMID- 25022497 TI - Metal complexes derived from hydrazoneoxime ligands: V. Spectral and structural studies on diacetylmonoxime n-alkanoylhydrazones and their nickel(II) and copper(II) complexes. AB - A series of diacetylmonoxime n-alkanoylhydrazones (H2L(n), n=4, 5, 6, 12 and 16) were prepared by the condensation of diacetylmonoxime with the corresponding n alkanoylhydrazine in ethanol. The X-ray crystal structure of diacetylmonoxime octadecanoyl hydrazone has been solved and its molecular and supramolecular structures have been discussed. Both neutral dinuclear Cu(II) and Ni(II) complexes, [{M(L(n))}2] (M=Cu, Ni and n=4, 5, 6, 12 and 16) as well as cationic dinuclear Cu(II) complexes, [Cu2(L(n))(HL(n))]NO3 (n=12 and 16) have been also prepared and characterized by elemental analyses, FD- and ESI-mass spectra as well as IR, UV-Vis, (1)H NMR, (13)C NMR spectra. Variable temperature magnetic susceptibility measurements for dinuclear Cu(II) complexes have been also discussed. PMID- 25022498 TI - FTIR, Raman and NMR spectroscopic and DFT theoretical studies on poly(N vinylimidazole). AB - In this study where the FTIR, Raman, (1)H NMR and (13)C NMR spectra of poly(N vinylimidazole) which can be abbreviated as poly(NVIM) are first reported, a comparison of the experimental and theoretical vibrational spectral data of monomer NVIM and water-soluble poly(NVIM) has been given; such a comparison over the vibrational modes and associated spectral data calculated at B3LYP/6-31+G(d) level of theory for NVIM and its stable dimer forms provided significant contributions for getting a reliable interpretation of the observed vibrational spectra of poly(NVIM). The obtained results revealed that the change from NVIM to poly(NVIM) should be characterized by the disappearance of the CH2CH bonds of the vinyl group and the appearance of the aliphatic CH and CH2 bonds. Besides this, the thermal properties of poly(NVIM) were elucidated by thermogravimetric analyses such as TGA, DTA and DSC, while some electronic structure parameters of the most stable dimers of NVIM were investigated through the structure calculations performed by using B3LYP method and 6-31+G(d) basis set within the density functional theory (DFT) methodology. PMID- 25022499 TI - Synthesis and spectroscopy studies of the inclusion complex of 3-amino-5-methyl pyrazole with beta-cyclodextrin. AB - Amino pyrazole belongs to anti-inflammatory class, and is characterized by a low solubility in water. (In order to increase its solubility in water, inclusion complex of amino pyrazole with beta-CD was obtained.) The inclusion complex obtained between AMP and beta-cyclodextrin, was characterized by FT-IR, (1)H NMR, (1)H-(1)H NOESY, (13)C NMR, DEPT, XHCOR, spectra, through TG analysis, DTA, DSC and Scanning Electron Microscopy (SEM). The stoichiometry of inclusion complex is 1:1 (guest-host) and K stability is 1.1 * 10(4)M(-1). PMID- 25022500 TI - Influence of calcination temperature on the luminescent properties of Eu3+ doped CaAl4O7 phosphor prepared by Pechini method. AB - Motivated by the need for new phosphor for white light emitting diode (WLED) applications, CaAl4O7 phosphors activated by Eu(3+) rare earth ion was synthesized using the Pechini method at different calcination temperatures. The crystal structure and luminescent properties were investigated by X-ray diffraction (XRD), scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), UV-Vis diffuse reflectance spectroscopy (DRS), and photoluminescence spectroscopy (PL). The XRD and SEM patterns confirm the presence of a single grossite monoclinic phase (311) and the particles exhibit good crystallinity and the particle size varies with calcination temperature. Absorption peak of FT-IR shows the decomposition of citrate ethylene glycol complex and the formation of CaAl4O7:Eu(3+) phosphor. Diffuse reflectance spectra indicate an absorption in the UV-region. The photoluminescence excitation spectrum exhibited a broad band covering from 340 to 420 nm with a sharp band at 395 nm. CaAl4O7:Eu(3+) phosphor excited by near UV (395 nm) light showed a strong red emission at 611 nm. The emission band is due to f-f transitions within the 4f(6) configuration of Eu(3+) ions, respectively. The photoluminescence properties were found to be strongly dependent on the calcination temperature and the PL properties are superior for sample calcined at 950 degrees C. PMID- 25022501 TI - Shedding light on the photostability of two intermolecular charge-transfer complexes between highly fluorescent bis-1,8-naphthalimide dyes and some pi acceptors: a spectroscopic study in solution and solid states. AB - Given the great importance of the various uses of 1,8-naphthalimides in the trends of biology, medicine and industry, the current study focused on extending the scope of these dyes by introducing some of their charge-transfer (CT) complexes. For this purpose, two highly fluorescent bis-1,8-naphthalimide dyes and their complexes with some pi-acceptors have been synthesized and characterized spectroscopically. The pi-acceptors include picric acid (PA), chloranilic acid (CLA), tetracyanoquinodimethane (TCNQ) and dichlorodicyanobenzoquinone (DDQ). The molecular structure, spectroscopic and fluorescence properties as well as the binding modes were deduced from IR, UV-vis and (1)H NMR spectral studies. The binding ratio of complexation was determined to be 1:1 according to the elemental analyses and photometric titrations. It has been found that the order of acceptance ability for the different acceptors is TCNQ>DDQ>CLA>PA. The photostability of 1,8-naphthalimide dye as a donor and its charge-transfer complex doped in polymethyl methacrylate/PMMA were exposed to UV Vis radiation and the change in the absorption spectra was achieved at different times during irradiation period. PMID- 25022502 TI - Characterization of Pb24Te76 quantum dot thin film synthesized by inert gas condensation. AB - Air-stable and thermal-stable lead telluride quantum dot was successfully prepared on glass substrate by inert gas condensation (IGC) method. Argon (Ar) is the inert gas used during deposition process with a constant flow rate of 3 * 10( 3)Torr. The effect of heat-treatment process at different times was studies for structure, optical and electrical properties for nanocrystalline thin films. The structures of the as deposited and heat-treated films were investigated using grazing incident in-plane X-ray diffraction (GIIXD). The GIIXD pattern showed nanostructure face centered cubic structure of PbTe thin films. The energy dispersive X-ray analysis (EDX) of as deposited PbTe thin film was carried out and showed that the atomic ratio of Pb/Te was 24/76. The particle size of the as deposited PbTe film and after stored it in an unhumid atmosphere are 6.8 +/- 0.3 nm and 7.2 +/- 0.3 nm respectively as estimated form TEM image (i.e. in the same level of particle size). However, the particle size was changed to be 11.8 +/- 0.3 nm after heat-treated for 5h at 473K. These particle size values of PbTe thin film are smaller than its Bohr radius. The estimated value of optical band gap Eg decreased from 1.71 eV for the as deposited film to 1.62 eV for film heat-treated (5 h at 473K). The dc electrical conductivity is increased with raising temperature in the range (303-473K) for all thin films under investigation. The deduced activation energy decreased from 0.222 eV for as deposited sample to 0.125 eV after heat-treated at 473K for 5 h. PMID- 25022503 TI - A study on the stability and green synthesis of silver nanoparticles using Ziziphora tenuior (Zt) extract at room temperature. AB - Biomolecules present in plant extracts can be used to reduce metal ions to nanoparticles in a single-step green synthesis process. This biogenic reduction of metal ion to base metal is quite rapid, readily conducted at room temperature and pressure, and easily scaled up. Mediated Synthesis by plant extracts is environmentally benign. The involved reducing agents include the various water soluble plant metabolites (e.g. alkaloids, phenolic compounds, terpenoids) and co enzymes. Silver (Ag) nanoparticles have the particular focus of plant-based syntheses. Extracts of a diverse range of Ziziphora tenuior (Zt) have been successfully used in making nanoparticles. The aim of this study was to investigate the antioxidant properties of this plant and its ability to synthesize silver nanoparticles. Z.tenuior leaves were used to prepare the aqueous extract for this study. Silver nanoparticles were characterized with different techniques such as UV-vis spectroscopy, Fourier transform infrared (FT IR) spectroscopy, X-ray diffraction (XRD), Scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Transmission electron microscopy experiments showed that these nanoparticles are spherical and uniformly distributed and its size is from 8 to 40 nm. FT-IR spectroscopy revealed that silver nanoparticles were functionalized with biomolecules that have primary amine group (NH2), carbonyl group, -OH groups and other stabilizing functional groups. X-ray diffraction pattern showed high purity and face centered cubic structure of silver nanoparticles with size of 38 nm. In addition to plant extracts, live plants can be used for the synthesis. Here were view the methods of making nanoparticles using plant extracts. The scanning electron microscopy (SEM) implies the right of forming silver nanoparticles. The results of TEM, SEM, FT-IR, UV-VIS and XRD confirm that the leaves extract of Zt can synthesis silver nanoparticles. PMID- 25022504 TI - Vibrational spectroscopic (FT-IR and FT-Raman) studies, HOMO-LUMO, NBO analysis and MEP of 6-methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]oxy}methyl) 1,2,3,4-tetra-hydroquinazoline-2,4-dione, a potential chemotherapeutic agent, using density functional methods. AB - 6-Methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]oxy}methyl)-1,2,3,4-tetra hydro quinazoline-2,4-dione was prepared via treatment of silylated 6 methylquinazoline-2,4-dione with bis-[(E)-2-methyl-3-phenylallyloxy]methane. FT IR and FT-Raman spectra were recorded and analyzed. The vibrational wavenumbers were computed using DFT methods and are assigned with the help of potential energy distribution method. The first hyperpolarizability, infrared intensities and Raman activities also reported. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated (B3LYP) values. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. MEP was performed by the B3LYP method and from the MEP it is evident that the negative charge covers the CO group and the positive region is over the phenyl ring and NH group. PMID- 25022505 TI - Facile green synthesis of silver nanoparticles using seed aqueous extract of Pistacia atlantica and its antibacterial activity. AB - In the present work, we describe the synthesis of silver nanoparticles (Ag-NPs) using seed aqueous extract of Pistacia atlantica (PA) and its antibacterial activity. UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infra red spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-ray energy dispersive spectrophotometer (EDAX) were performed to ascertain the formation of Ag-NPs. It was observed that the growths of Ag-NPs are stopped within 35 min of reaction time. The synthesized Ag NPs were characterized by a peak at 446 nm in the UV-visible spectrum. XRD confirmed the crystalline nature of the nanoparticles of 27 nm size. The XRD peaks at 38 degrees , 44 degrees , 64 degrees and 77 degrees can be indexed to the (111), (200), (220) and (311) Bragg's reflections of cubic structure of metallic silver, respectively. The FTIR result clearly showed that the extracts containing OH as a functional group act in capping the nanoparticles synthesis. Antibacterial activities of Ag-NPs were tested against the growth of Gram positive (S. aureus) using SEM. The inhibition was observed in the Ag-NPs against S. aureus. The results suggest that the synthesized Ag-NPs act as an effective antibacterial agent. It is confirmed that Ag-NPs are capable of rendering high antibacterial efficacy and hence has a great potential in the preparation of used drugs against bacterial diseases. The scanning electron microscopy (SEM), indicated that, the most strains of S. aureus was damaged and extensively disappeared by addition of Ag-NPs. The results confirmed that the (PA) is a very good eco friendly and nontoxic source for the synthesis of Ag-NPs as compared to the conventional chemical/physical methods. PMID- 25022506 TI - Synthesis, structural elucidation, biological, antioxidant and nuclease activities of some 5-Fluorouracil-amino acid mixed ligand complexes. AB - Some biologically active mixed ligand complexes (1-9) have been synthesized from 5-Fluorouracil (5-FU; A) and amino acids (B) such as glycine (gly), L-alanine (ala) and L-valine (val) with Ni(II), Cu(II) and Zn(II) ions. The synthesized mixed ligand complexes (1-9) were characterized by various physico-chemical, spectral, thermal and morphological studies. 5-Fluorouracil and its mixed ligand complexes have been tested for their in vitro biological activities against some pathogenic bacterial and fungal species by the agar well diffusion method. The in vitro antioxidant activities of 5-Fluorouracil and its complexes have also been investigated by using the DPPH assay method. The results demonstrate that Cu(II) mixed ligand complexes (4-6) exhibit potent biological as well as antioxidant activities compared to 5-Fluorouracil and Ni(II) (1-3) and Zn(II) (7-9) mixed ligand complexes. Further, the cleaving activities of CT DNA under aerobic conditions show moderate activity with the synthesized Cu(II) and Ni(II) mixed ligand complexes (1-6) while no activity is seen with Zn(II) complexes (7-9). Binding studies of CT DNA with these complexes show a decrease in intensity of the charge transfer band to the extent of 5-15% along with a minor red shift. The free energy change values (Delta(?)G) calculated from intrinsic binding constants indicate that the interaction between mixed ligand complex and DNA is spontaneous. PMID- 25022507 TI - Study on structural, morphological, optical and thermal properties of guanidine carbonate doped nickel sulfate hexahydrate crystal. AB - The single crystal of guanidine carbonate doped nickel sulfate hexahydrate was grown from solution for ultraviolet filters. The single crystal XRD confirms that the grown single crystal belongs to the tetragonal system with the space group of P41212. The crystallinity of the grown crystal was estimated by powder X-ray diffraction studies. The optical transmission and thermal stability of as-grown guanidine carbonate doped nickel sulfate single crystals have been studied. The optical transmission spectrum demonstrates the characteristics of ultraviolet filters. The TG/DTA studies confirm the thermal properties of grown crystals. Thermo-gravimetric analysis showed that the dehydration temperature of the guanidine carbonate doped nickel sulfate crystal is about 100 degrees C, which is much higher than that of pure nickel sulfate hexahydrate (NSH) crystals which is 72 degrees C. The growth behaviors and dislocation density were detected under the high resolution XRD and etching studies respectively. PMID- 25022508 TI - FT-IR and FT-Raman spectra, molecular structure and first-order molecular hyperpolarizabilities of a potential antihistaminic drug, cyproheptadine HCl. AB - Cyproheptadine hydrochloride (CYP HCl) {4-(5H-dibenzo[a,d]-cyclohepten-5-ylidene) 1-methylpiperidine hydrochloride} is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local-anesthetic properties. The geometry optimization, Mulliken atomic charges and wavenumber and intensity of the vibrational bands of all of the possible modes of CYP HCl have been calculated using ab initio Hartree-Fock (HF) and density functional theory (DFT) employing the B3LYP functional with the 6-311G(d,p) basis set. We have compared the calculated IR and Raman wavenumbers with experimental data. Quantum-chemical calculations of the geometrical structure, energies, and molecular electrostatic potential and NBO analysis of CYP HCl have been performed using the B3LYP/6 311G(d,p) method. The electric dipole moment (MU), static polarizability (alpha) and the first hyperpolarizability (beta) values of the title compound have been computed using HF and DFT methods. The study reveals that the antihistaminic pharmacological property of CYP HCl has a large beta value and, hence, may in general have potential applications in the development of non-linear optical materials. The experimental and calculated results for CYP HCl have also been compared with those for mianserin HCl. PMID- 25022509 TI - Overoxidized polypyrrole/graphene nanocomposite with good electrochemical performance as novel electrode material for the detection of adenine and guanine. AB - Most conducting polymer/graphene composites have excellent electrical conductivity. However, the background currents of these composites modified electrodes are much larger. In order to improve the sensitivities of these methods, it is necessary to decrease the background signal. In this paper, porous structure films of overoxidized polypyrrole/graphene (PPyox/GR) have been electrochemically coated onto glassy carbon electrode (GCE) and successfully utilized as an efficient electrode material for the quantitive detection of adenine and guanine, two of the most important components of DNA and RNA. The permselective polymer coatings with low background current could improve the selectivity and sensitivity of microelectrodes for the electropositive purine bases. The GRs into these polymers would further improve sensitivity by increasing the electroactive surface area. The electrochemical sensor can be applied to the quantification of adenine and guanine with a linear range covering 0.06-100 uM and 0.04-100 uM, and a low detection limit of 0.02 MUM and 0.01 MUM, respectively. More importantly, the proposed method was applied to quantify adenine and guanine in calf thymus DNA with satisfactory results. PMID- 25022510 TI - A novel electrochemical biosensor for ultrasensitive and specific detection of DNA based on molecular beacon mediated circular strand displacement and rolling circle amplification. AB - A novel electrochemical biosensing strategy was developed for ultrasensitive and specific detection of target DNA using a cascade signal amplification based on molecular beacon (MB) mediated circular strand displacement (CSD), rolling circle amplification (RCA), biotin-strepavidin system, and enzymatic amplification. The target DNA hybridized with the loop portion of MB probe immobilized on the gold electrode and triggered the CSD, leading to multiple biotin-tagged DNA duplex. Furthermore, via biotin-streptavidin interaction, the RCA was implemented, producing long massive tandem-repeat DNA sequences for binding numerous biotinylated detection probes. This enabled an ultrasensitive electrochemical readout by further employing the streptavidin-alkaline phosphatase. The proposed biosensor showed very high sensitivity and selectivity with a dynamic response range from 1 fM to 100 pM. The proposed strategy could have the potential for applying in clinical molecular diagnostics and environmental monitoring. PMID- 25022511 TI - Isothermal and rapid detection of pathogenic microorganisms using a nano-rolling circle amplification-surface plasmon resonance biosensor. AB - Rolling circle amplification (RCA) of DNA is a sensitive and cost effective method for the rapid identification of pathogens without the need for sequencing. In this study, a surface plasmon resonance DNA biosensor based on RCA with a gold (Au) nanoparticle surface was established for isothermal identification of DNA. The probes included a specific padlock probe, a capture probe (CP), which is bound to biotin, and an Au nanoparticle-modified probe, which hybridizes with the RCA products. The CP was assembled on gold nanoparticles to increase its ability to bind and hybridize. The linear padlock probe, which was designed to circularize by ligation upon recognition of the bacterial pathogen-specific sequence in 16S rDNA, hybridizes to fully complementary sequences within the CP. Upon recognition, each target gene DNA is distinguished by localization onto the corresponding channel on the chip surface. Then, the immobilized CPs act as primers to begin the in situ solid-phase RCA reaction, which produces long single stranded DNA. The RCA products fixed on the chip surface cause significant surface plasmon resonance angle changes. We demonstrated that six different bacterial pathogens can be identified simultaneously and that 0.5 pM of synthetic oligonucleotides and 0.5 pg MUl(-1) of genomic DNA from clinical samples can be detected by this method with low background signals. Therefore, the multiplex diagnostic method provides a highly sensitive and specific approach for the rapid identification of positive samples. PMID- 25022512 TI - Different compartmentation of responses to brain natriuretic peptide and C-type natriuretic peptide in failing rat ventricle. AB - We previously found a negative inotropic (NIR) and positive lusitropic response (LR) to C-type natriuretic peptide (CNP) in the failing heart ventricle. In this study, we investigated and compared the functional responses to the natriuretic peptides (NPs), brain (BNP) and C-type natriuretic peptide (CNP), and relate them to cGMP regulation and effects on downstream targets. Experiments were conducted in left ventricular muscle strips and ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. As opposed to CNP, BNP did not cause an NIR or LR, despite increasing cGMP levels. The BNP-induced cGMP elevation was mainly and markedly regulated by phosphodiesterase (PDE) 2 and was only marginally increased by PDE3 or PDE5 inhibition. Combined PDE2, -3, and -5 inhibition failed to reveal any functional responses to BNP, despite an extensive cGMP elevation. BNP decreased, whereas CNP increased, the amplitude of the Ca(2+) transient. BNP did not increase phospholamban (PLB) or troponin I (TnI) phosphorylation, Ca(2+) extrusion rate constant, or sarcoplasmatic reticulum Ca(2+) load, whereas CNP did. Both BNP and CNP reduced the peak of the L-type Ca(2+) current. Cyclic GMP elevations by BNP and CNP in cardiomyocytes were additive, and the presence of BNP did not alter the NIR to CNP or the CNP-induced PLB and TnI phosphorylation. However, a small increase in the LR to maximal CNP was observed in the presence of BNP. In conclusion, different responses to cGMP generated by BNP and CNP suggest different compartmentation of the cGMP signal and different roles of the two NPs in the failing heart. PMID- 25022513 TI - Uptake and protective effects of ergothioneine in human endothelial cells. AB - Ergothioneine is a thiourea derivative of histidine found in food, especially mushrooms. Experiments in cell-free systems and chemical assays identified this compound as a powerful antioxidant. Experiments were designed to test the ability of endothelial cells to take up ergothioneine and hence benefit from protection against oxidative stress. Reverse-transcription polymerase chain reaction and Western blotting demonstrated transcription and translation of an ergothioneine transporter in human brain microvascular endothelial cells (HBMECs). Uptake of [(3)H]ergothioneine occurred by the organic cation transporter novel type-1 (OCTN 1), was sodium-dependent, and was reduced when expression of OCTN-1 was silenced by small interfering RNA (siRNA). The effect of ergothioneine on the production of reactive oxygen species (ROS) in HBMECs was measured using dichlorodihydrofluorescein and lucigenin, and the effect on cell viability was studied using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. ROS production and cell death induced by pyrogallol, xanthine oxidase plus xanthine, and high glucose were suppressed by ergothioneine. The antioxidant and cytoprotective effects of ergothioneine were abolished when OCTN 1 was silenced using siRNA. The expression of NADPH oxidase 1 was decreased, and those of glutathione reductase, catalase, and superoxide dismutase enhanced by the compound. In isolated rat basilar arteries, ergothioneine attenuated the reduction in acetylcholine-induced relaxation caused by pyrogallol, xanthine oxidase plus xanthine, or incubation in high glucose. Chronic treatment with the compound improved the response to acetylcholine in arteries of rats with streptozotocin-induced diabetes. In summary, ergothioneine is taken up by endothelial cells via OCTN-1, where the compound then protects against oxidative stress, curtailing endothelial dysfunction. PMID- 25022515 TI - Service utilization among veterans with schizophrenia and a comorbid anxiety disorder. AB - OBJECTIVE: The objective was to assess the prevalence and impact of anxiety disorders on service utilization among Veterans Health Administration (VHA) patients with schizophrenia. METHODS: This cross-sectional study examined diagnostic, utilization, and medication records included in the VHA National Psychosis Registry. Relationships between schizophrenia and anxiety disorders were evaluated along demographic and service utilization dimensions. RESULTS: During fiscal year 2011, 23.8% (N=20,722) of 87,006 VHA patients with schizophrenia were diagnosed as having a comorbid anxiety disorder; 15.2% of the sample had a posttraumatic stress disorder (PTSD) diagnosis and 8.6% a non-PTSD anxiety disorder. Comorbid anxiety disorders were associated with increased psychiatric comorbidity (depression, personality disorder, and substance use disorder), higher rates of psychiatric and medical hospitalization, and increased utilization of outpatient mental health services. CONCLUSIONS: Anxiety disorders are common among individuals with schizophrenia within the VHA and appeared in this study to convey additional disability in terms of psychiatric comorbidity and the need for increased psychiatric care. Future research should investigate ways to improve detection and enhance treatment provided to this population. PMID- 25022514 TI - Targeted injection of a biocomposite material alters macrophage and fibroblast phenotype and function following myocardial infarction: relation to left ventricular remodeling. AB - A treatment target for progressive left ventricular (LV) remodeling prevention following myocardial infarction (MI) is to affect structural changes directly within the MI region. One approach is through targeted injection of biocomposite materials, such as calcium hydroxyapatite microspheres (CHAM), into the MI region. In this study, the effects of CHAM injections upon key cell types responsible for the MI remodeling process, the macrophage and fibroblast, were examined. MI was induced in adult pigs before randomization to CHAM injections (20 targeted 0.1-ml injections within MI region) or saline. At 7 or 21 days post MI (n = 6/time point per group), cardiac magnetic resonance imaging was performed, followed by macrophage and fibroblast isolation. Isolated macrophage profiles for monocyte chemotactic macrophage inflammatory protein-1 as measured by real-time polymerase chain reaction increased at 7 days post-MI in the CHAM group compared with MI only (16.3 +/- 6.6 versus 1.7 +/- 0.6 cycle times values, P < 0.05), and were similar by 21 days post-MI. Temporal changes in fibroblast function and smooth muscle actin (SMA) expression relative to referent control (n = 5) occurred with MI. CHAM induced increases in fibroblast proliferation, migration, and SMA expression-indicative of fibroblast transformation. By 21 days, CHAM reduced LV dilation (diastolic volume: 75 +/- 2 versus 97 +/- 4 ml) and increased function (ejection fraction: 48 +/- 2% versus 38 +/- 2%) compared with MI only (both P < 0.05). This study identified that effects on macrophage and fibroblast differentiation occurred with injection of biocomposite material within the MI, which translated into reduced adverse LV remodeling. These unique findings demonstrate that biomaterial injections impart biologic effects upon the MI remodeling process over any biophysical effects. PMID- 25022516 TI - [99mTc(CO)3]+ and [99mTcO2]+ radiolabeled cyclic melanotropin peptides for melanoma SPECT imaging. AB - The melanoma targeting peptides (Ala-triazol)Ac-Re(Arg(11))CCMSH and N4-CO Re(Arg(11))CCMSH were radiolabeled with [(99m)Tc(CO)3](+) and [(99m)TcO2](+), respectively, and examined for in vitro cell binding, in vivo biodistribution and imaging properties. The (Ala-triazol)Ac-Re(Arg(11))CCMSH and N4-CO Re(Arg(11))CCMSH were synthesized as protected peptides on resin followed by rhenium cyclization with [(C6H5)3P]2ReOCl3 in DMF. The peptides were labeled with (99m)Tc and examined for radiochemical stability and melanoma cell binding. In vivo biodistribution and SPECT/CT imaging studies were performed in B16/F1 melanoma tumor bearing C57 mice. (99m)Tc(CO)3-(Ala-Triazol)Ac- Re(Arg(11))CCMSH and (99m)TcO2-N4-CO-Re(Arg(11))CCMSH were stable and internalized in B16/F1 melanoma cells upon binding. In vivo biodistribution studies revealed that tumor uptake of (99m)Tc(CO)3-(Ala-Triazol)Ac-Re(Arg(11))CCMSH was 6.08+/-1.06% ID/g and 7.05+/-1.48% ID/g at 2 h and 4 h post injection, respectively. Tumor uptake of (99m)TcO2-N4-CORe(Arg(11))CCMSH was 7.54+/-1.82% ID/g and 2.28+/-0.22% ID/g at 1 h and 2 h post injection, respectively. SPECT/CT imaging studies showed that tumor selective uptake of the radiolabeled peptides, which was confirmed by competitive blocking studies. PMID- 25022517 TI - [Retroperitoneal emphysema after endoscopic retrograde cholangiopancreatography]. AB - Retroperitoneal emphysema represents a pathological situation with an abnormal amount of air in the retroperitoneal tissue. The diagnosis is made radiologically.The cause is mostly an iatrogenic complication of different diagnostic or therapeutic procedures. The most common cause is a perforation after endoscopic retrograde cholangiopancreatography (ERCP). In cases of clinically suspected complications after a procedure prompt diagnosis with computed tomography (CT) scan of the abdomen and an interdisciplinary decision on the suitable therapeutic measures is warranted, as immediate therapy reduces morbidity and mortality of patients. For selecting the ideal therapy it is essential to understand the underlying pathophysiological mechanism of retroperitoneal emphysema and to take the clinical situation of the patient into account. Thus periampullary or bile duct lesions facing the retroperitoneum can be treated conservatively in clinically stable patients, whereas in unstable patients with abscess formation, interventional radiological or endoscopic procedures are indicated. In cases of a duodenal lesion an endoscopic closure of the perforation can be performed in stable patients but if the patient shows signs of peritonism or if the clinical situation deteriorates, operative therapy is necessary. PMID- 25022518 TI - The optogenetic revolution in memory research. AB - Over the past 5 years, the incorporation of optogenetics into the study of memory has resulted in a tremendous leap in this field, initiating a revolution in our understanding of the networks underlying cognitive processes. This review will present recent breakthroughs in which optogenetics was applied to illuminate, both literally and figuratively, memory research, and describe the technical approach, together with the opportunities it offers. Specifically, a large body of literature has been generated, setting the foundation for deciphering the spatiotemporal organization of hippocampal-based memory processing and its underlying mechanisms, as well as the contribution of cortical and amygdalar regions to cognition. PMID- 25022520 TI - Characterization of dephosphocoenzyme A kinase from Streptomyces peucetius ATCC27952, and its application for doxorubicin overproduction. AB - Dephosphocoenzyme A (CoaE) catalyzes the last step in the biosynthesis of the cofactor coenzyme A. In this study, we report the identification and application of CoaE from Stretomyces peucetius ATCC27952. After expression of coaE, the protein was found to have a molecular mass of 28.6 kDa. Purification of the His tagged fused CoaE protein was done by immobilized metal-affinity chromatography, and then in vitro enzymatic coupling assay was performed. The increasing NADH consumption with time shed light on the phosphorylating activity of CoaE. Furthermore, the overexpression of coaA and coaE independently under the ermE(*) promoter in the doxorubicin -producing wild type strain, resulted in 1.4- and 1.5 fold enhancements in doxorubicin production, respectively. In addition, the overexpression of both genes together showed a 2.1-fold increase in doxorubicin production. These results established a positive role for secondary metabolite production from Streptomyces peucetius. PMID- 25022519 TI - Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink. AB - BACKGROUND: There is strong evidence of reductions in major vascular events from statins across all cardiovascular risk categories. However, trials of statin therapy have provided conflicting results regarding statin use and type 2 diabetes (T2DM). We aimed to assess the effect of statins on T2DM development. METHOD: We carried out a population-based cohort study using the Clinical Practice Research Datalink (CPRD), a database of computerized clinical records. Every patient aged 30-85 years old starting a statin between 1989 and 2009 was matched with up to five non-statin users. The observation period in CPRD ended in 31 December 2011. Cox proportional hazard regression was used to compare rates of T2DM between statin users and non-users, using propensity score method to adjust for systematic differences between groups. RESULTS: The study basis comprised 2,016,094 individuals, including 430,890 people who received a statin, matched to 1,585,204 people not prescribed a statin. Mean follow-up time was 5.43 years for statin users and 3.89 years for nonusers. During follow-up 130,395 individuals developed T2DM. Statin use was associated with an increased risk of T2DM (HR 1.57; 95% CI 1.54-1.59), which increases with longer duration of use. The increased risk was smaller among people with hypertension or cardiovascular disease and was only apparent after 5 or more years treatment with statins in these groups. Conversely, age-specific risk ratios decreased in older people. CONCLUSIONS: Statin use is associated with an increased risk of T2DM. Our results suggest that the relative risk is higher among people without diagnosed hypertension or cardiovascular disease. These findings should be considered in the context of the observational nature of the data which is prone to bias and unmeasured confounding. PMID- 25022521 TI - Screening and characterization of a novel cellulase gene from the gut microflora of Hermetia illucens using metagenomic library. AB - A metagenomic fosmid library was constructed using genomic DNA isolated from the gut microflora of Hermetia illucens, a black soldier fly. A cellulase-positive clone, with the CS10 gene, was identified by extensive Congo-red overlay screenings for cellulase activity from the fosmid library of 92,000 clones. The CS10 gene was composed of a 996 bp DNA sequence encoding the mature protein of 331 amino acids. The deduced amino acids of CS10 showed 72% sequence identity with the glycosyl hydrolase family 5 gene of Dysgonomonas mossii, displaying no significant sequence homology to already known cellulases. The purified CS10 protein presented a single band of cellulase activity with a molecular mass of approximately 40 kDa on the SDS-PAGE gel and zymogram. The purified CS10 protein exhibited optimal activity at 50 degrees C and pH 7.0, and the thermostability and pH stability of CS10 were preserved at the ranges of 20~50 degrees C and pH 4.0~10.0. CS10 exhibited little loss of cellulase activity against various chemical reagents such as 10% polar organic solvents, 1% non-ionic detergents, and 0.5 M denaturing agents. Moreover, the substrate specificity and the product patterns by thinlayer chromatography suggested that CS10 is an endo-beta-1,4 glucanase. From these biochemical properties of CS10, it is expected that the enzyme has the potential for application in industrial processes. PMID- 25022522 TI - A novel integrative expression vector for Sulfolobus species. AB - With the purpose of facilitating the process of stable strain generation, a shuttle vector for integration of genes via a double recombination event into two ectopic sites on the Sulfolobus acidocaldarius chromosome was constructed. The novel chromosomal integration and expression vector pINEX contains a pyrE gene from S. solfataricus P2 (pyrE(sso)) as an auxotrophic selection marker, a multiple cloning site with histidine tag, the internal sequences of malE and malG for homologous recombination, and the entire region of pGEM-T vector, except for the multiple cloning region, for propagation in E. coli. For stable expression of the target gene, an alpha-glucosidase-producing strain of S. acidocaldarius was generated employing this vector. The malA gene (saci_1160) encoding an alpha glucosidase from S. acidocaldarius fused with the glutamate dehydrogenase (gdhA(saci)) promoter and leader sequence was ligated to pINEX to generate pINEX_malA. Using the "pop-in" and "pop-out" method, the malA gene was inserted into the genome of MR31 and correct insertion was verified by colony PCR and sequencing. This strain was grown in YT medium without uracil and purified by His tag affinity chromatography. The alpha-glucosidase activity was confirmed by the hydrolysis of pNPalphaG. The pINEX vector should be applicable in delineating gene functions in this organism. PMID- 25022523 TI - Microbial community diversity in anaerobic reactors digesting turkey, chicken, and swine wastes. AB - The microbial community structures of two continuous stirred tank reactors digesting turkey manure with pine wood shavings as well as chicken and swine manure were investigated. The reactor fed with chicken/swine wastes displayed the highest organic acids concentration (up to 15.2 g/l) and ammonia concentration (up to 3.7 g/l ammonium nitrogen) and generated a higher biogas yield (up to 366 ml/g(VS)) compared with the reactor supplied with turkey wastes (1.5- 1.8 g/l of organic acids and 1.6-1.7 g/l of ammonium levels; biogas yield was up to 195 ml/g(VS)). The microbial community diversity was assessed using both sequencing and profiling terminal restriction fragment length polymorphisms of 16S rRNA genes. Additionally, methanogens were analyzed using methyl coenzyme M reductase alpha subunit (mcrA) genes. The bacterial community was dominated by members of unclassified Clostridiales with the prevalence of specific clostridial phylotypes in each reactor, indicating the effect of the substrate type on the community structure. Of the methanogenic archaea, methanogens of the genus Methanosarcina were found in high proportions in both reactors with specific methanosarcinas in each reactor, whereas the strict hydrogenotrophic methanogens of Methanoculleus sp. were found at significant levels only in the reactor fed with chicken/swine manure (based on the analyses of 16S rRNA gene). This suggests that among methanogenic archaea, Methanosarcina species which have different metabolic capabilities, including aceticlastic and hydrogenotrophic methanogenesis, were mainly involved in anaerobic digestion of turkey wastes. PMID- 25022524 TI - Lycopene-induced hydroxyl radical causes oxidative DNA damage in Escherichia coli. AB - Lycopene, which is a well-known red carotenoid pigment, has been drawing scientific interest because of its potential biological functions. The current study reports that lycopene acts as a bactericidal agent by inducing reactive oxygen species (ROS)-mediated DNA damage in Escherichia coli. Lycopene treatment elevated the level of ROS-in particular, hydroxyl radicals ((*)OH) -which can damage DNA in E. coli. Lycopene-induced DNA damage in bacteria was confirmed and we also observed cell filamentation caused by cell division arrest, an indirect marker of the DNA damage repair system, in lycopene-treated E. coli. Increased RecA expression was observed, indicating activation of the DNA repair system (SOS response). To summarize, lycopene exerts its antibacterial effects by inducing (*)OH -mediated DNA damage that cannot be ameliorated by the SOS response. Lycopene may be a clinically useful adjuvant for current antimicrobial therapies. PMID- 25022525 TI - Efficient expression, purification, and characterization of a novel FAD-dependent glucose dehydrogenase from Aspergillus terreus in Pichia pastoris. AB - Flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) can utilize a variety of external electron acceptors and also has stricter substrate specificity than any other glucose oxidoreductases, which makes it the ideal diagnostic enzyme in the field of glucose biosensors. A gene coding for a hypothetical protein, similar to glucose oxidase and derived from Aspergillus terreus NIH2624, was overexpressed in Pichia pastoris GS115 under the control of an AOX1 promoter with a level of 260,000 U/l in the culture supernatant after fed batch cultivation for 84 h. After a three-step purification protocol that included isopropanol precipitation, affinity chromatography, and a second isopropanol precipitation, recombinant FAD-GDH was purified with a recovery of 65%. This is the first time that isopropanol precipitation has been used to concentrate a fermentation supernatant and exchange buffers after affinity chromatography purification. The purified FAD-GDH exhibited a broad and diffuse band between 83 and 150 kDa. The recombinant FAD-GDH was stable across a wide pH range (3.5 to 9.0) with maximum activity at pH 7.5 and 55 degrees C. In addition, it displayed very high thermal stability, with a half-life of 82 min at 60 degrees C. These characteristics indicate that FAD-GDH will be useful in the field of glucose biosensors. PMID- 25022526 TI - An overlooked effect of glycine betaine on fermentation: prevents caramelization and increases the L-lysine production. AB - This article focuses on the effects of glycine betaine on preventing caramelization, and increasing DCW and L-lysine production. The additional glycine betaine not only decreased the browning intensity (decreased 4 times), and the concentrations of 5-hydroxymethylfurfural (decreased 7.8 times) and furfural (decreased 12 times), but also increased the availability of glucose (increased 17.5%) for L-lysine production. The DCW and L-lysine production were increased by adding no more than 20 mM glycine betaine, whereas the DCW and L lysine production were decreased with the reduction of pH values, although pH had a better response to prevent caramelization than did glycine betaine. For L lysine production, the highest increase (40%) was observed on the media with 20 mM glycine betaine. The crucial enzymes in glycolysis and L-lysine biosynthesis pathway were investigated. The results indicated that additional glycine betaine increases the activity of enzymes in glycolysis, in contrast to the effect of pH. All the results indicated that glycine betaine can be used to prevent caramelization and increase the L-lysine production. By applying this strategy, glucose would not be have to be separated from the culture media during autoclaving so that factories can save production costs and shorten the fermentation period. PMID- 25022527 TI - Large congenital coronary arteriovenous fistula between the left main coronary artery and right superior vena cava, associated with aneurysmal dilatation of the left main coronary artery: rare case report. AB - Coronary arteriovenous fistula is an uncommon clinical entity. The right coronary artery is the most common site of origin, and the fistula commonly drains into the right-sided cardiac chambers. Very rarely it can arise from the left main coronary artery, and fistulas draining into the superior vena cavity are extremely rare. We report a 12-year-old asymptomatic boy with a large coronary arteriovenous fistula between the left main coronary artery and superior vena cava, with aneurysmal dilatation of the left main coronary artery. As the fistula was very large and to prevent its complications, it was planned to close the fistula percutaneously. PMID- 25022528 TI - Cost-effectiveness of second-line chemotherapy/biologics among elderly metastatic colon cancer patients. AB - INTRODUCTION: Advancements in chemotherapy treatment have improved the clinical management of metastatic colon cancer (mCC) patients. An increasing number of elderly mCC patients receive various combinations of regimens in second-line chemotherapy/biologics treatment (Tx2) after first-line treatment (Tx1) to prolong survival and/or palliate symptoms, but these regimens have higher costs. This analysis investigated the survival benefit and incremental cost associated with Tx2 among elderly mCC patients. METHODS: Elderly (aged >=66 years) SEER Medicare patients diagnosed with mCC in 2003-2007 were identified and followed until death or the end of 2009. Cox regression and partitioned least squares regression were utilized to obtain the survival benefit and incremental cost associated with Tx2 within a 5-year study period. A time-varying model was used to reduce bias due to sequential ordering of Tx1 and Tx2. The regressions controlled for patient demographic characteristics, clinical variables, and a proxy for poor performance. Bootstrapping was used to generate 95% confidence intervals (CI). RESULTS: Of the 3,266 elderly mCC patients who received Tx1, 2,744 (84%) died within the observation period; 1,440 (44%) received Tx2. The survival benefit associated with receipt of Tx2 was 0.33 years (95% CI 0.19 0.43), and the associated incremental cost was $40,888 (95% CI 3,044-44,324). The incremental cost-effectiveness ratio (ICER) for Tx2 was $123,903 per life year gained (95% CI 9,600-216,082). CONCLUSION: The estimated survival benefit of receiving second-line chemotherapy/biologics was about 4 months, which is consistent with evidence from clinical trials. This improved survival was associated with an ICER that exceeds the traditional threshold. PMID- 25022530 TI - [Occupational exposure to silica and lung cancer: an evidence-based journey]. PMID- 25022529 TI - Rationale for early treatment of polycystic kidney disease. AB - In hereditary cystic disorders, renal injury begins with the formation of the first cyst. Renal injury may manifest as large kidneys, abdominal pain, hypertension and hematuria in children and young adults with autosomal dominant polycystic kidney disease (ADPKD). In autosomal recessive PKD (ARPKD) and ADPKD, cysts form primarily in collecting ducts and expand progressively. Collecting duct cysts that block urine flow have the potential to block urine formation in large numbers of upstream nephrons. In an ARPKD rat congenitally lacking vasopressin, only a few cysts developed until exogenous arginine vasopressin (AVP) was administered. AVP elevates cyclic AMP in vulnerable tubule cells to stimulate mitogenesis and fluid secretion, thereby causing cysts to form and enlarge indefinitely. The administration of an AVP-V2 receptor inhibitor or the consumption of sufficient water to persistently lower plasma AVP levels will ameliorate disease progression. Renal volume measurements provide the most reliable way to forecast long-term outcome in individual children and adult patients with ADPKD. Many drugs that have demonstrated efficacy in small clinical trials, preclinical trials and cell-based studies are in the treatment pipeline. Counseling, regular exercise, limitation of dietary calories, salt, protein and fat, increased fluid intake throughout the day and treatment of hypertension are components of a rational treatment program that can be offered at an early age to those with, or at risk for developing PKD. PMID- 25022531 TI - [Re-contact with immigrant workers in Spain through telephone interview (ITSAL II)]. AB - OBJECTIVE: Immigrants are recognized as a hard-to-reach-population. This study describes and assesses a three-year follow-up experience (final sample) with immigrant workers who participated in a survey three years earlier (initial sample), compares both samples and describes the final sample. METHODS: In 2008 a personal survey was carried out among 2434 immigrant workers (ITSAL I Project). Of these, 1229 had provided a telephone number allowing future recontact. In 2011, they were contacted for participation in a second project (ITSAL II Project). Outcome response rates of the American Association for Public Opinion Research were calculated. Sociodemographic and labour characteristics of workers of the initial and final samples were compared. In the final sample, sociodemographic and labour distribution of variables were compared by country of origin. Legal status, economic sector and occupation changes during this time were analyzed. RESULTS: The proportion of those interviewed who fully answered the second interview (response rate) was 29.5%. The final sample had higher participation of Ecuadorians, women, persons older than 45 years and those with the highest education level. Romanian and Moroccan participants had the highest unemployment (45.1%, 40.0%). Overall, 71.1% did not change economic sector, and 63.2% improved their legal situation. CONCLUSIONS: Our response rate is similar to those of similar studies. Re-contact was more difficult for some groups, depending on country of origin, age, education level and legal situation; for these, alternative means for followup should be sought out. PMID- 25022532 TI - [Effects of occupational exposure to chromium and its compounds: a systematic review]. AB - OBJECTIVES: To review the scientific literature on the health effects of exposure to chromium and chromium compounds on workers. METHODS: A systematic review of the scientific literature contained in the MEDLINE (via PubMed), EMBASE, Web of Knowledge, Cochrane Library Plus and LILACS databases through January 2013. The terms searched for, both as subject headings and in free text, were: "chromium", "chromium compounds", "occupational exposure" and "occupational diseases". The search was completed through additional review of the bibliographic references included in the selected papers. RESULTS: We recovered 227 references, from which we selected 22 articles after applying inclusion and exclusion criteria. Of these, genetic alterations were examined in eight studies; in one study, alterations in male reproduction; in fourstudies, respiratory alterations; in seven studies, cancer; and in two studies, dermatitis. Hexavalent chromium was the agent most frequently associated with the described health effects. CONCLUSIONS: Occupational exposure to chromium and chromium derivatives is associated with human health effects of varying severity. This is why adequate control measures should be implemented in the workplace to minimize exposure and diminish the number of associated diseases. More restrictive exposure limits for this agent, based on health criteria, should be established in the future. PMID- 25022533 TI - [An introduction to bibliometric analysis and its application to the field of occupational health]. PMID- 25022535 TI - Do NIA-AA criteria distinguish Alzheimer's disease from frontotemporal dementia? AB - BACKGROUND: Clinical criteria are important for improving diagnostic accuracy and ensuring comparability of patient cohorts in research studies. OBJECTIVE: The aim was to assess the National Institute on Aging and Alzheimer's Association (NIA AA) criteria for Alzheimer's disease (AD) dementia in AD and frontotemporal lobar degeneration (FTLD). METHODS: Two hundred twelve consecutive patients with pathologically confirmed AD or FTLD who were clinically assessed in a specialist cognitive unit were identified. Fifty-five patients were excluded predominantly because of insufficient clinical information. Anonymized clinical data were rated against the NIA-AA criteria by raters who were blinded to clinical and pathologic diagnosis. RESULTS: The NIA-AA AD dementia criteria had a sensitivity of 65.6% for probable and 79.5% for possible AD and a specificity of 95.2% and 94.0% for probable and possible, respectively. CONCLUSION: In patients with FTLD and predominantly early-onset AD, the NIA-AA AD dementia criteria have high specificity but lower sensitivity. The high specificity is due to the broad exclusion criteria. PMID- 25022534 TI - Biomarker progressions explain higher variability in stage-specific cognitive decline than baseline values in Alzheimer disease. AB - BACKGROUND: It is unknown which commonly used Alzheimer disease (AD) biomarker values-baseline or progression-best predict longitudinal cognitive decline. METHODS: 526 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI composite memory and executive scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values was compared with variability explained by biomarker progression values. RESULTS: About 40% of variability in memory and executive function declines was explained by ventricular volume progression among mild cognitive impairment patients. A total of 84% of memory and 65% of executive function declines were explained by fluorodeoxyglucose positron emission tomography (FDG-PET) score progression and ventricular volume progression, respectively, among AD patients. CONCLUSIONS: For most biomarkers, biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers. PMID- 25022536 TI - The influence of cerebrospinal fluid (CSF) biomarkers on clinical dementia evaluations. AB - BACKGROUND: Cerebrospinal fluid (CSF) proteins have become accepted biomarkers of Alzheimer's disease (AD) in research settings. The extent of their use, perceived utility, and influence on decision making in clinical settings, however, are less well studied. METHODS: Clinicians who evaluate older adults (N = 193) were randomized to view normal, borderline, AD-consistent, or no CSF information in two vignettes portraying patients with borderline and mild AD symptoms. Clinicians also reported on the use and perceived utility of CSF biomarkers. RESULTS: Although clinicians reported infrequent use and low perceived utility of CSF biomarkers, viewing AD-consistent CSF values made clinicians more likely to make an AD-related diagnosis, increased diagnostic confidence, and led clinicians to initiate treatment more often than clinicians who had no CSF information. CONCLUSIONS: CSF biomarkers influence decision making depending on the extent to which biomarkers reflect AD pathology, consistency between clinical-pathologic information, and the ambiguity of protein values. PMID- 25022537 TI - Development of a straightforward and sensitive scale for MCI and early AD clinical trials. AB - BACKGROUND: Although the Clinical Dementia Rating Scale-Sum of Boxes score (CDR SB) is a widely accepted and commonly used global scale, validated clinical endpoints of cognitive changes are unavailable in the predementia stages of Alzheimer's disease (AD), and a new clinical assessment with reliability and sensitivity is needed in the mild cognitive impairment (MCI) population. METHODS: Using Alzheimer's Disease Neuroimaging Initiative (ADNI)-1/GO data, signal-to noise ratios (SNRs) were calculated to quantify the sensitivity of a measure for detecting disease progression and hypothetical treatment effects. All possible combinations of selected sensitive measures were assessed for developing composite scores. The analyses were performed in the MCI population and subpopulations enriched by apolipoprotein E4 (APOE epsilon4), hippocampal volume, and cerebrospinal fluid beta-amyloid. RESULTS: The best composite score was "Word Recall + Delayed Word Recall + Orientation + CDR-SB + FAQ", more sensitive than 13-item Alzheimer's Disease Assessment Scale-cognitive subscale or CDR-SB. CONCLUSION: The proposed composite score derived from the existing clinical endpoints demonstrated higher sensitivity in the MCI population and is easy to implement and standardize across studies. PMID- 25022538 TI - Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy confirmed Alzheimer's disease. AB - We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular and Alzheimer's disease (AD) pathologies. Eighty-four AD patients underwent an assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA], or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVCs), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding the history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Furthermore, the presence of CVC was associated with lower Braak and Braak stage. These findings highlight the importance of aggregate risk in the vascular contribution to dementia. Interventions designed to maintain cerebrovascular health may represent important opportunities for preventing or delaying dementia, even when AD is the dominant pathology. PMID- 25022539 TI - Plasma beta-amyloid 40 levels are positively associated with mortality risks in the elderly. AB - BACKGROUND: We evaluated if plasma beta-amyloid (Abeta) levels were associated with mortality risks in a subsample of the French Three-City (3C) prospective cohort study. METHODS: Analyses were based on 1254 participants randomly selected from the initial 3C cohort stratified by center, sex, and age in the context of a nested case-cohort study to investigate biological variables. Associations between plasma Abeta and mortality were assessed with the Cox regression model with delayed entry including various potential confounding factors and testing possible mediators. RESULTS: A relationship between high plasma Abeta1-40 concentrations and risk of mortality (hazards ratio, 1.15; 95% confidence interval, 1.01-1.31, P = .03) was unveiled independently of age, educational level, vascular risk factors, diet, physical activity, cognitive impairment, or frailty status. It was only modified when we included cystatin C levels. CONCLUSIONS: Further investigations are needed to determine precisely the pathophysiological roles of plasma Abeta1-40 and cystatin C and before envisioning any future clinical applications. PMID- 25022541 TI - Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study. AB - OBJECTIVE: The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) and Follow-up Study (ADAPT-FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores. METHODS: A total of 2356 participants completed baseline and at least one follow-up cognitive evaluation between 2001 and 2004. Study treatments were discontinued in 2004, but participants were followed until 2007. A total of 1537 participants were reevaluated in 2010 to 2011. Outcomes include seven cognitive evaluations administered yearly in person in ADAPT and three of these evaluations that were administered by telephone near the end of ADAPT and again in ADAPT-FS. RESULTS: There were no important differences over time by treatment group on any ADAPT cognitive measure, a global composite, or the three cognitive measures reassessed in ADAPT-FS by telephone. CONCLUSIONS: Treatment for 1 to 3 years with naproxen or celecoxib did not protect against cognitive decline in older adults with a family history of AD. PMID- 25022542 TI - The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice. AB - Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-alpha-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis. PMID- 25022543 TI - Reliability and internal consistency of the Danish version of Loewenstein Occupational Therapy Cognitive Assessment 2nd Edition (LOTCA-II/D). AB - OBJECTIVE: To evaluate the intra-rater and inter-rater reliability and internal consistency of the Danish version of the Loewenstein Occupational Therapy Cognitive Assessment, second edition (LOTCA-II/D), an instrument designed to assess and evaluate cognitive functioning. METHODS: A reliability study was conducted at neurological acute care and rehabilitation units at three Danish hospitals. Fifty-four neurological patients participated in the study. Patients were tested with LOTCA-II/D by occupational therapists, and video recordings were made for reliability assessments. Intra-rater assessments were performed at least two weeks after the first assessment, and all occupational therapists were blinded to previous assessments. Intra-rater and inter-rater reliability were evaluated using percentage agreement and weighted kappa. Internal consistency was evaluated using Cronbach's alpha, and floor and ceiling effects were evaluated by calculating the proportion of observations in minimum and maximum categories of subtests. RESULTS: The results showed a lack of intra-rater and inter-rater reliability and a large variation of agreement due to a substantial ceiling effect. Internal consistency was below the acceptable value in half of the cognitive areas. CONCLUSION: The study found that LOTCA-II/D is not reliable in acute clinical practice, and it could thus not be validated for use in this setting. PMID- 25022544 TI - DPP-4 inhibitors repress NLRP3 inflammasome and interleukin-1beta via GLP-1 receptor in macrophages through protein kinase C pathway. AB - BACKGROUND: Anti-atherosclerotic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown in many studies. Since inflammation and immune response play a key role in atherogenesis, we examined the effect of DPP-4 inhibitors on the expression of nod-like receptor family, pyrin domain containing 3 (NLRP3) Inflammasome and Interleukin-1beta (IL-1beta) in human macrophages. METHODS AND RESULTS: THP-1 macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with or without DPP-4 inhibitors (sitagliptin and NVPDPP728). The effects of DPP-4 inhibitors on the expression of NLRP3, toll-like receptor 4 (TLR4) and pro-inflammatory cytokine IL-1beta were studied. Both DPP-4 inhibitors induced a significant reduction in NLRP3, TLR4 and IL-1beta expression; concurrently, there was an increase in glucagon like peptide 1 receptor (GLP-1R) expression. Simultaneously, DPP-4 inhibitors reduced phosphorylated-PKC, but not PKA, levels. To determine the role of PKC activation in the effects of DPP-4 inhibitors, cells were treated with PMA- which blocked the effect of DPP-4 inhibitors on NLRP3 and IL-1beta as well as TLR4 and GLP-1R. Over-expression of GLP-1R in macrophages with its agonist liraglutide also blocked the effects of PMA. CONCLUSION: DPP-4 inhibitors suppress NLRP3, TLR4 and IL-1beta in human macrophages through inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of inflammatory state and immune response in atherosclerosis by DPP-4 inhibitors. PMID- 25022546 TI - Guest editorial: responsive host-guest systems. PMID- 25022545 TI - Sanguinarine non- versus re-circulation during isolated heart perfusion--a Jekyll and Hyde effect? AB - AIMS: In isolated rat heart perfusion experiments, drug administration occurs via retrograde perfusion. This can be done in the non-recirculating mode (coronary effluent is discarded), or recirculating mode (coronary effluent is collected and reused). It was recently observed in our lab while using sanguinarine, an MKP-1 inhibitor, that there were differences in outcomes depending on the mode of recirculation used. METHODS AND RESULTS: Hearts from control (C); diet-induced obese (DIO) Wistar rats and their age matched controls (AMC) were perfused on the rig. Hearts received buffer (control) , insulin, sanguinarine, insulin + sanguinarine combination or methanol (vehicle) for 15 mins pre- and 10 mins post ischemia in either a non- or re-circulating manner. Hearts were subjected to 15 mins global ischemia and 30 mins reperfusion. Mechanical function was documented pre- and post-ischemia . When not-recirculated , sanguinarine alone and in combination with insulin in C, DIO and AMC groups, caused a significant decrease in functional recovery during reperfusion. However, when the coronary effluent was recirculated, hearts perfused with sanguinarine or sanguinarine + insulin exhibited a significant recovery in function when compared with their non recirculation counterparts (p < 0.01). No differences were seen with either control, insulin nor vehicle hearts. CONCLUSION: Sanguinarine elicited a vast improvement in perfusion outcomes when recirculated compared to non-recirculation . Since this was seen during perfusion only when sanguinarine was present, it is possible that recirculating reperfusion of the drug caused profound changes in its composition. More investigation is needed into the mechanisms involved. Thus caution should be exercised by researchers when designing a perfusion protocol for drug research. PMID- 25022540 TI - At the interface of sensory and motor dysfunctions and Alzheimer's disease. AB - Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses. PMID- 25022547 TI - Household hazardous waste quantification, characterization and management in China's cities: a case study of Suzhou. AB - A four-stage systematic tracking survey of 240 households was conducted from the summer of 2011 to the spring of 2012 in a Chinese city of Suzhou to determine the characteristics of household hazardous waste (HHW) generated by the city. Factor analysis and a regression model were used to study the major driving forces of HHW generation. The results indicate that the rate of HHW generation was 6.16 (0.16-31.74, 95% CI) g/person/day, which accounted for 2.23% of the household solid waste stream. The major waste categories contributing to total HHW were home cleaning products (21.33%), medicines (17.67%) and personal care products (15.19%). Packaging and containers (one-way) and products (single-use) accounted for over 80% of total HHW generation, implying a considerable potential to mitigate HHW generation by changing the packaging design and materials used by manufacturing enterprises. Strong correlations were observed between HHW generation (g/person/day) and the driving forces group of "household structure" and "consumer preferences" (among which the educational level of the household financial manager has the greatest impact). Furthermore, the HHW generation stream in Suzhou suggested the influence of another set of variables, such as local customs and culture, consumption patterns, and urban residential life style. This study emphasizes that HHW should be categorized at its source (residential households) as an important step toward controlling the HHW hazards of Chinese cities. PMID- 25022548 TI - Efficiency of physicochemical and biological treatments of vinasse and their influence on indigenous microbiota for disposal into the environment. AB - Molasses-based distilleries are one of the most polluting industries generating large volumes of high strength wastewater called vinasse. Different processes covering anaerobic, aerobic as well as physicochemical methods have been employed to treat this effluent. This study evaluated the microbial communities present in the vinasse during different stages of its treatment by traditional and molecular methods. The analysis of the efficiency of each treatment was performed by physicochemical parameters and toxicity analysis. The treatment of vinasse was performed in the following steps: high flow fermentation; filtration; chemical flakes; low-flow fermentation; filtration; and neutralization. The physicochemical analysis in different stages of the vinasse treatment demonstrated that phases of treatment influenced the performance of the evaluated parameters. Among the 37 parameters, 9 were within the limits established by the Commission for Environmental Policy of Minas Gerais, Brazil (COPAM), especially BOD (96.7% of pollution reduction), suspended solids (99.9%), pH, copper (88%), iron (92.9%), and manganese (88%). Some parameters, even after treatment, did not fit the maximum allowed by legislation. The microbial population decreased reaching 3 log CFU/ml present in the steps of the flakes chemical and disinfection treatment of vinasse. Lactobacillus brevis and Pichia kudriavzevii were present in all stages of the treatments, showing that these microorganisms were resistant and demonstrated that they might be important in the treatment of vinasse. The vinasse showed a significant reduction of pollution load after the disinfection treatment however still should not be discarded into water bodies because the high values of tannins and sediment solids, but suggest the use of the effluent in the cooling coil during the distillation process of the beverage. PMID- 25022549 TI - Air pollution control systems in WtE units: an overview. AB - All WtE (waste-to-energy) plants, based on combustion or other thermal processes, need an efficient gas cleaning for compliance with legislative air emission standards. The development of gas cleaning technologies started along with environment protection regulations in the late 1960s. Modern APC (air pollution control) systems comprise multiple stages for the removal of fly ashes, inorganic and organic gases, heavy metals, and dioxins from the flue gas. The main technologies and devices used for abatement of the various pollutants are described and their basic principles, their peculiarities, and their application are discussed. Few systems for cleaning of synthesis gas from waste gasification plants are included. Examples of APC designs in full scale plants are shown and cautious prospects for the future development of APC systems are made. PMID- 25022550 TI - Influence of traditional Chinese medicine constitution type on the susceptibility of hypertensive cases to intracerebral haemorrhage. AB - OBJECTIVE: To explore the influence of Chinese medicine constitution type on the susceptibility of hypertensive patients to intracerebral haemorrhage. METHODS: Primary hypertensive patients were studied and divided into the hypertension and the hypertensive intracerebral haemorrhage groups, depending on whether or not the patients had intracerebral haemorrhage. The demographic characteristics, physiological characteristics, living habits, biochemical tests, other chronic diseases, Chinese medicine constitution type, etc. were collected and compared between the two groups. The neurological deficit in the hypertensive intracerebral haemorrhage group was also compared among the different constitution types. RESULTS: A total of 304 patients participated in this investigation, including 213 cases in the hypertension group and 91 cases in the hypertensive intracerebral haemorrhage group. The percentages of dampness-heat and qi-depression types in the intracerebral haemorrhage group were greater than those with the same types in the hypertension group (20.9% vs 6.1%, 22.0% vs 8.0%; P<0.05). The percentages of each constitution type were different between genders in both groups. In addition, there were more male cases (14/20) with qi depression type and more female cases (7/8) with phlegm-dampness type in the hypertensive intracerebral haemorrhage group than those with the same types (3/17 and 9/34, respectively) in the hypertension group (P<0.05). The cases with phlegm dampness and qi-depression types had greater levels of blood lipids in the intracerebral haemorrhage group than those with the same types in the hypertension group (P<0.05). Furthermore, the cases with the qi-deficiency type presented with a more severe neurological deficit than those with the other types (P<0.05). CONCLUSIONS: Chinese medicine constitution type might have an impact on the susceptibility of hypertensive patients to have an intracerebral haemorrhage. The heat-dampness and qi-depression types might lead to greater susceptibility than the other types. In addition, the patient's gender and blood lipids might also influence the susceptibility along with the constitution type. PMID- 25022551 TI - Correlations among persistent viral infection, heart function and Chinese medicine syndromes in dilated cardiomyopathy patients. AB - OBJECTIVE: To investigate the correlations among persistent viral infection, heart function and Chinese medicine (CM) difined-syndromes in patients with dilated cardiomyopathy (DCM). METHODS: Fifty patients with DCM in the First Affiliated Hospital of Zhejiang Chinese Medical University from October 2009 to December 2011 were selected as the research subjects, and 30 healthy people were simultaneously selected as the normal control group to detect persistent viral infections after admission. The CM syndrome type and grade of heart function were then evaluated. The expression level of Coxsackie adenovirus receptor (CAR) was detected using the flow cytometry (FCM) technique, coxsackie virus RNA (CVB-RNA) using reverse transcription polymerase chain reaction (RTPCR), and the plasma brain natriuretic peptide (BNP) level with a Triage meter plus diagnosis instrument. Finally, the parameters such as left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by ultrasonic cardiogram. Person correlation analysis was used for measured data, Spearman correlation analysis for rating data, and the Chi-square test for numerical data. RESULTS: CVB-RNA was positive in 22 patients (44%) with DCM, while only 6 cases (20%) were CVB-RNA-positive in the normal control group, with a significant difference between the two groups (P<0.01). The expression level of CAR was significantly elevated in the DCM group compared with the normal control group (P<0.01). In CVB-RNA-positive patients (22 cases), the expression level of CAR was significantly higher than in CVB-RNA-negative patients (28 cases; P<0.01). In the DCM patients, there was a positive correlation between the CAR expression and the BNP level (r=0.34, P<0.05), while no significant difference was found between the CAR expression and the LVEF and LVEDd (r=-0.32, 0.30, P>0.05). There was no clear correlation between virus infection and the CM syndrome types in DCM patients (r=-0.22, P>0.05). According to the sequence of syndrome types: phlegm -> qi deficiency -> blood stasis -> hydroretention with asthenic yang (from low to high), a positive correlation was existed between the BNP levels and CM syndrome types (r=0.139, P<0.05). CONCLUSION: The expression of CAR on the surface of white cells could be used to detect persistent viral infection. The expression level of CAR and heart function in DCM patients were highly correlated. The expression level of BNP may serve as an objective index for differentiating CM syndromes for patients with DCM. PMID- 25022552 TI - Effects of Panax quinquefolium saponin on phosphatidylinositol 3-kinase/serine threonine kinase pathway of neonatal rat myocardial cells subjected to hypoxia. AB - OBJECTIVE: To explore the effects of Panax Quinquefolium Saponin (PQS) on phosphatidylinositol 3-kinase/serine threonine kinase (PI3K/Akt) pathway of neonatal rat myocardial cells subjected to hypoxia. METHODS: Neonatal rat myocardial cells were cultured in vitro. After the myocardial cell injury was induced by hypoxia, the cells were randomized into 5 groups: the normal group, the model group, the positive control group (Ciclosporin A, 2 u mol/L), the low dose PQS group (PQSL, 25mg/L), and the high-dose PQS group (PQSH, 50 mg/L). Morphology and behavior of myocardial cells were observed under an inverted microscope. Apoptosis rate and lactate dehydrogenase (LDH) leakage rate of myocardial cells were determined by colorimetry. Mitochondrial transmembrane potential was assessed using a fluorexon laser. Phospho-glycogen synthase kinase (GSK)-3beta and phospho-Akt as well as cytochrome C were determined by Western blot RESULTS: LDH leakage in the Ciclosporin A group, PQSH group and PQSL group reduced progressively compared with the model group (P<0.05). Akt and GSK-3beta was strongly phosphorylated after treatment with Ciclosporin A and PQS compared with the model group (P<0.05, P<0.01). Compared with the model group (16.41+/ 1.74; 35.28+/-6.30), both the integrated optical density of mitochondrial permeability transition pore (MPTP) and the mitochondrial transmembrane potential significantly increased in the PQSH group (42.74+/-2.12; 71.36+/-6.54) and the PQSL group (39.58+/-1.49; 66.99+/-5.45; P<0.05, P<0.01). However, the protein of cytochrome C outside the mitochondrion decreased in the PQSH group (273.66+/ 14.61) and the PQSL group (259.62+/-17.31) compared with the model group (502.41+/-17.76; P<0.05). CONCLUSION: Through activation of the PI3K/Akt pathway and inhibition of the MPTP, PQS might protect the heart against ischemia injury and apoptosis of myocardial cells. PMID- 25022553 TI - Gene mutation patterns in patients with minimally differentiated acute myeloid leukemia. AB - Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction-based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P=.001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P=.056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML. PMID- 25022554 TI - HER-2/neu is an independent prognostic factor in type I endometrial adenocarcinoma. AB - PURPOSE: To define the prognostic significance of HER-2/neu and PTEN expression in patients with endometrioid (type I) endometrial cancer. METHODS: Seventy-seven patients with endometrioid endometrial carcinoma were included in the study, in a period between 1996 and 2009. Patients with coexisting malignancy and those having incomplete immunohistochemical data or clinical follow-up were excluded. Histological staging was defined according to the revised FIGO staging (2009). Clinico-pathologic and immunohistochemical characteristics were correlated in a multivariate Cox regression analysis with overall survival (OS), cancer-related survival (CRS) and disease-free survival (DFS). RESULTS: Mean age of the patients was 62.7 years. The median follow-up was 67 months (9-124 months). HER-2/neu expression was detected in 18.2 % (n = 14), and PTEN expression in 72.7 % (n = 56) of our patients. Multivariate Cox regression analysis showed that patient's age, FIGO staging and HER-2/neu expression were independent prognostic factors for OS, CRS and DFS. PTEN expression did not significantly affect survival outcomes of the present study. CONCLUSIONS: HER-2/neu but not PTEN expression is an independent prognostic factor for type I endometrial carcinoma. PMID- 25022555 TI - Cornea in PCOS patients as a possible target of IGF-1 action and insulin resistance. AB - OBJECTIVES: Previous studies suggest that serum IGF-1 is higher in women with polycystic ovary syndrome (PCOS). The ophthalmologic effects of IGF-1 excess have not yet been investigated in women with PCOS. The aim of the current study is to compare the corneal thickness of patients with PCOS and those of healthy subjects. METHODS: Forty three patients with PCOS and 30 age-matched and gender matched healthy individuals were enrolled in this cross-sectional study. Central corneal thickness (CCT) was measured in patients with PCOS and in healthy individuals with an ultrasound pachymeter. IGF-1 values were also determined in the study group. RESULTS: Women with PCOS had significantly higher levels of IGF 1 and homeostasis model assessment (HOMA-IR) levels than the control group. Right and left CCT measurements were higher in the PCOS group than in the control group. A positive correlation between IGF-1 and right and left CCT was identified in both groups. In multiple linear stepwise regression analyses, IGF-1 independently and positively associated with HOMA-IR in women with PCOS. A correlation between total testosterone and CCT was identified in the whole group. In multiple stepwise regression analyses, total testosterone independently and positively associated with left central corneal thickness in the whole group. CONCLUSIONS: These findings indicate that PCOS has target organ effects on the eye. Consequently, it can change central corneal thickness. Higher IGF-1 levels seem to be the main causes of increased corneal thickness. Insulin resistance in PCOS is one of the underlying causes and promotes increase in IGF-1. We suggest a careful and detailed corneal evaluation in PCOS patients to prevent the potential risk of increased CCT, in addition to the already-known complications. PMID- 25022556 TI - Microsurgical principles should be considered in studies addressing adhesion prevention: Caglar et al. (2014). PMID- 25022557 TI - 3D sonohysterography vs hysteroscopy: a cross-sectional study for the evaluation of endouterine diseases. AB - PURPOSE: To assess the concordance between the presumed diagnosis obtained with the 3D sonohysterography (SHG) and with the diagnostic hysteroscopy (HYS); to determine whether the 3D SHG has the accuracy needed to be considered as a diagnostic screening standard in cases of suspected endouterine pathology. METHODS: We selected 224 patients who voluntarily decided to undergo 3D SHG from a population with suspected presence of endouterine disease at TVS. The patients underwent first 3D SHG and then diagnostic HYS. We recorded each patient's discomfort/pain during the two techniques. We used the "Bayes Theorem" to calculate the sensitivity and specificity of the 3D SHG as compared to HYS. RESULTS: Overall the 3D SHG diagnosis was confirmed in 156/224 cases (69.64 %). Concordance for endometrial thickening was 0 %; for Asherman's syndrome was 50.00 %; for polyp was 77.78 %; and for myoma, mucus accumulation and Mullerian anomalies (arcuate uterus, septate and subseptate uterus) was 100.00 %. Furthermore, 3D SHG was better tolerated than HYS. CONCLUSION: Despite the diagnostic accuracy and mini-invasiveness of 3D SHG, we suggest that it cannot be a substitute of HYS in endouterine disease diagnosis, but it could be considered as a good method of screening to address patients to hysteroscopic confirmation. PMID- 25022558 TI - An unusual long-term complication of transobturator polypropylene mesh. AB - Serious complications associated with surgical mesh for transvaginal repair of POP, as infections, vaginal mesh exposure, painful mesh shrinkage and dyspareunia, are not rare. A 48-year-old woman underwent the Perigee procedure because of a stage 3 anterior wall prolapse. Eleven months after surgery, the patient became suddenly unable to walk because of a strong pain to the left thigh root after running. The MRI revealed an external obturator left muscle hyperintensity consistent with muscular oedema; the patient was treated with oral corticosteroids with a complete resolution of the pain. We could hypothesize that the posterior arm of the mesh caused a laceration of the muscles of the obturator space with consequent oedema and pain. The use of the meshes in prolapse surgery can cause unexpected long-term complications. PMID- 25022559 TI - Introduction to the Special Issue: Assessment and Treatment of Stereotypy. AB - Stereotypy is often characterized as repetitious, invariant behavior that generates its own reinforcing consequence. Stereotypy represents a unique treatment challenge, because the consequences produced by stereotypy cannot be directly controlled by the practitioner. Likewise, practitioners have relatively few options for identifying the function of repetitive behavior. Recently, several researchers have been conducting empirical studies to address these issues. This article introduces a special issue presenting some of these recent developments in the assessment and treatment of stereotypy and related behavior. PMID- 25022560 TI - Artemisia annua as a possible contraceptive agent: a clue from mammalian rat model. AB - In a previous study, we evaluated the maternal and fetal safety of antimalarial herb Artemisia annua with artemisinin yield of 1.09%. Here, we attempted to ascertain the contraceptive claim of A. annua. Sexually matured female Wistar rats (180-220 g) were allotted into four study groups of six rats each. The control group received normal saline, while the A. annua-treated groups received 100, 200 and 300 mg/kg of A. annua for 2 weeks, followed by mating with proven fertile males (1:1). The rats were allowed to carry the pregnancy to term. At birth and weaning periods, selected reproductive outcome and fertility indices were determined. The results showed that A. annua significantly reduced litter size, reproductive outcome and fertility indices compared with the control (p < 0.05). These results imply that A. annua could serve as a prospective contraceptive agent in addition to its antimalarial activity. PMID- 25022561 TI - The role of endogenous and exogenous mechanisms in the formation of R&D networks. AB - We develop an agent-based model of strategic link formation in Research and Development (R&D) networks. Empirical evidence has shown that the growth of these networks is driven by mechanisms which are both endogenous to the system (that is, depending on existing alliances patterns) and exogenous (that is, driven by an exploratory search for newcomer firms). Extant research to date has not investigated both mechanisms simultaneously in a comparative manner. To overcome this limitation, we develop a general modeling framework to shed light on the relative importance of these two mechanisms. We test our model against a comprehensive dataset, listing cross-country and cross-sectoral R&D alliances from 1984 to 2009. Our results show that by fitting only three macroscopic properties of the network topology, this framework is able to reproduce a number of micro-level measures, including the distributions of degree, local clustering, path length and component size, and the emergence of network clusters. Furthermore, by estimating the link probabilities towards newcomers and established firms from the data, we find that endogenous mechanisms are predominant over the exogenous ones in the network formation, thus quantifying the importance of existing structures in selecting partner firms. PMID- 25022562 TI - Sex post Golding. PMID- 25022563 TI - Structure and functions of the gut microbiome. AB - Over the last decade our understanding of human gut microbiology underwent a tremendous transformation. The limitations of culture-based methods have given way to Next Generation Sequencing techniques, allowing us to understand the microbial gut community in greater depth. The human GI-tract harbours one of the most complex and abundant ecosystems colonized by more than 100 trillion microorganisms, among which Firmicutes and Bacteroidetes are the major phyla. Although stable over long periods, the composition and functions of the microbiome may be influenced by a number of factors including genetics, mode of delivery, age, diet, geographic location and medical treatments. Dysbiosis, changes in microbiome structure, has been linked to inflammatory, functional and metabolic disorders such as IBD, IBS and obesity. However, it is still not clear whether these changes are a contributing factor or a result of the disease. This synopsis provides a chronological overview of the techniques used to study the gut microbiota and the current knowledge with respect to the stability and variability of microbiome composition and functions. PMID- 25022564 TI - Weight loss maintenance: a hard nut to crack. PMID- 25022565 TI - Antithrombotic therapy in patients with thrombocytopenic cancer: outcomes associated with reduced-dose, low-molecular-weight heparin during hospitalization. AB - BACKGROUND: Guidelines are discordant concerning management of patients having thrombocytopenia with cancer-associated thrombosis (CAT). METHODS: Hospitalized adults with CAT and platelets <=50 * 10(9) cells/L were managed with dalteparin 100 units/kg subcutaneously once daily. Comparator patients with CAT and platelets >50 * 10(9) cells/L were managed with dalteparin 200 units/kg/d. RESULTS: Outcomes of 35 patients with thrombocytopenia (mean platelet count 26 +/ 8.3 * 10(9) cells/L) and 58 comparator patients (mean platelet count 155 +/- 75 * 10(9) cells/L) were evaluated. In all, 2 (5.7%) patients in the thrombocytopenia group and 1 patient (1.9%) in the comparator group experienced new-onset venous thromboembolism (odds ratio 3.31, 95% confidence interval [CI] 0.29-37.90, P = .556). The incidence of bleeding in patients with thrombocytopenia (8.6%) was similar to that in comparator patients (9.4%; risk ratio 0.94, 95% CI 0.37-2.39, P = .607). CONCLUSION: In hospitalized patients having thrombocytopenia with CAT, reduced-dose low-molecular-weight heparin was generally efficacious. PMID- 25022566 TI - Dried blood spot testing for the antenatal screening of HTLV, HIV, syphilis, toxoplasmosis and hepatitis B and C: prevalence, accuracy and operational aspects. AB - INTRODUCTION: Screening for vertically transmitted infection is mandatory and must be conducted at the first prenatal consultation. The most vulnerable women's groups are those at the lowest socio-economic level. Dried blood spot testing on filter paper could represent a secure way to screen pregnant women in the prenatal period. METHODS: A cross-sectional study was conducted between November 2009 and March 2010, in the Metropolitan Region of Salvador, Bahia, Brazil, to compare the accuracy of the dried blood spot in filter paper and venipuncture serological as screening methods for HIV, HTLV, VHB, VHC, Treponema pallidum, and Toxoplasma gondii during prenatal period. Results of the venous blood sample collected in tubes were considered the gold standard. RESULTS: Serum samples and dried blood spot were obtained from 692 pregnant women aged between 14 and 42 years, with a median age of 26. Thirteen women were seropositive for T. gondii (1.88%; 95% CI: 0.60-2.71%), five for T. pallidum (0.72%; 95% CI: 0.15-1.61%), two for HBV (0.29%; 95% CI: 0.050.95%) and one for HTLV-1 (0.14%; 95% CI: 0.01 0.71%). No one was positive for HCV and HIV. The dried blood spot accuracy for syphilis and HTLV were 100% (95% CI: 99.25-100) and 100% (95% CI: 99.45-100%), respectively. The average time between blood collection and recording of the sample in the reference laboratory was 4.93 (3.82) days and between dried blood spot processing and active search for pregnant women was 3.44 (4.27) days. CONCLUSIONS: The use of dried blood spot may represent a secure way to expedite access to results of vertically transmitted diseases in the prenatal period, particularly in regions with scarce healthcare resources. PMID- 25022567 TI - The burden of sepsis in critically ill human immunodeficiency virus-infected patients--a brief review. AB - Since the advent of highly active antiretroviral therapy in 1996, we have seen dramatic changes in morbi-mortality rates from human immunodeficiency virus positive patients. If on the one hand, the immunologic preservation-associated with the use of current antiretroviral therapy markedly diminishes the incidence of opportunistic infections, on the other hand it extended life expectancy of human immunodeficiency virus-infected individuals similarly to the general population. However, the management of critically ill human immunodeficiency virus-infected patients remains challenging and troublesome for practicing clinician. Sepsis - a complex systemic inflammatory syndrome in response to infection - is the second leading cause of intensive care unit admission in both human immunodeficiency virus-infected and uninfected populations. Recent data have emerged describing a substantial burden of sepsis in the infected population, in addition, to a much poorer prognosis in this group. Many factors contribute to this outcome, including specific etiologies, patterns of inflammation, underlying immune dysregulation related to chronic human immunodeficiency virus infection and delays in prompt diagnosis and treatment. This brief review explores the impact of sepsis in the context of human immunodeficiency virus infection, and proposes future directions for better management and prevention of human immunodeficiency virus-associated sepsis. PMID- 25022568 TI - MSD "regrets" tactics used to silence doctor over prescription advice. PMID- 25022569 TI - Combining hypoxia and bioreactor hydrodynamics boosts induced pluripotent stem cell differentiation towards cardiomyocytes. AB - Cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPSCs) hold great promise for patient-specific disease modeling, drug screening and cell therapy. However, existing protocols for CM differentiation of iPSCs besides being highly dependent on the application of expensive growth factors show low reproducibility and scalability. The aim of this work was to develop a robust and scalable strategy for mass production of iPSC-derived CMs by designing a bioreactor protocol that ensures a hypoxic and mechanical environment. Murine iPSCs were cultivated as aggregates in either stirred tank or WAVE bioreactors. The effect of dissolved oxygen and mechanical forces, promoted by different hydrodynamic environments, on CM differentiation was evaluated. Combining a hypoxia culture (4 % O2 tension) with an intermittent agitation profile in stirred tank bioreactors resulted in an improvement of about 1000-fold in CM yields when compared to normoxic (20 % O2 tension) and continuously agitated cultures. Additionally, we showed for the first time that wave-induced agitation enables the differentiation of iPSCs towards CMs at faster kinetics and with higher yields (60 CMs/input iPSC). In an 11-day differentiation protocol, clinically relevant numbers of CMs (2.3 * 10(9) CMs/1 L) were produced, and CMs exhibited typical cardiac sarcomeric structures, calcium transients, electrophysiological profiles and drug responsiveness. This work describes significant advances towards scalable cardiomyocyte differentiation of murine iPSC, paving the way for the implementation of this strategy for mass production of their human counterparts and their use for cardiac repair and cardiovascular research. PMID- 25022570 TI - Distinctive histopathologic phenotype in resection specimens from patients with Crohn's disease receiving anti-TNF-alpha therapy. AB - Anti-tumor necrosis factor alpha (anti-TNF-alpha) therapy can result in endoscopic healing, reduction of symptoms, and reduced need for surgery and hospitalization in many patients with Crohn's disease (CD). Earlier data suggested that anti-TNF-alpha therapy may be associated with fibrosis and stricturing. We sought to determine whether anti-TNF-alpha therapy affects histologic inflammation, fibrosis, and granuloma formation. Hematoxylin and eosin sections from 62 patients with CD treated with either infliximab or adalimumab and 80 controls undergoing the same surgery but without prior exposure to anti TNF-alpha therapy were compared. All patients with CD had undergone surgery within 6 months of therapy; CD controls were matched for steroid exposure, procedure, and indication for surgery and were subcategorized and case matched. Blinded histologic assessment of all slides was performed using a semiquantitative scoring system to assess inflammatory changes and fibrosis in all bowel layers. Compared with controls, the group treated with anti-TNF-alpha showed a reduction in mucosal and submucosal inflammation (P < .05), a decrease in granuloma formation (P < .05), and an increase in duplication of the muscularis mucosae (P < .05). A notable feature was a distinct pattern of hyalinizing submucosal fibrosis that was often devoid of inflammatory cells and that started directly below the muscularis mucosae; this pattern was not observed in the control group (P < .05). Resection specimens from patients with CD treated with anti-TNF-alpha therapy showed (a) reduced mucosal and submucosal inflammation; (b) a decrease in granuloma formation; and (c) a distinct pattern of submucosal hyaline fibrosis, with increased fibrosis in the muscularis mucosae and muscularis propria. PMID- 25022571 TI - Dose-dependent regulation of cell proliferation and collagen degradation by estradiol on ligamentum flavum. AB - BACKGROUND: Estradiol plays an important role in the regulation of collagen metabolism. Deficiency of estradiol has been reported to be associated with the degeneration of many connective tissues. However, the association of estradiol and hypertrophy of the ligamentum flavum was seldom explored. Therefore, we studied the effects of estradiol on cultured cells from the ligamentum flavum. METHODS: Primary cultures of human ligamentum flavum cells obtained from surgical specimens of 14 patients undergoing spinal surgery were used to investigate the effect of estradiol on cell proliferation and the expression of collagen, elastin, and matrix metalloproteinases. Downstream pathways of estrogen receptor underlying the regulation of metalloproteinases were also investigated. RESULTS: In our study, we revealed the existence of estrogen receptors on both female and male ligamentum flavum cells with a gender difference. 17beta-estradiol increased early (24 hours) proliferation of ligamentum flavum cells in a dose dependent manner and the effect could not be seen when the cell density increased. Estradiol with a concentration of 10(-9) M decreased collagen levels and increased the expression of MMP-13. Adding an antagonist of PI3K downstream pathway could reverse the expression of MMP-13 caused by estradiol. CONCLUSIONS: The results implied estradiol regulated the expression of MMP-13 via PI3K pathway and contributed to the homeostasis of extracellular matrix in the ligamentum flavum. PMID- 25022572 TI - Ultra-fast acting insulin analogues. AB - Insulin analogues are a major improvement in diabetes pharmacotherapy. Rapid acting insulins have certain advantages over regular insulin, but there is a need to develop even faster acting insulin preparations, which mimic physiological insulin release in a better manner. This review discusses recent developments and patents in the field of Ultra- fast acting insulins. It classifies various approaches towards creation of an Ultra-fast acting insulin profile based upon the method used to achieve a faster onset of action. These include change in formulation of insulin, addition of excipients to insulin, and utilization of novel insulin sites or delivery methods. It examines the current state of evidence, and the developments in the field of newer insulin analogues & delivery methods. PMID- 25022573 TI - MDM2 molecular imaging for the prediction of chemotherapeutic sensitivity in human breast cancer xenograft. AB - The aim of the present study was to investigate the possible use of mouse double minute 2 (MDM2) molecular imaging to predict chemotherapeutic sensitivity in breast cancer xenografts (BCXs). MCF-7 cells were transfected with MDM2 antisense oligonucleotides (ASONs), and MDM2 expression levels were determined by Western blotting. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay in MCF-7 cells transfected with ASONs and treated with paclitaxel. BCXs were established in nude mice by injection of ASONs, and tumor volumes were measured after paclitaxel treatment. MDM2 ASONs were labeled with 99mTc to generate an MDM2 molecular probe, and MDM2 expression levels were evaluated by imaging and Western blotting. MDM2 ASONs downregulated MDM2 expression in a dose-dependent manner and increased the rate of paclitaxel induced cell growth inhibition. Imaging of tumors revealed significant differences in the tumor to skeletal muscle (T/M) ratio between groups. Tumor MDM2 protein expression was correlated with T/M ratios at 4 hours (R = .880) and 10 hours (R = .886). The effect of paclitaxel varied among nude mice bearing BCXs with different concentrations of ASONs, as shown by differences in tumor growth. MDM2 molecular imaging could be a promising method for predicting the sensitivity of BCXs to chemotherapy. PMID- 25022574 TI - Precision of echocardiographic estimates of right atrial pressure in patients with acute decompensated heart failure. AB - BACKGROUND: Several methods that estimate right atrial pressure (RAP) from echocardiographic parameters have been proposed. However, their precision (i.e., how much they decrease RAP estimation uncertainty) is unknown. The aim of this prospective study was to evaluate and compare the precision of previously proposed RAP estimates in patients with acute decompensated heart failure. METHODS: Echocardiographic and invasive hemodynamic data were acquired in 75 patients with acute decompensated heart failure. Measurements were made at the start and 48 to 72 hours after the beginning of treatment. RAP was estimated by method 1, using the cutoffs defined by inferior vena cava diameter (IVCd) and IVCd percentage change (IVCd%change) during inspiration, and by method 2, using IVCd%change and systolic to diastolic hepatic flow ratio (S/Dhep). Method 3 was used in patients with sinus rhythm, using the ratio of early tricuspid inflow and early diastolic tissue Doppler tricuspid annular velocities (E/E'ta). RAP was also estimated by resting IVCd, IVCd during inspiration, IVCd%change, right ventricular regional isovolumetric relaxation time, E/E'ta, right atrial volume index, S/Dhep, right ventricular Tei index, right ventricular E/A, and right atrial emptying fraction. Precision gain was measured as the difference between the standard deviation of RAP and the standard error of the estimate of RAP. RESULTS: Method 1 (r = 0.48, P < .05), IVCd during inspiration (r = 0.49, P < .0001), IVCd%change (r = 0.41, P < .0001) and IVCd (r = 0.40, P < .0001) had the highest correlation with RAP. The highest gain in precision was also observed with the above methods (9%, 13%, 9%, and 8%, respectively). All other parameters had poor correlation with RAP. CONCLUSION: In patients with advanced heart failure, echocardiographic RAP prediction methods showed only modest precision. Furthermore, none of the tested methods resulted in clinically relevant improvements of RAP estimates. Estimating RAP from a single IVCd measurement is at least as precise as using complex prediction methods. PMID- 25022575 TI - Rapid sandwich ELISA-based in vitro diagnostic procedure for the highly-sensitive detection of human fetuin A. AB - A rapid sandwich enzyme-linked immunosorbent assay (ELISA)-based in vitro diagnostic (IVD) procedure has been developed for human fetuin A (HFA), an important disease biomarker for inflammatory diseases as well as malignancies. In this simplified and cost-effective procedure, the EDC-activated anti-HFA antibody (Ab) was admixed with 1% (v/v) 3-aminopropyltriethoxysilane (APTES) in 1:1 (v/v) and dispensed in a KOH-pretreated microtiter plate (MTP). APTES formed a stable complex with the capture antibody that was in turn covalently bonded on the KOH treated surface in 30 min. The resulting immunoassay (IA) format detects HFA with a dynamic range of 0.1-243 ng mL(-1), and a limit of detection (LOD) and analytical sensitivity of 0.3 ng mL(-1) and 1.0 ng mL(-1), respectively. For the determination of HFA spiked in diluted human whole blood and serum, and HFA in ethylenediaminetetraacetic acid (EDTA)-plasma of patients, the obtained analytical precision is similar to that of the conventional sandwich ELISA. The anti-HFA Ab-bound MTPs, stored at 4 degrees C in 0.1M PBS, pH 7.4, retained its biological activity for 8 weeks, thereby demonstrating excellent storage stability. This generic sandwich ELISA procedure can be extended for rapid, simplified and cost-effective detection of other disease biomarkers. PMID- 25022576 TI - Researcher who falsified HIV results pleads not guilty in US court. PMID- 25022577 TI - Comparison of N-methyl-D-aspartate receptor subunit 1 and 4-hydroxynonenal in the hippocampus of natural and chemical-induced aging accelerated mice. AB - In this study, we compared N-methyl-D-aspartate receptor type 1 (NMDAR1) and 4 hydroxynonenal (4-HNE) in the hippocampus of D-galactose (D-gal)-induced and naturally aging models of mice. These markers represent general phenotypes in aging, and they allowed us to examine the possibility of D-gal as a chemical model agent for aging. We observed an age-dependent reduction of NMDAR1 and an increase in 4-HNE in the dentate gyrus, CA1, and CA3 regions of the hippocampus via immunohistochemistry and western blot analyses. In the D-gal-induced chemical aging model, we observed similar changes in NMDAR1 and 4-HNE although the degree of reduction/increase in NMDAR1/4-HNE was not as severe as that in the naturally aged mice. These results suggest that the D-gal-induced aging model is comparable to naturally aged mice and may be useful for studies of the aging hippocampus. PMID- 25022578 TI - Avibactam and class C beta-lactamases: mechanism of inhibition, conservation of the binding pocket, and implications for resistance. AB - Avibactam is a novel non-beta-lactam beta-lactamase inhibitor that inhibits a wide range of beta-lactamases. These include class A, class C, and some class D enzymes, which erode the activity of beta-lactam drugs in multidrug-resistant pathogens like Pseudomonas aeruginosa and Enterobacteriaceae spp. Avibactam is currently in clinical development in combination with the beta-lactam antibiotics ceftazidime, ceftaroline fosamil, and aztreonam. Avibactam has the potential to be the first beta-lactamase inhibitor that might provide activity against class C mediated resistance, which represents a growing concern in both hospital- and community-acquired infections. Avibactam has an unusual mechanism of action: it is a covalent inhibitor that acts via ring opening, but in contrast to other currently used beta-lactamase inhibitors, this reaction is reversible. Here, we present a high-resolution structure of avibactam bound to a class C beta lactamase, AmpC, from P. aeruginosa that provided insight into the mechanism of both acylation and recyclization in this enzyme class and highlighted the differences observed between class A and class C inhibition. Furthermore, variants resistant to avibactam that identified the residues important for inhibition were isolated. Finally, the structural information was used to predict effective inhibition by sequence analysis and functional studies of class C beta lactamases from a large and diverse set of contemporary clinical isolates (P. aeruginosa and several Enterobacteriaceae spp.) obtained from recent infections to understand any preexisting variability in the binding pocket that might affect inhibition by avibactam. PMID- 25022579 TI - Revised reference broth microdilution method for testing telavancin: effect on MIC results and correlation with other testing methodologies. AB - The reference broth microdilution (BMD) antimicrobial susceptibility testing method for telavancin was revised to include dimethyl sulfoxide (DMSO) as a solvent and diluent for frozen-form panel preparation, following the CLSI recommendations for water-insoluble agents. Polysorbate 80 (P-80) was also added to the test medium to minimize proven drug losses associated with binding to plastic surfaces. Four hundred sixty-two Gram-positive isolates, including a challenge set of organisms with reduced susceptibilities to comparator agents, were selected and tested using the revised method for telavancin, and the MIC results were compared with those tested by the previously established method and several Sensititre dry-form BMD panel formulations. The revised method provided MIC results 2- to 8-fold lower than the previous method when tested against staphylococci and enterococci, resulting in MIC50 values of 0.03 to 0.06 MUg/ml for staphylococci and 0.03 and 0.12 MUg/ml for Enterococcus faecium and Enterococcus faecalis, respectively. Less-significant MIC decreases (1 to 2 log2 dilution steps) were observed when testing streptococci in broth supplemented with blood, which showed similar MIC50 values for both methods. However, Streptococcus pneumoniae had MIC50 results of 0.008 and 0.03 MUg/ml when tested by the revised and previous methods, respectively. Highest essential agreement rates (>=94.0%) were noted for one candidate dry-form panel formulation compared to the revised test. The revised BMD method provides lower MIC results for telavancin, especially when tested against staphylococci and enterococci. This is secondary to the use of DMSO for panel production and the presence of P-80, which ensure the proper telavancin testing concentration and result in a more accurate MIC determination. Moreover, earlier studies where the previous method was applied underestimated the in vitro drug potency. PMID- 25022580 TI - Musculoskeletal safety outcomes of patients receiving daptomycin with HMG-CoA reductase inhibitors. AB - Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P = 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P = 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin alone group (P = 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population. PMID- 25022581 TI - Synergistic effects of antimicrobial peptides and antibiotics against Clostridium difficile. AB - Accelerating rates of health care-associated infections caused by Clostridium difficile, with increasing recurrence and rising antibiotic resistance rates, have become a serious problem in recent years. This study was conducted to explore whether a combination of antibiotics with human antimicrobial peptides may lead to an increase in antibacterial activity. The in vitro activities of the antimicrobial peptides HBD1 to HBD3, HNP1, HD5, and LL-37 and the antibiotics tigecycline, moxifloxacin, piperacillin-tazobactam, and meropenem alone or in combination against 10 toxinogenic and 10 nontoxinogenic C. difficile strains were investigated. Bacterial viability was determined by flow cytometry and toxin production by enzyme-linked immunosorbent assay (ELISA). When combined at subinhibitory concentrations, antimicrobial peptides and antibiotics generally led to an additive killing effect against toxinogenic and nontoxinogenic C. difficile strains. However, LL-37 and HBD3 acted in synergism with all the antibiotics that were tested. Electron microscopy revealed membrane perturbation in bacterial cell walls by HBD3. In 3 out of 10 toxinogenic strains, HBD3, LL-37, piperacillin-tazobactam, and meropenem administration led to an increased toxin release which was not neutralized by the addition of HNP1. Antimicrobial peptides increase the bacterial killing of antibiotics against C. difficile regardless of the antibiotics' mode of action. Membrane perturbation in or pore formation on the bacterial cell wall may enhance the uptake of antibiotics and increase their antibacterial effect. Therefore, a combination of antibiotics with antimicrobial peptides may represent a promising novel approach to the treatment of C. difficile infections. PMID- 25022583 TI - MgrB inactivation is a common mechanism of colistin resistance in KPC-producing Klebsiella pneumoniae of clinical origin. AB - Klebsiella pneumoniae strains producing KPC-type carbapenemases (KPC-KP) are challenging multidrug-resistant pathogens due to their extensively drug-resistant phenotypes and potential for epidemic dissemination in health care settings. Colistin is a key component of the combination antimicrobial regimens used for treatment of severe KPC-KP infections. We previously reported that insertional inactivation of the mgrB gene, encoding a negative-feedback regulator of the PhoQ PhoP signaling system, can be responsible for colistin resistance in KPC-KP, due to the resulting upregulation of the Pmr lipopolysaccharide modification system. In this work we investigated the status of the mgrB gene in a collection of 66 colistin-resistant nonreplicate clinical strains of KPC-KP isolated from different hospitals in Italy and Greece. Overall, 35 strains (53%) exhibited alterations of the mgrB gene, including insertions of different types of mobile elements (IS5-like, IS1F-like, or ISKpn14), nonsilent point mutations, and small intragenic deletions. Four additional strains had a larger deletion of the mgrB locus, while the remaining 27 strains (41%) did not show mgrB alterations. Transcriptional upregulation of the phoQ and pmrK genes (part of the phoPQ and pmrHFIJKLM operon, respectively) was observed in all strains with mgrB alterations. Complementation experiments with a wild-type mgrB gene restored colistin susceptibility and basal expression levels of phoQ and pmrK genes in strains carrying different types of mgrB alterations. The present results suggest that mgrB alteration can be a common mechanism of colistin resistance among KPC KP in the clinical setting. PMID- 25022582 TI - Signaling of chloroquine-induced stress in the yeast Saccharomyces cerevisiae requires the Hog1 and Slt2 mitogen-activated protein kinase pathways. AB - Chloroquine (CQ) has been under clinical use for several decades, and yet little is known about CQ sensing and signaling mechanisms or about their impact on various biological pathways. We employed the budding yeast Saccharomyces cerevisiae as a model organism to study the pathways targeted by CQ. Our screening with yeast mutants revealed that it targets histone proteins and histone deacetylases (HDACs). Here, we also describe the novel role of mitogen activated protein kinases Hog1 and Slt2, which aid in survival in the presence of CQ. Cells deficient in Hog1 or Slt2 are found to be CQ hypersensitive, and both proteins were phosphorylated in response to CQ exposure. CQ-activated Hog1p is translocated to the nucleus and facilitates the expression of GPD1 (glycerol-3 phosphate dehydrogenase), which is required for the synthesis of glycerol (one of the major osmolytes). Moreover, cells treated with CQ exhibited an increase in intracellular reactive oxygen species (ROS) levels and the effects were rescued by addition of reduced glutathione to the medium. The deletion of SOD1, the superoxide dismutase in yeast, resulted in hypersensitivity to CQ. We have also observed P38 as well as P42/44 phosphorylation in HEK293T human cells upon exposure to CQ, indicating that the kinds of responses generated in yeast and human cells are similar. In summary, our findings define the multiple biological pathways targeted by CQ that might be useful for understanding the toxicity modulated by this pharmacologically important molecule. PMID- 25022584 TI - Microscopic and spectroscopic analyses of chlorhexidine tolerance in Delftia acidovorans biofilms. AB - The physicochemical responses of Delftia acidovorans biofilms exposed to the commonly used antimicrobial chlorhexidine (CHX) were examined in this study. A CHX-sensitive mutant (MIC, 1.0 MUg ml(-1)) was derived from a CHX-tolerant (MIC, 15.0 MUg ml(-1)) D. acidovorans parent strain using transposon mutagenesis. D. acidovorans mutant (MT51) and wild-type (WT15) strain biofilms were cultivated in flow cells and then treated with CHX at sub-MIC and inhibitory concentrations and examined by confocal laser scanning microscopy (CLSM), scanning transmission X ray microscopy (STXM), and infrared (IR) spectroscopy. Specific morphological, structural, and chemical compositional differences between the CHX-treated and untreated biofilms of both strains were observed. Apart from architectural differences, CLSM revealed a negative effect of CHX on biofilm thickness in the CHX-sensitive MT51 biofilms relative to those of the WT15 strain. STXM analyses showed that the WT15 biofilms contained two morphochemical cell variants, whereas only one type was detected in the MT51 biofilms. The cells in the MT51 biofilms bioaccumulated CHX to a similar extent as one of the cell types found in the WT15 biofilms, whereas the other cell type in the WT15 biofilms did not bioaccumulate CHX. STXM and IR spectral analyses revealed that CHX-sensitive MT51 cells accumulated the highest levels of CHX. Pretreating biofilms with EDTA promoted the accumulation of CHX in all cells. Thus, it is suggested that a subpopulation of cells that do not accumulate CHX appear to be responsible for greater CHX resistance in D. acidovorans WT15 biofilm in conjunction with the possible involvement of bacterial membrane stability. PMID- 25022585 TI - First description of a blaVIM-2-carrying Citrobacter freundii isolate in Spain. PMID- 25022586 TI - In vivo assessment of SMT19969 in a hamster model of clostridium difficile infection. AB - SMT19969 [2,2'-bis(4-pyridyl)3H,3'-H 5,5-bibenzimidazole] is a novel narrow spectrum nonabsorbable antibiotic currently in development for the treatment of Clostridium difficile infection. The comparative activities of SMT19969 and vancomycin against nonepidemic and epidemic strains of C. difficile were studied in an established hamster model. Against nonepidemic (VA11) strains, the survival rates of SMT19969-treated animals ranged from 80% to 95%. Vancomycin exhibited 100% protection during treatment, with relapse observed starting on day 9 and 50% survival at day 20. At 50 mg/kg of body weight, SMT19969 administered orally once daily for 5 days provided full protection of treated animals on the dosing days and through day 12 against epidemic strains. Vancomycin also protected during the dosing interval, but apparent relapse occurred earlier, starting on day 11. SMT19969 exhibited excellent in vitro activity, with MICs of 0.25 MUg/ml for all isolates. The MICs for vancomycin were 2- to 4-fold higher at <=0.5 to 1 MUg/ml. All plasma sample concentrations of SMT19969 were below the limit of quantification (25 ng/ml) at all time points, consistent with the reported lack of bioavailability of the compound. Cecal concentrations were significantly above the MIC (ranging from 96 MUg/ml to 172 MUg/ml). PMID- 25022587 TI - Case-case-control study of patients with carbapenem-resistant and third generation-cephalosporin-resistant Klebsiella pneumoniae bloodstream infections. AB - Strains of third-generation-cephalosporin-resistant Klebsiella pneumoniae (3GCRKP) and carbapenem-resistant K. pneumoniae (CRKP) are rapidly spreading. Evidence is needed to establish whether differences exist between patients at risk for 3GCRKP and those at risk for CRKP bloodstream infections (BSIs); thus, this retrospective case-case-control study was conducted to determine if the risk factors for these two infections differ. The inclusion criteria for cases were positive blood cultures for K. pneumoniae, first episode of BSI, age of >=18 years, and susceptibility results indicating resistance to either third generation cephalosporins (3GCRKP group) or carbapenems and cephalosporins (CRKP group). Controls were patients admitted for >=72 h and were matched to cases by month/year and medical unit. Variables of interest were analyzed by univariate analysis, and those of significance were analyzed by logistic regression. In total, 111 patients with 3GCRKP BSIs and 43 patients with CRKP BSIs were matched to 154 controls. Multivariate analyses of 3GCRKP case and control groups demonstrated that a length of stay (LOS) of >40 days (odds ratio [OR], 17.7; 95% confidence interval [CI], 3.7 to 84.3), the use of antibiotics in the past 90 days (OR, 4.3; 95% CI, 1.5 to 11.9), and the presence of a central venous catheter (OR, 4.1; 95% CI, 1.3 to 13.4) were independent risk factors. Multivariate analyses of the CRKP case and control groups demonstrated that a LOS of >40 days (OR, 13.5; 95% CI, 2.9 to 62.8) and the use of antibiotics in the past 90 days (OR, 5.9; 95% CI, 1.3 to 26.5) were independent risk factors. Similar factors put patients at risk for these two types of K. pneumoniae BSIs. PMID- 25022588 TI - Antistaphylococcal activity of oritavancin and its synergistic effect in combination with other antimicrobial agents. AB - Oritavancin exhibited in vitro activity against 169 strains of vancomycin susceptible, methicillin-resistant Staphylococcus aureus (MRSA) with MICs ranging from 0.03 to 1 MUg/ml and against vancomycin-intermediate MRSA (VISA; n = 29), heterogeneous vancomycin-intermediate MRSA (hVISA; n = 5), and vancomycin resistant MRSA (n = 5) strains, with MICs ranging from 0.12 to 4 MUg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method. PMID- 25022589 TI - Comparison of different drug susceptibility test methods to detect rifampin heteroresistance in Mycobacterium tuberculosis. AB - We compared the efficiencies of different drug susceptibility testing methods in detecting rifampin (RIF) heteroresistance in Mycobacterium tuberculosis. Our data revealed that the broth dilution method found more resistance than MGIT did (P=0.046) for the low-resistance group. Similarly, the broth dilution method was more sensitive in detecting RIF heteroresistance in subpopulations with low growth rates than was MGIT (P=0.033). In conclusion, our data demonstrated that the broth dilution method was more sensitive than MGIT in detecting RIF heteroresistance. PMID- 25022590 TI - Characterization of a melamino nitroheterocycle as a potential lead for the treatment of human african trypanosomiasis. AB - This paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential. PMID- 25022591 TI - Antibiotic resistance mechanisms inform discovery: identification and characterization of a novel amycolatopsis strain producing ristocetin. AB - Discovering new antibiotics is a major scientific challenge, made increasingly urgent by the continued development of resistance in bacterial pathogens. A fundamental understanding of the mechanisms of bacterial antibiotic resistance will be vital for the future discovery or design of new, more effective antibiotics. We have exploited our intimate knowledge of the molecular mechanism of glycopeptide antibiotic resistance in the harmless bacterium Streptomyces coelicolor to develop a new two-step cell wall bioactivity screen, which efficiently identified a new actinomycete strain containing a previously uncharacterized glycopeptide biosynthetic gene cluster. The screen first identifies natural product extracts capable of triggering a generalized cell wall stress response and then specifically selects for glycopeptide antibacterials by assaying for the induction of glycopeptide resistance genes. In this study, we established a diverse natural product extract library from actinomycete strains isolated from locations with widely varying climates and ecologies, and we screened them using the novel two-step bioassay system. The bioassay ultimately identified a single strain harboring the previously unidentified biosynthetic gene cluster for the glycopeptide ristocetin, providing a proof of principle for the effectiveness of the screen. This is the first report of the ristocetin biosynthetic gene cluster, which is predicted to include some interesting and previously uncharacterized enzymes. By focusing on screening libraries of microbial extracts, this strategy provides the certainty that identified producer strains are competent for growth and biosynthesis of the detected glycopeptide under laboratory conditions. PMID- 25022592 TI - Ceftaroline is active against heteroresistant methicillin-resistant Staphylococcus aureus clinical strains despite associated mutational mechanisms and intermediate levels of resistance. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important infectious human pathogen responsible for diseases ranging from skin and soft tissue infections to life-threatening endocarditis. beta-Lactam resistance in MRSA involves acquisition of penicillin-binding protein 2a (PBP2a), a protein with low affinity for beta-lactams that mediates cell wall assembly when the normal staphylococcal PBPs (PBP1 to -4) are blocked by these agents. Many MRSA strains display heterogeneous expression of resistance (HeR) against beta-lactam antibiotics. The beta-lactam-mediated homoresistant (HoR) phenotype is associated with both expression of the mecA gene and activation of the LexA-RecA-mediated SOS response, a regulatory network induced in response to DNA damage. Ceftaroline (CPT) is the only FDA-approved cephalosporin targeting PBP2a. We investigated the mechanistic basis of CPT activity against HeR-MRSA strains, including a set of strains displaying an intermediate level of resistance to CPT. Mechanistically, we found that 1 exposure of HeR-MRSA to subinhibitory concentrations of CPT selected for the HoR derivative activated the SOS response and increased mutagenesis. Importantly, CPT-selected HoR cells remained susceptible to CPT while still being resistant to most beta-lactams, and 2-CPT activity in HeR-MRSA resided in an attenuated induction of mecA expression in comparison to other beta lactams. In addition, 3-CPT intermediate-resistant strains displayed a significant increase in CPT-induced mecA expression accompanied by mutations in PBP2, which together may interfere with the complete repression by CPT of both PBP2a and PBP2a-PBP2 interactions and thus be a determining factor in the low level of CPT resistance in the absence of mecA gene mutations. The present study provides mechanistic evidence that CPT represents an alternative therapeutic option for the treatment of heteroresistant MRSA strains. PMID- 25022593 TI - Does arm swing emphasized deliberately increase the trunk stability during walking in the elderly adults? AB - The purpose of this study was to determine whether trunk stability while walking changes when arm swing is deliberately altered in elderly individuals. Participants included 21 community-dwelling elderly individuals (7 men and 14 women; age, 81.8 +/- 5.0 years). We measured trunk acceleration by using a wireless miniature sensor unit containing a tri-axial linear accelerometer under 3 walking conditions: normal walking (normal condition), deliberately walking without any arm swing (no swing condition), and walking with a deliberately emphasized arm swing (over swing condition). To evaluate trunk stability during walking, we calculated harmonic ratios (HRs) based on trunk tri-axial acceleration signals (anteroposterior: AP, vertical: VT, and mediolateral: ML). HR-AP and HR-VT were not significantly different across the 3 conditions, but HR ML in the over swing condition was significantly higher than that in the other 2 conditions by generalized estimating equations (GEE) adjusted for walking speed (p<0.05). These findings indicate that trunk stability in the ML direction increased when the elderly individuals walked with a deliberately emphasized arm swing. PMID- 25022594 TI - The influence of tester experience on the reliability of 3D kinematic information during running. AB - The efficacy of 3D motion capture in both sports and clinical research settings is largely dependent on the reliability of the obtained measurements. This study aimed to determine whether there are 3D kinematic differences both between and within researchers with three different levels of familiarity in 3D marker placement. Fifteen male participants ran across a 22 m laboratory at 4.0 m.s(-1). Three researchers (experienced, intermediate and novice) positioned lower extremity markers on two occasions. Differences in 3D joint kinetics/kinematics both between and within researchers were examined using mixed ANOVA's. The within researcher reliability of the kinetic/kinematic waveforms were further analysed using intraclass correlations. The results show that significant differences in discrete parameters were observed in the transverse plane between researchers and also in the coronal and transverse planes within researcher for the novice practitioner. Furthermore, the results also showed that the experienced researcher was associated with the highest levels of reliability in marker placement. This suggests that it may be prudent for 3D analyses, in particular those with a clinical component to be conducted using experienced practitioners and for analyses to state the experience level of the researchers conducting the anatomical marker placement. PMID- 25022595 TI - Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AB - OBJECTIVE AND DESIGN: Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. METHODS: CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. RESULTS: CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P < 0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P = 0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4 cell count or CNS penetration-efficacy score. CONCLUSION: Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury. PMID- 25022596 TI - Successful antiretroviral therapy delivery and retention in care among asymptomatic individuals with high CD4+ T-cell counts above 350 cells/MUl in rural Uganda. AB - BACKGROUND: HIV antiretroviral therapy (ART) is being rapidly scaled up in sub Saharan Africa, including recently patients with CD4 T-cell counts above 350 cells/MUl. However, concerns persist about adherence and virologic suppression among these asymptomatic, high CD4 cell count individuals. OBJECTIVE: To determine the virologic efficacy and safety of ART among asymptomatic HIV positive Ugandan adults with high CD4 cell counts above 350 cells/MUl via a streamlined model of care. DESIGN: Prospective nonrandomized clinical study (EARLI Study: clinicaltrials.gov NCT#01479634). SETTING: Prototypic rural Ugandan HIV clinic. PATIENTS/PARTICIPANTS: Asymptomatic, ART-naive adults (aged >18 years, N = 197) with CD4 at least 350 cells/MUl, without pregnancy or WHO stage 3/4 illness. INTERVENTIONS: ART included tenofovir/emtricitabine/efavirenz, with ritonavir/lopinavir substitution for efavirenz available. Streamlined ART model included nurse-driven visits with physician back-up, basic safety laboratory monitoring with HIV viral load, clinician telephone contact, and defaulter tracking. No incentives were provided. OUTCOMES: Undetectable viral load (<=400 copies/ml) at 24 and 48 weeks [intention to treat (ITT); missing = detectable), self-reported ART adherence, retention in care, and laboratory/clinical ART toxicities. RESULTS: Of the 197 patients with CD4 above 350 cells/MUl, median CD4 cell count was 569 cells/MUl (interquartile range 451-716). Undetectable viral load was achieved in 189 of 197 (95.9%, ITT) and 189 of 195 (96.9%, ITT) of participants at weeks 24 and 48, respectively. Self-reported adherence was 98% and 192 of 197 (97%) of the patients were retained at week 48. Laboratory adverse events and hospitalizations were rare. CONCLUSIONS: We demonstrate high virologic suppression, retention, and safety among asymptomatic individuals with CD4 above 350 cells/MUl in a prototypic Ugandan clinic. Our results challenge current concerns that individuals with high CD4 cell count lack motivation for ART, and may not achieve sustained virologic suppression. PMID- 25022598 TI - Hematologic response and stabilization of renal function in a patient with light chain deposition disease after lenalidomide treatment: a novel therapeutic approach? PMID- 25022597 TI - Deficient synthesis of class-switched, HIV-neutralizing antibodies to the CD4 binding site and correction by electrophilic gp120 immunogen. AB - OBJECTIVE: HIV is vulnerable to antibodies that recognize a linear CD4 binding site epitope of gp120 (C), but inducing C-directed antibody synthesis by traditional vaccine principles is difficult. We wished to understand the basis for deficient C-directed antibody synthesis and validate correction of the deficiency by an electrophilic gp120 analog (E-gp120) immunogen that binds B-cell receptors covalently. METHODS: Serum antibody responses to a C peptide and full length gp120 epitopes induced by HIV infection in humans and immunization of mice with gp120 or E-gp120 were monitored. HIV neutralization by monoclonal and variable domain-swapped antibodies was determined from tissue culture and humanized mouse infection assays. RESULTS: We describe deficient C-directed IgG but not IgM antibodies in HIV-infected patients and mice immunized with gp120 accompanied by robust synthesis of IgGs to the immunodominant gp120 epitopes. Immunization with the E-gp120 corrected the deficient C-directed IgG synthesis without overall increased immunogenicity of the C or other gp120 epitopes. E gp120-induced monoclonal IgGs neutralized diverse HIV strains heterologous to the immunogen. A C-directed IgG neutralized HIV more potently compared to its larger IgM counterpart containing the same variable domains, suggesting obstructed access to HIV surface-expressed C. An E-gp120-induced IgG suppressed HIV infection in humanized mice, validating the tissue culture neutralizing activity. CONCLUSION: A C-selective physiological defect of IgM->IgG class-switch recombination (CSR) or restricted post-CSR B-cell development limits the functional utility of the humoral immune response to gp120. The E-gp120 immunogen is useful to bypass the restriction and induce broadly neutralizing C-directed IgGs (see Supplemental Video Abstract, http://links.lww.com/QAD/A551). PMID- 25022599 TI - Myelomastocytic leukemia with aberrant CD25 expression: case report and review of the literature. PMID- 25022600 TI - Donor cell-derived myelodysplastic syndrome with ring chromosome 7 after allogeneic hematopoietic stem cell transplant in 2 patients with lymphomas as primary disease. PMID- 25022601 TI - Autoimmune manifestations in patients with Waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia represents a lymphoplasmacytic lymphoma with an indolent clinical course. The existing literature associates this hematologic malignancy with various autoimmune disorders. Notwithstanding, these autoimmune conditions have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. The authors offer a comprehensive review of the existing literature on various hematologic and nonhematologic autoimmune disorders documented in the course of Waldenstrom macroglobulinemia. Whereas some of them are thought to be secondary to a dysfunctional immune response associated with an underlying malignant process, others might be primary and might even play a role in its pathogenesis. Moreover, the observations that personal history and family history of certain autoimmune diseases were associated with an increased risk of subsequent Waldenstrom macroglobulinemia strengthen further the hypothesis that shared susceptibility genes and chronic antigenic stimulation might predispose individuals to both conditions. PMID- 25022602 TI - Efforts to reduce seclusion and restraint use in a state psychiatric hospital: a ten-year perspective. AB - OBJECTIVE: The authors previously demonstrated an 82.3% reduction in seclusion and restraint use at an inpatient psychiatric facility, largely attributable to changes to the physical environment. This study investigated whether the reduction was sustained over time. METHODS: This follow-up study examined archival data by using a longer preintervention baseline phase and examined the sustainability of intervention gains in the absence of a research agenda. Over ten years, 3,040 seclusion and restraint incidents were analyzed across 254,491 patient-days. RESULTS: The extended baseline phase (N=38 months) exhibited a linear trend upward in seclusion and restraint use, and the formal intervention period and subsequent follow-up periods (N=82 months) showed a stabilization effect (p<.001). CONCLUSIONS: The findings suggest that reduction in seclusion and restraint use is sustainable, and judicious use of seclusion and restraint can become the new normative practice-even in the face of potentially disruptive administrative and environmental changes. PMID- 25022603 TI - Therapeutic monoclonal antibodies and consistent ends: terminal heterogeneity, detection, and impact on quality. AB - Monoclonal antibodies (mAbs) are biological macromolecules with complex post translational modifications that can be observed when assessing product variants. The N- and C-terminal heterogeneities of commercially produced antibodies have been observed and extensively studied over the past 30 years. This review summarizes the current literature on detectable antibody termini variants from cultured cells. The presence of these heterogeneities can be detected by many different analytical methods, mostly based on sequence, charge and size differences. Examples are presented that highlight terminal heterogeneities, methods of detection, and their impact on the quality of mAbs. Regulatory considerations are also discussed regarding the potential impact on product quality, safety, and efficacy. PMID- 25022605 TI - Report on the results of treatment of pain with the sustained sinusoidal current on 100 patients during 1964 and 1965. AB - The first report on the use of the Sinusoidal current in the treatment of pain was given to the Physiotherapy Society of South Australia in February, 1964. Twenty-six patients were treated; they all had post-traumatic pain with well defined local tenderness and/or hypersensitivity, and, in the case of the amputees, some phantom pains and jactitations as well. This method of treatment was described in the Australian Journal of Physiotherapy, December, 1964. PMID- 25022604 TI - Stage-specific changes in neurogenic and glial markers in Alzheimer's disease. AB - BACKGROUND: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question. METHODS: Endogenous neurogenesis and glia in the subventricular zone and dentate gyrus neurogenic niches were evaluated using single and double immunohistochemistry and a validated antibody selection for stage-specific and type-specific markers in autopsy tissue from a representative cohort of 28 participants in the Medical Research Council Cognitive Function and Ageing Study. Immunopositive cells were measured blinded to diagnosis using bright-field and fluorescent microscopy. RESULTS: The number of newly generated neurons significantly declined only in the dentate gyrus of patients with severe tau pathology. No other changes in other neurogenic markers were observed in either of the neurogenic niches. Alterations in astrocytes and microglia were also observed in the dentate gyrus across the different stages of tau pathology. No change in any of the markers was observed in individuals who died with dementia compared with individuals who did not die with dementia. CONCLUSIONS: Alterations in endogenous neurogenesis appeared to be confined to a reduction in the generation of new neurons in the dentate gyrus of patients with AD and severe neurofibrillary tangle pathology and were accompanied by changes in the glia load. These data suggest that intervention enhancing endogenous neurogenesis may be a potential therapeutic target in AD. PMID- 25022606 TI - Ultrasonic in acute neuritis in leprosy: a preliminary study. AB - Neuritis may be observed in all the main types of leprosy and is known to occur in a single nerve or in a multiple form. The nerves, as a rule, are involved at definite anatomical levels. PMID- 25022607 TI - Everyday use of plastic. AB - There are several well-known methods of making plastic appliances; but the search here was for a simple quick way of producing something in a physiotherapy department, which could be used the same day as part of the treatment. For this reason plastics mixed from powder were eliminated, as problems with fumes, dermatitis, and curing time seemed to demand special premises and skill. Sheet plastics only were used. Nor was it intended to make a durable appliance which would last a lifetime but rather something cheap which could be frequently changed or adjusted during the recovery period. PMID- 25022609 TI - Adapting to extreme climates: raising animals in hot and arid ecosystems in Australia. AB - This paper provides an analysis of adaptation to extreme climate changes using the Australian animal husbandry data. The paper finds that farmers have adapted to a hot and arid climate regime through animal husbandry. The number of sheep vastly increases into arid ecosystems while the number of beef cattle does not decline in high temperatures. In the future climate system in which Australia becomes hotter and more arid, we predict that farmers will increase by large percentages the numbers of beef cattle and/or sheep owned in order to adapt to a highly unfavorable climate condition, especially into the arid ecosystems. This paper shows how humanity has adapted to climate extremes taking into account changing ecosystems. PMID- 25022608 TI - A rare case of sinus of valsalva-right atrial fistula secondary to an abscess perforation from underlying aortic valve endocarditis. AB - Sinus of Valsalva-right atrial fistulas are abnormal connections between the aorta and the right atrium, and present challenging surgical conditions. An extremely rare etiology of aorto-right atrial fistula is infective endocarditis. This case report presents a 21 year old Caucasian female patient who had native aortic valve Staphylococcus aureus endocarditis complicated by sinus of Valsalva abscess perforation associated with an acute heart block, an aorto-right atrial fistula, severe heart failure, and cardiogenic shock. She underwent emergent aortic valve replacement and complex sinus of Valsalva fistula pericardial patch reconstruction and repair. This case report further explores the advantages and disadvantages of different valves for different patient populations, and evaluates the patient's prosthesis mismatch and effective orifice area. PMID- 25022610 TI - Risk factors associated with malaria deaths in travellers: a literature review. AB - Malaria is the most frequently imported acute, life-treating, tropical disease in international travellers. We did a literature review in PubMed using pre-defined search terms to identify possible risk factors for malaria deaths in travellers. After screening, a total of 51 papers were selected for inclusion and were intensively scrutinised for details of "case fatality rates" and risk factors for fatal malaria associated with travel. The main risk factors were: non-use or inappropriate use of chemoprophylaxis, age, delay in seeking care, incorrect treatment, delay in diagnosis, infection with Plasmodium falciparum, non immunity, travelling as a tourist and sex. The "case fatality rate" in most of the studies lay in the range 0.2%-3%. Possible reasons for this case fatality rate variation are: small case series, different populations included in the studies with different physiological and social determinants, including different species of malaria parasite and different traveller destinations in the case series. PMID- 25022611 TI - Travel medicine for the President at the White House, aboard Air Force One, and around the world. PMID- 25022612 TI - Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease. AB - BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus associated lymphoproliferative disorder. It most often occurs in patients with immunodeficiency and the clinical course ranges from indolent behavior to that of an aggressive malignancy. Pulmonary, central nervous system and dermatological manifestations are most common. To our knowledge this is the first reported case of LYG related to azathioprine therapy in Crohn disease. CASE PRESENTATION: A twenty-six year old Caucasian woman with colonic Crohn disease on maintenance azathioprine therapy presented with right upper quadrant pain and fever. Diagnostic imaging revealed extensive liver, pulmonary and cerebral lesions. A diagnosis of LYG was made based on the pattern of organ involvement and the immunohistochemical features on liver and lung biopsy. CONCLUSIONS: Thiopurine therapy for inflammatory bowel disease is associated with an increased incidence of lymphoproliferative disorders. This report highlights the diagnostic challenges associated with LYG. As long-term thiopurine therapy remains central to the management of inflammatory bowel diseases it is essential that both patients and clinicians are aware of this potential adverse outcome. PMID- 25022613 TI - Effect of Red Blood Cells on Platelet Activation and Thrombus Formation in Tortuous Arterioles. AB - Thrombosis is a major contributor to cardiovascular disease, which can lead to myocardial infarction and stroke. Thrombosis may form in tortuous microvessels, which are often seen throughout the human body, but the microscale mechanisms and processes are not well understood. In straight vessels, the presence of red blood cells (RBCs) is known to push platelets toward walls, which may affect platelet aggregation and thrombus formation. However in tortuous vessels, the effects of RBC interactions with platelets in thrombosis are largely unknown. Accordingly, the objective of this work was to determine the physical effects of RBCs, platelet size, and vessel tortuosity on platelet activation and thrombus formation in tortuous arterioles. A discrete element computational model was used to simulate the transport, collision, adhesion, aggregation, and shear-induced platelet activation of hundreds of individual platelets and RBCs in thrombus formation in tortuous arterioles. Results showed that high shear stress near the inner sides of curved arteriole walls activated platelets to initiate thrombosis. RBCs initially promoted platelet activation, but then collisions of RBCs with mural thrombi reduced the amount of mural thrombus and the size of emboli. In the absence of RBCs, mural thrombus mass was smaller in a highly tortuous arteriole compared to a less tortuous arteriole. In the presence of RBCs however, mural thrombus mass was larger in the highly tortuous arteriole compared to the less tortuous arteriole. As well, smaller platelet size yielded less mural thrombus mass and smaller emboli, either with or without RBCs. This study shed light on microscopic interactions of RBCs and platelets in tortuous microvessels, which have implications in various pathologies associated with thrombosis and bleeding. PMID- 25022614 TI - Outcome After Operative Fusion of the Tarsal Joints: A Systematic Review. AB - Arthrodesis of 1 or more joints of the hindfoot is performed to treat severe functional impairment due to pain, deformity, and/or instability. Evaluation of the results of hindfoot arthrodesis from the published data has been difficult owing to the great variety of pathologic entities and surgical techniques reported in the studies. A comprehensive search for relevant reports, reference lists, and citation tracking of the included studies was conducted using the PubMed((r)), Embase((r)), and CINAHL((r)) databases. The studies had to have been prospective, included patients with hindfoot problems, evaluated arthrodesis of 1 or more tarsal joints, and had at least 1 of the following primary clinical outcome parameters: pain, function, or complications. Two of us independently selected the relevant studies using predefined criteria and graded the quality of evidence using a 0 to 9 star scale according to the Newcastle-Ottawa Scale. A total of 16 prospective case series were included; 5 studies scored 6 stars, 8 scored 5 stars, 2 scored 4 stars, and 1 scored 3 stars. A best evidence synthesis was performed, and improvement in function and pain was found for 3 combinations: talonavicular arthrodesis for rheumatoid arthritis, triple arthrodesis for rheumatoid arthritis, and subtalar arthrodesis for post-traumatic arthritis showed good results for pain and function, the last especially when performed arthroscopically. The best evidence syntheses revealed good results for pain and function for these disease-operative technique combinations. PMID- 25022615 TI - Role of Demineralized Allograft Subchondral Bone in the Treatment of Shoulder Lesions of the Talus: Clinical Results With Two-Year Follow-Up. AB - Cystic osteochondral lesions of the talus present a considerable challenge for foot and ankle surgeons. The purpose of the present study was to evaluate the effect of a medial malleolar osteotomy and implantation of demineralized allograft subchondral bone on pain and function 2 years after surgery. For inclusion, patients demonstrated radiographic evidence of a medial cystic full thickness osteochondral defect of the talus and previously failed microfracture (N = 12). We hypothesized that improvements in pain and disability would be maintained across time. Compared with the preoperative values, 2 years after surgery, pain and disability had significantly reduced (p < .001). Significant reductions had occurred in postoperative pain from 6 months to 1 year (p = .001) and from 6 months to 2 years (p = .005). Similarly, significant reductions had occurred in postoperative disability from 6 months to 1 year (p = .008) and from 6 months to 2 years (p = .03). The reductions in postoperative pain and disability were maintained from 1 year to 2 years (p >= .79). Multiple regression analyses identified depression as a predictor of 2-year postoperative pain (R(2) = 0.36, p = .04). No variables were identified as significant predictors of postoperative disability at 2 years. Other than 1 previously reported peroneal deep venous thrombosis, no additional complications occurred. With successful graft incorporation, no inflammatory response, and no additional complications, the allograft subchondral plug appears to successfully treat osteochondral lesions of the talus and maintain improvements in pain and disability at intermediate follow-up. PMID- 25022616 TI - Cytology for the detection of early recurrence of gynecologic cancer in the vaginal vault. AB - OBJECTIVE: The real benefit of follow-up cervical cytology in women treated for gynecological cancer is unclear. This study was designed to assess the rate of success of cytological examinations in the detection of early vaginal recurrence of gynecological cancer in women found by other methods to have vaginal recurrence of cervical and endometrial cancer. DATA SOURCES: Records of cytological examinations. STUDY SELECTION: Thirty-three women treated for early and invasive cervical and endometrial cancer with recurrence in the vaginal vault were retrospectively analyzed. DATA EXTRACTION: Records from 1979 to 2010. DATA SYNTHESIS: Sixteen women (48.5%) had symptomatic vaginal recurrence associated with distant metastases, whereas 17 (51.5%) had vaginal recurrence only. Cytology was negative in 12 women (36.4%) with both symptomatic and asymptomatic recurrence and positive in the other 21 (63.6%). In 9 of these 21 women (42.9%), the disease was limited to the vaginal vault, whereas the remaining 12 (57.1%) presented with vaginal lesions associated with distant metastases. Cytology was positive in 9 of the 17 (52.9%) women whose recurrence was limited to the vaginal vault and negative in 8 (47.1%). CONCLUSION: Vaginal cytology yielded false negative results in almost half of the women with vaginal recurrence of gynecological cancer. Patents of methods used for early diagnosis and detection of immortalization of cervical cancer are also reviewed in this article. PMID- 25022617 TI - A mixture of carcinoid tumors, extensive neuroendocrine proliferation, and multiple pulmonary sclerosing hemangiomas. AB - We encountered an extremely rare case of multiple pulmonary sclerosing hemangiomas (PSH) with extensive neuroendocrine lesions, including pulmonary neuroendocrine cell (PNC) hyperplasia, multiple carcinoid tumorlets and typical carcinoid tumors within one pulmonary lobe. To the best of our knowledge, this is the first reported case in the English medical literature of PSH combined and admixed with carcinoid tumors and extensive neuroendocrine proliferation. This case is noteworthy for several reasons. First, the lesion is multi-nodular and unusually large for a typical PSH, which may mimic malignancy on imaging studies and cause diagnostic difficulties. Second, sampling bias may lead to diagnostic errors for a lesion containing two different types of neoplasms. Third, our case displays a rare mixed and mosaic pattern of PSH with a full spectrum of pulmonary neuroendocrine lesions, which may imply a potential intrinsic association in pathogenesis between PSH and concomitant neuroendocrine neoplasms. The clinical implication of multiple PSHs is also discussed. PMID- 25022618 TI - Noninvasive imaging of apoptosis induced by adenovirus-mediated cancer gene therapy using a caspase-3 biosensor in living subjects. AB - We attempted to visualize the serial induction of caspase-3-dependent apoptosis mediated by Fas ligand/tumor necrosis factor-related apoptosis-inducing ligand (FasL/TRAIL) adenoviral gene therapy in mice bearing human glioma xenografts using a caspase-3 biosensor and monitored its therapeutic effects. Human D54 glioma cells expressing both the caspase-3 sensor and the Renilla luciferase (Rluc) gene were established (referred to as D54-CR cells). The bioluminescence imaging (BLI) signals of the caspase-3 sensor in the D54-CR cells were increased in a time- and virus dose-dependent manner by Ad-TRAIL or Ad-FasL transduction. Fluorescence-activated cell sorting (FACS) analysis revealed an increase in both cleaved caspase-3 or poly(ADP-ribose) polymerase (PARP) and annexin V- and propidium iodide-positive cells depending on the dosage of administered virus. Ad FasL treatment resulted in a significant increase in the BLI activity of the caspase-3 sensor in the D54-CR tumors, which were ~ 8.2, ~ 12.9, and ~ 46.6 times higher than those of control at 12 hours, 24 hours, and 96 hours posttreatment, respectively. In contrast, a significant reduction in Rluc activity, as a surrogate marker of cell viability, was detected in the tumors treated with Ad FasL but not in those treated with Ad-null. Overall, the activation of caspase-3 dependent apoptosis induced by Ad-FasL/Ad-TRAIL gene therapy was successfully monitored by a sensitive imaging platform for caspase-3 activation. PMID- 25022619 TI - Dietary inclusion level and time effects of taurine on broiler performance, meat quality, oxidative status and muscle taurine content. AB - Two experiments were conducted to investigate the effect of taurine on growth performance, meat quality, oxidative status and muscle taurine content in broilers. In Experiment 1, 50 one-day-old male Cobb chicks were given a diet supplemented with 0, 0.125, 0.50, 2.00 or 8.00 g/kg taurine from 1 to 42 d of age. In Experiment 2, 80 22-d-old male Cobb chicks were given a diet supplemented with 4.00 g/kg taurine for 0, 1, 2 or 3 weeks. Taurine contents of thigh and breast muscle increased linearly with increasing dietary taurine. Taurine supplementation for 1, 2 and 3 weeks significantly increased the taurine content of breast muscle. The taurine contents of liver and thigh meat were significantly increased by taurine supplementation for 3 weeks. The taurine contents of thigh and breast meat from broilers given a diet supplemented with 4 g/kg taurine for 3 weeks increased to 1.89 times the concentrations of the control group. There were no detrimental effects on growth performance, breast or thigh muscle yield, pH value or drip-water loss, and taurine supplementation did not affect the serum carbonyl content. Serum malondialdehyde concentration was significantly decreased by taurine supplementation for 1, 2 or 3 weeks. PMID- 25022620 TI - Different haemodynamic patterns in head-up tilt test on 400 paediatric cases with unexplained syncope. AB - OBJECTIVE: To assess haemodynamic patterns in head-up tilt testing on 400 paediatric cases with unexplained syncope. METHODS: Medical records of 520 children who underwent head-up tilt testing in the preceding year were retrospectively evaluated, and 400 children, 264 (66%) girls and 136 (34%) boys, aged 12.6+/-2.6 years (median 13; range 5-18), with unexplained syncope were enrolled in the study. Age, sex, baseline heart rate, baseline blood pressure, frequency of symptoms, and/or fainting attacks were recorded. The test protocol consisted of 25 minutes of supine resting followed by 20 minutes of 70 degrees upright positioning. Subjects were divided into nine groups according to their differing haemodynamic patterns. RESULTS: There were no statistically significant differences between the groups with regard to age, gender, baseline blood pressure, and frequency of syncope (p>0.05). The response was compatible with orthostatic intolerance in 28 cases (7.0%), postural orthostatic tachycardia syndrome in 24 cases (6.0%), asymptomatic postural orthostatic tachycardia syndrome in 26 cases (6.5%), orthostatic hypotension in seven cases (1.7%), vasovagal syncope in 38 cases (9.5%), and negative in 274 cases (69.2%). Vasovagal syncope response patterns were of type 3 in nine cases (2.2%), type 2A in 10 cases (2.5%), type 2B in two cases (0.5%), and type 1 (mixed) in 17 cases (4.25%). CONCLUSIONS: In the 400 paediatric cases with unexplained syncope, nine different haemodynamic response patterns to head-up tilt testing were discerned. Children with orthostatic intolerance syndromes are increasingly referred to hospitals because of difficulty in daily activities. Therefore, there is need for further clinical trials in these patient groups. PMID- 25022621 TI - A dehydration-responsive element binding (DREB) transcription factor from the succulent halophyte Salicornia brachiata enhances abiotic stress tolerance in transgenic tobacco. AB - Dehydration-responsive element binding (DREB) transcription factor (TF) plays a key role for abiotic stress tolerance in plants. Earlier, we have published the isolation and characterisation of an A-2-type SbDREB2A TF from an extreme halophyte Salicornia brachiata. The SbDREB2A protein lacks potential proline (P), glutamic acid (E), serine (S) and threonine (T) (PEST) sequence which is known to act as signal peptide for protein degradation. In this study, SbDREB2A TF was over-expressed in tobacco plants without any modification in polypeptide sequence. Transgenic plants showed better seed germination and growth characteristics in both hyperionic and hyperosmotic stresses. Transgenic plants exhibited higher water content, membrane stability and less electrolyte leakage in stress conditions. The transgenic plants accumulated less Na(+) and higher K(+) than wildtype (WT) plants. The transgenic plants revealed higher chlorophyll content, water use efficiency (WUE) and net photosynthesis rate. Transgenics exhibited higher level of proline and low amount of MDA and H2O2 under stress conditions. The real-time PCR of transgenics showed higher expression of downstream heat shock genes (Hsp18, Hsp26 and Hsp70), TFs (AP2 domain containing TF, HSF2 and ZFP), signalling components (PLC3 and Ca (2+) /calmodulin) and dehydrins (ERD10B, ERD10D and LEA5) under different abiotic stress treatments. PMID- 25022622 TI - Elevated antibody reactivity to measles virus NCORE protein among patients with multiple sclerosis and their healthy siblings with intrathecal oligoclonal immunoglobulin G production. AB - BACKGROUND: Patients with multiple sclerosis (MS) and their healthy siblings with the MS oligoclonal bands (OCB) trait, (a hyperimmune condition in form of two or more CSF enriched OCBs) harbor in cerebrospinal fluid (CSF) and serum elevated immunoglobulin G (IgG) titers against measles crude whole-cell antigen. The underlying mechanism resulting in the increased IgG antibody reactivity to measles remains unclear. The response may represent specific IgG reactivity to measles antigens or unspecific auto-antibodies targeting cellular components in the crude whole virus antigens commonly used in detection assays. OBJECTIVE: To determine the specificity of the measles IgG antibody reactivity by using a purified single nucleoprotein as antigen, thereby minimizing the contribution from auto-antibodies. STUDY DESIGN: The conserved N-terminal portion of the measles nucleocapsid protein (NCORE) was expressed as a specific antigen devoid of human or primate components. Serological analyses were performed on CSF and sera from MS patients, their clinically healthy siblings and healthy unrelated controls. RESULTS: MS patients demonstrated higher IgG reactivity compared to healthy controls in both CSF (P<0.001) and serum (P<0.001), and compared to siblings in CSF (P<0.001) and serum (P=0.2). Siblings with MS OCB trait showed higher IgG reactivity than healthy controls in CSF (P=0.002) and serum (P=0.01). Comparison between siblings with MS OCB trait and siblings without MS OCB trait showed (P=0.04) for CSF and (P=0.08) for serum. CONCLUSION: These findings suggest a measles-specific component in the antibody reactivity demonstrated by MS patients and their siblings with the MS OCB trait. PMID- 25022623 TI - The inquisitorial trial of a cross-dressing lesbian: reactions and responses to female homosexuality in 18th-century portugal. AB - This article analyzes the inquisitorial trial of Maria Duran, a Catalan novice in the Dominican convent of Nossa Senhora do Paraiso in Portugal. Maria Duran was arrested by the Inquisition in 1741 and, after a lengthy trial, condemned in 1744 to a public lashing and exile. She was suspected of having made a pact with the Devil and was accused by many female witnesses of possessing a "secret penis" that she had allegedly used in her amorous relations with fellow nuns and novices. Her voluminous trial dossier offers a rare and fascinating documentary insight into the often extreme reactions that female homosexuality provoked from both men and women in early modern Portugal. Using the evidence offered by the 18th-century trial of Maria Duran, this article highlights female bewilderment when faced with female-on-female sexual violence and the difficulty that men (in this case, churchmen) had coming to terms with the existence of female homosexuality. It also discusses the case in light of the acts/identity debate among historians of the history of sexuality. PMID- 25022624 TI - Primum non nocere. PMID- 25022626 TI - Keep it simple: easing the care burden of fibromyalgia. PMID- 25022627 TI - Do you have a secret researcher inside?: High-quality family medicine research at Family Medicine Forum. PMID- 25022630 TI - Practical research to improve outcomes. PMID- 25022631 TI - Contradicting the evidence for bisphosphonate therapy. PMID- 25022632 TI - Evolution of lipid management guidelines: evidence might set you free. AB - OBJECTIVE: To understand how the new guidelines for management of cardiovascular risk by the American Heart Association and the American College of Cardiology (AHA-ACC) can be interpreted and used in a Canadian setting. SOURCES OF INFORMATION: The AHA-ACC guidelines were reviewed, along with all references. Independent PubMed searches were done to include the addition of other lipid lowering therapy to statins and the use of medical calculators to enhance patient understanding. MAIN MESSAGE: The new AHA-ACC guidelines are based on the best current evidence related to lipid management. This includes use of 10-year cardiovascular disease (CVD) risk as the treatment threshold in place of low density lipoprotein cholesterol levels, as well as abandonment of low-density lipoprotein treatment targets. There is increased emphasis on dietary and exercise interventions, with the beginning of an effort to quantify the effect of these interventions. Statins are the main drug intervention, and the addition of other drugs to augment lipid lowering is no longer recommended. For application in Canada, Framingham risk tables are more appropriate for risk assessment than the pooled cohort equations used in the United States. Risk calculators for CVD risk should contain information on cardiovascular age and have the ability to represent risk and alternative interventions graphically in order to improve patient understanding and promote informed decision making. CONCLUSION: Focus on the best evidence in CVD risk can simplify lipid management for both the physician and the patient. PMID- 25022633 TI - Effect of domestic violence training: systematic review of randomized controlled trials. AB - OBJECTIVE: To describe and evaluate the effectiveness of domestic violence education in improving physicians' knowledge, recognition, and management of abused women. DATA SOURCES: The Cochrane Database of Systematic Reviews, MEDLINE, PubMed, PsycINFO, ERIC, and EMBASE were searched for articles published between January 1, 2000, and November 1, 2012. This search was supplemented by manual searches for relevant articles using a combined text-word and MeSH-heading search strategy. STUDY SELECTION: Randomized controlled trials were selected that used educational interventions among physicians and provided data on the effects of the interventions. SYNTHESIS: Nine randomized controlled trials were included that described different educational approaches with various outcome measures. Three studies examined the effects of educational interventions among postgraduate trainee physicians and found an increase in knowledge but no change in behaviour with regard to identifying victims of domestic violence. Six studies examined educational interventions for practising physicians. Three of these studies used multifaceted physician training that combined education with system support interventions to change physician behaviour, such as increasing general awareness of domestic violence with brochures and posters, providing aids to remind physicians how to identify victims, facilitating physician access to victim support services, and providing audits and feedback. Multifaceted educational interventions included interactive workshops, Web-based learning, and experiential training. Another study used focus-group discussions and training, and showed improved domestic violence reporting among physicians. The remaining 2 studies showed improved perceptions of practising physicians' self-efficacy using problem-based online learning. CONCLUSION: It was difficult to determine the most effective educational strategy, as the educational interventions and the outcome measures varied among the selected studies. Brief interventions for postgraduate trainee physicians improved knowledge but did not seem to affect behaviour. Online education using a problem-based learning format improved practising physicians' perceptions, knowledge, and skills in managing domestic violence. Physician training combined with system support interventions seemed to benefit domestic violence victims and increase referrals to domestic violence support resources. PMID- 25022634 TI - Optimizing pediatric clinical care and advocacy in an online era: report of the Canadian Paediatric Society Infectious Diseases and Immunization Committee. AB - OBJECTIVE: To help busy FPs find useful current information and keep up to date on pediatric infectious disease and immunization topics by highlighting the work of one excellent source of reliable information in this area, the Canadian Paediatric Society Infectious Diseases and Immunization Committee. COMPOSITION OF THE COMMITTEE: Committee members were appointed to represent the Canadian Paediatric Society, the College of Family Physicians of Canada, the Public Health Agency of Canada, the American Academy of Pediatrics, and the National Advisory Committee on Immunization. METHODS: This article highlights important pediatric practice points generated by the Canadian Paediatric Society Infectious Diseases and Immunization Committee at a typical meeting in January 2013 from the perspective of an FP liaison. It also describes the committee's work methods and its background thinking related to the most current and changing issues. REPORT: Learn specific online links to updated pediatric infectious disease topics from the detailed content of this report. Topics include caring for kids new to Canada, vaccine-hesitant parents, influenza, human papillomavirus, pertussis, sexually transmitted infections, multidrug-resistant bacteria, and advocacy, among others. CONCLUSION: Learn where to find this new and continuously changing information and how to stay evergreen in your knowledge. PMID- 25022635 TI - Safety of the newer class of opioid antagonists in pregnancy. AB - QUESTION: I have a patient recently confirmed to be 6 weeks pregnant. For the past 6 months she has been treated for an opioid addiction with buprenorphine naloxone combination. Should I be concerned about her exposure to this drug combination up to this point of the pregnancy? Should I switch her medication to methadone now that she is pregnant? ANSWER: The limited data on buprenorphine exposure during pregnancy show no increased risk of adverse outcomes in the newborn. There are limited data on naloxone exposure during pregnancy; however, oral use is not expected to be associated with an increased risk of adverse pregnancy outcomes. Physicians treating pregnant women or women who become pregnant while they are stable taking buprenorphine-naloxone treatment are advised to continue this treatment but to consider transition to buprenorphine monotherapy. PMID- 25022636 TI - A hot mess: a case of hyperemesis. PMID- 25022637 TI - Pericardial involvement as an initial presentation of anaplastic large cell lymphoma. PMID- 25022638 TI - Acetaminophen in pregnancy and future risk of ADHD in offspring. PMID- 25022639 TI - Effectiveness of omalizumab in severe persistent asthma under real-life conditions. PMID- 25022640 TI - Tobacco use disorder treatment in primary care: implementing a clinical system pathway in Alberta. AB - OBJECTIVE: To test a team-based, site-specific, multicomponent clinical system pathway designed for enhancing tobacco use disorder treatment by primary care physicians. DESIGN: A prospective cohort study. SETTING: Sixty primary care sites in Alberta. PARTICIPANTS: A convenience sample of 198 primary care physicians from the population of 2857. MAIN OUTCOME MEASURES: Data collection occurred between September 2010 and February 2012 on 3 distinct measures. Twenty-four weeks after the intervention, audits of the primary care practices assessed the adoption and sustainability of 10 tobacco clinical system pathway components, a survey measured changes in physicians' treatment intentions, and patient chart reviews examined changes in physicians' consistency with the treatment algorithm. RESULTS: The completion rate by physicians was 89.4%. An intention-to-treat approach was undertaken for statistical analysis. Intervention uptake was demonstrated by positive changes at 4 weeks in how many of the 10 clinical system measures were performed (mean [SD] = 4.22 [1.60] vs 8.57 [1.46]; P < .001). Physicians demonstrated significant favourable changes in 9 of the 12 measures of treatment intention (P < .05). The 18 282 chart reviews documented significant increases in 6 of the 8 algorithm components. CONCLUSION: Our findings suggest that the provision of a tobacco clinical system pathway that incorporates other members of the health care team and builds on existing office infrastructures will support positive and sustainable changes in tobacco use disorder treatment by physicians in primary care. This study reaffirms the substantive and important role of supporting how treatment is delivered in physicians' practices. PMID- 25022641 TI - The hero with a thousand faces visits the doctor. PMID- 25022642 TI - Jessica Hunter-Orange MD CCFP DipPDerm. PMID- 25022643 TI - Teaching clinical skills with patient resources. PMID- 25022644 TI - CPCSSN's role in improving pharmacovigilance. PMID- 25022646 TI - You are welcome here. PMID- 25022649 TI - Governance 3.0. PMID- 25022653 TI - Blood pressure targets in the very old: development of a tool in a geriatric day hospital. AB - PROBLEM ADDRESSED: Canadian hypertension guidelines do not address blood pressure (BP) targets in the very old (older than 85 years of age), making BP management in this group difficult. OBJECTIVE OF PROGRAM: To develop a BP target tool and implementation process in order to facilitate management of BP in the very old at the Bruyere Continuing Care Geriatric Day Hospital in Ottawa, Ont. PROGRAM DESCRIPTION: A BP target tool and implementation process were developed to target, monitor, and communicate BP goals within the care team, to the patient and family, and to other prescribers. An audit was conducted of the first 10 weeks of the tool's implementation and illustrated good use with areas for improvement noted. CONCLUSION: The development and use of a BP target tool increased prescriber consistency and confidence in managing BP in the very old. The tool filled a gap in the absence of guidelines specific to BP management in the very old. The BP target tool has implications for practice, as well as for the training of health care professionals involved in treating and monitoring BP in very old patients. PMID- 25022654 TI - Practising family medicine for adults with intellectual disabilities: patient perspectives on helpful interactions. AB - OBJECTIVE: To explore the perspectives of adults with intellectual disabilities (IDs) on helpful interactions with their family physicians. DESIGN: Exploratory, qualitative study. SETTING: Vancouver, BC. PARTICIPANTS: Purposive sample of 11 community-dwelling adults with IDs. METHODS: In-depth, semistructured interviews were conducted face to face with participants. Interviews were audiorecorded and transcribed verbatim. Research team members read the transcripts, which were then coded into categories and subcategories and discussed at collective analysis meetings. The main study themes were generated through this iterative, collective process. MAIN FINDINGS: Two themes about helpful interactions were identified: helping patients understand and helping patients navigate the health care system. The first theme reflected helpful ways of communicating with patients with IDs. These approaches focused on plain-language communication and other strategies developed jointly by the patients and their physicians. The second theme reflected ways in which the family physicians helped adults with IDs manage their health needs despite the complex constraints of their socioeconomic situations. CONCLUSION: Adults with IDs want to play an active role in managing their health as they age, and helpful interactions with family physicians make this possible. PMID- 25022655 TI - Delivering evidence-based smoking cessation treatment in primary care practice: experience of Ontario family health teams. AB - OBJECTIVE: To report on the delivery of evidence-based smoking cessation treatments (EBSCTs) within a sample of 40 Ontario family health teams (FHTs). DESIGN: In each FHT, consecutive patients were screened for smoking status and eligible patients completed a questionnaire immediately following their clinic visits (index visits). Multilevel analysis was used to examine FHT-level, provider-level, and patient-level predictors of EBSCT delivery. SETTING: Forty FHTs in Ontario. PARTICIPANTS: Across the 40 participating FHTs, 24,033 patients were screened and 2501 eligible patients contributed data. MAIN OUTCOME MEASURES: Provider performance in the delivery of EBSCTs during the preceding 12 months and during the index visits was assessed. RESULTS: The rate of provider delivery of EBSCT for the previous 12 months was 74.0% for the advise strategy. At the index visit, rates of EBSCT strategy delivery were 56.8% for ask; 46.9% for advise; 38.7% for assist; 11.6% for prescribing pharmacotherapy; and 11.3% for arrange follow-up. Significant intra-FHT and intraprovider variability in the rates of EBSCT delivery was identified. Family health teams with a physician champion (odds ratio [OR] 2.0; 95% CI 1.1 to 3.6; P < .01) and providers who highly ranked the importance of smoking cessation (OR 1.7; 95% CI 1.1 to 2.7; P < .01) were more likely to deliver EBSCTs. Patient readiness to quit (OR 1.6; 95% CI 1.3 to 1.9; P < .001), presence of smoking-related illness (OR 1.6; 95% CI 1.2 to 2.1; P < .01), and presenting for an annual health examination (OR 2.0; 95% CI 1.6 to 2.5; P < .001) were associated with the delivery of EBSCTs. CONCLUSION: Rates of smoking cessation advice were higher than previously reported for Canadian physicians; however, rates of assistance with quitting were lower. Future quality improvement initiatives should specifically target increasing the rates of screening and advising among low-performing FHTs and providers within FHTs, with a particular emphasis on doing so at all clinic appointments; and improving the rate at which assistance with quitting is delivered. PMID- 25022658 TI - Biosafety lapses prompt US CDC to shut labs and launch review. PMID- 25022659 TI - Biochemical hyperandrogenism is associated with metabolic syndrome independently of adiposity and insulin resistance in Romanian polycystic ovary syndrome patients. AB - The aim of the study was to determine whether Romanian polycystic ovary syndrome (PCOS) patients have an increased prevalence of metabolic syndrome (MetS) and to study the involvement of adiposity, insulin resistance and hyperandrogenism in the pathogenesis of MetS in PCOS. A total of 398 PCOS patients and 126 controls were evaluated between January 2006 and December 2012. MetS was defined by National Cholesterol Education Program, Adult Treatment Panel III criteria. Principal component analysis (PCA) was used to analyze the correlations among variables of interest by grouping them in few components, and principal component (PCs) scores were saved and used as independent variables in logistic regression. The prevalence of MetS was higher among patients with PCOS (20.4 %) than in controls (11.1 %, p < 0.05). In PCOS patients, PCA extracted three PCs from the analyzed variables. First PC aggregated variables related to adiposity and insulin resistance, with factor loadings showing strong relationship between these parameters. The second PC included markers of hyperandrogenemia and was best represented by free androgen index (FAI) which correlated strongly and exclusively with this PC. The third component was best represented by hirsutism. Logistic regression analysis revealed that in PCOS patients, the first and the second PCs were independently associated with MetS, whereas the third component was not. Romanian PCOS patients have an increased risk for MetS; adiposity, insulin resistance and hyperandrogenemia, but not hirsutism, are independent predictors of MetS presence. Our data also suggest that insulin resistance is only secondary to increased adiposity and FAI is a good marker of biochemical hyperandrogenism with little influences from the metabolic component. PMID- 25022660 TI - Atrial conduction times and left atrium mechanical functions in patients with active acromegaly. AB - The aim of this study was to evaluate atrial electromechanical delay (EMD), P wave dispersion (Pwd), and left atrial (LA) mechanical functions in patients with active acromegaly. Twenty-three patients with active acromegaly and 27 age- and sex-matched controls were included in this study. All atrial electromechanical interval parameters (PA lateral, PA septum, PA tricuspid, interatrial EMD, intra LA EMD, and intra-right atrial EMD) were measured from mitral lateral annulus, mitral septal annulus, and right ventricular tricuspid annulus by tissue Doppler imaging. LA volumes were measured by the disk method in the apical four-chamber view and were indexed to the body surface area. Mechanical function parameters of LA were calculated. Pwd was performed by 12-lead electrocardiograms. Atrial electromechanical intervals (PA lateral, PA septum, PA tricuspid, interatrial EMD, intra-LA EMD, and intra-right atrial EMD) and Pwd were similar between patients with acromegaly and control subjects (all p > 0.05). LA volumes (maximum, minimum, and presystolic) and LA mechanical functions were not significantly different between the groups (all p > 0.05). Additionally, serum levels of growth hormone and insulin-like growth factor-1 were not correlated with atrial electromechanical parameters and LA mechanical functions. Atrial electrical conduction times were not prolonged and LA mechanical functions were not impaired in patients with active acromegaly compared with controls. And the prevalence of supraventricular arrhythmia risk may not increase in this population. PMID- 25022661 TI - Ectopic cushing in a patient with medullary thyroid carcinoma: hypercortisolism control and tumor reduction with Sunitinib. PMID- 25022662 TI - Insecticidal properties and chemical composition of essential oils of some aromatic herbs from Morocco. AB - The essential oils (EOs) of Artemisia herba alba, Rutachalepensis and Satureja calamintha aerial parts were analysed by GC/MS and the EOs were tested for their toxicity against two flour beetles, Tribolium castaneum and Tribolium confusum. EO composition showed that the major compounds were pulegone, menthone and menthol for S. calamintha, camphor and beta-thujone for A. herba alba and 2 undecanone for R. chalepensis. Contact bioassay showed that all EOs were toxic to adults of T. castaneum and T. confusum. Higher toxicity was found with the EOs from S. calamintha and R. chalepensis (LD50 of 0.09-0.13 MUL/cm(2) and LD90 of 0.17-0.29 MUL/cm(2)). In fumigant toxicity test, A. herba alba and S. calamintha EOs produced insecticidal activity with S. calamintha EO being more toxic with LD50 and LD90 values of 10.5 and 19.1 MUL/L air, respectively, for T. confusum against 7.8 and 17.4 MUL/L air, respectively, for T. castaneum. PMID- 25022664 TI - Pyrosequencing analysis of bacterial community and assembly in activated sludge samples from different geographic regions in China. AB - In order to investigate if there are geographic differences of bacterial community in the activated sludge collected from different geographic regions (eastern, northwestern, and northern parts) of China and to determine the co occurrence patterns of bacterial community, activated sludge samples were collected from 10 municipal wastewater treatment plants located in 8 cities in China. High-throughput pyrosequencing combined with the bioinformatics analysis were used to examine the bacterial community compositions in the activated sludge samples. The result of taxonomy classifier indicated that a total of 76 genera were commonly shared by more than 7 samples, which accounted for 62 to 96 % of the classified sequences in each sample. Even though some core genera existed in all examined activated sludge samples regardless of the sampling geographic location and treatment process, significant geographic differences of bacterial community compositions among the activated sludge samples were revealed by the nonmetric multidimensional scaling (NMDS) and analyses of similarity (ANOSIM) analysis. A total of 165 pairs of significant and robust correlations (positive and negative) were identified from 61 bacterial genera based on the network analysis. The data obtained in this study could provide useful information to understand the bacterial community composition in geographically distributed wastewater treatment plants and discern the co-occurrence patterns of bacterial community. PMID- 25022663 TI - Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. AB - INTRODUCTION: It has been shown that progranulin (PGRN) deficiency causes age related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice. RESULTS: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b 245 heavy chain, complement C4, tumor necrosis factor-alpha and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice. CONCLUSIONS: The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated. PMID- 25022665 TI - Microbial production and applications of 5-aminolevulinic acid. AB - 5-Aminolevulinic acid (ALA), an important intermediate in tetrapyrrole biosynthesis in organisms, has been widely applied in many fields, such as medicine, agriculture, and the food industry, due to its biochemical characteristics. Research efforts supporting the microbial production of ALA have received increasing interest due to its dominant advantages over chemical synthesis, including higher yields, lesser pollutant emissions, and a lesser monetary cost. ALA synthesis using photosynthetic bacteria (PSB) is a promising approach in various microbial synthesis methods. In this review, recent advances on the microbial production of ALA with an emphasis on PSB are summarized, the key enzymes in the biosynthesis pathway (especially the relationship between key enzymes and key genes) are detailed, regulation strategies are described, and the significant influencing factors on the ALA biosynthesis and application of ALA are outlined. Furthermore, the eco-friendly perspective involving the combination of wastewater treatment and microbial production of ALA is conceived. PMID- 25022666 TI - SOCC 20th Anniversary 2014. PMID- 25022667 TI - Editorial. Previously published in Scandinavian Journal of Occupational Therapy 1994; 1: 5-6. PMID- 25022668 TI - Where are we going ... ? Previously published in Scandinavian Journal of Occupational Therapy 1996; 1:199. PMID- 25022669 TI - Editorial. Previously published in Scandinavian Journal of Occupational Therapy 2005; 12: 3. PMID- 25022671 TI - Editorial. Previously published in Scandinavian Journal of Occupational Therapy 2013; 20: 81. PMID- 25022670 TI - Editorial. Previously published in Scandinavian Journal of Occupational Therapy 2007; 14: 203-204. PMID- 25022672 TI - Response to letter to the editor: an evidence based algorithm for the management of marginal ulcers following Roux-en-Y gastric bypass. PMID- 25022673 TI - The effect of Medicaid status on weight loss, hospital length of stay, and 30-day readmission after laparoscopic Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Patients with Medicaid are much less likely to undergo bariatric surgery compared to those with commercial insurance. The aims of this study were to compare outcomes after laparoscopic Roux-en-Y gastric bypass (LRYGB) for patients covered by Medicaid, other (non-Medicaid) government insurance, and commercial insurance. METHODS: This was a retrospective cohort study of all eligible patients who underwent LRYGB between July 2004 and October 2011 at a single university hospital (n = 450). Multivariable regression analysis was used to compare percent weight loss (PWL), absolute weight loss (AWL), hospital length of stay (LOS) >=3 days, and 30-day readmission rates. Analyses were adjusted for appropriate covariates. RESULTS: There was a nonsignificant increase in PWL in Medicaid patients at 2 months (p = 0.08), 6 months (p = 0.09), and 12 months (p = 0.17) compared to commercial insurance patients. Similarly, there was a nonsignificant increase in AWL in Medicaid patients at 2 months (p = 0.054), 6 months (p = 0.08), and 12 months (p = 0.14) compared to commercial insurance patients. Medicaid patients had similar PWL and AWL compared to those with other government insurance (p >= 0.29 at all time points). Medicaid patients were more likely to have a hospital LOS >= 3 days (OR 2.03; 95 % confidence interval (CI) 1.09-3.77) and a hospital readmission within 30 days of discharge (odds ratio (OR) 2.84; 95 % CI 1.15-6.96) compared to commercial insurance patients. CONCLUSIONS: These data should be considered as states expand Medicaid and make decisions regarding treatment of severe obesity. Interventions to decrease hospital LOS and the 30-day readmission rate, particularly in Medicaid patients, should be explored. PMID- 25022674 TI - Effect of microbiological testing on subsequent mid-infrared milk component analysis of the same milk sample. AB - Our objectives were to determine if mixing and sampling of a raw milk sample at 4 degrees C for determination of total bacteria count (TBC) and if incubation at 14 degrees C for 18h and sampling for a preliminary incubation (PI) count influenced the accuracy of subsequent fat, protein, or lactose measurement by mid-infrared (IR) analysis of milk from the same sample container due to either nonrepresentative sampling or the presence of microbial metabolites produced by microbial growth in the milk from the incubation. Milks of 4 fat levels (2.2, 3, 4, and 5%) reflected the range of fat levels encountered in producer milks. If the portion of milk removed from a cold sample was not representative, then the effect on a milk component test would likely be larger as fat content increases. Within the milks at each fat level, 3 treatments were used: (1) 20 vials of the same milk sampled for testing TBC using a BactoScan FC and then used for a milk component test; (2) 20 vials for testing TBC plus PI count followed by component test; and (3) 20 vials to run for IR component test without a prior micro sampling and testing. This was repeated in 3 different weeks using a different batch of milk each week. No large effect on the accuracy of component milk testing [IR fat B (carbon hydrogen stretch) and fat A (carbonyl stretch)] due to the cold milk sample handling and mixing procedures used for TBC was detected, confirming the fact that the physical removal of milk from the vial by the BactoScan FC (Foss Electric, Hillerod, Denmark) was a representative portion of the milk. However, the representativeness of any other sampling procedure (manual or automated) of a cold milk sample before running milk component testing on the same container of milk should be demonstrated and verified periodically as a matter of routine laboratory quality assurance. Running TBC with a BactoScan FC first and then IR milk analysis after had a minimal effect on milk component tests by IR when milk bacteria counts were within pasteurized milk ordinance limits of <100,000 cfu/mL. Running raw milk PI counts (18h of incubation at 13-14 degrees C) with the BactoScan FC before milk component testing by IR milk analysis had an effect on component tests. The effect was largest on fat test results and would decrease the accuracy of milk payment testing on individual producer milks. The effect was most likely due to the absorption of light by bacterial metabolites resulting from microbial growth or other chemical degradation processes occurring in the milk during the PI count incubation, not by the sampling procedure of the BactoScan. The direction of the effect on component test results will vary depending on the bacteria count and the type of bacteria that grew in the milk, and this could be different in every individual producer milk sample. PMID- 25022675 TI - Interactions between acidified dispersions of milk proteins and dextran or dextran sulfate. AB - Polysaccharides are often used to stabilize cultured milk products, although the nature of these interactions is not entirely clear. The objective of this study was to investigate phase behavior of milk protein dispersions with added dextran (DX; molecular weight = 2 * 10(6) Da) or dextran sulfate (DS; molecular weight = 1.4 * 10(6) Da) as examples of uncharged and charged polysaccharides, respectively. Reconstituted skim milk (5-20% milk solids, wt/wt) was acidified to pH 4.4, 4.6, 4.8, or 4.9 at approximately 0 degrees C (to inhibit gelation) by addition of 3 N HCl. Dextran or DS was added to acidified milk samples to give concentrations of 0 to 2% (wt/wt) and 0 to 1% (wt/wt) polysaccharide, respectively. Milk samples were observed for possible phase separation after storage at 0 degrees C for 1 and 24h. Possible gelation of these systems was determined by using dynamic oscillatory rheology. The type of interactions between caseins and DX or DS was probed by determining the total carbohydrate analysis of supernatants from phase-separated samples. At 5.0 to 7.5% milk solids, phase separation of milk samples occurred after 24h even without DX or DS addition, due to destabilization of caseins in these acidic conditions, and a stabilizing effect was observed when 0.7 or 1.0% DS was added. At higher milk solids content, phase separation was not observed without DX or DS addition. Similar results were observed at all pH levels. Gelation occurred in samples containing high milk solids (>=10%) with the addition of 1.0 to 2.0% DX or 0.4 to 1.0% DS. Based on carbohydrate analysis of supernatants, we believe that DX interacted with milk proteins through a type of depletion flocculation mechanism, whereas DS appeared to interact via electrostatic-type interactions with milk proteins. This study helps to explain how uncharged and charged stabilizers influence the texture of cultured dairy products. PMID- 25022676 TI - Peroxisome proliferator-activated receptor gamma1 and gamma2 isoforms alter lipogenic gene networks in goat mammary epithelial cells to different extents. AB - In nonruminants, the alternative splicing of peroxisome proliferator-activated receptor gamma (PPARG) generates PPARG1 and PPARG2 isoforms. Although transcriptional control differences between isoforms have been reported in human adipose tissue, their roles in ruminant mammary cells are not well known. To assess which of these isoforms is more closely associated with the regulation of mammary lipogenic pathways, their tissue distribution was analyzed and the expression of key genes regulating lipogenic gene networks was measured after overexpression of the 2 isoforms in goat mammary epithelial cells (GMEC). The expression of PPARG2 was markedly greater in adipose tissue, whereas PPARG1 is the main isoform in goat mammary tissue (ratio of PPARG1:PPARG2 was close to 37:1). As was reported in previous work, PPARG1 upregulated the transcription regulators SREBF1 and PPARG and the lipogenic genes FASN, ACACA, and SCD. Along with a tendency for greater expression of AGPAT6, DGAT1, and PLIN2, these data suggest that PPARG1 is the isoform controlling lipogenesis in mammary cells. Addition of the PPARG ligand rosiglitazone (ROSI) to GMEC overexpressing both isoforms upregulated the expression of LPL and CD36, which help control uptake of long-chain fatty acids into mammary cells. Other responses to ROSI addition to GMEC overexpressing PPARG1 and PPARG2 included upregulation of AGPAT6, DGAT1, INSIG1, SREBF1, and NR1H3. Although the data suggest that both PPARG1 and PPARG2 could affect mammary lipogenesis via control of gene expression when stimulated (e.g., by ROSI), the fact that PPARG1 is more abundant in mammary tissue and that its overexpression alone upregulated key lipogenic gene networks suggest that it is the more important isoform in goat mammary cells. PMID- 25022677 TI - The effects of supplementation with a blend of cinnamaldehyde and eugenol on feed intake and milk production of dairy cows. AB - Plant extracts (PE) are naturally occurring chemicals in plants, and many of these molecules have been reported to influence production efficiency of dairy and beef animals. Two experiments were conducted to determine the effect of a PE additive (CE; an encapsulated blend of cinnamaldehyde and eugenol) on the milk production performance of lactating dairy cows across a range of doses. In experiment 1, 32 Holstein multi- and primiparous dairy cows in mid-lactation were assigned to no additive or supplementation with CE (350mg/d; n=16 cows/treatment) for 6 wk. In experiment 2, 48 Holstein multi- and primiparous dairy cows were assigned to no additive or supplementation with CE (200, 400, or 600mg/d; n=12 animals/treatment) for 8 wk. A 1-wk covariate period was included in both experiments. In both experiments, individual dry matter intake (DMI), milk production, milk composition, and somatic cell count were recorded daily. In experiment 1, CE was associated with an increase in DMI in both parity groups but an increase in milk production of multiparous cows only. In experiment 2, milk yield of multiparous cows was decreased at the 2 highest doses, whereas milk yield of primiparous cows was increased at the low and high doses of CE. These responses were accompanied by similar changes in DMI; therefore, CE did not affect feed efficiency. We observed no effect of CE on SCC or milk composition; however, treatment by parity interactions were detected for each of these variables that have not been described previously. Based on the results of these experiments, we conclude that a blend of cinnamaldehyde and eugenol can increase DMI and milk production in lactating dairy cows. In addition, environmental factors appear to influence the response to CE, including dose and parity, and these should be explored further. PMID- 25022678 TI - A single-step genomic model with direct estimation of marker effects. AB - Compared with the currently widely used multi-step genomic models for genomic evaluation, single-step genomic models can provide more accurate genomic evaluation by jointly analyzing phenotypes and genotypes of all animals and can properly correct for the effect of genomic preselection on genetic evaluations. The objectives of this study were to introduce a single-step genomic model, allowing a direct estimation of single nucleotide polymorphism (SNP) effects, and to develop efficient computing algorithms for solving equations of the single step SNP model. We proposed an alternative to the current single-step genomic model based on the genomic relationship matrix by including an additional step for estimating the effects of SNP markers. Our single-step SNP model allowed flexible modeling of SNP effects in terms of the number and variance of SNP markers. Moreover, our single-step SNP model included a residual polygenic effect with trait-specific variance for reducing inflation in genomic prediction. A kernel calculation of the SNP model involved repeated multiplications of the inverse of the pedigree relationship matrix of genotyped animals with a vector, for which numerical methods such as preconditioned conjugate gradients can be used. For estimating SNP effects, a special updating algorithm was proposed to separate residual polygenic effects from the SNP effects. We extended our single step SNP model to general multiple-trait cases. By taking advantage of a block diagonal (co)variance matrix of SNP effects, we showed how to estimate multivariate SNP effects in an efficient way. A general prediction formula was derived for candidates without phenotypes, which can be used for frequent, interim genomic evaluations without running the whole genomic evaluation process. We discussed various issues related to implementation of the single-step SNP model in Holstein populations with an across-country genomic reference population. PMID- 25022679 TI - The role of sodium in the salty taste of permeate. AB - Many food companies are trying to limit the amount of sodium in their products. Permeate, the liquid remaining after whey or milk is ultrafiltered, has been suggested as a salt substitute. The objective of this study was to determine the sensory and compositional properties of permeates and to determine if elements other than sodium contribute to the salty taste of permeate. Eighteen whey (n=14) and reduced-lactose (n=4) permeates were obtained in duplicate from commercial facilities. Proximate analyses, specific mineral content, and nonprotein nitrogen were determined. Organic acids and nucleotides were extracted followed by HPLC. Aromatic volatiles were evaluated by gas chromatography-mass spectrometry. Descriptive analysis of permeates and model solutions was conducted using a trained sensory panel. Whey permeates were characterized by cooked/milky and brothy flavors, sweet taste, and low salty taste. Permeates with lactose removed were distinctly salty. The organic acids with the highest concentration in permeates were lactic and citric acids. Volatiles included aldehydes, sulfur containing compounds, and diacetyl. Sensory tests with sodium chloride solutions confirmed that the salty taste of reduced-lactose permeates was not solely due to the sodium present. Permeate models were created with NaCl, KCl, lactic acid, citric acid, hippuric acid, uric acid, orotic acid, and urea; in addition to NaCl, KCl, lactic acid, and orotic acid were contributors to the salty taste. PMID- 25022680 TI - Short communication: alteration of priors for random effects in Gaussian linear mixed models. AB - Linear mixed models, for which the prior multivariate normal distributions of random effects are assumed to have a mean equal to 0, are commonly used in animal breeding. However, some statistical analyses (e.g., the consideration of a population under selection into a genomic scheme breeding, multiple-trait predictions of lactation yields, and Bayesian approaches integrating external information into genetic evaluations) need to alter both the mean and (co)variance of the prior distributions and, to our knowledge, most software packages available in the animal breeding community do not permit such alterations. Therefore, the aim of this study was to propose a method to alter both the mean and (co)variance of the prior multivariate normal distributions of random effects of linear mixed models while using currently available software packages. The proposed method was tested on simulated examples with 3 different software packages available in animal breeding. The examples showed the possibility of the proposed method to alter both the mean and (co)variance of the prior distributions with currently available software packages through the use of an extended data file and a user-supplied (co)variance matrix. PMID- 25022681 TI - Development and shelf-life determination of pasteurized, microfiltered, lactose hydrolyzed skim milk. AB - The segment of the world population showing permanent or temporary lactose intolerance is quite significant. Because milk is a widely consumed food with an high nutritional value, technological alternatives have been sought to overcome this dilemma. Microfiltration combined with pasteurization can not only extend the shelf life of milk but can also maintain the sensory, functional, and nutritional properties of the product. This studied developed a pasteurized, microfiltered, lactose hydrolyzed (delactosed) skim milk (PMLHSM). Hydrolysis was performed using beta-galactosidase at a concentration of 0.4mL/L and incubation for approximately 21h at 10+/-1 degrees C. During these procedures, the degree of hydrolysis obtained (>90%) was accompanied by evaluation of freezing point depression, and the remaining quantity of lactose was confirmed by HPLC. Milk was processed using a microfiltration pilot unit equipped with uniform transmembrane pressure (UTP) ceramic membranes with a mean pore size of 1.4 MUm and UTP of 60 kPa. The product was submitted to physicochemical, microbiological, and sensory evaluations, and its shelf life was estimated. Microfiltration reduced the aerobic mesophilic count by more than 4 log cycles. We were able to produce high quality PMLHSM with a shelf life of 21 to 27d when stored at 5+/-1 degrees C in terms of sensory analysis and proteolysis index and a shelf life of 50d in regard to total aerobic mesophile count and titratable acidity. PMID- 25022682 TI - Short communication: an in vitro assessment of the antibacterial activity of plant-derived oils. AB - Nonantibiotic treatments for mastitis are needed in organic dairy herds. Plant derived oils may be useful but efficacy and potential mechanisms of action of such oils in mastitis therapy have not been well documented. The objective of the current study was to evaluate the antibacterial activity of the plant-derived oil components of Phyto-Mast (Bovinity Health LLC, Narvon, PA), an herbal intramammary product, against 3 mastitis-causing pathogens: Staphylococcus aureus, Staphylococcus chromogenes, and Streptococcus uberis. Plant-derived oils evaluated were Thymus vulgaris (thyme), Gaultheria procumbens (wintergreen), Glycyrrhiza uralensis (Chinese licorice), Angelica sinensis, and Angelica dahurica. Broth dilution testing according to standard protocol was performed using ultrapasteurized whole milk instead of broth. Controls included milk only (negative control), milk + bacteria (positive control), and milk + bacteria + penicillin-streptomycin (antibiotic control, at 1 and 5% concentrations). Essential oil of thyme was tested by itself and not in combination with other oils because of its known antibacterial activity. The other plant-derived oils were tested alone and in combination for a total of 15 treatments, each replicated 3 times and tested at 0.5, 1, 2, and 4% to simulate concentrations potentially achievable in the milk within the pre-dry-off udder quarter. Thyme oil at concentrations >=2% completely inhibited bacterial growth in all replications. Other plant-derived oils tested alone or in various combinations were not consistently antibacterial and did not show typical dose-response effects. Only thyme essential oil had consistent antibacterial activity against the 3 mastitis-causing organisms tested in vitro. Further evaluation of physiological effects of thyme oil in various preparations on mammary tissue is recommended to determine potential suitability for mastitis therapy. PMID- 25022683 TI - Calcium release from milk concentrated by ultrafiltration and diafiltration. AB - The present work studied the solubilization of Ca during acidification in milk concentrated by ultrafiltration (UF) and diafiltration (DF). The effect of heating milk at 80 degrees C for 15min was also evaluated. In addition to measuring buffering capacity, the amount of Ca released as a function of pH was determined. The area of the maximum peak in buffering capacity observed at pH ~5.1, related to the presence of colloidal Ca phosphate, was significantly affected by casein volume fraction but did not increase proportionally with casein concentration. In addition, a lower buffering capacity and less solubilized Ca were measured in 2* DF milk compared with 2* UF milk. Heat treatment did not change the buffering capacity or Ca release in 1* and 2* concentrated milk. On the other hand, at a higher volume fraction (4*), more Ca was present in the soluble phase in heated 4* UF and DF milk compared with unheated milk. This is the first comprehensive study on the effect of concentration, distinguishing the effect of UF from that of DF, before and after heating, on Ca solubilization. PMID- 25022684 TI - Effects of thermally induced denaturation on technological-functional properties of whey protein isolate-based films. AB - This study examined how and to what extent the degree of denaturation affected the technological-functional properties of whey protein isolate (WPI)-based coatings. It was observed that denaturation affected the material properties of WPI-coated films significantly. Surface energy decreased by approximately 20% compared with native coatings. Because the surface energy of a coating should be lower than that of the substrate, this might result in enhanced wettability characteristics between WPI-based solution and substrate surface. Water vapor barrier properties increased by about 35% and oxygen barrier properties increased by approximately 33%. However, significant differences were mainly observed between coatings made of fully native WPI and ones with a degree of denaturation of 25%. Higher degrees of denaturation did not lead to further improvement of material properties. This observation offers cost-saving potential: a major share of denatured whey proteins may be replaced by fully native ones that are not exposed to energy-intensive heat treatment. Furthermore, native WPI solutions can be produced with higher dry matter content without gelatinizing. Hence, less moisture has to be removed through drying, resulting in reduced energy consumption. PMID- 25022685 TI - Effects of rumen-protected gamma-aminobutyric acid on performance and nutrient digestibility in heat-stressed dairy cows. AB - This experiment was conducted to investigate the effects of rumen-protected gamma aminobutyric acid (GABA) on performance and nutrient digestibility in heat stressed dairy cows. Sixty Holstein dairy cows (141+/-15 d in milk, 35.9+/-4.3kg of milk/d, and parity 2.0+/-1.1) were randomly assigned to 1 of 4 treatments according to a completely randomized block design. Treatments consisted of 0 (control), 40, 80, or 120mg of true GABA/kg of dry matter (DM). The trial lasted 10wk. The average temperature-humidity indices at 0700, 1400, and 2200h were 78.4, 80.2, and 78.7, respectively. Rectal temperatures decreased linearly at 0700, 1400, and 2200h with increasing GABA concentration. Supplementation of GABA had no effect on respiration rates at any time point. Dry matter intake, energy corrected milk, 4% fat-corrected milk, and milk fat yield tended to increase linearly with increasing GABA concentration. Supplementation of GABA affected, in a quadratic manner, milk protein and lactose concentrations, and milk protein yield, and the peak values were reached at a dose of 40mg of GABA/kg. Milk urea nitrogen concentration responded quadratically. Total solids content increased linearly with increasing GABA concentration. Supplementation of GABA had no effect on milk yield, lactose production, total solids, milk fat concentration, somatic cell score, or feed efficiency. Apparent total-tract digestibilities of DM, organic matter, crude protein, neutral detergent fiber, and acid detergent fiber were similar among treatments. These results indicate that rumen-protected GABA supplementation to dairy cows can alleviate heat stress by reducing rectal temperature, increase DM intake and milk production, and improve milk composition. The appropriate supplemental GABA level for heat-stressed dairy cows is 40mg/kg of DM. PMID- 25022686 TI - Short communication: antiviral activity of subcritical water extract of Brassica juncea against influenza virus A/H1N1 in nonfat milk. AB - Subcritical water extract (SWE) of Brassica juncea was studied for antiviral effects against influenza virus A/H1N1 and for the possibility of application as a nonfat milk supplement for use as an "antiviral food." At maximum nontoxic concentrations, SWE had higher antiviral activity against influenza virus A/H1N1 than n-hexane, ethanol, or hot water (80 degrees C) extracts. Addition of 0.5mg/mL of B. juncea SWE to culture medium led to 50.35% cell viability (% antiviral activity) for Madin-Darby canine kidney cells infected with influenza virus A/H1N1. Nonfat milk supplemented with 0.28mg/mL of B. juncea SWE showed 39.62% antiviral activity against influenza virus A/H1N1. Thus, the use of B. juncea SWE as a food supplement might aid in protection from influenza viral infection. PMID- 25022687 TI - Acute phase response elicited by experimental bovine diarrhea virus (BVDV) infection is associated with decreased vitamin D and E status of vitamin-replete preruminant calves. AB - Studies in young animals have shown an association between vitamin deficiencies and increased risk of infectious disease; however, there is a paucity of information regarding the effect of acute infection on the vitamin status of the vitamin-replete neonate. To characterize the effects of acute infection on vitamin D and E status of the neonate, 6 vitamin-replete preruminant Holstein bull calves were experimentally infected with bovine viral diarrhea virus (BVDV; strain BVDV2-1373). Six mock-inoculated calves served as controls. Sustained pyrexia, leukopenia, and asynchronous increases in serum haptoglobin and serum amyloid A characterized the response of calves to infection with BVDV. Infection was also associated with increased serum IFN-gamma, IL-2, and IL-6 concentrations. During the last 8 d of the 14-d postinoculation period, serum 25 hydroxyvitamin D and alpha-tocopherol concentrations in infected calves decreased by 51 and 82%, respectively. The observed inverse association between vitamin D and E status and serum amyloid A in infected calves suggests that the infection induced acute phase response contributed to the reduced vitamin status of these animals. Additional studies are necessary to determine if the negative effect of infection on status are unique to this specific infection model or is representative of preruminant calf's response to acute infection. Studies are also needed to characterize mechanisms underlying infection-related changes in vitamin D and E status and to determine whether additional vitamin D or E supplementation during an acute infection diminishes disease severity and duration in the young animal. PMID- 25022688 TI - Addition of gut active carbohydrates to colostrum replacer does not improve passive transfer of immunoglobulin G in Holstein dairy calves. AB - The primary objective of this study was to investigate the effects of supplementing a commercial colostrum replacer (CR) with gut active carbohydrates (GAC) on passive transfer of IgG in commercial dairy calves. A secondary objective was to evaluate the effect of treatment on preweaning health and growth. A total of 240 newborn Holstein dairy calves on a commercial dairy farm were enrolled in this study. Newborn heifer and bull calves were weighed and then randomly assigned to either the treated group [GAC: 30g of GAC mixed into 1.5 doses (150g of IgG) of commercial colostrum replacer; n=119] or the control group [CON: 1.5 doses (150g of IgG) of CR; n=121]. The assigned CR treatment was fed within 3.5h of birth using an esophageal tube feeder. Venous blood samples were collected at 0 and 24h of age and used to measure serum IgG (mg/mL) and serum total protein (g/dL) concentrations and to estimate the apparent efficiency of absorption of IgG (%). The 129 heifers calves enrolled (CON=60; GAC=69) were also followed until weaning to assess the effect of GAC addition on preweaning health and growth. Multivariable linear regression showed that the addition of GAC to CR did not influence passive transfer of IgG, as measured by apparent efficiency of absorption at 24h of age (CON=54.0 vs. GAC=54.3%), serum IgG (CON=20.3 vs. GAC=20.2mg/mL), and serum total protein (CON=5.69 vs. GAC=5.68g/dL). Although study sample sizes were not originally derived to evaluate health outcomes, treatment had no effect on weight gain or incidence of health events (diarrhea, pneumonia, mortality) for heifer calves between birth and 7 wk of age. PMID- 25022689 TI - Effects of reduced dietary protein and supplemental rumen-protected essential amino acids on the nitrogen efficiency of dairy cows. AB - When fed to meet the metabolizable protein requirements of the National Research Council, dairy cows consume an excess of N, resulting in approximately 75% of dietary N being lost to the environment as urine and feces. Reductions in environmental N release could be attained through an improvement in N efficiency. The objective of this study was to determine if the predicted reduction in milk yield associated with feeding a low-protein diet to lactating dairy cows could be avoided by dietary supplementation with 1 or more ruminally protected (RP) AA. Fourteen multiparous and 10 primiparous Holstein cows, and 24 multiparous Holstein * Jersey crossbred cows were used in a Youden square design consisting of 8 treatments and 3 periods. The 8 dietary treatments were (1) a standard diet containing 17% crude protein [CP; positive control (PC)], (2) a 15% CP diet [negative control (NC)], (3) NC plus RP Met (+M), (4) NC plus RP Lys (+K), (5) NC plus RP Leu (+L), (6) NC plus RP Met and Lys (+MK), (7) NC plus RP Met and Leu (+ML), and (8) NC plus RP Met, Lys, and Leu (+MKL). Dry matter intake was not affected by treatment. Crude protein intake was lower for NC and RP AA treatments compared with the PC treatment. No detrimental effect was detected of the low-CP diet alone or in combination with AA supplementation on milk and fat yield. However, milk protein yield decreased for NC and +MKL diets, and lactose yield decreased for the +MKL compared with the PC diet. Milk urea N concentrations were lower for all diets, suggesting that greater N efficiency was achieved by feeding the low-protein diet. Minimal effects of treatments on arterial plasma essential AA concentrations were detected, with only Ile and Val being significantly lower in the NC than in the PC diet. Phosphorylation ratios of signaling proteins known to regulate mRNA translation were not affected by treatments. This study highlights the limitations of requirement models aggregated at the protein level and the use of fixed postabsorptive efficiency to calculate milk protein requirements. Milk protein synthesis regulation by signaling pathways in vivo is still poorly understood. PMID- 25022690 TI - Effects of ingesting milk fermented by Lactococcus lactis H61 on skin health in young women: a randomized double-blind study. AB - We conducted a randomized double-blind trial to evaluate the effects of fermented milk produced using only Lactococcus lactis strain H61 as a starter bacterium (H61-fermented milk) on the general health and various skin properties of young women. Healthy female volunteers (n=23; age=19-21r) received H61-fermented milk (10(10) cfu of strain H61/d) or conventional yogurt (10(10) cfu of both Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus per day), as a reference food, daily for 4 wk. Before and at the end of 4 wk, blood samples were taken, and skin hydration (inner forearms and cheek) and melanin content, elasticity, and sebum content (cheek only) were measured. Skin hydration at the inner forearm was higher at wk 4 than at wk 0 in both groups. Sebum content in cheek rose significantly after intervention in the H61-fermented milk group, but not the conventional yogurt group. Other skin parameters did not differ in either group. Serum analysis showed that total protein concentration and platelet count were elevated and reactive oxygen species decreased in both groups after the intervention. Although H61-fermented milk and conventional yogurt had similar effects on skin status and some blood characteristics of participants, an increase of sebum content in cheek is preferable to H61 fermented milk. As skin lipids contribute to maintaining the skin barrier, H61 fermented milk would provide beneficial effects on skin for young women. PMID- 25022691 TI - Comparison of enriched palmitic acid and calcium salts of palm fatty acids distillate fat supplements on milk production and metabolic profiles of high producing dairy cows. AB - A variable response to fat supplementation has been reported in dairy cows, which may be due to cow production level, environmental conditions, or diet characteristics. In the present experiment, the effect of a high palmitic acid supplement was investigated relative to a conventional Ca salts of palm fatty acids (Ca-FA) supplement in 16 high-producing Holstein cows (46.6+/-12.4kg of milk/d) arranged in a crossover design with 14-d periods. The experiment was conducted in a non-heat-stress season with 29.5% neutral detergent fiber diets. Treatments were (1) high palmitic acid (PA) supplement fed as free FA [1.9% of dry matter (DM); 84.8% C16:0] and (2) Ca-FA supplement (2.3% of DM; 47.7% C16:0, 35.9% C18:1, and 8.4% C18:2). The PA supplement tended to increase DM intake, and increased the yields of milk and energy-corrected milk. Additionally, PA increased the yields of milk fat, protein, and lactose, whereas milk concentrations of these components were not affected. The yields of milk de novo and 16-C FA were increased by PA compared with Ca-FA (7 and 20%, respectively), whereas the yield of preformed FA was higher in Ca-FA. A reduction in milk fat concentration of de novo and 16-C FA and a marginal elevation in trans-10 C18:1 in Ca-FA is indicative of altered ruminal biohydrogenation and increased risk of milk fat depression. No effect of treatment on plasma insulin was observed. A treatment by time interaction was detected for plasma nonesterified fatty acids (NEFA), which tended to be higher in Ca-FA than in PA before feeding. Overall, the palmitic acid supplement improved production performance in high-producing cows while posing a lower risk for milk fat depression compared with a supplement higher in unsaturated FA. PMID- 25022692 TI - Genetic parameters across lactation for feed intake, fat- and protein-corrected milk, and liveweight in first-parity Holstein cattle. AB - Breeding values for dry matter intake (DMI) are important to optimize dairy cattle breeding goals for feed efficiency. However, generally, only small data sets are available for feed intake, due to the cost and difficulty of measuring DMI, which makes understanding the genetic associations between traits across lactation difficult, let alone the possibility for selection of breeding animals. However, estimating national breeding values through cheaper and more easily measured correlated traits, such as milk yield and liveweight (LW), could be a first step to predict DMI. Combining DMI data across historical nutritional experiments might help to expand the data sets. Therefore, the objective was to estimate genetic parameters for DMI, fat- and protein-corrected milk (FPCM) yield, and LW across the entire first lactation using a relatively large data set combining experimental data across the Netherlands. A total of 30,483 weekly records for DMI, 49,977 for FPCM yield, and 31,956 for LW were available from 2,283 Dutch Holstein-Friesian first-parity cows between 1990 and 2011. Heritabilities, covariance components, and genetic correlations were estimated using a multivariate random regression model. The model included an effect for year-season of calving, and polynomials for age of cow at calving and days in milk (DIM). The random effects were experimental treatment, year-month of measurement, and the additive genetic, permanent environmental, and residual term. Additive genetic and permanent environmental effects were modeled using a third-order orthogonal polynomial. Estimated heritabilities ranged from 0.21 to 0.40 for DMI, from 0.20 to 0.43 for FPCM yield, and from 0.25 to 0.48 for LW across DIM. Genetic correlations between DMI at different DIM were relatively low during early and late lactation, compared with mid lactation. The genetic correlations between DMI and FPCM yield varied across DIM. This correlation was negative (up to -0.5) between FPCM yield in early lactation and DMI across the entire lactation, but highly positive (above 0.8) when both traits were in mid lactation. The correlation between DMI and LW was 0.6 during early lactation, but decreased to 0.4 during mid lactation. The highest correlations between FPCM yield and LW (0.3-0.5) were estimated during mid lactation. However, the genetic correlations between DMI and either FPCM yield or LW were not symmetric across DIM, and differed depending on which trait was measured first. The results of our study are useful to understand the genetic relationship of DMI, FPCM yield, and LW on specific days across lactation. PMID- 25022693 TI - Are there any differences between age groups regarding colorectal surgery in elderly patients? AB - BACKGROUND: Surgical procedures with curative or palliative intentions in subjects aged over 70 represent a colorectal surgical challenge due to the issue they raise: Benefits versus increased morbidity. In this study, we proposed to compare the impact of surgery with the surgical intervention short-term results and analyze the factors that may influence these results in elderly age groups. METHODS: We retrospectively analyzed a database containing information about patients who underwent colorectal surgery from January 2008 to December 2013 at the Baskent University Istanbul Research Hospital and the Okmeydani Training and Research Hospital. RESULTS: A total of 265 patients were enrolled and analyzed in this retrospective study. Of these patients operated during the study period, 110 were between 60 and 69 years of age (group 1), 99 were between 70 and 79 years of age and 56 were older than 80 years of age. In total, there were 138 (52%) men and 127 (48%) women that underwent colorectal surgery. Intraoperative complications did not differ between group 1 and group 2, group 2 and group 3; however, some differences were observed between group 1 and group 3 (p = 0.001). Systemic complications were more frequent in group 3 than in groups 1 (p = 0.039) and 2 (p = 0.002). Furthermore, there were no significant systemic complication differences between groups 1 and 2. The mean length of postoperative hospital stay was 9.91 +/- 2.65 days in the first group, 9.38 +/- 2.44 days in the second group and 11.8 +/- 4.35 days in the third group. CONCLUSION: Colon surgery for both malignant and non-malignant diseases can be performed safely in different elderly age groups; thus, age should not be considered as an obstacle in elderly patients undergoing colorectal resection. PMID- 25022694 TI - Midfoot and forefoot osteoarthritis. AB - BACKGROUND: Foot osteoarthritis (OA) is linked with chronic foot pain and functional impairment. OBJECTIVE: To review the current knowledge on midfoot and forefoot OA. METHODS: PubMed, CINAHL, PEDro, and the ISI Web of Science databases (1950-2013) were searched for keywords: foot OA, midfoot OA, forefoot OA and metatarsal OA. The search was limited to reports in human subjects and English language. Published cohort, cross-sectional studies and clinical trials relating to epidemiology, clinical features, functional impairment, risk factors and treatment were included. RESULTS: We found heterogeneity in the design, radiographic views and grading systems used among studies. Most of the literature focused on radiographic OA, being the prevalence between 0.1% and 61%, depending on gender, age and joint evaluated. The age and female gender were the main associated factors, whereas structural (bone length) and mechanical factors (hypermobility, altered tarso-metatarsal stress, etc.) seemed to be related. Various treatments are widely used, i.e. physical therapy, orthotics, steroid injection, analgesics and arthrodesis. However, scarce research supports their efficacy. CONCLUSION: Most of the current knowledge comes from observational and small case-control studies. Future population-based studies as well as controlled studies are essential to understand the risk factors and to evaluate the effectiveness of treatment options. PMID- 25022695 TI - Reporting withdrawals due to adverse events in single-attack acute migraine clinical trials. PMID- 25022696 TI - Sleep apnea in patients with cluster headache: a case-control study. AB - OBJECTIVE: Polysomnographic investigations have shown an unspecific association between cluster headache and obstructive sleep apnea syndrome. The aim of this study was to investigate this association in a cluster episode compared with a symptom free interval, and to further characterize this association. METHODS: We investigated 42 patients with episodic (n = 26) or chronic (n = 16) cluster headache by means of polygraphic screening for sleep apnea and compared the data to 28 healthy control subjects matched according to age, sex, and BMI. The patients with episodic cluster headache were screened twice, once in a cluster episode and once in a symptom free interval. RESULTS: Patients with active cluster headache showed a significantly higher respiratory distress index (8.6 +/ 16.0) compared with healthy control subjects (3.4 +/- 2.1; p = 0.002). More patients fulfilled the criteria for an obstructive sleep apnea syndrome (29%) than control subjects (7%; p = 0.018). Patients only, but not the control subjects, had central apneas. These differences were only significant when measured during an active cluster episode but not during a symptom free interval. CONCLUSION: Cluster headache is associated with a sleep apnea syndrome only in the active cluster episode. The increased rate of central apneas might be a result of involvement of the hypothalamus in the pathophysiology of cluster headache. Out of five anecdotal cases treated with nasal continuous positive airway pressure, only one patient showed benefit with respect to cluster headache attack frequency. PMID- 25022697 TI - An autopsy case of subarachnoid hemorrhage due to ruptured cerebral aneurysm associated with polycystic kidney disease caused by a novel PKD1 mutation. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders and is characterized by the development and progressive enlargement of cysts in the kidneys. ADPKD is caused by mutations of either PKD1 or PKD2. The prevalence of brain aneurysm in patients with ADPKD is increased, and subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is one of the frequent complications. We describe an autopsy case of death of a 31-year-old woman by aneurysmal SAH. ADPKD as an underlining disease was suggested by the autopsy findings. Sequence analysis of the PKD1 and PKD2 genes revealed deletion of a guanine at position 8019 in PKD1 (8019delG) in a heterozygous state resulting in a shift in the reading frame and generation of a premature termination codon at amino acid 2684 (G2673fs12X). This mutation is novel and highly suspected as the causal mutation of ADPKD of this case. PMID- 25022698 TI - [International comparability of dysphagia examination use]. PMID- 25022699 TI - [Anesthesia and airway laser surgery]. PMID- 25022700 TI - Clinical outcomes after cataract surgery with implantation of the Tecnis ZMB00 multifocal intraocular lens. AB - BACKGROUND: The aim of this study was to evaluate visual performance, contrast sensitivity, and patient satisfaction in patients undergoing cataract surgery with bilateral implantation of the Tecnis ZMB00 diffractive multifocal IOL (intraocular lens). MATERIAL/METHODS: This was a prospective study of 40 eyes of 20 patients with an age range from 48 to 67 years and undergoing cataract surgery with implantation of the diffractive 1-piece IOL Tecnis ZMB00 (Abbott Medical Optics) in 1 eye and 3 weeks later in the other eye. The following parameters were evaluated at 3 and 6 months after the operation: binocular uncorrected distance, intermediate and near visual acuity (UDVA, UIVA, UNVA), uncorrected binocular photopic and mesopic distance and photopic near contrast sensitivity (CSV-1000), subjective symptoms, and patient satisfaction (VF-14). RESULTS: No significant change was observed in logMAR UDVA between 3 and 6 months postoperatively (-0.11+/-0.14 vs. -0.10+/-0.13, p>0.05). In contrast, UNVA (0.06+/-0.12 vs. -0.02+/-0.12, p=0.004) and UIVA (0.12+/-0.15 vs. 0.07+/-0.11, p=0.005) in this period improved significantly. At 3 and 6 months after surgery, 85% of patients no longer needed to wear corrective lenses. Contrast sensitivity under different conditions was within normal age-matched limits, with significant improvements for some spatial frequencies at 3 and 6 months after surgery (p<0.04). Mean overall patient satisfaction was 9.39+/-1.06 and 9.19+/-1.20 (scale from 1 to 10, with 10 being the best score) at 3 and 6 months, respectively. Low level of halo perception was reported in 75% of patients. CONCLUSIONS: The Tecnis ZMB00 IOL provides an effective restoration of the distance, intermediate, and near visual function, allowing patients to be totally free of need to wear corrective lenses and providing high levels of patient satisfaction. PMID- 25022702 TI - A 520 million-year-old chelicerate larva. AB - An important survival strategy for animal species is the so-called niche differentiation between larva and adult. Different developmental stages of the same animal occupy different ecological niches to avoid competing for food or other essential resources. Here, we describe an exceptionally preserved larval stage of the short great appendage (SGA) arthropod (megacheiran) Leanchoilia illecebrosa from the early Cambrian Chengjiang biota of China. The larval specimen preserves fine details of the main feeding limb, the SGA, which are unknown in the adult of the same species. This discovery demonstrates that niche differentiation during ontogeny was developed in this species of megacheiran--a group of fossil arthropods that has been considered to be early representatives of Chelicerata, which includes horseshoe crabs and arachnids. Hence, this type of niche differentiation, which is common today, originated from the early Cambrian. PMID- 25022703 TI - Predictors of incarceration among urban adults with co-occurring severe mental illness and a substance use disorder. AB - OBJECTIVE: People with severe mental illness and a co-occurring substance use disorder (co-occurring disorders) who live in urban areas experience high rates of incarceration. This study examined sociodemographic, clinical, economic, and community integration factors as predictors of incarceration among people with co occurring disorders. METHODS: This secondary analysis used data from a randomized controlled trial of assertive community treatment versus standard case management. In the parent study, researchers interviewed 198 people with co occurring disorders from two urban mental health centers in Connecticut at baseline and every six months for three years. Researchers tracked incarceration, clinical engagement and status, employment, living situation, social relationships, and substance use. The study reported here used bivariate analyses and logistic regression analyses to compare individuals who were incarcerated during the study period with those who were not. RESULTS: The overall incarceration rate was 38% during the study period. In multivariate analyses, prior incarceration predicted incarceration during the study period (odds ratio [OR]=3.26). Two factors were associated with a reduced likelihood of incarceration: friendships with individuals who did not use substances (OR=.19) and substance use treatment engagement (OR=.60). CONCLUSIONS: Positive social relationships and engagement in substance use treatment are promising service and policy targets to prevent incarceration in this high-risk population. PMID- 25022704 TI - Glycosaminoglycans can be associated with oxidative damage in mucopolysaccharidosis II patients submitted to enzyme replacement therapy. PMID- 25022705 TI - Combination treatment of low-fluence 1,064-nm Q-switched Nd: YAG laser with novel intense pulse light in Korean melasma patients: a prospective, randomized, controlled trial. AB - BACKGROUND: Recently, intense pulsed light (IPL) and low-fluence Q-switched neodymium-doped yttrium aluminum (LF-QS-Nd:YAG) laser have been successfully used to treat melasma. OBJECTIVE: To evaluate the effectiveness and safety of combined novel fractionated IPL (IPL-F) with LF-QS-Nd:YAG laser in patients with melasma. METHODS: Twelve patients underwent 6 treatment sessions of concomitant IPL-F and LF-QS-Nd:YAG laser (combination group), and 12 patients underwent 6 treatment session of IPL-F alone (IPL only group). Partial melasma area and severity index (MASI) scores were evaluated by 2 dermatologists using digital photography. RESULTS: In the combination group, the partial MASI score has significantly decreased by 47% at 1 month after the treatment (p < .05) and 50% at 2 months after the last treatment (p < .01). At 1 month and 2 months after the treatment, the decrease in the partial MASI score of the combination group was significantly larger than that of the IPL only group (p < .05). In both groups, treatment with IPL-F and LF-QS-Nd:YAG laser was well tolerated. CONCLUSION: Our results suggest that the combination of the IPL-F with LF-QS-Nd:YAG laser may be an effective and safe modality for melasma patients. PMID- 25022706 TI - Flexible blade fenestration of exposed auricular cartilage. PMID- 25022707 TI - Transarterial degradation of hyaluronic acid filler by hyaluronidase. AB - BACKGROUND: Hyaluronidase (HYAL) has been recommended in the emergency treatment of ischemia caused by accidental intra-arterial injection of hyaluronic acid (HA) dermal fillers. To date, there have been no published studies showing that HYAL can pass through intact arterial wall to hydrolyze HA emboli. OBJECTIVE: The goal of this study was to study whether or not HYAL could cross intact human facial arterial wall to hydrolyze HA filler. MATERIALS AND METHODS: Short tied-off segments of fresh human cadaver-sourced facial artery specimens, overfilled with a monophasic dermal filler (dermal filler "sausages"), were immersed in either HYAL or normal saline as controls. At 4 and 24 hours, the vessels were removed from the preparations, and one end of each vessel was cut open. RESULTS: Only the HYAL-immersed specimens showed degradation of filler gel. CONCLUSION: In conclusion, cross-linked HA is susceptible to hydrolysis by HYAL when contained within the intact facial artery in a cadaver model, indicating that direct intra arterial injection of HYAL is likely not necessary to help restore the circulation of ischemic tissues. This bench study provides support for the current recommended treatment of accidental intra-arterial injection with HYAL injection diffusely into ischemic tissues. PMID- 25022708 TI - Elongated dorsal nasal flap with superiorly based nasolabial flap for large nasal tip defects: 1-stage reconstruction. PMID- 25022709 TI - Opioid prescribing patterns after Mohs micrographic surgery and standard excision: a survey of American Society for Dermatologic Surgery members and a chart review at a single institution. AB - BACKGROUND: Little is known about postoperative opioid prescribing patterns among dermatologic surgeons. OBJECTIVE: To better understand postoperative opioid prescribing patterns among dermatologic surgeons in the United States. MATERIALS AND METHODS: Two-part analysis consisting of a retrospective chart review of 233 dermatologic surgery patients at a single institution and an e-mail survey of American Society for Dermatologic Surgery (ASDS) members. RESULTS: (1) Retrospective review: 35% (82/233) of the patients received an opioid prescription. Larger defect size, repair of the defect, perioral and nasal site, and surgeon A or B performing surgery predicted opioid prescription. (2) E-mail survey: 556 ASDS members practicing within the United States responded. Sixty four percent (357/556) reported prescribing opioids after <=10% of cases. Surgeons younger than 55 years old, male surgeons, and surgeons in the southern and western United States were more likely to prescribe opioids after >10% of cases. Seventy-six percent (397/520) believed patients used <=50% of the opioid pills prescribed. CONCLUSION: The retrospective review suggests that opioid prescribing is predicted by characteristics of the surgery (i.e., size, defect repair type, and anatomic location) and characteristics of the surgeon (i.e., age, sex, and practice location) with significant heterogeneity in prescribing habits. The national survey results raise the possibility that patients might not take all prescribed opioid pills after dermatologic surgery. Further investigation is warranted to determine how patients are actually using prescription pain pills to balance pain control with patient safety. PMID- 25022710 TI - Squamous cell carcinoma in a patient with dystrophic epidermolysis bullosa: a wound management strategy. PMID- 25022711 TI - Foam sclerotherapy for reticular veins of the dorsal hands: a retrospective review. AB - BACKGROUND: Despite being the gold standard for lower extremity reticular vein treatment, few studies have yet evaluated foam sclerotherapy for hand veins. OBJECTIVE: This retrospective study evaluates the safety and efficacy of foam sclerotherapy for reticular veins of the dorsal hands. METHODS: A telephone-based questionnaire was used for patient self-assessment of overall improvement, satisfaction, prevalence of adverse events, and willingness for repeat treatment after foam sclerotherapy with sodium tetradecyl sulfate (STS). All patients had been treated with foam STS of 0.25% to 1.0% concentration using room air. RESULTS: Twenty-one of 45 patients were successfully contacted, with a total of 54 treatment sessions performed on 38 hands. Overall, patients reported scores of 2.55 +/- 0.56 for overall improvement (0 = none, 1= mild, 2 = moderate, and 3 = complete resolution) and 1.79 +/- 0.41 for satisfaction with results (0 = not satisfied at all, 1 = mildly satisfied, and 2 = very satisfied), with few significant treatment-related adverse events. Most patients stated they would undergo another treatment if needed. CONCLUSION: This single-center experience found that foam sclerotherapy with STS is a safe and effective treatment for reticular veins of the dorsal hands with excellent long-term patient satisfaction. PMID- 25022712 TI - Early identification of cognitive impairment and dementia: Results from four years of the community consultation center. AB - The community consultation center was established as the core facility for a project entitled "Community Support Network for Citizens with Mild Cognitive Impairment (MCI) and Dementia." This study reports on our center's activity and user outcomes. Users consulted with medical staff regarding their memory problems and were self-screened using a touch-panel computer assisted screening tool (TPST). Dementia was suspected when the TPST score was 12 points or below, and the Mini-Mental State Examination (MMSE) was conducted by our onsite clinical psychologists, which served as the gold standard. All reports were provided to user's primary care physicians, or a nearby medical institute if users did not have a primary care physician. Patient outcomes were obtained from participating medical institutes. Informed consent was obtained for all users. In the four-year period, 2802 users visited the center. Of them, 1565 registered (men/women=519/1046; mean age, 74 years). Of 1354 people who used TPST, 622 (45.9%) scored 12 points or below. 409 confirmed diagnoses from the medical institutes revealed MCI in 11.2%, Alzheimer's disease in 37.1%, and vascular dementia in 8.0%. Among the 207 users who had no primary care physicians at consultation, 43 (20.8%) were diagnosed with MCI or dementia. Approximately half of the users who took the TPST were suspected of dementia following interview by a clinical psychologist. Both MCI and dementia were confirmed by the medical institutes in 59.6% of users. We conclude that our consultation center plays a pivotal role in early diagnosis of MCI and dementia. PMID- 25022713 TI - Application of screening tools to detect risk of hospital readmission in elderly patients in Valencian Healthcare System (VHS) (Spain). AB - The Sustainable Social and Healthcare Model (SSHM) is aimed to establish new care pathways in primary care systems contributing to the decrease of health services use and costs and improve the integration and efficiency of social and health care for elderly people with long-term care (LTC) needs. One of these strategies is the segmentation of population in risk groups through standardized tools. This paper is a retrospective study aimed to determine the viability of the implementation of the screening tools Probability of Repeated Admission - Pra - and The Community Assessment Risk Screen - CARS - to detect patients at risk of hospital readmission in a sample of 500 elderly people (65+) from the VHS in Spain. Patients were recruited from three Health Departments. Data from selected tools and predictive variables were collected through the healthcare database from the VHS. The most important results indicate that both instruments predict with high efficacy the proportion of patients not readmitted (negative predictive value between 91% and 92%). Moreover, the tools performed with a moderate efficiency being the Pra less sensitive (54%) and more specific (81%) than CARS (with a sensitivity and specificity of 64%). Results from this study suggest that the application of instruments as Pra and CARS are of interest to the Valencian Health Administration as they can be a good strategy to improve the management of elderly patients at risk with comorbidities and guiding clinical decision. PMID- 25022714 TI - Molecular dynamics simulations of polyamide membrane, calcium alginate gel, and their interactions in aqueous solution. AB - We perform molecular dynamics (MD) simulations to investigate the cross-linked polyamide (PA) membrane, the aggregation of alginate molecules in the presence of Ca(2+) ions, and their molecular binding mechanism in aqueous solution. We use a steered molecular dynamics (SMD) approach to simulate the unbinding process between a PA membrane and an alginate gel complex. Simulation results show that Ca(2+) ions are strongly associated with the carboxylate groups in alginate molecules, forming a web structure. The adhesion force between alginate gel and PA surface during unbinding originates from several important molecular interactions. These include the short-range hydrogen bonding and van der Waals attraction forces, and the ionic bridge binding that extends much longer pulling distances due to the significant chain deformations of alginate gel and PA membrane. PMID- 25022715 TI - Computer-assisted management of unconsumed drugs as a cost-containment strategy in oncology. AB - BACKGROUND: Cost-containment strategies are required to deal with rising drug expenditure, also in oncology. Drug wastage related to the preparation of chemotherapy drugs for patients is costly, but solutions exist for optimizing the use of unconsumed anticancer drugs. OBJECTIVE: Our pharmacy department makes use of a computerized drug storage bank, which records stability data and the amounts of unconsumed drugs available, and is connected to prescription software via an interface. We aimed to evaluate the real cost savings generated by this system. METHOD: We assessed the cost savings achieved with this system, for 37 different anticancer drugs, over a 1-year period. French drug pricing and the amounts of drugs from the storage bank potentially re-used were assessed. RESULTS: The re use of unconsumed anticancer drugs generated substantial cost savings, for nine drugs in particular: azacitidine, bevacizumab, bortezomib, cetuximab, docetaxel, liposomal doxorubicin, rituximab, topotecan and trastuzumab. Overall cost savings accounted for about 5 % of total anticancer drug expenditure at our hospital (8.5 M). CONCLUSION: In medical hematology-oncology, drug wastage reduction and a computerized physician order entry system could be applied in routine practice at centralized drug-processing units, with significant financial benefits. PMID- 25022717 TI - Mucociliary transport and histopathological changes in rotation flaps of the nasal mucosa. AB - Normal mucociliary transport in the mucoperichondrium of the nasal septum is from a distal (anterior) to proximal (posterior) direction. This study was to determine the direction of mucociliary transport and histopathological changes in nasal mucosal rotation flaps when their transport directions were anatomically reversed. Thirty-two rabbits were divided into four groups. Surgical septal rotational flaps were prepared in the experimental groups. Group I was the control group. The distal aspect of the flap was sutured through a large septal window to the other side of the nasal septum, thus changing the direction of the flap. Evaluation was performed 1 week, 1 month and 9 months later with each of these groups named as groups II, III, and IV, respectively. The rate and direction of the mucociliary transport was determined and histopathological investigations were performed from the flaps. The direction of mucociliary transport was observed to continue as distal to proximal direction in the rotated segments. The mucociliary transport rate was found to be decreased in group II, nearly normal in group III, and in normal limits in group IV after surgery. Intense inflammation and decreased number of cilia were present in group II. The inflammation was milder in group III and the epithelium was found to be nearly normal in group IV. The originally programmed direction of mucociliary transport in the nasal rotation flaps is maintained and is not altered or reprogrammed. Histopathological changes revert back to normal from an inflammatory state to reach pre-surgical status over time. PMID- 25022718 TI - Radiological findings of the cochlear aqueduct in patients with Meniere's disease using high-resolution CT and high-resolution MRI. AB - The objective of the present study was to evaluate the cochlear aqueduct (CA) in Meniere's disease (MD) and to disclose radiological differences of CA between MD and non-MD patients by means of high-resolution computed tomography (HRCT) and high-resolution magnetic resonance imaging (HRMRI). Radiological data of 86 ears of MD patients which were separated into 52 ears of diseased side group (MD-D group) and 34 ears of contralateral non-affected side group of unilateral MD (MD ND group), 27 ears of patients with sensorineural hearing loss (SNHL group) and 56 ears of patients with somatoform dizziness and normal hearing (control group) were analyzed retrospectively. The bony type of CA, the bony length of CA, and the bony width of CA medial orifice was measured in HRCT. The visibility of CA in HRMRI was scored. Fluid length in CA and fluid width in medial orifice were measured in HRMRI. Data were compared between MD-D, MD-ND, SNHL, and control group. There were no significant differences in the bony type of CA, bony length of CA, bony width of CA medial orifice, and fluid width of CA medial orifice between MD-D, MD-ND, SNHL and control group (p > 0.05). However, CA fluid length of MD-D (5.13 +/- 1.88 mm) and of MD-ND group (5.44 +/- 1.81 mm) was significantly shorter than fluid length of SNHL (6.90 +/- 1.55 mm) (p < 0.001, p = 0.001) and of control group (7.43 +/- 1.24 mm) (p < 0.001, p < 0.001). The ratio between CA fluid length and CA bony length was the smallest in MD-D group (0.403; p = 0.009). CA bony dimensions of affected ears of MD are normal, but CA fluid length is decreased. PMID- 25022716 TI - Impact of prophylactic central neck dissection on oncologic outcomes of papillary thyroid carcinoma: a review. AB - Prophylactic neck dissection (PND) for papillary thyroid carcinoma (PTC) is controversial. Our aim was to assess current levels of evidence (LE) according to the Oxford Centre for Evidence-based Medicine ( http://www.cebm.net/?O=1025 ) regarding the oncologic benefits of PND. Data were analyzed via MEDLINE keywords: PTC, differentiated thyroid carcinoma, PND, central lymph node metastases, central compartment, recurrence-free survival. There was conflicting evidence regarding the rate of reoperation for recurrence, with some studies showing a lower rate after PND with increased recurrence-free survival and a higher rate of undetectable pre- and post-ablation thyroglobulin levels (LE 4), whereas other studies did not show a difference (LE 4). Only one study (LE 4) showed improved disease-specific survival with PND. PND may improve recurrence-free survival, although this is supported by only a low LE. Current recommendations can only be based on low-level evidence. PMID- 25022719 TI - Efficacy and safety of pitavastatin versus simvastatin: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVES: Pitavastatin is the latest statin to be approved and has shown beneficial effects on plasma lipid profiles. The aim of the present meta-analysis was to assess both the efficacy and safety of pitavastatin versus simvastatin, one of the most commonly used statins. METHODS: A search of the MEDLINE, EMBASE, OVID and Cochrane Central Register of Controlled Trials (CENTRAL) databases was undertaken. Clinical trials evaluating the efficacy and safety of simvastatin versus pitavastatin, published up to February 2014, were identified. Trials were included if they (1) were randomized controlled trials (RCTs) of at least 12 weeks' duration; (2) included patients with primary hypercholesterolaemia or mixed dyslipidaemia; (3) studied outcomes included low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C); and (4) were published in the English language. A fixed-effects model was used for data analysis if no significant heterogeneity was present; otherwise a random-effects model was used. Efficacy is reflected by the mean difference in the percentage change of plasma lipid profiles. Treatment-emergent adverse events (TEAEs) are presented as risk ratio (RR). RESULTS: A total of 1,468 patients were included in the meta analysis. The results indicated similar efficacy of pitavastatin (versus simvastatin) in lowering LDL-C. Pitavastatin also had similar effects to simvastatin on other major aspects of plasma lipids, including TC, TG and HDL-C. Somewhat in contrast to common belief (based on distinct metabolism by P450 subtypes), the two statins did not differ in the incidence of TEAE. CONCLUSIONS: In clinical trials, pitavastatin was comparable to simvastatin in both efficacy and safety profile. Large-scale, high-quality observational studies are required to determine whether the advantage of pitavastatin in metabolism profiles could be translated into noticeable benefits. PMID- 25022720 TI - Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. AB - BACKGROUND AND OBJECTIVES: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clinical investigation in solid tumours. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics. METHODS: This Phase I, single-centre, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers. Three regimens were administered over three periods: Period (P) 1 (Days 1-8), P2 (Days 15-22) and P3 (Days 29-50), with a 14-day (first dose) and 28-day (second dose) washout period after lenvatinib mesylate administration (Day 1, Day 15 and Day 43). In P2, a single oral dose of rifampicin (600 mg) was coadministered with lenvatinib. In P3, rifampicin was administered daily (600 mg) for 21 days (Days 29-49). Serial blood samples were collected, and plasma concentrations of total (protein bound + unbound) and free (unbound) lenvatinib and total metabolites (M1, M2, M3 and M5) were measured by validated high performance liquid chromatography/tandem mass spectrometry. RESULTS: Single-dose rifampicin (P-gp inhibition) increased area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity) of free and total lenvatinib by 32 and 31 %, respectively. Multiple-dose rifampicin (simultaneous P-gp and CYP3A4 induction) decreased lenvatinib AUC0-infinity (total: 18 %; free: 9 %). Treatment emergent adverse events were mild or moderate and occurred in 7 subjects (47 %). CONCLUSION: Lenvatinib exposure was increased by P-gp inhibition; however, based on free concentrations, simultaneous P-gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval. Overall, the magnitude of these changes was relatively small, and likely not clinically meaningful. PMID- 25022721 TI - Evaluating options for balancing the water-electricity nexus in California: part 1--securing water availability. AB - The technical potential and effectiveness of different water supply options for securing water availability in a large-scale, interconnected water supply system under historical and climate-change augmented inflow and demand conditions were compared. Part 1 of the study focused on determining the scale of the options required to secure water availability and compared the effectiveness of different options. A spatially and temporally resolved model of California's major surface reservoirs was developed, and its sensitivity to urban water conservation, desalination, and water reuse was examined. Potential capacities of the different options were determined. Under historical (baseline) hydrology conditions, many individual options were found to be capable of securing water availability alone. Under climate change augment conditions, a portfolio approach was necessary. The water savings from many individual options other than desalination were insufficient in the latter, however, relying on seawater desalination alone requires extreme capacity installations which have energy, brine disposal, management, and cost implications. The importance of identifying and utilizing points of leverage in the system for choosing where to deploy different options is also demonstrated. PMID- 25022722 TI - Flow regulation effects on the hydrogeochemistry of the hyporheic zone in boreal rivers. AB - River-aquifer interfaces are essential for ecosystem functioning in terms of nutrient exchange and biological habitat, but are greatly threatened world-wide. This study examined geochemical aspects of river-aquifer interaction in one regulated and one unregulated boreal river in Northern Sweden to determine whether the geochemical functioning of the hyporheic zone is affected by hydrological alterations, e.g. regulated river discharge and river-aquifer connectivity. In the unregulated Kalix River, the hyporheic pore water was well oxygenated with orthogonal fluxes (~0.6-0.7 m d(-1)) and acted as a sink for Fe, Mn, Al, NH4, and Ca, with fractional losses of 95%, 92%, 45%, 31%, and 15%, respectively. A corresponding elevation in the concentrations of these elements in the hyporheic sediment was observed, with higher saturation indices of Fe-, Mn , and Al-bearing secondary minerals in hyporheic waters. In the regulated Lule River, hydraulic connectivity at the river-aquifer interface was altered by the presence of a clogging layer (0.04 m d(-1)). In addition, the river discharge oscillated daily, severely reducing exchange flows across the riverbed (<0.01 m d(-1)). As a result, the hyporheic pore water was suboxic, with elevated concentrations of filtered Fe and Mn (fractional increases of ~3700% and ~2500%, respectively) and other solutes (NH4, Si, S, Ca). A conceptual model revealed functional differences between geochemical features of the hyporheic zone of regulated and unregulated rivers. Overall, the results showed that hyporheic processes are altered along regulated rivers, with resulting impacts on the geochemistry of riverine, riparian and related marine ecosystems. PMID- 25022723 TI - A proposed approach may help systematic reviews retain needed expertise while minimizing bias from nonfinancial conflicts of interest. AB - OBJECTIVES: Groups such as the Institute of Medicine emphasize the importance of attention to financial conflicts of interest. Little guidance exists, however, on managing the risk of bias for systematic reviews from nonfinancial conflicts of interest. We sought to create practical guidance on ensuring adequate clinical or content expertise while maintaining independence of judgment on systematic review teams. STUDY DESIGN AND SETTING: Workgroup members built on existing guidance from international and domestic institutions on managing conflicts of interest. We then developed practical guidance in the form of an instrument for each potential source of conflict. RESULTS: We modified the Institute of Medicine's definition of conflict of interest to arrive at a definition specific to nonfinancial conflicts. We propose questions for funders and systematic review principal investigators to evaluate the risk of nonfinancial conflicts of interest. Once risks have been identified, options for managing conflicts include disclosure followed by no change in the systematic review team or activities, inclusion on the team along with other members with differing viewpoints to ensure diverse perspectives, exclusion from certain activities, and exclusion from the project entirely. CONCLUSION: The feasibility and utility of this approach to ensuring needed expertise on systematic reviews and minimizing bias from nonfinancial conflicts of interest must be investigated. PMID- 25022724 TI - Use of a computerized decision aid for developmental surveillance and screening: a randomized clinical trial. AB - IMPORTANCE: Developmental delays and disabilities are common in children. Research has indicated that intervention during the early years of a child's life has a positive effect on cognitive development, social skills and behavior, and subsequent school performance. OBJECTIVE: To determine whether a computerized clinical decision support system is an effective approach to improve standardized developmental surveillance and screening (DSS) within primary care practices. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial performed in 4 pediatric clinics from June 1, 2010, through December 31, 2012, children younger than 66 months seen for primary care were studied. INTERVENTIONS: We compared surveillance and screening practices after adding a DSS module to an existing computer decision support system. MAIN OUTCOMES AND MEASURES: The rates at which children were screened for developmental delay. RESULTS: Medical records were reviewed for 360 children (180 each in the intervention and control groups) to compare rates of developmental screening at the 9-, 18-, or 30-month well-child care visits. The DSS module led to a significant increase in the percentage of patients screened with a standardized screening tool (85.0% vs 24.4%, P < .001). An additional 120 records (60 each in the intervention and control groups) were reviewed to examine surveillance rates at visits outside the screening windows. The DSS module led to a significant increase in the percentage of patients whose parents were assessed for concerns about their child's development (71.7% vs 41.7%, P = .04). CONCLUSIONS AND RELEVANCE: Using a computerized clinical decision support system to automate the screening of children for developmental delay significantly increased the numbers of children screened at 9, 18, and 30 months of age. It also significantly improved surveillance at other visits. Moreover, it increased the number of children who ultimately were diagnosed as having developmental delay and who were referred for timely services at an earlier age. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01351077. PMID- 25022725 TI - Clinical characteristics of myocardial stunning in acute stroke. AB - Neurogenic stunned myocardium (NSM) after subarachnoid hemorrhage (SAH) is well known, but there is a paucity of data regarding its occurrence following acute stroke. The aim of this study is to investigate the clinical characteristics of NSM in acute non-hemorrhagic stroke. We performed an electronic literature search with Medline and Google Scholar for English-language articles using the terms "ischemic stroke" along with "stunned myocardium" or "Takotsubo cardiomyopathy". The search resulted in seven case reports/series, but no prospective studies. The mean age of patients with myocardial stunning following ischemic stroke was 72.5 years and 77% of these patients were females. Insular cortex was involved in 38.4% of cases. Mean National Institutes of Health Stroke Scale (NIHSS) score at admission was 12.6 and mean NIHSS at discharge was 10.8. T-wave inversions and ST segment elevations were noted in 84.6% and 69.2% of patients, respectively. Mean troponin elevation was 0.64 mcg/dL and mean left ventricular ejection fraction (LVEF) was 34.4%. In terms of outcomes, 84.6% of patients had significant improvement in LVEF, mostly within 4 weeks of onset of symptoms. To summarize, NSM was more common in females, with favorable prognosis. Less than half the patients with NSM following stroke had insular involvement. The mean troponin level in NSM after stroke was only half of that seen in SAH. While the lack of prospective studies on NSM in stroke patients precludes drawing further conclusions, more studies are warranted to investigate the risk factors for NSM and the effect on stroke outcomes. PMID- 25022726 TI - Birt-Hogg-Dube syndrome: a little known cause of pulmonary cysts. PMID- 25022727 TI - Diagnosis and standardized report for non-small cell lung cancer. AB - In the assessment of lung cancer, computed tomography guides the use of bronchoscopy and establishes whether local treatment may be appropriate for the NSCLC or whether it is at an advanced stage. Percutaneous biopsy of a lesion suspected to be a metastasis can provide histological confirmation, allowing staging to be carried out at the same time. The initial presentation depends on the staging and histological type, ranging from an isolated nodule or mass to atelectasis or obstructive pneumonia, isolated lymph node disease or isolated pleural effusion to miliary metastasis in tumors showing EGFR mutation. Tumor (T) status depends on tumor size, distance from the carina, and invasion of the chest wall and mediastinal organs. PET-CT is superior to CT in identifying lymph node invasion (N2 for ipsilateral mediastinal disease and N3 for contralateral or supraclavicular disease). As a general rule, all contraindications for surgery should be confirmed via histological examination, with the exception of cerebral metastases. PMID- 25022729 TI - The bobath concept in the treatment of cerebral palsy. AB - Dr. Bobath has defined cerebral palsy as "the result of a lesion or maldevelopment of the brain, nonprogressive in character and existing from earliest childhood. The motor deficit finds expression in abnormal patterns of posture and movement, in association with an abnormal postural tone. The lesion, which is present in the brain when it is still immature, interferes with the normal motor development of the child."(1) That is, he considers that the essential deficit is in the derangement of "the normal postural reflex mechanism", and he regards this "postural reflex mechanism" as comprising the integrated activity of automatic reactions, which are said to include equilibrium, righting and other protective reactions. These develop in sequence in the child and are related to normal tone. This postural reflex mechanism enables us to perform antigravity function and gives us postural fixation to enable us to perform skilled activities. PMID- 25022728 TI - Enzymatic hydrolysis of hardwood and softwood harvest residue fibers released by sulfur dioxide-ethanol-water fractionation. AB - The enzymatic hydrolysis of hardwood and softwood harvest residues treated by SO2 ethanol-water (SEW) fractionation was studied. The target was to convert these fibers with high yield into glucose monomers which could be further converted into biofuel by a subsequent fermentation stage. Hardwood biomass residues were efficiently digested at low enzyme dosage (5 FPU/g cellulose) whereas the softwood residues required notably higher enzyme dosage (20 FPU) for sufficient conversion. However, cellulase dosage of softwood could be reduced mannanase supplementation. Especially the high lignin content of softwood biomass pulps impairs the digestibility and thereby, improved delignification could notably enhance the hydrolysis yields. It was shown that inferior delignification of SW biomass is due to persistent polyphenolic acids present in coniferous bark, whereas no evidence of the negative effect of inorganics and acetone extractives was observed. Additionally, SW hydrolyzate was successfully converted into a mixture of butanol, acetone and ethanol through ABE fermentation. PMID- 25022730 TI - The activation or de-activation of receptors for the purpose of developing somatic, autonomic, and mental functions: introduction. Part I - philosophy. AB - At the present time there appears to be a growing interest in the work of Miss Rood - Professor and Chairman, Physical Therapy Department, University of Southern California, U.S.A. Her approach deals with the activation or de activation of receptors for the purpose of developing somatic, autonomic, and mental functions. The work is based upon what is presently known or believed in the field of physiology, and upon a re-evaluation of normal human ontogenesis. PMID- 25022731 TI - A preliminary report on the comparative value of bisgaard & quinaband-diachylon methods of treatment of venous ulceration. AB - In 1966, the Ulcer Clinic at The Queen Elizabeth Hospital, Woodville, South Australia, introduced the application of Quinaband and Diachylon bandages as a treatment for venous ulceration. Clinically, it appeared that the rate of healing using this method was as good, if not better, than that obtained with the Bisgaard method which was in use in the Department of Physical Medicine. PMID- 25022732 TI - Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy. AB - BACKGROUND: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children. METHODS: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population. RESULTS: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors. CONCLUSIONS: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials. PMID- 25022733 TI - The necessity for ocular assessment in atopic children: bilateral corneal hydrops in an 8 year old. AB - Acute corneal hydrops is a rare complication of advanced corneal ectasia. This case report describes the clinical course of a child with severe atopy and no previous ocular examination who developed bilateral, acute corneal hydrops, secondary to keratoconus, by 8 years of age. The report demonstrates the rapidity of progression in the pediatric phenotype of the disease. This case also provides an important clinical lesson in highlighting the necessity for children with atopy to be referred for comprehensive ophthalmic examination, even in the apparent absence of visual symptoms, to ensure the timely diagnosis and management of any atopy-associated ocular disease. Prompt referral is particularly essential for pediatric corneal ectasia, in which the rapidity of progression may preclude stabilizing treatments, such as corneal collagen cross linking, and result in significant childhood visual impairment, as was the case for this child. This case demonstrates the potential for significant ocular involvement in atopic children and identifies scope to enhance current international clinical guidelines relating to the management of childhood atopy through the inclusion of ocular screening for associated disease. PMID- 25022734 TI - Atopic dermatitis, melatonin, and sleep disturbance. AB - BACKGROUND AND OBJECTIVES: Sleep disturbance is common in patients with atopic dermatitis (AD). However, studies have largely been questionnaire-based, and the pathophysiology remains unclear. The aims of this study were to determine objective characteristics of sleep disturbance in children with AD and explore contributing factors and clinical predictors. METHODS: Sleep parameters were measured by actigraphy and polysomnography in 72 patients with AD and 32 controls ages 1 to 18 years. Urinary 6-sulfatoxymelatonin levels, serum cytokines, and total and allergen-specific immunoglobulin E (IgE) levels were also measured. RESULTS: The patients with AD had significantly reduced sleep efficiency, longer sleep onset latency, more sleep fragmentation, and less nonrapid eye movement sleep. Results from actigraphy correlated well with those from polysomnography. The AD disease severity was associated with sleep disturbance (r = 0.55-0.7), and a Scoring Atopic Dermatitis index of >=48.7 predicted poor sleep efficiency with a sensitivity of 83.3% and a specificity of 75% (area under the curve = 0.81, P = .001). Lower nocturnal melatonin secretion was significantly associated with sleep disturbance in the patients with AD. Other correlates of sleep disturbance included pruritus, scratching movements, higher total serum IgE levels, and allergic sensitization to dust mite and staphylococcal enterotoxins. CONCLUSIONS: Poor sleep efficiency is common in children with AD and can be predicted by the Scoring Atopic Dermatitis index. Melatonin and IgE might play a role in the sleep disturbance. Further studies are required to explore the mechanisms and clinical implications, and actigraphy could serve as a useful evaluating tool. PMID- 25022735 TI - Sleep environment risks for younger and older infants. AB - OBJECTIVE: Sudden infant death syndrome and other sleep-related causes of infant mortality have several known risk factors. Less is known about the association of those risk factors at different times during infancy. Our objective was to determine any associations between risk factors for sleep-related deaths at different ages. METHODS: A cross-sectional study of sleep-related infant deaths from 24 states during 2004-2012 contained in the National Center for the Review and Prevention of Child Deaths Case Reporting System, a database of death reports from state child death review teams. The main exposure was age, divided into younger (0-3 months) and older (4 months to 364 days) infants. The primary outcomes were bed-sharing, objects in the sleep environment, location (eg, adult bed), and position (eg, prone). RESULTS: A total of 8207 deaths were analyzed. Younger victims were more likely bed-sharing (73.8% vs. 58.9%, P < .001) and sleeping in an adult bed/on a person (51.6% vs. 43.8%, P < .001). A higher percentage of older victims had an object in the sleep environment (39.4% vs. 33.5%, P < .001) and changed position from side/back to prone (18.4% vs. 13.8%, P < .001). Multivariable regression confirmed these associations. CONCLUSIONS: Risk factors for sleep-related infant deaths may be different for different age groups. The predominant risk factor for younger infants is bed-sharing, whereas rolling into objects in the sleep area is the predominant risk factor for older infants. Parents should be warned about the dangers of these specific risk factors appropriate to their infant's age. PMID- 25022736 TI - Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. AB - OBJECTIVE: To describe the use of inhaled nitric oxide (INO) in newborns with congenital diaphragmatic hernia (CDH). METHODS: Pediatric Health Information System data were queried for newborns with CDH admitted at <8 days of age at tertiary care US pediatric hospitals between 2003 and 2011. INO treatment status and timing in relation to CDH repair were determined for each infant. Hospital specific rates of INO use, extracorporeal membrane oxygenation (ECMO) use, and mortality were determined. RESULTS: Data were analyzed for 1713 neonates with CDH admitted to 33 hospitals. More than half (57%) received INO during their inpatient stay, and utilization varied dramatically between hospitals (34% to 92%). Neonates treated with INO accumulated >$81 million in pharmacy charges. The proportion of infants receiving INO as well as their duration of therapy increased significantly during the study period. The rate of ECMO utilization and mortality did not change significantly during the study period. Hospital-specific mortality rates did not correlate with INO therapy, ECMO utilization, or case volume. CONCLUSIONS: INO use in neonates with CDH is widespread, and has increased at many US tertiary pediatric hospitals without contemporaneous change in ECMO utilization or mortality. The improvement of evidence-based guidelines for the use of INO in newborns with CDH could lead to a reduction in health care costs for these patients. PMID- 25022737 TI - Interventions to reduce pediatric medication errors: a systematic review. AB - BACKGROUND AND OBJECTIVE: Medication errors cause appreciable morbidity and mortality in children. The objective was to determine the effectiveness of interventions to reduce pediatric medication errors, identify gaps in the literature, and perform meta-analyses on comparable studies. METHODS: Relevant studies were identified from searches of PubMed, Embase, Scopus, Web of Science, the Cochrane Library, and the Cumulative Index to Nursing Allied Health Literature and previous systematic reviews. Inclusion criteria were peer-reviewed original data in any language testing an intervention to reduce medication errors in children. Abstract and full-text article review were conducted by 2 independent authors with sequential data extraction. RESULTS: A total of 274 full text articles were reviewed and 63 were included. Only 1% of studies were conducted at community hospitals, 11% were conducted in ambulatory populations, 10% reported preventable adverse drug events, 10% examined administering errors, 3% examined dispensing errors, and none reported cost-effectiveness data, suggesting persistent research gaps. Variation existed in the methods, definitions, outcomes, and rate denominators for all studies; and many showed an appreciable risk of bias. Although 26 studies (41%) involved computerized provider order entry, a meta-analysis was not performed because of methodologic heterogeneity. Studies of computerized provider order entry with clinical decision support compared with studies without clinical decision support reported a 36% to 87% reduction in prescribing errors; studies of preprinted order sheets revealed a 27% to 82% reduction in prescribing errors. CONCLUSIONS: Pediatric medication errors can be reduced, although our understanding of optimal interventions remains hampered. Research should focus on understudied areas, use standardized definitions and outcomes, and evaluate cost-effectiveness. PMID- 25022738 TI - Neonatal outcome following cord clamping after onset of spontaneous respiration. AB - BACKGROUND AND OBJECTIVE: Evolving data indicate that cord clamping (CC) beyond 30 to 60 seconds after birth is of benefit for all infants. Recent experimental data demonstrated that ventilation before CC improved cardiovascular stability by increasing pulmonary blood flow. The objective was to describe the relationship between time to CC, onset of spontaneous respirations (SR), and 24-hour neonatal outcome. METHODS: In a rural Tanzanian hospital, trained research assistants, working in shifts, have observed every delivery (November 2009-February 2013) and recorded data including time interval from birth to SR and CC, fetal heart rate, perinatal characteristics and outcome (normal, death, admission). RESULTS: Of 15,563 infants born, 12,780 (84.3%) initiated SR at 10.8 +/- 16.7 seconds, and CC occurred at 63 +/- 45 seconds after birth. Outcomes included 12,730 (99.7%) normal, 31 deaths, and 19 admitted; 11,967 were of birth weight (BW) >=2500 g and 813 <2500 g. By logistic modeling, the risk of death/admission was consistently higher if CC occurred before SR. Infants of BW <2500 g were more likely to die or be admitted. The risk of death/admission decreased by 20% for every 10-second delay in CC after SR; this risk declined at the same rate in both BW groups. CONCLUSIONS: Healthy self-breathing neonates are more likely to die or be admitted if CC occurs before or immediately after onset of SR. These clinical observations support the experimental findings of a smoother cardiovascular transition when CC is performed after initiation of ventilation. PMID- 25022739 TI - Pediatric drug formulations: a review of challenges and progress. AB - Children differ from adults in many aspects of pharmacotherapy, including capabilities for drug administration, medicine-related toxicity, and taste preferences. It is essential that pediatric medicines are formulated to best suit a child's age, size, physiologic condition, and treatment requirements. To ensure adequate treatment of all children, different routes of administration, dosage forms, and strengths may be required. Many existing formulations are not suitable for children, which often leads to off-label and unlicensed use of adult medicines. New regulations, additional funding opportunities, and innovative collaborative research initiatives have resulted in some recent progress in the development of pediatric formulations. These advances include a paradigm shift toward oral solid formulations and a focus on novel preparations, including flexible, dispersible, and multiparticulate oral solid dosage forms. Such developments have enabled greater dose flexibility, easier administration, and better acceptance of drug formulations in children. However, new pediatric formulations address only a small part of all therapeutic needs in children; moreover, they are not always available. Five key issues need to be addressed to stimulate the further development of better medicines for children: (1) the continued prioritization of unmet formulation needs, particularly drug delivery in neonates and treatment gaps in pediatric cancers and childhood diseases in developing countries; (2) a better use of existing data to facilitate pediatric formulation development; (3) innovative technologies in adults that can be used to develop new pediatric formulations; (4) clinical feedback and practice-based evidence on the impact of novel formulations; and (5) improved access to new pediatric formulations. PMID- 25022740 TI - Obstructive sleep apnea and sickle cell anemia. AB - OBJECTIVE: To ascertain the prevalence of and risk factors for obstructive sleep apnea syndrome (OSAS) in children with sickle cell anemia (SCA). METHODS: Cross sectional baseline data were analyzed from the Sleep and Asthma Cohort Study, a multicenter prospective study designed to evaluate the contribution of sleep and breathing abnormalities to SCA-related morbidity in children ages 4 to 18 years, unselected for OSAS symptoms or asthma. Multivariable logistic regression assessed the relationships between OSAS status on the basis of overnight in laboratory polysomnography and putative risk factors obtained from questionnaires and direct measurements. RESULTS: Participants included 243 children with a median age of 10 years; 50% were boys, 99% were of African heritage, and 95% were homozygous for beta(S) hemoglobin. OSAS, defined by obstructive apnea hypopnea indices, was present in 100 (41%) or 25 (10%) children at cutpoints of >=1 or >=5, respectively. In univariate analyses, OSAS was associated with higher levels of habitual snoring, lower waking pulse oxygen saturation (Spo2), reduced lung function, less caretaker education, and non-preterm birth. Lower sleep-related Spo2 metrics were also associated with higher obstructive apnea hypopnea indices. In multivariable analyses, habitual snoring and lower waking Spo2 remained risk factors for OSAS in children with SCA. CONCLUSIONS: The prevalence of OSAS in children with SCA is higher than in the general pediatric population. Habitual snoring and lower waking Spo2 values, data easily obtained in routine care, were the strongest OSAS risk factors. Because OSAS is a treatable condition with adverse health outcomes, greater efforts are needed to screen, diagnose, and treat OSAS in this high-risk, vulnerable population. PMID- 25022741 TI - iPad--increasing nickel exposure in children. AB - We discuss allergic contact dermatitis to the iPad to highlight a potential source of nickel exposure in children. PMID- 25022742 TI - Unit of measurement used and parent medication dosing errors. AB - BACKGROUND AND OBJECTIVES: Adopting the milliliter as the preferred unit of measurement has been suggested as a strategy to improve the clarity of medication instructions; teaspoon and tablespoon units may inadvertently endorse nonstandard kitchen spoon use. We examined the association between unit used and parent medication errors and whether nonstandard instruments mediate this relationship. METHODS: Cross-sectional analysis of baseline data from a larger study of provider communication and medication errors. English- or Spanish-speaking parents (n = 287) whose children were prescribed liquid medications in 2 emergency departments were enrolled. Medication error defined as: error in knowledge of prescribed dose, error in observed dose measurement (compared to intended or prescribed dose); >20% deviation threshold for error. Multiple logistic regression performed adjusting for parent age, language, country, race/ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease; site. RESULTS: Medication errors were common: 39.4% of parents made an error in measurement of the intended dose, 41.1% made an error in the prescribed dose. Furthermore, 16.7% used a nonstandard instrument. Compared with parents who used milliliter-only, parents who used teaspoon or tablespoon units had twice the odds of making an error with the intended (42.5% vs 27.6%, P = .02; adjusted odds ratio=2.3; 95% confidence interval, 1.2-4.4) and prescribed (45.1% vs 31.4%, P = .04; adjusted odds ratio=1.9; 95% confidence interval, 1.03-3.5) dose; associations greater for parents with low health literacy and non-English speakers. Nonstandard instrument use partially mediated teaspoon and tablespoon-associated measurement errors. CONCLUSIONS: Findings support a milliliter-only standard to reduce medication errors. PMID- 25022743 TI - Weighted blankets and sleep in autistic children--a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of a weighted-blanket intervention in treating severe sleep problems in children with autism spectrum disorder (ASD). METHODS: This phase III trial was a randomized, placebo-controlled crossover design. Participants were aged between 5 years and 16 years 10 months, with a confirmed ASD diagnosis and severe sleep problems, refractory to community-based interventions. The interventions were either a commercially available weighted blanket or otherwise identical usual weight blanket (control), introduced at bedtime; each was used for a 2-week period before crossover to the other blanket. Primary outcome was total sleep time (TST) recorded by actigraphy over each 2 week period. Secondary outcomes included actigraphically recorded sleep-onset latency, sleep efficiency, assessments of child behavior, family functioning, and adverse events. Sleep was also measured by using parent-report diaries. RESULTS: Seventy-three children were randomized and analysis conducted on 67 children who completed the study. Using objective measures, the weighted blanket, compared with the control blanket, did not increase TST as measured by actigraphy and adjusted for baseline TST. There were no group differences in any other objective or subjective measure of sleep, including behavioral outcomes. On subjective preference measures, parents and children favored the weighted blanket. CONCLUSIONS: The use of a weighted blanket did not help children with ASD sleep for a longer period of time, fall asleep significantly faster, or wake less often. However, the weighted blanket was favored by children and parents, and blankets were well tolerated over this period. PMID- 25022744 TI - The timing of cord clamping and oxidative stress in term newborns. AB - BACKGROUND: Clamping and cutting of the umbilical cord is the most prevalent of all operations, but the optimal timing of cord clamping is controversial, with different timings offering advantages and disadvantages. This study, for the first time, compares the influence of early and late cord clamping in correlation with oxidative stress and inflammation signaling, Because cord clamping timing may have a significant influence on placenta-to-infant blood transfer, thereby modifying oxygenation of maternal and fetal tissues, and on the transfer of inflammatory mediators throughout the placenta. METHODS: Sixty-four pregnant subjects were selected at the Gynecology and Obstetrics Services Department of the Clinico San Cecilio Hospital, Granada, Spain, based on disease-free women who experienced a normal course of pregnancy and a spontaneous, vaginal, single delivery. Half of the subjects had deliveries with early-clamped newborn infants (at 10 s), and the other half had late-clamped deliveries (at 2 min). RESULTS: Erythrocyte catalase activity was significantly greater in the late-clamped group than in the early-clamped group (P < .01 for the umbilical vein and P < .001 for the artery). The values for superoxide dismutase, total antioxidant status, and soluble tumor necrosis factor receptor II were all significantly higher in the late-clamped group compared with the early-clamped group (P < .01, P < .001, and P < .001, respectively). CONCLUSIONS: The results suggest a beneficial effect of late cord clamping, produced by an increase in antioxidant capacity and moderation of the inflammatory-mediated effects induced during delivery of term neonates. PMID- 25022745 TI - A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a condition with a highly variable outcome. Some infants have a relatively mild disease process, whereas others have significant pulmonary hypoplasia and hypertension. Identifying high risk infants postnatally may allow for targeted therapy. METHODS: Data were obtained on 2202 infants from the Congenital Diaphragmatic Hernia Study Group database from January 2007 to October 2011. Using binary baseline predictors generated from birth weight, 5-minute Apgar score, congenital heart anomalies, and chromosome anomalies, as well as echocardiographic evidence of pulmonary hypertension, a clinical prediction rule was developed on a randomly selected subset of the data by using a backward selection algorithm. An integer-based clinical prediction rule was created. The performance of the model was validated by using the remaining data in terms of calibration and discrimination. RESULTS: The final model included the following predictors: very low birth weight, absent or low 5-minute Apgar score, presence of chromosomal or major cardiac anomaly, and suprasystemic pulmonary hypertension. This model discriminated between a population at high risk of death (~50%) intermediate risk (~20%), or low risk (<10%). The model performed well, with a C statistic of 0.806 in the derivation set and 0.769 in the validation set and good calibration (Hosmer-Lemeshow test, P = .2). CONCLUSIONS: A simple, generalizable scoring system was developed for CDH that can be calculated rapidly at the bedside. Using this model, intermediate- and high-risk infants could be selected for transfer to high-volume centers while infants at highest risk could be considered for advanced medical therapies. PMID- 25022746 TI - Mechanisms to provide safe and effective drugs for children. PMID- 25022747 TI - Compensatory saccade differences between outward versus inward head impulses in chronic unilateral vestibular hypofunction. AB - The horizontal head impulse test (HIT) is a valuable clinical tool that can help identify peripheral vestibular hypofunction by the refixation (compensatory) saccade that returns the eyes to the target of interest after the head has stopped. We asked if there were differences in the compensatory saccade responses during the HIT when the head was rotated away or toward straight ahead (outward versus inward). We also investigated the influence of a fixation target. Using scleral search-coils, we tested five patients with chronic unilateral vestibular hypofunction (UVH) and three healthy control subjects. In UVH patients, the latencies of both overt and covert saccades were longer when the head was rotated inward from an initially eccentric position, regardless of a visual target. The proportion of HIT with covert saccades was independent of a visual target. In control subjects no compensatory saccades were observed and there were no differences in either angular vestibulo-ocular reflex gain or latency between inward and outward HIT. Our data suggest that inward applied HIT in chronic UVH is more likely to include an overt compensatory saccade based on its lengthened latency. Neither latency nor the occurrence of covert compensatory saccades during HIT depended on a visual target, suggesting they have become a learned behavior in response to chronic UVH. PMID- 25022748 TI - Polymicrobial bloodstream infections in the neonatal intensive care unit are associated with increased mortality: a case-control study. AB - BACKGROUND: Polymicrobial infections in adults and children are associated with increase in mortality, duration of intensive care and healthcare costs. Very few studies have characterized polymicrobial bloodstream infections in the neonatal unit. Considerable variation has been reported in incidence of polymicrobial infections and associated clinical outcomes. We characterized the risk factors and outcomes of polymicrobial bloodstream infections in our neonatal units in a tertiary hospital in North America. METHODS: In a retrospective case control study design, we identified infants in the neonatal intensive care unit with positive blood cultures at Texas Children's Hospital, over a 16-year period from January 1, 1997 to December 31, 2012. Clinical data from online databases were available from January 2009 to December 2012. For each polymicrobial bloodstream infection (case), we matched three infants with monomicrobial bloodstream infection (control) by gestational age and birth weight. RESULTS: We identified 2007 episodes of bloodstream infections during the 16 year study period and 280 (14%) of these were polymicrobial. Coagulase-negative Staphylococcus, Enterococcus, Klebsiella and Candida were the most common microbial genera isolated from polymicrobial infections. Polymicrobial bloodstream infections were associated with more than 3-fold increase in mortality and an increase in duration of infection. Surgical intervention was a significant risk factor for polymicrobial infection. CONCLUSION: The frequency and increased mortality emphasizes the clinical significance of polymicrobial bloodstream infections in the neonatal intensive care unit. Clinical awareness and focused research on neonatal polymicrobial infections is urgently needed. PMID- 25022749 TI - The relationship between providing neonatal palliative care and nurses' moral distress: an integrative review. AB - Moral distress has been identified in multiple clinical settings especially in critical care areas. The neonatal intensive care unit (NICU) has frequent situations in which moral distress may occur including providing palliative care. The purpose of this integrative review was to determine the relationship between the provision of palliative care in a NICU and nurses' moral distress. The evidence reviewed supports that moral distress does occur with the provision of neonatal palliative care. An interdisciplinary care team, an established protocol, and educational interventions may decrease moral distress in nurses providing end-of-life care to infants in the NICU. PMID- 25022750 TI - Hamartomatous polyposis syndromes: a review. AB - Hamartomatous Polyposis Syndromes (HPS) are genetic syndromes, which include Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumour syndrome (Cowden Syndrom, Bannayan-Riley-Ruvalcaba and Proteus Syndrome) as well as hereditary mixed polyposis syndrome. Other syndromes such as Gorlin Syndrome and multiple endocrine neoplasia syndrome 2B are sometimes referred to as HPS. HPS is characterized by the development of hamartomatous polyps in the gastrointestinal tract as well as several extra-intestinal findings such as dermatological and dysmorphic features or extra-intestinal cancer. The syndromes are rare and inherited in an autosomal dominant manner.The diagnosis of HPS has traditionally been based on clinical criteria, but can sometimes be difficult as the severity of symptoms range considerably from only a few symptoms to very severe cases - even within the same family. De novo cases are also frequent. However, because of the discovery of several associated germline-mutations as well as the rapid development in genetics it is now possible to use genetic testing more often in the diagnostic process. Management of the syndromes is different for each syndrome as extra-intestinal symptoms and types of cancers differs.Clinical awareness and early diagnosis of HPS is important, as affected patients and at-risk family members should be offered genetic counselling and surveillance. Surveillance in children with HPS might prevent or detect intestinal or extra-intestinal complications, whereas in adulthood surveillance is recommended due to an increased risk of cancer e.g. intestinal cancer or breast cancer. PMID- 25022751 TI - Comparison of two in vitro angiogenesis assays for evaluating the effects of netrin-1 on tube formation. AB - Netrin-1 is a neural guidance cue that also regulates vascular development. Controversial results, however, have been obtained concerning the roles of netrin 1 in vascular development both in vivo and in vitro. In the present study, two in vitro angiogenesis assays were compared to evaluate the effects of netrin-1 secreted by retrovirally transduced melanoma cells (Mel2a-netrin1) on tube formation. The results showed that there was no obvious difference in tube formation induced by conditioned media (CM) from the control, Mel2a-netrin1 and Mel2a cells in a matrigel assay. The results of another in vitro assay, in which endothelial cells were co-cultured with human fibroblasts, however, showed that Mel2a-netrin1 CM inhibited the tube formation, supposedly through blocking the elongation and coalescence of human umbilical vein endothelial cells (HUVECs). These results confirmed that the matrigel assay is not able to demonstrate the anti-angiogenic roles of netrin-1. PMID- 25022752 TI - Effects of 2'-O-methyl nucleotide on ligation capability of T4 DNA ligase. AB - To further understand the ligation mechanism, effects of 2'-O-methyl nucleotide (2'-OMeN) on the T4 DNA ligation efficiency were investigated. Fluorescence resonance energy transfer assay was used to monitor the nick-joining process by T4 DNA ligase. Results showed that substitutions at 5'- and 3'-ends of the nick decreased the ligation efficiency by 48.7% +/- 6.7% and 70.6% +/- 4.0%, respectively. Substitutions at both 5'- and 3'-ends decreased the ligation efficiency by 76.6% +/- 1.3%. Corresponding kinetic parameters, Vmax, Km, and kcat, have been determined in each case by using the Michaelis-Menten equation. The kinetic data showed that the 2'-OMeN substitutions reduced the maximal initial velocity and increased the Michaelis constant of T4 DNA ligase. Mismatches at 5'- and 3'-ends of the nick have also shown different influences on the ligation. Results here showed that the sugar pucker conformation at 3'-end impairs the ligation efficiency more profoundly than that at 5'-end. Different concentrations of Mg(2+), Ca(2+), K(+), Na(+), and ATP were also demonstrated to affect the T4 DNA ligase activity. These results enriched our knowledge about the effects of 2'-OMeN substitutions on the T4 DNA ligase. PMID- 25022753 TI - Interleukin-1beta-induced Wnt5a enhances human corneal endothelial cell migration through regulation of Cdc42 and RhoA. AB - Wnt5a can activate beta-catenin-independent pathways for regulation of various cellular functions, such as migration, that play critical roles in wound repair. Investigation of Wnt5a signaling may help identify therapeutic targets for enhancing corneal endothelial wound healing that could provide an alternative to corneal transplantation in patients with blindness from endothelial dysfunction. However, Wnt5a signaling in corneal endothelial cells (CECs) has not been well characterized. In this study, we show transient induction of Wnt5a by interleukin 1beta (IL-1beta) stimulation proceeds through NF-kappaB in human CECs. This leads to binding of Fzd5 to Ror2, resulting in activation of disheveled protein (Dvl) and subsequently disheveled-associated activator of morphogenesis 1 (DAAM1). This leads to activation of Cdc42 and subsequent inhibition of RhoA. Inhibition of RhoA leads to parallel dephosphorylation and inactivation of LIM domain kinase 2 along with dephosphorylation and activation of slingshot 1, resulting in dephosphorylation and activation of cofilin and leading to enhanced cell migration. These findings suggest that Wnt5a enhances cell migration through activation of Cdc42 and inactivation of RhoA in human CECs. PMID- 25022754 TI - IQGAP1 regulates endothelial barrier function via EB1-cortactin cross talk. AB - Cross talk between the actin cytoskeleton and microtubules (MT) has been implicated in the amplification of agonist-induced Rho signaling, leading to increased vascular endothelial permeability. This study tested the involvement of actin-MT cross talk in the mechanisms of barrier enhancement induced by hepatocyte growth factor (HGF) and evaluated the role of the adaptor protein IQGAP1 in integrating the MT- and actin-dependent pathways of barrier enhancement. IQGAP1 knockdown by small interfering RNA attenuated the HGF-induced increase in endothelial barrier properties and abolished HGF-activated cortical actin dynamics. IQGAP1 reduction abolished HGF-induced peripheral accumulation of Rac cytoskeletal effector cortactin and cortical actin remodeling. In addition, HGF stimulated peripheral MT growth in an IQGAP1-dependent fashion. HGF also induced Rac1-dependent IQGAP1 association with the MT fraction and the formation of a protein complex containing end-binding protein 1 (EB1), IQGAP1, and cortactin. Decreasing endogenous IQGAP1 abolished HGF-induced EB1-cortactin colocalization at the cell periphery. In turn, expression of IQGAP1DeltaC (IQGAP1 lacking the C-terminal domain) attenuated the cortactin association with EB1 and suppressed HGF-induced endothelial cell peripheral actin cytoskeleton enhancement. These results demonstrate for the first time the MT-actin cross talk mechanism of HGF-induced endothelial barrier enhancement and suggest that IQGAP1 functions as a hub linking HGF-induced signaling to MT and actin remodeling via EB1-IQGAP1-cortactin interactions. PMID- 25022755 TI - HSPA1A-independent suppression of PARK2 C289G protein aggregation by human small heat shock proteins. AB - The C289G mutation of the parkin E3-ubiquitin protein ligase (PARK2) is associated with autosomal recessive juvenile onset Parkinson's disease and was found to be associated with protein aggregation. Members of the human small heat shock proteins (HSPBs) have been implicated in protein degradation and prevention of protein aggregation. In this study, we show that of the 10 HSPB members, individual overexpression of HSPB1, HSPB2, HSPB4, and HSPB7 suppresses PARK2 C289G-associated protein aggregation. Intriguingly, the protective actions of these HSPBs are not impaired upon inactivation of the ATP-dependent HSP70 chaperone machines. Depending on the HSPB member the protective actions involve either autophagic or proteasomal degradation pathways. PMID- 25022756 TI - HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold. AB - Scaffold proteins play a critical role in controlling the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Shoc2 is a leucine rich repeat scaffold protein that acts as a positive modulator of ERK1/2 signaling. However, the precise mechanism by which Shoc2 modulates the activity of the ERK1/2 pathway is unclear. Here we report the identification of the E3 ubiquitin ligase HUWE1 as a binding partner and regulator of Shoc2 function. HUWE1 mediates ubiquitination and, consequently, the levels of Shoc2. Additionally, we show that both Shoc2 and HUWE1 are necessary to control the levels and ubiquitination of the Shoc2 signaling partner, RAF-1. Depletion of HUWE1 abolishes RAF-1 ubiquitination, with corresponding changes in ERK1/2 pathway activity occurring. Our results indicate that the HUWE1-mediated ubiquitination of Shoc2 is the switch that regulates the transition from an active to an inactive state of the RAF-1 kinase. Taken together, our results demonstrate that HUWE1 is a novel player involved in regulating ERK1/2 signal transmission through the Shoc2 scaffold complex. PMID- 25022758 TI - Dock-family exchange factors in cell migration and disease. AB - Dock family proteins are evolutionary conserved exchange factors for the Rho GTPases Rac and Cdc42. There are 11 Dock proteins in mammals, named Dock1 (or Dock180) to Dock11 that play different cellular functions. In particular, Dock proteins regulate actin cytoskeleton, cell adhesion and migration. Not surprisingly, members of the Dock family have been involved in various pathologies, including cancer and defects in the central nervous and immune systems. This review proposes an update of the recent findings regarding the function of Dock proteins, focusing on their role in the control of cell migration and invasion and the consequences in human diseases. PMID- 25022757 TI - Fetal globin gene repressors as drug targets for molecular therapies to treat the beta-globinopathies. AB - The human beta-globin locus is comprised of embryonic, fetal, and adult globin genes that are expressed in a developmental stage-specific manner. Mutations in the globin locus give rise to the beta-globinopathies, beta-thalassemia and sickle cell disease, which begin to manifest symptoms around the time of birth. Although the fetal globin genes are autonomously silenced in adult-stage erythroid cells, mutations lying both within and outside the locus lead to natural variations in the level of fetal globin gene expression, and some of these significantly ameliorate the clinical symptoms of the beta-globinopathies. Multiple reports have now identified several transcription factors that are involved in fetal globin gene repression in definitive (adult)-stage erythroid cells (the TR2/TR4 heterodimer, MYB, KLFs, BCL11A, and SOX6). To carry out their repression functions, chromatin-modifying enzymes (such as DNA methyltransferase, histone deacetylases, and lysine-specific histone demethylase 1) are additionally involved as a consequence of forming large macromolecular complexes with the DNA binding subunits of these cellular machines. This review focuses on the molecular mechanisms underlying fetal globin gene silencing and possible near-future molecularly targeted therapies for treating the beta-globinopathies. PMID- 25022759 TI - Making sense of continuous sedation in end-of-life care for cancer patients: an interview study with bereaved relatives in three European countries. AB - PURPOSE: The purpose of the study was to explore relatives' descriptions and experiences of continuous sedation in end-of-life care for cancer patients and to identify and explain differences between respondents from the Netherlands, Belgium, and the UK. METHODS: In-depth interviews were held between January 2011 and May 2012 with 38 relatives of 32 cancer patients who received continuous sedation until death in hospitals, the community, and hospices/palliative care units. RESULTS: Relatives' descriptions of the practice referred to the outcome, to practical aspects, and to the goals of sedation. While most relatives believed sedation had contributed to a 'good death' for the patient, yet many expressed concerns. These related to anxieties about the patient's wellbeing, their own wellbeing, and questions about whether continuous sedation had shortened the patient's life (mostly UK), or whether an alternative approach would have been better. Such concerns seemed to have been prompted by relatives witnessing unexpected events such as the patient coming to awareness during sedation. In the Netherlands and in Belgium, several relatives reported that the start of the sedation allowed for a planned moment of 'saying goodbye'. In contrast, UK relatives discerned neither an explicit point at which sedation was started nor a specific moment of farewell. CONCLUSIONS: Relatives believed that sedation contributed to the patient having a good death. Nevertheless, they also expressed concerns that may have been provoked by unexpected events for which they were unprepared. There seems to exist differences in the process of saying goodbye between the NL/BE and the UK. PMID- 25022760 TI - Associations between self-reported post-diagnosis physical activity changes, body weight changes, and psychosocial well-being in breast cancer survivors. AB - PURPOSE: Decreased physical activity and weight gain post-breast cancer diagnosis are associated with negative psychosocial, health, and disease outcomes, but little is known about how these factors interact. The purpose of the present study was to conduct a preliminary examination of the association between post diagnosis physical activity changes, weight changes, and psychosocial well-being in breast cancer survivors. METHODS: We examined the association between retrospectively collected, self-reported post-diagnosis changes in physical activity and body weight and post-diagnosis fatigue, anxiety, depression, stress, self-esteem, and health-related quality of life (HRQOL) in breast cancer survivors (N = 1,348) using univariate analyses of covariance with Bonferroni's adjustment. RESULTS: After adjusting for covariates, maintaining and/or increasing physical activity post-diagnosis was significantly (p < 0.05 for all), independently associated with lower fatigue, anxiety, depression and stress and higher physical self-worth, physical, social, emotional, functional and breast cancer specific well-being and overall HRQOL (effect sizes = 0.23 to 0.60). Maintaining and/or losing weight was significantly (p < 0.05), independently associated with lower fatigue and higher physical self-worth, physical and breast cancer-specific well-being, and overall HRQOL (effect sizes = .28 to 0.87). There were no significant interaction effects between physical activity and body weight changes. CONCLUSIONS: This study provides preliminary data to suggest that maintaining or increasing physical activity and controlling weight post-diagnosis may be independently, positively associated with psychosocial well-being and HRQOL in breast cancer survivors. In addition, weight management effects may be larger and more outcome-specific while physical activity effects may be more general. Future research is warranted to replicate and confirm these findings. PMID- 25022762 TI - IMpact of Platelet Rich plasma OVer alternative therapies in patients with lateral Epicondylitis (IMPROVE): protocol for a multicenter randomized controlled study: a multicenter, randomized trial comparing autologous platelet-rich plasma, autologous whole blood, dry needle tendon fenestration, and physical therapy exercises alone on pain and quality of life in patients with lateral epicondylitis. AB - INTRODUCTION: Lateral epicondylitis, commonly known as tennis elbow, is the most common cause of lateral elbow pain and the second most frequently diagnosed musculoskeletal disorder in the neck and upper limb in a primary care setting. Many therapeutic options, including conservative, surgical, and minimally invasive procedures, have been advocated for the treatment of lateral epicondylitis. Although numerous small studies have been performed to assess the efficacy of various treatments, there are conflicting results with no clear consensus on the optimal treatment. In an economic environment with limited health care resources, it is paramount that optimal cost-effective therapies with favorable patient-important outcomes be identified. METHODS AND ANALYSIS: This is a protocol paper which outlines a multicenter, multidisciplinary, single-blinded, four-arm randomized controlled trial, comparing platelet-rich plasma (PRP), whole blood injection, dry needle tendon fenestration, and sham injection with physical therapy alone for the treatment of lateral epicondylitis. Patients are screened based on pre-established eligibility criteria and randomized to one of the four study groups using an Internet-based system. The patients are followed at 6-week, 12-week, 24-week, and 52-week time points to assess the primary and secondary outcomes of the study. The primary outcome is pain. Secondary outcomes include health-related quality of life and ultrasound appearance of the common extensor tendon. Two university centers (McMaster University and the University of Michigan) are currently recruiting patients. We have planned a sample size of 100 patients (25 patients per arm) to ensure over 80% power to detect a three-point difference in pain scores at 52 weeks of follow-up. ETHICS AND DISSEMINATION: This study has ethics approval from the McMaster University Research Ethics Board (REB# 12-146) and the University of Michigan Institutional Review Board (IRB# HUM00067750). Successful completion of this proposed study will significantly impact clinical practice and enhance patients' lives. More broadly, this trial will develop a network of collaboration from which further high-quality trials in ultrasound-guided interventions will follow. PMID- 25022763 TI - Left atrial function and maximum volume as determined by MDCT are independently associated with atrial fibrillation. AB - RATIONALE AND OBJECTIVES: To assess whether left atrial (LA) volume, function, and diameter as determined by multidetector computed tomography (MDCT) are associated with the presence and chronicity of atrial fibrillation (AF). MATERIALS AND METHODS: A total of 232 subjects, 156 with AF (43 with chronic and 113 with paroxysmal) and 76 normal subjects, formed the study population. AF subjects underwent MDCT of the pulmonary veins and LA, and normal subjects underwent coronary computed tomography (CT), on which LA volume, function, and diameter were measured. Associations between each MDCT LA parameter and presence and chronicity of AF were assessed using logistic regression analysis. RESULTS: The indexed LA maximum volume (odds ratio [OR]=2.42; 95% confidence interval [CI], 1.43-4.08; P=.0009) was significantly associated with chronicity and presence of AF (OR=1.06; 95% CI, 1.03-1.10; P=.0003) after adjustment for traditional risk factors. The LA function was associated with presence of AF (OR=0.93; 95% CI, 0.89-0.97; P=.0005), but not with AF chronicity (OR=1.12; 95% CI, 0.93-1.33; P=.21). CONCLUSIONS: Decreased LA function is associated with presence of AF, and increased LA maximum volume is associated with presence and chronicity of AF, independent of traditional risk factors. PMID- 25022764 TI - Inflammation-based prognostic scores and nutritional prognostic index in patients with locally-advanced unresectable colorectal cancer. AB - BACKGROUND: Unresectable colorectal cancer has a poor prognosis. However, some patients survive intensive chemotherapy, and complete resection of primary and metastatic tumors may even be possible. In the present study, we examined the prognostic factors associated with survival after intensive chemotherapy in patients with unresectable colorectal cancer. METHODS: This retrospective study enrolled 61 patients diagnosed with unresectable locally advanced colorectal cancer between January 2004 and December 2013. Among the prognostic parameters, we found that the prognoses of patients with abnormal performance status (PS) of 2 or 3, high Glasgow Prognostic Score (GPS) of 1 or 2, high neutrophil/lymphocyte ratio (NLR) >5, and low prognostic nutritional index (PNI) <40 were poor. Thus, we scored each patient according to our scoring system (abnormal PS, 2 or 3 = +1; high GPS, 1 or 2 = +1; high NLR, >5 = +1; and low PNI, <40 = +1). If the patient showed abnormalities in every parameter, the score would be +4. RESULTS: Sixteen patients had a score of 0, 17 scored +1, 10 scored +2, 17 scored +3, and one scored +4. The median survival time (MST) of the 61 patients was 9 months. Patients were divided into two groups, a low-score group (0 and +1) and a high score group (+2, +3, and +4). The MST of the 33 patients in the low-score group was significantly longer than that of the 28 patients in the high-score group (15 months versus 4 months, P < 0.001). Also, conversion chemotherapy was performed in 4.9% (3/61) of patients. And these 3 patients were in a low-score group. CONCLUSIONS: This new prognostic scoring system may help to select patients with unresectable advanced colorectal cancer who are able to survive through intensive chemotherapy. PMID- 25022765 TI - Humidity-responsive liquid crystalline polymer actuators with an asymmetry in the molecular trigger that bend, fold, and curl. AB - We show a versatile method for the preparation of a variety of humidity responsive actuators based on a single sheet of a hydrogen-bonded, uniaxially aligned liquid crystal polymer network. In this approach, the asymmetry in the molecular trigger in the anisotropic polymer film plays a dominant role leading to programmed deformation events. The material is locally treated with a potassium hydroxide solution to create the asymmetry in the responsiveness toward humidity, which allows to prepare actuators that bend, fold, or curl. PMID- 25022767 TI - Observation of behavioural markers of non-technical skills in the operating room and their relationship to intra-operative incidents. AB - BACKGROUND: The importance of non-technical skills in improving surgical safety and performance is now well recognised. Better understanding is needed of the impact that non-technical skills of the multi-disciplinary theatre team have on intra-operative incidents in the operating room (OR) using structured theatre based assessment. The interaction of non-technical skills that influence surgical safety of the OR team will be explored and made more transparent. METHODS: Between May-August 2013, a range of procedures in general and vascular surgery in the Royal Infirmary of Edinburgh were performed. Non-technical skills behavioural markers and associated intra-operative incidents were recorded using established behavioural marking systems (NOTSS, ANTS and SPLINTS). Adherence to the surgical safety checklist was also observed. RESULTS: A total of 51 procedures were observed, with 90 recorded incidents - 57 of which were considered avoidable. Poor situational awareness was a common area for surgeons and anaesthetists leading to most intra-operative incidents. Poor communication and teamwork across the whole OR team had a generally large impact on intra-operative incidents. Leadership was shown to be an essential set of skills for the surgeons as demonstrated by the high correlation of poor leadership with intra-operative incidents. Team-working and management skills appeared to be especially important for anaesthetists in the recovery from an intra-operative incident. CONCLUSION: A significant number of avoidable incidents occur during operative procedures. These can all be linked to failures in non-technical skills. Better training of both individual and team in non-technical skills is needed in order to improve patient safety in the operating room. PMID- 25022766 TI - On the mechanism of respiratory complex I. AB - The energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, couples the transfer of electrons from NADH to ubiquinone with the translocation of protons across the membrane. Electron microscopy and X-ray crystallography revealed the two-part structure of the enzyme complex. A peripheral arm extending into the aqueous phase catalyzes the electron transfer reaction. Accordingly, this arm contains the redox-active cofactors, namely one flavin mononucleotide (FMN) and up to ten iron-sulfur (Fe/S) clusters. A membrane arm embedded in the lipid bilayer catalyzes proton translocation by a yet unknown mechanism. The binding site of the substrate (ubi) quinone is located at the interface of the two arms. The oxidation of one NADH is coupled with the translocation of four protons across the membrane. In this review, the binding of the substrates, the intramolecular electron transfer, the role of individual Fe/S clusters and the mechanism of proton translocation are discussed in the light of recent data obtained from our laboratory. PMID- 25022768 TI - Accuracy of imputation to whole-genome sequence data in Holstein Friesian cattle. AB - BACKGROUND: The use of whole-genome sequence data can lead to higher accuracy in genome-wide association studies and genomic predictions. However, to benefit from whole-genome sequence data, a large dataset of sequenced individuals is needed. Imputation from SNP panels, such as the Illumina BovineSNP50 BeadChip and Illumina BovineHD BeadChip, to whole-genome sequence data is an attractive and less expensive approach to obtain whole-genome sequence genotypes for a large number of individuals than sequencing all individuals. Our objective was to investigate accuracy of imputation from lower density SNP panels to whole-genome sequence data in a typical dataset for cattle. METHODS: Whole-genome sequence data of chromosome 1 (1737 471 SNPs) for 114 Holstein Friesian bulls were used. Beagle software was used for imputation from the BovineSNP50 (3132 SNPs) and BovineHD (40 492 SNPs) beadchips. Accuracy was calculated as the correlation between observed and imputed genotypes and assessed by five-fold cross validation. Three scenarios S40, S60 and S80 with respectively 40%, 60%, and 80% of the individuals as reference individuals were investigated. RESULTS: Mean accuracies of imputation per SNP from the BovineHD panel to sequence data and from the BovineSNP50 panel to sequence data for scenarios S40 and S80 ranged from 0.77 to 0.83 and from 0.37 to 0.46, respectively. Stepwise imputation from the BovineSNP50 to BovineHD panel and then to sequence data for scenario S40 improved accuracy per SNP to 0.65 but it varied considerably between SNPs. CONCLUSIONS: Accuracy of imputation to whole-genome sequence data was generally high for imputation from the BovineHD beadchip, but was low from the BovineSNP50 beadchip. Stepwise imputation from the BovineSNP50 to the BovineHD beadchip and then to sequence data substantially improved accuracy of imputation. SNPs with a low minor allele frequency were more difficult to impute correctly and the reliability of imputation varied more. Linkage disequilibrium between an imputed SNP and the SNP on the lower density panel, minor allele frequency of the imputed SNP and size of the reference group affected imputation reliability. PMID- 25022770 TI - Introduction. AB - Cognitive behavioral therapy evolved from systematic studies testing learning theories. This research led to the development of effective treatment approaches for a variety of disorders. In more recent years we have moved away from relying on experimental psychopathology studies to directly inform our treatment approaches. This paper describes why the alienation from experimental psychopathology studies is detrimental to the advancement of treatment approaches. Examples of how systematic research can be conducted to address questions regarding treatment mechanisms and moderators are provided. Drawing on experimental psychopathology research can also lead to a better understanding of core processes of psychopathology, which in turn can lead to transdiagnostic treatment approaches. PMID- 25022771 TI - Performance-based interpretation bias in clinically anxious youths: relationships with attention, anxiety, and negative cognition. AB - This preliminary investigation sought to examine basic interpretive biases, as assessed via performance-based means, in the context of anxious symptomatology, attention, and negative cognition in children and adolescents. At a single assessment, 26 youths diagnosed with primary separation anxiety, social phobia, or generalized anxiety disorder completed performance-based assessments of interpretation and attention. Youths and parents also completed diagnostic interviews and youths completed a measure of negative self-statements. Components of interpretation (threat-valence judgments and speed of responding) were examined, and interpretation was explored as a correlate of youth anxiety, attention bias, and negative self-statements. Results found percentage of negative interpretations endorsed as the strongest predictor of anxiety symptoms; this index was also correlated with attention bias. Slower rejection of benign interpretations was also associated with youth-reported negative self statements.This initial investigation provides support for a relationship between interpretation bias and anxiety and preliminary evidence for a relationship between attention and interpretation biases. Continued research dismantling the stages of basic cognition within the chain of information processing may provide a better understanding of the mechanisms underlying anxiety disorders in youths and lead to continued development and refinement of cognitive interventions. PMID- 25022769 TI - Synergistic Synthetic Biology: Units in Concert. AB - Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through in silico modeling by choosing the right complement of genetic parts and by experimental tuning through directed evolution and craftsmanship. In this review, we consider an additional and complementary tool available to the synthetic biologist for innovative design and successful construction of desired circuit functionalities: biological synergies. Synergy is a prevalent emergent property in biological systems that arises from the concerted action of multiple factors producing an amplification or cancelation effect compared with individual actions alone. Synergies appear in domains as diverse as those involved in chemical and protein activity, polypharmacology, and metabolic pathway complementarity. In conventional synthetic biology designs, synergistic cross talk between parts and modules is generally attenuated in order to verify their orthogonality. Synergistic interactions, however, can induce emergent behavior that might prove useful for synthetic biology applications, like in functional circuit design, multi-drug treatment, or in sensing and delivery devices. Synergistic design principles are therefore complementary to those coming from orthogonal design and may provide added value to synthetic biology applications. The appropriate modeling, characterization, and design of synergies between biological parts and units will allow the discovery of yet unforeseeable, novel synthetic biology applications. PMID- 25022772 TI - Behavior therapy and callous-unemotional traits: effects of a pilot study examining modified behavioral contingencies on child behavior. AB - The conduct problems of children with callous-unemotional (CU) traits (i.e., lack of empathy, lack of guilt/lack of caring behaviors) are particularly resistant to current behavioral interventions, and it is possible that differential sensitivities to punishment and reward may underlie this resistance. Children with conduct problems and CU (CPCU) are less responsive to behavioral punishment techniques (e.g., time-out), whereas reward techniques (e.g., earning points for prizes or activities) are effective for reducing conduct problems. This study examined the efficacy of modified behavioral interventions, which de-emphasized punishment (Condition B) and emphasized reward techniques (Condition C), compared with a standard behavioral intervention (Condition A). Interventions were delivered through a summer treatment program over 7 weeks with an A-B-A-C-A-BC-A design to a group of 11 children (7-11 years; 91% male). All children were diagnosed with either oppositional defiant disorder or conduct disorder, in addition to attention-deficit hyperactivity disorder. Results revealed the best treatment response occurred during the low-punishment condition, with rates of negative behavior (e.g., aggression, teasing, stealing) increasing over the 7 weeks. However, there was substantial individual variability in treatment response, and several children demonstrated improvement during the modified intervention conditions. Future research is necessary to disentangle treatment effects from order effects, and implications of group treatment of CPCU children (i.e., deviancy training) are discussed. PMID- 25022773 TI - De novo fear conditioning across diagnostic groups in the affective disorders: evidence for learning impairments. AB - De novo fear conditioning paradigms have served as a model for how clinical anxiety may be acquired and maintained. To further examine variable findings in the acquisition and extinction of fear responses between clinical and nonclinical samples, we assessed de novo fear conditioning outcomes in outpatients with either anxiety disorders or depression and healthy subjects recruited from the community. Overall, we found evidence for attenuated fear conditioning, as measured by skin conductance, among the patient sample, with significantly lower fear acquisition among patients with depression and posttraumatic stress disorder. These acquisition deficits were evident in both the simple (considering the CS+only) and differential (evaluating the CS+in relation to the CS-) paradigms. Examination of extinction outcomes were hampered by the low numbers of patients who achieved adequate conditioning, but the available data indicated slower extinction among the patient, primarily panic disorder, sample. Results are interpreted in the context of the cognitive deficits that are common to the anxiety and mood disorders, with attention to a range of potential factors, including mood comorbidity, higher-and lower-order cognitive processes and deficits, and medication use, that may modulate outcomes in fear conditioning studies, and, potentially, in exposure-based cognitive behavioral therapy. PMID- 25022774 TI - Altering impulsive decision making with an acceptance-based procedure. AB - Delay discounting is one facet of impulsive decision making and involves subjectively devaluing a delayed outcome. Steeply discounting delayed rewards is correlated with substance abuse and other problematic behaviors. To the extent that steep delay discounting underlies these clinical disorders, it would be advantageous to find psychosocial avenues for reducing delay discounting. Acceptance-based interventions may prove useful as they may help to decrease the distress that arises while waiting for a delayed outcome. The current study was conducted to determine if a 60-90 minute acceptance-based training would change delay discounting rates among 30 undergraduate university students in comparison to a waitlist control. Measures given at pre- and posttraining included a hypothetical monetary delay discounting task, the Acceptance and Action Questionnaire-II (AAQ-II), and the Distress Tolerance Scale. Those assigned to the treatment group decreased their discounting of delayed money, but not distress intolerance or psychological inflexibility when compared to the waitlist control group. After the waiting period, the control group received the intervention. Combining all participants' pre- to posttreatment data, the acceptance-based treatment significantly decreased discounting of monetary rewards and increased distress tolerance. The difference in AAQ-II approached significance. Acceptance-based treatments may be a worthwhile option for decreasing delay discounting rates and, consequently, affecting the choices that underlie addiction and other problematic behaviors. PMID- 25022775 TI - Behavioral approach system sensitivity and risk taking interact to predict left frontal EEG asymmetry. AB - The Behavioral Approach System (BAS) hypersensitivity theory of bipolar disorder (BD; Alloy & Abramson, 2010; Depue & Iacono, 1989) suggests that hyperreactivity in the BAS results in the extreme fluctuations of mood characteristic of BD. In addition to risk conferred by BAS hypersensitivity, cognitive and personality variables may play a role in determining risk. We evaluated relationships among BAS sensitivity, risk taking, and an electrophysiological correlate of approach motivation, relative left-frontal electroencephalography (EEG) asymmetry. BAS sensitivity moderated the relationship between risk taking and EEG asymmetry. More specifically, individuals who were high in BAS sensitivity showed left frontal EEG asymmetry regardless of their level of risk-taking behavior. However, among individuals who were moderate in BAS sensitivity, risk taking was positively associated with asymmetry. These findings suggest that cognitive and personality correlates of bipolar risk may evidence unique contributions to a neural measure of trait-approach motivation. Clinical implications of these findings are discussed. PMID- 25022776 TI - Associations among smoking, anhedonia, and reward learning in depression. AB - Depression and cigarette smoking co-occur at high rates. However, the etiological mechanisms that contribute to this relationship remain unclear. Anhedonia and associated impairments in reward learning are key features of depression, which also have been linked to the onset and maintenance of cigarette smoking. However, few studies have investigated differences in anhedonia and reward learning among depressed smokers and depressed nonsmokers. The goal of this study was to examine putative differences in anhedonia and reward learning in depressed smokers (n=36) and depressed nonsmokers (n=44). To this end, participants completed self-report measures of anhedonia and behavioral activation (BAS reward responsiveness scores) and as well as a probabilistic reward task rooted in signal detection theory, which measures reward learning (Pizzagalli, Jahn, & O'Shea, 2005). When considering self-report measures, depressed smokers reported higher trait anhedonia and reduced BAS reward responsiveness scores compared to depressed nonsmokers. In contrast to self-report measures, nicotine-satiated depressed smokers demonstrated greater acquisition of reward-based learning compared to depressed nonsmokers as indexed by the probabilistic reward task. Findings may point to a potential mechanism underlying the frequent co-occurrence of smoking and depression. These results highlight the importance of continued investigation of the role of anhedonia and reward system functioning in the co-occurrence of depression and nicotine abuse. Results also may support the use of treatments targeting reward learning (e.g., behavioral activation) to enhance smoking cessation among individuals with depression. PMID- 25022777 TI - Cognitive mediators of treatment for social anxiety disorder: comparing acceptance and commitment therapy and cognitive-behavioral therapy. AB - OBJECTIVE: To assess the relationship between session-by-session mediators and treatment outcomes in traditional cognitive-behavioral therapy (CBT) and acceptance and commitment therapy (ACT) for social anxiety disorder. METHOD: Session-by-session changes in negative cognitions (a theorized mediator of CBT) and experiential avoidance (a theorized mediator of ACT) were assessed in 50 adult outpatients randomized to CBT (n=25) or ACT (n=25) for DSM-IV social anxiety disorder. RESULTS: Multilevel modeling analyses revealed significant nonlinear decreases in the proposed mediators in both treatments, with ACT showing steeper decline than CBT at the beginning of treatment and CBT showing steeper decline than ACT at the end of treatment. Curvature (or the nonlinear effect) of experiential avoidance during treatment significantly mediated posttreatment social anxiety symptoms and anhedonic depression in ACT, but not in CBT, with steeper decline of the Acceptance and Action Questionnaire at the beginning of treatment predicting fewer symptoms in ACT only. Curvature of negative cognitions during both treatments predicted outcome, with steeper decline of negative cognitions at the beginning of treatment predicting lower posttreatment social anxiety and depressive symptoms. CONCLUSIONS: Rate of change in negative cognitions at the beginning of treatment is an important predictor of change across both ACT and CBT, whereas rate of change in experiential avoidance at the beginning of treatment is a mechanism specific to ACT. PMID- 25022778 TI - Visual, tactile, and auditory "not just right" experiences: associations with obsessive-compulsive symptoms and perfectionism. AB - "Not just right" experiences (NJREs), or uncomfortable sensations associated with the immediate environment not feeling "right," are thought to contribute to obsessive-compulsive disorder (OCD) symptomatology. The literature suggests that NJREs are experienced across sensory modalities; however, existing in vivo measures have been restricted to visual inductions (e.g., viewing and/or rearranging a cluttered table). The present study used a large undergraduate sample (N=284) to examine 4 in vivo tasks designed to elicit and assess NJREs across separate sensory modalities (i.e., visual, tactile, and auditory). Task ratings (discomfort evoked, and urge to counteract task-specific stimuli) were uniquely associated with self-report measures of NJREs, OC symptoms (ordering/arranging, checking, and washing), and certain maladaptive domains of perfectionism (doubts about actions, and organization). Findings have implications for experimental research and clinical work targeting NJREs specific to particular senses. PMID- 25022779 TI - A multifaceted assessment of emotional tolerance and intensity in hoarding. AB - Hoarding is characterized by emotionally reinforced saving behaviors, which often combine with excessive acquisition to give rise to clutter, distress, and impairment. Despite the central role emotional processes are thought to play in hoarding, very little research has directly examined this topic. There is suggestive evidence linking hoarding with several facets of emotional intolerance and avoidance, though one key limitation of this past research has been the exclusive reliance on self-report questionnaires. The aim of the current study was to conduct a multimethod investigation of the relationship between hoarding and perceptions of, and cognitions about, negative emotional states. A large unselected sample of nonclinical young adults (N=213) completed questionnaires, behavioral tasks, and a series of negative mood inductions to assess distress tolerance (DT), appraisals of negative emotions, and emotional intensity and tolerance. Hoarding symptoms were associated with lowered tolerance of negative emotions, as well as perceiving negative emotions as more threatening. Individuals high in hoarding symptoms also experienced more intense emotions during the mood inductions than individuals low in hoarding symptoms, though there was no association with poorer performance on a behavioral index of DT. Across measures, hoarding was consistently associated with experiencing negative emotions more intensely and reporting lower tolerance of them. This relationship was particularly pronounced for the difficulty discarding and acquiring facets of hoarding. Our results offer initial support for the important role of emotional processes in the cognitive-behavioral model of hoarding. A better understanding of emotional dysfunction may play a crucial role in developing more effective treatments for hoarding. PMID- 25022780 TI - Evidence that a very brief psychological intervention boosts weight loss in a weight loss program. AB - Reducing morbidity and mortality associated with being overweight is a crucial public health goal. The aim of the present research was to test the efficacy of a very brief psychological intervention (a volitional help sheet) that could be used as an adjunct to standard weight loss programs to support increased weight loss in an overweight sample. Seventy-two overweight participants currently participating in a weight loss program were randomly allocated to either an intervention (volitional help sheet) condition or a control (distracter task) condition. The main outcome measure was weight at 1-month follow-up. Participants in both conditions lost significant amounts of weight, but those in the intervention condition lost significantly more than those in the control condition (d=0.66). The findings support the efficacy of the volitional help sheet to promote additional weight loss in an overweight sample engaged in a weight loss program. The volitional help sheet therefore represents a very brief, low-cost intervention that could be used to supplement ongoing weight-loss programs. PMID- 25022781 TI - Shaking that icky feeling: effects of extinction and counterconditioning on disgust-related evaluative learning. AB - Learned disgust appears to play an important role in certain anxiety disorders, and can be explained by the process of evaluative conditioning, in which an affective evaluative reaction evoked by an unconditional stimulus (US) is transferred to a conditional stimulus (CS). Much remains unknown about how disgust-related evaluative learning can be effectively eliminated. Study 1 of the present investigation examined the effects of extinction on reducing the negative evaluation of a CS that was acquired during disgust conditioning. Participants completed acquisition trials, with a disgusting picture as US and two neutral pictures as CS (CS+ was paired with the US; CS- was unpaired), followed by extinction trials ("CS only"; experimental condition) or a filler task (control condition). Extinction trials reduced acquired US expectancy to the CS+, but did not extinguish negative evaluations of the CS+. Study 2 examined the effects of counterconditioning on evaluative learned disgust. After disgust acquisition trials, counterconditioning trials followed in which the CS+ was paired with a pleasant US (experimental condition) or a filler task (control condition). Counterconditioning trials reduced acquired US expectancy to the CS+ and reduced evaluative conditioned disgust. Implications of the potential differential effects of extinction and counterconditioning on evaluative learning for exposure based treatment of specific anxiety disorders are discussed. PMID- 25022782 TI - The influence of anticipatory processing on attentional biases in social anxiety. AB - Research on cognitive theories of social anxiety disorder (SAD) has identified individual processes that influence this condition (e.g., cognitive biases, repetitive negative thinking), but few studies have attempted to examine the interaction between these processes. For example, attentional biases and anticipatory processing are theoretically related and have been found to influence symptoms of SAD, but they rarely have been studied together (i.e., Clark & Wells, 1995). Therefore, the goal of the current study was to examine the effect of anticipatory processing on attentional bias for internal (i.e., heart rate feedback) and external (i.e., emotional faces) threat information. A sample of 59 participants high (HSA) and low (LSA) in social anxiety symptoms engaged in a modified dot-probe task prior to (Time 1) and after (Time 2) an anticipatory processing or distraction task. HSAs who anticipated experienced an increase in attentional bias for internal information from Time 1 to Time 2, whereas HSAs in the distraction condition and LSAs in either condition experienced no changes. No changes in biases were found for HSAs for external biases, but LSAs who engaged in the distraction task became less avoidant of emotional faces from Time 1 to Time 2. This suggests that anticipatory processing results in an activation of attentional biases for physiological information as suggested by Clark and Wells. PMID- 25022783 TI - Comparison of the offset distance of the tricuspid septal leaflet in neonates with Ebstein's anomaly and neonates with pulmonary atresia with intact ventricular septum. AB - An indexed offset distance of the tricuspid septal leaflet ?8 mm/m2 is a quantitative criterion for the diagnosis of Ebstein's anomaly. The purpose of this study was to investigate the validity of this criterion for the discrimination of Ebstein's anomaly from pulmonary atresia with intact ventricular septum in neonatal patients. A total of 122 neonatal patients, 56 with Ebstein's anomaly and 66 with pulmonary atresia with intact ventricular septum, were enrolled. Diagnosis of each anomaly was based on typical morphologic features. Echocardiographic variables, including the offset distance of the tricuspid septal leaflet, were measured via an offline analysis of images recorded before 1 month of age. The offset distance of the tricuspid septal leaflet was indexed by the body surface area, and the indexed offset distances in the Ebstein's anomaly and pulmonary atresia with intact ventricular septum groups were 34.2 mm/m2 (7.1-119.1 mm/m2) and 7.2 mm/m2 (0.0-25.6 mm/m2), respectively. The indexed offset distance was ?8 mm/m2 in 29 (43.9%) of the patients with pulmonary atresia with intact ventricular septum; clinical and echocardiographic characteristics were comparable between these 29 patients and the remaining 37 patients with pulmonary atresia with intact ventricular septum. When an indexed offset distance ?8 mm/m2 was applied as a cut-off for the diagnosis of Ebstein's anomaly, the sensitivity was 0.963 and the specificity was 0.561. In conclusion, indexed offset distance ?8 mm/m2 cannot be used as a cut-off for the diagnosis of complicated Ebstein's anomaly in neonatal patients with pulmonary atresia with intact ventricular septum. PMID- 25022784 TI - The necessity of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma using antiangiogenic targeted therapy after interferon alfa-2b. AB - BACKGROUND: Targeted therapy has improved the survival of patients with metastatic RCC. In the present study, we evaluated whether there was an effect of cytoreductive surgery on prognosis of patients with metastatic RCC using antiangiogenic tyrosine kinase inhibitor (TKI) agents. PATIENTS AND METHODS: A total of 52 patients with metastatic RCC from Akdeniz University, Afyon Kocatepe University, and Medipol University participated in the study. All the patients had received targeted antiangiogenic therapy after interferon alfa-2b. According to previous CRN, the patients were divided into 2 groups as CRN (+) and CRN (-). RESULTS: The CRN (+) group was younger than the CRN (-) group (P < .001) and the hemoglobin levels were significantly higher in the CRN (+) group (P = .023). The median progression-free survival time from the date of starting TKIs were 8.5 and 3.0 months for the CRN (+) and CRN (-) groups, respectively (P = .104). The median overall survival was 15.1 and 5.4 months for the CRN (+) and CRN (-) groups, respectively (P = .034). CONCLUSION: We speculate that CRN is still an important part of treatment modalities in patients with metastatic RCC in modern era targeted therapy, which is currently the best systemic therapy. However, the indications of CRN might be limited to good-risk patients with metastatic RCC. Further randomized studies are warranted to clarify the necessity of CRN in patients with metastatic RCC. PMID- 25022785 TI - 2014 GesEPOC and Systemic Steroids in chronic obstructive pulmonary disease (COPD) Exacerbation: An Update. PMID- 25022786 TI - Pneumomediastinum and pneumopericardium in a patient with squamous cell lung cancer. PMID- 25022787 TI - Effects of chemotherapy on patients with recurrent cervical cancer previously treated with concurrent chemoradiotherapy: a retrospective multicenter survey in Japan. AB - BACKGROUND: Predictive factors of the efficacy of chemotherapy for Japanese patients with recurrent cervical cancer who have been previously treated with concurrent chemoradiotherapy (CCRT) are currently unknown, and hence we aimed to investigate this. METHODS: We retrospectively studied the prognostic outcomes of patients with recurrent cervical cancer treated with CCRT between 2002 and 2010 at four medical facilities. RESULTS: A total of 64 patients were included in this study. Forty-two patients received definitive CCRT and 22 patients received postoperative adjuvant CCRT, with 55 receiving platinum-based combination chemotherapy and nine receiving single-agent chemotherapy. The overall response rate (ORR) was 12.5%, with one complete response. The median survival period was 12 months. The ORR and overall survival rate did not differ significantly according to recurrence site, post-CCRT interval, or chemotherapy regimen. CONCLUSION: None of the factors analyzed in this study were identified as positive predictive factors for the efficacy of chemotherapy in patients with recurrent cervical cancer after CCRT. Based on the results of previous studies, in order to improve long-term prognosis in recurrent cases, adjuvant chemotherapy should be considered as a potential treatment option for selected patients, especially as postoperative adjuvant therapy. PMID- 25022788 TI - The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be favorable: experience of two cancer centers in Japan. AB - BACKGROUND: Osteosarcoma as second malignancy of childhood cancers rarely occurs, and its clinical characteristics are unclear. METHODS: Patients with osteosarcoma occurring as second malignancy of childhood cancers were retrospectively surveyed. RESULTS: Of 323 patients with osteosarcoma registered in the database, 10 (3.1%) had a past history of childhood cancers. The mean age at the onset of the first childhood cancer was 2.7 years, and the diagnosis of the first childhood cancer was adrenocortical carcinoma, malignant teratoma, ovarian carcinoma, Ewing's sarcoma, and rhabdomyosarcoma in 1 patient each, and retinoblastoma in 5 patients. Osteosarcoma as second malignancy occurred 14.6 years after the first childhood cancer on average. Seven patients were alive and 3 died. In 1 patient, the cause of death was related to a complication of treatment for the first childhood cancer. Except for this patient, 7 (77.8%) of 9 patients survived with no disease (mean follow-up period: 10.9 years). CONCLUSIONS: Attention should be paid to complications of treatment for the first childhood cancer in the treatment for osteosarcoma occurring as second malignancy. The prognosis of osteosarcoma as second malignancy of childhood cancers may be more favorable than that of conventional osteosarcoma. PMID- 25022789 TI - Effect of cardiovascular drugs on mortality in atrial fibrillation and chronic heart failure. AB - OBJECTIVES: To study mortality rates among men and women with atrial fibrillation (AF) and concomitant chronic heart failure (CHF) prescribed different classes of cardiovascular drugs in primary health care. DESIGN: A cohort of men (n = 1159) and women (n = 1155) aged 45 years or above and diagnosed with both AF and CHF from patient records from 75 primary care centers in Sweden were included in the study. Regression models with mortality as the outcome were used, with adjustment for a propensity score comprising age, cardiovascular co-morbidities, education, marital status, and pharmacotherapy. We analysed using Cox regression with hazard ratio (HR), and Laplace regression with years until 10% of the patients had died, with 95% confidence intervals (95% CI). Independent variables were prescribed cardiovascular drugs. RESULTS: Individuals prescribed anticoagulants versus no treatment gained 1.95 years (95% CI 0.47-3.43), anticoagulants versus antiplatelets 1.26 years (95% CI 0.42-2.10), calcium channel blockers 1.17 years (95% CI 0.21-2.14), and statins 1.49 years (95% CI 0.39-2.59). Among patients 80 years or above no significant effect by anticoagulants was seen, HR 0.73 (95% CI 0.43-1.23). CONCLUSIONS: Our findings suggest that life may be prolonged in patients with AF and concomitant CHF in primary care prescribed anticoagulants, calcium channel blockers, and statins. PMID- 25022790 TI - Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. AB - INTRODUCTION: Short-term neural stem cell (NSC) transplantation improves cognition in Alzheimer's disease (AD) transgenic mice by enhancing endogenous synaptic connectivity. However, this approach has no effect on the underlying beta-amyloid (Abeta) and neurofibrillary tangle pathology. Long term efficacy of cell based approaches may therefore require combinatorial approaches. METHODS: To begin to examine this question we genetically-modified NSCs to stably express and secrete the Abeta-degrading enzyme, neprilysin (sNEP). Next, we studied the effects of sNEP expression in vitro by quantifying Abeta-degrading activity, NSC multipotency markers, and Abeta-induced toxicity. To determine whether sNEP expressing NSCs can also modulate AD-pathogenesis in vivo, control-modified and sNEP-NSCs were transplanted unilaterally into the hippocampus of two independent and well characterized transgenic models of AD: 3xTg-AD and Thy1-APP mice. After three months, stem cell engraftment, neprilysin expression, and AD pathology were examined. RESULTS: Our findings reveal that stem cell-mediated delivery of NEP provides marked and significant reductions in Abeta pathology and increases synaptic density in both 3xTg-AD and Thy1-APP transgenic mice. Remarkably, Abeta plaque loads are reduced not only in the hippocampus and subiculum adjacent to engrafted NSCs, but also within the amygdala and medial septum, areas that receive afferent projections from the engrafted region. CONCLUSIONS: Taken together, our data suggest that genetically-modified NSCs could provide a powerful combinatorial approach to not only enhance synaptic plasticity but to also target and modify underlying Alzheimer's disease pathology. PMID- 25022792 TI - Direct current shifts, high frequency oscillations and the epileptogenic zone. PMID- 25022791 TI - The antifungal metabolites obtained from the rhizospheric Aspergillus sp. YIM PH30001 against pathogenic fungi of Panax notoginseng. AB - Eight anthraquinones (1-8), three xanthones (11-13) and two phenols (9-10) were isolated from Aspergillus sp. associated with Panax notoginseng, and their structures were determined as ziganein-1-methyl ether (1), 8-O-methylchrysophanol (2), averythrin (3), averufin (4), 8-O-methyl averufin (5), versicolorin B (6), averantin (7), methyl-averantin (8), arugosin C (9), diorcinol (10), sterigmatocystin (11), demethylsterigmatocystin (12) and dihydrosterigmatocystin (13) by spectroscopic analyses. Compounds 1, 2 and 5 were the novel isolates from genus Aspergillus. Compounds 3, 6 and 7 exhibited antifungal activity against Fusariumsolani, pathogenic fungus of P. notoginseng, with minimum inhibitory concentrations (MICs) of 16-32 MUg/mL, and compounds 1, 3, 4, 7 and 9 showed antibacterial activity against Bacillussubtilis with MICs of 64-128 MUg/mL, 16-32 MUg/mL, 8-16 MUg/mL, 16-32 MUg/mL and 64-128 MUg/mL, respectively. The metabolites showed the potential value in the research of antifungal agents, especially in searching for a biocontrol of diseases of P. notoginseng. The preliminary structure-activity relationships have been discussed for some of the compounds. PMID- 25022793 TI - High-fidelity over the somatosensory cortex revisited: back to basics. PMID- 25022794 TI - Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: Fingolimod is an effective disease modifying therapy for multiple sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5mg/day. METHODS: Paired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5ms) and intracortical facilitation (at 7, 9, 11 and 13ms) were estimated at T0 and T1. RESULTS: Intracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition. CONCLUSIONS: Fingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate. SIGNIFICANCE: This is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitotoxicity in vivo, as already seen in animal models. PMID- 25022795 TI - The nodal response to chemoselection predicts the risk of recurrence following definitive chemoradiotherapy for pharyngeal cancer. AB - CONCLUSIONS: The poor response of neck tumors to induction chemotherapy (ICT) as chemoselection is related to a significantly worse prognosis, including higher risks of local recurrence and/or distant metastasis, after definitive chemoradiotherapy (CRT). OBJECTIVES: Neck dissection is frequently performed to treat residual lymph nodes after CRT for the purpose of locoregional control; however, the prognosis of patients with pathologically proven residual neck tumors is poor, and no methods for predicting unfavorable results before CRT have been established. Therefore, in the present study, we focused on the response of lymph nodes to ICT and its relationship with the prognosis among patients treated with chemoselection. METHODS: We retrospectively reviewed a total of 27 oropharyngeal and 24 hypopharyngeal squamous cell carcinoma stage III/IV consecutive patients with cervical lymph node metastasis who exhibited a response of >50% in the primary tumor to ICT followed by concurrent definitive CRT. RESULTS: The relapse-free survival of the patients who responded (partial response/complete response, PR/CR) to ICT was significantly superior to that of the patients who did not respond (stable disease, SD) to ICT (p = 0.008). PMID- 25022796 TI - A new combined therapy for functional organ preservation and survival in lateral oropharyngeal wall cancer. AB - CONCLUSION: The outcome of this treatment was good, indicating that it is safe and effective. A favorable outcome was obtained, especially in patients with T3, N0-1, and N2a-b cancer, while outcome remained unfavorable in patients with T4a and N2c cancer. Consideration should be given to the need for intensity-modulated radiation therapy (IMRT) and maintenance therapy. OBJECTIVE: To improve the survival and functional organ preservation rates in patients with lateral oropharyngeal squamous cell carcinoma. METHODS: The primary site was treated conservatively by neoadjuvant chemotherapy and/or concurrent chemoradiation therapy. Chemotherapy was administered by superselective intra-arterial infusion and cervical lymph node metastasis was treated by radical neck dissection. RESULTS: Among 71 patients, the 5- and 10-year overall survival rates were 85.1% and 63.5%, respectively; and the 5- and 10-year functional organ preservation rates were 61.0% and 51.6%, respectively. The outcomes were especially good in patients with T3 N0-1, and N2a-b cancer. All patients with N2c cancer had poor outcomes. PMID- 25022797 TI - Improving membrane based multiplex immunoassays for semi-quantitative detection of multiple cytokines in a single sample. AB - BACKGROUND: Inflammatory mediators can serve as biomarkers for the monitoring of the disease progression or prognosis in many conditions. In the present study we introduce an adaptation of a membrane-based technique in which the level of up to 40 cytokines and chemokines can be determined in both human and rodent blood in a semi-quantitative way. The planar assay was modified using the LI-COR (R) detection system (fluorescence based) rather than chemiluminescence and semi quantitative outcomes were achieved by normalizing the outcomes using the automated exposure settings of the Odyssey readout device. The results were compared to the gold standard assay, namely ELISA. RESULTS: The improved planar assay allowed the detection of a considerably higher number of analytes (n = 30 and n = 5 for fluorescent and chemiluminescent detection, respectively). The improved planar method showed high sensitivity up to 17 pg/ml and a linear correlation of the normalized fluorescence intensity with the results from the ELISA (r = 0.91). CONCLUSIONS: The results show that the membrane-based technique is a semi-quantitative assay that correlates satisfactorily to the gold standard when enhanced by the use of fluorescence and subsequent semi-quantitative analysis. This promising technique can be used to investigate inflammatory profiles in multiple conditions, particularly in studies with constraints in sample sizes and/or budget. PMID- 25022798 TI - Differences in ST-elevation and T-wave amplitudes do not reliably differentiate takotsubo cardiomyopathy from acute anterior myocardial infarction. AB - BACKGROUND: Previous efforts to distinguish acute anterior ST-elevation myocardial infarction (anterior-STEMI) from various forms of takotsubo cardiomyopathy (TTC) by electrocardiography (ECG) have produced differing results. METHODS: We performed a retrospective comparison of acute ECGs between 48 apical and 9 mid-ventricular TTC patients, with 96 anterior-STEMI patients. ECG was recorded in acute phase (<24h from onset of pain), and analyzed for ST changes, negative T-waves, abnormal Q-waves and QT-interval duration. Time from onset of pain to ECG was gathered from patient records. RESULTS: Anterior-STEMI patients had ST-elevation in lead V1 more frequently than apical (70% vs 15%, p<0.0001) or mid-ventricular TTC patients (70% vs 0%, p<0.0001), and higher ST elevation amplitudes in leads V2-V5 (p<0.02). Lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 distinguished TTC from anterior-STEMI patients with 63% sensitivity and 93% specificity, with 79% predictive value. CONCLUSIONS: In patients with anterior ST-elevation and acute chest pain, lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 suggests a TTC diagnosis. However, this criterion is not reliable enough in clinical practice to distinguish between TTC and anterior-STEMI patients. PMID- 25022799 TI - Electrocardiographic differentiation of Takotsubo syndrome from acute anterior ST elevation myocardial infarction. PMID- 25022800 TI - Are they family or friends? Social support instrument reliability in studying older lesbians. AB - We know little about the support needs and health of older lesbians because participant sexual identity has typically not been identified in aging studies. The Lubben Social Network Scale, Revised (LSNS-R) is found widely reliable for testing perceived social support among elders but has never been tested with an exclusively lesbian population. This pilot tested the instrument with an exclusively lesbian population in the Midwest. Our analysis suggests it may not be reliable with this population, even with minor modifications that were made. Further examination adding a category for "family of choice" is warranted and supported by the originator of the tool. PMID- 25022801 TI - Hydrolytic and acidogenic fermentation potential of food waste with source segregated feces-without-urine as co-substrate. AB - This study explored a new approach to enhance VFA productivity from anaerobic co digestion of food-waste (FW) with source-segregated brown-water (BW) [feces without-urine]. Effort was made to separate urine and BW from the source (using no-mix-toilet) mainly to expedite further treatment and resource-recovery. Effect of alkaline-pH [B] and acclimatized acidogenic inoculum [C] on acidification efficiency was investigated and compared with raw FW+BW co-digestion [A]. Batch assay results indicated that VFA productivity persists for 144-h with about 615%, 522% and 376% increase in VFA-COD, respectively for 3-conditions [A-C]; which accounted for 70%, 49% and 58% of CODs input, respectively. High butyric-acid was observed in [A] and [C], followed by acetic, propionic-acids; whereas, abundant acetic-acid (86% of TVFA) was observed in [B], which are the most favorable-forms for methane production or other value-added-products. For 144-h of acidification, this study validated the feasibility of maximizing VFA-yield by 7-12 times compared to FW or BW as a sole-substrate. PMID- 25022802 TI - Methylamidation for isomeric profiling of sialylated glycans by nanoLC-MS. AB - The analysis of isomeric glycans is a challenging task. In this work, a new strategy was developed for isomer-specific glycan profiling using nanoLC-MS with PGC as the stationary phase. Native glycans were derivatized in the presence of methylamine and trispyrrolidinophosphonium hexafluorophosphate and reduced by the ammonia-borane complex. Methylamidation stabilized the retention time and peak width and improved the detection sensitivity of sialylated glycans to 2-80-fold in comparison to previous ESI-MS methods using the positive-ion mode. Up to 19 tetrasialylated glycan species were identified in the derivatized human serum sample, which were difficult to detect in the sample without derivatization. Furthermore, due to high detection sensitivity and chromatographic resolution, more isomeric glycans could be identified from the model glycoprotein Fetuin and the human serum sample. As a result, up to seven isomers were observed for the disialylated biantennary glycan released from Fetuin, and three of them were identified for the first time in this study. Using the developed analytical strategy, a total of 293 glycan species were obtained from the human serum sample, representing an increase of over 100 peaks in comparison to the underivatized sample. The strategy greatly facilitates the profiling of isomeric glycans and the analysis of trace-level samples. PMID- 25022803 TI - Rosiglitazone attenuates cerebral vasospasm and provides neuroprotection in an experimental rat model of subarachnoid hemorrhage. AB - BACKGROUND: Glutamate and oxidative stress play important roles after subarachnoid hemorrhage (SAH). The ability to modulate glutamate transporter 1 (GLT-1) and the antioxidative effect of rosiglitazone have been demonstrated. We investigated the neuroprotective effect of rosiglitazone after SAH. METHODS: SAH was induced by double blood injection. The rats were randomly divided into sham, SAH + vehicle, and SAH + rosiglitazone groups and treated with dimethyl sulfoxide, dimethyl sulfoxide, and 6 mg/kg of rosiglitazone, respectively, at 2 and 12 h after SAH induction and then daily for 6 days. Cerebrospinal fluid dialysates were collected 30 min before SAH induction and then daily for 7 days for glutamate measurement. Mortality, body weight, and neurological scores were also measured daily. On day 7 after SAH, the wall thickness and the perimeter of the basilar artery (BA), neuron variability, GLT-1 levels, glial fibrillary acidic protein (GFAP) expression and activity, and malondialdehyde, superoxide dismutase, and catalase activities were also evaluated. RESULTS: Rosiglitazone improved survival (relative risk = 0.325) and neurological functions and reduced neuronal degeneration (5.7 +/- 0.8 vs. 10.0 +/- 0.9; P < 0.001) compared with the SAH + vehicle group. Rosiglitazone also lowered glutamate levels by 43.5-fold and upregulated GLT-1 expression by 1.5-fold and astrocyte activity by 1.8-fold compared with the SAH + vehicle group. The increase in BA wall thickness was significantly attenuated by rosiglitazone, whereas the perimeter of the BA was increased. In addition, rosiglitazone abated the 1.9-fold increase in malondialdehyde levels and the 1.6-fold increase in catalase activity after SAH. CONCLUSION: Rosiglitazone reduced SAH mortality, neurological deficits, body weight loss, GFAP loss, and cerebral vasospasm by preventing the neurotoxicity induced by glutamate and oxidative stress. PMID- 25022804 TI - Only very early oxygen therapy attenuates posthemorrhagic edema formation and blood-brain barrier disruption in murine intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Perihematomal edema exacerbates the mass effect of hematoma and contributes to early neurological deterioration after intracerebral hemorrhage (ICH). Oxygen therapy has protective effects on the blood-brain barrier (BBB). We aimed to examine the effects of oxygen therapy on edema formation and BBB permeability after ICH. METHODS: ICH was induced in mice by injecting autologous blood (30 uL) or collagenase (0.03 U) intrastriatally. Development of posthemorrhagic edema formation and BBB disruption was characterized by wet-dry-weight assays and sodium- fluorescein fluorospectrometry 1d, 3d, and 7d after ICH induction. In subsequent experiments, mice received air, normobaric (NBO), or hyperbaric oxygen (HBO; 3ata) for 60 min starting either 30, 60, or 120 min after ICH induction. Expression of occludin, claudin-5, zonula occludens-1, matrix metalloproteinases (MMPs), and hypoxia-inducible factor 1alpha (HIF-1alpha) was measured by Western blot and zymography. RESULTS: Posthemorrhagic edema formation (water content: blood-injection model 80.6 +/- 0.3 %; collagenase injection model 83.3 +/- 0.7 %) and BBB disruption (interhemispheric ratio of extravasated sodium fluorescein: blood-injection model 1.75 +/- 0.07; collagenase injection model 3.02 +/- 0.15) peaked 3d after ICH. NBO and HBO initiated within 30 min of ICH induction attenuated edema formation and BBB disruption (interhemispheric ratio of fluorescein; blood-injection air 1.75 +/- 0.12, NBO 1.52 +/- 0.08, HBO 1.49 +/- 0.09; collagenase: air 3.04 +/- 0.23, NBO 2.25 +/- 0.21, HBO 2.17 +/- 0.23) 3d after ICH, whereas delayed oxygen therapy had no effect. Early oxygen therapies prevented occludin degradation, MMP 9 activation, and reduced HIF-1alpha expression. CONCLUSION: Very early oxygen therapy can attenuate edema formation and BBB disruption after ICH, but the brief therapeutic time window suggests that the translational potential is limited. PMID- 25022805 TI - Ventilation practices in subarachnoid hemorrhage: a cohort study exploring the use of lung protective ventilation. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is common following aneurysmal subarachnoid hemorrhage (SAH), but the influence of mechanical ventilator settings on its development is unclear. We sought to determine adherence to lung protective thresholds in ventilated patients with SAH and describe the association between ventilator settings and subsequent development of ARDS. METHODS: We conducted a retrospective cohort study of consecutive patients receiving mechanical ventilation within 72 h of SAH at a single academic center. Ventilator settings and blood gas data were collected twice daily for the first 7 days of ventilation along with ICU and hospital outcomes. Lung protective ventilation was defined as follows: tidal volume <=8 mL/kg of predicted body weight, positive end-expiratory pressure (PEEP) >=5 cm H(2)O, and peak or plateau pressure <=30 cm H(2)O. The development of ARDS was ascertained retrospectively by PaO(2)/FiO(2) <=300 with new bilateral lung opacities on chest X-ray within one day of hypoxemia. RESULTS: We identified 62 patients who underwent early mechanical ventilation following SAH. PS and Continuous Positive Airway Pressure were common ventilator modes with a median tidal volume of 7.8 mL/kg [interquartile range 6.8-8.8], median peak pressure of 14 cm H(2)O [IQR 12-17], and median PEEP of 5 cm H(2)O [IQR 5-6]. Adherence to tidal volumes <=8 mL/kg was seen in 64 % of all observations and peak pressures <30 cm H(2)O were 94 % of all observations. All three lung protective criteria were seen in 58 % of all observations. Thirty-one patients (50 %) were determined to have ARDS. ARDS patients were more frequently ventilated with a peak pressure >30 cm H(2)O (11.3 % of ARDS ventilation days vs. 0 % of non-ARDS ventilation days; p < 0.01). Initial tidal volume was not associated with subsequent development of ARDS in univariate (p = 0.6) or multivariate analysis (p = 0.49). Only the number of ARDS risk factors was independently associated with the development of ARDS (Adjusted Odds Ratio 2.8 per additional risk factor [95 % CI 1.2-6.5]). CONCLUSION: Patients with SAH requiring mechanical ventilation frequently breathe spontaneously, generating tidal volumes above usual protective thresholds regardless of meeting ARDS criteria. In patients with SAH, the presence of an additional ARDS risk factor should prompt close screening for the development of ARDS and consideration of adjustment of ventilator settings to meet lung protective thresholds. PMID- 25022806 TI - Characteristics of brain magnetic resonance images at symptom onset in children with moyamoya disease. AB - OBJECTIVES: To clarify the characteristics of brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) at symptom onset in patients with childhood moyamoya disease (MD) according to developmental stage. METHODS: In 26 childhood MD patients who underwent brain MRI and MRA within 3 months from symptom onset, MRA scores and grades and MRI findings from symptomatic hemispheres were summarized according to developmental stage: infancy (0-1 years, three patients), toddlerhood/preschool age (2-5 years, nine patients), school age (6-10 years, seven patients), and adolescence (11-18 years, seven patients). RESULTS: Mean MRA score was 5.6, which was higher in adolescents (6.9). The most common MRA grade was grade 3, particularly in those under 10 years. Acute ischemic infarction presented in 17 patients (65%), was more common in patients below 5 years (83%) and was mainly in a gyral pattern (47%). Most hemorrhagic infarctions occurred in adolescents. Moyamoya vessels in the Sylvian valleys were apparent in 22 patients (85%), which were the most sensitive non-ischemic findings on T2 weighted images. The signal void in the distal internal carotid artery was diminished in 73% and apparent signal voids in basal ganglia were seen in three patients. The ivy sign was positive in 81% on fluid attenuated inversion recovery images and 69% on contrast-enhanced T1-weighted images in 21 and 16 patients, respectively. CONCLUSIONS: Brain MRIs and MRAs at symptom onset in childhood MD have characteristic findings, which differ in different developmental stage. PMID- 25022807 TI - The clinical significance, natural history and predictors of bone marrow lesion change over eight years. AB - INTRODUCTION: There is increasing evidence to suggest that bone marrow lesions (BMLs) play a key role in the pathogenesis of osteoarthritis (OA). However, there is a lack of long term data. The aim of this study was to describe the natural history of knee BMLs, their association with knee pain and examine predictors of BML change over eight years. METHODS: A total of 198 subjects (109 adult offspring of subjects who had a knee replacement and 89 community-based controls) were studied. Knee pain and BML size were assessed at two and ten year visits. RESULTS: At the two year visit, 64% of participants (n = 127) had 229 BMLs (34% patella, 26% femoral and 40% tibial). Over eight years, 24% (55/229) increased in size, 55% (125/229) remained stable and 21% (49/229) decreased in size or resolved completely. Of the participants without BMLs at baseline, 52% (37/71) developed incident BMLs. CONCLUSION: In this midlife cohort, the proportion of BMLs increasing in size was similar to those decreasing in size with the majority remaining stable. Change in BMLs was predicted by BMI and strenuous activity. An increase in BML size or a new BML resulted in an increase in pain especially in males and those with a family history of OA. PMID- 25022808 TI - Ethanol ablation of extradigital solid glomus tumors. AB - Glomus tumors are predominantly benign neoplasms accounting for less than 2% of all soft tissue tumors. While generally solitary, multiple lesions have been reported in approximately 10% of cases. Glomus tumors are typically under 1 cm in dimension accompanied by the classic triad of symptoms: debilitating pain, pinpoint tenderness, and hypersensitivity to cold temperatures. Excisional therapy is the accepted standard of care, however, past reports of non-invasive treatments for multiple glomangiomata variant tumors include laser therapy, irradiation, and sclerotherapy with STS and hypertonic saline. We present a case of a patient with multiple subcutaneous and intramuscular, lower-extremity benign solid glomus tumors treated successfully utilizing ethanol ablation, which has not been previously reported. This minimally invasive treatment allowed for control of symptoms from a benign condition previously requiring multiple invasive surgeries. PMID- 25022810 TI - Lateral pouch appendix associated with retroperitoneal terminal part of the ileum: a potential diagnostic and surgical challenge. AB - Knowledge of development and various possible positions of the appendix is important in understanding the pathophysiology of appendicitis. In the present case, we report on a lateral pouch type of appendix in a formalin-embalmed male cadaver. The appendix was found to be situated in a space between the caecum and the lateral abdominal wall. A short band of peritoneum extended from the right iliac fossa to the base of the appendix. The terminal part of the ileum was retroperitoneal and it was vertically situated in the right iliac fossa. Both the ileocaecal junction and the base of the appendix were located at the posterolateral wall of the caecum. The mesoappendix was unusual in position, and it extended from the appendix to the anterolateral wall of the caecum and commencement of the ascending colon. Documentation of rare anatomical variants of the appendix may hold significant clinical importance in diagnosis as well as surgical treatment of appendicitis. PMID- 25022809 TI - Benefits of submitral procedures for ischemic mitral regurgitation. AB - The surgical strategy for ischemic mitral regurgitation (MR) remains controversial. Ischemic MR is a secondary valve disease caused by left ventricular (LV) remodeling and subsequent papillary muscle displacement, usually without structural valve lesions. Reduction annuloplasty is the standard surgical procedure for this condition, though it cannot clearly provide a survival benefit for those with LV dysfunction and is associated with a high prevalence of late recurrence of MR. The valvular procedure alone could be insufficient to treat ischemic MR in terms of long-term survival and the prevention of recurrence because ischemic MR is primarily a ventricular disorder. Thus, recent studies have focused on alternative procedures that target the primary cause of ischemic MR, the papillary muscles and left ventricle. We believe that the appropriate selection of surgical procedures among valvular, subvalvular, and even ventricular ones, considering the severity of LV remodeling for each patient would be more beneficial. Here we review recent studies featuring various surgical approaches to ischemic MR, especially with submitral procedures. PMID- 25022811 TI - ACG clinical guideline: management of benign anorectal disorders. AB - These guidelines summarize the definitions, diagnostic criteria, differential diagnoses, and treatments of a group of benign disorders of anorectal function and/or structure. Disorders of function include defecation disorders, fecal incontinence, and proctalgia syndromes, whereas disorders of structure include anal fissure and hemorrhoids. Each section reviews the definitions, epidemiology and/or pathophysiology, diagnostic assessment, and treatment recommendations of each entity. These recommendations reflect a comprehensive search of all relevant topics of pertinent English language articles in PubMed, Ovid Medline, and the National Library of Medicine from 1966 to 2013 using appropriate terms for each subject. Recommendations for anal fissure and hemorrhoids lean heavily on adaptation from the American Society of Colon and Rectal Surgeons Practice Parameters from the most recent published guidelines in 2010 and 2011 and supplemented with subsequent publications through 2013. We used systematic reviews and meta-analyses when available, and this was supplemented by review of published clinical trials. PMID- 25022813 TI - Thyroid function: new mutation in human TRalpha proteins. PMID- 25022812 TI - Management of disorders of sex development. AB - The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the development of the urogenital tract and reproductive system. A variety of genetic factors have been identified that affect sex development during gonadal differentiation or in specific disorders associated with altered androgen biosynthesis or action. The diagnosis of DSDs in individuals and the subsequent management of patients and their families requires a targeted and structured approach, involving a multidisciplinary team with effective communication between the disciplines. This approach includes distinct clinical, imaging, laboratory and genetic evaluations of patients with DSDs. Although treatment of patients with DSDs can include endocrine and surgical options, many patients have concerns that arise from past incorrect treatments that were founded on the traditional binary concept of the sexes. To dispel these concerns, it is necessary to create centres of expertise for DSDs that include physicians, surgeons, psychologists and specialists in diagnostic procedures to manage patients and their families. Additionally, the inclusion of trained peer support in the multidisciplinary DSD team seems to be integral to the supportive management of patients with DSDs. Most importantly, dealing with DSDs requires acceptance of the fact that deviation from the traditional definitions of gender is not necessarily pathologic. PMID- 25022815 TI - US medical home model delivers savings and improves care, says health insurer. PMID- 25022816 TI - The seeded growth of graphene. AB - In this paper, we demonstrate the seeded growth of graphene under a plasma chemical vapor deposition condition. First, we fabricate graphene nanopowders (~5 nm) by ball-milling commercial multi-wall carbon nanotubes. The graphene nanoparticles were subsequently subject to a direct current plasma generated in a 100 Torr 10%CH4 - 90%H2 gas mixture. The plasma growth enlarged, over one hour, the nuclei to graphene sheets larger than one hundred nm(2) in area. Characterization by electron and X-ray diffraction, high-resolution transmission electron microscopy images provide evidence for the presence of monolayer graphene sheets. PMID- 25022814 TI - The management of patients with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The syndrome is typified by its heterogeneous presentation, which includes hirsutism (a function of hypersecretion of ovarian androgens), menstrual irregularity and infertility (that is due to infrequent or absent ovulation). Furthermore, PCOS predisposes patients to metabolic dysfunction and an increased risk of type 2 diabetes mellitus (T2DM). The aetiology of the syndrome has a major genetic component. Obesity exacerbates the insulin resistance that is a feature of PCOS in many women and amplifies the clinical and biochemical abnormalities. In clinical practice, the choice of investigations to be done depends mainly on the presenting symptoms. The approach to management is likewise dependent on the presenting complaint. Symptoms of androgen excess (hirsutism, acne and alopecia) require cosmetic measures, suppression of ovarian androgen function and anti-androgen therapy, alone or in combination. Ovulation rate is improved by diet and lifestyle intervention in overweight individuals but induction of ovulation by, in the first instance, anti-estrogens is usually required. Monitoring of glucose is important in overweight women and/or those with a family history of T2DM. Metformin is indicated for women with impaired glucose tolerance but whether this drug is otherwise useful in women with PCOS remains debatable. PMID- 25022817 TI - Trends in psychotropic polypharmacy among youths enrolled in Ohio Medicaid, 2002 2008. AB - OBJECTIVE: This study examined polypharmacy patterns and rates over time among Medicaid-enrolled youths by comparing three enrollment groups (youths in foster care, with a disability, or from a family with low income). METHODS: Serial cross sectional trend analyses of Medicaid claims data were conducted for youths age 17 and younger who were continuously enrolled in Ohio Medicaid for a one-year period and prescribed one or more psychotropic medications during fiscal years 2002 (N=26,252) through 2008 (N=50,311). Outcome measures were any polypharmacy (three or more psychotropic medications from any drug class) and multiclass polypharmacy (three or more psychotropic medications from different drug classes). RESULTS: Both types of polypharmacy increased across all three eligibility groups. Any polypharmacy increased from 8.8% to 11.5% for low-income youths (adjusted odds ratio [AOR]=1.12, 99% confidence interval [CI]=1.10-1.13), from 18.0% to 24.9% for youths with a disability (AOR=1.11, CI=1.09-1.13), and from 19.8% to 27.3% for youths in foster care (AOR=1.09, CI=1.07-1.11). Combinations associated with positive increases were two or more antipsychotics, two or more stimulants, and antipsychotics with stimulants. CONCLUSIONS: Polypharmacy increased across all enrollment groups, with the highest absolute rates for youths in foster care. Both the overall prevalence and increases in prescriptions for drug combinations with limited evidence of safety and efficacy, such as the prescription of two or more antipsychotics, underscore the need for targeted quality improvement efforts. System oversight and monitoring of psychotropic medication use appears to be warranted, especially for higher-risk groups, such as youths in foster care and those from low-income households who were prescribed multiple antipsychotics. PMID- 25022820 TI - The presence of hospital-based palliative care programs: A resource dependence perspective. AB - BACKGROUND: The presence of hospital-based palliative care programs has risen over time in the United States. Nevertheless, organizational and environmental factors that contribute to the presence of hospital-based palliative care programs are unclear. PURPOSE: The aim of this study was to examine the role of organizational and environmental factors associated with the presence of hospital based palliative care programs using resource dependence theory. METHODOLOGY: Panel data from 2000 to 2009 American Hospital Association Annual Survey and the Area Resource File were used in this study. A random-effect logistic regression was used to analyze the relationship between organizational and environmental factors and the presence of hospital-based palliative care programs. FINDINGS: Hospitals with higher Medicare inpatient days, located in counties with higher Medicare managed penetration, and larger hospitals had greater odds of having a hospital-based palliative care program. Although hospitals in counties that have a higher percentage of individuals 65 years and older, for-profit and government hospitals were less likely to have a hospital-based palliative care program. PRACTICE IMPLICATIONS: Hospitals will vary in the organizational resources available to them, as such, administrators' awareness of the relationship between resources and palliative care programs can help determine the relevance of a program in their hospital. PMID- 25022819 TI - Remote preconditioning and major clinical complications following adult cardiovascular surgery: systematic review and meta-analysis. AB - BACKGROUND: A number of 'proof-of-concept' trials suggest that remote ischaemic preconditioning (RIPC) reduces surrogate markers of end-organ injury in patients undergoing major cardiovascular surgery. To date, few studies have involved hard clinical outcomes as primary end-points. METHODS: Randomised clinical trials of RIPC in major adult cardiovascular surgery were identified by a systematic review of electronic abstract databases, conference proceedings and article reference lists. Clinical end-points were extracted from trial reports. In addition, trial principal investigators provided unpublished clinical outcome data. RESULTS: In total, 23 trials of RIPC in 2200 patients undergoing major adult cardiovascular surgery were identified. RIPC did not have a significant effect on clinical end points (death, peri-operative myocardial infarction (MI), renal failure, stroke, mesenteric ischaemia, hospital or critical care length of stay). CONCLUSION: Pooled data from pilot trials cannot confirm that RIPC has any significant effect on clinically relevant end-points. Heterogeneity in study inclusion and exclusion criteria and in the type of preconditioning stimulus limits the potential for extrapolation at present. An effort must be made to clarify the optimal preconditioning stimulus. Following this, large-scale trials in a range of patient populations are required to ascertain the role of this simple, cost effective intervention in routine practice. PMID- 25022818 TI - Parental involvement: contribution to childhood anxiety and its treatment. AB - Anxiety disorders are prevalent in youth. Despite demonstrated efficacy of cognitive behavioral therapy (CBT), approximately 40% of anxiety-disordered youth remain unresponsive to treatment. Because developmental and etiological models suggest that parental factors are relevant to the onset and maintenance of childhood anxiety, researchers have proposed and investigated family-based interventions with increased parent work in treatment, aiming to improve the efficacy of treatment for childhood anxiety. However, contrary to what theoretical models suggest, data to date did not indicate additive benefit of family-based CBT in comparison with child-centered modality. Is parent/family involvement unnecessary when treating childhood anxiety disorders? Or could there be the need for specificity (tailored family-based treatment) that is guided by a revised conceptualization that improves the implementation of a family-based intervention? The current review examines (1) relevant parental factors that have been found to be associated with the development and maintenance of childhood anxiety and (2) interventions that incorporate parental involvement. Relevant findings are integrated to formulate a "targeted" treatment approach for parental involvement in CBT for youth anxiety. Specifically, there is potential in the assessment of parent/family factors prior to treatment (for appropriateness) followed by a target-oriented implementation of parent training. PMID- 25022821 TI - The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy. AB - BACKGROUND: The mechanism of action of vagus nerve stimulation (VNS) in intractable epilepsy is not entirely clarified. It is believed that VNS causes alterations in cytokines, which can lead to rebalancing the release of neurotoxic and neuroprotective tryptophan metabolites. We aimed to evaluate VNS effects on tryptophan metabolites and on epileptic seizures and investigated whether the antiepileptic effectiveness correlated with changes in tryptophan metabolism. METHODS: Forty-one children with intractable epilepsy were included in a randomized, active-controlled, double-blind study. After a baseline period of 12 weeks, all children underwent implantation of a vagus nerve stimulator and entered a blinded active-controlled phase of 20 weeks. Half of the children received high-output (therapeutic) stimulation (n=21), while the other half received low-output (active control) stimulation (n=20). Subsequently, all children received high-output stimulation for another 19 weeks (add-on phase). Tryptophan metabolites were assessed in plasma and cerebrospinal fluid (CSF) by use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared between high- and low-output groups and between the end of both study phases and baseline. Seizure frequency was recorded using seizure diaries. Mood was assessed using Profile of Mood States (POMS) questionnaires. RESULTS: Regarding tryptophan metabolites, anthranilic acid (AA) levels were significantly higher at the end of the add-on phase compared with baseline (p=0.002) and correlated significantly with improvement of mood (tau=-0.39, p=0.037) and seizure frequency reduction (tau=-0.33, p<0.01). No significant changes were found between high- and low output groups regarding seizure frequency. CONCLUSION: Vagus nerve stimulation induces a consistent increase in AA, a neuroprotective and anticonvulsant tryptophan metabolite. Moreover, increased AA levels are associated with improvement in mood and reduction of seizure frequency. PMID- 25022822 TI - Empathy and emotion recognition in patients with idiopathic generalized epilepsy. AB - Patients with epilepsy have deficits in social cognition. In this study, we examined the changes in empathy and eye emotion recognition using the Interpersonal Reactivity Index and eye emotion recognition tasks. Forty-two patients with idiopathic generalized epilepsy and 47 healthy controls were involved. The eye emotion recognition and cognitive empathy abilities of the patients with IGE were impaired, but the affective empathy was intact. The cognitive empathy performance of the patients with IGE was positively correlated with their performance in sadness recognition, MoCA, verbal fluency, and the Stroop test. These results suggest that the empathy ability was impaired in patients with IGE, and this impairment may be caused by deficits in frontal lobe function. PMID- 25022823 TI - Ethical dilemmas in pediatric and adolescent psychogenic nonepileptic seizures. AB - To date, only a very narrow window of ethical dilemmas in psychogenic nonepileptic seizures (PNES) has been explored. Numerous distinct ethical dilemmas arise in diagnosing and treating pediatric and adolescent patients with PNESs. Important ethical values at stake include trust, transparency, confidentiality, professionalism, autonomy of all stakeholders, and justice. In order to further elucidate the ethical challenges in caring for this population, an ethical analysis of the special challenges faced in four specific domains is undertaken: (1) conducting and communicating a diagnosis of PNESs, (2) advising patients about full transparency and disclosure to community including patients' peers, (3) responding to requests to continue antiepileptic drugs, and (4) managing challenges arising from school policy and procedure. An analysis of these ethical issues is essential for the advancement of best care practices that promote the overall well-being of patients and their families. PMID- 25022824 TI - The effects of medication education and behavioral intervention on Chinese patients with epilepsy. AB - OBJECTIVES: The objectives of this study were to evaluate the effects of medication education and behavioral intervention on Chinese patients with epilepsy and to compare the difference between them. METHODS: A total of 109 patients with epilepsy who did not to take their antiepileptic drugs (AEDs) more than once were randomly assigned to two intervention groups: the medication education group (group I) and the medication education with behavioral intervention group (group II). Group I was initially provided with medication education in the form of oral education and written materials, and this education was reinforced by monthly calls from the pharmacist over the next six months. The behavioral intervention provided to group II consisted of a modified medication schedule which was based on cue-dose training therapy. The outcomes that were evaluated both in the beginning and in the end of the study included adherence, which was measured using the four-item Morisky Medication Adherence Scale (MMAS 4), the number of seizures, knowledge of AEDs, and the number of patients who missed a dose of their AEDs. Differences within and between the groups were analyzed. RESULTS: After intervention, the adherence and knowledge of AEDs increased greatly in all patients, and the number of patients who had seizures or missed AEDs decreased. However, no significant differences were observed between groups I and II. The observed changes were (group I vs group II, p value) increased adherence: 62.3% vs 64.3%, 0.827; increased knowledge of AEDs: 88.7% vs 80.4%, 0.231; and improved seizure control: 64.2% vs 64.3%, 0.988. In addition, the percentage of patients who forgot to take their AEDs decreased to 45.0% from more than 70%, and 44.9% of these patients took the missed AEDs as soon as they remembered. DISCUSSION: These findings clearly demonstrate that medication education and reinforced telephone calls from pharmacists can help to increase adherence to AEDs, the knowledge of patients regarding AEDs, and seizure control. However, the inclusion of a behavioral strategy that was easy to administer and use in this program did not lead to any significant effects on improving adherence. The results indicate that pharmacists can play an important role in improving the effects of medication regimens, but further research is required to identify strategies for improving adherence to behavioral theory. PMID- 25022826 TI - Molecular ordering of phenyl groups at the buried polystyrene/metal interface. AB - Understanding molecular structures of buried polymer/metal interfaces is important for the design and development of polymer adhesives used in advanced microelectronic devices and polymer anticorrosion coatings for metals. The buried interfacial molecular structure between polystyrene (PS) and silver (Ag) was investigated using infrared-visible sum frequency generation (SFG) vibrational spectroscopy via a "sandwiched" sample geometry. SFG resonant signals from the phenyl C-H stretching vibrational modes were detected from the PS/Ag interface, suggesting that the PS phenyl groups at this buried polymer/metal interface are ordered. Spectral analysis indicated that the phenyl groups at the buried PS/Ag interface tilt toward the interface, pointing away from the Ag side. PMID- 25022825 TI - Artificial microRNA mediated gene silencing in plants: progress and perspectives. AB - Homology based gene silencing has emerged as a convenient approach for repressing expression of genes in order to study their functions. For this purpose, several antisense or small interfering RNA based gene silencing techniques have been frequently employed in plant research. Artificial microRNAs (amiRNAs) mediated gene silencing represents one of such techniques which can utilize as a potential tool in functional genomics. Similar to microRNAs, amiRNAs are single-stranded, approximately 21 nt long, and designed by replacing the mature miRNA sequences of duplex within pre-miRNAs. These amiRNAs are processed via small RNA biogenesis and silencing machinery and deregulate target expression. Holding to various refinements, amiRNA technology offers several advantages over other gene silencing methods. This is a powerful and robust tool, and could be applied to unravel new insight of metabolic pathways and gene functions across the various disciplines as well as in translating observations for improving favourable traits in plants. This review highlights general background of small RNAs, improvements made in RNAi based gene silencing, implications of amiRNA in gene silencing, and describes future themes for improving value of this technology in plant science. PMID- 25022827 TI - The ability of volumetric capnography to distinguish between chronic obstructive pulmonary disease patients and normal subjects. AB - PURPOSE: The aim of our study was to evaluate volumetric capnography (VCap) in the differentiation between chronic obstructive pulmonary disease (COPD) patients and normal subjects. PATIENTS AND METHODS: Thirty-nine healthy male volunteers and 60 male COPD patients were enrolled. Regression equations between VCap indices and age, weight, height, and tidal volume in healthy volunteers were established by stepwise regression analysis. Predicted normal values of VCap indices in COPD patients were calculated. A paired t test was used to compare the difference between observed and predicted values for VCap indices in COPD patients. Receiver operating characteristic (ROC) curve analysis was used to evaluate the power of each VCap index alone in differentiating COPD patients and normal subjects. The power of the combination of VCap indices was assessed by discriminant analysis. RESULTS: All regression equations were significant (P < 0.01) as were the differences between the observed and predicted normal VCap indices in COPD patients (P < 0.001). ROC curve analysis showed that the volume between 25 and 50% of F CO2et (Vm25-50), slope of Phase II (dC2/dV), and slope of Phase III (dC3/dV) were valuable predictors. Nearly all (90.9%) subjects were correctly classified by discriminant analysis. CONCLUSION: Vm25-50, dC2/dV, or dC3/dV alone are valuable for differentiating COPD patients and normal subjects, but more powerful are the combinations of Vm25-50, dC2/dV, and dC3/dV, the ratio of dC2/dV to dC3/dV (SR23), dead space according to the Bohr method (VDB), and dead space according to the Wolff and Brunner methods (PIE). PMID- 25022828 TI - The influence of body size on the pharmacodynamic and pharmacokinetic response to clopidogrel and prasugrel: a retrospective analysis of the FEATHER study. AB - INTRODUCTION: Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5mg (Pras-5), and prasugrel 10mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups. MATERIALS AND METHODS: Aspirin-treated patients with stable coronary artery disease (N=72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20MUM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed. RESULTS: Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p<0.01). CONCLUSIONS: Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel. PMID- 25022829 TI - A comparison of active adverse event surveillance systems worldwide. AB - Post-marketing drug surveillance for adverse drug events (ADEs) has typically relied on spontaneous reporting. Recently, regulatory agencies have turned their attention to more preemptive approaches that use existing data for surveillance. We conducted an environmental scan to identify active surveillance systems worldwide that use existing data for the detection of ADEs. We extracted data about the systems' structures, data, and functions. We synthesized the information across systems to identify common features of these systems. We identified nine active surveillance systems. Two systems are US based-the FDA Sentinel Initiative (including both the Mini-Sentinel Initiative and the Federal Partner Collaboration) and the Vaccine Safety Datalink (VSD); two are Canadian the Canadian Network for Observational Drug Effect Studies (CNODES) and the Vaccine and Immunization Surveillance in Ontario (VISION); and two are European the Exploring and Understanding Adverse Drug Reactions by Integrative Mining of Clinical Records and Biomedical Knowledge (EU-ADR) Alliance and the Vaccine Adverse Event Surveillance and Communication (VAESCO). Additionally, there is the Asian Pharmacoepidemiology Network (AsPEN) and the Shanghai Drug Monitoring and Evaluative System (SDMES). We identified two systems in the UK-the Vigilance and Risk Management of Medicines (VRMM) Division and the Drug Safety Research Unit (DSRU), an independent academic unit. These surveillance systems mostly use administrative claims or electronic medical records; most conduct pharmacovigilance on behalf of a regulatory agency. Either a common data model or a centralized model is used to access existing data. The systems have been built using national data alone or via partnership with other countries. However, active surveillance systems using existing data remain rare. North America and Europe have the most population coverage; with Asian countries making good advances. PMID- 25022830 TI - The effect of early detection of anterolateral thigh free flap crisis on the salvage success rate, based on 10 years of experience and 1072 flaps. AB - The aim of this study was to assess the effectiveness of early exploration of anterolateral thigh (ALT) free flap compromise in head and neck reconstruction and to correlate this with the salvage success rate. The perioperative data of 1051 patients with 1072 ALT flap reconstructions were reviewed retrospectively for the period January 2002 to December 2012. Outcome measures included ethnicity, defect type, incidence and timing of flap compromise, type of flap compromise, causes of vascular occlusion, and salvage rate. The success rate of free flap reconstruction was 97.3% (1043/1072). Of the 29 failures, 21 were complete and eight were partial failures (10-40% of the flap). Venous occlusions occurred in 39 flaps (83.0%) and arterial occlusions in five flaps (17.0%). Six cases were detected within 8h postoperatively, 13 at 8-16 h postoperatively, seven at 16-24h postoperatively, and 18 at 24-48 h postoperatively, with respective salvage rates of 66.7%, 61.5%, 28.6%, and 22.2%; three cases detected after 48 h failed. The salvage rate at <=16 h (62.2%) was much higher than that at >16 h (21.4%, P=0.0039). Early detection, re-exploration, and effective handling of the flap crisis increases the rate of flap salvage tremendously. PMID- 25022831 TI - Inpatient treatment of children and adolescents with severe obesity in the Netherlands: a randomized clinical trial. AB - IMPORTANCE: Severe childhood obesity has become a major health problem, and effective, evidence-based interventions are needed. The relative effectiveness of inpatient compared with ambulatory treatment remains unknown. OBJECTIVE: To determine whether an inpatient treatment program is more effective than an ambulatory treatment program at achieving a sustained weight loss in children and adolescents with severe obesity. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized clinical trial with a 2-year follow-up at a tertiary referral center for pediatric obesity in the Netherlands. We recruited 90 children and adolescents aged 8 to 18 years with severe obesity (body mass index [BMI] z score, >=3.0 or >2.3 with obesity-related health problems). INTERVENTIONS: Patients were randomly assigned to an inpatient (6 months of hospitalization on working days) or an ambulatory (12 days of hospital visits at increasing intervals during a 6-month period) treatment program. Both treatment programs involved an intensive, family-based, lifestyle intervention, including exercise, nutritional education, and behavior modification for the patients and their caregiver(s). MAIN OUTCOMES AND MEASURES: Change in BMI z score. Secondary outcomes included fasting insulin, fasting plasma glucose, 2-hour plasma glucose, and lipid levels, insulin sensitivity, liver function test results, waist circumference, blood pressure, body composition, and aerobic fitness (peak oxygen consumption, Vo2). Outcomes were analyzed by intention to treat. RESULTS: Immediately after treatment, reductions in the BMI z score were significantly larger for the inpatient than the ambulatory groups (mean [SE] difference, -0.26 [0.12; 95% CI, -0.59 to -0.01]; P = .04). Change from baseline for the BMI z score in the inpatient group was -18.0% (P = .001) immediately after treatment, 8.5% (P = .008) at 18 months, and -6.3% (P = .38) at 30 months; in the ambulatory group, changes from baseline were -10.5% (P = .001), -6.2% (P = .39), and -1.5% (P > .99), respectively. The favorable outcomes of the inpatient group could not be sustained at 12 and 24 months after treatment. In addition, significant differences in favor of the inpatient group immediately after treatment were found for levels of fasting insulin (-6.37 IU/L; P = .02), total cholesterol ( 19.51 mg/dL; P = .01), low-density lipoprotein cholesterol (-13.48 mg/dL; P = .03), and triglycerides (-25.39 mg/dL; P = .01), and insulin sensitivity (-1.37; P = .02), fat mass (-3.31%; P = .03), and peak Vo2 (378.2 mL/min; P = .01). CONCLUSIONS AND RELEVANCE: In severely obese children and adolescents, inpatient treatment was superior to ambulatory treatment immediately after treatment, but effects were not sustained at long-term follow-up. These findings stress the need to further study maintenance strategies for sustainable weight loss. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1172. PMID- 25022832 TI - A prospective cohort study investigating readmission, symptom attribution and psychological health within six months of primary percutaneous coronary intervention. AB - AIMS: Following primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction, some patients are readmitted with potential ischaemic heart disease symptoms. This study investigated the proportion of PPCI patients readmitted due to potential ischaemic heart disease symptoms within six months, and the cause of symptoms and associated factors. METHODS AND RESULTS: A prospective cohort study included consecutive PPCI patients. Baseline variables incorporated the Global Registry of Acute Coronary Events, the Charlson Comorbidity Index and self-report measures ENRICHD Social Support Inventory, Seattle Angina Questionnaire (SAQ) and Hospital and Anxiety and Depression Scale (HADS). At six months, repeat SAQ, HADS and readmission data were collected. Of 202 PPCI patients (mean 59.7 years (SD 13.9), 75.7% male), 38 (18.8%; 95% confidence interval 14.0-24.8%) were readmitted due to potential ischaemic heart disease symptoms (16 cardiac events, 22 indeterminate diagnosis) at six months. Mean HADS anxiety scores were higher for the readmission compared with the non readmission group (baseline 9.5 vs. 7.1, p=0.006; six months 9.4 vs. 6.0, p<0.001). Angina symptoms were stable and infrequent throughout for both groups. Logistic regression modelling, including predictors HADS anxiety, SAQ angina stability, SAQ angina frequency, the Global Registry of Acute Coronary Events and the Charlson Comorbidity Index, determined HADS anxiety as a predictor of readmission with adjusted odds ratio of 1.12 (95% confidence interval 1.03-1.22, p=0.008). CONCLUSION: One in six patients were readmitted due to potential ischaemic heart disease symptoms, with the largest proportion receiving an indeterminate readmission diagnosis. Elevated levels of anxiety at baseline were predictive of readmission with potential ischaemic heart disease symptoms at six months. PMID- 25022833 TI - An exploration of the perceptions of emergency department nursing staff towards the role of a domestic abuse nurse specialist: a qualitative study. AB - There is a clear body of evidence which indicates that a substantial number of people who have experienced domestic violence and abuse attend the emergency department (ED). However, many individuals do not receive effective identification or support. The present study sought to explore the perceptions of ED staff about the perceived value and utilisation of a new domestic abuse nurse specialist role that has been created in one ED in the UK. A qualitative design was used and involved sixteen in-depth interviews with a range of practitioners. The findings highlight that staff highly valued the role of the nurse specialist as one which offered support both professionally and personally. However, the study has also drawn attention to the conundrum that surrounds identification and management of abuse and of enquiry more generally. The ED is ideally suited to identify at risk individuals but is not institutionally organised in a way that prioritises the social concerns of their patients and this nursing role is one way that this issue can be addressed. In light of recent UK and global policy directives further research is needed to explore the development and implementation of identification, management and support in the future. PMID- 25022834 TI - Sources and correlates of sodium consumption in the first 2 years of life. AB - BACKGROUND: High sodium intake during infancy and early childhood can change salt preference and blood pressure trajectories across life, representing a modifiable cardiovascular risk factor. Describing young children's sodium intake is important for informing effective targets for sodium reduction. OBJECTIVE: This study aimed to describe food sources and demographic and behavioral correlates of sodium intake in 295 young Australian children using three unscheduled 24-hour recalls (when children were 9 and then 18 months of age) with mothers participating within an existing randomized controlled trial, the Melbourne Infant Feeding Activity and Nutrition Trial (InFANT) Program. METHODS: Differences in individual-level and family-level demographic and behavioral variables were assessed across tertiles of sodium density (mg/1,000 kcal). Descriptive statistics were used to describe food-group contributions to total energy and sodium intakes at both ages. RESULTS: Mean sodium intake was 486 mg (standard deviation=232 mg) at 9 months and had more than doubled to 1,069 mg (standard deviation=331 mg) at 18 months of age. Fifty-four percent of children at 18 months exceeded the Recommended Daily Upper Level for sodium intake, with bread, cheese, breakfast cereal, soup, and mixed dishes all important sources of sodium at both ages. Yeast extracts, processed meats, and bread products became important additional sources at 18 months. A greater proportion of children in the highest sodium-density tertile had ceased breastfeeding and had commenced solids at an earlier age. CONCLUSIONS: The key food sources of sodium for children younger than 2 years are those that contribute to the whole population's high salt burden and highlight the essential role governments and food industry must play to reduce salt in commonly consumed foods. PMID- 25022835 TI - Biogas energy production from tropical biomass wastes by anaerobic digestion. AB - Anaerobic digestion (AD) is an attractive technology in tropical regions for converting locally abundant biomass wastes into biogas which can be used to produce heat, electricity, and transportation fuels. However, investigations on AD of tropical forestry wastes, such as albizia biomass and food wastes, such as taro, papaya, and sweet potato, are limited. In this study, these tropical biomass wastes were evaluated for biogas production by liquid AD (L-AD) and/or solid-state AD (SS-AD), depending on feedstock characteristics. When albizia leaves and chips were used as feedstocks, L-AD had greater methane yields (161 and 113 L kg(-1)VS, respectively) than SS-AD (156.8 and 59.6 L kg(-1)VS, respectively), while SS-AD achieved 5-fold higher volumetric methane productivity than L-AD. Mono-digestion and co-digestion of taro skin, taro flesh, papaya, and sweet potato achieved methane yields from 345 to 411 L kg(-1)VS, indicating the robustness of AD technology. PMID- 25022836 TI - Inhibitors of biofilm formation by biofuel fermentation contaminants. AB - Biofuel fermentation contaminants such as Lactobacillus sp. may persist in production facilities by forming recalcitrant biofilms. In this study, biofilm forming strains of Lactobacillus brevis, Lactobacillus fermentum, and Lactobacillus plantarum were isolated and characterized from a dry-grind fuel ethanol plant. A variety of potential biofilm inhibitors were tested, including microbial polysaccharides, commercial enzymes, ferric ammonium citrate, liamocins, phage endolysin, xylitol, and culture supernatants from Bacillus sp. A commercial enzyme mixture (Novozyme 188) and culture supernatants from Bacillus subtilis strains ALT3A and RPT-82412 were identified as the most promising biofilm inhibitors. In biofilm flow cells, these inhibitors reduced the density of viable biofilm cells by 0.8-0.9 log cfu/cm(2). Unlike B. subtilis strain RPT 82412, B. subtilis strain ALT3A and Novozyme 188 did not inhibit planktonic growth of Lactobacillus sp. MALDI-TOF mass spectra showed the production of surfactin-like molecules by both B. subtilis strains, and the coproduction of iturin-like molecules by strain RPT-82412. PMID- 25022837 TI - An efficient regioselective hydrodifluoromethylation of unactivated alkenes with TMSCF2CO2Et at ambient temperature. AB - A mild, versatile and efficient method for the regioselective hydrodifluoromethylation of unactivated alkenes has been developed. This Ag mediated Csp(3)-CF2 bond forming reaction provides easy access to a variety of vicinal alpha-difluoroacetate-containing alkanes. PMID- 25022838 TI - Development and evaluation of a novel low-cost sensor-based knee flexion angle measurement system. AB - BACKGROUND: Knee injuries form a large part of musculoskeletal trauma in sporting activities and the rehabilitation can require a long period, for both the patients and the specialists, to restore healthy condition. A reliable, portable, and low-cost system that could allow quick, simple, and effective measurement of knee flexion angles would greatly improve the evaluation of the rehabilitation process and the subsequent planning procedure, with meaningful reduction of recovery time and cost. METHODS: A novel tool for nonstop measurements of knee flexion angles based on the adoption of an elastic sensor embedded in an easy-to realize wearable kneepad has been proposed. We fully characterized this tool in terms of accuracy, repeatability, and reliability of measure, and validated it against the gold-standard Vicon. RESULTS: Our tool demonstrated good reproducibility and repeatability among testers (mean range of measures=5.82 degrees +/- 1.93 degrees ) and high accuracy (root mean square error<1.28 degrees ), together with good reliability (intraclass correlation coefficient between 0.80 and 0.91). CONCLUSIONS: The proposed tool demonstrates good performance, is portable, cheap, easy to use, and allows automatic measurements, so as to be a valuable system for accurate nonstop measurement of knee angles. CLINICAL RELEVANCE: Our sensor-based measurement system is suitable for the evaluation of the rehabilitation course after knee traumas, because it furnishes a low-cost but accurate monitor of knee flexion movements, during an amount of time as long as desired. PMID- 25022839 TI - Reliability of a semi-automated 3D-CT measuring method for tunnel diameters after anterior cruciate ligament reconstruction: A comparison between soft-tissue single-bundle allograft vs. autograft. AB - BACKGROUND: Post-operative widening of tibial and/or femoral bone tunnels is a common observation after ACL reconstruction, especially with soft-tissue grafts. There are no studies comparing tunnel widening in hamstring autografts versus tibialis anterior allografts. The goal of this study was to observe the difference in tunnel widening after the use of allograft vs. autograft for ACL reconstruction, by measuring it with a novel 3-D computed tomography based method. METHODS: Thirty-five ACL-deficient subjects were included, underwent anatomic single-bundle ACL reconstruction and were evaluated at one year after surgery with the use of 3-D CT imaging. Three independent observers semi automatically delineated femoral and tibial tunnel outlines, after which a best fit cylinder was derived and the tunnel diameter was determined. Finally, intra- and inter-observer reliability of this novel measurement protocol was defined. RESULTS: In femoral tunnels, the intra-observer ICC was 0.973 (95% CI: 0.922 0.991) and the inter-observer ICC was 0.992 (95% CI: 0.982-0.996). In tibial tunnels, the intra-observer ICC was 0.955 (95% CI: 0.875-0.985). The combined inter-observer ICC was 0.970 (95% CI: 0.987-0.917). Tunnel widening was significantly higher in allografts compared to autografts, in the tibial tunnels (p=0.013) as well as in the femoral tunnels (p=0.007). CONCLUSIONS: To our knowledge, this novel, semi-automated 3D-computed tomography image processing method has shown to yield highly reproducible results for the measurement of bone tunnel diameter and area. This series showed a significantly higher amount of tunnel widening observed in the allograft group at one-year follow-up. LEVEL OF EVIDENCE: Level II, Prospective comparative study. PMID- 25022840 TI - Subdoses of 17DD yellow fever vaccine elicit equivalent virological/immunological kinetics timeline. AB - BACKGROUND: The live attenuated 17DD Yellow Fever vaccine is one of the most successful prophylactic interventions for controlling disease expansion ever designed and utilized in larger scale. However, increase on worldwide vaccine demands and manufacturing restrictions urge for more detailed dose sparing studies. The establishment of complementary biomarkers in addition to PRNT and Viremia could support a secure decision-making regarding the use of 17DD YF vaccine subdoses. The present work aimed at comparing the serum chemokine and cytokine kinetics triggered by five subdoses of 17DD YF Vaccine. METHODS: Neutralizing antibody titers, viremia, cytokines and chemokines were tested on blood samples obtained from eligible primary vaccinees. RESULTS AND DISCUSSION: The results demonstrated that a fifty-fold lower dose of 17DD-YF vaccine (587 IU) is able to trigger similar immunogenicity, as evidenced by significant titers of anti-YF PRNT. However, only subdoses as low as 3,013 IU elicit viremia kinetics with an early peak at five days after primary vaccination equivalent to the current dose (27,476 IU), while other subdoses show a distinct, lower in magnitude and later peak at day 6 post-vaccination. Although the subdose of 587 IU is able to trigger equivalent kinetics of IL-8/CXCL-8 and MCP-1/CCL-2, only the subdose of 3,013 IU is able to trigger similar kinetics of MIG/CXCL-9, pro inflammatory (TNF, IFN-gamma and IL-2) and modulatory cytokines (IL-5 and IL-10). CONCLUSIONS: The analysis of serum biomarkers IFN-gamma and IL-10, in association to PRNT and viremia, support the recommendation of use of a ten-fold lower subdose (3,013 IU) of 17DD-YF vaccine. PMID- 25022841 TI - Pseudo pulmonary embolism in cancer patients: a new clinical syndrome. AB - To characterize the clinical features of oncology patients presenting with shortness of breath mistakenly diagnosed at first with pulmonary emboli, but later found instead to have extrinsic compression of the pulmonary artery or its tributaries by tumor. Medical charts and computed tomography (CT) angiographies of these patients were reviewed retrospectively. In a 7-year period, 11 patients from a single institute were identified. Five patients were excluded as they had a pleural and pericardial effusion that by itself could result in dyspnea. All had varied solid tumors and none had lymphoma. In three of six patients, an increased ratio between right and left ventricle was detected by CT angiography; however, in contradistinction to patients with pulmonary emboli, this was not found to be associated with short survival. The term 'pseudo pulmonary emboli' is suggested to describe this phenomenon. Anticoagulant treatment to avoid in-situ pulmonary artery thrombosis may be considered; however, misdiagnosis of pulmonary embolism may delay the appropriate treatment with chemotherapy, biological therapy, and radiotherapy. PMID- 25022842 TI - Intractable itch relieved by 4-phenylbutyrate therapy in patients with progressive familial intrahepatic cholestasis type 1. AB - BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4 phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1. METHODS: The therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected. RESULTS: 4PB therapy had no beneficial effect on the patients' liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy. CONCLUSIONS: 4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families. PMID- 25022843 TI - Treatment of haemorrhoids by transanal haemorrhoidal dearterialization. Experience of several specialized units. AB - INTRODUCTION: Milligan-Morgan and Ferguson haemorrhoidectomy has been the gold standard treatment for symptomatic haemorrhoids for many years. However, escisional techniques are associated with a significant morbidity rate. In recent years, diverse techniques have been described in an attempt to decrease these complications. The guided transanal haemorrhoidal dearterialization THD) doppler is one of these techniques. We report our experience with this new technique. METHODS: We performed a prospective study of 475 patients from 5 hospitals from the National Health System, in Spain. The majority of these patients suffered from third grade haemorrhoids (256 [56%]) and underwent THD. We analyse and compare preoperative and postoperative results as well as the homogeneity of the technique between hospitals. RESULTS: Spinal anaesthesia was the most elected procedure by the anaesthetist (81.0%). Statistically significant differences were found between pre and postoperative symptoms (P=.03), with an overall improvement after surgery. The average hospitalization was 0.4+/-0.3 days. The mean number of days of oral analgesics was 8.8+/-2.7 days. The cumulative complication rate is 16%. CONCLUSION: THD is a safe and easily reproducible procedure. Postoperative outcomes demonstrated a low rate of morbidity and recurrence together with early discharge; therefore, a rapid incorporation to daily activities was noted. PMID- 25022844 TI - Traumatic Horner syndrome without vascular injury. PMID- 25022845 TI - Extrapleural solitary fibrous tumor. PMID- 25022846 TI - Hepatic herniation after sternotomy. PMID- 25022847 TI - Clinical implications of diverticular disease of the appendix. Experience over the past 10 years. AB - BACKGROUND: Diverticular disease of the appendix is an uncommon condition, with an incidence from 0.004 to 2.1%. It usually occurs between the fourth or fifth decades of life, does not present gastrointestinal symptoms but only insidious abdominal pain. Patients usually delay consultation, leading to increased morbidity and mortality. The aim of this study was to determine the clinical features of diverticular disease of the appendix. METHODS: A retrospective study of all patients undergoing appendectomy in a tertiary hospital between September 2003 and September 2013 was performed. RESULTS: During this period, 7,044 appendectomies were performed, and 42 cases of diverticular disease of the appendix were found, which represents an incidence of 0.59%. A total of 27 patients were male. The mean age was 46.6+/-21 years. The average hospital stay was 4.5 days. A perforated appendix was identified in 46% of patients. In 80% of the cases, a complementary imaging test was performed. The incidence of neoplastic disease with diverticulum of the appendix was 7.1%. CONCLUSIONS: Diverticular disease of the appendix is an incidental finding. In its acute phase, it presents as an acute appendicitis. The treatment of choice is appendectomy. It presents a higher risk of developing neoplastic disease of the appendix. PMID- 25022848 TI - Simultaneous colectomy and nephectomy in synchronic tumours. PMID- 25022849 TI - Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients. AB - BACKGROUND: Evidence for the efficacy of various therapies of livedoid vasculopathy (LV) is limited. OBJECTIVE: We sought to determine efficacy and tolerability of 2 g/kg of intravenous immunoglobulins (IVIG) every 4 weeks in patients with LV. METHODS: This was a long-term follow-up study of 11 patients with LV treated with 2 g/kg of IVIG assessing the clinical characteristics, disease course, and quality of life. RESULTS: The treatment regimen led to complete remission of ulcerations and pain in 17 of 29 disease episodes (59%) after 3 cycles and in 25 of 29 episodes (86%) after 6 cycles. Two disease episodes showed remission after 7 and 8 cycles, resulting in a total number of remissions of 27 (93%). Subscore analysis showed resolution of pain in 80% after 2 IVIG cycles. Disease severity and quality of life were significantly improved after 6 cycles. Median duration of remissions was 26.7 months after initial and 7.5 months after subsequent disease episodes. LIMITATIONS: This was a retrospective study that did not include the comparison of IVIG efficacy and its impact on quality of life with treatment options. CONCLUSIONS: In our patients with LV, high-dose IVIG led to fast and complete resolution of pain and ulcerations and to substantial improvement in quality of life. PMID- 25022850 TI - Successful use of rituximab in the treatment of childhood and juvenile pemphigus. AB - BACKGROUND: There is a lack of data on outcomes of management of pemphigus in children. OBJECTIVE: We sought to evaluate rituximab treatment in childhood and juvenile pemphigus. METHOD: All cases of pemphigus treated with rituximab in patients younger than 18 years were included. Clinical and epidemiologic data and details of rituximab administration were recorded. Response to treatment was assessed as control of disease activity, partial remission, complete remission, and relapse/flare. RESULTS: Ten patients aged 9 to 17 years received rituximab treatment. After therapy, they were followed up for a median period of 16 months (range 8-36 months). Complete remission without concomitant therapy was achieved in 7 patients by a mean of 21 weeks. One patient each achieved complete remission (on immunosuppressant therapy), control of disease activity, and partial remission (on immunosuppressant therapy) by 15, 8, and 14 weeks, respectively. Relapse/flare occurred in 6 patients by a mean period of 13 months. Two patients received a second cycle of rituximab infusions with good clinical response. Infusion reactions were the most common adverse event. There were no long-term complications. LIMITATION: Small sample size and retrospective study design are limitations. CONCLUSION: The current data suggest that rituximab is useful in treating childhood and juvenile pemphigus. PMID- 25022851 TI - Biological cost of pyocin production during the SOS response in Pseudomonas aeruginosa. AB - LexA and two structurally related regulators, PrtR and PA0906, coordinate the Pseudomonas aeruginosa SOS response. RecA-mediated autocleavage of LexA induces the expression of a protective set of genes that increase DNA damage repair and tolerance. In contrast, RecA-mediated autocleavage of PrtR induces antimicrobial pyocin production and a program that lyses cells to release the newly synthesized pyocin. Recently, PrtR-regulated genes were shown to sensitize P. aeruginosa to quinolones, antibiotics that elicit a strong SOS response. Here, we investigated the mechanisms by which PrtR-regulated genes determine antimicrobial resistance and genotoxic stress survival. We found that induction of PrtR-regulated genes lowers resistance to clinically important antibiotics and impairs the survival of bacteria exposed to one of several genotoxic agents. Two distinct mechanisms mediated these effects. Cell lysis genes that are induced following PrtR autocleavage reduced resistance to bactericidal levels of ciprofloxacin, and production of extracellular R2 pyocin was lethal to cells that initially survived UV light treatment. Although typically resistant to R2 pyocin, P. aeruginosa becomes transiently sensitive to R2 pyocin following UV light treatment, likely because of the strong downregulation of lipopolysaccharide synthesis genes that are required for resistance to R2 pyocin. Our results demonstrate that pyocin production during the P. aeruginosa SOS response carries both expected and unexpected costs. PMID- 25022852 TI - Emerging roles for anionic non-bilayer phospholipids in fortifying the outer membrane permeability barrier. AB - Lately, researchers have been actively investigating Escherichia coli lptD mutants, which exhibit reduced transport of lipopolysaccharide to the cell surface. In this issue of the Journal of Bacteriology, Sutterlin et al. (H. A. Sutterlin, S. Zhang, and T. J. Silhavy, J. Bacteriol. 196:3214-3220, 2014) now reveal an important functional role for phosphatidic acid in fortifying the outer membrane permeability barrier in certain lptD mutant backgrounds. These findings come on the heels of the first reports of two LptD crystal structures, which now provide a structural framework for interpreting lptD genetics. PMID- 25022853 TI - Role of YpeB in cortex hydrolysis during germination of Bacillus anthracis spores. AB - The infectious agent of the disease anthrax is the spore of Bacillus anthracis. Bacterial spores are extremely resistant to environmental stresses, which greatly hinders spore decontamination efforts. The spore cortex, a thick layer of modified peptidoglycan, contributes to spore dormancy and resistance by maintaining the low water content of the spore core. The cortex is degraded by germination-specific lytic enzymes (GSLEs) during spore germination, rendering the cells vulnerable to common disinfection techniques. This study investigates the relationship between SleB, a GSLE in B. anthracis, and YpeB, a protein necessary for SleB stability and function. The results indicate that DeltasleB and DeltaypeB spores exhibit similar germination phenotypes and that the two proteins have a strict codependency for their incorporation into the dormant spore. In the absence of its partner protein, SleB or YpeB is proteolytically degraded soon after expression during sporulation, rather than escaping the developing spore. The three PepSY domains of YpeB were examined for their roles in the interaction with SleB. YpeB truncation mutants illustrate the necessity of a region beyond the first PepSY domain for SleB stability. Furthermore, site directed mutagenesis of highly conserved residues within the PepSY domains resulted in germination defects corresponding to reduced levels of both SleB and YpeB in the mutant spores. These results identify residues involved in the stability of both proteins and reiterate their codependent relationship. It is hoped that the study of GSLEs and interacting proteins will lead to the use of GSLEs as targets for efficient activation of spore germination and facilitation of spore cleanup. PMID- 25022854 TI - CysK2 from Mycobacterium tuberculosis is an O-phospho-L-serine-dependent S sulfocysteine synthase. AB - Mycobacterium tuberculosis is dependent on cysteine biosynthesis, and reduced sulfur compounds such as mycothiol synthesized from cysteine serve in first-line defense mechanisms against oxidative stress imposed by macrophages. Two biosynthetic routes to l-cysteine, each with its own specific cysteine synthase (CysK1 and CysM), have been described in M. tuberculosis, but the function of a third putative sulfhydrylase in this pathogen, CysK2, has remained elusive. We present biochemical and biophysical evidence that CysK2 is an S-sulfocysteine synthase, utilizing O-phosphoserine (OPS) and thiosulfate as substrates. The enzyme uses a mechanism via a central aminoacrylate intermediate that is similar to that of other members of this pyridoxal phosphate-dependent enzyme family. The apparent second-order rate of the first half-reaction with OPS was determined as kmax/Ks = (3.97 * 10(3)) +/- 619 M(-1) s(-1), which compares well to the OPS specific mycobacterial cysteine synthase CysM with a kmax/Ks of (1.34 * 10(3)) +/ 48.2. Notably, CysK2 does not utilize thiocarboxylated CysO as a sulfur donor but accepts thiosulfate and sulfide as donor substrates. The specificity constant kcat/Km for thiosulfate is 40-fold higher than for sulfide, suggesting an annotation as S-sulfocysteine synthase. Mycobacterial CysK2 thus provides a third metabolic route to cysteine, either directly using sulfide as donor or indirectly via S-sulfocysteine. Hypothetically, S-sulfocysteine could also act as a signaling molecule triggering additional responses in redox defense in the pathogen upon exposure to reactive oxygen species during dormancy. PMID- 25022855 TI - Repetitive sequence variations in the promoter region of the adhesin-encoding gene sabA of Helicobacter pylori affect transcription. AB - The pathogenesis of diseases elicited by the gastric pathogen Helicobacter pylori is partially determined by the effectiveness of adaptation to the variably acidic environment of the host stomach. Adaptation includes appropriate adherence to the gastric epithelium via outer membrane protein adhesins such as SabA. The expression of sabA is subject to regulation via phase variation in the promoter and coding regions as well as repression by the two-component system ArsRS. In this study, we investigated the role of a homopolymeric thymine [poly(T)] tract 50 to -33 relative to the sabA transcriptional start site in H. pylori strain J99. We quantified sabA expression in H. pylori J99 by quantitative reverse transcription-PCR (RT-PCR), demonstrating significant changes in sabA expression associated with experimental manipulations of poly(T) tract length. Mimicking the length increase of this tract by adding adenines instead of thymines had similar effects, while the addition of other nucleotides failed to affect sabA expression in the same manner. We hypothesize that modification of the poly(T) tract changes DNA topology, affecting regulatory protein interaction(s) or RNA polymerase binding efficiency. Additionally, we characterized the interaction between the sabA promoter region and ArsR, a response regulator affecting sabA expression. Using recombinant ArsR in electrophoretic mobility shift assays (EMSA), we localized binding to a sequence with partial dyad symmetry -20 and +38 relative to the sabA +1 site. The control of sabA expression by both ArsRS and phase variation at two distinct repeat regions suggests the control of sabA expression is both complex and vital to H. pylori infection. PMID- 25022856 TI - Coregulated genes link sulfide:quinone oxidoreductase and arsenic metabolism in Synechocystis sp. strain PCC6803. AB - Although the biogeochemistry of the two environmentally hazardous compounds arsenic and sulfide has been extensively investigated, the biological interference of these two toxic but potentially energy-rich compounds has only been hypothesized and indirectly proven. Here we provide direct evidence for the first time that in the photosynthetic model organism Synechocystis sp. strain PCC6803 the two metabolic pathways are linked by coregulated genes that are involved in arsenic transport, sulfide oxidation, and probably in sulfide-based alternative photosynthesis. Although Synechocystis sp. strain PCC6803 is an obligate photoautotrophic cyanobacterium that grows via oxygenic photosynthesis, we discovered that specific genes are activated in the presence of sulfide or arsenite to exploit the energy potentials of these chemicals. These genes form an operon that we termed suoRSCT, located on a transposable element of type IS4 on the plasmid pSYSM of the cyanobacterium. suoS (sll5036) encodes a light dependent, type I sulfide:quinone oxidoreductase. The suoR (sll5035) gene downstream of suoS encodes a regulatory protein that belongs to the ArsR-type repressors that are normally involved in arsenic resistance. We found that this repressor has dual specificity, resulting in 200-fold induction of the operon upon either arsenite or sulfide exposure. The suoT gene encodes a transmembrane protein similar to chromate transporters but in fact functioning as an arsenite importer at permissive concentrations. We propose that the proteins encoded by the suoRSCT operon might have played an important role under anaerobic, reducing conditions on primordial Earth and that the operon was acquired by the cyanobacterium via horizontal gene transfer. PMID- 25022857 TI - Pathological characteristics and radiographic correlates of complex renal cysts. AB - OBJECTIVES: To characterize pathological and cancer-specific outcomes of surgically resected cystic renal tumors and to identify clinical or radiographic features associated with these outcomes. METHODS AND MATERIALS: All patients at our institution who underwent radical or partial nephrectomy for complex renal cystic masses between 2004 and 2011 with available computed tomographic imaging were included. The Bosniak score was determined, as were 10 specific radiographic characteristics of renal cysts in patients with preoperative imaging available for review. These characteristics were correlated with cystic mass histopathology. Recurrence-free survival after surgery was determined. RESULTS: Overall, 133 patients underwent renal surgery for complex cystic lesions, 89 (67%) of whom had malignant lesions. Malignancy risk increased with Bosniak score (P<=0.01) and presence of mural nodules (P = 0.01). Most (63%) malignancies demonstrated clear cell histology. The papillary renal cell carcinomas (25%) exhibited lower enhancement levels (P = 0.04) and were less often septated (P<0.01). Of the malignancies, 79% were low stage (pT1), and 73% were Fuhrman grade 1 or 2. Large cyst size was associated with advanced tumor stage (P = 0.05). Neither Bosniak score nor any other radiographic parameter was associated with Fuhrman grade. In 70 patients with a median follow-up of 43 months, only 1 (1.4%) developed disease recurrence. CONCLUSIONS: Most cystic renal malignancies are low-stage, low-grade lesions. Papillary renal cell carcinomas account for nearly a quarter of cystic renal malignancies and have unique radiographic characteristics. Disease recurrence after surgical resection is rare. These findings suggest an indolent behavior for cystic renal tumors, and these lesions may be amenable to active surveillance. PMID- 25022858 TI - Degree of hydronephrosis predicts adverse pathological features and worse oncologic outcomes in patients with high-grade urothelial carcinoma of the upper urinary tract. AB - OBJECTIVE: To evaluate degree of hydronephrosis (HN) as a surrogate for adverse pathological features and oncologic outcomes in patients with high-grade (HG) and low-grade (LG) upper tract urothelial carcinomas (UTUCs). METHODS: We retrospectively reviewed 141 patients with localized UTUCs that underwent extirpative surgery at a tertiary referral center. Preoperative imaging was used to evaluate presence and degree of ipsilateral HN. We evaluated degree of HN (none/mild vs. moderate/severe), pathological findings, and oncologic outcomes. RESULTS: HG UTUC was present in 113 (80%) patients, muscle-invasive disease (>=pT2) in 49 (35%), and non-organ-confined disease (>=pT3) in 41 (29%). At a median follow-up of 34 months, 49 (35%) patients experienced intravesical recurrence, 28 (20%) developed local/systemic recurrence, and 24 (17%) died of UTUC. HN was graded as none/mild in 77 (55%) patients and moderate/severe in 64 (45%). In patients with HG UTUC, but not LG, degree of HN was associated with advanced pathological stage (P<0.001), positive lymph nodes (P = 0.01), local/systemic recurrence-free survival (hazard ratio [HR] = 5.5, P = 0.02), and cancer-specific survival (HR = 5.2, P = 0.02). On multivariable analysis of preoperative factors, degree of HN in patients with HG UTUC was associated with muscle invasion (HR = 9.3; 95% CI: 3.08-28.32; P<0.001), non-organ-confined disease (HR = 4.5; 95% CI: 1.66-12.06; P = 0.003), local/systemic recurrence-free survival (HR = 2.5; 95% CI: 1.07-5.64; P = 0.04), and cancer-specific survival (HR = 2.6; 95% CI: 1.05-6.22; P = 0.04). CONCLUSIONS: Degree of HN can serve as a surrogate for advanced disease and predict worse oncologic outcomes in HG UTUC. Degree of HN was not predictive of intravesical or local/systemic recurrence in LG UTUC. PMID- 25022860 TI - Randomized clinical trials: in pursuit of higher standards. PMID- 25022859 TI - Validity of the French version of the Core Outcome Measures Index for low back pain patients: a prospective cohort study. AB - PURPOSE: Among the many questionnaires available to evaluate low back pain (LBP) patients, the Core Outcome Measures Index (COMI) has the unique advantage to investigate five dimensions using seven short questions. The aim of this study was to explore additional properties of the questionnaire in a French-speaking non-surgical population. METHODS: This study was conducted on 168 patients suffering from subacute or chronic LBP and followed up for 6 months in three French-speaking countries. In addition to basic psychometric properties (e.g., construct validity, floor and ceiling effect, reproducibility), internal validity was analyzed by a factor analysis using Cronbach's alpha. Responsiveness and sensitivity to change were assessed through minimal detectable change (MDC), effect size, and Minimal Clinically Important Improvement (MCII). We used an anchor-based method with receiver operating characteristic (ROC) curve analysis to assess MCII and the Patient Acceptable Symptom State. RESULTS: Construct validity, reliability (Cronbach's alpha = 0.87), reproducibility and the absence of floor and ceiling effects were confirmed. Factor analysis indicated a one dimensional construct that validates the use of a sum score. The MDC (2.1) was inferior to the MCII (2.3). The limit below which the patient claims to be in a fair condition (Patient Acceptable Symptom State) was set at 3. CONCLUSIONS: The COMI is a self-report questionnaire with the capacity to easily and quickly explore several dimensions in patients with LBP that can be then summarized in a meaningful sum score. Additional knowledge provided by our study should encourage the widespread use of the COMI among the spine community. PMID- 25022861 TI - The influence of intrinsic disc degeneration of the adjacent segments on its stress distribution after one-level lumbar fusion. AB - INTRODUCTION: The presence of degeneration alters the stress within that particular degenerated disc. Therefore, the state of degeneration of the disc at the level adjacent to a single level fusion would influence the rate of subsequent further degeneration of that same adjacent disc. Therefore, the purpose of this study was to investigate the biomechanical effect of the disc degeneration at the adjacent segment on the stress of the corresponding segment after one segment lumbar fusion using validated finite element (FE) models. METHOD: Three validated L2-L5 FE models with different grades of disc degeneration (normal, mild, moderate) at the L2-L5 were simulated. Based on the intact models that represented each grade of disc degeneration, the matched L3-L4 instrumented fusion models were developed. Therefore, three intact models and three matched fusion models were simulated. Under the 400-N pre-compressive follower loading, 7.5 Nm moments simulating flexion, extension, lateral bending, and torsion in five steps were imposed on the L2 superior endplate of three intact models. The hybrid loading protocol was utilized for the fusion models. The intradiscal pressure and the maximal von Mises stress of the annulus fibrosus in the L2-L3 and L4-L5 segments were analyzed and compared between fusion and intact models with each grade of disc degeneration. RESULTS: Disc degeneration led to an increase of maximal von Mises stress of annulus fibrosus at this degenerated disc, related to disc degeneration under flexion, extension, lateral bending and torsion moments. Furthermore, the fusion also increased a maximal von Mises stress of annulus fibrous at both proximal and distal adjacent segments under hybrid protocol. The increases of annular stress were greater at the proximal adjacent segment than those at distal adjacent segment. However, the contribution of the fusion surgery to the increment rate of annulus fibrosus stress at the adjacent segment did not increase in relation with disc degeneration states at the adjacent segment. CONCLUSION: The present study demonstrates disc degeneration per se and fusion can cause the increase of disc stress at the adjacent segment. However, they seem not to act synergistically. Therefore, the proper decision of fusion extent needs comprehensive individual considerations about the degree of facet degeneration, canal stenosis and patient's activity. PMID- 25022862 TI - Laparoscopic resection of a gastrointestinal stromal tumor of the lower rectum in a patient with coronary artery disease following long-term neoadjuvant imatinib treatment and anticoagulation therapy. AB - Surgery is the mainstay of treatment for gastrointestinal stromal tumors (GISTs). However, complete resection of rectal GISTs is sometimes difficult because of bulkiness and/or anatomical reasons. Neoadjuvant imatinib therapy has gained attention as an alternative treatment to increase the chance of en bloc resection of rectal GISTs, although it usually takes several months. In this case report, we first demonstrated that neoadjuvant imatinib therapy can be performed safely not only to downsize tumors, but also to allow adequate time for the effective treatment of major comorbid illnesses. A 74-year-old man was diagnosed with a 45 mm GIST of the lower rectum. He also had severe stenosis in the proximal segment of the left anterior descending coronary artery. Following the implantation of a drug-eluting stent, the patient received imatinib together with dual anti platelet therapy for 12 months without obvious side effects. Follow-up image studies revealed tumor shrinkage as well as stent patency. En bloc resection of the GIST was performed laparoscopically, which preserved the anus. The patient is currently alive without any evidence of relapse for 12 months after surgery. PMID- 25022864 TI - Update of 2013 clinical practice guidelines dissemination and implementation. PMID- 25022863 TI - Socioeconomic status, cognitive-emotional factors, and health status following myocardial infarction: testing the Reserve Capacity Model. AB - Health disparities by socioeconomic status (SES) exist for many outcomes, including patients' subjective health status after myocardial infarction (MI). The Reserve Capacity Model (RCM), a theoretical means to understand such disparities, was tested to examine the possible mediating effects of cognitive emotional factors on the association between SES and health status. Data from 2,348 post-MI patients in PREMIER were used. Indicators of SES were collected during hospitalization via personal interviews, while participants completed measures of stress and reserves at 1 month, depressive symptoms at 6 months, and health status at 1 year through telephone interviews. Structural equation model results provide partial support for the RCM, as cognitive-emotional factors partially mediated the association between SES and mental health status. For physical health status, results supported direct rather than indirect effects of SES. Findings suggest psychosocial interventions with patients of low SES will have their greatest effects on appraisals of psychological health status. PMID- 25022865 TI - The ketogenic diet for the treatment of myoclonic astatic epilepsy in a child with type 1 diabetes mellitus. AB - Initiation of the ketogenic diet in a child with epilepsy and type 1 diabetes mellitus presents a challenge because the distinction between diet-induced ketosis and diabetic ketoacidosis is difficult to discern. We report the successful use of the ketogenic diet in a child with myoclonic astatic epilepsy and type 1 diabetes. PMID- 25022866 TI - Using haplotypes for the prediction of allelic identity to fine-map QTL: characterization and properties. AB - BACKGROUND: Numerous methods have been developed over the last decade to predict allelic identity at unobserved loci between pairs of chromosome segments along the genome. These loci are often unobserved positions tested for the presence of quantitative trait loci (QTL). The main objective of this study was to understand from a theoretical standpoint the relation between linkage disequilibrium (LD) and allelic identity prediction when using haplotypes for fine mapping of QTL. In addition, six allelic identity predictors (AIP) were also compared in this study to determine which one performed best in theory and application. RESULTS: A criterion based on a simple measure of matrix distance was used to study the relation between LD and allelic identity prediction when using haplotypes. The consistency of this criterion with the accuracy of QTL localization, another criterion commonly used to compare AIP, was evaluated on a set of real chromosomes. For this set of chromosomes, the criterion was consistent with the mapping accuracy of a simulated QTL with either low or high effect. As measured by the matrix distance, the best AIP for QTL mapping were those that best captured LD between a tested position and a QTL. Moreover the matrix distance between a tested position and a QTL was shown to decrease for some AIP when LD increased. However, the matrix distance for AIP with continuous predictions in the [0,1] interval was algebraically proven to decrease less rapidly up to a lower bound with increasing LD in the simplest situations, than the discrete predictor based on identity by state between haplotypes (IBS hap), for which there was no lower bound. The expected LD between haplotypes at a tested position and alleles at a QTL is a quantity that increases naturally when the tested position gets closer to the QTL. This behavior was demonstrated with pig and unrelated human chromosomes. CONCLUSIONS: When the density of markers is high, and therefore LD between adjacent loci can be assumed to be high, the discrete predictor IBS hap is recommended since it predicts allele identity correctly when taking LD into account. PMID- 25022867 TI - Modeling the Effects of Moisture-Related Skin-Support Friction on the Risk for Superficial Pressure Ulcers during Patient Repositioning in Bed. AB - Patient repositioning when the skin is moist, e.g., due to sweat or urine may cause skin breakdown since wetness increases the skin-support coefficient of friction (COF) and hence also the shear stresses that are generated in the skin when the patient is being moved. This everyday hospital scenario was never studied systematically however. The aim of this study was to simulate such interactions using a biomechanical computational model which is the first of its kind, in order to quantitatively describe the effects of repositioning on the pathomechanics of moisture-related tissue damage. We designed a finite element model to analyze skin stresses under a weight-bearing bony prominence while this region of interest slides frictionally over the support surface, as occurs during repositioning. Our results show, expectedly, that maximal effective stresses in the skin increase as the moisture-contents-related COF between the skin and the mattress rises. Interestingly however, the rise in stresses for a wet interface became more prominent when the skin tissue was stiffer - which represented aging or diabetes. This finding demonstrates how the aged/diabetic skin is more fragile than a young-adult skin when repositioning in a moist environment. The modeling used herein can now be extended to test effects of different moisturizers, creams, lubricants, or possibly other interventions at the skin-support interface for testing their potential in protecting the skin from superficial pressure ulcers in a standard, objective, and quantitative manner. PMID- 25022868 TI - Transcatheter closure of perimembranous ventricular septal defects with ductal occluders. AB - BACKGROUND: To study the feasibility and complications associated with the use of ductal occluders for closure of perimembranous ventricular septal defects. METHODS: A total of 126 patients, ranging from 1 to 41 years of age (median - 8 years), underwent closure of ventricular septal defects from August 2010 to April 2013. Small- and moderate-sized defects were closed using first-generation Patent ductus arteriosus occluders or Amplatzer Duct Occluder-II. Patients were followed up for the development of complications such as heart block, aortic regurgitation, and tricuspid regurgitation. RESULTS: Patent ductus arteriosus occluders were used in 81 patients, and the Amplatzer Duct Occluder-II device in 45 patients. The devices were successfully deployed in 99.2% of the cases. One patient had embolisation of an Amplatzer Duct Occluder-II device soon after deployment. There was one case of transient complete heart block (0.8%) needing temporary pacing, and two cases of isoarrhythmic atrioventricular dissociation (1.6%). One patient developed late-onset complete heart block 15 months after the procedure and underwent permanent pacemaker implantation. There were no instances of new-onset aortic regurgitation. New-onset mild tricuspid regurgitation was seen in two patients. Of the patients, three had small residual shunts on follow up, without haemolysis. CONCLUSIONS: Duct occluders can be used to effectively close small- and moderate-sized ventricular septal defects. The incidence of complete heart block and valvular regurgitations are much less than reported with other devices, and they are cost-effective. PMID- 25022869 TI - Complex function in the dynamic brain: Comment on "Understanding brain networks and brain organization" by Luiz Pessoa. PMID- 25022870 TI - Prediction of cell growth rate over scaffold strands inside a perfusion bioreactor. AB - Mathematical and computational modeling of the dynamic process where tissue scaffolds are cultured in perfusion bioreactors is able to provide insight into the cell and tissue growth which can facilitate the design of tissue scaffolds and selection of optimal operating conditions. To date, a resolved-scale simulation of cell growth in the culture process, by taking account of the influences of the supply of nutrients and fluid shear stress on the cells, is not yet available in the literature. This paper presents such a simulation study specifically on cartilage tissue regeneration by numerically solving the momentum, scalar transport and cell growth equations, simultaneously, based on the lattice Boltzmann method. The simulation uses a simplified scaffold that consists of two circular strands placed in tandem inside a microchannel, with the object of identifying the effect of one strand on the other. The results indicate that the presence of the front strand can reduce the cell growth rate on the surface of the rear strand, depending on the distance between them. As such, the present study allows for investigation into the influence of the scaffold geometry on the cell growth rate within scaffolds, thus providing a means to improve the scaffold design and the culture process. PMID- 25022871 TI - Correlation between epicardial fat and cigarette smoking: CT imaging in patients with metabolic syndrome. AB - BACKGROUND: The aim of our study was to assess the relationship between cigarette smoking and epicardial fat in a cohort of patients with metabolic syndrome (MetS) at risk for coronary artery disease. METHODS: We studied, in primary prevention, 54 subjects diagnosed with MetS. According to their smoking habits, the subjects were divided into two groups: smokers and non-smokers. Besides anthropometric characterization and screening laboratory tests, the subjects had a multidetector computerized tomography scan, which allowed epicardial fat quantification and calcium score (CS) evaluation. RESULTS: Compared with non-smokers, smokers showed older age (61.6 +/- 1.8 vs 56.8 +/- 1.2 yrs; p < 0.05). Also, the smokers displayed increased epicardial fat volume (138 [123; 150] vs 101[79; 130] ml; p < 0.01) as well as higher CS (94 [3; 301.5] vs 0 [0;10.2]; p < 0.001), in comparison with non-smokers. Notably, CS was positively correlated with smoking habit (rs 0.469; p < 0.01), epicardial fat (rs 0.377; p < 0.01), age (rs 0.502; p < 0.001) and uric acid (rs 0.498; p < 0.01). Accordingly, the associations between both CS or epicardial fat and cigarette smoking were still maintained after adjustment for age (r 0.317; p < 0.05; r 0.427; p < 0.01). Finally, multiple regression analysis showed that smoke was the variable that best predicted CS (R(2) 0.131; beta 0.362; p < 0.05) and epicardial fat (R(2) 0.177; beta 0.453; p = 0.01). CONCLUSIONS: Our findings suggest that, in subjects with MetS, cigarette smoking is an independent predictor of increased epicardial fat volume and higher CS. PMID- 25022872 TI - Improving the inference of population genetic structure in the presence of related individuals. AB - It is well known that the presence of related individuals can affect the inference of population genetic structure from molecular data. This has been verified, for example, on the unsupervised Bayesian clustering algorithm implemented in the software STRUCTURE. This methodology assumes, among others, Hardy-Weinberg and linkage equilibrium within subpopulations. The existence of groups of close relatives, such as full-sib families, may prevent these assumptions to be fulfilled, causing the algorithm to work suboptimally. The purpose of this study was to evaluate the effect of the presence of related individuals on a different methodology (implemented in CLUSTER_DIST) for population genetic structure inference. This approach arranges individuals to maximize the genetic distance between groups and does not make Hardy-Weinberg and linkage equilibrium assumptions. We study the robustness of this approach to the presence of close relatives in a sample using simulated scenarios involving combinations of several factors, including the number of subpopulations, the level of differentiation between them, the number, size and type (full or half sibs) of families in a sample, and the type and number of molecular markers available for clustering analysis. Results indicate that the methodology that maximizes the genetic distance between subpopulations is less influenced by the presence of related individuals than the program STRUCTURE. Therefore, the former can be used, in combination with the program STRUCTURE, to analyse population genetic structure when related individuals are suspected to be present in a sample. PMID- 25022873 TI - Strongyloidiasis in a healthy 8-year-old girl in north-eastern USA. AB - A previously healthy, white 8-year-old girl presented with a 1-week history of abdominal pain and vomiting after a trip to a lake in Pennsylvania, north-eastern USA. There was marked dehydration. A raised blood eosinophilic count prompted microscopy for ova and parasites which demonstrated a heavy load of larvae of Strongyloides stercoralis. Charcot-Leyden crystals were also detected. The child received oral ivermectin and made a complete recovery. PMID- 25022874 TI - Effect of malic enzyme on ethanol production by Synechocystis sp. PCC 6803. AB - We investigated effects of malic enzyme on ethanol production by Synechocystis sp. PCC 6803 under autotrophic conditions. Deletion of me, which encodes malic enzyme, decreased ethanol production, whereas its overexpression had no effect. Our results suggest that maintaining optimal malic enzyme activity controls ethanol production by Synechocystis sp. PCC 6803. PMID- 25022875 TI - Identification of extracellular signal-regulated kinase 1 (ERK1) direct substrates using stable isotope labeled kinase assay-linked phosphoproteomics. AB - Kinase mediated phosphorylation signaling is extensively involved in cellular functions and human diseases, and unraveling phosphorylation networks requires the identification of substrates targeted by kinases, which has remained challenging. We report here a novel proteomic strategy to identify the specificity and direct substrates of kinases by coupling phosphoproteomics with a sensitive stable isotope labeled kinase reaction. A whole cell extract was moderately dephosphorylated and subjected to in vitro kinase reaction under the condition in which (18)O-ATP is the phosphate donor. The phosphorylated proteins are then isolated and identified by mass spectrometry, in which the heavy phosphate (+85.979 Da) labeled phosphopeptides reveal the kinase specificity. The in vitro phosphorylated proteins with heavy phosphates are further overlapped with in vivo kinase-dependent phosphoproteins for the identification of direct substrates with high confidence. The strategy allowed us to identify 46 phosphorylation sites on 38 direct substrates of extracellular signal-regulated kinase 1, including multiple known substrates and novel substrates, highlighting the ability of this high throughput method for direct kinase substrate screening. PMID- 25022876 TI - Disclosure of selective advantages in the "modern" sublineage of the Mycobacterium tuberculosis Beijing genotype family by quantitative proteomics. AB - The Mycobacterium tuberculosis Beijing genotype, consisting of the more ancient (atypical) and modern (typical) emerging sublineage, is one of the most prevalent and genetically conserved genotype families and has often been associated with multidrug resistance. In this study, we employed a 2D-LC-FTICR MS approach, combined with dimethylation of tryptic peptides, to systematically compare protein abundance levels of ancient and modern Beijing strains and identify differences that could be associated with successful spread of the modern sublineage. The data is available via ProteomeXchange using the identifier PXD000931. Despite the highly uniform protein abundance ratios in both sublineages, we identified four proteins as differentially regulated between both sublineages, which could explain the apparent increased adaptation of the modern Beijing strains. These proteins are; Rv0450c/MmpL4, Rv1269c, Rv3137, and Rv3283/sseA. Transcriptional and functional analysis of these proteins in a large cohort of 29 Beijing strains showed that the mRNA levels of Rv0450c/MmpL4 are significantly higher in modern Beijing strains, whereas we also provide evidence that Rv3283/sseA is less abundant in the modern Beijing sublineage. Our findings provide a possible explanation for the increased virulence and success of the modern Beijing sublineage. In addition, in the established dataset of 1817 proteins, we demonstrate the pre-existence of several, possibly unique, antibiotic efflux pumps in the proteome of the Beijing strains. This may reflect an increased ability of Beijing strains to escape exposure to antituberculosis drugs. PMID- 25022878 TI - Embracing the "and": between queer and bisexual theory at Brighton BiFest. AB - Questions of bi identities can be invisibilized and overlooked by queer theorizing and LGBT studies. This article explores the ways in which complex performances of bisexuality can simultaneously encompass and deconstructively critique bi identity in a manner that embraces the "and" between bi and queer, offering important insights into how bi is lived, contested, and reaffirmed. Drawing on the BiCon and BiFest events in the UK, we argue that both the materialities (and supposed fixities) of bi erasures and exclusions and the fluidities that trouble the heterosexual/homosexual divides offer key insights into the spatial and temporal fixing and unfixing of identities. PMID- 25022877 TI - Genetic determinants of amidating enzyme activity and its relationship with metal cofactors in human serum. AB - BACKGROUND: alpha-amidation is a final, essential step in the biosynthesis of about half of all peptide hormones and neurotransmitters. Peptidylglycine alpha amidating monooxygenase (PAM), with enzymatic domains that utilize Cu and Zn, is the only enzyme that catalyzes this reaction. PAM activity is detected in serum, but its significance and utility as a clinical biomarker remain unexplored. METHODS: We used well-established enzymatic assays specific for the peptidylglycine-alpha -hydroxylating monooxygenase (PHM) and peptidyl-alpha hydroxyglycine alpha-amidating lyase (PAL) domains of PAM to quantify amidating activity in the sera of 144 elderly men. Relationships between PHM and PAL activity and serum levels of their respective active-site metals, Cu and Zn, were analyzed. Study participants were also genotyped for eight non-coding single nucleotide polymorphisms (SNPs) in PAM, and relationships between genotype and serum enzyme activity and metal levels were analyzed. RESULTS: Serum PHM and PAL activities were normally distributed and correlated linearly with each other. Serum PAL activity, but not serum PHM activity, correlated with serum Cu; neither activity correlated with serum Zn. Study subjects possessing the minor alleles for rs32680 had lower PHM and PAL activities, and subjects with minor alleles for rs11952361 and rs10515341 had lower PHM activities. CONCLUSIONS: Our results characterize large variation in serum amidating activity and provide unique insight into its potential origin and determinants. Common non-coding polymorphisms affect serum amidating activity and Cu levels. Serum amidating activity should be explored as a biomarker for functionality in the elderly and in additional study groups. PMID- 25022879 TI - Discovery of S-adenosyl-L-homocysteine hydrolase inhibitors based on non adenosine analogs. AB - High throughput screening using Automated Ligand Identification System (ALIS) resulted in the discovery of a new series of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs. The optimization campaign led to very potent and competitive compound 39 with a Ki value of 1.5 nM. Compound 39 could be a promising lead compound for research to reduce elevated homocysteine levels. PMID- 25022880 TI - Molecular determinants for improved activity at PPARalpha: structure-activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARalpha. AB - Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARalpha and PPARgamma agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARalpha particularly dual PPARalpha/gamma agonists with 2-((4-chloro-6 ((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure-activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARalpha. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARalpha LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction. PMID- 25022881 TI - Molecular modeling studies of atorvastatin analogues as HMGR inhibitors using 3D QSAR, molecular docking and molecular dynamics simulations. AB - 3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is generally regarded as targets for the treatment of hypercholesterolemia. HMGR inhibitors (more commonly known as statins) are discovered as plasma cholesterol lowering molecules. In this work, 120 atorvastatin analogues were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q(2)=0.558 and r(2)=0.977, and the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.582 and r(2)=0.919. Molecular docking and MD simulation explored the binding relationship of the ligand and the receptor protein. The calculation results indicated that the hydrophobic and electrostatic fields play key roles in QSAR model. After MD simulation, we found four vital residues (Lys735, Arg590, Asp690 and Asn686) and three hydrophobic regions in HMGR binding site. The calculation results show that atorvastatin analogues obtained by introduction of F atoms or gem-difluoro groups could obviously improve the inhibitory activity. The new HMGR inhibitor analogues design in this Letter had been submitted which is being currently synthesized by our laboratories. PMID- 25022882 TI - Tungsten carbide nanotubes supported platinum nanoparticles as a potential sensing platform for oxalic acid. AB - Supported tungsten carbide is an efficient and vital nanomaterial for the development of high-performance, sensitive, and selective electrochemical sensors. In this work, tungsten carbide with tube-like nanostructures (WC NTs) supported platinum nanoparticles (PtNPs) are synthesized and explored as an efficient catalyst toward electrochemical oxidation of oxalic acid for the first the time. The WC NTs supported PtNPs modified glassy carbon (GC) electrode is highly sensitive toward the electrochemical oxidation of oxalic acid. A large decrease in the oxidation overpotential (220 mV) and significant enhancement in the peak current compared to unmodified and Pt/C modified GC electrodes have been observed without using any redox mediator. Moreover, WC NTs supported PtNPs modified electrode possessed wide linear concentration ranges from 0 to 125 nM and a higher sensitivity toward the oxidation of oxalic acid (80 nA/nM) achieved by the amperometry method. The present modified electrode showed an experimentally determined lowest detection limit (LOD) of 12 nM (S/N = 3). Further, WC NTs supported PtNPs electrode can be demonstrated to have an excellent selectivity toward the detection of oxalic acid in the presence of a 200-fold excess of major important interferents. The practical application of WC NTs supported PtNPs has also been demonstrated in the detection of oxalic acid in tomato fruit sample, by differential pulse voltammetry under optimized conditions. PMID- 25022883 TI - Experimental study on the effect of electrostimulation on neural regeneration after oculomotor nerve injury. AB - The oculomotor nerve can regenerate anatomically and histologically after injury; however, the degree of functional recovery of extraocular muscles and the pupil sphincter muscle was not satisfactory. Electrostimulation was one potential intervention that was increasingly being studied for use in nerve injury settings. However, the effect of electrostimulation on regeneration of the injured oculomotor nerve was still obscure. In this study, we studied the effects of electrostimulation on neural regeneration in terms of neurofunction, myoelectrophysiology, neuroanatomy, and neurohistology after oculomotor nerve injury and found that electrostimulation on the injured oculomotor nerve enhanced the speed and final level of its functional and electrophysiological recovery, promoted neural regeneration, and enhanced the selectivity and specificity of reinnervation of the regenerated neuron, the conformity among the electrophysiological and functional recovery of extraocular muscles, and neural regeneration, and that the function of extraocular muscles recovered slower than electrophysiology. Thus, we speculated that electrostimulation on the injured oculomotor nerve produced a marked effect on all phases of neural regeneration including neuronal survival, sprout formation, axonal elongation, target reconnection, and synaptogenesis. We think that neural electrostimulation can be used in oculomotor nerve injury. PMID- 25022884 TI - A proteomic approach for the involvement of the GAPDH in Alzheimer disease in the blood of Moroccan FAD cases. AB - Several articles have highlighted the potential involvement of glyceraldehyde-3 phosphate dehydrogenase (GAPDH) in neurodegeneration by showing a non-glycolytic activity of GAPDH specifically in the brains of subjects with Alzheimer's disease (AD). The novel aim of this study was to elucidate the critical role of GAPDH and its interaction with beta-amyloid in the blood of Moroccan patients with familial AD (FAD) carrying presenilin mutations and in sporadic late onset AD (LOAD). Our results show a significant decrease in the activity of GAPDH in blood samples from patients with FAD as compared to sporadic cases and healthy controls. The expression level of GAPDH in brain specimens from mutant tau transgenic mice and patients with FAD was unchanged as compared to healthy controls. In contrast, the expression level of GAPDH in blood samples from mutant tau transgenic mice and patients with FAD was decreased as compared to sporadic cases and healthy controls. Moreover, there is an accumulation of beta-amyloid aggregates in the blood samples of patients with FAD and an increase in amyloid fibrils in both the blood and brain samples of these patients. Our study adds new insight to previous ones by showing the involvement of GAPDH in AD, which may influence the pathogenesis of this neurodegenerative disease. PMID- 25022885 TI - Genetic evidence for the involvement of variants at APOE, BIN1, CR1, and PICALM loci in risk of late-onset Alzheimer's disease and evaluation for interactions with APOE genotypes. AB - Alzheimer's disease (AD) is the most common form of dementia in older population. Growing evidence of genetic background that predisposes individuals to AD has been reported as the risk factors in recent years. The Department of Medical Genetics and the Immunology Research Centre investigated the distribution of 11 polymorphisms in 160 patients with late onset AD (LOAD) and in 163 healthy controls, using the sequencing technique. All participants were of Turkish Azeri ethnicity. We compared allele and genotype frequencies between the LOAD patients and control subjects using a chi-square or Fisher's exact test. Alleles and genotypes of APOE, PICALM rs3851179 and rs541458, and the BIN1 gene rs744373 polymorphism were significantly different between LOAD and control groups. The frequencies of the other investigated alleles were similar in the two groups. We also analyzed the association of BIN1, CR1 and PICALM SNPs with LOAD in subgroups stratified by the presence or absence of the APOE epsilon4 allele. After adjusting for APOE, statistical analysis revealed that the association with PICALM rs541458 and BIN1 rs744373 were only significant among subjects without the APOE epsilon4 allele. PMID- 25022886 TI - Description of dogs and owners in outdoor built-up areas and their more-than human issues. AB - Tensions are generated by the inevitable presence of dogs accompanying humans in cities. Built-up outdoor areas, spaces that are "in between" the home and dog parks, are widely frequented by dogs and their owners. The present case study, performed in Lyon (France), is the first to provide a description of these dyads in areas that vary according to terrain, district, dog legislation and use in three areas: a busy street where dogs are allowed and a park and a square where dogs are forbidden. Dog-owner profiles were identified. They adjusted their presence differently across areas and according to anthropogenic and ecological pressures, such as day of the week, time of day, weather, frequentation, and legislation. They mutually adapted their behaviors. Interactions between dogs or owners and other social agents were few; dogs primarily sniffed and urinated. There was little barking, no aggression, minor impact on the environment, and, despite instances of dogs appropriating forbidden areas and dogs off their leashes, the dogs seemed to go virtually unnoticed. The study shows how the need for more-than-human areas is evident in outdoor built-up areas (for instance, the results on types of interaction and activity across areas, absence of a leash, and appropriation of forbidden areas) as well as how the cultural and natural aspects of dogs play out. The results suggest that dog regulations should be adjusted in outdoor built-up areas and that dog parks should be developed. PMID- 25022887 TI - Implications of spatial data variations for protected areas management: an example from East Africa. AB - Geographic information systems and remote sensing technologies have become an important tool for visualizing conservation management and developing solutions to problems associated with conservation. When multiple organizations separately develop spatial data representations of protected areas, implicit error arises due to variation between data sets. We used boundary data produced by three conservation organizations (International Union for the Conservation of Nature, World Resource Institute, and Uganda Wildlife Authority), for seven Ugandan parks, to study variation in the size represented and the location of boundaries. We found variation in the extent of overlapping total area encompassed by the three data sources, ranging from miniscule (0.4 %) differences to quite large ones (9.0 %). To underscore how protected area boundary discrepancies may have implications to protected area management, we used a landcover classification, defining crop, shrub, forest, savanna, and grassland. The total area in the different landcover classes varied most in smaller protected areas (those less than 329 km(2)), with forest and cropland area estimates varying up to 65 %. The discrepancies introduced by boundary errors could, in this hypothetical case, generate erroneous findings and could have a significant impact on conservation, such as local-scale management for encroachment and larger-scale assessments of deforestation. PMID- 25022888 TI - Fish assemblage response to a small dam removal in the Eightmile River system, Connecticut, USA. AB - We examined the effects of the Zemko Dam removal on the Eightmile River system in Salem, Connecticut, USA. The objective of this research was to quantify spatiotemporal variation in fish community composition in response to small dam removal. We sampled fish abundance over a 6-year period (2005-2010) to quantify changes in fish assemblages prior to dam removal, during drawdown, and for three years following dam removal. Fish population dynamics were examined above the dam, below the dam, and at two reference sites by indicator species analysis, mixed models, non-metric multidimensional scaling, and analysis of similarity. We observed significant shifts in fish relative abundance over time in response to dam removal. Changes in fish species composition were variable, and they occurred within 1 year of drawdown. A complete shift from lentic to lotic fishes failed to occur within 3 years after the dam was removed. However, we did observe increases in fluvial and transition (i.e., pool head, pool tail, or run) specialist fishes both upstream and downstream from the former dam site. Our results demonstrate the importance of dam removal for restoring river connectivity for fish movement. While the long-term effects of dam removal remain uncertain, we conclude that dam removals can have positive benefits on fish assemblages by enhancing river connectivity and fluvial habitat availability. PMID- 25022889 TI - [Actinobaculum schaalii infection]. PMID- 25022890 TI - Characteristics and costs of carbapenemase-producing enterobacteria carriers (2012/2013). AB - OBJECTIVES: We had for aim to determine the characteristics of carbapenemase producing enterobacteria (CPE) carriers and to assess the economic impact of isolation measures leading to loss of activity (closed beds, prolonged hospital stays) and additional personnel hours. PATIENTS AND METHODS: We conducted a retrospective study for 2years (2012/2013), in a French general hospital, focusing on CPE carriers with clinical case description. The costs were estimated by comparing the activity of concerned units (excluding the ICU) during periods with CPE carriers or contacts, during the same periods of the year (n-1), plus additional hours and rectal swabs. RESULTS: Sixteen EPC carriers were identified: 10 men and 6 women, 65+/-10years of age. Seven patients acquired EPC in hospital during 2 outbreaks in 2012. Four patients presented with an infection (peritonitis, catheter infection, and 2 cases of obstructive pyelonephritis) with a favorable outcome. The median length of stay was 21days [4,150]. Six patients died, 1 death was indirectly due to CPE because of inappropriate empiric antibiotic therapy. A decrease in activity was observed compared to the previous year with an estimated 547,303? loss. The 1779 additional hours cost 63,870?, and 716 screening samples cost 30,931?. The total additional cost was estimated at 642,104? for the institution. CONCLUSIONS: Specialized teams for CPE carriers and isolation of contact patients, required to avoid/control epidemics, have an important additional cost. An appreciation of their support is needed, as well as participation of rehabilitation units. PMID- 25022891 TI - Outpatient parenteral antimicrobial therapy for infective endocarditis: a cost effective strategy. AB - OBJECTIVES: We evaluated the benefit/risk ratio of outpatient parenteral antimicrobial therapy (OPAT) in infective endocarditis (IE). METHOD: We performed an observational retrospective study of definite IE (Duke criteria) treated in an infectious diseases unit in 2012. We compared patients having completed the treatment in hospital (H), and those deemed sufficiently stable, and with adequate home environment, for OPAT. The costs were estimated through hospital bills, and, for OPAT, through the costs of drugs and their administration (material, staff), transportation, and outpatient visits. RESULTS: Eighteen out of 39 consecutive patients presenting with IE received OPAT, with a mean hospital stay of 23.5days (vs 34.7days for H group, P=0.014). No severe adverse event related to OPAT was reported. The global saving was estimated at 267,307euros, or 14,850euros per patient. CONCLUSIONS: OPAT in selected patients presenting with IE seems effective, safe, and reduces costs by approximately 15,000euros per patient. PMID- 25022892 TI - Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-kB mediated matrix metalloproteinase-1 gene regulation. AB - INTRODUCTION: UEV1A encodes a ubiquitin-conjugating enzyme variant (Ubc13), which is required for Ubc13-catalyzed Lys63-linked polyubiquitination of target proteins and nuclear factor kappaB (NF-kB) activation. Previous reports have correlated the level of UEV1A expression with tumorigenesis; however, the detailed molecular events leading to tumors particularly breast cancer and metastasis are unclear. This study is to investigate roles of different UEV1 splicing variants, and its close homolog MMS2, in promoting tumorigenesis and metastasis in breast cancer cells. METHODS: We experimentally manipulated the UEV1 and MMS2 levels in MDA-MB-231 breast cancer cells and monitored their effects on cell invasion and migration, as well as tumor formation and metastasis in xenograft mice. The underlying molecular mechanisms leading to metastasis were also examined. RESULTS: It was found that overexpression of UEV1A alone, but not UEV1C or MMS2, is sufficient to induce cell invasion in vitro and metastasis in vivo. This process is mediated by NF-kappaB activation and requires functional Ubc13. Our experimental data establish that among NF-kappaB target genes, UEV1A regulated matrix metalloproteinase-1 (MMP1) expression plays a critical role in cell invasion and metastasis. Interestingly, experimental depletion of UEV1 in MDA-MB-231 cells reduces MMP1 expression and prevents tumor formation and metastasis in a xenograft mouse model, while overexpression of MMP1 overrides the metastasis effects in UEV1-depleted cells. CONCLUSIONS: These results identify UEV1A as a potential therapeutic target in the treatment of metastasic breast cancers. PMID- 25022894 TI - [Epidemiology of multiple sclerosis in Germany: regional differences and drug prescription in the claims data of the statutory health insurance]. AB - BACKGROUND: Nationwide population-based information on the prevalence of multiple sclerosis (MS) in Germany has so far not been available. In this study the prevalence of MS was determined with the help of the claims data of the health insurance funds underlying the morbidity-based risk adjustment scheme (M-RSA). MATERIAL AND METHODS: Health insurance funds reported inpatient and outpatient diagnoses, outpatient prescriptions, costs and enrolment data for all persons insured in the German statutory health insurance (SHI). The data reported for 2010 form the basis of this study which collated data on the 12-month prevalence, prevalence related to age and gender, drug therapy, regional distribution pattern, combinations of diagnoses and hospitalization. RESULTS: Nearly 200,000 people insured in the SHI have been diagnosed with MS. Hence, the prevalence seems to be considerably higher than was previously assumed. In addition, a slight west-east gradient was apparent. On average 49 % of all MS patients (with a slight east-west gradient) received MS-specific inpatient drug therapy. Insured patients living in the east received on average 30 daily doses per year less than patients living in the western part. CONCLUSION: For the first time MS prevalence has been determined nationwide for Germany with the help of SHI data. It appears that previously applied methods have underestimated the prevalence. The regional differences found with respect to prevalence and drug therapy need further clarification. The data underlying the M-RSA do not allow more causal research. PMID- 25022893 TI - [New aspects in the field of epilepsy]. AB - Regarding epilepsy several new developments can be reported. The International League Against Epilepsy (ILAE) has suggested a new definition of epilepsy, for the first time including a definition of epilepsy resolution. Progress in the diagnosis relates to new genetic findings, improvements in magnetic resonance imaging (MRI) and the increasing use of stereo electroencephalograms (sEEG). Regarding treatment there are new clinically relevant data on the pathophysiology and prevention of sudden unexpected death in epilepsy (SUDEP). Zonisamide has been approved by the European Medicines Agency (EMA) for monotherapy in adults with focal seizures and combination therapy in children aged >= 6 years. Retigabin and perampanel have been approved but are currently taken off the market in Germany (only) because the Gemeinsamer Bundesausschuss (GBA, Joint Federal Committee) did not find any additional therapeutic value as compared to lamotrigine due to a lack of data. A decision regarding a new application for perampanel is pending. Regarding surgical treatment novel ablation techniques (e.g. stereotactic radiofrequency and laser ablation as well as focussed ultrasound ablation) and brain stimulation paradigms are under investigation. Experimental studies, generously supported by the European Union (EU) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) are focusing on (opto-)genetic (e.g. using lentoviral transfection), epigenetic (e.g. micro-RNA related) approaches and on the investigation of neuronal micronetworks. PMID- 25022895 TI - [Services for the early recognition of psychoses and bipolar disorders in Germany: inventory survey study]. AB - BACKGROUND: In order to successfully implement early recognition and intervention services in psychiatry, it is crucial to improve the attention to and recognition of severe mental disorders and to establish low threshold services that are available at short notice for diagnostic and treatment procedures. MATERIAL AND METHODS: For this inventory survey study, questionnaires regarding the presence and type of early recognition services for psychoses and bipolar disorders were sent separately to German psychiatric hospitals by mail in September and October 2012. Additionally, an internet search and telephone inquiries as well as an alignment of responses from the two surveys and with network lists from published and ongoing early recognition studies were performed. RESULTS: Response rates in the psychosis and bipolar disorder surveys were 21 % (51/246) and 36 % (91/255), respectively. Three quarters of participating institutions reported at least an interest in creating an early recognition service for psychoses and one half for bipolar disorders. Overall, 26 institutions were identified that already offer early recognition of psychoses and 18 of bipolar disorders. Of these 16 are low threshold early recognition centres with direct access at short notice for first episode patients and person from at-risk groups and separate specific public relations work. Of these early recognition centres five have a separate and easy to find homepage available; in an additional 15 institutions the specific websites are part of the institutions homepage. CONCLUSION: Despite widespread interest and the increasingly recognized importance of early recognition and intervention services in psychiatry, there is currently no nationwide coverage with early recognition services for severe mental disorders in Germany. Public relations and information activities are not (yet) sufficiently provided to reach affected persons and their environment. Common standards are (still) missing and interdisciplinary models are sparse. To correct these shortcomings, amongst other factors, acquisition of sufficient funding for such services is required. PMID- 25022896 TI - Open reduction internal fixation of lateral humeral condyle fractures in children. A series of 105 fractures from a single institution. AB - Lateral humeral condyle fractures account for 17 % of the distal humeral condyle fractures. Displaced and/or rotated fractures require appropriate reduction and stabilisation. There are, however, a number of controversies in the surgical management of these patients. The aim of the present study was to review the results of patients with a displaced lateral humeral condyle fracture treated with open reduction and internal fixation (ORIF). We retrospectively reviewed children treated with ORIF of lateral humeral condyle fractures at a single institution over a period of 13 years. All cases were identified through the trauma register. Case notes and radiographs were retrieved. Fracture classification, mode of fixation, time to union, and final outcomes at the latest follow-up were reviewed. One hundred and five lateral condyle fractures were identified in 76 male and 29 female patients. Average age was 6.2 years. Ninety two were Milch type II and 13 Milch type I. According to the Jacob's classification, 38 were type II and 67 type III. All fractures were treated with open reduction and fixation with K-wires. Average time to radiological union was 33 days. Follow-up ranged between 2 and 8 years (average 3.2 years). Radiological hypertrophy of the lateral condyle was present in 45 cases (42 %). Three patients developed a pseudo-cubitus varus deformity. Further four patients developed a true cubitus varus. There was one case of superficial infection of the K-wires and one case of delayed union. At the latest follow-up, 96 % of the patients achieved an excellent final result and 4 % a good final result. Our results demonstrate that fracture union and excellent final outcomes can be expected in all patients using our protocol, whereby all patients with a displaced fracture are managed by ORIF with K-wire fixation, with the wires only being removed after there is evidence of radiological union. Compared to recent reports of closed reduction internal fixation, this series demonstrates good results with no complications directly relating to the open reduction technique. Level of evidence Case series, Level IV. PMID- 25022897 TI - Chronic alcohol exposure affects the cell components involved in membrane traffic in neuronal dendrites. AB - The specific traffic of the membrane components in neurons is a major requirement to establish and maintain neuronal domains-the axonal and the somatodendritic domains-and their polarized morphology. Unlike axons, dendrites contain membranous organelles, which are involved in the secretory pathway, including the endoplasmic reticulum, the Golgi apparatus and post-Golgi apparatus carriers, the cytoskeleton, and plasma membrane. A variety of molecules and factors are also involved in this process. Previous studies have shown that chronic alcohol exposure negatively affects several of these cell components, such as the Golgi apparatus or cytoskeleton in neurons. Yet very little information is available on the possible effects of this exposure on the remaining cell elements involved in intracellular trafficking in neurons, particularly in dendrites. By qualitative and quantitative electron microscopy, immunofluorescence and immunoblotting, we herein show that chronic exposure to moderate levels (30 mM) of ethanol in cultured neurons reduces the volume and surface density of the rough endoplasmic reticulum, and increases the levels of GRP78, a chaperone involved in endoplasmic reticulum stress. Ethanol also significantly diminishes the proportion of neurons that show an extension of Golgi into dendrites and dendritic Golgi outposts, a structure present exclusively in longer, thicker apical dendrites. Both Golgi apparatus types were also fragmented into a large number of cells. We also investigated the effect of alcohol on the levels of microtubule-based motor proteins KIF5, KIF17, KIFC2, dynein, and myosin IIb, responsible for transporting different cargoes in dendrites. Of these, alcohol differently affects several of them by lowering dynein and raising KIF5, KIFC2, and myosin IIb. These results, together with other previously published ones, suggest that practically all the protein trafficking steps in dendrites are altered to a greater or lesser extent by chronic alcohol exposure in neuronal cells, which may have negative repercussions for the development and maintenance of their polarized morphology and function. PMID- 25022898 TI - Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy. AB - Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy. PMID- 25022899 TI - Targeting Th17 cells in immune diseases. AB - Last decade has seen quick developments in the understanding of a new type of T lymphocytes, Th17 cells. This information is benefiting the understanding and treatment of a variety of inflammatory diseases, as suggested by a recent paper in Immunity. PMID- 25022900 TI - Where cell fate conversions meet Chinese philosophy. AB - Accumulating evidence indicates that the mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT) are basic mechanisms for cell fate conversion and may help us understand both physiologic and pathologic processes such as development and carcinogenesis. Here, we further suggest that mammalian cells fall into two grand divisions, mesenchymal or epithelial; interconversions between these two grand divisions through EMT/MET resonate with some ancient Chinese philosophic ideas. PMID- 25022901 TI - Clinical and bacteriological characteristics of Helicobacter cinaedi infection. AB - Helicobacter cinaedi was first isolated from rectal cultures from homosexual men in 1984. In the 1980s to mid 1990s, the microorganism was mainly isolated from samples from homosexual men or immunocompromised patients; however, during the last two decades, H. cinaedi has been isolated from immunocompromised and from immunocompetent individuals worldwide. In Japan, the isolation of this microorganism was first reported in 2003. Since then, many cases have been reported in hospitals across the country. Despite many reports, the etiological properties and pathogenicity of H. cinaedi remain elusive; however, we are increasingly able to recognize some of the features and the clinical relevance of infection. In particular, a long incubation period is essential for detection in an automatic blood culture system and many of the recent isolates are resistant to both macrolides and quinolones. Furthermore, there is an association between infection and severe or chronic illnesses, such as meningitis or arteriosclerosis, in addition to mild diseases such as fever, abdominal pain, gastroenteritis, proctitis, diarrhea, erysipelas, cellulitis, arthritis, and bacteremia. In this review, we introduce the current knowledge and our latest findings relating to H. cinaedi. PMID- 25022902 TI - Identification and consequences of miRNA-target interactions--beyond repression of gene expression. AB - Comparative genomics analyses and high-throughput experimental studies indicate that a microRNA (miRNA) binds to hundreds of sites across the transcriptome. Although the knockout of components of the miRNA biogenesis pathway has profound phenotypic consequences, most predicted miRNA targets undergo small changes at the mRNA and protein levels when the expression of the miRNA is perturbed. Alternatively, miRNAs can establish thresholds in and increase the coherence of the expression of their target genes, as well as reduce the cell-to-cell variability in target gene expression. Here, we review the recent progress in identifying miRNA targets and the emerging paradigms of how miRNAs shape the dynamics of target gene expression. PMID- 25022905 TI - Gene regulation: a chromatin-based recruitment drive. PMID- 25022908 TI - Population genetics: Living the highlife after archaic introgression. PMID- 25022910 TI - Unified theory of surface-plasmonic enhancement and extinction of light transmission through metallic nanoslit arrays. AB - Metallic nanostructures are of immense scientific interest owing to unexpectedly strong interaction with light in deep subwavelength scales. Resonant excitations of surface and cavity plasmonic modes mediate strong light localization in nanoscale objects. Nevertheless, the role of surface plasmon-polaritons (SPP) in light transmission through a simple one-dimensional system with metallic nanoslits has been the subject of longstanding debates. Here, we propose a unified theory that consistently explains the controversial effects of SPPs in metallic nanoslit arrays. We show that the SPPs excited on the entrance and exit interfaces induce near-total internal reflection and abrupt phase change of the slit-guided mode. These fundamental effects quantitatively describe positive and negative effects of SPP excitation in a self-consistent manner. Importantly, the theory shows excellent agreement with rigorous numerical calculations while providing profound physical insight into the properties of nanoplasmonic systems. PMID- 25022906 TI - Non-viral vectors for gene-based therapy. AB - Gene-based therapy is the intentional modulation of gene expression in specific cells to treat pathological conditions. This modulation is accomplished by introducing exogenous nucleic acids such as DNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides. Given the large size and the negative charge of these macromolecules, their delivery is typically mediated by carriers or vectors. In this Review, we introduce the biological barriers to gene delivery in vivo and discuss recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems, some of which are currently undergoing testing in clinical trials. The diversity of these systems highlights the recent progress of gene based therapy using non-viral approaches. PMID- 25022911 TI - Fidelity to the housing first model and effectiveness of permanent supported housing programs in California. AB - OBJECTIVES: Permanent supported housing programs are being implemented throughout the United States. This study examined the relationship between fidelity to the Housing First model and residential outcomes among clients of full service partnerships (FSPs) in California. METHODS: This study had a mixed-methods design. Quantitative administrative and survey data were used to describe FSP practices and to examine the association between fidelity to Housing First and residential outcomes in the year before and after enrollment of 6,584 FSP clients in 86 programs. Focus groups at 20 FSPs provided qualitative data to enhance the understanding of these findings with actual accounts of housing-related experiences in high- and low-fidelity programs. RESULTS: Prior to enrollment, the mean days of homelessness were greater at high- versus low-fidelity (101 versus 46 days) FSPs. After adjustment for individual characteristics, the analysis found that days spent homeless after enrollment declined by 87 at high-fidelity programs and by 34 at low-fidelity programs. After adjustment for days spent homeless before enrollment, days spent homeless after enrollment declined by 63 at high-fidelity programs and by 53 at low-fidelity programs. After enrollment, clients at high-fidelity programs spent more than 60 additional days in apartments than clients at low-facility programs. Differences were found between high- and low-fidelity FSPs in client choice in housing and how much clients' goals were considered in housing placement. CONCLUSIONS: Programs with greater fidelity to the Housing First model enrolled clients with longer histories of homelessness and placed most of them in apartments. PMID- 25022912 TI - Cumulative effects of childhood traumas: polytraumatization, dissociation, and schizophrenia. AB - The study objective was to measure and compare the presence of childhood trauma and dissociative symptoms in a convenience sample of healthy controls and a probabilistic sample of outpatients with a diagnosis of schizophrenia. Patients reported more childhood trauma and more polytraumatization than the controls, and had a higher average dissociation score. In both cases and controls, the presence of childhood trauma was related to the intensity of the dissociation observed. Childhood trauma, clinical dissociation and schizophrenia are closely related, particularly when the patient has been the victim of more than one type of abuse. PMID- 25022914 TI - Sero-prevalence and associated risk factors of peste des petits ruminants and contagious caprine pleuro-pneumonia in goats and sheep in the Southern Zone of Tanzania. AB - A retrospective Sero-prevalence analysis was conducted in 2012 in order to find out whether contagious caprine pleuro-pneumonia (CCPP) and peste des petits ruminants (PPR) had already been introduced in Mtwara and Lindi regions of Southern Tanzania by 2007 and 2009. A total of 477 randomly selected sera from a bank of 3500 small ruminant samples that were collected as part of Rift Valley Fever surveillance of 2007 in Mtwara and Lindi regions were used in this study. Seroconversion was also evaluated in the 504 sera that were collected in 2009 as part of disease outbreak investigations in Tandahimba and Newala districts of Mtwara region. Seroconversions to CCPP and PPR were tested using competitive ELISA. In addition, information on different variables available in the existing surveillance forms gathered during sampling was used in the analysis of risk factors associated with seropositivity to the two diseases. The overall seroprevalence of CCPP for the sera of 2007 and 2009 in goats was 52.1% (n=447) and 35.5% (n=434) respectively; while in sheep the seroprevalence was 36.7% (n=30) and 22.9% (n=70) respectively. Seroconversion to PPR in goats and sheep was 28.7% (n=434) and 35.7% (n=70) respectively based on the sera of 2009. However, no antibodies were detected in the 2007 sera. Mixed infections were detected in 7.4% (n=434) of the goat and 12.9% (n=70) of sheep samples. Significant risk factors associated with seropositivity to CCPP in 2007 included introduction of new animals in flocks (OR=3.94; 95% CI 1.86-8.36; p<0.001) and raising animals in government farms (OR=4.92; 95% CI 1.57-15.76; p=0.02); whereas, seropositivity to CCPP in 2009 increased with introduction of new animals in flocks (OR=18.82; 95% CI 8.06-43.96; p<0.001), raising animals in government farms (OR=4.04; 95% CI 2.69-6.42; p<0.001) and raising animals in Newala district (OR=2.35; 95% CI 1.53-3.62; p<0.001). On the other hand, predictors for seropositivity to PPR in 2009 were introduction of new animals in flocks (OR=2.83; 95% CI 1.73-4.62; p<0.001) and communal grazing of animals (OR=7.60; 95% CI 1.77-32.58; p=0.01). Therefore, these results show that CCPP was already circulating in goats in the southern zone by 2007 and that PPR was probably introduced thereafter. Their presence in this emerging animal keeping area in Tanzania calls for improved surveillance and control systems. PMID- 25022915 TI - HIV is detected in child thought to have been cured. PMID- 25022913 TI - Acceptability of a web-based community reinforcement approach for substance use disorders with treatment-seeking American Indians/Alaska Natives. AB - Longstanding disparities in substance use disorders and treatment access exist among American Indians/Alaska Natives (AI/AN). Computerized, web-delivered interventions have potential to increase access to quality treatment and improve patient outcomes. Prior research supports the efficacy of a web-based version [therapeutic education system (TES)] of the community reinforcement approach to improve outcomes among outpatients in substance abuse treatment; however, TES has not been tested among AI/AN. The results from this mixed method acceptability study among a diverse sample of urban AI/AN (N = 40) show that TES was acceptable across seven indices (range 7.8-9.4 on 0-10 scales with 10 indicating highest acceptability). Qualitative interviews suggest adaptation specific to AI/AN culture could improve adoption. Additional efforts to adapt TES and conduct a larger effectiveness study are warranted. PMID- 25022917 TI - DRC to Dar: one physician's journey to emergency medicine. PMID- 25022916 TI - Assembly of photosynthetic apparatus in Rhodobacter sphaeroides as revealed by functional assessments at different growth phases and in synchronized and greening cells. AB - The development of photosynthetic membranes of intact cells of Rhodobacter sphaeroides was tracked by light-induced absorption spectroscopy and induction and relaxation of the bacteriochlorophyll fluorescence. Changes in membrane structure were induced by three methods: synchronization of cell growth, adjustment of different growth phases and transfer from aerobic to anaerobic conditions (greening) of the bacteria. While the production of the bacteriochlorophyll and carotenoid pigments and the activation of light harvesting and reaction center complexes showed cell-cycle independent and continuous increase with characteristic lag phases, the accumulation of phospholipids and membrane potential (electrochromism) exhibited stepwise increase controlled by cell division. Cells in the stationary phase of growth demonstrated closer packing and tighter energetic coupling of the photosynthetic units (PSU) than in their early logarithmic stage. The greening resulted in rapid (within 0-4 h) induction of BChl synthesis accompanied with a dominating role for the peripheral light harvesting system (up to LH2/LH1 ~2.5), significantly increased rate (~7.10(4) s(-1)) and yield (F v/F max ~0.7) of photochemistry and modest (~2.5-fold) decrease of the rate of electron transfer (~1.5.10(4) s(-1)). The results are discussed in frame of a model of sequential assembly of the PSU with emphasis on crowding the LH2 complexes resulting in an increase of the connectivity and yield of light capture on the one hand and increase of hindrance to diffusion of mobile redox agents on the other hand. PMID- 25022918 TI - BET 1: bedside ultrasound for the diagnosis of necrotising fasciitis. AB - A short-cut review was carried out to establish whether bedside ultrasound was accurate at diagnosing necrotising fasciitis in patients with limb infections. A total of 187 papers were found using the reported searches, of which one presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this paper is tabulated. It is concluded that there is limited evidence supporting the use of bedside ultrasound as an adjunct diagnostic tool in differentiating cellulitis from necrotising fasciitis in patients with a limb infection. PMID- 25022920 TI - BET 2: prophylactic antiemetic use in immobilised adult trauma patients. AB - A short-cut review was carried out to establish whether prophylactic antiemetic agents reduce the incidence of vomiting in immobilised patients who have suffered trauma. A total of 137 papers were found using the reported searches, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that prophylactic use of antiemetic agents in trauma patients may reduce the likelihood of vomiting some 5-12-fold. PMID- 25022921 TI - Short answer question case series: toddler groin pains. PMID- 25022922 TI - Response to Li and Zhang: infevers, a human gene mutation database for autoinflammatory diseases including disseminated superficial actinic porokeratosis. PMID- 25022923 TI - Chagas disease as a cause of heart failure and ventricular arrhythmias in patients long removed from endemic areas: an emerging problem in Europe. AB - Chagas disease is a parasitic disease caused by the protozoan Trypanosoma cruzi. In endemic areas (South and Central America), Chagas disease represents a relevant public health issue, and is the most frequent cause of cardiomyopathy. In nonendemic areas, such as Europe, Chagas disease represents an emerging problem following the establishment of sizeable communities from Brazil and Bolivia. Chagas cardiomyopathy represents the most frequent and serious complication of chronic Chagas disease, affecting about 20-30% of patients, potentially leading to heart failure, arrhythmias, thromboembolism, stroke and sudden death. Because late complications of Chagas disease may develop several years or even decades after the acute infection, it may be extremely challenging to reach the correct diagnosis in patients long removed from the countries of origin. We report two examples of Chagas cardiomyopathy in South American women permanently residing in Italy for more than 20 years, presenting with cardiac manifestations ranging from left ventricular dysfunction and heart failure to isolated ventricular arrhythmias. The present review emphasizes that Chagas disease should be considered as a potential diagnosis in patients from endemic areas presenting with 'idiopathic' cardiac manifestations, even when long removed from their country of origin, with potential implications for treatment and control of Chagas disease transmission. PMID- 25022924 TI - Implanting cardiac rhythm devices during uninterrupted warfarin therapy: a prospective, single center experience. AB - AIM: The aim of the present study was to assess the safety of cardiac rhythm device implantation during uninterrupted oral anticoagulant therapy. METHODS: Patients at high thromboembolic risk (venous thromboembolism <3 months, nonvalvular atrial fibrillation with CHADS2 score >2, valvular atrial fibrillation, prosthetic heart valves) underwent procedures during uninterrupted warfarin (on warfarin group) and were compared to low-risk patients who underwent procedures after warfarin withdrawal (off warfarin group). Primary endpoint was a composite of hematoma requiring warfarin interruption, reoperation, or blood transfusion; death; hemothorax; and tamponade. Secondary endpoints were nonsignificant hematoma and clinical arterial thromboembolism assessed at discharge and at a 2 month follow-up. RESULTS: One hundred and ninety-one patients were enrolled, 102 in the 'on warfarin group' and 89 in the 'off warfarin group'. The majority of procedures were first implants (73% in the 'on warfarin group' vs. 87% in the 'off warfarin group', P= 0.01). Pacemakers, implantable cardioverter defibrillators, and biventricular devices were included. International normalized ratio at implant was 2 +/- 0.28 (range 1.6-3.2) in the 'on warfarin group' and 1.3 +/- 0.19 (range 1-1.6) in the 'off warfarin group' (P= 0.0001). Incidence of hemathoma was five of 102 in the 'on warfarin group' vs. three of 89 in the 'off warfarin group' (5 vs. 3%, P = not significant) and all hemathomas resolved spontaneously. There were no significant hemathomas in either group. There was no death, hemothorax, or tamponade. There were no thromboembolic events at 2 months. CONCLUSION: Cardiac rhythm device implantation during uninterrupted warfarin was not associated with increased bleeding compared with warfarin interruption. PMID- 25022925 TI - Recoordination of opposing walls drives the response to cardiac resynchronization therapy: a longitudinal study using a strain discoordination index. AB - BACKGROUND AND AIMS: Intraventricular dyssynchrony has traditionally been studied by means of contraction delays between different myocardial segments. Recently, the discoordination of opposing wall contraction throughout the cardiac cycle has been proposed as a more faithful predictor of response. Aim of the current study was to evaluate which parameters - mechanical dyssynchrony or discoordination - normalize with left ventricular response to cardiac resynchronization therapy (CRT). METHODS: Cardiac mechanics were analysed before and after 6 months of CRT in 53 patients with left bundle branch block and advanced heart failure. Discoordination was quantified by means of the transverse strain discoordination index (TSDI) at basal and mid-ventricular segments; this index takes into account the percentage of time in the cardiac cycle in which cardiac deformation (transverse strain) of the two opposing walls occurs in noncoordinated directions. Dyssynchrony indices included septal to lateral peak-to-peak transverse strain delay and the standard deviation of time to peak tissue velocity in 12 mid-basal segments (Yu index). RESULTS: Around 63% of patients met the response criteria. Several baseline indices were predictive of reverse remodelling; TSDI at the mid-ventricular level demonstrated the best accuracy. Time from Q to peak velocity and strain tended to increase in all explored myocardial segments; despite a trend towards a decrease in septal-to-lateral strain delay, the latter decreased equally in responders and in nonresponding patients. Yu index decreased in responders more than in nonresponders, with borderline significance. Basal and medium TSDI remained unchanged in nonresponders and consistently normalized in patients who responded to CRT. The changes in TSDI were significantly correlated with improvements in left ventricular end-systolic volume and ejection fraction; the strongest correlation was observed for changes in TSDI measured at the mid-ventricular level. CONCLUSION: Left ventricular reverse remodelling after CRT is accompanied by the recoordination of opposite-wall contraction, as testified by changes in mid ventricular TSDI, which also reveals as a very good predictor of response. On the contrary, changes of segmental peak-to-peak delays (dyssynchrony indices) fail to capture the complex nature of left ventricular response to CRT. PMID- 25022926 TI - The fate at mid-term follow-up of the on-pump vs. off-pump coronary artery bypass grafting surgery. AB - AIMS: To evaluate the fate of on-pump coronary artery bypass grafting (ON-pump CABG) vs. off-pump coronary artery bypass grafting (OP-CABG) surgery at mid-term follow-up. METHODS: From January 2008 to December 2010, 369 patients underwent surgical myocardial revascularization by means of OP-CABG techniques (n = 166) or with ON-pump CABG (n = 203). Data of the two groups of patients were retrospectively analyzed. RESULTS: As compared with OP-CABG, in the ON-pump CABG patients, mean value of Logistic EuroSCORE (8.1 +/- 7.8% vs. 6.2 +/- 5.9%, P = 0.04), more extended coronary disease (2.7 +/- 0.5 vs. 2.5 +/- 0.7 diseased vessels/patient, P < 0.001) consequently requiring greater number of grafts/patient (2.9 +/- 0.9 vs. 2.3 +/- 0.9, P < 0.0001), and emergency surgery (12 vs. 6%, P = 0.03) were more frequently observed. Operative mortality was 1.9% in ON-pump CABG vs. 1.2% in OP-CABG (P = 0.6) and incidence of stroke 2.46 vs. 1.81% (P = 0.7). The incidence of stroke was reduced at 1.2% when OP-CABG PAS Port 'clamp-less' technique was used.Intraoperatively, costs per patient were higher for OP-CABG vs. ON-pump CABG (1.930,00 +1.050,00 ?, if PAS-port system was included, vs. 1.060,00 ? for ON-pump surgery). ICU stay (1.9 +/- 1.0 days vs. 1.4 +/- 0.7 days) and total postoperative in-hospital stay (5.3 +/- 3.3 days vs. 5.5 +/- 3.5 days) were similar in both groups.At 4 years, survival (91 +/- 13% in the ON-pump CABG vs. 84 +/- 19% in the OP-CABG), freedom from major adverse cardiac events (composite end-point of all-cause death, myocardial infarction, and repeat coronary revascularization of the target lesion) (82 +/- 9% vs. 76 +/- 14%), and major adverse cardiac and cerebrovascular events (80 +/- 11% vs. 72 +/- 16%) were not significantly different. Freedom from late cardiac death was slightly significant higher after ON-pump CABG (98 +/- 4% vs. 90 +/- 10%, P = 0.05). CONCLUSION: Mid-term freedom from composite end-points is similar after ON-pump CABG and OP-CABG. Freedom from cardiac death appears to be better after ON-pump CABG. OP-CABG needs for more expensive surgical technique. OP-CABG performed by an experienced surgical team using 'clamp-less' techniques can be an effective strategy in reducing postoperative stroke. PMID- 25022927 TI - Therapeutic hypothermia in the intensive cardiac care unit. AB - Therapeutic hypothermia has demonstrated to improve both survival and neurological outcome in patients who experienced an out-of-hospital cardiac arrest. Nevertheless, many aspects of its clinical application are still controversial. Current guidelines recommend to cool patients who survive a cardiac arrest due to either ventricular fibrillation or ventricular tachycardia, whereas the beneficial effect of lowering body temperature in nonshockable rhythms is still questionable due to the lack of randomized controlled trial involving this subgroup of patients. Although therapeutic hypothermia is often begun before hospital arrival, the optimal time to start cooling is still a matter of debate. Furthermore, different methods are available to low body temperature, but no direct comparisons are available to establish which device performs better than others, and a combination of external and endovascular cooling is usually preferred. The present review is aimed at summarizing the available evidence supporting the use in clinical practice of mild hypothermia in comatose survivors from cardiac arrest and at evaluating its adverse events and their treatment. PMID- 25022928 TI - Cardiac troponin I and creatine kinase-MB release after different cardiac surgeries. AB - AIMS: To conduct a comparative study of cardiac troponin I (cTnI) and MB isoenzyme of serum creatine kinase (CK-MB) after different cardiac surgeries. METHODS: Consecutive cardiac operations under cardiopulmonary bypass (200 adults, 144 men, 68 +/- 11 years): 67 coronary artery bypass graft (CABG), 27 aortic valve surgery, 21 mitral valve surgery, 11 thoracic aorta surgery, and 74 combined surgery. Postoperative cTnI and CK-MB were measured on admission to the ICU and at fixed time until the fifth postoperative day. RESULTS: Peak values of cTnI (median 5.8 ng/ml; interquartile range 3.6-11.9) and CK-MB (29.0 ng/ml; 15.6 60.4) were reached mainly within 18 h after the end of surgery (85% of cTnI and 95% of CK-MB highest determinations) without differences among groups. Cardiopulmonary bypass and cross-clamp time significantly correlated with markers' peak values. At multivariate analysis, mitral valve surgery showed greater cTnI, CK-MB, and their cumulative area under the curve than other isolated procedures. Thoracic aorta surgery showed lower cumulative area under the curve for both markers than CABG and combined surgery. Mitral valve surgery had significant later reduction of both markers in comparison with other procedures. No patient in mitral valve surgery group reached cTnI values in the normal laboratory range within 5 postoperative days. CONCLUSION: Release pattern of cTnI and CK-MB after heart surgery depends on the type of procedure. Mitral valve surgery was characterized by highest and longest elevation of postoperative markers' concentration. Determinants of differences in myocardial injury biomarkers and their prognostic value after valve surgery should be accurately assessed. PMID- 25022929 TI - Outcomes of heart failure with preserved ejection fraction in a Southeast Asian cohort. AB - BACKGROUND: Heart failure with preserved ejection fraction (HF-PEF) has been shown to be of better or equivalent prognosis than heart failure with reduced ejection fraction (HF-REF). We aimed to characterize and study the outcome of HF PEF in a multiethnic South East Asian context. METHODS: This is a single-centre retrospective analysis of 312 patients admitted with decompensated heart failure over 1 year from January to December 2009. We evaluated clinical characteristics of patients according to left ventricular ejection fraction at least 50 or less than 50%. Outcomes as defined by 1-year mortality and 90-day re-hospitalization rates for heart failure were compared between the two groups in an in-patient setting. RESULTS: The median age was 68 years and median length of hospitalization was 4 days. Around 21.8% had HF-PEF. Patients with preserved ejection fraction were more often older, female, hypertensive, with atrial fibrillation, had no coronary artery disease and had never smoked before. They were less often prescribed antiplatelets, angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker, aldosterone-receptor antagonists, digoxin and loop diuretics. After 1 year, mortality was 5.9% in patients with HF PEF and 11.3% in those with HF-REF, but the difference was nonsignificant (P = 0.195). There was also no difference in 90-day rehospitalization rates between the groups (16.2 vs. 17.6%, respectively, P = 0.780). Poor prognostic factors for the cohort of heart failure patients included increased age, diabetes and renal impairment, but not left ventricular ejection fraction. CONCLUSION: HF-PEF is associated with distinct risk factors from HF-REF, but has a similar morbidity and mortality to HF-REF. PMID- 25022930 TI - Validity of the Seattle Heart Failure Model for prognosis in a population at low coronary heart disease risk. AB - AIM: Validation of the Seattle Heart Failure Model (SHFM) for predicting the risk of death in a population different than the derivation cohort. METHODS: In a retrospective analysis of a cohort of chronic heart failure patients with left ventricular systolic dysfunction, consecutively referred between 2000 and 2011, we computed the score, according to characteristics at referral. We compared the observed risk of death with that predicted by the model, using receiver operating characteristic (ROC) curves to assess discrimination and a goodness-of-fit test for the comparison of predicted and observed risks. RESULTS: In 565 patients, 68.5% were men, the median age was 70 years, 46.0% had ischemic cause, 89.7% moderate-severe left ventricular systolic dysfunction and 61.2% New York Heart Association class II. The risk of death increased progressively with the model's score, with an area under the ROC curve between 0.69 and 0.72 when considering different follow-up periods. The model underestimated the risk of death (observed vs. predicted: 12.2 vs. 10.4%, P < 0.001; 28.1 vs. 25.1%, P < 0.001; and 43.4 vs. 35.7%, P < 0.001 at 1, 3 and 5 years, respectively). Accurate predictions, with nonsignificant differences between observed and predicted risks in a goodness-of fit test, were obtained after recalibration. CONCLUSION: In this study, the SHFM substantially underestimated the absolute risk of death in ambulatory chronic heart failure patients, mostly nonischemic and elderly. After adjustment for sample-specific circumstances, the recalibrated model demonstrated to be credible in clinical practice and may provide useful information to physicians. PMID- 25022931 TI - Incidence rate of primary cardiac tumors: a 14-year population study. AB - AIMS: Incidence of primary cardiac tumors (PCTs) is not known. Literature data derive from autoptic studies or echocardiographic registries. An incidence of 1 of 1000 autoptic and 1.5 of 1000 echocardiographic study is reported but data from a general population are not available. The aim of our study was to evaluate the incidence rate of PCTs in the general population. METHODS: All patients with suspected cardiac mass were evaluated with basal echocardiogram and/or transesophageal echocardiogram/cardiac magnetic resonance by Grosseto's cardiology department, the county referral center for both adult and pediatric populations. Diagnosis was confirmed at surgical excision (32), autoptic specimens (3) or by multimodal imaging when surgery was not indicated (7). The database of the county health system was interrogated to identify residents with The International Classification of Diseases-9 codes of PCT. Forty-two consecutive cases of PCTs were diagnosed from 1 January 1998, through 31 December 2011, among residents in Grosseto's county. RESULTS: Incidence rate of PCTs was 1.38 of 100,000 inhabitants per year. PCTs were benign in 38 patients (90.5%) and malignant in four (9.5%). Twenty myxomas were found (48%), followed by seven fibroelastomas (15%), six lipomas (15%), three rhabdomyomas (8%), two hemangioma (5%), two sarcomas (5%), one lymphoma (2%) and one pericardial hemangiopericytoma (2%). Incidence of benign PCT was 1.24 of 100,000/year; referring only to myxomas we found an incidence of 0.68 of 100,000/year. CONCLUSION: This is the first population study on PCT, a rare disease with an incidence rate of 1.38 new cases per 100,000 residents per year. PMID- 25022932 TI - Similar anti-inflammatory effects of intracoronary and intravenous abciximab during primary percutaneous coronary intervention: a randomized study. AB - BACKGROUND: Intracoronary Abciximab administration during primary percutaneous coronary intervention (pPCI) could offer theoretical advantages over the intravenous route. Besides antiplatelet effects, Abciximab can modulate inflammation via cross-reactivity with GPIIb/IIIa, avb3, and aMb2 receptors. The aim of our study was to assess whether the Abciximab administration route could influence its anti-inflammatory effects. METHODS: Eighty-nine consecutive ST elevation myocardial infarction patient candidates for pPCI were randomized to intracoronary (Group A-47 patients) or intravenous (Group B-42 patients) Abciximab bolus administration. The primary endpoint was the extent of inflammation, measured by C-reactive protein (CRP), vascular cell adhesion molecule 1 (VCAM-1) and inter-cellular adhesion molecule 1 (ICAM-1) levels. This study is registered with ClinicalTrials.gov, NCT01757457. RESULTS: Data are expressed in medians (interquartiles). In both groups, troponin levels were similar [baseline: 0.12 (0.03-0.94) vs. 0.27 (0.07-1.24) ng/ml, P = 0.73; postprocedural: 22.00 (14.75-69.43) vs. 31.96 (8.23-7.20) ng/ml, P = 0.83]. Both groups also showed similar baseline [0.31 (0.14-0.69) vs. 0.22 (0.09-0.59) mg/ml, P = 0.80] and postprocedural CRP levels [2.28 (1.37-4.23) vs. 2.16 (1.15-3.22) mg/dl, P = 0.69], similar baseline [272.5 (224.7-340.8) vs. 262.2 (221.2-306.4) ng/ml, P = 0.33] and postprocedural soluble ICAM-1 levels [281.5 (244.6-337.4) vs. 287.2 (226.9-359.2) ng/ml P = 0.71], and similar baseline [771.6 (620.9 971.0) vs. 748.6 (592.2-838.8) ng/ml, P = 0.30] and postprocedural soluble VCAM-1 levels [785.2 (671.6-947.1) vs. 745.9 (641.1-841.9) ng/ml, P = 0.17]. In-hospital and 6-month event rates were similar in the two groups. CONCLUSIONS: Our study suggests that Abciximab has similar anti-inflammatory effects irrespective of the administration route. It is unlikely that the potential clinical benefits of intracoronary Abciximab can be related to modulation of integrin receptors. PMID- 25022933 TI - Clinical characteristics and prognosis of 60 patients with midventricular obstructive hypertrophic cardiomyopathy. AB - BACKGROUND: Midventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is a rare form of hypertrophic cardiomyopathy. Knowledge regarding the diagnosis, morbidity and cardiovascular mortality is limited. In this study, we aimed to describe the long-term outcomes of patients with MVOHCM followed in a tertiary referral centre.Methods A retrospective study of 60 patients with MVOHCM diagnosed at FuWai Hospital was performed. Clinical features, mortality and cardiovascular morbidity were analysed. RESULTS: The 60 patients with MVOHCM represented 2.9% of all the hypertrophic cardiomyopathy cases (n = 2068). At diagnosis, the mean age was 40.2 +/- 15.0 years. During 7.1 +/- 6.3 years of follow-up after diagnosis, the cardiovascular mortality was 15.0%. The probability of survival at 10 years was 77.0 +/- 8.0%. The following two predictors of cardiovascular mortality were identified: severe ventricular septal hypertrophy at least 30 mm (hazard ratio, 3.19; P = 0.031) and unexplained syncope (hazard ratio, 4.59; P = 0.002) at baseline. Thirty patients (50.0%) had one or more morbid events, and the most frequent was nonsustained ventricular tachycardia. Apical aneurysm formation was identified in 20% of patients, and the patients with apical aneurysms were more inclined to experience nonsustained ventricular tachycardia than patients without apical aneurysm (58.3 vs. 16.7%; P = 0.003). Peak pressure gradient at least 70 mm Hg (hazard ratio, 3.00; P = 0.01) at baseline was identified as the only predictor of apical aneurysm. CONCLUSION: In Chinese patients, MVOHCM is associated with an unfavourable prognosis of cardiovascular mortality. One-half of these patients experience major cardiovascular events, and 20% develop an apical aneurysm, which significantly increases arrhythmia events. These data warrant measures to ensure the early recognition of MVOHCM followed by appropriate therapeutic interventions. PMID- 25022934 TI - Sleep-disordered breathing and echocardiographic measures of function and dyssynchrony: a complex approach to cardiac resynchronization therapy. AB - INTRODUCTION: We investigated the relationship between sleep-disordered breathing (SDB), cardiac function, and cardiac resynchronization therapy (CRT). METHODS: Fifty-five CRT patients with SDB diagnosed by Holter ECG (apnea/hypopnea index - AHI) were included in the study. We sought to determine right ventricle (RV) predictors of short-term SDB improvement and long-term outcome in patients with (AHI dippers) and without (AHI nondippers) 25% AHI improvement, markers of CRT response, and SDB influence on survival. RESULTS: Baseline tricuspid E-wave (AUC 0.925, cut-off value > 0.336 m/s; sensitivity - 90%, specificity - 100%) and RV E/E' - 0.864, <=16.25; 73%, 100%, respectively) were found as predictors of 25% AHI reduction. Spiroergometric tests, mitral regurgitation, and LVEF results improved significantly in AHI dippers. Regression analysis identified the absence of 25% AHI reduction (OR-7.67, 95% CI 1.52-38.6 and OR-9.92, 95%CI 6.02-15.3) and septal-lateral atrial velocities delay (OR-1.09, 95% CI 0.99-1.2 and 1.07, 95% CI 0.99-1.16) as independent predictors of both clinical and echocardiographic nonresponse. During median follow-up of 6.8 years, mortality was significantly reduced in patients with both AHI 25% reduction and 10% absolute LVEF increase in the first 3 months of CRT, compared with the subjects with only one or none of those criteria. CONCLUSION: The baseline RV diastolic indices were found as independent predictors of SDB improvement during CRT. Both clinical and echocardiographic long-term response can be independently predicted by SDB and intraatrial dyssynchrony. The best survival rate was observed in patients with SDB and LVEF improvement noted in the first 3 months of CRT. PMID- 25022935 TI - Serum levels of novel adipokines, omentin-1 and chemerin, in patients with acute myocardial infarction: KOZANI STUDY. AB - OBJECTIVES: The role of the novel adipokines, omentin-1 and chemerin, in coronary artery disease is still obscure. The present study analyzed the serum levels of omentin-1 and chemerin in patients with acute myocardial infarction (AMI) as well as prospectively 6 months post-AMI. METHODS: Seventy-eight patients (63 men and 15 women) with first AMI were enrolled. Thirty-two age-matched and sex-matched individuals without overt cardiovascular disease served as healthy controls. Serum levels of omentin-1, chemerin, interleukin-18 (IL-18), high-sensitivity C reactive protein (hsCRP), glycemic and lipid profiles, blood pressure, BMI and ejection fraction were assayed. In AMI patients, blood samples were obtained at hospital admission and after 6 months, whereas coronary angiography was performed within 7 days after admission. RESULTS: At baseline, AMI group appeared with significantly lower ejection fraction, omentin-1 and high-density lipoprotein serum levels, whereas it had higher concentrations of white blood cells count (WBC), hsCRP, IL-18 and chemerin compared with healthy controls (P < 0.05). After 6 months of follow-up, the concentrations of WBC, hsCRP and IL-18 significantly downregulated, whereas omentin-1 levels considerably increased (from 18.73 +/- 3.66 ng/ml to 28.62 +/- 5.61 ng/ml, P < 0.001) within AMI group. In contrast, serum chemerin did not significantly change (263.37 +/- 73.32 ng/ml vs. 195.90 +/ 84.32 ng/ml, P = 0.190). In standard multiple regression analyses, baseline levels and changes of hsCRP and IL-18 levels during follow-up remained independent determinants of omentin-1, respectively at baseline and after follow up. CONCLUSION: Patients with AMI showed at admission lower omentin-1 and higher chemerin serum levels compared with healthy controls. The suppression of inflammation in the 6-month post-AMI period might have mediated the significant upregulation of omentin-1, implicating a novel target of treatment. PMID- 25022936 TI - First symptom and initial diagnosis in sporadic CJD patients in Germany. AB - To describe the first symptom/sign and first diagnosis in patients with sporadic Creutzfeldt-Jakob disease (sCJD) in Germany with respect to M129V polymorphism of the prion protein gene and prion protein type. Data on the first symptom/sign and first diagnosis were studied in 492 sCJD patients with probable and definite sCJD and known M129V polymorphism. Unspecific prodromal symptoms such as headache, fatigue, sleep disturbances, "peculiar feeling in the head", photophobia or weight loss were found in about 10 % of the patients. No prodromal symptoms were found in MV2 and VV1 patients. Dementia was the most common first symptom (37 %) followed by cerebellar (34 %), visual (15 %), and psychiatric disturbances (14 %). The CJD diagnosis was the first diagnosis in only 35 % of the patients (in 42 % of MM, 28 % of MV, and 24.5 % of VV patients). We provide a detailed analysis on clinical presentation and first diagnosis in a large group of patients with sCJD with respect to M129V genotype and prion protein type. These data emphasize the importance of knowledge about CJD and especially rare CJD types among physicians of different specializations. Our findings may improve early recognition of atypical CJD forms. PMID- 25022937 TI - Euthanasia and physician-assisted suicide in amyotrophic lateral sclerosis: a prospective study. AB - The objective of this study is to determine if quality of care, symptoms of depression, disease characteristics and quality of life of patients with amyotrophic lateral sclerosis (ALS) are related to requesting euthanasia or physician-assisted suicide (EAS) and dying due to EAS. Therefore, 102 ALS patients filled out structured questionnaires every 3 months until death and the results were correlated with EAS. Thirty-one percent of the patients requested EAS, 69% of whom eventually died as a result of EAS (22% of all patients). Ten percent died during continuous deep sedation; only one of them had explicitly requested death to be hastened. Of the patients who requested EAS, 86% considered the health care to be good or excellent, 16% felt depressed, 45% experienced loss of dignity and 42% feared choking. These percentages do not differ from the number of patients who did not explicitly request EAS. The frequency of consultations of professional caregivers and availability of appliances was similar in both groups. Our findings do not support continuous deep sedation being used as a substitute for EAS. In this prospective study, no evidence was found for a relation between EAS and the quality and quantity of care received, quality of life and symptoms of depression in patients with ALS. Our study does not support the notion that unmet palliative care needs are related to EAS. PMID- 25022938 TI - Longitudinal course of cortical thickness decline in amyotrophic lateral sclerosis. AB - To determine longitudinal rates of cortical atrophy in classical Amyotrophic lateral sclerosis (ALS) and ALS variants. Rates of cortical thinning were determined between 2 scans, 3-15 months apart, in 77 ALS patients: 51 classical, 12 upper motor neuron (UMN), and 14 lower motor neuron (LMN) ALS variants. Cortical thickness at the first assessment was compared with 60 healthy controls matched by age and gender. Atrophy rates were compared between patient sub-groups and correlated with disease duration, progression, and severity. Using a cross sectional analysis, we found a significant difference in cortical thickness between ALS patients and controls in the motor and extra-motor areas (left medial orbito frontal gyrus, left inferior parietal gyrus, bilateral insular cortex, right fusiform gyrus, bilateral precuneus). Using a longitudinal analysis, we found a significant decline of cortical thickness in frontal, temporal, and parietal regions over the course of the study in ALS patients. Effects were independent of the clinical subtype, with exception of the precentral gyrus (p < 0.001). The LMN ALS variants demonstrated the highest rates of cortical thinning in the precentral gyrus, the UMN-dominant subjects exhibited intermediate rates of atrophy, and the classical ALS patients exhibited no such change. Atrophy of the precentral gyrus in classical ALS indicates a floor effect at the first assessment, resulting in a lack of further atrophy over time. Structural loss of the precentral gyrus appears to be an early sign of classical ALS. Over time, patterns of cortical thinning in extra-motor areas can be identified in ALS, regardless of the phenotype. PMID- 25022939 TI - Transdermal rotigotine in advanced Parkinson's disease: a randomized, double blind, placebo-controlled trial. AB - Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a randomized, double-blind, placebo controlled trial in Japanese patients with advanced Parkinson's disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on-off, delayed-on/no on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were -10.1 +/- 9.0 (mean +/- standard deviation) in the rotigotine group and -4.4 +/- 7.4 in the placebo group (p < 0.001). There was a significantly greater reduction in the off time (p = 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD. PMID- 25022940 TI - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype in a patient with a novel heterozygous POLG mutation. PMID- 25022941 TI - Ischemic stroke in prediabetic patients. AB - To describe the clinical characteristics of first-ever ischemic stroke (IS) patients with prediabetes, and to compare them with diabetes mellitus (DM) and non-DM patient characteristics. Retrospective analysis of a prospective series of first-ever acute IS patients. Patients were classified as non-DM (HbA1c during admission <5.7% and no previous evidence of 2 or more fasting glucose >126 mg/dL), prediabetes (HbA1c from 5.7 to 6.4%), and DM (previous DM diagnosis or HbA1c >=6.5% independently of current blood glucose). Demographic and clinical characteristics were compared between the three groups, along with outcome data [early neurological deterioration (END), 3-month poor outcome, 3-month mortality, outcome after rtPA treatment]. No demographic differences were observed. Prediabetic patients had more arterial hypertension (p = 0.006) and higher waist circumference (p < 0.0001) than non-DM patients, and DM patients had more hypercholesterolemia (p < 0.0001), body mass index (p = 0.017), and coronary artery disease (p = 0.005) than prediabetics. There were differences in TOAST subtype distribution (p < 0.0001). There were no differences in rtPA treatment success rate between groups. Multivariate analysis adjusted by age and stroke severity showed that DM but not prediabetes is an independent factor associated with END and 3-month poor outcome. Prediabetic patients with IS exhibit an "intermediate" vascular risk factor profile between that of non-DM and DM patients. In contrast to DM patients, IS prognosis in patients with prediabetes is similar to non-DM patients. PMID- 25022942 TI - Focal epilepsy in glucose transporter type 1 (Glut1) defects: case reports and a review of literature. AB - Mutations in SLC2A1, encoding the glucose transporter type 1 (Glut1), cause a wide range of neurological disorders: (1) classical Glut1 deficiency syndrome (Glut1-DS) with an early onset epileptic encephalopathy including a severe epilepsy, psychomotor delay, ataxia and microcephaly, (2) paroxysmal exercise induced dyskinesia (PED) and (3) various forms of idiopathic/genetic generalized epilepsies such as different forms of absence epilepsies. Up to now, focal epilepsy was not associated with SLC2A1 mutations. Here, we describe four cases in which focal seizures present the main or at least initial category of seizures. Two patients suffered from a classical Glut1-DS, whereas two individuals presented with focal epilepsy related to PED. We identified three novel SLC2A1 mutations in these unrelated individuals. Our study underscores that focal epilepsy can be caused by SLC2A1 mutations or that focal seizures may present the main type of seizures. Patients with focal epilepsy and PED should undergo genetic testing and can benefit from a ketogenic diet. But also individuals with pharmaco-resistant focal epilepsy and cognitive impairment might be candidates for genetic testing in SLC2A1. PMID- 25022943 TI - Distance. PMID- 25022946 TI - Composite factors, including mycoplasmal pneumonia, hypersensitivity syndrome, and medicine, leading to bronchiolitis obliterans in a school-age child. PMID- 25022944 TI - Continuing to illuminate the mechanisms underlying UV-mediated melanomagenesis. AB - The incidence of melanoma is one of the fastest growing of all tumor types in the United States and the number of cases worldwide has doubled in the past 30 years. Melanoma, which arises from melanocytes, is an extremely aggressive tumor that invades the vascular and lymphatic systems to establish tumors elsewhere in the body. Melanoma is a particularly resilient cancer and systemic therapy approaches have achieved minimal success against metastatic melanoma resulting in only a few FDA-approved treatments with limited benefit. Leading treatments offer minimal efficacy with response rates generally under 15% in the long term with no clear effect on melanoma-related mortality. Even the recent success of the specific BRAF mutant inhibitor vemurafenib has been tempered somewhat since acquired resistance is rapidly observed. Thus, understanding the mechanism(s) of melanoma carcinogenesis is paramount to combating this deadly disease. Not only for the treatment of melanoma but, ultimately, for prevention. In this report, we will summarize our work to date regarding the characterization of ultraviolet radiation (UVR)-mediated melanomagenesis and highlight several promising avenues of ongoing research. PMID- 25022947 TI - A pediatrician's guide to central precocious puberty. PMID- 25022948 TI - Rare diagnosis in a neonate who presents with fever. PMID- 25022949 TI - Adjustable bioadhesive control of PEGylated hyperbranch brushes on polystyrene microplate interface for the improved sensitivity of human blood typing. AB - A PEGylated 96-well polystyrene (PS) microplate was first introduced for applications in high-throughput screening for selective blood typing to minimize the risks in blood transfusions. Herein, we present a hemocompatible PS 96-well microplate with adjustable PEGylated hyperbranch brush coverage prepared by ozone pretreated activation and thermally induced surface PEGylation. The grafting properties, hydration capacity, and blood compatibility of the PEGylated hyperbrush immobilized PS surfaces in human blood were illustrated by the combined chemical and physical properties of the surface, and the dependence of the specific absorption of human plasma fibrinogen onto the PEGylated surfaces on the grafting density was analyzed by monoclonal antibodies. The surface coverage of PEGylated brushes plays a major role in the bioadhesive properties of modified PS microplates, which in turn control the level of agglutination sensitivity in blood typing. The bioadhesive resistance toward proteins, platelets, and erythrocytes in human whole blood showed a correlation to the controlled hydration properties of the PEGylated hyperbrush-modified surfaces. Therefore, we suggested that the surface coverage of PEGylated hyperbrushes on PS surfaces can increase the sensitivity of cross-matching blood agglutination by up to 16-fold compared to that of the conventional 96-well virgin PS due to the regulated biorecognition of hematocrit and antibodies of the PEGylated hyperbrush-modified surfaces. PMID- 25022950 TI - Nivolumab: a review of its use in patients with malignant melanoma. AB - Nivolumab (Opdivo((r))) is a fully human monoclonal antibody against programmed death receptor-1, a negative regulatory checkpoint molecule with a role in immunosuppression. The drug is administered intravenously and is approved for the treatment of unresectable malignant melanoma in Japan. The potential for intravenous nivolumab to be used in the treatment of advanced malignancies such as melanoma was initially demonstrated in phase I dose-ranging trials. Subsequently, in a noncomparative, open-label, phase II trial, almost one-quarter of Japanese patients with previously treated stage III/IV melanoma (recurrent or unresectable) achieved a partial tumour response with intravenous nivolumab 2 mg/kg every 3 weeks. The clinical benefit of the drug was durable, with patients surviving free from progression for a median of 172 days and median overall survival not yet reached. Nivolumab had an acceptable tolerability profile in this trial, with fewer than 18 % of patients experiencing grade 3 or 4 adverse events related to the drug, the most common of which was increased gamma-glutamyl transferase. Thus, nivolumab is an emerging, promising option for the treatment of malignant melanoma. PMID- 25022953 TI - Tafamidis: a review of its use in familial amyloid polyneuropathy. AB - Oral tafamidis (Vyndaqel((r))) is indicated in the EU for the treatment of transthyretin (TTR) amyloidosis in adult patients with early stage symptomatic polyneuropathy to delay peripheral neurologic impairment and, in Argentina, Japan and Mexico, for delaying the peripheral neurological impairment of TTR familial amyloid polyneuropathy (TTR-FAP). It is the first disease-modifying pharmacotherapy to be approved for use in adult patients with early-stage TTR FAP. The drug acts to kinetically stabilize the variant TTR tetramer and thereby prevent tetramer dissociation, the rate-limiting step in TTR misfolding and amyloidogenesis. In the 18-month Fx-005 study in adult patients with early-stage V30M TTR-FAP, there were no statistically significant differences between tafamidis and placebo recipients for the coprimary endpoints, the Neuropathy Impairment Score-Lower Limb (NIS-LL) response rate (increase in NIS-LL score of <2) and the least-square mean change in Norfolk Quality-of-Life (QOL) Diabetic Neuropathy Questionnaire total scores at 18 months, based on modified intent-to treat analyses. However, in prespecified per-protocol analyses of efficacy evaluable patients, tafamidis recipients experienced significantly better outcomes in terms of these coprimary endpoints, with most (98%) tafamidis recipients showing stabilization of TTR tetramers at study end. Secondary endpoint outcomes also favoured tafamidis treatment over placebo. The beneficial effects of tafamidis in slowing deterioration of neurological function and health related-QOL were maintained in long-term extension studies (up to 66 months). Tafamidis also stabilized TTR tetramers in patients with non-V30M TTR-FAP. Tafamidis was generally well tolerated, with most treatment-emergent adverse events being of mild to moderate intensity and very few patients discontinuing treatment because of these events. No new safety signals have emerged during long term extension studies and post-marketing experience. PMID- 25022951 TI - Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (gardasil((r))): a review of its use in the prevention of premalignant anogenital lesions, cervical and anal cancers, and genital warts. AB - Quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil((r)); Silgard((r))) is composed of virus-like particles formed by self assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16 and 18. It is indicated for use from the age of 9 years as a two- or three-dose vaccination course over 6 months for the prevention of premalignant anogenital lesions, cervical and anal cancers, and genital warts caused by the vaccine HPV types. In placebo-controlled trials, quadrivalent HPV vaccine provided high-level protection against infection or disease caused by the vaccine HPV types over 2-4 years in females aged 15-45 years who were negative for the vaccine HPV types, and provided a degree of cross-protection against certain non-vaccine HPV types. The vaccine also provided high-level protection against persistent infection, anogenital precancerous lesions and genital warts caused by the vaccine HPV types over 3 years in susceptible males aged 16-26 years. Protection has been demonstrated for up to 8 years. In subjects who were negative for the vaccine HPV types, high seroconversion rates and high levels of anti-HPV antibodies were observed in females of all age ranges from 9 to 45 years and in males aged 9-26 years. The vaccine was generally well tolerated and was usually predicted to be cost effective in girls and young women. Therefore, quadrivalent HPV vaccine offers an effective means to substantially reduce the burden of HPV-related anogenital disease in females and males, particularly cervical cancer and genital warts. PMID- 25022952 TI - Dehydroepiandrosterone (DHEA): hypes and hopes. AB - Dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS) are the most abundant circulating steroid hormones in humans. In animal studies, their low levels have been associated with age-related involuntary changes, including reduced lifespan. Extrapolation of animal data to humans turned DHEA into a 'superhormone' and an 'anti-aging' panacea. It has been aggressively marketed and sold in large quantities as a dietary supplement. Recent double-blind, placebo-controlled human studies provided evidence to support some of these claims. In the elderly, DHEA exerts an immunomodulatory action, increasing the number of monocytes, T cells expressing T-cell receptor gamma/delta (TCRgammadelta) and natural killer (NK) cells. It improves physical and psychological well-being, muscle strength and bone density, and reduces body fat and age-related skin atrophy stimulating procollagen/sebum production. In adrenal insufficiency, DHEA restores DHEA/DHEAS and androstenedione levels, reduces total cholesterol, improves well-being, sexual satisfaction and insulin sensitivity, and prevents loss of bone mineral density. Normal levels of CD4+CD25(hi) and FoxP3 (forkhead box P3) are restored. In systemic lupus erythematosus, DHEA is steroid-sparing. In an unblinded study, it induced remission in the majority of patients with inflammatory bowel disease. DHEA modulates cardiovascular signalling pathways and exerts an anti-inflammatory, vasorelaxant and anti-remodelling effect. Its low levels correlate with increased cardiovascular disease and all-cause mortality. DHEA/DHEAS appear protective in asthma and allergy. It attenuates T helper 2 allergic inflammation, and reduces eosinophilia and airway hyperreactivity. Low levels of DHEAS accompany adrenal suppression. It could be used to screen for the side effects of steroids. In women, DHEA improves sexual satisfaction, fertility and age-related vaginal atrophy. Many factors are responsible for the inconsistent/negative results of some studies. Overreliance on animal models (DHEA is essentially a human molecule), different dosing protocols with non-pharmacological doses often unachievable in humans, rapid metabolism of DHEA, co-morbidities and organ specific differences render data interpretation difficult. Nevertheless, a growing body of evidence supports the notion that DHEA is not just an overrated dietary supplement but a useful drug for some, but not all, human diseases. Large scale randomised controlled trials are needed to fine-tune the indications and optimal dosing protocols before DHEA enters routine clinical practice. PMID- 25022954 TI - Treatment strategy for preventing pouchitis as a postoperative complication of ulcerative colitis: the significance of the management of cuffitis. AB - PURPOSE: The aim of this study was to examine the risk factors for and to evaluate strategies for preventing pouchitis as a postoperative complication of ulcerative colitis (UC). METHODS: A total of 119 cases of UC in which restorative proctocolectomy with an ileal pouch-anal anastomosis (IPAA) was performed at our institution between 2000 and 2012 was investigated; nine patients in whom it was impossible to close the ileostomy due to an intractable anal fistula or pelvic abscess were excluded. RESULTS: The cumulative risk of developing pouchitis 5 years after IPAA with stoma closure was 31.0%. Significant relationships with pouchitis were found for the surgical indication (p = 0.0126) and surgical method (p = 0.0214). A significant correlation was found between pouchitis and cuffitis. Pouchitis was significantly more common in the cases with cuffitis than in those without (p = 0.0002). There was also a significantly different cumulative incidence observed between the cases with and without cuffitis (p < 0.0001). In addition, pouchitis had a greater tendency to recur in the cases with cuffitis than in those without (p = 0.2730). CONCLUSION: The cumulative incidence rate of pouchitis was 10.6% at 1 year, 15.1% at 2 years and 31.0% at 5 years. Controlling cuffitis is important to prevent pouchitis. PMID- 25022955 TI - IL-32gamma overexpression accelerates streptozotocin (STZ)-induced type 1 diabetes. AB - Interleukin-32 (IL-32) is a cytokine produced by T lymphocytes, natural killer (NK) cells, monocytes and epithelial cells. There are five splicing variants (alpha, beta, gamma, delta, and epsilon) and IL-32gamma is the most active isoform. We generated human IL-32gamma transgenic (IL-32gamma TG) mice, displaying a high level of IL-32gamma expression in the pancreas. We investigated the effect of IL-32gamma on streptozotocin (STZ)-induced type 1 diabetes model using IL-32gamma TG mice. After a suboptimal diabetogenic dose of STZ administration, IL-32gamma TG mice showed significantly increased blood glucose level comparing with that of wild type (WT) mice at day 5. Inflammatory cytokines levels such as, IL-6, TNFalpha, IFNgamma and IL-1beta, in pancreas and liver lysates were accessed by a specific cytokine ELISA. The proinflammatory cytokines were significantly enhanced in the pancreas of IL-32gamma TG mice comparing to that of WT mice whereas those cytokines levels in liver of IL-32gamma TG and WT mice were not changed by STZ. These data indicate that the overexpression of IL 32gamma contributes to initial islet beta-cells injury and inflammation in pancreas and aggravates STZ-induced type 1 diabetes. PMID- 25022956 TI - Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro. AB - BACKGROUND: CXCR1 and CXCR2, cell surface receptors of interleukin-8, regulate cell migration and alteration of their expression has been associated with poor prognosis of various cancers. The aim of this study was to detect their expression in gastric cancer to identify associations with another cell adhesion molecule, matrix metalloproteinase-9 (MMP9), and with clinicopathological data ex vivo, and then explore their potential role in gastric cancer cells in vitro. MATERIALS AND METHODS: A total of 172 cases of gastric cancer tissue specimens were collected for immunohistochemical analysis of CXCR1, CXCR2, and MMP9 expression. Expression of CXCR1 and CXCR2 proteins was knocked in or down using their cDNA and shRNA, respectively, in gastric cancer cell lines to assess the changed cell phenotypes and gene expression. RESULTS: CXCR1, CXCR2, and MMP9 were expressed in 61.0%, 77.9%, and 75.6% of gastric cancer tissues, respectively. Moreover, CXCR1 and CXCR2 expression was associated with tumor differentiations, advanced clinical stages, lymph node, and distant metastasis of gastric cancer. Similarly, MMP9 expression was associated with CXCR1 and CXCR2. Expression of these three proteins was interrelated. In vitro study showed that levels of CXCR1 and CXCR2 proteins were associated with the capacity of gastric cancer cell migration, while knockdown of their expression inhibited gastric cancer cell migration and invasion abilities in vitro. In contrast, overexpression of CXCR1 and CXCR2 proteins promoted tumor cell migration and invasion. At the gene levels, knockdown of CXCR1 or CXCR2 expression suppressed expression of Ets-1, SRC-1, and JNK proteins and phosphorylated c-Jun and Erk1/2. Conversely, upregulation of CXCR1 or CXCR2 promoted expression of Ets-1, SRC-1, JNK, and c Jun proteins and phosphorylated JNK, c-Jun and Erk1/2. CONCLUSIONS: These findings suggest that CXCR1 and CXCR2 play an important role in gastric cancer progression. Further study will be performed to investigate whether target of their expression can be used as a novel strategy in clinical control of gastric cancer metastasis. PMID- 25022957 TI - Pathological activation of canonical nuclear-factor kappaB by synergy of tumor necrosis factor alpha and TNF-like weak inducer of apoptosis in mouse acute colitis. AB - Tumor necrosis factor (TNF)-alpha is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF inducible molecule 14 (Fn14). Since both TWEAK and TNF-alpha have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. NF-kappaB activation was investigated with Western blot. Levels of transcript of TWEAK, Fn14 and NF kappaB-related molecules were measured in purified colon epithelial cells (ECs). As a result, activation of the canonical (p50/RelA), but not noncanonical (p100/RelB)-mediated pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-kappaB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-kappaB by TWEAK and TNF-alpha is critical for the induction of inflammatory tissue damage in acute inflammation. PMID- 25022958 TI - Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns. AB - INTRODUCTION: Erythropoietin, a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development, has recently been implicated in innate immune regulation. Data from the ELGAN Study allowed us to evaluate relationships between endogenous erythropoietin and 25 inflammation-related proteins in extremely premature newborns. METHODS: We measured the concentrations of 25 inflammation-related proteins and of erythropoietin in blood spots collected on postnatal days 1, 7, and 14 from 936 infants born before 28 weeks gestation. We calculated the odds that infants with an inflammation-related protein in the highest quartile for gestational age and collection day had an erythropoietin concentration in the highest or lowest quartile. RESULTS: The proportion of children with inflammation-associated protein concentrations in the top quartile tended to increase monotonically with increasing quartile of EPO concentrations on 2 of the 3 days assessed. To a large extent, on each of the 3 days assessed, the odds ratios for an erythropoietin concentration in the top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile. CONCLUSIONS: Our findings suggest that in very preterm newborns, circulating levels of endogenous erythropoietin vary significantly with circulating levels of inflammation-related proteins. Elevation of endogenous erythropoietin might not be an epiphenomenon, but instead might contribute to subsequent events, by either promoting or reducing inflammation, or by promoting an anti-injury or repair capability. PMID- 25022959 TI - Interleukin-18 directly protects cortical neurons by activating PI3K/AKT/NF kappaB/CREB pathways. AB - Interleukin-18 (IL-18), a member of the IL-1 family of cytokines, was initially identified as an interferon (IFN)-gamma-inducing factor. IL-18 is expressed in both immune and non-immune cells and participates in the adjustment of multitude cellular functions. Nonetheless, the effects of IL-18 on cortical neurons have not been explored. The present study was conducted to investigate the influence of IL-18 on rat primary cortical neurons and elucidate the underlying mechanisms. We proved that rrIL-18 increased the brain-derived neurotrophic factor (BDNF) expression in a time-dependent manner. Treatment with rrIL-18 (50 ng/ml) deactivated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by facilitating its phosphorylation, enhanced the expression of Phosphoinositide 3 OH kinase (PI3K) and p-Akt, standing for the activation of the PI3K/Akt pathway. As its pivotal downstream pathways, nuclear factor-kappa B (NF-kappaB), cAMP responsive element binding protein (CREB)/Bcl-2 and glycogen synthase kinase 3beta (GSK-3beta) were examined in further steps. Our data revealed that rrIL-18 stimulated NF-kappaB activation, improved p-CREB and anti-apoptotic Bcl-2 expression levels. But rrIL-18 had little or no effect on GSK-3beta pathway. Besides, rrIL-18 increased levels of BDNF and Bcl-2/Bax ratio and decreased cleaved caspase-3 expression to protect cortical neurons from damage induced by oxygen-glucose deprivation (OGD). These results in vitro showed the protection of IL-18 on cortical neurons. And this direct neuroprotective effect of IL-18 is crippled by PI3K inhibitor wortmannin. PMID- 25022960 TI - The critical role of macrophage migration inhibitory factor in insulin activity. AB - Macrophage migration inhibitory factor (MIF) is a molecule with plethora of functions such as regulation of immune response, hormone-like, enzymatic and chaperone-like activity. Further, MIF is a major participant in glucose homeostasis since it is an autocrine stimulator of insulin secretion. MIF absence in male knockout mice (MIF-KO) results in development of glucose intolerance, while sensitivity to insulin is fully preserved. Since our results confirm that beta cells from MIF-KO mice express, produce and secrete insulin similarly to beta cells of their wild type (WT) counterparts C57BL/6 mice, we hypothesize that MIF-KO-derived insulin is less active. Indeed, insulin from MIF-KO islets is unable to significantly induce glucose uptake into hepatocytes and to efficiently promote insulin-triggered Akt phosphorylation determined by immunoblot. However, MIF's tautomerase function is not crucial for insulin biosynthesis since MIF inhibitors had no impact on WT insulin activity. Importantly, MIF recognition by anti-MIF antibody (ELISA) after in vitro co-incubation with purified insulin was significantly lower suggesting that insulin covers MIF immunodominant epitope. In addition, MIF binds insulin within beta cell as confirmed by co immunoprecipitation. WT and MIF-KO-derived insulin exhibited different cleavage patterns suggesting different protein conformations. Finally, pre-incubation of recombinant MIF with insulin promotes formation of insulin hexamers. These results imply that MIF probably enables proper insulin folding what results in insulin full activity. This newly discovered feature of the cytokine MIF could be potentially important for commercially produced insulin, for increasing its stability and/or bioavailability. PMID- 25022961 TI - MIF inhibits monocytic movement through a non-canonical receptor and disruption of temporal Rho GTPase activities in U-937 cells. AB - Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that was initially identified by its ability to inhibit the movement of macrophages. Cell migration is a highly complex process involving changes to the cytoskeleton and cell adhesion molecules, and is regulated by the Rho GTPases. A simple model using human monocytic U-937 cells to elicit the classic MIF response was implemented to examine the mechanism of MIF-induced migration inhibition. Our results demonstrate that MIF inhibits migration of these U-937 cells through a non-canonical receptor, CXCR4, in the absence of the putative primary MIF receptor CD74. Migration inhibition is dependent upon a series of temporal perturbations of the activities of the Rho GTPases: initial activation followed by subsequent inactivation of RhoA, inactivation of Rac1, and cyclic activation of Cdc42. MIF-mediated changes in the activities of the Rho GTPases jointly contributed to migration inhibition in these cells. Collectively, these data suggest that the MIF-mediated migration inhibition is mediated by the outcome of G-protein signaling, and in less adherent cells such as those of the monocyte/macrophage lineage, RhoA directly affects net translocation through its ability to induce cell body contraction. These findings demonstrate that CXCR4 can mediate MIF signaling in the absence of CD74 in addition to serving as a MIF co-receptor along with CD74. These results correlate MIF activity to specific and sequential Rho GTPase activity perturbations, and given that CXCR4 functions in numerous processes, suggests potential roles for the modulation of cell movement in those events including development, cell survival and viral infection. PMID- 25022962 TI - In situ cytokines (IL-4, IL-10, IL-12, IFN-gamma) and chemokines (MCP-1, MIP 1alpha) gene expression in human Leishmania (Leishmania) Mexicana infection. AB - Crucial to the defense against Leishmania is the ability of the host to mount a cell-mediated immune response capable of controlling and/or eliminating the parasite. The composition of the cell populations recruited in the early phase of the infection seems to be essential for defining the infection outcomes. The signals that initiate and regulate the early immune response and local accumulation of cell subsets in the skin are poorly understood. We previously studied the in situ expression of cytokine genes in patients with localized cutaneous leishmaniasis (LCL) caused by Leishmania (Leishmania) mexicana. In the present study we examined in situ cytokine (IL-4, IL-10, IL-12, IFN-gamma) and chemokine (MCP-1, MIP-1alpha) gene expression in L. (L.) mexicana active LCL lesions, and in the delayed type hypersensitivity (DTH) skin response to Leishmania antigen in subjects with healed lesion and subclinical infection. Data regarding cytokines were similar to previous studies in patients with active LCL. There were no significant differences in the profile of cytokine and chemokine gene expression in DTH from subjects with healed or subclinical infection. IL-12 gene expression detected in both groups was similar. High expression of MCP-1 was detected in all patients with active LCL. There was no difference in the level of MCP-1 expression between the healed lesion and the subclinical infection groups (p = 0.876). IL-12 and MCP-1 in the absence of IFN-gamma might be playing a crucial role in infection outcomes at skin level. PMID- 25022963 TI - Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases. AB - The present study aimed at profiling inflammatory cytokines for neurological and psychiatric diseases. A total of 86 patients with meningitis, multiple sclerosis, tension-type headache, idiopathic facial nerve palsy (IFNP), affective and schizophrenic disorders were tested for both, serum and cerebrospinal fluid (CSF) using a multiplexed cytokine ELISA for IFN-gamma, TNF-alpha, IL-1beta, IL-2, IL 4, IL-5, IL-8/CXCL8, IL-10, IL12p70, IL-13 and IL-17. Cases with viral and bacterial meningitis had unequivocally higher cytokine concentrations in the CSF when compared with serum. Bacterial meningitis was unique by extremely elevated IL-17, TNF-alpha and IL-1beta, indicating a plethora of inflammatory pathways, selectively activated in the CSF. In relapsing multiple sclerosis, IFN-gamma and IL-10 were elevated in both, serum and CSF, but IL-12p70, IL-5, IL-13, and TNF alpha were more prominent in serum than in CSF. Qualitatively similar biomarker patterns were detected in patients with idiopathic facial nerve palsy and tension type cephalgia. Affective and schizophrenic disorders clearly present with an inflammatory phenotype in the CSF and also serum, the cytokines determined were in general higher in schizophrenia. Except IFN-gamma, schizophrenic patients had higher IL-12p70 and a trend of higher IL-10 and IL-13 in serum suggesting a more prominent TH2-type counter regulatory immune response than in affective disorders. These differences were also mirrored in the CSF. Elevated IL-8 appears to be the most sensitive marker for inflammation in the CSF of all diseases studied, whereas TNF-alpha was restricted to peripheral blood. With the exception of IL-8, all but viral and bacterial meningitis, studied, displayed higher means of elevated lymphokine concentrations in the serum than in the CSF. This observation supports the concept of immunological crosstalk between periphery and intrathecal immunity in neurological and psychiatric diseases. PMID- 25022964 TI - Immune-mediated experimental arthritis in IL-33 deficient mice. AB - Previous work suggested implication of the interleukin (IL)-1 family cytokine IL 33, signaling through its receptor ST2, in the pathogenesis of human and mouse arthritis. In this study, we directly investigated the role of endogenous IL-33 in antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) using IL 33 KO mice. AIA was induced by injection of methylated bovine serum albumin (mBSA) into knee joints of previously immunized mice. CIA was induced by immunization with bovine type II collagen. Disease severity was evaluated by clinical and histological scoring and cellular immune responses were assessed in cultured draining lymph node cells. Our results indicate that the development of AIA or CIA, as assessed by clinical or histological evaluation, is not impaired in IL-33 deficient mice. We did not observe any consistent modifications in humoral or cellular immune responses in IL-33 KO mice, although IL-33 deficiency enhanced antigen-specific IFN-gamma production, proliferation or IgG2a titers in some experiments, suggesting that endogenous IL-33 may contribute to shaping the adaptive immune response. In conclusion, our data suggest that IL-33 plays a modifying rather than a pivotal role in disease development in two models of immune-mediated arthritis. PMID- 25022965 TI - Effects of different transforming growth factor beta (TGF-beta) isomers on wound closure of bone cell monolayers. AB - This study aimed at determining the role of the transforming growth factor-beta (TGF-beta) isomers and their combinations in bone cell behaviour using MG63 cells. The work examined how TGF-beta1, 2 and 3 and their solvent and carrier (HCl and BSA, respectively) effected cell morphology, cell proliferation and integrin expression. This study also aimed at examining how the TGF-betas and their solvent and carrier influenced wound closure in an in vitro wound closure model and how TGF-betas influence extracellular matrix (ECM) secretion and integrin expression. The wound healing response in terms of healing rate to the TGF-betas and their solvent/carrier was investigated in 300 MUm +/- 10-30 MUm SD wide model wounds induced in fully confluent monolayers of MG63 bone cells. The effect of different TGF-beta isomers and their combinations on proliferation rate and cell length of human bone cells were also assessed. Immunostaining was used to determine if TGF-betas modifies integrin expression and ECM secretion by the bone cells. Imaging with WSPR allowed observation of the focal contacts without the need for immunostaining. The wound healing results indicated that TGF-beta3 has a significant effect on the wound healing process and its healing rate was found to be higher than the control (p < 0.001), TGF-beta1 (p < 0.001), TGF-beta2 (p < 0.001), BSA/HCl (p < 0.001) and HCl (p < 0.001) in ascending order. It was also found that TGF-beta1 and TGF-beta2 treatment significantly improved wound closure rate in comparison to the controls (p < 0.001). All TGF-beta combinations induced a faster healing rate than the control (p < 0.001). It was expected that the healing rate following treatment with TGF-beta combinations would be greater than those healing rates following treatments with TGF-beta isomers alone, but this was not the case. The results also suggest that cell morphological changes were observed significantly more in cells treated with TGF-beta(2 + 3) and TGF beta(1 + 3) (p < 0.001). Any cell treated with TGF-beta1, TGF-beta(1 + 2) and TGF beta(1 + 2 + 3) showed significantly less elongation compared to the control and other TGF-beta isomers. In terms of proliferation rate, TGF-beta3 and TGF-beta(2 + 3) increased cell numbers more than TGF-beta1, TGF-beta2 and other combinations. TGF-beta1 and its combinations did not show significant proliferation and attachment compared to the control. Immunostaining indicated that treatment with TGF-beta3 significantly enhanced the secretion of collagen type I, fibronectin and integrins alpha3 and beta1. The WSPR experiments also indicated that TGF-betas influenced the distribution of focal contacts. In conclusion, combining TGF-beta3 with any other TGF-beta isomer resulted in a faster model wound closure rate (p < 0.001), while treatment with TGF-beta1 in any TGF-beta combination reduced the healing rate (p < 0.001). It can therefore be concluded that the presence of TGF-beta1 has an inhibitory effect on bone wound healing while TGF-beta3 had the opposite effect and increased the rate of wound closure in a 2 dimensional cell culture environment. PMID- 25022966 TI - Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. AB - Interleukin (IL)-35 was initially described as an immunosuppressive cytokine specifically produced by CD4(+)FoxP3(+) regulatory T cells (Treg). Since Treg play a major role in autoimmunity control and protect from inflammation, we aimed at evaluating the role of IL-35 in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), using a non-viral gene transfer strategy. The clinical and histological effect of IL-35 was assessed in mice with CIA receiving an injection of two distinct plasmids encoding IL-35 gene (pIGneo-mIL-35 or pORF mIL-35) 3 and 18 days after CIA induction. Treg and Th17 were characterized by flow cytometry in the spleen and lymph nodes of treated mice. Our results showed that whatever the plasmid used, IL-35 gene transfer resulted in a statistically significant increase in clinical scores of CIA compared to results with empty plasmid. The underlying cellular mechanisms of this effect were shown to be related to an increased Th17/Treg ratio in the spleen of pORF-mIL-35 treated mice. In conclusion, we show an unexpected but clear exacerbating effect of IL-35 gene transfer in an autoimmune and inflammatory RA model, associated with a modification of the Th17/Treg balance. Altogether, these result shows that this cytokine can promote chronic inflammation. PMID- 25022967 TI - Association of interleukin-6 gene polymorphisms with hand osteoarthritis and hand osteoporosis. AB - OBJECTIVE: Several genes, including IL-6 encoding pro-inflammatory cytokines, are involved in development of osteoarthritis and osteoporosis. The association of radiographic hand osteoarthritis (RHOA) and osteoporosis related phenotypes (RHOP) with polymorphisms in IL-6 has been reported inconsistently. The aim of this study was to examine the association, between RHOA and RHOP and IL-6 polymorphisms in two independent samples. METHODS: Two samples: UK females, including 1440 individuals assessed for RHOA and 3470 assessed for RHOP; Chuvash pedigree including 1499 females and males were assessed for RHOP and RHOA. SNPs were genotyped in the IL-6 genomic region, and used in association analysis with RHOA and RHOP phenotypes. RESULTS: RHOP phenotypes showed similar heritability estimates in both samples, ranging from 34.5 +/- 5.5% to 61.0 +/- 2.4%. RHOA in Chuvash had substantially lower heritability estimates compared to twins (e.g. OSP scores: 11.8 +/- 2.3% vs. 39.2 +/- 4.1%) with much higher prevalence and considerably stronger correlation with age (r = 0.811 vs. r = 0.505). RHOA in Chuvash sample may be traumatic in nature, caused by heavy and prolonged manual work related to their private farming. There were a number of statistically significant association results with both types of phenotypes. The most consistent result was obtained for JSN in both samples with SNP from the same haploblock. Their combined probability of no association was only p = 0.000003. Additionally, there were SNPs common for both RHOA and RHOP. CONCLUSIONS: We have shown polymorphisms in IL_6 are significantly associated with RHOA and hand RHOP in two samples having different ethnicity and lifestyle. Age * environment * genes interaction appears as an important factor of RHOA manifestation and progression. PMID- 25022968 TI - Interferon-gamma production by human neutrophils upon stimulation by IL-12, IL-15 and IL-18 and challenge with Paracoccidioides brasiliensis. AB - Paracoccidiodomycosis is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb), which is endemic in Latin America. The host innate immune response against the fungus has been well characterized and several studies have shown the important role played by phagocytic cells. Our laboratory has studied the relationship between human neutrophils (PMNs)/Pb, focusing the effector mechanisms of these cells against the fungus. However, in last years, studies have shown that in addition to their phagocytic and killer functions, PMNs can modulate and instruct the immune response, since these cells have been shown to produce and release several cytokines. Thus, we evaluated whether PMNs stimulated with Pb can modulate the immune response to a Th1 phenotype through the production of IFN-gamma, as well as the role of "pattern-recognition receptors" (PRRs) such as TLR2, TLR4 and Dectin-1 in this production. Furthermore, we asked whether activation of the cells with the cytokines IL-12, IL-15 and IL-18 could result in increased levels of this cytokine. Peripheral blood PMNs obtained from 20 healthy donors were nonactivated or activated with IL-12, IL-15 or IL-18 in different concentrations and challenged with strain 18 Pb (Pb18) for 2 h, 4 h, 12 h, 24 h and 48 h and evaluated for IFN-gamma production, by ELISA. In other experiments, PMNs were treated with monoclonal antibodies anti-TLR2, TLR4 and Dectin-1, challenged with Pb and evaluated for IFN-gamma production. We found that Pb induces human PMNs to produce IFN-gamma, probably by binding to TLR4 and Dectin-1 receptors expressed by these cells. Moreover, IFN-gamma levels were significantly increased when cells were activated with each of the tested cytokines or a combination of two of them, being the association IL-12 plus IL-15 the most effective. The results support our hypothesis that during infection by Pb, human PMNs modulate the adaptive immune response to a Th1 response pattern, via IFN-gamma production. PMID- 25022970 TI - Periapical fluid RANKL and IL-8 are differentially regulated in pulpitis and apical periodontitis. AB - The dental pulp space can become infected due to a breach in the surrounding hard tissues. This leads to inflammation of the pulp (pulpitis), soft tissue breakdown, and finally to bone loss around the root apex (apical periodontitis). The succession of the molecular events leading to apical periodontitis is currently not known. The main inflammatory mediator associated with neutrophil chemotaxis is interleukin-8 (IL-8), and with bone resorption the dyad of receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG). The levels of RANKL, OPG and IL-8 were studied in periapical tissue fluid of human teeth (n = 48) diagnosed with symptomatic irreversible pulpitis (SIP) and asymptomatic apical periodontitis (AAP). SIP represents the starting point, and AAP an established steady state of the disease. Periapical tissue fluid samples were collected using paper points and then evaluated using enzyme-linked immunosorbent assays (ELISAs). Target protein levels per case were calibrated against the corresponding total protein content, as determined fluorometrically. RANKL was expressed at significantly higher levels in SIP compared to AAP (P < 0.05), whereas OPG was under the detection limit in most samples. In contrast, IL-8 levels were significantly lower in SIP compared to AAP (P < 0.05). Spearman's correlation analysis between RANKL and IL-8 revealed a significantly (P < 0.05) negative correlation between the two measures (rho = -.44). The results of this study suggest that, in the development of apical periodontitis, periapical bone resorption signaling, as determined by RANKL, occurs prior to inflammatory cell recruitment signaling, as determined by IL-8. PMID- 25022969 TI - The expression of cytokines and chemokines in the blood of patients with severe weight loss from anorexia nervosa: an exploratory study. AB - Anorexia nervosa (AN) is a serious, potentially life-threatening disorder characterized by severe weight loss, dysregulated eating, and often excessive exercise. While psychiatric illnesses such as depression are associated with increased levels of pro-inflammatory mediators, evidence for such disturbances in patients with AN has been less clear. In an exploratory study of possible disturbances in immune responses in AN, we assayed a panel of cytokines and chemokines in the blood of patients undergoing inpatient treatment, testing the hypothesis that metabolic disturbances in this disease would lead to a pattern of immune disturbances distinct from that of other psychiatric diseases. For this purpose, we evaluated patients by the Beck Depression Inventory-II (BDI-II) and the Eating Disorders Examination-Questionnaire and assessed cytokines and chemokines by enzyme-linked immunosorbent assays. Patients reported a moderate level of depression (mean BDI-II = 22.6) but exhibited few immunologic abnormalities of the kind associated with major depressive disorder [e.g., increased interleukin (IL)-6]; RANTES showed the most frequent elevations and was increased in 4 of the patients studied. Together, these findings suggest that features of AN such as loss of adipose tissue and excessive exercise may attenuate cytokine production and thus modulate the experience of illness that impacts on core features of disease. PMID- 25022971 TI - Furazan and furoxan sulfonamides are strong alpha-carbonic anhydrase inhibitors and potential antiglaucoma agents. AB - A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma. PMID- 25022972 TI - Bicyclic tetrapeptides as potent HDAC inhibitors: effect of aliphatic loop position and hydrophobicity on inhibitory activity. AB - Several histone deacetylase (HDAC) inhibiting bicyclic tetrapeptides have been designed and synthesized through intramolecular ring-closing metathesis (RCM) reaction and peptide cyclization. We designed bicyclic tetrapeptides based on CHAP31, trapoxin B and HC-toxin I. The HDAC inhibitory and p21 promoter assay results showed that the aliphatic loop position as well as the hydrophobicity plays an important role toward the activity of the bicyclic tetrapeptide HDAC inhibitors. PMID- 25022974 TI - Durhane Wong-Rieger: championing patients. PMID- 25022973 TI - Novel N-terminal domain mutation in prion protein detected in 2 patients diagnosed with frontotemporal lobar degeneration syndrome. AB - Prion protein gene mutations have been associated with clinical pictures mimicking neurodegenerative diseases different from inherited prion diseases (IPD). We report a novel missense P39L mutation in the N-terminal domain of prion protein in 2 patients affected by frontotemporal lobar degeneration syndrome, negative for mutations in genes causative of dementia. Neither the first carrier, a 67-year-old male in which the onset was a progressive non-fluent aphasia, nor the second carrier, a 78-year-old male affected by frontotemporal dementia and parkinsonism, showed any clinical or instrumental findings suggestive of IPD. Genetic screening of healthy controls and in silico analysis provide support for the potential pathogenicity of this variant. Patient phenotypes, unclassifiable as prion disease, may depend on the location of the mutation in the N-terminal domain, outside the amyloid core of pathologic prion protein, although further functional studies are required to determine whether and how this mutation exerts its pathogenic effect. However, genetic screening of prion protein gene becomes relevant in familial degenerative dementia, particularly in geographical areas with high IPD prevalence. PMID- 25022975 TI - Country in Focus: Diabetes and obesity in South Africa. PMID- 25022976 TI - Quantification of myocardial delayed enhancement and wall thickness in hypertrophic cardiomyopathy: multidetector computed tomography versus magnetic resonance imaging. AB - OBJECTIVES: To evaluate the accuracy of multidetector computed tomography (MDCT) in assessing myocardial delayed enhancement and left ventricle wall thickness in hypertrophic cardiomyopathy (HCM) compared with cardiac magnetic resonance (CMR) as the reference standard. MATERIALS AND METHODS: Eighty consecutive patients (59 male; 53.2 +/- 13.0 years) were examined with MDCT, followed by CMR 1 day later. Cardiac CT angiography and a delayed CT were performed. CMR was performed according to a standardized protocol. Left ventricle wall thickness and positions of myocardial delayed enhancement were identified in both CMR and CT images according to the American Heart Association left ventricle 17-segment model. Myocardial delayed enhancement was characterized as "dense" (areas with clear defined borders) or "diffuse" and then quantified using both techniques. RESULTS: Left ventricle wall thickness determined by MDCT was significantly correlated with CMR (R=0.88, P<0.01). Compared with CMR, MDCT accurately diagnosed 74 of 78 (94.9%) patients and 1243 of 1326 (93.7%) segments. For dense myocardial delayed enhancement, MDCT significantly correlated with CMR (R=0.88, P<0.01) and slightly underestimated myocardial delayed enhancement (mean, -3.85%; lower and upper limits of agreement, -13.40% and 5.70%, respectively). CONCLUSIONS: MDCT provides reliable quantification of myocardial delayed enhancement and evaluation of left ventricle wall thickness and has a good correlation with CMR in patients with HCM when a comprehensive cardiac CT protocol is used and can be applied for intervention planning. PMID- 25022977 TI - Interobserver variability of CT angiography for evaluation of aortic annulus dimensions prior to transcatheter aortic valve implantation (TAVI). AB - OBJECTIVE: Assessment of aortic annulus dimensions prior to transcatheter aortic valve implantation (TAVI) is crucial for accurate prosthesis sizing in order to avoid prosthesis-annulus-mismatch possibly resulting in complications like valve dislodgement, paravalvular regurgitation or annulus rupture. Contrast-enhanced multidetector computed tomography allows 3-dimensional assessment of aortic annulus dimensions. Only limited data exist about its interobserver variability. METHODS: In 100 consecutive patients with symptomatic severe aortic stenosis (51 male, BMI 27+/-5kg/m(2), age 81+/-7 years, heart rate 72+/-15bpm, Logistic Euroscore 31+/-14%, STS-Score 7+/-4%), pre-interventional aortic annulus assessment was performed by dual source computed tomography (collimation 2*128*0.6mm, high pitch spiral data acquisition mode, 40-60ml contrast agents, radiation dose 3.5+/-0.9mSv). The following aortic annulus characteristics were determined by three independent observers: aortic annulus maximum, minimum and mean diameters (Dmax, Dmin, Dmean), eccentricity index (EI), effective aortic annulus diameter according to its circumference (Dcirc), effective aortic annulus diameter according to its area (Darea), distance from the aortic annulus plane to the left (LCA) and right coronary artery (RCA) ostia, maximum (DmaxAR) and minimum aortic root diameter (DminAR), maximum (DmaxSTJ) and minimum diameter of the sinotubular junction (DminSTJ). Subsequently, interobserver variabilities were assessed. RESULTS: Correlation between the three observers showed moderate to close agreement (between r=0.67 and r=0.97, all p<0.001). Mean differences (SE) between the three observers ranged from 0.07 (0.06)mm to 0.24 (0.07)mm for assessing the mean AA diameter (Dmean), from 0.28 (0.04)mm to 0.60 (0.06)mm for determining the effective AA diameter derived from the annulus area (Darea) and from 0.03 (0.07)mm to 0.07 (0.11)mm derived from the AA perimeter (Dcirc). For measurements of LCA and RCA distances to the AA level, mean interobserver differences (SE) ranged from 0.36 (0.07)mm to 0.76 (0.09)mm and from 0.15 (0.06)mm to 0.45 (0.11)mm. CONCLUSION: Computed tomography provides reproducible measurements of the aortic annulus and root geometry in patients scheduled for TAVI. The perimeter-derived aortic annulus diameter shows the lowest interobserver differences. Interobserver variabilities in prosthesis size recommendation were further reduced, if all three sizing methods were considered and stated as a "consensus result". PMID- 25022978 TI - Ultrasound elastography and contrast-enhanced ultrasound in infants, children and adolescents. AB - OBJECTIVE: To describe prerequisites, use, and safety of ultrasound elastography and contrast-enhanced ultrasound in infants, children, and adolescents. METHOD: This review deals with two latest developments in ultrasonography in children. The principle of strain elastography, transient elastography, and acoustic radiation force imaging is discussed, including limitations, and advantages of the different techniques in diagnosing focal and diffuse organ disease. The intravesical (contrast-enhanced voiding ultrasonography) and intravascular use of contrast-media to outline blood, and urinary flow is described, with special emphasis on indications, off-label use, and diagnostic gain. Examples of indications for performing the advanced ultrasound techniques are presented. SUMMARY AND CONCLUSION: Latest developments in ultrasound machine engineering, and the availability of contrast-media that interact with ultrasound waves allow for assessment of tissue stiffness/elasticity properties, blood, and urinary flow. Thereby ultrasound is capable not only to depict morphology, but gives the additional information on organ, and focal lesion perfusion, and urinary flow dynamics. The information gap to other cross-sectional techniques such as magnetic resonance imaging, that make potential harmful sedation, and anaesthesia in the youngest children necessary, thereby gets closer. PMID- 25022979 TI - 3.0 T conventional hip MR and hip MR arthrography for the acetabular labral tears confirmed by arthroscopy. AB - OBJECTIVE: To evaluate the value of hip MR for diagnosing acetabular labrum tears, and to further compare the diagnostic performances of conventional MR with MR arthrography in acetabular labrum tears. METHODS: 90 patients undergoing both hip MR examination and subsequent hip arthroscopy were retrospectively evaluated. Of these patients, 34 accepted both conventional MR and MR arthrography; while the other 56 only underwent conventional MR examination. All hip MR images were independently reviewed by two radiologists, and further compared with the results of hip arthroscopy. RESULTS: 59 of 90 patients were confirmed with acetabular labral tears by hip arthroscopy and 31 without tears. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of conventional MR for evaluating the acetabular labral tears were 61.0%, 77.4%, 83.7% and 51.1% (radiologist A), and 66.1%, 74.2%, 82.9% and 53.4% (radiologist B), respectively, with good consistency between the two observers (K=0.645). The sensitivity, specificity, PPV and NPV of MR arthrography for assessing the acetabular labral tears were 90.5%, 84.6%, 90.5% and 84.6% (radiologist A), and 95.2%, 84.6%, 90.9% and 91.7% (radiologist B), respectively, with excellent good consistency between the two observers (K=0.810). The sensitivity and NPV of MR arthrography for diagnosing the acetabular labral tears were significantly higher than those of conventional MR (both P<0.05). CONCLUSION: Hip MR arthrography is a reliable evaluation modality for diagnosing the acetabular labral tears, and its diagnostic performance is superior to that of conventional MR at 3.0 T. PMID- 25022980 TI - An increased flip angle in late phase Gd-EOB-DTPA MRI shows improved performance in bile duct visualization compared to T2w-MRCP. AB - OBJECTIVES: To estimate the additional value of an increased flip angle of 35 degrees in late phase Gd-EOB-DTPA-enhanced magnetic resonance cholangiography, as compared to T2w-MRCP. METHODS: 40 adult patients underwent Gd-EOB-DTPA enhanced MRI of the liver including a T2-weighted 3D TSE MRCP (T2w-MRCP) as well as a late phase T1-weighted THRIVE sequences applying a flip angle of 35 degrees (fa35). Two experienced observers evaluated the images regarding the delineation of the different biliary regions using a three-point grading system. A five-point scale was applied to determine the readers' confidence in identifying anatomical variations of the biliary tree. ROI analysis was performed to compare the signal to-noise (SNR) and contrast-to-noise (CNR) ratios. RESULTS: The quality for visualizing the biliary tree differed between T2w-MRCP and fa35 (p=<0.001). Late phase EOB-MRC was rated as good for delineating the entire biliary system, whereas T2w-MRCP received an overall poor rating. Especially the depiction of the intrahepatic bile ducts was estimated as problematic in T2w-MRCP. T2w-MRCP and fa35 revealed a discordant assessment of anatomical variations in 12.5% of the cases, comprising a generally higher confidence level for fa35 (4.0 +/- 1.1 vs. 2.2 +/- 1.2, p=<0.001). SNR proofed to be significantly higher in fa35 (p=<0.001), whereas T2w-MRCP revealed a significantly higher CNR (<0.001). CONCLUSIONS: Gd-EOB-DTPA enhanced magnetic resonance cholangiography acquired with a flip angle of 35 degrees revealed a better diagnostic performance compared to T2w-MRCP and might be a valuable adjunct in assessing functional bile duct abnormalities. PMID- 25022981 TI - Perioperative antibiotics covering bile contamination prevent abdominal infectious complications after pancreatoduodenectomy in patients with preoperative biliary drainage. AB - BACKGROUND: Although bile contamination caused by preoperative biliary drainage (PBD) is a risk factor for infectious complications after pancreatoduodenectomy, the appropriate perioperative antibiotic regimen remains unclear. We evaluated a perioperative antibiotic strategy targeting bile contamination associated with PBD procedures for preventing abdominal infectious complications after pancreatoduodenectomy. METHODS: Consecutive patients (n = 254) underwent pancreatoduodenectomy at a single center. Perioperative antibiotics were mainly cefazolin in non-PBD cases (n = 116) and cefozopran in internal-PBD cases (n = 87). They were based on preoperative bile cultures in 51 of the external-PBD cases. Intraoperative bile cultures were examined prospectively. Morbidity and abdominal infectious complication rates were evaluated. RESULTS: The incidence of positive intraoperative bile cultures was significantly higher in the internal PBD (85 %) and external-PBD (90 %) cases than in the non-PBD cases (26 %) (p < 0.001). The 91 % susceptibility to cefazolin for non-PBD was significantly higher than the 61 % for internal-PBD or 45 % for external-PBD (p < 0.001). Overall morbidity rates (23, 23, and 25 %) and abdominal infectious complications (13, 17, and 14 %) did not differ among the non-PBD, internal-PBD, and external-PBD cases, respectively. Only susceptibility to perioperative antibiotics of biliary microorganisms classified as resistant was a significant independent risk factor for abdominal infectious complications (p = 0.003). CONCLUSIONS: A perioperative antibiotic strategy particular to PBD procedures is valid for covering biliary microorganisms during pancreatoduodenectomy. Perioperative antibiotics covering bile contamination may prevent abdominal infectious complications after pancreatoduodenectomy in patients with and without PBD. PMID- 25022983 TI - Digital resolution enhancement of intracardiac excitation maps during atrial fibrillation. AB - Atrial fibrillation (AF) is often successfully treated by catheter ablation. Those cases of AF that do not readily succumb to ablation therapy would benefit from improved methods for mapping the complex spatial patterns of tissue activation that typify recalcitrant AF. To this end, the purpose of our study was to investigate the use of numerical deconvolution to improve the spatial resolution of activation maps provided by 2-D arrays of intra-cardiac recording electrodes. We simulated tissue activation patterns and their corresponding electric potential maps using a computational model of cardiac electrophysiology, and sampled the maps over a grid of locations to generate a mapping data set. Following cubic spline interpolation, followed by edge-extension and windowing, we deconvolved the data and compared the results to the model current density fields. We performed a similar analysis on voltage-sensitive dye maps obtained in isolated sheep hearts. For both the synthetic data and the voltage-sensitive dye maps, we found that deconvolution led to visually improved map resolution for arrays of 10*10 up to 30*30 electrodes placed within a few mm of the atrial surface when the activation patterns included 3-4 features that spanned the recording area. Root mean square error was also reduced by deconvolution. Deconvolution of arrays of intracardiac potentials, preceded by appropriate interpolation and edge processing, leads to potentially useful improvements in map resolution that may allow more effective assessment of the spatiotemporal dynamics of tissue excitation during AF. PMID- 25022982 TI - Cholera outbreaks (2012) in three districts of Nepal reveal clonal transmission of multi-drug resistant Vibrio cholerae O1. AB - BACKGROUND: Although endemic cholera causes significant morbidity and mortality each year in Nepal, lack of information about the causal bacterium often hinders cholera intervention and prevention. In 2012, diarrheal outbreaks affected three districts of Nepal with confirmed cases of mortality. This study was designed to understand the drug response patterns, source, and transmission of Vibrio cholerae associated with 2012 cholera outbreaks in Nepal. METHODS: V. cholerae (n = 28) isolated from 2012 diarrhea outbreaks {n = 22; Kathmandu (n = 12), Doti (n = 9), Bajhang (n = 1)}, and surface water (n = 6; Kathmandu) were tested for antimicrobial response. Virulence properties and DNA fingerprinting of the strains were determined by multi-locus genetic screening employing polymerase chain reaction, DNA sequencing, and pulsed-field gel electrophoresis (PFGE). RESULTS: All V. cholerae strains isolated from patients and surface water were confirmed to be toxigenic, belonging to serogroup O1, Ogawa serotype, biotype El Tor, and possessed classical biotype cholera toxin (CTX). Double-mismatch amplification mutation assay (DMAMA)-PCR revealed the V. cholerae strains to possess the B-7 allele of ctx subunit B. DNA sequencing of tcpA revealed a point mutation at amino acid position 64 (N -> S) while the ctxAB promoter revealed four copies of the tandem heptamer repeat sequence 5'-TTTTGAT-3'. V. cholerae possessed all the ORFs of the Vibrio seventh pandemic island (VSP)-I but lacked the ORFs 498-511 of VSP-II. All strains were multidrug resistant with resistance to trimethoprim-sulfamethoxazole (SXT), nalidixic acid (NA), and streptomycin (S); all carried the SXT genetic element. DNA sequencing and deduced amino acid sequence of gyrA and parC of the NAR strains (n = 4) revealed point mutations at amino acid positions 83 (S -> I), and 85 (S -> L), respectively. Similar PFGE (NotI) pattern revealed the Nepalese V. cholerae to be clonal, and related closely with V. cholerae associated with cholera in Bangladesh and Haiti. CONCLUSIONS: In 2012, diarrhea outbreaks in three districts of Nepal were due to transmission of multidrug resistant V. cholerae El Tor possessing cholera toxin (ctx) B-7 allele, which is clonal and related closely with V. cholerae associated with cholera in Bangladesh and Haiti. PMID- 25022984 TI - SPE-8, a protein-tyrosine kinase, localizes to the spermatid cell membrane through interaction with other members of the SPE-8 group spermatid activation signaling pathway in C. elegans. AB - BACKGROUND: The SPE-8 group gene products transduce the signal for spermatid activation initiated by extracellular zinc in C. elegans. Mutations in the spe-8 group genes result in hermaphrodite-derived spermatids that cannot activate to crawling spermatozoa, although spermatids from mutant males activate through a pathway induced by extracellular TRY-5 protease present in male seminal fluid. RESULTS: Here, we identify SPE-8 as a member of a large family of sperm-expressed non-receptor-like protein-tyrosine kinases. A rescuing SPE-8::GFP translational fusion reporter localizes to the plasma membrane in all spermatogenic cells from the primary spermatocyte stage through spermatids. Once spermatids become activated to spermatozoa, the reporter moves from the plasma membrane to the cytoplasm. Mutations in the spe-8 group genes spe-12, spe-19, and spe-27 disrupt localization of the reporter to the plasma membrane, while localization appears near normal in a spe-29 mutant background. CONCLUSIONS: These results suggest that the SPE-8 group proteins form a functional complex localized at the plasma membrane, and that SPE-8 is correctly positioned only when all members of the SPE 8 group are present, with the possible exception of SPE-29. Further, SPE-8 is released from the membrane when the activation signal is transduced into the spermatid. PMID- 25022985 TI - Leg movements and periodic leg movements during sleep in the development across childhood and adolescence from 1 to 18 years. AB - OBJECTIVE: Age specific reference values of leg movements (LMS) and periodic leg movements (PLMS) in sleep considering their true periodicity to evaluate sleep pathologies, especially possible childhood RLS or PLMD. METHODS: In a prospective first night study of 52 healthy children/adolescents divided into six age groups from 1 to 18 years, polysomnographies were conducted and scored considering AASM rules. The frequency of LMS and PLMS were evaluated for NREM, REM, total sleep time (TST), including attention to time structure (inter-leg movement intervals, time distribution during the night) and periodicity of LMS. RESULTS: LMS and PLMS decreased with increasing age (P < 0.05). Children and adolescents older than 10 years had a PLMS index less than 5/h TST, in younger children the PLMS index was higher; 34.7% of total LMS and PLMS were accompanied by an EEG-arousal without age dependence. Periodicity index was low (median 0.2 decreasing with age to 0.1). Inter-leg movement intervals showed a decreasing incidence of shorter intervals with age. The course of LMS during the night displayed a lack of clear structure of distribution. CONCLUSIONS: To evaluate pediatric motoric sleep disturbances it is necessary to consider the age dependence of LMS/PLMS and their true periodicity. PMID- 25022986 TI - The influence of job stress, social support and health status on intermittent and chronic sleep disturbance: an 8-year longitudinal analysis. AB - OBJECTIVE: To determine the role of health status and social support in the relationship between job stress and sleep disturbance, for both intermittent and chronic sleep disturbance. METHODS: A total of 1946 mid-life adults completed three questionnaires spanning an 8-year time frame. Sleep disturbance was assessed at each time point, and participants were classified as experiencing intermittent, chronic or no sleep disturbance across this 8-year period. Independent variables included a range of job stress measures, social support, physical and mental health, and demographic characteristics. RESULTS: After controlling for physical and mental health, perceived lack of job marketability increased risk of intermittent sleep disturbance (odds ratio (OR)=1.33, p=0.012). No other job stress measures were associated with either intermittent or chronic sleep disturbance after adjusting for years of education, social support, and employment status. Poorer mental and physical health status, although significantly increasing odds for intermittent sleep disturbance, represented a significantly greater increase in the odds for chronic sleep disturbance over and above intermittent disturbance (OR=0.96, p<0.001 for both SF-12 mental and physical health). CONCLUSION: This population-based cohort study found little evidence that job stress had an independent effect on chronic or intermittent sleep disturbance independent of health, social support, and education. Risk profiles for intermittent and chronic sleep disturbance did not differ with regard to job stress; however, various demographic and social support factors were distinguishing factors. Health status, both physical and mental, also showed a significantly greater impact on chronic sleep disturbance than intermittent sleep disturbance. Karasek's model of job strain had little value in predicting sleep disturbance outcomes. PMID- 25022987 TI - Nuclear receptors and epigenetic regulation: opportunities for nutritional targeting and disease prevention. AB - Posttranslational modifications of histones, alterations in the recruitment and functions of non-histone proteins, DNA methylation, and changes in expression of noncoding RNAs contribute to current models of epigenetic regulation. Nuclear receptors (NRs) are a group of transcription factors that, through ligand binding, act as sensors to changes in nutritional, environmental, developmental, pathophysiologic, and endocrine conditions and drive adaptive responses via gene regulation. One mechanism through which NRs direct gene expression is the assembly of transcription complexes with cofactors and coregulators that possess chromatin-modifying properties. Chromatin modifications can be transient or become part of the cellular "memory" and contribute to genomic imprinting. Because many food components bind to NRs, they can ultimately influence transcription of genes associated with biologic processes, such as inflammation, proliferation, apoptosis, and hormonal response, and alter the susceptibility to chronic diseases (e.g., cancer, diabetes, obesity). The objective of this review is to highlight how NRs influence epigenetic regulation and the relevance of dietary compound-NR interactions in human nutrition and for disease prevention and treatment. Identifying gene targets of unliganded and bound NRs may assist in the development of epigenetic maps for food components and dietary patterns. Progress in these areas may lead to the formulation of disease-prevention models based on epigenetic control by individual or associations of food ligands of NRs. PMID- 25022988 TI - Relations between metabolic homeostasis, diet, and peripheral afferent neuron biology. AB - It is well established that food intake behavior and energy balance are regulated by crosstalk between peripheral organ systems and the central nervous system (CNS), for instance, through the actions of peripherally derived leptin on hindbrain and hypothalamic loci. Diet- or obesity-associated disturbances in metabolic and hormonal signals to the CNS can perturb metabolic homeostasis bodywide. Although interrelations between metabolic status and diet with CNS biology are well characterized, afferent networks (those sending information to the CNS from the periphery) have received far less attention. It is increasingly appreciated that afferent neurons in adipose tissue, the intestines, liver, and other tissues are important controllers of energy balance and feeding behavior. Disruption in their signaling may have consequences for cardiovascular, pancreatic, adipose, and immune function. This review discusses the diverse ways that afferent neurons participate in metabolic homeostasis and highlights how changes in their function associate with dysmetabolic states, such as obesity and insulin resistance. PMID- 25022989 TI - Supplemental substances derived from foods as adjunctive therapeutic agents for treatment of neurodegenerative diseases and disorders. AB - Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-L-carnitine, and omega-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury. PMID- 25022991 TI - Understanding sustainable diets: a descriptive analysis of the determinants and processes that influence diets and their impact on health, food security, and environmental sustainability. AB - The confluence of population, economic development, and environmental pressures resulting from increased globalization and industrialization reveal an increasingly resource-constrained world in which predictions point to the need to do more with less and in a "better" way. The concept of sustainable diets presents an opportunity to successfully advance commitments to sustainable development and the elimination of poverty, food and nutrition insecurity, and poor health outcomes. This study examines the determinants of sustainable diets, offers a descriptive analysis of these areas, and presents a causal model and framework from which to build. The major determinants of sustainable diets fall into 5 categories: 1) agriculture, 2) health, 3) sociocultural, 4) environmental, and 5) socioeconomic. When factors or processes are changed in 1 determinant category, such changes affect other determinant categories and, in turn, the level of "sustainability" of a diet. The complex web of determinants of sustainable diets makes it challenging for policymakers to understand the benefits and considerations for promoting, processing, and consuming such diets. To advance this work, better measurements and indicators must be developed to assess the impact of the various determinants on the sustainability of a diet and the tradeoffs associated with any recommendations aimed at increasing the sustainability of our food system. PMID- 25022990 TI - Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. AB - Flavonoids are important natural compounds with diverse biologic activities. Citrus flavonoids constitute an important series of flavonoids. Naringin and its aglycone naringenin belong to this series of flavonoids and were found to display strong anti-inflammatory and antioxidant activities. Several lines of investigation suggest that naringin supplementation is beneficial for the treatment of obesity, diabetes, hypertension, and metabolic syndrome. A number of molecular mechanisms underlying its beneficial activities have been elucidated. However, their effect on obesity and metabolic disorder remains to be fully established. Moreover, the therapeutic uses of these flavonoids are significantly limited by the lack of adequate clinical evidence. This review aims to explore the biologic activities of these compounds, particularly on lipid metabolism in obesity, oxidative stress, and inflammation in context of metabolic syndrome. PMID- 25022992 TI - Toward a new philosophy of preventive nutrition: from a reductionist to a holistic paradigm to improve nutritional recommendations. AB - The reductionist approach has been predominant to date in human nutrition research and has unraveled some of the fundamental mechanisms at the basis of food nutrients (e.g., those that involve deficiency diseases). In Western countries, along with progress in medicine and pharmacology, the reductionist approach helped to increase life expectancy. However, despite 40 y of research in nutrition, epidemics of obesity and diabetes are growing each year worldwide, both in developed and developing countries, leading to a decrease in healthy life years. Yet, interactions between nutrition-health relations cannot be modeled on the basis of a linear cause-effect relation between 1 food compound and 1 physiologic effect but rather from multicausal nonlinear relations. In other words, explaining the whole from the specific by a bottom-up reductionist approach has its limits. A top-down approach becomes necessary to investigate complex issues through a holistic view before addressing any specific question to explain the whole. However, it appears that both approaches are necessary and mutually reinforcing. In this review, Eastern and Western research perspectives are first presented, laying out bases for what could be the consequences of applying a reductionist versus holistic approach to research in nutrition vis-a vis public health, environmental sustainability, breeding, biodiversity, food science and processing, and physiology for improving nutritional recommendations. Therefore, research that replaces reductionism with a more holistic approach will reveal global and efficient solutions to the problems encountered from the field to the plate. Preventive human nutrition can no longer be considered as "pharmacology" or foods as "drugs." PMID- 25022994 TI - Rhodes D.G., Adler M.E., Clemens J.C., LaComb R.P., Moshfegh A.J. Consumption of pizza: what we eat in America, NHANES 2007-2010. Food Surveys Research Group Dietary Data Brief No. 11. February 2014. PMID- 25022993 TI - Considering the value of dietary assessment data in informing nutrition-related health policy. AB - Dietary assessment has long been known to be challenged by measurement error. A substantial amount of literature on methods for determining the effects of error on causal inference has accumulated over the past decades. These methods have unrealized potential for improving the validity of data collected for research studies and national nutritional surveillance, primarily through the NHANES. Recently, the validity of dietary data has been called into question. Arguments against using dietary data to assess diet-health relations or to inform the nutrition policy debate are subject to flaws that fall into 2 broad areas: 1) ignorance or misunderstanding of methodologic issues; and 2) faulty logic in drawing inferences. Nine specific issues are identified in these arguments, indicating insufficient grasp of the methods used for assessing diet and designing nutritional epidemiologic studies. These include a narrow operationalization of validity, failure to properly account for sources of error, and large, unsubstantiated jumps to policy implications. Recent attacks on the inadequacy of 24-h recall-derived data from the NHANES are uninformative regarding effects on estimating risk of health outcomes and on inferences to inform the diet-related health policy debate. Despite errors, for many purposes and in many contexts, these dietary data have proven to be useful in addressing important research and policy questions. Similarly, structured instruments, such as the food frequency questionnaire, which is the mainstay of epidemiologic literature, can provide useful data when errors are measured and considered in analyses. PMID- 25022996 TI - Overview of spontaneous preterm birth: a complex and multifactorial phenotype. AB - The phenotype of spontaneous preterm birth (SPTB) refers to the biochemical and physical characteristics present at the time of preterm delivery. These are the result of the processes that cause this complication. The lack of understanding about the etiologies and our inability to prevent SPTB are because of the complex nature and multiple processes responsible for maintenance of pregnancy and the transition to labor. Any of these processes, when activated prematurely, may lead to SPTB. This article provides an overview of the SPTB phenotype, which may assist with future attempts to reduce in the incidence of SPTB. PMID- 25022997 TI - The clinical approach to obesity in pregnancy. AB - Over one third of reproductive age women are obese, and this marked prevalence is impacting pregnancy. Obese women face many challenges from preconception to postpartum. They are at increased risk for both maternal and fetal complications including gestational diabetes, hypertension, preeclampsia, congenital anomalies, stillbirth, fetal macrosomia, cesarean delivery, venous thromboembolism, wound complications, breast-feeding difficulty, postpartum depression, postpartum weight retention, and neonatal death. This discussion is designed to help clinicians understand how obesity affects pregnancy, how to counsel patients regarding gestational weight gain, and how to implement management strategies during pregnancy to optimize health outcomes for these patients. PMID- 25022995 TI - The efficacy of molecular subtyping in predicting postoperative recurrence in breast-conserving therapy: a 15-study meta-analysis. AB - BACKGROUND: Recent research displays that breast cancer (BC) is a heterogeneous disease and distinct molecular subtypes yield different prognostic outcomes. METHODS: We conducted a meta-analysis to clarify the role of molecular subtypes in recurrence risk after breast-conserving therapy (BCT). Eligible studies of single- (ER, PR, Her-2, and p53) and triple-molecular (Luminal A, Luminal B, Her 2, triple-negative) subtypes were identified through multiple search strategies. Pooled hazard ratios with 95% confidence intervals were calculated to assess this research topic. RESULTS: Fifteen studies involving 21,645 participants were included in the meta-analysis. Her-2 positive patients had a significantly higher recurrence risk in both overall merge (HR = 1.97, 95% CI: 1.41-2.75) and subtotal merge of local recurrence (LR) (HR = 1.93, 95% CI: 1.34-2.78). Significantly higher risk of recurrence was also observed in p53 positive patients by overall merge (HR = 1.78, 95% CI: 1.49 -2.12) and subtotal merge of LR (HR = 1.73, 95% CI: 1.44-2.07). When setting Luminal A as a baseline, Luminal B, Her-2, and triple-negative all showed significantly increased risk for both LR and distant recurrence (DR). Comparing triple-negative and non-triple-negative subtypes showed the biggest risk for overall recurrence (HR = 3.19, 95% CI: 1.91-5.31) and LR (HR = 3.31, 95% CI: 1.69-6.45). CONCLUSIONS: Our meta-analysis showed significant differences in recurrence risk among various molecular subtypes after BCT. Although Her-2 and p53 positive subtypes can be considered independent prognostic biomarkers for indicating high LR risk, triple-molecular biomarkers showed higher clinical value. Triple-negative subtype showed the highest recurrence risk among all subtypes, and adjuvant chemotherapy should be considered for it. PMID- 25022998 TI - Maternal activity restriction in pregnancy and the prevention of preterm birth: an evidence-based review. AB - Activity restriction is one of the most common practices used for the prevention of preterm birth. Despite the lack of evidence to support the efficacy of activity restriction, and newer data that highlight potential harms to the mother, the intervention is still prescribed. This review of the literature describes the potential benefits, harms, and efficacy of activity restriction in the prevention of preterm birth. PMID- 25022999 TI - Call to action: continuum of care for females of reproductive age to prevent obesity and ensure better health outcomes of offspring through nutrition. AB - The health and nutritional status of women of reproductive age has tremendous impact on the health of future populations; therefore, special attention should be paid to promoting women's health, especially a healthy weight at this critical time period. The purpose of the paper is to provide information on the nutritional needs of women at various stages of the reproductive age spectrum, including preconception/interconception and during pregnancy to achieve and maintain a healthy weight. The Socio-Ecological Model (SEM) is presented to help practitioners understand the importance of intervening where women of reproductive age live, work, and frequent. PMID- 25023000 TI - Foreword. Prevention of preterm birth in 2014. PMID- 25023001 TI - Commentary on "Temporary aneurysm sac perfusion as an adjunct for prevention of spinal cord ischaemia after branched endovascular repair of thoracoabdominal aneurysms". PMID- 25023002 TI - Future directions for positive development intervention research. AB - The emergence of multiple universal prevention efforts that reduce psychopathology symptoms, along with growing interest in the promotion of healthy development, presents an exciting opportunity for advancing child and adolescent mental health. Multiple frameworks and related construct models of positive development have been developed-and are all driving substantial findings. In addition, efforts under way to understand and systematically review existing interventions as promoting effective development are proving valuable not only for reducing risk but also for improving emotional and social functioning. Principal contributors to this exciting convergence of interests and advancements are described in this article. Moreover, this article presents important challenges and opportunities for moving forward toward a robust integration of positive development and child and adolescent clinical psychology. PMID- 25023003 TI - Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing. AB - While genetic factors in all likelihood contribute to stress fracture (SF) pathogenesis, a few studies focusing on candidate genes have previously been reported. The objective of this study is to gain better understanding on the genetic basis of SF in a gene-naive manner. Exome sequence capture followed by massive parallel sequencing of two pooled DNA samples from Israeli combat soldiers was employed: cases with high grade SF and ethnically matched healthy controls. The resulting sequence variants were individually verified using the SequenomTM platform and the contribution of the genetic alterations was validated in a second cohort of cases and controls. In the discovery set that included DNA pool of cases (n = 34) and controls (n = 60), a total of 1174 variants with >600 reads/variant/DNA pool were identified, and 146 (in 127 genes) of these exhibited statistically significant (P < 0.05) different rates between SF cases and controls after multiple comparisons correction. Subsequent validation of these 146 sequence variants individually in a total of 136 SF cases and 127 controls using the SequenomTM platform validated 20/146 variants. Of these, three missense mutations (rs7426114, rs4073918, rs3752135 in the NEB, SLC6A18 and SIGLEC12 genes, respectively) and three synonymous mutations (rs2071856, rs2515941, rs716745 in the ELFN2, GRK4, LRRC55 genes) displayed significant different rates in SF cases compared with controls. Exome sequencing seemingly unravelled novel candidate genes as involved in SF pathogenesis and predisposition. PMID- 25023004 TI - Imaging of functional and structural alterations of large arteries after acute ischaemic atherothrombotic stroke or acute coronary syndromes. AB - BACKGROUND: Non-invasive methods allow the evaluation of structural and functional arterial abnormalities. So far, no study has focused on the comparison of vascular parameters by type of cardiovascular event. METHODS: In this pilot study, cardiovascular risk factors, carotid parameters, carotid-to-femoral pulse wave velocity (PWV), brachial flow-mediated dilation and ambulatory blood pressure were assessed in patients who presented with acute coronary syndromes (ACS) or ischaemic atherothrombotic stroke (IAS). Groups were matched for age and gender. RESULTS: Prevalences of hypertension, diabetes and dyslipidaemia and heredity, smoking and body mass index were similar in the ACS (n=50) and IAS (n=50) groups. Carotid intima-media thickness (IMT) and PWV were significantly higher in the IAS vs. ACS group (769+/-180 vs. 701+/-136 MUm; P=0.039 and 12.5+/ 3.5 vs. 10.7+/-2.4 m/s; P=0.006). Carotid distensibility was significantly lower in the IAS vs. ACS group (16.2+/-3.2 vs. 18.9+/-7.6 10(-3)/kPa; P=0.02). These differences persisted after adjustment for blood pressure for carotid distensibility but not for PWV. The prevalences of endothelial dysfunction and carotid plaques were not significantly different in the ACS and IAS groups (86% and 74%; 80% and 78%). In a multivariable model, carotid distensibility remained associated with ACS (odds ratio 1.19; 95% confidence interval 1.03-1.38; P=0.016). CONCLUSIONS: Stiffness and carotid wall thickness were higher in IAS than in ACS patients. These differences may support the interest in new therapeutic targets for cardiovascular secondary prevention. NCT NO: NCT00926874. PMID- 25023006 TI - Tumour-related neoangiogenesis: functional dynamic perfusion computed tomography for diagnosis and treatment efficacy assessment in hepatocellular carcinoma. AB - BACKGROUND: Aim of the study was to determine the value of perfusion computed tomography in the quantitative assessment of tumour-related neoangiogenesis for the diagnosis and treatment of hepatocellular carcinoma lesions. METHODS: Overall, 47 consecutive patients with cirrhotic liver disease, with a high risk of hepatocellular carcinoma, and undergoing standard surveillance (six-month intervals) were eligible for inclusion in this prospective study; based on Barcelona Clinic Liver Cancer guidelines, 27 patients were enrolled. Perfusion computed tomography was performed in 29 biopsy-proven hepatocellular carcinoma lesions before and after treatment with transarterial chemoembolization or radiofrequency ablation. The dynamic study was performed with a 256-slice multidetector-computed tomography scanner; the following parameters were measured: hepatic perfusion, arterial perfusion, blood volume, hepatic perfusion index, and time-to-peak in all patients. RESULTS: Hepatocellular carcinoma lesions had the following median perfusion values: perfusion 46.3mL/min/100g; blood volume 20.4mL/100mg; arterial perfusion 42.9mL/min; hepatic perfusion index 92.5%; time to peak 18.7s. Significantly lower perfusion values were obtained in correctly treated lesions or surrounding parenchyma than in viable hepatocellular carcinoma tissue. CONCLUSIONS: In hepatocellular carcinoma, perfusion computed tomography could contribute to a non-invasive quantification of tumour blood supply related to the formation of new arterial structures, and enable the assessment of therapeutic response. PMID- 25023005 TI - Expression and putative functions of melatonin receptors in malignant cells and tissues. AB - Melatonin, the popular hormone of the darkness, is primarily synthesized in the pineal gland, and acts classically through the G-protein coupled plasma membrane melatonin receptors MT1 and MT2, respectively. Although some of the receptor mediated functions of melatonin, especially those on the (central) circadian system, have been more or less clarified, the functional meaning of MT-receptors in various peripheral organs are still not sufficiently investigated yet. There is, however, accumulating evidence for oncostatic effects of melatonin with both, antioxidative and MT-receptor mediated mechanisms possibly playing a role. This review briefly summarizes the physiology of melatonin and MT-receptors, and discusses the expression and function of MT-receptors in human cancer cells and tissues. PMID- 25023007 TI - Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment. AB - BACKGROUND: Tacrolimus in refractory ulcerative colitis often serves as a bridge to long-term maintenance therapy with thiopurines. Our aim was to review efficacy and safety of tacrolimus in active ulcerative colitis resistant to conventional therapies, including anti-tumour necrosis factor. METHODS: Charts of consecutive outpatients with refractory ulcerative colitis, in whom tacrolimus was orally administered as a 12 week-induction (target trough levels 10-15ng/mL) followed by a maintenance therapy (target trough levels 5-10ng/mL), were retrospectively reviewed. Clinical remission and response at weeks 4, 12 and 52 as well as adverse events within 1-year therapy were reported. RESULTS: Twelve (40%) and six (20%) of the 30 patients included (14 males, mean age 37.1+/-1.4 years) achieved a clinical remission and response, respectively, at week 12. Three responders to tacrolimus initiation experienced drug-related adverse events requiring discontinuation. Among the 18 remaining initial responders who tolerated tacrolimus, 8 (27%) were in clinical remission at week 52, whereas the remainder either experienced adverse events requiring drug withdrawal (n=4) or relapsed (n=6). Overall adverse events were recorded in 14 patients (46%), mainly finger tremor and urinary infections. CONCLUSION: Oral monotherapy with tacrolimus may be a valuable long-term therapeutic option in selected patients with moderate-to severe active refractory ulcerative colitis. PMID- 25023008 TI - Biventricular non-compaction hypertrophic cardiomyopathy in association with congenital complete heart block and type I mitochondrial complex deficiency. AB - We report a baby girl with an antenatal diagnosis of biventricular non-compaction and complete heart block detected at 22 weeks' gestation. Postnatal echocardiography confirmed severe biventricular non-compaction hypertrophic cardiomyopathy, multiple muscular ventricular septal defects, and mild-moderate pulmonary valve stenosis. Skeletal muscle biopsy confirmed complex 1 mitochondrial respiratory chain deficiency. An epicardial VVI pacemaker was implanted on day 3 of life and revised at 7 years of age. She remains stable at 8 years of age following pacing and medical treatment with carvedilol, aspirin, co enzyme Q10, and carnitine. This represents the first report of biventricular non compaction hypertrophic phenotype in association with congenital complete heart block and complex 1 mitochondrial respiratory chain deficiency in a child. PMID- 25023009 TI - A new sealed lithium-peroxide battery with a co-doped Li2O cathode in a superconcentrated lithium bis(fluorosulfonyl)amide electrolyte. AB - We propose a new sealed battery operating on a redox reaction between an oxide (O(2-)) and a peroxide (O2(2-)) with its theoretical specific energy of 2570 Wh kg(-1) (897 mAh g(-1), 2.87 V) and demonstrate that a Co-doped Li2O cathode exhibits a reversible capacity over 190 mAh g(-1), a high rate capability, and a good cyclability with a superconcentrated lithium bis(fluorosulfonyl)amide electrolyte in acetonitrile. The reversible capacity is largely dominated by the O(2-)/O2(2-) redox reaction between oxide and peroxide with some contribution of the Co(2+)/Co(3+) redox reaction. PMID- 25023011 TI - Grand Challenges in Bionics. PMID- 25023010 TI - Trend of change in retentive force for bar attachments with different materials. AB - STATEMENT OF PROBLEM: Attachment wear can decrease the retentive force of 2 implant overdentures (2-IODs). PURPOSE: The purpose of this in vitro study was to investigate the trend of change in retentive force for 6 different bar attachments during dislodgement. MATERIAL AND METHODS: Round and Dolder bars were made of platinum-added gold alloy (PGA), cobalt chromium alloy (Co-Cr), and commercially pure titanium grade IV (Ti). Clips were made of PGA. Retentive force was measured during 7200 dislodging cycles. Simple linear regression analysis was performed in order to investigate the relationship between number of cycles and retentive force (P<.05). Subsequently, wear debris was analyzed, and the surface of the attachments was observed. RESULTS: The retentive force of the Co-Cr round bar attachment (CoCr-R) increased from 57.5 N to 68.3 N and the Ti round bar attachment (Ti-R) from 54.8 N to 59.7 N. However, the retentive force of the PGA round bar attachment (PGA-R) decreased from 69.3 N to 64.0 N. A positive relationship was found between the number of cycles and the retentive force of both CoCr-R and Ti-R. The composition of the wear debris was almost the same as for PGA. For the Dolder bar attachment, no changes were seen in retentive force (between 7.0 N to 12.0 N). CONCLUSIONS: For the round bar attachment, the PGA clip and PGA bar showed wear. The retentive force of PGA-R slightly decreased. The retentive force of CoCr-R and Ti-R tended to increase. For the Dolder bar attachment, all 3 types of bar attachment showed no wear. PMID- 25023012 TI - The use of Research Electronic Data Capture (REDCap) software to create a database of librarian-mediated literature searches. AB - Expert-mediated literature searching, a keystone service in biomedical librarianship, would benefit significantly from regular methodical review. This article describes the novel use of Research Electronic Data Capture (REDCap) software to create a database of literature searches conducted at a large academic health sciences library. An archive of paper search requests was entered into REDCap, and librarians now prospectively enter records for current searches. Having search data readily available allows librarians to reuse search strategies and track their workload. In aggregate, this data can help guide practice and determine priorities by identifying users' needs, tracking librarian effort, and focusing librarians' continuing education. PMID- 25023013 TI - Developing a best practices plan for tutorials in a multi-library system. AB - In 2010, the University of Iowa's library system administration created a task force to conduct a reevaluation of tools and spaces used for video tutorial creation across a multi-library system. Following this effort, a working group was charged with improving documentation and staff awareness of resources for developing video tutorials. The group observed that librarians were often independently creating videos that were variable in quality, lacked consistent branding, and were not often shared with others. This article will describe experiences at the Hardin Library for the Health Sciences at the University of Iowa in selecting video tutorial software, and striving to establish a more structured process, including team-developed guidelines, for tutorial creation in a multi-library system. Project limitations and areas for future work will also be presented. PMID- 25023014 TI - Adapting an embedded model of librarianship, college by college. AB - Librarians are increasingly moving out of the library and into the wider university setting as patrons spend more time seeking information online and less time visiting the library. The move to embed librarians in colleges, departments, or customer groups has been going on for some time but has recently received more attention as libraries work to find new ways to reach patrons that no longer need to come to the physical library. Few universities have attempted to embed all their librarians. This case study describes how one group of health sciences librarians dispersed its professional staff throughout its campuses and medical centers. PMID- 25023015 TI - Transcribing and digitizing eighteenth- and nineteenth-century letters for a historical digital repository. AB - In fall 2011, the Scott Memorial Library purchased 53 letters belonging to an 1841 graduate of Jefferson Medical College, John Plimpton Green. The library staff transcribed and digitized the letters, creating an online collection in the university's institutional repository, Jefferson Digital Commons. This article will detail the process of transcribing and digitizing the collection along with sharing statistics and the benefits of this project to global researchers. PMID- 25023016 TI - Web-based technologies for health sciences reference and instruction. AB - New web-based instructional technologies provide health sciences librarians with tools to enhance delivery of reference services, reinforce library instruction, and facilitate outreach activities. Of the many emerging, new web technologies recently available to health information professionals, 12 resources are presented in this article to explain the value these tools bring to informational and instructional settings to enhance demonstration, facilitate collaborative activities, encourage communication, and evaluate learning/understanding. PMID- 25023017 TI - Expanding our roles: embedded in curriculum design. AB - This article describes how librarians became involved as members of an interdisciplinary curricular team in a problem-based learning course for first- and second-year medical students. The experience illustrates how librarians can become part of a team, collaborating with medical faculty to assist in revising curricula, incorporating innovative teaching techniques, and creating effective simulated patient case scenarios. Working within an interdisciplinary collaborative team on curriculum development allows librarians to move beyond the traditional role of instruction and can lead to additional opportunities, including research and ongoing involvement in curricular changes. PMID- 25023018 TI - Information literacy skills retention over the first professional year of pharmacy school. AB - The authors aimed to determine if first-professional-year pharmacy students retain library literature search skills throughout the school year. Students (n = 61 consented) were given an identical seven-item quiz on basic library search skills prior to library instruction in the fall semester and at the end of the spring semester. There was no significant difference between median scores on the two quizzes, nor were any significant differences noted in subgroup analyses. Search competency may be retained to a higher degree if library instruction is moved later in the pharmacy curriculum when literature search skills are used more often. PMID- 25023019 TI - Dentistry & Oral Sciences Source (DOSS): a collection for dental research and education. AB - Dentistry & Oral Sciences Source from EBSCO Information Services provides indexing and full-text access to an extensive selection of dental journal literature, as well some full-text dental monographs. As stated by EBSCO, titles are chosen from those commonly held in dental school libraries. The database aims to support practitioners, researchers, and advanced dental education. This column includes sample searches from Dentistry & Oral Sciences Source as well as a discussion of its special content and features. PMID- 25023020 TI - Big data: an introduction for librarians. AB - Modern life produces data at an astounding rate and shows no signs of slowing. This has lead to new advances in data storage and analysis and the concept of "big data," that is, massive data sets that can yield surprising insights when analyzed. This column will briefly describe what big data is and why it is important. It will also briefly explore the possibilities and problems of big data and the implications it has for librarians. A list of big data projects and resources is also included. PMID- 25023021 TI - Librarian contributions to clinical practice guidelines. AB - Librarians have become more involved in developing high quality systematic reviews. Evidence-based practice guidelines are an extension of systematic reviews and offer another significant area for librarian involvement. This column highlights opportunities and challenges for the librarian working on guideline panels and provides practical considerations for meaningful contributions to the guideline creation process. PMID- 25023022 TI - Focused library instruction for occupational therapy, physical therapy, and respiratory care students and faculty: library instruction in allied health. AB - The integration of librarians into allied health programs presents many exciting opportunities for collaboration. This column will describe how a library instruction program is integrated into the occupational therapy, respiratory care, and physical therapy curricula at the University of Texas Health Science Center at San Antonio. The allied health faculty have welcomed and recognized the librarians' expertise in teaching evidence-based practice and library research skills. PMID- 25023028 TI - Effect of tooth displacement and vibration on frictional force and stick-slip phenomenon in conventional brackets: a preliminary in vitro mechanical analysis. AB - OBJECTIVE: To evaluate the effects of tooth displacement and vibration on frictional force and stick-slip phenomenon (SSP) when conventional brackets were used with a levelling/alignment wire. MATERIALS AND METHODS: The samples consisted of six groups (n = 10 per group) with combinations of tooth displacement (2mm lingual displacement [LD], 2mm gingival displacement [GD], and no displacement [control]) and vibration conditions (absence and presence at 30 Hz and 0.25 N). A stereolithographically made typodont system was used with conventional brackets and elastomeric ligatures. After application of artificial saliva, static/kinetic frictional forces (SFF/KFF) and frequency/amplitude of SSP were measured while drawing a 0.018-inch copper nickel-titanium (Cu-NiTi) archwire at a speed of 0.5mm/min for 5 minutes at 36.5 degree celsius. Two-way analysis of variance and independent t-test were performed. RESULTS: Tooth displacement increased SFF and KFF (control < LD < GD, all P < 0.001) and reduced SSP frequency (control > [LD, GD], P < 0.01). Vibration reduced SFF, KFF, and SSP amplitude in the control group (P < 0.05, P < 0.05, and P < 0.001, respectively), but not in the LD and GD groups. SSP frequency was increased by vibration in the control, LD, and GD groups (all P < 0.001), and it was lower in the LD and GD groups than in the control group (P < 0.01). CONCLUSIONS: When conventional brackets and a 0.018-inch Cu-NiTi archwire were used in the tooth displacement conditions (LD and GD), vibration did not significantly reduce SFF, KFF, or SSP amplitude. PMID- 25023029 TI - Immobilization of glucose oxidase on modified electrodes with composite layers based on poly(3,4-ethylenedioxythiophene). AB - Two modified electrodes with immobilized glucose oxidase were developed. Modification with poly(3,4-ethylenedioxythiophene) (PEDOT) and polyacrylic acid (PAA) doped with poly(4-lithium styrenesulfonic acid) (PSSLi) in a newly elaborated procedure was used in the first electrode. The second one presents innovative solution and consists of two sublayers; one of them was PEDOT doped with PSSLi and the other was composed of PEDOT and anthranilic acid (AA) doped with poly(4-styrenesulfonic acid) (PSSH). Glucose oxidase was covalently bonded with the carboxyl groups of the polymer through N-(3-dimethylaminopropyl)-N' ethylcarbodiimide hydrochloride (WSC). The activity of immobilized enzyme was confirmed by spectrophotometry using the reaction of the produced hydrogen peroxide with o-dianisidine. The procedure for immobilization was optimized. It was found that the choice of an appropriate doping agent and its concentration were significant and 0.1M PSSLi proved to be the best doping agent. The most efficient immobilization was established for WSC and GOD concentration at the level of 4mg/ml and 5mg/ml respectively. In both cases, it was found that a small deviation from the concentrations determined to cause a sharp decrease in the activity of the enzyme, which was proven by spectrophotometric measurements. Prepared electrodes were active over a month with repeatable measurement results. PMID- 25023030 TI - Liver transplantation. Out in the cold: new supercooling technique extends liver storage time. PMID- 25023031 TI - Hepatitis. Chronic HCV infection, diabetes and liver-related outcomes. AB - There is increasing interest in the role that diabetes has in liver-related outcomes in patients with chronic HCV. Elkrief and colleagues have furthered this discussion by indicating that diabetes may be considered a prognostic factor for major liver-related outcomes in patients with chronic HCV infection, including death and transplantation. PMID- 25023032 TI - Recurrent HCV after liver transplantation-mechanisms, assessment and therapy. AB - Chronic HCV infection is the leading indication for liver transplantation. However, as a result of HCV recurrence, patient and graft survival after liver transplantation are inferior compared with other indications for transplantation. HCV recurrence after liver transplantation is associated with considerable mortality and morbidity. The development of HCV-related fibrosis is accelerated after liver transplantation, which is influenced by a combination of factors related to the virus, donor, recipient, surgery and immunosuppression. Successful antiviral therapy is the only treatment that can attenuate fibrosis. The advent of direct-acting antiviral agents (DAAs) has changed the therapeutic landscape for the treatment of patients with HCV. DAAs have improved tolerability, and can potentially be used without PEG-IFN for a shorter time than previous therapies, which should result in better outcomes. In this Review, we describe the important risk factors that influence HCV recurrence after liver transplantation, highlighting the mechanisms of fibrosis and the integral role of hepatic stellate cells. Indirect and direct assessment of fibrosis, in addition to new antiviral therapies, are also discussed. PMID- 25023033 TI - IBD. Sequential rescue therapy in steroid-refractory ulcerative colitis. AB - Treatment of patients with steroid-refractory ulcerative colitis is still a challenge for physicians. A recent study has evaluated the effectiveness and safety of sequential rescue therapies in this subgroup of patients. PMID- 25023034 TI - Liver transplantation. Immune responses to HCV infection linked to liver transplant tolerance. PMID- 25023035 TI - Procoagulant therapeutics in liver disease: a critique and clinical rationale. AB - The complex nature of haemostasis in patients with liver disease can result in bleeding and/or thrombosis. These opposing outcomes, which have multiple contributing factors, can pose diagnostic and therapeutic dilemmas for physicians. With the high rate of haemorrhagic complications in patients with cirrhosis, we examine the various procoagulants available for use in this population. In this Review, we describe the clinical and current rationale for using each of the currently available procoagulants-vitamin K, fresh frozen plasma (FFP), cryoprecipitate, platelets, recombinant factor VIIa (rFVIIa), antifibrinolytics, prothrombin concentrate complexes (PCC), desmopressin and red blood cells. By examining the evidence and use of these agents in liver disease, we provide a framework for targeted, goal-directed therapy with procoagulants. PMID- 25023036 TI - Genetics. Driver genes are mutated early in the course of oesophageal adenocarcinoma. PMID- 25023037 TI - Pancreatitis. Secretin increases the diagnostic yield of MRCP. AB - The presence of ductal abnormalities after an unexplained acute attack of acute pancreatitis or in patients with recurrent acute pancreatitis might lead to a misdiagnosis of chronic pancreatitis or complications of acute pancreatitis. A new study suggests secretin administered during magnetic resonance cholangiopancreatography (MRCP) leads to a better diagnostic yield than MRCP alone. PMID- 25023038 TI - Antibacterial activities of Beilschmiedia obscura and six other Cameroonian medicinal plants against multi-drug resistant Gram-negative phenotypes. AB - BACKGROUND: The rapid spread of bacteria expressing multi-drug resistance propels the search for new antibacterial agents. The present study was designed to evaluate the antibacterial activities of the methanol extracts from Beilschmiedia obscura and six other Cameroonian plants against a panel of twenty nine Gram negative bacteria including Multi-drug resistant (MDR) phenotypes. METHODS: The phytochemical investigations of the extracts were carried out according to the standard methods and the liquid micro-dilution assay was used for all antibacterial assays. RESULTS: Phytochemical analysis showed the presence of alkaloids in all studied extracts. Other chemical classes of secondary metabolites such as anthocyanines, anthraquinones flavonoids, saponins, tannins, sterols and triterpenes were selectively detected in the extracts. The extract from the fruits of Beilschmiedia obscura, Pachypodanthium staudtii leaves and Peperomia fernandopoiana (whole plant) displayed the best spectrum of activity with MIC values ranging from 16 to 1024 MUg/mL against at least 65% and above of the tested bacteria. The extract from Beilschmiedia obscura was the most active with MIC values below 100 MUg/mL against ten of the tested bacteria. This extract also showed MBC values below 1024 MUg/mL against 55.17% of the studied microorganisms. Phenylalanine arginine beta-naphthylamide (PAbetaN) significantly modulated the activities of extracts from the leaves and fruits of Pachypodanthium staudtii and Beilschmiedia obscura respectively, by increasing their inhibitory activity against Klebsiella pneumoniae KP55 strain at least four fold. CONCLUSION: The overall results of the present investigation provide information for the possible use of the methanol extracts of the studied plant species, especially B. obscura to fight infectious diseases caused by Gram negative bacteria including MDR phenotypes. PMID- 25023040 TI - The successful contribution by the Trans-Tasman Radiation Oncology Group to intergroup radiation oncology trials (2010-2012) and a proposal for accrual definitions. PMID- 25023039 TI - Neuropathic symptoms, quality of life, and clinician perception of patient care in medical oncology outpatients with colorectal, breast, lung, and prostate cancer. AB - PURPOSE: We investigated how treatment-induced neuropathic symptoms are associated with patients' quality of life (QOL) and clinician-reported difficulty in caring for patients. METHODS: Data were obtained from 3,106 outpatients with colorectal, breast, lung, or prostate cancer on numbness/tingling (N/T), neuropathic pain, and QOL. Clinicians reported the degree of difficulty in caring for patients' physical and psychological symptoms. RESULTS: For all patients, moderate to severe N/T was associated with poor QOL (OR = 1.82, 95% CI = 1.47 2.26, P < 0.001) but neuropathic pain was not (OR = 1.31, 95% CI = 0.94-1.83, P = 0.114). Moderate to severe N/T and neuropathic pain were associated with increased care difficulty (OR = 1.49, 95% CI = 1.27-1.74, P < 0.001 for N/T, and OR = 1.46, 95% CI = 1.15-1.84, P = 0.002 for neuropathic pain). The association of neuropathic pain with care difficulty was most significant in patients with colorectal cancer (CRC) (OR = 2.32, 95% CI = 1.41-3.83, P = 0.001). Baseline neuropathic pain was associated with declining QOL in CRC patients (OR = 2.08, 95% CI = 1.21-3.58, P = 0.008). CONCLUSIONS: Clinicians may experience increased care difficulty for patients of all cancer types with moderate to severe N/T or neuropathic pain; care difficulty due to neuropathic pain may be higher for CRC patients. Nearly half the patients of all cancer types with moderate to severe N/T may expect poor short-term QOL; CRC-but not other-patients with baseline neuropathic pain are likely to experience declining QOL. IMPLICATIONS FOR CANCER SURVIVORS: About half of patients with moderate to severe N/T (any cancer type) may expect poor QOL in the short term; CRC patients with baseline neuropathic pain in particular may experience declining QOL. PMID- 25023041 TI - An alternative approach to account for patient organ doses from imaging guidance procedures. AB - PURPOSE: To investigate the feasibility of an alternative method of accounting for additional organ doses resulting from image guidance procedures during patient treatment planning through tabulated values based on scan protocol and scan site. METHODS AND MATERIALS: Patient-specific imaging dose to 30 patients resulting from Varian OBI kV-CBCT scans using the Standard Head (17 patients), Low-dose Thorax (8 patients), and Pelvic (5 patients) scan protocols were retrospectively calculated using Monte Carlo methods. Dose dependence on scan location and patient geometry was explored. Patient organ doses were analyzed by using dose-volume histograms and expressed by the mean, minimum dose delivered to 50% of the organ volume, D50. The reported doses are dose-to-medium instead of dose-to-water. RESULTS: The organ doses from all patient-specific calculations show predictable and limited ranges across patients. For brain isocenters using Standard Head Scans: Bone: 0.7-1.1 cGy, Brain: 0.2-0.3 cGy, Brainstem: 0.2-0.3 cGy, Skin: 0.3-0.4 cGy, Eye: 0.03-0.3 cGy. For head and neck patients using the Standard Head Scan: Bone: 0.3-0.6 cGy, Parotids: 0.3-0.4 cGy, Spinal Cord: 0.15 0.25 cGy, Thyroid: 0.1-0.25 cGy, Skin: 0.2-0.3 cGy, Trachea-Esophagus: 0.1-0.2 cGy. For chest using Thorax Scans: Bone: 1.1-1.8 cGy, Soft tissue organs (Bowel, Lung, Heart, Kidney, Esophagus, and Spinal Cord): 0.3-0.6 cGy. For abdominal site using Pelvic Scans: Bone: 3.2-4.2 cGy. Soft tissue organs (Bladder, Bowel, Rectum, Prostate, and Skin) D50s fell between 1.2 and 2.2 cGy. Femoral Heads: 2.5 3.4 cGy. CONCLUSIONS: It is adequate to estimate and account for organ dose by using tabulated values based on scan procedure and site because organ doses from imaging procedures are only modestly dependent upon scan location and body size. Considering the dose variation and magnitude of dose from each scan protocol in comparison to therapeutic doses, this approach provides a simple alternative to account for additional imaging guidance doses during patient treatment planning. Clinicians can use these tabulated values to make informed decisions in selecting the appropriate imaging procedures and imaging frequency during radiotherapy treatment. PMID- 25023042 TI - The impact of stool and gas volume on intrafraction prostate motion in patients undergoing radiotherapy with daily endorectal balloon. AB - PURPOSE: The aim of this study was to quantify the impact of rectal stool/gas volumes on intrafraction prostate motion for patients undergoing prostate radiotherapy with daily endorectal balloon (ERB). METHODS: Total and anterior stool/gas rectal volumes were quantified in 30 patients treated with daily ERB. Real-time intrafraction prostate motion from 494 treatment sessions, at most 6 min in length, was evaluated using Calypso((r)) tracking system. RESULTS: The deviation of prostate intrafraction motion distribution was a function of stool/gas volume, especially when stool/gas is located in the anterior part of the rectum. Compared to patients with small anterior stool/gas volumes (<10 cm(3)), those with large volume (10-60 cm(3)) had a twofold increase in 3D prostate motion and interquartile data range within the 6th minute of treatment time. The 10% of the overall CBCT session where large anterior rectal volumes were observed demonstrated larger percentage of time at displacement greater than our proposed internal margin 3 mm. CONCLUSION: Volume and location of stool/gas can directly impact the ERB's intrafraction immobilization ability. Although our patient preparation protocol and the 100 cm(3) daily ERB effectively stabilized prostate motion for 90% of the fractions, a larger-sized ERB may improve prostate fixation for patients with greater and/or variable daily rectal volume. PMID- 25023043 TI - Overall response rates to radiation therapy for patients with painful uncomplicated bone metastases undergoing initial treatment and retreatment. AB - INTRODUCTION: Radiation therapy has been shown to successfully palliate bone metastases. A number of systematic reviews and large clinical trials have reported response rates for initial treatment and retreatment. OBJECTIVE: To determine overall response rates of patients with painful uncomplicated bone metastases undergoing initial treatment and retreatment. METHODS: Intent-to-treat and evaluable patient statistics from a systematic review of palliative radiotherapy trials for initial treatment of bone metastases and a randomized clinical trial of retreatment were pooled and analyzed to determine the overall response rates for patients receiving initial treatment and retreatment. RESULTS: In the intent-to-treat calculation, 71-73% of patients had an overall response to radiation treatment and in the evaluable patient population; 85-87% of patients did so. Response rates varied slightly whether patients underwent single or multiple fractions in initial treatment or retreatment. CONCLUSIONS: Single and multiple fraction radiation treatment yielded very similar overall response rates. Patients treated with a single fraction for both initial and repeat radiation experience almost identical overall response to those patients treated with multiple fraction treatment. It is therefore recommended that patients with uncomplicated painful bone metastases be treated with a single 8 Gy fraction of radiation at both the initial treatment and retreatment. PMID- 25023044 TI - Postoperative Tamoxifen for ductal carcinoma in situ: Cochrane systematic review and meta-analysis. AB - This review aimed to assess the effects of postoperative Tamoxifen following surgical resection of ductal carcinoma in situ (DCIS). Data on local DCIS recurrence, new invasive carcinoma, distant disease, mortality and adverse effects were extracted from randomised controlled trials (RCTs) comparing Tamoxifen after surgery for DCIS (regardless of oestrogen receptor (ER) status), with or without adjuvant radiotherapy. Meta-analysis was performed using the fixed-effect model and the results expressed as relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs). Two RCTs which recruited 3375 women were included. Tamoxifen after surgery for DCIS reduced recurrence of ipsilateral DCIS (HR 0.75; 95% CI 0.61-0.92) and contralateral DCIS (RR 0.50; 95% CI 0.28-0.87). Contralateral invasive cancer was reduced (RR 0.57; 95% CI 0.39 0.83), and there was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62-1.01). The number needed to treat in order for Tamoxifen to have a protective effect against all breast events is 15. There was no evidence of a difference in all-cause mortality (RR 1.11; 95% CI 0.89-1.39). Only one trial involving 1799 participants followed-up for 163 months (median) reported on adverse events with no significant difference in event rate between Tamoxifen and placebo groups, but there was a non-significant trend towards more endometrial cancer in the Tamoxifen group. This review concludes that while Tamoxifen after local excision for DCIS, with or without adjuvant radiotherapy, reduced the risk of recurrent DCIS, it did not reduce the risk of all-cause mortality. PMID- 25023045 TI - Clinical, anthropometric, biochemical, and histological characteristics of nonobese nonalcoholic fatty liver disease patients of Bangladesh. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is considered to be a disease of obese individuals, yet lean patients are increasingly susceptible to have NAFLD. The aim of this study was to evaluate the profile of nonobese patients by comparing with obese NAFLD patients. METHODS: We have included 465 patients of NAFLD after exclusion of other diseases, and 220 with elevated alanine aminotransferase (ALT) were biopsied. Patients were biochemically and clinically evaluated: blood pressure, body mass index (BMI), and waist circumference (WC) were recorded for every patient. A BMI >= 25 kg/m(2) was defined as obese, and those with a BMI of <25 kg/m(2) were labeled as nonobese. Histological activity was expressed with NAFLD activity score (NAS). RESULTS: Of 465 cases, 119 (25.6 %) were nonobese. Diabetes was noted in 122 (26.2 %) and hypertension in 122 (26.2 %). Metabolic syndrome was present in 253 (59.7 %), low HDL cholesterol in 228 (64.8 %), hypertriglyceridemia in 297 (73.2 %), and WC above normal in 308 (70.2 %). Males were predominating in the nonobese compared to females in the obese (p = 0.001). Hypertriglyceridemia and low high-density lipoprotein was similar in the obese and nonobese (76.2 % vs. 72.3 %, p = 0.5 and 65.2 % vs. 64.6 %, p = 1.0, respectively). The grades of steatosis, lobular inflammation, ballooning, NAS, and the stage of fibrosis did not also significantly differ between obese and nonobese patients. Nonalcoholic steatohepatitis (NASH) was 53.1 % in nonobese. CONCLUSION: Nonobese was 25.6 % among NAFLD patients of Bangladesh, and 53.1 % of nonobese NAFLD cases were NASH. Though they were nonobese by BMI grade, they were metabolically similar to obese. Males were predominant in the nonobese, whereas females in the obese. NASH and fibrosis were similar in the obese and nonobese. PMID- 25023046 TI - Menopause and the workplace. PMID- 25023047 TI - Education and cognitive reserve. PMID- 25023048 TI - Electron mediators accelerate the microbiologically influenced corrosion of 304 stainless steel by the Desulfovibrio vulgaris biofilm. AB - In the microbiologically influenced corrosion (MIC) caused by sulfate reducing bacteria (SRB), iron oxidation happens outside sessile cells while the utilization of the electrons released by the oxidation process for sulfate reduction occurs in the SRB cytoplasm. Thus, cross-cell wall electron transfer is needed. It can only be achieved by electrogenic biofilms. This work hypothesized that the electron transfer is a bottleneck in MIC by SRB. To prove this, MIC tests were carried out using 304 stainless steel coupons covered with the Desulfovibrio vulgaris (ATCC 7757) biofilm in the ATCC 1249 medium. It was found that both riboflavin and flavin adenine dinucleotide (FAD), two common electron mediators that enhance electron transfer, accelerated pitting corrosion and weight loss on the coupons when 10ppm (w/w) of either of them was added to the culture medium in 7-day anaerobic lab tests. This finding has important implications in MIC forensics and biofilm synergy in MIC that causes billions of dollars of damages to the US industry each year. PMID- 25023049 TI - [Is controlled drinking a reasonable therapy target for alcohol dependence? Against]. PMID- 25023050 TI - Elevated apolipoprotein A-I levels are associated with favorable prognosis in metastatic nasopharyngeal carcinoma. AB - The survival outcomes of patients with metastatic nasopharyngeal carcinoma (NPC) differ significantly between individuals. Serum lipids and lipoproteins have been reported to be associated with prognosis in some cancers, but it has not been studied in metastatic NPC. The aim of this study was to evaluate whether serum lipid and lipoproteins could predict the prognosis of metastatic NPC patients. Eight hundred and seven patients with metastatic NPC were analyzed retrospectively, and the values of serum lipids and lipoproteins at baseline were retrieved. Receiver operating characteristic curve analysis and univariate and multivariate Cox proportional hazards analyses were used to evaluate the associations of serum lipids and lipoproteins with overall survival (OS). Univariate analysis revealed that higher values of baseline cholesterol (>=4.655 mmol/L), baseline high-density lipoprotein cholesterol (>=0.965 mmol/L), and baseline apolipoprotein A-I (ApoA-I) (>=1.065 g/L) were significantly associated with superior OS (p < 0.001), respectively. Multivariate Cox proportional hazard analysis showed that higher ApoA-I level (vs. lower ApoA-I level, HR 0.64, 95 % CI 0.52-0.80, p < 0.001) was an independent protective factor against progression. In addition, higher body mass index, earlier N stages, single lesion, and absence of liver metastasis were also revealed to be independent protective factors. In conclusion, the elevated baseline ApoA-I level may predict those patients likely to have a favorable OS. PMID- 25023051 TI - The role of c2orf68 and PI3K/Akt/mTOR pathway in human colorectal cancer. AB - The aim of the research is to determine whether c2orf68 gene plays a role in the carcinogenesis of human colorectal cancer and to study the function of c2orf68 belonging to the UPF0561 family. The mRNA expression levels of c2orf68 were examined in 30 pairs of human colorectal adenocarcinoma tissues and adjacent normal colorectal tissues by qRT-PCR. The SW480 and SW620 cell lines were transfected with siRNA against the c2orf68 gene and set gene. The expressed mRNA levels of Akt, PI3K, Bax, Bcl-2, caspase3, c-Myc, cyclinD1, pp2a and set were determined by qRT-PCR, and the protein levels of C2ORF68, c-Myc, PP2A and SET were examined by Western blot. Cell proliferation was tested by MTT assay, and apoptosis and cell cycle were studied by flow cytometry. Cancer metastasis assay was performed by transwell chamber. The c2orf68 mRNA expression was down regulated in 63.33 % of the cancer samples, and a positive correlation was found between the mRNA expression of c-Myc and pp2a that of c2orf68. Meanwhile, there was a negative correlation between the mRNA expression of c2orf68 and set. The c2orf68 mRNA was significantly down-regulated in SW480(-c2orf68) and SW620( c2orf68) cells. The inhibitory rate in the two cell lines was, respectively, 65.2 and 71.6 % by qRT-PCR. A 22.7 % inhibition on cell proliferation in SW480( c2orf68) cells and a 21.2 % inhibition in SW620(-c2orf68) cells were observed using the MTT assay. Flow cytometry analysis indicates that the cell apoptosis rate was 21.42 % in SW480(-c2orf68) cells and 17.78 % in SW620(-c2orf68) cells, whereas the percentage of G1 phase cells was 61.8 and 58.6 % in SW480(-c2orf68) and SW620(-c2orf68) cells, respectively. In addition, the mRNA expression of set and Bax was up-regulated after c2orf68 interfered in SW480(-c2orf68) and SW620( c2orf68) cells, whereas that of Bcl-2, c-Myc, cyclinD1, caspase3 and pp2a was down-regulated. Consistent with the mRNA results, the protein expression of C2ORF68, PP2A and c-Myc was down-regulated, whereas that of SET was up-regulated. Our data thus suggest that c2orf68 promotes carcinogenesis through the regulation of mammalian target of rapamycin signaling pathway. PMID- 25023053 TI - CIP2A is overexpressed and involved in the pathogenesis of chronic myelocytic leukemia by interacting with breakpoint cluster region-Abelson leukemia virus. AB - To detect the expression of cancerous inhibitor of phosphatase 2A (CIP2A) in chronic myelocytic leukemia (CML) and investigate the mechanism underlying CIP2A knockdown-mediated cell proliferation and apoptosis as well as the interaction of CIP2A with breakpoint cluster region-Abelson leukemia virus (BCR-ABL). CIP2A mRNA and protein expression in chronic myelocytic leukemia-chronic (CML-CP) patients and healthy controls were determined by RT-PCR and Western blot. In vivo, c-Myc expression, PP2A activity, cell proliferation, and apoptosis of CML cells were detected with CIP2A depletion. In addition, the relationship among CIP2A, BCR ABL, and tyrosine phosphatase SHP-1 was explored by depleting/overexpressing CIP2A or inhibiting BCR-ABL. The level of CIP2A mRNA was higher in CML-CP patients than healthy controls (56/74, 75.7 % vs. 1/35, 2.9 %, P < 0.001), and CIP2A protein was overexpressed in corresponding specimens. CIP2A knockdown by siRNA reduced the level of c-Myc protein and clonogenic formation, inhibited the activity of PP2A, K562 cell proliferation, and promoted cell apoptosis. Suppressing BCR-ABL by imatinib mesylate (IM) significantly decreased CIP2A expression. CIP2A knockdown decreased BCR-ABL but increased SHP-1 expression, and CIP2A overexpression had the reverse effect. CIP2A is overexpressed in CML-CP patients, and its expression may promote CML pathogenesis. CIP2A and BCR-ABL can regulate each other in a positive feedback loop. CIP2A may be a useful therapeutic target in CML-CP, particularly in patients with IM resistance. However, further studies are needed to validate the interaction between CIP2A and BCR-ABL using other tyrosine kinase inhibitors than IM. PMID- 25023054 TI - Comparison of the clinicopathological characteristics and the survival outcomes between the Siewert type II/III adenocarcinomas. AB - The aim of the study was to analyze the clinicopathological characteristics and survival outcomes in Siewert type II and Siewert type III tumors. The clinicopathological characteristics and survival outcomes were analyzed in patients diagnosed with Siewert II/III tumors, who underwent transabdominal gastrectomy from Jan 2006 to Dec 2010. A total of 321 patients diagnosed with Siewert II/III tumors who underwent gastrectomy were enrolled in this study. Siewert III tumors are larger and have a higher proportion of Borrmann 3-4 types than Siewert II tumors (p < 0.05). For Siewert II and the Siewert III tumors, the 3-year overall survival rate was 59.1 versus 57.1 %, respectively, and the median survival time was 46.0 (31.5-60.5) months versus 46.0 (31.3-60.7) months, respectively. Positive proximal resection margin, large tumor size, Borrmann 3-4 types, poor or undifferentiated degree and advanced T stages and N stages were found to be poor prognostic risk factors for the overall survival outcomes by univariate analysis. Multivariate analysis revealed that the differentiation degree (poor and undifferentiated) and advanced T and N stages were independent prognostic factors for poor overall survival. Siewert III tumors were larger and had a lower differentiation degree than Siewert II tumors, whereas there was no difference in the survival outcomes. PMID- 25023052 TI - Ubiquitination involved enzymes and cancer. AB - Ubiquitination is a post-translational modification process that regulates multiple cell functions. It also plays important roles in the development of cancer. Mechanistically, ubiquitination is a complex process that is comprised of a series of events involving ubiquitin-activating enzymes, ubiquitin-conjugating enzymes and ubiquitin ligases. In general, covalent attachment of ubiquitin to the target proteins marks them for degradation. Dysregulation of the ubiquitination process may cause carcinogenesis. In this review, we summarize recent developments in understanding the relationship between ubiquitination enzymes and carcinogenesis. PMID- 25023055 TI - Hepatitis B virus reactivation in hepatitis B surface antigen seropositive patients with metastatic non-small cell lung cancer receiving cytotoxic chemotherapy: the efficacy of preemptive lamivudine and identification of risk factors. AB - Little is known about the likelihood and degree of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) seropositive patients with disseminated non-small cell lung cancer (NSCLC) receiving chemotherapy. Between January 2003 and December 2013, all HBsAg seropositive patients with metastatic NSCLC receiving cytotoxic chemotherapy were retrospectively evaluated. The morbidity and mortality of HBV reactivation, risk factors associated with reactivation, as well as the efficacy of preemptive lamivudine were investigated. Of 258 patients who were eligible for the present study, 176 were treated without antiviral prophylaxis and 82 received preemptive lamivudine. Patients without lamivudine prophylaxis had a significantly higher prevalence of HBV reactivation (19.3 vs 6.1 %, p = 0.006) and severe hepatitis attributable to reactivation (11.8 vs 3.7 %, p = 0.034) than those with preemptive lamivudine. However, no significant difference in mortality due to reactivation was noted between patients with or without prophylactic lamivudine (0 vs 2.3 %, p = 0.310). Furthermore, patients who developed HBV reactivation were indentified to have a higher rate of HBeAg seropositivity (74.4 vs 43.4 %, p < 0.001), serum HBV-DNA level of 10(4) copies/ml or greater (76.9 vs 47.9 %, p = 0.001), coexisting liver metastasis (50.0 vs 40.6 %, p = 0.033) and treatment with more than 4 cycles of chemotherapy (56.4 vs 39.3 %, p = 0.046) than those who did not experienced reactivation. The current study has demonstrated that preemptive lamivudine significantly reduced the prevalence of HBV reactivation in HBsAg seropositive patients with metastatic NSCLC receiving systemic chemotherapy. PMID- 25023056 TI - Assessment of biochemical markers in the early post-burn period for predicting acute kidney injury and mortality in patients with major burn injury: comparison of serum creatinine, serum cystatin-C, plasma and urine neutrophil gelatinase associated lipocalin. AB - INTRODUCTION: The reported mortality rates range from 28% to 100% in burn patients who develop acute kidney injury (AKI) and from 50% to 100% among such patients treated with renal replacement therapy. Recently, the serum cystatin C and plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) levels have been introduced as early biomarkers for AKI; the levels of these biomarkers are known to increase 24 to 48 hours before the serum creatinine levels increase. In this study, we aimed to estimate the diagnostic utility of the cystatin C and plasma and urine NGAL levels in the early post-burn period as biomarkers for predicting AKI and mortality in patients with major burn injuries. METHODS: From May 2011 to July 2012, 90 consecutive patients with a burn wound area comprising >= 20% of the total body surface area (TBSA) were enrolled in this study. Whole blood and urine samples were obtained for measuring the serum creatinine, serum cystatin C, and urine and plasma NGAL levels at 0, 3, 6, 12, 24, and 48 hours after admission. Receiver operating characteristic curve, area under the curve, and multivariate logistic regression analyses were performed to assess the predictive values of these biomarkers for AKI and mortality. RESULTS: In the multivariate logistic regression analysis, all variables, including age, percentage TBSA burned, sex, inhalation injury, and serum creatinine levels, serum cystatin C levels, and plasma and urine NGAL levels were independently associated with AKI development. Moreover, age, sex, percentage TBSA burned, and plasma and urine NGAL levels were independently associated with mortality. However, inhalation injury and the serum creatinine and cystatin C levels were not independently associated with mortality. CONCLUSIONS: Massively burned patients who maintained high plasma and urine NGAL levels until 12 hours after admission were at the risk of developing early AKI and early mortality with burn shock. However, the plasma and urine NGAL levels in the early post-burn period failed to predict late AKI and non-burn shock mortality in this study. Nevertheless, the plasma and urine NGAL levels were independently associated with AKI development and mortality within 48 hours after admission. PMID- 25023057 TI - A systematic review of self-management health care models for individuals with serious mental illnesses. AB - OBJECTIVE: The general medical health of individuals with serious mental illnesses is compromised relative to those without serious mental illnesses. To address this health disparity, numerous integrated care strategies are being employed from the system level to the level of individual patients. However, self management of health care, a strategy considered an integral aspect of typical care, has been infrequently included in interventions for this population. Despite reservations about the capacity of those with serious mental illnesses to self-manage health care, a subset of new interventions focused on general medical health in this population has tested whether models including self-management strategies have empirical support. To understand whether these models are supported, the authors reviewed the evidence for self-management models. METHODS: This systematic review examined collaborative and integrated care models that include self-management components for individuals with serious mental illnesses. RESULTS: Across the 14 studies identified in this review, promising evidence was found that individuals with serious mental health issues can collaborate with health professionals or be trained to self-manage their health and health care. The evidence supports the use of mental health peers or professional staff to implement health care interventions. However, the substantial heterogeneity in study design, types of training, and examined outcomes limited conclusions about the comparative effectiveness of existing studies. CONCLUSIONS: This review found preliminary support that self-management interventions targeting the general medical health of those with serious mental illnesses are efficacious, but future work is needed to determine what elements of training or skills lead to the most salient changes. PMID- 25023058 TI - Diet and risk of amyotrophic lateral sclerosis: is lifestyle important? PMID- 25023059 TI - Enhancing multimodality functional and molecular imaging using glucose-coated gold nanoparticles. AB - AIM: To describe how pegylated glucose-coated gold nanoparticles (PEG-Glu-GNPs) can help improve computed tomography (CT) imaging. MATERIALS AND METHODS: PEG-Glu GNPs were designed for use as an imaging nanoprobe to act an effective contrast agent for both CT and PET scans. Twelve BALB/c mice were divided into two groups: mice with injected with PEG-Glu-GNPs and control mice. The mice were examined using high-resolution micro-CT at different time intervals (24 h, 7 days, and 15 days) after the injection of the particles. Greyscale density and CT attenuation values were determined to trace the excretion of the particles over time. RESULTS: Tumour contours were easily distinguished from surrounding tissue in mice injected with PEG-Glu-GNPs but not controls. This distinction was still visible at 7 days, but not at 15 days post-injection. CONCLUSION: Molecular imaging technology has enabled the development of a new generation of imaging probes. These sophisticated probes can visualize biological processes or enable early diagnosis of diseases in vivo. Compared to conventional CT images and PET scans, PEG-Glu-GNPs significantly improved image quality at the cellular and molecular level, which can significantly aid the early detection of cancer or cancer metastases. PMID- 25023060 TI - Analysis of genetic regulation and cytokine expressions of distraction osteogenesis reconstruction for cleft palate. AB - Because cleft palate (CP) is one of the most common congenital deformities, surgeons have tried for longtime to achieve an ideal reconstruction of the palatal bone defects and restoration of muscle attachments. In this study, a new CP model on rhesus was established and corrected by an approach of distraction osteogenesis (DO), and then quantitative studies of regulation of osteogenesis genes and expression of alkaline phosphatase (ALP), insulin-like growth factor-I (IGF-I), osteopontin (OPN), and osteocalcin (OC) in different phases of new bone formation were preformed. The CP models (23 animals) were established surgically. In the experimental group (21 animals), the tissue defects were repaired by means of DO at the rhythm of 0.4 mm twice per day. The specimens were retrieved in 1, 2, 4, 6, 8, 12, and 24 weeks (3 animals each) after completion of distraction. The IGF-I, ALP, OPN, and OC messenger RNA (mRNA) were detected by real-time reverse transcription polymerase chain reaction, and their proteins were then analyzed by enzyme-linked immunosorbent assay tests. The results are compared with those of the experimental control and empty control groups (2 animals each). In the distraction gap, the mRNA and protein expressions levels of IGF-I and ALP were both highly upregulated and reaching apex in the early phase of new bone formation. Otherwise, the mRNA and protein expressions of OPN and OC demonstrated high level during intermediate and later remodeling stages. These results suggest that the reconstruction of CP bone defect by means of DO could get definitely intramembraneous new bone formation and eventually quite normal bone structure via consecutive remodeling in situ. PMID- 25023061 TI - Nanomolar detection limits of Cd2+, Ag+, and K+ using paper-strip ion-selective electrodes. AB - Paper-based ion-selective electrodes (ISEs) are simple, flexible, and cost efficient in comparison to conventional solid-contact ISEs. Yet, paper-based ISEs have poor limits of detection (in the micromolar range) relative to conventional solid-contact ISEs. Here we describe the construction and optimization of ISEs based on commercially available filter paper modified with single-walled carbon nanotubes (SWCNTs), sputtered gold, and conductive polymer poly(3-octylthiophene) to support an ion-selective membrane. The ion-selective membrane presented here is based on the copolymer methyl methacrylate-decyl methacrylate (MMA-DMA). The copolymer MMA-DMA is highly water-repellent and has a low coefficient of diffusion, which makes it particularly suitable for the creation of sensors with high performance in reaching low limits of detection. Three different configurations of the electrodes have been characterized by using contact angle surface analysis, oxygen influence, and testing for the presence of a water layer. Paper-strip ISEs for cadmium, silver, and potassium ions were developed with groundbreaking limits of detection of 1.2, 25.1, and 11.0 nM, respectively. In addition to such low limits of detection, paper-strip ISEs display high selectivity for their ion of interest and high reproducibility. PMID- 25023062 TI - Cardiotoxicity following cyclophosphamidetherapy: a case report. AB - INTRODUCTION: Cardiac toxicity is one of the life-threatening complications of cancer therapy. Systemic anticancer treatments may exert their own toxic effects or can aggravate adverse effects of other drugs. We report a case of cyclophosphamide-induced cardiotoxicity in a patient with normal cardiac functions before chemotherapy. CASE PRESENTATION: A 66-year-old Caucasian woman with a mediastinal mass diagnosed with Burkitt lymphoma underwent chemotherapy with rituximab-hyperfractionated-cyclophosphamide-vincristine-doxorubicin dexamethasone. On the seventh day of chemotherapy, she developed dyspnea. An electrocardiogram demonstrated low voltage in the limb and precordial leads. It also showed diffusely increased myocardial echogenicity, mild pericardial and pleural effusion, generally impaired biventricular systolic functions with a left ventricular ejection fraction of 31%, and right ventricular mid-apical akinesia, even though she had normal biventricular functions before chemotherapy. Cyclophosphamide-induced cardiotoxicity was suspected and she was given treatment for congestive heart failure. Her dyspnea decreased and she was discharged on the tenth day with a left ventricular ejection fraction of 37% and normal right ventricular function. After 1 month, echocardiography showed normal biventricular functions with a left ventricular ejection fraction of 60%. CONCLUSIONS: Drug induced cardiotoxicity, therefore, should be taken into consideration when using cyclophosphamide therapy, especially when anthracyclines are co-administered. Close communication between hematologists and cardiologists is required. PMID- 25023063 TI - Regulation of RIG-I-like receptor signaling by host and viral proteins. AB - Vertebrate innate immunity is characterized by an effective immune surveillance apparatus, evolved to sense foreign structures, such as proteins or nucleic acids of invading microbes. RIG-I-like receptors (RLRs) are key sensors of viral RNA species in the host cell cytoplasm. Activation of RLRs in response to viral RNA triggers an antiviral defense program through the production of hundreds of antiviral effector proteins including cytokines, chemokines, and host restriction factors that directly interfere with distinct steps in the virus life cycle. To avoid premature or abnormal antiviral and proinflammatory responses, which could have harmful consequences for the host, the signaling activities of RLRs and their common adaptor molecule, MAVS, are delicately controlled by cell-intrinsic regulatory mechanisms. Furthermore, viruses have evolved multiple strategies to modulate RLR-MAVS signal transduction to escape from immune surveillance. Here, we summarize recent progress in our understanding of the regulation of RLR signaling through host factors and viral antagonistic proteins. PMID- 25023065 TI - What causes some patients with drug-induced QT interval prolongation to develop torsades de pointes but not others? The elusive missing link. PMID- 25023066 TI - Synthesis and preclinical evaluation of 68Ga-labeled collagelin analogs for imaging and quantification of fibrosis. AB - OBJECTIVES: Fibrosis affecting functionality of vital organs such as liver, lung, heart, and kidney, is involved in many chronic diseases. Positron emission tomography (PET) would not only provide precise localization and extent of the affected tissue but also allow the accurate quantification of the fibrotic process for the subsequent prognosis. METHODS: A cyclic peptide c[CPGRVMHGLHLGDDEGPC] conjugated either to 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl) 1,4,7-triazonan-1-yl)acetic acid (NOTA(tBu)2) or 4-(4,7-bis(2-(tert-butoxy)-2 oxoethyl)-1,4,7-triazacyclononan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (NODAGA(tBu)3) via polyethylene glycol link (PEG2) was synthesized and labeled with (68)Ga. Non-specific organ distribution, blood clearance, and excretion were investigated ex vivo in healthy rats. The binding specificity of the radioligands was assessed in vitro using autoradiography on cryosections of dog fibrotic heart tissue. RESULTS: The yield of NOTA-PEG2-c[CPGRVMHGLHLGDDEGPC] and NODAGA-PEG2 c[CPGRVMHGLHLGDDEGPC] was 56% and 41%, respectively. Non-decay-corrected radiochemical yield was 80 +/- 5% with radiochemical purity of 95 +/- 4%. Pharmacokinetic studies in healthy male Sprague-Dawley rats showed fast blood clearance and renal excretion. Lower uptake in liver, spleen, and kidney was found for [[(68)Ga]Ga-NOTA](+1)-PEG2-c[CPGRVMHGLHLGDDEGPC] as compared to [[(68)Ga]Ga-NODAGA](0)-PEG2-c[CPGRVMHGLHLGDDEGPC]. Histologic evaluation of the left ventricle (LV) myocardium from a dog with severe mitral regurgitation (MR), revealed mild to moderate perivascular and subendocardial, and mild diffuse interstitial fibrosis. The tracer binding to the cryosections of the tissue was specific with the equilibrium Kd of 2.3 +/- 0.8 MUM and 2.1 +/- 0.9 MUM, respectively for [(68)Ga]Ga-NO2A-Col and [(68)Ga]Ga-NODAGA-Col. CONCLUSIONS: Two novel peptide based agents for the imaging of fibrosis by PET were developed. Moderation of the biodistribution could be achieved by variation of the charge on the complex moiety of the agents. The combination of the fast clearance from non target organs as well as organs of interest such as lung, heart, and liver and binding specificity to the target tissue suggests the potential of the analogs for the imaging of fibrosis. PMID- 25023068 TI - The effects of mirror therapy on the gait of subacute stroke patients: a randomized controlled trial. AB - OBJECTIVE: To investigate the effect of mirror therapy on the gait of patients with subacute stroke. DESIGN: Randomized controlled experimental study. SETTING: Outpatient rehabilitation hospital. SUBJECTS: Thirty-four patients with stroke were randomly assigned to two groups: a mirror therapy group (experimental) and a control group. INTERVENTIONS: The stroke patients in the experimental group underwent comprehensive rehabilitation therapy and mirror therapy for the lower limbs. The stroke patients in the control group underwent sham therapy and comprehensive rehabilitation therapy. Participants in both groups received therapy five days per week for four weeks. MAIN MEASURES: Temporospatial gait characteristics, such as single stance, stance phase, step length, stride, swing phase, velocity, and cadence, were assessed before and after the four weeks therapy period. RESULTS: A significant difference was observed in post-training gains for the single stance (10.32 SD 4.14 vs. 6.54 SD 3.23), step length (8.47 SD 4.12 vs. 4.83 SD 2.14), and stride length (17.03 SD 6.57 vs 10.54 SD 4.34) between the experimental group and the control group (p < 0.05). However, there were no significant differences between two groups on stance phase, swing phase, velocity, cadence, and step width (P > 0.05). CONCLUSION: We conclude that mirror therapy may be beneficial in improving the effects of stroke on gait ability. PMID- 25023067 TI - Alveolar type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis. AB - BACKGROUND: Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. METHODS: Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. RESULTS: The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. CONCLUSION: One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of lung surfactant protein levels, which is required for proper respiratory function. PMID- 25023069 TI - Meta-analysis of differentially expressed genes in osteosarcoma based on gene expression data. AB - BACKGROUND: To uncover the genes involved in the development of osteosarcoma (OS), we performed a meta-analysis of OS microarray data to identify differentially expressed genes (DEGs) and biological functions associated with gene expression changes between OS and normal control (NC) tissues. METHODS: We used publicly available GEO datasets of OS to perform a meta-analysis. We performed Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Protein-Protein interaction (PPI) networks analysis. RESULTS: Eight GEO datasets, including 240 samples of OS and 35 samples of controls, were available for the meta-analysis. We identified 979 DEGs across the studies between OS and NC tissues (472 up-regulated and 507 down-regulated). We found GO terms for molecular functions significantly enriched in protein binding (GO: 0005515, P = 3.83E-60) and calcium ion binding (GO: 0005509, P = 3.79E-13), while for biological processes, the enriched GO terms were cell adhesion (GO:0007155, P = 2.26E-19) and negative regulation of apoptotic process (GO: 0043066, P = 3.24E-15), and for cellular component, the enriched GO terms were cytoplasm (GO: 0005737, P = 9.18E-63) and extracellular region (GO: 0005576, P = 2.28E-47). The most significant pathway in our KEGG analysis was Focal adhesion (P = 5.70E-15). Furthermore, ECM-receptor interaction (P = 1.27E-13) and Cell cycle (P = 4.53E-11) are found to be highly enriched. PPI network analysis indicated that the significant hub proteins containing PTBP2 (Degree = 33), RGS4 (Degree = 15) and FXYD6 (Degree = 13). CONCLUSIONS: Our meta-analysis detected DEGs and biological functions associated with gene expression changes between OS and NC tissues, guiding further identification and treatment for OS. PMID- 25023070 TI - Parasite load estimation by qPCR differentiates between asymptomatic and symptomatic infection in Indian visceral leishmaniasis. AB - Using quantitative PCR (qPCR), we differentiated asymptomatic and symptomatic Indian Leishmania donovani infection. qPCR on blood of 40 visceral leishmaniasis, 130 endemic, and 40 non-endemic healthy controls showed 500 times less (P < .0001) parasitemia in asymptomatic compared to the symptomatic ones and threshold of 5 parasite genome/mL for the clinical disease. PMID- 25023071 TI - Use of aspirin for primary and secondary cardiovascular disease prevention in the United States, 2011-2012. AB - BACKGROUND: Aspirin use has been shown to be an effective tool in cardiovascular disease (CVD) prevention among high-risk patients. The patient-reported physician recommendation for aspirin as preventive therapy among high- and low-risk patients is unknown. METHODS AND RESULTS: We conducted an analysis of the National Health and Nutrition Examination Survey 2011-2012 to examine the use of aspirin for CVD prevention. Patients without previously diagnosed CVD were classified into high and low risk based on their Framingham Risk Score (10-year coronary heart disease risk). Among patients without previously diagnosed CVD, 22.5% were classified as high risk. Of the high-risk individuals, 40.9% reported being told by their physician to take aspirin, with 79.0% complying. Among those who were at low risk, 26.0% were told by their physician to take aspirin, with 76.5% complying. Logistic regression analysis indicated that age, access to a regular source of care, education, and insurance status were significant predictors of patient-reported physician recommendations for aspirin use for primary prevention. Among high-risk patients, age, race, and insurance status were significant predictors of reported recommendations for aspirin use. Among low-risk patients, age, education, obesity, and insurance status were significant predictors of reported recommendations for aspirin use. CONCLUSIONS: Patient reports indicate nonideal rates of being told to take aspirin, for both high- and low-risk patients for primary prevention. Clinical decision support tools that could assist physicians in identifying patients at risk may increase patient reports of physician recommendations for aspirin use. PMID- 25023072 TI - Karyotypic diversification in Mytilus mussels (Bivalvia: Mytilidae) inferred from chromosomal mapping of rRNA and histone gene clusters. AB - BACKGROUND: Mussels of the genus Mytilus present morphologically similar karyotypes that are presumably conserved. The absence of chromosome painting probes in bivalves makes difficult verifying this hypothesis. In this context, we comparatively mapped ribosomal RNA and histone gene families on the chromosomes of Mytilus edulis, M. galloprovincialis, M. trossulus and M. californianus by fluorescent in situ hybridization (FISH). RESULTS: Major rRNA, core and linker histone gene clusters mapped to different chromosome pairs in the four taxa. In contrast, minor rRNA gene clusters showed a different behavior. In all Mytilus two of the 5S rDNA clusters mapped to the same chromosome pair and one of them showed overlapping signals with those corresponding to one of the histone H1 gene clusters. The overlapping signals on mitotic chromosomes became a pattern of alternate 5S rRNA and linker histone gene signals on extended chromatin fibers. Additionally, M. trossulus showed minor and major rDNA clusters on the same chromosome pair. CONCLUSION: The results obtained suggest that at least some of the chromosomes bearing these sequences are orthologous and that chromosomal mapping of rRNA and histone gene clusters could be a good tool to help deciphering some of the many unsolved questions in the systematic classification of Mytilidae. PMID- 25023074 TI - Extended-spectrum beta-lactamase-producing Escherichia coli infections in children: are community-acquired strains different from nosocomial strains? AB - Infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli are an important cause of morbidity and mortality, especially in children. We compared 58 epidemiologically unrelated ESBL-producing E. coli strains that caused infections. They were isolated between 2008 and 2012 in two Parisian pediatric hospitals and grouped according to their origin into either community-acquired (CA) (n=37) or nosocomially acquired (NA) (n=21) strains. Molecular characteristics of the ESBLs, phylogenetic traits of the strains including their belonging to clone O25b-ST131, prevalence of associated virulence genes, growth capacities in different media, metabolic phenotype and biofilm formation abilities were studied. ESBL type, associated resistance and distribution of phylogenetic groups were similar in the CA and NA groups. More than 60% of the B2 phylogroup strains in both groups belonged to the ST131 clone. Interestingly, CA strains possessed more genes encoding virulence factors and the distribution of these genes differed significantly between the two groups: fyuA, hlyC, papC and papGII were more frequent in the CA group, whereas iroN was more frequent in the NA group. CA strains also showed enhanced growth capacities in Luria Bertani rich medium. They tended to produce more biofilm but the difference was not significant. This study confirms the wide spread of clone ST131 among infected children, regardless of whether their infections were community- or nosocomially acquired. It highlights genotypic and phenotypic differences according to the origin of the strains that could indicate adaptability of these multi-resistant bacteria to specific environmental and host factors. PMID- 25023075 TI - Analysis of the Staphylococcus aureus capsule biosynthesis pathway in vitro: characterization of the UDP-GlcNAc C6 dehydratases CapD and CapE and identification of enzyme inhibitors. AB - Polysaccharide capsules significantly contribute to virulence of invasive pathogens, and inhibition of capsule biosynthesis may offer a valuable strategy for novel anti-infective treatment. We purified and characterized the enzymes CapD and CapE of the Staphylococcus aureus serotype 5 biosynthesis cluster, which catalyze the first steps in the synthesis of the soluble capsule precursors UDP-D FucNAc and UDP-L-FucNAc, respectively. CapD is an integral membrane protein and was obtained for the first time in a purified, active form. A capillary electrophoresis (CE)-based method applying micellar electrokinetic chromatography (MEKC) coupled with UV detection at 260 nm was developed for functional characterization of the enzymes using a fused-silica capillary, electrokinetic injection, and dynamic coating with polybrene at pH 12.4. The limits of detection for the CapD and CapE products UDP-2-acetamido-2,6-dideoxy-alpha-D-xylo-hex-4 ulose and UDP-2-acetamido-2,6-dideoxy-beta-L-arabino-hex-4-ulose, respectively, were below 1 MUM. Using this new, robust and sensitive method we performed kinetic studies for CapD and CapE and screened a compound library in search for enzyme inhibitors. Several active compounds were identified and characterized, including suramin (IC50 at CapE 1.82 MUM) and ampicillin (IC50 at CapD 40.1 MUM). Furthermore, the cell wall precursors UDP-D-MurNAc-pentapeptide and lipid II appear to function as inhibitors of CapD enzymatic activity, suggesting an integrated mechanism of regulation for cell envelope biosynthesis pathways in S. aureus. Corroborating the in vitro findings, staphylococcal cells grown in the presence of subinhibitory concentrations of ampicillin displayed drastically reduced CP production. Our studies contribute to a profound understanding of the capsule biosynthesis in pathogenic bacteria. This approach may lead to the identification of novel anti-virulence and antibiotic drugs. PMID- 25023076 TI - The role of ZmpC in the clinical manifestation of invasive pneumococcal disease. AB - INTRODUCTION: The clinical severity and course of invasive pneumococcal disease (IPD) differs substantially between patients. Streptococcus pneumoniae harbors large genetic variability. Zinc metalloproteinase C (ZmpC), a secreted pneumococcal protein involved in neutrophil extravasation, inflammation and tissue remodeling, is present in a minority of IPD isolates. We investigated whether the presence of zmpC was associated with the clinical manifestation of IPD. MATERIAL AND METHODS: IPD patients admitted to two Dutch hospitals between 2000 and 2013 were included in the study. Detailed clinical data were collected and the serotype and presence of zmpC were determined in the corresponding blood culture isolates. RESULTS: ZmpC was present in 21% of the 542 included IPD cases and was mainly associated with serotypes 8, 4, 33A/F and 11A/D. Infection with S. pneumoniae positive for zmpC was more frequently observed in females (p=0.048) and patients with a history of smoking (p=0.033). Although no relation to clinical syndrome was observed, zmpC positive cases more often presented with cough, dyspnea and sepsis (p-values 0.026, 0.001 and 0.018), and more frequently required ICU admission (p=0.011) compared to zmpC negative cases. CONCLUSION: The presence of zmpC was associated with a more severe clinical manifestation of IPD. This study demonstrates that information on pneumococcal genetic background may be useful to identify vulnerable individuals, to monitor clinical presentation and to predict the course of IPD. PMID- 25023077 TI - Phloem sugar flux and jasmonic acid-responsive cell wall invertase control extrafloral nectar secretion in Ricinus communis. AB - Plants secrete extrafloral nectar (EFN) that attracts predators. The efficiency of the resulting anti-herbivore defense depends on the quantity and spatial distribution of EFN. Thus, according to the optimal defense hypothesis (ODH), plants should secrete EFN on the most valuable organs and when herbivore pressure is high. Ricinus communis plants secreted most EFN on the youngest (i.e., most valuable) leaves and after the simulation of herbivory via the application of jasmonic acid (JA). Here, we investigated the physiological mechanisms that might produce these seemingly adaptive spatiotemporal patterns. Cell wall invertase (CWIN; EC 3.2.1.26) was most active in the hours before peak EFN secretion, its decrease preceded the decrease in EFN secretion, and CWIN activity was inducible by JA. Thus, CWIN appears to be a central player in EFN secretion: its activation by JA is likely to cause the induction of EFN secretion after herbivory. Shading individual leaves decreased EFN secretion locally on these leaves with no effect on CWIN activity in the nectaries, which is likely to be because it decreased the content of sucrose, the substrate of CWIN, in the phloem. Our results demonstrate how the interplay of two physiological processes can cause ecologically relevant spatiotemporal patterns in a plant defense trait. PMID- 25023078 TI - Phytohormone profiles induced by trichoderma isolates correspond with their biocontrol and plant growth-promoting activity on melon plants. AB - The application of Trichoderma strains with biocontrol and plant growth-promoting capacities to plant substrates can help reduce the input of chemical pesticides and fertilizers in agriculture. Some Trichoderma isolates can directly affect plant pathogens, but they also are known to influence the phytohormonal network of their host plant, thus leading to an improvement of plant growth and stress tolerance. In this study, we tested whether alterations in the phytohormone signature induced by different Trichoderma isolates correspond with their ability for biocontrol and growth promotion. Four Trichoderma isolates were collected from agricultural soils and were identified as the species Trichoderma harzianum (two isolates), Trichoderma ghanense, and Trichoderma hamatum. Their antagonistic activity against the plant pathogen Fusarium oxysporum f. sp. melonis was tested in vitro, and their plant growth-promoting and biocontrol activity against Fusarium wilt on melon plants was examined in vivo, and compared to that of the commercial strain T. harzianum T-22. Several growth- and defense-related phytohormones were analyzed in the shoots of plants that were root-colonized by the different Trichoderma isolates. An increase in auxin and a decrease in cytokinins and abscisic acid content were induced by the isolates that promoted the plant growth. Principal component analysis (PCA) was used to evaluate the relationship between the plant phenotypic and hormonal variables. PCA pointed to a strong association of auxin induction with plant growth stimulation by Trichoderma. Furthermore, the disease-protectant ability of the Trichoderma strains against F. oxysporum infection seems to be more related to their induced alterations in the content of the hormones abscisic acid, ethylene, and the cytokinin trans-zeatin riboside than to the in vitro antagonism activity against F. oxysporum. PMID- 25023079 TI - Chelation therapy after the trial to assess chelation therapy: results of a unique trial. AB - PURPOSE OF REVIEW: EDTA chelation therapy has been in off-label use for the treatment of atherosclerosis. We review the results of the first large-scale randomized trial of this treatment. RECENT FINDINGS: The trial to assess chelation therapy was a $30 million National Institutes of Health-funded study of the safety and efficacy of EDTA-based chelation infusions in 1708 post-myocardial infarction (MI) patients. The trial to assess chelation therapy demonstrated a significant (P=0.035) 18% reduction in a combined primary endpoint of death, MI, stroke, coronary revascularization, or hospitalization for angina. In diabetic patients the benefit was more extreme, with a 41% relative reduction in risk (P=0.0002) and a 43% reduction in total mortality (P=0.011). Safety data were favorable. A reduction of oxidative stress by chelation of toxic metals has been proposed as a possible mechanism of action. SUMMARY: Recent research suggests that EDTA chelation may be a well-tolerated and effective treatment for post-MI patients. Future replication and mechanistic studies are important prior to implementation in all post-MI patients. PMID- 25023080 TI - The ethics and editorial challenges of internet-based research. AB - The internet has opened up vast possibilities for research. An increasing number of studies are being conducted using the internet as both a source of data and a venue for research. Use of the internet in research has created many challenges, not just for those conducting and reviewing the studies, but also for editors publishing this work. Two key issues raised by internet-based research are ethics approval and informed consent. While some guidance exists regarding the ethics and consent of internet-based research, and some institutions provide their own guidelines, there appears to be a lack of definitive national standards. We discuss the issues surrounding ethics and consent for internet-based research and the need for a consensus on how to address these issues to ensure consistency. PMID- 25023081 TI - Health effects in populations living around the uraniferous gold mine tailings in South Africa: gaps and opportunities for research. PMID- 25023082 TI - Breast-conserving surgery is contraindicated for recurrent giant multifocal phyllodes tumours of breast. AB - BACKGROUND: The controversy between breast conserving surgery and simple mastectomy for phyllodes tumours of the breast remains because of the unpredictable nature of the disease. Although some benign tumours may show an unusually aggressive behaviour, modified radical surgery for phyllodes tumours offers no survival advantage, and recently more conservative surgical approaches have been deployed. CASE PRESENTATION: A 30-year-old woman with a giant multifocal tumour of the breast underwent breast-conserving surgery that made use of the well- circumscribed feature of the tumour. The case demonstrates the safety, and cosmetic benefit of the breast-conserving approach for multifocal phyllodes tumours except for the high recurrence rate. CONCLUSIONS: Large size, multifocality, and borderline or malignant histology are contraindications for breast-conserving surgery. PMID- 25023083 TI - Depressive symptoms and cognitive performance in older adults. AB - Many longitudinal studies have found that older adults with depressive symptoms or depression have increased risk of cognitive impairment. We investigated the relationships between depressive symptoms or depression, cognitive function, serum brain-derived neurotrophic factor (BDNF), and volumetric MRI measurements in older adults. A total of 4352 individuals aged 65 years or older (mean age 72 years) participated in the study. We investigated medical history and geriatric depression scale-15 (GDS-15) items to determine depression and depressive symptoms. Cognitive tests included the mini-mental state examination (MMSE), story memory, word list memory, trail-making tests, and the symbol digit substitution task. Of the 4352 participants, 570 (13%) fulfilled the criteria for depressive symptoms (GDS-15: 6 + points) and 87 (2%) were diagnosed with depression. All cognitive tests showed significant differences between the 'no depressive symptoms', 'depressive symptoms', and 'depression' groups. The 'depressive symptoms' and 'depression' groups showed lower serum BDNF (p < 0.001) concentrations than the 'no depressive symptoms' group. The 'depressive symptoms' group exhibited greater atrophy of the right medial temporal lobe than did the 'no depressive symptoms' group (p = 0.023). These results suggest that memory, executive function, and processing speed examinations are useful to identify cognitive decline in older adults who have depressive symptoms and depression. Serum BDNF concentration and atrophy of the right medial temporal lobe may in part mediate the relationships between depressive symptoms and cognitive decline. PMID- 25023084 TI - Prevalence of sickle cell disease in a pediatric population suffering from severe infections: a Congolese experience. AB - Neonatal screening for sickle cell anemia is not a common practice in the Democratic Republic of Congo (DRC). Children with sickle cell disease are known to have an increased risk of infections. We conducted a pilot study to determine the prevalence of sickle cell anemia during episodes of severe infection. A prospective study was conducted from July 2009 to July 2011. The study sites included four public hospitals at Kinshasa, DRC. The study population was selected from the source population using three-stage sampling. A total of 247 children with severe infection were consecutively recruited and screened for sickle cell disease. There were 124 boys (50.2%) and 123 girls (49.8%) with a sex ratio of 1:1. More than two-thirds of patients (66.0%) were children between 1 and 24 months of age. Among these 247 children, 19 (7.7%) were homozygous sickle cell anemia patients (Hb SS). No patient had received Hemophilus influenzae, streptococcus pneumoniae and salmonella sp vaccines. Sepsis was the most common form of severe infection observed in 44.5% of patients. A total of 19 (7.7%) positive blood cultures were recorded. Most cases were reported in sickle cell patients (15.8%) compared to 6.1% in children who were negative for Hb S [beta6(A3)Glu->Val; HBB: c.20A>T] (p > 0.05). Of 247 children with severe infection, approximately 8.0% carried unknown sickle cell anemia mutations. Based on the findings in this study, opportunistic testing for sickle cell anemia is possible and worthwhile in children who present with severe infection in DRC until neonatal screening is universal. PMID- 25023085 TI - Prevalence of the beta(S) gene among scheduled castes, scheduled tribes and other backward class groups in Central India. AB - Sickle cell disease is an inherited disorder of the blood, and characterized by vasoocclusive crises (VOC), risks for pneumococcal infections and organ toxicities, is associated with morbidity and premature mortality. India, with a population of 1.2 billion individuals, is estimated to be home to over 50.0% of the world's patients with sickle cell disease. The beta(S) gene [beta6(A3)Glu >Val; HBB: c.20A>T] has the highest prevalence in three socio-economically disadvantaged ethnic categories: the Scheduled Castes (SC), the Scheduled Tribes (ST), and Other Backward Class (OBC) groups in India. The tradition of endogamy practiced by the ethnic groups in India provides the rationale for the screening of individual populations to better understand the distribution of the beta(S) gene, guide counseling and awareness programs and aid development of public policy. We undertook a study to describe the prevalence of the beta(S) gene in these ethnic groups in the district of Nagpur, Maharashtra in Central India. Through community screening and subsequent targeted screening of high risk individuals, 35,636 individuals were screened, of whom 5466 were found to have sickle cell trait and 1010 were identified with sickle cell disease. Community screening revealed a sickle cell trait prevalence of 13.0% in the SC, 12.0% in the ST and 3.4% in the OBC population. This study describes the prevalence of the beta(S) gene within these groups in Central India determined by large scale community screening. This program has uncovered previously undiagnosed cases, provided detailed information to guide population-based disease counseling, prevention and comprehensive care programs. PMID- 25023086 TI - Interaction of iron deficiency anemia and hemoglobinopathies among college students and pregnant women: a multi center evaluation in India. AB - Although iron deficiency anemia is very common in India, systematic large studies on the prevalence and hematological consequences of iron deficiency among carriers of beta-thalassemia (beta-thal) and other hemoglobinopathies are lacking. A multi center project was undertaken to screen college/university students and pregnant women for iron deficiency anemia and various hemoglobinopathies. Fifty-six thousand, seven hundred and seventy-two subjects from six states, Maharashtra, Gujarat, Karnataka, West Bengal, Assam and Punjab, were studied. Iron deficiency anemia was evaluated by measuring zinc protoporphyrin (ZPP) and hemoglobin (Hb) levels, while beta-thal and other hemoglobinopathies were detected by measuring the red cell indices and by Hb analysis using high performance liquid chromatography (HPLC). College boys (2.2%), college girls (14.3%) and antenatal women (27.0%) without any hemoglobinopathies had iron deficiency anemia. Among the beta-thal carriers, the prevalence of iron deficiency anemia was 17.3% in college boys, 38.1% in college girls and 55.9% in pregnant women, while in the Hb E [beta26(B8)Glu->Lys; HBB: c.79G>A] carriers, it was 7.3% in college boys, 25.4% in college girls and 78.0% in antenatal women. In individuals with Hb E disease, the prevalence of iron deficiency anemia varied from 31.2-77.3% in the three groups. A significant reduction in Hb levels was seen when iron deficiency anemia was associated with hemoglobinopathies. However, the Hb A2 levels in beta-thal carriers were not greatly reduced in the presence of iron deficiency anemia. PMID- 25023087 TI - The effect and side effect of hydroxyurea therapy on patients with beta thalassemia: a systematic review to December 2012. AB - Hydroxyurea (HU) is being used for patients with transfusion-dependent beta thalassemia major (beta-TM) as well as non transfusion-dependent beta-TM. As controversy exists regarding efficacy and safety of HU, we searched the published literature on efficacy, effectiveness and toxicity of HU in patients with beta TM. The research sources we used were: Medline, SID, PubMed, Scopus, Request, Web of Knowledge, Springer, Ovid, Cochrane searched up to October 2012. Using search terms sensitive to studies of clinical trials combined with searches on terms related to thalassemia and HU. We selected studies on randomized trials, quasi experimental trials (before and after design), case reports (with 1-5 cases), side effect studies in patients with beta-TM, studies related to the mechanism of action and toxicity when used in patients with other hemoglobinopathies. We researched studies in English and Persian. Eligible articles were reviewed by two independent reviewers. Patient's characteristics, duration of trial, outcome and side effects were extracted. The main outcomes were synthesized under a random effects model. Heterogeneity was assessed using the Q statistic, Tau(2) and I(2). Subgroup analyses were performed and the statistics data (STATA) software used. More than 500 articles were reviewed. No randomized clinical trial was found. Seventeen trials with before and after designs were found, 16 case reports (1-5 cases), 19 articles for mechanism of action and 16 studies for side effects were published from 1969 to October 2012. Hemoglobin levels after treatment showed modest but significant increase in non transfusion-dependent beta-TM (p < 0.0001) and in transfusion-dependent beta-TM (p < 0.0001). PMID- 25023089 TI - The comprehensive transcriptional analysis in Caenorhabditis elegans by integrating ChIP-seq and gene expression data. AB - The fundamental step of learning transcriptional regulation mechanism is to identify the target genes regulated by transcription factors (TFs). Despite numerous target genes identified by chromatin immunoprecipitation followed by high-throughput sequencing technology (ChIP-seq) assays, it is not possible to infer function from binding alone in vivo. This is equally true in one of the best model systems, the nematode Caenorhabditis elegans (C. elegans), where regulation often occurs through diverse TF binding features of transcriptional networks identified in modENCODE. Here, we integrated ten ChIP-seq datasets with genome-wide expression data derived from tiling arrays, involved in six TFs (HLH 1, ELT-3, PQM-1, SKN-1, CEH-14 and LIN-11) with tissue-specific and four TFs (CEH 30, LIN-13, LIN-15B and MEP-1) with broad expression patterns. In common, TF bindings within 3 kb upstream of or within its target gene for these ten studies showed significantly elevated level of expression as opposed to that of non target controls, indicated that these sites may be more likely to be functional through up-regulating its target genes. Intriguingly, expression of the target genes out of 5 kb upstream of their transcription start site also showed high levels, which was consistent with the results of following network component analysis. Our study has identified similar transcriptional regulation mechanisms of tissue-specific or broad expression TFs in C. elegans using ChIP-seq and gene expression data. It may also provide a novel insight into the mechanism of transcriptional regulation not only for simple organisms but also for more complex species. PMID- 25023088 TI - Messenger RNA expression and immunolocalization of psoriasin in the goat mammary gland and its milk concentration after an intramammary infusion of lipopolysaccharide. AB - Psoriasin (S100A7) is a member of the S100 protein family of calcium-binding proteins and plays a crucial role in local host defenses. The present study aimed to identify the expression of S100A7 in the goat mammary gland and in milk. The goat S100A7 coding DNA sequence was identified using direct sequencing. An S100A7 antibody was raised in rabbits by immunization with a synthetic S100A7 peptide consisting of 13 amino acids. Messenger RNA expression and protein localization in different regions of a healthy mammary gland were detected by reverse transcription-polymerase chain reaction and immunohistochemistry. Changes in the concentration of S100A7 in the milk after an intramammary infusion of Escherichia coli lipopolysaccharide (LPS) were examined by an enzyme immunoassay. The goat S100A7 peptide had 98% and 86% sequence similarity to that of sheep and bovines, respectively. The S100A7 mRNA expression was higher in the teat and udder skin than in the cistern and parenchyma of the mammary gland. Immunoreactive S100A7 was localized in the epithelial cells of the alveolus and gland cistern, and stratified squamous epithelium of the teat. Psoriasin as a secreted protein was detectable in healthy milk, and an intramammary LPS infusion increased the concentration of S100A7 in the milk. The results suggest that S100A7 is produced in the epithelial cells of the mammary gland and is secreted into the milk. PMID- 25023090 TI - Synergistic delivery of gold nanorods using multifunctional microbubbles for enhanced plasmonic photothermal therapy. AB - Plasmonic photothermal therapy (PPTT) using plasmonic nanoparticles as efficient photoabsorbing agents has been proposed previously. One critical step in PPTT is to effectively deliver gold nanoparticles into the cells. This study demonstrates that the delivery of gold nanorods (AuNRs) can be greatly enhanced by combining the following three mechanisms: AuNRs encapsulated in protein-shell microbubbles (AuMBs), molecular targeting, and sonoporation employing acoustic cavitation of microbubbles (MBs). Both in vitro and in vivo tests were performed. For molecular targeting, the AuMBs were modified with anti-VEGFR2. Once bound to the angiogenesis markers, the MBs were destroyed by ultrasound to release the AuNRs and the release was confirmed by photoacoustic measurements. Additionally, acoustic cavitation was induced during MB destruction for sonoporation (i.e., increase in transient cellular permeability). The measured inertial cavitation dose was positively correlated with the temperature increase at the tumor site. The quantity of AuNRs delivered into the cells was also determined by measuring the mass spectrometry and observed using third-harmonic-generation microscopy and two-photon fluorescence microscopy. A temperature increase of 20 degrees C was achieved in vitro. The PPTT results in vivo also demonstrated that the temperature increase (>45 degrees C) provided a sufficiently high degree of hyperthermia. Therefore, synergistic delivery of AuNRs was demonstrated. PMID- 25023091 TI - Fruit and vegetable consumption in a sample of 11-year-old children in ten European countries--the PRO GREENS cross-sectional survey. AB - OBJECTIVE: To describe fruit and vegetable intake of 11-year-old children in ten European countries and compare it with current dietary guidelines. DESIGN: Cross sectional survey. Intake was assessed using a previously validated questionnaire containing a pre-coded 24 h recall and an FFQ which were completed in the classroom. Portion sizes were calculated using a standardized protocol. SETTING: Surveys were performed in schools regionally selected in eight countries and nationally representative in two countries. SUBJECTS: A total of 8158 children from 236 schools across Europe participating in the PRO GREENS project. RESULTS: The total mean consumption of fruit and vegetables was between 220 and 345 g/d in the ten participating countries. Mean intakes did not reach the WHO population goal of >=400 g/d in any of the participating countries. Girls had a significantly higher intake of total fruit and vegetables than boys in five of the countries (Sweden, Finland, Iceland, Bulgaria and Slovenia). Mean total fruit intake ranged between 114 and 240 g/d and vegetable intake between 73 and 141 g/d. When using the level >=400 g/d as a cut-off, only 23.5 % (13.8-37.0 %) of the studied children, depending on country and gender, met the WHO recommendation (fruit juice excluded). CONCLUSIONS: Fruit and vegetable consumption was below recommended levels among the schoolchildren in all countries and vegetable intake was lower than fruit intake. The survey shows that there is a need for promotional activities to improve fruit and vegetable consumption in this age group. PMID- 25023092 TI - Familial cases of Norrie disease detected by copy number analysis. AB - PURPOSE: Norrie disease (ND, MIM#310600) is an X-linked disorder characterized by severe vitreoretinal dysplasia at birth. We report the results of causative NDP gene analysis in three male siblings with Norrie disease and describe the associated phenotypes. METHODS: Three brothers with suspected Norrie disease and their mother presented for clinical examination. After obtaining informed consent, DNA was extracted from the peripheral blood of the proband, one of his brothers and his unaffected mother. Exons 1-3 of the NDP gene were amplified by polymerase chain reaction (PCR), and direct sequencing was performed. Multiplex ligation-dependent probe amplification (MLPA) was also performed to search for copy number variants in the NDP gene. RESULTS: The clinical findings of the three brothers included no light perception, corneal opacity, shallow anterior chamber, leukocoria, total retinal detachment and mental retardation. Exon 2 of the NDP gene was not amplified in the proband and one brother, even when the PCR primers for exon 2 were changed, whereas the other two exons showed no mutations by direct sequencing. MLPA analysis showed deletion of exon 2 of the NDP gene in the proband and one brother, while there was only one copy of exon 2 in the mother. CONCLUSION: Norrie disease was diagnosed in three patients from a Japanese family by clinical examination and was confirmed by genetic analysis. To localize the defect, confirmation of copy number variation by the MLPA method was useful in the present study. PMID- 25023093 TI - Parental monitoring affects the relationship between depressed mood and alcohol related problems in adolescents. AB - BACKGROUND: Parental monitoring has been identified as a protective factor for adolescent drinking, whereas depressed mood, peer substance use, and peer tolerance of substance use have been identified as risk factors. The purpose of this study was to test the association between depressed mood and alcohol-related problems in adolescents, and to test whether parental monitoring and peer substance use/tolerance of use moderate the strength of this relationship. METHODS: Participants included 227 adolescents (Mage = 15.36; 51.5% female) recruited from a hospital emergency department and surrounding community who completed self-report assessments. RESULTS: Hierarchical linear regression analysis demonstrated that depressed mood was associated with more alcohol related problems. A significant interaction between depressed mood and parental monitoring indicated a moderating effect, with high levels of depressed mood being associated with alcohol-related problems when parental monitoring was low; at low levels of depressed mood, parental monitoring was not related to alcohol related problems. CONCLUSIONS: This study highlights the protective role that parental monitoring may play in the association between depressed mood and alcohol-related problems and suggests that parenting practices, in addition to individual counseling, should be addressed in treatment of depressed adolescents who drink. PMID- 25023094 TI - Efficacy of therapeutic ultrasound in pain and joint mobility in whiplash traumatic acute and subacute phases. AB - To determine if ultrasound (US) is effective in reducing pain and mobility limitation in the treatment of traumatic cervical sprain, we performed an experimental study. The sample comprised 54 diagnosed subjects with a mean age of 36.54 y (standard deviation = 12.245), assigned by simple random selection to an experimental group with ultrasound treatment and a control group with placebo ultrasound. Treatment consisted of 10 sessions of an ultrasound treatment protocol, followed by 15 sessions of a protocol identical for both groups without ultrasound. The variables assessed were pain and joint mobility. There was no significant difference (p > 0.05) between groups in the first 10 sessions of treatment. However, there was a statistically significant difference (p < 0.05) between groups on the pain variable, 20 days after completion of the US. High active ultrasound treatment is more effective than placebo in reducing pain. PMID- 25023096 TI - Influence of repetitive contrast agent injections on functional and molecular ultrasound measurements. AB - Quantitative contrast-enhanced ultrasound plays an important role in tumor characterization and treatment assessment. Besides established functional ultrasound techniques, ultrasound molecular imaging using microbubbles targeted to disease-associated markers is increasingly being applied in pre-clinical studies. Often, repeated injections of non-targeted or targeted microbubbles during the same imaging session are administered. However, the influence of repeated injections on the accuracy of the quantitative data is unclear. Therefore, in tumor-bearing mice, we investigated the influence of multiple injections of non-targeted microbubbles (SonoVue) on time to peak and peak enhancement in liver and tumor tissue and of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agents (MicroMarker) on specific tumor accumulation. We found significantly decreasing values for time to peak and a tendency for increased values for peak enhancement after multiple injections. Repeated injections of VEGFR2-targeted microbubbles led to significantly increased tumor accumulation, which may result from the exposure of additional binding sites at endothelial surfaces caused by mechanical forces from destroyed microbubbles. PMID- 25023095 TI - High-intensity focused ultrasound sonothrombolysis: the use of perfluorocarbon droplets to achieve clot lysis at reduced acoustic power. AB - The purpose of this study was to evaluate use of intravascular perfluorocarbon droplets to reduce the sonication power required to achieve clot lysis with high intensity focused ultrasound. High-intensity focused ultrasound with droplets was initially applied to blood clots in an in vitro flow apparatus, and inertial cavitation thresholds were determined. An embolic model for ischemic stroke was used to illustrate the feasibility of this technique in vivo. Recanalization with intravascular droplets was achieved in vivo at 24 +/- 5% of the sonication power without droplets. Recanalization occurred in 71% of rabbits that received 1-ms pulsed sonications during continuous intravascular droplet infusion (p = 0.041 vs controls). Preliminary experiments indicated that damage was confined to the ultrasonic focus, suggesting that tolerable treatments would be possible with a more tightly focused hemispheric array that allows the whole focus to be placed inside of the main arteries in the human brain. PMID- 25023097 TI - Comparing efficiency of micro-RNA and mRNA biomarker liberation with microbubble enhanced ultrasound exposure. AB - Blood biomarkers are potentially powerful diagnostic tools that are limited clinically by low concentrations, the inability to determine biomarker origin and unknown patient baseline. Recently, ultrasound has been shown to liberate proteins and large mRNA biomarkers, overcoming many of these limitations. We have since demonstrated that adding lipid-stabilized microbubbles elevates mRNA concentration an order of magnitude compared with ultrasound without microbubbles, in vitro. Unfortunately the large size of some mRNA molecules may limit efficiency of release and hinder efficacy as an ultrasound-liberated biomarker. We hypothesize that smaller molecules will be released more efficiently with ultrasound than larger molecules. Although investigation of large libraries of biomarkers should be performed to fully validate this hypothesis, we focus on a small subset of mRNA and micro-RNAs. Specifically, we focus on miR-21 (22 base pairs [bp]), which is upregulated in certain forms of cancer, compared with previously investigated mammaglobin mRNA (502 bp). We also report release of micro-RNA miR-155 (22 bp) and housekeeping rRNA S18 (1869 bp). More than 10 million additional miR-21 copies per 100,000 cells are released with ultrasound-microbubble exposure. The low- molecular-weight miR-21 proved to be liberated 50 times more efficiently than high-molecular-weight mammaglobin mRNA, releasing orders of magnitude more miR-21 than mammaglobin mRNA under comparable conditions. PMID- 25023098 TI - Comparison of two contrast agents for right-to-left shunt diagnosis with contrast enhanced transcranial Doppler. AB - We compared two contrast agents, agitated saline and agitated saline with blood, with respect to their efficacy in the diagnosis of right-to-left shunt with contrast-enhanced transcranial Doppler. Three hundred thirty Chinese patients underwent examinations with one of four different methods in random order: (i) 9 mL agitated saline solution with 1 mL air without the Valsalva maneuver (ASwoVM); (ii) 9 mL agitated saline solution with 1 mL air with the Valsalva maneuver (ASwVM); (iii) 9 mL agitated saline solution, 1 mL air and a drop of the patient's blood without the Valsalva maneuver (ASbwoVM); and (iv) 9 mL agitated saline solution, 1 mL air and a drop of the patient's blood, with the Valsalva maneuver (ASbwVM). Rates of detection were 11.5%, 17.9%, 16.7% and 23.6% for the ASwoVM, ASwVM, ASbwoVM, and ASbwVM examinations, respectively. The embolus track numbers for these examinations were 4.0 +/- 1.83, 11.5 +/- 6.2, 10.5 +/- 4.9 and 33.7 +/- 14.9, respectively. There were significant differences between the four groups (all comparisons, p < 0.001). For contrast-enhanced transcranial Doppler examinations, the agitated saline/blood agent yielded better rates of diagnosis of right to-left shunt than did the agitated saline alone. PMID- 25023099 TI - Elastography can effectively decrease the number of fine-needle aspiration biopsies in patients with calcified thyroid nodules. AB - When calcification, frequently found in both benign and malignant nodules, is present in thyroid nodules, non-invasive differentiation with ultrasound becomes challenging. The goal of this study was to evaluate the utility of elastography in differentiating calcified thyroid nodules. Consecutive patients (165 patients with 196 nodules) referred for fine-needle aspiration who had undergone both ultrasound elastography and B-mode examinations were analyzed retrospectively. Calcification was present in 45 benign and 20 malignant nodules. On 65 calcified nodules, elastography had 95% sensitivity, 51.1% specificity, 46.3% positive predictive value and 95.8% negative predictive value in detecting malignancy. Twenty-three of 45 benign calcified nodules were correctly diagnosed with elastography compared with 4 of 45 by B-mode ultrasound. Although it is difficult to differentiate benign and malignant calcified thyroid nodules solely with B mode ultrasound, elastography has the potential to reduce the number of fine needle aspiration biopsies performed on calcified nodules. PMID- 25023100 TI - Feasibility of ultrasound imaging of osteochondral defects in the ankle: a clinical pilot study. AB - Talar osteochondral defects (OCDs) are imaged using magnetic resonance imaging (MRI) or computed tomography (CT). For extensive follow-up, ultrasound might be a fast, non-invasive alternative that images both bone and cartilage. In this study the potential of ultrasound, as compared with CT, in the imaging and grading of OCDs is explored. On the basis of prior CT scans, nine ankles of patients without OCDs and nine ankles of patients with anterocentral OCDs were selected and classified using the Loomer CT classification. A blinded expert skeletal radiologist imaged all ankles with ultrasound and recorded the presence of OCDs. Similarly to CT, ultrasound revealed typical morphologic OCD features, for example, cortex irregularities and loose fragments. Cartilage disruptions, Loomer grades IV (displaced fragment) and V (cyst with fibrous roof), were visible as well. This study encourages further research on the use of ultrasound as a follow up imaging modality for OCDs located anteriorly or centrally on the talar dome. PMID- 25023101 TI - Dynamic contrast-enhanced ultrasound of slaughterhouse porcine livers in machine perfusion. AB - The aim of this study was to enable investigations into novel imaging and surgical techniques by developing a readily accessible, versatile liver machine perfusion system. Slaughterhouse pig livers were used, and dynamic contrast enhanced ultrasound was introduced to optimize the procurement process and provide real-time perfusion monitoring. The system comprised a single pump, oxygenator, bubble trap and two flowmeters for pressure-controlled perfusion of the vessels using an off-the-shelf perfusate at room temperature. Successful livers exhibited homogeneous perfusion in both the portal vein and hepatic artery with dynamic contrast-enhanced ultrasound, which correlated with stable oxygen uptake, bile production and hepatic resistance and normal histology at the end of 3 h of perfusion. Dynamic contrast-enhanced ultrasound revealed perfusion abnormalities invisible to the naked eye, thereby providing context to the otherwise systemic biochemical/hemodynamic measurements and focal biopsy findings. The model developed here is a simple, cost-effective approach for stable ex vivo whole-organ machine perfusion. PMID- 25023102 TI - Age-related ultrasonic properties of breast tissue in vivo. AB - The aim of the current work was to quantify the ultrasonic properties of the whole breast in vivo as a function of age. Forty-four women were scanned using a computerized ultrasonic scanner developed in our laboratory. Raster scans in two orthogonal views, mediolateral and craniocaudal, were obtained using the ultrasonic through-transmission method. By combining the information from the two views, we estimated two acoustic properties: speed of sound and attenuation coefficient. On the basis of the results, both the attenuation coefficient and the speed of sound follow a three-phase age-related pattern. During the first phase, which corresponds to ages 20 to 35 y, both properties decrease with time and then remain roughly unchanged until about 55 y. During the third phase corresponding to ages >55 y, values decrease again with time. The mean speed of sound decreases from 1504 +/- 35 m/s at <30 y to 1452 +/- 9 m/s at >60 y (p < 0.01), and the attenuation coefficient decreases from 1.27 +/- 0.32 to 0.96 +/- 0.13 dB/cm/MHz (p < 0.03), respectively. In conclusion, both the ultrasonic speed of sound and the attenuation coefficient of breast tissue are age related. Both parameters decrease during life, markedly during the first and third phases. These changes may be attributed to anatomic and physiologic changes associated with reproductivity and menopause. PMID- 25023103 TI - Correlation of quantitative texture analysis of cranial ultrasound with later neurobehavior in preterm infants. AB - The purpose of the study was to evaluate the association between a quantitative texture analysis of early neonatal brain ultrasound images and later neurobehavior in preterm infants. A prospective cohort study including 120 preterm (<33 wk of gestational age) infants was performed. Cranial ultrasound images taken early after birth were analyzed in six regions of interest using software based on texture analysis. The resulting texture scores were correlated with the Neonatal Behavioural Assessment Scale (NBAS) at term-equivalent age. The ability of texture scores, in combination with clinical data and standard ultrasound findings, to predict the NBAS results was evaluated. Texture scores were significantly associated with all but one NBAS domain and better predicted NBAS results than clinical data and standard ultrasound findings. The best predictive value was obtained by combining texture scores with clinical information and ultrasound standard findings (area under the curve = 0.94). We conclude that texture analysis of neonatal cranial ultrasound-extracted quantitative features that correlate with later neurobehavior has a higher predictive value than the combination of clinical data with abnormalities in conventional cranial ultrasound. PMID- 25023104 TI - Shunt flow evaluation in congenital heart disease based on two-dimensional speckle tracking. AB - High-frame-rate ultrasound speckle tracking was used for quantification of peak velocity in shunt flows resulting from septal defects in congenital heart disease. In a duplex acquisition scheme implemented on a research scanner, unfocused transmit beams and full parallel receive beamforming were used to achieve a frame rate of 107 frames/s for full field-of-view flow images with high accuracy, while also ensuring high-quality focused B-mode tissue imaging. The setup was evaluated in vivo for neonates with atrial and ventricular septal defects. The shunt position was automatically tracked in B-mode images and further used in blood speckle tracking to obtain calibrated shunt flow velocities throughout the cardiac cycle. Validation toward color flow imaging and pulsed wave Doppler with manual angle correction indicated that blood speckle tracking could provide accurate estimates of shunt flow velocities. The approach was less biased by clutter filtering compared with color flow imaging and was able to provide velocity estimates beyond the Nyquist range. Possible placements of sample volumes (and angle corrections) for conventional Doppler resulted in a peak shunt velocity variations of 0.49-0.56 m/s for the ventricular septal defect of patient 1 and 0.38-0.58 m/s for the atrial septal defect of patient 2. In comparison, the peak velocities found from speckle tracking were 0.77 and 0.33 m/s for patients 1 and 2, respectively. Results indicated that complex intraventricular flow velocity patterns could be quantified using high-frame-rate speckle tracking of both blood and tissue movement. This could potentially help increase diagnostic accuracy and decrease inter-observer variability when measuring peak velocity in shunt flows. PMID- 25023105 TI - Microcalcifications versus artifacts: initial evaluation of a new ultrasound image processing technique to identify breast microcalcifications in a screening population. AB - A new commercial image processing technique (MicroPure, Toshiba America Medical Systems, Tustin, CA, USA) that identifies breast microcalcifications was evaluated at the time of patients' annual screening mammograms. Twenty women scheduled for annual screening mammography were enrolled in the study. Patients underwent bilateral outer-upper-quadrant real-time dual gray scale ultrasound and MicroPure imaging using an Aplio XG scanner (Toshiba). MicroPure combines non linear imaging and speckle suppression to mark suspected calcifications as white spots in a blue overlay image. Four independent and blinded readers analyzed digital clips to determine the presence or absence of microcalcifications and artifacts. The presence of microcalcifications determined by readers was not significantly different from that of mammography (p = 0.57). However, the accuracy was low overall (52%) and also in younger women (<50 years, 54%). In conclusion, although microcalcifications can be identified using MicroPure imaging, this method is not currently appropriate for a screening population and should be used in more focused applications. PMID- 25023106 TI - Relationship between CHADS2 score and complex aortic plaques by transesophageal echocardiography in patients with nonvalvular atrial fibrillation. AB - The CHADS2 score is widely used for risk stratification of thromboembolism in patients with non-valvular atrial fibrillation (NVAF). Although the correlation of CHADS2 score with left atrial (LA) abnormality as detected by transesophageal echocardiography (TEE) has been reported in previous studies, the relationship between CHADS2 score and complex aortic plaque, which is also a significant risk factor for thromboembolism, has not been fully investigated. We assessed aortic plaques by TEE in 150 patients age >= 55 y with NVAF. The prevalence of complex aortic plaques increased along with increases in CHADS2 score (p = 0.001). In a multivariate analysis that included atherosclerotic risk factors and LA abnormality, a CHADS2 score >=2 was independently associated with the presence of complex aortic plaques (odds ratio [OR] 3.39; 95% confidence interval [CI], 1.29 8.90). A high CHADS2 score is closely associated with the presence of complex aortic plaques, which explains, in part, the increased risk of thromboembolism in NVAF patients with high CHADS2 score. PMID- 25023107 TI - Association between forearm muscle thickness and age-related loss of skeletal muscle mass, handgrip and knee extension strength and walking performance in old men and women: a pilot study. AB - Very little information is available concerning the relationship between handgrip strength and muscle size in the upper and lower extremities, especially the forearm muscle itself. To investigate the relationships among ultrasound-measured forearm muscle thickness from the radius and ulna bone interface with handgrip strength, knee extension strength, walking speed and absolute/relative total skeletal muscle mass (TMM), 32 Japanese men and 21 Japanese women ages 70-83 years had muscle thickness (MT) measured by ultrasound. In the forearm, two MTs (forearm-radius and forearm-ulna MT) were measured. TMM was estimated from an ultrasound-derived prediction equation. Handgrip-strength was significantly correlated with forearm-ulna MT in both men and women. There were no significant correlations between forearm MT and walking speed in either sex. In men, both forearm-radius and forearm-ulna MT were significantly correlated with TMM and TMM index. In women, a significant correlation was only observed between forearm-ulna MT and TMM index. Our results suggest that forearm-ulna MT may be a useful parameter for evaluating handgrip strength and TMM index in older Japanese men and women. PMID- 25023108 TI - Application of vertebral artery ultrasonography in enlistment-age male student pilots. AB - The aim of this study was to investigate the vertebral artery (VA) morphology of enlistment-age male student pilots with ultrasound to provide a basis for early diagnosis of potentially asymptomatic cervical vertigo. Ultrasound results of the origin position, diameter and hemodynamics of the VA in 935 cases of student pilots with a mean age of 18.0 y were analyzed. The inner diameters of both sides of the VA differ: the left is larger than the right statistically (p < 0.001). Moreover, the peak systolic velocity of the left VA is significantly greater than that of the right (p < 0.001). Congenital VA anomalies in age-appropriate male student pilots included inner diameter variation, course variation and origin position variation. The incidence of course variation or origin position proportion was low (3.46%, 32/925), and origin position variation was often accompanied by inner diameter variation or course variation. This study confirms that there are a variety of congenital abnormalities in the vertebral arteries of enlistment-age male student pilots, and a VA diameter <2.5 mm may be a reasonable criterion for diagnosis of VA hypoplasia. PMID- 25023109 TI - Non-contact high-frequency ultrasound microbeam stimulation for studying mechanotransduction in human umbilical vein endothelial cells. AB - We describe how contactless high-frequency ultrasound microbeam stimulation (HFUMS) is capable of eliciting cytoplasmic calcium (Ca(2+)) elevation in human umbilical vein endothelial cells. The cellular mechanotransduction process, which includes cell sensing and adaptation to the mechanical micro-environment, has been studied extensively in recent years. A variety of tools for mechanical stimulation have been developed to produce cellular responses. We developed a novel tool, a highly focused ultrasound microbeam, for non-contact cell stimulation at a microscale. This tool, at 200 MHz, was applied to human umbilical vein endothelial cells to investigate its potential to elicit an elevation in cytoplasmic Ca(2+) levels. It was found that the response was dose dependent, and moreover, extracellular Ca(2+) and cytoplasmic Ca(2+) stores were involved in the Ca(2+) elevation. These results suggest that high-frequency ultrasound microbeam stimulation is potentially a novel non-contact tool for studying cellular mechanotransduction if the acoustic pressures at such high frequencies can be quantified. PMID- 25023110 TI - Differentiation of neural stem/progenitor cells using low-intensity ultrasound. AB - Herein, we report the evaluation of apoptosis, cell differentiation, neurite outgrowth and differentiation of neural stem/progenitor cells (NSPCs) in response to low-intensity ultrasound (LIUS) exposure. NSPCs were cultured under different conditions, with and without LIUS exposure, to evaluate the single and complex effects of LIUS. A lactic dehydrogenase assay revealed that the cell viability of NSPCs was maintained with LIUS exposure at an intensity range from 100 to 500 mW/cm(2). Additionally, in comparison with no LIUS exposure, the cell survival rate was improved with the combination of medium supplemented with nerve growth factor and LIUS exposure. Our results indicate that LIUS exposure promoted NSPC attachment and differentiation on a glass substrate. Neurite outgrowth assays revealed the generation of longer, thicker neurites after LIUS exposure. Furthermore, LIUS stimulation substantially increased the percentage of differentiating neural cells in NSPCs treated with nerve growth factor in comparison with the unstimulated group. The high percentage of differentiated neural cells indicated that LIUS induced neuronal networks denser than those observed in the unstimulated groups. Furthermore, the release of nitric oxide, an important small-molecule neurotransmitter, was significantly upregulated after LIUS exposure. It is therefore reasonable to suggest that LIUS promotes the differentiation of NSPCs into neural cells, induces neurite outgrowth and regulates nitric oxide production; thus, LIUS may be a potential candidate for NSPC induction and neural cell therapy. PMID- 25023111 TI - Ultrasound arthroscopy of human knee cartilage and subchondral bone in vivo. AB - Arthroscopic ultrasound imaging enables quantitative evaluation of articular cartilage. However, the potential of this technique for evaluation of subchondral bone has not been investigated in vivo. In this study, we address this issue in clinical arthroscopy of the human knee (n = 11) by determining quantitative ultrasound (9 MHz) reflection and backscattering parameters for cartilage and subchondral bone. Furthermore, in each knee, seven anatomical sites were graded using the International Cartilage Repair Society (ICRS) system based on (i) conventional arthroscopy and (ii) ultrasound images acquired in arthroscopy with a miniature transducer. Ultrasound enabled visualization of articular cartilage and subchondral bone. ICRS grades based on ultrasound images were higher (p < 0.05) than those based on conventional arthroscopy. The higher ultrasound-based ICRS grades were expected as ultrasound reveals additional information on, for example, the relative depth of the lesion. In line with previous literature, ultrasound reflection and scattering in cartilage varied significantly (p < 0.05) along the ICRS scale. However, no significant correlation between ultrasound parameters and structure or density of subchondral bone could be demonstrated. To conclude, arthroscopic ultrasound imaging had a significant effect on clinical grading of cartilage, and it was found to provide quantitative information on cartilage. The lack of correlation between the ultrasound parameters and bone properties may be related to lesser bone change or excessive attenuation in overlying cartilage and insufficient power of the applied miniature transducer. PMID- 25023112 TI - A prediction model for unstable carotid atheromatous plaque in acute ischemic stroke patients: proposal and internal validation. AB - The aim of this prospective study was to analyze the utility of a gray-scale median (GSM) system for identifying unstable plaques and to design and validate a prediction model for unstable plaques in symptomatic atheromatous carotid arteries. Fifty-two patients with non-cardioembolic cerebral infarction were included in the study. The receiver operating characteristic analysis revealed 76% sensitivity and 82% specificity for a GSM of 29 (p < 0.001) as a cutoff point for unstable plaques. A logistic regression model indicated that a GSM <29, male gender and not having been treated with angiotensin-converting enzyme inhibitors were independently associated with an unstable plaque classification. A probability model for unstable plaques was achieved by combining the strength of each variable (high blood pressure, hypercholesterolemia, smoking, previous stroke, anti-hypertensive drugs, calcium channel blockers, intima-media thickness). The model was tested with receiver operating characteristic curve analysis (p < 0.001) and validated by the leave-one-out cross-validation method (p < 0.001). The prediction model based on a GSM <29, male gender and not having been treated with angiotensin-converting enzyme inhibitors resulted in a probable unstable plaque assessment. PMID- 25023113 TI - Dynamics of targeted microbubble adhesion under pulsatile compared with steady flow. AB - Hemodynamic flow variations at low fluid shear stress are thought to play a critical role in local atherosclerotic plaque initiation and development and to affect plaque instability. Targeted microbubbles are being developed as intravascular agents for identifying atherosclerotic lesions using ultrasound. How variations in local hydrodynamic flow influence the adhesiveness of targeted microbubbles is not well understood. We postulated that rates of targeted microbubble binding and accumulation differ when subjected to steady flow (SF) as compared with oscillatory or pulsatile flow (PF), because PF imposes non-uniform blood rheology and periodic acceleration and deceleration of blood velocity, when compared with SF. We assessed the binding rates of targeted microbubbles in seven randomly assigned PF and seven matched SF replicate runs at low (<1 Pa) and intermediate (>=1 and <2.5 Pa) wall shear stress (WSS) by drawing 4.8 * 10(6) microbubbles mL(-1) over streptavidin-coated substrates, immobilized within a parallel plate flow chamber at a calculated density of 81 binding sites MUm(-2). Selective binding and accumulation of targeted microbubbles was recorded in a single field of view using real-time video microscopy. Microbubble accumulation was modeled to obtain flow-mediated microbubble binding kinetics (amplitude, A, and rate constant, k). PF elicited higher microbubble accumulation rates, in comparison to SF. The rates of microbubble accumulation differed significantly between PF and SF (p < 0.05) at intermediate WSS but not at low WSS (p > 0.05). The rate of microbubble accumulation decreased as WSS increased. PMID- 25023114 TI - 5-Aminolevulinic acid-mediated sonodynamic therapy reverses macrophage and dendritic cell passivity in murine melanoma xenografts. AB - Sonodynamic therapy (SDT) uses a combination of sonosensitizing drugs and low intensity therapeutic ultrasound to cause apoptosis and autophagy of tumor cells. However, its effects on the tumor microenvironment, especially on the immune state, remain unknown. In this study, we investigated the transformation of macrophages and dendritic cells (DCs) in the tumor microenvironment during 5 aminolevulinic acid (5-ALA)-mediated SDT in mice transplanted with B16F10 melanomas. Tumor growth and mouse weight were measured. Hematoxylin-eosin staining was used to evaluate tumor morphology to quantify the anti-tumor efficacy of 5-ALA-mediated SDT. We investigated anti-tumor immunity in the tumor microenvironment by immunocytochemical staining of CD68, CD163, CD80, CD86, tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10) and interferon gamma (IFN-gamma). Tumor growth was restrained by 5-ALA-mediated SDT in B16F10 melanoma bearing mice. CD68 levels increased and CD163 decreased, indicating that M2 macrophages were converted to the M1 phenotype in the tumor. The increase in CD80 and CD86 showed that DCs in the tumor microenvironment tend to mature after SDT treatment. The cytokines INF-gamma, TNF-alpha and IL-10 significantly increased in SDT. Application of low-intensity therapeutic ultrasound alone also led to similar trends in our study, but combined treatment with 5-ALA yielded a change. The original stabilized immune state in the tumor microenvironment can be interrupted by low-intensity therapeutic ultrasound combined with 5-ALA, which enhanced the pro-inflammatory response and reversed the passive properties of macrophages and dendritic cells. PMID- 25023115 TI - Early detection of liver fibrosis in rats using 3-D ultrasound Nakagami imaging: a feasibility evaluation. AB - We investigated the feasibility of using 3-D ultrasound Nakagami imaging to detect the early stages of liver fibrosis in rats. Fibrosis was induced in livers of rats (n = 60) by intraperitoneal injection of 0.5% dimethylnitrosamine (DMN). Group 1 was the control group, and rats in groups 2-6 received DMN injections for 1-5 weeks, respectively. Each rat was sacrificed to perform 3-D ultrasound scanning of the liver in vitro using a single-element transducer of 6.5 MHz. The 3-D raw data acquired at a sampling rate of 50 MHz were used to construct 3-D Nakagami images. The liver specimen was further used for histologic analysis with hematoxylin and eosin and Masson staining to score the degree of liver fibrosis. The results indicate that the Metavir scores of the hematoxylin and eosin-stained sections in Groups 1-4 were 0 (defined as early liver fibrosis in this study), and those in groups 5 and 6 ranged from 1 to 2 and 2 to 3, respectively. To quantify the degree of early liver fibrosis, the histologic sections with Masson stain were analyzed to calculate the number of fiber-related blue pixels. The number of blue pixels increased from (2.36 +/- 0.79) * 10(4) (group 1) to (7.68 +/- 2.62) * 10(4) (group 4) after DMN injections for 3 weeks, indicating that early stages of liver fibrosis were successfully induced in rats. The Nakagami parameter increased from 0.36 +/- 0.02 (group 1) to 0.55 +/- 0.03 (group 4), with increasing numbers of blue pixels in the Masson-stained sections (p-value < 0.05, t-test). We concluded that 3-D Nakagami imaging has potential in the early detection of liver fibrosis in rats and may serve as an image-based pathologic model to visually track fibrosis formation and growth. PMID- 25023116 TI - Evaluation of gastric emptying in diabetic gastropathy by an ultrasonic whole stomach cylinder method. AB - In order to explore the accuracy of ultrasonic whole stomach cylinder measurement (UWSCM) in the evaluation of gastric emptying, we measured the gastric emptying times (ET) at 25% (T1), 50% (T2) and 75% (T3) of healthy subjects and patients with diabetic gastropathy by UWSCM and scintigraphy. The ET of patients were compared with their clinical symptom scores. We found that the ET measured by UWSCM showed no significant difference with scintigraphy (p > 0.05). The correlation between them was good, and the correlation coefficient of T3 reached 0.744 (p < 0.05). All emptying times in the diabetic patients were longer than those in the healthy subjects (p < 0.05). The T3 in the diabetic group measured by UWSCM had the best correlation with the symptom index (r = 0.469, p < 0.05). We conclude that ET measured by UWSCM is accurate and T3 combining the symptoms index provides an accurate clinical basis for gastropathy. PMID- 25023117 TI - Monitoring plant response to environmental stimuli by ultrasonic sensing of the leaves. AB - Described here is the application of a technique based on the excitation, sensing and spectral analysis of thickness resonances of plant leaves using air-coupled and wide-band ultrasound pulses (150-900 kHz) to monitor variations in leaf properties caused by plant responses to different environmental stimuli, such as a sudden variation in light intensity (from 2000 to 150 MUmol m(-2) s(-1)), sudden watering after a drought period, and along the diurnal cycle (3-5 days, with continuous variation in light intensity from 150 to 2000 MUmol m(-2) s(-1) and change in temperature of about 5 degrees C). Four different widely available species, both monocots and dicots and evergreen and deciduous, with different leaf features (shape, size, thickness, flatness, vascular structure), were selected to test the technique. After a sudden decrease in light intensity, and depending on the species, there was a relative increase in the thickness resonant frequency from 8% to 12% over a 25- to 50-min period. After sudden watering, the relative increase in the resonant frequency varied from 5% to 30% and the period from 10 to 400 min. Finally, along the diurnal cycle, the measured relative variation is between 4% and 10%. The technique revealed differences in both the amplitude of the frequency oscillations and the kinetics of the leaf response for different species and also within the same species, but for specimens grown under different conditions that present different cell structures at the tissue level. The technique can be equally applied to the leaves of any species that present thickness resonances. PMID- 25023118 TI - Polymerase chain reaction amplifying mycobacterial DNA from aspirates obtained by endoscopic ultrasound allows accurate diagnosis of mycobacterial disease in HIV positive patients with abdominal lymphadenopathy. AB - Abdominal lymphadenopathy in human immunodeficiency virus (HIV) infection remains a diagnostic challenge. We performed a prospective cohort study by recruiting 31 symptomatic HIV + patients with abdominal lymphadenopathy and assessing the diagnostic yield of endoscopic ultrasound fine-needle aspiration (EUS-FNA). Mean age was 38 years; 52% were female; and mean CD4 count and viral load were 124 cells/MUL and 4 log, respectively. EUS confirmed additional mediastinal nodes in 26%. The porta hepatis was the most common abdominal site. Aspirates obtained by EUS-FNA were subjected to cytology, culture and polymerase chain reaction (PCR) analysis. Mycobacterial infections were confirmed in 67.7%, and 31% had reactive lymphadenopathy. Cytology and culture had low sensitivity, whereas PCR identified 90% of mycobacterial infections. By combining the appearance of aspirates obtained by EUS-FNA and cytologic specimens, we developed a diagnostic algorithm to indicate when analysis with PCR would be useful. PCR performed on material obtained by EUS-FNA was highly accurate in confirming mycobacterial disease and determining genotypic drug resistance. PMID- 25023119 TI - Visual screening of muscle ultrasound images in children. AB - In children, non-invasive muscle ultrasound (MU) imaging has become increasingly important for the detection of neuromuscular pathology, by either quantitative or visual assessment. MU quantification requires time, expertise and equipment. If application of visual MU screening provides reliable results, ubiquitous application could be advocated. Previously, we found that visual MU screening can reliably detect segmental neuromuscular alterations within a patient. Analogously, we reasoned that visual MU screening could discern pathologic MU images from healthy controls. We therefore investigated visual screening results by 20 clinical observers (involving 100 MU images, with [n = 53] and without [n = 47] neuromuscular pathology). MU screening revealed adequate sensitivity, specificity and negative predictive value (85%, 75% and 82%, respectively). MU experienced observers revealed higher specificity than MU-inexperienced observers (86% vs. 69%, p = 0.005). We conclude that clinical observers can identify neuromuscular pathology by visual screening. To enhance specificity, a secondary view by an expert appears advisory. PMID- 25023121 TI - Erratum: are the "memory wars" over? A scientist-practitioner gap in beliefs about repressed memory. AB - Patihis, L., Ho, L. Y., Tingen, I. W., Lilienfeld, S. O., & Loftus, E. F. (2014). Are the "memory wars" over? A scientist-practitioner gap in beliefs about repressed memory. Psychological Science, 25, 519-530. (Original DOI: 10.1177/0956797613510718). PMID- 25023122 TI - The Regulation of Light Sensing and Light-Harvesting Impacts the Use of Cyanobacteria as Biotechnology Platforms. AB - Light is harvested in cyanobacteria by chlorophyll-containing photosystems embedded in the thylakoid membranes and phycobilisomes (PBSs), photosystem associated light-harvesting antennae. Light absorbed by the PBSs and photosystems can be converted to chemical energy through photosynthesis. Photosynthetically fixed carbon pools, which are constrained by photosynthetic light capture versus the dissipation of excess light absorbed, determine the available organismal energy budget. The molecular bases of the environmental regulation of photosynthesis, photoprotection, and photomorphogenesis are still being elucidated in cyanobacteria. Thus, the potential impacts of these phenomena on the efficacy of developing cyanobacteria as robust biotechnological platforms require additional attention. Current advances and persisting needs for developing cyanobacterial production platforms that are related to light sensing and harvesting include the development of tools to balance the utilization of absorbed photons for conversion to chemical energy and biomass versus light dissipation in photoprotective mechanisms. Such tools can be used to direct energy to more effectively support the production of desired bioproducts from sunlight. PMID- 25023120 TI - Novel bacterial ADP-ribosylating toxins: structure and function. AB - Bacterial ADP-ribosyltransferase toxins (bARTTs) transfer ADP-ribose to eukaryotic proteins to promote bacterial pathogenesis. In this Review, we use prototype bARTTs, such as diphtheria toxin and pertussis toxin, as references for the characterization of several new bARTTs from human, insect and plant pathogens, which were recently identified by bioinformatic analyses. Several of these toxins, including cholix toxin (ChxA) from Vibrio cholerae, SpyA from Streptococcus pyogenes, HopU1 from Pseudomonas syringae and the Tcc toxins from Photorhabdus luminescens, ADP-ribosylate novel substrates and have unique organizations, which distinguish them from the reference toxins. The characterization of these toxins increases our appreciation of the range of structural and functional properties that are possessed by bARTTs and their roles in bacterial pathogenesis. PMID- 25023123 TI - Anti-diabetic effect of mulberry leaf polysaccharide by inhibiting pancreatic islet cell apoptosis and ameliorating insulin secretory capacity in diabetic rats. AB - Diabetes mellitus is a clinically complex disease characterized by chronic hyperglycemia with metabolic disturbances. In this study, we investigated the effect of mulberry leaf polysaccharide (MLPII) on pancreatic islet cell apoptosis and insulin secretory function in diabetic rats induced by a high fat diet and streptozotocin. Our results showed that MLPII treatment inhibited pancreatic islet cell apoptosis and ameliorated insulin secretory capacity of pancreatic beta-cells in diabetic rats. And further study demonstrated that chronic treatment of diabetic rats with MLPII resulted in up-regulation of anti-apoptotic B-cell leukaemia/lymphoma 2 (Bcl-2) protein and down-regulation of pro-apoptotic Bcl2-associated X (Bax) and caspase-3 protein in pancreatic islet cells. Moreover, MLPII significantly restored pancreatic duodenal homeobox-1 (PDX-1) protein nuclear localization, and increased mRNA and protein expression of PDX-1 and its downstream targets, glucose transporter 2 (GLUT2) and glucokinase (GCK) in pancreatic islet cells of diabetic rats. These findings suggested that MLPII might play a critical role in protecting pancreatic islet cell from apoptosis via elevation of Bcl-2/Bax ratio, and ameliorating insulin secretory capacity of pancreatic beta-cells via restoration of PDX-1 nuclear localization and expression levels in diabetic rats. This is the first report to explore the potential molecular mechanism involved in the hypoglycemic activity of the polysaccharide from mulberry leaves. PMID- 25023124 TI - MT1 receptor expression and AA-NAT activity in lymphatic tissue following melatonin administration in male golden hamster. AB - Exogenous melatonin as a marker of the chemical expression of darkness is playing a key role in the synchronization of circadian functions and seasonal biological rhythms. Our study was designed to elucidate whether melatonin treatment can modulate the melatonin synthesis via the rate limiting enzyme arylalkylamine-N acetyltransferase (AA-NAT) in spleen, thymus and bone marrow thereby the proliferation rate of splenocytes, thymocytes and bone marrow mononuclear cells (BM-MNCs) of golden hamsters. The AA-NAT activity in different lymphoid tissue documented the synthesis of melatonin in those organs. Exogenous melatonin treatment to hamsters enhanced the AA-NAT activity in spleen and thymus along with an increase in the inflammatory response by DTH reactions that could be related to the increased level of interleukin-2 and IFN-gamma by T lymphocytes in serum/culture medium, proliferation rate and expression of melatonin membrane receptor MT(1). Thus, the relevance of melatonin synthesis by lymphatic tissues might be maintaining surveillance and local defence responses. PMID- 25023125 TI - Oryeongsan inhibits LPS-induced production of inflammatory mediators via blockade of the NF-kappaB, MAPK pathways and leads to HO-1 induction in macrophage cells. AB - BACKGROUND: Oryeongsan (OR) is an herbal medication used in east-Asian traditional medicine to treat dysuresia, such as urinary frequency, hematuria, and dysuria due to renal disease and chronic nephritis. Recent studies showed that protective effect against acute gastric mucosal injury and an inhibitory effect on the renin-angiotensin-aldosterone pathway of OR. However, its effect on inflammation still remains unknown. In this study, to provide insight into the biological effects of OR, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in the RAW 264.7 macrophage cells. METHODS: We investigated the pharmacological and biological effects of OR on the production of pro-inflammatory cytokines, inflammatory mediators, and related products through Enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Also, we examined the activation and suppression of nuclear factor (NF)-kappaB and mitogen activated protein kinases (MAPKs) pathways in LPS-stimulated macrophages via Western blot analysis in order to explore inhibitory mechanism of OR. RESULTS: OR had anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1 beta. In addition, it strongly suppressed cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), NO synthesizing enzymes. It also induced heme oxygenase (HO)-1 expression and inhibited NF-kappaB signaling pathway activation and phosphorylation of MAPKs. CONCLUSIONS: We further demonstrate the anti inflammatory effects and inhibitory mechanism of OR in LPS-stimulated macrophages for the first time. OR contains strong anti-inflammatory activity and affects various mechanism pathways including NF-kappaB, MAPKs and HO-1. Our results suggest that OR has potential value to be developed as an inflammatory therapeutic agent from a natural substance. PMID- 25023126 TI - Venous thromboembolism prophylaxis guideline compliance: a pilot study of augmented medication charts. AB - INTRODUCTION: Venous thromboembolism (VTE) is a common complication of hospital admission. The incidence of hospital-acquired deep vein thrombosis is approximately 10-40% amongst medical and general surgical patients without prophylaxis. Pulmonary embolism accounts for 5-10% of deaths in hospitalised patients, making hospital-acquired VTE the most common preventable cause of in hospital death. Studies suggest that prophylactic measures are widely under- and inappropriately used. AIMS: We hypothesised that the introduction of a medication chart with a dedicated VTE prophylaxis section would improve compliance with local guidelines. METHODS: Trial medication charts were piloted over a 4-week period in one surgical and two medical wards. Data on compliance with hospital guidelines were collected before and after introduction using a detailed chart review. The difference in prescribing compliance was assessed with the Chi squared test. RESULTS: 70 patients were assessed before and 38 after the introduction of the new charts. Initially, only 58.6% (n = 41) of patients' prescriptions were in compliance with local guidelines. In 28.6% (n = 20) of patients, VTE prophylaxis was needed and not prescribed. 7.1% (n = 5) of patients were prescribed an inappropriately low dose of low molecular weight heparin (LMWH) prophylaxis. 2.9% (n = 2) of patients were prescribed inappropriately high dose of LMWH prophylaxis. After introduction of the new medication chart, compliance with guidelines rose to 71% (n = 27, p = 0.09). CONCLUSION: Compliance with VTE guidelines is inadequate. Medication charts with specific sections on VTE assessment and prophylaxis may increase compliance with guidelines. PMID- 25023127 TI - Identifying Ca2+-binding sites in proteins by liquid chromatography-mass spectrometry using Ca2+-directed dissociations. AB - Here we describe a new method to identify calcium-binding sites in proteins using high-resolution liquid chromatography-mass spectrometry in concert with calcium directed collision-induced dissociations. Our method does not require any modifications to the liquid chromatography-mass spectrometry apparatus, uses standard digestion protocols, and can be applied to existing high-resolution MS data files. In contrast to NMR, our method is applicable to very small amounts of complex protein mixtures (femtomole level). Calcium-bound peptides can be identified using three criteria: (1) the calculated exact mass of the calcium containing peptide; (2) specific dissociations of the calcium-containing peptide from threonine and serine residues; and (3) the very similar retention times of the calcium-containing peptide and the free peptide. PMID- 25023128 TI - Predicting antidisease immunity using proteome arrays and sera from children naturally exposed to malaria. AB - Malaria remains one of the most prevalent and lethal human infectious diseases worldwide. A comprehensive characterization of antibody responses to blood stage malaria is essential to support the development of future vaccines, sero diagnostic tests, and sero-surveillance methods. We constructed a proteome array containing 4441 recombinant proteins expressed by the blood stages of the two most common human malaria parasites, P. falciparum (Pf) and P. vivax (Pv), and used this array to screen sera of Papua New Guinea children infected with Pf, Pv, or both (Pf/Pv) that were either symptomatic (febrile), or asymptomatic but had parasitemia detectable via microscopy or PCR. We hypothesized that asymptomatic children would develop antigen-specific antibody profiles associated with antidisease immunity, as compared with symptomatic children. The sera from these children recognized hundreds of the arrayed recombinant Pf and Pv proteins. In general, responses in asymptomatic children were highest in those with high parasitemia, suggesting that antibody levels are associated with parasite burden. In contrast, symptomatic children carried fewer antibodies than asymptomatic children with infections detectable by microscopy, particularly in Pv and Pf/Pv groups, suggesting that antibody production may be impaired during symptomatic infections. We used machine-learning algorithms to investigate the relationship between antibody responses and symptoms, and we identified antibody responses to sets of Plasmodium proteins that could predict clinical status of the donors. Several of these antibody responses were identified by multiple comparisons, including those against members of the serine enriched repeat antigen family and merozoite protein 4. Interestingly, both P. falciparum serine enriched repeat antigen-5 and merozoite protein 4 have been previously investigated for use in vaccines. This machine learning approach, never previously applied to proteome arrays, can be used to generate a list of potential seroprotective and/or diagnostic antigens candidates that can be further evaluated in longitudinal studies. PMID- 25023129 TI - Systematic review on the primary and secondary reporting of the prevalence of ghostwriting in the medical literature. AB - BACKGROUND: Ghostwriting of industry-sponsored articles is unethical and is perceived to be common practice. OBJECTIVE: To systematically review how evidence for the prevalence of ghostwriting is reported in the medical literature. DATA SOURCES: MEDLINE via PubMed 1966+, EMBASE 1966+, The Cochrane Library 1988+, Medical Writing 1998+, The American Medical Writers Association (AMWA) Journal 1986+, Council of Science Editors Annual Meetings 2007+, and the Peer Review Congress 1994+ were searched electronically (23 May 2013) using the search terms ghostwrit*, ghostauthor*, ghost AND writ*, ghost AND author*. ELIGIBILITY CRITERIA: All publication types were considered; only publications reporting a numerical estimate of possible ghostwriting prevalence were included. DATA EXTRACTION: Two independent reviewers screened the publications; discrepancies were resolved by consensus. Data to be collected included a numerical estimate of the prevalence of possible ghostwriting (primary outcome measure), definitions of ghostwriting reported, source of the reported prevalence, publication type and year, study design and sample population. RESULTS: Of the 848 publications retrieved and screened for eligibility, 48 reported numerical estimates for the prevalence of possible ghostwriting. Sixteen primary publications reported findings from cross-sectional surveys or descriptive analyses of published articles; 32 secondary publications cited published or unpublished evidence. Estimates on the prevalence of possible ghostwriting in primary and secondary publications varied markedly. Primary estimates were not suitable for meta analysis because of the various definitions of ghostwriting used, study designs and types of populations or samples. Secondary estimates were not always reported or cited correctly or appropriately. CONCLUSIONS: Evidence for the prevalence of ghostwriting in the medical literature is limited and can be outdated, misleading or mistaken. Researchers should not inflate estimates using non-standard definitions of ghostwriting nor conflate ghostwriting with other unethical authorship practices. Editors and peer reviewers should not accept articles that incorrectly cite or interpret primary publications that report the prevalence of ghostwriting. PMID- 25023130 TI - Future Care Planning for patients approaching end-of-life with advanced heart disease: an interview study with patients, carers and healthcare professionals exploring the content, rationale and design of a randomised clinical trial. AB - OBJECTIVE: To explore the optimal content and design of a clinical trial of an end-of-life intervention for advanced heart disease with patients, carers and healthcare professionals. DESIGN: Qualitative interview and focus group study. SETTING: Community and hospital-based focus groups and interviews. PARTICIPANTS: Stable community-dwelling patients, informal carers (PC, n=15) and primary and secondary care based healthcare professionals (HCP, n=11). RESULTS: PC highlighted fragmentation of services and difficulty in accessing specialist care as key barriers to good care. They felt that time for discussion with HCP was inadequate within current National Health Service (NHS) healthcare systems. HCP highlighted uncertainty of prognosis, explaining mortality risk to patients and switching from curative to palliative approaches as key challenges. Patient selection, nature of the intervention and relevance of trial outcomes were identified by HCP as key challenges in the design of a clinical trial. CONCLUSIONS: PC and HCP expressed a number of concerns relevant to the nature and content of an end-of-life intervention for patients with advanced heart disease. The findings of this study are being used to support a phase II randomised clinical trial of Future Care Planning in advanced heart disease. PMID- 25023131 TI - Lower levels of high-density lipoprotein cholesterol in urban Africans presenting with communicable versus non-communicable forms of heart disease: the 'Heart of Soweto' hospital registry study. AB - OBJECTIVES: To investigate if urban Africans displayed lower levels of atheroprotective high-density lipoprotein cholesterol (HDLC) when presenting with communicable versus non-communicable forms of heart disease (HD) as both acute infection and chronic inflammation reduce HDLC levels. DESIGN: Hospital registry of 5328 de novo cases of HD over a 3-year period. SETTING: Cardiology Unit, Baragwanath Hospital in Soweto, South Africa. PARTICIPANTS: A total of 1199 patients of African descent (59% women; 57.0+/-13.4 years) had fasting blood lipid levels (total cholesterol (TC), triglyceride, HDLC and low-density lipoprotein cholesterol (LDLC)) documented on admission. Serum inflammatory marker C reactive protein (CRP) was measured in a subset of 367 patients (31% of cases). MAIN OUTCOME MEASURES: Lipid profiles were compared according to prespecified classification of non-communicable (eg, hypertensive HD) versus communicable (eg, rheumatic HD) HD. Low HDLC was defined as <1.0 mmol/L for men and <1.2 mmol/L for women, according to applicable South African Clinical Guidelines. RESULTS: Overall 694 (58%) of those presenting with HD had low HDLC levels; 344 of 678 (51%) and 350 of 521 (67%) for non-communicable and communicable, respectively (p<0.001). Comparatively, overall prevalence of high TC was 32% and high LDLC was 37%. On an adjusted basis, those with non communicable HD were more likely to record a low HDLC relative to non communicable presentations (odds ratio (OR) 1.91, 95% CI 1.42 to 2.57; p<0.001). There was a strong relationship between low HDLC and higher levels of CRP, but only in women. CONCLUSIONS: Despite largely favourable lipid profiles, there are clear differences according to aetiology of underlying HD in urban Africans, with younger patients with communicable HD having particularly low levels of HDLC. Appropriate prospective evidence is needed to determine if persistent low levels of HDLC expose patients to increased, long-term risk of atherosclerotic forms of HD. The women-only inverse association between HDLC and CRP warrants further investigation. PMID- 25023132 TI - Postnatal epigenetic modification of glucocorticoid receptor gene in preterm infants: a prospective cohort study. AB - OBJECTIVE: To examine the environmental effects on cytosine methylation of preterm infant's DNA, because early life experiences are considered to influence the physiological and mental health of an individual through epigenetic modification of DNA. DESIGN: A prospective cohort study, comparison of epigenetic differences in the glucocorticoid receptor (GR) gene between healthy term and preterm infants. SETTING: Neonatal Intensive Care Unit in a Japanese University Hospital. PARTICIPANTS: A cohort of 40 (20 term and 20 preterm) infants was recruited on the day of birth, and peripheral blood was obtained from each infant at birth and on postnatal day 4. MAIN OUTCOME MEASURES: The methylation rates in the 1-F promoter region of the GR gene using the Mquant method. RESULTS: The methylation rate increased significantly between postnatal days 0 and 4 in preterm infants but remained stable in term infants. Thus, the methylation rate was significantly higher in preterm than in term infants at postnatal day 4. Several perinatal parameters were significantly correlated with this change in the methylation rate. Logistic regression analysis revealed that methylation rates at postnatal day 4 predicted the occurrence of later complications that required glucocorticoid administration during the neonatal period. No gene polymorphism was detected within the GR promoter region analysed. CONCLUSIONS: Although further large-scale studies are needed to detect the environmental factors that explain the difference in epigenetic modification among infants after birth, our data show that the postnatal environment influences epigenetic programming of GR expression through methylation of the GR gene promoter in premature infants, which may result in relative glucocorticoid insufficiency during the postnatal period. PMID- 25023133 TI - Work outcomes of sickness absence related to mental disorders: a systematic literature review. AB - OBJECTIVES: The purpose of this systematic literature review is to examine the current state of knowledge regarding the return-to-work outcomes of sickness absences related to mental disorders that increase costs borne by employers. We address two questions: (1) Based on the existing literature, from the employer's perspective, what are the relevant economic return-to-work outcomes for sickness absences related to mental disorders? and (2) From the employer's economic perspective, are there gaps in knowledge about the relevant return-to-work outcomes for sickness absences related to mental disorders? SETTING: The included studies used administrative data from either an employer, insurer or occupational healthcare provider. PARTICIPANTS: Studies included working adults between 18 and 65 years old who had a sickness absence related to a mental disorder. PRIMARY AND SECONDARY OUTCOME MEASURES: The studies considered two general return-to-work outcome categories: (1) outcomes focusing on return-to-work and (2) outcomes focusing on sickness absence recurrence. RESULTS: A total of 3820 unique citations were identified. Of these, 10 studies were identified whose quality ranged from good to excellent. Half of the identified studies came from one country. The studies considered two characteristics of sickness absence: (1) whether and how long it took for a worker to return-to-work and (2) sickness absence recurrence. None of the studies examined return-to-work outcomes related to work reintegration. CONCLUSIONS: The existing literature suggests that along with the incidence of sickness absence related to mental disorders, the length of sickness absence episodes and sickness absence recurrence (ie, number and time between) should be areas of concern. However, there also seems to be gaps in the literature regarding the work reintegration process and its associated costs. PMID- 25023134 TI - The effects of poststroke aerobic exercise on neuroplasticity: a systematic review of animal and clinical studies. AB - Aerobic exercise may be a catalyst to promote neuroplasticity and recovery following stroke; however, the optimal methods to measure neuroplasticity and the effects of training parameters have not been fully elucidated. We conducted a systematic review and synthesis of clinical trials and studies in animal models to determine (1) the extent to which aerobic exercise influences poststroke markers of neuroplasticity, (2) the optimal parameters of exercise required to induce beneficial effects, and (3) consistent outcomes in animal models that could help inform the design of future trials. Synthesized findings show that forced exercise at moderate to high intensity increases brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I), nerve growth factor (NGF), and synaptogenesis in multiple brain regions. Dendritic branching was most responsive to moderate rather than intense training. Disparity between clinical stroke and stroke models (timing of initiation of exercise, age, gender) and clinically viable methods to measure neuroplasticity are some of the areas that should be addressed in future research. PMID- 25023136 TI - Reprint of "genetics of autoimmunity: an update". AB - The advent of genome-wide association studies (GWAS) has produced tremendous insights into the genetics of immune-mediated diseases allowing to identify hundreds of associated variants, some of which disease-specific and some others shared by groups of diseases. However, each variant usually accounts for a small genetic risk and all together they explain a relatively small portion of heritability for each disease. In addition, many of the associated variants map in regions of still undisclosed functions. This opens up to a new era of studies in search of the "missing heritability" which might partially be explained by gene-gene interactions and/or additive effects impacting on biochemical pathways relevant for the disease pathogenesis. The introduction of the immunochip analysis that allows to analyze thousands of patients for variations more strictly correlated with the immune/inflammatory functions is now allowing to single out relevant pathways shared by different diseases. Finally, great expectations are brought about from the studies on the effects that epigenetic modifications can have on the tuning of the expression of single allele/s in myeloid cells as well as in target tissues. Some of these topics have been discussed at the 15th International Congress of Immunology. PMID- 25023135 TI - Aboriginal community-level predictors of injury-related hospitalizations in British Columbia, Canada. AB - Population-level statistics indicating disparities in injury rates between Aboriginal and non-Aboriginal populations disguise considerable community-level heterogeneity. Using an ecological approach, we analyzed linked data from British Columbia's (BC) universal health care insurance plan, worker compensation, vital statistics, and census databases to identify community-level risk markers for hospitalization due to injury among the Aboriginal population of BC, Canada. Community standardized relative risks (SRR) of injury hospitalization relative to the total population of BC ranged from 0.24 to 9.35. Variables associated with increased SRRs included the following: higher proportions of crowded housing, housing in poor condition, participating in industries with greater risk of a work injury claim, being more remote, and at higher latitude. Higher income and more high school graduates were protective. In the best-fitting multivariable model, variables independently associated with SRR were proportion of the population with a high school certificate (RR = 0.89 per unit standard deviation change, 95 % confidence interval 0.83 to 0.94), and remoteness index (RR = 1.06, 95 % confidence interval (CI) 1.01 to 1.11). Results confirm profound diversity in Aboriginal communities across BC. SRRs of injury hospitalization increased as proportion of high school graduates dropped and remoteness increased. Promoting the educational attainment of community members should be an important focus of initiatives to improve health. PMID- 25023137 TI - Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II. AB - Adriamycin (ADR) increases the production of reactive oxygen species (ROS), which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors protect against ADR-induced mitochondrial function impairment. Rats were divided into five groups as control, ADR, co treatment ADR with captopril, co-treatment ADR with aliskiren, co-treatment ADR with both captopril and aliskiren. Left ventricular function and blood pressures were assessed at the end of treatment period. Mitochondrial membrane potential (MMP) and ATP levels were determined. ADR treatment decreased the left ventricular pressure and increased the left ventricular end-diastolic pressure. ADR decreased MMP and ATP levels in myocyte mitochondria due to increasing oxidative stress. ADR decreased MMP and ATP levels due to increased oxidative stress in the heart. Inhibitors of ACE and renin caused the elevation of the decreased of MMP and ATP levels. The pathologic changes in electrocardiogram, blood pressure and left ventricular function were decreased by inhibition of Ang II production. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo. PMID- 25023138 TI - Musical space synesthesia: automatic, explicit and conceptual connections between musical stimuli and space. AB - In musical-space synesthesia, musical pitches are perceived as having a spatially defined array. Previous studies showed that symbolic inducers (e.g., numbers, months) can modulate response according to the inducer's relative position on the synesthetic spatial form. In the current study we tested two musical-space synesthetes and a group of matched controls on three different tasks: musical space mapping, spatial cue detection and a spatial Stroop-like task. In the free mapping task, both synesthetes exhibited a diagonal organization of musical pitch tones rising from bottom left to the top right. This organization was found to be consistent over time. In the subsequent tasks, synesthetes were asked to ignore an auditory or visually presented musical pitch (irrelevant information) and respond to a visual target (i.e., an asterisk) on the screen (relevant information). Compatibility between musical pitch and the target's spatial location was manipulated to be compatible or incompatible with the synesthetes' spatial representations. In the spatial cue detection task participants had to press the space key immediately upon detecting the target. In the Stroop-like task, they had to reach the target by using a mouse cursor. In both tasks, synesthetes' performance was modulated by the compatibility between irrelevant and relevant spatial information. Specifically, the target's spatial location conflicted with the spatial information triggered by the irrelevant musical stimulus. These results reveal that for musical-space synesthetes, musical information automatically orients attention according to their specific spatial musical-forms. The present study demonstrates the genuineness of musical-space synesthesia by revealing its two hallmarks-automaticity and consistency. In addition, our results challenge previous findings regarding an implicit vertical representation for pitch tones in non-synesthete musicians. PMID- 25023139 TI - (1)H, (15)N and (13)C resonance assignments and secondary structure prediction of Q4D059, a conserved and kinetoplastid-specific hypothetical protein from Trypanosoma cruzi. AB - Trypanosoma cruzi is a human parasite that causes Chagas disease, an illness affecting millions of people and without an efficient treatment available. Sequencing the pathogen genome has revealed that near half of protein-coding genes correspond to hypothetical proteins of unknown function, increasing the possibilities for novel target discovery. Q4D059 is a putative essential hypothetical protein from T. cruzi and it is specific and conserved among the trypanosomatid genomes. Here, we report the sequential backbone and side chain resonance assignments and secondary structure analysis of Q4D059, as first step for protein structure determination, function elucidation and drug screening. PMID- 25023140 TI - Erasing stigma is much more than changing words. AB - Some opinion leaders and mental health experts have called for replacing diagnostic terms such as schizophrenia with words that are less stigmatizing and that more clearly reflect recovery. Although the author notes that such efforts are laudable, he describes three concerns in regard to diagnostic relabeling. It gives the task of changing stigma to mental health professionals rather than anchoring it among people with lived experience. Proponents of diagnostic relabeling misunderstand the enduring force of prejudice and discrimination. The focus on relabeling makes stigma change look easy, which undermines the stigma change agenda. The author points to lessons that can be learned from other efforts to promote civil rights. PMID- 25023141 TI - Genome-wide analysis of the heritability of amyotrophic lateral sclerosis. AB - IMPORTANCE: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations. OBJECTIVE: To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies. DESIGN, SETTING, AND PARTICIPANTS: We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland. MAIN OUTCOMES AND MEASURES: A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability. RESULTS: With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk. CONCLUSIONS AND RELEVANCE: We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS. PMID- 25023142 TI - Structural and dynamic investigation of bovine folate receptor alpha (FOLR1), and role of ultra-high temperature processing on conformational and thermodynamic characteristics of FOLR1-folate complex. AB - The folate receptor alpha (FOLR1) present in milk has widely been studied to investigate the effects of pasteurization, ultra-high temperature (UHT) processing and fermentation on net folate concentration. However, the folate binding mechanism with FOLR1, and effect of temperature on FOLR1-folate complex is poorly explored till now in bovine milk which is a chief resource of folate. Despite of enormous importance of folic acid and the routine intake of bovine milk, folic acid deficiency diseases are common in human race. To understand the folate deficiency in milk after processing, in absence of experimental structure, 3D model of bovine FOLR1 (bvFOLR1) was built followed by 40ns molecular dynamics (MD) simulation. The folate and its derivatives binding sites in bvFOLR1 were anticipated by molecular docking using AutoDock 4.2. Essential MD studies suggested the presence of a longer signal peptide (22 residues) and a short propeptide (7 residues) at the C-terminus that may cleaved during post translational modification. MD analysis of bvFOLR1-folate complex at 298, 323, 353, 373 and 408K followed by binding energy (BE) calculation showed maximum binding affinity at ~353K. However, at 373K and UHT (408K), the folate BE is significantly decreased with substantial conformational alteration. Heating at UHT followed by cooling within 298-408K range demoed no structural reformation with temperature reduction, and the folate was displaced from the active site. This study presented the disintegration of folate from bvFOLR1 during high temperature processing and revealed a lower folate concentration in UHT milk and dairy products. PMID- 25023143 TI - The genetic architecture of pediatric cognitive abilities in the Philadelphia Neurodevelopmental Cohort. AB - The objective of this analysis was to examine the genetic architecture of diverse cognitive abilities in children and adolescents, including the magnitude of common genetic effects and patterns of shared and unique genetic influences. Subjects included 3689 members of the Philadelphia Neurodevelopmental Cohort, a general population sample comprising those aged 8-21 years who completed an extensive battery of cognitive tests. We used genome-wide complex trait analysis to estimate the SNP-based heritability of each domain, as well as the genetic correlation between all domains that showed significant genetic influence. Several of the individual domains suggested strong influence of common genetic variants (for example, reading ability, h(2)g=0.43, P=4e-06; emotion identification, h(2)g=0.36, P=1e-05; verbal memory, h(2)g=0.24, P=0.005). The genetic correlations highlighted trait domains that are candidates for joint interrogation in future genetic studies (for example, language reasoning and spatial reasoning, r(g)=0.72, P=0.007). These results can be used to structure future genetic and neuropsychiatric investigations of diverse cognitive abilities. PMID- 25023144 TI - Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits. AB - Alterations of the dopaminergic system are associated with the cognitive and functional dysfunctions that characterize complex neuropsychiatric disorders. We modeled a dysfunctional dopaminergic system using mice with targeted ablation of dopamine (DA) D2 autoreceptors in mesencephalic dopaminergic neurons. Loss of D2 autoreceptors abolishes D2-mediated control of DA synthesis and release. Here, we show that this mutation leads to a profound alteration of the genomic landscape of neurons receiving dopaminergic afferents at distal sites, specifically in the prefrontal cortex. Indeed, we observed a remarkable downregulation of gene expression in this area of ~2000 genes, which involves a widespread increase in the histone repressive mark H3K9me2/3. This reprogramming process is coupled to psychotic-like behaviors in the mutant mice. Importantly, chronic treatment with a DA agonist can revert the genomic phenotype. Thus, cortical neurons undergo a profound epigenetic reprogramming in response to dysfunctional D2 autoreceptor signaling leading to altered DA levels, a process that may underlie a number of neuropsychiatric disorders. PMID- 25023146 TI - Harm concerns predict moral judgments of suicide: comment on Rottman, Kelemen and Young (2014). AB - Two prominent theories offer different perspectives on the role of harm in moral cognition. Dyadic morality suggests that harm-related concerns are pervasive, whereas moral pluralism suggests that these concerns apply only to canonically harmful violations (e.g., murder), and not impure violations (e.g., suicide). Rottman et al. (2014) contrast these two theories by examining moral judgments of suicide. They conclude that suicide wrongness is independent of harm, therefore arguing against dyadic morality and for moral pluralism. However, these conclusions may be overstated; across all these studies, a meta-analysis reveals that harm is a significant predictor of suicide judgments. Moreover, the association between harm and suicide wrongness may be suppressed in individual studies by insufficient power, restrictive exclusion criteria, a single bivariate outlier, and reliance upon the conventional significance threshold of p<.05. In revised analyses harm is robustly associated with suicide wrongness, consistent with dyadic morality. PMID- 25023145 TI - HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study. AB - Several retrospective epidemiological studies report that utilization of 3 hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion. PMID- 25023147 TI - Short-term efficacy of intravitreal aflibercept for patients with treatment-naive polypoidal choroidal vasculopathy. AB - PURPOSE: To evaluate the short-term efficacy of aflibercept monotherapy for patients with treatment-naive polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, consecutive case series. METHODS: Thirty-three consecutive eyes of 33 symptomatic PCV patients (17 men, 16 women, mean age 75 +/- 8.7 years), not treated previously, received an intravitreal injection of 2.0 mg of aflibercept monthly for 3 months. Changes in best-corrected visual acuity (BCVA), optical coherence tomography (OCT) findings, and indocyanine green angiography (ICGA) findings 3 months after initial injection were evaluated. RESULTS: Compared with baseline, mean BCVA at 3-month visit significantly improved (0.40 +/- 0.34 vs 0.22 +/- 0.20 log minimum angle of resolution [logMAR] unit, P < 12 0.001). Eight eyes (24 %) showed improvement in BCVA >= 0.3 logMAR unit, and no eyes (0 %) showed a decrease in BCVA of >= 0.3 logMAR unit. Mean foveal thickness improved significantly (348 +/- 184 MUm at baseline vs 194 +/- 32 MUm at 3-month visit, P < 15 0.001). At 3-month visit, 31 eyes (97 %) achieved dry macula evaluated on OCT. Polypoidal lesions disappeared completely on ICGA in 16 eyes (48 %), and the number and/or the size of polypoidal lesions decreased in nine eyes (27 %). The remaining eight eyes (24 %) had unchanged polypoidal lesions. A branching vascular network remained and was unchanged in diameter in all 27 eyes in which it was detected at baseline. CONCLUSION: Intravitreal aflibercept was well tolerated in patients with treatment-naive PCV over the short-term. PMID- 25023149 TI - An exaggerated blood pressure response to exercise is associated with subclinical myocardial dysfunction in normotensive individuals. AB - OBJECTIVES: An exaggerated blood pressure (BP) response to exercise is associated with adverse cardiovascular outcomes, even in normotensive individuals. The purpose of this study was to compare myocardial function between normotensive individuals with and without an exaggerated BP response. METHODS: We evaluated global myocardial function using speckle tracking echocardiography in normotensive individuals. Two-dimensional speckle tracking echocardiography and a treadmill exercise test were performed simultaneously in 171 normotensive individuals (mean age: 48 +/- 8 years; 97 men) without any structural heart disease. RESULTS: Among 171 normotensive individuals, 19 (11%) exhibited an exaggerated BP response (>=200 mmHg for men and >=190 mmHg for women) during the treadmill test. Conventional echocardiographic parameters were similar between the two groups. However, on strain analyses, the systolic and early diastolic global longitudinal strains of the left ventricle (LV) and left atrium were lower in individuals with an exaggerated BP response to exercise. The peak SBP during exercise was inversely related to systolic global longitudinal strain of the LV (r = -0.35, P < 0.01) and left atrium (r = -0.41, P < 0.01). On multivariate analyses, an exaggerated BP response to exercise was shown to be an independent determinant of reduced global longitudinal strain of the LV (beta = 0.20, P < 0.05) and left atrium (beta = -0.28, P < 0.05). CONCLUSION: Normotensive individuals with an exaggerated BP response to exercise exhibit impairment in longitudinal myocardial function. Even without apparent hypertension, an exaggerated BP response could cause repeated increases in afterload and result in subclinical myocardial dysfunction. PMID- 25023148 TI - Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes. AB - BACKGROUND: Microglial activation has been recognized as a neuropathological feature in diabetic retinopathy. But the early spatiotemporal characterization of microglial activation in the retina and the optic nerve of diabetic animals has not been fully investigated. The purpose of this study was to investigate early sequential changes of microglia in the retinas of rats with streptozotocin induced diabetes. Microglia in the optic nerves of rats with streptozotocin induced diabetes were also studied. METHODS: In 4-week, 8-week, and 12-week diabetic and normal control rats, microglial activation in the retinas and optic nerves was evaluated by immunolabeling with OX-42 antibody. Density, proportion of activation, and laminar distribution of retinal microglia were quantified. The retinal mRNA level of Iba-1, a microglial-specific marker, was measured by real time PCR. RESULTS: The density of retinal microglia was not different between diabetic and control rats, but the proportion of activated microglia increased significantly in diabetic rats at each time point. The proportion of microglia increased obviously in the nerve fiber layer and the ganglion cell layer while decreasing in the inner plexiform layer in 12-week diabetic rats. Moreover, retinal Iba-1 mRNA expression increased in 8-week and 12-week diabetic rats. Processes of microglia in the optic nerves of control rats were aligned with the long axis of nerve fibers, while the alignment was disturbed in diabetic rats. CONCLUSIONS: Morphology, proportion of activation, distribution, and mRNA expression of retinal microglia changed characteristically with the progression of the disease in early-stage diabetic rats. PMID- 25023151 TI - Association between high nocturnal blood pressure and white matter change and its interaction by obstructive sleep apnoea among normotensive adults. AB - OBJECTIVES: A reverse dipping pattern, characterized by higher night-time blood pressure (BP) than daytime BP, is associated with the increased risk for cerebrovascular disease, cardiovascular events and all-cause mortality. However, little has known about the association between white matter change (WMC) and reverse dipping pattern, particularly in normotensive adults. We aimed to examine whether WMC is associated with BP dipping patterns as measured with a 24-h ambulatory BP monitoring and whether obstructive sleep apnoea (OSA) is involved in this relationship METHODS: : A total of 703 normotensive adults were from an ongoing longitudinal study in a general population. WMC was measured with brain MRI. BP dipping patterns were defined as the ratio of the change in night-time and daytime SBP. OSA was categorized with the apnoea-hypopnea index, as measured with polysomnography. To avoid the influence of hypertensive medications, we only included normotensive adults for the final analysis. To examine the associations between WMC and dipping patterns, we built logistic models. To elucidate the role of OSA, we also conducted both modification and mediation tests. RESULTS: Reverse dipping pattern was significantly associated with WMC (odds ratio 1.49, 95% confidence interval 1.02-2.18). Further, OSA modified the association between dipping patterns and WMC (P = 0.0118). No mediation effect of OSA was assessed. CONCLUSION: In 703 normotensive adults, the reverse dipping pattern showed a significant association with WMC, after adjusting for covariates. Further, according to the presence of OSA, the association between reverse dipping and WMC was varied. PMID- 25023150 TI - Rapid increases in infant adiposity and overweight/obesity in childhood are associated with higher central and brachial blood pressure in early adulthood. AB - BACKGROUND: Small size at birth and greater BMI in childhood are associated with greater brachial blood pressure (BP) in later life. Aortic (central) BP differs from brachial BP and is more predictive of organ damage and cardiovascular events; the relationship between BMI in childhood and central BP is not known. METHODS: Using data from 3154 people from the Avon Longitudinal Study of Parents and Children, we assessed associations between repeated measures of BMI from birth to age 10 with central and brachial BP at age 17. RESULTS: Lower BMI at birth (thinness) was associated with greater central and brachial BP. No associations were seen between BMI in early childhood (<7 years) and later BP, but greater BMI from 7 to 10 years was associated with higher BP. Associations were similar for central and brachial SBP and for DBP, and were stronger in males compared with females. The highest BP was seen in participants who were low-birth weight and overweight or obese at both the end of infancy (age 2) and at the time of BP assessment (age 17); mean central SBP was 104.2 mmHg (SD = 11.0) compared with 100.7 (SD = 10.5) in participants who were normal-birth-weight and overweight or obese at 2 and 17 years. CONCLUSION: Small size at birth followed by rapid adiposity gain in infancy and continued overweight/obesity are associated with greater BP in young adulthood. These findings emphasize the importance of maintenance of normal weight in childhood for the prevention of high BP. PMID- 25023152 TI - The long-term effect of exercise on vascular risk factors and aerobic fitness in those with transient ischaemic attack: a randomized controlled trial. AB - OBJECTIVE: Exercise has beneficial effects on vascular risk factors in transient ischaemic attack (TIA) patients within the sub-acute phase. This study examined whether TIA patients randomized to an early exercise and education programme within 2 weeks of TIA diagnosis would demonstrate improvements in cardiovascular risk factors and aerobic fitness 12 months post-diagnosis compared with control patients. METHODS: A single-centre, randomized, parallel-group clinical trial. Sixty TIA patients (69 +/- 11 years) completed a vascular risk stratification baseline assessment and a physical fitness examination. Individuals were randomized to either an 8-week early exercise and education group or control group. Fifty-one patients attended post-intervention assessments that were completed immediately (post-intervention) and 12 months after (12PI). RESULTS: A significantly greater improvement in resting SBP was observed between baseline and post-intervention for EX than for CON (-11 mmHg cf. -1 mmHg, respectively; P < 0.05). The improvement in SBP was maintained between post-intervention and 12PI (P > 0.05). Similar findings were demonstrated for BMI, bodyweight and peak oxygen uptake (P < 0.05). Exercise blood pressure, pulse pressure and double product (SBP x heart rate; an indication of myocardial workload) were significantly lower at post-intervention and 12PI for EX than for CON (all P < 0.05). CONCLUSION: An 8-week exercise programme soon after TIA resulted in beneficial changes in resting and exercise blood pressure that were maintained for 12 months. CLINICAL TRIAL REGISTRATION: http://www.anzctr.org.au/ TRIAL REGISTRATION NUMBER: ACTRN12611000630910. PMID- 25023153 TI - Not nondipping but nocturnal blood pressure predicts left ventricular hypertrophy in the essential hypertensive patients: the Korean Ambulatory Blood Pressure multicenter observational study. AB - OBJECTIVE: The aim of this study was to investigate whether nocturnal blood pressure (BP), established on the basis of a single 24-h BP monitoring, is a stronger predictor of left ventricular hypertrophy (LVH) compared with nondipping status in the essential hypertensive patients. METHODS: A total of 682 hypertensive patients (mean age 56.1 +/- 14.5 years, 50.7% women) who underwent echocardiography were enrolled. 'Nondipping status' was defined as a nocturnal SBP fall less than 10% of daytime mean SBP. LVH was defined as a left ventricular mass index exceeding 54.0 g/m in men and 53.0 g/m in women. Each patient was categorized in three groups according to the total cardiovascular risk using 2007 European Society of Hypertension/ European Society of Cardiology guidelines as average or low, moderate, and high or very high added risk. RESULTS: Among 682 participants, 184 (26.9%) showed LVH on echocardiography. The proportion of individuals with high or very high added cardiovascular risk profile was 356 (52.1%). In multiple logistic regression analysis, age 56 years at least [odds ratio (OR) 1.047, 95% confidence interval (CI) 1.031-1.063, P < 0.0001], female participants (OR 1.751, 95% CI 1.172-2.616, P = 0.0062), BMI higher than 24.6 kg/m (OR 1.178, 95% CI 1.110-1.250, P < 0.0001), smoking (OR 1.793, 95% CI 1.028 3.127, P = 0.0397), and nocturnal SBP at least 127 mmHg (OR 1.032, 95% CI 1.009 1.055, P = 0.0059) were significant independent predictors for LVH whereas nondipping was not (OR 0.857, 95% CI 0.481-1.528, P = 0.6013). CONCLUSION: These findings suggest that nocturnal BP rather than nondipping may be a better predictor of LVH, especially in secondary or tertiary referral hospital setting targeting relatively high cardiovascular risk patients. PMID- 25023154 TI - Estimating the glomerular filtration rate in the Spanish working population: chronic kidney disease prevalence and its association with risk factors. AB - OBJECTIVE: This study aims to investigate the influence of estimated glomerular filtration rate (eGFR) with two equations (and by one or two separate measurements), on the prevalence of chronic kidney disease (CKD) and its association with blood pressure, and cardiovascular and metabolic risk factors. METHODS: Between January 2010 and October 2011, the Ibermutuamur CArdiovascular RIsk Assessment project included 128 588 workers (77.2% men, mean age 39.3 years, range 16-75), who underwent two consecutive yearly medical check-ups and had information for eGFR according to the MDRD-IDMS and CKD-EPI equations (serum creatinine was measured by a isotope-dilution mass spectrometry traceable method in a single central laboratory). CKD was defined by an eGFR less than 60 ml/min per 1.73 m. Subclinical (occult) renal disease was defined as an eGFR less than 60 ml/min per 1.73 m in patients with serum creatinine below 1.3 mg/dl and below 1.2 mg/dl in men and women, respectively. RESULTS: In this working population, prevalence of CKD was very low, but two to six times lower when two separate eGFRs below 60 ml/min per 1.73 m were used. The prevalence of CKD was significantly lower with the CKD-EPI compared to the MDRD-IDMS equation. The same applies to occult CKD. In male workers, occult CKD was practically nonexistent.Multivariate analyses show that blood pressure, total serum cholesterol, and serum glucose (positively), and high-density lipoprotein and low density lipoprotein (negatively) were associated with CKD, with both equations. Another metabolic factor (waist circumference) was only associated (positively) with CKD defined by the CKD-EPI equation, which appears to be associated with most components of the metabolic syndrome. CONCLUSIONS: The CKD-EPI formula, calculated on the basis of two reported blood samples, may provide the most specific definition of CKD. PMID- 25023155 TI - Prevalence of hypertension in China: a systematic review and meta-regression analysis of trends and regional differences. AB - Hypertension has become a growing public health concern in rapidly developing countries. We estimated trends of hypertension prevalence in adults in China over the past 10 years and identified demographical and geographical determinants of these trends. A systematic search was conducted for studies published between 2002 and 2012 using PubMed and China National Knowledge Infrastructure electronic databases. In total, 47 studies were selected out of 4512 hits. The age standardized prevalence of hypertension increased by 1.4% per year. Hypertension prevalence in north China was 9.1% (95% confidence interval 4.1-14.1), which was higher than south China. After adjustments for survey year and region, the age standardized prevalence of hypertension did not differ significantly between men and women (P = 0.18). Our findings suggest a significant increase in the prevalence of hypertension in China over the period of 2002-2012 with considerable regional differences within China. PMID- 25023156 TI - The effects of midday nap duration on the risk of hypertension in a middle-aged and older Chinese population: a preliminary evidence from the Tongji-Dongfeng Cohort Study, China. AB - OBJECTIVE: Evidence from epidemiological studies suggested that shorter and longer duration of nocturnal sleeping may increase the risk of hypertension for older adults. Little is known about the duration of midday nap on the variability of blood pressure among older adults. In this study, we examined whether duration of habitual midday nap is associated with level of blood pressure or the risk of hypertension in a middle-aged and older Chinese population. METHODS: A total of 27 009 participants (mean age 63.6 years) from Dongfeng-Tongji Cohort Study received baseline examination including physical examination and laboratory tests, and a face-to-face-interview including demographic information, disease history, and lifestyle. Participants were categorized into five groups according to nap duration, such as no napping, less than 30 min, 30~60 min, 60~90 min, and at least 90 min. A series of categorical logistic regression models was used to examine the odd ratios of nap duration with hypertension. RESULTS: The level of SBP and DBP increased significantly with longer duration of habitual midday napping. Nappers with longer nap duration had considerably higher rate of hypertension. The longer duration of napping was related to higher blood pressure level and was associated with a higher risk of hypertension. After adjusting for possible confounders, the longer duration (>60 min) of napping was still associated with hypertension CONCLUSION: : Our findings showed that the practice of longer afternoon nap is associated with a higher increased risk of hypertension, independent of several covariates. Further prospective researches are needed to examine the midday nap duration for development of hypertension. PMID- 25023157 TI - Diagnostic accuracy of the Berlin questionnaire in detecting obstructive sleep apnea in patients with resistant hypertension. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is strongly associated with resistant hypertension. The Berlin questionnaire is the most widely used screening tool to identify patients at high risk of having OSA. The objective was to test the diagnostic accuracy of the Berlin questionnaire in detecting OSA in resistant hypertensive patients. METHODS: A cross-sectional analysis of 422 resistant hypertensive patients [31% men; mean (SD) age 62.4 (9.9) years] submitted to polysomnography (PSG), in whom the Berlin questionnaire was previously applied. OSA was defined by an apnea-hypopnea index of at least 5 per hour and moderate-to severe OSA by an apnea-hypopnea index of at least 15. Statistical analysis included bivariate comparisons between patients at high and low risk by the Berlin questionnaire, and logistic regression to assess the predictors of agreement between the Berlin questionnaire and PSG. Sensitivity, specificity, positive and negative predictive values and likelihood ratios for the Berlin questionnaire in detecting OSA were calculated. RESULTS: OSA was diagnosed in 347 patients (82.2%) and moderate-to-severe OSA in 234 patients (55.5%). In patients at high risk, moderate-to-severe OSA was confirmed in 58.3%, whereas in those at low risk, it was excluded in 50.4%. The accuracy of the Berlin questionnaire in detecting OSA was 55.6%. The specificity, sensitivity, positive and negative predictive value of the Berlin questionnaire in detecting moderate-to-severe OSA was 40, 69, 58 and 50%, respectively. The positive and negative likelihood ratios were 1.15 and 0.78, with a very low agreement (kappa = 0.081). CONCLUSION: In a large cohort of resistant hypertensive patients, the Berlin questionnaire had a low accuracy of identifying patients with OSA and should not be used as a screening method for selecting patients to PSG. PMID- 25023158 TI - The blood pressure-lowering effect of renal denervation is inversely related to kidney function. AB - OBJECTIVES: In renal denervation (RDN), a wide range in the blood pressure (BP) lowering effect has been reported. On the basis of the current knowledge of pathophysiology, we hypothesized that the BP-lowering effect of RDN would be inversely related to kidney function. Second, we investigated whether direct and indirect variables of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) would be related as well. METHODS: Sixty-seven patients from a prospective cohort of patients treated with RDN with completed 6 months follow-up were included. Data collected during routine standardized work up before RDN were used: 24-h urine excretion of creatinine, albumin, sodium and catecholamines, plasma creatinine, renin activity and aldosterone, ambulatory BP monitoring and a captopril challenge test. When considered well tolerated, antihypertensive drugs were stopped before these investigations. RESULTS: The BP lowering was inversely related to estimated glomerular filtration rate (eGFR) in patients who stopped antihypertensive drugs prior to testing (beta: 0.46, P = 0.013). There was a positive relation between SBP at baseline and the BP-lowering effect of RDN (beta:-0.55 mmHg per mmHg, P < 0.001). Parameters related to the rennin-angiotensin system (aldosterone, captopril test) and the sympathetic nervous system (dipping pattern and catecholamines in urine) positively related to the BP-lowering effect of RDN. CONCLUSION: The present explorative study shows an inverse relation between the BP-lowering effect of RDN and eGFR. Second, we found relations between variables of the RAAS and SNS with the BP-lowering effect of RDN. The data complement current concepts on pathophysiology of sympathetic hyperactivity and hypertension and may give some insight in the wide range of the effect of RDN. PMID- 25023159 TI - Hepatitis C virus screening practices and seropositivity among US veterans born during 1945 - 1965. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force (USPSTF) recently augmented risk-based hepatitis C (HCV) screening guidelines with a recommendation to perform one-time screening in all persons born during 1945 - 1965, a birth cohort known to have a higher prevalence of HCV. We sought to estimate the proportion of veterans seen at the Atlanta VA Medical Center (AVAMC) who had ever been screened for HCV infection by birth year. METHODS: We used an administrative database of all veterans seen at the AVAMC between January 1, 2011 and December 31, 2011, and a laboratory generated list of all HCV antibody tests and HCV RNA viral loads that were performed at the AVAMC to determine receipt of screening and HCV antibody positivity. Odds ratios and 95% confidence intervals were estimated using SAS version 9.2 (SAS institute, Cary, North Carolina). RESULTS: HCV antibody testing had ever been performed on 48% (41,556) of the veterans seen in 2011; 10% of those tested had a positive antibody. Confirmatory viral loads were performed in 96% of those with a positive antibody screen. Those born during 1945 - 1965 were more likely to have a HCV antibody performed when compared with those born in other years (54% vs. 41%, odds ratio [OR] 1.70, 95% Confidence Interval [CI] 1.65 1.74). Among veterans ever tested for HCV antibody (n = 41,556), those born during 1945 - 1965 were 6 times more likely to have a positive HCV antibody (15% vs. 3%, OR 5.87, 95% CI 5.32-6.78), and 3 times more likely to have chronic HCV infection (76% vs. 50%, OR 3.25, 95% CI 2.65-4.00). CONCLUSIONS: Nearly half of the veterans seen in 2011 at the AVAMC had ever been tested for HCV infection. When examined by birth cohort, over half of the veterans born during 1945 - 1965 had been screened for HCV and 15% of those screened had a positive HCV antibody. Our findings confirm the increased prevalence of HCV infection in persons born during 1945 - 1965 as identified in the updated CDC and USPSTF recommendations. PMID- 25023161 TI - Autism spectrum disorder: underlying neurobiology. PMID- 25023162 TI - Identification and classification of involuntary leg muscle contractions in electromyographic records from individuals with spinal cord injury. AB - Involuntary muscle contractions (spasms) are common after human spinal cord injury (SCI). Our aim was to compare how well two raters independently identified and classified different types of spasms in the same electromyographic records (EMG) using predefined rules. Muscle spasms were identified by the presence, timing and pattern of EMG recorded from paralyzed leg muscles of four subjects with chronic cervical SCI. Spasms were classified as one of five types: unit, tonic, clonus, myoclonus, mixed. In 48h of data, both raters marked the same spasms most of the time. More variability in the total spasm count arose from differences between muscles (84%; within subjects) than differences between subjects (6.5%) or raters (2.6%). Agreement on spasm classification was high (89%). Differences in spasm count, and classification largely occurred when EMG was marked as a single spasm by one rater but split into multiple spasms by the other rater. EMG provides objective measurements of spasm number and type in contrast to the self-reported spasm counts that are often used to make clinical decisions about spasm management. Data on inter-rater agreement and discrepancies on muscle spasm analysis can both drive the design and evaluation of software to automate spasm identification and classification. PMID- 25023163 TI - Validity of resting myotonometric assessment of lower extremity muscles in chronic stroke patients with limited hypertonia: a preliminary study. AB - The aim of this preliminary study was to examine the validity of a recently introduced tool (MyotonPRO) for the assessment of mechanical parameters of the main lower extremity muscles in patients with chronic stroke. Thigh and shank muscles of 20 stroke patients with limited hypertonia (11 men and 9 women; mean age: 52+/-11yrs) and 20 healthy controls (11 men and 9 women; mean age: 53+/ 10yrs) were bilaterally evaluated with (i) MyotonPRO for muscle stiffness, tone and elasticity, (ii) ultrasonography for muscle and subcutaneous thickness, and (iii) dynamometry for isometric muscle strength. MyotonPRO parameters of stroke patients were reassessed a week later (inter-day test-retest design). For all the investigated muscles, MyotonPRO variables did not differ between the more affected and the less affected side of patients (P>0.05 for main side effect), and neither differed between patients and controls (P>0.05 for main group effect), except for gastrocnemius medialis stiffness that was higher in patients (300+/-51N/m) than in controls (281+/-29N/m; P<0.05). Thigh muscle stiffness was negatively correlated to subcutaneous thickness (r=-0.84 for the vastus lateralis; P<0.001), while only tibialis anterior stiffness and tone correlated positively with muscle thickness (both r=0.46; P<0.01). Test-retest reliability of MyotonPRO parameters was adequate, except for muscle elasticity. The validity of MyotonPRO for the evaluation of thigh muscles in chronic stroke patients is partially challenged by the poor discriminant ability and by the considerable impact of subcutaneous tissue thickness (sex-dependent) on mechanical parameters. The potential validity of MyotonPRO for the assessment of shank muscles requires further investigation. PMID- 25023164 TI - Evolution of integrin I domains. AB - In humans, an ~200-residue "inserted" I domain, a von Willebrand factor A domain (vWFA), buds out from the beta-propeller domain in 9 of 18 integrin alpha subunits. The vWFA domain is not unique to the alpha subunit as it is an integral part of all integrin beta subunits and many other proteins. The betaI domain has always been a component of integrins but the alphaI domain makes its appearance relatively late, in early chordates, since it is found in tunicates and later diverging species. The tunicate alphaI domains are distinct from the human collagen and leukocyte recognizing integrin alpha subunits, but fragments of integrins from agnathastomes suggest that the human-type alphaI domains arose in an ancestor of the very first vertebrate species. The rise of integrins with alphaI domains parallels the enormous changes in body plan and systemic development of the chordate line that began some 550 million or more years ago. PMID- 25023165 TI - Integrin alpha1beta1. AB - Integrin alpha1beta1 is widely expressed in mesenchyme and the immune system, as well as a minority of epithelial tissues. Signaling through alpha1 contributes to the regulation of extracellular matrix composition, in addition to supplying in some tissues a proliferative and survival signal that appears to be unique among the collagen binding integrins. alpha1 provides a tissue retention function for cells of the immune system including monocytes and T cells, where it also contributes to their long-term survival, providing for peripheral T cell memory, and contributing to diseases of autoimmunity. The viability of alpha1 null mice, as well as the generation of therapeutic monoclonal antibodies against this molecule, have enabled studies of the role of alpha1 in a wide range of pathophysiological circumstances. The immune functions of alpha1 make it a rational therapeutic target. PMID- 25023166 TI - alpha2beta1 Integrin. AB - The alpha2beta1 integrin, also known as VLA-2, GPIa-IIa, CD49b, was first identified as an extracellular matrix receptor for collagens and/or laminins [55, 56]. It is now recognized that the alpha2beta1 integrin serves as a receptor for many matrix and nonmatrix molecules [35, 79, 128]. Extensive analyses have clearly elucidated the alpha2 I domain structural motifs required for ligand binding, and also defined distinct conformations that lead to inactive, partially active or highly active ligand binding [3, 37, 66, 123, 136, 137, 140]. The mechanisms by which the alpha2beta1 integrin plays a critical role in platelet function and homeostasis have been carefully defined via in vitro and in vivo experiments [76, 104, 117, 125]. Genetic and epidemiologic studies have confirmed human physiology and disease states mediated by this receptor in immunity, cancer, and development [6, 20, 21, 32, 43, 90]. The role of the alpha2beta1 integrin in these multiple complex biologic processes will be discussed in the chapter. PMID- 25023167 TI - Integrin alpha10beta1: a collagen receptor critical in skeletal development. AB - Integrin alpha10beta1 is the most abundant collagen-binding integrin in cartilaginous tissues and its expression pattern is distinct from that of other collagen-binding integrins. In vitro and in vivo studies have identified integrin alpha10beta1 as a unique phenotypic marker for chondrocyte differentiation and a crucial mediator of cell-matrix interactions required for proper cartilage development. This chapter describes the structure of the integrin subunit alpha10, the tissue distribution of the integrin 10beta1 and updates available information regarding its regulation and ligand binding. We also summarize current information on the functional roles of alpha10beta1 in chondrogenesis of mesenchymal stem cells and in skeletal growth. PMID- 25023168 TI - Integrin alpha11beta1: a major collagen receptor on fibroblastic cells. AB - Integrin alpha11 is the last addition to the vertebrate integrin family. In this chapter we will summarize some basic facts about this integrin and update with information that has been gained in the last decade. Integrin alpha11beta1 is a major collagen receptor on a subset of fibroblasts. Extensive characterization of the expression pattern in developing mouse embryos has demonstrated expression restricted to subsets of fibroblasts and a transient expression in odontoblasts, but comprehensive characterization of corresponding expression in adult tissues is still lacking. Mice lacking integrin alpha11 are dwarfed, primarily due to defective incisor eruption defect, which can be traced back to need for alpha11 on periodontal ligament fibroblasts during incisor eruption. Separate studies have suggested reduced levels of IGF-1 in mice lacking alpha11. Analysis of lung cancer has identified alpha11beta1 as a functional important collagen receptor on carcinoma associated fibroblasts (CAFs) and a number of disease models are awaiting analysis to see the importance of this collagen receptor in pathological models. PMID- 25023169 TI - Regulation of integrin activity by phosphorylation. AB - Integrins are heterodimeric complex type I membrane proteins involved in cellular adhesion and signaling. They exist as inactive molecules in resting cells, and need activation to become adhesive. Although much is known about their structure, and a large number of interacting molecules have been described, we still only partially understand how their activities are regulated. In this review we focus on the leukocyte-specific beta2-integrins and, specifically, on the role of integrin phosphorylation in the regulation of activity. Phosphorylation reactions can be fast and reversible, thus enabling strictly directed regulatory activities both time-wise and locally in specific regions of the plasma membrane in different leukocytes. PMID- 25023170 TI - Integrin alphaEbeta7: molecular features and functional significance in the immune system. AB - Alpha E beta 7 (alphaEbeta7) is an alpha-I domain-containing integrin that is highly expressed by a variety of leukocyte populations at mucosal sites including intraepithelial T cells, dendritic cells, mast cells, and T regulatory cells (Treg). Expression depends largely or solely on transforming growth factor beta (TGF-beta) isoforms. The best characterized ligand for alphaEbeta7 is E-cadherin on epithelial cells, though there is evidence of a second ligand in the human system. An exposed acidic residue on the distal aspect of E-cadherin domain 1 interacts with the MIDAS site in the alphaE alpha-I domain. By binding to E cadherin, alphaEbeta7 contributes to mucosal specific retention of leukocytes within epithelia. Studies on alphaE knockout mice have identified an additional important function for this integrin in allograft rejection and have also indicated that it may have a role in immunoregulation. Recent studies point to a multifaceted role for alphaEbeta7 in regulating both innate and acquired immune responses to foreign antigen. PMID- 25023171 TI - Structural aspects of integrins. AB - Structural studies on integrins have recently made great strides in recent years. Crystal structures of the complete extracellular fragments of three integrins in open and closed conformations, 6 alpha-I domains in complex with ligands, and at least 20 intracellular proteins in complex with cytosolic tails have been obtained; and several transmembrane and cytosolic complexes have been determined by NMR. High resolution EM studies complement these atomic resolution techniques by studying the integrin in different activation states. Although we still have only a few experimental examples among integrin family members, the high level of sequence homology between integrins means that reliable models can be built for the other members of the integrin family. These structures make sense of a lot of preceding biochemical, biophysical and mutagenesis studies, and generate many new testable hypotheses of integrin function. This chapter emphasizes new structural insights applicable to all integrins, with an emphasis on those integrins that contain an alpha-I domain. The structural data reinforce the notion of the integrin as a molecule in dynamic equilibrium at the cell surface, regulated by binding both to extracellular and intracellular ligands. PMID- 25023172 TI - Integrin recognition motifs in the human collagens. AB - The best-known (fibrillar) collagens support cellular adhesion primarily through a subset of collagen-binding integrins, alpha1beta1, alpha2beta1, alpha10beta1 and alpha11beta1, which have been shown to recognise a series of similar sequences. These contain Gxx'GEx''motifs (where x is a hydrophobic residue, x' is usually O (hydroxyproline) and x'' is often R). Here, we review the variations within such sequences that support integrin reactivity, and their distribution across the 28 human collagens. The main basis for our understanding is the use of triple-helical, homotrimeric collagen peptides, but this work is far from exhaustive, and there is good evidence that heterotrimeric collagens where the sequence of interest occurs in two or even just a single chain may still support integrin binding. The fibrillar collagens I, II and III are rich in GxOGER motifs, whereas GxOGEK is more widely distributed, and less frequent in these three archetypal fibrillar collagens. PMID- 25023173 TI - Cellular signaling by collagen-binding integrins. AB - The four collagen-binding alphaI domain integrins form their own subgroup among cell adhesion receptors. The signaling functions of alpha1beta1 and alpha2beta1 integrins have been analyzed in many experimental models, whereas less studies are available about the more recently found alpha10beta1 and alpha11beta1 heterodimers. Interestingly, collagen binding by alpha1beta1 and alpha2beta1 often generates opposite cellular responses. For example alpha1beta1 has often been reported to promote cell proliferation and to suppress collagen synthesis, whereas alpha2beta1 can in many model systems inhibit growth and promote collagen synthesis. There are obviously cell type dependent factors modifying the signaling. Additionally the structure and the organization of collagenous matrix play a critic role. Many recent studies have also stressed the importance of the crosstalk between the integrins and other cell surface receptors. PMID- 25023174 TI - The therapeutic potential of I-domain integrins. AB - Due to their role in processes central to cancer and autoimmune disease I-domain integrins are an attractive drug target. Both antibodies and small molecule antagonists have been discovered and tested in the clinic. Much of the effort has focused on alphaLbeta2 antagonists. Maybe the most successful was the monoclonal antibody efalizumab, which was approved for the treatment of psoriasis but subsequently withdrawn from the market due to the occurrence of a serious adverse effect (progressive multifocal leukoencephalopathy). Other monoclonal antibodies were tested for the treatment of reperfusion injury, post-myocardial infarction, but failed to progress due to lack of efficacy. New potent small molecule inhibitors of alphav integrins are promising reagents for treating fibrotic disease. Small molecule inhibitors targeting collagen-binding integrins have been discovered and future work will focus on identifying molecules selectively targeting each of the collagen receptors and identifying appropriate target diseases for future clinical studies. PMID- 25023175 TI - Author's response to troponin leak-Janus face of polypharmacy. PMID- 25023177 TI - [Effects of age and educational background in understanding the written information normally deliver to our patients]. PMID- 25023176 TI - Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay. AB - BACKGROUND: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans. METHODS: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice. RESULTS: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience. CONCLUSIONS: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy. PMID- 25023179 TI - Outcome following a negative CT Angiogram for gastrointestinal hemorrhage. AB - OBJECTIVE: This study was designed to evaluate the role of a negative computed tomography angiogram (CTA) in patients who present with gastrointestinal (GI) hemorrhage. METHODS: A review of all patients who had CTAs for GI hemorrhage over an 8-year period from January 2005 to December 2012 was performed. Data for patient demographics, location of hemorrhage, hemodynamic stability, and details of angiograms and/or the embolization procedure were obtained from the CRIS/PACS database, interventional radiology database, secure electronic medical records, and patient's clinical notes. RESULTS: A total of 180 patients had 202 CTAs during the 8-year period: 87 CTAs were performed for upper GI hemorrhage (18 positive for active bleeding, 69 negative) and 115 for lower GI hemorrhage (37 positive for active bleeding, 78 negative); 58.7 % (37/63) of patients with upper GI bleed and 77.4 % (48/62) of patients with lower GI bleed who had an initial negative CTA did not rebleed without the need for radiological or surgical intervention. This difference was statistically significant (p = 0.04). The relative risk of rebleeding, following a negative CTA, in lower GI bleeding versus upper GI bleeding patients is 0.55 (95 % confidence interval 0.32-0.95). CONCLUSIONS: Patients with upper GI bleed who had negative CTAs usually require further intervention to stop the bleeding. In contrast, most patients presenting with lower GI hemorrhage who had a negative first CTA were less likely to rebleed. PMID- 25023178 TI - Global copy number analyses by next generation sequencing provide insight into pig genome variation. AB - BACKGROUND: Copy number variations (CNVs) confer significant effects on genetic innovation and phenotypic variation. Previous CNV studies in swine seldom focused on in-depth characterization of global CNVs. RESULTS: Using whole-genome assembly comparison (WGAC) and whole-genome shotgun sequence detection (WSSD) approaches by next generation sequencing (NGS), we probed formation signatures of both segmental duplications (SDs) and individualized CNVs in an integrated fashion, building the finest resolution CNV and SD maps of pigs so far. We obtained copy number estimates of all protein-coding genes with copy number variation carried by individuals, and further confirmed two genes with high copy numbers in Meishan pigs through an enlarged population. We determined genome-wide CNV hotspots, which were significantly enriched in SD regions, suggesting evolution of CNV hotspots may be affected by ancestral SDs. Through systematically enrichment analyses based on simulations and bioinformatics analyses, we revealed CNV related genes undergo a different selective constraint from those CNV-unrelated regions, and CNVs may be associated with or affect pig health and production performance under recent selection. CONCLUSIONS: Our studies lay out one way for characterization of CNVs in the pig genome, provide insight into the pig genome variation and prompt CNV mechanisms studies when using pigs as biomedical models for human diseases. PMID- 25023180 TI - Microwave ablation of giant hepatic cavernous hemangiomas. AB - PURPOSE: This study was designed to explore the safety and efficacy of percutaneous microwave (MW) ablation as an alternative treatment for symptomatic giant hepatic hemangiomas. METHODS: Patients (n = 7; 6 females, 1 male; mean age = 44 years) with symptomatic, giant hemangiomas (n = 8) were treated with ultrasound-guided percutaneous MW ablation and followed for a mean of 18 months. Patient pain was recorded both before and after the procedure according to the 10 point visual analog scale. All patients were treated using one or three gas cooled 17-gauge antennas powered by a 2.4-GHz generator (Neuwave Medical, Madison, WI). Mean ablation time was 11.6 min. Four patients received hydrodissection to protect the abdominal wall, colon, or gallbladder (5 % dextrose in water, mean volume 900 mL). Immediate postablation biphasic CT of the abdomen was performed, and four of seven patients have undergone delayed follow up imaging. RESULTS: All ablations were technically successful with no major or minor complications. Average pain score decreased from 4.6 to 0.9 (p < 0.05), and six of seven patients report resolution or improvement of symptoms at 18-month average follow-up (range 1-33 months). Immediately postablation, mean tumor diameter decreased 25 % (from 7.3 to 5.5 cm, p < 0.05) and volume decreased 62 % (from 301 to 113 cm(3), p < 0.05). DISCUSSION: In this series, percutaneous MW ablation was safe, well-tolerated, and effective in markedly shrinking large hepatic hemangiomas and improving symptoms in most patients. PMID- 25023181 TI - The evaluation of the individual impact factor of researchers and research centers using the RC algorithm. AB - The RC algorithm quantitatively evaluates the personal impact factor of the scientific production of isolated researchers. The authors propose an adaptation of RC to evaluate the personal impact factor of research centers, hospitals and other research groups. Thus, these could be classified according to the accredited impact of the results of their scientific work between researchers of the same scientific area. This could be useful for channelling budgets and grants for research. PMID- 25023182 TI - [Perspectives of Spanish psychiatrists on the management of dementias: the PsicoDem survey]. AB - INTRODUCTION: Mental health services are not systematically involved in the care of dementias in Spain. Nevertheless, many patients with dementia attend these services. The perspective of psychiatrist as regards this situation has not been evaluated at the national level to date, and it may be of interest to determine their actual involvement and the strategies to foster it. MATERIAL AND METHODS: A survey was conducted on 2,000 psychiatrists on a range of mental health care services. Respondents provided socio-demographic data and information about clinical aspects, together with their opinions regarding the management of dementia. Responses were described by their raw frequencies and measures of association for cross-tabulations resulting from selected pairs of questions. Inferences were made by calculating their 95% confidence intervals. RESULTS: Psychiatrist involvement in the management of dementias was limited, aside from those involved in psycho-geriatric units or nursing homes facilities. However, there were wide, regional differences. Nearly all respondents (81%) were ready to augment their knowledge and skills in the area of dementia. In particular, the insufficient medical education, together with other organizational factors, such as the difficulties in ordering diagnostic tests (i.e. neuroimaging), or prescribing anti-dementia drugs in some regions, were common barriers psychiatrists faced when approaching patients with dementia. CONCLUSIONS: Increasing psychiatrist involvement and boosting coordinated efforts with other specialists in a form of integrated care may advance the care of dementias in Spain to a more valuable level. PMID- 25023183 TI - Exposure to Free-Play Modes in Simulated Online Gaming Increases Risk-Taking in Monetary Gambling. AB - This study examined the behavioral effects of practice modes in simulated slot machine gambling. A sample of 128 participants predominantly aged 18-24 years were randomly allocated to 1 of 4 pre-exposure conditions: control (no practice), standard 90% return to player, inflated return to player and inflated return with pop-up messages. Participants in all conditions engaged in monetary gambling using a realistic online simulation of a slot machine. As predicted, the results showed that those players exposed to inflated or 'profit' demonstration modes placed significantly higher bets in the real-play mode as compared to the other groups. However, the groups did not differ in relation to how long they persisted in the real-play mode. Pop-up messages had no significant effect on monetary gambling behavior. The results of this study confirm that exposure to inflated practice or "demo" modes lead to short-term increases in risk-taking. These findings highlight the need for careful regulation and monitoring of internet gambling sites, as well as further research on the potential risks of simulated gambling activities for vulnerable segments of the gambling population. PMID- 25023184 TI - Gambling Related Cognitive Distortions in Adolescence: Relationships with Gambling Problems in Typically Developing and Special Needs Students. AB - The present study examined the link between problematic gambling and gambling related cognitions (GRCs) in a large sample of adolescents with (N = 266) and without (N = 1,738) special education needs (SEN) between the ages of 14 and 18 years attending several high schools in eastern central Ontario. The adolescents with SENs were identified as having various learning disorders and/or internalizing and externalizing problems [e.g., attention deficit hyperactivity disorder (ADHD)]. All adolescents completed a self-report questionnaire package that included the GRC Scale (GRCS; Raylu and Oei in Addiction 99:757-769, 2004), as well as measures of problem gambling, negative affect, and ADHD symptomatology. Results showed that adolescents with SEN hold more erroneous beliefs about gambling and had a higher risk of developing problematic patterns of gambling behaviour than their typically developing peers. Moreover, the GRCS subscales were found to be strong predictors of problem gambling among adolescents both with and without SEN, accounting for a substantial amount of the variance even when controlling for the effects of age, gender, ADHD, and negative affect. It is suggested that intervention and prevention programs aimed at adolescent gambling need to give particular attention to those with SEN. PMID- 25023185 TI - Aluminum contamination in parenteral products. AB - PURPOSE OF REVIEW: In 1986, the US Food and Drug Administration issued an aluminum mandate in hopes of minimizing patient exposure to aluminum contaminates contained in parenteral nutrition additives. The purpose of this article is to revisit the status of aluminum contamination as it relates to parenteral nutrition and to survey the recent literature to determine if any new findings have emerged. A special emphasis will be placed on the complications associated with aluminum toxicity. RECENT FINDINGS: In addition to metabolic bone disease, patients with aluminum toxicity are also prone to other complications such as neurodevelopmental delays and cholestasis. Other potentially serious consequences, including osteoporosis, growth failure, and dementia, can arise years after the initial exposure to aluminum, showing that preventing toxicity is imperative. SUMMARY: Unlike the rapid response to eliminating aluminum toxicity in the dialysis patient population, similar successes have not been realized in patients receiving parenteral nutrition solutions. Product formulation changes have been slow to emerge from manufacturers. It remains the responsibility of healthcare practitioners to recognize the patient populations at risk for toxicity and act accordingly. Monitoring aluminum status and purchasing products known to possess the least amount of aluminum are two such approaches. PMID- 25023186 TI - Imaging of trace elements in tissues: with a focus on laser ablation inductively coupled plasma mass spectrometry. AB - PURPOSE OF REVIEW: Elemental imaging techniques are capable of showing the spatial distribution of elements in a sample. Their application in biomedical sciences is promising, but they are not yet widely employed. The review gives a short overview about techniques available and then focuses on the advantages of using laser ablation inductively coupled plasma mass spectrometry for elemental bioimaging. Current examples for the use of elemental imaging with medical context are given to illustrate the potential of this type of analysis for clinical applications. RECENT FINDINGS: Recently, synchrotron-based techniques and laser ablation inductively coupled plasma mass spectrometry have been successfully applied to analyse the spatial distribution of elements in biological samples of medical relevance. SUMMARY: Elemental bioimaging methods have a great potential for medical applications. They are complementary to molecular imaging and histological staining and are especially attractive when used in combination with stable isotope tracer experiments. PMID- 25023187 TI - Pouchitis: prevention and treatment. AB - PURPOSE OF REVIEW: Pouchitis, representing a spectrum of disease phenotypes, is the most common long-term complication in patients who have undergone restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Its management and prevention are challenging. RECENT FINDINGS: Treatment modalities vary according to phenotypes of pouchitis. The medical therapy of pouchitis remains largely empiric and antibiotic-based. However, patients may develop de-novo chronic antibiotic-refractory pouchitis (CARP) or progress from acute antibiotic responsive phenotype. Patients with CARP often require alternative medical approaches to routine antibiotics, including the use of oral or topical mesalazine, corticosteroids, and sometimes immunomodulators or biological agents against tumour necrosis factor. There are two strategies to prevent pouchitis, the primary (i.e., the prevention of the initial episode) and secondary (i.e., the prevention of recurrent episodes) prophylaxis. There are scant data in the literature on nutritional aspects. SUMMARY: We evaluated the efficacy of current strategies of prevention and treatments of pouchitis and propose algorithms, including attention to nutrition wherein data exist. PMID- 25023188 TI - The Mediterranean diet, hepatic steatosis and nonalcoholic fatty liver disease. AB - PURPOSE OF REVIEW: The purpose of this review is to present the pathophysiological mechanisms and most recent clinical evidence regarding the role of the Mediterranean diet in preventing and treating nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Several components of the Mediterranean diet have proven benefits in controlling the pathophysiological mechanisms involved in NAFLD. However, the few clinical studies that have assessed the diet have involved low numbers of patients and lacked methodological rigor. The results of these studies suggest that the Mediterranean diet attenuates the progression of NAFLD once it is established, but does not contribute to preventing the disease in patients at risk. SUMMARY: Although there is a lack of clinical evidence derived from studies with high-quality methodology, the pathophysiological mechanisms of NAFLD shared with other associated pathologies suggest that there is a role for the Mediterranean diet in managing NAFLD. Studies with better methodology are needed to confirm the impact of the diet. PMID- 25023189 TI - Do low-calorie drinks 'cheat' the enteral-brain axis? AB - PURPOSE OF REVIEW: The consumption of low-calorie beverages has increased worldwide, mainly because of their combination of sweet taste without adding significant calories to the diet. However, some epidemiological studies have linked the higher consumption of low-calorie beverages with increased body weight gain. RECENT FINDINGS: Although a matter of debate, this paradoxical association between low-calorie beverages and weight gain has been attributed to their effect on the enteral-brain axis. More specifically, artificial sweeteners present in low-calorie beverages could induce appetite increase, probably due to an ambiguous psychobiological signal (uncoupling sweet taste from calorie intake) that confounds the appetite's regulatory mechanisms, promoting overeating and, ultimately, leading to weight gain. However, many studies do not support this assumption, and the mechanisms underlying the interaction between low-calorie beverages and the enteral-brain axis remain to be defined. SUMMARY: The understanding of the effects of low-calorie drinks on the enteral-brain axis still remains in its infancy and needs to be unveiled. The consumption of low calorie beverages reduces the calories from that drink, but compensatory phenomena may increase energy intake, and if so must be recognized and avoided. PMID- 25023190 TI - Bedside ultrasound measurement of skeletal muscle. AB - PURPOSE OF REVIEW: Skeletal muscle and lean body mass may be vital to prognosis and functional recovery in chronic and acute illness, particularly in conditions in which muscle atrophy is prevalent. Ultrasound provides a precise and expedient method to measure muscle mass and changes in skeletal muscle at the bedside. RECENT FINDINGS: Here, we describe the various methodological approaches along with the validation and reliability tests that have been performed in various populations. Current applications of ultrasound in chronic and acute illness as well as its limitations and strengths in quantifying the muscle mass and changes in muscle over time are discussed. To capitalize on the beneficial features of ultrasound for measuring muscle, we describe the work that is needed to optimize the usefulness of ultrasound in chronic disease and acute care. SUMMARY: Given the precision, practicality, and ease of use, ultrasound is emerging as a highly useful tool in expediently measuring the muscle mass and changes in muscle tissue at the bedside. Ultrasound may be valuable in identifying patients who are at risk of malnutrition, in tracking muscle atrophy for the purpose of calculating nutrient delivery, and in assessing the success or failure of nutrition, pharmacological and rehabilitative interventions that aim to counter muscle atrophy. PMID- 25023191 TI - Dysmotility disorders: a nutritional approach. AB - PURPOSE OF REVIEW: Chronic intestinal pseudo-obstruction (CIPO) results in markedly compromised peristalsis mimicking an intestinal occlusion. The main goals of CIPO management are to improve intestinal propulsion and to maintain adequate nutrition status. The review describes the global management of CIPO including methods of diagnosis and nutritional, pharmacological and surgical therapies. RECENT FINDINGS: The principles of CIPO management are to perform a physiological assessment of the gastrointestinal tract involved, to improve symptoms and to prevent malnutrition. We shall discuss the place of physiological motility tests such as intestinal manometry and the cine-magnetic resonance imaging to facilitate diagnosis. Home parenteral nutrition (HPN) is a frequently used therapy with a high dependence level. However, recent data are consistent with a good long-term prognosis. Currently, CIPO becomes a significant cause of chronic intestinal failure. We discuss the outcomes of HPN and surgery. SUMMARY: CIPO is a rare and complex disease. Small bowel manometry remains a gold standard for diagnosis, but new imaging tools appear promising. The management of CIPO requires the cooperation of specialists involved in the intestinal failure field. The better knowledge of CIPO prognosis should encourage clinicians to propose intestinal transplantation in selected cases. PMID- 25023192 TI - Effects of magnesium depletion on inflammation in chronic disease. AB - PURPOSE OF REVIEW: To update findings supporting the opinion that commonly occurring subclinical magnesium deficiency induced by a low dietary intake is a predisposing factor for chronic inflammatory stress that contributes to the incidence of chronic diseases such as cardiovascular disease and diabetes. RECENT FINDINGS: Both deficient magnesium intakes (<250 mg/day) and serum magnesium concentrations (<= 0.75 mmol/l) have been associated with elevated serum C reactive protein concentration, a widely used indicator of inflammation. Achieving magnesium intakes or serum magnesium concentrations that indicate an adequate magnesium status generally attenuates elevated serum C-reactive protein to concentrations that are not indicative of chronic low-grade inflammation. Individuals that are obese or have chronic diseases for which low-grade inflammation is a risk factor are commonly found to be magnesium-deficient. SUMMARY: Subclinical magnesium deficiency caused by low dietary intake often occurring in the population is a predisposing factor for chronic inflammatory stress that is conducive for chronic disease. Magnesium deficiency should be considered a nutrient of significant concern for health and well-being. PMID- 25023193 TI - Minimal and maximal incidence rates of skin cancer in Caucasians estimated by use of sigmoidal UV dose-incidence curves. AB - BACKGROUND: Sigmoidal (S-shaped) dose-cancer incidence relationships are often observed in animal bioassays for carcinogenicity. Ultraviolet (UV) radiation is an established skin carcinogen. The aim of this study is to examine if S-shaped curves describe the relationship between solar UV doses and skin cancer incidences, and if such relationships can be used to estimate threshold levels of non-carcinogenic UV exposure, as well as maximal incidence rates. METHODS: We studied the incidence rate-annual erythema-effective UV dose relationship for squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and cutaneous melanoma (CM) among different Caucasian populations in Europe, Australia and New Zealand. RESULTS: Our analysis indicates that S-shaped associations describe the data well (P < 0.0001). The age-adjusted incidence rates for cases expected to be due to other causes than solar UV exposure (at zero UV dose) were found to be around 0.6, 9.7 and 4.0 per 100,000 for women in 1997-2007 for SCC, BCC and CM, respectively, and around 1.2, 14.3 and 2.6 per 100,000 for men. The analysis indicates that SCC, BCC and CM have maximal incidence of 361 +/- 24, 1544 +/- 49 and 36 +/- 4 per 100,000 for women, and 592 +/- 35, 2204 +/- 109 and 50 +/- 4 per 100,000 for men. CONCLUSIONS: Between 89 and 95% of the annual CM cases, around 99.8% SCC and 99.4% BCC cases are caused by solar UV exposure. The analysis did not identify any "safe" UV dose below which the risk for skin cancer was absent. Avoidance of UV radiation has a potential to reduce the incidence of skin cancer in fair-skinned population. PMID- 25023194 TI - Do uterine natural killer cell numbers in peri-implantation endometrium predict hypertensive disorder in pregnancy in women with a history of reproductive failure? AB - The aim of this study was to investigate whether or not increased uterine natural killer (uNK) cell numbers in the peri-implantation endometrium are associated with an increased risk of hypertensive disorders in a subsequent pregnancy. This is a retrospective study including 80 women with a history of unexplained recurrent miscarriage or recurrent implantation failure. Precisely timed endometrial biopsies were obtained from women 7-9 days after the luteinising hormone surge. uNK cells were immunostained for CD56+ and expressed as a percentage of total stromal cells. Patients were defined as having a high uNK cell count if the percentage of total stromal cells was more than 13.9%. Five out of 29 (17.2%) women in the high uNK cell count group and 5 out of 51 (9.8%) women in the normal uNK cell count group developed gestational hypertension. Pre eclampsia was diagnosed in 2 (6.9%) patients in the high uNK cell count group and 1 (2.0%) patient from the normal uNK cell count group. There was no significant difference in the incidence of either gestational hypertension (P=0.483) and pre eclampsia (P=0.296) between groups. The overall incidence of hypertensive disease in women with high uNK cell count (24.1%) was two times higher than women with normal uNK cell count (11.8%), but it was not statistically significant (P=0.208). An increased uNK cells count in the peri-implantation period in a cycle prior to conception did not appear to significantly increase the likelihood of hypertensive disease of pregnancy. PMID- 25023196 TI - Intramuscular distribution of botulinum toxin--visualized by MRI. AB - OBJECTIVE: A precise knowledge of the spread of botulinum toxin (BoNT) in muscle tissue is required to efficiently access endplate zones and increase BoNT's therapeutic efficacy. Here, we aimed to understand the spatiotemporal dynamics of BoNT distribution in skeletal muscle and its modulating factors, such as injected volume and exercise after injection. METHODS: To visualize distribution in muscle tissue, sagittal, dynamic, balanced fast field echo (BFFE) MRI imaging was performed during injection of 1 ml BoNT/NaCl bolus in spastic biceps brachii muscles (SBB, n=4), and 1 ml NaCl in the right and 2 ml NaCl in the left healthy biceps brachii (HBB, n=6), with or without successive muscle exercise. The pattern of extracellular fluid distribution was evaluated by T2-weighted and diffusion tensor imaging (DTI) sequences. RESULTS: BFFE indicated an immediate increase in hyperintensity, parallel to the muscle fibers, in the shape of a long (5.3+/-1.7 cm) and thin (0.52+/-1.3 cm) layer in HBB. The layer in SBB was shorter (3.25+/-0.6 cm, p=0.01) and tended to be thicker (0.74+/-2.9 cm, p=0.27). In HBB, an increase in volume (2 ml) resulted in an increase in thickness (0.95+/ 0.2 cm, p=0.015), but a consistent length (5.67+/-1.3 cm, p=0.54). DTI visualized a change of diffusion, which exceeded the bolus region by approximately 0.5 cm. Redistribution occurred 10 min after injection and was more prominent in HBB, compared to SBB. Additional muscle activity did not alter the diffusion pattern or bolus distribution. CONCLUSION: Injecting BoNT at different depths perpendicular to the direction of the muscle fiber might optimize the efficacy of BoNT treatment. Additional sites along muscle fibers should be considered in SBB. PMID- 25023197 TI - Combined genetic and nutritional risk models of triple negative breast cancer. AB - Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and beta-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01-7.64) and 10.89 (95% confidence interval = 3.50-33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women. PMID- 25023195 TI - The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model. AB - BACKGROUND: Breast cancer is the most frequently diagnosed cancer in women in the United States. Approximately 70% of breast cancers are diagnosed in postmenopausal women. Major clinical trials and experimental studies showed that aromatase inhibitors are effective against postmenopausal breast cancer. Despite their effectiveness in reducing tumor recurrence, aromatase inhibitors have adverse effects on the cardiovascular system and increase osteoporosis and bone fractures. Our study is aimed at investigating the role of natural steroid hormones on serum cardiovascular and bone resorption markers in an established mouse model mimicking postmenopausal breast cancer. METHODS: Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively expressing aromatase. The mice were treated with different combinations and doses of steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100 ug). Serum levels of HDL, LDL/VLDL, free and total cholesterol, total and bone specific alkaline phosphatase and triglycerides were analyzed after 5, 10 and 15 months. RESULTS: Free cholesterol and LDL/VLDL levels in serum were reduced in groups mimicking estrous cycle and menstrual cycle hormones treatment. HDL cholesterol was increased in all the hormone treated groups except the estrous cycle-mimicking group. Bone specific alkaline phosphatase was decreased in menstrual cycle levels of estrogen and progesterone treatment. CONCLUSIONS: All together our results show that use of natural hormones in appropriate combinations have beneficial effects on cardiac and bone toxicity, along with better tumor reduction than current treatments. PMID- 25023198 TI - Sequencing your genome: your future is here, but are you sure you want to know it? PMID- 25023199 TI - Good intentions and ICH-GCP: Trial conduct training needs to go beyond the ICH GCP document and include the intention-to-treat principle. AB - BACKGROUND: It is assumed investigators and statisticians fully understand the importance of avoiding missing outcomes and the intention-to-treat principle during design and analysis phases of a randomised controlled trial in order to obtain the most valuable and reliable results. However, many personnel undertaking day-to-day trial conduct and data collection commonly rely exclusively for guidance on the widely implemented, indeed regulated, International Conference on Harmonisation-Good Clinical Practice document as the guideline and standard for trial conduct. PURPOSE: This article describes adverse consequences of omission of intention-to-treat principles from training for trial personnel and explores the need for training in addition to the International Conference on Harmonisation-Good Clinical Practice guideline document. METHODS: Data from the Breast Boost Study were used to illustrate a comparison of actual results, where vigilant senior investigators re-enforced intention-to-treat requirements throughout all aspects of trial conduct with results that could easily have occurred if study personnel did not understand the importance of intention-to-treat principles. Experience as a co-ordinating centre for an international trial (Trans-Tasman Radiation Oncology Group 08.06 Breast STARS) acted as an audit of data-management culture regarding intention-to-treat in Australia and New Zealand. RESULTS: Despite the Breast Boost Study exceeding planned accrual, it was demonstrated that the study, which found a statistically significant result, could have reported a negative or inconclusive result under the scenario of trial conduct personnel having lack of understanding of the importance of avoiding losses to follow-up. Trans-Tasman Radiation Oncology 08.06 co-ordination experience verified that data-management culture in Australia and New Zealand does not adequately recognise intention-to-treat principles, and this is reflected in trial conduct. LIMITATIONS: Trial data described are limited to two trials and in the Australian and New Zealand setting. CONCLUSION: To be both scientifically and ethically valid, guidelines for trial conduct should include and stress the importance of the intention-to-treat principle and in particular avoiding missing outcomes. Our discussion highlights the vitally important role played by personnel involved in day-to-day trial conduct. Inclusion of scientific principles in guideline documents and/or training which goes beyond International Conference on Harmonisation-Good Clinical Practice to include intention-to-treat is essential to achieve robust research results. Related aspects of randomised trial consent and ethics are discussed. PMID- 25023200 TI - A trial of in-hospital, electronic alerts for acute kidney injury: design and rationale. AB - BACKGROUND: Acute kidney injury is common in hospitalized patients, increases morbidity and mortality, and is under-recognized. To improve provider recognition, we previously developed an electronic alert system for acute kidney injury. To test the hypothesis that this electronic acute kidney injury alert could improve patient outcome, we designed a randomized controlled trial to test the effectiveness of this alert in hospitalized patients. The study design presented several methodologic, ethical, and statistical challenges. PURPOSE: To highlight the challenges faced and the solutions employed in the design and implementation of a clinical trial to determine whether the provision of an early electronic alert for acute kidney injury would improve outcomes in hospitalized patients. Challenges included how to randomize the delivery of the alert system and the ethical framework for waiving informed consent. Other methodologic challenges included the selection and statistical evaluation of our study outcome, a ranked-composite of a continuous covariate (creatinine) and two dichotomous outcomes (dialysis and death), and the use of the medical record as a source of trial data. METHODS: We have designed a randomized trial to assess the effectiveness of an electronic alert system for acute kidney injury. With broad inclusion criteria, and a waiver of informed consent, we enroll and randomize virtually every patient with acute kidney injury in our hospital. RESULTS: As of 31 March 2014, we have enrolled 2373 patients of 2400 targeted. Pre-alert data demonstrated a strong association between severity of acute kidney injury and inpatient mortality with a range of 6.4% in those with mild, stage 1 acute kidney injury, to 29% among those with stage 3 acute kidney injury (p < 0.001). We judged that informed consent would undermine the scientific validity of the study and present harms that are out of proportion to the very low risk intervention. CONCLUSION: Our study demonstrates the feasibility of designing an ethical randomized controlled trial of an early electronic alert for acute kidney injury without obtaining informed consent from individual participants. Our study outcome may serve as a model for other studies of acute kidney injury, insofar as our paradigm accounts for the effect that early death and dialysis have on assessment of acute kidney injury severity as defined by maximum achieved serum creatinine. PMID- 25023201 TI - Synthetic apatite nanoparticles as a phosphorus fertilizer for soybean (Glycine max). AB - Some soluble phosphate salts, heavily used in agriculture as highly effective phosphorus (P) fertilizers, cause surface water eutrophication, while solid phosphates are less effective in supplying the nutrient P. In contrast, synthetic apatite nanoparticles could hypothetically supply sufficient P nutrients to crops but with less mobility in the environment and with less bioavailable P to algae in comparison to the soluble counterparts. Thus, a greenhouse experiment was conducted to assess the fertilizing effect of synthetic apatite nanoparticles on soybean (Glycine max). The particles, prepared using one-step wet chemical method, were spherical in shape with diameters of 15.8 +/- 7.4 nm and the chemical composition was pure hydroxyapatite. The data show that application of the nanoparticles increased the growth rate and seed yield by 32.6% and 20.4%, respectively, compared to those of soybeans treated with a regular P fertilizer (Ca(H2PO4)2). Biomass productions were enhanced by 18.2% (above-ground) and 41.2% (below-ground). Using apatite nanoparticles as a new class of P fertilizer can potentially enhance agronomical yield and reduce risks of water eutrophication. PMID- 25023202 TI - Navigation lymphatic supermicrosurgery for iatrogenic lymphorrhea: supermicrosurgical lymphaticolymphatic anastomosis and lymphaticovenular anastomosis under indocyanine green lymphography navigation. AB - BACKGROUND: Lymphorrhea can occur after surgical intervention to the lymphatic system. Most cases with lymphorrhea can be treated conservatively, but some cases are refractory to conservative treatments and require further surgical treatments. METHODS: Eight patients developed inguinal lymphorrhea after surgical intervention in the groin region. Navigation lymphatic supermicrosurgery (NLS) was performed for the treatment of iatrogenic lymphorrhea refractory to conservative treatments. Lymphatic vessels ruptured in a lymphorrhea lesion were identified under intraoperative indocyanine green (ICG) lymphography navigation and were anastomosed to a recipient vessel; an intact lymphatic vessel or a vein was selected as a recipient. Feasibility and efficacy of the method were evaluated. RESULTS: Among eight inguinal lymphorrhea patients, four patients with refractory lymphorrhea underwent NLS under local anesthesia. In all cases, a lymphatic vessel that caused an intractable lymphorrhea was successfully anastomosed to a recipient vessel (to an intact lymphatic vessel in one case, and to a venule in three cases), and the lymphorrhea was completely cured without lymphorrhea recurrence or lymphedema development. Treatment duration in NLS was significantly shorter than that in conservative treatments (5.0 +/- 2.4 vs. 30.0 +/- 8.1 days, P = 0.006). CONCLUSIONS: Intraoperative ICG lymphography helps a surgeon to find lymphatic vessels in and near a lymphorrhea lesion, which allows secure and easier treatment for an intractable lymphorrhea with preservation of lymph drainage function. PMID- 25023203 TI - Relationship between chemical composition and in situ rumen degradation characteristics of maize silages in dairy cows. AB - Several in situ studies have been conducted on maize silages to determine the effect of individual factors such as maturity stage, chop length and ensiling of maize crop on the rumen degradation but the information on the relationship between chemical composition and in situ rumen degradation characteristics remains scarce. The objectives of this study were to determine and describe relationships between the chemical composition and the rumen degradation characteristics of dry matter (DM), organic matter (OM), CP, starch and aNDFom (NDF assayed with a heat stable amylase and expressed exclusive of residual ash) of maize silages. In all, 75 maize silage samples were selected, with a broad range in chemical composition and quality parameters. The samples were incubated in the rumen for 2, 4, 8, 16, 32, 72 and 336 h, using the nylon bag technique. Large range was found in the rumen degradable fractions of DM, OM, CP, starch and aNDFom because of the broad range in chemical composition and quality parameters. The new database with in situ rumen degradation characteristics of DM, OM, CP, starch and aNDFom of the maize silages was obtained under uniform experimental conditions; same cows, same incubation protocol and same chemical analysis procedures. Regression equations were developed with significant predictors (P<0.05) describing moderate and weak relationships between the chemical composition and the washout fraction, rumen undegradable fraction, potentially rumen degradable fraction, fractional degradation rate and effective rumen degradable fraction of DM, OM, CP, starch and aNDFom. PMID- 25023204 TI - Oral warfarin and the thrombin inhibitor dabigatran increase blood pressure in rats: hidden danger of anticoagulants? AB - BACKGROUND: Hypertension is a common comorbidity in patients with chronic kidney disease (CKD). We reported earlier that oral anticoagulants, including warfarin and dabigatran, may induce acute kidney injury. No effects of oral anticoagulants on blood pressure (BP) have been previously reported. The aim of this study was to examine in detail the relationship of anticoagulant therapy and BP in rats. METHODS: Sham-operated and 5/6 nephrectomy rats were treated with different doses of oral anticoagulants (warfarin and dabigatran), superoxide scavenger N acetylcysteine (NAC), vitamin K, and protease activated receptor 1 (PAR-1) inhibitor SCH79797. BP was measured by a tail cuff daily. RESULTS: Warfarin and dabigatran both increased systolic BP in sham-operated and 5/6 nephrectomy rats in a dose-dependent manner. SCH79797 also increased systolic BP in a dose dependent manner. Vitamin K prevented warfarin-induced increase in BP but did not affect BP when administered alone. NAC delayed the warfarin-associated increase in BP. Warfarin effects on BP were similar in 5/6 nephrectomy rats with different CKD stages. CONCLUSIONS: Both warfarin and dabigatran increase systolic BP in rats. The mechanism of this effect is not clear, but our data suggest that it is related to decreased thrombin activity associated with anticoagulant treatment. The superoxide scavenger NAC delayed, but did not prevent, warfarin-induced hypertension. PMID- 25023205 TI - Progression of kidney injury and cardiac remodeling in obese spontaneously hypertensive rats: the role of renal sympathetic innervation. AB - BACKGROUND: Hypertension and metabolic syndrome (MetS) are associated with increased sympathetic activation possibly contributing to the progression of renal damage and cardiac remodeling. Renal sympathetic denervation (RDN) decreases sympathetic renal efferent and afferent nerve activity. METHODS: Obese spontaneously hypertensive rats (SHRs-ob) were subjected to RDN at the age of 34 weeks (SHRs-ob + RDN) and were compared with sham-operated SHRs-ob and their normotensive lean controls (Ctrs). Blood pressure was measured by telemetry. Kidney and heart function were determined by magnetic resonance imaging (MRI). Renal and cardiac remodeling were characterized by immunohistochemical analyses. Animals were killed at the age of 48 weeks. RESULTS: In SHRs-ob, RDN attenuated the progressive increase in blood pressure and preserved a mean blood pressure of 156+/-7mm Hg compared with 220+/-8mm Hg in sham-operated SHRs-ob at 100 days after RDN, whereas heart rate, body weight, and metabolic parameters remained unchanged. Renal catecholamine and tyrosine hydroxylase levels were significantly reduced after RDN, suggesting effective renal denervation. Progression of renal dysfunction as characterized by increased urinary albumin/creatinine ratio and reduced glomerular filtration rate were attenuated by RDN. In SHRs-ob, renal perfusion was significantly reduced and normalized by RDN. Cardiac fibrosis and cardiac diastolic dysfunction measured by MRI and invasive pressure measurements were significantly attenuated by RDN. CONCLUSIONS: In SHRs-ob, progressive increase in blood pressure and progression of renal injury and cardiac remodelling are mediated by renal sympathetic activation as they were attenuated by RDN. PMID- 25023206 TI - Psychiatric morbidity in ketamine users attending counselling and youth outreach services. AB - BACKGROUND: No study has examined ketamine users' psychiatric morbidity using structured diagnostic instruments. The aim of this study was thus to determine the psychiatric comorbidity of community-based ketamine users using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), Axis I Disorders (SCID). METHODS: A convenience sample of 200 frequent ketamine users was recruited from community organizations in Hong Kong. Participants were screened with the Severity of Dependence Scale (SDS), Beck Depression Inventory (BDI), Anxiety subscale of the Hospital Anxiety Depression Scale (HADSA), and SCID psychotic symptoms. Those who scored above the threshold (cutoff point of 8/9 on the BDI and 4/5 on HADSA) or displayed evidence of psychotic symptoms were referred for a structured clinical interview conducted by a psychiatrist. RESULTS: One hundred and seventy participants scored above the cutoff point on 1 or more of the scales, and 115 participants attended the SCID interview. Fifty-one of these 115 participants received a psychiatric diagnosis of 1 or more comorbidities for the month preceding the interview. Mood disorders accounted for 80.4% of the diagnoses, anxiety disorders for 33.3%, and psychotic disorders for 7.8%. CONCLUSIONS: Female gender and history of psychiatric/psychological clinic attendance were significantly associated with comorbid psychiatric disorders, whereas ketamine dependence had a borderline association. PMID- 25023207 TI - Intermittent androgen deprivation therapy with antagonist: really new information? PMID- 25023208 TI - A lottery incentive system to facilitate dialogue and social support for workplace HIV counselling and testing: a qualitative inquiry. AB - Despite South African mid-sized companies' efforts to offer HIV counselling and testing (HCT) in the workplace, companies report relatively poor uptake rates. An urgent need for a range of different interventions aimed at increasing participation in workplace HCT has been identified. The aim of this study was to explore qualitatively the influence of a lottery incentive system (LIS) as an intervention to influence shop-floor workers' workplace HIV testing behaviour. A qualitative study was conducted among 17 shop-floor workers via convenience sampling in two mid-sized South African automotive manufacturing companies in which an LIS for HCT was implemented. The in-depth interviews employed a semi structured interview schedule and thematic analysis was used to analyse the data. The interviews revealed that the LIS created excitement in the companies and renewed employees' personal interest in HCT. The excitement facilitated social interactions that resulted in a strong group cohesion pertaining to HCT that mitigated the burden of HIV stigma in the workplace. Open discussions allowed for the development of supportive social group pressure to seek HCT as a collective in anticipation of a reward. Lotteries were perceived as a supportive and innovative company approach to workplace HCT. The study identified important aspects for consideration by companies when using an LIS to enhance workplace HIV testing. The significance of inter- and intra-player dialogue in activating supportive social norms for HIV testing in collectivist African contexts was highlighted. PMID- 25023209 TI - Basic research: Critical role of mTORC1 in tubular cells. PMID- 25023210 TI - Acute kidney injury: Mechanism of AKI sensitivity in diabetic nephropathy. PMID- 25023211 TI - Determination of selective serotonin reuptake inhibitors in plasma and urine by micellar liquid chromatography coupled to fluorescence detection. AB - Citalopram, paroxetine and fluoxetine are selective serotonin reuptake inhibitor (SSRIs) currently used in the treatment of psychiatric disorders. We present an analytical method using micellar liquid chromatography to quantify these three drugs in pharmaceutical formulations, plasma and urine. The resolution was performed using a mobile phase of 0.075 M SDS - 6% (v/v) butanol buffered at pH 7 running through a C18 column under isocratic mode at 1 mL/min at 25 degrees C. The analytes were eluted in less than 20 min. The fluorescence detection was programmed at the maximum excitation (236, 295 and 230 nm) and emission (310, 350 and 305 nm) wavelengths for citalopram, paroxetine and fluoxetine, respectively. The experimental procedure was expedited to 1/5 dilution of the sample in the micellar mobile phase and filtration, thus avoiding clean-up and extraction steps. An aliquot of 20 MUL was injected after 80 min of preparation, to obtain maximum sensitivity. The method was validated according to the guidelines of the Food and Drug Administration (FDA) in terms of calibration range (20-500 ng/mL; r(2)>0.999), sensitivity, accuracy (91.3-103.2%), precision (<9.3%), and robustness (<6.1%). The suitability of the method was successfully evaluated by analyzing plasma and urine samples from patients treated with SSRIs and checking the content of the active principle in tablets. Thus, the method can be applied to pharmacokinetics studies and in forensic cases, as well as in quality control of commercial pharmaceutical formulations. PMID- 25023212 TI - An efficient preparative procedure for main flavonoids from the peel of Trichosanthes kirilowii Maxim. using polyamide resin followed by semi-preparative high performance liquid chromatography. AB - In this study, a simple and efficient preparative procedure was developed for preparation of seven flavonoids from the peel of Trichosanthes kirilowii Maxim. using polyamide resin followed by semi-preparative high performance liquid chromatography (SPHPLC). First, the ethyl acetate fraction from the peel of T. kirilowii Maxim. obtained "prefractionation" using polyamide resin, which yielded two subfractions. And then the two subfractions were isolated by SPHPLC with an isocratic elution of methanol-water. Finally, seven known flavonoids were purified from 35 g of ethyl acetate extract including quercetin-3-O-[alpha-l rhamnose (1->2)-beta-d-glucopyranosyl]-5-O-beta-d-glucopyranoside (19 mg), quercetin-3-O-rutinoside (24 mg), apigenin-7-O-beta-d-glucopyranoside (10mg), diosmetin-7-O-beta-d-glucopyranoside (45 mg), luteolin (21 mg), apigenin (15 mg), and diosmetin (56 mg). The purities of the compounds were determined by HPLC and the chemical structures were confirmed by UV and NMR analysis. In the present study, a simple, effective, and rapid procedure was established for preparative separation of multiple components from the peel of T. kirilowii Maxim. Furthermore, it was scalable and economical, so it was a promising basis for large-scale preparation of flavonoids from other plant extracts. PMID- 25023213 TI - Metabolic abnormalities in the pathogenesis of type 1 diabetes. AB - Clinical onset of type 1 diabetes (T1D) is thought to result from a combination of overt beta cell loss and beta cell dysfunction. However, our understanding of how beta cell metabolic abnormalities arise during the pathogenesis of disease remains incomplete. Despite extensive research on the autoimmune nature of T1D, questions remain regarding the time frame and nature of beta cell destruction and dysfunction. This review focuses on the characterizations of beta cell dysfunction in the prediabetic and T1D human and mouse model. Studies have shown evidence supporting progressive loss of beta cell mass and function prior to T1D onset, while other scientists argue beta cell destruction occurs later in the disease process. Determining the time frame of beta cell destruction and identifying metabolic mechanisms that drive beta cell dysfunction has high potential for successful interventions to maintain insulin secretion for individuals with established T1D as well as those with prediabetes. PMID- 25023215 TI - The medical malpractice in Milan-Italy. A retrospective survey on 14 years of judicial autopsies. AB - The medical malpractice is a rising and central topic for the forensic pathologist and forensic autopsies are a mandatory step in the judicial evaluation of the suspected medical malpractice. Reliable national and international registers about the medical malpractice are still missing and nowadays the necroscopic archives are therefore one of the best sources of data about such a complex phenomenon. We analyzed the archive of the Institute of Forensic Medicine of the Milan University from 1996 to 2009 and selected 317 lethal cases of suspected medical malpractice. The mean age of our cases was 60+/ 18 years for males and 58+/-19 years for the females. In 70% of such cases the patient death occurred in a hospital setting. The first 24h of hospitalization turned out to be the hottest period for deaths followed by malpractice claims. The surgical branches were obviously the most involved, with abdominal surgery, orthopedics, neurosurgery and gynecology as the main contributors. Just 12% of the total amount of cases came from all the internistic branches put together. Non-hospital malpractice was typically caused by misdiagnosed myocardial infarctions and aortic ruptures. A full forensic report was present in 71 cases (all belonging to the 2007-2009 period): in 69% of cases the judicial autopsy revealed as a sufficient tool for diagnosing the cause of death; medical malpractice was confirmed in only 17% of the whole cases and a causal link between the ascertained malpractice and the patient death was recognized in only 12.7% cases. PMID- 25023214 TI - Use of technology when assessing adherence to diabetes self-management behaviors. AB - During the last several decades, a proliferation of sophisticated technology has taken place to facilitate diabetes self-management and improve health outcomes. Blood glucose monitors, insulin pumps, and continuous glucose monitors have significant data storage capacity, which can be used to summarize diabetes health management and outcomes. In the absence of technology errors or failures, and in the context of the multiple psychosocial factors associated with nonadherence, these data have the potential to elucidate diabetes care because they reflect actual patient behaviors. This review provides a summary of the diabetes adherence literature in the context of current American Diabetes Association Clinical Practice Recommendations with a focus on studies that have used objective methods (ie, data derived from technology) to assess diabetes care provider and patient adherence in the areas of glucose monitoring; insulin administration and antihyperglycemic medications; medical nutrition therapy; and physical activity. PMID- 25023216 TI - Facial soft tissue thickness database for craniofacial reconstruction in the Turkish adult population. AB - 320 Turkish adults (160 men, 160 women) who had undergone brain CT in the radiology clinic and showed no sign of maxillofacial pathology were analyzed in order to create a facial soft-tissue thickness database of the Turkish adult population. The soft-tissue thicknesses were measured at 31 landmarks, 10 midline and 21 bilateral anatomical landmarks. Average thickness values for each landmark as well as the standard deviation and range classified according to gender and age are reported. The differences of these mean values related to age and sexes were calculated. The values were then statistically compared to the findings of the European and Korean adults. Overall, the soft-tissue thickness measurements obtained in this study can be used as a database for the forensic craniofacial reconstruction of Turkish adult faces. PMID- 25023217 TI - Transcutaneous oxygen pressure (TcPO2): a novel diagnostic tool for peripheral neuropathy in type 2 diabetes patients. AB - AIMS: The assessment of transcutaneous oxygen pressure (TcPO2) may serve as a non invasive and lower-cost alternative to nerve conduction studies (NCSs) for the diagnosis of diabetic peripheral neuropathy (DPN). The aim of this study was to determine whether the measurement of TcPO2 is useful for evaluating DPN. METHODS: We performed a cross-sectional study of 381 consecutive hospitalized diabetic patients classified by clinical examination and NCS as having DPN. Anthropometric and metabolic parameters were assessed. The TcPO2 examination was performed in both supine and sitting positions. RESULTS: Three hundred and one patients had DPN. The TcPO2 in both the supine and sitting positions was highest in the Non DPN group and lower in the confirmed DPN group than the other three groups (p<0.001). The Non-DPN group had the lowest sitting-supine position difference in TcPO2 among the groups (p<0.001). The risk factors strongly associated with DPN included sitting-supine position difference in TcPO2 (OR=4.971, p<0.001), diabetic retinopathy (DR) (odds ratio [OR]=3.794, p=0.002), and HbA1c (OR=1.534, p=0.033). The area under the curve (AUC) of the sitting-supine position difference in TcPO2 was 0.722 and revealed an optimal cut-off point for the identification of DPN (19.5 mmHg) that had a sensitivity of 0.611 and a specificity of 0.738 based on AUC analysis. CONCLUSIONS: This large study of diabetic patients confirms that the sitting-supine position difference in TcPO2 is higher in DPN patients than control subjects, indicating that TcPO2 examination is a promising valuable diagnostic tool for DPN. PMID- 25023218 TI - 'My body's falling apart.' Understanding the experiences of patients with advanced multimorbidity to improve care: serial interviews with patients and carers. AB - OBJECTIVE: Multimorbidity is increasingly common in the last year of life, and associated with frequent hospital admissions. The epidemiology is well described, but patient perspectives are less understood. We report the experiences and perceptions of people with advanced multimorbidity to inform improvements in palliative and end-of-life care. DESIGN: Multicentre study including serial, multiperspective interviews with patients and their family carers; an interpretive analysis of experiences and understanding of living with advanced multimorbidity. PARTICIPANTS: We recruited patients and their family carers using established UK clinical guidance for the identification of people anticipated to be in their last year of life. SETTINGS: An acute admissions unit in a Scottish regional hospital; a large English general practice; a London respiratory outpatient clinic. RESULTS: We analysed 87 interviews with 37 patients and 17 carers. They struggled with multiple changing medications, multiple services better aligned with single conditions such as cancer, and a lack of coordination and continuity of care. Family carers spoke of physical, mental and emotional exhaustion and feeling undervalued by professionals. Patients and carers frequently saw deteriorating health as part of 'growing old'. Many used a 'day-to day' approach to self-management that hindered engagement with advance care planning and open discussions about future care. 'Palliative care' and 'dying soon' were closely related concepts for many patients, carers and professionals, so rarely discussed. CONCLUSIONS: Patients with advanced multimorbidity received less care than their illness burden would appear to merit. Some people did restrict their interactions with care providers to preserve autonomy, but many had a limited understanding of their multiple conditions, medications and available services, and found accessing support impersonal and challenging. Greater awareness of the needs associated with advanced multimorbidity and the coping strategies adopted by these patients and carers is necessary, together with more straightforward access to appropriate care. PMID- 25023219 TI - Xenogene vaccination in the therapy of cancer. AB - INTRODUCTION: The advent of cancer immunotherapy is going to profoundly transform the therapy of cancer. In this context, therapeutic cancer vaccines will offer significant opportunities, provided an efficient and robust technology is developed. AREAS COVERED: Targeting tumor-associated antigens via immunization with homologous immunogens derived from other species, an approach called xeno vaccination, combined with gene delivery is believed to be a viable strategy. Xenogene vaccination has demonstrated to be more efficient than vaccination with 'self' antigens in rodent models in prophylactic and therapeutic settings against cancer. Depending upon the targeted antigen, the mechanism of action of xeno vaccines has been shown to depend upon the development of antibody and/or cytotoxic T-cell responses. More importantly, xenogene vaccination has been shown to reproducibly affect cancer growth and to improve survival in veterinary cancer patients, mainly in dogs affected by spontaneous disease. One of these vaccines against dog melanoma has been approved by regulatory authorities in USA. Finally, several xenogene vaccines have been advanced to early Phase I/II human clinical trials where they have shown to be safe, well tolerated and capable to induce detectable immune responses against human tumor antigens. EXPERT OPINION: Based on this compendium of results we believe that xenogene vaccination may soon become a well-established weapon in the fight against cancer. PMID- 25023220 TI - The Exploration of Acculturation and Health Among Immigrants From Non-Eastern Cultures. AB - Literature on acculturation has been mainly focused on how acculturation influences the perception of health and well-being among immigrants from non Western cultures. Conversely, we sought to explore immigration experiences associated with health and well-being among immigrants from non-Eastern cultures during their acculturation process. With a sample of 9 participants, we identified two major themes as outcomes of acculturation: psychological well being and social benefits. We found that during acculturation, Western immigrants improved their sense of happiness, experienced reduced stress, and discovered meaning through activities, and that overall, acculturation facilitated personal growth. In addition, they developed a sense of cross-group friendships with Korean people and facilitated group cohesion within their own ethnic group. Further implications and future research avenues are discussed. PMID- 25023221 TI - Brothers' Experiences Caring for a Sibling With Down Syndrome. AB - I used a phenomenological method to examine the caregiving experiences of Taiwanese men with their siblings with Down syndrome (DS). Four themes emerged after drawing on stories shared by 7 men: taking responsibility for the caregiving, adjusting to an unfamiliar caregiving role, and counting on help from women and reframing. The results of the study show that the Taiwanese brother caregivers were raised according to the cultural norm, because of which they accepted the caregiving responsibility, even though they had rarely been included in the early life of their sibling with DS. These brothers thus encountered chaos in the process of transferring into the role of main caregiver. Greater attention must be paid to the promotion of earlier involvement of brothers in the life of their sibling with DS, and the special challenges surrounding a brother giving care to a sister with DS. PMID- 25023222 TI - Development of a Human Cranial Bone Surrogate for Impact Studies. AB - In order to replicate the fracture behavior of the intact human skull under impact it becomes necessary to develop a material having the mechanical properties of cranial bone. The most important properties to replicate in a surrogate human skull were found to be the fracture toughness and tensile strength of the cranial tables as well as the bending strength of the three-layer (inner table-diploe-outer table) architecture of the human skull. The materials selected to represent the surrogate cranial tables consisted of two different epoxy resins systems with random milled glass fiber to enhance the strength and stiffness and the materials to represent the surrogate diploe consisted of three low density foams. Forty-one three-point bending fracture toughness tests were performed on nine material combinations. The materials that best represented the fracture toughness of cranial tables were then selected and formed into tensile samples and tested. These materials were then used with the two surrogate diploe foam materials to create the three-layer surrogate cranial bone samples for three point bending tests. Drop tower tests were performed on flat samples created from these materials and the fracture patterns were very similar to the linear fractures in pendulum impacts of intact human skulls, previously reported in the literature. The surrogate cranial tables had the quasi-static fracture toughness and tensile strength of 2.5 MPa? m and 53 +/- 4.9 MPa, respectively, while the same properties of human compact bone were 3.1 +/- 1.8 MPa? m and 68 +/- 18 MPa, respectively. The cranial surrogate had a quasi-static bending strength of 68 +/- 5.7 MPa, while that of cranial bone was 82 +/- 26 MPa. This material/design is currently being used to construct spherical shell samples for drop tower and ballistic tests. PMID- 25023223 TI - Federal environmental and occupational toxicology regulations and reporting requirements: a practical approach to what the medical toxicologist needs to know, part 1. AB - Toxicologists are often called upon to assist in environmental, industrial, occupational and public health assessments. Accordingly, medical toxicologists may find it prudent to be aware of applicable federal toxicological regulations and reporting requirements and of the roles of relevant federal agencies. These regulations are numerous, complex, and have evolved and expanded over time, making it difficult for toxicologists to sustain a current knowledge base. This article reviews the pertinent federal toxicological reporting requirements with regard to the Toxic Substances Control Act (TSCA), the Atomic Energy Act (AEA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Resource Conservation and Recovery Act (RCRA), the Clean Air Act, the Clean Water Act, the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), the Emergency Planning and Community Right to Know Act (EPCRA), the Occupational Safety and Health Act, the Department of Transportation, and information about the National Response Center. We reference internet-based government resources and offer direct links to applicable websites in an attempt to offer rapid and current sources of practical information. The format of the article is a series of hypothetical scenarios followed by commentary. Discussions of the Safe Drinking Water Act, the Food, Drug, and Cosmetic Act, and the Dietary Supplement Health and Education Act are beyond the scope of this paper. For those desiring a more in-depth discussion of the relevant federal environmental laws and statutes and applicable case law, the reader is directed to resources such as the Environmental Law Handbook, the websites of individual laws found at www.epa.gov and the decisions of individual courts of appeal. It is our hope that this article provides not only useful practical information for the practicing toxicologist but also serves as a key reference for medical toxicology core content on environmental laws and regulations. PMID- 25023224 TI - Using drug-intoxicated deaths as potential organ donors: impression of attendees at the American college of medical toxicology 2014 annual scientific meeting. AB - INTRODUCTION: Over the last decade, there has been a reduction of organ donation from intracranial haemorrhage-, stroke- and blunt trauma-related deaths in the USA. There has been a corresponding increase in the use of drug-intoxicated patients as organ donors from 2.1 % in 2003 to 6.8 % in 2013. METHODS: Questionnaire survey of attendees at the American College of Medical Toxicology 2014 Annual Scientific Meeting breakout session on transplantation from deaths related to poisoning was performed. Participants were asked whether they would recommend the use of solid organs from cocaine- or carbon monoxide-related death before and after the breakout session. RESULTS: Forty-eight US participants (attending 23, fellow 15, resident 3 and other (including non-medical) 7) completed the survey, and 97.8 and 89.1 % of participants would consider cocaine- and carbon monoxide-related deaths for potential organ donation pre-breakout session, respectively; this increased to 100 % for both post-breakout sessions. There was variability in the consideration of different solid organs (the heart, lungs, liver, pancreas and kidneys)-76.2-95.2 and 76.2-85.7 % for individual solid organs for cocaine- and carbon monoxide-related deaths, respectively. For both scenarios, participants were least likely to consider potential heart donation (76.2 % of participants for both), which increased to 100 % following the breakout session. CONCLUSIONS: Medical toxicologists have some reservation in recommending solid organs for transplantation from deaths from cocaine and carbon monoxide. Given the decrease in potential organ donors from typical methods of death, further work is needed to promote organ donation in deaths related to acute poisoning. PMID- 25023225 TI - Gait stability improvement after fusion surgery for adolescent idiopathic scoliosis is influenced by corrective measures in coronal and sagittal planes. AB - To achieve optimal results after fusion for adolescent idiopathic scoliosis (AIS), radiographic parameters must be aligned with motion and performance. The effects of fusion on balance are poorly understood. Center of mass (COM) excursion and instantaneous interaction with center of pressure (COP) provides information about patients' balancing ability during gait. This study investigates the interaction between COM and COP (COM-COP) in AIS patients before and one year after spine fusion and determines what radiographic goals predict restoration of harmonious COM-COP. This was a prospective study that investigated sixteen adolescents with AIS curvature >30 requiring surgical correction. Clinical outcomes measures, X-rays, and 3D motion-capture gait analysis were collected. Sagittal and coronal COM and COP offsets and inclination angles were calculated from positional data. COM excursion was calculated as peak COM displacement based on mediolateral and vertical deviation from a line fitted to the patient's path. Radiographic parameters were measured to determine variables predictive of change in COM excursion. Post-operatively, average COM peak displacement decreased (42.6 to 13.1 mm, p=0.001) and COM peak vertical displacement remained unchanged (17.0 to 16.3 mm, p=0.472). COM-COP inclination angles reduced in the coronal, but not sagittal plane. Coronal lower extremity peak inclination angles reduced (8.8 to 7.5, p=0.025), correlating with C7 plumb line offset (R=0.581, p=0.018). Thoracic Cobb, thoracic kyphosis, and C7 plumb line were predictors of change in COM excursion. Mediolateral COM excursion post surgery may reflect an attempt to reduce kinetic demands with improved spinal alignment. Although AIS correction has historically focused on the coronal plane, sagittal parameters may be more important for motion than previously theorized. PMID- 25023226 TI - Pneumonia after endoscopic resection for gastric neoplasm. AB - BACKGROUND: Pneumonia following endoscopic procedures may affect the clinical course and prolong hospital stay. AIM: To investigate the incidence and risk factors for pneumonia after endoscopic resection (ER) for gastric neoplasm. METHODS: Subjects who underwent ER for gastric neoplasm at the Asan Medical Center from January 1997 to March 2013 were included. To investigate risk factors, control patients were randomly selected from these subjects. RESULTS: Of the 7,149 subjects who underwent ER for gastric neoplasm, 44 (0.62 %) developed pneumonia. The median age of these 44 patients was 68 years (range 31-82 years), and the male to female ratio was 3:1. Twenty-five of the pneumonia patients (56.8 %) were smokers, and 8 (18.2 %) had underlying pulmonary diseases. The median procedure time was 23 min (range 2-126 min), and pathologic diagnoses included adenocarcinoma (n = 29), dysplasia (n = 10), and hyperplastic polyp (n = 5). Compared with the control group, smoking (current smoker vs. never smoker, odds ratio [OR] 2.366, p = 0.021), total procedure time (OR 1.011, p = 0.048), and hemostasis time (OR 1.026, p = 0.028) were risk factors for the development of pneumonia. In multivariate analysis, age >65 years (OR 2.073, p = 0.031), smoking (current smoker vs. never smoker, OR 2.324, p = 0.023), and hemostasis time (OR 1.025, p = 0.038) were independent risk factors. All patients recovered from pneumonia, and the duration of hospital stay did not differ between patients with pneumonia and the control group (p = 0.077). CONCLUSIONS: Whereas old age, smoking, and longer hemostasis time are risk factors for pneumonia, its incidence after ER is not associated with clinically significant adverse outcomes. PMID- 25023227 TI - Evaluation of cardiac function by two-dimensional speckle tracking echocardiography in ulcerative colitis patients. AB - PURPOSE: Although ulcerative colitis (UC) shows obvious similarities with other autoimmune diseases, cardiac consequences have not adequately introduced. The aim of our study was to evaluate left ventricular (LV) function in UC patients by using novel echocardiographic parameters. RESULTS: Forty-five UC patients (mean age 37, 18 female) and 90 age- and sex-matched healthy volunteers (mean age 40, 38 female) included in the study. The mean disease activity score according to partial Mayo score was 2.16 +/- 2.13. Mean global longitudinal strain (GLS) and global longitudinal strain rate (GLSR) measurements were significantly lower ( 21.16 +/- 2.71 vs. -23.36 +/- 3.34; p < 0.001 and -1.33 +/- 0.24 vs. -1.43 +/- 0.24; p = 0.037, respectively), whereas global circumferential (-22.67 +/- 3.66 vs. -23.37 +/- 3.99; p = 0.140) and global radial strain (43.07 +/- 8.58 vs. 44.12 +/- 9.32; p = 0.545) measurements of the LV were similar in patients with UC compared with controls. The correlation coefficient (r) between GLS and partial Mayo score was -0.578 (p < 0.001). CONCLUSION: Our study suggests that systolic cardiac deformation values are impaired in UC patients. Reduced GLS and GLSR might be an early indicator of cardiac involvement in this population. PMID- 25023229 TI - Simultaneous solid phase extraction coupled with liquid chromatography tandem mass spectrometry and gas chromatography tandem mass spectrometry for the highly sensitive determination of 15 endocrine disrupting chemicals in seafood. AB - This study aimed to develop a sensitive and reliable multi-residue method for the determination of trace amounts of endocrine disrupting chemicals including five phthalate esters (PAEs), five monoalky phthalate esters (MPEs), four alkylphenols (APs) and bisphenol A (BPA) in seafood. Ultrasonic liquid extraction was selected for extraction based on acetonitrile, instead of frequently-used n-hexane, due to its lower background of PAEs. Application of solid phase extraction (SPE) with primary secondary amine (PSA, 1g/6 mL) cartridge achieved the relatively low matrix effects for MPEs and BPA in seafood. To our knowledge, it is the first study reporting about simultaneous extraction and purification of PAEs, MPEs, APs and BPA in biota samples. To obtain the maximum sensitivity, both liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS) were applied for analysis. This method was validated and tested on fish, mollusk and prawn. Sufficient linearity was verified by Mandel's fitting test for the matrix-matched calibrations used in this study for MPEs, APs and BPA, between 0.5 ng/g and 200 ng/g or 400 ng/g. And correlation coefficients of all calibrations suppressed 0.99 for all analytes. Good recoveries were obtained, ranging from 60% to 127% for most compounds. The sensitivity was good with method detection limits (MDLs) of 0.015-2.2 ng/g wet weight (ww) for all compounds. Most MDLs are much lower than those in previous reports. The sensitive method was then applied on real fish, mollusk and prawn samples from the Yangtze River Delta sea area (China), and all the target compounds were detected with the maximum concentrations of PAEs, MPEs, APs and BPA up to 219.3 ng/g ww, 51.4 ng/g ww, 62.0 ng/g ww and 8.6 ng/g ww, respectively. PMID- 25023228 TI - Quantification of five plasticizers used in PVC tubing through high performance liquid chromatographic-UV detection. AB - Searching for alternatives to di-(2-ethylhexyl)-phthalate, a plasticizer that has been widely used in the manufacturing of PVC medical devices, has become a major challenge since a European regulation underlined some clinical risks. The aim of this study is to develop an HPLC-UV method to quantify the currently used alternative plasticizers to DEHP. Five plasticizers, acetyl tributyl citrate, di (2-ethylhexyl)-phthalate, di-(ethylhexyl)-terephthalate, di-isononyl-1,2 cyclohexane-dicarboxylate, and trioctyl trimellitate, were separated on a C8 stationary phase (2.6 MUm, 100 mm * 4.6mm) under gradient elution in 13 min. They were detected at 221 nm leading to a quantification threshold from 0.3 to 750 MUg/mL as a function of the plasticizer. Within-day and between-day precisions were inferior to 0.9% and 18%, respectively. The assays were validated according to the accuracy profile method. Plasticizers were extracted from PVC-tubing by dissolving PVC in THF then precipitating it in methanol with a yield of over 90% for each plasticizer. This assay could feasibly be used to quantify plasticizers in PVC medical devices. PMID- 25023230 TI - Influence of growth rate and onset of boar contact on puberty attainment of replacement gilts raised in Thailand. AB - This study aimed to investigate the influence of growth rate and onset of boar contact on age at first observed estrus of the replacement gilts raised in Thailand. In total, 766 gilts were measured for body weight and backfat thickness prior to insemination. Body weight was further calculated for growth rate. Estrus detection was performed twice a day by back pressure test with an existence of mature boars with high libido. The first date of boar exposure and that of first observed estrus were individually recorded. Due to growth rate, they were classified into three groups: high (>700 g/day), moderate (600-700 g/day), and low (<600 g/day). According to onset of boar contact, the gilts were grouped into two categories: early (<150 days) and late (>=150 days). The results revealed that the gilts expressed first observed estrus, averagely, at age 205.1 +/- 34.1 days, had a growth rate of 615.5 +/- 57.6 g/day, and first contact with boars at 160.7 +/- 19.9 days of age. The gilts with low growth rate expressed first estrus later than those with moderate (208.6 +/- 2.0 vs 198.0 +/- 3.2 days, P = 0.033) and high growth rate (208.6 +/- 2.0 vs 193.9 +/- 6.7 days, P = 0.005) groups. Together with the influence of boar exposure, the gilts contacted boar earlier with high growth rate showed first estrus at age 180.3 +/- 10.1 days, whereas those with later boar contact with low growth rate showed first estrus at age 197.9 +/- 3.2 days. In summary, the replacement gilts should have high growth rate and contact boar early to attain puberty faster and possess decent subsequent reproductive performance. PMID- 25023231 TI - Performance of goats fed on low quality veld hay supplemented with fresh spiny cactus (Opuntia megacantha) mixed with browse legumes hay in Zimbabwe. AB - Nutrition is a major constraint in smallholder livestock production; hence, the use of alternative sources which are adaptive to long dry seasons is imperative. The study was conducted to establish options of improving nutrition and palatability and also to determine the performance of goats fed on cactus-browse hay as dry season supplements. Palatability and adequacy of nutrition was investigated using 32 castrated male goat kids. The kids were housed in individual metabolism cages for 84 days in a complete randomised design (CRD) with eight replicates for the four treatment diets. Daily experimental diet, basal diet and water intake were measured, and live mass was measured at weekly intervals. Daily diet intake was significantly different (P < 0.05) among treatments. Kids that were supplemented with cactus-Leucaena leucocephala meal (CLLM) consumed more than those on cactus-Acacia angustissima meal (CAAM), cactus Gliricidia sepium meal (CGSM) and cactus-Pennisetum purpureum meal (CPPM) in that order. CGSM was not readily palatable as goat kids refused to take it when mixed with fresh cactus. Animals that were not supplemented with a source of nitrogen together with those that were supplemented with less palatable diet of CGSM lost weight significantly (P < 0.05) initially but gained weight slightly towards the end of the study. Significantly higher weight gains (P < 0.05) were observed in animals in CLLM and CAAM treatment. It was concluded that fresh cactus could be used to improve poor quality roughage intakes in goats, and therefore, there is need to promote its use in periods of feed deficit especially in smallholder sector. PMID- 25023232 TI - Clinical usefulness of a novel program "Heart Function View" for evaluating cardiac function from gated myocardial perfusion SPECT. AB - OBJECTIVE: To investigate clinical usefulness of a novel program "Heart Function View (HFV)" for evaluating left ventricular (LV) function from myocardial perfusion SPECT (MPS), we compared LV functional parameters (F(x)) calculated by HFV with those obtained by the other similar programs QGS and cardioGRAF or by ultrasound echocardiography (UCG) and examined their correlations with clinical markers of heart failure: plasma BNP concentrations (BNPs) and exercise capacity. METHODS: Studied patients (n = 60) underwent technetium-99m tetrofosmin quantitative gated MPS including treadmill exercise for examining heart disease. Myocardial stress images were acquired 30 min after the first tracer injection during maximal exercise. Three hours later, the second tracer was injected, and resting images were acquired. LV systolic F(x) [ejection fraction (EF), peak ejection rate (PER)] and diastolic F(x) [first third filling fraction (1/3FF), first third filling rate (1/3FR), peak filling rate (PFR), time to PFR (TPF)] were analyzed, and phase standard deviation (SD) and histogram bandwidth were obtained by phase analysis. RESULTS: LV end-diastolic volume (EDV), end-systolic volume (ESV) and EF obtained from HFV were well correlated with those from QGS, cardioGRAF and UCG. A diastolic parameter Doppler E/e' from UCG was significantly with PFR from HFV. There were good correlations between LVEDV, LVESV, LVEF, PER, PFR, 1/3FR, TPF and 1/3FF from HFV and those from cardioGRAF. LVEF, PER, 1/3FR, and PFR were significantly correlated with plasma BNP concentrations. In patients with non-ischemic heart disease (n = 42), phase SD and histogram bandwidth were correlated negatively with exercise capacity or PFR. CONCLUSIONS: HFV-derived LVF(x) are correlated with LVF(x) from the other programs or UCG, or with the clinical markers of heart failure and are thus useful in the functional assessment for patients with heart disease. PMID- 25023233 TI - Synthesis, characterization and in vivo evaluation of [(62)Zn]-benzo-delta-sultam complex as a possible pet imaging agent. AB - OBJECTIVE: The development of a new tracer based on the cyclic sulfonamides (sultams) was investigated. METHODS: 3-(Methoxy-phenyl-methyl)-1,6-dimethyl-1H benzo[c][1,2] thiazine 2,2-dioxide (benzo-delta-sultam) was synthesized and characterized by elemental analysis, FT-IR spectroscopy and single crystal X-ray structure determination. The prepared cyclic sulfonamide was labeled with non commercial (62)Zn radioisotope for fast in vivo targeting and Coincidence imaging purposes (radiochemical purity 97 % ITLC, 96 % HPLC, specific activity 20-23 GBq/mmol). In vivo biodistribution of the final complex was investigated in Sprague Dawley((r)) rats bearing fibro sarcoma tumor after 2, 4 and 8 h post injection and compared with free Zn(+2) cation. RESULTS: Using instant paper chromatography method, the physicochemical properties of labeled compounds were found sufficiently stable in organic phases, e.g. a human serum, to be reliably used in bioapplications. CONCLUSIONS: The complex exhibited a rapid as well as high tumor uptake (tumor to blood ratio 4.38 and tumor to muscle ratio 9.63) resulting in an efficient tumor targeting agent. PMID- 25023234 TI - [Radical prostatectomy. Detection and management of intra- and postoperative complications]. AB - Radical prostatectomy is the most common treatment for organ-confined prostate cancer. Performed without complications and limitations, surgery will allow complete removal of the tumor and, therefore, cure the patient. Operative techniques have been improved during the last few decades to reduce invasiveness of the procedure. Furthermore, optimized perioperative management has shortened hospital stay. To ensure rapid recovery of each patient, early detection of complications is highly relevant. Herein, different scenarios for peri- and postoperative complications are described, and recommendations for best practice solutions are reviewed. PMID- 25023235 TI - [Management of complications after residual tumor resection for metastatic testicular cancer]. AB - Residual tumor resection (RTR) in patients with metastatic testicular cancer plays a pivotal role in a multimodal treatment. It can be performed unilaterally or as an extended bilateral RTR. Additional surgical procedures might be necessary, such as nephrectomy, splenectomy, partial colectomy, or vascular interventions with possible caval resection, cavotomy, or aortic resection with aortic grafting. Consequently, several complications can be seen in the intra- and postoperative course, most common of which are superficial wound infections, intestinal paralysis, lymphocele, and chylous ascites. We sought to describe complication management and how to prevent complications before they arise. PMID- 25023236 TI - [Complications of hypospadias repairs]. AB - Hypospadias is the most common congenital abnormality of the lower urinary tract affecting one of 300 male newborns. More than 300 different surgical hypospadias repair techniques have been described. Currently, tubularized incised plate and meatal advancement and glansplasty integrated repair are the preferred techniques for distal hypospadias, whereas two-staged procedures are most frequently used in proximal forms. Success rates are high in the hands of dedicated surgeons, although studies on long-term results are sparse. The most frequent complications of hypospadias repairs include urethrocutaneous fistulas, meatal stenosis, and urethral strictures. Urological follow-up into puberty is warranted, as well as further studies with standardized reporting of long-term results and complications. PMID- 25023238 TI - [Complication management in prolapse and incontinence surgery]. AB - Tension-free alloplastic slings (TFAS) have revolutionized surgery for female stress urinary incontinence for more than 20 years. The procedure is easy to perform, minimally invasive with a short operating time in an outpatient setting and has proven efficacy comparable to retropubic colposuspension. The frequency of surgery for female stress incontinence has tripled within one decade which has to have an impact on the number of complications. In contrast, sacrocolpopexy has remained the gold standard in urological prolapse surgery as none of the new techniques has reached similar efficacy or safety; however, possible complications have to be named and their causes have to be understood to maintain the highest quality of care in the future. Possible complications of TFAS are potentially underestimated with respect to prevalence and manageability. Possible complications of prolapse and incontinence surgery are presented and the underlying causes are identified. Knowledge of the pathophysiology and the cause of complications together with the results of a postoperative diagnostic work-up, allow complication management to be tailored to each individual patient. To prevent complications all conservative treatment options should have been tried preoperatively and a complete evaluation (including urodynamics) should have been carried out for every patient. Postoperative urodynamics may help to document treatment success and to identify and quantify complications. PMID- 25023239 TI - [Low-risk prostate cancer]. PMID- 25023240 TI - [Prostate biopsy. Update for indication, procedure, and future developments]. AB - Transrectal ultrasound-guided prostate biopsy is considered the gold standard in the primary investigation of a suspicious prostate-related finding. The procedure can be carried out with ten probes or more on the lateral side of the prostate, after administering antibiotic prophylaxis and applying local anesthesia. The indication for a biopsy depends on the results of the digitorectal examination, on the serum prostate-specific antigen level, on the individual patient's wish and on his comorbidities. Whether multiparametric imaging should be used before or during the course of a primary or repeated biopsy in order to identify suspicious prostate lesions is the subject of current investigations. Extended biopsy protocols require further clinical investigations before they can become the new standard in the diagnostic work-up. This review delivers an update on the indication for, and technique of, prostate biopsies. PMID- 25023241 TI - [Sonographic imaging of the prostate]. AB - Accurate identification of the location of carcinoma in the prostate is essential for long-term therapeutic success, in particular for minimally invasive procedures. In recent years many new positive study results for prostate imaging have been reported which must be compared and evaluated and previous conservative assessments may need to be re-evaluated. In addition, combinations of different imaging techniques are increasingly being used in daily clinical routine. Due to technical advancements in sonographic imaging, such as elastography and contrast enhanced ultrasound (CEUS), the detection rate of prostate cancer can be increased. An overview of the different imaging modalities and current literature are presented in this article. PMID- 25023244 TI - [Urinary incontinence in men and women. Diagnostics and conservative therapy]. AB - Urinary incontinence can affect men and women to the same degree. A differentiation is made between stress incontinence (i.e. urine discharge as a result of physical activities, sneezing or coughing), urge incontinence (i.e. strong urge to void with involuntary discharge of urine), mixed urinary incontinence and special forms. While men and women share the pathophysiology of urge-associated urinary incontinence, the multifactorial female urinary stress incontinence is in contrast to the stress incontinence in men which is almost exclusively caused by prostatectomy (postprostatectomy). The basic diagnostic procedure for urinary incontinence is largely non-invasive. Special diagnostic procedures are reserved for recurrences and preparation for operative measures. Therapy is oriented to the degree of suffering and patient compliance and incorporates conservative measures as first line therapy (e.g. lifestyle changes, bladder and continence training). Duloxetin is approved for the medicinal therapy of female urinary stress incontinence. The treatment of urge-associated urinary incontinence is primarily with anticholinergic agents. Alternatively, procedures for neuromodulation, a beta mimetic or injection therapy with botulinum toxin can be used in the future. PMID- 25023245 TI - Lack of a surface layer in Tannerella forsythia mutants deficient in the type IX secretion system. AB - Tannerella forsythia, a Gram-negative anaerobic bacterium, is an important pathogen in periodontal disease. This bacterium possesses genes encoding all known components of the type IX secretion system (T9SS). T. forsythia mutants deficient in genes orthologous to the T9SS-encoding genes porK, porT and sov were constructed. All porK, porT and sov single mutants lacked the surface layer (S layer) and expressed less-glycosylated versions of the S-layer glycoproteins TfsA and TfsB. In addition, these mutants exhibited decreased haemagglutination and increased biofilm formation. Comparison of the proteins secreted by the porK and WT strains revealed that the secretion of several proteins containing C-terminal domain (CTD)-like sequences is dependent on the porK gene. These results indicate that the T9SS is functional in T. forsythia and contributes to the translocation of CTD proteins to the cell surface or into the extracellular milieu. PMID- 25023246 TI - Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan. AB - P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other beta-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128 resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains. PMID- 25023248 TI - Burden of changes in pill appearance for patients receiving generic cardiovascular medications after myocardial infarction: cohort and nested case control studies. AB - BACKGROUND: Generic prescription drugs made by different manufacturers may vary in color or shape, and switching among these drug products may interrupt medication use. OBJECTIVE: To determine whether nonpersistent use of generic drugs among patients with cardiovascular disease after myocardial infarction (MI) is associated with inconsistent appearance of their medications. DESIGN: Cohort and nested case-control studies. SETTING: Claims from a commercial health insurance database in the United States. PATIENTS: Patients discharged after hospitalization for MI between 2006 and 2011 who initiated treatment with a generic beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or statin. Case patients discontinued their index medication for at least 1 month; control patients continued treatment. Control patients were matched to case patients on therapeutic class, number of dispensings before nonpersistence, sex, and age. MEASUREMENTS: Rates of changes in pill color and shape during the year after MI were calculated. Next, 2 refills preceding nonpersistence were evaluated to determine whether pill color or shape had changed. Odds of discordance among case and control patients were compared using conditional logistic regression. RESULTS: A total of 29% of patients (3286 of 11,513) had a change in pill shape or color during the study. Statins had the most changes in appearance, whereas beta-blockers had the fewest. A total of 4573 episodes of nonpersistence was matched to 19,881 control episodes. The odds of nonpersistence in case patients increased by 34% after a change in pill color (adjusted odds ratio, 1.34 [95% CI, 1.12 to 1.59]) and 66% after a change in pill shape (adjusted odds ratio, 1.66 [CI, 1.43 to 1.94]). LIMITATION: Only 3 categories of drugs indicated after MI were evaluated, and clinical outcomes were not addressed. CONCLUSION: Variation in the appearance of generic pills is associated with nonpersistent use of these essential drugs after MI among patients with cardiovascular disease. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and the Harvard Program in Therapeutic Science. PMID- 25023247 TI - Social integration and suicide mortality among men: 24-year cohort study of U.S. health professionals. AB - BACKGROUND: Suicide is a major public health problem. Current thinking about suicide emphasizes the study of psychiatric, psychological, or biological determinants. Previous work in this area has largely relied on surrogate outcomes or samples enriched for psychiatric morbidity. OBJECTIVE: To evaluate the relationship between social integration and suicide mortality. DESIGN: Prospective cohort study initiated in 1988. SETTING: United States. PARTICIPANTS: 34,901 men aged 40 to 75 years. MEASUREMENTS: Social integration was measured with a 7-item index that included marital status, social network size, frequency of contact, religious participation, and participation in other social groups. Vital status of study participants was ascertained through 1 February 2012. The primary outcome of interest was suicide mortality, defined as deaths classified with codes E950 to E959 from the International Classification of Diseases, Ninth Revision. RESULTS: Over 708,945 person-years of follow-up, there were 147 suicides. The incidence of suicide decreased with increasing social integration. In a multivariable Cox proportional hazards regression model, the relative hazard of suicide was lowest among participants in the highest (adjusted hazard ratio [AHR], 0.41 [95% CI, 0.24 to 0.69]) and second-highest (AHR, 0.52 [CI, 0.30 to 0.91]) categories of social integration. Three components (marital status, social network size, and religious service attendance) showed the strongest protective associations. Social integration was also inversely associated with all-cause and cardiovascular-related mortality, but accounting for competing causes of death did not substantively alter the findings. LIMITATIONS: The study lacked information on participants' mental well-being. Some suicides could have been misclassified as accidental deaths. CONCLUSION: Men who were socially well integrated had a more than 2-fold reduced risk for suicide over 24 years of follow-up. PRIMARY FUNDING SOURCE: National Institutes of Health and Robert Wood Johnson Foundation. PMID- 25023250 TI - Effects of nurse-managed protocols in the outpatient management of adults with chronic conditions: a systematic review and meta-analysis. AB - BACKGROUND: Changes in federal health policy are providing more access to medical care for persons with chronic disease. Providing quality care may require a team approach, which the American College of Physicians calls the "medical home." One new model may involve nurse-managed protocols. PURPOSE: To determine whether nurse-managed protocols are effective for outpatient management of adults with diabetes, hypertension, and hyperlipidemia. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and CINAHL from January 1980 through January 2014. STUDY SELECTION: Two reviewers used eligibility criteria to assess all titles, abstracts, and full texts and resolved disagreements by discussion or by consulting a third reviewer. DATA EXTRACTION: One reviewer did data abstractions and quality assessments, which were confirmed by a second reviewer. DATA SYNTHESIS: From 2954 studies, 18 were included. All studies used a registered nurse or equivalent who titrated medications by following a protocol. In a meta-analysis, hemoglobin A1c level decreased by 0.4% (95% CI, 0.1% to 0.7%) (n = 8); systolic and diastolic blood pressure decreased by 3.68 mm Hg (CI, 1.05 to 6.31 mm Hg) and 1.56 mm Hg (CI, 0.36 to 2.76 mm Hg), respectively (n = 12); total cholesterol level decreased by 0.24 mmol/L (9.37 mg/dL) (CI, 0.54-mmol/L decrease to 0.05-mmol/L increase [20.77-mg/dL decrease to 2.02-mg/dL increase]) (n = 9); and low-density-lipoprotein cholesterol level decreased by 0.31 mmol/L (12.07 mg/dL) (CI, 0.73-mmol/L decrease to 0.11-mmol/L increase [28.27-mg/dL decrease to 4.13-mg/dL increase]) (n = 6). LIMITATION: Studies had limited descriptions of the interventions and protocols used. CONCLUSION: A team approach that uses nurse-managed protocols may have positive effects on the outpatient management of adults with chronic conditions, such as diabetes, hypertension, and hyperlipidemia. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. PMID- 25023249 TI - Personalizing age of cancer screening cessation based on comorbid conditions: model estimates of harms and benefits. AB - BACKGROUND: Harms and benefits of cancer screening depend on age and comorbid conditions, but reliable estimates are lacking. OBJECTIVE: To estimate the harms and benefits of cancer screening by age and comorbid conditions to inform decisions about screening cessation. DESIGN: Collaborative modeling with 7 cancer simulation models and common data on average and comorbid condition level specific life expectancy. SETTING: U.S. population. PATIENTS: U.S. cohorts aged 66 to 90 years in 2010 with average health or 1 of 4 comorbid condition levels: none, mild, moderate, or severe. INTERVENTION: Mammography, prostate-specific antigen testing, or fecal immunochemical testing. MEASUREMENTS: Lifetime cancer deaths prevented and life-years gained (benefits); false-positive test results and overdiagnosed cancer cases (harms). For each comorbid condition level, the age at which harms and benefits of screening were similar to that for persons with average health having screening at age 74 years. RESULTS: Screening 1000 women with average life expectancy at age 74 years for breast cancer resulted in 79 to 96 (range across models) false-positive results, 0.5 to 0.8 overdiagnosed cancer cases, and 0.7 to 0.9 prevented cancer deaths. Although absolute numbers of harms and benefits differed across cancer sites, the ages at which to cease screening were consistent across models and cancer sites. For persons with no, mild, moderate, and severe comorbid conditions, screening until ages 76, 74, 72, and 66 years, respectively, resulted in harms and benefits similar to average health persons. LIMITATION: Comorbid conditions influenced only life expectancy. CONCLUSION: Comorbid conditions are an important determinant of harms and benefits of screening. Estimates of screening benefits and harms by comorbid condition can inform discussions between providers and patients about personalizing screening cessation decisions. PRIMARY FUNDING SOURCE: National Cancer Institute and Centers for Disease Control and Prevention. PMID- 25023251 TI - Engaging patients and stakeholders in research proposal review: the patient centered outcomes research institute. AB - The inaugural round of merit review for the Patient-Centered Outcomes Research Institute (PCORI) in November 2012 included patients and other stakeholders, as well as scientists. This article examines relationships among scores of the 3 reviewer types, changes in scoring after in-person discussion, and the effect of inclusion of patient and stakeholder reviewers on the review process. In the first phase, 363 scientists scored 480 applications. In the second phase, 59 scientists, 21 patients, and 31 stakeholders provided a "prediscussion" score and a final "postdiscussion" score after an in-person meeting for applications. Bland Altman plots were used to characterize levels of agreement among and within reviewer types before and after discussion. Before discussion, there was little agreement among average scores given by the 4 lead scientific reviewers and patient and stakeholder reviewers. After discussion, the 4 primary reviewers showed mild convergence in their scores, and the 21-member panel came to a much stronger agreement. Of the 25 awards with the best (and lowest) scores after phase 2, only 13 had ranked in the top 25 after the phase 1 review by scientists. Five percent of the 480 proposals submitted were funded. The authors conclude that patient and stakeholder reviewers brought different perspectives to the review process but that in-person discussion led to closer agreement among reviewer types. It is not yet known whether these conclusions are generalizable to future rounds of peer review. Future work would benefit from additional data collection for evaluation purposes and from long-term evaluation of the effect on the funded research. PMID- 25023252 TI - Potential bias of instrumental variable analyses for observational comparative effectiveness research. AB - Instrumental variable analysis is an increasingly popular method in comparative effectiveness research (CER). In theory, the instrument controls for unobserved and observed patient characteristics that affect the outcome. However, the results of instrumental variable analyses in observational settings may be biased if the instrument and outcome are related through an unadjusted third variable: an "instrument-outcome confounder." The authors identified published CER studies that used instrumental variable analysis and searched the literature for potential confounders of the most common instrument-outcome pairs. Of the 187 studies identified, 114 used 1 or more of the 4 most common instrument categories: distance to facility, regional variation, facility variation, and physician variation. Of these, 65 used mortality as an outcome. Potential unadjusted instrument-outcome confounders were observed in all studies, including patient race, socioeconomic status, clinical risk factors, health status, and urban or rural residency; facility and procedure volume; and co-occurring treatments. Only 4 (6%) instrumental variable CER studies considered potential instrument-outcome confounders outside the study data. Many effect estimates may be biased by the failure to adjust for instrument-outcome confounding. The authors caution against overreliance on instrumental variable studies for CER. PMID- 25023253 TI - Approaching suicide as a public health issue. PMID- 25023254 TI - Are nurses an answer to new primary care needs? PMID- 25023255 TI - Remembering Johnnie. PMID- 25023256 TI - Prevention of diabetes with Mediterranean diets. PMID- 25023257 TI - Prevention of diabetes with mediterranean diets. PMID- 25023258 TI - Rivaroxaban in a patient with disseminated intravascular coagulation associated with an aortic aneurysm: a case report. PMID- 25023261 TI - Summaries for patients. Social integration and suicide mortality among men. PMID- 25023262 TI - Summaries for patients. Personalizing age of cancer screening cessation. PMID- 25023263 TI - Web Exclusives. The consult guys - spinal or general anesthesia? PMID- 25023264 TI - In persons at average risk, stool DNA tests had higher sensitivity than FIT for detecting colorectal cancer. PMID- 25023265 TI - In adults, use of anxiolytic or hypnotic drugs was associated with increased risk for mortality. PMID- 25023266 TI - Bowel preparation with sodium picosulfate was linked to hyponatremia compared with polyethylene glycol. PMID- 25023267 TI - In suspected PE, an age-adjusted D-dimer cutpoint improved ability to exclude PE. PMID- 25023268 TI - Review: preoperative behavioral interventions increase smoking cessation and reduce postoperative complications. PMID- 25023269 TI - Review: statins do not increase minor or serious symptomatic adverse events in placebo-controlled trials. PMID- 25023270 TI - Review: evidence for the effect of vitamin D supplementation on many patient outcomes was assessed. PMID- 25023271 TI - Review: vitamin D3 supplementation may reduce mortality in adults; vitamin D2 does not. PMID- 25023272 TI - In patients with severe sepsis, adding albumin to crystalloid solution did not reduce 28- or 90-day mortality. PMID- 25023273 TI - In septic shock, MAP targets of 80 to 85 mm Hg vs 65 to 70 mm Hg did not differ for 28-day mortality. PMID- 25023274 TI - Review: voriconazole for prevention or treatment of invasive fungal infections in cancer with neutropenia. PMID- 25023275 TI - An "unlikely" Wells rule score (<= 1) plus a negative D-dimer result excluded DVT in noncancer patients. PMID- 25023276 TI - Dietary omega-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis. AB - IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a severe progressive disease that cannot be prevented or cured. Diet-derived long-chain polyunsaturated fatty acids (PUFAs) are incorporated in brain lipids and modulate oxidative and inflammatory processes and could thus affect ALS risk and progression. OBJECTIVE: To examine the association between omega-6 and omega-3 PUFA consumption and ALS risk. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal analyses based on 1,002,082 participants (479,114 women and 522,968 men) in 5 prospective cohorts: the National Institutes of Health-AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-up Study, the Multiethnic Cohort Study, and the Nurses' Health Study. Diet was assessed via food frequency questionnaire developed or modified for each cohort. Participants were categorized into cohort-specific quintiles of intake of energy-adjusted dietary variables. MAIN OUTCOMES AND MEASURES: Cohort-specific multivariable adjusted risk ratios (RRs) of ALS incidence or death estimated by Cox proportional hazards regression and pooled using random-effects methods. RESULTS: A total of 995 ALS cases were documented during the follow-up. A greater omega-3 PUFA intake was associated with a reduced risk for ALS. The pooled, multivariable adjusted RR for the highest to the lowest quintile was 0.66 (95% CI, 0.53-0.81; P < .001 for trend). Consumption of both alpha-linolenic acid (RR, 0.73; 95% CI, 0.59-0.89; P = .003 for trend) and marine omega-3 PUFAs (RR, 0.84; 95% CI, 0.65 1.08; P = .03 for trend) contributed to this inverse association. Intakes of omega-6 PUFA were not associated with ALS risk. CONCLUSIONS AND RELEVANCE: Consumption of foods high in omega-3 PUFAs may help prevent or delay the onset of ALS. PMID- 25023277 TI - Defective entry into mitosis 1 (Dim1) negatively regulates osteoclastogenesis by inhibiting the expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). AB - Bone remodeling is a continuous process of osteoblastic bone formation and osteoclastic bone resorption to maintain normal bone mass. NFATc1 is the master regulator of osteoclastogensis and transcriptionally activated by c-Fos and NF kappaB in response to receptor activator of NF-kappaB ligand (RANKL) treatment. Defective entry into mitosis 1 (Dim1) is a nuclear protein that is implicated in pre-mRNA splicing and cell cycle progression, but the possible role of Dim1 in regulating other cellular processes remains unknown. Here, we demonstrate that Dim1 attenuates RANKL-induced osteoclastogenesis by targeting NFATc1 signaling pathway. Expression levels of Dim1 and NFATc1 are significantly increased during the formation of multinucleated osteoclasts. RNAi-mediated knockdown of Dim1 markedly enhances the expression of NFATc1 and its target genes, leading to the increase of RANKL-induced osteoclastogenesis in bone marrow-derived macrophages. Conversely, ectopic expression of Dim1 decreases RANKL-induced osteoclast differentiation by silencing NFATc1 and its target genes, further linking Dim1 to the dynamic regulation of osteoclastogenesis. Consistent with this notion, ChIP and interaction studies show that Dim1 directly associates with c-Fos and prevents c-Fos from binding to the NFATc1 promoter, resulting in targeted inactivation of the NFATc1 gene. Therefore, our studies reveal an unrecognized role for Dim1 as a master modulator of osteoclast differentiation, as well as the molecular mechanism underlying its repressive action toward osteoclastogensis. PMID- 25023278 TI - Protein interacting with C-kinase 1 (PICK1) binding promiscuity relies on unconventional PSD-95/discs-large/ZO-1 homology (PDZ) binding modes for nonclass II PDZ ligands. AB - PDZ domain proteins control multiple cellular functions by governing assembly of protein complexes. It remains unknown why individual PDZ domains can bind the extreme C terminus of very diverse binding partners and maintain selectivity. By employing NMR spectroscopy, together with molecular modeling, mutational analysis, and fluorescent polarization binding experiments, we identify here three structural mechanisms explaining why the PDZ domain of PICK1 selectively binds >30 receptors, transporters, and kinases. Class II ligands, including the dopamine transporter, adopt a canonical binding mode with promiscuity obtained via differential packing in the binding groove. Class I ligands, such as protein kinase Calpha, depend on residues upstream from the canonical binding sequence that are likely to interact with flexible loop residues of the PDZ domain. Finally, we obtain evidence that the unconventional ligand ASIC1a has a dual binding mode involving a canonical insertion and a noncanonical internal insertion with the two C-terminal residues forming interactions outside the groove. Together with an evolutionary analysis, the data show how unconventional binding modes might evolve for a protein recognition domain to expand the repertoire of functionally important interactions. PMID- 25023279 TI - Transactivation of the receptor-tyrosine kinase ephrin receptor A2 is required for the low molecular weight hyaluronan-mediated angiogenesis that is implicated in tumor progression. AB - Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ~2500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs is poorly defined. Our data indicate that treatment of human EC with LMW HA induced CD44v10 association with the receptor-tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ, or Dbs (RhoGEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration, and tubule formation). In addition, silencing EphA2, PATJ, Src, or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted Matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis associated diseases including tumor progression. PMID- 25023280 TI - Coupling of g proteins to reconstituted monomers and tetramers of the M2 muscarinic receptor. AB - G protein-coupled receptors can be reconstituted as monomers in nanodiscs and as tetramers in liposomes. When reconstituted with G proteins, both forms enable an allosteric interaction between agonists and guanylyl nucleotides. Both forms, therefore, are candidates for the complex that controls signaling at the level of the receptor. To identify the biologically relevant form, reconstituted monomers and tetramers of the purified M2 muscarinic receptor were compared with muscarinic receptors in sarcolemmal membranes for the effect of guanosine 5' [beta,gamma-imido]triphosphate (GMP-PNP) on the inhibition of N [(3)H]methylscopolamine by the agonist oxotremorine-M. With monomers, a stepwise increase in the concentration of GMP-PNP effected a lateral, rightward shift in the semilogarithmic binding profile (i.e. a progressive decrease in the apparent affinity of oxotremorine-M). With tetramers and receptors in sarcolemmal membranes, GMP-PNP effected a vertical, upward shift (i.e. an apparent redistribution of sites from a state of high affinity to one of low affinity with no change in affinity per se). The data were analyzed in terms of a mechanistic scheme based on a ligand-regulated equilibrium between uncoupled and G protein coupled receptors (the "ternary complex model"). The model predicts a rightward shift in the presence of GMP-PNP and could not account for the effects at tetramers in vesicles or receptors in sarcolemmal membranes. Monomers present a special case of the model in which agonists and guanylyl nucleotides interact within a complex that is both constitutive and stable. The results favor oligomers of the M2 receptor over monomers as the biologically relevant state for coupling to G proteins. PMID- 25023281 TI - Human METTL20 methylates lysine residues adjacent to the recognition loop of the electron transfer flavoprotein in mitochondria. AB - In mammalian mitochondria, protein methylation is a relatively uncommon post transcriptional modification, and the extent of the mitochondrial protein methylome, the modifying methyltransferases, and their substrates have been little studied. As shown here, the beta-subunit of the electron transfer flavoprotein (ETF) is one such methylated protein. The ETF is a heterodimer of alpha- and beta-subunits. Lysine residues 199 and 202 of mature ETFbeta are almost completely trimethylated in bovine heart mitochondria, whereas ETFalpha is not methylated. The enzyme responsible for the modifications was identified as methyltransferase-like protein 20 (METTL20). In human 143B cells, the methylation of ETFbeta is less extensive and is diminished further by suppression of METTL20. Tagged METTL20 expressed in HEK293T cells specifically associates with the ETF and promotes the trimethylation of ETFbeta lysine residues 199 and 202. ETF serves as a mobile electron carrier linking dehydrogenases involved in fatty acid oxidation and one-carbon metabolism to the membrane-associated ubiquinone pool. The methylated residues in ETFbeta are immediately adjacent to a protein loop that recognizes and binds to the dehydrogenases. Suppression of trimethylation of ETFbeta in mouse C2C12 cells oxidizing palmitate as an energy source reduced the consumption of oxygen by the cells. These experiments suggest that the oxidation of fatty acids in mitochondria and the passage of electrons via the ETF may be controlled by modulating the protein-protein interactions between the reduced dehydrogenases and the beta-subunit of the ETF by trimethylation of lysine residues. METTL20 is the first lysine methyltransferase to be found to be associated with mitochondria. PMID- 25023282 TI - Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. AB - ALPL encodes the tissue nonspecific alkaline phosphatase (TNSALP), which removes phosphate groups from various substrates. Its function is essential for bone and tooth mineralization. In humans, ALPL mutations lead to hypophosphatasia, a genetic disorder characterized by defective bone and/or tooth mineralization. To date, 275 ALPL mutations have been reported to cause hypophosphatasia, of which 204 were simple missense mutations. Molecular evolutionary analysis has proved to be an efficient method to highlight residues important for the protein function and to predict or validate sensitive positions for genetic disease. Here we analyzed 58 mammalian TNSALP to identify amino acids unchanged, or only substituted by residues sharing similar properties, through 220 millions years of mammalian evolution. We found 469 sensitive positions of the 524 residues of human TNSALP, which indicates a highly constrained protein. Any substitution occurring at one of these positions is predicted to lead to hypophosphatasia. We tested the 204 missense mutations resulting in hypophosphatasia against our predictive chart, and validated 99% of them. Most sensitive positions were located in functionally important regions of TNSALP (active site, homodimeric interface, crown domain, calcium site, ...). However, some important positions are located in regions, the structure and/or biological function of which are still unknown. Our chart of sensitive positions in human TNSALP (i) enables to validate or invalidate at low cost any ALPL mutation, which would be suspected to be responsible for hypophosphatasia, by contrast with time consuming and expensive functional tests, and (ii) displays higher predictive power than in silico models of prediction. PMID- 25023283 TI - The N-terminal domain of the Drosophila mitochondrial replicative DNA helicase contains an iron-sulfur cluster and binds DNA. AB - The metazoan mitochondrial DNA helicase is an integral part of the minimal mitochondrial replisome. It exhibits strong sequence homology with the bacteriophage T7 gene 4 protein primase-helicase (T7 gp4). Both proteins contain distinct N- and C-terminal domains separated by a flexible linker. The C-terminal domain catalyzes its characteristic DNA-dependent NTPase activity, and can unwind duplex DNA substrates independently of the N-terminal domain. Whereas the N terminal domain in T7 gp4 contains a DNA primase activity, this function is lost in metazoan mtDNA helicase. Thus, although the functions of the C-terminal domain and the linker are partially understood, the role of the N-terminal region in the metazoan replicative mtDNA helicase remains elusive. Here, we show that the N terminal domain of Drosophila melanogaster mtDNA helicase coordinates iron in a 2Fe-2S cluster that enhances protein stability in vitro. The N-terminal domain binds the cluster through conserved cysteine residues (Cys(68), Cys(71), Cys(102), and Cys(105)) that are responsible for coordinating zinc in T7 gp4. Moreover, we show that the N-terminal domain binds both single- and double stranded DNA oligomers, with an apparent Kd of ~120 nm. These findings suggest a possible role for the N-terminal domain of metazoan mtDNA helicase in recruiting and binding DNA at the replication fork. PMID- 25023284 TI - Defining the far-red limit of photosystem I: the primary charge separation is functional to 840 nm. AB - The far-red limit of photosystem I (PS I) photochemistry was studied by EPR spectroscopy using laser flashes between 730 and 850 nm. In manganese-depleted spinach thylakoid membranes, the primary donor in PS I, P700, was oxidized simultaneously with tyrosine Z, the secondary donor in PS II. It was found that at 295 K PS I photochemistry, observed as P700 (+) formation, was functional up to 840 nm. This is 30 nm further to the red region than was reported for PS II photochemistry (Thapper, A., Mamedov, F., Mokvist, F., Hammarstrom, L., and Styring, S. (2009) Plant Cell 21, 2391-2401). The same far-red limit for the P700 (+) formation was observed in a PS I reaction center core preparation from Nostoc punctiforme. The reduction of the acceptor side of PS I, observed as reduction of the iron-sulfur centers FA and FB by low temperature EPR measurements, was also functional at 15 K with light up to >830 nm. Taken together, these results, obtained from both plants and cyanobacteria, most likely rule out involvement of the red-absorbing antenna chlorophylls in this reaction. Instead we propose the existence of weak charge transfer bands absorbing in the far-red region in the ensemble of excitonically coupled chlorophyll a molecules around P700 similar to what has been found in the reaction center of PS II. These charge transfer bands could be responsible for the far-red light absorption leading to PS I photochemistry at wavelengths up to 840 nm. PMID- 25023285 TI - Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: relative activation of TLR4 and TLR2 pathways in different mutants. AB - Outer membrane particles from Gram-negative bacteria are attractive vaccine candidates as they present surface antigens in their natural context. We previously developed a high yield production process for genetically derived particles, called generalized modules for membrane antigens (GMMA), from Shigella. As GMMA are derived from the outer membrane, they contain immunostimulatory components, especially lipopolysaccharide (LPS). We examined ways of reducing their reactogenicity by modifying lipid A, the endotoxic part of LPS, through deletion of late acyltransferase genes, msbB or htrB, in GMMA producing Shigella sonnei and Shigella flexneri strains. GMMA with resulting penta-acylated lipid A from the msbB mutants showed a 600-fold reduced ability, and GMMA from the S. sonnei DeltahtrB mutant showed a 60,000-fold reduced ability compared with GMMA with wild-type lipid A to stimulate human Toll-like receptor 4 (TLR4) in a reporter cell line. In human peripheral blood mononuclear cells, GMMA with penta-acylated lipid A showed a marked reduction in induction of inflammatory cytokines (S. sonnei DeltahtrB, 800-fold; DeltamsbB mutants, 300 fold). We found that the residual activity of these GMMA is largely due to non lipid A-related TLR2 activation. In contrast, in the S. flexneri DeltahtrB mutant, a compensatory lipid A palmitoleoylation resulted in GMMA with hexa acylated lipid A with ~10-fold higher activity to stimulate peripheral blood mononuclear cells than GMMA with penta-acylated lipid A, mostly due to retained TLR4 activity. Thus, for use as vaccines, GMMA will likely require lipid A penta acylation. The results identify the relative contributions of TLR4 and TLR2 activation by GMMA, which need to be taken into consideration for GMMA vaccine development. PMID- 25023286 TI - Bcl-xL protein protects from C/EBP homologous protein (CHOP)-dependent apoptosis during plasma cell differentiation. AB - Although it is known that the unfolded protein response (UPR) plays a significant role in the process of plasma cell differentiation, the contribution of the individual sensors of the UPR to this process remains unclear. In this study we examine the death signals and compensatory survival signals activated during B cell activation and the first stages of plasma cell differentiation. During in vitro differentiation of both primary murine B cells and the Bcl1 cell line, we demonstrate that in addition to activation of the physiological UPR, changes in the expression of several Bcl-2 proteins occur, which are consistent with a lowering of the apoptotic threshold of the cell. Specifically, we observed decreased expression of Bcl-2 and Mcl-1 and increased expression of the proapoptotic protein Bim. However, these changes were countered by Bcl-xL induction, which is necessary to protect differentiating cells both from ER stress-induced death by tunicamycin and from the death signals inherent in differentiation. Consistent with differentiating cells becoming dependent on Bcl xL for survival, the addition of ABT-737 resulted in apoptosis in differentiating cells through the inhibition of sequestration of Bim. Confirming this result, differentiation in the context of RNAi-mediated Bcl-xL knockdown also induced apoptosis. This cell death is C/EBP homologous protein (CHOP)-dependent, connecting these events to the UPR. Thus plasma cell differentiation proceeds through a Bcl-xL-dependent intermediate. PMID- 25023287 TI - Stearoyl-CoA desaturase 1 activity is required for autophagosome formation. AB - Autophagy is one of the major degradation pathways for cytoplasmic components. The autophagic isolation membrane is a unique membrane whose content of unsaturated fatty acids is very high. However, the molecular mechanisms underlying formation of this membrane, including the roles of unsaturated fatty acids, remain to be elucidated. From a chemical library consisting of structurally diverse compounds, we screened for novel inhibitors of starvation induced autophagy by measuring LC3 puncta formation in mouse embryonic fibroblasts stably expressing GFP-LC3. One of the inhibitors we identified, 2,5 pyridinedicarboxamide, N2,N5-bis[5-[(dimethylamino)carbonyl]-4-methyl-2 thiazolyl], has a molecular structure similar to that of a known stearoyl-CoA desaturase (SCD) 1 inhibitor. To determine whether SCD1 inhibition influences autophagy, we examined the effects of the SCD1 inhibitor 28c. This compound strongly inhibited starvation-induced autophagy, as determined by LC3 puncta formation, immunoblot analyses of LC3, electron microscopic observations, and p62/SQSTM1 accumulation. Overexpression of SCD1 or supplementation with oleic acid, which is a catalytic product of SCD1 abolished the inhibition of autophagy by 28c. Furthermore, 28c suppressed starvation-induced autophagy without affecting mammalian target of rapamycin activity, and also inhibited rapamycin induced autophagy. In addition to inhibiting formation of LC3 puncta, 28c also inhibited formation of ULK1, WIPI1, Atg16L, and p62/SQSTM1 puncta. These results suggest that SCD1 activity is required for the earliest step of autophagosome formation. PMID- 25023288 TI - Endocytic adaptor epidermal growth factor receptor substrate 15 (Eps15) is involved in the trafficking of ubiquitinated alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptors. AB - AMPA-type glutamate receptors (AMPARs) play a critical role in mediating fast excitatory synaptic transmission in the brain. Alterations in receptor expression, distribution, and trafficking have been shown to underlie synaptic plasticity and higher brain functions, including learning and memory, as well as brain dysfunctions such as drug addiction and psychological disorders. Therefore, it is essential to elucidate the molecular mechanisms that regulate AMPAR dynamics. We have shown previously that mammalian AMPARs are subject to posttranslational modification by ubiquitin, with AMPAR ubiquitination enhancing receptor internalization and reducing AMPAR cell surface expression. Here we report a crucial role for epidermal growth factor receptor substrate 15 (Eps15), an endocytic adaptor, in ubiquitination-dependent AMPAR internalization. We find that suppression or overexpression of Eps15 results in changes in AMPAR surface expression. Eps15 interacts with AMPARs, which requires Nedd4-mediated GluA1 ubiquitination and the ubiquitin-interacting motif of Eps15. Importantly, we find that Eps15 plays an important role in AMPAR internalization. Knockdown of Eps15 suppresses the internalization of GluA1 but not the mutant GluA1 that lacks ubiquitination sites, indicating a role of Eps15 for the internalization of ubiquitinated AMPARs. These results reveal a novel molecular mechanism employed specifically for the trafficking of the ubiquitin-modified AMPARs. PMID- 25023289 TI - PTPN14 forms a complex with Kibra and LATS1 proteins and negatively regulates the YAP oncogenic function. AB - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Pivotal effectors of this pathway are YAP/TAZ, transcriptional co-activators whose dysfunction contributes to epithelial-to-mesenchymal transition and malignant transformation. Therefore, it is of great importance to decipher the mechanisms underlying the regulations of YAP/TAZ at various levels. Here we report that non receptor tyrosine phosphatase 14 (PTPN14) interacts with the Kibra protein. The interaction between PTPN14 and Kibra is through the PPXY domain of PTPN14 and WW domain of Kibra. PTPN14 and Kibra can induce the LATS1 activation independently and cooperatively. Interestingly, activation of LATS1 by PTPN14 is dependent on the C terminus of PTPN14 and independent of the upstream mammalian STE20-like kinase (MST) proteins. Furthermore, we demonstrate that PTPN14 increases the LAST1 protein stability. Last, overexpression of Kibra rescues the increased cell migration and aberrant three-dimensional morphogenesis induced by knockdown of PTPN14, and this rescue is mediated through the activation of the upstream LATS1 kinase and subsequent cytoplasmic sequestration of YAP. In summary, our results indicate a potential regulatory role of PTPN14 in the Hippo pathway and demonstrate another layer of regulation in the YAP oncogenic function. PMID- 25023291 TI - Magnetic resonance imaging-based tumour perfusion parameters are biomarkers predicting response after radiation to brain metastases. AB - PURPOSE: To investigate whether early relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and permeability (Ktrans(2)) measurements may serve as magnetic resonance imaging (MRI) biomarkers of radiation response or progression for brain metastases. MATERIALS AND METHODS: Seventy brain metastases in 44 patients treated with either stereotactic radiosurgery or whole brain radiotherapy were imaged with dynamic susceptibility and dynamic contrast enhancement MRI at baseline, 1 week and 1 month after treatment. The final response status was determined according to volume criteria derived from a 1 year post-treatment MRI or last available follow-up MRI. Tumours were characterised as responders, non-responders, progressors and non-progressors and compared for Ktrans(2), rCBF and rCBV differences. Uni- and multivariate analysis evaluated factors associated with tumour response and progression at 1 week and 1 month. A generalised estimating equations (GEE) model accounted for multiple tumours per subject. Receiver operator characteristic (ROC) analysis identified optimal cut off values, sensitivity and specificity for response or progression. RESULTS: Tumour responders showed lower Ktrans(2) and reduced rCBF at 1 week (P < 0.05 each). Progressive disease showed lower rCBF and reduced rCBV at 1 month (P < 0.05 each). GEE and multivariate analysis revealed lower Ktrans(2) at 1 week, an absence of prior radiation predicted response. At 1 month only lower rCBV predicted progressive disease on GEE and multivariate analysis. Optimal cut-off points for Ktrans(2) and rCBV were 1.37 and 2.03 with sensitivity and specificity of 61.5 and 81.1% and 73.9 and 81.8%, respectively. CONCLUSION: Lower Ktrans(2) at 1 week and rCBV at 1 month discriminated responders and progressive disease, respectively. PMID- 25023290 TI - Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide 1-phosphate 4'-kinase LpxK. AB - The membrane-bound tetraacyldisaccharide-1-phosphate 4'-kinase, LpxK, catalyzes the sixth step of the lipid A (Raetz) biosynthetic pathway and is a viable antibiotic target against emerging Gram-negative pathogens. We report the crystal structure of lipid IVA, the LpxK product, bound to the enzyme, providing a rare glimpse into interfacial catalysis and the surface scanning strategy by which many poorly understood lipid modification enzymes operate. Unlike the few previously structurally characterized proteins that bind lipid A or its precursors, LpxK binds almost exclusively to the glucosamine/phosphate moieties of the lipid molecule. Steady-state kinetic analysis of multiple point mutants of the lipid-binding pocket pinpoints critical residues involved in substrate binding, and characterization of N-terminal helix truncation mutants uncovers the role of this substructure as a hydrophobic membrane anchor. These studies make critical contributions to the limited knowledge surrounding membrane-bound enzymes that act upon lipid substrates and provide a structural template for designing small molecule inhibitors targeting this essential kinase. PMID- 25023292 TI - More effort is needed to improve the practice of radiotherapy in Africa. PMID- 25023294 TI - Comparison of three devices for the automated detection of estrus in dairy cows. AB - Considerable technological advances have been made in the automated detection of estrus in dairy cattle, but few studies have evaluated their relative performance on the same animals or assessed cow-related factors that affect their performance. Our objective was to assess the performance and reliability of three devices commercially available in France for cow estrus detection. The devices were a pedometer (PM; Afitag) and two activity meters (AM1; Heatime-RuminAct, and AM2; HeatPhone). Two algorithms were tested for AM2. We fitted 63 lactating Holstein cows with the three detectors from calving to 90 days after calving. The onset and pattern of cyclicity were monitored from 7 to 90 days postpartum measuring progesterone concentration in milk twice weekly. A total of 211 ovulations were identified. Cyclicity was classified as normal in 60% of cows (38/63). Calculated over the operating period of all the devices (179 periods of estrus), the sensitivities and positive predictive values were, respectively, 71% and 71% for PM, 62% and 84% for AM1, 61% and 67% for the first algorithm of AM2, and 62% and 87% for the second algorithm of AM2. Both activity meters had a lower sensitivity but a higher positive predictive value than the PM (P < 0.05). For all devices, the performance in estrus detection was much poorer at the first postpartum ovulation than at subsequent ovulations (P < 0.05). Lactation rank and milk production affected some devices (P < 0.05). These devices could be used to reinforce visual observations, especially after 50 days postpartum, the minimum recommended delay to insemination. However, their full benefit remains to be verified in different farming systems and taking into account the specific objectives of the dairy farmer. PMID- 25023295 TI - Genome-wide profiling of sperm DNA methylation in relation to buffalo (Bubalus bubalis) bull fertility. AB - The DNA methylation pattern in spermatozoa of buffalo bulls of different fertility status was investigated. Spermatozoa isolated DNA from two groups of buffalo bulls (n = 5), selected based on their artificial insemination-generated conception rate data followed by IVF efficiency, were studied for global methylation changes using a custom-designed 180 K buffalo (Bubalus bubalis) CpG island/promoter microarray. A total of 96 individual genes with another 55 genes covered under CpG islands were found differentially methylated in sperm of high fertile and subfertile buffalo bulls. Important genes associated with biological processes, cellular components, and functions were identified to be differentially methylated in buffalo bulls with differential fertility status. The identified differentially methylated genes were found to be involved in germ cell development, spermatogenesis, capacitation, and embryonic development. The observations hint that methylation defects of sperm DNA may play a crucial role in determining the fertility of breeding bulls. This growing field of sperm epigenetics will be of great benefit in understanding the graded fertility conditions of breeding bulls in commercial livestock production system. PMID- 25023296 TI - Fertility and uterine hemodynamic in cows after artificial insemination with semen assessed by fluorescent probes. AB - Fluorescent probes (propidium iodide, Hoechst 33342, fluorescein isothiocyanate conjugated Pisum sativum agglutinin, and 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolcarbocyanine iodide) were used to simultaneously evaluate the integrity of plasma and acrosomal membranes as well as mitochondrial membrane function in cryopreserved bovine semen and to verify its influence on fertility and postinsemination uterine vascularization. One hundred eighty-two Nellore cows were distributed for artificial insemination (AI) using semen batches separated according to the cell percentage presenting intact plasma membrane, intact acrosome, and high mitochondrial function (IPIAH): group G (44.5% IPIAH, n = 68), group M (23.0% IPIAH, n = 56), and group R (8.5% IPIAH, n = 58). The uterine hemodynamic was evaluated by Doppler sonogram in three periods: 30 hours before AI, 4 and 24 hours after AI were considered the resistance index and the uterine vascularization score. The pregnancy rate of group G (64.7%) was greater (P > 0.05) compared with group R (36.2%), but both did not differ from group M (50.0%). There was no effect (P > 0.05) of semen quality on uterine vascularization. Greater vascularization was noticed 4 hours after AI than 30 hours before and 24 hours after AI. Semen evaluation using fluorescent probes contributes to predicting fertilizing potential of semen. The use of semen with less percentage of IPIAH sperm does not alter uterine hemodynamic in cows. PMID- 25023297 TI - Genetic relationships among traits related to reproduction and growth of Nelore females. AB - The objective of the study presented here was to analyze the genetic relationships among heifer pregnancy (HP), age at first calving (AFC), stayability (STAY), average annual productivity of the cow, in kilograms of weaned calf per cow per year (PRODAM), postweaning weight gain (PWG), and hip height (HH) of Nelore females from 12 Brazilian herds. (Co)variance components were obtained by six-trait animal model using Gibbs sampling. The posterior mean of the heritability estimates were 0.37, 0.18, 0.19, 0.16, 0.21, and 0.37 for HP, AFC, STAY, PRODAM, PWG, and HH, respectively. In general, the genetic correlations were strong between traits related to reproduction, for example, 0.85 between HP and AFC, and 0.94 between STAY and PRODAM. Weak genetic correlations were obtained between reproductive and growth traits (absolute values ranging from 0.02 to 0.30). Although weak, the genetic correlations between PWG and reproductive traits were favorable, whereas the genetic correlations between HH and reproductive traits were close to zero and slightly unfavorable for HP, AFC, and STAY. An increase of HH is therefore expected to have little or no negative effect on the reproductive performance of females. The posterior mean of genetic correlation between PWG and HH was moderate (0.50). On the basis of the heritability, genetic correlation estimates, and time to obtain data, HP and PRODAM seems to show the best potential as selection criteria to improve the productive and reproductive performance of Nelore females. In principle, it is possible to select for increased PWG without compromising the reproduction of Nelore females. However, selection for PWG may result in an increase of female HH as a correlated response, a fact that could increase management costs in advanced generations of selection. In the light of the results, all traits studied here can be used as selection criteria and there is no strong evidence of genetic antagonism among traits related to reproduction and growth of Nelore females. PMID- 25023298 TI - The influence of recombinant feline oviductin on different aspects of domestic cat (Felis catus) IVF and embryo quality. AB - Oviductin is known to be a key player providing a convenient environment for the process of fertilization affecting this by direct interaction with oocytes and sperm. As in vitro embryo production in the context of assisted reproduction for endangered felids is still in the process of optimization, oviductin might be used to improve IVF results. Recombinant His-tagged feline oviductin was expressed by transformed Escherichia coli BL21DE3 cells. The protein was purified by immobilized metal ion affinity chromatography. The effect of the recombinant protein was characterized in three experiments: a hemizona assay for sperm binding analysis, the IVF outcome, and the relative mRNA expression levels in blastocysts after IVF. A significant higher number of bound sperm cells were found after incubation in oviductin. No significant effect on cleavage, morula, and blastocyst rates with or without oviductin incubation during IVF could be observed. However, the relative mRNA abundance of GJA1, a gene, whose expression level is known to be a marker of embryo quality, was significantly increased (P value less than 0.05) in blastocysts after oviductin treatment. In contrast to this, expression of OCT4, HSP70, DNMT1, DNMT3A, BAX, IGF1R, and GAPDH was not significantly affected. We assume that our recombinant oviductin in its current nonglycosylated form is able to enhance sperm binding. Despite of a missing significant effect on IVF outcome, embryo quality in terms of relative GJA1 expression is influenced positively. These promising results demonstrate the value of recombinant oviductin for the IVF in cats. PMID- 25023299 TI - History of electrophysiology and the patch clamp. AB - We provide a historic outlook on the development of the concept of bioelectricity, with emphasis on the neuromuscular junction as a model that revolutionized our thinking of the nerve, nervous, and muscle tissue excitability. We abridge some crucial experiments in defining the electrical excitability of biological cells. We also provide an insight into developments of tools and methods, which gradually yielded a contemporary "palette" of electrophysiology approaches, including the patch clamp. Pioneering steps in this journey, ranging from Galvani's experiments using the Leyden jar to those of Neher and Sakmann using a gigaseal patch-clamp approach, are pictorially illustrated. This chapter is meant to be a perspective to the following sections in this volume dedicated to patch-clamp methods and protocols. PMID- 25023300 TI - Whole-cell patch-clamp analysis of recombinant NMDA receptor pharmacology using brief glutamate applications. AB - N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that are essential for synaptic plasticity, learning and memory. Dysfunction of NMDARs has been implicated in many nervous system disorders; therefore, pharmacological modulation of NMDAR activity has great therapeutic potential. However, given the broad physiological importance of NMDARs, modulating their activity often has detrimental side effects precluding pharmaceutical use of many NMDAR modulators. One approach to possibly improve the therapeutic potential of NMDAR modulators is to identify compounds that modulate subsets of NMDARs. An obvious target for modulating NMDAR subsets is the many NMDAR subtypes produced through different combinations of NMDAR subunits. With seven identified genes that encode NMDAR subunits, there are many neuronal NMDAR subtypes with distinct properties and potentially differential pharmacological sensitivities. Study of NMDAR subtype specific pharmacology is complicated in neurons, however, because most neurons express at least three NMDAR subtypes. Thus, use of an approach that permits study in isolation of a single receptor subtype is preferred. Additionally, the effects of drugs on agonist-activated responses typically depend on duration of agonist exposure. To evaluate drug effects on synaptic transmission, an approach should be used that allows for activation of receptor responses as brief as those observed during synaptic transmission, both in the absence and presence of drug. To address these issues, we designed a fast perfusion system capable of (1) delivering brief (~5 ms) and consistent applications of glutamate to recombinant NMDARs of known subunit composition, and (2) easily and quickly (~5 s) changing between glutamate applications in the absence and presence of drug. PMID- 25023301 TI - Patch clamp combined with voltage/concentration clamp to determine the kinetics and voltage dependency of N-methyl-D-aspartate (NMDA) receptor open channel blockers. AB - Electrophysiological techniques can be used to great effect to help determine the mechanism of action of a compound. However, many factors can compromise the resulting data and their analysis, such as the speed of solution exchange, expression of additional ion channel populations including other ligand-gated receptors and voltage-gated channels, compounds having multiple binding sites, and current desensitization and rundown. In this chapter, such problems and their solutions are discussed and illustrated using data from experiments involving the uncompetitive NMDA receptor antagonist memantine. Memantine differs from many other NMDA receptor channel blockers in that it is well tolerated and does not cause psychotomimetic effects at therapeutic doses. Various electrophysiological parameters of NMDA-induced current blockade by memantine have been proposed to be important in determining therapeutic tolerability; potency, onset and offset kinetics, and voltage dependency. These were all measured using whole cell patch clamp techniques using hippocampal neurons. Full results are shown here for memantine, and these are summarized and compared to those from similar experiments with other NMDA channel blockers. The interpretation of these results is discussed, as are theories concerning the tolerability of NMDA channel blockers, with the aim of illustrating how electrophysiological data can be used to form and support a physiological hypothesis. PMID- 25023302 TI - State-of-the-art automated patch clamp: heat activation, action potentials, and high throughput in ion channel screening. AB - A successful robotic approach of the patch clamp technique is based on planar patch clamp chips where a glass pipette, as used in conventional patch clamping, is replaced by a thin planar glass sheet with a small hole in the middle. Automated patch clamp (APC) systems utilizing this chip design offer higher throughput capabilities and ease of use and thus have become common in basic research, drug development, and safety screening. Further development of existing devices and introduction of new systems widen the range of possible experiments and increase throughput. Here, two features with different areas of applications that meet the needs of drug discovery researchers and basic researchers alike are described. The utilized system is a medium throughput APC device capable of recording up to eight cells simultaneously. The temperature control capability and the possibility to perform recordings not only in the voltage clamp but also in the current clamp mode are described in detail. Since eight recordings can be generated in parallel without compromising data quality, reliable and cost effective and time-effective screening of compounds against ion channels using voltage clamp and current clamp electrophysiology can be performed. PMID- 25023303 TI - Industrializing electrophysiology: HT automated patch clamp on SyncroPatch(r) 96 using instant frozen cells. AB - Patch-clamping is a powerful technique for investigating the ion channel function and regulation. However, its low throughput hampered profiling of large compound series in early drug development. Fortunately, automation has revolutionized the area of experimental electrophysiology over the past decade. Whereas the first automated patch-clamp instruments using the planar patch-clamp technology demonstrated rather a moderate throughput, few second-generation automated platforms recently launched by various companies have significantly increased ability to form a high number of high-resistance seals. Among them is SyncroPatch((r)) 96 (Nanion Technologies GmbH, Munich, Germany), a fully automated giga-seal patch-clamp system with the highest throughput on the market. By recording from up to 96 cells simultaneously, the SyncroPatch((r)) 96 allows to substantially increase throughput without compromising data quality. This chapter describes features of the innovative automated electrophysiology system and protocols used for a successful transfer of the established hERG assay to this high-throughput automated platform. PMID- 25023304 TI - Planar patch clamp for neuronal networks--considerations and future perspectives. AB - The patch-clamp technique is generally accepted as the gold standard for studying ion channel activity allowing investigators to either "clamp" membrane voltage and directly measure transmembrane currents through ion channels, or to passively monitor spontaneously occurring intracellular voltage oscillations. However, this resulting high information content comes at a price. The technique is labor intensive and requires highly trained personnel and expensive equipment. This seriously limits its application as an interrogation tool for drug development. Patch-clamp chips have been developed in the last decade to overcome the tedious manipulations associated with the use of glass pipettes in conventional patch clamp experiments. In this chapter, we describe some of the main materials and fabrication protocols that have been developed to date for the production of patch-clamp chips. We also present the concept of a patch-clamp chip array providing high resolution patch-clamp recordings from individual cells at multiple sites in a network of communicating neurons. On this chip, the neurons are aligned with the aperture-probes using chemical patterning. In the discussion we review the potential use of this technology for pharmaceutical assays, neuronal physiology and synaptic plasticity studies. PMID- 25023305 TI - Methods for the study of synaptic receptor functional properties. AB - The generation of a synaptic current at the postsynaptic element (PSCs) is the result of a dynamic sequence of events including the release of the neurotransmitter, its diffusion in the synaptic cleft, and the activation of neurotransmitter receptors located at the postsynaptic side. It is widely accepted that the amplitude and the duration of PSCs are largely dictated by the gating properties of postsynaptic receptors. However, the knowledge of the properties of postsynaptic receptors is mostly derived from steady-state analysis, a condition that is substantially different from the non-equilibrium activation of synaptic receptors imposed by submillisecond neurotransmitter exposures. Given the technical limitations to reproduce the brief "synaptic-like" agonist pulse durations, the functioning of postsynaptic receptors during synaptic transmission is not fully elucidated and the "on-demand" postsynaptic activation of synapses cannot be easily achieved. In this chapter, we review the diverse approaches to study receptor gating at times relevant for synaptic transmission and novel optical/optogenetic techniques for controlling synaptic activity at the postsynaptic level. In addition, we emphasize the role of non equilibrium in unmasking specific features of synaptic receptor gating and the recent advances in photonics for the light-control of neuronal activity at the single-receptor level. PMID- 25023306 TI - Single-cell RT-PCR, a technique to decipher the electrical, anatomical, and genetic determinants of neuronal diversity. AB - The patch-clamp technique has allowed for detailed studies on the electrical properties of neurons. Dye loading through patch pipettes enabled characterizing the morphological properties of the neurons. In addition, the patch-clamp technique also allows for harvesting mRNA from single cells to study gene expression at the single cell level (known as single-cell RT-PCR). The combination of these three approaches makes possible the study of the GEM profile of neurons (gene expression, electrophysiology, and morphology) using a single patch pipette and patch-clamp recording. This combination provides a powerful technique to investigate and correlate the neuron's gene expression with its phenotype (electrical behavior and morphology). The harvesting and amplification of single cell mRNA for gene expression studies is a challenging task, especially for researchers with sparse or no training in molecular biology (see Notes 1,2 and 5). Here we describe in detail the GEM profiling approach with special attention to the gene expression profiling. PMID- 25023307 TI - Whole-cell voltage clamp on skeletal muscle fibers with the silicone-clamp technique. AB - Control of membrane voltage and membrane current measurements are of critical importance for the study of numerous aspects of skeletal muscle physiology and pathophysiology. The silicone-clamp technique makes use of a conventional patch clamp apparatus to achieve whole-cell voltage clamp of a restricted portion of a fully differentiated adult skeletal muscle fiber. The major part of an isolated muscle fiber is insulated from the extracellular medium with silicone grease and the tip of a single microelectrode connected to the amplifier is then inserted within the fiber through the silicone layer. The method is extremely easy to implement. It represents an alternative to the traditional vaseline-gap isolation and two or three microelectrodes voltage-clamp techniques. The present chapter reviews the benefits of the silicone-clamp technique and provides updated detailed insights into its practical implementation. PMID- 25023308 TI - Multiphoton imaging approaches for studying striatal dendritic excitability. AB - As the main input nucleus to the basal ganglia, the striatum is responsible for receiving and integrating highly convergent afferents to ultimately guide action selection and movement initiation. Although the majority of this synaptic integration occurs in the dendrites of striatal projection neurons (SPNs), their thin diameter makes them inaccessible with traditional recording electrodes. Recent advances in optical imaging technologies have allowed us and others to start lifting the veil on the mechanisms governing synaptic integration in the striatum by enabling direct dendritic measurements and manipulations. Here we describe how our lab has approached combining 2-photon imaging and photolysis with electrophysiological recordings to study dendritic excitability and synaptic integration in the striatum. PMID- 25023309 TI - Investigation of synaptic microcircuits using patch-clamp paired recordings in acute brain slices. AB - Multiple patch clamp recordings represent a powerful tool to investigate functional synaptic connectivity among individual cells. This technical approach is particularly useful to study the synaptic organization of microcircuits in certain brain areas, e.g., the striatum, which are characterized by heterogeneous cell populations and an apparent lack of an anatomically ordered cytoarchitecture. Fast-spiking interneurons (FSIs) represent less than 1 % of striatal neurons, but despite their rareness they exert a strong influence on signal processing by striatal microcircuits and principal cells output. Little is known about the functional properties of chemical and electrical synapses connecting striatal FSIs to each other. Here we describe a simple dual patch clamp approach to investigate electrical and GABAergic synapses in mouse neostriatal slices. PMID- 25023310 TI - Outside-out "sniffer-patch" clamp technique for in situ measures of neurotransmitter release. AB - The mechanism underlying neurotransmitter release is a critical research domain for the understanding of neuronal network function; however, few techniques are available for the direct detection and measurement of neurotransmitter release. To date, the sniffer-patch clamp technique is mainly used to investigate these mechanisms from individual cultured cells. In this study, we propose to adapt the sniffer-patch clamp technique to in situ detection of neurosecretion. Using outside-out patches from donor cells as specific biosensors plunged in acute cerebral slices, this technique allows for proper detection and quantification of neurotransmitter release at the level of the neuronal network. PMID- 25023311 TI - A cost-effective method for preparing, maintaining, and transfecting neurons in organotypic slices. AB - The cellular and molecular mechanisms that underlie brain function are challenging to study in the living brain. The development of organotypic slices has provided a welcomed addition to our arsenal of experimental brain preparations by allowing both genetic and prolonged pharmacological manipulations in a system that, much like the acute slice preparation, retains several core features of the cellular and network architecture found in situ. Neurons in organotypic slices can survive in culture for several weeks, can be molecularly manipulated by transfection procedures and their function can be interrogated by traditional cellular electrophysiological or imaging techniques. Here, we describe a cost-effective protocol for the preparation and maintenance of organotypic slices and also describe a protocol for biolistic transfection that can be used to introduce plasmids in a small subset of neurons living in an otherwise molecularly unperturbed network. The implementation of these techniques offers a flexible experimental paradigm that can be used to study a multitude of neuronal mechanisms. PMID- 25023312 TI - Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. AB - The development of the living acute brain slice preparation for analyzing synaptic function roughly a half century ago was a pivotal achievement that greatly influenced the landscape of modern neuroscience. Indeed, many neuroscientists regard brain slices as the gold-standard model system for detailed cellular, molecular, and circuitry level analysis and perturbation of neuronal function. A critical limitation of this model system is the difficulty in preparing slices from adult and aging animals, and over the past several decades few substantial methodological improvements have emerged to facilitate patch clamp analysis in the mature adult stage. In this chapter we describe a robust and practical protocol for preparing brain slices from mature adult mice that are suitable for patch clamp analysis. This method reduces swelling and damage in superficial layers of the slices and improves the success rate for targeted patch clamp recordings, including recordings from fluorescently labeled populations in slices derived from transgenic mice. This adult brain slice method is suitable for diverse experimental applications, including both monitoring and manipulating neuronal activity with genetically encoded calcium indicators and optogenetic actuators, respectively. We describe the application of this adult brain slice platform and associated methods for screening kinetic properties of Channelrhodopsin (ChR) variants expressed in genetically defined neuronal subtypes. PMID- 25023313 TI - Synaptic connectivity in engineered neuronal networks. AB - We have developed a method to organize cells in dissociated cultures using engineered chemical clues on a culture surface and determined their connectivity patterns. Although almost all elements of the synaptic transmission machinery can be studied separately in single cell models in dissociated cultures, the complex physiological interactions between these elements are usually lost. Thus, factors affecting synaptic transmission are generally studied in organotypic cultures, brain slices, or in vivo where the cellular architecture generally remains intact. However, by utilizing engineered neuronal networks complex phenomenon such as synaptic transmission or synaptic plasticity can be studied in a simple, functional, cell culture-based system. We have utilized self-assembled monolayers and photolithography to create the surface templates. Embryonic hippocampal cells, plated on the resultant patterns in serum-free medium, followed the surface clues and formed the engineered neuronal networks. Basic whole-cell patch clamp electrophysiology was applied to characterize the synaptic connectivity in these engineered two-cell networks. The same technology has been used to pattern other cell types such as cardiomyocytes or skeletal muscle fibers. PMID- 25023314 TI - Modeling of action potential generation in NG108-15 cells. AB - In order to explore the possibility of identifying toxins based on their effect on the shape of action potentials, we created a computer model of the action potential generation in NG108-15 cells (a neuroblastoma/glioma hybrid cell line). To generate the experimental data for model validation, voltage-dependent sodium, potassium and high-threshold calcium currents, as well as action potentials, were recorded from NG108-15 cells with conventional whole-cell patch-clamp methods. Based on the classic Hodgkin-Huxley formalism and the linear thermodynamic description of the rate constants, ion-channel parameters were estimated using an automatic fitting method. Utilizing the established parameters, action potentials were generated using the Hodgkin-Huxley formalism and were fitted to the recorded action potentials. To demonstrate the applicability of the method for toxin detection and discrimination, the effect of tetrodotoxin (a sodium channel blocker) and tefluthrin (a pyrethroid that is a sodium channel opener) were studied. The two toxins affected the shape of the action potentials differently, and their respective effects were identified based on the predicted changes in the fitted parameters. PMID- 25023315 TI - Whole-cell patch-clamp recordings in freely moving animals. AB - The patch-clamp technique and the whole-cell measurements derived from it have greatly advanced our understanding of the coding properties of individual neurons by allowing for a detailed analysis of their excitatory/inhibitory synaptic inputs, intrinsic electrical properties, and morphology. Because such measurements require a high level of mechanical stability they have for a long time been limited to in vitro and anesthetized preparations. Recently, however, a considerable amount of effort has been devoted to extending these techniques to awake restrained/head-fixed preparations allowing for the study of the input output functions of neurons during behavior. In this chapter we describe a technique extending patch-clamp recordings to awake animals free to explore their environments. PMID- 25023316 TI - Pressure-polished borosilicate pipettes are "universal sealer" yielding low access resistance and efficient intracellular perfusion. AB - Whole-cell recording is the most widely used configuration of the patch recording technique, mainly because it allows to manipulate the intracellular environment while recording membrane current. However, the patch pipette tapered shank and the small tip opening give high access resistances and preclude efficient exchange between pipette solution and cell cytosol. Independently by the recording configuration, another problem of this technique is to gain consistently tight seals.Here we describe a method to enlarge the pipette shank without affecting the tip opening diameter, through the calibrated combination of heat and air pressure, with a custom-made inexpensive setup. These pressure polished pipettes give small access resistances and allow for the accommodation of pulled quartz or plastic perfusion tubes very close to the pipette tip (to deliver exogenous molecules into the cytosol with a controlled timing). Finally, we describe a method to consistently attain seals with pipettes made from just one glass type, for a wide variety of cell types, isolated from different amphibian, reptilian, fish, and mammalian tissues, and on artificial membranes composed of many different lipid mixtures. PMID- 25023317 TI - Current recordings at the single channel level in adult mammalian isolated cardiomyocytes. AB - This chapter describes appropriate methods to investigate mammalian cardiac channels properties at the single channel level. Cell isolation is performed from new born or adult heart by enzymatic digestion on minced tissue or using the Langendorff apparatus. Isolation proceeding is suitable for rabbit, rat, and mouse hearts. In addition, isolation of human atrial cardiomyocytes is described. Such freshly isolated cells or cells maintained in primary culture are suitable for patch-clamp studies. Here we describe the single channel variants of the patch-clamp technique (cell-attached, inside-out, outside-out) used to investigate channel properties. Proceedings for the evaluation of biophysical properties such as conductance, ionic selectivity, regulations by extracellular and intracellular mechanisms are described. To illustrate the study, we provide an example by the characterization of a calcium-activated non-selective cation channel (TRPM4). PMID- 25023318 TI - Dynamic clamp as a tool to study the functional effects of individual membrane currents. AB - Today, the patch-clamp technique is the main technique in electrophysiology to record action potentials or membrane current from isolated cells, using a patch pipette to gain electrical access to the cell. The common recording modes of the patch-clamp technique are current clamp and voltage clamp. In the current clamp mode, the current injected through the patch pipette is under control while the free-running membrane potential of the cell is recorded. Current clamp allows for measurements of action potentials that may either occur spontaneously or in response to an injected stimulus current. In voltage clamp mode, the membrane potential is held at a set level through a feedback circuit, which allows for the recording of the net membrane current at a given membrane potential.A less common configuration of the patch-clamp technique is the dynamic clamp. In this configuration, a specific non-predetermined membrane current can be added to or removed from the cell while it is in free-running current clamp mode. This current may be computed in real time, based on the recorded action potential of the cell, and injected into the cell. Instead of being computed, this current may also be recorded from a heterologous expression system such as a HEK-293 cell that is voltage-clamped by the free-running action potential of the cell ("dynamic action potential clamp"). Thus, one may directly test the effects of an additional or mutated membrane current, a synaptic current or a gap junctional current on the action potential of a patch-clamped cell. In the present chapter, we describe the dynamic clamp on the basis of its application in cardiac cellular electrophysiology. PMID- 25023319 TI - Dynamic clamp in cardiac and neuronal systems using RTXI. AB - The injection of computer-simulated conductances through the dynamic clamp technique has allowed researchers to probe the intercellular and intracellular dynamics of cardiac and neuronal systems with great precision. By coupling computational models to biological systems, dynamic clamp has become a proven tool in electrophysiology with many applications, such as generating hybrid networks in neurons or simulating channelopathies in cardiomyocytes. While its applications are broad, the approach is straightforward: synthesizing traditional patch clamp, computational modeling, and closed-loop feedback control to simulate a cellular conductance. Here, we present two example applications: artificial blocking of the inward rectifier potassium current in a cardiomyocyte and coupling of a biological neuron to a virtual neuron through a virtual synapse. The design and implementation of the necessary software to administer these dynamic clamp experiments can be difficult. In this chapter, we provide an overview of designing and implementing a dynamic clamp experiment using the Real Time eXperiment Interface (RTXI), an open-source software system tailored for real-time biological experiments. We present two ways to achieve this using RTXI's modular format, through the creation of a custom user-made module and through existing modules found in RTXI's online library. PMID- 25023320 TI - Ion selectivity of pore-forming peptides and ion channels measured in Xenopus oocytes. AB - The Xenopus laevis oocyte is a widely used system for heterologous expression of exogenous ion channel proteins. They are easy to obtain, mechanically and electrically stable, have a large size, enabling multiple types of electrophysiological recordings: two-electrode voltage clamp, single cell attached or cell-free patch-clamp and macropatch recordings. The size of an oocyte (1 mm in diameter) also allows for the use of additional electrodes (from 1 to 3) for injection of diverse materials (Ca(2+) chelators, peptides, chemicals, antibodies, proteic-partners, etc.) before or during the course of the electrophysiological experiment.We have successfully used this system to analyze the biophysical properties of pore-forming peptides. Simple extracellular perfusion of these peptides induced the formation of channels in the oocyte plasma membrane; these channels can then be studied and characterized in diverse ionic conditions. The ease of the perfusion and the stability of the voltage clamped oocyte make it a powerful tool for such analyses. Compared to artificial bilayers, oocytes offer a real animal plasma membrane where biophysical properties and toxicity can be studied in the stable environment. PMID- 25023321 TI - Principles of single-channel kinetic analysis. AB - Single-channel recording provides high resolution information on gating mechanisms of ion channels that are generally difficult to obtain from macroscopic measurements. Analysis of the data, however, has proven to be challenging. Early approaches rely on half-amplitude threshold detection to idealize the record into dwell-times, followed by fitting duration histograms to resolve kinetics. More recent analyses exploit explicit modeling of the data to improve the idealization accuracy. The dwell-time fitting has also evolved into direct fitting of dwell-time sequences using the maximum likelihood approach while taking account of effects of missed events. Finally, hidden Markov modeling provides an ultimate approach by which both single channel amplitudes and kinetics are analyzed simultaneously without the need of idealization. The progress in theory, along with the advance in computing power as well as the development of user-friendly software, has transformed single-channel analysis, once a specialty task, now readily accessible to a broader community of scientists. PMID- 25023322 TI - High-throughput screening and stability optimization of anti-streptavidin IgG1 and IgG2 formulations. AB - Selection of a suitable formulation that provides adequate product stability is an important aspect of the development of biopharmaceutical products. Stability of proteins includes not only resistance to chemical modifications but also conformational and colloidal stabilities. While chemical degradation of antibodies is relatively easy to detect and control, propensity for conformational changes and/or aggregation during manufacturing or long-term storage is difficult to predict. In many cases, the formulation factors that increase one type of stability may significantly decrease another type under the same or different conditions. Often compromise is necessary to minimize the adverse effects of an antibody formulation by careful optimization of multiple factors responsible for overall stability. In this study, high-throughput stress and characterization techniques were applied to 96 formulations of anti streptavidin antibodies (an IgG1 and an IgG2) to choose optimal formulations. Stress and analytical methods applied in this study were 96-well plate based using an automated liquid handling system to prepare the different formulations and sample plates. Aggregation and clipping propensity were evaluated by temperature and mechanical stresses. Multivariate regression analysis of high throughput data was performed to find statistically significant formulation factors that alter measured parameters such as monomer percentage or unfolding temperature. The results of the regression models were used to maximize the stabilities of antibodies under different formulations and to find the optimal formulation space for each molecule. Comparison of the IgG1 and IgG2 data indicated an overall greater stability of the IgG1 molecule under the conditions studied. The described method can easily be applied to both initial preformulation screening and late-stage formulation development of biopharmaceutical products. PMID- 25023323 TI - In memoriam--Professor Ragnar Norrby (1943-2014). PMID- 25023324 TI - A transdisciplinary approach to the decision-making process in extreme prematurity. AB - BACKGROUND: A wide range of dilemmas encountered in the health domain can be addressed more efficiently by a transdisciplinary approach. The complex context of extreme prematurity, which is raising important challenges for caregivers and parents, warrants such an approach. METHODS: In the present work, experts from various disciplinary fields, namely biomedical, epidemiology, psychology, ethics, and law, were enrolled to participate in a reflection. Gathering a group of experts could be very demanding, both in terms of time and resources, so we created a web-based discussion forum to facilitate the exchanges. The participants were mandated to solve two questions: "Which parameters should be considered before delivering survival care to a premature baby born at the threshold of viability?" and "Would it be acceptable to give different information to parents according to the sex of the baby considering that outcome differences exist between sexes?" RESULTS: The discussion forum was performed over a period of nine months and went through three phases: unidisciplinary, interdisciplinary and transdisciplinary, which required extensive discussions and the preparation of several written reports. Those steps were successfully achieved and the participants finally developed a consensual point of view regarding the initial questions. This discussion board also led to a concrete knowledge product, the publication of the popularized results as an electronic book. CONCLUSIONS: We propose, with our transdisciplinary analysis, a relevant and innovative complement to existing guidelines regarding the decision-making process for premature infants born at the threshold of viability, with an emphasis on the respective responsabilities of the caregivers and the parents. PMID- 25023325 TI - Artificial symbiosis for acetone-butanol-ethanol (ABE) fermentation from alkali extracted deshelled corn cobs by co-culture of Clostridium beijerinckii and Clostridium cellulovorans. AB - BACKGROUND: Butanol is an industrial commodity and also considered to be a more promising gasoline substitute compared to ethanol. Renewed attention has been paid to solvents (acetone, butanol and ethanol) production from the renewable and inexpensive substrates, for example, lignocellulose, on account of the depletion of oil resources, increasing gasoline prices and deteriorating environment. Limited to current tools for genetic manipulation, it is difficult to develop a genetically engineered microorganism with combined ability of lignocellulose utilization and solvents production. Mixed culture of cellulolytic microorganisms and solventogenic bacteria provides a more convenient and feasible approach for ABE fermentation due to the potential for synergistic utilization of the metabolic pathways of two organisms. But few bacteria pairs succeeded in producing biobutanol of high titer or high productivity without adding butyrate. The aim of this work was to use Clostridium cellulovorans 743B to saccharify lignocellulose and produce butyric acid, instead of adding cellulase and butyric acid to the medium, so that the soluble sugars and butyric acid generated can be subsequently utilized by Clostridium beijerinckii NCIMB 8052 to produce butanol in one pot reaction. RESULTS: A stable artificial symbiotic system was constructed by co-culturing a celluloytic, anaerobic, butyrate-producing mesophile (C. cellulovorans 743B) and a non-celluloytic, solventogenic bacterium (C. beijerinckii NCIMB 8052) to produce solvents by consolidated bioprocessing (CBP) with alkali extracted deshelled corn cobs (AECC), a low-cost renewable feedstock, as the sole carbon source. Under optimized conditions, the co-culture degraded 68.6 g/L AECC and produced 11.8 g/L solvents (2.64 g/L acetone, 8.30 g/L butanol and 0.87 g/L ethanol) in less than 80 h. Besides, a real-time PCR assay based on the 16S rRNA gene sequence was performed to study the dynamics of the abundance of each strain during the co-culturing process, which figured out the roles of each strain at different periods in the symbiosis. CONCLUSION: Our work illustrated the great potential of artificial symbiosis in biofuel production from lignocellulosic biomass by CBP. The dynamics of the abundance of C. beijerinckii and C. cellulovorans revealed mechanisms of cooperation and competition between the two strains during the co-culture process. PMID- 25023327 TI - Systemic administration of platelets incorporating inactivated Sendai virus eradicates melanoma in mice. AB - Tumor microenvironments include a number of fibrin clots due to the microbleeding caused by cancer cell invasion into blood vessels, which suggests the potential utility of a platelet vector for systemic cancer treatment. We previously reported that inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) activates anti-tumor immunity and induces cancer cell-selective apoptosis. The hemagglutination activity that blocks the systemic administration of HVJ-E was dramatically attenuated by incorporation into platelets. Platelets incorporating HVJ-E (PH complex) were then injected into the tail veins of B16F10 melanoma-bearing mice. The PH complex primarily accumulated in tumor tissues and caused the significant accumulation of various immune cells in the tumor bed. Injections of the PH complex to the melanoma-bearing mouse significantly reduced the tumor size, and the tumor growth was ultimately arrested. Secretion of the chemokine regulated upon activation normal T-expressed and presumably secreted (RANTES) was upregulated following PH stimulation. The RANTES-depletion in melanoma-bearing mice significantly attenuated the cytotoxic T lymphocyte activity and led to a dramatic abrogation of the mouse melanoma suppression induced by the PH complex. Thus, a platelet vector incorporating viral particles, a Trojan horse for cancer treatment, will provide a new approach for cancer therapy using oncolytic viruses. PMID- 25023326 TI - Baculovirus-mediated miRNA regulation to suppress hepatocellular carcinoma tumorigenicity and metastasis. AB - MicroRNA 122 (miR-122) is a tumor suppressor for hepatocellular carcinoma (HCC) but is lowly expressed in HCC cells. MiR-151 is aberrantly overexpressed in HCC cells and promotes HCC metastasis yet its roles on HCC tumorigenicity are unknown. To combat HCC tumorigenicity/metastasis, we developed Sleeping Beauty (SB)-based hybrid baculovirus (BV) vectors that expressed (i) miR-122 precursors (pre-miR-122), (ii) miR-151 sponges, or (iii) pre-miR-122 and miR-151 sponges. Transduction of aggressive HCC cells (Mahlavu) with the pre-miR-122-expressing BV tremendously enhanced miR-122 levels for >6 weeks, suppressed the levels of downstream effectors (e.g., ADAM10 and Bcl-w), proliferation, anchorage independent growth, motility and migration/invasion in vitro. Intratumoral injection of the pre-miR-122-expressing BV attenuated the HCC growth/metastasis. The miR-151 sponges-expressing BV diminished the miR-151 levels for 6 weeks, enhanced RhoGDIA expression, suppressed RhoGTPases, as well as motility and migration/invasion of Mahlavu cells. Intratumoral injection of the miR-151 sponge expressing BV impeded not only HCC metastasis but also cell proliferation, MMP expression and tumor growth in vivo. The BV co-expressing pre-miR-122 and miR-151 sponges also simultaneously enhanced miR-122 expression and inhibited miR-151, and conferred antitumor/anti-metastasis effects albeit lack of synergism. These data implicate the potentials of the SB-based hybrid BV for persistently modulating miRNA and suppressing HCC tumorigenicity/metastasis. PMID- 25023329 TI - Chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in the gelsolin amyloidosis mouse model. AB - Gelsolin amyloidosis is an autosomal dominant incurable disease caused by a point mutation in the GSN gene (G654A/T), specifically affecting secreted plasma gelsolin. Incorrect folding of the mutant (D187N/Y) second gelsolin domain leads to a pathological proteolytic cascade. D187N/Y gelsolin is first cleaved by furin in the trans-Golgi network, generating a 68 kDa fragment (C68). Upon secretion, C68 is cleaved by MT1-MMP-like proteases in the extracellular matrix, releasing 8 kDa and 5 kDa amyloidogenic peptides which aggregate in multiple tissues and cause disease-associated symptoms. We developed nanobodies that recognize the C68 fragment, but not native wild type gelsolin, and used these as molecular chaperones to mitigate gelsolin amyloid buildup in a mouse model that recapitulates the proteolytic cascade. We identified gelsolin nanobodies that potently reduce C68 proteolysis by MT1-MMP in vitro. Converting these nanobodies into an albumin-binding format drastically increased their serum half-life in mice, rendering them suitable for intraperitoneal injection. A 12-week treatment schedule of heterozygote D187N gelsolin transgenic mice with recombinant bispecific gelsolin-albumin nanobody significantly decreased gelsolin buildup in the endomysium and concomitantly improved muscle contractile properties. These findings demonstrate that nanobodies may be of considerable value in the treatment of gelsolin amyloidosis and related diseases. PMID- 25023328 TI - Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. AB - Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 * 10(13) vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 * 10(12) vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I 1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF. PMID- 25023330 TI - Co-expression of tumor antigen and interleukin-2 from an adenoviral vector augments the efficiency of therapeutic tumor vaccination. AB - We have previously shown that for the majority of antigens, adenoviral vaccines expressing the target antigen fused to the MHC associated invariant chain (Ii) induce an accelerated, augmented, and prolonged transgene-specific CD8(+) T-cell response. Here we describe a new adenoviral vaccine vector approach where the target antigen fused to Ii is expressed from the adenoviral E1 region and IL-2 is expressed from the E3 region. Immunization of mice with this new vector construct resulted in an augmented primary effector CD8(+) T-cell response. Furthermore, in a melanoma model we observed significantly prolonged tumor control in vaccinated wild type (WT) mice. The improved tumor control required antigen-specific cells, since no tumor control was observed, unless the melanoma cells expressed the vaccine targeted antigen. We also tested our new vaccine in immunodeficient (CD80/86 deficient) mice. Following vaccination with the IL-2 expressing construct, these mice were able to raise a delayed but substantial CD8(+) T-cell response, and to control melanoma growth nearly as efficaciously as similarly vaccinated WT mice. Taken together, these results demonstrate that current vaccine vectors can be improved and even tailored to meet specific demands: in the context of therapeutic vaccination, the capacity to promote an augmented effector T-cell response. PMID- 25023331 TI - Vulvar lichen sclerosus: a comparison of the short-term topical application of clobetasol dipropionate 0.05% versus mometasone furoate 0.1%. AB - OBJECTIVE: To compare the efficacy of the short-term application of clobetasol propionate 0.05% (CLB) and mometasone furoate 0.05% (MMF) in the treatment of vulvar lichen sclerosus (VLS). STUDY DESIGN: This study was a retrospective review of 96 women who were diagnosed with lichen sclerosus with a follow-up of at least 1 year. Of these 96 women, 47 were treated with the topical application of CLB and 49 were treated with the topical application of MMF. All patients received treatment for 8 weeks. The drug was administered once daily for 4 weeks and then twice weekly for another 4 weeks in combination with a moisturizing cream that was continued as maintenance therapy. Subsequently, a topical steroid was applied on an as-needed basis if symptoms recurred. Follow-up visits were scheduled at 3, 6, and 12 months. The primary endpoint was the clinical response of the patients. RESULTS: A mean of 77.3% of the patients were defined as responders at the 12-month observation, without any significant difference between the 2 treatment groups (CLB mean 73% vs MMF mean 81.6%, p = .2). A pronounced improvement in itching was observed after 3 months of treatment in the MMF group (p = .04), whereas the other symptoms were not significantly different between the 2 groups. CONCLUSIONS: This study indicates that CLB 0.05% and MMF 0.1% in a short protocol regimen are effective, safe, and reliable treatments for VLS, with no significant difference between the 2 steroids in their efficacy. However, a moisturizing cream should be an integral part of the treatment. PMID- 25023332 TI - Utility of microscopic techniques and quantitative real-time polymerase chain reaction for the diagnosis of vaginal microflora alterations. AB - OBJECTIVE: The aim of the study was to evaluate the diagnostic value of Nugent score, wet mount microscopy, and polymerase chain reaction (PCR) test developed in Russia for bacterial vaginosis (BV) diagnosis. MATERIALS AND METHODS: One hundred Caucasian women were enrolled in this study. Three vaginal samples were taken from each participant: 1 for PCR analysis, 1 for Nugent score evaluation, and 1 for wet mount microscopy. The smears for microscopy were air-dried and sent to Femicare, Tienen, Belgium, for blinded analysis by microscopy. Multiplex real time PCR was performed using primers and probes targeting Gardnerella vaginalis, Atopobium vaginae, Lactobacillus species, and total quantity of bacterial DNA (16SrRNA gene). RESULTS: Agreement among the 3 methods was 72 (73.5%) of 98 samples. Agreement between Nugent score and PCR results was 77 (78.6%) of 98 samples; between wet mount microscopy and PCR, 81 (82.65%) of 98 samples; between wet mount microscopy and Nugent score, 84 (85.7%) of 98 samples. The sensitivity and specificity of the methods studied were as follows: 75% (21/28) and 97.1% (68/70) for Nugent score, 96.4% (27/28) and 94.3% (66/70) for wet mount microscopy, 92.8% (26/28) and 85.7% (60/70) for PCR, respectively. CONCLUSIONS: This study demonstrated that wet mount microscopy is a superior method for BV diagnosis. The PCR test under study showed a high sensitivity and can be used for discrimination between normal flora and BV. PMID- 25023333 TI - Vaginal Misoprostol for Overcoming Inadequate Colposcopies: A Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVE: Inadequate colposcopic results due to inadequate visualization of the cervical transformation zone is a diagnostic problem that is encountered in approximately 10% to 15% of these procedures. The objective of the present systematic review and meta-analysis was to investigate whether misoprostol effectively converts inadequate colposcopic examinations to adequate. MATERIALS AND METHODS: We searched MEDLINE (1966-2014), Scopus (2004-2014), Popline (1974 2014), ClinicalTrials.gov (2008-2014), CENTRAL (1999-2014), and Google Scholar (2004-2014) search engines along with reference lists of all electronically retrieved articles. For the meta-analysis of selected indices, we used the RevMan 5.2 program. RESULTS: Treatment with misoprostol significantly increases the rates of adequate colposcopic examinations (odds ratio [OR] = 6.78, 95% confidence interval [CI] = 2.94-15.61). Its principal adverse effect is abdominal pain (OR = 10.19, 95% CI = 2.19-47.45). Neither nausea (105 women, random effects model [REM], OR = 4.99, 95% CI = 0.54-45.71) nor fever (111 women, REM, OR = 3.90, 95% CI = 0.59-25.56) or diarrhea (111 women, REM, OR = 2.21, 95% CI = 0.49 10.00) was found increased among women receiving misoprostol. The conversion rates toward an adequate examination ranged between 55.5% and 78.9% in the misoprostol group. CONCLUSIONS: According to our meta-analysis, misoprostol seems to improve the conversion rates from inadequate colposcopic examinations to adequate diagnoses. However, firm results to generalize our findings among specific populations, such as those already having a previous conization, are precluded by the small number of enrolled studies. Thus, future research in the field becomes necessary. PMID- 25023334 TI - Characterization and genome sequence of Dev2, a new T7-like bacteriophage infecting Cronobacter turicensis. AB - Cronobacter spp. are opportunistic pathogenic bacteria that are responsible for severe infections in neonates. Powdered infant formula was confirmed to be the source in some cases. Bacteriophages offer a safe means for eliminating this pathogen. In the present study, we investigated the growth parameters and genome organization of a new bacteriophage, Dev2, isolated from sewage. The Dev2 phage contains DNA with a length of 39 kb and belongs to the T7 branch of the subfamily Autographivirinae, with the highest degree of identity to the phage K1F. The host specificity of Dev2 is limited to C. turicensis strains of the CT O:1 serotype. With a lower efficiency, this phage also infects some Salmonella and E. coli strains. The Dev2 phage can inactivate sensitive Cronobacter strains in reconstituted milk formula. The results obtained in this study are an important prerequisite for application of Dev2 in food control. PMID- 25023335 TI - Complete nucleotide sequence and genome structure of a Japanese isolate of hibiscus latent Fort Pierce virus, a unique tobamovirus that contains an internal poly(A) region in its 3' end. AB - In this study, we detected a Japanese isolate of hibiscus latent Fort Pierce virus (HLFPV-J), a member of the genus Tobamovirus, in a hibiscus plant in Japan and determined the complete sequence and organization of its genome. HLFPV-J has four open reading frames (ORFs), each of which shares more than 98 % nucleotide sequence identity with those of other HLFPV isolates. Moreover, HLFPV-J contains a unique internal poly(A) region of variable length, ranging from 44 to 78 nucleotides, in its 3'-untranslated region (UTR), as is the case with hibiscus latent Singapore virus (HLSV), another hibiscus-infecting tobamovirus. The length of the HLFPV-J genome was 6431 nucleotides, including the shortest internal poly(A) region. The sequence identities of ORFs 1, 2, 3 and 4 of HLFPV-J to other tobamoviruses were 46.6-68.7, 49.9-70.8, 31.0-70.8 and 39.4-70.1 %, respectively, at the nucleotide level and 39.8-75.0, 43.6-77.8, 19.2-70.4 and 31.2-74.2 %, respectively, at the amino acid level. The 5'- and 3'-UTRs of HLFPV-J showed 24.3 58.6 and 13.0-79.8 % identity, respectively, to other tobamoviruses. In particular, when compared to other tobamoviruses, each ORF and UTR of HLFPV-J showed the highest sequence identity to those of HLSV. Phylogenetic analysis showed that HLFPV-J, other HLFPV isolates and HLSV constitute a malvaceous-plant infecting tobamovirus cluster. These results indicate that the genomic structure of HLFPV-J has unique features similar to those of HLSV. To our knowledge, this is the first report of the complete genome sequence of HLFPV. PMID- 25023336 TI - In vitro and in vivo characterization of a West Nile virus MAD78 infectious clone. AB - The viral determinants governing the varied neuropathogenicity of different West Nile virus (WNV) strains are poorly understood. Here, we generated an infectious clone (WNV-MAD(IC)) of the non-pathogenic strain WNV-MAD78 and compared its replication to that of parental WNV-MAD78 and a WNV-MAD78 infectious clone (WNV MAD(TX-UTRs)) containing the 5' and 3' untranslated regions (UTRs) of the pathogenic strain WNV-TX. All three viruses replicated at similar rates and caused similar lethality in mice. Thus, the infectious clone is indistinguishable from parental virus in replication and neurovirulence, and the UTRs alone do not account for the increased virulence of WNV-TX compared to WNV-MAD78. PMID- 25023338 TI - Glomerulonephropathies in Plasmodium inui-infected rhesus monkey: a primate model and possible applications for human quartan malaria. AB - SUMMARY None of the few animal models proposed for the study of human quartan malaria nephritic syndrome have shown complete pathological findings that are similar to those seen in humans. This study investigated the histopathological changes in kidneys in 10 Plasmodium inui infected Macaca mulatta monkeys by light and electron microscopy in order to develop a suitable animal model for human quartan malaria. Ten healthy adult rhesus monkeys were infected with P. inui and clinical chemistry and haematologic tests were done before and after infection. A renal biopsy sample was collected before infection as a baseline control and another biopsy was collected after infection. Histopathological changes examined by light and transmission electron microscopy (TEM) revealed abnormalities in all infected monkeys to variable degrees. Several electron-dense discrete or diffused mesangial deposits, and increase in mesangial cells and matrix were associated with the morphological changes observed by light microscope. This pattern is consistent with membranoproliferative glomerulonephritis type reported in humans infected with Plasmodium malariae. Results strongly support that the P. inui infected rhesus monkey develop an immune-complex-mediated glomerulonephritis in the course of the infection. Therefore, this experimental model represents a useful tool to better understand the different parameters and the consequences of quartan malaria infections comparable to situations in humans. PMID- 25023337 TI - Selective non operative management of gunshot wounds to the abdomen: a collective review. AB - BACKGROUND: Over the past four decades there has been a shift from operative to selective conservatism in trauma. Selective nonoperative management (SNOM) of stab wounds to the abdomen is widely accepted in trauma centres. However, selective conservatism with gunshot wounds to the abdomen is controversial. This collective review assesses the evidence of SNOM of gunshot wounds to the abdomen. METHODS: A Medline search between 1 January 1960 and 31 July 2013 was conducted identifying studies that investigated SNOM of gunshot wounds to the abdomen. Case reports, review articles and editorials were excluded. All other studies that investigated SNOM of gunshot wounds to the abdomen and its outcomes were included. RESULTS: A total of 37 studies were included of which 22 were prospective, 14 were retrospective and 1 case series. A total of 21330 patients with gunshot wounds to the abdomen were included, of which 6468 (30.3%) were managed nonoperatively. Successful SNOM was possible in 5510 (85.18%) patients and 958 (14.8%) failed SNOM and underwent delayed laparotomies. SNOM reduces rates of non-therapeutic laparotomies and the associated morbidity. Special aspects reviewed include the prehospital and nursing involvement in this modality of care. CONCLUSIONS: Current evidence supports SNOM of gunshot wounds to the abdomen. It is associated with a decreased rate of non therapeutic laparotomy. Careful patient selection and specially designed protocols should be established and adhered to. PMID- 25023339 TI - Medical error disclosure: from the therapeutic alliance to risk management: the vision of the new Italian code of medical ethics. AB - BACKGROUND: The Italian code of medical deontology recently approved stipulates that physicians have the duty to inform the patient of each unwanted event and its causes, and to identify, report and evaluate adverse events and errors. Thus the obligation to supply information continues to widen, in some way extending beyond the doctor-patient relationship to become an essential tool for improving the quality of professional services. DISCUSSION: The new deontological precepts intersect two areas in which the figure of the physician is paramount. On the one hand is the need for maximum integrity towards the patient, in the name of the doctor's own, and the other's (the patient's) dignity and liberty; on the other is the physician's developing role in the strategies of the health system to achieve efficacy, quality, reliability and efficiency, to reduce errors and adverse events and to manage clinical risk. SUMMARY: In Italy, due to guidelines issued by the Ministry of Health and to the new code of medical deontology, the role of physicians becomes a part of a complex strategy of risk management based on a system focused approach in which increasing transparency regarding adverse outcomes and full disclosure of health- related negative events represent a key factor. PMID- 25023341 TI - Motor neuron disease: Improved imaging biomarkers in amyotrophic lateral sclerosis. PMID- 25023342 TI - Neurodevelopmental disorders: Accelerating progress in autism through developmental research. PMID- 25023343 TI - Overly simplistic substitution models obscure green plant phylogeny. AB - Phylogenetic analysis is an increasingly common and valuable component of plant science. Knowledge of the phylogenetic relationships between plant groups is a prerequisite for understanding the origin and evolution of important plant features, and phylogenetic analysis of individual genes and gene families provides fundamental insights into how those genes and their functions evolved. However, despite an active research community exploring and improving phylogenetic methods, the analytical methods commonly used, and the phylogenetic results they produce, are accorded far more confidence than they warrant. In this opinion article, I emphasise that important parts of the green plant phylogeny are inconsistently resolved and I argue that the lack of consistency arises due to inadequate modelling of changes in the substitution process. PMID- 25023340 TI - Guillain-Barre syndrome: pathogenesis, diagnosis, treatment and prognosis. AB - Guillain-Barre syndrome (GBS) is a potentially life-threatening postinfectious disease characterized by rapidly progressive, symmetrical weakness of the extremities. About 25% of patients develop respiratory insufficiency and many show signs of autonomic dysfunction. Diagnosis can usually be made on clinical grounds, but lumbar puncture and electrophysiological studies can help to substantiate the diagnosis and to differentiate demyelinating from axonal subtypes of GBS. Molecular mimicry of pathogen-borne antigens, leading to generation of crossreactive antibodies that also target gangliosides, is part of the pathogenesis of GBS; the subtype and severity of the syndrome are partly determined by the nature of the antecedent infection and specificity of such antibodies. Intravenous immunoglobulin and plasma exchange are proven effective treatments but many patients have considerable residual deficits. Discrimination of patients with treatment-related fluctuations from those with acute-onset chronic inflammatory demyelinating polyneuropathy is important, as these conditions may require different treatments. Novel prognostic models can accurately predict outcome and the need for artificial ventilation, which could aid the selection of patients with a poor prognosis for more-individualized care. This Review summarizes the clinical features of and diagnostic criteria for GBS, and discusses its pathogenesis, treatment and prognosis. PMID- 25023344 TI - Molecular analysis for therapy choice: NCI MATCH. PMID- 25023345 TI - Guest editorial: Platelets and cancer. PMID- 25023346 TI - Platelets and cancer-associated thrombosis. AB - Platelets have a newly appreciated and important role in many cancer-related processes, including tumor growth and metastases, angiogenesis, and promotion of a hypercoagulable state. Cancer patients commonly experience venous thromboembolism (VTE), a leading cause of mortality and a source of considerable morbidity and cost. The role of platelets in arterial thrombosis is well established, but emerging evidence supports the concept that platelets are also involved in initiation of VTE. This is particularly true in cancer-associated thrombosis as extensive new evidence shows that thrombocytosis and platelet activation are predictive biomarkers of VTE. The role of therapeutic anti platelet agents has been proven effective at preventing VTE in non-cancer patients, and there are early data suggesting benefit in cancer patients as well. This review summarizes platelet-related predictive biomarkers of cancer associated thrombosis, platelet-mediated mechanisms for VTE promotion in cancer patients, and anti-platelet agents in prevention of VTE. PMID- 25023347 TI - Effects of cancer on platelets. AB - The main function of circulating platelets is to stop bleeding upon vascular injury by the formation of a hemostatic plug. The presence of cancer results in numerical and functional abnormalities of platelets. Thrombocytosis is commonly observed in cancer patients and is associated with decreased survival. Conversely, thrombocytopenia has been shown to have antimetastatic effects in experimental models. Tumor cells also can induce changes in the platelet activation status, both in direct and indirect manners. Direct tumor cell-induced platelet aggregation enables the formation of a cloak of aggregated platelets around circulating tumor cells (CTCs) that shields them from attacks by the immune system and facilitates metastasis to distant sites. Cancer also can induce platelet activation in various indirect ways. Tumor cells shed small extracellular vesicles that expose the transmembrane protein tissue factor (TF)- the initiator of the extrinsic coagulation cascade. The abundant presence of TF in the circulation of cancer patients can result in local generation of thrombin, the most potent platelet activator. Another pathway of indirect platelet activation is by increased formation of neutrophil extracellular traps in the presence of tumor-secreted granulocyte colony-stimulating factor (G-CSF). Last, tumor cells may regulate the selective secretion of angiogenic proteins from platelet granules, which enables the tumor to stimulate and stabilize the immature neovasculature in the tumor environment. Since there is little doubt that the cancer-induced platelet alterations are beneficial to tumor growth and dissemination, it could be worthwhile to intervene in the underlying mechanisms for anticancer purposes. Antiplatelet and anticoagulant agents that inhibit platelet activation and thrombin generation can potentially slow cancer progression, although the clinical evidence thus far is not unequivocal. PMID- 25023348 TI - Therapy for cancer-related thromboembolism. AB - Cancer is an independent and major risk factor for venous thromboembolism (VTE), defined by symptomatic or asymptomatic DVT, including catheter-related thrombosis (CRT), and/or pulmonary embolism (PE). Over the past 20 years, VTE has become the second cause of death in cancer patients, where it accounts for increased morbidity, mortality, and healthcare costs. Incidental VTE is increasingly diagnosed on systematic computed tomography in cancer patients, raising new questions in daily oncology practice. Risk factors for VTE in cancer include patient-, cancer-, and treatment-related parameters, which vary for a single patient throughout the course of cancer disease and necessitate repeated individual risk assessments. The use of biomarkers and risk assessment models allow identification of cancer patients at high risk for VTE. Anticoagulant therapy for the prophylaxis and the treatment of established VTE is efficient and relatively safe when contraindications are respected, but the variety of risk factors and the number of comorbidities remain major challenges for adequate VTE treatment in cancer patients. Several national guidelines for primary prevention and treatment of VTE in cancer patients were issued in the past 10 years. To homogeneize existing Clinical Practice Guidelines (CPGs), an international consensus working group released specific guidelines for the treatment and prophylaxis of VTE in cancer patients in 2013, so as to make each CPG easier to use at the national level. In cancer patients treated for VTE, the use of low molecular-weight heparins (LMWHs) is preferred over other anticoagulants in most cases, and LMWHs were shown to be superior to vitamin K antagonists (VKAs). For the prophylaxis of VTE, LMWHs have been validated in surgical patients. For medical cancer patients, ongoing or recent clinical trials will inform our practice. However, several questions remain unanswered due to the number of comorbities in a single patient and expert opinion regarding special situations is required. Better adherence worldwide to CPGs necessitates adequate educational and active implementation strategies, which could substantially decrease the burden of VTE and increase survival in cancer patients. PMID- 25023349 TI - The newer anticoagulants in thrombosis control in cancer patients. AB - Cancer and hemostasis are strongly correlated and the development of venous thromboembolism (VTE) has a major adverse impact on the outcome of cancer patients. Treatment of cancer-associated VTE is far more challenging than treating VTE in the non-cancer population, as the clinical course of cancer patients is characterized by increased rates of both recurrent thromboembolic episodes and bleeding complications. This has led to the development of a distinct management approach towards VTE in patients with active cancer. Low molecular-weight heparins (LMWHs) currently represent the therapeutic agent of choice, as a result of a proven higher efficacy compared to vitamin K antagonists (VKAs). However, as LMWHs require daily subcutaneous injections, weight-adjusted doses, and still confers high risks of recurrent VTE and bleeding complications, management of cancer-associated VTE warrants further optimization. In recent years several novel, target-specific oral anticoagulants have been introduced and evaluated in clinical trials. These new anticoagulants display several advantages compared to conventional anticoagulants. This review will evaluate their trial results up-to-date with a particular focus on the cancer patients included in these trials. The potential of these agents in the setting of cancer-associated VTE will be discussed and directions for future research will be provided. PMID- 25023350 TI - Involvement of platelet-derived microparticles in tumor progression and thrombosis. AB - Platelet-derived microparticles (PMPs) represent the most abundant microparticle (MP) subtype. Their presence reflects platelet activity, physiopathology, and the thrombotic state of cancer patients. The quantity and composition of PMPs strictly depends on the way MPs were generated. Because platelets play a key role in cancer progression, as well as formation of metastasis, PMPs also may be important in the proliferation of cancer cells, cancer cell interactions, metastatic progression, angiogenesis, and inflammation. Alternatively, the concentration of circulating PMPs may differ according to the stage of a cancer and thus potentially could be used as a biomarker. Here we review the mechanisms underlying the generation and composition of PMPs and the clinical and experimental studies describing the involvement of PMPs in cancer and the Trousseau syndrome. Lastly, we focus on their clinical relevance, as well as their potential application as biomarkers in cancer. PMID- 25023351 TI - Platelets effects on tumor growth. AB - Unlike other blood cells, platelets are small anucleate structures derived from marrow megakaryocytes. Thought for almost a century to possess solely hemostatic potentials, platelets, however, play a much wider role in tissue regeneration and repair and interact intimately with tumor cells. On one hand, tumor cells induce platelet aggregation (TCIPA), known to act as the trigger of cancer-associated thrombosis. On the other hand, platelets recruited to the tumor microenvironment interact, directly, with tumor cells, favoring their proliferation, and, indirectly, through the release of a wide palette of growth factors, including angiogenic and mitogenic proteins. In addition, the role of platelets is not solely confined to the primary tumor site. Indeed, they escort tumor cells, helping their intravasation, vascular migration, arrest, and extravasation to the tissues to form distant metastasis. As expected, nonspecific or specific inhibition of platelets and their content represents an attractive novel approach in the fight against cancer. This review illustrates the role played by platelets at primary tumor sites and in the various stages of the metastatic process. PMID- 25023352 TI - Pharmacological regulation of platelet factors that influence tumor angiogenesis. AB - In addition to maintaining hemostasis, platelets play an important pathological role driving tumor growth and metastasis. One mechanism by which platelets contribute to tumor growth and metastasis is their potent promotion of angiogenesis. This is accomplished in large part by the numerous factors stored, generated, and released by platelets that have the potential to influence every stage of angiogenesis. In this review, we provide an overview of the many platelet-secreted pro- and anti-angiogenic factors. We examine the basic science and clinical evidence supporting their contributions to tumor angiogenesis. Finally, we review the pharmacological regulation of their release from platelets and discuss the potential of anti-platelet drugs as adjuvant anti-angiogenesis therapy. PMID- 25023354 TI - Platelets, cyclooxygenases, and colon cancer. AB - A growing body of evidence supports the central role of platelets in early events of tumorigenesis and metastasis. Activated platelets, in response to tissue damage, induce a proinflammatory program involving the aberrant expression of cyclooxygenase (COX)-2, which leads to increased tissue concentrations of the proinflammatory and protumorigenic prostaglandin E2. The central role of platelet activation in cancer development is sustained by the analysis of clinical studies with aspirin showing an anti-cancer efficacy by the drug, even at the low doses used for the prevention of atherothrombosis. Low-dose aspirin acts as an antiplatelet agent by causing an irreversible inactivation of platelet COX-1 activity and the synthesis of thromboxane A2. Further experimental and clinical studies are ongoing to confirm the central role of platelets in the development of inflammation and cancer. The corroboration of this hypothesis will open new opportunities for the prevention and treatment of cancer. In addition to the possible use of traditional antithrombotic agents, the recent identification of novel molecular determinants involved in the cross-talk between platelets and other cellular player of tumorigenesis and metastasis has led to the suggestion of novel therapeutic strategies in oncology. PMID- 25023353 TI - Platelet effects on ovarian cancer. AB - Growing understanding of the role of thrombocytosis, high platelet turnover, and the presence of activated platelets in the circulation in cancer progression and metastasis has brought megakaryocytes into focus. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. However, before megakaryocyte/platelet directed therapies can be considered for clinical use, understanding of the mechanism and biology of paraneoplastic thrombocytosis in malignancy is required. Here, we provide an overview of the clinical implications, biological significance, and mechanisms of paraneoplastic thrombocytosis in the context of ovarian cancer. PMID- 25023355 TI - Prevention and treatment of cancer with aspirin: where do we stand? AB - Aspirin is arguably the synthesized drug that has been used most commonly in human history. Aspirin was originally developed and marketed for the treatment of inflammatory disorders at the end of the 19th century, but its mechanism of action remained unknown until the second half of the 20th century. Since the latter part of the 20th century aspirin also has been used for the primary and secondary prevention of cardiovascular diseases given its anti-thrombotic properties. An association between intake of aspirin and decreased cancer risk was identified in the past decades. Whether aspirin can be used as an anticancer agent in patients with a diagnosis of cancer was unknown until recently. Recent studies suggest that aspirin might provide therapeutic benefit in the adjuvant treatment of certain forms of cancer. This review provides a critical update on this topic, which has potential implications for oncologists and their patients. PMID- 25023356 TI - Platelets promote liver immunopathology contributing to hepatitis B virus mediated hepatocarcinogenesis. AB - Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC). Among the pathogenetic factors triggered by HBV, virus-specific CD8(+) T cells play and important role in disease pathogenesis by promoting necroinflammatory liver damage. Accordingly, amelioration of immune-mediated chronic liver injury may prevent HCC. Platelets facilitate this process by sustaining the hepatic accumulation of virus-specific CD8(+) T cells and subsequently other virus nonspecific inflammatory cells that contribute to liver disease. Importantly, a recent study shows that the long-term use of clinically relevant doses of the anti-platelet drugs aspirin and clopidogrel, administered after the onset of liver disease, in an HBV transgenic mouse model of immune-mediated chronic hepatitis and HCC, can prevent hepatocarcinogenesis improving overall survival. Platelets therefore, act as key players in the pathogenesis of HBV-associated liver cancer supporting the notion that immune-mediated necroinflammatory liver disease is sufficient to trigger HCC and that interference with platelet activation may have clinical implications for HCC prevention. PMID- 25023357 TI - Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters. AB - Previous work has shown that two general processes contribute to hepatocellular cancer (HCC) prognosis: liver damage, monitored by indices such as blood bilirubin, prothrombin time (PT), and aspartate aminostransferase (AST); and tumor biology, monitored by indices such as tumor size, tumor number, presence of portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. These processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied network phenotyping strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Our aim was to validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory-based approach that compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Without reference to the actual tumor sizes, patients were classified by NPS into two subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-platelets relationship. These trends were combined with patient age, gender, and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual scan data) that patients in L phenotype group had 1.5* larger mean tumor masses relative to S, P = 6 * 10(-16). Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7* longer survival compared to L-phenotype patients. NPS integrated the liver, tumor, and basic demographic factors. Cirrhosis-associated thrombocytopenia was typical for smaller S tumors. In L tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient. PMID- 25023358 TI - Platelet-related phenotypic patterns in hepatocellular carcinoma patients. AB - Small hepatocellular carcinomas (HCCs) usually arise in cirrhosis, often with associated thrombocytopenia. Many patients with large HCCs have normal blood platelet counts. In this review, we compare parameter and phenotype patterns of patients with small (<= 3 cm) and larger HCCs. A retrospective analysis was undertaken of a 4,139-patient HCC database to compare patient demographics, and liver and tumor characteristics associated with small and large HCCs, especially with respect to platelet counts. We found that patients with larger HCCs had more tumor nodules and portal vein thrombosis (PVT) positivity, and had higher blood alpha-fetoprotein (AFP), bilirubin, and platelet counts. In patients with larger tumors and normal platelets (43.7% of the cohort), tumors were larger and AFP levels were higher, with lower bilirubin and aspartate aminotransferase (AST) levels than in patients with larger tumors and thrombocytopenia (17.5%). A parsimonious multinomial regression model showed a high odds ratio for AFP and platelets for tumors>3 cm with PVT. We conclude that platelet levels are associated with distinct large HCC phenotypes. PMID- 25023359 TI - Platelets, selectins, and the control of tumor metastasis. AB - The significant role of platelets and P-selectin in assisting tumor cell metastasis to the lungs has been frequently reported and reviewed. However, evidence recently has come to light on other pro-metastatic mechanisms of platelets beyond that of tumor cell protection from immune cell attack and aiding extravasation, such as promoting epithelial to mesenchymal transition in tumor cells and conveying signals from the primary tumor to distant tissues that optimize conditions for metastasis. Moreover, the role of platelets and selectins in hematogenous metastasis to frequently targeted organs other than the lungs has been less well examined. This review aims to summarize the literature on the roles of platelets in all stages of the metastatic process and to examine the participation of platelets and selectins in hematogenous metastasis to the lungs, liver, bone, and brain. In the light of the available evidence, potential therapeutic avenues for the control of metastasis are also discussed. PMID- 25023360 TI - Primary non-Hodgkin lymphoma of the ovary. PMID- 25023361 TI - Mitochondrial toxicity assessment in industry--a decade of technology development and insight. PMID- 25023363 TI - Psychotherapy for compulsive buying disorder: a systematic review. AB - Based on a literature review, the purpose is to identify the main therapeutic approaches for the compulsive buying disorder, a present time disorder characterized by excessive and uncontrollable concerns or behaviors related to buying or expenses, which may lead to adverse consequences. The systematic review was carried out by searching the electronic scientific bases Medline/Pubmed, ISI, PsycInfo. The search was comprised of full-text articles, written in Portuguese and English, with no time limit or restrictions on the type of study and sample. A total of 1659 references were found and, by the end, 23 articles were selected for this review. From the articles found, it was determined that, although there are case studies and clinical trials underlining the effectiveness of the treatment for compulsive buying, only those studies with a focus on the cognitive behavioral therapy approach make evident the successful response to the treatment. The publication of new studies on the etiology and epidemiology of the disorder is necessary, in order to establish new forms of treatment and to verify the effectiveness and response of the Brazilian population to the existing protocols. PMID- 25023364 TI - Body size estimation in anorexia nervosa: a brief review of findings from 2003 through 2013. AB - Body size overestimation is a fundamental feature in anorexia nervosa (AN). The extent or even existence of body size overestimation in AN is controversial. The most recent review (Farrell et al., 2005) found that only half the studies reported overestimation of body size in individuals diagnosed with AN. The remaining studies found no overestimation or in some instances underestimation. The discrepancy in these findings has been attributed to the wide variety of assessment techniques that are used, including many with questionable psychometric properties. We review all 9 contemporary studies conducted in this area since the last review in 2005. For each study we describe the number of participants, methodology, reliability/validity data, amount of whole body distortion, effect sizes, and a summary of findings. In all studies that included a healthy control group, individuals with AN overestimated their whole body size more than healthy controls did. The difference was significant in all except two studies. Based on these contemporary findings, we conclude that individuals with AN overestimate their body size and that the greater consistency of findings in the studies conducted over the last decade is attributable to the use of improved methodologies and assessment tools with documented psychometric properties. PMID- 25023365 TI - The severity of Internet addiction risk and its relationship with the severity of borderline personality features, childhood traumas, dissociative experiences, depression and anxiety symptoms among Turkish university students. AB - The aim of this study was to investigate the relationship of Internet addiction (IA) risk with the severity of borderline personality features, childhood traumas, dissociative experiences, depression and anxiety symptoms among Turkish university students. A total of 271 Turkish university students participated in this study. The students were assessed through the Internet Addiction Scale (IAS), the Borderline Personality Inventory (BPI), the Dissociative Experiences Scale (DES), the Childhood Trauma Questionnaire (CTQ-28), the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). The rates of students were 19.9% (n=54) in the high IA risk group, 38.7% (n=105) in the mild IA risk group and 41.3% (n=112) in the group without IA risk. Correlation analyses revealed that the severity of IA risk was related with BPI, DES, emotional abuse, CTQ-28, depression and anxiety scores. Univariate covariance analysis (ANCOVA) indicated that the severity of borderline personality features, emotional abuse, depression and anxiety symptoms were the predictors of IAS score, while gender had no effect on IAS score. Among childhood trauma types, emotional abuse seems to be the main predictor of IA risk severity. Borderline personality features predicted the severity of IA risk together with emotional abuse, depression and anxiety symptoms among Turkish university students. PMID- 25023366 TI - Risk of violence of inpatients with severe mental illness--do patients with schizophrenia pose harm to others? AB - Individuals suffering from schizophrenia are frequently considered to be dangerous. The current longitudinal chart review was carried out to investigate the diagnostic mix of patients who were admitted to the Department of Psychiatry and Psychotherapy at the Medical University Innsbruck due to risk of harm to others. The sample consisted of all adult inpatients admitted to psychiatric acute care units in the years 1992, 1997, 2002, and 2007. Data collection included diagnoses, criteria for risk of harm to others, and the use of mechanical restraint. Altogether, 7222 admissions were reviewed. Of these, 529 patients had to be admitted to a locked unit because of risk of harm to others. Among those mechanical restraint was more often used in patients with organic mental disorders, Cluster B personality disorders, and mania than in patients with schizophrenia. Patients suffering from schizophrenia with comorbid psychoactive substance use constitute a potentially harmful population and are therefore frequently admitted to locked units due to risk of harm to others. However, in the current study additional coercive measures were more commonly applied in patients suffering from personality disorders and organic mental disorders. PMID- 25023367 TI - Metamemory with ageing in schizophrenia: a first study. AB - The aim was to study metamemory during encoding in older schizophrenia patients. Thirteen older patients were compared to 13 healthy controls. Despite their memory impairment, older schizophrenia patients were able to assess the material accurately. They were not able, however, to adapt their learning time as efficiently as controls. PMID- 25023368 TI - Personality traits and violent behavior: a comparison between psychopathic and non-psychopathic male murderers. AB - The relationship between psychopathy and traits of temperament and character in a specific population of criminals, such as murderers, has not been sufficiently investigated. This study assesses the relationship between psychopathy and temperament and character traits in murderers. The sample consisted of 118 men divided into three groups: psychopathic murderers (N=40), non-psychopathic murderers (N=40) and 38 non-psychopathic non-criminals (controls). All individuals were evaluated by Psychopathy Checklist Revised (PCL-R) and The Temperament and Character Inventory (TCI). Psychopathic murderers presented higher scores than the other two groups in PCL-R; both criminal groups presented higher scores than non-psychopathic non-criminals. Psychopathic murderers showed lower scores than non-psychopathic murderers on Harm Avoidance, Reward Dependence, Persistence, Self-Directness and Cooperativeness. There was no difference between murderers groups regarding Novelty Seeking and Self transcendence. In all TCI personality traits psychopathic and non-psychopathic murderers showed scores lower than controls, except Harm Avoidance for non psychopathic murderers. In conclusion, most personality traits assessed by TCI were associated with psychopathy, while Novelty Seeking and Self-transcendence were associated with homicidal behavior independently of the psychopathy. PMID- 25023369 TI - Forgiveness and PTSD among veterans: the mediating role of anger and negative affect. AB - Man-made traumatic events such as combat and terrorism may cause individuals to develop various forms of psychopathology, including Post-Traumatic Stress Disorder (PTSD) and depression. Veterans who engage in combat experienced negative emotions such as anger, hostility and aggression. Forgiveness may buffer these feelings and prevent the development of psychiatric problems, in that it is a way of decreasing negative feelings and increasing positive feelings. The aim of the current study was to examine the mediating role of anger and negative affect on the relationship between forgiveness and both PTSD and depression co morbid to PTSD among Turkish veterans who were exposed to combat experience because of terrorist attacks during their compulsory military service. Two hundred and forty-seven injured veterans participated in this study. Veterans were assessed using the Traumatic Stress Symptom Checklist (TSSC), Heartland Forgiveness Scale (HFS), State Trait Anger Expression Inventory (STAXI), and Positive and Negative Affect Schedule (PANAS). A path analysis supported the hypothesized model that both anger and negative affect fully mediated the relationship between forgiveness and both PTSD and depression co-morbid to PTSD. PMID- 25023370 TI - A pilot study to investigate the induction and manipulation of learned helplessness in healthy adults. AB - Eliminating the controllability of a noxious stimulus may induce a learned helplessness (LH) that resembles aspects of depression and post-traumatic stress disorder (PTSD). This study examined whether repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) promotes resilience in an aversive stimulus model of LH. All 55 participants were told that an undisclosed sequence of button presses would terminate an aversive stimulus on their forearm. In truth, only half had control (+C). The other half had no control (-C). All participants received real (R) or sham (S) left DLPFC rTMS during the paradigm (+C/R, -C/S,+C/S,-C/R). We evaluated the cognitive effects of LH using an anagram task. The LH paradigm successfully reduced perceived control in the -C groups. As predicted, the +C/R and +C/S groups tended to give up less quickly and take less time to solve each anagram than did the C/S group. Superior anagram performance in the -C/R group approached statistical significance. Our preliminary results suggest that manipulating the controllability of an aversive stimulus may induce an LH effect that manifests as impaired anagram performance. Further research is needed to refine this model and determine if DLPFC rTMS mitigates any LH effects. PMID- 25023371 TI - Coil embolization with side-holed catheter to preserve peripheral flow for visceral artery pseudoaneurysm: an experimental study in Swine. AB - PURPOSE: To evaluate the safety and efficacy of coil embolization with an indwelling catheter with side holes to control visceral artery bleeding while simultaneously preserving peripheral artery flow. MATERIALS AND METHODS: A 6-F anticoagulant-coated catheter with two symmetrically arranged side holes was used with coil embolization to induce hemostasis in the superior mesenteric artery (SMA) of 13 pigs. The SMA was punctured with a metal needle to induce bleeding. The catheter was advanced into the SMA immediately after the puncture, and the midpoint between its tip and side holes was adjusted to conform to the puncture site. The SMA was embolized by using microcoils placed around the catheter to achieve hemostasis. Hemostasis and gross ischemic changes of the intestine were visually observed during the abdominal surgery. Peripheral blood flow was assessed by using abdominal aortography for as long as 2 hours in 13 pigs and was assessed again at 7 days in three pigs. RESULTS: Antegrade peripheral artery flow through the indwelling catheter was preserved without stagnation for as long as 2 hours in all 13 pigs and at 7 days in two of three pigs. One catheter occlusion was seen at the 7-day time point. There were no observable instances of recurrent bleeding, ischemic changes in the intestine, or vascular adverse events during or after the procedure. CONCLUSIONS: The hemostatic method described here is a technically feasible method of controlling acute visceral artery bleeding while preserving peripheral artery flow and may be particularly useful in cases of absence of collateral circulation. Further experiments are warranted for clinical application. PMID- 25023372 TI - [Principles of antisepsis, disinfection and sterilization]. AB - This article aims to provide a brief review of the main concepts on which the prevention and control of infection are based. Antisepsis comprises a set of techniques aimed at the total sterilization, or at most, disinfection, removing germs that contaminate an environment. Both procedures must be preceded by an environmental cleanup in the location in which they intend to be applied. The disinfection is carried out using biocides or germicides. Antimicrobial chemicals, that have mechanisms of action and resistances very similar to antibiotics, are generating concern due to the possibility of crossing genetic information that aggravates the problem of bacterial resistance. Most biocides can act as antiseptics, and applied to skin tissue, or disinfectants on inanimate materials. The spectrum of action of germicides depends on the product itself and external controllable factors: temperature, concentration, exposure time, etc. Sterilization techniques are primarily physical, by exposing the material to steam, or sterilizing gas, using autoclaves. Major advances are the use of low temperatures with shorter exposure times, in parallel with technological advances in instrumentation in order to avoid high temperatures and high use rotations due to workload. PMID- 25023373 TI - Cobalt vanadium oxide thin nanoplates: primary electrochemical capacitor application. AB - Co3V2O8 thin nanoplates are firstly described as a kind of electrode material for supercapacitors. More importantly, from electrochemical measurements, the obtained Co3V2O8 nanoplate electrode shows a good specific capacitance (0.5 A g( 1), 739 F g(-1)) and cycling stability (704 F g(-1) retained after 2000 cycles). This study essentially offers a new kind of metal vanadium oxides as electrochemical active material for the development of supercapacitors. PMID- 25023374 TI - Middle-down mass spectrometry enables characterization of branched ubiquitin chains. AB - Protein ubiquitylation, one of the most prevalent post-translational modifications in eukaryotes, is involved in regulating nearly every cellular signaling pathway. The vast functional range of ubiquitylation has largely been attributed to the formation of a diverse array of polymeric ubiquitin (polyUb) chains. Methods that enable the characterization of these diverse chains are necessary to fully understand how differences in structure relate to function. Here, we describe a method for the detection of enzymatically derived branched polyUb conjugates in which a single Ub subunit is modified by two Ub molecules at distinct lysine residues. Using a middle-down mass spectrometry approach in which restricted trypsin-mediated digestion is coupled with mass spectrometric analysis, we characterize the polyUb chains produced by bacterial effector E3 ligases NleL (non-Lee-encoded effector ligase from enterohemorrhagic Escherichia coli O157:H7) and IpaH9.8 (from Shigella flexneri). Because Ub is largely intact after minimal trypsinolysis, multiple modifications on a single Ub moiety can be detected. Analysis of NleL- and IpaH9.8-derived polyUb chains reveals branch points are present in approximately 10% of the overall chain population. When unanchored, well-defined polyUb chains are added to reaction mixtures containing NleL, longer chains are more likely to be modified internally, forming branch points rather than extending from the end of the chain. These results suggest that middle-down mass spectrometry can be used to assess the extent to which branched polyUb chains are formed by various enzymatic systems and potentially evaluate the presence of these atypical conjugates in cell and tissue extracts. PMID- 25023376 TI - Editorial comment on "Urinary bladder cancer treated with radical cystectomy: perioperative parameters and early complications prospectively registered in a national population-based database". PMID- 25023377 TI - The Relation Between Moment-to-Moment Mindful Attention and Anxiety Among Young Adults in Substance Use Treatment. AB - BACKGROUND: A growing body of research has examined the intersection of mindfulness and substance use, and a large body of research has examined the relation between mindfulness and anxiety. Unfortunately, no research has been conducted on the relation between mindfulness and anxiety symptoms among young adults (i.e., 18-25 years old) in treatment for substance use. The purpose of the current study was to examine the relation between one facet of mindfulness, moment-to-moment attention, and anxiety (panic and generalized anxiety) among young adults in treatment for substance use. METHODS: Preexisting patient records from a residential substance use treatment center for young adults were reviewed (N = 148). Patient records were examined from May 2012 to August 2013, which represented all young adult patients admitted to the residential treatment facility during this time. RESULTS: Findings demonstrated that moment-to-moment mindful attention was associated with symptoms of panic disorder and generalized anxiety disorder even after controlling for gender, age, education, alcohol use, drug use, and the shared variance in generalized and panic symptoms. There were no gender differences in moment-to-moment mindful attention. CONCLUSIONS: These findings provide preliminary evidence that moment-to-moment mindful attention is associated with panic and generalized anxiety in young adults in substance use treatment. Combined with previous research on mindfulness-based interventions among adults in substance use treatment, research should examine the efficacy of mindfulness-based interventions for young adults in substance use treatment. PMID- 25023375 TI - Genome-wide microarray analysis of Atlantic cod (Gadus morhua) oocyte and embryo. AB - BACKGROUND: Regulation of gene expression plays a central role in embryonic development. Early stages are controlled by gametic transcripts, which are subsequently substituted with transcripts from the genome of the zygote. Transcriptomic analyses provide an efficient approach to explore the temporal gene expression profiles in embryos and to search for the developmental regulators. We report a study of early Atlantic cod development that used a genome-wide oligonucleotide microarray to examine the composition and putative roles of polyadenylated transcripts. RESULTS: The analyses were carried out in unfertilized oocytes, newly fertilized oocytes and embryos at the stages of mid blastula transition and segmentation. Numerous genes transcribed in oocytes are involved in multiple aspects of cell maintenance and protection, including metabolism, signal perception and transduction, RNA processing, cell cycle, defense against pathogens and DNA damage. Transcripts found in unfertilized oocytes also encoded a large number of proteins implicated in cell adherence, tight junction and focal adhesion, suggesting high complexity in terms of structure and cellular interactions in embryos prior to midblastula transition (MBT). Prezygotic transcripts included multiple regulators that are most likely involved in developmental processes that take place long after fertilization, such as components of ErbB, hedgehog, notch, retinoid, TGFb, VEGF and Wnt signaling pathways, as well as transcripts involved in the development of nervous system. The major event of MBT was the activation of a large group of histones and other genes that modify chromatin structure preceding massive gene expression changes. A hallmark of events observed during segmentation was the induction of multiple transcription factors, including a large group of homeobox proteins in pace with decay of a large fraction of maternal transcripts. Microarray analyses detected a suite of master developmental regulators that control differentiation and maintenance of diverse cell lineages. CONCLUSIONS: Transcriptome profiling of the early stages in Atlantic cod revealed the presence of transcripts involved in patterning and development of tissues and organs long before activation of the zygotic genome. The switch from maternal to zygotic developmental programs is associated with large-scale modification of chromosomes. PMID- 25023378 TI - Comparison of immediate and long-term results between the single balloon and inoue balloon techniques for percutaneous pulmonary valvuloplasty. AB - BACKGROUND: This study was undertaken to compare the immediate and long-term follow-up results of balloon pulmonary valvuloplasty (BPV) between the single balloon and Inoue balloon for isolated pulmonary valve stenosis (PS). METHODS: A retrospective analysis of outcomes following BPV in 38 children using the single balloon and 42 adults using the Inoue balloon at a single institution was performed. RESULTS: The majority of children (76.3%) were asymptomatic while 26 adults (61.9%) presented with symptoms. The ratio of balloon size to pulmonary valve annulus was 1.23 +/- 0.12 in the children group and 1.22 +/- 0.10 in the adult group (P=0.641). The children group had a right ventricle-pulmonary artery systolic gradient of 52.79 +/- 35.08 mmHg that decreased to 22.55 +/- 12.92 mmHg following BPV (P<0.001). The adult group had a gradient of 94.79 +/- 42.19 mmHg that decreased to 34.02 +/- 15.00 mmHg following BPV (P<0.001). Mild pulmonary regurgitation occurred in eight children (21.1%) and 10 adults (23.8%) (P=0.768). During a median follow-up of 15 years, gradients were not significantly different from that obtained at one-month follow-up in children (P=0.280) and adults (P=0.373). CONCLUSIONS: Adults can be treated with BPV using the Inoue balloon with encouraging immediate and long-term follow-up results that are similar to those in children using the single balloon. PMID- 25023379 TI - Non-ST elevation myocardial infarction with occluded artery and its clinical implications. AB - BACKGROUND: This study aimed to determine the prevalence and differences between Non-ST elevation Myocardial Infarction (NSTEMI) with an occluded culprit artery (NSTEMIOA) and NSTEMI with a patent culprit artery (NSTEMIPA). METHODS: We conducted a retrospective observational study on NSTEMI patients admitted between 01/01/2010 to 30/06/2010. The inclusion criteria were diagnosis of NSTEMI and inpatient coronary angiogram. Patients were followed up for 12 months. The primary endpoints of interest were the differentiating characteristics between NSTEMIOA and NSTEMIOA. The secondary endpoints of interest were clinical outcomes in 12 months and the effect of delay in percutaneous coronary intervention on the extent of myocardial damage. RESULTS: Of 143 NSTEMI patients, 34 (24%) patients had NSTEMIOA. NSTEMIOA patients had higher rates of hypercholesterolaemia (85.3% vs. 64.2%, p=0.015), ST-depression abnormality on ECGs (32.4% vs. 11.9%, p=0.008), multi-vessel disease on coronary angiogram (76.5% vs. 48.6%, p=0.004) and LV dysfunction on echo (75% vs 48%, p=0.016). At 12 months post-discharge, there was a trend of higher heart failure rate in NSTEMIOA subgroup but otherwise no difference between the two cohorts in death, myocardial infarction, revascularisation, arrhythmia, and re-admission for angina. There was no correlation between the peak CK level and the timing of percutaneous revascularisation in both cohorts. CONCLUSIONS: A quarter of NSTEMI patients had an occluded culprit coronary artery. They were more likely to have hypercholesterolaemia, ECG abnormalities, multi-vessel disease and LV dysfunction. PMID- 25023380 TI - Endoscopic therapy for chronic pancreatitis. AB - PURPOSE OF REVIEW: To summarize recent data on techniques, efficacy and complications of endoscopic management of chronic pancreatitis. RECENT FINDINGS: Extracorporeal shock wave lithotripsy with or without endoscopic retrograde cholangiopancreatography is the first-line treatment for large painful obstructive pancreatic duct calculi. Use of preextracorporeal shock wave lithotripsy secretin could result in better stone clearance. The first-line treatment for dominant pancreatic duct strictures is placement of a single 10-Fr polyethylene stent with planned exchanges every 3 months until 1 year. Other endoscopic approaches that have shown good efficacy include placement of simultaneous multiple plastic stents and fully covered self-expanding metallic stents. Endoscopic options to treat chronic pancreatitis-associated benign biliary strictures include single and simultaneous multiple plastic stenting and fully covered self-expanding metallic stents. The European Society of Gastrointestinal Endoscopy recommends multiple plastic stenting for such strictures, although fully covered self-expanding metallic stents should be currently used under research settings. Endoscopic ultrasonography-guided cholangiopancreatography and pancreatobiliary drainage is an evolving option for chronic pancreatitis-related ductal obstruction after failed endoscopic retrograde cholangiopancreatography. Recent data have supported the safety and efficacy of endotherapy for chronic pancreatitis in children. SUMMARY: Endotherapy is the first line of management in chronic pancreatitis with symptomatic pancreatobiliary ductal obstruction. Further studies are required in certain key areas such as use of fully covered self-expanding metallic stents for pancreatic ductal and biliary strictures and endoscopic ultrasonography-guided pancreatobiliary drainage after failed endoscopic retrograde cholangiopancreatography. PMID- 25023381 TI - Endoscopic approach to the diagnosis and treatment of pancreatic disease. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on the diagnosis and treatment of pancreatic disorders using endoscopy. RECENT FINDINGS: The role of endoscopy in the diagnosis and management of pancreatic disorders continues to increase in importance. The use of post-endoscopic retrograde cholangio-pancreatography (ERCP) provides therapy for many pancreatic disorders, including in the treatment of pancreatitis, its complications and pancreatic neoplasia. In recent years, there has been a focus on improving its safety in the prevention of post-ERCP pancreatitis. Pancreatic endotherapy by ERCP for the treatment of biliary strictures and chronic pain in chronic pancreatitis will also be reviewed. Endoscopic ultrasound (EUS) has a vital diagnostic role in pancreatic disorders; however, much of the recent focus has been on its therapeutic role for simple and complex pancreatic fluid collections. As for the role of EUS in pancreatic cancer, recent technical advances in conjunction with on-site cytopathology service continue to improve pancreatic cancer diagnosis. EUS has an increasing role in treatment with fiducial placement for stereotactic body radiation therapy. SUMMARY: In this review, I will examine the literature over the last year in ERCP and EUS as they apply to specific pancreatic disorders. PMID- 25023382 TI - Molecular biology of pancreatic ductal adenocarcinoma. AB - PURPOSE OF REVIEW: Recent advances in sequencing technology have led to a deeper and more comprehensive understanding of the molecular biology of pancreatic ductal adenocarcinoma. This timely review seeks to summarize these recent advances which will provide a foundation for future studies in the field. RECENT FINDINGS: Stereotypical genetic alterations have been identified and confirmed. However, additional alterations have highlighted the importance and complexity of a number of intracellular signaling pathways that present unique opportunities for therapeutic targeting. SUMMARY: A genetic signature of pancreatic ductal adenocarcinoma has been identified. This recent and important work is currently in the process of being applied in many clinical applications from early diagnostics to customized therapeutic regimens for this disease. A fundamental understanding of these findings will thus be of utmost importance for future research in the field and in the clinical care of patients with this lethal disease. PMID- 25023383 TI - Intrusive trauma recollections is associated with impairment of interference inhibition and psychomotor speed in PTSD. AB - BACKGROUND: Intrusive cognitions that enter consciousness involuntarily are prominent symptoms of posttraumatic stress disorder (PTSD). The present study aimed to identify neuropsychological mechanisms involved. METHOD: Fifty PTSD outpatients and 50 healthy controls were tested using Finger Tapping, Simple and Choice Reaction Times and Stroop Tasks, to measure motor, psychomotor speed, response selection, and interference inhibition ability respectively. RESULTS: PTSD patients performed poorly in all tests, presumably owing to their generalized slowness of information processing and motor reaction. Psychomotor speed was a predictor of slowness and high error rate during the Stroop. Impaired inhibition, as measured by the interference index of the Stroop task, explained 9.7% of the predicated variance in frequency of re-experiencing PTSD symptoms and 23.5% of the predicated variance in augmentation of the interference response time. CONCLUSION: Impaired interference control may be related to internal (re experiencing) and external (sensory) stimuli that leads to cognitive deficits in PTSD patients. PMID- 25023384 TI - Diagnostic validity Polish language version of the questionnaire MINI-KID (Mini International Neuropsychiatry Interview for Children and Adolescent). AB - OBJECTIVE: Since over forty years structuralized interviews for clinical and epidemiological research in child and adolescent psychiatry are being developed that should increase validity and reliability of diagnoses according to classification systems (DSM and ICD). The aim of the study is to assess the validity of the Polish version of MINI-KID (Mini International Neuropsychiatric Interview for Children and Adolescents) in comparison to clinical diagnosis made by a specialist in the field of child and adolescent psychiatry. MATERIALS AND METHODS: There were 140 patients included in the study (93 boys, 66.4%, mean age 11.8+/-3.0 and 47 girls 33.5%, mean age 14.0+/-2.9). All the patients were diagnosed by the specialist in the field of child and adolescent psychiatry according to ICD-10 criteria and by the independent interviewer with the Polish version of MINI-KID (version 2.0, 2001). RESULTS: There was higher agreement between clinical diagnoses and diagnoses based on MINI-KID interview with respect to eating disorders and externalizing disorders (kappa 0.43-0.56) and lower in internalizing disorders (kappa 0.13-0.45). In the clinical interview, there was smaller number of diagnostic categories (maximum 3 diagnoses per one patient) in comparison to MINI-KID (maximum 10 diagnoses per one patient), and the smaller percentage of patients with one diagnosis (65,7%) in comparison to MINI-KID interview (72%). CONCLUSION: Our study has shown satisfactory validity parameters of MINI-KID questionnaire, promoting its use for clinical and epidemiological settings. IMPLICATIONS AND CONTRIBUTION: The Mini International Neuropsychiatry Interview for Children and Adolescent (MINI-KID) is the first structuralized diagnostic interview for assessing mental status in children and adolescents, which has been translated into Polish language. Our validation study demonstrated satisfactory psychometric properties of the questionnaire, enabling its use in clinical practice and in research projects. PMID- 25023385 TI - Effectiveness of functional hand splinting and the cognitive orientation to occupational performance (CO-OP) approach in children with cerebral palsy and brain injury: two randomised controlled trial protocols. AB - BACKGROUND: Cerebral palsy (CP) and brain injury (BI) are common conditions that have devastating effects on a child's ability to use their hands. Hand splinting and task-specific training are two interventions that are often used to address deficits in upper limb skills, both in isolation or concurrently. The aim of this paper is to describe the method to be used to conduct two randomised controlled trials (RCT) investigating (a) the immediate effect of functional hand splints, and (b) the effect of functional hand splints used concurrently with task specific training compared to functional hand splints alone, and to task-specific training alone in children with CP and BI. The Cognitive Orientation to Occupational Performance (CO-OP) approach will be the task-specific training approach used. METHODS/DESIGN: Two concurrent trials; a two group, parallel design, RCT with a sample size of 30 participants (15 per group); and a three group, parallel design, assessor blinded, RCT with a sample size of 45 participants (15 per group). INCLUSION CRITERIA: age 4-15 years; diagnosis of CP or BI; Manual Abilities Classification System (MACS) level I - IV; hand function goals; impaired hand function; the cognitive, language and behavioural ability to participate in CO-OP. Participants will be randomly allocated to one of 3 groups; (1) functional hand splint only (n=15); (2) functional hand splint combined with task-specific training (n=15); (3) task-specific training only (n=15). Allocation concealment will be achieved using sequentially numbered, sealed opaque envelopes opened by an off-site officer after baseline measures. Treatment will be provided for a period of 2 weeks, with outcome measures taken at baseline, 1 hour after randomisation, 2 weeks and 10 weeks. The functional hand splint will be a wrist cock-up splint (+/- thumb support or supination strap). Task-specific training will involve 10 sessions of CO-OP provided in a group of 2-4 children. Primary outcome measures will be the Canadian Occupational Performance Measure (COPM) and the Goal Attainment Scale (GAS). Analysis will be conducted on an intention-to treat basis. DISCUSSION: This paper outlines the protocol for two randomised controlled trials investigating functional hand splints and CO-OP for children with CP and BI. PMID- 25023386 TI - Pb-inhibited mitotic activity in onion roots involves DNA damage and disruption of oxidative metabolism. AB - Plant responses to abiotic stress significantly affect the development of cells, tissues and organs. However, no studies correlating Pb-induced mitotic inhibition and DNA damage and the alterations in redox homeostasis during root division per se were found in the literature. Therefore, an experiment was conducted to evaluate the impact of Pb on mitotic activity and the associated changes in the oxidative metabolism in onion roots. The cytotoxic effect of Pb on cell division was assessed in the root meristems of Allium cepa (onion). The mitotic index (MI) was calculated and chromosomal abnormalities were sought. Pb-treatment induced a dose-dependent decrease in MI in the onion root tips and caused mitotic abnormalities such as distorted metaphase, fragments, sticky chromosomes, laggards, vagrant chromosomes and bridges. Single Cell Gel Electrophoresis was also performed to evaluate Pb induced genotoxicity. It was accompanied by altered oxidative metabolism in the onion root tips suggesting the interference of Pb with the redox homeostasis during cell division. There was a higher accumulation of malondialdehyde, conjugated dienes and hydrogen peroxide, and a significant increase in the activities of superoxide dismutases, ascorbate peroxidases, guaiacol peroxidases and glutathione reductases in Pb-treated onion roots, whereas catalases activity exhibited a decreasing pattern upon Pb exposure. The study concludes that Pb-induced cytotoxicity and genotoxicity in the onion roots is mediated through ROS and is also tightly linked to the cell cycle. The exposure to higher concentrations arrested cell cycle leading to cell death, whereas different repair responses are generated at lower concentrations, thereby allowing the cell to complete the cell cycle. PMID- 25023387 TI - Investigating the response of tropical maize (Zea mays L.) cultivars against elevated levels of O3 at two developmental stages. AB - Tropospheric ozone (O3) concentrations are rising in Indo-Gangetic plains of India, causing potential threat to agricultural productivity. Maize (Zea mays L.) is the third most important staple crop at global level after rice and wheat. Two high yielding cultivars of Indian maize (HQPM1-quality protein maize and DHM117 normal/non quality protein maize) were exposed to two levels of elevated O3 above the ambient level (NFC) viz. NFC + 15 ppb O3 (NFC + 15) and NFC + 30 ppb O3 (NFC + 30) using open top chambers under field conditions. The study was conducted to evaluate the biochemical responses of two cultivars at different developmental stages leading to change in yield responses. Initially at lower O3 dose, photosynthetic pigments showed an increase but reduction at later stage, while higher dose caused a decline at both the stages of sampling. Levels of superoxide radical (O2 (-)) and hydrogen peroxide (H2O2) significantly increased and contributed to lipid peroxidation at elevated O3. Histochemical localization assay of O2 (-) and H2O2 showed that guard cells of stomata and cells around trichomes took deeper stain at elevated O3 reflecting more formation of reactive oxygen species. Secondary metabolites like total phenol, flavonoids and anthocyanin pigments also increased in plants under O3 stress. Enzymatic antioxidants were triggered in both the cultivars due to elevated O3, while induction of non-enzymatic antioxidants was more in HQPM1. Native PAGE analysis also showed that SOD, POX, CAT, APX and GPX were stimulated at elevated O3 concentrations compared to NFC. SDS-PAGE showed reductions of major photosynthetic proteins with higher decrease in DHM117. Principal Component Analysis showed that both the cultivars showed differential response against O3 at two developmental stages. HQPM1 maintained the analogous defense strategy at both the sampling stages while DHM117 showed variable response. Overall metabolic induction of antioxidants related to defense was more in DHM117 than HQPM1. This suggests that DHM117 utilized more assimilates in maintaining the homeostasis against imposed oxidative stress, causing less translocation of assimilates to reproductive parts and thus affecting the final yield. In terms of yield it is suggested that performance of HQPM1 (quality protein maize) was better than the DHM117 (non quality protein maize). PMID- 25023388 TI - Hollow fiber cell fishing with high-performance liquid chromatography for rapid screening and analysis of an antitumor-active protoberberine alkaloid group from Coptis chinensis. AB - A novel hollow fiber cell fishing procedure with high-performance liquid chromatography (HFCF-HPLC) was developed and used for rapid screening, fishing, and analysis of bioactive compounds from traditional Chinese medicines. Human breast cancer cell MCF7, mouse breast cancer cell MADB106, and gastric cancer cell SGC7901 were seeded on the internal surface of hollow fibers that were used to screen, fish, and analyze an antitumor-active protoberberine alkaloid group from Coptis chinensis decoction. The main variables that affect the HFCF-HPLC process were investigated and optimized. The surface properties of the hollow fiber-seeded cells, cell survival rate, non-specific binding between active centers in the hollow fiber and the target compounds, repeatability, reliability, and recovery of HFCF-HPLC were investigated in detail. Several active compounds structures that were screened from Coptis chinensis by using HFCF-HPLC were identified by comparing the retention time of the reference substances. The cell membrane and cell organelle were separated from MCF7 cells for a preliminary study of the target effect of active compounds on MCF7 cells. The living cell, cell membrane, and cell organelle fishing factors of the active compound, as the indexes of drug binding ability in HFCF-HPLC, were defined and discussed. In addition, tamoxifen as positive control substance and indomethacin as negative control substance were screened by using HFCF-HPLC to further verify the method's reliability. The results demonstrated that HFCF-HPLC is an effective, rapid, stable, and reliable method to screen and analyze bioactive compounds. PMID- 25023389 TI - A non-aqueous procedure to synthesize amino group bearing nanostructured organic inorganic hybrid materials. AB - Amino-functionalized organic-inorganic hybrid materials with a narrow distributed nanostructure of 2-4 nm in size were obtained by means of a template-free and non aqueous procedure. Simultaneous twin polymerization of novel amino group containing twin monomers with 2,2'-spirobi[4H-1,3,2-benzodioxasiline] has been applied for this purpose. The amino groups of the organic-inorganic hybrid material are useful for post derivatization. PMID- 25023390 TI - Frequency of sternal foramen evaluated by MDCT: a minor variation of great relevance. AB - Due to inadvertent cardiac or great vessel injury, sternal foramina may pose as a great hazard during sternal puncture. They can also be misinterpreted as osteolytic lesions in cross-sectional imaging of the sternum. The distribution of these variations differs between populations, but data from Brazilians are scarcely reported. Therefore, this study aimed to verify the frequency of midline sternal foramen and double-ended xiphoid process, as developmental variations, in order to avoid fatal complications following sternal puncture of sternal acupuncture treatment. A total of 114 chest computed tomograms were evaluated. The frequency of midline sternal foramen in a complication risk bearing feature is of approximately 10.5%. The double-ended xiphoid process was present in 17.5%. We conclude that sternal acupuncture should be planned in the region of corpus previous CT should be done to rule out this variation. Furthermore, we strongly recommend the acupuncture technique which prescribes a safe superficial-oblique approach to the sternum. PMID- 25023391 TI - Metabolic differences in hepatocytes of obese and lean pigs. AB - There are important differences in terms of metabolic activity, energy utilization and capacity of protein and fat deposition when Iberian and modern pigs are compared. Primary culture of hepatocytes was used to evaluate hepatic function and sensitivity to hormones between breeds without the interference of circulating blood factors. Hepatocytes were isolated from pure Iberian (n=10) and Landrace (n=8) pigs of similar BW (24.5+/-12.1 and 32.9+/-6.1 kg BW, respectively), by collagenase perfusion. Monolayers were established in medium containing fetal bovine serum for 1 day and switched to serum-free medium for the remainder of the culture period. Hepatocytes were maintained in William's E supplemented with beta-mercaptoethanol (0.1 mM), glutamine (2 mM), antibiotics (gentamicin, penicillin, streptomycin and amphotericin B), dimethyl sulfoxide (1 ug/ml), dexamethasone (10-8 M), insulin (0.173 and 17.3 nM) and glucagon (0.287, 2.87 and 28.7 nM) for 24 to 48 h. Gluconeogenesis (GNG), glycogen degradation, triglycerides (TG) content and esterification, beta-hydroxybutyrate (BHB) synthesis, IGF-1 synthesis, albumin and urea synthesis were determined. Iberian pigs had greater capacity of GNG than Landrace (24%, P<0.05), although no difference in glycogen degradation was found (P>0.10). TG content and esterification tended to be lower in hepatocytes from Iberian compared with Landrace pigs (12% and 31%, respectively; 0.100.10). IGF-1 synthesis was diminished in hepatocytes from Iberian compared with Landrace pigs (16%, P<0.05). On the contrary, rate of albumin synthesis was greater in Iberian compared with Landrace pigs (58%, P<0.05). Finally, the capacity of urea synthesis was lower in hepatocytes of Iberian compared with Landrace pigs (37%, P<0.05). When ammonia was added to the media, urea concentration increased (648%, 1108% and 2791% when 0 mM was compared with 2.5, 5 and 10 mM, respectively). Urea synthesis increased on increasing ammonia content (55% and 325% when 0 mM was compared with 5 and 10 mM, respectively; P<0.0001). In conclusion, the genetic background accounts for important differences in protein and energy metabolism pathways found in primary culture of hepatocytes from lean and obese pigs. PMID- 25023392 TI - The effect of stable macromolecular complexes of ionic polyphosphazene on HIV Gag antigen and on activation of human dendritic cells and presentation to T-cells. AB - Neonates and infants are susceptible to infection due to distinct immune responses in early life. Therefore, development of vaccine formulation and delivery systems capable of activating human newborn leukocytes is of global health importance. Poly[di(carboxylatophenoxy)phosphazene] (PCPP) belongs to a family of ionic synthetic polyphosphazene polyelectrolyte compounds that can form non-covalent interactions with protein antigens and demonstrate adjuvant activity in animals and in human clinical trials. However, little is known about their ability to activate human immune cells. In this study, we characterized the effects of PCPP alone or in combination with a model antigen (recombinant HIV-Gag (Gag)), on the maturation, activation and antigen presentation by human adult and newborn dendritic cells (DCs) in vitro. PCPP treatment induced DC activation as assessed by upregulation of co-stimulatory molecules and cytokine production. Studies benchmarking PCPP to Alum, the most commonly used vaccine adjuvant, demonstrated that both triggered cell death and release of danger signals in adult and newborn DCs. When complexed with Gag antigen, PCPP maintained its immunostimulatory characteristics while permitting internalization and presentation of Gag by DCs to HIV-Gag-specific CD4(+) T cell clones. The PCPP vaccine formulation outlined here has intrinsic adjuvant activity, can facilitate effective delivery of antigen to DCs, and may be advantageous for induction of beneficial T cell-mediated immunity. Moreover, polyphosphazenes can further reduce cost of vaccine production and distribution through their dose-sparing and antigen-stabilizing properties, thus potentially eliminating the need for cold chain distribution. PMID- 25023393 TI - Inhibition of foreign body giant cell formation by 4- hexylresorcinol through suppression of diacylglycerol kinase delta gene expression. AB - Grafted macromolecules often induce granuloma formation with foreign body giant cell (FBGC) infiltration, and this is the main reason for graft failure. Diacylglycerol kinase (DAGK) is an important intracellular mediator of FBGC formation in macrophages. In this study, 4-hexylresorcinol (4HR) inhibited DAGKdelta in a macrophage cell line (RAW264.7 cells). As a result of DAGK-delta inhibition by 4HR, FBGC formation was significantly inhibited in RAW264.7 cells. Silk fibroin is a well-known natural macromolecule, and when it is grafted into bone defects, it results in granuloma formation with massive FBGC formation. 4HR incorporating silk graft materials displayed significant reduction of granuloma formation and increases in the extent of new bone formation in a rabbit calvarial defect model. In conclusion, 4HR could inhibit foreign body reaction via a DAGK mediated pathway. PMID- 25023394 TI - Tumor penetrability and anti-angiogenesis using iRGD-mediated delivery of doxorubicin-polymer conjugates. AB - Tumor-penetrating peptide, iRGD (internalizing RGD, CRGDK/RGPD/EC) with the similar affinity to alphav integrins as conventional RGD cyclopeptide could enhance the tumor penetrability of drugs by binding to neuropilin-1 (NRP-1) that over-expressed on both angiogenic blood vessels and tumor cells. Comparing with our previous study, in which a RGD cyclopeptide (RGDyC) was bound to PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) by acid-sensitive cis aconityl linkage (PEG-PAMAM-cis-aconityl-DOX, PPCD), the present study selected iRGD instead of previous RGD to produce iRGD-PPCD conjugate. The effect of iRGD mediated PPCD on tumor penetration was compared with the conventional RGD ones via administration of RGDs-modified PPCD (iRGD/RGDs-PPCD) and co-administration of RGDs and PPCD (iRGD/RGD + PPCD). C6 cells were selected as the cell model owing to the highest expression of alphav integrins and NRP-1 among four tumor cell lines. In vitro cytotoxicity and cellular uptake showed no significant difference between RGD-PPCD and iRGD-PPCD, but glioma spheroid penetration study showed that RGD-PPCD, iRGD-PPCD and iRGD + PPCD penetrated into C6 spheroids with a depth of 115 MUm, 144 MUm and 150 MUm, respectively, indicating that the iRGD mediated PPCD delivery system had a stronger penetrating ability than the RGD ones. In vivo results also demonstrated the superiority of iRGD system over RGD ones. After systemic administration, iRGD-mediated PPCD increased tumor vascular permeability, decreased tumor vascular density and average vascular diameter. Correspondingly, the iRGD system exhibited stronger penetration ability, higher accumulation in brain tumor. The median survival time of iRGD + PPCD, iRGD-PPCD and RGD-PPCD treatment groups were 61, 57.5 and 43.5 days. The present findings strongly suggested that the iRGD-mediated drug delivery system could significantly improve the efficacy of tumor therapy through enhancing tumor accumulation and penetration as compared to the conventional RGD ones. PMID- 25023395 TI - Heparin-chitosan nanoparticle functionalization of porous poly(ethylene glycol) hydrogels for localized lentivirus delivery of angiogenic factors. AB - Hydrogels have been extensively used for regenerative medicine strategies given their tailorable mechanical and chemical properties. Gene delivery represents a promising strategy by which to enhance the bioactivity of the hydrogels, though the efficiency and localization of gene transfer have been challenging. Here, we functionalized porous poly(ethylene glycol) hydrogels with heparin-chitosan nanoparticles to retain the vectors locally and enhance lentivirus delivery while minimizing changes to hydrogel architecture and mechanical properties. The immobilization of nanoparticles, as compared to homogeneous heparin and/or chitosan, is essential to lentivirus immobilization and retention of activity. Using this gene-delivering platform, we over-expressed the angiogenic factors sonic hedgehog (Shh) and vascular endothelial growth factor (Vegf) to promote blood vessel recruitment to the implant site. Shh enhanced endothelial recruitment and blood vessel formation around the hydrogel compared to both Vegf delivering and control hydrogels. The nanoparticle-modified porous hydrogels for delivering gene therapy vectors can provide a platform for numerous regenerative medicine applications. PMID- 25023396 TI - Prostate-specific antigen bounce after high-dose-rate prostate brachytherapy and hypofractionated external beam radiotherapy. AB - PURPOSE: To report the frequency, timing, and magnitude of prostate-specific antigen (PSA) bounce (PB) in patients who received high-dose-rate (HDR) brachytherapy (HDRB) plus hypofractionated external beam radiation therapy (HypoRT) and to assess a possible correlation between PB and biochemical failure (BF). METHODS AND MATERIALS: Patients with intermediate-risk prostate cancer received 10Gy single-fraction (192)Ir HDRB followed by 50Gy in 20 daily fractions of HypoRT without androgen deprivation therapy. All patients had a minimum 2-year followup. The PB was defined as PSA elevation higher than 0.2ng/mL from previous measurement with subsequent drop to pre-bounce level. The BF was defined as PSA nadir+2ng/mL. RESULTS: A total of 114 patients treated between 2001 and 2009 were eligible for analysis. At a median followup of 66 months, the PB was found in 45 (39%) patients with a median time to bounce of 16 months (range, 3-76 months). The median time to PSA normalization after a PB was 9 months (range, 2-40 months). The median magnitude of PB was 0.45ng/mL (range, 0.2-6.62). The BF occurred in 12 (10.5%) patients of whom three had a PB. Median time to BF was 52.5 months. Four patients (3.5%) in the PB group fit the criteria for BF. CONCLUSIONS: The PB is common after HDRB and HypoRT and can occur up to 76 months after treatment. It can rarely fit the criteria for BF. The time to PB is shorter than the time to BF. There is a lower incidence of BF in patients with a PB. An acknowledgment of this phenomenon should be made when interpreting PSA results during followup to prevent unnecessary interventions. PMID- 25023397 TI - Mantle cell lymphoma: taking therapeutic advantage of new insights into the biology. AB - Mantle cell lymphoma (MCL) is an uncommon, incurable B-cell non-Hodgkin's lymphoma that afflicts the elderly. There is no standard course of treatment, with options varying from observation in asymptomatic patients to aggressive induction/consolidation regimens in younger patients with rapidly progressive disease. Emerging data regarding the role of the ubiquitin-proteasome system, B cell receptor and mTOR signaling pathways, cell cycle regulation, and epigenetic and immune-modulation in the pathogenesis of MCL have resulted in the development of novel therapies, with a shift away from conventional cytotoxic chemotherapy to relatively less toxic, more targeted treatment. The challenge now is to determine the optimal sequence and combination of the various available and emerging therapies for use in patients with MCL. PMID- 25023398 TI - Consistent and heritable alterations of DNA methylation are induced by tissue culture in maize. AB - Plants regenerated from tissue culture and their progenies are expected to be identical clones, but often display heritable molecular and phenotypic variation. We characterized DNA methylation patterns in callus, primary regenerants, and regenerant-derived progenies of maize using immunoprecipitation of methylated DNA (meDIP) to assess the genome-wide frequency, pattern, and heritability of DNA methylation changes. Although genome-wide DNA methylation levels remained similar following tissue culture, numerous regions exhibited altered DNA methylation levels. Hypomethylation events were observed more frequently than hypermethylation following tissue culture. Many of the hypomethylation events occur at the same genomic sites across independent regenerants and cell lines. The DNA methylation changes were often heritable in progenies produced from self pollination of primary regenerants. Methylation changes were enriched in regions upstream of genes and loss of DNA methylation at promoters was associated with altered expression at a subset of loci. Differentially methylated regions (DMRs) found in tissue culture regenerants overlap with the position of naturally occurring DMRs more often than expected by chance with 8% of tissue culture hypomethylated DMRs overlapping with DMRs identified by profiling natural variation, consistent with the hypotheses that genomic stresses similar to those causing somaclonal variation may also occur in nature, and that certain loci are particularly susceptible to epigenetic change in response to these stresses. The consistency of methylation changes across regenerants from independent cultures suggests a mechanistic response to the culture environment as opposed to an overall loss of fidelity in the maintenance of epigenetic states. PMID- 25023399 TI - PHYTOCHROME C is an essential light receptor for photoperiodic flowering in the temperate grass, Brachypodium distachyon. AB - We show that in the temperate grass, Brachypodium distachyon, PHYTOCHROME C (PHYC), is necessary for photoperiodic flowering. In loss-of-function phyC mutants, flowering is extremely delayed in inductive photoperiods. PHYC was identified as the causative locus by utilizing a mapping by sequencing pipeline (Cloudmap) optimized for identification of induced mutations in Brachypodium. In phyC mutants the expression of Brachypodium homologs of key flowering time genes in the photoperiod pathway such as GIGANTEA (GI), PHOTOPERIOD 1 (PPD1/PRR37), CONSTANS (CO), and florigen/FT are greatly attenuated. PHYC also controls the day length dependence of leaf size as the effect of day length on leaf size is abolished in phyC mutants. The control of genes upstream of florigen production by PHYC was likely to have been a key feature of the evolution of a long-day flowering response in temperate pooid grasses. PMID- 25023400 TI - Conditional asymmetric linkage disequilibrium (ALD): extending the biallelic r2 measure. AB - For multiallelic loci, standard measures of linkage disequilibrium provide an incomplete description of the correlation of variation at two loci, especially when there are different numbers of alleles at the two loci. We have developed a complementary pair of conditional asymmetric linkage disequilibrium (ALD) measures. Since these measures do not assume symmetry, they more accurately describe the correlation between two loci and can identify heterogeneity in genetic variation not captured by other symmetric measures. For biallelic loci the ALD are symmetric and equivalent to the correlation coefficient r. The ALD measures are particularly relevant for disease-association studies to identify cases in which an analysis can be stratified by one of more loci. A stratified analysis can aid in detecting primary disease-predisposing genes and additional disease genes in a genetic region. The ALD measures are also informative for detecting selection acting independently on loci in high linkage disequilibrium or on specific amino acids within genes. For SNP data, the ALD statistics provide a measure of linkage disequilibrium on the same scale for comparisons among SNPs, among SNPs and more polymorphic loci, among haplotype blocks of SNPs, and for fine mapping of disease genes. The ALD measures, combined with haplotype-specific homozygosity, will be increasingly useful as next-generation sequencing methods identify additional allelic variation throughout the genome. PMID- 25023401 TI - Association between APE1 T1349G polymorphism and prostate cancer risk: evidence from a meta-analysis. AB - APE1 T1349G polymorphism was considered to be associated with risk of cancer, but studies on the association between APE1 T1349G polymorphism and risk of prostate cancer remained inconclusive. A meta-analysis of published studies was performed to precisely assess the association between APE1 Asp148Glu polymorphism and prostate cancer risk. PubMed, Embase, and Wanfang databases were searched for published case-control studies investigating the association between APE1 T1349G polymorphism and prostate cancer risk. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. Overall, seven studies with a total of 3,063 individuals were finally included into the meta-analysis. The heterogeneity analysis did not find obvious heterogeneity among those included studies. Meta-analysis of total seven studies did not find an obvious association between APE1 T1349G polymorphism and prostate cancer risk (G vs T OR (95 % CI) = 1.11 (0.99-1.24); GG vs TT OR (95 % CI) = 1.25 (0.96-1.62); TG vs TT OR (95 % CI) = 1.11 (0.95-1.30); GG/TG vs T OR (95 % CI) = 1.13 (0.97-1.32); GG vs TT/TG OR (95 % CI) = 1.16 (0.91-1.48)). Subgroup analyses by ethnicity showed that APE1 T1349G polymorphism was associated with increased risk of prostate cancer in Caucasians (G vs T OR (95 % CI) = 1.26 (1.02-1.56), P = 0.033; TG vs TT OR (95 % CI) = 1.44 (1.06-1.94), P = 0.019; GG/TG vs T OR (95 % CI) = 1.45 (1.08-1.94), P = 0.013). The meta-analysis suggests that APE1 T1349G polymorphism is associated with increased risk of prostate cancer, especially in Caucasians. More studies are needed to further identify the obvious association above. PMID- 25023402 TI - Tumor markers CEA and CA 19-9 correlate with radiological imaging in metastatic colorectal cancer patients receiving first-line chemotherapy. AB - In patients with metastatic colorectal cancer (mCRC), radiological imaging represents the current standard to evaluate the efficacy of chemotherapy. However, with growing knowledge about tumor biology, other diagnostic tools become of interest which can supplement radiology. The aim of the present study was to examine the correlation of tumor and serum markers with radiological imaging in patients with mCRC receiving first-line therapy. Patients were included if tumor (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9)) and serum marker (lactatdehydrogenase (LDH), gamma-glutamyltransferase (gammaGT), alkaline phosphatase (AP), C-reactive protein (CRP), leucocyte count (WBC), hemoglobin (Hb)) levels were available at baseline and at least two times during treatment. The decline and increase of tumor and serum markers over time were approximated for each patient by estimating slopes depending on the radiological assessment. A linear mixed effects multiple regression model for each subject was used to evaluate the intra-class correlation of these slopes modeling tumor and serum marker changes with radiological imaging. Data of 124 patients (41 female, 83 male; median age 62.9 years, range 27-85) who received first-line chemotherapy for mCRC from 11/2007 to 04/2010 were analyzed retrospectively. CEA level slopes (n = 49; slopes = 102) differed between radiologically determined progressive disease (PD) and partial response (PR) (p = 0.005) and between PD and stable disease (SD) (p = 0.042). CA 19-9 level slopes (n = 57; slopes = 127) also showed a significant difference between PD and PR (p = 0.002) and PD and SD (p = 0.058). Furthermore, CRP slopes (n = 62; slopes = 134) differed significantly between PD and PR (p = 0.009). For LDH, ALP, gammaGT, Hb, and WBC, no correlations were observed. The results indicate the correlation of the tumor markers CEA, CA 19-9, and the serum marker CRP with radiological imaging in patients with mCRC receiving first-line chemotherapy. Further data analyses would be helpful to develop a predictive model for tumor response based on an early tumor marker increase or decrease. PMID- 25023404 TI - Common polymorphism in the MMP-13 gene may contribute to the risk of human cancers: a meta-analysis. AB - Cancer was viewed to be driven by accumulating genetic abnormalities that generally include chromosomal abnormalities, mutations in tumor-suppressor genes, and oncogenes. The aim of this meta-analysis was to systematically summarize the possible associations between MMP-13 rs2252070 A>G variant and cancer risks. We systematically reviewed studies focusing on MMP-13 polymorphisms with human cancer susceptibility that were published before April 30, 2014. Relevant articles were identified through research of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases. All analyses were calculated using the Version 12.0 STATA software. Odds ratios (OR) and 95 % confidence interval (95 % CI) were calculated. Eleven independent case control studies were included in the meta-analysis, which involved 3,465 patients with cancers and 4,073 healthy controls. The results identified a positive association between rs2252070 A>G polymorphism and susceptibility to cancer under five genetic models (all P < 0.05). Ethnicity subgroup analysis implied that significant difference was detected for rs2252070 A>G polymorphism with increased risk of cancers among Asians and Caucasians in majority of the groups. Our findings suggest significant association for MMP-13 rs2252070 A>G to increased susceptibility to human cancer, especially in the progression of lung carcinoma. PMID- 25023403 TI - Prognostic significance of preoperative serum carcinoembryonic antigen in non small cell lung cancer: a meta-analysis. AB - Observational studies on the prognostic role of preoperative serum carcinoembryonic antigen (CEA) in non-small cell lung cancer (NSCLC) are controversial. Electronic databases updated until June 1, 2014 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between preoperative serum CEA level and survival of patients with NSCLC. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 16 studies (n = 4,296 patients) that evaluated the correlation between preoperative serum CEA level and survival in patients with NSCLC. Combined hazard ratios suggested that preoperative serum CEA overexpression was associated with poor prognosis of overall survival (OS) (hazard ratio (HR) = 2.28, 95 % confidence interval (CI) 2.24-2.31) in patients with NSCLC. Meanwhile, for p-stage I NSCLC, the HR (95 % CI) was 1.98 (1.73-2.15). In the stratified analysis by patient source, significant risks were found among Asians and non-Asians. However, significant heterogeneity was observed among all studies. In the present meta-analysis, preoperative serum CEA overexpression indicates a poor prognosis for patients with NSCLC. PMID- 25023405 TI - Expression of NF45 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth. AB - Nuclear factor of activated T cells 45 kDa (NF45), is a transcription factor that interacts with NF90 to regulate gene expression. It has been proved to be associated with tumor proliferation in various human malignancies. However, the role of NF45 in glioma is poorly understood. The aim of our study was to examine the relationship between NF45 expression and pathological grade in glioma and the impact of NF45 on the proliferation of glioma cells. Expression levels of NF45 are significantly elevated in high-grade human tissue samples compared with low grade human glioma tissues samples (P < 0.0001) in Western blot analysis. The result of immunohistochemical also revealed that the expression of NF45 was overexpressed in 121 resected gliomas of different pathologic grades and associated with Ki-67. To investigate the role of NF45 in glioma carcinogenesis, we reduced the expression of NF45 by small interfering RNAs, and results showed suppression of cell proliferation, arrest of the cell cycle, and reduction in clone in vitro. Importantly, we show that SiNF45 can induce the expression of p21 and reduce the expression of proliferating cell nuclear antigen (PCNA) and cyclin E. These findings indicate that NF45 plays an important role in the growth regulation of glioma cells, suggesting that NF45 maybe a molecular marker for pathology and a novel therapeutic target for malignant glioma. PMID- 25023406 TI - ERCC polymorphisms and prognosis of patients with osteosarcoma. AB - Osteosarcoma is the most common primary bone malignancy in children and teenagers, and its clinical outcome remains poor. Previous studies have investigated the association between excision repair cross-complementing (ERCC) and prognosis of osteosarcoma patients, but their results were inconsistent. We aimed to clarify the associations between ERCC polymorphisms and osteosarcoma prognosis by using meta-analysis. We searched relevant studies in PubMed, Embase, coupled with Chinese National Knowledge Infrastructure (CNKI) in human osteosarcoma published prior to April, 2014. Hazard ratios (HR) together with their 95 % confidence intervals (95 % CI) were used to measure the relationship between ERCC mutations and prognosis in patients with osteosarcoma. Pooled results showed that polymorphism of ERCC2 Lys751Gln was associated with the overall survival of osteosarcoma (GG vs. AA, HR = 0.40; 95 % CI 0.18-0.86), and ERCC5 His46His mutation was associated with the event-free survival of osteosarcoma (CC vs. TT, HR = 0.37; 95 % CI 0.15, 0.93). In addition, there is no evidence of association on ERCC1 Asn118Asn, ERCC1 Gln504Lys, and ERCC2 Asp312Asn polymorphisms with prognosis in osteosarcoma. In summary, the ERCC2 Lys751Gln and ERCC5 His46His polymorphisms might influence osteosarcoma prognosis. PMID- 25023407 TI - Hospital variation in thrombolysis times among patients with acute ischemic stroke: the contributions of door-to-imaging time and imaging-to-needle time. AB - IMPORTANCE: Given the limited time window available for treatment with tissue plasminogen activator (tPA) in patients with acute ischemic stroke, guidelines recommend door-to-imaging time (DIT) within 25 minutes of hospital arrival and door-to-needle (DTN) time within 60 minutes for patients with acute ischemic stroke. Despite improvements in DITs, DTN times for tPA treatment in patients with acute ischemic stroke remain suboptimal. OBJECTIVES: To examine the contributions of DIT and imaging-to-needle (ITN) time to delays in timely delivery of tPA to patients with acute ischemic stroke and to assess between hospital variation in DTN times. DESIGN, SETTING, AND PARTICIPANTS: A cohort analysis of 1193 patients having acute ischemic stroke treated with intravenous tPA between January 2009 and December 2012. Multilevel linear regression models included random effects for 25 Michigan hospitals participating in the Paul Coverdell National Acute Stroke Registry. MAIN OUTCOMES AND MEASURES: The primary outcome was a continuous measure of DTN time, in minutes, from emergency department arrival to thrombolytic delivery. RESULTS: The mean age was 68.1 years, the median National Institutes of Health Stroke Scale score was 11.0 (interquartile range, 6-17), 51.4% were female, and 37.5% were of nonwhite race/ethnicity.The mean (SD) DTN time was 82.9 (35.4) minutes, the mean (SD) DIT was 22.8 (15.9) minutes, and the mean (SD) ITN time was 60.1 (32.3) minutes. Most patients (68.4%) had DIT within 25 minutes, while 28.7% had DTN time within 60 minutes. Hospital variation accounted for 12.7% of variability in DTN times. Neither annual stroke volume nor primary stroke center designation was a significant predictor of shorter DTN time. Patient factors (age, sex, race/ethnicity, arrival mode, onset-to-arrival time, and stroke severity) explained 15.4% of the between-hospital variation in DTN times. After adjustment for patient-level factors, DIT explained 10.8% of the variation in hospital risk adjusted DTN times, while ITN time explained 64.6%. CONCLUSIONS AND RELEVANCE: Compared with DIT, ITN time is a much greater source of variability in hospital DTN times and is a more common contributor to delays in timely tPA therapy for acute ischemic stroke. More attention is needed to determine systems changes that can decrease ITN time for patients with acute ischemic stroke. PMID- 25023408 TI - Genetic dissection of temperature-dependent sorghum growth during juvenile development. AB - KEY MESSAGE: Promising genome regions for improving cold tolerance of sorghum were identified on chromosomes SBI-01, SBI-03, SBI-07, and SBI-10. Chlorophyll fluorescence had no major effect on growth rates at low temperatures. Developing fast growing sorghum seedlings is an important breeding goal for temperate climates since low springtime temperatures are resulting in a prolonged juvenile development. The adaptation of sorghum to tropical and subtropical highlands gives hint for certain genetic variation. The goals of the present study were to detect marker-trait associations for leaf and dry matter growth rate and for chlorophyll fluorescence and content (SPAD) in relation to temperature. A diversity set comprising 194 genotypes was tested in eight controlled environments with temperatures ranging from 9.4 to 20.8 degrees C. Significant marker-trait associations (p < 0.05) were identified for each individual temperature regime and on the parameters of regression analyses describing the responses of growth or chlorophyll related traits to temperatures. The diversity set was fingerprinted with 171 diversity array technology (DArT) and 31 simple sequence repeat (SSR) markers. SSRs were used to analyze the population structure while association studies were performed on DArT markers. Promising marker-trait associations for growth rates in relation to temperature were detected on chromosomes SBI-01, SBI-03, SBI-07, and SBI-10. Many promising loci were also significantly associated to the results obtained in individual low-temperature environments. Marker-trait associations for chlorophyll content and fluorescence did occasionally co-locate to those for growth during juvenile development but there was no evidence supporting our hypothesis that seedling growth at low temperatures is largely influenced by SPAD or fluorescence. PMID- 25023409 TI - Recent Advances in Nanostructured Biomimetic Dry Adhesives. AB - The relatively large size of the gecko and its ability to climb a multitude of structures with ease has often been cited as the inspiration upon which the field of dry adhesives is based. Since 2010, there have been many advances in the field of dry adhesives with much of the new research focusing on developing nanoscale and hierarchical features in a concentrated effort to develop synthetic gecko like dry adhesives which are strong, durable, and self-cleaning. A brief overview of the geckos and the hairs which it uses to adhere to many different surfaces is provided before delving into the current methods and materials used to fabricate synthetic gecko hairs. A summary of the recently published literature on bio inspired, nanostructured dry adhesives is presented with an emphasis being placed on fabrication techniques. PMID- 25023410 TI - Protein mistranslation: friend or foe? AB - The translation of genes into functional proteins involves error. Mistranslation is a known cause of disease, but, surprisingly, recent studies suggest that certain organisms from all domains of life have evolved diverse pathways that increase their tolerance of translational error. Although the reason for these high error rates are not yet clear, evidence suggests that increased mistranslation may have a role in the generation of diversity within the proteome and other adaptive functions. Error rates are regulated, and there appears to be an optimal mistranslation rate that varies by organism and environmental condition. Advances in unbiased interrogation of error types and experiments involving wild organisms may help our understanding of the potentially adaptive roles for protein translation errors. PMID- 25023411 TI - Evaluating communities of practice and knowledge networks: a systematic scoping review of evaluation frameworks. AB - Communities of Practice (CoPs) are increasingly considered a part of ecohealth and other sectors such as health care, education, and business. However, there is little agreement on approaches to evaluate the influence and effectiveness of CoPs. The purpose of this review was to understand what frameworks and methods have been proposed or used to evaluate CoPs and/or knowledge networks. The review searched electronic databases in interdisciplinary, health, education, and business fields, and further collected references and forward citations from relevant articles. Nineteen articles with 16 frameworks were included in the synthesis. The purposes of the evaluation frameworks varied; while some focused on assessing the performance of CoPs, several frameworks sought to learn about CoPs and their critical success factors. Nine of the frameworks had been applied or tested in some way, most frequently to guide a case study. With limited applications of the frameworks, strong claims about generalizability could not be made. The review results can inform the development of tailored frameworks. However, there is a need for more detailed and targeted CoP evaluation frameworks, as many imperative CoP evaluation needs would be unmet by the available frameworks. PMID- 25023412 TI - Analytical Green's function for the fluorescence simplified spherical harmonics equations in turbid medium. AB - It is more complicated to write the analytical expression for the fluorescence simplified spherical harmonics ( SPN) equations in a turbid medium, since both the processes of the excitation and emission light and the composite moments of the fluence rate are described by coupled equations. Based on an eigen decomposition strategy and the well-developed analytical methods of diffusion approximation (DA), we derive the analytical solutions to the fluorescence SPN equations for regular geometries using the Green's function approach. By means of comparisons with the results of fluorescence DA and Monte Carlo simulations, we have shown the effectiveness of our proposed method and the expected advantages of the SPN equations in the case of small source-detector separation and high absorption. PMID- 25023413 TI - Evaluation of fractional photothermolysis effect in a mouse model using nonlinear optical microscopy. AB - Fractional photothermolysis (FP) induces discrete columns of photothermal damage in skin dermis, thereby promoting collagen regeneration. This technique has been widely used for treating wrinkles, sun damage, and scar. In this study, we evaluate the potential of multiphoton microscopy as a noninvasive imaging modality for the monitoring of skin rejuvenation following FP treatment. The dorsal skin of a nude mouse underwent FP treatment in order to induce microthermal zones (MTZs). We evaluated the effect of FP on skin remodeling at 7 and 14 days after treatment. Corresponding histology was performed for comparison. After 14 days of FP treatment at 10 mJ, the second harmonic generation signal recovered faster than the skin treated with 30 mJ, indicating a more rapid regeneration of dermal collagen at 10 mJ. Our results indicate that nonlinear optical microscopy is effective in detecting the damaged areas of MTZ and monitoring collagen regeneration following FP treatment. PMID- 25023414 TI - Mesoscopic reflectance angular domain spectroscopic imaging. AB - The advancement of angular domain imaging in mesoscopic reflectance multispectral imaging is reported. The key component is an angular filter array that performs the angular filtration of the back-scattered photons and generates image contrast due to the variances in tissue optical properties. The proposed modality enables multispectral imaging of subsurface features for samples too thick for transillumination angular domain spectroscopic imaging (ADSI) approaches. The validation was carried out with tissue-mimicking phantoms with multiple absorptive features embedded below the surface. Multispectral images in the range of 666 to 888 nm clearly revealed the location of the features with the background scattering levels up to 20 cm-1. The shape of the features was recoverable at depths of up to three to four times the transport mean free path. The spatial resolution was <1 mm and the field-of-view was larger than 2.5 cm x 30. cm. Furthermore, the attenuation spectra of measured absorptive features were successfully extracted. Target detectability and imaging quality with different background scattering levels, target depths, and illumination focal depths were discussed, as well as the capability of ADSI in reflectance optical mesoscopic imaging and its potential applications. PMID- 25023415 TI - Phantoms for diffuse optical imaging based on totally absorbing objects, part 2: experimental implementation. AB - We present the experimental implementation and validation of a phantom for diffuse optical imaging based on totally absorbing objects for which, in the previous paper [J. Biomed. Opt.18(6), 066014, (2013)], we have provided the basic theory. Totally absorbing objects have been manufactured as black polyvinyl chloride (PVC) cylinders and the phantom is a water dilution of intralipid-20% as the diffusive medium and India ink as the absorber, filled into a black scattering cell made of PVC. By means of time-domain measurements and of Monte Carlo simulations, we have shown the reliability, the accuracy, and the robustness of such a phantom in mimicking typical absorbing perturbations of diffuse optical imaging. In particular, we show that such a phantom can be used to generate any absorption perturbation by changing the volume and position of the totally absorbing inclusion. PMID- 25023416 TI - Measurement of the retinal arteriolar response to a hyperoxic provocation in nonsmokers and smokers, using a high-resolution confocal scanning laser ophthalmoscope. AB - We used a high-resolution confocal scanning laser ophthalmoscope to measure the magnitude of change in retinal arteriolar diameters in response to oxygen breathing in young, healthy nonsmokers and smokers. Image sequences were obtained before and during oxygen breathing. Image sequences were desinusoided, registered, and averaged, before vessel diameters were measured using a sliding linear regression filter. Arteriole diameters were observed to constrict during the first 5 min. of oxygen breathing, plateau, and remain stable while hyperoxia was maintained, returning to baseline at the end of the hyperoxic period. Blood flow to the temporal retina was found to be higher than to the nasal retina (p=0.008). The percentage constriction of vessels did not vary across retinal quadrants (p=0.372, analysis of variance) and did not depend on vessel size (p=0.538). Baseline diameters were unaffected by acute cigarette smoking. The magnitude of vasoconstriction was diminished in smokers compared to nonsmokers (p=0.017), while acute smoking did not influence the percentage constriction attained by the vessels (p=0.621). Using a high-resolution imaging technique allowed us to measure reactivity to a high degree of accuracy and to assess it in vessels of smaller caliber than were previously studied. PMID- 25023417 TI - [Radiation exposure from shoe-fitting fluoroscopes]. AB - It is 40 years ago that a very popular X-ray device disappeared in German shoe shops: the shoe-fitting fluoroscope or Pedoskop. Since the 1930s, these X-ray machines were an integral part of any good shoe business. Following the entry into force X-Ray Regulation (RoV 1973) the use of these devices was prohibited in Germany. PMID- 25023419 TI - Ethical issues associated with the use of animal experimentation in behavioral neuroscience research. AB - This chapter briefly explores whether there are distinct characteristics in the field of Behavioral Neuroscience that demand specific ethical reflection. We argue that although the ethical issues in animal-based Behavioral Neuroscience are not necessarily distinct from those in other research disciplines using animal experimentation, this field of endeavor makes a number of specific, ethically relevant, questions more explicit and, as a result, may expose to discussion a series of ethical issues that have relevance beyond this field of science. We suggest that innovative research, by its very definition, demands out of-the-box thinking. At the same time, standardization of animal models and test procedures for the sake of comparability across experiments inhibits the potential and willingness to leave well-established tracks of thinking, and leaves us wondering how open minded research is and whether it is the researcher's established perspective that drives the research rather than the research that drives the researcher's perspective. The chapter finishes by introducing subsequent chapters of this book volume on Ethical Issues in Behavioral Neuroscience. PMID- 25023418 TI - Pre-clinical functional Magnetic Resonance Imaging Part II: The heart. AB - One third of all deaths worldwide in 2008 were caused by cardiovascular diseases (CVD), and the incidence of CVD related deaths rises ever more. Thus, improved imaging techniques and modalities are needed for the evaluation of cardiac morphology and function. Cardiac magnetic resonance imaging (CMRI) is a minimally invasive technique that is increasingly important due to its high spatial and temporal resolution, its high soft tissue contrast and its ability of functional and quantitative imaging. It is widely accepted as the gold standard of cardiac functional analysis. In the short period of small animal MRI, remarkable progress has been achieved concerning new, fast imaging schemes as well as purpose-built equipment. Dedicated small animal scanners allow for tapping the full potential of recently developed animal models of cardiac disease. In this paper, we review state-of-the-art cardiac magnetic resonance imaging techniques and applications in small animals at ultra-high fields (UHF). PMID- 25023420 TI - The effect of induction of endogenous CO by heme-oxygenase inducer, hemin versus heme-oxygenase blocker, zinc mesoporphyrin on gastric secretion and ulceration under different conditions in adult male albino rats. AB - Although its role and importance is less well studied, carbon monoxide (CO) has been identified as the second gasotransmitter in the GI tract. This study was performed to investigate the effect of modifying the endogenous CO production by altering heme oxygenase (HO) activity either by induction through hemin administration or inhibition by zinc mesoporphyrin administration on gastric secretion and ulceration induced by either cold restraint stress (CRS) or indomethacin (IND) treatment in adult male albino rats. Our results revealed that hemin significantly increased HO-1 levels with an increase in carboxyhemoglobin (COHb) level while zinc mesoporphyrin significantly decreased HO-1 levels with a decrease in COHb level in all groups. Hemin pretreatment significantly attenuated the gastric mucosal lesions induced by CRS and IND administration, which was accompanied by significant reduction in free and total acidity of gastric secretion, decreased proteolytic activity and marked attenuation of lipid peroxidation inspite of decreased NO and PGE2 levels. On the other hand, Inhibition of HO-1 activity by zinc mesoporphyrin prevented most of the effects caused by hemin administration except for its similar reduction in gastric mucosal NO and PGE2 levels. On conclusion, Hemin exerts a protective effect against CRS and IND-induced gastric ulcers possibly via inducing HO-1 and increasing endogenous production of CO (Tab. 2, Fig. 4, Ref. 75). PMID- 25023421 TI - Changes of serum angiogenic biomarkers and their correlations with serum leptin concentration. AB - AIM: Obesity is considered as a major health problem. Angiogenic vessels by providing oxygen, nutrients and growth factors trigger growth and survival signals in adipocytes. We aimed to investigate the effect of high-fat diet (HFD) on serum angiogenic biomarkers including vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR1), nitric oxide (NO) concentrations and their correlations with serum leptin level in obese and control groups. METHODS: Twenty male C57BL/6 mice were randomly assigned into the control and obese groups. Obese group received HFD for 15 weeks. At the end of experiment, blood samples were collected for blood glucose, serum insulin, VEGF, sVEGFR1, NO and leptin level measurements and correlation between serum angiogenic factors and leptin levels were analyzed. RESULTS: HFD induced higher serum NO and leptin levels compared to the control group, while, it did not affect serum VEGF and sVEGFR1 concentrations. There was a strong positive correlation between serum leptin and NO levels (r=0.78), however, a weak correlation was found between serum leptin and VEGF and VEGFR-1 concentrations. CONCLUSION: It seems that the angiogenic activities in obese mice are through the mechanisms that were not regulated by VEGF or VEGF receptors rather; other factors such as leptin and NO are involved (Tab. 1, Fig. 4, Ref. 32). PMID- 25023422 TI - Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect. AB - OBJECTIVES: It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. BACKGROUND: Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. METHODS: Nociception was evaluated by tail flick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. RESULTS: PPIX, SIN 1, SNAP and NOC-18 significantly increased expression of morphine tolerance while ODQ decreased. CONCLUSION: These data suggested that sGC activators have a significant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29). PMID- 25023423 TI - In vitro motility changes in Roux limb after Roux-en-Y reconstruction. AB - BACKGROUND: The aim of this study is to compare the motility of Roux limb with that of normal segment. MATERIALS AND METHODS: Rats were divided into 3 equal groups as control, Roux-en-Y (Group A) and Roux-en-Y with vagotomy (Group B). Only midline incision and manipulations were applied in control group. Following distal gastrectomy, Roux-en-Y reconstruction was applied in Group A, while vagotomy Roux-en-Y gastrojejunostomy was applied in Group B. Rats were sacrificed 1 month later by cervical dislocations under anesthesia. The obtained jejunal segments were cut into four equal parts. The bath was 37 degrees C warm while 95 % O2 and 5 % CO2 gases were supplied in 10 ml bicarbonate Krebs' solution. RESULTS: KCl responses were similar in all three groups. Acetylcholine contraction responses in the vagotomy and non-vagotomy Roux-en-Y groups was higher than in those in control group significantly (p < 0.05). This response in vagotomy Roux-en-Y group was also higher than that in non-vagotomy group (p < 0.05). The induced electrical field stimulation contraction response in the vagotomy + Roux-en-Y group was lower than those in control group and non-vagotomy group (p < 0.05). CONCLUSIONS: These results show that muscarinic receptor density and/or function may increase after vagotomy and non-vagotomy group operation, and vagotomy may contribute to this increase. The decrease in electrical signal response in vagotomy Roux-en-Y group may depend on the decrease in acetylcholine oscillation from the cholinergic nerve ending (Tab. 1, Fig. 5, Ref. 25). PMID- 25023424 TI - Combined usage of estrogen and melatonin restores bladder contractility and reduces kidney and bladder damage in ovariectomized and pinealectomized rat. AB - OBJECTIVE: The incidence of urinary bladder disturbances and renal structural changes and functional decline are found to increase with age. METHODS: We investigated the effect of melatonin treatment in addition to estrogen replacement therapy in pinealectomized (Px) and ovariectomized (Ovx) rats. 56 female Wistar rats were divided into seven groups, each containing eight animals: Sham, (Ovx), (Px), Px+Ovx, Px+Ovx receiving estrogen (Px+Ovx+E), Px+Ovx receiving melatonin (Px+Ovx+M) and Px+Ovx estrogen and melatonin supplemented (Px+Ovx+EM) group (EM group). We evaluated reduced glutathione (GSH) levels and malondialdehyde (MDA) levels. The mean collagen fiber (CF)/smooth muscle (SM) ratio in the bladder wall and structure of the kidney were examined histolologically. We also recorded response of the bladder contractility to acetylcholine (Ach). RESULTS: Px and Ovx groups showed statistically significant reductions of antioxidant defenses, impaired Ach-evoked contraction, histological changes compared with the control group. Also, these changes were prominent in Px+Ovx group compared with all other groups. Both estrogen and melatonin reversed these changes however best restoration was observed in the EM group. CONCLUSIONS: Px performed in addition to Ovx led to a distinct increase in oxidative damage in bladder and renal tissue and deteriorate of the detrussor function. Either estradiol or melatonin replacement alone or in combination prevents significant alterations of tissue histology and bladder contractility following Ovx and Px. Thus, combination treatment appears to be the best method to restore both contractility and histomorphology of bladder and kidney tissues after Ovx and Px (Tab. 3, Fig. 4, Ref. 44). PMID- 25023425 TI - Hepatocyte apoptotic index and p53 expression in obstructive jaundice rats. AB - OBJECTIVE: Obstructive jaundice is a serious disease. It can deteriorate critical functions in the liver. MATERIAL AND METHOD: A total of 20 male Wistar-Albino rats were randomly allocated into two groups consisting of ten in each as follows: Group I (Control) was subjected to a sham operation isolating the bile duct. Group II(Study) was subjected to acute cholestasis induced by bile duct ligation with 4/0 silk suture from two different places and full fold cut between ligatures. On the 7th day, group II rats were re-operated for liver sampling and sacrification-aimed histological analysis through the old incision with anaesthesia. Hepatic tissues were histologically and immunohistochemically processed. The number of apoptotic and p53(+) cells were measured. RESULTS: On the 7th day, the averages of direct and indirect bilirubin values in Group II rats were found to be 6.99 and 11.70 mg/dl, respectively. They were observed to be statistically significant. In the immunohistochemical evaluation p53 expression in hepatocytes was assessed, p53-positive hepatocytes were determined to exist quite widely in the tissue samples taken from the livers of rats in the study group. Nevertheless, no cells exhibiting p53 expression were found in the tissue samples of the control group. CONCLUSION: Apoptosis is a closed box and it might make it possible to stop the many disease processes or accelerate the healing. If the principal effective mechanism in the liver under a certain stress factor is apoptosis, it is definite that it will make a difference in the treatment approach. Consequently, we can say that both apoptotic index and p53 expression increase in the rats' liver with biliary obstruction (Fig. 4, Ref. 51). PMID- 25023426 TI - The olive leaf extract attenuates bacterial translocation and liver damage in obstructive jaundice. AB - OBJECTIVES: The olive leaf extract (OLext) is known to possess many biological properties including a powerful antioxidant. This study aimed to investigate the protective effects of postoperative nutrition with OLext and glutamine on bacterial translocation (BT) and liver damage in obstructive jaundice. MATERIALS AND METHODS: Totally, 50 rats were randomly divided into the five groups of 10 each. The common bile duct was ligated in all animals, excepting in the group 1. Postoperative nutrition was given to all groups for ten days. The rats in the Group 1 and 2 were fed a normal diet, Group 3 rats were fed an additional glutamine (1 g/kg/day), and Group 4 and 5 rats were fed an additional OLext (1 ml of 1/2 diluted and pure form/kg/day). Biochemical, microbiological and liver histopathological changes were evaluated. RESULTS: BT in the Groups 3, 4, and 5 was significantly lower than in the Group 2. The values of aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (gamma-GT) and alkalen phosphatase (ALP) in blood were increased in obstructive jaundice, but the levels of these tests were statistically lower in glutamine and OLext groups when compared to the Group 2. Histopathological changes were observed low in the liver in OLext and glutamine groups. CONCLUSIONS: The present data has demonstrated that the supplementation of olive leaf extract and glutamine reduce the incidence of BT and liver damage in obstructive jaundiced rats (Tab. 4, Fig. 1, Ref. 23). PMID- 25023427 TI - Iron and its relation to glycoconjugates in human globus pallidus. AB - Iron and eosinophilic, argyrophilic spheroid structures of glycoconjugates are observed in the pallido-nigral system of human and nonhuman primates. In the present study, we map the localization and distribution of ferritin and hemosiderin and their relation to neutral and acidic (sulphated and carboxylated) glycoconjugates in human globus pallidus. We investigated tissues of human globus pallidus without any motor abnormalities and psychiatric symptoms. Acidic (Alcian blue, AB pH 2.5) and neutral glycoconjugates (PAS reaction) showed spheroid deposits with the size of 5-15 um. Staining reaction utilizing AB (pH 1.0) displays sulphated fibers and highly sulphated (AB pH 0.5) glycoconjugates round deposits. AF/AB pH 2.5 for separating sulphated from carboxylated glycoconjugates revealed the presence of both sulphated and carboxylated glycoconjugates. Perls' and Turnbull's positive reaction showed the presence of Fe(III) and Fe(II) (hemosiderin) and Ag-NOR reaction showed ferric phosphate (ferritin) deposits. Scanning electron microscope with microanalysis revealed the iron in glycoconjugates globular deposits. We suppose the presence of glycoconjugates in the samples is the result of elimination and inactivation of iron as inductor of reactive oxygen species. They can be a useful neuroprotective agent in CNS degradation (Tab. 2, Fig. 7, Ref. 44). PMID- 25023428 TI - Effects of aqueous soybean, mistletoe and red clover extracts on activities of adenosine deaminase and xanthine oxidase enzyme. AB - Soybean (Glycine max), mistletoe (Viscum album) and red clover (Trifolium pratence) have been argued to have anti-cancer effects. In the present study it was aimed to investigate possible effects of these plant extracts on the activities of DNA turn-over enzymes, namely adenosine deaminase (ADA) and xanthine oxidase (XO) in cancerous and non-cancerous gastric and colon tissues. For this aim, 6 cancerous and 6 non-cancerous adjacent human gastric tissues, and 7 cancerous and 7 non-cancerous adjacent colon tissues were obtained by surgical operations. Our results suggest that aqueous soybean, mistletoe and red clover extracts may exhibit anti-tumoral activity by depleting hypoxanthine concentration in the cancer cells through XO activation, which may lead to lowered salvage pathway activity necessary for the cancer cells to proliferate in the cancerous colon tissue. Some foods like soybean, mistletoe and red clover may provide nutritional support to medical cancer therapy through inhibiting and/or activating key enzymes in cancer metabolism (Tab. 4, Ref. 33). PMID- 25023429 TI - Homocysteine levels and bad obstetric outcome among female operating room personnel occupationally exposed to nitrous oxide. AB - It is known that nitrous oxide (N2O) inactivates vitamin B12 and causes hyperhomocysteinemia. The personnel working at the operating theatres are repeatedly exposed to N2O in the ambient air. This prompted us to investigate the biochemical indices of vitamin B12 metabolic status among female personnel working under various levels of N2O exposure. In this study, the homocysteine and folic acid levels were assessed and bad obstetric outcome was questioned. Sixty operating theatre female personnel were examined. Vitamin B12 and folic acid, total homocysteine level, anticardiolipin IgM, IgG, antiphospholipid IgM, IgG levels were measured in serum. A questionnaire inquiring about obstetric history was given. The serum concentration of folic acid was 10 +/- 3.3 nmol liter-1. The vitamin B12 level was 332 +/- 134 pmol liter-1, the serum concentration of homocysteine was 9.1 +/- 2.4 nmol liter-1 and all were within normal ranges. There was no difference regarding homocysteine, folic acid, vitamin B12 levels and the obstetric history between the subjects who had abortus history and the subjects who had not abortus history. Exposure to N2O in healthcare workers was not associated with alterations of homocysteine, folic acid status and bad obstetric outcome (Tab. 4, Ref. 18). PMID- 25023430 TI - Idiopatic lobular necrotizing paniculitis. AB - 42-year old patient was presented to our clinic with a fever lasting for seven months and a ten month history of subcutaneous nodules on all extremities and trunk. Further examination revealed anaemia, lymphocytopenia and elevation of inflammatory parameters and liver enzymes. Authors comment their difficulties in differential diagnostic process. The bone marrow biopsy and reappraisal of subcutaneous lesions confirmed idiopathic lobular panniculitis, known as Weber Christian disease. A combined immunosuppressive therapy was followed by improvement of clinical state as well as laboratory parameters (Tab. 2, Fig. 3, Ref. 11). PMID- 25023431 TI - Neuron-specific enolase in the intestinal wall in Crohn's disease. AB - The authors described the localization of neuron-specific enolase in the intestinal wall in Crohn's disease. We have used samples obtained by biopsy from the colon lining of five people affected by Crohn's disease for our examination. We have processed samples using the formol paraffin technique. From paraffin blocks, we have prepared histological sections approximately 5 MUm thick. For immunohistochemic examinations, we have revitalised the sections by acquiring the heat-induced epitope. We detected NSE by monoclonal mouse antibodies against human neuron-specific enolase, clone BBS/NC/VI-H14 (DakoCytomation, Denmark) (Fig. 4, Ref. 7). PMID- 25023433 TI - Effect of intravenous hyoscine-N-butyl bromide on active phase of labor progress: a randomized double blind placebo controlled trial. AB - INTRODUCTION: Appropriate cervical dilatation and effacement are essential for the progression of labor. With the active management of labor, number of cesarean deliveries reduces and the duration of labor shortens. Cervical dilatation can be facilitated by mechanical, pharmacological and non-pharmacologic methods. Cervix is richly supplied by autonomic nerves, which may play a role in the dilatation of cervix. Hyoscine-N-butylbromide (HBB) is a muscarinic antagonist and acts as a cervical spasmolytic agent. After intravenous administration it is rapidly distributed into the tissues. We aimed to study the effects and safety of a single dose 20 mg HBB injection during the active phase of labor in both primi- and multigravid women. MATERIALS AND METHOD: A randomized, double-blinded, controlled trial, with healthy primigravid and multigravid women in spontaneous labor at term was considered in this study. Once the active phase of labor was achieved, either a single dose of 20 mg (1 mL) of HBB or placebo (1 mL saline) was given intravenously. RESULTS: The mean duration of the first stage of labor was 191.1 +/- 43.06 min in the primigravid patients of the HBB group, while it was 248.2 +/- 66.1 min in the placebo group, a statistically significant difference of 57 min (p < 0.001). The mean duration of the first stage of labor was 170.1 +/- 50.8 min in the multigravid patients of the HBB group, while it was 224.06 +/- 53.7 min in the placebo group (difference of 54 min, p < 0.001). The mean duration of the first stage of labor was significantly different both for multigravida and primigravid patients. There was no significant change in the times for the second and third stages of labor. There were no significant differences in terms of APGAR scores noted at 1 and 5 min, prepartum and postpartum hemoglobin levels and birth weight. No adverse maternal and fetal effects were observed in both HBB and placebo groups. CONCLUSION: A single dose of 20 mg intravenous HBB is effective and safe in shortening the duration of the first stage of labor without any adverse effects on fetus and mother. PMID- 25023434 TI - Risk factors for early postpartum hemorrhage (PPH) in the first vaginal delivery, and obstetrical outcomes in subsequent pregnancy. AB - OBJECTIVE: To investigate risk factors for postpartum hemorrhage (PPH) in vaginal deliveries and the influence of previous PPH on the subsequent pregnancy. STUDY DESIGN: A retrospective cohort study including first singleton deliveries between the years 1988 and 2012 was performed comparing deliveries with and without PPH. In addition, perinatal outcomes of the subsequent pregnancy were evaluated. Multivariable analysis was performed to control for confounders. RESULTS: PPH complicated 0.8% of all first vaginal deliveries. Significant risk factors for PPH in vaginal delivery, using a multiple logistic regression model, were: post term pregnancy, fertility treatments, hypertensive disorders, labor dystocia during the 2nd, and perineal tears grade 2 and 3, respectively. Previous PPH was found to be an independent risk factor for PPH in the subsequent pregnancy. Moreover, previous PPH was found to be a significant risk factor for cesarean section (CS) deliver, to complicate delivery with revision of uterus cavity, anemia, and to require blood transfusion. CONCLUSION: Previous PPH poses a risk for recurrent PPH in subsequent delivery and an increased risk for CS. As PPH remains one of the major causes of maternal morbidity, this study strengthens the need for a comprehensive evaluation of prior PPH as a major risk factor for PPH recurrence. PMID- 25023435 TI - Identification of appropriate reference genes for qPCR studies in Staphylococcus pseudintermedius and preliminary assessment of icaA gene expression in biofilm embedded bacteria. AB - BACKGROUND: Quantitative PCR is rapidly becoming the standard method for analyzing gene expression in a wide variety of biological samples however it can suffer from significant error if stably expressed reference genes are not identified on which to base the analysis. Suitable reference genes for qPCR experiments on Staphylococcus pseudintermedius have yet to be identified. RESULTS: Three reference genes in S. pseudintermedius were identified and validated from a set of eight potential genes (proC, gyrB, rplD, rho, rpoA, ftsZ, recA, sodA). Two strains of S. pseudintermedius were used, and primer specificity and efficiency were confirmed and measured. Ranking of the genes with respect to expression stability revealed gyrB, rho and recA as the best reference genes. This combination was used to quantify expression of a single biofilm associated gene, icaA, in logarithmic, stationary and biofilm growth phases, revealing that expression was significantly upregulated in the biofilm growth phase in both strains. CONCLUSION: Three reference genes, gyrB, rho and recA, were identified and validated for use as reference genes for quantitative PCR experiments in S. pseudintermedius. Also, the biofilm associated gene icaA was shown to be significantly upregulated in biofilm samples, consistent with its role in biofilm production. PMID- 25023436 TI - Deregulation of purine pathway in Bacillus subtilis and its use in riboflavin biosynthesis. AB - BACKGROUND: Purine nucleotides are essential metabolites for living organisms because they are involved in many important processes, such as nucleic acid synthesis, energy supply, and biosynthesis of several amino acids and riboflavin. Owing to the pivotal roles of purines in cell physiology, the pool of intracellular purine nucleotides must be maintained under strict control, and hence the de novo purine biosynthetic pathway is tightly regulated by transcription repression and inhibition mechanism. Deregulation of purine pathway is essential for this pathway engineering in Bacillus subtilis. RESULTS: Deregulation of purine pathway was attempted to improve purine nucleotides supply, based on a riboflavin producer B. subtilis strain with modification of its rib operon. To eliminate transcription repression, the pur operon repressor PurR and the 5'-UTR of pur operon containing a guanine-sensing riboswitch were disrupted. Quantitative RT-PCR analysis revealed that the relative transcription levels of purine genes were up-regulated about 380 times. Furthermore, site directed mutagenesis was successfully introduced into PRPP amidotransferase (encoded by purF) to remove feedback inhibition by homologous alignment and analysis. Overexpression of the novel mutant PurF (D293V, K316Q and S400W) significantly increased PRPP amidotransferase activity and triggered a strong refractory effect on purine nucleotides mediated inhibition. Intracellular metabolite target analysis indicated that the purine nucleotides supply in engineered strains was facilitated by a stepwise gene-targeted deregulation. With these genetic manipulations, we managed to enhance the metabolic flow through purine pathway and consequently increased riboflavin production 3-fold (826.52 mg/L) in the purF-VQW mutant strain. CONCLUSIONS: A sequential optimization strategy was applied to deregulate the rib operon and purine pathway of B. subtilis to create genetic diversities and to improve riboflavin production. Based on the deregulation of purine pathway at transcription and metabolic levels, an extended application is recommended for the yield of products, like inosine, guanosine, adenosine and folate which are directly stemming from purine pathway in B. subtilis. PMID- 25023437 TI - Radioactivity levels in mussels and sediments of the Golden Horn by the Bosphorus Strait, Marmara Sea. AB - The Golden Horn is an estuary located in the center of Istanbul receiving freshwater discharges from two creeks and connecting to the Bosphorus Strait. Activity concentrations of natural and artificial radionuclides were determined in mussels (Mytilus galloprovincialis) and sediments from the Golden Horn sampled in February 2012. Mean activity concentrations of (137)Cs, (40)K, (226)Ra, (228)Ra, (210)Po and (210)Pb in the mussels were determined at 1.03+/-0.23, 389+/ 41.6, 2.61+/-1.23, not detected (ND), 91.96+/-37.88 and 11.48+/-4.85 Bq kg(-1), respectively. In sediments, it was observed that (137)Cs, (40)K, (226)Ra, (228)Ra, (210)Po and (210)Pb activity concentrations in<63 MUm particle fraction of sediment were generally higher than those determined in mussels. Po-210 and (210)Po/(210)Pb ratios in mussels from the Golden Horn were much lower than in mussels from other coastal regions and this was related to low plankton productivity and eutrophication of the Golden Horn. PMID- 25023438 TI - Suspended microplastics in the surface water of the Yangtze Estuary System, China: first observations on occurrence, distribution. AB - Levels of microplastics (MPs) in China are completely unknown. This study characterizes suspended MPs quantitatively and qualitatively for the Yangtze Estuary and East China Sea. MPs were extracted via a floatation method. MPs were counted and categorized according to shape and size under a stereomicroscope. The MP densities were 4137.3+/-2461.5 and 0.167+/-0.138 n/m(3), respectively, in the estuarine and the sea samples. Plastic abundances varied significantly in the estuary. Higher densities in three sea trawls confirmed that rivers were the important sources of MP to the marine environment. Plastic particles (>5mm) were observed with a maximum size of 12.46 mm, but MPs (0.5-5 mm) constituted more than 90% by number of items. The most frequent geometries were fibres, followed by granules and films. Plastic spherules occurred sparsely. Transparent and coloured plastics comprised the majority of the particles. This study provides clues in understanding the fate and potential sources of MPs. PMID- 25023439 TI - Biomechanical Comparison of Arthroscopic Single- and Double-Row Repair Techniques for Acute Bony Bankart Lesions. AB - BACKGROUND: Single- and double-row arthroscopic reconstruction techniques for acute bony Bankart lesions have been described in the literature. HYPOTHESIS: The double-row fixation technique would provide superior reduction and stability of a simulated bony Bankart lesion at time zero in a cadaveric model compared with the single-row technique. STUDY DESIGN: Controlled laboratory study. METHODS: Testing was performed on 14 matched pairs of glenoids with simulated bony Bankart fractures with a defect width of 25% of the glenoid diameter. Half of the fractures were repaired with a double-row technique, while the contralateral glenoids were repaired with a single-row technique. The quality of fracture reduction was measured with a coordinate measuring machine. To determine the biomechanical stability of the repairs, specimens were preconditioned with 10 sinusoidal cycles between 5 and 25 N at 0.1 Hz and then pulled to failure in the anteromedial direction at a rate of 5 mm/min. Loads at 1 mm and 2 mm of fracture displacement were determined. RESULTS: The double-row technique required significantly higher forces to achieve fracture displacements of 1 mm (mean, 60.6 N; range, 39.0-93.3 N; P = .001) and 2 mm (mean, 94.4 N; range, 43.4-151.2 N; P = .004) than the single-row technique (1 mm: mean, 30.2 N; range, 14.0-54.1 N and 2 mm: mean, 63.7 N; range, 26.6-118.8 N). Significantly reduced fracture displacement was seen after double-row repair for both the unloaded condition (mean, 1.1 mm; range, 0.3-2.4 mm; P = .005) and in response to a 10-N anterior force applied to the defect (mean, 1.6 mm; range, 0.5-2.7 mm; P = .001) compared with single-row repair (unloaded: mean, 2.1 mm; range, 1.3-3.4 mm and loaded: mean, 3.4 mm; range, 1.9-4.7 mm). CONCLUSION: The double-row fixation technique resulted in improved fracture reduction and superior stability at time zero in this cadaveric model. CLINICAL RELEVANCE: This information may influence the surgical technique used to treat large osseous Bankart fractures and the postoperative rehabilitation protocols implemented when such repair techniques are used. PMID- 25023440 TI - Meniscal repair with concurrent anterior cruciate ligament reconstruction: operative success and patient outcomes at 6-year follow-up. AB - BACKGROUND: Meniscal repair is commonly performed concurrently with anterior cruciate ligament reconstruction (ACLR) in the acutely injured knee. No large scale, prospective multicenter studies have evaluated the long-term success and patient-oriented outcomes after combined ACLR and meniscal repair. PURPOSE: To define the operative success and patient-oriented outcome scores 6 years after combined meniscal repair and ACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All ipsilateral primary ACLR and meniscal repair cases from a multicenter study group between 2002 and 2004 were selected. Validated patient oriented outcome instruments were completed at 3 time points: preoperatively and then 2 and 6 years after the index procedure. Subsequent ipsilateral knee reoperations were confirmed by operative reports to evaluate for the failure of meniscal repairs. RESULTS: In total, 286 patients with 1440 primary ACLRs underwent concurrent meniscal repairs (298 meniscal repairs). Of these, 235 (82.2%) were available for follow-up at 6 years (154 medial, 72 lateral, and 9 both lateral and medial meniscal repairs). Repaired menisci most commonly involved the peripheral one third of the meniscus (84%); patterns were typically longitudinal (84%) or displaced bucket-handle (10%), with a mean length of 16.5 +/- 5.8 mm. Overall, the meniscal repair failure rate was 14% (medial: 21/154; lateral: 10/72; both: 2/9) at 6 years. Medial repairs failed earlier than lateral repairs (2.1 vs 3.7 years, respectively; P = .01). Significant improvements in outcome scores were sustained at 6-year follow-up. No differences in the suture number or type were detected between repair failures and successes. The rate of meniscal reoperations was higher in patients who underwent repair compared with those who did not have an identified meniscal injury at the time of ACLR (P < .01. CONCLUSION: Concurrent meniscal repair with ACLR is associated with failure rates approximating 14% at 6-year follow-up. Improvements in patient-oriented outcome scores were sustained at 6-year follow-up. Surgeons may expect good clinical outcomes 6 years after combined ACLR and meniscal repair. PMID- 25023441 TI - Three-dimensional analysis of bone tunnel changes after anatomic double-bundle anterior cruciate ligament reconstruction using multidetector-row computed tomography. AB - BACKGROUND: The femoral and tibial bone tunnel enlargement after anatomic double bundle anterior cruciate ligament reconstruction (ACL-R) has not been fully documented. PURPOSE: To evaluate the region-specific bone tunnel volume changes and those transpositions using 3-dimensional multidetector-row computed tomography (MDCT) after anatomic double-bundle ACL-R. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eleven patients who underwent unilateral double bundle ACL-R with hamstring tendon autografts were included in this study. MDCT scanning of their knees was performed at 3 weeks and 1 year after surgery. The bone tunnel regions were extracted from the MDCT images, and the longitudinal axis of each bone tunnel was divided into 3 equal sections. The centroids of the outside and the articular thirds were then extracted from the bone tunnel position. Changes in the bone tunnel volume and the transposition of the articular third were calculated and compared. RESULTS: At 1 year postoperatively, as compared with the 3-week postoperative value (set at 100%), the femoral bone tunnel volume of the anteromedial bundle (AMB) and posterolateral bundle (PLB) changed to 77.4% +/- 15.3% and 102.3% +/- 19.2% in the outside third and 122.3% +/- 31.8% and 112.5% +/- 34.4% in the articular third, respectively. The tibial bone tunnel volume of the AMB and the PLB changed to 108.6% +/- 28.7% and 105.4% +/- 22.6% in the tibial articular third and 54.9% +/- 25.8% and 52.5% +/- 26.9% in the outside third, respectively. The femoral outside third of the AMB and the tibial outside third of both the AMB and PLB were significantly reduced in bone tunnel volume. The centroid of the femoral articular third of the AMB moved 13 degrees , 1.1 +/- 0.6 mm posterodistally, and that of the PLB moved 35 degrees , 0.8 +/- 0.4 mm anterodistally. Furthermore, the centroid of the tibial articular third of the AMB moved 14 degrees , 2.0 +/- 1.6 mm posterolaterally, and that of the PLB moved 72 degrees , 1.0 +/- 1.3 mm posterolaterally. CONCLUSION: Compared with 3 weeks postoperatively, the articular side outlets of the femoral and tibial bone tunnels at 1 year postoperatively had enlarged slightly but statistically maintained their volume, and they had moved a little in the direction that the grafts were pulled. PMID- 25023442 TI - Aortic valve reimplantation for aortic root aneurysms: trainer and trainee differences on long-term results. AB - PURPOSE: The advantages of aortic valve-preserving surgery are still hampered by a higher rate of reoperations compared to root replacement with valved conduits. This study evaluates whether valve deterioration rate is related to the method or depends on stringent adherence to technical concepts, which might be lost once trainees perform this complex surgery on their own. METHODS: From 1991 to 2011, the David procedure was performed in 209 consecutive patients. Mean age was 57 +/ 14 years. The patients were operated either by the senior author or trainees under his supervision (group 1, n = 130) or by surgeons on their own after training by the senior author (group 2, n = 79). Clinical and echocardiography data were evaluated pre- and postoperatively and at follow-up (mean 6.0 +/- 4 years). RESULTS: In-hospital mortality was 1.5 % in group 1 and 5 % in group 2 (p = 0.29), and late mortality was 12 % (n = 12 in group 1 and n = 14 in group 2, p = 0.11), three were cardiac related. Nine patients (4.3 %) had to be reoperated; three for endocarditis in group 1, six for structural valve deterioration in group 2 (p = 0.14). The 9-year freedom from reoperation or aortic valve insufficiency (AI) >=2 degrees was 93 % in group 1 and 78 % in group 2 (p < 0.01). As groups showed differences in preoperative variables, results were compared also in a propensity matched subgroup. Despite no difference in perioperative results, long-term valve competence remained inferior in group 2. CONCLUSIONS: With stringent adherence to technical concepts, structural valve deterioration may virtually be considerably reduced in aortic valve reimplantation. Once performing this operation on their own, trainees-after training by the senior-achieved results as independent surgeons well comparable to published series. As long-term performance seems to depend more on judgment of the geometry achieved intraoperatively than on technical steps, a means of measurement of effective coaptation height with a caliper might facilitate evaluation of perfect repair. PMID- 25023444 TI - Bovine complex milk lipid containing gangliosides for prevention of rotavirus infection and diarrhoea in northern Indian infants. AB - Rotavirus (RV) is a leading cause of morbidity and mortality in children younger than 5 years of age, presenting commonly with diarrhoeal symptoms. In a prospective 12-week double-blind randomised controlled trial we assessed acceptability and efficacy of a high-ganglioside complex milk lipid (CML) for prevention of RV infection in 450 infants, ages 8 to 24 months, at 3 sites in northern India. Prevalence of diarrhoea and RV was unseasonably low at baseline (all-cause diarrhoea [ACD], n = 16; RV diarrhoea [RVD], n = 2; RV infection, RV positive [RV+], n = 20) and throughout the trial, with only 110 total episodes of ACD for 12 weeks (CML, n = 62; control, n = 48) of which 10 were RVD (CML, n = 4; control, n = 6). Mean duration that RVD persisted was lower in the CML group (2.3 +/- 0.5 days) than that in the control group (3.8 +/- 1.3 days, P = 0.03), but only 3 of 450 end of trial stool samples were identified as RV+ (<1%; CML, n = 2; control, n = 1). This hampered the assessment of efficacy of CML, despite the large a priori determined sample size. During the trial similar numbers of infants reported adverse events (AEs: CML 41%, control 46%), with the majority of events classified as mild and not related to the intervention. In conclusion, further clinical trials against a higher background of seasonal prevalence are necessary to assess efficacy of this nutritional intervention to prevent RVD. More important, however, high-ganglioside CML was acceptable for long-term consumption in infants ages 8 to 24 months. PMID- 25023443 TI - Substrate-bound outward-open state of the betaine transporter BetP provides insights into Na+ coupling. AB - The Na(+)-coupled betaine symporter BetP shares a highly conserved fold with other sequence unrelated secondary transporters, for example, with neurotransmitter symporters. Recently, we obtained atomic structures of BetP in distinct conformational states, which elucidated parts of its alternating-access mechanism. Here, we report a structure of BetP in a new outward-open state in complex with an anomalous scattering substrate, adding a fundamental piece to an unprecedented set of structural snapshots for a secondary transporter. In combination with molecular dynamics simulations these structural data highlight important features of the sequential formation of the substrate and sodium binding sites, in which coordinating water molecules play a crucial role. We observe a strictly interdependent binding of betaine and sodium ions during the coupling process. All three sites undergo progressive reshaping and dehydration during the alternating-access cycle, with the most optimal coordination of all substrates found in the closed state. PMID- 25023445 TI - [Usefulness of a multidimensional self-administered questionnaire for the clinical management of a pain treatment unit]. AB - OBJECTIVE: To study the feasibility of a multidimensional self-administered questionnaire before the patient is seen at the first visit in a clinical Pain Treatment Unit (PTU) of a tertiary hospital, and its impact on the management of patients in the first visit. PATIENTS AND METHODS: Cross-sectional study. Self administered questionnaire that gathered: socio-demographic data, medical history of pain, pain perception (intensity and characteristics), comorbidity of pain and patient expectations of analgesic treatment ("What do you expect from our treatment? If we cannot resolve your pain, what level of pain would you be willing to live with?). A descriptive analysis was performed. RESULTS: A total of 293 consecutive patients (31% men, 69% women), mean age (SD) 62 (16) years-old, were included in 2011. All patients completed and returned the questionnaire before the first visit to the PTU. The questionnaire was completed fully and correctly by 80% (234, 95% CI: 75-84) of the patients, and the rest completed the questionnaire with some points unanswered. About 24% (70/293, 95% CI: 19-29) of the patients should not have been referred to the PTU [20% were not attended]. A small percentage (9%,26/293, 95% CI: 6-13) were evaluated as "urgent'" and visited over the following 7 days, with 19% (56/293, 95%CI: 15-24) being "preferential" (visited before 15 days) and 52% (152/293, 95% CI: 46-58) as "non urgent/non-preferential" (visited before 60 days). Almost one third (30%, 87/293, 95% CI: 25-35) did not need a second visit to the PTU. Patient expectations: 21% expected complete pain relief and 64% would accept a lower pain intensity score of 4. CONCLUSION: The use of a multidimensional self-administered questionnaire before the first visit to a clinical Pain Treatment Unit of a tertiary hospital was a practicable and useful tool for the management of patients on the first visit. Likewise, the questionnaire provided information on the patient's perception of pain and the expectations concerning the analgesic treatment. PMID- 25023446 TI - Smad2 overexpression reduces the proliferation of the junctional epithelium. AB - The overexpression of the intracellular signaling molecule of the transforming growth factor-beta family (TGF-beta) Smad2 was found to induce apoptosis and inhibit the proliferation rate of oral epithelial cells. Therefore, the aim of this study was to investigate in vivo the effect of Smad2 overexpression on the proliferation rate of the junctional epithelium (JE). Smad2 overexpression was driven by the cytokeratin 14 promoter (K14-Smad2) in transgenic mice. The K14 Smad2 mice were compared with wild-type (WT) mice selected as the control group. Samples were stained with hematoxylin and eosin stains and analyzed by image analysis. Immunohistochemistry was conducted for proliferating cell nuclear antigen (PCNA) and c-Myc as markers of cell proliferation. The expression of cyclin-dependent kinase inhibitors (P15, P21, and P27) was determined by real time polymerase chain-reaction (RT-PCR). The quantity of phosphorylated retinoblastoma (pRB) was determined with Western blots. The overexpression of Smad2 altered the area of the junctional epithelial cells in one-year-old K14 Smad2 mice. The area was 32,768 (+/- 3,473) MUm(2) for the WT and 24,937.25 (+/- 1,965) MUm(2) for the K14-Smad2 mice. There was a significant difference in the proliferation rates of the JE (PCNA-positive cells) between the WT and K14-Smad2 mice, 20.7% (+/- 1.1) and 2.1% (+/- 0.5), respectively. A significant difference in c-Myc expression occurred between experimental and control samples. The K14 Smad2 mice had a mean of 2.3% (+/- 0.6), and the WT mice had a mean of 20.1% (+/- 3.6). Smad2 overexpression up-regulated the mRNA expression of P15 by 2.3-fold and that of P27 by 5.5-fold in the K14-Smad2 mice. Finally, the pRB protein showed a 2.3 (+/- 0.5)-fold increase in K14-Smad2 mice when compared with WT mice. Smad2 overexpression inhibits the proliferation of JE cells by down regulating c-Myc and up-regulating P15 and P27, which resulted in an increase in pRB, leading to cell-cycle arrest. PMID- 25023447 TI - Dietary L-glutamine supplementation modulates microbial community and activates innate immunity in the mouse intestine. AB - This study was conducted to determine effects of dietary supplementation with 1 % L-glutamine for 14 days on the abundance of intestinal bacteria and the activation of intestinal innate immunity in mice. The measured variables included (1) the abundance of Bacteroidetes, Firmicutes, Lactobacillus, Streptococcus and Bifidobacterium in the lumen of the small intestine; (2) the expression of toll like receptors (TLRs), pro-inflammatory cytokines, and antibacterial substances secreted by Paneth cells and goblet cells in the jejunum, ileum and colon; and (3) the activation of TLR4-nuclear factor kappa B (NF-kappaB), mitogen-activated protein kinases (MAPK), and phosphoinositide-3-kinases (PI3K)/PI3K-protein kinase B (Akt) signaling pathways in the jejunum and ileum. In the jejunum, glutamine supplementation decreased the abundance of Firmicutes, while increased mRNA levels for antibacterial substances in association with the activation of NF kappaB and PI3K-Akt pathways. In the ileum, glutamine supplementation induced a shift in the Firmicutes:Bacteroidetes ratio in favor of Bacteroidetes, and enhanced mRNA levels for Tlr4, pro-inflammatory cytokines, and antibacterial substances participating in NF-kappaB and JNK signaling pathways. These results indicate that the effects of glutamine on the intestine vary with its segments and compartments. Collectively, dietary glutamine supplementation of mice beneficially alters intestinal bacterial community and activates the innate immunity in the small intestine through NF-kappaB, MAPK and PI3K-Akt signaling pathways. PMID- 25023448 TI - Mucosal healing in Crohn's disease - are we reaching as far as possible with capsule endoscopy? PMID- 25023449 TI - Using surveillance and monitoring data of different origins in a Salmonella source attribution model: a European Union example with challenges and proposed solutions. AB - Microbial subtyping approaches are commonly used for source attribution of human salmonellosis. Such methods require data on Salmonella in animals and humans, outbreaks, infection abroad and amounts of food available for consumption. A source attribution model was applied to 24 European countries, requiring special data management to produce a standardized dataset. Salmonellosis data on animals and humans were obtained from datasets provided by the European Food Safety Authority. The amount of food available for consumption was calculated based on production and trade data. Limitations included different types of underreporting, non-participation in prevalence studies, and non-availability of trade data. Cases without travel information were assumed to be domestic; non subtyped human or animal records were re-identified according to proportions observed in reference datasets; missing trade information was estimated based on previous years. The resulting dataset included data on 24 serovars in humans, broilers, laying hens, pigs and turkeys in 24 countries. PMID- 25023450 TI - Concordance between decision analysis and matching systematic review of randomized controlled trials in assessment of treatment comparisons: a systematic review. AB - BACKGROUND: Systematic review (SR) of randomized controlled trials (RCT) is the gold standard for informing treatment choice. Decision analyses (DA) also play an important role in informing health care decisions. It is unknown how often the results of DA and matching SR of RCTs are in concordance. We assessed whether the results of DA are in concordance with SR of RCTs matched on patient population, intervention, control, and outcomes. METHODS: We searched PubMed up to 2008 for DAs comparing at least two interventions followed by matching SRs of RCTs. Data were extracted on patient population, intervention, control, and outcomes from DAs and matching SRs of RCTs. Data extraction from DAs was done by one reviewer and from SR of RCTs by two independent reviewers. RESULTS: We identified 28 DAs representing 37 comparisons for which we found matching SR of RCTs. Results of the DAs and SRs of RCTs were in concordance in 73% (27/37) of cases. The sensitivity analyses conducted in either DA or SR of RCTs did not impact the concordance. Use of single (4/37) versus multiple data source (33/37) in design of DA model was statistically significantly associated with concordance between DA and SR of RCTs. CONCLUSIONS: Our findings illustrate the high concordance of current DA models compared with SR of RCTs. It is shown previously that there is 50% concordance between DA and matching single RCT. Our study showing the concordance of 73% between DA and matching SR of RCTs underlines the importance of totality of evidence (i.e. SR of RCTs) in the design of DA models and in general medical decision-making. PMID- 25023451 TI - The source of consciousness. AB - Why does a relentless stream of experiences normally fill your mind? No answer is entirely satisfactory. We are not sure how the normal operation of the human brain might exude subjective experiences. Consciousness can thus seem miraculous, and research on consciousness a waste of time and money, ultimately doomed to fail. Yet, there are good reasons for optimism that should be shared with the public to justify research in this area. PMID- 25023452 TI - Experimental arthritis: Inflammasome-driven arthritis: a new model of RA? PMID- 25023453 TI - Connective tissue diseases: stem cell transplant prolongs systemic sclerosis survival. PMID- 25023454 TI - Osteoarthritis: Is OA a mechanical or systemic disease? PMID- 25023455 TI - Impact of tonsillectomy on health-related quality of life and healthcare costs in children and adolescents. AB - BACKGROUND: Tonsillectomy is a common surgical intervention in children, but its efficacy is under debate. We studied whether tonsillectomy is a cost-effective intervention with a positive impact on health-related quality of life (HRQoL). METHODS: Children (aged 7-11 years) and adolescents (aged 12-15 years) undergoing tonsillectomy answered the 17D or 16D HRQoL questionnaires before tonsillectomy and at 6 and 12 months postoperatively. At the same time-points, data on the use of healthcare services and school absenteeism were collected by questionnaire. RESULTS: Altogether 49 children and 42 adolescents returned all HRQoL questionnaires. Tonsillectomy improved the mean total HRQoL score clinically and statistically significantly in both children (from 0.935 at baseline to 0.958 at 12 months, p = 0.002) and adolescents (from 0.930 to 0.957, p = 0.004). The mean direct self-reported healthcare service costs diminished after tonsillectomy in both groups. The mean number of days on sick leave due to oropharyngeal problems during the preceding 3 months decreased from the preoperative 4.6 days to postoperative 0.5 days (p < 0.001) in children, and from 4.9 days to 0.8 days (p < 0.001) in adolescents at 12 months. CONCLUSIONS: Tonsillectomy improves HRQoL in both school-aged children and adolescents and reduces healthcare service needs and school absenteeism due to oropharyngeal symptoms. PMID- 25023456 TI - A high prevalence of abnormal nutrition parameters found in predialysis end-stage kidney disease: is it a result of uremia or poor eating habits? AB - OBJECTIVE: To describe the baseline nutritional characteristics of a cohort of end-stage kidney disease (ESKD) patients attending a pre-dialysis clinic. SETTING: Outpatient clinic of a metropolitan tertiary teaching hospital in Sydney, Australia. SUBJECTS: All ESKD patients attending the multidisciplinary pre-dialysis assessment clinic between April 2002 and March 2008. METHODS: Retrospective analysis of data extracted from the routine initial nutrition assessment records. These included anthropometric and biochemical measures, Subjective Global Assessment, appetite score, presence of symptoms, dietary energy, protein, and other macro- and micronutrient intakes. RESULTS: Of the 210 patients assessed, 60.5% were male; mean age was 65.7 +/- 13.6 years with a mean glomerular filtration rate of 17.3 +/- 6.5 mL/min/1.73 m(2); 17.1% and 62.4% were underweight (body mass index <23 kg/m(2)) and overweight or obese (BMI >=26 kg/m(2)), respectively; 40.5% were rated as malnourished (Subjective Global Assessment scores B and C) with 19.0% overweight/obese and malnourished. Energy and protein intakes correlated positively with glomerular filtration rate, with r = 0.17, P = .01, and r = 0.29, P < .0001 respectively. Mean energy and protein intakes were 23.7 +/- 6.7 kcal/kg IBW/day and 1.18 +/- 0.42 g/kg IBW/day, with 62.6% and 13.1% not meeting the recommended intake, respectively. The positive predictive values (95%CI) of self-rated appetite score for energy and protein were 0.41 (0.36-0.45) and 0.92 (0.88-0.95), respectively, indicating subjective rating of a good appetite was associated with adequate protein but not energy intake. Fifty-one percent of the patients experienced the symptoms, whereas 17.5% of the patients self-imposed a dietary regimen inappropriately due to beliefs on dietary needs in ESKD. Suboptimal nutrient intakes were observed, including vitamin B2 (41.2%), vitamin E (61.8%), folate (67.6.2%), vitamin D (100.0%), and zinc (64.2%). CONCLUSION: Patients presented to the pre-dialysis assessment clinic with abnormal nutrition parameters associated with decreased renal function, symptoms burden, and poor dietary intake. This clinic may provide an opportunity to optimize the nutritional status of ESKD patients in the pre dialysis period. PMID- 25023457 TI - Associations among epoetin therapy, inflammation, nutritional status, and mortality in patients on hemodialysis. AB - OBJECTIVE: Inflammation contributes to hemopoiesis by lowering responses to epoetin (EPO) and to an increase in the mortality of patients on hemodialysis. However, nutritional status might alter associations among inflammation, EPO responsiveness, and the risk of mortality. We assessed the effect of inflammation on mortality according to nutritional status among EPO responses in a cohort of prevalent hemodialysis patients. DESIGN AND METHODS: The observational cohort study analyzed data from the Japanese Dialysis Registry (2005-2006; n = 36,956; mean follow-up 11.5 months). Patients were categorized into tertiles of the EPO responsiveness index (ERI; the weekly weight-adjusted EPO dose [IU/kg/week] divided by hemoglobin [g/dL]) and an EPO-free group. Body mass index (BMI) and C reactive protein (CRP) levels were measured. RESULTS: Bimodal peaks indicated associations between CRP and BMI in each group. Hazard ratio (HR) curves of CRP for mortality according to BMI in the upper ERI tertile, particularly among those with diabetes mellitus (DM), were reverse J-shaped. However, HR curves in the other groups were increased below a threshold BMI of 21 kg/m(2). These associations were confirmed in propensity score-matched populations. CONCLUSION: Risk of CRP for death is apparently changed by BMI in hemodialysis patients with a lower EPO response, especially in those with DM. PMID- 25023458 TI - Treatment of Alzheimer disease using combination therapy with plasma exchange and haemapheresis with albumin and intravenous immunoglobulin: Rationale and treatment approach of the AMBAR (Alzheimer Management By Albumin Replacement) study. AB - INTRODUCTION: There is a growing interest in new therapeutic strategies for the treatment of Alzheimer disease (AD) which focus on reducing the beta-amyloid peptide (Abeta) burden in the brain by sequestering plasma Abeta, a large proportion of which is bound to albumin and other proteins. This review discusses the concepts of interaction between Abeta and albumin that have given rise to AMBAR (Alzheimer's Disease Management by Albumin Replacement) project, a new multicentre, randomised, controlled clinical trial for the treatment of AD. DEVELOPMENT: Results from preliminary research suggest that Albutein((r)) (therapeutic albumin, Grifols) contains no quantifiable levels of Abeta. Studies also show that Albutein((r)) has Abeta binding capacity. On the other hand, AD entails a high level of nitro-oxidative stress associated with fibrillar aggregates of Abeta that can induce albumin modification, thus affecting its biological functions. Results from the phase ii study confirm that using therapeutic apheresis to replace endogenous albumin with Albutein((r)) 5% is feasible and safe in patients with AD. This process resulted in mobilisation of Abeta and cognitive improvement in treated patients. The AMBAR study will test combination therapy with therapeutic apheresis and haemopheresis with the possible leverage effect of Albutein((r)) with intravenous immunoglobulin replacement (Flebogamma((r)) DIF). Cognitive, functional, and behavioural changes in patients with mild to moderate AD will be assessed. CONCLUSIONS: the AMBAR study represents a new therapeutic perspective for AD. PMID- 25023459 TI - Memory improves precision of cell sensing in fluctuating environments. AB - Biological cells are often found to sense their chemical environment near the single-molecule detection limit. Surprisingly, this precision is higher than simple estimates of the fundamental physical limit, hinting towards active sensing strategies. In this work, we analyse the effect of cell memory, e.g. from slow biochemical processes, on the precision of sensing by cell-surface receptors. We derive analytical formulas, which show that memory significantly improves sensing in weakly fluctuating environments. However, surprisingly when memory is adjusted dynamically, the precision is always improved, even in strongly fluctuating environments. In support of this prediction we quantify the directional biases in chemotactic Dictyostelium discoideum cells in a flow chamber with alternating chemical gradients. The strong similarities between cell sensing and control engineering suggest universal problem-solving strategies of living matter. PMID- 25023460 TI - siRNA: novel therapeutics from functional genomics. AB - Long-term research on RNA interference led to an unfathomed understanding of the mechanism of siRNA-mediated silencing and finally siRNA has emerged as a powerful therapeutic tool. With siRNAs virtually every gene in the human genome contributing to a disease becomes amenable to regulation, thus opening unprecedented opportunities for drug discovery. siRNA has a well-established role as a tool for in vitro target screening and validation, besides these recent progresses of siRNA delivery in vivo, this has raised more expectations for siRNA based drugs as the up-and-coming 'magic bullet'. Although a plethora of articles have been published with siRNA, the fundamentals of siRNA-mediated gene silencing and transforming the functional genomics to novel therapeutics are reviewed in this article with consideration to present hurdles as a new generation challenge. PMID- 25023461 TI - Does nature make provision for backups in the modification of bacterial community structures? AB - Self-balancing is an inherent character in nature in response to community structure modification pressure and modern biotechnology has revolutionized the way such detections are made. Presented here is an overview of the forces and process interactions between released bacteria and indigenous microflora which encompass soil bacterial diversity, community structure, indigenous endorhizosphere micro-organisms, molecular detection methodologies, and transgenic plants and microbes. Issues of soil bacterial diversity and community structure as well as the interpretation of results from various findings are highlighted and discussed as inferred from research articles. An understanding of the factors influencing bio-inoculant modification of bacterial community structure in the colonization of the rhizosphere is essential for improved establishment of biocontrol agents, and is critically reviewed. PMID- 25023462 TI - From molecular evolution to biobricks and synthetic modules: a lesson by the bacterial flagellum. AB - The bacterial flagellum is a motility structure and represents one of the most sophisticated nanomachines in the biosphere. Here, we review the current knowledge on the flagellum, its architecture with respect to differences between Gram-negative and Gram-positive bacteria and other species-specific variations (e.g. the flagellar filament protein, Flagellin). We further focus on the mechanism by which the two nucleotide-binding proteins FlhF and FlhG ensure the correct reproduction of flagella place and number (the flagellation pattern). We will finish the review with an overview of current biotechnological applications, and a perspective of how understanding flagella can contribute to developing modules for synthetic approaches. PMID- 25023463 TI - Advances and applications of molecular cloning in clinical microbiology. AB - Molecular cloning is based on isolation of a DNA sequence of interest to obtain multiple copies of it in vitro. Application of this technique has become an increasingly important tool in clinical microbiology due to its simplicity, cost effectiveness, rapidity, and reliability. This review entails the recent advances in molecular cloning and its application in the clinical microbiology in the context of polymicrobial infections, recombinant antigens, recombinant vaccines, diagnostic probes, antimicrobial peptides, and recombinant cytokines. Culture based methods in polymicrobial infection have many limitation, which has been overcome by cloning techniques and provide gold standard technique. Recombinant antigens produced by cloning technique are now being used for screening of HIV, HCV, HBV, CMV, Treponema pallidum, and other clinical infectious agents. Recombinant vaccines for hepatitis B, cholera, influenza A, and other diseases also use recombinant antigens which have replaced the use of live vaccines and thus reduce the risk for adverse effects. Gene probes developed by gene cloning have many applications including in early diagnosis of hereditary diseases, forensic investigations, and routine diagnosis. Industrial application of this technology produces new antibiotics in the form of antimicrobial peptides and recombinant cytokines that can be used as therapeutic agents. PMID- 25023464 TI - Advances in the use of nanoscale bilayers to study membrane protein structure and function. AB - Within the last decade, nanoscale lipid bilayers have emerged as powerful experimental systems in the analysis of membrane proteins (MPs) for both basic and applied research. These discoidal lipid lamellae are stabilized by annuli of specially engineered amphipathic polypeptides (nanodiscs) or polymers (SMALPs/Lipodisqs(r)). As biomembrane mimetics, they are well suited for the reconstitution of MPs within a controlled lipid environment. Moreover, because they are water-soluble, they are amenable to solution-based biochemical and biophysical experimentation. Hence, due to their solubility, size, stability, and monodispersity, nanoscale lipid bilayers offer technical advantages over more traditional MP analytic approaches such as detergent solubilization and reconstitution into lipid vesicles. In this article, we review some of the most recent advances in the synthesis of polypeptide- and polymer-bound nanoscale lipid bilayers and their application in the study of MP structure and function. PMID- 25023466 TI - PACAP-induced migraine: a possible CNS effect? PMID- 25023467 TI - DNA damage and innate immunity: links and trade-offs. AB - To counteract DNA damage, cells employ genome maintenance pathways that are directed inward, relentlessly to scan and repair the genome. Adaptive and innate immune mechanisms are often directed outward, protecting self against pathogens. Recent work has revealed direct links between innate immune signaling and the DNA damage response (DDR). Here we review current understanding of the mechanism by which cells sense damaged and foreign DNA. We examine the functional role of DNA damage signaling in immune activation and discuss the relevance of these processes to DNA damage-driven chronic inflammation in disease and in aging. PMID- 25023468 TI - Assessing trainee surgeons' nontechnical skills: five cases are sufficient for reliable assessments. AB - BACKGROUND: Trainee surgeons would benefit from regular, formative assessments to ensure they learn the nontechnical aspects of surgical performance. Non-Technical Skills for Surgeons in Denmark (NOTSSdk) is a tool to assess surgeons' nontechnical skills (NTS) during an operation. The aims of this study were to explore which parts of NOTSSdk supervisors use to assess trainee surgeons' NTS, to determine the internal consistency reliability of NOTSSdk, and to estimate how many operations were needed to obtain reliable ratings of a trainee surgeon's NTS. METHODS: A total of 12 supervisors from 2 hospitals assessed 13 trainees in 48 procedures including laparoscopic cholecystectomies, inguinal hernia repairs, and laparoscopic appendectomies. RESULTS: NOTSSdk showed good internal consistency reliability (R(2) = 0.95). Supervisors used both categories and elements of the tool to provide assessments, although 2 elements of leadership ("supporting others" and "coping with pressure") were considered irrelevant in 27% to 31% of the cases. Assessments of 5 procedures were sufficient to gain reliable ratings (Generalizability coefficient > 0.80) of a trainee surgeon's NTS. CONCLUSION: As supervisors used the full tool, the internal consistency reliability was high and assessment of 5 procedures could be achieved in clinical practice, we suggest that NOTSSdk could be implemented as a formative assessment tool to facilitate the training of surgeons' NTS. PMID- 25023465 TI - Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors. AB - BACKGROUND: Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public genome-wide expression datasets, provide an opportunity to reassess neuroendocrine tumors at a more fundamental level. We hypothesized that stringent analysis of expression profiles as well as regulatory networks of the neoplastic cell would provide novel information that facilitates further delineation of the genomic basis of small intestinal neuroendocrine tumors. RESULTS: We re-analyzed two publically available small intestinal tumor transcriptomes using stringent quality control parameters and network-based approaches and validated expression of core secretory regulatory elements e.g., CPE, PCSK1, secretogranins, including genes involved in depolarization e.g., SCN3A, as well as transcription factors associated with neurodevelopment (NKX2-2, NeuroD1, INSM1) and glucose homeostasis (APLP1). The candidate metastasis associated transcription factor, ST18, was highly expressed (>14-fold, p < 0.004). Genes previously associated with neoplasia, CEBPA and SDHD, were decreased in expression (-1.5 - -2, p < 0.02). Genomic interrogation indicated that intestinal tumors may consist of two different subtypes, serotonin-producing neoplasms and serotonin/substance P/tachykinin lesions. QPCR validation in an independent dataset (n = 13 neuroendocrine tumors), confirmed up-regulated expression of 87% of genes (13/15). CONCLUSIONS: An integrated cellular transcriptomic analysis of small intestinal neuroendocrine tumors identified that they are regulated at a developmental level, have key activation of hypoxic pathways (a known regulator of malignant stem cell phenotypes) as well as activation of genes involved in apoptosis and proliferation. Further refinement of these analyses by RNAseq studies of large-scale databases will enable definition of individual master regulators and facilitate the development of novel tissue and blood-based tools to better understand diagnose and treat tumors. PMID- 25023469 TI - Stem cells, megakaryocytes, and platelets. AB - PURPOSE OF REVIEW: Stem cells are an important tool for the study of ex-vivo models of megakaryopoiesis and the production of functional platelets. In this manuscript, we review the optimization of megakaryocyte and platelet differentiation and discuss the mechanistic studies and disease models that have incorporated stem cell technologies. RECENT FINDINGS: Mechanisms of cytoskeletal regulation and signal transduction have revealed insights into hierarchical dynamics of hematopoiesis, highlighting the close relationship between hematopoietic stem cells and cells of the megakaryocyte lineage. Platelet disorders have been successfully modeled and genetically corrected, and differentiation strategies have been optimized to the extent that utilizing stem cell-derived platelets for cellular therapy is feasible. SUMMARY: Studies that utilize stem cells for the efficient derivation of megakaryocytes and platelets have played a role in uncovering novel molecular mechanisms of megakaryopoiesis, modeling and correcting relevant diseases, and differentiating platelets that are functional and scalable for translation into the clinic. Efforts to derive megakaryocytes and platelets from pluripotent stem cells foster the opportunity of a revolutionary cellular therapy for the treatment of multiple platelet associated diseases. PMID- 25023470 TI - Recent advances in the antiphospholipid antibody syndrome. AB - PURPOSE OF REVIEW: The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent thrombosis and/or obstetrical morbidity in the presence of persistently positive antiphospholipid antibodies. Recent insights into the pathogenesis of APS have begun to elucidate pathophysiology and led to the identification of potential therapeutic interventions. The objective of this review is to examine the advances in this field and highlight the areas of further investigation. RECENT FINDINGS: Several mechanisms of thrombosis and pregnancy loss in APS have been proposed. These include activation of endothelial cells, monocytes, and platelets, and/or inhibition of natural anticoagulant and fibrinolytic systems by antiphospholipid antibodies. However, in many cases the underlying molecular mechanisms and their relevance to the human disorder remain uncertain. New therapeutic agents such as statins, hydroxychloroquine, rituximab, complement inhibitors, and interventions aimed at disruption of intracellular signaling pathways have shown promise in preclinical and clinical studies. SUMMARY: Indefinite anticoagulation remains the mainstay of treatment for thrombotic APS. Despite advances in diagnostic techniques, it remains difficult to predict thrombotic risk in asymptomatic patients with antiphospholipid antibodies. Further mechanistic and clinical studies are needed to predict thrombotic risk and develop improved therapies for this devastating illness. PMID- 25023472 TI - Physical-, chemical-, and microbiological-based identification of electron beam- and gamma-irradiated frozen crushed garlic. AB - Identification of frozen crushed garlic, commercially available in the Korean market, was performed using four different analytical techniques (three screening and one confirmation). The garlic samples produced in Korea and China were irradiated (electron-beam and gamma-rays) at 0, 1, 4, and 7 kGy. Non-irradiated samples showed a relatively moderate population of aerobic bacteria and yeasts/molds around 10(5) CFU/g. Irradiation treatments unequivocally reduced the microbial/fungal populations with dose increments. Microbiological screening through direct epifluorescent filter technique/aerobic plate count (DEFT/APC) method effectively differentiated the non-irradiated and irradiated samples. An electronic nose method positively differentiated the odor patterns of samples based on chemical sensing. However, photostimulated luminescence technique (PSL) exhibited poor sensitivity. Minerals separated from irradiated samples produced thermoluminescence (TL) glow curves in the specific temperature range of 150-250 degrees C. In conclusion, TL confirmatory analysis gave the most promising results in detecting the irradiation status of garlic samples irrespective of the production origin and type of ionizing radiation treatment. PMID- 25023471 TI - Shaping the platelet response to vascular injury. AB - PURPOSE OF REVIEW: Several decades of work by many investigators have elucidated the major signaling pathways responsible for platelet activation. Still to be fully understood is how these pathways are integrated into a single network and how changing conditions within a growing thrombus affect that network. In this review we will consider some of the recent studies that address these issues and describe a model that provides insights into platelet activation as it occurs in vivo. RECENT FINDINGS: Genetic and pharmacologic studies performed in vivo have demonstrated that platelet activation during hemostasis and thrombosis is heterogeneous. Those studies indicate that distinct platelet activation pathways are not merely redundant, but are coordinated in time and space to achieve an optimal response. This coordination is achieved at least in part by the evolving distribution of platelet agonists and changes in solute transport within a hemostatic plug. SUMMARY: Studies examining the coordination of platelet signaling in time and space continue to increase our understanding of hemostasis and thrombosis. In addition to helping to decipher platelet biology, the results have implications for the understanding of new and existing antiplatelet agents and their potential risks. PMID- 25023474 TI - Sexually transmitted infections: progress and challenges since the 1994 International Conference on Population and Development (ICPD). AB - BACKGROUND: Despite being recognized as an important challenge at the 1994 International Conference on Population and Development (ICPD), sexually transmitted infections (STIs) other than HIV are one of the most neglected dimensions of sexual and reproductive health. STIs, often undiagnosed and untreated, have especially harmful consequences for women and their neonates. PROGRESS SINCE ICPD: During the last two decades, substantial knowledge and experience have accumulated in behavior change programming during the global response to the HIV epidemic which can also be used for prevention of STIs. There has been progress in development and implementation of vaccines against certain STIs such as hepatitis B and the human papilloma virus. Development of a rapid, point-of-care test for syphilis has opened the door to control this infection. CHALLENGES: The estimated annual incidence of non-HIV STIs has increased by nearly 50% during the period 1995-2008. The growth in STIs has been aggrevated by a combination of factors: lack of accurate, inexpensive diagnostic tests, particularly for chlamydia and gonorrhea; lack of investment to strengthen health systems that can deliver services for diagnosis and management of STIs; absence of surveillance and reporting systems in the majority of countries; political, socioeconomic and cultural barriers that limit recognition of STIs as an important public health problem; and failure to implement policies that are known to work. RECOMMENDATIONS: Governments, donors and the international community should give higher priority to preventing STIs and HIV; fully implementing behavior change interventions that are known to work; ensuring access of young people to information and services; investing in development of inexpensive technologies for STI diagnosis,treatment and vaccines; and strengthening STI surveillance, including of microbial resistance. PMID- 25023475 TI - Featured research at the 2014 North American Forum on Family Planning. PMID- 25023476 TI - Photo Quiz. Recurrent breast abscess in a 33-year-old woman. PMID- 25023473 TI - Dual method use at last sexual encounter: a nationally representative, episode level analysis of US men and women. AB - OBJECTIVES: Male condom use in conjunction with other contraceptives increases protection against pregnancy and sexually transmitted infections. However, few analyses contextualize dual method use within the sexual episode, include reports from men or explore gendered patterns in reporting. STUDY DESIGN: We analyzed dual method use patterns using a nationally representative dataset of 18-44 years old in the US (N=404 men, 416 women). Respondents indicated contraceptive methods used at last penile-vaginal intercourse, condom practices and relationship and sexual information about that particular partner. RESULTS: More than one-in-three penile-vaginal intercourse episodes (40%) involved male condom use: 28% condom only and 12% condom plus a highly effective method. Dual method reporting did not differ significantly by gender. Among dual method users, only 59% reported condom use during the entire intercourse episode, while 35% began intercourse without one and 6% removed the condom during intercourse. A greater proportion of men than women reported incorrect use of condoms (49% versus 35%), though this difference was not statistically significant. Only 50% of dual method users reported condom use in all of their last 10 intercourse episodes. CONCLUSIONS: Many people classified as "dual users" in previous studies may not be using dual methods consistently or correctly. Researchers and practitioners should inquire how and how often condoms are used when assessing and addressing dual method use. Furthermore, though men have rarely been surveyed about dual method use, they can provide consistent contraceptive estimates and may be more likely to report condom practices such as late application or early removal. IMPLICATIONS STATEMENT: Many US women and men reporting dual method use also reported late application and early removal of condoms, as well as multiple condom-less prior sexual acts with that partner. Clinicians may wish to inquire how and how often clients use condoms; they may also wish to provide condom instruction and/or tips on better integrating condoms into the sexual experience with one's partner. PMID- 25023478 TI - Barriers, motivators and facilitators related to prenatal care utilization among inner-city women in Winnipeg, Canada: a case-control study. AB - BACKGROUND: The reasons why women do not obtain prenatal care even when it is available and accessible are complex. Despite Canada's universally funded health care system, use of prenatal care varies widely across neighborhoods in Winnipeg, Manitoba, with the highest rates of inadequate prenatal care found in eight inner city neighborhoods. The purpose of this study was to identify barriers, motivators and facilitators related to use of prenatal care among women living in these inner-city neighborhoods. METHODS: We conducted a case-control study with 202 cases (inadequate prenatal care) and 406 controls (adequate prenatal care), frequency matched 1:2 by neighborhood. Women were recruited during their postpartum hospital stay, and were interviewed using a structured questionnaire. Stratified analyses of barriers and motivators associated with inadequate prenatal care were conducted, and the Mantel-Haenszel common odds ratio (OR) was reported when the results were homogeneous across neighborhoods. Chi square analysis was used to test for differences in proportions of cases and controls reporting facilitators that would have helped them get more prenatal care. RESULTS: Of the 39 barriers assessed, 35 significantly increased the odds of inadequate prenatal care for inner-city women. Psychosocial issues that increased the likelihood of inadequate prenatal care included being under stress, having family problems, feeling depressed, "not thinking straight", and being worried that the baby would be apprehended by the child welfare agency. Structural barriers included not knowing where to get prenatal care, having a long wait to get an appointment, and having problems with child care or transportation. Attitudinal barriers included not planning or knowing about the pregnancy, thinking of having an abortion, and believing they did not need prenatal care. Of the 10 motivators assessed, four had a protective effect, such as the desire to learn how to protect one's health. Receiving incentives and getting help with transportation and child care would have facilitated women's attendance at prenatal care visits. CONCLUSIONS: Several psychosocial, attitudinal, economic and structural barriers increased the likelihood of inadequate prenatal care for women living in socioeconomically disadvantaged neighborhoods. Removing barriers to prenatal care and capitalizing on factors that motivate and facilitate women to seek prenatal care despite the challenges of their personal circumstances may help improve use of prenatal care by inner-city women. PMID- 25023479 TI - Heavy metals and polycyclic aromatic hydrocarbons in municipal sewage sludge from a river in highly urbanized metropolitan area in Hanoi, Vietnam: levels, accumulation pattern and assessment of land application. AB - Concentrations of heavy metals and polycyclic aromatic hydrocarbons (PAHs) in sludge from Kim Nguu River, Hanoi, Vietnam, were analyzed to understand the contamination levels, distribution and accumulation pattern of municipal sludge from a highly urbanized area that receive direct discharge of wastewater. High concentrations of heavy metals such as As, Cd, Pb, Cu and Zn were observed in sludge, which were exceeded the Vietnamese regulation threshold values. In general, contamination status of heavy metals in sludge was in the similar range or slightly lower than those previously reported in sludge from the same area. The mean concentrations of As, Cd, Cr, Cu, Ni, Pb and Zn were 24.3, 2.65, 105, 166, 60.8, 73.7 and 569 mg/kg dry wt., respectively. Our result also indicates increased levels of PAHs, which are among the first data on PAHs accumulation in municipal sludge from metropolitan area in Vietnam. PAH concentrations ranged from 218 to 751 mg/kg dry wt. (mean: 456 mg/kg dry wt.), which were greater than those reported in sewage sludge from other countries as well as in sediments and soils collected from the same area. Accumulation pattern revealed the predominant of higher-ringed PAH compounds. Indicator ratios suggest the sources of PAHs were probably derived from biomass (wood and coal) and fossil fuel combustion and petroleum emissions. Most of the sludge samples contain PAHs concentrations exceeding various international guidelines values for sludge and sediment, such as probable effect levels, suggesting the possible risk for adverse biological effects in the study area and in the landfill sites where dredged sludge was dumped. PMID- 25023480 TI - Victimization, social anxiety, and body dysmorphic concerns: appearance-based rejection sensitivity as a mediator. AB - Body dysmorphic disorder (BDD) is characterized by extreme preoccupation with perceived deficits in physical appearance, and sufferers experience severe impairment in functioning. Previous research has indicated that individuals with BDD are high in social anxiety, and often report being the victims of appearance based teasing. However, there is little research into the possible mechanisms that might explain these relationships. The current study examined appearance based rejection sensitivity as a mediator between perceived appearance-based victimization, social anxiety, and body dysmorphic symptoms in a sample of 237 Australian undergraduate psychology students. Appearance-based rejection sensitivity fully mediated the relationship between appearance-based victimization and body dysmorphic symptoms, and partially mediated the relationship between social anxiety and body dysmorphic symptoms. Findings suggest that individuals high in social anxiety or those who have a history of more appearance-based victimization may have a bias towards interpreting further appearance-based rejection, which may contribute to extreme appearance concerns such as BDD. PMID- 25023481 TI - Plant natural products: inspiring sources for drugs development. PMID- 25023482 TI - Prevalence of Candida albicans-closely related yeasts, Candida africana and Candida dubliniensis, in vulvovaginal candidiasis. AB - Isolates of Candida africana and C. dubliniensis were recovered from patients with vulvovaginal candidiasis (VVC). The isolates were initially identified as C. albicans through use of the API Candida System. We retrospectively reexamined 1014 vaginal isolates presumptively determined to be C. albicans at the Department of Obstetrics and Gynecology of Peking University Shenzhen Hospital from 1 January 2003 through 31 December 2012. Our objective was to determine, via detection of the HWP1 gene, if any of the isolates were C. africana or C. dubliniensis. One and a half percent of these isolates (15/1014) were found to be C. africana, whereas C. dubliniensis was not detected. The 15 C. africana isolates were susceptible to nystatin, fluconazole, itraconazole, miconazole, and clotrimazole. Candida africana could not be recovered from clinical vaginal specimens from the 15 patients at follow-up on days 7-14 and days 30-35 when treated with different antifungal agents. We conclude that C. africana, but not C. dubliniensis, was present in the vaginal samples of patients with VVC. The C. africana isolates were susceptible to the tested antifungal agents. VVC caused by C. africana appears to respond well to current therapies. PMID- 25023484 TI - Performance of MycAssay Aspergillus DNA real-time PCR assay compared with the galactomannan detection assay for the diagnosis of invasive aspergillosis from serum samples. AB - Invasive aspergillosis (IA) is a major problem in the immunocompromised population, and its diagnosis is difficult due to the low sensitivity of available tests. Detection of Aspergillus nucleic acid by polymerase chain reaction (PCR) in serum samples is a promising diagnostic tool; however, use of multiple "in-house" methods precludes standardization. The first commercial PCR assay, MycAssay Aspergillus (Myconostica, Ltd), became available recently, and its performance in the diagnosis of IA was evaluated and compared with the galactomannan (GM) assay. Serum samples obtained from patients with hematological cancer were tested retrospectively with MycAssay Aspergillus PCR. Per-episode and per-test analyses were undertaken with 146 sera from 35 hematological patients. Sixteen patients had proven or probable IA and 19 had possible or no IA. In per episode analysis, MycAssay Aspergillus had a sensitivity of 43.8% (95% confidence interval [CI], 19.8%-70.1%) and a specificity of 63.2% (95% CI, 38.4%-83.7%) for IA diagnosis. In per-test analyses, MycAssay Aspergillus had a lower specificity than the GM assay (83.3% vs. 93.1%, P = 0.04). The addition of PCR to routine clinical practice would have permitted the diagnosis of one additional probable IA in our cohort. Use of PCR instead of GM assay would have delayed the diagnosis in two cases. Aspergillus DNA detection by PCR with serum specimens using MycAssay showed a lower specificity than the GM assay and was associated with a low sensitivity for IA diagnosis. More studies are needed to determine the exact role of MycAssay in IA diagnosis in patients with hematological malignancy. PMID- 25023483 TI - New insights into innate immune control of systemic candidiasis. AB - Systemic infection caused by Candida species is the fourth leading cause of nosocomial bloodstream infection in modern hospitals and carries high morbidity and mortality despite antifungal therapy. A recent surge of immunological studies in the mouse models of systemic candidiasis and the parallel discovery and phenotypic characterization of inherited genetic disorders in antifungal immune factors that are associated with enhanced susceptibility or resistance to the infection have provided new insights into the cellular and molecular basis of protective innate immune responses against Candida. In this review, the new developments in our understanding of how the mammalian immune system responds to systemic Candida challenge are synthesized and important future research directions are highlighted. PMID- 25023485 TI - Identification, molecular characterization, and expression analysis of a DOMON like type 9 carbohydrate-binding module domain-containing protein of Coccidioides posadasii. AB - Previously, we investigated the effect of N-acetylglucosamine (GlcNAc) on Coccidioides posadasii chitinolytic enzymes during in vitro spherule-endospore (S/E) phase culture. During those studies, sodium dodecyl sulfatepolyacrylamide gel electrophoresis analysis of supernatants from S/E phase cultures grown in Converse medium with or without added GlcNAc revealed a ~ 28-kDa band (CFP28), whose abundance was increased by GlcNAc in parallel with the chitinolytic enzymes. Mass spectrometry (MS) of the CFP28 band revealed peptides that matched an open reading frame found in the tentative consensus sequence, TC20325, retrieved from the Dana Farber Cancer Institute C. posadasii Gene Index Database. The TC20325 cDNA sequence was used to design internal primers based on MS peptides and a full-length cDNA was isolated using a combination of rapid amplification of cDNA ends and reverse transcription-polymerase chain reaction. The deduced amino acid sequence of the full-length cDNA consists of 231 amino acid residues with a 19 aa signal peptide. The mature protein has a calculated molecular mass of ~ 24.5 kDa, a theoretical pI of 6.09, and consists of a single DOMON-like type 9 carbohydrate-binding module (CBM9-like-3) conserved domain. The protein shares the highest sequence similarity (>=57%) to hypothetical proteins from fungi within the Pezizomycotina subphylum of Ascomycota. Antiserum against a recombinant version of CFP28 recognized native CFP28 in S/E phase cells and culture supernatants. CFP28 mRNA and protein expression were detectable in S/E phase in Converse medium, but were increased in the presence of added GlcNAc. Purified native CFP28 reacted with pooled sera from patients with coccidioidomycosis. PMID- 25023486 TI - Content coding of pharmacist-patient interactions in medication counseling in mental health. PMID- 25023488 TI - Gastric cancer with para-aortic lymph nodes metastasis: curable dissection possible but be cautiously selected. AB - This is a reply letter to Dr. M Daniele et al. entitled as "gastric cancer with para-aortic lymph nodes metastasis: do not miss a chance of cure!". Para-aortic lymph node metastasis has been regarded as a pattern of distant metastasis in gastric cancer. Even patients with PAN metastasis undergo extensive lymph nodes, the prognosis is unsatisfactory and the overall survival is not better than the patients receiving palliative chemotherapy. However, for the patients who were responded to the preoperative chemotherapy, subsequent radical gastrectomy performed prolonged survival. Meanwhile, patients who were resistant to the previous chemotherapy were not optimal candidates for curative resection in advanced gastric cancer patients with PAN metastasis. How large with lymph nodes dissection for the patients with initially PAN metastasis after effective neo chemotherapy is still a controversial issue and needs further large-scale randomized trials. PMID- 25023487 TI - Advanced cancer patients' and caregivers' use of a Question Prompt List. AB - OBJECTIVE: The objective of this study was to provide insight into how advanced cancer patients and their caregivers use a Question Prompt List (QPL) during a consultation and for preparation for future consultations. METHODS: Audiotaped consultations and follow-up phone calls of 28 advanced cancer patients were coded and content analyzed. Questions asked and concerns expressed in consultations were coded for initiator, content, inclusion in the QPL and exact wording. Patients' reported and future use of the QPL were coded from the phone calls. RESULTS: The majority of patients reported that they used the QPL. Questions asked by patients and caregivers predominately coincided with questions from the prognosis section of the QPL. Questions were rarely asked literally from the QPL, instead questions were tailored to patients' own circumstances. CONCLUSION: QPLs are useful to stimulate discussion on prognosis among advanced cancer patients and caregivers. Patients tailored questions from the QPL to their own circumstances which may suggest high involvement and engagement. The development of more specific tailored communication interventions for advanced cancer patients is warranted. PRACTICE IMPLICATIONS: Implementation of QPLs in the advanced cancer setting may be beneficial for patients, caregivers and healthcare providers to facilitate discussion of topics such as prognosis. PMID- 25023489 TI - Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors. AB - PURPOSE: Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib. METHODS: Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m(2) on days 1 and 8), cisplatin (70 mg/m(2)), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12, and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules. RESULTS: Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1-5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment. CONCLUSIONS: Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression. PMID- 25023490 TI - HPV Awareness and Vaccine Willingness Among Dominican Immigrant Parents Attending a Federal Qualified Health Clinic in Puerto Rico. AB - The purpose of this study was to describe the socio-demographic characteristics, awareness of human papillomavirus (HPV), and willingness to vaccinate among a convenience sample of 60 immigrant Dominican parents of adolescent sons in a Federal Qualified Health Clinic in Puerto Rico. Participation involved completing a self-administered survey. Even though more than half of the parents had not received proper HPV vaccine orientation from healthcare provider (58.3 %) nor asked provider for vaccination recommendation for their adolescent sons (56.7 %), most parents were aware of HPV (91.7 %) and HPV vaccination among males (55.0 %). Among those with unvaccinated sons, willingness to vaccinate the son within the next year was high (83.8 %). The low vaccination percentage (31.7 %) and information exchange between the parents and the son's healthcare provider indicates an opportunity for future culturally tailored interventions to target HPV vaccination among healthcare providers and parents of foreign descent in order to increase HPV vaccine uptake among males. PMID- 25023491 TI - Social Determinants of Physical Activity Among Adult Asian-Americans: Results from a Population-Based Survey in California. AB - The objective of this study was to evaluate the key social determinants of physical activity among six Asian-American subgroups using public access 2007 California Health Interview Survey data. Physical activity was defined as meeting the American College of Sports Medicine recommendation of 450 metabolic equivalent-minutes per week. Factors positively associated with meeting physical activity recommendations included being bilingual among Chinese and Vietnamese, and increasing age for Chinese only. On the other hand, being middle aged, currently married, and low neighborhood safety were significantly associated with lower odds of meeting physical activity recommendations, as were being female for Japanese and Koreans, and living above the poverty level for Vietnamese. Such results highlight the heterogeneity among Asian-Americans and need for health messages targeted at specific subgroups. Additionally, the role of built environment, particularly in areas with high Filipino residents, should be a public health priority for increasing physical activity outcomes. PMID- 25023492 TI - Before the beginning: the development of tools of the trade. AB - Before the beginning of the Journal of Child Language in 1974 three technological innovations had set the stage for a fundamental expansion and revision of our understanding of the processes of child language acquisition. Portable audio and video recorders changed both the quantity and quality of data. Computers made it possible to store and search large corpora, to rapidly carry out statistical analyses of the distribution of linguistic forms and their changes over time, and to simulate models of acquisition. This essay is a personal and historical overview of the unexpected consequences of those technological innovations for the study of child language. In looking to the future, another tool, linguistic typology, is essential for building models of language acquisition. PMID- 25023493 TI - Data and beyond. AB - Perusing early issues of this Journal from nearly forty years ago, we find many topics on the contents lists that could appear in a current issue. But the resources available to contributors for addressing questions of interest have changed dramatically, not least in the public availability of data. Here we look briefly at two assets which have accrued to the field in the intervening decades, and at the contributions they make. CHILDES provides a level playing field on which debates about the import of language sample data, especially longitudinal data, can be played out. The MBCDI and its offspring encourage the collection of data from large samples of individuals and so promote the exploration of factors that may explain individual differences. Both have been major contributions to the field. PMID- 25023494 TI - Cross-linguistic comparisons in child language research. AB - Major large-scale research projects in the early years of developmental psycholinguistics were English-based, yet even then numerous studies were available or under way in a range of different languages (Ferguson & Slobin, 1973). Since then, the field of cross-linguistic child language research has burgeoned in several directions. First, rich information is now available on the acquisition of dozens of languages from around the world in numerous language families, spearheaded by the five-volume series edited by Slobin (1985-1997) and complemented by in-depth examination of specific constructions - e.g. causative alternation, motion verbs, passive voice, subject elision, noun compounding - in various languages, culminating in an in-depth examination of the acquisition of ergativity in over a dozen languages (Bavin & Stoll, 2013). A second fruitful direction is the application of carefully comparable designs targeting a range of issues among children acquiring different languages, including: production of early lexico-grammatical constructions (Slobin, 1982), sentence processing comprehension (MacWhinney & Bates, 1989), expression of spatial relations (Bowerman, 2011), discourse construction of oral narratives based on short picture series (Hickmann, 2003) and longer storybooks (Berman & Slobin, 1994), and extended texts in different genres (Berman, 2008). Taken together, research motivated by the question of what is particular and what universal in child language highlights the marked, and early, impact of ambient language typology on processes of language acquisition. The challenge remains to operationalize such insights by means of psychologically sound and linguistically well-motivated measures for evaluating the interplay between the variables of developmental level, linguistic domain, and ambient language typology. PMID- 25023495 TI - Children with specific language impairment and their contribution to the study of language development. AB - Children with specific language impairment (SLI) are distinguishable from typically developing children primarily in the pace and course of their language development. For this reason, they are appropriate candidates for inclusion in any theory of language acquisition. In this paper, the areas of overlap between children with SLI and those developing in typical fashion are discussed, along with how the joint study of these two populations can enhance our understanding of the language development process. In particular, evidence from children with SLI can provide important information concerning the role of language typology in language development, the optimal ages for acquiring particular linguistic details, the robustness of the bilingual advantage for children, the role of input in children's acquisition of grammatical details, the unintended influence of processing demands during language assessment, the contributions of treatment designs to the study of typically developing children, and the study of individual differences in language development. PMID- 25023496 TI - First language development: a usage-based perspective on past and current research. AB - I first outline three major developments in child language research over the past forty years: the use of computational modelling to reveal the structure of information in the input; the focus on quantifying productivity and abstraction; and developments in the explanation of systematic errors. Next, I turn to what I consider to be major outstanding issues: how the network of constructions builds up and the relationship between social and cognitive development and language learning. Finally, I briefly consider a number of other areas of importance to a psychologically realistic understanding of children's language development. PMID- 25023497 TI - In search of resilient and fragile properties of language. AB - Young children are skilled language learners. They apply their skills to the language input they receive from their parents and, in this way, derive patterns that are statistically related to their input. But being an excellent statistical learner does not explain why children who are not exposed to usable linguistic input nevertheless communicate using systems containing the fundamental properties of language. Nor does it explain why learners sometimes alter the linguistic input to which they are exposed (input from either a natural or an artificial language). These observations suggest that children are prepared to learn language. Our task now, as it was in 1974, is to figure out what they are prepared with - to identify properties of language that are relatively easy to learn, the resilient properties, as well as properties of language that are more difficult to learn, the fragile properties. The new tools and paradigms for describing and explaining language learning that have been introduced into the field since 1974 offer great promise for accomplishing this task. PMID- 25023498 TI - Arguing about innateness. AB - This paper lays out the components of a language acquisition model, the interconnections among the components, and the differing stances of nativism and empiricism about syntax. After demonstrating that parsimony cannot decide between the two stances, the paper analyzes nine examples of evidence that have been used to argue for or against nativism, concluding that most pieces of evidence are either irrelevant or suggest that language is special but need not invoke innate ideas. Two pieces of evidence - the development of home sign languages and the acquisition of Determiners - do show not just that language is special but that the child has innate syntactic content. The existential claim that nativism makes - there is at least one innate syntactic idea - is an easier claim to verify than the universal claim that empiricism makes - there are no innate syntactic ideas. PMID- 25023499 TI - A matter of meaning: reflections on forty years of JCL. AB - The entry into language via first words and, the acquisition of word meanings is considered from the perspective of publications in the Journal of Child Language over the past forty years. Problems in achieving word meanings include the disparate and sparse concepts available to the child from past prelanguage experience. Variability in beginning word learning and in its progress along a number of dimensions suggests the problems that children may encounter, as well as the strategies and styles they adopt to make progress. Social context and adult practices are vitally involved in the success of this process. Whereas much headway has been made over the past decades, much remains to be revealed through dynamic systems theory and developmental semiotic analyses, as well as laboratory research aimed at social context conditions. PMID- 25023500 TI - Pragmatics in acquisition. AB - Recent research has highlighted several areas where pragmatics plays a central role in the process of acquiring a first language. In talking with their children, adults display their uses of language in each context, and offer extensive feedback on form, meaning, and usage, within their conversational exchanges. These interactions depend critically on joint attention, physical co presence, and conversational co-presence - essential factors that help children assign meanings, establish reference, and add to common ground. For young children, getting their meaning across also depends on realizing language is conventional, that words contrast in meaning, and that they need to observe Grice's cooperative principle in conversation. Adults make use of the same pragmatic principles as they solicit repairs to what children say, and thereby offer feedback on both what the language is and how to use it. PMID- 25023501 TI - Input to interaction to instruction: three key shifts in the history of child language research. AB - In the early years of the Journal of Child Language, there was considerable disagreement about the role of language input or adult-child interaction in children's language acquisition. The view that quantity and quality of input to language-learning children is relevant to their language development has now become widely accepted as a principle guiding advice to parents and the design of early childhood education programs, even if it is not yet uncontested in the field of language development. The focus on variation in the language input to children acquires particular educational relevance when we consider variation in access to academic language - features of language particularly valued in school and related to success in reading and writing. Just as many children benefit from language environments that are intentionally designed to ensure adequate quantity and quality of input, even more probably need explicit instruction in the features of language that characterize its use for academic purposes. PMID- 25023502 TI - What we have learned. PMID- 25023503 TI - Reflections: 40 years of JCL. PMID- 25023505 TI - How the changing payment systems could benefit heart failure patients. PMID- 25023506 TI - A perfect storm. PMID- 25023504 TI - Feasibility study of unattended polysomnography in medical intensive care unit patients. AB - OBJECTIVES: To evaluate the feasibility of using unattended, portable polysomnography (PSG) to measure sleep among patients in the medical intensive care unit (MICU). BACKGROUND: Accurate measurement of sleep is critical to studies of MICU sleep deprivation. Although PSG is the gold standard, there is limited data regarding the feasibility of utilizing unattended, portable PSG modalities in the MICU. METHODS: MICU based observational pilot study. We conducted unattended, 24-h PSG studies in 29 patients. Indicators of feasibility included attainment of electroencephalography data sufficient to determine sleep stage, sleep efficiency, and arousal indices. RESULTS: Electroencephalography data were not affected by electrical interference and were of interpretable quality in 27/29 (93%) of patients. Overnight sleep efficiency was 48% reflecting a mean overnight sleep duration of 3.7 h. CONCLUSIONS: Unattended, portable PSG produces high quality sleep data in the MICU and can facilitate investigation of sleep deprivation among critically ill patients. Patient sleep was short and highly fragmented. PMID- 25023507 TI - Coaching: a key model of leadership. PMID- 25023508 TI - Optimal dose for whole-body (18)F-fluorodeoxyglucose PET/CT imaging. PMID- 25023509 TI - Here come the exchange patients. PMID- 25023510 TI - Association between medical school radiology curricula and application rates to US radiology residency programs. AB - PURPOSE: Data are limited on how radiology curricula vary across US medical schools and the association between characteristics of these curricula and application rates to radiology residency programs. The purpose of this study was to gather more information about medical school radiology curricula and to determine the association between radiology education and application rates to radiology residency programs. METHODS: An anonymous web-based survey was e-mailed to residency program directors affiliated with 129 accredited US medical schools. Residency program directors were instructed to forward the survey to a radiology clerkship director or complete the survey themselves. Electronic Residency Application Service data were also obtained for 122 participating medical schools. RESULTS: Fifty-five of 122 schools responded, a response rate of 45%. The majority of medical schools (76%) had a dedicated radiology curriculum, which was most often offered in the third and fourth years. The majority (87%) of schools integrated radiology education into other courses throughout all 4 years. The application data revealed that application rates were similar across schools, ranging from 6% to 8%. Applications rates did not significantly vary across several characteristics of educational curricula. CONCLUSIONS: Although schools vary in the characteristics of radiology education, application rates to radiology residency programs are similar across schools and are not associated with specific characteristics of these educational programs. This lack of an association may be explained by universal exposure of medical students to radiology curricula and the fact that a career choice is a complex process that involves multiple factors. PMID- 25023512 TI - Advances and controversies in military posttraumatic stress disorder screening. AB - As the longest war in American history draws to a close, an unprecedented number of service members and veterans are seeking care for health challenges related to transitioning home and to civilian life. Congressionally mandated screening for mental health concerns in the Department of Defense (DoD), as well as screening efforts Veterans Affairs (VA) facilities, has been established with the goal of decreasing stigma and ensuring service members and veterans with depression and posttraumatic stress disorder (PTSD) receive needed treatment. Both the DoD and VA have also developed integrated behavioral health in primary-care based initiatives, which emphasize PTSD screening, treatment, and care coordination. This article discusses the rationale for population-level deployment-related mental health screening, recent changes to screening frequency, commonly used screening instruments such as the primary care PTSD screen (PC-PTSD), PTSD checklist (PCL), and Davidson Trauma Scale (DTS); as well as the strengths/limitations of each, and recommended cut-off scores based on expected PTSD prevalence. PMID- 25023511 TI - Current understanding of the neurobiology and longitudinal course of geriatric depression. AB - Late life depression is a complex disease associated with a number of contributing neurobiological factors, including cerebrovascular disease, neurodegeneration, and inflammation, which also contribute to its longitudinal prognosis and course. These factors create a context in which the brain is more vulnerable to the impact of stress, and thus, to depression. At the same time, some individuals are protected from late life depression and its consequences, even in the face of neurobiological vulnerability, through benefitting from one or more attributes associated with resilience, including social support, engagement in physical and cognitive activities, and brain reserve. Enhanced understanding of how neurobiological and environmental factors interact in predicting vulnerability and resilience is needed to predict onset and course of depression in late life and develop more effective interventions. PMID- 25023513 TI - Cognitive and neuropsychiatric impairments in Alzheimer's disease: current treatment strategies. AB - This update on Alzheimer's disease (AD) discusses treatment strategies for cognitive and neuropsychiatric symptoms (such as agitation, psychosis, anxiety, and depression) common in this illness, emphasizing in particular nonpharmacologic strategies such as cognitive interventions, physical exercise, and psychotherapy. We provide an overview of cognitive enhancers and their combination strategies and medications commonly used for treatment of neuropsychiatric symptoms in AD. Finally, we give recommendations for providing support to caregivers and suggest how to identify caregiver/patient pairs most in need of intensive dementia care services. PMID- 25023514 TI - Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase beta and regulates complex V activity. AB - Adenosine triphosphate (ATP) synthase beta, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase beta is deacetylated by a human nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue, dSirt2. dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase beta and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase beta, mimicking deacetylation, increased complex V activity, whereas substitution with Gln, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from wild-type and dsirt2 mitochondria identified the Drosophila mitochondrial acetylome and revealed dSirt2 as an important regulator of mitochondrial energy metabolism. Additionally, we unravel a ceramide-NAD(+)-sirtuin axis wherein increased ceramide, a sphingolipid known to induce stress responses, resulted in depletion of NAD(+) and consequent decrease in sirtuin activity. These results provide insight into sirtuin-mediated regulation of complex V and reveal a novel link between ceramide and Drosophila acetylome. PMID- 25023515 TI - The SUN protein UNC-84 is required only in force-bearing cells to maintain nuclear envelope architecture. AB - The nuclear envelope (NE) consists of two evenly spaced bilayers, the inner and outer nuclear membranes. The Sad1p and UNC-84 (SUN) proteins and Klarsicht, ANC 1, and Syne homology (KASH) proteins that interact to form LINC (linker of nucleoskeleton and cytoskeleton) complexes connecting the nucleoskeleton to the cytoskeleton have been implicated in maintaining NE spacing. Surprisingly, the NE morphology of most Caenorhabditis elegans nuclei was normal in the absence of functional SUN proteins. Distortions of the perinuclear space observed in unc-84 mutant muscle nuclei resembled those previously observed in HeLa cells, suggesting that SUN proteins are required to maintain NE architecture in cells under high mechanical strain. The UNC-84 protein with large deletions in its luminal domain was able to form functional NE bridges but had no observable effect on NE architecture. Therefore, SUN-KASH bridges are only required to maintain NE spacing in cells subjected to increased mechanical forces. Furthermore, SUN proteins do not dictate the width of the NE. PMID- 25023516 TI - Direct kinetochore-spindle pole connections are not required for chromosome segregation. AB - Segregation of genetic material occurs when chromosomes move to opposite spindle poles during mitosis. This movement depends on K-fibers, specialized microtubule (MT) bundles attached to the chromosomes' kinetochores. A long-standing assumption is that continuous K-fibers connect every kinetochore to a spindle pole and the force for chromosome movement is produced at the kinetochore and coupled with MT depolymerization. However, we found that chromosomes still maintained their position at the spindle equator during metaphase and segregated properly during anaphase when one of their K-fibers was severed near the kinetochore with a laser microbeam. We also found that, in normal fully assembled spindles, K-fibers of some chromosomes did not extend to the spindle pole. These K-fibers connected to adjacent K-fibers and/or nonkinetochore MTs. Poleward movement of chromosomes with short K-fibers was uncoupled from MT depolymerization at the kinetochore. Instead, these chromosomes moved by dynein mediated transport of the entire K-fiber/kinetochore assembly. Thus, at least two distinct parallel mechanisms drive chromosome segregation in mammalian cells. PMID- 25023517 TI - Force on spindle microtubule minus ends moves chromosomes. AB - The spindle is a dynamic self-assembling machine that coordinates mitosis. The spindle's function depends on its ability to organize microtubules into poles and maintain pole structure despite mechanical challenges and component turnover. Although we know that dynein and NuMA mediate pole formation, our understanding of the forces dynamically maintaining poles is limited: we do not know where and how quickly they act or their strength and structural impact. Using laser ablation to cut spindle microtubules, we identify a force that rapidly and robustly pulls severed microtubules and chromosomes poleward, overpowering opposing forces and repairing spindle architecture. Molecular imaging and biophysical analysis suggest that transport is powered by dynein pulling on minus ends of severed microtubules. NuMA and dynein/dynactin are specifically enriched at new minus ends within seconds, reanchoring minus ends to the spindle and delivering them to poles. This force on minus ends represents a newly uncovered chromosome transport mechanism that is independent of plus end forces at kinetochores and is well suited to robustly maintain spindle mechanical integrity. PMID- 25023519 TI - Investigation of a fatigue failure in a stainless steel femoral plate. AB - Surgical implants are exposed to severe working conditions and therefore a wide range of failure mechanisms may occur, including fatigue, corrosion, wear, fretting and combinations of them. The mechanical failures of metallic implants may also be influenced by several other factors, including the design, material, manufacturing, installation, postoperative complications and misuse. An 83-year old patient suffered an oblique femoral shaft fracture due to a fall at home. A stainless steel locking compression plate (LCP) employed in the fracture reduction failed after four months and was sent back to the producer. A second LCP of the same type was implanted and also failed after six months. A failure analysis of the second femoral LCP is performed in this paper. The results demonstrate that poor material quality was decisive to the failure. The chemical analysis revealed a high P content in the steel, which is not in accordance to the standards. A combination of factors lead to LCP fracture and these include: brittle crack initiation due to phosphorus, segregation at grain boundaries, crack propagation due to cyclic loading and final fast fracture favored by the loss of ductility due to cold work. PMID- 25023518 TI - DNA damage-specific deubiquitination regulates Rad18 functions to suppress mutagenesis. AB - Deoxyribonucleic acid (DNA) lesions encountered during replication are often bypassed using DNA damage tolerance (DDT) pathways to avoid prolonged fork stalling and allow for completion of DNA replication. Rad18 is a central E3 ubiquitin ligase in DDT, which exists in a monoubiquitinated (Rad18*Ub) and nonubiquitinated form in human cells. We find that Rad18 is deubiquitinated when cells are treated with methyl methanesulfonate or hydrogen peroxide. The ubiquitinated form of Rad18 does not interact with SNF2 histone linker plant homeodomain RING helicase (SHPRH) or helicase-like transcription factor, two downstream E3 ligases needed to carry out error-free bypass of DNA lesions. Instead, it interacts preferentially with the zinc finger domain of another, nonubiquitinated Rad18 and may inhibit Rad18 function in trans. Ubiquitination also prevents Rad18 from localizing to sites of DNA damage, inducing proliferating cell nuclear antigen monoubiquitination, and suppressing mutagenesis. These data reveal a new role for monoubiquitination in controlling Rad18 function and suggest that damage-specific deubiquitination promotes a switch from Rad18*Ub-Rad18 complexes to the Rad18-SHPRH complexes necessary for error-free lesion bypass in cells. PMID- 25023520 TI - New directions in evidence-based policy research: a critical analysis of the literature. AB - Despite 40 years of research into evidence-based policy (EBP) and a continued drive from both policymakers and researchers to increase research uptake in policy, barriers to the use of evidence are persistently identified in the literature. However, it is not clear what explains this persistence - whether they represent real factors, or if they are artefacts of approaches used to study EBP. Based on an updated review, this paper analyses this literature to explain persistent barriers and facilitators. We critically describe the literature in terms of its theoretical underpinnings, definitions of 'evidence', methods, and underlying assumptions of research in the field, and aim to illuminate the EBP discourse by comparison with approaches from other fields. Much of the research in this area is theoretically naive, focusing primarily on the uptake of research evidence as opposed to evidence defined more broadly, and privileging academics' research priorities over those of policymakers. Little empirical data analysing the processes or impact of evidence use in policy is available to inform researchers or decision-makers. EBP research often assumes that policymakers do not use evidence and that more evidence - meaning research evidence - use would benefit policymakers and populations. We argue that these assumptions are unsupported, biasing much of EBP research. The agenda of 'getting evidence into policy' has side-lined the empirical description and analysis of how research and policy actually interact in vivo. Rather than asking how research evidence can be made more influential, academics should aim to understand what influences and constitutes policy, and produce more critically and theoretically informed studies of decision-making. We question the main assumptions made by EBP researchers, explore the implications of doing so, and propose new directions for EBP research, and health policy. PMID- 25023521 TI - Increased Risk of Severe Hypoglycemic Events with Increasing Frequency of Non severe Hypoglycemic Events in Patients with Type 1 and Type 2 Diabetes. AB - INTRODUCTION: Severe hypoglycemic events (SHEs) are associated with significant morbidity, mortality and costs. However, the more common non-severe hypoglycemic events (NSHEs) are less well explored. We investigated the association between reported frequency of NSHEs and SHEs among patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in the PREDICTIVE study. METHODS: PREDICTIVE was a global, prospective, observational study. Patients with T1DM (n = 7,420) or T2DM (n = 12,981), starting treatment with insulin detemir, reported the number of NSHEs and SHEs experienced during the 4 weeks prior to baseline and follow-up visits (mean 14.4 weeks). Logistic regression was used to determine the odds ratio (OR) of experiencing >=1 SHE, in patients having 1-4 or >=5 NSHEs, versus those having 0 NSHEs, while controlling for baseline covariates. RESULTS: Hypoglycemia rates were lower at follow-up than baseline. At baseline 59.2% (T1DM) and 18.8% (T2DM) reported any hypoglycemia and at follow-up 39.5% (T1DM) and 8.6% (T2DM). There was a significant (P < 0.0001) increase in the odds of >=1 SHEs with increasing frequency of NSHEs in T1DM and T2DM, for both crude and adjusted estimates. At baseline, in T1DM, ORs for >=1 SHE were 1.92 and 2.13 for 1-4 and >=5 NSHEs, respectively; the corresponding ORs in T2DM were 10.83 and 15.36, respectively. At follow-up, the ORs for >=1 SHE were 2.01 and 3.20 (T1DM) and 18.99 and 24.29 (T2DM) for 1-4 and >=5 NSHEs, respectively. CONCLUSION: A statistically significant association between NSHE and SHE frequency was found in T1DM and T2DM. These data provide a clear rationale for the reduction of hypoglycemic events, regardless of severity, while striving for optimal glycemic control. PMID- 25023522 TI - Measuring the effectiveness of androgen-deprivation therapy for prostate cancer in the medicare population: adequate data are neither the same as nor the enemy of perfect data. PMID- 25023523 TI - The influence of a clinical classification system on the management of patients with positional dependent obstructive sleep apnoea. PMID- 25023524 TI - Early lung ultrasonography predicts the occurrence of acute respiratory distress syndrome in blunt trauma patients. AB - PURPOSE: Extent of lung contusion on initial computed tomography (CT) scan predicts the occurrence of acute respiratory distress syndrome (ARDS) in blunt chest trauma patients. We hypothesized that lung ultrasonography (LUS) on admission could also predict subsequent ARDS. METHODS: Forty-five blunt trauma patients were prospectively studied. Clinical examination, chest radiography, and LUS were performed on arrival at the emergency room. Lung contusion extent was quantified using a LUS score and compared to CT scan measurements. The ability of the LUS score to predict ARDS was tested using the area under the receiver operating characteristic curve (AUC-ROC). The diagnostic accuracy of LUS was compared to that of combined clinical examination and chest radiography for pneumothorax, lung contusion, and hemothorax, with thoracic CT scan as reference. RESULTS: Lung contusion extent assessed by LUS on admission was predictive of the occurrence of ARDS within 72 h (AUC-ROC = 0.78 [95 % CI 0.64-0.92]). The extent of lung contusion on LUS correlated well with CT scan measurements (Spearman's coefficient = 0.82). A LUS score of 6 out of 16 was the best threshold to predict ARDS, with a 58 % [95 % CI 36-77] sensitivity and a 96 % [95 % CI 76-100] specificity. The diagnostic accuracy of LUS was higher than that of combined clinical examination and chest radiography: (AUC-ROC) 0.81 [95 % CI 0.50-1.00] vs. 0.74 [0.48-1.00] (p = 0.24) for pneumothorax, 0.88 [0.76-1.00] vs. 0.69 [0.47 0.92] (p < 0.05) for lung contusion, and 0.84 [0.59-1.00] vs. 0.73 [0.51-0.94] (p < 0.05) for hemothorax. CONCLUSIONS: LUS on admission identifies patients at risk of developing ARDS after blunt trauma. In addition, LUS allows rapid and accurate diagnosis of common traumatic thoracic injuries. PMID- 25023525 TI - Untangling ICU delirium: is establishing its prevention in high-risk patients the final frontier? PMID- 25023527 TI - Severe hepatic portal venous gas that spontaneously resolved within a day. PMID- 25023526 TI - Pediatric cancer type predicts infection rate, need for critical care intervention, and mortality in the pediatric intensive care unit. AB - PURPOSE: Up to 38 % of children with cancer require pediatric intensive care unit (PICU) admission within 3 years of diagnosis, with reported PICU mortality of 13 27 % far exceeding that of the general PICU population. PICU outcomes data for individual cancer types are lacking and may help identify patients at risk for poor clinical outcomes. METHODS: We performed a retrospective multicenter analysis of 10,365 PICU admissions of cancer patients no greater than 21 years old among 112 PICUs between 1 January 2009 and 30 June 2012. We evaluated the effect of cancer type, age, gender, genetic syndrome, stem cell transplantation, PRISM3 score, infections, and critical care interventions on PICU mortality. RESULTS: After excluding scheduled perioperative admissions, cancer patients represented 4.2 % of all PICU admissions (10,365/246,346), had overall mortality of 6.8 % (708/10,365) vs. 2.4 % (5,485/230,548) in the general PICU population (RR = 2.9, 95 % CI 2.7-3.1, p < 0.001), and accounted for 11.4 % of all PICU deaths (708/6,215). Hematologic cancer patients had greater median PRISM3 score (8 vs 2, p < 0.001), rates of sepsis (27 vs 9 %, RR = 2.9, 95 % CI 2.6-3.1, p < 0.001), and mortality (9.6 vs 4.5 %, RR = 2.1, 95 % CI 1.8-2.5, p < 0.001) compared to solid cancer patients. Among hematologic cancer patients, stem cell transplantation, diagnosis of acute myeloid leukemia, PRISM3 score, and infection were all independently associated with PICU mortality. CONCLUSIONS: Children with cancer account for 4.2 % of PICU admissions and 11.4 % of PICU deaths. Hematologic cancer patients have significantly higher admission illness severity, rates of infections, and PICU mortality than solid cancer patients. These data may be useful in risk stratification for closer monitoring and patient counseling. PMID- 25023528 TI - Untangling ICU delirium: is establishing its prevention in high-risk patients the final frontier? Reply to van der Jagt et al. PMID- 25023529 TI - Cancer patients with ARDS: survival gains and unanswered questions. PMID- 25023530 TI - Thyrotoxic cardiomyopathy with recurrent ventricular fibrillation and multi-organ failure. PMID- 25023531 TI - Multichannel biomedical time series clustering via hierarchical probabilistic latent semantic analysis. AB - Biomedical time series clustering that automatically groups a collection of time series according to their internal similarity is of importance for medical record management and inspection such as bio-signals archiving and retrieval. In this paper, a novel framework that automatically groups a set of unlabelled multichannel biomedical time series according to their internal structural similarity is proposed. Specifically, we treat a multichannel biomedical time series as a document and extract local segments from the time series as words. We extend a topic model, i.e., the Hierarchical probabilistic Latent Semantic Analysis (H-pLSA), which was originally developed for visual motion analysis to cluster a set of unlabelled multichannel time series. The H-pLSA models each channel of the multichannel time series using a local pLSA in the first layer. The topics learned in the local pLSA are then fed to a global pLSA in the second layer to discover the categories of multichannel time series. Experiments on a dataset extracted from multichannel Electrocardiography (ECG) signals demonstrate that the proposed method performs better than previous state-of-the-art approaches and is relatively robust to the variations of parameters including length of local segments and dictionary size. Although the experimental evaluation used the multichannel ECG signals in a biometric scenario, the proposed algorithm is a universal framework for multichannel biomedical time series clustering according to their structural similarity, which has many applications in biomedical time series management. PMID- 25023532 TI - Performance optimization of current focusing and virtual electrode strategies in retinal implants. AB - The electrode configuration in an implanted visual prosthesis array affects the spatial electric field distribution within the retina, contributing to current focusing and virtual electrode (VE) stimulation strategies. In this paper, a finite element model incorporating various electrode configurations was used to study the interaction between electrode size and electrode-to-cell distance in current focusing and VE stimulation paradigms. The electrode array unit comprises an active electrode, six flanking return electrodes and a distant monopolar return. A quasi-monopolar (QMP) fraction is defined as the proportion of current which can be preferentially returned through the distant return, in comparison with the more adjacent flanking electrodes. The simulation results indicate that current focusing and VE strategies can be optimized by tuning the QMP fraction. The QMP fraction is adjusted to optimize the electric field spread based on retinal ganglion cell (RGC) density in the degenerate retina, thereby offsetting the effect of inhomogeneous distribution of surviving RGCs and leading to a uniform stimulation paradigm across electrodes. Importantly, there is negligible difference in functional performance across electrode configurations for distances less than the electrode diameter, implying that the stimulation mode does not significantly affect activation threshold or activated retinal area for electrode diameters greater than the retinal thickness. Furthermore, the QMP fraction has a significant effect on VE performance, defined by activation threshold and activated retinal area, when threshold current is evenly divided between two adjacent active electrodes. PMID- 25023533 TI - Editorial. PMID- 25023534 TI - HELOW: a program for testing extreme homogeneity in meta-analysis. AB - Meta-analysis aims to synthesize results from different studies. Although, in a meta-analysis the presence of large between-study heterogeneity is routinely evaluated, in some instances is also important to probe whether there is extreme between-study homogeneity (i.e. extreme low between-study heterogeneity). HELOW (HEterogeneity LOW) is a program for testing extreme homogeneity in a meta analysis of risk ratios when binary outcome and Mantel-Haenszel fixed effects summary risk ratio estimate are employed. The significance of extreme homogeneity is assessed using a Monte Carlo test. Extreme homogeneity may yield insights for the statistical and clinical interpretation of the data. PMID- 25023535 TI - Cardiovascular risk analysis by means of pulse morphology and clustering methodologies. AB - The purpose of this study was the development of a clustering methodology to deal with arterial pressure waveform (APW) parameters to be used in the cardiovascular risk assessment. One hundred sixteen subjects were monitored and divided into two groups. The first one (23 hypertensive subjects) was analyzed using APW and biochemical parameters, while the remaining 93 healthy subjects were only evaluated through APW parameters. The expectation maximization (EM) and k-means algorithms were used in the cluster analysis, and the risk scores (the Framingham Risk Score (FRS), the Systematic COronary Risk Evaluation (SCORE) project, the Assessing cardiovascular risk using Scottish Intercollegiate Guidelines Network (ASSIGN) and the PROspective Cardiovascular Munster (PROCAM)), commonly used in clinical practice were selected to the cluster risk validation. The result from the clustering risk analysis showed a very significant correlation with ASSIGN (r=0.582, p<0.01) and a significant correlation with FRS (r=0.458, p<0.05). The results from the comparison of both groups also allowed to identify the cluster with higher cardiovascular risk in the healthy group. These results give new insights to explore this methodology in future scoring trials. PMID- 25023536 TI - Feature extraction of the first difference of EMG time series for EMG pattern recognition. AB - This paper demonstrates the utility of a differencing technique to transform surface EMG signals measured during both static and dynamic contractions such that they become more stationary. The technique was evaluated by three stationarity tests consisting of the variation of two statistical properties, i.e., mean and standard deviation, and the reverse arrangements test. As a result of the proposed technique, the first difference of EMG time series became more stationary compared to the original measured signal. Based on this finding, the performance of time-domain features extracted from raw and transformed EMG was investigated via an EMG classification problem (i.e., eight dynamic motions and four EMG channels) on data from 18 subjects. The results show that the classification accuracies of all features extracted from the transformed signals were higher than features extracted from the original signals for six different classifiers including quadratic discriminant analysis. On average, the proposed differencing technique improved classification accuracies by 2-8%. PMID- 25023537 TI - Artificial enzymes with protein scaffolds: structural design and modification. AB - Recent development in biochemical experiment techniques and bioinformatics has enabled us to create a variety of artificial biocatalysts with protein scaffolds (namely 'artificial enzymes'). The construction methods of these catalysts include genetic mutation, chemical modification using synthetic molecules and/or a combination of these methods. Designed evolution strategy based on the structural information of host proteins has become more and more popular as an effective approach to construct artificial protein-based biocatalysts with desired reactivities. From the viewpoint of application of artificial enzymes for organic synthesis, recently constructed artificial enzymes mediating oxidation, reduction and C-C bond formation/cleavage are introduced in this review article. PMID- 25023538 TI - Whole-cell biotransformation with recombinant cytochrome P450 for the selective oxidation of Grundmann's ketone. AB - 25-Hydroxy-Grundmann's ketone is a key building block in the chemical synthesis of vitamin D3 and its derivatives through convergent routes. Generally, the chemical synthesis of this compound involves tedious procedures and results in a mixture of several products. Recently, the selective hydroxylation of Grundmann's ketone at position C25 by cytochrome P450 (CYP) 154E1 from Thermobifida fusca YX was described. In this study a recombinant whole-cell biocatalyst was developed and applied for hydroxylation of Grundmann's ketone. Biotransformation was performed by Escherichia coli cells expressing CYP154E1 along with two redox partner systems, Pdx/PdR and YkuN/FdR. The system comprising CYP154E1/Pdx/PdR showed the highest production of 25-hydroxy-Grundmann's ketone and resulted in 1.1mM (300mgL(-1)) product concentration. PMID- 25023539 TI - Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine substituted losartan for imaging AT1 receptors. AB - The 2-[(18)F]fluoro-3-pent-4-yn-1-yloxypyridine ([(18)F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [(18)F]FPyKYNE to azide-modified tetrazole protected losartan followed by TFA deprotection. Preliminary small animal imaging with positron emission tomography (PET) in rats displayed high uptake in the kidneys with good contrast to surrounding tissue. Rat metabolism displayed the presence of 23% unchanged tracer in plasma at 30 min. Upon co-administration with AT1R blocker candesartan (2.5, 5 and 10 mg/kg), a dose-dependent reduction (47 65%) in tracer uptake was observed in the kidney, while no difference was observed following AT2R blocker PD123,319 (5 mg/kg), indicating binding selectivity for AT1R over AT2R and potential for imaging AT1R using PET. PMID- 25023541 TI - Preface. Unlocking nature through Chemistry. PMID- 25023540 TI - An azido-oxazolidinone antibiotic for live bacterial cell imaging and generation of antibiotic variants. AB - An azide-functionalised analogue of the oxazolidinone antibiotic linezolid was synthesised and shown to retain antimicrobial activity. Using facile 'click' chemistry, this versatile intermediate can be further functionalised to explore antimicrobial structure-activity relationships or conjugated to fluorophores to generate fluorescent probes. Such probes can report bacteria and their location in a sample in real time. Modelling of the structures bound to the cognate 50S ribosome target demonstrates binding to the same site as linezolid is possible. The fluorescent probes were successfully used to image Gram-positive bacteria using confocal microscopy. PMID- 25023542 TI - The cytoskeleton and its interactions with small molecules. PMID- 25023543 TI - More harm than good? PMID- 25023544 TI - Survival and recurrence patterns after neoadjuvant docetaxel, cisplatin, and 5 fluorouracil (DCF) for locally advanced esophagogastric adenocarcinoma. AB - INTRODUCTION: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a safe, tolerable, and effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophagogastric junction (EGJ). We hypothesized that DCF combined with enhanced surgical control would result in a low rate of local or regional recurrence, and thus reviewed our outcomes with this treatment regimen. METHODS: A prospectively entered database of all esophageal and EGJ ADC patients resected at a high-volume referral center over 6 years (9/07-9/13) was reviewed for cases treated with curative intent neoadjuvant DCF followed by en bloc resection with extended lymphadenectomy (D2/D3). Recurrences was defined as locoregional (biopsy on endoscopy/regional lymph nodes (LNs)) and distant. Standard statistical techniques were used. RESULTS: Of 279 patients with ADC, 86 (85% male, mean age 63 years (interquartile range 56-70)) underwent preoperative DCF and curative intent resection for locally advanced ADC (cT3 93%; cN+ 69%) of the EGJ (54%) or distal esophagus (46%). After median follow-up of 40 months, the overall 5-year survival was 54% and 43 (52%) had recurred at a median time of 14 months. Sites of recurrence included locoregional only in 2 of 45 (4%), distant only in 40 of 45 (89%), and locoregional and distant in 3 of 45 (7%). DISCUSSION: The present study demonstrates favourable oncologic outcomes with low local/regional recurrence and an excellent overall 5-year survival after neoadjuvant DCF for esophageal and EGJ ADCs. Because the majority of recurrences were distant, our data support the notion that efforts to improve outcomes in these patients should concentrate on enhancing systemic, rather than local, therapy. PMID- 25023545 TI - Prognostic significance of lymphovascular invasion in patients with esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy. AB - OBJECTIVE: To investigate the prognostic significance of lymphovascular invasion (LVI) in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT). METHODS: We retrospectively reviewed the charts of 416 consecutive patients with ESCC who underwent surgical resection following nCRT at the Chang Gung Memorial Hospital between 1998 and 2008. After exclusion of patients with non-R0 resection or showing no residual tumor (ypT0Nx), the histological tumor sections of 231 patients were reviewed for LVI. Univariate and multivariate analyses were used to identify the independent predictors of overall survival (OS). RESULTS: LVI was observed in 85 patients (36.8 %). The presence of LVI was related to close circumferential resection margins (CRMs), a greater depth of invasion, poor tumor differentiation, and an increased occurrence of lymph node metastases (LNM). The 5 year OS was significantly lower (10 %) in patients with LVI than in those without (31 %; p < 0.001). By multivariate Cox regression analyses, LVI (hazard ratio [HR] 1.5; p = 0.002) and LNM (HR 1.6; p = 0.007) were identified as independent adverse prognostic factors for OS. The 5 year OS rates according to the number of risk factors present were 35, 21, 20, and 5 for LVI(-)LNM(-), LVI(+)LNM(-), LVI( )LNM(+), and LVI(+)LNM(+) patients, respectively (p < 0.001). CONCLUSIONS: The presence of LVI is independently associated with shorter OS in ESCC patients receiving nCRT. Links between LVI and LNM may provide new clues for the prognostic stratification of esophageal cancer. PMID- 25023546 TI - Nipple-sparing mastectomy in BRCA1/2 mutation carriers: an interim analysis and review of the literature. AB - BACKGROUND: There are few large-scale studies that have examined outcomes for BRCA1/2 carriers who have undergone nipple-sparing mastectomy (NSM). The objective of our study was to examine incidental cancers, operative complications, and locoregional recurrences in BRCA1/2 mutation carriers who underwent NSM for both risk reduction and cancer treatment. METHODS: This was a retrospective review of pathology results and outcomes of 201 BRCA1/2 carriers from two different institutions who underwent NSM from 2007 to 2014. RESULTS: NSM was performed in 397 breasts of 201 BRCA1/2 carriers. One hundred and twenty-five (62.2 %) patients had a BRCA1 mutation and 76 (37.8 %) had a BRCA2 mutation; 150 (74.6 %) patients underwent NSM for risk reduction and 51 (25.4 %) for cancer. Incidental cancers were found in four (2.7 %) of the 150 risk-reduction patients and two (3.9 %) of the 51 cancer patients. The nipple-areolar complex (NAC) was involved with cancer in three (5.8 %) patients. No prophylactic mastectomy had a positive NAC margin. There was loss of the NAC in seven breasts (1.8 %) and flap necrosis in ten (2.5 %) breasts. With a mean follow-up of 32.6 months (1-76 months), there have been four cancer events-three in cancer patients and one in a risk-reduction patient but none at the NAC. CONCLUSION: NSM in BRCA1/2 carriers is associated with a low rate of complications and locoregional recurrence but these patients require long-term follow-up in both the cancer and risk-reduction setting. PMID- 25023547 TI - Surgical approaches to advanced gallbladder cancer : a 40-year single-institution study of prognostic factors and resectability. AB - PURPOSE: The aim was to evaluate prognostic factors and factors associated with the resectability of advanced gallbladder cancer (GBC). METHODS: This was a single-institution retrospective review of 274 consecutive surgically-treated cases of advanced GBC (excluding incidental GBC and early GBC). Univariate and multivariate analysis were performed to assess prognostic variables. R0 resection and survival rates were investigated for each local extension factor. RESULTS: Long-term survival was uncommon among patients with multiple liver metastases (H2 3: n = 22; 2-year survival, 0 %), dissemination (P1-3: n = 16; 3-year survival, 0 %), invasion through the hepatoduodenal ligament (Binf3: n = 45; 5-year survival, 4.6 %), or group 3 lymph node (LN) metastasis including of the para-aortic LN (N3: n = 52; 13.7 %). Long-term survival rates did not differ significantly between patients who did and did not undergo bile duct resection or pancreaticoduodenectomy. Survival did not differ significantly according to the type of hepatectomy performed. CONCLUSION: Surgery may not be indicated for patients with multiple liver metastasis, dissemination, Binf3, or visible para aortic LN metastasis. Furthermore, it is important to achieve R0 surgery in cases of GBC. PMID- 25023551 TI - Relationship between leukocyte telomere length, telomerase activity, and hippocampal volume in early aging. PMID- 25023552 TI - Features of neuromyelitis optica spectrum disorders with aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies. PMID- 25023548 TI - SMO expression in colorectal cancer: associations with clinical, pathological, and molecular features. AB - BACKGROUND: Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear. METHODS: Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1. RESULTS: SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status). CONCLUSIONS: Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed. PMID- 25023553 TI - Moving to fingolimod from natalizumab in multiple sclerosis: the ENIGM is not solved. PMID- 25023554 TI - Features of neuromyelitis optica spectrum disorders and aquaporin-4 with myelin oligodendrocyte glycoprotein antibodies-reply. PMID- 25023555 TI - Tau, s-100 calcium-binding protein B, and neuron-specific enolase as biomarkers of concussion. PMID- 25023556 TI - Moving to fingolimod from natalizumab in multiple sclerosis-reply. PMID- 25023557 TI - Tau, s-100 calcium-binding protein B, and neuron-specific enolase as biomarkers of concussion-reply. PMID- 25023559 TI - Digital doctor. AB - As telemedicine gains momentum, so does policy interest at the state and federal levels. A new Federation of State Medical Boards model policy aims to create a roadmap for the safe and appropriate practice of telemedicine. But a provision that has sparked debate says a telephone call or online visit alone won't suffice for newly established patient relationships. PMID- 25023560 TI - Cyber crimes. AB - Since it began offering cyber liability coverage in December 2011, the Texas Medical Liability Trust has received more than 150 cyber liability claims, most of which involved breaches of electronic protected health information. TMLT's cyber liability insurance will protect practices financially should a breach occur. The insurance covers a breach notification to customers and business partners, expenses for legal counsel, information security and forensic data services, public relations support, call center and website support, credit monitoring, and identity theft restoration services. PMID- 25023561 TI - Lifting the veil. AB - As governments and employers look for ways to curb growing health care costs, and as patients bear a higher share of their medical bills, policymakers in Texas and beyond increasingly target physicians in their efforts to unveil health care prices. They couch such "price transparency" as a way to help patients make more informed health care decisions. But Texas Medical Association's Board of Trustees member Gary W. Floyd, MD, of Fort Worth, cautions that for a complex health care payment system, coupled with individual patients' complex needs, coming up with a so-called "sticker price" is not as simple as it seems. PMID- 25023562 TI - The more your patients know. AB - In February, the Texas Institute of Health Care Quality and Efficiency released its strategic plan to guide the institute's activities for the next five years, including an initiative to improve health literacy in the state. Many physicians already are taking steps to improve health literacy among their patients. TMA is helping doctors promote health literacy by participating in the national Walk With a Doc program, which promotes patient-physician communication and healthy lifestyles, and the Choosing Wisely campaign, which allows physicians to play a key role in health care literacy by not ordering and recommending tests or treatments that cost a lot of money that have not proven to be effective. PMID- 25023563 TI - A necessary pain. AB - In October 2013, the Texas Department of Public Safety officially began allowing physicians to electronically prescribe schedule II controlled substances. The practice of electronic prescription of controlled substances (EPCS) for schedule II drugs became more commonplace in March 2014, after DPS completed a small pilot program to test the accuracy of reporting schedule II drugs to the Texas Prescription Program. Sending prescription requests to a pharmacy through an electronic vendor helps reduce the risk of prescription fraud. PMID- 25023564 TI - An estimation method for improved extraction of the decay curve signal from CPMG like measurements with a unilateral scanner. AB - Unilateral NMR devices are valuable tools used to study non-invasively arbitrarily-sized objects. They have been utilized in various applications, including non-destructive testing and well logging. However, measurements with such scanners are characterized by a low sensitivity, which is mainly the result of the low and inhomogeneous magnetic field B0. The resulting poor signal to noise ratio (SNR) is a prominent limitation, as it deteriorates the accuracy of data analysis. Improving the SNR is typically done by the use of averaging repetitions that result in too long scan times. This work presents a statistical signal-processing method that can improve the sensitivity of a Carr-Purcell Meiboom-Gill (CPMG)-like sequence for measurements of transverse-relaxation with unilateral scanners. The method improves the extraction of the decay curve from the noisy data. This is done by exploiting the redundancy in the acquired signal and by the use of the noise characteristics, which are both incorporated into a weighted least-squares estimation approach. This technique is especially effective in applications where RF shielding is not in use, and the measurements are corrupted by dominant non-white noise. The method performance was evaluated with a series of CPMG-like measurements applied on two samples. Decay curves were extracted from each measurement with the proposed method and were compared to a conventional extraction of the decay curve. All measurements showed a significant improvement in the accuracy of estimation of the decaying signal. Thus, the improvement in the sensitivity can be translated into a reduction in the acquisition times (by reducing the need in averaging repetitions) or to a more accurate fitting process of the traverse relaxation distribution. PMID- 25023565 TI - COMPOZER-based longitudinal cross-polarization via dipolar coupling under MAS. AB - We propose a cross polarization (CP) sequence effective under magic-angle spinning (MAS) which is tolerant to RF field inhomogeneity and Hartmann-Hahn mismatch. Its key feature is that spin locking is not used, as CP occurs among the longitudinal (Z) magnetizations modulated by the combination of two pulses with the opposite phases. We show that, by changing the phases of the pulse pairs synchronized with MAS, the flip-flop term of the dipolar interaction is restored under MAS. PMID- 25023566 TI - Multiple acquisition/multiple observation separated local field/chemical shift correlation solid-state magic angle spinning NMR spectroscopy. AB - Multiple acquisition spectroscopy (MACSY) experiments that enable multiple free induction decays to be recorded during individual experiments are demonstrated. In particular, the experiments incorporate separated local field spectroscopy into homonuclear and heteronuclear correlation spectroscopy. The measured heteronuclear dipolar couplings are valuable in structure determination as well as in enhancing resolution by providing an additional frequency axis. In one example four different three-dimensional spectra are obtained in a single experiment, demonstrating that substantial potential saving in experimental time is available when multiple multi-dimensional spectra are required as part of solid-state NMR studies. PMID- 25023567 TI - The distribution of human surfactant proteins within the oral cavity and their role during infectious diseases of the gingiva. AB - The oral cavity with the teeth and the surrounding gingival epithelium, the periodontium, the salivary glands and other structures are open to the oral environment and thus exposed to multiple microbiological and pathogenic influences. To prevent permanent inflammatory processes such as gingivitis or periodontitis an efficient defense system is essential to ensure healthy and physiological function of the oral cavity and other interacting organic systems. Surfactant proteins (SPs), originally found in pulmonary tissue are important factors of the immune system and beyond this, support the stability and rheology of gas or fluid interfaces. This study aimed to analyze the distribution of surfactant proteins by means of Western blot and immunohistochemistry in salivary glands as well as in healthy and pathological saliva. The different expression patterns of SP-A, -B, -C and -D in healthy and pathological (periodontitis) saliva were determined using ELISA quantification. One further objective of the study was the first detection of two recent discovered proteins belonging to the surfactant protein family within human salivary glands and saliva. The results of the study reveal differences in protein expression of SP-A, -B, -C and -D within healthy and pathologic saliva. The concentration of the surfactant proteins SP-A, SP-C and SP-D is increased in saliva of people suffering from periodontal diseases, whereas by contrast, SP-B shows an opposite expression pattern. Furthermore, the results evidence the presence of SP-G and SP-H within saliva and salivary glands for the first time. PMID- 25023569 TI - Management of patients with clinical stage I nonseminomatous germ cell testicular cancer: Active surveillance versus adjuvant chemotherapy - single-centre experience. AB - Surveillance after orchiectomy alone has become popular in the management of clinical stage I nonseminomatous germ cell testicular tumors (CSI NSGCTT). Efforts to identify patients at high risk of disease progression led to a search for risk factors in CSI NSGCTT. The aim of the present study was to analyse single-centre experience with risk-adapted therapeutic approaches (active surveillance versus adjuvant chemotherapy). From 1/1992 to 12/2013 a total of 431 CSI NSGCTT patients were included in the study and stratified into two groups according to risk-adapted therapeutic approaches. Group A (low-risk CSI NSGCTT) consisted of 276 patients who underwent active surveillance, progression of disease occurred in 46 (16.7%) patients with a median follow-up of 7.2 months. Six patients (2.2 %) of this group died with a median follow-up of 34.3 months. Group B (high-risk CSI NSGCTT) consisted of 155 patients who were treated with adjuvant chemotherapy, disease progression occurred in two (1.3 %) of them with a median follow-up of 56.2 months. One patient (0.6 %) died 139.4 months following orchiectomy. Overall survival rate of all CSI NSGCTT patients in both groups was 424/431 (98.4 %) with median follow-up of 130.4 months following orchiectomy. Surveillance policy is recommended only in patients with low-risk CSI NSGCTT. KEYWORDS: testicular cancer, surveillance, adjuvant chemotherapy, disease progression. PMID- 25023568 TI - Energetics of oxo- and thio-dipeptide formation via amino acid condensation: a systematic computational analysis. AB - Oxo-dipeptides and thio-dipeptides are built via condensation between couples of amino acids and amino thioacids, the latter with the carbonyl oxygen replaced by an sp(2) sulfur. We explored via in silico methods (PBE0/6-31G(d,p) and PBE0/6 311G(d,p)) all the possible combinations and built 800 dipeptides, whose structures were fully optimized. Maps of condensation energies are presented to highlight optimal partners leading to stable dipeptides and critical situations for which lower stability or instability is predicted in terms of Gibbs reaction free energies. To validate the feasibility of our computational investigation, we synthesized and compared the stabilities of two thionated dimers, namely Gly[Psi(CSNH)]Gly- and -Phe[Psi(CSNH)]Phe-, characterized by diverging physico chemical properties. To the best of our knowledge, this is the first systematic analysis reported for dipeptides built from natural amino acids as well as for their corresponding thio-analogs. PMID- 25023573 TI - Efficacy of a slow-release imidacloprid (10%)/flumethrin (4.5%) collar for the prevention of canine leishmaniosis. AB - BACKGROUND: The efficacy of a slow-release insecticidal and repellent collar containing 10% imidacloprid and 4.5% flumethrin (Seresto, Bayer Animal Health) in preventing Leishmania infantum infection was evaluated in a large population of dogs living in a hyper-endemic area of Sicily (Italy). METHODS: A total of 219 dogs, negative for L. infantum were enrolled in a multicentre, controlled study. Dogs were divided into two homogeneous groups, defined as G1 (n = 102) and G2 (n = 117). Before the start of the sand fly season, dogs in G1 were treated with the collar while animals in G2 were left untreated, serving as negative controls. Dogs were serially sampled on day D90, D180, D210 and D300 in order to assess Leishmania infection by IFAT, PCR on skin (D210-D300) and bone marrow (D300) and cytology on bone marrow aspirate (D300). RESULTS: Three dogs (2.9%) in G1 and 41 (40.2%) in G2 became positive for L. infantum in at least one of the diagnostic tests employed in the study. The number of seropositive dogs in G2 increased in the course of the study from 15 (D90) to 41 (D300), with some of them also positive in other diagnostic tests. Eight (19.6%) of the seropositive dogs in G2 showed an increase in antibody titers ranging from 1:160 to 1:1,280. At the last follow-up, some of dogs in G2 displayed overt clinical signs suggestive of leishmaniosis. The mean incidence density rate at the final follow-up was 4.0% for G1 and 60.7% for G2, leading to a mean efficacy of the collar in protecting dogs at both sites of 93.4%. CONCLUSIONS: The slow-release collar tested in this study was shown to be safe and highly effective in preventing L. infantum infection in a large population of dogs. Protection conferred by a single collar (up to eight months) spanned an entire sand fly season in a hyper-endemic area of southern Italy. The regular use of collars, at least during the sand fly season, may represent a reliable and sustainable strategy for the prevention of leishmaniosis in dogs living in or travelling to an endemic area. PMID- 25023574 TI - Development of a two-step cultivation strategy for the production of vitamin B12 by Bacillus megaterium. AB - BACKGROUND: Vitamin B12 is a fascinating molecule which acts as a co-factor in the metabolism of many organisms, especially affecting DNA synthesis and regulation, fatty acid synthesis and energy production. The synthesis of vitamin B12 is limited to a few of bacteria and archaea. Therefore, industrial microbial fermentation is used to meet annual demands worldwide of vitamin B12 and as an alternative method to the chemical synthesis which requires at least 60 steps that is uneconomical. Bacillus megaterium is one of vitamin B12 producers and an ideal host for many biotechnology applications and being one of the best tools for the industrial production of several enzymes. Therefore, a two-step optimization strategy was established to produce high yield of vitamin B12 by B. megaterium through the provision of the production requirements and the suitable conditions for the biosynthesis of vitamin B12. RESULTS: We achieved the optimum conditions for the fermentation process of B. megaterium to produce high yield of vitamin B12 in a practical way based on statistical design and analysis which allowed vitamin B12 production to increase up to 759-fold (204.46 MUg/l) as compared with control without parameters (0.26 MUg/L). High performance liquid chromatography coupled to variable wavelength detector and mass spectrometry has been used to identify vitamin B12 forms and confirm the results. CONCLUSIONS: We developed the fermentation process of B. megaterium to enhance the production of vitamin B12 by providing the required supplements for the synthesis of vitamin B12 (CoCl2, delta-aminolevulinic acid (ALA) and 5,6-dimethylbenzimidazole (DMB)) and dividing the fermentation process into three stages. In addition, the optimum incubation times of the three fermentation stages were investigated and performed with reducing number of experimental and evaluated multiple parameters and their interactions by using statistical experimental design and analysis. All of these strategies has proven successful in enhancing the production of vitamin B12 up to 204.46 MUg/l and demonstrated that B. megaterium could be a good candidate for the industrial production of vitamin B12. PMID- 25023575 TI - Atomic scale real-space mapping of holes in YBa2Cu3O(6+delta). AB - The high-temperature superconductor YBa2Cu3O(6+delta) consists of two main structural units--a bilayer of CuO2 planes that are central to superconductivity and a CuO(2+delta) chain layer. Although the functional role of the planes and chains has long been established, most probes integrate over both, which makes it difficult to distinguish the contribution of each. Here we use electron energy loss spectroscopy to directly resolve the plane and chain contributions to the electronic structure in YBa2Cu3O6 and YBa2Cu3O7. We directly probe the charge transfer of holes from the chains to the planes as a function of oxygen content, and show that the change in orbital occupation of Cu is large in the chain layer but modest in CuO2 planes, with holes in the planes doped primarily into the O 2p states. These results provide direct insight into the local electronic structure and charge transfers in this important high-temperature superconductor. PMID- 25023576 TI - High rate of clinical and endoscopic relapse after healing of erosive peptic esophagitis in children and adolescents. AB - OBJECTIVES: The aim of the present study was to estimate the rate of clinical and endoscopic relapse after initial treatment of erosive peptic esophagitis in children and adolescents. METHODS: A total of 24 patients (2.1-16.4 years old, mean +/- standard deviation [SD] 9.9 +/- 3.1; male:female 3) with healed endoscopic erosive esophagitis and without gastroesophageal reflux disease (GERD) predisposing conditions were followed up for 4 to 32.9 months (mean 20.8 +/- 10.6 years). Structured clinical evaluation was performed every other week during the initial treatment and maintenance, and every 3 months after that. Whenever a clinical relapse happened, a new endoscopic evaluation was performed. Severity and frequency were scored on 10-point and 6-point semiquantitative scales, respectively. RESULTS: At baseline, epigastric pain was the most reported symptom (70.8%), with intensity scored as >5 in 88.3% of patients, and median frequency of 3 (weekly; daily in 5, 20.8%). Clinical relapse was detected in 20 of 24 (83.3%) patients after a median period of 14.65 months (95% confidence interval [CI] 6.7-25.7 months). Endoscopic relapse was observed in 9 of 20 (45%) patients after a median of 25.7 months. The dose of lansoprazole needed to heal the esophagitis was not significantly associated with the risk for clinical relapse (hazard ratio [HR] 1.74, 0.94, 7.72, P = 0.06), whereas the body mass index (BMI) was directly associated with endoscopic relapse (HR 1.3, 1, 1.69, P = 0.05). CONCLUSIONS: Children with healed erosive esophagitis have up to 83% clinical relapse and of the 83%, 45% had endoscopic relapse. Correlation of endoscopic relapse with clinical symptom is poor. Higher grades of esophagitis and higher BMI are risk factors for endoscopic relapse. PMID- 25023577 TI - Inflammatory Bowel Disease and Diverticulosis in an Adolescent With DiGeorge Syndrome. PMID- 25023578 TI - Efficacy of fecal microbiota transplantation in 2 children with recurrent Clostridium difficile infection and its impact on their growth and gut microbiome. AB - Fecal microbiota transplantation (FMT) is recognized as an alternative therapeutic modality for recurrent Clostridium difficile infection (RCDI); however, data on its efficacy in children are lacking, including its effect on their growth and fecal microbiota. We report on 2 young children (<3 years old) who failed available therapeutics for RCDI, but responded remarkably well to FMT. Besides resolution of clinical features of C difficile infection (CDI), FMT administration led to marked improvement in their growth, along with increased microbiota diversity, especially proportion of Bacteroides. Our 2 cases illustrate the efficacy of FMT in children with RCDI and its positive effect on their growth and gut microbiota. PMID- 25023579 TI - Ustekinumab for Resistant Pediatric Crohn Disease. PMID- 25023580 TI - Ultrasonographic diagnosis of midgut volvulus with malrotation in children. AB - OBJECTIVES: Midgut volvulus with malrotation is typical in newborns. We present our experience to emphasize the importance of suspecting midgut volvulus as a cause of abdominal pain also beyond infancy, particularly in relation to malrotation, and the relevance of ultrasonographic (US) signs in its diagnosis. METHODS: A total of 34 patients (10 boys, 24 girls; ages between 1 day and 12 years) diagnosed as having malrotation or malrotation with volvulus, surgically confirmed, between 2006 and 2013 were retrospectively selected among all of the patients referred to our institution for acute abdomen and bilious vomiting. All of them underwent US and color Doppler examination before surgery. The US examinations were performed with 6 to 10 MHz microconvex and 7.5 to 10 Mhz linear transducer. The transducer was placed under xiphoid, and, with axial projection, the presence of anatomic position reversed between superior mesenteric vein (SMV) and superior mesenteric artery (SMA), as a sign of malrotation, and the presence of "whirlpool sign" (WS) (wrapping of the SMV and the mesentery around the SMA), as a sign of midgut volvulus, were evaluated. RESULTS: In 27 of these 34 patients, midgut volvulus was present; 7 patients had intestinal malrotation. In 2 of 7 (28%) patients with malrotation, SMA and SMV were inverted. Among the patients with volvulus, 2 showed reversed vessel position and 22 patients presented the WS in association with SMA/SMV inversion (22/27, 81%). CONCLUSIONS: Midgut volvulus with malrotation can appear beyond the neonatal age group as demonstrated in our case. The WS sign is sufficiently sensitive for its diagnosis and should be routinely researched at all ages of pediatric population. Anatomic inversion between SMV and SMA seems to be not enough sensitive in isolated malrotation diagnosis. PMID- 25023581 TI - Utility of gastrointestinal fluoroscopic studies in detecting stricture after neonatal necrotizing enterocolitis. AB - OBJECTIVES: We report our institution's 5-year experience with upper gastrointestinal study with small bowel follow-through (UGI-SBFT) and contrast enema (CE) for the diagnosis of a post-necrotizing enterocolitis (NEC) stricture. We hypothesized that sensitivity and specificity of UGI-SBFT and CE were <85% in diagnosing a post-NEC stricture. METHODS: A retrospective observational cohort study was performed. Included patients were neonates diagnosed as having Bell's modified stage 2 or 3 NEC who had undergone UGI-SBFT and/or CE to evaluate for a stricture. Exploratory laparotomy was used to definitively determine the stricture presence, which was confirmed by pathology. An infant was categorized as having no stricture if no surgical intervention occurred or if no stricture was reported on pathology following surgical resection. RESULTS: A total of 56 patients met inclusion criteria, with 51 UGI-SBFT and 85 CE performed. A total of 25 patients were diagnosed as having a stricture. For small bowel (SB) strictures, CE compared with UGI-SBFT has a higher sensitivity (0.667 vs 0.00) and a similar specificity (0.857 vs 0.833). For SB and/or colonic strictures, CE has a sensitivity of 0.667 and a specificity of 0.951. Strictures were more likely to be found on imaging in symptomatic infants compared with those in asymptomatic infants (28% vs 8%, P = 0.002). CONCLUSIONS: CE should be the initial study in the diagnostic workup for a post-NEC stricture because this test has a higher likelihood of detecting a stricture if it is present. As a result of low sensitivity of UGI-SBFT and/or CE in the diagnosis of a post-NEC stricture, a negative study should not rule out the diagnosis of a stricture in persistently symptomatic patients. PMID- 25023582 TI - Inflammatory Bowel Disease With Lethal Disease Course Caused by a Nonsense Mutation in BIRC4 Encoding X-Linked Inhibitor of Apoptosis Protein (XIAP). PMID- 25023584 TI - ESPGHAN position paper on management of percutaneous endoscopic gastrostomy in children and adolescents. AB - OBJECTIVES: This European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position statement provides a comprehensive guide for health care providers to manage percutaneous endoscopic gastrostomy tubes in a safe, effective, and appropriate way. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of evidence, recommendations reflect the expert opinion of the authors. Final consensus was obtained by multiple e-mail exchange and during 3 face-to-face meetings of the gastroenterology committee of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. RESULTS: Endoscopically placed gastrostomy devices are essential in the management of children with feeding and nutritional problems. The article focuses on practical issues such as indications and contraindications. CONCLUSIONS: The decision to place an endoscopic gastrostomy has to be made by an appropriate multidisciplinary team, which then provides active follow-up and care for the child and the device. PMID- 25023585 TI - Deciphering the role of omega3 fatty acids in nonalcoholic steatohepatitis. PMID- 25023586 TI - Dilated intercellular spaces in eosinophilic esophagitis. AB - OBJECTIVES: Dilated intercellular spaces (DIS) in the esophageal epithelium can be induced by acid and reduced by proton pump inhibitors (PPI), and are thus considered a marker of gastroesophageal reflux disease (GERD). Over the years, however, DIS have also been reported in esophagitis unrelated to GERD. Because DIS have never been formally measured in eosinophilic esophagitis (EoE), we aimed at detecting and measuring DIS in EoE before and after nutritional or pharmacological therapy. METHODS: In 22 children with EoE, DIS were measured by morphometry and transmission electron microscopy (TEM), before and after treatment with topical steroids (n = 16) and/or exclusion diet (n = 13). A total of 30 children undergoing upper gastrointestinal endoscopy with biopsy for nonesophageal disorders acted as controls. RESULTS: In controls, the mean (+/- standard deviation [SD]) number of esophageal eosinophils was 0.91 (+/- 0.47) and the mean DIS values were 0.62 (+/- 0.08) MUm at morphometry and 0.33 (+/- 0.24) MUm at TEM. In patients with EoE, the mean (+/- SD) number of esophageal eosinophils decreased from 31.8 (+/- 6.96) to 6.64 (+/- 5.01) (P < 0.0001), and the mean DIS values decreased from 2.26 (+/- 0.21) to 1.23 (+/- 0.20) MUm at morphometry (P < 0.0001), and from 2.24 (+/- 0.28) to 0.98 (+/- 0.19) MUm at TEM (P < 0.0001), respectively, before and after treatment. CONCLUSIONS: DIS are a prominent morphological feature of EoE, in which they can be significantly reduced by an appropriate non-PPI therapy. PMID- 25023587 TI - IL-6 572 C/G, 190 C/T, and 174 G/C gene polymorphisms in children's malnutrition. AB - OBJECTIVES: The aim of the present study was to establish the correlations between the polymorphisms of the genes interleukin-6 (IL-6) 572, 190, and 174 in children's malnutrition. METHODS: We assessed 283 hospitalized children and divided them into 2 groups: group I (control) included 110 patients with normal nutritional status, median (range) age 10.90 (1-18) years; and group II consisted of 173 malnourished patients, median (range) age 10.70 (1-18) years. RESULTS: The 2 groups underwent IL-6 572 cytosine allele (C)/guanine allele (G), 190 C/thymine allele (T), and 174 G/C polymorphism testing, measurement of anthropometric indicators (mid-upper arm circumference and tricipital skinfold thickness [TST]), and paraclinical evaluation (protein, albumin). We observed that the GG and CG genotypes were more frequent in malnourished children for the IL-6 174 gene (P = 0.0001), whereas the CT heterozygous genotype was more frequent in the malnourished group for the IL-6 190 gene (P = 0.003). Body mass index (BMI), middle upper arm circumference (MUAC), TST, and low serum albumin levels correlated with the GG and CG genotypes of the IL-6 572 and IL-6 174 genes, and with the CT genotype of the IL-6 190 gene, in children with malnutrition, whereas the IL-6 190 TT genotype was a protective factor for malnutrition (P = 0.0001). CONCLUSIONS: Malnutrition is more frequently associated in children with IL-6 174 G allele carriers (GG and CG genotypes), whereas IL-6 190 TT genotype has a protective function. In malnourished children, the IL-6 572/190/174 GG/CT/CG, GG/CT/GG, GG/CC/GG, and GG/CC/CG combined genotypes are more frequent. PMID- 25023588 TI - [Stereotactic body radiation therapy: uncertainties and margins]. AB - The principles governing stereotactic body radiation therapy are tight margins and large dose gradients around targets. Every step of treatment preparation and delivery must be evaluated before applying this technique in the clinic. Uncertainties remain in each of these steps: delineation, prescription with the biological equivalent dose, treatment planning, patient set-up taking into account movements, the machine accuracy. The calculation of margins to take into account uncertainties differs from conventional radiotherapy because of the delivery of few fractions and large dose gradients around the target. The quest of high accuracy is complicated by the difficulty to reach it and the lack of consensus regarding the prescription. Many schemes dose/number of fractions are described in clinical studies and there are differences in the way describing the delivered doses. While waiting for the ICRU report dedicated to this technique, it seems desirable to use the quantities proposed in ICRU Report 83 (IMRT) to report the dose distribution. PMID- 25023589 TI - Male factor infertility: In vitro spermatogenesis and fertilization from cryopreserved murine testicular tissue. PMID- 25023597 TI - Prostate cancer: Phasing in new treatment. PMID- 25023593 TI - Enhanced recovery programmes for patients undergoing radical cystectomy. AB - Radical cystectomy is associated with high rates of surgical morbidity. The magnitude of the surgical insult is associated with the degree of stress response, particularly in ageing patients with multiple comorbidities. Attempts to limit this response and identify areas of improvement with respect to patient selection and optimization, anaesthesia, surgical technique and postoperative care underpin the multimodal approach to enhanced recovery pathways. No single intervention significantly reduces morbidity, but the combination of many interventions at all levels of the pathway is likely to accelerate the patient journey from diagnosis to return to normal function. PMID- 25023600 TI - Financial protection effects of modification of China's New Cooperative Medical Scheme on rural households with chronic diseases. AB - BACKGROUND: Several years have passed since the rural New Cooperative Medical Scheme (NCMS) in China was established and policies kept continuous improvement. Its policies on chronic diseases vary by county but have certain shared characteristics. Following this modification of medical insurance policy, this study reassesses the provision of insurance against expenditure on chronic diseases in rural areas, and analyzes its effect on impoverishment. METHODS: We conducted an empirical study using multi-stage stratified random sampling. We surveyed 1,661 rural households in three provinces and analyzed the responses from 1,525 households that participated in NCMS, using descriptive and logistic regression analysis. RESULTS: The NCMS has reduced the prevalence of poverty and catastrophic health expenditure (CHE), as measured by out-of-pocket (OOP) payments exceeding 40% of total household expenditure, by decreasing medical expenditure. It provides obvious protection to households which include someone with chronic diseases. However, these households continue to face a higher financial risk than those without anyone suffering from chronic diseases. Variables about health service utilization and OOP payment differed significantly between households with or without people suffering from chronic disease. And CHE risk is commonly associated with household income, the number of family members with chronic diseases, OOP payment of outpatient and inpatient service in all three provinces. CONCLUSION: To reduce CHE risk for these households, it is critical to decrease OOP payments for health services by enhancing the effective reimbursement level of NCMS and strictly regulating the providers' behaviors. We recommend that a combinatory changes should be made to the rural health insurance scheme in China to improve its effect. These include improving the NCMS benefit package by broadening the catalogue of drugs and treatments covered, decreasing or abolishing deductible and increasing the reimbursement ratio of outpatient services for people with chronic diseases, together with expansion of insurance fund, and modifying health providers' behaviors by payment reform. PMID- 25023601 TI - Soft contact lens fitting after intrastromal corneal ring segment implantation to treat keratoconus. AB - PURPOSE: To assess the feasibility of fitting a lathed soft toric contact lens (STCL) after the implant of intrastromal corneal ring segments (ICRSs) to treat keratoconus. METHODS: Six months after ICRS implantation, 47 eyes of 47 patients (18-45 years) were fitted with a STCL. In each eye, we determined refractive error, uncorrected (UDVA) and corrected distance visual acuity (CDVA), and keratometry and asphericity measures. The outcome of STCL fitting was defined according to CDVA as successful (<=0.2logMAR) or unsuccessful (>0.2logMAR). Patients in the unsuccessful group were refitted with a piggy-back (PB) system. The above variables and the change in CDVA observed after STCL and PB lens fitting from spectacle CDVA were compared in the two groups. RESULTS: STCL fitting was successful in 75%, 66.66% and 0% of the ICRS implanted eyes with stages I-III keratoconus, respectively. Spectacle-CDVA was 1.5 lines better and mean corneal power was 3.62D lower in the successful STCL group. In this group, the difference in cylinder axis between spectacles and STCL was 24.25 degrees lower. PB refitting achieved a PB-CDVA <=0.2logMAR in all cases. A similar difference in the CDVA change achieved by contact lenses versus spectacles was observed in the successful STCL and PB refitted groups. CONCLUSION: STCL fitting is a feasible option in a large proportion of patients implanted with ICRS. When these lenses are unsatisfactory, a PB system is a good alternative. PMID- 25023602 TI - Regarding "in vitro profiles of multifocal "simultaneous vision" contact lenses". PMID- 25023603 TI - Harmonizing influenza primary-care surveillance in the United Kingdom: piloting two methods to assess the timing and intensity of the seasonal epidemic across several general practice-based surveillance schemes. AB - General Practitioner consultation rates for influenza-like illness (ILI) are monitored through several geographically distinct schemes in the UK, providing early warning to government and health services of community circulation and intensity of activity each winter. Following on from the 2009 pandemic, there has been a harmonization initiative to allow comparison across the distinct existing surveillance schemes each season. The moving epidemic method (MEM), proposed by the European Centre for Disease Prevention and Control for standardizing reporting of ILI rates, was piloted in 2011/12 and 2012/13 along with the previously proposed UK method of empirical percentiles. The MEM resulted in thresholds that were lower than traditional thresholds but more appropriate as indicators of the start of influenza virus circulation. The intensity of the influenza season assessed with the MEM was similar to that reported through the percentile approach. The MEM pre-epidemic threshold has now been adopted for reporting by each country of the UK. Further work will continue to assess intensity of activity and apply standardized methods to other influenza-related data sources. PMID- 25023604 TI - Phenotypic and QTL allelic associations among embryonic developmental rate, body size, and precocious maturation in male rainbow trout. AB - We examined associations among embryonic developmental rate (EDR) as measured by hatching time, juvenile body weight (BW) and propensity for precocial sexual maturation (PM) at two years in two sets of diallel crosses of rainbow trout produced in two spawning seasons (September and December) at both the phenotypic and genotypic levels. Dams and sires had highly significant effects on the body weight of their male juvenile progeny on three measurement dates where parental effects remained consistent through time. Dams spawning earlier in the season produced a greater number of mature male progeny (56.7%) than did later spawning females (25.6%). The families from the December lot showed the expected associations among traits in that earlier hatching fish were significantly heavier on all three measurement dates than later hatching fish and were more likely to mature earlier when families were combined. Moreover, earlier maturing fish were significantly heavier on the third measurement date than those that did not mature. In the September lot, mature fish were significantly heavier as juveniles on all three measurement dates than immature fish as predicted but no significant associations were detected between EDR and BW or between PM and EDR. Significant QTL were detected for all three traits but the linkage group location varied depending on the trait and half-sib group analyzed (across dams and sires in each lot). A strong QTL for EDR with genome-wide effects was detected on linkage group RT-8 in all four half-sib analyses. None of the four linkage groups analyzed had QTL for all three traits. However, the phenotypic association between EDR and BW observed in the December lot was supported by the co localization of QTL to linkage group RT-8 and a positive coupling of allelic effects. RT-8 marker alleles significantly associated with faster EDR were also associated with larger BW and this was observed in numerous families on all three measurement dates. Linkage group RT-24 had weaker QTL for all three traits in the September lot but these were not detected in the same half-sib group simultaneously. At the allelic level, marker alleles for faster EDR were also associated with BW but only at the third measurement date and the progeny of one male. Similarly, RT-30 had weaker QTL for EDR and PM in the December paternal half-sib analysis but no associations were evident at the allelic level. The detection of associations between life history traits and growth at both the phenotypic and genotypic levels has significant implications to aquaculture breeding programs where selection for a desirable trait may lead to unwanted alterations of other traits. Furthermore, the differences between spawning season lots emphasize the complex interaction between environment and genotype on economically important traits and the resulting challenges for aquaculture. PMID- 25023605 TI - Study on the Antimicrobial Properties of Citrate-Based Biodegradable Polymers. AB - Citrate-based polymers possess unique advantages for various biomedical applications since citric acid is a natural metabolism product, which is biocompatible and antimicrobial. In polymer synthesis, citric acid also provides multiple functional groups to control the crosslinking of polymers and active binding sites for further conjugation of biomolecules. Our group recently developed a number of citrate-based polymers for various biomedical applications by taking advantage of their controllable chemical, mechanical, and biological characteristics. In this study, various citric acid derived biodegradable polymers were synthesized and investigated for their physicochemical and antimicrobial properties. Results indicate that citric acid derived polymers reduced bacterial proliferation to different degrees based on their chemical composition. Among the studied polymers, poly(octamethylene citrate) showed ~70 80% suppression to microbe proliferation, owing to its relatively higher ratio of citric acid contents. Crosslinked urethane-doped polyester elastomers and biodegradable photoluminescent polymers also exhibited significant bacteria reduction of ~20 and ~50% for Staphylococcus aureus and Escherichia coli, respectively. Thus, the intrinsic antibacterial properties in citrate-based polymers enable them to inhibit bacteria growth without incorporation of antibiotics, silver nanoparticles, and other traditional bacteria-killing agents suggesting that the citrate-based polymers are unique beneficial materials for wound dressing, tissue engineering, and other potential medical applications where antimicrobial property is desired. PMID- 25023608 TI - Manzamine alkaloids as antileishmanial agents: A review. AB - Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, caused by protozoan parasites of the genus Leishmania. Leishmaniasis control profoundly depends upon chemotherapy which includes pentavalent antimonials, paromomycin, pentamidine, amphotericin B and miltefosine. Miltefosine is the only oral drug used for the treatment of Visceral Leishmaniasis with high cure rate but decrease in susceptibility is observed in countries like India where it is extensively used. Hence, there is an urgent need to develop novel antileishmanial agents with good potency and better therapeutic profile. Manzamines are unique group of beta-carboline alkaloids isolated from marine sponges and exhibited potent antileishmanial activity. In the present study, we described antileishmanial activity, cytotoxicity and structure activity relationship of natural manzamine alkaloids. PMID- 25023607 TI - Altered and dynamic ion selectivity of K+ channels in cell development and excitability. AB - K(+) channels play a key role in regulating cellular excitability. It was thought that the strong K(+) selectivity of these channels was static, only altered by mutations in their selectivity filter, which can cause severe genetic disorders. Recent studies demonstrate that selectivity of K(+) channels can also exhibit dynamic changes. Under acidic conditions or in low extracellular K(+) concentrations, the two-pore domain K(+) channel (K2P) TWIK1 becomes permeable to Na(+), shifting from an inhibitory role to an excitatory role. This phenomenon is responsible for the paradoxical depolarization of human cardiomyocytes in pathological hypokalemia, and therefore may contribute to cardiac arrhythmias. In other cell types, TWIK1 produces depolarizing leak currents under physiological conditions. Dynamic ion selectivity also occurs in other K2P channels. Here we review evidence that dynamic selectivity of K2P channels constitutes a new regulatory mechanism of cellular excitability, whose significance is only now becoming appreciated. PMID- 25023611 TI - Are bisexually active men a 'bridge' for HIV transmission to the 'general population' in Germany? Data from the European Men-Who-Have-Sex-With-Men Internet Survey (EMIS). AB - To assess the situation of bisexually active men in the German HIV epidemic, data from a 2010 internet survey about sexual health among men who have sex with men were used to assess HIV testing rates, condom use and risk contact among the following groups of respondents: bisexually active single men, bisexually active men with a regular female partner, bisexually active men with a regular male partner and exclusively homosexually active men. Of the 54,387 respondents from Germany, 12% reported having sex contacts with both men and women in the previous year. Descriptive statistics were used to explore the sample's socio-demographic characteristics and to identify relevant inter-group differences in sexual attraction, identity, awareness among contacts of attraction to men, number of sex partners, history of anal intercourse, recruitment of partners online, history of HIV testing and drug use. Multivariable regression analyses were used to assess potential associations between these variables and risk contacts, defined as having reported unprotected anal intercourse with male partners of unknown or discordant serostatus in the previous year. Bisexually active groups reported relatively few risk contacts, strengthening the argument that there is little support for the existence of a substantial 'bisexual bridge' in Germany. PMID- 25023609 TI - Inhibition of the HIF1alpha-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II). AB - Protein-protein interactions between the hypoxia inducible factor (HIF) and the transcriptional coactivators p300/CBP are potential cancer targets due to their role in the hypoxic response. A natural product based screen led to the identification of indandione and benzoquinone derivatives that reduce the tight interaction between a HIF-1alpha fragment and the CH1 domain of p300. The indandione derivatives were shown to fragment to give ninhydrin, which was identified as the active species. Both the naphthoquinones and ninhydrin were observed to induce Zn(II) ejection from p300 and the catalytic domain of the histone demethylase KDM4A. Together with previous reports on the effects of related compounds on HIF-1alpha and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds. PMID- 25023612 TI - An integrated genomic and metabolomic framework for cell wall biology in rice. AB - BACKGROUND: Plant cell walls are complex structures that full-fill many diverse functions during plant growth and development. It is therefore not surprising that thousands of gene products are involved in cell wall synthesis and maintenance. However, functional association for the majority of these gene products remains obscure. One useful approach to infer biological associations is via transcriptional coordination, or co-expression of genes. This approach has proved useful for several biological processes. Nevertheless, combining co expression with other large-scale measurements may improve the biological inferences. RESULTS: In this study, we used a combined approach of co-expression and cell wall metabolomics to obtain new insight into cell wall synthesis in rice. We initially created a weighted gene co-expression network from publicly available datasets, and then established a comprehensive cell wall dataset by determining cell wall compositions from 29 tissues that almost cover the whole life cycle of rice. We subsequently combined the datasets through the conversion of co-expressed gene modules into eigen-vectors, representing expression profiles for the genes in the modules, and performed comparative analyses against the cell wall contents. Here, we made three major discoveries. First, we confirmed our approach by finding primary and secondary wall cellulose biosynthesis modules, respectively. Second, we found co-expressed modules that strongly correlated with re-organization of the secondary cell walls and with modifications and degradation of hemicellulosic structures. Third, we inferred that at least one module is likely to play a regulatory role in the production of G-rich lignification. CONCLUSIONS: Here, we integrated transcriptomic associations and cell wall metabolism and found that certain co-expressed gene modules are positively correlated with distinct cell wall characteristics. We propose that combining multiple data-types, such as coordinated transcription and cell wall analyses, may be a useful approach to glean new insight into biological processes. The combination of multiple datasets, as illustrated here, can further improve the functional inferences that typically are generated via a single type of datasets. In addition, our data extend the typical co-expression approach to allow deeper insight into cell wall biology in rice. PMID- 25023613 TI - Controls for immunohistochemistry: the Histochemical Society's standards of practice for validation of immunohistochemical assays. AB - Immunohistochemistry is widely used in biomedical research to localize specific epitopes of molecules in cells and tissues. The validity of interpretations based on immunohistochemistry requires appropriate positive and negative controls that are often not reported in publications. This omission may lead to incorrect interpretations and irreproducible results in the literature and contribute to wasted time, effort, and resources as well as erosion of confidence in scientific investigation by the general public, legislative bodies and funding agencies. The present article summarizes essential controls required for validation of immunohistochemical findings and represents a standard of practice for the use of immunohistochemistry in research and diagnostic investigations. Adherence to the guidelines described in the present article can be cited by authors as support for the validity of interpretations of the immunohistochemistry reported in their publications. PMID- 25023615 TI - Iranian nurses and nursing students' attitudes on barriers and facilitators to patient education: a survey study. AB - The aim of this study is to describe the attitudes of Iranian nurses and students on barriers and facilitators to patient education. In this descriptive quantitative study, 103 nurses and 84 nursing students in two teaching hospitals in an urban area of Iran responded to a questionnaire investigating their attitudes on patient education. Results showed that all nurses and the majority (87.3%) of the students mentioned that they performed patient education. Moreover, 95% and 63.3% of the nurses and students respectively accepted that patient education was one of their roles. The nurses stated that heavy workload, inadequate time and lack of educational facilities were main barriers to patient education. The students believed that lack of knowledge, lack of communication skills and heavy workload were main barriers to patient education from their perspectives. While Iranian nurses and nursing students had positive attitudes towards patient education, it could not guarantee the implementation of patient education. Therefore, the clarification of patient education activities and development of a patient education team with the support of healthcare settings' administrators can facilitate the process of patient education in the Iranian healthcare settings. PMID- 25023614 TI - Picrosirius red staining: a useful tool to appraise collagen networks in normal and pathological tissues. AB - Specific staining of the extracellular matrix components is especially helpful in studying tissue remodeling, particularly in the case of connective tissue pathologies. As developed by Junqueira and colleagues in 1979, specific staining by Picrosirius red is one of the most important stains to study collagen networks in different tissues. Under polarized light, collagen bundles appear green, red or yellow, and are easily differentiated from the black background, thus allowing for quantitative morphometric analysis. As Junqueira and colleagues point out, many studies use color staining to differentiate collagen bundles and to specify collagen types, yet other studies report that polarized colors only reflect fiber thickness and packing. Using a simple histological example, our study illustrates the inability of Picrosirius red staining to differentiate collagen types, since the absorbed amount of polarized light by this dye strictly depends on the orientation of the collagen bundles. PMID- 25023616 TI - Meta-analysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma. AB - INTRODUCTION: Bortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta analysis of bortezomib-based retreatment in relapsed/refractory myeloma. PATIENTS AND METHODS: A systematic literature review identified studies of bortezomib based retreatment in relapsed/refractory myeloma. Proportions of bortezomib refractory patients and additional prognostic factors were extracted and used in weighted stratified analyses of TTP and OS. Random-effect pooled estimates were calculated for overall response rate (ORR) and rates of common AEs. RESULTS: Twenty-three studies (n = 1051 patients) were identified. Bortezomib was administered intravenously in all studies. Across studies in which data were available, pooled, weighted average ORR was 39.1% (95% confidence interval, 30.8% 47.4%), and pooled, weighted average median TTP and OS were 7.5 and 16.6 months, respectively. Patients with fewer previous therapies (<= 4) and relapsed (not refractory) patients achieved higher ORRs, of 43.4% and 57.2%, respectively. Random-effects meta-regression analysis confirmed that relapsed patients were associated with a higher ORR by 28 to 41 percentage points versus refractory patients. In relapsed patients, median TTP and OS were 8.5 and 19.7 months, respectively. Common Grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%). CONCLUSION: Based on these findings, bortezomib retreatment is well tolerated and appears efficacious in relapsed patients. In an era of new and emerging treatment options for relapsed and/or refractory myeloma, these data indicate that bortezomib retreatment might be a highly effective option in previously treated patients. PMID- 25023617 TI - Discovery and investigation of anticancer ruthenium-arene Schiff-base complexes via water-promoted combinatorial three-component assembly. AB - The structural diversity of metal scaffolds makes them a viable alternative to traditional organic scaffolds for drug design. Combinatorial chemistry and multicomponent reactions, coupled with high-throughput screening, are useful techniques in drug discovery, but they are rarely used in metal-based drug design. We report the optimization and validation of a new combinatorial, metal based, three-component assembly reaction for the synthesis of a library of 442 Ru arene Schiff-base (RAS) complexes. These RAS complexes were synthesized in a one pot, on-a-plate format using commercially available starting materials under aqueous conditions. The library was screened for their anticancer activity, and several cytotoxic lead compounds were identified. In particular, [(eta6-1,3,5 triisopropylbenzene)RuCl(4-methoxy-N-(2-quinolinylmethylene)aniline)]Cl (4) displayed low micromolar IC50 values in ovarian cancers (A2780, A2780cisR), breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence of p53 activation or changes in IC50 value between p53+/+ and p53-/- cells suggests that 4 and possibly the other lead compounds may act independently of the p53 tumor suppressor gene frequently mutated in cancer. PMID- 25023618 TI - How functional coupling between the auditory cortex and the amygdala induces musical emotion: a single case study. AB - Music is a sound structure of remarkable acoustical and temporal complexity. Although it cannot denote specific meaning, it is one of the most potent and universal stimuli for inducing mood. How the auditory and limbic systems interact, and whether this interaction is lateralized when feeling emotions related to music, remains unclear. We studied the functional correlation between the auditory cortex (AC) and amygdala (AMY) through intracerebral recordings from both hemispheres in a single patient while she listened attentively to musical excerpts, which we compared to passive listening of a sequence of pure tones. While the left primary and secondary auditory cortices (PAC and SAC) showed larger increases in gamma-band responses than the right side, only the right side showed emotion-modulated gamma oscillatory activity. An intra- and inter hemisphere correlation was observed between the auditory areas and AMY during the delivery of a sequence of pure tones. In contrast, a strikingly right-lateralized functional network between the AC and the AMY was observed to be related to the musical excerpts the patient experienced as happy, sad and peaceful. Interestingly, excerpts experienced as angry, which the patient disliked, were associated with widespread de-correlation between all the structures. These results suggest that the right auditory-limbic interactions result from the formation of oscillatory networks that bind the activities of the network nodes into coherence patterns, resulting in the emergence of a feeling. PMID- 25023619 TI - Possible mechanisms of anosognosia of hemiplegia. AB - Unawareness of hemiplegia was first called anosognosia by Babinski one century ago. This paper reviews some of the major theories that may account for this disorder. Weinstein and Kahn posited that anosognosia was a psychological defense mechanism; however, clinical as well as studies using transient hemispheric anesthesia reveal anosognosia for hemiplegia is more commonly associated with right than left hemisphere dysfunction, which is not entirely compatible with this denial hypothesis. Discovery is dependent on sensory feedback. Some patients with anosognosia will recognize their hemiparesis when their paretic hand is placed into ipsilesional hemispace suggesting that de-afferentation and inattention-neglect may be important mechanisms. Some patients with anosognosia have asomatognosia and hence being unaware that their paretic arm belongs to them they do not recognize that they have a deficit. Some patients have phantom movements and some may confabulate because they have a hemispheric disconnection. The feed-forward hypothesis posits that without an attempt to move, there is no expectation of movement and in the absence of arm movement there will be no discord that leads to discovery. Thus, motor neglect may be another cause of anosognosia. A defect in a theoretical comparator where expectations are compared to feedback may also be a cause of anosognosia, but further evidence is needed to support this postulate. Based on the studies of anosognosia for hemiplegia we have reviewed it appears that normal self-awareness depends on several modular systems. Further research of these possible mechanisms is needed to discern their relative importance and treatment. If these mechanisms do not fully account for anosognosia, investigators will need to develop and test new hypotheses. PMID- 25023621 TI - B-cell exhaustion in HIV infection: the role of immune activation. AB - PURPOSE OF REVIEW: To discuss a component of the pathogenic mechanisms of HIV infection in the context of phenotypic and functional alterations in B cells that are due to persistent viral replication leading to aberrant immune activation and cellular exhaustion. We explore how B-cell exhaustion arises during persistent viremia and how it compares with T-cell exhaustion and similar B-cell alterations in other diseases. RECENT FINDINGS: HIV-associated B-cell exhaustion was first described in 2008, soon after the demonstration of persistent virus-induced T cell exhaustion, as well as the identification of a subset B cells in tonsil tissues with immunoregulatory features similar to those observed in T-cell exhaustion. Our understanding of B-cell exhaustion has since expanded in two important areas: the role of inhibitory receptors in the unresponsiveness of exhausted B cells and the increasing evidence that similar B cells are found in other diseases that are associated with aberrant immune activation and inflammation. SUMMARY: The phenomenon of B-cell exhaustion is now well established in HIV infection and other diseases characterized by immune activation. Over the coming years, it will be important to understand how cellular exhaustion affects the capacity of the immune system to respond to persisting primary pathogens, as well as to other microbial antigens, whether encountered as secondary infections or following immunization. PMID- 25023620 TI - The dysfunction of T follicular helper cells. AB - PURPOSE OF REVIEW: T follicular helper (Tfh) cells play a critical role as providers of B-cell help and dysfunction in Tfh/B-cell interactions can lead to autoimmunity or immunodeficiency. These observations have generated a great deal of interest in understanding how these cells are affected during HIV infection and how their functional changes might affect antibody responses. RECENT FINDINGS: Recent studies have shown that HIV/simian immunodeficiency virus (SIV) infection affects both Tfh-cell frequency and function and suggest that Tfh-cell perturbations might contribute to the relative inefficiency of HIV-infected individuals to generate broadly neutralizing antibodies (bNAbs). SUMMARY: The present review will highlight these recent findings addressing the role of Tfh cells in HIV infection as well as the impact HIV infection has on Tfh and circulating memory Tfh (cTfh) cell frequency and function. PMID- 25023622 TI - Animal models for viral infection and cell exhaustion. AB - PURPOSE OF REVIEW: Despite eliciting an early antiviral T cell response, HIV specific T cells are unable to prevent disease progression, partly because of their loss of effector functions, known as T cell exhaustion. Restoring this T cell functionality represents a critical step for regaining immunological control of HIV-1 replication, and may be fundamental for the development of a functional cure for HIV. In this context, the use of animal models is invaluable for evaluating the efficacy and mechanisms of novel therapeutics aimed at reinvigorating T cell functions. RECENT FINDINGS: Although nonhuman primates continue to be a mainstay for studying HIV pathogenesis and therapies, recent advances in humanized mouse models have improved their ability to recapitulate the features of cell exhaustion during HIV infection. Targeting coinhibitory receptors in HIV-infected and simian immunodeficiency virus (SIV)-infected animals has resulted in viral load reductions, presumably by reinvigorating the effector functions of T cells. Additionally, studies combining programmed death-1 (PD-1) blockade with suppressive antiretroviral therapy provide further support to the use of coinhibitory receptor blockades in restoring T cell function by delaying viral load rebound upon antiretroviral therapy interruption. Future in vivo studies should build on recent in-vitro data, supporting the simultaneous targeting of multiple regulators of cell exhaustion. SUMMARY: In this review, we describe the most recent advances in the use of animal models for the study of cell exhaustion following HIV/SIV infection. These findings suggest that the use of animal models is increasingly critical in translating immunotherapeutics into clinical practice. PMID- 25023624 TI - Editorial overview: cell dysfunction and exhaustion in HIV infection. PMID- 25023623 TI - Distinctive features of CD4+ T cell dysfunction in chronic viral infections. AB - PURPOSE OF REVIEW: To describe recent advances in the understanding of virus specific CD4 T cell dysfunction in chronic viral infections, with an emphasis on HIV disease. We highlight features that are distinctive for CD4 T cells, as opposed to their CD8 T cell counterparts. RECENT FINDINGS: CD4 T cell activation and differentiation are tightly controlled. Regulation of these processes depends on the context of initial encounter of the naive CD4 T cell with the cognate antigen and on ongoing external cues to the antigen-experienced CD4 T cell, in particular the inflammatory environment, which is prominent in HIV infection. Virus-specific CD4 T cell dysfunction results from a combination of an exhaustion program and skewing in T helper lineage differentiation which impact function. The CD4 and CD8 T cell exhaustion programs present similarities and distinct features. The sets of inhibitory coreceptors expression differ, although programmed-death 1 (PD-1) and T cell immunoglobulin mucin-3 (Tim-3) are upregulated on both HIV-specific CD4 and CD8 T cells, cytotoxic T-lymphocyte antigen 4 (CTLA-4) is largely specific to CD4 T cells, whereas 2B4 and CD160 are biased toward CD8 T cells. SUMMARY: Understanding the molecular basis of HIV specific CD4 T cell exhaustion and identifying key differences with CD8 T cell impairment will be critical to design effective therapeutic and preventive immunotherapies against HIV. PMID- 25023625 TI - MicroRNA modulation of key targets associated with T cell exhaustion in HIV-1 infection. AB - PURPOSE OF REVIEW: The emergence of studies linking microRNAs (miRNAs), a species of small RNA molecules important in gene regulation, with HIV-1 infection has led to a better understanding of the complex molecular changes that occur following infection. We aim to discuss these changes and show how miRNAs may be involved with regulating key immunomodulatory molecules linked to T cell exhaustion at the post-transcriptional level. RECENT FINDINGS: Blimp-1 is a recently described T cell exhaustion marker. Reduced levels of miR-9 have been shown to have a functional role in the higher levels of Blimp-1 in CD4 T cells from patients with HIV-1 infection. Reduced levels of let-7 miRNAs have been linked to higher levels of IL-10, again with potential pathophysiological significance in HIV-1 infection. The advent of deep sequencing technologies is allowing detection of virally derived miRNAs expressed at extremely low levels, although some controversy still exists. SUMMARY: miRNAs have emerged as important players in the T cell dysfunction observed with HIV-1 infection. It is likely that they may emerge as novel markers of T cell dysfunction and provide potential targets for new therapeutics to reverse dysfunction. PMID- 25023626 TI - Comparison of molecular and immunocytochemical methods for detection of disseminated tumor cells in bone marrow from early breast cancer patients. AB - BACKGROUND: Disseminated tumor cells (DTCs) have potential to predict the effect of adjuvant treatment. The purpose of this study was to compare two methods, reverse transcription quantitative PCR (RT-qPCR) and immunocytochemisty (ICC), for detecting breast cancer DTCs in bone marrow (BM) from early breast cancer patients. METHODS: We investigated a subset (n = 313) of BM samples obtained from 271 early breast cancer patients in the "Secondary Adjuvant Taxotere Treatment" (SATT)-trial. All patients in this study had node positive or intermediate/high risk node negative non-metastatic disease. The DTCs were detected by ICC using AE1-AE3 anti-cytokeratin monoclonal antibodies. Patients with DTCs detected in their BM by ICC after standard adjuvant fluorouracil, cyclophosphamide, epirubicin (FEC) chemotherapy were offered docetaxel treatment. For comparison, 5 * 106 mononuclear cells from the aliquoted BM samples were also analyzed by RT qPCR using a multimarker (MM) assay based on the tumor cell mRNA markers keratin 19 (KRT19), mammaglobin A (hMAM), and TWIST1. In the MM-assay, a sample was defined as positive for DTCs if at least one of the mRNA markers was positive. RESULTS: The MM RT-qPCR assay identified DTCs in 124 (40%) of the 313 BM samples compared with 23/313 (7%) of the samples analyzed by ICC. The concordance between the MM RT-qPCR and ICC was 61% (Kappa value = 0.04) and twelve of the BM samples were positive by both methods. By RT-qPCR, 46/313 (15%) samples were positive for KRT19, 97/313 (31%) for TWIST1, and 3/313 (1%) for hMAM mRNA. There were no statistically significant associations between the individual mRNA markers. CONCLUSION: The RT-qPCR based method demonstrated more DTC-positive samples than ICC. The relatively low concordance of positive DTC-status between the two different assessment methods suggests that they may be complementary. The clinical relevance of the methods will be evaluated based on future clinical outcome data. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00248703. PMID- 25023627 TI - Assessment of risk factors for developing incident aortic stenosis: the Tromso Study. AB - To disclose risk factors of incident aortic stenosis (AS) and progression of established AS. A prospective cohort study. The Tromso Study, a population based health survey. Over a 14 years span we performed three repeated echocardiographic examinations (1994, 2001 and 2008) of a random sample of initially 3,243 participants. Data from the only hospital serving this population were included in the follow up. Throughout the study 132 participants were diagnosed with incident AS, defined as mean aortic valve gradient >=15 mmHg. Cox proportional hazards regression disclosed age (HR 1.11, 95 %CI 1.08-1.14), systolic blood pressure (BP) (HR 1.01, 95 % CI 1.00-1.02), active smoking (HR 1.71, 95 % CI 1.09 2.67), and waist circumference (HR 1.02, 95 % CI 1.00-1.03) as independent predictors of incident AS. Analysis of risk factors for progression of AS disclosed a higher mean aortic gradient at first measurement (p = 0.015), weight (p = 0.015), a low haemoglobin (Hgb) (p = 0.030) and high density lipoprotein (HDL) (p = 0.032) as significant independent predictors. Age, systolic BP, smoking and waist circumference were independent predictors of incident AS, whereas cholesterol was not. Mean aortic gradient at first measurement, weight, an elevated HDL and low Hgb increase the progression rate of the disease. Our data indicate that calcific aortic valve disease is a distinct pathophysiological process, with age, smoking and "wear and tear" of the valve being major contributors to the disease development. PMID- 25023628 TI - Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells. AB - A functionally responsive natural killer (NK)-cell repertoire requires the acquisition of inhibitory NKG2A and killer immunoglobulin-like receptors (KIR) through pathways that remain undefined. Functional donor NK cells expressing KIRs for non-self class I MHC ligands contribute to a positive outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT) by targeting HLA matched recipient leukemic cells. Insofar as circulating donor conventional dendritic cells (DC) reconstitute with comparable kinetics with donor NK cells after alloHSCT, we used hyporesponsive KIRnegNKG2Aneg precursor cells to evaluate how specific DC subtypes generate a functionally active NK-cell repertoire. Both monocyte-derived DCs (moDC) and Langerhans-type DCs (LC) induce KIRnegNKG2Aneg precursor cells to express the inhibitory receptors NKG2A and KIR, without requiring cell proliferation. Poly(I:C)-matured moDCs significantly augmented the expression of NKG2A, but not KIR, in an IL12p70-dependent manner. Although all DC stimulated KIRnegNKG2Aneg cells were able to acquire cytolytic activity against class I MHC-negative targets, the ability to secrete IFNgamma was restricted to cells that were stimulated by IL12p70-producing, poly(I:C)-matured moDCs. This critical ability of poly(I:C)-matured moDCs to provide IL12p70 to developing KIRnegNKG2Aneg precursors results in a dom4inant, multifunctional, NKG2Apos NK cell population that is capable of both cytolysis and IFNgamma production. Poly(I:C)-matured moDCs are, therefore, the most effective conventional DC subtype for generating a functionally competent NK-cell repertoire by an IL12p70 dependent mechanism. PMID- 25023629 TI - Cloning and characterization of a novel fructan 6-exohydrolase strongly inhibited by sucrose in Lolium perenne. AB - MAIN CONCLUSION: The first 6-fructan exohydrolase (6-FEH) cDNA from Lolium perenne was cloned and characterized. Following defoliation, Lp6 - FEHa transcript level unexpectedly decreased together with an increase in total FEH activity. Lolium perenne is a major forage grass species that accumulates fructans, mainly composed of beta(2,6)-linked fructose units. Fructans are mobilized through strongly increased activities of fructan exohydrolases (FEHs), sustaining regrowth following defoliation. To understand the complex regulation of fructan breakdown in defoliated grassland species, the objective was to clone and characterize new FEH genes in L. perenne. To find FEH genes related to refoliation, a defoliated tiller base cDNA library was screened. Characterization of the recombinant protein was performed in Pichia pastoris. In this report, the cloning and enzymatic characterization of the first 6-FEH from L. perenne is described. Following defoliation, during fructan breakdown, Lp6-FEHa transcript level unexpectedly decreased in elongating leaf bases (ELB) and in mature leaf sheaths (tiller base) in parallel to increased total FEH activities. In comparison, transcript levels of genes coding for fructosyltransferases (FTs) involved in fructan biosynthesis also decreased after defoliation but much faster than FEH transcript levels. Since Lp6-FEHa was strongly inhibited by sucrose, mechanisms modulating FEH activities are discussed. It is proposed that differences in the regulation of FEH activity among forage grasses influence their tolerance to defoliation. PMID- 25023630 TI - Modulations of physiological responses and possible involvement of defense related secondary metabolites in acclimation of Artemisia annua L. against short term UV-B radiation. AB - MAIN CONCLUSION: UV - B radiation exposure for upto 3 h did not cause direct damage to physiology, but adjusted secondary metabolism and metabolites accumulation as an effective acclimation mechanism to mitigate the adverse effects of radiation. Artemisia annua L. plants were irradiated with UV-B radiation (280-315 nm; 2.8 Wm(-2)) for different short-term (1, 2, 3 and 4 h) durations. UV-B irradiation of 3 h reduced the photosynthetic rate, stomatal conductance and transpiration rate. However, F v/F m, a sensitive indicator of photosynthetic inhibition, remained stable (0.78) upto 3 h, thereafter it declined sharply (0.72). Interestingly, transcript level of LHCB1, PSBA and PSBO genes related to photosystem II (PSII) were induced under UV-B exposure. In addition, genes coding for Rubisco small (RBCS1B) and large (RBCL) subunits were also upregulated upto 3 h. To mitigate the adverse effects of UV-B radiation, plants tremendously induced defense-related secondary metabolites such as antioxidative phenolics, UV-B absorbing flavonoids, anthocyanins and protective terpenes. The GC-MS analysis of essential oils revealed relatively higher production of monoterpenes over sesquiterpenes as well as 1.2-folds higher total oil yield under UV-B radiation. Owing to its diverse biological activities, the altered quantity and quality of essential oil of A. annua may contribute towards improving its therapeutic properties. The results suggest that UV-B irradiation upto 3 h reduced photosynthesis, probably due to stomatal limitations rather than any direct injury to photosynthetic apparatus as evident from stable F v/F m value, upregulated genes and greater accumulation of their corresponding proteins which gauge PSII health, elevated UV-B absorbing compounds and other protective metabolites. Correlation analysis indicates a significant positive correlation of photosynthetic rate with stomatal conductance while a negative correlation with anthocyanin and monoterpene contents under UV-B radiation. The present study provides first hand information regarding photosynthesis, related physiological parameters and essential oil profiling in response to UV-B radiation in A. annua. PMID- 25023631 TI - Lipid-dissolved gamma-carotene, beta-carotene, and lycopene in globular chromoplasts of peach palm (Bactris gasipaes Kunth) fruits. AB - MAIN CONCLUSION: High levels of beta-carotene, lycopene, and the rare gamma carotene occur predominantly lipid-dissolved in the chromoplasts of peach palm fruits. First proof of their absorption from these fruits is reported. The structural diversity, the physical deposition state in planta, and the human bioavailability of carotenoids from the edible fruits of diverse orange and yellow-colored peach palm (Bactris gasipaes Kunth) varieties were investigated. HPLC-PDA-MS(n) revealed a broad range of carotenes, reaching total carotenoid levels from 0.7 to 13.9 mg/100 g FW. Besides the predominant (all-E)-beta carotene (0.4-5.4 mg/100 g FW), two (Z)-isomers of gamma-carotene (0.1-3.9 mg/100 g FW), and one (Z)-lycopene isomer (0.04-0.83 mg/100 g FW) prevailed. Approximately 89-94 % of total carotenoid content pertained to provitamin A carotenoids with retinol activity equivalents ranging from 37 to 609 ug/100 g FW. The physical deposition state of these carotenoids in planta was investigated using light, transmission electron, and scanning electron microscopy. The plastids found in both orange and yellow-colored fruit mesocarps were amylo chromoplasts of the globular type, containing carotenoids predominantly in a lipid-dissolved form. The hypothesis of lipid-dissolved carotenoids was supported by simple solubility estimations based on carotenoid and lipid contents of the fruit mesocarp. In our study, we report first results on the human bioavailability of gamma-carotene, beta-carotene, and lycopene from peach palm fruit, particularly proving the post-prandial absorption of the rarely occurring gamma-carotene. Since the physical state of carotenoid deposition has been shown to be decisive for carotenoid bioavailability, lipid-dissolved carotenoids in peach palm fruits are expected to be highly bioavailable, however, further studies are required. PMID- 25023632 TI - A fatty acid condensing enzyme from Physaria fendleri increases hydroxy fatty acid accumulation in transgenic oilseeds of Camelina sativa. AB - MAIN CONCLUSION: Co-expression of a lesquerella fatty acid elongase and the castor fatty acid hydroxylase in camelina results in higher hydroxy fatty acid containing seeds with normal oil content and viability. Producing hydroxy fatty acids (HFA) in oilseed crops has been a long-standing goal to replace castor oil as a renewable source for numerous industrial applications. A fatty acid hydroxylase, RcFAH, from Ricinus communis, was introduced into Camelina sativa, but yielded only 15 % of HFA in its seed oil, much lower than the 90 % found in castor bean. Furthermore, the transgenic seeds contained decreased oil content and the germination ability was severely affected. Interestingly, HFA accumulation was significantly increased in camelina seed when co-expressing RcFAH with a fatty acid condensing enzyme, LfKCS3, from Physaria fendleri, a native HFA accumulator relative to camelina. The oil content and seed germination of the transgenic seeds also appeared normal compared to non-transgenics. LfKCS3 has been previously characterized to specifically elongate the hydroxylated ricinoleic acid to lesquerolic acid, the 20-carbon HFA found in lesquerella oil. The elongation reaction may facilitate the HFA flux from phosphatidylcholine (PC), the site of HFA formation, into the acyl-CoA pool for more efficient utilization in triacylglycerol (TAG) biosynthesis. This was demonstrated by increased HFA accumulation in TAG concurrent with reduced HFA content in PC during camelina seed development, and increased C20-HFA in HFA-TAG molecules. These effects of LfKCS3 thus may effectively relieve the bottleneck for HFA utilization in TAG biosynthesis and the feedback inhibition to fatty acid synthesis, result in higher HFA accumulation and restore oil content and seed viability. PMID- 25023633 TI - Large cell carcinoma of lung: On the verge of extinction? AB - Pulmonary large cell carcinoma is a tumor whose existence as a defined entity has been challenged in recent years in the wake of advances in techniques to subtype lung cancer. Large cell carcinoma has been defined in the past as a tumor that lacks morphologic evidence of either glandular or squamous differentiation. This rather vague definition and the inclusion of more specific entities such as large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype as subtypes of large cell carcinoma has not only diluted the homogeneity of this entity but has also contributed to its use as a "wastebin" category for tumors lacking a definitive morphologic pattern. Today, there is increasing evidence that a large proportion of these tumors can be subtyped further using modern immunohistochemical and molecular methods. This is of special value not only from a diagnostic point of view but becomes increasingly important in terms of treatment choice since the selection of therapeutic modalities is often based on specific tumor histology. When viewed in this light, large cell carcinoma of the lung--as defined today--appears to be an outdated entity that needs to be reevaluated taking into account not only light microscopic findings but also the results of adjunct techniques such as immunohistochemistry and molecular profiling so that patients can benefit from more targeted therapies. This review examines the entity of pulmonary large cell carcinoma from these aspects and tries to delineate a practical diagnostic approach until further redefinition of this tumor is in place. PMID- 25023635 TI - Rural-urban focus of canine visceral leishmaniosis in the far western region of Santa Catarina State, Brazil. AB - The aim of this work was to investigate the occurrence of canine visceral leishmaniosis (CVL) in the far western region of Santa Catarina State, bordering Argentina and Parana State, southern Brazil, where in recent years, VL has been recorded in both dogs and humans. Clinical signs, enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescent antibody test (IFAT) and polymerase chain reaction (PCR) were used for Leishmania investigation. Among the 252 dogs surveyed, 41 were positive by ELISA assay, 43 in IFAT (titer>40), and 55 by PCR. From the 48 positive for VL by both serological and molecular methods, 19 (39.6%) presented clinical symptoms of leishmaniosis, 35 (72.9%) were from rural areas, and 13 (27.1%) were from urban areas. This pilot study confirms the occurrence of VL among dogs in the far western region of Santa Catarina, southern Brazil, with high risk of CVL outbreaks and presenting a threat to humans. PMID- 25023634 TI - Analysis of metabolic syndrome components in >15 000 african americans identifies pleiotropic variants: results from the population architecture using genomics and epidemiology study. AB - BACKGROUND: Metabolic syndrome (MetS) refers to the clustering of cardiometabolic risk factors, including dyslipidemia, central adiposity, hypertension, and hyperglycemia, in individuals. Identification of pleiotropic genetic factors associated with MetS traits may shed light on key pathways or mediators underlying MetS. METHODS AND RESULTS: Using the Metabochip array in 15 148 African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study, we identify susceptibility loci and investigate pleiotropy among genetic variants using a subset-based meta-analysis method, ASsociation-analysis-based-on-subSETs (ASSET). Unlike conventional models that lack power when associations for MetS components are null or have opposite effects, Association-analysis-based-on-subsets uses 1-sided tests to detect positive and negative associations for components separately and combines tests accounting for correlations among components. With Association-analysis-based-on subsets, we identify 27 single nucleotide polymorphisms in 1 glucose and 4 lipids loci (TCF7L2, LPL, APOA5, CETP, and APOC1/APOE/TOMM40) significantly associated with MetS components overall, all P<2.5e-7, the Bonferroni adjusted P value. Three loci replicate in a Hispanic population, n=5172. A novel African American specific variant, rs12721054/APOC1, and rs10096633/LPL are associated with >=3 MetS components. We find additional evidence of pleiotropy for APOE, TOMM40, TCF7L2, and CETP variants, many with opposing effects (eg, the same rs7901695/TCF7L2 allele is associated with increased odds of high glucose and decreased odds of central adiposity). CONCLUSIONS: We highlight a method to increase power in large-scale genomic association analyses and report a novel variant associated with all MetS components in African Americans. We also identify pleiotropic associations that may be clinically useful in patient risk profiling and for informing translational research of potential gene targets and medications. PMID- 25023636 TI - In vitro activity of new cephalosporins vs Streptococcus pneumoniae from the Canadian Bacterial Surveillance Network: 2008-2011. AB - Between 2008 and 2011, 6,895 Streptococcus pneumoniae isolates were submitted to the Canadian Bacterial Surveillance Network and underwent in vitro susceptibility testing. Fifteen percent of S. pneumoniae isolates were collected from pediatric patients (0-15 years old), 48.6 % of isolates were collected from adults between 16 and 64 years of age, and 36.1 % from adults aged >=65 years; age data were not available for 11 patients. Forty-five percent of S. pneumoniae isolates were recovered from sterile specimens, and 55 % of isolates were from nonsterile specimens. Overall, 0.4 % of isolates were resistant to penicillin, 0.4 % to ceftriaxone, 3 % to amoxicillin, 25 % to erythromycin, and 13 % to trimethoprim/sulfamethoxazole; 6.6 % of isolates were multidrug resistant (MDR). Among MDR isolates, resistance rates exceeded 95 % for erythromycin, tetracycline, and trimethoprim/sulfamethoxazole. The MIC90 of cethromycin, ceftaroline, and ceftobiprole against MDR isolates were 0.12, 0.25, and 1 mg/L, respectively. Ceftaroline, the active form of the prodrug ceftaroline fosamil, exhibited potent in vitro activity against the tested S. pneumoniae including all 456 multidrug-resistant strains. No ceftaroline-resistant isolates were identified. PMID- 25023637 TI - Role of biofilm in protection of the replicative form of Legionella pneumophila. AB - The dual nature of Legionella pneumophila enables its survival in free and intracellular environments and underpins its infection and spread mechanisms. Experiments using bacterial cultures and improved RTqPCR protocols were devised to gain fresh insights into the role of biofilm in protecting the replicative form of L. pneumophila. mip gene expression was used as a marker of virulence in sessile (biofilm-bound) and planktonic (free-floating) cells of L. pneumophila serotype 1 ATCC 33152. The ratio of mip gene expression to transcriptionally active Legionella cells increased both in sessile and free-floating cells demonstrating an up-regulation of mip gene under nutrient depletion. However, a different trend was observed between the two forms, in planktonic cells the mip gene expression/transcriptionally active Legionella cells increased until the end of the experiment, while in the biofilm such increase was observed at the end of the experiment. These findings suggest a possible association between the switch to the transmissive phase of Legionella and a mip up-regulation and a role for biofilm in preserving Legionella cells in replicative form. Moreover, it has been shown that improved RTqPCR protocols are valuable tools to explore bacterial virulence. PMID- 25023638 TI - Metal resistance-related genes are differently expressed in response to copper and zinc ion in six Acidithiobacillus ferrooxidans strains. AB - Metal resistance of acidophilic bacteria is very significant during bioleaching of copper ores since high concentration of metal is harmful to the growth of microorganisms. The resistance levels of six Acidithiobacillus ferrooxidans strains to 0.15 M copper and 0.2 M zinc were investigated, and eight metal resistance-related genes (afe-0022, afe-0326, afe-0329, afe-1143, afe-0602, afe 0603, afe-0604, and afe-1788) were sequenced and analyzed. The transcriptional expression levels of eight possible metal tolerance genes in six A. ferrooxidans strains exposed to 0.15 M Cu(2+) and 0.2 M Zn(2+) were determined by real-time quantitative PCR (RT-qPCR), respectively. The copper resistance levels of six A. ferrooxidans strains declined followed by DY26, DX5, DY15, GD-B, GD-0, and YTW. The zinc tolerance levels of six A. ferrooxidans strains exposed to 0.2 M Zn(2+) from high to low were YTW > GD-B > DY26 > GD-0 > DX5 > DY15. Seven metal tolerance-related genes all presented in the genome of six strains, except afe 0604. The metal resistance-related genes showed different transcriptional expression patterns in six A. ferrooxidans strains. The expression of gene afe 0326 and afe-0022 in six A. ferrooxidans strains in response to 0.15 M Cu(2+) showed the same trend with the resistance levels. The expression levels of genes afe-0602, afe-0603, afe-0604, and afe-1788 in six strains response to 0.2 M Zn(2+) did not show a clear correlation between the zinc tolerance levels of six strains. According to the results of RT-qPCR and bioinformatics analysis, the proteins encoded by afe-0022, afe-0326, afe-0329, and afe-1143 were related to Cu(2+) transport of A. ferrooxidans strains. PMID- 25023639 TI - Impregnation of the bacterial cellulose membrane with biologically produced silver nanoparticles. AB - Different wound dressings with antibacterial property have been surveyed and one among them is bacterial cellulose (BC). Since the BC does not have antibacterial property, the biologically produced silver nanoparticles (SNPs) were impregnated into the BC. For the BC production, Hestrin-Schramm broth was used. Formation of the BC was proven by enzymatic hydrolysis. For SNPs production, the bacterial supernatant was treated with AgNO3 and formation of SNPs was monitored through spectrophotometer, TEM and XRD. For impregnation of SNPs into the BC, the cleaned membrane was placed in the bacterial supernatant that contained 1 mmol of AgNO3. The antibacterial assay was done for the BC/SNPs. Enzymatic hydrolysis proved the presence of the BC. Spectrophotometer and XRD results showed the formation of SNPs. TEM analysis revealed the presence of SNPs with sizes around 5-100 nm. SEM micrographs showed the impregnation of SNPs into the BC. Antibacterial test exhibited the antibacterial activity of the BC/SNPs. PMID- 25023640 TI - Magainin 2 induces bacterial cell death showing apoptotic properties. AB - Magainin 2 is pore-forming antimicrobial peptide on lipid matrix of bacterial membrane, secreted from the skin of the African clawed frog Xenopus laevis. The aim of this study was to investigate a new concept for antibacterial mechanisms called bacterial apoptosis-like cell death. We examined the morphological changes induced by magainin 2 in Escherichia coli, regarding apoptosis. Specifically, phosphatidylserine externalization from the inner to outer membrane surface was detected by Annexin V staining, and DNA fragmentation and chromatin condensation was detected by TUNEL and DAPI assay. We also found much mechanistic evidence to support the hypothesis that magainin 2 induces bacterial apoptosis-like death including disturbance of membrane detected by DiBAC4(3), caspase activation observed by FITC-VAD-FMK staining, and analyzing the role of RecA in bacterial apoptosis-like death through the RecA expression assay by Western blot-in E. Coli when treated with magainin 2. On the basis of these results, magainin 2 exerts antibacterial activity with a new mechanism which is bacterial apoptosis-like death. Searching antimicrobial agents with novel mechanisms of action can be an effective strategy to coping with the emergence of new resistance mechanisms. Magainin 2 deserves further research as a potential antimicrobial therapeutic agent. PMID- 25023641 TI - Coronary artery bypass grafting in high-RISk patients randomised to off- or on Pump surgery: a randomised controlled trial (the CRISP trial). AB - BACKGROUND: Coronary artery bypass grafting (CABG) is the treatment of choice for patients with multivessel coronary artery disease (CAD). Evidence from randomised controlled trials (RCTs) in low-risk populations shows that 'off-pump' CABG is at least as safe as 'on-pump' CABG, but high-quality trial data in high-risk populations are lacking. OBJECTIVES: To test the hypothesis that, in high-risk patients, off-pump coronary artery bypass grafting (OPCABG) reduces mortality and morbidity without causing a higher risk of reintervention compared with on-pump coronary artery bypass grafting (ONCABG). DESIGN: Open parallel-group RCT with a 1 : 1 allocation ratio and expertise-based randomisation. SETTING: Eight specialist cardiac surgery centres in the UK and one specialist centre in Kolkata, India. PARTICIPANTS: Patients with an additive European system for cardiac operative risk evaluation score (EuroSCORE) of >= 5, undergoing non emergency isolated CABG via a median sternotomy. INTERVENTIONS: CABG without cardiopulmonary bypass (CPB), i.e. OPCABG on the beating heart, or CABG with CPB, i.e. ONCABG on a chemically arrested heart. MAIN OUTCOME MEASURES: Primary outcome - a composite of death or serious morbidity [all-cause mortality, myocardial infarction (MI), stroke, prolonged initial ventilation, sternal wound dehiscence] within 30 days of surgery. Secondary outcomes - quality of life (QoL) [Rose Angina Questionnaire, Canadian Cardiovascular Society (CCS) angina class, European QoL-5 Dimensions (EQ-5D), Coronary Revascularisation Outcome Questionnaire (CROQ)] and resource utilisation. RESULTS: The organisation of a tertiary cardiac surgery service in the UK presented several barriers to recruitment. Referral information was often inadequate to confirm eligibility. Limited surgeon participation at a centre, the need to meet referral-to-treatment performance targets and complex referral pathways did not support an expertise based allocation. Urgent patients waiting for surgery in local 'feeder' hospitals were often not transferred until late the night before surgery, which limited the time available to take consent and organise the surgery on an expertise basis. Several elective patients declined to take part because they wanted the surgeon they had met when the surgery was first discussed in clinic to operate. Several initiatives were explored to boost recruitment. After 10 months of recruitment, the trial design was modified to permit both within-surgeon and expertise-based randomisation within a centre. However, this did not have sufficient impact and the trial was stopped on the grounds of futility after 106 patients (< 2% of the target sample size) had been recruited in 18 months. Ninety-eight patients were included in the trial analyses, six patients were withdrawn and two died before surgery. In both groups, 6% of patients experienced the primary outcome [adjusted odds ratio (OR) (OPCABG to ONCABG) 1.07; 95% confidence interval (CI) 0.27 to 4.14]. QoL scores at 4-8 weeks post surgery were similar in the two groups. Patients randomised to OPCABG had a shorter stay in the intensive care unit and in hospital after surgery (median 26.0 vs. 27.7 hours in intensive care and 7 vs. 8 days in hospital). CONCLUSIONS: The Coronary artery bypass grafting in high RISk patients randomised to off- or on-Pump surgery (CRISP) trial was not successful for a range of logistical reasons. However, the experience gained is of value for the design and conduct of future trials. The surgical community have polarised views. A qualitative evaluation of the reasons behind the views held by the advocates of the two techniques is an area for future research. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29161170. FUNDING: This project was funded by the Medical Research Council/National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Health Technology Assessment; Vol. 18, No. 44. See the NIHR Journals Library website for further project information. PMID- 25023642 TI - EU alerting and reporting systems for potential chemical public health threats and hazards. AB - A number of European and international IT platforms are used to notify competent authorities of new potential chemical exposures. Recently the European Parliament and the Council of European Union adopted new legislation that aims to improve the co-ordinated response to cross border health threats (Decision 1082/2013/EU). The Decision, inter alia, sets provisions on notification, ad hoc monitoring and coordination of public health measures following serious cross border threats to health from biological, chemical and environmental events as well as events that have an unknown origin. The legal instrument applies to all European Union Member States and is comparable to the International Health Regulations in its content, requirements and adoption of a multiple hazards approach. An inter-sectoral and multidisciplinary response to events with potentially dangerous cross border exposure pathways is often required. For example, European Poisons Centres may be aware of cases of toxic exposure to a product and, in parallel, trading standards may be aware of the same product due to a breach of consumer product standards. Whilst both cases would have been recorded for separate purposes in different alerting systems, they relate to the same exposure pathway; therefore a process for linking these records would allow a more robust approach to risk assessment and risk mitigation. The Decision seeks to reconcile this issue for serious threats by linking relevant platforms into one overarching higher level risk management IT platform called the Early Warning Response System (EWRS). This system will serve to link other sectors within the European Commission (EC) to public health (e.g. medicines), as well as other EU agencies and international bodies via co-notification features. Other European alert systems will be linked to EWRS to facilitate information sharing at both the assessment and management levels. This paper provides a timely overview of the main systems run by the EC and other international organisations that provide alerts following chemical incidents that have, or may have, the potential to affect public health. The advantages and further considerations of linking these different systems and sectors are also highlighted. Recommendations are made with the purpose of ensuring that modifications to these systems made to satisfy with EU legislation enable a more timely coordinated response and greater awareness of events in Europe, thereby reducing the public health impact from chemical exposures. PMID- 25023643 TI - Sporting injuries. AB - Barbara Mortimer Thomas graduated in "Arts" at Sydney University in 1928, and then commenced a medical course. In her second year, however, she was chosen to represent Australia at hockey, and toured South Africa, Europe and Great Britain. She was unable to resume her medical course, and remained in London, training as a physiotherapist at St. Thomas' Hospital. She continued her work there until she was killed during the "Battle of Britain," when the hospital was bombed. I understand that she was herself keenly interested in the subject of sporting injuries, and, as an international hockey player, would have had many opportunities to deal with them. The subject of this talk would, I am sure, have interested her. PMID- 25023644 TI - Extension or flexion for the lumbar spine. AB - One of the most common conditions referred for physiotherapy is low back pain and yet I suppose there would be few of us who have any clear-cut idea on the relative place of flexion and extension exercises in its treatment. Similarly, I suppose few of us who have read overseas literature on the subject have not been confused by the differences of opinion expressed as to whether people should be taught to stand with a flattened lumbar curve or not, or whether a patient should be rested with a lumbar pillow or with the knees supported in Fowler's position to allow the lumbar curve to flatten. The problem can be divided into two parts, one dealing with the treatment of pain and the other dealing with prophylaxis, and it is the latter which I will discuss first. PMID- 25023645 TI - The use of a remedial tilting table in physical medicine and rehabilitation. AB - One of the problems in treating all types of long term patients both young and old is the physical handling involved. Therapists are often faced with the major task of getting heavy patients who have been in bed for a long time or have significant muscle weakness or paralysis, on to their feet again. Additional difficulties relate to the fact that there is often a loss of postural reflex adjustment, in that: (1) Elderly patients forget how to stand after not having done so for a long time, and treating a frightened, heavy, elderly man who will not straighten his legs as he is lifted upright can put a strain on a therapist, which may well result in injury. (2) All patients who have been lying for a length of time need to be brought to the upright position progressively, to allow their circulation to adjust to the changes in gravitational pull, and an easily progressed change of angle whilst lying fully supported is desirable. PMID- 25023646 TI - New use for old drugs? Prospective targets of chloroquines in cancer therapy. AB - During the last decade research is gradually repositioning the antimalarial drug chloroquine, and certain related quinoline derivatives, as anticancer agents. Chloroquine and hydroxychloroquine, in particular, have relatively well characterized toxicity profiles due to several decades of use for treatment of malaria. Previously published review articles provide an excellent overview of the diversity of chloroquine effects on cancer cells, both in the cell culture as well as on human tumors grafted into mice; and an account of the increasing pace of incorporation of hydroxychloroquine in combination treatment schemes for clinical studies. In this review we present some features that are common between cancers that are sensitive to quinoline derivatives, in particular features that are amenable to pharmaceutical intervention. PMID- 25023648 TI - Coupling of ultrafast LC with mass spectrometry by DESI. AB - Recently we reported a desorption electrospray ionization (DESI) interface to combine liquid chromatography (LC) with mass spectrometry (MS) using a new LC eluent splitting strategy through a tiny orifice on LC capillary tube [J. Am. Soc. Mass Spectrom. 25, 286 (2014)]. The interface introduces negligible dead volume and back pressure, thereby allowing "near real-time" MS detection, fast LC elution, and online MS-directed purification. This study further evaluates the LC/DESI-MS performance with focus of using ultra-fast LC. Using a monolithic C18 column, metabolites in urine can be separated within 1.6 min and can be online collected for subsequent structure elucidation (e.g., by NMR, UV, IR) in a recovery yield up to 99%. Using a spray solvent with alkaline pH, negative ions could be directly generated for acidic analytes (e.g., ibuprofen) in acidic LC eluent by DESI, offering a novel protocol to realize "wrong-way around" ionization for LC/MS analysis. In addition, DESI-MS is found to be compatible with ultra-performance liquid chromatography (UPLC) for the first time. PMID- 25023647 TI - Polymorphisms in human heat shock factor-1 and analysis of potential biological consequences. AB - The stress-activated transcription factor, heat shock factor-1 (HSF1), regulates many genes including cytoprotective heat shock proteins (HSPs). We hypothesized that polymorphisms in HSF1 may alter the level or function of HSF1 protein accounting for interindividual viability in disease susceptibility or prognosis. We searched for exomic variants in HSF1 by querying human genome databases and directly sequencing DNA from 80 anonymous genomic DNA samples. Overall, HSF1 sequence was highly conserved, with no common variations. We found 31 validated deviations from a reference sequence in the dbSNP database and an additional 5 novel variants by sequencing, with allele frequencies that were 0.06 or less. Of these 36, 2 were in 5'-untranslated region (5'UTR), 10 in 3'UTR, and 24 in the coding region. The potential effects of 5'UTR on secondary structure, protein structure/function, and 3'UTR targets of microRNAs were analyzed using RNAFold, PolyPhen-2, SIFT, and MicroSNiper. One of the 5'UTR variants was predicted to strengthen secondary structure. Eight of 3'UTR variants were predicted to modify microRNA target sequences. Eight of the coding region variants were predicted to modify HSF1 structure/function. Reducing HSF1 levels in A549 cells using short hairpin RNA (shRNA) increased sensitivity to heat-induced killing demonstrating the impact that genetic variants that reduce HSF1 levels might have. Using the pmirGLO expression system, we found that the wild-type HSF1 3'UTR suppressed translation of a firefly luciferase reporter plasmid by 65 %. Introducing two of four 3'UTR single nucleotide polymorphisms (SNPs) increased HSF1 3'UTR translational suppression by 27-44 % compared with the wild-type HSF1 3'UTR sequence while a third SNP reduced suppression by 25 %. HSF1 variants may alter HSF1 protein levels or function with potential effects on cell functions, including sensitivity to stress. PMID- 25023649 TI - Mir-208 promotes cell proliferation by repressing SOX6 expression in human esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancer in developing countries. The prognosis and survival rate of ESCC are very poor. Recently, microRNAs (miRNAs) have emerged as important regulators of cancer cell biological processes. To better understanding the molecular mechanisms by which they regulate the behavior of cancer cells is needed. METHODS: The expression of miR-208 was examined in ESCC cell lines and tumor tissues by real-time PCR. Proliferation capability of ESCC cells upon regulation of miR-208 expression was detected by MTT assay, colony formation assay, anchorage-independent growth ability assay and flow cytometry analysis. The target of miR-208 was determined by western blotting analysis, luciferase reporter assay and real-time PCR. RESULTS: miR-208 was upregulated in ESCC cell lines and tissues. Overexpression of miR-208 in ESCC cells increased cell proliferation, tumorigenicity and cell cycle progression, whereas inhibition of miR-208 reduced cells proliferation, tumorigenicity and cell cycle progression. Additionally, SOX6 was identified as a direct target of miR-208. Ectopic expression of miR-208 led to downregulation of SOX6 protein, which resulted in the downregulation of p21, upregulation of cyclin D1 and phosphorylation of Rb. CONCLUSIONS: These results suggest that miR-208 represents a potential onco-miR and participates in ESCC carcinogenesis by suppressing SOX6 expression. PMID- 25023651 TI - A new method based for diagnosis of breast cancer cells from microscopic images: DWEE--JHT. AB - In these days, there are many various diseases, whose diagnosis is very hardly. Breast cancer is one of these type diseases. In this paper, accuracy diagnosis of normal, benign, and malign breast cancer cell were found by combining mean success rates Jensen Shannon, Hellinger, and Triangle measure which connected with each other. In this article, an diagnostic method based on feature extraction Discrete Wavelet Entropy Energy (DWEE) and Jensen Shannon, Hellinger, Triangle Measure (JHT) Classifier for diagnosis of breast cancer. This diagnosis method is called as DWEE--JHT this paper. With this diagnosis method have found optimal feature subset using discrete wavelet transform feature extraction. Then these convenient features are given to Jensen Shannon, Hellinger, Triangle Measure (JHT) classifier. Then, between classifiers which are Jensen Shannon, Hellinger, and triangle distance have been validated the measures via relationships. Afterwards, breast cancer cells are classified using Jensen Shannon, Hellinger, and Triangle distance. Mean success rate of 16 feature vector with Jensen Shannon classifier is found % 97.81. Mean success rate of 16 feature vector with Hellinger classifier is found % 97.75. Mean success rate of 16 feature vector with Triangle classifier is found % 97.87. By averaging of results obtained from these 3 classifiers are found as 97.81 % average of accuracy diagnosis. PMID- 25023650 TI - Physician variation in management of low-risk prostate cancer: a population-based cohort study. AB - IMPORTANCE: Up-front treatment of older men with low-risk prostate cancer can cause morbidity without clear survival benefit; however, most such patients receive treatment instead of observation. The impact of physicians on the management approach is uncertain. OBJECTIVE: To determine the impact of physicians on the management of low-risk prostate cancer with up-front treatment vs observation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort of men 66 years and older with low-risk prostate cancer diagnosed from 2006 through 2009. Patient and tumor characteristics were obtained from the Surveillance, Epidemiology, and End Results cancer registries. The diagnosing urologist, consulting radiation oncologist, cancer-directed therapy, and comorbid medical conditions were determined from linked Medicare claims. Physician characteristics were obtained from the American Medical Association Physician Masterfile. Mixed effects models were used to evaluate management variation and factors associated with observation. MAIN OUTCOMES AND MEASURES: No cancer-directed therapy within 12 months of diagnosis (observation). RESULTS: A total of 2145 urologists diagnosed low-risk prostate cancer in 12,068 men, of whom 80.1% received treatment and 19.9% were observed. The case-adjusted rate of observation varied widely across urologists, ranging from 4.5% to 64.2% of patients. The diagnosing urologist accounted for 16.1% of the variation in up-front treatment vs observation, whereas patient and tumor characteristics accounted for 7.9% of this variation. After adjustment for patient and tumor characteristics, urologists who treat non-low-risk prostate cancer (adjusted odds ratio [aOR], 0.71 [95% CI, 0.55 0.92]; P = .01) and graduated in earlier decades (P = .004) were less likely to manage low-risk disease with observation. Treated patients were more likely to undergo prostatectomy (aOR, 1.71 [95% CI, 1.45-2.01]; P < .001), cryotherapy (aOR, 28.2 [95% CI, 19.5-40.9]; P < .001), brachytherapy (aOR, 3.41 [95% CI, 2.96 3.93]; P < .001), or external-beam radiotherapy (aOR, 1.31 [95% CI, 1.08-1.58]; P = .005) if their urologist billed for that treatment. Case-adjusted rates of observation also varied across consulting radiation oncologists, ranging from 2.2% to 46.8% of patients. CONCLUSIONS AND RELEVANCE: Rates of management of low risk prostate cancer with observation varied widely across urologists and radiation oncologists. Patients whose diagnosis was made by urologists who treated prostate cancer were more likely to receive up-front treatment and, when treated, more likely to receive a treatment that their urologist performed. Public reporting of physicians' cancer management profiles would enable informed selection of physicians to diagnose and manage prostate cancer. PMID- 25023652 TI - A wavelet transform based feature extraction and classification of cardiac disorder. AB - This paper approaches an intellectual diagnosis system using hybrid approach of Adaptive Neuro-Fuzzy Inference System (ANFIS) model for classification of Electrocardiogram (ECG) signals. This method is based on using Symlet Wavelet Transform for analyzing the ECG signals and extracting the parameters related to dangerous cardiac arrhythmias. In these particular parameters were used as input of ANFIS classifier, five most important types of ECG signals they are Normal Sinus Rhythm (NSR), Atrial Fibrillation (AF), Pre-Ventricular Contraction (PVC), Ventricular Fibrillation (VF), and Ventricular Flutter (VFLU) Myocardial Ischemia. The inclusion of ANFIS in the complex investigating algorithms yields very interesting recognition and classification capabilities across a broad spectrum of biomedical engineering. The performance of the ANFIS model was evaluated in terms of training performance and classification accuracies. The results give importance to that the proposed ANFIS model illustrates potential advantage in classifying the ECG signals. The classification accuracy of 98.24 % is achieved. PMID- 25023653 TI - Cytotoxicity, genotoxicity and oxidative stress of malachite green on the kidney and gill cell lines of freshwater air breathing fish Channa striata. AB - The cytotoxicity, genotoxicity and oxidative stress of malachite green (MG) was investigated using the fish Channa striata kidney (CSK) and Channa striata gill (CSG) cell lines. Five concentrations ranging from 0.001 to 10 MUg mL(-1) were tested in three independent experiments. Cytotoxicity was assessed by 3-(4, 5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Rhodamine 123 and Alamar Blue. The mitochondrial changes and apoptosis of MG-exposed cells were observed by Rhodamine 123 and acridine orange/ethidium bromide (AO/EB) staining, respectively. In vitro potential DNA damaging effect of MG was tested using comet assay. Mitochondrial damage, apoptosis and DNA fragmentation increased in a concentration-dependent manner. Additionally, DNA electrophoretic mobility experiments were carried out to study the binding effect of MG to double-stranded DNA (dsDNA) of cells. DNA shift mobility experiments showed that MG is capable of strongly binding to linear dsDNA causing its degradation. Biochemical parameters such as lipid peroxidation (MDA), catalase (CAT) activity and reduced glutathione (GSH) levels were evaluated after exposure to MG. In CSK and CSG cell lines exposed to MG for 48 h, a significant increase in lipid peroxidation, which might be associated with decreased levels of reduced glutathione and catalase activity in these cell lines (p < 0.001), was observed. PMID- 25023654 TI - Screening of Bangladeshi winter wheat (Triticum aestivum L.) cultivars for sensitivity to ozone. AB - The sensitivity to ozone of ten Bangladeshi wheat cultivars was tested by exposing plants to eight ozone exposure regimes (50, 60, 80, 100, 120, 135, 150, and 200 ppb for 14, 11, 8, 6, 5, 4, 3, and 1 days, respectively, for 8 h/day) in controlled environment chambers. Visible leaf injury, dry weight, chlorophyll, carotenoid content, leaf greenness (SPAD value), quantum yield of photosynthesis, and stomatal resistance were measured to evaluate response. Shoot biomass, total chlorophyll, leaf greenness, and carotenoid content were reduced in ozone-exposed plants. Based on the results of principal component analysis (PCA)-biplot analysis, the order of sensitivity to ozone was: Akbar >> Sufi >= Bijoy >= Shatabdi > Bari-26 >= Gourab > Bari-25 >= Prodip >= Sourav >> Kanchan. The most important parameters to discriminate cultivars with respect to ozone sensitivity were visible injury and chlorophyll b/a ratio, whereas quantum yield of photosynthesis was less important. Differences in stomatal resistance were not a significant factor in ozone response. Regression of cultivars' PCA scores against year of release revealed no trend, suggesting that ozone tolerance was not incorporated during cultivar breeding. PMID- 25023655 TI - Emergy-based assessment on industrial symbiosis: a case of Shenyang Economic and Technological Development Zone. AB - Industrial symbiosis is the sharing of services, utility, and by-product resources among industries. This is usually made in order to add value, reduce costs, and improve the environment, and therefore has been taken as an effective approach for developing an eco-industrial park, improving resource efficiency, and reducing pollutant emission. Most conventional evaluation approaches ignored the contribution of natural ecosystem to the development of industrial symbiosis and cannot reveal the interrelations between economic development and environmental protection, leading to a need of an innovative evaluation method. Under such a circumstance, we present an emergy analysis-based evaluation method by employing a case study at Shenyang Economic and Technological Development Zone (SETDZ). Specific emergy indicators on industrial symbiosis, including emergy savings and emdollar value of total emergy savings, were developed so that the holistic picture of industrial symbiosis can be presented. Research results show that nonrenewable inputs, imported resource inputs, and associated services could be saved by 89.3, 32.51, and 15.7 %, and the ratio of emergy savings to emergy of the total energy used would be about 25.58 %, and the ratio of the emdollar value of total emergy savings to the total gross regional product (GRP) of SETDZ would be 34.38 % through the implementation of industrial symbiosis. In general, research results indicate that industrial symbiosis could effectively reduce material and energy consumption and improve the overall eco-efficiency. Such a method can provide policy insights to industrial park managers so that they can raise appropriate strategies on developing eco-industrial parks. Useful strategies include identifying more potential industrial symbiosis opportunities, optimizing energy structure, increasing industrial efficiency, recovering local ecosystems, and improving public and industrial awareness of eco-industrial park policies. PMID- 25023656 TI - Comparison of metals extractability from Al/Fe-based drinking water treatment residuals. AB - Recycling of drinking water treatment residuals (WTRs) as environment amendments has attracted substantial interest due to their productive reuse concomitant with waste minimization. In the present study, the extractability of metals within six Al/Fe-hydroxide-comprised WTRs collected throughout China was investigated using fractionation, in vitro digestion and the toxicity characteristic leaching procedure (TCLP). The results suggested that the major components and structure of the WTRs investigated were similar. The WTRs were enriched in Al, Fe, Ca, and Mg, also contained varying quantities of As, Ba, Be, Cd, Co, Cr, Cu, K, Mn, Mo, Na, Ni, Pb, Sr, V, and Zn, but Ag, Hg, Sb, and Se were not detected. Most of the metals within the WTRs were largely non-extractable using the European Community Bureau of Reference (BCR) procedure, but many metals exhibited high bioaccessibility based on in vitro digestion. However, the WTRs could be classified as non-hazardous according to the TCLP assessment method used by the US Environmental Protection Agency (USEPA). Further analysis showed the communication factor, which is calculated as the ratio of total extractable metal by BCR procedure to the total metal, for most metals in the six WTRs, was similar, whereas the factor for Ba, Mn, Sr, and Zn varied substantially. Moreover, metals in the WTRs investigated had different risk assessment code. In summary, recycling of WTRs is subject to regulation based on assessment of risk due to metals prior to practical application. PMID- 25023657 TI - Chromium (VI) remediation by a native strain: effect of environmental conditions and removal mechanisms involved. AB - A native bacterial strain with high capability for Cr (VI) removal was isolated from tannery sediments located in Elena (Cordoba Province, Argentina). The strain was characterized by amplification of 16S rRNA gene and identified as Serratia sp. C8. It was able to efficiently remove different Cr (VI) concentrations in a wide range of pHs and temperatures. The addition of different carbon sources as well as initial inoculum concentration were analyzed, demonstrating that Serratia sp. C8 could reduce 80 % of 20 mg/L Cr (VI) in a medium containing glucose 1 g/L, at pH 6-7 and 28 degrees C as optimal conditions, using 5 % inoculum concentration. The mechanisms involved in Cr (VI) removal were also evaluated. The strain was capable of biosorpting around 7.5-8.5 % of 20 mg/L Cr on its cell surface and to reduce Cr (VI). In addition, approximately a 54 and 46 % of total Cr was detected in the biomass and in the culture medium, respectively, and in the culture medium, Cr (III) was the predominant species. In conclusion, Serratia sp. C8 removed Cr (VI) and the mechanisms involved in decreasing order of contribution were as follows: reduction catalyzed by intracellular enzymes, accumulation into the cells, and biosorption to the microbial biomass. This strain could be a suitable microorganism for Cr (VI) bioremediation of tannery sediments and effluents or even for other environments contaminated with Cr. PMID- 25023658 TI - Bathymetric variation of epiphytic assemblages on Posidonia oceanica (L.) Delile leaves in relation to anthropogenic disturbance in the southeastern Mediterranean. AB - A survey of the epiphytic leaves of Posidonia oceanica was conducted along a depth transect at both the control station Attaya in the Kerkennah Islands and the disturbed Mahres station on the Sfax coast (Tunisia). Samples were collected by scuba divers at depths of 5, 10, 15, and 20 m in July 2008. We evaluated whether the pattern of spatial variability of the macroepiphyte assemblages of leaves of Posidonia oceanica differed in relation to anthropogenic interference. The results indicate that the decrease in shoot density and leaf length according to depth was low at Mahres. The biomass of epiphytic leaves and the percentage cover of epiphytic assemblages decreased with depth for both stations and heavily at Mahres, this decline being related to anthropogenic disturbance. This study shows that the highest values of epifauna and epiflora were detected at the disturbed station Mahres. Macroalgae assemblages decreased with depth at both stations and were dominated by Rhodophyta, whereas the percentage cover of the epifauna leaf that decreases according to depth was dominated by Hydrozoa and Bryozoa. Changes in epiphyte assemblages, epiphytic biomass, percentage cover, and species richness in proportion to Heterokontophyta, Rhodophyta, Cyanobacteria, Hydrozoa, Porifera, and Tunicata between the two stations constitute promising tools for detecting environmental disturbance. PMID- 25023659 TI - Acellular blood vessels combined human hair follicle mesenchymal stem cells for engineering of functional arterial grafts. AB - Tissue-engineered vessels offer options for autologous vascular grafts in cardiovascular repair and regeneration. The experiments aimed to construct functional arterial grafts by combining human hair follicle mesenchymal stem cells (HF-MSCs) with acellular umbilical arteries. We isolated mesenchymal stem cells from human hair follicles. Under appropriate culture conditions, these cells displayed CD44, CD90 and CD105, and exhibited the potential for differentiation to adipocytes, osteoblasts and chondrocytes. Very promisingly, HF MSCs expressed the vascular smooth muscle specific markers in the presence of transforming growth factor-beta. We created acellular arterial scaffolds by digesting human umbilical arteries with trypsin and sodium dodecyl sulfate. These acellular arterial scaffolds retained major components of the extracellular matrix. The mechanical properties of these acellular arterial scaffolds were very similar to those of native blood vessels. We then seeded HF-MSCs into acellular arterial scaffolds and found that they still expressed vascular smooth muscle specific markers. The arterial grafts derived from HF-MSCs demonstrated vasoreactivity in response to humoral constrictors. We constructed arterial grafts that are very close to native blood vessels in their structures and physiological functions. These properties suggest that these arterial grafts could be used as small diameter arterial grafts for cardiovascular repair and regeneration. PMID- 25023660 TI - Passive-dynamic ankle-foot orthoses substitute for ankle strength while causing adaptive gait strategies: a feasibility study. AB - Bending stiffness of passive-dynamic ankle-foot orthoses (PD-AFOs) is a functional characteristic thought to restore lost ankle function due to weakened plantar flexors. However, lower extremity impairment profiles of patients are seldom limited to plantar flexion weakness, and PD-AFO characteristics often influence gait in other ways. Combined, all PD-AFO characteristics and patient impairments likely mask the main effect of PD-AFO bending stiffness and complicate the PD-AFO bending stiffness prescription process. In this study, we propose a biomechanical probing paradigm, where customized PD-AFOs with a range of precise stiffness values are worn by healthy subjects, to experimentally test a PD-AFO strength substitution hypothesis while simultaneously documenting gait adaptations to PD-AFO use. Two healthy subjects walked at a scaled velocity while wearing a series of three PD-AFOs that ranged in bending stiffness levels. Supporting the strength substitution hypothesis, peak ankle plantar flexion moments remained unchanged across PD-AFO stiffness conditions. Further biomechanical analyses documented a complex series of ankle related kinematic and kinetic adaptive movement strategies due to PD-AFO use. This study demonstrated the utility of the biomechanical probing paradigm to help understand the contribution of PD-AFO stiffness to ankle strength and its secondary effects on ankle biomechanics. PMID- 25023661 TI - Patellofemoral arthroplasty influences tibiofemoral kinematics: the effect of patellar thickness. AB - PURPOSE: Although controversy still remains, isolated patellofemoral arthroplasty recently gained in popularity as a treatment option for patellofemoral osteoarthritis. It has compared to total knee arthroplasty the advantage of preserving the tibiofemoral articulation, which in theory would allow the preservation of natural tibiofemoral kinematics. Today, however, no data exist to support this assumption. This study was therefore performed in order to investigate the effect of isolated patellofemoral arthroplasty on the native three-dimensional tibiofemoral kinematic behaviour and whether a change in patellar thickness would have an influence. METHODS: Six fresh-frozen cadavers were fixed on a custom-made mechanical knee rig. Full 3D kinematics was analysed during passive flexion-extension cycles, open chain extension, with and without mechanical resistance, as well as deep knee squats, using infrared motion capture cameras and retroflective markers. Measurements were taken for the native knee and after prosthetic trochlear resurfacing with and without patellar resurfacing in three different patellar thicknesses. RESULTS: Compared to the natural knee, patellofemoral arthroplasty resulted in significant changes in tibiofemoral kinematics, which were most pronounced in the most loaded motor tasks. Increased internal tibial rotation was noted in the mid- and high flexion ranges, reaching at 120 degrees of flexion a mean difference of 4.5 degrees +/-4.3 degrees (p<0.0001) during squat motion, over the whole flexion range during open chain motion and in deeper flexion beyond 50 degrees (mean at 70 degrees , 1.9 degrees +/-3.7 degrees ) during resisted open chain. During squats, also, a more posterior translation of the lateral femoral condyle was observed. The effect was accentuated in case of patella overstuffing, whereas kinematics was closer to normal with patellar thinning. CONCLUSION: Isolated patellofemoral arthroplasty alters natural tibiofemoral kinematics, and the effects become more pronounced in case of increased patellar thickness. Therefore, it might be recommended to aim for a slight over-resection of patellar bone if sufficient bone stock is available. PMID- 25023662 TI - The homeobox gene EMX2 is a prognostic and predictive marker in malignant pleural mesothelioma. AB - OBJECTIVES: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. EMX2 is a homeobox transcription factor that may regulate key developmental pathways known to promote tumorigenesis. In this study, we evaluated the prognostic and predictive significance of EMX2 expression in MPM. MATERIALS AND METHODS: Fifty surgically resected MPM specimens were studied. Quantitative real-time RT-PCR was used to analyze EMX2 mRNA expression. Association of EMX2 levels with clinical outcomes was evaluated with using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model. RESULTS: EMX2 expression was significantly associated with IMIG stage (p<0.001) and smoking history (p=0.006). Cox hazard regression modeling identified low-EMX2 expression as a negative prognostic factor in progression-free survival by both univariate (p=0.002) and multivariate analysis (p=0.002). Kaplan-Meier analysis revealed significant differences in progression-free survival between low- and high-EMX expressing groups in all patients (p=0.001), and also when grouped by early (I/II) stage disease (p<0.001), patients undergoing pleurectomy (p<0.001) and patients with an epitheliod subtype (p<0.004). Furthermore, EMX2 expression predicted response to neoadjuvant chemotherapy. High-EMX2 expression was associated with decreased progression-free survival after neoadjuvant therapy, suggesting that induction therapy should be avoided in these patients. CONCLUSIONS: EMX2 expression is downregulated in advanced cases of malignant pleural mesothelioma and may serve as an important prognostic and predictive molecular biomarker of progression-free survival. PMID- 25023663 TI - Development of a receptor model for efficient in silico screening of HIV-1 integrase inhibitors. AB - Integrase (IN) is a key viral enzyme for the replication of the type-1 human immunodeficiency virus (HIV-1), and as such constitutes a relevant therapeutic target for the development of anti-HIV agents. However, the lack of crystallographic data of HIV IN complexed with the corresponding viral DNA has historically hindered the application of modern structure-based drug design techniques to the discovery of new potent IN inhibitors (INIs). Consequently, the development and validation of reliable HIV IN structural models that may be useful for the screening of large databases of chemical compounds is of particular interest. In this study, four HIV-1 IN homology models were evaluated respect to their capability to predict the inhibition potency of a training set comprising 36 previously reported INIs with IC50 values in the low nanomolar to the high micromolar range. Also, 9 inactive structurally related compounds were included in this training set. In addition, a crystallographic structure of the IN-DNA complex corresponding to the prototype foamy virus (PFV) was also evaluated as structural model for the screening of inhibitors. The applicability of high throughput screening techniques, such as blind and ligand-guided exhaustive rigid docking was assessed. The receptor models were also refined by molecular dynamics and clustering techniques to assess protein sidechain flexibility and solvent effect on inhibitor binding. Among the studied models, we conclude that the one derived from the X-ray structure of the PFV integrase exhibited the best performance to rank the potencies of the compounds in the training set, with the predictive power being further improved by explicitly modeling five water molecules within the catalytic side of IN. Also, accounting for protein sidechain flexibility enhanced the prediction of inhibition potencies among the studied compounds. Finally, an interaction fingerprint pattern was established for the fast identification of potent IN inhibitors. In conclusion, we report an exhaustively validated receptor model if IN that is useful for the efficient screening of large chemical compounds databases in the search of potent HIV-1 IN inhibitors. PMID- 25023664 TI - The conformational behavior, geometry and energy parameters of Menshutkin-like reaction of O-isopropylidene-protected glycofuranoid mesylates in view of DFT calculations. AB - The formation of pyridinium salts in the transformation of three O-isopropylidene protected mesylates of furanoid sugar derivatives under pyridine action is considered at the B3LYP/6-31+G** computation level. All the structures were optimized in the gas phase, in chloroform and water. Activation barrier heights in the gas phase were also estimated at the B3LYP/6-311++G**, MPW1K/6-31+G** and MPW1K/6-311++G** levels. The conducted calculations, both in the gas phase (regardless of the computation level) and in solvents, revealed the barrier height increasing order as follows: 1>2>3 for the three reactions studied. The conformational behavior of the five-membered ring is discussed in the gas phase and in solvents. The fused dioxolane ring makes the furanoid ring less likely to undergo conformational changes. In the case of reaction 3, the furanoid ring shape does not change either in the gas phase or in solvents. All conformers are close to E0 or (0)E. PMID- 25023665 TI - Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: In silico ligand screening and molecular dynamics studies of inhibition. AB - The allosteric pocket of the Dengue virus (DENV2) NS2B/NS3 protease, which is proximal to its catalytic triad, represents a promising drug target (Othman et al., 2008). We have explored this binding site through large-scale virtual screening and molecular dynamics simulations followed by calculations of binding free energy. We propose two mechanisms for enzyme inhibition. A ligand may either destabilize electronic density or create steric effects relating to the catalytic triad residues NS3-HIS51, NS3-ASP75, and NS3-SER135. A ligand may also disrupt movement of the C-terminal of NS2B required for inter-conversion between the "open" and "closed" conformations. We found that chalcone and adenosine derivatives had the top potential for drug discovery hits, acting through both inhibitory mechanisms. Studying the molecular mechanisms of these compounds might be helpful in further investigations of the allosteric pocket and its potential for drug discovery. PMID- 25023667 TI - Complete mitochondrial genome of the Zebra bullhead shark Heterodontus zebra (Heterodontiformes: Heterodontidae). AB - The complete mitochondrial genome of the Zebra bullhead shark Heterodontus zebra was first presented in this study. It was 16,720 bp in length, encoding 37 genes and one control region. The gene order and translate orientation were identical to most vertebrates. Overall nucleotide base composition of H. zebra mitogenome was 31.6% A; 26.8% C; 13.1% G and 28.4% T. Total 27 bp overlaps and 20 bp short intergenic spaces were found in 17 gene junctions in the genome. Two start codons (ATG and GTG) and three terminate codons (TAG, TAA and T) were found in 13 protein-coding genes. Except for tRNA-Ser2, which lost the dihydrouridine (DHU) arm and formed one simple loop, the remaining tRNAs could fold into the typical clover-leaf secondary structures. The termination-associated sequences and three short conserved blocks (CBS I-III) were identified in the control region. PMID- 25023668 TI - Low-energy-electron induced permanently reactive CO2 molecules. AB - Ab initio quantum chemical studies show that a very weak molecular complexation of CO2 with a dipolar molecule is able to suppress the autoionization of the electron from its transient negative ion states. Since the autoionization is suppressed, the transient negative ion can efficiently relax its geometry to form the reductively activated CO2 moiety. Unlike the reductively activated isolated CO2 molecules, which are deactivated immediately due to their thermodynamic metastability, the reductively activated CO2 moieties of the weak molecular complexes are infinitely long-lived and, hence, permanently reactive. PMID- 25023666 TI - The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold. AB - More than 33,000 glycosyltransferases have been identified. Structural studies, however, have only revealed two distinct glycosyltransferase (GT) folds, GT-A and GT-B. Here we report a 1.34-A resolution X-ray crystallographic structure of a previously uncharacterized 'domain of unknown function' 1792 (DUF1792) and show that the domain adopts a new fold and is required for glycosylation of a family of serine-rich repeat streptococcal adhesins. Biochemical studies reveal that the domain is a glucosyltransferase, and it catalyses the transfer of glucose to the branch point of the hexasaccharide O-linked to the serine-rich repeat of the bacterial adhesin, Fap1 of Streptococcus parasanguinis. DUF1792 homologues from both Gram-positive and Gram-negative bacteria also exhibit the activity. Thus, DUF1792 represents a new family of glycosyltransferases; therefore, we designate it as a GT-D glycosyltransferase fold. As the domain is highly conserved in bacteria and not found in eukaryotes, it can be explored as a new antibacterial target. PMID- 25023669 TI - Rapid genetic typing of diarrheagenic Escherichia coli using a two-tube modified molecular beacon based multiplex real-time PCR assay and its clinical application. AB - BACKGROUND: Diarrheagenic Escherichia coli (DEC), including Enterotoxigenic E.coli (ETEC), Enteroaggregative E.coli (EAEC), Enteropathogenic E.coli (EPEC), Enterohemolysin E.coli (EHEC) and Enteroinvasive E.coli (EIEC) causes diarrhea or hemolytic uremic syndromes among infants and travelers around the world. A rapid, reliable and repeatable method is urgent for identifying DEC so as to provide the reference for responding to diarrheal disease outbreak and the treatment of the diarrheal patients associated with DEC. METHODS: In this study, specific primers and modified molecular beacon probes of nine specific virulence genes, whose 5'end were added with homo tail sequence, were designed; and a two-tube modified molecular beacon based multiplex real-time PCR (rtPCR) assay for the identification of five Escherichia coli pathotypes, including ETEC, EAEC, EPEC, EHEC and EIEC was developed and optimized. Totally 102 bacterial strains, including 52 reference bacterial strains and 50 clinical strains were detected to confirm whether the target genes selected were specific. Then detection limits of the assay were tested. Lastly, the assay was applied to the detection of 11860 clinical samples to evaluate the specificity and sensitivity of the developed assay compared with the conventional PCR. RESULTS: The target genes were 100% specific as assessed on 102 bacterial strains since no cross-reactions were observed. The detection limits ranged from 88 CFU/mL (EHEC) to 880 CFU/mL (EPEC). Compared with the conventional PCR, the specificity and sensitivity of the multiplex rtPCR was 100% and over 99%, respectively. The coefficient of variation (CV) for each target gene ranged from 0.45% to 1.53%. 171 positive clinical samples were mostly identified as ETEC (n = 111, 64.9%) and EPEC (n = 38, 22.2%), which were the dominating pathotypes of DEC strains. CONCLUSION: The developed multiplex rtPCR assay for the identification of DEC was high sensitive and specific and could be applied to the rapid identification of DEC in clinical and public health laboratories. PMID- 25023670 TI - Olmesartan, other antihypertensives, and chronic diarrhea among patients undergoing endoscopic procedures: a case-control study. AB - OBJECTIVE: To investigate a recent association between the use of the angiotensin receptor-blocker (ARB) olmesartan and a severe enteropathy resembling celiac disease. PATIENTS AND METHODS: We searched our endoscopy database for all outpatient esophagogastroduodenoscopy (EGD) or colonoscopy examinations in patients aged at least 50 years during the period January 1, 2007, to March 31, 2013. Cases were those whose examination indication was diarrhea, and controls were those whose examination indication was esophageal reflux (EGD) or colorectal cancer screening (colonoscopy). We compared cases with controls with regard to the proportion of those listing olmesartan among their medications. Secondary exposures were the proportion of those taking nonolmesartan ARBs or other antihypertensive medications. We also examined biopsy results to determine whether there were histologic changes associated with the use of olmesartan. RESULTS: We identified 2088 patients undergoing EGD and 12,428 patients undergoing colonoscopy meeting inclusion criteria. On multivariate analysis, there was no statistically significant association between olmesartan and diarrhea among those undergoing EGD (odds ratio, 1.99; 95% CI, 0.79-5.00) or colonoscopy (odds ratio, 0.63; 95% CI, 0.23-1.74). Review of pathology reports of the EGD and colonoscopy groups showed no association between the use of olmesartan and the histologic diagnosis of celiac disease (P=.61) or microscopic colitis (P=1.0), respectively. CONCLUSION: Our findings suggest that neither olmesartan nor other ARBs were associated with diarrhea among patients undergoing endoscopy. The spruelike enteropathy recently associated with olmesartan is likely a rare adverse effect and milder presentations are unlikely. PMID- 25023671 TI - Embryo implantation - coordination of maternal and embryonic adaptations. PMID- 25023672 TI - Decidua and implantation of the embryo from a historical perspective. AB - Implantation of the embryo is critical for the initiation of intrauterine development of early embryos. It depends on the proper soil formed by the decidualized pregnant uterus. In the present article I have reviewed the evolution of the modern concepts of decidualization and embryonic implantation, emphasizing how closely interrelated these two processes are. Special emphasis and recognition is given to the Boston pathologist Arthur T. Hertig, who studied for 15 years with another Bostonian, John Rock, a gynecologist, human implantation and early embryogenesis, thus providing the basis for future studies of human reproductive biology, infertility and contraception. PMID- 25023673 TI - A lifetime of deciphering complexities of embryo implantation. AB - This interview chronicles the story of Sudhansu K. Dey in his journey from Calcutta, India to Kansas City, Kansas, establishing a research enterprise in the field of female reproduction. His research of over four decades has focused specifically on implantation biology using various model systems and reveling the impact of implantation on female reproductive medicine. This interview also reveals qualities of SK's character - his resolution, mentoring spirit, and humble nature - that contributed to his successes. SK is not shy to approach individuals for expertise or help, and in the same spirit, he is ready to offer his help to others irrespective of their positions or stature. He constantly attributes his success to the hard work of his laboratory members, the intellectual stimulation from his collaborators, and the support from his family. His ability to overcome challenges throughout his career is a reminder to students and junior investigators in the scientific community that each individual is endowed with talents and can accomplish their dreams if they pursue them. This interview tells the story of how he progressed from an inquisitive child to becoming a true servant to the cause of science and humankind. PMID- 25023674 TI - Exploring the world of human development and reproduction. AB - Susan Fisher has spent her career studying human development, proteomics, and the intersection between the two. When she began studying human placentation, there had been extensive descriptive studies of this fascinating organ that intertwines with the mother's vasculature during pregnancy. Susan can be credited with numerous major findings on the mechanisms that regulate placental cytotrophoblast invasion. These include the discovery that cytotrophoblasts undergo vascular mimicry to insert themselves into uterine arteries, the finding that oxygen tension greatly effects placentation, and identifying how these responses go awry in pregnancy complications such as preeclamsia. Other important work has focused on the effect of post-translational modifications such as glycosylation on bacterial adhesion and reproduction. Susan has also forayed into the world of proteomics to identify cancer biomarkers. Because her work is truly groundbreaking, many of these findings inspire research in other laboratories around the world resulting in numerous follow up papers. Likewise, her mentoring and support inspires young scientists to go on and make their own important discoveries. In this interview, Susan shares what drove her science, how she continued to do important research while balancing other aspects of life, and provides insights for the next generation. PMID- 25023677 TI - Evolution of mammalian pregnancy and the origin of the decidual stromal cell. AB - Reproduction in eutherian mammals is characterized by extended intrauterine retention of the fetus after implantation. We summarize evolutionary innovations that enable this form of vivipary, including early maternal recognition of pregnancy, invasive placentation, and emergence of the decidual cell type. We first review the structure of the marsupial endometrium and its relationship to that of eutherian mammals. While the tissue components of endometrium are the same in marsupials and eutherians, an important difference is the amount of stromal cells, which are much more abundant in eutherians. Moreover, the nature of the invasive placentation differs in marsupials and eutherians. In the opossum, it consists of cytoplasmatic extensions of trophoblast cells that penetrate between the luminal epithelial cells to contact maternal capillaries. In bandicoots, the trophoblast and luminal epithelial cells fuse, and the maternal epithelium is replaced by a layer of multinucleated cells. In no case has there been evidence of a direct interaction between trophoblast and stromal cells. The direct interface between the trophoblast and maternal stroma is a derived feature of eutherian mammals, coincidental with the origin of decidual cells. Gene expression studies are suggestive of "categorical reprograming" of endometrial fibroblasts during decidualization. This reprogramming suggests that the decidual cell is a distinct cell type rather than a modulation of endometrial fibroblasts. Further support for this hypothesis is the origin of derived transcription factor interactions that are necessary for the regulation of decidual gene expression, in particular the interactions between HOXA11 and CEBPB with FOXO1A. PMID- 25023676 TI - Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization. AB - All mammalian uteri contain glands in the endometrium that synthesize or transport and secrete substances essential for survival and development of the conceptus (embryo/fetus and associated extraembryonic membranes). This review summarizes information related to the biological roles of uterine glands and their secretions in uterine receptivity, blastocyst/conceptus survival and implantation, and stromal cell decidualization. Studies with the ovine uterine gland knockout (UGKO) model support a primary role for uterine glands and, by inference, their secretions present in uterine luminal fluid histrotroph for conceptus survival and development. In rodents, studies with mutant and progesterone-induced UGKO mice found that uterine glands and their secretions are unequivocally required for establishment of uterine receptivity and blastocyst implantation and also may influence blastocyst trophectoderm activation and stromal cell decidualization in the uterus. Similarly in humans, histotroph from uterine glands appears critical for blastocyst implantation, uterine receptivity, and conceptus nutrition during the first trimester and uterine glands likely have a role in stromal cell decidualization. An increased understanding of uterine gland biology is important for diagnosis, prevention and treatment of fertility problems, particularly infertility and recurrent pregnancy loss, in domestic animals and humans. PMID- 25023678 TI - Transcriptomics of the human endometrium. AB - During the mid-secretory phase, the endometrium acquires the receptive phenotype, which corresponds to the only period throughout the endometrial cycle in which embryo implantation is viable. Endometrial receptivity is a crucial process and even more important in Assisted Reproductive Technologies (ART) where embryo endometrial synchronization is coordinated through embryo transfer timing. Over the last decade, transcriptomic analyses performed on the human endometrium have shown that specific genomic signatures can be used to successfully phenotype different phases of the menstrual cycle including the receptive stage, independently of the histological appereance of the endometrial tissue. In this paper, we review current evidence demonstrating that endometrial transcriptomics objectively identifies the implantation window in a personalized manner, opening the field for the diagnosis of the endometrial factor in ART and moving to stratified medicine at this level, using microarray technology and soon high throughput next generation sequencing coupled with functional and systems genomics approach. PMID- 25023675 TI - Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus. AB - Infertility and reproductive-associated disease are global problems in the world today affecting millions of women. A successful pregnancy requires a healthy uterus ready to receive and support an implanting embryo. As an endocrine organ, the uterus is dependent on the secretions of the ovarian hormones estrogen and progesterone which signal via their cognate receptors, the estrogen and progesterone receptors. The progesterone receptor not only functions using classical nuclear receptor signaling, but also participates in non-genomic signaling at the cellular membrane. The complexity of progesterone signaling is further enhanced by the existence of multiple isoforms and post-translational regulation via kinases and transcription coregulators. This dynamic means of regulation of the progesterone receptor is evidenced in its necessary role in a successful pregnancy. Within early pregnancy, the progesterone receptor elicits activation of its target genes in a spatiotemporal manner in order to allow for successful embryo attachment and uterine decidualization. Additionally, appropriate progesterone signaling is important for the prevention of uterine disease such as endometrial cancer, endometriosis, and leiomyoma. The utilization of progesterone receptor modulators in the treatment of these devastating uterine diseases is promising. This review presents a general overview of progesterone receptor structure, function, and regulation and highlights its important role in the establishment of pregnancy and as a therapeutic target in uterine disease. PMID- 25023679 TI - Role of uterine stromal-epithelial crosstalk in embryo implantation. AB - Embryo implantation is a crucial step for successful pregnancy. Prior to implantation, the luminal epithelium undergoes steroid hormone-induced structural and functional changes that render it competent for embryo attachment. Subsequent invasion of the embryo into the maternal tissue triggers differentiation of the underlying stromal cells to form the decidua, a transient tissue which supports the developing embryo. Many molecular cues of both stromal and epithelial origin have been identified that are critical mediators of this process. An important aspect of uterine biology is the elaborate crosstalk that occurs between these tissue compartments during early pregnancy through expression of paracrine factors regulated by the steroid hormones estrogen and progesterone. Aberrant expression of these factors often leads to implantation failure and infertility. Genetically-engineered mouse models have been instrumental in elucidating what these paracrine factors are, what drives their expression, and what their effects are on neighboring cells. This review provides an overview of several well characterized signaling pathways that span both epithelial and stromal compartments and their function during implantation in the mouse. PMID- 25023680 TI - Molecular determinants of uterine receptivity. AB - Uterine receptivity is defined as a limited period when the uterine environment is conducive to blastocyst acceptance and implantation. Any disturbance of this early pregnancy event will compromise pregnancy success. In this review, we first briefly summarize uterine morphological coordination for the attainment of receptivity, then focus on elucidating the molecular complexity in establishing uterine receptivity and hence embryo implantation. A better understanding of the molecular basis governing uterine receptivity will help to improve the outcome of natural pregnancy and pregnancy conceived via assisted reproductive techniques. PMID- 25023681 TI - The evolution of embryo implantation. AB - Embryo implantation varies widely in placental mammals. We review this variation in mammals with a special focus on two features: the depth of implantation and embryonic diapause. We discuss the two major types of implantation depth, superficial and interstitial, and map this character on a well-resolved molecular phylogenetic tree of placental mammals. We infer that relatively deep interstitial implantation has independently evolved at least eight times within placental mammals. Moreover, the superficial type of implantation represents the ancestral state for placental mammals. In addition, we review the genes involved in various phases of implantation, and suggest a future direction in investigating the molecular evolution of implantation-related genes. PMID- 25023682 TI - Embryonic diapause: development on hold. AB - Embryonic diapause, the temporary suspension of development of the embryo, is a fascinating reproductive strategy that has been frequently exploited across the animal kingdom. It is characterized by an arrest in development that occurs at the blastocyst stage in over 130 species of mammals. Its presumed function is to uncouple mating from parturition, to ensure that both occur at the most propitious moment for survival of the species. Diapause can be facultative, i.e. induced by physiological conditions, or obligate, i.e. present in every gestation of a species. In the latter case, the proximal signals for regulation are related to photoperiod. Three diverse models, the mouse, the mustelid carnivores and the wallaby have been studied in detail. From these studies it can be discerned that, although the endocrine cues responsible for induction of diapause and re initiation of development vary widely between species, there are a number of commonalities. Evidence to date indicates that the uterus exercises the proximal regulatory influence over whether an embryo enters into and when it exits from diapause. Some factors have been identified that appear crucial to this regulation, in particular, the polyamines. Recent studies indicate that diapause can be induced in species where it does not exist in nature. This suggests that the potential for diapause in mammals to be due to a single evolutionary event, to which control mechanisms adapted when the trait was beneficial to reproductive success. Further work at the molecular, cellular and organismic levels will be required before the physiological basis of diapause is resolved. PMID- 25023683 TI - Embryo-endometrial interactions during early development after embryonic diapause in the marsupial tammar wallaby. AB - The marsupial tammar wallaby has the longest period of embryonic diapause of any mammal. Reproduction in the tammar is seasonal, regulated by photoperiod and also lactation. Reactivation is triggered by falling daylength after the austral summer solstice in December. Young are born late January and commence a 9-10 month lactation. Females mate immediately after birth. The resulting conceptus develops over 6- 7 days to form a unilaminar blastocyst of 80-100 cells and enters lactationally, and later seasonally, controlled diapause. The proximate endocrine signal for reactivation is an increase in progesterone which alters uterine secretions. Since the diapausing blastocyst is surrounded by the zona and 2 other acellular coats, the mucoid layer and shell coat, the uterine signals that maintain or terminate diapause must involve soluble factors in the secretions rather than any direct cellular interaction between uterus and embryo. Our studies suggest involvement of a number of cytokines in the regulation of diapause in tammars. The endometrium secretes platelet activating factor (PAF) and leukaemia inhibitory factor, which increase after reactivation. Receptors for PAF are low on the blastocyst during diapause but are upregulated at reactivation. Conversely, there is endometrial expression of the muscle segment homeobox gene MSX2 throughout diapause, but it is rapidly downregulated at reactivation. These patterns are consistent with those observed in diapausing mice and mink after reactivation, despite the very different patterns of endocrine control of diapause in these 3 divergent species. These common patterns suggest a similar underlying mechanism for diapause, perhaps common to all mammals, but which is activated in only a few. PMID- 25023684 TI - Evolving tales of autophagy in early reproductive events. AB - Cells learn to thrive under unfavorable conditions by various mechanisms, and autophagy, self-eating, is one such mechanism. Autophagy is always ongoing in cells at a basal level to turn over old proteins, provide building blocks for new proteins, and to dispose of unnecessary byproducts of metabolism, and normally it does not cause deleterious effects on other parts of basic cellular processes. Autophagy is often dubbed a "double-edged sword", as it is a necessary process for many cells, but its exaggeration may lead to cell death. Evidence is accumulating that autophagy is crucially involved in specific aspects of reproduction. Several recent studies have illustrated how the uniqueness of self eating is manifested in germ cells and embryos. In this review, we attempt to portray where this relatively young field of autophagy research is heading in the context of reproductive biology research. PMID- 25023686 TI - Uterine natural killer cells as modulators of the maternal-fetal vasculature. AB - Precise and local control of the innate immune system within the placenta is an essential component for achieving a normal and healthy pregnancy. One of the most abundant immune cells of the placenta is a subpopulation of natural killer (NK) cells that profusely populates the uterine decidua during early pregnancy. Uterine NK (uNK) cells and trophoblast cells of the placenta communicate both directly and indirectly to contribute to the critical process of spiral artery remodeling. Here, we discuss recent findings that expand our knowledge of uNK cell-trophoblast cell crosstalk and the important role it plays in the maternal vascular adaptation to pregnancy. PMID- 25023685 TI - T cell behavior at the maternal-fetal interface. AB - Understanding the function of T cells at the maternal-fetal interface remains one of the most difficult problems in reproductive immunology. A great deal of work over the last two decades has led to the view that the T cells that populate the decidua have important roles in both normal and pathological pregnancies, but the exact nature of these roles has remained unclear. Indeed, the old assumption that decidual T cells are uniformly threatening to fetal survival because the placenta is fundamentally an 'allograft' has given way to the idea that different T cell subsets contribute in different ways to pregnancy success or failure. Accordingly, some T cells are thought to protect the placenta from immune rejection and facilitate embryo implantation, while others are thought to contribute to pregnancy pathologies such as preeclampsia and spontaneous abortion. Here, we review the current state of information on the behavior of decidual T cells with a focus on both mouse and human studies, and with an emphasis on the many unresolved areas within this overall emerging framework. PMID- 25023687 TI - Immunological determinants of implantation success. AB - The capacity of the immune system to maintain the integrity of the individual requires recognition and control of entities identified as genetically distinct, or 'non-self'. In mammalian reproduction, the embryo and subsequent fetus and placenta are all recognized as non-self by the maternal immune system, and are vulnerable to immunological attack. An active system to prevent rejection must exist from when conceptus and maternal tissues first come into contact at implantation. Crucial mediators of immune protection are inducible regulatory T cells (Treg cells). Unless sufficient Treg cells are present in the endometrium, successful implantation and progression to pregnancy cannot ensue. This key role of Treg cells confers to the female immune system substantial capability to influence reproductive events, particularly around the time of conception and embryo implantation. While on the one hand this risks susceptibility to immune based reproductive disorders, the potential evolutionary trade-off is the benefit of quality control to avoid poor reproductive outcomes. Here we summarize current knowledge of the factors required to establish a robust Treg cell response and an immune environment conducive to successful implantation and pregnancy. These factors include (a) appropriate cytokine balance; (b) correct phenotype of endometrial leukocytes to enable Treg cell activation; (c) sufficient estrogen and progesterone to stabilize and strengthen Treg cell phenotype, and (d) appropriate priming of Treg cell populations by male partner seminal fluid. Compromises in the quality of this immune adaptation at conception can influence the early embryo and either prevent implantation or impair placental morphogenesis. Failure to successfully establish Treg cell-mediated immune tolerance can result in poor fertility or impart long-term adverse consequences for the fetus and offspring. PMID- 25023689 TI - DNA methylation and its role in the trophoblast cell lineage. AB - DNA methylation functions as cellular memory beyond generations of cells and is involved in many biological processes. Because of its relatively stable nature compared with the transcriptome, the DNA methylation profile of cells can also be used to evaluate developmental similarity and cellular phenotypes. Recent insights into 5-hydroxymethylcytosine have started to reshape our view of the epigenetic regulation of mammalian development. Both global DNA methylation and hydroxymethylation levels change dynamically during preimplantation embryogenesis. It is known that DNA methylation plays an essential role in embryonic cell fate restriction, whereas its role in trophoblast development requires further research. Two distinct blastocyst-derived stem cell lines, embryonic stem (ES) cells and trophoblast stem (TS) cells, are used to study the epigenetic mechanisms underlying cell lineage maintenance and the regulation of cell differentiation. Such studies will allow us to understand the details of the epigenetic landscape of trophoblast development, which should offer valuable information for managing pregnancy-related diseases in humans. PMID- 25023688 TI - Natural killer cells and regulatory T cells in early pregnancy loss. AB - Survival of the allogeneic embryo in the uterus depends on the maintenance of immune tolerance at the maternal-fetal interface. The pregnant uterus is replete with activated maternal immune cells. How this immune tolerance is acquired and maintained has been a topic of intense investigation. The key immune cells that predominantly populate the pregnant uterus are natural killer (NK) cells. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation. In placental mammals, an array of highly orchestrated immune elements to support successful pregnancy outcome has been incorporated. This includes active cooperation between maternal immune cells, particularly NK cells, and trophoblast cells. This intricate process is required for placentation, immune regulation and to remodel the blood supply to the fetus. During the past decade, various types of maternal immune cells have been thought to be involved in cross-talk with trophoblasts and in programming immune tolerance. Regulatory T cells (Tregs) have attracted a great deal of attention in promoting implantation and immune tolerance beyond implantation. However, what has not been fully addressed is how this immune-trophoblast axis breaks down during adverse pregnancy outcomes, particularly early pregnancy loss, and in response to unscheduled inflammation. Intense research efforts have begun to shed light on the roles of NK cells and Tregs in early pregnancy loss, although much remains to be unraveled in order to fully characterize the mechanisms underlying their detrimental activity. An increased understanding of host-environment interactions that lead to the cytotoxic phenotype of these otherwise pregnancy compatible maternal immune cells is important for prediction, prevention and treatment of pregnancy maladies, particularly recurrent pregnancy loss. In this review, we discuss relevant information from experimental and human models that may explain the pregnancy disrupting roles of these pivotal sentinel cells at the maternal-fetal interface. PMID- 25023690 TI - BMP4 regulation of human trophoblast development. AB - Since the derivation of human embryonic stem cells, and the subsequent generation of induced pluripotent stem cells, there has been much excitement about the ability to model and evaluate human organ development in vitro. The finding that these cells, when treated with BMP4, are able to generate the extraembryonic cell type, trophoblast, which is the predominant functional epithelium in the placenta, has not been widely accepted. This review evaluates this model, providing comparison to early known events during placentation in both human and mouse and addresses specific challenges. Keeping in mind the ultimate goal of understanding human placental development and pregnancy disorders, our aim here is two-fold: to distinguish gaps in our knowledge arising from mis- or over interpretation of data, and to recognize the limitations of both mouse and human models, but to work within those limitations towards the ultimate goal. PMID- 25023692 TI - Cell signaling in trophoblast-uterine communication. AB - Intricate and precise communication between the blastocyst and the uterus orchestrates embryo implantation. However, many questions remain unanswered regarding the molecular complexities of implantation. On-time implantation requires a receptive uterus and a mature blastocyst with trophoblast cells capable of adhering to and invading the endometrium. Defects in uterine receptivity or embryo/uterine signaling can cause implantation failure or early pregnancy loss, whereas deficient trophoblast differentiation can generate placental abnormalities that produce adverse pregnancy outcomes. This review will discuss several examples of signaling pathways that regulate trophoblast and uterine development during this period. Leukemia inhibitory factor is involved in uterine priming for implantation. The epidermal growth factor signaling system contributes to trophoblast-uterine communication, as well as trophoblast adhesion and invasion. Indian hedgehog signaling synchronizes tissue compartments within the uterus, and WNT signaling mediates numerous interactions within the implantation site and developing placenta. The autocrine, paracrine and juxtacrine interactions mediated by these signaling pathways contribute significantly to the establishment of pregnancy, although there are many other known and yet to be discovered factors that synchronize the maternal and embryonic developmental programs. PMID- 25023693 TI - Pregnancy-specific glycoproteins: complex gene families regulating maternal-fetal interactions. AB - The pregnancy-specific glycoproteins (PSGs) are the most abundant trophoblastic proteins in maternal blood during human pregnancy and they appear to be exclusive to species with hemochorial placentation. There are ten protein-coding human PSG genes (PSG1 - PSG9, PSG11) and also multiple PSG genes in non-human primates, rodents and bats. Several studies indicate that PSGs have immunoregulatory, pro angiogenic, and anti-platelet functions. Some PSGs have been shown to bind different moieties on the surface of cells, including the tetraspanin CD9, heparan sulphate, and specific integrins. Recently, PSG1 was shown to associate with and activate the anti-inflammatory cytokines transforming growth factor (TGF)-beta1 and TGF- beta2 making PSG1 one of the few known biological activators of these important cytokines. TGF-betas regulate many biological processes essential for pregnancy success including trophoblast invasion and proliferation, angiogenesis, extracellular matrix formation and tolerance to the fetal semi allograft. As summarized in this review, progress has been made in recent years towards a better understanding of the functions of these proteins which were originally described in the early 1970s, but more research will likely contribute to demonstrate their importance for a successful pregnancy. PMID- 25023691 TI - Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy. AB - Implantation of the embryo into the uterus triggers the initiation of hemochorial placentation. The hemochorial placenta facilitates the acquisition of maternal resources required for embryo/fetal growth. Uterine spiral arteries form the nutrient supply line for the placenta and fetus. This vascular conduit undergoes gestation stage-specific remodeling directed by maternal natural killer cells and embryo-derived invasive trophoblast lineages. The placentation site, including remodeling of the uterine spiral arteries, is shaped by environmental challenges. In this review, we discuss the cellular participants controlling pregnancy dependent uterine spiral artery remodeling and mechanisms responsible for their development and function. PMID- 25023695 TI - Epigenetics and imprinting in human disease. AB - Most genes are expressed from both parental chromosomes; however, a small number of genes in mammals are imprinted and expressed in a parent-of-origin specific manner. These imprinted genes play an important role in embryonic and extraembryonic growth and development, as well as in a variety of processes after birth. Many imprinted genes are clustered in the genome with the establishment and maintenance of imprinted gene expression governed by complex epigenetic mechanisms. Dysregulation of these epigenetic mechanisms as well as genomic mutations at imprinted gene clusters can lead to human disease. PMID- 25023694 TI - The role of trophoblastic microRNAs in placental viral infection. AB - During the past decade, various types of small non-coding RNAs were found to be expressed in all kingdoms and phyla of life. Intense research efforts have begun to shed light on their biological functions, although much remains to be determined in order to fully characterize their scope of biological action. Typically, small RNAs provide sequence specificity to a protein complex that is driven to silence a long target RNA. MicroRNAs (miRNAs) are small RNAs that are coded in the genome of most eukaryotes, and contribute to the cellular identity by regulating cell-specific gene networks by translational repression or degradation of mRNA. These effects commonly fine-tune gene expression associated with developmental or environmental cues. Different cell types can be characterized by their distinctive cellular miRNA landscape. The human placenta expresses a unique set of miRNAs, a high proportion of which is derived from a large cluster located on chromosome 19, (termed chromosome 19 miRNA cluster, or C19MC). Interestingly, a fraction of these placenta-enriched miRNAs are released to the extracellular environment through exosomes that were recently found to induce an antiviral immunity. In this review, we explore relevant placental viral infections and discuss the antiviral role of exosome-packaged placental C19MC miRNAs in this context. PMID- 25023696 TI - Cloning, recombinant expression and characterization of a new phytase from Penicillium chrysogenum. AB - The phy gene, which encodes a phytase in Penicillium chrysogenum CCT 1273, was cloned into the vector pAN-52-1-phy and the resulting plasmid was used for the cotransformation of Penicillium griseoroseum PG63 protoplasts. Among the 91 transformants obtained, 23 were cotransformants. From there, the phytase activity of these 23 transformants was evaluated and P. griseoroseum T73 showed the highest. The recombinant strain P. griseoroseum T73 contained the phy gene integrated in at least three sites of the genome and showed a 5.1-fold increase in phytase activity in comparison to the host strain (from 0.56 +/- 0.2 to 2.86 +/- 0.4 U MUg protein(-1)). The deduced PHY protein has 483 amino acids; an isoelectric point (pI) higher than that reported for phytases from filamentous fungi (7.6); higher activity at pH 2.0 (73%), pH 5.0 (100%) and 50 degrees C; and is stable at pH values 3.0-8.0 and temperatures 70-80 degrees C. PHY produced by the recombinant strain P. griseoroseum T73 was stable after four weeks of storage at -20, 8 and 25 degrees C and was effective in releasing Pi, especially from soybeans. The data presented here show that P. griseoroseum is a successful host for expression of heterologous protein and suggest the potential use of PHY in the animal nutrition industry. PMID- 25023697 TI - Submicroscopic malaria infection during pregnancy and the impact of intermittent preventive treatment. AB - BACKGROUND: Malaria during pregnancy results in adverse outcomes for mothers and infants. Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) is the primary intervention aimed at reducing malaria infection during pregnancy. Although submicroscopic infection is common during pregnancy and at delivery, its impact throughout pregnancy on the development of placental malaria and adverse pregnancy outcomes has not been clearly established. METHODS: Quantitative PCR was used to detect submicroscopic infections in pregnant women enrolled in an observational study in Blantyre, Malawi to determine their effect on maternal, foetal and placental outcomes. The ability of SP to treat and prevent submicroscopic infections was also assessed. RESULTS: 2,681 samples from 448 women were analysed and 95 submicroscopic infections were detected in 68 women, a rate of 0.6 episodes per person-year of follow-up. Submicroscopic infections were most often detected at enrolment. The majority of women with submicroscopic infections did not have a microscopically detectable infection detected during pregnancy. Submicroscopic infection was associated with placental malaria even after controlling for microscopically detectable infection and was associated with decreased maternal haemoglobin at the time of detection. However, submicroscopic infection was not associated with adverse maternal or foetal outcomes at delivery. One-third of women with evidence of placental malaria did not have documented peripheral infection during pregnancy. SP was moderately effective in treating submicroscopic infections, but did not prevent the development of new submicroscopic infections in the month after administration. CONCLUSIONS: Submicroscopic malaria infection is common and occurs early in pregnancy. SP-IPT can clear some submicroscopic infections but does not prevent new infections after administration. To effectively control pregnancy-associated malaria, new interventions are required to target women prior to their first antenatal care visit and to effectively treat and prevent all malaria infections. PMID- 25023698 TI - Dual inhibition of REV-ERBbeta and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells. AB - REV-ERBalpha and REV-ERBbeta nuclear receptors regulate several physiological processes, including circadian rhythm and metabolism. A previous study reported the REV-ERBalpha gene to be co-overexpressed with ERBB2 in breast cancer cell lines. Surprisingly, we found that several tumor types, including a number of breast cancer cell lines, predominantly express the REV-ERBbeta variant. This pattern was independent of ERBB2 and ER status, and opposite to that of non cancer mammary epithelial HMEC cells, in which REV-ERBalpha was the major variant. Consistent with this molecular profile, REV-ERB target genes in both circadian and metabolic pathways were derepressed upon silencing of REV-ERBbeta, but not REV-ERBalpha. Strikingly, we found that REV-ERBbeta is a determinant of sensitivity to chloroquine, a clinically relevant lysosomotropic agent that suppresses autophagy. The cytoprotective function of REV-ERBbeta appears to operate downstream of autophagy blockade. Through compound screening, we identified ARN5187, a novel lysosomotropic REV-ERBbeta ligand with a dual inhibitory activity toward REV-ERB-mediated transcriptional regulation and autophagy. Remarkably, although ARN5187 and chloroquine share similar lysosomotropic potency and have a similar effect on autophagy inhibition, ARN5187 is significantly more cytotoxic. Collectively, our results reveal that dual inhibition of REV-ERBbeta and autophagy is an effective strategy for eliciting cytotoxicity in cancer cells. Furthermore, our discovery of a novel inhibitor compound of both REV-ERB and autophagy may provide a scaffold for the discovery of new multifunctional anticancer agents. PMID- 25023699 TI - Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs. AB - Cancer cells undergo a metabolic transformation that allows for increased anabolic demands, wherein glycolytic and tricarboxylic acid (TCA) cycle intermediates are shunted away for the synthesis of biological molecules required for cell growth and division. One of the key shunts is the exit of citrate from the mitochondria and the TCA cycle for the generation of cytosolic acetyl coenzyme A that can be used for fatty acid and cholesterol biosynthesis. With the loss of mitochondrial citrate, cancer cells rely on the 'conditionally essential' amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates. Although Q deprivation causes G1 cell cycle arrest in non transformed cells, its impact on the cancer cell cycle is not well characterized. We report here a correlation between bypass of the Q-dependent G1 checkpoint and cancer cells harboring K-Ras mutations. Instead of arresting in G1 in response to Q-deprivation, K-Ras-driven cancer cells arrest in either S- or G2/M-phase. Inhibition of K-Ras effector pathways was able to revert cells to G1 arrest upon Q deprivation. Blocking anaplerotic utilization of Q mimicked Q deprivation- causing S- and G2/M-phase arrest in K-Ras mutant cancer cells. Significantly, Q deprivation or suppression of anaplerotic Q utilization created synthetic lethality to the cell cycle phase-specific cytotoxic drugs, capecitabine and paclitaxel. These data suggest that disabling of the G1 Q checkpoint could represent a novel vulnerability of cancer cells harboring K-Ras and possibly other mutations that disable the Q-dependent checkpoint. PMID- 25023701 TI - DACT2 is a functional tumor suppressor through inhibiting Wnt/beta-catenin pathway and associated with poor survival in colon cancer. AB - Dapper homolog (DACT) 2 is one of the Dact gene family members, which are important modulators of Wnt signaling pathway. We aim to clarify its epigenetic inactivation, biological function and clinical implication in colon cancer. DACT2 was silenced in five out of eight colon cancer cell lines, but robustly expressed in normal colon tissues. The loss of DACT2 expression was regulated by promoter hypermethylation. Restoring DACT2 expression in colon cancer cell lines suppressed tumor cell growth by inducing cell apoptosis and inhibiting cell proliferation both in vitro and in vivo. Moreover, DACT2 overexpression effectively reduced lung metastasis of colon cancer cells in nude mice. These effects by DACT2 were attributed to inhibition of Wnt/beta-catenin signaling. Reexpression of DACT2 significantly suppressed the transcriptional activity of both wild-type beta-catenin and degradation-resistant form mutant beta-catenin (S33Y). DACT2 could actively shuttle into and out of nuclei, with its predominant steady-state localization in the cytoplasm dependent on its nuclear export signal. Co-immunoprecipitation results indicated that DACT2 strongly associated beta-catenin as well as lymphoid enhancer-binding factor 1 (LEF1) and directly disrupted the formation of the beta-catenin-LEF1 complex in the nucleus. Whereas in the cytoplasm, DACT2 restored junctional localization of E-cadherin-beta catenin complexes and prevented beta-catenin nuclear translocation through direct interaction with beta-catenin. DACT2 methylation was detected in 43.3% (29/67) of colon cancer tissues, but none in normal controls. Multivariate analysis revealed that patients with DACT2 methylation had a significant decrease in overall survival (P=0.006). Kaplan-Meier survival curves showed that DACT2 methylation was significantly associated with shortened survival in stage I-III colon cancer patients. In conclusion, DACT2 acts as a functional tumor suppressor in colon cancer through inhibiting Wnt/beta-catenin signaling. Its methylation at early stages of colon carcinogenesis is an independent prognostic factor. PMID- 25023700 TI - MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways. AB - Oncogenic RAS promotes production of reactive oxygen species (ROS), which mediate pro-malignant signaling but can also trigger DNA damage-induced tumor suppression. Thus RAS-driven tumor cells require redox-protective mechanisms to mitigate the damaging aspects of ROS. Here, we show that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase that sanitizes oxidative damage in the nucleotide pool, is important for maintaining several KRAS-driven pro-malignant traits in a nonsmall cell lung carcinoma (NSCLC) model. MTH1 suppression in KRAS-mutant NSCLC cells impairs proliferation and xenograft tumor formation. Furthermore, MTH1 levels modulate KRAS-induced transformation of immortalized lung epithelial cells. MTH1 expression is upregulated by oncogenic KRAS and correlates positively with high KRAS levels in NSCLC human tumors. At a molecular level, in p53 competent KRAS-mutant cells, MTH1 loss provokes DNA damage and induction of oncogene-induced senescence. In p53-nonfunctional KRAS-mutant cells, MTH1 suppression does not produce DNA damage but reduces proliferation and leads to an adaptive decrease in KRAS expression levels. Thus, MTH1 not only enables evasion of oxidative DNA damage and its consequences, but can also function as a molecular rheostat for maintaining oncogene expression at optimal levels. Accordingly, our results indicate MTH1 is a novel and critical component of oncogenic KRAS-associated malignancy and its inhibition is likely to yield significant tumor-suppressive outcomes in KRAS-driven tumors. PMID- 25023703 TI - Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. AB - Mutations of the tumor suppressor gene von Hippel-Lindau (VHL) can lead to benign and malignant tumors, including clear-cell renal cell carcinoma (ccRCC). To understand the progression of ccRCC, we generated a novel mouse Vhlh conditional knockout, using Hoxb7-driven Cre that is specific for the collecting ducts and a subset of distal tubules. These mice exhibited wide-spread epithelial disruption and interstitial inflammation as early as 2 months of age with high penetrance. Lesions are cystic, show severe fibrosis and display significant hyperplasia. An abundance of infiltrating macrophages and lymphocytes was detected. Interestingly, the Vhlh mutant lesions could be rescued when Hif-1alpha, but not Hif-2alpha, was also knocked out. In addition, administration of a JAK1/2 kinase inhibitor alleviated the Vhlh knockout phenotypes. Taken together, these results suggest that HIF-1alpha-dependent inflammation and fibrosis may be an early event in the development of ccRCC. PMID- 25023702 TI - EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination. AB - The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin A3 through a novel hypoxia-inducible factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (lnc) RNAs from EFNA3 locus and these lncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation. PMID- 25023705 TI - Serological study of antibodies to influenza A viruses among general population in Wuhan city China. PMID- 25023704 TI - Ash2L enables P53-dependent apoptosis by favoring stable transcription pre initiation complex formation on its pro-apoptotic target promoters. AB - Chromatin conformation has a major role in all cellular decisions. We showed previously that P53 pro-apoptotic target promoters are enriched with H3K9me3 mark and induction of P53 abrogates this repressive chromatin conformation by downregulating SUV39H1, the writer of this mark present on these promoters. In the present study, we demonstrate that in response to P53 stabilization, its pro apoptotic target promoters become enriched with the H3K4me3 epigenetic mark as well as its readers, Wdr5, RbBP5 and Ash2L, which were not observed in response to SUV39H1 downregulation alone. Overexpression of Ash2L enhanced P53-dependent apoptosis in response to chemotherapy, associated with increased P53 pro apoptotic gene promoter occupancy and target gene expression. In contrast, pre silencing of Ash2L abrogated P53's ability to induce the expression of these transcriptional targets, without affecting P53 or RNAP II recruitment. However, Ash2L pre-silencing, under the same conditions, resulted in reduced RNAP II ser5 CTD phosphorylation on these same pro-apoptotic target promoters, which correlated with reduced promoter occupancy of TFIIB as well as TFIIF (RAP74). Based on these findings, we propose that Ash2L acts in concert with P53 promoter occupancy to activate RNAP II by aiding formation of a stable transcription pre initiation complex required for its activation. PMID- 25023706 TI - Fatal acute liver failure in a child due to acquired rubella infection. PMID- 25023707 TI - Effect of time and pH on physical-chemical properties of orthodontic brackets and wires. AB - OBJECTIVE: To test the hypothesis that treatment time, debris/biofilm, and oral pH have an influence on the physical-chemical properties of orthodontic brackets and arch wires. MATERIALS AND METHODS: One hundred twenty metal brackets were evaluated. They were divided into four groups (n = 30) according to treatment time: group C (control) and groups T12, T24, and T36 (brackets recovered after 12, 24, and 36 months of treatment, respectively). Rectangular stainless-steel arch wires that remained in the oral cavity for 12 to 24 months were also analyzed. Dimensional stability, surface morphology, composition of brackets, resistance to sliding of the bracket-wire set, surface roughness of wires, and oral pH were analyzed. One-way analysis of variance, followed by a Tukey multiple comparisons test, was used for statistical analysis (P < .05). RESULTS: Carbon and oxygen were shown to be elements that increased expressively and in direct proportion to time, and there was a progressive increase in the coefficient of friction and roughness of wires as a function of time of clinical use after 36 months. Oral pH showed a significant difference between group T36 and its control (P = .014). CONCLUSIONS: The hypothesis was partially accepted: treatment time and biofilm and debris accumulation in bracket slots were shown to have more influence on the degradation process and frictional force of these devices than did oral pH. PMID- 25023708 TI - Contact of dual mobility implants: effects of cup wear and inclination. AB - Cup wear and inclination on the pelvic bone are significant factors, which change the contact of the articulating surfaces, thus, impacting the long-term performance of hip implants. This paper presents a finite element (FE) analysis of the contact of the dual mobility implants under the influence of cup wear and inclination. A 3D FE model of the implant was developed with the application of equivalent physiological loading and boundary conditions. Effects of cup inclination angle ranging from 45 degrees to 60 degrees and the wear depth ranging from 0 to 2.46 mm equivalent to up to 30 years of the implant's life on the contact pressure and von Mises stress were investigated. Simulation results show that the contact pressure and von Mises stress decrease significantly with a modest wear depth and remains quite in-sensitive to the cup inclination angle and wear depth up to 1.64 mm. With wear depth further up to 2.46 mm, the cup thickness (i.e. cup thinning on worn region) may be more predominant than increasing of contact area between the cup and the head. The wear on the inner surface of the cup is found to rule out the overall contact pressure and stress in the implant. Furthermore, individual and combined effects of both important parameters are analysed and discussed with respect to available clinical/laboratory studies. PMID- 25023711 TI - CT-guided nucleoplasty with radiofrequency energy for the treatment of lumbar disk herniation. AB - STUDY DESIGN: A clinical randomized controlled trial. OBJECTIVE: This study sought to compare the clinical effectiveness of CT-guided nucleoplasty, CT-guided nucleoplasty combined with nerve root injection, and CT-guided transforaminal lumbar epidural injections in treating patients with contained lumbar disk herniation and leg pain, which are caused by radicular encroachment. SUMMARY OF BACKGROUND DATA: Lumbar disk herniation is the most common cause of nerve root pain. The conservative treatment is proved to be effective for the majority of these patients, and the remaining patients are not ideal surgical candidates. Studies have found that minimally invasive percutaneous disk procedures may be preferable to open surgery in certain clinical situations. However, nucleoplasty in treating contained lumbar disk herniation and leg pain caused by radicular encroachment is still a controversy. DESIGN: A total of 97 patients with leg pain and MRI evidence of small-sized or medium-sized herniated disks correlating with the symptoms participated in the study. The patients were randomly allocated into 3 groups: the CT-guided nucleoplasty group (N=33), the CT-guided nucleoplasty with nerve root injection group (N=35), and CT-guided transforaminal lumbar epidural injections group (N=29). Numeric Rating Scale (NRS) pain score and Oswestry Disability Index (ODI) values were applied at pretreatment and 1 week, 1 month, 3 months, and 12 months at posttreatment. RESULTS: There were statistically significant decreases (P=0.000) in the NRS and ODI scores for all posttreatment time points when compared with the pretreatment values in all the 3 groups. The average NRS and ODI results for the transforaminal lumbar epidural injections group were significantly higher than those for the other 2 groups at 3 and 12 months posttreatment (P<0.05). The combination of nucleoplasty with nerve root injection produced a significantly greater reduction in the NRS and ODI scores when compared with nucleoplasty at 1 week (P=0.000 for NRS and P=0.004 for ODI) and 1 month (P=0.000 for NRS and P=0.007 for ODI) after the treatment. CONCLUSIONS: The results of this study suggest that CT-guided nucleoplasty with radiofrequency energy is a relative effective and safe technique for treating leg pain caused by radicular encroachment. Furthermore, nucleoplasty combined with nerve root injection had achieved a significant greater improvement in pain management and functional level in short term (within 1 mo) after treatment than nucleoplasty alone. PMID- 25023709 TI - Ticks infesting humans in Italy and associated pathogens. AB - BACKGROUND: Ticks may transmit a large variety of pathogens, which cause illnesses in animals and humans, commonly referred to as to tick-borne diseases (TBDs). The incidence of human TBDs in Italy is underestimated because of poor surveillance and the scant amount of studies available. METHODS: Samples (n = 561) were collected from humans in four main geographical areas of Italy (i.e., northwestern, northeastern, southern Italy, and Sicily), which represent a variety of environments. After being morphologically identified, ticks were molecularly tested with selected protocols for the presence of pathogens of the genera Rickettsia, Babesia, Theileria, Candidatus Neoehrlichia mikurensis, Borrelia and Anaplasma. RESULTS: Ticks belonged to 16 species of the genera Argas, Dermacentor, Haemaphysalis, Hyalomma, Ixodes and Rhipicephalus, with Ixodes ricinus (59.5%) being the species most frequently retrieved, followed by Rhipicephalus sanguineus sensu lato (21.4%). Nymphs were the life stage most frequently retrieved (41%), followed by adult females (34.6%). The overall positivity to any pathogen detected was 18%. Detected microorganisms were Rickettsia spp. (17.0%), Anaplasma phagocytophilum (0.8%), Borrelia afzelii (0.5%), Borrelia valaisiana (0.3%), C. N. mikurensis (0.5%) and Babesia venatorum (0.6%). CONCLUSIONS: Results indicate that people living in the Italian peninsula are at risk of being bitten by different tick species, which may transmit a plethora of TBD causing pathogens and that co-infections may also occur. PMID- 25023712 TI - Effect of Mini-plate Fixation on Hinge Fracture and Bony Fusion in Unilateral Open-door Cervical Expansive Laminoplasty. AB - STUDY DESIGN: This was a retrospective study. OBJECTIVE: The aim of this study was to investigate the effect of Centerpiece mini-plate fixation on the complete fracture and bony fusion of the hinge side in unilateral open-door cervical expansive laminoplasty. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is an effective and safe surgery for cervical canal stenosis. The Centerpiece mini plate is an instrument used to secure the laminae and maintain the cervical canal expansion. Stability of the new laminae is largely dependent on healing of the hinge side bone fracture and the degree of bony fusion. To date, few studies have reported on the effects of mini-plate fixation on these 2 important factors. MATERIALS AND METHODS: Between September 2009 and March 2011, 58 patients received unilateral open-door cervical expansive laminoplasty at the authors' hospital. The group included 47 male and 11 female patients, with a mean age of 61 (range, 35-81) years. Two hundred twenty-five laminae were fixed using the Centerpiece mini-plate (group A), whereas 62 laminae were fixed using suture suspension (group B). The rates of fracture and bony fusion of the hinge were observed using computed tomography scan and compared between the 2 groups. The complete fractures were subdivided into 4 groups based on the degree of displacement of the fractured ends: type I (no displacement), type II (mild to moderate displacement), type III (complete displacement or separation), or type IV (the hinge had collapsed into the cervical canal). RESULTS: The number of incomplete fractures and type I to IV fractures in group A were 95, 93, 25, 8, and 4 and 29, 25, 4, 2, 2 in group B, respectively. There were no significant differences between the 2 groups in terms of complete fracture rates (P=0.309) and complete fracture type distribution (P=0.694). Group A had a significantly higher rate of bony fusion of the hinge 3 months after surgery (82% vs. 70%, P=0.042); however, this rate was not statistically significant 6 months after surgery (P=0.141). For type I complete hinge fracture, group A had higher bony fusion rates, both 3 months (86% vs. 57%, P=0.004) and 6 months (92% vs. 85%, P=0.048) postoperatively. The rates of bony fusion were also significantly different among all complete fracture types 3 months (P<0.001) and 6 months (P<0.001) postoperatively. CONCLUSIONS: Centerpiece mini-plate fixation in unilateral open-door cervical expansive laminoplasty might not increase the complete fracture rate compared with suture suspension and might promote bony fusion of type I complete hinge fractures. PMID- 25023715 TI - Risk Factors for Proximal Junctional Kyphosis Associated With Dual-rod Growing rod Surgery for Early-onset Scoliosis. AB - STUDY DESIGN: A retrospective, multicenter study. OBJECTIVE: To identify risk factors for proximal junctional kyphosis (PJK) when treating early-onset scoliosis (EOS) with dual-rod growing-rod (GR) procedure. SUMMARY OF BACKGROUND DATA: The risk factors for PJK associated with GR treatment for EOS have not been adequately studied. METHODS: We evaluated clinical and radiographic results from 88 patients with EOS who underwent dual-rod GR surgery in 12 spine centers in Japan. The mean age at the time of the initial surgery was 6.5+/-2.2 years (range, 1.5-9.8 y), and the mean follow-up period was 3.9+/-2.6 years (range, 2.0 12.0 y). Risk factors for PJK were analyzed by binomial multiple logistic regression analysis. The potential factors analyzed were sex, etiology, age, the number of rod-lengthening procedures, coronal and sagittal parameters on radiographs, the type of foundation (pedicle screws or hooks), the uppermost level of the proximal foundation, and the lowermost level of the distal foundation. RESULTS: PJK developed in 23 patients (26%); in 19 of these, the proximal foundation became dislodged following PJK. Binomial multiple logistic regression analysis identified the following significant independent risk factors for PJK: a lower instrumented vertebra at or cranial to L3 [odds ratio (OR), 3.32], a proximal thoracic scoliosis of >=40 degrees (OR, 2.95), and a main thoracic kyphosis of >=60 degrees (OR, 5.08). CONCLUSIONS: The significant independent risk factors for PJK during dual-rod GR treatment for EOS were a lower instrumented vertebra at or cranial to L3, a proximal thoracic scoliosis of >=40 degrees, and a main thoracic kyphosis of >=60 degrees. PMID- 25023716 TI - Characteristics and quality of life of opioid-dependent pregnant women in Austria. AB - This study investigated pregnant opioid-dependent women undergoing maintenance therapy, applying a multidisciplinary, case-management approach at the Addiction Clinic of the Medical University of Vienna, Austria. It aimed at characterizing the patients' basic demographic and clinical parameters and evaluating their overall quality of life (QoL) prepartum and postpartum. Three hundred ninety women were treated between 1994 and 2009 with buprenorphine (n = 77), methadone (n = 184), or slow-release oral morphine (SROM) (n = 129) on an outpatient basis throughout their pregnancy and postpartum period. All patients were subject to standardized prepartum and postpartum medical and psychiatric assessments, including QoL assessments using a German adaptation of the Lancashire QoL Profile (Berliner Lebensqualitaetsprofil), and regular supervised urine toxicologies. No medication group differences were revealed regarding basic demographic or clinical data. Mean maintenance doses (SD) at time of delivery were as follows: 64 mg (36 mg) methadone, 10 mg (6 mg) buprenorphine, 455 mg (207 mg) SROM. However, buprenorphine-medicated women showed significantly less concomitant benzodiazepine consumption than methadone- or SROM-maintained women (p = 0.005), and significantly less concomitant opioid consumption than methadone-maintained women (p = 0.033) during the last trimester. Overall QoL was good prepartum and postpartum in all measured domains except "finances" and "prospect of staying in the same housing situation," and no differences were observed in QoL among the three medication groups (p = 0.177). QoL improved significantly after delivery in most of the domains (p < 0.001). Although opioid-dependent pregnant women face high-risk pregnancies and show variability in addiction severity, they report good QoL independent of the medication administered. These results show that individually tailored treatment interventions are effective for this patient population and suggest a QoL improvement after delivery. PMID- 25023718 TI - ERK1/2 mediates sperm acrosome reaction through elevation of intracellular calcium concentration. AB - Mammalian sperm acquire fertilization capacity after residing in the female reproductive tract for a few hours in a process called capacitation. Only capacitated sperm can bind the zona pellucida (ZP) of the egg and undergo the acrosome reaction, a process that allows penetration and fertilization. Extracellular signal regulated kinase (ERK1/2) mediates signalling in many cell types, however its role in sperm function is largely unknown. Here we show that ERK1/2 is highly phosphorylated/activated after a short incubation of mouse sperm under capacitation conditions and that this phosphorylation is reduced after longer incubation. Further phosphorylation was observed upon addition of crude extract of egg ZP or epidermal growth factor (EGF). The mitogen-activated ERK kinase (MEK) inhibitor U0126 abolished ERK1/2 phosphorylation, in vitro fertilization rate and the acrosome reaction induced by ZP or EGF but not by the Ca2+-ionophore A23187. Moreover, inhibition of ERK1/2 along the capacitation process diminished almost completely the sperm's ability to go through the acrosome reaction, while inhibition at the end of capacitation attenuated the acrosome reaction rate by only 45%. The fact that the acrosome reaction, induced by the Ca2+ -ionophore A23187, was not inhibited by U0126 suggests that ERK1/2 mediates the acrosome reaction by activating Ca2+ transport into the cell. Direct determination of intracellular [Ca2+] revealed that Ca2+ influx induced by EGF or ZP was completely blocked by U0126. Thus, it has been established that the increase in ERK1/2 phosphorylation/activation in response to ZP or by activation of the EGF receptor (EGFR) by EGF, is a key event for intracellular Ca2+ elevation and the subsequent occurrence of the acrosome reaction. PMID- 25023717 TI - The prevalence of aminoglycoside-modifying enzymes among coagulase negative staphylococci in Iranian pediatric patients. AB - In spite of widespread emergence of aminoglycoside resistance, these drugs are still used in the treatment of staphylococcal infections. This study aimed to investigate the distribution of aminoglycoside resistance and genes encoding aminoglycoside - modifying enzymes (AMEs) as well as Staphylococcal Cassette Chromosome mec (SCCmec) type in coagulase negative staphylococci (CoNS) in pediatric patients. Totally, 93 CoNS isolates were examined for susceptibility to aminoglycosides using disk diffusion and/or E-test methods. AMEs genes and SCCmec types were detected using multiplex PCR. Strain typing was performed using repetitive extragenic palindromic (REP) - PCR assay. The non-susceptibility rates to kanamycin, tobramycin, gentamicin, amikacin and netilmicin were 73%, 59%, 49.5%, 16% and 7.5%, respectively. aac(6')-Ie-aph(2")-Ia, ant(4')-Ia and aph(3') IIIa were encountered in 56 (60.2%), 38 (40.8%) and 18 (19.3%) isolates, respectively. In aac(6')-Ie-aph(2")-Ia- positive isolates, the non- susceptibility rates to kanamycin, gentamicin, tobramycin, amikacin and netilmicin were 83%, 74%, 73%, 49% and 43%, respectively. SCCmec types included type IV (n = 31), I (n = 17), II (n = 5), III (n = 4), and V (n = 2). Three isolates had two types; I + III (n = 2) and III + IV (n = 1) whereas 11 isolates were non-typeable. AMEs genes carriers were distributed frequently into type IV. We found diverse fingerprint patterns among our isolates. In conclusion, there was a strong correlation between alarming rate of aminoglycoside resistance and methicillin resistance. Discordances between phenotypic and genotypic detection of aminoglycoside resistance were discernible. AMEs genes might be related to SCCmec types. PMID- 25023719 TI - Microbial Synthesis of Alka(e)nes. AB - Alka(e)nes are the predominant constituents of gasoline, diesel, and jet fuels. They can be produced naturally by a wide range of microorganisms. Bio-alka(e)nes can be used as drop-in biofuels. To date, five microbial pathways that convert free fatty acids or fatty acid derivatives into alka(e)nes have been identified or reconstituted. The discoveries open a door to achieve microbial production of alka(e)nes with high efficiency. The modules derived from these alka(e)ne biosynthetic pathways can be assembled as biological parts and synthetic biology strategies can be employed to optimize the metabolic pathways and improve alka(e)ne production. PMID- 25023720 TI - [Cardiac magnetic resonance imaging and cardiac computed tomography in clinical practice]. AB - Technological advances have enabled the rapid development of cardiovascular imaging techniques. Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (MRI) have become diagnostic and prognostic tools for the management of patients in routine clinical practice. This review gives the main indications and describes the performance of both techniques. PMID- 25023721 TI - Long-term follow-up of cortical hyperexcitability in Japanese Unverricht-Lundborg disease. AB - PURPOSE: To delineate chronological changes of cortical hyperexcitability by long term follow-up of the amplitudes of somatosensory evoked potentials (SEPs) in patients with Japanese Unverricht-Lundborg disease (ULD). METHOD: SEPs to median nerve stimulation were repeatedly examined in 7 genetically diagnosed ULD patients with the mean interval of 11.9 years. The degree of temporal changes in the amplitude of 3 early cortical components, N20, P25 and N35, to the age was analyzed and compared with that of healthy subjects. RESULTS: Their clinical course was almost stable during the follow-up period, namely cessation of generalized tonic-clonic seizures and little or no progression of myoclonus. SEP amplitudes of P25 and N35 were enlarged in all patients and were gradually decreased with aging in ULD on average. The degree of temporal changes of P25 and N35 in ULD was similar or even lower than that of healthy subjects. CONCLUSION: Enlarged but relatively stable SEP amplitudes had a consistency with so-called self-limited clinical course in Japanese ULD. SEP amplitude could be one of the surrogate markers of the degree of cortical hyperexcitability in ULD during the long-term follow-up period. PMID- 25023722 TI - Outpatient anti-epileptic drug prescribing errors in a Children's Hospital: an audit and literature review. AB - PURPOSE: Prescription errors are a common and potentially hazardous problem and may cause patient harm. This review evaluates all new anti-epileptic drug (AED) outpatient prescriptions over one year and reviews the subject literature. METHODS: A 12-month retrospective review of all outpatient prescriptions of AEDs within a large Children's Hospital. Copies of all prescriptions were obtained from the Trust's Pharmacy. The evaluation included the completeness of the required information, prescribing errors and the need for pharmacist intervention before the drug could be dispensed. It did not address the severity of prescribing errors or the potential harm to the patient. RESULTS: Two hundred and sixty two new prescriptions were evaluated. Incomplete prescriptions (that omitted at least one piece of required information) were found in 72.1%. The most common omission was the dose strength (mg/ml) or actual dose (mg) of the AED. No clinical diagnosis was documented in 62.6% and in 22%, only the word 'epilepsy', was stated with no reference to the epilepsy syndrome or seizure type. Pharmacist intervention was required in approximately 17% (approximately 1 in 6) of all prescriptions before the AED could be dispensed. CONCLUSION: This review highlights the importance of clinical information on prescriptions and that incomplete or poor documentation may contribute to prescribing errors. It also emphasises the importance of pharmacists in the identification and correction or resolution of potential prescribing errors. There is a need to develop a well validated measure to assess the severity of prescribing errors that will better address their clinical significance and risk. PMID- 25023723 TI - First-ever population-based study on status epilepticus in French Island of La Reunion (France) - incidence and fatality. AB - PURPOSE: We aimed to determine the incidence and case-fatality of first-ever status epilepticus (SE) among the general population living in La Reunion Island, a French overseas territory in the Indian Ocean near Madagascar. METHODS: We recruited cases (1st July 2004-30th June 2005) in a population-based manner using neurology, neurosurgery, electroencephalogram, emergency, paediatric and neuroradiology services; emergency medical aid service; emergency and admission service of private and public clinics; neurologists (public and private); private paediatricians and practitioners of various rural hospitals. All cases had an electroencephalogram (EEG) and were assessed by an epileptologist. Standard definition and classification schemes were used. Those with known epilepsy were not part of this analysis. RESULTS: Sixty-five cases (males: n=41, 63.1%) had epileptologist-confirmed SE, with 38.5% (n=25) being >60 years of age. Global incidence rate was 8.52/100 000 (95% confidence interval 6.5-10.5). A bimodal age distribution with high frequency and incidence among young (<10 years age) (frequency: 12.3%; incidence 6.6/100,000) and aged (>60 years) (frequency: 40.0%; incidence 35.0/100,000) was observed. We found that 60%, 32.3%, 6.7% had convulsive, partial and non-convulsive SE respectively (1% remained unclassified). Of the cases identified, 44.6%, 38.5%, 16.9% had unprovoked, provoked or cryptogenic seizures respectively. The most important aetiological factors identified included: stroke (27.7%), alcoholism/toxicity (18.5%), cryptogenic (16.9%), infections (10.8%). Mortality was 18.5%. CONCLUSION: The incidence of SE incidence in La Reunion Island was lower than that described elsewhere. The status type was found to be dependent on aetiology and age. The study confirms that SE is more frequent in men and in older adults and is associated with significant short-term case mortality. PMID- 25023724 TI - Seronegative arthritis in Latin America: a current review. AB - In many Latin American countries seronegative arthritis, especially the spondyloarthritides (SpA), is commonly characterized by associated axial and peripheral involvement. In this article, the authors review the ethnic distribution of the population and the different SpA in 10 Latin American countries, and the main characteristics of the Ibero-American Registry of Spondyloarthropathies (RESPONDIA) compared with other international registries. The peripheral component of SpA is more frequent in mixed-race populations, whereas psoriatic arthritis is significantly more frequent in countries with predominantly white populations. PMID- 25023725 TI - Vasculitis in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex heterogeneous autoimmune disease with a wide variety of clinical and serological manifestations that may affect any organ. Vasculitis prevalence in SLE is reported to be between 11% and 36%. A diverse clinical spectrum, due to inflammatory involvement of vessels of all sizes, is present. Even though cutaneous lesions, representing small vessel involvement, are the most frequent, medium and large vessel vasculitis may present with visceral affection, with life-threatening manifestations such as mesenteric vasculitis, pulmonary hemorrhage, or mononeuritis multiplex, with detrimental consequences. Early recognition and an appropriate treatment are crucial. Recent studies have shown that vasculitis in patients with SLE may present different clinical forms based on the organ involved and the size of the affected vessel. It is noteworthy that the episodes of vasculitis are not always accompanied by high disease activity. Recent articles on this topic have focused on new treatments for the control of vascular disease, such as biological therapies such as Rituximab and Belimumab, among others. PMID- 25023726 TI - Associations between relational sexual behaviour, pornography use, and pornography acceptance among US college students. AB - Pornography use among emerging adults in the USA has increased in recent decades, as has the acceptance of such consumption. While previous research has linked pornography use to both positive and negative outcomes in emerging adult populations, few studies have investigated how attitudes toward pornography may alter these associations, or how examining pornography use together with other sexual behaviours may offer unique insights into the outcomes associated with pornography use. Using a sample of 792 emerging adults, the present study explored how the combined examination of pornography use, acceptance, and sexual behaviour within a relationship might offer insight into emerging adults' development. Results suggested clear gender differences in both pornography use and acceptance patterns. High male pornography use tended to be associated with high engagement in sex within a relationship and was associated with elevated risk-taking behaviours. High female pornography use was not associated with engagement in sexual behaviours within a relationship and was general associated with negative mental health outcomes. PMID- 25023727 TI - Cognitive and aggressive reactions of male dating violence perpetrators to anger arousal. AB - In the current study, 20 dating violent and 27 non-violent college males provided verbal articulations and self-report data regarding cognitive biases, change in affect, and aggressive reactions following anger induction through the articulated thoughts in simulated situations paradigm. Violent, relative to non violent, males articulated more cognitive biases and verbally aggressive statements during provocation. These same relationships did not hold for a retrospective self-report measure. Greater cognitive biases and aggressive articulations reliably distinguished between violent and non-violent males in the current study. Results suggest that assessing cognitive and affective content "in the heat of the moment" may be a more sensitive indicator of dating violence than retrospective self-reports. PMID- 25023728 TI - Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression. AB - Resistance to receptor tyrosine kinase (RTK) blockade in breast cancer is often mediated by activation of bypass pathways that sustain growth. Src and mammalian target of rapamycin (mTOR) are two intrinsic targets that are downstream of most RTKs. To date, limited clinical efficacy has been observed with either Src or mTOR inhibitors when used as single agents. Resistance to mTOR inhibitors is associated with loss of negative feedback regulation, resulting in phosphorylation and activation of AKT. Herein, we describe a novel role for Src in contributing to rapalog-induced AKT activation. We found that dual activation of Src and the mTOR pathway occurs in nearly half of all breast cancers, suggesting potential cross-talk. As expected, rapamycin inhibition of mTOR results in feedback activation of AKT in breast cancer cell lines. Addition of the Src/c-Abl inhibitor, dasatinib, completely blocks this feedback activation, confirming convergence between Src and the mTOR pathway. Analysis in vivo revealed that dual Src and mTOR inhibition is highly effective in two mouse models of breast cancer. In a luminal disease model, combined dasatinib and rapamycin is more effective at inducing regression than either single agent. Furthermore, the combination of dasatinib and rapamycin delays tumor recurrence following the cessation of treatment. In a model of human EGFR-2-positive (HER2(+)) disease, dasatinib alone is ineffective, but potentiates the efficacy of rapamycin. These data suggest that combining mTOR and Src inhibitors may provide a new approach for treating multiple breast cancer subtypes that may circumvent resistance to targeted RTK therapies. PMID- 25023729 TI - How do prostitution customers value health and position health in their discussions? Qualitative analysis of online forums. AB - AIM: Information on the health values and positioning of health among prostitution customers is limited. The aim is to explore the positioning of health among prostitution customers using data from Internet forums in Finland. METHODS: Qualitative study using a purposive sample of public online forums among prostitution customers in 2002-2012. RESULTS: Health beliefs in relation to infections and risky sexual behavior were diverse, from correct to false. Although men were aware of health risks in prostitution, it was common to have multiple sexual partners and unprotected sex. Although there were men who warned others about possible health consequences when a condom is not used, typically men were proud not to use a condom with a prostitute and found different explanations for not using a condom. Condom breakage was not an issue discussed in forums. Unexpected findings were beliefs that one fifth of the Nordic population is resistant to HIV, that the possibility of HIV transmission is exaggerated by medical specialists, and that men should control their behavior in order not to degrade prostitutes. Discussions on health service use were few. CONCLUSIONS: Sexual satisfaction and entertainment were the main reasons to post in the analyzed forums health discussion was not common although condom use was reported, attention to health risks was selective information on health service use was limited, which may suggest this topic was not valued among men and should be a topic of future studies. PMID- 25023732 TI - The different faces of central nervous system metastases. AB - Cerebral metastases are the commonest central nervous system tumors. The MR assessment should include T1-weighted images with and without enhancement and T2/FLAIR images. They usually appear as multiple lesions with nodular or annular enhancement and are surrounded by edema. They are hypervascularized and have no restriction of their diffusion coefficient in their necrotic area and contain lipids on 1H spectroscopy. Metastases can be distinguished from primary tumors by the lack of malignant cell infiltration around the tumor. Stereotactic radiotherapy may temporarily increase tumor volume, although this is not of adverse oncological value. Less commonly, spinal disease may be asymptomatic and should be examined by MR. PMID- 25023731 TI - AAV vectors expressing LDLR gain-of-function variants demonstrate increased efficacy in mouse models of familial hypercholesterolemia. AB - RATIONALE: Familial hypercholesterolemia is a genetic disorder that arises because of loss-of-function mutations in the low-density lipoprotein receptor (LDLR) and homozygous familial hypercholesterolemia is a candidate for gene therapy using adeno-associated viral vectors. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL) negatively regulate LDLR protein and could dampen adeno-associated viral vector encoded LDLR expression. OBJECTIVE: We sought to create vectors expressing gain-of-function human LDLR variants that are resistant to degradation by human PCSK9 (hPCSK9) and IDOL and thereby enhance hepatic LDLR protein abundance and plasma LDL cholesterol reduction. METHODS AND RESULTS: Amino acid substitutions were introduced into the coding sequence of human LDLR cDNA to reduce interaction with hPCSK9 and human IDOL. A panel of mutant human LDLRs was initially screened in vitro for escape from PCSK9. The variant human LDLR-L318D was further evaluated using a mouse model of homozygous familial hypercholesterolemia lacking endogenous LDLR and apolipoprotein B mRNA editing enzyme catalytic, APOBEC-1 (double knockout). Administration of wild-type human LDLR to double knockout mice, expressing hPCSK9, led to diminished LDLR activity. However, LDLR-L318D was resistant to hPCSK9-mediated degradation and effectively reduced cholesterol levels. Similarly, the LDLR-K809R?C818A construct avoided human IDOL regulation and achieved stable reductions in serum cholesterol. An adeno-associated viral vector serotype 8.LDLR-L318D?K809R?C818A vector that carried all 3 amino acid substitutions conferred partial resistance to both hPCSK9- and human IDOL mediated degradation. CONCLUSIONS: Amino acid substitutions in the human LDLR confer partial resistance to PCSK9 and IDOL regulatory pathways with improved reduction in cholesterol levels and improve on a potential gene therapeutic approach to treat homozygous familial hypercholesterolemia subjects. PMID- 25023733 TI - Axial traction in magnetic resonance arthrography of the wrist: How to do? PMID- 25023735 TI - Activity-dependent structural plasticity of Purkinje cell spines in cerebellar vermis and hemisphere. AB - The environmental enrichment (EE) paradigm is widely used to study experience dependent brain plasticity. In spite of a long history of research, the EE influence on neuronal morphology has not yet been described in relation to the different regions of the cerebellum. Thus, aim of the present study was to characterize the EE effects on density and size of dendritic spines of Purkinje cell proximal and distal compartments in cerebellar vermian and hemispherical regions. Male Wistar rats were housed in an enriched or standard environment for 3.5 months from the 21st post-natal day onwards. The morphological features of Purkinje cell spines were visualized on calbindin immunofluorescence-stained cerebellar vermian and hemispherical sections. Density, area, length and head diameter of spines were manually (ImageJ) or automatically (Imaris) quantified. Results demonstrated that the Purkinje cell spine density was higher in enriched rats than in controls on both proximal and distal dendrite compartments in the hemisphere, while it increased only on distal compartment in the vermis. As for spine size, a significant increase of area, length and head diameter was found in the distal dendrites in both vermis and hemisphere. Thus, the exposure to a complex environment enhances synapse formation and plasticity either in the vermis involved in balance and locomotion and in the hemisphere involved in complex motor adaptations and acquisition of new motor strategies. These data highlight the importance of cerebellar activity-dependent structural plasticity underling the EE-related high-level performances. PMID- 25023734 TI - Transcranial magnetic stimulation reveals two functionally distinct stages of motor cortex involvement during perception of emotional body language. AB - Studies indicate that perceiving emotional body language recruits fronto-parietal regions involved in action execution. However, the nature of such motor activation is unclear. Using transcranial magnetic stimulation (TMS) we provide correlational and causative evidence of two distinct stages of motor cortex engagement during emotion perception. Participants observed pictures of body expressions and categorized them as happy, fearful or neutral while receiving TMS over the left or right motor cortex at 150 and 300 ms after picture onset. In the early phase (150 ms), we observed a reduction of excitability for happy and fearful emotional bodies that was specific to the right hemisphere and correlated with participants' disposition to feel personal distress. This 'orienting' inhibitory response to emotional bodies was also paralleled by a general drop in categorization accuracy when stimulating the right but not the left motor cortex. Conversely, at 300 ms, greater excitability for negative, positive and neutral movements was found in both hemispheres. This later motor facilitation marginally correlated with participants' tendency to assume the psychological perspectives of others and reflected simulation of the movement implied in the neutral and emotional body expressions. These findings highlight the motor system's involvement during perception of emotional bodies. They suggest that fast orienting reactions to emotional cues--reflecting neural processing necessary for visual perception--occur before motor features of the observed emotional expression are simulated in the motor system and that distinct empathic dispositions influence these two neural motor phenomena. Implications for theories of embodied simulation are discussed. PMID- 25023737 TI - The posterior impingement view: an alternative conventional projection to detect bony posterior ankle impingement. AB - PURPOSE: The purpose of the current study was to clinically evaluate the diagnostic value of the new posterior impingement (PIM) view in the detection of an os trigonum, compared with the standard lateral view, using computed tomography (CT) as a reference standard. METHODS: Three observers, 2 experienced (orthopaedic surgeon and radiologist) and one inexperienced (resident), independently scored 142 radiographic images for the presence of an os trigonum. The diagnostic performance was assessed using the computed tomographic scan as the reference standard. Accuracy, sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) were calculated. RESULTS: The PIM view had significantly superior accuracy compared with the lateral view for each observer: orthopaedic surgeon, PIM view = 90 versus lateral view = 75 (P = .013); radiologist, PIM view = 80 versus lateral view = 64 (P = .019); resident, PIM view = 90 versus lateral view = 79 (P = .039). The mean sensitivity and specificity of the lateral view for all observers was 50% and 81%, respectively. For the PIM view, this was 78% and 89%, respectively. The PPV was 50% for the lateral view and 70% for the PIM view. The NPV was 84% for the lateral view and 93% for the PIM view. CONCLUSIONS: The PIM view has significantly superior diagnostic accuracy compared with the conventional lateral view in the detection of an os trigonum. In cases of symptomatic posterior ankle impingement, we advise that a PIM view be used instead of or in addition to the standard lateral view for detection of posterior talar pathologic conditions. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria on basis of consecutive patients with universally applied reference gold standard. PMID- 25023736 TI - Working memory training impacts the mean diffusivity in the dopaminergic system. AB - Dopaminergic transmission plays a critical role in working memory (WM). Mean diffusivity (MD) is a sensitive and unique neuroimaging tool for detecting microstructural differences particularly in the areas of the dopaminergic system. Despite previous investigation of the effects of WM training (WMT) on dopamine receptor binding potentials, the effects of WMT on MD remain unknown. In this study, we investigated these effects in young adult subjects who either underwent WMT or received no intervention for 4 weeks. Before and after the intervention or no-intervention periods, subjects underwent scanning sessions in diffusion weighted imaging to measure MD. Compared with no intervention, WMT resulted in an increase in MD in the bilateral caudate, right putamen, left dorsolateral prefrontal cortex (DLPFC), right anterior cingulate cortex (ACC), right substantia nigra, and ventral tegmental area. Furthermore, the increase in performance on WMT tasks was significantly positively correlated with the mean increase in MD in the clusters of the left DLPFC and of the right ACC. These results suggest that WMT caused microstructural changes in the regions of the dopaminergic system in a way that is usually interpreted as a reduction in neural components. PMID- 25023738 TI - Living with sensor-augmented pump therapy in type 1 diabetes: adolescents' and parents' search for harmony. AB - OBJECTIVE: Adolescents have difficulty successfully sustaining use of continuous glucose monitoring even when it is introduced to experienced pump users. However, little is known about how adolescents and parents perceive and manage sensor augmented pump therapy (SAPT) in daily life. The purpose of this study was to explore adolescents' and parents' daily experience of living with SAPT. METHODS: We used an interpretive phenomenological study design. We conducted in-depth, digitally recorded interviews with 7 adolescents and 9 parents recruited through 1 Canadian pediatric diabetes program. Adolescents who participated were 13 to 17 years of age with type 1 diabetes mellitus and had experience (current or past) living with SAPT. Transcripts of the interviews were subjected to a thematic analysis guided by the procedure outlined by Colaizzi. RESULTS: The overarching theme, seeking harmony, reflected adolescents' and parents' daily struggles with balancing multiple tensions that arose from managing SAPT and harmonizing seemingly opposing choices that were brought to the fore, while also struggling to live with both wellness and chronic illness. Four themes constituted the struggle to find harmony living with diabetes managed with SAPT: struggling with hopes and expectations for SAPT, being ready for SAPT, living the burdens of continuous glucose monitoring and creating partnerships. CONCLUSIONS: Healthcare providers can facilitate adolescent and parental decision-making about the optimal timing for SAPT introduction. Success with SAPT requires exploration of adolescent and parental expectations for SAPT as well as the degree to which parents have previously fostered their adolescent's involvement in and responsibility for diabetes management. PMID- 25023739 TI - Prospective assessment of hypoglycemia symptoms in children and adults with type 1 diabetes. AB - PURPOSE: To compare the characteristics of symptoms of hypoglycemia in children and in adults with type 1 diabetes. METHODS: Adults with diabetes and parents of children with diabetes who were participants were asked to call a phone system to report episodes of hypoglycemia (presence of symptoms and a blood glucose <4.0 mmol/L). For each episode, blood glucose reading and a scoring of 28 symptoms on a 7-point scale (1 = not present, 7 = very intense) were collected. RESULTS: Sixty six children (49.2% males, mean age = 12.1+/-2.4 years, mean age at diagnosis = 7.5+/-2.9 years) and 53 adults (41.2% males, mean age 38.7+/-14.5 years, mean age at diagnosis = 17.5+/-12.9 years) with type 1 diabetes participated. The most common symptoms in adults were hunger, sweating, trembling and weakness. The most common symptoms in children were weakness, trembling and hunger. The 2 most discriminating variables between children and adults were sleepiness and tiredness, which were more common in children (p<0.01). In a comparative factor analysis, 3 factors emerged: factor 1, autonomic and neuroglycopenic; factor 2, behavioural; and factor 3, general malaise. Factors 2 and 3 were significantly more common or intense in children than in adults; MANOVA: F(1, 113) = 6.72, p<0.05 and F(1, 113) = 4.64, p<0.05, respectively. CONCLUSIONS: Symptoms relating to behaviour and general malaise are more common in children than in adults with type 1 diabetes. The results of this study may assist providers in educating caregivers of children and patients with diabetes how to better recognize episodes of hypoglycemia. PMID- 25023740 TI - Recent advances in adherence and invasion of pathogenic Escherichia coli. AB - PURPOSE OF REVIEW: Colonization of the host epithelia by pathogenic Escherichia coli is influenced by the ability of the bacteria to interact with host surfaces. Because the initial step of an E. coli infection is to adhere, invade, and persist within host cells, some strategies used by intestinal and extraintestinal E. coli to infect host cell are presented. RECENT FINDINGS: This review highlights recent progress understanding how extraintestinal pathogenic E. coli strains express specific adhesins or invasins that allow colonization of the urinary tract or the meninges, while intestinal E. coli strains are able to colonize different regions of the intestinal tract using other specialized adhesins or invasins. Finally, evaluation of different diets and environmental conditions regulating the colonization of these pathogens is discussed. SUMMARY: Discovery of new interactions between pathogenic E. coli and the host epithelial cells unravels the need for more mechanistic studies that can provide new clues regarding how to combat these infections. PMID- 25023742 TI - Chagas disease in solid organ and heart transplantation. AB - PURPOSE OF REVIEW: The diagnosis and management of acute and chronic infections with the microorganism Trypanosoma cruzi, which causes Chagas disease, is important in solid organ transplantation in both endemic and nonendemic countries. In this review, we examine recently published data on the topic of Chagas disease in solid organ transplantation, with an emphasis on data relevant to heart transplantation. RECENT FINDINGS: Most people with chronic T. cruzi infection have the intermediate form of disease, but approximately 2% of infected persons will progress to Chagas cardiomyopathy per year. The risk of T. cruzi transmission with liver or kidney transplantation appears to be substantially less than that with heart transplantation. For patients with Chagas cardiomyopathy undergoing heart transplant, a structured clinical and laboratory monitoring protocol is necessary to monitor for T. cruzi reactivation. Recent data indicate that laboratory monitoring of peripheral blood with polymerase chain reaction testing can identify reactivation prior to the occurrence of symptoms and allograft injury. SUMMARY: Transplant clinicians should exercise vigilance in surveillance for Chagas disease in both organ donors and recipients. Although Chagas disease may seem uncommon, it is pervasive in endemic and several nonendemic countries, including the United States and Spain. PMID- 25023743 TI - Nucleopalladation-initiated oxyalkenylation of alkenes: a strategy to construct functionalized oxygenated heterocycles. AB - A convenient and efficient approach to construct functionalized oxygen heterocycles, i.e., tetrahydrofurans, tetrahydropyrans, and gamma-lactones, has been reported. This process successfully provides a route to construct derivatives of naturally occurring biologically active tetrahydrofurans, especially ones with spirocyclic structure. Highly regio- and stereoselective nucleopalladation of alkynes initiates the cross-coupling between alkynamides and alkenes to give the olefin oxyalkenylation products in good to excellent yields. The hydroxyl group in the olefins cooperates with the amide in alkynamides to promote the cyclization by suppressing the beta-H elimination. PMID- 25023741 TI - Update on the burden of Campylobacter in developing countries. AB - PURPOSE OF REVIEW: Recent work has added to the understanding of the burden of Campylobacter jejuni, C. coli, and non-jejuni/coli Campylobacter strains in children living in the developing world. RECENT FINDINGS: New diagnostic modalities and carefully designed field studies are demonstrating that the burden of Campylobacter diarrhea in children in the developing world has been greatly underestimated. Furthermore, there is emerging recognition of an association between Campylobacter infection and malnutrition. Important progress has been made toward a Campylobacter jejuni vaccine. Finally, evidence of antibiotic resistance continues to be an important issue that is accentuated by the realization that the burden of disease is greater than previously recognized. SUMMARY: Additional research is needed to refine our understanding of the epidemiology of Campylobacter infections in developing countries, in particular to improve estimates of the burden of Campylobacter diarrhea in endemic settings, to determine the impact of recurrent Campylobacter infections on child development, and to describe the prevalence and clinical significance of non jejuni/coli Campylobacter infections. Progressive antibiotic resistance of isolates argues for augmented and expanded control measures of antibiotics in livestock. Continued work in vaccine development is warranted as is the extension of data available on the serotypes related to burden in different areas of the world and the relationship of serotypes to disease severity. PMID- 25023744 TI - The effects of grassland degradation on plant diversity, primary productivity, and soil fertility in the alpine region of Asia's headwaters. AB - A 3-year survey was conducted to explore the relationships among plant composition, productivity, and soil fertility characterizing four different degradation stages of an alpine meadow in the source region of the Yangtze and Yellow Rivers, China. Results showed that plant species diversity, productivity, and soil fertility of the top 30-cm soil layer significantly declined with degradation stages of alpine meadow over the study period. The productivity of forbs significantly increased with degradation stages, and the soil potassium stock was not affected by grassland degradation. The vegetation composition gradually shifted from perennial graminoids (grasses and sedges) to annual forbs along the degradation gradient. The abrupt change of response in plant diversity, plant productivity, and soil nutrients was demonstrated after heavy grassland degradation. Moreover, degradation can indicate plant species diversity and productivity through changing soil fertility. However, the clear relationships are difficult to establish. In conclusion, degradation influenced ecosystem function and services, such as plant species diversity, productivity, and soil carbon and nitrogen stocks. Additionally, both plant species diversity and soil nutrients were important predictors in different degradation stages of alpine meadows. To this end, heavy degradation grade was shown to cause shift of plant community in alpine meadow, which provided an important basis for sustaining ecosystem function, manipulating the vegetation composition of the area and restoring the degraded alpine grassland. PMID- 25023745 TI - Occurrence of virulence genes among Vibrio cholerae and Vibrio parahaemolyticus strains from treated wastewaters. AB - Pathogenic Vibrio species are an important cause of foodborne illnesses. The aim of this study was to describe the occurrence of potentially pathogenic Vibrio species in the final effluents of a wastewater treatment plant and the risk that they may pose to public health. During the 1-year monitoring, a total of 43 Vibrio strains were isolated: 23 Vibrio alginolyticus, 1 Vibrio cholerae, 4 Vibrio vulnificus, and 15 Vibrio parahaemolyticus. The PCR investigation of V. parahaemolyticus and V. cholerae virulence genes (tlh, trh, tdh, toxR, toxS, toxRS, toxT, zot, ctxAB, tcp, ace, vpi, nanH) revealed the presence of some of these genes in a significant number of strains. Intraspecies variability and genetic relationships among the environmental isolates were analyzed by random amplified polymorphic DNA-PCR (RAPD-PCR). We report the results of the first isolation and characterization of an environmental V. cholerae non-O1 non-O139 and of a toxigenic V. parahaemolyticus strain in Tunisia. We suggest that non pathogenic Vibrio might represent a marine reservoir of virulence genes that can be transmitted between strains by horizontal transfer. PMID- 25023746 TI - Applicability of universal Bacteroidales genetic marker for microbial monitoring of drinking water sources in comparison to conventional indicators. AB - Water quality monitoring is essential for the provision of safe drinking water. In this study, we compared a selection of fecal indicators with universal Bacteroidales genetic marker to identify fecal pollution of a variety of drinking water sources. A total of 60 samples were collected from water sources. The microbiological parameters included total coliforms, fecal coliforms, Escherichia coli and fecal streptococci as the fecal indicator bacteria (FIB), Clostridium perfringens and H2S bacteria as alternative indicators, universal Bacteroidales genetic marker as a promising alternative fecal indicator, and Salmonella spp., Shigella spp., and E. coli O157 as pathogenic bacteria. From 60 samples analyzed, Bacteroidales was the most frequently detected indicator followed by total coliforms. However, the Bacteroidales assay failed to detect the marker in nine samples positive for FIB and other alternative indicators. The results of our study showed that the absence of Bacteroidales is not necessarily an evidence of fecal and pathogenic bacteria absence and may be unable to ensure the safety of the water. Further research, however, is required for a better understanding of the use of a Bacteroidales genetic marker as an indicator in water quality monitoring programs. PMID- 25023747 TI - Monitoring of trace amounts of heavy metals in different food and water samples by flame atomic absorption spectrophotometer after preconcentration by amine functionalized graphene nanosheet. AB - We are introducing graphene oxide modified with amine groups as a new solid phase for extraction of heavy metal ions including cadmium(II), copper(II), nickel(II), zinc(II), and lead(II). Effects of pH value, flow rates, type, concentration, and volume of the eluent, breakthrough volume, and the effect of potentially interfering ions were studied. Under optimized conditions, the extraction efficiency is >97 %, the limit of detections are 0.03, 0.05, 0.2, 0.1, and 1 MUg L(-1) for the ions of cadmium, copper, nickel, zinc, and lead, respectively, and the adsorption capacities for these ions are 178, 142, 110, 125, and 210 mg g( 1). The amino-functionalized graphene oxide was characterized by thermogravimetric analysis, transmission electron microscopy, scanning electron microscopy, and Fourier transform infrared spectrometry. The proposed method was successfully applied in the analysis of environmental water and food samples. Good spiked recoveries over the range of 95.8-100.0 % were obtained. This work not only proposes a useful method for sample preconcentration but also reveals the great potential of modified graphene as an excellent sorbent material in analytical processes. PMID- 25023748 TI - Source identification of polycyclic aromatic hydrocarbons (PAHs) in sediment samples from the northern part of the Persian Gulf, Iran. AB - Samples of surface sediments from the Iranian coast of the Persian Gulf were examined to determine the levels and sources of 15 polycyclic aromatic hydrocarbons (PAHs). Samples were collected from 30 sampling sites and analyzed for PAHs by gas chromatography-mass spectrometry (GC-MS). Total concentrations of PAHs ranged from 93 to 4,077 ng g(-1) dry weight. The PAH composition from 30 sampling sites was dominated by four-ring PAH compounds. Molecular indices based on the ratios of PAH concentrations were used to differentiate PAHs from pyrolitic to petrogenic and mixed origins. The results suggested that the main sources of PAHs in sediments from the studied region were mixed pyrolitic and petrogenic. Furthermore, benthic organisms in most of the investigated areas were not at ecotoxicological risk, according to the results from the effects range low (ERL)/effects range median (ERM) techniques suggested by the US Sediment Quality Guidelines (SQGs). PMID- 25023749 TI - Dynamic response of the scenic beauty value of different forests to various thinning intensities in central eastern China. AB - Forest management has a significant influence on the preferences of people for forest landscapes. This study sought to evaluate the dynamic effects of thinning intensities on the landscape value of forests over time. Five typical stands in Wuxiangsi National Forest Park in Nanjing, China, were subjected to a thinning experiment designed with four intensities: unthinned, light thinning, moderate thinning, and heavy thinning. People's preferences for landscape photographs taken in plots under various thinning intensities were assessed through scenic beauty estimation (SBE) at 2 and 5 years after thinning. The differences in scenic beauty value between different thinning intensities were then analyzed with a paired samples t test for the two periods. The results indicated that the landscape value of all of the thinned plots significantly exceeded that of the unthinned plots 2 years after thinning (p < 0.01) and that the heavily thinned plots were most appreciated, showing an average improvement of 9.71 % compared with the control plots. Additionally, the heavily thinned plots were judged to be more beautiful than the lightly thinned and moderately thinned plots, whereas there was no significant difference between moderate thinning and light thinning. At 5 years after thinning, however, the moderately thinned plots received the highest preference scores among the four intensities, displaying an average improvement of 11.32 % compared with the unthinned plots. A multiple linear regression (MLR) model indicated that landscape value improved with increases in the average diameter at breast height (DBH) and with the improvement of environmental cleanliness in the stand, whereas the value decreased with an increasing stem density, species diversity, litter coverage, and canopy density. In addition, we found that the performance of a neural network model based on a multilayer perception (MLP) algorithm for predicting scenic beauty was slightly better than that of the MLR model. The findings of our study suggest that moderate to heavy thinning should be recommended to manage forests for the improvement of forest landscape value. PMID- 25023751 TI - The value of exercises in obstetrics. AB - Since the turn of the century, the belief has persisted that women who attain a high standard of physical fitness through exercise, would tend to have normal, easy labours with good uterine function. Based on this belief, extensive exercise programmes were evolved by Read, Vaughan, Randell and Heardman to facilitate labour. However, the benefits of these exercises have been extensively debated in medical literature. The majority of opinions have accepted that antenatal education is of no significance in shortening the period of labour or influencing the occurrence of complications, but is of psychological value only (Buxton, 1962). Although the value of exercises is not entirely that which has been attributed to them and some exercises can be refuted, it will be shown that they have a definite place in the management of the obstetric patient. PMID- 25023750 TI - Functional significance of nuclear export and mRNA binding of meiotic regulator Spo5 in fission yeast. AB - BACKGROUND: Meiotic cells undergo two rounds of nuclear division and generate gametes. Previous studies have indicated that a number of transcription factors modulate the transcriptome in successive waves during meiosis and spore formation in fission yeast. However, the mechanisms underlying the post-transcriptional regulation in meiosis are not fully understood. The fission yeast spo5+ gene encodes a meiosis-specific RNA-binding protein, which is required for the progression of meiosis II and spore formation. However, the target RNA molecules of Spo5 are yet to be identified. Characterization of meiosis-specific RNA binding proteins will provide insight into how post-transcriptional regulation influence gene expression during sexual differentiation. RESULTS: To assess the functional significance of RNA-recognition motifs (RRMs) of Spo5, we constructed a series of new spo5 truncated mutants and previously reported spo5 missense mutants. In addition, we isolated novel spo5 missense mutants. The phenotypic characteristics of these mutants indicated that the RRMs are essential for both the localization and function of the protein. Interestingly, Spo5 is exported from the nucleus to the cytoplasm via the Rae1-dependent mRNA export pathway, but is unlikely to be involved in global mRNA export. Furthermore, cytoplasmic localization of Spo5 is important for its function, which suggests the involvement of Spo5 in post-transcriptional regulation. We identified pcr1+ mRNA as one of the critical targets of Spo5. The pcr1+ gene encodes an activating transcription factor/cAMP response element binding (ATF/CREB) transcription factor family. Among the four family members, namely Pcr1, Atf1, Atf21, and Atf31, only the mRNA encoding Pcr1 binds to Spo5. CONCLUSIONS: Spo5 is exported from the nucleus with mRNAs via the Rae1-dependent pathway. RRMs are necessary for this process and also for the function of Spo5 after the nuclear export. Spo5 appears to influence the activity of pcr1+ mRNA, and the mechanism of how Spo5 stimulates the mRNA to promote the progression of meiosis II and spore formation remains an intriguing question for future research. PMID- 25023752 TI - Primary dysmenorrhea. AB - Primary dysmenorrhea is the term applied to disabling menstrual pain of obscure aetiology. It is a condition rather than a disease and applies to the type of pain which forces the patient to relinquish, for days or hours, her mode of living and seek medical advice for its relief. Uterine colic is present, associated with headache, backache, nausea and vomiting. PMID- 25023753 TI - A discussion on the use of muscle stretch in re-education. AB - Application of the physiological principles of muscle stretch for facilitatory and inhibitory purposes has formed a major part of the proprioceptive neuromuscular facilitation techniques of Dr. Herman Kabat and Margaret Knott (Kabat, 1947; Knott and Voss, 1956), and is also used by many other workers. One of the most accurate interpretations of this physiological knowledge has been made by Professor Margaret S. Rood, of the University of Southern California (Rood, 1964), and in this paper I will describe her work along with certain other fundamental considerations. PMID- 25023754 TI - The value of sport as a recreation in paraplegia. AB - On an afternoon in 1944, an able-bodied man attempted to move about in a wheel chair and, using the curved handle of a walking stick as a mallet, to hit a ball and chase after it, at the same time endeavouring to prevent his opponent in a wheel chair from counteracting his movements. The man was Dr. Ludwig Guttmann; the activity was later to become wheel-chair polo and from his simple experiment was born the idea of competitive team sport for paraplegics. Two decades later in Tokyo, paralyzed men and women from twenty-three nations competed in sports demanding of their patiently trained bodies skill, strength, speed and endurance. This was the occasion of the 1964 International Games for the Paralyzed. Paraplegic sport is a success story and the history of its growth of great interest. PMID- 25023755 TI - Do depressed patients on adjunctive atypical antipsychotics demonstrate a better quality of life compared to those on antidepressants only? A comparative cross sectional study of a nationally representative sample of the US population. AB - BACKGROUND: The adjunctive use of some atypical antipsychotics (AAPs) has been popular for patients with treatment-resistant depression. However, little is known about the impact of these agents on patients' Health-related quality of life (HRQoL). OBJECTIVES: The objective of this study is to examine the impact of the adjunctive AAPs use on HRQoL among users of antidepressants with self reported depression. METHODS: Patients with depression (ICD-9-CM: 296, 300, and 311), and to have used the given AAPs and/or antidepressants for at least a year, were identified in the Medical Expenditure Panel Survey of 2008-2011. The patients were classified into users of adjunctive AAPs (i.e., antidepressants plus AAPs) and users of antidepressants only. Adjusted multivariate linear regression analyses were conducted to examine the association between the utilization of AAPs and HRQoL measure.(c) RESULTS: A total of 3638 participants who met the inclusion criteria were identified (306 on AAPs vs. 3332 on antidepressants only). The study subjects were >=18 years, predominately White (91.9%) and female (71%). The AAPs utilization was not associated with higher scores in the Physical Component Summary (PCS-12) of the Short Form Health Survey (SF-12v2) (beta = 1.542, 95% CI = -0.0142 to 3.0977, P = 0.0521). Rather, it was negatively associated with the Mental Component Summary (MCS-12) scores of the SF 12v2 (beta = -1.5537, 95% CI = -3.0247 to -0.0827, P = 0.0385). CONCLUSIONS: The utilization of AAPs was not associated with higher scores of HRQoL. The findings of this study should underscore the need to consider other treatment options as add-on therapy for depression before resorting to AAPs. PMID- 25023756 TI - Chronic inflammatory arthritis prevalence estimates for children and adolescents in three Canadian provinces. AB - There is a paucity of published population-based estimates of the prevalence of chronic inflammatory arthritis in the pediatric population. We used administrative health data to estimate the prevalence of chronic inflammatory arthritis in individuals <=18 years in three Canadian provinces: Quebec, Manitoba, and Saskatchewan. Cases aged <=18 years were identified by meeting any one of the following criteria: (a) >=1 hospital discharge abstract with an ICD-9 code of 714 or ICD-10-CA codes of M05, M06 or M08, or (b) >=2 ICD-9 714 billing codes >=8 weeks apart, but within 2 years, or (c) >=1 ICD-9 714 billing code by a rheumatologist. Crude prevalence estimates per 10,000 population were estimated with 95 % confidence intervals (CIs). Prevalence estimates were 11.7 per 10,000 individuals <=18 years of age in Manitoba, 9.8 per 10,000 in Saskatchewan, and 8.0 per 10,000 in Quebec. In pairwise comparisons of rate differences, Manitoba and Saskatchewan had higher estimates than Quebec. Prevalence estimates were higher for females than males, with a difference of 5.9 cases per 10,000 residents (95 % CI 5.1, 6.7). Saskatchewan was the only province with a higher estimate in urban compared to rural residents (5.2, 95 % CI 2.5, 8.0). Variations in provincial estimates may be due to differences in underlying population characteristics. Although these estimates have face validity and are in keeping with the range of previously published pediatric prevalence estimates, studies to establish the empiric validity of case-finding algorithms are needed to advance research in pediatric chronic disease epidemiology. PMID- 25023757 TI - Appropriate incidence angle for fundamental research on new skyline radiography development. AB - Our purpose in this study was to elucidate the relationship between the angles formed between the anterior patella, tibial tuberosity, and the knee joint cavity and the flexion angle, sex, and age of the subjects. We investigated 368 images of 280 patients ranging in age from 16 to 60 years (179 knees of 150 men, mean age 36.4 years; 189 knees of 130 women, mean age 41.4 years) who underwent lateral radiography of the knee. The tibial tuberosity on the lateral radiograph of the knee was defined as a reference point, and a line tangent to the anterior patella was used as a reference line. The angle between the reference line and the straight line from the reference point to the knee joint cavity (incidence angle) was measured. The average incidence angle was 19 degrees (SD 1.8 degrees ). There was almost no correlation between the incidence angle and the flexion angle, and neither the knee flexion angle nor age had any influence on the incidence angle. There was a difference between the sexes in the average incidence angle, but this difference was less than 1 degrees . Further study on the same patients is required for comparison of this technique with the conventional technique that uses the femur for reference. PMID- 25023758 TI - Contemporary controversies and perspectives in the staging and treatment of patients with lymph node metastasis from melanoma, especially with regards positive sentinel lymph node biopsy. AB - The management of melanoma lymph node metastasis particularly when detected by sentinel lymph node biopsy (SLNB) is still controversial. Results of the only randomized trial conducted to assess the therapeutic value of SLNB, the Multicenter Selective Lymphadenectomy Trial (MSLT-1), have not conclusively proven the effectiveness of this procedure but are interpreted by the authors and guidelines as indicating SLNB is standard of care. After surgery, interferon alpha had a small survival benefit and radiotherapy has limited effectiveness for patient at high-risk of regional recurrence. New drugs, including immune modulating agents and targeted therapies, already shown to be effective in patients with distant metastasis, are being evaluated in the adjuvant setting. In this regard, ensuring high quality of surgery through the identification of reliable quality assurance indicators and improving the homogeneity of prognostic stratification of patients entered onto clinical trials is paramount. Here, we review the controversial issues regarding the staging and treatment of melanoma patients with lymph node metastasis, present a summary of important and potentially practice changing ongoing research and provide a commentary on what it all means at this point in time. PMID- 25023759 TI - Ectopic pregnancy among American Indian and Alaska Native women, 2002-2009. AB - To examine rates of ectopic pregnancy (EP) among American Indian and Alaska Native (AI/AN) women aged 15-44 years seeking care at Indian Health Service (IHS), Tribal, and urban Indian health facilities during 2002-2009. We used 2002 2009 inpatient and outpatient data from the IHS National Patient Information Reporting System to identify EP-associated visits and obtain the number of pregnancies among AI/AN women. Repeat visits for the same EP were determined by calculating the interval between visits; if more than 90 days between visits, the visit was considered related to a new EP. We identified 229,986 pregnancies among AI/AN women 15-44 years receiving care at IHS-affiliated facilities during 2002 2009. Of these, 2,406 (1.05 %) were coded as EPs, corresponding to an average annual rate of 10.5 per 1,000 pregnancies. The EP rate among AI/AN women was lowest in the 15-19 years age group (5.5 EPs per 1,000 pregnancies) and highest among 35-39 year olds (18.7 EPs per 1,000 pregnancies). EP rates varied by geographic region, ranging between 6.9 and 24.4 per 1,000 pregnancies in the Northern Plains East and the East region, respectively. The percentage of ectopic pregnancies found among AI/AN women is within the national 1-2 % range. We found relatively stable annual rates of EP among AI/AN women receiving care at IHS affiliated facilities during 2002-2009, but considerable variation by age group and geographic region. Coupling timely diagnosis and management with public health interventions focused on tobacco use and sexually transmitted diseases may provide opportunities for reducing EP and EP-associated complications among AI/AN women. PMID- 25023760 TI - Systemic vascular safety of ranibizumab for age-related macular degeneration: systematic review and meta-analysis of randomized trials. AB - BACKGROUND: We conducted a meta-analysis of randomized trials of ranibizumab for age-related macular degeneration (AMD) to elucidate systemic vascular risk. CLINICAL RELEVANCE: Although intravitreal vascular endothelial growth factor inhibitors are widely used to treat AMD, whether they produce systemic adverse effects remains uncertain. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials through March 2014 to identify the randomized trials that compared systemic safety among different intensities of ranibizumab treatment for AMD. The outcome measures were the incidence of cerebrovascular accidents (CVAs), myocardial infarctions, nonocular hemorrhages, overall arterial thromboembolic events (ATEs), and all-cause mortality. We calculated the Peto odds ratio (OR) with 95% confidence interval for the comparisons between different intensities of regimens in terms of dose and retreatment frequency. RESULTS: Eleven trials comprising 6596 patients with AMD were included in the meta-analysis. A significant increase was observed in the following comparisons: 0.5 versus 0.3/0.0 mg for CVA (OR, 1.86; 95% CI, 1.05 3.29; P = 0.03), monthly versus pro re nata (PRN)/0.0 mg for CVA (OR, 1.89; 95% CI, 1.06-3.38; P = 0.03), and 0.3/0.5 versus 0.0 mg for nonocular hemorrhage (OR, 1.57; 95% CI, 1.01-2.44; P = 0.04). A nonsignificant increase was observed in the following comparisons: 0.5 versus 0.0 mg for CVA (OR, 2.27; 95% CI, 0.90-5.69; P = 0.08), monthly versus PRN for CVA (OR, 2.04; 95% CI, 0.94-4.45; P = 0.07), 0.5 versus 0.0 mg for nonocular hemorrhage (OR, 1.68; 95% CI, 0.98-2.88; P = 0.06), 0.3 versus 0.0 mg for nonocular hemorrhage (OR, 1.68; 95% CI, 0.95-2.98; P = 0.07), monthly versus PRN/0.0 mg for nonocular hemorrhage (OR, 1.54; 95% CI, 0.98 2.42; P = 0.06), monthly versus PRN for ATE (OR, 1.58; 95% CI, 0.96-2.61; P = 0.07), and monthly versus PRN/0.0 mg for ATE (OR, 1.42; 95% CI, 0.99-2.05; P = 0.06). Among the other analyses, no protective or harmful effects of ranibizumab were observed. CONCLUSIONS: In ranibizumab treatment for patients with AMD, a possible relationship of more intensive treatment to more systemic vascular adverse events was identified, but no relationship with mortality was identified. PMID- 25023761 TI - Low-density lipoprotein receptor affects the fertility of female mice. AB - Low-density lipoprotein receptor (LDLR) has been demonstrated to play a central role in lipoprotein metabolism, with Ldlr-deficient (Ldlr(-/-)) mice developing severe dyslipidemia. In the present study we investigated whether Ldlr knockout could harm female reproduction and explored the mechanisms involved. The results indicate that although the number of litters born to Ldlr(-/-) mice did not differ significantly from that born to controls, the number of pups per litter was significantly lower in the former group. Interestingly, although Ldlr(-/-) mice were obese, the weight of their ovaries was lower than that in control mice. Serum cholesterol levels was significantly higher in Ldlr(-/-) mice than in their wild-type counterparts. In contrast, there were significant decreases in cholesterol, triglyceride and total lipid levels in ovaries of Ldlr(-/-) mice. Both ovarian lipid deposition, as detected by Oil red O staining, and lipid droplets, as evaluated by transmission electron microscopy, supported decreased lipid levels in ovaries from Ldlr(-/-) mice. In addition, Ldlr(-/-) mice had fewer ovarian follicles, more atretic follicles, lower oestrogen levels and spent significantly less time in oestrus than did the controls. Superovulation assays indicated immature Ldlr(-/-) mice ovulated fewer ova than controls. These results indicate that lack of Ldlr results in dyslipidaemia and poor fertility. PMID- 25023762 TI - Streptococcus mitis/oralis endophthalmitis management without phakic intraocular lens removal in patient with iris-fixated phakic intraocular lens implantation. AB - BACKGROUND: To report a case of Streptococcus mitis/oralis endophthalmitis management which had developed after complicated iris-fixated phakic intraocular (pIOL) lens implantation. CASE PRESENTATION: A 23-year-old-woman received pIOL implantation followed secondary intraocular intervention to lower intraocular pressure. The patient presented with severe pain and decreased visual acuity and was managed with intravitreal and intracameral antibiotic injection with topical applications of fortified antibiotics. Culture of aqueous humor was positive for S. mitis/oralis, which was sensitive to the empiric antibiotic regimen. Clinical features started to improve 5 days after treatment and the pIOL was left in place. The uncorrected distant visual acuity and endothelial cell count were 20/32 and 3143 cells/mm2 four weeks after treatment, respectively. CONCLUSION: S. mitis/oralis endophthalmitis after pIOL implantation could be managed with appropriate antibiotic administration without pIOL removal if accompanied by rapid clinical improvement after the initial intensive management in the absence of vitreous involvement. PMID- 25023763 TI - Expression of H1.5 and PLZF in granulosa cell tumors and normal ovarian tissues: a short report. AB - PURPOSE: Ovarian granulosa cell tumors (GCTs) typically exhibit an excellent prognosis, but their recurrences are associated with high mortality rates. In the past, immunohistochemistry (IHC)-based approaches have been used to facilitate the distinction between GCTs and other, more frequently occurring, primary or metastatic tumors. The purpose of this study was to assess the added value of H1.5 and PLZF protein expression in the correct delineation of GCTs. METHODS: Consecutive 5-MUm thick sections from routinely fixed and paraffin embedded tissues from 30 GCTs and 33 benign ovaries were processed for IHC using anti-PLZF and anti-H1.5 monoclonal antibodies. The respective protein staining intensities and distributions were quantified into reported scores for all tissue samples. Student's t-test and Fisher's exact test were used to compare the mean scores for each group. A p-value of <0.05 was considered statistically significant. Also, both the sensitivity and the specificity of the two antibodies were evaluated. RESULTS: A statistically significant difference in the expression of H1.5 between the GCT and normal ovary groups was observed (p < 0.0001). Normal ovarian tissues were found to strongly express H1.5, whereas GCTs were found to weakly express this protein. In contrast, PLZ expression was not found to be significantly different between both study groups. CONCLUSIONS: From our results we conclude that H1.5 is down-regulated in GCTs compared to normal ovarian tissues. Additional investigations on larger and more heterogeneous study populations, and on the molecular mechanism (s) underlying down-regulation of the H1.5 protein, may further substantiate the use of H1.5 as a diagnostic/prognostic marker and, in addition, provide insight into the pathogenesis of GCTs. PMID- 25023764 TI - Reducing recidivism and symptoms in emerging adults with serious mental health conditions and justice system involvement. AB - The peak years of offending in the general population and among those with serious mental health conditions (SMHC) are during emerging adulthood. There currently are no evidence-based interventions for reducing offending behavior among 18-21 year olds, with or without SMHC. This open trial examined outcomes from an adaptation of Multisystemic Therapy (MST), an effective juvenile recidivism reduction intervention, modified for use with emerging adults with SMHC and recent justice system involvement. MST for emerging adults (MST-EA) targets MH symptoms, recidivism, problem substance use, and young adult functional capacities. All study participants (n = 41) were aged 17-20 and had a MH diagnosis and recent arrest or incarceration. Implementation outcomes indicated that MST-EA was delivered with strong fidelity, client satisfaction was high, and the majority of participants successfully completed the intervention. Research retention rates also were high. Pre-post-analyses revealed significant reductions in participants' MH symptoms, justice system involvement, and associations with antisocial peers. PMID- 25023765 TI - Twelve tips for a successful interprofessional team-based high-fidelity simulation education session. AB - Simulation-based education allows experiential learning without risk to patients. Interprofessional education aims to provide opportunities to different professions for learning how to work effectively together. Interprofessional simulation-based education presents many challenges, including the logistics of setting up the session and providing effective feedback to participants with different backgrounds and mental models. This paper aims to provide educators with a series of practical and pedagogical tips for designing, implementing, assessing, and evaluating a successful interprofessional team-based simulation session. The paper is organized in the sequence that an educator might use in developing an interprofessional simulation-based education session. Collectively, this paper provides guidance from determining interprofessional learning objectives and curricular design to program evaluation. With a better understanding of the concepts and pedagogical methods underlying interprofessional education and simulation, educators will be able to create conditions for a unique educational experience where individuals learn with and from other specialties and professions in a controlled, safe environment. PMID- 25023766 TI - Prevention of cardiovascular diseases: a spearhead for control of noncommunicable diseases. PMID- 25023767 TI - Breastfeeding practice in Kuwait: determinants of success and reasons for failure. AB - To explore the possible determinants of duration of breastfeeding in Kuwait, 234 mothers completed a questionnaire concerning the feeding of their youngest infant. The questionnaire addressed the factors that contributed to their willingness to continue breastfeeding and enquired about the factors leading to their decision to end it. Only 26.5% of the mothers had continued breastfeeding for 6 months or more. Separate family housing, higher maternal age, late initiation of breastfeeding, being employed without the feasibility to breastfeed at work, breastfeeding information given after rather than before birth, and maternal and infant sickness were all significant contributors influencing early cessation. Father's support was a significant factor that encouraged the practice. In conclusion, preventive strategies are recommended for boosting breastfeeding, with special emphasis on the factors linked to early cessation, aiming at full implementation of the WHO global public health recommendations for successful breastfeeding in Kuwait. PMID- 25023768 TI - Dietary habits and physical activity levels in Jordanian adolescents attending private versus public schools. AB - The present study examined differences in dietary habits and physical activity levels between students attending private and public high schools in Jordan. A total of 386 secondary-school males and 349 females aged 14-18 years were randomly recruited using a multistage, stratified, cluster sampling technique. Dietary habits and physical activity level were self-reported in a validated questionnaire. The prevalence of obesity was significantly higher among adolescents in private (26.0%) than in public schools (16.7%). The frequency of breakfast intake was significantly higher among adolescents in private schools, whereas French fries and sweets intake was significantly higher in public schools. Television viewing showed a significant interaction with school type by sex. A higher rate of inactivity was found among students attending private schools. Despite a slightly better overall dietary profile for students in private schools, they had a higher rate of overweight and obesity compared with those in public schools. PMID- 25023769 TI - FEV1 and FVC pulmonary function reference values among 6-18-year-old children: a multi-centre study in Saudi Arabia. AB - It is important to establish lung function reference values for each population. This study aimed to determine the spirometric reference values for healthy Saudi Arabian children and adolescents and to derive prediction equations for these. A cross-sectional study was conducted among healthy schoolboys and girls aged 6-18 years old, selected randomly from the 6 administrative regions of Saudi Arabia. Data were collected by questionnaire and physical examinations including spirometry. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were significantly higher in males than females. Height was the anthropometric variable most strongly correlated with FEV1 (r = 0. 61), more so for males (r = 0.71) than females (r = 0.50). In males the multivariate linear regression model explained 53.9% of FEV1 and 35.1% of FVC variations. In females it explained 25.3% of FEV1 and 16.5% of FVC variations. All changes in R2 were statistically significant. PMID- 25023770 TI - Childhood very severe pneumonia and meningitis-related hospitalization and death in Yemen, before and after introduction of H. influenzae type b (Hib) vaccine. AB - Haemophilus influenzae type b (Hib) vaccine was included in the Yemen immunization programme in 2005. This study compared the rates of very severe pneumonia and all-cause meningitis hospitalization and death, before and after introduction of conjugate Hib vaccine, and reports the results of the 2010 bacterial meningitis surveillance. A retrospective analysis was made of data collected for 2000-2010 for all children aged 2-60 months in the main children's hospital in Sana'a. Compared with the pre-Hib vaccination period, the post-Hib period showed significant and impressive reductions in the rates of hospitalization and death for all-cause meningitis. However, hospitalization and death for very severe pneumonia improved only modestly, and there was evidence of a decreasing but non-significant trend indicting that very severe pneumonia was a non-specific endpoint with multi-etiologies (both viral and bacterial). Very severe pneumonia remains the leading cause of severe morbidity and death for young children, particularly those aged < 12 months. PMID- 25023771 TI - Case management of childhood tuberculosis in children's hospitals in Khartoum. AB - No published information is available on the case management of childhood tuberculosis (TB) in Sudan. The aim of this study was to describe the case management of childhood TB in 4 children's hospitals in Khartoum State, Sudan. Data on 467 children aged 0-14 years registered in 2009 were collected from patient records; 52.9% males and 53.0% aged 5-14 years. Most cases were registered as new cases (89.5%) and most had pulmonary TB (72.4%). Of all cases, 31.0% had sputum smear microscopy done, 35.8% had X-ray and none had a record of being culture confirmed. Category III regimen was given to 58.5%. Reported outcomes were: cured (1.5%), completed treatment (14.6%), transferred out (13.1%), default (17.3%), death (4.3%) and treatment failure (0.6%). Age was significantly associated with treatment outcome, while sex, type of patient, site of TB and treatment category were not significant. Case management of childhood TB is suboptimal in this region. PMID- 25023772 TI - Qualitative adaptation of child behaviour problem instruments in a developing country setting. AB - A key barrier to epidemiological research on child behaviour problems in developing countries is the lack of culturally relevant, internationally recognized psychometric instruments. This paper proposes a model for the qualitative adaptation of psychometric instruments in developing-country settings and presents a case study of the adaptation of 3 internationally recognized instruments in Pakistan: the Child Behavior Checklist, the Youth Self-Report and the Teacher's Report Form. This model encompassed a systematic procedure with 6 distinct phases to minimize bias and ensure equivalence with the original instruments: selection, deliberation, alteration, feasibility, testing and formal approval. The process was conducted in collaboration with the instruments' developer. A multidisciplinary working group of experts identified equivalence issues and suggested modifications. Focus group discussions with informants highlighted comprehension issues. Subsequently modified instruments were thoroughly tested. Finally, the instruments' developer approval further validated the qualitative adaptation. The study proposes a rigorous and systematic model to effectively achieve cultural adaptation of psychometric instruments. PMID- 25023773 TI - Association of cerebral palsy with consanguineous parents and other risk factors in a Palestinian population. AB - This case-control study investigated risk factors for cerebral palsy in a Palestinian population. Cases were 107 children aged 1-15 years at a cerebral palsy referral centre in Jerusalem; controls were 233 children without cerebral palsy from West Bank outpatient clinics. Data were collected from medical records and a structured questionnaire to parents. In stepwise logistical regression, consanguinity and birth deficits in other family members were positively associated with cerebral palsy (OR = 4.62; 95% CI: 2.07-10.3 and OR = 12.7; 95% CI: 3.13-51.7 respectively), suggesting a possible genetic link. Other risk factors were: perinatal hypoxia (OR = 92.5; 95% CI: 24.5-350), low birth weight (OR = 4.98; 95% CI: 2.01-12.3), twin births (OR = 9.25; 95% CI: 1.29-66.8) and no prenatal medical care (OR = 5.22; 95% CI: 1.18-23.1). This first stepwise model of significant and modifiable risk factors in our population provides useful evidence for policy-makers. PMID- 25023774 TI - WHO events addressing public health priorities. Promoting physical activity: a regional call for action. PMID- 25023775 TI - Phosphorylation of Ser8 promotes zinc-induced dimerization of the amyloid-beta metal-binding domain. AB - Zinc-induced aggregation of the amyloid-beta peptide (Abeta) is a hallmark molecular feature of Alzheimer's disease (AD). Recently it was shown that phosphorylation of Abeta at Ser8 promotes the formation of toxic aggregates. In this work, we have studied the impact of Ser8 phosphorylation on the mode of zinc interaction with the Abeta metal-binding domain 1-16 using isothermal titration calorimetry, electrospray ionization mass spectrometry and NMR spectroscopy. We have discovered a novel zinc binding site ((6)HDpS(8)) in the phosphorylated peptide, in which the zinc ion is coordinated by the imidazole ring of His6, the phosphate group attached to Ser8 and a backbone carbonyl group of His6 or Asp7. Interaction of the zinc ion with this site involves His6, thereby withdrawing it from the interaction pattern observed in the non-modified peptide. This event was found to stimulate dimerization of peptide chains through the (11)EVHH(14) site, where the zinc ion is coordinated by the two pairs of Glu11 and His14 in the two peptide subunits. The proposed molecular mechanism of zinc-induced dimerization could contribute to the understanding of initiation of pathological Abeta aggregation, and the (11)EVHH(14) tetrapeptide can be considered as a promising drug target for the prevention of amyloidogenesis. PMID- 25023776 TI - Unfractionated heparin suppresses lipopolysaccharide-induced monocyte chemoattractant protein-1 expression in human microvascular endothelial cells by blocking Kruppel-like factor 5 and nuclear factor-kappaB pathway. AB - Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), apart from anticoagulant activities, contain a variety of biological properties such as anti inflammatory actions possibly affecting sepsis. Chemokines are vital for promoting the movement of circulating leukocytes to the site of infection and are involved in the pathogenesis of sepsis. The purpose of this study was to investigate the effects and potential mechanisms of UFH on lipopolysaccharide (LPS)-induced chemokine production in human pulmonary microvascular endothelial cells (HPMECs). HPMECs were pretreated with UFH (0.1 U/ml and 1 U/ml), 15 min prior to stimulation with LPS (10 MUg/ml). Cells were cultured under various experimental conditions for 2 h and 6 h for analysis. UFH markedly decreased LPS induced interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression in HPMECs. UFH also attenuated the secretion of these chemokines in culture supernatants. In addition, UFH blocked the chemotactic activities of LPS-stimulated HPMECs supernatants on monocytes migration as expected. UFH inhibited LPS-induced Kruppel-like factor 5 (KLF-5) mRNA and protein levels. Concurrently, UFH reduced nuclear factor (NF)-kappaB nuclear translocation. Importantly, transfection with siRNA targeting KLF-5 reduced NF kappaB activation and chemokines expression. These results demonstrate that interfering with KLF-5 mediated NF-kappaB activation might contribute to the inhibitory effects of chemokines and monocytes migration by UFH in LPS-stimulated HPMECs. PMID- 25023777 TI - Costs of staged versus simultaneous bilateral total knee arthroplasty: a population-based study of the Taiwanese National Health Insurance Database. AB - BACKGROUND: Bilateral total knee arthroplasty (TKA) is required for many patients. There are few studies comparing the overall costs of staged and simultaneous bilateral TKA. METHODS: The Taiwan National Health Insurance Research Database (NHIRD) was searched, and the total medical costs of 452 patients who received simultaneous bilateral TKAs were compared with those of 690 who received staged bilateral TKAs. RESULTS: All categories of medical costs were lower in the simultaneous TKA group, with the exception of therapeutic procedure fees which were higher in the simultaneous bilateral TKA group. The 10-year prosthesis survival rates for simultaneous and staged bilateral TKA were 90.9% and 87.5% (p > 0.05), respectively. CONCLUSIONS: These results indicate that simultaneous bilateral TKA is more cost effective than staged bilateral TKA. Prosthesis survival is not affected by the choice for staged or simultaneous bilateral TKA. PMID- 25023778 TI - Validation of the Female Sexual Function Index (FSFI) for web-based administration. AB - INTRODUCTION AND HYPOTHESIS: Web-based questionnaires are becoming increasingly valuable for clinical research. The Female Sexual Function Index (FSFI) is the gold standard for evaluating female sexual function; yet, it has not been validated in this format. We sought to validate the Female Sexual Function Index (FSFI) for web-based administration. METHODS: Subjects enrolled in a web-based research survey of sexual function from the general population were invited to participate in this validation study. The first 151 respondents were included. Validation participants completed the web-based version of the FSFI followed by a mailed paper-based version. Demographic data were collected for all subjects. Scores were compared using the paired t test and the intraclass correlation coefficient. RESULTS: One hundred fifty-one subjects completed both web- and paper-based versions of the FSFI. Those subjects participating in the validation study did not differ in demographics or FSFI scores from the remaining subjects in the general population study. Total web-based and paper-based FSFI scores were not significantly different (mean 20.31 and 20.29 respectively, p = 0.931). The six domains or subscales of the FSFI were similar when comparing web and paper scores. Finally, intraclass correlation analysis revealed a high degree of correlation between total and subscale scores, r = 0.848-0.943, p < 0.001. CONCLUSIONS: Web-based administration of the FSFI is a valid alternative to the paper-based version. PMID- 25023779 TI - Choice of pelvic organ prolapse surgery: vaginal or abdominal, native tissue or synthetic grafts, open abdominal versus laparoscopic or robotic. PMID- 25023781 TI - A systematic review on soft-to-hard tissue ratios in orthognathic surgery part I: maxillary repositioning osteotomy. AB - INTRODUCTION: Changes occurring in facial soft tissues after orthognathic surgery have been studied over the past 45 years. In this systematic review, we analyzed soft-to-hard tissue ratios regarding maxillary repositioning surgery. METHODS: We searched major online databases according to the guidelines of the CONSORT/QUORUM flowchart, and selected studies based on their inclusion and exclusion criteria. RESULTS: Our search identified 27 articles, and 10 additional articles were found in the reference sections. Of these, six were evidence level IIIb, three were evidence level IIb, and the rest were evidence level IV. Only three articles were prospective. A high variability of soft-to-hard tissue ratios regarding Le Fort I surgery seemed to vanish if data were stratified according to confounding factors. With the available data, a ratio of 0.6:1 (labrale superius to upper incisor tip) could be used in Le Fort I advancement surgery if alar base cinch suture is not performed, and a ratio of 0.9:1 if it is performed. CONCLUSION: Although there are many publications on soft tissue changes after orthognathic surgery, more prospective studies are needed that stratify by confounding factors such as type of osteotomy technique, magnitude of the movement, age, sex, race, quantity, and quality of the soft tissues. PMID- 25023782 TI - Analysis of MRI findings in minimum invasive treatment for habitual temporomandibular joint dislocation by autologous blood injection around the temporomandibular joint capsule. AB - The aim of this study was to investigate magnetic resonance imaging (MRI) findings following autologous blood injection (ABI) for habitual temporomandibular joint (TMJ) dislocation. MRI was performed one hour and four and twelve weeks after ABI, revealing three types of significant findings. The first type was similar to hematoma and/or joint effusion in the articular capsule of the TMJ (type I). The second showed sporadic and diffuse T2 emphasis around the TMJ capsule (type II). The third involved a decreased range of condyle movement compared to before ABI (type III). Furthermore, we analyzed the three types of significant MRI findings. At one hour after ABI, type I was Grade 0 in 0 of 14 patients, Grade 1 in 8, Grade 2 in 2, and Grade 3 in 4. Type II was seen in 9 of the 14 cases and type III in 8. After twelve weeks, all cases of type I were Grade 0, no type II cases were evident, and type III was seen in 11 cases. Injecting autologous blood into surrounding TMJ tissues is an important factor in ABI. Minimally invasive treatment for habitual TMJ dislocation using ABI around the TMJ capsule appears to represent a very effective and safe treatment. PMID- 25023783 TI - A systematic review and meta-analysis of the standard versus mini-incision posterior approach to total hip arthroplasty. AB - The mini-incision posterior approach may appeal to surgeons comfortable with the standard posterior approach to the hip. We present the first systematic review and meta-analysis of these two approaches. Twelve randomised controlled trials and four non-randomised trials comprising of 1498 total hip arthroplasties were included. The mini-incision posterior approach was associated with an early improvement in Harris hip score of 1.8 points (P<0.001), reduced operating time (5minutes, P<0.001), length of hospital stay (14hours, P<0.001), intraoperative and total blood loss (63ml, P<0.001 and 119ml, P<0.001 respectively). There were no statistically significant differences in the incidence of dislocation, nerve injury, infection or venous thromboembolic events. The minimally invasive posterior approach appears to provide a safe and acceptable alternative to the standard incision posterior approach. PMID- 25023784 TI - Effect of supplementation with ferrous sulfate or iron bis-glycinate chelate on ferritin concentration in Mexican schoolchildren: a randomized controlled trial. AB - BACKGROUND: Iron deficiency is one of the most common nutritional deficiencies worldwide. It is more prevalent when iron requirements are increased during pregnancy and during growth spurts of infancy and adolescence. The last stage in the process of iron depletion is characterized by a decrease in hemoglobin concentration, resulting in iron deficiency anemia. Iron deficiency, even before it is clinically identified as anemia, compromises the immune response, physical capacity for work, and intellectual functions such as attention level. Therefore, interventions addressing iron deficiency should be based on prevention rather than on treatment of anemia. The aim of this study was to compare short- and medium-term effects on ferritin concentration of daily supplementation with ferrous sulfate or iron bis-glycinate chelate in schoolchildren with iron deficiency but without anemia. METHODS: Two hundred schoolchildren from public boarding schools in Mexico City who had low iron stores as assessed by serum ferritin concentration but without anemia were randomly assigned to a daily supplement of 30 mg/day of elemental iron as ferrous sulfate or iron bis glycinate chelate for 12 weeks. Iron status was evaluated at baseline, one week post-supplementation (short term), and 6 months (medium term) after supplementation. RESULTS: Ferritin concentration increased significantly between baseline and post-supplementation as well as between baseline and 6 months after supplementation. One week post-supplementation no difference was found in ferritin concentration between iron compounds, but 6 months after supplementation ferritin concentration was higher in the group that received bis-glycinate chelate iron. However, there is no difference in the odds for low iron storage between 6 months after supplementation versus the odds after supplementation; nor were these odds different by type of supplement. Hemoglobin concentration did not change significantly in either group after supplementation. CONCLUSIONS: Supplementing with 30 mg/d of elementary iron, either as ferrous sulfate or iron bis-glycinate chelate for 90 days, showed positive effects on increasing ferritin concentration in schoolchildren with low iron stores, and this effect persisted 6 months after supplementation. PMID- 25023785 TI - Grand Challenge: Computational Models Validated Against Critical Experiments. PMID- 25023786 TI - Assessment of diagnostic gain with hexaminolevulinate (HAL) in the setting of newly diagnosed non-muscle-invasive bladder cancer with positive results on urine cytology. AB - OBJECTIVE: In accordance with the European Association of Urology guidelines, a second transurethral resection of the bladder (TURB) is recommended for high grade or T1-category tumors. This practice brings into question the benefit of photodynamic diagnosis (PDD) in reducing the residual disease after TURB in patients with positive results on urine cytology showing high-grade cancer cells. METHODS AND MATERIALS: A prospective, bicentric, randomized study comparing white light cystoscopy (WLC)+PDD with hexaminolevulinate arm with WLC alone (control arm) during the first TURB in patients with primary non-muscle-invasive bladder cancer and with positive results on urine cytology showing high-grade cancer cells. Patients underwent a first TURB with WLC and PDD or WLC alone, and then a second TURB with WLC and PDD, after 4 to 6 weeks. The number of tumors visualized in WLC and PDD and histology of the TURB specimen was recorded to perform a statistical analysis comparing both the 2 arms. RESULTS: A total of 151 patients were enrolled (hexaminolevulinate, n = 72; control, n = 79). The number of visualized tumors did not increase with PDD in the first or second TURB. During the second TURB, the residual tumor rate was not reduced in patients who had PDD during the first TURB. No significant difference was observed regarding the pattern of category and grade, the size, and the recurrence and progression risks during either the first or the second TURB. CONCLUSIONS: In the setting of primary non-muscle-invasive bladder cancer with positive results on urine cytology, performing a second TURB allows to diagnose residual tumor in approximately half of the cases. This rate was not significantly reduced by the use of the PDD during the first TURB. PMID- 25023787 TI - The effect of smoking and timing of smoking cessation on clinical outcome in non muscle-invasive bladder cancer. AB - OBJECTIVES: Cigarette smoking is the most important risk factor for urinary bladder cancer. The prognostic effect of cigarette smoking on disease recurrence and progression in patients with non-muscle-invasive bladder cancer (NMIBC), however, is still unclear. We evaluated the effect of smoking status and intensity, and timing of smoking cessation, on NMIBC prognosis. METHODS AND MATERIALS: A population-based series of patients diagnosed with NMIBC from 1995 until 2010 was identified through the Netherlands Cancer Registry. Self-reported smoking history was obtained by a postal lifestyle questionnaire at study inclusion. Detailed clinical data concerning diagnosis, treatment, and disease course were collected retrospectively through a medical file survey. The association of smoking variables with recurrence- and progression-free survival of 963 patients with primary NMIBC was studied using cumulative incidence curves and competing risk regression analyses. RESULTS: The study population comprised 181 never smokers (18.8%), 490 former smokers (50.9%), and 292 current smokers (30.3%) at the time of diagnosis. No statistically significant difference or trend in risk of recurrence (Ptrend = 0.47) or progression (Ptrend = 0.23) across the 3 smoking status categories was found. Moreover, no dose-response association was observed across categories of smoking quantity, duration, or cumulative exposure in relation to NMIBC prognosis. The timing of smoking cessation (i.e., ceased smoking>=10y before diagnosis,<10y before diagnosis, vs. current smoker at diagnosis) did not significantly affect the risk of recurrence (Ptrend = 0.31) and progression (Ptrend = 0.19). CONCLUSIONS: Based on our study, smoking status, smoking intensity, or cessation at any time before diagnosis does not seem to alter the risks of recurrence and progression among patients with NMIBC. Patients' smoking history is not useful for the guidance of clinical management decisions. Patients should nevertheless be advised to quit considering the known beneficial effects on other non-NMIBC-related end points such as cardiovascular disease and second primary cancers. PMID- 25023788 TI - The effect of length of ureteral resection on benign ureterointestinal stricture rate in ileal conduit or ileal neobladder urinary diversion following radical cystectomy. AB - OBJECTIVES: To assess the effect of the length of the ureter resected and other clinical variables on ureterointestinal anastomotic (UIA) stricture rate following radical cystectomy and ileal segment urinary diversion. METHODS AND MATERIALS: We identified 519 consecutive patients who underwent cystectomy and ileal conduit or ileal orthotopic neobladder diversion from January 2007 to August 2012. The length of the ureter resected was defined as the length of the ureter in the cystectomy specimen plus the length of the distal ureter submitted for pathologic analysis. The primary end point was the risk of UIA stricture formation, assessed by Cox proportional hazards analysis. RESULTS: A total of 463 patients met the inclusion criteria with complete data. Median follow-up was 459 days (interquartile range [IQR]: 211-927). Median time to stricture formation was 235 (IQR: 134-352) and 232 days (IQR: 132-351) on the right and the left ureter, respectively. Overall stricture rate per ureter was 5.9% on the right vs. 10.0% on the left (P = 0.03). There was no difference in demographic, operative, or perioperative variables between patients with and without UIA strictures. On multivariate analysis adjusted for age, sex, anastomosis technique (running vs. interrupted), and length of ureter resected, only a Clavien complication>=III (hazard ratio = 2.11, 1.01-4.40) and urine leak (hazard ratio = 3.37, 1.08-10.46) significantly predicted for left- and right-sided stricture formation, respectively. The length of the ureter resected did not predict UIA stricture formation on either side. CONCLUSIONS: The etiology of benign UIA strictures following ileal urinary diversion is likely multifactorial. Our data suggest that a complicated postoperative course and urine leak are risk factors for UIA stricture formation. The length of the distal ureter resected did not significantly affect stricture rate. PMID- 25023789 TI - NADPH oxidase hyperactivity induces plantaris atrophy in heart failure rats. AB - BACKGROUND: Skeletal muscle wasting is associated with poor prognosis and increased mortality in heart failure (HF) patients. Glycolytic muscles are more susceptible to catabolic wasting than oxidative ones. This is particularly important in HF since glycolytic muscle wasting is associated with increased levels of reactive oxygen species (ROS). However, the main ROS sources involved in muscle redox imbalance in HF have not been characterized. Therefore, we hypothesized that NADPH oxidases would be hyperactivated in the plantaris muscle of infarcted rats, contributing to oxidative stress and hyperactivation of the ubiquitin-proteasome system (UPS), ultimately leading to atrophy. METHODS: Rats were submitted to myocardial infarction (MI) or Sham surgery. Four weeks after surgery, MI and Sham groups underwent eight weeks of treatment with apocynin, a NADPH oxidase inhibitor, or placebo. NADPH oxidase activity, oxidative stress markers, NF-kappaB activity, p38 MAPK phosphorylation, mRNA and sarcolemmal protein levels of NADPH oxidase components, UPS activation and fiber cross sectional area were assessed in the plantaris muscle. RESULTS: The plantaris of MI rats displayed atrophy associated with increased Nox2 mRNA and sarcolemmal protein levels, NADPH oxidase activity, ROS production, lipid hydroperoxides levels, NF-kappaB activity, p38 MAPK phosphorylation and UPS activation. NADPH oxidase inhibition by apocynin prevented MI-induced skeletal muscle atrophy by reducing ROS production, NF-kappaB hyperactivation, p38 MAPK phosphorylation and proteasomal hyperactivity. CONCLUSION: Our data provide evidence for NADPH oxidase hyperactivation as an important source of ROS production leading to plantaris atrophy in heart failure rats, suggesting that this enzyme complex plays key role in skeletal muscle wasting in HF. PMID- 25023790 TI - HMG-CoA reductase inhibition prior reperfusion improves reparative fibrosis post myocardial infarction in a preclinical experimental model. AB - BACKGROUND: Studies in patients support a beneficial effect of statin treatment early after acute coronary syndrome and/or prior percutaneous coronary intervention. However, statin effect during total occlusion remains unknown. OBJECTIVES: To investigate whether infusion of activated simvastatin during ischemia and prior reperfusion and oral administration thereafter confers cardioprotection and improves cardiac healing in a preclinical model of myocardial infarction. METHODS: Pigs (n=24) fed a 10 day Western-type diet underwent a 90 min coronary-balloon occlusion (MI) being randomized to a single intravenous infusion of active beta-hydroxy acid derivative of simvastatin (beta OH-S; 0.3 mg/kg) 15 min prior to reperfusion or vehicle. Animals were either sacrificed 2.5 h post-reperfusion or kept under the same regime +/- simvastatin (p.o., 20 mg/day) for 3 weeks. Jeopardized and remote myocardium was obtained for molecular/histological studies. Echocardiography was assessed. RESULTS: beta-OH-S infusion prior to reperfusion reduced coronary and cardiac oxidative DNA-damage, diminished neutrophil infiltration at the site of ischemia, preserved mitochondrial membrane potential and reduced apoptosis in the ischemic myocardium (lower mRNA levels of Fas, casp8, p53, and casp3 and mitochondrial-p-Bcl2; and reduced TUNEL and active caspase-3; p<0.05 vs. vehicle/control). This treatment regime attenuated reperfusion-related arrhythmias and stunning leading to a 40% increased myocardial salvage (p<0.05 vs. vehicle/control). 3 weeks post-MI simvastatin-treated animals showed P-PKCepsilon increase, lower intramyocardial lipotoxicity, TbetaRII/Smad2/3 signaling restoration and subsequent myofibroblast differentiation and collagen-fibril formation in the evolving scar (p<0.05 vs. control). Simvastatin suppressed cardiac RhoA mobilization and triggered Akt/eNOS signaling. CONCLUSIONS: Acute HMG-CoA-reductase inhibition during total ischemia and prior reperfusion limits reperfusion injury and prolonged oral simvastatin treatment thereafter improves cardiac healing post-MI. PMID- 25023791 TI - Predictors of response to intramyocardial bone marrow cell treatment in patients with refractory angina and chronic myocardial ischemia. AB - BACKGROUND: We previously showed that intramyocardial bone marrow cell (BMC) injection in patients with refractory angina and chronic myocardial ischemia improves myocardial perfusion, cardiac function and disease-related complaints. Treatment effect varied between patients, but the predictors of response remain to be identified. Therefore, the aim of the present study was to assess whether patient characteristics, procedural data and baseline measurements influence the response to intramyocardial BMC treatment in a large cohort of refractory angina patients. METHODS AND RESULTS: In 120 patients (64 +/- 9 years, 88% men) with refractory angina, 97 +/- 13 * 10(6) BMCs were injected intramyocardially in regions with stress-inducible ischemia as assessed by single photon emission computed tomography (SPECT). Canadian Cardiovascular Society angina (CCS) class, quality-of-life score, exercise testing, SPECT and magnetic resonance imaging were performed at baseline and at 3 months follow-up demonstrating significant improvements in CCS class, quality-of-life, exercise capacity, myocardial perfusion and left ventricular function (all variables P<0.001). Multivariate analysis was performed to evaluate the influence of patient characteristics, procedural data and baseline measurements on BMC treatment response. Based on the improvement of myocardial perfusion at stress, diabetes and a large number of ischemic segments at baseline were shown to be independently associated with a large response to BMC therapy. CONCLUSION: The present study demonstrates that diabetes and a large number of ischemic segments are predictors of a large response to intramyocardial BMC injection in refractory angina and chronic ischemia. Furthermore, the safety and efficacy results of previous trials are now confirmed in a larger study population. PMID- 25023792 TI - Radiofrequency ablation of left atrial flutter mediated with double potentials in a seemingly normally structured heart. AB - BACKGROUND: Left atrial flutter (left AFL) is common in patients who undergo atrial fibrillation ablation and cardiac surgery; however, few reports describe left AFL in detail in a seemingly normally structured heart, and the mechanisms of the occurrence of such arrhythmia are still not clear. We describe left AFL in patients without prior cardiac surgery or catheter ablation and discuss the electrophysiological characteristics that may explain the preferential generation and perpetuation of such tachycardia. METHODS AND RESULTS: Eleven patients with left AFL, who had no history of cardiac surgery or interventions, underwent electrophysiological studies and 3-dimensional electroanatomic mapping studies. Echocardiography revealed a relatively mild dilation of the left atrium, mild to moderate mitral regurgitation, and a normal left ventricular ejection fraction. The electroanatomic mapping during tachycardia showed a "reentrant" activation pattern in all patients. The mean tachycardia cycle length was 266 +/- 17 ms. A single-loop reentrant circuit was identified in 7 patients. A counterclockwise left atrial flutter evolved around the mitral valve annulus in 6 patients. The tachycardia rotated around the left atrial anterior wall in 1 patient. Four patients exhibited a double-loop reentrant circuit with a "figure of 8" pattern reentry. Double potentials as the critical isthmus of the circuit were identified in the left atrial anterior wall near the mitral annulus which displayed a low voltage area matched with the left atrium-aorta contiguity. The conduction velocity was significantly slower in the double-potential recording area than in the lateral mitral annulus (0.36 +/- 0.03 m/s vs 0.74 +/- 0.12 m/s; P<0.05). Successful ablation around the double-potential recording site caused an interruption of the tachycardia, and remained free of recurrence during a 12 month follow-up in all patients. CONCLUSION: Left AFL in patients without a history of surgery or ablation is rarely observed in clinical practice. The successful site of ablation was within the anterior wall near the mitral annulus showing the double potentials as the critical part of the reentrant circuit. This suggests that perhaps a double potential-targeted ablation may be effective for these patients. PMID- 25023793 TI - Multilayered adipose-derived regenerative cell sheets created by a novel magnetite tissue engineering method for myocardial infarction. AB - BACKGROUND: Adipose-derived regenerative cells (ADRCs) are a promising source of autologous stem cells for regeneration and repair of damaged tissue. Herein, we investigated the therapeutic potential of ADRC sheets created by a magnetite tissue engineering technology (Mag-TE) for myocardial infarction. METHODS AND RESULTS: Adipose tissue was obtained from wild-type (WT) mice and ADRCs were isolated. ADRCs incubated with magnetic nanoparticle-containing liposomes (MCLs) were cultured. MCL-labeled ADRCs were mixed with a diluted extracellular matrix (ECM) precursor, and a magnet was placed on the reverse side. Magnetized ADRCs formed multilayered cell sheets after a 24-h incubation. WT mice were subjected to myocardial infarction by permanent ligation of the left anterior descending artery. We then transplanted the constructed ADRC sheet or a cell-free collagen gel sheet, as a control, onto the infarcted myocardium using an Alnico magnet before skin closure. Cardiac parameters were measured by echocardiogram, and angiogenesis was determined by tissue capillary density. ADRC sheet-treated mice showed significant improvements in systolic function, infarct wall thinning, and fibrotic length after myocardial infarction. ADRC sheet implantation also promoted angiogenesis in both the infarct area and the border zone in WT mice after myocardial infarction. The angiogenic effects of ADRC sheets were attributed to an increased expression of VEGF and bFGF mRNA in ischemic hearts. CONCLUSIONS: ADRC sheets created by this Mag-TE method protect the heart against pathological cardiac remodeling. Our ADRC sheets have the potential to be a novel regenerative strategy for ischemic heart disease. PMID- 25023794 TI - Hemodynamic causes of exercise intolerance in Fontan patients. AB - BACKGROUND: Exercise intolerance is frequent among Fontan patients and an important determinant for quality of life. This study investigated the hemodynamic causes of impaired exercise capacity in Fontan patients with particular focus on the influence of stroke volume index (SVI) and heart rate (HR). METHODS AND RESULTS: In 38 Fontan patients, peak oxygen consumption (VO2), SVI and HR were recorded during incremental load exercise test and compared with 19 age and gender matched controls. SVI (ml/m(2)) was lower in patients than controls during warm-up (28[26-31] vs. 35[30-39], p=0.0093), at submaximal (40[37 43] vs. 55[51-59], p<0.0001) and at maximal exercise (38[35-40] vs. 54[51-58], p<0.0001). Similarly, HR (% of expected maximum) was lower in patients at warm-up (45[43-48]% vs. 64[57-64]%, p<0.0001), submaximal (71[68-75]% vs 85[82-88]%, p<0.0001) and maximal exercise (84[80-88]% vs. 97[95-99]%, p<0.0001). Furthermore, SVI dropped 14% (from 44[41-48] to 38[35-40] ml/m(2)) in Fontan patients from the peak plateau to maximal exercise vs. 5% (from 57[53-61] to 54[51-58] ml/m(2)) in controls, p<0.0001. The low SVI and HR explained 67% and 20% of the difference in peak VO2 between Fontan patients and controls respectively. CONCLUSION: SVI decreased significantly in Fontan patients near the end of maximal effort exercise. The low SVI at maximal exercise was the most important hemodynamic factor limiting exercise capacity in Fontan patients, whereas chronotropic impairment had a smaller impact. The low SVI and HR at maximal exercise accounted for the difference in peak VO2 between Fontan patients and controls in this study. CLINICAL TRIAL REGISTRATION: http://www.cvk.sum.dk/CVK/Home/English.aspx (protocol nr: H-3-2010-045). PMID- 25023796 TI - Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. AB - IMPORTANCE: One in 6 American men will be diagnosed as having prostate cancer during their lifetime. Although there are no data to support the use of primary androgen-deprivation therapy (ADT) for early-stage prostate cancer, primary ADT has been widely used for localized prostate cancer, especially among older patients. OBJECTIVE: To determine the long-term survival impact of primary ADT in older men with localized (T1/T2) prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a population-based cohort study of 66,717 Medicare patients 66 years or older diagnosed from 1992 through 2009 who received no definitive local therapy within 180 days of prostate cancer diagnosis. The study was conducted in predefined US geographical areas covered by the Surveillance, Epidemiology, and End Results (SEER) Program. Instrumental variable analysis was used to assess the impact of primary ADT and control for potential biases associated with unmeasured confounding variables. The instrumental variable comprised combined health services areas with various usage rates of primary ADT. The analysis compared survival outcomes in the top tertile areas with those in the bottom tertile areas. MAIN OUTCOMES AND MEASURES: Prostate cancer-specific survival and overall survival. RESULTS: With a median follow-up of 110 months, primary ADT was not associated with improved 15-year overall or prostate cancer specific survival following the diagnosis of localized prostate cancer. Among patients with moderately differentiated cancers, the 15-year overall survival was 20.0% in areas with high primary ADT use vs 20.8% in areas with low use (difference: 95% CI, -2.2% to 0.4%), and the 15-year prostate cancer survival was 90.6% in both high- and low-use areas (difference: 95% CI, -1.1% to 1.2%). Among patients with poorly differentiated cancers, the 15-year cancer-specific survival was 78.6% in high-use areas vs 78.5%, in low-use areas (difference: 95% CI, -1.8% to 2.4%), and the 15-year overall survival was 8.6% in high-use areas vs 9.2% in low-use areas (difference: 95% CI, -1.5% to 0.4%). CONCLUSIONS AND RELEVANCE: Primary ADT is not associated with improved long-term overall or disease-specific survival for men with localized prostate cancer. Primary ADT should be used only to palliate symptoms of disease or prevent imminent symptoms associated with disease progression. PMID- 25023795 TI - H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway. AB - Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signalling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. Here we propose that HNO is generated as a result of the reaction of the two gasotransmitters NO and H2S. We show that H2S and NO production colocalizes with transient receptor potential channel A1 (TRPA1), and that HNO activates the sensory chemoreceptor channel TRPA1 via formation of amino-terminal disulphide bonds, which results in sustained calcium influx. As a consequence, CGRP is released, which induces local and systemic vasodilation. H2S-evoked vasodilatatory effects largely depend on NO production and activation of HNO TRPA1-CGRP pathway. We propose that this neuroendocrine HNO-TRPA1-CGRP signalling pathway constitutes an essential element for the control of vascular tone throughout the cardiovascular system. PMID- 25023798 TI - Effects of meloxicam administration on physiological and performance responses of transported feeder cattle. AB - This experiment evaluated the effects of meloxicam administration on physiological and performance responses of transported cattle during feedlot receiving. Eighty-four Angus * Hereford steers were ranked by BW on d -10 and assigned to 21 dry lot pens. From d -10 to 0, pens were fed alfalfa-grass hay ad libitum and 2.4 kg/steer daily (DM basis) of a corn-based concentrate. On d 0, pens were randomly assigned to 1) transport for 1,440 km in a livestock trailer and oral administration of meloxicam (1 mg/kg of BW) at loading (d 0), unloading (d 1), and daily from d 2 to 7 of feedlot receiving (MEL; n = 7); 2) the same transportation and treatment schedule of MEL but oral administration of lactose monohydrate (1 mg/kg of BW) instead of meloxicam (TRANS; n = 7); or 3) no transport and oral administration of lactose monohydrate (1 mg/kg of BW) concurrently with treatment administration to MEL and TRANS (CON; n = 7). Upon arrival (d 1), MEL and TRANS steers returned to their pens for a 21-d feedlot receiving with the same diet offered from d -10 to 0. Treatments were administered to steers via oral drench on d 0 and 1 or mixed daily with the concentrate from d 2 to 7. Full BW was recorded before (d -2, -1, and 0) treatment application and at the end of experiment (d 20, 21, and 22) for ADG calculation. Daily DMI was recorded from d 1 to 21. Blood samples were collected on d 0, 1, 3, 5, 7, 10, 14, and 21. During the initial 7 d of feedlot receiving, hay and total DMI were reduced (P <= 0.03) in TRANS vs. CON and MEL and similar between CON and MEL (P >= 0.26), whereas concentrate DMI did not differ (P = 0.16) among treatments. Mean ADG was reduced (P <= 0.03) in TRANS vs. MEL and CON but similar (P = 0.82) between MEL and CON. Moreover, TRANS had reduced G:F vs. CON (P = 0.01) and MEL (P = 0.05), whereas G:F was similar (P = 0.39) between CON and MEL. Serum NEFA concentrations were greater (P < 0.01) for TRANS and MEL vs. CON on d 1. Plasma haptoglobin concentrations were greater (P <= 0.03) for TRANS vs. CON and MEL on d 5 and greater (P <= 0.03) for CON vs. TRANS on d 10. Plasma ceruloplasmin concentrations were greater (P <= 0.04) for TRANS vs. CON on d 3, 5, 7, 10, and 14, greater (P <= 0.03) for TRANS vs. MEL on d 5 and 7, and also greater (P = 0.05) for MEL vs. CON on d 3. In conclusion, meloxicam administration to feeder steers modulated the haptoglobin and ceruloplasmin responses and prevented the performance losses caused by long-distance transportation. PMID- 25023797 TI - Delayed insemination of non-estrous heifers and cows when using conventional semen in timed artificial insemination. AB - Two experiments were designed to test the hypothesis that pregnancy rates after fixed-time artificial insemination (FTAI) in beef heifers and cows may be improved by delaying insemination of females that have not expressed estrus before FTAI. In Exp. 1, estrus was synchronized for 931 heifers across 3 locations using the 14-d CIDR-PG protocol (controlled internal drug-release [CIDR] insert [1.38 gm progesterone] on d 0 with removal of CIDR insert on d 14; 25 mg PGF2alpha 16 d after CIDR insert removal on d 30; and 100 MUg GnRH on d 33, 66 h after PGF2alpha). Estrous detection aids (Estrotect) were applied at PGF2alpha on d 30, and estrous expression was recorded at GnRH on d 33. Heifers within each location were randomly assigned to 1 of 2 treatments based on weight and reproductive tract score (RTS): 1) FTAI (concurrent with GnRH, 66 h after PGF2alpha) regardless of estrous expression or 2) FTAI for heifers expressing estrus and delayed AI (20 h after GnRH) for heifers failing to express estrus. Heifers assigned to treatment 2 achieved a higher AI pregnancy rate than heifers assigned to treatment 1 (54 versus 46%; P = 0.01). The observed increase in AI pregnancy rate is attributed to the delayed AI of non-estrous heifers in treatment 2, as AI pregnancy rates for non-estrous heifers were significantly higher for treatment 2 (49 versus 34%; P = 0.02), while AI pregnancy rates of estrous heifers did not differ by treatment (P = 0.24). In Exp. 2, estrus was synchronized for 951 mature, suckled cows across 9 locations using the 7-d CO Synch + CIDR protocol (100 MUg GnRH + CIDR insert [1.38 gm progesterone] on d 0; 25 mg PGF2alpha at CIDR insert removal on d 7; and 100 MUg GnRH on d 10, 66 h after CIDR insert removal). Estrus detection aids (Estrotect) were applied at PGF2alpha and CIDR insert removal on d 7, and estrous expression was recorded at GnRH on d 10. Cows within each location were assigned to 1 of 2 treatments based on age, days postpartum, and BCS: 1) FTAI (concurrent with GnRH, 66 h after PGF2alpha) regardless of estrous expression or 2) FTAI for cows expressing estrus and delayed AI (20 h after GnRH) for cows failing to express estrus. No significant effect of treatment was found on AI pregnancy rate (P = 0.76). In summary, FTAI pregnancy rates in heifers can be improved through a strategy of "split-time" AI. However, a statistically significant increase was not observed in the pregnancy rates of mature suckled cows when using a similar strategy. PMID- 25023799 TI - Effects of feeding dry-rolled corn-based diets with and without wet distillers grains with solubles and zilpaterol hydrochloride on performance, carcass characteristics, and heat stress in finishing beef steers. AB - Zilpaterol hydrochloride (ZH) has been approved for use since 2006; however, there is no research on any interactions between ZH and coproducts. Additionally, there is no published information on the potential effects of ZH on heat stress in feedlot cattle. Therefore, an experiment was conducted to determine the effects of feeding dry-rolled corn (DRC)-based diets with and without wet distillers grains with solubles (WDGS) and ZH on performance, carcass characteristics, and heat stress in feedlot cattle. Four hundred thirty-eight steers were used in a randomized complete block design with a 2 * 2 factorial arrangement of treatments in 16 pens with 26 to 28 steers in each pen. Factors consisted of inclusion of 0 or 30% (on a DM basis) WDGS and inclusion of ZH at 0 or 84 mg/steer daily for 21 d at the end of the finishing period. Therefore, cattle were blocked by BW and randomly assigned to 1 of the resulting 4 treatment combinations: 1) DRC-based diet with 0% WDGS and 84 mg/steer ZH, 2) DRC-based diet with 0% WDGS and no ZH, 3) DRC-based diet with 30% WDGS and 84 mg/steer of ZH, and 4) DRC-based diet with 30% WDGS and no ZH. Final live BW, carcass adjusted BW, ADG, and G:F were greater for cattle fed ZH than non-ZH-fed cattle (P < 0.01). Additionally, cattle fed ZH consumed 7.4% less DM than cattle not fed ZH (P < 0.01). Cattle fed ZH for 21 d also had a 2.9% greater HCW (P < 0.01), a 1.1% greater dressing percentage (P < 0.01), 7.3% greater LM area (P < 0.01), and an 8.4% improvement in yield grade (P < 0.01) than cattle not fed ZH. For the main effect of WDGS inclusion, ADG was greater for cattle fed 0 vs. 30% WDGS (P = 0.04) and G:F also tended to be greater for cattle fed 0 vs. 30% WDGS (P = 0.07) for the 21-d ZH feeding period. However, when evaluated over the entire experiment, cattle fed 30 vs. 0% WDGS had a greater ADG and G:F (P < 0.01). Furthermore, cattle fed 30 vs. 0% WDGS had a greater dressing percentage and tended to have a greater amount of 12th rib fat (P < 0.07). Heat stress measurements were collected during the time cattle were fed ZH, from May 31 to July 12, 2013. The slopes for change in respiration rate and panting score per day were positive but were not different across dietary treatments (P > 0.71); in addition, the slopes for change in respiration rate and panting score when accounting for environmental conditions were positive but were not different across dietary treatments (P > 0.32). PMID- 25023800 TI - Temporal dynamics in the ruminal microbiome of dairy cows during the transition period. AB - The transition period in dairy cows refers to the period from 3 wk before calving to 3 wk post-calving and is a critical time for influencing milk production and cow health. We hypothesize that the ruminal microbiome shifts as dairy cows transition from a non-lactation period into lactation due to changes in dietary regimen. The purpose of this study was to identify differences in the ruminal microbiome of primiparous and multiparous (study group) cows during the transition period. Five primiparous and 5 multiparous cows were randomly selected from a herd, and ruminal contents were sampled, via stomach tube, 4 times (study day) at 3 wk before calving date (S1), 1 to 3 d post-calving (S2), and 4 (S3) and 8 wk (S4) into lactation and were evaluated for bacterial diversity using 16S pyrotags. Both groups received the same pre-fresh diet (14.6% CP, 44.0% NDF, 21.9% starch) and 3 different lactation diets (L1, L2, and L3) varying in forage base but not amount and formulated to have similar nutrient specifications (16.8% to 17.7% CP; 32.5% to 33.6% NDF; 26.2% to 29.1% starch) post-calving. Forty bacterial communities were analyzed on the basis of annotations of 100,000 reads, resulting in 15,861 operational taxonomic units grouped into 17 bacterial phyla. The UniFrac distance metric revealed that both study group and study day had an effect on the community compositions (P < 0.05; permutational multivariate ANOVA test). The most abundant phyla observed were Bacteroidetes and Firmicutes across all the communities. As the cows transitioned into lactation, the ratio of Bacteroidetes to Firmicutes increased from 6:1 to 12:1 (P < 0.05; Mann-Whitney U test), and this ratio was greater in primiparous cows than in multiparous cows (P < 0.05). This report is the first to explore the effect of parity on dynamics in the ruminal microbiome of cows during the transition period. PMID- 25023801 TI - Influence of single nucleotide polymorphisms in the myostatin and myogenic factor 5 muscle growth-related genes on the performance traits of Marchigiana beef cattle. AB - The Marchigiana is famous for its large body size and favorable dressing percentage. A myostatin (MSTN) gene mutation (a G to T transversion) was identified in the breed. The homozygote "GG" yields a "normal" phenotype, the homozygote "TT" yields a double muscled body shape but sometimes causes survival problems, and the heterozygote genotype produces an extremely muscled body without defects. In practice, Marchigiana "TT" homozygotes are culled from reproduction, but the heterozygotes are chosen as sires. The objective of this study was to assess genes involved in Marchigiana muscle development to improve selection procedures. The effects of the MSTN and myogenic factor 5 (MYF5) genes on the growth and muscle traits in the Marchigiana breed were assessed. The effects of MSTN together with the genotype of the causative mutation (g.874G > T) and the effects of the two SNP in the promoter were studied (g.-371T > A and g. 805G > C). The SNP effects were evaluated in a comparison between the means of the several genotypes or for the average gene substitution and dominance effect. Two hundred forty-nine bullocks were evaluated using a performance test. At the beginning and end of the trial, the animals were weighed and their bodies were measured every 21 d up to 12 mo of age. In addition to these observations, morphological scores and the BLUP indices were estimated at the end of the performance test. The obtained results suggested that the MSTN g.874G > T and MYF5 SNP could be considered in the selection program of the Marchigiana breed. A MSTN g.874G > T genotyping service for the breeders could help to avoid the "TT" genotype and to select for the "GT" genotype. The "AA" MYF5 SNP genotype could also be selected for even if good muscle development yields a certain size reduction. PMID- 25023802 TI - Bill E. Kunkle Interdisciplinary Beef Symposium: Temperament and acclimation to human handling influence growth, health, and reproductive responses in Bos taurus and Bos indicus cattle. AB - Temperament in cattle is defined as the fear-related behavioral responses when exposed to human handling. Our group evaluates cattle temperament using 1) chute score on a 1 to 5 scale that increases according to excitable behavior during restraint in a squeeze chute, 2) exit velocity (speed of an animal exiting the squeeze chute), 3) exit score (dividing cattle according to exit velocity into quintiles using a 1 to 5 scale where 1=cattle in the slowest quintile and 5=cattle in the fastest quintile), and 4) temperament score (average of chute and exit scores). Subsequently, cattle are assigned a temperament type of adequate temperament (ADQ; temperament score<=3) or excitable temperament (EXC; temperament score>3). To assess the impacts of temperament on various beef production systems, our group associated these evaluation criteria with productive, reproductive, and health characteristics of Bos taurus and Bos indicus-influenced cattle. As expected, EXC cattle had greater plasma cortisol vs. ADQ cattle during handling, independent of breed type (B. indicus*B. taurus, P<0.01; B. taurus, P<0.01; B. indicus, P=0.04) or age (cows, P<0.01; heifers or steers, P<0.01). In regards to reproduction, EXC females had reduced annual pregnancy rates vs. ADQ cohorts across breed types (B. taurus, P=0.03; B. indicus, P=0.05). Moreover, B. taurus EXC cows also had decreased calving rate (P=0.04), weaning rate (P=0.09), and kilograms of calf weaned/cow exposed to breeding (P=0.08) vs. ADQ cohorts. In regards to feedlot cattle, B. indicus EXC steers had reduced ADG (P=0.02) and G:F (P=0.03) during a 109-d finishing period compared with ADQ cohorts. Bos taurus EXC cattle had reduced weaning BW (P=0.04), greater acute-phase protein response on feedlot entry (P<=0.05), impaired feedlot receiving ADG (P=0.05), and reduced carcass weight (P=0.07) vs. ADQ cohorts. Acclimating B. indicus*B. taurus or B. taurus heifers to human handling improved temperament (P<=0.02), reduced plasma cortisol (P<0.01), and hastened puberty attainment (P<=0.02). However, no benefits were observed when mature cows or feeder cattle were acclimated to human handling. In conclusion, temperament impacts productive, reproductive, and health characteristics of beef cattle independent of breed type. Hence, strategies to improve herd temperament are imperative for optimal production efficiency of beef operations based on B. taurus and B. indicus-influenced cattle. PMID- 25023803 TI - Small intestinal digestion of raw cornstarch in cattle consuming a soybean hull based diet is improved by duodenal casein infusion. AB - Six duodenally and ileally cannulated steers were used in 3 sequential studies to measure 1) basal nutrient flows from a soybean hull-based diet, 2) small intestinal digestibility of raw cornstarch continuously infused into the duodenum, and 3) responses of small intestinal starch digestion to duodenal infusion of 200 or 400 g/d casein. Our objective was to evaluate responses in small intestinal starch digestion in cattle over time and to measure responses in small intestinal starch digestion to increasing amounts of MP. On average, cattle consumed 3.7 kg/d DM, 68 g/d dietary N, and 70 g/d dietary starch. Starch flow to the duodenum was small (38 g/d), and N flow was 91 g/d. Small intestinal digestibility of duodenal N was 57%, and small intestinal digestion of duodenal starch flow was extensive (92%). Small intestinal starch digestibility was 34% when 1.5 kg/d raw cornstarch was continuously infused into the duodenum. Subsequently, cattle were placed in 1 of 2 replicated Latin squares that were balanced for carryover effects to determine response to casein infusions and time required for adaptation. Duodenal infusion of casein linearly increased (P <= 0.05) small intestinal starch digestibility, and small intestinal starch digestion adapted to infusion of casein in 6 d. Ethanol-soluble starch and unpolymerized glucose flowing to the ileum increased linearly (P <= 0.05) with increasing infusion of casein. Plasma cholecystokinin was not affected by casein infusion, but circulating levels of glucose were increased by casein supplementation (P <= 0.05). Responses in small intestinal starch digestion in cattle adapted to casein within 6 d, and increases in duodenal supply of casein up to 400 g/d increased small intestinal starch digestion in cattle. PMID- 25023804 TI - Interactions between pre- or postservice climatic factors, parity, and weaning-to first-mating interval for total number of pigs born of female pigs serviced during hot and humid or cold seasons. AB - The objective of this study was to examine interactions between climatic factors, parity, and weaning-to-first-mating interval (WMI) for total number of pigs born at subsequent parity (TPB) of female pigs serviced during 2 seasons. The present study analyzed records of 27,739 gilts and 127,670 parity records of sows in 95 Japanese herds; the records included females that were serviced between June and September (hot and humid season) or between December and March (cold season) in 2007 through 2009. The climate data were obtained from 20 weather stations located close to the studied herds. Mean daily maximum temperatures (Tmax), mean daily minimum temperatures (Tmin), and daily average relative humidity (RH) for 21 d preservice and 15 d postservice for each female were coordinated with that female's reproductive data. Linear regression models with random intercept and slopes were applied to the data. Mean TPB (+/-SEM) was 11.9 +/- 0.01 pigs. Mean values (ranges) of Tmax in the hot and humid season and Tmin in the cold season were 28.4 (13.6 to 39.8 degrees C) and 2.0 degrees C (-13.2 to 17.6 degrees C), respectively. Also, mean RH in the hot and humid season and the cold season were 73.2 (35 to 98%) and 65.2% (25 to 99%), respectively. In the hot and humid season, TPB in gilts decreased by 0.05 pigs for each degree Celsius increase in preservice Tmax (P < 0.05). However, there was no association between gilt TPB and either postservice Tmax (P = 0.11) or pre- and postservice RH (P >= 0.66). In sows, as preservice Tmax increased from 25 to 30 degrees C, TPB in parity groups 1 and 2 or higher decreased by 0.6 and 0.4 pigs, respectively (P < 0.05). Also, sow TPB decreased by 0.1 to 0.4 pigs as postservice Tmax increased from 25 to 30 degrees C (P < 0.05). In sows with WMI of 0 to 12 d, TPB decreased by 0.2 to 0.5 pigs as pre- or postservice Tmax increased from 25 to 30 degrees C (P < 0.05). However, in sows with WMI of 13 d or more, TPB was not associated with pre- or postservice Tmax (P >= 0.10). As preservice Tmax increased from 25 to 30 degrees C, TPB in sows under 81.6% RH (90th percentile) decreased by 0.5 pigs (P < 0.05), whereas TPB in sows under 65.7% RH (10th percentile) decreased by only 0.3 pigs (P < 0.05). Postservice RH in the hot and humid season was not associated with sow TPB (P = 0.18). During the cold season there was no association between TPB and pre- or postservice Tmin (P >= 0.09) or RH (P >= 0.45). Therefore, we recommend that producers apply cooling management for females during periservice in summer to increase TPB. PMID- 25023805 TI - Effects of dietary humic and butyric acid on growth performance and response to lipopolysaccharide in young pigs. AB - Humic acid (MFG) and fat-protected butyric acid (BA) has been shown to modulate energy metabolism and inflammation. Therefore, the objectives of this study were to determine the effects of MFG and BA, alone and in combination, on growth performance and response to lipopolysaccharide (LPS)-induced inflammation in young pigs. An experiment was conducted using 448 crossbred weanling pigs, which were stratified by gender and BW and were randomly assigned to 1 of 4 dietary treatments in a 2 * 2 factorial arrangement consisting of control and MFG with or without BA. The pigs were housed at a density of 8 pigs/pen and with 14 pens/dietary treatment. Growth performance and feed intake were assessed for 35 d. To assess the inflammation-related properties of MFG and BA, on d 36 a subset of 48 pigs from each treatment was intramuscular injected with either sterile saline or Escherichia coli LPS (20 MUg/kg BW; E. coli serotype O55:B5) for 4 h in a 2 * 2 * 2 factorial arrangement (+/- LPS, +/- MFG and +/- BA; n = 6 pigs/treatment group) to assess their febrile response as well as serum, liver, and muscle cytokine responses. Results from this study showed that neither BA nor MFG alone or in combination altered pig ADG, ADFI, and G:F. Moreover, in the presence of LPS, the combination of MFG and BA resulted in a 62% decrease (P = 0.08) in serum cortisol compared to when neither compound was added to the diet. In contrast, serum IGF-I was increased (P < 0.01) by 59% from the use of both MFG and BA, as opposed to when neither was added, with pigs subjected to LPS. However, both MFG and BA inclusion appear to have a complex role in modulating different aspects of the immune response to LPS, particularly when both are fed in combination. Humic acid also appeared to play a role in decreasing oxidative stress. PMID- 25023807 TI - Effects of wet corn distillers grains with solubles on visceral organ mass, trace mineral status, and polioencephalomalacia biomarkers of individually-fed cattle. AB - Twenty-four steers (initial BW = 385 +/- 1.1 kg) were blocked by BW and randomly assigned to 3 dietary treatments (0, 30, or 60% wet distillers grains with solubles [WDGS]; DM basis) and were fed individually to determine the effect of WDGS on live growth and carcass performance, visceral organ mass, trace mineral status, and polioencephalomalacia biomarkers. Steers were slaughtered at 125, 150, 164, and 192 d (2 blocks/slaughter date) when external fat depth was approximately 1.3 cm based on visual appraisal. Steers fed 30% WDGS had greater DMI than those fed 0 or 60% WDGS (P < 0.05), and steers fed 60% WDGS had the lowest carcass-adjusted ADG (P < 0.09) of the 3 treatments. Nonetheless, WDGS concentration did not alter feed efficiency (P > 0.41) on either live or carcass adjusted basis. Steers fed 30% WDGS had greater liver S and Mn concentrations (DM basis) and lower liver Fe concentrations than control steers (P < 0.10; initial values used as a covariate), and feeding 60% WDGS decreased liver Cu and increased liver Fe (P < 0.10) compared with feeding 30% WDGS. Cytochrome c oxidase (COX) activity in brain tissue tended to be decreased with 60 vs. 30% WDGS (P = 0.12), and COX activity decreased linearly (P = 0.06) in lung tissue as dietary WDGS concentration increased. Likewise, gut fill linearly increased (P = 0.01) with increasing WDGS concentration. Feeding 30% WDGS increased fractional mass (g/kg of empty BW) of the small intestine (P < 0.10) compared with controls, whereas 60% WDGS increased fractional kidney mass (P < 0.10) compared with 30% WDGS. Overall, results suggest that gut fill, Cu status, and COX activity seem to be compromised by WDGS when fed at 60% of diet DM in diets based on steam-flaked corn, which suggests a greater susceptibility to polioencephalomalacia. PMID- 25023808 TI - So nice to see you again: physician continuity and outcomes for heart failure. PMID- 25023809 TI - Differences in the clinical characteristics of ethnic minority groups with heart failure managed in specialized heart failure clinics. AB - OBJECTIVES: The purpose of our study was to compare the clinical features of Chinese and South Asians, the 2 largest minority populations in Canada, with non Chinese/non-South Asian (NCH/NSA) patients managed in common social macroenvironments and healthcare systems. BACKGROUND: Heart failure is an increasingly prevalent condition. Although ethnic minorities comprise a growing proportion of the population in Western countries, the clinical profiles of ethnic minorities with heart failure are largely unknown. METHODS: We analyzed records of patients with heart failure managed in 2 specialized clinics in Ontario, Canada. Of the 1,671 patients, 181 (11%) were identified as Chinese and 215 (13%) as South Asian. RESULTS: Our analyses showed that fewer Chinese patients were found to have a history of myocardial infarction (MI) (30% vs. 52%), 3 occluded/stenosed coronary vessels on angiogram (47% vs. 51%), grade 3 or worse left ventricular dysfunction (22% vs. 42%), and a prescription of angiotensin-converting enzyme inhibitors (42% vs. 63%) compared with their NCH/NSA counterparts. In contrast, South Asian patients more frequently had a past history of an MI (70% vs. 52%), 3 occluded/stenosed coronary vessels on angiogram (68% vs. 51%), and treatment with coronary revascularizations (55% vs. 40%) compared with NCH/NSA patients. CONCLUSIONS: Our study demonstrates important differences in comorbid conditions, clinical characteristics, and treatment patterns among Chinese and South Asian patients compared with NCH/NSA patients with heart failure. Awareness of these differences will help to develop differential strategies necessary to prevent and manage heart failure among ethnic minority groups. PMID- 25023810 TI - Heart failure in ethnic minorities: slow and steady progress. PMID- 25023811 TI - Does the UNOS heart transplant allocation system favor men over women? AB - OBJECTIVES: The aim of this paper was to identify sex differences in survival of patients awaiting orthotopic heart transplantation (OHT). BACKGROUND: Women have a higher mortality rate while awaiting OHT than men, and the reason has not been fully determined. METHODS: We included all adult patients in the Scientific Registry of Transplant Recipients (SRTR) placed on the OHT waiting list from 2000 to 2010. The primary endpoint was all-cause mortality before receiving OHT, analyzed using time-to-event analysis. Multivariate Cox proportional hazards models were used to evaluate sex differences in survival, with data stratified by United Network for Organ Sharing (UNOS) status at time of listing. RESULTS: There were 28,852 patients (24% women) awaiting OHT. This cohort included 6,163 UNOS status 1A (25% women), 9,168 UNOS status 1B (25% women), and 13,521 UNOS status 2 (24% women) patients. During a median follow-up of 3.7 years, 1,290 women and 4,286 men died. Female sex was associated with a significant risk of death among UNOS status 1A (adjusted hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.05 to 1.37, p = 0.01) after adjusting for more than 30 baseline variables. In contrast, female sex was significantly protective for time to death among UNOS status 2 patients (adjusted HR: 0.75; 95% CI: 0.67 to 0.84, p < 0.001). No sex differences were noted among UNOS status 1B patients. CONCLUSIONS: There are sex differences in survival between women and men awaiting heart transplantation, and the current UNOS transplant criteria do not account for this disparity. PMID- 25023812 TI - Body position and activity, but not heart rate, affect pump flows in patients with continuous-flow left ventricular assist devices. AB - OBJECTIVES: The aim of this study was to determine the contribution of pre-load and heart rate to pump flow in patients implanted with continuous-flow left ventricular assist devices (cfLVADs). BACKGROUND: Although it is known that cfLVAD pump flow increases with exercise, it is unclear if this increment is driven by increased heart rate, augmented intrinsic ventricular contraction, or enhanced venous return. METHODS: Two studies were performed in patients implanted with the HeartWare HVAD. In 11 patients, paced heart rate was increased to approximately 40 beats/min above baseline and then down to approximately 30 beats/min below baseline pacing rate (in pacemaker-dependent patients). Ten patients underwent tilt-table testing at 30 degrees , 60 degrees , and 80 degrees passive head-up tilt for 3 min and then for a further 3 min after ankle flexion exercise. This regimen was repeated at 20 degrees passive head-down tilt. Pump parameters, noninvasive hemodynamics, and 2-dimensional echocardiographic measures were recorded. RESULTS: Heart rate alteration by pacing did not affect LVAD flows or LV dimensions. LVAD pump flow decreased from baseline 4.9 +/- 0.6 l/min to approximately 4.5 +/- 0.5 l/min at each level of head-up tilt (p < 0.0001 analysis of variance). With active ankle flexion, LVAD flow returned to baseline. There was no significant change in flow with a 20 degrees head-down tilt with or without ankle flexion exercise. There were no suction events. CONCLUSIONS: Centrifugal cfLVAD flows are not significantly affected by changes in heart rate, but they change significantly with body position and passive filling. Previously demonstrated exercise-induced changes in pump flows may be related to altered loading conditions, rather than changes in heart rate. PMID- 25023814 TI - Functional status and outcome after coronary artery bypass grafting. PMID- 25023815 TI - Physician continuity improves outcomes for heart failure patients treated and released from the emergency department. AB - OBJECTIVES: The goal of this study was to evaluate the effect of physician continuity for patients with heart failure (HF) treated and released from the emergency department (ED). BACKGROUND: Although current guidelines recommend early follow-up after hospital discharge, it is unclear if it is beneficial in patients sent home from the ED and whether this follow-up should be with a familiar physician. METHODS: This was a retrospective cohort of all adults treated and released from 93 EDs in Alberta, Canada, from 1999 to 2009 with a first-time most responsible diagnosis of HF. Cox proportional hazards models with time-varying covariates for post-ED outpatient visits were used. RESULTS: In 12,285 patients (mean age 74.9 years), the rate of death or all-cause hospitalization at 6 months was lower in those who saw a familiar physician (37.3%; adjusted hazard ratio [aHR]: 0.89 [95% confidence interval (CI): 0.83 to 0.96]) in the first month versus those with no outpatient visits (58.1%; aHR: 1.00 [referent]) or visits only with unfamiliar physicians (40.2%; aHR: 1.04 [95% CI: 0.94 to 1.15]). Taking into account all outpatient visits over each observation period and excluding those without follow-up, death or hospitalization was less common in those patients being followed up by a familiar physician (aHR of 0.79 [95% CI: 0.71 to 0.89] at 3 months; aHR of 0.86 [95% CI: 0.77 to 0.95] at 6 months; and aHR of 0.87 [95% CI: 0.80 to 0.96] at 12 months compared with unfamiliar physician follow-up). Any follow-up within 30 days of ED release was associated with a lower risk of repeat ED visit or death at 6 months (aHR: 0.78 [95% CI: 0.73 to 0.82] for familiar physicians; aHR: 0.79 [95% CI: 0.72 to 0.86] for unfamiliar physicians). CONCLUSIONS: Early follow-up after an ED visit is associated with better outcomes, particularly if conducted with a familiar physician. PMID- 25023813 TI - Exercise capacity and mortality in patients with ischemic left ventricular dysfunction randomized to coronary artery bypass graft surgery or medical therapy: an analysis from the STICH trial (Surgical Treatment for Ischemic Heart Failure). AB - OBJECTIVES: The objective of this study was to assess the prognostic significance of exercise capacity in patients with ischemic left ventricular (LV) dysfunction eligible for coronary artery bypass graft surgery (CABG). BACKGROUND: Poor exercise capacity is associated with mortality, but it is not known how this influences the benefits and risks of CABG compared with medical therapy. METHODS: In an exploratory analysis, physical activity was assessed by questionnaire and 6 min walk test in 1,212 patients before randomization to CABG (n = 610) or medical management (n = 602) in the STICH (Surgical Treatment for Ischemic Heart Failure) trial. Mortality (n = 462) was compared by treatment allocation during 56 months (interquartile range: 48 to 68 months) of follow-up for subjects able (n = 682) and unable (n = 530) to walk 300 m in 6 min and with less (Physical Ability Score [PAS] >55, n = 749) and more (PAS <=55, n = 433) limitation by dyspnea or fatigue. RESULTS: Compared with medical therapy, mortality was lower for patients randomized to CABG who walked >=300 m (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.59 to 0.99; p = 0.038) and those with a PAS >55 (HR: 0.79; 95% CI: 0.62 to 1.01; p = 0.061). Patients unable to walk 300 m or with a PAS <=55 had higher mortality during the first 60 days with CABG (HR: 3.24; 95% CI: 1.64 to 6.83; p = 0.002) and no significant benefit from CABG during total follow-up (HR: 0.95; 95% CI: 0.75 to 1.19; p = 0.626; interaction p = 0.167). CONCLUSIONS: These observations suggest that patients with ischemic left ventricular dysfunction and poor exercise capacity have increased early risk and similar 5 year mortality with CABG compared with medical therapy, whereas those with better exercise capacity have improved survival with CABG. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595). PMID- 25023817 TI - U.S. donor heart allocation bias for men over women?: A closer look. PMID- 25023816 TI - Low bone mineral density predicts incident heart failure in men and women: the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk prospective study. AB - OBJECTIVES: It is unknown whether bone mineral density as a measure of osteoporosis is associated with development of heart failure. BACKGROUND: Recent evidence suggests shared risk factors between heart failure and osteoporosis. Additionally, patients with osteoporosis are at increased risk for cardiovascular disease. METHODS: We examined the prospective association of bone mineral density measured as broadband ultrasound attenuation by quantitative ultrasound of the heel with incident heart failure events in 13,666 apparently healthy persons 42 to 82 years of age participating in the EPIC (European Prospective Investigation into Cancer and Nutrition) study in Norfolk, United Kingdom. RESULTS: During a mean follow-up of 9.3 years, 380 incident cases of heart failure occurred. The risk of heart failure decreased with increasing bone mineral density. The hazard ratios comparing each quartile with the lowest were 0.40 (95% confidence intervals [CI]: 0.27 to 0.59), 0.54 (95% CI: 0.37 to 0.79), and 0.46 (95% CI: 0.32 to 0.68) in analysis adjusting for age, sex, smoking, alcohol consumption, physical activity, occupational social class, educational level, systolic blood pressure, diabetes, cholesterol concentration, and body mass index (p for trend = 0.002), with a 23% risk decrease associated with every increase in 1 standard deviation of bone mineral density (hazard ratio [HR]: 0.77; 95% CI: 0.66 to 0.89). The association was stronger with heart failure without (HR: 0.75; 95% CI: 0.63 to 0.89) than with antecedent myocardial infarction (HR: 0.82; 95% CI: 0.62 to 1.09). CONCLUSIONS: We observed an inverse association between bone mineral density and the risk of heart failure in apparently healthy individuals. Our findings give support for cardiac assessment in people with reduced bone mineral density and warrant further exploration of underlying biological mechanisms linking osteoporosis and heart failure. PMID- 25023818 TI - Spectrum and outcome of primary cardiomyopathies diagnosed during fetal life. AB - OBJECTIVES: The purpose of this study was to determine the phenotypic presentation, causes, and outcome of fetal cardiomyopathy (CM) and to identify early predictors of outcome. BACKGROUND: Although prenatal diagnosis is possible, there is a paucity of information about fetal CM. METHODS: This was a retrospective review of 61 consecutive fetal cases with a diagnosis of CM at a single center between 2000 and 2012. RESULTS: Nonhypertrophic CM (NHCM) was diagnosed in 40 and hypertrophic CM (HCM) in 21 fetuses at 24.7 +/- 5.7 gestational weeks. Etiologies included familial (13%), inflammatory (15%), and genetic-metabolic (28%) disorders, whereas 44% were idiopathic. The pregnancy was terminated in 13 of 61 cases (21%). Transplantation-free survival from diagnosis to 1 month and 1 year of life for actively managed patients was better in those with NHCM (n = 31; 58% and 58%, respectively) compared with those with HCM (n = 17; 35% and 18%, respectively; hazard ratio [HR]: 0.44; 95% confidence interval [CI]: 0.12 to 0.72; p = 0.007). Baseline echocardiographic variables associated with mortality in actively managed patients included ventricular septal thickness (HR: 1.21 per z-score increment; 95% CI: 1.07 to 1.36; p = 0.002), cardiothoracic area ratio (HR: 1.06 per percent increment; 95% CI: 1.02 to 1.10; p = 0.006), >=3 abnormal diastolic Doppler flow indexes (HR: 1.44; 95% CI: 1.07 to 1.95; p = 0.02), gestational age at CM diagnosis (HR: 0.91 per week increment; 95% CI: 0.83 to 0.99; p = 0.03), and, for fetuses in sinus rhythm, a lower cardiovascular profile score (HR: 1.45 per point decrease; 95% CI: 1.16 to 1.79; p = 0.001). CONCLUSIONS: Fetal CM originates from a broad spectrum of etiologies and is associated with substantial mortality. Early echocardiographic findings appear useful in predicting adverse perinatal outcomes. PMID- 25023819 TI - Factors influencing the rate of flow through continuous-flow left ventricular assist devices at rest and with exercise. PMID- 25023821 TI - Disease progression in pulmonary arterial hypertension: refining the phenotype with a prognostic biomarker profile from collagen. PMID- 25023820 TI - Circulating collagen biomarkers as indicators of disease severity in pulmonary arterial hypertension. AB - OBJECTIVES: The goal of this study was to determine if biomarkers of collagen metabolism in PAH identify patients with worse disease and higher risk of death. BACKGROUND: The relationship between circulating markers of collagen metabolism, degree of disease severity, and outcome in pulmonary arterial hypertension (PAH) is unknown. METHODS: Patients with stable idiopathic, anorexigen-associated, and hereditary PAH were prospectively enrolled. Levels of the following collagen biomarkers were measured: N-terminal pro-peptide of type III procollagen (PIIINP), C-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Patients were divided into mild, moderate, and severe PAH groups. Data were compared between tertiles of each biomarker. Pearson correlation and Spearman rank coefficient analyses were performed. Data on time to death or transplantation were examined by Kaplan-Meier survival curves. RESULTS: Circulating levels of PIIINP, CITP, MMP-9, and TIMP-1 were higher in the PAH group (n = 68) as compared with age- and sex-matched healthy controls (n = 37) (p < 0.001 for each). PIIINP levels increased with the severity of disease (p = 0.002). PIIINP tertile data indicated that with increasing levels, 6-min walk distance and cardiac index decreased, World Health Organization functional classification worsened, and resting heart rate increased. A significant correlation existed between PIIINP levels and worsening World Health Organization functional classification (rs = 0.320; p < 0.01), and there was a negative correlation between cardiac index and 6-min walk distance (r = -0.304 and r = 0.362, respectively; p < 0.05). PIIINP tertiles showed a trend toward worse outcome in patients with higher tertiles (lung transplant or death) (p = 0.07; log-rank test). CONCLUSIONS: Markers of collagen metabolism were associated with worse disease in patients with PAH. PMID- 25023823 TI - Does low bone mineral density cause a broken heart? PMID- 25023822 TI - Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis. BACKGROUND: Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD). METHODS: Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product. RESULTS: Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 +/- 0.15 ml/g/min vs. 0.88 +/- 0.23 ml/g/min; p = 0.004), stress MBF (0.85 +/- 0.29 ml/g/min vs. 1.85 +/- 0.45 ml/g/min; p < 0.0001), and CFR (1.19 +/- 0.38 vs. 2.23 +/- 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 +/- 40 ml/g/min/mm Hg vs. 70 +/- 19 ml/g/min/mm Hg; p = 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator function. CONCLUSIONS: Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis. PMID- 25023824 TI - Reliability and Validity of the NDNQI(r) Injury Falls Measure. AB - Although remarkable efforts have been made to improve patient fall reporting through the utilization of standardized definitions, injury falls reporting has rarely been examined. This study used an overall intra-class correlation coefficient (ICC) estimate and factor analysis to assess the reliability and validity of the National Database of Nursing Quality Indicators(r) (NDNQI(r)) falls with injury measure. Data were collected from an online Fall Injury Level Survey that was administered to 1,159 NDNQI site coordinators (39.7% response rate; 91% registered nurses [RNs]). Estimated overall ICC was .85. Exploratory factor analysis (EFA) with a Promax rotation (root mean square error of approximation [RMSEA] = 0.053) identified three latent factors: No Injury, Minor Injury, and Moderate/Major Injuries. Final confirmatory factor analysis (CFA) assessment (comparative fit index [CFI] = 0.914, Tucker Lewis Index [TLI] = 0.910, RMSEA = 0.048) confirmed an acceptable model fit. Results provided strong evidence that the NDNQI falls with injury measure is reliable and valid in supporting hospitals' fall prevention efforts and future injurious falls research. PMID- 25023825 TI - Simultaneous sonication assistance for the synthesis of pyrroloacridinones and its efficient catalyst HBF4 supported on uniform spherical silica nanoparticles. AB - Fluoroboric acid (HBF4) adsorbed on mesoporous silica nanoparticles of 600nm dimension was synthesized and characterized by N2 adsorption, HRTEM, EDX, XPS. The applicability of silica-HBF4 was probed through the sonication assisted synthesis of pyrroloacridinones in ecofriendly solvent ethanol. Standard leaching experiment was performed to show that the reaction was heterogeneous with this recyclable catalyst. PMID- 25023826 TI - Real-time detection of intracellular reactive oxygen species and mitochondrial membrane potential in THP-1 macrophages during ultrasonic irradiation for optimal sonodynamic therapy. AB - Reactive oxygen species (ROS) elevation and mitochondrial membrane potential (MMP) loss have been proven recently to be involved in sonodynamic therapy (SDT) induced macrophage apoptosis and necrosis. This study aims to develop an experimental system to monitor intracellular ROS and MMP in real-time during ultrasonic irradiation in order to achieve optimal effect in SDT. Cultured THP-1 derived macrophages were incubated with 5-aminolevulinic acid (ALA), and then sonicated at different intensities. Intracellular ROS elevation and MMP loss were detected in real-time by fluorospectrophotometer using fluorescence probe DCFH-DA and jc-1, respectively. Ultrasound at low intensities (less than 0.48W/cm(2)) had no influence on ROS and MMP in macrophages, whereas at an intensity of 0.48W/cm(2), ROS elevation and MMP loss were observed during ultrasonic irradiation. These effects were strongly enhanced in the presence of ALA. Quantitative analysis showed that ROS elevation and MMP loss monotonically increased with the rise of ultrasonic intensity between 0.48 and 1.16W/cm(2). SDT at 0.48 and 0.84W/cm(2) induced mainly apoptosis in THP-1 macrophages while SDT at 1.16W/cm(2) mainly cell necrosis. This study supports the validity and potential utility of real-time ROS and MMP detection as a dosimetric tool for the determination of optimal SDT. PMID- 25023827 TI - Ultrasound as pretreatment to convective drying of Andean blackberry (Rubus glaucus Benth). AB - In this study, we evaluated the use of ultrasound as a pretreatment for convective drying of Andean blackberry (Rubus glaucus Benth). For this, a Box Behnken experimental design was used to study the effect of ultrasound vibration amplitude (0-90MUm), time of sonication (10-30min) and air temperature (40-60 degrees C) on the retention of antioxidant compounds and on the kinetics of convective drying. The results showed that the antioxidant activity on fruit was reduced as the vibration amplitude and time of sonication increased, while was found that vibration amplitude ultrasound and air drying temperature were the variables that more affect the drying rate of blackberries. The drying rate increased by almost five times when samples were treated with ultrasound at 90MUm for 20min. They were then dried using air at 60 degrees C. It is concluded that the application of ultrasound in blackberry processing allows to obtain a dehydrated product with better functional quality and shows to be effective in reducing the time necessary to achieve a given value of moisture during convective drying. PMID- 25023828 TI - Application and optimization of electric field-assisted ultrasonication for disintegration of waste activated sludge using response surface methodology with a Box-Behnken design. AB - In the present study, an electric field is applied in order to disintegrate waste activated sludge (WAS). As a preliminary step, feasibility tests are investigated using different applied voltages of 10-100V for 60min. As the applied voltage increases, the disintegration degrees (DD) are gradually enhanced, and thereby the soluble N, P, and carbohydrate concentrations increase simultaneously due to the WAS decomposition. Subsequently, an optimization process is conducted using a response surface methodology with a Box-Behnken design (BBD). The total solid concentration, applied voltage, and reaction time are selected as independent variables, while the DD is selected as the response variable. The overall results demonstrate that the BBD with an experimental design can be used effectively in the optimization of the electric field treatment of WAS. In the confirmation test, a DD of 10.26+/-0.14% is recorded, which corresponds to 99.1% of the predicted response value under the statistically optimized conditions. Finally, the statistic optimization of the combined treatment (electric field+ultrasonication) demonstrated that even though this method is limited to highly disintegrated WAS when it is applied individually, a high DD of 47.28+/ 0.20% was recorded where the TS concentration was 6780mg/l, the strength of ultrasonication was 8.0W, the applied voltage was 68.4V, and the reaction time was 44min. E-SEM images clearly revealed that the application of the electric field is a significant alternative method for the combined treatment of WAS. This study was the first attempt to increase disintegration using the electric field for a combined treatment with ultrasonication. PMID- 25023830 TI - Sarcopenia risk screening tool: a new strategy for clinical practice. PMID- 25023829 TI - Characterisation of a secretory serine protease inhibitor (SjB6) from Schistosoma japonicum. AB - BACKGROUND: Proteins belonging to the serine protease inhibitor (serpin) superfamily play essential physiological roles in many organisms. In pathogens, serpins are thought to have evolved specifically to limit host immune responses by interfering with the host immune-stimulatory signals. Serpins are less well characterised in parasitic helminths, although some are thought to be involved in mechanisms associated with host immune modulation. In this study, we cloned and partially characterised a secretory serpin from Schistosoma japonicum termed SjB6, these findings provide the basis for possible functional roles. METHODS: SjB6 gene was identified through database mining of our previously published microarray data, cloned and detailed sequence and structural analysis and comparative modelling carried out using various bioinformatics and proteomics tools. Gene transcriptional profiling was determined by real-time PCR and the expression of native protein determined by immunoblotting. An immunological profile of the recombinant protein produced in insect cells was determined by ELISA. RESULTS: SjB6 contains an open reading frame of 1160 base pairs that encodes a protein of 387 amino acid residues. Detailed sequence analysis, comparative modelling and structural-based alignment revealed that SjB6 contains the essential structural motifs and consensus secondary structures typical of inhibitory serpins. The presence of an N-terminal signal sequence indicated that SjB6 is a secretory protein. Real-time data indicated that SjB6 is expressed exclusively in the intra-mammalian stage of the parasite life cycle with its highest expression levels in the egg stage (p < 0.0001). The native protein is approximately 60 kDa in size and recombinant SjB6 (rSjB6) was recognised strongly by sera from rats experimentally infected with S. japonicum. CONCLUSIONS: The significantly high expression of SjB6 in schistosome eggs, when compared to other life cycle stages, suggests a possible association with disease pathology, while the strong reactivity of sera from experimentally infected rats against rSjB6 suggests that native SjB6 is released into host tissue and induces an immune response. This study presents a comprehensive demonstration of sequence and structural-based analysis of a secretory serpin from a trematode and suggests SjB6 may be associated with important functional roles in S. japonicum, particularly in parasite modulation of the host microenvironment. PMID- 25023831 TI - Dementia and "obesity paradox": is this for real or are we missing something? An epidemiologist's perspective. PMID- 25023832 TI - Next steps for achieving person-centered care in nursing homes. PMID- 25023833 TI - The God card: spirituality in the nursing home. PMID- 25023834 TI - That was then, this is now. PMID- 25023836 TI - Have echocardiograms affected recommended therapy in geriatric trauma patients? AB - GOAL: Geriatric trauma patients tend to have worse outcomes than their younger counterparts. The American Heart Association (AHA) recommends preoperative cardiac clearance to stratify patients according to perioperative cardiac risk. The utility of this in the trauma setting remains unclear. We sought to identify the role of preoperative echocardiograms (echo) in geriatric trauma patients. METHODS: We performed a retrospective review of geriatric trauma patients who required operative intervention over a 1-year period. Patients with echocardiograms performed were compared with those who did not. RESULTS: Three hundred thirty geriatric trauma patients required an operation. A preoperative echo was performed in 25% (82/330). Abnormalities on echocardiogram were identified in 13% (11/82) of patients. One patient had a change in management based on the echo. None of the patients who died in the perioperative period had a management alteration as a result of the echo. Echo patients had a longer LOS and to operative intervention (P<.006). CONCLUSION: Echocardiograms had an exceeding low rate of management change in the acutely injured geriatric trauma patient. Further studies to evaluate the need for echocardiogram in this population are warranted. PMID- 25023837 TI - An examination of co-occurring conditions and management of psychotropic medication use in soldiers with traumatic brain injury. AB - There are approximately 1.4 million cases of traumatic brain injury (TBI) per year in the United States, with about 23 000 survivors requiring hospitalization. The incidence of TBI has increased in the patient population of the Department of Defense and Veterans Healthcare Administration as a result of injuries suffered during recent military and combat operations. Within the past few years, TBI has emerged as a common form of injury in service members with a subset of patients experiencing postinjury symptoms that greatly affect their quality of life. Traumatic brain injury can occur when sudden trauma (ie, penetration blast or blunt) causes damage to the brain. Traumatic brain injury produces a cascade of potentially injurious processes that include focal contusions and cytotoxic damage. The results of TBI can include impaired physical, cognitive, emotional, and behavioral functioning, which may or may not require the initiation of pharmacological and nonpharmacological interventions when deemed appropriate. Associated outcomes of TBI include alterations in mental state at the time of injury (confusion, disorientation, slowed thinking, and alteration of consciousness). Neurological deficits include loss of balance, praxis, aphasia, change in vision that may or may not be transient. Individuals who sustain a TBI are more likely to have or developed co-occurring conditions (ie, sleep problems, headaches, depression, anxiety, and posttraumatic stress disorder) that may require the administration of multiple medications. It has been identified that veterans being discharged on central nervous system and muscular skeletal drug classes can develop addiction and experience medication misadventures. With the severity of TBI being highly variable but typically categorized as either mild, moderate, or severe, it can assist health care providers in determining which patients are more susceptible to medication misadventures compared with others. The unique development of cognitive and emotional symptoms of TBI can lead to significant impairments, so it is important for all health care providers, including pharmacists, to promote proper use of high-risk psychotropic medications among this patient population by providing effective medication education. PMID- 25023839 TI - Burnout, compassion fatigue, compassion satisfaction, and secondary traumatic stress in trauma nurses. AB - The relationship of burnout (BO), compassion fatigue (CF), compassion satisfaction (CS), and secondary traumatic stress (STS) to personal/environmental characteristics, coping mechanisms, and exposure to traumatic events was explored in 128 trauma nurses. Of this sample, 35.9% had scores consistent with BO, 27.3% reported CF, 7% reported STS, and 78.9% had high CS scores. High BO and high CF scores predicted STS. Common characteristics correlating with BO, CF, and STS were negative coworker relationships, use of medicinals, and higher number of hours worked per shift. High CS correlated with greater strength of supports, higher participation in exercise, use of meditation, and positive coworker relationships. Caring for trauma patients may lead to BO, CF, and STS; identifying predictors of these can inform the development of interventions to mitigate or minimize BO, CF, and STS in trauma nurses. PMID- 25023840 TI - Evidence-based practice: best imaging practice in musculoskeletal disorders. AB - As musculoskeletal disorders are a common cause of emergency department visits in the United States, it is vital for nurses and nurse practitioners to understand the decision rules for ordering imaging tests when triaging patients with musculoskeletal complaints. Proper knowledge and command of selecting the most appropriate imaging for these frequent emergency department presentations will help reduce costs, decrease ionizing radiation exposure, and increase patient throughput. This article reviews the current evidence-based literature for musculoskeletal imaging in the emergency department and discusses the epidemiology, etiology, management, and prevention of the most common musculoskeletal disorders. PMID- 25023842 TI - Falls in the neurologic illness population. AB - Falls among hospital inpatients are a primary concern for all associated health care providers. Falls can result in injury to the patient and sometimes to caregivers, as well as increase health care costs through management of those injuries and potential for increased length of stay. Despite the use of fall risk assessments and fall-prevention techniques, patients continue to fall. It is possible that fall risk indicators routinely used are not capturing all of the risks, especially for unique populations, such as those with neurologic illness. The purpose of this study was to identify if other fall risk indicators would be helpful in identifying fall risk and if these new indicators are unique to the neurologic illness population. From the literature, 5 fall risk indicators that may pertain to the neurologic population were compared to the use of the Hendrich fall risk indicators. History of falls (P=.045), unilateral neglect (P=.044), communication deficits (.025), and unsteady gait (.002) were all statistically significant for being present more in the neurologic population. One measure, the use of a home assist device (P=.547), was not statistically significant as being associated with neurologic diagnosis. The use of neurologic specific indicators may be useful in identifying patients with neurologic illness at risk for falls. PMID- 25023843 TI - Ethical issues in using deception to facilitate rehabilitation for a patient with severe traumatic brain injury. AB - OBJECTIVE: To explore ethical issues in using deception to improve participation in a patient with severe traumatic brain injury who had not responded to traditional behavioral and pharmacologic approaches. DESIGN: Case study. PARTICIPANT: A male in inpatient neurorehabilitation with history of severe traumatic brain injury and significant behavioral disruption that limited his therapy participation. METHODS: Behavior modification program using principles of operant conditioning that required deception. RESULTS: Participation in therapies significantly improved and disruptive behaviors decreased. CONCLUSION: When used cautiously and with careful consideration of the ethical implications, deception may be permissible as part of an intervention strategy with this population but only as a last resort. PMID- 25023844 TI - Removing the cobwebs: one nurse's experience understanding the role of the trauma research nurse. AB - Trauma research nursing and nursing research in general are not always understood or readily embraced by clinicians in the nursing profession. A reflective journey of a trauma nurse, new to the world of trauma research, is presented with an overview of the lessons learned along the way to becoming more experienced in this role. Various aspects of the role of a trauma research nurse are discussed along with suggestions for how a nurse can potentially make the transition into and growth in this role a smooth one. PMID- 25023845 TI - Predicting factors of care burden among caregivers of assault victims of the unrest in southern border provinces of Thailand. AB - OBJECTIVE: This study aimed to investigate predictive factors of caregiver burden among caregivers of assault victims of the unrest situations in southern border provinces of Thailand. MATERIALS AND METHODS: Self-Report Questionnaire of Family Burden was used to collect the data from 100 family caregivers who cared for assault victims of the Southern unrest. The Barthel Index was used to assess the victims' capability to perform daily living activities. The Cronbach alpha coefficient of the Family Burden questionnaire was 0.96 and the correlation coefficient of the Barthel Index was 0.99. Data were analyzed using mean standard deviation and multiple linear regressions. RESULTS: The victims' capability to perform daily living activities, amount of time giving care, having secondary caregiver, and health status of the caregiver were accounted for 10.3% (R=0.103) of the variance of the caregiving burden (P=.03). The victims' capability to perform daily living activities (P=.01) and having secondary caregiver (P=.03) were significant predictors of caregiver burden. CONCLUSION: Nurses are recommended to design interventions or strategies to reduce burden among family caregivers as well as enhance victims' capability to function more independently after being assaulted during the unrest. PMID- 25023846 TI - Iron-homeostasis and obesity. PMID- 25023847 TI - Quantification of strontium in human serum by ICP-MS using alternate analyte-free matrix and its application to a pilot bioequivalence study of two strontium ranelate oral formulations in healthy Chinese subjects. AB - A rapid, sensitive and accurate ICP-MS method using alternate analyte-free matrix for calibration standards preparation and a rapid direct dilution procedure for sample preparation was developed and validated for the quantification of exogenous strontium (Sr) from the drug in human serum. Serum was prepared by direct dilution (1:29, v/v) in an acidic solution consisting of nitric acid (0.1%) and germanium (Ge) added as internal standard (IS), to obtain simple and high-throughput preparation procedure with minimized matrix effect, and good repeatability. ICP-MS analysis was performed using collision cell technology (CCT) mode. Alternate matrix method by using distilled water as an alternate analyte-free matrix for the preparation of calibration standards (CS) was used to avoid the influence of endogenous Sr in serum on the quantification. The method was validated in terms of selectivity, carry-over, matrix effects, lower limit of quantification (LLOQ), linearity, precision and accuracy, and stability. Instrumental linearity was verified in the range of 1.00-500ng/mL, corresponding to a concentration range of 0.0300-15.0MUg/mL in 50MUL sample of serum matrix and alternate matrix. Intra- and inter-day precision as relative standard deviation (RSD) were less than 8.0% and accuracy as relative error (RE) was within +/-3.0%. The method allowed a high sample throughput, and was sensitive and accurate enough for a pilot bioequivalence study in healthy male Chinese subjects following single oral administration of two strontium ranelate formulations containing 2g strontium ranelate. PMID- 25023848 TI - Chemical form of selenium differentially influences DNA repair pathways following exposure to lead nitrate. AB - Lead, an environmental toxin is known to induce a broad range of physiological and biochemical dysfunctions in humans through a number of mechanisms including the deactivation of antioxidants thus leading to generation of reactive oxygen species (ROS) and subsequent DNA damage. Selenium on the other hand has been proven to play an important role in the protection of cells from free radical damage and oxidative stress, though its effects are thought to be form and dose dependent. As the liver is the primary organ required for metabolite detoxification, HepG2 cells were chosen to assess the protective effects of various selenium compounds following exposure to the genotoxic agent lead nitrate. Initially DNA damage was quantified using a comet assay, gene expression patterns associated with DNA damage and signalling were also examined using PCR arrays and the biological pathways which were most significantly affected by selenium were identified. Interestingly, the organic type selenium compounds (selenium yeast and selenomethionine) conferred protection against lead induced DNA damage in HepG2 cells; this is evident by reduction in the quantity of DNA present in the comet tail of cells cultured in their presence with lead. This trend also followed through the gene expression changes noted in DNA damage pathways analysed. These results were in contrast with those of inorganic sodium selenite which promoted lead induced DNA damage evident in both the comet assay results and the gene expression analysis. Over all this study provided valuable insights into the effects which various selenium compounds had on the DNA damage and signalling pathway indicating the potential for using organic forms of selenium such as selenium enriched yeast to protect against DNA damaging agents. PMID- 25023849 TI - [Mantle cell lymphoma: Towards a personalized therapeutic strategy?]. AB - Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. PMID- 25023850 TI - [Clinical guidelines: old and new challenges]. PMID- 25023851 TI - [Obesity and cancer: "Dangerous friendship"]. AB - Obesity and cancer are one of the most important health problems is Spain. Between 23 and 28% of the adult population in Spain are obese, 39% are overweight and 36% have abdominal obesity. The association between obesity and type 2 diabetes mellitus, hypertension, dyslipidemia and sleep obstructive apnea is well known. On the contrary, the association between obesity and cancer is less known, because the recent evidence on it. Several prospective studies have shown during the last years the strong relationship between obesity and cancer of colon, breast in post-menopausal women, endometrial, kidney and pancreas as well as esophageal adenocarcinoma. Furthermore there is recent evidence showing that liver, gallbladder, thyroid and ovarian cancer as well as leukemia, multiple myeloma and Hodgkin lymphomas are probably associated with obesity, yet more studies are needed. A better knowledge of the relation between cancer and obesity will allow improving the prevention strategies against cancer, a more efficient early detection, and a more suitable treatment of obesity and overweight. Although the mechanisms of carcinogenesis of obesity are not well established, avoiding overweight and obesity are considered one of the best approaches to reduce the risk of cancer. Therefore the general population must be aware that cancer is one of the most important hazards associated with the current obesity epidemic in our society. PMID- 25023852 TI - [Cholangitis and bacteraemia caused by Raoultella planticola]. PMID- 25023853 TI - [Neurological manifestations of hypothermia in patients with craniopharyngioma and hypothalamic involvement]. PMID- 25023854 TI - [Systemic secondary AA amyloidosis]. PMID- 25023855 TI - Nurse Education Today: Special issue on compassionate care. PMID- 25023857 TI - Cognitive screening for dementia in primary care: a systematic review. AB - BACKGROUND: Identifying dementia in primary care could minimize the impact of a late intervention; however, it shows high rates of misdiagnosis. One of the reasons seems to be the lack of knowledge of adequate cognitive screening instruments. This is a systematic review of the available instruments for the primary care context. METHOD: For this systematic review, articles were collected according to the following combined key terms: "cognitive screening" and "dementia" and "primary care" and "review". Studies should be reviews focusing on cognitive screening instruments best used in primary care setting. RESULTS: Thirteen reviews were selected. In total, it was considered 34 cognitive screening instruments. Half of the instruments can be applied in an adequate time limit for primary care context. Memory is the most commonly assessed cognitive function (91%). Almost half of the tests are mentioned to have influence of education or cultural factors (44%). CONCLUSION: Tests such as 6CIT, AMT, GPCOG, Mini-Cog, MIS, MoCA, and STMS seem to be good alternatives to the use of the Mini Mental State Examination when considering factors such as application time, sensitivity, specificity, and number of studies. However, there is a wide range of tests with different characteristics, therefore it is recommended that the professional gets some expertise in a few number of instruments in order to be able to choose which to use, or use in combination, depending on the setting and the profile of the patient. PMID- 25023856 TI - Tyrosine oxidation in heme oxygenase: examination of long-range proton-coupled electron transfer. AB - Heme oxygenase is responsible for the degradation of a histidine-ligated ferric protoporphyrin IX (Por) to biliverdin, CO, and the free ferrous ion. Described here are studies of tyrosyl radical formation reactions that occur after oxidizing Fe(III)(Por) to Fe(IV)=O(Por(.+)) in human heme oxygenase isoform-1 (hHO-1) and the structurally homologous protein from Corynebacterium diphtheriae (cdHO). Site-directed mutagenesis on hHO-1 probes the reduction of Fe(IV)=O(Por(.+)) by tyrosine residues within 11 A of the prosthetic group. In hHO-1, Y58. is implicated as the most likely site of oxidation, based on the pH and pD dependent kinetics. The absence of solvent deuterium isotope effects in basic solutions of hHO-1 and cdHO contrasts with the behavior of these proteins in the acidic solution, suggesting that long-range proton-coupled electron transfer predominates over electron transfer. PMID- 25023858 TI - Alcohol hangover as a cause of impairment in apprehended drivers. AB - OBJECTIVE: Previous studies have already shown the possibility of impairment during a hangover phase, after alcohol ingestion, when the blood alcohol concentration has returned to zero. The prevalence of drivers being in a hangover phase, in the driving population, and the relation to impairment relevant for traffic safety has, however, not been previously studied. The aim of this study was to investigate the prevalence and the concentrations of the 2 ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), in blood, indicating very recent alcohol intake, among apprehended drivers, in which no psychoactive substances, including alcohol, were detected. The aim was also to study these findings in relation to the impairment observed in these drivers. METHODS: Blood samples, drawn from suspected drunk or drugged drivers, were analyzed for a broad repertoire of psychoactive substances, with a clinical test for impairment (CTI) being performed at the same time. One hundred and forty-six cases, in which no psychoactive substances were detected and where a valid CTI was performed, were analyzed for EtG and EtS in blood. The prevalence and concentrations were related to the conclusions of the CTIs. RESULTS: EtS and EtG were detected in a total of 19 of the 146 cases (13%). Among the "impaired" drivers, EtG and EtS were detected in 16 cases (18%), whereas among "not impaired" drivers they were detected in 3 cases (5%). There were significantly more detections of EtS (and EtG) among the impaired group of drivers compared to the nonimpaired drivers (P =.030), and the concentrations of both EtG (P =.027) and EtS (P =.026) were significantly higher in the group of impaired drivers compared to the nonimpaired drivers. There was a statistically significant positive correlation between the concentrations of EtG (Spearman's rho = 0.170, P =.041) and EtS (Spearman's rho = 0.189, P =.022) and the degree of impairment. CONCLUSIONS: EtG and EtS were prevalent findings in blood collected from the apprehended drivers, testing negative for all psychoactive substances. The higher rates of detections of EtG and EtS in impaired compared to nonimpaired drivers, and also the positive correlation between concentrations of EtG and EtS and the degree of impairment, indicate that hangover symptoms may be relevant for traffic safety. PMID- 25023859 TI - Effective diagnosis and treatment of pulmonary embolism: Improving patient outcomes. AB - Pulmonary embolism can be life threatening and difficult to diagnose as signs and symptoms are not specific. European guidelines recommend stratification of pulmonary embolism by risk of early mortality. Patients with suspected pulmonary embolism should be assessed for clinical probability of pulmonary embolism using a validated risk score. A low or intermediate clinical probability plus a negative high-sensitivity D-dimer test excludes pulmonary embolism. Anticoagulation is indicated in patients with a positive multidetector computed tomography or high-probability lung scan. An important part of the management of patients with pulmonary embolism has traditionally been anticoagulant treatment with parenteral heparins and oral vitamin K antagonists. Although effective, this dual-drug approach is associated with limitations. Direct oral anticoagulants that may overcome some of these problems have been tested in phase III clinical trials for the treatment of venous thromboembolism. Of these, rivaroxaban and apixaban have demonstrated non-inferiority to standard therapy when given as single-drug approaches for venous thromboembolism treatment, and provided significant reductions in major bleeding rates. Dabigatran and edoxaban were non inferior to standard therapy when given as part of a dual-drug approach after initial parenteral anticoagulation, and reduced clinically relevant bleeding rates. There may be a benefit to extended anticoagulation with direct oral anticoagulants for the prevention of recurrent venous thromboembolism. Registry studies will provide more information on the use of these agents in real-world populations. Accurate diagnosis and risk stratification of patients with pulmonary embolism, together with simplified anticoagulation therapy, is likely to improve outcomes. PMID- 25023860 TI - Lower urinary tract function in spinal cord-injured rats: midthoracic contusion versus transection. AB - OBJECTIVES: To compare changes in lower urinary tract (LUT) function with modifications in pathways that regulate LUT function using two different animal models (incomplete and complete) of spinal cord injury (SCI). METHODS: Female Sprague-Dawley rats were used. SCI was made at Th8/9 by a contusion injury (contusion, n=9) or a complete transection (transection, n=9). Unoperated rats were used as normal controls (normal, n=6). LUT function was evaluated by micturition behavior in metabolic cages for 24 h and cystometry in awake animals. Immunocytochemical staining at the L6 spinal cord, spinal areas associated with LUT, was performed to identify descending modulatory fibers and dorsal root afferents that project to the L6 spinal cord. RESULTS: Volume/micturition in metabolic cages gradually increased in both contusion and transection groups compared with normals, and operated groups did not differ from each other. Urodynamic parameters from cystometry were significantly different in contusion and transection groups compared with normals, but again there was no significant difference between contusion and transection groups. Immunocytochemical analyses at the L6 spinal cord showed no serotonergic or noradrenergic fibers in transection group, but some descending fibers remained in contusion group, indicating sparing. Small dorsal root afferents were denser in both contusion and transection groups than in normals, indicating sprouting. CONCLUSIONS: Although differences were not found in LUT function in operated animals, supraspinal and dorsal root projections to the L6 spinal cord responded differently to contusion and transection. This suggests that the benefits of pharmacologic treatments may be different in two lesion models. PMID- 25023861 TI - Dual energy X-ray absorptiometry of the knee in spinal cord injury: methodology and correlation with quantitative computed tomography. AB - STUDY DESIGN: Comparison of diagnostic tests; methodological validation. OBJECTIVES: Primary: to investigate the precision and reliability of a knee bone mineral density (BMD) assessment protocol that uses an existing dual energy X-ray absorptiometry (DXA) forearm acquisition algorithm in individuals with spinal cord injury (SCI). Secondary: to correlate DXA-based knee areal BMD with volumetric BMD assessments derived from quantitative computed tomography (QCT). SETTING: Academic medical center, Chicago, IL, USA. METHODS: PARTICIPANTS: a convenience sample of 12 individuals with acute SCI recruited for an observational study of bone loss and 34 individuals with chronic SCI who were screened for a longitudinal study evaluating interventions to increase BMD. MAIN OUTCOME MEASURES: Root-mean-square standard deviation (RMS-SD) and intra/inter rater reliability of areal BMD acquired at three knee regions using an existing DXA forearm acquisition algorithm; correlation of DXA-based areal BMD with QCT derived volumetric BMD. RESULTS: The RMS-SD of areal BMD at the distal femoral epiphysis, distal femoral metaphysis and proximal tibial epiphysis averaged 0.021, 0.012 and 0.016 g cm(-2), respectively, in acute SCI and 0.018, 0.02 and 0.016 g cm(-2) in chronic SCI. All estimates of intra/inter-rater reliability exceeded 97% and DXA-based areal BMD was significantly correlated with QCT derived volumetric BMD at all knee regions analyzed. CONCLUSIONS: Existing DXA forearm acquisition algorithms are sufficiently precise and reliable for short term assessments of knee BMD in individuals with SCI. Future work is necessary to quantify the reliability of this approach in longitudinal investigations and to determine its ability to predict fractures and recovery potential. SPONSORSHIP: This work was funded by the Department of Defense, grant number DOD W81XWH-10-1 0951, with partial support from Merck & Co, Inc. PMID- 25023863 TI - Movement control. AB - Movement is one of the primary signs of life. Controlled volitional movement is a high development of vertebrate life. The mechanism of controlled movement is highly complex and indeed is only partially understood. PMID- 25023862 TI - Reliability of the spine adverse events severity system (SAVES) for individuals with traumatic spinal cord injury. AB - STUDY DESIGN: Test-retest analysis. OBJECTIVES: To determine the intra- and inter rater reliability of the Spine Adverse Events Severity System for Spinal Cord Injury (SAVES-SCI) in patients with traumatic SCI. SETTING: Quaternary care spine program in Vancouver, Canada. METHODS: Ten hypothetical patient cases were developed. The cases were completed by 10 raters (seven physicians, one nurse, one physiotherapist and one researcher) who were asked to identify and grade the severity of adverse events using SAVES-SCI twice with 1-week interval. Intra- and inter-rater reliability were calculated using kappa statistics and intraclass correlation coefficients (ICC). RESULTS: Intra-rater reliability for both identifying and grading AEs were high with all AEs (kappa greater than 0.6) except for bone implant, diathermy burn, massive blood loss, myocardial infarction, neurological deterioration, pressure ulcer, return to operating room and tracheostomy requirement. The inter-rater reliability measured with ICC were all above 0.6 for identifying and grading intraoperative, pre and postoperative AEs and consequences of SCI. CONCLUSIONS: The SAVES-SCI demonstrated acceptable intra-and inter-rater reliability for a majority of the AEs. Further clarification and definition of some of the AEs as well as provision of sample training cases for clinicians would assist in reducing measurement errors. The SAVES-SCI is a useful tool to assess and capture AEs in patients with acute traumatic SCI. PMID- 25023864 TI - Peripheral nerve lesions. AB - Nerve injuries are more common in the upper limb than in the lower. The principles governing repair, however, are the same. PMID- 25023865 TI - Immediate ambulation after amputation. AB - It has long been realized that many patients who have their lower limbs amputated have a difficult and prolonged period of rehabilitation consequent upon stump difficulties. We would like to describe a scheme which eliminates, to a large degree, many of these troubles. The "immediate" walking of a patient who has had his lower limb amputated was first suggested by Professor Marian Weiss of Poland during the Ninth World Congress of the International Society for Rehabilitation of the Disabled held in Copenhagen in 1963. PMID- 25023866 TI - Occipito-maxillary traction. AB - A disadvantage of the cervical harnesses in general use is that they compress the temporomandibular joints, chin and cheeks, producing discomfort and, sometimes, pain at these sites. Patients frequently try to minimize their discomfort by tensing or by fighting against the distracting force and it would seem reasonable to entirely bypass the mandibular region as an area of purchase. PMID- 25023867 TI - Personal experiences with cervical traction. AB - The technique described here has evolved over a period of time in a busy physiotherapy practice. The results have improved so much over the last three years, that 90% of patients referred for cervical traction have been treated successfully. This success is due both to the positioning of the patient and to the use of Varitrak machines, which have made the application much easier, both from a mechanical and relaxant point of view. The positions described are the same for intermittent and fixed traction. PMID- 25023868 TI - Mechanical properties of human bone-implant interface tissue in aseptically loose hip implants. AB - The main cause of failure in total hip replacement is aseptic loosening which is associated with the formation of a periprosthetic fibrous (interface) tissue. Despite important applications for finite element modeling of loose implants, the mechanical properties of the bone-implant interface tissue have never been measured in humans. In this study, we performed unconfined compression tests to characterize the mechanical properties of the interface tissue and to determine the parameters of various hyperelastic material models which were fitted to the measurements. Human interface tissues were retrieved during 21 elective revision surgeries from aseptically loosened cemented (N=10) and uncemented hip implants (N=11). Specimens were tested at a fixed deformation rate of 0.1mm/min up to a maximum force of 10N. Elastic moduli for low and high strain regions of the stress-strain curves were determined. Interface tissue from aseptically loose cemented prostheses shows higher elastic moduli (mean=1.85MPa, 95% C.I.=1.76 1.95MPa) in the high strain region as compared to that of the interface tissue from the cementless group (mean=1.65MPa, 95% C.I.=1.43-1.88MPa). The 5-terms Mooney-Rivlin model ( [Formula: see text] ) described the stress-strain behavior the best. Large variations in the mechanical behavior were observed both between specimens from the same patient as between those of different patients. The material model parameters were therefore estimated for the mean data as well as for the curves with the highest and lowest strain at the maximum load. The model parameters found for the mean data were C1=-0.0074MPa, C2=0.0019MPa, C3=0MPa, C4= 0.0032MPa and C5=0MPa in the cemented group and C1=-0.0137MPa, C2=0.0069MPa, C3=0.0026MPa, C4=-0.0094MPa and C5=0MPa in the cementless group. The results of this study can be used in finite element computer. PMID- 25023869 TI - Risks of Infection among the Older Inflammatory Bowel Disease Patients. AB - OPINION STATEMENT: Accumulating evidence has demonstrated improved clinical outcomes with earlier initiation of immunosuppressive therapy for patients with inflammatory bowel disease (IBD). However, current evidence-based treatment paradigms are not often applied to the older IBD patients, as they represent a higher-risk group for disease and medication-associated complications, particularly infection. Serious infections, associated with increased hospitalizations, morbidity, and mortality, are more common among the older IBD patients. Although immunosuppression and advanced age are risk factors for infection, additional variables such as increasing disease activity, comorbidity, and declining functional status also play a role. Finding the optimal balance between therapeutic efficacy and safety for older IBD patients with moderate to severe disease activity poses a great challenge to the practicing clinician particularly as the therapeutic armamentarium expands to include more immunologic targets in the future to be used in combination with currently available therapies. Patient selection, looking beyond numeric age, with prompt and appropriate medication prescribing relative to disease activity and corticosteroid dependence is key to maximizing efficacy and decreasing infection related risks. Additionally, practitioners should be proactive with respect to older IBD patients with an emphasis on preventative care, including vaccinations and nutritional and functional status assessments, to address potentially modifiable risk factors for serious infection. PMID- 25023870 TI - Annotation of gene function in citrus using gene expression information and co expression networks. AB - BACKGROUND: The genus Citrus encompasses major cultivated plants such as sweet orange, mandarin, lemon and grapefruit, among the world's most economically important fruit crops. With increasing volumes of transcriptomics data available for these species, Gene Co-expression Network (GCN) analysis is a viable option for predicting gene function at a genome-wide scale. GCN analysis is based on a "guilt-by-association" principle whereby genes encoding proteins involved in similar and/or related biological processes may exhibit similar expression patterns across diverse sets of experimental conditions. While bioinformatics resources such as GCN analysis are widely available for efficient gene function prediction in model plant species including Arabidopsis, soybean and rice, in citrus these tools are not yet developed. RESULTS: We have constructed a comprehensive GCN for citrus inferred from 297 publicly available Affymetrix Genechip Citrus Genome microarray datasets, providing gene co-expression relationships at a genome-wide scale (33,000 transcripts). The comprehensive citrus GCN consists of a global GCN (condition-independent) and four condition dependent GCNs that survey the sweet orange species only, all citrus fruit tissues, all citrus leaf tissues, or stress-exposed plants. All of these GCNs are clustered using genome-wide, gene-centric (guide) and graph clustering algorithms for flexibility of gene function prediction. For each putative cluster, gene ontology (GO) enrichment and gene expression specificity analyses were performed to enhance gene function, expression and regulation pattern prediction. The guide gene approach was used to infer novel roles of genes involved in disease susceptibility and vitamin C metabolism, and graph-clustering approaches were used to investigate isoprenoid/phenylpropanoid metabolism in citrus peel, and citric acid catabolism via the GABA shunt in citrus fruit. CONCLUSIONS: Integration of citrus gene co-expression networks, functional enrichment analysis and gene expression information provide opportunities to infer gene function in citrus. We present a publicly accessible tool, Network Inference for Citrus Co Expression (NICCE, http://citrus.adelaide.edu.au/nicce/home.aspx), for the gene co-expression analysis in citrus. PMID- 25023871 TI - The association between resting heart rate and blood pressure among children and adolescents with different waist circumferences. AB - Resting heart rate (RHR) is an accessible index of sympathetic activity. The objective of this study was to assess the associations between blood pressure (BP) and RHR in children with different waist circumferences (WCs). The data of the Chinese National Survey on Students' Constitution and Health in 2010 were used. A total of 91,762 participates aged 9 to 18 years with complete records were included. RHR was categorised into quintile groups and WC was stratified into small (<-1.035), medium (>=-1.035 and <1.035) and large (>=1.035) groups respectively, after they were converted into age- and sex-specific z-score. Multivariate linear regression revealed that the association between RHR z-score and BP was similar before and after WC was adjusted for. With 1 standard deviation variation in RHR, BP changed from 2.22 (95 % confidence interval (CI): 1.51, 2.93) to 3.58 mmHg (95 % CI: 2.54, 4.62) in small WC group and 1.83 (95 % CI: 1.10, 2.56) to 4.23 mmHg (95 % CI: 3.38, 5.09) in large WC group respectively. CONCLUSIONS: This study revealed that BP was positively associated with RHR among children with different WCs, which implied the positive association between sympathetic activity and BP in children regardless of the amount of abdominal fat. PMID- 25023872 TI - RNA-seq analysis of Rubus idaeus cv. Nova: transcriptome sequencing and de novo assembly for subsequent functional genomics approaches. AB - KEY MESSAGE: Using Illumina sequencing technology, we have generated the large scale transcriptome sequencing data containing abundant information on genes involved in the metabolic pathways in R. idaeus cv. Nova fruits. Rubus idaeus (Red raspberry) is one of the important economical crops that possess numerous nutrients, micronutrients and phytochemicals with essential health benefits to human. The molecular mechanism underlying the ripening process and phytochemical biosynthesis in red raspberry is attributed to the changes in gene expression, but very limited transcriptomic and genomic information in public databases is available. To address this issue, we generated more than 51 million sequencing reads from R. idaeus cv. Nova fruit using Illumina RNA-Seq technology. After de novo assembly, we obtained 42,604 unigenes with an average length of 812 bp. At the protein level, Nova fruit transcriptome showed 77 and 68 % sequence similarities with Rubus coreanus and Fragaria versa, respectively, indicating the evolutionary relationship between them. In addition, 69 % of assembled unigenes were annotated using public databases including NCBI non-redundant, Cluster of Orthologous Groups and Gene ontology database, suggesting that our transcriptome dataset provides a valuable resource for investigating metabolic processes in red raspberry. To analyze the relationship between several novel transcripts and the amounts of metabolites such as gamma-aminobutyric acid and anthocyanins, real time PCR and target metabolite analysis were performed on two different ripening stages of Nova. This is the first attempt using Illumina sequencing platform for RNA sequencing and de novo assembly of Nova fruit without reference genome. Our data provide the most comprehensive transcriptome resource available for Rubus fruits, and will be useful for understanding the ripening process and for breeding R. idaeus cultivars with improved fruit quality. PMID- 25023873 TI - Transcriptomic analysis of floral initiation in litchi (Litchi chinensis Sonn.) based on de novo RNA sequencing. AB - KEY MESSAGE: Comparative transcriptome analysis of litchi ( Litchi chinensis Sonn.) buds at two developmental stages revealed multiple processes involving various phytohormones regulating floral initiation, and expression of numerous flowering-related genes. Floral initiation is a critical and complicated plant developmental process involving interactions of numerous endogenous and environmental factors, but little is known about the complex network regulating floral initiation in litchi (Litchi chinensis Sonn.). Illumina second-generation sequencing is an efficient method for obtaining massive transcriptional information resulting from phase changes in plant development. In this study, comparative transcriptomic analysis was performed with resting and emerging panicle stage buds, to gain further understanding of the molecular mechanisms involved in floral initiation in litchi. Abundance analysis identified 5,928 unigenes exhibiting at least twofold differences in expression between the two bud stages. Of these, 4,622 unigenes were up-regulated and 1,306 were down regulated in panicle-emerging buds compared with resting buds. KEGG pathway enrichment analysis revealed that unigenes exhibiting differential expression were involved in the metabolism and signal transduction of various phytohormones. The expression levels of unigenes annotated as auxin, cytokinin, jasmonic acid, and salicylic acid biosynthesis were up-regulated, whereas those unigenes annotated as abscisic acid biosynthesis were down-regulated during floral initiation. In addition, 188 unigenes exhibiting sequence similarities to known flowering-related genes from other plants were differentially expressed during floral initiation. Thirteen genes were selected for confirmation of expression levels using quantitative-PCR. Our results provide abundant sequence resources for studying mechanisms underlying floral initiation in litchi and establish a platform for further studies of litchi and other evergreen fruit trees. PMID- 25023874 TI - Protein accumulation in aleurone cells, sub-aleurone cells and the center starch endosperm of cereals. AB - There are mainly three endosperm storage tissues in the cereal endosperm: aleurone cells, sub-aleurone cells and the center starch endosperm. The protein accumulation is very different in the three endosperm storage tissues. The aleurone cells accumulate protein in aleurone granules. The sub-aleurone cells and the center starch endosperm accumulate protein in endoplasmic reticulum derived protein bodies and vacuolar protein bodies. Proteins are deposited in different patterns within different endosperm storage tissues probably because of the special storage properties of these tissues. There are several special genes and other molecular factors to mediate the protein accumulation in these tissues. Different proteins have distinct functions in the protein body formation and the protein interactions determine protein body assembly. There are both cooperation and competition relationships between protein, starch and lipid in the cereal endosperm. This paper reviews the latest investigations on protein accumulation in aleurone cells, sub-aleurone cells and the center starch endosperm. Useful information will be supplied for future investigations on the cereal endosperm development. PMID- 25023876 TI - Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma. AB - Approximately 10 % of all cutaneous melanoma cases occur in a familial context. The major susceptibility gene for familial melanoma is CDKN2A. In Latin America, genetic studies investigating melanoma predisposition are scarce. The aim of this work was to investigate germline CDKN2A point mutations and genomic rearrangements in a cohort of 59 Brazilian melanoma-prone patients. Screening of CDKN2A alterations was performed by sequencing and multiplex ligation probe amplification. Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions. Although this study adds to the literature on melanoma susceptibility in Latin America, it is limited by the small size of the cohort. Our findings suggest that stringent inclusion criteria led to a substantially increased rate of CDKN2A mutation detection. This consideration should be taken into account when referring patients for genetic screening in a setting of limited budget, such as in developing countries. PMID- 25023877 TI - What Symbionts Teach us about Modularity. AB - The main goal of Synthetic Biology (SB) is to apply engineering principles to biotechnology in order to make life easier to engineer. These engineering principles include modularity: decoupling of complex systems into smaller, orthogonal sub-systems that can be used in a range of different applications. The successful use of modules in engineering is expected to be reproduced in synthetic biological systems. But the difficulties experienced up to date with SB approaches question the short-term feasibility of designing life. Considering the "engineerable" nature of life, here we discuss the existence of modularity in natural living systems, particularly in symbiotic interactions, and compare the behavior of such systems, with those of engineered modules. We conclude that not only is modularity present but it is also common among living structures, and that symbioses are a new example of module-like sub-systems having high similarity with modularly designed ones. However, we also detect and stress fundamental differences between man-made and biological modules. Both similarities and differences should be taken into account in order to adapt SB design to biological laws. PMID- 25023875 TI - Plant chitinase responses to different metal-type stresses reveal specificity. AB - KEY MESSAGE: Chitinases in Glycine max roots specifically respond to different metal types and reveal a polymorphism that coincides with sensitivity to metal toxicity. Plants evolved various defense mechanisms to cope with metal toxicity. Chitinases (EC 3.2.1.14), belonging to so-called pathogenesis-related proteins, act as possible second line defense compounds in plants exposed to metals. In this work their activity was studied and compared in two selected soybean (Glycine max L.) cultivars, the metal-tolerant cv. Chernyatka and the sensitive cv. Kyivska 98. Roots were exposed to different metal(loid)s such as cadmium, arsenic and aluminum that are expected to cause toxicity in different ways. For comparison, a non-metal, NaCl, was applied as well. The results showed that the sensitivity of roots to different stressors coincides with the responsiveness of chitinases in total protein extracts. Moreover, detailed analyses of acidic and neutral proteins identified one polymorphic chitinase isoform that distinguishes between the two cultivars studied. This isoform was stress responsive and thus could reflect the evolutionary adaptation of soybean to environmental cues. Activities of the individual chitinases were dependent on metal type as well as the cultivar pointing to their more complex role in plant defense during this type of stress. PMID- 25023878 TI - Facile synthesis of block copolymers by tandem ROMP and eROP from esters precursors. AB - In the present study, block copolymers were first synthesized through a tandem ring-opening metathesis polymerization (ROMP) and conventional enzymatic ring opening polymerization (eROP) from hydroxyl initiator. Furthermore, a novel synthesis route, single-step eROP from ester precursor was successfully developed to synthesize targeted copolymers. The as-prepared polymers were analyzed by NMR, GPC, DSC, and MALDI-TOF-MS. There was no difference in the characteristic peaks of NMR between the end products obtained from these two synthetic routes. The GPC data showed that the copolymer obtained from single-step eROP was similar to the end product obtained from the traditional multistep synthesis method. Afterward, we used model compounds to carry out the conventional eROP and the single-step eROP. Finally, through the kinetic analysis and structural analysis of the resulting product, a reasonable initiation mechanism for this single-step eROP was elucidated. PMID- 25023880 TI - Hepatoid tenosynovial giant cell tumor - a rare morphologic variant case report. AB - We report a morphologically rare type of tenosynovial giant cell tumor (TSGCT), localized type, occurring in a 49-year-old man. Imaging examination revealed multiple nodular lesions around the right knee joint. The largest one extended to both intra- and extra-osseous region of the right distal femur. Histologically, the tumor consisted of epithelioid mononuclear cells and they looked like to have abundant eosinophilic cytoplasm reminiscent of hepatic tissues. In some areas, however, typical histologic features of TSGCT were observed. Electron microscopy revealed that the eosinophilic cytoplasm-like substance was intercellular fibrinous material surrounding the mononuclear tumor cells. Immunohistochemically, mononuclear tumor cells and multinucleate giant cells were positive for CD68 (Kp1) and some of the mononuclear tumor cells were also positive for desmin. Finally, we made the diagnosis of hepatoid TSGCT. PMID- 25023881 TI - Toxopathological and cytogenetic effects of aflatoxin B1 (AFB1) on pregnant rats. AB - The present study was carried out to evaluate the toxopathological effects and macro-DNA damage of Aflatoxin B1 (AFB1) in pregnant rats at a dose of 1mg/kg. body wt., given from 6th to 15th day of gestation. The effects and damage are represented by histopathological changes and different types of chromosomal aberrations in dams, in addition to teratogenic changes in the feti. Pregnant dams revealed a significant decrease in their body weights and gross enlargement of the liver. Histologically, the liver showed necrotic areas and congested central vein. The kidneys revealed interstitial hemorrhages, renal casts, degeneration and necrosis. The lungs revealed lymphocytic infiltrates in the interstitial tissue, while the spleen revealed lymphoid depletion. Chromosomal analysis revealed both structural and numerical chromosomal aberration, including centromeric attenuations, chromatid gaps, chromatid breaks, end-to-end associations, fragments, ring chromosomes, deletions, dicentric chromosomes, chromosomal fusions, centric fusions, stickness and hypoployploidy. Centromeric attenuations and end-to-end associations were more frequent than other chromosomal aberrations. Concerning the teratogenic effects in the fetuses, the toxin induced multiple skeletal anomalies. These anomalies included incomplete ossification of skull bones and failure of ossification of long and flat bones. PMID- 25023882 TI - Positive and negative effects of glitazones in carcinogenesis: experimental models vs. clinical practice. AB - Diabetes increases cancer risk, which may be modulated by careful choice of treatment. Experimental reports showed efficacy of glitazones in various in vitro and in vivo models of carcinogenesis, but procarcinogenic effects in some models were reported too, and, similarly, data on cancer incidence in glitazone users are inconsistent. This review summarizes oncostatic effects of glitazones in preclinical and clinical studies and brings a brief summary of their impact on cancer risk in diabetic patients, with a focus on the association between pioglitazone use and bladder cancer. PMID- 25023883 TI - Subjective social status and health. AB - PURPOSE OF REVIEW: Subjective social status (SSS) predicts health outcomes above and beyond traditional objective measures of social status, such as education, income and occupation. This review summarizes and integrates recent findings on SSS and health. RECENT FINDINGS: Current studies corroborate associations between low SSS and poor health indicators by extending previous findings to further populations and biological risk factors, providing meta-analytic evidence for adolescents and by demonstrating that negative affect may not confound associations between SSS and self-rated health. Recent findings also highlight the relevance of SSS changes (e.g. SSS loss in immigrants) and the need to consider cultural/ethnical differences in psychological mediators and associations between SSS and health. SUMMARY: SSS is a comprehensive measure of one's social position that is related to several poor health outcomes and risk factors for disease. Future investigation, particularly prospective studies, should extend research on SSS and health to further countries/ethnic groups, also considering additional psychological and biological mediators and dynamic aspects of SSS. Recently developed experimental approaches to manipulate SSS may also be promising. PMID- 25023884 TI - When time stands still: an integrative review on the role of chronodisruption in posttraumatic stress disorder. AB - PURPOSE OF REVIEW: The human circadian system creates and maintains cellular and systemic rhythmicity essential to homeostasis. Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune and autonomic system, similar to chronic stress and, thus, may play a central role in the development of stress related disorders. This article focuses on the role of circadian misalignment in the pathophysiology of posttraumatic stress disorder (PTSD). RECENT FINDINGS: Sleep disruption is a core feature of PTSD supporting the important supraordinate pathophysiological role of circadian system in PTSD. Furthermore, direct and indirect human and animal PTSD research suggests circadian system linked neuroendocrine, immune, metabolic and autonomic dysregulation with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as endocannabinoid and neuropeptide Y system alterations and altered circadian gene expression, linking circadian misalignment to PTSD pathophysiology. SUMMARY: PTSD development is associated with chronodisruption findings. Evaluation and treatment of sleep and circadian disruption should be the first steps in PTSD management. State-of-the-art methods of circadian rhythm assessment should be applied to bridge the gap between clinical significance and limited understanding of the relationship between traumatic stress, sleep and circadian system. PMID- 25023885 TI - The future of somatoform disorders: somatic symptom disorder, bodily distress disorder or functional syndromes? PMID- 25023886 TI - Real-time functional MRI neurofeedback: a tool for psychiatry. AB - PURPOSE OF REVIEW: The aim of this review is to provide a critical overview of recent research in the field of neuroscientific and clinical application of real time functional MRI neurofeedback (rtfMRI-nf). RECENT FINDINGS: RtfMRI-nf allows self-regulating activity in circumscribed brain areas and brain systems. Furthermore, the learned regulation of brain activity has an influence on specific behaviors organized by the regulated brain regions. Patients with mental disorders show abnormal activity in certain regions, and simultaneous control of these regions using rtfMRI-nf may affect the symptoms of related behavioral disorders. SUMMARY: The promising results in clinical application indicate that rtfMRI-nf and other metabolic neurofeedback, such as near-infrared spectroscopy, might become a potential therapeutic tool. Further research is still required to examine whether rtfMRI-nf is a useful tool for psychiatry because there is still lack of knowledge about the neural function of certain brain systems and about neuronal markers for specific mental illnesses. PMID- 25023887 TI - Coping with infertility: a transcultural perspective. AB - PURPOSE OF REVIEW: To review the most important and interesting articles in infertility published in the last year. RECENT FINDINGS: This systematic review covers 60 studies published in journals or dissertations in Science Direct and PubMed in the last year, including those related to prevention and treatment as well as related psychosocial services in infertility. We also propose some suggestions about coping with infertility in China. SUMMARY: Infertility is a multidisciplinary problem that requires medical, social, and political efforts to prevent and offer infertile patients the best diagnostic, therapeutic, and psychosocial services. Cultural factors should be taken into consideration when designing coping strategies. PMID- 25023888 TI - GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. AB - Mood disorder patients that are on long-term atypical antipsychotics treatment frequently experience metabolic dysfunctions. In addition to this, accumulating evidences points to increased risk of structural abnormalities, brain volume changes, altered neuroplasticity and behavioral depression with long-term antipsychotics use. However, there is paucity of preclinical evidences for long term antipsychotic associated depression-like behavior. The objectives of the present study were: (1) to evaluate influence of long-term antipsychotic (olanzapine) treatment on rat behavior in forced swim test (FST) as a model for depression and; (2) to examine impact of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide - an antidiabetic medication for type II diabetes, on long term olanzapine associated metabolic and behavioral changes in rats. Daily olanzapine treatment (0.5 mg/kg; p.o.) for 8-9 weeks significantly increased body weights, food and water intake, plasma cholesterol and triglycerides and immobility time in FST with parallel reduction in plasma HDL cholesterol levels. These results points to development of metabolic abnormalities and depression like behavior with long-term olanzapine treatment. Acute liraglutide (50 MUg/kg; i.p.) and imipramine (10 mg/kg, i. p.) treatment per se significantly decreased duration of immobility in FST compared to vehicle treated rats. Additionally, 3 week liraglutide treatment (50 MUg/kg; i.p., daily) partially reversed metabolic abnormalities and depression-like behavior with long-term olanzapine-treatment in rats. None of these treatment regimens affected locomotor behavior of rats. In summary, add-on GLP-1 receptor agonists promise novel alternatives to counteract long-term antipsychotics associated behavioral and metabolic complications. PMID- 25023889 TI - Cost-effectiveness of programs to eliminate disparities in elderly vaccination rates in the United States. AB - BACKGROUND: There are disparities in influenza and pneumococcal vaccination rates among elderly minority groups and little guidance as to which intervention or combination of interventions to eliminate these disparities is likely to be most cost-effective. Here, we evaluate the cost-effectiveness of four hypothetical vaccination programs designed to eliminate disparities in elderly vaccination rates and differing in the number of interventions. METHODS: We developed a Markov model in which we assumed a healthcare system perspective, 10-year vaccination program and lifetime time horizon. The cohort was the combined African-American and Hispanic 65 year-old birth cohort in the United States in 2009. We evaluated five different vaccination strategies: no vaccination program and four vaccination programs that varied from "low intensity" to "very high intensity" based on the number of interventions deployed in each program, their cumulative cost and their cumulative impact on elderly minority influenza and pneumococcal vaccination rates. RESULTS: The very high intensity vaccination program ($24,479/quality-adjusted life year; QALY) was preferred at willingness to-pay-thresholds of $50,000 and $100,000/QALY and prevented 37,178 influenza cases, 342 influenza deaths, 1,158 invasive pneumococcal disease (IPD) cases and 174 IPD deaths over the birth cohort's lifetime. In one-way sensitivity analyses, the very high intensity program only became cost-prohibitive (>$100,000/QALY) at less likely values for the influenza vaccination rates achieved in year 10 of the high intensity (>73.5%) or very high intensity (<76.8%) vaccination programs. CONCLUSIONS: A practice-based vaccination program designed to eliminate disparities in elderly minority vaccination rates and including four interventions would be cost-effective. PMID- 25023890 TI - Oocytes recovered after ovarian tissue slow freezing have impaired H2AX phosphorylation and functional competence. AB - It has been shown that oocytes isolated from ovarian tissue cryopreservation acquire DNA damage during the process of freeze-thawing. Using a mouse model, here we have investigated the functional competence and phosphorylation of H2AX (gamma-H2AX) in germinal vesicle (GV) and parthenogenetically activated oocytes derived from conventional ovarian tissue slow freezing and vitrification techniques. The number of GV-stage oocytes with gamma-H2AX foci was not significantly different between the slow-freezing and vitrification groups. Although the in vitro maturation (IVM) potential of GV oocytes in the slow freezing group showed a significant delay (P<0.0001) in the process of germinal vesicle breakdown, no difference in the maturation rate was observed between the two protocols. Nevertheless, parthenogenetic activation of IVM oocytes using strontium chloride showed a significantly lower activation rate in the slow freezing group compared with the vitrification (P<0.05) and control (P<0.01) groups. Importantly, H2AX phosphorylation was significantly perturbed in the slow freezing group in comparison to the control (P<0.05). Therefore, we conclude that impaired sensing of DNA strand breaks and repair processes are associated with the reduced functional competence of the oocytes recovered from the slow-freezing group, which may have a significant impact on the reproductive outcome. PMID- 25023891 TI - A two-stage search of visual working memory: investigating speed in the change detection paradigm. AB - A popular procedure for investigating working memory processes has been the visual change-detection procedure. Models of performance based on that procedure, however, tend to be based on performance accuracy and treat working memory search as a one-step process, in which memory representations are compared to a test probe to determine if a match is present. To gain a clearer understanding of how search of these representations operate in the change-detection task, we examined reaction time in two experiments, with a single-item probe either located centrally or at the location of an array item. Contrary to current models of visual working memory capacity, our data point to a two-stage search process: a fast first step to check for the novelty of the probe and, in the absence of such novelty, a second, slower step to search exhaustively for a match between the test probe and a memory representation. In addition to these results, we found that participants tended not to use location information provided by the probe that theoretically could have abbreviated the search process. We suggest some basic revisions of current models of processing in this type of visual working memory task. PMID- 25023892 TI - Extracting the parameters of the double-dispersion Cole bioimpedance model from magnitude response measurements. AB - In the field of bioimpedance measurements, the Cole impedance model is widely used for characterizing biological tissues and biochemical materials. In this work, a nonlinear least squares fitting is applied to extract the double dispersion Cole impedance parameters from simulated magnitude response datasets without requiring the direct impedance data or phase information. The technique is applied to extract the impedance parameters from MATLAB simulated noisy magnitude datasets showing less than 1.2 % relative error when 60 dB SNR Gaussian white noise is present. This extraction is verified experimentally using apples as the Cole impedances showing less than 3 % relative error between simulated responses (using the extracted impedance parameters) and the experimental results over the entire dataset. PMID- 25023893 TI - Hiding message into DNA sequence through DNA coding and chaotic maps. AB - The paper proposes an improved reversible substitution method to hide data into deoxyribonucleic acid (DNA) sequence, and four measures have been taken to enhance the robustness and enlarge the hiding capacity, such as encode the secret message by DNA coding, encrypt it by pseudo-random sequence, generate the relative hiding locations by piecewise linear chaotic map, and embed the encoded and encrypted message into a randomly selected DNA sequence using the complementary rule. The key space and the hiding capacity are analyzed. Experimental results indicate that the proposed method has a better performance compared with the competing methods with respect to robustness and capacity. PMID- 25023894 TI - Predictors of use of evidence-based practices for children and adolescents in usual care. AB - Practice data from 74 therapists providing public mental health services to 519 youth ages 5-19 were examined. Multilevel modeling suggested child and therapist characteristics predicted use of practices derived from the evidence-base (PDEB) and use of practices with minimal evidence support (PMES). Longer episode length predicted greater receipt of PDEB; older youth, males, and youth in out-of-home levels of care were more likely to receive PMES; and youth receiving an evidence based treatment program were less likely to receive PMES. Professional specialty and theoretical orientation significantly predicted PDEB whereas therapist characteristics did not predict PMES. Implementation implications are discussed. PMID- 25023895 TI - Effects of silencing connexin43 on expression of pituitary tumor-transforming gene in prolactinomas. AB - OBJECTIVES: Pituitary tumor transforming gene (PTTG) is thought to play an important role in prolactinomas, and its overexpression is influenced by estrogen action in the pituitary. Changes in estrogen levels in the rat anterior pituitary increase the number of gap junctions (GJs) increasing both Connexin43 (Cx43) expression and intercellular communication, contributing to pituitary tumor growth. The aim of this study was to investigate the effect of Cx43 on PTTG expression by silencing Cx43 expression using RNA interference (RNAi) in vivo. METHODS: An experimental rat model of prolactinoma induced by estradiol (E2) treatment was used. Connexin43 RNAi was applied in vivo through the arachnoid space by injection of double-stranded RNA (dsRNA). Pituitary Cx43 immunostaining was examined using immunofluorescence and Cx43 and PTTG expression by both reverse-transcription-PCR (RT-PCR) and western blotting, respectively. RESULTS: (1) Pituitaries treated with E2 were hypertrophic, but this was reduced by dsRNA treatment. (2) Pituitary Cx43 immunofluorescence increased following E2 treatment, but returned to normal levels following dsRNA treatment. (3) Estradiol induced Cx43 and PTTG expression, which decreased following dsRNA treatment. DISCUSSION: Altered Cx43 expression modulates PTTG expression, which correlates with prolactinoma development. Thus, inhibiting gap junction intercellular communication (GJIC) as a means of weakening the pathologic role PTTG in prolactinomas may be of therapeutic interest. PMID- 25023896 TI - TAT-mediated delivery of neuroglobin attenuates apoptosis induced by oxygen glucose deprivation via the Jak2/Stat3 pathway in vitro. AB - OBJECTIVES: Neuroglobin (Ngb), an identified globin in vertebrate brain, is a potential novel protective protein against brain ischemia. In our previous study, the human immunodeficiency virus trans-activator of transcription (TAT) protein transduction domain successfully delivered exogenous Ngb into neurons in the mouse, and protected the brain from cerebral ischemia-induced apoptosis. The aim of this study is to investigate the role of TAT-Ngb in attenuating oxygen-glucose deprivation (OGD) induced apoptosis and to explore the possible mechanism. METHODS: Nerve growth factor (NGF)-induced PC12 cells were divided into (1) the control group, (2) the OGD group (just OGD), (3) the Ngb treatment group (OGD and Ngb treatment), and (4) the TAT-Ngb treatment group (OGD and TAT-Ngb treatment). Cell viability and apoptosis were assessed by the MTT assay and the AnnexinV/propidium iodide (PI) staining, respectively. The mitochondrial transmembrane potential was measured by JC-1 staining. Caspase-3, Bcl-2, Bax, Stat3, Jak2, and Akt were determined by western blot analysis. RESULTS: Trans activator of transcription effectively delivered Ngb into NGF-induced PC12 cells. Neuroglobin-mediated neuroprotection rescued cultured cells from OGD. We also confirmed previous findings that TAT-Ngb inhibited mitochondrial apoptosis following OGD. Inhibition of apoptosis by Ac-DEVD-CHO showed that caspase-3 was a crucial factor in OGD-induced apoptosis cascades. AG490, a specific Jak2 inhibitor, attenuated the protective effects of TAT-Ngb. The TAT-Ngb promoted expression of the anti-apoptotic protein Bcl-2 through the Jak2/Stat3 signal pathway, and inhibited apoptosis by blocking caspase-3 activation, while the Jak Akt-Stat3 signal network was not involved. CONCLUSION: Our results demonstrate that TAT-Ngb can protect neuron-like cells against OGD-induced apoptosis by activating the Jak2/Stat3 pathway. PMID- 25023897 TI - Total synthesis of the cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole. AB - The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate. PMID- 25023898 TI - The mutation profile of JAK2 and CALR in Chinese Han patients with Philadelphia chromosome-negative myeloproliferative neoplasms. AB - Mutations in JAK2, MPL and CALR are highly relevant to the Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs). We performed high resolution melting analysis and Sanger sequencing together with T-A cloning to elucidate the unique mutation profile of these genes, in Chinese patients with MPNs. Peripheral blood DNA samples were obtained from 80 patients with polycythemia vera (PV), 80 patients with essential thrombocytosis (ET) and 50 patients with primary myelofibrosis (PMF). Ten PV patients were identified with diverse JAK2 exon 12 mutations. Five novel JAK2 Exon 12 mutation patterns (M532V/E543G, N533D, M535I/H538Y/K549I, E543G and D544N) were described. JAK2 V617F was detected in 140 samples (66 PV, 45 ET and 29 PMF). JAK2 Exon 12 mutations were prevalent (13%) and variable in the Chinese patients. Compared with PV patients with JAK2 V617F mutations, PV patients with JAK2 exon 12 mutations had an earlier median onset of disease (P = 0.0013). MPL W515L/K mutations were discerned in 4 ET and 3 PMF patients. Two kinds of CALR mutation, c. 1179_1230del and c. 1234_1235insTTGTC were detected in 20 ET and 16 PMF patients. A novel CALR mutation pattern (c. 1173_1223del/c. 1179_1230del) was identified in 2 PMF samples. In addition, 17 scattered point mutations in CALR c.1153 to c.1255 were also detected in 13 cases with CALR frame-shifting variations and 2 cases without CALR frame-shifting variations. Female patients showed a predisposition to CALR mutations (P = 0.0035). Chinese Ph-negative MPN patients have a unique mutation landscape in the common molecular markers of MPN diagnosis. Validation of the molecular diagnostic pipeline should be emphasized since there is a considerable ethnical diversity in the molecular profiles of Ph negative MPNs. PMID- 25023899 TI - The natural history of chronic urticaria in childhood: a prospective study. AB - BACKGROUND: There are few prospective studies on the natural course of chronic urticaria (CU) in children. OBJECTIVE: We sought to examine the natural history of CU in children and to identify predictors for remission. METHODS: Children 4 to 15 years of age with CU were investigated with a complete blood cell count, erythrocyte sedimentation rate, antinuclear antibody titer, complement CH50 level, thyroid studies, autologous serum skin test, skin-prick tests, food challenges, and stool examination for parasites. They were considered to be in remission if symptoms did not recur for at least 12 months without medication. RESULTS: In all, 92 children (53.3% female) with CU were recruited and followed up for a median duration of 4.3 years (range 2.5-5.8 years). Chronic autoimmune urticaria (CAU) was identified in 40% of the patients. Food allergy was found in 8.7% and parasitic infestations in 5.4%. Remission rates at 1, 3, and 5 years after the onset of CU symptoms were 18.5%, 54%, and 67.7%, respectively. The remission rate did not differ in CAU compared with non-CAU. No predictor of CU remission was identified. LIMITATIONS: The basophil histamine release assay was not performed. CONCLUSION: Children with CU have a favorable outcome. CAU did not have an intractable course. PMID- 25023902 TI - Enhanced electrocatalytic oxidation of isoniazid at electrochemically modified rhodium electrode for biological and pharmaceutical analysis. AB - A simple and sensitive electrochemical method has been proposed for the determination of isoniazid (INZ). For the first time, rhodium (Rh) modified glassy carbon electrode (GCE) has been employed for the determination of INZ by linear sweep voltammetry technique (LSV). Compared with the unmodified electrode, the proposed Rh modified electrode provides strong electrocatalytic activity toward INZ with significant enhancement in the anodic peak current. Scanning electron microscopy (SEM) and field emission scanning electron microscopy (FESEM) results reveal the morphology of Rh particles. With the advantages of wide linearity (70-1300MUM), good sensitivity (0.139MUAMUM(-1)cm(-2)) and low detection limit (13MUM), this proposed sensor holds great potential for the determination of INZ in real samples. The practicality of the proposed electrode for the detection of INZ in human urine and blood plasma samples has been successfully demonstrated using LSV technique. Through the determination of INZ in commercially available pharmaceutical tablets, the practical applicability of the proposed method has been validated. The recovery results are found to be in good agreement with the labeled amounts of INZ in tablets, thus showing its great potential for use in clinical and pharmaceutical analysis. PMID- 25023903 TI - Tunable pDNA/DODAB:MO lipoplexes: the effect of incubation temperature on pDNA/DODAB:MO lipoplexes structure and transfection efficiency. AB - Dioctadecyldimethylammonium bromide (DODAB):1-monooleoyl-rac-glycerol (MO) cationic liposomes were reported as a promising alternative to common transfection agents, showing superior effectiveness on the transfection of the 293T mammalian cell line with pSV-beta-gal plasmid DNA. The study of DODAB:MO aggregates in the absence of DNA has indicated that their morphology depends on the balance between DODAB's tendency to form bilayer structures and MO's propensity to form inverted non-lamellar structures. Other parameters, such as the temperature have proved to be crucial in the definition of the morphology of the developed nanocarrier. Therefore, in this work, a step forward to the current gene carrier system will be given by studying the effect of the tunable parameters (incubation temperature and MO content) on the structure of pDNA:DODAB:MO lipoplexes. More importantly, the implications that these tunable parameters could have in terms of lipoplex transfection efficiency will be investigated. Dynamic light scattering (DLS), zeta (zeta) potential, cryo transmission electron microscopy (cryo-TEM) and ethidium bromide (EtBr) exclusion were used to assess the formation, structure and destabilization of pDNA:DODAB:MO lipoplexes at DODAB molar fractions of (1:1) and above equimolarity (2:1, 4:1) prepared at incubation temperatures from 25 to 50 degrees C. Experimental results indicate that pDNA:DODAB:MO's structure is sensitive to the lipoplex incubation temperature, resulting in particles of distinct size, superficial charge and structure. These variations are also visible on the complexation dynamics of pDNA, and subsequent release upon incubation with the model proteoglycan heparin (HEP), at 25 and 50 degrees C. Increase in temperature leads to re-organization of DODAB and MO molecules within the liposomal formulation, causing a positive charge re-localization in the lipoplex surface, which not only alters its structure but also its transfection efficiency. Altogether, these results confirm that in the DODAB:MO carriers, an increase in the incubation temperature has a similar effect on aggregate morphology as the observed with an increase in MO content. This conclusion is extended to the pDNA:DODAB:MO lipoplexes morphology and subsequent transfection efficiency defining new strategies in lipoplexes preparation that could be used to modulate the properties of other lipid formulations for nonviral gene delivery applications. PMID- 25023900 TI - Management of osteoporosis of the oldest old. AB - This consensus article reviews the diagnosis and treatment of osteoporosis in geriatric populations. Specifically, it reviews the risk assessment and intervention thresholds, the impact of nutritional deficiencies, fall prevention strategies, pharmacological treatments and their safety considerations, the risks of sub-optimal treatment adherence and strategies for its improvement. INTRODUCTION: This consensus article reviews the therapeutic strategies and management options for the treatment of osteoporosis of the oldest old. This vulnerable segment (persons over 80 years of age) stands to gain substantially from effective anti-osteoporosis treatment, but the under-prescription of these treatments is frequent. METHODS: This report is the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores some of the reasons for this and presents the arguments to counter these beliefs. The risk assessment of older individuals is briefly reviewed along with the differences between some intervention guidelines. The current evidence on the impact of nutritional deficiencies (i.e. calcium, protein and vitamin D) is presented, as are strategies to prevent falls. One possible reason for the under-prescription of pharmacological treatments for osteoporosis in the oldest old is the perception that anti-fracture efficacy requires long-term treatment. However, a review of the data shows convincing anti fracture efficacy already by 12 months. RESULTS: The safety profiles of these pharmacological agents are generally satisfactory in this patient segment provided a few precautions are followed. CONCLUSION: These patients should be considered for particular consultation/follow-up procedures in the effort to convince on the benefits of treatment and to allay fears of adverse drug reactions, since poor adherence is a major problem for the success of a strategy for osteoporosis and limits cost-effectiveness. PMID- 25023904 TI - Could four-dimensional contrast-enhanced ultrasound replace computed tomography angiography during follow up of fenestrated endografts? Results of a preliminary experience. AB - OBJECTIVE: To evaluate four-dimensional contrast-enhanced ultrasound (4D-CEUS) as an alternative imaging method to computed tomography angiography (CTA) during follow up of fenestrated endovascular aneurysm repair (FEVAR) for juxta- and para renal abdominal aortic aneurysms (AAA). METHODS: Between October 2011 and March 2012, all consecutive patients who underwent FEVAR follow up were included in the study and evaluated with both 4D-CEUS and CTA. The interval between the two examinations was always <= 30 days. Endpoints were the comparison of postoperative AAA diameter, AAA volume, presence of endoleaks, revascularized visceral vessel (RVV) visualization, and patency. Comparative analysis was performed using Bland-Altman plots and McNemar's Chi-square test. RESULTS: Twenty two patients (96% male, 4% female; mean age 74 +/- 7 years; American Society of Anesthesiologists grade III/IV 82%/18%) were enrolled. Seventy-eight RVV (fenestrations: 60; scallops: 17; branches: 1) were analyzed. The mean AAA diameter evaluated by 4D-CEUS and CTA was 45 +/- 10 mm (range 30-69 mm) and 48 +/ 9 mm (range 32-70 mm), respectively. The mean difference was 3 +/- 3 mm. The mean AAA volume evaluated by 4D-CEUS and CTA was 150 +/- 7 cc (range 88-300 cc) and 159 +/- 68 cc (range 80-310 cc), respectively. The mean difference was 7 +/- 4 cc; a Bland-Altman plot revealed agreement in AAA diameter and volume evaluation (p < .01) between 4D-CEUS and CTA. The observed agreement for the detection of endoleaks was 95%. McNemar's Chi-square test confirmed that 4D-CEUS and CTA were equivalent (p > .05) at detecting endoleaks. The first segment of six (8%) RVVs (four renal and two superior mesenteric arteries) was not directly visualized by 4D-CEUS owing to obesity, but the contrast enhancement into the distal part of vessel or into the relative parenchyma gave indirect information about their patency. McNemar's Chi-square test demonstrated the superiority of CTA (p = .031) in visualizing RVVs. The patency of 77/78 RVVs was confirmed with both techniques. McNemar's Chi-square test confirmed that 4D-CEUS and CTA were equivalent in their ability to detect visceral vessel patency. CONCLUSIONS: The data suggest that 4D-CEUS is as accurate as CTA in the evaluation of postoperative AAA diameter and volume, endoleak detection, and RVV patency after FEVAR. Four-dimensional CEUS could provide hemodynamic information regarding RVVs, and reduce radiation exposure and renal impairment during follow up. Obesity limits the diagnostic accuracy of 4D-CEUS. PMID- 25023905 TI - In vitro antimicrobial activity of Medilox(r) super-oxidized water. AB - AIM: Super-oxidized water is one of the broad spectrum disinfectants, which was introduced recently. There are many researches to find reliable chemicals which are effective, inexpensive, easy to obtain and use, and effective for disinfection of microorganisms leading hospital infections. Antimicrobial activity of super-oxidized water is promising. The aim of this study was to investigate the in-vitro antimicrobial activity of different concentrations of Medilox(r) super-oxidized water that is approved by the Food and Drug Administration (FDA) as high level disinfectant. MATERIAL AND METHODS: In this study, super-oxidized water obtained from Medilox(r) [Soosan E & C, Korea] device, which had been already installed in our hospital, was used. Antimicrobial activities of different concentrations of super-oxidized water (1/1, 1/2, 1/5, 1/10, 1/20, 1/50, 1/100) at different exposure times (1, 2, 5, 10, 30 min) against six ATCC strains, eight antibiotic resistant bacteria, yeasts and molds were evaluated using qualitative suspension test. Dey-Engley Neutralizing Broth [Sigma-Aldrich, USA] was used as neutralizing agent. RESULTS: Medilox(r) was found to be effective against all standard strains (Acinetobacter baumannii 19606, Escherichia coli 25922, Enterococcus faecalis 29212, Klebsiella pneumoniae 254988, Pseudomonas aeruginosa 27853, Staphylococcus aureus 29213), all clinical isolates (Acinetobacter baumannii, Escherichia coli, vancomycin-resistant Enterococcus faecium, Klebsiella pneumoniae, Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, Bacillus subtilis, Myroides spp.), and all yeastsat 1/1 dilution in >=1 minute. It was found to be effective on Aspergillus flavus at 1/1 dilution in >=2 minutes and on certain molds in >=5 minutes. CONCLUSION: Medilox(r) super-oxidized water is a broad spectrum, on-site producible disinfectant, which is effective on bacteria and fungi and can be used for the control of nosocomial infection. PMID- 25023906 TI - Bovine tuberculosis in Northern Ireland: risk factors associated with time from post-outbreak test to subsequent herd breakdown. AB - Compulsory bovine tuberculosis testing has been implemented since 1959 in Northern Ireland. Initial rapid progress in the eradication of the disease was followed by a situation where disease levels tended to fluctuate around a low level. This study explores recrudescence of bovine tuberculosis (bTB) in Northern Ireland herds by assessing risk factors associated with time from the six-month post-outbreak skin test until a further herd breakdown. Bovine herds (n=3377) were recruited in 2002 and 2003 and their survival analysed using Kaplan-Meier survival estimates and a Cox proportional hazards model, with follow-up extending to August 2008. Exclusion criteria applied for study entry were bTB infection in a contiguous herd, changing of post restriction test to one of a higher risk status or chronic infection. Chronic infection was defined as any situation where disclosure preceded the post-outbreak test by two years or more. The application of these exclusion criteria meant that herds recruited to the study were largely cleared of infection and not directly contiguous to other infected herds. Of the 3377 herds, 1402 (41.5%) suffered a further herd breakdown before the end of follow-up. Median survival time was 582 days (interquartile range=336-1002 days). Breakdown severity (defined as the number of Single Intradermal Comparative Tuberculin Test (SICTT) reactors at disclosure test), local bTB prevalence, herd size and type were identified as significant risk factors (p<0.05), as was the purchase of higher numbers (n>27.38 per year) of cattle. Consistent with other studies this work shows bTB confirmation to not be predictive of a future herd breakdown. This work shows bTB history as not being a risk factor for a future breakdown. This result could be reflective of the exclusion criteria used in the study, which may have selected for incidents where historical status was of less importance. PMID- 25023907 TI - Bulk tank milk somatic cell counts in dairy herds with different bovine viral diarrhoea virus status in Poland. AB - The aim of the study was to examine the effect of bovine viral diarrhoea virus (BVDV) infection on bulk tank milk somatic cell counts (BMSCC). Twenty nine dairy farms supplying milk to a dairy in Eastern Poland were recruited for the study. Bulk milk ELISA and RT-PCR were used to determine the BVDV infection status and the presence of PI animals in the farms. The BMSCC mean values for the BVDV seronegative (218.7 * 10(3)cells/ml; SD: 89.8) and seropositive (214.9 * 10(3)cells/ml; SD: 74.0) herds did not differ significantly. To assess the relationship between BVDV infection and BMSCC a multilevel mixed-effects linear model was used. No statistically significant effect of BVDV infection on BMSCC was found. The mean values of BMSCC for the herds with PI individuals measured before (230.1 * 10(3)cells/ml, SD: 64.9) and after (223.3 * 10(3)cells/ml, SD: 62.4) the PI removal were not statistically different. An increase in herd size was associated with a significant decrease in BMSCC. An increase in BMSCC was observed during summer (from May to September) compared to during winter (from October to April). PMID- 25023908 TI - Rescuing my grandmothers. PMID- 25023909 TI - Relationship between Bone Mineral Density and Balance Disorders in Osteoporotic Patients. PMID- 25023910 TI - Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding. AB - Amino-terminal acetylation is among the most ubiquitous of protein modifications in eukaryotes. Although loss of N-terminal acetylation is associated with many abnormalities, the molecular basis of these effects is known for only a few cases, where acetylation of single factors has been linked to binding avidity or metabolic stability. In contrast, the impact of N-terminal acetylation for the majority of the proteome, and its combinatorial contributions to phenotypes, are unknown. Here, by studying the yeast prion [PSI(+)], an amyloid of the Sup35 protein, we show that loss of N-terminal acetylation promotes general protein misfolding, a redeployment of chaperones to these substrates, and a corresponding stress response. These proteostasis changes, combined with the decreased stability of unacetylated Sup35 amyloid, reduce the size of prion aggregates and reverse their phenotypic consequences. Thus, loss of N-terminal acetylation, and its previously unanticipated role in protein biogenesis, globally resculpts the proteome to create a unique phenotype. PMID- 25023911 TI - Long-term outcome of defibrillator recipients included in the federal audit conducted by the Department of Justice. AB - Institutions across the United States have been subjected to a federal audit for defibrillator implantable cardioverter defibrillator [ICD] implantations that violated the Centers for Medicare and Medicaid payment policy. We examined the long-term outcome of ICD recipients whose implantation procedures were audited by the Department of Justice (DOJ). Patients (n = 225) included in the DOJ audit at the University of Pittsburgh Medical Center between the years 2003 and 2010 were followed to the end point of all-cause mortality. A cohort of 206 consecutive and contemporary ICD recipients not included in the federal audit served as controls. Compared with the controls, the audited cases were older (p <0.001), had more preserved ejection fraction (p <0.001), and were less likely to be implanted for a primary prevention indication (p = 0.001). They also had significantly shorter time from myocardial infarction (p <0.001) or revascularization (p <0.001) to ICD implantation. Over a median follow-up of 3.6 years, 187 patients died and 71 received ICD therapy for ventricular arrhythmias. Patients whose cases were audited had worse survival compared with controls (hazard ratio 1.41, 95% confidence interval 1.05 to 1.90, p = 0.023) even after correcting for differences in baseline characteristics (hazard ratio 1.46, 95% confidence interval 1.05 to 2.02, p = 0.023). Rates of appropriate and inappropriate ICD therapies were similar between the audited cases and controls. In conclusion, patients whose ICD implantations were audited by the DOJ have worse long-term survival compared with nonaudited control patients. These data support compliance with the Centers for Medicare and Medicaid guidelines when the individual patient's clinical condition allows it. PMID- 25023912 TI - Localized prostate cancer: regional variation and national policy. PMID- 25023914 TI - Multiple chronic conditions and life expectancy: a life table analysis. AB - BACKGROUND: The number of people living with multiple chronic conditions is increasing, but we know little about the impact of multimorbidity on life expectancy. OBJECTIVE: We analyze life expectancy in Medicare beneficiaries by number of chronic conditions. RESEARCH DESIGN: A retrospective cohort study using single-decrement period life tables. SUBJECTS: Medicare fee-for-service beneficiaries (N=1,372,272) aged 67 and older as of January 1, 2008. MEASURES: Our primary outcome measure is life expectancy. We categorize study subjects by sex, race, selected chronic conditions (heart disease, cancer, chronic obstructive pulmonary disease, stroke, and Alzheimer disease), and number of comorbid conditions. Comorbidity was measured as a count of conditions collected by Chronic Conditions Warehouse and the Charlson Comorbidity Index. RESULTS: Life expectancy decreases with each additional chronic condition. A 67-year-old individual with no chronic conditions will live on average 22.6 additional years. A 67-year-old individual with 5 chronic conditions and >=10 chronic conditions will live 7.7 fewer years and 17.6 fewer years, respectively. The average marginal decline in life expectancy is 1.8 years with each additional chronic condition-ranging from 0.4 fewer years with the first condition to 2.6 fewer years with the sixth condition. These results are consistent by sex and race. We observe differences in life expectancy by selected conditions at 67, but these differences diminish with age and increasing numbers of comorbid conditions. CONCLUSIONS: Social Security and Medicare actuaries should account for the growing number of beneficiaries with multiple chronic conditions when determining population projections and trust fund solvency. PMID- 25023913 TI - Understanding regional variation in Medicare expenditures for initial episodes of prostate cancer care. AB - OBJECTIVES: To evaluate the contributions of patient and treatment factors to overall expenditures and regional variation for initial treatment of localized prostate cancer (CaP) in the Medicare program. RESEARCH DESIGN: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 47,517 beneficiaries with localized CaP during 2005-2009 and matched noncancer controls. We employed hierarchical generalized linear models to estimate risk standardized cancer-related expenditures for each hospital referral region. To identify key contributors to the variation, we sequentially added patient characteristics, treatment intensity (the percentage of patients receiving curative treatments), ancillary procedures (biopsy, hormone therapy, and imaging), and specific treatment modalities into the model. We categorized the expenditures according to the type of services to identify their relative impact on the expenditure variations. RESULTS: The mean expenditure on CaP-related care per CaP beneficiary was $15,900, including $1800 on surgery, $11,200 on radiotherapy, and $1900 on ancillary procedures. The expenditure difference between quintiles 5 and 1 was $6200. Patient characteristics explained 8.4% of this difference. Treatment intensity and treatment modalities accounted for an additional 21.2% and 31.2% of the variation, respectively. Between the highest and lowest expenditure quintiles, the difference in radiotherapy expenditure was $5000, whereas that in surgery or ancillary procedures was <$200. CONCLUSIONS: There is substantial geographic variation in CaP expenditures, and the specific modality of radiotherapy is the most important contributor to this variation. Efforts to address the CaP care costs, such as bundled payment development, require targeting both treatment intensity and use of costly modalities. PMID- 25023915 TI - Part-year coverage and access to care for nonelderly adults. AB - BACKGROUND: The association between uninsurance and reduced access to care is well known. Few studies, however, examine the relationship between the length of time without coverage and measures of access to care among adults. OBJECTIVES: To examine the association between access to care and the length of time without coverage during a 12-month period among nonelderly adults. METHODS: Multivariate logistic regression models of 15 measures of access to care are estimated, using data from the 2005-2010 Medical Expenditure Panel Survey. These models control for length of time without coverage and other factors. The study then examines how access to care varies by the length of time without coverage. RESULTS: There were large differences in access to care between those with and without coverage for all 12 months. For most of the measures, those lacking coverage for 1-5 months also had less access to care compared with those covered all 12 months. Lastly, for most of the measures, those lacking coverage for all 12 months had less access to care compared with either those lacking coverage for 6-11 months, or those lacking coverage for 1-5 months. CONCLUSIONS: The study shows the importance of considering the length of time without coverage when examining access to care of the uninsured. Even relatively short periods of uninsurance may be associated with some barriers to health care. In contrast, having some coverage during the year is associated with greater access to care than having no coverage at all. PMID- 25023916 TI - The effect of the Affordable Care Act's expanded coverage policy on access to dental care. AB - BACKGROUND: The Affordable Care Act included a dependent coverage policy that extends parents' or guardians' health insurance to adults aged 19-25. This policy does not apply directly to private dental benefits. However, for various reasons it could still have an indirect "spillover" effect if employers voluntarily expand dental coverage in conjunction with medical coverage. OBJECTIVE: To assess the effect of the Affordable Care Act's dependent coverage policy on private dental benefits coverage, utilization, and financial barriers to dental care. RESEARCH DESIGN: Difference-in-differences models were used to measure the association between the dependent coverage policy and private dental benefits coverage, utilization, and financial barriers to dental care. We analyze 2008 2012 National Health Interview Survey data, comparing results in 2011 and 2012 with results from 2008 to 2010 (prereform period). SUBJECTS: Adults aged 19-25 were compared with adults aged 26-34. MEASURES: Private dental benefits coverage, dental care utilization, and financial barriers to obtaining needed dental care. RESULTS: Relative to the prereform period, private dental benefits coverage among adults aged 19-25 increased by 5.6 percentage points in 2011 (P<0.001) and 6.9 percentage points in 2012 (P<0.001) compared with adults aged 26-34. Dental care utilization among adults aged 19-25 increased by 2.8 percentage points in 2011 (P=0.062) and 3.3 percentage points in 2012 (P=0.038) compared with adults aged 26-34. Adults aged 19-25 experienced a 2.1 percentage point decrease in 2011 (P=0.068) and a 2.0 percentage point decrease in 2012 (P=0.087) in financial barriers to dental care compared with adults aged 26-34. CONCLUSIONS: The dependent coverage policy was associated with an increase in private dental benefits coverage and dental care utilization, and a decrease in financial barriers to dental care among young adults aged 19-25. PMID- 25023917 TI - Barriers to care in an ethnically diverse publicly insured population: is health care reform enough? AB - BACKGROUND: The Affordable Care Act provides for the expansion of Medicaid, which may result in as many as 16 million people gaining health insurance coverage. Yet it is unclear to what extent this coverage expansion will meaningfully increase access to health care. OBJECTIVE: The objective of the study was to identify barriers that may persist even after individuals are moved to insurance and to explore racial/ethnic variation in problems accessing health care services. RESEARCH DESIGN: Data are from a 2008 cross-sectional mixed-mode survey (mail with telephone follow-up in 4 languages), which is unique in measuring a comprehensive set of barriers and in focusing on several select understudied ethnic groups. We examine racial/ethnic variation in cost and coverage, access, and provider-related barriers. The study adhered to a community-based participatory research process. SUBJECTS: Surveys were obtained from a stratified random sample of adults enrolled in Minnesota Health Care Programs who self report ethnicity as white, African American, American Indian, Hispanic, Hmong, or Somali (n=1731). RESULTS: All enrollees reported barriers to getting needed care; enrollees from minority cultural groups (Hmong and American Indian in particular) were more likely to experience problems than whites. Barriers associated with cost and coverage were the most prevalent, with 72% of enrollees reporting 1 or more of these problems. Approximately 63% of enrollees reported 1 or more access barriers. Provider-related barriers were the least prevalent (about 29%) yet revealed the most pervasive disparities. CONCLUSIONS: Many challenges to care persist for publicly insured adults, particularly minority racial and ethnic groups. The ACA expansion of Medicaid, although necessary, is not sufficient for achieving improved and equitable access to care. PMID- 25023918 TI - Development of the Primary Care Quality-Homeless (PCQ-H) instrument: a practical survey of homeless patients' experiences in primary care. AB - BACKGROUND: Homeless patients face unique challenges in obtaining primary care responsive to their needs and context. Patient experience questionnaires could permit assessment of patient-centered medical homes for this population, but standard instruments may not reflect homeless patients' priorities and concerns. OBJECTIVES: This report describes (a) the content and psychometric properties of a new primary care questionnaire for homeless patients; and (b) the methods utilized in its development. METHODS: Starting with quality-related constructs from the Institute of Medicine, we identified relevant themes by interviewing homeless patients and experts in their care. A multidisciplinary team drafted a preliminary set of 78 items. This was administered to homeless-experienced clients (n=563) across 3 VA facilities and 1 non-VA Health Care for the Homeless Program. Using Item Response Theory, we examined Test Information Function (TIF) curves to eliminate less informative items and devise plausibly distinct subscales. RESULTS: The resulting 33-item instrument (Primary Care Quality Homeless) has 4 subscales: Patient-Clinician Relationship (15 items), Cooperation among Clinicians (3 items), Access/Coordination (11 items), and Homeless-specific Needs (4 items). Evidence for divergent and convergent validity is provided. TIF graphs showed adequate informational value to permit inferences about groups for 3 subscales (Relationship, Cooperation, and Access/Coordination). The 3-item Cooperation subscale had lower informational value (TIF<5) but had good internal consistency (alpha=0.75) and patients frequently reported problems in this aspect of care. CONCLUSIONS: Systematic application of qualitative and quantitative methods supported the development of a brief patient-reported questionnaire focused on the primary care of homeless patients and offers guidance for future population-specific instrument development. PMID- 25023920 TI - An enlightening scan. PMID- 25023921 TI - Acute abdomen. PMID- 25023919 TI - Risk prediction models to predict emergency hospital admission in community dwelling adults: a systematic review. AB - BACKGROUND: Risk prediction models have been developed to identify those at increased risk for emergency admissions, which could facilitate targeted interventions in primary care to prevent these events. OBJECTIVE: Systematic review of validated risk prediction models for predicting emergency hospital admissions in community-dwelling adults. METHODS: A systematic literature review and narrative analysis was conducted. Inclusion criteria were as follows; POPULATION: community-dwelling adults (aged 18 years and above); Risk: risk prediction models, not contingent on an index hospital admission, with a derivation and >=1 validation cohort; PRIMARY OUTCOME: emergency hospital admission (defined as unplanned overnight stay in hospital); STUDY DESIGN: retrospective or prospective cohort studies. RESULTS: Of 18,983 records reviewed, 27 unique risk prediction models met the inclusion criteria. Eleven were developed in the United States, 11 in the United Kingdom, 3 in Italy, 1 in Spain, and 1 in Canada. Nine models were derived using self-report data, and the remainder (n=18) used routine administrative or clinical record data. Total study sample sizes ranged from 96 to 4.7 million participants. Predictor variables most frequently included in models were: (1) named medical diagnoses (n=23); (2) age (n=23); (3) prior emergency admission (n=22); and (4) sex (n=18). Eleven models included nonmedical factors, such as functional status and social supports. Regarding predictive accuracy, models developed using administrative or clinical record data tended to perform better than those developed using self-report data (c statistics 0.63-0.83 vs. 0.61-0.74, respectively). Six models reported c statistics of >0.8, indicating good performance. All 6 included variables for prior health care utilization, multimorbidity or polypharmacy, and named medical diagnoses or prescribed medications. Three predicted admissions regarded as being ambulatory care sensitive. CONCLUSIONS: This study suggests that risk models developed using administrative or clinical record data tend to perform better. In applying a risk prediction model to a new population, careful consideration needs to be given to the purpose of its use and local factors. PMID- 25023922 TI - Extra-tracheal air. PMID- 25023923 TI - High rates of obstructive sleep apnea symptoms among patients with schizophrenia. AB - BACKGROUND: Patients with schizophrenia have high rates of obesity and cardiovascular morbidity, which are strongly associated with obstructive sleep apnea (OSA). The prevalence and risk factors for OSA are not well studied in patients with schizophrenia. OBJECTIVE: The purpose of this study was to evaluate the frequency of OSA symptoms in a sample of outpatients with schizophrenia. METHODS: This cross-sectional study was a secondary analysis of data generated from an insomnia study that evaluated 175 outpatients with schizophrenia or schizoaffective disorder in a single, large urban community mental health center. Results of scales evaluating insomnia were used to complete the STOP questionnaire, which is a screening tool for OSA validated in surgical populations. Appropriate statistical analysis was done to compare participants across groups. RESULTS: Patients were classified into high risk for OSA (STOP >= 2) (57.7%), and low risk for OSA (STOP score < 2) (42.3%). We also identified patients with a known diagnosis of OSA (14.9%). Patients with diagnosed OSA had significantly higher STOP scores (mean 2.7 vs. 1.6 [t = 6.3; p < 0.001]). Only 23.8% of patients in the high-risk group were diagnosed with OSA. Body mass index was significantly higher in the diagnosed group (F[2,169] = 25; p < 0.001) as was diabetes (chi2 [2, N = 175] = 35, p < 0.001). CONCLUSION: A large number of outpatients with severe mental illness are at high risk for OSA. The STOP questionnaire is easy to use and appears to have a very high clinical utility to detect OSA. Based on our findings, further studies are warranted to validate the tool in patients with severe mental illness. PMID- 25023924 TI - Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria- history, rationale, description, and significance. AB - BACKGROUND: In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis-Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. METHODS: The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. RESULTS: Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. CONCLUSIONS: The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research. PMID- 25023925 TI - Neurocognitive dysfunction and grey matter density deficit in children with obstructive sleep apnoea. AB - BACKGROUND: Cerebral structural changes related to obstructive sleep apnoea (OSA) have been reported in adult OSA patients; however, similar data and their associations with neurocognitive dysfunction are scarce in childhood OSA. OBJECTIVE: To compare neurocognitive function, regional grey matter density and cerebral volume in children with and without OSA. METHODS: Fifty OSA cases and 27 normal controls underwent a panel of neurocognitive tests. High resolution 3 dimensional magnetic resonance images of the brain were obtained from 23 OSA cases and 15 gender and age matched controls. Total cerebral volume and regional grey matter density were analyzed using voxel-based morphometry technique and compared between the two groups. Individuals with an obstructive apnoea hypopnoea index (OAHI) > 5 were defined as having moderate-to-severe OSA. RESULTS: Children with OSA showed significantly reduced attention and visual-fine motor coordination scores compared with controls. Grey matter volume deficit was observed in prefrontal and temporal regions of cases with moderate-to-severe OSA only. Significant negative correlations were found between the visual-fine motor coordination score and the ratio of grey matter volume over total brain volume. CONCLUSION: Children with OSA had impaired attention and visual-fine motor coordination. Regional grey matter reduction was evident in children with more severe OSA. PMID- 25023926 TI - A modified portfolio diet complements medical management to reduce cardiovascular risk factors in diabetic patients with coronary artery disease. AB - BACKGROUND & AIMS: Secondary prevention can improve outcomes in high risk patients. This study investigated the magnitude of cardiovascular risk reduction associated with consumption of a modified portfolio diet in parallel with medical management. DESIGN: 30 patients with type II diabetes, 6 weeks post bypass surgery received dietary counseling on a Modified Portfolio Diet (MPD) (low fat, 8 g/1000 kcal viscous fibres, 17 g/1000 kcal soy protein and 22 g/1000 kcal almonds). Lipid profiles, endothelial function and markers of glycemic control, oxidative stress and inflammation were measured at baseline and following two and four weeks of intervention. Seven patients with no diet therapy served as time controls. RESULTS: Consumption of the MPD resulted in a 19% relative reduction in LDL (1.9 +/- 0.8 vs 1.6 +/- 0.6 mmol/L, p < 0.001) with no change in HDL cholesterol. Homocysteine levels dropped significantly (10.1 +/- 2.7 vs 7.9 +/- 4 MUmol/L, p = 0.006) over the study period. Flow mediated dilatation increased significantly in treated patients (3.8 +/- 3.8% to 6.5 +/- 3.6%, p = 0.004) while remaining constant in controls (p = 0.6). Endothelial progenitor cells numbers (CD34+, CD 133+ and UEA-1+) increased significantly following MPD consumption (p < 0.02) with no difference in migratory capacity. In contrast, time controls showed no significant changes. CONCLUSION: Dietary intervention in medically managed, high risk patients resulted in important reductions in risk factors. Clinical Trials registry number NCT00462436. PMID- 25023927 TI - Association between "loco-check" and EuroQol, a comprehensive instrument for assessing health-related quality of life: a study of the Japanese general population. AB - BACKGROUND: The concept of "locomotive syndrome" (LS) was proposed by the Japanese Orthopaedic Association (JOA) in 2007 to refer to the risk of elderly individuals becoming bedridden because of reduced function of locomotive organs, for example muscles, bones, and joints. The purpose of this study was to clarify the association between LS screening results based on "loco-check" and health related quality of life (HRQoL) assessed by use of EuroQol. MATERIALS AND METHODS: Four-hundred and forty-two Japanese subjects (183 males and 259 females) were evaluated for LS and HRQoL by use of "loco-check," EuroQol-5 dimensions (EQ 5D), and EuroQol-VAS (EQ-VAS). If the subjects answered "yes" to one or more of the seven items of "loco-check," they were assigned to a locomotive syndrome suspected group (L group). If they answered "no" to all seven items, they were assigned to a locomotive syndrome not suspected group (NL group). We investigated the association between the screening LS results obtained by use of "loco-check" and HRQoL status determined by use of EQ-5D utility value and EQ-VAS score. RESULTS: LS was suspected among 39.6% of the subjects on the basis of "loco check." In univariate analysis, significantly higher age, higher female-to-male ratio, and more reduced HRQoL were observed in the L group than in the NL group, according to EQ-5D and EQ-VAS. Logistic regression analysis showed that EQ-5D utility value and EQ-VAS score were associated with LS and the difference was statistically significant. Furthermore, correlations were found between the number of items with a "yes" answer on "loco-check", EQ-5D, or EQ-VAS. That is, a larger number of items with a "yes" answer on "loco-check" was associated with reduced HRQoL assessed by use of EQ-5D and EQ-VAS. CONCLUSIONS: We demonstrated that a finding of LS on the basis of "loco-check" is significantly associated with EQ-5D utility value and EQ-VAS score, and that a population identified as having LS by use of "loco-check" also had reduced HRQoL. Furthermore, it is speculated that the severity of reduced HRQoL because of locomotive dysfunction can be determined by use of "loco-check". PMID- 25023928 TI - Serum cholesterol and cognitive functions: the Lothian Birth Cohort 1936. AB - BACKGROUND: We examined the associations between serum cholesterol measures, statin use, and cognitive function measured in childhood and in old age. The possibility that lifelong (trait) cognitive ability accounts for any cross sectional associations between cholesterol and cognitive performance in older age, seen in observational studies, has not been tested to date. METHODS: Participants were 1,043 men and women from the Lothian Birth Cohort 1936 Study, most of whom had participated in a nationwide IQ-type test in childhood (Scottish Mental Survey of 1947), and were followed up at about age 70 years. Serum cholesterol measures included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and cholesterol:HDL cholesterol ratio. Cognitive outcome measures were age 70 IQ (using the same test as at age 11 years), general cognitive ability (g), processing speed, memory, and verbal ability. RESULTS: Higher TC, higher HDL-C, and lower triglycerides were associated with higher age 70 cognitive scores in most cognitive domains. These relationships were no longer significant after covarying for childhood IQ, with the exception a markedly attenuated association between TC and processing speed, and triglycerides and age 70 IQ. In the fully adjusted model, all conventionally significant (p < 0.05) effects were removed. Childhood IQ predicted statin use in old age. Statin users had lower g, processing speed, and verbal ability scores at age 70 years after covarying for childhood IQ, but significance was lost after adjusting for TC levels. CONCLUSIONS: These results suggest that serum cholesterol and cognitive function are associated in older age via the lifelong stable trait of intelligence. Potential mechanisms, including lifestyle factors, are discussed. PMID- 25023929 TI - Factors influencing the oblique impact test of motorcycle helmets. AB - PURPOSE: Oblique impact tests can provide important information regarding the level of protection of a helmet. Two factors that influence the results of oblique impact tests on motorcycle helmets are discussed in this work. The first factor is the angle of the anvil on which the helmet impacts. The second one is the friction between the headform and the helmet's interior. METHODS: To study the first factor, 2 anvil angles are provided, one 30 degrees and the other one 15 degrees to the vertical. To analyze the second factor, we consider 2 types of headform surfaces: the original metal surface of the standard headform and the same headform covered uniformly with a layer of silicone rubber that is 1 mm thick. RESULTS: The results show that varying the anvil's angle and surface friction can directly affect the linear and rotational acceleration of the headform. CONCLUSION: Testing helmets for different oblique impact angles can help assess their protection capability. The coefficient of friction between the helmet's interior and the headform plays an important role in the headform's rotational acceleration during an impact. Using a standard surface friction for headform similar or close to that of the human scalp can ensure that the results of the oblique impact tests are more consistent and realistic. PMID- 25023930 TI - Endovascular aortic injury repair after thoracic pedicle screw placement. AB - Our objective was to describe the management and prevention of thoracic aortic injuries caused by a malposition of pedicle screws in corrective surgery of major spine deformities. Positioning pedicle screws in thoracic vertebras by posterior approach exposes to the risk of injury of the elements placed ahead of the thoracic spine, as the descending thoracic aorta. This complication can result in a cataclysmic bleeding, needing urgent vascular care, but it can also be totally asymptomatic, resulting in the long run in a pseudoaneurysm, justifying the systematic removal of the hardware. We report the case of a 76-year-old woman who underwent spinal correction surgery for thoraco-lumbar degenerative kypho scoliosis. Immediately after the surgery, a thoracic aortic injury caused by the left T7 pedicle screw was diagnosed. The patient underwent a two-step surgery. The first step was realized by vascular surgeons and aimed to secure the aortic wall by short endovascular aortic grafting. During the second step, spine surgeons removed the responsible screw by posterior approach. The patient was discharged in a rehabilitation center 7 days after the second surgery. When such a complication occurs, a co-management by vascular and spine surgeons is necessary to avoid major complications. Endovascular management of this kind of vascular injuries permits to avoid an open surgery that have a great rate of morbi-mortality in frail patients. Nowadays, technologies exist to prevent this kind of event and may improve the security when positioning pedicle screws. PMID- 25023931 TI - Immunoexpression of S100A4 in canine skin melanomas and correlation with histopathological parameters. AB - BACKGROUND: Melanoma is one of the most common skin neoplasms in humans and dogs. The tumor microenvironment in melanoma comprises cancer cells and stromal cells that interact to accelerate tumor progression. Several prognostic markers for melanomas have been studied in many human tumors, including fibroblast-specific protein 1 (S100A4). S100A4 is a member of the S100 family of calcium-binding proteins in stromal cells. HYPOTHESIS/OBJECTIVES: The objective of this study was to describe the immunohistochemical patterns of S100A4 in stroma and neoplastic cells of canine skin melanomas and correlate them with some histological parameters. ANIMALS AND METHODS: Forty-eight samples (38 pigmented and 10 non pigmented melanomas) were first selected and their nature confirmed using S100, Melan A and vimentin. All cases were examined by immunohistochemistry using S100A4 to correlate expression, histotype, and level of invasion. RESULTS: All the tumors, including 10 non-pigmented, were positive for S100, Melan A, vimentin and negative for cytokeratin AE1/AE3 (consistent with melanomas). The 48 melanomas were classified as epithelioid (n = 21), spindle (n = 14), and mixed (n = 13). S100A4 was preferentially expressed in epithelioid and spindle cell types compared with mixed melanomas and S100A4 expression was not associated with level of invasion (Clark's levels IV to V). CONCLUSION: S100A4 expression in melanoma samples varied among histotypes but not between levels of invasion. PMID- 25023932 TI - Second thoughts on treating shoulders. AB - This statement unfortunately is made all too often by our patients with painful shoulders whilst they are undergoing treatment. It is my intention to examine the causes that bring this state about. PMID- 25023933 TI - Adverse drug reactions. AB - "The desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures. It is really one of the most serious difficulties with which we have to contend." PMID- 25023934 TI - The origins and purposes of antenatal preparation. AB - Many of our thoughts are coloured by past problems which may no longer exist, but the philosophies they gave rise to are still perpetuated. Antenatal education has not escaped this trend; thus through an historical analysis of how our attitudes have arisen, a better perspective can be gained of the aims and implications of modern antenatal preparation. In this way confusing opinions can be clarified. PMID- 25023935 TI - Physiotherapy treatment and clinical investigation of talipes equinovarus. AB - At the request of Doctor B. Bevan at the Royal Brisbane Women's Hospital, and Doctor D. Watson and Doctor J. Gallagher at the Royal Children's Hospital, a number of babies have been treated by physiotherapy for the congenital deformity of talipes equinovarus. PMID- 25023936 TI - Report on internal fixation of the femur. AB - During a recent survey of all cases involving fractures of the femur treated over a four-year period at the Ipswich General Hospital, it was found that a total of 78 were given operative treatment and had some form of metal fixation. This article will deal with these particular cases and summarize the treatment, time involvement and eventual rehabilitation, with consideration given to those which did not follow the general pattern, because of other complications. PMID- 25023937 TI - Current understanding of chronic traumatic encephalopathy. AB - OPINION STATEMENT: Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease found in individuals with a history of repetitive head impacts. The neuropathology of CTE is increasingly well defined. Prospective, longitudinal studies with post-mortem neuropathologic validation as well as in vivo diagnostic techniques are needed in order to advance the understanding of CTE clinically. Given the large number of individuals who incur concussions and other forms of brain trauma, this is an important area for scientific and public health inquiry. PMID- 25023938 TI - A residue-free green synergistic antifungal nanotechnology for pesticide thiram by ZnO nanoparticles. AB - Here we reported a residue-free green nanotechnology which synergistically enhance the pesticides efficiency and successively eliminate its residue. We built up a composite antifungal system by a simple pre-treating and assembling procedure for investigating synergy. Investigations showed 0.25 g/L ZnO nanoparticles (NPs) with 0.01 g/L thiram could inhibit the fungal growth in a synergistic mode. More importantly, the 0.25 g/L ZnO NPs completely degraded 0.01 g/L thiram under simulated sunlight irradiation within 6 hours. It was demonstrated that the formation of ZnO-thiram antifungal system, electrostatic adsorption of ZnO NPs to fungi cells and the cellular internalization of ZnO thiram composites played important roles in synergy. Oxidative stress test indicated ZnO-induced oxidative damage was enhanced by thiram that finally result in synergistic antifungal effect. By reducing the pesticides usage, this nanotechnology could control the plant disease economically, more significantly, the following photocatalytic degradation of pesticide greatly benefit the human social by avoiding negative influence of pesticide residue on public health and environment. PMID- 25023939 TI - Safety and efficacy of targeted therapy for renal cell carcinoma with brain metastasis. AB - BACKGROUND: Brain metastases are associated with a poor prognosis in patients with renal cell carcinoma (RCC). The role of targeted therapy in this setting is not well established. The primary objective was to assess overall survival (OS) and neurologic events in patients with brain metastasis treated with targeted agents. PATIENTS AND METHODS: Patients with RCC treated with targeted agents for brain metastasis between 2002 and 2012 were retrospectively identified. Kaplan Meier methodology and a Cox proportional hazards model were used to analyze the association between clinical features and OS. RESULTS: Of 65 patients identified, 52 (80%) were treated with antiangiogenic agents and 13 (20%) received inhibitors of mTOR (mechanistic target of rapamycin [serine/threonine kinase]); 57 (88%) had local therapy for brain metastasis, including surgery in 3 (5%), radiation therapy in 36 (55%), and both surgery and radiotherapy in 18 (28%). Median follow up was 12.3 months (1.1-58.8). Median treatment duration for targeted therapy as first-line therapy was 3.4 months (0.3-31.9). The median OS was 12.2 months (95% CI, 8.0-15.5). The risk group according to the Memorial Sloan Kettering Cancer Center (MSKCC) stratification (P = .001), the histology subtype (clear vs. other) (P < .0001), and the number of brain lesions (1 vs. >= 2) (P = .004) correlated with OS on multivariate analysis. Neurologic complications were identified in 5 patients (8%), including 2 with radiation necrosis and 3 with brain metastasis hemorrhage. CONCLUSION: The use of targeted agents in the multimodal treatment of patients with RCC and brain metastasis was not associated with excessive neurologic adverse events. Clear cell histology, favorable MSKCC risk status, and solitary brain metastasis are associated with more favorable OS. PMID- 25023940 TI - Piperlongumine induces cell death through ROS-mediated CHOP activation and potentiates TRAIL-induced cell death in breast cancer cells. AB - PURPOSE: Piperlongumine (PL) has been shown to selectively induce apoptotic cell death in cancer cells via reactive oxygen species (ROS) accumulation. In this study, we characterized a molecular mechanism for PL-induced cell death. METHODS: Cell viability and cell death were assessed by MTT assay and Annexin V-FITC/PI staining, respectively. ROS generation was measured using the H2DCFDA. Small interfering RNA (siRNA) was used for suppressing gene expression. The mRNA and protein expression were analyzed by RT-PCR and Western blot analysis, respectively. RESULTS: We found that PL promotes C/EBP homologous protein (CHOP) induction, which leads to the up-regulation of its targets Bim and DR5. Pretreatment with the ROS scavenger N-acetyl-cysteine abolishes the PL-induced up regulation of CHOP and its target genes, suggesting an essential role for ROS in PL-induced CHOP activation. The down-regulation of CHOP or Bim with siRNA efficiently attenuates PL-induced cell death, suggesting a critical role for CHOP in this cell death. Furthermore, PL potentiates TRAIL-induced cytotoxicity in breast cancer cells by upregulating DR5, as DR5 knockdown abolished the sensitizing effect of PL on TRAIL responses. CONCLUSIONS: Overall, our data suggest a new mechanism for the PL-induced cell death in which ROS mediates CHOP activation, and combination treatment with PL and TRAIL could be a potential strategy for breast cancer therapy. PMID- 25023942 TI - Surgical acquired aganglionosis: myth or reality? AB - PURPOSE: A number of patients operated on for Hirschsprung disease continue to have constipation and abdominal distension for years after surgery. Some authors have proposed that ischemia during surgery may induce secondary aganglionosis. The aim of the present study was to study the effects of ischemia on the enteric nervous system of sigmoid colon in an animal model. METHODS: A surgical model of colonic ischemia was created. 34 adult Sprague-Dawley rats underwent a laparotomy where the marginal arterioles of the sigmoid colon were ligated. After that, a section in the middle segment of the sigmoid colon was performed followed by an anastomosis. The presence of ischemia was assessed by measurement of visible light spectroscopy tissue oximetry and histological examination. Colonic function was assessed by evaluation of stool weight. Rats were killed at 1, 8 and 12 weeks after the operation. 12 rats were sham-operated. Enteric nervous system was evaluated by means of immunohistochemistry with NGFR p75. Quantitative analysis of the number of ganglia and ganglion cells in the myenteric plexus was performed. RESULTS: The surgical model of colonic ischemia significantly decreased tissue oxygenation (pre-surgical = 54.69 +/- 7.32 %; post-surgical = 27.37 +/- 9.2 %; p < 0.001). There was no disturbance in body-weight gaining in experimental groups and daily stool output did not vary after surgery (pre surgical = 4.24 +/- 0.94 g; post-surgical = 3.82 +/- 1 g; p = 0.09). All experimental groups showed persistent ganglia. However, there was a significant decrease in the number of ganglia in all the experimental groups compared to control (1w: 45.91 +/- 7.66; 8w: 44.17 +/- 10.56; 12w: 36.17 +/- 15.06 vs control: 56.88 +/- 8.66; p < 0.01). The number of total ganglion cells was significantly reduced only in the experimental group killed at week 12 compared to control (1w: 539 +/- 167.58; 8w: 488.58 +/- 154.41; 12w: 343.94 +/- 161.91 vs control: 513.96 +/- 126.97; p < 0.01). The rate of ganglion cells per ganglia was significantly higher in the groups killed at week 1 and 8 versus control group (1w: 11.63 +/- 2.53; 8w: 11.11 +/- 2.56; 12w: 9.34 +/- 1.16 vs control: 9.02 +/- 1.81; p < 0.05). CONCLUSION: Long-term follow-up after surgically induced colonic ischemia in the rat showed a decreased number of ganglion cells and ganglia. Nevertheless, it did not produce aganglionosis. PMID- 25023944 TI - Endoscopic cubital tunnel release. PMID- 25023943 TI - Evidence for decreased lipofibroblast expression in hypoplastic rat lungs with congenital diaphragmatic hernia. AB - PURPOSE: Pulmonary hypoplasia (PH) is a serious condition in newborns with congenital diaphragmatic hernia (CDH). Lipid-containing interstitial fibroblasts (LIFs) play an essential role in fetal lung maturation by stimulating alveolarization and lipid homeostasis. In rodents, LIFs are first evident during the canalicular phase of lung development with a significant increase over the last 4 days of gestation. Adipocyte differentiation-related protein (ADRP), a functional lipogenic molecular marker characterizing LIFs, is highly expressed in fetal lungs during this critical time period. We hypothesized that LIF expression in hypoplastic rat lungs is decreased in the nitrofen-induced CDH model, which is accompanied by reduced alveolar ADRP expression and lipid content. METHODS: On embryonic day 9.5 (E9.5), time-mated rats received either nitrofen or vehicle. Fetuses were sacrificed on selected time points E18.5 and E21.5, and dissected lungs were divided into controls and CDH-associated PH. Pulmonary gene expression levels of ADRP were determined by quantitative real-time polymerase chain reaction. ADRP immunohistochemistry and oil red O staining were used to assess pulmonary protein expression and lipid content. Immunofluorescence double staining for alpha smooth muscle actin, which is known to be absent in LIFs, and lipid droplets was performed to evaluate the pulmonary expression of this specific subset of fibroblasts. RESULTS: Relative mRNA expression of ADRP was significantly reduced in lungs of CDH-associated PH on E18.5 and E21.5 compared to controls. ADRP immunoreactivity and lipid staining were markedly diminished in alveolar mesenchymal cells of CDH-associated PH on E18.5 and E21.5 compared to controls. Confocal laser scanning microscopy demonstrated markedly decreased LIF expression in alveolar interstitium of CDH-associated PH on E18.5 and E21.5 compared to controls. CONCLUSION: Decreased pulmonary LIF expression during late gestation suggests impaired LIF functioning in the nitrofen-induced CDH model, which may cause disruption in fetal alveolarization and lipid homeostasis, and thus contribute to the development of PH. PMID- 25023945 TI - Towards an empirical ethics in care: relations with technologies in health care. AB - This paper describes the approach of empirical ethics, a form of ethics that integrates non-positivist ethnographic empirical research and philosophy. Empirical ethics as it is discussed here builds on the 'empirical turn' in epistemology. It radicalizes the relational approach that care ethics introduced to think about care between people by drawing in relations between people and technologies as things people relate to. Empirical ethics studies care practices by analysing their intra-normativity, or the ways of living together the actors within these practices strive for or bring about as good practices. Different from care ethics, what care is and if it is good is not defined beforehand. A care practice may be contested by comparing it to alternative practices with different notions of good care. By contrasting practices as different ways of living together that are normatively oriented, suggestions for the best possible care may be argued for. Whether these suggestions will actually be put to practice is, however, again a relational question; new actors need to re-localize suggestions, to make them work in new practices and fit them in with local intra normativities with their particular routines, material infrastructures, know-how and strivings. PMID- 25023947 TI - Novel orally swallowable IntelliCap((r)) device to quantify regional drug absorption in human GI tract using diltiazem as model drug. AB - Typically, colonic absorption of a drug is mandatory for a sustained release formulation to hold the drug's plasma level for more than 12 or 24 h above the minimum therapeutic plasma concentration (efficacy). According to Drugs@FDA, only 7.4% of the oral drugs are extended release forms probably showing colonic absorption. Therefore an early determination of a drug's colonic absorption using the IntelliCap(r) in animals or humans will provide the mandatory information to initiate or stop a SR form development. Diltiazem (60 mg) is used in the oral swallowable IntelliCap(r) and the marketed SR form from Mylan (coated beads). A human study with 14 healthy volunteers compared the Mylan formulation with the IntelliCap(r) device that releases the drug identical to the in-vitro dissolution of the Mylan product. The plasma profiles of IntelliCap(r) and Mylan formulation are highly similar. The mean AUC (bioequivalence fulfilled) and mean Cmax of IntelliCap(r) shows only a difference of +15% and -12%, respectively. But the PK profile of the Mylan formulation shows a broader peak around Cmax. About 81.8% diltiazem was absorbed in the colon (IntelliCap(r)) comparable to former publications. The Mylan is a SR diffusion coated beads form whereas the IntelliCap(r) is a monolithic capsule. The beads are transported in the gut and spread which results in a longer Tmax and a broader Cmax peak. The IntelliCap(r) device can quantitatively measure the colonic absorption of a drug in excellent accordance to a standard oral SR dosage form. PMID- 25023946 TI - Latent Tuberculosis: Models, Computational Efforts and the Pathogen's Regulatory Mechanisms during Dormancy. AB - Latent tuberculosis is a clinical syndrome that occurs after an individual has been exposed to the Mycobacterium tuberculosis (Mtb) Bacillus, the infection has been established and an immune response has been generated to control the pathogen and force it into a quiescent state. Mtb can exit this quiescent state where it is unresponsive to treatment and elusive to the immune response, and enter a rapid replicating state, hence causing infection reactivation. It remains a gray area to understand how the pathogen causes a persistent infection and it is unclear whether the organism will be in a slow replicating state or a dormant non-replicating state. The ability of the pathogen to adapt to changing host immune response mechanisms, in which it is exposed to hypoxia, low pH, nitric oxide (NO), nutrient starvation, and several other anti-microbial effectors, is associated with a high metabolic plasticity that enables it to metabolize under these different conditions. Adaptive gene regulatory mechanisms are thought to coordinate how the pathogen changes their metabolic pathways through mechanisms that sense changes in oxygen tension and other stress factors, hence stimulating the pathogen to make necessary adjustments to ensure survival. Here, we review studies that give insights into latency/dormancy regulatory mechanisms that enable infection persistence and pathogen adaptation to different stress conditions. We highlight what mathematical and computational models can do and what they should do to enhance our current understanding of TB latency. PMID- 25023948 TI - The influence of social networks on self-management support: a metasynthesis. AB - BACKGROUND: There is increasing recognition that chronic illness management (CIM) is not just an individual but a collective process where social networks can potentially make a considerable contribution to improving health outcomes for people with chronic illness. However, the mechanisms (processes, activities) taking place within social networks are insufficiently understood. The aim of this review was to focus on identifying the mechanisms linking social networks with CIM. Here we consider network mechanisms as located within a broader social context that shapes practices, behaviours, and the multiplicity of functions and roles that network members fulfil. METHODS: A systematic search of qualitative studies was undertaken on Medline, Embase, and Web for papers published between 1st January 2002 and 1st December 2013. Eligible for inclusion were studies dealing with diabetes, and with conditions or health behaviours relevant for diabetes management; and studies exploring the relationship between social networks, self-management, and deprivation. 25 papers met the inclusion criteria. A qualitative metasynthesis was undertaken and the review followed a line of argument synthesis. RESULTS: The main themes identified were: 1) sharing knowledge and experiences in a personal community; 2) accessing and mediation of resources; 3) self-management support requires awareness of and ability to deal with network relationships. These translated into line of argument synthesis in which three network mechanisms were identified. These were network navigation (identifying and connecting with relevant existing resources in a network), negotiation within networks (re-shaping relationships, roles, expectations, means of engagement and communication between network members), and collective efficacy (developing a shared perception and capacity to successfully perform behaviour through shared effort, beliefs, influence, perseverance, and objectives). These network mechanisms bring to the fore the close interdependence between social and psychological processes in CIM, and the intertwining of practical and moral dilemmas in identifying, offering, accepting, and rejecting support. CONCLUSIONS: CIM policy and interventions could be extended towards: raising awareness about the structure and organisation of personal communities; building individual and network capacity for navigating and negotiating relationships and CIM environments; maximising the possibilities for social engagement as a way of increasing the effectiveness of individual and network efforts for CIM. PMID- 25023949 TI - Extra sensory perception: the role of Gpr receptors in the kidney. AB - PURPOSE OF REVIEW: This review will summarize recent literature highlighting the roles of sensory Gpr receptors and their roles in renal function. RECENT FINDINGS: Chemoreceptors play important roles in renal physiology wherein they modulate renal function in response to ligands from a variety of sources. SUMMARY: As specialized chemical detectors, chemoreceptors in the kidney monitor the level of a variety of chemical ligands in the body and adjust renal function accordingly. In addition to olfactory receptors and taste receptors, G-protein coupled receptors of the orphan Gpr family are now being found to play a 'sensory' role in renal physiology. Identifying the physiological roles of these receptors and elucidating the cell biology underlying these signaling pathways can give us novel insights into renal function. PMID- 25023950 TI - Angiotensin-(1-7) as a strategy in the treatment of hypertension? AB - PURPOSE OF REVIEW: The renin-angiotensin system plays an important role in cardiovascular disease via the production of angiotensin II. Over the past decades, however, more and more evidence has accumulated suggesting an important role for another angiotensin: Angiotensin-(1-7) [Ang-(1-7)]. In this review, we discuss the recent findings on the effects of Ang-(1-7) and the angiotensin converting enzyme2/Ang-(1-7)/Mas axis on the cardiovascular system. RECENT FINDINGS: Recent studies demonstrated that Ang-(1-7) exerts a vasodilatory and antiproliferative effect via stimulation of the Mas receptor and inhibition of the effects of angiotensin-type 1 receptor stimulation by angiotensin II. This results in a dynamic equilibrium between Ang-(1-7) and angiotensin II. Various animal studies have demonstrated that Ang-(1-7) has beneficial effects on blood pressure, kidney function, and the prevention of cardiovascular disease. Although targeting the angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis has been difficult so far, several new therapeutic strategies are being developed. Promising results of these new strategies on blood pressure and cardiovascular disease were demonstrated in animal studies. SUMMARY: The beneficial effects of the angiotensin-converting enzyme2/Ang-(1-7)/Mas axis have been widely demonstrated in animal studies and provide a promising basis for further development of drugs targeting this axis of the renin-angiotensin system. Further research in humans, however, is necessary to make a serious step forward. VIDEO ABSTRACT: http://links.lww.com/CONH/A8. PMID- 25023951 TI - Parents' experience of the transition with their child from a pediatric intensive care unit (PICU) to the hospital ward: searching for comfort across transitions. AB - Parents of children in pediatric intensive care units (PICUs) have many needs and stressors, but research has yet to examine their experience of their child's transfer from PICU to the hospital ward. Ten parents were interviewed following transfer from PICU to a hospital ward at a children's hospital in Canada. Parents' experience involved a search for comfort through transitions. The themes were: 'being a parent with a critically ill child is exhausting', 'being kept in the know', 'feeling supported by others', and 'being transferred'. Findings from this study can help nurses and health professionals working with parents during transitions. PMID- 25023952 TI - Low level of basal testosterone: a significant risk factor for poor oocyte yield after ovulation induction. AB - The objective of this study was to further investigate the association of low androgen levels and poor ovarian response or negative pregnancy outcome in in vitro fertilisation treatment using a retrospective cohort study. Chinese women (n=1950) of relatively young age, with normal range of basal FSH and antral follicle count undergoing an in vitro fertilisation cycle were selected and testosterone and dehydroepiandrosterone sulfate levels were measured on Day 3 of the menstrual cycle before subsequent in vitro fertilisation treatment. The main outcome measures of the study were ovarian stimulation parameters and clinical pregnancy. Basal testosterone levels of poor responders and non-pregnant women were significantly lower than normal responders and pregnant women, respectively. Patients with low basal testosterone levels had significantly lower number of mature oocytes, cleavage-stage embryos, frozen embryos, lower fertilisation and pregnancy rates and required higher doses of gonadotrophins. Androgen levels had no correlation with early spontaneous abortion rates. Multivariable logistic analysis revealed that low basal testosterone (<0.88nmolL(-1)) was an independent risk factor for poor oocyte yield (odds ratio: 1.61; 95% confidence interval: 1.01-2.57; P=0.045). In conclusion, a low level of basal testosterone was a significant risk factor for poor oocyte yield after ovarian stimulation and might negatively influence pregnancy chances with in vitro fertilisation. Basal dehydroepiandrosterone sulfate levels were not predictive for poor ovarian response or negative pregnancy outcome in this population. PMID- 25023953 TI - Reliability and validity of the Chinese version of the Patient Health Questionnaire (PHQ-9) in the general population. AB - OBJECTIVE: Depression is one of the most common mental illnesses. The reliability and the validity of the Patient Health Questionnaire (PHQ)-9, a depression screening tool, have not been examined in the general population in China. Thus, this study evaluated the reliability and the validity of the Chinese version of the PHQ-9 in detecting major depression in residents of a Chinese community. METHODS: A total of 1045 participants from a Shanghai community were enrolled in our study. Participants completed the Chinese versions of the PHQ-9, the Self Rating Depression Scale (SDS), the 36-item Short Form Health Survey (SF-36), and the Mini International Neuropsychiatric Interview. One hundred participants were randomly selected to complete the PHQ-9 again 2 weeks after the initial assessment. The reliability, the validity and the receiver operating characteristic (ROC) curve of the PHQ-9 were analyzed. RESULTS: Cronbach's alpha for the internal consistency reliability of the Chinese version of the PHQ-9 was 0.86 for the entire scale. The correlation coefficient for the 2-week test-retest of the total score was 0.86. The PHQ-9 scale correlated positively with the SDS (r=0.29, p<0.001) and correlated negatively with all subscale scores of the SF-36 (correlation coefficients ranged from -0.11 to -0.47, p<0.001). The area under the curve of the ROC was 0.92 (95% confidence interval: 0.86-0.97). A cutoff score of 7 or higher on the PHQ-9 had a sensitivity of 0.86 and a specificity of 0.86. CONCLUSIONS: In the general Chinese population, the Chinese version of the PHQ-9 is a valid and efficient tool for screening depression, with a recommended cutoff score of 7 or more. PMID- 25023954 TI - How is letter position coding attained in scripts with position-dependent allography? AB - We examined how letter position coding is achieved in a script (Arabic) in which the different letter forms (i.e., allographs) may vary depending on their position within the letter string (e.g., compare the same-ligation pair [see text] and [see text] vs. the different-ligation pair [see text] and [see text]. To that end, we conducted an experiment in Uyghur, an agglutinative language from the Turkic family that employs an Arabic-based script in which both consonants and vowels are explicitly written. Participants had to reproduce the correct word forms in rapid serial visual presentation sentences that either contained jumbled words (with the same ligation or different ligation) or were intact. The results revealed that readers had more difficulty correctly reporting the target words in the jumbled sentences when the letter transposition involved changes in the ligation pattern, thus demonstrating that position-dependent allography affects letter position coding. This finding poses constraints to a universal model of letter position encoding. PMID- 25023955 TI - Learned face-voice pairings facilitate visual search. AB - Voices provide a rich source of information that is important for identifying individuals and for social interaction. During search for a face in a crowd, voices often accompany visual information, and they facilitate localization of the sought-after individual. However, it is unclear whether this facilitation occurs primarily because the voice cues the location of the face or because it also increases the salience of the associated face. Here we demonstrate that a voice that provides no location information nonetheless facilitates visual search for an associated face. We trained novel face-voice associations and verified learning using a two-alternative forced choice task in which participants had to correctly match a presented voice to the associated face. Following training, participants searched for a previously learned target face among other faces while hearing one of the following sounds (localized at the center of the display): a congruent learned voice, an incongruent but familiar voice, an unlearned and unfamiliar voice, or a time-reversed voice. Only the congruent learned voice speeded visual search for the associated face. This result suggests that voices facilitate the visual detection of associated faces, potentially by increasing their visual salience, and that the underlying crossmodal associations can be established through brief training. PMID- 25023956 TI - The effects of increasing target prevalence on information processing during visual search. AB - The proportion of trials on which a target is presented (referred to as the target prevalence) during visual search influences the probability that the target will be detected. As prevalence increases, participants become biased toward reporting that the target is present. This bias results in an increase in detection rates for the target, coupled with an increased likelihood of making a false alarm. Previous work has demonstrated that, as prevalence increases, participants spend an increasing period of time searching on target-absent trials. The goal of the present study was to determine the information processing during the additional time spent searching on target-absent trials as prevalence increased. We recorded participants' eye movement behavior as they were engaged in low-prevalence (25% target-present trials), medium-prevalence (50%), or high prevalence (75%) search. Increased prevalence primarily influenced search by increasing the time spent examining objects in the display, rather than by increasing the proportion of objects examined in each display. In addition, the additional time spent examining objects in high-prevalence target-absent trials was the result of revisiting objects. We discuss the implications of these results in relation to current models of search as well as ongoing efforts to alleviate the prevalence effect. PMID- 25023957 TI - A tissue stabilization device for MRI-guided breast biopsy. AB - We present a breast tissue stabilization device that can be used in magnetic resonance imaging-guided biopsy. The device employs adjustable support plates with an optimized geometry to minimize the biopsy target displacement using smaller compression than the conventional parallel plates approach. It is expected that the reduced compression will cause less patient discomfort and improve image quality by enhancing the contrast intake. Precomputed optimal positions of the stabilization plates for a given biopsy target location are provided in a look-up table. The results of several experiments with a prototype of the device carried out on chicken breast tissue demonstrate the effectiveness of the new design when compared with conventional stabilization methods. The proposed stabilization mechanism provides excellent flexibility in selecting the needle insertion point and can be used in manual as well as robot-assisted biopsy procedures. PMID- 25023958 TI - Fast computation of voxel-level brain connectivity maps from resting-state functional MRI using l1-norm as approximation of Pearson's temporal correlation: proof-of-concept and example vector hardware implementation. AB - An outstanding issue in graph-based analysis of resting-state functional MRI is choice of network nodes. Individual consideration of entire brain voxels may represent a less biased approach than parcellating the cortex according to pre determined atlases, but entails establishing connectedness for 1(9)-1(11) links, with often prohibitive computational cost. Using a representative Human Connectome Project dataset, we show that, following appropriate time-series normalization, it may be possible to accelerate connectivity determination replacing Pearson correlation with l1-norm. Even though the adjacency matrices derived from correlation coefficients and l1-norms are not identical, their similarity is high. Further, we describe and provide in full an example vector hardware implementation of l1-norm on an array of 4096 zero instruction-set processors. Calculation times <1000 s are attainable, removing the major deterrent to voxel-based resting-sate network mapping and revealing fine-grained node degree heterogeneity. L1-norm should be given consideration as a substitute for correlation in very high-density resting-state functional connectivity analyses. PMID- 25023959 TI - Mathematical analysis of spontaneous emergence of cell polarity. AB - Cell polarization, in which intracellular substances are asymmetrically distributed, enables cells to carry out specialized functions. While cell polarity is often induced by intracellular or extracellular spatial cues, spontaneous polarization (the so-called symmetry breaking) may also occur in the absence of spatial cues. Many computational models have been used to investigate the mechanisms of symmetry breaking, and it was proved that spontaneous polarization occurs when the lateral diffusion of inactive signaling molecules is much faster than that of active signaling molecules. This conclusion leaves an important question of how, as observed in many biological systems, cell polarity emerges when active and inactive membrane-bound molecules diffuse at similar rates while cycling between cytoplasm and membrane takes place. The recent studies of Ratz and Roger showed that, when the cytosolic and membrane diffusion are very different, spontaneous polarization is possible even if the membrane bound species diffuse at the same rate. In this paper, we formulate a two equation non-local reaction-diffusion model with general forms of positive feedback. We apply Turing stability analysis to identify parameter conditions for achieving cell polarization. Our results show that spontaneous polarization can be achieved within some parameter ranges even when active and inactive signaling molecules diffuse at similar rates. In addition, different forms of positive feedback are explored to show that a non-local molecule-mediated feedback is important for sharping the localization as well as giving rise to fast dynamics to achieve robust polarization. PMID- 25023960 TI - Apoptotic agents inducing genotoxicity-specific chromatin changes. AB - To visualize characteristic chromatin distortions we have distinguished first among regularly occurring intermediates of chromatin structures in mammalian (Indian muntjac, CHO, murine preB, rat liver, rat myeloid leukemia, K562 human erythroid leukemia) and Drosophila nuclei. Fluorescence microscopy of chromatin structures isolated from nuclei of reversibly permeable cells revealed a common pathway of chromatin condensation in mammalian cells. Different intermediates in mammalian and Drosophila cells indicate alternative mechanisms of chromosome condensation. Genotoxic agents such as irradiation (alpha, gamma, UV-B) and heavy metals (Cd, Pb, Ni, Hg, Ag) caused alterations in chromatin structures leading to apoptosis. Injury-specific chromatin changes manifested at significantly lower concentrations than non-specific signs of cellular toxicity, suggesting that preapoptotic events are useful indicators of genotoxicity. PMID- 25023961 TI - Eukaryotic elongation factor-2 kinase (eEF2K): a potential therapeutic target in cancer. AB - Eukaryotic elongation factor-2 kinase (eEF2K), encoded by the EEF2K gene, is well known to be a Ca(2+)/calmodulin (CaM)-dependent kinase which can negatively modulate protein synthesis. It is highly conserved among eukaryotes from mammals to invertebrates, of which human and mouse may have 99 % overall amino acid identity. This kinase can phosphorylate eukaryotic elongation factor-2 (eEF2) or undergo the process of autophosphorylation at multiple sites to inhibit its function in translation elongation. Due to the fact that regulation of eEF2 by eEF2K is an evolutionarily conserved mechanism, eEF2K activity may confer tumor cell adaption to metabolic stress under acute nutrient depletion, and the high expressed level of eEF2K has been found in several types of malignancies. eEF2K may modulate the expression of some apoptotic proteins such as XIAP, c-FLIPL, Bcl XL, PI3KCI and p70(S6K) to inhibit apoptotic process in cancer. On the other hand, it plays a regulatory role in autophagy involved in mTORC1, AMPK and Atg8, thereby promoting cancer cell survival. Additionally, eEF2K may play a crucial role in the crosstalk between apoptosis and autophagy in cancer. Collectively, these findings have led to the conclusions that eEF2K may contribute to carcinogenesis, and thus being utilized as a potential target for future cancer therapy. PMID- 25023965 TI - Enantioselective synthesis of alpha,alpha-difluoro-beta-lactams using amino alcohol ligands. AB - A practical and highly enantioselective Reformatsky reaction of ethyl bromodifluoroacetate with imines using a cheap and commercially available amino alcohol ligand is described. A variety of alpha,alpha-difluoro-beta-lactams were obtained in up to 74% yield with high enantioselectivity in excess of 99% ee. The use of ethyl bromodifluoroacetate provides for ease of operation because of the inherent chemical stability of this reagent. PMID- 25023966 TI - Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients. AB - BACKGROUND: Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed. METHODS: We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients. RESULTS: We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b. CONCLUSIONS: In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype. PMID- 25023967 TI - Altered (transition) states: mechanisms of solution and enzyme catalyzed RNA 2'-O transphosphorylation. AB - Although there have been great strides in defining the mechanisms of RNA strand cleavage by 2'-O-transphosphorylation, long-standing questions remain. How do different catalytic modes such as acid/base and metal ion catalysis influence transition state charge distribution? Does the large rate enhancement characteristic of biological catalysis result in different transition states relative to solution reactions? Answering these questions is important for understanding biological catalysis in general, and revealing principles for designing small molecule inhibitors. Recent application of linear free energy relationships and kinetic isotope effects together with multi-scale computational simulations are providing tentative answers to these questions for this fundamentally important class of phosphoryl transfer reactions. PMID- 25023968 TI - Glycosaminoglycan profiling in different cell types using infrared spectroscopy and imaging. AB - We recently identified vibrational spectroscopic markers characteristic of standard glycosaminoglycan (GAG) molecules. The aims of the present work were to further this investigation to more complex biological systems and to characterize, via their spectral profiles, cell types with different capacities for GAG synthesis. After recording spectral information from individual GAG standards (hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate) and GAG-GAG mixtures, GAG-defective mutant Chinese hamster ovary (CHO) 745 cells, wild-type CHO cells, and chondrocytes were analyzed as suspensions by high-throughput infrared spectroscopy and as single isolated cells by infrared imaging. Spectral data were processed and interpreted by exploratory unsupervised chemometric methods based on hierarchical cluster analysis and principal component analysis. Our results showed that the spectral information obtained was discriminant enough to clearly delineate between the different cell types both at the cell suspension and single-cell levels. The abilities of the technique are to perform spectral profiling and to identify single cells with different potentials to synthesize GAGs. Infrared microspectroscopy/imaging could therefore be developed for cell screening purposes and further for identifying GAG molecules in normal tissues during physiological conditions (aging, healing process) and numerous pathological states (arthritis, cancer). PMID- 25023969 TI - Bioluminescence imaging to track real-time armadillo promoter activity in live Drosophila embryos. AB - We established a method for bioluminescence imaging (BLI) to track real-time gene expression in live Drosophila embryos. We constructed a transgenesis vector containing multiple cloning sites and enhanced green-emitting luciferase (ELuc; Emerald Luc), a brighter and pH-insensitive luciferase for promoter analysis. To evaluate the utility of BLI using an ELuc reporter together with an optimized microscope system, we visualized the expression pattern of armadillo (arm), a member of the Wnt pathway in Drosophila, throughout embryogenesis. We generated transgenic flies carrying the arm:: ELuc fusion gene, and successfully performed BLI continuously for 22 h in the same embryos. Our study showed, for the first time, that arm::Eluc expression was dramatically increased in the anterior midgut rudiment, myoblasts of the dorsal/lateral musculature, and the posterior spiracle after stage 13, and the cephalic region at stage 17. To further demonstrate the application of our BLI system, we revealed that arm transcriptional activity in embryos was modulated inversely by treatment with ionomycin or 6-bromoindirubin-3 oxime (BIO), an inhibitor and activator of Wnt/beta-catenin signaling, respectively. Therefore, our microscopic BLI system is useful for monitoring gene expression in live Drosophila embryos, and for investigating regulatory mechanisms by using chemicals and mutations that might affect expression. PMID- 25023970 TI - A paper-based lateral flow assay for morphine. AB - Morphine was used as a model analyte to examine the possibility of using cellulose, physically modified by papermaking and converting techniques, as a capillary matrix in a lateral flow type of diagnostic assay. This research was directed toward low-cost, disposable, and portable paper-based diagnostics, with the aim of addressing the analytical performance of paper as a substrate in the analysis for drugs of abuse. Antibody Fab fragments were used as sensing molecules, and gold nanoparticle detection was employed. Inkjet printing was used to pattern sensing biomolecules as detection zones on paper. To validate the usefulness of paper as a diagnostic platform, the principle of a direct sandwich assay, based on immunocomplex formation between morphine and the anti-morphine Fab fragment and detection of the formed immunocomplex by another Fab fragment, was implemented. Results were compared with that achieved by using nitrocellulose as a reference material. Possible interfering from the sample matrix on assay quality was investigated with spiked oral fluid samples. Under optimized conditions, a visually assessed limit of detection for the sandwich assay was 1 ng/mL, indicating that the paper-based test devices developed in this work can perform screening for drugs of abuse and can fulfill the requirement for a sensitive assay in diagnostically relevant ranges. PMID- 25023971 TI - Correlative organelle fluorescence microscopy and synchrotron X-ray chemical element imaging in single cells. AB - X-ray chemical element imaging has the potential to enable fundamental breakthroughs in the understanding of biological systems because chemical element interactions with organelles can be studied at the sub-cellular level. What is the distribution of trace metals in cells? Do some elements accumulate within sub cellular organelles? What are the chemical species of the elements in these organelles? These are some of the fundamental questions that can be addressed by use of X-ray chemical element imaging with synchrotron radiation beams. For precise location of the distribution of the elements, identification of cellular organelles is required; this can be achieved, after appropriate labelling, by use of fluorescence microscopy. As will be discussed, this approach imposes some limitations on sample preparation. For example, standard immunolabelling procedures strongly modify the distribution of the elements in cells as a result of the chemical fixation and permeabilization steps. Organelle location can, however, be performed, by use of a variety of specific fluorescent dyes or fluorescent proteins, on living cells before cryogenic fixation, enabling preservation of element distribution. This article reviews the methods used for fluorescent organelle labelling and X-ray chemical element imaging and speciation of single cells. Selected cases from our work and from other research groups are presented to illustrate the potential of the combination of the two techniques. PMID- 25023972 TI - Using color histograms and SPA-LDA to classify bacteria. AB - In this work, a new approach is proposed to verify the differentiating characteristics of five bacteria (Escherichia coli, Enterococcus faecalis, Streptococcus salivarius, Streptococcus oralis, and Staphylococcus aureus) by using digital images obtained with a simple webcam and variable selection by the Successive Projections Algorithm associated with Linear Discriminant Analysis (SPA-LDA). In this sense, color histograms in the red-green-blue (RGB), hue saturation-value (HSV), and grayscale channels and their combinations were used as input data, and statistically evaluated by using different multivariate classifiers (Soft Independent Modeling by Class Analogy (SIMCA), Principal Component Analysis-Linear Discriminant Analysis (PCA-LDA), Partial Least Squares Discriminant Analysis (PLS-DA) and Successive Projections Algorithm-Linear Discriminant Analysis (SPA-LDA)). The bacteria strains were cultivated in a nutritive blood agar base layer for 24 h by following the Brazilian Pharmacopoeia, maintaining the status of cell growth and the nature of nutrient solutions under the same conditions. The best result in classification was obtained by using RGB and SPA-LDA, which reached 94 and 100 % of classification accuracy in the training and test sets, respectively. This result is extremely positive from the viewpoint of routine clinical analyses, because it avoids bacterial identification based on phenotypic identification of the causative organism using Gram staining, culture, and biochemical proofs. Therefore, the proposed method presents inherent advantages, promoting a simpler, faster, and low-cost alternative for bacterial identification. PMID- 25023973 TI - Quantification of 33 antidepressants by LC-MS/MS--comparative validation in whole blood, plasma, and serum. AB - In the present study, a liquid chromatography-mass spectrometry (LC-MS/MS) multi analyte approach based on a simple liquid-liquid extraction was developed for fast target screening and quantification of 33 antidepressants in whole blood, plasma, and serum. The method was validated with respect to selectivity, matrix effects, recovery, process efficiency, accuracy and precision, stabilities, and limits. In addition, cross-calibration between the three biosamples was done to assess the impact of the different matrices on the calibration. Whole blood, plasma, and serum (500 MUL each) were extracted twice at pH 7.4 and at pH 10 with ether-ethyl acetate (1:1). Separation, detection, and quantification were performed using LC-MS/MS with electrospray ionization in positive mode. For accuracy and precision, full calibration was performed with ranges from subtherapeutic to toxic concentrations. The approach was sensitive and selective for 33 analytes in whole blood and 31 analytes in plasma and serum and accurate and precise for 30 of the 33 tested drugs in whole blood, 31 in plasma, and 28 in serum. Cross-calibration was successful only for 13 analytes in whole blood and 16 analytes in serum calculated over a calibration curve made in plasma, 12 analytes in whole blood and 15 analytes in plasma calculated over a calibration curve made in serum, and 10 analytes in plasma and 15 analytes in serum calculated over a calibration curve made in whole blood. PMID- 25023975 TI - A rare cause of acute cerebellar ataxia: familial hemophagocytic lymphohistiocytosis. PMID- 25023974 TI - Involvement of beta-arrestin-2 and clathrin in agonist-mediated internalization of the human cannabinoid CB2 receptor. AB - The CB2 cannabinoid receptor is a promising therapeutic target for the treatment of inflammatory diseases, neuropathic pain, liver diseases, cancer and cardiovascular diseases. Obtaining detailed information on the internalization and trafficking of the human CB2 receptor in response to agonist will have a significant impact on drug discovery. Visualization and quantitative detection of EGFP-tagged CB2 receptor showed that, upon WIN55,212-2 stimulation, the CB2 receptor was rapidly internalized in a dose- and time-dependent manner from the cell membrane into the cytoplasm. Pretreatment with hypertonic sucrose, MDC clathrin inhibitor, or siRNA-mediated knock-down of clathrin heavy chain led to significant inhibition of agonist-induced CB2 internalization. Using the RNA interference method, we showed that knockdown of beta-arrestin2 expression significantly impaired receptor internalisation. Further investigation demonstrated that the internalized CB2 receptors were co-localized with the early endosome probe and were recycled to the cell surface after the removal of agonist, but treatment with specific cell-permeable proteasome inhibitor MG132 a inhibited the recycling of internalized CB2 receptor, suggesting that the proteasome-mediated degradation pathway may be involved in CB2 internalization. Moreover, the single residue Ser(352) and residue cluster S(335)S(336)T(338)T(340) at the C-terminal tail are shown to be essential for receptor phosphorylation and beta-arrestin2 association. These data provide new insights into the mechanisms regulating agonist-mediated internalization and trafficking of the human CB2 receptor. PMID- 25023976 TI - Connatal cyst in a preterm twin infant with maternal comorbidities. AB - BACKGROUND: Connatal cysts are rare but recognized periventricular cysts that represent anatomic variants and are associated with good neurological outcomes. These cysts can be differentiated from cysts that portend graver prognoses by their location in relation to the ventricles, size, laterality, and temporal resolution. PATIENT PRESENTATION: We describe a preterm twin infant born to a mother with diabetes and cardiovascular disease who was found to have connatal cysts on head ultrasound at 3 days of age. These cysts were present again on head ultrasound at 12 days of age and on brain magnetic resonance imaging at 27 days of age. The infant had a normal neurological examination in the neonatal period and on follow-up at 3 and 6 months of age. Repeated head ultrasound at 3 months of age demonstrated near resolution of the cysts. CONCLUSION: Connatal cysts are normal anatomic variants which clinicians should be able to distinguish from similar appearing cysts with less favorable outcomes. Although the etiology of connatal cysts remains unknown, this case raises the possibility of maternal comorbidities or perinatal hypoperfusion playing a role in their formation. PMID- 25023977 TI - Efficacy and safety of cinnarizine in the prophylaxis of migraine in children: a double-blind placebo-controlled randomized trial. AB - BACKGROUND: In spite of the high occurrence of migraine headaches in school-age children, there are currently no approved and widely accepted pharmacologic agents for migraine prophylaxis in children. Our previous open-label study in children revealed the efficacy of cinnarizine, a calcium channel blocker, in migraine prophylaxis. A placebo-controlled trial was conducted to demonstrate the efficacy and safety of cinnarizine in the prophylaxis of migraine in children. TRIAL DESIGN: A double-blind, placebo-controlled, parallel-group study conducted in a tertiary medical center in Tehran, Iran. METHODS: Children (5-17 years) who experienced migraines with and without aura, as defined on the basis of 2004 International Headache Society criteria, were recruited into the study. Children were excluded if they had complicated migraine, epilepsy, or a history of use of migraine prophylactic agents. Each participant was randomly assigned to receive cinnarizine (a single 1.5 mg/kg/day dose in children weighing less than 30 kg and a single 50 mg dose in children weighing more than 30 kg, administered at bedtime) or placebo. The frequency, severity, and duration of headaches over the trial period were assessed and adverse effects were monitored. RESULTS: A total of 68 children (34 in each group) with migraine were enrolled and 62 participants completed the study. After 3 months of taking cinnarizine or placebo, children in both groups experienced significantly reduced frequency, severity, and duration of headaches compared with baseline measurements (P < 0.001). However, compared with 31.3% of children in the placebo group, 60% of children in the cinnarizine group reported more than 50% reduction in monthly headache frequency (P = 0.023), suggesting that cinnarizine was significantly more effective than placebo in reducing the frequency of headaches. No serious adverse effects of the medications were observed in the treated children, including no abnormal weight gain or extrapyramidal signs. CONCLUSION: Our results indicate that the use of cinnarizine at doses administered in this study is effective and safe for prophylaxis of migraine headaches in children. PMID- 25023978 TI - Comments on "Progression of stages 3b-5 chronic kidney disease--preliminary results of Taiwan national pre-ESRD disease management program in Southern Taiwan". PMID- 25023979 TI - Knowledge of the female athlete triad, and prevalence of triad risk factors among female high school athletes and their coaches. AB - STUDY OBJECTIVE: This study aimed to determine awareness/knowledge of the Triad and its health implications among female high school athletes and their coaches, and to evaluate coaches' Triad screening/intervention practices. DESIGN: Cross sectional survey. SETTING: Two high schools in the western United States. PARTICIPANTS: Female athletes from a variety of sports (N = 240) ages 14-18 years and their coaches (N = 10). INTERVENTION: Participants completed surveys that assessed Triad knowledge and athlete Triad risk factors. MAIN OUTCOME MEASURES: Frequency of responses to Triad knowledge, Triad risk factor, and Triad education/screening procedures questions; athlete summative knowledge score. RESULTS: Half (N = 120) of participants reported menstrual irregularity, and 42% (N = 101) had 2 or more Triad risk factors: past amenorrhea (N = 39), past stress fracture (N = 41), self-reported not eating enough (N = 53), underweight (BMI-for age < 5(th) percentile) (N = 10), pressure to be a certain weight (N = 143), and wanting to lose >10 pounds when self-reported weight was in a healthy range (N = 34). Average athlete Triad knowledge score was 2.97 +/- 1.61 out of 8. Coach Triad knowledge was limited; however, most (9/10) were comfortable discussing menstruation with their athletes. Barriers to Triad screening/education were coaches' insufficient time, knowledge, and educational resources. CONCLUSION: Triad risk factors were prevalent among athletes and coach and athlete Triad knowledge was low. Providing coaches with Triad screening/education training may increase Triad knowledge and decrease Triad risk among high school athletes. PMID- 25023980 TI - Adolescents: their futures and their contraceptive decisions. AB - PURPOSE: Pregnancy prevention counseling addresses future goals as a motivator for contraceptive use, but this is often unsuccessful. This study investigated how adolescent females define success and whether they believe teen childbearing will be a barrier to their success. METHODS: A racially and ethnically diverse group of 84 nulliparous, high-risk adolescent females in teen clinics completed a survey asking about how they define success, future plans, and barriers to their success and future plans. RESULTS: Most respondents defined a successful person as one who has a higher education (73%) and/or a good job (73%). Most saw themselves finishing high school (70%), in college (62%), or working at a job (75%) in 3-5 years. Participants who left with a prescription contraceptive method were not more likely to feel that education/career were important for success. Most reported that having a child would have no (52%) or a positive effect (30%) on their education. The majority felt childbearing would have a negative impact on many aspects of their life. But feeling their finances would be negatively affected was the only predictor of obtaining contraception. CONCLUSIONS: We found that high-risk adolescents did not differ in conventional goals and aspirations regardless of their contraceptive choice. Although most girls felt that education/career was important, many of them felt that childbearing would not be a barrier to or may even improve their educational attainment. This challenges counseling that uses conventional goals as a motivator to remain non-pregnant. Further study of novel motivators for contraceptive use is needed. PMID- 25023981 TI - Frequency and types of chromosomal abnormalities in Turkish women with amenorrhea. AB - STUDY OBJECTIVE: To estimate the frequency and the type of chromosomal abnormalities (CA) in patients with primary (PA) and secondary amenorrhea (SA). DESIGN: This retrospective study was comprised of patients had been referred to our laboratory between 1990 to 2008 and designed as original article. SETTING: Medical Faculty of Cukurova University in Turkey. PARTICIPANTS: Chromosomal analysis was carried out on 393 patients with PA and SA that were referred to Cytogenetic laboratory of Medical Biology and Genetic Department, Faculty of Medicine, Cukurova University. INTERVENTIONS: Lymphocyte culturing depended karyotyping. MAIN OUTCOME MEASURES: Standard lymphocyte culturing procedure and karyotyping was performed to all samples. RESULTS: PA and SA were identified in 393 patients. The karyotype was normal in 337 cases (85.8%) and abnormal in 56 (14.2%) patients. CAs were found in 54 (13.7%) and 2 (0.5%) of women with PA and SA, respectively. Females carrying rearrangements between autosomal and sex chromosomes were detected in 2% (8/393). The numerical abnormalities of the X chromosome were detected in 39.3% (22/56) (monosomy and mosaic). Structural abnormalities of the X and the other chromosomes were detected in 25.5% (13 of 56). Structural mosaicism of X chromosome was found in 5.4% (3 of 56). Male karyotype (46, XY) was found in 33.9% (19/56). The most frequently detected abnormality were X chromosome monosomies or mosaics. CONCLUSIONS: Our study revealed that some causes of amenorrhea could be due to CAs. Therefore, cytogenetic study should be important test in the evaluation of patients with PA or SA. The most common abnormality seen is 45,X karyotype (monosomy X/Turner Syndrome) and its variants. PMID- 25023982 TI - Parent-child relationships, parental attitudes towards sex, and birth outcomes among adolescents. AB - STUDY OBJECTIVE: To examine how parent-child relationships, parental control, and parental attitudes towards sex were related to pregnancy outcomes among adolescent mothers. DESIGN: Prospective cohort study. Parental report of relationship satisfaction, disapproval of adolescent having sex, discussion around sexual health, and sexual communication attitudes, and adolescent report of relationship satisfaction, parental control, and parental disapproval of sex were examined as predictors of self-reported birth outcomes. Weighted multivariable linear regression models were run incorporating interactions by race. SETTING: United States. PARTICIPANTS: 632 females who participated in Waves I and IV of the National Longitudinal Study of Adolescent Health (Add Health), a nationally-representative sample of students enrolled in grades 7-12 in 1994-95 and followed up in 2007-2008. MAIN OUTCOME MEASURES: Birthweight and gestational age. RESULTS: For Black adolescents, better parent-child relationship was associated with higher birthweight (0.14 kg, P < .05) and gestational age (0.75 weeks, P < .01), while higher parental disapproval of having sex (adjusted beta 0.15 kg, P < .05) were associated with higher birthweight. For non-Black adolescents, a moderate amount of discussion of birth control was associated with higher birthweight (0.19 kg, P < .01 and lower child-perceived parental disapproval of having sex was associated with higher birthweight (0.08 kg, P < .05) and gestational age (0.37 weeks, P < .05). Higher parental control was associated with a reduced likelihood of smoking during pregnancy and a greater likelihood of early prenatal care. CONCLUSION: Parent-child relationships and attitudes about sex affect outcomes of pregnant adolescents. PMID- 25023984 TI - Municipal solid waste management in rural areas and small counties: an economic analysis using contingent valuation to estimate willingness to pay for Yunnan, China. AB - Municipal solid waste management (SWM) is a major challenge for local governments in rural China. One key issue is the low priority assigned by the local government which is faced with limited financing capacity. We conducted an economic analysis in Eryuan, a poor county in Yunnan, China, where the willingness- to- pay (WTP) for an improved solid waste collection and disposal service was valuated and compared with project cost. Similar to most previous studies in developing countries, this study found that the mean WTP is approximately 1% of the household income. The economic internal rate of return of the project is about 5%, which signifies the estimated social benefit to be already higher than the project cost. Moreover, we believe our estimation of social benefit to be a conservative one since our study only focuses on the local people who will be directly served by the project; wider positive externality of the project, such as CO2 emission reduction and groundwater pollution alleviation, etc., whose impact most probably surpass the frontier of Eryuan county, are not considered explicitly in our survey. The analysis also reveals that the poorest households are not only willing to pay more than the rich households in terms of percentage income but are also willing to pay no less than the rich in terms of absolute value in locations where solid waste services are unavailable. This result reveals the fact that the poorest households have stronger demands for public SWM services, whereas the rich may have the ability to employ private solutions. PMID- 25023983 TI - HOXA9 promotes homotypic and heterotypic cell interactions that facilitate ovarian cancer dissemination via its induction of P-cadherin. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is a lethal disease that frequently involves the peritoneal cavity. Dissemination of EOC is a multi-step process in which exfoliated tumor cells survive in the peritoneal fluid as multi-cellular aggregates and then form invasive implants on peritoneal surfaces. The mechanisms that control this process are poorly understood. We previously identified that high expression of the developmental patterning gene HOXA9 is associated with poor survival in EOC patients. In this study, we investigated the significance and mechanisms of HOXA9 in controlling aggregation and implantation of floating EOC cells. METHODS: HOXA9 was inhibited by shRNAs or expressed in EOC cells that were propagated in suspension cultures and in the peritoneal cavity of mice. Cell death was assayed by flow cytometry and ELISA. Cell aggregation, attachment and migration were evaluated by microscopy, transwell chamber assays and histopathologic analysis. DNA-binding of HOXA9 and its effect on expression of the cell adhesion molecule P-cadherin were assayed by chromatin immunoprecipitation, quantitative RT-PCR and Western blot. HOXA9 and P-cadherin expression was evaluated in publicly available datasets of EOC clinical specimens. RESULTS: We identified that HOXA9 promotes aggregation and inhibits anoikis in floating EOC cells in vitro and in xenograft models. HOXA9 also stimulated the ability of EOC cells to attach to peritoneal cells and to migrate. HOXA9 bound the promoter of the CDH3 gene that encodes P-cadherin, induced CDH3 expression in EOC cells, and was associated with increased CDH3 expression in clinical specimens of EOC. Inhibiting P-cadherin in EOC cells that expressed HOXA9 abrogated the stimulatory effects of HOXA9 on cell aggregation, implantation and migration. Conversely, these stimulatory effects of HOXA9 were restored when P-cadherin was reconstituted in EOC cells in which HOXA9 was inhibited. CONCLUSION: These findings indicate that HOXA9 contributes to poor outcomes in EOC in part by promoting intraperitoneal dissemination via its induction of P-cadherin. PMID- 25023985 TI - The challenges for solid waste management in accordance with Agenda 21: a Brazilian case review. AB - This paper aims to evaluate the suitability of the Brazilian solid waste policy (BSWP) with global Agenda 21 and the challenges of implementing the BSWP in municipalities. For this, a review of the principles that guided the creation of this policy was performed to demonstrate that international pressures were important in determining its effectiveness. The contradictory relationship between the satisfactory legal framework that established the Brazilian waste management policy and its weakened implementation in the municipalities is also examined . To illustrate the difficulties faced at the local level, a case study involving municipalities that compose the state of Espirito Santowe was undertaken. In this state, the municipalities signed terms of environmental commitment with supervisory agencies who undertook, within a pre-established schedule, to implement a set of actions to shape the proper management of solid waste, adapted to the requirements of national policy and the guidelines of Agenda 21. Finally, the various difficulties in meeting the requirements are discussed. It is necessary and urgent that Brazil finds a way to coordinate the mechanisms of an innovative and well formulated legal instrument to ensure the successful implementation of solid waste management at the local level to achieve the environmental, economic and social objectives. PMID- 25023986 TI - Waste reduction and recycling initiatives in Japanese cities: lessons from Yokohama and Kamakura. AB - Waste reduction and recycling at the city level will acquire greater significance in the near future due to rising global volumes of waste. This paper seeks to identify policy-relevant drivers for successful promotion of waste reduction and recycling. Factors influencing the success of waste reduction and recycling campaigns are identified. Two case study cities in Japan which depict the successful use of the 3Rs (reduce, reuse and recycle) at the municipal level are presented. In these cases, the existence of incinerators, which are generally considered as disincentives for recycling, was not functioning as a disincentive but rather as an incentive for waste reduction. Owing to the high cost of incineration facilities, the movement to close incinerators has become a strong incentive for waste reduction and recycling in these two cities. The study suggests that careful consideration is necessary when making decisions concerning high-cost waste treatment facilities with high installation, maintenance and renewal outlays. In addition, intensive source separation and other municipal recycling initiatives have a high potential for producing positive results. PMID- 25023987 TI - Quantitative performance targets by using balanced scorecard system: application to waste management and public administration. AB - This article demonstrates how decision-makers can be guided in the process of defining performance target values in the balanced scorecard system. We apply a method based on sensitivity analysis with Monte Carlo simulation to the municipal solid waste management system in Loule Municipality (Portugal). The method includes two steps: sensitivity analysis of performance indicators to identify those performance indicators with the highest impact on the balanced scorecard model outcomes; and sensitivity analysis of the target values for the previously identified performance indicators. Sensitivity analysis shows that four strategic objectives (IPP1: Comply with the national waste strategy; IPP4: Reduce nonrenewable resources and greenhouse gases; IPP5: Optimize the life-cycle of waste; and FP1: Meet and optimize the budget) alone contribute 99.7% of the variability in overall balanced scorecard value. Thus, these strategic objectives had a much stronger impact on the estimated balanced scorecard outcome than did others, with the IPP1 and the IPP4 accounting for over 55% and 22% of the variance in overall balanced scorecard value, respectively. The remaining performance indicators contribute only marginally. In addition, a change in the value of a single indicator's target value made the overall balanced scorecard value change by as much as 18%. This may lead to involuntarily biased decisions by organizations regarding performance target-setting, if not prevented with the help of methods such as that proposed and applied in this study. PMID- 25023988 TI - A low carbohydrate, high protein diet combined with celecoxib markedly reduces metastasis. AB - We recently demonstrated that both murine and human carcinomas grow significantly slower in mice on low carbohydrate (CHO), high protein diets than on isocaloric Western diets and that a further reduction in tumor growth rates occur when the low CHO diets are combined with the cyclooxygenase-2 inhibitor, celecoxib. Following upon these studies, we asked herein what effect low CHO, high protein diets, with or without celecoxib, might have on tumor metastasis. In the highly metastatic 4T1 mouse mammary tumor model, a 15% CHO, high protein diet supplemented with celecoxib (1 g/kg chow) markedly reduced lung metastases. Moreover, in longer-term studies using male Transgenic Adenocarcinoma of the Mouse Prostate mice, which are predisposed to metastatic prostate cancer, the 15% CHO diet, with and without celecoxib (0.3 g/kg chow), gave the lowest incidence of metastases, but a more moderate 25% CHO diet containing celecoxib led to the best survival. Metabolic studies with 4T1 tumors suggested that the low CHO, high protein diets may be forcing tumors to become dependent on amino acid catabolism for survival/growth. Taken together, our results suggest that a combination of a low CHO, high protein diet with celecoxib substantially reduces metastasis. PMID- 25023989 TI - A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study. AB - Only a fraction of colorectal cancer heritability is explained by known risk conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta analysis of colorectal cancer in participants from a population-based case control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 * 10( 9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study. PMID- 25023990 TI - Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis. AB - Prostate cancer (PCa) is the second cause of cancer deaths in men in the USA. When the cancer recurs, early stages can be controlled with hormone ablation therapy to delay the rate of cancer progression but, over time, the cancer overcomes its hormone dependence, becomes highly aggressive and metastasizes. Clinical trials have shown that pomegranate juice (PJ) inhibits PCa progression. We have previously shown that the PJ components luteolin (L), ellagic acid (E) and punicic acid (P) together inhibit growth of hormone-dependent and independent PCa cells and inhibit their migration and chemotaxis towards CXCL12, a chemokine that is important in PCa metastasis. On the basis of these findings, we hypothesized that L+E+P inhibit PCa metastasis in vivo. To test this possibility, we used a severe combined immunodeficiency mouse model in which luciferase-expressing human PCa cells were injected subcutaneously near the prostate. Tumor progression was monitored with bioluminescence imaging weekly. We found that L+E+P inhibits PC-3M-luc primary tumor growth, inhibits the CXCL12/CXCR4 axis for metastasis and none of the tumors metastasized. In addition, L+E+P significantly inhibits growth and metastasis of highly invasive Pten (-/-) ;K-ras (G12D) prostate tumors. Furthermore, L+E+P inhibits angiogenesis in vivo, prevents human endothelial cell (EC) tube formation in culture and disrupts preformed EC tubes, indicating inhibition of EC adhesion to each other. L+E+P also inhibits the angiogenic factors interleukin-8 and vascular endothelial growth factor as well as their induced signaling pathways in ECs. In conclusion, these results show that L+E+P inhibits PCa progression and metastasis. PMID- 25023991 TI - Second trimester postload glucose level as an important predictor of low birth weight infants: Tanaka Women's Clinic Study. AB - Although it is well known that the maternal prepregnancy BMI is a strong contributor to fetal growth, our results showed that a low postload glucose level, although within normal range, independent of maternal BMI was strongly associated with an increased risk of low birth weight births among Japanese mothers. PMID- 25023992 TI - Assessment of the association between glycemic variability and diabetes-related complications in type 1 and type 2 diabetes. AB - Chronic hyperglycemia is the main risk factor for the development of diabetes related complications in both type 1 and type 2 diabetes, but it is thought that frequent or large glucose fluctuations may contribute independently to diabetes related complications. A systematic literature review was performed using the PubMed, EMBASE and Cochrane Library databases with searches limited to studies published from June 2002 to March 2014, in English and including >=50 patients. Twenty eight articles were included in the final review. Eighteen studies reported the association between glucose variability and diabetes-related complications exclusively in type 2 diabetes. A positive association between increased variability and microvascular complications and coronary artery disease was consistently reported. Associations between glucose variability and other macrovascular complications were inconsistent in type 2 diabetes. Seven studies examined the association between glucose variability and complications exclusively in type 1 diabetes. Increased glucose variability appears to play a minimal role in the development of micro- and macrovascular complications in type 1 diabetes. Consistent findings suggest that in type 2 diabetes glucose variability is associated with development of microvascular complications. The role of increased glucose variability in terms of microvascular and macrovascular complications in type 1 diabetes is less clear; more data in are needed. PMID- 25023994 TI - The potential risks of expedited approval of drugs for acute bacterial infections. PMID- 25023993 TI - Mutations within the conserved NS1 nuclear export signal lead to inhibition of influenza A virus replication. AB - BACKGROUND: The influenza A virus NS1 protein is a virulence factor and an antagonist of host cell innate immune responses. During virus infection NS1 protein has several functions both in the nucleus and in the cytoplasm and its intracellular localization is regulated by one or two nuclear localization signals (NLS) and a nuclear export signal (NES). METHODS: In order to investigate the role of NS1 NES in intracellular localization, virus life cycle and host interferon responses, we generated recombinant A/Udorn/72 viruses harboring point mutations in the NES sequence. RESULTS: NS1 NES was found to be inactivated by several of the mutations resulting in nuclear retention of NS1 at late stages of infection confirming that this sequence is a bona fide functional NES. Some of the mutant viruses showed reduced growth properties in cell culture, inability to antagonize host cell interferon production and increased p-IRF3 levels, but no clear correlation between these phenotypes and NS1 localization could be made. Impaired activation of Akt phosphorylation by the replication-deficient viruses indicates possible disruption of NS1-p85beta interaction by mutations in the NES region. CONCLUSION: We conclude that mutations within the NS1 NES result in impairment of several NS1 functions which extends further from the NES site being only involved in regulating the nuclear-cytoplasmic trafficking of NS1. PMID- 25023995 TI - Syria: health in a country undergoing tragic transition. AB - OBJECTIVES: To document the ongoing destruction as a result of the tragic events in Syria, to understand the changing health care needs and priorities of Syrians. METHODS: A directed examination of the scientific literature and reports about Syria before and during the Syrian conflict, in addition to analyzing literature devoted to the relief and rebuilding efforts in crisis situations. RESULTS: The ongoing war has had high direct war casualty, but even higher suffering due to the destruction of health system, displacement, and the breakdown of livelihood and social fabric. Millions of Syrians either became refugees or internally displaced, and about half of the population is in urgent need for help. Access to local and international aid organizations for war-affected populations is an urgent and top priority. CONCLUSIONS: Syrians continue to endure one of the biggest human tragedies in modern times. The extent of the crisis has affected all aspects of Syrians' life. Understanding the multi-faceted transition of the Syrian population and how it reflects on their health profile can guide relief and rebuilding efforts' scope and priorities. PMID- 25023996 TI - Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype. AB - The self-assembly of alternative conformations of normal proteins into amyloid aggregates has been implicated in both the acquisition of new functions and in the appearance and progression of disease. However, while these amyloidogenic pathways are linked to the emergence of new phenotypes, numerous studies have uncoupled the accumulation of aggregates from their biological consequences, revealing currently underappreciated complexity in the determination of these traits. Here, to explore the molecular basis of protein-only phenotypes, we focused on the Saccharomyces cerevisiae Sup35/[PSI(+)] prion, which confers a translation termination defect and expression level-dependent toxicity in its amyloid form. Our studies reveal that aggregated Sup35 retains its normal function as a translation release factor. However, fluctuations in the composition and size of these complexes specifically alter the level of this aggregate-associated activity and thereby the severity and toxicity of the amyloid state. Thus, amyloid heterogeneity is a crucial contributor to protein only phenotypes. PMID- 25023997 TI - Brain 18F-FDG-PET characteristics in patients with paraneoplastic neurological syndrome and its correlation with clinical and MRI findings. AB - AIM: This study aimed to examine the imaging characteristics and clinical and MRI correlates of brain F-fluorodeoxyglucose (F-FDG)-PET imaging in patients with paraneoplatic neurological syndrome. MATERIALS AND METHODS: Data of patients diagnosed with paraneoplastic neurological syndrome were retrospectively reviewed using the electronic medical records of the patients, looking specifically at records of hospital stays, laboratory findings and imaging reports. Both brain MRI and F-FDG-PET imaging characteristics were analyzed and compared. RESULTS: A total of 19 patients (ages 26-78; 13 female and six male patients) with clinical diagnoses of PNS were analyzed in this study. Limbic encephalitis (paraneoplastic limbic encephalitis) was found in 10 patients, seven of whom had a diagnosis of cancer. Brain F-FDG-PET showed bilaterally increased mesial temporal F-FDG uptake in eight of 10 patients with limbic encephalitis; seven of these eight patients exhibited memory loss. There was also a notable reduction in general cortical F FDG uptake (including in the primary visual cortex) in six of the 10 patients with limbic encephalitis; three of the six patients had their primary motor cortices spared, two of them being spared bilaterally. Five of the seven limbic encephalitis patients with diagnosed cancer and two of the three without it had the aforementioned cortical and temporal lobe findings. Of the eight patients with onconeuronal antibodies, seven had temporal lobe enhancement and a total of six had diffuse cortical dysfunction. One patient with paraneoplastic limbic encephalitis without antibodies had demonstrated severely increased F-FDG uptake in both occipital lobes extending to the temporal lobes. The other patient without antibodies had a normal PET scan. Only one patient among four with paraneoplastic cerebellar degeneration had demonstrated decreased cerebellar uptake on F-FDG-PET that correlated with atrophy of the cerebellar vermis on MRI. Three patients had a clinical diagnosis of sensory neuropathy, of whom one demonstrated mild bilateral decrease in F-FDG uptake in the mesial temporal lobes, one showed notable increase in F-FDG uptake in the right mesial temporal lobe (with normal MRI) and the other had a normal brain F-FDG-PET. One patient was found to have cerebellar findings paired with oculomotor findings and showed increased F-FDG uptake in the cerebellum. One patient with stiff-person syndrome had normal brain F-FDG-PET. CONCLUSION: The pattern of abnormalities in the brain F-FDG-PET images usually correlates well with the corresponding clinical settings and presentations. Although quite frequently findings correlate with those of MRI, at times F-FDG-PET can demonstrate functional abnormality in the absence of any MRI finding, which could give a therapeutic window before anatomical changes set in. PMID- 25023998 TI - Potential performance of dual-time-point 18F-FDG PET/CT compared with single-time point imaging for differential diagnosis of metastatic lymph nodes: a meta analysis. AB - In recent years, dual-time-point (DTP) fluorine-18 fluorodeoxyglucose PET/computed tomography (CT) has emerged as a new method for evaluating metastatic lymph nodes in cancer patients. We performed this meta-analysis to evaluate the performance of DTP PET/CT compared with single-time-point (STP) imaging for differential diagnosis of lymph nodes metastases. On the basis of data from included studies, pooled sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, and negative likelihood ratio were calculated. Summary receiver-operating characteristic curves were also constructed to assess the diagnostic value of DTP PET/CT and STP imaging in detecting metastatic lymph nodes. Totally, 17 articles were included in the analysis. On a per-patient basis, the pooled sensitivity and specificity were 0.74 [95% confidence interval (CI): 0.68-0.79] and 0.77 (95% CI: 0.72-0.81) for DTP PET/CT and 0.68 (95% CI: 0.61-0.73) and 0.81 (95% CI: 0.78-0.85) for STP PET/CT, respectively. On a per lesion basis, the pooled sensitivity of DTP and STP PET/CT was 0.82 (95% CI: 0.79 0.84) and 0.80 (95% CI: 0.78-0.83), respectively. The pooled specificity was 0.88 (95% CI: 0.86-0.89) for DTP PET/CT and 0.82 (95% CI: 0.80-0.84) for STP PET/CT. Compared with STP imaging, DTP PET/CT has higher sensitivity but lower specificity in detecting lymph nodes metastases on a per-patient analysis, and DTP PET/CT performs only a little better than STP PET/CT on a per-lesion basis. The current results of our meta-analysis do not support the routine use of DTP imaging for the diagnosis of metastatic lymph nodes. Further prospective research with large samples is required to better define the potential benefits of DTP PET/CT imaging. PMID- 25023999 TI - Dual-phase 18F-FDG PET/CT imaging in the characterization of pancreatic lesions: does it offer prognostic information? AB - OBJECTIVE: The primary aim of our prospective study was to evaluate the usefulness of dual-phase F-fluoro-deoxy-glucose PET/computed tomography (F-FDG PET/CT) in the characterization of pancreatic masses. The secondary aim was to assess whether delayed imaging revealed any prognostic information. MATERIALS AND METHODS: Fifty patients with periampullary or pancreatic masses on conventional imaging were included in this study. Early and delayed PET/CT was performed, followed by pathological examination in all patients. PET/CT parameters including uptake pattern, SUVearly, SUVdelayed, lesion to background ratio (L/B), and retention index (RI) were assessed for their ability to differentiate benign from malignant lesions. Patients with malignant lesions were followed up for a median duration of 26 months. The association of 11 variables with survival was analyzed by univariate and multivariate methods. RESULTS: Thirty-one patients had malignant lesions and 19 had benign lesions. The mean SUVearly, L/B, SUVdelayed, and RI between the malignant and benign lesions were statistically significant. The F-FDG uptake pattern of the lesions had higher sensitivity (93.5%) and specificity (100%) compared with RI (cutoff 25.7%) (84 and 37%, respectively) for diagnosing malignancy (P<0.05). In univariate analysis both RI (>18.7%) and tumor size (>2.6 cm) predicted significantly poor survival, whereas in multivariate analysis RI (P=0.04) was the only predictor of poor survival. CONCLUSION: Dual phase F-FDG PET/CT is not useful in characterizing pancreatic masses as it cannot differentiate benign from malignant lesions, and focal uptake on early PET imaging is the best indicator of malignancy. A possible benefit in performing a delayed scan is that a high RI (>18.7) can predict poor survival and hence may be useful in treatment planning. PMID- 25024000 TI - The importance of a supportive environment in clinical audit: a pilot study of doctors' engagement with the NHS National PET-CT audit programme. AB - PURPOSE: The NHS National PET-CT Audit Programme was launched in 2008 as part of a national NHS programme to widen patient access to PET-computed tomography (CT) imaging in England. However, to implement clinical audit effectively, healthcare professionals need to be fully engaged with the process. The purpose of the pilot study was to identify and explore the different factors that influence doctors' engagement with the National NHS PET-CT Audit Programme. METHODS: A single embedded case study was undertaken, which centred on the NHS National PET-CT Audit Programme. Seven theoretical propositions drawn from a review of the literature were tested and their influence evaluated. A purposeful sample of 13 semistructured interviews with consultant doctors was taken from different hospitals over a 6-month period. The data were analysed using directed thematic content analysis, with the themes compared against the study's propositions. RESULTS: Doctors' perspectives of clinical audit changed in response to the way in which the audit was implemented. The main barriers to engagement were the lack of a common vision and poor communication, which contributed to poor interprofessional relationships and a perceived culture of blame. In contrast, factors that facilitated engagement centred on the adoption of a more supportive and collaborative approach, which in turn facilitated higher levels of trust between professionals. The dissemination of performance data was found to be a key influencing factor. CONCLUSION: The study makes use of a unique data set and to the best of our knowledge is one of the first studies to document how the dissemination of doctors' performance data positively influences engagement with clinical audit in England. In addition, the study also shows how, contrary to some studies in the literature, clinical audit can reduce professional anxiety by providing a validation of professional competence. The study supports the premise that clinical audit will be fully embraced by doctors only if they are sufficiently involved in the process so as to be able to redefine and clarify its purpose and meaning. The preliminary findings of this pilot study provide the theoretical underpinning for a national survey into reporter perspectives of the National PET-CT Audit Programme. PMID- 25024001 TI - Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. AB - BACKGROUND: The aim of this study was to assess efficacy and safety of eribulin with trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ breast cancer. PATIENTS AND METHODS: In this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2+ breast cancer received eribulin mesylate at 1.4 mg/m(2) intravenously (I.V.) on days 1 and 8 of each 21 day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary end point was ORR, and secondary end points included PFS, TTR, DOR, and safety. RESULTS: Fifty-two patients were enrolled. Fifty-one patients (98.1%) had metastatic disease, 25 (48.1%) with liver metastases, 24 (46.2%) with lung metastases, and 19 (36.5%) with bone metastases. Patients received a median of 10.0 cycles of eribulin and 11.0 cycles of trastuzumab. The ORR was 71.2% (n = 37) with median TTR of 1.3 months, DOR of 11.1 months, and PFS of 11.6 months. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 20 (38.5%) patients, peripheral neuropathy in 14 (26.9%; all Grade 3) patients, fatigue in 4 (7.7%) patients, and febrile neutropenia in 4 (7.7%) patients. CONCLUSIONS: Because of the high ORR, prolonged median PFS, and acceptable safety profile, combination eribulin/trastuzumab is an acceptable treatment option for locally recurrent or metastatic HER2+ breast cancer. PMID- 25024002 TI - [Analysis of factors conditioning admission at the critical care unit of surgical patients. Prospective study of 764 patients operated for 1 year at a university and reference hospital]. AB - OBJECTIVE: Assess what factors determine the income of surgical patients in critical care unit after surgery. MATERIAL AND METHODS: It included a survey of the 10% of all patients operated by the services of General Surgery, Thoracic Surgery, Maxillofacial Surgery, Vascular Surgery, Urology and Otolaryngology during 2012. We performed a prospective, observational study. Pre-, intra-, and post-operative variables were analyzed. Comparisons were made between patients operated under elective and emergency surgery, and between patients admitted in critical care and admitted directly in the ward, using chi(2) of Pearson correlation with a confidence interval of 95%. RESULTS: Seven hundred and sixty four patients were included into the study, 304 were admitted in critical care after surgery and 460 were admitted in the ward. The medical history showed a statistically significant association with intensive care unit admission, well as the fact of being labeled with a high risk for the risk scales. Complexity and duration of the surgery showed a statistically significant association with intensive care unit admission, as well as the fact of present intra-operative complications. Emergency surgery was not significantly associated with intensive care unit admission of surgical patients, although these patients had significantly higher numbers of intra- and post-operative complications, and more exitus than those undergoing elective surgery. CONCLUSIONS: A greater incidence of intensive care unit admission of patients undergoing emergency surgery should significantly reduce morbimortality rate. The existence of specific protocols for intensive care unit admission for urgent surgery, and greater availability of beds could be useful in this regard. PMID- 25024003 TI - Misdiagnosis of plexiform neurofibroma of the medial plantar nerve: case report. AB - Plexiform neurofibromas are benign tumors of the peripheral nerve. Diagnosis may be challenging, if they present mimicking other peripheral nerve pathologies. We report the case of a patient who had severe foot pain, which progressively hampered her walking ability, erroneously attributed to recurrent Morton's neuroma. Diagnosis of plexiform neurofibroma of her right medial plantar nerve was made 15 years after the appearance of symptoms. Pain and function recovered after radical neurotomy of the medial plantar nerve. A correct diagnosis is an essential starting point in the treatment of neurofibromas and a misdiagnosis may lead to an inappropriate treatment. PMID- 25024004 TI - [Role of renal inflammation in the physiopathology of salt-sensitive hypertension]. AB - Salt-sensitive hypertension is produced by a decrease in salt renal excretion after a salt overload. Over the last few years, a new theory has been developed to explain this condition based on renal tissue inflammation. This process begins with free radicals production in renal tissue due to oxidative metabolism. Then they favor a renal inflammation mechanism with T-lymphocytes infiltration and other immune cells. Essentially, T-lymphocytes determine an increase in angiotensin ii production which raises sodium and water retention. Association among autoimmune diseases and hypertension may be explained, in part, by the relationship between salt-sensitive hypertension and renal inflammation. The use of antioxidant drugs and the development of new medicaments may be a choice for treating patients affected with this condition. PMID- 25024005 TI - [Association between biochemical markers and left ventricular dysfunction in the ST-elevation acute myocardial infarction]. AB - OBJECTIVE: The association between biochemical markers and left ventricular ejection fraction in patients with myocardial infarction was not completely studied. Our goal is to study the association between biochemical markers and left ventricular dysfunction in patients with ST-elevation acute myocardial infarction. METHODS: With an observational and prospective design we included patients with less than 24h ST-elevation myocardial infarction. Leukocytes, glucose, B-type natriuretic peptide and T troponin were measured at admission, and creatine-phosphokinase and creatine-phosphokinase-MB were measured at admission and serially, and correlated with the ejection fraction estimated by echocardiography. RESULTS: A total of 108 patients were included. The median left ventricular ejection fraction was 48% (interquartile range 41-57). Simple linear regression analysis showed that B-type natriuretic peptide (P=.005), peak creatine-phosphokinase-MB (P=.01), leukocyte count (P=.001) and glucose (P=.033) were inversely and significantly associated with the left ventricular ejection fraction. The other parameters showed no association. B-type natriuretic peptide (P=.01) and peak creatine-phosphokinase-MB (P=.02) were the only two variables significantly associated with the left ventricular ejection fraction in the multiple linear regression analysis. Both markers were significantly associated with a left ventricular ejection fraction < 50%, independently of other clinical variables. CONCLUSION: B-type natriuretic peptide and peak creatine-phosphokinase MB showed significant association with left ventricular ejection fraction in the acute phase of ST elevation acute myocardial infarction. This association was independent of the presence of other biochemical markers and clinical variables related to ventricular dysfunction. PMID- 25024006 TI - Biochemical assays for the discovery of TDP1 inhibitors. AB - Drug screening against novel targets is warranted to generate biochemical probes and new therapeutic drug leads. TDP1 and TDP2 are two DNA repair enzymes that have yet to be successfully targeted. TDP1 repairs topoisomerase I-, alkylation-, and chain terminator-induced DNA damage, whereas TDP2 repairs topoisomerase II induced DNA damage. Here, we report the quantitative high-throughput screening (qHTS) of the NIH Molecular Libraries Small Molecule Repository using recombinant human TDP1. We also developed a secondary screening method using a multiple loading gel-based assay where recombinant TDP1 is replaced by whole cell extract (WCE) from genetically engineered DT40 cells. While developing this assay, we determined the importance of buffer conditions for testing TDP1, and most notably the possible interference of phosphate-based buffers. The high specificity of endogenous TDP1 in WCE allowed the evaluation of a large number of hits with up to 600 samples analyzed per gel via multiple loadings. The increased stringency of the WCE assay eliminated a large fraction of the initial hits collected from the qHTS. Finally, inclusion of a TDP2 counter-screening assay allowed the identification of two novel series of selective TDP1 inhibitors. PMID- 25024007 TI - Individualized follow up programme and early discharge in term neonates. AB - BACKGROUND: Early discharge of mother/neonate dyad has become a common practice, and its effects are measured by readmission rates. We evaluated the safety of early discharge followed by an individualized Follow-up programme and the efficacy in promoting breastfeeding initiation and duration. METHODS: During a nine-month period early discharge followed by an early targeted Follow-up was carried out in term neonates in the absence of weight loss <10% or hyperbilirubinaemia at risk of treatment. Follow-up visits were performed at different timepoints with a specific flow-chart according to both bilirubin levels and weight loss at discharge. RESULTS: During the study period early discharge was performed in 419 neonates and Follow-up was carried out in 408 neonates (97.4%). No neonates required readmission for hyperbilirubinaemia and dehydration during the first 28 days of life. Breastfeeding rate was 90.6%, 75.2%, 41.5% at 30, 90 and 180 days of life, respectively. A six-month phone interview was performed for 383 neonates (93.8%) and satisfaction of parents about early discharge was high in 345 cases (90.1%). CONCLUSIONS: Early discharge in association with an individualized Follow-up programme resulted safe for the neonate and effective for breastfeeding initation and duration. PMID- 25024009 TI - Substituent effects in hydrogen bonding: DFT and QTAIM studies on acids and carboxylates complexes with formamide. AB - Four series of hydrogen bonded complexes of formamide and substituted benzoic acids and benzoates were studied in the light of substituent effect on intermolecular interactions. The analysis based on energy of interaction, geometry, QTAIM-derived properties of hydrogen bond critical point and energy of hydrogen bonds were made and discussed. The opposite effect of the substituent on hydrogen bond donor and acceptor in acid series was found and analyzed. The isodesmic reactions were used to further study the interaction preferences. PMID- 25024008 TI - A unified coarse-grained model of biological macromolecules based on mean-field multipole-multipole interactions. AB - A unified coarse-grained model of three major classes of biological molecules- proteins, nucleic acids, and polysaccharides--has been developed. It is based on the observations that the repeated units of biopolymers (peptide groups, nucleic acid bases, sugar rings) are highly polar and their charge distributions can be represented crudely as point multipoles. The model is an extension of the united residue (UNRES) coarse-grained model of proteins developed previously in our laboratory. The respective force fields are defined as the potentials of mean force of biomacromolecules immersed in water, where all degrees of freedom not considered in the model have been averaged out. Reducing the representation to one center per polar interaction site leads to the representation of average site site interactions as mean-field dipole-dipole interactions. Further expansion of the potentials of mean force of biopolymer chains into Kubo's cluster-cumulant series leads to the appearance of mean-field dipole-dipole interactions, averaged in the context of local interactions within a biopolymer unit. These mean-field interactions account for the formation of regular structures encountered in biomacromolecules, e.g., alpha-helices and beta-sheets in proteins, double helices in nucleic acids, and helicoidally packed structures in polysaccharides, which enables us to use a greatly reduced number of interacting sites without sacrificing the ability to reproduce the correct architecture. This reduction results in an extension of the simulation timescale by more than four orders of magnitude compared to the all-atom representation. Examples of the performance of the model are presented. PMID- 25024010 TI - Conformational space and vibrational spectra of 2-[(2,4-dimethoxyphenyl)amino] 1,3-thiazolidin-4-one. AB - In this work we present the results of a study of the X-ray structure of 2-[(2,4 dimethoxyphenyl)amino]-1,3-thiazolidin-4-one. Using the FTIR spectra in solid state and results of ab initio calculations we explain the issue of the tautomerism of this molecule. The compound is shown to exist as the 2-amino tautomer rather 2-imino tautomer. Here we consider eight possible tautomers. On the basis of the vibrational spectra we can eliminate five possible tautomers, as not existing in the solid state. As the most possible tautomeric form we have found keto 2-amino form. PMID- 25024011 TI - A study of the interaction between HIV-1 protease and C 2-symmetric inhibitors by computational methods. AB - The human immunodeficiency virus type 1 protease (HIV-1 PR) is a major target for the design of anti-AIDS (acquired immune deficiency syndrome) drugs. Some C2 symmetric inhibitors have been designed for the C2-symmetric binding pocket of HIV-1PR. The crystallographic structures reveal that the binding modes are not C2 symmetric for C2-symmetric inhibitors binding to PR. In this work, four molecular dynamics (MD) simulations were performed to investigate the binding modes between four C2-symmetric inhibitors (6 AD, 6AG, 6FD and 6FG) and PR, as well as the stabilities of these inhibitors in the binding pocket. Analysis of the hydrophobic surface of the binding pocket shows that it is necessary to add a polar group to the P1 (benzyl) and P2 (phenyl) groups of the inhibitor 6AD. Analysis of the hydrogen bonds formed between inhibitors and residues (Asp25/Asp25', Ile50/Ile50') indicates that the steric structures of the inhibitors are not suitable for the binding pocket. The two increased polar groups of trifluoromethyl and formamido meet the needs of the binding pocket for polar molecules. The inhibitor with both these groups (6FG) has stronger stability than the other three inhibitors, which have only one (6AG and 6FD) or none (6AD) of these groups. The ranking of binding free energies calculated by molecular mechanics-generalized born surface area (MM-GBSA) method agrees well with the experimental data. It is expected that this study will provide theoretical guidance for the design of anti-AIDS drugs targeting HIV-1PR. PMID- 25024012 TI - Development and psychometric evaluation of an observational coding system measuring person-centered care in spouses of people with dementia. AB - BACKGROUND: The notion of person-centered care has been important in investigating relationships between people with dementia and paid carers, and measures are available to assess this. It has been suggested that person-centered care may be a useful construct to apply to understand family-care relationships. However, no measures of person-centered care in this context exist. The study aimed to develop an observational measure of person-centered care for this purpose. METHOD: First, a coding system incorporating a range of behaviors that could be considered person-centered or non-person-centered was constructed. Examples included a code relating to whether the person with dementia was involved in planning a task, and a code relating to how the spouse responded to confusion/distress. Second, 11 couples, where one partner had a dementia, were recruited and videotaped cooperating on an everyday task. The system was applied to the care-giving spouse's behaviors, labeling examples of behavior as person centered or non-person-centered. The final step involved assessing the inter rater reliability of the system. RESULTS: The system captured nine categories of behavior, which were each divided into person-centered and non-person-centered types. The system had good reliability (Cohen's kappa coefficients were: 0.65 for category and whether behaviors needed to be placed in a category; 0.81 for category excluding the decision about whether behaviors needed to be placed in a category; and 0.79 in relation to whether behaviors were person-centered or non person-centered.). CONCLUSIONS: Although the small sample size limits the implications of the results, the system is a promising quantitative measure of spousal person-centered care. PMID- 25024013 TI - Crash pulse optimization for occupant protection at various impact velocities. AB - OBJECTIVE: Vehicle deceleration has a large influence on occupant kinematic behavior and injury risks in crashes, and the optimization of the vehicle crash pulse that mitigates occupant loadings has been the subject of substantial research. These optimization research efforts focused on only high-velocity impact in regulatory or new car assessment programs though vehicle collisions occur over a wide range of velocities. In this study, the vehicle crash pulse was optimized for various velocities with a genetic algorithm. METHOD: Vehicle deceleration was optimized in a full-frontal rigid barrier crash with a simple spring-mass model that represents the vehicle-occupant interaction and a Hybrid III 50th percentile male multibody model. To examine whether the vehicle crash pulse optimized at the high impact velocity is useful for reducing occupant loading at all impact velocities less than the optimized velocity, the occupant deceleration was calculated at various velocities for the optimized crash pulse determined at a high speed. The optimized vehicle deceleration-deformation characteristics that are effective for various velocities were investigated with 2 approaches. RESULTS: The optimized vehicle crash pulse at a single impact velocity consists of a high initial impulse followed by zero deceleration and then constant deceleration in the final stage. The vehicle deceleration optimized with the Hybrid III model was comparable to that determined from the spring-mass model. The optimized vehicle deceleration-deformation characteristics determined at a high speed did not necessarily lead to an occupant deceleration reduction at a lower velocity. The maximum occupant deceleration at each velocity was normalized by the maximum deceleration determined in the single impact velocity optimization. The resulting vehicle deceleration-deformation characteristic was a square crash pulse. The objective function was defined as the number of injuries, which was the product of the number of collisions at the velocity and the probability of occupant injury. The optimized vehicle deceleration consisted of a high deceleration in the initial phase, a small deceleration in the middle phase, and then a high deceleration in the final phase. CONCLUSION: The optimized vehicle crash pulse at a single impact velocity is effective for reducing occupant deceleration in a crash at the specific impact velocity. However, the crash pulse does not necessarily lead to occupant deceleration reduction at a lower velocity. The optimized vehicle deceleration-deformation characteristics, which are effective for all impact velocities, depend on the weighting of the occupant injury measures at each impact velocity. PMID- 25024014 TI - Epidemiology and evolution of the genetic variability of Anaplasma marginale in South Africa. AB - Bovine anaplasmosis caused by infection of cattle with Anaplasma marginale has been considered to be endemic in South Africa, an assumption based primarily on the distribution of the tick vectors of A. marginale and serological studies on the prevalence of anaplasmosis in Limpopo, Free State, and North West. However, molecular evidence of the distribution of anaplasmosis has only been reported in the Free State province. In order to establish effective control measures for anaplasmosis, epidemiological surveys are needed to define the prevalence and distribution of A. marginale in South Africa. In addition, a proposed control strategy for anaplasmosis is the development of an A. marginale major surface protein 1a (MSP1a)-based vaccine. Nevertheless, regional variations of this gene would need to be characterized prior to vaccine development for South Africa. The objectives of the present study were therefore to conduct a national survey of the prevalence of A. marginale in South Africa, followed by an evaluation of the diversity and evolution of msp1a in South African strains of A. marginale. To accomplish these objectives, species-specific PCR was used to test 250 blood samples from cattle collected from all South African provinces (including 26 districts and municipalities), except the Free State province where similar studies were reported previously. The prevalence of A. marginale ranged from 65% to 100%, except in Northern Cape province where A. marginale was not detected. A correlation was found between the prevalence and genetic diversity of A. marginale MSP1a. Additionally, the genetic diversity of the A. marginale MSP1a was found to evolve under negative and positive selection, and 23 new tandem repeats in South Africa were shown to have evolved from the extant tandem repeat 4. Despite the MSP1a genetic variability, some types of tandem repeats were found to be conserved among the A. marginale strains, and low-variable peptides in MSP1a tandem repeats were subsequently identified. The results of this research confirmed that anaplasmosis is endemic in South Africa. The results of the molecular characterization of the MSP1a can then be used as the basis for development of new and novel vaccines for anaplasmosis control in South Africa. PMID- 25024015 TI - Mothers' experiences of home treatment for adolescents with anorexia nervosa: an interpretative phenomenological analysis. AB - Home treatment (HT) is emerging as an alternative to admission for adolescents with anorexia nervosa. It relies heavily on parental (often maternal) input to be effective. Given the high levels of carer stress reported by mothers, the current study aimed to explore mothers' experience of HT. A qualitative study using purposeful sampling was conducted. Nine interviews were analyzed using interpretative phenomenological analysis. Two contextual themes described the mother-daughter relationship and maternal stress and distress prior to HT. The third theme, "experience of help," included sub-themes of when help is needed, the need for containment, gaining strength and skills, and how HT met families' philosophy and values. The results support previous research on the stress that mothers particularly are under when their adolescent daughters have anorexia nervosa, and provides rich data on their experiences. HT is perceived as having both helpful and unhelpful aspects. Further research on its effectiveness is needed. PMID- 25024016 TI - Drug therapy in respiratory disease. AB - In a specialized Medical Thoracic Unit, the greater proportion of patients presenting for treatment will be those who have what we call obstructive airways disease. This is a descriptive term, used to describe the physiological impairment which occurs in patients with asthma, emphysema, and/or chronic bronchitis. PMID- 25024017 TI - Pain and labour - fact and fallacy. AB - Over 100 years ago midwifery was unable to combat successfully the high incidence of maternal deaths. In the search for solutions to this unfortunate situation, some people began to look to pain as a possible cause of the hazards of labour. PMID- 25024018 TI - Some aspects of the theory, performance, and interpretation of the strength duration test. AB - The strength duration test was first used for clinical purposes by Adrian (1916), and later developed by Ritchie (1944). The classical galvanic-faradic test, first used about 1859 by Baierlacher (Licht, 1961), was considered by Hickock in 1961 to be the most commonly used electro-diagnostic procedure. Today this test has been almost completely superseded by the strength duration test. PMID- 25024019 TI - The value of diaphragmatic breathing in the patient with obstructive airways disease. AB - It has been assumed that, by diaphragmatic breathing, a patient could vary his basal expansion. PMID- 25024020 TI - Modelling lipid competition dynamics in heterogeneous protocell populations. AB - Recent experimental work in the field of synthetic protocell biology has shown that prebiotic vesicles are able to 'steal' lipids from each other. This phenomenon is driven purely by asymmetries in the physical state or composition of the vesicle membranes, and, when lipid resource is limited, translates directly into competition amongst the vesicles. Such a scenario is interesting from an origins of life perspective because a rudimentary form of cell-level selection emerges. To sharpen intuition about possible mechanisms underlying this behaviour, experimental work must be complemented with theoretical modelling. The aim of this paper is to provide a coarse-grain mathematical model of protocell lipid competition. Our model is capable of reproducing, often quantitatively, results from core experimental papers that reported distinct types vesicle competition. Additionally, we make some predictions untested in the lab, and develop a general numerical method for quickly solving the equilibrium point of a model vesicle population. PMID- 25024021 TI - Neuroendocrine breast carcinoma metastatic to the liver: Report of a case and review of the literature. AB - INTRODUCTION: Primary neuroendocrine breast carcinoma (NEBC) is a rare entity of breast cancer. PRESENTATION OF CASE: We herein report a case of right hepatectomy for a NEBC liver metastasis. DISCUSSION: Little is known about its evolution, bilologic behavior and optimal treatment. Its malignant potential has been addressed in few reports, with cases of metachronous metastases in diverse sites, even years following treatment of the breast primarily. CONCLUSION: Treating this kind of cancer implies both breast and hepatic surgery. Primary neuroendocrine breast carcinoma (NEBC) is a rare entity of breast cancer. Little is known about its evolution, biologic behavior and optimal treatment. Its malignant potential has been addressed in few reports, with cases of metachronous metastases in diverse sites, even years following treatment of the breast primarily. We herein report a case of right hepatectomy for a NEBC liver metastasis. PMID- 25024022 TI - Nematode infection: A rare mimic of acute appendicitis. AB - INTRODUCTION: Acute appendicitis is a common condition seen in all surgical units. One rare condition that can mimic acute appendicitis is a nematode infection of the bowel. There have been few reported cases of nematode infection within the appendix and none that have been accompanied by intra-operative pictures. PRESENTATION OF CASE: A 16-year-old female presented with a 12h history of right iliac fossa pain and mild pyrexia. Bloods showed a neutrophilia and normal C-reactive protein. Laparoscopy was performed which revealed a non inflamed appendix. The appendix was dissected and a live nematode was visualised exiting the base of the appendix. Anti-helminthics were given and the infection resolved. DISCUSSION: Nematode infection is most commonly seen in Africa, Asia and South America. When seen within the United Kingdom (UK), it is seen most commonly within high-risk populations. Testing for these infections is not routine within the UK and when they are performed, the results take a considerable amount of time to return. These tests should be considered within high-risk populations so that unnecessary surgery can be avoided. CONCLUSION: This case highlights the importance of considering rare causes of right iliac fossa pain including nematode infection in a young patient. The case highlights this by giving intra-operative pictures of live nematodes upon dissection of the appendix. PMID- 25024023 TI - The surgical options and clinical evidence for treatment of wear or corrosion occurring with THA or TKA. AB - BACKGROUND: Wear and corrosion occurring in patients with hip and knee arthroplasty are common causes of failure leading to revision surgery. A variety of surgical approaches to these problems have been described, with varying efficacy. Polyethylene wear, metal-on-metal (MoM) hip bearing wear, and problems associated with modular taper corrosion are the areas of greatest clinical impact; results of revisions for these problems are likely to dictate a large portion of revision resources for the foreseeable future, and so they call for specific study. QUESTIONS/PURPOSES: We identified the most frequently reported procedures to treat hip polyethylene wear, knee polyethylene wear, MoM wear after THA, and modular taper corrosion and determined the timing and reasons these failed. METHODS: We performed systematic reviews of the published literature on the four topics using MEDLINE((r)) and Embase in October 2013; searches were supplemented by hand searches of bibliographies. Prespecified criteria resulted in the identification of 38 relevant articles, of which 33 were either case reports or Level IV evidence. Followup was generally at short term and ranged from 0.2 to 8 years. RESULTS: The most frequently reported procedures for treating clinically important wear were a partial or complete revision. When treating polyethylene wear, the more frequently reported reasons for hip and knee rerevisions were loosening, continued wear, and instability. Soft tissue reactions were more common and occasionally extensive in patients with MoM or modular taper corrosion. Patients with soft tissue reactions had more complications and higher rerevision rates. CONCLUSIONS: Studies with longer followup and higher levels of evidence are needed to direct the treatment of wear and corrosion. When soft tissue damage secondary to MoM wear or taper corrosion is present, the results of treatment can be poor. There is an urgent need to better understand these two mechanisms of failure. PMID- 25024025 TI - Bilateral clubfeet are highly correlated: a cautionary tale for researchers. AB - BACKGROUND: Congenital talipes equinovarus, or clubfoot, is a common pediatric orthopaedic condition of unknown origin. In many clubfoot clinical trials, interventions are assigned to a patient, but response to treatment is assessed separately in each foot. Trials commonly report x patients with y feet where y is greater than x (eg, 35 patients with 56 feet). However, common statistical tests assume that each data point is independent. Although data from unilateral cases of clubfoot are independent, it is unknown if each foot of patients with bilateral clubfeet are correlated. QUESTIONS/PURPOSES: The purpose of this study was to assess the correlation in the feet of patients with bilateral clubfeet by (1) evaluating the degree of severity between lower limbs of each patient with bilateral clubfeet at baseline; (2) determining if right and left feet of each patient responded to intervention in the same way; (3) determining the proportion of bilateral relapse; and (4) determining the proportion of right and left feet which required the same intervention to correct bilateral relapse. METHODS: We performed a chart review of the records of 33 patients with bilateral clubfeet (66 feet). Baseline severity was assessed using the Pirani score. The number of Ponseti serial casts to correct the deformity, the proportion of patients who underwent bilateral Achilles tenotomy, the proportion of bilateral relapse, and the treatment to correct bilateral relapse were examined. RESULTS: The degree of severity between right (Pirani score mean, 5.2; SD, 0.8) and left (Pirani score mean, 5.2; SD, 0.5) feet for each patient at baseline was highly correlated (r=0.76, p<0.001). Response to intervention between lower limbs was highly correlated for the number of Ponseti casts required for initial correction (right mean, 5.2, SD, 1.1; left mean, 5.2, SD, 1.3) (r=0.89, p<0.001) and the proportion of patients who underwent bilateral Achilles tenotomy (right, 17/18; left, 16/18) (r=0.94, p<0.001). In the nine patients who experienced relapse, eight experienced bilateral involvement. In all cases of bilateral relapse, the right and left foot of each patient required the same intervention to correct the relapse. CONCLUSIONS: In patients with bilateral clubfeet, baseline severity, response to initial Ponseti treatment, Achilles tenotomy, and relapse outcomes were highly correlated in the right and left feet of each patient. Pooling clinical results of patients who present with bilateral clubfeet is statistically inappropriate, since results in two limbs of the same patient do not represent independent observations. These results support analogous work in other specialties suggesting that patients with bilateral presentations should not be analyzed as independent data points. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 25024024 TI - Molecular basis of intervertebral disc degeneration and herniations: what are the important translational questions? AB - BACKGROUND: Intervertebral disc degeneration is a common condition with few inexpensive and effective modes of treatment, but current investigations seek to clarify the underlying process and offer new treatment options. It will be important for physicians to understand the molecular basis for the pathology and how it translates to developing clinical treatments for disc degeneration. In this review, we sought to summarize for clinicians what is known about the molecular processes that causes disc degeneration. RESULTS: A healthy disc requires maintenance of a homeostatic environment, and when disrupted, a catabolic cascade of events occurs on a molecular level resulting in upregulation of proinflammatory cytokines, increased degradative enzymes, and a loss of matrix proteins. This promotes degenerative changes and occasional neurovascular ingrowth potentially contributing to the development of pain. Research demonstrates the molecular changes underlying the harmful effects of aging, smoking, and obesity seen clinically while demonstrating the variable influence of exercise. Finally, oral medications, supplements, biologic treatments, gene therapy, and stem cells hold great promise but require cautious application until their safety profiles are better outlined. CONCLUSIONS: Intervertebral disc degeneration occurs where there is a loss of homeostatic balance with a predominantly catabolic metabolic profile. A basic understanding of the molecular changes occurring in the degenerating disc is important for practicing clinicians because it may help them to inform patients to alter lifestyle choices, identify beneficial or harmful supplements, or offer new biologic, genetic, or stem cell therapies. PMID- 25024026 TI - CORR Insights(r): Undiagnosed vertebral fractures influence quality of life in postmenopausal women with reduced ultrasound parameters. PMID- 25024027 TI - CORR Insights(r): New total knee arthroplasty designs: do young patients notice? PMID- 25024028 TI - The Otto Aufranc Award: Modifiable versus nonmodifiable risk factors for infection after hip arthroplasty. AB - BACKGROUND: Periprosthetic joint infections (PJIs) are associated with increased morbidity and cost. It would be important to identify any modifiable patient- and surgical-related factors that could be modified before surgery to decrease the risk of PJI. QUESTIONS/PURPOSES: We sought to identify and quantify the magnitude of modifiable risk factors for deep PJIs after primary hip arthroplasty. METHODS: A series of 3672 primary and 406 revision hip arthroplasties performed at a single specialty hospital over a 3-year period were reviewed. All deep PJIs were identified using the Centers for Disease Control and Prevention case definitions (ie, occurs within 30-90 days postoperatively, involves deep soft tissues of the incision, purulent drainage, dehiscence and fever, localized pain or tenderness). Univariate and multivariate analyses determined the association between patient and surgical risk factors and PJIs. For the elective patients, the procedure was performed on the day of admission ("same-day procedure"), whereas for the fracture and nonelective patients, the procedure was performed 1 or more days postadmission ("nonsame-day procedure"). Staphylococcus aureus colonization, tobacco use, and body mass index (BMI) were defined as patient-related modifiable risk factors. RESULTS: Forty-seven (1.3%) deep PJIs were identified. Infection developed in 20 of 363 hips of nonsame-day procedures and 27 of 3309 same-day procedures (p=0.006). There were eight (2%) infections in the revision group. After controlling for confounding variables, our multivariate analysis showed that BMI?40 kg/m2 (odds ratio [OR], 4.13; 95% confidence interval [CI], 1.3 12.88; p=0.01), operating time>115 minutes (OR, 3.38; 95% CI, 1.23-9.28; p=0.018), nonsame-day surgery (OR, 4.16; 95% CI, 1.44-12.02; p=0.008), and revision surgery (OR, 4.23; 95% CI, 1.67-10.72; p<0.001) are significant risk factors for PJIs. Tobacco use and S aureus colonization were additive risk factors when combined with other significant risk factors (OR, 12.76; 95% CI, 2.47-66.16; p=0.017). CONCLUSIONS: Nonsame-day hip and revision arthroplasties have higher infection rates than same-day primary surgeries. These characteristics are not modifiable and should be categorized as a separate cohort for complication-reporting purposes. Potentially modifiable risk factors in our patient population include operating time, elevated BMI, tobacco use, and S aureus colonization. Modifying risk factors may decrease the incidence of PJIs. When reporting deep PJI rates, stratification into preventable versus nonpreventable infections may provide a better assessment of performance on an institutional and individual surgeon level. LEVEL OF EVIDENCE: Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 25024029 TI - What design and material factors impact the wear and corrosion performance in total elbow arthroplasties? AB - BACKGROUND: The survivorship of total elbow arthroplasties is lower than surgeons and patients would like it to be, especially in patients with posttraumatic arthritis of the elbow. To improve durability, it is important to understand the failure modes of existing implants. Total elbow arthroplasties were designed primarily for low-demand rheumatoid patients. As surgical indications have extended to more active patient populations, the mechanical performance of current designs must meet an increased mechanical burden. Evaluating the degree to which they do this will guide conclusions about which contemporary devices might still meet the need and, as importantly, what design and material changes might be needed to improve performance. WHERE ARE WE NOW?: The reasons for failures of total elbow arthroplasties include infection, loosening, polyethylene wear, locking mechanism failure, periprosthetic fracture, implant fracture, and instability. Implant design factors that have influenced wear include implant constraint, material, coatings, and metal backing. Surgical factors associated with increased wear and subsequent total elbow arthroplasty failure include soft tissue balancing and restoration of alignment and implant positioning. WHERE DO WE NEED TO GO?: A clear need exists for improving the performance of total elbow arthroplasty. Many of the failures that have limited the survivorship of elbow arthroplasties thus far are mechanical in nature with wear-related problems a dominating influence. Much of what we know about the results of total elbow arthroplasty is from small studies frequently involving the designer of the implant. The establishment of total elbow arthroplasty registries coupled with the increasing regulatory burden of postmarket surveillance would lead to a better understanding of the complications and survivorship of elbow arthroplasties. Another primary goal must be to achieve a better understanding of the biomechanics of the normal elbow and how the mechanics are altered after the insertion of elbow arthroplasty components. HOW DO WE GET THERE?: Improving the performance and survivorship of total elbow arthroplasty will require the integration of clinical and implant performance data gained through the establishment of registries with a concerted basic science effort to better understand the functional loads across the joint and to incorporate these loads into experimental and computational models to allow assessment of design and material changes intended to improve durability. PMID- 25024030 TI - Editorial comment: Symposium: Recent advances in amputation surgery and rehabilitation. PMID- 25024032 TI - Editor's spotlight/Take 5: CORR(r) ORS Richard A. Brand Award for Outstanding Orthopaedic Research: Engineering flexor tendon repair with lubricant, cells, and cytokines in a canine model. PMID- 25024031 TI - Small improvements in mechanical axis alignment achieved with MRI versus CT-based patient-specific instruments in TKA: a randomized clinical trial. AB - BACKGROUND: Patient-specific instrumentation in TKA has the proposed benefits of improving coronal and sagittal alignment and rotation of the components. In contrast, the literature is inconsistent if the use of patient-specific instrumentation improves alignment in comparison to conventional instrumentation. Depending on the manufacturer, patient-specific instrumentation is based on either MRI or CT scans. However, it is unknown whether one patient-specific instrumentation approach is more accurate than the other and if there is a potential benefit in terms of reduction of duration of surgery. QUESTIONS/PURPOSES: We compared the accuracy of MRI- and CT-based patient specific instrumentation with conventional instrumentation and with each other in TKAs. The three approaches also were compared with respect to validated outcomes scores and duration of surgery. METHODS: A randomized clinical trial was conducted in which 90 patients were enrolled and divided into three groups: CT based, MRI-based patient-specific instrumentation, and conventional instrumentation. The groups were not different regarding age, male/female sex distribution, and BMI. In all groups, coronal and sagittal alignments were measured on postoperative standing long-leg and lateral radiographs. Component rotation was measured on CT scans. Clinical outcomes (Knee Society and WOMAC scores) were evaluated preoperatively and at a mean of 3 months postoperatively and the duration of surgery was analyzed for each patient. MRI- and CT-based patient-specific instrumentation groups were first compared with conventional instrumentation, the patient-specific instrumentation groups were compared with each other, and all three approaches were compared for clinical outcome measures and duration of surgery. RESULTS: Compared with conventional instrumentation MRI- and CT-based patient-specific instrumentation showed higher accuracy regarding the coronal limb axis (MRI versus conventional, 1.0 degrees [range, 0 degrees -4 degrees ] versus 4.5 degrees [range, 0 degrees -8 degrees ], p < 0.001; CT versus conventional, 3.0 degrees [range, 0 degrees -5 degrees ] versus 4.5 degrees [range, 0 degrees -8 degrees ], p = 0.02), femoral rotation (MRI versus conventional, 1.0 degrees [range, 0 degrees -2 degrees ] versus 4.0 degrees [range, 1 degrees -7 degrees ], p < 0.001; CT versus conventional, 1.0 degrees [range, 0 degrees -2 degrees ] versus 4.0 degrees [range, 1 degrees -7 degrees ], p < 0.001), and tibial slope (MRI versus conventional, 1.0 degrees [range, 0 degrees -2 degrees ] versus 3.5 degrees [range, 1 degrees -7 degrees ], p < 0.001; CT versus conventional, 1.0 degrees [range, 0 degrees -2 degrees ] versus 3.5 degrees [range, 1 degrees -7 degrees ], p < 0.001), but the differences were small. Furthermore, MRI-based patient-specific instrumentation showed a smaller deviation in the postoperative coronal mechanical limb axis compared with CT based patient-specific instrumentation (MRI versus CT, 1.0 degrees [range, 0 degrees -4 degrees ] versus 3.0 degrees [range, 0 degrees -5 degrees ], p = 0.03), while there was no difference in femoral rotation or tibial slope. Although there was a significant reduction of the duration of surgery in both patient-specific instrumentation groups in comparison to conventional instrumentation (MRI versus conventional, 58 minutes [range, 53-67 minutes] versus 76 minutes [range, 57-83 minutes], p < 0.001; CT versus conventional, 63 minutes [range, 59-69 minutes] versus 76 minutes [range, 57-83 minutes], p < .001), there were no differences in the postoperative Knee Society pain and function and WOMAC scores among the groups. CONCLUSIONS: Although this study supports that patient-specific instrumentation increased accuracy compared with conventional instrumentation and that MRI-based patient-specific instrumentation is more accurate compared with CT-based patient-specific instrumentation regarding coronal mechanical limb axis, differences are only subtle and of questionable clinical relevance. Because there are no differences in the long term clinical outcome or survivorship yet available, the widespread use of this technique cannot be recommended. PMID- 25024033 TI - Correlation of knee and hindfoot deformities in advanced knee OA: compensatory hindfoot alignment and where it occurs. AB - BACKGROUND: Many patients undergoing TKA have both knee and ankle pathology, and it seems likely that some compensatory changes occur at each joint in response to deformity at the other. However, it is not fully understood how the foot and ankle compensate for a given varus or valgus deformity of the knee. QUESTIONS/PURPOSES: (1) What is the compensatory hindfoot alignment in patients with end-stage osteoarthritis who undergo total knee arthroplasty (TKA)? (2) Where in the hindfoot does the compensation occur? METHODS: Between January 1, 2005, and December 31, 2009, one surgeon (JJC) obtained full-length radiographs on all patients undergoing primary TKA (N=518) as part of routine practice; patients were analyzed for the current study and after meeting inclusion criteria, a total of 401 knees in 324 patients were reviewed for this analysis. Preoperative standing long-leg AP radiographs and Saltzman hindfoot views were analyzed for the following measurements: mechanical axis angle, Saltzman hindfoot alignment and angle, anatomic lateral distal tibial angle, and the ankle line convergence angle. Statistical analysis included two-tailed Pearson correlations and linear regression models. Intraobserver and interobserver intraclass coefficients for the measurements considered were evaluated and all were excellent (in excess of 0.8). RESULTS: As the mechanical axis angle becomes either more varus or valgus, the hindfoot will subsequently orient in more valgus or varus position, respectively. For every degree increase in the valgus mechanical axis angle, the hindfoot shifts into varus by -0.43 degrees (95% confidence interval [CI], -0.76 degrees to -0.1 degrees ; r=-0.302, p=0.0012). For every degree increase in the varus mechanical axis angle, the hindfoot shifts into valgus by -0.49 degrees (95% CI, -0.67 degrees to -0.31 degrees ; r= 0.347, p<0.0001). In addition, the subtalar joint had a strong positive correlation (r=0.848, r2=0.72, p<0.0001) with the Saltzman hindfoot angle, whereas the anatomic lateral distal tibial angle (r=0.450, r2=0.20, p<0.0001) and the ankle line convergence angle (r=0.319, r2=0.10, p<0.0001) had a moderate positive correlation. The coefficient of determination (r2) shows that 72% of the variance in the overall hindfoot angle can be explained by changes in the subtalar joint orientation. CONCLUSIONS: These findings have implications for treating patients with both knee and foot/ankle problems. For example, a patient with varus arthritis of the knee should be examined for fixed hindfoot valgus deformity. The concern is that patients undergoing TKA, who also present with a stiff subtalar joint, may have exacerbated, post-TKA foot/ankle pain or disability or malalignment of the lower extremity mechanical axis as a result of the inability of the subtalar joint to reorient itself after knee realignment. A prospective study is underway to confirm this speculation. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 25024035 TI - Variations on a common STRUCTURE: new algorithms for a valuable model. PMID- 25024034 TI - The "domestication syndrome" in mammals: a unified explanation based on neural crest cell behavior and genetics. AB - Charles Darwin, while trying to devise a general theory of heredity from the observations of animal and plant breeders, discovered that domesticated mammals possess a distinctive and unusual suite of heritable traits not seen in their wild progenitors. Some of these traits also appear in domesticated birds and fish. The origin of Darwin's "domestication syndrome" has remained a conundrum for more than 140 years. Most explanations focus on particular traits, while neglecting others, or on the possible selective factors involved in domestication rather than the underlying developmental and genetic causes of these traits. Here, we propose that the domestication syndrome results predominantly from mild neural crest cell deficits during embryonic development. Most of the modified traits, both morphological and physiological, can be readily explained as direct consequences of such deficiencies, while other traits are explicable as indirect consequences. We first show how the hypothesis can account for the multiple, apparently unrelated traits of the syndrome and then explore its genetic dimensions and predictions, reviewing the available genetic evidence. The article concludes with a brief discussion of some genetic and developmental questions raised by the idea, along with specific predictions and experimental tests. PMID- 25024037 TI - Approaches for improving literature review methods. PMID- 25024038 TI - Socialized medicine and mortality. AB - Over the last century life expectancy has increased substantially and so has the share of health care expenditures financed by governments. In cross-country comparisons, the US, which has the lowest government health expenditure share, often has the poorest health outcomes. Is there a plausible connection between health outcomes and government financing of health care? This paper addresses this question with panel data from 20 developed countries from 1950 to 2010. I review the history of government involvement in health care financing over this period. Then I use panel regression methods to examine whether a variety of mortality based outcome measures are correlated with the extent of government involvement. The answers are robustly negative. PMID- 25024039 TI - Health care expenditure decisions in the presence of devolution and equalisation grants. AB - In a model where health care provision, its regional distribution and the equalisation grant are the result of a utilitarian bargaining between a (relatively) rich region and a poor one, a First Best solution can be reached only if the two Regions have the same bargaining power. From a policy point of view, our model may explain the observed cross-national differences in the redistributive power of health care expenditure and it suggests that to equalise resources across Regions an income based equalisation grant may be preferred because it causes less distortions than an expenditure based one. PMID- 25024040 TI - Polymorphism of DEFA in Chinese Han population with IgA nephropathy. AB - Our recent genome-wide association study (GWAS) had discovered a new locus at 8p23 (rs2738048) associated with IgA nephropathy (IgAN) in Chinese Han patients, implicating the DEFA gene family within this locus as susceptibility genes. However, it is still unknown whether there are additional variations within these genes associated with the disease susceptibility. The aim of this study is to investigate the polymorphisms of DEFA genes in the susceptibility to IgAN and explore possible disease mechanisms. Sixteen tag single-nucleotide polymorphisms (tag SNPs) were selected for association study in 1,000 IgAN cases and 1,000 controls by using Sequenom MassArray system or TaqMan SNP genotyping assays. We found seven SNPs within DEFA genes that were significantly associated with IgAN, including rs2738048 discovered in our previous GWAS (p = 0.0007, OR = 0.77) and additional 6 SNPs (rs2615787, p = 0.0001, OR = 0.74; rs2738081, p = 0.0003, OR = 0.72; rs2738058, p = 0.0001, OR = 0.73; rs4288398, p = 0.0008, OR = 0.78; rs6984215, p = 0.002, OR = 0.63; rs12716641, p = 0.00002, OR = 0.71). Electrophoretic mobility shift assays and luciferase assays demonstrated that fragments containing rs2738048, rs2738081 and rs6984215 were transcription factor binding sites for CTF, SP1 and CdxA, respectively, and the allele status of rs2738048 and rs6984215 could significantly change the luciferase activity. These results suggest that polymorphisms within DEFA genes are involved in gene transcriptional regulation, and this may have some effect in mediating susceptibility to IgAN in southern Chinese. PMID- 25024041 TI - The role of adjuvant chemotherapy in stage II colorectal cancer patients. AB - PURPOSE: Adjuvant chemotherapy use in stage II colorectal cancer (CRC) is debated. We evaluated the prognostic significance of clinicopathological features recommended by most guidelines for identifying high-risk stage II CRC and adjuvant chemotherapeutic response. METHODS: We enrolled 1,039 stage II CRC patients who underwent curative surgery at Taipei Veterans General Hospital from January 2005 to December 2010. Seventy-seven patients who received radiotherapy were excluded. The endpoint was disease-free survival. RESULTS: Of 962 patients, 37 had stage T4 tumors; 50, lymphovascular invasion; 39, poor differentiation; 249, preoperative carcinoembryonic antigen (CEA) levels >5 ng/mL; and 53 underwent emergent operations. One hundred ninety-four patients received 5 fluorouracil-based adjuvant chemotherapy. During a median follow-up period of 60.2 months, recurrence developed in 110 patients (11.4 %). The 5-year disease free survival (DFS) was 87.6 %. In multivariate analysis, preoperative CEA >5 ng/ml (p = 0.001), emergent operation for obstruction/perforation (p = 0.008), lymphovascular invasion (p = 0.014), and T4 disease (p = 0.030) were significantly associated with poor DFS. High-risk stage II patients (n = 484) benefited from adjuvant chemotherapy (5-year DFS with and without adjuvant chemotherapy, 87.3 vs. 78.9 %; p = 0.028). CONCLUSIONS: Adjuvant chemotherapy improved DFS in high-risk stage II CRC patients, but not in low-risk patients. PMID- 25024042 TI - Comment on Ribaric et al: STARR with CONTOUR(r) TRANSTARTM device for obstructed defecation syndrome: one-year real-world outcomes of the European TRANSTAR registry. PMID- 25024043 TI - Improved survival for older patients undergoing surgery for colorectal cancer between 2008 and 2011. AB - INTRODUCTION: Older colorectal cancer patients have a higher risk of postoperative complications, and the impact of adverse events on survival is also significantly higher. Innovations like laparoscopic surgery which improve short term outcome for older patients can also benefit their overall prognosis. We set out to analyse the impact of an increased utilisation of laparoscopic surgery for colorectal cancer in the Netherlands on overall survival. METHODS: All patients diagnosed with stages I-III colorectal cancer in the Netherlands between 2008 and 2011 were selected from the Netherlands Cancer Registry. Changes in perioperative mortality, 3-month mortality and 1-year mortality rates were analysed using year of diagnosis as an instrumental variable. RESULTS: Over 33,000 patients were included in the analyses. Data on surgical approach were not precisely known for 2008 and 2009; in 2010, 36.6 % of definitive surgical procedures were performed laparoscopically and 45.9 % in 2011. A laparoscopic approach was used less frequently in the patients aged >=75 years (in 2011, 40.3 versus 49.2 % of younger patients; p < 0.001). Between 2008 and 2011, perioperative mortality decreased from 2.0 to 1.5 % (p = 0.02), 3-month mortality from 4.8 to 3.9 % (p = 0.01) and 1-year mortality from 9.6 to 8.3 % (p < 0.001). The absolute risk reduction was greatest for patients aged >=75 years, reaching 2.1 % for 1-year mortality. CONCLUSION: Between 2008 and 2011, the utilisation of a laparoscopic approach increases significantly, resulting in reduced mortality rates, particularly for the elderly. Therefore, a laparoscopic approach should be used whenever possible, which may allow for further improvement of outcomes. PMID- 25024044 TI - Dissolved organic matter adsorption to model surfaces: adlayer formation, properties, and dynamics at the nanoscale. AB - Adlayers of dissolved organic matter (DOM) form on many surfaces in natural and engineered systems and affect a number of important processes in these systems. Yet, the nanoscalar properties and dynamics of DOM adlayers remain poorly investigated. This work provides a systematic analysis of the properties and dynamics of adlayers formed from a diverse set of eight humic and fulvic acids, used as DOM models, on surfaces of self-assembled monolayers (SAMs) of different alkylthiols covalently bound to gold supports. DOM adsorption to positively charged amine-terminated SAMs resulted in the formation of water-rich adlayers with nanometer thicknesses that were relatively rigid, irreversibly adsorbed, and collapsed upon air drying, as demonstrated by combined quartz crystal microbalance and ellipsometry measurements. DOM adlayer thicknesses varied only slightly with solution pH from 5 to 8 but increased markedly with increasing ionic strength. Contact angle measurements revealed that the DOM adlayers were relatively polar, likely due to the high water contents of the adlayers. Comparing DOM adsorption to SAM-coated sensors that systematically differed in surface charge and polarity characteristics showed that electrostatics dominated DOM-surface interactions. Laccase adsorption to DOM adlayers on amine-terminated SAMs served to demonstrate the applicability of the presented experimental approach to study the interactions of (bio)macromolecules and (nano)particles with DOM. PMID- 25024045 TI - Oligo-microarray analysis and identification of stress-immune response genes from manila clam (Ruditapes philippinarum) exposure to heat and cold stresses. AB - Thermal stress regulates the complex system of gene expression and downstream biochemical and physiological responses in aquatic species. To identify genes involved in heat stress responses in manila clam (Ruditapes philippinarum), microarray analysis was conducted using clam transcriptome generated by pyrosequencing of cDNA library. Manila clams were exposed to heat (30 +/- 1 degrees C) and cold (4 +/- 1 degrees C) stresses and compared with control animals (18 +/- 1 degrees C). Heat stressed animals have changed greater number of transcripts (8,306) than cold stress (7,573). Results of both heat and cold exposure has shown that over 2-fold up-regulated or down regulated (>2-or <2 fold) transcripts were higher at 24 h than at 6 h. It suggests that silent and constitutive express genes can activate at critical stage of thermal stress which could be between 6 and 24 h post stresses. We identified wide range of stress immune response genes such as transcription factors, heat shock proteins, antioxidant and detoxification enzymes, inflammatory and apoptosis related genes, cell adhesion molecules, cytokines, and IFN regulatory proteins. Histological results revealed that non-specific cellular alterations such as lesions, hypertrophy, and necrosis in stressed gills could be due to decrease of gas exchange rate which may cause hypoxia. PMID- 25024046 TI - The complete mitochondrial genome of Neobenedenia melleni (Platyhelminthes: Monogenea): mitochondrial gene content, arrangement and composition compared with two Benedenia species. AB - The complete mitochondrial (mt) genome sequences of Neobenedenia melleni were determined and compared with those of Benedenia seriolae and B. hoshinai. This circular genome comprises 13,270 bp and includes all 36 typical mt genes found in flatworms. Total AT content of N. melleni is 75.9 %. ATG is the most common start codon, while nad4L is initiated by GTG. All protein-coding genes are predicted to terminate with TAG and TAA. N. melleni has the trnR with a TCG anticodon, which is the same to B. seriolae but different from B. hoshinai (ACG). The mt gene arrangement of N. melleni is similar to that of B. seriolae and B. hoshinai with the exception of three translocations (trnF, trnT and trnG). The overlapped region between nad4L and nad4 was found in the N. melleni mt genome, which was also reported for the published Gyrodactylus species, but it was not found in those of B. seriolae and B. hoshinai, which are non-coding regions instead. The present study provides useful molecular characters for species or strain identification and systematic studies of this parasite. PMID- 25024047 TI - Minimum length of direct repeat sequences required for efficient homologous recombination induced by zinc finger nuclease in yeast. AB - Zinc finger nuclease (ZFN) technology is a powerful molecular tool for targeted genome modifications and genetic engineering. However, screening for specific ZFs and validation of ZFN activity are labor intensive and time consuming. We previously designed a yeast-based ZFN screening and validation system by inserting a ZFN binding site flanked by a 164 bp direct repeat sequence into the middle of a Gal4 transcription factor, disrupting the open reading frame of the yeast Gal4 gene. Expression of the ZFN causes a double stranded break at its binding site, which promotes the cellular DNA repair system to restore expression of a functional Gal transcriptional factor via homologous recombination. Expression of Gal4 transcription factor leads to activation of three reporter genes in an AH109 yeast two-hybrid strain. However, the 164 bp direct repeat appears to generate spontaneous homologous recombination frequently, resulting in many false positive ZFNs. To overcome this, a series of DNA fragments of various lengths from 10 to 150 bp with 10 bp increase each and 164 bp direct repeats flanking the ZFN binding site were designed and constructed. The results demonstrated that the minimum length required for ZFN-induced homologous recombination was 30 bp, which almost eliminated spontaneous recombination. Using the 30 bp direct repeat sequence, ZFN could efficiently induce homologous recombination, while false positive ZFNs resulting from spontaneous homologous recombination were minimized. Thus, this study provided a simple, fast and sensitive ZFN screening and activity validation system in yeast. PMID- 25024048 TI - Blood cells transcriptomics as source of potential biomarkers of articular health improvement: effects of oral intake of a rooster combs extract rich in hyaluronic acid. AB - The aim of the study was to explore peripheral blood gene expression as a source of biomarkers of joint health improvement related to glycosaminoglycan (GAG) intake in humans. Healthy individuals with joint discomfort were enrolled in a randomized, double-blind, placebo-controlled intervention study in humans. Subjects ate control yoghurt or yoghurt supplemented with a recently authorized novel food in Europe containing hyaluronic acid (65 %) from rooster comb (MobileeTM as commercial name) for 90 days. Effects on functional quality-of-life parameters related to joint health were assessed. Whole-genome microarray analysis of peripheral blood samples from a subset of 20 subjects (10 placebo and 10 supplemented) collected pre- and post-intervention was performed. MobileeTM supplementation reduced articular pain intensity and synovial effusion and improved knee muscular strength indicators as compared to placebo. About 157 coding genes were differentially expressed in blood cells between supplemented and placebo groups post-intervention, but not pre-intervention (p < 0.05; fold change >=1.2). Among them, a reduced gene expression of glucuronidase-beta (GUSB), matrix metallopeptidase 23B (MMP23B), xylosyltransferase II (XYLT2), and heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) was found in the supplemented group. Correlation analysis indicated a direct relationship between blood cell gene expression of MMP23B, involved in the breakdown of the extracellular matrix, and pain intensity, and an inverse relationship between blood cell gene expression of HS6ST1, responsible for 6-O-sulfation of heparan sulfate, and indicators of knee muscular strength. Expression levels of specific genes in blood cells, in particular genes related to GAG metabolism and extracellular matrix dynamics, are potential biomarkers of beneficial effects on articular health. PMID- 25024049 TI - Midlife insomnia and subsequent mortality: the Hordaland health study. AB - BACKGROUND: Previous research suggests a possible link between insomnia and mortality, but findings are mixed and well-controlled studies are lacking. The aim of the current study was to examine the effect of insomnia in middle age on all-cause mortality. METHODS: Using a cohort design with 13-15 years follow-up, mortality registry data were linked to health information obtained during 1997 99, as part of the community-based Hordaland Health Study (HUSK), in Western Norway. 6,236 participants aged 40-45 provided baseline information on self- reported insomnia using the Karolinska Sleep Questionnaire Scale (defined according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), sociodemographic factors, health behaviors, shift/night-work, obstructive sleep apnea symptoms, sleep duration, sleep medication use, anxiety, depression, as well as a range of somatic diagnoses and symptoms. Height, weight and blood pressure were measured. Information on mortality was obtained from the Norwegian Cause of Death Registry. RESULTS: Insomnia was reported by 5.6% (349/6236) at baseline and a significant predictor of all-cause-mortality (hazard ratio [HR] = 2.74 [95% CI:1.75-4.30]). Adjusting for all confounders did not attenuate the effect (HR = 3.34 [95% CI:1.67-6.69]). Stratifying by gender, the effect was especially strong in men (HR = 4.72 [95% CI:2.48-9.03]); but also significant in women (adjusted HR = 1.96 [95% CI:1.04-3.67]). The mortality risk among participants with both insomnia and short sleep duration (<6.5 hours) was particularly high, whereas insomnia in combination with normal/greater sleep duration was not associated with mortality. CONCLUSIONS: Insomnia was associated with a three-fold risk of mortality over 13-15 years follow-up. The risk appeared even higher in males or when insomnia was combined with short sleep duration, although such unadjusted subgroup analyses should be interpreted with caution. Establishing prevention strategies and low-threshold interventions should consequently be a prioritized task for public health policy. PMID- 25024050 TI - Cyanobacteria as an Experimental Platform for Modifying Bacterial and Plant Photosynthesis. PMID- 25024051 TI - Antibody drug conjugates. AB - PURPOSE OF REVIEW: Antibody conjugates are a diverse complex class of therapeutics, consisting of a potent cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells or an extracellular target, that are having impact in the clinic. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The more than 30-year history of antibody conjugates is marked by hurdles that have been identified and overcome. RECENT FINDINGS: Technology is continuing to evolve the protein and small molecule components, and it is likely that soon single-chemical entities will be the norm for antibody drug conjugates. More than 20 antibody conjugates are currently in clinical trials. SUMMARY: The time has arrived for this technology to become a major contributor to improving treatment for cancer patients. PMID- 25024052 TI - Adult granulosa cell tumours of the ovary. AB - PURPOSE OF REVIEW: Adult ovarian granulosa cell tumours (AGCTs) are the most common sex cord-stromal tumours. Although the prognosis is generally favourable, recurrent or advanced AGCT shows poor prognosis. An overview of the main findings on the management of AGCT published recently is provided. RECENT FINDINGS: Novel biomarkers, including FOXL2, SMAD3 and GATA4, have been identified as potential diagnostic and therapeutic targets for this type of tumour. Interesting therapeutic implications are also emerging from studies on preclinical models, supporting the possible activity of anti-vascular endothelial growth factor A therapy for the treatment of AGCTs. Further, potentially active drugs could be targeting agents directed against epidermal growth factor receptor and/or insulin growth factor receptor-1. Recent data confirmed the importance of surgery in the management of AGCTs, in which hysterectomy can be avoided in young patients, as a recent study demonstrated that the risk of endometrial cancer after salpingo oophorectomy for AGCT, with negative endometrial evaluation, is lower than the risk of endometrial cancer in the general population. SUMMARY: The present review highlights current challenges and future directions in the treatment of AGCTs.Optimization of existing treatment modalities and the addition of novel drugs may hopefully lead to improved oncologic outcomes. PMID- 25024053 TI - Diffusion weighted MRI in ovarian cancer. AB - PURPOSE OF REVIEW: The role of diffusion weighted MRI (DW-MRI) in ovarian cancer management has been the focus of recent research. In this article, the main research interests and the current and future clinical applications of DW-MRI in ovarian cancer will be discussed. RECENT FINDINGS: For characterization of complex adnexal masses, the absence of residual signal intensity on high b-value diffusion weighted images in the solid component of a mass is a strong indicator of benignity, with a high negative predictive value for cancer. Detection of malignant peritoneal implants can be achieved with a high sensitivity and specificity. This is mainly due to the high contrast resolution obtained on DW MRI images. Changes in the quantifiable parameter of diffusion, the apparent diffusion coefficient (ADC), can be measured to identify response following chemotherapy. Changes in ADC may reflect biological events in the tissue and ultimately may allow the early identification of nonresponders. Differences in ADC or ADC change post-therapy at different tumour sites within the same patient may reflect tumour heterogeneity. SUMMARY: The use of DW-MRI in the characterization of indeterminate adnexal masses is becoming well established and may have an important role in the preoperative confirmation of benignity. DW-MRI in the detection of sites of peritoneal disease and in the early detection of response to chemotherapy remain areas of research interest with great potential. PMID- 25024054 TI - Phosphoinositide 3-kinase inhibitors in lymphoma. AB - PURPOSE OF REVIEW: The phosphoinositide 3-kinase (PI3K) pathway, with downstream targets including Akt and mammalian target of rapamycin, has been implicated in numerous human cancers, including hematologic malignancies and lymphomas. The development and refinement of PI3K inhibitors directed toward this pathway show promising clinical efficacy. This review will discuss the emerging body of clinical data in lymphoid malignancies and present future directions for research utilizing these inhibitors. RECENT FINDINGS: The PI3Kdelta inhibitor, idelalisib, has been most widely studied in lymphoma, and has shown promising results both as a single agent and in combination with other therapies. IPI-145, a dual inhibitor of PI3Kdelta and PI3Kgamma, has also shown efficacy and several clinical trials are underway. Other PI3K inhibitors are in active development, with several entering early phase clinical trials. SUMMARY: The PI3K pathway appears to be important in lymphoma and targeting this pathway shows promising clinical efficacy. PMID- 25024055 TI - To play or not to play: a personal dilemma in pathological gambling. AB - Research has shown that healthy people would rather avoid losses than gamble for even higher gains. On the other hand, research on pathological gamblers (PGs) demonstrates that PGs are more impaired than non-pathological gamblers in choice under risk and uncertainty. Here, we investigate loss aversion by using a rigorous and well-established paradigm from the field of economics, in conjunction with personality traits, by using self-report measures for PGs under clinical treatment. Twenty pathological gamblers, at the earlier and later stages of clinical treatment, were matched to 20 non-gamblers (NG). They played a "flip coin task" by deciding across 256 trials whether to accept or reject a 50-50 bet with a variable amount of gains and losses. They completed questionnaires aimed at assessing impulsivity. Compared to NG, pathological gamblers, specifically those in the later stages of therapy, were more loss averse and accepted a lower number of gambles with a positive expected value, whereas their impulsivity traits were significantly higher. This study shows for the first time that changes in loss aversion, but not in personality traits, are associated with the time course of pathology. These findings can be usefully employed in the fields of both gambling addiction and decision-making. PMID- 25024056 TI - Failure to utilize feedback causes decision-making deficits among excessive Internet gamers. AB - Internet gaming addiction (IGA) is an increasing mental health issue worldwide. Previous studies have revealed decision-making impairments in excessive Internet gamers (EIGs) with high symptoms of IGA. However, the role of feedback processing in decision-making deficits among EIGs remains unknown. The present study aimed to investigate the effect of feedback processing on decision-making deficits under risk among EIGs, using the Game of Dice Task (GDT) and a modified version of the GDT in which no feedback was provided. Twenty-six EIGs and 26 matched occasional Internet gamers (OIGs) were recruited. The results showed: (a) OIGs performed better on the original GDT than on the modified GDT (no feedback condition); however, EIGs performed similarly on both tasks; (b) EIGs and OIGs performed equally on the modified GDT; however, EIGs chose more disadvantageous options than OIGs on the original GDT; (c) EIGs utilized feedback less frequently on the original GDT relative to OIGs. These results suggest that EIGs are not able to utilize feedback to optimize their decisions, which could underlie their poor decision-making under risk. PMID- 25024057 TI - Association of the CHRNA7 promoter variant -86T with Tourette syndrome and comorbid obsessive-compulsive disorder. PMID- 25024058 TI - Family functioning in families of first-episode psychosis patients as compared to chronic mentally ill patients and healthy controls. AB - The present study aimed to investigate possible differences in family environment among patients experiencing their First Episode of Psychosis (FEP), chronic patients and controls. Family cohesion and flexibility (FACES-IV) and psychological distress (GHQ-28) were evaluated in families of 50 FEP and 50 chronic patients, as well as 50 controls, whereas expressed emotion (FQ) and family burden (FBS) were assessed in families of FEP and chronic patients. Multivariable linear regression analysis, adjusted for confounders, indicated impaired cohesion and flexibility for families of FEP patients compared to controls, and lower scores for families of chronic patients compared to those of FEP patients. Caregivers of chronic patients scored significantly higher in criticism, and reported higher burden and psychological distress than those of FEP patients. Our findings suggest that unbalanced levels of cohesion and flexibility, high criticism and burden appeared to be the outcome of psychosis and not risk factors triggering the onset of the illness. Furthermore, emotional over-involvement both in terms of positive (i.e. concern) and negative behaviors (i.e. overprotection) is prevalent in Greek families. Psychoeducational interventions from the early stages of the illness should be considered to promote caregivers' awareness regarding the patients' illness, which in turn, may ameliorate dysfunctional family interactions. PMID- 25024059 TI - Predictors of dementia in Parkinson's disease; findings from a 5-year prospective study using the SCOPA-COG. AB - OBJECTIVE: Aim of this study was to identify risk factors for the development of dementia in patients with Parkinson's disease (PD). METHODS: A broad range of motor and non-motor features was assessed at baseline and the following five years in 406 PD patients. Cross-sectional analyses of baseline data and longitudinal analyses of follow-up data were performed to identify risk factors for dementia. RESULTS: Thirty-two percent of patients (n = 129) had dementia at baseline, while 26% of patients (n = 68) without dementia at baseline developed dementia during follow-up. Univariate survival analysis showed that higher age, fewer years of education, longer disease duration, higher age-at-onset, higher levodopa dose, higher Hoehn & Yahr stage, presence of dyskinesias, excessive daytime sleepiness (EDS), presence of hallucinations, and more severe autonomic and depressive symptoms were associated with an increased risk of dementia. Higher baseline Postural-Instability-and-Gait-Difficulty scores were also associated with an increased risk of dementia, whereas no effect of tremor severity was found. These findings largely corresponded with the variables that were associated with the presence of dementia at baseline. In a stepwise regression model, higher age at baseline, fewer years of education, higher daily levodopa dose and excessive daytime sleepiness (EDS) emerged as independent risk factors of future dementia. CONCLUSIONS: In this large prospective cohort study, we identified a combination of potentially interacting risk factors for dementia in PD that are associated with higher age and more advanced disease. PMID- 25024060 TI - Validation of the CT-MRI image registration with a dedicated phantom. AB - PURPOSE: The present study was aimed at verifying the automatic registration of the Focal (Elekta) platform with a dedicated phantom. MATERIALS AND METHODS: A phantom that simulates the pelvis region in a stylised way and finalised to the registration of computed tomography-magnetic resonance images was designed and realised. After acquiring the two sets of images, the registration was performed both in automatic and manual mode to verify whether they were comparable. To test the repeatability of the automatic registration, some known rigid transformations were imposed to the original images. If the registration method works correctly, parameters which bring the images into alignment must always be the same. RESULTS: Automatic registration performed by the software did not prove satisfactory, whereas if a specific tool [volume of interest (VOI) tool] allowing the calculation to be limited to the landmark region was used, the registration parameters were comparable with those of the manual registration. Regarding the repeatability of the automatic registration, the software brought the images in the correct alignment performing translations and rotations along the longitudinal axis up to 40 degrees , while it was not satisfactory for rotations along the transverse axes. CONCLUSION: The experimental results showed that in clinical application automatic registration is reliable if the VOI tool that includes visible landmarks in both studies is used. However, because the algorithm did not prove sensitive to rotations along the transverse axes, the position of the patient during the examinations plays a crucial role. PMID- 25024061 TI - Radiofrequency thermal ablation of renal tumors. AB - Percutaneous radiofrequency ablation (PRFA) of renal malignancies is currently a therapeutic option for patients who are not able to undergo surgery. Some authors consider PRFA as the therapeutic standard in the treatment of renal neoplasms in non-operable patients due to comorbid conditions and in patients with mild moderate renal failure, to preserve residual renal functionality. The use of PRFA has become more and more widespread due to a rise in the incidental detection of renal cell carcinomas with the ever-increasing use of Imaging for the study of abdominal diseases. Clinical studies indicate that RF ablation is an effective therapy with a low level of risk of complications, which provides good results in selected patients over short and medium term periods of time, however up to now few long-term studies have been carried out which can confirm the effectiveness of PRFA. PMID- 25024063 TI - Open source software in a practical approach for post processing of radiologic images. AB - PURPOSE: The purpose of this paper is to evaluate the use of open source software (OSS) to process DICOM images. MATERIALS AND METHODS: We selected 23 programs for Windows and 20 programs for Mac from 150 possible OSS programs including DICOM viewers and various tools (converters, DICOM header editors, etc.). The programs selected all meet the basic requirements such as free availability, stand-alone application, presence of graphical user interface, ease of installation and advanced features beyond simple display monitor. Capabilities of data import, data export, metadata, 2D viewer, 3D viewer, support platform and usability of each selected program were evaluated on a scale ranging from 1 to 10 points. RESULTS: Twelve programs received a score higher than or equal to eight. Among them, five obtained a score of 9: 3D Slicer, MedINRIA, MITK 3M3, VolView, VR Render; while OsiriX received 10. CONCLUSIONS: OsiriX appears to be the only program able to perform all the operations taken into consideration, similar to a workstation equipped with proprietary software, allowing the analysis and interpretation of images in a simple and intuitive way. OsiriX is a DICOM PACS workstation for medical imaging and software for image processing for medical research, functional imaging, 3D imaging, confocal microscopy and molecular imaging. This application is also a good tool for teaching activities because it facilitates the attainment of learning objectives among students and other specialists. PMID- 25024064 TI - "Throwing the baby out with the bathwater": the demise of vaginismus in favor of genito-pelvic pain/penetration disorder. PMID- 25024065 TI - Will vaginismus remain a "lifelong" baby? Response to Reissing et al. (2014). PMID- 25024067 TI - Ex vivo DNA Assembly. AB - Even with decreasing DNA synthesis costs there remains a need for inexpensive, rapid, and reliable methods for assembling synthetic DNA into larger constructs or combinatorial libraries. Advances in cloning techniques have resulted in powerful in vitro and in vivo assembly of DNA. However, monetary and time costs have limited these approaches. Here, we report an ex vivo DNA assembly method that uses cellular lysates derived from a commonly used laboratory strain of Escherichia coli for joining double-stranded DNA with short end homologies embedded within inexpensive primers. This method concurrently shortens the time and decreases costs associated with current DNA assembly methods. PMID- 25024068 TI - Testicular cancer: a reflection on 50 years of discovery. PMID- 25024066 TI - A cross-sectional study on attitudes toward gender equality, sexual behavior, positive sexual experiences, and communication about sex among sexually active and non-sexually active adolescents in Bolivia and Ecuador. AB - BACKGROUND: It is widely agreed upon that gender is a key aspect of sexuality however, questions remain on how gender exactly influences adolescents' sexual health. OBJECTIVE: The aim of this research was to study correlations between gender equality attitudes and sexual behavior, sexual experiences and communication about sex among sexually active and non-sexually active adolescents in 2 Latin American countries. DESIGN: In 2011, a cross-sectional study was carried out among 5,913 adolescents aged 14-18 in 20 secondary schools in Cochabamba (Bolivia) and 6 secondary schools in Cuenca (Ecuador). Models were built using logistic regressions to assess the predictive value of attitudes toward gender equality on adolescents' sexual behavior, on experiences and on communication. RESULTS: The analysis shows that sexually active adolescents who consider gender equality as important report higher current use of contraceptives within the couple. They are more likely to describe their last sexual intercourse as a positive experience and consider it easier to talk with their partner about sexuality than sexually experienced adolescents who are less positively inclined toward gender equality. These correlations remained consistent whether the respondent was a boy or a girl. Non-sexually active adolescents, who consider gender equality to be important, are more likely to think that sexual intercourse is a positive experience. They consider it less necessary to have sexual intercourse to maintain a relationship and find it easier to communicate with their girlfriend or boyfriend than sexually non-active adolescents who consider gender equality to be less important. Comparable results were found for boys and girls. CONCLUSIONS: Our results suggest that gender equality attitudes have a positive impact on adolescents' sexual and reproductive health (SRH) and wellbeing. Further research is necessary to better understand the relationship between gender attitudes and specific SRH outcomes such as unwanted teenage pregnancies and sexual pleasure among adolescents worldwide. PMID- 25024069 TI - Developmental and adaptive functioning in children with retinoblastoma: a longitudinal investigation. AB - PURPOSE: To determine the developmental trajectory of early cognitive and adaptive skills in young children with retinoblastoma from diagnosis to 5 years of age. PATIENTS AND METHODS: Ninety-four patients with retinoblastoma treated according to an institutional protocol underwent serial assessments of cognitive and adaptive functioning at age 6 months and 1, 2, 3, and 5 years. Data were analyzed by treatment strata, with patients with 13q deletion analyzed separately. RESULTS: At baseline, across all patients (except those with 13q deletion), developmental functioning was comparable with the normative mean, with mean scores for all strata within the average range. However, at age 5 years, developmental functioning was in the low average range and significantly below normative means. The trajectories of developmental functioning demonstrated significant decline over time, although this varied by treatment group/strata. Patients treated with enucleation only evidenced the greatest decline in cognitive functioning; significant change was not observed in patients treated with other modalities. Notable declines in parent-reported communication skills were observed in the majority of patients. Patients with 13q deletion evidenced delayed cognitive functioning at baseline, but minimal declines were observed through age 3 years. However, significant decreases in adaptive functioning were demonstrated over time for the 13q deletion subset. CONCLUSION: The declines in functioning observed in this study were unexpected, as was the poorer performance of the enucleation-only group. This highlights the necessity of continuing to assess cognitive functioning in patients with retinoblastoma as they age. Additional research is necessary to determine the long-term trajectory of cognitive development in this population. PMID- 25024070 TI - Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. AB - PURPOSE: The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) -targeted, antitumor properties of trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. PATIENTS AND METHODS: Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. RESULTS: Among 884 T-DM1-exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%. CONCLUSION: In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings. PMID- 25024071 TI - Partner diagnostics and the "choosing wisely" campaign. PMID- 25024072 TI - Vascular Endothelial Growth Factor Receptor-Targeted Therapy in Succinate Dehydrogenase C Kidney Cancer. PMID- 25024073 TI - Differences in parent-provider concordance regarding prognosis and goals of care among children with advanced cancer. AB - PURPOSE: Concordance between parents of children with advanced cancer and health care providers has not been described. We aimed to describe parent-provider concordance regarding prognosis and goals of care, including differences by cancer type. PATIENTS AND METHODS: A total of 104 pediatric patients with recurrent or refractory cancer were enrolled at three large children's hospitals. On enrollment, their parents and providers were invited to complete a survey assessing perceived prognosis and goals of care. Patients' survival status was retrospectively abstracted from medical records. Concordance was assessed via discrepancies in perceived prognosis, statistics, and McNemar's test. Distribution of categorical variables and survival rates across cancer type were compared with Fisher's exact and log-rank tests, respectively. RESULTS: Data were available from 77 dyads (74% of enrolled). Parent-provider agreement regarding prognosis and goals of care was poor (kappa, 0.12 to 0.30). Parents were more likely to report cure was likely (P < .001). The frequency of perceived likelihood of cure and the goal of cure varied by cancer type for both parents and providers (P < .001 to .004). Relatively optimistic responses were more common among parents and providers of patients with hematologic malignancies, although there were no differences in survival. CONCLUSION: Parent-provider concordance regarding prognosis and goals in advanced pediatric cancer is generally poor. Perceptions of prognosis and goals of care vary by cancer type. Understanding these differences may inform parent-provider communication and decision making. PMID- 25024074 TI - Case of Rectal GI Stromal Tumor Demonstrating that KIT and PDGFRA Mutations Are Not Always Mutually Exclusive. PMID- 25024075 TI - Solidifying liquid biopsies: can circulating tumor cell monitoring guide treatment selection in breast cancer? PMID- 25024076 TI - Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. AB - PURPOSE: The three-drug combination of lenalidomide, bortezomib, and dexamethasone (RVD) has shown significant efficacy in multiple myeloma (MM). The Intergroupe Francophone du Myelome (IFM) decided to evaluate RVD induction and consolidation therapies in a sequential intensive strategy for previously untreated transplantation-eligible patients with MM. PATIENTS AND METHODS: In this phase II study, 31 symptomatic patients age < 65 years were enrolled to receive three RVD induction cycles followed by cyclophosphamide harvest and transplantation. Patients subsequently received two RVD consolidation cycles and 1-year lenalidomide maintenance. RESULTS: Very good partial response rate or better at the completion of induction, transplantation, and consolidation therapy was 58%, 70%, and 87%, respectively. Maintenance upgraded responses in 27% of patients. Overall, 58% of patients achieved complete response, and 68% were minimal residual disease (MRD) negative by flow cytometry. The most common toxicities with RVD were neurologic and hematologic, including grade 1 to 2 sensory neuropathy (55%), grade 3 to 4 neutropenia (35%), and thrombocytopenia (13%). Two basal cell carcinomas in the same patient and one case of breast cancer were observed. There was no treatment-related mortality. With a median follow-up of 39 months, estimated 3-year progression-free and overall survival were 77% and 100%, respectively. None of the patients who achieved MRD negativity relapsed. CONCLUSION: The transplantation program with RVD induction and consolidation followed by lenalidomide maintenance produced high-quality responses and showed favorable tolerability in patients with newly diagnosed MM. Overall, 68% of patients achieved MRD negativity; none of these patients relapsed. This program is being evaluated in the ongoing IFM/Dana-Farber Cancer Institute 2009 phase III study. PMID- 25024077 TI - BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. AB - PURPOSE: To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC). PATIENTS AND METHODS: We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 +/- 14.0 years (mean +/- SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months). RESULTS: Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation-positive versus negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI, 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000 person-years; 95% CI, 22.96 to 39.74) in TERT mutation-positive versus -negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI, 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000 person-years; 95% CI, 14.59 to 31.97) in patients harboring both mutations versus patients harboring neither mutation (HR, 8.51; 95% CI, 4.84 to 14.97), which remained significant after clinicopathologic cofactor adjustments. Disease-free patient survival curves displayed a moderate decline with BRAF V600E or TERT C228T alone but a sharp decline with two coexisting mutations. CONCLUSION: Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications. PMID- 25024078 TI - Reply to L.k. Griffeth et al and J.E. Battley et al. PMID- 25024079 TI - Plasma cell neoplasms, their precursor States, and their prediction of organ damage. PMID- 25024080 TI - Positron emission tomography for subsequent treatment strategy in oncology. PMID- 25024081 TI - Early and Severe Radiation Esophagitis Associated With Concurrent Sirolimus. PMID- 25024082 TI - Increased serum free light chains precede the presentation of immunoglobulin light chain amyloidosis. AB - PURPOSE: Patients with immunoglobulin light chain amyloidosis (AL amyloidosis) generally present with advanced organ dysfunction and have a high risk of early death. We sought to characterize monoclonal immunoglobulin (M-Ig) light chains before clinical presentation of AL amyloidosis. PATIENTS AND METHODS: We obtained prediagnostic sera from 20 cases with AL amyloidosis and 20 healthy controls matched for age, sex, race, and age of serum sample from the Department of Defense Serum Repository. Serum protein electrophoresis with immunofixation and serum free light chain (FLC) analysis were performed on all samples. RESULTS: An M-Ig was detected in 100% of cases and 0% of controls (P < .001). The M-Ig was present in 100%, 80%, and 42% of cases at less than 4 years, 4 to 11 years, and more than 11 years before diagnosis, respectively. The median FLC differential (FLC-diff) was higher in cases compared with controls at all time periods, less than 4 years (174.8 v 0.3 mg/L; P < .001), 4 to 11 years (65.1 v 2.2 mg/L; P < .001), and more than 11 years (4.5 v 0.4 mg/L; P = .03) before diagnosis. The FLC diff was greater than 23 mg/L in 85% of cases and 0% of controls (P < .001). The FLC-diff level increased more than 10% per year in 84% of cases compared with 16% of controls (P < .001). CONCLUSION: Increase of FLCs, including within the accepted normal range, precedes the development of AL amyloidosis for many years. PMID- 25024083 TI - TERT and BRAF in thyroid cancer: teaming up for trouble. PMID- 25024084 TI - Extensive Squamous Cell Carcinoma of the Skin Related to Use of Sorafenib for Treatment of FLT3-Mutant Acute Myeloid Leukemia. PMID- 25024085 TI - Differential RNA-seq: the approach behind and the biological insight gained. AB - RNA-sequencing has revolutionized the quantitative and qualitative analysis of transcriptomes in both prokaryotes and eukaryotes. It provides a generic approach for gene expression profiling, annotation of transcript boundaries and operons, as well as identifying novel transcripts including small noncoding RNA molecules and antisense RNAs. We recently developed a differential RNA-seq (dRNA-seq) method which in addition to the above, yields information as to whether a given RNA is a primary or processed transcript. Originally applied to describe the primary transcriptome of the gastric pathogen Helicobacter pylori, dRNA-seq has since provided global maps of transcriptional start sites in diverse species, informed new biology in the CRISPR-Cas9 system, advanced to a tool for comparative transcriptomics, and inspired simultaneous RNA-seq of pathogen and host. PMID- 25024086 TI - Access to novel functionalized trifluoromethyl beta-lactams by ring expansion of aziridines. AB - From carboxylic acid trifluoromethyl aziridines, halogeno beta-lactams were obtained stereoselectively by ring expansion. Different conditions such as radical, organometallic reactions allowed easy and selective access to CF3-beta lactams substituted at the C-3 position. PMID- 25024087 TI - The Supreme Court decision in the Hobby Lobby Case: conscience, complicity, and contraception. PMID- 25024089 TI - Minimally-invasive endoscopically-assisted neck dissection for lateral cervical metastases of thyroid papillary carcinoma. AB - Traditional open operations for lateral neck dissection in patients with papillary thyroid carcinoma leave an unsightly scar. We report complete lateral neck dissection and thyroidectomy for papillary thyroid carcinoma using an endoscopically-assisted approach through a small incision, and evaluate its feasibility and safety. Between March 2010 and January 2013, 6 patients with no definite metastases to the lymph nodes at levels II-IV, and 20 with definite metastases to the lymph nodes at levels II-V were selected. Thyroidectomy, dissection of the central compartment (level VI), and ipsilateral level II-IV and II-V neck dissections were done through a small incision in the neck. The steps of endoscopic lateral neck dissection were similar to those of conventional operations. The mean operating time for the whole procedure was 3.57 hours (range 2.5 - 5.0). It was successful in all patients and there were no serious complications or serious blood loss. A total of 21 patients had lymph node metastases in the central and lateral zones. The mean yield of lymph nodes was 38.6 (range 16-61). There was no evidence of residual or recurrent disease at follow-up, and the cosmetic result was excellent. Minimally invasive, video assisted comprehensive neck dissection for metastatic papillary thyroid carcinoma is feasible and safe, and has excellent cosmetic results. Further studies with a larger number of patients and long-term follow-up are needed to verify its oncological validity. PMID- 25024088 TI - Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling. AB - Wnt proteins control diverse biological processes through beta-catenin-dependent canonical signalling and beta-catenin-independent non-canonical signalling. The mechanisms by which these signalling pathways are differentially triggered and controlled are not fully understood. Dishevelled (Dvl) is a scaffold protein that serves as the branch point of these pathways. Here, we show that cholesterol selectively activates canonical Wnt signalling over non-canonical signalling under physiological conditions by specifically facilitating the membrane recruitment of the PDZ domain of Dvl and its interaction with other proteins. Single-molecule imaging analysis shows that cholesterol is enriched around the Wnt-activated Frizzled and low-density lipoprotein receptor-related protein 5/6 receptors and plays an essential role for Dvl-mediated formation and maintenance of the canonical Wnt signalling complex. Collectively, our results suggest a new regulatory role of cholesterol in Wnt signalling and a potential link between cellular cholesterol levels and the balance between canonical and non-canonical Wnt signalling activities. PMID- 25024090 TI - Role of chemoradiotherapy in the adjuvant and neoadjuvant settings for resectable pancreatic cancer. AB - Pancreatic cancer is the 10th most commonly diagnosed malignancy in the USA and the fourth most common cause of cancer-related death. Worldwide, the mortality incidence ratio approaches 98%. Although only 15-20% of patients present with resectable disease, there is international consensus that complete surgical resection (R0, i.e. grossly and microscopically negative margins) is a vital part of any curative treatment paradigm. Despite advances in surgical technique, peri operative care, chemotherapy and radiation delivery techniques over the past two decades, 5 year overall survival rates for resected pancreatic cancer with modern therapies remain around 20-25%. There is level I evidence for adjuvant chemotherapy in fully resected pancreatic cancer, but randomised trials examining the role of adjuvant chemoradiotherapy to date do not provide clear support for radiation therapy in this setting. In addition, efforts to increase the proportion of long-term survivors have recently centred on increasing the resectability of locoregional disease by incorporating neoadjuvant treatment before definitive surgery. Post-hoc analysis of randomised data as well as retrospective reviews have shown that there are several independent prognostic factors that may have considerable impact on survival outcomes, complicating interpretation and comparison of historical data. There is considerable interest in adjuvant and neoadjuvant therapy, but there is significant controversy as to whether radiation is of value, especially in the adjuvant context. Herein, we explore the sources of those controversies. PMID- 25024091 TI - Nature, extent and implications of belief in Kikombe cha babu and other herbal HIV cures in Tanzania. AB - This study's objective was to describe awareness of, access to, belief in, and utilization of the healing tea Kikombe cha babu and other alternative treatments for HIV in Tanzania. Associations with HIV testing, treatment, and prevention behaviors are also explored. A survey with questions about alternative medicine was administered to a sample in Tanzania using a stratified, multistage random selection method. Adults were interviewed face-to-face. Items concerning alternative HIV treatments addressed awareness, access, beliefs, and treatment seeking behaviors. Questions about HIV prevention and treatment were also asked. Results showed participants indicated a high awareness of alternative treatments available in Tanzania, with 95.3% of 2313 adults having heard of these treatments. Of those, 6.0% had actually sought the treatment, and 46.8% had an acquaintance seek it. However, 81.0% indicated these treatments were not easily accessible. There is a high level of belief in the ability of these alternative treatments to cure HIV, with 44.0% of people who had heard of these treatments indicating they believe such treatments can cure HIV. Additionally, many people indicated having these alternative treatments available would result in decreased condom use (15.6%), no need to use condoms (94.9%), and no need to take antiretroviral therapy (81.7%). However, 57.4% indicated they would be more likely to get tested for HIV if alternative treatments were available. Belief in the ability of alternative treatments to cure HIV in Tanzania is high and should be further explored due to its implications for potentially sidelining HIV prevention and treatment initiatives. PMID- 25024092 TI - Risk of permanent medical impairment (RPMI) in car crashes correlated to age and gender. AB - OBJECTIVE: As fatalities from car crashes decrease, focus on medical impairment following car crashes becomes more essential. This study assessed the risk of permanent medical impairment based on car occupant injuries. The aim was to study whether the risk of permanent medical impairment differs depending on age and gender. METHODS: In total, 36,744 injured occupants in car crashes that occurred between 1995 and 2010 were included. All initial injuries (n = 61,440) were classified according to the Abbreviated Injury Scale (AIS) 2005. If a car occupant still had residual symptoms 3 years after a crash, the case was classed as a permanent medical impairment. In total, 5,144 injuries led to permanent medical impairment. The data were divided into different groups according to age and gender as well as levels of permanent impairment. The risk of permanent medical impairment was established for different body regions and injury severity levels, according to the AIS. RESULTS: The cervical spine was the body region that had the highest number of diagnoses, and occupants who sustained injuries to the upper and lower extremities had the highest risk of medical impairment for both genders. Females aged 60 and above had a higher risk of permanent medical impairment from fractures in the extremities compared to males in the same age group and younger females. Females aged 44 or younger had a higher risk of permanent medical impairment from whiplash-associated disorders (WAD) than males in the same age group. Minor and moderate injuries (AIS 1-2) had a higher risk of permanent medical impairment among older car occupants compared to younger ones. CONCLUSIONS: Differences in long-term outcome were dependent on both gender and age. Differences between age groups were generally greater than between genders. The vast majority of permanent medical impairments resulted from diagnoses with a low risk of fatality. The results emphasize the impact of age and gender in long term consequences from car crashes. They could be used when designing safety technology in cars as well as to improve health care by contributing to better allocation of rehabilitation resources following trauma. PMID- 25024093 TI - Ontogeny and osmoregulatory function of the urinary system in the Persian sturgeon, Acipenser persicus (Borodin, 1897). AB - The structure of the kidney and the localization of Na(+), K(+)-ATPase (NKA) immunopositive cells were examined throughout the postembryonic development of the Persian sturgeon, Acipenser persicus, from newly hatched prelarvae (10mm) to 20 days post hatch (20 DPH) larvae (31mm). Investigations were conducted through histology and immunohistochemistry by using the light and immunofluorescence microscopy. The pronephros was observed in newly hatched prelarvae. The cells lining the distal pronephric tubules and their collecting ducts showed laterally expressed NKA immunofluorescence that later extended throughout the whole cytoplasm. Mesonephrogenous placodes and pre-glomeruli were distinguished at 2 DPH along the collecting ducts posteriorly. Their tubules were formed and present in kidney mesenchyma, differentiated into neck, proximal, distal and collecting segments at 7 DPH when NKA immunopositive cells were observed. Their distal and collecting tubules showed an increasing immunofluorescence throughout their cytoplasm while the glomeruli remained unstained. From D 9 to D 17, the epithelial layer of pronephric collecting duct changed along the mesonephros to form ureters. Ureters, possessing isolated strong NKA immunopositive cells, appeared as two sac-like structures hanging under the trunk kidney. Since NKA immunopositive cells were not observed on the tegument or along the digestive tract of newly hatched prelarva, and also the gills are not formed yet, the pronephros is the only osmoregulatory organ until 4 DPH. At the larval stage, the pronephros and mesonephros are functional osmoregulatory organs and actively reabsorb necessary ions from the filtrate. PMID- 25024094 TI - Systematic engineering tools for describing and improving medication administration processes at rural healthcare facilities. AB - This study demonstrates a series of systematic methods for mapping medication administration processes and for elaborating violations of work standards at two rural hospitals. Thirty-four observational periods were conducted to capture the details of clinical activities, and hierarchical task analysis (HTA) was used to demonstrate the current medication administration process. Facility nurse managers in five units across the two facilities participated in focus group discussions to validate the observational data and to generate a reliable context appropriate medication administration process. The potential errors or misconduct when passing the drugs were identified, such as unsafe storage and transportation of drugs from room to room. Those hazards would cause drug contamination, loss, or access by unauthorized individuals. Hospitals without 24-hour pharmacy coverage and other interruptions would hinder the medication administration process. Preparing drugs for more than one patient at a time would increase the risk of passing the drugs to the wrong patient. This study shows the use of observation and focus groups to describe and identify violations in the medication administration process. A clear road map for continuous clinical process improvement obtained from the current study could be used to help future health information technology implementation. PMID- 25024095 TI - Dynamic changes in the numbers of different subsets of peripheral blood NK cells in patients with systemic lupus erythematosus following classic therapy. AB - Imbalance of natural killer (NK) cells is associated with the development of systemic lupus erythematosus (SLE). However, little is known about the dynamic changes on NK cells following therapy. This study aimed at examining the impact of classic therapies on the numbers of different subsets of NK cells in new-onset SLE patients. The numbers of different subsets of peripheral blood NK cells in 24 new-onset SLE patients before, 4 and 12 weeks post the classic therapies, and 7 healthy controls were determined by flow cytometry. The potential correlation between the numbers of NK cells and the values of clinical measures was analyzed. In comparison with that before treatment, the numbers of NK, NKG2C+, and KIR2DL3+ NK cells were significantly increased while the numbers of NKp46+ and NKG2A + NK cells significantly decreased at 4 and/or 12 weeks post the treatment only in the drug well-responding patients, but not in those poor responders (P < 0.05 for all). The numbers of NKG2C + NK cells were correlated positively with the levels of serum C3 while the numbers of KIR2DL3+ NK cells were correlated negatively with the scores of SLEDAI in these patients at 4 weeks post the treatment. The classic therapies modulated the numbers of some subsets of NK cells in drug well responding SLE patients. The changes in the numbers of some subsets of NK cells may serve as biomarkers for evaluating the therapeutic responses of SLE. PMID- 25024096 TI - The new 2010 ACR/EULAR criteria as predictor of clinical and radiographic response in patients with early arthritis. AB - New American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for the classification of rheumatoid arthritis (RA) have recently been proposed. The aim of this cohort study was to examine whether fulfilling these 2010 ACR/EULAR criteria at the first visit has an impact on the clinical course and on the radiographic progression of the disease. For this observational cohort study, we included patients from the Swiss RA registry SCQM with early RA or undifferentiated arthritis (UA, disease duration <=1 year), as defined by the treating rheumatologist, who had not received any previous disease modifying anti-rheumatic drugs (DMARDs). Patients were categorized into two groups depending on whether or not they fulfilled the 2010 ACR/EULAR criteria (>=6 points vs <6 points) at the first visit. The primary outcome measures were the evolution of the DAS 28 and of radiographic erosions as measured by the Ratingen score over time. Of the 592 patients fulfilling the inclusion criteria, 352 satisfied the 2010 ACR/EULAR criteria at baseline, whereas 240 were not classifiable as definite RA. The ACR/EULAR criteria scores correlated with disease activity at disease onset (R (2) = 0.31). DMARD treatment was subsequently initiated in all patients, mostly with methotrexate (MTX). There were no significant differences in the therapeutic strategies between patients fulfilling or not fulfilling the classification criteria. Six months after inclusion, patients fulfilling the ACR/EULAR criteria developed a 39.1 % reduction of DAS 28 scores, as compared to a 33.6 % reduction in patients not fulfilling the ACR/EULAR criteria (p = 0.0002), independently of their respective treatment strategy. Importantly, the DAS 28 scores were higher in those patients fulfilling the ACR/EULAR criteria (ACR/EULAR positive patients) throughout the observation, as compared to patients not fulfilling those (ACR/EULAR negative patients). Average radiographic progression was higher among ACR/EULAR positive than negative patients (progression of Ratingen score/year 0.50 vs 0.32, resp., p = 0.03) after 3 years of follow-up. Among early RA/UA patients, a score of the 2010 ACR/EULAR criteria sufficient to classify RA selects patients with worse clinical outcome and more radiographic progression. PMID- 25024097 TI - Smoking is associated with a worse self-reported health status in patients with psoriatic arthritis: data from a Swedish population-based cohort. AB - The aim was to study possible associations between smoking habits and self reported clinical features in a large population-based cohort of patients with psoriatic arthritis (PsA). All subjects with PsA who had sought health care in the period 2003-2007 were identified using a regional health-care register. In 2009, all those identified who were 18 years of age or more (n = 2,003) were sent a questionnaire with questions on smoking, health-related quality of life [EuroQol five-dimension (EQ-5D)questionnaire], function [Health Assessment Questionnaire (HAQ)], pain, fatigue, and global health. We performed age- and sex adjusted regression analysis to compare health status outcomes in never and ever smokers. Altogether, 1,185 subjects (59%) returned the questionnaire. Mean age was 57 years (SD 13.5), and 58% were women; 38% were never smokers and 62% were ever smokers. Mean age at disease onset was 38.2 years (SD 13.2) and 41.2 years (SD 13.6), respectively (p = 0.001). In age- and sex-adjusted data, ever smokers reported worse EQ-5D (p = 0.009); worse reports of global health (p = 0.01), pain (p = 0.01), and fatigue (p = 0.04); and a higher number of painful body regions (p = 0.04) compared to never smokers. In this population-based PsA cohort, patients who were ever smokers reported worse health status than never smokers. Besides being a possible result of a worse PsA in ever smokers, impaired health status could also be an effect of unstudied comorbidities. Further longitudinal studies are needed to gain a better understanding of cause and effect. However, smoking cessation should be recommended because of general health considerations as well as disease-specific issues. PMID- 25024098 TI - Enhancement of anammox activity by addition of compatible solutes at high salinity conditions. AB - The enhancement effect of compatible solutes on anammox activity under salinity stress was investigated. Glycine betaine (GB) was the most effective in alleviating salt toxicity, although all the compatible solutes (GB, trehalose and ectoine) were found to be valid. Acclimation potential of anammox biomass under salinity of 30 g/L increased significantly with GB addition. The recovery time in the reactor with GB addition (RB) (49 days) accompanied by a more stable stoichiometric ratio was 2.65 times shorter than in the control reactor (RC) (130 days). After 49 days, the extracellular polymeric substances and the tetrazolium chloride-dehydrogenase activity were 217.9 mg/g VSS and 38.7 MUg TF/g VSS/h in RB, 1.86 times lower and 3.17 times higher than the levels in RC, respectively. RB possessed evident superiority in the aspects of microbial population proportion. And thus, compatible solutes addition was regarded as one of the feasible solution to counteract saline inhibition on anammox. PMID- 25024099 TI - Fate and risk assessment of heavy metals in residue from co-liquefaction of Camellia oleifera cake and sewage sludge in supercritical ethanol. AB - The fate and risk assessment of heavy metals (HMs) in solid residue from co liquefaction of sewage sludge (SS) and Camellia oleifera cake (COC) in supercritical ethanol (SCE) were investigated. SCE effectively stabilized HMs in solid residues and a better stabilization was presented on Zn than Cd. Moreover, SCE significantly transformed Cd, Cu and Zn into F4, which reduced the risk to the environment. Furthermore, risk assessments of Igeo, Er(i), RI and RAC demonstrated that the addition of COC was beneficial to the contamination decrement of HMs since pollution levels of HMs all decreased after treatment, and the lowest pollution level was obtained with SC-350. Therefore, SS treated by SCE with the addition of COC could be a promising technology for disposal of SS, especially considering the safety of COC as regards HMs problem. PMID- 25024100 TI - Transport and removal of viruses in saturated sand columns under oxic and anoxic conditions--Potential implications for groundwater protection. AB - To protect groundwater as a drinking water resource from microbiological contamination, protection zones are installed. While travelling through these zones, concentrations of potential pathogens should decline to levels that pose no risks to human health. Removal of viruses during subsurface passage is influenced by physicochemical conditions, such as oxygen concentration, which also affects virus survival. The aim of our study was to evaluate the effect of redox conditions on the removal of viruses during sand filtration. Experiments in glass columns filled with medium-grained sand were conducted to investigate virus removal in the presence and absence of dissolved oxygen. Bacteriophages MS2 and PhiX174, as surrogates for human enteric viruses were spiked in pulsed or in continuous mode and pumped through the columns at a filter velocity of about 1m/d. Virus breakthrough curves were analyzed by calculating total viral elimination and fitted using one-dimensional transport models (CXTFIT and HYDRUS 1D). While short-term experiments with pulsed virus application showed only small differences with regard to virus removal under oxic and anoxic conditions, a long term experiment with continuous dosing revealed a clearly lower elimination of viruses under anoxic conditions. These findings suggest that less inactivation and less adsorption of viruses in anoxic environments affect their removal. Therefore, in risk assessment studies aimed to secure drinking water resources from viral contamination and optimization of protection zones, the oxic and anoxic conditions in the subsurface should also be considered. PMID- 25024101 TI - Cost, outcomes, treatment pathways and challenges for diabetes care in Italy. AB - BACKGROUND: In Italy both incidence and prevalence of diabetes are increasing and age at diagnosis is decreasing in type 2 diabetes. Diabetes is one of the major causes of morbidity in Italy, causing several disabilities and affecting the economically active population. The objective of this paper is to identify and discuss costs, outcomes and some of the challenges of diabetes care in Italy in the context of recent policy changes. METHODS: The study collected data and evidence from both primary and secondary sources. A total of 10 experts, including clinicians (diabetologists/endocrinologists) and decision makers, both at national and regional levels, were interviewed through face-to-face semi structured interviews. The secondary sources include peer review literature from Medline, grey literature, reports from national and international sources, including professional bodies and organizations. RESULTS: The total direct cost of diabetes for the Italian NHS in 2012 is estimated to be above ?9 billion, of which more than half for hospital admissions (57%), and the remaining half for drugs (30%) and outpatient care (13%). However, there is scant evidence on indirect and intangible costs of diabetes in Italy. The quality of care addressed via the AMD Annals found overall good performance with both process and intermediate outcome indicators showing positive and improving results from 2004 to 2011, except for few parameters, including renal function and foot monitoring, which are still inadequate. Major challenges are the rising diabetes prevalence, the difficulty in meeting the rising demand for care and the scant development of multidisciplinary delivery of care, especially in the predominantly ambulatory setting of the Southern diabetes centres. CONCLUSIONS: Prevention of diabetes, especially adopting a multi-sectorial approach, should be further empowered by policy makers through promoting healthy lifestyles and specifically targeting child obesity. Other key strategies include more information and education, better diabetes management through the adoption of a chronic model of care, more focus on appropriateness and efficiency of care and better communication between diabetes centres within every Region. PMID- 25024102 TI - Refractive outcomes comparison between the Lenstar LS 900(r) optical biometry and immersion A-scan ultrasound. AB - To determine the accuracy of intraocular lens (IOL) calculations in eyes undergoing phacoemulsification cataract surgery with IOL implantation using immersion A-scan ultrasound (US) and Lenstar LS 900((r)) biometry. In this prospective study, 200 eyes of 200 patients were randomized to undergo either Lenstar LS 900((r)) or immersion A-scan US biometry to determine the IOL dioptric power prior to phacoemulsification cataract surgery. Post-operative refractive outcomes of these two groups of patients were compared. The result showed no significant difference between the target spherical equivalent (SE) and the post operative SE value by the Lenstar LS 900((r)) (p value = 0.632) or immersion A scan US biometry (p value = 0.438) devices. The magnitude of difference between the two biometric devices were not significantly different (p value = 0.868). There was no significant difference in the predicted post-operative refractive outcome between immersion A-scan US biometry and Lenstar LS 900((r)). Based on the results, the immersion A-scan US technique is as accurate as Lenstar LS 900((r)) in the hands of an experienced operator. PMID- 25024103 TI - Niche-habitat mechanisms and biotic interactions explain the coexistence and abundance of congeneric sandgrouse species. AB - Ascertaining which niche processes allow coexistence between closely related species is of special interest in ecology. We quantified variations in the environmental niches and densities of two congeneric species, the pin-tailed and the black-bellied sandgrouse (Pterocles alchata and Pterocles orientalis) in allopatry and sympatry under similar abiotic, habitat and dispersal contexts to understand their coexistence. Using principal component analysis, we defined environmental gradients (niche dimensions) including abiotic, habitat and anthropogenic variables, and calculated niche breadth, position and overlap of both species in sympatry and allopatry. Additionally, sandgrouse density was modelled as a function of the niche dimensions and the density of the other species. We found evidence that each species occupies distinct environmental niches in sympatry and in allopatry. The black-bellied sandgrouse exploits a broader range of environmental conditions (wider niche breadth) while the pin tailed sandgrouse reaches high densities where conditions seem to match its optimum. In sympatry, both species shift their niches to intermediate positions, indicating the importance of abiotic factors in setting coexistence areas. Environmental conditions determine regional densities of pin-tailed sandgrouse whereas biotic interactions explain the density of the black-bellied sandgrouse in areas with abiotic conditions similarly conducive for both species. Highly suitable areas for the pin-tailed sandgrouse fall beyond the upper thermal limit of the black-bellied sandgrouse, leading to niche segregation and low densities for the latter. Finally, local niche shift and expansion plus possible heterospecific aggregation allow the pin-tailed sandgrouse to thrive in a priori less favourable environments. This work provides insight into how different mechanisms allow species coexistence and how species densities vary in sympatry compared to allopatry as a result of environmental filtering and biotic interactions. PMID- 25024104 TI - Does the temporal mismatch hypothesis match in boreal populations? AB - The temporal mismatch hypothesis suggests that fitness is related to the degree of temporal synchrony between the energetic needs of the offspring and their food supply. The hypothesis has been a basis in studying the influence of climate warming on nature. This study enhances the knowledge on prevalence of temporal mismatches and their consequences in boreal populations, and questions the role of the temporal mismatch hypothesis as the principal explanation for the evolution of timing of breeding. To test this, we examined if synchrony with caterpillar prey or timing of breeding per se better explains reproductive output in North European parid populations. We compared responses of temperate-origin species, the great tit (Parus major) and the blue tit (Cyanistes caeruleus), and a boreal species, the willow tit (Poecile montanus). We found that phenologies of caterpillars and great tits, but not of blue tits, have advanced during the past decades. Phenologies correlated with spring temperatures that may function as cues about the timing of the food peak for great and blue tits. The breeding of great and blue tits and their caterpillar food remained synchronous. Synchrony explained breeding success better than timing of breeding alone. However, the synchrony effect arose only in certain conditions, such as with high caterpillar abundances or high breeding densities. Breeding before good synchrony seems advantageous at high latitudes, especially in the willow tit. Thus, the temporal mismatch hypothesis appears insufficient in explaining the evolution of timing of breeding. PMID- 25024106 TI - Strontium isotopes test long-term zonal isolation of injected and Marcellus formation water after hydraulic fracturing. AB - One concern regarding unconventional hydrocarbon production from organic-rich shale is that hydraulic fracture stimulation could create pathways that allow injected fluids and deep brines from the target formation or adjacent units to migrate upward into shallow drinking water aquifers. This study presents Sr isotope and geochemical data from a well-constrained site in Greene County, Pennsylvania, in which samples were collected before and after hydraulic fracturing of the Middle Devonian Marcellus Shale. Results spanning a 15-month period indicated no significant migration of Marcellus-derived fluids into Upper Devonian/Lower Mississippian units located 900-1200 m above the lateral Marcellus boreholes or into groundwater sampled at a spring near the site. Monitoring the Sr isotope ratio of water from legacy oil and gas wells or drinking water wells can provide a sensitive early warning of upward brine migration for many years after well stimulation. PMID- 25024105 TI - Family ties: maternal-offspring attachment and young adult nonmedical prescription opioid use. AB - BACKGROUND: Nonmedical prescription drug use is prevalent among young adults, yet little is known about modifiable determinants of use. We examined whether maternal-offspring attachment reported at mean age 21 was associated with nonmedical prescription opioid use at mean age 26, and investigated whether a history of depressive symptoms and substance use played a role in associations between maternal-offspring attachment and nonmedical prescription opioid use. METHODS: We used data from the Growing Up Today Study, a longitudinal cohort of United States adolescents followed into young adulthood. Maternal-offspring attachment was reported by young adults and their mothers, and defined as mutual low, mutual medium or high, and dissonant. Analyses were carried out in the full sample using generalized estimating equation models, and in a sibling subsample, using conditional fixed effects models to control for stable aspects of the family environment. RESULTS: Analyses with the full sample and the sibling subsample both showed that mutual medium/high maternal-offspring attachment at age 21 was associated with lower odds of nonmedical prescription opioid use at age 26 (RR=0.74; 95% CI=0.57-0.97 in full sample). The association was partly mediated by mean age 23 offspring smoking, heavy episodic drinking, and illicit drug use. CONCLUSIONS: Promoting reciprocal attachment in the maternal-offspring dyad should be investigated as a strategy to prevent nonmedical prescription opioid use by young adulthood. Even in young adulthood, programs that target both parents and offspring may have greater impact on offspring substance use than programs that target offspring alone. PMID- 25024107 TI - Reconstituted oil bodies characterization at the air/water and at the air/oil/water interfaces. AB - Oil bodies (OBs) are micelle-like structures with an outer phospholipid monolayer embedding some specific proteins (oleosins) and surrounding a hydrophobic core of triacylglycerols (TAGs). Oleosins are alkaline hairpin-like proteins that are anchored into the OBs structure with their hydrophilic domains covering the surface. We performed surface pressure (Pi) and Brewster Angle Microscopy investigations of reconstituted OBs (ROBs) and of trypsin digested ROBs. The obtained Pi vs time isotherms clearly show the formation of a surface layer. Upon ROBs suspension injection into the subphase, a clear-cut Pi enhancement is recorded, followed by a long plateau region for ROBs suspensions more concentrated than 12.5MUg/ml. The BAM analysis highlighted the presence of a dark background, ascribable to a 2D layer due to free components rearrangement and brilliant circular 3D domains, due to unaltered ROBs or small aggregates of ROBs. Increasing ROBs concentration, large domains appeared. We hypothesize that the presence of an excess of free TAGs in the 2D layer is crucial for the generation of such domains. We verified the generation of such typical structures, studying the behavior of a ROBs suspension (concentration of 12.5MUg/ml) with two different approaches: after injection under a concentrated TAGs floating layers and after digestion with trypsin. These two procedures resulted in similar effects since proteinase digestion is like to induce the same morphology of a TAGs excess. PMID- 25024108 TI - Characterisation and functional properties of antimicrobial bio-barriers formed by natural fibres. AB - Antimicrobial bio-barriers formed on cotton (CO), silk (SE), and woollen (WO) fabrics were prepared by the application of 3-(trimethoxysilyl) propyldimethyloctadecyl ammonium chloride (Si-QAC) at 11 concentrations ranging from 0.5% to 20% using an exhaustion method. The presence of the Si-QAC coating on the treated fabric samples was detected by X-ray photoelectron spectroscopy. The bromophenol blue reagent was used to determine the concentration of quaternary ammonium groups in the coating. The antimicrobial activity of the coated fibres against Gram-negative and Gram-positive bacteria (Escherichia coli and Staphylococcus aureus), fungi (Aspergillus niger and Chaetomium globosum), and soil microflora was assessed using standard microbiological methods. The antimicrobial protection of the fibres increased with increases in the applied concentration of Si-QAC. The fibre type strongly influenced the antimicrobial activity of Si-QAC. Si-QAC was most effective for CO fibres, less effective for WO fibres, and least effective for SE fibres, suggesting that Si-QAC is less accessible for interactions with microorganisms when applied to protein fibres than to cellulose. Although Si-QAC reduced the microbial growth, it did not significantly hinder the biodegradability or sustainability of the coated fibres when exposed to soil microflora. The extent of rotting was more influenced by the morphological and chemical properties of the fibres than by the presence of Si QAC. PMID- 25024109 TI - Enhanced laminin adsorption on nanowires compared to flat surfaces. AB - Semiconductor nanowires are widely used to interface living cells, and numerous nanowire-based devices have been developed to manipulate or sense cell behavior. We have, however, little knowledge on the nature of the cell-nanowire interface. Laminin is an extracellular matrix protein promoting cell attachment and growth. Here, we used a method based on fluorescence microscopy and measured the relative amount of laminin adsorbed on nanowires compared to flat surfaces. The amount of adsorbed laminin per surface area is up to 4 times higher on 55nm diameter gallium phosphide nanowires compared to the flat gallium phosphide surface between the nanowires. We show that this enhanced adsorption on nanowires cannot be attributed to electrostatic effects, nor to differences in surface chemistry, but possibly to pure geometrical effects, as increasing the nanowire diameter results in a decreased amount of adsorbed protein. The increased adsorption of laminin on nanowires may explain the exceptionally beneficial properties of nanowire substrates for cellular growth reported in the literature since laminin is often used as surface coating prior to cell cultures in order to promote cell growth, and also because primary cell suspensions contain endogenous laminin. PMID- 25024110 TI - The deformation and longitudinal excursion of median nerve during digits movement and wrist extension. AB - The use of electronic devices, such as mobile phones and computers, has increased drastically among the young generation, but the potential health effects of carpal tunnel syndrome (CTS) on university students has not been comprehensively examined. Thirty-one university students aged 18 to 25 y with no symptoms of CTS were successfully recruited in this study. By using noninvasive ultrasonography, the morphological characteristics of the median nerve of each volunteer, and the extent of its longitudinal excursion movement under experimental conditions, in which a real operating environment of electronic devices was simulated, were quantified. The results demonstrated that the median nerve at the carpal tunnel inlet was flattened during wrist extension: the flattening ratio increased from 3.40 +/- 0.91 at the neutral position to 4.10 +/- 1.11 at the angle of 30 degrees and 4.09 +/- 1.11 at the angle of 45 degrees . In addition, the median nerve became swollen after the students performed rapid mobile-phone keying for 5 min, indicated by a significant increase in the cross-sectional area from 6.05 +/- 0.97 mm(2) to 7.56 +/- 1.39 mm(2). Passive longitudinal excursion was observed at the median nerve when the students performed mouse-clicking (2.4 +/- 1.0 mm) and mobile-phone keying tasks (1.7 +/- 0.6 mm), with the mouse-clicking task generating a greater extent of longitudinal excursion than the mobile-phone keying task did. In conclusion, the findings of the present study verify the potential harm caused by using electronic devices while maintaining an inappropriate wrist posture for a substantial period. PMID- 25024111 TI - Vaccination perceptions of school employees in a rural school district. AB - BACKGROUND: There continues to be a need for increases in adult vaccination rates, especially among those working in environments which may easily become communicable disease outbreak centers, such as school employees in the school environment. The purpose of this study was to evaluate why rural Utah school employees were non-compliant with the influenza and measles, mumps, and rubella (MMR) vaccines, as well as to identify their views on mandatory vaccination policies. METHODS: A questionnaire was distributed to all school employees in a rural Utah school district. Data analysis included frequencies and measures of central tendency and dispersion for quantitative items and theme identification for qualitative items. RESULTS: Only 51% of school employees were adequately vaccinated for influenza. Reasons for noncompliance with the influenza vaccine included inconvenience, lack of perceived need, and questionable vaccine efficacy. There were 39.3% school employees who had not received an MMR during adulthood, which was commonly attributed to lack of knowledge regarding the need for this vaccine. Almost half (45.7%) of school employees believed a mandatory vaccination policy should be instituted, although 24.2% of school employees were opposed to mandatory adult vaccination policies. Reasons for opposing vaccination mandates included violation of personal choice, lack of perceived vaccination safety and efficacy, lack of perceived need for adult vaccines, and vaccine cost. CONCLUSIONS: Suboptimal vaccination rates of school employees may negatively affect the health and well-being of individuals in the school environment. School employees report a variety of beliefs regarding the influenza and MMR vaccines. While over half of school employees support mandatory vaccination policies for adults working in the school environment, those opposing such a policy report concerns regarding violation of personal choice. Public health officials and school administrators should coordinate efforts to increase vaccination rates among adults in the school environment. PMID- 25024112 TI - Mannose-binding lectin and ficolin-2 do not influence humoral immune response to hepatitis B vaccine. AB - BACKGROUND: Host genetics appear to be an important factor in the failure to generate a protective immune response after hepatitis B (HBV) vaccination. Mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway of complement, influence the clinical outcome of HBV, and MBL deficiency has been shown to augment the humoral response to HBV vaccination in several experimental models. Here, we investigated the association of MBL and FCN2 with the humoral response to HBV vaccination in a candidate gene and functional study. PATIENTS AND METHODS: A post hoc analysis of a prospective, interventional HBV vaccination study among human immunodeficiency virus type 1 (HIV-1) uninfected individuals in Kenya was conducted. Serum levels and polymorphisms of MBL and FCN2 were analysed in relation to the immune response to HBV vaccination. RESULTS: Protective hepatitis B surface antibody levels (>= 10 mI U/mL) were evident in 251/293 (85.7%) individuals. Median MBL and FCN2 levels were similar in responders vs. non-responders with a weak trend towards lower median MBL levels in non-responders (1.0 vs. 1.6MUg/mL, p=0.1). Similarly, there was no difference in four MBL and six FCN2 polymorphisms analysed in the two groups with the exception of an increased frequency of a homozygous MBL codon 57 mutation in non-responders (4 (9.5%) vs. 8 (3.2%), p=0.05) corresponding to lower MBL levels. Results were similar after adjusting for age and sex. CONCLUSIONS: Our study does not support a prominent role of the lectin pathway of complement in general and MBL and FCN2 in particular in the humoral immune response to HBV vaccination in African adults. PMID- 25024113 TI - Examining Ontario's universal influenza immunization program with a multi-strain dynamic model. AB - Seasonal influenza imposes a significant worldwide health burden each year. Mathematical models help us to understand how changes in vaccination affect this burden. Here, we develop a new dynamic transmission model which directly tracks the four dominant seasonal influenza strains/lineages, and use it to retrospectively examine the impact of the switch from a targeted to a universal influenza immunization program (UIIP) in the Canadian province of Ontario in 2000. According to our model results, averaged over the first four seasons post UIIP, the rates of influenza-associated health outcomes in Ontario were reduced to about half of their pre-UIIP values. This is conservative compared to the results of a study estimating the UIIP impact from administrative data, though that study finds age-specific trends similar to those presented here. The strain interaction in our model, together with its flexible parameter calibration scheme, make it readily extensible to studying scenarios beyond the one explored here. PMID- 25024114 TI - MicroRNAs as potential biomarkers for VERO cell tumorigenicity. AB - MicroRNA expression appears to capture the process of neoplastic development in vitro in the VERO line of African green monkey kidney (AGMK) cells (Teferedegne et al. PLoS One 2010;5(12):e14416). In that study, specific miRNA signatures were correlated with the transition, during serial tissue-culture passage, of low density passaged 10-87 VERO cells from a non-tumorigenic phenotype at passage (p) 148 to a tumorigenic phenotype at p256. In the present study, six miRNAs (miR 376a, miR-654-3p, miR-543, miR-299-3p, miR-134 and miR-369-3p) were chosen from the identified signature miRNAs for evaluation of their use as potential biomarkers to track the progression of neoplastic development in VERO cells. Cells from the 10-87 VERO cell line at passage levels from p148 to p256 were inoculated into newborn and adult athymic nude mice. No tumors were observed in animals inoculated with cells from p148 to p186. In contrast, tumor incidences of 20% developed only in newborn mice that received 10-87 VERO cells at p194, p234 and p256. By qPCR profiling of the signature miRNAs of 10-87 VERO cells from these cell banks, we identified p194 as the level at which signature miRNAs elevated concurrently with the acquisition of tumorigenic phenotype with similar levels expressed beyond this passage. In wound-healing assays at 10-passage intervals between p150 to p250, the cells displayed a progressive increase in migration from p165 to p186; beginning at p194 and higher passages thereafter, the cells exhibited the highest rates of migration. By qPCR analysis, the same signature miRNAs were overexpressed with concomitant acquisition of the tumorigenic phenotype in another lineage of 10-87 VERO cells passaged independently at high density. Correlation between the passages at which the cells expressed a tumorigenic phenotype and the passages representing peaks in expression levels of signature miRNAs indicates that these miRNAs are potential biomarkers for the expression of the VERO cell tumorigenic phenotype. PMID- 25024115 TI - Do daughters really cause divorce? Stress, pregnancy, and family composition. AB - Provocative studies have reported that in the United States, marriages producing firstborn daughters are more likely to divorce than those producing firstborn sons. The findings have been interpreted as contemporary evidence of fathers' son preference. Our study explores the potential role of another set of dynamics that may drive these patterns: namely, selection into live birth. Epidemiological evidence indicates that the characteristic female survival advantage may begin before birth. If stress accompanying unstable marriages has biological effects on fecundity, a female survival advantage could generate an association between stability and the sex composition of offspring. Combining regression and simulation techniques to analyze real-world data, we ask, How much of the observed association between sex of the firstborn child and risk of divorce could plausibly be accounted for by the joint effects of female survival advantage and reduced fecundity associated with unstable marriage? Using data from the National Longitudinal Survey of Youth (NLSY79), we find that relationship conflict predicts the sex of children born after conflict was measured; conflict also predicts subsequent divorce. Conservative specification of parameters linking pregnancy characteristics, selection into live birth, and divorce are sufficient to generate a selection-driven association between offspring sex and divorce, which is consequential in magnitude. Our findings illustrate the value of demographic accounting of processes which occur before birth-a period when many outcomes of central interest in the population sciences begin to take shape. PMID- 25024118 TI - The influence of halogen derivatives of thyronine and fluorescein on the dipole potential of phospholipid membranes. AB - The effects of halogen derivatives of thyronine (tetraiodotironine and triiodothyronine) and fluorescein (Rose Bengal, phloxine B, erythrosin, eosin Y, and fluorescein) on the dipole potential of membranes composed of diphytanoylphosphocholine, diphytanoylphosphoserine, and diphytanoylphosphoethanolamine were investigated. A quantitative description of the modifying action of the agents was presented as characteristic parameters of the Langmuir adsorption isotherm: the maximum changes in the dipole potential of the membrane at an infinitely high concentration of modifiers and the desorption constant, characterizing their inverse affinities to the lipid phase. It was shown that the iodine-containing hormones led to a less significant reduction in the dipole potential of phospholipid membranes compared to the xanthene dyes, Rose Bengal, phloxine B, and erythrosin. The latter were characterized by the highest affinity for the lipid membranes compared to tetraiodotironine and triiodothyronine. It was found that the effect of iodine-containing hormones and xanthene dyes on the membrane dipole potential was caused by their uncharged and charged forms, respectively. PMID- 25024116 TI - Fast spectroscopic multiple analysis (FASMA) for brain tumor classification: a clinical decision support system utilizing multi-parametric 3T MR data. AB - INTRODUCTION: A clinical decision support system (CDSS) for brain tumor classification can be used to assist in the diagnosis and grading of brain tumors. A Fast Spectroscopic Multiple Analysis (FASMA) system that uses combinations of multiparametric MRI data sets was developed as a CDSS for brain tumor classification. METHODS: MRI metabolic ratios and spectra, from long and short TE, respectively, as well as diffusion and perfusion data were acquired from the intratumoral and peritumoral area of 126 patients with untreated intracranial tumors. These data were categorized based on the pathology, and different machine learning methods were evaluated regarding their classification performance for glioma grading and differentiation of infiltrating versus non infiltrating lesions. Additional databases were embedded to the system, including updated literature values of the related MR parameters and typical tumor characteristics (imaging and histological), for further comparisons. Custom Graphical User Interface (GUI) layouts were developed to facilitate classification of the unknown cases based on the user's available MR data. RESULTS: The highest classification performance was achieved with a support vector machine (SVM) using the combination of all MR features. FASMA correctly classified 89 and 79% in the intratumoral and peritumoral area, respectively, for cases from an independent test set. FASMA produced the correct diagnosis, even in the misclassified cases, since discrimination between infiltrative versus non infiltrative cases was possible. CONCLUSIONS: FASMA is a prototype CDSS, which integrates complex quantitative MR data for brain tumor characterization. FASMA was developed as a diagnostic assistant that provides fast analysis, representation and classification for a set of MR parameters. This software may serve as a teaching tool on advanced MRI techniques, as it incorporates additional information regarding typical tumor characteristics derived from the literature. PMID- 25024119 TI - Special interaction of anionic phosphatidic acid promotes high secondary structure in tetrameric potassium channel. AB - Anionic phosphatidic acid (PA) has been shown to stabilize and bind stronger than phosphatidylglycerol via electrostatic and hydrogen bond interaction with the positively charged residues of potassium channel KcsA. However, the effects of these lipids on KcsA folding or secondary structure are not clear. In this study, the secondary structure analyses of KcsA potassium channel was carried out using circular dichroism spectroscopy. It was found that PA interaction leads to increases in alpha-helical and beta-sheet content of KcsA protein. In PA, KcsA alpha-helical structure was further stabilized by classical membrane-active cosolvent trifluoroethanol followed by reduction in the beta-sheet content indicating cooperative transformation from the beta-sheet to an alpha-helical structure. The data further uncover the role of anionic PA in KcsA folding and provide mechanism by which strong hydrogen bonds/electrostatic interaction among PA headgroup and basic residues on lipid binding domains may induce high helical structure thereby altering the protein folding and increasing the stability of tetrameric assembly. PMID- 25024120 TI - Trends in childhood mortality in Kenya: the urban advantage has seemingly been wiped out. AB - BACKGROUND: We describe trends in childhood mortality in Kenya, paying attention to the urban-rural and intra-urban differentials. METHODS: We use data from the Kenya Demographic and Health Surveys (KDHS) collected between 1993 and 2008 and the Nairobi Urban Health and Demographic Surveillance System (NUHDSS) collected in two Nairobi slums between 2003 and 2010, to estimate infant mortality rate (IMR), child mortality rate (CMR) and under-five mortality rate (U5MR). RESULTS: Between 1993 and 2008, there was a downward trend in IMR, CMR and U5MR in both rural and urban areas. The decline was more rapid and statistically significant in rural areas but not in urban areas, hence the gap in urban-rural differentials narrowed over time. There was also a downward trend in childhood mortality in the slums between 2003 and 2010 from 83 to 57 for IMR, 33 to 24 for CMR, and 113 to 79 for U5MR, although the rates remained higher compared to those for rural and non-slum urban areas in Kenya. CONCLUSIONS: The narrowing gap between urban and rural areas may be attributed to the deplorable living conditions in urban slums. To reduce childhood mortality, extra emphasis is needed on the urban slums. PMID- 25024121 TI - What can local authorities do to improve the social care-related quality of life of older adults living at home? Evidence from the Adult Social Care Survey. AB - Local authorities spend considerable resources on social care at home for older adults. Given the expected growth in the population of older adults and budget cuts on local government, it is important to find efficient ways of maintaining and improving the quality of life of older adults. The ageing in place literature suggests that policies in other functions of local authorities may have a significant role to play. This study aims to examine the associations between social care-related quality of life (SCRQoL) in older adults and three potential policy targets for local authorities: (i) accessibility of information and advice, (ii) design of the home and (iii) accessibility of the local area. We used cross-sectional data from the English national Adult Social Care Survey (ASCS) 2010/2011 on service users aged 65 years and older and living at home (N=29,935). To examine the association between SCRQoL, as measured by the ASCOT, and three single-item questions about accessibility of information, design of the home and accessibility of the local area, we estimate linear and quantile regression models. After adjusting for physical and mental health factors and other confounders our findings indicate that SCRQoL is significantly lower for older adults who find it more difficult to find information and advice, for those who report that their home design is inappropriate for their needs and for those who find it more difficult to get around their local area. In addition, these three variables are as strongly associated with SCRQoL as physical and mental health factors. We conclude that in seeking to find ways to maintain and improve the quality of life of social care users living at home, local authorities could look more broadly across their responsibilities. Further research is required to explore the cost-effectiveness of these options compared to standard social care services. PMID- 25024123 TI - Cardiovascular management in pregnancy: congenital heart disease. AB - The population of adults with CHD continues to expand,and thus the number of women with CHD who contemplate pregnancy or become pregnant is also growing. Mothers with low-risk defects can be managed by general cardiologist,whereas those with more complex defects should be managed by or with the assistance of ACHD cardiologists. It is important to acknowledge that all patients with CHD may have unique anatomy or physiology, despite their classification as having a simple, moderate, or complex defect. As such, clinicians evaluating these patients should have adequate knowledge and expertise when assessing patient's risk for pregnancy,when performing imaging or hemodynamic studies, and when managing these patients during pregnancy. The American Board of Medical Specialties has recently recognized ACHD as a subspecialty of cardiovascular disease to treat the specialized needs of these patients in adulthood. ACHD experts can provide expertise in the management of specific defects or lesions, imaging techniques, prepregnancy risk assessment,and can manage these patients or comanage them with other medical providers during their pregnancy. Because many of these ACHD patients are lost to follow-up in adulthood, pregnancy represents a time when these patients seek medical care(and for some, represents a time of vulnerability and increased risk). This represents an opportunity to establish or reestablish care with ACHD specialists and to reestablish continuing long-term care for their CHD. Pregnancy also provides an opportunity to create partnerships between primary care physicians,adult cardiologists, and ACHD specialists to provide optimal care for these women throughout their lives. PMID- 25024122 TI - Effect of the Degenerative State of the Intervertebral Disk on the Impact Characteristics of Human Spine Segments. AB - Models of the dynamic response of the lumbar spine have been used to examine vertebral fractures (VFx) during falls and whole body vibration transmission in the occupational setting. Although understanding the viscoelastic stiffness or damping characteristics of the lumbar spine are necessary for modeling the dynamics of the spine, little is known about the effect of intervertebral disk degeneration on these characteristics at high loading rates. We hypothesize that disk degeneration significantly affects the viscoelastic response of spinal segments to high loading rate. We additionally hypothesize the lumbar spine stiffness and damping characteristics are a function of the degree of preload. A custom, pendulum impact tester was used to impact 19 L1-L3 human spine segments with an end mass of 20.9 kg under increasing preloads with the resulting force response measured. A Kelvin-Voigt model, fitted to the frequency and decay response of the post-impact oscillations was used to compute stiffness and damping constants. The spine segments exhibited a second-order, under-damped response with stiffness and damping values of 17.9-754.5 kN/m and 133.6-905.3 Ns/m respectively. Regression models demonstrated that stiffness, but not damping, significantly correlated with preload (p < 0.001). Degenerative disk disease, reflected as reduction in magnetic resonance T2 relaxation time, was weakly correlated with change in stiffness at low preloads. This study highlights the need to incorporate the observed non-linear increase in stiffness of the spine under high loading rates in dynamic models of spine investigating the effects of a fall on VFx and those investigating the response of the spine to vibration. PMID- 25024124 TI - Thrombophilia testing, recurrent thrombosis, and women's health. PMID- 25024125 TI - ECG Response: July 15, 2014. PMID- 25024126 TI - Fibrosing mediastinitis: a squeeze on arterial and venous segments of the heart. PMID- 25024127 TI - Rare presentation of asymptomatic pericardial effusion: hemangioma of the atrioventricular groove in cardiac magnetic resonance imaging. PMID- 25024128 TI - Letter by Argulian and Messerli regarding article, "effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial". PMID- 25024129 TI - Response to letter regarding article, "effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial". PMID- 25024132 TI - Enhancing lung cancer diagnosis: electrochemical simultaneous bianalyte immunosensing using carbon nanotubes-chitosan nanocomposite. AB - A label-free electrochemical bianalyte immunosensor has been designed for simultaneous detection of lung cancer biomarkers (anti-MAGE A2 and anti-MAGE A11) using carbon nanotubes-chitosan (CNT-CHI) composite. To achieve this, acid functionalized single-walled CNTs were used to prepare CNT-CHI gel and electrodes were fabricated by drop casting method onto graphite surface. Lung cancer biomarkers specific antigens (Ag), i.e., MAGE A2 and MAGE A11, were covalently immobilized onto CNT-CHI/graphite electrode separately for fabrication process. Fabricated immunoelectrodes (MAGE A2/CNT-CHI/graphite and MAGE A11/CNT CHI/graphite) were characterized at each modification step by cyclic voltammetry (CV), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Both immunoelectrodes showed successful detection of respective analytes (anti-MAGE A2 and anti-MAGE A11) from 5 fg mL(-1) to 50 ng mL(-1) using differential pulse voltammetry (DPV). Both Ag/CNT-CHI/graphite immunoelectrodes (using MAGE A2 and MAGE A11) were independently capable of distinguishing specific and nonspecific analytes like CD59, D-dimers, etc. Response studies of both immunoelectrodes revealed successful demonstration of simultaneous detection of anti-MAGE A2 and A11 independently in a single experimental run when exposed to a mixture of various analyte concentrations in different combinations irrespective of the presence of other analyte present in the same vessel. PMID- 25024133 TI - Validity and reliability of the abdominal test and evaluation systems tool (ABTEST) to accurately measure abdominal force. AB - OBJECTIVES: Ability to generate force from the core musculature is a critical factor for sports and general activities with insufficiencies predisposing individuals to injury. This study evaluated isometric force production as a valid and reliable method of assessing abdominal force using the abdominal test and evaluation systems tool (ABTEST). Secondary analysis estimated 1-repetition maximum on commercially available abdominal machine compared to maximum force and average power on ABTEST system. DESIGN: This study utilized test-retest reliability and comparative analysis for validity. Reliability was measured using test-retest design on ABTEST. Validity was measured via comparison to estimated 1 repetition maximum on a commercially available abdominal device. METHODS: Participants applied isometric, abdominal force against a transducer and muscular activation was evaluated measuring normalized electromyographic activity at the rectus-abdominus, rectus-femoris, and erector-spinae. RESULTS: Test, re-test force production on ABTEST was significantly correlated (r=0.84; p<0.001). Mean electromyographic activity for the rectus-abdominus (72.93% and 75.66%), rectus femoris (6.59% and 6.51%), and erector-spinae (6.82% and 5.48%) were observed for trial-1 and trial-2, respectively. Significant correlations for the estimated 1 repetition maximum were found for average power (r=0.70, p=0.002) and maximum force (r=0.72, p<0.001). CONCLUSIONS: Data indicate the ABTEST can accurately measure rectus-abdominus force isolated from hip-flexor involvement. Negligible activation of erector-spinae substantiates little subjective effort among participants in the lower back. Results suggest ABTEST is a valid and reliable method of evaluating abdominal force. PMID- 25024134 TI - Structural integrity is decreased in both Achilles tendons in people with unilateral Achilles tendinopathy. AB - OBJECTIVES: A high proportion of Achilles tendinopathy patients develop bilateral symptoms with human and animal studies showing bilateral histological changes associated with overuse/pathology in one tendon. The current study examined changes in tendon structure, assessed semi-quantitatively using ultrasound tissue characterisation, in both the symptomatic and asymptomatic tendon in unilateral Achilles tendinopathy patients in comparison to individuals with no history of tendinopathy. DESIGN: Cross-sectional case-control study. METHODS: Participants with Achilles tendinopathy (n=21), with varying severity and length of clinical symptoms, and six participants with no history of tendinopathy were recruited. Tendons were scanned using ultrasound tissue characterisation, which captures contiguous transverse ultrasound images every 0.2mm and renders a 3-dimensional image. Ultrasound tissue characterisation quantifies tendon structure by measuring the stability of echopattern over contiguous transverse images. Four echo-types were discriminated and expressed as a percentage. Antero-posterior diameter of all tendons was measured. RESULTS: Significant differences were observed in the proportion of normal tendon structure between all three groups (p<0.01), with the symptomatic tendon containing the least amount of normal tendon structure (symptomatic - 79.5%, asymptomatic - 81.8%, control - 86.4%). The asymptomatic tendon contained significantly less normal tendon in comparison to the control tendon (p=0.008), suggesting the asymptomatic tendon is structurally compromised despite the absence of symptoms. CONCLUSIONS: Both Achilles tendons are structurally compromised in patients with unilateral Achilles tendinopathy. Future studies need to investigate whether these changes increase the risk of developing symptoms. PMID- 25024135 TI - Running with a minimalist shoe increases plantar pressure in the forefoot region of healthy female runners. AB - OBJECTIVES: Minimalist running shoes have been proposed as an alternative to barefoot running. However, several studies have reported cases of forefoot stress fractures after switching from standard to minimalist shoes. Therefore, the aim of the current study was to investigate the differences in plantar pressure in the forefoot region between running with a minimalist shoe and running with a standard shoe in healthy female runners during overground running. DESIGN: Randomized crossover design. METHODS: In-shoe plantar pressure measurements were recorded from eighteen healthy female runners. Peak pressure, maximum mean pressure, pressure time integral and instant of peak pressure were assessed for seven foot areas. Force time integral, stride time, stance time, swing time, shoe comfort and landing type were assessed for both shoe types. A linear mixed model was used to analyze the data. RESULTS: Peak pressure and maximum mean pressure were higher in the medial forefoot (respectively 13.5% and 7.46%), central forefoot (respectively 37.5% and 29.2%) and lateral forefoot (respectively 37.9% and 20.4%) for the minimalist shoe condition. Stance time was reduced with 3.81%. No relevant differences in shoe comfort or landing strategy were found. CONCLUSIONS: Running with a minimalist shoe increased plantar pressure without a change in landing pattern. This increased pressure in the forefoot region might play a role in the occurrence of metatarsal stress fractures in runners who switched to minimalist shoes and warrants a cautious approach to transitioning to minimalist shoe use. PMID- 25024137 TI - Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. AB - The transcription factor Gata6 regulates proliferation and differentiation of epithelial and endocrine cells and cancers. Among hematopoietic cells, Gata6 is expressed selectively in resident peritoneal macrophages. We thus examined whether the loss of Gata6 in the macrophage compartment affected peritoneal macrophages, using Lyz2-Cre x Gata6(flox/flox) mice to tackle this issue. In Lyz2 Cre x Gata6(flox/flox) mice, the resident peritoneal macrophage compartment, but not macrophages in other organs, was contracted, with only a third the normal number of macrophages remaining. Heightened rates of death explained the marked decrease in peritoneal macrophage observed. The metabolism of the remaining macrophages was skewed to favor oxidative phosphorylation and alternative activation markers were spontaneously and selectively induced in Gata6-deficient macrophages. Gene expression profiling revealed perturbed metabolic regulators, including aspartoacylase (Aspa), which facilitates generation of acetyl CoA. Mutant mice lacking functional Aspa phenocopied the higher propensity to death and led to a contraction of resident peritoneal macrophages. Thus, Gata6 regulates differentiation, metabolism, and survival of resident peritoneal macrophages. PMID- 25024136 TI - CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. AB - Interleukin (IL)-22-producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX3CR1+ mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX3CR1+ MNPs that were dependent on MyD88 signaling. CX3CR1+MNPs from both mouse and human tissue produced more IL 23 and IL-1beta than conventional CD103(+) dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn's disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23- and IL-1beta induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX3CR1+ mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD. PMID- 25024138 TI - A peptide inhibitor of synuclein-gamma reduces neovascularization of human endometriotic lesions. AB - Endometriosis is a chronic painful gynecological condition characterized by adherence and growth of endometrium outside of the uterine cavity. Neovascularization is essential to the developing endometriosis lesion to support its growth. Synuclein-gamma (SNCG), a protein implicated in cellular proliferation, is associated with a broad range of malignancies as well as endometriosis. We hypothesized that SNCG plays an important role in the neovascularization and growth of endometriosis and blocking of SNCG will interfere with survival of endometriotic lesions in a mouse model. We developed SP012, a novel 12 amino acid peptide inhibitor of SNCG. SP012 inhibited three dimensional endothelial cell tube formation in a dose-dependent manner. Using intravital microscopy, SP012 was shown to be successfully delivered to human endometriotic lesions in a xenograft mouse model in vivo. Alymphoid (BALB/c-Rag2 /-Il2rgamma-/- lacking T, B and NK cells) mice were surgically induced with human endometriotic lesions and treated with SP012 or phosphate-buffered saline control. SP012 treated endometriotic lesions had decreased growth, development and vascularization at the time of necroscopy. Endometriotic lesions treated with SP012 also had fewer isolectin (+) microvessels. These results, using a mouse model, indicate that SNCG plays a role in the neovascularization and subsequent growth of human endometriotic lesions. Targeting SNCG function using peptide inhibitor might provide a potential therapeutic option for the treatment of endometriosis in the future. PMID- 25024139 TI - Epigenetic mechanisms regulate placental c-myc and hTERT in normal and pathological pregnancies; c-myc as a novel fetal DNA epigenetic marker for pre eclampsia. AB - Placental development is known for its resemblance with tumor development, such as in the expression of oncogenes (c-myc) and telomerase (hTERT). The expression of c-myc and hTERT is up-regulated during early pregnancy and gestational trophoblastic diseases (GTDs). To determine the role of DNA methylation [via methylation-sensitive high resolution melting (MS-HRM)] and histone modifications [via chromatin immunoprecipitation (ChIP assay)] in regulating the differential expression of c-myc and hTERT during normal gestation and their dysregulation during placental disorders, we obtained placental samples from 135 pregnant women, in five groups: normal first, second and third trimester (n = 30 each), pre-eclamptic pregnancy (n = 30) and molar pregnancy (n = 15). Two placental cell lines (JEG-3 and HTR-8/SVneo) and isolated first-trimester cytotrophoblasts were also studied. Quantitative RT-PCR revealed decreased mRNA expression levels of c myc and hTERT, which were associated with a higher level of H3K9me3 (1.5-fold, P < 0.05) and H3K27me3 (1.9-fold, P < 0.05), respectively, in third-trimester placental villi versus first-trimester villi. A significantly lower level of H3K27me3 in molar placenta was associated with a higher mRNA expression of c-myc and hTERT. The development of pre-eclampsia (PE) was associated with increased methylation (P < 0.001) and H3K27me3 (P < 0.01) at the c-myc promoter and reduced H3K9me3 (P < 0.01) and H3K27me3 (P < 0.05) at the hTERT promoter. Further, mRNA expression of c-myc and hTERT was strongly correlated in molar villi (r = 0.88, P < 0.01) and JEG-3 cells (r = 0.99, P < 0.02). Moreover, on the basis of methylation data, we demonstrate the potential of c-myc as a fetal DNA epigenetic marker for pre-eclamptic pregnancies. Thus we suggest a role for epigenetic mechanisms in regulating differential expression of c-myc and hTERT during placental development and use of the c-myc promoter region as a potential fetal DNA marker in the case of PE. PMID- 25024140 TI - Stable isotope analysis of termite food habits in East African grasslands. AB - Stable carbon isotope techniques were employed to study the food habits of the termite Macrotermes michaelseni (Isoptera: Termitidae) in a semiarid savanna habitat in Kenya. At Kajiado this species utilized approximately 70% herbaceous vegetation (mostly grass) and 30% woody vegetation, while at Ruiru approximately 64% of the vegetation utilized was woody and 36% herbaceous. Stabel carbon isotope ratios varied between castes within sites, but were consistent with the manner in which carbon flows through termite colonies. delta(13)C values increased in the sequence: diet->fungus comb->nonreproductive castes >reproductive castes. These results are in agreement with the idea that organic carbon becomes enriched in (13)C as it passes through a food chain. PMID- 25024141 TI - Are big mammals simply little mammals writ large? AB - Populations are regulated intrinsically (self-regulated) when the animals lower their rate of increase behaviorally or physiologically as a reaction to rising density. They are regulated extrinsically if the equilibrium is a mechanical consequence of interaction between the population and the organisms providing its food. We suggest that, at least for mammalian herbivores, self-regulation is unlikely to evolve unless the population's intrinsic rate of increase exceeds about 0.45 on a yearly basis. That value corresponds to a body weight of about 30 kg, the intrinsic rate being related inversely to body weight by r m=1.5 W(-0.36) with W in kg.The two dynamic strategies, self-regulation and extrinsic regulation, should enforce a bimodality of the frequency distribution of observed intrinsic rates of increase. This in turn might be reflected in a bimodality of body sizes, the smaller herbivores constituting the lower mode generally showing intrinsic regulation and the larger herbivores of the upper mode generally being regulated by extrinsic mechanisms. There is some empirical support for these predictions but it is by no means clearcut.Mechanisms of self-regulation can evolve either by individual or group selection. Individual selection may act in two ways. By inhibiting their neighbours with some form of interference, individuals may increase their relative fitness without increasing their reproductive rate. Alternatively, individual selection may raise the absolute fitness of individuals and thereby raise the populations's intrinsic rate of increase. The population is destabilized if that process continues beyond a certain threshold and the population is then at significant risk of extinction at the troughs of the consequent oscillations. Selection between such populations will favour those carrying the beginnings of a self-regulating mechanism, and with that mechanism strengthened and fixed by continuing group selection, individual selection is again freed of the dynamic restraints on raising further the intrinsic rate of increase. PMID- 25024143 TI - Community development following removal of urchins, Strongylocentrotus droebachiensis, from the rocky subtidal zone of the St. Lawrence Estuary, Eastern Canada. AB - The role of sea urchins, Strongylocentrotus droebachiensis, in structuring the rocky subtidal community was examined at Anse aux Basques on the north shore of the St. Lawrence Estuary, Quebec. In an experimental area, measuring 20x20 m and extending from 0 to 10 m in depth, we greatly reduced the intensity of urchin grazing by eliminating all urchins larger than 10 mm in test diameter. This area was observed for two years and compared to an adjacent control area. In the upper portion of the experimental area during the first month after urchin removal, mid July to mid-August 1978, a dense diatom cover developed, and during the second month the diatoms were overgrown by Ulvaria obscura. After four months (November) an Alaria esculenta overstory was present from near low water level to 3 m deep. Community development was much slower at greater depths and it took a year for the Alaria zone to extend to 4-5 m deep, and two years to extend to 6 m deep. The low light penetration at this estuarine location was probably the main factor for the slow algal development at 6-10 m deep. At the end of the experiment Agarum cribrosum was second in importance after Alaria and was most common at 3 to 6 m in depth. Laminaria spp. was found in low numbers in the first year and did not show an increase during the second year. There was a dramatic increase in the number of species and abundance of algae in the experimental area. Also, there was a marked increase in many animal species, particularly Acmaea testudinalis, Mytilus edulis and Margarites helicinus, and a decrease in Metridium senile. By contrast, in the control area, the number of algal and invertebrate species remained low. In the experimental area a sharp increase in the growth rate of a cohort of very small urchins, which was not eliminated by our removal effort, demonstrated that there is strong intraspecific competition amongst urchins when the food supply is limited. In the St. Lawrence Estuary, there are few predators of urchins and the urchin dominated community appears to be a stable situation. PMID- 25024142 TI - Reproductive effort and value in different populations of the marine mussel, Mytilus edulis L. AB - Fecundity, reproductive effort (estimated both from production measurements and from physiological data), the energetic costs of reproduction and the reproductive value of different size classes were measured for mussels at different sites and related to age and to tissue weight. Variability between sites was considerable and differences as great as 10 x were recorded between minimum and maximum values for egg production, reproductive effort and reproductive value. However, similarities between mussels from different sites were also apparent, as regards egg size, the estimated metabolic costs of egg production (based on measurements of oxygen consumption), the relationship (isometric) between egg production and body size, the fact of an increase in reproductive effort with increase in size, and the age at which maximum residual reproductive values was expressed. These relationships are discussed in terms of the fundamental reproductive strategy of the species and the degree of environmental stress imposed on the mussels at the different sites. PMID- 25024144 TI - Nectar production of Epilobium angustifolium L. at different air humidities; nectar sugar in individual flowers and the optimal foraging theory. AB - The nectar production of Epilobium angustifolium L. was investigated at 20 degrees C and 50%, 78% and 94% ambient humidity in the climatic test chamber. By means of permanent pipettes, freshly produced nectar was sucked off immediately after secretion, and nectar samples were also taken at 10-h and 48-h intervals to investigate the postsecretory influence of ambient humidity. Volume and sugar concentration of samples from individual flowers were measured and the sugar contained was calculated. The rate of sugar production remains constant for all ambient humidities and extraction intervals investigated; the mean value for all 180 samples is 1.55 mg sucrose equivalents/24h. Sugar concentration of secretion nectar is linearly dependent on ambient humidity over the range investigated, and nectar volume and sugar concentration change according to the theoretically expected curve for solutions with a sugar content of 1.55 mg sucrose. The response of secretion nectar to steplike changes in ambient humidity was investigated and the transient function described. The nectaries respond immediately to changes in ambient humidity. The consequences of the results for nectar production and nectar reward of individual flowers in the field and for the optimal foraging of pollinators are discussed. Discussion concentrates particularly on the following questions: what influence the variability of nectar reward in individual flowers may have on flower-visiting bumble-bees; whether these animals have the sensory capabilities to measure sugar exactly; and whether the water relations of pollinators may also influence foraging behaviour. PMID- 25024145 TI - Utilization of red oak acorns in non-bumper crop year. AB - Utilization of acorns from individual red oaks Quercus rubra Fagaceae) was examined in the tree canopies during fall and from the ground beneath the canopies during winter in a Missouri oak-hickory forest. The goal of the study was to determine whether vertebrates show preference for acorns from individual trees on the basis of acorn or crop characteristics. Seed production, percentage of crop which was viable, maldeveloped, or infested by insects, average seed weight and tannin content of mature, viable acorns were measured for 11 red oak adults. Behavioral observations were conducted in September and October during the peak period of seed fall. Over winter removal was determined by counting the number of acorns removed from 3x3 m plots underneath the trees' canopies between December and mid-April. Canopy removal of acorns was surprisingly low-an estimated average of 52 acorns per tree compared with a mean estimated crop size of approximately 1,200 mature acorns. Over winter, approximately 50% of the acorns were removed from ground plots (range 7% to 93.1%). Number removed corresponded more to the density of nuts rather than to seed and crop characteristics. The low rate of acorn utilization by canopy visitors contrasts with other studies in the literature and may have been due to 1) the fact that this study was done in a relatively homogeneous forest where high density of conspecifics reduces the impact on any one individual or 2) perhaps an unusually low density of birds and mammals. PMID- 25024147 TI - Selection and migration in two distinct phenotypes of Littorina saxatilis in Sweden. AB - Two distinct phenotypes of the marine snail L. saxatilis, the 'E morph' from exposed rocky habitats, and the 'S morph' from nearby sheltered boulder shores, were released and survivors recaptured at 3-monthly intervals. Survival rate of E morphs was significantly higher than that of S morphs in the exposed habitat, whilst the revers was true for the sheltered site. When released in an environment intermediate between the exposed and sheltered habitats, both morphs survived equally well. However, snails native of this area, 'I morphs', survived better than both E and S morphs here. Recapture rates were highest in spring. Large snails of both phenotypes were selected against in the exposed habitat. In the sheltered environment, small E morph snails survived better than large ones, and both sizes of S morphs survived equally well. E morph individuals transplanted to a different exposed locality than their native one, had lower survival rates compared to native individuals. This effect was not found among transplanted S morph snails.Distances migrated since time of release were on average greater in the sheltered than in the exposed habitat, and within the range of 1-4 m per 3 months, for both habitats. In a laboratory experiment, both morphs showed a shelter-seeking behaviour, most pronounced in the E morph.It is proposed that the strong selection differences between the morphs within the two different habitats, the absence of a planktonic larval stage, and a restricted migration among juvenile and adult snails, maintain a genetic polymorphism within the species, responsibel for considerable parts of the large phenotypic differences observed between the two morphs E and S. PMID- 25024146 TI - Use of doubly-labeled water ((3)HH (18)O) for determination of H 2O flux and CO 2 production by a mammal in a humid environment. AB - The accuracy of the doubly labeled water ((3)HH(18)O) technique for estimating H2O flux and CO2 production in pocket gophers was evaluated in laboratory experiments. Experiments were conducted under conditions of elevated humidity in order to determine the influence of unlabeled H2O vapor input on H2O flux and CO2 production rates which are determined from isotope turnover. High humidity is commonplace in burrows of many small mammals, including those of the pocket gopher, and theoretically could introduce substantial errors when determining these rates with isotopic procedures.Water influx that was estimated from tritium turnover was not significantly different from actual H2O influx which was determined from feeding rates. Also, (3)HH(18)O techniques yielded estimates of CO2 production that were not significantly different from values determined from energy intake rates. Such close agreement was not anticipated. The unexpected accuracy probably results due to offsetting errors associated with (1) the influx of unlabeled H2O vapor through the skin and lungs of labeled pocket gophers and (2) the effects of biological fractionation of isotopes in the body H2O of labeled pocket gophers. PMID- 25024148 TI - Selective predation and habitat shift in a copepod species - support for the predation hypothesis. AB - In studying the relevance of the predation hypothesis as an explanation for the vertical migration of zooplankton two predictions were tested: 1) The egg sacs of Eurytemora are sufficient to cause different predation pressure in food selection experiments with visually hunting planktivores as predators and ovigerous vs. non ovigerous Eurytemora females as prey. 2) If copepods avoid predation by vertical migration, there should occur differences in the vertical distribution pattern of ovigerous and non-ovigerous females according to selective predation. The results showed that, when ovigerous and non-ovigerous females were presented to predators, a significant preference for ovigerous females was found in high densities of prey. No preference was found in experiments with males vs. non ovigerous females and at low copepod densities. In a field study we found that non-ovigerous females distributed throughout the water column preferred the deeper parts. Ovigerous females were also abundant in deeper waters but almost totally avoided the surface layer above 20 m. Thus our results support the predation hypothesis when the adaptive value of vertical migration is considered.On the basis of our results we deduced testable predictions on the evolutionary effects of predation: 1) In heavily foraged communities there is strong coevolution among the prey to resemble each other in terms of which are critical in selective predation. 2) If the carrying of an egg sac is considered as parental care, it is likely that parental care occurs more seldom in environments with high predation. PMID- 25024149 TI - A field study of prey selection in planktivorous fish larvae. AB - The food selection of larval fish was studied from field samples collected in two areas that differ in productivity. In the area where planktonic primary and secondary production was high the fish larvae showed a tendency to specialise and they selected the largest prey species available as food; in the area of lower production fish were generalists and they fed equally on all size classes.Abundance of prey was found to be one of the decisive factors in the prey selection of planktivorous fish larvae. Large prey species (calanoids) were selected when their absolute abundance was high but when their abundance was low, small-sized cladocerans were preferred. Visibility and stage of life history were also assumed to affect the mode of selection. PMID- 25024150 TI - The spatial and temporal distribution pattern of the stoat (Mustela erminea L.). AB - The distribution and movements of two stoat populations were studied by capture recapture and tracking in the Swiss Jura Mountains. On the Brevine area in summer 1977 the population was at a high density phase and evenly distributed. A well established intrasexual territorial system was observed, with a high degree of sedentarity in adults. During the decline and the following phase of scarcity, the stoats were progressively restricted to a peat-bog area and the territorial system broke down. The adult males became transient and a high degree of dispersal was recorded among the juveniles. On the Val de Ruz area, the population was fairly stable and the stoats had home ranges and movements adapted to habitat characteristics. Adult males in March-April and juveniles moved around considerably. These aspects of the spatio-temporal distribution pattern of Mustela erminea are discussed in relation to the main factors affecting it, such as population density, habitat, sex and age, activity, and seasons. PMID- 25024151 TI - Experimental field evidence of interspecific aggression between two species of kangaroo rat (Dipodomys). AB - The competitive coexistence of heteromyid rodents has been primarily ascribed to differential utilization of resources such as microhabitats and seeds. An examination of the use of space by the kangaroo rat Dipodomys merriami indicates this species is aggressively subordinate to a larger species, Dipodomys spectabilis and is excluded from the larger species home range during the crtical fall harvesting season. These experiments suggest that interspecific aggression may be involved in the coexistence of these species. Additional evidence is presented that small scale spatial variations in resource productivity may promote the coexistence of these two species. PMID- 25024152 TI - Presence of an urban gradient demonstrated for carabid associations. AB - Using carabid associations from Leipzig (GDR) as an example, the effect of an urban gradient("arborealeremial") is demonstrated. Equations for calculation of gradient values are given. Furthermore the associations are characterized by an index of temporal homogeneity as a measure of balance during the year. Species diversities for small time intervals are used to calculate homogeneity. A more or less linear correlation between gradient value and homogeneity was demonstrated for the associations investigated. PMID- 25024153 TI - Diurnal and seasonal variations in activity of crassulacean acid metabolism and plant water status in a northern latitude population of Opuntia erinacea. AB - A northern latitude population of Opuntia erinacea in eastern Washington State, U.S.A. was investigated with regard to daily and seasonal activity of Crassulacean acid metabolism and water relations. Fresh samples were collected throughout the light and dark periods on 21 dates between October 1979 and December 1980. Daily activity of CAM varied seasonally with daily maximum titratable acidity values ranging from 190 MUEq.g(-1) fresh weight in October 1979 to 84 MUEq.g(-1) in January 1980, to 230 MUEq. g(-1) fresh weight in June 1980. Daily patterns of acid fluctuation were generally typical of CAM plants. Afternoon increases in acid concentration were noticed occasionally, and morning peaks in acidity were frequently observed. Plant water potentials were generally more closely correlated with median cladophyll temperature than with precipitation patterns, exhibiting sharply increased negativity around 6C. The data suggest the importance of available moisture and temperature in regulation of CAM, the existence of a cryoprotection mechanism involving reduction of plant water content, and the necessity of spring recovery for post-winter resumption of CAM activity. PMID- 25024154 TI - Wound induced defences in plants and their consequences for patterns of insect grazing. AB - Three scales of wound-induced chemical responses in plants are identified: (1) highly localised chemical changes associated with disruption of cell compartmentation; (2) changes induced in cells surrounding the damaged area, forming a kind of halo around the damage, and (3) more widely-dispersed changes which may affect an entire organ, branch or plant. A brief review of the literature reveals that such chemical responses are very widespread in plants, and many of the substances formed are known to affect adversely the growth, development, or reproduction of insects. It is argued that wound-induced changes in plant chemistry represent for insects a powerful selective pressure for the dispersal of grazing. Levels and patterns of invertebrate grazing in a range of herbaceous and deciduous woody plants sampled at the end of the growing seasons were examined. Leaves of many species exhibited a strikingly evident over dispersion of grazing initiations, and in some cases the arrangement of holes appeared close to regularity. The pattern of damage between leaves was, in most cases, heavily biased towards a large proportion of leaves receiving a low level of grazing. These highly dispersed patterns of grazing damage are consistent with the hypothesis that wound-induced responses play an important role in determining patterns of insect feeding. They have important implications for the expected levels of insect exploitation of host plants and for the advantages to the plant of distributing grazing damage evenly through the canopy. PMID- 25024155 TI - Social organization and foraging success in Lasius neoniger (Hymenoptera: Formicidae): behavioral and ecological aspects of recruitment communication. AB - Live, moribund, or dead arthropods are gathered by Lasius neoniger through individual and social retrieval. 85% of the total biomass of prey (fresh weight) in the diet is cooperatively retrieved by groups of workers. Short-and long-range chemical recruitment signals coordinate cooperative foraging. Stort-range recruitment of workers to assist in the retrieval or defense of prey is achieved by simultaneous discharge of hindgut material and poison gland secretion. In long range recruitment, workers discovering prey deposit a trail of hindgut material while returning to the nest. Hindgut pheromone both stimulates nestmates to leave the nest and orients them to the food source. Colony response is adjusted according to prey weight. Group retrieval of prey follows after a sufficient number of foragers have been recruited to move the prey. Rapid prey movement decreases the exposure of food sources to neighboring conspecific and interspecific competitors. The ability to move prey rapidly is limited to prey on the order of 130 mg or less in weight. The probability of interference during foraging and resource loss to competitors increases with increasing prey size, but the probability of loss is significantly less than the probability of interference for intermediate size prey (~20 mg), which can be moved quickly. The foraging and recruitment behaviors of Lasius neoniger appear to have a prey size dependent effectiveness which results in greater foraging success on prey of a relatively narrow size range above those prey that can be retrieved by solitary foragers. PMID- 25024156 TI - Photosynthetic characteristics of Sonoran Desert winter annuals. AB - Photosynthesis in Sonoran Desert winter annuals appeared to be similar to those observed in other C3 photosynthetic pathway herbs, although photosynthetic capacities ranged from 18 to 65 MUmol CO1 m(-2) s(-1) under natural conditions. The higher photosynthetic capacities were associated with high leaf conductances to water vapor (up to 39 mm s(-1)). Leaf Kjeldahl nitrogen contents were high, ranging up to 44.9 mg g(-1). We suggest that the high photosynthetic capacities in several species may be related to resource availability and enable successful exploitation of the short, unpredictable growth periods experienced by these annuals. Although photosynthetic rates in desert winter annuals spanned a wide range, the relationship between leaf conductance and maximum photosynthesis appeared simiar to that of other C3 vascular plants. It is possible that the resulting constant intercellular, CO2 concentrations were related to minimizing excessive water loss, while not severely imposing limitations to photosynthetic gains. PMID- 25024157 TI - Influence of pollen feeding and physiological condition on pesticide sensitivity of the honey bee Apis mellifera carnica. AB - In two consecutive years heavy bee mortality at end April/early May followed the use of pesticides classed as harmless for bees along road verges. It was thought that old weak winter bees had succumbed to a preparation otherwise innocuous. Extensive tests to reveal any links between the bees' physiological condition and pesticide sensitivity involved 6 hormone herbicides, 11 fungicides and 2 insecticides, all approved harmless for bees and functioning on them wholly or mainly as stomach poisons. As a rule bee sensitivity was measured as LD 50 per os, in smaller tests as percentage mortality. Amount and quality of pollen ingested in the first days of life affected the pesticide sensitivity of young and older bees. Bees fed adequate high quality pollen are less sensitive than counterparts fed inadequate or inferior pollen or pollen substitute; such differences persisted if the LD 50 was calculated for the same body weight. Pesticides containing manganese are an exception. To these, bees fed inadequate pollen are no more or even less sensitive than comparable well-fed bees. Pesticide sensitivity decreases generally from early to late summer. Quality of pollen available for larvae has no effect on poison sensitivity of imagines. Food supply conditions however exert a clear influence: tested with the same pesticides, hive bees from colonies having had a rich early food supply, and young bees bred then, are less sensitive than their counterparts having had moderate or no early food supply. Poison sensitivity of summer bees increases with age; most sensitive are old winter bees which had practiced broodcare in early spring.Inadequate pollen intake can be regarded as causing protein deficiency. Investigation of this in mammals and man indicate that the higher poison sensitivity in bees results from inhibition of the enzymatic decomposition of pesticides. For practical bee protection it is important that all organic fungicides tested are effectively harmless. Hormone hebicides can be ranked as practically harmless even for bees inadequately protein-fed, as long as the approved concentrations are observed. Our tests raised doubts however about the registration as harmless for bees of insecticides based on Endosulfan and Phosalon. Of interest in practice and for the official testing of pesticides are also the high pesticide sensitivity of old winter bees, the decrease in sensitivity of bees on a stable feed from early to late summer, and the sensitivity-reducing influence of pollen-rich food supply promoting development.It is important ecologically that pollens of different plant species vary in nutrient quality for the honey bee: there are perfectly worthless (conifers), poor-to-medium, and highly effective pollen types. As shown in this paper, these differences are relevant not only for the development of the physiological condition and breeding potential of the bee, but also for pesticide sensitivity. That bees gather worthless and poor-quality, sometimes even poisonous, pollen (some Ranunculus sp.) is evidently due to the phagostimulant present in all pollen types. PMID- 25024158 TI - Nutrient dynamics of vegetation and detritus following two intensities of fire in the New Jersey pine barrens. AB - The nutrient dynamics of upland forest sites in the New Jersey Pine Barrens exposed to different fire intensities were determined. Nutrient concentrations and inventories in biomass, litter, humus, and standing dead wood were determined for an unburned site, two sites burned by severe wildfire and two sites burned by light prescribed burning. Humus nutrient levels were similar among sites despite differing fire histories. Amounts of calcium, magnesium, and potassium in biomass and in litter were lower in wildfire sites than in prescribed burn sites, all of which were lower than the control. Standing dead wood nutrient levels were much higher in the wildfire sites than in the other three sites. Output of nutrients to groudwater correlated poorly with the amounts of nutrients retained in humus or standing dead wood; however strong inverse correlations were found between nutrient output and nutrient storage in biomass or biomass plus litter and humus. These results emphasize the central role of nutrient immobilization in regrowing biomass in after fire on nutrient poor soils. PMID- 25024159 TI - Individual flowering phenology, plant size, and reproductive success in Linanthus androsaceus, a California annual. AB - For natural selection to shape population flowering phenologies, individual phenological variation must be correlated with variation in reproductive success. I therefore marked and followed individual plants of Linanthus androsaceus (a California grassland annual) throughout the flowering season, recording individual flowering phenology, flower number, mortality, and seed production. Although date of first flowering was unrelated to number of flowers, plants first flowering during an intermediate interval had a greater probability of setting seed, and a stronger relationship between seed number and flower number, than plants first flowering early or late in the season. The actual distribution of first flowering date in the population was clustered around this intermediate interval. In contrast with first flowering date, flowering duration was correlated with flower number, with a positively skewed distribution that reflected the skewed size structure of the population. The combined distributions of individual flowering dates and furations resulted in an overall population flowering curve that was skewed to the right. Within individual quadrats, Linanthus density was positively correlated with skewness if the quadrat flowering phenology curve, and negatively correlated with the percentage of plants in bloom at flowering peak. Thus, although individual variation in first flowering date was related to reproductive success in L. androsaceus, the size dependence of flowering duration provides a mechanism whereby ecological factors can shape population flowering phenologies without evolutionary change. PMID- 25024160 TI - Do archipelagoes really preserve fewer species than one island of the same total area. AB - The optimal strategy in the design of nature reserves is investigated by means of the theory of island biogeography. Some previous results are revised. A new form of the incidence functions is presented. Their merit is that they do not ignore the minimum area requirements, they are more flexible, and in a number of instances describe reality better than those formerly used. They lead to the conclusion that in order to preserve as many species as possible in refuges whose total size is given, the number of refuges must be limited and depends on the parameters of the incidence functions and on the area available. PMID- 25024161 TI - T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity. AB - The T-cell receptor (TCR) repertoire is formed by random recombinations of genomic precursor elements; the resulting combinatorial diversity renders unlikely extensive TCR sharing between individuals. Here, we studied CDR3beta amino acid sequence sharing in a repertoire-wide manner, using high-throughput TCR-seq in 28 healthy mice. We uncovered hundreds of public sequences shared by most mice. Public CDR3 sequences, relative to private sequences, are two orders of magnitude more abundant on average, express restricted V/J segments, and feature high convergent nucleic acid recombination. Functionally, public sequences are enriched for MHC-diverse CDR3 sequences that were previously associated with autoimmune, allograft, and tumor-related reactions, but not with anti-pathogen-related reactions. Public CDR3 sequences are shared between mice of different MHC haplotypes, but are associated with different, MHC-dependent, V genes. Thus, despite their random generation process, TCR repertoires express a degree of uniformity in their post-genomic organization. These results, together with numerical simulations of TCR genomic rearrangements, suggest that biases and convergence in TCR recombination combine with ongoing selection to generate a restricted subset of self-associated, public CDR3 TCR sequences, and invite reexamination of the basic mechanisms of T-cell repertoire formation. PMID- 25024162 TI - Decoding ChIP-seq with a double-binding signal refines binding peaks to single nucleotides and predicts cooperative interaction. AB - The comprehension of protein and DNA binding in vivo is essential to understand gene regulation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) provides a global map of the regulatory binding network. Most ChIP-seq analysis tools focus on identifying binding regions from coverage enrichment. However, less work has been performed to infer the physical and regulatory details inside the enriched regions. This research extends a previous blind-deconvolution approach to develop a post-peak-calling algorithm that improves binding site resolution and predicts cooperative interactions. At the core of our new method is a physically motivated model that characterizes the binding signal as an extreme value distribution. This model suggests a mathematical framework to study physical properties of DNA shearing from the ChIP-seq coverage. The model explains the ChIP-seq coverage with two signals: The first considers DNA fragments with only a single binding event, whereas the second considers fragments with two binding events (a double-binding signal). The model incorporates motif discovery and is able to detect multiple sites in an enriched region with single-nucleotide resolution, high sensitivity, and high specificity. Our method improves peak caller sensitivity, from less than 45% up to 94%, at a false positive rate < 11% for a set of 47 experimentally validated prokaryotic sites. It also improves resolution of highly enriched regions of large-scale eukaryotic data sets. The double-binding signal provides a novel application in ChIP-seq analysis: the identification of cooperative interaction. Predictions of known cooperative binding sites show a 0.85 area under an ROC curve. PMID- 25024163 TI - Evolutionarily diverse determinants of meiotic DNA break and recombination landscapes across the genome. AB - Fission yeast Rec12 (Spo11 homolog) initiates meiotic recombination by forming developmentally programmed DNA double-strand breaks (DSBs). DSB distributions influence patterns of heredity and genome evolution, but the basis of the highly nonrandom choice of Rec12 cleavage sites is poorly understood, largely because available maps are of relatively low resolution and sensitivity. Here, we determined DSBs genome-wide at near-nucleotide resolution by sequencing the oligonucleotides attached to Rec12 following DNA cleavage. The single oligonucleotide size class allowed us to deeply sample all break events. We find strong evidence across the genome for differential DSB repair accounting for crossover invariance (constant cM/kb in spite of DSB hotspots). Surprisingly, about half of all crossovers occur in regions where DSBs occur at low frequency and are widely dispersed in location from cell to cell. These previously undetected, low-level DSBs thus play an outsized and crucial role in meiosis. We further find that the influence of underlying nucleotide sequence and chromosomal architecture differs in multiple ways from that in budding yeast. DSBs are not strongly restricted to nucleosome-depleted regions, as they are in budding yeast, but are nevertheless spatially influenced by chromatin structure. Our analyses demonstrate that evolutionarily fluid factors contribute to crossover initiation and regulation. PMID- 25024165 TI - Magnetic sensor for arterial distension and blood pressure monitoring. AB - A novel sensor for measuring arterial distension, pulse and pressure waveform is developed and evaluated. The system consists of a magnetic sensor which is applied and fixed to arterial vessels without any blood vessel constriction, hence avoiding stenosis. The measurement principle could be validated by in vitro experiments on silicone tubes, and by in vivo experiments in an animal model, thereby indicating the non-linear viscoelastic characteristics of real blood vessels. The sensor is capable to provide absolute measurements of the dynamically varying arterial diameter. By calibrating the sensor, a long-term monitoring system for continuously measuring blood pressure and other cardiovascular parameters could be developed based on the method described. This will improve diagnostics for high risk patients and enable a better, specific treatment. PMID- 25024164 TI - Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma. AB - Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors. PMID- 25024166 TI - Rat strain differences in levels and effects of chronic inflammation due to intratracheal instillation of quartz on lung tumorigenesis induced by DHPN. AB - Chronic inflammatory effects of single intratracheal instillation (i.t.) of quartz on rat lung tumorigenesis were examined using 4 different animal models. At first, in order to determine an appropriate dose of quartz i.t. to promote lung tumorigenesis, F344 male rats were administrated single 0, 0.5, 1, 2 or 4 mg quartz/rat after initiation by N-bis(2-hydroxypropyl) nitrosamine (DHPN). Further studies were performed to examine strain differences of the effects of chronic inflammation caused by quartz i.t. in 3 strains of rat, i.e. F344, Wistar Hannover and SD. Each was instilled with 2mg quartz/rat after DHPN administration and sacrificed in week 24. In addition, strain differences in generation of inflammation were determined at days 1 and 28. Finally, for determination of long term effects period, F344 and Wistar-Hannover rats were similarly treated, but the experiment was terminated at week 52. In F344 rats, the tumor areas in DHPN treated groups showed a tendency to increase along with the dose of quartz. F344 rats demonstrated the highest and Wistar-Hannover rats the lowest sensitivity to quartz in acute and chronic phases in the 3 strains. In 52 week, in F344 rats, the multiplicity of tumors and the serum concentration of IL-6 in the group treated with DHPN and quartz were significantly increased. The present experiments indicated that chronic inflammation due to quartz instillation exerted promoting effects on lung carcinogenesis in F344, SD and Wistar-Hannover rats. The strain differences in tumor promotion appeared to correlate with inflammatory reactions to quartz and increase of IL-6. PMID- 25024167 TI - Grand Challenges in Synthetic Biology to be Accomplished. PMID- 25024168 TI - Gibberellin-to-abscisic acid balances govern development and differentiation of the nucellar projection of barley grains. AB - In cereal grains, the maternal nucellar projection (NP) constitutes the link to the filial organs, forming a transfer path for assimilates and signals towards the endosperm. At transition to the storage phase, the NP of barley (Hordeum vulgare) undergoes dynamic and regulated differentiation forming a characteristic pattern of proliferating, elongating, and disintegrating cells. Immunolocalization revealed that abscisic acid (ABA) is abundant in early non elongated but not in differentiated NP cells. In the maternally affected shrunken endosperm mutant seg8, NP cells did not elongate and ABA remained abundant. The amounts of the bioactive forms of gibberellins (GAs) as well as their biosynthetic precursors were strongly and transiently increased in wild-type caryopses during the transition and early storage phases. In seg8, this increase was delayed and less pronounced together with deregulated gene expression of specific ABA and GA biosynthetic genes. We concluded that differentiation of the barley NP is driven by a distinct and specific shift from lower to higher GA:ABA ratios and that the spatial-temporal change of GA:ABA balances is required to form the differentiation gradient, which is a prerequisite for ordered transfer processes through the NP. Deregulated ABA:GA balances in seg8 impair the differentiation of the NP and potentially compromise transfer of signals and assimilates, resulting in aberrant endosperm growth. These results highlight the impact of hormonal balances on the proper release of assimilates from maternal to filial organs and provide new insights into maternal effects on endosperm differentiation and growth of barley grains. PMID- 25024169 TI - Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2. AB - The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly be divided into two groups with most likely two topographically distinct binding sites. The aim of the current study was to identify the binding site of one such group of ligands, exemplified by three allosteric antagonists, CCR2-RA-[R], JNJ-27141491, and SD 24. We first used a chimeric CCR2/CCR5 receptor approach to obtain insight into the binding site of the allosteric antagonists and additionally introduced eight single point mutations in CCR2 to further characterize the putative binding pocket. All constructs were studied in radioligand binding and/or functional IP turnover assays, providing evidence for an intracellular binding site for CCR2-RA [R], JNJ-27141491, and SD-24. For CCR2-RA-[R] the most important residues for binding were found to be the highly conserved tyrosine Y(7.53) and phenylalanine F(8.50) of the NPxxYx(5,6)F motif, as well as V(6.36) at the bottom of TM-VI and K(8.49) in helix-VIII. These findings demonstrate for the first time the presence of an allosteric intracellular binding site for CCR2 antagonists. This contributes to an increased understanding of the interactions of diverse ligands at CCR2 and may allow for a more rational design of future allosteric antagonists. PMID- 25024170 TI - Limitations in experimental design mean that the jury is still out on lecturing. PMID- 25024171 TI - Immunosignature system for diagnosis of cancer. AB - Although the search for disease biomarkers continues, the clinical return has thus far been disappointing. The complexity of the body's response to disease makes it difficult to represent this response with only a few biomarkers, particularly when many are present at low levels. An alternative to the typical reductionist biomarker paradigm is an assay we call an "immunosignature." This approach leverages the response of antibodies to disease-related changes, as well as the inherent signal amplification associated with antigen-stimulated B-cell proliferation. To perform an immunosignature assay, the antibodies in diluted blood are incubated with a microarray of thousands of random sequence peptides. The pattern of binding to these peptides is the immunosignature. Because the peptide sequences are completely random, the assay is effectively disease agnostic, potentially providing a comprehensive diagnostic on multiple diseases simultaneously. To explore the ability of an immunosignature to detect and identify multiple diseases simultaneously, 20 samples from each of five cancer cohorts collected from multiple sites and 20 noncancer samples (120 total) were used as a training set to develop a reference immunosignature. A blinded evaluation of 120 blinded samples covering the same diseases gave 95% classification accuracy. To investigate the breadth of the approach and test sensitivity to biological diversity further, immunosignatures of >1,500 historical samples comprising 14 different diseases were examined by training with 75% of the samples and testing the remaining 25%. The average accuracy was >98%. These results demonstrate the potential power of the immunosignature approach in the accurate, simultaneous classification of disease. PMID- 25024172 TI - Platelets guide the formation of early metastatic niches. AB - During metastasis, host cells are recruited to disseminated tumor cells to form specialized microenvironments ("niches") that promote metastatic progression, but the mechanisms guiding the assembly of these niches are largely unknown. Tumor cells may autonomously recruit host cells or, alternatively, host cell-to-host cell interactions may guide the formation of these prometastatic microenvironments. Here, we show that platelet-derived rather than tumor cell derived signals are required for the rapid recruitment of granulocytes to tumor cells to form "early metastatic niches." Granulocyte recruitment relies on the secretion of CXCL5 and CXCL7 chemokines by platelets upon contact with tumor cells. Blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, platelets recruit granulocytes and guide the formation of early metastatic niches, which are crucial for metastasis. PMID- 25024173 TI - Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition. AB - Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ~ 50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzled-like sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen alpha1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition. PMID- 25024174 TI - Expansion of the fusion stalk and its implication for biological membrane fusion. AB - Over the past 20 years, it has been widely accepted that membrane fusion proceeds via a hemifusion step before opening of the productive fusion pore. An initial hourglass-shaped lipid structure, the fusion stalk, is formed between the adjacent membrane leaflets (cis leaflets). It remains controversial if and how fusion proteins drive the subsequent transition (expansion) of the stalk into a fusion pore. Here, we propose a comprehensive and consistent thermodynamic understanding in terms of the underlying free-energy landscape of stalk expansion. We illustrate how the underlying free energy landscape of stalk expansion and the concomitant pathway is altered by subtle differences in membrane environment, such as leaflet composition, asymmetry, and flexibility. Nonleaky stalk expansion (stalk widening) requires the formation of a critical trans-leaflet contact. The fusion machinery can mechanically enforce trans leaflet contact formation either by directly enforcing the trans-leaflets in close proximity, or by (electrostatically) condensing the area of the cis leaflets. The rate of these fast fusion reactions may not be primarily limited by the energetics but by the forces that the fusion proteins are able to exert. PMID- 25024175 TI - Small-scale universality in fluid turbulence. AB - Turbulent flows in nature and technology possess a range of scales. The largest scales carry the memory of the physical system in which a flow is embedded. One challenge is to unravel the universal statistical properties that all turbulent flows share despite their different large-scale driving mechanisms or their particular flow geometries. In the present work, we study three turbulent flows of systematically increasing complexity. These are homogeneous and isotropic turbulence in a periodic box, turbulent shear flow between two parallel walls, and thermal convection in a closed cylindrical container. They are computed by highly resolved direct numerical simulations of the governing dynamical equations. We use these simulation data to establish two fundamental results: (i) at Reynolds numbers Re ~ 10(2) the fluctuations of the velocity derivatives pass through a transition from nearly Gaussian (or slightly sub-Gaussian) to intermittent behavior that is characteristic of fully developed high Reynolds number turbulence, and (ii) beyond the transition point, the statistics of the rate of energy dissipation in all three flows obey the same Reynolds number power laws derived for homogeneous turbulence. These results allow us to claim universality of small scales even at low Reynolds numbers. Our results shed new light on the notion of when the turbulence is fully developed at the small scales without relying on the existence of an extended inertial range. PMID- 25024176 TI - Accuracy of forecasts in strategic intelligence. AB - The accuracy of 1,514 strategic intelligence forecasts abstracted from intelligence reports was assessed. The results show that both discrimination and calibration of forecasts was very good. Discrimination was better for senior (versus junior) analysts and for easier (versus harder) forecasts. Miscalibration was mainly due to underconfidence such that analysts assigned more uncertainty than needed given their high level of discrimination. Underconfidence was more pronounced for harder (versus easier) forecasts and for forecasts deemed more (versus less) important for policy decision making. Despite the observed underconfidence, there was a paucity of forecasts in the least informative 0.4 0.6 probability range. Recalibrating the forecasts substantially reduced underconfidence. The findings offer cause for tempered optimism about the accuracy of strategic intelligence forecasts and indicate that intelligence producers aim to promote informativeness while avoiding overstatement. PMID- 25024178 TI - Neural correlates of dueling affective reactions to win-win choices. AB - Win-win choices cause anxiety, often more so than decisions lacking the opportunity for a highly desired outcome. These anxious feelings can paradoxically co-occur with positive feelings, raising important implications for individual decision styles and general well-being. Across three studies, people chose between products that varied in personal value. Participants reported feeling most positive and most anxious when choosing between similarly high valued products. Behavioral and neural results suggested that this paradoxical experience resulted from parallel evaluations of the expected outcome (inducing positive affect) versus the cost of choosing a response (inducing anxiety). Positive feelings were reduced when there was no high-value option, and anxiety was reduced when only one option was highly valued. Dissociable regions within the striatum and the medial prefrontal cortex (mPFC) tracked these dueling affective reactions during choice. Ventral regions, associated with stimulus valuation, tracked positive feelings and the value of the best item. Dorsal regions, associated with response valuation, tracked anxiety. In addition to tracking anxiety, the dorsal mPFC was associated with conflict during the current choice, and activity levels across individual items predicted whether that choice would later be reversed during an unexpected reevaluation phase. By revealing how win-win decisions elicit responses in dissociable brain systems, these results help resolve the paradox of win-win choices. They also provide insight into behaviors that are associated with these two forms of affect, such as why we are pulled toward good options but may still decide to delay or avoid choosing among them. PMID- 25024177 TI - Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. AB - Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [(11)C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [(11)C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors. PMID- 25024179 TI - On the evolution of hoarding, risk-taking, and wealth distribution in nonhuman and human populations. AB - This paper applies the theory of the evolution of risk-taking in the presence of idiosyncratic and environmental risks to the example of food hoarding by animals and explores implications of the resulting theory for human attitudes toward risk. PMID- 25024181 TI - Bargaining and fairness. AB - The idea that human morality might be the product of evolution is not popular. The reason is partly that the moral principles that actually govern our day-to day behavior have been idealized in a way that makes a natural origin seem impossible. This paper puts the case for a more down-to-earth assessment of human morality by arguing that the evolution of our sense of fairness can be traced to the practicalities of food-sharing. When animals share food, they can be seen as enjoying the fruits of an implicit bargain to ensure each other against hunger. The implications of this observation are explored using the tools of game theory. The arguments lead to a structure for fair bargains that closely resembles the structure proposed by John Rawls, the leading moral philosopher of the last century. PMID- 25024180 TI - Copy number alteration burden predicts prostate cancer relapse. AB - Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts. PMID- 25024182 TI - Maximization, learning, and economic behavior. AB - The rationality assumption that underlies mainstream economic theory has proved to be a useful approximation, despite the fact that systematic violations to its predictions can be found. That is, the assumption of rational behavior is useful in understanding the ways in which many successful economic institutions function, although it is also true that actual human behavior falls systematically short of perfect rationality. We consider a possible explanation of this apparent inconsistency, suggesting that mechanisms that rest on the rationality assumption are likely to be successful when they create an environment in which the behavior they try to facilitate leads to the best payoff for all agents on average, and most of the time. Review of basic learning research suggests that, under these conditions, people quickly learn to maximize expected return. This review also shows that there are many situations in which experience does not increase maximization. In many cases, experience leads people to underweight rare events. In addition, the current paper suggests that it is convenient to distinguish between two behavioral approaches to improve economic analyses. The first, and more conventional approach among behavioral economists and psychologists interested in judgment and decision making, highlights violations of the rational model and proposes descriptive models that capture these violations. The second approach studies human learning to clarify the conditions under which people quickly learn to maximize expected return. The current review highlights one set of conditions of this type and shows how the understanding of these conditions can facilitate market design. PMID- 25024183 TI - Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. AB - Haploinsufficiency of the voltage-gated sodium channel NaV1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of NaV1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the NaV1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome. PMID- 25024184 TI - Properties of artificial networks evolved to contend with natural spectra. AB - Understanding why spectra that are physically the same appear different in different contexts (color contrast), whereas spectra that are physically different appear similar (color constancy) presents a major challenge in vision research. Here, we show that the responses of biologically inspired neural networks evolved on the basis of accumulated experience with spectral stimuli automatically generate contrast and constancy. The results imply that these phenomena are signatures of a strategy that biological vision uses to circumvent the inverse optics problem as it pertains to light spectra, and that double opponent neurons in early-level vision evolve to serve this purpose. This strategy provides a way of understanding the peculiar relationship between the objective world and subjective color experience, as well as rationalizing the relevant visual circuitry without invoking feature detection or image representation. PMID- 25024185 TI - Paradoxical thinking as a new avenue of intervention to promote peace. AB - In societies involved in an intractable conflict, there are strong socio psychological barriers that contribute to the continuation and intractability of the conflict. Based on a unique field study conducted in the context of the Israeli-Palestinian conflict, we offer a new avenue to overcome these barriers by exposing participants to a long-term paradoxical intervention campaign expressing extreme ideas that are congruent with the shared ethos of conflict. Results show that the intervention, although counterintuitive, led participants to express more conciliatory attitudes regarding the conflict, particularly among participants with center and right political orientation. Most importantly, the intervention even influenced participants' actual voting patterns in the 2013 Israeli general elections: Participants who were exposed to the paradoxical intervention, which took place in proximity to the general elections, reported that they tended to vote more for dovish parties, which advocate a peaceful resolution to the conflict. These effects were long lasting, as the participants in the intervention condition expressed more conciliatory attitudes when they were reassessed 1 y after the intervention. Based on these results, we propose a new layer to the general theory of persuasion based on the concept of paradoxical thinking. PMID- 25024186 TI - Evolutionary shaping of demographic schedules. AB - Evolutionary processes of natural selection may be expected to leave their mark on age patterns of survival and reproduction. Demographic theory includes three main strands--mutation accumulation, stochastic vitality, and optimal life histories. This paper reviews the three strands and, concentrating on mutation accumulation, extends a mathematical result with broad implications concerning the effect of interactions between small age-specific effects of deleterious mutant alleles. Empirical data from genomic sequencing along with prospects for combining strands of theory hold hope for future progress. PMID- 25024187 TI - Spatial interactions and cooperation can change the speed of evolution of complex phenotypes. AB - Complex traits arise from the interactions among multiple gene products. In the case where the complex phenotype is separated from the wild type by a fitness valley or a fitness plateau, the generation of a complex phenotype may take a very long evolutionary time. Interestingly, the rate of evolution depends in nontrivial ways on various properties of the underlying stochastic process, such as the spatial organization of the population and social interactions among cells. Here we review some of our recent work that investigates these phenomena in asexual populations. The role of spatial constraints is quite complex: there are realistic cases where spatial constrains can accelerate or delay evolution, or even influence it in a nonmonotonic fashion, where evolution works fastest for intermediate-range constraints. Social interactions among cells can be studied in the context of the division-of-labor games. Under a range of circumstances, cooperation among cells can lead to a relatively fast creation of a complex phenotype as an emerging (distributed) property. If we further assume the presence of cheaters, we observe the emergence of a fully mutated population of cells possessing the complex phenotype. Applications of these ideas to cancer initiation and biofilm formation in bacteria are discussed. PMID- 25024188 TI - Absence of lipofuscin in motor neurons of SOD1-linked ALS mice. AB - Lipofuscin, or aging pigment, is accreted as red autofluorescence in the lysosomes of motor neuron cell bodies in the ventral horn of WT mice by 3 mo of age. Strikingly, in two presymptomatic ALS mouse strains transgenic for mutant human Cu/Zn superoxide dismutase (SOD1), G85R SOD1YFP and G93A SOD1, little or no lipofuscin was detected in motor neuron cell bodies. Two markers of autophagy, sequestosome 1 (SQSTM1/p62) and microtubule-associated protein 1 light chain 3 (LC3), were examined in the motor neuron cell bodies of G85R SOD1YFP mice and found to be reduced relative to WT SOD1YFP transgenic mice. To elucidate whether the autophagy/lysosome pathway was either impaired or hyperactive in motor neurons, chloroquine was administered to 3-mo-old G85R SOD1YFP mice to block lysosomal hydrolysis. After 2 wk, lipofuscin was now observed in motor neurons, and SQSTM1 and LC3 levels approached those of WT SOD1YFP mice, suggesting that the autophagy/lysosome pathway is hyperactive in motor neurons of SOD1-linked ALS mice. This seems to be mediated at least in part through the mammalian target of rapamycin complex 1 (MTORC1) pathway, because levels of Ser757-phosphorylated Unc 51-like kinase 1 (ULK1), an MTORC1 target, were greatly reduced in the G85R SOD1YFP motor neurons, correspondent to an activated state of ULK1 that initiates autophagy. PMID- 25024189 TI - Complexity in models of cultural niche construction with selection and homophily. AB - Niche construction is the process by which organisms can alter the ecological environment for themselves, their descendants, and other species. As a result of niche construction, differences in selection pressures may be inherited across generations. Homophily, the tendency of like phenotypes to mate or preferentially associate, influences the evolutionary dynamics of these systems. Here we develop a model that includes selection and homophily as independent culturally transmitted traits that influence the fitness and mate choice determined by another focal cultural trait. We study the joint dynamics of a focal set of beliefs, a behavior that can differentially influence the fitness of those with certain beliefs, and a preference for partnering based on similar beliefs. Cultural transmission, selection, and homophily interact to produce complex evolutionary dynamics, including oscillations, stable polymorphisms of all cultural phenotypes, and simultaneous stability of oscillation and fixation, which have not previously been observed in models of cultural evolution or gene culture interactions. We discuss applications of this model to the interaction of beliefs and behaviors regarding education, contraception, and animal domestication. PMID- 25024190 TI - Object grouping based on real-world regularities facilitates perception by reducing competitive interactions in visual cortex. AB - In virtually every real-life situation humans are confronted with complex and cluttered visual environments that contain a multitude of objects. Because of the limited capacity of the visual system, objects compete for neural representation and cognitive processing resources. Previous work has shown that such attentional competition is partly object based, such that competition among elements is reduced when these elements perceptually group into an object based on low-level cues. Here, using functional MRI (fMRI) and behavioral measures, we show that the attentional benefit of grouping extends to higher-level grouping based on the relative position of objects as experienced in the real world. An fMRI study designed to measure competitive interactions among objects in human visual cortex revealed reduced neural competition between objects when these were presented in commonly experienced configurations, such as a lamp above a table, relative to the same objects presented in other configurations. In behavioral visual search studies, we then related this reduced neural competition to improved target detection when distracter objects were shown in regular configurations. Control studies showed that low-level grouping could not account for these results. We interpret these findings as reflecting the grouping of objects based on higher level spatial-relational knowledge acquired through a lifetime of seeing objects in specific configurations. This interobject grouping effectively reduces the number of objects that compete for representation and thereby contributes to the efficiency of real-world perception. PMID- 25024191 TI - Rapid innovation diffusion in social networks. AB - Social and technological innovations often spread through social networks as people respond to what their neighbors are doing. Previous research has identified specific network structures, such as local clustering, that promote rapid diffusion. Here we derive bounds that are independent of network structure and size, such that diffusion is fast whenever the payoff gain from the innovation is sufficiently high and the agents' responses are sufficiently noisy. We also provide a simple method for computing an upper bound on the expected time it takes for the innovation to become established in any finite network. For example, if agents choose log-linear responses to what their neighbors are doing, it takes on average less than 80 revision periods for the innovation to diffuse widely in any network, provided that the error rate is at least 5% and the payoff gain (relative to the status quo) is at least 150%. Qualitatively similar results hold for other smoothed best-response functions and populations that experience heterogeneous payoff shocks. PMID- 25024192 TI - Public goods in relation to competition, cooperation, and spite. AB - Public goods and common-pool resources are fundamental features of biological and social systems, and pose core challenges in achieving sustainability; for such situations, the immediate interests of individuals and the societies in which they are embedded are in potential conflict, involving game-theoretic considerations whose resolution need not serve the collective good. Evolution has often confronted such dilemmas--e.g., in bacterial biofilms--in the challenges of cancer, in nitrogen fixation and chelation, in the production of antibiotics, and in collective action problems across animal groups; there is much to learn from the Darwinian resolution of these situations for how to address problems our societies face today. Addressing these problems involves understanding the emergence of cooperative agreements, from reciprocal altruism and insurance arrangements to the social norms and more formal institutions that maintain societies. At the core are the issues of how individuals and societies discount the future and the interests of others, and the degree that individual decisions are influenced by regard for others. Ultimately, as Garrett Hardin suggested, the solution to problems of the commons is in "mutual coercion, mutually agreed upon," and hence in how groups of individuals form and how they arrive at decisions that ultimately benefit all. PMID- 25024193 TI - Human (Clovis)-gomphothere (Cuvieronius sp.) association ~ 13,390 calibrated yBP in Sonora, Mexico. AB - The earliest known foragers to populate most of North America south of the glaciers [~ 11,500 to >= ~ 10,800 (14)C yBP; ~ 13,300 to ~ 12,800 calibrated (Cal) years] made distinctive "Clovis" artifacts. They are stereotypically characterized as hunters of Pleistocene megamammals (mostly mammoth) who entered the continent via Beringia and an ice-free corridor in Canada. The origins of Clovis technology are unclear, however, with no obvious evidence of a predecessor to the north. Here we present evidence for Clovis hunting and habitation ~ 11,550 yBP (~ 13,390 Cal years) at "El Fin del Mundo," an archaeological site in Sonora, northwestern Mexico. The site also includes the first evidence to our knowledge for gomphothere (Cuvieronius sp.) as Clovis prey, otherwise unknown in the North American archaeological record and terminal Pleistocene paleontological record. These data (i) broaden the age and geographic range for Clovis, establishing El Fin del Mundo as one of the oldest and southernmost in situ Clovis sites, supporting the hypothesis that Clovis had its origins well south of the gateways into the continent, and (ii) expand the make-up of the North American megafauna community just before extinction. PMID- 25024194 TI - Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. AB - Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin dependent kinase inhibitor 1A (CDKN1A, also known as p21(WAF1/CIP1)) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53. PMID- 25024196 TI - Culture-dependent strategies in coordination games. AB - We examine different populations' play in coordination games in online experiments with over 1,000 study participants. Study participants played a two player coordination game that had multiple equilibria: two equilibria with highly asymmetric payoffs and another equilibrium with symmetric payoffs but a slightly lower total payoff. Study participants were predominantly from India and the United States. Study participants residing in India played the strategies leading to asymmetric payoffs significantly more frequently than study participants residing in the United States who showed a greater play of the strategy leading to the symmetric payoffs. In addition, when prompted to play asymmetrically, the population from India responded even more significantly than those from the United States. Overall, study participants' predictions of how others would play were more accurate when the other player was from their own populations, and they coordinated significantly more frequently and earned significantly higher payoffs when matched with other study participants from their own population than when matched across populations. PMID- 25024195 TI - Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis. AB - Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy. PMID- 25024197 TI - Recency, consistent learning, and Nash equilibrium. AB - We examine the long-term implication of two models of learning with recency bias: recursive weights and limited memory. We show that both models generate similar beliefs and that both have a weighted universal consistency property. Using the limited-memory model we produce learning procedures that both are weighted universally consistent and converge with probability one to strict Nash equilibrium. PMID- 25024198 TI - Charge transport and rectification in molecular junctions formed with carbon based electrodes. AB - Molecular junctions formed using the scanning-tunneling-microscope-based break junction technique (STM-BJ) have provided unique insight into charge transport at the nanoscale. In most prior work, the same metal, typically Au, Pt, or Ag, is used for both tip and substrate. For such noble metal electrodes, the density of electronic states is approximately constant within a narrow energy window relevant to charge transport. Here, we form molecular junctions using the STM-BJ technique, with an Au metal tip and a microfabricated graphite substrate, and measure the conductance of a series of graphite/amine-terminated oligophenyl/Au molecular junctions. The remarkable mechanical strength of graphite and the single-crystal properties of our substrates allow measurements over few thousand junctions without any change in the surface properties. We show that conductance decays exponentially with molecular backbone length with a decay constant that is essentially the same as that for measurements with two Au electrodes. More importantly, despite the inherent symmetry of the oligophenylamines, we observe rectification in these junctions. State-of-art ab initio conductance calculations are in good agreement with experiment, and explain the rectification. We show that the highly energy-dependent graphite density of states contributes variations in transmission that, when coupled with an asymmetric voltage drop across the junction, leads to the observed rectification. Together, our measurements and calculations show how functionality may emerge from hybrid molecular-scale devices purposefully designed with different electrodes beyond the so-called "wide band limit," opening up the possibility of assembling molecular junctions with dissimilar electrodes using layered 2D materials. PMID- 25024199 TI - A CRISPR-Cas system enhances envelope integrity mediating antibiotic resistance and inflammasome evasion. AB - Clustered, regularly interspaced, short palindromic repeats-CRISPR associated (CRISPR-Cas) systems defend bacteria against foreign nucleic acids, such as during bacteriophage infection and transformation, processes which cause envelope stress. It is unclear if these machineries enhance membrane integrity to combat this stress. Here, we show that the Cas9-dependent CRISPR-Cas system of the intracellular bacterial pathogen Francisella novicida is involved in enhancing envelope integrity through the regulation of a bacterial lipoprotein. This action ultimately provides increased resistance to numerous membrane stressors, including antibiotics. We further find that this previously unappreciated function of Cas9 is critical during infection, as it promotes evasion of the host innate immune absent in melanoma 2/apoptosis associated speck-like protein containing a CARD (AIM2/ASC) inflammasome. Interestingly, the attenuation of the cas9 mutant is complemented only in mice lacking both the AIM2/ASC inflammasome and the bacterial lipoprotein sensor Toll-like receptor 2, but not in single knockout mice, demonstrating that Cas9 is essential for evasion of both pathways. These data represent a paradigm shift in our understanding of the function of CRISPR-Cas systems as regulators of bacterial physiology and provide a framework with which to investigate the roles of these systems in myriad bacteria, including pathogens and commensals. PMID- 25024201 TI - In situ studies of a platform for metastable inorganic crystal growth and materials discovery. AB - Rapid shifts in the energy, technological, and environmental demands of materials science call for focused and efficient expansion of the library of functional inorganic compounds. To achieve the requisite efficiency, we need a materials discovery and optimization paradigm that can rapidly reveal all possible compounds for a given reaction and composition space. Here we provide such a paradigm via in situ X-ray diffraction measurements spanning solid, liquid flux, and recrystallization processes. We identify four new ternary sulfides from reactive salt fluxes in a matter of hours, simultaneously revealing routes for ex situ synthesis and crystal growth. Changing the flux chemistry, here accomplished by increasing sulfur content, permits comparison of the allowable crystalline building blocks in each reaction space. The speed and structural information inherent to this method of in situ synthesis provide an experimental complement to computational efforts to predict new compounds and uncover routes to targeted materials by design. PMID- 25024200 TI - Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma. AB - Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1beta expression and RGC death via a caspase-1-dependent pathway involving Nod like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1-independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1beta production and RGC death and highlight signal transduction in a caspase-1-dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1-independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy. PMID- 25024202 TI - The replicator equation and other game dynamics. AB - The replicator equation is the first and most important game dynamics studied in connection with evolutionary game theory. It was originally developed for symmetric games with finitely many strategies. Properties of these dynamics are briefly summarized for this case, including the convergence to and stability of the Nash equilibria and evolutionarily stable strategies. The theory is then extended to other game dynamics for symmetric games (e.g., the best response dynamics and adaptive dynamics) and illustrated by examples taken from the literature. It is also extended to multiplayer, population, and asymmetric games. PMID- 25024204 TI - Effects of explicit atmospheric convection at high CO2. AB - The effect of clouds on climate remains the largest uncertainty in climate change predictions, due to the inability of global climate models (GCMs) to resolve essential small-scale cloud and convection processes. We compare preindustrial and quadrupled CO2 simulations between a conventional GCM in which convection is parameterized and a "superparameterized" model in which convection is explicitly simulated with a cloud-permitting model in each grid cell. We find that the global responses of the two models to increased CO2 are broadly similar: both simulate ice-free Arctic summers, wintertime Arctic convection, and enhanced Madden-Julian oscillation (MJO) activity. Superparameterization produces significant differences at both CO2 levels, including greater Arctic cloud cover, further reduced sea ice area at high CO2, and a stronger increase with CO2 of the MJO. PMID- 25024203 TI - Pla2g16 phospholipase mediates gain-of-function activities of mutant p53. AB - p53(R172H/+) mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53(+/-) mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53(R172H/+) mice with metastasis to osteosarcomas from p53(+/ ) mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53(R172H/+) osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformation-specific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis. PMID- 25024205 TI - Fast running restricts evolutionary change of the vertebral column in mammals. AB - The mammalian vertebral column is highly variable, reflecting adaptations to a wide range of lifestyles, from burrowing in moles to flying in bats. However, in many taxa, the number of trunk vertebrae is surprisingly constant. We argue that this constancy results from strong selection against initial changes of these numbers in fast running and agile mammals, whereas such selection is weak in slower-running, sturdier mammals. The rationale is that changes of the number of trunk vertebrae require homeotic transformations from trunk into sacral vertebrae, or vice versa, and mutations toward such transformations generally produce transitional lumbosacral vertebrae that are incompletely fused to the sacrum. We hypothesize that such incomplete homeotic transformations impair flexibility of the lumbosacral joint and thereby threaten survival in species that depend on axial mobility for speed and agility. Such transformations will only marginally affect performance in slow, sturdy species, so that sufficient individuals with transitional vertebrae survive to allow eventual evolutionary changes of trunk vertebral numbers. We present data on fast and slow carnivores and artiodactyls and on slow afrotherians and monotremes that strongly support this hypothesis. The conclusion is that the selective constraints on the count of trunk vertebrae stem from a combination of developmental and biomechanical constraints. PMID- 25024206 TI - Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling. AB - High-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance. PMID- 25024208 TI - Friendship and natural selection. AB - More than any other species, humans form social ties to individuals who are neither kin nor mates, and these ties tend to be with similar people. Here, we show that this similarity extends to genotypes. Across the whole genome, friends' genotypes at the single nucleotide polymorphism level tend to be positively correlated (homophilic). In fact, the increase in similarity relative to strangers is at the level of fourth cousins. However, certain genotypes are also negatively correlated (heterophilic) in friends. And the degree of correlation in genotypes can be used to create a "friendship score" that predicts the existence of friendship ties in a hold-out sample. A focused gene-set analysis indicates that some of the overall correlation in genotypes can be explained by specific systems; for example, an olfactory gene set is homophilic and an immune system gene set is heterophilic, suggesting that these systems may play a role in the formation or maintenance of friendship ties. Friends may be a kind of "functional kin." Finally, homophilic genotypes exhibit significantly higher measures of positive selection, suggesting that, on average, they may yield a synergistic fitness advantage that has been helping to drive recent human evolution. PMID- 25024207 TI - Infants' brain responses to speech suggest analysis by synthesis. AB - Historic theories of speech perception (Motor Theory and Analysis by Synthesis) invoked listeners' knowledge of speech production to explain speech perception. Neuroimaging data show that adult listeners activate motor brain areas during speech perception. In two experiments using magnetoencephalography (MEG), we investigated motor brain activation, as well as auditory brain activation, during discrimination of native and nonnative syllables in infants at two ages that straddle the developmental transition from language-universal to language specific speech perception. Adults are also tested in Exp. 1. MEG data revealed that 7-mo-old infants activate auditory (superior temporal) as well as motor brain areas (Broca's area, cerebellum) in response to speech, and equivalently for native and nonnative syllables. However, in 11- and 12-mo-old infants, native speech activates auditory brain areas to a greater degree than nonnative, whereas nonnative speech activates motor brain areas to a greater degree than native speech. This double dissociation in 11- to 12-mo-old infants matches the pattern of results obtained in adult listeners. Our infant data are consistent with Analysis by Synthesis: auditory analysis of speech is coupled with synthesis of the motor plans necessary to produce the speech signal. The findings have implications for: (i) perception-action theories of speech perception, (ii) the impact of "motherese" on early language learning, and (iii) the "social-gating" hypothesis and humans' development of social understanding. PMID- 25024209 TI - Some dynamics of signaling games. AB - Information transfer is a basic feature of life that includes signaling within and between organisms. Owing to its interactive nature, signaling can be investigated by using game theory. Game theoretic models of signaling have a long tradition in biology, economics, and philosophy. For a long time the analyses of these games has mostly relied on using static equilibrium concepts such as Pareto optimal Nash equilibria or evolutionarily stable strategies. More recently signaling games of various types have been investigated with the help of game dynamics, which includes dynamical models of evolution and individual learning. A dynamical analysis leads to more nuanced conclusions as to the outcomes of signaling interactions. Here we explore different kinds of signaling games that range from interactions without conflicts of interest between the players to interactions where their interests are seriously misaligned. We consider these games within the context of evolutionary dynamics (both infinite and finite population models) and learning dynamics (reinforcement learning). Some results are specific features of a particular dynamical model, whereas others turn out to be quite robust across different models. This suggests that there are certain qualitative aspects that are common to many real-world signaling interactions. PMID- 25024210 TI - Policy folklists and evolutionary theory. AB - Policy folklists present a set of alleged historical facts seen as relevant to some social issue. Although the validity of these folklists is dubious, leaders and writers circulate them in the media, variants arise, and the lists continue on, sometimes for decades. Folklists are repeated because their messages are appealing and their users are credible. Because folklists are on the record, we can examine their origins and changes. This report draws an analogy with evolutionary theory and suggests that biological mechanisms of self-repair, boundary maintenance, plasticity, speciation, and predation have significant interpretations for folklists, and clarify how the lists win the credence of otherwise skeptical people. PMID- 25024211 TI - Labor union members play an OLG repeated game. AB - Humans are capable of cooperating with one another even when it is costly and a deviation provides an immediate gain. An important reason is that cooperation is reciprocated or rewarded and deviations are penalized in later stages. For cooperation to be sustainable, not only must rewards and penalties be strong enough but individuals should also have the right incentives to provide rewards and punishments. Codes of conduct with such properties have been studied extensively in game theory (as repeated game equilibria), and the literature on the evolution of cooperation shows how equilibrium behavior might emerge and proliferate in society. We found that community unions, a subclass of labor unions that admits individual affiliations, are ideal to corroborate these theories with reality, because (i) their activities are simple and (ii) they have a structure that closely resembles a theoretical model, the overlapping generations repeated game. A detailed case study of a community union revealed a possible equilibrium that can function under the very limited observability in the union. The equilibrium code of conduct appears to be a natural focal point based on simple heuristic reasoning. The union we studied was created out of necessity for cooperation, without knowing or anticipating how cooperation might be sustained. The union has successfully resolved about 3,000 labor disputes and created a number of offspring. PMID- 25024212 TI - Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation. AB - Atrial fibrillation (AF) is the most common heart rhythm disorder. Transient postoperative AF can be elicited by high sympathetic nervous system activity. Catecholamines and serotonin cause arrhythmias in atrial trabeculae from patients with sinus rhythm (SR), but whether these arrhythmias occur in patients with chronic AF is unknown. We compared the incidence of arrhythmic contractions caused by norepinephrine, epinephrine, serotonin, and forskolin in atrial trabeculae from patients with SR and patients with AF. In the patients with AF, arrhythmias were markedly reduced for the agonists and abolished for forskolin, whereas maximum inotropic responses were markedly blunted only for serotonin. Serotonin and forskolin produced spontaneous diastolic Ca(2+) releases in atrial myocytes from the patients with SR that were abolished or reduced in myocytes from the patients with AF. For matching L-type Ca(2+)-current (ICa,L) responses, serotonin required and produced ~ 100-fold less cAMP/PKA at the Ca(2+) channel domain compared with the catecholamines and forskolin. Norepinephrine-evoked ICa,L responses were decreased by inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) in myocytes from patients with SR, but not in those from patients with AF. Agonist-evoked phosphorylation by CaMKII at phospholamban (Thr 17), but not of ryanodine2 (Ser-2814), was reduced in trabeculae from patients with AF. The decreased CaMKII activity may contribute to the blunting of agonist evoked arrhythmias in the atrial myocardium of patients with AF. PMID- 25024213 TI - Structural plasticity of 4-alpha-helical bundles exemplified by the puzzle-like molecular assembly of the Rop protein. AB - The dimeric Repressor of Primer (Rop) protein, a widely used model system for the study of coiled-coil 4-alpha-helical bundles, is characterized by a remarkable structural plasticity. Loop region mutations lead to a wide range of topologies, folding states, and altered physicochemical properties. A protein-folding study of Rop and several loop variants has identified specific residues and sequences that are linked to the observed structural plasticity. Apart from the native state, native-like and molten-globule states have been identified; these states are sensitive to reducing agents due to the formation of nonnative disulfide bridges. Pro residues in the loop are critical for the establishment of new topologies and molten globule states; their effects, however, can be in part compensated by Gly residues. The extreme plasticity in the assembly of 4-alpha helical bundles reflects the capacity of the Rop sequence to combine a specific set of hydrophobic residues into strikingly different hydrophobic cores. These cores include highly hydrated ones that are consistent with the formation of interchain, nonnative disulfide bridges and the establishment of molten globules. Potential applications of this structural plasticity are among others in the engineering of bio-inspired materials. PMID- 25024214 TI - Spatially segregated transcription and translation in cells of the endomembrane containing bacterium Gemmata obscuriglobus. AB - The dogma of coupled transcription and translation in bacteria has been challenged by recent reports of spatial segregation of these processes within the relatively simple cellular organization of the model organisms Escherichia coli and Bacillus subtilis. The bacterial species Gemmata obscuriglobus possesses an extensive endomembrane system. The membranes generate a very convoluted intracellular architecture in which some of the cell's ribosomes appear to have less direct access to the cell's nucleoid(s) than others. This observation prompted us to test the hypothesis that a substantial proportion of G. obscuriglobus translation may be spatially segregated from transcription. Using immunofluorescence and immunoelectron microscopy, we showed that translating ribosomes are localized throughout the cell, with a quantitatively greater proportion found in regions distal to nucleoid(s). Our results extend information about the phylogenetic and morphological diversity of bacteria in which the spatial organization of transcription and translation has been studied. These findings also suggest that endomembranes may provide an obstacle to colocated transcription and translation, a role for endomembranes that has not been reported previously for a prokaryotic organism. Our studies of G. obscuriglobus may provide a useful background for consideration of the evolutionary development of eukaryotic cellular complexity and how it led to decoupled processes of gene expression in eukaryotes. PMID- 25024215 TI - Contrasted coevolutionary dynamics between a bacterial pathogen and its bacteriophages. AB - Many antagonistic interactions between hosts and their parasites result in coevolution. Although coevolution can drive diversity and specificity within species, it is not known whether coevolutionary dynamics differ among functionally similar species. We present evidence of coevolution within simple communities of Pseudomonas aeruginosa PAO1 and a panel of bacteriophages. Pathogen identity affected coevolutionary dynamics. For five of six phages tested, time-shift assays revealed temporal peaks in bacterial resistance and phage infectivity, consistent with frequency-dependent selection (Red Queen dynamics). Two of the six phages also imposed additional directional selection, resulting in strongly increased resistance ranges over the entire length of the experiment (ca. 60 generations). Cross-resistance to these two phages was very high, independent of the coevolutionary history of the bacteria. We suggest that coevolutionary dynamics are associated with the nature of the receptor used by the phage for infection. Our results shed light on the coevolutionary process in simple communities and have practical application in the control of bacterial pathogens through the evolutionary training of phages, increasing their virulence and efficacy as therapeutics or disinfectants. PMID- 25024216 TI - Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated alpha-synuclein. AB - Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient high-throughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein alpha helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, alpha-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complex-disease targets that are traditionally deemed "undruggable." PMID- 25024217 TI - The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells. AB - The transcription factor NF-kappaB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-kappaB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNgamma, correlated with sustained nuclear expression of NF-kappaB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-kappaB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNgamma and TNFalpha and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy. PMID- 25024219 TI - Genetic information transfer promotes cooperation in bacteria. AB - Many bacterial species are social, producing costly secreted "public good" molecules that enhance the growth of neighboring cells. The genes coding for these cooperative traits are often propagated via mobile genetic elements and can be virulence factors from a biomedical perspective. Here, we present an experimental framework that links genetic information exchange and the selection of cooperative traits. Using simulations and experiments based on a synthetic bacterial system to control public good secretion and plasmid conjugation, we demonstrate that horizontal gene transfer can favor cooperation. In a well-mixed environment, horizontal transfer brings a direct infectious advantage to any gene, regardless of its cooperation properties. However, in a structured population transfer selects specifically for cooperation by increasing the assortment among cooperative alleles. Conjugation allows cooperative alleles to overcome rarity thresholds and invade bacterial populations structured purely by stochastic dilution effects. Our results provide an explanation for the prevalence of cooperative genes on mobile elements, and suggest a previously unidentified benefit of horizontal gene transfer for bacteria. PMID- 25024218 TI - Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity. AB - Allergic diseases, orchestrated by hyperactive CD4(+) Th2 cells, are some of the most common global chronic diseases. Therapeutic intervention relies upon broad scale corticosteroids with indiscriminate impact. To identify targets in pathogenic Th2 cells, we took a comprehensive approach to identify the microRNA (miRNA) and mRNA transcriptome of highly purified cytokine-expressing Th1, Th2, Th9, Th17, and Treg cells both generated in vitro and isolated ex vivo from allergy, infection, and autoimmune disease models. We report here that distinct regulatory miRNA networks operate to regulate Th2 cells in house dust mite allergic or helminth-infected animals and in vitro Th2 cells, which are distinguishable from other T cells. We validated several miRNA (miR) candidates (miR-15a, miR-20b, miR-146a, miR-155, and miR-200c), which targeted a suite of dynamically regulated genes in Th2 cells. Through in-depth studies using miR-155( /-) or miR-146a(-/-) T cells, we identified that T-cell-intrinsic miR-155 was required for type-2 immunity, in part through regulation of S1pr1, whereas T-cell intrinsic miR-146a was required to prevent overt Th1/Th17 skewing. These data identify miR-155, but not miR-146a, as a potential therapeutic target to alleviate Th2-medited inflammation and allergy. PMID- 25024220 TI - Synergy of aromatic residues and phosphoserines within the intrinsically disordered DNA-binding inhibitory elements of the Ets-1 transcription factor. AB - The E26 transformation-specific (Ets-1) transcription factor is autoinhibited by a conformationally disordered serine-rich region (SRR) that transiently interacts with its DNA-binding ETS domain. In response to calcium signaling, autoinhibition is reinforced by calmodulin-dependent kinase II phosphorylation of serines within the SRR. Using mutagenesis and quantitative DNA-binding measurements, we demonstrate that phosphorylation-enhanced autoinhibition requires the presence of phenylalanine or tyrosine (phi) residues adjacent to the SRR phosphoacceptor serines. The introduction of additional phosphorylated Ser-phi-Asp, but not Ser Ala-Asp, repeats within the SRR dramatically reinforces autoinhibition. NMR spectroscopic studies of phosphorylated and mutated SRR variants, both within their native context and as separate trans-acting peptides, confirmed that the aromatic residues and phosphoserines contribute to the formation of a dynamic complex with the ETS domain. Complementary NMR studies also identified the SRR interacting surface of the ETS domain, which encompasses its positively charged DNA-recognition interface and an adjacent region of neutral polar and nonpolar residues. Collectively, these studies highlight the role of aromatic residues and their synergy with phosphoserines in an intrinsically disordered regulatory sequence that integrates cellular signaling and gene expression. PMID- 25024221 TI - Hierarchical random walks in trace fossils and the origin of optimal search behavior. AB - Efficient searching is crucial for timely location of food and other resources. Recent studies show that diverse living animals use a theoretically optimal scale free random search for sparse resources known as a Levy walk, but little is known of the origins and evolution of foraging behavior and the search strategies of extinct organisms. Here, using simulations of self-avoiding trace fossil trails, we show that randomly introduced strophotaxis (U-turns)--initiated by obstructions such as self-trail avoidance or innate cueing--leads to random looping patterns with clustering across increasing scales that is consistent with the presence of Levy walks. This predicts that optimal Levy searches may emerge from simple behaviors observed in fossil trails. We then analyzed fossilized trails of benthic marine organisms by using a novel path analysis technique and find the first evidence, to our knowledge, of Levy-like search strategies in extinct animals. Our results show that simple search behaviors of extinct animals in heterogeneous environments give rise to hierarchically nested Brownian walk clusters that converge to optimal Levy patterns. Primary productivity collapse and large-scale food scarcity characterizing mass extinctions evident in the fossil record may have triggered adaptation of optimal Levy-like searches. The findings suggest that Levy-like behavior has been used by foragers since at least the Eocene but may have a more ancient origin, which might explain recent widespread observations of such patterns among modern taxa. PMID- 25024222 TI - Functional genomics of Lactobacillus casei establishment in the gut. AB - Although the composition of the gut microbiota and its symbiotic contribution to key host physiological functions are well established, little is known as yet about the bacterial factors that account for this symbiosis. We selected Lactobacillus casei as a model microorganism to proceed to genomewide identification of the functions required for a symbiont to establish colonization in the gut. As a result of our recent development of a transposon-mutagenesis tool that overcomes the barrier that had prevented L. casei random mutagenesis, we developed a signature-tagged mutagenesis approach combining whole-genome reverse genetics using a set of tagged transposons and in vivo screening using the rabbit ligated ileal loop model. After sequencing transposon insertion sites in 9,250 random mutants, we assembled a library of 1,110 independent mutants, all disrupted in a different gene, that provides a representative view of the L. casei genome. By determining the relative quantity of each of the 1,110 mutants before and after the in vivo challenge, we identified a core of 47 L. casei genes necessary for its establishment in the gut. They are involved in housekeeping functions, metabolism (sugar, amino acids), cell wall biogenesis, and adaptation to environment. Hence we provide what is, to our knowledge, the first global functional genomics analysis of L. casei symbiosis. PMID- 25024223 TI - The dynamic history of plastid genomes in the Campanulaceae sensu lato is unique among angiosperms. AB - Why have some plants lost the organizational stability in plastid genomes (plastomes) that evolved in their algal ancestors? During the endosymbiotic transformation of a cyanobacterium into the eukaryotic plastid, most cyanobacterial genes were transferred to the nucleus or otherwise lost from the plastome, and the resulting plastome architecture in land plants confers organizational stability, as evidenced by the conserved gene order among bryophytes and lycophytes, whereas ferns, gymnosperms, and angiosperms share a single, 30-kb inversion. Although some additional gene losses have occurred, gene additions to angiosperm plastomes were previously unknown. Plastomes in the Campanulaceae sensu lato have incorporated dozens of large ORFs (putative protein coding genes). These insertions apparently caused many of the 125+ large inversions now known in this small eudicot clade. This phylogenetically restricted phenomenon is not biogeographically localized, which indicates that these ORFs came from the nucleus or (less likely) a cryptic endosymbiont. PMID- 25024224 TI - Recent evolution of equine influenza and the origin of canine influenza. AB - In 2004 an hemagglutinin 3 neuraminidase 8 (H3N8) equine influenza virus was transmitted from horses to dogs in Florida and subsequently spread throughout the United States and to Europe. To understand the molecular basis of changes in the antigenicity of H3 hemagglutinins (HAs) that have occurred during virus evolution in horses, and to investigate the role of HA in the equine to canine cross species transfer, we used X-ray crystallography to determine the structures of the HAs from two antigenically distinct equine viruses and from a canine virus. Structurally all three are very similar with the majority of amino acid sequence differences between the two equine HAs located on the virus membrane-distal molecular surface. HAs of canine viruses are distinct in containing a Trp-222 -> Leu substitution in the receptor binding site that influences specificity for receptor analogs. In the fusion subdomain of canine and recent equine virus HAs a unique difference is observed by comparison with all other HAs examined to date. Analyses of site-specific mutant HAs indicate that a single amino acid substitution, Thr-30 -> Ser, influences interactions between N-terminal and C terminal regions of the subdomain that are important in the structural changes required for membrane fusion activity. Both structural modifications may have facilitated the transmission of H3N8 influenza from horses to dogs. PMID- 25024225 TI - Stromal response to Hedgehog signaling restrains pancreatic cancer progression. AB - Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention. PMID- 25024226 TI - Microspatial gene expression patterns in the Amazon River Plume. AB - We investigated expression of genes mediating elemental cycling at the microspatial scale in the ocean's largest river plume using, to our knowledge, the first fully quantitative inventory of genes and transcripts. The bacterial and archaeal communities associated with a phytoplankton bloom in Amazon River Plume waters at the outer continental shelf in June 2010 harbored ~ 1.0 * 10(13) genes and 4.7 * 10(11) transcripts per liter that mapped to several thousand microbial genomes. Genomes from free-living cells were more abundant than those from particle-associated cells, and they generated more transcripts per liter for carbon fixation, heterotrophy, nitrogen and phosphorus uptake, and iron acquisition, although they had lower expression ratios (transcripts ? gene(-1)) overall. Genomes from particle-associated cells contributed more transcripts for sulfur cycling, aromatic compound degradation, and the synthesis of biologically essential vitamins, with an overall twofold up-regulation of expression compared with free-living cells. Quantitatively, gene regulation differences were more important than genome abundance differences in explaining why microenvironment transcriptomes differed. Taxa contributing genomes to both free-living and particle-associated communities had up to 65% of their expressed genes regulated differently between the two, quantifying the extent of transcriptional plasticity in marine microbes in situ. In response to patchiness in carbon, nutrients, and light at the micrometer scale, Amazon Plume microbes regulated the expression of genes relevant to biogeochemical processes at the ecosystem scale. PMID- 25024227 TI - Conciliatory gestures promote forgiveness and reduce anger in humans. AB - Conflict is an inevitable component of social life, and natural selection has exerted strong effects on many organisms to facilitate victory in conflict and to deter conspecifics from imposing harms upon them. Like many species, humans likely possess cognitive systems whose function is to motivate revenge as a means of deterring individuals who have harmed them from harming them again in the future. However, many social relationships often retain value even after conflicts have occurred between interactants, so natural selection has very likely also endowed humans with cognitive systems whose function is to motivate reconciliation with transgressors whom they perceive as valuable and nonthreatening, notwithstanding their harmful prior actions. In a longitudinal study with 337 participants who had recently been harmed by a relationship partner, we found that conciliatory gestures (e.g., apologies, offers of compensation) were associated with increases in victims' perceptions of their transgressors' relationship value and reductions in perceptions of their transgressors' exploitation risk. In addition, conciliatory gestures appeared to accelerate forgiveness and reduce reactive anger via their intermediate effects on relationship value and exploitation risk. These results strongly suggest that conciliatory gestures facilitate forgiveness and reduce anger by modifying victims' perceptions of their transgressors' value as relationship partners and likelihood of recidivism. PMID- 25024228 TI - A dual role for planar cell polarity genes in ciliated cells. AB - In the nervous system, cilia dysfunction perturbs the circulation of the cerebrospinal fluid, thus affecting neurogenesis and brain homeostasis. A role for planar cell polarity (PCP) signaling in the orientation of cilia (rotational polarity) and ciliogenesis is established. However, whether and how PCP regulates cilia positioning in the apical domain (translational polarity) in radial progenitors and ependymal cells remain unclear. By analysis of a large panel of mutant mice, we show that two PCP signals are operating in ciliated cells. The first signal, controlled by cadherin, EGF-like, laminin G-like, seven-pass, G type receptor (Celsr) 2, Celsr3, Frizzled3 (Fzd3) and Van Gogh like2 (Vangl2) organizes multicilia in individual cells (single-cell polarity), whereas the second signal, governed by Celsr1, Fzd3, and Vangl2, coordinates polarity between cells in both radial progenitors and ependymal cells (tissue polarity). Loss of either of these signals is associated with specific defects in the cytoskeleton. Our data reveal unreported functions of PCP and provide an integrated view of planar polarization of the brain ciliated cells. PMID- 25024229 TI - Arhgap36-dependent activation of Gli transcription factors. AB - Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers. PMID- 25024230 TI - Acuity-independent effects of visual deprivation on human visual cortex. AB - Visual development depends on sensory input during an early developmental critical period. Deviation of the pointing direction of the two eyes (strabismus) or chronic optical blur (anisometropia) separately and together can disrupt the formation of normal binocular interactions and the development of spatial processing, leading to a loss of stereopsis and visual acuity known as amblyopia. To shed new light on how these two different forms of visual deprivation affect the development of visual cortex, we used event-related potentials (ERPs) to study the temporal evolution of visual responses in patients who had experienced either strabismus or anisometropia early in life. To make a specific statement about the locus of deprivation effects, we took advantage of a stimulation paradigm in which we could measure deprivation effects that arise either before or after a configuration-specific response to illusory contours (ICs). Extraction of ICs is known to first occur in extrastriate visual areas. Our ERP measurements indicate that deprivation via strabismus affects both the early part of the evoked response that occurs before ICs are formed as well as the later IC selective response. Importantly, these effects are found in the normal-acuity nonamblyopic eyes of strabismic amblyopes and in both eyes of strabismic patients without amblyopia. The nonamblyopic eyes of anisometropic amblyopes, by contrast, are normal. Our results indicate that beyond the well-known effects of strabismus on the development of normal binocularity, it also affects the early stages of monocular feature processing in an acuity-independent fashion. PMID- 25024231 TI - prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies. AB - Recent analyses in flies, mice, zebrafish, and humans showed that mutations in prickle orthologs result in epileptic phenotypes, although the mechanism responsible for generating the seizures was unknown. Here, we show that Prickle organizes microtubule polarity and affects their growth dynamics in axons of Drosophila neurons, which in turn influences both anterograde and retrograde vesicle transport. We also show that enhancement of the anterograde transport mechanism is the cause of the seizure phenotype in flies, which can be suppressed by reducing the level of either of two Kinesin motor proteins responsible for anterograde vesicle transport. Additionally, we show that seizure-prone prickle mutant flies have electrophysiological defects similar to other fly mutants used to study seizures, and that merely altering the balance of the two adult prickle isoforms in neurons can predispose flies to seizures. These data reveal a previously unidentified pathway in the pathophysiology of seizure disorders and provide evidence for a more generalized cellular mechanism whereby Prickle mediates polarity by influencing microtubule-mediated transport. PMID- 25024232 TI - Are viral small RNA regulating Dengue virus replication beyond serotype 2? PMID- 25024233 TI - Regional cerebral glucose metabolism and gait speed in healthy community-dwelling older women. AB - BACKGROUND: The objective of this study was to investigate the relationship between normalized regional cerebral metabolic rates of glucose (normalized rCMRglc) and gait function in physically and mentally high-functioning older women. METHODS: One hundred eighty-two community-dwelling older women (mean age [SD], 69.4 [6.6] years) without disability in instrumental activities of daily living and without mobility limitations underwent positron emission tomography with 18F-fluorodeoxyglucose at rest to assess brain activity associated with gait function. We measured normalized-rCMRglc in 16 regions of interest. Within 6 months of the positron emission tomography with 18F-fluorodeoxyglucose scan, gait speed, step length, and step frequency both at comfortable and maximum paces were measured as indices of gait function. Associations between normalized-rCMRglc and gait indices were examined with multiple linear regression analyses adjusted for demographic characteristics, including age, height, body weight, blood pressure, past illness, and education. RESULTS: Slower maximum gait speed even in the range of individual difference was associated with lower normalized-rCMRglc in the prefrontal, posterior cingulate, and parietal cortices. Lower step frequency at the maximum pace was also associated with lower normalized-rCMRglc in these regions. However, there was no significant association between step length at the maximum pace and normalized-rCMRglc or between all gait variables at a comfortable pace and normalized-rCMRglc. CONCLUSIONS: The normalized-rCMRglc values in specific regions were associated with individual differences in gait function, even in healthy older women. These regions of the cerebrum could play an important role in gait control. Understanding the cerebral glucose metabolism in these brain regions may enable early detection of mobility limitation. PMID- 25024234 TI - The effects of an 8-week Hatha yoga intervention on executive function in older adults. AB - BACKGROUND: Few scientific studies have examined movement-based embodied contemplative practices such as yoga and their effects on cognition. The purpose of this randomized controlled trial was to examine the effects of an 8-week Hatha yoga intervention on executive function measures of task switching and working memory capacity. METHODS: Community-dwelling older adults (N = 118; mean age = 62.0) were randomized to one of two groups: a Hatha yoga intervention or a stretching-strengthening control. Both groups participated in hour-long exercise classes 3*/week over the 8-week study period. All participants completed established tests of executive function including the task switching paradigm, n back and running memory span at baseline and follow-up. RESULTS: Analysis of covariances showed significantly shorter reaction times on the mixed and repeat task switching trials (partial eta(2) = .04, p < .05) for the Hatha yoga group. Higher accuracy was recorded on the single trials (partial eta(2) = .05, p < .05), the 2-back condition of the n-back (partial eta(2) = .08, p < .001), and partial recall scores (partial eta(2) = .06, p < .01) of running span task. CONCLUSIONS: Following 8 weeks of yoga practice, participants in the yoga intervention group showed significantly improved performance on the executive function measures of working memory capacity and efficiency of mental set shifting and flexibility compared with their stretching-strengthening counterparts. Although the underlying mechanisms need to be investigated, these results demand larger systematic trials to thoroughly examine effects of yoga on executive function as well as across other domains of cognition, and its potential to maintain or improve cognitive functioning in the aging process. PMID- 25024236 TI - Tips for readers, reviewers, and authors advancing health and primary health care. PMID- 25024235 TI - Association of hearing impairment and mortality in older adults. AB - BACKGROUND: Hearing impairment (HI) is highly prevalent in older adults and is associated with social isolation, depression, and risk of dementia. Whether HI is associated with broader downstream outcomes is unclear. We undertook this study to determine whether audiometric HI is associated with mortality in older adults. METHODS: Prospective observational data from 1,958 adults >=70 years of age from the Health, Aging, and Body Composition Study were analyzed using Cox proportional hazards regression. Participants were followed for 8 years after audiometric examination. Mortality was adjudicated by obtaining death certificates. Hearing was defined as the pure-tone average of hearing thresholds in decibels re: hearing level (dB HL) at frequencies from 0.5 to 4kHz. HI was defined as pure-tone average >25 dB HL in the better ear. RESULTS: Of the 1,146 participants with HI, 492 (42.9%) died compared with 255 (31.4%) of the 812 with normal hearing (odds ratio = 1.64, 95% CI: 1.36-1.98). After adjustment for demographics and cardiovascular risk factors, HI was associated with a 20% increased mortality risk compared with normal hearing (hazard ratio = 1.20, 95% CI: 1.03-1.41). Confirmatory analyses treating HI as a continuous predictor yielded similar results, demonstrating a nonlinear increase in mortality risk with increasing HI (hazard ratio = 1.14, 95% CI: 1.00-1.29 per 10 dB of threshold elevation up to 35 dB HL). CONCLUSIONS: HI in older adults is associated with increased mortality, independent of demographics and cardiovascular risk factors. Further research is necessary to understand the basis of this association and whether these pathways might be amenable to hearing rehabilitation. PMID- 25024237 TI - Risk of cardiovascular disease among postmenopausal women with prior pregnancy loss: the women's health initiative. AB - PURPOSE: Metabolic, hormonal, and hemostatic changes associated with pregnancy loss (stillbirth and miscarriage) may contribute to the development of cardiovascular disease (CVD) in adulthood. This study evaluated prospectively the association between a history of pregnancy loss and CVD in a cohort of postmenopausal women. METHODS: Postmenopausal women (77,701) were evaluated from 1993-1998. Information on baseline reproductive history, sociodemographic, and CVD risk factors were collected. The associations between 1 or 2 or more miscarriages and 1 or more stillbirths with occurrence of CVD were evaluated using multiple logistic regression. RESULTS: Among 77,701 women in the study sample, 23,538 (30.3%) reported a history of miscarriage; 1,670 (2.2%) reported a history of stillbirth; and 1,673 (2.2%) reported a history of both miscarriage and stillbirth. Multivariable-adjusted odds ratio (OR) for coronary heart disease (CHD) for 1 or more stillbirths was 1.27 (95% CI, 1.07-1.51) compared with no stillbirth; for women with a history of 1 miscarriage, the OR=1.19 (95% CI, 1.08 1.32); and for 2 or more miscarriages the OR=1.18 (95% CI, 1.04-1.34) compared with no miscarriage. For ischemic stroke, the multivariable odds ratio for stillbirths and miscarriages was not significant. CONCLUSIONS: Pregnancy loss was associated with CHD but not ischemic stroke. Women with a history of 1 or more stillbirths or 1 or more miscarriages appear to be at increased risk of future CVD and should be considered candidates for closer surveillance and/or early intervention; research is needed into better understanding the pathophysiologic mechanisms behind the increased risk of CVD associated with pregnancy loss. PMID- 25024238 TI - A school-based study of adolescent all-terrain vehicle exposure, safety behaviors, and crash experience. AB - PURPOSE: More youth are killed every year in the United States in all-terrain vehicle (ATV) crashes than on bicycles, and since 2001, one-fifth of all ATV fatalities have involved victims aged 15 years or younger. Effectively preventing pediatric ATV-related deaths and injuries requires knowledge about youth riding practices. Our objective was to examine ATV use, crash prevalence, and riding behaviors among adolescent students in a rural state. METHODS: We administered a cross-sectional survey to 4,684 youths aged 11 to 16 years at 30 schools across Iowa from November 2010 to April 2013. Descriptive and comparative analyses were performed. RESULTS: Regardless of rurality, at least 75% of students reported having been on an ATV, with 38% of those riding daily or weekly. Among ATV riders, 57% had been in a crash. Most riders engaged in risky behaviors, including riding with passengers (92%), on public roads (81%), or without a helmet (64%). Almost 60% reported engaging in all 3 behaviors; only 2% engaged in none. Multivariable modeling revealed male youth, students riding daily/weekly, and those reporting both riding on public roads and with passengers were 1.61 (95% CI, 1.36-1.91), 3.73 (95% CI, 3.10-4.50), and 3.24 (95% CI, 2.09-5.04) times more likely to report a crash, respectively. CONCLUSIONS: Three-fourths of youths surveyed were exposed to ATVs. The majority of riders had engaged in unsafe behaviors and experienced a crash. Given this widespread use and the potentially considerable morbidity of pediatric ATV crashes, prevention efforts, including anticipatory guidance by primary care clinicians serving families at risk, should be a higher priority. PMID- 25024239 TI - Effect of payment incentives on cancer screening in Ontario primary care. AB - PURPOSE: There is limited evidence for the effectiveness of pay for performance despite its widespread use. We assessed whether the introduction of a pay-for performance scheme for primary care physicians in Ontario, Canada, was associated with increased cancer screening rates and determined the amounts paid to physicians as part of the program. METHODS: We performed a longitudinal analysis using administrative data to determine cancer screening rates and incentive costs in each fiscal year from 1999/2000 to 2009/2010. We used a segmented linear regression analysis to assess whether there was a step change or change in screening rate trends after incentives were introduced in 2006/2007. We included all Ontarians eligible for cervical, breast, and colorectal cancer screening. RESULTS: We found no significant step change in the screening rate for any of the 3 cancers the year after incentives were introduced. Colon cancer screening was increasing at a rate of 3.0% (95% CI, 2.3% to 3.7%) per year before the incentives were introduced and 4.7% (95% CI, 3.7% to 5.7%) per year after. The cervical and breast cancer screening rates did not change significantly from year to year before or after the incentives were introduced. Between 2006/2007 and 2009/2010, $28.3 million, $31.3 million, and $50.0 million were spent on financial incentives for cervical, breast, and colorectal cancer screening, respectively. CONCLUSIONS: The pay-for-performance scheme was associated with little or no improvement in screening rates despite substantial expenditure. Policy makers should consider other strategies for improving rates of cancer screening. PMID- 25024241 TI - Practice environments and job satisfaction in patient-centered medical homes. AB - PURPOSE: We undertook a study to evaluate the effects of medical home transformation on job satisfaction in the primary care setting. METHODS: We collected primary data from 20 primary care practices participating in medical home pilot projects in Rhode Island and Colorado from 2009 to 2011. We surveyed clinicians and staff about the quality of their practice environments (eg, office chaos, communication, difficulties in providing safe, high-quality care) and job satisfaction at baseline and 30 months, and about stress, burnout, and intention to leave at 30 months. We interviewed practice leaders about the impact of pilot project participation. We assessed longitudinal changes in the practice environment and job satisfaction and, in the final pilot year, examined cross sectional associations between the practice environment and job satisfaction, stress, burnout, and intention to leave. RESULTS: Between baseline and 30 months, job satisfaction improved in Rhode Island (P=.03) but not in Colorado. For both pilot projects, reported difficulties in providing safe, high-quality care decreased (P<.001), but emphasis on quality and the level of office chaos did not change significantly. In cross-sectional analyses, fewer difficulties in providing safe, high-quality care and more open communication were associated with greater job satisfaction. Greater office chaos and an emphasis on electronic information were associated with greater stress and burnout. CONCLUSIONS: Medical home transformations that emphasize quality and open communication while minimizing office chaos may offer the best chances of improving job satisfaction. PMID- 25024240 TI - Influence of shared medical appointments on patient satisfaction: a retrospective 3-year study. AB - PURPOSE: Shared medical appointments (SMAs) are becoming popular, but little is known about their association with patient experience in primary care. We performed an exploratory analysis examining overall satisfaction and patient centered care experiences across key domains of the patient-centered medical home among patients attending SMAs vs usual care appointments. METHODS: We undertook a cross-sectional study using a mailed questionnaire measuring levels of patient satisfaction and other indicators of patient-centered care among 921 SMA and 921 usual care patients between 2008 and 2010. Propensity scores adjusted for potential case mix differences between the groups. Multivariate logistic regression assessed propensity-matched patients' ratings of care. Generalized estimating equations accounted for physician-level clustering. RESULTS: A total of 40% of SMA patients and 31% of usual care patients responded. In adjusted analyses, SMA patients were more likely to rate their overall satisfaction with care as "very good" when compared with usual care counterparts (odds ratio=1.26; 95% CI, 1.05-1.52). In the analysis of patient-centered medical home elements, SMA patients rated their care as more accessible and more sensitive to their needs, whereas usual care patients reported greater satisfaction with physician communication and time spent during their appointment. CONCLUSIONS: Overall, SMA patients appear more satisfied with their care relative to patients receiving usual care. SMAs may also improve access to care and deliver care that patients find to be sensitive to their needs. Further research should focus on enhancing patient-clinician communication within an SMA as this model of care becomes more widely adopted. PMID- 25024242 TI - Changes in office visit use associated with electronic messaging and telephone encounters among patients with diabetes in the PCMH. AB - PURPOSE: Telephone- and Internet-based communication are increasingly common in primary care, yet there is uncertainty about how these forms of communication affect demand for in-person office visits. We assessed whether use of copay-free secure messaging and telephone encounters was associated with office visit use in a population with diabetes. METHODS: We used an interrupted time series design with a patient-quarter unit of analysis. Secondary data from 2008-2011 spanned 3 periods before, during, and after a patient-centered medical home (PCMH) redesign in an integrated health care delivery system. We used linear regression models to estimate proportional changes in the use of primary care office visits associated with proportional increases in secure messaging and telephone encounters. RESULTS: The study included 18,486 adults with diabetes. The mean quarterly number of primary care contacts increased by 28% between the pre-PCMH baseline and the postimplementation periods, largely driven by increased secure messaging; quarterly office visit use declined by 8%. In adjusted regression analysis, 10% increases in secure message threads and telephone encounters were associated with increases of 1.25% (95% CI, 1.21%-1.29%) and 2.74% (95% CI, 2.70%-2.77%) in office visits, respectively. In an interaction model, proportional increases in secure messaging and telephone encounters remained associated with increased office visit use for all study periods and patient subpopulations (P<.001). CONCLUSIONS: Before and after a medical home redesign, proportional increases in secure messaging and telephone encounters were associated with additional primary care office visits for individuals with diabetes. Our findings provide evidence on how new forms of patient-clinician communication may affect demand for office visits. PMID- 25024243 TI - Electronic health records for intervention research: a cluster randomized trial to reduce antibiotic prescribing in primary care (eCRT study). AB - PURPOSE: This study aimed to implement a point-of-care cluster randomized trial using electronic health records. We evaluated the effectiveness of electronically delivered decision support tools at reducing antibiotic prescribing for respiratory tract infections in primary care. METHODS: Family practices from England and Scotland participating in the Clinical Practice Research Datalink (CPRD) were included in the trial; 53 family practices were allocated to intervention and 51 practices were allocated to usual care. Patients aged 18 to 59 years consulting for respiratory tract infections were eligible. The intervention was through remotely installed, computer-delivered decision support tools accessed during the consultations. Control practices provided usual care. The primary outcome was the proportion of consultations for respiratory tract infections with an antibiotic prescribed based on electronic health records. Family practice-specific proportions were included in a cluster-level analysis. RESULTS: Data were analyzed for 603,409 patients: 317,717 at intervention practices and 285,692 at control practices. Use of the intervention was less than anticipated, varying among practices. There was a reduction in proportion of consultations with antibiotics prescribed of 1.85% (95% CI, 0.10%-3.59%, P=.038) and in the rate of antibiotic prescribing for respiratory tract infections (9.69%; 95% CI, 0.75%-18.63%, fewer prescriptions per 1,000 patient-years, P=.034). There were no adverse events. CONCLUSIONS: Cluster randomized trials may be implemented efficiently in large samples from routine care settings by using primary care electronic health records. Future studies should develop and test multicomponent methods for remotely delivered intervention. PMID- 25024244 TI - A technology-based quality innovation to identify undiagnosed hypertension among active primary care patients. AB - PURPOSE: The goal of this study was to develop a technology-based strategy to identify patients with undiagnosed hypertension in 23 primary care practices and integrate this innovation into a continuous quality improvement initiative in a large, integrated health system. METHODS: In phase 1, we reviewed electronic health records (EHRs) using algorithms designed to identify patients at risk for undiagnosed hypertension. We then invited each at-risk patient to complete an automated office blood pressure (AOBP) protocol. In phase 2, we instituted a quality improvement process that included regular physician feedback and office based computer alerts to evaluate at-risk patients not screened in phase 1. Study patients were observed for 24 additional months to determine rates of diagnostic resolution. RESULTS: Of the 1,432 patients targeted for inclusion in the study, 475 completed the AOBP protocol during the 6 months of phase 1. Of the 1,033 at risk patients who remained active during phase 2, 740 (72%) were classified by the end of the follow-up period: 361 had hypertension diagnosed, 290 had either white-coat hypertension, prehypertension, or elevated blood pressure diagnosed, and 89 had normal blood pressure. By the end of the follow-up period, 293 patients (28%) had not been classified and remained at risk for undiagnosed hypertension. CONCLUSIONS: Our technology-based innovation identified a large number of patients at risk for undiagnosed hypertension and successfully classified the majority, including many with hypertension. This innovation has been implemented as an ongoing quality improvement initiative in our medical group and continues to improve the accuracy of diagnosis of hypertension among primary care patients. PMID- 25024245 TI - Developing an international register of clinical prediction rules for use in primary care: a descriptive analysis. AB - PURPOSE: We describe the methodology used to create a register of clinical prediction rules relevant to primary care. We also summarize the rules included in the register according to various characteristics. METHODS: To identify relevant articles, we searched the MEDLINE database (PubMed) for the years 1980 to 2009 and supplemented the results with searches of secondary sources (books on clinical prediction rules) and personal resources (eg, experts in the field). The rules described in relevant articles were classified according to their clinical domain, the stage of development, and the clinical setting in which they were studied. RESULTS: Our search identified clinical prediction rules reported between 1965 and 2009. The largest share of rules (37.2%) were retrieved from PubMed. The number of published rules increased substantially over the study decades. We included 745 articles in the register; many contained more than 1 clinical prediction rule study (eg, both a derivation study and a validation study), resulting in 989 individual studies. In all, 434 unique rules had gone through derivation; however, only 54.8% had been validated and merely 2.8% had undergone analysis of their impact on either the process or outcome of clinical care. The rules most commonly pertained to cardiovascular disease, respiratory, and musculoskeletal conditions. They had most often been studied in the primary care or emergency department settings. CONCLUSIONS: Many clinical prediction rules have been derived, but only about half have been validated and few have been assessed for clinical impact. This lack of thorough evaluation for many rules makes it difficult to retrieve and identify those that are ready for use at the point of patient care. We plan to develop an international web-based register of clinical prediction rules and computer-based clinical decision support systems. PMID- 25024247 TI - The immortality of Ms Jones. AB - When I began my medical student clinical rotations, I quickly became overwhelmed by feelings of inadequacy. While the doctors around me conjured appropriate diagnoses and treatment approaches, I fumbled with the only tools I possessed: my time and a smile. It was only when I met the patient Ms Jones that I came to understand the potential impact of these simple tools. My encouragement became part of her recovery process. She gave me the confidence to construct this ability of comforting patients into a small platform of confidence from which I could safely venture to educate patients or suggest treatments to residents. It could be something that I could reliably fall back on in times of doubt and something I could pass along to other people I met. PMID- 25024246 TI - Validating the 8 CPCSSN case definitions for chronic disease surveillance in a primary care database of electronic health records. AB - PURPOSE: The Canadian Primary Care Sentinel Surveillance Network (CPCSSN) is Canada's first national chronic disease surveillance system based on electronic health record (EHR) data. The purpose of this study was to develop and validate case definitions and case-finding algorithms used to identify 8 common chronic conditions in primary care: chronic obstructive pulmonary disease (COPD), dementia, depression, diabetes, hypertension, osteoarthritis, parkinsonism, and epilepsy. METHODS: Using a cross-sectional data validation study design, regional and local CPCSSN networks from British Columbia, Alberta (2), Ontario, Nova Scotia, and Newfoundland participated in validating EHR case-finding algorithms. A random sample of EHR charts were reviewed, oversampling for patients older than 60 years and for those with epilepsy or parkinsonism. Charts were reviewed by trained research assistants and residents who were blinded to the algorithmic diagnosis. Sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) were calculated. RESULTS: We obtained data from 1,920 charts from 4 different EHR systems (Wolf, Med Access, Nightingale, and PS Suite). For the total sample, sensitivity ranged from 78% (osteoarthritis) to more than 95% (diabetes, epilepsy, and parkinsonism); specificity was greater than 94% for all diseases; PPV ranged from 72% (dementia) to 93% (hypertension); NPV ranged from 86% (hypertension) to greater than 99% (diabetes, dementia, epilepsy, and parkinsonism). CONCLUSIONS: The CPCSSN diagnostic algorithms showed excellent sensitivity and specificity for hypertension, diabetes, epilepsy, and parkinsonism and acceptable values for the other conditions. CPCSSN data are appropriate for use in public health surveillance, primary care, and health services research, as well as to inform policy for these diseases. PMID- 25024248 TI - STFM launches new task force to develop leading change live events and training. PMID- 25024249 TI - Family medicine must find and use its power to improve the health of the nation. PMID- 25024250 TI - From family medicine milestones to entrustable professional activities (EPAS). PMID- 25024251 TI - Primary care research priorities identified and shared with stakeholders. PMID- 25024252 TI - AHRQ updates on primary care research: self-management support resource library and companion videos. PMID- 25024253 TI - Graham Center projects increase in physicians working in shortage areas. PMID- 25024255 TI - Discourse compression of elderly adults in a dyadic context. AB - OBJECTIVES: Elderly adults demonstrate a reduced ability to produce increasingly concise and coherent discourse with repetition when compared with their younger counterparts. We explored whether discourse efficiency and quality would increase with story retelling in a dialogic context. METHOD: Participants were 30 elderly adults aged between 65 and 91 years (M = 77.03, SD = 9.214). Fifteen participants were paired with an elderly adult (EE group) and 15 with a young adult (EY group). Within their dyads, participants constructed a story from a series of cartoon frames. Variables analyzed were narrative duration, word count, fluency, and cohesion. Narratives were repeated 3 times. RESULTS: A compression index was calculated for each variable. For fluency and duration, the compression index for the EY group was significantly higher than for the EE group. While the EY group produced more coherent discourse with repetition, discourse cohesion did not improve with retelling for the EE group. DISCUSSION: A young conversational partner offers a model of consistently compressed and coherent discourse for their older interlocutor. Producing discourse in tandem with a younger adult may thus support older adults' use of social platforms (such as SMS or Facebook) that require a highly compressed message. PMID- 25024256 TI - Arabinogalactan protein-rich cell walls, paramural deposits and ergastic globules define the hyaline bodies of rhinanthoid Orobanchaceae haustoria. AB - BACKGROUND AND AIMS: Parasitic plants obtain nutrients from their hosts through organs called haustoria. The hyaline body is a specialized parenchymatous tissue occupying the central parts of haustoria in many Orobanchaceae species. The structure and functions of hyaline bodies are poorly understood despite their apparent necessity for the proper functioning of haustoria. Reported here is a cell wall-focused immunohistochemical study of the hyaline bodies of three species from the ecologically important clade of rhinanthoid Orobanchaceae. METHODS: Haustoria collected from laboratory-grown and field-collected plants of Rhinanthus minor, Odontites vernus and Melampyrum pratense attached to various hosts were immunolabelled for cell wall matrix glycans and glycoproteins using specific monoclonal antibodies (mAbs). KEY RESULTS: Hyaline body cell wall architecture differed from that of the surrounding parenchyma in all species investigated. Enrichment in arabinogalactan protein (AGP) epitopes labelled with mAbs LM2, JIM8, JIM13, JIM14 and CCRC-M7 was prominent and coincided with reduced labelling of de-esterified homogalacturonan with mAbs JIM5, LM18 and LM19. Furthermore, paramural bodies, intercellular deposits and globular ergastic bodies composed of pectins, xyloglucans, extensins and AGPs were common. In Rhinanthus they were particularly abundant in pairings with legume hosts. Hyaline body cells were not in direct contact with haustorial xylem, which was surrounded by a single layer of paratracheal parenchyma with thickened cell walls abutting the xylem. CONCLUSIONS: The distinctive anatomy and cell wall architecture indicate hyaline body specialization. Altered proportions of AGPs and pectins may affect the mechanical properties of hyaline body cell walls. This and the association with a transfer-like type of paratracheal parenchyma suggest a role in nutrient translocation. Organelle-rich protoplasts and the presence of exceptionally profuse intra- and intercellular wall materials when attached to a nitrogen-fixing host suggest subsequent processing and transient storage of nutrients. AGPs might therefore be implicated in nutrient transfer and metabolism in haustoria. PMID- 25024257 TI - Enhancer-trap flippase lines for clonal analysis in the Drosophila ovary. AB - The Drosophila melanogaster genetic tool box includes many stocks for generating genetically mosaic tissue in which a clone of cells, related by lineage, contain a common genetic alteration. These tools have made it possible to study the postembryonic function of essential genes and to better understand how individual cells interact within intact tissues. We have screened through 201 enhancer-trap flippase lines to identify lines that produce useful clone patterns in the adult ovary. We found that approximately 70% of the lines produced clones that were present in the adult ovary and that many ovarian cell types were represented among the different clone patterns produced by these lines. We have also identified and further characterized five particularly useful enhancer-trap flippase lines. These lines make it possible to generate clones specifically in germ cells, escort cells, prefollicle cells, or terminal filament cells. In addition, we have found that chickadee is specifically upregulated in the posterior escort cells, follicle stem cells, and prefollicle cells that comprise the follicle stem cell niche region. Collectively, these studies provide several new tools for genetic mosaic analysis in the Drosophila ovary. PMID- 25024258 TI - Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors. AB - PURPOSE: RGB-286638 is a multitargeted inhibitor with targets comprising the family of cyclin-dependent kinases (CDK) and a range of other cancer-relevant tyrosine and serine/threonine kinases. The objectives of this first in human trial of RGB-286638, given i.v. on days 1 to 5 every 28 days, were to determine the maximum tolerated dose (MTD) and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this new drug. EXPERIMENTAL DESIGN: Sequential cohorts of 3 to 6 patients were treated per dose level. Blood, urine samples, and skin biopsies for full PK and/or PD analyses were collected. RESULTS: Twenty-six patients were enrolled in 6-dose levels from 10 to 160 mg/d. Four dose-limiting toxicities were observed in 2 of the 6 patients enrolled at the highest dose level. These toxicities were AST/ALT elevations in 1 patient, paroxysmal supraventricular tachycardias (SVTs), hypotension, and an increase in troponin T in another patient. The plasma PK of RGB-286638 was shown to be linear over the studied doses. The interpatient variability in clearance was moderate (variation coefficient 7%-36%). The PD analyses in peripheral blood mononuclear cells, serum (apoptosis induction) and skin biopsies (Rb, p-Rb, Ki-67, and p27(KIP1) expression) did not demonstrate a consistent modulation of mechanism-related biomarkers with the exception of lowered Ki-67 levels at the MTD level. The recommended MTD for phase II studies is 120 mg/d. CONCLUSIONS: RGB-286638 is tolerated when administered at 120 mg/d for 5 days every 28 days. Prolonged disease stabilization (range, 2-14 months) was seen across different dose levels. PMID- 25024259 TI - Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. AB - PURPOSE: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. EXPERIMENTAL DESIGN: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. RESULTS: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. CONCLUSIONS: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. PMID- 25024265 TI - Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis. AB - Missense mutations at arginine residues in the S4 voltage-sensor domains of NaV1.4 are an established cause of hypokalemic periodic paralysis, an inherited disorder of skeletal muscle involving recurrent episodes of weakness in conjunction with low serum K(+). Expression studies in oocytes have revealed anomalous, hyperpolarization-activated gating pore currents in mutant channels. This aberrant gating pore conductance creates a small inward current at the resting potential that is thought to contribute to susceptibility to depolarization in low K(+) during attacks of weakness. A critical component of this hypothesis is the magnitude of the gating pore conductance relative to other conductances that are active at the resting potential in mammalian muscle: large enough to favor episodes of paradoxical depolarization in low K(+), yet not so large as to permanently depolarize the fiber. To improve the estimate of the specific conductance for the gating pore in affected muscle, we sequentially measured Na(+) current through the channel pore, gating pore current, and gating charge displacement in oocytes expressing R669H, R672G, or wild-type NaV1.4 channels. The relative conductance of the gating pore to that of the pore domain pathway for Na(+) was 0.03%, which implies a specific conductance in muscle from heterozygous patients of ~ 10 uS/cm(2) or 1% of the total resting conductance. Unexpectedly, our data also revealed a substantial decoupling between gating charge displacement and peak Na(+) current for both R669H and R672G mutant channels. This decoupling predicts a reduced Na(+) current density in affected muscle, consistent with the observations that the maximal dV/dt and peak amplitude of the action potential are reduced in fibers from patients with R672G and in a knock-in mouse model of R669H. The defective coupling between gating charge displacement and channel activation identifies a previously unappreciated mechanism that contributes to the reduced excitability of affected fibers seen with these mutations and possibly with other R/X mutations of S4 of NaV, CaV, and KV channels associated with human disease. PMID- 25024266 TI - Three charged amino acids in extracellular loop 1 are involved in maintaining the outer pore architecture of CFTR. AB - The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) bears six extracellular loops (ECL1-6); ECL1 is the site of several mutations associated with CF. Mutation R117H has been reported to reduce current amplitude, whereas D110H, E116K, and R117C/L/P may impair channel stability. We hypothesized that these amino acids might not be directly involved in ion conduction and permeation but may contribute to stabilizing the outer vestibule architecture in CFTR. We used cRNA injected oocytes combined with electrophysiological techniques to test this hypothesis. Mutants bearing cysteine at these sites were not functionally modified by extracellular MTS reagents and were blocked by GlyH-101 similarly to WT-CFTR. These results suggest that these three residues do not contribute directly to permeation in CFTR. In contrast, mutants D110R-, E116R-, and R117A CFTR exhibited instability of the open state and significantly shortened burst duration compared with WT-CFTR and failed to be locked into the open state by AMP PNP (adenosine 5'-(beta,gamma-imido) triphosphate); charge-retaining mutants showed mainly the full open state with comparably longer open burst duration. These interactions suggest that these ECL1 residues might be involved in maintaining the outer pore architecture of CFTR. A CFTR homology model suggested that E116 interacts with R104 in both the closed and open states, D110 interacts with K892 in the fully closed state, and R117 interacts with E1126 in the open state. These interactions were confirmed experimentally. The results suggest that D110, E116, and R117 may contribute to stabilizing the architecture of the outer pore of CFTR by interactions with other charged residues. PMID- 25024267 TI - The conserved potassium channel filter can have distinct ion binding profiles: structural analysis of rubidium, cesium, and barium binding in NaK2K. AB - Potassium channels are highly selective for K(+) over the smaller Na(+). Intriguingly, they are permeable to larger monovalent cations such as Rb(+) and Cs(+) but are specifically blocked by the similarly sized Ba(2+). In this study, we used structural analysis to determine the binding profiles for these permeant and blocking ions in the selectivity filter of the potassium-selective NaK channel mutant NaK2K and also performed permeation experiments using single channel recordings. Our data revealed that some ion binding properties of NaK2K are distinct from those of the canonical K(+) channels KcsA and MthK. Rb(+) bound at sites 1, 3, and 4 in NaK2K, as it does in KcsA. Cs(+), however, bound predominantly at sites 1 and 3 in NaK2K, whereas it binds at sites 1, 3, and 4 in KcsA. Moreover, Ba(2+) binding in NaK2K was distinct from that which has been observed in KcsA and MthK, even though all of these channels show similar Ba(2+) block. In the presence of K(+), Ba(2+) bound to the NaK2K channel at site 3 in conjunction with a K(+) at site 1; this led to a prolonged block of the channel (the external K(+)-dependent Ba(2+) lock-in state). In the absence of K(+), however, Ba(2+) acts as a permeating blocker. We found that, under these conditions, Ba(2+) bound at sites 1 or 0 as well as site 3, allowing it to enter the filter from the intracellular side and exit from the extracellular side. The difference in the Ba(2+) binding profile in the presence and absence of K(+) thus provides a structural explanation for the short and prolonged Ba(2+) block observed in NaK2K. PMID- 25024268 TI - Ionic interactions of Ba2+ blockades in the MthK K+ channel. AB - The movement and interaction of multiple ions passing through in single file underlie various fundamental K(+) channel properties, from the effective conduction of K(+) ions to channel blockade by Ba(2+) ions. In this study, we used single-channel electrophysiology and x-ray crystallography to probe the interactions of Ba(2+) with permeant ions within the ion conduction pathway of the MthK K(+) channel. We found that, as typical of K(+) channels, the MthK channel was blocked by Ba(2+) at the internal side, and the Ba(2+)-blocking effect was enhanced by external K(+). We also obtained crystal structures of the MthK K(+) channel pore in both Ba(2+)-Na(+) and Ba(2+)-K(+) environments. In the Ba(2+)-Na(+) environment, we found that a single Ba(2+) ion remained bound in the selectivity filter, preferably at site 2, whereas in the Ba(2+)-K(+) environment, Ba(2+) ions were predominantly distributed between sites 3 and 4. These ionic configurations are remarkably consistent with the functional studies and identify a molecular basis for Ba(2+) blockade of K(+) channels. PMID- 25024270 TI - In vitro conversion of morphine to 6-acetylmorphine in urine samples during enzymatic hydrolysis. PMID- 25024271 TI - The genetic structure of Asian corn borer, Ostrinia furnacalis, populations in China: haplotype variance in northern populations and potential impact on management of resistance to transgenic maize. AB - Asian corn borer, Ostrinia furnacalis (Guenee), is a severe pest that infests cultivated maize in the major production regions of China. Populations show genotype-by-environment variation in voltinism, such that populations with a single generation (univoltine) are fixed in Northern China where growing seasons are short. Low genetic differentiation was found among samples from 33 collection sites across China and one site from North Korea (n=1673) using variation at 6 nuclear microsatellite loci (ENA corrected global FST=0.020; P value<0.05). Analysis of molecular variance indicated that geographic region, number of generations or voltinism accounted for <0.38% of the total genetic variation at nuclear loci and was corroborated by clustering of co-ancestries among genotypes using the program STRUCTURE. In contrast, a mitochondrial haplotype network identified 4 distinct clusters, where 70.5% of samples from univoltine populations were within a single group. Univoltine populations were also placed into a unique cluster using Population Graph and Principal component analyses, which showed significant differentiation with multivoltine populations (phiST=0.400; P value<0.01). This study suggests that gene flow among O. furnacalis in China may be high among regions, with the exception of northeastern localities. Haplotype variation may be due to random genetic drift resulting from partial reproductive isolation between univoltine and multivoltine O. furnacalis populations. Such reproductive isolation might impact the potential spread of alleles that confer resistance to transgenic maize in China. PMID- 25024272 TI - Critical care and severe sepsis in resource poor settings. PMID- 25024274 TI - On manhood and Movember ...or why the moustache works. AB - The unprecedented success of the Movember campaign in raising money for, and awareness of, prostate cancer (PCa) brings with it a novel opportunity to consider how masculinity and men's health can connect. In this essay we first detail the history of some less fruitful endeavors for advancing PCa awareness that played on masculine stereotypes. We then consider how Movember's moustache motif has succeeded. Included are commentaries about why the strongly masculine motifs of combat, loyalty, and aggression couched in military language were not successful when used to promote concern about men's health. Movember in contrast succeeds by focusing on a way that men can express their individuality without resorting to overt acts or signs of aggression or militarism. PMID- 25024275 TI - [The Internet as a source of health information: the vision of students of Andalusia, Spain]. PMID- 25024276 TI - Plant community feedbacks and long-term ecosystem responses to multi-factored global change. AB - While short-term plant responses to global change are driven by physiological mechanisms, which are represented relatively well by models, long-term ecosystem responses to global change may be determined by shifts in plant community structure resulting from other ecological phenomena such as interspecific interactions, which are represented poorly by models. In single-factor scenarios, plant communities often adjust to increase ecosystem response to that factor. For instance, some early global change experiments showed that elevated CO2 favours plants that respond strongly to elevated CO2, generally amplifying the response of ecosystem productivity to elevated CO2, a positive community feedback. However, most ecosystems are subject to multiple drivers of change, which can complicate the community feedback effect in ways that are more difficult to generalize. Recent studies have shown that (i) shifts in plant community structure cannot be reliably predicted from short-term plant physiological response to global change and (ii) that the ecosystem response to multi-factored change is commonly less than the sum of its parts. Here, we survey results from long-term field manipulations to examine the role community shifts may play in explaining these common findings. We use a simple model to examine the potential importance of community shifts in governing ecosystem response. Empirical evidence and the model demonstrate that with multi-factored change, the ecosystem response depends on community feedbacks, and that the magnitude of ecosystem response will depend on the relationship between plant response to one factor and plant response to another factor. Tradeoffs in the ability of plants to respond positively to, or to tolerate, different global change drivers may underlie generalizable patterns of covariance in responses to different drivers of change across plant taxa. Mechanistic understanding of these patterns will help predict the community feedbacks that determine long-term ecosystem responses. PMID- 25024277 TI - Growth and physiological adaptation of whole plants and cultured cells from a halophyte turf grass under salt stress. AB - Understanding the mechanisms used by halophytic members of the Poaceae to cope with salt stress will contribute to the knowledge necessary to genetically engineer salt-tolerant crops. In this study, we identified a genotype of Sporobolus virginicus, a halophytic turf grass collected in Japan, and investigated its growth rate, ion concentration and secretion, and proline concentration in comparison with the reported properties of genotypes collected from the USA, South Africa and Egypt. Surprisingly, the Japanese genotype showed a salinity tolerance up to 1.5 M NaCl, a 3-fold higher concentration than seawater salinity. Shoot growth was stimulated by 100 mM NaCl and root growth was stimulated at salinities of up to 1 M NaCl. Accumulation of Na(+) and CI(-) in shoots and roots was rapidly elevated by salinity stress but did not exceed the levels required for osmotic adjustment, due in part to ion secretion by salt glands, which are present in genotypes of S. virginicus. However, the Japanese genotypes accumulated K(+) to a higher level than other genotypes, resulting in a relatively high K(+)/Na(+) ratio even under salinity stress. An increase in proline concentration was observed that was proportional to the NaCl concentration in the culture solution and might partially account for osmotic adjustment in the shoots. We also generated and characterized cultured cells of S. virginicus. In 500 mM NaCl, the cultured cells showed an enhanced growth compared with cultured cells of rice. The concentration of Na(+) and CI(-) in the cultured cells in 300-500 mM NaCl was lower than in 100 mM NaCl. Cultured cells of S. virginicus accumulated proline to higher levels than rice cells cultured under salinity stress. The active regulation of Na(+), Cl(-) and K(+) influx/efflux and proline accumulation might be involved in salt tolerance mechanisms at the cellular level as well as in planta. PMID- 25024279 TI - Linkage analysis and the study of Mendelian disease in the era of whole exome and genome sequencing. AB - Whole exome and whole genome sequencing are now routinely used in the study of inherited disease, and some of their major successes have been the identification of genes involved in disease predisposition in pedigrees where disease seems to follow Mendelian inheritance patterns. These successes include scenarios where only a single individual was sequenced and raise the question whether linkage analysis has become superfluous. Linkage analysis requires genome-wide genotyping on family-based data, and traditionally the linkage analysis was performed before the targeting sequencing stage. However, methods are emerging that seek to exploit the capability of linkage analysis to integrate data both across individuals and across pedigrees. This ability has been exploited to select samples used for sequencing studies and to identify among the variants uncovered by sequencing those mapping to regions likely to contain the gene of interest and, more generally, to improve variant detection. So, although the formal isolated linkage analysis stage is less commonly seen, when uncovering the genetic basis of Mendelian disease, methods relying heavily on genetic linkage analysis principles are being integrated directly into the whole mapping process ranging from sample selection to variant calling and filtering. PMID- 25024278 TI - Parents' self-reported attachment styles: a review of links with parenting behaviors, emotions, and cognitions. AB - For decades, attachment scholars have been investigating how parents' adult attachment orientations relate to the ways in which they parent. Traditionally, this research has been conducted by developmental and clinical psychologists who typically employ the Adult Attachment Interview (AAI) to measure adult attachment. However, dating back to the mid-1990s, social and personality psychologists have been investigating how self-reported adult attachment styles relate to various facets of parenting. The literature on self-reported attachment and parenting has received less attention than AAI research on the same topic and, to date, there is no comprehensive review of this literature. In this article, we review more than 60 studies of the links between self-reported attachment styles and parenting, integrate the findings to reach general conclusions, discuss unresolved questions, and suggest future directions. Finally, we discuss the potential benefits to the study of parenting of collaborations among researchers from the developmental and social attachment research traditions. PMID- 25024280 TI - NS2 is dispensable for efficient assembly of hepatitis C virus-like particles in a bipartite trans-encapsidation system. AB - Infectious hepatitis C virus (HCV) particle production in the genotype 2a JFH-1 based cell culture system involves non-structural proteins in addition to canonical virion components. NS2 has been proposed to act as a protein adaptor, co-ordinating the early stages of virion assembly. However, other studies have identified late-acting roles for this protein, making its precise involvement in infectious particle production unclear. Using a robust, bipartite trans encapsidation system based upon baculovirus expression of HCV structural proteins, we have generated HCV-like particles (HCV-LP) in the absence of NS2 with overt similarity to wild-type virions. HCV-LP could transduce naive cells with trans-encapsidated subgenomic replicon RNAs and shared similar biochemical and biophysical properties with JFH-1 HCV. Both genotype 1b and JFH-1 intracellular HCV-LP were produced in the absence of NS2, whereas restoring NS2 to the JFH-1 system dramatically enhanced secreted infectivity, consistent with a late-acting role. Our system recapitulated authentic HCV particle assembly via trans-complementation of bicistronic, NS2-deleted, chimeric HCV, which is otherwise deficient in particle production. This closely resembled replicon mediated NS2 trans-complementation, confirming that baculovirus expression of HCV proteins did not unduly affect particle production. Furthermore, this suggests that separation of structural protein expression from replicating HCV RNAs that are destined to be packaged alleviates an early stage requirement for NS2 during particle formation. This highlights our current lack of understanding of how NS2 mediates assembly, yet comparison of full-length and bipartite systems may provide further insight into this process. PMID- 25024281 TI - Ultrasensitive detection of PrP(Sc) in the cerebrospinal fluid and blood of macaques infected with bovine spongiform encephalopathy prion. AB - Prion diseases are characterized by the prominent accumulation of the misfolded form of a normal cellular protein (PrP(Sc)) in the central nervous system. The pathological features and biochemical properties of PrP(Sc) in macaque monkeys infected with the bovine spongiform encephalopathy (BSE) prion have been found to be similar to those of human subjects with variant Creutzfeldt-Jakob disease (vCJD). Non-human primate models are thus ideally suited for performing valid diagnostic tests and determining the efficacy of potential therapeutic agents. In the current study, we developed a highly efficient method for in vitro amplification of cynomolgus macaque BSE PrP(Sc). This method involves amplifying PrP(Sc) by protein misfolding cyclic amplification (PMCA) using mouse brain homogenate as a PrP(C) substrate in the presence of sulfated dextran compounds. This method is capable of amplifying very small amounts of PrP(Sc) contained in the cerebrospinal fluid (CSF) and white blood cells (WBCs), as well as in the peripheral tissues of macaques that have been intracerebrally inoculated with the BSE prion. After clinical signs of the disease appeared in three macaques, we detected PrP(Sc) in the CSF by serial PMCA, and the CSF levels of PrP(Sc) tended to increase with disease progression. In addition, PrP(Sc) was detectable in WBCs at the clinical phases of the disease in two of the three macaques. Thus, our highly sensitive, novel method may be useful for furthering the understanding of the tissue distribution of PrP(Sc) in non-human primate models of CJD. PMID- 25024282 TI - Preventing autoimmunity protects against the development of hypertension and renal injury. AB - Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production, and the prevalence of hypertension is increased markedly in this patient population compared with normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or immunoglobulin G antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-alpha expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein-1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation are an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus. PMID- 25024283 TI - Regulatory T cells prevent angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E knockout mice. AB - To test the hypothesis that adoptive transfer of regulatory T cells (Tregs) may dose-dependently inhibit the formation of angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E knockout mice, we established an animal model of abdominal aortic aneurysm by angiotensin II infusion in apolipoprotein E knockout mice. Then mice received different treatment with PBS, low-dose Tregs, high-dose Tregs, or CD25-depleting PC61 antibody. Histopathologic analysis showed that the incidence of abdominal aortic aneurysm was 80%, 76%, 27%, and 71% in the PBS, low dose Tregs, high-dose Tregs, and PC61 groups, respectively. Tregs treatment markedly decreased macrophage and CD4+ T-cell infiltration and preserved the medial smooth muscle cells. Furthermore, Tregs decreased the levels of proinflammatory cytokines, matrix metalloproteinase-2 (MMP-2) and MMP-9, increased the expression of anti-inflammatory interleukin-10 and transforming growth factor-beta, and suppressed apoptosis and oxidative stress. In vitro, Tregs inhibited the response of human aortic smooth muscle cells to angiotensin II and reduced the expression of proinflammatory cytokines, MMP-2 and MMP-9, possibly by inhibiting the activation of nuclear factor-kappaB and extracellular signal-regulate kinase 1/2. In addition, Tregs downregulated macrophage type 1 related genes and upregulated macrophage type 2-related genes. However, Tregs mediated effects were largely reversed by disrupting cell-cell contact or using neutralizing antibodies against interleukin-10 and transforming growth factor beta. Adoptive transfer of Tregs dose-dependently prevents angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E knockout mice. The mechanisms may involve declined proinflammatory cytokine expression and MMP-2 and MMP-9 levels and enhanced anti-inflammatory cytokine expression, which is mediated by direct cell-cell contact and soluble mediators. PMID- 25024284 TI - Cost-benefit analysis of home blood pressure monitoring in hypertension diagnosis and treatment: an insurer perspective. AB - Home blood pressure (BP) monitoring has been shown to be more effective than clinic BP monitoring for diagnosing and treating hypertension. However, reimbursement of home BP monitoring is uncommon in the United States because of a lack of evidence that it is cost beneficial for insurers. We develop a decision analytic model, which we use to conduct a cost-benefit analysis from the perspective of the insurer. Model inputs are derived from the 2008 to 2011 claims data of a private health insurer in the United States, from 2009 to 2010 National Health and the Nutrition Examination Survey data, and from published meta analyses. The model simulates the transitions among health states from initial physician visit to hypertension diagnosis, to treatment, to hypertension-related cardiovascular diseases, and patient death or resignation from the plan. We use the model to estimate cost-benefit ratios and both short- and long-run return on investment for home BP monitoring compared with clinic BP monitoring. Our results suggest that reimbursement of home BP monitoring is cost beneficial from an insurer's perspective for diagnosing and treating hypertension. Depending on the insurance plan and age group categories considered, estimated net savings associated with the use of home BP monitoring range from $33 to $166 per member in the first year and from $415 to $1364 in the long run (10 years). Return on investment ranges from $0.85 to $3.75 per dollar invested in the first year and from $7.50 to $19.34 per dollar invested in the long run. PMID- 25024285 TI - Aortic stiffness and interstitial myocardial fibrosis by native T1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy. AB - Increased aortic stiffness is related to increased ventricular stiffness and remodeling. Myocardial fibrosis is the pathophysiological hallmark of failing heart. We investigated the relationship between noninvasive imaging markers of myocardial fibrosis, native T1, and late gadolinium enhancement, respectively, and aortic stiffness in ventricular remodeling. Consecutive patients with known dilated cardiomyopathy (n=173) underwent assessment of cardiac volumes and function, T1 mapping, scar imaging, and pulse wave velocity, a measure of aortic stiffness. Asymptomatic healthy volunteers served as controls (n=47). Controls and patients showed an increase in pulse wave velocity with age, which was accelerated in the presence of cardiovascular disease. On the contrary, native T1 increased with age in patients, but not in controls. Pulse wave velocity was associated with native T1 in the presence of disease, but not in health. Native T1 showed a strong relationship with markers of structural and functional left ventricular remodeling and diastolic impairment. Ischemic and nonischemic pathophysiology of ventricular remodeling showed a similar slope of relationship between pulse wave velocity and native T1. However, in nonischemic patients, increase in pulse wave velocity was associated with greater increase in native T1. Aortic stiffness is related to age, and this process is accelerated in the presence of disease. On the contrary, increase in interstitial myocardial fibrosis is associated with age in the presence of disease. Patients with ischemic and nonischemic dilated cardiomyopathy have a similar relationship between native T1 and pulse wave velocity, which is stronger in the latter group. PMID- 25024286 TI - Sestrin2 decreases renal oxidative stress, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of reactive oxygen species production. AB - The dopamine D2 receptor (D2R) decreases renal reactive oxygen species (ROS) production and regulates blood pressure, in part, via positive regulation of paraoxonase 2. Sestrin2, a highly conserved antioxidant protein, regulates intracellular ROS level by regenerating hyperoxidized peroxiredoxins. We hypothesized that sestrin2 may be involved in preventing excessive renal ROS production and thus contribute to the maintenance of normal blood pressure. Moreover, the D2R may decrease ROS production, in part, through the regulation of sestrin2. Renal sestrin2 expression was lower (-62+/-13%) in D2R(-/-) than in D2R(+/+) mice. Silencing D2R in human renal proximal tubule cells decreased sestrin2 expression (-53+/-3%) and increased hyperoxidized peroxiredoxins (2.9 fold). Stimulation of D2R in renal proximal tubule cells increased sestrin2 expression (1.6-fold), decreased hyperoxidized peroxiredoxins (-61+/-3%), and reduced ROS production (-31+/-4%). Silencing sestrin2 in renal proximal tubule cells increased hyperoxidized peroxiredoxins (2.1-fold) and ROS production (1.3 fold). Silencing sestrin2 also abolished D2R-induced decrease in peroxiredoxin hyperoxidation and partially prevented the inhibitory effect of D2R stimulation on ROS production. Silencing paraoxonase 2 increased sestrin2 ubiquitinylation (2.8-fold), decreased sestrin2 expression (-30+/-3%), and increased ROS production (1.3-fold), peroxiredoxin hyperoxidation (2.9-fold), and lipid peroxidation (2.3-fold), and blocked the increase in sestrin2 that occurs with D2R stimulation. In vivo renal selective silencing of sestrin2 by the renal subcapsular infusion of sestrin2 small interfering RNA (3 MUg/day; 7 days) in mice increased renal oxidative stress (1.3-fold) and blood pressure. These results suggest that the D2R, via paraoxonase 2 and sestrin2, keeps normal renal redox balance, which contributes to the maintenance of normal blood pressure. PMID- 25024287 TI - Pulse pressure relation to aortic and left ventricular structure in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. AB - High pulse pressure, a major cardiovascular risk factor, has been attributed to medial elastic fiber degeneration and aortic dilation, which transfers hemodynamic load to stiffer collagen. However, recent studies suggest higher pulse pressure is instead associated with smaller aortic diameter. Thus, we sought to elucidate relations of pulse pressure with aortic stiffness and aortic and cardiac dimensions. We used magnetic resonance imaging to examine relationships of pulse pressure with lumen area and wall stiffness and thickness in the thoracic aorta and left ventricular structure in 526 participants (72-94 years of age, 295 women) in the community-based Age, Gene/Environment Susceptibility-Reykjavik Study. In a multivariable model that adjusted for age, sex, height, weight, and standard vascular risk factors, central pulse pressure had a negative relationship with aortic lumen area (all effects expressed as mm Hg/SD; B=-8.1+/-1.2; P<0.001) and positive relationships with left ventricular end-diastolic volume (B=3.8+/-1.0; P<0.001), carotid-femoral pulse wave velocity (B=3.6+/-1.0; P<0.001), and aortic wall area (B=3.0+/-1.2; P=0.015). Higher pulse pressure in older people is associated with smaller aortic lumen area and greater aortic wall stiffness and thickness and left ventricular volume. Relationships of larger ventricular volume and smaller aortic lumen with higher pulse pressure suggest mismatch in hemodynamic load accommodation by the heart and aorta in older people. PMID- 25024288 TI - The Bioinformatics Open Source Conference (BOSC) 2013. PMID- 25024289 TI - Summary of the BioLINK SIG 2013 meeting at ISMB/ECCB 2013. AB - The ISMB Special Interest Group on Linking Literature, Information and Knowledge for Biology (BioLINK) organized a one-day workshop at ISMB/ECCB 2013 in Berlin, Germany. The theme of the workshop was 'Roles for text mining in biomedical knowledge discovery and translational medicine'. This summary reviews the outcomes of the workshop. Meeting themes included concept annotation methods and applications, extraction of biological relationships and the use of text-mined data for biological data analysis. AVAILABILITY AND IMPLEMENTATION: All articles are available at http://biolinksig.org/proceedings-online/. PMID- 25024290 TI - An improved method for computing q-values when the distribution of effect sizes is asymmetric. AB - MOTIVATION: Asymmetry is frequently observed in the empirical distribution of test statistics that results from the analysis of gene expression experiments. This asymmetry indicates an asymmetry in the distribution of effect sizes. A common method for identifying differentially expressed (DE) genes in a gene expression experiment while controlling false discovery rate (FDR) is Storey's q value method. This method ranks genes based solely on the P-values from each gene in the experiment. RESULTS: We propose a method that alters and improves upon the q-value method by taking the sign of the test statistics, in addition to the P values, into account. Through two simulation studies (one involving independent normal data and one involving microarray data), we show that the proposed method, when compared with the traditional q-value method, generally provides a better ranking for genes as well as a higher number of truly DE genes declared to be DE, while still adequately controlling FDR. We illustrate the proposed method by analyzing two microarray datasets, one from an experiment of thale cress seedlings and the other from an experiment of maize leaves. AVAILABILITY AND IMPLEMENTATION: The R code and data files for the proposed method and examples are available at Bioinformatics online. PMID- 25024291 TI - Spike count, spike timing and temporal information in the cortex of awake, freely moving rats. AB - OBJECTIVE: Sensory processing of peripheral information is not stationary but is, in general, a dynamic process related to the behavioral state of the animal. Yet the link between the state of the behavior and the encoding properties of neurons is unclear. This report investigates the impact of the behavioral state on the encoding mechanisms used by cortical neurons for both detection and discrimination of somatosensory stimuli in awake, freely moving, rats. APPROACH: Neuronal activity was recorded from the primary somatosensory cortex of five rats under two different behavioral states (quiet versus whisking) while electrical stimulation of increasing stimulus strength was delivered to the mystacial pad. Information theoretical measures were then used to measure the contribution of different encoding mechanisms to the information carried by neurons in response to the whisker stimulation. MAIN RESULTS: We found that the behavioral state of the animal modulated the total amount of information conveyed by neurons and that the timing of individual spikes increased the information compared to the total count of spikes alone. However, the temporal information, i.e. information exclusively related to when the spikes occur, was not modulated by behavioral state. SIGNIFICANCE: We conclude that information about somatosensory stimuli is modulated by the behavior of the animal and this modulation is mainly expressed in the spike count while the temporal information is more robust to changes in behavioral state. PMID- 25024292 TI - A thin film polyimide mesh microelectrode for chronic epidural electrocorticography recording with enhanced contactability. AB - OBJECTIVE: Epidural electrocorticography (ECoG) activity may be more reliable and stable than single-unit-activity or local field potential. Invasive brain computer interface (BCI) devices are limited by mechanical mismatching and cellular reactive responses due to differences in the elastic modulus and the motion of stiff electrodes. We propose a mesh-shaped electrode to enhance the contactability between surface of dura and electrode. APPROACH: We designed a polyimide (PI) electrode with a mesh pattern for more conformal contact with a curved surface. We compared the contact capability of mesh PI electrodes with conventionally used sheet PI electrode. The electrical properties of the mesh PI electrode were evaluated for four weeks. We recorded the epidural ECoG (eECoG) activity on the surface of rhesus monkey brains while they performed a saccadic task for four months. MAIN RESULTS: The mesh PI electrode showed good contact with the agarose brain surface, as evaluated by visual inspection and signal measurement. It was about 87% accurate in predicting the direction of saccade eye movement. SIGNIFICANCE: Our results indicate that the mesh PI electrode was flexible and good contact on the curved surface and can record eECoG activity maintaining close contact to dura, which was proved by in vivo and in vitro test. PMID- 25024293 TI - Reducing the risk of infection in a 74-year-old man who is to receive prednisone. PMID- 25024294 TI - Nurse supply grows despite shortage fears. PMID- 25024296 TI - When postpublication peer review stings. PMID- 25024297 TI - Quebec hospitals allow inpatient use of weed. PMID- 25024298 TI - Patients and their medical records: it is time to embrace transparency. PMID- 25024299 TI - Pyoderma gangrenosum triggered by red tattoo dye. PMID- 25024300 TI - Portal simplifies medical registration. PMID- 25024301 TI - Peripheral nerve reconstruction with epsilon-caprolactone conduits seeded with vasoactive intestinal peptide gene-transfected mesenchymal stem cells in a rat model. AB - OBJECTIVE: Attempts have been made to improve nerve conduits in peripheral nerve reconstruction. We investigated the potential therapeutic effect of a vasoactive intestinal peptide (VIP), a neuropeptide with neuroprotective, trophic and developmental regulatory actions, in peripheral nerve regeneration in a severe model of nerve injury that was repaired with nerve conduits. APPROACH: The sciatic nerve of each male Wistar rat was transected unilaterally at 10 mm and then repaired with Dl-lactic-epsilon-caprolactone conduits. The rats were treated locally with saline, with the VIP, with adipose-derived mesenchymal stem cells (ASCs) or with ASCs that were transduced with the VIP-expressing lentivirus. The rats with the transected nerve, with no repairs, were used as untreated controls. At 12 weeks post-surgery, we assessed their limb function by measuring the ankle stance angle and the percentage of their muscle mass reduction, and we evaluated the histopathology, immunohistochemistry and morphometry of the myelinated fibers. MAIN RESULTS: The rats that received a single injection of VIP-expressing ASCs showed a significant functional recovery in the ankle stance angle (p = 0.049) and a higher number of myelinated fibers in the middle and distal segments of the operated nerve versus the other groups (p = 0.046). SIGNIFICANCE: These results suggest that utilization of a cellular substrate, plus a VIP source, is a promising method for enhancing nerve regeneration using Dl-lactic-epsilon caprolactone conduits and that this method represents a potential useful clinical approach to repairing peripheral nerve damage. PMID- 25024302 TI - Modeling self-organized spatio-temporal patterns of PIP3 and PTEN during spontaneous cell polarization. AB - During spontaneous cell polarization of Dictyostelium discoideum cells, phosphatidylinositol (3,4,5)-triphoshpate (PIP3) and PTEN (phosphatase tensin homolog) have been identified as key signaling molecules which govern the process of polarization in a self-organized manner. Recent experiments have quantified the spatio-temporal dynamics of these signaling components. Surprisingly, it was found that membrane-bound PTEN can be either in a high or low state, that PIP3 waves were initiated in areas lacking PTEN through an excitable mechanism, and that PIP3 was degraded even though the PTEN concentration remained low. Here we develop a reaction-diffusion model that aims to explain these experimental findings. Our model contains bistable dynamics for PTEN, excitable dynamics for PIP3, and postulates the existence of two species of PTEN with different dephosphorylation rates. We show that our model is able to produce results that are in good qualitative agreement with the experiments, suggesting that our reaction-diffusion model underlies the self-organized spatio-temporal patterns observed in experiments. PMID- 25024303 TI - A prospective study of mediastinal gray-zone lymphoma. AB - Mediastinal B-cell lymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray-zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median age of 33 years (range, 14 to 59 years), and 46% had mediastinal masses >=10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20, and have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.gov (NCT00001337). PMID- 25024304 TI - Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study. AB - This prospective, observational study investigated the utility of Fibtem A5 and Clauss fibrinogen as predictors of progression of postpartum hemorrhage (PPH). A consecutive cohort of 356 women experiencing 1000 to 1500 mL PPH was recruited. Fibtem and fibrinogen were measured and subsequent transfusions, invasive procedures, and bleed volume recorded. Women progressing to 8 U blood products (red blood cells [RBCs] + fresh frozen plasma [FFP] + platelets) had a median (interquartile range) fibrinogen and Fibtem A5 of 2.1 (1.8-3.4) g/L and 12 (7-17) mm, respectively, compared with 3.9 (3.2-4.5) and 19 (17-23) for those not progressing. On multivariate analysis, Fibtem was an independent predictor for progression to bleeds >2500 mL (95% confidence interval [CI], 0.85 [0.77-0.95]). Receiver operating characteristic area under the curve (95% CI) for progression to RBC transfusion was 0.67 (0.60-0.74) for fibrinogen and 0.61 (0.54-0.68) for Fibtem, and progression to >2500 mL was 0.71 (0.61-0.81) and 0.75 (0.66-0.85) for fibrinogen and Fibtem, respectively. Fibtem A5 <10 mm was associated with more prolonged bleeds (median [95% CI], 127 [44-210] compared with 65 [59-71] minutes; P = .018) and longer stay in the high-dependency unit (23.5 [18.4-28.5] compared with 10.8 [9.7-11.8] hours). Fibtem is a rapidly available early biomarker for progression of PPH. PMID- 25024305 TI - Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment. AB - P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 MUg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup. PMID- 25024307 TI - Differential responses of individuals with late-stage dementia to two novel environments: a multimedia room and an interior garden. AB - The purpose of this study was to determine the responses of individuals with advanced dementia to two novel sensory environments in a nursing home facility. The first was a multisensory Snoezelen room; the second was a temporary Japanese garden. Subjects viewed each environment twice a week for 15 minutes during the study. Stress was measured using heart rate and informant-based behavioral changes. By these criteria, the garden-viewing group showed positive behavioral changes while the responses of the subjects in the Snoezelen group were more negative. The response of the subjects' pulse rate was most dramatic. During the 15 minutes in the garden, the average rate (all subjects/all visits) was significantly less than in their residential room. In the Snoezelen room, we detected little or no change. The impact of the garden could also be seen in the negative behavioral signs elicited upon returning the subjects to the garden room after the installation had been replaced with plants and furniture arranged with no formal design. We propose that exposure to a small interior Japanese garden could be an effective intervention for individuals suffering from late stage Alzheimer's disease. PMID- 25024306 TI - Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer's disease brain and correlates with neurofibrillary tangle pathology. AB - Recent genome wide association studies have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer's disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (n = 71) of AD cases and controls from five different brain regions (hippocampus, inferior parietal cortex, inferior temporal cortex, frontal cortex (BA9), and superior and middle temporal gyri). We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-beta peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology. PMID- 25024308 TI - Integration of genomic information in development of pharmacological vascular dementia prevention and treatment strategies. AB - Treatment of hypertension reduces vascular dementia (VaD) risk but not all anti hypertensive drugs (AHDs) are equally effective, suggesting drug-gene interactions. To understand this relationship, publicly accessible databases were searched for genes deregulated in VaD and their interactions with AHDs. Genes that were downregulated in association with VaD were MTHFR, SYK, AGT, and RPGRIP1L. Genes that were upregulated in VaD were MMP9 and VEGFA. TNFSF14, AR, and PHLDB2 were also associated with VaD, however, transcription or protein level changes could not be ascertained. Analysis of gene expression data suggests that AHDs differentially regulate VaD-associated genes. Information about AHD up- or downregulation of VaD-associated genes could be used as an empirical basis for the optimal selection of AHDs in clinical trials and, ultimately, for VaD prevention and treatment. PMID- 25024309 TI - The prevalence of age-related macular degeneration in Alzheimer's disease. AB - BACKGROUND: Age-related macular degeneration (AMD) and Alzheimer's disease (AD) share several features, including the presence of extracellular abnormal deposits associated with neuronal degeneration, drusen, and plaques, respectively. Investigation of any association of AMD and specifically AD is worthwhile but has rarely been done. OBJECTIVES: The aim of this study was to determine the prevalence of AMD in subjects with AD in comparison with an age-matched cognitively normal cohort. METHODS: Cases were defined as those diagnosed with AD using standardized criteria as part of their clinical care, while controls were cognitively intact individuals aged 65 years or more. Dilated retinal photographs were taken, and a range of potentially confounding factors measured including APOE genotype. AMD features were recorded and AMD grades given. RESULTS: Data was collected on 322 controls and 258 cases. While AMD was associated with AD, and the proportion of cases of advanced AMD in AD cases was twice that of controls, when corrected the association was lost. AD was associated with age, the presence of an APOE allele, and smoking, while being 'generally unwell recently' was associated with a reduced risk of AD. CONCLUSION: AD and AMD are both associated with age, but our study does not find evidence they are associated with each other. However the retina offers an opportunity to non-invasively image neuronal tissue, and more sophisticated imaging techniques may shed light on ocular biomarkers of AD. PMID- 25024310 TI - Positive relationship between mortality from Alzheimer's disease and soil metal concentration in mainland China. AB - An imbalance of metal ions is implicated in the development of Alzheimer's disease (AD). We investigated the relationship between the annual mortality of AD and ionic concentration (iron, zinc, copper, and aluminum) in the soil in mainland China. The AD annual mortality data were from 26 provinces and 3 municipal districts within mainland China between the years 1991 and 2000 and provided by the National Death Cause Surveillance Database of China. The ionic concentration in soil was provided by the China State Environmental Protection Bureau, which was published in 1990. The results showed that the relative risk of mortality in the regions with the highest copper concentrations (60-80 mg/kg) reached 2.634 (95% CI: 2.626-2.642) compared with the regions that had the lowest copper concentrations. The relative risk was 1.292 (95% CI: 1.290-1.294) and 1.248 (95% CI: 1.245-1.251) when the soil iron concentrations exceeded 3 mg/kg and 4 mg/kg, respectively. When the soil zinc concentration was over 100 mg/kg and 200 mg/kg, the relative risk was 1.870 (95% CI: 1.859-1.881) and 2.289 (95% CI: 2.276-2.304), respectively. However, the relative risk was 0.560 (95% CI: 0.559-0.561), 0.604 (95% CI: 0.603-0.605), and 0.267 (95% CI: 0.265-0.268) when the soil aluminum concentration was over 6 mg/kg, 7 mg/kg, and 8 mg/kg, respectively. This study suggests that high concentrations of iron and copper in the soil might be associated with the high AD annual mortality in this region in China, while aluminum had no association with AD mortality. PMID- 25024311 TI - Possible association between SNAP-25 single nucleotide polymorphisms and alterations of categorical fluency and functional MRI parameters in Alzheimer's disease. AB - Synaptosomal-associated protein of 25 kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer's disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n = 607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n = 148) and in two groups of age-matched healthy controls (HC1: n = 615 and HC2: n = 310). Results showed that the intronic rs363050 (A) and rs363043 (T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo-parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD. PMID- 25024312 TI - Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer's disease. AB - The amyloid-beta protein precursor/presenilin 1 (AbetaPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on AbetaPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1beta and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AbetaPP/PS1 mouse hippocampus, preventing memory loss. PMID- 25024313 TI - The phoenix from the ashes: cardiovascular autonomic dysfunction in behavioral variant of frontotemporal dementia. AB - BACKGROUND: Patients with autonomic failure may experience postural dizziness, syncope, and falls. Identifying symptomatic dysautonomia in dementia is of importance to ensure appropriate management and reduce risk of falls. OBJECTIVE: The aim of this prospective study is to identify cardiovascular autonomic dysfunction in patients suffering from behavioral variant of frontotemporal dementia (bvFTD), compared to Alzheimer's disease (AD). METHODS: Patients were prospectively recruited from 2009 until 2013. Clinical autonomic function tests were carried out in an Autonomic Unit according to Ewing's cardiovascular battery. Parasympathetic tests included resting heart rate variability, deep breathing, and Valsalva. Sympathetic function tests compromised blood pressure regulation on valsalva, cutaneous cold stimulation, and 70 degrees head up tilt including of plasma noradrenaline. RESULTS: 26 patients (17 female) with bvFTD and 18 patients (10 female) with AD were examined. Mean age of bvFTD was 69 +/- 11 years, AD 74 +/- 9 years. History taking was often not conclusive and did not correlate with autonomic signs. In 42% bvFTD patients and 44% AD patients, autonomic dysfunction was demonstrated. Manifest orthostatic hypotension (OH) was present in 19% of bvFTD and 33% AD patients. Frequency of autonomic dysfunction and orthostatic hypotension did not differ between bvFTD and AD, but were significantly higher than in healthy controls. Autonomic dysfunction was associated with an increased risk of falling (assessed with Tinetti Score). CONCLUSION: This is the first prospective study to elucidate autonomic dysfunction in bvFTD patients. There is a considerable higher frequency of cardiovascular dysfunction and OH in bvFTD. History taking may be not conclusive thus cannot exclude cardiovascular dysautonomia. PMID- 25024314 TI - A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer's dementia. AB - BACKGROUND: ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers. OBJECTIVE: Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer's dementia. METHODS: The study used a randomized, double-blind, placebo- and active controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. RESULTS: The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT 288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting. CONCLUSION: ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer's dementia. PMID- 25024315 TI - Typicality of words produced on a semantic fluency task in amnesic mild cognitive impairment: linguistic analysis and risk of conversion to dementia. AB - Semantic and, to a lesser extent, phonological verbal fluency tasks are impaired in Alzheimer's disease (AD) and in amnesic mild cognitive impairment (aMCI). Furthermore, both fluency tasks have been considered as possible markers of conversion from aMCI to AD. Up to recent years, the use of fluency tasks has been limited to word count, but, more recently, linguistic variables, such as word frequency, age of acquisition, familiarity, and typicality, have also been considered. In particular, attention has been focused on typicality of words produced on semantic verbal fluency tasks, because the tendency to produce only the more typical members of various categories points to an impoverishment of semantic memory. The aim of our study was to compare in aMCI, AD, and control subjects a lexical (word frequency) and a lexical-semantic variable (item typicality) in a semantic verbal fluency task, and to evaluate the possible value of these variables in predicting conversion from aMCI to AD during a 2 years follow-up period. We found no difference in mean typicality of words produced by aMCI and AD subjects whereas both groups produced words of higher mean typicality than control subjects. Furthermore, to assess the relationship between typicality values and risk of conversion to AD, the aMCI group was split in two subgroups, including subjects who obtained a mean typicality value lower or higher than the median value of the whole aMCI group. Consistent with our hypothesis, conversion to AD was significantly more frequent in high typicality than in low typicality subjects. PMID- 25024316 TI - Adapting to dementia in society: a challenge for our lifetimes and a charge for public health. AB - For the last several decades, Alzheimer's disease (AD) has been widely regarded as a late life event, but is now being redefined as a chronic condition that develops over decades. Concurrently, a preponderance of evidence emerging from basic and clinical research in diverse fields such as cardiovascular, endocrine, and mental health has suggested that the environmental component of clinical AD is not only multifactorial in populations and in individuals, but is also modifiable across the life-course, from conception until death. Re conceptualizing the environmental component of AD to account for these observations necessitates an approach to brain health that eschews singular, short- and medium-term methodology and instead reflects long-term complexity. Such thinking is consistent with the ecological models of public health, which emphasize the development of community infrastructure that can foster population and individual health over the life-course by minimizing risk through multifaceted, systemic approaches. PMID- 25024317 TI - Macular pigment, visual function, and macular disease among subjects with Alzheimer's disease: an exploratory study. AB - BACKGROUND: The macula (central retina) contains a yellow pigment, comprising the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin, known as macular pigment (MP). The concentrations of MP's constituent carotenoids in retina and brain tissue correlate, and there is a biologically-plausible rationale, supported by emerging evidence, that MP's constituent carotenoids are also important for cognitive function. OBJECTIVE: To investigate if patients with Alzheimer's disease (AD) are comparable to controls in terms of MP and visual function. METHODS: 36 patients with moderate AD and 33 controls with the same age range participated. MP was measured using dual-wavelength autofluorescence (Heidelberg Spectralis(r)); cognitive function was assessed using a battery of cognition tests (including Cambridge Neuropsychological Test Automated Battery). Visual function was recorded by measuring best corrected visual acuity (BCVA) and contrast sensitivity (CS). Serum L and Z concentrations (by HPLC) and age-related macular degeneration (AMD, by retinal examination) status were also assessed. RESULTS: In the AD group, central MP (i.e., at 0.23 degrees ) and MP volume were significantly lower than the control group (p < 0.001 for both), as were measures of BCVA, CS, and serum L and Z concentrations (p < 0.05, for all). CONCLUSION: AD patients were observed to exhibit significantly less MP, lower serum concentrations of L and Z, poorer vision, and a higher occurrence of AMD when compared to control subjects. A clinical trial in AD patients designed to investigate the impact of macular carotenoid supplementation with respect to MP, visual function, and cognitive function is merited. PMID- 25024318 TI - The dysexecutive syndrome of Alzheimer's disease: the GREFEX study. AB - BACKGROUND: Dysexecutive disorders are common in early-stage Alzheimer's disease (AD) but have yet to be characterized in detail. OBJECTIVE: The objectives of the present study based on validated diagnostic criteria were to determine the frequency and characterize the profile of behavioral and cognitive dysexecutive disorders in AD. METHODS: 102 patients with AD (mild: n = 92; moderate: n = 10; mean MMSE score: 23.2) were examined with the GREFEX battery. Neuropsychological data were interpreted within a validated framework based on the performance levels of 780 control participants from the GREFEX study. RESULTS: Dysexecutive syndrome was observed in 87.5% (95%CI: 79-96) of the AD patients (p = 0.0001). The dysexecutive disorder profile was characterized by prominent impairments of planning, inhibition flexibility and generation in the cognitive domain (p = 0.0001 as compared to controls for all) and global hypoactivity in the behavioral domain (p = 0.0001 as compared to controls). CONCLUSIONS: Dysexecutive syndrome is observed in over 80% of AD patients and has a distinct profile. PMID- 25024319 TI - Novel multipotent AChEI-CCB attenuates hyperhomocysteinemia-induced memory deficits and Neuropathologies in rats. AB - Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3beta. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD. PMID- 25024320 TI - Is there more to subjective cognitive impairment than meets the eye? Raising awareness. PMID- 25024321 TI - A mutation in the 5'-UTR of GRN gene associated with frontotemporal lobar degeneration: phenotypic variability and possible pathogenetic mechanisms. AB - Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5' splice site A > G in the 5'-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5' splice site A > G mutation widens the GRN regions affected by null mutations, including the 5'-UTR, and confirms once more the large phenotypic variability linked to GRN mutations. PMID- 25024322 TI - Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer's disease. AB - BACKGROUND: An increase in YKL-40 levels seems to correlate with disease severity and poor prognosis in many diseases, including several neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). Specifically, YKL-40 protein is increased in mild AD with respect to controls, both in cerebrospinal fluid (CSF) and plasma. OBJECTIVE: We hypothesize that subjects in the preclinical (Pre-AD) and prodromal (Prod-AD) stage of AD could already present an increase in CSF YKL-40 levels with respect to healthy controls and idiopathic REM sleep behavior disorder (iRBD) subjects, included as a control group of a distinct neurological disease. METHODS: We measured CSF YKL-40 levels using a commercial ELISA kit in a cohort of 95 subjects, consisting of controls (n = 43), Pre-AD (n = 18), Prod-AD (n = 22), and iRBD (n = 12) subjects. We explored for possible correlations of YKL-40 levels with demographic characteristics, a wide battery of neuropsychological tests, and the AD CSF biomarkers: amyloid-beta42 (Abeta42), total-tau protein (t-tau), and phosphorylated-tau protein (p-tau). RESULTS: We detected statistically significant differences between Prod-AD patients and controls. YKL-40 levels showed a significant correlation with t-tau and p-tau levels in the predementia AD continuum and the Pre-AD group. We also observed significant correlations with the MMSE, FCSRT, and M@T tests within the AD continuum, but not in iRBD subjects. CONCLUSION: Our data suggest that CSF YKL-40 levels, although not useful as a diagnostic marker for Prod-AD, may be a valuable marker to detect early physiopathological changes potentially linked with the neurodegenerative process. PMID- 25024323 TI - The efficacy and safety of atypical antipsychotics for the treatment of dementia: a meta-analysis of randomized placebo-controlled trials. AB - BACKGROUND: The application of atypical antipsychotics (SGAs) for treatment of psychiatric and behavioral symptoms of dementia is controversial since their efficacy might be offset by their adverse events (AEs). OBJECTIVE: To assess the efficacy, safety, and tolerability of SGAs for treatment of psychological and behavioral symptoms of dementia. METHODS: Two researchers searched MEDLINE, PsychINFO, and the Cochrane Central Register of Controlled Trials independently for double-blind, placebo-controlled, randomized controlled trials (DB-PC-RCTs) as of June 2013, written in English. Efficacy was measured using the Brief Psychiatric Rating Scale (BPRS), Cohen-Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI), Clinical Global Impression of Change (CGI-C), and (or) Clinical Global Impression of Severity (CGI-S). Safety and tolerability were measured by frequencies of drop-outs, AEs, and death. In total, 19 treatment comparisons drawn from 16 DB-PC-RCTs were included, and 3,343 patients randomized to the antipsychotic group and 1,707 to the placebo group were assessed. RESULTS: This meta-analysis demonstrated a significant efficacy of atypical antipsychotics on BPRS (MD = -1.58, 95% CI = -2.52 - -0.65), CMAI (-1.84, -3.01 - -0.61), NPI ( 2.81, -4.35 - -1.28), CGI-C (-0.32, -0.44 - -0.20), and CGI-S (-0.19, -0.30 - 0.09), compared to placebo (p < 0.01 for all). Patients receiving atypical antipsychotics showed no difference in risk for discontinuation (p > 0.05), significantly higher risks (p < 0.05 for all) for somnolence (OR = 2.95), extrapyramidal symptoms (1.74), cerebrovascular AEs (2.50), urinary tract infection (1.35), edema (1.80), gait abnormality (3.35), and death (1.52), and a lower risk for agitation (OR = 0.80, p = 0.03). CONCLUSIONS: The higher risks for AEs and mortality may offset the efficacy of atypical antipsychotics for treatment of dementia. Efficacy, safety, and tolerability thus should be carefully considered against clinical need. PMID- 25024324 TI - Cholinesterase inhibitors: cardioprotection in Alzheimer's disease. AB - Alzheimer's disease is a life shortening disease, and the lack of disease modifying therapy implies a huge impact on life expectancy as well as an outgrowing financial and socioeconomic burden. Cholinesterase inhibitors (ChEIs) represent the first line symptomatic therapy, whose benefit to harm ratio is still a matter of debate. Acetylcholinesterase enzyme is a core interest for pharmacological and toxicological research to unmask the fine balance between therapeutic drug efficacy, tolerability, safety, and detrimental effects up to adverse drug reaction. So far, a body of evidence advocated that an increased vagal tone was associated to an increased risk of gastrointestinal and cardiac side effects (negative chronotropic, arrhytmogenic, hypotensive effects), able to hamper ChEIs effects on cognition, reducing administration feasibility and compliance, especially in older and comorbid patients. Conversely, a growing body of evidence is indicating a protective role of ChEIs on overall cardiovascular mortality in patients with dementia, through a series of in vitro and in vivo investigations. The present review is aimed to report the up to date literature in the controversial field of ChEIs and cardioprotection in dementia, offering a state of the art, which may constitute the conceptual framework to be enlarged in order to build higher evidence. Chronic vagal nerve stimulation acted upon by donepezil might improve long term survival through pharmacological properties apart from cholinesterase inhibition, able to offer cardioprotection, abating the overall cardiovascular risk, and, thus profiling a new line of therapeutic intervention for ChEI drug class. PMID- 25024325 TI - Biomarkers for preclinical Alzheimer's disease. AB - Currently, there is a pressing need to shift the focus to accurate detection of the earliest phase of increasingly preclinical Alzheimer's disease (AD). Meanwhile, the growing recognition that the pathophysiological process of AD begins many years prior to clinically obvious symptoms and the concept of a presymptomatic or preclinical stage of AD are becoming more widely accepted. Advances in clinical identification of new measurements will be critical not only in the discovery of sensitive, specific, and reliable biomarkers of preclinical AD but also in the development of tests that will aid in the early detection and differential diagnosis of dementia and in monitoring disease progression. The goal of this review is to provide an overview of biomarkers for preclinical AD, with emphasis on neuroimaging and neurochemical biomarkers. We conclude with a discussion of emergent directions for AD biomarker research. PMID- 25024326 TI - Association of diabetes mellitus and mild cognitive impairment in middle-aged men and women. AB - BACKGROUND: Several studies reported on the association of type 2 diabetes (T2DM) with dementia. Studies on the association of T2DM and mild cognitive impairment (MCI) are rare. OBJECTIVE: To evaluate the gender-specific association of T2DM with MCI and MCI subtypes (amnestic MCI (aMCI) and non-amnestic MCI (naMCI)) in a middle-aged (50-65 years) and old-aged (66-80 years) population-based study sample. METHODS: We compared 560 participants with MCI (aMCI n = 289, naMCI n = 271) with 1,376 cognitively normal participants from the Heinz Nixdorf Recall study. Diabetic status was based on self-reported physician's diagnosis or treatment with anti-diabetic medication. We performed group comparisons regarding all cognitive subtests for participants with and without T2DM. Logistic regression models (adjusted for age, education, cardiovascular risk factors, and depression) were used to determine the association of T2DM with MCI and MCI subtypes. RESULTS: In the middle-aged group, fully adjusted models showed an association (odds ratio, 95% CI) of T2DM with MCI that was more pronounced in men (total: 2.03, 1.23-3.36, men: 2.16, 1.12-4.14, women 1.69, 0.73-3.89). T2DM was associated with MCI subtypes (aMCI: 2.01, 1.08-3.73; naMCI: 2.06, 1.06-3.98), whereas, the association was stronger with naMCI in men (2.61, 1.14-5.98) and with aMCI in women (3.02, 1.27-7.17). We found no total or gender-specific association of T2DM with MCI or MCI subtypes in the old-aged group. CONCLUSIONS: Our data show that T2DM is associated with MCI and MCI subtypes in middle-aged, but not in old-aged participants. Furthermore, the results indicate a gender specific vulnerability of T2DM on cognition, especially in MCI subtypes. PMID- 25024327 TI - The potential therapeutic effects of THC on Alzheimer's disease. AB - The purpose of this study was to investigate the potential therapeutic qualities of Delta9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-beta protein precursor (AbetaPP) cells were incubated with THC and assayed for amyloid-beta (Abeta) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Abeta level in N2a/AbetaPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti Abeta aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3beta (GSK-3beta) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Abeta levels in N2a/AbetaPPswe cells at extremely low concentrations in a dose dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Abeta peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3beta levels and phosphorylated GSK-3beta in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways. PMID- 25024328 TI - Depression in mild cognitive impairment is associated with progression to Alzheimer's disease: a longitudinal study. AB - BACKGROUND: Behavioral and psychological signs and symptoms of dementia (BPSD) belong to the core symptoms of dementia and are also common in mild cognitive impairment (MCI). OBJECTIVE: This study would like to contribute to the understanding of the prognostic role of BPSD in MCI for the progression to dementia due to Alzheimer's disease (AD). METHODS: Data were generated through an ongoing prospective longitudinal study on BPSD. Assessment was performed by means of the Middelheim Frontality Score, Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale 30-questions (GDS-30). Cox proportional hazard models were used to test the hypothesis that certain BPSD in MCI are predictors of developing AD. RESULTS: The study population consisted of 183 MCI patients at baseline. At follow-up, 74 patients were stable and 109 patients progressed to AD. The presence of significant depressive symptoms in MCI as measured by the CSDD (HR: 2.06; 95% CI: 1.23-3.44; p = 0.011) and the GDS-30 (HR: 1.77; 95% CI: 1.10-2.85; p = 0.025) were associated with progression to AD. The severity of depressive symptoms as measured by the GDS-30 was a predictor for progression too (HR: 1.06; 95% CI: 1.01-1.11; p = 0.020). Furthermore, the severity of agitated behavior, especially verbal agitation and the presence of purposeless activity, was also associated with progression, whereas diurnal rhythm disturbances were associated with no progression to AD. CONCLUSION: Depressive symptoms in MCI appear to be predictors for progression to AD. PMID- 25024329 TI - Neuropsychological syndromes associated with Alzheimer's/vascular dementia: a latent class analysis. AB - BACKGROUND: Epidemiologic autopsy studies show mixed Alzheimer's disease (AD)/vascular pathology in many patients. Moreover, clinical research shows that it is not uncommon for AD and vascular dementia (VaD) patients to be equally impaired on memory, executive, or other neurocognitive tests. However, this clinical heterogeneity has not been incorporated into the new diagnostic criteria for AD (Dubois et al., 2010; McKhann et al., 2011). OBJECTIVE: The current research applied Latent Class Analysis (LCA) to a protocol of six neuropsychological parameters to identify phenotypic subtypes from a large group of AD/VaD participants. Follow-up analyses examined difference between groups on neuroradiological parameters and neuropsychological measures of process and errors. METHODS: 223 AD/VaD patients were administered a comprehensive neuropsychological protocol. Measures of whole brain and hippocampal volume were available for a portion of the sample (n = 76). RESULTS: LCA identified four distinct groups: moderate/mixed dementia (n = 54; 24.21%), mild/mixed dementia (n = 91; 40.80%); dysexecutive (n = 49, 21.97%), and amnestic (n = 29, 13.00%). Follow-up analyses comparing the groups on neuropsychological process and error scores showed that the dysexecutive group exhibited difficulty sustaining mental set. The moderate/mixed group evidenced pronounced impairment on tests of lexical retrieval/naming along with significant amnesia. Amnestic patients also presented with gross amnesia, but showed relative sparing on other neuropsychological measures. Mild/mixed patients exhibited milder memory deficits that were intermediary between the amnestic and moderate/mixed groups. CONCLUSIONS: There are distinct neuropsychological profiles in patients independent of clinical diagnosis, suggesting that the two are not wholly separate and that this information should be integrated into new AD diagnostic paradigms. PMID- 25024330 TI - Fibroblast aggregation rate converges with validated peripheral biomarkers for Alzheimer's disease. AB - The inaccuracy of the diagnosis for Alzheimer's disease (AD) has made its therapeutic intervention difficult, particularly early enough to prevent significant neurodegeneration and cognitive dysfunction. Here, we describe a novel, highly accurate peripheral diagnostic for AD patients based on quantitatively measured aggregation rate of human skin fibroblasts. The elevated aggregation rate with increasing cell density in AD cases is the basis of this new biomarker. The new biomarker was successfully cross-validated with two more mature assays, AD-Index, based on the imbalances of ERK1/2, and Morphology, based on network dynamics, and showed 92% overlap. A significant number of cases tested with this new biomarker were freshly obtained (n = 29), and 82% of the cases are hyper-validated cases, i.e., autopsy and/or genetically confirmed AD or non Alzheimer's disease demented patients (Non-ADD) and non-demented age-matched controls. Furthermore, we show that by using a simple majority rule, i.e., two out of the three assays have the same outcome, we significantly increase the agreement with clinical AD diagnosis (100%). Based on the high accuracy of this strategy, the biomarker profile appears to accurately identify AD patients for therapeutic intervention. PMID- 25024331 TI - Circulating miRNAs as potential biomarkers in Alzheimer's disease. AB - Several micro(mi)RNA are deregulated in brain, cerebrospinal fluid (CSF), and serum/plasma from patients with Alzheimer's disease (AD). The aim of the study was to profile circulating miRNAs in serum as non-invasive biomarkers for AD, correlating them with those identified in CSF, the biological fluid which better reflects biochemical changes occurring during pathological processes in the brain and may provide a robust indicator of AD-related disease pathogenesis thanks to the evidence of low amyloid and high levels of tau and hyperphosphorylated tau. Using a two-step analysis (array and validation through real-time PCR), a down regulation (mean fold change +/- SEM) of miR-125b (0.415 +/- 0.11 versus 1.381 +/ 0.36, p = 0.009), miR-23a (0.111 +/- 0.03 versus 0.732 +/- 0.14, p < 0.001), and miR-26b (0.414 +/- 0.11 versus 1.353 +/- 0.39, p < 0.01), out of 84 tested, was shown in serum from 22 AD patients compared with 18 non-inflammatory and 8 inflammatory neurological controls (NINDCs and INDCs) and 10 patients with frontotemporal dementia. Significant down-regulation of miR-125b and miR-26b was also confirmed in CSF from AD patients versus NINDCs (miR-125b: 0.089 +/- 0.03 versus 0.230 +/- 0.08, p < 0.001; miR-26b: 0.217 +/- 0.06 versus 1.255 +/- 0.29, p < 0.001, mean fold change +/- SEM, respectively), whereas data were not replicated for miR-23a. In serum, miR-125b had an AUC of 0.82 to distinguish AD from NINDCs (95% CI: 0.65-0.98, p = 0.005). In conclusion, we demonstrated that cell-free miR-125b serum levels are decreased in serum from patients with AD as compared with NINDC and distinguish between AD and NINDCs with an accuracy of 82%. PMID- 25024332 TI - Upregulation of miR-181 decreases c-Fos and SIRT-1 in the hippocampus of 3xTg-AD mice. AB - MicroRNAs are a group of small RNAs that regulate diverse cellular processes including neuronal function. Recent studies have shown that dysregulation of specific microRNAs is critically involved in the development of Alzheimer's disease (AD). Most of these reports have focused on microRNAs implicated in alterations of amyloid-beta and tau. However, studies exploring the relation between microRNAs dysregulation in AD and synaptic plasticity are scarce despite the well-known involvement of microRNAs in synaptic plasticity. Since impairments in synaptic plasticity and neuronal loss are two important features displayed in AD patients, it is feasible to hypothesize that alterations in plasticity-related microRNAs underlie AD progression. Here, levels of a small number of microRNAs implicated in normal neuronal function and/or plasticity were examined in an AD model. Twelve-month old 3xTg-AD mice with plaques and tangles presented a significant upregulation of miR-181 in the hippocampus compared to age-matched wild type mice. Increased miR-181 was not detected in pre-pathological 3xTg-AD mice. Analysis of predicted targets of miR-181 identified c-Fos and SIRT-1, proteins critically involved in memory formation. Both c-Fos and SIRT-1 levels were significantly decreased in the ventral hippocampus of twelve-month old 3xTg AD mice. Overexpression of miR-181 in SH-SY5Y cells significantly decreased c-Fos and SIRT-1, strongly suggesting that miR-181 directly regulates the expression of these two proteins. These findings indicate a connection between miR-181 and proteins involve in synaptic plasticity and memory processing in a transgenic mouse model of AD. Our results suggest that microRNAs involved in synaptic plasticity might be an important factor that contributes to AD neuropathology. PMID- 25024333 TI - Grey matter changes associated with deficit awareness in mild cognitive impairment: a voxel-based morphometry study. AB - Reduced awareness of cognitive deficits in mild cognitive impairment (MCI) is associated with poorer outcomes although little is known about the anatomical correlates of this. We examined the association of insight and grey matter volume using a voxel-based morphometry approach in 65 volunteers with MCI and 55 healthy age-matched controls. Participants with MCI had multiple areas of subtle grey matter volume loss compared with controls, although these did not survive correction for multiple comparisons. These were predominantly in the temporal and anterior portions of the brain. Individuals with MCI did not differ from each other on a number of demographic and cognitive variables according to level of insight. Reduced awareness of cognitive deficits was associated with few differences in grey matter volume apart from a subtle loss of grey matter in the medial frontal gyri. Given the modest nature of these findings, the routine assessment of insight in non-clinical populations of individuals with MCI is therefore not supported. Prospective data in larger samples, however, would be helpful to clarify this further and determine if impaired insight predicts brain atrophy and cognitive decline. PMID- 25024334 TI - Alzheimer's disease costs: what we know and what we should take into account. AB - BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is a very costly pathology. Total costs of AD result from the sum of direct and indirect costs. Intangible costs represent an additional burden that is difficult to quantify. This paper has reviewed the evaluation of the costs of AD and the methodologies to estimate them, and proposes the use of some tools which may be useful in establishing the financial weight of the disease. METHOD: A systematic literature search was conducted using the Pubmed and Medline databases as a source of published papers. RESULTS: In AD, direct and indirect costs and their sum (total costs) are very high and tend to increase parallel with the evolution of the pathology. The evolution of AD is characterized by the loss of functional autonomy, the onset of behavioral and sleep disorders, and the development of delusions and hallucinations. This requires more frequent medical examinations and hospitalizations resulting in higher direct costs, which become the relevant weight. None of the papers reviewed investigated intangible cost. CONCLUSION: The calculation of costs of AD is frequently based on cognitive decline and the degree of dependence of patients. The evaluation of intangible costs (psychological pain of the patient and of the unpaid caregivers' and their impaired quality of life) is a missing aspect in all reviewed studies. Due to the complexity of AD, it will be necessary to adopt cost evaluation systems including the different dimensions of the problem and its various aspects. PMID- 25024335 TI - Cognitive dysfunctions in middle-aged type 2 diabetic patients and neuroimaging correlations: a cross-sectional study. AB - BACKGROUND/OBJECTIVE: The aim was to assess the neuropsychological performance of a group of middle-aged patients with well-controlled type 2 diabetes mellitus (T2DM) and to examine whether the neuropsychological deficits correlate with structural and functional brain alterations. METHODS: We compared 25 subjects with T2DM aged 45-65 years with 25 control participants matched for age, gender, and educational level. The neuropsychological battery was designed to examine executive functions, attention, information processing speed, and verbal memory. Severity of depression was assessed using the Hamilton Depression Rating Scale and cardiovascular risk factors were assessed using the Framingham Cardiovascular Risk Profile Score. The presence of at least one APOEepsilon4 allele was determined. Reduced gray matter density was analyzed using voxel-based morphometry and brain glucose metabolic changes were assessed by 18FDG-PET. RESULTS: T2DM subjects had significantly lower scores than subjects without T2DM in the Trail-making Test B (p < 0.004), Color-Word Stroop test (p < 0.005), Semantic Fluency (p < 0.006), Digit-Symbol modalities test (p < 0.02), Text Recall from the Wechsler Memory Scale (p < 0.0001), Rey-Osterrieth Complex Figure copy (p < 0.004), and delayed reproduction (p < 0.03). Worse executive functions and memory functioning correlated predominantly with less gray matter density and reduced glucose metabolism in the orbital and prefrontal cortex, temporal (middle gyrus, parahippocampus and uncus), and cerebellum regions (p < 0.001). CONCLUSIONS: T2DM subjects presented cognitive dysfunctions compared with controls. Clinical-neuroimaging correlations corresponded to brain changes (reduced gray matter density and glucose metabolism) mainly in fronto-temporal areas. PMID- 25024336 TI - Increased levels of hyaluronic acid in cerebrospinal fluid in patients with vascular dementia. AB - Hyaluronic acid (HA) has been shown to affect angiogenesis and the function of the blood-brain barrier, and a crucial role for HA in atherosclerosis has been described. We have recently demonstrated changes in the levels of HA in cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) with documented vascular alterations. To further investigate if the level of HA in CSF can be used as a clinical diagnostic biomarker to identify vascular pathology in dementia, we analyzed the levels of HA in the CSF of patients with vascular dementia (VaD) (n = 46), AD (n = 45), and controls without dementia (n = 26). In line with our previous data, we found significantly increased levels of HA in CSF from patients with VaD compared with controls, whereas the levels of HA in patients with AD were found to be unaltered compared with controls and patients with VaD. We also detected increased levels of HA in individuals with vascular changes determined as significant white matter changes or previous infarction on cranial computed tomography or magnetic resonance imaging, compared with individuals without these findings. Furthermore, we found a significant positive correlation between the levels of HA and the CSF/serum albumin ratio, an indicator of blood-brain barrier integrity, in patients with VaD and AD, supporting the role of HA in vascular changes in the brain. Our results indicate a potential diagnostic value for the detection of vascular brain changes in dementia using CSF levels of HA, but emphasize the importance of further development of more sensitive HA assays. PMID- 25024337 TI - Apathy and APOE4 are associated with reduced BDNF levels in Alzheimer's disease. AB - Reduced brain-derived neurotrophic factor (BDNF) signaling is considered as a pathogenic event in early Alzheimer's disease (AD), but the influence of apathy and apolipoprotein E epsilon4 allele (APOE4) on serum BDNF values was not previously investigated in AD. We evaluated serum BDNF levels in AD, amnestic mild cognitive impairment (MCI), and control subjects. Baseline BDNF levels were similar in AD, MCI, and controls. AD patients having apathy showed lower BDNF values than patients without apathy (p < 0.05). After correction for the influence of apathy, APOE4 carriers showed lower BDNF levels (p < 0.01) and MMSE scores (p < 0.01) than non-APOE4 carriers in the subgroup of AD females, but not in males. Significant (p < 0.05) positive correlations between BDNF values and MMSE scores were only observed in subgroups of AD males and of AD patients without apathy. These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers. PMID- 25024338 TI - Midlife vascular risk factors and the risk of Alzheimer's disease: a systematic review and meta-analysis. AB - BACKGROUND/OBJECTIVE: We examine whether midlife vascular risk factors (VRFs) are associated with increased risk of incident Alzheimer's disease (AD) in a systematic review and meta-analysis of published cohort studies. METHODS: Original cohort studies were included if they reported adjusted combined odds ratio (COR) and corresponding 95% confidence intervals (CIs) or enough information to quantify the association between risk for AD in late-life and baseline VRFs of midlife. RESULTS: There were positive and significant associations between high blood pressure (COR 1.31; 95% CI: 1.01-1.70), hypercholesterolemia (COR 1.72; 95% CI: 1.32-2.24), obesity (COR 1.88; 95% CI: 1.32-2.69), and diabetes mellitus in midlife (COR 1.4; 95% CI: 1.25-1.57). Smoking and hyperhomocysteinemia (although only one high-quality paper) were also associated with an increased risk of AD generally. CONCLUSIONS: These results strengthen the epidemiological evidence that VRFs of midlife significantly increase risk for AD. PMID- 25024339 TI - RanBP9 modulates AICD localization and transcriptional activity via direct interaction with Tip60. AB - Proteolytic processing of the amyloid-beta protein precursor (AbetaPP) occurs via alternative pathways, culminating with the production of the AbetaPP intracellular domain (AICD). AICD can translocate to the nucleus and regulate transcription, but its activity is modulated by interactions with other proteins. In the nucleus, AICD, FE65, and Tip60 associate into AFT complexes, which are targeted to nuclear spots which correspond to transcription factories. Here we report that RanBP9 interacts with the cytoplasmic domain of AbetaPP, through the NPXY internalization motif. Moreover, RanBP9 interaction with Tip60 is also described. The RanBP9-Tip60 interaction dramatically relocated RanBP9 from a widespread cellular distribution to nuclear speckles. AbetaPP processing is a central aspect in determining the protein's function and that of its resulting proteolytic fragments, among them AICD. The latter results from the amyloidogenic pathway and is the peptidic species predominantly involved in nuclear signaling. Of note RanBP9 transfection was previously demonstrated to increase amyloid-beta generation. Here we show that RanBP9 relocates AICD to the Tip60-enriched nuclear speckles, and prevented the formation of nuclear spots formation, having therefore a negative effect on AICD mediated nuclear signaling and consequently AFT complex formation. Furthermore, by transfecting cells with increasing amounts of RanBP9, the expression of AICD-regulated genes, including AbetaPP itself, was reduced. Given the data presented, one can deduce that RanBP9 has an inhibitory regulatory effect on AICD-mediated transcription and the effect is mediated by relocating AICD away from transcription factories. PMID- 25024340 TI - OXPHOS, pyrimidine nucleotides, and Alzheimer's disease: a pharmacogenomics approach. AB - We present a new hypothesis on the contribution of a dysfunction of the oxidative phosphorylation system, through a decrease in the de novo synthesis of pyrimidine nucleotides, to the pathogenesis of late onset Alzheimer's disease (AD). In the light of this proposition, different treatments for AD patients, such as enhancing the electron flow downstream the coenzyme Q10 of the mitochondrial respiratory chain or increasing mitochondrial biogenesis or directly providing pyrimidines, would be possible. AD is a multifactorial disorder and not all patients would benefit from these treatments. Those healthy individuals harboring mtDNA haplotypes related to a coupled OXPHOS function would probably be the better candidates for these preventive therapies. PMID- 25024341 TI - Autoantibodies to GM1 and GQ1balpha are not biological markers of Alzheimer's disease. AB - A few studies have reported the association of autoantibodies to GM1 or GQ1balpha with Alzheimer's disease (AD) or vascular dementia. Here we investigated whether patients with AD or vascular dementia had high titers of the anti-ganglioside antibodies. Sera were obtained from patients with AD (n = 22), vascular dementia (n = 14), Guillain-Barre syndrome, and multifocal motor neuropathy as well as normal controls. Enzyme-linked immunosorbent assay showed titers of IgG and IgM anti-GM1, anti-GQ1balpha, and anti-GT1aalpha antibodies did not differ among AD, vascular dementia, and normal controls, and being remarkably lower than those in Guillain-Barre syndrome and multifocal motor neuropathy. The anti-ganglioside antibodies are not biological markers of AD. PMID- 25024342 TI - Age-associated changes of brain copper, iron, and zinc in Alzheimer's disease and dementia with Lewy bodies. AB - Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p < 0.001) and iron higher (10-16%; p < 0.001) in severe AD compared with controls. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age associated changes in brain elements warrant further investigation. PMID- 25024343 TI - Multidimensional prognostic index in a cognitive impairment outpatient setting: mortality and hospitalizations. The Treviso Dementia (TREDEM) study. AB - BACKGROUND: The Multidimensional Prognostic Index (MPI) based on a comprehensive geriatric assessment has been developed to predict mortality in hospitalized elderly patients. The Treviso Dementia (TREDEM) Study is an observational prospective cohort study of 1,364 outpatients evaluated at the Cognitive Impairment Center in Treviso, Italy from 2000 to January 2010. OBJECTIVE: To use the MPI in the TREDEM outpatient setting to assess the correlation of MPI with mortality and hospitalizations for acute cases that occurred after the date of assessment. METHODS: MPI was consecutively applied to the last 340 of 1,364 outpatients who were evaluated at the Center from 2008 to January 2010, after the first publication of MPI index in 2008. Participants' mortality was verified by linking the cohort with Registries of Municipalities, National Register of Revenue Authorities, and Nominal Register of Causes of Death. Data about hospitalizations for acute cases that occurred within 12 months after the date of assessment were obtained from all Italian hospitals. A Cox regression method was used to investigate the effect of MPI upon mortality and hospitalizations, also considering confounder factors such as age and gender. RESULTS: 114 men and 226 women, aged 52.1-99 years (mean age 80.4 years), were studied and had an MPI mean of 0.41. On 15 February 2013, 100 were deceased, and average hospitalizations for acute cases were 0.3, days 3.8. For MPI scores between 0 and 1, the increase in the probability of death was more than nine times (odds: 9.53 p = 0.0002) and of hospitalization was more than six times (odds: 6.50, p = 0.0079). CONCLUSION: MPI discloses the risk of death and of hospitalizations for acute cases in outpatients affected by cognitive impairment. PMID- 25024344 TI - Dietary supplementation of walnuts improves memory deficits and learning skills in transgenic mouse model of Alzheimer's disease. AB - Previous in vitro studies have shown that walnut extract can inhibit amyloid-beta (Abeta) fibrillization, can solubilize its fibrils, and has a protective effect against Abeta-induced oxidative stress and cellular death. In this study, we analyzed the effect of dietary supplementation with walnuts on learning skills, memory, anxiety, locomotor activity, and motor coordination in the Tg2576 transgenic (tg) mouse model of Alzheimer's disease (AD-tg). From the age of 4 months, the experimental groups of AD-tg mice were fed custom-mixed diets containing 6% walnuts (T6) or 9% walnuts (T9), i.e., equivalent to 1 or 1.5 oz, respectively, of walnuts per day in humans. The control groups, i.e., AD-tg and wild-type mice, were fed a diet without walnuts (T0, Wt). These experimental and control mice were examined at the ages of 13-14 months by Morris water maze (for spatial memory and learning ability), T maze (for position discrimination learning ability), rotarod (for psychomotor coordination), and elevated plus maze (for anxiety-related behavior). AD-tg mice on the control diet (T0) showed memory deficit, anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability, and motor coordination compared to the Wt mice on the same diet. The AD-tg mice receiving the diets with 6% or 9% walnuts (T6 and T9) showed a significant improvement in memory, learning ability, anxiety, and motor development compared to the AD-tg mice on the control diet (T0). There was no statistically significant difference in behavioral performance between the T6/T9 mice on walnuts-enriched diets and the Wt group on the control diet. These findings suggest that dietary supplementation with walnuts may have a beneficial effect in reducing the risk, delaying the onset, or slowing the progression of, or preventing AD. PMID- 25024346 TI - Repetitive pupil light reflex: potential marker in Alzheimer's disease? AB - It was investigated whether alterations of the pupil's light reflex might reflect Alzheimer's disease (AD) pathology. Changes in the pupil's system might be expected due to AD pathology present in the oculomotor system of the Edinger Westphal nucleus, and a cholinergic deficit caused by degeneration of the nucleus basalis Meynert. A rather new method of repetitive light stimulation was applied assessing variations in pupil size, latency, and amplitude over time. We analyzed 44 healthy controls, 42 subjects with mild cognitive impairment (MCI), and 66 AD patients. AD and MCI showed a less pronounced pupil size decrease and amplitude increase over time than controls. A higher MMSE was associated with a higher increase of relative amplitude and greater decrease of latency in AD and MCI, and absolute amplitude increase in AD alone. Pupil size increase correlated with cerebrospinal fluid markers in AD. Summarized pupil light reflex is not stable under repetitive stimulation, but changes systematically and less pronounced in AD and MCI. Thus repetitive stimulation of the pupil's response potentially indicates AD pathology. PMID- 25024345 TI - Validation of a serum screen for Alzheimer's disease across assay platforms, species, and tissues. AB - BACKGROUND: There is a significant need for rapid and cost-effective biomarkers of Alzheimer's disease (AD) for advancement of clinical practice and therapeutic trials. OBJECTIVE: The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson's disease, PD). METHODS: Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were analyzed from 49 PD cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD versus AD versus controls. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD. RESULTS: Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90 100% of the samples. SVM analyses were highly accurate at distinguishing PD versus AD versus controls. CONCLUSIONS: This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers. PMID- 25024347 TI - Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer's disease transgenic mice. AB - Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimer's disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AbetaPPSwe/PS1DeltaE9 (AbetaPP * PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AbetaPP * PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition. PMID- 25024348 TI - Somatic signature of brain-specific single nucleotide variations in sporadic Alzheimer's disease. AB - BACKGROUND: Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown. OBJECTIVE: The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. METHODS: By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. RESULTS: We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. CONCLUSION: Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals. PMID- 25024349 TI - Cofilin rods and aggregates concur with tau pathology and the development of Alzheimer's disease. AB - BACKGROUND: Imaging of human brain as well as cellular and animal models has highlighted a role for the actin cytoskeleton in the development of cell pathology in Alzheimer's disease (AD). Rods and aggregates of the actin associated protein cofilin are abundant in grey matter of postmortem AD brain and rods are found inside neurites in animal and cell models of AD. OBJECTIVE: We sought further understanding of the significance of cofilin rods/aggregates to the disease process: Do rods/aggregates correlate with AD progression and the development of hallmark neurofibrillary tangles and neuropil threads? Are cofilin rods/aggregates found in the same neurites as hyperphosphorylated tau? METHODS: The specificity of rods/aggregates to AD compared with general aging and their spatial relationship to tau protein was examined in postmortem human hippocampus, inferior temporal cortex, and anterior cingulate cortex. RESULTS: The presence of cofilin rods/aggregates correlated with the extent of tau pathology independent of patient age. Densities of rods/aggregates were fourfold greater in AD compared with aged-matched control brains and rods/aggregates were significantly larger in AD brain. We did not find evidence for our hypothesis that intracellular cofilin rods are localized to tau-positive neuropil threads. Instead, data suggest the involvement of microglia in the clearance of cofilin rods/aggregates and/or in their synthesis in and around amyloid plaques and surrounding neuropil. CONCLUSION: Cofilin rods and aggregates signify events initiated early in the pathological cascade. Further definition of the mechanisms leading to their formation in the human brain will provide insights into the cellular causes of AD. PMID- 25024350 TI - OMICtools: an informative directory for multi-omic data analysis. AB - Recent advances in 'omic' technologies have created unprecedented opportunities for biological research, but current software and database resources are extremely fragmented. OMICtools is a manually curated metadatabase that provides an overview of more than 4400 web-accessible tools related to genomics, transcriptomics, proteomics and metabolomics. All tools have been classified by omic technologies (next-generation sequencing, microarray, mass spectrometry and nuclear magnetic resonance) associated with published evaluations of tool performance. Information about each tool is derived either from a diverse set of developers, the scientific literature or from spontaneous submissions. OMICtools is expected to serve as a useful didactic resource not only for bioinformaticians but also for experimental researchers and clinicians. Database URL: http://omictools.com/. PMID- 25024351 TI - yStreX: yeast stress expression database. AB - Over the past decade genome-wide expression analyses have been often used to study how expression of genes changes in response to various environmental stresses. Many of these studies (such as effects of oxygen concentration, temperature stress, low pH stress, osmotic stress, depletion or limitation of nutrients, addition of different chemical compounds, etc.) have been conducted in the unicellular Eukaryal model, yeast Saccharomyces cerevisiae. However, the lack of a unifying or integrated, bioinformatics platform that would permit efficient and rapid use of all these existing data remain an important issue. To facilitate research by exploiting existing transcription data in the field of yeast physiology, we have developed the yStreX database. It is an online repository of analyzed gene expression data from curated data sets from different studies that capture genome-wide transcriptional changes in response to diverse environmental transitions. The first aim of this online database is to facilitate comparison of cross-platform and cross-laboratory gene expression data. Additionally, we performed different expression analyses, meta-analyses and gene set enrichment analyses; and the results are also deposited in this database. Lastly, we constructed a user-friendly Web interface with interactive visualization to provide intuitive access and to display the queried data for users with no background in bioinformatics. Database URL: http://www.ystrexdb.com. PMID- 25024352 TI - Woman with history of hiding her pregnancies can be removed from her home, court rules. PMID- 25024353 TI - The global peripheral chemoreflex drive in patients with systemic sclerosis: a rebreathing and exercise study. AB - BACKGROUND: Exercise intolerance (EI) in systemic sclerosis (SSc) is difficult to manage by the clinician. The peripheral chemoreflex drive compensates for metabolic acidosis during exercise and may be related to EI. AIM: To assess the global peripheral chemoreflex drive (GPCD) in patients with SSc at rest and during exercise. METHODS: Consecutively tested SSc patients (n = 49) were evaluated by pulmonary function tests, carbon dioxide (CO2) rebreathing studies and non-invasive cardiopulmonary exercise testing (CPET). Results of their CO2 rebreathing tests were compared with those of controls (n = 32). Respiratory compensation for metabolic acidosis during CPET was defined by the occurrence of a sharp increase in minute ventilation (VdotE) and the ventilatory equivalent for CO2 (V'E and V'CO2) at the end of the isocapnic buffer phase. Euoxic (eVHR) and hyperoxic (hVHR) ventilatory responses to hypercapnia were measured and its difference (eVHR - hVHR) was considered to reflect the GPCD. RESULTS: In 45 patients with SSc, CPET results showed respiratory compensation at the occurrence of metabolic acidosis. eVHR - hVHR in patients with diffuse cutaneous SSc (dcSSc) differed significantly from that in patients with limited cutaneous SSc (lcSSc) and from that in controls (0.47 +/- 0.38 (dcSSc) vs. 0.90 +/- 0.77 (lcSSc) and 0.90 +/- 0.49 (controls) l/min/mmHg; P = 0.04 and P = 0.03, respectively). CONCLUSIONS: Respiratory compensation for metabolic acidosis occurred in all patients. However, the GPCD was diminished in dcSSc patients, suggesting an altered control of breathing. Its assessment may help the clinician to better understand reported EI and exertional dyspnea in dcSSc patients. PMID- 25024354 TI - An unusual case of metastatic renal clear cell carcinoma presented as a solitary subcutaneous mass invading the manubrium. PMID- 25024355 TI - Moth-eaten essential syphilitic alopecia. PMID- 25024356 TI - The association between chronic obstructive pulmonary disease and Parkinson's disease: a nationwide population-based retrospective cohort study. AB - OBJECTIVE: Previous research has shown that patients with chronic obstructive pulmonary disease (COPD) tend to have a higher risk for cognitive impairment and dementia, a neurodegenerative disorder. The goal of this study was to examine what relationship, if any, exists between COPD and Parkinson's disease (PD), which is also a neurodegenerative disorder. METHOD: Our study analyzed medical data from the population of Taiwan from 1998 to 2008, with a follow-up period extending to the end of 2010. We identified patients with COPD by the Taiwan National Health Insurance Research Database (NHIRD). We selected a comparison cohort from the general population that was random frequency-matched by age (in 5 year increments), sex and index year, and further analyzed the risk of PD using Cox's regression model, including sex, age and comorbidities. RESULTS: The study enrolled 20 728 COPD patients (71.1% male, mean age = 68.2 years) and 41 147 controls. The risk of developing PD was 1.37 times greater in patients with COPD compared with patients without COPD after adjusting for age, sex and comorbidities. A significantly increased risk of PD was also found in patients with COPD who had any comorbidity other than diabetes. CONCLUSION: This nationwide retrospective cohort study demonstrates that PD risk is significantly increased in patients with COPD compared with those of the general population. PMID- 25024359 TI - Point/counterpoint: is there a role for radiotherapy in the treatment of primary CNS lymphoma? PMID- 25024357 TI - Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer. AB - While previous studies reported aberrant expression of microRNAs (miRNAs) in non small cell lung cancer (NSCLC), little is known about which miRNAs play central roles in NSCLC's pathogenesis and its regulatory mechanisms. To address this issue, we presented a robust computational framework that integrated matched miRNA and mRNA expression profiles in NSCLC using feed-forward loops. The network consists of miRNAs, transcription factors (TFs), and their common predicted target genes. To discern the biological meaning of their associations, we introduced the direction of regulation. A network edge validation strategy using three independent NSCLC expression profiling data sets pinpointed reproducible biological regulations. Reproducible regulation, which may reflect the true molecular interaction, has not been applied to miRNA-TF co-regulatory network analyses in cancer or other diseases yet. We revealed eight hub miRNAs that connected to a higher proportion of targets validated by independent data sets. Network analyses showed that these miRNAs might have strong oncogenic characteristics. Furthermore, we identified a novel miRNA-TF co-regulatory module that potentially suppresses the tumor suppressor activity of the TGF-beta pathway by targeting a core pathway molecule (TGFBR2). Follow-up experiments showed two miRNAs (miR-9-5p and miR-130b-3p) in this module had increased expression while their target gene TGFBR2 had decreased expression in a cohort of human NSCLC. Moreover, we demonstrated these two miRNAs directly bind to the 3' untranslated region of TGFBR2. This study enhanced our understanding of miRNA-TF co-regulatory mechanisms in NSCLC. The combined bioinformatics and validation approach we described can be applied to study other types of diseases. PMID- 25024361 TI - Effect of apoptotic cell recognition on macrophage polarization and mycobacterial persistence. AB - Intracellular Mycobacterium leprae infection modifies host macrophage programming, creating a protective niche for bacterial survival. The milieu regulating cellular apoptosis in the tissue plays an important role in defining susceptible and/or resistant phenotypes. A higher density of apoptotic cells has been demonstrated in paucibacillary leprosy lesions than in multibacillary ones. However, the effect of apoptotic cell removal on M. leprae-stimulated cells has yet to be fully elucidated. In this study, we investigated whether apoptotic cell removal (efferocytosis) induces different phenotypes in proinflammatory (Mphi1) and anti-inflammatory (Mphi2) macrophages in the presence of M. leprae. We stimulated Mphi1 and Mphi2 cells with M. leprae in the presence or absence of apoptotic cells and subsequently evaluated the M. leprae uptake, cell phenotype, and cytokine pattern in the supernatants. In the presence of M. leprae and apoptotic cells, Mphi1 macrophages changed their phenotype to resemble the Mphi2 phenotype, displaying increased CD163 and SRA-I expression as well as higher phagocytic capacity. Efferocytosis increased M. leprae survival in Mphi1 cells, accompanied by reduced interleukin-15 (IL-15) and IL-6 levels and increased transforming growth factor beta (TGF-beta) and IL-10 secretion. Mphi1 cells primed with M. leprae in the presence of apoptotic cells induced the secretion of Th2 cytokines IL-4 and IL-13 in autologous T cells compared with cultures stimulated with M. leprae or apoptotic cells alone. Efferocytosis did not alter the Mphi2 cell phenotype or cytokine secretion profile, except for TGF-beta. Based on these data, we suggest that, in paucibacillary leprosy patients, efferocytosis contributes to mycobacterial persistence by increasing the Mphi2 population and sustaining the infection. PMID- 25024362 TI - Protection against Mycobacterium leprae infection by the ID83/GLA-SE and ID93/GLA SE vaccines developed for tuberculosis. AB - Despite the dramatic reduction in the number of leprosy cases worldwide in the 1990s, transmission of the causative agent, Mycobacterium leprae, is still occurring, and new cases continue to appear. New strategies are required in the pursuit of leprosy elimination. The cross-application of vaccines in development for tuberculosis may lead to tools applicable to elimination of leprosy. In this report, we demonstrate that the chimeric fusion proteins ID83 and ID93, developed as antigens for tuberculosis (TB) vaccine candidates, elicited gamma interferon (IFN-gamma) responses from both TB and paucibacillary (PB) leprosy patients and from healthy household contacts of multibacillary (MB) patients (HHC) but not from nonexposed healthy controls. Immunization of mice with either protein formulated with a Toll-like receptor 4 ligand (TLR4L)-containing adjuvant (glucopyranosyl lipid adjuvant in a stable emulsion [GLA-SE]) stimulated antigen specific IFN-gamma secretion from pluripotent Th1 cells. When immunized mice were experimentally infected with M. leprae, both cellular infiltration into the local lymph node and bacterial growth at the site were reduced relative to those of unimmunized mice. Thus, the use of the Mycobacterium tuberculosis candidate vaccines ID83/GLA-SE and ID93/GLA-SE may confer cross-protection against M. leprae infection. Our data suggest these vaccines could potentially be used as an additional control measure for leprosy. PMID- 25024363 TI - Asymptomatic carriage of group A streptococcus is associated with elimination of capsule production. AB - Humans commonly carry pathogenic bacteria asymptomatically, but despite decades of study, the underlying molecular contributors remain poorly understood. Here, we show that a group A streptococcus carriage strain contains a frameshift mutation in the hasA gene resulting in loss of hyaluronic acid capsule biosynthesis. This mutation was repaired by allelic replacement, resulting in restoration of capsule production in the isogenic derivative strain. The "repaired" isogenic strain was significantly more virulent than the carriage strain in a mouse model of necrotizing fasciitis and had enhanced growth ex vivo in human blood. Importantly, the repaired isogenic strain colonized the mouse oropharynx with significantly greater bacterial burden and had significantly reduced ability to internalize into cultured epithelial cells than the acapsular carriage strain. We conducted full-genome sequencing of 81 strains cultured serially from 19 epidemiologically unrelated human subjects and discovered the common theme that mutations negatively affecting capsule biosynthesis arise in vivo in the has operon. The significantly decreased capsule production is a key factor contributing to the molecular detente between pathogen and host. Our discoveries suggest a general model for bacterial pathogens in which mutations that downregulate or ablate virulence factor production contribute to carriage. PMID- 25024364 TI - Aggregatibacter actinomycetemcomitans outer membrane vesicles are internalized in human host cells and trigger NOD1- and NOD2-dependent NF-kappaB activation. AB - Aggregatibacter actinomycetemcomitans is an oral and systemic pathogen associated with aggressive forms of periodontitis and with endocarditis. We recently demonstrated that outer membrane vesicles (OMVs) disseminated by A. actinomycetemcomitans could deliver multiple proteins, including biologically active cytolethal distending toxin (CDT), into the cytosol of HeLa cells and human gingival fibroblasts (HGF). In the present work, we have used immunoelectron and confocal microscopy analysis and fluorescently labeled vesicles to further investigate mechanisms for A. actinomycetemcomitans OMV mediated delivery of bacterial antigens to these host cells. Our results supported that OMVs were internalized into the perinuclear region of HeLa cells and HGF. Colocalization analysis revealed that internalized OMVs colocalized with the endoplasmic reticulum and carried antigens, detected using an antibody specific to whole A. actinomycetemcomitans serotype a cells. Consistent with OMV internalization mediating intracellular antigen exposure, the vesicles acted as strong inducers of cytoplasmic peptidoglycan sensor NOD1- and NOD2-dependent NF kappaB activation in human embryonic kidney cells. Moreover, NOD1 was the main sensor of OMV-delivered peptidoglycan in myeloid THP1 cells, contributing to the overall inflammatory responses induced by the vesicles. This work reveals a role of A. actinomycetemcomitans OMVs as a trigger of innate immunity via carriage of NOD1- and NOD2-active pathogen-associated molecular patterns (PAMPs). PMID- 25024365 TI - An optimized, synthetic DNA vaccine encoding the toxin A and toxin B receptor binding domains of Clostridium difficile induces protective antibody responses in vivo. AB - Clostridium difficile-associated disease (CDAD) constitutes a large majority of nosocomial diarrhea cases in industrialized nations and is mediated by the effects of two secreted toxins, toxin A (TcdA) and toxin B (TcdB). Patients who develop strong antitoxin antibody responses can clear C. difficile infection and remain disease free. Key toxin-neutralizing epitopes have been found within the carboxy-terminal receptor binding domains (RBDs) of TcdA and TcdB, which has generated interest in developing the RBD as a viable vaccine target. While numerous platforms have been studied, very little data describes the potential of DNA vaccination against CDAD. Therefore, we created highly optimized plasmids encoding the RBDs from TcdA and TcdB in which any putative N-linked glycosylation sites were altered. Mice and nonhuman primates were immunized intramuscularly, followed by in vivo electroporation, and in these animal models, vaccination induced significant levels of both anti-RBD antibodies (blood and stool) and RBD specific antibody-secreting cells. Further characterization revealed that sera from immunized mice and nonhuman primates could detect RBD protein from transfected cells, as well as neutralize purified toxins in an in vitro cytotoxicity assay. Mice that were immunized with plasmids or given nonhuman primate sera were protected from a lethal challenge with purified TcdA and/or TcdB. Moreover, immunized mice were significantly protected when challenged with C. difficile spores from homologous (VPI 10463) and heterologous, epidemic (UK1) strains. These data demonstrate the robust immunogenicity and efficacy of a TcdA/B RBD-based DNA vaccine in preclinical models of acute toxin-associated and intragastric, spore-induced colonic disease. PMID- 25024366 TI - Role for streptococcal collagen-like protein 1 in M1T1 group A Streptococcus resistance to neutrophil extracellular traps. AB - Streptococcal collagen-like protein 1 (Scl-1) is one of the most highly expressed proteins in the invasive M1T1 serotype group A Streptococcus (GAS), a globally disseminated clone associated with higher risk of severe invasive infections. Previous studies using recombinant Scl-1 protein suggested a role in cell attachment and binding and inhibition of serum proteins. Here, we studied the contribution of Scl-1 to the virulence of the M1T1 clone in the physiological context of the live bacterium by generating an isogenic strain lacking the scl-1 gene. Upon subcutaneous infection in mice, wild-type bacteria induced larger lesions than the Deltascl mutant. However, loss of Scl-1 did not alter bacterial adherence to or invasion of skin keratinocytes. We found instead that Scl-1 plays a critical role in GAS resistance to human and murine phagocytic cells, allowing the bacteria to persist at the site of infection. Phenotypic analyses demonstrated that Scl-1 mediates bacterial survival in neutrophil extracellular traps (NETs) and protects GAS from antimicrobial peptides found within the NETs. Additionally, Scl-1 interferes with myeloperoxidase (MPO) release, a prerequisite for NET production, thereby suppressing NET formation. We conclude that Scl-1 is a virulence determinant in the M1T1 GAS clone, allowing GAS to subvert innate immune functions that are critical in clearing bacterial infections. PMID- 25024367 TI - Pathogenic bacterial species associated with endodontic infection evade innate immune control by disabling neutrophils. AB - Endodontic infections, in which oral bacteria access the tooth pulp chamber, are common and do not resolve once established. To investigate the effects of these infections on the innate immune response, we established a mouse subcutaneous chamber model, where a mixture of four oral pathogens commonly associated with these infections (endodontic pathogens [EP]), i.e., Fusobacterium nucleatum, Streptococcus intermedius, Parvimonas micra, and Prevotella intermedia, was inoculated into subcutaneously implanted titanium chambers. Cells that infiltrated the chamber after these infections were primarily neutrophils; however, these neutrophils were unable to control the infection. Infection with a nonpathogenic oral bacterial species, Streptococcus mitis, resulted in well controlled infection, with bacterial numbers reduced by 4 to 5 log units after 7 days. Propidium iodide (PI) staining of the chamber neutrophils identified three distinct populations: neutrophils from EP-infected chambers were intermediate in PI staining, while cells in chambers from mice infected with S. mitis were PI positive (apoptotic) or negative (live). Strikingly, neutrophils from EP-infected chambers were severely impaired in their ability to phagocytose and to generate reactive oxygen species in vitro after removal from the chamber compared to cells from S. mitis-infected chambers. The mechanism of neutrophil impairment was necrotic cell death as determined by morphological analyses. P. intermedia alone could induce a similar neutrophil phenotype. We conclude that the endodontic pathogens, particularly P. intermedia, can efficiently disable and kill infiltrating neutrophils, allowing these infections to become established. These results can help explain the persistence of endodontic infections and demonstrate a new virulence mechanism associated with P. intermedia. PMID- 25024368 TI - Use of transgenic parasites and host reporters to dissect events that promote interleukin-12 production during toxoplasmosis. AB - The intracellular parasite Toxoplasma gondii has multiple strategies to alter host cell function, including the injection of rhoptry proteins into the cytosol of host cells as well as bystander populations, but the consequence of these events is unclear. Here, a reporter system using fluorescent parasite strains that inject Cre recombinase with their rhoptry proteins (Toxoplasma-Cre) was combined with Ai6 Cre reporter mice to identify cells that have been productively infected, that have been rhoptry injected but lack the parasite, or that have phagocytosed T. gondii. The ability to distinguish these host-parasite interactions was then utilized to dissect the events that lead to the production of interleukin-12 p40 (IL-12p40), which is required for resistance to T. gondii. In vivo, the use of invasion-competent or invasion-inhibited (phagocytosed) parasites with IL-12p40 (YET40) reporter mice revealed that dendritic cell (DC) and macrophage populations that phagocytose the parasite or are infected can express IL-12p40 but are not the major source, as larger numbers of uninfected cells secrete this cytokine. Similarly, the use of Toxoplasma-Cre parasite strains indicated that dendritic cells and inflammatory monocytes untouched by the parasite and not cells injected by the parasite are the primary source of IL 12p40. These results imply that a soluble host or parasite factor is responsible for the bulk of IL-12p40 production in vivo, rather than cellular interactions with T. gondii that result in infection, infection and clearance, injection of rhoptry proteins, or phagocytosis of the parasite. PMID- 25024369 TI - Type II Toxoplasma gondii induction of CD40 on infected macrophages enhances interleukin-12 responses. AB - Toxoplasma gondii is an obligate intracellular parasite that can cause severe neurological disease in infected humans. CD40 is a receptor on macrophages that plays a critical role in controlling T. gondii infection. We examined the regulation of CD40 on the surface of T. gondii-infected bone marrow-derived macrophages (BMdMs). T. gondii induced CD40 expression both at the transcript level and on the cell surface, and interestingly, the effect was parasite strain specific: CD40 levels were dramatically increased in type II T. gondii-infected BMdMs compared to type I- or type III-infected cells. Type II induction of CD40 was specific to cells harboring intracellular parasites and detectable as early as 6 h postinfection (hpi) at the transcript level. CD40 protein expression peaked at 18 hpi. Using forward genetics with progeny from a type II * type III cross, we found that CD40 induction mapped to a region of chromosome X that included the gene encoding the dense granule protein 15 (GRA15). Using type I parasites stably expressing the type II allele of GRA15 (GRA15II), we found that type I GRA15II parasites induced the expression of CD40 on infected cells in an NF-kappaB-dependent manner. In addition, stable expression of hemagglutinin tagged GRA15II in THP-1 cells resulted in CD40 upregulation in the absence of infection. Since CD40 signaling contributes to interleukin-12 (IL-12) production, we examined IL-12 from infected macrophages and found that CD40L engagement of CD40 amplified the IL-12 response in type II-infected cells. These data indicate that GRA15II induction of CD40 promotes parasite immunity through the production of IL-12. PMID- 25024370 TI - Early induction of interleukin-10 limits antigen-specific CD4+ T cell expansion, function, and secondary recall responses during persistent phagosomal infection. AB - Diverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4(+) T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen specific CD4(+) T cells during persistent Ehrlichia muris infection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistent Ehrlichia infection. Notably, we demonstrated that the functional production of gamma interferon (IFN-gamma) by antigen-specific CD4(+) T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-gamma production by antigen-specific CD4(+) T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4(+) T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4(+) T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4(+) T cells may provide a basis to induce a protective immune response against persistent infections. PMID- 25024371 TI - The Legionella longbeachae Icm/Dot substrate SidC selectively binds phosphatidylinositol 4-phosphate with nanomolar affinity and promotes pathogen vacuole-endoplasmic reticulum interactions. AB - Legionella spp. cause the severe pneumonia Legionnaires' disease. The environmental bacteria replicate intracellularly in free-living amoebae and human alveolar macrophages within a distinct, endoplasmic reticulum (ER)-derived compartment termed the Legionella-containing vacuole (LCV). LCV formation requires the bacterial Icm/Dot type IV secretion system (T4SS) that translocates into host cells a plethora of different "effector" proteins, some of which anchor to the pathogen vacuole by binding to phosphoinositide (PI) lipids. Here, we identified by unbiased pulldown assays in Legionella longbeachae lysates a 111 kDa SidC homologue as the major phosphatidylinositol 4-phosphate [PtdIns(4)P] binding protein. The PI-binding domain was mapped to a 20-kDa P4C [PtdIns(4)P binding of SidC] fragment. Isothermal titration calorimetry revealed that SidC of L. longbeachae (SidC(Llo)) binds PtdIns(4)P with a K(d) (dissociation constant) of 71 nM, which is 3 to 4 times lower than that of the SidC orthologue of Legionella pneumophila (SidC(Lpn)). Upon infection of RAW 264.7 macrophages with L. longbeachae, endogenous SidC(Llo) or ectopically produced SidC(Lpn) localized in an Icm/Dot-dependent manner to the PtdIns(4)P-positive LCVs. An L. longbeachae DeltasidC deletion mutant was impaired for calnexin recruitment to LCVs in Dictyostelium discoideum amoebae and outcompeted by wild-type bacteria in Acanthamoeba castellanii. Calnexin recruitment was restored by SidC(Llo) or its orthologues SidC(Lpn) and SdcA(Lpn). Conversely, calnexin recruitment was restored by SidC(Llo) in L. pneumophila lacking sidC and sdcA. Together, biochemical, genetic, and cell biological data indicate that SidC(Llo) is an L. longbeachae effector that binds through a P4C domain with high affinity to PtdIns(4)P on LCVs, promotes ER recruitment to the LCV, and thus plays a role in pathogen-host interactions. PMID- 25024372 TI - FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. AB - Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARalpha KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARalpha KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain. PMID- 25024373 TI - Myeloperoxidase deletion prevents high-fat diet-induced obesity and insulin resistance. AB - Activation of myeloperoxidase (MPO), a heme protein primarily expressed in granules of neutrophils, is associated with the development of obesity. However, whether MPO mediates high-fat diet (HFD)-induced obesity and obesity-associated insulin resistance remains to be determined. Here, we found that consumption of an HFD resulted in neutrophil infiltration and enhanced MPO expression and activity in epididymal white adipose tissue, with an increase in body weight gain and impaired insulin signaling. MPO knockout (MPO(-/-)) mice were protected from HFD-enhanced body weight gain and insulin resistance. The MPO inhibitor 4 aminobenzoic acid hydrazide reduced peroxidase activity of neutrophils and prevented HFD-enhanced insulin resistance. MPO deficiency caused high body temperature via upregulation of uncoupling protein-1 and mitochondrial oxygen consumption in brown adipose tissue. Lack of MPO also attenuated HFD-induced macrophage infiltration and expression of proinflammatory cytokines. We conclude that activation of MPO in adipose tissue contributes to the development of obesity and obesity-associated insulin resistance. Inhibition of MPO may be a potential strategy for prevention and treatment of obesity and insulin resistance. PMID- 25024374 TI - Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release. AB - Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDH(H454Y)) result in fasting and amino acid-induced hypoglycemia in hyperinsulinemia hyperammonemia (HI/HA). Surprisingly, hypoglycemia may occur in this disorder despite appropriately suppressed insulin. To better understand the islet-specific contribution, transgenic mice expressing the human activating mutation in beta-cells (H454Y mice) were characterized in vivo. As in the humans with HI/HA, H454Y mice had fasting hypoglycemia, but plasma insulin concentrations were similar to the controls. Paradoxically, both glucose- and glutamine-stimulated insulin secretion were severely impaired in H454Y mice. Instead, lack of a glucagon response during hypoglycemic clamps identified impaired counterregulation. Moreover, both insulin and glucagon secretion were impaired in perifused islets. Acute pharmacologic inhibition of GDH restored both insulin and glucagon secretion and normalized glucose tolerance in vivo. These studies support the presence of an mtGTP-dependent signal generated via beta-cell GDH that inhibits alpha-cells. As such, in children with activating GDH mutations of HI/HA, this insulin-independent glucagon suppression may contribute importantly to symptomatic hypoglycemia. The identification of a human mutation causing congenital hypoglucagonemic hypoglycemia highlights a central role of the mtGTP-GDH-glucagon axis in glucose homeostasis. PMID- 25024375 TI - Negative regulation of DsbA-L gene expression by the transcription factor Sp1. AB - Disulfide-bond A oxidoreductase-like protein (DsbA-L) possesses beneficial effects such as promoting adiponectin multimerization and stability, increasing insulin sensitivity, and enhancing energy metabolism. The expression level of DsbA-L is negatively correlated with obesity in mice and humans, but the underlying mechanisms remain unknown. To address this question, we generated reporter gene constructs containing the promoter sequence of the mouse DsbA-L gene. Deletion analysis showed that the proximal promoter of mouse DsbA-L is located between -186 and -34 bp relative to the transcription start site. In silico analysis identified a putative Sp1 transcription factor binding site in the first intron of the DsbA-L gene. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 bound to this intron region in vitro and in intact cells. Overexpression of Sp1 or suppressing Sp1 expression by siRNA reduced or increased DsbA-L promoter activity, respectively. The binding activity of Sp1 was gradually decreased during 3T3-L1 cell differentiation and was significantly increased in adipose tissues of obese mice. Our results identify Sp1 as an inhibitor of DsbA-L gene transcription, and the Sp1-mediated inhibition of DsbA-L gene expression may provide a mechanism underlying obesity-induced adiponectin downregulation and insulin resistance. PMID- 25024376 TI - Giant pseudoaneurysm on left ventricular posterolateral wall with an orifice between papillary muscles. AB - A left ventricular pseudoaneurysm develops when myocardial rupture is contained by the pericardium. Although left ventricular pseudoaneurysm has been a topic of discussion since the pioneering days of open heart surgery, it still remains a technical challenge in reconstructive cardiac surgery. Reoperation following pseudoaneurysm repair is also frequent. We report surgical treatment in two patients with a pseudoaneurysm on the left ventricular posterolateral wall. The pseudoaneurysm and left ventricular cavity communicated at a point just between the anterolateral and posteromedial papillary muscle attachments. Such a manifestation is highly infrequent but potentially lethal. During aneurysmectomy, special attention was paid to avoid the development of mitral regurgitation because the papillary muscle geometry changes after removal of the pseudoaneurysm. In both cases, surgical decision-making was facilitated by preoperative assessment using electrocardiographic-gated multislice computed tomography. PMID- 25024377 TI - The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling. AB - IL-17 is a proinflammatory cytokine implicated in the pathogenesis of autoimmune diseases including psoriasis. ACT1 is an essential adaptor molecule in the IL-17 signaling pathway. A missense single nucleotide polymorphism (rs33980500; SNP D10N) that resulted in the substitution of an asparagine for an aspartic acid at position 10 of ACT1 (ACT1-D10N) is associated with psoriasis susceptibility. Due to alternative splicing in humans, SNP-D10N encodes two mutated ACT1 proteins, ACT1-D10N and ACT1-D19N. Although both ACT1 isoforms are Hsp90 client proteins, the nine additional amino acids in ACT1-D19N provide an additional Hsp90 binding site that is absent in ACT1-D10N. Therefore, whereas ACT1-D10N is a dead protein that is unable to transduce IL-17 signals for gene expression, ACT1-D19N is fully responsive to IL-17. Intriguingly, the two ACT1 isoforms are differentially expressed in ACT1(D10N/D10N) fibroblasts and T cells. Fibroblasts express both isoforms equally, enabling ACT1-D19N to compensate for the loss of ACT1-D10N function. ACT1(D10N/D10N) T cells, however, express predominantly ACT1-D10N. Lacking this compensatory mechanism, ACT1(D10N/D10N) T cells behave like ACT1 deficient T cells, exhibiting a dysregulated and hyperactive Th17 phenotype with overproduction of IL-22 and IL-17. The hyperactive Th17 response combined with fully responsive fibroblasts likely synergized to contribute to psoriasis susceptibility in SNP-D10N patients. PMID- 25024378 TI - Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1. AB - Canonical neutrophil antimicrobial effector mechanisms, such as degranulation, production of reactive oxygen species, and release of neutrophil extracellular traps (NETs), can result in severe pathology. Activation of neutrophils through immune complexes (ICs) plays a central role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report that immobilized ICs (iICs), which are hallmarks of several autoimmune diseases, induce the release of NETs from primary human neutrophils. The iIC-induced NET formation was found to require production of reactive oxygen species by NADPH oxidase and myeloperoxidase and to be mediated by FcgammaRIIIb. Blocking of the beta2 integrin macrophage-1 Ag but not lymphocyte function-associated Ag-1 abolished iIC-induced NET formation. This suggests that FcgammaRIIIb signals in association with macrophage-1 Ag. As intracellular signaling pathways involved in iIC-induced NET formation we identified the tyrosine kinase Src/Syk pathway, which downstream regulates the PI3K/Akt, p38 MAPK, and ERK1/2 pathways. To our knowledge, the present study shows for the first time that iICs induce NET formation. Thus, we conclude that NETs contribute to pathology in autoimmune inflammatory disorders associated with surface-bound ICs. PMID- 25024379 TI - The NKG2D ligand ULBP2 is specifically regulated through an invariant chain dependent endosomal pathway. AB - Soluble ULBP2 is a marker for poor prognosis in several types of cancer. In this study we demonstrate that both soluble and cell surface-bound ULBP2 is transported via a so far unrecognized endosomal pathway. ULBP2 surface expression, but not MICA/B, could specifically be targeted and retained by affecting endosomal/lysosomal integrity and protein kinase C activity. The invariant chain was further essential for endosomal transport of ULBP2. This novel pathway was identified through screening experiments by which methylselenic acid was found to possess notable NKG2D ligand regulatory properties. The protein kinase C inhibitor methylselenic acid induced MICA/B surface expression but dominantly blocked ULBP2 surface transport. Remarkably, by targeting this novel pathway we could specifically block the production of soluble ULBP2 from different, primary melanomas. Our findings strongly suggest that the endosomal transport pathway constitutes a novel therapeutic target for ULBP2-producing tumors. PMID- 25024380 TI - A reporter mouse reveals lineage-specific and heterogeneous expression of IRF8 during lymphoid and myeloid cell differentiation. AB - The IFN regulatory factor family member 8 (IRF8) regulates differentiation of lymphoid and myeloid lineage cells by promoting or suppressing lineage-specific genes. How IRF8 promotes hematopoietic progenitors to commit to one lineage while preventing the development of alternative lineages is not known. In this study, we report an IRF8-EGFP fusion protein reporter mouse that revealed previously unrecognized patterns of IRF8 expression. Differentiation of hematopoietic stem cells into oligopotent progenitors is associated with progressive increases in IRF8-EGFP expression. However, significant induction of IRF8-EGFP is found in granulocyte-myeloid progenitors and the common lymphoid progenitors but not the megakaryocytic-erythroid progenitors. Surprisingly, IRF8-EGFP identifies three subsets of the seemingly homogeneous granulocyte-myeloid progenitors with an intermediate level of expression of EGFP defining bipotent progenitors that differentiation into either EGFP(hi) monocytic progenitors or EGFP(lo) granulocytic progenitors. Also surprisingly, IRF8-EGFP revealed a highly heterogeneous pre-pro-B population with a fluorescence intensity ranging from background to 4 orders above background. Interestingly, IRF8-EGFP readily distinguishes true B cell committed (EGFP(int)) from those that are noncommitted. Moreover, dendritic cell progenitors expressed extremely high levels of IRF8 EGFP. Taken together, the IRF8-EGFP reporter revealed previously unrecognized subsets with distinct developmental potentials in phenotypically well-defined oligopotent progenitors, providing new insights into the dynamic heterogeneity of developing hematopoietic progenitors. PMID- 25024381 TI - Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells. AB - Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl 4'-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCII(high) dendritic cells were higher after the injection of the AS01 adjuvanted vaccine than after Ag alone. However, only MHCII(high) dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag presenting dendritic cells. PMID- 25024383 TI - Cutting edge: An antibody recognizing ancestral endogenous virus glycoproteins mediates antibody-dependent cellular cytotoxicity on HIV-1-infected cells. AB - The failure of antiviral vaccines is often associated with rapid viral escape from specific immune responses. In the past, conserved epitope or algorithmic epitope selections, such as mosaic vaccines, have been designed to diversify immunity and to circumvent potential viral escape. An alternative approach is to identify conserved stable non-HIV-1 self-epitopes present exclusively in HIV-1 infected cells. We showed previously that human endogenous retroviral (HERV) mRNA transcripts and protein are found in cells of HIV-1-infected patients and that HERV-K (HML-2)-specific T cells can eliminate HIV-1-infected cells in vitro. In this article, we demonstrate that a human anti-HERV-K (HML-2) transmembrane protein Ab binds specifically to HIV-1-infected cells and eliminates them through an Ab-dependent cellular cytotoxicity mechanism in vitro. Thus, Abs directed against epitopes other than HIV-1 proteins may have a role in eliminating HIV-1 infected cells and could be targeted in novel vaccine approaches or immunotherapeutic modalities. PMID- 25024385 TI - Lymph node stromal cells negatively regulate antigen-specific CD4+ T cell responses. AB - Lymph node (LN) stromal cells (LNSCs) form the functional structure of LNs and play an important role in lymphocyte survival and the maintenance of immune tolerance. Despite their broad spectrum of function, little is known about LNSC responses during microbial infection. In this study, we demonstrate that LNSC subsets display distinct kinetics following vaccinia virus infection. In particular, compared with the expansion of other LNSC subsets and the total LN cell population, the expansion of fibroblastic reticular cells (FRCs) was delayed and sustained by noncirculating progenitor cells. Notably, newly generated FRCs were preferentially located in perivascular areas. Viral clearance in reactive LNs preceded the onset of FRC expansion, raising the possibility that viral infection in LNs may have a negative impact on the differentiation of FRCs. We also found that MHC class II expression was upregulated in all LNSC subsets until day 10 postinfection. Genetic ablation of radioresistant stromal cell-mediated Ag presentation resulted in slower contraction of Ag-specific CD4(+) T cells. We propose that activated LNSCs acquire enhanced Ag-presentation capacity, serving as an extrinsic brake system for CD4(+) T cell responses. Disrupted function and homeostasis of LNSCs may contribute to immune deregulation in the context of chronic viral infection, autoimmunity, and graft-versus-host disease. PMID- 25024382 TI - Aerosol vaccination with AERAS-402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high-dose Mycobacterium tuberculosis challenge. AB - Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag-specific CD4 and CD8 T cells in the lung. The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans. In this study, we used an aerosol vaccination strategy to administer AERAS-402, a replication-defective recombinant adenovirus (rAd) type 35 expressing Mycobacterium tuberculosis Ags Ag85A, Ag85B, and TB10.4, in bacillus Calmette Guerin (BCG)-primed or unprimed rhesus macaques. Immunization with BCG generated low purified protein derivative-specific CD4 T cell responses in blood and bronchoalveolar lavage. In contrast, aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific CD4 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-gamma, as well as TNF and IL-2. Such responses induced by BCG, AERAS-402, or both failed to confer overall protection following challenge with 275 CFUs M. tuberculosis Erdman, although vaccine-induced responses associated with reduced pathology were observed in some animals. Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge. Overall, our data suggest that a high M. tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model. However, the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens, alternative rAd serotypes with enhanced immunogenicity, and a physiological challenge dose may achieve protection against M. tuberculosis. PMID- 25024384 TI - Moderate alcohol induces stress proteins HSF1 and hsp70 and inhibits proinflammatory cytokines resulting in endotoxin tolerance. AB - Binge or moderate alcohol exposure impairs host defense and increases susceptibility to infection because of compromised innate immune responses. However, there is a lack of consensus on the molecular mechanism by which alcohol mediates this immunosuppression. In this study, we show that cellular stress proteins HSF1 and hsp70 play a mechanistic role in alcohol-mediated inhibition of the TLR4/MyD88 pathway. Alcohol exposure induced transcription factor HSF1 mRNA expression and DNA binding activity in primary human monocytes and murine macrophages. Furthermore, HSF1 target gene hsp70 mRNA and protein are upregulated by alcohol in monocytes. In vitro pre-exposure to moderate alcohol reduced subsequent LPS-induced NF-kappaB promoter activity and downstream TNF-alpha, IL-6 and IL-1beta production in monocytes and macrophages, exhibiting endotoxin tolerance. Mechanistic analysis demonstrates that alcohol-induced HSF1 binds to the TNF-alpha promoter in macrophages at early time points, exerting transrepression and decreased TNF-alpha expression. Furthermore, association of hsp70 with NF-kappaB subunit p50 in alcohol-treated macrophages correlates with reduced NF-kappaB activation at later time points. Hsp70 overexpression in macrophages was sufficient to block LPS-induced NF-kappaB promoter activity, suggesting alcohol-mediated immunosuppression by hsp70. The direct crosstalk of hsp70 and HSF1 was further confirmed by the loss of alcohol-mediated endotoxin tolerance in hsp70- and HSF1-silenced macrophages. Our data suggest that alcohol mediated activation of HSF1 and induction of hsp70 inhibit TLR4-MyD88 signaling and are required for alcohol-induced endotoxin tolerance. Using stress proteins as direct drug targets would be clinically relevant in alcohol abuse treatment and may serve to provide a better understanding of alcohol-mediated immunosuppression. PMID- 25024386 TI - Fcgamma receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization. AB - Immunomodulatory mAbs, led by the anti-CTLA4 mAb ipilimumab, are an exciting new class of drugs capable of promoting anticancer immunity and providing durable control of some tumors. Close analysis of a number of agents has revealed a critical yet variable role for Fcgamma receptors in their efficacy. In this article, we reveal that agonistic anti-CD40 mAbs have an absolute requirement for cross-linking by inhibitory FcgammaRIIB when used systemically to treat established BCL1 syngeneic lymphoma, and therapy is lost when using a mouse IgG2a mAb not cross-linked by FcgammaRIIB. Furthermore, in FcgammaRIIB-deficient mice the lymphoma itself can provide FcgammaRIIB to cross-link anti-CD40 on neighboring cells, and only when this is blocked does therapy fail. The dependence on FcgammaRIIB for immunostimulatory activity was not absolute, however, because when anti-CD40 mAbs were administered systemically with the TLR3 agonist polyinosinic:polycytidylic acid or were given subcutaneously, activatory FcgammaR could also provide cross-linking. Using this mechanistic insight, we designed multimeric forms of anti-CD40 mAb with intrinsic FcgammaR-independent activity that were highly effective in the treatment of lymphoma-bearing mice. In conclusion, FcgammaR-independent anti-CD40 activation is a viable strategy in vivo. These findings have important translational implications, as humans, unlike mice, do not have IgG that binds strongly to FcgammaRIIB; therefore FcgammaR independent derivatives represent an attractive therapeutic option. PMID- 25024388 TI - Antigen targeting to CD11b+ dendritic cells in association with TLR4/TRIF signaling promotes strong CD8+ T cell responses. AB - Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant. Two therapeutic vaccine candidates against human papilloma viruses and melanoma have been developed recently, based on the CyaA vector, and are currently in clinical trials. We took advantage of one of these highly purified vaccines, produced under good manufacturing practice-like conditions, to decipher the mechanisms by which CyaA induces immune responses. In this study, we demonstrate that CyaA binds both human and mouse CD11b(+) dendritic cells (DCs) and induces their maturation, as shown by the upregulation of costimulatory and MHC molecules and the production of proinflammatory cytokines. Importantly, we show that DCs sense CyaA through the TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-beta pathway, independent of the presence of LPS. These findings show that CyaA possesses the intrinsic ability to not only target DCs but also to activate them, leading to the induction of strong immune responses. Overall, this study demonstrates that Ag delivery to CD11b(+) DCs in association with TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-beta activation is an efficient strategy to promote strong specific CD8(+) T cell responses. PMID- 25024387 TI - Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP. AB - CD8(+) CTLs detect virus-infected cells through recognition of virus-derived peptides presented at the cell surface by MHC class I molecules. The cowpox virus protein CPXV012 deprives the endoplasmic reticulum (ER) lumen of peptides for loading onto newly synthesized MHC class I molecules by inhibiting the transporter associated with Ag processing (TAP). This evasion strategy allows the virus to avoid detection by the immune system. In this article, we show that CPXV012, a 9-kDa type II transmembrane protein, prevents peptide transport by inhibiting ATP binding to TAP. We identified a segment within the ER-luminal domain of CPXV012 that imposes the block in peptide transport by TAP. Biophysical studies show that this domain has a strong affinity for phospholipids that are also abundant in the ER membrane. We discuss these findings in an evolutionary context and show that a frameshift deletion in the CPXV012 gene in an ancestral cowpox virus created the current form of CPXV012 that is capable of inhibiting TAP. In conclusion, our findings indicate that the ER-luminal domain of CPXV012 inserts into the ER membrane, where it interacts with TAP. CPXV012 presumably induces a conformational arrest that precludes ATP binding to TAP and, thus, activity of TAP, thereby preventing the presentation of viral peptides to CTLs. PMID- 25024389 TI - Lnk/Sh2b3 controls the production and function of dendritic cells and regulates the induction of IFN-gamma-producing T cells. AB - Dendritic cells (DCs) are proficient APCs that play crucial roles in the immune responses to various Ags and pathogens and polarize Th cell immune responses. Lnk/SH2B adaptor protein 3 (Sh2b3) is an intracellular adaptor protein that regulates B lymphopoiesis, megakaryopoiesis, and expansion of hematopoietic stem cells by constraining cytokine signals. Recent genome-wide association studies have revealed a link between polymorphism in this adaptor protein and autoimmune diseases, including type 1 diabetes and celiac disease. We found that Lnk/Sh2b3 was also expressed in DCs and investigated its role in the production and function of DC lineage cells. In Lnk(-/-) mice, DC numbers were increased in the spleen and lymph nodes, and growth responses of bone marrow-derived DCs to GM-CSF were augmented. Mature DCs from Lnk(-/-) mice were hypersensitive and showed enhanced responses to IL-15 and GM-CSF. Compared to normal DCs, Lnk(-/-) DCs had enhanced abilities to support the differentiation of IFN-gamma-producing Th1 cells from naive CD4(+) T cells. This was due to their elevated expression of IL 12Rbeta1 and increased production of IFN-gamma. Lnk(-/-) DCs supported the appearance of IFN-gamma-producing T cells even under conditions in which normal DCs supported induction of regulatory T cells. These results indicated that Lnk/Sh2b3 plays a regulatory role in the expansion of DCs and might influence inflammatory immune responses in peripheral lymphoid tissues. PMID- 25024390 TI - Distinct Fcgamma receptors mediate the effect of serum amyloid p on neutrophil adhesion and fibrocyte differentiation. AB - The plasma protein serum amyloid P (SAP) reduces neutrophil adhesion, inhibits the differentiation of monocytes into fibroblast-like cells called fibrocytes, and promotes phagocytosis of cell debris by macrophages. Together, these effects of SAP reduce key aspects of inflammation and fibrosis, and SAP injections improve lung function in pulmonary fibrosis patients. SAP functions are mediated, in part, by FcgammaRs, but the contribution of each FcgammaR is not fully understood. We found that aa Q55 and E126 in human SAP affect human fibrocyte differentiation and SAP binding to FcgammaRI. E126, K130, and Q128 affect neutrophil adhesion and SAP affinity for FcgammaRIIa. Q128 also affects phagocytosis by macrophages and SAP affinity for FcgammaRI. All the identified functionally significant amino acids in SAP form a binding site that is distinct from the previously described SAP-FcgammaRIIa binding site. Blocking FcgammaRI with an IgG-blocking Ab reduces the SAP effect on fibrocyte differentiation, and ligating FcgammaRIIa with Abs reduces neutrophil adhesion. Together, these results suggest that SAP binds to FcgammaRI on monocytes to inhibit fibrocyte differentiation, and binds to FcgammaRIIa on neutrophils to reduce neutrophil adhesion. PMID- 25024391 TI - The effect of adjuvanting cancer vaccines with herpes simplex virus glycoprotein D on melanoma-driven CD8+ T cell exhaustion. AB - Two vaccines expressing CD4(+) and CD8(+) T cell epitopes of melanoma-associated Ags (MAAs) by a chimpanzee-derived replication-defective AdC68 vector were compared in a mouse model of melanoma. In one vaccine, termed AdC68-gDMelapoly, the epitopes were expressed as a fusion protein within HSV-1 glycoprotein D (gD), which blocks immunoinhibitory signaling through the herpes virus entry mediator pathway. The other vaccine, termed AdC68-Melapoly, expressed only the MAA epitopes. AdC68-gDMelapoly induced more potent MAA-specific CD8(+) T cell responses especially to the subdominant MAA epitopes. Upon prophylactic vaccination, mice that developed CD8(+) T cell responses to the two vaccines that were comparable in magnitude showed equal protection against tumor challenge. When mice were first challenged with tumor cells and then vaccinated results differed. In animals with comparable CD8(+) T cell responses, the AdC68 gDMelapoly vaccine was more efficacious compared with the AdC68-Melapoly vaccine in delaying tumor growth. This effect was linked to reduced expression of 2B4, LAG-3, and programmed death-1 on tumor-infiltrating MAA-specific CD8(+) T cells elicited by the gD-adjuvanted vaccine, suggesting that CD8(+) T cells induced in presence of gD are less susceptible to tumor-driven exhaustion. PMID- 25024393 TI - Recombinant human IgA1 and IgA2 autoantibodies to type VII collagen induce subepidermal blistering ex vivo. AB - Subepidermal autoimmune blistering dermatoses (AIBD) are prototypic autoantibody mediated diseases. In epidermolysis bullosa acquisita (EBA), an autoimmune disease with severe and chronic skin blistering, autoantibodies are directed against type VII collagen. IgG is the predominant autoantibody isotype of EBA, the pathogenicity of which has been demonstrated in a variety of in vivo and ex vivo disease models. In contrast, there is not much evidence for the pathogenicity of IgA, which may appear as the only autoantibody isotype in some EBA patients. To investigate the pathogenic potential of IgA autoantibodies, we generated chimeric V gene-matched human IgA1, IgA2, and control IgG1 autoantibodies directed against type VII collagen. Immobilized immune complexes containing the rIgA1 and rIgA2 autoantibodies induced the dose-dependent release of reactive oxygen species from neutrophil granulocytes, a precondition for blister formation. Moreover, both rIgA1 and rIgA2 induced leukocyte-dependent dermal-epidermal separation in cryosections of human skin. In contrast with rIgG1, neither rIgA1 nor rIgA2 was capable of inducing complement deposition at the dermal-epidermal junction. Because complement activation is a prerequisite for blister induction, this lack of function compared with IgG1 may be compensated for by the stronger activation of neutrophil granulocytes by both IgA1 and IgA2. For IgG-mediated AIBD, immunoadsorption therapy is a convenient treatment modality for the removal of pathogenic autoantibodies, particularly in treatment-resistant cases. The results of this study show the pathogenic potential of IgA autoantibodies and support the development of adsorber matrices for IgA-mediated AIBD. PMID- 25024392 TI - T cell antigen discovery using soluble vaccinia proteome reveals recognition of antigens with both virion and nonvirion association. AB - Vaccinia virus (VACV) is a useful model system for understanding the immune response to a complex pathogen. Proteome-wide Ab profiling studies reveal the humoral response to be strongly biased toward virion-associated Ags, and several membrane proteins induce Ab-mediated protection against VACV challenge in mice. Some studies have indicated that the CD4 response is also skewed toward proteins with virion association, whereas the CD8 response is more biased toward proteins with early expression. In this study, we have leveraged a VACV strain Western Reserve (VACV-WR) plasmid expression library, produced previously for proteome microarrays for Ab profiling, to make a solubilized full VACV-WR proteome for T cell Ag profiling. Splenocytes from VACV-WR-infected mice were assayed without prior expansion against the soluble proteome in assays for Th1 and Th2 signature cytokines. The response to infection was polarized toward a Th1 response, with the distribution of reactive T cell Ags comprising both early and late VACV proteins. Interestingly, the proportions of different functional subsets were similar to that present in the whole proteome. In contrast, the targets of Abs from the same mice were enriched for membrane and other virion components, as described previously. We conclude that a "nonbiasing" approach to T cell Ag discovery reveals a T cell Ag profile in VACV that is broader and less skewed to virion association than the Ab profile. The T cell Ag mapping method developed in the present study should be applicable to other organisms where expressible "ORFeome" libraries are also available, and it is readily scalable for larger pathogens. PMID- 25024394 TI - Economic contraction, alcohol intoxication and suicide: analysis of the National Violent Death Reporting System. AB - OBJECTIVES: Although there is a large and growing body of evidence concerning the impact of contracting economies on suicide mortality risk, far less is known about the role alcohol consumption plays in the complex relationship between economic conditions and suicide. The aims were to compare the postmortem alcohol intoxication rates among male and female suicide decedents before (2005-2007), during (2008-2009) and after (2010-2011) the economic contraction in the USA. METHODS: Data from the restricted National Violent Death Reporting System (2005 2011) for male and female suicide decedents aged 20 years and older were analysed by Poisson regression analysis to test whether there was significant change in the fractions of suicide decedents who were acutely intoxicated at the time of death (defined as blood alcohol content >=0.08 g/dL) prior, during and after the downturn. RESULTS: The fraction of all suicide decedents with alcohol intoxication increased by 7% after the onset of the recession from 22.2% in 2005 2007 to 23.9% in 2008-2011. Compared with the years prior to the recession, male suicide decedents showed a 1.09-fold increased risk of alcohol intoxication within the first 2 years of the recession. Surprisingly, there was evidence of a lag effect among female suicide decedents, who had a 1.14-fold (95% CI 1.02 to 1.27) increased risk of intoxication in 2010-2011 compared with 2005-2007. CONCLUSIONS: These findings suggest that acute alcohol intoxication in suicide interacts with economic conditions, becoming more prevalent during contractions. PMID- 25024395 TI - Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients. AB - OBJECTIVE: Betatrophin, a newly identified hormone, has been recently characterized as a potent stimulator that increases the production and expansion of insulin-secreting beta-cells in mice, but the physiological role of betatrophin remains poorly understood. This study measured for the first time serum betatrophin levels in newly diagnosed patients with type 2 diabetes (T2DM) and explored the correlations between its serum levels and various metabolic parameters in T2DM. RESEARCH DESIGN AND METHODS: We analyzed the concentrations of betatrophin by ELISA in blood samples of 166 well-characterized individuals in whom anthropometric parameters, oral glucose tolerance test (OGTT), glycosylated hemoglobin, blood lipids, insulin sensitivity (1/homeostasis model assesment of insulin resistance [1/HOMA-IR] and Matsuda index [ISIM]), and insulin secretion were measured. The participants were divided into newly diagnosed T2DM patients (n = 83) and age-, sex- and BMI-matched healthy control subjects (n = 83). RESULTS: Serum betatrophin levels were significantly higher in T2DM patients than in healthy control subjects (613.08 [422.19-813.08] vs. 296.57 [196.53-509.46] pg/mL; P < 0.01). Serum betatrophin positively correlated with age, 2-h post-OGTT glucose (2hPG), and postprandial serum insulin (PSI), but negatively with 1/HOMA IR and ISIM in T2DM patients. In the control group, betatrophin was only positively associated with age. In T2DM subjects, multivariate regression analyses showed that age, 2hPG, and PSI were independent factors influencing serum betatrophin levels. CONCLUSIONS: Circulating concentrations of betatrophin are significantly increased in T2DM patients. Our results suggest that betatrophin may play a role in the pathogenesis of T2DM. PMID- 25024396 TI - Effects of weight loss, weight cycling, and weight loss maintenance on diabetes incidence and change in cardiometabolic traits in the Diabetes Prevention Program. AB - OBJECTIVE: This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors. RESEARCH DESIGN AND METHODS: This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years. RESULTS: Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: beta = 0.57 mg/dL per kg, 95% CI -0.66, -0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0-6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (beta = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (beta = 0.25 units per cycle; P = 0.04), and systolic blood pressure (beta = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits. CONCLUSIONS: Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits. PMID- 25024398 TI - Coalescence of B cell receptor and invariant chain MHC II in a raft-like membrane domain. AB - The BCR binds antigen for processing and subsequent presentation on MHC II molecules. Polyvalent antigen induces BCR clustering and targeting to endocytic processing compartments, which are also accessed by Ii-MHC II. Here, we report that clustered BCR is able to team up with Ii-MHC II already at the plasma membrane of mouse B-lymphocytes. Colocalization of BCR and Ii-MHC II on the cell surface required clustering of both types of molecules. The clustering of only one type did not trigger the recruitment of the other. Ii-bound MIF (a ligand of Ii) also colocalized with clustered BCR upon oligomerization of MIF on the surface of the B cell. Abundant surface molecules, such as B220 or TfnR, did not cocluster with the BCR. Some membrane raft-associated molecules, such as peptide loaded MHC II, coclustered with the BCR, whereas others, such as GM1, did not. The formation of a BCR- and Ii-MHC II-containing membrane domain by antibody mediated clustering was independent of F-actin and led to the coendocytosis of its constituents. With a rapid Brij 98 extraction method, it was possible to capture this membrane domain biochemically as a DRM. Ii and clustered BCR were present on the same DRM, as shown by immunoisolation. The coalescence of BCR and Ii-MHC II increased tyrosine phosphorylation, indicative of enhanced BCR signaling. Our work suggests a novel role for MIF and Ii-MHC II in BCR-mediated antigen processing. PMID- 25024397 TI - IgG4-related disease and its pathogenesis-cross-talk between innate and acquired immunity. AB - IgG4-related disease (IgG4-RD) is a novel clinical entity proposed in Japan in the 21th century and is attracting strong attention over the world. The characteristic manifestations of IgG4-RD are increased serum IgG4 concentration and tumefaction by IgG4(+) plasma cells. Although the clinical manifestations in various organs have been established, the pathogenesis of IgG4-RD is still unknown. Recently, many reports of aberrant acquired immunity such as Th2 diminated immune responses have been published. However, many questions still remain, including questions about the pathogenesis of IgG4-RD and the roles of IgG4. In this review, we discuss the pathogenesis of IgG4-RD by focusing on the cross-talk between innate and acquired immunity. PMID- 25024399 TI - Diet-induced (epigenetic) changes in bone marrow augment atherosclerosis. AB - Alterations in DNA methylation patterns in peripheral blood leukocytes precede atherosclerotic lesion development in mouse models of atherosclerosis and have been linked to cardiovascular death in patients. The aim of this study is to investigate the long-term changes induced by WTD feeding on BM cells and the consequences for atherosclerosis susceptibility. Hereto, WTD BM or Chow BM was transplanted into LDLR KO mice on chow. BM from WTD BM recipient mice exhibited hypomethylation of CpG regions in the genes encoding Pu.1 and IRF8, key regulators of monocyte proliferation and macrophage differentiation. In agreement, in blood, the numbers of leukocytes were 40% (P<0.05) higher as a result of an increase in F4/80(+) monocytes (3.4-fold; P<0.01). An increase of CD11c(++) cells was also found (2.4-fold; P<0.05). Furthermore, spleens were enlarged, and the percentage of F4/80(+) cells expressing CD86 was induced (1.8 fold; P<0.01), indicating increased activation of splenic macrophages. Importantly, mice reconstituted with WTD BM showed a significant, 1.4-fold (P<0.05) increase in aortic root plaque size in the absence of changes in serum cholesterol. We conclude that WTD challenge induces transplantable epigenetic changes in BM, alterations in the hematopoietic system, and increased susceptibility to atherosclerosis. Manipulation of the epigenome, when used in conjunction with blood lipid reduction, could thus prove beneficial to treat cardiovascular disorders. PMID- 25024400 TI - An essential role for IFN-beta in the induction of IFN-stimulated gene expression by LPS in macrophages. AB - TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-alpha and -beta, by macrophages. To examine the role of IFN-beta in the induction of ISGs by LPS, we compared the ability of LPS to induce ISGF3 activity and ISG expression in bone marrow-derived macrophages from WT and Ifnb1(-/-) mice. We found that LPS treatment activated ISGF3 and induced expression of ISGs such as Oas1, Mx1, Ddx58 (RIG-I), and Ifih1 (MDA5) in WT macrophages, but not in macrophages derived from Ifnb1(-/-) mice or Ifnar1(-/-) mice. The inability of LPS to induce activation of ISGF3 and ISG expression in Ifnb1(-/-) macrophages correlated with the failure of LPS to induce activation of STAT1 and -2 in these cells. Consistent with these findings, LPS treatment also failed to induce ISG expression in bone marrow-derived macrophages from Stat2 KO mice. Although activation of ISGF3 and induction of ISG expression by LPS was abrogated in Ifnb1(-/-) and Ifnar1(-/-) macrophages, activation of NF-kappaB and induction of NF-kappaB-responsive genes, such as Tnf (TNF-alpha) and Il1b (IL-1beta), were not affected by deletion of either the IFN-beta or IFN-alphaR1 genes. These findings demonstrate that induction of ISGF3 activity and ISG expression by LPS is critically dependent on intermediate production of IFN-beta and autocrine signaling through type I IFN receptors. PMID- 25024401 TI - Application of FcRn binding assays to guide mAb development. AB - Monoclonal antibodies (mAbs) represent an important class of therapeutic modalities. To optimize their pharmaceutical properties, studies have focused on improving mAb pharmacokinetic/pharmacodynamic profiles by modulating their interactions with the neonatal Fc receptor (FcRn). The influence of both the chemical and physical properties of IgGs has been examined in the context of FcRn interactions. In this regard, a variety of FcRn binding assays and tools have been developed and used to characterize the interaction with IgGs. However, a predictive relationship between the FcRn binding interaction of IgGs in vitro and their pharmacokinetics in vivo broadly across mAbs remains elusive. Many studies have increasingly suggested that the interplay between the characteristics of the mAb and the nature of its target can influence disposition and elimination. Thus, it is becoming increasingly evident that along with FcRn interactions, consideration of the non-FcRn-based biologic processes active in mAb disposition should be integrated into mAb development and optimization. Herein, we describe how the pharmacokinetics of mAbs can be modulated through FcRn interactions and provide perspectives on interpreting the receptor binding parameters in relation to other mechanisms involved in antibody disposition to aid in guiding mAb development. PMID- 25024402 TI - Toward a unified model of passive drug permeation II: the physiochemical determinants of unbound tissue distribution with applications to the design of hepatoselective glucokinase activators. AB - In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. Passive distribution is modeled via a Fick-Nernst-Planck approach, using in vitro experimental data to estimate the permeability of both ionized and neutral species. The model accounts for pH and electrochemical potential across cellular membranes, ionization according to Henderson-Hasselbalch, passive permeation of the neutral species using Fick's law, and passive permeation of the ionized species using the Nernst Planck equation. The mathematical model of the physiochemical system allows derivation of a single set of parameters governing the distribution of drug molecules across multiple conditions both in vitro and in vivo. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide-mediated hepatic uptake and impaired passive distribution to the pancreas is described. The results for these molecules indicate the permeability penalty of the ionized form is offset by its relative abundance, leading to passive pancreatic exclusion according to the Nernst-Planck extension of Fickian passive permeation. Generally, this model serves as a useful construct for drug discovery scientists to understand subcellular exposure of acids or bases using specific physiochemical properties. PMID- 25024403 TI - Cytochrome p450-mediated metabolic activation of diosbulbin B. AB - Diosbulbin B (DIOB), a furan-containing diterpenoid lactone, is the most abundant component of Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Administration of purified DIOB or DB extracts has been reported to cause liver injury in animals. The mechanisms of DIOB-induced hepatotoxicity remain unknown. The major objective of this study was to identify reactive metabolites of DIOB. A DIOB-derived cis-enedial was trapped by N-acetyl lysine (NAL) and glutathione (GSH) or N-acetyl cysteine (NAC) in rat and human liver microsomal incubation systems after exposure to DIOB. Four metabolites (M1-M4) associated with GSH were detected by liquid chromatography coupled to tandem mass spectrometry. Apparently, M1 was derived from both NAL and GSH. M2 and M3 resulted from the reaction of GSH without the involvement of NAL. Two molecules of GSH participated in the formation of M4. M2 and M3 were also detected in bile and urine of rats given DIOB. M5, a DIOB-derived NAC/NAL conjugate, was detected in microsomal incubations with DIOB fortified with NAC and NAL as trapping agents. Biomimetic M1-M5 were prepared by oxidation of DIOB with Oxone for metabolite identification. Microsomal incubation study demonstrated that ketoconazole inhibited the production of the enedial in a concentration-dependent manner, and CYP3A4 was found to be the enzyme responsible for the metabolic activation of DIOB. The metabolism study facilitates the understanding of the role of bioactivation of DIOB in its hepatotoxicity. PMID- 25024404 TI - The adipogenic transcriptional cofactor ZNF638 interacts with splicing regulators and influences alternative splicing. AB - Increasing evidence indicates that transcription and alternative splicing are coordinated processes; however, our knowledge of specific factors implicated in both functions during the process of adipocyte differentiation is limited. We have previously demonstrated that the zinc finger protein ZNF638 plays a role as a transcriptional coregulator of adipocyte differentiation via induction of PPARgamma in cooperation with CCAAT/enhancer binding proteins (C/EBPs). Here we provide new evidence that ZNF638 is localized in nuclear bodies enriched with splicing factors, and through biochemical purification of ZNF638's interacting proteins in adipocytes and mass spectrometry analysis, we show that ZNF638 interacts with splicing regulators. Functional analysis of the effects of ectopic ZNF638 expression on a minigene reporter demonstrated that ZNF638 is sufficient to promote alternative splicing, a function enhanced through its recruitment to the minigene promoter at C/EBP responsive elements via C/EBP proteins. Structure function analysis revealed that the arginine/serine-rich motif and the C-terminal zinc finger domain required for speckle localization are necessary for the adipocyte differentiation function of ZNF638 and for the regulation of the levels of alternatively spliced isoforms of lipin1 and nuclear receptor co-repressor 1. Overall, our data demonstrate that ZNF638 participates in splicing decisions and that it may control adipogenesis through regulation of the relative amounts of differentiation-specific isoforms. PMID- 25024405 TI - Fsh and Lh direct conserved and specific pathways during flatfish semicystic spermatogenesis. AB - The current view of the control of spermatogenesis by Fsh and Lh in non-mammalian vertebrates is largely based on studies carried out in teleosts with cystic and cyclic spermatogenesis. Much less is known concerning the specific actions of gonadotropins during semicystic germ cell development, a type of spermatogenesis in which germ cells are released into the tubular lumen where they transform into spermatozoa. In this study, using homologous gonadotropins and a candidate gene approach, for which the genes' testicular cell-type-specific expression was established, we investigated the regulatory effects of Fsh and Lh on gene expression during spermatogenesis in Senegalese sole (Solea senegalensis), a flatfish with asynchronous and semicystic germ cell development. During early spermatogenesis, Fsh and Lh upregulated steroidogenesis-related genes and nuclear steroid receptors, expressed in both somatic and germ cells, through steroid dependent pathways, although Lh preferentially stimulated the expression of downstream genes involved in androgen and progestin syntheses. In addition, Lh specifically promoted the expression of spermatid-specific genes encoding spermatozoan flagellar proteins through direct interaction with the Lh receptor in these cells. Interestingly, at this spermatogenic stage, Fsh primarily regulated genes encoding Sertoli cell growth factors with potentially antagonistic effects on germ cell proliferation and differentiation through steroid mediation. During late spermatogenesis, fewer genes were regulated by Fsh or Lh, which was associated with a translational and posttranslational downregulation of the Fsh receptor in different testicular compartments. These results reveal that conserved and specialized gonadotropic pathways regulate semicystic spermatogenesis in flatfish, which may spatially adjust cell germ development to maintain a continuous reservoir of spermatids in the testis. PMID- 25024408 TI - Bicuspid aortic valve stenosis with successful transfemoral transcatheter aortic valve replacement (TAVI) using the Sapien 3 valve. PMID- 25024406 TI - Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology. AB - Transcriptional coactivators have evolved as an important new class of functional proteins that participate with virtually all transcription factors and nuclear receptors (NRs) to intricately regulate gene expression in response to a wide variety of environmental cues. Recent findings have highlighted that coactivators are important for almost all biological functions, and consequently, genetic defects can lead to severe pathologies. Drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases. PMID- 25024407 TI - Platelet function and long-term antiplatelet therapy in women: is there a gender specificity? A 'state-of-the-art' paper. AB - Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles. PMID- 25024409 TI - The history of coronary reperfusion. PMID- 25024410 TI - Left main coronary arterial endothelial function and heterogenous segmental epicardial vasomotor reactivity in vivo: novel insights with intravascular ultrasonography. AB - AIMS: While the relationship between epicardial coronary vasomotor reactivity and cardiovascular events is well established, this observation has yet to be evaluated within the left main coronary artery (LMCA) in humans in vivo. Our aims were to test the endothelium-dependent vasomotor properties of the LMCA, and to compare these responses to downstream epicardial segments. METHODS AND RESULTS: Thirty patients referred for coronary angiography underwent intracoronary (IC) salbutamol provocation during intravascular ultrasound imaging within a non critically diseased, left-sided conduit vessel. Macrovascular vasomotor response [change in average lumen area (LA) at baseline and following 5 min of 0.30 ug/min IC salbutamol] and percent atheroma volume (PAV) were evaluated in 30 LMCA, 42 proximal, 109 mid, and 132 distal epicardial coronary segments. In comparison with all other segments, the LMCA had the greatest lumen and vessel areas (P < 0.001), yet the proximal epicardial segments contained the greatest PAV (P < 0.02). The mid and distal epicardial segments displayed significant endothelium dependent vasodilatation from baseline (P = 0.017 and <0.001, respectively); however, the proximal epicardial and LMCA segments did not (P = 0.45 and 0.16, respectively). Significant segmental vasomotor heterogeneity was noted in all 30 patients, with opposing vasomotor responses between adjacent LMCA and epicardial segments. Across all segments, baseline LA inversely correlated with the % change in LA (r = -0.16, P = 0.0005). CONCLUSION: Endothelium-dependent vasomotor reactivity is heterogenous within the conduit coronary system. Vascular dynamic responses were less prominent in the larger calibre LMCA and proximal epicardial segments. This may, in part, relate to higher shear stress in smaller, distal segments and yet also may explain the propensity for culprit plaques to cluster proximally. PMID- 25024411 TI - High-fidelity simulations of unsteady civil aircraft aerodynamics: stakes and perspectives. Application of zonal detached eddy simulation. AB - This paper provides an up-to-date survey of the use of zonal detached eddy simulations (ZDES) for unsteady civil aircraft applications as a reflection on the stakes and perspectives of the use of hybrid methods in the framework of industrial aerodynamics. The issue of zonal or non-zonal treatment of turbulent flows for engineering applications is discussed. The ZDES method used in this article and based on a fluid problem-dependent zonalization is briefly presented. Some recent landmark achievements for conditions all over the flight envelope are presented, including low-speed (aeroacoustics of high-lift devices and landing gear), cruising (engine-airframe interactions), propulsive jets and off-design (transonic buffet and dive manoeuvres) applications. The implications of such results and remaining challenges in a more global framework are further discussed. PMID- 25024412 TI - Advancing predictive models for particulate formation in turbulent flames via massively parallel direct numerical simulations. AB - Combustion of fossil fuels is likely to continue for the near future due to the growing trends in energy consumption worldwide. The increase in efficiency and the reduction of pollutant emissions from combustion devices are pivotal to achieving meaningful levels of carbon abatement as part of the ongoing climate change efforts. Computational fluid dynamics featuring adequate combustion models will play an increasingly important role in the design of more efficient and cleaner industrial burners, internal combustion engines, and combustors for stationary power generation and aircraft propulsion. Today, turbulent combustion modelling is hindered severely by the lack of data that are accurate and sufficiently complete to assess and remedy model deficiencies effectively. In particular, the formation of pollutants is a complex, nonlinear and multi-scale process characterized by the interaction of molecular and turbulent mixing with a multitude of chemical reactions with disparate time scales. The use of direct numerical simulation (DNS) featuring a state of the art description of the underlying chemistry and physical processes has contributed greatly to combustion model development in recent years. In this paper, the analysis of the intricate evolution of soot formation in turbulent flames demonstrates how DNS databases are used to illuminate relevant physico-chemical mechanisms and to identify modelling needs. PMID- 25024413 TI - Enabling the environmentally clean air transportation of the future: a vision of computational fluid dynamics in 2030. AB - As global air travel expands rapidly to meet demand generated by economic growth, it is essential to continue to improve the efficiency of air transportation to reduce its carbon emissions and address concerns about climate change. Future transports must be 'cleaner' and designed to include technologies that will continue to lower engine emissions and reduce community noise. The use of computational fluid dynamics (CFD) will be critical to enable the design of these new concepts. In general, the ability to simulate aerodynamic and reactive flows using CFD has progressed rapidly during the past several decades and has fundamentally changed the aerospace design process. Advanced simulation capabilities not only enable reductions in ground-based and flight-testing requirements, but also provide added physical insight, and enable superior designs at reduced cost and risk. In spite of considerable success, reliable use of CFD has remained confined to a small region of the operating envelope due, in part, to the inability of current methods to reliably predict turbulent, separated flows. Fortunately, the advent of much more powerful computing platforms provides an opportunity to overcome a number of these challenges. This paper summarizes the findings and recommendations from a recent NASA-funded study that provides a vision for CFD in the year 2030, including an assessment of critical technology gaps and needed development, and identifies the key CFD technology advancements that will enable the design and development of much cleaner aircraft in the future. PMID- 25024414 TI - High-performance computing-based exploration of flow control with micro devices. AB - The dielectric barrier discharge (DBD) plasma actuator that controls flow separation is one of the promising technologies to realize energy savings and noise reduction of fluid dynamic systems. However, the mechanism for controlling flow separation is not clearly defined, and this lack of knowledge prevents practical use of this technology. Therefore, large-scale computations for the study of the DBD plasma actuator have been conducted using the Japanese Petaflops supercomputer 'K' for three different Reynolds numbers. Numbers of new findings on the control of flow separation by the DBD plasma actuator have been obtained from the simulations, and some of them are presented in this study. Knowledge of suitable device parameters is also obtained. The DBD plasma actuator is clearly shown to be very effective for controlling flow separation at a Reynolds number of around 10(5), and several times larger lift-to-drag ratio can be achieved at higher angles of attack after stall. For higher Reynolds numbers, separated flow is partially controlled. Flow analysis shows key features towards better control. DBD plasma actuators are a promising technology, which could reduce fuel consumption and contribute to a green environment by achieving high aerodynamic performance. The knowledge described above can be obtained only with high-end computers such as the supercomputer 'K'. PMID- 25024415 TI - Large eddy simulations in 2030 and beyond. AB - Since its introduction, in the early 1970s, large eddy simulations (LES) have advanced considerably, and their application is transitioning from the academic environment to industry. Several landmark developments can be identified over the past 40 years, such as the wall-resolved simulations of wall-bounded flows, the development of advanced models for the unresolved scales that adapt to the local flow conditions and the hybridization of LES with the solution of the Reynolds averaged Navier-Stokes equations. Thanks to these advancements, LES is now in widespread use in the academic community and is an option available in most commercial flow-solvers. This paper will try to predict what algorithmic and modelling advancements are needed to make it even more robust and inexpensive, and which areas show the most promise. PMID- 25024416 TI - Delivering better power: the role of simulation in reducing the environmental impact of aircraft engines. AB - The growth in simulation capability over the past 20 years has led to remarkable changes in the design process for gas turbines. The availability of relatively cheap computational power coupled to improvements in numerical methods and physical modelling in simulation codes have enabled the development of aircraft propulsion systems that are more powerful and yet more efficient than ever before. However, the design challenges are correspondingly greater, especially to reduce environmental impact. The simulation requirements to achieve a reduced environmental impact are described along with the implications of continued growth in available computational power. It is concluded that achieving the environmental goals will demand large-scale multi-disciplinary simulations requiring significantly increased computational power, to enable optimization of the airframe and propulsion system over the entire operational envelope. However even with massive parallelization, the limits imposed by communications latency will constrain the time required to achieve a solution, and therefore the position of such large-scale calculations in the industrial design process. PMID- 25024417 TI - A second golden age of aeroacoustics? AB - In 1992, Sir James Lighthill foresaw the dawn of a second golden age in aeroacoustics enabled by computer simulations (Hardin JC, Hussaini MY (eds) 1993 Computational aeroacoustics, New York, NY: Springer (doi:10.1007/978-1-4613-8342 0)). This review traces the progress in large-scale computations to resolve the noise-source processes and the methods devised to predict the far-field radiated sound using this information. Keeping focus on aviation-related noise sources a brief account of the progress in simulations of jet noise, fan noise and airframe noise is given highlighting the key technical issues and challenges. The complex geometry of nozzle elements and airframe components as well as the high Reynolds number of target applications require careful assessment of the discretization algorithms on unstructured grids and modelling compromises. High-fidelity simulations with 200-500 million points are not uncommon today and are used to improve scientific understanding of the noise generation process in specific situations. We attempt to discern where the future might take us, especially if exascale computing becomes a reality in 10 years. A pressing question in this context concerns the role of modelling in the coming era. While the sheer scale of the data generated by large-scale simulations will require new methods for data analysis and data visualization, it is our view that suitable theoretical formulations and reduced models will be even more important in future. PMID- 25024418 TI - Large eddy simulation for predicting turbulent heat transfer in gas turbines. AB - Blade cooling technology will play a critical role in the next generation of propulsion and power generation gas turbines. Accurate prediction of blade metal temperature can avoid the use of excessive compressed bypass air and allow higher turbine inlet temperature, increasing fuel efficiency and decreasing emissions. Large eddy simulation (LES) has been established to predict heat transfer coefficients with good accuracy under various non-canonical flows, but is still limited to relatively simple geometries and low Reynolds numbers. It is envisioned that the projected increase in computational power combined with a drop in price-to-performance ratio will make system-level simulations using LES in complex blade geometries at engine conditions accessible to the design process in the coming one to two decades. In making this possible, two key challenges are addressed in this paper: working with complex intricate blade geometries and simulating high-Reynolds-number (Re) flows. It is proposed to use the immersed boundary method (IBM) combined with LES wall functions. A ribbed duct at Re=20 000 is simulated using the IBM, and a two-pass ribbed duct is simulated at Re=100 000 with and without rotation (rotation number Ro=0.2) using LES with wall functions. The results validate that the IBM is a viable alternative to body conforming grids and that LES with wall functions reproduces experimental results at a much lower computational cost. PMID- 25024419 TI - High-order computational fluid dynamics tools for aircraft design. AB - Most forecasts predict an annual airline traffic growth rate between 4.5 and 5% in the foreseeable future. To sustain that growth, the environmental impact of aircraft cannot be ignored. Future aircraft must have much better fuel economy, dramatically less greenhouse gas emissions and noise, in addition to better performance. Many technical breakthroughs must take place to achieve the aggressive environmental goals set up by governments in North America and Europe. One of these breakthroughs will be physics-based, highly accurate and efficient computational fluid dynamics and aeroacoustics tools capable of predicting complex flows over the entire flight envelope and through an aircraft engine, and computing aircraft noise. Some of these flows are dominated by unsteady vortices of disparate scales, often highly turbulent, and they call for higher-order methods. As these tools will be integral components of a multi-disciplinary optimization environment, they must be efficient to impact design. Ultimately, the accuracy, efficiency, robustness, scalability and geometric flexibility will determine which methods will be adopted in the design process. This article explores these aspects and identifies pacing items. PMID- 25024421 TI - The prospect of using large eddy and detached eddy simulations in engineering design, and the research required to get there. AB - In this paper, we try to look into the future to envision how large eddy and detached eddy simulations will be used in the engineering design process about 20 30 years from now. Some key challenges specific to the engineering design process are identified, and some of the critical outstanding problems and promising research directions are discussed. PMID- 25024420 TI - Aerodynamics, computers and the environment. PMID- 25024422 TI - Large eddy simulation of flows in industrial compressors: a path from 2015 to 2035. AB - A better understanding of turbulent unsteady flows is a necessary step towards a breakthrough in the design of modern compressors. Owing to high Reynolds numbers and very complex geometry, the flow that develops in such industrial machines is extremely hard to predict. At this time, the most popular method to simulate these flows is still based on a Reynolds-averaged Navier-Stokes approach. However, there is some evidence that this formalism is not accurate for these components, especially when a description of time-dependent turbulent flows is desired. With the increase in computing power, large eddy simulation (LES) emerges as a promising technique to improve both knowledge of complex physics and reliability of flow solver predictions. The objective of the paper is thus to give an overview of the current status of LES for industrial compressor flows as well as to propose future research axes regarding the use of LES for compressor design. While the use of wall-resolved LES for industrial multistage compressors at realistic Reynolds number should not be ready before 2035, some possibilities exist to reduce the cost of LES, such as wall modelling and the adaptation of the phase-lag condition. This paper also points out the necessity to combine LES to techniques able to tackle complex geometries. Indeed LES alone, i.e. without prior knowledge of such flows for grid construction or the prohibitive yet ideal use of fully homogeneous meshes to predict compressor flows, is quite limited today. PMID- 25024423 TI - Trends in high-performance computing for engineering calculations. AB - High-performance computing has evolved remarkably over the past 20 years, and that progress is likely to continue. However, in recent years, this progress has been achieved through greatly increased hardware complexity with the rise of multicore and manycore processors, and this is affecting the ability of application developers to achieve the full potential of these systems. This article outlines the key developments on the hardware side, both in the recent past and in the near future, with a focus on two key issues: energy efficiency and the cost of moving data. It then discusses the much slower evolution of system software, and the implications of all of this for application developers. PMID- 25024424 TI - Fetal and maternal absorbed dose estimates for positron-emitting molecular imaging probes. AB - PET and hybrid (PET/CT and PET/MR) imaging currently play a pivotal role in clinical diagnosis, staging and restaging, treatment, and surveillance of several diseases. As such, limiting the radiation exposure of special patients, such as pregnant women, from PET procedures is an important challenge that needs to be appropriately addressed because of the high sensitivity of the developing embryo/fetus to ionizing radiation. Therefore, accurate radiation dose calculation for the embryo/fetus and pregnant patient from common positron emitting radiotracers is highly desired. METHODS: To obtain representative estimates of radiation dose to the human body, realistic biologic and physical models should be used. In this work, we evaluate the S values of 9 positron emitting radionuclides ((11)C, (13)N, (15)O, (18)F, (64)Cu, (68)Ga, (82)Rb, (86)Y, and (124)I) and the absorbed and effective doses for 21 positron-emitting labeled radiotracers using realistic anthropomorphic computational phantoms of early pregnancy and at 3-, 6-, and 9-mo of gestation and the most recent biokinetic data available. The Monte Carlo N-Particle eXtended general-purpose Monte Carlo code was used for radiation transport simulation. RESULTS: The absorbed dose to the pregnant model is less influenced by the gestation for most organs or tissues, but the anatomic changes of the maternal body increases the effective dose for some radiotracers. For (18)F-FDG, the estimated absorbed doses to the embryo/fetus are 3.05E-02, 2.27E-02, 1.50E-02, and 1.33E-02 mGy/MBq at early pregnancy and 3-, 6-, and 9-mo gestation, respectively. The absorbed dose is nonuniformly distributed in the fetus and would be 1.03-2 times higher in the fetal brain than in other fetal soft tissues. CONCLUSION: The generated S values can be exploited to estimate the radiation dose delivered to pregnant patients and the embryo/fetus from various PET radiotracers used in clinical and research settings. The generated dosimetric database of radiotracers using new-generation computational models can be used for the assessment of radiation risks to pregnant women and the embryo/fetus undergoing PET/CT imaging procedures. This work also contributes to a better understanding of the absorbed dose distribution in the fetus. PMID- 25024425 TI - Preclinical evaluation of robotic-assisted sentinel lymph node fluorescence imaging. AB - An ideal substance to provide convenient and accurate targeting for sentinel lymph node (SLN) mapping during robotic-assisted surgery has yet to be found. We used an animal model to determine the ability of the FireFly camera system to detect fluorescent SLNs after administration of a dual-labeled molecular imaging agent. METHODS: We injected the footpads of New Zealand White rabbits with 1.7 or 8.4 nmol of tilmanocept labeled with (99m)Tc and a near-infrared fluorophore, IRDye800CW. One and 36 h after injection, popliteal lymph nodes, representing the SLNs, were dissected with the assistance of the FireFly camera system, a fluorescence-capable endoscopic imaging system. After excision of the paraaortic lymph nodes, which represented non-SLNs, we assayed all lymph nodes for radioactivity and fluorescence intensity. RESULTS: Fluorescence within all popliteal lymph nodes was easily detected by the FireFly camera system. Fluorescence within the lymph channel could be imaged during the 1-h studies. When compared with the paraaortic lymph nodes, the popliteal lymph nodes retain greater than 95% of the radioactivity at both 1 and 36 h after injection. At both doses (1.7 and 8.4 nmol), the popliteal nodes had higher (P < 0.050) optical fluorescence intensity than the paraaortic nodes at the 1- and 36-h time points. CONCLUSION: The FireFly camera system can easily detect tilmanocept labeled with a near-infrared fluorophore at least 36 h after administration. This ability will permit image acquisition and subsequent verification of fluorescence-labeled SLNs during robotic-assisted surgery. PMID- 25024426 TI - In vivo mesenchymal stem cell tracking with PET using the dopamine type 2 receptor and 18F-fallypride. AB - Human mesenchymal stem cells (hMSCs) represent a promising treatment approach for tissue repair and regeneration. However, little is known about the underlying mechanisms and the fate of the transplanted cells. The objective of the presented work was to determine the feasibility of PET imaging and in vivo monitoring after transplantation of dopamine type 2 receptor-expressing cells. METHODS: An hMSC line constitutively expressing a mutant of the dopamine type 2 receptor (D2R80A) was generated by lentiviral gene transfer. D2R80A messenger RNA expression was confirmed by reverse transcriptase-polymerase chain reaction. Localization of the transmembrane protein was analyzed by confocal fluorescence microscopy. The stem cell character of transduced hMSCs was investigated by adipogenic and osteogenic differentiation. Migration capacity was assessed by scratch assays in time-lapse imaging. In vitro specific binding of ligands was tested by fluorescence activated cell sorting analysis and by radioligand assay using (18)F-fallypride. Imaging of D2R80A overexpressing hMSC transplanted into athymic rats was performed by PET using (18)F-fallypride. RESULTS: hMSCs showed long-term overexpression of D2R80A. As expected, the fluorescence signal suggested the primary localization of the protein in the membrane of the transduced cells. hMSC and D2R80A retained their stem cell character demonstrated by their osteogenic and adipogenic differentiation capacity and their proliferation and migration behavior. For in vitro hMSCs, at least 90% expressed the D2R80A transgene and hMSC-D2R80A showed specific binding of (18)F-fallypride. In vivo, a specific signal was detected at the transplantation site up to 7 d by PET. CONCLUSION: The mutant of the dopamine type 2 receptor (D2R80A) is a potent reporter to detect hMSCs by PET in vivo. PMID- 25024427 TI - Nucleus reuniens of the thalamus contains head direction cells. AB - Discrete populations of brain cells signal heading direction, rather like a compass. These 'head direction' cells are largely confined to a closely-connected network of sites. We describe, for the first time, a population of head direction cells in nucleus reuniens of the thalamus in the freely-moving rat. This novel subcortical head direction signal potentially modulates the hippocampal CA fields directly and, thus, informs spatial processing and memory. PMID- 25024428 TI - Disparate substrates for head gaze following and face perception in the monkey superior temporal sulcus. AB - Primates use gaze cues to follow peer gaze to an object of joint attention. Gaze following of monkeys is largely determined by head or face orientation. We used fMRI in rhesus monkeys to identify brain regions underlying head gaze following and to assess their relationship to the 'face patch' system, the latter being the likely source of information on face orientation. We trained monkeys to locate targets by either following head gaze or using a learned association of face identity with the same targets. Head gaze following activated a distinct region in the posterior STS, close to-albeit not overlapping with-the medial face patch delineated by passive viewing of faces. This 'gaze following patch' may be the substrate of the geometrical calculations needed to translate information on head orientation from the face patches into precise shifts of attention, taking the spatial relationship of the two interacting agents into account. PMID- 25024429 TI - Removal of reprogramming transgenes improves the tissue reconstitution potential of keratinocytes generated from human induced pluripotent stem cells. AB - Human induced pluripotent stem cell (hiPSC) lines have a great potential for therapeutics because customized cells and organs can be induced from such cells. Assessment of the residual reprogramming factors after the generation of hiPSC lines is required, but an ideal system has been lacking. Here, we generated hiPSC lines from normal human dermal fibroblasts with piggyBac transposon bearing reprogramming transgenes followed by removal of the transposon by the transposase. Under this condition, we compared the phenotypes of transgene residual and -free hiPSCs of the same genetic background. The transgene-residual hiPSCs, in which the transcription levels of the reprogramming transgenes were eventually suppressed, were quite similar to the transgene-free hiPSCs in a pluripotent state. However, after differentiation into keratinocytes, clear differences were observed. Morphological, functional, and molecular analyses including single-cell gene expression profiling revealed that keratinocytes from transgene-free hiPSC lines were more similar to normal human keratinocytes than those from transgene-residual hiPSC lines, which may be partly explained by reactivation of residual transgenes upon induction of keratinocyte differentiation. These results suggest that transgene-free hiPSC lines should be chosen for therapeutic purposes. PMID- 25024430 TI - Targeting cancer stem cell plasticity through modulation of epidermal growth factor and insulin-like growth factor receptor signaling in head and neck squamous cell cancer. AB - Emerging data suggest that cancer stem cells (CSCs) exist in equilibrium with differentiated cells and that stochastic transitions between these states can account for tumor heterogeneity and drug resistance. The aim of this study was to establish an in vitro system that recapitulates stem cell plasticity in head and neck squamous cell cancers (HNSCCs) and identify the factors that play a role in the maintenance and repopulation of CSCs. Tumor spheres were established using patient-derived cell lines via anchorage-independent cell culture techniques. These tumor spheres were found to have higher aldehyde dehydrogenase (ALD) cell fractions and increased expression of Kruppel-like factor 4, SRY (sex determining region Y)-box 2, and Nanog and were resistant to gamma-radiation, 5-fluorouracil, cisplatin, and etoposide treatment compared with monolayer culture cells. Monolayer cultures were subject to single cell cloning to generate clones with high and low ALD fractions. ALDHigh clones showed higher expression of stem cell and epithelial-mesenchymal transition markers compared with ALDLow clones. ALD fractions, representing stem cell fractions, fluctuated with serial passaging, equilibrating at a level specific to each cell line, and could be augmented by the addition of epidermal growth factor (EGF) and/or insulin. ALDHigh clones showed increased EGF receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) phosphorylation, with increased activation of downstream pathways compared with ALDLow clones. Importantly, blocking these pathways using specific inhibitors against EGFR and IGF-1R reduced stem cell fractions drastically. Taken together, these results show that HNSCC CSCs exhibit plasticity, with the maintenance of the stem cell fraction dependent on the EGFR and IGF-1R pathways and potentially amenable to targeted therapeutics. PMID- 25024431 TI - Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells. AB - Human embryonic and induced pluripotent stem cells are potential cell sources for regenerative approaches in Parkinson disease. Inductive differentiation protocols can generate midbrain dopamine neurons but result in heterogeneous cell mixtures. Therefore, selection strategies are necessary to obtain uniform dopamine cell populations. Here, we developed a selection approach using lentivirus vectors to express green fluorescent protein under the promoter region of FOXA2, a transcription factor that is expressed in the floor plate domain that gives rise to dopamine neurons during embryogenesis. We first validated the specificity of the vectors in human cell lines against a promoterless construct. We then selected FOXA2-positive neural progenitors from several human pluripotent stem cell lines, which demonstrated a gene expression profile typical for the ventral domain of the midbrain and floor plate, but failed to enrich for dopamine neurons. To investigate whether this was due to the selection approach, we overexpressed FOXA2 in neural progenitors derived from human pluripotent stem cell lines. FOXA2 forced expression resulted in an increased expression of floor plate but not mature neuronal markers. Furthermore, selection of the FOXA2 overexpressing fraction also failed to enrich for dopamine neurons. Collectively, our results suggest that FOXA2 is not sufficient to induce a dopaminergic fate in this system. On the other hand, our study demonstrates that a combined approach of promoter activation and lentivirus vector technology can be used as a versatile tool for the selection of a defined cell population from a variety of human pluripotent stem cell lines. PMID- 25024432 TI - Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project. AB - BACKGROUND: Median diagnostic delay of five to six years seen in primary hypogammaglobulinaemia results in morbidity including bronchiectasis. Patients typically have multiple health care encounters and blood tests before the diagnosis is considered. We report outcomes from using the difference between total protein and albumin (globulin fraction) to reduce diagnostic delay in unsuspected hypogammaglobulinaemia. METHODS: A prospective >5 year programme in the setting of a National Health Services Hospital Blood Sciences pathology service processing serum samples from primary and secondary care. Patients with globulin fraction below the first percentile were reviewed in the context of supplied clinical details. Immunoglobulin measurements were performed in selected patients. RESULTS: Of 2,910,850 globulin fractions 27,304 (0.9%) were below the 1st percentile globulin fraction (<18 g/L). After exclusions, 933 (3% of these) had immunoglobulins measured. Of these, 292 had IgG < 5 g/L, 186 < 4 g/L and 80 < 3 g/L, giving respective positive predictive values of 31%, 20% and 8.6%. Positive predictive value for common variable immunodeficiency was 1.3%. We identified 12 new cases of common variable immunodeficiency, 10 new haematological disorders and 20 hypogammaglobulinaemias secondary to medication. Locally derived cut-offs are required as small differences between analysers have a significant effect on screen-positive rates. CONCLUSIONS: Use of a 1st percentile globulin fraction improved early detection of hypogammaglobulinaemia. This is a useful adjunct to alert clinicians to unsuspected hypogammaglobulinaemia but should not replace immunoglobulin measurement. Patients with globulin fraction below the first percentile should be reviewed for possible hypogammaglobulinaemia. PMID- 25024433 TI - The NB-LRR proteins RGA4 and RGA5 interact functionally and physically to confer disease resistance. AB - Plant resistance proteins of the class of nucleotide-binding and leucine-rich repeat domain proteins (NB-LRRs) are immune sensors which recognize pathogen derived molecules termed avirulence (AVR) proteins. We show that RGA4 and RGA5, two NB-LRRs from rice, interact functionally and physically to mediate resistance to the fungal pathogen Magnaporthe oryzae and accomplish different functions in AVR recognition. RGA4 triggers an AVR-independent cell death that is repressed in the presence of RGA5 in both rice protoplasts and Nicotiana benthamiana. Upon recognition of the pathogen effector AVR-Pia by direct binding to RGA5, repression is relieved and cell death occurs. RGA4 and RGA5 form homo- and hetero complexes and interact through their coiled-coil domains. Localization studies in rice protoplast suggest that RGA4 and RGA5 localize to the cytosol. Upon recognition of AVR-Pia, neither RGA4 nor RGA5 is re-localized to the nucleus. These results establish a model for the interaction of hetero-pairs of NB-LRRs in plants: RGA4 mediates cell death activation, while RGA5 acts as a repressor of RGA4 and as an AVR receptor. PMID- 25024435 TI - Integration of microenvironmental and stress signaling antagonizes colorectal cancer progression. PMID- 25024434 TI - K-Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation. AB - Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)--a HAT that has not been studied for its role in memory function so far--shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation. PMID- 25024438 TI - Hemispheric asymmetry measured by texture analysis and diffusion tensor imaging in two multiple sclerosis subtypes. AB - BACKGROUND: This paper addresses two subtypes of multiple sclerosis (MS), primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS). The separation of PPMS and RRMS is challenging in certain cases. PURPOSE: To quantitatively determine MS subtypes using texture analysis (TA) and diffusion tensor imaging (DTI). MATERIAL AND METHODS: T1-weighted (T1W) magnetic resonance imaging (MRI) and DTI of the left and right brain hemispheres of 17 patients with PPMS and 19 patients with RRMS were studied. Areas of the caudate nucleus and thalamus were investigated as normal appearing gray matter (NAGM), and areas of the cerebral peduncle and centrum semiovale were investigated as normal appearing white matter (NAWM). The described locations were symmetrical and were accurately marked. TA was performed on the T1W images, and the fractional anisotropy and apparent diffusion coefficient were determined from the DTI data. RESULTS: Hemispherical differences were found with both TA and DTI. Several texture and diffusion tensor parameter values calculated for the left and right hemispheres of the patients showed statistically significant differences. The patients with RRMS had greater significant differences (P < 0.01) in the thalamus between the hemispheres than did the patients with PPMS. The TA classification accuracy of the PPMS and RRMS subtypes was above 80%. CONCLUSION: TA can be helpful when distinguishing between PPMS and RRMS, while DTI appears to reveal the hemispherical asymmetry of RRMS patients. PMID- 25024436 TI - A virus capsid-like nanocompartment that stores iron and protects bacteria from oxidative stress. AB - Living cells compartmentalize materials and enzymatic reactions to increase metabolic efficiency. While eukaryotes use membrane-bound organelles, bacteria and archaea rely primarily on protein-bound nanocompartments. Encapsulins constitute a class of nanocompartments widespread in bacteria and archaea whose functions have hitherto been unclear. Here, we characterize the encapsulin nanocompartment from Myxococcus xanthus, which consists of a shell protein (EncA, 32.5 kDa) and three internal proteins (EncB, 17 kDa; EncC, 13 kDa; EncD, 11 kDa). Using cryo-electron microscopy, we determined that EncA self-assembles into an icosahedral shell 32 nm in diameter (26 nm internal diameter), built from 180 subunits with the fold first observed in bacteriophage HK97 capsid. The internal proteins, of which EncB and EncC have ferritin-like domains, attach to its inner surface. Native nanocompartments have dense iron-rich cores. Functionally, they resemble ferritins, cage-like iron storage proteins, but with a massively greater capacity (~30,000 iron atoms versus ~3,000 in ferritin). Physiological data reveal that few nanocompartments are assembled during vegetative growth, but they increase fivefold upon starvation, protecting cells from oxidative stress through iron sequestration. PMID- 25024437 TI - Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation. AB - The antimitotic anti-cancer drugs, including taxol, perturb spindle dynamics, and induce prolonged, spindle checkpoint-dependent mitotic arrest in cancer cells. These cells then either undergo apoptosis triggered by the intrinsic mitochondrial pathway or exit mitosis without proper cell division in an adaptation pathway. Using a genome-wide small interfering RNA (siRNA) screen in taxol-treated HeLa cells, we systematically identify components of the mitotic apoptosis and adaptation pathways. We show that the Mad2 inhibitor p31(comet) actively promotes mitotic adaptation through cyclin B1 degradation and has a minor separate function in suppressing apoptosis. Conversely, the pro-apoptotic Bcl2 family member, Noxa, is a critical initiator of mitotic cell death. Unexpectedly, the upstream components of the mitochondrial apoptosis pathway and the mitochondrial fission protein Drp1 contribute to mitotic adaption. Our results reveal crosstalk between the apoptosis and adaptation pathways during mitotic arrest. PMID- 25024439 TI - Imaging characteristics of sinonasal organized hematoma. AB - BACKGROUND: Sinonasal organized hematoma is a rare benign disease that may be mistaken for malignancy. PURPOSE: To define the imaging characteristics of sinonasal organized hematoma. MATERIAL AND METHODS: We retrospectively reviewed computed tomography (CT) images of eight patients (4 male patients, 4 female patients; mean age, 40 years; range, 9-83 years) with pathologically proven sinonasal organized hematomas; magnetic resonance imaging (MRI) was performed in one patient among them. The following lesions characteristics were analyzed: size, shape, location, expansile nature, density, signal intensity, internal structure, enhancement pattern, and surrounding bony wall change. RESULTS: The lesion sizes were in the range of 2-5.2 cm (mean, 3.55 cm), and the shapes were lobular, lumpy, or nodular. They were located in the nasal cavity (n = 1), maxillary sinuses (n = 2), or both nasal cavities and maxillary sinuses (n = 5). Expansile lesions with locally aggressive margins were observed in two cases. All lesions were hyperdense on precontrast CT scans; the smaller lesions showed even hyperdensity, whereas the larger lesions showed uneven density. The signal intensity was mixed on MRI, consisting of hemorrhage, fibrosis, and neovascularization. Papillary or frond-like enhancement was noted after contrast injection. All cases showed smooth erosion of the medial walls of the maxillary sinuses, and the epicenters were the secondary maxillary ostia. Two lesions showed erosion of the lateral walls of the maxillary sinuses and were expansile in nature. Non-hemorrhagic polyps accompanied the organized hematomas in three cases. CONCLUSION: Although sinonasal organized hematoma can be mistaken for a malignant tumor, the following characteristic imaging findings facilitate the diagnosis of an organized hematoma: erosion of the bony sinus walls, markedly heterogeneous signal intensity, and papillary or frond-like enhancement. PMID- 25024440 TI - Radiation dose and mortality risk to children undergoing therapeutic interventional cardiology. AB - BACKGROUND: Children undergoing interventional cardiology procedures deserve special concern due to the greater radiation sensitivity of their tissues and more remaining years of life during which a radiation-induced cancer may develop. PURPOSE: To determine the patient radiation dose for pediatric therapeutic interventional cardiology and to estimate the patient effective dose and lifetime mortality risk to children associated with five common procedures. MATERIAL AND METHODS: Ninety children with congenital heart defects undergoing interventional therapy were enrolled in this study. Data regarding fluoroscopy and radiography time, dose-area product (DAP) and peak skin dose (PSD) for each case were measured. Patients were divided into five groups. The patient effective dose (E) was calculated using a multiplicative model of ICRP 60. The overall lifetime mortality risk was evaluated using appropriate risk coefficients. RESULTS: The mean, median, standard deviation, and range of time, PSD, DAP, and E were presented for the five study groups. When these metrics were considered, there were wide variations for different cases within the same group and statistically significant differences between the five groups. The PSD correlated significantly with DAP (Pearson r = 0.70; P < 0.01), but the correlation in individual cases was poor. For all cases, the range of E was found to be between 0.44 and 66.7 mSv. The corresponding risk of lifetime mortality was 1.16 per thousand. CONCLUSION: The current study provides overall data on the time, PSD, E, and lifetime mortality risk for pediatric therapeutic interventional cardiology. Radio frequency ablation showed the highest radiation risk. PMID- 25024441 TI - Magnetic resonance imaging characteristics of invasive breast cancer in women aged less than 35 years. AB - BACKGROUND: With regard to clinicopathological findings and disease prognosis, breast cancer in young women is different from that in older women. However, few studies have investigated magnetic resonance imaging (MRI) characteristics of young age-onset breast cancer. PURPOSE: To retrospectively evaluate and compare the MR images and clinicopathological characteristics of invasive breast cancer in young women (aged <35 years) with those of breast cancers in older premenopausal women (35-45 years). MATERIAL AND METHODS: A total of 270 invasive breast cancers in 266 premenopausal women aged 45 years and younger who underwent preoperative breast MRI and curative surgery were identified between 2009 and 2013. The subjects were divided into a young group (< 35 years, n = 56) and an older group (35-45 years, n = 214). MRI features and clinicopathological data were compared between the two groups. RESULTS: The young group had more positive axillary lymph nodes, higher histologic grade, negative estrogen receptor (ER), negative progesterone receptor (PR), and higher p53 and Ki-67 expression compared to the older group. Using MRI, the young group was more likely to display a round/oval or lobular mass shape, a smooth mass margin, and a high signal intensity on T2-weighted images when compared to the older group. In multivariate analysis, positive axillary nodal status (adjusted odds ratio [OR], 4.070; P = 0.002), higher expression of p53 (adjusted OR, 2.902; P = 0.038), lobular mass shape (adjusted OR, 4.979; P = 0.028), and smooth mass margin (adjusted OR, 5.123; P = 0.048) were independently associated with the young group. CONCLUSION: MR morphologic features, including lobular mass shape and smooth mass margin, were independently associated with breast cancer in young women, in addition to positive axillary nodal status and higher p53 expression status. PMID- 25024443 TI - Gerstmann, Straussler, and Scheinker: the persecution of the men behind the syndrome. AB - In 1936, Austrian neuroscientists Josef Gerstmann and Ernst Straussler, along with expatriate Russian neuroscientist Ilya Mark Scheinker, described the familial prion disorder later named for them from a case they mutually treated at a Viennese neurologic hospital. In 1938, Austria was annexed to Nazi Germany in the Anschluss, effectively ending any collaboration between the 3 men. Gerstmann and Scheinker eventually immigrated to America, and Straussler, although dismissed from his faculty position, remained protected from persecution in Vienna throughout the war likely because of his marriage to an "Aryan woman." Although he attained some degree of success in exile, Gerstmann was never again director of a hospital and primarily maintained a private practice after some brief consulting positions in New York in the 1940s. His medical degree was retroactively stripped by the Nazis without his knowledge, and was not reinstated until 1955. Gerstmann also became embroiled in a bitter struggle to regain his confiscated property in Vienna. Scheinker, aided by the refugee resettlement committee, settled in Cincinnati where he had several successful years and published 3 textbooks, but was denied university tenure and entered private practice until his untimely death. All 3 neurologists lost significant career momentum, and had to pick up the pieces of their fractured lives after the war or their forced exile. Their stories reflect many of the tragic realities of Nazi persecution of Jewish physicians. PMID- 25024444 TI - MADSAM neuropathy: an unusual cause of pseudoathetosis. PMID- 25024445 TI - B-type natriuretic peptides and mortality after stroke: a systematic review and meta-analysis. PMID- 25024446 TI - Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. PMID- 25024447 TI - Pearls & oy-sters: familial epileptic encephalopathy due to methylenetetrahydrofolate reductase deficiency. PMID- 25024449 TI - Teaching NeuroImages: extracranial internal carotid artery aneurysm causing embolic stroke. PMID- 25024450 TI - Benefits and Limitations of Macrotextured Breast Implants and Consensus Recommendations for Optimizing Their Effectiveness. AB - Implant texture is an important factor influencing implant selection for breast augmentation. Natrelle Biocell implants are characterized by macrotextured shell surfaces containing irregularly arranged concavities with large open-pore diameters and depths. These properties facilitate adhesion of the implant to the surrounding tissue, thereby promoting implant immobilization. Relative to implants with other surfaces, macrotextured implants offer low rates of capsular contracture; low rates of malposition, rotation, and rippling; and high rates of patient satisfaction. However, macrotextured implants are associated with a slightly higher risk of double capsule and late seroma. The surgeon can minimize these risks with straightforward techniques that encourage tissue adhesion. This report presents experience-based recommendations to optimize the effectiveness of Biocell anatomic implants. The authors discuss the application of best practices to all aspects of the breast implantation process, from implant selection and surgical planning to operative technique and postoperative management. LEVEL OF EVIDENCE 3. PMID- 25024451 TI - Achieving quicker recovery after breast augmentation. PMID- 25024452 TI - Surgical consideration of the anatomic origin of the risorius in relation to facial planes. AB - BACKGROUND: Confusion exists as to the plane of the risorius with respect to the superficial musculoaponeurotic system (SMAS), the parotid fascia, and the masseteric fascia, which generally are considered origins of the risorius. OBJECTIVES: The authors attempted to clarify the origin of the risorius by topographic examination and dissection, which would provide valuable anatomic information for flap dissection in facelift surgery. METHODS: Detailed dissection was performed in the perioral region of 46 cadaveric specimens to discern the origin of the risorius in relation to the fascial layer. The anatomic aspects of the muscular arrangement and origin of the risorius were classified according to the location of attachment. RESULTS: The risorius originated solely from the fascial layer superficial to the SMAS in 27 specimens (58.7%; type A). It originated solely from the masseter tendon in 3 specimens (6.5%; type B) and from the fascial layers, both superficial and deep to the SMAS, in 16 specimens (34.8%; type C). CONCLUSIONS: The patterns of risorius origination identified in this study represent important anatomic reference information for flap dissection in facelift surgery. PMID- 25024453 TI - Using altmetrics and social media to supplement impact factor: maximizing your article's academic and societal impact. PMID- 25024454 TI - Role of traditional nonsteroidal anti-inflammatory drugs in Alzheimer's disease: a meta-analysis of randomized clinical trials. AB - The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in prevention of Alzheimer's disease (AD) has been evaluated in many studies. We performed a meta analysis to summarize the existing evidence on the relation between use of classical NSAIDs and AD. Randomized controlled trials (RCTs) evaluating the role of classical NSAIDs in AD was searched using different search engines. The RCTs in patients who had the degree of AD measured on Mini-Mental State Examination (MMSE) or AD Assessment Scale-Cognitive subscale (ADAS-cog) were included in the study. The RCTs and data (AD scores) were independently assessed by 2 reviewers, and data were included in meta-analysis only after a common consensus was reached. The pooled results from the ADAS-cog and MMSE scores failed to show any difference between the treatment and the placebo groups as opposed to findings from some observational studies. However, in view of heterogeneity of results, there is a need to conduct more RCTs to arrive at confirmatory findings. PMID- 25024455 TI - Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid beta deposits and peroxidation in mice with Alzheimer-like lesions. AB - Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly individuals and its effective therapies are still unavailable. This study was designed to investigate the neuroprotection of sulforaphane (SFN) in AD-lesion mice induced by combined administration of d-galactose and aluminium. Results showed that SFN ameliorated spatial cognitive impairment and locomotor activity decrease in Morris water maze and open field test, respectively. And attenuated numbers of amyloid beta (Abeta) plaques in both hippocampus and cerebral cortex of AD-lesion mice were detected by immunohistochemistry. According to spectrophotometry and quantitative reverse-transcriptase polymerase chain reaction results, a significant increase in carbonyl group level and obvious decreases in both activity and messenger RNA expression of glutathione peroxidase were found in brain of AD-lesion mice compared with control, but not in SFN treated AD-lesion mice. In conclusion, SFN ameliorates neurobehavioral deficits and protects the brain from Abeta deposits and peroxidation in mice with Alzheimer-like lesions, suggesting SFN is likely a potential phytochemical to be used in AD therapeutics. PMID- 25024456 TI - Navigating the cell: how motors function in vivo. AB - The Company of Biologists Workshop entitled 'Navigating the Cell: How Motors Function in vivo' was held in March 2014 at Wiston House in Steyning, West Sussex, UK. The meeting was an opportunity for a diverse group of experts in the biology and physics of cytoskeletal dynamics, and molecular motors to come together in a setting that promoted scientific interactions and the development of new collaborations. Here, we summarize the highlights of the meeting, one of which was the unique organizational principle that promoted cross-fertilization of ideas and approaches among the participants. PMID- 25024457 TI - Myelination at a glance. AB - The myelin sheath is a plasma membrane extension that is laid down in regularly spaced segments along axons of the nervous system. This process involves extensive changes in oligodendrocyte cell shape and membrane architecture. In this Cell Science at a Glance article and accompanying poster, we provide a model of how myelin of the central nervous system is wrapped around axons to form a tightly compacted, multilayered membrane structure. This model may not only explain how myelin is generated during brain development, but could also help us to understand myelin remodeling in adult life, which might serve as a form of plasticity for the fine-tuning of neuronal networks. PMID- 25024458 TI - Timing of Palliative Care Consultations and Recommendations: Understanding the Variability. AB - Palliative care consultation teams (PCCTs) provide care that enhances quality of life. The effectiveness of PCCTs depends, however, on their timely utilization by other providers. The goal of this study was to examine the timing of palliative care consultation requests and responses at a single Veteran Affairs Medical Center. The median interval between admission and consultation request was 5 days (range = 0-73 days). The median interval between consultation request and death was 23 days (range = 0-847 days). In logistic regressions, timing variables were not significant predictors of whether consultation recommendations were made or implemented. There is substantial variability in when patients receive a palliative care consultation. Many patients receive palliative care within the first week of hospitalization and their final month of life. PMID- 25024459 TI - Psychosocial care and the role of clinical psychologists in palliative care. AB - OBJECTIVES: The aim of this study was to explore the works of clinical psychologists in palliative care in Taiwan. METHODS: Clinical psychologists who were working or had experience in palliative care were recruited. A 2-stage qualitative method study was conducted, including semistructured interviews and a focus group. RESULTS: The following 4 main themes were identified: (1) the essential nature of the psychologists' care were caring and company; (2) the dynamic process included psychological assessment, intervention, and evaluation based on psychological knowledge; (3) they needed to modify their care using an integrative framework, by setting practical goals and using techniques with flexibility; and (4) they faced external and internal challenges in this field. CONCLUSION: Clinical psychologists have beneficial contributions but have to modify psychosocial care based on the patients' needs and clinical situations. PMID- 25024460 TI - Access to outpatient specialty care: solutions from an integrated health care system. PMID- 25024461 TI - Neutrophil to Lymphocyte Ratio is Related to Stent Thrombosis and High Mortality in Patients With Acute Myocardial Infarction. AB - We investigated whether the neutrophil to lymphocyte ratio (NLR) can predict stent thrombosis (STh) and high mortality rate in patients with ST-segment elevation myocardial infarction (STEMI). We analyzed data of 102 patients with STh and 450 patients with STEMI admitted to 2 high volume hospitals. Preprocedural NLR was significantly higher in patients with STh (P < .001). There was a significantly higher mortality rate in patients with high NLR during hospitalization (P < .001). Also, in the STh group there was a significantly higher mortality rate in patients with high NLR (P < .001). In receiver-operating characteristic analysis, NLR >4.8 had 56% sensitivity and 68% specificity for predicting STh. The NLR >4.9 had 70% sensitivity and 65% specificity for predicting in-hospital mortality. On multivariate regression analysis, NLR was found to be significantly related to STh. In patients with STEMI, preprocedural high NLR is associated with both STh and higher mortality rates. PMID- 25024462 TI - Predictors of Chronic Total Occlusion in Nonculprit Artery in Patients With Acute Coronary Syndrome: Mean Platelet Volume and Uric Acid. AB - Chronic total occlusion (CTO) in a noninfarct-related artery (non-IRA) is an independent predictor of mortality in acute coronary syndrome (ACS). Mean platelet volume (MPV) and serum uric acid (SUA) are associated with cardiovascular events in ACS. We investigated the relationship between the presence of non-IRA-CTO with MPV and SUA levels in patients with ACS. Patients (n = 1024) who underwent urgent coronary angiography for ACS were included in this study. Blood samples were drawn on admission. Patients were categorized into 2 groups: non-IRA-CTO (-) and non-IRA-CTO (+). The MPV and SUA levels on admission were significantly higher in the non-IRA-CTO (+) group than in the non-IRA-CTO ( ) group (P < .001). At multivariate analysis, MPV (odds ratio [OR]: 4.705, P < .001) and SUA (OR: 2.535, P < .001) were independent predictors of non-IRA-CTO together with age, hemoglobin, ejection fraction, and non-ST-segment elevation ACS. The MPV and SUA levels were significant and independent predictors for the presence of non-IRA-CTO in patients with ACS. PMID- 25024463 TI - Auricular reconstruction after human bite amputation using the Baudet technique. AB - OBJECTIVE: This study aimed to present a case of a successful re-implantation of an amputated auricle following a human bite using the Baudet technique. METHODS: Case report and review of the literature. RESULTS: The patient had a very satisfactory postoperative result in terms of appearance and function of the reattached auricle. Cartilage loss was minimal. CONCLUSION: Reattachment of an amputated auricle as a composite graft following a traumatic human bite is feasible. The Baudet technique is a simple alternative that avoids the complexity of microsurgical anastomosis while improving upon the high failure rate associated with simple reattachment. PMID- 25024464 TI - From pre-operative comorbidities to post-operative cognitive dysfunction: The challenging face of geriatric anaesthesia. PMID- 25024465 TI - Post-operative delirium in elderly patients. AB - Delirium is a common, but an often underdiagnosed complication in the elderly following major surgery. Recognising delirium in early stages and diagnosing the condition based on established criteria can improve the outcome and management. Managing delirium with environmental, supportive and pharmacological interventions will possibly reduce the incidence and side-effects associated with post-operative delirium. The purpose of this article is to provide an over view of the current knowledge about the disease, diagnosis, pathogenesis, preventive strategies, and treatment of post-operative delirium. PMID- 25024466 TI - Randomised double-blind comparative study of dexmedetomidine and tramadol for post-spinal anaesthesia shivering. AB - BACKGROUND AND AIMS: Dexmedetomidine (alpha2 adrenergic agonist) has been used for prevention of post anaesthesia shivering. Its use for the treatment of post spinal anaesthesia shivering has not been evaluated. The aim of this study was to evaluate and compare the efficacy, haemodynamic and adverse effects of dexmedetomidine with those of tramadol, when used for control of post-spinal anaesthesia shivering. METHODS: A prospective, randomised, and double-blind study was conducted in 50 American Society of Anaesthesiologists Grade I and II patients of either gender, aged between 18 and 65 years, scheduled for various surgical procedures under spinal anaesthesia. The patients were randomised in two groups of 25 patients each to receive either dexmedetomidine 0.5 MUg/kg or tramadol 0.5 mg/kg as a slow intravenous bolus. Grade of shivering, onset of shivering, time for cessation of shivering, recurrence, response rate, and adverse effects were observed at scheduled intervals. Unpaired t-test was used for analysing the data. RESULTS: Time taken for cessation of shivering was significantly less with dexmedetomidine when compared to tramadol. Nausea and vomiting was observed only in tramadol group (28% and; 20% respectively). There was not much difference in the sedation profile of both the drugs. CONCLUSION: We conclude that although both drugs are effective, the time taken for cessation of shivering is less with dexmedetomidine when compared to tramadol. Moreover, dexmedetomidine has negligible adverse effects, whereas tramadol is associated with significant nausea and vomiting. PMID- 25024467 TI - Post-operative cognitive dysfunction in the elderly: A prospective clinical study. AB - BACKGROUND AND AIMS: Aging population is a major demographic trend worldwide. Globally, 50% of all the elderly individuals are estimated to undergo atleast one surgical procedure and post-operative cognitive dysfunction (POCD) is one of the most common and often poorly understood post-operative complications in this section of the population. This randomised prospective study was conducted to assess the post-operative cognitive status in the elderly undergoing non-cardiac surgery, evaluate the cognitive parameters affected, evaluate the potential risk factors and thereby analyse the potential for implementation of preventive strategies. METHODS: This study was conducted on 200 patients aged 60 years or older scheduled for elective non-cardiac surgeries. The baseline cognitive status of the patients was assessed 2 days prior to the date of the surgery. The post operative cognitive status was assessed on the 3(rd) day, 7(th) day and after 1 month. Statistical analysis was performed using SAS and SPSS. RESULTS: The incidence of POCD showed a gradual decline from postoperative day 3 to 30. Females were found to be at significant risk in developing POCD. Advancing age and level of education emerged as dominant factors, while type of anaesthesia, duration of surgery, and presence of coexisting comorbidities had no influence on the incidence of cognitive dysfunction. CONCLUSION: POCD is a definite complication after surgery and anaesthesia in the elderly population. Gender emerged as a significant risk factor with increasing age as a dominating factor contributing to POCD. PMID- 25024468 TI - Tracheal intubation in patients with cervical spine immobilization: A comparison of McGrath((r)) video laryngoscope and Truview EVO2((r)) laryngoscope. AB - BACKGROUND AND AIMS: Literature suggests that glottic view is better when using McGrath((r)) Video laryngoscope and Truview((r)) in comparison with McIntosh blade. The purpose of this study was to evaluate the effectiveness of McGrath Video laryngoscope in comparison with Truview laryngoscope for tracheal intubation in patients with simulated cervical spine injury using manual in-line stabilisation. METHODS: This prospective randomised study was undertaken in operation theatre of a tertiary referral centre after approval from the Institutional Review Board. A total of 100 consenting patients presenting for elective surgery requiring tracheal intubation were randomly assigned to undergo intubation using McGrath((r)) Video laryngoscope (n = 50) or Truview((r)) (n = 50) laryngoscope. In all patients, we applied manual-in-line stabilisation of the cervical spine throughout the airway management. Statistical testing was conducted with the statistical package for the social science system version SPSS 17.0. Demographic data, airway assessment and haemodynamics were compared using the Chi-square test. A P < 0.05 was considered significant. RESULTS: The time to successful intubation was less with McGrath video laryngoscope when compared to Truview (30.02 s vs. 38.72 s). However, there was no significant difference between laryngoscopic views obtained in both groups. The number of second intubation attempts required and incidence of complications were negligible with both devices. Success rate of intubation with both devices was 100%. Intubation with McGrath Video laryngoscope caused lesser alterations in haemodynamics. CONCLUSIONS: Both laryngoscopes are reliable in case of simulated cervical spine injury using manual-in-line stabilisation with 100% success rate and good glottic view. PMID- 25024469 TI - Ketofol-Dexmedetomidine combination in ECT: A punch for depression and agitation. AB - BACKGROUND AND AIMS: The choice of anaesthetic agent for electroconvulsive therapy (ECT) depends on seizure duration, haemodynamic, and recovery parameters. The aim of the study was to assess the effects of ketamine-propofol induction with dexmedetomidine preadministration (ketofol-dex group) and without its preadministration (ketofol group) on haemodynamics, depression, seizure duration, recovery characteristics, and agitation following ECT in patients with depression. METHODS: 40 patients aged 18-60 years were scheduled for ECT for treatment of depression. Dexmedetomidine (0.5 MUg/kg) diluted to a volume of 10 ml with 0.9% saline or 10 ml 0.9% saline were infused intravenously over 10 minutes before induction of anaesthesia with ketamine and propofol (ketofol). Statistical analysis was carried out using the Statistical Software for the Social Sciences (SPSS) package. RESULTS: Motor seizure duration in ketofol group was significantly less compared to ketofol-dex group (35.8 +/- 6.6s versus 38.9 +/- 4.9s). Total ketofol used was significantly less in ketofol-dex group compared to ketofol group (78.5 +/- 10.8mg versus 90 +/- 13.2mg). The number of patients with agitation score >2 was significantly lower in ketofol-dex group (1.4%) compared to ketofol group (8.6%). There was significant decrease (P = 0.000) in mean arterial pressure (MAP) and heart rate (HR) in ketofol-dex group compared to ketofol group at 20, 30, and 40 minutes for MAP and at 10, 20, 30, and 40 minutes for HR. CONCLUSIONS: Ketofol-dex mixture in ECT is associated with longer mean seizure duration, effective anti-depression, less incidence of agitation, more patient satisfaction, and acceptable decreases in blood pressure and HR when compared to ketofol alone. PMID- 25024470 TI - Effects of dexmedetomidine on procedural pain and discomfort associated with central venous catheter insertion. AB - BACKGROUND AND AIM: Central venous catheter (CVC) insertion induces pain and discomfort to a conscious patient despite application of a local anaesthetic (LA) field block and this pain can be greatly lessened by using additional analgesics. The aim of this study was to evaluate the efficacy of dexmedetomidine along with LA field infiltration in controlling pain and discomfort associated with CVC insertion. METHODS: A prospective, randomised, double-blind, placebo-controlled trial of 54 patients scheduled for planned CVC insertion was undertaken. Patients were randomly assigned into two groups of 27 each, to receive either dexmedetomidine (1 MUg/kg) or 0.9% normal saline, along with LA field infiltration. Pain and discomfort score was measured at 5 time points. RESULTS: The median pain score was worst for placebo group at local anaesthetic injection (6 [4-7]) and at the end of procedure (5 [4-5]), which was significantly attenuated in the dexmedetomidine group (4 [4-5] and 4 [3-5]; P = 0.007 and 0.040 respectively). The lower procedure related discomfort score in the immediate post procedural period was statistically significant in dexmedetomidine group compared to placebo (4 [4-5] vs. 5 [4-6]; P = 0.008). CONCLUSIONS: Pre-procedural bolus dexmedetomidine infusion provides adequate analgesia and patient comfort for CVC insertion along LA field block. However, the tendency for excessive sedation and bradycardia associated with dexmedetomidine render it less desirable for this purpose. PMID- 25024471 TI - Intrathecal clonidine with hyperbaric bupivacaine administered as a mixture and sequentially in caesarean section: A randomised controlled study. AB - BACKGROUND AND AIMS: Mixing adjuvants with hyperbaric bupivacaine in a single syringe before injecting the drugs intrathecally is an age old practice. In doing so, the density of the hyperbaric solution and also of the adjuvant drugs may be altered, thus affecting the spread of drugs. Administering local anaesthetic and the adjuvants separately may minimise the effect of the changes in densities. We aimed to compare block characteristics, intraoperative haemodynamics and post operative pain relief in parturients undergoing caesarean section (CS) after administering hyperbaric bupivacaine and clonidine intrathecally as a mixture and sequentially. METHODS: In this single-blind prospective randomised controlled study at a tertiary care centre from 2010 to 12, 60 full-term parturients scheduled for elective CSs were divided into two groups on the basis of technique of intrathecal drug administration. Group M received mixture of clonidine (75 mcg) and hyperbaric bupivacaine 0.5% (10 mg) intrathecally, whereas Group B received clonidine (75 mcg) followed by hyperbaric bupivacaine 0.5% (10 mg) through separate syringes. Observational descriptive statistics, analysis of variance test, Wilcoxon test and Chi-square test were used as applicable. RESULTS: Duration of analgesia was significantly longer in Group B (474.33 +/- 20.79 min) in which the drug was given sequentially than in Group M (337 +/- 18.22 min). Furthermore, the time to achieve highest sensory block and complete motor block was significantly less in Group B without any major haemodynamic instability and neonatal outcome. CONCLUSIONS: When clonidine and hyperbaric bupivacaine were administered in a sequential manner, block characteristics improved significantly compared to the administration of the mixture of the two drugs. PMID- 25024472 TI - Ultrasound guided peritubal infiltration of 0.25% Bupivacaine versus 0.25% Ropivacaine for postoperative pain relief after percutaneous nephrolithotomy: A prospective double blind randomized study. AB - BACKGROUND AND AIM: Percutaneous nephrolithotomy (PCNL) is a common for managing renal calculi. Pain in the initial post operatie period is relieved by infiltration of local anaesthetic around the nephrostomy tract. We aimed to compare the analgesic efficacy of bupivacaine and ropivacaine. METHODS: A total of 100 adult patients undergoing elective PCNL-under balanced general anaesthesia were randomly divided into bupivacaine group (Group B) and ropivacaine group (Group R). After completion of procedure, 23G spinal needle was inserted at 6 and 12 O'clock position under ultrasonic guidance up to renal capsule along the nephrostomy tube. A volume of 10 ml of either 0.25% bupivacaine or 0.25% ropivacaine solution was infiltrated in each tract while withdrawing the needle. Post-operative pain was assessed using visual analogue scale (VAS) and dynamic visual analogue scale (D-VAS) for initial 24 h. Intravenous tramadol was given as rescue analgesia when VAS >4. Time to first rescue analgesic, number of doses and total amount of tramadol required in initial 24 h and side-effects were noted. RESULTS: Visual analogue scale and D-VAS at 6 h and 8 h in Group B was significantly higher than Group R. Mean time to first rescue analgesia in Group R was significantly longer than Group B. Mean number of doses of tramadol and total consumption of tramadol in 24 h was less in Group R, though not statistically significant. CONCLUSION: Peritubal infiltration of 0.25% ropivacaine infiltration along the nephrostomy tract is more effective than 0.25% bupivacaine in alleviating initial post-operative pain after PCNL. PMID- 25024473 TI - Sensitivity of palm print sign in prediction of difficult laryngoscopy in diabetes: A comparison with other airway indices. AB - BACKGROUND AND AIMS: Diabetic patients are prone for the limited joint mobility syndrome. The atlanto-occipital joint involvement limits adequate extension of head and neck during laryngoscopy making intubation difficult. The collagen glycosylation starts in the fourth and fifth inter-phalangeal joints. The degree of inter-phalangeal involvement can be assessed by scoring the ink impression made by the palm of the dominant hand (palm print [PP] sign) The aim of our study was to evaluate the PP sign as a screening tool for predicting difficult laryngoscopy in diabetic patients. METHODS: A total of 60 diabetic patients undergoing general anaesthesia with endotracheal intubation were assessed pre operatively for their airway indices using the modified Mallampati test, thyromental distance, degree of head extension, the PP test and the prayer sign and their corresponding Cormack-Lehane scores were noted. Statistical analysis was performed using Fischer exact test. RESULTS: Of the 60 patients, 15 had positive PP sign. Of the 13 difficult laryngoscopies encountered, 10 patients had a positive PP sign. PP sign was the most sensitive index in predicting difficult laryngoscopy. P =0.000 was obtained and considered as statistically significant. The sensitivity was 76.9%, specificity 89.4%, positive and negative predictive value 71.4% and 91.3% and accuracy 86.7%, respectively. The other signs were not significant in predicting difficult laryngoscopy. CONCLUSION: The PP test appears to be the most sensitive and specific in the prediction of difficult laryngoscopy in diabetic patients. PMID- 25024474 TI - Effects of pretreatment with different neuromuscular blocking agents on facilitation of intubation with rocuronium: A prospective randomized comparative study. AB - BACKGROUND AND AIMS: Priming principle refers to administration of a small dose of non-depolarising blocker, which when followed by a large intubating dose produces a relatively rapid and profound blockade to ensure suitable conditions for endotracheal intubation. We aimed to compare the effects of rocuronium, vecuronium, and atracurium as "pretreatment" drugs on intubating conditions with rocuronium facilitated endotracheal intubation. METHODS: This double-blinded, randomised controlled prospective study was carried out at a tertiary health care hospital on patients undergoing surgical procedures under general anaesthesia. They were randomly allocated into three groups (n = 35) by computer generated randomisation chart to receive either rocuronium (0.06 mg/kg body weight) (Group A); vecuronium (0.01 mg/kg body weight) (Group B) or, atracurium (0.05 mg/kg body weight) (Group C), followed by intubating dose (0.6 mg/kg body weight) of rocuronium. The haemodynamic parameters and intubating conditions were studied and statistically analysed by ANOVA test and Student's t-test as applicable using statistical package for the social sciences 16.0 for windows (SPSS Inc., Chicago, IL, USA). RESULTS: Excellent intubating conditions were noted in maximum number of patients in Group C (97.41%). No significant differences were observed in the systolic blood pressure in all the three groups at all-time intervals. The mean arterial pressure rose significantly from baseline value to maximum, at '0' min in all the groups; however, no significant difference was observed amongst the groups (P > 0.05). CONCLUSION: Pretreatment with rocuronium bromide can facilitate endotracheal intubation in 60 s irrespective of non-depolarising muscle relaxants used for priming; however, it cannot attenuate haemodynamic changes associated with laryngoscopy and intubation. PMID- 25024475 TI - Anaesthetic management of shoulder arthroscopic repair in Parkinson's disease with deep brain stimulator. AB - We describe the anaesthetic management of arthroscopic repair for complete rotator cuff tear of shoulder in a 59-year-old female with Parkinson's disease (PD) with deep brain stimulator (DBS) using a combination of general anaesthesia with interscalene approach to brachial plexus block. The DBS consists of implanted electrodes in the brain connected to the implantable pulse generator (IPG) normally placed in the anterior chest wall subcutaneously. It can be programmed externally from a hand-held device placed directly over the battery stimulator unit. In our patient, IPG with its leads was located in close vicinity of the operative site with potential for DBS malfunction. Implications of DBS in a patient with PD for shoulder arthroscopy for anaesthesiologist are discussed along with a brief review of DBS. PMID- 25024476 TI - Acute cyanide Intoxication: A rare case of survival. AB - A 30-year-old male jewellery factory worker accidentally ingested silver potassium cyanide and was brought to the emergency department in a state of shock and profound metabolic acidosis. This patient was managed hypothetically with use of injection thiopentone sodium intravenously until the antidote was received. Cyanide is a highly cytotoxic poison and it rapidly reacts with the trivalent iron of cytochrome oxidase thus paralysing the aerobic respiration. The result is severe lactic acidosis, profound shock, and its fatal outcome. The patient dies of cardio-respiratory arrest secondary to dysfunction of the medullary centres. It is rapidly absorbed, symptoms begin few seconds after exposure and death usually occurs in <30 min. The average lethal dose for potassium cyanide is about 250 mg. We used repeated doses of thiopentone sodium till the antidote kit was finally in our hands, hypothesising that it contains thiol group similar to the antidote thiosulphate. Moreover, it is an anticonvulsant. We were successful in our attempts and the patient survived though the specific antidotes could be administered after about an hour. PMID- 25024477 TI - Leukemoid like reaction in a post CABG patient. AB - The presentation of leukemoid reaction in patients post-cardiac surgery is rare with limited prior reports in the English language literature. We report a case of raised leukocyte count with no evidence of infection in a patient post coronary artery bypass graft surgery. The exaggerated inflammatory response by the patient to extra-corporeal circulation was drastically elevated, but fell short of the leukaemoid reaction definition - so we have defined it as a leukaemoid like reaction. A clear correlation between the extra-corporeal circulation and inflammatory response is documented. PMID- 25024478 TI - Perioperative considerations in a sickle cell patient undergoing cardiopulmonary bypass. AB - An 11-year-old child, a known case of sickle cell anaemia with a history suggestive of sickling crisis in the past was scheduled for surgical pulmonary valvotomy. Pre-operative blood transfusion and hydroxyurea were administered. Pre operative blood transfusion is indicated in sickle cell disease patients to raise the haematocrit level and lower sickle haemoglobin (HbS) levels. Before the start of cardiopulmonary bypass (CPB), exchange transfusion was performed to reduce HbS level and raise adult haemoglobin level. Hypothermia was prevented by employing normothermic CPB. PMID- 25024479 TI - Emphysematous pancreatitis predisposed by Olanzapine. AB - A 32-year-old male presented to our intensive care unit with severe abdominal pain and was diagnosed as acute pancreatitis after 2 months of olanzapine therapy for bipolar disorder. His serum lipase was 900 u/L, serum triglyceride 560 mg/dL, and blood sugar, fasting and postprandial were 230 and 478 mg/dL, respectively on admission. Contrast enhanced computed tomography (CECT) of abdomen was suggestive of acute pancreatitis. Repeat CECT showed gas inside pancreas and collection in peripancreatic area and patient underwent percutaneous drainage and antibiotics irrigation through the drain into pancreas. We describe the rare case of emphysematous pancreatitis due to development of diabetes, hypertriglyceridemia and immunosuppression predisposed by short duration olanzapine therapy. PMID- 25024480 TI - Ultrasound guided selective cervical nerve root block and superficial cervical plexus block for surgeries on the clavicle. AB - We report the anaesthetic management of two cases involving surgeries on the clavicle, performed under superficial cervical plexus block and selective C5 nerve root block under ultrasound (US) guidance, along with general anaesthesia. Regional analgesia for clavicular surgeries is challenging. Our patients also had significant comorbidities necessitating individualised approach. The first patient had a history of emphysema, obesity, and was allergic to morphine and hydromorphone. The second patient had clavicular arthritis and pain due to previous surgeries. He had a history of smoking, Stevens-Johnson syndrome, along with daily marijuana and prescription opioid use. Both patients had an effective regional block and required minimal supplementation of analgesia, both being discharged on the same day. Interscalene block with its associated risks and complications may not be suitable for every patient. This report highlights the importance of selective regional blockade and also the use of US guidance for an effective and safe block. PMID- 25024481 TI - Re-expansion pulmonary oedema - differential lung ventilation comes to the rescue. AB - Re-expansion pulmonary oedema (REPE) is a rare complication following re inflation of a chronically collapsed lung, which is often fatal. We present a case of a 22-year-old male who presented to the hospital with severe respiratory distress and a history of blunt abdominal trauma 3 months back. He was diagnosed to have left sided diaphragmatic hernia with a mediastinal shift to the right, and was posted for emergency repair of the same. After surgical decompression of the left hemi-thorax and reduction of the abdominal contents, re-expansion of the left lung was achieved, following which patient developed REPE. A left sided double lumen tube was then inserted to prevent flooding and cross contamination of the right lung and ventilation of both lungs was maintained intraoperatively. Post-operatively, REPE was successfully managed by differential lung ventilation with a lung salvage strategy to the left lung and a lung protective strategy to the right lung. PMID- 25024482 TI - Predictors of postoperative cognitive dysfunction in adult patients undergoing elective cardiac surgery. PMID- 25024483 TI - Comparison of 0.75% ropivacaine and 0.5% bupivacaine for epidural anaesthesia in lower extremity orthopaedic surgeries. PMID- 25024484 TI - Missed nasopharyngeal teratoma: A cause for recurrent respiratory distress in a neonate. PMID- 25024485 TI - Klippel-Feil syndrome and neuraxial anaesthesia. PMID- 25024486 TI - Anaesthetic management of a case of hereditary spherocytosis for splenectomy and cholecystectomy. PMID- 25024487 TI - Colostomy in an ischiopagus, 3(rd) PND conjoined twins with cross-circulation: Anaesthetic management. PMID- 25024488 TI - A case of subacute intestinal obstruction with overt hypothyroidism in stupor scheduled for emergency laparotomy. PMID- 25024490 TI - John Scott Haldane: The father of oxygen therapy. AB - John Scott Haldane was a versatile genius who solved several problems of great practical significance. His ability to look beyond the laboratory and investigate theory added crucial findings in the field of respiratory physiology. His work on high altitude physiology, diving physiology, oxygen therapy, and carbon monoxide poisoning led to a sea change in clinical medicine and improved safety and reduced mortality and morbidity in many high risk situations. PMID- 25024491 TI - Massive haemoptysis and endotracheal tube blockade during subclavian vein cannulation. PMID- 25024492 TI - Split cord malformation and the anaesthesiologist. PMID- 25024493 TI - Parathyroidectomy under superficial cervical plexus block in a patient with severe kyphoscoliosis. PMID- 25024494 TI - Posterior tracheal wall rupture following uneventful general endotracheal anaesthesia. PMID- 25024495 TI - Right molar approach for uvulectomy of secondary non-hodgkins lymphoma of uvula. PMID- 25024496 TI - A patient with acute abducens nerve palsy for lower segment caesarean section. PMID- 25024497 TI - Lithotripsy under low dose spinal anaesthesia with dexmedetomidine in a patient with hypertrophic obstructive cardiomyopathy. PMID- 25024498 TI - Post-operative pulmonary embolism: Transthoracic echocardiography as a diagnostic tool. PMID- 25024499 TI - Foreign body oesophagus: The case of a missing second coin. PMID- 25024500 TI - Unusual cause for raised airway pressures related to anaesthesia workstation. PMID- 25024501 TI - Macintosh blade entrapment during direct laryngoscopy. PMID- 25024502 TI - Monitor screen display inversion: Potential for risk during anaesthesia. PMID- 25024503 TI - Mishap due to error in labelling-word of caution! PMID- 25024504 TI - Warming measures in paediatric cleft surgeries. PMID- 25024505 TI - Using 2D Correlation Analysis to Enhance Spectral Information Available from Highly Spatially Resolved AFM-IR Spectra. AB - The recent combination of atomic force microscopy and infrared spectroscopy (AFM IR) has led to the ability to obtain IR spectra with nanoscale spatial resolution, nearly two orders-of-magnitude better than conventional Fourier transform infrared (FT-IR) microspectroscopy. This advanced methodology can lead to significantly sharper spectral features than are typically seen in conventional IR spectra of inhomogeneous materials, where a wider range of molecular environments are coaveraged by the larger sample cross section being probed. In this work, two-dimensional (2D) correlation analysis is used to examine position sensitive spectral variations in datasets of closely spaced AFM IR spectra. This analysis can reveal new key insights, providing a better understanding of the new spectral information that was previously hidden under broader overlapped spectral features. Two examples of the utility of this new approach are presented. Two-dimensional correlation analysis of a set of AFM-IR spectra were collected at 200-nm increments along a line through a nucleation site generated by remelting a small spot on a thin film of poly(3-hydroxybutyrate co-3-hydroxyhexanoate). There are two different crystalline carbonyl band components near 1720 cm-1 that sequentially disappear before a band at 1740 cm-1 due to more disordered material appears. In the second example, 2D correlation analysis of a series of AFM-IR spectra spaced every 1 micrometer of a thin cross section of a bone sample measured outward from an osteon center of bone growth. There are many changes in the amide I and phosphate band contours, suggesting changes in the bone structure are occurring as the bone matures. PMID- 25024506 TI - Comparative plasma protein profiling of hemoglobin H disease. AB - HbH and HbH-constant spring (HbH-CS) are the most common forms of alpha thalassemia detected in the Thai population. The accumulation of excess beta globin chains in these diseases results in increased red cell hemolysis, and patients with HbH-CS normally have a more severe clinical presentation than patients with HbH disease. This study aimed to detect alterations in the expression of plasma proteins of HbH and HbH-CS patients as compared to normal plasma. Platelet poor plasma was separated from HbH and HbH-CS and normal subjects and differential plasma proteins were detected using two-dimensional gel electrophoresis and identified using LC/MS/MS. A total of 14 differentially expressed proteins were detected of which 5 proteins were upregulated and 9 were downregulated. Most of the differentially expressed proteins are liver secreted proteins involved in hemolysis, oxidative stress response, and hemoglobin degradation. Seven proteins were found to be differentially expressed between HbH and HbH-CS. Levels of haptoglobin, a hemoglobin scavenging protein, were significantly increased in HbH patients as compared to HbH-CS patients. The identification of differentially expressed proteins may lead to a better understanding of the biological events underlying the clinical presentation of HbH and HbH-CS patients and can have application as hemolytic markers or severity predictors. PMID- 25024507 TI - Interpreting consumer preferences: physicohedonic and psychohedonic models yield different information in a coffee-flavored dairy beverage. AB - Designed experiments provide product developers feedback on the relationship between formulation and consumer acceptability. While actionable, this approach typically assumes a simple psychophysical relationship between ingredient concentration and perceived intensity. This assumption may not be valid, especially in cases where perceptual interactions occur. Additional information can be gained by considering the liking-intensity function, as single ingredients can influence more than one perceptual attribute. Here, 20 coffee-flavored dairy beverages were formulated using a fractional mixture design that varied the amount of coffee extract, fluid milk, sucrose, and water. Overall liking (liking) was assessed by 388 consumers using an incomplete block design (4 out of 20 prototypes) to limit fatigue; all participants also rated the samples for intensity of coffee flavor (coffee), milk flavor (milk), sweetness (sweetness) and thickness (thickness). Across product means, the concentration variables explained 52% of the variance in liking in main effects multiple regression. The amount of sucrose (beta = 0.46) and milk (beta = 0.46) contributed significantly to the model (p's <0.02) while coffee extract (beta = -0.17; p = 0.35) did not. A comparable model based on the perceived intensity explained 63% of the variance in mean liking; sweetness (beta = 0.53) and milk (beta = 0.69) contributed significantly to the model (p's <0.04), while the influence of coffee flavor (beta = 0.48) was positive but marginally (p = 0.09). Since a strong linear relationship existed between coffee extract concentration and coffee flavor, this discrepancy between the two models was unexpected, and probably indicates that adding more coffee extract also adds a negative attribute, e.g. too much bitterness. In summary, modeling liking as a function of both perceived intensity and physical concentration provides a richer interpretation of consumer data. PMID- 25024508 TI - Integrating traditional medicine into modern inflammatory diseases care: multitargeting by Rhus verniciflua Stokes. AB - Despite the fact that numerous researches were performed on prevention and treatment of inflammation related diseases, the overall incidence has not changed remarkably. This requires new approaches to overcome inflammation mediated diseases, and thus traditional medicine could be an efficacious source for prevention and treatment of these diseases. In this review, we discuss the contribution of traditional medicine, especially Rhus verniciflua Stokes, to modern medicine against diverse inflammation mediated diseases. Traditionally, this remedy has been used in Eastern Asia for the treatment of gastric problems, hepatic disorders, infectious diseases, and blood disorders. Modern science has provided the scientific basis for the use of Rhus verniciflua Stokes against such disorders and diseases. Various chemical constituents have been identified from this plant, including phenolic acid, and flavonoids. Cell-based studies have exhibited the potential of this as antibacterial, antioxidant, neuroprotective, anti-inflammatory, growth inhibitory, and anticancer activities. Enormous animal studies have shown the potential of this against proinflammatory diseases, neurodegenerative diseases, diabetes, liver diseases, and chemical insults. At the molecular level, this medicinal plant has been shown to modulate diverse cell signaling pathways. In clinical studies, Rhus verniciflua Stokes has shown efficacy against various cancer patients such as colorectal, gastric, hepatic, renal, pancreatic, and pulmonary cancers. Thus, this remedy is now exhibiting activities in the clinic. PMID- 25024509 TI - The impact of Staphylococcus aureus-associated molecular patterns on staphylococcal superantigen-induced toxic shock syndrome and pneumonia. AB - Staphylococcus aureus is capable of causing a spectrum of human illnesses. During serious S. aureus infections, the staphylococcal pathogen-associated molecular patterns (PAMPs) such as peptidoglycan, lipoteichoic acid, and lipoproteins and even intact S. aureus, are believed to act in conjunction with the staphylococcal superantigens (SSAg) to activate the innate and adaptive immune system, respectively, and cause immunopathology. However, recent studies have shown that staphylococcal PAMPs could suppress inflammation by several mechanisms and protect from staphylococcal toxic shock syndrome, a life-threatening systemic disease caused by toxigenic S. aureus. Given the contradictory pro- and anti inflammatory roles of staphylococcal PAMPs, we examined the effects of S. aureus derived molecular patterns on immune responses driven by SSAg in vivo using HLA DR3 and HLA-DQ8 transgenic mice. Our study showed that neither S. aureus-derived peptidoglycans (PGN), lipoteichoic acid (LTA), nor heat-killed Staphylococcus aureus (HKSA) inhibited SSAg-induced T cell proliferation in vitro. They failed to antagonize the immunostimulatory effects of SSAg in vivo as determined by their inability to attenuate systemic cytokine/chemokine response and reduce SSAg induced T cell expansion. These staphylococcal PAMPs also failed to protect HLA DR3 as well as HLA-DQ8 transgenic mice from either SSAg-induced toxic shock or pneumonia induced by a SSAg-producing strain of S. aureus. PMID- 25024512 TI - Mentorship-challenges ahead. PMID- 25024511 TI - Topical herbal application in the management of atopic dermatitis: a review of animal studies. AB - Herbs are widely used in the treatment of atopic dermatitis (AD) in Eastern Asian countries, and certain herbs regarded have anti-inflammatory properties that can help with AD. With the goal of developing a topical herbal agent for AD, we conducted a systematic review of in vivo studies of AD-like skin models for screening potential herbs. Searches were conducted from PubMed and EMBASE. After all, 22 studies were included for this review. We judged most of the domains of all studies to be at unclear risk of bias. Among 22 included studies, 21 herbs have been reported to reduce AD-like skin lesions in mouse models by suppressing Th2 cell response. Our findings may offer potential herbs for the topical application treatment of AD. PMID- 25024513 TI - Data mining in radiology. AB - Data mining facilitates the study of radiology data in various dimensions. It converts large patient image and text datasets into useful information that helps in improving patient care and provides informative reports. Data mining technology analyzes data within the Radiology Information System and Hospital Information System using specialized software which assesses relationships and agreement in available information. By using similar data analysis tools, radiologists can make informed decisions and predict the future outcome of a particular imaging finding. Data, information and knowledge are the components of data mining. Classes, Clusters, Associations, Sequential patterns, Classification, Prediction and Decision tree are the various types of data mining. Data mining has the potential to make delivery of health care affordable and ensure that the best imaging practices are followed. It is a tool for academic research. Data mining is considered to be ethically neutral, however concerns regarding privacy and legality exists which need to be addressed to ensure success of data mining. PMID- 25024510 TI - Proteomic analysis of lung tissue in a rat acute lung injury model: identification of PRDX1 as a promoter of inflammation. AB - Acute respiratory distress syndrome (ARDS) remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI) lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS) challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-alpha), whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI. PMID- 25024514 TI - Erratum. PMID- 25024515 TI - PET reconstruction artifact can be minimized by using sinogram correction and filtered back-projection technique. AB - Filtered Back-Projection (FBP) has become an outdated image reconstruction technique in new-generation positron emission tomography (PET)/computed tomography (CT) scanners. Iterative reconstruction used in all new-generation PET scanners is a much improved reconstruction technique. Though a well-calibrated PET system can only be used for clinical imaging in few situations like ours, when compromised PET scanner with one PET module bypassed was used for PET acquisition, FBP with sinogram correction proved to be a better reconstruction technique to minimize streak artifact present in the image reconstructed by the iterative technique. PMID- 25024516 TI - Simultaneous PET/MRI: Impact on cancer management-A comprehensive review of cases. AB - The metabolic mapping of malignancy in whole body in a single examination by PET/CT has gained widespread acceptance where the CT provides an anatomical correlate for the PET. MRI offers advantage over CT in providing better anatomical information owing to its high soft tissue resolution especially in brain, liver, neck, pelvis and bone marrow. Simultaneous PET/MRI is a new multimodal imaging modality that is expected to improve the diagnostic performance of imaging wherein better anatomical and metabolic information can be acquired at the same time and space during a single examination time. Also, MR attributes like diffusion, perfusion and spectroscopy may further add to its diagnostic potential. In this article, we present our initial experience in illustrated cases done with simultaneous PET/MRI and outline its potential for several clinical applications in oncology. PMID- 25024517 TI - IgG4-related disease with sinonasal involvement: A case series. AB - We present the imaging findings in two cases of IgG4-related disease involving the sinonasal region in the pediatric age group. Imaging findings in IgG4-related disease affecting the nasal cavity and paranasal sinuses have been rarely reported in literature. The diagnosis is made by a combination of clinical, imaging, and histopathologic findings. Radiologists should be aware of the imaging findings of this condition to ensure early diagnosis and treatment. PMID- 25024518 TI - Persistent pulmonary interstitial emphysema in a case of Langerhans cell histiocytosis. AB - We present the case of a 10-month-old boy with multisystem Langerhans cell histiocytosis showing thin-walled lung cysts along with computed tomography (CT) evidence of persistent pulmonary interstitial emphysema (PPIE), in the absence of pneumothorax or pneumomediastinum. Follow-up CT performed after 6 months demonstrated complete resolution of interstitial emphysema. PMID- 25024519 TI - Automatic scan triggering software "confused": Computed tomography angiography in foot arteriovenous malformation! AB - Multidetector computed tomography angiography (MDCTA) has become a well established modality for limb angiography for a variety of indications. The technique of MDCTA depends on the scanner features including the number of detector rows, rotation speeds and single or dual source energy. Integral to a diagnostic quality CTA is the acquisition timing. Various techniques are available for determining the appropriate timing of scan acquisition which includes fixed delay, test bolus and the bolus tracking technique. The transit times of contrast from the aorta to the peripheral arteries shows a wide variability and is dependent upon the inter individual hemodynamic states. The bolus tracking technique is the most preferred one which allows reliable scan timing with acceptable contrast volume and radiation dose. Pitfalls with all these techniques are well described and we report one such technical pitfall in a case of left foot arteriovenous malformation (AVM) where the bolus tracking technique employed for scan triggering failed to initiate acquisition. PMID- 25024520 TI - Bilateral transrenal ureteral occlusion by means of n-butyl cyanoacrylate and AMPLATZER vascular plug. AB - AMPLATZER vascular plug is a widely used embolic agent. In the present paper, we present a case of an 86-year-old female patient who underwent bilateral ureteral occlusion by means of AMPLATZER vascular plug II coupled to n-butyl cyanoacrylate (NBCA) because of recurring pyelonephritis following cystectomy with subsequent bilateral ureterosigmoidostomy (sec. Mainz type II). PMID- 25024521 TI - An indigenous model for learning ultrasound-guided interventions. AB - Ultrasound-guided interventions require good hand-eye coordination with respect to probe control and needle orientation. We describe a method of making an ultrasound phantom for practice purpose using an edible jelly mixture. The phantom is easy to make, reproducible, cheap, and simulates in vivo target. PMID- 25024522 TI - Intercostal artery pseudoaneurysm complicating corrosive acid poisoning: Diagnosis with CT and treatment with transarterial embolisation. AB - Pseudoaneurysms of intercostal artery are very rare. All the published cases have been caused by trauma, either iatrogenic or otherwise. They can cause hemothorax, retroperitoneal hemorrhage or can present as pulsatile chest mass. Doppler ultrasound, contrast-enhanced CT and conventional angiogram can accurately diagnose this condition. All the reported cases have been treated by embolisation, stenting or surgery. We report an unusual case of intercostal artery pseudoaneurysm arising as a complication of corrosive poisoning presenting with hematemesis and treated by glue embolisation. The authors believe this to be the first case of intercostal artery pseudoaneurysm that is non-traumatic, complicating corrosive poisoning and presenting with hematemesis. PMID- 25024523 TI - Imaging and intervention in prostate cancer: Current perspectives and future trends. AB - Prostate cancer is the commonest malignancy in men that causes significant morbidity and mortality worldwide. Screening by digital rectal examination (DRE) and serum prostate-specific antigen (PSA) is used despite its limitations. Gray scale transrectal ultrasound (TRUS), used to guide multiple random prostatic biopsies, misses up to 20% cancers and frequently underestimates the grade of malignancy. Increasing the number of biopsy cores marginally increases the yield. Evolving techniques of real-time ultrasound elastography (RTE) and contrast enhanced ultrasound (CEUS) are being investigated to better detect and improve the yield by allowing "targeted" biopsies. Last decade has witnessed rapid developments in magnetic resonance imaging (MRI) for improved management of prostate cancer. In addition to the anatomical information, it is capable of providing functional information through diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and dynamic contrast-enhanced (DCE) MRI. Multi-parametric MRI has the potential to exclude a significant cancer in majority of cases. Inclusion of MRI before prostatic biopsy can reduce the invasiveness of the procedure by limiting the number of cores needed to make a diagnosis and support watchful waiting in others. It is made possible by targeted biopsies as opposed to random. With the availability of minimally invasive therapeutic modalities like high-intensity focused ultrasound (HIFU) and interstitial laser therapy, detecting early cancer is even more relevant today. [18F]--fluorodeoxyglucose positron emission tomography/computed tomography ((18)FDG PET/CT) has no role in the initial evaluation of prostate cancer. Choline PET has been recently found to be more useful. Fluoride-PET has a higher sensitivity and resolution than a conventional radionuclide bone scan in detecting skeletal metastases. PMID- 25024524 TI - Computed tomography and magnetic resonance imaging in the evaluation of pelvic peritoneal adhesions: What radiologists need to know? AB - Pelvic peritoneal adhesions constitute an important cause of concern which affects the life of millions of people worldwide due to complications like abdominal pain, bowel obstruction and infertility along with challenges in surgical exploration. Precise pre-operative diagnosis of the presence and extent of peritoneal adhesions is of great clinical and surgical importance. Diagnostic laparoscopy to detect peritoneal adhesions may itself lead to formation of adhesions. Routine CT and MRI studies are therefore useful non-invasive modalities to achieve this objective. This review article provides a brief background about the causation and patho-physiology of peritoneal adhesions. The article also addresses the range of clinical presentations in these patients, mainly from the gynecologic perspective. This article provides an illustrative review of CT and MRI findings with laparoscopic correlation. A new 'imaging-based grading system' for pre-operative quantification of the burden of peritoneal adhesions is also proposed. Despite practical challenges in accurate pre operative diagnosis of peritoneal adhesions on imaging, detection of peritoneal adhesions is certainly feasible on routine CT and MRI scans and should be an integral part of image interpretation. PMID- 25024525 TI - MR in complete dorsal pancreatic agenesis: Case report and review of literature. AB - The morphogenesis of the pancreas is a complex process having a very low frequency of anatomic variation. The congenital anomalies are rare. Complete pancreatic and ventral pancreatic agenesis are incompatible with life. Dorsal pancreatic agenesis is exceedingly rare with less than 100 cases reported in the world literature. Patients with this anomaly may be asymptomatic or may present with abdominal pain, hyperglycemia, diabetes mellitus, and acute or chronic pancreatitis. Such anomalies are rarely reported; therefore, clinical awareness of agenesis of the dorsal pancreas as a cause of these symptoms can expand the differential diagnosis and improve patient management. PMID- 25024526 TI - Fetal gastric pseudomass at 30 weeks of gestation and its regression after 17 days of birth. AB - Second trimester fetal ultrasonography (USG) occasionally reveals an echogenic intragastric mass. These masses are usually small due to the organized debris from swallowed amniotic fluid, and they normally disappear in the third trimester. This report shows a fetal intragastric echogenic mass detected at 30 weeks of gestation that persisted as a large heterogeneously echoic mass even on the 10(th) day after birth. The immediate postnatal USG features were consistent with the possibility of an intragastric soft tissue mass, though abdominal radiographs and computed tomography (CT) with oral contrast were non-specific. The baby remained asymptomatic in the neonatal period and USG scanning again after a week showed normal stomach and other intra-abdominal visceral echoes. PMID- 25024527 TI - Sonography of acute appendicitis and its mimics in children. AB - The diagnosis of acute right lower quadrant pain in a pediatric population is challenging. Acute appendicitis is the most common cause of an acute surgical abdomen. The common mimics of acute appendicitis are acute gastrointestinal and gynecologic diseases. This article reviews the sonographic findings of the spectrum of common acute abdominal emergencies in children with a focus on imaging clues to a specific diagnosis. This awareness can impact on diagnostic accuracy and impact patient management. PMID- 25024528 TI - Stretched bowel sign in combined transmesocolic and transomental internal hernia: A case report and review of literature. AB - Transomental and transmesenteric hernias are rare types of internal hernia, with a reported frequency of upto 4% and 8%, respectively. Combined transomental and transmesocolic hernia is even rare. Only in a few types of internal hernia, the dilated small bowel loops will be seen extending from the antero-superior aspect of the distal stomach and cause stretching effect over the adjacent bowel loops with increase in the size of the herniated bowel segment or intestinal obstruction. We report a rare case of idiopathic combined transomental (across the lesser omentum) and transmesocolic internal hernia with "stretched bowel sign," its diagrammatic representations, and review of literature. PMID- 25024529 TI - Hydrocele of the canal of Nuck - Rare differential for vulval swelling. AB - Patent canal of Nuck is one of the rare developmental entities in females, presenting clinically as an inguino-labial swelling. The usual content of this sac is fluid being secreted by the peritoneal mesothelium. In rare cases, ovary alone or with fallopian tube may prolapsed out into the sac. We report the rationale use of diagnostic algorithm in a case of ovarian hernia into the patent canal of Nuck, to differentiate it from more common clinical mimics. Furthermore, in the present case, a knowledge of the entity and targeted scrutiny, led to a correct identification of the prolapsed ovary, preventing an unwarranted oophorectomy in the garb of neoplasia. PMID- 25024530 TI - Imaging diagnosis of accessory and cavitated uterine mass, a rare mullerian anomaly. AB - Accessory and Cavitated Uterine Mass (ACUM) is a rare form of developmental Mullerian anomaly seen in young females, which presents as chronic recurrent pelvic pain and severe dysmenorrhea. It is an accessory cavity lying within an otherwise normal uterus. It is lined by functional endometrium and surrounded by myometrium-like smooth muscle cells; hence, it bears striking macroscopic and microscopic resemblance to the uterus. Hysterosalpingography (HSG), Ultrasonography (USG), and Magnetic Resonance Imaging (MRI) form the mainstay of diagnostic imaging. The entity is often under diagnosed; therefore, a high index of suspicion combined with HSG and MRI imaging can help in making an accurate diagnosis. PMID- 25024531 TI - Cysts and cystic-appearing lesions of the knee: A pictorial essay. AB - Cysts and cystic-appearing lesions around the knee are common and can be divided into true cysts (synovial cysts, bursae, ganglia, and meniscal cysts) and lesions that mimic cysts (hematomas, seromas, abscesses, vascular lesions, and neoplasms). The specific anatomic location of the cystic lesion often permits the correct diagnosis. In difficult cases, identifying a cystic mass in an atypical location and/or visualizing internal solid contrast enhancement on magnetic resonance imaging (MRI) should raise concern for a neoplasm and the need for further evaluation and intervention. PMID- 25024532 TI - Melorheostosis: Two atypical cases. AB - Melorheostosis is an uncommon mesenchymal dysplasia that rarely affects the axial skeleton. We describe two atypical cases of melorheostosis with classical imaging findings - the first one involving the cervico-dorsal spine with encroachment of left vertebral artery canal causing attenuation of the left vertebral artery and the second one of mixed sclerosing bony dysplasia (monomelic involvement coexisting with osteopoikilosis). PMID- 25024533 TI - Accuracy of ultrasonography in detecting radiolucent soft-tissue foreign bodies. AB - BACKGROUND AND OBJECTIVE: Detection of radiolucent soft-tissue foreign bodies is a challenging problem, which is especially further complicated when retained foreign body is highly suggested by clinicians but radiography is negative. So, blind exploration is sometimes hazardous for patients. The purpose of this study was to determine the accuracy of ultrasonography (USG) in detecting radiolucent soft-tissue foreign bodies in the extremities. MATERIALS AND METHODS: From November 2011 to January 2012, patients with clinically suspected radiolucent soft-tissue foreign body and negative radiography were evaluated by USG with a 12 MHz linear array transducer. The patients with positive clinical and USG examination were included in our study and underwent exploration or USG removal. RESULTS: Fifty-one patients underwent foreign body removal under ultrasonography guided or surgical exploration and 47 patients had foreign body (31, 12, 3, and 1 case had thorn, wood, glass, and plastic, respectively). Ultrasound was positive in 50 patients. USG falsely predicted the presence of foreign body in four cases and was falsely negative in one of the cases. Accuracy, sensitivity, and positive predictive value were determined as 90.2%, 97.9%, and 92%, respectively. CONCLUSIONS: The real-time high-frequency USG is a highly sensitive and accurate tool for detecting and removing radiolucent foreign bodies which are difficult to be visualized by routine radiography. PMID- 25024534 TI - Re:Utility of mobile devices in the computerized tomography evaluation of intracranial hemorrhage. PMID- 25024535 TI - Utility of mobile devices in the computerized tomography evaluation of intracranial hemorrhage. PMID- 25024536 TI - Can't find your article online? Have you used the right keywords?? PMID- 25024537 TI - Cruise control. PMID- 25024538 TI - Host modulation therapy: An indispensable part of perioceutics. AB - Traditionally, only antimicrobials have been used as the chemotherapeutic modality for the treatment of periodontitis. Though bacteria are the primary etiologic factors of periodontal diseases, yet the extent and severity of tissue destruction seen in periodontitis is determined by the host immuno-inflammatory response to these bacteria. This increasing awareness and knowledge of the host microbial interaction in periodontal pathogenesis has presented the opportunity for exploring new therapeutic strategies for periodontitis by means of targeting host response via host-modulating agents. This has lead to the emergence of the field of "Perioceutics" i.e. the use of parmacotherapeutic agents including antimicrobial therapy as well as host modulatory therapy for the management of periodontitis. These host-modulating agents used as an adjunct tip the balance between periodontal health and disease progression in the direction of a healing response. In this article the host-modulating role of various systemically and locally delivered perioceutic agents will be reviewed. PMID- 25024539 TI - An insight into the possibilities of fibroblast growth factor in periodontal regeneration. AB - Periodontitis is caused by bacterial biofilms and is modulated by a variety of risk factors. The periodontal ligament comprises heterogeneous cell populations which are lost in the disease process. A variety of regenerative therapies, such as bone grafts, guided tissue regeneration treatment, application of enamel matrix derivative, have been introduced, with some success in periodontal tissue regeneration. Topical application of recombinant cytokines is now one of the most effective methods to stimulate stem cells. Researchers are now exploring the potential applications and uses of fibroblast growth factor in periodontal regeneration. PMID- 25024540 TI - Modulation of P-selection and platelet aggregation in chronic periodontitis: A clinical study. AB - BACKGROUND: The primary etiologic factor of periodontitis is the subgingival infection with a group of Gram negative pathogens. Transient bacteremia in periodontitis patients underlie chronic production and systemic increases of various proinflammatory mediators, including Interleukin (IL)-1alpha, IL-6, C reactive protein and Tumor necrosis factor (TNF)-alpha. P- selectin is a member of selectin family of cell surface receptor which is located in the membrane of the secretory granules (alpha granules) of platelets and in the membrane of the Weibel-Palade bodies of the vascular endothelial cells. P selectin redistributes from the membrane of the granules to the plasma membrane when platelets and endothelial cells are activated and thus degranulated. AIM: To compare the level of platelet activation, soluble P Selectin level and morphological changes and aggregation of platelets in patients in periodontitis patients compared to healthy controls. MATERIALS AND METHODS: 80 patients were included in the study with the age group of 35-60. The patients were divided into 2 groups, 40 subjects with generalized chronic periodontitis and 40 healthy subjects taken as control. Periodontal Examination using clinical parameters namely, Bleeding Index, Plaque Index, Probing Pocket Depth and Clinical Attachment Level were recorded. Collection of blood samples for estimation of serum soluble P- selectin level by ELISA method. Evaluation of Platelet morphology and grading the platelet aggregation. RESULTS: P-selectin expression shows that the mean value for control group is 4.97 +/- 16.56 ng/mL and study group 13.05 +/- 29.94 ng/mL which was significantly higher than control group with P value 0.001. Platelet morphological changes shows small form - mean value for control group is 75.83% +/- 14.24% while for study group is 39.08%. +/- 21.59; Big form - mean value for control group 0.80% +/- 0.35% while for study group 0.48% +/- 1.3%and Spider form mean value for control group 23.88% +/- 14.13 while study group 59.32% +/-. 23.42. The observation showed high statistical significance with P- value < 0.001 for small and spider form and no statistical significance for big form P = 0.075. CONCLUSION: Increased expression of P-selectin, spider form of platelets and pathological aggregation pattern which indicates that platelet activation may be associated with chronic periodontitis. The results of the study showed, higher number of spider forms and significant pathological aggregation pattern in periodontitis patients which indicates activation of platelets thus emphasized that periodontitis can be an contributing factor in the development of cardiovascular disease. PMID- 25024541 TI - Estimation of tissue inhibitor of matrix metalloproteinase-1 levels in gingival crevicular fluid in periodontal health, disease and after treatment. AB - BACKGROUND: Initial research has shown a negative correlation between the severity of periodontal disease and tissue inhibitor of matrix metalloproteinases (TIMPs) concentrations in gingival crevicular fluid (GCF). However, there are no enough reports to correlate the TIMP-1 concentrations in GCF in periodontal health, disease and after treatment. Hence, the present study aim is to estimate the levels of TIMP-1 in GCF in periodontal health, disease and to evaluate the effect of periodontal therapy on TIMP-1 concentrations in GCF. MATERIALS AND METHODS: Periodontal examination and collection of GCF by extracrevicular method was performed in 25 subjects selected randomly and categorized into three groups. Group I (Healthy, n = 10), Group II (chronic periodontitis (CP), n = 15) and Group III (After treatment group, n = 15). Scaling and root planning was performed and GCF was collected after 8 weeks of treatment. TIMP-1 levels were estimated in GCF samples by using enzyme linked immunosorbent assay. RESULTS: TIMPs-1 was detected in all samples. Highest mean TIMP-1 concentrations in GCF were obtained for Group I, whereas the lowest concentrations were seen in Group II. This suggests that TIMP-1 levels in GCF decreases proportionally with the progression of periodontal disease and increases after treatment. CONCLUSION: There is a substantial decrease in the concentrations of TIMP-1 in CP patients than in healthy and after treatment individuals. Since TIMP-1 levels in GCF are negatively correlated with periodontal disease, TIMP-1 may be considered as a biomarker in periodontal disease progression. However, controlled, longitudinal studies are needed to confirm this possibility. PMID- 25024542 TI - Salivary TNF-alpha: A potential marker of periodontal destruction. AB - AIMS AND OBJECTIVES: (1) To evaluate the effect of type 2 diabetes mellitus on salivary TNF-alpha level in chronic periodontitis. (2) To evaluate the effect of smoking on salivary TNF-alpha level in chronic periodontitis. (3) To compare and correlate TNF-alpha level with the healthy individuals. MATERIALS AND METHODS: Subjects aged 30-35 years were included for the study and divided into four groups as a group of 20 systemically and periodontally healthy individuals (group I), a group of 20 subjects with pocket probing depth (PPD) >=5 mm and clinical attachment loss (CAL) of >=2 mm (group II), a group of 20 diabetic subjects (of more than 5 years) with periodontal parameters as of group II as (group III) and a group of 20 subjects smoking (>=10 cigarettes a day) with periodontal parameters of group II as (group IV). Periodontal parameters of PPD, CAL, gingival index (GI), and plaque index (PI) were measured using standard indices and criteria. Three milliliter of unstimulated saliva was taken and salivary TNF alpha determined by using ELISA technique (Quantikine Human total TNF-A immunoassay kit). RESULTS: Data revealed highest mean TNF-alpha in group III followed by group IV, group II, and group I. Mean TNF-alpha of both group III (76.1%) and group IV (48.8%) was significantly higher as compared to group I (P < 0.001). Mean TNF-alpha of group III was also found to be significantly different and higher (68.1%) as compared to group II (P < 0.001). Although higher mean TNF alpha (31.5%) was found in group IV in comparison to group II, the difference was not statistically significant. Besides above, TNF-alpha also showed a direct positive correlation with PPD in group II (r = 0.30, P > 0.05) and a significant negative correlation was observed between CAL and TNF-alpha in group IV. CONCLUSION: Our study clearly underlines a profound impact of diabetes and smoking on salivary TNF-alpha in chronic periodontitis subjects in comparison to healthy subjects. Moreover, diabetes status increased TNF-alpha significantly in comparison to smoking in chronic periodontitis patients. PMID- 25024543 TI - Treatment of drug-induced gingival overgrowth by full-mouth disinfection: A non surgical approach. AB - BACKGROUND: Drug-induced gingival overgrowth is a common finding in the modern era. These gingival overgrowths are usually treated by various modalities namely substitution of drugs, surgical, and non-surgical treatment. The recent concept mainly involves full-mouth scaling and root planing (the entire dentition in two visits within 24 hours, i.e., two consecutive days) followed by chair side mouth rinsing by the patient with a 0.2% chlorhexidine solution for 2 minutes and brushing the tongue of the patient with 1% chlorhexidine gel. This is followed by an additional subgingival irrigation (three times, repeated within 10 minutes) of all pockets with a 1% chlorhexidine gel. MATERIALS AND METHODS: Twenty patients between the ages of 20 and 50 years with drug-induced gingival overgrowth were treated using the full-mouth disinfection approach. The patients were evaluated at 3 months and 6 months after therapy. The data obtained for plaque index, bleeding on probing index, probing pocket depth, and gingival overgrowth scores were tabulated and compared statistically using the one sample unpaired t test. STATISTICAL ANALYSIS: Statistically significant difference (P < 0.05) was found in PI GBI, PPD, and GO score between baseline, 3 months, and 6 months. RESULTS: All clinical parameters improved significantly after therapy without the need of further surgical treatment. CONCLUSIONS: Full-mouth disinfection might be a beneficial treatment concept in patients with drug-induced gingival overgrowth, thus decreasing the need for surgical therapy. PMID- 25024544 TI - A comparative study of antiplaque and antigingivitis effects of herbal mouthrinse containing tea tree oil, clove, and basil with commercially available essential oil mouthrinse. AB - BACKGROUND: The relatively safe nature and cost-effectiveness of herbal extracts have led to a resurgent interest in their utility as therapeutic agents. Therefore, this prospective, double-blind, randomly controlled clinical trial was designed to compare the antiplaque and antigingivitis effects of newly formulated mouthrinse containing tea tree oil (TTO), clove, and basil with those of commercially available essential oil (EO) mouthrinse. MATERIALS AND METHODS: Forty patients were selected for a 21-day study period and randomly divided into two groups. The test group patients were given newly formulated herbal mouthrinse and the control group patients were given commercially available EO mouthrinse. The Plaque Index (PI), Gingival Index (GI), and Papillary Marginal Attachment (PMA) Index were recorded at baseline, 14 days, and 21 days. The microbial colony forming units (CFU) were assessed at baseline and 21 days. RESULTS: Test group patients using herbal mouthrinse showed significant improvement in GI (0.16), PI (0.57), and PMA (0.02) scores. These improvements were comparable to those achieved with commercially available EO mouthrinse. However, the aerobic and anaerobic CFU of microbiota were reduced with the herbal mouthrinse (P = 0.0000). CONCLUSION: The newly formulated herbal mouthrinse and commercially available mouthrinse were beneficial clinically as antiplaque and antigingivitis agents. Newly formulated mouthrinses showed significant reduction in microbial CFU at 21 days. So, our findings support the regular use of herbal mouthrinse as an antiplaque, antigingivitis, and antimicrobial rinse for better efficacy. PMID- 25024545 TI - Poor periodontal health as a risk factor for development of pre-eclampsia in pregnant women. AB - AIMS: Periodontal disease has been considered a systemic exposure implicated in a higher risk of adverse pregnancy outcomes. The aim of the present study was to determine whether maternal oral health is associated with an increased risk of pre-eclampsia. SUBJECTS AND METHODS: A case-control study was conducted which included 40 pregnant women patients admitted to the Department of Obstetrics and Gynecology, J.N. Medical College, A.M.U, Aligarh. Pre-eclampsia was defined as classic triad of hypertension, proteinuria and symptoms such as swelling/edema esp. in hands and face, headache, visual changes etc., A periodontal examination was done during 48 h after child delivery. Maternal oral status was evaluated using gingival index by Loe and Silness, oral hygiene index (simplified) by greene and vermillion and periodontal pockets and clinical attachment level (CAL). STATISTICAL ANALYSIS: Null hypothesis that no difference exist between the two groups (pre-eclamptic and non-pre-eclamptic Group) was calculated using paired t-test, Chi-square and Mann-Whitney U statistical tests using SPSS 11.5 (Statistical Package for Social sciences, Chicago). P < 0.05 was considered to be statistically significant. RESULTS: The amount of gingival inflammation, oral hygiene levels, pocket depth and CALs as measured by their respective indices were higher in the pre-eclamptic group when compared to non-pre-eclamptic group. Furthermore CAL was significantly increased in the test group. This study showed that pre-eclamptic cases were more likely to develop periodontal disease (P < 0.05). 30% of the test group and 65% of the case group had periodontal disease (P < 0.05) which had shown that pre-eclamptic cases were 4.33 times more likely to have periodontal disease (odds ratio = 4.33). CONCLUSIONS: Maternal oral status was determined to be associated with an increased risk of pre-eclampsia. PMID- 25024546 TI - A comparison between connective tissue grafts combined with either double pedicle grafts or coronally positioned pedicle grafts: A clinical study. AB - BACKGROUND: Various surgical techniques have been proposed for treating gingival recession. This randomized clinical study compared the effectiveness of using a sub-epithelial connective tissue graft (SCTG) combined with an overlying double pedical graft (DPG) or a coronally positioned flap (CPF) in the treatment of isolated gingival recession. MATERIALS AND METHODS: A total of 20, healthy, non smoking subjects with single Miller's Class I or Class II recession defects were selected. The defects, at least 3.0 mm deep, were randomly assigned to the test (DPG + SCTG) or control group (CPF + SCTG). Gingival recession (REC), probing pocket depth (PPD), clinical attachment level (CAL), width of keratinized gingival tissue (WKG), plaque index and papillary bleeding index were assessed at baseline and 6 months post-operatively. RESULTS: Recession depth was significantly reduced 6 months post-operatively (P < 0.05) for both groups. Mean root coverage was 88% and 84% in the test and control groups, respectively. There were no significant differences between the two groups in REC, PPD, CAL, or WKG at baseline. However, at 6 months post-operatively, there were statistically significant changes in REC, CAL and WKG in favor of the test group (P < 0.05) from the baseline, but the comparison between the two was not statistically significant. The percentage of teeth with complete root coverage was greater in the test group when compared to the control group, but the results were not statistically significant. CONCLUSIONS: The results indicate that both surgical approaches are effective in addressing root coverage. Furthermore, when an increase in keratinized tissue width is a desired outcome, both the treatment modalities have shown comparable outcomes. PMID- 25024547 TI - Periosteum as a barrier membrane in the treatment of intrabony defect: A new technique. AB - OBJECTIVE: The purpose of the study was to evaluate the clinical effectiveness of periosteum as a barrier membrane for the treatment of intrabony defects. MATERIALS AND METHODS: The study was conducted in patients having bilateral intrabony defects. A total of 20 intrabony defects in 10 patients were treated, out of which 10 defects received periosteal barrier and the other 10 defects received conventional open flap debridement procedure. The efficacy of the treatment was assessed using clinical parameters and dentascan. RESULTS: Statistically significant gain in clinical attachment level (CAL) was found in the test group (2.00 +/- 0.26 mm) as compared to the control group (0.60 +/- 0.22 mm). In both the treatment modalities (test and control groups), a significant decrease in probing pocket depth of 3.90 +/- 0.35 mm and 2.90 +/- 0.31 mm was observed, respectively. The difference between the two groups was not statistically significant. Bone defect fill was 1.40 +/- 0.16 mm for the test group and 0.90 +/- 0.18 mm for the control group, but the difference observed was not statistically significant. CONCLUSION: The results of this study show that periosteal barrier membrane can be a better alternative of barrier membranes for the treatment of intrabony defects. PMID- 25024548 TI - A comparative evaluation of bovine-derived xenograft (Bio-Oss Collagen) and type I collagen membrane (Bio-Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of intrabony defects: A clinico-radiographic study. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to compare the efficacy of bovine-derived xenograft (Bio-Oss Collagen) and Type I collagen membrane (Bio Gide) with bovine-derived xenograft (Bio-Oss Collagen) and fibrin fibronectin sealing system (TISSEEL) in the treatment of periodontal infrabony defects. MATERIALS AND METHODS: Fourteen healthy patients in the age range of 20 to 60 years, showing bilateral or contralateral infrabony defects were selected. The defects were assigned randomly to Site A (bovine-derived xenograft [Bio-Oss Collagen] with bioresorbable Type I collagen membrane [Bio-Gide]) and Site B (fibrin fibronectin sealing system [TISSEEL] with bovine-derived xenograft [Bio Oss Collagen]). The radiographic parameters were recorded at baseline, 6 months, and 9 months postoperatively. RESULTS: All fourteen patients returned for recall at regular intervals till the completion of the study. Both the experimental groups showed clinically and radiographically statistically significant reduction in probing pocket depth and gain in clinical attachment level. CONCLUSION: Both groups showed potential for enhancing the periodontal regeneration with no statistically significant between the two groups; however, on comparison the Bio Oss Collagen and TISSEEL group were slightly better. PMID- 25024549 TI - Comparative evaluation of clinical efficacy of beta-tri calcium phosphate (Septodont-RTR)TM alone and in combination with platelet rich plasma for treatment of intrabony defects in chronic periodontitis. AB - AIM: To assess the clinical outcome by comparing beta-tri calcium phosphate (Septodont RTR)TM along with platelet rich plasma (PRP) and beta-tri calcium phosphate (beta-TCP) alone in intrabony defects, by clinical evaluation in a 6 month analysis. METHODOLOGY: Ten patients participated in the study. Using a split-mouth design, interproximal bony defects were surgically treated with either platelet rich plasma (PRP) combined with beta-tri calcium phosphate (beta TCP) or beta-TCP alone. Plaque Index (PI), Gingival Index, Probing Pocket Depth (PPD), Clinical Attachment Level (CAL) were recorded 6 months after surgery. RESULTS: At 6 months after therapy, the PRP combined with beta-TCP group showed mean PPD reduction of 2.50, CAL mean gain of 2.60 + 1.43. The beta-TCP group showed mean PPD reduction of 2.80 mm, mean CAL gain of 2.60 mm. On intra-group comparison, there was greater PPD reduction and CAL gain at 6 months in both the groups. In intergroup comparison of PRP/beta-TCP and beta-TCP alone, there was no statistical significant difference observed. (P = 0.55, and 0.87 for PPD and CAL gain). CONCLUSION: Both therapies resulted in significant PPD reduction, CAL gain. The present study shows that treatment of intrabony periodontal defects with combination of PRP and beta-TCP does not have additional improvements when compared with beta-TCP alone within 6 months follow-up. PMID- 25024550 TI - Analysis of patient acceptance following treatment of Miller's class II gingival recession with acellular dermal matrix and connective tissue graft. AB - OBJECTIVE: Obtaining predictable and aesthetic root coverage has become an important part of periodontal therapy. The search for the appropriate root coverage techniques has resulted in many different approaches. The goal of this study was to evaluate the degree of patient acceptance with acellular dermal matrix (ADM) allograft in the treatment of buccal gingival recession and to compare it with subepithelial connective tissue graft. MATERIALS AND METHODS: Thirty patients with Miller's class II recessions were treated and randomly assigned to the test group (ADM) and control group (subepithelial connective tissue graft). All patients underwent full periodontal evaluation and pre surgical preparation, including oral hygiene instructions and scaling and root planing. The exposed roots were thoroughly planed and covered by a graft without any further root treatment. Results were evaluated based on the parameters measuring patient satisfaction and clinical outcome after 6 months of the surgical procedure. RESULTS: Postoperatively, significant root coverage, reduction in probing depth, gain in clinical attachment level, and increase in widths of keratinized tissue and attached gingiva were observed on intra-group comparison. There was no significant difference in any of the parameters between test and control groups. CONCLUSION: The subepithelial connective tissue graft and ADM graft were able to successfully treat gingival recession defects; however, the ADM showed better patient acceptance than the connective tissue graft. PMID- 25024551 TI - Self-perceived halitosis and oral hygiene habits among undergraduate dental students. AB - BACKGROUND: Halitosis or oral malodor is characterized by unpleasant odor arising from the oral cavity. The prevalence of halitosis however is not studied extensively. The aim of this study was to evaluate the self perception of oral malodor and oral hygiene habits amongst dental students. MATERIALS AND METHODS: A structured questionnaire consisting of ten questions was administered to 285 undergraduate students of Madha Dental College and Hospital. The questionnaire was designed to evaluate the self perception of halitosis, oral hygiene aids used, presence of dental caries, gingival bleeding, and dryness of mouth. RESULTS: Of the 285 students, 259 students completed the questionnaire. The response rate was 90%, with male response rate being 85.7% and female 95.8%. Self perceived halitosis was reported by 44.1% males and 45.32% females. The difference in reporting self-perception of halitosis between females and males was found to be statistically significant (P < 0.05). Significant difference was found for use of mouth wash, presence of carious teeth, bleeding gums, and use of tongue cleaners between females and males (P < 0.05). CONCLUSION: The results of this study indicate higher prevalence of halitosis among this population consisting of dental students. The awareness of halitosis was also higher among this population. The awareness of halitosis as an individual entity should be promoted to the general population and the therapeutic measures should be made available to all. PMID- 25024552 TI - A knowledge, attitude, and practices study regarding dental floss among dentists in India. AB - OBJECTIVES: To assess the knowledge, attitude, self-reported practices, and prescription patterns regarding dental floss amongst a select population of dentists in India. MATERIALS AND METHODS: A pretested 30-item questionnaire was self-administered by authors to the dental faculty and postgraduate students in dental schools in Delhi-National Capital Region (NCR). Nine dental institutes were selected by simple random sampling procedure among 15 institutions and a total of 255 dentists were included in the study. STATISTICAL ANALYSIS: The data obtained were analyzed by SPSS version 18. Descriptive statistics such as frequencies were calculated and Pearson's Chi-square test was used with P value fixed at 0.05. RESULTS: There was lack of adequate knowledge regarding dental floss, among dentists in India. 78% of the dentists responded that the routine use of dental floss was necessary for good periodontal health. Majority of the dentists cited lack of awareness, availability, and cost as the major factors affecting floss usage. Lack of training in the dental education programs may have an impact on the prescription patterns as well. 15.3% of those surveyed do not use floss at all. 63.9% of the dentists prescribed floss routinely to their patients and considered factors like education, occupation, and socioeconomic status of the patient before prescribing dental floss. CONCLUSION: Health education programs regarding dental floss are necessary to create awareness among the general population and adequate training at undergraduate level is also essential to increase the prescription practices. Dentists should practice recommended oral self-care and act as role models. PMID- 25024553 TI - Evaluating awareness regarding oral hygiene practices and exploring gender differences among patients attending for oral prophylaxis. AB - BACKGROUND: Oral hygiene is intimated in health of all parts of the body including oral cavity. The understanding of actual practices in keeping the oral heath at standard based on patient's perceptions of oral health care is vital. Understanding the effect of gender on oral health would facilitate the development of successful attitude and behavior modification approach towards sustainable oral health. PURPOSE OF STUDY: To evaluate awareness regarding oral hygiene practices and exploring gender differences among patients attending for oral prophylaxis. MATERIALS AND METHODS: A survey was conducted among 250 patients attending the department of periodontology, Maulana Azad institute of dental sciences for oral prophylaxis. A structured questionnaire was used to collect information regarding practices and perception about oral hygiene. RESULTS: Majority of the patients (60.4%) felt that oral hygiene is mandatory for overall health of the body. The use of toothpaste and toothbrush (83.6%) was the most preferred cleaning aid among the study population in the present study. The major constraint for avoiding dental examination was no felt need (41.2%) followed by cost of dental treatment (26.8%) and time constraints (24.0%). CONCLUSIONS: Professional plaque removal and regular follow-up combined with oral hygiene instructions to the patients can minimize the level of gingival inflammation and swelling. The poor resources for dental care, common malpractices and nonavailability of professional care are the main barriers in seeking optimum oral hygiene. PMID- 25024554 TI - Inflammatory myofibroblastic tumor of maxilla showing sarcomatous change in an edentulous site with a history of tooth extraction following periodontitis: A case report with discussion. AB - Inflammatory myofibroblastic tumor (IMT) is a rare tumor of uncertain origin with variable biological behavior ranging from reactive lesions to highly aggressive malignancy. Oral IMTs are extremely rare and only 25 cases had been reported so far. A case of IMT with sarcomatous transformation in an extraction site with a history of tooth extraction following tooth mobility of an upper left molar tooth is presented here. The tooth was extracted following a complaint of gingival swelling and mobility of tooth. Though malignant transformation in IMTs had been documented in the extra oral sites, wide search of associated literature suggests, this is the first case of oral IMT showing malignant change associated with gingiva. The case report attempts to highlight the variant possibilities of tooth mobility other than periodontitis and the importance of assessing the primary cause of such conditions. PMID- 25024555 TI - Plasma cell mucositis with gingival enlargement and severe periodontitis. AB - Plasma cell mucositis (PCM) is a very rare, chronic, multifocal, idiopathic, non neoplastic plasma cell proliferative disorder of the upper aerodigestive tract. The classic clinical presentation is an intensely erythematous mucosa with surface changes described variously as papillomatous, cobblestone, nodular or velvety. It is a very rare condition <50 cases reported in literature. A 72-year old male patient complained of sore throat, stomatodynia, dysphagia, multiple oral ulcers, enlarged swollen bleeding gums and mobile teeth. There was chronic inflammatory enlargement of the gingiva and palate with severe periodontitis. Histopathological examination revealed a hyperplastic epithelium with a dense infiltrate of mature polyclonal plasma cells in the superficial layer of the lamina propria. PCM is a diagnosis of exclusion, to be differentiated from other infective, reactive, autoimmune, allergic and neoplastic disorders with plasma cell infiltrates. Management with surgical and immunosuppressive therapy is mostly ineffective with short remissions and frequent relapses. PMID- 25024556 TI - Chronic desquamative gingivitis in siblings: A report of two cases. AB - Desquamative gingivitis is a gingival response associated with a variety of clinical conditions and characterized by intense erythema, desquamation and ulceration of free and attached gingiva. A variety of diseases such as lichen planus, pemphigus, pemphigoid, dermatitis herpetiformis, linear IgA disease, lupus erythematosus, erythema multiformae manifest clinically as desquamative gingivitis. Of all the disease entities, Lichen Planus is a relatively common disorder affecting the skin and mucous membrane. Very often it has oral manifestations. These lesions of oral lichen planus (OLP) have myriad but distinct morphology. As they mimic other mucocutaneous disorders with regard to clinical appearance, many lesions of oral lichen planus go undiagnosed or are wrongly diagnosed. Reported here are two cases of desquamative gingivitis. One of these was diagnosed as erosive lichen planus based on the symptoms, clinical findings, histologic, and immunofluorescent examination. Further management was done in consultation with a dermatologist. PMID- 25024557 TI - Gingival enlargement in von Willebrand disease: A case report. AB - von Willebrand disease (vWD) is an inherited bleeding disorder affecting both the sexes with a prevalence of approximately 1% in general population. The cause for bleeding in this disorder can be attributed to the primary deficiency or defect in von Willebrand factor (vWF) that results in the platelet adhesion abnormalities. It is characterized by bleeding episodes that may be severe and life threatening, menorrhagia in females, epistaxis, and gingival bleeding and enlargement. A case of 29-year-old female having all the characteristic features of vWD is presented. The family history revealed consanguineous marriage of the parents. The patient was initially on oral contraceptives, but later she underwent diagnostic hysteroscopy with endometrial ablation with roller ball to treat menorrhagia. PMID- 25024558 TI - Clipping the (tongue) tie. AB - Ankyloglossia is an uncommon congenital oral anomaly that can cause difficulty with breast-feeding and speech articulation. For many years, the subject of ankyloglossia has been controversial with practitioners of many specialties having widely different views regarding its significance and management. This study is about a series of five cases of ankyloglossia subjected to surgical correction by frenectomy procedure. Three cases were treated with electrocautery, one case with diode laser and one case with conventional scalpel technique. 1 week and 1 month post-operative follow-ups were done and healing was compared with the available literature. Manipulation of tissues was better in laser and electrocautery techniques when compared with scalpel. Post-operative complication of swelling and pain was seen in scalpel technique whereas it was largely uneventful in other techniques. Though, there was no difference in healing at the end of first month clinically, scalpel technique has shown better results in organization of muscle fibers. This clinical study indicates that laser and electrocautery treatment used for frenectomy operations provides better patient perception in terms of postoperative pain and function than that obtained by the scalpel technique. Considering the above advantages, when used correctly, the laser and electrocautery offers a safe, effective, acceptable and impressive alternative for frenectomy operations. PMID- 25024559 TI - Platelet-rich fibrin as an adjunct to palatal wound healing after harvesting a free gingival graft: A case series. AB - BACKGROUND: Owing to its stimulatory effect on angiogenesis and epithelialization, platelet-rich fibrin (PRF) is an excellent material for enhancing wound healing. The use of PRF dressings may be a simple and effective method of reducing the morbidity associated with donor sites of autogenous free gingival grafts (FGGs). The purpose of this case series is to document the beneficial role of PRF in the healing of FGG donor sites. MATERIALS AND METHODS: A total of 18 patients treated with FGGs could be classified into two groups. PRF was prepared, compressed and used to dress the palatal wound followed by a periodontal pack in one group (10 patients) and only a periodontal pack was used in the other group (8 patients). Post-operative healing was assessed clinically at 7, 14 and 21 days and the morbidity was assessed qualitatively by an interview. RESULTS: Sites where PRF was used showed complete wound closure by 14 days and these patients reported lesser post-operative morbidity than patients in whom PRF was not used. CONCLUSIONS: PRF as a dressing is an effective method of enhancing the healing of the palatal donor site and consequently reducing the post-operative morbidity. PMID- 25024560 TI - Effect of low level laser therapy on revascularization of free gingival graft using ultrasound Doppler flowmetry. AB - Low level laser therapy (LLLT) is widely used during the post-operative period to accelerate the healing process. It promotes beneficial biological action on neovascularization with anti-inflammatory and analgesic effects. Two systemically healthy patients with Miller's grade II recession on 33 and 41, respectively, were treated with free gingival graft. After surgery, second patient received LLLT using a 830 nm diode laser, with output power of 0.1 W on the first day half hour following surgery, on the third day, seventh day, and lastly on the ninth day. Both the patients were asked to assess the pain on second, fourth and tenth day using a Numerical Rating Scale and revascularization of the grafted area was assessed using a color Doppler ultrasound imaging on the fourth and the ninth day. Neovascularization was noted in both the patients but the second patient elicited marked increase in vascularity on the fourth as well as the tenth day and drastic reduction in pain on day four, with no change on the tenth day. The results showed that LLLT was an effective adjunctive treatment in promoting reevascularization and pain control during early healing of free gingival graft. PMID- 25024561 TI - Use of cyanoacrylate as barrier in guided tissue regeneration in class II furcation defects. AB - The guided bone regeneration (GBR) is a technique that uses resorbable and non resorbable membranes in association with other filling biomaterials. GBR is one of the optional treatments for therapy of class II furcation defects. The current case report evaluates clinically and radiographically the use of the cyanoacrylate membrane (Glubran (r)2) associated with organic bovine bone (GenOx) for the treatment of vestibular class II furcation defect on the lower left molar. CONCLUSION: The GBR is an option in the treatment of vestibular class II furcation defects and cyanoacrylate surgical glue, acting as a mechanic barrier and providing an efficient stability for the graft. PMID- 25024562 TI - Extracorporeal shock wave therapy in periodontics: A new paradigm. AB - The quest for exploring new frontiers in the field of medical science for efficient and improved treatment modalities has always been on a rise. Extracorporeal shock wave therapy (ESWT) has been enormously used in medical practice, principally, for the management of urolithiasis, cholelithiasis and also in various orthopedic and musculoskeletal disorders. The efficacy of ESWT in the stimulation of osteoblasts, fibroblasts, induction of neovascularization and increased expression of bone morphogenic proteins has been well documented in the literature. However, dentistry is no exception to this trend. The present article enlightens the various applications of ESWT in the field of dentistry and explores its prospective applications in the field of periodontics, and the possibility of incorporating the beneficial properties of shock waves in improving the treatment outcome. PMID- 25024564 TI - A seventy year old man with intractable vomiting, Parkinsonism, memory loss and ptosis. PMID- 25024563 TI - Pseudo-dementia: A neuropsychological review. AB - Ever since Kiloh (1961)[2] coined the term pseudo-dementia, it has been used a little loosely for describing the cognitive deficits in depression, especially, which is found in old age. However, several diagnostic dilemmas persist regarding the nosological status of this condition. Teasing out these individual diagnostic problems is important not only for administering appropriate therapy, but also for preventing them from the unnecessary diagnostic assessments towards the other diagnoses. Thus, it is important to have a detailed knowledge of the cognitive or neuropsychological deficits in this condition. In this review, we start by addressing the important issue of diagnostic confusion between dementia and pseudo-dementia. Subsequently, we proceed by reviewing the present scientific literature on the cognitive deficits found in this clinical condition. For the sake of convenience, we will divide the cognitive deficits into: Memory deficitsExecutive function deficits andDeficits in speech and language domains. Finally, we will look at the progression of this condition to see the components of this condition, which can be actually called "Pseudo". PMID- 25024565 TI - Limbic encephalitis: Clinical spectrum and long-term outcome from a developing country perspective. AB - INTRODUCTION: Limbic encephalitis (LE) is characterized by rapidly progressive short-term memory loss, psychiatric symptoms and seizures. We describe the clinical spectrum, underlying etiology and long-term follow-up of patients with LE from India. MATERIALS AND METHODS: This prospective study included patients during the period of January 2009 and December 2011 with the clinical features consistent with LE with one or more of the following: (1) Magnetic resonance imaging (MRI) evidence of temporal lobe involvement; (2) cerebrospinal fluid inflammatory abnormalities, or (3) detection of antineuronal antibodies. Patients with metastasis, infection, metabolic and nutritional deficits, stroke, were excluded. RESULTS: There were 16 patients (9 females), mean age of presentation was 36.6 years (range 15-69 years). The mean duration of symptoms before presentation was 11 months (range 5 days-2 years). The most common symptom at presentation was short-term memory impairment in 7 patients followed by seizures in 5 and behavioral changes in three. Nine patients had seizures, 11 had change in behavior, language involvement in eight, cerebellar features in 3 and autonomic dysfunction in two. Four patients had associated malignancy, 3 of four presented with neurological symptoms and on investigations found to be have malignancy. Antineuronal antibody testing was done in 6 of 12 non paraneoplastic and two paraneoplastic patients, one positive for N-methyl-D-aspartate and one for anti-Hu antibody. MRI brain showed typical fluid attenuated inversion recovery or T2 bilateral temporal lobe hyperintensities in 50% of patients. At a mean follow-up of 21 months (3-36 months), 10 patients improved, 4 patients remained same and two patients expired. CONCLUSION: Early recognition of LE is important based upon clinical, MRI data in the absence of antineuronal surface antibody screen in developing nations. Early institution of immunotherapy will help in improvement in outcome of these patients in long-term. PMID- 25024566 TI - Progressive limbic encephalopathy: Problems and prospects. AB - BACKGROUND: It was observed that a good number of patients presenting with psychiatric manifestations when investigated later because of unresponsiveness to treatment or late development of organic features turned out to be treatable limbic syndromes. INTRODUCTION: The aim of this study is to assess the patients presenting with new onset neuropsychiatric symptoms satisfying the criteria for probable limbic encephalitis. PATIENTS AND METHODS: Patients referred to neurology department following a period of treatment for neuropsychiatric symptoms, which did not respond to conventional treatment were analyzed using Electroencephalography (EEG), magnetic resonance imaging, cerebrospinal fluid, screening for malignancy Vasculitic work-up, histopathology and autoantibody done when feasible. RESULTS: There were 22 patients satisfying criteria for probable limbic encephalitis. Their mean age was 34.5 years. Symptoms varied from unexplained anxiety, panic and depression, lack of inhibition, wandering, incontinence, myoclonus, seizures and stroke like episodes. Three had systemic malignancy, 10 had chronic infection, one each with vasculitis, acute disseminated encephalomyelitis, Hashimoto encephalitis and two each with non convulsive status, cryptogenic and Idiopathic inflammation. CONCLUSION: All patients who present with new onset neuropsychiatric symptoms need to be evaluated for sub-acute infections, inflammation, autoimmune limbic encephalitis and paraneoplastic syndrome. A repeated 20 minute EEG is a very effective screening tool to detect organicity. PMID- 25024567 TI - Cerebrospinal fluid cytokines and matrix metalloproteinases in human immunodeficiency seropositive and seronegative patients of tuberculous meningitis. AB - BACKGROUND: Some important clinical differences exist between human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients. Alterations in the cerebrospinal fluid (CSF) cytokines and matrix metalloproteinase have been noted in tuberculous meningitis. In HIV-infected patients, the immunopathogenesis is expected to be different. MATERIALS AND METHODS: In this study, 64 patients of tuberculous meningitis (28 HIV seropositive and 36 seronegative) were included. The patients were followed up for six months. Cerebrospinal fluid (CSF) samples of tuberculous meningitis patients and 20 controls were subjected to tissue necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, IL-10, matrix metalloproteinase (MMP)-2, and MMP-9 estimations. The levels were correlated with the patients' baseline clinical characteristics, CSF parameters, neuroimaging findings, and the outcome. The outcome was assessed and modified with the Barthel index. RESULTS: The CSF cytokines and MMP levels were significantly elevated in tuberculous meningitis when compared with the controls. There was no significant difference seen between HIV seropositive and seronegative tuberculous meningitis, except for the IL-1beta level, which was significantly lower in the HIV-infected patients. The cytokine and MMP levels did not correlate with the baseline clinical characteristics, disease severity, cerebrospinal fluid characteristics, neuroimaging findings, and outcome. CONCLUSION: In conclusion, HIV infection did not affect a majority of the CSF cytokines and MMP levels in tuberculous meningitis except for IL-1beta level. None of the estimated inflammatory parameters correlated with the outcome. PMID- 25024568 TI - The sensitivity comparison of bar electrode and disposable ring electrode for recording of lateral femoral cutaneous nerve. AB - OBJECTIVES: To compare the sensitivity of bar electrode and disposable ring electrode for recording of lateral femoral cutaneous (LFCN). MATERIALS AND METHODS: A total of 23 subjects (13 females, 10 males, mean age: 49.6 +/- 9.6 (range: 29-63) were recruited in the study. A total of 36 recordings were obtained with each electrode (with bar and disposable ring electrodes) from the subjects. The comparison of data was performed with percentages and student T table test. RESULTS: The response rate was 98% (35 out of 36 recordings) with bar electrode and 88% (32 out of 36 recordings) with disposable ring electrode. Although the sensitivity rate of bar electrode is slightly higher than of disposable ring electrode, there were no statistically significant differences in detecting the onset latency, peak latency, and amplitude of LFCN. CONCLUSION: The recording sensitivity of LFCN is higher with bar electrode than disposable ring electrode. However, disposable ring electrode can be used alternatively. PMID- 25024569 TI - An institutional experience of 26 patients with Moyamoya disease: A study from Northwest India. AB - AIM: Moyamoya disease (MMD) is a slowly progressive bilateral stenocclusive process of the distal internal carotid and proximal portions of the anterior and middle cerebral arteries and the formation of an abnormal vascular network at the base of the brain. The purpose of this retrospective study was to identify clinical features, salient features, radiological features and yield of diagnostic cerebral angiography in MMD. MATERIALS AND METHODS: We analyzed the records of 26 patients with MMD evaluated and treated at our institute from August 2010 until March 2013. Diagnosis of MMD was made on the basis of features of angiographic findings. Cerebral angiography showed typically fine network of vessels at the base of the brain with puff of smoke appearance suggestive of MMD. CT angiography (CTA) was done in 25 (96.15%) patients where as Digital substraction angiography (DSA) was done in 18 (69.23%) patients. RESULTS: Out of the 26 patients 13 were in the pediatric age group and 13 were adults. At presentation 14 patients had infarcts and 10 patients had hemorrhages. Among the hemorrhagic group 20% had isolated intracerebral hemorrhage (ICH), 50% patients had ICH with intraventricular extension (IVE) and 30% patients had primary intraventricular hemorrhage (PIVH). 50 % of the patients had involvement of the posterior circulation. CONCLUSION: Posterior circulation involvement is frequent in MMD. Though parenchymal bleed with/without intraventricular extension is the usual presentation of hemorrhagic MMD, isolated intraventricular hemorrhage could also be the mode of presentation. PMID- 25024570 TI - A clinical profile of patients with Parkinson's disease and psychosis. AB - AIMS: The aim of the study was to study the clinical profile of the patients with Parkinson's disease (PD) and psychosis. SETTINGS AND DESIGN: This was a prospective, cross sectional, hospital-based study done at the Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India from September 2009 to January 2011. All patients with PD, diagnosed by United Kingdom PD Society Brain Bank criteria, having with features of psychosis as diagnosed by the neuropsychiatric inventory (NPI) were included. Patients without a caregiver who could validate the patient's symptoms were excluded. RESULTS: A total of 40 patients (5 women, 35 men) with PD with psychosis (mean age: 54.2 +/- 11.5 years, mean duration of illness: 6.5 +/- 4.5 years, and mean duration of psychosis: 4.3 +/- 4.3 years) were included in the study. The Global NPI score was 19.1 +/- 11.5. Majority of the patients had pure hallucinations (85%), while the rest had either pure delusions (7.5%) or a combination of delusions and hallucinations (7.5%). In those with hallucinations, visual hallucinations were the commonest (60%) (pure only in 22.5%), followed by auditory (45%), minor hallucinations (45%), and tactile (20%). Only one person reported having olfactory hallucinations (2.5%). Loss of insight was most often observed during the visual hallucinations (52%), followed by tactile (44.4%), auditory (38.9 %), and minor hallucinations (33.3%). CONCLUSIONS: In patients with PD and psychosis, pure hallucinations are common and visual hallucinations are the commonest among the hallucinations. A large proportion of patients have minor hallucinations, which need to be recognized early for effective and early management. The limitations of the study were small sample size, use of a single scale to assess psychosis and subjective assessment of insight. PMID- 25024571 TI - A voxel based comparative analysis using magnetization transfer imaging and T1 weighted magnetic resonance imaging in progressive supranuclear palsy. AB - AIMS: In progressive supranuclear palsy (PSP) tissue damage occurs in specific cortical and subcortical regions. Voxel based analysis using T1-weighted images depict quantitative gray matter (GM) atrophy changes. Magnetization transfer (MT) imaging depicts qualitative changes in the brain parenchyma. The purpose of our study was to investigate whether MT imaging could indicate abnormalities in PSP. SETTINGS AND DESIGN: A total of 10 patients with PSP (9 men and 1 woman) and 8 controls (5 men and 3 women) were studied with T1-weighted magnetic resonance imaging (MRI) and 3DMT imaging. Voxel based analysis of T1-weighted MRI was performed to investigate brain atrophy while MT was used to study qualitative abnormalities in the brain tissue. We used SPM8 to investigate group differences (with two sample t-test) using the GM and white matter (WM) segmented data. RESULTS: T1-weighted imaging and MT are equally sensitive to detect changes in GM and WM in PSP. Magnetization transfer ratio images and magnetization-prepared rapid acquisition of gradient echo revealed extensive bilateral volume and qualitative changes in the orbitofrontal, prefrontal cortex and limbic lobe and sub cortical GM. The prefrontal structures involved were the rectal gyrus, medial, inferior frontal gyrus (IFG) and middle frontal gyrus (MFG). The anterior cingulate, cingulate gyrus and lingual gyrus of limbic lobe and subcortical structures such as caudate, thalamus, insula and claustrum were also involved. Cerebellar involvement mainly of anterior lobe was also noted. CONCLUSIONS: The findings suggest that voxel based MT imaging permits a whole brain unbiased investigation of central nervous system structural integrity in PSP. PMID- 25024572 TI - Intact thumb reflex in areflexic Guillain Barre syndrome: A novel phenomenon. AB - INTRODUCTION: Areflexia is one of the cardinal clinical features for the diagnosis of Guillain Barre syndrome. However, some patients may have sluggish proximal muscle stretch reflexes. Presence of thumb reflex, a distal stretch muscle reflex has not been documented in Guillain Barre syndrome. MATERIALS AND METHODS: We prospectively evaluated thumb reflex in Guillain Barre syndrome patients and age matched controls from April to September 2013. RESULTS: There were 31 patients with Guillain Barre syndrome in whom thumb reflex could be elicited in all (24 brisk, 7 sluggish), whereas all the other muscle stretch reflexes were absent in 29 patients at presentation and the remaining two had sluggish biceps and quadriceps reflexes (P = 0.001). Serial examination revealed gradual diminution of the thumb reflex (P < 0.001). Rapid progression of weakness was associated with early loss of the thumb reflex. CONCLUSION: Thumb reflex, a distal stretch reflex is preserved in the early phase of Guillain Barre syndrome. PMID- 25024573 TI - Atlantoaxial instability as the presenting feature of Morquio syndrome. PMID- 25024574 TI - Acute stroke-like presentation of acquired hepatocerebral degeneration. AB - Neurological manifestations in liver diseases have been well-described. Parkinsonism developing in cirrhotic patients is a unique clinical, neuroradiological, and biological entity. The symptoms are often insidious in onset and occur after liver disease has made its presentation. Acute dysarthria as the presenting manifestation of cirrhosis is rare. Here we report three cases where liver disease made an unusual presentation as acute dysarthria. In all cases the abruptness of the onset prompted the treating physicians to make a diagnosis of stroke. The computed tomography (CT) scans of all these patients did not show any evidence of stroke. This was followed by magnetic resonance imaging (MRI) which showed the characteristic symmetric high-signal intensities in globus pallidus and substantia nigra in T1-weighted images, a reflection of increased tissue concentrations of manganese that helped in making a retrospective diagnosis of liver disease, confirmed later by altered serum albumin to globulin ratios and altered liver echo texture in ultra sonogram. PMID- 25024575 TI - Unusual presentation of Sturge-Weber syndrome: Progressive megalencephaly with bilateral cutaneous and cortical involvement. AB - The Sturge Weber syndrome is characterized by developmental delay, seizures in infancy, unilateral cutaneous lesions with ipsilateral leptomeningeal enhancement. We report an unusual presentation of Sturge Weber syndrome with bilateral port wine nevus on the trunk and face along with bilateral cortical involvement in a developmentally normal child with progressive megalencephaly. PMID- 25024576 TI - A clue in the diagnosis of Cri-du-chat syndrome: Pontine hypoplasia. PMID- 25024577 TI - Intramyelinic edema in maple syrup urine disease. PMID- 25024578 TI - Pulvinar sign in acute disseminated encephalomyelitis. PMID- 25024579 TI - Hoffmann's syndrome with unusually long duration: Report on clinical, laboratory and muscle imaging findings in two cases. AB - Two adult men presented with the rare Hoffmann's syndrome (HS). Case 1: A 35-year old male patient had progressive stiffness of lower limbs of 13 years and generalized muscle hypertrophy and myalgia of 3 years duration. Had periorbital edema, dry skin, generalized muscle hypertrophy and spastic dysarthria with hoarseness. Muscle power was normal. Jaw jerk and deep tendon reflexes were exaggerated. Case 2: A 24-year-old male patient presented with muscle hypertrophy from childhood, slowness in motor activities and hearing impairment. For 6 months, he had severe muscle pains, cramps and further increase in hypertrophy. He had yellow tinged, dry skin, hoarseness of voice, gross muscle hypertrophy and minimal weakness. Both had markedly elevated serum creatine kinase (CK) levels and high thyroid stimulating hormone, low free triiodothyronine and free thyroxine levels. Levothyroxine treatment demonstrated remarkable reduction in muscle bulk at 2 months in both and no symptoms at 6 months. Magnetic resonance imaging of lower limbs in both cases revealed almost identical features with involvement of the muscles of posterior and adductor compartment of thighs and posterior and lateral compartments of the legs. Differential diagnosis of long duration muscle pseudohypertrophy and elevated CK levels should include HS. PMID- 25024580 TI - Reversible "Pulvinar sign" in Wernicke's encephalopathy. AB - Young onset dementia is a challenge. We describe a case, where a patient presented with psychosis, dementia and MRI showing pulvinar sign, all of this typical of variant Cruetzfelt Jacob disease (CJD). Subsequent investigations lead to the diagnosis of a treatable illness and patient was improved and MRI sign reversed, underlining again the importance of search needed for treatable diseases in any "typical" case of fatal illness. PMID- 25024581 TI - Undulating tongue in Wilson's disease. AB - We report an unusual occurrence of involuntary movement involving the tongue in a patient with confirmed Wilson's disease (WD). She manifested with slow, hypophonic speech and dysphagia of 4 months duration, associated with pseudobulbar affect, apathy, drooling and dystonia of upper extremities of 1 month duration. Our patient had an uncommon tongue movement which was arrhythmic. There was no feature to suggest tremor, chorea or dystonia. It might be described as athetoid as there was a writhing quality, but of lesser amplitude. Thus, the phenomenology was uncommon in clinical practice and the surface of the tongue was seen to "ripple" like a liquid surface agitated by an object or breeze. Isolated lingual dyskinesias are rare in WD. It is important to evaluate them for WD, a potentially treatable disorder. PMID- 25024582 TI - Primary diffuse leptomeningeal gliomatosis: An autopsy case report. AB - Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare condition, characterized by infiltration of the meninges by glial cells without evidence of the primary tumor in the brain or spinal cord parenchyma. Glioma arising primarily from the leptomeninges is extremely rare and often diagnosed only in post mortem examination and the diagnosis may be missed in meningeal biopsy. We describe a young female who presented with symptoms of raised intracranial pressure with imaging evidence of diffuse leptomeningeal enhancement in whom autopsy confirmed the diagnosis of PDLG. Our case illustrates the diagnostic difficulties in making the pre-mortem diagnosis even with multiple cerebrospinal fluid cytologies and leptomeningeal biopsy. PMID- 25024583 TI - Erb's paraplegia with primary optic atrophy: Unusual presentation of neurosyphilis: Case report and review of literature. AB - SYMPTOMATIC NEUROSYPHILIS (NS) CAN HAVE VARIED SYNDROMIC PRESENTATIONS: Meningitis, meningovascular and parenchymatous involvement. Non-tabetic syphilis affecting the spinal cord is rare and only sporadic case reports have been published. The variant of meningomyelitis known as Erb's paraplegia refers to patients of spinal syphilis with very slow progression over many years and predominantly motor signs. Primary optic atrophy occurs twice as frequently in tabes dorsalis as in other types of NS. We describe here a case of a 32-year-old truck driver who presented with Erb's paraplegia with primary optic atrophy. This clinical overlap in NS is extremely rare and to our knowledge is the first case report of its type. PMID- 25024584 TI - Aromatic L-Amino acid decarboxylase deficiency: A new case from Turkey with a novel mutation. AB - Aromatic L-amino acid decarboxylase (AADC), a vitamin B6-requiring enzyme that converts L-dopa to dopamine and 5-hydroxytryptophan to serotonin. Deficiency of this enzyme results in developmental delay, muscular hypotonia, dystonia, involuntary movements, autonomic dysfunction, and oculogyric crises. We now report a 2-year-old Turkish boy with AADC deficiency confirmed by greatly reduced AADC activity in the plasma and by genetic studies. Mutation analysis revealed a homozygous mutation c.208C > T (p. His70Tyr) in exon 3 of the AADC gene which has not been described to date. PMID- 25024585 TI - An interesting case of reversible metabolic myopathy: Tumor induced osteomalacia. PMID- 25024586 TI - Alcohol-related seizures: Need for clarity. PMID- 25024587 TI - Seasonal and monthly trends in the occurrence of Guillain-Barre syndrome over a 5 year period: A tertiary care hospital-based study from South India. PMID- 25024588 TI - Accounting for attitude in a KAP Study: A comment on knowledge, attitude and practice of stroke in India versus other developed and developing countries. PMID- 25024589 TI - Author's reply: Evolution of mobile plaque to complete division of carotid lumen. PMID- 25024590 TI - Brain natriuretic peptide among stroke patients. PMID- 25024591 TI - Experiences and the use of BNP POCT platform on suspected stroke patients by a Chinese emergency department. PMID- 25024592 TI - Proteomic and genomic studies of non-alcoholic fatty liver disease--clues in the pathogenesis. AB - Non-alcoholic fatty liver disease (NAFLD) is a widely prevalent hepatic disorder that covers wide spectrum of liver pathology. NAFLD is strongly associated with liver inflammation, metabolic hyperlipidaemia and insulin resistance. Frequently, NAFLD has been considered as the hepatic manifestation of metabolic syndrome. The pathophysiology of NAFLD has not been fully elucidated. Some patients can remain in the stage of simple steatosis, which generally is a benign condition; whereas others can develop liver inflammation and progress into non-alcoholic steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The mechanism behind the progression is still not fully understood. Much ongoing proteomic researches have focused on discovering the unbiased circulating biochemical markers to allow early detection and treatment of NAFLD. Comprehensive genomic studies have also begun to provide new insights into the gene polymorphism to understand patient-disease variations. Therefore, NAFLD is considered a complex and mutifactorial disease phenotype resulting from environmental exposures acting on a susceptible polygenic background. This paper reviewed the current status of proteomic and genomic studies that have contributed to the understanding of NAFLD pathogenesis. For proteomics section, this review highlighted functional proteins that involved in: (1) transportation; (2) metabolic pathway; (3) acute phase reaction; (4) anti-inflammatory; (5) extracellular matrix; and (6) immune system. In the genomic studies, this review will discuss genes which involved in: (1) lipolysis; (2) adipokines; and (3) cytokines production. PMID- 25024593 TI - Modern approach to the clinical management of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D3. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease. PMID- 25024594 TI - Nonalcoholic fatty liver disease and polycystic ovary syndrome. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world comprising a spectrum of liver damage from fatty liver infiltration to end-stage liver disease, in patients without significant alcohol consumption. Increased prevalence of NAFLD has been reported in patients with polycystic ovary syndrome (PCOS), one of the most common endocrinopathies in premenopausal women, which has been redefined as a reproductive and metabolic disorder after the recognition of the important role of insulin resistance in the pathophysiology of the syndrome. Obesity, in particular central adiposity and insulin resistance are considered as the main factors related to NAFLD in PCOS. Moreover, existing data support that androgen excess, which is the main feature of PCOS and is interrelated to insulin resistance, may be an additional contributing factor to the development of NAFLD. Although the natural history of NAFLD remains unclear and hepatic steatosis seems to be a relatively benign condition in most patients, limited data imply that advanced stage of liver disease is possibly more frequent in obese PCOS patients with NAFLD. PCOS patients, particularly obese patients with features of the metabolic syndrome, should be submitted to screening for NAFLD comprising assessment of serum aminotransferase levels and of hepatic steatosis by abdominal ultrasound. Lifestyle modifications including diet, weight loss and exercise are the most appropriate initial therapeutic interventions for PCOS patients with NAFLD. When pharmacologic therapy is considered, metformin may be used, although currently there is no medical therapy of proven benefit for NAFLD. Long-term follow up studies are needed to clarify clinical implications and guide appropriate diagnostic evaluation, follow-up protocol and optimal treatment for PCOS patients with NAFLD. PMID- 25024595 TI - Experimental models of non-alcoholic fatty liver disease in rats. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease. PMID- 25024596 TI - Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosis and treatment. AB - Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus. PMID- 25024597 TI - Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. AB - Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases. PMID- 25024598 TI - Nonalcoholic fatty liver disease and cardiovascular disease. AB - Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are two diseases that are common in the general population. To date, many studies have been conducted and demonstrate a direct link between NAFLD and CVD, but the exact mechanisms for this complex relationship are not well established. A systematic search of the PubMed database revealed that several common mechanisms are involved in many of the local and systemic manifestations of NAFLD and lead to an increased cardiovascular risk. The possible mechanisms linking NAFLD and CVD include inflammation, oxidative stress, insulin resistance, ectopic adipose tissue distribution, dyslipidemia, endothelial dysfunction, and adiponectin, among others. The clinical implication is that patients with NAFLD are at an increased risk of CVD and should undergo periodic cardiovascular risk assessment. PMID- 25024599 TI - Role of small bowel capsule endoscopy in the diagnosis and management of iron deficiency anemia in elderly: a comprehensive review of the current literature. AB - Iron deficiency anemia (IDA) is common and often under recognized problem in the elderly. It may be the result of multiple factors including a bleeding lesion in the gastrointestinal tract. Twenty percent of elderly patients with IDA have a negative upper and lower endoscopy and two-thirds of these have a lesion in the small bowel (SB). Capsule endoscopy (CE) provides direct visualization of entire SB mucosa, which was not possible before. It is superior to push enteroscopy, enteroclysis and barium radiography for diagnosing clinically significant SB pathology resulting in IDA. Angioectasia is one of the commonest lesions seen on the CE in elderly with IDA. The diagnostic yield of CE for IDA progressively increases with advancing age, and is highest among patients over 85 years of age. Balloon assisted enteroscopy is used to treat the lesions seen on CE. CE has some limitations mainly lack of therapeutic capability, inability to provide precise location of the lesion and false positive results. Overall CE is a very safe and effective procedure for the evaluation of IDA in elderly. PMID- 25024601 TI - Colonic polyps: is it useful to characterize them with advanced endoscopy? AB - There have been major developments in endoscopic imaging techniques in recent years. Endoscopes with high definition and magnification can provide high quality images that allow for the histological estimation of lesions in vivo and in situ when combined with ancillary enhancement techniques such as chromoendoscopy (CE) and virtual CE (narrow band imaging fujinon intelligent chromoendoscopy, or i Scan). Despite the enormous potential for these advanced techniques, their value and feasibility in the clinic are still doubted, particularly in cases of colonic polyps that are slated for removal, where in vivo characterization may be deemed unnecessary. However, there are several advantages offered by such advanced endoscopic imaging. CE with or without magnification demonstrates highly accurate histology and invasion depth prediction, and virtual CE is a feasible and less cumbersome alternative to CE in terms of histological estimation, though not sufficiently accurate for depth invasion prediction. Furthermore, the supplementary information provided by advanced imaging systems can assist the endoscopist in the selection of a strategic approach, such as in deciding whether a colonic lesion should be resected, left in situ, or requires more intensive surgical treatment. Lastly, advanced high-resolution imaging techniques may be more cost effective, such that histopathology of low-risk lesions following resection can be eliminated. The results of these evaluations and comparisons with traditional CE are presented and discussed. Taken together, the benefits provided by these advanced capabilities justify their development, and advocates their use for the treatment and management of colonic polyps. PMID- 25024600 TI - Endoscopic ultrasound-guided treatments: are we getting evidence based--a systematic review. AB - The continued need to develop less invasive alternatives to surgical and radiologic interventions has driven the development of endoscopic ultrasound (EUS)-guided treatments. These include EUS-guided drainage of pancreatic fluid collections, EUS-guided necrosectomy, EUS-guided cholangiography and biliary drainage, EUS-guided pancreatography and pancreatic duct drainage, EUS-guided gallbladder drainage, EUS-guided drainage of abdominal and pelvic fluid collections, EUS-guided celiac plexus block and celiac plexus neurolysis, EUS guided pancreatic cyst ablation, EUS-guided vascular interventions, EUS-guided delivery of antitumoral agents and EUS-guided fiducial placement and brachytherapy. However these procedures are technically challenging and require expertise in both EUS and interventional endoscopy, such as endoscopic retrograde cholangiopancreatography and gastrointestinal stenting. We undertook a systematic review to record the entire body of literature accumulated over the past 2 decades on EUS-guided interventions with the objective of performing a critical appraisal of published articles, based on the classification of studies according to levels of evidence, in order to assess the scientific progress made in this field. PMID- 25024602 TI - c-Met signaling in the development of tumorigenesis and chemoresistance: potential applications in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma is the 4(th) leading cause of cancer deaths in the United States. The majority of patients are candidates only for palliative chemotherapy, which has proven largely ineffective in halting tumor progression. One proposed mechanism of chemoresistance involves signaling via the mesenchymal epithelial transition factor protein (MET), a previously established pathway critical to cell proliferation and migration. Here, we review the literature to characterize the role of MET in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of MET as a therapeutic target in pancreatic cancer. In this review, we characterize the role of c-Met in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of c-Met as a therapeutic target in pancreatic cancer. PMID- 25024603 TI - Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation. AB - Pancreatic cancer carries a terrible prognosis, as the fourth most common cause of cancer death in the Western world. There is clearly a need for new therapies to treat this disease. One of the reasons no effective treatment has been developed in the past decade may in part, be explained by the diverse influences exerted by the tumour microenvironment. The tumour stroma cross-talk in pancreatic cancer can influence chemotherapy delivery and response rate. Thus, appropriate preclinical in vitro models which can bridge simple 2D in vitro cell based assays and complex in vivo models are required to understand the biology of pancreatic cancer. Here we discuss the evolution of 3D organotypic models, which recapitulare the morphological and functional features of pancreatic ductal adenocarcinoma (PDAC). Organotypic cultures are a valid high throughput preclinical in vitro model that maybe a useful tool to help establish new therapies for PDAC. A huge advantage of the organotypic model system is that any component of the model can be easily modulated in a short time-frame. This allows new therapies that can target the cancer, the stromal compartment or both to be tested in a model that mirrors the in vivo situation. A major challenge for the future is to expand the cellular composition of the organotypic model to further develop a system that mimics the PDAC environment more precisely. We discuss how this challenge is being met to increase our understanding of this terrible disease and develop novel therapies that can improve the prognosis for patients. PMID- 25024604 TI - hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: a systematic review. AB - High human equilibrative nucleoside transporter 1 (hENT1)-expression has shown a survival benefit in pancreatic cancer patients treated with gemcitabine in several studies. The aim of this systematic review was to summarize the results and try to assess the predictive value of hENT1 for determining gemcitabine outcome in pancreatic cancer. Relevant articles were obtained from PubMed, Embase and Cochrane databases. Studies evaluating hENT1-expression in pancreatic tumor cells from patients treated with gemcitabine were selected. Outcome measures were overall survival, disease-free survival (DFS), toxicity and response rate. The database searches identified 10 studies that met the eligibility criteria, and a total of 855 patients were included. Nine of 10 studies showed a statistically significant longer overall survival in univariate analyses in patients with high hENT1-expression compared to those with low expression. In the 7 studies that reported DFS as an outcome measure, 6 had statistically longer DFS in the high hENT1 groups. Both toxicity and response rate were reported in only 2 articles and it was therefore hard to draw any major conclusions. This review provides evidence that hENT1 is a predictive marker for pancreatic cancer patients treated with gemcitabine. Some limitations of the review have to be taken into consideration, the majority of the included studies had a retrospective design, and there was no standardized scoring protocol for hENT1-expression. PMID- 25024605 TI - Liver zonation: Novel aspects of its regulation and its impact on homeostasis. AB - Liver zonation, the spatial separation of the immense spectrum of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ. Recent progress in elucidating localization and interactions of different metabolic pathways by using "omics" techniques and novel approaches to couple them with refined spatial resolution and in characterizing novel master regulators of zonation by using transgenic mice has created the basis for a deeper understanding of core mechanisms of zonation and their impact on liver physiology, pathology and metabolic diseases. This review summarizes the fascinating technical achievements for investigating liver zonation and the elucidation of an emerging network of master regulators of zonation that keep the plethora of interrelated and sometimes opposing functions of the liver in balance with nutritional supply and specific requirements of the entire body. In addition, a brief overview is given on newly described zonated functions and novel details on how diverse the segmentation of metabolic zonation may be. From these facts and developments a few fundamental principles are inferred which seem to rule zonation of liver parenchyma. In addition, we identify important questions that still need to be answered as well as interesting fields of research such as the connection of zonation with circadian rhythm and gender dimorphism which need to be pushed further, in order to improve our understanding of metabolic zonation. Finally, an outlook is given on how disturbance of liver zonation and its regulation may impact on liver pathology and the development of metabolic diseases. PMID- 25024607 TI - High fat diet feeding results in gender specific steatohepatitis and inflammasome activation. AB - AIM: To develop an animal model that encompasses the different facets of non alcoholic steatohepatitis (NASH), which has been a challenge. METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o staining; biochemical studies to look at ALT and triglyceride levels; RNA analysis using quantitative polymerase chain reaction; and cytokine analysis, which included the enzyme-linked immunosorbent assay method to look at interleukin (IL)-1beta and tumor necrosis factor-alpha (TNFalpha) levels. Furthermore, at each length of feeding we also looked at insulin resistance and glucose tolerance using insulin tolerance tests (ITT) and glucose tolerance tests. RESULTS: There was no insulin resistance, steatosis, or inflammasome activation at 6 wk. In contrast, at 16 wk we found significant insulin resistance demonstrated by impaired glucose and ITT in male, but not female mice. In males, elevated alanine aminotransferase and triglyceride levels, indicated liver damage and steatosis, respectively. Increased liver TNFalpha and monocyte chemoattractant protein-1 mRNA and protein, correlated with steatohepatitis. The inflammasome components, adaptor molecule, Aim2, and NOD-like receptor 4, increased at the mRNA level, and functional inflammasome activation was indicated by increased caspase-1 activity and IL-1beta protein levels in male mice fed a long-term HFD. Male mice on HFD had increased alpha-smooth muscle actin and pro collagen-1 mRNA indicating evolving fibrosis. In contrast, female mice displayed only elevated triglyceride levels, steatosis, and no fibrosis. CONCLUSION: Our data indicate gender differences in NASH. Male mice fed a long-term HFD display steatohepatitis and inflammasome activation, whereas female mice have steatosis without inflammation. PMID- 25024606 TI - Gastroenteric tube feeding: techniques, problems and solutions. AB - Gastroenteric tube feeding plays a major role in the management of patients with poor voluntary intake, chronic neurological or mechanical dysphagia or gut dysfunction, and patients who are critically ill. However, despite the benefits and widespread use of enteral tube feeding, some patients experience complications. This review aims to discuss and compare current knowledge regarding the clinical application of enteral tube feeding, together with associated complications and special aspects. We conducted an extensive literature search on PubMed, Embase and Medline using index terms relating to enteral access, enteral feeding/nutrition, tube feeding, percutaneous endoscopic gastrostomy/jejunostomy, endoscopic nasoenteric tube, nasogastric tube, and refeeding syndrome. The literature showed common routes of enteral access to include nasoenteral tube, gastrostomy and jejunostomy, while complications fall into four major categories: mechanical, e.g., tube blockage or removal; gastrointestinal, e.g., diarrhea; infectious e.g., aspiration pneumonia, tube site infection; and metabolic, e.g., refeeding syndrome, hyperglycemia. Although the type and frequency of complications arising from tube feeding vary considerably according to the chosen access route, gastrointestinal complications are without doubt the most common. Complications associated with enteral tube feeding can be reduced by careful observance of guidelines, including those related to food composition, administration rate, portion size, food temperature and patient supervision. PMID- 25024608 TI - Novel diagnostics for aggravating pancreatic fistulas at the acute phase after pancreatectomy. AB - AIM: To identify sensitive predictors of clinically relevant postoperative pancreatic fistula (POPF) at the acute phase after pancreatectomy. METHODS: This study included 153 patients diagnosed as having POPFs at postoperative day (POD) 3 after either open pancreatoduodenectomy or distal pancreatectomy between January 2008 and March 2013. The POPFs were categorized into three grades based on the International Study Group on Pancreatic Fistula Definition, and POPFs of grades B or C were considered to be clinically relevant. The predictive performance for the clinically relevant POPF formation of values at PODs 1, 3 and 5 as well as time-dependent changes in levels of inflammatory markers, including white blood cell count, neutrophil count, total lymphocyte count, C-reactive protein (CRP), procalcitonin level, platelet-to-lymphocyte ratio and neutrophil to-lymphocyte ratio, and amylase content in the drain fluid were compared using the receiver operating characteristic (ROC) curve and multivariable analyses. A scoring system for the prediction of clinically relevant POPFs was created using five risk factors identified in this study, and its diagnostic performance was also evaluated. RESULTS: Over time, 77 (50%) of 153 enrolled patients followed a protracted course and were categorized as having clinically relevant POPFs. ROC curve analyses revealed that changes in CRP levels from POD 1 to POD 3 had the greatest area under the curve value (0.767) and that an elevated CRP level of 28.4 mg/L yielded the most optimal predictive value for clinically relevant POPFs. Multivariable analyses for the risk factors of clinically relevant POPFs identified invasive carcinomas of the pancreas and elevation of the CRP level (>= 28.4 mg/L, from POD 1 to POD 3) as independent diagnostic factors for clinically relevant POPFs (OR 2.94, 95%CI: 1.08-8.55, P = 0.035 and OR 4.82, 95%CI: 1.25 20.2, P = 0.022, respectively). A gradual increase in the prevalence of clinically relevant POPFs in proportion to the risk classification score was confirmed. A highly elevated CRP level and a risk score >= 8 were significantly associated with a prolonged duration of drain placement and postoperative hospitalization. CONCLUSION: A steep rise in the serum CRP level from POD 1 to POD 3 was a highly predictive factor for subsequent clinically relevant POPFs. PMID- 25024609 TI - Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer. AB - AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a pancreatic cancer cell line. METHODS: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptors in pancreatic cancer cells was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. An in vivo study with a Panc-1 xenograft mouse model was also performed. RESULTS: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E cadherin, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 +/- 46 mg vs combination 154 +/- 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down regulation of Zeb1 in Panc-1 xenograft mouse. CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process. PMID- 25024610 TI - Changes in circulating Foxp3(+) regulatory T cells and interleukin-17-producing T helper cells during HBV-related acute-on-chronic liver failure. AB - AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV) related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression. METHODS: We measured the expression of seven Th17/Treg differentiation-related genes and serum concentrations of the corresponding cytokines in 18 ACHBLF, 18 chronic hepatitis B (CHB) disease controls and 10 healthy controls (HCs) by real-time quantitative PCR and enzyme linked immunosorbent assay. Peripheral Th17 and Treg cell frequencies were analyzed by flow cytometry. RESULTS: From the onset of ACHBLF, patients presented with a conductive Th17 differentiation cytokine environment accompanied by high Th17 frequency and high serum IL-17 levels, which were sustained throughout the disease course. The Treg-related cytokine IL-2 and Foxp3 were also up-regulated from disease onset, and Foxp3 gene expression showed a gradually increasing trend during ACHBLF. The circular phenotype of Treg and Th17 cells showed changes from the onset of ACHGLF. At disease onset, Th17 frequency increased significantly compared with both CHB and HCs, but Treg cell frequency decreased significantly compared with CHB. During the ACHBLF event, Th17 frequency remained higher compared with HCs, but decreased sharply from the peak point to the recovery point; Treg cell frequency increased gradually during the ACHBLF event. Treg and Th17 cell counts correlated with ACHBLF development; in all patients, serum IL-17 levels significantly correlated with patient serum ALT levels. In survivors, Th17 frequency at the onset point and the Treg to Th17 ratio at the peak point correlated with the patient's model for end stage liver disease (MELD) plus sodium (MELD-Na) score. The Treg to Th17 ratio and the Th17 frequency at onset were significant predictors of patient survival. Low Treg/Th17 cell ratios at the onset predicted poor survival. Survivors exhibited an initial decrease in the circulating Treg/Th17 ratio from the onset to the peak time, and subsequently displayed a continuous increase. CONCLUSION: Treg and Th17 cells showed changes in genes, protein levels and T cell phenotypes during ACHBLF events. An increased Treg/Th17 ratio was associated with the survival of ACHBLF patients. PMID- 25024611 TI - Zinc protoporphyrin IX enhances chemotherapeutic response of hepatoma cells to cisplatin. AB - AIM: To investigate the effect of zinc protoporphyrin IX on the response of hepatoma cells to cisplatin and the possible mechanism involved. METHODS: Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Apoptosis was determined by a flow cytometric assay. Western blotting was used to measure protein expression. Heme oxygenase (HO)-1 activity was measured by determining the level of bilirubin generated in isolated microsomes. Reactive oxygen species (ROS) production was monitored by flow cytometry. Caspase-3 activity was measured with a colorimetric assay kit. Mice were inoculated with 1 * 10(7) tumor cells subcutaneously into the right flanks. All mice were sacrificed 6 wk after the first treatment and tumors were weighed and measured. RESULTS: Overexpression of HO-1 in HepG2 cell line was associated with increased chemoresistance to cis-diaminedichloroplatinum (cisplatin; CDDP) compared to other cell lines in vitro. Inhibition of HO-1 expression or activity by zinc protoporphyrin IX (ZnPP IX) markedly augmented CDDP-mediated cytotoxicity towards all liver cancer cell lines in vitro and in vivo. In contrast, induction of HO-1 with hemin increased resistance of tumor cells to CDDP-mediated cytotoxicity in vitro and in vivo. Furthermore, cells treated with ZnPP IX plus CDDP exhibited marked production of intracellular ROS and caspase-3 activity, which paralleled the incidence of cell apoptosis, whereas hemin decreased cellular ROS and caspase-3 activity induced by CDDP. CONCLUSION: ZnPP IX increases cellular sensitivity and susceptibility of liver cancer cell lines to CDDP and this may represent a mechanism of increasing ROS. PMID- 25024612 TI - Prognostic significance of preoperative fibrinogen in patients with colon cancer. AB - AIM: To investigate the prognostic significance of preoperative fibrinogen levels in colon cancer patients. METHODS: A total of 255 colon cancer patients treated at the Affiliated Tumor Hospital of Xinjiang Medical University from June 1(st) 2005 to June 1(st) 2008 were enrolled in the study. All patients received radical surgery as their primary treatment method. Preoperative fibrinogen was detected by the Clauss method, and all patients were followed up after surgery. Preoperative fibrinogen measurements were correlated with a number of clinicopathological parameters using the Student t test and analysis of variance. Survival analyses were performed by the Kaplan-Meier method and Cox regression modeling to measure 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: The mean preoperative fibrinogen concentration of all colon cancer patients was 3.17 +/- 0.88 g/L. Statistically significant differences were found between preoperative fibrinogen levels and the clinicopathological parameters of age, smoking status, tumor size, tumor location, tumor-node-metastasis (TNM) stage, modified Glasgow prognostic scores (mGPS), white blood cell (WBC) count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA) levels. Univariate survival analysis showed that TNM stage, tumor cell differentiation grade, vascular invasion, mGPS score, preoperative fibrinogen, WBC, NLR, PLR and CEA all correlated with both OS and DFS. Alpha-fetoprotein (AFP) and body mass index correlated only with OS. Kaplan Meier analysis revealed that both OS and DFS of the total cohort, as well as of the stage II and III patients, were higher in the hypofibrinogen group compared to the hyperfibrinogen group (all P < 0.05). In contrast, there was no significant difference between OS and DFS in stage I patients with low or high fibrinogen levels. Cox regression analysis indicated preoperative fibrinogen levels, TNM stage, mGPS score, CEA, and AFP levels correlated with both OS and DFS. CONCLUSION: Preoperative fibrinogen levels can serve as an independent prognostic marker to evaluate patient response to colon cancer treatment. PMID- 25024613 TI - Risk of gastric cancer is associated with PRKAA1 gene polymorphisms in Koreans. AB - AIM: To evaluate the association between genetic polymorphisms of the gene encoding AMP-activated protein kinase (PRKAA1) and the risk of gastric cancer. METHODS: The study subjects consisted of 477 age- and sex-matched case-control pairs. Genotyping was performed for 5 tag single nucleotide polymorphisms (SNPs): rs13361707, rs154268, rs3805486, rs6882903, and rs10074991. Associations between gastric cancer and putative risk factors (including the SNPs) were analyzed with multivariate conditional logistic regression models, after adjusting for potential confounding factors. Multiple testing corrections were implemented following methodology for controlling the false discovery rate. Gene-based association tests were performed by using the versatile gene-based association study (VEGAS) method. RESULTS: In the dominant model, SNPs rs13361707 [odds ratio (OR) = 1.51, 95%CI: 1.07-2.11)], rs154268 (OR = 1.65, 95%CI: 1.22-2.22), rs6882903 (OR = 1.48, 95%CI: 1.09-2.00), and rs10074991 (OR = 1.53, 95%CI: 1.09 2.16) were significantly associated with an increased risk of gastric cancer. In the recessive model, SNPs rs154268 (OR = 1.66, 95%CI: 1.22-2.26), rs3805486 (OR = 0.63, 95%CI: 0.46-0.85), and rs10074991 (OR = 1.47, 95%CI: 1.15-1.88) were significant risk or protective factors for gastric cancer. In the codominant model, the ORs of each of the 5 SNPs were statistically significant. All SNPs in the model showed a dose-response relationship between the minor allele frequency and the risk of gastric cancer. Most notably, subjects with a homozygous minor allele in SNP rs10074991 showed 2.15 times the risk of gastric cancer as subjects without a minor allele. The PRKAA1 gene showed a significant gene-based association with gastric cancer in the VEGAS test. CONCLUSION: All 5 tested tag SNPs of the PRKAA1 gene (rs13361707, rs154268, rs3805486, rs6882903, and rs10074991) were significantly associated with gastric cancer. PMID- 25024614 TI - Endoscopic ultrasound-guided fine-needle aspiration for suspected malignancies adjacent to the gastrointestinal tract. AB - AIM: To investigate the impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in association with a multidisciplinary team evaluation for the detection of gastrointestinal malignancies. METHODS: A cohort of 1019 patients with suspected malignant lesions adjacent to the gastrointestinal tract received EUS-FNA after a standardized multidisciplinary team evaluation (MTE) and were divided into 4 groups according to their specific malignant risk score (MRS). Patients with a MRS of 0 (without detectable risk of malignancy) received only EUS without FNA. For patients with a MRS score ranging from 1 (low risk) - through 2 (intermediate risk) - to 3 (high risk), EUS-FNA cytology of the lesion was planned for a different time and was prioritized for those patients at higher risk for cancer. The accuracy, efficiency and quality assessment for the early detection of patients with potentially curable malignant lesions were evaluated for the whole cohort and in the different classes of MRSs. The time to definitive cytological diagnosis (TDCD), accuracy, sensitivity, specificity, positive and negative predictive values, and the rate of inconclusive tests were calculated for all patients and for each MRS group. RESULTS: A total of 1019 patients with suspected malignant lesions were evaluated by EUS-FNA. In 515 patients of 616 with true malignant lesions the tumor was diagnosed by EUS-FNA; 421 patients with resectable lesions received early surgical treatment, and 94 patients received chemo-radiotherapy. The overall diagnostic accuracy for the 1019 lesions in which a final diagnosis was obtained by EUS-FNA was 0.95. When patients were stratified by MTE into 4 classes of MRSs, a higher rate of patients in the group with higher cancer risk (MRS-3) received early treatment and EUS-FNA showed the highest level of accuracy (1.0). TDCD was also shorter in the MRS-3 group. The number of patients who received surgical treatment or chemo-radiotherapy was significantly higher in the MRS-3 patient group (36.3% in MRS-3, 10.7% in MRS-2, and 3.5% in MRS-1). CONCLUSION: EUS-FNA can effectively detect a curable malignant lesions at an earlier time and at a higher rate in patients with a higher cancer risk that were evaluated using MTE. PMID- 25024615 TI - Birthplace is not a determinant of colorectal adenomas. AB - AIM: To examine the impact of the patient's birthplace on the prevalence of colonic polyps and histopathological subtypes. METHODS: This is a retrospective audit of the colonoscopy practice of one Gastroenterologist in a tertiary referral hospital from 2008 to 2011. Data collected include demography, birthplace, language spoken, details of the colonoscopy including indications, completion rates, complications, results including prevalence and histopathology of polyps. Statistical methods used were binary logistic regression, chi(2) and Mann-Whitney U. RESULTS: A total of 623 patients (48% male, 67% aged over 50 years) were recruited and categorised according to birthplace: Australia/New Zealand 42%, European 20%, Asian 15%, Middle Eastern/African 11%, South American 9% and Pacific Islander 3%. The median age of the cohort was 56.3 years (range: 17-91 years), median body mass index 27.3 kg/m(2) (range: 16-51 kg/m(2)), 25% were smokers, 25% had hypercholesterolemia, 20% had diabetes mellitus 16% were on aspirin and 7% were on non-steroidal anti-inflammatory drugs. A total of 651 colonoscopies were performed for standard indications. The prevalence of polyps varied according to patient's birthplace: Europe 45.1%, Australia and New Zealand 39.5%, Pacific Islands 33.3%, Asia 30.3%, Middle East and Africa 26.9% and South America 24.5% (P = 0.027, df = 6). However, multivariate analysis revealed that birthplace was not an independent predictor of developing polyps, including adenomas and advanced adenomas after correcting for age and male sex. CONCLUSION: Birthplace is not a predictor for developing colorectal neoplasia, including adenomas and advanced adenomas; hence, should not influence the recommendations for colorectal cancer screening. PMID- 25024616 TI - Follow-up of patients with pseudotumoral chronic pancreatitis: outcome and surveillance. AB - AIM: To follow up patients with pseudotumoral chronic pancreatitis (PCP) to assess their outcome and identify an optimal surveillance interval. METHODS: Data obtained prospectively were analyzed in a retrospective manner. Patients with clinical evidence of chronic pancreatitis (abdominal pain in the epigastrium, steatorrhea, and diabetes mellitus), endoscopic ultrasound (EUS) criteria > 4, and EUS-fine needle aspiration (FNA) were included. A pseudotumor was defined as a non-neoplastic space-occupying lesion, a cause of chronic pancreatitis that may mimic changes typical of pancreatic cancer on CT or endoscopic ultrasound but without histological evidence. A real tumor was defined as a neoplastic space occupying lesion because of pancreatic cancer confirmed by histology. RESULTS: Thirty-five patients with chronic pancreatitis were included, 26 (74.2%) of whom were men. Nine (25.7%) patients were diagnosed with pseudotumoral chronic pancreatitis and two (2/35; 5.7%) patients with pseudotumoral chronic pancreatitis were diagnosed with pancreatic cancer on follow-up. The time between the diagnosis of pseudotumoral chronic pancreatitis and pancreatic adenocarcinoma was 35 and 30 d in the two patients. Definitive diagnosis of pancreatic adenocarcinoma was made by surgery. In the remaining six patients with pseudotumoral chronic pancreatitis, the median of follow-up was 11 mo (range 1-22 mo) and they showed no evidence of malignancy on surveillance. In the follow-up of patients without pseudotumoral chronic pancreatitis but with chronic pancreatitis, none were diagnosed with pancreatic cancer. According to our data, older patients with chronic pancreatitis are at risk of pseudotumoral chronic pancreatitis. CONCLUSION: According to characteristics of patient, detection of PCP should lead a surveillance program for pancreatic cancer with EUS-FNA in < 1 mo or directly to surgical resection. PMID- 25024617 TI - Need for pancreatic stenting after sphincterotomy in patients with difficult cannulation. AB - AIM: To investigate the need for pancreatic stenting after endoscopic sphincterotomy (EST) in patients with difficult biliary cannulation. METHODS: Between April 2008 and August 2013, 2136 patients underwent endoscopic retrograde cholangiopancreatography (ERCP)-related procedures. Among them, 55 patients with difficult biliary cannulation who underwent EST after bile duct cannulation using the pancreatic duct guidewire placement method (P-GW) were divided into two groups: a stent group (n = 24; pancreatic stent placed) and a no-stent group (n = 31; no pancreatic stenting). We retrospectively compared the two groups to examine the need for pancreatic stenting to prevent post-ERCP pancreatitis (PEP) in patients undergoing EST after biliary cannulation by P-GW. RESULTS: No differences in patient characteristics or endoscopic procedures were observed between the two groups. The incidence of PEP was 4.2% (1/24) and 29.0% (9/31) in the Stent and no-stent groups, respectively, with the no-stent group having a significantly higher incidence (P = 0.031). The PEP severity was mild for all the patients in the stent group. In contrast, 8 had mild PEP and 1 had moderate PEP in the no-stent group. The mean serum amylase levels (means +/- SD) 3 h after ERCP (183.1 +/- 136.7 vs 463.6 +/- 510.4 IU/L, P = 0.006) and on the day after ERCP (209.5 +/- 208.7 vs 684.4 +/- 759.3 IU/L, P = 0.002) were significantly higher in the no-stent group. A multivariate analysis identified the absence of pancreatic stenting (P = 0.045; odds ratio, 9.7; 95%CI: 1.1-90) as a significant risk factor for PEP. CONCLUSION: In patients with difficult cannulation in whom the bile duct is cannulated using P-GW, a pancreatic stent should be placed even if EST has been performed. PMID- 25024618 TI - Selection of appropriate endoscopic therapies for duodenal tumors: an open-label study, single-center experience. AB - AIM: To determine an appropriate compartmentalization of endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) for duodenal tumors. METHODS: Forty-six duodenal lesions (excluding papillary lesions) from 44 patients with duodenal tumors treated endoscopically between 2005 and 2013 were divided into the ESD and EMR groups for retrospective comparison and analysis. RESULTS: The mean age was 65 +/- 9 years (35-79 years). There were 24 lesions from men and 22 from women. The lesions consisted of 6 early cancers, 31 adenomas and 9 neuroendocrine tumors. Lesion location was the duodenal bulb in 15 cases and the descending part of the duodenum in 31 cases. The most common macroscopic morphology was elevated type in 21 cases (45.6%). Mean tumor diameter was 11.9 +/ 9.7 mm (3-60 mm). Treatment procedure was ESD (15 cases) vs EMR (31 cases). The examined parameters in the ESD vs EMR groups were as follows: mean tumor diameter, 12.9 +/- 14.3 mm (3-60 mm) vs 11.4 +/- 6.7 mm (4-25 mm); en bloc resection rate, 86.7% vs 83.9%; complete resection rate, 86.7% vs 74.2%; procedure time, 86.5 +/- 63.1 min (15-217 min) vs 13.2 +/- 17.0 min (2-89 min) (P < 0.0001); intraprocedural perforation, 3 cases vs none (P = 0.0300); delayed perforation, none in either group; postprocedural bleeding, 1 case vs none; mean postoperative length of hospitalization, 8.2 +/- 2.9 d (5-16 d) vs 6.1 +/- 2.0 d (2-12 d) (P = 0.0067); recurrence, none vs 1 case (occurring at 7 mo postoperatively). CONCLUSION: ESD was associated with a longer procedure time and a higher incidence of intraprocedural perforation; EMR was associated with a lower rate of complete resection. PMID- 25024619 TI - Impact of tumor location on clinical outcomes of gastric endoscopic submucosal dissection. AB - AIM: To determine whether there is a correlation between the location of the lesion and endoscopic submucosal dissection (ESD) outcome. METHODS: From January 2008 to December 2010, ESD of 1443 gastric tumors was performed. En bloc resection rate, complete resection rate, procedure time and complication rate were analyzed according to the tumor location. RESULTS: The rates of en bloc resection and complete resection were 91% (1318/1443) and 89% (1287/1443), respectively. The post-ESD bleeding rate was 4.3%, and perforation rate was 2.7%. Tumors located in the upper third of the stomach were associated with a longer procedure time and significantly higher rates of incomplete resection, piecemeal resection, and perforation than tumors below the upper third of the stomach. Posterior wall lesions had significantly longer procedure times and higher rates of incomplete resection and piecemeal resection than lesions in other locations. In multivariate analysis, posterior wall lesions and upper third lesions were significantly associated with incomplete resection and perforation, respectively. In post-ESD bleeding analysis, location was not a significant related factor. CONCLUSION: More advanced endoscopic techniques are required during ESD for lesions located in the upper third or posterior wall of the stomach to decrease complications and improve therapeutic outcomes. PMID- 25024620 TI - Outcomes of simple saline-coupled bipolar electrocautery for hepatic resection. AB - AIM: To evaluate the application of bipolar coagulation (BIP) in hepatectomy by comparing the efficacy of BIP alone, cavitron ultrasonic surgical aspirator (CUSA) + BIP and conventional clamp crushing (CLAMP). METHODS: Based on our database of patient records, a total of 380 consecutive patients who underwent hepatectomy at our hospital were retrospectively studied for the efficacy of BIP alone, CUSA + BIP and CLAMP. Of all the patients, 75 received saline-coupled BIP (Group A), 53 received CUSA + BIP (Group B), and 252 received CLAMP (Group C). The pre-, mid-, and postoperative clinical manifestations were compared, and the effects of those maneuvers were evaluated. RESULTS: There was no obvious difference among the preoperative indexes between the different groups. The operative time was longer in Groups A and B than in Group C (P < 0.001 for both). The amount of bleeding and the rate of transfusion during the operation were significantly higher in Group C than in Groups A and B (P < 0.001 for all). The incidence of postoperative complications in Group C (46.43%) was higher than that in Groups A (30.67%, P = 0.015) and B (28.30%, P = 0.016). The patients' liver function recovery and postoperative hospital stay were not significantly different. BIP could decrease intraoperative hemorrhage and postoperative complications compared to CLAMP. CONCLUSION: Simple saline-coupled BIP should be considered a safe and reliable technique for liver resection to decrease intraoperative hemorrhage and postoperative complications. PMID- 25024621 TI - Lipid levels in serum and cancerous tissues of colorectal cancer patients. AB - AIM: To investigate the correlations between lipid metabolism disorder and the occurrence and development of colorectal cancer by monitoring the alterations in lipid levels in cancerous tissue and serum in patients with colorectal cancer. METHODS: The levels of total and free cholesterol (TCH and FCH), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein- cholesterol (HDL-C), apolipoprotein A1 (ApoA-1) and ApoB in serum of 206 patients with colorectal cancer, 70 patients with benign colorectal disease and 300 healthy participants, and in the cancerous tissue and paracancerous tissue of 152 patients with colorectal cancer were measured with an Olympus 600 auto biochemical analyzer. The obtained data were statistically analyzed. RESULTS: Serum FCH level was significantly higher (1.9 +/- 0.4 mmol/L vs 1.3 +/- 0.3 mmol/L, 1.9 +/- 0.4 mmol/L vs 1.2 +/- 0.4 mmol/L, P < 0.05), whereas serum levels of TCH, LDL-C, ApoA-I and ApoB were significantly lower in patients with colorectal cancer than in patients with benign colorectal disease and healthy controls. The levels of FCH and TG in cancerous tissue were significantly lower (14.5 +/- 9.6 MUmol/g vs 19.3 +/- 13.9 MUmol/g, P < 0.05; 16.3 +/- 19.8 MUmol/g vs 44.1 +/- 38.1 MUmol/g, P < 0.05), whereas HDL-C level was significantly higher (7.9 +/- 4.5 MUmol/g vs 5.7 +/- 3.9 MUmol/g, P < 0.01) in cancerous tissue than in paracancerous tissue. The levels of TCH and TG in serum and the levels of TCH and HDL-C in cancerous tissue in patients with colorectal cancer were significantly correlated with TNM stage. The levels of TCH and LDL-C in serum were significantly lower, whereas HDL-C level in cancerous tissue was significantly higher in patients with lymph node metastasis than in patients without lymph node metastasis. The levels of TCH, FCH, TG, HDL-C and LDL-C in cancerous tissue were not significantly different from those in paracancerous tissue. The serum levels of FCH and TG were significantly higher, whereas serum HDL-C levels were significantly lower in patients with rectum cancer than in patients with colon cancer. CONCLUSION: The disordered and abnormally altered levels of lipids in cancerous tissue and serum of patients with colorectal cancer may be correlated with the occurrence and development of colorectal cancer. PMID- 25024622 TI - Plasma free amino acid profiling of esophageal cancer using high-performance liquid chromatography spectroscopy. AB - AIM: To perform plasma free amino acid (PFAA) profiling of esophageal squamous cell carcinoma (ESCC) patients at different pathological stages and healthy subjects. METHODS: Plasma samples from ESCC patients (n = 51) and healthy control adults (n = 60) were analyzed by high-performance liquid chromatography (HPLC). The ESCC patients included moderate/poorly-differentiation (n = 24), lymph node metastasis (n = 17) and clinical stage > Ib2 (n = 36). Partial least squares discriminant analysis was performed to demonstrate that the PFAA metabolic patterns enabled discrimination between ESCC patients and controls, and the Student t test was applied to assess significant differences in PFAA concentrations between the two groups. RESULTS: There were significant differences in the PFAA profiles between controls and ESCC patients. Compared with healthy controls, the levels of Asp, Glu, Gly, His, Thr, Tau, Ala, Met, Ile, Leu, and Phe were decreased in ESCC patients, but Cys was increased. There exists a strong correlation between PFAA profiles and clinicopathological characteristics in ESCC patients. The levels of many PFAAs (i.e., Glu, Asp, Ser, Gly, Tau, Ala, Tyr, Val, Ile, and Leu) were related to pathological grading, lymph node metastasis, and ESCC clinical stage. Very good discrimination between ESCC patients and control subjects was achieved by multivariate modeling of plasma profiles. CONCLUSION: HPLC-based plasma profiling analysis was shown to be an effective approach to differentiate between ESCC patients and controls. PFAA profiles may have potential value for screening or diagnosing ESCC. PMID- 25024623 TI - Outcomes of autologous bone marrow mononuclear cell transplantation in decompensated liver cirrhosis. AB - AIM: To determine the long-term efficacy of autologous bone marrow mononuclear cells (BM-MNCs) transplantation in terms of improving liver function and reducing complications in patients with decompensated cirrhosis. METHODS: A total of 47 inpatients with decompensated liver cirrhosis were enrolled in this trial, including 32 patients undergoing a single BM-MNCs transplantation plus routine medical treatment, and 15 patients receiving medical treatment only as controls. Forty-three of 47 patients were infected with hepatitis B virus. Bone marrow of 80-100 mL was obtained from each patient and the BM-MNCs suspension was transfused into the liver via the hepatic artery. The efficacy of BM-MNCs transplantation was monitored during a 24-mo follow-up period. RESULTS: Liver function parameters in the two groups were observed at 1 mo after BM-MNCs transfusion. Prealbumin level was 118.3 +/- 25.3 mg/L vs 101.4 +/- 28.7 mg/L (P = 0.047); albumin level was 33.5 +/- 3.6 g/L vs 30.3 +/- 2.2 g/L (P = 0.002); total bilirubin 36.9 +/- 9.7 mmol/L vs 45.6 +/- 19.9 mmol/L (P = 0.048); prothrombin time 14.4 +/- 2.3 s vs 15.9 +/- 2.8 s (P = 0.046); prothrombin activity 84.3% +/- 14.3% vs 74.4% +/- 17.8% (P = 0.046); fibrinogen 2.28 +/- 0.53 g/L vs 1.89 +/- 0.44 g/L (P = 0.017); and platelet count 74.5 +/- 15.7 * 10(9)/L vs 63.3 +/- 15.7 * 10(9)/L (P = 0.027) in the treatment group and control group, respectively. Differences were statistically significant. The efficacy of BM-MNCs transplantation lasted 3-12 mo as compared with the control group. Serious complications such as hepatic encephalopathy and spontaneous bacterial peritonitis were also significantly reduced in BM-MNCs transfused patients compared with the controls. However, these improvements disappeared 24 mo after transplantation. CONCLUSION: BM-MNCs transplantation is safe and effective in patients with decompensated cirrhosis. It also decreases the incidence of serious complications. PMID- 25024624 TI - Pro-atherosclerotic markers and cardiovascular risk factors one year after liver transplantation. AB - AIM: To investigate pro-atherosclerotic markers (endothelial dysfunction and inflammation) in patients one year after liver transplantation. METHODS: Forty four consecutive liver transplant (LT) outpatients who were admitted between August 2009 and July 2010, were followed-up by for 1 year, exhibited no evidences of infection or rejection, all of them underwent tacrolimus-based immunosuppressive regimens were consecutively enrolled. Inflammatory cytokines (TNFalpha, IFNgamma, IL-8, and IL-10), endothelial biomarkers (sVCAM-1, sICAM-1, MPO, adiponectin, PAI-1, SAP, SAA, E-selectin, and MMP-9), high sensitive C reactive protein, and Framingham risk score (FRS) were assessed. The anthropometric data, aminotransferases, metabolic syndrome features, glucose and lipid profiles, and insulin resistance data were also collected. The LT recipients were compared to 22 biopsy-proven non-alcoholic steatohepatitis (NASH) patients and 20 healthy controls (non-obese, non-diabetics, and non dyslipidemic). RESULTS: The LT recipients had significantly younger ages and lower body mass indices, aminotransferases, fasting glucose and insulin levels, glucose homeostasis model and metabolic syndrome features than the NASH patients. Classic cardiovascular risk markers, such as Hs-CRP and FRS [2.0 (1.0-8.75)], were lower in the LT patients compared to those observed in the NASH patients (P = 0.009). In contrast, the LT recipients and NASH patients had similar inflammatory and endothelial serum markers compared to the controls (pg/mL): lower IL-10 levels (32.3 and 32.3 vs 62.5, respectively, P = 0.019) and higher IFNgamma (626.1 and 411.9 vs 67.9, respectively, P < 0.001), E-selectin (48.5 and 90.03 vs 35.7, respectively, P < 0.001), sVCAM-1 (1820.6 and 1692.4 vs 1167.2, respectively, P < 0.001), and sICAM-1 (230.3 and 259.7 vs 152.9, respectively, P = 0.015) levels. CONCLUSION: Non-obese LT recipients have similar pro atherosclerotic serum profiles after a short 1-year follow-up period compared to NASH patients, suggesting a high risk of atherosclerosis in this population. PMID- 25024625 TI - Combination of symptoms, syndrome and disease: treatment of refractory diabetic gastroparesis. AB - AIM: To assess effect of combination of symptoms, syndrome and disease on treatment of diabetic gastroparesis with severe nausea and vomiting. METHODS: Professor Tong Xiaolin's clinical electronic medical records of patients who were treated between January 1, 2006 and October 1, 2012 were used as a database. Patients who met the inclusion criteria were enrolled. General information (name, sex and age), symptoms and blood glucose levels were obtained from the clinic electronic medical record, which was supplemented by a telephone interview. The patient-rated Gastroparesis Cardinal Symptom Index (GCSI) was used to evaluate the severity of the symptoms of gastroparesis. The effects of the treatment were assessed by the change in the severity of the symptoms of gastroparesis and the change in blood glucose between the baseline levels and the post-treatment levels at 1, 2, 4, 8 and 12 wk. RESULTS: Forty-five patients had a mean GCSI nausea and vomiting severity score of 4.21 +/- 0.67 and a total GCSI score of 2.77 +/- 0.63 before treatment. There was a significant improvement in the nausea and vomiting score at every return visit compared with the baseline score (1 wk: 3.02 +/- 1.04 vs 4.18 +/- 0.71, P < 0.001; 2 wk: 2.32 +/- 1.25 vs 4.16 +/- 0.73, P < 0.001; 4 wk: 2.12 +/- 1.26 vs 4.12 +/- 0.73, P < 0.001; 8 wk: 1.79 +/- 1.09 vs 4.24 +/- 0.77, P < 0.001; 12 wk: 0.69 +/- 0.92 vs 4.25 +/- 0.70, P < 0.001). Twenty-five of the 45 patients had complete resolution of vomiting during the observation period (mean time to resolution was 37.9 +/- 27.3 d). The postprandial fullness and early satiety subscale, bloating subscale and total GCSI scores were also improved. Finally, the blood glucose levels improved after treatment, although the change was not significant. CONCLUSION: Use of the combination of symptoms, syndrome and disease to treat diabetic gastroparesis with refractory nausea and vomiting may be a new treatment option. PMID- 25024626 TI - Expression of P450 and nuclear receptors in normal and end-stage Chinese livers. AB - AIM: To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers. METHODS: The end-stage liver disease samples [n = 93, including hepatocellular carcinoma (HCC), peri-HCC tissue, hepatitis B virus cirrhosis, alcoholic cirrhosis, and severe cirrhosis] and trimmed normal Chinese donor livers (n = 35) from The Institute of Organ Transplantation in Beijing, China. Total RNA was extracted, purified, and subjected to real-time RT-PCR analysis. RESULTS: For cytochrome P450 enzymes 1 (CYP1) family, the expression of CYP1A2 was decreased 90% in HCC, 80% in alcoholic cirrhosis, and 65% in severe cirrhosis. For CYP2 family, the expression of CAR was decreased 50% in HCC, but increased 50% in peri-HCC tissues. Similar decreases (about 50%) of CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 were observed in HCC, as compared to peri-HCC tissues and normal livers. CYP2C19 were decreased in all end-stage liver diseases and CYP2E1 also decreased in alcoholic cirrhosis and severe cirrhosis. For CYP3 family, the expression of PXR was decreased 60% in HCC, together with decreases in CYP3A4, CYP3A5, and CYP3A7. In contrast, the expression of CYP3A7 was slightly increased in HBV cirrhosis. The expression of CYP4A11 was decreased 85% in HCC, 7% in alcoholic cirrhosis and severe liver cirrhosis, along with decreases in PPARalpha. The 93 end-stage livers had much higher inter-individual variations in gene expression than 35 normal livers. CONCLUSION: The expression of CYP enzyme genes and corresponding nuclear receptors was generally decreased in end-stage liver diseases, and significant differences in gene expression were evident between peri-HCC and HCC. PMID- 25024627 TI - Drain amylase value as an early predictor of pancreatic fistula after cephalic duodenopancreatectomy. AB - AIM: To determine predictors of clinically relevant pancreatic fistulas (CRPF) by measuring drain fluid amylase (DFA) in the early postoperative period. METHODS: This prospective clinical study included 382 patients with periampullary tumors that were surgically resected at our department between March 2005 and October 2012. A cephalic duodenopancreatectomy (DP) was performed on all patients. Two closed suction drains were placed at the end of the surgery. The highest postoperative DFA value was recorded and analyzed during the first three postoperative days and on subsequent days if the drains were kept longer. Pancreatic fistula (PF) was classified according to the International Study Group of Pancreatic Fistula (ISGPF) criteria. Postoperative complications were defined according to the Dindo-Clavien classification. All data were statistically analyzed. The optimal thresholds of DFA levels on the first, second and third postoperative days were estimated by constructing receiver operating curves, generated by calculating the sensitivities and specificities of the DFA levels. The DFA level limits were used to differentiate between the group without PF and the groups with biochemical pancreatic fistula (BPF) and CRPF. RESULTS: Pylorus preserving duodenopancreatectomy was performed on 289 (75.6%) patients, while the remaining patients underwent a classic Whipple procedure (CW). The total incidence of PF was 37.7% (grade A 22.8%, grade B 11.0% and grade C 3.9%). Soft pancreatic texture (SPT) was present in 58.3% of patients who developed PF. Mortality was 4.2%. The median DFA value on the first postoperative day (DFA1) in patients who developed PF was 4520 U/L (range 350-99000 U/L) for grade A fistula (BPF) with a SPT and a diameter of the main pancreatic duct (MPD) of <= 3 mm. For grade B/C (CRPF), the median DFA1 value was 8501 U/L (range 377-92060 U/L) with a SPT and MPD of <= 3 mm. These values were significantly higher when compared to the patients who did not have PF (122; range 5-37875 U/L). The upper limit of DFA values for the first 3 postoperative days in the examined stages of PF were: DFA1 1200 U/L for the BPF and CRPF; DFA3 350 U/L for BPF and DFA3 800 U/L for CRPF. The determined values were highly significant and demonstrated a reliable diagnostic test for both BPF and CRPF. CONCLUSION: DFA1 >= 1200 U/L is an important predictive factor for PF of any degree. The trend of DFA3 (decrease of < 50%) compared to DFA1 is a significant factor in the differentiation of CRPF from transient BPF. PMID- 25024628 TI - APE1 polymorphisms are associated with colorectal cancer susceptibility in Chinese Hans. AB - AIM: To study the association between four base excision repair gene polymorphisms and colorectal cancer risk in a Chinese population. METHODS: Two hundred forty-seven colorectal cancer (CRC) patients and three hundred cancer free controls were enrolled in this study. Four polymorphisms (OGG1 Ser326Cys, APE1 Asp148Glu, -141T/G in the promoter region, and XRCC1 Arg399Gln) in components of the base excision repair pathway were determined in patient blood samples using polymerase chain reaction with confronting two-pair primers. The baseline information included age, gender, family history of cancer, and three behavioral factors [smoking status, alcohol consumption, and body mass index (BMI)]. chi(2) tests were used to assess the Hardy-Weinberg equilibrium, the distributions of baseline characteristics, and the four gene polymorphisms between the cases and controls. Multivariate logistic regression analyses were conducted to analyze the correlations between the four polymorphisms and CRC risk, adjusted by the baseline characteristics. Likelihood ratio tests were performed to analyze the gene-behavior interactions of smoking status, alcohol consumption, and BMI on polymorphisms and CRC susceptibility. RESULTS: The APE1 148 Glu/Glu genotype was significantly associated with an increased risk of colorectal cancer (OR = 2.411, 95%CI: 1.497-3.886, P < 0.001 relative to Asp/Asp genotype). There were no associations between OGG1, XRCC1, or APE1 promoter polymorphisms and CRC risk. A multivariate analysis including three behavioral factors showed that the APE1 148 Glu/Glu genotype was associated with an increased risk for CRC among both smokers and non-smokers, non-drinkers and individuals with a BMI >= 25 kg/m(2) (ORs = 2.356, 3.299, 2.654, and 2.581, respectively). The XRCC1 399 Arg/Gln genotype was associated with a decreased risk of CRC among smokers and drinkers (OR = 0.289, 95%CI: 0.152-0.548, P < 0.001, and OR = 0.327, 95%CI: 0.158-0.673, P < 0.05, respectively). The APE1 promoter polymorphism -141 T/G genotype was associated with a reduced risk of colorectal cancer among subjects with a BMI < 25 kg/m(2) (OR = 0.214, 95%CI: 0.069-0.660, P < 0.05 relative to T/T genotype). There were significant gene behavior interactions between smoking status and XRCC1 Arg399Gln, as well as BMI and APE1 -141T/G polymorphism (all P < 0.05). CONCLUSION: APE1 Asp148Glu is associated with increased CRC risk and smoking alters the association between XRCC1 Arg399Gln and CRC risk in the Chinese Han population. PMID- 25024630 TI - Acute abdomen: rare and unusual presentation of right colic xanthogranulomatosis. AB - Xanthogranulomatous inflammation (XGI) is a disease of unknown origin, most frequently described in the kidney and gallbladder; its localization in the colorectal tract is extremely rare. The extension of the typical inflammatory process to the surrounding tissues may lead to misdiagnosis as cancer. We report the case of a 56-year-old woman presenting to the Emergency Department with pain, increased levels of alpha1 and alpha2 proteins and C-reactive protein (17.5 mg/dL; normal value 0-0.5), and a palpable mass, localized in the right lower quadrant of the abdomen. A computed tomography scan showed a large right cecal mass with necrotic areas, local inflammation of retroperitoneal fat, and enlargement of local lymph nodes. Because of the high suspicion of colic abscess as well as malignancy and worsening of the clinical condition, the patient underwent right colectomy after 4 d of antibiotic treatment. Pathology revealed xanthogranulomatous inflammation involving the ileocecal valve. We review the reports of large bowel tract XGI in the international literature. PMID- 25024629 TI - I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life. AB - AIM: To determine the dose-related effects of a novel probiotic combination, I.31, on irritable bowel syndrome (IBS)-related quality of life (IBS-QoL). METHODS: A multicenter, randomized, double-blind, placebo-controlled intervention clinical trial with three parallel arms was designed. A total of 84 patients (53 female, 31 male; age range 20-70 years) with IBS and diarrhea according to Rome III criteria were randomly allocated to receive one capsule a day for 6 wk containing: (1) I.31 high dose (n = 28); (2) I.31 low dose (n = 27); and (3) placebo (n = 29). At baseline, and 3 and 6 wk of treatment, patients filled the IBSQoL, Visceral Sensitivity Index (VSI), and global symptom relief questionnaires. RESULTS: During treatment, IBS-QoL increased in all groups, but this increment was significantly larger in patients treated with I.31 than in those receiving placebo (P = 0.008). After 6 wk of treatment, IBS-QoL increased by 18 +/- 3 and 22 +/- 4 points in the high and the low dose groups, respectively (P = 0.041 and P = 0.023 vs placebo), but only 9 +/- 3 in the placebo group. Gut specific anxiety, as measured with VSI, also showed a significantly greater improvement after 6 wk of treatment in patients treated with probiotics (by 10 +/ 2 and 14 +/- 2 points, high and low dose respectively, P < 0.05 for both vs 7 +/ 1 score increment in placebo). Symptom relief showed no significant changes between groups. No adverse drug reactions were reported following the consumption of probiotic or placebo capsules. CONCLUSION: A new combination of three different probiotic bacteria was superior to placebo in improving IBS-related quality of life in patients with IBS and diarrhea. PMID- 25024631 TI - HBsAg clearance by Peg-interferon addition to a long-term nucleos(t)ide analogue therapy. AB - The ideal endpoint of hepatitis B virus (HBV) antiviral therapy is HBsAg loss, a difficult goal to obtain, especially in HBeAg negative patients. Herein, we report the results obtained by the addition of peg-interferon alpha-2a to a long lasting nucleos(t)ide analogue therapy in a HBeAg negative, genotype D patient with steadily HBV-DNA negative/HBsAg positive values. In 2002, our Caucasian 44 year-old male patient received lamivudine and, 4 years later, added adefovir because of a virological breakthrough. In 2011, considering his young age, liver stiffness (4.3 kPa) and HBsAg levels (3533 IU/mL), we added Peg-interferon alpha 2a for six months (3 in combination with nucleos(t)ide analogues followed by 3 mo of Peg-interferon alpha-2a monotherapy). A decrease of HBsAg levels was observed after 1 mo (1.21 log) of Peg-interferon and 3 mo (1.88 log) after the discontinuation of all drugs. Later, a complete clearance of HBsAg was obtained with steadily undetectable HBV-DNA serum levels (< 9 IU/mL). HBsAg clearance by the addition of a short course of Peg-interferon alpha-2a represents an important result with clinical and pharmaco-economic implications, considering that nucleos(t)ide analogues therapy in HBeAg negative chronic hepatitis B patients is considered a long-lasting/life-long treatment. PMID- 25024632 TI - Perihepatic adhesions: an unusual complication of hemolysis, elevated liver enzymes and low platelet syndrome. AB - We present a case of symptomatic perihepatic adhesions, which developed after a pregnancy complicated by hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, in which a subcapsular liver hematoma occurred. Our patient presented with complaints of persistent, severe right-sided upper abdominal pain. The complaints developed gradually, one year after a pregnancy that had been complicated by HELLP syndrome with a subcapsular liver hematoma. The hematoma had resolved spontaneously. An upper-abdominal magnetic resonance imaging revealed a density between liver and diaphragm at the site of the former subcapsular hematoma, suspect of perihepatic adhesions. The presence of perihepatic adhesions was confirmed during a laparoscopy and treated by adhesiolysis in the same session. The adhesions may have developed in response to the degradation process of the subcapsular liver hematoma during conservative treatment. This case of perihepatic adhesions may therefor be the first presentation of a long term sequel of subcapsular liver hematoma in HELLP syndrome. PMID- 25024633 TI - Two-stage treatment with hepatectomy and carbon-ion radiotherapy for multiple hepatic epithelioid hemangioendotheliomas. AB - Hepatic epithelioid hemangioendothelioma (HEH) is a rare neoplasm of vascular origin with variable malignant potential. Because most patients with this condition have multiple bilobar lesions, liver transplantation is the standard treatment, and hepatectomy is much less frequently indicated. We describe a case of a 35-year-old woman with unresectable multiple bilobar HEH successfully treated by combination treatment with hepatectomy and carbon-ion radiotherapy. This case is very meaningful since it demonstrated the effectiveness of carbon ion radiotherapy for HEH and the possibility of expanding the curative treatment options for multiple bilobar hepatic tumors. PMID- 25024634 TI - Tubulopapillary adenoma of the gallbladder accompanied by bile duct tumor thrombus. AB - Intraductal papillary mucinous neoplasm of the bile duct (IPNB) is recognized as a precancerous lesion; however, both its pathogenesis and progression remain unclear. We present here a case of IPNB arising from the gallbladder accompanied by bile duct tumor thrombus in a 79-year-old female. The resected specimen revealed a tubulopapillary adenoma with no malignant cells. This case suggests that even in the absence of malignant cells, these tumors can behave as malignant tumors requiring aggressive treatment. Even if no malignant cells are present, intraepithelial neoplasms occurring in the ampullopancreatobiliary tract can behave as malignant tumors. PMID- 25024635 TI - First case of IgG4-related sclerosing cholangitis associated with autoimmune hemolytic anemia. AB - To our knowledge, patients with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) associated with autoimmune hemolytic anemia (AIHA) have not been reported previously. Many patients with IgG4-SC have autoimmune pancreatitis (AIP) and respond to steroid treatment. However, isolated cases of IgG4-SC are difficult to diagnose. We describe our experience with a patient who had IgG4-SC without AIP in whom the presence of AIHA led to diagnosis. The patient was a 73 year-old man who was being treated for dementia. Liver dysfunction was diagnosed on blood tests at another hospital. Imaging studies suggested the presence of carcinoma of the hepatic hilus and primary sclerosing cholangitis, but a rapidly progressing anemia developed simultaneously. After the diagnosis of AIHA, steroid treatment was begun, and the biliary stricture improved. IgG4-SC without AIP was thus diagnosed. PMID- 25024637 TI - Variance in male lifetime reproductive success and estimation of the degree of polygyny in a primate. AB - The degree of polygyny is predicted to influence the strength of direct male-male competition, leading to a high variance in male lifetime reproductive success and to reproduction limited to the prime period of adulthood. Here, we explore the variance in male lifetime reproductive success and reproductive time in an anthropoid primate forming multimale-multifemale groups. Males of this species form dominance hierarchies, which are expected to skew reproduction toward few high-ranking males. At the same time, however, females mate with multiple males (polygynandry), which should limit the degree of polygyny. Using 20 years of genetic and demographic data, we calculated lifetime reproductive success for the free-ranging rhesus macaque (Macaca mulatta) population of Cayo Santiago for subjects that died naturally or reached senescence. Our results show that 1) male lifetime reproductive success was significantly skewed (range: 0-47 offspring; males reproducing below average: 62.8%; nonbreeders: 17.4%), 2) variance in male lifetime reproductive success was 5 times larger than in females, and 3) male lifetime reproductive success was more influenced by variation in fecundity (60%) than longevity (25%), suggesting that some direct male-male competition takes place. However, the opportunity for selection (i.e., standardized variance in male lifetime reproductive success) is low compared with that in other large mammal species characterized by a high degree of polygyny. Moreover, male reproductive life extended much beyond the prime period, showing that physical strength was not required to acquire mates. We conclude that rhesus macaques exhibit a moderate degree of polygyny and, therefore, low levels of direct male male competition for fertile females, despite the fact that males form linear dominance hierarchies. PMID- 25024636 TI - Laparoscopic segmental colectomy for colonic lymphangiomas: a definitive, minimally invasive surgical option. AB - Colonic lymphangioma is an unusual benign malformation. We herein describe two cases. A 36-year-old woman was admitted with one year of intermittent abdominal pain; colonoscopy, abdominopelvic computed tomography and endoscopic ultrasonography (EUS) revealed enlarged cystic masses at the ascending colon. In another 40-year-old man, colonoscopy and EUS revealed an asymptomatic lobulated cystic mass with four small sessile polyps at the sigmoid colon. Both patients underwent laparoscopic segmental colectomy. Both masses were histologically confirmed as cystic lymphangiomas, and the patients were discharged without complications. The management of colonic lymphangioma depends on the individual situation; close surveillance or endoscopic therapy may be appropriate for asymptomatic lesions smaller than 2.5 cm in diameter. Surgical intervention can be considered for larger lesions or in patients who develop complication risks. Laparoscopic segmental colon resection may be recommended to excise relatively large submucosal lesions because it is a definitive, minimally invasive intervention with a fast postoperative recovery. PMID- 25024638 TI - Vocal fundamental and formant frequencies are honest signals of threat potential in peripubertal males. AB - Fundamental and formant frequencies influence perceived pitch and are sexually dimorphic in humans. The information content of these acoustic parameters can illuminate the forces of sexual selection shaping vocal sex differences as well as the mechanisms that ensure signal reliability. We use multiple regression to examine the relationships between somatic (height, adiposity, and strength) and acoustic (fundamental frequency [F0], formant position [Pf], and fundamental frequency variation [F0-SD]) characteristics in a sample of peripubertal Bolivian Tsimane. Results indicate that among males-but not females-strength is the strongest predictor of F0 and Pf and that F0 and Pf are independent predictors of strength when height and adiposity are controlled. These findings suggest that listeners may attend to vocal frequencies because they signal honest, nonredundant information about male strength and threat potential, which are strongly related to physical maturity and which cannot be ascertained from visual or other indicators of height or adiposity alone. PMID- 25024639 TI - Adult versus Pediatric Neuroblastoma: The M.D. Anderson Cancer Center Experience. AB - Background. Staging and treatment of adult neuroblastoma has yet to be formalized. We sought to determine the utility of the pediatric classification system in adults and determine the efficacy of different treatment modalities. Methods. Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2-17), who were treated for neuroblastoma at M.D. Anderson Cancer Center from January 1994 to September 2012, were reviewed. International neuroblastoma risk group (INRG) variables were abstracted. The primary outcome of interest was actuarial progression-free survival. Results. Median age of pediatric patients was 5 years (range 3-16) and 47 years (range 18-82) for adult patients. There were no differences in PFS or OS between stage-matched risk categories between pediatric and adult patients (L1-P = 0.40, L2-P = 0.54, and M P = 0.73). In the treatment of L1 disease, median PFS for adults treated with surgery and radiation was 11.1 months compared with single modality local treatment +/- chemotherapy (6.4 and 5.1 months, resp.; P = 0.07). Median PFS in L2 adult patients was 5.2 months with local therapy and 4 months with the addition of chemotherapy (P = 0.23). Conclusions. Adult and pediatric patients with neuroblastoma achieve similar survival outcomes. INRG classification should be employed to stratify adult neuroblastoma patients and help select treatment. PMID- 25024640 TI - Cost-effectiveness of pazopanib in advanced soft tissue sarcoma in the United kingdom. AB - In the phase III PALETTE trial, pazopanib improved progression-free survival (PFS) compared with placebo in patients with advanced/metastatic soft tissue sarcomas (mSTS) who had received prior chemotherapy. We used a multistate model to estimate expected PFS, overall survival (OS), lifetime STS treatment costs, and quality-adjusted life-years (QALYs) for patients receiving pazopanib, placebo, trabectedin, ifosfamide, or gemcitabine plus docetaxel as second-line mSTS therapies. The cost-effectiveness of pazopanib was expressed as the incremental costs per QALY gained. Estimates of PFS/OS, adverse events, and utilities for pazopanib and placebo were from the PALETTE trial. Estimates of relative effectiveness of the other comparators were from an unadjusted indirect comparison versus pazopanib. Costs were from published sources. Pazopanib is estimated to increase QALYs by 0.128 and costs by L7,976 versus placebo; cost per QALY gained with pazopanib versus placebo is estimated to be L62,000. Compared with the other chemotherapies, pazopanib provides similar QALYs at a lower cost. Pazopanib may not be cost-effective versus placebo but may be cost-effective versus the most commonly used active treatments, although this conclusion is uncertain. Given the unmet need for effective treatments for mSTS, pazopanib may be an appropriate alternative to some currently used medications in the United Kingdom. PMID- 25024641 TI - Giant osteoclasts in patients under bisphosphonates. AB - BACKGROUND: Bisphosphonates have been widely used for treatment of high bone resorption states. It lowers bone turnover by inhibiting osteoclasts bone resorption with various mechanisms of actions: inhibition of osteoclast formation and attachment to the bone surface, induction of metabolic injury, alteration of vesicle trafficking and induction of osteoclast apoptosis. Bone biopsies studies from patients under bisphosphonates have shown that some resorption parameters are decreased as expected but the number of osteoclasts seems not to be necessarily decreased. The description of osteoclasts morphology from patients treated with bisphosphonates has rarely been reported in the literature. CASE PRESENTATION: We describe in this paper two patients treated with bisphosphonates from whom iliac crest bone biopsies have shown large, multinucleated and apoptotic osteoclasts that were not associated with bone resorption activities. The characteristics of these osteoclasts are described and the literature reviewed. CONCLUSION: The appropriate recognition of these giant osteoclasts in bone tissues from patients treated with bisphosphonates is of primary importance for bone pathologists and should not be interpreted as signs of increased bone resorption as seen in hyperparathyroidism, bone cancer or Paget's disease of bone. PMID- 25024642 TI - Pressure ulcer related pain in community populations: a prevalence survey. AB - BACKGROUND: Pressure ulcers are costly to the healthcare provider and can have a major impact on patient's quality of life. One of the most distressing symptoms reported is pain. There is very little published data on the prevalence and details of pain experienced by patients with pressure ulcers, particularly in community populations. The study was conducted in two community NHS sites in the North of England. METHODS: The aim was to estimate the prevalence of pressure area related pain within a community population. We also explored the type and severity of the pain and its association with pressure ulcer classification. A cross-sectional survey was performed of community nurses caseloads to identify adult patients with pressure ulcers and associated pain. Consenting patients then had a full pain assessment and verification of pressure ulcer grade. RESULTS: A total of 287 patients were identified with pressure ulcers (0.51 per 1000 adult population). Of the 176 patients who were asked, 133 (75.6%) reported pain. 37 patients consented to a detailed pain assessment. Painful pressure ulcers of all grades and on nearly all body sites were identified. Pain intensity was not related to number or severity of pressure ulcer. Both inflammatory and neuropathic pain were reported at all body sites however the proportion of neuropathic pain was greater in pressure ulcers on lower limbs. CONCLUSIONS: This study has identified the extent and type of pain suffered by community patients with pressure ulcers and indicates the need for systematic and regular pain assessment and treatment. PMID- 25024643 TI - Enhanced pre-operative thrombolytic status is associated with the incidence of deep venous thrombosis in patients undergoing total knee arthroplasty. AB - BACKGROUND: Deep venous thrombosis (DVT), which is often associated with pulmonary embolism (PE), is a serious complication after total knee arthroplasty (TKA). In the present study, we examined the overall thrombotic and thrombolytic status using Global Thrombosis Test (GTT) in non-anticoagulated blood of patients undergoing TKA to develop the predictable marker for the incidence of DVT. METHODS: DVT was diagnosed using doppler ultrasonography a day after the surgery in 31 patients with osteoarthritis (n = 24), rheumatoid arthritis (n = 6) and ankylosing spondylitis (n = 1) by the well-trained operator. We measured overall thrombotic and thrombolytic status using GTT and other biomarkers, which is associated with blood coagulation and fibrinolysis, before and immediately after the surgery. RESULTS: Newly-generated DVT during the operation was detected in 11 of 31 patients (35.4%) 1 day after TKA. There were no differences in markers of coagulation (PT and APTT), platelet activity (platelet aggregation-induced by ADP and collagen) and fibrinolysis (FDP and D-dimer) between non-DVT and DVT group both before and after the surgery. Both Pre- and Post-operative GTT-occlusion times (OT), an index of platelet reactivity, were tended to be shorter, but not significant, in DVT group compared with non-DVT group. Pre-operative GTT-lysis time (LT), an index of thrombolytic activity, was significantly shorter in DVT group compared with non-DVT group, while there were no differences in post operative value of this index between DVT group and non-DVT group, suggesting overall thrombolytic activity was enhanced in DVT group before surgery. CONCLUSIONS: Our data suggest that enhancement of pre-operative thrombolytic activity assessed by GTT may be a predictable marker for the incidence of DVT after TKA. PMID- 25024645 TI - Risk of venous thromboembolic disease and adequacy of prophylaxis in hospitalized patients in Argentina: a multicentric cross-sectional study. AB - BACKGROUND: Venous thromboembolic disease (VTE) is associated with high morbi mortality. Adherence rate to the recommendations of antithrombotic prophylaxis guidelines (ATPG) is suboptimal. The aim of this study was to describe the adequacy of antithrombotic prophylaxis (ATP) in hospitalized patients as the initial stage of a program designed to improve physician adherence to -ATP recommendations in Argentina. METHODS: This study was a multicenter, cross sectional study that included 28 Institutions throughout 5 provinces in Argentina. RESULTS: 1315 patients were included, 729 (55.4%) were hospitalized for medical (clinical) reasons, and 586 (44.6%) for surgical reasons. Adequate ATP was provided to 66.9% of the patients and was more frequent in surgical (71%) compared to clinical (63.6%) subjects (p < 0.001). Inadequate ATP resulted from underuse in 76.6% of the patients. Among clinical, 203 (16%) had increased bleeding risk and mechanical ATP was used infrequently. CONCLUSIONS: The adequacy of ATP was better in low VTE risk clinical and surgical patients and high VTE risk in orthopedic patients. There was worse adequacy in high risk patients (with active neoplasm) and in those with pharmacological ATP contraindications, in which the use of mechanical methods was scarce. The adequacy of ATP was greater at institutions with < 150 beds compared with larger institutions. This is the first multicentric study reporting ATP in Argentina. Understanding local characteristics of medical performance within our territory is the first step in order to develop measures for improving ATP in our environment. PMID- 25024644 TI - Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression. AB - BACKGROUND: Atrial fibrillation (AF) patients frequently require anticoagulation with vitamin K antagonists (VKAs) to prevent thromboembolic events, but their use increases the risk of hemorrhage. We evaluated time spent in therapeutic range (TTR), proportion of international normalized ratio (INR) measurements in range (PINRR), adverse events in relation to INR, and predictors of INR control in AF patients using VKAs. METHODS: We searched MEDLINE, CENTRAL and EMBASE (1990-June 2013) for studies of AF patients receiving adjusted-dose VKAs that reported INR control measures (TTR and PINRR) and/or reported an INR measurement coinciding with thromboembolic or hemorrhagic events. Random-effects meta-analyses and meta regression were performed. RESULTS: Ninety-five articles were included. Sixty eight VKA-treated study groups reported measures of INR control, while 43 studies reported an INR around the time of the adverse event. Patients spent 61% (95% CI, 59-62%), 25% (95% CI, 23-27%) and 14% (95% CI, 13-15%) of their time within, below or above the therapeutic range. PINRR assessments were within, below, and above range 56% (95% CI, 53-59%), 26% (95% CI, 23-29%) and 13% (95% CI, 11-17%) of the time. Patients receiving VKA management in the community spent less TTR than those managed by anticoagulation clinics or in randomized trials. Patients newly receiving VKAs spent less TTR than those with prior VKA use. Patients in Europe/United Kingdom spent more TTR than patients in North America. Fifty-seven percent (95% CI, 50-64%) of thromboembolic events and 42% (95% CI, 35 - 51%) of hemorrhagic events occurred at an INR <2.0 and >3.0, respectively; while 56% (95% CI, 48-64%) of ischemic strokes and 45% of intracranial hemorrhages (95% CI, 29 63%) occurred at INRs <2.0 and >3.0, respectively. CONCLUSIONS: Patients on VKAs for AF frequently have INRs outside the therapeutic range. While, thromboembolic and hemorrhagic events do occur patients with a therapeutic INR; patients with an INR <2.0 make up many of the cases of thromboembolism, while those >3.0 make up many of the cases of hemorrhage. Managing anticoagulation outside of a clinical trial or anticoagulation clinic is associated with poorer INR control, as is, the initiation of therapy in the VKA-naive. Patients in Europe/UK have better INR control than those in North America. PMID- 25024647 TI - Prolonged sleep under Stone Age conditions. AB - STUDY OBJECTIVES: We report on a unique experiment designed to investigate the impact of prehistoric living conditions on sleep-wake behavior. METHODS: A group of five healthy adults were assessed during life in a Stone Age-like settlement over two months. RESULTS: The most notable finding was that nocturnal time in bed and estimated sleep time, as measured by actigraphy, markedly increased during the experimental period compared to the periods prior to and following the experiment. These increases were primarily driven by a phase-advance shift of sleep onset. Subjective assessments of health and functioning did not reveal any relevant changes across the study. CONCLUSIONS: Our observations provide further evidence for the long-held belief that the absence of modern living conditions is associated with an earlier sleep phase and prolonged sleep duration. COMMENTARY: A commentary on this article appears in this issue on page 723. PMID- 25024648 TI - The "realities" of our modern light-dark cycle. PMID- 25024649 TI - Sleep complaints in older blacks: do demographic and health indices explain poor sleep quality and duration? AB - OBJECTIVE: To examine the relationship between measures of sleep quality and the presence of commonly encountered comorbid and sociodemographic conditions in elderly Black subjects. METHOD: Analyses included participants from the Baltimore Study of Black Aging (BSBA; n = 450; mean age 71.43 years; SD 9.21). Pittsburgh Sleep Quality Index (PSQI) measured overall sleep pattern and quality. Self reported and objective measures of physical and mental health data and demographic information were collected for all participants. RESULTS: Sociodemographic and comorbid health factors were significantly associated with sleep quality. Results from regression analyses revealed that older age, current financial strain, interpersonal problems, and stress were unique predictors of worse sleep quality. Sleep duration was significantly correlated with age, depressive affect, interpersonal problems, and stress; only age was a unique significant predictor. While participants 62 years or younger had worse sleep quality with increasing levels of stress, there was no significant relationship between sleep quality and stress for participants 81 years and older. CONCLUSIONS: Several potential mechanisms may explain poor sleep in urban, community dwelling Blacks. Perceived stressors, including current financial hardship or hardship experienced for an extended time period throughout the lifespan, may influence sleep later in life. PMID- 25024650 TI - Development and evaluation of a measure to assess restorative sleep. AB - BACKGROUND: There are validated measures assessing insomnia and disturbed sleep, but few psychometrically sound instruments to assess perceptions of the restorative or inadequate properties of sleep are available. STUDY OBJECTIVES: To develop and evaluate a new instrument, the Restorative Sleep Questionnaire (RSQ). DESIGN AND SETTING: Focus groups were conducted using participants with and without nonrestorative sleep complaints. Questions were designed to elicit the feelings and experiences people have about their sleep and their view of daytime consequences of sleep. Expert panels confirmed the importance of nonrestorative sleep (NRS) as a frequently encountered problem either with or without other sleep complaints. The resulting RSQ was administered in three studies: (1) a telephone interview with healthy controls and individuals with sleep problems; (2) a randomized clinical trial of patients with primary insomnia assessed by polysomnography (PSG); (3) a PSG study of subjects with NRS complaints. MEASUREMENT AND RESULTS: Across all studies, the new measures were shown to be significantly correlated with health-related quality of life (HRQL) domains hypothesized to be related to NRS. The RSQ had good psychometric properties (alpha > 0.90; rtest-retest > 0.80), and factor analysis confirmed the unidimensionality of the measure. The RSQ was able to distinguish between healthy controls, patients with primary insomnia, and insomnia patients with isolated NRS complaints but without PSG defined sleep onset, duration, or maintenance problems. Normal sleepers reported sleep that was about a standard deviation more restorative than that of those with NRS on the RSQ. CONCLUSIONS: The results of the study provide support for the reliability and validity of the RSQ as a measure of NRS in subjects with and without self-reported or PSG confirmed sleep initiation and maintenance difficulties. CLINICALTRIALSGOV IDENTIFIERS: NCT00655369; NCT00705601. PMID- 25024651 TI - Short duration of sleep is associated with elevated high-sensitivity C-reactive protein level in Taiwanese adults: a cross-sectional study. AB - BACKGROUND: Elevated plasma levels of high-sensitivity C-reactive protein (hs CRP) have been associated with increased adverse health outcomes. The aim of this study was to investigate the association of sleep duration with risk of elevated hs-CRP levels in Taiwanese adults. METHODS: We examined the association between sleep duration and hs-CRP in 353 healthy adults recruited from the physical examination center at a regional hospital in southern Taiwan. Elevated hs-CRP was defined as a plasma level >= 0.20 mg/dL. Short sleep duration was defined as <= 5.5 h per day. Multiple logistic regression analysis was used to assess the association of short duration of sleep with elevated hs-CRP levels. RESULTS: In this study, short duration of sleep (odds ratio [OR] = 2.20; 95% confidence interval [CI]: 1.11-4.30), aged 70 years or older (OR = 4.58; 95% CI: 1.70 12.66), menopause (OR = 2.81; 95% CI: 1.52-5.3), higher heart rate (OR = 1.38; 95% CI: 1.10-1.75), higher body mass index (OR = 1.20; 95% CI: 1.09-1.34), higher white blood cell count (OR = 1.38; 95% CI: 1.14-1.66), and higher uric acid level (OR = 1.31; 95% CI: 1.06-1.63) were significantly associated with an increased risk of elevated hs-CRP levels. CONCLUSIONS: In this study of healthy Taiwanese adults, short duration of sleep was significantly associated with elevated hs-CRP levels. Activation of pro-inflammatory pathways might represent a mechanism by which short sleep duration affects health. PMID- 25024652 TI - Validation of a portable monitor for the diagnosis of obstructive sleep apnea in morbidly obese patients. AB - STUDY OBJECTIVES: We aimed to validate the diagnostic accuracy and night-to-night variability of a simple 3-channel (type IV monitor) portable sleep monitor, ApneaLink (AL), in a population of morbidly obese subjects. DESIGN: Cross sectional validation and diagnostic accuracy study. SETTING: Public tertiary care obesity center in Norway. PARTICIPANTS: A total of 105 (67 females) treatment seeking morbidly obese subjects were included, mean (SD) age 44.3 (11.4) years and BMI 43.6 (5.6) kg/m2. INTERVENTIONS: The patients underwent two successive nights of recordings; the first night with the AL only, and the following night with both the reference instrument Embletta (E), a type III portable somnograph, and the AL. MEASUREMENTS AND RESULTS: Main outcomes were diagnostic accuracy of AL as assessed by sensitivity, specificity and area under ROC curves, and level of agreement between AL and E. AL had high diagnostic accuracy at all levels of OSA, and the Bland-Altman plots showed good agreement between AL and E. The sensitivity and specificity of the instrument were 93% and 71% at the AHI cutoff 5 events/h, and 94% and 94% at the AHI cutoff 15, respectively. The night-to night variability was low. CONCLUSION: Our results indicate that a simple 3 channel portable sleep monitor (ApneaLink) has a high diagnostic accuracy in diagnosing OSA in morbidly obese treatment seeking patients. Accordingly, this and similar instruments might help non-specialists to diagnose OSA in morbidly obese patients, and, importantly, help non-specialists to refer patients who need specific treatment to specialist without unnecessary delay. PMID- 25024653 TI - Circulation time measurement from sleep studies in patients with obstructive sleep apnea. AB - INTRODUCTION: Lung to finger circulation time (LFCT) can be estimated from polysomnography (PSG) in the presence of an apneic event by using oxygen as an indicator and a finger as the site of detection. The purpose of this study was to refine the methodology of LFCT measurement and to compare LFCT in patients with obstructive sleep apnea (OSA) with and without heart failure (HF). METHODS: In a retrospective manner, 10 LFCT measurements per patient were made from the PSG in 171 consecutive patients with a diagnosis of OSA who were divided into two groups: (a) those with a clinical history of underlying HF (N = 42) and (b) those without HF (N = 129). Mean values were compared between the two groups. We also examined associations of LFCT with various factors in each group and the combined group separately using multiple regression analysis. RESULTS: Gender and age were significantly associated with LFCT in patients with OSA alone. Use of beta blockers was associated with LFCT in the group with OSA with HF. Among the entire cohort, HF, beta-blocker, gender, and age were found to be significantly associated with LFCT. The presence of HF was the strongest predictor of a prolonged LFCT (adjusted mean LFCT: OSA only = 18.5 [95% CI: 17.2-19.7 sec] vs. OSA with HF = 26.1 [95% CI: 24.3-28.0 sec], p < 0.0001). CONCLUSION: LFCT can be reliably measured and is prolonged in patients with OSA and underlying HF. LFCT based on PSG may be a useful marker for detection of coexisting HF in patients with OSA. PMID- 25024654 TI - Sleep disordered breathing and polysomnography in Australia: trends in provision from 2005 to 2012 and the impact of home-based diagnosis. AB - STUDY OBJECTIVES: To describe the growth of publicly funded polysomnography (PSG) in Australia since 2004 and to compare this with earlier growth. METHODS: Longitudinal census-level data stratified by jurisdiction were retrieved from the Medicare Australia online database. RESULTS: There has been a near doubling in provision of PSG since the introduction of publicly funded in-home PSG under the Australian national Medicare program available to all Australian citizens in 2008. Overall annual PSG rates have risen from 339 in 2005 to 608 in 2012 per 100,000. This growth has exceeded that of comparable diagnostic procedures and all Medicare services overall. Queensland remains the leading jurisdiction per 100,000 Medicare enrollees for accessing Medicare-funded PSG. CONCLUSION: The continued growth in publicly funded PSG provision in Australia is unlikely to abate. The disparity in Australia between the estimated prevalence of sleep disorders, particularly obstructive sleep apnea, and the number of people having PSGs would suggest there remain a large number of undiagnosed cases. Support for the development of appropriate diagnostic and screening algorithms will be key in ensuring sustainable, effective, efficient, and accessible PSG services. PMID- 25024655 TI - The impact of hypoxemia on nephropathy in extremely obese patients with type 2 diabetes mellitus. AB - STUDY OBJECTIVES: Diabetes mellitus (DM) is associated with obstructive sleep apnea (OSA) and nephropathy. The hypoxemia associated with OSA may exacerbate renal deterioration in DM nephropathy. We examined the role of hypoxemia in the development of DM nephropathy in severely obese patients. METHODS: This cross sectional study examined anonymized data from 90 DM patients with extreme obesity attending a weight management service. All patients underwent a routine overnight sleep study. Respiratory parameters measured included apnea-hypopnea index (AHI), mean and minimum oxygen (O2) saturations, and time spent under 90% O2 saturation (%TST < 90%). Chronic kidney disease (CKD+) was defined as estimated glomerular filtration rate (eGFR) <= 60 mL/min/1.73 m(2). RESULTS: Twenty (22%) patients were CKD+. These patients were 7 years older (mean age +/- SD 57 +/- 11 years, p = 0.003) and had greater adiposity (mean body mass index [BMI] +/- SD 50.6 +/- 8.7 kg/m(2), p = 0.012). No significant differences were found for median AHI and minimum O2 saturation. %TST < 90% was 4 times greater in CKD+ group (p = 0.046). Multivariate regression analysis showed that AHI (beta = -0.17, 95% CI: -0.316 to -0.024) and %TST < 90% (beta = -0.215, 95% CI: -0.406 to -0.023) were negatively correlated with eGFR after adjustment for age, gender, BMI, comorbidities, insulin treatment, and drugs affecting the renin-angiotensin system. No associations were found between mean and minimum O2 saturations, and eGFR. CONCLUSION: Apnea and hypopnea events as well as duration of nocturnal hypoxemia were inversely associated with renal function after adjusting for potential confounders. Given the significant burden of renal disease in diabetes, greater vigilance is required in identifying OSA in DM patients with extreme obesity. PMID- 25024656 TI - Restless legs syndrome, sleep, and quality of life among adolescents and young adults. AB - OBJECTIVE: Clinical reports in children implicate restless legs syndrome (RLS) with sleep and behavior problems. However, population-based studies on this association in adolescents and young adults are limited. Furthermore, few studies have evaluated the association between symptoms consistent with RLS and quality of life (QoL). STUDY DESIGN: This cross-sectional study included 214 Caucasian and Hispanic adolescents and young adults aged 12-20 years. Symptoms consistent with RLS were based on four essential criteria and if the symptoms occurred >= 5 days/ month. Trouble falling asleep was present if reported "yes, still have the problem." Quality of life (QoL) was assessed using the Pediatric QoL Inventory. Three summary QoL scores ranging from 0-100 were evaluated; higher scores indicated better QoL. RESULTS: Participants were 50% male and 68.1% Caucasian. Prevalence of RLS was 8.4% (n = 18). RLS was associated with trouble falling asleep (OR = 3.1, p = 0.049), and trouble falling asleep was associated with worse Psychosocial Health scores (Coeff. -5.6, p = 0.004) and Total Scale scores for quality of life (Coeff. -4.6, p = 0.007). CONCLUSIONS: The prevalence of symptoms consistent with RLS in this community-based sample of adolescents and young adults, aged 12-20, is comparable to rates reported in older cohorts. Symptoms consistent with RLS may be associated with trouble falling asleep and psychosocial distress that may contribute to a lower health-related quality of life. PMID- 25024657 TI - Sleep education improves the sleep duration of adolescents: a randomized controlled pilot study. AB - PURPOSE: To determine the feasibility and pilot a sleep education program in New Zealand high school students. METHODS: A parallel, two-arm randomized controlled pilot trial was conducted. High school students (13 to 16 years) were randomly allocated to either a classroom-based sleep education program intervention (n = 15) or to a usual curriculum control group (n = 14). The sleep education program involved four 50-minute classroom-based education sessions with interactive groups. Students completed a 7-day sleep diary, a sleep questionnaire (including sleep hygiene, knowledge and problems) at baseline, post-intervention (4 weeks) and 10 weeks follow-up. RESULTS: An overall treatment effect was observed for weekend sleep duration (F 1,24 = 5.21, p = 0.03). Participants in the intervention group slept longer during weekend nights at 5 weeks (1:37 h:min, p = 0.01) and 10 weeks: (1:32 h:min, p = 0.03) compared to those in the control group. No differences were found between groups for sleep duration on weekday nights. No significant differences were observed between groups for any of the secondary outcomes (sleep hygiene, sleep problems, or sleep knowledge). CONCLUSIONS: A sleep education program appears to increase weekend sleep duration in the short term. Although this program was feasible, most schools are under time and resource pressure, thus alternative methods of delivery should be assessed for feasibility and efficacy. Larger trials of longer duration are needed to confirm these findings and determine the sustained effect of sleep education on sleep behavior and its impact on health and psychosocial outcomes. COMMENTARY: A commentary on this article appears in this issue on page 793. PMID- 25024658 TI - Evidence for a school-based sleep health education program? PMID- 25024659 TI - The mediating effect of sleep quality on the relationship between PTSD and physical activity. AB - STUDY OBJECTIVES: Physical inactivity is linked to health outcomes such as obesity, diabetes, and psychiatric disorders. Sleep disturbance has been linked to the same adverse outcomes. We examine the influence of sleep on physical activity as a novel approach to understand these relationships. Specifically, our objective was to determine whether low sleep quality predicts low physical activity in posttraumatic stress disorder (PTSD), a disorder associated with sleep disturbance, physical inactivity, and poor health outcomes. METHODS: We used data from the Mind Your Heart Study, a prospective cohort study of 736 outpatients recruited from two Department of Veterans Affairs (VA) medical centers. We assessed PTSD with the Clinician Administered PTSD Scale, sleep quality using an item from the Pittsburgh Sleep Quality Index, and physical activity by self-report at baseline and again one year later. Hierarchical multiple regression models and structural equation modeling were used to examine the relationships among PTSD, sleep, and physical activity. RESULTS: Sleep quality but not PTSD status was prospectively associated with lower physical activity in a model adjusting for age, sex, apnea probability, depression, body mass index, and baseline physical activity (beta = 0.129, SE = 0.072, p < 0.01). Structural equation modeling indicated that the results were consistent with sleep quality statistically mediating the relationship between PTSD status at baseline and physical activity one year later. CONCLUSIONS: Worse sleep quality predicts lower physical activity in PTSD, providing possible evidence for a behavioral pathway from disturbed sleep to poor physical health outcomes. PMID- 25024660 TI - The AASM recommended and acceptable EEG montages are comparable for the staging of sleep and scoring of EEG arousals. AB - STUDY OBJECTIVE: To examine the measurement differences in sleep and EEG arousal statistics between the American Academy of Sleep Medicine (AASM) recommended EEG montage (F4-M1, C4-M1, O2-M1) and acceptable EEG montage (Fz-Cz, C4-M1, Oz-Cz). DESIGN: Prospective, blinded, randomized comparison. SETTING: Australian clinical sleep laboratory in a tertiary hospital. PATIENTS OR PARTICIPANTS: 50 consecutive patients undertaking polysomnography (PSG) for the clinical suspicion of sleep disordered breathing. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patient EEGs were recorded using both the AASM recommended and acceptable EEG montages during the PSG. Two scorers were used to examine the difference in PSG statistics using the two EEG montages. The scorers analyzed the 50 studies using the two EEG montages. Ten of the studies were scored twice for each montage by each scorer to calculate intra-scorer and inter-scorer agreement. No statistically significant differences were observed between the PSG statistics of the recommended and acceptable EEG montages. The recommended EEG montage had greater inter-scorer agreement but no difference in intra-scorer agreement. CONCLUSIONS: This study demonstrates that the two EEG montages endorsed by the AASM Manual produce similar sleep and EEG arousal statistics. PMID- 25024661 TI - gamma-Hydroxybutyric acid-induced electrographic seizures. AB - We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of gamma-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the first reported human case of absence-like electrographic seizure associated with sodium oxybate. PMID- 25024662 TI - Resolution of severe obstructive sleep apnea after treatment of anti-muscle kinase receptor-positive myasthenia gravis despite 60-pound weight gain. AB - Obstructive sleep apnea (OSA) in patients with myasthenia gravis (MG) may be caused by reduced pharyngeal dilator muscle activity. We report a patient with anti-muscle kinase receptor MG with severe OSA and hypoventilation that resolved upon successful treatment of MG despite a 60-lb weight gain. PMID- 25024663 TI - Elevated body position early after delivery increased airway size during wakefulness, and decreased apnea hypopnea index in a woman with pregnancy related sleep apnea. AB - We report a patient with pregnancy related obstructive sleep apnea ([OSA]; apnea hypopnea index [AHI] 18/h) early after delivery, with improvement of AHI by 87% following 45-degree elevation in body position compared with the non-elevated position. Improvement associated with this position may be explained, at least in part, by an increased upper airway diameter (as measured during wakefulness). Sleep apnea in this patient resolved at 9 months postpartum. This observation suggests that 45-degree elevated body position may be an effective treatment of pregnancy related OSA during the postpartum period. PMID- 25024664 TI - PAPnip: an "Alarming" source of leak during ASV therapy. PMID- 25024666 TI - Safety of alternative antiviral agents for neonatal herpes simplex virus encephalitis and disseminated infection. AB - OBJECTIVE: To review the evidence describing the safety of ganciclovir and foscarnet in neonates in order to guide treatment for central nervous system or disseminated herpes simplex infections in cases of acyclovir shortage or resistance. METHODS: PubMed, Ovid Medline, and International Pharmaceutical Abstracts were searched using the thesaurus and text-word terms "ganciclovir" and "foscarnet," with birth to 1 month age limits. Thirty-two eligible publications describing safety in neonates were identified. RESULTS: In 340 neonates treated for cytomegalovirus (CMV), life-threatening neutropenia (absolute neutrophil count <0.5 * 10(9)/L) was reported in 8.8% of patients following up to 12 months of ganciclovir administered intravenously. Neutropenia and thrombocytopenia occurred in 25.6% and 6.2% of neonates, respectively. Changes in serum creatinine concentration of >0.2 mg/dL occurred in <1% of neonates. Hepatic transaminase increases or unspecified changes in liver function tests were reported in 6.2% of neonates with hyperbilirubinemia being observed in 3.5% of total neonates. Three out of four neonates receiving foscarnet for acyclovir-resistant herpes infection or CMV survived with minimal sequelae. Neither nephrotoxicity nor electrolyte or mineral imbalances were reported. CONCLUSIONS: Similar to what is seen in adolescents and adults, ganciclovir use in neonates is commonly associated with neutropenia, and the frequency of occurrence is comparable. The link between hepatotoxicity and ganciclovir should be interpreted with caution because of overlapping clinical manifestations of CMV. Only case reports are available describing foscarnet use in neonates, but adverse drug reactions were not observed. More research on these two agents is needed to draw conclusions about adverse drug reaction rates in the neonatal population. PMID- 25024667 TI - Epidemiology of infections due to extended-spectrum Beta-lactamase-producing bacteria in a pediatric intensive care unit. AB - OBJECTIVES: To determine the proportion of infections caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella or Escherichia coli Gram-negative organisms in the pediatric intensive care unit (PICU), and to identify risk factors for these infections. METHODS: A retrospective, single-center chart review of patients admitted to a PICU in a 5-year period with infections caused by Klebsiella species or E coli was completed. Data collected include demographics, length of stay, outcome, and relevant risk factors previously defined in the literature. RESULTS: A total of 110 isolates were cultured from 94 patients. A total of 53% of the isolates were E coli, and the remainder were Klebsiella subspecies. Of the 110 isolates, 13 isolates (11.8%) in 7 patients were ESBL positive. The ESBL-producing isolates were equally distributed amongE coli and Klebsiella and were primarily cultured from tracheal aspirates. Most of the ESBL-positive isolates (9 of 13; 69%) were cultured from patients who received ceftazidime and/or cefotaxime in the preceding 30 days. Patients infected with E coli had higher PRISM 1 scores and were more likely to have a Foley catheter, whereas infections with Klebsiella were more common in mechanically ventilated males. Although not statistically significant, 80% of patients who were infected with non-ESBL-producing organisms survived to hospital discharge versus 57% of those infected with ESBL-producing E coli and Klebsiella. CONCLUSIONS: Almost 12% of E coli and Klebsiella isolates in this patient population tested positive for ESBL production. ESBL production was equally distributed between E coli and Klebsiella species. These organisms were cultured from 7% of the study patients. As reported in previous studies, patients infected with ESBL-producing organisms most often had received prior cephalosporins and had a longer length of stay in the PICU. PMID- 25024668 TI - Use of intravenous magnesium sulfate for the treatment of an acute asthma exacerbation in pediatric patients. AB - OBJECTIVES: The standard of care for treatment of an asthma exacerbation includes oxygen, inhaled short-acting bronchodilators, and systemic corticosteroids; adjunctive therapies, such as intravenous magnesium sulfate, can be used for patients who are having life-threatening exacerbations. The purpose of this study was to analyze the prescribing patterns as well as the safety of intravenous magnesium sulfate for the treatment of acute asthma exacerbations in pediatric patients across multiple hospitals in New Jersey. METHODS: This retrospective chart review was conducted at 4 medical centers in New Jersey on patients who presented to the emergency department between January 1, 2010, and December 31, 2010. RESULTS: Fifty-three patients were included in the study. In the emergency department, 98% of patients received inhaled albuterol plus ipratropium and 85% received systemic corticosteroids before intravenous magnesium sulfate administration. The median dose of magnesium sulfate was 40 mg/kg with a median time of administration of 20 minutes. One patient experienced hypotension that was thought to be related to magnesium sulfate administration. CONCLUSIONS: This study demonstrates that weight-based dosage, as well as time of administration of magnesium sulfate for pediatric patients with an acute asthma exacerbation, varies across different institutions in New Jersey. Magnesium sulfate use was safe in this patient population. PMID- 25024669 TI - Establishment and evaluation of pharmacist-managed admission medication history and reconciliation process for pediatric patients. AB - OBJECTIVE: This was a single-center, prospective, pilot study aiming to evaluate the impact of pharmacist involvement in the admission medication history and reconciliation process and to quantify discrepancies found by pharmacists when compared to information collected by other health care providers at a pediatric institution. METHODS: A pharmacist completed a thorough medication history and reconciled discrepancies with the medical team. Discrepancies included incorrect medication, dose, route, frequency; omitted information; missing medications; or any other inconsistencies outside of these categories. Information was documented in the electronic medical record via a standardized template, and pertinent discrepancies were communicated with the medical team. RESULTS: Of the 100 medication histories included in the study, a total of 309 discrepancies were identified and corrected in the electronic medical record. The median length of time it took pharmacists to complete the medication history process was 15 minutes per patient (interquartile range, 10-20 minutes). Thirty discrepancies were determined as pertinent and were reported as intervened on and communicated to the medical team. CONCLUSION: This study provides evidence that pharmacist obtained admission medication histories and reconciliation have the potential to prevent potentially significant adverse drug reactions and have a positive impact on patient care.Index terms admission, history, medication, pharmacist, reconciliation. PMID- 25024670 TI - Comparison of 3 body size descriptors in critically ill obese children and adolescents: implications for medication dosing. AB - OBJECTIVE: To compare 3 methods of weight determination for medication dose calculations in obese children and to discuss feasibility for use in routine care. METHODS: This was a patient safety and quality improvement study evaluating patients (2-19 years old) admitted to the pediatric intensive care unit during a 13-month period (July 2010-July 2011). Patients identified as obese (>=95th percentile body mass index [BMI] for age), including severely obese (>=99th percentile BMI for age), were included in the weight method comparison portion of this study. Lean body mass estimations, using equations derived by the Peters and Foster methods, were compared to ideal body weight estimates by using the BMI method. Absolute differences between values generated by the 3 methods, intraclass correlation (ICC), and Bland-Altman plots were calculated. RESULTS: A total of 1369 patients met initial criteria; 176 met criteria for the dosing weight comparison (age +/- SD = 9.28 +/- 5 years; actual weight +/- SD = 55.5 +/- 33.9 kg; 46% female). Sixty were severely obese and 116 were obese. Mean ICC between methods was 0.968 (95% Confidence interval (CI): 0.959, 0.975). The Peters method estimated higher weights than the Foster or BMI method. Bland Altman plots illustrated good agreement between methods in children with weight below 50 kg, but decreased agreement above 50 kg, which was influenced by sex. CONCLUSIONS: All methods demonstrated strong correlation and acceptable agreement in children below 50 kg. Systematic biases were identified in children above 50 kg where variance was higher. The BMI method was least complex to calculate and the most feasible method for daily use. PMID- 25024671 TI - Medication waste reduction in pediatric pharmacy batch processes. AB - OBJECTIVES: To inform pediatric cart-fill batch scheduling for reductions in pharmaceutical waste using a case study and simulation analysis. METHODS: A pre and post intervention and simulation analysis was conducted during 3 months at a 205-bed children's center. An algorithm was developed to detect wasted medication based on time-stamped computerized provider order entry information. The algorithm was used to quantify pharmaceutical waste and associated costs for both preintervention (1 batch per day) and postintervention (3 batches per day) schedules. Further, simulation was used to systematically test 108 batch schedules outlining general characteristics that have an impact on the likelihood for waste. RESULTS: Switching from a 1-batch-per-day to a 3-batch-per-day schedule resulted in a 31.3% decrease in pharmaceutical waste (28.7% to 19.7%) and annual cost savings of $183,380. Simulation results demonstrate how increasing batch frequency facilitates a more just-in-time process that reduces waste. The most substantial gains are realized by shifting from a schedule of 1 batch per day to at least 2 batches per day. The simulation exhibits how waste reduction is also achievable by avoiding batch preparation during daily time periods where medication administration or medication discontinuations are frequent. Last, the simulation was used to show how reducing batch preparation time per batch provides some, albeit minimal, opportunity to decrease waste. CONCLUSIONS: The case study and simulation analysis demonstrate characteristics of batch scheduling that may support pediatric pharmacy managers in redesign toward minimizing pharmaceutical waste. PMID- 25024672 TI - Standard dose development for medications commonly used in the neonatal intensive care unit. AB - OBJECTIVES: To establish standardized, rounded doses of medications for neonates in the neonatal intensive care unit (NICU) through a multi-institutional peer reviewed process. METHODS: Pediatric faculty and pediatric pharmacy residents from the Ernest Mario School of Pharmacy (Piscataway, NJ) conducted a systematic review of rounded, weight-based medication information for neonatal patients from September 2010 to April 2011. After initial review, an expanded workgroup of expert neonatal pharmacy clinicians from academic institutions throughout the United States were invited to conduct a final review. The workgroup identified 74 medications or indications in the NICU. Recommended standardized doses were established for discrete weight categories at workgroup consensus web meetings conducted from June to December 2011. Workgroup recommendations were cross referenced with published neonatal pharmacology resources. Consensus was obtained when references provided insufficient information on medication information. RESULTS: Seventeen weight categories of increasing ranges were used, from 40 g for the lowest weights (e.g., 410-450 g) to 840 g for the highest weights (e.g., 3660-4500 g). Medications were divided into 3 categories of administration routes: oral (n = 4), intermittent intravenous (n = 64), and other (e.g., intramuscular; n=6). A significant majority of standardized doses (84%) were within 15% of their corresponding weight-calculated dose. CONCLUSIONS: Establishment of a portfolio of standardized, rounded doses of medications commonly used in the NICU was feasibly established by a multi-institutional peer review process, with the great majority of standardized doses being within clinically acceptable ranges of administration. Use of standardized, rounded doses for reduction in dosing errors may be feasible on a systematic level. PMID- 25024673 TI - Aprepitant and fosaprepitant use in children and adolescents at an academic medical center. AB - OBJECTIVE: To describe the use of aprepitant and fosaprepitant, a neurokinin 1 (NK-1) receptor inhibitor, in children and adolescents at a large academic medical center, for the prevention and management of chemotherapy-induced nausea and vomiting (CINV). METHODS: A retrospective chart review was conducted using an electronic medical record system to evaluate the use of aprepitant and fosaprepitant in all pediatric patients that were discharged from a single academic medical center between February 25, 2009 and May 25, 2012. RESULTS: Twenty-six patients were included in this review and received a total of 287 doses over the span of 114 cycles. Mean age was 10.1 years, with a range of 11 months to 17 years old. In 16 of 26 patients, aprepitant was used as the primary prophylaxis. Of those patients who received primary prophylaxis, 6 of 16 received it for highly emetogenic chemotherapy, and 10 of 16 received it for moderately emetogenic chemotherapy. Intravenous fosaprepitant was used in 7 of 26 patients, ages 13 to 17 (median 14) years old. No adverse effects attributable to aprepitant were reported. CONCLUSIONS: Use of aprepitant and fosaprepitant in pediatric patients appeared to be well tolerated. No currently published reports data using aprepitant in a patient younger than 32 months old, whereas we reported its use in patients as young as 11 months old. PMID- 25024674 TI - Neonatal inflammatory submandibular sialadenitis associated with prenatal methyldopa exposure. AB - Inflammation of a salivary gland is an uncommon condition in the neonatal period, and an isolated form of submandibular acute inflammatory sialadenitis is an exceptionally rare phenomenon. Among various conditions that might lead to submandibular acute inflammatory sialadenitis, maternal use of drugs during pregnancy should be questioned as there may be possible associations. Herein, we describe a late preterm infant who presented with a large submandibular mass. After excluding possible pathogenic causes, maternal use of methyldopa was believed to be the only factor associated with this condition. To the best of our knowledge, no such relationship has been documented in previously published literature. PMID- 25024675 TI - Ceftaroline Fosamil for Methicillin-Resistant Staphylococcus aureus Pulmonary Exacerbation in a Pediatric Cystic Fibrosis Patient. AB - Ceftaroline, an advanced generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA), may present a new therapeutic alternative for treating lung infections among patients with cystic fibrosis. We report a case of ceftaroline therapy in a pediatric patient with cystic fibrosis, whose dose was increased from 9.7 mg/kg/dose every 12 hours to 10.8 mg/kg/dose every 8 hours by using pharmacokinetic analyses. PMID- 25024676 TI - Synthesis and characterization of HDPE/N-MWNT nanocomposite films. AB - In this work, a series of nitrogen-doped multi-walled carbon nanotubes (N-MWCNTs) with several weight percentages (0.1, 0.4, 0.8, and 1.0 wt.%) were synthesized by catalytic chemical vapor deposition (CCVD) technique. The N-MWCNTs were first characterized and then dispersed in high-density polyethylene (HDPE) polymer matrix to form a nanocomposite. The HDPE/N-MWCNT nanocomposite films were prepared by melt mixing and hot pressing; a good dispersion in the matrix and a good N-MWCNT-polymer interfacial adhesion have been verified by scanning electron microscopy (SEM). Raman spectroscopy measurements have been performed on prepared samples to confirm the presence and nature of N-MWNTs in HDPE matrix. The X-ray diffraction (XRD) analysis demonstrated that the crystalline structure of HDPE matrix was not affected by the incorporation of the N-MWNTs. PMID- 25024677 TI - The effect of colloidal solution of molybdenum nanoparticles on the microbial composition in rhizosphere of Cicer arietinum L. AB - The use of colloidal solutions of metals as micronutrients enhances plant resistance to unfavorable environmental conditions and ensures high yields of food crops due to the active penetration of nanoelements into the plant cells. Microbiological examination of rhizosphere soil have revealed that combined use of colloidal solution of nanoparticles of molybdenum (CSNM, 8 mg/l), and microbial preparation for pre-sowing inoculation of chickpea seeds stimulates the development of 'agronomically valuable' microflora. It was shown that combined seed treatment with colloidal solution of Mo nanoparticles with microbial preparation have stimulated nodule formation per plant by four times compared to controls. Single treatment with CSNM increased the number of nodules by two times, while the treatment of microbial preparation have not significantly affected the number of nodules per plant. PACS: Colloids, 82.70.Dd; Ecology, 87.23.-n. PMID- 25024678 TI - In vitro enhancement of dendritic cell-mediated anti-glioma immune response by graphene oxide. AB - Malignant glioma has extremely poor prognosis despite combination treatments with surgery, radiation, and chemotherapy. Dendritic cell (DC)-based immunotherapy may potentially serve as an adjuvant treatment of glioma, but its efficacy generally needs further improvement. Here we explored whether graphene oxide (GO) nanosheets could modulate the DC-mediated anti-glioma immune response in vitro, using the T98G human glioma cell line as the study model. Pulsing DCs with a glioma peptide antigen (Ag) generated a limited anti-glioma response compared to un-pulsed DCs. Pulsing DCs with GO alone failed to produce obvious immune modulation effects. However, stimulating DCs with a mixture of GO and Ag (GO-Ag) significantly enhanced the anti-glioma immune reaction (p < 0.05). The secretion of interferon gamma (IFN-gamma) by the lymphocytes was also markedly boosted by GO-Ag. Additionally, the anti-glioma immune response induced by GO-Ag appeared to be target-specific. Furthermore, at the concentration used in this study, GO exhibited a negligible effect on the viability of the DCs. These results suggested that GO might have potential utility for boosting a DC-mediated anti glioma immune response. PMID- 25024679 TI - PLGA/nHA hybrid nanofiber scaffold as a nanocargo carrier of insulin for accelerating bone tissue regeneration. AB - The development of tissue engineering in the field of orthopedic surgery is booming. Two fields of research in particular have emerged: approaches for tailoring the surface properties of implantable materials with osteoinductive factors as well as evaluation of the response of osteogenic cells to these fabricated implanted materials (hybrid material). In the present study, we chemically grafted insulin onto the surface of hydroxyapatite nanorods (nHA). The insulin-grafted nHAs (nHA-I) were dispersed into poly(lactide-co-glycolide) (PLGA) polymer solution, which was electrospun to prepare PLGA/nHA-I composite nanofiber scaffolds. The morphology of the electrospun nanofiber scaffolds was assessed by field emission scanning electron microscopy (FESEM). After extensive characterization of the PLGA/nHA-I and PLGA/nHA composite nanofiber scaffolds by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction spectroscopy (XRD), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectrometry (EDS), and transmission electron microscopy (TEM), the PLGA/nHA-I and PLGA/nHA (used as control) composite nanofiber scaffolds were subjected to cell studies. The results obtained from cell adhesion, alizarin red staining, and Von Kossa assay suggested that the PLGA/nHA-I composite nanofiber scaffold has enhanced osteoblastic cell growth, as more cells were proliferated and differentiated. The fact that insulin enhanced osteoblastic cell proliferation will open new possibilities for the development of artificial scaffolds for bone tissue regeneration. PMID- 25024680 TI - 1-D nanoporous anodic alumina rugate filters by means of small current variations for real-time sensing applications. AB - A rugate filter based on nanoporous anodic alumina was fabricated using an innovative sinusoidal current profile with small current variation. The resulting structure consisted of highly parallel pores with modulations of the pore diameter along the pore axis and with no branching. The effect of the period time and the pore widening post-treatment was studied. From reflectance measurements, it was seen that the position of the reflection band can be tuned by adjusting the period time and the width by pore-widening post-treatments. We tested one of the rugate filters by infiltrating the structure with EtOH and water in order to evaluate its sensing capabilities. This method allows the fabrication of complex in-depth modulated nanoporous anodic alumina structures that open up the possibility of new kinds of alumina-based optical sensing devices. PMID- 25024681 TI - In vivo and in vitro evaluation of the cytotoxic effects of Photosan-loaded hollow silica nanoparticles on liver cancer. AB - This study aimed to compare the inhibitory effects of photosensitizers loaded in hollow silica nanoparticles and conventional photosensitizers on HepG2 human hepatoma cell proliferation and determine the underlying mechanisms. Photosensitizers (conventional Photosan-II or nanoscale Photosan-II) were administered to in vitro cultured HepG2 hepatoma cells and treated by photodynamic therapy (PDT) with various levels of light exposure. To assess photosensitizers' effects, cell viability was determined by 3-(4, 5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, apoptotic and necrotic cells were measured by flow cytometry and the expression of caspase-3 and caspase-9 evaluated by western blot. Finally, the in vivo effects of nanoscale and conventional photosensitizers on liver cancer were assessed in nude mice. Nanoscale Photosan-II significantly inhibited hepatoma cell viability in a concentration-dependent manner and this effect was more pronounced with high laser doses. Moreover, nanoscale photosensitizers performed better than the conventional ones under the same experimental conditions (p < 0.05). Flow cytometry data demonstrated that laser-induced cell death was markedly increased after treatment with nanoscale Photosan-II in comparison with free Photosan-II (p < 0.05). Activated caspase-3 and caspase-9 levels were significantly higher in cells treated with Photosan-II loaded in silica nanoparticles than free Photosan-II (p < 0.05). Accordingly, treatment with nanoscale photosensitizers resulted in improved outcomes (tumor volume) in a mouse model of liver cancer, in comparison with conventional photosensitizers. Hollow silica nanoparticles containing photosensitizer more efficiently inhibited hepatoma cells than photosensitizer alone, through induction of apoptosis, both in vivo and in vitro. PMID- 25024682 TI - A review of roll-to-roll nanoimprint lithography. AB - Since its introduction in 1995, nanoimprint lithography has been demonstrated in many researches as a simple, low-cost, and high-throughput process for replicating micro- and nanoscale patterns. Due to its advantages, the nanoimprint lithography method has been rapidly developed over the years as a promising alternative to conventional nanolithography processes to fulfill the demands generated from the recent developments in the semiconductor and flexible electronics industries, which results in variations of the process. Roll-to-roll (R2R) nanoimprint lithography (NIL) is the most demanded technique due to its high-throughput fulfilling industrial-scale application. In the present work, a general literature review on the various types of nanoimprint lithography processes especially R2R NIL and the methods commonly adapted to fabricate imprint molds are presented to provide a clear view and understanding on the nanoimprint lithography technique as well as its recent developments. PACS: 81.16.Nd. PMID- 25024683 TI - Graphitic platform for self-catalysed InAs nanowires growth by molecular beam epitaxy. AB - We report the self-catalysed growth of InAs nanowires (NWs) on graphite thin films using molecular beam epitaxy via a droplet-assisted technique. Through optimising metal droplets, we obtained vertically aligned InAs NWs with highly uniform diameter along their entire length. In comparison with conventional InAs NWs grown on Si (111), the graphite surface led to significant effects on the NWs geometry grown on it, i.e. larger diameter, shorter length with lower number density, which were ascribed to the absence of dangling bonds on the graphite surface. The axial growth rate of the NWs has a strong dependence on growth time, which increases quickly in the beginning then slows down after the NWs reach a length of approximately 0.8 MUm. This is attributed to the combined axial growth contributions from the surface impingement and sidewall impingement together with the desorption of adatoms during the diffusion. The growth of InAs NWs on graphite was proposed following a vapour-solid mechanism. High-resolution transmission electron microscopy reveals that the NW has a mixture of pure zinc blende and wurtzite insertions. PMID- 25024684 TI - The effect of multiple martensitic transformations on diffusion of Fe and Ni atoms in Fe-31.7%Ni-0.06%C alloy. AB - Diffusion characteristics of iron and nickel atoms were investigated using radioactive isotopes method in phase-hardened metastable iron-nickel Fe-31.7%Ni 0.06%C alloy with nanofragmented structure. It has been found that diffusion mobility of nickel and iron atoms in reverted austenite of Fe-31.7%Ni-0.06%C alloy significantly increases as the result of multiple gamma-alpha-gamma martensitic transformations. The diffusion coefficients of nickel and iron in the austenite at 400 degrees C corresponded to the stationary diffusion coefficients at the temperatures above 900 degrees C. The revealed diffusion acceleration at low temperatures is caused by high-density dislocations and additional low-angle subboundaries of disoriented nanofragments of reverted austenite and deformation twin subboundaries formed during multiple gamma-alpha-gamma cycles. PMID- 25024685 TI - Rapid identification of bacteria utilizing amplified dielectrophoretic force assisted nanoparticle-induced surface-enhanced Raman spectroscopy. AB - Dielectrophoresis (DEP) has been widely used to manipulate, separate, and concentrate microscale particles. Unfortunately, DEP force is difficult to be used in regard to the manipulation of nanoscale molecules/particles. For manipulation of 50- to 100-nm particles, the electrical field strength must be higher than 3 * 10(6) V/m, and with a low applied voltage of 10 Vp-p, the electrode gap needs to be reduced to submicrons. Our research consists of a novel and simple approach, using a several tens micrometers scale electrode (low cost and easy to fabricate) to generate a dielectrophoretic microparticle assembly to form nanogaps with a locally amplified alternating current (AC) electric field gradient, which is used to rapidly trap nanocolloids. The results show that the amplified DEP force could effectively trap 20-nm colloids in the nanogaps between the 5-MUm particle aggregates. The concentration factor at the local detection region was shown to be approximately 5 orders of magnitude higher than the bulk solution. This approach was also successfully used in bead-based surface-enhanced Raman spectroscopy (SERS) for the rapid identification of bacteria from diluted blood. PMID- 25024686 TI - Research progress on electronic phase separation in low-dimensional perovskite manganite nanostructures. AB - Perovskite oxide manganites with a general formula of R1-x AxMnO3 (where R is a trivalent rare-earth element such as La, Pr, Sm, and A is a divalent alkaline earth element such as Ca, Sr, and Ba) have received much attention due to their unusual electron-transport and magnetic properties, which are indispensable for applications in microelectronic, magnetic, and spintronic devices. Recent advances in the science and technology have resulted in the feature sizes of microelectronic devices based on perovskite manganite oxides down-scaling into nanoscale dimensions. At the nanoscale, low-dimensional perovskite manganite oxide nanostructures display novel physical properties that are different from their bulk and film counterparts. Recently, there is strong experimental evidence to indicate that the low-dimensional perovskite manganite oxide nanostructures are electronically inhomogeneous, consisting of different spatial regions with different electronic orders, a phenomenon that is named as electronic phase separation (EPS). As the geometry sizes of the low-dimensional manganite nanostructures are reduced to the characteristic EPS length scale (typically several tens of nanometers in manganites), the EPS is expected to be strongly modulated, leading to quite dramatic changes in functionality and more emergent phenomena. Therefore, reduced dimensionality opens a door to the new functionalities in perovskite manganite oxides and offers a way to gain new insight into the nature of EPS. During the past few years, much progress has been made in understanding the physical nature of the EPS in low-dimensional perovskite manganite nanostructures both from experimentalists and theorists, which have a profound impact on the oxide nanoelectronics. This nanoreview covers the research progresses of the EPS in low-dimensional perovskite manganite nanostructures such as nanoparticles, nanowires/nanotubes, and nanostructured films and/or patterns. The possible physical origins of the EPS are also discussed from the signatures of electronic inhomogeneities as well as some theoretical scenarios, to shed light on understanding this phenomenon. Finally, the perspectives to the future researches in this area are also outlined. PMID- 25024687 TI - Thermal conductivity reduction of crystalline silicon by high-pressure torsion. AB - We report a dramatic and irreversible reduction in the lattice thermal conductivity of bulk crystalline silicon when subjected to intense plastic strain under a pressure of 24 GPa using high-pressure torsion (HPT). Thermal conductivity of the HPT-processed samples were measured using picosecond time domain thermoreflectance. Thermal conductivity measurements show that the HPT processed samples have a lattice thermal conductivity reduction by a factor of approximately 20 (from intrinsic single crystalline value of 142 Wm(-1) K(-1) to approximately 7.6 Wm(-1) K(-1)). Thermal conductivity reduction in HPT-processed silicon is attributed to the formation of nanograin boundaries and metastable Si III/XII phases which act as phonon scattering sites, and because of a large density of lattice defects introduced by HPT processing. Annealing the samples at 873 K increases the thermal conductivity due to the reduction in the density of secondary phases and lattice defects. PMID- 25024688 TI - Controllable synthesis of branched ZnO/Si nanowire arrays with hierarchical structure. AB - A rational approach for creating branched ZnO/Si nanowire arrays with hierarchical structure was developed based on a combination of three simple and cost-effective synthesis pathways. The crucial procedure included growth of crystalline Si nanowire arrays as backbones by chemical etching of Si substrates, deposition of ZnO thin film as a seed layer by magnetron sputtering, and fabrication of ZnO nanowire arrays as branches by hydrothermal growth. The successful synthesis of ZnO/Si heterogeneous nanostructures was confirmed by morphologic, structural, and optical characterizations. The roles of key experimental parameters, such as the etchant solution, the substrate direction, and the seed layer on the hierarchical nanostructure formation, were systematically investigated. It was demonstrated that an etchant solution with an appropriate redox potential of the oxidant was crucial for a moderate etching speed to achieve a well-aligned Si nanowire array with solid and round surface. Meanwhile, the presence of gravity gradient was a key issue for the growth of branched ZnO nanowire arrays. The substrate should be placed vertically or facedown in contrast to the solution surface during the hydrothermal growth. Otherwise, only the condensation of the ZnO nanoparticles took place in a form of film on the substrate surface. The seed layer played another important role in the growth of ZnO nanowire arrays, as it provided nucleation sites and determined the growing direction and density of the nanowire arrays for reducing the thermodynamic barrier. The results of this study might provide insight on the synthesis of hierarchical three-dimensional nanostructure materials and offer an approach for the development of complex devices and advanced applications. PMID- 25024689 TI - Diatomite silica nanoparticles for drug delivery. AB - Diatomite is a natural fossil material of sedimentary origin, constituted by fragments of diatom siliceous skeletons. In this preliminary work, the properties of diatomite nanoparticles as potential system for the delivery of drugs in cancer cells were exploited. A purification procedure, based on thermal treatments in strong acid solutions, was used to remove inorganic and organic impurities from diatomite and to make them a safe material for medical applications. The micrometric diatomite powder was reduced in nanoparticles by mechanical crushing, sonication, and filtering. Morphological analysis performed by dynamic light scattering and transmission electron microscopy reveals a particles size included between 100 and 300 nm. Diatomite nanoparticles were functionalized by 3-aminopropyltriethoxysilane and labeled by tetramethylrhodamine isothiocyanate. Different concentrations of chemically modified nanoparticles were incubated with cancer cells and confocal microscopy was performed. Imaging analysis showed an efficient cellular uptake and homogeneous distribution of nanoparticles in cytoplasm and nucleus, thus suggesting their potentiality as nanocarriers for drug delivery. PACS: 87.85.J81.05.Rm; 61.46. + w. PMID- 25024690 TI - Thin and long silver nanowires self-assembled in ionic liquids as a soft template: electrical and optical properties. AB - Thin and long silver nanowires were successfully synthesized using the polyvinylpyrrolidone (PVP)-assisted polyol method in the presence of ionic liquids, tetrapropylammonium chloride and tetrapropylammonium bromide, which served as soft template salts. The first step involved the formation of Ag nanoparticles with a diameter of 40 to 50 nm through the reduction of silver nitrate. At the growing stage, the Ag nanoparticles were converted into thin and long one-dimensional wires, with uniform diameters of 30 +/- 3 nm and lengths of up to 50 MUm. These Ag nanowires showed an electrical conductivity of 0.3 * 10(5) S/cm, while the sheet resistance of a two-dimensional percolating Ag nanowire network exhibited a value of 20 Omega/sq with an optical transmittance of 93% and a low haze value. PMID- 25024691 TI - Controlling the Er content of porous silicon using the doping current intensity. AB - The results of an investigation on the Er doping of porous silicon are presented. Electrochemical impedance spectroscopy, optical reflectivity, and spatially resolved energy dispersive spectroscopy (EDS) coupled to scanning electron microscopy measurements were used to investigate on the transient during the first stages of constant current Er doping. Depending on the applied current intensity, the voltage transient displays two very different behaviors, signature of two different chemical processes. The measurements show that, for equal transferred charge and identical porous silicon (PSi) layers, the applied current intensity also influences the final Er content. An interpretative model is proposed in order to describe the two distinct chemical processes. The results can be useful for a better control over the doping process. PACS: 81.05.Rm; 82.45.Rr. PMID- 25024692 TI - Indium droplet formation in InGaN thin films with single and double heterojunctions prepared by MOCVD. AB - Indium gallium nitride (InGaN) samples with single heterojunction (SH) and double heterojunction (DH) were prepared using metal-organic chemical vapor deposition. SH has a layer of InGaN thin film (thicknesses, 25, 50, 100, and 200 nm) grown on an uGaN film (thickness, 2 MUm). The DH samples are distinguished by DH uGaN film (thickness, 120 nm) grown on the InGaN layer. Reciprocal space mapping measurements reveal that the DH samples are fully strained with different thicknesses, whereas the strain in the SH samples are significantly relaxed with the increasing thickness of the InGaN film. Scanning electron microscopy results show that the surface roughness of the sample increases when the sample is relaxed. High-resolution transmission electron microscopy images of the structure of indium droplets in the DH sample indicate that the thickness of the InGaN layer decreases with the density of indium droplets. The formation of these droplets is attributed to the insufficient kinetic energy of indium atom to react with the elements of group V, resulting to aggregation. The gallium atoms in the GaN thin film will not be uniformly replaced by indium atoms; the InGaN thin film has an uneven distribution of indium atoms and the quality of the epitaxial layer is degraded. PMID- 25024693 TI - Atomistic deformation mechanisms in twinned copper nanospheres. AB - In the present study, we perform molecular dynamic simulations to investigate the compression response and atomistic deformation mechanisms of twinned nanospheres. The relationship between load and compression depth is calculated for various twin spacing and loading directions. Then, the overall elastic properties and the underlying plastic deformation mechanisms are illuminated. Twin boundaries (TBs) act as obstacles to dislocation motion and lead to strengthening. As the loading direction varies, the plastic deformation transfers from dislocations intersecting with TBs, slipping parallel to TBs, and then to being restrained by TBs. The strengthening of TBs depends strongly on the twin spacing. PMID- 25024694 TI - Seedless growth of zinc oxide flower-shaped structures on multilayer graphene by electrochemical deposition. AB - A seedless growth of zinc oxide (ZnO) structures on multilayer (ML) graphene by electrochemical deposition without any pre-deposited ZnO seed layer or metal catalyst was studied. A high density of a mixture of vertically aligned/non aligned ZnO rods and flower-shaped structures was obtained. ML graphene seems to generate the formation of flower-shaped structures due to the stacking boundaries. The nucleation of ZnO seems to be promoted at the stacking edges of ML graphene with the increase of applied current density, resulting in the formation of flower-shaped structures. The diameters of the rods/flower-shaped structures also increase with the applied current density. ZnO rods/flower-shaped structures with high aspect ratio over 5.0 and good crystallinity were obtained at the applied current densities of -0.5 and -1.0 mA/cm(2). The growth mechanism was proposed. The growth involves the formation of ZnO nucleation below 80 degrees C and the enhancement of the growth of vertically non-aligned rods and flower-shaped structures at 80 degrees C. Such ZnO/graphene hybrid structure provides several potential applications in sensing devices. PMID- 25024696 TI - Presynaptic neuromuscular action of a methanolic extract from the venom of Rhinella schneideri toad. AB - BACKGROUND: Rhinella schneideri, previously known as Bufo paracnemis, is a common toad in many regions of Brazil. Its venom exerts important cardiovascular effects on humans and other animals. Although this toad venom has been the subject of intense investigations, little is known about its neuromuscular activity. METHODS: The neurotoxicity of a methanolic extract of R. schneideri venom was tested on mouse phrenic nerve-diaphragm (PND) preparations mounted for conventional twitch tension recording - in response to indirect stimulation - and for electrophysiological measurements. RESULTS: Venom extract (50 MUg/mL) increased the muscle twitch tension in PND preparations but did not significantly alter the resting membrane potential values. Electrophysiological evaluations showed that the extract (50 MUg/mL) significantly augmented the frequency of miniature end-plate potential (from 38 +/- 3.5 to 88 +/- 15 after 60 minutes; n = 5; p < 0.05) and quantal content (from 128 +/- 13 to 272 +/- 34 after five minutes; n = 5; p < 0.05). Pretreatment with ouabain (1 MUg/mL) for five minutes prevented the increase in quantal content (117 +/- 18 and 154 +/- 33 after five and 60 minutes, respectively). CONCLUSION: These results indicate that the methanolic extract of R. schneideri venom acts primarily presynaptically to enhance neurotransmitter release in mouse phrenic-diaphragm preparations. PMID- 25024697 TI - Retrospective Analysis of Corticosteroid Treatment in Stevens-Johnson Syndrome and/or Toxic Epidermal Necrolysis over a Period of 10 Years in Vajira Hospital, Navamindradhiraj University, Bangkok. AB - Background. Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN) are uncommon and life-threatening drug reaction associated with a high morbidity and mortality. Objective. We studied SJS and/or TEN by conducting a retrospective analysis of 87 patients treated during a 10-year period. Methods. We conducted a retrospective review of the records of all patients with a diagnosis of SJS and/or TEN based on clinical features and histological confirmation of SJS and/or TEN was not available at the Department of Medicine, Vajira hospital, Bangkok, Thailand. The data were collected from two groups from 2003 to 2007 and 2008 to 2012. Results. A total of 87 cases of SJS and/or TEN were found, comprising 44 males and 43 females whose mean age was 46.5 years. The average length of stay was 17 days. Antibiotics, anticonvulsants, and allopurinol were the major culprit drugs in both groups. The mean SCORTEN on admission was 2.1 in first the group while 1.7 in second the group. From 2008 to 2012, thirty nine patients (76.5%) were treated with corticosteroids while only eight patients (22.2%) were treated between 2003 and 2007. The mortality rate declined from 25% from the first group to 13.7% in the second group. Complications between first and second groups had no significant differences. Conclusions. Short-term corticosteroids may contribute to a reduced mortality rate in SJS and/or TEN without increasing secondary infection. Further well-designed studies are required to compare the effect of corticosteroids treatment for SJS and/or TEN. PMID- 25024698 TI - Different trichoscopic features of tinea capitis and alopecia areata in pediatric patients. AB - Background. Diagnosis of patchy hair loss in pediatric patients is often a matter of considerable debate among dermatologists. Trichoscopy is a rapid and noninvasive tool to detect more details of patchy hair loss. Like clinical dermatology, trichoscopy works parallel to the skin surface and perpendicular to the histological plane; like the histopathology, it thus allows the viewing of structures not discovered by the naked eye. Objective. Aiming to compare the different trichoscopic features of tinea capitis and alopecia areata in pediatric patients. Patients and Methods. This study included 40 patients, 20 patients with tinea capitis and 20 patients with alopecia areata. They were exposed toclinical examination, laboratory investigations (10% KOH and fungal culture), and trichoscope examination. Results. Our obtained results reported that, in tinea capitis patients, comma shaped hairs, corkscrew hairs, and zigzag shaped hairs are the diagnostic trichoscopic features of tinea capitis. While in alopecia areata patients, the most trichoscopic specific features were yellow dots, exclamation mark, and short vellus hairs. Conclusion. Trichoscopy can be used as a noninvasive tool for rapid diagnosis of tinea capitis and alopecia areata in pediatric patients. PMID- 25024695 TI - Glutathione and mitochondria. AB - Glutathione (GSH) is the main non-protein thiol in cells whose functions are dependent on the redox-active thiol of its cysteine moiety that serves as a cofactor for a number of antioxidant and detoxifying enzymes. While synthesized exclusively in the cytosol from its constituent amino acids, GSH is distributed in different compartments, including mitochondria where its concentration in the matrix equals that of the cytosol. This feature and its negative charge at physiological pH imply the existence of specific carriers to import GSH from the cytosol to the mitochondrial matrix, where it plays a key role in defense against respiration-induced reactive oxygen species and in the detoxification of lipid hydroperoxides and electrophiles. Moreover, as mitochondria play a central strategic role in the activation and mode of cell death, mitochondrial GSH has been shown to critically regulate the level of sensitization to secondary hits that induce mitochondrial membrane permeabilization and release of proteins confined in the intermembrane space that once in the cytosol engage the molecular machinery of cell death. In this review, we summarize recent data on the regulation of mitochondrial GSH and its role in cell death and prevalent human diseases, such as cancer, fatty liver disease, and Alzheimer's disease. PMID- 25024699 TI - The Relationship between H. pylori Infection and Osteoporosis in Japan. AB - Background and Objective. H. pylori infection causes a chronic inflammation in the gastric mucosa. However, this local inflammation may result in extra digestive conditions. Our aim is to investigate the relationship between H. pylori infection and osteoporosis in Japan. Methods. This cross-sectional study was conducted among outpatients at the Juntendo University Hospital between 2008 and 2014. Participants for patient profile, H. pylori infection status, comorbidity, internal medical therapies, lumbar dual-energy X-ray absorptiometry (DXA), and bone turnover marker were collected and upper gastrointestinal endoscopy for reflux esophagitis, hiatal hernia, peptic ulcer disease (PUD), and endoscopic gastric mucosal atrophy (EGA) was performed. The diagnosis of osteoporosis was performed in accordance with the Japanese criteria. We investigated risk factors of osteoporosis. Results. Of the eligible 200 study subjects, 41 cases were of osteoporosis. Bivariate analysis showed that age, being female, BMI, alcohol, smoking, H. pylori, bone-specific ALP, PUD, and EGA were related to osteoporosis. Multivariate analysis showed that age (OR 1.13; 95%CI 1.07-1.20), being female (OR 4.77; 95%CI 1.78-12.77), BMI (OR 0.79; 95%CI 0.68-0.92), H. pylori (OR 5.33; 95%CI 1.73-16.42), and PUD (OR 4.98; 95%CI 1.51 16.45) were related to osteoporosis. Conclusions. H. pylori infection may be a risk factor of osteoporosis in Japan. PMID- 25024701 TI - A modified technique reduced operative time of laparoendoscopic rendezvous endoscopic retrograde cholangiopancreatography combined with laparoscopic cholecystectomy for concomitant gallstone and common bile ductal stone. AB - Laparoendoscopic rendezvous (LERV) endoscopic retrograde cholangiopancreatography (ERCP) and laparoscopic cholecystectomy (LC+ERCP/LERV) are considered an optimal approach for concomitant gallstones and common bile duct stones. The rendezvous technique is essential for the success of procedure. We applied two different LERV techniques, traditional technique and modified technique, in 60 consecutive cases from January 2011 to November 2012. 32 cases who underwent modified technique (group 1) from February 2012 to November 2012 were retrospectively compared to 28 cases (group 2) who underwent traditional technique from January 2011 to January 2012. There was no significant difference between two groups with respect to preoperative demographic features. Although the difference was not statistically significant, the procedure was successfully performed in 31 cases (96.9%) in group 1 and 24 cases (86.2%) in group 2. The mean operative time and time of endoscopic part were 82.6 +/- 19.6 min and 26.5 +/- 5.99 min in group 1 which were significantly shorter than those in group 2 (118.0 +/- 23.1 min and 58.7 +/- 13.3 min, resp.). There was no postoperative pancreatitis and mortality in both groups. The mean hospital stay, blood loss, incidence of complications, and residual stone were of no difference in both groups. This study proved that this modified technique can effectively reduce the operative time and time of endoscopic part of LC+ERCP/LERV compared with traditional technique. PMID- 25024700 TI - Gut Microbiota in HIV Infection: Implication for Disease Progression and Management. AB - Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART) in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression. PMID- 25024702 TI - Effectiveness of Flexible Ureterorenoscopy and Laser Lithotripsy for Multiple Unilateral Intrarenal Stones Smaller Than 2 cm. AB - Purpose. To evaluate the safety and efficacy of RIRS for the treatment of multiple unilateral intrarenal stones smaller than 20 mm. Methods. Between March 2007 and April 2013, patients with multiple intrarenal stones smaller than 20 mm were treated with RIRS and evaluated retrospectively. Each patient was evaluated for stone number, stone burden (cumulative stone length), operative time, SFRs, and complications. Results. 173 intrarenal stones in 48 patients were included. Mean age, mean number of stones per patient, mean stone burden, and mean operative time were 40.2 +/- 10.9 years (23-63), 3.6 +/- 3.0 (2-18), 22.2 +/- 8.4 mm (12-45), and 60.3 +/- 22.0 minutes (30-130), respectively. The overall SFR was 91.7%. SFRs for patients with a stone burden less and greater than 20 mm were 100% (23/23) and 84% (21/25), respectively (chi (2) = 26.022, P < 0.001). Complications occurred in six (12.5%-6/48) patients, including urinary tract infection or high-grade fever >38.5 degrees C in three cases, prolonged hematuria in two cases, and ureteral perforation in one case, all of whom were treated conservatively. No major complications occurred. Conclusions. RIRS is an effective treatment option in patients with multiple unilateral intrarenal stones especially when the total stone burden is less than 20 mm. PMID- 25024703 TI - Age as a prognostic factor in anaplastic thyroid cancer. AB - Background. Anaplastic thyroid cancer (ATC) is one of the tumors with the shortest survival in human medicine. Aim. The aim was to determine the importance of age in survival of patients with ATC. Material and Methods. We analyzed the data on 150 patients diagnosed with ATC in the period from 1995 to 2006. The Kaplan-Meier method and log-rank test were used to determine overall survival. Prognostic factors were identified by univariate and multivariate Cox regression analysis. Results. The youngest patient was 35 years old and the oldest was 89 years old. According to univariate regression analysis, age was significantly associated with longer survival in patients with ATC. In multivariate regression analysis, patients age, presence of longstanding goiter, whether surgical treatment is carried out or not, type of surgery, tumor multicentricity, presence of distant metastases, histologically proven preexistent papillary carcinoma, radioiodine therapy, and postoperative radiotherapy were included. According to multivariate analysis, besides surgery (P = 0.000, OR = 0.43, 95% CI = 0.29 0.63), only patients age (P = 0.023, OR = 0.68, 95% CI = 0.49-0.95) was independent prognostic factor of favorable survival in patients with ATC. Conclusion. Age is a factor that was independently associated with survival time in ATC. Anaplastic thyroid cancer has the best prognosis in patients younger than 50 years. PMID- 25024704 TI - Development of a gas chromatography-mass spectrometry method for the quantification of glucaric Acid derivatives in beverage substrates. AB - A gas chromatography-mass spectrometry (GC-MS) method using the standard addition methodology was developed for the determination of glucuronolactone (GL) and glucuronic acid (DGuA) in four beverages categorized as detoxification, recovery, or energy drinks. The method features a precolumn derivatization step with a combination of BSTFA (N,O-bis(trimethylsilyl)trifluoroacetamide) and TMCS (trimethylchlorosilane) to silylate the analytes. The sample pretreatment required no extraction, filtration, or reduction step prior to the injection. The quantification of the analytes was performed using a five-point standard addition protocol. The proposed method presented excellent intraday precision (%RSD < 10) and linearity for GL calibration curves (correlation coefficients > 0.995) and acceptable linearity for DGuA calibration curves (correlation coefficients > 0.97). The estimated limits of detection (LOD) and quantification (LOQ) for GL ranged from 0.006 ppm to 0.14 ppm, and 0.02 ppm to 0.47 ppm, respectively. The estimated LOD and LOQ for DGuA determination ranged, respectively, from 0.06 ppm to 1.1 ppm and 0.2 ppm to 3.8 ppm. The results demonstrated that the method should be regarded as a reliable alternative to the simultaneous determination of GL and DGuA. PMID- 25024705 TI - Cholangiocarcinoma presenting with hypercalcemia and thrombocytopenia. AB - Malignant hypercalcemia and thrombocytopenia may result from bone metastasis of cholangiocarcinoma (CC). Our case was 53-year-old man admitted to emergency department with symptoms of anorexia, weight loss, nausea, vomiting, and general fatigue in February 2012. His laboratory findings showed hypercalcemia and thrombocytopenia. CT showed a large multinodular mass in the right lobe and, extending through left lobe of the liver. We considered the diagnosis of hypercalcemia of malignancy with elevated calcium levels and suppressed PTH level with the existence of skeletal bone metastasis and the absence of parathyroid gland pathology. Treatment of hypercalcemia with IV saline, furosemide, and calcitonin improved the patient symptoms. After the 8th day of admission, calcium level, thrombocytopenia, and other symptoms were normalized. Patient was sustained surgically inoperable and transferred to medical oncology department for the purpose of palliative chemotherapy and intended radiotherapy for bone metastasis. Hypercalcemia relapsed 4 weeks after discharge and patient died at the 5th month after admission due to disseminated metastasis. We should be aware of CC with symptomatic hypercalcemia and rarely low platelet count. The correction of hypercalcemia provides symptomatic relief and stability of patients. PMID- 25024706 TI - Strongyloidiasis and diffuse alveolar hemorrhage in a patient with systemic lupus erythematosus. AB - The presence of Strongyloides stercoralis infection in patients with systemic lupus erythematosus (SLE) has been described previously. Strongyloides stercoralis hyperinfection syndrome (SHS) that usually develops in patients under immunosuppressive therapy may affect a variety of organs, but the presentation with diffuse alveolar hemorrhage (DAH) is rare with only a few cases described in the literature. We present the case of a 36-year-old Hispanic female with a past medical history relevant for SLE and a recent diagnosis of lupus nephritis and hypertension. The patient who developed sudden and progressive abdominal pain and respiratory distress, with the presence of bilateral crackles and severe hypoxemia, is currently under treatment with steroids and cyclophosphamide for worsening of lupus nephritis. The patient underwent endotracheal intubation and mechanical ventilation, and computed tomography showed the presence of bilateral pulmonary infiltrates suggestive of DAH. Bronchoalveolar lavage was done and showed the presence of filariform larvae, morphologically consistent with Strongyloides stercoralis. Treatment with ivermectin was started and patient responded to treatment with improvement of clinical status. In conclusion, the development of SHS in patients with lupus, especially when receiving immunosuppressive therapy, is a severe and potentially fatal complication. Early detection and treatment may decrease mortality. PMID- 25024707 TI - Disseminated BCG: Complications of Intravesical Bladder Cancer Treatment. AB - Intravesical bacillus Calmette-Guerin (BCG) has been established as an effective treatment of superficial bladder cancer (Parker and Kommu, 2013). However, major side effects, including pneumonitis, sepsis, and even death, may occur in <5% of patients (Gonzalez et al., 2003). Here we present a case of severe disseminated Mycobacterium bovis following intravesical BCG administration. Our patient is a 76-year-old gentleman with newly diagnosed superficial transitional cell carcinoma of the bladder who recently received his first intravesical BCG treatment. He initially presented with hemoptysis and was found to have extensive patchy infiltrates bilaterally. He was treated for pneumonia with antibiotics and then with steroids for hypersensitivity pneumonitis but continued to deteriorate. Due to the temporal proximity of his exposure to BCG, we administered treatment for presumed disseminated BCG infection with rifampin, isoniazid, and ethambutol. Within a 48-hour period, the patient improved dramatically. The reported cases of infection from intravesical BCG illustrate an insidious onset with initial symptoms of low-grade fevers and cystitis but may progress to pneumonitis. If the symptoms persist for more than 7 days or if there is clinical deterioration, RIPE therapy (with rifampin, isoniazid, pyridoxine, and ethambutol) and a fluoroquinolone should be administered for a 6-9-month course along with steroids for 4-6 weeks (Naudziunas et al., 2012). PMID- 25024708 TI - Acute Sciatic Neuritis following Lumbar Laminectomy. AB - It is commonly accepted that the common cause of acute/chronic pain in the distribution of the lumbosacral nerve roots is the herniation of a lumbar intervertebral disc, unless proven otherwise. The surgical treatment of lumbar disc herniation is successful in radicular pain and prevents or limits neurological damage in the majority of patients. Recurrence of sciatica after a successful disc surgery can be due to many possible etiologies. In the clinical setting we believe that the term sciatica might be associated with inflammation. We report a case of acute sciatic neuritis presented with significant persistent pain shortly after a successful disc surgery. The patient is a 59-year-old female with complaint of newly onset sciatica after complete pain resolution following a successful lumbar laminectomy for acute disc extrusion. In order to manage the patient's newly onset pain, the patient had multiple pain management visits which provided minimum relief. Persistent sciatica and consistent physical examination findings urged us to perform a pelvic MRI to visualize suspected pathology, which revealed right side sciatic neuritis. She responded to the electrical neuromodulation. Review of the literature on sciatic neuritis shows this is the first case report of sciatic neuritis subsequent to lumbar laminectomy. PMID- 25024709 TI - Lupus flare: an uncommon presentation of disseminated gonorrhea. AB - Gonorrhea is one of the most common sexually transmitted diseases in the US with 700,000 annual cases. Although most cases of gonorrhea are localized, approximately 0.5-3% become disseminated. Here we discuss a rare case of a patient with systemic lupus erythematosus (SLE) who developed septic shock from disseminated gonorrhea infection (DGI). Our patient is a 24-year-old woman with SLE, mixed connective tissue disease with cutaneous vasculitis, and lupus nephritis who presented with several weeks of malaise and generalized body aches associated with a diffuse rash along her fingers, palms, and trunk. Infectious workup was unrevealing with the exception of a positive gonorrhea test obtained from a cervical swab. Given her symptoms of tenosynovitis, the appearance of her skin lesions, and her positive gonorrhea test, she was diagnosed with septic shock secondary to DGI. With antibiotic treatment, the patient reported a dramatic improvement of the pain in her swollen joints and her rash receded. Patients diagnosed with SLE carry an increased risk of gonorrhea regardless of whether or not they are being treated for their SLE. Although it is well documented that SLE is associated with severe DGI, few describe it resulting in overt septic shock. PMID- 25024710 TI - Effects of fiber supplementation on glycemic excursions and incidence of hypoglycemia in children with type 1 diabetes. AB - BACKGROUND: Nutritional therapy is an important component of diabetes management. There is data to suggest that fiber content of foods may affect glycemic response. MATERIALS AND METHODS: 10 children, diagnosed with type 1 diabetes, participated. In the first phase of the study, children followed their usual meal plan. In the second phase, subjects followed the same meal plan except that fiber was added to the diet using a powder supplement (wheat dextrin). Data was collected using a continuous glucose monitoring device. The blood glucose excursion level following each meal was compared between the two phases of the study by fitting a repeated measures regression model. The incidence of hypoglycemia was also compared by fitting a logistic regression model. RESULTS: There was no difference in the mean blood glucose excursion after meals or the incidence of hypoglycemia between the two phases. There was a strong negative correlation between the amount of fiber supplemented and the mean maximum post prandial blood sugar after the lunch and breakfast meals (Spearman rank correlation coefficient = -0.86 lunch and -0.76 breakfast). CONCLUSION: Our study did not show an overall decrease in glucose excursion or incidence of hypoglycemia with fiber supplementation. We did find a strong negative correlation between the amount of fiber added during the supplemental phase and the mean maximum post-prandial blood sugar after the lunch and breakfast meals. We speculate that different types of fiber may have different effects on blood glucose with wheat dextrin having a greater dampening effect. PMID- 25024711 TI - Lawson Wilkins: portrait of a pioneer. PMID- 25024712 TI - Lawson Wilkins: recollections by his daughter. AB - Lawson Wilkins is well known as the "father" of the field of pediatric endocrinology, and his scientific accomplishments and legacy are thoroughly documented in this edition and elsewhere. Less well known, though, is what the man himself was like. Here, his daughter, Elizabeth McMaster, recalls the personal side of Dr. Wilkins including his upbringing as the son of a prominent Baltimore doctor, his medical education, establishment of a successful pediatric practice, and eventually the founding of the endocrine clinic at Johns Hopkins. Interwoven with anecdotes and reminiscences, this account provides a vivid sense of Wilkins' personality and life, from his boisterous nature and devotion to his family and career, to the tragic personal losses he endured. He was a man who threw himself fully into everything he did, whether it was making his own liqueur during Prohibition, collecting specimens from abnormally large circus performers as part of his earliest endocrine research, arranging raucous, impromptu singing parties, sailing the Chesapeake with friends, writing a definitive textbook of Pediatric Endocrinology, training a legion of fellows, or the pioneering work for which he is still known today. PMID- 25024713 TI - Lawson Wilkins and my life: part 1. PMID- 25024714 TI - Lawson Wilkins and my life: part 2. PMID- 25024715 TI - Lawson Wilkins and my life: part 3. PMID- 25024716 TI - Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit. AB - BACKGROUND: Oral antihistamines that target the histamine receptor-1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise. METHODS: Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396). RESULTS: PF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events. CONCLUSIONS: PF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls. PMID- 25024717 TI - Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study. AB - BACKGROUND: Thiazolidinediones are oral diabetes medications that selectively activate peroxisome proliferator-activated receptor gamma and have potent anti inflammatory properties. While a few studies have found improvements in pulmonary function with exposure to thiazolidinediones, there are no studies of their impact on asthma exacerbations. Our objective was to assess whether exposure to thiazolidinediones was associated with a decreased risk of asthma exacerbation. METHODS: We performed a cohort study of diabetic Veterans who had a diagnosis of asthma and were taking oral diabetes medications during the period of 10/1/2005 - 9/30/2006. The risk of asthma exacerbations and oral steroid use during 10/1/2006 - 9/30/2007 was compared between patients who were prescribed thiazolidinediones and patients who were on alternative oral diabetes medications. Multivariable logistic regression and negative binomial regression analyses were used to characterize this risk. A sensitivity analysis was performed, restricting our evaluation to patients who were adherent to diabetes therapy. RESULTS: We identified 2,178 patients who were on thiazolidinediones and 10,700 who were not. Exposure to thiazolidinediones was associated with significant reductions in the risk of asthma exacerbation (OR = 0.79, 95% CI, 0.62 - 0.99) and oral steroid prescription (OR = 0.73, 95% CI 0.63 - 0.84). Among patients who were adherent to diabetes medications, there were more substantial reductions in the risks for asthma exacerbation (OR = 0.64, 95% CI 0.47 - 0.85) and oral steroid prescription (OR = 0.68, 95% CI 0.57 - 0.81). CONCLUSIONS: Thiazolidinediones may provide a novel anti-inflammatory approach to asthma management by preventing exacerbations and decreasing the use of oral steroids. PMID- 25024718 TI - Tuberculosis treatment in patients with comorbidities. AB - Tuberculosis is a significant infectious problem in elderly patients with comorbidities in Korea. The age-associated diseases such as malignancy and diabetes mellitus may increase the risk of tuberculosis in this population. The medication treatments of tuberculosis in patients with comorbidities can cause adverse reactions to antituberculosis drugs and inadequate treatment responses. Thus, clinicians must carefully monitor the toxicity of antituberculosis therapy and the efficacy of treatment in patients with comorbidities. PMID- 25024719 TI - Diagnosis and Treatment of Latent Tuberculosis Infection due to Initiation of Anti-TNF Therapy. AB - Patients with immune-mediated inflammatory diseases (IMIDs) are increasingly being treated with anti-tumor necrosis factor (TNF) agents and are at increased risk of developing tuberculosis (TB). Therefore, diagnosis and treatment of latent TB infection (LTBI) is recommended in these patients due to the initiation of anti-TNF therapy. Traditionally, LTBI has been diagnosed on the basis of clinical factors and a tuberculin skin test. Recently, interferon-gamma releasing assays (IGRAs) that can detect TB infection have become available. Considering the high-risk of developing TB in patients on anti-TNF therapy, the use of both a tuberculin skin test and an IGRA should be considered to detect and treat LTBI in patients with IMIDs. The traditional LTBI treatment regimen consisted of isoniazid monotherapy for 9 months. However, shorter regimens such as 4 months of rifampicin or 3 months of isoniazid/rifampicin are increasingly being used to improve treatment completion rates. In this review, the screening methods for diagnosing latent and active TB before anti-TNF therapy in patients with IMIDs will be briefly described, as well as the current LTBI treatment regimens, the recommendations for managing TB that develops during anti-TNF therapy, the necessity of regular monitoring to detect new TB infection, and the re-initiation of anti-TNF therapy in patients who develop TB. PMID- 25024720 TI - Reference equations for the six-minute walk distance in healthy korean adults, aged 22-59 years. AB - BACKGROUND: The six-minute walk test has been widely used in people with chronic cardiopulmonary disorders as an outcome assessment with regards to therapeutic or prognostic determinants. This study was undertaken to determine the six-minute walk distance (6MWD) in a sample of healthy Koreans and to create a reference equation. We also compared the 6MWD of our cohort with previously published equations. METHODS: Two hundred fifty-nine healthy subjects (95 males) aged 22-59 years performed two walking tests using a standardized protocol. 6MWD was defined as the greatest distance achieved from the two tests. The effect of anthropometrics on the 6MWD was also investigated. RESULTS: The average 6MWD was 598.5+/-57.92 m, with significantly longer distances by males (628.9+/-59.51 m) than females (580.9+/-47.80 m) (p<0.001). Age, height, weight, and body mass index were significantly correlated with 6MWD in univariate analysis. Stepwise multiple regression showed height to be single independent predictor of 6MWD (r(2)=0.205, p<0.001). The reference equations derived in Caucasian and North African populations tend to overestimate the distance walked by Korean subjects, while Asian equations underestimate it. CONCLUSION: The average 6MWD in these Korean populations was 600 m. The regression equation revealed that individual's height was the most significant predictor of distance, explaining 20.5% of the distance variance. PMID- 25024722 TI - p53 Expression in a Malignant Mesothelioma Patient during Seven-Year Follow-up. AB - Malignant mesothelioma (MM) is the aggressive tumor of serosal surfaces. There are crude pathogenetic results regarding the biology of MM. Coordinated upregulations of p53 gene expression are shown in malignancies. We believed that there are changes in the p53 expression with transformation from reactive hyperplasia to MM. A 65-year-old male was admitted the hospital because of left pleuritic chest pains in 2004. Chest computed tomography (CT) results showed left pleural effusions with loculation and pleural thickening. Pathologic findings revealed reactive mesothelial hyperplasia. In 2008, the patient again felt left pleuritic chest pains. Chest CT showed progressive thickening of the left pleura. Pathologic diagnosis was atypical mesothelial hyperplasia. In 2011, chest CT showed progressive thickening of his left pleura. He was diagnosed with well differentiated papillary mesothelioma. Serial change was analyzed by immunohistochemical staining for p53 of pleural tissues. There were no remarkable changes in p53 expressions during the transformation to MM. PMID- 25024721 TI - Effectiveness of smoking cessation using motivational interviewing in patients consulting a pulmonologist. AB - BACKGROUND: We aimed to investigate the role of the physician in practice and the factors that influence the success rate of smoking cessation. METHODS: This study retrospectively analyzed 126 adult smokers who had visited the outpatient department of pulmonology, and received motivational interviewing with or without supplement drugs. The findings include continuous smoking abstinence rate, which was evaluated at 6, 12 and 24 weeks, and the factors associated with continuous abstinence for 6 months or longer. RESULTS: The patients with only motivational interviewing accounted for 57.9%, while the nicotine patch therapy was applied to 30.2%; and varenicline was prescribed to 11.9%. The smoking cessation success rates of at 6, 12, and 24 weeks were 55.6%, 47.6%, and 33.3%, respectively. However, even in the failure group at six months, tobacco consumption was decreased under 10 cigarettes per day in 42.1% (53/126). In multivariate logistic regression analysis, degree of Fagerstom Test for Nicotine Dependence (p=0.034; odds ratio, 3.607; 95% confidence interval [CI], 1.102-1.807), the absence of smoking-related lung disease (p=0.008; odds ratio, 4.693; 95% CI, 1.497-14.707), and education level (p=0.001; odds ratio, 181.420; 95% CI, 8.414-3,911.502) were the predictors of successful smoking cessation. CONCLUSION: An improved continuous smoking abstinence rate can be obtained by motivational interviewing, regardless of the association with pharmacotherapy. PMID- 25024723 TI - Primary malignant fibrous histiocytoma of the chest wall misdiagnosed as traumatic hemothorax. AB - Malignant fibrous histiocytoma (MFH), a type of sarcoma, is a malignant neoplasm with uncertain origins that arise from both the soft tissues and the bone. The occurrence of MFH on the chest wall is extremely rare. We hereby report a case of a 72-year-old woman who was incidentally detected with MFH after a traffic accident. PMID- 25024724 TI - Silicone stent placement for primary tracheal amyloidosis accompanied by cartilage destruction. AB - Primary tracheal amyloidosis (PTA) can lead to airway obstructions, and patients with severe PTA should undergo bronchoscopic interventions in order to maintain airway patency. Focal airway involvements with amyloidosis can only be treated with mechanical dilatation. However, the PTA with diffused airway involvements and concomitant cartilage destructions requires stent placement. Limited information regarding the usefulness of silicone stents in patients with PTA has been released. Therefore, we report a case of diffused PTA with tracheomalacia causing severe cartilage destruction, which is being successfully managed with bronchoscopic interventions and silicone stent placements. PMID- 25024725 TI - Anomalous arterial supply to normal Basal segment of the right lower lobe: endovascular treatment with the amplatzer vascular plug. AB - Pulmonary systemic arterialization to normal basal lung without sequestration is a rare congenital anomaly. In this rare abnormality, arterialization of the left lower lobe is the most common type. In general, surgical treatments have been performed. Recently, for reducing the complications and risks of surgery, embolization is mainly attempted by using coils. We report a case of 22-year-old male patient with a 10 mm anomalous arterial supply to his normal lung, which is being successfully treated by transcatheter embolization when using the Amplatzer Vascular Plug that has been adapted for the treatment of high-flows and large artery occlusions. PMID- 25024726 TI - Differential Effects of Naja naja atra Venom on Immune Activity. AB - Previous studies reported that Naja naja atra venom (NNAV) inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1 phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-gamma, IL-4) secretion and inhibition of Th17 cytokine (IL-17) production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases. PMID- 25024727 TI - The effect of scalp point cluster-needling on learning and memory function and neurotransmitter levels in rats with vascular dementia. AB - We observed the effect of scalp point cluster-needling treatment on learning and memory function and neurotransmitter levels in rats with vascular dementia (VD). Permanent ligation of the bilateral carotid arteries was used to create the VD rat model. A Morris water maze was used to measure the rats' learning and memory function, and the changes in neurotransmitter levels in the rats' hippocampus were analyzed. The results show that scalp point cluster-needling can increase the VD rat model's learning and memory score. The VD rat model's learning and memory score was significantly different when compared with that of the sham operation group (P < 0.05). Hippocampal acetylcholine (ACh), dopamine (DA), and 5 hydroxytryptamine (5-HT) concentrations significantly decreased in the rat model. Compared with the model group, the scalp point cluster-needling group's ACh concentration markedly increased and DA and 5-HT levels increased as well. In conclusion, scalp point cluster-needling can improve learning and memory function in VD rats, and its function may be related to an increase in neurotransmitter release. PMID- 25024728 TI - Acupoint-specific, frequency-dependent, and improved insulin sensitivity hypoglycemic effect of electroacupuncture applied to drug-combined therapy studied by a randomized control clinical trial. AB - The application of electroacupuncture (EA) to specific acupoints can induce a hypoglycemic effect in streptozotocin-induced rats, normal rats, and rats with steroid-induced insulin resistance. EA combined with the oral insulin sensitizer rosiglitazone improved insulin sensitivity in rats and humans with type II diabetes mellitus (DM). There are different hypoglycemic mechanisms between Zhongwan and Zusanli acupoints by EA stimulation. On low-frequency (2 Hz) stimulation at bilateral Zusanli acupoints, serotonin was involved in the hypoglycemic effect in normal rats. Moreover, after 15 Hz EA stimulation at the bilateral Zusanli acupoints, although enhanced insulin activity mainly acts on the insulin-sensitive target organs, the muscles must be considered. In addition, 15 Hz EA stimulation at the bilateral Zusanli acupoints has the combined effect of enhancing cholinergic nerve activity and increasing nitric oxide synthase (NOS) activity to enhance insulin activity. Despite the well-documented effect of pain control by EA in many systemic diseases, there are few high-quality long term clinical trials on the hypoglycemic effect of EA in DM. Combination treatment with EA and other medications seems to be an alternative treatment to achieve better therapeutic goals that merit future investigation. PMID- 25024729 TI - Differential activation patterns of FMRI in sleep-deprived brain: restoring effects of acupuncture. AB - Previous studies suggested a remediation role of acupuncture in insomnia, and acupuncture also has been used in insomnia empirically and clinically. In this study, we employed fMRI to test the role of acupuncture in sleep deprivation (SD). Sixteen healthy volunteers (8 males) were recruited and scheduled for three fMRI scanning procedures, one following the individual's normal sleep and received acupuncture SP6 (NOR group) and the other two after 24 h of total SD with acupuncture on SP6 (SD group) or sham (Sham group). The sessions were counterbalanced approximately two weeks apart. Acupuncture stimuli elicited significantly different activation patterns of three groups. In NOR group, the right superior temporal lobe, left inferior parietal lobule, and left postcentral gyrus were activated; in SD group, the anterior cingulate cortex, bilateral insula, left basal ganglia, and thalamus were significantly activated while, in Sham group, the bilateral thalamus and left cerebellum were activated. Different activation patterns suggest a unique role of acupuncture on SP6 in remediation of SD. SP6 elicits greater and anatomically different activations than those of sham stimuli; that is, the salience network, a unique interoceptive autonomic circuit, may indicate the mechanism underlying acupuncture in restoring sleep deprivation. PMID- 25024730 TI - Retracted: Chemistry and biology of essential oils of genus boswellia. PMID- 25024731 TI - Effects of Inhalation of Essential Oil of Citrus aurantium L. var. amara on Menopausal Symptoms, Stress, and Estrogen in Postmenopausal Women: A Randomized Controlled Trial. AB - This study aimed to investigate the effects of inhalation of the essential oil of Citrus aurantium L. var. amara (neroli oil) on menopausal symptoms, stress, and estrogen in postmenopausal women. Sixty-three healthy postmenopausal women were randomized to inhale 0.1% or 0.5% neroli oil or almond oil (control) for 5 minutes twice daily for 5 days. Menopause-related symptoms, as determined by the Menopause-Specific Quality of Life Questionnaire (MENQOL); sexual desire visual analog scale (VAS); serum cortisol and estrogen concentrations, blood pressure, pulse, and stress VAS, were measured before and after inhalation. Compared with the control group, the two neroli oil groups showed significant improvements in the physical domain score of the MENQOL and in sexual desire. Systolic blood pressure was significantly lower in the group inhaling 0.5% neroli oil than in the control group. Compared with the control group, the two neroli oil groups showed significantly lower diastolic blood pressure and tended to improve pulse rate and serum cortisol and estrogen concentrations. These findings indicate that inhalation of neroli oil helps relieve menopausal symptoms, increase sexual desire, and reduce blood pressure in postmenopausal women. Neroli oil may have potential as an effective intervention to reduce stress and improve the endocrine system. PMID- 25024732 TI - Mild moxibustion decreases the expression of prokineticin 2 and prokineticin receptor 2 in the colon and spinal cord of rats with irritable bowel syndrome. AB - It has been proven that prokineticin 2 (PK2) and its receptor PKR2 play an important role in hyperalgesia, while mild moxibustion can relieve visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). The goal of the present study was to determine the effects of mild moxibustion on the expression of PK2 and PKR2 in colon and spinal cord in IBS rat model, which was induced by colorectal distension using inflatable balloons. After mild moxibustion treatment, abdominal withdrawal reflex (AWR) scores were assessed by colorectal distension; protein and mRNA expression of PK2 and PKR2 in rat colon and spinal cord was determined by immunohistochemistry and fluorescence quantitative PCR. Compared with normal rats, the AWR scores of rats and the expressions of PK2/PKR2 proteins and mRNAs in colon and spinal cord tissue were significantly increased in the model group; compared with the model group, the AWR scores of rats and the expressions of PK2/PKR2 proteins and mRNAs in colon and spinal cord tissue were significantly decreased in the mild moxibustion group. These findings suggest that the analgesia effect of mild moxibustion may be associated with the reduction of the abnormally increased expression of the PK2/PKR2 proteins and mRNAs in the colon and spinal cord. PMID- 25024733 TI - Evaluation of the effect of green tea extract on the prevention of gingival bleeding after posterior mandibular teeth extraction: a randomized controlled trial. AB - Background. Removing tooth results in gingival bleeding. Several measures are taken to stop bleeding. In this study, the effect of green tea extract on cessation of bleeding and oozing after removing of mandibular molars was investigated. Methods. This was a randomized controlled clinical trial carried out on 62 patients who were referred for extraction of their mandibular molars. The volunteers were randomly and equally divided into treatment and control groups. In the first group, green tea extract-impregnated sterile gauze was used after removing the tooth while in the second group, green tea extract-free gauze was applied. Active bleeding and oozing monitoring was done every 5 minutes until cessation of bleeding and one hour after that, respectively. The results were compared using t-test. Results. The mean +/- SD of bleeding duration in green tea group was significantly lower than control group (5.87 +/- 1.76 versus 10.09 +/- 3.61 minutes, P = 0.001). In addition, the number of people with oozing one hour after surgery was significantly lower in the green tea group (6 versus 29 persons, P = 0.001). Conclusion. This study showed that green tea extract contributes to significant decline in bleeding of the socket caused by tooth extraction as well as reduction of oozing. PMID- 25024734 TI - The Correlation between Chemical Composition, as Determined by UPLC-TOF-MS, and Acute Toxicity of Veratrum nigrum L. and Radix paeoniae alba. AB - The eighteen incompatible medicaments is an important theory in traditional Chinese medicine. The theory suggests that drugs in the eighteen incompatible medicaments can be toxic when used together. Veratrum nigrum L. and Radix paeoniae alba belong to the eighteen incompatible medicaments and have been prohibited for thousands of years. This study offers preliminary insight into the mechanism and chemical constituents responsible for the incompatibility and toxicity of these two agents. Specifically, we performed toxicology studies to identify and quantify the constituent substances of the two agents. Experiments revealed that acute toxicity increases when the dose of V. nigrum L. is higher than, or equal to, RPA. UPLC-TOF-MS analysis showed that, although the volumes of V. nigrum L. were the same, the content of some veratrum alkaloids changed significantly and had a trend toward a highly positive correlation (|r| >= 0.8) with toxicity. This suggests that the increased toxicity of the V. nigrum L. and RPA combination was due mainly to increased content of the special veratrum alkaloids. The cytotoxicity of veratridine in SH-SY5Y cells was decreased with increasing paeoniflorin concentrations. This study provides insight into the mechanism behind the incompatibility theory of TCM. PMID- 25024735 TI - Complementary and alternative medicine for respiratory tract infectious diseases: prevention and treatments. PMID- 25024736 TI - Naive hosts of avian brood parasites accept foreign eggs, whereas older hosts fine-tune foreign egg discrimination during laying. AB - BACKGROUND: Many potential hosts of social parasites recognize and reject foreign intruders, and reduce or altogether escape the negative impacts of parasitism. The ontogenetic basis of whether and how avian hosts recognize their own and the brood parasitic eggs remains unclear. By repeatedly parasitizing the same hosts with a consistent parasitic egg type, and contrasting the responses of naive and older breeders, we studied ontogenetic plasticity in the rejection of foreign eggs by the great reed warbler (Acrocephalus arundinaceus), a host species of the common cuckoo (Cuculus canorus). RESULTS: In response to experimental parasitism before the onset of laying, first time breeding hosts showed almost no egg ejection, compared to higher rates of ejection in older breeders. Young birds continued to accept foreign eggs when they were subjected to repeated parasitism, whereas older birds showed even higher ejection rates later in the same laying cycle. CONCLUSIONS: Our results are consistent with the hypotheses that (i) naive hosts need to see and learn the appearance of their own eggs to discriminate and reject foreign eggs, whereas (ii) experienced breeders possess a recognition template of their own eggs and reject parasitic eggs even without having to see their own eggs. However, we cannot exclude the possibility that other external cues and internal processes, accumulated simply with increasing age, may also modify age-specific patterns in egg rejection (e.g. more sightings of the cuckoo by older breeders). Future research should specifically track the potential role of learning in responses of individual hosts between first and subsequent breeding attempts by testing whether imprinting on a parasitized clutch reduces the rates of rejecting foreign eggs in subsequent parasitized clutches. PMID- 25024737 TI - Development and juvenile anatomy of the nemertodermatid Meara stichopi (Bock) Westblad 1949 (Acoelomorpha). AB - INTRODUCTION: Nemertodermatida is the sister group of the Acoela, which together form the Acoelomorpha, a taxon that comprises bilaterally symmetric, small aquatic worms. While there are several descriptions of the embryology of acoel species, descriptions of nemertodermatid development are scarce. To be able to reconstruct the ground pattern of the Acoelomorpha it is crucial to gain more information about the development of several nemertodermatid species. Here we describe the development of the nemertodermatid Meara stichopi using light and fluorescent microscopic methods. RESULTS: We have collected Meara stichopi during several seasons and reconstruct the complex annual reproductive cycle dependent on the sea cucumber Parastichopus tremulus. Using common fluorescent markers for musculature (BODIPY FL-phallacidin) and neurons (antibodies against FMRFamide, serotonin, tyrosinated-tubulin) and live imaging techniques, we followed embryogenesis which takes approximately 9-10 weeks. The cleavage pattern is stereotypic up to the 16-cell stage. Ring- and longitudinal musculature start to develop during week 6, followed by the formation of the basiepidermal nervous system. The juvenile is hatching without mouth opening and has a basiepidermal nerve net with two dorsal neurite bundles and an anterior condensation. CONCLUSIONS: The development of Meara stichopi differs from the development of Acoela in that it is less stereotypic and does not follow the typical acoel duet cleavage program. During late development Meara stichopi does not show a temporal anterior to posterior gradient during muscle and nervous system formation. PMID- 25024738 TI - The DNA repair component Metnase regulates Chk1 stability. AB - Chk1 both arrests replication forks and enhances repair of DNA damage by phosphorylation of downstream effectors. Metnase (also termed SETMAR) is a SET histone methylase and transposase nuclease protein that promotes both DNA double strand break (DSB) repair and re-start of stalled replication forks. We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination. These data define a novel pathway for Chk1 regulation, whereby a target of Chk1, Metnase, feeds back to amplify Chk1 stability, and therefore enhance replication fork arrest. PMID- 25024740 TI - An interactive method based on the live wire for segmentation of the breast in mammography images. AB - In order to improve accuracy of computer-aided diagnosis of breast lumps, the authors introduce an improved interactive segmentation method based on Live Wire. This paper presents the Gabor filters and FCM clustering algorithm is introduced to the Live Wire cost function definition. According to the image FCM analysis for image edge enhancement, we eliminate the interference of weak edge and access external features clear segmentation results of breast lumps through improving Live Wire on two cases of breast segmentation data. Compared with the traditional method of image segmentation, experimental results show that the method achieves more accurate segmentation of breast lumps and provides more accurate objective basis on quantitative and qualitative analysis of breast lumps. PMID- 25024739 TI - Dynamic regulatory network reconstruction for Alzheimer's disease based on matrix decomposition techniques. AB - Alzheimer's disease (AD) is the most common form of dementia and leads to irreversible neurodegenerative damage of the brain. Finding the dynamic responses of genes, signaling proteins, transcription factor (TF) activities, and regulatory networks of the progressively deteriorative progress of AD would represent a significant advance in discovering the pathogenesis of AD. However, the high throughput technologies of measuring TF activities are not yet available on a genome-wide scale. In this study, based on DNA microarray gene expression data and a priori information of TFs, network component analysis (NCA) algorithm is applied to determining the TF activities and regulatory influences on TGs of incipient, moderate, and severe AD. Based on that, the dynamical gene regulatory networks of the deteriorative courses of AD were reconstructed. To select significant genes which are differentially expressed in different courses of AD, independent component analysis (ICA), which is better than the traditional clustering methods and can successfully group one gene in different meaningful biological processes, was used. The molecular biological analysis showed that the changes of TF activities and interactions of signaling proteins in mitosis, cell cycle, immune response, and inflammation play an important role in the deterioration of AD. PMID- 25024741 TI - Role of parental occupation in autism spectrum disorder diagnosis and severity. PMID- 25024742 TI - Improved production of fatty alcohols in cyanobacteria by metabolic engineering. AB - BACKGROUND: Fatty alcohols are widely used in industrial chemicals. The biosynthetic pathways for fatty alcohols are diverse and widely existing in nature. They display a high capacity to produce fatty alcohols by the metabolic engineering of different microbe hosts. Direct recycling of carbon dioxide to fatty alcohols can be achieved by introducing a fatty alcohol-producing pathway into photosynthetic cyanobacteria. According to our precious reports, a relatively low yield of fatty alcohols was obtained in the genetically engineered cyanobacterium Synechocystis sp. PCC 6803. RESULTS: The photosynthetic production of fatty alcohols in Synechocystis sp. PCC 6803 was improved through heterologously expressing fatty acyl-Coenzyme A (acyl-CoA) reductase gene maqu_2220 from the marine bacterium Marinobacter aquaeolei VT8. Maqu_2220 has been proved to catalyze both the four-electron reduction of fatty acyl-CoA or acyl-Acyl Carrier Protein (acyl-ACP) and the two-electron reduction of fatty aldehyde to fatty alcohol. The knockout of the aldehyde-deformylating oxygenase gene (sll0208) efficiently blocked the hydrocarbon accumulation and redirected the carbon flux into the fatty alcohol-producing pathway. By knocking-out both sll0208 and sll0209 (encoding an acyl-ACP reductase), the productivity of fatty alcohols was further increased to 2.87 mg/g dry weight. CONCLUSIONS: The highest yield of fatty alcohols was achieved in cyanobacteria by expressing the prokaryotic fatty acyl-CoA reductase Maqu_2220 and knocking-out the two key genes (sll0208 and sll0209) that are involved in the alka(e)ne biosynthesis pathway. Maqu_2220 was demonstrated as a robust enzyme for producing fatty alcohols in cyanobacteria. The production of fatty alcohols could be significantly increased by blocking the hydrocarbon biosynthesis pathway. PMID- 25024743 TI - Ensiling and hydrothermal pretreatment of grass: consequences for enzymatic biomass conversion and total monosaccharide yields. AB - BACKGROUND: Ensiling may act as a pretreatment of fresh grass biomass and increase the enzymatic conversion of structural carbohydrates to fermentable sugars. However, ensiling does not provide sufficient severity to be a standalone pretreatment method. Here, ensiling of grass is combined with hydrothermal treatment (HTT) with the aim of improving the enzymatic biomass convertibility and decrease the required temperature of the HTT. RESULTS: Grass silage (Festulolium Hykor) was hydrothermally treated at temperatures of 170, 180, and 190 degrees C for 10 minutes. Relative to HTT treated dry grass, ensiling increased the solubilization of dry matter (DM) during HTT and gave increased glucan content, but lower lignin in the insoluble fiber fraction. Ensiling improved glucose yields in the enzymatic hydrolysis of the washed solid fiber fraction at the lower HTT temperatures. At 170 degrees C glucose yield improved from 17 to 24 (w/w)% (45 to 57% cellulose convertibility), and at 180 degrees C glucose yield improved from 22 to 29 (w/w)% (54 to 69% cellulose convertibility). Direct HTT of grass at 190 degrees C gave the same high glucose yield as for grass silage (35 (w/w)% (77% cellulose convertibility)) and improved xylan yields (27% xylan convertibility). The effect of ensiling of grass prior to HTT improved the enzymatic conversion of cellulose for HTT at 170 and 180 degrees C, but the increased glucose release did not make up for the loss of water soluble carbohydrates (WSC) during ensiling. Overall, sugar yields (C6 + C5) were similar for HTT of grass and grass silage at both 170 and 180 degrees C, but at 190 degrees C the overall sugar yield was better for HTT of dry grass. CONCLUSIONS: This study unequivocally establishes that ensiling of grass as a biomass pretreatment method comes with a loss of WSC. The loss of WSC by ensiling is not necessarily compensated for by providing a lower temperature requirement for HTT for high enzymatic monosaccharide release. However, ensiling can be an advantageous storage method prior to grass processing. PMID- 25024745 TI - HDAC class I inhibitor, Mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+ cardiac myofibroblast activation. AB - BACKGROUND: Interstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure. Recent studies showed that histone deacetylase (HDAC) inhibitors retard fibrosis formation in acute MI settings. However, it is unknown whether HDAC inhibition can reverse cardiac fibrosis in ischemic heart failure. In addition, specific HDAC isoforms involved in cardiac fibrosis and myofibroblast activation are not well defined. Thus, the purpose of this study is to determine the effects of selective class I HDAC inhibition on cardiac fibroblasts activation and cardiac fibrosis in a congestive heart failure (CHF) model secondary to MI. METHODS: MI was created by left anterior descending (LAD) coronary artery occlusion. Class I HDACs were selectively inhibited via Mocetinostat in CD90+ fibroblasts isolated from atrial and ventricular heart tissue in vitro. In vivo, Class I HDACs were inhibited in 3 weeks post MI rats by injecting Mocetinostat for the duration of 3 weeks. Cardiac function and heart tissue were analyzed at 6 weeks post MI. RESULTS: In sham hearts, HDAC1 and HDAC2 displayed differential expression patterns where HDAC1 mainly expressed in cardiac fibroblast and HDAC2 in cardiomyocytes. On the other hand, we showed that HDAC1 and 2 were upregulated in CHF hearts, and were found to co-localize with CD90+ cardiac fibroblasts. In vivo treatment of CHF animals with Mocetinostat improved left ventricle end diastolic pressure and dp/dt max and decreased the total collagen amount. In vitro treatment of CD90+ cells with Mocetinostat reversed myofibroblast phenotype as indicated by a decrease in alpha-Smooth muscle actin (alpha-SMA), Collagen III, and Matrix metalloproteinase-2 (MMP2). Furthermore, Mocetinostat increased E-cadherin, induced beta-catenin localization to the membrane, and reduced Akt/GSK3beta signaling in atrial cardiac fibroblasts. In addition, Mocetinostat treatment of atrial CD90+ cells upregulated cleaved-Caspase3 and activated the p53/p21 axis. CONCLUSIONS: Taken together, our results demonstrate upregulation of HDAC1 and 2 in CHF. In addition, HDAC inhibition reverses interstitial fibrosis in CHF. Possible anti fibrotic actions of HDAC inhibition include reversal of myofibroblast activation and induction of cell cycle arrest/apoptosis. PMID- 25024744 TI - Zymomonas mobilis: a novel platform for future biorefineries. AB - Biosynthesis of liquid fuels and biomass-based building block chemicals from microorganisms have been regarded as a competitive alternative route to traditional. Zymomonas mobilis possesses a number of desirable characteristics for its special Entner-Doudoroff pathway, which makes it an ideal platform for both metabolic engineering and commercial-scale production of desirable bio products as the same as Escherichia coli and Saccharomyces cerevisiae based on consideration of future biomass biorefinery. Z. mobilis has been studied extensively on both fundamental and applied level, which will provide a basis for industrial biotechnology in the future. Furthermore, metabolic engineering of Z. mobilis for enhancing bio-ethanol production from biomass resources has been significantly promoted by different methods (i.e. mutagenesis, adaptive laboratory evolution, specific gene knock-out, and metabolic engineering). In addition, the feasibility of representative metabolites, i.e. sorbitol, bionic acid, levan, succinic acid, isobutanol, and isobutanol produced by Z. mobilis and the strategies for strain improvements are also discussed or highlighted in this paper. Moreover, this review will present some guidelines for future developments in the bio-based chemical production using Z. mobilis as a novel industrial platform for future biofineries. PMID- 25024747 TI - Does family history of metabolic syndrome affect the metabolic profile phenotype in young healthy individuals? AB - BACKGROUND: Early identification of high-risk individuals is key for the prevention of cardiovascular disease (CVD). The aim of this study was to assess the potential impact of a family history of metabolic syndrome (fhMetS) on the risk of metabolic disorders (abnormal body mass, lipid profile, glucose metabolism, insulin resistance, and blood pressure) in healthy young individuals. METHODS: We studied CVD risk factors in 90 healthy volunteers, aged 27-39 years; of these, 78 had fhMetS and 12 were without fhMetS (control group). Fasting serum lipids, glucose, and insulin levels were assayed, and anthropometric parameters and blood pressure using, an ambulatory blood pressure monitoring system, were measured. Nutritional and physical activity habits were assessed. RESULTS: Despite similar nutritional and physical activity habits, abnormal body mass was found in 53.2% of the fhMetS participants and 46.1% of the control participants (p = 0.54). The occurrence of obesity was 19.4% and 0%, respectively (p = 0.69). Compared to the control participants, fhMetS was associated with significantly higher total cholesterol (5.46 mmol/L vs. 4.69 mmol/L, p < 0.030), low-density lipoprotein cholesterol ( 3.28 mmol/L vs. 2.90 mmol/L, p < 0.032), and non-high density lipoprotein cholesterol ( 3.74 mmol/L vs. 3.25 mmol/L, p < 0.016) levels, in addition to lower fasting glucose levels ( 4.51 mmol/L vs. 4.81 mmol/L, p < 0.042). A positive correlation between fasting glucose and insulin levels (r = 0.28; p < 0.015) was detected in the fhMetS participants. Higher mean daytime systolic blood pressure (121.5 mmHg vs. 113.3 mmHg, p < 0.035), mean daytime diastolic blood pressure ( 79.0 mmHg vs. 74.5 mmHg, p < 0.045), and mean nighttime diastolic blood pressure ( 64.0 mmHg vs. 59.5 mmHg, p < 0.019) were observed in the fhMetS group. CONCLUSIONS: More than 50% of the fhMetS participants had excess weight or a lipid disorder, which may indicate an increased risk of cardiovascular disease and the need for regular ambulatory assessment of serum lipid concentrations in young people with a family history of MetS. PMID- 25024746 TI - Brachial-to-ankle pulse wave velocity as an independent prognostic factor for ovulatory response to clomiphene citrate in women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) has a risk for cardiovascular disease. Increased arterial stiffness has been observed in women with PCOS. The purpose of the present study was to investigate whether the brachial-to-ankle pulse wave velocity (baPWV) is a prognostic factor for ovulatory response to clomiphene citrate (CC) in women with PCOS. METHODS: This study was a retrospective cohort study of 62 women with PCOS conducted from January 2009 to December 2012 at the university hospital, Yamagata, Japan. We analyzed 62 infertile PCOS patients who received CC. Ovulation was induced by 100 mg CC for 5 days. CC non-responder was defined as failure to ovulate for at least 2 consecutive CC-treatment cycles. The endocrine, metabolic, and cardiovascular parameters between CC responder (38 patients) and non-responder (24 patients) groups were analyzed. RESULTS: In univariate analysis, waist-to-hip ratio, level of free testosterone, percentages of patients with dyslipidemia, impaired glucose tolerance, and diabetes mellitus, blood glucose and insulin levels at 60 min and 120 min, the area under the curve of glucose and insulin after 75-g oral glucose intolerance test, and baPWV were significantly higher in CC non-responders compared with responders. In multivariate logistic regression analysis, both waist-to-hip ratio (odds ratio, 1.77; 95% confidence interval, 2.2-14.1; P=0.04) and baPWV (odds ratio, 1.71; 95% confidence interval, 1.1-2.8; P=0.03) were independent predictors of ovulation induction by CC in PCOS patients. The predictive values of waist-to-hip ratio and baPWV for the CC resistance in PCOS patients were determined by the receiver operating characteristic curves. The area under the curves for waist-to-hip ratio and baPWV were 0.76 and 0.77, respectively. Setting the threshold at 0.83 for waist-to-hip ratio offered the best compromise between specificity (0.65) and sensitivity (0.84), while the setting the threshold at 1,182 cm/s for baPWV offered the best compromise between specificity (0.80) and sensitivity (0.71). CONCLUSIONS: Both metabolic and cardiovascular parameters were predictive for CC resistance in PCOS patients. The measurement of baPWV may be a useful tool to predict ovulation in PCOS patients who receive CC. PMID- 25024748 TI - Crystal structure reveals conservation of amyloid-beta conformation recognized by 3D6 following humanization to bapineuzumab. AB - INTRODUCTION: Immunotherapy targeting amyloid-beta peptide is under active clinical investigation for treatment of Alzheimer's disease (AD). Among the hypotheses being investigated for impact on clinical outcome are the preferred epitope or conformation of amyloid-beta to target for treatment, and the mechanism of action underlying immunotherapy. Bapineuzumab (humanized 3D6), a neo epitope specific antibody recognizing amyloid-beta1-5 with strong preference for an exposed Asp residue at the N-terminus of the peptide, has undergone advanced clinical testing for treatment of AD. METHODS: To gain further insight into the epitope conformation, we interrogated structural details of amino-terminal epitopes in amyloid-beta using x-ray crystallography of 3D6Fab:amyloid-beta complexes. Humanization of 3D6 was carried out using standard procedures integrating recombinant methods, sequence informatics, and homology modeling predictions to identify important mouse framework residues for retention in the finished humanized product. RESULTS: Here we report the crystal structure of a recombinant Fab fragment of 3D6 in complex with amyloid-beta1-7 solved at 2.0 A resolution. The N-terminus of amyloid-beta is bound to 3D6 as a 310 helix. The amino-terminal Asp residue is buried deepest in the antibody binding pocket, with the Cbeta atom of residue 6 visible at the entrance to the binding pocket near the surface of the antibody. We further evaluate homology model based predictions used to guide humanization of 3D6 to bapineuzumab, with actual structure of the Fab. The structure of the Fab:amyloid-beta complex validates design of the humanized antibody, and confirms the amyloid-beta epitope recognized by 3D6 as previously mapped by ELISA. CONCLUSIONS: The conformation of amyloid-beta antigen recognized by 3D6 is novel and distinct from other antibodies recognizing N terminal epitopes. Our result provides the first report demonstrating structural conservation of antigen contact residues, and conformation of antigen recognized, between the parent murine antibody and its humanized version. PMID- 25024749 TI - Cardiovascular medication burden in dementia disorders: a nationwide study of 19,743 dementia patients in the Swedish Dementia Registry. AB - INTRODUCTION: Administration of several cardiovascular drugs has an effect on dementia. We aimed to investigate whether there are differences in the use of cardiovascular medication between different dementia disorders. METHODS: We obtained information about dementia patients from the Swedish Dementia Registry. Patients were diagnosed with one of these dementia disorders: Alzheimer's disease (n = 8,139), mixed dementia (n = 5,203), vascular dementia (n = 4,982), Lewy body dementia (n = 605), frontotemporal dementia (n = 409) and Parkinson's disease dementia (n = 405). Multivariate logistic regression analysis was performed to investigate the association between use of cardiovascular medication and dementia disorders, after adjustment for age, gender, living alone, cognitive status and total number of drugs (a proxy for overall co-morbidity). RESULTS: Seventy percent of all the dementia patients used cardiovascular medication. Use of cardiovascular drugs is common in patients with vascular and mixed dementia. Male gender, higher age, slightly better cognitive status and living with another person was associated with use of cardiovascular medication. CONCLUSIONS: Cardiovascular medication is used extensively across dementia disorders and particularly in vascular and mixed dementia. Future research should investigate the tolerability and effectiveness of these drugs in the different dementia disorders. PMID- 25024750 TI - Alzheimer's disease drug-development pipeline: few candidates, frequent failures. AB - INTRODUCTION: Alzheimer's disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD. METHODS: We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline. RESULTS: During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure). CONCLUSIONS: The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support. PMID- 25024752 TI - Development and performance of electronic acute kidney injury triggers to identify pediatric patients at risk for nephrotoxic medication-associated harm. AB - BACKGROUND: Nephrotoxic medication-associated acute kidney injury (NTMx-AKI) is a costly clinical phenomenon and more common than previously recognized. Prior efforts to use technology to identify AKI have focused on detection after renal injury has occurred. OBJECTIVES: Describe an approach and provide a technical framework for the creation of risk-stratifying AKI triggers and the development of an application to manage the AKI trigger data. Report the performance characteristics of those triggers and the refinement process and on the challenges of implementation. METHODS: Initial manual trigger screening guided design of an automated electronic trigger report. A web-based application was designed to alleviate inefficiency and serve as a user interface and central workspace for the project. Performance of the NTMx exposure trigger reports from September 2011 to September 2013 were evaluated using sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). RESULTS: Automated reports were created to replace manual screening for NTMx-AKI. The initial performance of the NTMx exposure triggers for SN, SP, PPV, and NPV all were >=0.78, and increased over the study, with all four measures reaching >=0.95 consistently. A web-based application was implemented that simplifies data entry and couriering from the reports, expedites results viewing, and interfaces with an automated data visualization tool. Sociotechnical challenges were logged and reported. CONCLUSION: We have built a risk-stratifying system based on electronic triggers that detects patients at-risk for NTMx-AKI before injury occurs. The performance of the NTMx-exposed reports has neared 100% through iterative optimization. The complexity of the trigger logic and clinical workflows surrounding NTMx-AKI led to a challenging implementation, but one that has been successful from technical, clinical, and quality improvement standpoints. This report summarizes the construction of a trigger-based application, the performance of the triggers, and the challenges uncovered during the design, build, and implementation of the system. PMID- 25024751 TI - Impact of decitabine on immunohistochemistry expression of the putative tumor suppressor genes FHIT, WWOX, FUS1 and PTEN in clinical tumor samples. AB - BACKGROUND: Since tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) and phosphatase and tensin homolog (PTEN), immunohistochemistry scores from pre- and post-decitabine tumor biopsies (25 patients) were correlated with methylation of the long interspersed nuclear element-1 (LINE-1) repetitive DNA element (as a surrogate for global DNA methylation) and with tumor regression. RESULTS: With negative staining pre-decitabine (score = 0), the number of patients converting to positive staining post-decitabine was 1 of 1 for FHIT, 3 of 6 for WWOX, 2 of 3 for FUS1 and 1 of 10 for PTEN. In tumors with low pre-decitabine tumor suppressor gene scores (<=150), expression was higher post-treatment in 8 of 8 cases for FHIT (P = 0.014), 7 of 17 for WWOX (P = 0.0547), 7 of 12 for FUS1 (P = 0.0726), and 1 of 16 for PTEN (P = 0.2034). If FHIT, WWOX and FUS1 were considered together, median pre- versus post-decitabine scores were 60 versus 100 (P = 0.0002). Overall, tumor suppressor gene expression change did not correlate with LINE-1 demethylation, although tumors converting from negative to positive had a median decrease in LINE-1 methylation of 24%, compared to 6% in those not converting (P = 0.069). Five of 15 fully evaluable patients had reductions in tumor diameter (range 0.2% to 33.4%). Of these, three had simultaneous increases in three tumor suppressor genes (including the two patients with the greatest tumor regression) compared to 2 of 10 with tumor growth (P = 0.25). CONCLUSIONS: In tumors with low tumor suppressor gene expression, decitabine may be associated with increased expression of the tumor suppressor genes FHIT, FUS1, and WWOX, but not PTEN. PMID- 25024753 TI - Presenting multiple drug alerts in an ambulatory electronic prescribing system: a usability study of novel prototypes. AB - OBJECTIVE: This study explores alternative approaches to the display of drug alerts, and examines whether and how human-factors based interface design can be used to improve the prescriber's perception about drug alert presentation, signal detection from noisy alert data, and their comprehension of clinical decision support during electronic prescribing. METHODS: We reviewed issues with presenting multiple drug alerts in electronic prescribing systems. User-centered design, consisting of iterative usability and prototype testing was applied. After an iterative design phase, we proposed several novel drug alert presentation interfaces; expert evaluation and formal usability testing were applied to access physician prescribers' perceptions of the tools. We mapped drug alert attributes to different interface constructs. We examined four different interfaces for presenting multiple drug alerts. RESULTS: A TreeDashboard View was better perceived than a text-based ScrollText View with respect to the ability to detect critical information, the ability to accomplish tasks, and the perceptional efficacy of finding information. CONCLUSION: A robust model for studying multiple drug-alert presentations was developed. Several drug alert presentation interfaces were proposed. The TreeDashboard View was better perceived than the text-based ScrollText View in delivering multiple drug alerts during a simulation of electronic prescribing. PMID- 25024754 TI - Representation of information about family relatives as structured data in electronic health records. AB - BACKGROUND: The ability to manage and leverage family history information in the electronic health record (EHR) is crucial to delivering high-quality clinical care. OBJECTIVES: We aimed to evaluate existing standards in representing relative information, examine this information documented in EHRs, and develop a natural language processing (NLP) application to extract relative information from free-text clinical documents. METHODS: We reviewed a random sample of 100 admission notes and 100 discharge summaries of 198 patients, and also reviewed the structured entries for these patients in an EHR system's family history module. We investigated the two standards used by Stage 2 of Meaningful Use (SNOMED CT and HL7 Family History Standard) and identified coverage gaps of each standard in coding relative information. Finally, we evaluated the performance of the MTERMS NLP system in identifying relative information from free-text documents. RESULTS: The structure and content of SNOMED CT and HL7 for representing relative information are different in several ways. Both terminologies have high coverage to represent local relative concepts built in an ambulatory EHR system, but gaps in key concept coverage were detected; coverage rates for relative information in free-text clinical documents were 95.2% and 98.6%, respectively. Compared to structured entries, richer family history information was only available in free-text documents. Using a comprehensive lexicon that included concepts and terms of relative information from different sources, we expanded the MTERMS NLP system to extract and encode relative information in clinical documents and achieved a corresponding precision of 100% and recall of 97.4%. CONCLUSIONS: Comprehensive assessment and user guidance are critical to adopting standards into EHR systems in a meaningful way. A significant portion of patients' family history information is only documented in free-text clinical documents and NLP can be used to extract this information. PMID- 25024755 TI - Developing clinical decision support within a commercial electronic health record system to improve antimicrobial prescribing in the neonatal ICU. AB - OBJECTIVE: To develop and implement a clinical decision support (CDS) tool to improve antibiotic prescribing in neonatal intensive care units (NICUs) and to evaluate user acceptance of the CDS tool. METHODS: Following sociotechnical analysis of NICU prescribing processes, a CDS tool for empiric and targeted antimicrobial therapy for healthcare-associated infections (HAIs) was developed and incorporated into a commercial electronic health record (EHR) in two NICUs. User logs were reviewed and NICU prescribers were surveyed for their perceptions of the CDS tool. RESULTS: The CDS tool aggregated selected laboratory results, including culture results, to make treatment recommendations for common clinical scenarios. From July 2010 to May 2012, 1,303 CDS activations for 452 patients occurred representing 22% of patients prescribed antibiotics during this period. While NICU clinicians viewed two culture results per tool activation, prescribing recommendations were viewed during only 15% of activations. Most (63%) survey respondents were aware of the CDS tool, but fewer (37%) used it during their most recent NICU rotation. Respondents considered the most useful features to be summarized culture results (43%) and antibiotic recommendations (48%). DISCUSSION: During the study period, the CDS tool functionality was hindered by EHR upgrades, implementation of a new laboratory information system, and changes to antimicrobial testing methodologies. Loss of functionality may have reduced viewing antibiotic recommendations. In contrast, viewing culture results was frequently performed, likely because this feature was perceived as useful and functionality was preserved. CONCLUSION: To improve CDS tool visibility and usefulness, we recommend early user and information technology team involvement which would facilitate use and mitigate implementation challenges. PMID- 25024756 TI - Care everywhere, a point-to-point HIE tool: utilization and impact on patient care in the ED. AB - BACKGROUND: Emergency departments (EDs) routinely struggle with gaps in information when providing patient care. A point to point health information exchange (HIE) model has the potential to effectively fill those gaps. OBJECTIVE: To examine the utility, perceived and actual, of a point-to-point HIE tool called Care Everywhere (CE) and its impact on patient care in the ED. METHODS: This mixed methods study was performed at four large hospital EDs between January 2012 and November 2012. Retrospective data was extracted from the electronic health record (EHR) to evaluate CE utilization since implementation. ED notes data were extracted from ED visits occurring between January 2012 and June 2012 and were reviewed to evaluate the impact of exchanged information on patient care. RESULTS: Per focus group discussions, physicians thought the information received via CE was of value to patient care, particularly laboratory results, imaging, medication lists, discharge summaries and ECG interpretations. They feel the greatest impact of HIE is the avoidance of duplicative diagnostic testing and the identification of drug-seeking behavior. Nursing and ancillary staff expressed somewhat less enthusiasm but still felt HIE positively impacted patient care. Over a period of six months, CE was used in approximately 1.46% of ED encounters. A review of ED provider notes over that time period revealed CE use resulted in 560 duplicate diagnostic procedures being avoided and 28 cases of drug seeking behavior identified. CONCLUSION: Our study provides insight into the perceived value of HIE from the point of view of our ED physicians and staff. It also demonstrates that a point-to-point HIE tool such as Epic System's Care Everywhere has the potential to generate greater efficiencies within the ED and impact to patient care through elimination of duplicative diagnostic imaging or testing and resource utilization associated with those procedures. PMID- 25024757 TI - An analysis of free-text alcohol use documentation in the electronic health record: early findings and implications. AB - BACKGROUND: Alcohol use is a significant part of a patient's history, but details about consumption are not always documented. Electronic Health Record (EHR) systems have the potential to improve assessment of alcohol use and misuse; however, a challenge is that critical information may be documented primarily in free-text rather than in a structured and standardized format, thereby limiting its use. OBJECTIVE: To characterize the use and contents of free-text documentation for alcohol use in the social history module of an EHR. METHODS: This study involved a retrospective analysis of 500 alcohol use entries that include structured fields as well as a free-text comment field. Two coding schemes were developed and used to analyze these entries for: (1) quantifying the reasons for using free-text comments and (2) categorizing information in the free text into separate elements. In addition, for entries indicating possible alcohol misuse, a preliminary review of other structured parts of the EHR was conducted to determine if this was also documented elsewhere. RESULTS: The top three reasons for using free-text were limited ability to describe alcohol use frequency (75%), amount (22%), and status (18%) with available structured fields. Within the free-text, descriptions of frequency were most common (79%) using words or phrases conveying occasional (61%), daily (13%), or weekly (12%) use. Of the 36 cases suggesting alcohol misuse, 44% had mention of alcohol problems in the problem list or past medical history. CONCLUSIONS: BASED ON THE EARLY FINDINGS, IMPLICATIONS FOR IMPROVING THE STRUCTURED COLLECTION AND USE OF ALCOHOL USE INFORMATION IN THE EHR ARE PROVIDED IN FOUR AREAS: (1) system enhancements, (2) user training, (3) decision support, and (4) standards. Next steps include examining how alcohol use is documented in other parts of the EHR (e.g., clinical notes) and how documentation practices vary based on patient, provider, and clinic characteristics. PMID- 25024758 TI - Personal health records for patients with chronic disease: a major opportunity. AB - BACKGROUND: Personal health records (PHRs) connected to a physician's electronic health record system hold substantial promise for supporting and engaging patients with chronic disease. OBJECTIVES: To explore how U.S. health care organizations are currently utilizing PHRs for chronic disease populations. METHODS: A mixed methods study including semi-structured interviews and a questionnaire was conducted. A purposive sample was developed of health care organizations which were recognized as exemplars for PHRs and were high performers in national patient satisfaction surveys (H-CAHPS or CAHPS). Within each organization, participants were health IT leaders or those managing high risk or chronic disease populations. RESULTS: Interviews were conducted with 30 informants and completed questionnaires were received from 16 organizations (84% response rate). Most PHRs allowed patients to access health records and educational material, message their provider, renew prescriptions and request appointments. Patient generated data was increasingly being sought and combined with messaging, resulted in greater understanding of patient health and functioning outside of the clinic visit. However for chronic disease populations, there was little targeted involvement in PHR design and few tools to help interpret and manage their conditions beyond those offered for all. The PHR was largely uncoupled from high risk population management interventions and no clear framework for future PHR development emerged. CONCLUSION: This technology is currently underutilized and represents a major opportunity given the potential benefits of patient engagement and shared decision making. A coherent patient centric PHR design and evaluation strategy is required to realize its potential and maximize this natural hub for multidisciplinary care co-ordination. PMID- 25024759 TI - What do physicians read (and ignore) in electronic progress notes? AB - OBJECTIVE: Several studies have documented the preference for physicians to attend to the impression and plan section of a clinical document. However, it is not clear how much attention other sections of a document receive. The goal of this study was to identify how physicians distribute their visual attention while reading electronic notes. METHODS: We used an eye-tracking device to assess the visual attention patterns of ten hospitalists as they read three electronic notes. The assessment included time spent reading specific sections of a note as well as rates of reading. This visual analysis was compared with the content of simulated verbal handoffs for each note and debriefing interviews. RESULTS: Study participants spent the most time in the "Impression and Plan" section of electronic notes and read this section very slowly. Sections such as the "Medication Profile", "Vital Signs" and "Laboratory Results" received less attention and were read very quickly even if they contained more content than the impression and plan. Only 9% of the content of physicians' verbal handoff was found outside of the "Impression and Plan." CONCLUSION: Physicians in this study directed very little attention to medication lists, vital signs or laboratory results compared with the impression and plan section of electronic notes. Optimizing the design of electronic notes may include rethinking the amount and format of imported patient data as this data appears to largely be ignored. PMID- 25024760 TI - Impact of homecare electronic health record on timeliness of clinical documentation, reimbursement, and patient outcomes. AB - BACKGROUND: Homecare is an important and effective way of managing chronic illnesses using skilled nursing care in the home. Unlike hospitals and ambulatory settings, clinicians visit patients at home at different times, independent of each other. Twenty-nine percent of 10,000 homecare agencies in the United States have adopted point-of-care EHRs. Yet, relatively little is known about the growing use of homecare EHRs. OBJECTIVE: Researchers compared workflow, financial billing, and patient outcomes before and after implementation to evaluate the impact of a homecare point-of-care EHR. METHODS: The design was a pre/post observational study embedded in a mixed methods study. The setting was a Philadelphia-based homecare agency with 137 clinicians. Data sources included: (1) clinician EHR documentation completion; (2) EHR usage data; (3) Medicare billing data; (4) an EHR Nurse Satisfaction survey; (5) clinician observations; (6) clinician interviews; and (7) patient outcomes. RESULTS: Clinicians were satisfied with documentation timeliness and team communication. Following EHR implementation, 90% of notes were completed within the 1-day compliance interval (n = 56,702) compared with 30% of notes completed within the 7-day compliance interval in the pre-implementation period (n = 14,563; OR 19, p <. 001). Productivity in the number of clinical notes documented post-implementation increased almost 10-fold compared to pre-implementation. Days to Medicare claims fell from 100 days pre-implementation to 30 days post-implementation, while the census rose. EHR implementation impact on patient outcomes was limited to some behavioral outcomes. DISCUSSION: Findings from this homecare EHR study indicated clinician EHR use enabled a sustained increase in productivity of note completion, as well as timeliness of documentation and billing for reimbursement with limited impact on improving patient outcomes. As EHR adoption increases to better meet the needs of the growing population of older people with chronic health conditions, these results can inform homecare EHR development and implementation. PMID- 25024761 TI - A distribution-based method for assessing the differences between clinical trial target populations and patient populations in electronic health records. AB - OBJECTIVE: To improve the transparency of clinical trial generalizability and to illustrate the method using Type 2 diabetes as an example. METHODS: Our data included 1,761 diabetes clinical trials and the electronic health records (EHR) of 26,120 patients with Type 2 diabetes who visited Columbia University Medical Center of New-York Presbyterian Hospital. The two populations were compared using the Generalizability Index for Study Traits (GIST) on the earliest diagnosis age and the mean hemoglobin A1c (HbA1c) values. RESULTS: Greater than 70% of Type 2 diabetes studies allow patients with HbA1c measures between 7 and 10.5, but less than 40% of studies allow HbA1c<7 and fewer than 45% of studies allow HbA1c>10.5. In the real-world population, only 38% of patients had HbA1c between 7 and 10.5, with 12% having values above the range and 52% having HbA1c<7. The GIST for HbA1c was 0.51. Most studies adopted broad age value ranges, with the most common restrictions excluding patients >80 or <18 years. Most of the real-world population fell within this range, but 2% of patients were <18 at time of first diagnosis and 8% were >80. The GIST for age was 0.75. CONCLUSIONS: We contribute a scalable method to profile and compare aggregated clinical trial target populations with EHR patient populations. We demonstrate that Type 2 diabetes studies are more generalizable with regard to age than they are with regard to HbA1c. We found that the generalizability of age increased from Phase 1 to Phase 3 while the generalizability of HbA1c decreased during those same phases. This method can generalize to other medical conditions and other continuous or binary variables. We envision the potential use of EHR data for examining the generalizability of clinical trials and for defining population-representative clinical trial eligibility criteria. PMID- 25024762 TI - Relationship between documentation method and quality of chronic disease visit notes. AB - OBJECTIVE: To assses the relationship between methods of documenting visit notes and note quality for primary care providers (PCPs) and specialists, and to determine the factors that contribute to higher quality notes for two chronic diseases. METHODS: Retrospective chart review of visit notes at two academic medical centers. Two physicians rated the subjective quality of content areas of the note (vital signs, medications, lifestyle, labs, symptoms, assessment & plan), overall quality, and completed the 9 item Physician Documentation Quality Instrument (PDQI-9). We evaluated quality ratings in relation to the primary method of documentation (templates, free-form or dictation) for both PCPs and specialists. A one factor analysis of variance test was used to examine differences in mean quality scores among the methods. RESULTS: A total of 112 physicians, 71 primary care physicians (PCP) and 41 specialists, wrote 240 notes. For specialists, templated notes had the highest overall quality scores (p<=0.001) while for PCPs, there was no statistically significant difference in overall quality score. For PCPs, free form received higher quality ratings on vital signs (p = 0.01), labs (p = 0.002), and lifestyle (p = 0.002) than other methods; templated notes had a higher rating on medications (p<=0.001). For specialists, templated notes received higher ratings on vital signs, labs, lifestyle and medications (p = 0.001). DISCUSSION: There was no significant difference in subjective quality of visit notes written using free-form documentation, dictation or templates for PCPs. The subjective quality rating of templated notes was higher than that of dictated notes for specialists. CONCLUSION: As there is wide variation in physician documentation methods, and no significant difference in note quality between methods, recommending one approach for all physicians may not deliver optimal results. PMID- 25024763 TI - Investigation of The Omaha System for dentistry. AB - OBJECTIVE: Today, dentists and hygienists have inadequate tools to identify contributing factors to dental disease, diagnosis of disease or to document outcomes in a standardized and machine readable format. Increasing demand to find the most effective care methodologies make the development of further terminologies for dentistry more urgent. Preventive care is the focus of early efforts to define best practices. We reviewed one possibility with a history of public health documentation that might assist in these early efforts at identifying best practices. METHODS: This paper examines, through a survey of dentists, the Omaha System Problem Classification Scheme. The survey requested that dentists rate the usefulness of knowing about specific signs and symptoms for each of the 42 problems within the Problem list of the Omaha System. RESULTS: Using a weighted scoring system, 22 of the 42 problems received over 50% of the possible maximum score and 30 of the 42 problems received at least 25% of the possible points. CONCLUSION: These findings suggests that further evaluation of The Omaha System, may be useful to dentistry. At a minimum, the survey provides additional information about non-physiological problems, signs, and symptoms that may be appropriate for documentation purposes within an electronic health record (EHR) used in dentistry. PMID- 25024764 TI - Telemonitoring of patients with Parkinson's disease using inertia sensors. AB - BACKGROUND: Medical treatment in patients suffering from Parkinson's disease is very difficult as dose-finding is mainly based on selective and subjective impressions by the physician. OBJECTIVES: To allow for the objective evaluation of patients' symptoms required for optimal dosefinding, a telemonitoring system tracks the motion of patients in their surroundings. The system focuses on providing interoperability and usability in order to ensure high acceptance. METHODS: Patients wear inertia sensors and perform standardized motor tasks. Data are recorded, processed and then presented to the physician in a 3D animated form. In addition, the same data is rated based on the UPDRS score. Interoperability is realized by developing the system in compliance with the recommendations of the Continua Health Alliance. Detailed requirements analysis and continuous collaboration with respective user groups help to achieve high usability. RESULTS: A sensor platform was developed that is capable of measuring acceleration and angular rate of motions as well as the absolute orientation of the device itself through an included compass sensor. The system architecture was designed and required infrastructure, and essential parts of the communication between the system components were implemented following Continua guidelines. Moreover, preliminary data analysis based on three-dimensional acceleration and angular rate data could be established. CONCLUSION: A prototype system for the telemonitoring of Parkinson's disease patients was successfully developed. The developed sensor platform fully satisfies the needs of monitoring patients of Parkinson's disease and is comparable to other sensor platforms, although these sensor platforms have yet to be tested rigorously against each other. Suitable approaches to provide interoperability and usability were identified and realized and remain to be tested in the field. PMID- 25024765 TI - Structuring clinical workflows for diabetes care: an overview of the OntoHealth approach. AB - BACKGROUND: Electronic health records (EHRs) play an important role in the treatment of chronic diseases such as diabetes mellitus. Although the interoperability and selected functionality of EHRs are already addressed by a number of standards and best practices, such as IHE or HL7, the majority of these systems are still monolithic from a user-functionality perspective. The purpose of the OntoHealth project is to foster a functionally flexible, standards-based use of EHRs to support clinical routine task execution by means of workflow patterns and to shift the present EHR usage to a more comprehensive integration concerning complete clinical workflows. OBJECTIVES: The goal of this paper is, first, to introduce the basic architecture of the proposed OntoHealth project and, second, to present selected functional needs and a functional categorization regarding workflow-based interactions with EHRs in the domain of diabetes. METHODS: A systematic literature review regarding attributes of workflows in the domain of diabetes was conducted. Eligible references were gathered and analyzed using a qualitative content analysis. Subsequently, a functional workflow categorization was derived from diabetes-specific raw data together with existing general workflow patterns. RESULTS: This paper presents the design of the architecture as well as a categorization model which makes it possible to describe the components or building blocks within clinical workflows. The results of our study lead us to identify basic building blocks, named as actions, decisions, and data elements, which allow the composition of clinical workflows within five identified contexts. CONCLUSIONS: The categorization model allows for a description of the components or building blocks of clinical workflows from a functional view. PMID- 25024766 TI - Crucial factors for the acceptance of a computerized national medication list: insights into findings from the evaluation of the Austrian e-Medikation pilot. AB - OBJECTIVE: The objective of this paper is to present crucial factors among registered doctors and pharmacists for acceptance of the Austrian 'e-Medikation' system which is aimed at providing, on a national level, complete and recent information on all the medication that were prescribed or dispensed to a patient. METHODS: As the accompanying formative evaluation study of the pilot project showed different overall acceptance rates among participating physicians and pharmacists, a decision tree analysis of 30 standardized survey items was performed to identify crucial acceptance factors. RESULTS: For the physicians' group, only two items (fear of improper data use and satisfaction with software support) were crucial for overall e-Medikation acceptance. The analysis of the pharmacists' data resulted in five crucial factors primarily focusing on functional aspects and the perceived benefits of e-Medikation. CONCLUSION: The results indicate that the acceptance among physicians and pharmacists depends on quite different factors. This must be taken into account during the planned rollout of e-Medikation or of comparable products. PMID- 25024767 TI - A proposal for an Austrian Nursing Minimum Data Set (NMDS): a Delphi study. AB - OBJECTIVE: Nursing Minimum Data Sets can be used to compare nursing care across clinical populations, settings, geographical areas, and time. NMDS can support nursing research, nursing management, and nursing politics. However, in contrast to other countries, Austria does not have a unified NMDS. The objective of this study is to identify possible data elements for an Austrian NMDS. METHODS: A two round Delphi survey was conducted, based on a review of available NMDS, 22 expert interviews, and a focus group discussion. RESULTS: After reaching consensus, the experts proposed the following 56 data elements for an NMDS: six data elements concerning patient demographics, four data elements concerning data of the healthcare institution, four data elements concerning patient's medical condition, 20 data elements concerning patient problems (nursing assessment, nursing diagnoses, risk assessment), eight data elements concerning nursing outcomes, 14 data elements concerning nursing interventions, and no additional data elements concerning nursing intensity. CONCLUSION: The proposed NMDS focuses on the long-term and acute care setting. It must now be implemented and tested in the nursing practice. PMID- 25024768 TI - A toolbox to improve algorithms for insulin-dosing decision support. AB - BACKGROUND: Standardized insulin order sets for subcutaneous basal-bolus insulin therapy are recommended by clinical guidelines for the inpatient management of diabetes. The algorithm based GlucoTab system electronically assists health care personnel by supporting clinical workflow and providing insulin-dose suggestions. OBJECTIVE: To develop a toolbox for improving clinical decision-support algorithms. METHODS: The toolbox has three main components. 1) Data preparation: Data from several heterogeneous sources is extracted, cleaned and stored in a uniform data format. 2) Simulation: The effects of algorithm modifications are estimated by simulating treatment workflows based on real data from clinical trials. 3) ANALYSIS: Algorithm performance is measured, analyzed and simulated by using data from three clinical trials with a total of 166 patients. RESULTS: Use of the toolbox led to algorithm improvements as well as the detection of potential individualized subgroup-specific algorithms. CONCLUSION: These results are a first step towards individualized algorithm modifications for specific patient subgroups. PMID- 25024769 TI - Development and validation of a computer-based algorithm to identify foreign-born patients with HIV infection from the electronic medical record. AB - OBJECTIVE: To develop and validate an efficient and accurate method to identify foreign-born patients from a large patient data registry in order to facilitate population-based health outcomes research. METHODS: We developed a three-stage algorithm for classifying foreign-born status in HIV-infected patients receiving care in a large US healthcare system (January 1, 2001-March 31, 2012) (n = 9,114). In stage 1, we classified those coded as non-English language speaking as foreign-born. In stage 2, we searched free text electronic medical record (EMR) notes of remaining patients for keywords associated with place of birth and language spoken. Patients without keywords were classified as US-born. In stage 3, we retrieved and reviewed a 50-character text window around the keyword (i.e. token) for the remaining patients. To validate the algorithm, we performed a chart review and asked all HIV physicians (n = 37) to classify their patients (n = 957).We calculated algorithm sensitivity and specificity. RESULTS: We excluded 160/957 because physicians indicated the patient was not HIV-infected (n = 54), "not my patient" (n = 103), or had unknown place of birth (n = 3), leaving 797 for analysis. In stage 1, providers agreed that 71/95 foreign language speakers were foreign-born. Most disagreements (23/24) involved patients born in Puerto Rico. In stage 2, 49/50 patients without keywords were classified as US-born by chart review. In stage 3, token review correctly classified 55/60 patients (92%), with 93% (CI: 84.4, 100%) sensitivity and 90% (CI: 74.3, 100%) specificity compared with full chart review. After application of the three-stage algorithm, 2,102/9,114 (23%) patients were classified as foreign-born. When compared against physician response, estimated sensitivity of the algorithm was 94% (CI: 90.9, 97.2%) and specificity 92% (CI: 89.7, 94.1%), with 92% correctly classified. CONCLUSION: A computer-based algorithm classified foreign-born status in a large HIV-infected cohort efficiently and accurately. This approach can be used to improve EMR-based outcomes research. PMID- 25024770 TI - Evaluation of a Korean version of a tool for assessing the incorporation of human factors into a medication-related decision support system: the I-MeDeSA. AB - OBJECTIVE: The Instrument for Evaluating Human-Factor Principles in Medication Related Decision Support Alerts (I-MeDeSA) was developed recently in the US with a view towards improving considerations of human-factor principles when designing alerts for clinical decision support (CDS) systems. This study evaluated the generalizability of this tool, in cooperation with its authors, across cultures by applying it to a Korean system. We also examined opportunities to promote user acceptance of the system. METHODS: We developed a Korean version of the I-MeDeSA (K-I-MeDeSA) and used it to evaluate drug-drug interaction alerts in a large academic tertiary hospital in Seoul. We involved four reviewers (A, B, C, and D). Two (A and B) conducted the initial independent scoring, while the other two (C and D) performed a final review and assessed feedback from the initial reviewers. The obtained scores were compared with those from 13 previously reported CDS systems. The feedback was summarized qualitatively. RESULTS: The translation of the I-MeDeSA had excellent interrater agreement in terms of face validity (scale level content validity index = 0.95). The system's K-I-MeDeSA score was 10 out of 26, with a good agreement between reviewers (kappa = 0.77), which showed a lack of human-factor considerations. The reviewers readily identified two of the nine principles that needed primary improvement: prioritization and text-based information. The reviewers also expressed difficulty judging the following four principles: alarm philosophy, visibility, color, and learnability and confusability. CONCLUSION: The K-I-MeDeSA was semantically and operationally equivalent to the original tool. Only minor cultural problems were identified, leading the reviewers to suggest the need for clarification of certain words plus a more detailed description of the tool's rationale and exemplars. Further evaluation is needed to empirically assess whether the implementation of changes in an electronic health record system could improve the adoption of CDS alerts. PMID- 25024771 TI - Death, taxes and advance directives. AB - Suboptimal care at the end-of-life can be due to lack of access or knowledge of patient wishes. Ambiguity is often the result of non-standardized formats. Borrowing digital technology from other industries and using existing health information infrastructure can greatly improve the completion, storage, and distribution of advance directives. We believe several simple, low-cost adaptations to regional and federal programs can raise the standard of end-of life care. PMID- 25024772 TI - State funding for health information technology and selected ambulatory healthcare quality measures. AB - BACKGROUND: Previous studies on the effects of health information technology (health IT) on ambulatory quality have had mixed results. New York State has invested heavily in health IT throughout the State, creating a unique opportunity to assess effects on health care quality across multiple communities. OBJECTIVE: To determine any association between primary care providers' receipt of funding from New York State's Healthcare Efficiency and Affordability Law for New Yorkers Program (HEAL NY) and ambulatory quality of care. METHODS: A statewide, longitudinal cohort study of primary care physicians in New York State was conducted. Data regarding which primary care physicians received funding through the HEAL NY program (Phase 5 or Phase 10) in 2008 or 2009 were obtained from the New York State Department of Health. Health care quality in 2010 was measured using claims data that had been aggregated across 7 commercial health plans across the state. Physicians were divided into 2 groups, based on receipt of HEAL funding (yes/no). Any association was measured between study group and each of 7 quality measures, all of which appear in the Stage 1 federal Meaningful Use program. Negative binomial regression was used, adjusting for provider gender and specialty. RESULTS: The study included 3,988 primary care providers, of whom 863 (22%) had received HEAL NY funding. The HEAL-funded physicians provided higher quality of care on 5 of the 7 measures: breast cancer screening, eye exams in patients with diabetes, nephropathy screening in patients with diabetes, influenza vaccination and pneumococcal vaccination (p<0.0001 for all adjusted comparisons). The HEAL-funded group provided higher quality of care by an absolute 2 to 6 percentage points per measure for those 5 measures. CONCLUSION: Primary care physicians who received state funding for health IT provided higher quality of care than those who did not receive such funding. PMID- 25024773 TI - Hypertensive emergency and type 2 myocardial infarction resulting from pheochromocytoma and concurrent capnocytophaga canimorsus infection. AB - A diagnosis of myocardial infarction is made using a combination of clinical presentation, electrocardiogram and cardiac biomarkers. However, myocardial infarction can be caused by factors other than coronary artery plaque rupture and thrombosis. We describe an interesting case presenting with hypertensive emergency and type 2 myocardial infarction resulting from Pheochromocytoma associated with Capnocytophaga canimorsus infection from a dog bite. We also review current literature on the management of hypertensive emergency and Pheochromocytoma. PMID- 25024774 TI - Quality of diabetes care in primary health centres in north Al-batinah of oman. AB - OBJECTIVE: To assess the quality of diabetic care provided in primary health care settings in Oman. METHODS: This was a cross-sectional study of randomly selected 500 patients with diabetes mellitus (DM) attending 6 primary care diabetic clinics in the north Al-Batinah region of Oman from January to December 2010. Nine standards on the quality of diabetes care were audited. RESULTS: The mean age of the sample was 51+/-13 years, ranging from 15 to 87 years; the majority (61%) were females. The mean duration of DM was 4+/-3 years, ranging from 1 to 18 years. Seventy-seven percent of the patients attended diabetic clinics at least 4 times per year. Of the 9 assessed diabetic standards, HbA1c was documented in 33% of the patients, body mass index in 12%, low-density lipoprotein cholesterol (LDL C) in 40%, urinary albumin:creatinine ratio in 28%, creatinine in 63% and blood pressure (BP) in 96%. Optimal control among the documented indicators was noted in 32, 21, 25, 85, 95 and 19%, respectively. Twenty percent of the patients had their ECGs done while only 39% of the patients had foot examination. No patient had attained control in all of HbA1c., BP and LDL-C. CONCLUSION: There is a gap between the recommended DM care guidelines and current practice with consequent poor quality of care in these patients. PMID- 25024775 TI - Leg ulcers in antiphospholipid syndrome secondary to systemic lupus erythematosus treated with intravenous immunoglobulin. AB - BACKGROUND: Despite encouraging reports on the efficacy of intravenous immunoglobulin (IVIg) in antiphospholipid syndrome, the clinical value of this treatment is not well established, and most of the data are based on case reports and small series of patients. OBSERVATION: We describe the significant improvement of leg ulcers with IVIg in a 61-year-old female, with diabetes mellitus, venous peripherical insufficiency and secondary antiphospholipid syndrome to systemic lupus erythematosus. CONCLUSIONS: This case illustrates a rare cause of leg ulcers and documents that IVIg may be an effective adjuvant treatment in the management of selected patients with antiphospholipid syndrome when conventional strategies using subcutaneous heparin and low-dose aspirin are insufficient. PMID- 25024776 TI - Pustular psoriasis complicated with acute generalized exanthematous pustulosis. AB - BACKGROUND: Pustular psoriasis of the digits (acrodermatitis continua of Hallopeau) may be localized to one or more digits for over an extended period of time. Characteristic presentation is that of tender, diffusely eroded, and fissured pustular plaques on one or more digits. Transition to other forms of psoriasis and to generalized pustular psoriasis is known to occur. These patients have an increased risk of acute generalized exanthematous pustulosis (AGEP) compared to the general population. Pustular psoriasis is often therapy resistant. MAIN OBSERVATIONS: We report the case of a 54-year-old Caucasian woman who presented with a pustular psoriasis flare complicated by AGEP. Treatment course included hospital admission, cyclosporine, acitretin, and discontinuation of cephalexin. CONCLUSION: The precipitating factor in the course of treatment is thought to be cephalexin. When treating patients with pustular psoriasis the occurrence of druginduced complications should be carefully examined. Our case suggests that avoidance of beta-lactam antibiotics in these patients is warranted unless absolutely indicated. PMID- 25024777 TI - Secondary cutaneous marginal zone B-cell lymphoma presenting as lipoatrophy in a patient with hepatitis C. AB - BACKGROUND: Hepatitis C viral infection is a significant public health problem; 170 million persons are infected worldwide and the prevalence in the southern part of the United States exceeds two percent. Extrahepatic manifestations of hepatitis C viral infection are common; notably, 15-20% of patients will develop cutaneous manifestations of their disease. There are numerous dermatologic diseases associated with hepatitis C infection, including lichen planus, leukocytoclasticvasculitis, and porphyria cutaneatarda. MAIN OBSERVATION: Recently, epidemiological studies have also demonstrated an association between hepatitis C infection and the development of non-Hodgkin lymphoma, especially marginal zone B-cell lymphoma. Herein we report the unusual case of a systemic marginal zone lymphoma in a patient with hepatitis C infection presenting clinically as localized lipoatrophy. CONCLUSIONS: Lipoatrophy can be a rare and diagnostically challenging presentation of secondary cutaneous marginal zone B cell lymphoma. The importance of early recognition and detection cannot be over emphasized, as new and effective anti-viral treatments can lead to lymphoma regression in up to 75% of patients. To our knowledge, this is the first case of hepatitis C viral infection associated marginal zone lymphoma to present as localized lipoatrophy. PMID- 25024778 TI - Enlarged, painful cervical and axillary lymph nodes in chronic paracoccidioidomycosis. AB - BACKGROUND: Paracoccidioidomycosis is an important medical and social problem mainly in rural areas of Brazil, because of the high incidence of the diseases, its long clinical evolution, frequent recurrences and sequels leading to anatomical and functional incapacities. MAIN OBSERVATION: We present a 73-year old patient with paracoccidioidomycosis showing significant lymph node manifestations, which are only common in children and teenagers. CONCLUSIONS: Paracoccidioidomycosis may have a long incubation period, and it can be diagnosed outside of the endemic regions, where it was acquired. Thus, all dermatologists should maintain a high index of suspicion, especially in unusual cases of extensive lymph node enlargement in the elderly patients. PMID- 25024779 TI - Pemphigus vulgaris localized to the tongue. AB - BACKGROUND: Pemphigus vulgaris is an autoimmune blistering disease that may initially present as localized lesions. It rarely remains localized throughout its clinical course. OBSERVATIONS: A 53-year-old woman with non-progressive pemphigus vulgaris localized to the tongue for 18 years is presented. Clinical examination showed erosions and ulcerations limited to the lateral margins of the tongue. Patient was treated with sublesional triamcinolone-acetonide injections as lesions recurred. Finally, triamcinolone- acetonide injections at three weeks intervals for three months induced a longterm sustained clinical remission for 18 months. The indirect immunofluorescence did not correlate with disease activity. Anti-desmoglein 3 antibodies (ELISA) remained elevated throughout the clinical course and during remission. CONCLUSIONS: This case highlights the recognition of localized pemphigus vulgaris and demonstrates the importance of local therapy and its potential to induce longterm remission. Similar report of additional cases may create a standard of care for non-progressive, localized pemphigus. PMID- 25024781 TI - Canadian Urological Association - Association des urologues du Canada 69(th) Annual Meeting - St. John's, NL - June 28-July 1, 2014. PMID- 25024780 TI - Photoletter to the editor: A neurocutaneous rarity: phacomatosis pigmentokeratotica. AB - Phacomatosis pigmentokeratotica is characterized by the coexistence of nevus sebaceus, papular nevus spilus and associated neurologic abnormalities. We report a case of phacomatosis pigmentokeratotica in a 28-year-old male who presented with palmar-plantar dysesthesia and ipsilateral brain hemiatrophy. As a characteristic neuroimaging finding of the disorder, we found multiple hypointense lesions involving the ipsilateral hemisphere. PMID- 25024782 TI - A roadmap to the future. PMID- 25024783 TI - Good servants, poor masters. PMID- 25024784 TI - Royal College surgical objectives of urologic training: A survey of faculty members from Canadian training programs. AB - INTRODUCTION: According to the Royal College objectives of training in urology, urologic surgical procedures are divided as category A, B and C. We wanted to determine the level of proficiency required and achieved by urology training faculty for Royal College accreditation. METHODS: We conducted a survey that was sent electronically to all Canadian urology training faculty. Questions focused on demographics (i.e., years of practice, geographic location, subspecialty, access to robotic surgery), operating room contact with residents, opinion on the level of proficiency required from a list of 54 surgical procedures, and whether their most recent graduates attained category A proficiency in these procedures. RESULTS: The response rate was 43.7% (95/217). Among respondents, 92.6% were full timers, 21.1% practiced urology for less than 5 years and 3.2% for more than 30 years. Responses from Quebec and Ontario formed 69.4% (34.7% each). Of the respondents, 37.9% were uro-oncologists and 75.7% reported having access to robotic surgery. Sixty percent of faculty members operate with R5 residents between 2 to 5 days per month. When respondents were asked which categories should be listed as category A, only 8 procedures received 100% agreement. Also, results varied significantly when analyzed by sub-specialty. For example, almost 50% or more of uro-oncologists believed that radical cystectomy, anterior pelvic exenteration and extended pelvic lymphadenectomy should not be category A. The following procedures had significant disagreement suggesting the need for re classification: glanular hypospadias repair, boari flap, entero-vesical and vesicovaginal fistulae repair. Overall, more than 80% of faculty reported that their recent graduating residents had achieved category A proficiency, in a subset of procedures. However, more than 50% of all faculty either disagreed or were ambivalent that all of their graduating residents were Category A proficient in several procedures. CONCLUSIONS: There is sufficient disagreement among Canadian urology faculty to suggest another revision of the current Royal College list of category A procedures. PMID- 25024785 TI - The trouble with technical competence: Defining it, measuring it and achieving it! PMID- 25024786 TI - Double anticholinergic therapy for refractory neurogenic and nonneurogenic detrusor overactivity in children: Long-term results of a prospective open-label study. AB - INTRODUCTION: In this study, we optimize pharmacotherapy in children who failed anticholinergic monotherapy by simultaneous administration of 2 anticholinergics (oxybutynin and/or tolterodine and/or solifenacin). METHODS: This report is an update of our previously published study on double anticholinergic regimen in children with refractory incontinence due to neurogenic (NDO) and non-neurogenic (DO) detrusor overactivity. Patients with an insufficient response (clinically/urodynamically) to an optimized dose of a single anticholinergic (oxybutynin or tolterodine) received a second anticholinergic (tolterodine or solifenacin), in addition to the pre-existing medication. The primary end-point was efficacy (continence) and the secondary end-points were tolerability and safety. The Patient Perception of Bladder Condition (PPBC) scale was used to rate subjective improvement of patients. RESULTS: In total, 56 patients with DO (n = 31) or NDO (n = 25) were enrolled at a mean age of 11.4 +/- 3.5 years and were followed for a minimum of 3 months. The duration of double treatment was 36 +/- 23 months. Our results found that 23 patients became dry, 18 improved significantly and 15 improved moderately. Urodynamic capacity improved from 158 +/- 87 mL to 359 +/- 148 mL and maximal pressure of contractions decreased from 76 +/- 24 to 22 +/- 22 cmH2O (p < 0.0001). The overall success rate was 82%, since 10 patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 28 patients, mild side effects by 20, moderate side effects by 8; 2 patients withdrew from the study due to their side effects. Of the 35 patients who voided spontaneously, 8 developed post-void residuals (>20%). CONCLUSIONS: With a larger cohort and prospective follow-up, we reiterated that double anticholinergic regimen in children with DO or NDO refractory to anticholinergic monotherapy is a feasible and efficient approach. PMID- 25024787 TI - Opening the door to new therapeutic options with open label studies for children with detrusor overactivity. PMID- 25024788 TI - Surgeon-specific factors affecting treatment decisions among Canadian urologists in the management of pT1a renal tumours. AB - INTRODUCTION: The ubiquitous use of diagnostic imaging has resulted in an increased incidental detection of small renal masses (SRM). Patient- and tumour related factors affect treatment decisions greatly; however, with multiple treatment options available, surgeon-specific characteristics and biases may also influence treatment recommendations. We determine the impact of surgeon-specific factors on treatment decisions in the management of SRM in Canada. METHODS: An online survey study was conducted among Canadian urologists currently registered with the Canadian Urological Association. The questionnaire collected demographic information and recommended treatments for 6 SRM index cases involving theoretical patients of various ages (51-80 years) and comorbidities. RESULTS: A total of 110 urologists responded (17% response rate) to the survey. Of these, 18% were over 65 years old and 45% were from academic centres. With increasing patient age and comorbidity, active surveillance and thermal ablative therapies were more the recommended treatment. Laparoscopic/robotic surgery was more commonly recommended by academic urologists and those under 65. Recommending surgery (radical nephrectomy or partial nephrectomy) for both elderly (about 80 years old) index patients correlated with surgeon age (surgeons over 65, p < 0.001), surgeons with no oncologic fellowship training (p = 0.021), surgeons with a non-academic practice (p = 0.003), surgeons with a personal history of cancer (p = 0.038) and surgeons with a family history of cancer death in the last 10 years (p = 0.022). CONCLUSIONS: There are various factors that influence the management options offered to patients with SRMs. Our results suggest that surgeon age, personal history of cancer, practice-type and other surgeon-specific variables may affect treatments offered among urologists across Canada. PMID- 25024789 TI - Kidney cancer survivorship survey of urologists and survivors: The gap in perceptions of care, but agreement on needs. AB - INTRODUCTION: There is lack of evidence-based literature addressing comprehensive long-term care for kidney cancer (KC) survivors. Additionally, it is unclear if the concerns of KC patients/caregivers are being adequately addressed. Therefore, Kidney Cancer Canada, a patient-led support organization for Canadians with KC, commissioned this first recorded survivorship survey specific to KC patients/caregivers. METHODS: We conducted a cross-sectional online survey of Canadian patients/caregivers diagnosed with localized KC, and a separate parallel survey of Canadian urologists. The primary objectives were to assess patient/caregivers' and urologists' perceptions of information provided, as well as the physical/psychological/emotional impact of KC treatment. RESULTS: Urologists recalled providing information about surgical complications (90%) and their management (63%), while patients/caregiver recalled much less (33% and 35%). Of the urologists, 93% recalled providing information on cancer recurrence, but only 42% of patients/caregivers remembered receiving this information. Concerns identified by patients/caregivers and urologists were similar: fear of recurrence, concerns about cancer, fatigue, and anxiety. Importantly, all agreed that survivorship information was paramount. Education of both patients/caregivers and physicians and the development of guidelines were factors identified to ensure optimal KC survivorship. Study limitations include potential biases in recall and selection of participants. CONCLUSION: There was some discordance between urologists' and patients/caregivers' rates of recall of information provided. Patients/caregivers would have desired more information about their cancer, long-term follow-up, and potential complications. A survivorship care plan (SCP) tailored to KC may be an effective measure to address these needs. The impact of this SCP on survivor outcomes should be rigorously assessed. PMID- 25024790 TI - Oncological and functional outcomes of 722 robot-assisted radical prostatectomy (RARP) cases: The largest Canadian 5-year experience. AB - INTRODUCTION: While RARP (robotic-assisted radical prostatectomy) has become the predominant surgical approach to treat localized prostate cancer, there is little Canadian data on its oncological and functional outcomes. We describe the largest RARP experience in Canada. METHODS: Data from 722 patients who underwent RARP performed by 7 surgeons (AEH performed 288, TH 69, JBL 23, SB 17, HW 15, QT 7, and KCZ 303 patients) were collected prospectively from October 2006 to December 2013. Preoperative characteristics, as well as postoperative surgical and pathological outcomes, were collected. Functional and oncological outcomes were also assessed up to 72 months postoperative. RESULTS: The median follow-up (Q1 Q3) was 18 months (9-36). The D'Amico risk stratification distribution was 31% low, 58% intermediate and 11% high-risk. The median operative time was 178 minutes (142-205), blood loss was 200 mL (150-300) and the postoperative hospital stay was 1 day (1-23). The transfusion rate was only 1.0%. There were 0.7% major (Clavien III-IV) and 10.1% minor (Clavien I-II) postoperative complications, with no mortality. Pathologically, 445 men (70%) were stage pT2, of which 81 (18%) had a positive surgical margin (PSM). In addition, 189 patients (30%) were stage pT3 and 87 (46%) with PSM. Urinary continence (0-pads/day) returned at 3, 6, and 12 months for 68%, 80%, and 90% of patients, respectively. Overall, the potency rates (successful penetration) for all men at 6, 12, and 24 months were 37%, 52%, and 59%, respectively. Biochemical recurrence was observed in 28 patients (4.9%), and 14 patients (2.4%) were referred for early salvage radiotherapy. In total, 49 patients (8.4%) underwent radio-therapy and/or hormonal therapy. CONCLUSIONS: This study shows similar results compared to other high-volume RARP programs. Being the largest RARP experience in Canada, we report that RARP is safe with acceptable oncologic outcomes in a Canadian setting. PMID- 25024791 TI - Incontinence after radical prostatectomy: Anything new in its management? AB - INTRODUCTION: With the increasing number of radical prostatectomies (RP) performed, male stress urinary incontinence (SUI) has become common. The artificial urinary sphincter (AUS) is the gold standard to treat SUI post-RP, but new devices have recently been developed. We review the recent studies on the treatment of SUI post-RP; we also describe the surgical techniques, mechanisms of action and results of these new procedures. METHODS: We conducted a literature review search in the PubMed/Medline and Embase databases. Our search was restricted to recent articles. We included studies even if the urinary incontinence was due to sphincter deficiency after RP in non-neurologic patients. RESULTS: We found 8 cohort studies for the surgical procedure: 3 studies concerning slings, 1 involving balloons adjustable implant, and 4 involving new devices. The only randomized controlled trial (RCT) was a pharmacologic clinical trial comparing duloxetine to placebo. The social continence rates were analyzed for 6 studies and were up to 66%. CONCLUSION: New minimally invasive surgical procedures have emerged as the main alternative to AUS, with social continence rates up to 60% despite just 1 RCT studying the pharmacologic approach. There is an urgent need for well-designed clinical trials to clarify the role of new surgical alternatives in the management of SUI post-RP. New technologies should continue to be evaluated and compared with the AUS, which remains the gold standard. PMID- 25024792 TI - Peritoneal metastases from renal cell carcinoma: Images in urology. PMID- 25024793 TI - The clinical research office of the endourological society percutaneous nephrolithotomy global study: Outcomes in the morbidly obese patient - a case control analysis. AB - BACKGROUND: Efficacy and safety of percutaneous nephrolithotomy (PCNL) have been demonstrated in obese individuals. Yet, there is a paucity of data on the outcomes of PCNL in morbidly obese patients (body mass index [BMI] >40). METHODS: Perioperative and stone-related outcomes following PCNL in morbidly obese patients was assessed using a prospective database administered by the Clinical Research Office of the Endourological Society (CROES). A multidimensional match of 97 morbidly obese patients with those of normal weight was created using propensity score matching. Student's t-test and Chi-square tests were used to assess for differences between the groups. RESULTS: In total, 97 patients with a BMI >40 kg/m(2) were matched by stone characteristics with 97 patients of normal weight. The morbidly obese population demonstrated higher rates of diabetes mellitus (43% vs. 6%, p < 0.001) and cardiovascular disease (56% vs. 18%, (p < 0.001). Access was achieved more frequently by radiologists in the morbidly obese group (19% vs. 6%, p = 0.016). Mean operative duration was longer in the morbidly obese group (112 +/- 56 min vs. 86 +/- 43.5 min, p < 0.001). Stone-free rates were lower in the morbidly obese group (66% vs. 77%, p = 0.071). There was no significant difference in length of hospital stay or transfusion rate. Morbidly obese patients were significantly more likely to experience a postoperative complication (22% vs. 6%, p = 0.004). INTERPRETATION: PCNL in morbidly obese patients is associated with longer operative duration, higher rates of re intervention and an increased risk of perioperative complications. With this knowledge, urologists should seek to develop strategies to optimize the perioperative management of such patients. PMID- 25024795 TI - Hydrogen sulfide treatment ameliorates long-term renal dysfunction resulting from prolonged warm renal ischemia-reperfusion injury. AB - INTRODUCTION: The incidence of renal cell carcinoma (RCC) continues to rise concurrently with the increased prevalence of end-stage renal disease worldwide. Treatment for small renal masses continues to be partial nephrectomy mostly involving the clamping of renal blood vessels. Although necessary, this technique results in warm renal ischemia and reperfusion injury (IRI) to the afflicted kidney. We have recently demonstrated that hydrogen sulfide (H2S), a novel endogenous gaseous molecule, protects against prolonged cold and short-term warm renal IRI. In the current study, we examined whether exogenous H2S has long-term protective effects against warm renal IRI associated with renal surgical procedures. METHODS: Uni-nephrectomized Lewis rats underwent 1 hour of warm ischemia induced by clamping of the renal pelvis. Animals underwent either intraperitoneal treatment with phosphate buffered saline (PBS; IRI group) or PBS supplemented with 150 MUM NaHS (H2S group), and were compared against Sham operated rats. RESULTS: H2S treatment improved long-term renal function as serum creatinine at day 7 was significantly decreased in the H2S group compared to IRI animals (p < 0.05). H2S treatment decreased the expression of pro-inflammatory markers TLR-4, TNF-alpha, IFNgamma, IL-2 and ICAM-1, increased the expression of pro-survival molecule Bcl-2 and decreased the expression of pro-apoptotic marker BID at postoperative day 1. H2S-treated kidneys also showed a significant decrease (p < 0.05) in infiltration of macrophages at day 7 post-IRI compared to no treatment. CONCLUSION: H2S treatment improved long-term renal function and decreased long-term inflammation associated with warm IRI, and may offer a novel therapeutic approach to preventing warm IRI-induced renal injury associated with renal surgical procedures. PMID- 25024796 TI - Comparison between complication rates of laser prostatectomy electrocautery transurethral resection of the prostate: A population-based study. AB - INTRODUCTION: We compare the complication rates and length of stay (LOS) of laser transurethral resection of the prostate (L-TURP) versus electrocautery transurethral resection of the prostate (E-TURP) in a population-based cohort. L TURP has shown enhanced intraoperative safety and equivalent efficacy relative to E-TURP in several high volume centres. METHODS: Relying on the Florida Datafile as part of the Healthcare Cost and Utilization Project State Inpatient Databases (SID) between 2006 and 2008, we identified 8066 men with benign prostate hyperplasia who underwent L-TURP or E-TURP. Chi-square and Mann-Whitney tests were used to compare baseline characteristics. A multivariable linear regression model was used to analyze the effect of L-TURP versus E-TURP on complication rates and LOS. RESULTS: Overall complication rates did not differ significantly for L-TURP compared to E-TURP in univariable (8.8 vs. 7.4%, p = 0.1) and multivariable analyses (odds ratio [OR]: 1.06, confidence interval [CI]: 0.85 1.32, p = 0.6). Individuals undergoing E-TURP were less likely to experience a LOS in excess of 1 day (46.2 vs. 59.7%, p < 0.001). A lower risk to experience a LOS in excess of 1 day was confirmed for patients undergoing L-TURP after a multivariable linear regression model (OR: 0.37, CI: 0.23-0.58, p < 0.001), but not for a LOS in excess of 2 days (OR: 0.96, CI: 0.83-1.10, p = 0.2). CONCLUSIONS: Patient characteristics and perioperative safety were similar for L TURP and E-TURP patients. However, LOS patterns demonstrated a modest benefit for L-TURP compared to E-TURP patients. PMID- 25024797 TI - A modification of the TIP procedure for distal hypospadias: The burrowing technique. AB - INTRODUCTION: The tubularized incised plate urethroplasty (TIP) hypospadias repair is a commonly performed procedure for hypospadias. Multiple series document excellent cosmetic outcome in conjunction with low complication rates. We describe a modification that we have named the "burrowing technique." We believe that this technique facilitates dissection of the glans, which improves mobility, decreases tension with closure, and potentially improves outcomes. METHODS: A retrospective review was performed of 193 coronal or mid-shaft hypospadias repairs by a single surgeon. The first 98 were performed using the TIP procedure, then the burrowing technique was developed and a subsequent 95 were analyzed for outcomes using this modification. Urethral plate characteristics and glandular size did not influence the choice of surgical technique. Cases were selected to allow for a "learning curve," and were consecutively accrued. None of the boys had undergone prior hypospadias surgery. Proximal 2 stage repairs and distal (glanular) repairs were excluded. RESULTS: A total of 193 boys underwent repair, 98 with the traditional TIP procedure and 95 using the burrowing modification. In total, 37 (19.2%) patients required re operation for either fistulas or dehiscence; 23 (23.5%) in the non-burrowing group and 14 (14.7%) in the burrowing group, odds ratio 0.54 (p = 0.10). CONCLUSIONS: The TIP procedure has revolutionized the management of distal hypospadias. The burrowing modification increases glandular mobility simplifying the procedure and demonstrates a non-statistically significant trend in reducing reoperation rates. PMID- 25024798 TI - Inguinoscrotal hernias involving urologic organs: A case series. AB - We report 2 cases of inguinoscrotal hernias involving urologic organs. The first case involved an elderly gentleman with a history of micturition by squeezing his scrotum. He was diagnosed as having a right-sided indirect inguinal hernia involving the right ureter and bladder. Treatment was surgical. The second case involved an achondroplastic male who presented with acute kidney injury. He had bilateral hydronephrosis and ureteric obstruction secondary to an ureteroinguinal herniation bilaterally. The presentation, diagnosis, and treatment of inguinoscrotal hernias involving the bladder and ureters are discussed. PMID- 25024794 TI - Surgical management of renal cell carcinoma: Canadian Kidney Cancer Forum Consensus. PMID- 25024799 TI - Hidden penile squamous cell carcinoma: A case report. AB - Penile cancer is a rare malignancy that typically presents as a superficial lesion. We present an interesting case of subepithelial penile cancer presenting without superficial manifestation. PMID- 25024800 TI - Pediatric vasitis: A rare complication of epididymitis. AB - Vasitis represents an inflammation of the vas deferens. This is a rare entity seen mostly in adult males following local surgery (e.g., vasectomy, hernia repair). Children with groin masses have a wide differential diagnosis. We describe a child with a groin mass following epididymitis diagnosed with vasitis and review the known literature regarding diagnostic tools and treatment. Vasitis in children, although rare, can be seen as a complication of epididymitis. PMID- 25024801 TI - Robotic intra-abdominal vasectomy reversal: A new approach to a difficult problem. AB - The management of obstructive azoospermia resulting from intra-abdominal vasal obstruction poses a formidable surgical challenge. A number of surgical methods have been described to address this problem, including both open and laparoscopic approaches to mobilize and sometimes even re-route the abdominal vas deferens prior to performing a re-anastamosis. We present the first report, to our knowledge, of robotic intra-abdominal vasectomy reversal used to repair obstructive azoospermia resulting from prior laparoscopic vasectomy. In doing so, we summarize the techniques described previously in the literature and build upon this body of surgical experience by combining robotic-assisted laparoscopic mobilization of the vas with robotic vasovasostomy. We believe this novel approach for repairing intra-abdominal vasal defects minimizes morbidity, while at the same time obviating the need for the operating microscope, and thus represents a practical alternative to existing techniques. PMID- 25024802 TI - Primary renal MALToma: A rare differential diagnosis for a recurrent renal mass after primary ablative therapy. AB - We report a case of primary renal lymphoma of mucosa-associated lymphoid tissue in an 82-year-old woman. She presented with a history of renal mass previously treated with kidney percutaneous cryoablation at another centre. PMID- 25024803 TI - The use of TPA in combination with alcohol in the treatment of the recurrent complex hydrocele. AB - A hydrocele is an abnormal collection of serous fluid in the space between the parietal and visceral layers of the tunica vaginalis. Hydrocele is the most common cause of painless scrotal swelling which affects about 1% of men. Generally, adult hydroceles are idiopathic in origin; however, inguinal surgery, varicocelectomy, infection, trauma and a patent processus vaginalis are each associated with the subsequent development of a hydrocele. Surgical removal of hydroceles is the gold standard of care. However, multiple cases have reported high success rates (ranging from 85% to 96%) using a combination of aspiration and sclerotherapy. We present a case of a patient with recurring complex hydrocele and effective treatment utilizing a combination of thrombolytic therapy, catheter drainage and subsequent alcohol ablation. PMID- 25024804 TI - Lumbar artery branch injury secondary to ureteroscopic manipulation. AB - Iatrogenic vascular injury in ureteroscopy is relatively uncommon and typically presents as a subcapsular hematoma. We report the case of an injury to a branch of the lumbar artery secondary to ureteral trauma during ureteroscopy. In the immediate postoperative period, the patient became hypotensive and tachycardic, prompting a workup that revealed an active hemorrhage. The patient then underwent subsequent angiogram and successful coil embolization. PMID- 25024805 TI - Pancake kidney: A rare developmental anomaly. AB - There are many developmental anomalies of the kidney. Pancake kidney is one of the rarest types of renal ectopia. We report a case of pancake kidney which was detected incidentally while treating a female patient for a urinary tract infection. Although urinary system anomalies often coexist with malformations of other organs and systems, no associated anomalies could be detected in this case. Pancake kidney is usually managed by surgery, but this case was managed conservatively without any complication. PMID- 25024806 TI - Distal ureteral stricture: An unexpected complication of further adjuvant intravesical mitomycin C thermotherapy. AB - We present a case of distal ureteral obstruction in relation to further adjuvant intravesical thermochemotherapy with mitomycin C (MMC) for non-muscle invasive bladder cancer (NMIBC). We also discuss the diagnostic procedures and management of this recurrent case. PMID- 25024807 TI - Primary perivascular epithelioid cell tumour (PEComa) of the prostate. AB - Perivascular epithelioid cell tumours (PEComas) are a family of rare mesenchymal tumours arising in various anatomic locations. PEComas are defined by the presence of perivascular epithelioid cells that coexpress muscle and melanotic markers, especially HMB-45. They have unpredictable biological behaviour and are mostly benign, but some tumours can become unresectable or metastatic. Surgical resection, when possible, is the best treatment option. Radiation therapy, cytotoxic chemotherapy or immunotherapy have been reported as treatment options, either alone or in combination therapy. Prostatic PEComa is extremely rare, with only 1 malignant case reported. We report the first case of prostatic PEComa, which was benign and treated with transurethral resection. PMID- 25024808 TI - Hepatic failure induced by cyproterone acetate: A case report and literature review. AB - Cyproterone acetate (CPA) is an anti-androgenic drug that has been used to manage prostate cancer. The drug is well-tolerated, but has hepatotoxic effects. Hepatic failure induced by CPA is rare urologists tend to overlook its severity. We report a patient with metastatic prostate cancer who developed CPA-induced hepatic failure that manifested as bilirubinuria, which was initially misinterpreted as gross hematuria. The patient died despite receiving critical care. The aim of this study is to sound the alarm about CPA-induced hepatic failure. PMID- 25024809 TI - Pyelonephritis can be a source of a life-threatening necrotizing myofasciitis. AB - Necrotizing fasciitis is a progressive, rapidly spreading, inflammatory infection located in deep fascia. It may cause necrosis of skin and subcutaneous tissue and can even results in involvement of adjacent soft tissues such as muscles resulting in necrotizing myositis. We report the case of an adult male presenting with necrotizing myofasciitis secondary to left pyelonephritis. We also review the relevant literature. PMID- 25024810 TI - The robotic invasion of Canada. PMID- 25024811 TI - Secondary sarcoma of bone post-prostate brachytherapy: A case report. AB - Malignancies associated with brachytherapy for prostate cancer are largely unreported in the literature. We report a case of post-brachytherapy osteogenic sarcoma in the pelvis 6 years after permanent (125)I implant for intermediate risk prostate cancer. The patient was treated with neoadjuvant chemotherapy, limb sparing surgical resection and postoperative radiation therapy for unexpected positive margins. PMID- 25024812 TI - Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer. AB - Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer. PMID- 25024813 TI - Advances and new perspectives in the treatment of metastatic colon cancer. AB - During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer. Anti angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes. However, this progress has paradoxically leaded us into new challenges. In many cases the clinical development was done in parallel and the lack of head to-head comparison evolved into circumstances where several valid new "standards of care" are available. Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision. In addition, progress never stops and new agents are continuously tested. For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature. Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease. PMID- 25024814 TI - Novel diet-related mouse model of colon cancer parallels human colon cancer. AB - AIM: To investigate the close parallels between our novel diet-related mouse model of colon cancer and human colon cancer. METHODS: Twenty-two wild-type female mice (ages 6-8 wk) were fed the standard control diet (AIN-93G) and an additional 22 female mice (ages 6-8 wk) were fed the control diet supplemented with 0.2% deoxycholic acid [diet + deoxycholic acid (DOC)] for 10 mo. Tumors occurred in the colons of mice fed diet + DOC and showed progression to colon cancer [adenocarcinoma (AC)]. This progression is through the stages of tubular adenoma (TA), TA with high grade dysplasia or adenoma with sessile serrated morphology, intramucosal AC, AC stage T1, and AC stage T2. The mouse tumors were compared to human tumors at the same stages by histopathological analysis. Sections of the small and large intestines of mice and humans were evaluated for glandular architecture, cellular and nuclear morphology including cellular orientation, cellular and nuclear atypia, pleomorphism, mitotic activity, frequency of goblet cells, crypt architecture, ulceration, penetration of crypts through the muscularis mucosa and presence of malignant crypts in the muscularis propria. In addition, preserved colonic tissues from genetically similar male mice, obtained from a prior experiment, were analyzed by immunohistochemistry. The male mice had been fed the control diet or diet + DOC. Four molecular markers were evaluated: 8-OH-dG, DNA repair protein ERCC1, autophagy protein beclin-1 and the nuclear location of beta-catenin in the stem cell region of crypts. Also, male mice fed diet + DOC plus 0.007% chlorogenic acid (diet + DOC + CGA) were evaluated for ERCC1, beclin-1 and nuclear location of beta-catenin. RESULTS: Humans with high levels of diet-related DOC in their colons are at a substantially increased risk of developing colon cancer. The mice fed diet + DOC had levels of DOC in their colons comparable to that of humans on a high fat diet. The 22 mice without added DOC in their diet had no colonic tumors while 20 of the 22 mice (91%) fed diet + DOC developed colonic tumors. Furthermore, the tumors in 10 of these mice (45% of mice) included an adenocarcinoma. All mice were free of cancers of the small intestine. Histopathologically, the colonic tumor types in the mice were virtually identical to those in humans. In humans, characteristic aberrant changes in molecular markers can be detected both in field defects surrounding cancers (from which cancers arise) and within cancers. In the colonic tissues of mice fed diet + DOC similar changes in biomarkers appeared to occur. Thus, 8-OH-dG was increased, DNA repair protein ERCC1 was decreased, autophagy protein beclin-1 was increased and, in the stem cell region at the base of crypts there was substantial nuclear localization of beta-catenin as well as increased cytoplasmic beta-catenin. However, in mice fed diet + DOC + CGA (with reduced frequency of cancer) and evaluated for ERCC1, beclin-1, and beta-catenin in the stem cell region of crypts, mouse tissue showed amelioration of the aberrancies, suggesting that chlorogenic acid is protective at the molecular level against colon cancer. This is the first diet-related model of colon cancer that closely parallels human progression to colon cancer, both at the histomorphological level as well as in its molecular profile. CONCLUSION: The diet-related mouse model of colon cancer parallels progression to colon cancer in humans, and should be uniquely useful in model studies of prevention and therapeutics. PMID- 25024815 TI - Growth inhibition of colon cancer cells by compounds affecting AMPK activity. AB - AIM: To determine if other molecules reported to modulate AMP-dependent protein kinase (AMPK) activity would have effects resembling those of metformin and phenformin on colon cancer cell proliferation and metabolism. METHODS: Studies were performed with four human colon cancer cell lines, Caco-2, HCT116, HT29 and SW1116. The compounds that were studied included A-769662, 5-aminoimidazole-4 carboxamide-1-ribofuranoside, butyrate, (-)-epigallocatechin gallate (EGCG), KU 55933, quercetin, resveratrol and salicylates. The parameters that were measured were cell proliferation and viability, glucose uptake, lactate production and acidification of the incubation medium. RESULTS: Investigations with several molecules that have been reported to be associated with AMPK activation (A 769662, 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside, EGCG, KU-55933, quercetin, resveratrol and salicylates) or AMPK inhibition (compound C) failed to reveal increased medium acidification and increased glucose uptake in colon cancer cells as previously established with metformin and phenformin. The only exception was 5-aminosalicylic acid with which there were apparently lower glucose levels in the medium after incubation for 72 h. Further study in the absence of cells revealed that the effect was an artifact due to inhibition of the enzyme-linked glucose assay. The compounds were studied at concentrations that inhibited cell proliferation. CONCLUSION: It was concluded that treatment with several agents that can affect AMPK activity resulted in the inhibition of the proliferation of colon cancer cells under conditions in which glucose metabolism is not enhanced, in contrast to the effect of biguanides. PMID- 25024816 TI - Prevalence and clinicopathological characteristics of appendiceal carcinoids in Sharjah (United Arab Emirates). AB - AIM: To determine the incidence and clinico-pathological profile of appendiceal carcinoids in a cohort of patients undergoing emergency appendicectomies for clinically suspected acute appendicitis in Sharjah, United Arab Emirates (UAE). METHODS: The study included the retrospective data of 964 patients operated for clinically suspected acute appendicitis, and the resected specimens were received at Al-Qasmi Hospital (Sharjah) from January 2010 to December 2010. The data of the patients who were histologically reported to have carcinoid tumors of the appendix were extensively evaluated for the patient's demographics, indication for surgery, surgical procedure, tumor localization in the appendix, diameter of the lesion, concomitant appendicitis, immunohistochemistry studies and clinical follow-up. RESULTS: Out of the 964 patients included in the study, 9 (0.93%) were found to have appendiceal carcinoids. The mean age reported was 28.7 years with a male to female ratio of 2:1. Eight tumors were located near the tip of the appendix with a mean diameter of 3.3 mm, while the remaining one was near the proximal end of the appendix. All the cases were associated with concomitant suppurative appendicitis. In seven reported cases, tumors were confined to the muscular layer while in one case each there was an extension to the serosa and mesoappendix, respectively. All tumors were found to be positive for chromogranin A, synaptophysin and neuron-specific enolase on immunohistochemistry but negative for cytokeratin-7. None of the patients developed recurrence or any reportable complications in the short follow-up period (12-26 mo) that was arranged as a six monthly re-evaluation by abdominal ultrasonography. CONCLUSION: Our study found a higher incidence of appendiceal carcinoids in patients undergoing emergency appendectomy for acute appendicitis in Sharjah, UAE compared to two previous studies from the Persian Gulf region. Interestingly, tumors were found to be more commonly in young males, which is in contrast to previous studies. Moreover, all the tumors were positive for common neuroendocrine markers. PMID- 25024817 TI - Patient prompting of their physician resulted in increased colon cancer screening referrals. AB - AIM: To determine whether a communication instrument provided to patients prior to their primary care physician (PCP) visit initiates a conversation with their PCP about colorectal cancer screening (CRC-S), impacting screening referral rates in fully insured and underinsured patients. METHODS: A prospective randomized control study was performed at a single academic center outpatient internal medicine (IRMC, underinsured) and family medicine (FMRC, insured) resident clinics prior to scheduled visits. In the intervention group, a pamphlet about the benefit of CRC-S and a reminder card were given to patients before the scheduled visit for prompting of CRC-S referral by their PCP. The main outcome measured was frequency of CRC-S referral in each clinic after intervention. RESULTS: In the IRMC, 148 patients participated, a control group of 72 patients (40F and 32M) and 76 patients (48F and 28M) in the intervention group. Referrals for CRC-S occurred in 45/72 (63%) of control vs 70/76 (92%) in the intervention group (P <= 0.001). In the FMRC, 126 patients participated, 66 (39F:27M) control and 60 (33F:27M) in the intervention group. CRC-S referrals occurred in 47/66 (71%) of controls vs 56/60 (98%) in the intervention group (P <= 0.001). CONCLUSION: Patient initiated physician prompting produced a significant referral increase for CRC-S in underinsured and insured patient populations. Additional investigation aimed at increasing CRC-S acceptance is warranted. PMID- 25024818 TI - Possible mechanism and clinical potentials of allostery. AB - Allostery is involved in the dynamic regulation of biological functions in proteins. Advances in allostery research have recently drawn great interest and brought allostery closer to the clinic. The present commentary describes the mechanism by which allostery may involve in from a cell-wide view and its contribution to the discovery of new therapeutics to diseases. PMID- 25024819 TI - Incorporating translational research with clinical research to increase effectiveness in healthcare for better health. AB - BACKGROUND: The transfer of new scientific discoveries into healthcare interventions requires that basic and clinical researchers work together with health care providers to generate team science. These innovative models require translational teams, and need to extend beyond the academic environment. The future of translational science requires partnerships with the healthcare community as well as the broader, general community. This new integrated model of effective translational teams holds promise for addressing thorny and persistent health disparities, is consistent with the nation's strategic priority of eliminating health disparities, and bodes well for increasing healthcare effectiveness aimed at better health for all. DISCUSSION: As part of the 13th Research Centers in Minority Institutions (RCMI) International Symposium on Health Disparities, several senior academic leaders joined efforts to hold a workshop to discuss a model that considers the incorporation of two translational research strategies in research career development programs: Comparative effectiveness research (CER) and community-based participatory research (CBPR) for increasing healthcare effectiveness and eliminating healthcare disparities. Discussion included what issues may be most germane to the concept of a unified model for research workforce development through formal training and career development leading to increased effectiveness in healthcare for better health. SUMMARY: We believe that there is a gap in knowledge and skills in formal research career development programs that will enable physicians, other clinicians, and basic scientists to actively participate in these two translational research strategies. The purpose of this paper is to share the outcomes of these discussions, and encourage further discussion and possible innovation in the formulation of a new model for translational research workforce development. PMID- 25024820 TI - Usefulness of Dexmedetomidine during Intracerebral Aneurysm Coiling. AB - OBJECTIVE: General anesthesia is often preferred for endovascular coiling of intracranial aneurysm at most centers. But in the authors' hospital, it is performed under monitored anesthesia care (MAC) using dexmedetomidine. To determine the feasibility and safety of this approach, the authors reviewed our initial experience. METHODS: Retrospective data was analyzed from July 2012 to November 2012. We performed coil embolization in 28 cases using this method. Among them, for statistical significance, we analyzed 12 cases in which the procedure time exceeded an hour. Vital signs were analyzed every 10 minutes. Depth of sedation was measured according to the Ramsay sedation scale and frequency of the repeated roadmap image(s) caused by movement of the patient's head during the procedure. RESULTS: All procedures were completed without occurrence of procedure related complications. Under MAC using dexmedetomidine, vital signs of the patients were stable, no statistical significance regarding hemodynamic and respiratory parameters was observed between time points (p>0.05). Adequate sedation was achieved. Mean Ramsay sedation scale was 3.67+/-1.61 (2 to 6). Repeated roadmap image(s) due to patient's factor occurred in only one case. The mean dosage of drug for adequate sedation for the procedure was 0.65+/-0.12 mcg/kg/hr without loading doses. CONCLUSION: To the best of my knowledge, this is the first report published in English using the method of monitored anesthesia with dexmedetomidine for intracranial aneurysm coiling. Monitored anesthesia care using dexmedetomidine without loading dose for embolization of intracranial aneurysms appeared to be a safe and effective alternative to general anesthesia. PMID- 25024821 TI - Incidence of post-traumatic stress disorder after a mild traumatic brain injury: preliminary investigation using the brief neuropsychological screening test. AB - OBJECTIVE: Post-traumatic stress disorder (PTSD) is a group of diseases that are observed in patients who had experienced a serious trauma or accident. However, some experienced it even after only a mild traumatic brain injury (TBI), and they are easily ignored due to the relatively favorable course of mild TBI. Herein, the authors investigated the incidence of PTSD in mild TBI using brief neuropsychological screening test (PTSD checklist, PCL). METHODS: This study was conducted on patients with mild TBI (Glasgow coma scale >=13) who were admitted from January 2012 to December 2012. As for PCL, it was done on patients who showed no difficulties in communication upon admission and agreed to participate in this study. By using sum of PCL, the patients were divided into high-risk group and low-risk group. PTSD was diagnosed as the three major symptoms of PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edifion. RESULTS: A total of 314 TBI patients were admitted and 71 of them met the criteria and were included in this study. The mean age was 52.9 years-old (range: 15-94). The mean PCL score was 28.8 (range: 17-68), and 10 patients were classified as high-risk group. During follow-up, 2 patients (2.7%) of high risk group, were confirmed as PTSD and there was no patient who was suspected of PTSD in the low-risk group (p=0.017). CONCLUSION: PTSD is observed 2.8% in mild TBI. Although PTSD after mild TBI is rare, PCL could be considered as a useful tool for screening of PTSD after mild TBI. PMID- 25024822 TI - Surgical decision making for the elderly patients in severe head injuries. AB - OBJECTIVE: Age is a strong predictor of mortality in traumatic brain injuries. A surgical decision making is difficult especially for the elderly patients with severe head injuries. We studied so-called 'withholding a life-saving surgery' over a two year period at a university hospital. METHODS: We collected data from 227 elderly patients. In 35 patients with Glasgow Coma Score 3-8, 28 patients had lesions that required operation. A life-saving surgery was withheld in 15 patients either by doctors and/or the families (Group A). Surgery was performed in 13 patients (Group B). We retrospectively examined the medical records and radiological findings of these 28 patients. We calculated the predicted probability of 6 month mortality (IPM) and 6 month unfavorable outcome (IPU) to compare the result of decision by the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) calculator. RESULTS: Types of the mass lesion did not affect on the surgical decision making. None of the motor score 1 underwent surgery, while all patients with reactive pupils underwent surgery. Causes of injury or episodes of hypoxia/hypotension might have affected on the decision making, however, their role was not distinct. All patients in the group A died. In the group B, the outcome was unfavorable in 11 of 13 patients. Patients with high IPM or IPU were more common in group A than group B. Wrong decisions brought futile cares. CONCLUSION: Ethical training and developing decision-making skills are necessary including shared decision making. PMID- 25024823 TI - Sensory complications in patients after scalp mass excision and its anatomical considerations. AB - OBJECTIVE: To evaluate the incidence of postsurgical sensory complications in patients with scalp masses and classify the locations of them from a surgical standpoint according to anatomical considerations. METHODS: A total of 121 patients who underwent surgery for scalp mass were included in this study. The authors reviewed medical records and preoperative radiologic images. We investigated the complications related to sensory changes after procedure. Enrolled patients have been divided into three groups. Group A included patients with tumors above the superior nuchal line (SNL), Group B with tumors within the trapezius muscle area and patients who had tumors on the lateral trapezius muscle area were assigned to Group C. We compared the incidence related to postoperative sensory complications and summarized their additional treatments for these with clinical outcome. RESULTS: There were 12 patients (10%) with sensory complications related on the mass excision site (Group A: 1 patient, Group B: 2 patients, Group C: 9 patients). Six patients were affected with lesser occipital nerve (LON), 2 patients on greater occipital nerve (GON) and 4 patients on GON and LON. Over 6 months after surgery, two of the twelve patients with sensory complications did not have complete recovered pain in spite of proper medications and local chemical neurolysis with 1.0% lidocaine and dexamethasone. CONCLUSION: Occipital neuropathy should be considered as a complication related excision of scalp mass. The sensory complications are more frequent in Group C because of the anatomical characteristics of the occipital nerves and there were no statistical difference for other variables. PMID- 25024824 TI - Extracranial extension of intracranial atypical meningioma en plaque with osteoblastic change of the skull. AB - Meningioma is a common primary tumor of central nervous system. However, extracranial extension of the intracranial meningioma is unusual, and mostly accompanied the osteolytic change of the skull. We herein describe an atypical meningioma having extracranial extension with hyperostotic change of the skull. The patient was a 72-year-old woman who presented a large mass in the right frontal scalp and left hemiparesis. Brain magnetic resonance imaging and computed tomography scans revealed an intracranial mass, diffuse meningeal thickening, hyperostotic change of the skull with focal extension into the right frontal scalp. She underwent total removal of extracranial tumor, bifrontal craniectomy, and partial removal of intracranial tumor followed by cranioplasty. Tumor pathology was confirmed as atypical meningioma, and she received adjuvant radiotherapy. In this report, we present and discuss a meningioma en plaque of atypical histopathology having an extracranial extension with diffuse intracranial growth and hyperostotic change of the skull. PMID- 25024825 TI - Preservation of Facial Nerve Function Repaired by Using Fibrin Glue-Coated Collagen Fleece for a Totally Transected Facial Nerve during Vestibular Schwannoma Surgery. AB - Recently, the increasing rates of facial nerve preservation after vestibular schwannoma (VS) surgery have been achieved. However, the management of a partially or completely damaged facial nerve remains an important issue. The authors report a patient who was had a good recovery after a facial nerve reconstruction using fibrin glue-coated collagen fleece for a totally transected facial nerve during VS surgery. And, we verifed the anatomical preservation and functional outcome of the facial nerve with postoperative diffusion tensor (DT) imaging facial nerve tractography, electroneurography (ENoG) and House-Brackmann (HB) grade. DT imaging tractography at the 3rd postoperative day revealed preservation of facial nerve. And facial nerve degeneration ratio was 94.1% at 7th postoperative day ENoG. At postoperative 3 months and 1 year follow-up examination with DT imaging facial nerve tractography and ENoG, good results for facial nerve function were observed. PMID- 25024826 TI - Odontoid synchondrosis fracture treated by c1-2 polyaxial screw-rod fixation. AB - The synchondrosis between the dens and the body of axis normally fuses between 5 and 7 years of age. Until this age, synchondrosis fractures can occur in children. Most synchondrosis fractures are conventionally treated by external immobilization alone. We report a 10-year-old child with odontoid synchondrosis fracture who was treated by C1 lateral mass and C2 pars screw rod fixation with a successful outcome and discuss the possible reasons for occurrence of odontoid synchondrosis fracture in this older child as well as the indications for surgery in this condition. PMID- 25024827 TI - Brown-sequard syndrome caused by a cervical synovial cyst. AB - Synovial cysts are recognized as an uncommon cause of radicular and myelopathic symptoms. They are most frequently found in the lumbar region. The cervical spine or cervicothoracic junction is a rare location for a degenerative intraspinal synovial cyst as compared with the lumbar spine. At given cervical spinal levels, synovial cysts probably share clinical features with disc herniation and stenosis. However, the pathogenesis of synovial cysts remains still controversial. Here, we report a rare case of a synovial cyst in the lower cervical spine presented as Brown-Sequard syndrome and include a brief review of the literature. To the best of our knowledge, no previous report has been issued in the English literature on a synovial cyst presenting with Brown-Sequard syndrome. Neurologic function recovered completely after complete removal of the cyst and expansive laminoplasty. PMID- 25024828 TI - The surgical treatment of three young chronic subdural hematoma patients with different causes. AB - Chronic subdural hematoma (CSDH), which rarely happens in the young, is thought to be a disease of the elderly. Whereas unspecific symptoms and insidious onset in juveniles and young adults, as a result of its relative low morbidity, CSDH is usually neglected even undertreated in the young. Through the three cases and review of the current literature on this subject, we tried to illustrate the clinical and etiopathological characteristics of this entity and find out the most appropriate treatment strategy. We report three young CSDH patients with different but similar symptoms. The present histories, tests and examinations revealed different predisposing factors accounting for the genesis of CSDH. Their preoperative symptoms were all resolved with burr hole and drainage operation. Juveniles and young adults suffering from CSDH differ from that of their elderly counterparts in their clinical and etiopathological characteristics. Although trauma is the most important risk factor in young and old CSDH patients, some other predisposing factors may exist. Burr hole and drainage surgery could resolve the problem most of the time. But further tests and examinations even specific management should be made in some cases. PMID- 25024829 TI - Traumatic aneurysm of the callosomarginal artery-cortical artery junction from penetrating injury by scissors. AB - Traumatic intracranial aneurysms (TICAs) are rare and are associated with high rates of morbidity and mortality. TICAs usually result from head injuries caused by traffic accidents, industrial accidents, or gunshots. We report a traumatic aneurysm of the callosomarginal artery-cortical artery junction arising from a penetrating injury by scissors. A 51-year-old woman was admitted to our hospital after suffering a penetrating injury caused by scissors. Computed tomography (CT) and CT-angiography demonstrated a right orbital roof fracture, subarachnoid hemorrhage, frontal lobe hemorrhage, intraventricular hemorrhage, and a traumatic aneurysm of the right callosomarginal artery-cortical artery junction. We trapped the traumatic aneurysm and repositioned a galeal flap. Postoperative CT showed a small infarction in the left frontal lobe. Follow-up angiography two months later showed no residual aneurysm. We suggest that an aggressive surgical intervention be performed whenever TICA is diagnosed. PMID- 25024830 TI - A case of intradural-extramedullary form of primary spinal cysticercosis misdiagnosed as an arachnoid cyst. AB - We describe a rare case of intradural-extramedullary primary spinal cysticercosis. A 42-year-old man visited our institute for lower back pain. He denied having consumed raw meet. Magnetic resonance (MR) images revealed an intradural pure cystic mass at the L3-L4 level. A radiologic diagnosis of spinal arachnoid cyst was established. Three years later, he complained of aggravated back pain, and follow-up MR examination showed a markedly expanded cyst, occupying the subarachnoid space from the T11 to the S1 level. L2 hemilaminectomy was performed, and a yellowish infected cyst bulged out through the dural opening. The cyst was removed en bloc. The histopathological findings of the cyst were consistent with parasitic infection. Serum enzyme-linked immunosorbent assay (ELISA) confirmed the presence of spinal cysticercosis. As there was no intracranial lesion, the final diagnosis was primary spinal cysticercosis, which is very rare. MR imaging is a sensitive diagnostic tool for detecting cystic lesions in the spine; however, it is difficult to distinguish cysticercosis from non-infectious cysts such as an arachnoid cyst without using gadolinium enhancement. Clinicians treating spinal cysts with an unusual clinical course should include cysticercosis as a differential diagnosis. We recommend contrast enhanced MR imaging and serum ELISA in the diagnostic work-up of such cases. PMID- 25024831 TI - Fires and Burns Occurring in an Electrocautery after Skin Preparation with Alcohol during a Neurosurgery. AB - While there are reports regarding burns occurring to patients during the surgery, there are little reports concerning the incidents of the burns related to neurosurgical operations. Moreover, in Korea, even surveys and statistics on the incidents of burns in operating rooms are not known. This report explores burns occurring to a patient in an electrocautery scenario after disinfecting the surgical site with alcohol during the preparation of a neurosurgical operation in an operating room where there is much exposure to oxygen. The authors show a case of a 33-year-old male patient who undergoing evacuation of hematoma on occipital lesion, suffered second degree burns as a result of surgical fires. PMID- 25024832 TI - The Effect of Low-level Laser Therapy on Trigeminal Neuralgia: A Review of Literature. AB - The effect of low intensity laser radiation in the treatment of acute and chronic pain is now established in many studies. Tri-geminal neuralgia is a pain passes through nerve's branches and its trigger is located in skin or mucosa that could lead to pain with a trigger stimulus. The pain involved branches of trigeminal nerve that sometimes has patients to seek the treatment for several years. Nowadays different treatments are used for relief of pain that most of them cause tolerance and various side effects. This paper reviews and summarizes scientific papers available in English literature publishedin PubMed, Scopus, Science Direct, Inter science, and Iran Medex from 1986 until July 2011 about the effect of these types of lasers on trigeminal neuralgia which is one of the most painful afflictions known. In different studies, the effect of laser therapy has been compared with placebo irradiation or medicinal and surgical treatment modalities. Low-level laser therapy (LLLT) is a treatment strategy which uses a single wavelength light source. Laser radiation and monochromatic light may alter cell and tissue function. However, in most studies laser therapy was associated with significant reduction in the intensity and frequency of pain compared with other treatment strategies, a few studies revealed that between laser and placebo group there was not any significant difference according to the analgesic effect. Low level laser therapy could be considered in treatment of trigeminal neuralgia without any side effects. PMID- 25024833 TI - Oral potentially malignant disorders: an overview of more than 20 entities. AB - Cancer of the oral cavity accounts for approximately 3% of all malignancies diagnosed annually in 270,000 patients world-wide. Oral cancer is the 12th most common cancer in women and the 6th in men. Many oral squamous cell carcinomas develop from potentially malignant disorders (PMDs). Lack of awareness about the signs and symptoms of oralPMDs in the general population and even healthcare providers is believed to be responsible for the diagnostic delay of these entities. The aim of this article is to update and improve the knowledge of healthcare providers about oral PMDs. PMID- 25024834 TI - Increased mast cell counts in benign and malignant salivary gland tumors. AB - Background and aims. Mast cells are one of the characteristic factors in angiogenesis, growth, and metastatic spread of tumors. The distribution and significance of mast cells in many tumors have been demonstrated. However, few studies have evaluated mast cell infiltration in salivary gland tumors. In this study, mast cell counts were evaluated in benign and malig-nant salivary gland tumors. Materials and methods. This descriptive and cross-sectional study assessed 30 cases of pleomorphic adenoma, 13 cases of adenoid cystic carcinoma, 7 cases of mucoepidermoid carcinoma (diagnosed on the basis of 2005 WHO classifica tion), with adequate stroma in peritumoral and intratumoral areas, and 10 cases of normal salivary glands. The samples were stained with 5% diluted Giemsa solution and the average stained cell counts were calculated in 10 random microscopic fields in peri- and intra-tumoral areas. Data were analyzed by t-test and Mann-Whitney and Krusskal-Wallis tests. Results. The average mast cell counts increased in the tumors compared to normal salivary glands. There was no signifi cant difference between benign and malignant tumors and also between different malignant tumors. Infiltration was signifi-cantly denser in peri-tumoral stroma in both tumoral groups (P = 0.001). Minor salivary glands contained significantly more numerous mast cells. Conclusion. Although mast cell counts increased in benign and malignant salivary gland tumors, there were no signifi-cant differences between the tumoral groups. Further studies are suggested to determine the type of these cells which might be useful in the assessment of biological nature of the tumor and its future treatment modality. PMID- 25024835 TI - Microleakage evaluation of adhesive systems following pulp chamber irrigation with sodium hypochlorite. AB - Background and aims. This in vitro study evaluated the effect of delaying composite resin restorative procedures bonded with total-etch and self-etch adhesive systems on microleakage following root canal irrigation with sodium hy pochlorite (NaOCl) solution. Materials and methods. The roofs of pulp chambers and roots (1–2 mm below furcation) of 40 human first molar teeth were cut and pulp tissues completely removed. The teeth were randomly divided into two main groups (n = 20). Group E (experimental) was irrigated with 5% NaOCl and group C (control) was left untreated. For the experimental group, after obturation of root canals with gutta-percha and sealing the cavity with Cavit, the specimens were stored in artificialsaliva for two weeks. Then each group was divided into two subgroups according to the total-etch or self-etch adhesive application protocol: Scotchbond Multi-Purpose and Clearfil SE Bond. The specimens were restored with composite resin using each bonding agent: Z250 and Clearfil Photo Core, respectively. Fluid filtration method was used for evaluation of microleakage. Data was analyzed using two-way ANOVA ( alpha= 0.05). Results. Two types of dentin adhesive systems showed no statistically significant differences in microleakage (P = 0.77). NaOCl-treated groups demonstrated significantly higher microleakage values compared to the non-NaOCl-treated groups (P= 0.001). The interaction between the two factors was not significant (P = 0.78). Conclusion. Differences in inlay temperature had no effect on microleakage. CAD/CAM inlays had lower cement thick-ness than laboratory-made inlays, but this was not related to their microleakage. PMID- 25024836 TI - A Comparison of Shear Bond Strengths of Metal and Ceramic Brackets using Conventional Acid Etching Technique and Er:YAG Laser Etching. AB - Background and aims. The aim of this study was to compare shear bond strength (SBS) of metal and ceramic brackets bonded to enamel using acid versus Er:YAG laser etching. Materials and methods. Eighty premolars were divided into 4 groups: AM (acid etching/ metal brackets), AC (acid etching/ ceramic brackets), LM (laser etching/ metal brackets) and LC (laser etching/ ceramic brackets). Enamel condition-ing was done using acid in AC and AM and Er:YAG laser in LC and LM. Brackets were debonded with a Dartec machine and the SBSs were determined. Adhesive remnant index was evaluated under a stereomicroscope. Two additional teeth were conditioned with acid and laser for scanning electron microscopy examination. Comparisons of SBS value were done by ANOVA test. Results. statistical analyses showed that SBSs of acid groups were significantly higher than that of laser groups, but dif-ferences between SBS values of AC/ AM and LC/LM were not significant. SEM examination revealed different etching pattern. Conclusion. Low power Er:YAG laser etching offers clinically acceptable SBS which besides its other superiorities to acid etching can be an appropriate alternative for bonding of ceramic brackets. PMID- 25024837 TI - Salivary total antioxidant capacity and lipid peroxidation in patients with erosive oral lichen planus. AB - Background and aims. Oral lichen planus is a common chronic inflammatory disease of the oral mucosa with malignant potential, pathogenesis of which is not still well known. Free radicals and reactive oxygen species can play an important role in the pathogenesis of oral lichen planus. The aim of this study was to investigate salivary oxidative stress and antioxidant systems in patients with oral lichen planus. Materials and methods. In this case-control study, 30 patients with oral lichen planus (case group) and 30 age-and gender-matched healthy subjects (control group), referring to Dental School of Babol University of Medical Sciences, were selected using simple sampling method. Unstimulated saliva of the two groups was collected. Salivary total antioxidant capacity (TAC) and lipid peroxidation products were investigated and compared, using ferric reducing antioxidant power (FRAP) and thiobarbituric acid reactive substance (TBARS) methods, respectively. Data were analyzed using Student' t-test. Results. The mean and standard deviation of salivary TAC in patients with oral lichen planus (297.23 +/- 149.72 MUM) was significantly lower than that in the controls (791.43 +/- 183.95 MUM; P & 0.0001), and mean and standard deviation of salivary malondialdehyde (MDA) (0.49 +/- 0.30 MUM) was remarkably higher in oral lichen planus patients compared to the control group (0.15 +/- 0.11 MUM) (P & 0.0001). TAC was also reduced in both groups in line with an increase in the level of MDA (P & 0.0001, r = -0.48). Conclusion. The results of this study suggested that an increase in oxidative stress and an imbalance in antioxidant defense system in the saliva of oral lichen planus patients may be involved in the pathogenesis of oral lichen planus. PMID- 25024838 TI - Hardness Evaluation of Composite Resins Cured with QTH and LED. AB - Background and aims. Today light cured composites are widely used. Physical and mechanical properties of composites are related to the degree of conversion. Light curing unit (LCU) is an important factor for composite polymerization. Aim of this study is evaluation of composite resins hardness using halogen and LED light curing units. Materials and methods. In this study, 30 samples of Filtek Z250 and C-Fill composite resins were provided. Samples were light cured with Ultralume2, Valo and Astralis7. Vickers hardness number (VHN) was measured in 0, 1, 2 mm depth. STATISTICAL ANALYSIS USED: Data were analysed by SPSS software and compared with each other by T-test, one-way and two-way ANOVA and Post-hoc Tukey test. Results. In Filtek Z250, at top surface, VHN of Ultralume2 was higher than VHN of Valo (P = 0.02) and Astralis7 (P =0.04), but in depth of 1, 2 mm, VHN of Ultralume2 and Astralis7 were almost the same and both LCUs were more than Valo which the difference between Ultralume2 and Valo was significant in depth of 1mm (0.05) and 2mm (0.02). In C-Fill composite, at top surface, Astralis7 showed higher VHN, but in depth of 2 mm, performance of all devices were rather simi lar. Conclusion. In Z250, which contains camphorquinone initiator, light cure LED Ultra-lume2 with narrow wavelength showed higher hardness number than Valo. In C fill, in top surface, Astralis7 with more exposure time, resulted higher VHN. But In depth of 2 mm, various light curing devices had rather similar hardness number. PMID- 25024839 TI - Comparison of microleakage and thickness of resin cement in ceramic inlays with various temperatures. AB - Background and aims. Microleakage is still one of the major problems of composite based restorations.This study compared the microleakage and thickness of resin cement in ceramic inlays with various temperatures. Materials and methods. Class V cavities were prepared on the buccal and lingual aspects of thirty human molars with occlusal margins in enamel and gingival margins in dentin (3 mm wide, 5 mm long and 2 mm deep). Laboratory-made inlays (LMI) were used for buccal cavities, and CAD/CAM inlays (CMI) were used for lingual cavities. All the cavities were divided into six groups (n=10): 1) LMI at -5 degrees C; 2) LMI at 50 degrees C; 3) LMI at room temperature (25 degrees C); 4) CMI at -5 degrees C; 5) CMI at 50 degrees C; 6) CMI at room temperature (25 degrees C). Inlays were bonded to cavities in a pulp pressure- and temperature-simulating device. After thermocycling and dye penetration, the teeth were divided into two mesiodistal halves. Amount of dye penetration and film thickness were measured under a stereomicroscope and analyzed with Kruskal-Wallis, Wilcoxon and Spearman's correlation tests ( = 0.05). Results. There were no statistically significant differences in leakage between different inlay temperatures (P > 0.05). The mean cement thickness in laboratory-made inlays (gingival margin, 83.7 +/- 11 and occlusal margin, 84.7 +/- 19) was greater than that in CAD/CAM inlays (gingival margin, 69 +/- 16 and occlusal margin, 84.7 +/- 16). No correlation was found be tween cement thickness and microleakage either in enamel or dentin for any of the ceramic systems. Conclusion. Differences in inlay temperature had no effect on microleakage. CAD/CAM inlays had lower cement thickness than laboratory-made inlays, but this was not related to their microleakage. PMID- 25024840 TI - A large multifocal aggressive osteoblastoma of mandible: an immunohistochemistry case study report. AB - Aggressive osteoblastoma (AO) is a benign osteoblastic tumor which is rare in the head and neck region. Clinical and histo-logical features are therefore overlap with other benign and low-grade malignant tumors. The aim of this article is to report and discuss the differential diagnosis of an aggressive osteoblastoma in the mandible. A 25-year-old male patient reported with pain and asymmetry on the left side of the face since 8 months previously. Radiographic evaluation showed a mixed lesion extending from approximately the lower left premolar to the third molar region. After incisional biopsy, resection with continuity defect was carried out. Microscopic findings showed woven bone and bony trabeculae with varied degrees of mineralization along with sheets of osteoblast cells. Immunohistochemistry showed that p53 and cytokeratin (CK) were negative and ki-67 index was 7%. Postoperative follow-up for 15 months showed no evidence of recurrence. PMID- 25024841 TI - Photodynamic therapy for the endodontic treatment of a traumatic primary tooth in a diabetic pediatric patient. AB - Conservation of deciduous teeth with pulp alterations caused by caries or trauma is a major therapeutic challenge in pediatric dentistry. It is essential that the sanitizers used in root canal procedures perform well in eliminating bacteria. Antimicrobial photodynamic therapy (PDT) is an emerging and promising adjuvant therapy for endodontic treatment in an attempt to eliminate microorganisms persistent after chemomechanical preparation. This paper reports the case of a five-year-old male with type I diabetes mellitus, presenting the need for pulp therapy in maxillary primary left central incisor due to injury. The proposed treatment included the use of PDT for decontamination of root canals with the application of 50 MUg/mL of methylene blue dye for 3-5 minutes and 40 J/cm(2) as energy density, taking into account the need for tissue penetration and effec tiveness of PDT inside the dentinal tubules. PMID- 25024842 TI - Echocardiographic estimation of mean pulmonary artery pressure in critically ill patients. AB - BACKGROUND: Indirect assessment of mean pulmonary arterial pressure (MPAP) may assist management of critically ill patients with pulmonary hypertension and right heart dysfunction. MPAP can be estimated as the sum of echocardiographically derived mean right ventricular to right atrial systolic pressure gradient and right atrial pressure; however, this has not been validated in critically ill patients. METHODS: This prospective validation study was conducted in patients undergoing pulmonary artery catheterisation during intensive care admission. Pulmonary artery catheter (PAC) measurements of MPAP were contemporaneously compared to MPAP estimated utilising transthoracic echocardiography (TTE)-derived mean right ventricular to right atrial systolic pressure gradient added to invasively measured right atrial pressure. RESULTS: Of 53 patients assessed, 23 had estimable MPAP using TTE. The mean difference between TTE- and PAC-derived MPAP was 1.9 mmHg (SD 5.0), with upper and lower limits of agreement of 11.6 and -7.9 mmHg, respectively. The median absolute percentage difference between TTE- and PAC-derived MPAP was 7.5%. Inter-rater reliability assessment was performed for 15 patients, giving an intra-class correlation coefficient of 0.96 (95% confidence intervals, 0.89 to 0.99). CONCLUSIONS: This echocardiographic method of estimating MPAP in critically ill patients was not equivalent to invasively measured MPAP, based on our predefined clinically acceptable range (+/-5 mmHg). The accuracy of this method in critically ill patients was similar to the results obtained in ambulatory patients and compared favourably with regard to the accuracy with echocardiographic estimation of systolic pulmonary arterial pressure. The utility of this technique is limited by frequent inability to obtain an adequate tricuspid regurgitant time-velocity integral in critically ill patients. PMID- 25024844 TI - Work-related Musculoskeletal Disorders in Korea and Japan: A Comparative Description. AB - OBJECTIVES: Work related Musculoskeletal disorders (WMSD) is one of the most important problem in occupational health system of Korea and Japan, where the OHS system developed in similar socio-cultural environment. This study compared WMSD in Korea and Japan to review similarities and differences in their historical background, and development of prevention policies. METHODS: Scientific articles, government reports, and related official and non-official statistics on WMSD since the 1960s in Japan and Korea were reviewed. RESULTS: The historical background and basic structure of the compensation system in Korea and Japan largely overlapped. The issuing of WMSD in both countries appeared as upper limb disorder (ULD), named occupational cervicobrachial diseases (OCD) in Japan, and neck-shoulder-arm syndrome (NSA) 30 years later in Korea, following the change from an industrial structure to automated office work. Both countries developed manuals for diagnosis, guidelines for workplace management, and prevention policies. At present, compensation cases per covered insurers for WMSD are higher in Korea than in Japan, due to the social welfare system and cultural environment. Prevention policies in Korea are enforced more strongly with punitive measures than in Japan. In contrast, the Japanese system requires autonomous effort toward risk control and management, focusing on specific risky processes. CONCLUSIONS: WMSD in Korea and Japan have a similar history of identification and compensation structure, yet different compensation proportions per covered insurer and prevention policies. Follow-up study with international cooperation is necessary to improve both systems. PMID- 25024843 TI - Absence of gamma-sarcoglycan alters the response of p70S6 kinase to mechanical perturbation in murine skeletal muscle. AB - BACKGROUND: The dystrophin glycoprotein complex (DGC) is located at the sarcolemma of muscle fibers, providing structural integrity. Mutations in and loss of DGC proteins cause a spectrum of muscular dystrophies. When only the sarcoglycan subcomplex is absent, muscles display severe myofiber degeneration, but little susceptibility to contractile damage, suggesting that disease occurs not by structural deficits but through aberrant signaling, namely, loss of normal mechanotransduction signaling through the sarcoglycan complex. We extended our previous studies on mechanosensitive, gamma-sarcoglycan-dependent ERK1/2 phosphorylation, to determine whether additional pathways are altered with the loss of gamma-sarcoglycan. METHODS: We examined mechanotransduction in the presence and absence of gamma-sarcoglycan, using C2C12 myotubes, and primary cultures and isolated muscles from C57Bl/6 (C57) and gamma-sarcoglycan-null (gamma-SG(-/-)) mice. All were subjected to cyclic passive stretch. Signaling protein phosphorylation was determined by immunoblotting of lysates from stretched and non-stretched samples. Calcium dependence was assessed by maintaining muscles in calcium-free or tetracaine-supplemented Ringer's solution. Dependence on mTOR was determined by stretching isolated muscles in the presence or absence of rapamycin. RESULTS: C2C12 myotube stretch caused a robust increase in P-p70S6K, but decreased P-FAK and P-ERK2. Neither Akt nor ERK1 were responsive to passive stretch. Similar but non-significant trends were observed in C57 primary cultures in response to stretch, and gamma-SG(-/-) cultures displayed no p70S6K response. In contrast, in isolated muscles, p70S6K was mechanically responsive. Basal p70S6K activation was elevated in muscles of gamma-SG(-/-) mice, in a calcium-independent manner. p70S6K activation increased with stretch in both C57 and gamma-SG(-/-) isolated muscles, and was sustained in gamma-SG(-/ ) muscles, unlike the transient response in C57 muscles. Rapamycin treatment blocked all of p70S6K activation in stretched C57 muscles, and reduced downstream S6RP phosphorylation. However, even though rapamycin treatment decreased p70S6K activation in stretched gamma-SG(-/-) muscles, S6RP phosphorylation remained elevated. CONCLUSIONS: p70S6K is an important component of gamma-sarcoglycan dependent mechanotransduction in skeletal muscle. Our results suggest that loss of gamma-sarcoglycan uncouples the response of p70S6K to stretch and implies that gamma-sarcoglycan is important for inactivation of this pathway. Overall, we assert that altered load-sensing mechanisms exist in muscular dystrophies where the sarcoglycans are absent. PMID- 25024845 TI - Parasitic contamination of commonly consumed fresh leafy vegetables in benha, egypt. AB - This study evaluated the degree of parasitic contamination of vegetables which are commercialized and consumed fresh in Benha, Egypt. It included 530 vegetables: lettuce, watercress, parsley, green onion, and leek. Vegetables were collected randomly from markets within Benha. Samples were washed in saline, and the resulting washing solution was filtered and centrifuged to concentrate the parasitic stages. Sediments and supernatants were examined by iodine and modified Ziehl-Neelsen stained smears. Intestinal parasites were detected in 157/530 (29.6%) samples. Giardia lamblia cysts were the most prevalent parasite (8.8%) followed by Entamoeba spp. cysts (6.8%), Enterobius vermicularis eggs (4.9%), various helminth larvae (3.6%), Hymenolepis nana eggs (2.8%), Hymenolepis diminuta eggs (2.1%), and Ascaris lumbricoides eggs (0.6%). The highest contaminated vegetable was lettuce (45.5%) followed by watercress (41.3%), parsley (34.3%), green onion (16.5%), and leek (10.7%). These results indicate a significant seasonal variation (P < 0.05), with highest prevalence in summer (49%) and the lowest in winter (10.8%). These findings provide evidence for the high risk of acquiring parasitic infection from the consumption of raw vegetables in Benha, Egypt. Effective measures are necessary to reduce parasitic contamination of vegetables. PMID- 25024846 TI - Examining the choroid in ocular inflammation: a focus on enhanced depth imaging. AB - The choroid is the vascular layer that supplies the outer retina and is involved in the pathogenesis of several ocular conditions including choroidal tumors, age related macular degeneration, central serous chorioretinopathy, diabetic retinopathy, and uveitis. Nevertheless, difficulties in the visualization of the choroid have limited our understanding of its exact role in ocular pathology. Enhanced depth imaging optical coherent topography (EDI-OCT) is a novel, noninvasive technique that is used to evaluate choroidal thickness and morphology in these diseases. The technique provides detailed objective in vivo visualization of the choroid and can be used to characterize posterior segment inflammatory disorders, monitor disease activity, and evaluate efficacy of treatment. In this review we summarize the current application of this technique in ocular inflammatory disorders and highlight its utility as an additional tool in monitoring choroidal involvement in ocular inflammation. PMID- 25024847 TI - Residual negative symptoms differentiate cognitive performance in clinically stable patients with schizophrenia and bipolar disorder. AB - Cognitive deficits in various domains have been shown in patients with bipolar disorder and schizophrenia. The purpose of the present study was to examine if residual psychopathology explained the difference in cognitive function between clinically stable patients with schizophrenia and bipolar disorder. We compared the performance on tests of attention, visual and verbal memory, and executive function of 25 patients with schizophrenia in remission and 25 euthymic bipolar disorder patients with that of 25 healthy controls. Mediation analysis was used to see if residual psychopathology could explain the difference in cognitive function between the patient groups. Both patient groups performed significantly worse than healthy controls on most cognitive tests. Patients with bipolar disorder displayed cognitive deficits that were milder but qualitatively similar to those of patients with schizophrenia. Residual negative symptoms mediated the difference in performance on cognitive tests between the two groups. Neither residual general psychotic symptoms nor greater antipsychotic doses explained this relationship. The shared variance explained by the residual negative and cognitive deficits that the difference between patient groups may be explained by greater frontal cortical neurophysiological deficits in patients with schizophrenia, compared to bipolar disorder. Further longitudinal work may provide insight into pathophysiological mechanisms that underlie these deficits. PMID- 25024848 TI - Work Status and Return to the Workforce after Coronary Artery Bypass Grafting and/or Heart Valve Surgery: A One-Year-Follow Up Study. AB - Background. Several characteristics appear to be important for estimating the likelihood of reentering the workforce after surgery. The aim of the present study was to describe work status in a two-year time period around the time of cardiac surgery and estimate the probability of returning to the workforce. Methods. We included 681 patients undergoing coronary artery bypass grafting and/or heart valve procedures from 2003 to 2007 in the North Denmark Region. We linked hospital data to data in the DREAM database which holds information of everyone receiving social benefits. Results. At the time of surgery 17.3% were allocated disability pension and 2.3% were allocated a permanent part-time benefit. Being unemployed one year before surgery reduced the likelihood of return to the workforce (RR = 0.74 (0.60-0.92)) whereas unemployment at the time of surgery had no impact on return to the workforce (RR = 0.96 (0.78-1.18)). Sickness absence before surgery reduced the likelihood of return to the workforce. Conclusion. This study found the work status before surgery to be associated with the likelihood of return to the workforce within one year after surgery. Before surgery one-fifth of the population either was allocated disability pension or received a permanent part-time benefit. PMID- 25024850 TI - Opiate withdrawal complicated by tetany and cardiac arrest. AB - Patients with symptoms of opiate withdrawal, after the administration of opiate antagonist by paramedics, are a common presentation in the emergency department of hospitals. Though most of opiate withdrawal symptoms are benign, rarely they can become life threatening. This case highlights how a benign opiate withdrawal symptom of hyperventilation led to severe respiratory alkalosis that degenerated into tetany and cardiac arrest. Though this patient was successfully resuscitated, it is imperative that severe withdrawal symptoms are timely identified and immediate steps are taken to prevent catastrophes. An easier way to reverse the severe opiate withdrawal symptom would be with either low dose methadone or partial opiate agonists like buprenorphine. However, if severe acid base disorder is identified, it would be safer to electively intubate these patients for better control of their respiratory and acid-base status. PMID- 25024849 TI - Modulation of electrocortical brain activity by attention in individuals with and without tinnitus. AB - Age and hearing-level matched tinnitus and control groups were presented with a 40 Hz AM sound using a carrier frequency of either 5 kHz (in the tinnitus frequency region of the tinnitus subjects) or 500 Hz (below this region). On attended blocks subjects pressed a button after each sound indicating whether a single 40 Hz AM pulse of variable increased amplitude (target, probability 0.67) had or had not occurred. On passive blocks subjects rested and ignored the sounds. The amplitude of the 40 Hz auditory steady-state response (ASSR) localizing to primary auditory cortex (A1) increased with attention in control groups probed at 500 Hz and 5 kHz and in the tinnitus group probed at 500 Hz, but not in the tinnitus group probed at 5 kHz (128 channel EEG). N1 amplitude (this response localizing to nonprimary cortex, A2) increased with attention at both sound frequencies in controls but at neither frequency in tinnitus. We suggest that tinnitus-related neural activity occurring in the 5 kHz but not the 500 Hz region of tonotopic A1 disrupted attentional modulation of the 5 kHz ASSR in tinnitus subjects, while tinnitus-related activity in A1 distributing nontonotopically in A2 impaired modulation of N1 at both sound frequencies. PMID- 25024851 TI - Pulmonary arterial hypertension secondary to ethanol sclerotherapy for renal artery embolization. AB - Pulmonary arterial hypertension (PAH) has been reported as a major complication to consider and promptly manage in the use of ethanol sclerotherapy. Most of the available data on the development of PAH is derived from the use of ethanol for embolization of arteriovenous malformation, but it has been rarely reported in its other fields of application. We describe a case of outpatient renal artery embolization using ethanol, in which respiratory failure develops secondary to PAH despite adhering to safe practice protocols. We highlight the importance of pulmonary arterial pressure monitoring and the treatment steps to follow in order to avoid irreversible fatal outcomes. PMID- 25024852 TI - Orthodontic treatment of a mandibular incisor extraction case with invisalign. AB - Mandibular incisor extraction for orthodontic treatment is considered an unusual treatment option because of the limited number of patients that meet the criteria for such treatment. Accurate diagnosis and treatment planning is essential to achieve the desired results. Adult orthodontic patients are increasingly motivated by esthetic considerations and reject the idea of conventional fixed appliances. In recent years, Invisalign appliances have gained tremendous attention for orthodontic treatment of adult patients to meet their esthetic demands. In this case report, a case of Class I malocclusion was treated with mandibular incisor extraction using the Invisalign appliance system. Successful tooth alignment of both arches was achieved. The use of Invisalign appliance is an effective treatment option in adult patients with Class I malocclusion that requires incisor extraction due to moderate to severe mandibular anterior crowding. PMID- 25024853 TI - Debilitating chronic diarrhea caused by generalized gastrointestinal cytomegalovirus infection in an immunocompetent adult. AB - Gastrointestinal cytomegalovirus (CMV) infection is a common opportunistic infection in immunocompromised patients, especially patients with acquired immunodeficiency syndrome and transplant recipients. In contrast, CMV infection of the gastrointestinal tract is rare in immunocompetent individuals. We report a case of severe, protracted, and debilitating diarrhea caused by generalized CMV infection of the gastrointestinal tract in an elderly woman with no apparent immunosuppression. An extensive diagnostic investigation demonstrated CMV associated disease affecting both the upper and lower gastrointestinal tracts (esophagus, small intestine, and colon). Such extensive simultaneous involvement of the alimentary tract in an immunocompetent patient is rare and presents a diagnostic and therapeutic challenge. The diagnosis was based on a combination of endoscopic, histopathological, serological, and polymerase chain reaction analysis findings and our patient was successfully treated with intravenous ganciclovir. Our case demonstrates that gastrointestinal CMV infection should be considered in the differential diagnosis of severe chronic diarrhea in immunocompetent patients and that antiviral treatment may be justified in this setting. PMID- 25024854 TI - Autoimmune hemolytic anemia induced by levofloxacin. AB - Drug-induced autoimmune hemolytic anemia is a rare condition. We report the case of a 32-year-old white female who presented to the emergency department with generalized fatigue, fever, and jaundice. The patient reported using levofloxacin few days prior to presentation for urinary tract infection. The patient had evidence of hemolytic anemia with a hemoglobin of 6.7 g/dL which dropped to 5 g/dL on day 2, the direct Coombs test was positive, indirect bilirubin was 5.5 mg/dL, and LDH was 1283 IU/L. Further testing ruled out autoimmune disease, lymphoma, and leukemia as etiologies for the patient's hemolytic anemia. Levofloxacin was immediately stopped with a gradual hematologic recovery within few days. PMID- 25024855 TI - A Highly Rare Cause of Lumbar Spondylodiscitis with Epidural Abscess: Actinomyces israelii. AB - Actinomyces species may lead to slowly progressive infection of almost any site once mucosal breakdown exists; hence, it has the name "great pretender." Its diagnosis may be unthinkable unless proper cultures/histologies are taken. We describe a patient with lumbar spondylodiscitis and epidural abscess. This is an exceptional another disease by actinomycosis. PMID- 25024856 TI - Atypical pyoderma gangrenosum mimicking an infectious process. AB - We present a patient with atypical pyoderma gangrenosum (APG), which involved the patient's arm and hand. Hemorrhagic bullae and progressive ulcerations were initially thought to be secondary to an infectious process, but a biopsy revealed PG. Awareness of APG by infectious disease services may prevent unnecessary use of broad-spectrum antibiotics. PMID- 25024857 TI - Conus Medullaris Syndrome following Radionuclide Cisternography. AB - Radionuclide cisternography is generally considered to be a safe procedure without significant neurological complications. However, in this report we present a patient who developed conus medullaris syndrome following radionuclide cisternography. A 46-year-old woman underwent lumbar puncture followed by radionuclide cisternography with the diagnosis of hydrocephalus. After the cisternography, she developed voiding difficulty with perineal sensory loss. Lumbar MRI revealed a high signal intensity lesion on T2-weighted images at the level of conus medullaris. Considering its clinical course and MRI findings, a spinal cord infarction is highly suggested as a cause of the conus medullaris lesion in this patient. PMID- 25024858 TI - Concurrent rotator cuff tear and axillary nerve palsy associated with anterior dislocation of the shoulder and large glenoid rim fracture: a "terrible tetrad". AB - We present a case of concurrent rotator cuff tear and axillary nerve palsy resulting from anterior dislocation of the shoulder and a large glenoid rim fracture-a "terrible tetrad." A 61-year-old woman fell on her right shoulder. Radiographs showed anterior dislocation of the shoulder with a glenoid rim fracture, and an MRI two months after injury revealed a rotator cuff tear. Upon referral to our hospital, physical and electrophysiological examinations revealed axillary nerve palsy. The axillary nerve palsy was incomplete and recovering, and displacement of the glenoid rim fracture was minimal and already united; therefore, we surgically repaired only the rotator cuff tear three months after injury. The patient recovered satisfactorily following the operation. In patients whose axillary nerve palsy is recovering, surgeons should consider operating on rotator cuff tears in an attempt to prevent rotator cuff degeneration. PMID- 25024859 TI - Squamous cell carcinoma in combination with a symbrachydactyly: initial management and long-term followup. AB - A 68-year-old female patient presented with a rapidly growing, exulcerating tumor of the left hand in the area of a congenital symbrachydactyly at the digiti II and III. A biopsy of the tumor showed a squamous cell carcinoma. Further workup showed two suspicious axillar enhancements with no evidence of bony infiltration and no further metastasis. An amputation of the second and third ray of the left hand at the metacarpal level and additionally an axillar revision and lymph node dissection were performed and confirmed the suspicion of a squamous cell carcinoma, fortunately without affection of any lymph nodes. After 9 years the patient showed an excellent function of the left hand. Symbrachydactyly malformations and squamous cell carcinoma of the hand are both rare conditions. We could not find a reference that shows a common genetic condition to both and so far this is the first description of a squamous cell carcinoma in the region of a symbrachydactyly. It remains unclear whether our case is a coincidence of two rare independent diseases or there is a pathogenetic link between the malformation and the tumor on a genetic level. PMID- 25024860 TI - Description of the first case of adenomyomatosis of the gallbladder in an infant. AB - We report here the case of the youngest patient with adenomyomatosis of the gallbladder in a female infant diagnosed at 4 months of age. This diagnosis was made based on characteristic ultrasonography findings in a patient that was undergoing routine surveillance for a suspected clinical diagnosis of Beckwith Wiedemann syndrome. The patient remains asymptomatic and currently no surgical interventions have been needed. We review the pathophysiology and ultrasonographic findings of this rare condition and present a comparison with the only other four pediatric cases of adenomyomatosis of the gallbladder. PMID- 25024861 TI - Apparent Life-Threatening Event following Maternal Use of Temazepam during Labour. AB - Benzodiazepines are one of the most frequently prescribed psychotropic drugs during pregnancy. Despite the fact that these drugs have been in use for a long time, there is still debate about the safety for the developing fetus and neonate. We present a case of a newborn with an apparent life-threatening event shortly after birth following maternal temazepam use during labour and advise to be reserved in prescribing any dose of any kind of benzodiazepine during labour. PMID- 25024862 TI - Adult intramedullary ewing sarcoma of the proximal hip. AB - Ewing sarcoma of bone is classically a permeative lesion in the diaphysis of long bones in children. While they occur primarily in children and adolescents, they can be seen in young adults in their 20s, but these are typically seen in flat bones. The permeative nature of the lesion can elicit new bone formation creating a partially sclerotic appearance, cortical expansion presenting as a "Codman triangle," or have an "onion-skin" type of aggressive periosteal reaction/periostitis. Ewing sarcoma is rarely seen without an associated soft tissue mass and is even rarer to just have benign-appearing periostitis (e.g., thick, uniform, or wavy cortex). We present such a case of Ewing sarcoma in a young adult confined to just the medullary metadiaphysis without cortical erosion or soft-tissue mass. To the best of our knowledge, this is the first case to be reported in the radiology literature. PMID- 25024863 TI - A case of myxoid liposarcoma of the retroperitoneum: a challenging tumour for diagnosis and treatment. AB - Retroperitoneal sarcomas are rare neoplasms that account for only 1%-2% of all solid tumors and liposarcomas represent the most frequent histological type. We describe the case of a 44-year-old female with a retroperitoneal myxoid liposarcoma of 22 * 19 * 8 cm in size. The only symptoms were persistent pain and progressive tenderness of the abdomen lasting for two months. The mass was radically excised during laparotomy. CT and MRI were useful to clarify the site of origin of the tumor, relationships with other organs, and planning surgery but final diagnosis was based on histological findings. Here we review the literature about the challenging diagnosis, treatment, and prognostic factors of this disease. PMID- 25024864 TI - A 55-Year-Old Man with Stage IV Squamous Cell Carcinoma of the Right Groin after External Beam Radiation for Testicular Cancer. AB - Treating testicular cancer with adjuvant radiation has been associated with a number of second malignancies affecting the genitourinary tract and retroperitoneal structures; however, there have been few reported cases of cutaneous second malignancies. We report the case of a man who developed stage IV squamous cell carcinoma (SCC) of a condyloma after orchiectomy and adjuvant radiation for testicular cancer. We also review relevant literature available to date. A 55-year-old Caucasian man presented to the hospital with a large growth at the right groin which had grown into his right thigh preventing ambulation. His past medical history was significant for right testicular cancer of unknown pathology treated with orchiectomy and adjuvant radiation twenty years ago. Punch biopsy of the lesion revealed superficially invasive squamous cell carcinoma. He underwent excision of the growth with subsequent Cisplatin, radiation boost, and Paclitaxel regimens. Despite an aggressive treatment regimen and an initial good response, the patient's cancer progressed requiring palliative care. It is unclear whether or not therapeutic radiation in this case promoted the conversion of the patient's condyloma to a malignant lesion. Further studies are required at this time to clarify the clinical implications of these findings. PMID- 25024865 TI - Retracted: A Study on Course of Infection and Haematological Changes in falciparum-Infected in Comparison with Artemisinin(s)-Treated Mice. PMID- 25024866 TI - Quasireversible Process of Dopamine on Copper-Nickel Hydroxide Composite/Nitrogen Doped Graphene/Nafion Modified GCE and Its Electrochemical Application. AB - Cu-Ni(OH)2/N-GR/Nafion/GCE has been prepared by electrodeposition and activation with NaOH. The proposed modified GCE was studied by electrochemical methods. It is found that dopamine shows favorable redox cyclic voltammetric response on the proposed modified GCE with peak separation of 25 mV and large current compared with on single-component modified GCE. The kinetic of electrode process has also been investigated with rate constant of 6.618 * 10(-3) cm/s, which can be deduced to be a quasireversible or near-reversible process. The proposed method has been used for DA detection with linear range of 1.0 * 10(-7) mol/L to 4.6 * 10(-5) mol/L, and the detection limit is 3.3 * 10(-8) mol/L. The proposed method has favorable stability and reproducibility and has also been used to determine DA in simulated samples and DA injections with favorable recoveries of 98.4% to 102.6%. PMID- 25024867 TI - Perfluorocarbon nanoparticles: evolution of a multimodality and multifunctional imaging agent. AB - Perfluorocarbon nanoparticles offer a biologically inert, highly stable, and nontoxic platform that can be specifically designed to accomplish a range of molecular imaging and drug delivery functions in vivo. The particle surface can be decorated with targeting ligands to direct the agent to a variety of biomarkers that are associated with diseases such as cancer, cardiovascular disease, obesity, and thrombosis. The surface can also carry a high payload of imaging agents, ranging from paramagnetic metals for MRI, radionuclides for nuclear imaging, iodine for CT, and florescent tags for histology, allowing high sensitivity mapping of cellular receptors that may be expressed at very low levels in the body. In addition to these diagnostic imaging applications, the particles can be engineered to carry highly potent drugs and specifically deposit them into cell populations that display biosignatures of a variety of diseases. The highly flexible and robust nature of this combined molecular imaging and drug delivery vehicle has been exploited in a variety of animal models to demonstrate its potential impact on the care and treatment of patients suffering from some of the most debilitating diseases. PMID- 25024868 TI - Etiology and clinical outcomes of acute respiratory virus infection in hospitalized adults. AB - BACKGROUND: Etiologies and clinical profiles of acute respiratory viral infections need to be clarified to improve preventive and therapeutic strategies. MATERIALS AND METHODS: A retrospective observational study at a single, university-affiliated center was performed to evaluate the respiratory viral infection etiologies in children compared to that in adults and to document the clinical features of common viral infections for adults from July 2009 to April 2012. RESULTS: The common viruses detected from children (2,800 total patients) were human rhinovirus (hRV) (31.8%), adenovirus (AdV) (19.2%), respiratory syncytial virus (RSV) A (17.4%), RSV B (11.7%), and human metapneumovirus (hMPV) (9.8%). In comparison, influenza virus A (IFA) had the highest isolation rate (28.5%), followed by hRV (15.5%), influenza virus B (IFB) (15.0%), and hMPV (14.0%), in adults (763 total patients). Multiple viruses were detected in single specimens from 22.4% of children and 2.0% of adults. IFA/IFB, RSV A/B, and hMPV exhibited strong seasonal detection and similar circulating patterns in children and adults. Adult patients showed different clinical manifestations according to causative viruses; nasal congestion and rhinorrhea were more common in hRV and human coronavirus (hCoV) infection. Patients with RSV B, hRV, or AdV tended to be younger, and those infected with RSV A and hMPV were likely to be older. Those with RSV A infection tended to stay longer in hospital, enter the intensive care unit more frequently, and have a fatal outcome more often. The bacterial co detection rate was 26.5%, and those cases were more likely to have lower respiratory tract involvement (P = 0.001), longer hospital stay (P = 0.001), and higher mortality (P = 0.001). CONCLUSIONS: The etiologic virus of an acute respiratory infection can be cautiously inferred based on a patient's age and clinical features and concurrent epidemic data. Large-scale prospective surveillance studies are required to provide more accurate information about respiratory viral infection etiology, which could favorably influence clinical outcomes. PMID- 25024869 TI - Disclosure and Experienced Social Support are not Related to Anxiety or Depression in a German HIV Patient Cohort. AB - BACKGROUND: It is unclear to which extent the rate of disclosure of the diagnosis "HIV" to the social environment and the nature of experienced responses are correlated with the current mental health status of HIV-infected patients living in Germany. MATERIALS AND METHODS: Eighty consecutive patients of two German HIV outpatient clinics were enrolled. Patients performed the Hospital Anxiety and Depression Scale (HADS) in its German version. Disclosure behaviour and the experienced responses after disclosing as perceived by the participants were assessed using a questionnaire. In addition, patients were asked to state whether they felt guilty for the infection on a 1-4 point Likert scale. RESULTS: Pathological results on the anxiety scale were reached by 40% of male and 73% of female patients, and on the depression scale by 30% of male and 47% of female patients, thus significantly exceeding recently assessed values in the German general population, except for depression in males. None of the HADS scale results was interrelated either with the rate of disclosure or the experienced responses. 36% of patients reported to feel guilty for the infection, which was positively correlated with results from the HADS. LIMITATION: The time since the single disclosure events was not assessed, and the subgroup of women was comparably small. CONCLUSIONS: Despite substantial improvement in treatment, HIV infected patients in Germany still suffer from an elevated level of anxiety and, in part, depression. However, mental health status was neither related with disclosure behaviour nor with experienced responses. We hypothesize that internal beliefs may play a more important role. PMID- 25024870 TI - Increase in the Prevalence of Carbapenem-Resistant Acinetobacter Isolates and Ampicillin-Resistant Non-Typhoidal Salmonella Species in Korea: A KONSAR Study Conducted in 2011. AB - BACKGROUND: Antimicrobial surveillance is important for providing an up-to-date understanding of the epidemiology of antimicrobial resistance and for creating a forum for rational drug development. In this study, we analyzed antimicrobial test data generated in 2011 by hospitals and commercial laboratories participating in the Korean Nationwide Surveillance of Antimicrobial Resistance program (KONSAR). MATERIALS AND METHODS: Data on the results of susceptibility tests conducted in 32 hospitals and two commercial laboratories were analyzed. Data on isolates from patients admitted to an intensive care unit (ICU) and those admitted to other wards were compared. Intermediate susceptibility was not analyzed and duplicate isolates were excluded. RESULTS: Escherichia coli was the most prevalent organism identified in both the hospital and commercial laboratories. Among the hospital isolates, methicillin-resistant Staphylococcus aureus (MRSA), penicillin G-non-susceptible Streptococcus pneumoniae, and ampicillin-resistant Enterococcus faecium remained as prevalent as they were in 2009. The proportion of vancomycin-resistant E. faecium (VR-EFM) slightly decreased from 29% in 2009 to 23% in 2011. Resistance rates of Klebsiella pneumoniae to ceftazidime, cefoxitin, fluoroquinolone, and amikacin were 24%, 14%, 27%, and 8%, respectively. Resistance rates of Pseudomonas aeruginosa to fluoroquinolone, ceftazidime, imipenem, and amikacin were 33%, 20%, 22%, and 16%, respectively, whereas those of Acinetobacter spp. resistance were 71%, 66%, 64, and 51%, respectively. The prevalence of oxyimino-cephalosporin-resistant E. coli and K. pneumoniae, carbapenem-resistant Acinetobacter spp. and P. aeruginosa, MRSA, and VR-EFM among ICU isolates was higher than those among non-ICU isolates. Extended-spectrum beta-lactamase-producing E. coli and K. pneumoniae, imipenem resistant P. aeruginosa, and VR-EFM were more prevalent among isolates from commercial laboratories than those from hospitals. Resistance rates of K. pneumoniae to ceftazidime and amikacin decreased from 32% and 24% in 2005 to 24% and 8% in 2011, respectively. The resistance rate of P. aeruginosa to amikacin decreased from 22% in 2005 to 16% in 2011. The proportion of imipenem-resistant Acinetobacter spp. increased from 16% in 2005 to 64% in 2011. CONCLUSIONS: The prevalence of MRSA, penicillin G-non-susceptible S. pneumoniae, and ampicillin resistant E. faecium among clinical isolates tested in laboratories remained high. Multidrug resistance was more prevalent among isolates from ICUs. The prevalence of ceftazidime-resistant and amikacin-resistant K. pneumoniae and amikacin-resistant P. aeruginosa decreased after 2005, while the prevalence of imipenem-resistant Acinetobacter spp. increased. PMID- 25024871 TI - Delta neutrophil index as a prognostic marker of early mortality in gram negative bacteremia. AB - BACKGROUND: Sepsis is a syndrome that results in high morbidity and mortality. We investigated the delta neutrophil index (DN) as a predictive marker of early mortality in patients with gram-negative bacteremia. MATERIALS AND METHODS: We conducted a retrospective study at a tertiary referral hospital in South Korea from November 2010 to March 2011. The DN was measured at onset of bacteremia and 24 hours and 72 hours later. The DN was calculated using an automatic hematology analyzer. Factors associated with 10-day mortality were assessed using logistic regression. RESULTS: A total of 172 patients with gram-negative bacteremia were included in the analysis; of these, 17 patients died within 10 days of bacteremia onset. In multivariate analysis, Sequental organ failure assessment scores (odds ratio [OR]: 2.24, 95% confidence interval [CI]: 1.31 to 3.84; P = 0.003), DN-day 1 >= 7.6% (OR: 305.18, 95% CI: 1.73 to 53983.52; P = 0.030) and DN-day 3 >= DN day 1 (OR: 77.77, 95% CI: 1.90 to 3188.05; P = 0.022) were independent factors associated with early mortality in gram-negative bacteremia. Of four multivariate models developed and tested using various factors, the model using both DN-day 1 >= 7.6% and DN-day 3 >= DN-day 1 was most predictive early mortality. CONCLUSIONS: DN may be a useful marker of early mortality in patients with gram negative bacteremia. We found both DN-day 1 and DN trend to be significantly associated with early mortality. PMID- 25024872 TI - Alopecia areata associated with abacavir therapy. AB - Abacavir is a nucleoside reverse-transcriptase inhibitor that has been approved for use in combination with other retroviral agents in the treatment of HIV infection. Common adverse reactions include headache, fatigue, nausea, and rash. A fatal hypersensitivity reaction may occur in 5% of patients receiving abacavir; therefore, screening for HLA-B5701 should be performed before starting abacavir. Alopecia areata (AA) is infrequently reported in HIV-infected patients. Certain underlying conditions have been associated with AA, including a decreased CD4:CD8 ratio related to the progression of HIV infection, some opportunistic infections, and syphilis. Several antiretroviral drugs, such as zidovudine, indinavir, indinavir/ritonavir, lopinavir/ritonavir, and atazanavir/ritonavir have been implicated in the development of AA. At present, the occurrence of AA has not been associated with abacavir use. We cannot exclude that the use of abacavir and the development of AA could be coincidental. Nevertheless, patients given abacavir should be monitored for hair loss and the drug discontinued promptly if such signs appear. PMID- 25024873 TI - Isolation of Vibrio vulnificus from Seawater and Emerging Vibrio vulnificus Septicemia on Jeju Island. AB - Vibrio vulnificus is an opportunistic human pathogen, transmitted from seawater, raw oyster, and shellfish and responsible for severe septicemia. We studied V. vulnificus from surface seawater around Jeju Island between 2010 and 2011. In 2010, V. vulnificus was isolated and V. vulnificus septicemia was reported. Surface seawater temperature is an important factor for growth of V. vulnificus, and here we showed that high surface seawater temperature may influence growth of V. vulnificus and occurrence of emerging V. vulnificus septicemia on Jeju Island. This is the first report of isolation of V. vulnificus and emerging V. vulnificus septicemia on Jeju Island. PMID- 25024874 TI - Sternal Osteomyelitis Caused by Gordonia bronchialis after Open-Heart Surgery. AB - We report the case of a deep sternal wound infection with sternal osteomyelitis caused by Gordonia bronchialis after open-heart surgery. The isolate was identified as a G. bronchialis by 16S rRNA and hsp65 gene sequencing, having initially been misidentified as a Rhodococcus by a commercial phenotypic identification system. PMID- 25024875 TI - A Case of Severe HIV-Associated Psoriasis Successfully Treated with Acitretin Therapy. AB - Psoriasis is a chronic inflammatory skin disease that involves immune-mediated cutaneous inflammation and keratinocyte hyperproliferation. Psoriasis in patients with HIV responds poorly to treatment and has a high morbidity rate, thus posing a challenge to clinicians. Until now, there have been no documented cases of acitretin therapy for HIV-associated psoriasis in Korea. Here, we report a case of safe and successful therapy with acitretin in a 52-year-old man with HIV associated psoriasis that responded poorly to previous treatments including steroids and ultraviolet B phototherapy. We also review the relevant literature. PMID- 25024876 TI - A Case of Ventriculitis Associated with Renal Abscess Caused by Serotype K1 Klebsiella pneumoniae. AB - Recently, serotype K1 Klebsiella pneumoniae has been a major agent of an invasive syndrome characterized by liver abscess and its metastatic infection. Extrahepatic infection and its characteristics in patients with renal abscess caused by K. pneumoniae are poorly understood, and few cases of central nervous system infection have been reported. This is a report of 80-year-old woman with uncontrolled type 2 diabetes mellitus with renal abscess caused by serotype K1 K. pneumoniae, complicated with ventriculitis despite of appropriate use of antibiotics. Physicians need to be aware of possibility of metastatic infection in patients with serotype K1 K. pneumoniae infection, if they develop neurologic symptom and focus of infection is still present. PMID- 25024877 TI - Clinical guidelines for the antimicrobial treatment of bone and joint infections in Korea. AB - There are many various diseases in the bone and joint infections, and we tried to make antimicrobial treatment guidelines for common infectious diseases based on available data for microbiology and clinical trials. This guidelines focused on the treatment of osteomyelitis and septic arthritis, which can be experienced by physicians at diverse clinical settings. This guidelines is not applicable to diabetic foot infections, postoperative infections or post-traumatic infections which need special considerations. The guidelines for those conditions will be separately developed later. Surgical treatment of bone and joint infections, pediatric bone and joint infection, tuberculous bone and joint infection, and prophylactic antibiotic use were not included in this guideline. PMID- 25024878 TI - HIV Stigmatization Harms Individuals and Public Health. PMID- 25024879 TI - Improvement plan for the korean nationwide surveillance of antimicrobial resistance program. PMID- 25024881 TI - Combined use of covered stent and flow diversion to seal iatrogenic carotid injury with vessel preservation during transsphenoidal endoscopic resection of clival tumor. AB - BACKGROUND: Transsphenoidal tumor resection can lead to internal carotid artery (ICA) injury. Vascular disruption is often treated with emergent vessel deconstruction, incurring complications in a subset of patients with poor collateral circulation and resulting in minor and major ischemic strokes. METHODS: We attempted a novel approach combining a covered stent graft (Jostent) and two flow diverter stents [Pipeline embolization devices (PEDs)] to treat active extravasation from a disrupted right ICA that was the result of a transsphenoidal surgery complication. This disruption occurred during clival tumor surgery and required immediate sphenoidal sinus packing. Emergent angiography revealed continued petrous carotid artery extravasation, warranting emergent vessel repair or deconstruction for treatment. To preserve the vessel, we utilized a covered Jostent. Due to tortuosity and lack of optimal wall apposition, there was reduced, yet persistent extravasation from an endoleak after Jostent deployment that failed to resolve despite multiple angioplasties. Therefore, we used PEDs to divert the flow. RESULTS: Flow diversion relieved the extravasation. The patient remained neurologically intact post-procedure. CONCLUSIONS: This case demonstrates successful combined use of a covered stent and flow diverters to treat acute vascular injury resulting from transsphenoidal surgery. However, concerns remain, including the requirement of dual antiplatelet agents increasing postoperative bleeding risks, stent-related thromboembolic events, and delayed in-stent restenosis rates. PMID- 25024880 TI - Anemia and red blood cell transfusion in critically ill cardiac patients. AB - Anemia and red blood cell (RBC) transfusion occur frequently in hospitalized patients with cardiac disease. In this narrative review, we report the epidemiology of anemia and RBC transfusion in hospitalized adults and children (excluding premature neonates) with cardiac disease, and on the outcome of anemic and transfused cardiac patients. Both anemia and RBC transfusion are common in cardiac patients, and both are associated with mortality. RBC transfusion is the only way to rapidly treat severe anemia, but is not completely safe. In addition to hemoglobin (Hb) concentration, the determinant(s) that should drive a practitioner to prescribe a RBC transfusion to cardiac patients are currently unclear. In stable acyanotic cardiac patients, Hb level above 70 g/L in children and above 70 to 80 g/L in adults appears safe. In cyanotic children, Hb level above 90 g/L appears safe. The appropriate threshold Hb level for unstable cardiac patients and for children younger than 28 days is unknown. The optimal transfusion strategy in cardiac patients is not well characterized. The threshold at which the risk of anemia outweighs the risk of transfusion is not known. More studies are needed to determine when RBC transfusion is indicated in hospitalized patients with cardiac disease. PMID- 25024882 TI - Bilateral inverted vertebral arteries (V3 segment) in a case of congenital atlantoaxial dislocation: Distinct entity or a lateral variant of persistent first intersegmental artery? AB - BACKGROUND: Anomalous vertebral arteries (VAs), commonly involving the persistent first intersegmental artery (FIA), are often seen with congenital atlantoaxial dislocations (AAD). Here we describe an unusual variant consisting of bilateral VAs with normal loops but passing below the C1 (inverted VA) arch, distinctly different from the FIA. CASE DESCRIPTION: A 9-year-old boy presented with a spastic quadriparesis. Preoperative radiographic studies showed an irreducible AAD with an occipitalized CO-C1 and C2-3 fusion. Although both VAs exhibited proximal and distal loops like normal VA, the distal loops did not pass through the C1 transverse foramina and coursed inferior to the C1 arch instead. With this critical preoperative information, both VAs could be better safeguarded during dissection of the C1-2 facets. CONCLUSION: In the case presented, although the course of the inverted VAs is similar, the norm, they coursed inferior to both C1 arches. Careful evaluation of the preoperative radiological studies allowed for careful dissection of the inverted VA (horizontal loop) while opening the C1-2 joint for subsequent alignment (e.g. reduction) and bony fusion. This information also facilitates safer insertion of lateral mass screws (e.g. choosing the appropriate C1 screw length to gain adequate bony purchase without compromising anomalous VA). PMID- 25024884 TI - The "Cuban Epidemic Neuropathy" of the 1990s: A glimpse from inside a totalitarian disease. AB - During the 1990s, Cuba was struck by a rare epidemic disease. Up to 50,000 people were affected by a pathology compromising primarily the optic nerve but also peripheral nerves and even spinal cord. This is a testimony from a direct witness and participant in the initial study of the epidemics showing that in spite of claims of a "multifactorial" etiology, still in the literature, the root cause of this disease is just result of the deliberate deprivation of the most elementary economic rights by extreme Government control over a population left unable to tend to its elementary survival by itself, in spite of a thorough Government sponsored, universally celebrated Universal Healthcare System. PMID- 25024883 TI - Neurological susceptibility to a skull defect. AB - BACKGROUND: There continues to be considerable interest in the use of decompressive craniectomy in the management of neurological emergencies. The procedure is technically straightforward; however, it is becoming increasingly apparent that it is associated with significant complications. One complication that has received relatively little attention is the neurological dysfunction that can occur due to the absence of the bone flap and the subsequent distortion of the brain under the scalp as cerebral swelling subsides. The aim of this narrative review was to examine the literature available regarding the clinical features described, outline the proposed pathophysiology for these clinical manifestations and highlight the implications that this may have for rehabilitation of patients with a large skull defect. METHODS: A literature search was performed in the MEDLINE database (1966 to June 2012). The following keywords were used: Hemicraniectomy, decompressive craniectomy, complications, syndrome of the trephined, syndrome of the sinking scalp flap, motor trephined syndrome. The bibliographies of retrieved reports were searched for additional references. RESULTS: Various terms have been used to describe the different neurological signs and symptoms with which patients with a skull defect can present. These include; syndrome of the trephined, posttraumatic syndrome, syndrome of the sinking scalp flap, and motor trephined syndrome. There is, however, considerable overlap between the conditions described and a patient's individual clinical presentation. CONCLUSION: It is becoming increasingly apparent that certain patients are particularly susceptible to the presence of a large skull defect. The term "Neurological Susceptibility to a Skull Defect" (NSSD) is therefore suggested as a blanket term to describe any neurological change attributable to the absence of cranial coverage. PMID- 25024885 TI - The preparation of anastomosis site at the insular segment of middle cerebral artery. AB - BACKGROUND: An anastomosis at the insular segment of the middle cerebral artery (M2) is often required in cerebral reconstruction with high- or low-flow bypass. It is necessary to create a shallow, wide, fixed, and bloodless anastomosis field to achieve a safe and quick anastomosis for low surgical morbidity. We describe a method to perform a safe and quick anastomosis. METHODS: From 2009 to 2013, the technique was used in 20 procedures to create an extracranial M2 high-flow bypass. The Sylvian fissure was dissected wide open to expose the M2. A silicon sheet was laid under M2 and the absorbable gelatin-compressed sponges were inserted between M2 and the insula cortex to lift up the M2 and fix it. The rolling surgical sheets were placed at each edge of the dissected Sylvian fissure, instead of brain spatulas. Finally, a small suction tube was placed at the Sylvian fissure and cerebrospinal fluid was continuously sucked. The postoperative patency of the bypass was evaluated by three-dimensional computed tomographic angiography (3D-CTA) in the acute and chronic stages. RESULTS: In all cases, the operation field acquired for the anastomosis was adequate. The average time required for the procedure was 19 min 27 s. Good patency of all high-flow grafts was confirmed by postoperative three-dimensional computed tomography angiography (3D-CTA). CONCLUSION: In our series, there were no technical complications related to the anastomosis at M2 performed according to our method. PMID- 25024886 TI - Is intracranial pressure monitoring still required in the management of severe traumatic brain injury? Ethical and methodological considerations on conducting clinical research in poor and low-income countries. PMID- 25024887 TI - Neurologic injury in snowmobiling. AB - BACKGROUND: Snowmobiles are increasingly popular recreational, all-terrain utility vehicles that require skill and physical strength to operate given their inherent maneuverability, acceleration, and top speed capabilities. These same characteristics increase the risk of injury with the operation of these vehicles, particularly neurological injury. We characterize our series of 107 patients involved in snowmobiling accidents. METHODS: From January 2004 to January 2012, all snowmobiling-related injuries referred to our regional trauma center were reviewed. Information had been recorded in the hospital's trauma registry and medical records were retrospectively reviewed for data pertaining to the injuries, with particular emphasis on neurological injuries and any associated details. RESULTS: A total of 107 patients were identified. Ninety percent of injured riders were male. The mean age was 34.4 years (range 10-70), with 7% younger than age 16. The mean Injury Severity Score was 12.0 +/- 0.69 (range 1 34). Although not documented in all patients, alcohol use was found in 7.5% of the patients and drug use found in one patient. Documentation of helmet use was available for only 31 of the patients; of which 13% were not helmeted. Causes included being thrown, flipped, or roll-over (33%), striking a stationary object (27%), being struck by a snowmobile (9%), striking another snowmobile (5.5%) or a car, train, or truck (5.5%), being injured by the machine itself (9%), other (2%) or unspecified (18%). Head injuries occurred in 35% patients, including concussion, subarachnoid hemorrhage, subdural hematoma, contusion, and facial/skull fracture. Spinal fractures occurred in 21% of the patients. Fractures to the thoracic spine were the most common (50%), followed by the cervical (41%) and lumbar (36%) spine. There were also three brachial plexus injuries, one tibial nerve injury, and one internal carotid artery dissection. Average length of stay was 4.98 +/- 0.56 days. Disposition was home (78%), home with services (12%), rehabilitation placement (9%), and one death. Details regarding other systemic injuries will also be reviewed. CONCLUSIONS: Snowmobiles are a significant source of multi-trauma, particularly neurological injury. Neurosurgeons can play key roles in advocating for neurological safety in snowmobiling. PMID- 25024888 TI - Chronic encapsulated intracerebral hematoma: Three case reports and a literature review. AB - BACKGROUND: Chronic encapsulated intracerebral hematoma (CEIH) is one type of intracerebral hematoma that sometimes grows progressively while forming a capsule and presenting with neurological deficits. Although many cases of CEIH have been reported, correct preoperative diagnosis is very difficult. Only around 20% of cases are diagnosed preoperatively. CASE DESCRIPTION: We encountered three cases of CEIH in which causes were unidentified and difficult to diagnose. All three cases were treated surgically. In the first case, a 59-year-old male was diagnosed preoperatively with metastatic brain tumor. In the second case, a 62 year-old female was diagnosed preoperatively with glioblastoma. The third case involved a 58-year-old female diagnosed preoperatively with CEIH. CONCLUSION: We should keep in mind that CEIH is a differential diagnosis for intracerebral space occupying lesions. This report describes these three cases and discusses imaging findings and characteristics of CEIH. PMID- 25024889 TI - Prognostic value of the preoperative immunological profile in patients with glioblastoma. AB - BACKGROUND: Aim of our study was to determine the predictive impact of certain serum immunological markers on overall survival (OS) in patients with glioblastoma multiforme (GBM). METHODS: We assayed prospectively values of interleukin 2 (IL-2), immunoglobulin G (IgG), C4, CD3+, CD4+ and CD8+ cells via flow cytometry, enzyme-linked immunosorbent assay (ELISA) and radial immunodiffusion in preoperative sera of adult patients with de novo histologically confirmed supratentorial GBM. Kaplan-Meier method and Cox proportional hazards models were used to assess clinical, laboratory, and treatment prognostic factors for OS. RESULTS: Twenty-six consecutive patients were identified with a mean age of 59.6 years. Median follow up was 12 months. Lower IL-2 values (<7.97 pg/ml vs. >=7.97 pg/ml, P = 0.029) und CD4+ counts (<200 cells/MUl vs. >=200 cells/MUl, P < 0.001) correlated significantly with a shorter OS. The independent prognostic relevance of CD4 + counts was confirmed by the multivariate analysis (HR = 0.010, 95% CI 0.001-0.226, P = 0.011). Further independent prognostic factors for OS were type of resection (resection vs. biopsy) and administration of radiotherapy (yes/no). CONCLUSION: Preoperative values IL-2 and CD4+ cells in sera may carry a prognostic impact. Novel diagnostic models prior to histopathological confirmation may be used to predict prognosis of patients with GBM. Future studies should investigate whether targeting immune factors, such as CD4+ and IL-2, may improve the prognosis of patients with GBM. PMID- 25024890 TI - John Edwin Scarff (1898-1978) and endoscopic choroid plexus coagulation: A historical vignette. AB - John Edwin Scarff (1898-1978) was one of the pioneers of neuroendoscopy and the head of the Department of Neurological Surgery at Columbia University in New York from 1947 to 1949. In this article, we highlight the pioneering and longstanding efforts of John E. Scarff in support of endoscopic choroid plexus coagulation. These efforts represent an important part of the rich history of neuroendoscopy and a legacy to which the current procedure owes a great credit. PMID- 25024891 TI - Sideline concussion testing in high school football on Guam. AB - BACKGROUND: The risks of repeat concussions and returning to play (RTP) prior to the resolution of concussive symptoms are medically established. However, RTP guidelines for high school sports are varied and often notably absent. The island of Guam, a US territory, has a robust athletics program but lacks structure to reduce concussions or establish RTP protocols. Consequently, there is an opportunity to limit the incidence of "second-hit syndrome" and other harmful effects through education and testing. METHODS: We evaluated the feasibility of Sideline Concussion Testing SCT) as a novel feature of Guam high school athletics. Thirteen high school football players were observed over three consecutive football games. They were first given a questionnaire about concussion history, symptoms, medical evaluation, and RTP. Researchers used the King-Devick Test, a SCT tool, and baseline scores were recorded. If players were then observed to have significant head trauma or to show concussive symptoms, they were sidelined and tested. RESULTS: Five of 13 students had a previous concussion and limited awareness of RTP guidelines. Of those five, four received no medical consultation or stand down period before RTP. There was also a lack of understanding of what constitutes a concussion; five out of eight individuals who denied previous concussion confirmed having bell ringers, seeing stars, and other classic concussive symptoms. Over the course of the study the SCT identified three concussions, with significant deviations from baseline time on a test that measured visual and speech disturbances. CONCLUSIONS: The feasibility of SCT use in Guam high school football was established and our pilot study identified areas for improvement. Established definitions of concussion and RTP guidelines were lacking. Therefore, an opportunity exists through public health efforts that involve the entire community to increase concussion awareness and reduce injuries in high school sports on Guam. PMID- 25024892 TI - Primary angiosarcoma of the skull: A rare case report. AB - BACKGROUND: Angiosarcomas are rare high grade endothelial tumors characterized by rapidly proliferating anaplastic cells derived from blood vessels and lining irregular blood filled spaces. Primary neoplasms of the skull are rare, representing 2.6% of primary neoplasms of bone. Primary malignant neoplasms of the skull are even rarer, accounting for only 0.8% of primary malignant neoplasms of bone. CASE DESCRIPTION: We report a 32-year-old female who presented with right parieto-occipital swelling, which gradually increased in size. Radiology was suggestive of a calvarial soft tissue lesion in the right parieto-occipital region with destruction of the adjacent parieto-occipital bone with intracranial extra-axial extension. Complete surgical excision of the calvarial lesion was done under general anesthesia. Postoperative computed tomography (CT) scan of brain (plain and with contrast) showed complete excision of the tumor mass. Histopathological diagnosis was consistent with 'an angiosarcoma of the skull'. On immunohistochemistry, the atypical endothelial cells were highlighted by CD34, CD31, and factor VIII-related antigen. The patient received adjuvant radiotherapy to the tumor bed. CONCLUSION: Primary angiosarcoma of the skull is a rare tumor with less than 20 cases reported worldwide till date. The treatment should include complete surgical excision with a wide bony margin followed by adjuvant radiotherapy, which in our case has given a good locoregional control even at the end of 2 years. However, these patients should be followed up with repeated scans yearly to rule out locoregional as well as distant recurrence. PMID- 25024893 TI - Surgical embolectomy for middle cerebral artery occlusion after thrombolytic therapy: A report of two cases. AB - BACKGROUND: Occlusion of the intracranial main trunk results in a poor functional outcome and a high mortality rate. Accordingly, some revascularization procedures such as intravenous administration of recombinant tissue plasminogen activator (rt-PA), endovascular surgery, or surgical embolectomy in the very acute stage have been attempted. CASE DESCRIPTION: We describe two patients with middle cerebral artery occlusion due to cardiogenic embolism. One patient was subjected to surgical embolectomy shortly after intravenous rt-PA and the other was subjected to same after intra-arterial urokinase. Complete recanalization without new cerebral infarction territory was achieved in both patients. CONCLUSION: Based on our experience, we think that surgical embolectomy is an effective and safe procedure and should be attempted when no response to early thrombolytic therapy is obtained. PMID- 25024894 TI - Rescue revision techniques for end-to-side anastomosis: Technical note. AB - BACKGROUND: Extracranial-intracranial bypass operation is an essential procedure for cerebrovascular surgeons. Proper procedure of the bypass requires special skills, selected instruments, and training in the microsurgical laboratory. In spite of the high success rate for extracranial-intracranial bypass, a potential pitfall while performing an end-to-side anastomosis is poor blood flow or occlusion at the anastomotic site during surgery. If this happens, revision procedure is necessary. METHODS: We introduce our salvage techniques for anastomosis revision with or without recipient artery occlusion. RESULTS: With this method, ischemic complication related to revision procedure minimizes ischemic complications. CONCLUSIONS: The present technique is a simple method for anastomosis revision. PMID- 25024895 TI - Mobilizing a talent revolution in healthcare. PMID- 25024896 TI - Inter-observer variability in diagnosing radiological features of aneurysmal subarachnoid hemorrhage; a preliminary single centre study comparing observers from different specialties and levels of training. AB - BACKGROUND: A noncontrast computed tomography (CT) scan remains the initial radiological investigation of choice for a patient with suspected aneurysmal subarachnoid hemorrhage (aSAH). This initial scan may be used to derive key information about the underlying aneurysm which may aid in further management. The interpretation, however, is subject to the skill and experience of the interpreting individual. The authors here evaluate the interpretation of such CT scans by different individuals at different levels of training, and in two different specialties (Radiology and Neurosurgery). METHODS: Initial nonontrast CT scan of 35 patients with aSAH was evaluated independently by four different observers. The observers selected for the study included two from Radiology and two from Neurosurgery at different levels of training; a resident currently in mid training and a resident who had recently graduated from training of each specialty. Measured variables included interpreter's suspicion of presence of subarachnoid blood, side of the subarachnoid hemorrhage, location of the aneurysm, the aneurysm's proximity to vessel bifurcation, number of aneurysm(s), contour of aneurysm(s), presence of intraventricular hemorrhage (IVH), intracerebral hemorrhage (ICH), infarction, hydrocephalus and midline shift. To determine the inter-observer variability (IOV), weighted kappa values were calculated. RESULTS: There was moderate agreement on most of the CT scan findings among all observers. Substantial agreement was found amongst all observers for hydrocephalus, IVH, and ICH. Lowest agreement rates were seen in the location of aneurysm being supra or infra tentorial. There were, however, some noteworthy exceptions. There was substantial to almost perfect agreement between the radiology graduate and radiology resident on most CT findings. The lowest agreement was found between the neurosurgery graduate and the radiology graduate. CONCLUSION: Our study suggests that although agreements were seen in the interpretation of some of the radiological features of aSAH, there is still considerable IOV in the interpretation of most features among physicians belonging to different levels of training and different specialties. Whether these might affect management or outcome is unclear. PMID- 25024898 TI - Endoscopic removal of subgaleal hematoma in a 7-year-old patient treated with anticoagulant and antiplatelet agents. AB - BACKGROUND: Subgaleal hematomas frequently occur in children after head trauma and extend over the cranial sutures. Although conservative treatment suffices in most cases, surgical removal of a subgaleal hematoma is indicated when the patient presents with anemia and headache associated with its progressive enlargement. CASE DESCRIPTION: We present the case of a 7-year-old boy who was medicated with warfarin and aspirin due to a hypoplastic left ventricle and fell from a rock wherein he hit his head in the frontal region. Although a computed tomography scan of the head revealed no intracranial lesion, an extracranial hematoma was found to extend over the cranial sutures, leading to the diagnosis of subgaleal hematoma. The hematoma continued to grow gradually despite the cessation of warfarin and aspirin therapy immediately after the head trauma. Since the patient's headache and anemia were progressing as the hematoma enlarged, removal of the hematoma was performed 3 days after admission. Endoscopic hematoma removal was planned to enable accurate coagulation of the sites of bleeding and removal of the maximal amount of hematoma through minimal incision. The hematoma was completely removed, and the patient's postoperative course was excellent with alleviation of both the anemia and the headache. No sign of hematoma recurrence could be detected during 2 years follow-up. CONCLUSION: An angled endoscope can allow visualization of the deep subgaleal space, and this technique enabled direct visualization of the bleeding sites and accurate coagulation to prevent recurrence of hematoma. Endoscopic techniques, such as minimally invasive techniques, can allow sufficient removal of subgaleal hematoma with minimal morbidity, especially in patients such as ours. PMID- 25024899 TI - Benign scalp lump as an unusual presentation of extranodal Rosai-Dorfman disease. AB - BACKGROUND: Rosai-Dorfman disease (RDD) is a rare benign histioproliferative disease. It is typically characterized by benign histiocyte proliferation with lymphadenopathy, fever, and leukocytosis and was first described in 1969 by Rosai and Dorfman. Extranodal involvement has been reported in approximately up to 43% of the cases with isolated central nervous system (CNS) manifestations being even rarer. CASE DESCRIPTION: We report our management of a 41-year-old female with extranodalpurely CNS RDD presenting as a benign scalp lump. Her lump progressed from an asymptomatic benign lesion to one causing localized cerebral edema. Treatment was surgical excision of both the cervical and CNS lesions achieving complete removal of the lesions and resolution of her symptoms. CONCLUSION: RDD is a rare condition and isolated CNS RDD is even less common. Benign scalp lumps have a myriad of differential diagnoses, but RDD should be a consideration in the presence of preexisting RDD lesions at other sites given its potential to progress and result in morbidity. It is imperative to be aware that symptoms may be especially deceiving as the absence of lymphadenopathy may point away from RDD as the diagnosis. PMID- 25024900 TI - Movement and ranging patterns of the Common Chaffinch in heterogeneous forest landscapes. AB - The partitioning of production forests into discretely managed forest stands confronts animals with diversity in forest attributes at scales from point-level tree assemblages to distinct forest patches and range-level forest cover. We have investigated the movement and ranging patterns of male Common Chaffinches, Fringilla coelebs, in heterogeneous forest production landscapes during spring and summer in south-western Germany. We radio-tracked a total of 15 adult males, each for up to six days, recording locations at 10-min intervals. We then performed point-level tree surveys at all tracking locations and classified forest stand attributes for the areal covering of birds' ranges. Movement distances were shortest in beech forest stands and longer in spruce-mixed and non spruce conifer stands. Movement distances increased with stand age in beech stands but not in others, an effect that was only detectable in a multilevel hierarchical model. We found negligible effects of point-level tree assemblages and temperature on movement distances. Daily range estimates were from 0.01 to 8.0 hectare (median of 0.86 ha) with no evident impact of forest attributes on ranging patterns but considerable intra-individual variation in range sizes over consecutive days. Most daily ranges covered more than one forest stand type. Our results show that forest management impacts the movement behaviour of chaffinches in heterogeneous production forest. Although point-level effects of movement distances are weak compared with stand-level effects in this study, the hierarchical organization of forest is an important aspect to consider when analysing fine-scale movement and might exert more differentiated effects on bird species that are more sensitive to habitat changes than the chaffinch. PMID- 25024897 TI - Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration. AB - The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup((r)), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage. PMID- 25024901 TI - Limited geographic genetic structure detected in a widespread Palearctic corvid, Nucifraga caryocatactes. AB - The Eurasian or spotted nutcracker (Nucifraga caryocatactes) is a widespread resident corvid found throughout the Palearctic from Central Europe to Japan. Characterized by periodic bouts of irruptive dispersal in search of Pinus seed crops, this species has potential for high levels of gene flow across its range. Previous analysis of 11 individuals did not find significant range-wide population genetic structure. We investigated population structure using 924 base pairs of mitochondrial DNA control region sequence data from 62 individuals from 12 populations distributed throughout the nutcracker's range. We complemented this analysis by incorporating additional genetic data from previously published sequences. High levels of genetic diversity and limited population genetic structure were detected suggesting that potential barriers to dispersal do not restrict gene flow in nutcrackers. PMID- 25024902 TI - Beyond birth-weight: early growth and adolescent blood pressure in a Peruvian population. AB - Background. Longitudinal investigations into the origins of adult essential hypertension have found elevated blood pressure in children to accurately track into adulthood, however the direct causes of essential hypertension in adolescence and adulthood remains unclear. Methods. We revisited 152 Peruvian adolescents from a birth cohort tracked from 0 to 30 months of age, and evaluated growth via monthly anthropometric measurements between 1995 and 1998, and obtained anthropometric and blood pressure measurements 11-14 years later. We used multivariable regression models to study the effects of infantile and childhood growth trends on blood pressure and central obesity in early adolescence. Results. In regression models adjusted for interim changes in weight and height, each 0.1 SD increase in weight for length from 0 to 5 months of age, and 1 SD increase from 6 to 30 months of age, was associated with decreased adolescent systolic blood pressure by 1.3 mm Hg (95% CI -2.4 to -0.1) and 2.5 mm Hg (95% CI -4.9 to 0.0), and decreased waist circumference by 0.6 (95% CI -1.1 to 0.0) and 1.2 cm (95% CI -2.3 to -0.1), respectively. Growth in infancy and early childhood was not significantly associated with adolescent waist-to-hip ratio. Conclusions. Rapid compensatory growth in early life has been posited to increase the risk of long-term cardiovascular morbidities such that nutritional interventions may do more harm than good. However, we found increased weight growth during infancy and early childhood to be associated with decreased systolic blood pressure and central adiposity in adolescence. PMID- 25024903 TI - Diversity and antimicrobial potential of culturable heterotrophic bacteria associated with the endemic marine sponge Arenosclera brasiliensis. AB - Marine sponges are the oldest Metazoa, very often presenting a complex microbial consortium. Such is the case of the marine sponge Arenosclera brasiliensis, endemic to Rio de Janeiro State, Brazil. In this investigation we characterized the diversity of some of the culturable heterotrophic bacteria living in association with A. brasiliensis and determined their antimicrobial activity. The genera Endozoicomonas (N = 32), Bacillus (N = 26), Shewanella (N = 17), Pseudovibrio (N = 12), and Ruegeria (N = 8) were dominant among the recovered isolates, corresponding to 97% of all isolates. Approximately one third of the isolates living in association with A. brasiliensis produced antibiotics that inhibited the growth of Bacillus subtilis, suggesting that bacteria associated with this sponge play a role in its health. PMID- 25024904 TI - Geographic variation in the advertisement calls of Hyla eximia and its possible explanations. AB - Populations of species occupying large geographic ranges are often phenotypically diverse as a consequence of variation in selective pressures and drift. This applies to attributes involved in mate choice, particularly when both geographic range and breeding biology overlap between related species. This condition may lead to interference of mating signals, which would in turn promote reproductive character displacement (RCD). We investigated whether variation in the advertisement call of the mountain treefrog (Hyla eximia) is linked to geographic distribution with respect to major Mexican river basins (Panuco, Lerma, Balsas and Magdalena), or to coexistence with its sister (the canyon treefrog, Hyla arenicolor) or another related species (the dwarf treefrog, Tlalocohyla smithii). We also evaluated whether call divergence across the main river basins could be linked to genetic structure. We found that the multidimensional acoustic space of calls from two basins where H. eximia currently interacts with T. smithii, was different from the acoustic space of calls from H. eximia elsewhere. Individuals from these two basins were also distinguishable from the rest by both the phylogeny inferred from mitochondrial sequences, and the genetic structure inferred from nuclear markers. The discordant divergence of H. eximia advertisement calls in the two separate basins where its geographic range overlaps that of T. smithii can be interpreted as the result of two independent events of RCD, presumably as a consequence of acoustic interference in the breeding choruses, although more data are required to evaluate this possibility. PMID- 25024905 TI - Photobacterium sanctipauli sp. nov. isolated from bleached Madracis decactis (Scleractinia) in the St Peter & St Paul Archipelago, Mid-Atlantic Ridge, Brazil. AB - Five novel strains of Photobacterium (A-394T, A-373, A-379, A-397 and A-398) were isolated from bleached coral Madracis decactis (scleractinian) in the remote St Peter & St Archipelago (SPSPA), Mid-Atlantic Ridge, Brazil. Healthy M. decactis specimens were also surveyed, but no strains were related to them. The novel isolates formed a distinct lineage based on the 16S rRNA, recA, and rpoA gene sequences analysis. Their closest phylogenetic neighbours were Photobacterium rosenbergii, P. gaetbulicola, and P. lutimaris, sharing 96.6 to 95.8% 16S rRNA gene sequence similarity. The novel species can be differentiated from the closest neighbours by several phenotypic and chemotaxonomic markers. It grows at pH 11, produces tryptophane deaminase, presents the fatty acid C18:0, but lacks C16:0 iso. The whole cell protein profile, based in MALDI-TOF MS, distinguished the strains of the novel species among each other and from the closest neighbors. In addition, we are releasing the whole genome sequence of the type strain. The name Photobacterium sanctipauli sp. nov. is proposed for this taxon. The G + C content of the type strain A-394(T) (= LMG27910(T) = CAIM1892(T)) is 48.2 mol%. PMID- 25024906 TI - SHAPS-C: the Snaith-Hamilton pleasure scale modified for clinician administration. AB - Anhedonia, a diminished or lack of ability to experience and anticipate pleasure represents a core psychiatric symptom in depression. Current clinician assessment of anhedonia is generally limited to one or two all-purpose questions and most well-known psychometric scales of anhedonia are relatively long, self administered, typically not state sensitive, and are unsuitable for use in clinical settings. A user-friendly tool for a more in-depth clinician assessment of hedonic capacity is needed. The present study assessed the validity and reliability of a clinician administered version of the Snaith-Hamilton Pleasure Scale, the SHAPS-C, in 34 depressed subjects. We compared total and specific item scores on the SHAPS-C, SHAPS (self-report version), Montgomery-Asberg Depression Rating Scale (MADRS), and the Inventory of Depressive Symptomatology-Self Rating version (IDS-SR). We also examined construct, content, concurrent, convergent, and discriminant validity, internal consistency, and split-half reliability of the SHAPS-C. The SHAPS-C was found to be valid and reliable. The SHAPS and the SHAPS-C were positively correlated with one another, with levels of depression severity, as measured by the MADRS, and the IDS-SR total scores, and with specific items of the MADRS and IDS-SR sensitive to measuring hedonic capacity. Our investigation indicates that the SHAPS-C is a user friendly, reliable, and valid tool for clinician assessment of hedonic capacity in depressed bipolar and unipolar patients. PMID- 25024907 TI - Prediction uncertainty assessment of a systems biology model requires a sample of the full probability distribution of its parameters. AB - Multi-parameter models in systems biology are typically 'sloppy': some parameters or combinations of parameters may be hard to estimate from data, whereas others are not. One might expect that parameter uncertainty automatically leads to uncertain predictions, but this is not the case. We illustrate this by showing that the prediction uncertainty of each of six sloppy models varies enormously among different predictions. Statistical approximations of parameter uncertainty may lead to dramatic errors in prediction uncertainty estimation. We argue that prediction uncertainty assessment must therefore be performed on a per-prediction basis using a full computational uncertainty analysis. In practice this is feasible by providing a model with a sample or ensemble representing the distribution of its parameters. Within a Bayesian framework, such a sample may be generated by a Markov Chain Monte Carlo (MCMC) algorithm that infers the parameter distribution based on experimental data. Matlab code for generating the sample (with the Differential Evolution Markov Chain sampler) and the subsequent uncertainty analysis using such a sample, is supplied as Supplemental Information. PMID- 25024908 TI - QSpec: online control and data analysis system for single-cell Raman spectroscopy. AB - Single-cell phenotyping is critical to the success of biological reductionism. Raman-activated cell sorting (RACS) has shown promise in resolving the dynamics of living cells at the individual level and to uncover population heterogeneities in comparison to established approaches such as fluorescence-activated cell sorting (FACS). Given that the number of single-cells would be massive in any experiment, the power of Raman profiling technique for single-cell analysis would be fully utilized only when coupled with a high-throughput and intelligent process control and data analysis system. In this work, we established QSpec, an automatic system that supports high-throughput Raman-based single-cell phenotyping. Additionally, a single-cell Raman profile database has been established upon which data-mining could be applied to discover the heterogeneity among single-cells under different conditions. To test the effectiveness of this control and data analysis system, a sub-system was also developed to simulate the phenotypes of single-cells as well as the device features. PMID- 25024909 TI - Laboratory generation of new parthenogenetic lineages supports contagious parthenogenesis in Artemia. AB - Contagious parthenogenesis-a process involving rare functional males produced by a parthenogenetic lineage which mate with coexisting sexual females resulting in fertile parthenogenetic offspring-is one of the most striking mechanisms responsible for the generation of new parthenogenetic lineages. Populations of the parthenogenetic diploid brine shrimp Artemia produce fully functional males in low proportions. The evolutionary role of these so-called Artemia rare males is, however, unknown. Here we investigate whether new parthenogenetic clones could be obtained in the laboratory by mating these rare males with sexual females. We assessed the survival and sex ratio of the hybrid ovoviviparous offspring from previous crosses between rare males and females from all Asiatic sexual species, carried out cross-mating experiments between F1 hybrid individuals to assess their fertility, and estimated the viability and the reproductive mode of the resulting F2 offspring. Molecular analysis confirmed the parentage of hybrid parthenogenetic F2. Our study documents the first laboratory synthesis of new parthenogenetic lineages in Artemia and supports a model for the contagious spread of parthenogenesis. Our results suggest recessive inheritance but further experiments are required to confirm the likelihood of the contagious parthenogenesis model. PMID- 25024910 TI - Effectiveness of accommodation and constant resistance training on maximal strength and power in trained athletes. AB - Accommodation resistance is a training technique that may improve strength and power gains beyond those achieved by traditional free weights. In this method, chains are either added on a free-weight bar and combined with traditional plates or added to the bar as the entire load. Purpose. The aim of the current study was to compare the effectiveness of accommodation and constant resistance training methods during a four-week period on maximal strength and power in trained athletes. Methods. This study was comprised of 24 trained athletes, including 16 trained males [8 Wushu athletes (Kung-Fu) and 8 wrestlers, age: 20.5 +/- 2.00 yrs. old]. Participants were initially tested on weight, body circumference, fat percent, upper and lower body maximal strength, determined by the 1-repetition maximum (1RM) test, which determines the greatest amount of weight a person can successfully lift, and upper and lower body power. Participants were equally randomized to either accommodation or constant resistance training groups. Both groups underwent resistance training for a four-week period that consisted of three sessions per week. Multivariate repeated-measures analyses of variance of the data were used to verify significant differences in strength and power between groups. The modified Bonferroni post hoc test was used to compare the obtained results in pre-, mid-, and post test. Results. In the accommodation resistance group, there was a significant difference in lower body maximal strength compared to the constant group (163.12 +/- 18.82 kg in the accommodation group vs. 142.25 +/- 20.04 kg in the constant group, P = 0.04). No significant differences were found in upper body power, lower body power, and upper body maximal strength between the two groups (P > 0.05). Conclusion. Although there was only a significant difference in lower body maximal strength between groups, accommodation resistance training may induce a physiological training response by improving the strength and power of stabilizing muscle groups required to balance the bar if consistently used over time. PMID- 25024911 TI - Cascading effects of a highly specialized beech-aphid-fungus interaction on forest regeneration. AB - Specialist herbivores are thought to often enhance or maintain plant diversity within ecosystems, because they prevent their host species from becoming competitively dominant. In contrast, specialist herbivores are not generally expected to have negative impacts on non-hosts. However, we describe a cascade of indirect interactions whereby a specialist sooty mold (Scorias spongiosa) colonizes the honeydew from a specialist beech aphid (Grylloprociphilus imbricator), ultimately decreasing the survival of seedlings beneath American beech trees (Fagus grandifolia). A common garden experiment indicated that this mortality resulted from moldy honeydew impairing leaf function rather than from chemical or microbial changes to the soil. In addition, aphids consistently and repeatedly colonized the same large beech trees, suggesting that seedling depauperate islands may form beneath these trees. Thus this highly specialized three-way beech-aphid-fungus interaction has the potential to negatively impact local forest regeneration via a cascade of indirect effects. PMID- 25024912 TI - Identification of MHCII variants associated with chlamydial disease in the koala (Phascolarctos cinereus). AB - Chlamydiosis, the most common infectious disease in koalas, can cause chronic urogenital tract fibrosis and infertility. High titres of serum immunoglobulin G against 10 kDa and 60 kDa chlamydial heat-shock proteins (c-hsp10 and c-hsp60) are associated with fibrous occlusion of the koala uterus and uterine tube. Murine and human studies have identified associations between specific major histocompatibility complex class II (MHCII) alleles or genotypes, and higher c hsp 60 antibody levels or chlamydia-associated disease and infertility. In this study, we characterised partial MHCII DAB and DBB genes in female koalas (n = 94) from a single geographic population, and investigated associations among antibody responses to c-hsp60 quantified by ELISA, susceptibility to chlamydial infection, or age. The identification of three candidate MHCII variants provides additional support for the functional role of MHCII in the koala, and will inform more focused future studies. This is the first study to investigate an association between MHC genes with chlamydial pathogenesis in a non-model, free-ranging species. PMID- 25024913 TI - Facelock: familiarity-based graphical authentication. AB - Authentication codes such as passwords and PIN numbers are widely used to control access to resources. One major drawback of these codes is that they are difficult to remember. Account holders are often faced with a choice between forgetting a code, which can be inconvenient, or writing it down, which compromises security. In two studies, we test a new knowledge-based authentication method that does not impose memory load on the user. Psychological research on face recognition has revealed an important distinction between familiar and unfamiliar face perception: When a face is familiar to the observer, it can be identified across a wide range of images. However, when the face is unfamiliar, generalisation across images is poor. This contrast can be used as the basis for a personalised 'facelock', in which authentication succeeds or fails based on image-invariant recognition of faces that are familiar to the account holder. In Study 1, account holders authenticated easily by detecting familiar targets among other faces (97.5% success rate), even after a one-year delay (86.1% success rate). Zero acquaintance attackers were reduced to guessing (<1% success rate). Even personal attackers who knew the account holder well were rarely able to authenticate (6.6% success rate). In Study 2, we found that shoulder-surfing attacks by strangers could be defeated by presenting different photos of the same target faces in observed and attacked grids (1.9% success rate). Our findings suggest that the contrast between familiar and unfamiliar face recognition may be useful for developers of graphical authentication systems. PMID- 25024914 TI - You can't teach speed: sprinters falsify the deliberate practice model of expertise. AB - Many scientists agree that expertise requires both innate talent and proper training. Nevertheless, the highly influential deliberate practice model (DPM) of expertise holds that talent does not exist or makes a negligible contribution to performance. It predicts that initial performance will be unrelated to achieving expertise and that 10 years of deliberate practice is necessary. We tested these predictions in the domain of sprinting. In Studies 1 and 2 we reviewed biographies of 15 Olympic champions and the 20 fastest American men in U.S. history. In all documented cases, sprinters were exceptional prior to initiating training, and most reached world class status rapidly (Study 1 median = 3 years; Study 2 = 7.5). In Study 3 we surveyed U.S. national collegiate championships qualifiers in sprinters (n = 20) and throwers (n = 44). Sprinters recalled being faster as youths than did throwers, whereas throwers recalled greater strength and throwing ability. Sprinters' best performances in their first season of high school, generally the onset of formal training, were consistently faster than 95 99% of their peers. Collectively, these results falsify the DPM for sprinting. Because speed is foundational for many sports, they challenge the DPM generally. PMID- 25024915 TI - Functional connectivity in task-negative network of the Deaf: effects of sign language experience. AB - Prior studies investigating cortical processing in Deaf signers suggest that life long experience with sign language and/or auditory deprivation may alter the brain's anatomical structure and the function of brain regions typically recruited for auditory processing (Emmorey et al., 2010; Penicaud et al., 2013 inter alia). We report the first investigation of the task-negative network in Deaf signers and its functional connectivity-the temporal correlations among spatially remote neurophysiological events. We show that Deaf signers manifest increased functional connectivity between posterior cingulate/precuneus and left medial temporal gyrus (MTG), but also inferior parietal lobe and medial temporal gyrus in the right hemisphere- areas that have been found to show functional recruitment specifically during sign language processing. These findings suggest that the organization of the brain at the level of inter-network connectivity is likely affected by experience with processing visual language, although sensory deprivation could be another source of the difference. We hypothesize that connectivity alterations in the task negative network reflect predictive/automatized processing of the visual signal. PMID- 25024916 TI - Mobile phones carry the personal microbiome of their owners. AB - Most people on the planet own mobile phones, and these devices are increasingly being utilized to gather data relevant to our personal health, behavior, and environment. During an educational workshop, we investigated the utility of mobile phones to gather data about the personal microbiome - the collection of microorganisms associated with the personal effects of an individual. We characterized microbial communities on smartphone touchscreens to determine whether there was significant overlap with the skin microbiome sampled directly from their owners. We found that about 22% of the bacterial taxa on participants' fingers were also present on their own phones, as compared to 17% they shared on average with other people's phones. When considered as a group, bacterial communities on men's phones were significantly different from those on their fingers, while women's were not. Yet when considered on an individual level, men and women both shared significantly more of their bacterial communities with their own phones than with anyone else's. In fact, 82% of the OTUs were shared between a person's index and phone when considering the dominant taxa (OTUs with more than 0.1% of the sequences in an individual's dataset). Our results suggest that mobile phones hold untapped potential as personal microbiome sensors. PMID- 25024917 TI - Digital dissection of the masticatory muscles of the naked mole-rat, Heterocephalus glaber (Mammalia, Rodentia). AB - The naked mole-rat, Heterocephalus glaber, of the family Bathyergidae is a subterranean rodent that feeds on underground roots and tubers and digs extensive tunnel systems with its incisors. It is a highly unusual mammal with regard to its social structure, longevity, pain insensitivity and cancer resistance, all of which have made it the subject of a great deal of research in recent years. Yet, much of the basic anatomy of this species remains undocumented. In this paper, we describe the morphology of the jaw-closing musculature of the naked mole-rat, as revealed by contrast-enhanced micro-computed tomography. This technique uses an iodine stain to enable the imaging of soft tissues with microCT. The iodine enhanced scans were used to create 3D reconstructions of the naked mole-rat masticatory muscles from which muscle masses were calculated. The jaw-closing musculature of Heterocephalus glaber is relatively very large compared to other rodents and is dominated by the superficial masseter, the deep masseter and the temporalis. The temporalis in particular is large for a rodent, covering the entirety of the braincase and much of the rear part of the orbit. The morphology of the masseter complex described here differs from two other published descriptions of bathyergid masticatory muscles, but is more similar to the arrangement seen in other rodent families. The zygomaticomandibularis (ZM) muscle does not protrude through the infraorbital foramen on to the rostrum and thus the naked mole-rat should be considered protrogomorphous rather than hystricomorphous, and the morphology is consistent with secondarily lost hystricomorphy as has been previously suggested for Bathyergidae. Overall, the morphology of the masticatory musculature indicates a species with a high bite force and a wide gape-both important adaptations for a life dominated by digging with the incisors. PMID- 25024918 TI - A third-generation dispersion and third-generation hydrogen bonding corrected PM6 method: PM6-D3H+. AB - We present new dispersion and hydrogen bond corrections to the PM6 method, PM6 D3H+, and its implementation in the GAMESS program. The method combines the DFT D3 dispersion correction by Grimme et al. with a modified version of the H+ hydrogen bond correction by Korth. Overall, the interaction energy of PM6-D3H+ is very similar to PM6-DH2 and PM6-DH+, with RMSD and MAD values within 0.02 kcal/mol of one another. The main difference is that the geometry optimizations of 88 complexes result in 82, 6, 0, and 0 geometries with 0, 1, 2, and 3 or more imaginary frequencies using PM6-D3H+ implemented in GAMESS, while the corresponding numbers for PM6-DH+ implemented in MOPAC are 54, 17, 15, and 2. The PM6-D3H+ method as implemented in GAMESS offers an attractive alternative to PM6 DH+ in MOPAC in cases where the LBFGS optimizer must be used and a vibrational analysis is needed, e.g., when computing vibrational free energies. While the GAMESS implementation is up to 10 times slower for geometry optimizations of proteins in bulk solvent, compared to MOPAC, it is sufficiently fast to make geometry optimizations of small proteins practically feasible. PMID- 25024919 TI - Unexplained abdominal pain as a driver for inappropriate therapeutics: an audit on the use of intravenous proton pump inhibitors. AB - Background. Proton pump inhibitors (PPIs) are currently the most effective agents for acid-related disorders. However, studies show that 25-75% of patients receiving intravenous PPIs had no appropriate justification, indicating high rates of inappropriate prescribing. Objective. To examine the appropriate use of intravenous PPIs in accordance with guidelines and the efficacy of a prescribing awareness intervention at an Asian teaching institution. Setting. Prospective audit in a tertiary hospital in Malaysia. Method. Every 4th intravenous PPI prescription received in the pharmacy was screened against hospital guidelines. Interventions for incorrect indication/dose/duration were performed. Patients' demographic data, medical history and the use of intravenous PPI were collected. Included were all adult inpatients prescribed intravenous PPI. Main Outcome Measure. Proportion of appropriate IV PPI prescriptions. Results. Data for 106 patients were collected. Most patients were male [65(61.3%)], Chinese [50(47.2%)], with mean age +/- SD = 60.3 +/- 18.0 years. Most intravenous PPI prescriptions were initiated by junior doctors from the surgical [47(44.3%)] and medical [42(39.6%)] departments. Only 50/106(47.2%) patients had upper gastrointestinal endoscopy/surgery performed to verify the source of bleeding. Unexplained abdominal pain [81(76.4%)] was the main driver for prescribing intravenous PPIs empirically, out of which 73(68.9%) were for suspected upper gastrointestinal bleed. Overall, intravenous PPI was found to be inappropriately prescribed in 56(52.8%) patients for indication, dose or duration. Interventions on the use of intravenous PPI were most effective when performed by senior doctors (100%), followed by clinical pharmacists (50%), and inpatient pharmacists (37.5%, p = 0.027). Conclusion. Inappropriate intravenous PPI usage is still prevalent despite the enforcement of hospital guidelines. The promotion of prescribing awareness and evidence-based prescribing through education of medical staff could result in more judicious use of intravenous PPI and dose optimization. PMID- 25024920 TI - Single cell transcriptional analysis reveals novel innate immune cell types. AB - Single-cell analysis has the potential to provide us with a host of new knowledge about biological systems, but it comes with the challenge of correctly interpreting the biological information. While emerging techniques have made it possible to measure inter-cellular variability at the transcriptome level, no consensus yet exists on the most appropriate method of data analysis of such single cell data. Methods for analysis of transcriptional data at the population level are well established but are not well suited to single cell analysis due to their dependence on population averages. In order to address this question, we have systematically tested combinations of methods for primary data analysis on single cell transcription data generated from two types of primary immune cells, neutrophils and T lymphocytes. Cells were obtained from healthy individuals, and single cell transcript expression data was obtained by a combination of single cell sorting and nanoscale quantitative real time PCR (qRT-PCR) for markers of cell type, intracellular signaling, and immune functionality. Gene expression analysis was focused on hierarchical clustering to determine the existence of cellular subgroups within the populations. Nine combinations of criteria for data exclusion and normalization were tested and evaluated. Bimodality in gene expression indicated the presence of cellular subgroups which were also revealed by data clustering. We observed evidence for two clearly defined cellular subtypes in the neutrophil populations and at least two in the T lymphocyte populations. When normalizing the data by different methods, we observed varying outcomes with corresponding interpretations of the biological characteristics of the cell populations. Normalization of the data by linear standardization taking into account technical effects such as plate effects, resulted in interpretations that most closely matched biological expectations. Single cell transcription profiling provides evidence of cellular subclasses in neutrophils and leukocytes that may be independent of traditional classifications based on cell surface markers. The choice of primary data analysis method had a substantial effect on the interpretation of the data. Adjustment for technical effects is critical to prevent misinterpretation of single cell transcript data. PMID- 25024921 TI - scikit-image: image processing in Python. AB - scikit-image is an image processing library that implements algorithms and utilities for use in research, education and industry applications. It is released under the liberal Modified BSD open source license, provides a well documented API in the Python programming language, and is developed by an active, international team of collaborators. In this paper we highlight the advantages of open source to achieve the goals of the scikit-image library, and we showcase several real-world image processing applications that use scikit-image. More information can be found on the project homepage, http://scikit-image.org. PMID- 25024922 TI - Out of control mortality matters: the effect of perceived uncontrollable mortality risk on a health-related decision. AB - Prior evidence from the public health literature suggests that both control beliefs and perceived threats to life are important for health behaviour. Our previously presented theoretical model generated the more specific hypothesis that uncontrollable, but not controllable, personal mortality risk should alter the payoff from investment in health protection behaviours. We carried out three experiments to test whether altering the perceived controllability of mortality risk would affect a health-related decision. Experiment 1 demonstrated that a mortality prime could be used to alter a health-related decision: the choice between a healthier food reward (fruit) and an unhealthy alternative (chocolate). Experiment 2 demonstrated that it is the controllability of the mortality risk being primed that generates the effect, rather than mortality risk per se. Experiment 3 showed that the effect could be seen in a surreptitious experiment that was not explicitly health related. Our results suggest that perceptions about the controllability of mortality risk may be an important factor in people's health-related decisions. Thus, techniques for adjusting perceptions about mortality risk could be important tools for use in health interventions. More importantly, tackling those sources of mortality that people perceive to be uncontrollable could have a dual purpose: making neighbourhoods and workplaces safer would have the primary benefit of reducing uncontrollable mortality risk, which could lead to a secondary benefit from improved health behaviours. PMID- 25024923 TI - Bird-window collisions in the summer breeding season. AB - Birds that reside in urban settings face numerous human-related threats to survival, including mortality from bird-window collisions (BWCs). Our current understanding of this issue has largely been driven by data collected during spring and fall migration, and patterns of collision mortality during the summer breeding season remain relatively unexplored. We assessed BWCs during four breeding seasons (2009-2012) at a site in northwestern Illinois, USA, by comparing the abundance, richness, migratory class, and age of the species living around buildings to species mortally wounded by window collisions. We also systematically assessed the daily timing of BWCs throughout the breeding season. We documented BWCs in 4 of 25 (16%) species and 7 of 21 (33%) species in 2009 and 2010, respectively. The relationship between BWCs and abundance depended on age. For adults, BWCs were highest in the least abundant species, e.g., Red-eyed Vireo (Vireo olivaceus), and lowest in species with high abundance values, e.g., Chipping Sparrow (Spizella passerina). For juveniles, mortality was greatest for the most abundant species, and the American Robin (Turdus migratorius) accounted for 62% of all juvenile carcasses. Early in the breeding season, collision mortality was restricted to adults of Long-distance Migrants, whereas juveniles of all three migratory guilds (Long-distance and Short-distance Migrants and Permanent Residents) died at windows from late June through early August. Daily mortality for all species was highest between sunrise-1600 h and lowest from 1600 h-sunrise the next day. Generally, the species observed as carcasses matched birds considered a 'high risk' for BWCs, e.g., Ruby-throated Hummingbird (Archilochus colubris), and those considered 'low risk' were not observed as carcasses, e.g., Blue-gray Gnatcatcher (Polioptila caerulea). Our results suggest that the number of BWCs during the breeding season does not necessarily increase with abundance, but rather appears related to variation among species and age classes, which may have important implications on the population health of affected species. The mechanisms driving these differences are unknown, but may be related reproductive behavior, flight speed, distance movements, and dispersal patterns. PMID- 25024924 TI - Characterisation of the interaction of neuropilin-1 with heparin and a heparan sulfate mimetic library of heparin-derived sugars. AB - Background. Neuropilin-1 (NRP-1) is a multidomain membrane protein with soluble isoforms interacting with a complex network of other membrane receptors, their respective ligands and heparan sulfate (HS). It is involved in the development of vasculature, neural patterning, immunological responses and pathological angiogenesis. Methods. We have characterised the binding of a Fc fusion of rat NRP-1 (Fc rNRP-1) and of a soluble isoform, corresponding to the first four extracellular domains of human NRP-1, shNRP-1, using optical biosensor-based binding assays with a library of heparin derivatives. Selective labelling of lysines protected upon heparin binding allowed their identification by mass spectrometry. Results. Fc rNRP-1 bound to heparin with high affinity (2.5 nM) and fast ka (9.8 * 10(6) M(-1)s(-1)). Unusually, NRP-1 bound both highly sulfated and completely desulfated stretches of heparin and exhibited a complex pattern of preferences for chemically modified heparins possessing one or two sulfate groups, e.g., it bound heparin with just a 6-O sulfate group better than heparin with any two of N-sulfate, 6-O sulfate and 2-O sulfate. Mass-spectrometry based mapping identified that, in addition to the expected the b1 domain, the a1, and c domains and the L2 linker were also involved in the interaction. In contrast, shNRP-1 bound heparin far more weakly. This could only be shown by affinity chromatography and by differential scanning fluorimetry. Discussion. The results suggest that the interaction of NRP-1 with HS is more complex than anticipated and involving a far greater extent of the protein than just the b1-b2 domains. NRP-1's preference for binding long saccharide structures suggests it has the potential to bind large segments of HS chains and so organise their local structure. In contrast, the four domain soluble isoform, shNRP-1 binds heparin weakly and so would be expected to diffuse away rapidly from the source cell. PMID- 25024925 TI - The impact of maths support tutorials on mathematics confidence and academic performance in a cohort of HE Animal Science students. AB - Students embarking on a bioscience degree course, such as Animal Science, often do not have sufficient experience in mathematics. However, mathematics forms an essential and integral part of any bioscience degree and is essential to enhance employability. This paper presents the findings of a project looking at the effect of mathematics tutorials on a cohort of first year animal science and management students. The results of a questionnaire, focus group discussions and academic performance analysis indicate that small group tutorials enhance students' confidence in maths and improve students' academic performance. Furthermore, student feedback on the tutorial programme provides a deeper insight into student experiences and the value students assign to the tutorials. PMID- 25024926 TI - Drivers of macroinvertebrate community structure in unmodified streams. AB - Often simple metrics are used to summarise complex patterns in stream benthic ecology, thus it is important to understand how well these metrics can explain the finer-scale underlying environmental variation often hidden by coarser-scale influences. I sampled 47 relatively pristine streams in the central North Island of New Zealand in 2007 and (1) evaluated the local-scale drivers of macroinvertebrate community structure as well as both diversity and biomonitoring metrics in this unmodified landscape, and (2) assessed whether these drivers were similar for commonly used univariate metrics and multivariate structure. The drivers of community metrics and multivariate structure were largely similar, with % canopy cover and resource supply metrics the most commonly identified environmental drivers in these pristine streams. For an area with little to no anthropogenic influence, substantial variation was explained in the macroinvertebrate community (up to 70% on the first two components of a partial least squares regression), with both uni- and multivariate approaches. This research highlights two important points: (1) the importance of considering natural underlying environmental variation when assessing the response to coarse environmental gradients, and (2) the importance of considering canopy cover presence when assessing the impact of stressors on stream macroinvertebrate communities. PMID- 25024927 TI - No association between autistic traits and contextual influences on eye-movements during reading. AB - Individuals with autism spectrum disorders are claimed to show a local cognitive bias, termed "weak central coherence", which manifests in a reduced influence of contextual information on linguistic processing. Here, we investigated whether this bias might also be demonstrated by individuals who exhibit sub-clinical levels of autistic traits, as has been found for other aspects of autistic cognition. The eye-movements of 71 university students were monitored as they completed a reading comprehension task. Consistent with previous studies, participants made shorter fixations on words that were highly predicted on the basis of preceding sentence context. However, contrary to the weak central coherence account, this effect was not reduced amongst individuals with high levels of autistic traits, as measured by the Autism Spectrum Quotient (AQ). Further exploratory analyses revealed that participants with high AQ scores fixated longer on words that resolved the meaning of an earlier homograph. However, this was only the case for sentences where the two potential meanings of the homograph result in different pronunciations. The results provide tentative evidence for differences in reading style that are associated with autistic traits, but fail to support the notion of weak central coherence extending into the non-autistic population. PMID- 25024928 TI - Degradative actions of microbial xylanolytic activities on hemicelluloses from rhizome of Arundo donax. AB - Polysaccharidases from extremophiles are remarkable for specific action, resistance to different reaction conditions and other biotechnologically interesting features. In this article the action of crude extracts of thermophilic microorganisms (Thermotoga neapolitana, Geobacillus thermantarcticus and Thermoanaerobacterium thermostercoris) is studied using as substrate hemicellulose from one of the most interesting biomass crops, the giant reed (Arundo donax L.). This biomass can be cultivated without competition and a huge amount of rhizomes remains in the soil at the end of cropping cycle (10-15 years) representing a further source of useful molecules. Optimization of the procedure for preparation of the hemicellulose fraction from rhizomes of Arundo donax, is studied. Polysaccharidases from crude extracts of thermophilic microorganisms revealed to be suitable for total degradative action and/or production of small useful oligosaccharides from hemicelluloses from A. donax. Xylobiose and interesting tetra- and pentasaccharide are obtained by enzymatic action in different conditions. Convenient amount of raw material was processed per mg of crude enzymes. Raw hemicelluloses and pretreated material show antioxidant activity unlike isolated tetra- and pentasaccharide. The body of results suggest that rhizomes represent a useful raw material for the production of valuable industrial products, thus allowing to increase the economic efficiency of A. donax cultivation. PMID- 25024929 TI - Demand for abortion and post abortion care in Ibadan, Nigeria. AB - BACKGROUND: While induced abortion is considered to be illegal and socially unacceptable in Nigeria, it is still practiced by many women in the country. Poor family planning and unsafe abortion practices have daunting effects on maternal health. For instance, Nigeria is on the verge of not meeting the Millennium development goals on maternal health due to high maternal mortality ratio, estimated to be about 630 maternal deaths per 100,000 live births. Recent evidences have shown that a major factor in this trend is the high incidence of abortion in the country. The objective of this paper is, therefore, to investigate the factors determining the demand for abortion and post-abortion care in Ibadan city of Nigeria. METHODS: The study employed data from a hospital based/exploratory survey carried out between March to September 2010. Closed ended questionnaires were administered to a sample of 384 women of reproductive age from three hospitals within the Ibadan metropolis in South West Nigeria. However, only 308 valid responses were received and analysed. A probit model was fitted to determine the socioeconomic factors that influence demand for abortion and post-abortion care. RESULTS: The results showed that 62% of respondents demanded for abortion while 52.3% of those that demanded for abortion received post-abortion care. The findings again showed that income was a significant determinant of abortion and post-abortion care demand. Women with higher income were more likely to demand abortion and post-abortion care. Married women were found to be less likely to demand for abortion and post-abortion care. Older women were significantly less likely to demand for abortion and post-abortion care. Mothers' education was only statistically significant in determining abortion demand but not post-abortion care demand. CONCLUSION: The findings suggest that while abortion is illegal in Nigeria, some women in the Ibadan city do abort unwanted pregnancies. The consequence of this in the absence of proper post-abortion care is daunting. There is the need for policymakers to intensify public education against indiscriminate abortion and to reduce unwanted pregnancies. In effect, there is need for effective alternative family planning methods. This is likely to reduce the demand for abortion. Further, with income found as a major constraint, post abortion services should be made accessible to both the rich and poor alike so as to prevent unnecessary maternal deaths as a result of abortion related complications. PMID- 25024930 TI - Camelid reporter gene imaging: a generic method for in vivo cell tracking. AB - BACKGROUND: To combine the sensitivity of bioluminescent imaging (BLI) with the 3D and quantitative properties of pinhole single-photon emission computed tomography (SPECT)/micro-computed tomography (CT) (phSPECT/micro-CT), we generated stable cell lines that express a yellow-fluorescent protein (YFP) and Gaussia luciferase (GLuc) fusion protein (YFP/GLuc). For in vivo phSPECT detection of this YFP/GLuc protein, a nanobody, targeted against yellow and green fluorescent proteins (anti-YFP-Nb), was site specifically labelled with (99m)Tc. METHODS: Human embryonic kidney cells (HEK293T) were cultured and passaged every 3 days. 10E5 cells were transduced with YFP/GLuc-containing vector: both membrane targeted (MT-YFP/GLuc) and non-targeted (YFP/GLuc) fusion proteins were developed. These vectors were compared against a SKOV-3 cell line stably expressing green fluorescent-firefly luciferase (GFP/Fluc) and HEK293T cells expressing red fluorescent protein in combination with a Gaussia luciferase (Red/GLuc). Transduction efficiencies were scored by fluorescence microscopy, and transduced cells were enriched by fluorescence-activated cell sorting (FACS). GLuc and FLuc functionality was tested in vitro by list-mode BLI. Subsequently, cells were transplanted subcutaneously in athymic (nu/nu) mice (MT-YFP/GLuc: n = 4, YFP/GLuc: n = 6, GFP/FLuc: n = 6, Red/GLuc: n = 4). Labelling efficiency of anti-YFP-Nb was measured using instant thin layer chromatography. One week after transplantation, (99m)Tc-labelled anti-YFP-Nb was injected intravenously and pinhole (ph) SPECT/micro-CT was performed, followed by in vivo BLI. RESULTS: Cells showed high levels of fluorescence after transduction. The cells containing the MT-YFP/GLuc were positive on fluorescence microscopy, with the fluorescent signal confined to the cell membrane. After cell sorting, transduced cells were assayed by BLI and showed a significantly higher light output both in vitro and in vivo compared with non-transduced HEK293T cells. The anti-YFP-Nb labelling efficiency was 98%, and subsequent phSPECT/micro-CT demonstrated visible cell binding and significantly higher transplant-to-muscle ratio for both the MT YFP/GLuc and YFP/GLuc transplanted cells, compared with the GFP/FLuc and Red/GLuc group. CONCLUSION: This study provides a proof of principle for a nanobody-based cell tracking method, using a YFP/GLuc fusion protein and anti-YFP-Nb in a model of subcutaneously transplanted transduced HEK293T cells. PMID- 25024931 TI - Personalized predictive lung dosimetry by technetium-99m macroaggregated albumin SPECT/CT for yttrium-90 radioembolization. AB - BACKGROUND: For yttrium-90 ((90)Y) radioembolization, the common practice of assuming a standard 1,000-g lung mass for predictive dosimetry is fundamentally incongruent with the modern philosophy of personalized medicine. We recently developed a technique of personalized predictive lung dosimetry using technetium 99m ((99m)Tc) macroaggregated albumin (MAA) single photon emission computed tomography with integrated CT (SPECT/CT) of the lung as part of our routine dosimetric protocol for (90)Y radioembolization. Its rationales are the technical superiority of SPECT/CT over planar scintigraphy, ease and convenience of lung auto-segmentation CT densitovolumetry, and dosimetric advantage of patient specific lung parenchyma masses. METHODS: This is a retrospective study of our pulmonary clinical outcomes and comparison of lung dosimetric accuracy and precision by (99m)Tc MAA SPECT/CT versus conventional planar methodology. (90)Y resin microspheres (SIR-Spheres) were used for radioembolization. Diagnostic CT densitovolumetry was used as a reference for lung parenchyma mass. Pulmonary outcomes were based on follow-up diagnostic CT chest or X-ray. RESULTS: Thirty patients were analyzed. The mean lung parenchyma mass of our Southeast Asian cohort was 822 +/- 103 g standard deviation (95% confidence interval 785 to 859 g). Patient-specific lung parenchyma mass estimation by CT densitovolumetry on (99m)Tc MAA SPECT/CT is accurate (bias -21.7 g) and moderately precise (95% limits of agreement -194.6 to +151.2 g). Lung mean radiation absorbed doses calculated by (99m)Tc MAA SPECT/CT and planar methodology are both accurate (bias <0.5 Gy), but (99m)Tc MAA SPECT/CT offers better precision over planar methodology (95% limits of agreement -1.76 to +2.40 Gy versus -3.48 to +3.31 Gy, respectively). None developed radiomicrosphere pneumonitis when treated up to a lung mean radiation absorbed dose of 18 Gy at a median follow-up of 4.4 months. CONCLUSIONS: Personalized predictive lung dosimetry by (99m)Tc MAA SPECT/CT is clinically feasible, safe, and more precise than conventional planar methodology for (90)Y radioembolization radiation planning. PMID- 25024932 TI - Phytochemical analysis and radical scavenging profile of juices of Citrus sinensis, Citrus anrantifolia, and Citrus limonum. AB - BACKGROUND: The aim of the current investigation was to identify bioactive secondary metabolites including phenols, tannins, flavonoids, terpinedes, and steroids and compare the phytochemical analysis and antioxidant profile of the juice extracted from the fruits of Citrus sinensis, Citrus anrantifolia, and Citrus limonum. RESULTS: Phytochemical screening is important for the isolation of new, novel, and rare secondary metabolites before bulk extraction. Phytochemical analysis of the desired plant fruits of family Rutaceae revealed the presence of phenols, flavonoids, reducing sugars, steroids, terpinedes and tannins. The fruits of C. sinensis and C. anrantifolia exhibited the presence of phenols, flavonoids, reducing sugars, steroids, terpinedes and tannins, while the fruits of C. limonum indicated the presence of phenols, flavonoids, reducing sugars, terpinedes, and tannins. The fruits of selected plants were also subjected to antioxidant potential by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay against ascorbic acid at various concentrations. Among the tested plants, C. sinensis showed promising antiradical effect (84.81%) which was followed by C. Anrantifolia (80.05%) at 100 MUg/ml against ascorbic acid (96.36%). The C. limonum showed low antioxidant activity among the three selected plants of family Rutaceae. CONCLUSIONS: The current finding is baseline information in the use of the fruits of selected plants as food supplement which may be due to the presence of antioxidant molecules in the family Rutaceae. Further research is needed in this area to isolate the phenolic constituents which possess ideal antiradical potential. PMID- 25024933 TI - Infections caused by fluoroquinolone-resistant Escherichia coli following transrectal ultrasound-guided biopsy of the prostate. AB - An increase in the number of infections with fluoroquinolone (FQ)-resistant Escherichia coli following transrectal ultrasound-guided biopsy of the prostate (TRUBP) was observed in Louis Stokes Cleveland Department of Veterans Affairs Medical Center. This study investigated whether these infections were caused by a single strain of E. coli possessing distinct resistance and virulence determinants. Of 15 patients with urinary tract infection, 5 were complicated with bacteraemia and 1 with prostate abscess. Thirteen FQ-resistant isolates demonstrated mutations in the quinolone resistance-determining regions (QRDRs) of gyrA and parC but did not contain plasmid-mediated quinolone resistance determinants; blaCTX-M and blaCMY as well as genes coding for extended-spectrum beta-lactamases were also absent. Genes encoding aminoglycoside-modifying enzymes were discovered in an isolate that was gentamicin-resistant. The most prevalent sequence type (ST) was ST43 (n = 7), corresponding to ST131 in Achtman's multilocus sequence typing (MLST) scheme. These isolates (i) were distinguished as >95% similar by repetitive sequence-based PCR (rep-PCR), (ii) belonged to the virulent phylogenetic group B2 and (iii) contained plasmid types FIB, FIA and Frep. Several other strain types were present (ST2, ST27, ST30, ST44, ST472, ST494, ST511 and ST627). Non-ST43 isolates infected patients with more co morbidities but contained similar virulence factors (kpsMTII, iutA, papAH/papC and sfa/focDE). In our hospital, E. coli isolates causing TRUBP-related infection are quite heterogeneous (ST131 and other ST types) and are part of phylogenetic groups containing multiple virulence factors. PMID- 25024934 TI - Biochemical and Physiological Improvement in a Mouse Model of Smith-Lemli-Opitz Syndrome (SLOS) Following Gene Transfer with AAV Vectors. AB - Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis resulting from a defect in 7-dehydrocholesterol reductase (DHCR7), the enzyme that produces cholesterol from its immediate precursor 7-dehydrocholesterol. Current therapy employing dietary cholesterol is inadequate. As SLOS is caused by a defect in a single gene, restoring enzyme functionality through gene therapy may be a direct approach for treating this debilitating disorder. In the present study, we first packaged a human DHCR7 construct into adeno-associated virus (AAV) vectors having either type-2 (AAV2) or type-8 (AAV2/8) capsid, and administered treatment to juvenile mice. While a positive response (assessed by increases in serum and liver cholesterol) was seen in both groups, the improvement was greater in the AAV2/8-DHCR7 treated mice. Newborn mice were then treated with AAV2/8-DHCR7 and these mice, compared to mice treated as juveniles, showed higher DHCR7 mRNA expression in liver and a greater improvement in serum and liver cholesterol levels. Systemic treatment did not affect brain cholesterol in any of the experimental groups. Both juvenile and newborn treatments with AAV2/8-DHCR7 resulted in increased rates of weight gain indicating that gene transfer had a positive physiological effect. PMID- 25024935 TI - What's new in critical illness and injury science? State of the art in management of ARDS. PMID- 25024936 TI - Bench-to-bedside: The use of local anesthetics to attenuate inflammation in acute respiratory distress syndrome. AB - The acute respiratory distress syndrome (ARDS) remains a world-wide treatment challenge, with high morbidity and mortality. The central pathophysiology of ARDS centers around inflammation in the lung and increased microvascular permeability. Local anesthetics have been shown to have anti-inflammatory effects at the basic science level and the advent of local anesthetics with improved cardiovascular safety profiles has made use of local anesthetics in attenuating the inflammation in ARDS a recent research interest. In this review, we will provide a brief summary of some of the basic science work in local anesthetics and lung inflammation and provide a case for the bench to bedside research in this potential therapy. PMID- 25024937 TI - Predictors of mortality in patients of poisonous snake bite: Experience from a tertiary care hospital in Central India. AB - BACKGROUND AND AIMS: This study was undertaken, to assess the clinical parameters in patients of poisonous snakebite, complications which occurred in them, their outcome and to evaluate various clinical predictors of mortality. MATERIALS AND METHODS: Four hundred and thirty-two patients of snake bite were admitted, of which 172 did not show any signs of envenomation and excluded. Two hundred and sixty patients had signs of local or systemic envenomation and included. Complete clinical examination, blood counts, kidney function tests, serum electrolytes, coagulation profile was done in all patients. All received tetanus toxoid and anti-snake venom (ASV). Appropriate supportive treatment was given. Clinical and laboratory parameters were compared between patients who were discharged (Group A) and those who expired (Group B). All data analysis was performed by using stata software version 10 [StataCorp LP, Texas, USA] and SPSS version 11 [SPSS Inc, Chicago, USA]. RESULTS: Out of 260 patients, 58 died and 202 survived. Mean age was 34.97 +/- 14.07 years. One hundred and eighty-six (71.5%) patients were from rural areas and 74 (28.5%) from urban. 63.4% of bites occurred during rainy season. One hundred and ninety-seven (75.8%) had bite on lower limb and 62 (23.8%) on upper limbs. All 260 patients (100%) had pain at site of bite, local swelling in 252 (96.9%) and blackening of skin, blebs in 18 (6.9%). Seventy-seven (29.6%) had bleeding tendencies. Ptosis was present in all the 65 patients with signs of neuroparalysis. Eighty (30.8%) patients had acute renal failure. The mean duration of stay in survivors was 7.50 + 4.13 days and in non-survivors it was 3.45 + 3.02 days. Out of 58 who died 18 (31%) patients, succumbed within 24 hrs. On multivariate analysis, significant predictors o mortality were bleeding tendency (P = 0.013), mean PTTK (sec) (P = 0.047), respiratory failure (P = 0.045), shock (P = 0.013), mean ASV dose (cc) (P < 0.001). CONCLUSIONS: Mortality in patients with snake bite can be predicted by simple variables like presence of bleeding tendencies, respiratory failure, and shock. These parameters can help the doctors at peripheral health centers to predict outcome, so that such high risk cases can be referred to higher centers for expertise management without wasting time. PMID- 25024938 TI - Effect of gamma-hydroxybutyrate on keratinocytes proliferation: A preliminary prospective controlled study in severe burn patients. AB - BACKGROUND: Hypermetabolism and hyposomatotropism related to severe burns lead to impaired wound healing. Growth hormone (GH) boosts wound healing notably following stimulation of the production of insulin-like growth factor-1 (IGF1), a mitogen factor for keratinocytes. Gamma-hydroxybutyrate (GHB) stimulates endogenous GH secretion. AIM: To assess effects of GHB sedation on keratinocytes proliferation (based on immunohistochemical techniques). DESIGN: Monocentric, prospective, controlled trial. MATERIALS AND METHODS: Patients (aging 18-65 years, burn surface area >30%, expected to be sedated for at least one month) were alternately allocated, at the 5(th) day following injury, in three groups according to the intravenous GHB dose administered for 21 days: Evening bolus of 50 mg/kg (Group B), continuous infusion at the rate of 10 mg/kg/h (Group C), or absence of GHB (Group P). They all received local standard cares. Immunohistochemistry (Ki67/MIB-1, Ulex europaeus agglutinin-1 and Mac 387 antibodies) was performed at D21 on adjacent unburned skin sample for assessing any keratinocyte activation. Serum IGF1 levels were measured at initiation and completion of the protocol. STATISTICAL ANALYSIS: Categorical variables were compared with Chi-square test. Comparisons of medians were made using Kruskal Wallis test. Post hoc analyses were performed using Mann-Whitney test with Bonferroni correction for multiple comparisons. A P < 0.05 was considered to be statistically significant. RESULTS: A total of 14 patients completed the study (Group B: n = 5, Group C: n = 5, Group P: n = 4). Continuous administration of GHB was associated with a significant higher Ki67 immunolabeling at D21 (P = 0.049) and with a significant higher increase in the IGF1 concentrations at D21 (P = 0.024). No adverse effects were disclosed. CONCLUSIONS: Our preliminary data support a positive effect of GHB on keratinocyte proliferation and are encouraging enough to warrant large prospective studies. PMID- 25024939 TI - The 2014 Academic College of Emergency Experts in India's INDO-US Joint Working Group (JWG) White Paper on "Developing Trauma Sciences and Injury Care in India". AB - It is encouraging to see the much needed shift in the understanding and recognition of the concept of "burden of disease" in the context of traumatic injury. Equally important is understanding that the impact of trauma burden rivals that of nontraumatic morbidities. Subsequently, this paradigm shift reinstates the appeal for timely interventions as the standard for management of traumatic emergencies. Emergency trauma care in India has been disorganized due to inadequate sensitivity toward patients affected by trauma as well as the haphazard, nonuniform acceptance of standardization as the norm. Some of the major hospitals across various regions in the country do have trauma care units, but even those lack protocols to ensure that all trauma cases are handled by those units, largely owing to lack of structured referral system. As a first step to reform the state of trauma care in the country, a detailed overview is needed to gain insight into the prevailing reality. The objectives of this paper are to thus weave a foundation based on the statistical and qualitative burden of trauma in the country; the available infrastructure of trauma care centers equipped to deal with trauma; the need and scope of standardized protocols for intervention; and most importantly, the application of these in shaping educational initiatives in advancing emergency trauma care in the country. PMID- 25024940 TI - Pediatric neurotrauma. AB - Traumatic brain injury (TBI) is the leading cause of death and disability in children over 1 year of age. Knowledge about the age-specific types of injury and how to manage children with neurotrauma is essential to understanding and recognizing the extent and degree of injury and to optimize outcomes. In this article, we review the epidemiology, pathophysiology, and clinical management of pediatric neurotrauma. PMID- 25024941 TI - The use of heliox in critical care. AB - This paper reviews the medical use of helium oxygen mixture in obstructive airway disease in patients with croup, narrow endotracheal tubes (ETTs), respiratory distress syndrome, asthma, bronchiolitis, as well as patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and acute lung injury. In addition, some other indications of heliox use and some innovative methods of ventilation applied in pediatrics and adults are presented through review of the literature of current decade. Yet, to recommend heliox use seems to require more research based on clinical practice and observation through vaster and more robust investigations. PMID- 25024943 TI - Implementation of critical care response team. AB - Analyses of hospital deaths have indicated that a significant proportion of the reported deaths might have been prevented had the patients received intensive level care early enough. Over the past few decades the critical care response team has become an important means of preventing these deaths. As the proactive arm of intensive care delivery, the critical care response team places emphasis on early identification of signs of clinical deterioration, which then prompts the mobilization of intensive care brought right to the patient's bedside. However, the setting up of a critical care response team is a difficult undertaking involving different levels of cooperation between all service stakeholders, and a bringing together of professional expertise and experience in its operations. The implementation of a critical care response team often involves a high-level restructuring of a hospital's service orientation. In the present work, the various factors and different models to be considered in implementing a critical care response team are addressed. PMID- 25024942 TI - Thoracostomy tubes: A comprehensive review of complications and related topics. AB - Tube thoracostomy (TT) placement belongs among the most commonly performed procedures. Despite many benefits of TT drainage, potential for significant morbidity and mortality exists. Abdominal or thoracic injury, fistula formation and vascular trauma are among the most serious, but more common complications such as recurrent pneumothorax, insertion site infection and nonfunctioning or malpositioned TT also represent a significant source of morbidity and treatment cost. Awareness of potential complications and familiarity with associated preventive, diagnostic and treatment strategies are fundamental to satisfactory patient outcomes. This review focuses on chest tube complications and related topics, with emphasis on prevention and problem-oriented approaches to diagnosis and treatment. The authors hope that this manuscript will serve as a valuable foundation for those who wish to become adept at the management of chest tubes. PMID- 25024944 TI - Catheter-related bloodstream infections. AB - Central-venous-catheter-related bloodstream infections (CRBSIs) are an important cause of hospital-acquired infection associated with morbidity, mortality, and cost. Consequences depend on associated organisms, underlying pre-morbid conditions, timeliness, and appropriateness of the treatment/interventions received. We have summarized risk factors, pathogenesis, etiology, diagnosis, and management of CRBSI in this review. PMID- 25024945 TI - Changing trends of hemodynamic monitoring in ICU - from invasive to non-invasive methods: Are we there yet? AB - Hemodynamic monitoring in the form of invasive arterial, central venous pressure and pulmonary capillary wedge pressure monitoring may be required in seriously ill Intensive care unit patients, in patients undergoing surgeries involving gross hemodynamic changes and in patients undergoing cardiac surgeries. These techniques are considered the gold standards of hemodynamic monitoring but are associated with their inherent risks. A number of non-invasive techniques based on various physical principles are under investigation at present. The goal is to not only avoid the risk of invasive intervention, but also to match the gold standard set by them as far as possible. Techniques based on photoplethysmography, arterial tonometry and pulse transit time analysis have come up for continuous arterial pressure monitoring. Of these the first has been studied most extensively and validated, however it has been shown to be substandard in patients with gross hemodynamic instability. The other two still need further evaluation. While the non-invasive methods for arterial blood pressure monitoring are based on diverse technologies, those for measurement of central venous and pulmonary pressures are mostly based on imaging techniques such as echocardiography, Doppler ultrasound, computed tomography scan and chest X ray. Most of these techniques are based on measurement of the dimensions of the great veins. This makes them operator and observer dependent. However, studies done till now have revealed adequate inter-observer agreement. These techniques are still in their incipience and although initial studies are encouraging, further research is needed on this front. PMID- 25024946 TI - Community-acquired pseudomonas aeruginosa liver abscess with portal vein thrombosis in a child. AB - Pseudomonas aeruginosa is usually considered a relatively rare pathogen of pyogenic liver abscess in healthy children. A 3-year-old girl presented with fever, abdominal pain, and vomiting. Ultrasonography of the abdomen showed multiple liver abscesses. During her stay in hospital, she developed portal vein thrombosis, hepatic encephalopathy, and multiorgan dysfunction. Her blood culture and pus culture grew pseudomonas aeruginosa. She was started on intravenous antibiotics and supportive treatment. Ultrasound guided aspiration was done and a pigtail catheter was inserted. However, she did not respond to the treatment and died on the 14(th) day of admission. The immune work up of the patient was normal. Through this case, we wish to highlight this unusual case of community acquired pseudomonas aeruginosa liver abscess in a previously healthy child. Clinicians should be aware of this association for early diagnosis and timely management. PMID- 25024947 TI - Tulipalin A induced phytotoxicity. AB - Tulipalin A induced phytotoxicity is a persistent allergic contact dermatitides documented in floral workers exposed to Alstroemeria and its cultivars.[1] The causative allergen is tulipalin A, a toxic glycoside named for the tulip bulbs from which it was first isolated.[2] The condition is characterized by fissured acropulpitis, often accompanied by hyperpigmentation, onychorrhexis, and paronychia. More of the volar surface may be affected in sensitized florists. Dermatitis and paronychia are extremely common conditions and diagnostic errors may occur. A thorough patient history, in conjunction with confirmatory patch testing with a bulb sliver and tuliposide A exposure, can prevent misdiagnosis. We report a case of Tulipalin A induced phytotoxicity misdiagnosed as an unresolved tinea manuum infection in a patient evaluated for occupational exposure. PMID- 25024948 TI - Chlorhexidine mediated access site ulceration. PMID- 25024949 TI - Paying medical bills at Kiosks in China: Is it a viable model for the USA? PMID- 25024950 TI - Traumatic cardiac injury by gun nails. PMID- 25024951 TI - Interhemispheric modulation of dual-mode, noninvasive brain stimulation on motor function. AB - OBJECTIVE: To investigate the effects of simultaneous, bihemispheric, dual-mode stimulation using repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on motor functions and cortical excitability in healthy individuals. METHODS: Twenty-five healthy, right-handed volunteers (10 men, 15 women; mean age, 25.5 years) were enrolled. All participants received four randomly arranged, dual-mode, simultaneous stimulations under the following conditions: condition 1, high-frequency rTMS over the right primary motor cortex (M1) and sham tDCS over the left M1; condition 2, high-frequency rTMS over the right M1 and anodal tDCS over the left M1; condition 3, high-frequency rTMS over the right M1 and cathodal tDCS over the left M1; and condition 4, sham rTMS and sham tDCS. The cortical excitability of the right M1 and motor functions of the left hand were assessed before and after each simulation. RESULTS: Motor evoked potential (MEP) amplitudes after stimulation were significantly higher than before stimulation, under the conditions 1 and 2. The MEP amplitude in condition 2 was higher than both conditions 3 and 4, while the MEP amplitude in condition 1 was higher than condition 4. The results of the Purdue Pegboard test and the box and block test showed significant improvement in conditions 1 and 2 after stimulation. CONCLUSION: Simultaneous stimulation by anodal tDCS over the left M1 with high frequency rTMS over the right M1 could produce interhemispheric modulation and homeostatic plasticity, which resulted in modulation of cortical excitability and motor functions. PMID- 25024952 TI - Effect of the order of test diets on the accuracy and safety of swallowing studies. AB - OBJECTIVE: To assess whether the order of test diets influences the results of swallowing studies with regard to their accuracy and safety. METHODS: Subjects with suspected dysphagia underwent a videofluoroscopic swallowing study (VFSS) and/or a fiberoptic endoscopic evaluation of swallowing (FEES) and repeated the study on the same day or within a week. The order of test diets comprised of two different sets: trial 1 with the fluid first and trial 2 with the semi-solid food first. Main outcome measurements were the modified penetration-aspiration scale (mPAS) and the pharyngeal residue severity scale (PRSS) for the vallecula and the pyriform sinus. RESULTS: Sixty-six patients (44 men and 22 women, aged 65.0+/ 15.0 years) were enrolled in this study. Forty-three subjects were evaluated with VFSS only and 23 with both VFSS and FEES. As a result of the swallowing studies, there was no significant difference in each chosen diet sequence regarding mPAS and PRSS. Furthermore, there was no difference regarding the duration of studies, rate of premature study termination, rate of abnormal findings in post-study chest X-ray, and rate of fever or pneumonia post-study. CONCLUSION: The accuracy and safety of the swallowing studies do not rely on the order of test diets. PMID- 25024953 TI - Functional electrical stimulation to ankle dorsiflexor and plantarflexor using single foot switch in patients with hemiplegia from hemorrhagic stroke. AB - OBJECTIVE: To evaluate the effects of functional electrical stimulation (FES) to ankle dorsiflexor (DF) and ankle plantarflexor (PF) on kinematic and kinetic parameters of hemiplegic gait. METHODS: Fourteen post-stroke hemiplegic patients were considered in this study. Electrical stimulation was delivered to ankle DF during the swing phase and ankle PF during the stance phase via single foot switch. Kinematic and kinetic data were collected using a computerized motion analysis system with force plate. Data of no stimulation (NS), DF stimulation only (DS), DF and PF stimulation (DPS) group were compared among each other. RESULTS: Peak ankle dorsiflexion angle during swing phase is significantly greater in DS group (-1.55 degrees +/-9.10 degrees ) and DPS group (-2.23 degrees +/-9.64 degrees ), compared with NS group (-6.71 degrees +/-11.73 degrees ) (p<0.05), although there was no statistically significant difference between DS and DPS groups. Ankle plantarflexion angle at toe-off did not show significant differences among NS, DS, and DPS groups. Peak knee flexion in DPS group (34.12 degrees +/-13.77 degrees ) during swing phase was significantly greater than that of NS group (30.78 degrees +/-13.64 degrees ), or DS group (32.83 degrees +/ 13.07 degrees ) (p<0.05). CONCLUSION: In addition to the usual FES application stimulating ankle DF during the swing phase, stimulation of ankle PF during stance phase can help to increase peak knee flexion during the swing phase. This study shows the advantages of stimulating the ankle DF and PF using single foot switch for post-stroke gait. PMID- 25024954 TI - Ultrasonographic measurement of transverse abdominis in stroke patients. AB - OBJECTIVE: To compare transverse abdominis (TrA) contractility in stroke patients with hemiparesis and healthy adults using musculoskeletal ultrasonography. METHODS: Forty-seven stroke patients with hemiparesis and 25 age-matched healthy control subjects participated in this study. Stroke patients were divided into three groups on the basis of their degree of ambulation. Group A consisted of 9 patients with wheelchair ambulation, group B of 23 patients with assisted ambulation, and group C of 15 patients with independent ambulation. Inter-rater reliability regarding ultrasonographic measurement of abdominal muscle thickness in the control group was assessed by two examiners. The TrA contraction ratio (TrA contracted thickness/TrA resting thickness) was measured during abdominal drawing-in maneuver and was compared between the patients and the control group and between the ambulation groups. RESULTS: The inter-rater reliability ranged from 0.900 to 0.947. The TrA contraction ratio was higher in the non-paretic side than in the paretic side (1.40+/-0.62 vs. 1.14+/-0.35, p<0.01). The TrA contraction ratio of the patient group was lower in the non-paretic side as well as in the paretic side than that of the control group (right 1.85+/-0.29, left 1.92+/-0.42; p<0.001). No difference was found between the ambulation regarding the TrA contraction ratio. CONCLUSION: The TrA contractility in hemiparetic stroke patients is significantly decreased in the non-paretic side as well as in the paretic side compared with that of healthy adults. Ultrasonographic measurement can be clinically used in the evaluation of deep abdominal muscles in stroke patients. PMID- 25024955 TI - Characteristics of neuropathic pain in patients with spinal cord injury. AB - OBJECTIVE: To characterize neuropathic pain in patients with spinal cord injury (SCI) according to classification used in the study by Baron et al. (Baron classification), a classification of neuropathic pain based on the mechanism. To also compare the patterns of neuropathic pain in SCI patients with those in patients with other etiologies and to determine the differences in patterns of neuropathic pain between the etiologies. METHODS: This was a descriptive cross sectional study. We used the Baron classification to investigate the characteristics of neuropathic pain in SCI. Sixty-one SCI patients with neuropathic pain (The Leeds assessment of neuropathic symptoms and signs score >=12) were enrolled in this study between November 2012 and August 2013, after excluding patients <20 of age, patients with visual analog scale (VAS) score <3, pregnant patients, and patients with systemic disease or pain other than neuropathic pain. RESULTS: The most common pain characteristic was pricking pain followed by electrical pain and numbness. The mean VAS score of at-level neuropathic pain was 7.51 and that of below-level neuropathic pain was 6.83. All of the patients suffered from rest pain, but 18 (54.6%) patients with at-level neuropathic pain and 20 (50.0%) patients with below-level neuropathic pain suffered from evoked pain. There was no significant difference in between at level and below-level neuropathic pains. CONCLUSION: The result was quite different from the characteristics of post-herpetic neuralgia, but it was similar to the characteristics of diabetic neuropathy as shown in the study by Baron et al., which means that sensory nerve deafferentation may be the most common pathophysiologic mechanism of neuropathic pain after SCI. Since in our study, we included short and discrete symptoms and signs based on diverse mechanisms, our results could be helpful for determining further evaluation and treatment. PMID- 25024956 TI - Changes of functional outcomes according to the degree of completeness of spinal cord injury. AB - OBJECTIVE: To evaluate whether an initial complete impairment of spinal cord injury (SCI) contributes to the functional outcome prediction, we analyzed the relationship between the degree of complete impairment according to the American Spinal Injury Association impairment scale (AIS), the posterior tibial nerve somatosensory evoked potential (PTSEP) and the changes of functional indices. METHODS: Sixty subjects with SCI were studied who received rehabilitative management for over 2 months. The degree of completeness on basis of the initial AIS and PTSEP were evaluated at the beginning of rehabilitation. Following treatment, several functional indices, such as walking index for spinal cord injury version II (WISCI II), spinal cord independence measure version III (SCIM III), Berg Balance Scale (BBS), and Modified Barthel Index (MBI), were evaluated until the index score reached a plateau value. RESULTS: The recovery efficiency of WISCI and BBS revealed a statistically significant difference between complete and incomplete impairments of initial AIS and PTSEP. The SCIM and MBI based analysis did not reveal any significant differences in terms of the degree of AIS and PTSEP completeness. CONCLUSION: AIS and PTSEP were highly effective to evaluate the prognosis in post-acute phase SCI patients. BBS and WISCI might be better parameters than other functional indices for activities of daily living to predict the recovery of the walking ability in post-acute SCI. PMID- 25024957 TI - Phasic changes in bladder compliance during filling cystometry of the neurogenic bladder. AB - OBJECTIVE: To investigate phasic changes during filling cystometry that most accurately represent detrusor properties, regardless of other factors affecting detrusor contractility. METHODS: Seventy-eight patients (59 males, 19 females; mean age, 48.2 years) with spinal cord injuries were enrolled. Urodynamic studies were performed using a normal saline filling rate of 24 mL/min. We calculated bladder compliance values of the detrusor muscle in each of three filling phase intervals, which divided the filling cystometrogram into three phases referable to the cystometric capacity or maximum cystometric capacity. The three phases were sequentially delineated by reference to the pressure-volume curve reflecting bladder filling. RESULTS: Bladder compliance during the first and second phases of filling cystometry was significantly correlated with overall bladder compliance in overactive detrusors. The highest coefficient of determination (r(2)=0.329) was obtained during the first phase of the pressure-volume curve. Bladder compliance during all three phases was significantly correlated with overall bladder compliance of filling cystometry in underactive detrusors. However, the coefficient of determination was greatest (r(2)=0.529) during the first phase of filling cystometry. CONCLUSION: Phasic bladder compliance during the early filling phase (first filling phase) was the most representative assessment of overall bladder compliance during filling cystometry. Careful determination of early phase filling is important when seeking to acquire reliable urodynamic data on neurogenic bladders. PMID- 25024958 TI - Differences in urodynamic variables for vesicoureteral reflux depending on the neurogenic bladder type. AB - OBJECTIVE: To compare the urodynamic study variables at the onset of vesicoureteral reflux (VUR) between the overactive and underactive bladders in patients with spinal cord injury who presented with VUR. METHODS: A total of 28 (13 cases of detrusor overactivity and 15 detrusor underactivity) men were enrolled. We compared the urodynamic variables between the two groups; detrusor pressure and bladder compliance, the infused volume at the onset of VUR measured on a voiding cystourethrography and cystometric capacity, maximum detrusor pressure, and bladder compliance during filling cystometry were recorded. RESULTS: At the onset of VUR, the bladder volume and compliance, except for the detrusor pressure, showed a significant difference between the two groups. The detrusor pressure, bladder volume, and bladder compliance relative to the cystometric capacity showed a significant difference between the two groups. The detrusor pressure, bladder volume, and bladder compliance at the onset of VUR relative to the cystometric bladder capacity did not show any significant difference between the two groups. CONCLUSION: There were differences in some variables at the onset of VUR depending on the type of neurogenic bladder. The VUR occurred at a lower capacity in neurogenic bladder with detrusor overactivity than in neurogenic bladder with detrusor underactivity at the same pressure. VUR occurred at a lower intravesical pressure compared to that known as the critical detrusor pressure (>=40 cm H2O) required for the development of VUR. The results of our study demonstrate that the detrusor pressure should be maintained lower than the well known effective critical detrusor pressure for the prevention and treatment of VUR. PMID- 25024959 TI - Clinical significance of urodynamic study parameters in maintenance of renal function in spinal cord injury patients. AB - OBJECTIVE: To analyze association between urodynamic study (UDS) parameters and renal function in spinal cord injured (SCI) patients with neurogenic detrusor overactivity. METHODS: Patients with a suprasacral SCI, who underwent UDS and radioisotope renogram at least twice between January 1, 2006 and January 31, 2013, were included. UDS (cystometric capacity, reflex volume, compliance, and maximal detrusor pressure) and radioisotope renogram (total effective renal plasma flow [ERPF] of both kidneys) data were collected. The following were conducted to reanalyze any association between reflex volume and ERPF: initial and follow-up results of consecutive evaluations were compared; a mixed-model regression analysis to account for clustered data was conducted to evaluate the association between UDS parameters and ERPF; and finally, a mixed-model analysis type 3 test with data pairs, of which the first evaluation showed involuntary detrusor contraction. RESULTS: A total of 150 patients underwent 390 evaluations which were arranged into 240 pairs of consecutive evaluations, of which 171 had first evaluations with observed involuntary detrusor contraction. The following results were obtained: cystometric capacity was significantly larger and maximal detrusor pressure was significantly lower on follow-up; on univariate analysis, reflex volume and maximal detrusor pressure were significant, and multivariate analysis using these two parameters showed that maximal detrusor pressure is significantly associated with total ERPF; and no significant differences were observed. CONCLUSION: Maximal detrusor pressure should be closely monitored in the urologic management of neurogenic detrusor overactivity in SCI patients. The results also may serve as a reference for regular UDS follow-up. PMID- 25024960 TI - Randomized controlled trial for efficacy of capsular distension for adhesive capsulitis: fluoroscopy-guided anterior versus ultrasonography-guided posterolateral approach. AB - OBJECTIVE: To find the most effective procedure to treat adhesive capsulitis of the shoulder, we evaluated the clinical effects of an ultrasonographic-guided anterior approach capsular distension and a fluoroscopy-guided posterolateral approach capsular distension. We expected the anterior approach to be better than the posterolateral approach because the rotator interval, a triangular anatomic area in the anterosuperior aspect of the shoulder, which is considered an important component of the pathology of adhesive capsulitis. METHODS: PARTICIPANTS WERE RANDOMLY ASSIGNED TO TWO GROUPS: 27 patients in group A were injected by an anterior approach with 2% lidocaine (5 mL), contrast dye (5 mL), triamcinolone (40 mg), and normal saline (9 mL) under fluoroscopic guidance in the operating room. Twenty-seven patients in group B were injected using a posterolateral approach with 2% lidocaine (5 mL), triamcinolone (40 mg), and normal saline (14 mL) under ultrasonographic guidance. After injection, all patients received physiotherapy four times in the first postoperative week and then two times each week for eight more weeks. Treatment effects were assessed using the shoulder pain and disability index (SPADI), visual numeric scale (VNS), passive range of motion (PROM), hand power (grip and pinch) at baseline and at one week, five and nine weeks after injection. RESULTS: SPADI, VNS, PROM, and hand power improved in one week, five and nine weeks in both groups. Statistically significant differences were not observed in SPADI, VNS, PROM, or hand power between groups. CONCLUSION: Ultrasonography-guided capsular distension by a posterolateral approach has similar effects to fluoroscopy-guided capsular distension by an anterior approach. PMID- 25024961 TI - Effects of custom-made rigid foot orthosis on pes planus in children over 6 years old. AB - OBJECTIVE: To identify the effects of a custom-made rigid foot orthosis (RFO) in children over six years old with pes planus. METHODS: The medical records of 39 children (mean age, 10.3+/-4.09 years) diagnosed with pes planus, fitted with RFOs, and had who more than two consecutive radiological studies were reviewed. The resting calcaneal stance position (RCSP), anteroposterior talocalcaneal angle (APTCA), lateral talocalcaneal angle (LTTCA), the lateral talometatarsal angle (LTTMA), and calcaneal pitch (CP) of both feet were measured to evaluate foot alignment. After diagnosis, children were fitted with a pair of RFOs and recommended to walk with heel strike and reciprocal arm swing to normalize the gait pattern. A follow-up clinical evaluation with radiological measurements was performed after 12-18 months and after 24 months of RFO application. Post-hoc analysis was used to test for significant differences between the radiological indicators and RCSP. RESULTS: With RFOs, all radiological indicators changed in the corrective direction except LTTCA. RCSP and CP in the third measurement showed significant improvement in comparison with the second and baseline measurements. Additionally, APTCA and LTTMA revealed improvements at the third measurement versus the baseline measurements. CONCLUSION: This study revealed that radiological indicators improved significantly after 24 months of RFO application. A prospective long-term controlled study with radiographical evaluation is necessary to confirm the therapeutic effects of RFOs and to determine the optimal duration of wear in children with pes planus. PMID- 25024962 TI - The Usefulness of M-B CDI-K Short Form as Screening Test in Children With Language Developmental Delay. AB - OBJECTIVE: To investigate the usefulness of MacArthur-Bates Communicative Development Inventories-Korean (M-B CDI-K) short form as a screening test in children with language developmental delay. METHODS: From April 2010 to May 2012, a total of 87 patients visited the department of physical medicine and rehabilitation of National Health Insurance Service Ilsan Hospital with the complaint of language developmental delay and were enrolled in this study. All patients took M-B CDI-K short form and Sequenced Language Scale for Infants (SELSI) or Preschool Receptive-Expressive Language Scale (PRES) according to their age. RESULTS: The study group consisted of 58 male patients and 29 female patients and the mean age was 25.9 months. The diagnosis are global developmental delay in 26 patients, selective language impairment in 31 patients, articulation disorder in 7 patients, cerebral palsy in 8 patients, autism spectrum disorder in 4 patients, motor developmental delay in 4 patients, and others in 7 patients. Seventy-one patients are diagnosed with language developmental delay in SELSI or PRES and of them showed 69 patients a high risk in the M-B CDI-K short form. Sixteen patients are normal in SELSI or PRES and of them showed 14 patients non high risk in the M-B CDI-K short form. The M-B CDI-K short form has 97.2% sensitivity, 87.5% specificity, a positive predictive value of 0.97, and a negative predictive value of 0.88. CONCLUSION: The M-B CDI-K short form has a high sensitivity and specificity so it is considered as an useful screening tool in children with language developmental delay. Additional researches targeting normal children will be continued to supply the specificity of the M-B CDI-K short form. PMID- 25024963 TI - Diagnostic Value of Facial Nerve Antidromic Evoked Potential in Patients With Bell's Palsy: A Preliminary Study. AB - OBJECTIVE: To assess the practical diagnostic value of facial nerve antidromic evoked potential (FNAEP), we compared it with the diagnostic value of the electroneurography (ENoG) test in Bell's palsy. METHODS: In total, 20 patients with unilateral Bell's palsy were recruited. Between the 1st and 17th days after the onset of facial palsy, FNAEP and ENoG tests were conducted. The degeneration ratio and FNAEP latency difference between the affected and unaffected sides were calculated in all subjects. RESULTS: In all patients, FNAEP showed prolonged latencies on the affected side versus the unaffected side. The difference was statistically significant. In contrast, there was no significant difference between sides in the normal control group. In 8 of 20 patients, ENoG revealed a degeneration ratio less than 50%, but FNAEP show a difference of more than 0.295+/-0.599 ms, the average value of normal control group. This shows FNAEP could be a more sensitive test for Bell's palsy diagnosis than ENoG. In particular, in 10 patients tested within 7 days after onset, an abnormal ENoG finding was noted in only four of them, but FNAEP showed a significant latency difference in all patients at this early stage. Thus, FANEP was more sensitive in detecting facial nerve injury than the ENoG test (p=0.031). CONCLUSION: FNAEP has some clinical value in the diagnosis of facial nerve degeneration. It is important that FNAEP be considered in patients with facial palsy at an early stage and integrated with other relevant tests. PMID- 25024964 TI - Impact of aerobic exercise training on endothelial function in acute coronary syndrome. AB - OBJECTIVE: To confirm the improvement in arterial endothelial function by aerobic exercise training, flow-mediated dilation (FMD) was tested by ultrasonography. METHODS: Patients who received percutaneous coronary intervention due to acute coronary syndrome were included. The patients who participated in cardiac rehabilitation (CR) program were categorized as the CR group, and others who did not participate as the control. Both groups underwent initial graded exercise test (GXT) and FMD testing. Subsequently, the CR group performed aerobic exercise training sessions. Patients in control only received advice regarding the exercise methods. After six weeks, both groups received follow-up GXT and FMD testing. RESULTS: There were 16 patients in each group. There were no significant differences in the general characteristics between the groups. The VO2peak was 28.6+/-4.7 mL/kg/min in the CR group and 31.5+/-7.4 mL/kg/min in the control at first GXT, and was 31.1+/-5.1 ml/kg/min in the CR group and 31.4+/-6.0 ml/kg/min in the control at the follow-up GXT in six weeks. There was a statistically significant improvement in VO2peak only for CR group patients. FMD value was 7.59%+/-1.26% in the CR group, 7.36%+/-1.48% in the control at first and 9.46%+/ 1.82% in the CR group, and 8.31%+/-2.04% in the control after six weeks. There was a statistically significant improvement in FMD value in the CR group. CONCLUSION: According to the results of GXT and FMD testing, six-week exercise based CR program improved VO2peak and endothelial functions significantly. Thus, exercise-based CR program is necessary in patients with coronary artery disease. PMID- 25024965 TI - Exercise therapy for an older patient with left ventricular assist device. AB - A left ventricular assist device (LVAD) is a mechanical circulation support implanted for patients with end-stage heart failure. It may be used either as a bridge to cardiac transplantation or as a destination therapy. The health of a 75 year-old man with a medical history of systolic heart failure worsened. Therefore, he was recommended to have implanted a LVAD (Thoratec Corp.) as a destination therapy. After the surgery, he was enrolled in patient cardiac rehabilitation for the improvement of dyspnea and exercise capacity. In results, there is an improvement on his exercise capacity and quality of life. For the first time in Korea, we reported a benefit of exercise therapy after being implanted with a LVAD. PMID- 25024966 TI - Arnold-Chiari Malformation Type III With Meningoencephalocele: A Case Report. AB - Arnold-Chiari malformation type III (CM III) is an extremely rare anomaly with poor prognosis. An encephalocele with brain anomalies as seen in CM II, and herniation of posterior fossa contents like the cerebellum are found in CM III. The female infant was a twin, born at 33 weeks, weighing 1.7 kg with a huge hydrocele on the craniocervical junction. After operations were performed, she was referred to the department of rehabilitation medicine for poor motor development, swallowing dysfunction, and poor eye fixation at 22 months. The child was managed with neurodevelopmental treatment, oromotor facilitation, and light perception training. After 14 months, improvement of gross motor function was observed, including more stable head control, rolling, and improvement of visual perception. CM III has been known as a condition with poor prognosis. However, with the improvement in operative techniques and intensive rehabilitations, the prognosis is more promising than ever before. Therefore, more attention must be paid to the rehabilitation issues concerning patients with CM III. PMID- 25024967 TI - Paralysis developing as a paradoxical response during the treatment for tuberculous spondylitis: a case report. AB - It can be difficult for clinicians to distinguish a paradoxical response to antituberculous therapy, worsening of an existing lesion despite adequate treatment, treatment failure, and drug resistance. We report a case of a 69-year old woman who experienced bilateral lower extremity paralysis secondary to a paradoxical response. She had been suffering for 1 month from low back pain, due to tuberculous spondylitis. Her low back pain improved after antituberculous therapy. The low back pain, however, reappeared 2 months after treatment, accompanied by newly developed lower extremity weakness. Imaging studies showed an increased extent of her previous lesions. Consequently, the patient underwent a vertebral corpectomy with interbody fusion of the thoracolumbar spine. Histopathological examination showed chronic inflamed granulation tissue with no microorganisms. Although the antituberculous medication was not changed, the patient's symptoms and signs, including the paralysis, resolved after surgery. PMID- 25024968 TI - Atypical traumatic pneumorrhachis accompanied by paraparesis. AB - Pneumorrhachis, caused by intraspinal air, is an exceptional but important radiographic finding that is accompanied by different etiologies. Pneumorrhachis, by itself, is usually asymptomatic and gets reabsorbed spontaneously. Therefore, the patients with pneumorrhachis are mostly managed conservatively. We encountered a unique case of atypical traumatic pneumorrhachis accompanied by paraparesis. PMID- 25024969 TI - Therapeutic approach of wrist ganglion using electroacupuncture: two case reports. AB - A ganglion cyst is a relatively common benign tumor on the wrist. Conservative and surgical approaches have been used for its treatment. Various conservative treatment methods have been suggested such as reassurance, aspiration, sclerosant injection, and direct compression. But, there is no acceptable treatment of choice yet because each suggested method has a relatively high recurrence rate. We want to report two cases in which the size of the wrist ganglion was decreased by using electroacupuncture. One patient presented with a chronic ganglion for six years and the other patient presented with a recently occurred acute ganglion. We applied electroacupuncture for 20 minutes once a week for eight weeks to both of them. Afterwards, the size of the wrist ganglion diminished in the follow-up sonography and the accompanying pain was also relieved. Herein we report both cases along with a review of the relevant literature. PMID- 25024970 TI - Compressive radial neuropathy developed under a fibrotic band associated with rhabdomyolysis and successfully treated with surgery. AB - A 34-year-old male patient visited the emergency room with complaint of right wrist drop and foot drop. The day before, he was intoxicated and fell asleep in a room containing barbeque briquettes; After waking up, he noticed that his right wrist and foot were dropped. Upon physical examination, his right wrist extensor, thumb extensor, ankle dorsiflexor, and big toe extensor showed Medical Research Council (MRC) grade 1 power. The initial laboratory tests suggested rhabdomyolysis induced by unrelieved pressure on the right side during sleep. Right foot drop was improved after conservative care and elevated muscle enzyme became normalized with hydration therapy with no resultant acute renal failure. However, the wrist drop did not show improvement and a hard mass was palpated on the follow-up physical examination. Ultrasonography and magnetic resonance imaging studies were conducted and an abnormal mass in the lateral head of the tricep was detected. Axonopathy was suggested by the electrodiagnostic examination. A surgical decompression was done and a fibrotic cord lesion compressing the radial nerve was detected. After adhesiolysis, his wrist extensor power improved to MRC grade 4. Herein, we describe a compressive radial neuropathy associated with rhabdomyolysis successfully treated with surgery and provide a brief review of the related literature. PMID- 25024971 TI - Acetabular paralabral cyst as a rare cause of obturator neuropathy: a case report. AB - An acetabular paralabral cyst is a benign soft tissue cyst usually seen in association with a tear of the acetabular labrum. Acetabular paralabral cysts are often the cause of joint pain, but they rarely cause compression of the adjacent neurovascular structures. We present a case of a 63-year-old male patient who had paresis and atrophy of right hip adductor muscles. Right obturator neuropathy was confirmed through an electrodiagnostic study. In addition, magnetic resonance imaging showed a paralabral cyst in the right acetabulum which extended to the pelvic wall. The patient underwent conservative treatment without surgical procedure. The pain was decreased after 1 month of conservative therapy. The pain was decreased at the 1-month follow-up. Follow-up electromyography showed polyphasic motor unit potentials in adductor magnus and adductor longus muscles. Based on the experience of this case, an acetabular paralabral cyst should be considered as one of the rare causes of obturator neuropathy. PMID- 25024972 TI - Patent ductus arteriosus ligation and adverse outcomes: causality or bias? AB - Observational studies have associated patent ductus arteriosus (PDA) ligation in preterm infants with increased chronic lung disease (CLD), retinopathy of prematurity, and neurodevelopmental impairment at long-term follow-up. Although the biological rationale for this association is incompletely understood, there is an emerging secular trend toward a permissive approach to the PDA. However, insufficient adjustment for postnatal, pre-ligation confounders, such as intraventricular hemorrhage and the duration and intensity of mechanical ventilation, suggests the presence of residual bias due to confounding by indication, and obliges caution in interpreting the ligation-morbidity relationship. A period of conservative management after failure of medical PDA closure may be considered to reduce the number of infants treated with surgery. Increased mortality and CLD in infants with persistent symptomatic PDA suggests that surgical ligation remains an important treatment modality for preterm infants. PMID- 25024973 TI - A Systematic Review and Meta-analysis of the Timing of Early Intraventricular Hemorrhage in Preterm Neonates: Clinical and Research Implications. AB - A considerable number of intraventricular hemorrhages (IVH) occur within the first hours of life (HOL). Temporality between IVH and its antecedents as well as a consistent definition of "early IVH" is lacking in a large and growing body of literature. We performed a systematic review of prospective studies that reported onset of IVH in preterm neonates within the first HOL and afterwards. The English literature was searched using three databases up to March 2013. Four timing periods of IVH can be compared in 16 identified studies: 0-6; 7-12; 13-24; after 24 HOL. The 0-6 and after 24 HOL were the major modes of IVH timing. Pooled IVH proportions were estimated through a meta-analysis of studies that were conducted after antenatal steroid and surfactant era. In neonates weighing <=1500 g at birth: 48% of IVH (95% CI: 42-58%, 5 studies, 279 IVH cases) occurred during 0-6 HOL and 38% (95% CI: 19-57%, 4 studies, 241 IVH cases) after 24 HOL. The 0-6 HOL is the shortest, most vulnerable period for IVH, thus, an early IVH is an IVH occurs in it. Such early IVH had prognostic, etiological/preventive and medicolegal implications. Accordingly, preterm neonates at risk of IVH should have their first routine screening head ultrasound at about 6 HOL. Future research exploring the antecedents of IVH should guaranty the temporality between these antecedents and IVH. Additional research will be required to determine whether the long term neurological outcomes of early and late IVH are the same. PMID- 25024974 TI - Hemostatic profile in healthy premature neonates; does birth weight affect the coagulation profile? AB - CONTEXT: There are limited studies assessing the neonatal hemostatic factors in relation to birth weight. AIMS: This study aims to compare the coagulation factors between three groups of neonates with different birth weight for gestational age (GA). SETTINGS AND DESIGN: In a cross-sectional study, 74 healthy premature neonates were involved. SUBJECTS AND METHODS: Serum prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), thrombin clotting time (TT), and levels of fibrinogen, anti-thrombin III, protein S and protein C were measured. Neonates were classified into three groups according to birth weight, including small, appropriate and large for gestational age (SGA, AGA, and LGA). STATISTICAL ANALYSIS USED: Statistical analysis was performed using SPSS software. RESULTS: There was a significant difference in the levels of protein S (P < 0.001), protein C (P = 0.004), and values of APTT (P = 0.01) between three groups. Other coagulation factors however, did not represent a significant pattern (P > 0.05). Protein S concentration, directly (B = 0.78, P < 0.001), and APTT, inversely (B = -0.29, P = 0.03), associated with birth weight after adjustment for GA and sex. CONCLUSIONS: Despite the decrease in APTT from SGA to AGA, and LGA neonates, levels of protein S increases directly with birth weight. However, no other coagulation factors revealed an explainable pattern in relation to the state of SGA, AGA, or LGA. PMID- 25024975 TI - Polycythemia in neonatal intensive care unit, risk factors, symptoms, pattern, and management controversy. AB - BACKGROUND: Polycythemia (PC) is defined as venous hematocrit (hct) >=65%.( ) Its incidence is high among certain risk factors (RFs). Its management is controversy. AIMS: TO DETERMINE: (1) The incidence of PC in our neonatal intensive care unit (NICU). (2) Most common RF, symptoms, and laboratory abnormalities (LA) associated with PC and their effect on the length of hospital stay (LOS). (3) Whether noninvasive interventions are effective in reducing hct. (4) Hct pattern of PC neonates. DESIGN: Retrospective cohort study. SETTING: NICU at a maternity and children hospital. MATERIALS AND METHODS: Records review of all neonates from March 2011 to August 2013. Inclusions criteria were: (1) Venous hct >=65%. (2) Neonates born in our institution. (3) Early umbilical cord clamping. (4) Gestational age >=34 weeks. STATISTICAL ANALYSIS: Chi-square and multiple regression analysis. RESULTS: One hundred and one PC neonates were eligible. Incidence of PC in our NICU is 14.5%. The most common RF, symptoms, and LA were: Small for gestational age, jaundice and hypoglycemia respectively. Tachypnea ( P - 0.04) and oliguria (P - 0.03) significantly prolonged LOS. Noninvasive interventions or observation could not reduce the hct significantly (P - 0.24). The hcts mean peaked maximally at a mean of 2.8 h of age. CONCLUSION: PC incidence in our NICU is higher than the reported incidence in healthy newborns. Most of the PC neonates were either symptomatic or having LA. Noninvasive interventions or observation were not effective in reducing hct in polycythemic neonates. Hct in both healthy and PC neonates peaked at the same pattern. PMID- 25024976 TI - The main etiologies of acute kidney injury in the newborns hospitalized in the neonatal intensive care unit. AB - INTRODUCTION: Acute kidney injury (AKI) is one of the most common diseases among the newborns hospitalized in the neonatal intensive care units (NICUs), which is usually resulted from predisposing factors including sepsis, hypovolemia, asphyxia, respiratory distress syndrome (RDS), and heart failure. The goal of this study was to assess main etiologies, relevant risk factors, and early outcome of neonatal AKI. MATERIALS AND METHODS: In a cross- sectional study, 49 consecutive neonates hospitalized in NICU of Besat hospital with diagnosis of AKI from October 2009 to October 2011 were investigated through census sampling method. AKI was diagnosed based on urine output and serum creatinine levels. RESULTS: The prevalence of AKI was 1.54% (49 out of 3166 newborns hospitalized in NICU) with the female: male was 7:1. Thirty-nine patients (79.5%) were full-term neonates. Oliguria was observed in 38 (77.5%) patients. Sepsis was the most common predisposing factor for AKI in 77.5% of patients (n = 38) accompanied with the highest mortality rate among other factors (30.5%). Other leading causes of AKI included hypovolemia secondary to dehydration, followed by hypoxia secondary to RDS, patent ductus arteriosus, posterior urethral valve, asphyxia, and renal venous thrombosis. A positive relationship was observed between neonates' age, sex, urine output, and also between serum creatinine levels with initiation of dialysis. The mortality rate among the newborns hospitalized with AKI was 36.7%. Eighteen (36.7%) newborns were treated with peritoneal dialysis (PD) of whom 10 patients (55.6%) died, 31 patients were managed conservatively of whom five neonate died (25.9%). DISCUSSION: Prognosis of AKI in the oliguric neonates requiring PD is very poor. It is thus recommended to prevent AKI by predicting and rapid diagnosis of AKI in patients with potential risk factors and also by early and effective treatment of such factors in individuals with AKI. PMID- 25024977 TI - Diagnosing intussusception in preterm neonates: case report and overview. AB - Intussusception is extremely rare in preterm neonates and is often confused with necrotizing enterocolitis leading to considerable delay in its diagnosis. We present a case report of a preterm with colo-colic intussusception, which was diagnosed preoperatively using ultrasound. We examine the pitfalls in diagnosing intussusception in preterm neonates. Intussusception, though rare, should be considered in the differential diagnosis while managing a preterm with abdominal symptomatology. Abdominal ultrasound is useful in diagnosing intussusception in neonates. PMID- 25024978 TI - Sonographic features of physiologic neonatal breast enlargement. AB - The varying presentations of neonatal breast enlargement on imaging have been underreported in the literature. Our case report profiles a 3-week-old female patient who presented with a history of left breast enlargement with redness and tenderness for 2 days, who was clinically diagnosed and managed for neonatal mastitis, which was actually a neonatal breast enlargement with adjacent cellulitis. Awareness that physiologic neonatal breast enlargement can be associated with adjacent cellulitis without mastitis can prevent unnecessary hospitalization and treatment with parenteral antibiotics. PMID- 25024979 TI - Unusual neonatal presentation of type I leukocyte adhesion deficiency. AB - Leukocyte adhesion deficiency type I is an extremely serious and rare form of congenital immunodeficiency with recurrent episodes of infection since neonatal period. It is usually diagnosed in childhood, but if diagnosed early in neonatal period then definitive treatment can be instituted early with promising results. High index of suspicion is necessary to diagnose this condition in neonates. Neonate may present with serious bacterial infections with a leukemoid reaction. PMID- 25024980 TI - A case of duodenal atresia with apple peel appearance: challenging the current embryology. AB - Classically, embryology of duodenal atresia has been linked to defect in recanalization process, while apple-peal atresia of small bowel has been considered as due to vascular accident during embryonic life. We present a 33 week preterm neonate with duodenal atresia with the apple-peal appearance of proximal jejunum for which resection of the jejunum with apple-peal configuration, plication of the duodenum, and duodono-jejunal anastomosis was done. Thus, this rare case of ours questions the embryology of duodenal atresia with the apple-peal appearance suggesting it to be due to a vascular disruption phenomenon during embryonic life. PMID- 25024981 TI - An unusual case of perinatal tuberous sclerosis. AB - We report a case of a neonate who presented to us with multiple rhabdomyomas of heart, cortical tubers in the brain and skeletal anomalies such as Pierre Robin sequence, bilateral clubfoot and lower small bowel obstruction. Though a diagnosis of neonatal tuberous sclerosis was made, the association of skeletal anomalies and intestinal obstruction was a rare and unusual finding. PMID- 25024982 TI - A newborn with facial hemangioma and sternal defect. AB - Large facial segmental hemangiomas tend to be associated with extracutaneous abnormalities. We report a case of large progressive segmental facial hemangioma, sternal cleft and talipes equinovarus deformity. PMID- 25024983 TI - Unusual birth trauma involving face: a completely preventable iatrogenic injury. AB - Birth injuries involving face are easily recognizable, but are often under reported. Most of these injuries are associated with face presentation. We report an iatrogenic, but potentially preventable facial birth injury sustained by an unborn child in institutional setup. PMID- 25024984 TI - Leukemia cutis in an infant with congenital leukemia and tetralogy of fallot. AB - Congenital leukemia is a very rare severe condition and leukemia cutis may represent the presenting sign of this malignancy, sometimes preceding hematological findings of weeks. Typical clinical features include multiple red to purple papules, macules and nodules due to direct infiltration of the skin by malignant cells. We illustrate these cutaneous findings in a patient with congenital leukemia and tetralogy of Fallot. PMID- 25024985 TI - Acute kidney injury in hypernatremic dehydration in exclusively breastfed babies: don't ignore it! PMID- 25024986 TI - Inversion of ileum causing intestinal obstruction: rare complication in cloacal exstrophy. PMID- 25024987 TI - Severe hemolytic disease of fetus and newborn due to anti-s antibodies. PMID- 25024988 TI - Fast-track is more than physiological anaesthesia. PMID- 25024990 TI - Treatment options for patients with mobile left ventricular thrombus and ventricular dysfunction: a case series. AB - INTRODUCTION: Little is known about the optimal management of large, mobile, pedunculated left ventricular clots. The management is particularly challenging in patients with advanced heart failure considered for left ventricular assist device implantation, because the clot may cause pump thrombosis. METHODS: We retrospectively reviewed the records of patients with left ventricular thrombi identified by echocardiography, and found three cases with large protruding mobile clots. RESULTS: In this paper, we are presenting three challenging cases where the clots were successfully treated surgically. In two cases, the removal of clot was performed simultaneously with the implantation of ventricular assist devices. In the third case, the patient underwent only thrombectomy. Overall, the early outcomes were good in all three patients, but one subsequently died from unrelated causes. CONCLUSIONS: These clinical cases give evidence for surgical treatment of large mobile clots without systemic embolism, even if ventricular assist device is implanted during the same operation. PMID- 25024989 TI - Major themes for 2013 in cardiothoracic and vascular anaesthesia and intensive care. AB - There has been significant progress throughout 2013 in cardiothoracic and vascular anaesthesia and intensive care. There has been a revolution in the medical and interventional management of atrial fibrillation. The medical advances include robust clinical risk scoring systems, novel oral anticoagulants, and growing clinical experience with a new antiarrhythmic agent. The interventional advances include left atrial appendage occlusion for stroke reduction, generalization of ablation techniques in cardiac surgery, thoracoscopic ablation techniques, and the emergence of the hybrid ablation procedure. Recent European guidelines have defined the organization and practice of two subspecialties, namely general thoracic surgery and grown-up congenital heart disease. The pivotal role of an effective multidisciplinary milieu is a central theme in both these clinical arenas. The anaesthesia team features prominently in each of these recent guidelines aimed at harmonizing delivery of perioperative care for these patient cohorts across Europe. Web-Enabled Democracy Based Consensus is a system that allows physicians worldwide to agree or disagree with statements and expert consensus meetings and has the potential to increase the understanding of global practice and to help clinicians better define research priorities. This "Democratic based medicine", firstly used to assess the interventions that might reduce perioperative mortality has been applied in 2013 to the setting of critically ill patient with acute kidney injury. These advances in 2013 will likely further improve perioperative outcomes for our patients. PMID- 25024991 TI - Validation of a novel duplex ultrasound objective structured assessment of technical skills (DUOSATS) for arterial stenosis detection. AB - INTRODUCTION: Duplex ultrasound facilitates bedside diagnosis and hence timely patient care. Its uptake has been hampered by training and accreditation issues. We have developed an assessment tool for Duplex arterial stenosis measurement for both simulator and patient based training. METHODS: A novel assessment tool: duplex ultrasound assessment of technical skills was developed. A modified duplex ultrasound assessment of technical skills was used for simulator training. Novice, intermediate experience and expert users of duplex ultrasound were invited to participate. Participants viewed an instructional video and were allowed ample time to familiarize with the equipment. Participants' attempts were recorded and independently assessed by four experts using the modified duplex ultrasound assessment of technical skills. 'Global' assessment was also done on a four point Likert scale. Content, construct and concurrent validity as well as reliability were evaluated. RESULTS: Content and construct validity as well as reliability were demonstrated. The simulator had good satisfaction rating from participants: median 4; range 3-5. Receiver operator characteristic analysis has established a cut point of 22/ 34 and 25/ 40 were most appropriate for simulator and patient based assessment respectively. We have validated a novel assessment tool for duplex arterial stenosis detection. Further work is underway to establish transference validity of simulator training to improved skill in scanning patients. CONCLUSIONS: We have developed and validated duplex ultrasound assessment of technical skills for simulator training. PMID- 25024992 TI - An updated systematic review and meta-analysis on impedance threshold devices in patients undergoing cardiopulmonary resuscitation. AB - INTRODUCTION: Uncertainty persists on the clinical impact of impedance threshold devices in out-of-hospital cardiac arrest. We conducted an updated systematic review on impedance threshold devices. METHODS: Several databases were searched for studies testing the effectiveness of impedance threshold devices in patients with cardiac arrest. The primary endpoint was long-term survival. RESULTS: Seven trials (11,254 patients) were included. In 4 studies (2,284 patients) impedance threshold devices were used with active compression-decompression-cardiopulmonary resuscitation, and in the others alone. Overall, impedance threshold devices did not impact on the rate of return of spontaneous circulation (odds ratio=1.17 [0.96-1.43], p=0.114), favorable neurologic outcome (odds ratio=1.56 [0.97-2.50], p=0.065), or long-term survival (odds ratio=1.22 [0.94-1.58], p=0.127). These analyses were fraught with heterogeneity (respectively, p=0.055, p=0.236, and p=0.011) and inconsistency (respectively, I-squared=51% , I-squared=27% , and I squared=67%). Exploratory analysis showed that combined use of impedance threshold devices with active compression-decompression significantly increased the likelihood of return of spontaneous circulation (odds ratio=1.19 [1.00-1.40], p=0.045), favorable neurologic outcome (odds ratio=1.60 [1.14-2.25], p=0.006), and long-term survival (odds ratio=1.52 [1.11-2.08], p=0.009). The favorable impact of the interaction between impedance threshold devices and active compression-decompression was also confirmed at meta-regression analysis (respectively, b=0.195 [0.004-0.387], p=0.045, b=0.500 [0.079-0.841], p=0.018, b=0.413 [0.063-0.764], p=0.021). CONCLUSIONS: The evidence base on impedance threshold devices is apparently inconclusive, with a neutral impact on clinically relevant outcomes. However, exploratory analysis focusing on the combined use of impedance threshold devices with active compression-decompression suggests that this combo treatment may be useful to improve patient prognosis. PMID- 25024993 TI - ARDS with septic shock due to Legionella longbeachae pneumonia in a patient with polymyalgia rheumatica. AB - Legionella longbeachae is a very uncommon cause of community acquired pneumonia in Western countries. L. longbeachae does not grow on blood agar media and is usually not detected by sputum gram stain or blood culture. Furthermore Legionella urinary antigen testing fails to detect it. In this report we described a 79-year-old man with polymyalgia rheumatica under systemic corticosteroid treatment without other additional risk factors who developed a cultured-proven L. longbeachae community-acquired pneumonia complicated by an acute respiratory distress syndrome with septic shock. This case report demonstrates that non-pneumophila Legionella species must be taken into account as casual agents of community acquired pneumonia even in mild immunosuppressed patients, and empiric anti-Legionella antimicrobial coverage might be indicated until Legionella has definitively been rule out by adequate testing. PMID- 25024994 TI - Early molecular diagnosis of aspergillosis in a patient with acute myeloid leukaemia. AB - Diagnosis of invasive fungal infection remains challenging. Here we report a case of early diagnosis of invasive aspergillosis in a neutropenic patient affected by acute myeloid leukaemia, achieved through the detection of Aspergillus fumigatus species-specific ribonucleic acid sequences by a sensitive multiplex real-time polymerase chain reaction-based molecular assay. Thanks to the early diagnosis, targeted therapy was promptly established and the severe fungal infection controlled, allowing the patient to subsequently receive allogeneic hematopoietic stem cell transplantation from a haploidentical donor, her only curative option. Also in this instance, targeted secondary antifungal prophylaxis with voriconazole avoided any other fungal infection afterwards. This report suggests how the implementation of molecular assays in combination with routine diagnostic procedures, can improve microbiological diagnosis in sepsis, particularly in case of fungal infection, difficult to detect with standard microbiological culture methods. PMID- 25024995 TI - Femoral artery cannulation through a side graft in extracorporeal membrane oxygenation. PMID- 25024996 TI - Caseous calcification of the mitral annulus: a neglected lesion mimicking intracardiac mass. PMID- 25024997 TI - Potential chronic abscess cavity that masqueraded as sinus of Valsalva aneurysm: is TEE a vital tool? PMID- 25024998 TI - Guiding the surgeon's finger by transesophageal echocardiography. PMID- 25024999 TI - Systemic intravenous lidocaine for perioperative pain management: a call for changing indications in the package sheet. PMID- 25025001 TI - Hypertrophic osteoarthropathy in patient with Crohn's disease: a case report. AB - Numerous causes of hypertrophic osteoarthropathy (HOA) have been reported. Commonly, secondary osteoarthropathy accompanies pulmonary diseases such as carcinoma of the lung, pleural tumors, lung abscesses, and bronchiectasis. However, HOA in inflammatory bowel disease is a rare complication. There are only a few reports of secondary HOA with Crohn's disease. Our purpose was to report another case of HOA in Crohn's disease. We describe a case of a 27-year-old man with underlying Crohn's disease presenting with 2 years of pain in multiple joints. Radiographic findings suggested HOA in extremities. We performed a conservative treatment including medication and rehabilitations. The patient's symptoms were much improved at the latest follow-up. Although numerous studies on HOA have been published, the pathogenesis of HOA is still unclear. Various treatment modalities were recommended but further studies to uncover the pathogenesis of HOA with Crohn's disease and to establish a treatment modality are needed. PMID- 25025000 TI - Pathobiology of Paget's Disease of Bone. AB - Paget's disease of bone is characterized by highly localized areas of increased bone resorption accompanied by exuberant, but aberrant new bone formation with the primary cellular abnormality in osteoclasts. Paget's disease provides an important paradigm for understanding the molecular mechanisms regulating both osteoclast formation and osteoclast-induced osteoblast activity. Both genetic and environmental etiologies have been implicated in Paget's disease, but their relative contributions are just beginning to be defined. To date, the only gene with mutations in the coding region linked to Paget's disease is sequestosome-1 (SQSTM1), which encodes the p62 protein, and these mutations lead to elevated cytokine activation of NF-B in osteoclasts but do not induce a "pagetic osteoclast" phenotype. Further, genetic mutations linked to Paget's appear insufficient to cause Paget's disease and additional susceptibility loci or environmental factors may be required. Among the environmental factors suggested to induce Paget's disease, chronic measles (MV) infection has been the most studied. Expression of the measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-like osteoclasts and bone lesions in mice. Further, mice expressing both MVNP in osteoclasts and germline mutant p62 develop dramatic pagetic bone lesions that were strikingly similar to those seen in patients with Paget's disease. Thus, interactions between environmental and genetic factors appear important to the development of Paget's disease. In this article we review the mechanisms responsible for the effects of mutant p62 gene expression and MVNP on osteoclast and osteoblast activity, and how they may contribute to the development of Paget's disease of bone. PMID- 25025002 TI - Atypical femoral fracture combined with osteonecrosis of jaw during osteoporosis treatment with bisphosphonate. AB - Bisphosphonate, a potent anti-resorptive agent, is generally accepted as a safe, effective, well tolerated treatment for postmenopausal osteoporosis. Atypical femoral fracture (AFF) and bisphosphonate related osteonecrosis of jaw (BRONJ) are the increasing morbidities in patients treated with long term bisphosphonate. Pathogenic mechanisms of AFF and BRONJ are not fully identified and not identical. We report a case of BRONJ followed by AFF and its nonunion in a 67 year-old woman patient receiving an oral bisphosphonate during 7 years for the treatment of osteoporosis. PMID- 25025003 TI - Compression fracture in postpartum osteoporosis. PMID- 25025004 TI - How old is old: the beginning of a new era for therapeutic challenges for elderly patients with AML. PMID- 25025005 TI - Direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism. PMID- 25025006 TI - Current status and future directions of clinical research and practice in adult acute lymphoblastic leukemia patients in Korea. PMID- 25025007 TI - (18)F-fluoro-2-deoxy-D-glucose positron emission tomography findings of neurolymphomatosis. PMID- 25025008 TI - Osteomalacia and myelofibrosis as a manifestation of vitamin D deficiency. PMID- 25025009 TI - Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. AB - Hypercoagulability can result from a variety of inherited and, more commonly, acquired conditions. Testing for the underlying cause of thrombosis in a patient is complicated both by the number and variety of clinical conditions that can cause hypercoagulability as well as the many potential assay interferences. Using an algorithmic approach to hypercoagulability testing provides the ability to tailor assay selection to the clinical scenario. It also reduces the number of unnecessary tests performed, saving cost and time, and preventing potential false results. New oral anticoagulants are powerful tools for managing hypercoagulable patients; however, their use introduces new challenges in terms of test interpretation and therapeutic monitoring. The coagulation laboratory plays an essential role in testing for and treating hypercoagulable states. The input of laboratory professionals is necessary to guide appropriate testing and synthesize interpretation of results. PMID- 25025010 TI - Clinical characteristics and treatment outcome of acute myeloid leukemia in elderly patients in Korea: a retrospective analysis. AB - BACKGROUND: The clinical characteristics of elderly patients with AML differ from those of younger patients, resulting in poorer survival and treatment outcomes. We analyzed retrospectively the clinical data of AML patients 65 years old and above to describe patients' characteristics and treatment patterns, and to define meaningful prognostic factors of survival in the Korean population. METHODS: Basic patients' characteristics, clinical outcomes according to treatments, and prognostic factors associated with survival and treatment intensity were examined in a total of 168 patients diagnosed in 5 institutes between 1996 and 2012 as having AML. RESULTS: Herein, 84 patients (50.0%) received high-intensity regimens (HIR), 18 (10.7%) received low-intensity regimens (LIR), and 66 (39.3%) received supportive care (SC) only. The median survival of all patients was 4.5 months; and median survival times with HIR, LIR, and SC were 6.8 months, 10.2 months, and 1.6 months, respectively. Median survival times with HIR and LIR were significantly longer than that with SC (P<0.0001 and P=0.006, respectively). Multivariate analysis identified age, Eastern Cooperative Oncology Group performance status (ECOG-PS), hemoglobin (Hb) level, and serum creatinine (Cr) level as statistically significant prognostic factors for survival. In the HIR group, prognostic factors for survival were ECOG-PS, Hb level, and C-reactive protein level. CONCLUSION: Even in elderly AML patients, an intensive treatment regimen could be beneficial with careful patient selection. Further prospective studies designed to identify specific prognostic factors are required to establish an optimal treatment strategy for elderly AML patients. PMID- 25025011 TI - Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis. AB - BACKGROUND: The safety of extracorporeal photopheresis (ECP) in steroid refractory chronic graft-versus-host disease (SR-cGVHD) has been explored in multiple studies but reported response rates (RR) vary significantly across studies. METHODS: We conducted a meta-analysis to assess the efficacy of ECP for SR-cGVHD. A search of electronic databases for studies published between 1984 and 2012 was conducted. End points included RR: complete response (CR), overall response rates (ORR), and organ-specific RR. The initial search generated 312 studies, of which 18 met the selection criteria (N=595). A random effects model was used for pooled rates. RESULTS: Pooled CR rates and ORR were 29% (confidence interval [CI], 19-42%) and 64% (CI, 65-82%), respectively. One-year overall survival was available for 4 studies only and was 49% (CI, 29-70%). The pooled RR for skin, liver, ocular, oral, lung, gastrointestinal and musculoskeletal SR cGVHD was 74%, 68%, 60%, 72%, 48%, 53%, and 64%, respectively. There was a significant heterogeneity among studies due to differences in ECP schedules and duration. No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be undertaken due to a limited number of prospective studies. CONCLUSION: ECP is an effective therapy for oral, skin, and liver SR-cGVHD, with modest activity in lung and gastrointestinal SR-cGVHD. PMID- 25025012 TI - R-CHOP chemoimmunotherapy followed by autologous transplantation for the treatment of diffuse large B-cell lymphoma. AB - BACKGROUND: We investigated factors that influence outcomes in diffuse large B cell lymphoma (DLBCL) patients treated with rituximab combined with the CHOP regimen (R-CHOP) followed by upfront autologous stem cell transplantation (Auto SCT). METHODS: We retrospectively evaluated survival differences between subgroups based on the age-adjusted International Prognostic Index (aaIPI) and revised-IPI (R-IPI) at diagnosis, disease status, and positron emission tomographic/computerized tomographic (PET/CT) status at transplantation in 51 CD20-positive DLBCL patients treated with R-CHOP followed by upfront Auto-SCT. RESULTS: Patients had either stage I/II bulky disease (5.9%) or stage III/IV disease (94.1%). The median patient age at diagnosis was 47 years (range, 22-66 years); 53.3% and 26.7% had high-intermediate and high risks according to aaIPI, respectively. At the time of Auto-SCT, 72.5% and 27.5% experienced complete (CR) and partial remission (PR) after R-CHOP, respectively. The median time from diagnosis to Auto-SCT was 7.27 months (range, 3.4-13.4 months). The 5-year overall (OS) and progression-free survival (PFS) were 77.3% and 72.4%, respectively. The 5-year OS and PFS rates according to aaIPI, R-IPI, and PET/CT status did not differ between the subgroups. More importantly, the 5-year OS and PFS rates of the patients who achieved PR at the time of Auto-SCT were not inferior to those of the patients who achieved CR (P=0.223 and 0.292, respectively). CONCLUSION: Survival was not influenced by the aaIPI and R-IPI at diagnosis, disease status, or PET/CT status at transplantation, suggesting that upfront Auto-SCT might overcome unfavorable outcomes attributed to PR after induction chemoimmunotherapy. PMID- 25025013 TI - Abbreviated chemotherapy for limited-stage diffuse large B-cell lymphoma after complete resection. AB - BACKGROUND: Abbreviated chemotherapy followed by radiotherapy or full cycles of chemotherapy is recommended as a standard treatment for limited-stage (LS) diffuse large B-cell lymphoma (DLBCL). After complete resection of tumors, however, Burkitt and childhood B-cell Non-Hodgkin lymphoma show favorable outcomes, even after abbreviated chemotherapy of only 2 or 3 cycles. We investigated the effectiveness of abbreviated chemotherapy in patients with LS DLBCL after complete tumor resection. METHODS: We retrospectively reviewed 18 patients with LS DLBCL who underwent complete tumor resection followed by either 3 or 4 cycles of chemotherapy between March 2002 and May 2010. RESULTS: With a median follow-up period of 57.9 months (range, 31.8-130.2 months), no patients experienced disease relapse or progression; however, 1 patient experienced secondary acute myeloid leukemia during follow-up. The 5-year progression-free survival rate and overall survival rate were 93.3% and 94.1%, respectively. CONCLUSION: These results warrant further investigation into abbreviated chemotherapy as an alternative treatment for patients who have undergone complete resection of LS DLBCL. PMID- 25025014 TI - White blood cell differential counts in severely leukopenic samples: a comparative analysis of different solutions available in modern laboratory hematology. AB - BACKGROUND: We evaluated the efficacy of white blood cell (WBC) differential counts in severely leukopenic samples by the Hematoflow method and by automated hematology analyzers and compared the results with manual counts. METHODS: EDTA anticoagulated blood samples (175 samples) with WBC counts of 40-990/uL were selected. Hematoflow differential counts were performed in duplicates employing flow cytometry using the CytoDiff reagent and analysis software. Differential counts were also performed using the DxH 800 (Beckman Coulter) and XE-2100 (Sysmex) automated hematology analyzers. The sum of the manual counts by a hematology technician and a resident were used as the manual counts. RESULTS: The total analysis time and hands-on time required by the Hematoflow method were shorter than those required by manual counting. Hematoflow counts were reproducible, showed a good correlation with automated analyzers, and also showed strong correlation with manual counts (r > 0.8) in neutrophils, lymphocytes, and monocytes. None of the cases containing less than 4% blasts as analyzed by the Hematoflow method had blasts in the manual counts, but 8 cases of 21 cases (38.1%) with over 4% blasts by Hematoflow had blasts in manual counts. CONCLUSION: Hematoflow counts of severely leukopenic samples were reproducible and showed a good correlation with manual counts in terms of neutrophil, lymphocyte, and monocyte counts. The Hematoflow method also detected the presence of blasts. Manual slide review is recommended when over 4% blasts are found by Hematoflow. PMID- 25025015 TI - A case of chronic myeloid leukemia with features of essential thrombocythemia in peripheral blood and bone marrow. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by overproduction of myeloid white blood cells. Philadelphia chromosome is an essential finding for CML diagnosis. Generally, a clinical diagnosis of essential thrombocythemia (ET) can be established from isolated marked thrombocytosis in peripheral blood. However, Philadelphia chromosome-positivity or bcr/abl rearrangement with isolated thrombocytosis should be diagnosed as CML, not ET, according to World Health Organization diagnostic criteria. Therefore, CML should not be excluded before confirming the presence of the Philadelphia chromosome or bcr/abl rearrangement in cases of isolated thrombocytosis in peripheral blood. We report a case of CML with clinical features of ET in a patient successfully treated with imatinib. PMID- 25025016 TI - Long-term hematological response in a patient with 5q- syndrome after suspension of lenalidomide therapy and further improvement with deferasirox therapy. PMID- 25025017 TI - A case of myelodysplastic syndrome with a der(1;18)(q10;q10) translocation. PMID- 25025018 TI - Simultaneous presentation of JAK2 V617F mutation-related essential thrombocythemia and B-cell chronic lymphocytic leukemia. PMID- 25025019 TI - Transanal natural orifice transluminal endoscopic surgery total mesorectal excision in animal models: endoscopic inferior mesenteric artery dissection made easier by a retroperitoneal approach. AB - PURPOSE: We report the performance of natural orifice transluminal endoscopic surgery (NOTES) low anterior resection in animals using transanal total mesorectal excision (TME) with laparoscopic assistance and endoscopic inferior mesenteric artery (IMA) dissection. METHODS: Four pigs weighing 45 kg each, and one dog weighing 25 kg, underwent surgery via a transanal approach. The rectum was occluded transanally using a purse-string suture, approximately 3-4 cm from the anal verge. The rectal mucosa was incised circumferentially just distal to the purse-string. A SILS or GelPOINT port was inserted transanally. Transanal TME was assisted by laparoscopy and proceeded up to the peritoneal reflection. More proximal dissection, including IMA dissection, was performed along the retroperitoneal avascular plane by endoscopy alone and facilitated by CO2 insufflation. The IMA was clipped and divided endoscopically. The mobilized rectosigmoid were exteriorized transanally and transected. A colorectal anastomosis was performed using a circular stapler with a single stapling technique. RESULTS: Endoscopic dissection of the IMA was successful in all five animals. The mean operation time was 125 minutes (range, 90-170 minutes). There were no intraoperative complications or hemodynamic instability. The mean length of the resected specimen was 14.4 cm (range, 12-16 cm). CONCLUSION: A NOTES retroperitoneal approach to the IMA with CO2 insufflation and intact peritoneal covering overcame the difficulties of retraction and exposure of endoscopic dissection in animals. PMID- 25025020 TI - Prognosis of early mucinous gastric carcinoma. AB - PURPOSE: Little is known about the clinicopathological features of early mucinous gastric carcinoma (MGC). The purpose of this study was to compare the clinicopathological features and prognosis between patients with early MGC and those with early nonmucinous gastric carcinoma (NMGC). METHODS: We reviewed the records of 2,732 patients diagnosed with gastric carcinoma who were treated surgically. There were 14 patients (0.5%) with early MGC and 958 with early NMGC. RESULTS: Early MGC patients had a higher prevalence of elevated type (71.4%) compared with early NMGC patients (29.5%). More early MGC patients had submucosal carcinoma, compared with early NMGC patients (78.6% vs. 64.1%). The overall 5 year survival of the patients with early MGC was 97.2% as compared with 92.7% for the patients with early NMGC (P < 0.01). The statistically significant prognostic parameters influencing the 5-year survival rate according to Cox's proportional hazard regression model were: age (risk ratio, 2.22; 95% confidence interval [CI], 1.62-3.04; P < 0.01); sex (risk ratio, 1.97; 95% CI, 1.42-2.73; P < 0.01); and lymph node metastases (risk ratio, 1.88; 95% CI, 1.28-2.77; P < 0.01). CONCLUSION: Patients with early MGC had a better prognosis than those with early NMGC. Mucinous histology itself appears not to be an independent prognostic factor. Therefore, early detection is important for improving the prognosis for patients with gastric carcinoma regardless of tumor histology. PMID- 25025021 TI - Multicenter nonrandomized trial of ramosetron versus palonosetron in controlling chemotherapy-induced nausea and vomiting for colorectal cancer. AB - PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) have a negative impact on patients' quality of life and frequently pointed to as a major factor for treatment abandonment. Serotonin (5-HT3) receptor antagonist is considered as key treatment for CINV. Ramosetron and palonosetron are recently developed 5-HT3 receptor antagonists and known as more superior than other first-generation 5-HT3 receptor antagonists. The purpose of this study was to compare the efficacy of ramosetron and palonosetron and determine which drug is more effective for prevention of CINV. METHODS: Colorectal cancer patients treated with chemotherapy were enrolled consecutively. Patients were assigned to receive intravenous injection of ramosetron 0.3 mg or palonosetron 0.25 mg at 30 minutes before initiation of moderately emetogenic chemotherapy. Ramosetron group added oral administration of 0.1 mg ramosetron on the second and third days of chemotherapy. Efficacy parameter consisted of nausea and vomiting. RESULTS: Ninety-one patients received ramosetron and 89 patients received palonosetron. Presentation of vomiting and nausea symptoms was not significantly different between the two groups during acute (0-24 hours) and delayed period (after 24 hours). CONCLUSION: The incidence of CINV between the ramosetron and the palonosetron group has not shown any difference during acute, delayed, and overall period. PMID- 25025022 TI - Histopathologic factors affecting tumor recurrence after hepatic resection in colorectal liver metastases. AB - PURPOSE: Hepatic resection is a standard method of treatment for colorectal liver metastases (CRLM). However, the pathologic factors of metastatic lesions that affect tumor recurrence are less well defined in CRLM. The aim of this study was to evaluate the risk factors for recurrence of CRLM, focusing on histopathologic factors of metastatic lesions of the liver. METHODS: From January 2003 to December 2008, 117 patients underwent curative hepatic resection for CRLM were reviewed. Tumor size and number, differentiation, tumor budding, angio-invasion, dedifferentiation and tumor infiltrating inflammation of metastatic lesions were investigated. RESULTS: The mean number of hepatic tumors was 2 (range, 1-8). The mean size of the largest tumor was 2.9 cm (range, 0.3-18.5 cm) in diameter. The moderate differentiation of the hepatic tumor was the most common in 86.3% of the patients. Tumor budding, angio-invasion, and dedifferentiation were observed in 81%, 34%, and 12.8% of patients. Inflammation infiltrating tumor was detected in 6.8% of patients. Recurrence after hepatic resection appeared in 69 out of 117 cases (58.9%). Recurrence-free survival at 1, 2 and 5 years were 62.4%, 43.6%, and 34.3%. The multivariate analysis showed the number of metastases >=3 (P = 0.007), the tumor infiltrating inflammation (P = 0.047), and presence of dedifferentiation (P = 0.020) to be independent risk factors for tumor recurrence. CONCLUSION: Histopathological factors, i.e., dedifferentiation and tumor infiltrating inflammation of the metastatic lesion, could be one of the risk factors of aggressive behavior as well as the number of metastases even after curative resection for CRLM. PMID- 25025023 TI - Balanced approach can help initial outcomes: analysis of initial 50 cases of a new liver transplantation program in East Asia. AB - PURPOSE: To evaluate patient triage pattern and outcomes according to types of liver transplantation as part of a new liver transplant program developed in an East Asian country with a limited number of deceased donors. METHODS: Medical records of initial 50 liver transplantations were reviewed retrospectively. RESULTS: Twenty-nine patients underwent deceased donor liver transplantation (DDLT) and 21 patients underwent living donor liver transplantation (LDLT). Mean model for end-stage liver disease scores of recipients of DDLT and LDLT were 24.9 +/- 11.6 and 13.1 +/- 5.4, respectively (P < 0.0001). Twenty-eight patients had HCCs and 17 of them (60.7%) underwent LDLT, which was 80.9% of LDLTs. There were 2 cases of perioperative mortality; each was from DDLT and LDLT, respectively. Median follow-up was 18 months. Overall patient and graft survival rates at 6 months, 1 and 2 years were 95.7%, 93.4%, and 89.8%, respectively. There was no significant difference in survival between DDLT and LDLT. Overall recurrence-free survival rates of hepatocellular carcinoma (HCC) patients at 6 month, 1, and 2 years were 96.3%, 96.3%, and 90.3%, respectively. There was no significant difference in recurrence-free survival between DDLT and LDLT. CONCLUSION: As a new liver transplant program with limited resource and waiting list, patients with critical condition could undergo DDLT whereas relatively stable patients with HCCs were mostly directed to LDLT. We recommend a balanced approach between DDLT and LDLT for initiating liver transplant programs. PMID- 25025024 TI - Mechanical thromboprophylaxis is sufficient to prevent the lower extremity deep vein thrombosis after kidney transplantation. AB - PURPOSE: Deep vein thrombosis (DVT) is a severe and common complication that occurs after the major operation. Despite the commonality of DVT there is limited data on the incidence of DVT after kidney transplantation (KT). Furthermore, most studies have been retrospective in design and were conducted in western countries. The aim of this study was to evaluate the incidence of lower extremity DVT with mechanical thromboprophylaxis within 1 month of KT in Korea. METHODS: A total of 187 consecutive patients who underwent KT were included in this study. Patients used a graduated elastic stocking (n = 93) or an intermittent pneumatic compression device (n = 94) to prevent DVT. The frequency of DVT during the first month after KT was evaluated using serial color duplex ultrasound on postoperative days 7 +/- 2, 14 +/- 2, and 28 +/- 3. All patients were tested for eight thrombophilic factors before KT. RESULTS: DVT occurred in four patients (2.1%) during the first month after KT. All DVT developed in the graduated elastic stocking group. Interestingly, none of the patients had the factor V Leiden mutation or the prothrombin gene 20210A mutation. CONCLUSION: The incidence of DVT in this study was relatively lower than that of western populations. We did not encounter a factor V Leiden mutation or a prothrombin gene 20210A mutation in our study population. These findings suggest that inherited thrombophilic risk factors may be partially responsible for the difference in DVT incidence rates between different nationalities and/or ethnicities. PMID- 25025025 TI - Comparisons between prosthetic vascular graft and saphenous vein graft in femoro popliteal bypass. AB - PURPOSE: Infrainguinalfemoropopliteal bypass (IFPB) is recommended to peripheral arterial disease (PAD) with a long occlusion of the superficial femoral artery (SFA). The aims of our study were to determine the patency of graft materials, and identify the risk factors of graft failure. METHODS: From January 1995 to April 2011, we had performed 380 IFPBs in 351 patients, including 302 femoro above the knee (AK) bypasses and 78 femoro-below the knee (BK) bypasses. We compare age, sex, severity of ischemia between polytetra-uoroethylene (PTFE) graft and saphenous vein (SV) graft, and evaluate patency rate rates of the two groups. RESULTS: The primary patency rates at 5 years for SV (n = 76 limbs) and PTFE grafts (n = 226 limbs) in AK were 85.2% and 64.5% (log rank = 0.03), and the secondary patency rates at 5 years for SV and PTFE grafts in AK were 88.2% and 79.0% (log rank = 0.13). The primary patency rates at 5 years for SV (n = 50 limbs) and PTFE grafts (n = 28 limbs) in BK were 63.2% and 40.0% (log rank = 0.08), and the secondary patency rates at 5 years for SV and PTFE grafts in BK were 71.6% and 55.5% (log rank = 0.18). CONCLUSION: There was no statistical significant difference in secondary patency rates between SV and PTFE in IFPB. PTFE grafts as SV grafts can be a good alternative bypass material in IFPB instead of SV grafts. PMID- 25025026 TI - Delayed hepatic rupture after radiofrequency ablation for colorectal hepatic metastasis: management with transcatheter arterial embolization. AB - Intraperitoneal bleeding after radiofrequency ablation (RFA) is the most common major vascular complication due to direct needle injury to a vessel or liver capsule. However, intraperitoneal bleeding as a result of a delayed hepatic rupture after RFA for liver tumors is an extremely rare complication. The present report describes a case of intraperitoneal hemorrhage caused by delayed hepatic rupture resulting from arterioportal fistula after RFA for hepatic metastasis from colorectal cancer and successful management using transcatheter embolization. PMID- 25025027 TI - Spontaneous splenic rupture in Plasmodium vivax malaria. AB - Malaria can present with various clinical symptoms and complications. While a tertian malaria form that is especially prevalent in Korea is characterized by mild clinical progression, occasional splenic complications are known to occur. A 26-year-old Korean male soldier without prior medical history visited The Armed Forces Capital Hospital with left upper quadrant abdominal pain one day ago. Hemostasis under laparoscopic approach was attempted. The operation was converted into laparotomy due to friable splenic tissue and consequently poor hemostasis. Splenectomy was performed. The patient was discharged at postoperative day 17 without complication. While numerous diseases can result in splenic complications, such as splenic rupture, malarial infection is known as the most common cause. The incidence of malarial infection in Korea is increasing annually, and there are occasional reports of splenic rupture due to the infection, which requires attention. PMID- 25025028 TI - The paracholedochal vein: a feasible option as portal inflow in living donor liver transplantation. AB - Extensive thrombosis of the portal and splenomesenteric veins combined with cavernous transformation of the portal vein (CTPV) has been considered to be a contraindication for living donor liver transplantation (LDLT) due to technical difficulties and perioperative risks. In recent years, several surgical innovations including cavoportal hemitransposition, renoportal anastomosis, and portal arterialization have been introduced to overcome diffuse portal vein thrombosis (PVT) and CTPV, but their outcomes were unsatisfactory with significant morbidity and mortality. Herein, we report two successful cases of adult LDLT in diffuse PVT with CTPV managed using the paracholedochal vein as portal inflow to the graft. PMID- 25025030 TI - Planning for serious illness by the general public: a population-based survey. AB - Background. While rates of advance care documentation amongst the general public remain low, there is increasing recognition of the value of informal planning to address patient preferences in serious illness. Objectives. To determine the associations between personal attributes and formal and informal planning for serious illness across age groups. Methods. This population-based, online survey was conducted in Saskatchewan, Canada, in April, 2012, using a nonclinical sample of 827 adults ranging from 18 to 88 years of age and representative of age, sex, and regional distribution of the province. Associations between key predictor variables and planning for serious illness were assessed using binary logistic regression. Results. While 16.6% of respondents had completed a written living will or advance care plan, half reported having conversations about their treatment wishes or states of health in which they would find it unacceptable to live. Lawyers were the most frequently cited source of assistance for those who had prepared advance care plans. Personal experiences with funeral planning significantly increased the likelihood of activities designed to plan for serious illness. Conclusions. Strategies designed to increase the rate of planning for future serious illness amongst the general public must account for personal readiness. PMID- 25025031 TI - Performance and logistical challenges of alternative HIV-1 virological monitoring options in a clinical setting of Harare, Zimbabwe. AB - We evaluated a low-cost virological failure assay (VFA) on plasma and dried blood spot (DBS) specimens from HIV-1 infected patients attending an HIV clinic in Harare. The results were compared to the performance of the ultrasensitive heat denatured p24 assay (p24). The COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0, served as the gold standard. Using a cutoff of 5,000 copies/mL, the plasma VFA had a sensitivity of 94.5% and specificity of 92.7% and was largely superior to the VFA on DBS (sensitivity = 61.9%; specificity = 99.0%) or to the p24 (sensitivity = 54.3%; specificity = 82.3%) when tested on 302 HIV treated and untreated patients. However, among the 202 long-term ART-exposed patients, the sensitivity of the VFA decreased to 72.7% and to 35.7% using a threshold of 5,000 and 1,000 RNA copies/mL, respectively. We show that the VFA (either on plasma or on DBS) and the p24 are not reliable to monitor long-term treated, HIV-1 infected patients. Moreover, achieving acceptable assay sensitivity using DBS proved technically difficult in a less-experienced laboratory. Importantly, the high level of virological suppression (93%) indicated that quality care focused on treatment adherence limits virological failure even when PCR-based viral load monitoring is not available. PMID- 25025032 TI - Evaluation of clinical contributions provided by addition of the brain, calvarium, and scalp to the limited whole body imaging area in FDG-PET/CT tumor imaging. AB - PURPOSE: The aim of this study was to detect additional findings in whole body FDG-PET/CT scan including the brain, calvarium, and scalp (compared to starting from the base of the skull) in cancer patients and to determine contributions of these results to tumor staging and treatment protocols. MATERIALS AND METHODS: We noted whether the findings related to the brain, calvarium, and scalp in 1359 patients had a potential to modify staging of the disease, chemotherapy protocol, radiotherapy protocol, and surgical management. We identified rates of metastatic findings on the brain, calvarium, and scalp according to the tumor types on FDG PET/CT scanning. RESULTS: We found FDG-PET/CT findings for malignancy above the base of the skull in 42 patients (3.1%), one of whom was a patient with an unknown primary tumor. Twenty-two of the metastatic findings were in the brain, 16 were in the calvarium, and two were in the scalp. CONCLUSION: This study has demonstrated that addition of the brain to the limited whole body FDG-PET/CT scanning may provide important contributions to the patient's clinical management especially in patients with lung cancer, bladder cancer, malignant melanoma, breast cancer, stomach cancer, and unknown primary tumor. PMID- 25025033 TI - Increased upper and lower tract urothelial carcinoma in patients with end-stage renal disease: a nationwide cohort study in Taiwan during 1997-2008. AB - BACKGROUND: Urothelial cancer (UC) is the leading cancer of patients with end stage renal disease (ESRD) in Taiwan. The aims of this study were to explore the time trends of UC incidences and propose possible etiologic factors. METHODS: Abstracting from the National Health Insurance Research Database (NHIRD), there were 90,477 newly diagnosed cases of ESRD between 1997 and 2008 covering the patients aged 40-85. Among them, 2,708 had developed UC after diagnosis of ESRD. The CIR40-85 (cumulative incidence rate) of upper tract UC (UTUC) and lower tract UC (LTUC) were calculated for ESRD patients and general population, as well as SIR40-85 (standardized incidence ratio) for comparison. RESULTS: Female ESRD patients were found to have 9-18 times of elevated risks of UC, while those of males were increased up to 4-14 times. The time trends of CIR40-84 and SIR40-84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA associated herbal products after 1998. CONCLUSIONS: Patients with ESRD are at increased risks for both LTUC and UTUC in Taiwan. We hypothesize that the time trends associate with the consumption of aristolochic acid in Chinese herbal products (female predominant). PMID- 25025034 TI - A review on biodentine, a contemporary dentine replacement and repair material. AB - Biodentine is a calcium-silicate based material that has drawn attention in recent years and has been advocated to be used in various clinical applications, such as root perforations, apexification, resorptions, retrograde fillings, pulp capping procedures, and dentine replacement. There has been considerable research performed on this material since its launching; however, there is scarce number of review articles that collates information and data obtained from these studies. Therefore, this review article was prepared to provide the reader with a general picture regarding the findings about various characteristics of the material. The results of a PubMed search were classified and presented along with some critical comments where necessary. The review initially focuses on various physical properties of the material with subheadings and continues with biocompatibility. Another section includes the review of studies on Biodentine as a vital pulp treatment material and the article is finalized with the summary of some case reports where the material has been used. PMID- 25025035 TI - An investigation of cigarettes smoking behavior and nicotine dependence among Chinese methamphetamine users in two provinces. AB - OBJECTIVE: To survey cigarette behaviors and nicotine dependence among Chinese MA users, explore risk factors for high nicotine dependence, and analyze the relationship between nicotine dependence and MA-related euphoria and sexual impulse. METHODS: A cross-sectional study, applying a self-designed questionnaire with the Fagerstrom Test for Nicotine Dependence (FTND) and Visual Analog Scale (VAS), was performed among 391 MA users in Beijing and Guangdong, China. RESULTS: Most MA users were smokers, including 159 having high dependence on nicotine (HD users, FTND > 5) and 197 low or medium dependent (LMD users, FTND <= 5). Men or married users were more likely to be highly dependent than women or unmarried users. Higher MA dose and ever-use of ketamine or alcohol were associated with higher likelihood of high nicotine dependence. HD users reported significantly higher euphoria and stronger sexual impulse after using MA, indicated by higher VAS scores. CONCLUSIONS: Potential risk factors for high nicotine dependence among MA users may include male gender, being married, higher MA dosage, and ever use of ketamine or alcohol, which should be taken into consideration in individualized health promotion on smoking cessation. Severe nicotine dependence was associated with stronger MA-related euphoria and sexual impulse and it should be confirmed by further studies. PMID- 25025036 TI - Acetylcholinesterase inhibition by biofumigant (Coumaran) from leaves of Lantana camara in stored grain and household insect pests. AB - Recent studies proved that the biofumigants could be an alternative to chemical fumigants against stored grain insect pests. For this reason, it is necessary to understand the mode of action of biofumigants. In the present study the prospectus of utilising Lantana camara as a potent fumigant insecticide is being discussed. Inhibition of acetylcholinesterase (AChE) by Coumaran, an active ingredient extracted from the plant L. camara, was studied. The biofumigant was used as an enzyme inhibitor and acetylthiocholine iodide as a substrate along with Ellman's reagent to carry out the reactions. The in vivo inhibition was observed in both dose dependent and time dependent in case of housefly, and the nervous tissue (ganglion) and the whole insect homogenate of stored grain insect exposed to Coumaran. The possible mode of action of Coumaran as an acetylcholinesterase inhibitor is discussed. PMID- 25025037 TI - Comparison of two assays to determine anti-citrullinated peptide antibodies in rheumatoid arthritis in relation to other chronic inflammatory rheumatic diseases: assaying anti-modified citrullinated vimentin antibodies adds value to second-generation anti-citrullinated cyclic peptides testing. AB - Determination of anti-citrullinated peptide antibodies (ACPA) plays a relevant role in the diagnosis of rheumatoid arthritis (RA). To date, it is still unclear if the use of several tests for these autoantibodies in the same patient offers additional value as compared to performing only one test. Therefore, we evaluated the performance of using two assays for ACPA: second-generation anti citrullinated cyclic peptides antibodies (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV) antibodies for the diagnosis of RA. We compared three groups: RA (n = 142), chronic inflammatory disease (CIRD, n = 86), and clinically healthy subjects (CHS, n = 56) to evaluate sensitivity, specificity, predictive values, and likelihood ratios (LR) of these two assays for the presence of RA. A lower frequency of positivity for anti-CCP2 was found in RA (66.2%) as compared with anti-MCV (81.0%). When comparing RA versus other CIRD, sensitivity increased when both assays were performed. This strategy of testing both assays had high specificity and LR+. We conclude that adding the assay of anti-MCV antibodies to the determination of anti-CCP2 increases the sensitivity for detecting seropositive RA. Therefore, we propose the use of both assays in the initial screening of RA in longitudinal studies, including early onset of undifferentiated arthritis. PMID- 25025038 TI - Dipeptidyl peptidase 10 (DPP10(789)): a voltage gated potassium channel associated protein is abnormally expressed in Alzheimer's and other neurodegenerative diseases. AB - The neuropathological features associated with Alzheimer's disease (AD) include the presence of extracellular amyloid-beta peptide-containing plaques and intracellular tau positive neurofibrillary tangles and the loss of synapses and neurons in defined regions of the brain. Dipeptidyl peptidase 10 (DPP10) is a protein that facilitates Kv4 channel surface expression and neuronal excitability. This study aims to explore DPP10789 protein distribution in human brains and its contribution to the neurofibrillary pathology of AD and other tauopathies. Immunohistochemical analysis revealed predominant neuronal staining of DPP10789 in control brains, and the CA1 region of the hippocampus contained strong reactivity in the distal dendrites of the pyramidal cells. In AD brains, robust DPP10789 reactivity was detected in neurofibrillary tangles and plaque associated dystrophic neurites, most of which colocalized with the doubly phosphorylated Ser-202/Thr-205 tau epitope. DPP10789 positive neurofibrillary tangles and plaque-associated dystrophic neurites also appeared in other neurodegenerative diseases such as frontotemporal lobar degeneration, diffuse Lewy body disease, and progressive supranuclear palsy. Occasional DPP10789 positive neurofibrillary tangles and neurites were seen in some aged control brains. Western blot analysis showed both full length and truncated DPP10789 fragments with the later increasing significantly in AD brains compared to control brains. Our results suggest that DPP10789 is involved in the pathology of AD and other neurodegenerative diseases. PMID- 25025039 TI - Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next generation sequencing. AB - Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency. PMID- 25025041 TI - CNB-001 a novel curcumin derivative, guards dopamine neurons in MPTP model of Parkinson's disease. AB - Copious experimental and postmortem studies have shown that oxidative stress mediated degeneration of nigrostriatal dopaminergic neurons underlies Parkinson's disease (PD) pathology. CNB-001, a novel pyrazole derivative of curcumin, has recently been reported to possess various neuroprotective properties. This study was designed to investigate the neuroprotective mechanism of CNB-001 in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD. Administration of MPTP (30 mg/kg for four consecutive days) exacerbated oxidative stress and motor impairment and reduced tyrosine hydroxylase (TH), dopamine transporter, and vesicular monoamine transporter 2 (VMAT2) expressions. Moreover, MPTP induced ultrastructural changes such as distorted cristae and mitochondrial enlargement in substantia nigra and striatum region. Pretreatment with CNB-001 (24 mg/kg) not only ameliorated behavioral anomalies but also synergistically enhanced monoamine transporter expressions and cosseted mitochondria by virtue of its antioxidant action. These findings support the neuroprotective property of CNB-001 which may have strong therapeutic potential for treatment of PD. PMID- 25025042 TI - Diagnosis system for hepatocellular carcinoma based on fractal dimension of morphometric elements integrated in an artificial neural network. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) remains a leading cause of death by cancer worldwide. Computerized diagnosis systems relying on novel imaging markers gained significant importance in recent years. Our aim was to integrate a novel morphometric measurement--the fractal dimension (FD)--into an artificial neural network (ANN) designed to diagnose HCC. MATERIAL AND METHODS: The study included 21 HCC and 28 liver metastases (LM) patients scheduled for surgery. We performed hematoxylin staining for cell nuclei and CD31/34 immunostaining for vascular elements. We captured digital images and used an in house application to segment elements of interest; FDs were calculated and fed to an ANN which classified them as malignant or benign, further identifying HCC and LM cases. RESULTS: User intervention corrected segmentation errors and fractal dimensions were calculated. ANNs correctly classified 947/1050 HCC images (90.2%), 1021/1050 normal tissue images (97.23%), 1215/1400 LM (86.78%), and 1372/1400 normal tissues (98%). We obtained excellent interobserver agreement between human operators and the system. CONCLUSION: We successfully implemented FD as a morphometric marker in a decision system, an ensemble of ANNs designed to differentiate histological images of normal parenchyma from malignancy and classify HCCs and LMs. PMID- 25025043 TI - The role of NBI HDTV magnifying endoscopy in the prehistologic diagnosis of laryngeal papillomatosis and spinocellular cancer. AB - Narrow band imaging (NBI) HDTV (high definition television) magnifying endoscopy is considered to be superior for the accurate display of the microvascular patterns of superficial mucosal lesions. Observation of changes in intraepithelial papillary capillary loops (IPCL) can help distinguish benign from malignant lesions as part of an "optical biopsy." However, IPCL changes in papillomas may be mistaken for spinocellular cancer (SCC). The aim of the study was to determine whether observing microvascular changes alone is sufficient for discriminating between laryngeal SCC and papillomatosis. An additional aim was to identify associated characteristics that could clarify the diagnosis. The study included 109 patients with a suspected laryngeal tumor or papilloma. HDTV NBI magnifying endoscopy was performed during direct laryngoscopy. It was possible to visualize IPCL changes in 82 out of 109 patients (75.2%). In 71 (86.6%) patients, the diagnosis was correctly determined. In 4 (4.9%) cases, the diagnosis of SCC was expressed on the basis of finding pathologic IPCL, but histology did not demonstrate malignancy. To achieve a correct diagnosis using HDTV NBI magnifying endoscopy, it is important not only to observe changes in the shape of IPCL but also to note possible papillary structures with central-axis capillaries typical of papillomatosis. PMID- 25025040 TI - Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far? AB - Mesenchymal stromal cells (MSCs) are multipotent cells, which can give rise to several cell types including osteoblasts, adipocytes, and chondroblasts. These cells can be found in a variety of adult and fetal tissues, such as bone marrow, adipose tissue, cord blood, and placenta. In recent years, the biological properties of MSCs have attracted the attention of researchers worldwide due to their potential application for treating a series of clinical situations. Among these properties, special attention should be given to the immunoregulatory potential of those cells. MSCs are able to act on all cells of the immune system, which includes the capacity to inhibit the proliferation and function of T-cells. This feature renders them natural candidates to treat several diseases in which cellular immune response is exacerbated. In this review, we outline the main mechanisms by which MSCs immunosuppress T-cell response, focusing on cell-cell contact, secretion of soluble factors, and regulatory T-cell generation. The influence of surface markers in the immunosuppression process and features of MSCs isolated from different sources are also discussed. Finally, the influences of toll-like receptors and cytokines on the inflammatory microenvironment are highlighted regarding the activation of MSCs to exert their immunoregulatory function. PMID- 25025044 TI - Follicular fluid oocyte/cumulus-free DNA concentrations as a potential biomolecular marker of embryo quality and IVF outcome. AB - The present prospective study examined the follicular fluid oocyte/cumulus-free DNA concentrations (ff o/c-free DNA) during ovarian stimulation and the possible association between ff o/c-free DNA and embryological results such as embryo quality and pregnancy rate. Eighty-three women undergoing IV/ICSI-ET treatments were prospectively included in this study. ff o/c-free DNA was determined by conventional quantitative real time PCR-Sybr green detection approach. The 83 ff samples were categorized in two groups: group 1 (n = 62) with cumulus oocytes complexes (CoCs) >=2 and group 2 (n = 21) with CoCs = 1. Group 1 revealed significant higher embryo quality in terms of mean score of embryo transfer (MSET), but lower ff o/c-free DNA concentrations compared to group 2. The two groups showed comparable pregnancy rates (positive hCG and clinical pregnancy). The higher the ff o/c-free DNA concentration, the lower the number of produced oocytes. ff o/c-free DNA did not seem to have any direct role in the IVF outcome. Further research is required to clarify whether ff o/c-free DNA is a biomolecular marker of embryo quality and IVF outcome. PMID- 25025045 TI - Outcomes of a joint replacement surgical home model clinical pathway. AB - Optimizing perioperative care to provide maximum benefit at minimum cost may be best achieved using a perioperative clinical pathway (PCP). Using our joint replacement surgical home (JSH) model PCP, we examined length of stay (LOS) following total joint arthroplasty (TJA) to evaluate patient care optimization. We reviewed a spectrum of clinical measurements in 190 consecutive patients who underwent TJA. Patients who had surgery earlier in the week and who were earlier cases of the day had a significantly lower LOS than patients whose cases started both later in the week and later in the day. Patients discharged home had significantly lower LOS than those discharged to a secondary care facility. Patients who received regional versus general anesthesia had a significantly lower LOS. Scheduling patients discharged to home and who will likely receive regional anesthesia for the earliest morning slot and earlier in the week may help decrease overall LOS. PMID- 25025047 TI - Toxic potential of synthesized graphene zinc oxide nanocomposite in the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg9. AB - In the present study the graphene zinc oxide nanocomposite (GZNC) was synthesized, characterized, and evaluated for its toxic potential on third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg(9). The synthesized GZNC was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The GZNC in 0.1% dimethyl sulphoxide (DMSO) was sonicated for 10 minutes and the final concentrations 0.033, 0.099, 0.199, and 3.996 MUg/MUL of diet were established. The third instar larvae were allowed to feed on it separately for 24 and 48 hr. The hsp70 expression was measured by o-nitrophenyl-beta-D-galactopyranoside assay, tissue damage was measured by trypan blue exclusion test, and beta galactosidase activity was monitored by in situ histochemical beta-galactosidase staining. Oxidative stress was monitored by performing lipid peroxidation assay and total protein estimation. Ethidium bromide/acridine orange staining was performed on midgut cells for apoptotic index and the comet assay was performed for the DNA damage. The results of the present study showed that the exposure of 0.199 and 3.996 MUg/MUL of GZNC was toxic for both 24 hr and 48 hr of exposure. The doses of 0.033 MUg/MUL and 0.099 of GZNC showed no toxic effects on its exposure to the third instar larvae for 24 hr as well as 48 hr of duration. PMID- 25025046 TI - Chronic neuroinflammation in Alzheimer's disease: new perspectives on animal models and promising candidate drugs. AB - Chronic neuroinflammation is now considered one of the major factors in the pathogenesis of Alzheimer's disease (AD). However, the most widely used transgenic AD models (overexpressing mutated forms of amyloid precursor protein, presenilin, and/or tau) do not demonstrate the degree of inflammation, neurodegeneration (particularly of the cholinergic system), and cognitive decline that is comparable with the human disease. Hence a more suitable animal model is needed to more closely mimic the resulting cognitive decline and memory loss in humans in order to investigate the effects of neuroinflammation on neurodegeneration. One of these models is the glial fibrillary acidic protein interleukin 6 (GFAP-IL6) mouse, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6) in astrocytes. These transgenic mice show substantial and progressive neurodegeneration as well as a decline in motor skills and cognitive function, starting from 6 months of age. This animal model could serve as an excellent tool for drug discovery and validation in vivo. In this review, we have also selected three potential anti inflammatory drugs, curcumin, apigenin, and tenilsetam, as candidate drugs, which could be tested in this model. PMID- 25025048 TI - Quercetin significantly inhibits the metabolism of caffeine, a substrate of cytochrome P450 1A2 unrelated to CYP1A2*1C (-2964G>A) and *1F (734C>A) gene polymorphisms. AB - BACKGROUND: Quercetin is abundant in plants and human diets. Previous studies indicated that quercetin inhibited the activity of CYP1A2, and the combination of quercetin with the substrates of CYP1A2 might produce herb-drug interactions. This research aims to determine the effects of quercetin and the CYP1A2 gene polymorphisms, namely, CYP1A2*1C (-2964G>A) and *1F (734C>A), on the metabolism of caffeine. METHOD: The experiment was designed into two treatment phases separated by a 2-week washout period. Six homozygous individuals for the CYP1A2*1C/*1F (GG/AA) genotype and 6 heterozygous individuals for the CYP1A2*1C/*1F (GA/CA) genotype were enrolled in the study. Quercetin capsules (500 mg) were given to each volunteer once daily for 13 consecutive days, and after that, each subject was coadministrated 100 mg caffeine capsules with 500 mg quercetin on the 14th day. Then a series of venous blood samples were collected for HPLC analysis. Correlation was determined between pharmacokinetics of caffeine and paraxanthine with caffeine metabolite ratio. RESULTS: Quercetin significantly affected the pharmacokinetics of caffeine and its main metabolite paraxanthine, while no differences were found in the pharmacokinetics of caffeine and paraxanthine between GG/AA and GA/CA genotype groups. CONCLUSION: Quercetin significantly inhibits the caffeine metabolism, which is unrelated to CYP1A2*1C ( 2964G>A) and *1F (734C>A) gene polymorphisms. PMID- 25025049 TI - Treatment of acute pulmonary embolism: update on newer pharmacologic and interventional strategies. AB - Acute pulmonary embolism (PE) is a common complication in hospitalized patients, spanning multiple patient populations and crossing various therapeutic disciplines. Current treatment paradigm in patients with massive PE mandates prompt risk stratification with aggressive therapeutic strategies. With the advent of endovascular technologies, various catheter-based thrombectomy and thrombolytic devices are available to treat patients with massive or submassive PE. In this paper, a variety of newer treatment strategies for PE are analyzed, with special emphasis on various interventional treatment strategies. Clinical evidence for utilizing endovascular treatment modalities, based on our institutional experience as well as a literature review, is provided. PMID- 25025050 TI - Scanning electron microscopy and X-ray microanalysis for chemical and morphological characterisation of the inorganic component of gunshot residue: selected problems. AB - Chosen aspects of examinations of inorganic gunshot particles by means of scanning electron microscopy and energy dispersive X-ray spectrometry technique are presented. The research methodology of particles was worked out, which included a precise and repeatable procedure of the automatic detection and identification of particles as well as the representation of the obtained analytical data in the form of the frequencies of occurrence of particles of certain chemical or morphological class within the whole population of particles revealed in a specimen. On this basis, there were established relationships between the chemical and morphological properties of populations of particles and factors, such as the type of ammunition, the distance from the gun muzzle to the target, the type of a substrate the particles sediment on, and the time between shooting and collecting the specimens. Each of these aspects of examinations of particles revealed a great potential of being utilised in casework, while establishing various circumstances of shooting incidents leads to the reconstruction of the course of the studied incident. PMID- 25025051 TI - Construction and biomechanical properties of polyaxial self-locking anatomical plate based on the geometry of distal tibia. AB - In order to provide scientific and empirical evidence for the clinical application of the polyaxial self-locking anatomical plate, 80 human tibias from healthy adults were scanned by spiral CT and their three-dimensional images were reconstructed using the surface shaded display (SSD) method. Firstly, based on the geometric data of distal tibia, a polyaxial self-locking anatomical plate for distal tibia was designed and constructed. Biomechanical tests were then performed by applying axial loading, 4-point bending, and axial torsion loading on the fracture fixation models of fresh cadaver tibias. Our results showed that variation in twisting angles of lateral tibia surface was found in various segments of the distal tibia. The polyaxial self-locking anatomical plate was constructed based on the geometry of the distal tibia. Compared to the conventional anatomical locking plate, the polyaxial self-locking anatomical plate of the distal tibia provides a better fit to the geometry of the distal tibia of the domestic population, and the insertion angle of locking screws can be regulated up to 30 degrees . Collectively, this study assesses the geometry of the distal tibia and provides variable locking screw trajectory to improve screw plate stability through the design of a polyaxial self-locking anatomical plate. PMID- 25025052 TI - Capitalizing on the autophagic response for treatment of liver disease caused by alpha-1-antitrypsin deficiency and other genetic diseases. AB - Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ) within liver cells. In the case of ATD-associated liver disease, the resulting "gain-of-function" toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease. PMID- 25025053 TI - Characterization and potential use of cuttlefish skin gelatin hydrolysates prepared by different microbial proteases. AB - Composition, functional properties, and in vitro antioxidant activities of gelatin hydrolysates prepared from cuttlefish skin were investigated. Cuttlefish skin gelatin hydrolysates (CSGHs) were obtained by treatment with crude enzyme preparations from Bacillus licheniformis NH1, Bacillus mojavensis A21, Bacillus subtilis A26, and commercial alcalase. All CSGHs had high protein contents, 74.3 78.3%, and showed excellent solubility (over 90%). CSGH obtained by alcalase demonstrated high antioxidant activities monitored by beta-carotene bleaching, DPPH radical scavenging, lipid peroxidation inhibition, and reducing power activity. Its antioxidant activity remained stable or increased in a wide range of pH (1-9), during heating treatment (100 degrees C for 240 min) and after gastrointestinal digestion simulation. In addition, alcalase-CSGH was incorporated into turkey meat sausage to determine its effect on lipid oxidation during 35 days of storage period. At 0.5 mg/g, alcalase-CSGH delayed lipid oxidation monitored by TBARS and conjugated diene up to 10 days compared to vitamin C. The results reveal that CSGHs could be used as food additives possessing both antioxidant activity and functional properties. PMID- 25025055 TI - A performance/cost evaluation for a GPU-based drug discovery application on volunteer computing. AB - Bioinformatics is an interdisciplinary research field that develops tools for the analysis of large biological databases, and, thus, the use of high performance computing (HPC) platforms is mandatory for the generation of useful biological knowledge. The latest generation of graphics processing units (GPUs) has democratized the use of HPC as they push desktop computers to cluster-level performance. Many applications within this field have been developed to leverage these powerful and low-cost architectures. However, these applications still need to scale to larger GPU-based systems to enable remarkable advances in the fields of healthcare, drug discovery, genome research, etc. The inclusion of GPUs in HPC systems exacerbates power and temperature issues, increasing the total cost of ownership (TCO). This paper explores the benefits of volunteer computing to scale bioinformatics applications as an alternative to own large GPU-based local infrastructures. We use as a benchmark a GPU-based drug discovery application called BINDSURF that their computational requirements go beyond a single desktop machine. Volunteer computing is presented as a cheap and valid HPC system for those bioinformatics applications that need to process huge amounts of data and where the response time is not a critical factor. PMID- 25025054 TI - Associations of prenatal growth with metabolic syndrome, insulin resistance, and nutritional status in Chilean children. AB - INTRODUCTION: The association of prenatal growth with nutritional status, metabolic syndrome (MS), and insulin resistance (IR) was studied in school-age children. METHODS: A retrospective cohort study was designed linking present data of children with perinatal records. 3325 subjects were enrolled. Anthropometry, blood pressure (BP), and pubertal status were assessed. Blood lipids, glucose, and insulin were measured. Linear associations were assessed using the Cochran Armitage test. Odds ratios and nonlinear associations were computed. RESULTS: 3290 children (52% females, mean age of 11.4 +/- 1 years) were analyzed. Prevalence of obesity, stunting, MS, and IR was 16.0%, 3.6%, 7.3%, and 25.5%, respectively. The strongest positive association was between birth weight (BW) and obesity (OR 2.97 (95% CI 2.01-4.40) at BW >= 4,000 g compared to BW 2,500 2,999). The strongest inverse association was between birth length (BL) and stunting (OR 8.70 (95% CI 3.66-20.67) at BL < 48 cm compared to BL 52-53 cm). A U shaped association between BL and BP >= 90th percentile was observed. Significant ORs were also found for MS and IR. Adjustments for present fat mass increased or maintained the most prenatal growth influences. CONCLUSIONS: Prenatal growth influences MS, IR, and nutritional status. Prenatal growth was more important than present body composition in determining these outcomes. PMID- 25025056 TI - Investigation of antiarthritic potential of Plumeria alba L. leaves in acute and chronic models of arthritis. AB - AIM: The present investigation was designed to evaluate antiarthritic potential of fractions of hydroalcoholic extract from leaves of P. alba. MATERIALS AND METHODS: Plumeria alba L. leaves were extracted with hydroalcohol (30 : 70) to obtain hydroalcoholic extract of P. alba. This extract was further fractionated with solvents ethyl acetate and n-butanol to obtain EAPA and BPA, respectively. These fractions were tested against formaldehyde and Freund's complete adjuvant (FCA) induced arthritis. Arthritis assessment, paw volume, body weight, motor incoordination, and nociceptive threshold were measured. On day 21, the animals were sacrificed and histopathology was done. RESULTS: The 100 and 200 mg/kg doses of EAPA and BPA caused a significant (P <= 0.05-0.01) reduction in paw swelling in both models. Erythrocyte sedimentation rate (ESR) and spleen weight decreased significantly (P < 0.01) in arthritic rats treated with extracts. There was significant (P < 0.05) improvement in thymus weight in EAPA treated rats whereas significant (P < 0.01) improvement was also seen in haemoglobin level (Hb) in diclofenac treated group. Motor incoordination and nociceptive threshold were also significantly (P <= 0.05-0.01) improved. CONCLUSION: The present study suggests that Plumeria alba L. has protective activity against arthritis and supports the traditional use of P. alba for rheumatism and other inflammatory diseases. PMID- 25025058 TI - Very low birth weight and perinatal periods of risk: disparities in St. Louis. AB - OBJECTIVE: Very low birth weight (VLBW) is a significant issue in St. Louis, Missouri. Our study evaluated risk factors associated with VLBW in this predominantly urban community. METHODS: From 2000 to 2009, birth and fetal death certificates were evaluated (n = 160, 189), and mortality rates were calculated for perinatal periods of risk. The Kitagawa method was used to explore fetoinfant mortality rates (FIMR) in terms of birth weight distribution and birthweight specific mortality. Multivariable logistic regression was used to assess the magnitude of association of selected risk factors with VLBW. RESULTS: VLBW contributes to 50% of the excess FIMR in St. Louis City and County. The highest proportion of VLBW can be attributed to black maternal race (40.6%) in St. Louis City, inadequate prenatal care (19.8%), and gestational hypertension (12.0%) among black women. Medicaid was found to have a protective effect for VLBW among black women (population attributable risk (PAR) = -14.5). DISCUSSION: Interventions targeting the health of women before and during conception may be most successful at reducing the disparities in VLBW in this population. Interventions geared towards smoking cessation and improvements in Medicaid and prenatal care access for black mothers and St. Louis City residents can greatly reduce VLBW rates. PMID- 25025057 TI - The effects of beta-glucan rich oat bread on serum nitric oxide and vascular endothelial function in patients with hypercholesterolemia. AB - INTRODUCTION: Oats are high in soluble fibers and effective in reducing the risk of cardiovascular diseases (CVD). We assessed the effects of beta-glucan from oat bran on serum nitric oxide (NO) endothelial function in patients with hypercholesterolemia. METHOD: Sixty hypercholesterolemic patients were randomly divided to receive an experimental bread rich in beta-glucan from oat bran (intervention) or bread rich in wheat fiber (control) for four weeks. All subjects had the same diet for two-week baseline period and hypocaloric diet for four weeks of intervention. Serum NO concentration and flow-mediated dilation (FMD) were determined before and after the experiment. RESULTS: Mean age of the participants was 51.1 +/- 9.3 years and 65% (n = 39) were female. After intervention, serum NO concentration increased by 50.2 +/- 19.8 MUmol/lit in the intervention group (P = 0.017), but no change was observed in the control group (17.5 +/- 27.5 MUmol/lit; P = 0.530). No change of FMD was observed in the intervention (0.48 +/- 0.78%; P = 0.546) or in the control group (0.59 +/- 0.92%; P = 0.533). CONCLUSION: Consumption of oat bread for four weeks increases serum NO concentration but has no effect on FMD. Further studies are warranted in this regard. PMID- 25025059 TI - Phosphate/zinc interaction analysis in two lettuce varieties reveals contrasting effects on biomass, photosynthesis, and dynamics of Pi transport. AB - Inorganic phosphate (Pi) and Zinc (Zn) are essential nutrients for normal plant growth. Interaction between these elements has been observed in many crop plants. Despite its agronomic importance, the biological significance and genetic basis of this interaction remain largely unknown. Here we examined the Pi/Zn interaction in two lettuce (Lactuca sativa) varieties, namely, "Paris Island Cos" and "Kordaat." The effects of variation in Pi and Zn supply were assessed on biomass and photosynthesis for each variety. Paris Island Cos displayed better growth and photosynthesis compared to Kordaat under all the conditions tested. Correlation analysis was performed to determine the interconnectivity between Pi and Zn intracellular contents in both varieties. Paris Island Cos showed a strong negative correlation between the accumulation levels of Pi and Zn in shoots and roots. However, no relation was observed for Kordaat. The increase of Zn concentration in the medium causes a decrease in dynamics of Pi transport in Paris Island Cos, but not in Kordaat plants. Taken together, results revealed a contrasting behavior between the two lettuce varieties in terms of the coregulation of Pi and Zn homeostasis and provided evidence in favor of a genetic basis for the interconnection of these two elements. PMID- 25025060 TI - Extremely low frequency magnetic fields induce spermatogenic germ cell apoptosis: possible mechanism. AB - The energy generated by an extremely low frequency electromagnetic field (ELF EMF) is too weak to directly induce genotoxicity. However, it is reported that an extremely low frequency magnetic field (ELF-MF) is related to DNA strand breakage and apoptosis. The testes that conduct spermatogenesis through a dynamic cellular process involving meiosis and mitosis seem vulnerable to external stress such as heat, MF exposure, and chemical or physical agents. Nevertheless the results regarding adverse effects of ELF-EMF on human or animal reproductive functions are inconclusive. According to the guideline of the International Commission on Non-Ionizing Radiation Protection (ICNIRP; 2010) for limiting exposure to time varying MF (1 Hz to 100 kHz), overall conclusion of epidemiologic studies has not consistently shown an association between human adverse reproductive outcomes and maternal or paternal exposure to low frequency fields. In animal studies there is no compelling evidence of causal relationship between prenatal development and ELF-MF exposure. However there is increasing evidence that EL-EMF exposure is involved with germ cell apoptosis in testes. Biophysical mechanism by which ELF MF induces germ cell apoptosis has not been established. This review proposes the possible mechanism of germ cell apoptosis in testes induced by ELF-MF. PMID- 25025061 TI - Xanthium strumarium L. extracts produce DNA damage mediated by cytotoxicity in in vitro assays but does not induce micronucleus in mice. AB - Xanthium strumarium L. is a member of the Asteraceae commonly used in Cuba, mainly as diuretic. Some toxic properties of this plant have also been reported and, to date, very little is known about its genotoxic properties. The present work aims was to evaluate the potential cytotoxic and genotoxic risk of whole extract from Xanthium strumarium L. whole extract of aerial parts. No positive response was observed in a battery of four Salmonella typhimurium strains, when exposed to concentrations up to 5 mg/plate, with and without mammalian metabolic activation (liver microsomal S9 fraction from Wistar rats). In CHO cells, high concentrations (25-100 MUg/mL) revealed significant reduction in cell viability. Results from sister chromatid exchanges, chromosome aberrations, and comet assay showed that X. strumarium extract is genotoxic at the highest concentration used, when clear cytotoxic effects were also observed. On the contrary, no increase in micronuclei frequency in bone marrow cells was observed when the extract was orally administered to mice (100, 500, and 2000 mg/Kg doses). The data presented here constitute the most complete study on the genotoxic potential of X. strumarium L. and show that the extract can induce in vitro DNA damage at cytotoxic concentrations. PMID- 25025062 TI - Genetic characterization and evolution of H1N1pdm09 after circulation in a swine farm. AB - Following the emergence of the A(H1N1)pdm09 in humans, this novel influenza virus was reverse transmitted from infected people to swine population worldwide. In this study we investigated the molecular evolution of A(H1N1)pdm09 virus identified in pigs reared in a single herd. Nasal swabs taken from pigs showing respiratory distress were tested for influenza type A and A(H1N1)pdm09 by real time RT-PCR assays. Virus isolation from positive samples was attempted by inoculation of nasal swabs samples into specific pathogen free embryonated chicken eggs (ECE) and complete genome sequencing was performed on virus strains after replication on ECE or from original swab sample. The molecular analysis of hemagglutinin (HA) showed, in four of the swine influenza viruses under study, a unique significant amino acid change, represented by a two-amino acid insertion at the HA receptor binding site. Phylogenetic analysis of HA, neuraminidase, and concatenated internal genes revealed a very similar topology, with viruses under study forming a separate cluster, branching outside the A(H1N1)pdm09 isolates recognized until 2014. The emergence of this new cluster of A(H1N1)pdm09 in swine raises further concerns about whether A(H1N1)pdm09 with new molecular characteristics will become established in pigs and potentially transmitted to humans. PMID- 25025063 TI - Differential expression of cholecystokinin A receptor in gallbladder cancer in the young and elderly suggests two subsets of the same disease? AB - BACKGROUND: Cholecystokinin type A receptor (CCKAR) is known to be overexpressed in variety of human malignancies but information regarding its expression in gallbladder cancer (GBC) is limited. Attempts were now made to investigate expression pattern of CCKAR mRNA and protein in controls and GBC patients and correlate it with various clinicopathological parameters following surgical resection. MATERIALS AND METHODS: Gallbladder tissue samples from 64 subjects (GBC: 39; control: 25) were studied. Expression of CCKAR mRNA was evaluated by reverse transcriptase-polymerase chain reaction and confirmed using real-time polymerase chain reaction. Protein expression was studied by enzyme-linked immunosorbent assay. RESULTS: Significantly higher expression of CCKAR mRNA (P < 0.0001) and protein (P < 0.0001) was observed in GBC tissues. Overexpression was also observed for stage III and in moderately and poorly differentiated tumors. When the clinicopathological parameters were compared, we found age dependent decrease in CCKAR expression. Relatively higher expression of CCKAR was observed in younger patients (age < 45 years) having more aggressive disease when compared with elderly ones (age >= 45 years). CONCLUSIONS: Age related differential expression of CCKAR in GBC may suggest two possible variants of the disease in this endemic belt. PMID- 25025064 TI - Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation. AB - Central nervous system (CNS) involvement is a severe complication of BCR-ABL positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT. PMID- 25025066 TI - Data mining in translational bioinformatics. PMID- 25025065 TI - The association between platelet count and acute phase response in chronic spontaneous urticaria. AB - BACKGROUND: The platelet parameters and C-reactive protein (CRP) are markers reflecting a systemic inflammatory response. Among those, CRP is one of the major proteins helpful in determination of severity/activity of chronic spontaneous urticaria (CSU). AIM: To determine relationships between platelet activation indices and serum concentration of CRP, the best marker of acute phase response, and their potential clinical use in CSU patients. METHODS: Mean platelet volume (MPV), platelet distribution width (PDW), and platelet count as well as serum CRP concentration were measured in CSU patients, showing different degrees of urticarial severity, and in the healthy subjects. RESULTS: No significant differences were found in MPV and PDW between CSU group and the healthy subjects. The platelet count was significantly higher in moderate-severe CSU than that of the controls and mild CSU patients. Serum CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects and significantly correlated with the platelet count in CSU patients. CONCLUSIONS: Acute phase response in CSU is associated with the increased number of circulating platelets in patients with more severe symptoms. It seems that simple determination of platelet size indices is not a reliable indicator of CSU severity/activity. PMID- 25025067 TI - Amelioration of LPS-induced inflammation response in microglia by AMPK activation. AB - Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80 MUM and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-alpha production. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX 2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-kappaB. Inhibition of AMPK with compound C restored decreased NF-kappaB translocation by ENERGI-F704. In conclusion, ENERGI-F704 exerts inhibitory activity on LPS-induced inflammation through manipulating AMPK signaling and exhibits a potential therapeutic agent for neuroinflammatory disease. PMID- 25025068 TI - Morphological study of the newly designed cementless femoral stem. AB - A morphology study was essential to the development of the cementless femoral stem because accurate dimensions for both the periosteal and endosteal canal ensure primary fixation stability for the stem, bone interface, and prevent stress shielding at the calcar region. This paper focused on a three-dimensional femoral model for Asian patients that applied preoperative planning and femoral stem design. We measured various femoral parameters such as the femoral head offset, collodiaphyseal angle, bowing angle, anteversion, and medullary canal diameters from the osteotomy level to 150 mm below the osteotomy level to determine the position of the isthmus. Other indices and ratios for the endosteal canal, metaphyseal, and flares were computed and examined. The results showed that Asian femurs are smaller than Western femurs, except in the metaphyseal region. The canal flare index (CFI) was poorly correlated (r < 0.50) to the metaphyseal canal flare index (MCFI), but correlated well (r = 0.66) with the corticomedullary index (CMI). The diversity of the femoral size, particularly in the metaphyseal region, allows for proper femoral stem design for Asian patients, improves osseointegration, and prolongs the life of the implant. PMID- 25025069 TI - Big data and network biology. PMID- 25025071 TI - Carbapenemases in gram-negative bacteria: laboratory detection and clinical significance. PMID- 25025070 TI - Sexual enhancement products for sale online: raising awareness of the psychoactive effects of yohimbine, maca, horny goat weed, and Ginkgo biloba. AB - INTRODUCTION: The use of unlicensed food and herbal supplements to enhance sexual functions is drastically increasing. This phenomenon, combined with the availability of these products over the Internet, represents a challenge from a clinical and a public health perspective. METHODS: A comprehensive multilingual assessment of websites, drug fora, and other online resources was carried out between February and July 2013 with exploratory qualitative searches including 203 websites. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN). Once the active constitutes of the products were identified, a comprehensive literature search was carried out using PsycInfo and PubMed. RESULTS: The most common sexual enhancement products available on the Internet were identified. Their active ingredients included yohimbine, maca, horny goat weed and Ginkgo biloba. These four substances were reported with the occurrence of adverse events and the induction of psychological symptoms, such as mood changes, anxiety, and hallucinations as well as addictive behaviours. CONCLUSIONS: Uncontrolled availability of sexual enhancement products that contain potentially harmful substances is a major public health concern. The possible impact on population health, particularly among subjects with psychiatric disorders, usually at risk for sexual dysfunction, may be significant. This new trend needs to be extensively studied and monitored. PMID- 25025072 TI - Massive exploration of perturbed conditions of the blood coagulation cascade through GPU parallelization. AB - The introduction of general-purpose Graphics Processing Units (GPUs) is boosting scientific applications in Bioinformatics, Systems Biology, and Computational Biology. In these fields, the use of high-performance computing solutions is motivated by the need of performing large numbers of in silico analysis to study the behavior of biological systems in different conditions, which necessitate a computing power that usually overtakes the capability of standard desktop computers. In this work we present coagSODA, a CUDA-powered computational tool that was purposely developed for the analysis of a large mechanistic model of the blood coagulation cascade (BCC), defined according to both mass-action kinetics and Hill functions. coagSODA allows the execution of parallel simulations of the dynamics of the BCC by automatically deriving the system of ordinary differential equations and then exploiting the numerical integration algorithm LSODA. We present the biological results achieved with a massive exploration of perturbed conditions of the BCC, carried out with one-dimensional and bi-dimensional parameter sweep analysis, and show that GPU-accelerated parallel simulations of this model can increase the computational performances up to a 181* speedup compared to the corresponding sequential simulations. PMID- 25025073 TI - Cardiac proteomics. PMID- 25025074 TI - Number of polyploid giant cancer cells and expression of EZH2 are associated with VM formation and tumor grade in human ovarian tumor. AB - To investigate the associations among the number of polyploid giant cancer cells (PGCCs) and vasculogenic mimicry (VM), EZH2 expression, and serous ovarian tumor grade, a total of 80 paraffin-embedded serous ovarian tumor samples including 21 cases of primary carcinoma and their metastatic tumors, 26 cases of primary carcinoma without metastasis, and 12 cases of serous borderline cystadenoma were analyzed. PGCCs and VM were detected in human serous ovarian tumor. The metastatic foci of ovarian carcinoma had the highest number of PGCCs and VM. The number of PGCCs and VM increased with the grade of ovarian carcinomas. PGCCs generated erythrocytes via budding and together they formed VM. Tumor cells and cancer-associated fibroblasts were positive for EZH2 immunohistochemical staining. The tumor cells and cancer associated fibroblasts in the metastatic foci had the highest staining index of EZH2 staining. Both tumor cells and cancer associated fibroblasts express EZH2 which then contributes to the malignant grade of serous ovarian tumor. PMID- 25025075 TI - Pediatric Index of Mortality and PIM2 scores have good calibration in a large cohort of children from a developing country. AB - OBJECTIVE: Our objective was to validate the Pediatric Index of Mortality (PIM) and PIM2 scores in a large cohort of children from a developing country. DESIGN: Prospective observational study. SETTING: Pediatric intensive care unit of a tertiary care teaching hospital. PATIENTS: All children aged <18 years admitted between June 2011 and July 2013. MEASUREMENTS AND MAIN RESULTS: We evaluated the discriminative ability and calibration as measured by the area under the receiver operating characteristic (ROC) curves, the Hosmer-Lemeshow goodness-of-fit (GOF), and standardized mortality ratio (SMR), respectively. Of the 819 children enrolled, 232 (28%) died. The median (IQR) age of the study subjects was 4 years (0.8, 10). The major reasons for ICU admission as well as mortality were sepsis/severe sepsis. The area under ROC curves for PIM and PIM2 was 0.72 (95% CI: 0.67-0.75) and 0.74 (95% CI: 0.70-0.78), respectively. The goodness-of-fit test showed a good calibration across deciles of risk for the two scores with P values being >0.05. The SMR (95% CI) was 0.99 (0.85-1.15) and 1 (0.85-1.16) for PIM and PIM2, respectively. The calibration across different age and diagnostic subgroups was also good. CONCLUSION: PIM and PIM2 scores had good calibration in our setup. PMID- 25025076 TI - Biomedical properties of a natural dietary plant metabolite, zerumbone, in cancer therapy and chemoprevention trials. AB - Zerumbone (ZER) is a naturally occurring dietary compound, present in many natural foods consumed today. The compound derived from several plant species of the Zingiberaceae family that has been found to possess multiple biomedical properties, such as antiproliferative, antioxidant, anti-inflammatory, and anticancer activities. However, evidence of efficacy is sparse, pointing to the need for a more systematic review for assessing scientific evidence to support therapeutic claims made for ZER and to identify future research needs. This review provides an updated overview of in vitro and in vivo investigations of ZER, its cancer chemopreventive properties, and mechanisms of action. Therapeutic effects of ZER were found to be scientifically plausible and could be explained partially by in vivo and in vitro pharmacological activities. Much of the research outlined in this paper will serve as a foundation to explain ZER anticancer bioactivity, which will open the door for the development of strategies in the treatment of malignancies using ZER. PMID- 25025078 TI - Integrative genomics and computational systems medicine. PMID- 25025077 TI - The role of genetic factors and kidney and liver function in glycemic control in type 2 diabetes patients on long-term metformin and sulphonylurea cotreatment. AB - This study investigated the influence of genetic polymorphisms of metformin transporters on long-term glycemic control and lipid status in type 2 diabetes patients in the everyday clinical setting. In total 135 patients treated with combination of metformin and sulphonylurea for at least 6 months were genotyped for SLC22A1 rs628031 and SLC47A1 rs2289669 polymorphisms. Relatively good blood glucose control with median HbA1c 6.9 (6.4-7.6) % was achieved on prescribed metformin dosage of 2550 (2000-2550) mg per day. Only 28 (20.7%) patients experienced mild hypoglycemia events, while no severe hypoglycemia events were observed. Most patients had normal or mildly impaired renal function. Parameters indicating renal function were not correlated with fasting glucose, HbA1c, or lipid parameters. Rs628031 and rs2289669 had minor allele frequencies of 0.385 and 0.355, respectively, and were not associated with HbA1c levels. Rs628031 was marginally associated with risk for hypoglycemia events (P = 0.046; OR = 0.51; 95% CI 0.26-0.99), while significant correlation was observed between rs2289669 and total cholesterol levels (P = 0.018). In conclusion, in patients on long-term metformin and sulphonylurea combination treatment, metformin transporters polymorphisms do not play a major role in glycemic control; however, they may influence lipid status. PMID- 25025079 TI - JNK3 is required for the cytoprotective effect of exendin 4. AB - Preservation of beta cell against apoptosis is one of the therapeutic benefits of the glucagon-like peptide-1 (GLP1) antidiabetic mimetics for preserving the functional beta cell mass exposed to diabetogenic condition including proinflammatory cytokines. The mitogen activated protein kinase 10 also called c jun amino-terminal kinase 3 (JNK3) plays a protective role in insulin-secreting cells against death caused by cytokines. In this study, we investigated whether the JNK3 expression is associated with the protective effect elicited by the GLP1 mimetic exendin 4. We found an increase in the abundance of JNK3 in isolated human islets and INS-1E cells cultured with exendin 4. Induction of JNK3 by exendin 4 was associated with an increased survival of INS-1E cells. Silencing of JNK3 prevented the cytoprotective effect of exendin 4 against apoptosis elicited by culture condition and cytokines. These results emphasize the requirement of JNK3 in the antiapoptotic effects of exendin 4. PMID- 25025080 TI - Markers of biological stress and mucosal immunity during a week leading to competition in adolescent swimmers. AB - In this study we examined changes in the salivary concentrations of immunoglobulin A (sIgA), cortisol (sC), testosterone (sT), and testosterone-to cortisol ratio (T/C) in 21 competitive swimmers, 11-15 years old, during a week leading to competition as compared to a control (noncompetition) week. No day-to day changes or significant differences between weeks were observed for sIgA (47.9 +/- 4.4 versus 54.9 +/- 5.2 MUg/mL for control versus competition week, resp.), sC (2.7 +/- 0.2 versus 2.5 +/- 0.2 ng/mL for control versus competition week, resp.), and T/C ratio (83.4 +/- 7.0 versus 77.9 +/- 7.7 for control versus competition week, resp.). In contrast, sT was significantly lower during the week of competition (154.5 +/- 11.3 pg/mL) as compared to the control week (181.3 +/- 11.5 pg/mL) suggesting that the swimmers were in a catabolic state, although this did not have a negative effect on their performance. In conclusion, salivary cortisol did not change between the two weeks, and thus competition stress was relatively low, and mucosal immunity was unaffected in these young athletes prior to competition. PMID- 25025082 TI - Evaluation of compressive strength and stiffness of grouted soils by using elastic waves. AB - Cement grouted soils, which consist of particulate soil media and cementation agents, have been widely used for the improvement of the strength and stiffness of weak ground and for the prevention of the leakage of ground water. The strength, elastic modulus, and Poisson's ratio of grouted soils have been determined by classical destructive methods. However, the performance of grouted soils depends on several parameters such as the distribution of particle size of the particulate soil media, grouting pressure, curing time, curing method, and ground water flow. In this study, elastic wave velocities are used to estimate the strength and elastic modulus, which are generally obtained by classical strength tests. Nondestructive tests by using elastic waves at small strain are conducted before and during classical strength tests at large strain. The test results are compared to identify correlations between the elastic wave velocity measured at small strain and strength and stiffness measured at large strain. The test results show that the strength and stiffness have exponential relationship with elastic wave velocities. This study demonstrates that nondestructive methods by using elastic waves may significantly improve the strength and stiffness evaluation processes of grouted soils. PMID- 25025083 TI - On the security of a novel probabilistic signature based on bilinear square Diffie-Hellman problem and its extension. AB - Probabilistic signature scheme has been widely used in modern electronic commerce since it could provide integrity, authenticity, and nonrepudiation. Recently, Wu and Lin proposed a novel probabilistic signature (PS) scheme using the bilinear square Diffie-Hellman (BSDH) problem. They also extended it to a universal designated verifier signature (UDVS) scheme. In this paper, we analyze the security of Wu et al.'s PS scheme and UDVS scheme. Through concrete attacks, we demonstrate both of their schemes are not unforgeable. The security analysis shows that their schemes are not suitable for practical applications. PMID- 25025081 TI - Monocytes as regulators of inflammation and HIV-related comorbidities during cART. AB - Combined antiretroviral therapy (cART) extends the lifespan and the quality of life for HIV-infected persons but does not completely eliminate chronic immune activation and inflammation. The low level of chronic immune activation persisting during cART-treated HIV infection is associated with the development of diseases which usually occur in the elderly. Although T-cell activation has been extensively examined in the context of cART-treated HIV infection, monocyte activation is only beginning to be recognized as an important source of inflammation in this context. Here we examine markers and sources of monocyte activation during cART-treated HIV infection and discuss the role of monocytes during cardiovascular disease, HIV-associated neurocognitive disorder, and innate immune aging. PMID- 25025084 TI - Bioinspired computation and its applications in operation management. PMID- 25025085 TI - On generalized difference Hahn sequence spaces. AB - We construct some generalized difference Hahn sequence spaces by mean of sequence of modulus functions. The topological properties and some inclusion relations of spaces h p ((F, u, Delta(r)) are investigated. Also we compute the dual of these spaces, and some matrix transformations are characterized. PMID- 25025087 TI - m-Polar fuzzy sets: an extension of bipolar fuzzy sets. AB - Recently, bipolar fuzzy sets have been studied and applied a bit enthusiastically and a bit increasingly. In this paper we prove that bipolar fuzzy sets and [0,1](2)-sets (which have been deeply studied) are actually cryptomorphic mathematical notions. Since researches or modelings on real world problems often involve multi-agent, multi-attribute, multi-object, multi-index, multi-polar information, uncertainty, or/and limit process, we put forward (or highlight) the notion of m-polar fuzzy set (actually, [0,1] (m)-set which can be seen as a generalization of bipolar fuzzy set, where m is an arbitrary ordinal number) and illustrate how many concepts have been defined based on bipolar fuzzy sets and many results which are related to these concepts can be generalized to the case of m-polar fuzzy sets. We also give examples to show how to apply m-polar fuzzy sets in real world problems. PMID- 25025088 TI - Reduction of free edge peeling stress of laminated composites using active piezoelectric layers. AB - An analytical approach is proposed in the reduction of free edge peeling stresses of laminated composites using active piezoelectric layers. The approach is the extended Kantorovich method which is an iterative method. Multiterms of trial function are employed and governing equations are derived by taking the principle of complementary virtual work. The solutions are obtained by solving a generalized eigenvalue problem. By this approach, the stresses automatically satisfy not only the traction-free boundary conditions, but also the free edge boundary conditions. Through the iteration processes, the free edge stresses converge very quickly. It is found that the peeling stresses generated by mechanical loadings are significantly reduced by applying a proper electric field to the piezoelectric actuators. PMID- 25025086 TI - The interaction of bacteria with engineered nanostructured polymeric materials: a review. AB - Bacterial infections are a leading cause of morbidity and mortality worldwide. In spite of great advances in biomaterials research and development, a significant proportion of medical devices undergo bacterial colonization and become the target of an implant-related infection. We present a review of the two major classes of antibacterial nanostructured materials: polymeric nanocomposites and surface-engineered materials. The paper describes antibacterial effects due to the induced material properties, along with the principles of bacterial adhesion and the biofilm formation process. Methods for antimicrobial modifications of polymers using a nanocomposite approach as well as surface modification procedures are surveyed and discussed, followed by a concise examination of techniques used in estimating bacteria/material interactions. Finally, we present an outline of future sceneries and perspectives on antibacterial applications of nanostructured materials to resist or counteract implant infections. PMID- 25025089 TI - Ant colony optimization analysis on overall stability of high arch dam basis of field monitoring. AB - A dam ant colony optimization (D-ACO) analysis of the overall stability of high arch dams on complicated foundations is presented in this paper. A modified ant colony optimization (ACO) model is proposed for obtaining dam concrete and rock mechanical parameters. A typical dam parameter feedback problem is proposed for nonlinear back-analysis numerical model based on field monitoring deformation and ACO. The basic principle of the proposed model is the establishment of the objective function of optimizing real concrete and rock mechanical parameter. The feedback analysis is then implemented with a modified ant colony algorithm. The algorithm performance is satisfactory, and the accuracy is verified. The m groups of feedback parameters, used to run a nonlinear FEM code, and the displacement and stress distribution are discussed. A feedback analysis of the deformation of the Lijiaxia arch dam and based on the modified ant colony optimization method is also conducted. By considering various material parameters obtained using different analysis methods, comparative analyses were conducted on dam displacements, stress distribution characteristics, and overall dam stability. The comparison results show that the proposal model can effectively solve for feedback multiple parameters of dam concrete and rock material and basically satisfy assessment requirements for geotechnical structural engineering discipline. PMID- 25025090 TI - One new royleanumoate from Teucrium royleanum Wall. ex Benth. AB - One new royleanumoate, a benzene ester (1), has been isolated from T. royleanum Wall. ex Benth along with two known compounds, namely, 3,4-dihydroxymethyl benzoate (2) and oleanolic acid (3). The structure elucidation of the isolated compounds was established on two-dimensional (2D) NMR techniques including heteronuclear multiple bond correlation (HMBC), heteronuclear multiple quantum Coherence (HMQC), and correlation spectroscopy (COSY) experiment. PMID- 25025091 TI - Stability of ceftiofur sodium and cefquinome sulphate in intravenous solutions. AB - Stability of ceftiofur sodium and cefquinome sulphate in intravenous solutions was studied. Chromatographic separation and quantitative determination were performed by using a high-performance liquid chromatography with UV-DAD detection. During the stability study, poly(vinylchloride) minibags were filled with a solution containing 5 mg of ceftiofur sodium or cefquinome sulphate and diluted to 0.2 mg/mL with suitable intravenous solution depending on the test conditions. The solutions for the study were protected from light and stored at room temperature (22 degrees C), refrigerated (6 degrees C), frozen (-20 degrees C) for 30 days, and then thawed at room temperature. A comparison of results obtained at 22 degrees C and 6 degrees C for the same intravenous solutions showed that temperature as well as components of solutions and their concentration had an influence on the stability of ceftiofur sodium and cefquinome sulphate. It was found that ceftiofur sodium and cefquinome sulphate dissolved in intravenous solutions used in this study may be stored at room temperature and at 6 degrees C for up to 48 h. PMID- 25025092 TI - Beneficial mycorrhizal symbionts affecting the production of health-promoting phytochemicals. AB - Fresh fruits and vegetables are largely investigated for their content in vitamins, mineral nutrients, dietary fibers, and plant secondary metabolites, collectively called phytochemicals, which play a beneficial role in human health. Quantity and quality of phytochemicals may be detected by using different analytical techniques, providing accurate quantification and identification of single molecules, along with their molecular structures, and allowing metabolome analyses of plant-based foods. Phytochemicals concentration and profiles are affected by biotic and abiotic factors linked to plant genotype, crop management, harvest season, soil quality, available nutrients, light, and water. Soil health and biological fertility play a key role in the production of safe plant foods, as a result of the action of beneficial soil microorganisms, in particular of the root symbionts arbuscular mycorrhizal fungi. They improve plant nutrition and health and induce changes in secondary metabolism leading to enhanced biosynthesis of health-promoting phytochemicals, such as polyphenols, carotenoids, flavonoids, phytoestrogens, and to a higher activity of antioxidant enzymes. In this review we discuss reports on health-promoting phytochemicals and analytical methods used for their identification and quantification in plants, and on arbuscular mycorrhizal fungi impact on fruits and vegetables nutritional and nutraceutical value. PMID- 25025093 TI - Peptidomic study of Spanish blue cheese (Valdeon) and changes after simulated gastrointestinal digestion. AB - It is increasingly evident that digestion can affect the biological activity of cheese by the release of new active peptides from their precursors or, on the contrary, giving rise to fragments without activity. The characterization of the peptidome of a Spanish blue cheese, Valdeon, has been conducted before and after gastrointestinal digestion, and the digests have been compared to those obtained from pasteurized skimmed milk powder (SMP) using a bioinformatics platform. Peptidomic profiling of digests revealed several regions that are especially resistant to digestion (among them beta-casein 60-93, 128-140, and 193-209). Some of them correspond to well-conserved regions between species (human, cow, sheep, and goat) and include peptide sequences with reported bioactivity. The great peptide homology found between both digests, cheese and SMP, suggests that the gastrointestinal digestion could bring closer the profile of products with different proteolytic state. Although most of the biologically active peptides found in cheese after digestion were also present in SMP digest, there were some exceptions that can be attributed to the absence of the relevant precursor peptide before digestion. PMID- 25025094 TI - Evaluation of mesoporous silicas functionalized with C18 groups as stationary phases for the solid-phase extraction of steroid hormones in milk. AB - In this work, two mesoporous silicas functionalized with C18 groups (SM-C18 and SBA-15-C18) have been synthesized for their evaluation as stationary phases in SPE for the extraction and preconcentration of seven steroid hormones (estrone, estradiol, estriol, ethinyl estradiol, diethylstilbestrol, testosterone, and progesterone ) from milk. The characterization of both materials by diverse techniques such as transmission electron microscopy, SEM, thermogravimetric analysis, X-ray diffraction, and adsorption-desorption isotherms showed that the mesoporous silicas had a high surface area, high pore volume, and a homogeneous distribution of the pores and that both silicas presented a similar degree of functionalization. An analytical methodology for the simultaneous separation of the seven selected steroids by HPLC-DAD was developed. Both silicas were evaluated as stationary phases in SPE for the extraction of the steroid hormones from milk. This HPLC-DAD method was applied to the analysis of all extracts obtained in the SPE experiments, showing that from the two synthesized mesoporus silicas, SBA-15-C18 silica enabled the extraction of the seven compounds with recoveries between 88 and 108% for all except for estriol, for which a recovery of 62% was obtained. The analytical characteristics of this methodology were evaluated, showing good precision and linearity (R2 > 0.994) for all analytes. The comparison of the results obtained with this silica and those obtained with commercial C18 particles and with some other commercial cartridges usually employed in the extraction of steroids showed that SBA-15-C18 silica was able to extract the seven steroids with higher recovery values. PMID- 25025095 TI - Assessment of adulteration of soybean proteins in dairy products by 2D microchip CE device. AB - To determine the adulteration of soybean proteins in dairy product, a microchip CE device was developed to isolate selected fraction of soybean and milk proteins in pI range from 5.5 ~ 7.0 by 1D IEF, followed by ITP/CZE in the embedded capillary for preconcentration, separation and UV detection at 280 nm. Compared to IEF-CZE without ITP preconcentration, the enhancement factor (EF) in detection of soybean proteins was 20 times. Adulteration of 0.1% soybean protein in total dairy proteins can be detected in less than 10 min. PMID- 25025096 TI - Chip electrophoresis as a novel approach to measure the polyphenols reactivity toward human saliva. AB - Saliva is a biological fluid with a multifunctional role that makes it interesting in terms of research and diagnostic possibilities. In food research, human saliva represented a useful tool by which we measure the tactile sensation elicited by polyphenol-rich beverages called astringency. A method based on SDS PAGE analysis of saliva before and after the binding reaction with wine polyphenols has been successfully used in previous studies for measuring wine astringency by means of the saliva precipitation index. In this work, chip electrophoresis was used alternatively to SDS-PAGE and results were compared. Chip electrophoresis provides a very good reproducibility for wine and grape astringency. Moreover, this approach is much faster than the conventional SDS PAGE method requiring several hours for an analysis. Another advantage over traditional gel is lower sample and reagent volume requirements, as well as the lower and less toxic wastes, contributing benefits to health and environment. The application of this novel method allowed, using the principal component analysis, to distinguish grapes and wines according to the saliva precipitation index and structural characteristics determined by the phoroglucinolysis analysis. PMID- 25025097 TI - Quantitative and functional dynamics of Dehalococcoides spp. and its tceA and vcrA genes under TCE exposure. AB - This study aimed at monitoring the dynamics of phylogenetic and catabolic genes of a dechlorinating enrichment culture before, during, and after complete dechlorination of chlorinated compounds. More specifically, the effect of 40 MUM trichloroethene (TCE) and 5.6 mM lactate on the gene abundance and activity of an enrichment culture was investigated for 40 days. Although tceA and vcrA gene copy numbers were relatively stable in DNA extracts over time, tceA and vcrA mRNA abundances were upregulated from undetectable levels to 2.96 * and 6.33 * 104 transcripts/mL, respectively, only after exposure to TCE and lactate. While tceA gene transcripts decreased over time with TCE dechlorination, the vcrA gene was expressed steadily even when the concentration of vinyl chloride was at undetectable levels. In addition, ratios between catabolic and phylogenetic genes indicated that tceA and vcrA gene carrying organisms dechlorinated TCE and its produced daughter products, while vcrA gene was mainly responsible for the dechlorination of the lower VC concentrations in a later stage of degradation. PMID- 25025098 TI - Mitochondrial deoxyribonucleic acid may play a role in a subset of sudden infant death syndrome cases. AB - AIM: It has been suggested that progressive adenosine triphosphate (ATP) depletion could play a key role in sudden infant death syndrome (SIDS). Because mitochondrial deoxyribonucleic acid (mtDNA) codes for a subset of essential genes for oxidative phosphorylation, we investigated 22 mtDNA polymorphisms in a large sample of Caucasian SIDS cases. METHODS: A total of 774 samples were analysed, 365 from infant SIDS cases (mean age 131 days) and 409 from controls. These were investigated for the presence of 22 haplogroup-specific single nucleotide polymorphisms (SNPs), using a SNaPshot assay, a mini-sequencing assay that combines polymerase chain reaction (PCR) and sequencing. RESULTS: No significant differences in assigned haplogroups could be detected between the groups. With regard to gender and age, we found significant correlations for SNP positions 3010, 8251, 13 708, 14 470, 15 904 and 16 519. The most prominent result was the A allele in SNP 14 470 in male SIDS cases (p = 0.01). CONCLUSION: This is the largest study on mtDNA polymorphisms in SIDS to date, and our results indicate that mtDNA may play a role in a subset of SIDS cases. In order to complement these significant results, it is important to consider nuclear gene coding for mitochondrial proteins in future studies. PMID- 25025099 TI - Ebola emergency meeting establishes new control centre. PMID- 25025100 TI - Iraq's growing health crisis. PMID- 25025101 TI - Profile: NIH's Fogarty International Center. PMID- 25025102 TI - Preface. Animal influenza virus. PMID- 25025103 TI - The burden of the mystery: the education of a physician. PMID- 25025104 TI - Arnold "Bud" Relman. PMID- 25025105 TI - miR-252 of the Asian tiger mosquito Aedes albopictus regulates dengue virus replication by suppressing the expression of the dengue virus envelope protein. AB - The Asian tiger mosquito, Aedes albopictus isa major vector of dengue in mainland China. Dengue epidemics have spread from the southern coastal regions to the relatively northern and western regions since 1990s. Dengue has become an emerging public health problem in the southern coastal regions. microRNAs(miRNAs) are short non-coding RNAs that regulate gene expression at the post transcription allevel. A highly abundant miRNA, miR-252, was induced more than threefold after dengue virus serotype 2 (DENV-2) infection in the Ae. albopictus C6/36 cellline. Transfection with miR-252 inhibitor resulted in the increase of DENV-2 RNA copies and the up-regulation of DENV-2 envelop protein(E protein) expression, whereas over expression of miR-252 with its mimic decreased DENV RNA copies and the down regulation of E protein expression. MiR-252 mimic reduced luciferase activity of a luciferase reporter that contained the predicted miR-252 target on the DENV-2 envelope gene sequence. The present results indicated that the miR-252 of Ae. albopictus could regulate the gene expression of DENV-2 E protein and may act asa cellular antiviral regulator in Ae. albopictus. PMID- 25025106 TI - Reply: To PMID 24329961. PMID- 25025107 TI - Reply: To PMID 24433563. PMID- 25025111 TI - Retraction notice to: The hepcidin-binding site on ferroportin is evolutionarily conserved. PMID- 25025112 TI - J. P. Morgan 32nd Annual Healthcare Conference. PMID- 25025115 TI - Minimum pricing on hold in New Zealand. PMID- 25025116 TI - Call for nominations for the 2014 Isaje Griffith Edwards Prize. PMID- 25025117 TI - New global drug survey results. PMID- 25025118 TI - E-cigarettes banned in Western Australia. PMID- 25025120 TI - Help for drug using refugees in Iran. PMID- 25025119 TI - Opium cultivation rising in Golden Triangle. PMID- 25025122 TI - The plant cell cycle in context. PMID- 25025123 TI - Member of ANUBiH Dusan Kecmanovic. PMID- 25025124 TI - Chromatin: domestication of the monsters. PMID- 25025126 TI - Infection prevention and control guideline for cystic fibrosis: 2013 update. PMID- 25025127 TI - Environmental implications of United States coal exports: a comparative life cycle assessment of future power system scenarios. AB - Stricter emissions requirements on coal-fired power plants together with low natural gas prices have contributed to a recent decline in the use of coal for electricity generation in the United States. Faced with a shrinking domestic market, many coal companies are taking advantage of a growing coal export market. As a result, U.S. coal exports hit an all-time high in 2012, fueled largely by demand in Asia. This paper presents a comparative life cycle assessment of two scenarios: a baseline scenario in which coal continues to be burned domestically for power generation, and an export scenario in which coal is exported to Asia. For the coal export scenario we focus on the Morrow Pacific export project being planned in Oregon by Ambre Energy that would ship 8.8 million tons of Powder River Basin (PRB) coal annually to Asian markets via rail, river barge, and ocean vessel. Air emissions (SOx, NOx, PM10 and CO2e) results assuming that the exported coal is burned for electricity generation in South Korea are compared to those of a business as usual case in which Oregon and Washington's coal plants, Boardman and Centralia, are retrofitted to comply with EPA emissions standards and continue their coal consumption. Findings show that although the environmental impacts of shipping PRB coal to Asia are significant, the combination of superior energy efficiency among newer South Korean coal-fired power plants and lower emissions from U.S. replacement of coal with natural gas could lead to a greenhouse gas reduction of 21% in the case that imported PRB coal replaces other coal sources in this Asian country. If instead PRB coal were to replace natural gas or nuclear generation in South Korea, greenhouse gas emissions per unit of electricity generated would increase. Results are similar for other air emissions such as SOx, NOx and PM. This study provides a framework for comparing energy export scenarios and highlights the importance of complete life cycle assessment in determining net emissions effects resulting from energy export projects and related policy decisions. PMID- 25025128 TI - A novel moisture adjusted vegetation index (MAVI) to reduce background reflectance and topographical effects on LAI retrieval. AB - A new moisture adjusted vegetation index (MAVI) is proposed using the red, near infrared, and shortwave infrared (SWIR) reflectance in band-ratio form in this paper. The effectiveness of MAVI in retrieving leaf area index (LAI) is investigated using Landsat-5 data and field LAI measurements in two forest and two grassland areas. The ability of MAVI to retrieve forest LAI under different background conditions is further evaluated using canopy reflectance of Jack Pine and Black Spruce forests simulated by the 4-Scale model. Compared with several commonly used two-band vegetation index, such as normalized difference vegetation index, soil adjusted vegetation index, modified soil adjusted vegetation index, optimized soil adjusted vegetation index, MAVI is a better predictor of LAI, on average, which can explain 70% of variations of LAI in the four study areas. Similar to other SWIR-related three-band vegetation index, such as modified normalized difference vegetation index (MNDVI) and reduced simple ratio (RSR), MAVI is able to reduce the background reflectance effects on forest canopy LAI retrieval. MAVI is more suitable for retrieving LAI than RSR and MNDVI, because it avoids the difficulty in properly determining the maximum and minimum SWIR values required in RSR and MNDVI, which improves the robustness of MAVI in retrieving LAI of different land cover types. Moreover, MAVI is expressed as ratios between different spectral bands, greatly reducing the noise caused by topographical variations, which makes it more suitable for applications in mountainous area. PMID- 25025129 TI - Whole-body water flow stimulation to the lower limbs modulates excitability of primary motor cortical regions innervating the hands: a transcranial magnetic stimulation study. AB - Whole-body water immersion (WI) has been reported to change sensorimotor integration. However, primary motor cortical excitability is not affected by low intensity afferent input. Here we explored the effects of whole-body WI and water flow stimulation (WF) on corticospinal excitability and intracortical circuits. Eight healthy subjects participated in this study. We measured the amplitude of motor-evoked potentials (MEPs) produced by single transcranial magnetic stimulation (TMS) pulses and examined conditioned MEP amplitudes by paired-pulse TMS. We evaluated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) using the paired-TMS technique before and after 15-min intervention periods. Two interventions used were whole-body WI with water flow to the lower limbs (whole-body WF) and whole-body WI without water flow to the lower limbs (whole-body WI). The experimental sequence included a baseline TMS assessment (T0), intervention for 15 min, a second TMS assessment immediately after intervention (T1), a 10 min resting period, a third TMS assessment (T2), a 10 min resting period, a fourth TMS assessment (T3), a 10 min resting period, and the final TMS assessment (T4). SICI and ICF were evaluated using a conditioning stimulus of 90% active motor threshold and a test stimulus adjusted to produce MEPs of approximately 1-1.2 mV, and were tested at intrastimulus intervals of 3 and 10 ms, respectively. Whole-body WF significantly increased MEP amplitude by single-pulse TMS and led to a decrease in SICI in the contralateral motor cortex at T1, T2 and T3. Whole-body WF also induced increased corticospinal excitability and decreased SICI. In contrast, whole-body WI did not change corticospinal excitability or intracortical circuits. PMID- 25025130 TI - OMIT: dynamic, semi-automated ontology development for the microRNA domain. AB - As a special class of short non-coding RNAs, microRNAs (a.k.a. miRNAs or miRs) have been reported to perform important roles in various biological processes by regulating respective target genes. However, significant barriers exist during biologists' conventional miR knowledge discovery. Emerging semantic technologies, which are based upon domain ontologies, can render critical assistance to this problem. Our previous research has investigated the construction of a miR ontology, named Ontology for MIcroRNA Target Prediction (OMIT), the very first of its kind that formally encodes miR domain knowledge. Although it is unavoidable to have a manual component contributed by domain experts when building ontologies, many challenges have been identified for a completely manual development process. The most significant issue is that a manual development process is very labor-intensive and thus extremely expensive. Therefore, we propose in this paper an innovative ontology development methodology. Our contributions can be summarized as: (i) We have continued the development and critical improvement of OMIT, solidly based on our previous research outcomes. (ii) We have explored effective and efficient algorithms with which the ontology development can be seamlessly combined with machine intelligence and be accomplished in a semi-automated manner, thus significantly reducing large amounts of human efforts. A set of experiments have been conducted to thoroughly evaluate our proposed methodology. PMID- 25025132 TI - Reducing the complexity of an agent-based local heroin market model. AB - This project explores techniques for reducing the complexity of an agent-based model (ABM). The analysis involved a model developed from the ethnographic research of Dr. Lee Hoffer in the Larimer area heroin market, which involved drug users, drug sellers, homeless individuals and police. The authors used statistical techniques to create a reduced version of the original model which maintained simulation fidelity while reducing computational complexity. This involved identifying key summary quantities of individual customer behavior as well as overall market activity and replacing some agents with probability distributions and regressions. The model was then extended to allow external market interventions in the form of police busts. Extensions of this research perspective, as well as its strengths and limitations, are discussed. PMID- 25025131 TI - Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. AB - The Wilms' tumor transcription factor (WT1) was originally classified as a tumor suppressor, but it is now known to also be associated with cancer progression and poor prognosis in several malignancies. WT1 plays an essential role in orchestrating a developmental process known as mesenchymal-to-epithelial transition (MET) during kidney development, but also induces the reverse process, epithelial-to-mesenchymal transition (EMT) during heart development. WT1 is not expressed in the adult kidney, but shows elevated expression in clear cell renal cell carcinoma (ccRCC). However, the role of WT1 in this disease has not been characterized. In this study, we demonstrate that WT1 is upregulated in ccRCC cells that are deficient in the expression of the von Hippel-Lindau tumor suppressor protein (VHL). We found that WT1 transcriptionally activated Snail, a master transcriptional repressor that is known to induce EMT. Although Snail represses E-cadherin and induces mesenchymal characteristics, we found partial maintenance of E-cadherin and associated epithelial characteristics in kidney cells and ccRCC cells that express WT1, since WT1 upregulates E-cadherin expression and competes with Snail repression. These findings support a novel paradigm in which WT1 induces an epithelial-mesenchymal hybrid transition (EMHT), characterized by Snail up-regulation with E-cadherin maintenance, a tumor cell differentiation state in which cancer cells keep both EMT and MET characteristics which may promote tumor cell plasticity and tumor progression. PMID- 25025133 TI - Switch in the aggregation pathway of bovine serum albumin mediated by electrostatic interactions. AB - A strong denaturant, guanidinium hydrochloride (GdnHCl), is shown to delay and alter the inherent aggregation pathway of bovine serum albumin (BSA) from a downhill polymerization to a nucleated polymerization. We hypothesize that such an alteration is closely connected to the conformational population of the protein, and ion-binding to such an ensemble. Hindered molecular collisions due to electrostatic repulsions in an ion-bound denatured ensemble increase the activation barrier for aggregation to such an extent that the growth, which was spontaneous in the absence of any cosolute, goes through an unfavorable nucleation phase. Our study shows that the behavior in GdnHCl is not unique to it, but occurs in a certain class of cosolutes-those which are charged and bind to BSA. Variation in pH of the medium, which gives rise to extra charges on the protein backbone, also showed such repulsive effects, further confirming the involvement of electrostatic interactions. We have further shown that the coexistence of both an appropriate population and an appropriate cosolute is necessary. An absence of either of these prevents a switch in the pathway. PMID- 25025134 TI - Conservation strategies for orangutans: reintroduction versus habitat preservation and the benefits of sustainably logged forest. AB - The Sumatran orangutan is currently listed by the IUCN as critically endangered and the Bornean species as endangered. Unless effective conservation measures are enacted quickly, most orangutan populations without adequate protection face a dire future. Two main strategies are being pursued to conserve orangutans: (i) rehabilitation and reintroduction of ex-captive or displaced individuals; and (ii) protection of their forest habitat to abate threats like deforestation and hunting. These strategies are often mirrored in similar programs to save other valued and endangered mega-fauna. Through GIS analysis, collating data from across the literature, and combining this information within a modelling and decision analysis framework, we analysed which strategy or combination of strategies is the most cost-effective at maintaining wild orangutan populations, and under what conditions. We discovered that neither strategy was optimal under all circumstances but was dependent on the relative cost per orangutan, the timescale of management concern, and the rate of deforestation. Reintroduction, which costs twelve times as much per animal as compared to protection of forest, was only a cost-effective strategy at very short timescales. For time scales longer than 10-20 years, forest protection is the more cost-efficient strategy for maintaining wild orangutan populations. Our analyses showed that a third, rarely utilised strategy is intermediate: introducing sustainable logging practices and protection from hunting in timber production forest. Maximum long term cost-efficiency is achieved by working in conservation forest. However, habitat protection involves addressing complex conservation issues and conflicting needs at the landscape level. We find a potential resolution in that well-managed production forests could achieve intermediate conservation outcomes. This has broad implications for sustaining biodiversity more generally within an economically productive landscape. Insights from this analysis should provide a better framework to prioritize financial investments, and facilitate improved integration between the organizations that implement these strategies. PMID- 25025147 TI - Old tracer for a new purpose: potential role for 99mTc-2 Methoxyisobutylisonitrile (99mTc-MIBI) in renal transplant care. AB - AIM: Calcineurin inhibitors are substrates for P-glycoprotein (P-gp), the expression of which is associated with ABCB1 C3435T polymorphism. Individual P-gp response to calcineurin inhibitor may be linked to nephrotoxicity or rejection. Tc-2-Methoxyisobutylisonitrile (Tc-MIBI) is also a P-gp substrate. The aim of this study, therefore, was to determine Tc-MIBI organ kinetics and compare them with ABCB1 genotype with a view to replacing Tc-mercaptoacetyltriglycine (Tc MAG3) with Tc-MIBI in renal transplant care. METHODS: Thirty prospective donors (13 male) were imaged for 20 min after administration of Tc-MIBI (400 MBq) intravenously. Posterior images of the abdomen were acquired at 30 and 120 min. Organ 30 min/peak count rate ratios and exponential two-point (30-120 min) rate constants (k, min) were calculated. Nineteen donors were genotyped for C3435T (exon 26), G2677T (exon 21), C1236T (exon 12), and G1199A (exon 11) ABCB1 polymorphisms using a PCR-based technique. RESULTS: Tc-MIBI and Tc-MAG3 gave similar perfusion images. Although their patterns of renal elimination were different, differential renal function was not significantly different. There was a negative trend between the hepatic 30 min/peak ratio and C3435T genotype (CC: 0.8374 +/- 0.0502; TC: 0.6806 +/- 0.1300; TT: 0.6919 +/- 0.1506; P=0.083). Renal k showed a negative trend with C3435T (CC: 0.0021 +/- 0.0020; TC: 0.0037 +/- 0.0013; TT: 0.0040 +/- 0.0012 min; P=0.087) but with no other genotypes. There were no significant sex-related differences in Tc-MIBI kinetics. CONCLUSION: Tc MIBI can replace Tc-MAG3 for pretransplant workup. The ABCB1 C3435T polymorphism may influence Tc-MIBI kinetics and thus have a role in renal transplant care. Further prospective trials are required to establish the full potential of Tc MIBI in renal transplant management. PMID- 25025148 TI - Design, synthesis and biological evaluation of C6-modified celastrol derivatives as potential antitumor agents. AB - New six C6-celastrol derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activities against nine human cancer cell lines (BGC 823, H4, Bel7402, H522, Colo 205, HepG2 and MDA-MB-468). The results showed that most of the compounds displayed potent inhibition against BGC823, H4, and Bel7402, with IC50s of 1.84-0.39 MUM. The best compound NST001A was tested in an in vivo antitumor assay on nude mice bearing Colo 205 xenografts, and showed significant inhibition of tumor growth at low concentrations. Therefore, celastrol C-6 derivatives are potential drug candidates for treating cancer. PMID- 25025149 TI - Phenolic profiles and antioxidant properties of young wines made from Yan73 (Vitis vinifera L.) and Cabernet Sauvignon (Vitis vinifera L.) grapes treated by 24-epibrassinolide. AB - The grape berries of two varieties, Yan73 (Vitis vinifera L.) and Cabernet Sauvignon (CS) (Vitis vinifera L.) were treated with 0.40 mg/L 24-epibrassinolide (EBR), 1.00 mg/L brassinazole (Brz), and deionized water (control), at the veraison period. The EBR treatment significantly increased total phenolic content (TPC), total tannin content (TTC) and total anthocyanin content (TAC) of Yan73 and CS wines, whereas Brz treatment decreased TPC, total flavonoid content (TFC), TAC in the two wines. Moreover, the content of most of the phenolic compounds identified by HPLC-DAD/ESI-MS in EBR-treated wines was significantly higher than that in control. The antioxidant capacities, which determined using DPPH, ABTS and HRSA methods, of the wines were increased by EBR treatment as well. There was a good correlation between the antioxidant capacity and phenolic content. The results demonstrated that EBR could enhance the phenolic compounds and antioxidant capacity of Yan73 and CS wines, but the effects may vary by different cultivars. PMID- 25025150 TI - Identification of catechol as a new marker for detecting propolis adulteration. AB - Adulteration of propolis with poplar extract is a serious issue in the bee products market. The aim of this study was to identify marker compounds in adulterated propolis, and examine the transformation of chemical components from poplar buds to propolis. The chemical profiles of poplar extracts and propolis were compared, and a new marker compound, catechol, was isolated and identified from the extracts of poplar buds. The polyphenol oxidase, catechol oxidase, responsible for catalyzing oxidation of catechol was detected in poplar buds and propolis. The results indicate catechol can be used as a marker to detect propolis adulterated with poplar extract. PMID- 25025152 TI - The whiplash syndrome. AB - This review examines the biomechanics of flexion-extension injuries of the cervical spine and the resultant pathological and clinical features. In view of rational evidence concerning pathology and clinical features, a treatment regime is designed. PMID- 25025151 TI - Is DWI/ADC a useful tool in the characterization of focal hepatic lesions suspected of malignancy? AB - OBJECTIVE: Apparent diffusion coefficient (ADC) values calculated through magnetic resonance imaging have been proposed as a useful tool to distinguish benign from malignant liver lesions. Most studies however included simple cysts in their analysis. Liver cysts are easy to diagnose, have very high ADC values and their inclusion facilitates differentiation in the ADC values between benign and malignant liver lesions groups. We prospectively evaluated the ability of ADC values to differentiate metastatic liver lesions from all benign or only solid benign liver lesions. MATERIAL AND METHODS: Sixty-seven adult cancer patients with 188 liver lesions were evaluated. Lesions were categorized as metastatic or benign throughout imaging and clinical evaluation. One hundred and five (105) metastatic lesions and 83 benign lesions including hemangiomas (37), cysts (42), adenomas (2) and focal nodular hyperplasias (2) were evaluated. ADC values were calculated for each lesion utilizing two b values (0 and 600 sec/mm2). RESULTS: The average ADC value for cysts was 2.4*10(-3) mm2/sec (CI: 2.1-2.6), for solid benign lesions was 1.4*10(-3) mm2/sec (CI: 1.1-1.7) and for metastases was 1.0*10(-3) mm2/sec (CI: 0.8-1.3). There was a difference between the ADC values of metastases and benign solid lesions (p<0.0001). With the ADC value of 1.5*10( 3) mm2/sec as a cut off it is possible to distinguish metastatic from benign liver lesions, including cysts, with an accuracy of 78%. But to distinguish metastatic from benign solid liver lesions the best ADC cut off value was 1.2*10( 3) mm2/sec and the accuracy drops to 71%. CONCLUSIONS: ADC values proved to be helpful in the distinction between metastasis and benign solid hepatic lesions. But the exclusion of cysts in the analysis point out to a lower cut off value and lower accuracy than previously reported. PMID- 25025153 TI - Disturbances of muscle tone in the paralysed upper extremity following hemiplegia. AB - After a minimum period of eleven weeks post cerebrovascular accident and resulting hemiplegia, one hundred adult patients were assessed for sensory-motor deficits affecting the function of the paralysed upper extremity. This paper presents only the assessment of muscle tone, the disturbances of tone and its inter-relationship with other clinical manifestations. Kendall rank order correlations were computed for this purpose. A highly significant relationship (P < .001) was observed between selective spasticity of proximal joints and distal joints and between wrist and finger clonus with selective spasticity of wrist, finger and shoulder muscles. The spasticity in wrist flexors related highly with the inability to perform functional tasks. Inability to perform muscle function was also related to limitation of joint motion. PMID- 25025154 TI - Prevention and treatment of some obstetric and gynaecological conditions. AB - Some obstetric and gynaecological conditions are examined and measures suggested from preventive and therapeutic angles with a view to alerting specialists to a broad spectrum of patient management in this field. PMID- 25025155 TI - The effects of age on the ranges of motions of the lumbar region. AB - The ranges of all movements of the lumbar spine for both sexes and all ages are tabulated. The data was obtained by measurement of 200 fresh cadaver specimens within twenty-four hours of death. A decrease in the range of all movements with increasing age is apparent. PMID- 25025156 TI - SSU rDNA sequence diversity and seasonally differentiated distribution of nanoplanktonic ciliates in neritic Bohai and Yellow Seas as revealed by T-RFLP. AB - Nanociliates have been frequently found to be important players in the marine microbial loop, however, little is known about their diversity and distribution in coastal ecosystems. We investigated the molecular diversity and distribution patterns of nanoplanktonic oligotrich and choreotrich (OC) ciliates in surface water of three neritic basins of northern China, the South Yellow Sea (SYS), North Yellow Sea (NYS), and Bohai Sea (BS) in June and November 2011. SSU rRNA gene clone libraries generated from three summertime samples (sites B38, B4 and H8) were analyzed and revealed a large novel ribotype diversity, of which many were low-abundant phylotypes belonging to the subclass Oligotrichia, but divergent from described morphospecies. Based on the data of terminal-restriction fragment length polymorphism (T-RFLP) analysis of all 35 samples, we found that the T-RF richness was generally higher in the SYS than in the BS, and negatively correlated with the molar ratio of P to Si. Overall, multidimensional scaling and permutational multivariate analysis of variance of the community turnover demonstrated a distinct seasonal pattern but no basin-to-basin differentiation across all samples. Nevertheless, significant community differences among basins were recognized in the winter dataset. Mantel tests showed that the environmental factors, P:Si ratio, water temperature and concentration of dissolved oxygen (DO), determined the community across all samples. However, both biogeographic distance and environment shaped the community in winter, with DO being the most important physicochemical factor. Our results indicate that the stoichiometric ratio of P:Si is a key factor, through which the phytoplankton community may be shaped, resulting in a cascade effect on the diversity and community composition of OC nanociliates in the N-rich, Si-limited coastal surface waters, and that the Yellow Sea Warm Current drives the nanociliate community, and possibly the microbial food webs, in the coastal ecosystem in winter. PMID- 25025157 TI - Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses. AB - Postsynaptic scaffolding proteins regulate coordinated neurotransmission by anchoring and clustering receptors and adhesion molecules. Gephyrin is the major instructive molecule at inhibitory synapses, where it clusters glycine as well as major subsets of GABA type A receptors (GABAARs). Here, we identified palmitoylation of gephyrin as an important mechanism of strengthening GABAergic synaptic transmission, which is regulated by GABAAR activity. We mapped palmitoylation to Cys212 and Cys284, which are critical for both association of gephyrin with the postsynaptic membrane and gephyrin clustering. We identified DHHC-12 as the principal palmitoyl acyltransferase that palmitoylates gephyrin. Furthermore, gephyrin pamitoylation potentiated GABAergic synaptic transmission, as evidenced by an increased amplitude of miniature inhibitory postsynaptic currents. Consistently, inhibiting gephyrin palmitoylation either pharmacologically or by expression of palmitoylation-deficient gephyrin reduced the gephyrin cluster size. In aggregate, our study reveals that palmitoylation of gephyrin by DHHC-12 contributes to dynamic and functional modulation of GABAergic synapses. PMID- 25025158 TI - Impact of genotype imputation on the performance of GBLUP and Bayesian methods for genomic prediction. AB - The aim of this study was to evaluate the impact of genotype imputation on the performance of the GBLUP and Bayesian methods for genomic prediction. A total of 10,309 Holstein bulls were genotyped on the BovineSNP50 BeadChip (50 k). Five low density single nucleotide polymorphism (SNP) panels, containing 6,177, 2,480, 1,536, 768 and 384 SNPs, were simulated from the 50 k panel. A fraction of 0%, 33% and 66% of the animals were randomly selected from the training sets to have low density genotypes which were then imputed into 50 k genotypes. A GBLUP and a Bayesian method were used to predict direct genomic values (DGV) for validation animals using imputed or their actual 50 k genotypes. Traits studied included milk yield, fat percentage, protein percentage and somatic cell score (SCS). Results showed that performance of both GBLUP and Bayesian methods was influenced by imputation errors. For traits affected by a few large QTL, the Bayesian method resulted in greater reductions of accuracy due to imputation errors than GBLUP. Including SNPs with largest effects in the low density panel substantially improved the accuracy of genomic prediction for the Bayesian method. Including genotypes imputed from the 6 k panel achieved almost the same accuracy of genomic prediction as that of using the 50 k panel even when 66% of the training population was genotyped on the 6 k panel. These results justified the application of the 6 k panel for genomic prediction. Imputations from lower density panels were more prone to errors and resulted in lower accuracy of genomic prediction. But for animals that have close relationship to the reference set, genotype imputation may still achieve a relatively high accuracy. PMID- 25025159 TI - Low levels of blood lipids are associated with etiology and lethal outcome in acute liver failure. AB - BACKGROUND/AIMS: Emerging data links different aspects of lipid metabolism to liver regeneration. In patients with acute liver failure (ALF), low levels of lipids may correlate with disease severity. Thus, we determined whether there is an etiology-specific link between lipid levels in patients suffering from ALF and aimed to investigate an effect of lipid levels on the prognosis of ALF. METHODS: In this retrospective single center study, we reviewed 89 consecutive ALF patients, who met the criteria of the "Acute Liver Failure Study Group". Patient characteristics, clinical data and laboratory parameters were individually analyzed at admission and correlated with the patients' outcome after a four week follow up. Possible endpoints were either discharge, or death or liver transplantation. RESULTS: High-density lipoprotein (HDL), cholesterol and triglyceride levels were significantly lower in patients who died or required a liver transplant. HDL levels were significantly higher in patients with ALF caused by acetaminophen intoxication, compared to fulminant HBV infection or drug induced liver injury. HDL levels correlated with hepatic injury by ALT levels, and Albumin, and inversely correlated with the MELD score, INR, and bilirubin. CONCLUSION: In our cohort of patients with ALF, we could show that HDL and cholesterol are suppressed. In addition novel etiology specific patterns between acteminophen and non-acteminophen induced liver failure were detected for serum lipid components. Further studies are needed to address the role of cholesterol and lipid metabolism and the according pathways in different etiologies of ALF. PMID- 25025160 TI - Bioluminescence of beetle luciferases with 6'-amino-D-luciferin analogues reveals excited keto-oxyluciferin as the emitter and phenolate/luciferin binding site interactions modulate bioluminescence colors. AB - Beetle luciferases produce different bioluminescence colors from green to red using the same d-luciferin substrate. Despite many studies of the mechanisms and structural determinants of bioluminescence colors with firefly luciferases, the identity of the emitters and the specific active site interactions responsible for bioluminescence color modulation remain elusive. To address these questions, we analyzed the bioluminescence spectra with 6'-amino-D-luciferin (aminoluciferin) and its 5,5-dimethyl analogue using a set of recombinant beetle luciferases that naturally elicit different colors and different pH sensitivities (pH-sensitive, Amydetes vivianii lambdamax=538 nm, Macrolampis sp2 lambdamax=564 nm; pH-insensitive, Phrixotrix hirtus lambdamax=623 nm, Phrixotrix vivianii lambdamax=546 nm, and Pyrearinus termitilluminans lambdamax=534 nm), a luciferase like enzyme (Tenebrionidae, Zophobas morio lambdamax=613 nm), and mutants of C311 (S314). The green-yellow-emitting luciferases display red-shifted bioluminescence spectra with aminoluciferin in relation to those with D-luciferin, whereas the red-emitting luciferases displayed blue-shifted spectra. Bioluminescence spectra with 5,5-dimethylaminoluciferin, in which enolization is blocked, were almost identical to those of aminoluciferin. Fluorescence probing using 2-(4 toluidino)naphthalene-6-sulfonate and inference with aminoluciferin confirm that the luciferin binding site of the red-shifted luciferases is more polar than in the case of the green-yellow-emitting luciferases. Altogether, the results show that the keto form of excited oxyluciferin is the emitter in beetle bioluminescence and that bioluminescence colors are essentially modulated by interactions of the 6'-hydroxy group of oxyluciferin and basic moieties under the influence of the microenvironment polarity of the active site: a strong interaction between a base moiety and oxyluciferin phenol in a hydrophobic microenvironment promotes green-yellow emission, whereas a more polar environment weakens such interaction promoting red shifts. In pH-sensitive luciferases, a pH mediated switch from a closed hydrophobic conformation to a more open polar conformation promotes the typical red shift. PMID- 25025161 TI - Chariots of freedom: wheeled mobility at regency park centre for young disabled, South australia. AB - This paper concerns wheeled mobility aids, or 'Chariots of Freedom'. Wheelchairs are the most commonly used wheeled mobility aids. The rationale for mobility management at Regency Park Centre for Young Disabled is based on the research findings of others, research at the Centre into seating for children with cerebral palsy and children with Duchenne muscular dystrophy, and our development of a Skill Evaluator and Trainer, and a crashworthy restraint for wheelchair occupants in motor vehicles. In summary, wheeled mobility aids, and wheelchairs in particular, while entailing responsibilities, present a form of liberation from dependence for disabled children. PMID- 25025162 TI - Planning instruction in gerontology. AB - The gerontology course taught in the Physical and Occupational Therapy Programme, McGill University, was scrutinized using a) knowledge identified by researchers as necessary for professionals tending the aged and b) the results of a questionnaire administered to graduates working with the aged. Researchers revealed that professionals should be able to provide support for the aged and their families, frequently evaluate their problems, encourage their independence and avoid stereotyping them. Results of the questionnaire showed that graduates prioritized the amount of time they spent on various tasks in this order; listening, talking to clients, consulting with team members and lastly performing physiotherapeutic tasks. An approach to Multidisciplinary Services is described which would ensure quality care for the aged and enhance the accessibility of these services. PMID- 25025163 TI - The first five years of development of children born pre-term. AB - This study investigated the first five years of developmental progress of a group of pre-term infants. Of an initial group of 136 surviving infants born five or more weeks before term in Brisbane in 1975, more than 82% were assessed regularly through their pre-school years. Results indicated that a normal sequence of development was followed by the majority of the children. Although the incidence of cerebral palsy, speech difficulties and minor motor incoordination was higher than average, all but two children were ready to enter school with their peers. Except for a small group of neurologically related signs, factors predictive of development at five years generally differed with age. Regular comprehensive developmental assessment is recommended for identification of age related problems. PMID- 25025164 TI - Reducing dysfunctional beliefs about sleep does not significantly improve insomnia in cognitive behavioral therapy. AB - The present study examined to examine whether improvement of insomnia is mediated by a reduction in sleep-related dysfunctional beliefs through cognitive behavioral therapy for insomnia. In total, 64 patients with chronic insomnia received cognitive behavioral therapy for insomnia consisting of 6 biweekly individual treatment sessions of 50 minutes in length. Participants were asked to complete the Athens Insomnia Scale and the Dysfunctional Beliefs and Attitudes about Sleep scale both at the baseline and at the end of treatment. The results showed that although cognitive behavioral therapy for insomnia greatly reduced individuals' scores on both scales, the decrease in dysfunctional beliefs and attitudes about sleep with treatment did not seem to mediate improvement in insomnia. The findings suggest that sleep-related dysfunctional beliefs endorsed by patients with chronic insomnia may be attenuated by cognitive behavioral therapy for insomnia, but changes in such beliefs are not likely to play a crucial role in reducing the severity of insomnia. PMID- 25025165 TI - Clinical examination and the physiotherapist. AB - Physiotherapists have been criticized at times on the grounds that some of their treatments are unscientific, palliative in nature or of psychological benefit only. This criticism has stimulated many of us to improve methods of physical examination so that treatment can be accurately applied to the structure at fault. Detailed examination and the ability to interpret findings are also essential in the assessment of progress and the modifications of treatment that may be required. PMID- 25025166 TI - Looking at physiology in the treatment of asthma. AB - In this paper, I propose to consider some principles of Physiology in relation to our treatment of the asthmatic child or adult who has suffered the disease for a relatively short time, compared with the adult whose asthma is long standing and who has progressed to some degree of Obstructive Airways Disease. The first is a functional, reversible disease, characterised by episodes of wheeze of varying degree, and with periods of normalcy in between. The second is a structural disease characterised by impairment of activity at all times and the production of copious sputum. This is in itself an irreversible disease but may have an overlying reversible component of varying degree. My recent experience has come from the treatment of out-patients, so that I have not included here treatment for the disabled in-patient with obstructive airways disease, who requires more intensive care. PMID- 25025167 TI - Intellectual retardation. AB - The aim of this paper is to discuss some general aspects of intellectual retardation, the physiotherapist's role in the treatment of children suffering the effects of this handicap and to mention briefly some of the techniques and problems of physiotherapy for these children. PMID- 25025168 TI - Report on some hungarian rehabilitation units. AB - In Hungary, rehabilitation of the physically disabled is carried out in separate5 specialized units, e.g. neurology, rheumatology, traumatology, orthopaedics, etc. ..., each under a medical practitioner qualified in that particular section. Members of the staff engaged in these separate units meet in "The Hungarian Society for the Rehabilitation of the Disabled", which, in turn, has contact with the Minister for Health and the Trade Unions. This arrangement is important in determining the eventual placement of the rehabilitated. PMID- 25025169 TI - Lipopolysaccharide exposure during pregnancy leads to aortic dysfunction in offspring rats. AB - BACKGROUND: Prenatal exposure to Lipopolysaccharide (LPS) produces hypertension in adult offspring rats. The present study was to explore the effects of prenatal inflammation on morphological and functional changes in the aorta from offspring rats and to further assess its susceptibility to cardiovascular diseases. METHODS AND RESULTS: Pregnant rats were treated intraperitoneally on gestation Days 8, 10 and 12 with saline, LPS (0.79 mg/kg), or pyrrolidine dithiocarbamate (PDTC, 100 mg/kg)+LPS, respectively. Aortic ring reactivity and histopathological alteration were analyzed in offspring at the age of 12 weeks. The detections of connexin (Cx) 37, Cx40, Cx43, and Cx45, including immunofluorescent patterns, protein levels and mRNA expression in the aorta, were performed as well. Furthermore, the expressions of Nuclear factor (NF)-kappaB (p65), IkappaBalpha, phospho IkappaBalpha and IkappaBbeta were determined. The results showed that prenatal LPS exposure leads to morphological abnormalities and impaired aortic reactivity in offspring. Prenatal LPS exposure also decreased the protein and mRNA expression of Cx37 in the aorta from offspring rats. NF-kappaB and phospho IkappaBalpha levels were both increased, IkappaBalpha level, however, was decreased in the aorta of offspring from the maternal LPS exposure compared to the controls. Simultaneously, PDTC treatment markedly reversed the action of LPS. CONCLUSIONS: Decreased expression of Cx37 contributed to the aortic dysfunction of prenatal LPS exposure offspring, which should be associated with NF-kappaB activation. PMID- 25025172 TI - Wheelchair design for people with neuromuscular disability. AB - The observation that wheelchairs often failed to provide the mobility and support needed by patients with neuromuscular disability facilitated this study. Three groups of subjects with multiple sclerosis, spinal cord injury and muscular dystrophy were examined to determine their various disabilities and anthropometric measurement. These were then compared with wheelchair dimensions in an endeavour to determine whether the problem was wheelchair design or poor prescription. An evaluation of wheelchair use was also included. Results showed that several wheelchair dimensions including seat depth, arm rest height, backrest height and lack of contour support failed to match the sample population, indicating the need for greater care in selection of wheelchairs for patients with neuromuscular disabilities in addition to the need for design revision. PMID- 25025170 TI - Characteristics of spondylotic myelopathy on 3D driven-equilibrium fast spin echo and 2D fast spin echo magnetic resonance imaging: a retrospective cross-sectional study. AB - In patients with spinal stenosis, magnetic resonance imaging of the cervical spine can be improved by using 3D driven-equilibrium fast spin echo sequences to provide a high-resolution assessment of osseous and ligamentous structures. However, it is not yet clear whether 3D driven-equilibrium fast spin echo sequences adequately evaluate the spinal cord itself. As a result, they are generally supplemented by additional 2D fast spin echo sequences, adding time to the examination and potential discomfort to the patient. Here we investigate the hypothesis that in patients with spinal stenosis and spondylotic myelopathy, 3D driven-equilibrium fast spin echo sequences can characterize cord lesions equally well as 2D fast spin echo sequences. We performed a retrospective analysis of 30 adult patients with spondylotic myelopathy who had been examined with both 3D driven-equilibrium fast spin echo sequences and 2D fast spin echo sequences at the same scanning session. The two sequences were inspected separately for each patient, and visible cord lesions were manually traced. We found no significant differences between 3D driven-equilibrium fast spin echo and 2D fast spin echo sequences in the mean number, mean area, or mean transverse dimensions of spondylotic cord lesions. Nevertheless, the mean contrast-to-noise ratio of cord lesions was decreased on 3D driven-equilibrium fast spin echo sequences compared to 2D fast spin echo sequences. These findings suggest that 3D driven-equilibrium fast spin echo sequences do not need supplemental 2D fast spin echo sequences for the diagnosis of spondylotic myelopathy, but they may be less well suited for quantitative signal measurements in the spinal cord. PMID- 25025173 TI - Enhancing Physiotherapy Students' Attitudes toward Disabled People. AB - Negative or narrow attitudes toward the physically disabled can be detrimental to success in rehabilitation, yet programmes aimed at improving attitudes frequently fail. An 18 hour programme aimed at increasing first-year physiotherapy students' knowledge of the disabled and reasons for negative attitudes was evaluated. At course commencement when compared with an Australia-wide sample, students revealed more positive attitudes regarding the needs but not the characteristics of the disabled. At course completion students perceived the disabled as more similar to other people in their characteristics and needs. Students felt less ignorant about disability and exhibited more of a coping perspective: pitying and admiring the disabled less and fearing disability less. They still experienced guilt and discomfort regarding interaction. PMID- 25025174 TI - Developmental physiotherapy for children with both minimal cerebral dysfunction and learning difficulties. AB - Early research studies have suggested that learning gains accompany improvement in neurological factors after developmental physiotherapy treatment, and some physiotherapists consider that an adequate sensory motor system is of primary importance in the utilisation of full learning abilities. To determine the existence of any link between these two, a study was undertaken to evaluate educational progress of children with both MCD and learning difficulties: the experimental group received continuous physiotherapy management for six months and the control group received no physiotherapy, if possible, while all continued their remedial education programme. Analysis of school performance data revealed that the educational progress in most areas assessed by teachers was significantly greater for the children in the experimental group than for the control group. This paper describes the study and compares the scholastic achievement of children, with and without physiotherapy intervention. PMID- 25025175 TI - The three receptor tyrosine kinases c-KIT, VEGFR2 and PDGFRalpha, closely spaced at 4q12, show increased protein expression in triple-negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer with poor prognosis and no targeted therapy available. Receptor tyrosine kinases (RTKs) are emerging targets in anticancer therapy and many RTK inhibiting drugs are currently being developed. The aim of this study was to elucidate if there is a correlation between the protein expression of three RTKs c-KIT, VEGFR2 and PDGFRalpha, their gene copy number, and prognosis in TNBC compared to non-TNBC. METHODS: Tumor tissue samples from patients diagnosed with primary breast cancer were stained with immunohistochemistry (IHC) for protein assessment, and with fluorescence in situ hybridization (FISH) for gene copy number determination. Breast cancer mortality (BCM), measured from the date of surgery to death, was used as endpoint. RESULTS: The cohort included 464 patients, out of which 34 (7.3%) had a TNBC. High expression of the three RTKs was more common in TNBC compared to non-TNBC: c-KIT 49% vs. 10% (P<0.001), PDGFRalpha 32% vs. 19% (P = 0.07) and VEGFR2 32% vs. 6% (P<0.001). The odds ratio (OR) of c-KIT, VEGFR2 and PDGFRalpha positivity, adjusted for tumor characteristics, was 6.8, 3.6 and 1.3 times higher for TNBC than for non-TNBC. 73.5% of the TNBC had high expression of at least one of the three investigated receptors, compared to 30.0% of the non-TNBC (P<0.001). Survival analysis showed no significant difference in BCM for TNBC patients with high vs. low c-KIT, PDGFRalpha or VEGFR2 protein expression. 193 (42%) tumors were evaluated with FISH. No correlation was seen between increased gene copy number and TNBC, or between increased gene copy number and high protein expression of the RTK. CONCLUSION: c-KIT, VEGFR2 and PDGFRalpha show higher protein expression in TNBC compared to non-TNBC. Further investigation clarifying the importance of these RTKs in TNBC is encouraged, as they are possible targets for anticancer therapy. PMID- 25025176 TI - Fate and degradation kinetics of nonylphenol compounds in aerobic batch digesters. AB - Nonylphenol (NP) compounds are toxic and persistent chemicals that are not fully degraded either in natural or engineered systems. Current knowledge indicates that these compounds concentrate in sewage sludge. Therefore, investigating the degradation patterns and types of metabolites formed during sludge treatment are important for land application of sewage sludge. Unfortunately, the information on the fate of nonylphenol compounds in sludge treatment is very limited. This study aims to investigate the biodegradation patterns of nonylphenol diethoxylate (NP2EO) in aerobic batch digesters. For this purpose, two NP2EO spiked and two control laboratory aerobic batch digesters were operated. The spiked digester contained 3 mg/L NP2EO in the whole reactor content. The compounds of interest (parent compound and expected metabolites) were extracted with sonication and analyzed by gas chromatography-mass spectrometry (GC-MS) as a function of time. Results showed that, following the day of spike, NP2EO degraded rapidly. The metabolites observed were nonylphenol monoethoxylate (NP1EO), NP and dominantly, nonylphenoxy acetic acid (NP1EC). The mass balance over the reactors indicated that the total mass spiked was highly accounted for by the products analyzed. The time dependent analysis indicated that the parent compound degradation and daughter product formation followed first order kinetics. The digester performance parameters analyzed (VS and COD reduction) indicated that the spike of NP2EO did not affect the digester performance. PMID- 25025177 TI - Mechanisms of nitrite addition for simultaneous sludge fermentation/nitrite removal (SFNR). AB - Simultaneous sludge fermentation and nitrite removal (SFNR) was investigated as a novel sludge/wastewater treatment process with high nitrogen concentrations. The results showed that introducing nitrite improved the primary sludge (PS) fermentation system by improving the chemical oxygen demand (COD) yields and the volatile suspend solid (VSS) reduction. At a nitrite dosage of 0.2 g g SS(-1), the COD production was 1.02 g g VSS(-1) and the VSS reduction was 63.4% within 7 day fermentation, while the COD production was only 0.17 g g VSS(-1) and the VSS reduction was only 4.9% in the blank test. Nitrite contained in wastewater was removed through denitrification process in the SFNR system. The solubility of carbohydrate and protein was substantially enhanced, and their contents reached the peak once nitrite was consumed. In addition, the nutrient release and methane generation were inhibited in the SFNR system, which alleviated the environmental pollution. Unlike traditional fermentation systems, neither alkaline condition nor high free nitrite acid (FNA) concentration affected the PS fermentation in the SFNR system. Molecular weight distribution (MWD) and Live/Dead cell analysis indicated that the sludge disruption by nitrite and the consumption of soluble organic substances in sludge might play important roles in SFNR. PMID- 25025178 TI - Removal of pharmaceuticals from MWTP effluent by nanofiltration and solar photo Fenton using two different iron complexes at neutral pH. AB - In recent years, membrane technologies (nanofiltration (NF)/reverse osmosis (RO)) have received much attention for micropollutant separation from Municipal Wastewater Treatment Plant (MWTP) effluents. Practically all micropollutants are retained in the concentrate stream, which must be treated. Advanced Oxidation Processes (AOPs) have been demonstrated to be a good option for the removal of microcontaminants from water systems. However, these processes are expensive, and therefore, are usually combined with other techniques (such as membrane systems) in an attempt at cost reduction. One of the main costs in solar photo-Fenton comes from reagent consumption, mainly hydrogen peroxide and chemicals for pH adjustment. Thus, in this study, solar photo-Fenton was used to treat a real MWTP effluent with low initial iron (less than 0.2 mM) and hydrogen peroxide (less than 2 mM) concentrations. In order to work at neutral pH, iron complexing agents (EDDS and citrate) were used in the two cases studied: direct treatment of the MWTP effluent and treatment of the concentrate stream generated by NF. The degradation of five pharmaceuticals (carbamazepine, flumequine, ibuprofen, ofloxacin and sulfamethoxazole) spiked in the effluent at low initial concentrations (MUg L(-1)) was monitored as the main variable in the pilot-plant scale photo-Fenton experiments. In both effluents, pharmaceuticals were efficiently removed (>90%), requiring low accumulated solar energy (2 kJUV L(-1), key parameter in scaling up the CPC photoreactor) and low iron and hydrogen peroxide concentrations (reagent costs, 0.1 and 1.5 mM, respectively). NF provided a clean effluent, and the concentrate was positively treated by solar photo-Fenton with no significant differences between the direct MWTP effluent and NF concentrate treatments. PMID- 25025179 TI - Increased set shifting costs in fasted healthy volunteers. AB - We investigated the impact of temporary food restriction on a set shifting task requiring participants to judge clusters of pictures against a frequently changing rule. 60 healthy female participants underwent two testing sessions: once after fasting for 16 hours and once in a satiated state. Participants also completed a battery of questionnaires (Hospital Anxiety and Depression Scale [HADS]; Persistence, Perseveration and Perfectionism Questionnaire [PPPQ-22]; and Eating Disorders Examination Questionnaire [EDE-Q6]). Set shifting costs were significantly increased after fasting; this effect was independent of self reported mood and perseveration. Furthermore, higher levels of weight concern predicted a general performance decrement under conditions of fasting. We conclude that relatively short periods of fasting can lead to set shifting impairments. This finding may have relevance to studies of development, individual differences, and the interpretation of psychometric tests. It also could have implications for understanding the etiology and maintenance of eating disorders, in which impaired set shifting has been implicated. PMID- 25025180 TI - Predicting full thickness skin sensitization using a support vector machine. AB - To assess the public's propensity for allergic contact dermatitis (ACD), many alternatives to in vivo chemical screening have been developed which generally incorporate a small panel of cell surface and secreted dendritic cell biomarkers. However, given the underlying complexity of ACD, one cell type and limited cellular metrics may be insufficient to predict contact sensitizers accurately. To identify a molecular signature that can further characterize sensitization, we developed a novel system using RealSkin, a full thickness skin equivalent, in co culture with MUTZ-3 derived Langerhan's cells. This system was used to distinguish a model moderate pro-hapten isoeugenol (IE) and a model strong pre hapten p-phenylenediamine (PPD) from irritant, salicylic acid (SA). Commonly evaluated metrics such as CD86, CD54, and IL-8 secretion were assessed, in concert with a 27-cytokine multi-plex screen and a functional chemotaxis assay. Data were analyzed with feature selection methods using ANOVA, hierarchical cluster analysis, and a support vector machine to identify the best molecular signature for sensitization. A panel consisting of IL-12, IL-9, VEGF, and IFN gamma predicted sensitization with over 90% accuracy using this co-culture system analysis. Thus, a multi-metric approach that has the potential to identify a molecular signature may be more predictive of contact sensitization. PMID- 25025181 TI - In vitro toxicity evaluation of Ti(4+)-stabilized gamma-Bi2O3 sillenites. AB - We report results regarding the in vitro toxicology of gamma-Bi2O3 represented by its isomorphous phase Bi12TiO20 (gamma-BTO). The gamma-BTO microparticles were synthesized by two methods: coprecipitation from a bismuth nitrate-tetrabutyl titanate solution and solid state reaction of Bi2O3 and TiO2 oxides. The structural and morphological characteristics of the obtained materials were determined using X-ray diffraction (XRD), selected area electron diffraction (SAED), transmission (TEM) and scanning (SEM) electron microscopy. The elemental composition was investigated using energy dispersive spectrometry (EDS). The cytotoxicity and oxidative/nitrosative stress (intracellular reactive oxygen species (ROS) and nitric oxide (NO) release) induced by the studied microparticles in HepG2, SH-SY5Y and 3T3-L1 cell cultures were determined using the MTT, DCF-DA (2',7'-dichlorfluorescein-diacetate) and Griess methods respectively. Depending on the cell type and gamma-BTO concentration, results showed only weak cytotoxic effects after 24h of gamma-BTO exposure and cell proliferation effects for longer treatment times. Only reduced NO release increases (corresponding to high gamma-BTO concentrations) were detected in case of SH-SY5Y and 3T3-L1 cells. The intracellular ROS production (higher for HepG2 cells) appeared inversely proportional to the gamma-BTO concentration. The obtained results indicated a promising in vitro biocompatibility of gamma-BTO and encourage further studies regarding its potential for biomedical applications. PMID- 25025182 TI - Cyclic estradiol treatment modulates the orexigenic effects of ghrelin in ovariectomized rats. AB - Data from a wide variety of mammalian species indicate that feeding behavior can be influenced by changes in endogenous estrogens and exogenous estrogenic treatments. Ghrelin is an important physiological signal for the regulation of energy balance, and ghrelin treatment increases eating and body weight in male rodents. The following studies evaluated the hypothesis that the inhibitory effects of estradiol on feeding involve interactions with orexigenic peptides by examining the ability of estradiol to modulate the behavioral effects of ghrelin in female rats. In these experiments, adult rats were ovariectomized and assigned to an estradiol benzoate (EB) or an oil (control) group. Three weeks after ovariectomy, animals received two daily subcutaneous injections of EB or the oil vehicle. Animals then received intraperitoneal (ip) injections of ghrelin (6.0 or 12.0 nmol) or saline during the nocturnal and diurnal periods three days after the first injection of estradiol or oil. Food intake, meal size, and meal number were determined during the 2-hour period following ghrelin or saline treatments. Ghrelin significantly increased food intake during nocturnal tests in oil-treated but not estradiol-treated rats. The hyperphagic effects of ghrelin on nocturnal food intake were also accompanied by an increase in meal size, and this effect of ghrelin on meal size was attenuated in estradiol-treated females. These findings support the hypothesis that the effects of estradiol on feeding behavior involve an attenuation of orexigenic signals, possibly by modulating the effects of the peripheral ghrelin signal on hypothalamic neuropeptides involved in the control of food intake. PMID- 25025183 TI - Geographic variation in age structure and longevity in the nine-spined stickleback (Pungitius pungitius). AB - Variation in age and size of mature nine-spined sticklebacks (Pungitius pungitius) within and among 16 Fennoscandian populations were assessed using skeletochronology. The average age of individuals in a given population varied from 1.7 to 4.7 years. Fish from pond populations were on average older than those from lake and marine populations, and females tended to be older than males. Reproduction in marine and lake populations commenced typically at an age of two years, whereas that in ponds at an age of three years. The maximum life span of the fish varied from 3 to 7 years. Mean body size within and among populations increased with increasing age, but the habitat and population differences in body size persisted even after accounting for variation in population age (and sex) structure. Hence, the population differences in mean body size are not explainable by age differences alone. As such, much of the pronounced intraspecific variation in population age structure can be attributed to delayed maturation and extended longevity of the pond fish. The results are contrasted and discussed in the context of similar data from the three-spined stickleback (Gasterosteus aculeatus) occupying the same geographic area. PMID- 25025184 TI - STED super-resolution microscopy of clinical paraffin-embedded human rectal cancer tissue. AB - Formalin fixed and paraffin-embedded human tissue resected during cancer surgery is indispensable for diagnostic and therapeutic purposes and represents a vast and largely unexploited resource for research. Optical microscopy of such specimen is curtailed by the diffraction-limited resolution of conventional optical microscopy. To overcome this limitation, we used STED super-resolution microscopy enabling optical resolution well below the diffraction barrier. We visualized nanoscale protein distributions in sections of well-annotated paraffin embedded human rectal cancer tissue stored in a clinical repository. Using antisera against several mitochondrial proteins, STED microscopy revealed distinct sub-mitochondrial protein distributions, suggesting a high level of structural preservation. Analysis of human tissues stored for up to 17 years demonstrated that these samples were still amenable for super-resolution microscopy. STED microscopy of sections of HER2 positive rectal adenocarcinoma revealed details in the surface and intracellular HER2 distribution that were blurred in the corresponding conventional images, demonstrating the potential of super-resolution microscopy to explore the thus far largely untapped nanoscale regime in tissues stored in biorepositories. PMID- 25025185 TI - Depletion of penicillin G residues in heavy sows after intramuscular injection. Part I: tissue residue depletion. AB - Heavy sows (n = 126) were treated with penicillin G procaine at a 5* label dose (33 000 IU/kg) for 3 consecutive days by intramuscular (IM) injection using three patterns of drug administration. Treatments differed by injection pattern and injection volume. Sets of sows were slaughtered 5, 10, 15, 20, 25, 32, and 39 days after the last treatment; skeletal muscle, kidney, serum, and urine were collected for penicillin G analysis by LC-MS/MS. Penicillin G at withdrawal day 5 averaged 23.5 +/- 10.5 and 3762 +/- 1932 ng/g in muscle and kidney, respectively. After 15 days of withdrawal, muscle penicillin G residues were quantifiable in only one treated hog (3.4 ng/g) but averaged 119 +/- 199 ng/g in kidneys. Using a hypothetical tolerance of 50 ng/g and a natural log-linear depletion model, the withdrawal period required for penicillin depletion to 50 ng/g was 11 days for skeletal muscle and 47 days for kidney. PMID- 25025187 TI - Peroneal muscle weakness in female basketballers following chronic ankle sprain. AB - Female A-grade basketballers were examined for invertor and evertor muscle strength. Two test groups participated. The injured group were players who had persisting disability following ankle sprains. The control group were players who had never sustained an ankle sprain. Test apparatus was the Orthotron isokinetic dynamometer at contraction speed of 180 degrees per second. Trends towards higher invertor and evertor strength in uninjured group when compared with the injured group found in the present study have been supported by one other report. Invertors were found to be significantly stronger than evertors in both injured and uninjured groups, with the exception of the dominant leg of the uninjured group. A significant weakness in non-dominant evertors of the uninjured group was detected. Dominance did not significantly alter strength differences in the invertor or evertor muscle groups within the uninjured population. The clinical importance of strengthening the peroneal muscles in ankle sprain rehabilitation is discussed, and further research considerations provided. PMID- 25025186 TI - Novel missense variants of ZFPM2/FOG2 identified in conotruncal heart defect patients do not impair interaction with GATA4. AB - Conotruncal heart defect (CTD) is a complex form of congenital heart disease and usually has a poor prognosis. ZFPM2/FOG2 encodes a transcription cofactor that interacts with GATA4 to regulate cardiac development. This regulation has been established in knockout mouse models that display a range of heart malformations, especially CTD. Although previous studies have identified several missense variants in ZFPM2/FOG2 that may cause CTD, it remains unclear whether they are involved in CTD pathogenesis because the study populations were limited and the functional status was unknown. In this report, we screened a larger CTD population, which comprised 145 tetralogy of Fallot (TOF), 37 double-outlet ventricle outflow (DORV), and 18 transposition of the great artery (TGA), to investigate exon mutations as well as copy number variations in ZFPM2/FOG2. Four variants (p.V339I in one DORV, p.A426T in one DORV, p.M703L in three TOF, p.T843M in one TOF) were found in six patients, of which two are reported here for the first time. No copy number variations of the gene were detected. GST pull-down assays demonstrated that all potentially deleterious variants, including those previously reported, did not impair the interaction with GATA4, except for variant p.M544I and p.K737E, which subtly impaired the binding. Thus, these missense variants may be involved in other mechanisms underlying CTD or may be unrelated to CTD occurrence. PMID- 25025188 TI - Computer-based video analysis of movement. AB - Movement can be recorded and analysed using the combined techniques of video recording and computer processing. The actions of turning pages of a journal, drawing objects on a sheet of paper and standing from a chair are used to illustrate how modern developments in video recording, transfer of video images to computer, and computer processing can be combined to provide for objective and detailed recording and analysis of movement. Such systems for computer-based image analysis should become a major assessment and research tool for physiotherapy in the future. PMID- 25025189 TI - Hydrotherapy and chronic lower back pain: A pilot study. AB - In a pilot study which investigated the effectiveness of hydrotherapy in the management of lumbar spondylosis, a group of 20 people suffering from chronic lower back pain were given a four week trial of hydrotherapy treatment, consisting of three individual sessions each week. The group was assessed both before and after the course of hydrotherapy and each person was also sent a questionnaire three months after the conclusion of their treatment. Results demonstrated a reduction in pain levels and suggested that thoraco-lumbar mobility could be improved, especially if the range was less than normal before treatment. Results from the questionnaires showed that the beneficial effects from hydrotherapy may not be long lasting, suggesting the need for continuing sessions to maintain improved mobility and reduced pain levels. Further studies including a matching control group are indicated to confirm these results. PMID- 25025190 TI - Inhibitive castings for the upper limb: A case study. AB - Inhibitive casting of the upper limb was used in the rehabilitation of an eight year-old girl who sustained a severe closed head injury. The procedure involved concurrent casting of both upper and lower limbs on the left. The wrist and fingers of the right hand were also casted during the initial program. The casting of the upper limbs proved to be a major factor in the subsequent reduction of contracture and hypertonicity and in the establishment of normal movement patterns. Furthermore, a widespread effect on muscle tone was noted during the casting procedure. PMID- 25025191 TI - Self-directed learning as part of the mainstream of physiotherapy education. AB - A frequently stated aim of physiotherapy educational programs is to produce graduates capable of, and wishing to pursue, lifelong learning. To help achieve this goal, curricula commonly include the promotion of independent or self directed learning. This paper supports the need for developing self-directed learning, orientation and skills and argues that this can be best achieved by bringing these skills into the mainstream of tertiary education programs such as physiotherapy, rather than isolating them to specific subjects. The challenge of mainstreaming is to appreciate how the basic ideas of self-directed learning can be incorporated into all areas of the curriculum. This paper presents strategies, issues and problems associated with mainstreaming of self-directed learning. PMID- 25025192 TI - Why do physical treatments relieve pain? AB - Those engaged in the clinical rather than the experimental field of medicine are constantly striving to improve their methods of relieving pain, using chemotherapy, surgery or physical therapy according to their particular specialization. This is hardly surprising, since all hospital departments, wards and private clinics are filled with a large proportion of patients seeking, primarily, relief from pain. PMID- 25025193 TI - Hand splinting in children. AB - Normal hand function is essential to carry out all the activities of daily living independently. The child using his hands in play prepares himself for this independence. PMID- 25025194 TI - Problems of the ballet dancer. AB - The needs of ballet dancers have been overlooked by many medical and para-medical workers in the past due to a failure to understand the basic techniques of the dancers. It is with a view to rectifying this omission that we are describing our recent experience in the field of ballet injuries. PMID- 25025195 TI - The cervical syndrome. AB - At the present stage of our ignorance I think we must continue to use the term "Cervical Syndrome" to cover the effects which may accrue from disease or injury of the cervical spine. For the purpose of this paper, I would ask you to dismiss fractures, dislocations, infections, new growths and such serious calamities affecting the cervical vertebrae. PMID- 25025196 TI - "Zinc ionization as a treatment for chronic rhinitis". AB - Zinc ionization was used for many years as a method of treatment for chronic rhinitis, but with the introduction of antihistamine drugs and densitization techniques, the indications for its use diminished markedly; a point has been reached where it is generally overlooked when methods of treatment are considered. PMID- 25025198 TI - The application of piaget's theory to physiotherapy. AB - Jean Piaget is a Swiss psychologist who has presented an extensive theory of the growth of the human intellect from birth to maturity. For more than fifty years he has been producing books and articles on human development, conducting research studies on thousands of children, especially those in the schools of Geneva. He is recognized as the world's foremost authority on cognitive development, and his work has led to the publishing of thousands of studies by other research workers around the world, particularly in the U.S.A., Canada, U.K., Australia, France and Scandinavia. He was 80 years of age in 1976, and in retirement has been producing publications at a consistently high rate. PMID- 25025199 TI - An intervention programme for mentally retarded infants: a behaviour modification approach. AB - The purpose of my paper is to demonstrate the application of behaviour modification principles in the education of young Down's Syndrome children. Illustrations will be drawn from an intervention programme currently in operation at Macquarie University, Sydney, N.S.W., which began in 1975, with 18 Down's Syndrome children aged from four months to five years. Further details of this programme are given elsewhere (Pieterse, 1976; Thorley et al., 1976). The focus of attention here will be the use of behaviour change techniques especially that of consequential events. PMID- 25025197 TI - Structural integrity of the antigen is a determinant for the induction of T helper type-1 immunity in mice by gene gun vaccines against E. coli beta galactosidase. AB - The type of immune response is critical for successful protection and typically determined by pathogen-associated danger molecules. In contrast, protein antigens are usually regarded as passive target structures. Here, we provide evidence that the structure of the antigen can profoundly influence the type of response that is elicited under else identical conditions. In mice, gene gun vaccines induce predominantly Th2-biased immune reactions against most antigens. One exception is E. coli beta-galactosidase (betaGal) that induces a balanced Th1/Th2 response. Because both, the delivered material (plasmid DNA-coated gold particles) as well as the procedure (biolistic delivery to the skin surface) is the same as for other antigens we hypothesized that Th1 induction could be a function of betaGal protein expressed in transfected cells. To test this we examined gene gun vaccines encoding structural or functional variants of the antigen. Employing a series of gene gun vaccines encoding individual structural domains of betaGal, we found that neither of them induced IgG2a antibodies. Even disruption of the homo tetramer association of the native protein by deletion of a few N-terminal amino acids was sufficient to abrogate IgG2a production. However, enzymatically inactive betaGal with only one point mutation in the catalytic center retained the ability to induce Th1 reactions. Thus, structural but not functional integrity of the antigen must be retained for Th1 induction. betaGal is not a Th1 adjuvant in the classical sense because neither were betaGal-transgenic ROSA26 mice particularly Th1-biased nor did co-administration of a betaGal-encoding plasmid induce IgG2a against other antigens. Despite this, gene gun vaccines elicited Th1 reactions to antigens fused to the open reading frame of betaGal. We interpret these findings as evidence that different skin-borne antigens may be differentially handled by the immune system and that the three-dimensional structure of an antigen is an important determinant for this. PMID- 25025200 TI - An infant enrichment programme. AB - I will describe briefly a programme which I have devised for the developmental enrichment of infants up to 12 months old. This programme is intended for those infants whose generalized developmental delay is associated with mental retardation. It is not designed for infants with brain damage, who require more specialized care for the complicated movement disorders associated with hypertonus or athetosis. This is a parent-orientated programme carried out by parents under the guidance of a physiotherapist. PMID- 25025201 TI - Haematoma and myositis ossificans. AB - Knocks and bruises are an accepted risk of participation in contact or potentially contact sports. In fact exhibiting one's patches of black and blue seems to be a part of the game. PMID- 25025202 TI - The use of a punchcard information system: 1. The significance of early treatment in spinogenic pain. AB - Spinogenic assessment has received voluminous attention (Cyriax, 1969; Grieve, 1970; Maitland, 1973; Mennell, 1952). However, spinogenic data recording is rarely presented. Although proforma systems have been used, they have typically served only as worksheets for the treatment and observation of individual patients (Grieve, op. cit.; James and Stuart, 1975; Maitland, op. cit.). Conclusions about even routine clinical information has rarely been subjected to statistical analysis for error. PMID- 25025203 TI - Physiotherapy - open minds? AB - Among the major issues being debated within the physiotherapy profession at present are three which concern all and which must have a profound effect on the practice of physiotherapy in the future. They are: 1. the rescinding of the first ethical principle of the Australian Physiotherapy Association which allows physiotherapists to act as first-contact practitioners; 2. the inroading of other practitioners into what are regarded by the profession as traditional physiotherapy areas; and 3. the need to create senior management positions for physiotherapists within the various health departments to help plan and co ordinate services. PMID- 25025204 TI - Synthesis and spectroscopic properties of a soluble semiconducting porphyrin polymer. AB - A semiconducting porphyrin polymer that is solution processable and soluble in organic solvents has been synthesized, and its spectroscopic and electrochemical properties have been investigated. The polymer consists of diarylporphyrin units that are linked at meso-positions by aminophenyl groups, thus making the porphyrin rings an integral part of the polymer backbone. Hexyl chains on two of the aryl groups impart solubility. The porphyrin units interact only weakly in the ground electronic state. Excitation produces a local excited state that rapidly evolves into a state with charge-transfer character (CT) involving the amino nitrogen and the porphyrin macrocycle. Singlet excitation energy is transferred between porphyrin units in the chain with a time constant of ca. 210 ps. The final CT state has a lifetime of several nanoseconds, and the first oxidation of the polymer occurs at ca. 0.58 V vs. SCE. These properties make the polymer a suitable potential excited state electron donor to a variety of fullerenes or other acceptor species, suggesting that the polymer may find use in organic photovoltaics, sensors, and similar applications. PMID- 25025205 TI - Protein preconcentration using nanofractures generated by nanoparticle-assisted electric breakdown at junction gaps. AB - Sample preconcentration is an important step that increases the accuracy of subsequent detection, especially for samples with extremely low concentrations. Due to the overlapping of electrical double layers in the nanofluidic channel, the concentration polarization effect can be generated by applying an electric field. Therefore, a nonlinear electrokinetic flow is induced, which results in the fast accumulation of proteins in front of the induced ionic depletion zone, the so-called exclusion-enrichment effect. Nanofractures were created in this work to preconcentrate proteins via the exclusion-enrichment effect. The protein sample was driven by electroosmotic flow and accumulated at a specific location. The preconcentration chip for proteins was fabricated using simple standard soft lithography with a polydimethylsiloxane replica. Nanofractures were formed by utilizing nanoparticle-assisted electric breakdown. The proposed method for nanofracture formation that utilizes nanoparticle deposition at the junction gap between microchannels greatly decreases the required electric breakdown voltage. The experimental results indicate that a protein sample with an extremely low concentration of 1 nM was concentrated to 1.5*10(4)-fold in 60 min using the proposed chip. PMID- 25025209 TI - Physiotherapy for the pelvic floor. AB - The inefficiencies of the physiotherapy profession in its attitude to the treatment of pelvic floor insufficiency and urinary stress incontinence are discussed, together with a description of the different types of urinary stress incontinence, their causes and a brief outline of the anatomy of the pelvic floor. The total concept of the authors' treatment regime is described in detail exercises done per vaginam by the physiotherapists as well as the patient, and the reasons for the choice and application of interferential therapy as an adjunct to these exercises. The authors consider that only physiotherapists possess the necessary combined skills in kinesiology and electrotherapy, and a knowledge of anatomy, and, therefore, physiotherapy is the most appropriate profession to undertake the task of retraining thousands of women who are, at the moment, literally told to 'grin and bear it' until their condition is bad enough to warrant surgery, which is often not very effective. PMID- 25025210 TI - DECISION MAKING IN RESEARCH AND CLINICAL PRACTICE: Part II: The decision and its interpretation. AB - This is Part II of a two-part paper. Part I laid the foundation for what is discussed here-decision making and its interpretation. Included are discussions of decision rules and their relevance to the research process, the meaning of decision errors, how to interpret tests of significance and how to distinguish between statistical significance and practical significance. An understanding of the concepts and techniques presented in Parts I and II of this paper will enable clinical therapists to evaluate more judicously the clinical importance of research papers in physical therapy as well as to better prepare them to design and conduct their own clinical research projects. PMID- 25025207 TI - Artificial neural network inference (ANNI): a study on gene-gene interaction for biomarkers in childhood sarcomas. AB - OBJECTIVE: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). METHOD: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross validation to minimize the risk of over-fitting and to optimize generalization ability of the model. RESULTS: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing's sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. CONCLUSIONS: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas. PMID- 25025211 TI - Effects of carbon monoxide on three groups of people. AB - I first became interested in this topic when I saw a newspaper article in the Western Australian, dated Wednesday, May 14th, 1980. This article was suggesting that the nicotine in cigarettes might not be the cause of prematurity, still birth, malformation and low birth weight in babies of smoking mothers, as had previously been thought. The article suggested that the carbon monoxide in the fumes of cigarettes might be causing more harm, as carbon monoxide's finity [sic] for haemoglobin is 50C times that of oxygen joining the Hb in the red blood cells and, if a high level was in the bloodstream, then the foetus could be deprived of oxygen. PMID- 25025212 TI - Why do sleeping nematodes adopt a hockey-stick-like posture? AB - A characteristic posture is considered one of the behavioral hallmarks of sleep, and typically includes functional features such as support for the limbs and shielding of sensory organs. The nematode C. elegans exhibits a sleep-like state during a stage termed lethargus, which precedes ecdysis at the transition between larval stages. A hockey-stick-like posture is commonly observed during lethargus. What might its function be? It was previously noted that during lethargus, C. elegans nematodes abruptly rotate about their longitudinal axis. Plausibly, these "flips" facilitate ecdysis by assisting the disassociation of the old cuticle from the new one. We found that body-posture during lethargus was established using a stereotypical motor program and that body bends during lethargus quiescence were actively maintained. Moreover, flips occurred almost exclusively when the animals exhibited a single body bend, preferentially in the anterior or mid section of the body. We describe a simple biomechanical model that imposes the observed lengths of the longitudinally directed body-wall muscles on an otherwise passive elastic rod. We show that this minimal model is sufficient for generating a rotation about the anterior-posterior body axis. Our analysis suggests that posture during lethargus quiescence may serve a developmental role in facilitating flips and that the control of body wall muscles in anterior and posterior body regions are distinct. PMID- 25025213 TI - The headgroup (a)symmetry strongly determines the aggregation behavior of single chain phenylene-modified bolalipids and their miscibility with classical phospholipids. AB - In the present work, we describe the synthesis of two single-chain phenylene modified bolalipids, namely PC-C17pPhC17-PC and PC-C17pPhC17-OH, with either symmetrical (phosphocholine) or asymmetrical (phosphocholine and hydroxyl) headgroups using a Sonogashira cross-coupling reaction as key step. The temperature-dependent aggregation behavior of both bolalipids in aqueous suspension was studied using transmission electron microscopy (TEM), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, small angle neutron scattering (SANS), and X-ray scattering. We show that different headgroup symmetries lead to a change in the aggregation behavior: Whereas PC C17pPhC17-PC forms nanofibers with a diameter of 5.7 nm that transform into small ellipsoidal micelles at 23 degrees C, the PC-C17pPhC17-OH self-assembles into lamellae with bolalipid molecules in an antiparallel orientation up to high temperatures. Furthermore, the mixing behavior of both bolalipids with bilayer forming phospholipids (DPPC and DSPC) was studied by means of DSC and TEM. The aim was to stabilize bilayer membranes formed of phospholipids in order to improve these mixed lipid vesicles for drug delivery purposes. We show that the symmetrical PC-C17pPhC17-PC is miscible with DPPC and DSPC; however, closed lipid vesicles are not observed, and elongated micelles and bilayer fragments are found instead. In contrast, the asymmetrical PC-C17pPhC17-OH shows no miscibility with phospholipids at all. PMID- 25025214 TI - Rapid identification of the genus Dekkera/Brettanomyces, the Dekkera subgroup and all individual species. AB - The genus Dekkera/Brettanomyces comprises five described species: Dekkera bruxellensis, D. anomala, Brettanomyces custersianus, B. naardenensis and B. nanus. Some of them, especially D. bruxellensis, are important spoilage organisms, particularly in the wine and beverage industries. Because of their economic importance many different methods have been developed to identify members of the genus in general and D. bruxellensis in particular. These methods vary in their rapidity, complexity and cost but, partly because of confidentiality issues, it is unclear which methods are used, or how widely, in the relevant industries. Building on previous work with the genera Saccharomyces and Zygosaccharomyces, a suite of eight PCR primer pairs has been designed either on the D1-D2 region of the 26S rRNA gene or translation elongation factor TEF1 alpha. These primers can specifically identify the genus as a whole, only Dekkera species, each one of the five recognised species as well as a significant subgroup of D. bruxellensis represented by NCYC 3426. Multiplexing has also been tried and it has been shown to be possible with some combinations of genus or Dekkera-level and species-specific primers. Using direct colony PCR amplification followed by gel electrophoresis, a clear positive result can be obtained in less than 3h, thus providing a quick, reliable and inexpensive way to identify target species. PMID- 25025215 TI - Anchoring a plant cytochrome P450 via PsaM to the thylakoids in Synechococcus sp. PCC 7002: evidence for light-driven biosynthesis. AB - Plants produce an immense variety of specialized metabolites, many of which are of high value as their bioactive properties make them useful as for instance pharmaceuticals. The compounds are often produced at low levels in the plant, and due to their complex structures, chemical synthesis may not be feasible. Here, we take advantage of the reducing equivalents generated in photosynthesis in developing an approach for producing plant bioactive natural compounds in a photosynthetic microorganism by functionally coupling a biosynthetic enzyme to photosystem I. This enables driving of the enzymatic reactions with electrons extracted from the photosynthetic electron transport chain. As a proof of concept, we have genetically fused the soluble catalytic domain of the cytochrome P450 CYP79A1, originating from the endoplasmic reticulum membranes of Sorghum bicolor, to a photosystem I subunit in the cyanobacterium Synechococcus sp. PCC 7002, thereby targeting it to the thylakoids. The engineered enzyme showed light driven activity both in vivo and in vitro, demonstrating the possibility to achieve light-driven biosynthesis of high-value plant specialized metabolites in cyanobacteria. PMID- 25025217 TI - The only African wild tobacco, Nicotiana africana: alkaloid content and the effect of herbivory. AB - Herbivory in some Nicotiana species is known to induce alkaloid production. This study examined herbivore-induced defenses in the nornicotine-rich African tobacco N. africana, the only Nicotiana species indigenous to Africa. We tested the predictions that: 1) N. africana will have high constitutive levels of leaf, flower and nectar alkaloids; 2) leaf herbivory by the African bollworm Helicoverpa armigera will induce increased alkaloid levels in leaves, flowers and nectar; and 3) increased alkaloid concentrations in herbivore-damaged plants will negatively affect larval growth. We grew N. africana in large pots in a greenhouse and exposed flowering plants to densities of one, three and six fourth instar larvae of H. armigera, for four days. Leaves, flowers and nectar were analyzed for nicotine, nornicotine and anabasine. The principal leaf alkaloid was nornicotine (mean: 28 ug/g dry mass) followed by anabasine (4.9 ug/g) and nicotine (0.6 ug/g). Nornicotine was found in low quantities in the flowers, but no nicotine or anabasine were recorded. The nectar contained none of the alkaloids measured. Larval growth was reduced when leaves of flowering plants were exposed to six larvae. As predicted by the optimal defense theory, herbivory had a localized effect and caused an increase in nornicotine concentrations in both undamaged top leaves of herbivore damaged plants and herbivore damaged leaves exposed to one and three larvae. The nicotine concentration increased in damaged compared to undamaged middle leaves. The nornicotine concentration was lower in damaged leaves of plants exposed to six compared to three larvae, suggesting that N. africana rather invests in new growth as opposed to protecting older leaves under severe attack. The results indicate that the nornicotine-rich N. africana will be unattractive to herbivores and more so when damaged, but that potential pollinators will be unaffected because the nectar remains alkaloid-free even after herbivory. PMID- 25025219 TI - The management of chondromalacia patellae: a long term solution. AB - Patellofemoral pain syndrome can be a difficult condition to manage effectively. The success rate of most treatment regimes has been poor and in the long term the condition frequently recurs. The author has developed a treatment programme which has a ninety-six percent success rate. Long term follow up of patients, after twelve months demonstrated that all patients reviewed have remained pain free. The programme involves two major components: a thorough understanding of the mechanics of the patellofemoral joint so that an adequate assessment of the patient's lower limb can be made, and context specific training of certain muscles which contribute to patellar alignment. This training must be relatively pain free so that muscle control can be enhanced. PMID- 25025218 TI - Effect of diabetes mellitus type 2 on salivary glucose--a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Early screening of type 2 diabetes mellitus (DM) is essential for improved prognosis and effective delay of clinical complications. However, testing for high glycemia often requires invasive and painful blood testing, limiting its large-scale applicability. We have combined new, unpublished data with published data comparing salivary glucose levels in type 2 DM patients and controls and/or looked at the correlation between salivary glucose and glycemia/HbA1c to systematically review the effectiveness of salivary glucose to estimate glycemia and HbA1c. We further discuss salivary glucose as a biomarker for large-scale screening of diabetes or developing type 2 DM. METHODS AND FINDINGS: We conducted a meta-analysis of peer-reviewed published articles that reported data regarding mean salivary glucose levels and/or correlation between salivary glucose levels and glycemia or HbA1c for type 2 DM and non-diabetic individuals and combined them with our own unpublished results. Our global meta analysis of standardized mean differences on salivary glucose levels shows an overall large positive effect of type 2 DM over salivary glucose (Hedge's g = 1.37). The global correlation coefficient (r) between salivary glucose and glycemia was large (r = 0.49), with subgroups ranging from medium (r = 0.30 in non-diabetics) to very large (r = 0.67 in diabetics). Meta-analysis of the global correlation between salivary glucose and HbA1c showed an overall association of medium strength (r = 0.37). CONCLUSIONS: Our systematic review reports an overall meaningful salivary glucose concentration increase in type 2 DM and a significant overall relationship between salivary glucose concentration and associated glycemia/HbA1c values, with the strength of the correlation increasing for higher glycemia/HbA1c values. These results support the potential of salivary glucose levels as a biomarker for type 2 DM, providing a less painful/invasive method for screening type 2 DM, as well as for monitoring blood glucose levels in large cohorts of DM patients. PMID- 25025220 TI - Treatment of arm pain associated with abnormal brachial plexus tension. AB - An outline is given of the possible effect passive movement has on pathological conditions involving cervical nerve roots in order to cause a resolution of the condition. Techniques for the treatment of arm pain conditions such as Repetitive Strain Injury (RSI), which are accompanied by signs of abnormal brachial plexus tension, are described. The techniques are outlined in order to give the clinician further insight into an understanding of cervical nerve root conditions and an increased range of treatment choice. PMID- 25025221 TI - A survey of netball injuries and conditions related to these injuries. AB - In 1983, during the winter Saturday afternoon season at the Western Australian Matthew's Netball Centre, 3108 players participated in the netball competition. The study examines the incidence of netball injuries and conditions related to these injuries. One hundred and fifty-eight injuries were surveyed throughout this fourteen week season. Each injured player filled in the first two pages of the questionnaire; the final page was filled in by the physiotherapist. Data was compiled and processed using the S.P.S.S. systems file including frequencies and cross tabulations. Many statistically significant results were recorded and recommendations for further investigation are included. PMID- 25025222 TI - Physiotherapy - a feminine profession. AB - The female-dominated professions in health care are not as powerful as the male dominated medical profession. This paper suggests that the key factor in shaping the discrepancies in pay, status and power between medicine and the female dominated professions is gender. It is argued that physiotherapy developed as a profession for middle-class women and that family responsibilities continue to take priority over professional responsibilities for the majority of physiotherapists. Physiotherapy enjoys higher occupational prestige than social work, speech therapy, occupational therapy and nursing and it is suggested that physiotherapy has achieved this status through recruitment of women from middle and upper middle class backgrounds. The history of physiotherapy is the history of a middle class feminine profession. PMID- 25025223 TI - The Absolute Visual Analogue Scale (AVAS) as a Measure of Pain Intensity. AB - Research in physiotherapy often necessitates measurement of the intensity of clinical pain. Numerous methods have been devised, and recommended for this purpose. However, many are time consuming and unnecessarily complex both to carry out and to analyse. The absolute visual analogue scale (AVAS) is a simple and adequate measure of pain intensity. PMID- 25025224 TI - Transient 2D-IR spectroscopy of inorganic excited states. AB - Time-resolved infrared spectroscopy has been proven to be a powerful tool for investigating the structure, dynamics and reactivity of electronically-excited states of inorganic molecules. As applications drive the production of ever more complex molecules however, experimental tools that can deliver more detailed spectroscopic information, or separate multiple contributions to complex signals will become increasingly valuable. In this Perspective, the extension of ultrafast infrared spectroscopy of inorganic excited states to a second frequency dimension using transient 2D-IR spectroscopy (T-2D-IR) methods is discussed. Following a brief discussion of the experimental methodologies, examples will be given of applications of T-2D-IR ranging from studies of the spectroscopy, structure and dynamics of photochemical intermediates to new tools for correlating vibrational modes in ground and excited electronic states and the investigation of excited state solvation dynamics. Future directions for these experiments are also discussed. PMID- 25025225 TI - Detecting novel genetic variants associated with isoniazid-resistant Mycobacterium tuberculosis. AB - BACKGROUND: Isoniazid (INH) is a highly effective antibiotic central for the treatment of Mycobacterium tuberculosis (MTB). INH-resistant MTB clinical isolates are frequently mutated in the katG gene and the inhA promoter region, but 10 to 37% of INH-resistant clinical isolates have no detectable alterations in currently known gene targets associated with INH-resistance. We aimed to identify novel genes associated with INH-resistance in these latter isolates. METHODOLOGY/PRINCIPAL FINDINGS: INH-resistant clinical isolates of MTB were pre screened for mutations in the katG, inhA, kasA and ndh genes and the regulatory regions of inhA and ahpC. Twelve INH-resistant isolates with no mutations, and 17 INH-susceptible MTB isolates were subjected to whole genome sequencing. Phylogenetically related variants and synonymous mutations were excluded and further analysis revealed mutations in 60 genes and 4 intergenic regions associated with INH-resistance. Sanger sequencing verification of 45 genes confirmed that mutations in 40 genes were observed only in INH-resistant isolates and not in INH-susceptible isolates. The ratios of non-synonymous to synonymous mutations (dN/dS ratio) for the INH-resistance associated mutations identified in this study were 1.234 for INH-resistant and 0.654 for INH-susceptible isolates, strongly suggesting that these mutations are indeed associated with INH resistance. CONCLUSION: The discovery of novel targets associated with INH resistance described in this study may potentially be important for the development of improved molecular detection strategies. PMID- 25025227 TI - Ultrafast excited state dynamics in 9,9'-bifluorenylidene. AB - 9,9'-Bifluorenylidene has been proposed as an alternative and flexible electron acceptor in organic photovoltaic cells. Here we characterize its excited state properties and photokinetics, combining ultrafast fluorescence and transient IR measurements with quantum chemical calculations. The fluorescence decay is ultrafast (sub-100 fs) and remarkably independent of viscosity. This suggests that large scale structure change is not the primary relaxation mode. The ultrafast decay populates a dark state characterized by distinct vibrational and electronic spectra. This state decays with a 6 ps time constant to a hot ground state that ultimately populates the initial state with a 20 ps time constant; these times are also insensitive to solvent viscosity. No metastable intermediate structures are resolved in the photocycle after population of the dark state. The implications of these results for the operation of 9,9'-bifluorenylidene as an electron acceptor and as a potential molecular switch are discussed. PMID- 25025226 TI - Crosslinking constraints and computational models as complementary tools in modeling the extracellular domain of the glycine receptor. AB - The glycine receptor (GlyR), a member of the pentameric ligand-gated ion channel superfamily, is the major inhibitory neurotransmitter-gated receptor in the spinal cord and brainstem. In these receptors, the extracellular domain binds agonists, antagonists and various other modulatory ligands that act allosterically to modulate receptor function. The structures of homologous receptors and binding proteins provide templates for modeling of the ligand binding domain of GlyR, but limitations in sequence homology and structure resolution impact on modeling studies. The determination of distance constraints via chemical crosslinking studies coupled with mass spectrometry can provide additional structural information to aid in model refinement, however it is critical to be able to distinguish between intra- and inter-subunit constraints. In this report we model the structure of GlyBP, a structural and functional homolog of the extracellular domain of human homomeric alpha1 GlyR. We then show that intra- and intersubunit Lys-Lys crosslinks in trypsinized samples of purified monomeric and oligomeric protein bands from SDS-polyacrylamide gels may be identified and differentiated by MALDI-TOF MS studies of limited resolution. Thus, broadly available MS platforms are capable of providing distance constraints that may be utilized in characterizing large complexes that may be less amenable to NMR and crystallographic studies. Systematic studies of state dependent chemical crosslinking and mass spectrometric identification of crosslinked sites has the potential to complement computational modeling efforts by providing constraints that can validate and refine allosteric models. PMID- 25025228 TI - Novel hierarchically porous carbon materials obtained from natural biopolymer as host matrixes for lithium-sulfur battery applications. AB - Novel hierarchically porous carbon materials with very high surface areas, large pore volumes and high electron conductivities were prepared from silk cocoon by carbonization with KOH activation. The prepared novel porous carbon-encapsulated sulfur composites were fabricated by a simple melting process and used as cathodes for lithium sulfur batteries. Because of the large surface area and hierarchically porous structure of the carbon material, soluble polysulfide intermediates can be trapped within the cathode and the volume expansion can be alleviated effectively. Moreover, the electron transport properties of the carbon materials can provide an electron conductive network and promote the utilization rate of sulfur in cathode. The prepared carbon-sulfur composite exhibited a high specific capacity and excellent cycle stability. The results show a high initial discharge capacity of 1443 mAh g(-1) and retain 804 mAh g(-1) after 80 discharge/charge cycles at a rate of 0.5 C. A Coulombic efficiency retained up to 92% after 80 cycles. The prepared hierarchically porous carbon materials were proven to be an effective host matrix for sulfur encapsulation to improve the sulfur utilization rate and restrain the dissolution of polysulfides into lithium sulfur battery electrolytes. PMID- 25025230 TI - Retraction: GREB1 functions as a growth promoter and is modulated by IL6/STAT3 in breast cancer. PMID- 25025229 TI - Behavior of the edible seaweed Sargassum fusiforme to copper pollution: short term acclimation and long-term adaptation. AB - Aquatic agriculture in heavy-metal-polluted coastal areas faces major problems due to heavy metal transfer into aquatic organisms, leading to various unexpected changes in nutrition and primary and/or secondary metabolism. In the present study, the dual role of heavy metal copper (Cu) played in the metabolism of photosynthetic organism, the edible seaweed Sargassum fusiforme, was evaluated by characterization of biochemical and metabolic responses using both 1H NMR and GC MS techniques under acute (47 uM, 1 day) and chronic stress (8 uM, 7 days). Consequently, photosynthesis may be seriously inhibited by acute Cu exposure, resulting in decreasing levels of carbohydrates, e.g., mannitol, the main products of photosynthesis. Ascorbate may play important roles in the antioxidant system, whose content was much more seriously decreased under acute than that under chronic Cu stress. Overall, these results showed differential toxicological responses on metabolite profiles of S. fusiforme subjected to acute and chronic Cu exposures that allowed assessment of impact of Cu on marine organisms. PMID- 25025231 TI - Association of adjuvant antiviral therapy with risk of cancer progression and deaths in patients with hepatitis-B-virus-related hepatocellular carcinoma following curative treatment: a nationwide cohort study. AB - BACKGROUND: Limited information about tumor status and the time at which antiviral therapy was initiated may have influenced effect estimation in previous research. The aim of this study was to investigate the effect of antiviral therapies on HBV-related HCC progression and deaths in patients receiving curative treatment based on clear clinical-pathological cancer status and the association of start time of adjuvant antiviral therapy initiation and outcomes. METHODOLOGY: A nationwide inception cohort study of newly diagnosed HCC patients who suffered from viral hepatitis B and received curative HCC therapy as the first course of treatment were identified from the Taiwan Cancer Registry between January 1, 2004, and December 31, 2009. Matched Cox proportional hazards models based on propensity score matching and incorporated time-varying exposure were used to estimate adjusted hazard ratios and 95% confidence intervals (CIs). FINDINGS: Among 3,855 HCC patients with HBV, antiviral therapy was administered to 490 (12.7%) following curative treatment. Antiviral-treated patients had a higher percentage of young age, early stage, and smaller tumor size of HCC compared with untreated patients. After propensity score matching, treated patients demonstrated a higher risk of HCC progression (hazard ratio, 1.42; 95%CI, 1.20-1.69) and death from all causes (1.45; 1.15-1.82) than untreated patients. Similar results were also obtained in sub-cohort of patients who were alive with cancer-free status at least one year after receiving curative treatment and the sub-cohort of patients with liver resection. The interval length between initiation of antiviral therapy and first-line curative treatment did not show a significant association with all-cause mortality. CONCLUSIONS: This study found that adjuvant antiviral therapy did not reduce the risk of HCC progression or mortality in HBV-related HCC patients after cancer status adjusting. PMID- 25025232 TI - Reported estimates of adverse pregnancy outcomes among women with and without syphilis: a systematic review and meta-analysis. AB - BACKGROUND: To estimate probability of adverse pregnancy outcomes (APOs) among women with and without syphilis through a systematic review of published literatures. METHODOLOGY/PRINCIPAL FINDINGS: Chinese and English literatures were searched for studies assessing pregnancy outcomes in the presence of maternal syphilis through August 2013. The prevalence estimates were summarized and analyzed by meta-analysis. Fifty-four literatures involving 11398 syphilitic women and 43342 non-syphilitic women were included from 4187 records initially found. Among untreated mothers with syphilis, pooled estimates were 76.8% for all APOs, 36.0% for congenital syphilis, 23.2% for preterm, 23.4% for low birth weight, 26.4% for stillbirth or fetal loss, 14.9% for miscarriage and 16.2% for neonatal deaths. Among syphilitic mother receiving treatment only in the late trimester (>28 weeks), pooled estimates were 64.4% for APOs, 40.6% for congenital syphilis, 17.6% for preterm, 12.4% for low birth weight, and 21.3% for stillbirth or fetal loss. Among syphilitic mothers with high titers (>=1?8), pooled estimates were 42.8% for all APOs, 25.8% for congenital syphilis, 15.1% for preterm, 9.4% for low birth weight, 14.6% for stillbirth or fetal loss and 16.0% for neonatal deaths. Among non-syphilitic mothers, the pooled estimates were 13.7% for all APOs, 7.2% for preterm birth, 4.5% for low birth weight, 3.7% for stillbirth or fetal loss, 2.3% for miscarriage and 2.0% for neonatal death. Begg's rank correlation test indicated little evidence of publication bias (P>0.10). Substantial heterogeneity was found across studies in the estimates of all adverse outcomes for both women with syphilis (I2 = 93.9%; P<0.0001) and women without syphilis (I2 = 94.8%; P<0.0001). CONCLUSIONS/SIGNIFICANCE: Syphilis continues to be an important cause of substantial perinatal morbidity and mortality, which reminds that policy-makers charged with resource allocation that the elimination of mother-to-child transmission of syphilis is a public health priority. PMID- 25025233 TI - Efficacy of imiquimod-based transcutaneous immunization using a nano-dispersed emulsion gel formulation. AB - BACKGROUND: Transcutaneous immunization (TCI) approaches utilize skin associated lymphatic tissues to elicit specific immune responses. In this context, the imidazoquinoline derivative imiquimod formulated in Aldara applied onto intact skin together with a cytotoxic T lymphocyte (CTL) epitope induces potent CTL responses. However, the feasibility and efficacy of the commercial imiquimod formulation Aldara is limited by its physicochemical properties as well as its immunogenicity. METHODOLOGY/PRINCIPAL FINDINGS: To overcome these obstacles, we developed an imiquimod-containing emulsion gel (IMI-Gel) and characterized it in comparison to Aldara for rheological properties and in vitro mouse skin permeation in a Franz diffusion cell system. Imiquimod was readily released from Aldara, while IMI-Gel showed markedly decreased drug release. Nevertheless, comparing vaccination potency of Aldara or IMI-Gel-based TCI in C57BL/6 mice against the model cytotoxic T-lymphocyte epitope SIINFEKL, we found that IMI-Gel was equally effective in terms of the frequency of peptide-specific T-cells and in vivo cytolytic activity. Importantly, transcutaneous delivery of IMI-Gel for vaccination was clearly superior to the subcutaneous or oral route of administration. Finally, IMI-Gel based TCI was at least equally effective compared to Aldara-based TCI in rejection of established SIINFEKL-expressing E.G7 tumors in a therapeutic setup indicated by enhanced tumor rejection and survival. CONCLUSION/SIGNIFICANCE: In summary, we developed a novel imiquimod formulation with feasible pharmaceutical properties and immunological efficacy that fosters the rational design of a next generation transcutaneous vaccination platform suitable for the treatment of cancer or persistent virus infections. PMID- 25025234 TI - The role of language ability and self-regulation in the development of inattentive-hyperactive behavior problems. AB - Previous research has found associations but not established mechanisms of developmental linkage between language ability and inattentive-hyperactive (I-H) behavior problems. The present study examined whether self-regulation mediates the effect of language ability on later I-H behavior problems among young children (N = 120) assessed at 30, 36, and 42 months of age. Cross-lagged panel models tested the direction of effect between language ability and self regulation and longitudinal effects of language ability on later I-H problems mediated by self-regulation. Language ability was measured by children's scores on the receptive and expressive language subtests of the Differential Ability Scales. Self-regulation was measured by three behavioral tasks requiring inhibitory control. I-H problems were reported by parents and secondary caregivers. Language ability predicted later self-regulation as measured by all three tasks. There was no association, however, between self-regulation and later language ability, suggesting that the direction of effect was stronger from language ability to later self-regulation. Moreover, the effect of language ability on later I-H behavior problems was mediated by children's self-regulation in one of the tasks (for secondary caregivers' but not parents' ratings). Findings suggest that language deficits may explain later I-H behavior problems via their prediction of poorer self-regulatory skills. PMID- 25025235 TI - The importance of implementation strategy in scaling up Xpert MTB/RIF for diagnosis of tuberculosis in the Indian health-care system: a transmission model. AB - BACKGROUND: India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population level impact may be limited. METHODS AND FINDINGS: We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: 1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research. CONCLUSIONS: The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary. PMID- 25025236 TI - The long noncoding RNA expression profile of hepatocellular carcinoma identified by microarray analysis. AB - BACKGROUND: Thousands of long noncoding RNAs (lncRNAs) have been reported in mammalian genomes. These RNAs represent an important subset of pervasive genes involved in a broad range of biological functions. Aberrant expression of lncRNAs is associated with many types of cancers. Here, in order to explore the potential lncRNAs involved in hepatocellular carcinoma (HCC) oncogenesis, we performed lncRNA gene expression profile analysis in 3 pairs of human HCC and adjacent non tumor (NT) tissues by microarray. METHODOLOGY: Differentially expressed lncRNAs and mRNAs were detected by human lncRNA microarray containing 33,045 lncRNAs and 30,215 coding transcripts. Bioinformatic analyses (gene ontology, pathway and network analysis) were applied for further study of these differentially expressed mRNAs. By qRT-PCR analysis in nineteen pairs of HCC and adjacent normal tissues, we found that eight lncRNAs were aberrantly expressed in HCC compared with adjacent NT tissues, which is consistent with microarray data. CONCLUSIONS: We identified 214 lncRNAs and 338 mRNAs abnormally expressed in all three HCC tissues (Fold Change >=2.0, P<0.05 and FDR <0.05) with the genome-wide lncRNAs and mRNAs expression profile analysis. The lncRNA-mRNA co-expression network was constructed, which may be used for predicting target genes of lncRNAs. Furthermore, we demonstrated for the first time that BC017743, ENST00000395084, NR_026591, NR_015378 and NR_024284 were up-regulated, whereas NR_027151, AK056988 and uc003yqb.1 were down-regulated in nineteen pairs of HCC samples compared with adjacent NT samples. Expression of seven lncRNAs was significantly correlated to their nearby coding genes. In conclusion, our results indicated that the lncRNA expression profile in HCC was significantly changed, and we identified a series of new hepatocarcinoma associated lncRNAs. These results provide important insights about the lncRNAs in HCC pathogenesis. PMID- 25025237 TI - Comparison of the efficacy and safety between interspinous process distraction device and open decompression surgery in treating lumbar spinal stenosis: a meta analysis. AB - OBJECTIVES: The present study performed a meta-analysis to evaluate the efficacy and safety of interspinous process distraction device (IPD) compared with open decompression surgery (ODS) in treating lumbar spinal stenosis. METHODS: Literatures were searched in the databases including Cochrane Library, Pubmed, OvidSP, Sciencedirect, Web of Science, and Springerlin. Published reviews were checked to track missed original research papers. The quality and bias of publications with randomized controlled trial were evaluated using the tool for assessing risk of bias in the Cochrane handbook. The quality and bias of publications with cohort trial were evaluated using the Newcastle-Ottawa Scale. The grades of literatures were evaluated with the guidelines of Grading of Recommendations Assessment Development and Evaluation (GRADE). RESULTS: Totally, 21 publications matched the inclusion criteria, including 20 different clinical trials and 54,138 patients. The results indicated that there was no significant difference in improvement rate, Oswestry disability index questionnaire (ODI) score, and visual analog scale (VAS) score of back pain or leg pain between IPD group and ODS group. The postoperation complication rate, perioperation blood loss, hospitalization time, and operation time were lower/shorter in IPD group than ODS group. However, the reoperation rate in IPD group was higher than ODS group. CONCLUSION: The results indicated that IPD has better effects and less complication than ODS. However, because of the higher reoperation rate in IPD than ODS, we failed to conclude that IPD could replace ODS as golden standard but may be a viable alternative in treating lumbar spinal stenosis. PMID- 25025238 TI - Baseline hypovitaminosis D is not associated with poor clinical outcomes in osteoarticular infections. AB - OBJECTIVES: Although vitamin D is recognized as an important factor in bone health, its role in osteoarticular infections is unclear. We hypothesized that low vitamin D (25-hydroxycholecalciferol) levels are associated with a lower likelihood of treatment success in osteoarticular infections. METHODS: This was a retrospective cohort study of patients with orthopedic infections who had a 25 hydroxycholecalciferol level drawn when their infection was diagnosed. Outcomes were determined at early (3-6 months) and late (>= 6 months) follow-up after completing intravenous antibiotics. RESULTS: We included 223 patients seen during an 11-month period with osteoarticular infections and baseline 25 hydroxycholecalciferol levels. During the initial inpatient management of the infection, hypovitaminosis D was identified and treated. The mean 25 hydroxycholecalciferol level was 23 +/- 14 ng/ml; 167 (75%) patients had levels <30 ng/ml. Overall, infection treatment success was 91% (159/174) at early follow up and 88% (145/164) at late follow-up. 25-Hydroxycholecalciferol baseline levels were similar in those with and without successful clinical outcomes, both at early (25 +/- 15 vs. 21 +/- 9 ng/ml; p=0.3) and late follow-up (25 +/- 15 vs. 23 +/- 16 ng/ml; p=0.6). CONCLUSIONS: To our knowledge this is the first report on hypovitaminosis D and its impact on outcomes of osteoarticular infections. Hypovitaminosis D was frequent in this cohort. With vitamin D repletion, there was no difference in treatment success whether patients had baseline hypovitaminosis or not. PMID- 25025240 TI - Bioactive constituents of Cirsium japonicum var. australe. AB - Cirsium japonicum var. australe, used as a folk medicine in Taiwan, has been employed traditionally in the treatment of diabetes and inflammatory symptoms. Bioactivity-guided fractionation of its ethanolic extract, utilizing centrifugal partition chromatography monitored by DPPH-TLC analysis, led to the isolation of three new acetylenic phenylacrylic acid esters (1-3) and two new polyacetylenes (4 and 5), together with seven known compounds (6-12). The structures of 1-5 were elucidated by spectroscopic methods including 1D and 2D NMR techniques. The absolute configurations of 4 and 7 were determined utilizing Mosher's method and ECD/CD experiments. The DPPH scavenging activity of the constituents isolated from the C. japonicum var. australe ethanolic extract was evaluated. The potential antidiabetic activity of some of the isolates was evaluated using in vitro cellular glucose uptake and oil red staining assays. PMID- 25025241 TI - Letters. PMID- 25025239 TI - Program evaluation of remote heart failure monitoring: healthcare utilization analysis in a rural regional medical center. AB - BACKGROUND: Remote monitoring for heart failure (HF) has had mixed and heterogeneous effects across studies, necessitating further evaluation of remote monitoring systems within specific healthcare systems and their patient populations. "Care Beyond Walls and Wires," a wireless remote monitoring program to facilitate patient and care team co-management of HF patients, served by a rural regional medical center, provided the opportunity to evaluate the effects of this program on healthcare utilization. MATERIALS AND METHODS: Fifty HF patients admitted to Flagstaff Medical Center (Flagstaff, AZ) participated in the project. Many of these patients lived in underserved and rural communities, including Native American reservations. Enrolled patients received mobile, broadband-enabled remote monitoring devices. A matched cohort was identified for comparison. RESULTS: HF patients enrolled in this program showed substantial and statistically significant reductions in healthcare utilization during the 6 months following enrollment, and these reductions were significantly greater compared with those who declined to participate but not when compared with a matched cohort. CONCLUSIONS: The findings from this project indicate that a remote HF monitoring program can be successfully implemented in a rural, underserved area. Reductions in healthcare utilization were observed among program participants, but reductions were also observed among a matched cohort, illustrating the need for rigorous assessment of the effects of HF remote monitoring programs in healthcare systems. PMID- 25025245 TI - Let's chat: bedside reporting in the ED. PMID- 25025246 TI - It's about quality of life, not quantity. PMID- 25025247 TI - Chew on this: reducing postoperative ileus with chewing gum. AB - BACKGROUND: Postoperative ileus (POI), a common postoperative complication, increases length of stay and costs. Although bowel rest and delayed oral intake were once thought to help prevent POI, newer evidence shows that chewing gum can be beneficial. METHODS--LITERATURE SEARCH: The literature was searched for the terms ileus, gum, chewing, and gum chewing for 2006 to 2013. STUDY SELECTION: All prospective randomized controlled trials comparing gum chewing in adults with a control treatment after abdominal surgery (except cesarean section) were included; an outcome measure was required as a dependent variable. FINDINGS: Seven primary research studies from around the world were gathered. RESULTS: Across all studies, patients in the gum-chewing experimental group both passed flatus and defecated before those in the non-gum-chewing control group. Where length of stay was studied, patients in all but one experimental group were in the hospital for less time. LIMITATIONS: These included small sample sizes, lack of blinding in all but one study, differences in standards of care among hospitals and countries represented, unspecified types of gum, and variable timing and frequency of gum chewing among studies. DISCUSSION: Patients who chewed gum postoperatively had less POI, passed flatus sooner, had an earlier bowel movement and a shorter length of stay, and were more satisfied. Gum chewing is recommended as adjunctive therapy to reduce postoperative POI. PMID- 25025251 TI - Migraine headache. PMID- 25025252 TI - Sharing your nursing story. PMID- 25025253 TI - Mrs. M's garden. PMID- 25025255 TI - Spotlight on frontotemporal dementia. PMID- 25025254 TI - Recognizing and treating Takotsubo cardiomyopathy. PMID- 25025256 TI - Intraosseous vascular access: Boning up on the basics. PMID- 25025257 TI - What does DNR/DNI really mean? PMID- 25025258 TI - STI resources. PMID- 25025259 TI - Improving fire safety in an ambulatory setting. PMID- 25025260 TI - Assessing wounds in palliative care. PMID- 25025262 TI - Dietary management of hepatic encephalopathy revisited. AB - PURPOSE OF REVIEW: The burden of hepatic encephalopathy on health services is increasing, and some degree of consensus in relation to drug therapy and prophylaxis has been reached. This review focuses on the role of nutritional interventions in the management of hepatic encephalopathy. RECENT FINDINGS: A number of relatively new pieces of evidence are emerging in relation to nutrition and hepatic encephalopathy as follows: first, reduction of protein intake is not useful for hepatic encephalopathy, but protein selection should be considered; second, oral supplementation with branched chain amino acids has a role not only for its nutritional effect in cirrhosis per se, but also for its effect in reducing the risk of recurrence of hepatic encephalopathy; third, alterations in gut microbiota develop in parallel with decompensation of cirrhosis, and modulation of gut microbiota may be effective for treating and preventing hepatic encephalopathy; fourth, prebiotics and probiotics are potentially useful in this aim, thus further research or trials on prebiotics and probiotics are required; fifth, micronutrient deficiency, which is common in end-stage liver disease, has adverse effects on the brain and may either directly cause encephalopathy per se, or interact with the mechanisms leading to hepatic encephalopathy. SUMMARY: Properly performed nutritional interventions are likely to be useful for patients with hepatic encephalopathy, but well conducted clinical trials are required. VIDEO ABSTRACT: http://links.lww.com/COCN/A7. PMID- 25025263 TI - The Patello-Femoral Pain Syndrome: A Clinical Trial of the McConnell Programme. AB - In an uncontrolled clinical trial, 116 patients from a general population were treated with the McConnell programme for patello-femoral pain syndrome. This programme, consisting of a detailed knee assessment and treatment using a taping technique for pain relief, isometric and eccentric exercise, produced excellent to good results in 86 per cent of patients within five treatments and maintained those results one year after the cessation of treatment. Sex, current activities, duration of symptoms, abnormal foot pronation, iliotibial tract and hamstring tightness and other positive passive movement tests had no effect on the outcome of the treatment. Patients over 38 years of age had only an equal chance of being pain free with five treatments. The presence of concurrent lumbar symptoms increased the time required for positive response to the treatment (p<0.001). PMID- 25025264 TI - Transcutaneous electrical nerve stimulation in labour: practicality and effectiveness in a public hospital labour ward. AB - The aim of this study was to assess the practical aspects of Transcutaneous Electrical Nerve Stimulation (TENS) and its effectiveness in relieving pain in an Australian public hospital labour ward. Thirty women volunteered from the Antenatal classes to use TENS in labour and took part in a pre-labour TENS education session. Evaluation was made by use of the numerical pain rating scale and two questionnaires. The results showed a high level of patient and staff satisfaction and a statistically significant change in pain perception when subjects acted as their own controls. Significantly less pethidine was used by the study group compared to a matched comparison group. It was recommended that information be provided to mid wives and clients on TENS analgesia, and that it should be available as a choice in a public hospital labour ward. PMID- 25025265 TI - The inter-therapist reliability of the slump test. AB - This study examined the inter-therapist reliability of the slump test. Six pairs of physiotherapists tested a total of 93 patients currently receiving treatment for lumbar and/or lower limb symptoms. Each pair performed two slump tests on patients during a normal clinical visit. The slump test was positive if the patients' symptoms were reproduced, and subsequently decreased with cervical extension. A second definition of positive slump required decreased symptoms and increased knee extension with cervical extension. The results indicated that the slump test has high inter-therapist reliability which is consistent with reliability findings for related clinical tests of pain. PMID- 25025266 TI - Restricted shoulder movement: capsular contracture or cervical referral - a clinical study. AB - When shoulder movements become restricted in all directions, the literature reports that contracture of the joint capsule is not present in every case. These findings suggest a different underlying pathology in some cases, which restricts shoulder movements in a manner resembling contracture. In order to investigate the concept of another mechanism, fourteen patients were selected with a specific pattern of shoulder stiffness: a gross restriction of lateral rotation associated with only moderate restrictions of abduction and medial rotation. The patients were treated with mobilization of the lower cervical spine, which resulted in an improvement in the range of lateral rotation of the shoulder, the most restricted movement. These results suggest a correlation between the cervical spine and shoulders with this pattern of movement restrictions. PMID- 25025267 TI - Keeping australians healthy: the challenge to physiotherapy practice posed by the concept of the new public health. AB - This Keynote Address considers issues around 'The Healthy Australian', the theme of the 1988 APA National Conference. The concept of the New Public Health requires physiotherapists to review the role they traditionally have held in health care delivery, and to address some key issues in order to meet the needs of their patients and clients more effectively. These issues include developing the most appropriate client/professional relationship, and considering the main elements in education for health and in supporting clients achieve effective coping skills. This paper also addresses some practicalities in legitimizing physiotherapists' involvement in disease prevention and health promotion, and in working with clients in ways that allow a balance of responsibility to be shared appropriately by both parties. PMID- 25025268 TI - Preparing an E-learning-based Speech Therapy (EST) efficacy study: Identifying suitable outcome measures to detect within-subject changes of speech intelligibility in dysarthric speakers. AB - We explored the suitability of perceptual and acoustic outcome measures to prepare E-learning based Speech Therapy (EST) efficacy tests regarding speech intelligibility in dysarthric speakers. Eight speakers with stroke (n=3), Parkinson's disease (n=4) and traumatic brain injury (n=1) participated in a 4 weeks EST trial. A repeated measures design was employed. Perceptual measures were (a) scale ratings for "ease of intelligibility" and "pleasantness" in continuous speech and (b) orthographic transcription scores of semantically unpredictable sentences. Acoustic measures were (c) "intensity during closure" (DeltaIDC) in the occlusion phase of voiceless plosives, (d) changes in the vowel space of /a/, /e/ and /o/ and (e) the F0 variability in semantically unpredictable sentences. The only consistent finding concerned an increased (instead of the expected decreased) DeltaIDC after EST, possibly caused by increased speech intensity without articulatory adjustments. The importance of suitable perceptual and acoustic measures for efficacy research is discussed. PMID- 25025269 TI - An electrochemically switched smart surface for peptide immobilization and conformation control. AB - We report an electrochemically switched smart surface for controlled peptide immobilization and conformation control. This dynamic surface is based on self assembled monolayers (SAMs) containing surface-bound trimethoxybenzene moieties, which can undergo electrochemically modulated surface activation to be stepwisely converted to two catechol derivatives. This new smart surface can be used to realize stepwise immobilization of a peptide, and more importantly, to control peptide conformation on a surface. We demonstrate herein that with one electrochemical activation step, a linear peptide containing an RGD sequence can be attached onto the SAMs. With the subsequence activation step, the attached linear RGD peptide can be converted into cyclic conformation. The SAMs bounded with linear and cyclic RGD exhibit different adhesion behaviors to fibroblasts cells. The reaction procedure can be well-monitored by cyclic voltammetry (CV), electrochemical surface enhanced Raman microscopy (EC-SERS), and X-ray photoelectron spectroscopy (XPS). It is believed this robust smart surface can find wide applications in surface immobilization of bioactive moieties. PMID- 25025270 TI - Hydrothermal photochemistry as a mechanistic tool in organic geochemistry: the chemistry of dibenzyl ketone. AB - Hydrothermal organic transformations under geochemically relevant conditions can result in complex product mixtures that form via multiple reaction pathways. The hydrothermal decomposition reactions of the model ketone dibenzyl ketone form a mixture of reduction, dehydration, fragmentation, and coupling products that suggest simultaneous and competitive radical and ionic reaction pathways. Here we show how Norrish Type I photocleavage of dibenzyl ketone can be used to independently generate the benzyl radicals previously proposed as the primary intermediates for the pure hydrothermal reaction. Under hydrothermal conditions, the benzyl radicals undergo hydrogen atom abstraction from dibenzyl ketone and para-coupling reactions that are not observed under ambient conditions. The photochemical method allows the primary radical coupling products to be identified, and because these products are generated rapidly, the method also allows the kinetics of the subsequent dehydration and Paal-Knorr cyclization reactions to be measured. In this way, the radical and ionic thermal and hydrothermal reaction pathways can be studied separately. PMID- 25025271 TI - Mannan biotechnology: from biofuels to health. AB - Mannans of different structure and composition are renewable bioresources that can be widely found as components of lignocellulosic biomass in softwood and agricultural wastes, as non-starch reserve polysaccharides in endosperms and vacuoles of a wide variety of plants, as well as a major component of yeast cell walls. Enzymatic hydrolysis of mannans using mannanases is essential in the pre treatment step during the production of second-generation biofuels and for the production of potentially health-promoting manno-oligosaccharides (MOS). In addition, mannan-degrading enzymes can be employed in various biotechnological applications, such as cleansing and food industries. In this review, fundamental knowledge of mannan structures, sources and functions will be summarized. An update on various aspects of mannan-degrading enzymes as well as the current status of their production, and a critical analysis of the potential application of MOS in food and feed industries will be given. Finally, emerging areas of research on mannan biotechnology will be highlighted. PMID- 25025272 TI - Immobilized biocatalytic process development and potential application in membrane separation: a review. AB - Biocatalytic membrane reactors have been widely used in different industries including food, fine chemicals, biological, biomedical, pharmaceuticals, environmental treatment and so on. This article gives an overview of the different immobilized enzymatic processes and their advantages over the conventional chemical catalysts. The application of a membrane bioreactor (MBR) reduces the energy consumption, and system size, in line with process intensification. The performances of MBR are considerably influenced by substrate concentration, immobilized matrix material, types of immobilization and the type of reactor. Advantages of a membrane associated bioreactor over a free-enzyme biochemical reaction, and a packed bed reactor are, large surface area of immobilization matrix, reuse of enzymes, better product recovery along with heterogeneous reactions, and continuous operation of the reactor. The present research work highlights immobilization techniques, reactor setup, enzyme stability under immobilized conditions, the hydrodynamics of MBR, and its application, particularly, in the field of sugar, starch, drinks, milk, pharmaceutical industries and energy generation. PMID- 25025273 TI - Myceliophthora thermophila syn. Sporotrichum thermophile: a thermophilic mould of biotechnological potential. AB - Myceliophthora thermophila syn. Sporotrichum thermophile is a ubiquitous thermophilic mould with a strong ability to degrade organic matter during optimal growth at 45 degrees C. Both genome analysis and experimental data have suggested that the mould is capable of hydrolyzing all major polysaccharides found in biomass. The mould is able to secrete a large number of hydrolytic enzymes (cellulases, laccases, xylanases, pectinases, lipases, phytases and some other miscellaneous enzymes) employed in various biotechnological applications. Characterization of the biomass-hydrolyzing activity of wild and recombinant enzymes suggests that this mould is highly efficient in biomass decomposition at both moderate and high temperatures. The native enzymes produced by the mould are more efficient in activity than their mesophilic counterparts beside their low enzyme titers. The mould is able to synthesize various biomolecules, which are used in multifarious applications. Genome sequence data of M. thermophila also supported the physiological data. This review describes the biotechnological potential of thermophilic mould, M. thermophila supported by genomic and experimental evidences. PMID- 25025274 TI - Liver cell-targeted delivery of therapeutic molecules. AB - The liver is the largest internal organ in mammals and is involved in metabolism, detoxification, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune/inflammatory responses. Hepatitis, alcoholic or non alcoholic liver disease, hepatocellular carcinoma, hepatic veno-occlusive disease, and liver fibrosis and cirrhosis are the most common liver diseases. Safe and efficient delivery of therapeutic molecules (drugs, genes or proteins) into the liver is very important to increase the clinical efficacy of these molecules and to reduce their side effects in other organs. Several liver cell targeted delivery systems have been developed and tested in vivo or ex vivo/in vitro. In this review, we discuss the literature concerning liver cell-targeted delivery systems, with a particular emphasis on the results of in vivo studies. PMID- 25025275 TI - In vitro spatially organizing the differentiation in individual multicellular stem cell aggregates. AB - With significant potential as a robust source to produce specific somatic cells for regenerative medicine, stem cells have attracted increasing attention from both academia and government. In vivo, stem cell differentiation is a process under complicated regulations to precisely build tissue with unique spatial structures. Since multicellular spheroidal aggregates of stem cells, commonly called as embryoid bodies (EBs), are considered to be capable of recapitulating the events in early stage of embryonic development, a variety of methods have been developed to form EBs in vitro for studying differentiation of embryonic stem cells. The regulation of stem cell differentiation is crucial in directing stem cells to build tissue with the correct spatial architecture for specific functions. However, stem cells within the three-dimensional multicellular aggregates undergo differentiation in a less unpredictable and spatially controlled manner in vitro than in vivo. Recently, various microengineering technologies have been developed to manipulate stem cells in vitro in a spatially controlled manner. Herein, we take the spotlight on these technologies and researches that bring us the new potential for manipulation of stem cells for specific purposes. PMID- 25025276 TI - High throughput platform to explore RNA-protein interactomes. AB - RNA binding proteins (RBPs) and RNA interaction is an emerging topic in molecular biology. Many reports showed that such interactions contribute to many cellular processes as well as disease development. Several standard in vitro and in vivo methods were developed to fulfill the needs of this RBP-RNA interaction study to explore their biological functions. However, these methods have their limitations in terms of throughput. In this review, we emphasize two important high throughput methods to studying RBP-RNA interactions, affinity purification and protein microarray. These methods have recently become robust techniques regarding their efficiency in systematically analyzing RBP-RNA interactions. Here, we provide technique overviews, strategies and applications of these methods during biological research. Although these technologies are just beginning to be explored, they will be most important methods in this study. PMID- 25025277 TI - Microbial biosynthesis and secretion of l-malic acid and its applications. AB - l-Malic acid has many uses in food, beverage, pharmaceutical, chemical and medical industries. It can be produced by one-step fermentation, enzymatic transformation of fumaric acid to l-malate and acid hydrolysis of polymalic acid. However, the process for one-step fermentation is preferred as it has many advantages over any other process. The pathways of l-malic acid biosynthesis in microorganisms are partially clear and three metabolic pathways including non oxidative pathway, oxidative pathway and glyoxylate cycle for the production of l malic acid from glucose have been identified. Usually, high levels of l-malate are produced under the nitrogen starvation conditions, l-malate, as a calcium salt, is secreted from microbial cells and CaCO3 can play an important role in calcium malate biosynthesis and regulation. However, it is still unclear how it is secreted into the medium. To enhance l-malate biosynthesis and secretion by microbial cells, it is very important to study the mechanisms of l-malic acid biosynthesis and secretion at enzymatic and molecular levels. PMID- 25025278 TI - Host cytokine responses induced after overnight stimulation with novel M. tuberculosis infection phase-dependent antigens show promise as diagnostic candidates for TB disease. AB - BACKGROUND: We previously identified Mycobacterium tuberculosis (M.tb) antigen induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulated culture supernatants. METHODS: We recruited 15 culture confirmed TB cases and 15 non-TB cases from a high-TB endemic community in Cape Town, South Africa into a pilot case-control study from an on going larger study. Blood samples collected from study participants were stimulated with 4 M.tb antigens that were previously identified as promising (ESAT6/CFP10 (early secreted), Rv2029c (latency), Rv2032 (latency) and Rv2389c (rpf)) in a 7-day or overnight culture assay. Supernatants were also collected form the standard QuantiFERON In Tube (QFT-IT) test. The levels of 26 host markers were evaluated in the three culture supernatants using the Luminex platform. RESULTS: The unstimulated levels of CRP, Serum amyloid P (SAP) and serum amyloid A (SAA) and ESAT-6/CFP-10 specific IP-10 and SAA were amongst the best discriminatory markers in all 3 assays, ascertaining TB with AUC of 72-84%. Four-marker models accurately classified up to 92%, 100% and 100% of study participants in the overnight, 7-day and Quantiferon culture supernatants, respectively, after leave-one-out cross validation. CONCLUSION: Unstimulated and antigen-specific levels of CRP, SAA, IP-10, MMP-2 and sCD40L hold promise as diagnostic candidates for TB disease in short-term stimulation assays. Larger studies are required to validate these findings but the data suggest that antigen specific cytokine production and in particular mutimarker biosignatures might contribute to future diagnostic strategies. PMID- 25025279 TI - Plasticity of the MAPK signaling network in response to mechanical stress. AB - Cells display versatile responses to mechanical inputs and recent studies have identified the mitogen-activated protein kinase (MAPK) cascades mediating the biological effects observed upon mechanical stimulation. Although, MAPK pathways can act insulated from each other, several mechanisms facilitate the crosstalk between the components of these cascades. Yet, the combinatorial complexity of potential molecular interactions between these elements have prevented the understanding of their concerted functions. To analyze the plasticity of the MAPK signaling network in response to mechanical stress we performed a non-saturating epistatic screen in resting and stretched conditions employing as readout a JNK responsive dJun-FRET biosensor. By knocking down MAPKs, and JNK pathway regulators, singly or in pairs in Drosophila S2R+ cells, we have uncovered unexpected regulatory links between JNK cascade kinases, Rho GTPases, MAPKs and the JNK phosphatase Puc. These relationships have been integrated in a system network model at equilibrium accounting for all experimentally validated interactions. This model allows predicting the global reaction of the network to its modulation in response to mechanical stress. It also highlights its context dependent sensitivity. PMID- 25025280 TI - Activities of daily living, depression, and quality of life in Parkinson's disease. AB - This study examined whether activities of daily living (ADL) mediate the relationship between depression and health-related quality of life (HR-QOL) in people with Parkinson's disease (PD). A cross-sectional, correlational research design examined data from 174 participants who completed the Geriatric Depression Scale (GDS-15), Parkinson's Disease Questionnaire-39 (PDQ-39), and Unified Parkinson's Disease Rating Scale-section 2 (UPDRS-section 2 [ADL]). Multiple Regression Analysis (MRA) was used to examine the mediator model. Depression and ADL significantly (p<.001) predicted HR-QOL, and depression significantly (p<.001) predicted ADL. Whilst ADL did not impact on the relationship between depression and HR-QOL, there was a significant (p<.001) indirect effect of depression on HR-QOL via ADL, suggesting both direct and indirect (via ADL) effects of depression on HR-QOL. The magnitude of this effect was moderate (R2 = .13). People with PD who report depression also experience greater difficulty completing ADL, which impacts upon their HR-QOL. It is recommended that clinicians adopt a multidisciplinary approach to care by combining pharmacological treatments with psycho/occupational therapy, thereby alleviating the heterogeneous impact of motor and non-motor symptoms on HR-QOL in people with PD. PMID- 25025281 TI - The health effects of US unemployment insurance policy: does income from unemployment benefits prevent cardiovascular disease? AB - OBJECTIVE: Previous studies suggest that unemployment predicts increased cardiovascular disease (CVD) risk, but whether unemployment insurance programs mitigate this risk has not been assessed. Exploiting US state variations in unemployment insurance benefit programs, we tested the hypothesis that more generous benefits reduce CVD risk. METHODS: Cohort data came from 16,108 participants in the Health and Retirement Study (HRS) aged 50-65 at baseline interviewed from 1992 to 2010. Data on first and recurrent CVD diagnosis assessed through biennial interviews were linked to the generosity of unemployment benefit programmes in each state and year. Using state fixed-effect models, we assessed whether state changes in the generosity of unemployment benefits predicted CVD risk. RESULTS: States with higher unemployment benefits had lower incidence of CVD, so that a 1% increase in benefits was associated with 18% lower odds of CVD (OR:0.82, 95%-CI:0.71-0.94). This association remained after introducing US census regional division fixed effects, but disappeared after introducing state fixed effects (OR:1.02, 95%-CI:0.79-1.31).This was consistent with the fact that unemployment was not associated with CVD risk in state-fixed effect models. CONCLUSION: Although states with more generous unemployment benefits had lower CVD incidence, this appeared to be due to confounding by state-level characteristics. Possible explanations are the lack of short-term effects of unemployment on CVD risk. Future studies should assess whether benefits at earlier stages of the life-course influence long-term risk of CVD. PMID- 25025282 TI - Increased risk of cerebrovascular events in patients with cancer treated with bevacizumab: a meta-analysis. AB - Arterial ischemia and hemorrhage are associated with bevacizumab, an inhibitor of vascular endothelial growth factor that is widely used to treat many types of cancers. As specific types of arterial ischemia and hemorrhage, cerebrovascular events such as central nervous system (CNS) ischemic events and CNS hemorrhage are serious adverse events. However, increased cerebrovascular events have not been uniformly reported by previous studies. New randomized controlled trials (RCTs) have been reported in recent years and we therefore conducted an up-to date meta-analysis of RCTs to fully characterize the risk of cerebrovascular events with bevacizumab. We searched the databases of PubMed, Web of Science, and the American Society of Clinical Oncology conferences to identify relevant clinical trials up to February 2014. Eligible studies included prospective RCTs that directly compared patients with cancer treated with and without bevacizumab. A total of 12,917 patients from 17 RCTs were included in our analysis. Patients treated with bevacizumab had a significantly increased risk of cerebrovascular events compared with patients treated with control medication, with a relative risk of 3.28 (95% CI, 1.97-5.48). The risks of CNS ischemic events and CNS hemorrhage were increased compared with control, with RRs of 3.22 (95% CI, 1.71 6.07) and 3.09 (95% CI, 1.36-6.99), respectively. Risk varied with the bevacizumab dose, with RRs of 3.97 (95% CI, 2.15-7.36) and 1.96 (95% CI, 0.76 5.06) at 5 and 2.5 mg/kg/week, respectively. Higher risks were observed in patients with metastatic colorectal cancer (RR, 6.42; 95% CI, 1.76-35.57), and no significant risk was observed in other types of tumors. In conclusion, the addition of bevacizumab significantly increased the risk of cerebrovascular events compared with controls, including CNS ischemic events and CNS hemorrhage. The risk may vary with bevacizumab dose and tumor type. PMID- 25025283 TI - Chronopharmacodynamics and chronopharmacokinetics of pethidine in mice. AB - BACKGROUND: Many studies have demonstrated that the pharmacokinetics and pharmacodynamics of analgesic drugs vary according to the circadian time of drug administration. This study aims at determining whether the analgesic effect and pharmacokinetics of pethidine in male BALB/c mice are influenced by administration time. METHODS: A hot-plate test was used to evaluate the analgesic effect after pethidine (20 mg/kg) or saline injection at different dosing times. Mouse blood samples were collected at different intervals after dosing at 9:00 am and 9:00 pm, and were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: A significant 24-h rhythm was observed in the latency to thermal response at 30 min after dosing, with the peak during the dark phase and the nadir during the light phase. Tolerance to analgesic effect was produced after chronic pethidine injection at 9:00 am or 9:00 pm, and the recovery from tolerance was faster during the dark phase. The peak concentration (Cmax) and area under the concentration-time curve (AUC) of pethidine and its metabolite norpethidine were significantly higher during the dark phase than during the light phase, but the total serum clearance (CL/F) exhibited the opposite trend. The rhythm of drug plasma concentration was positively correlated with the analgesic effect. CONCLUSION: These results suggest that the pharmacodynamics and pharmacokinetics of pethidine in mice vary significantly according to the dosing time, which implies that the time of administration should be considered in the rational clinical use of pethidine to maximise analgesia and minimise the adverse effects. PMID- 25025284 TI - Generation and characterization of an HIV-1 subtype C transmitted and early founder virus consensus sequence. AB - The tight bottleneck during HIV-1 transmission generally results in only a single virus variant being transmitted. Investigation of the HIV-1 envelope glycoprotein (Env) can identify vulnerabilities of transmitting viruses that can be targeted by vaccines designed to elicit protection against global HIV-1. This study generated an HIV-1 subtype C consensus transmitted and early founder virus Env (EnvFVC) after detailed sequence analysis of 1,894 env genes obtained from 80 acutely infected individuals from South Africa, Malawi, and Zambia. The inferred EnvFVC sequence incorporates characteristics of transmitted and early founder viruses and results in the expression of a functional and conformationally intact Env. Overall, the "subtype-based" or "region-based" EnvFVC described here can be used in the development of a useful immunogen for novel vaccine design. PMID- 25025285 TI - A high-affinity peptide for nicotinic acetylcholine receptor-alpha1 and its potential use in pulmonary drug delivery. AB - In pulmonary drug delivery, the ability of an affinity molecule to bind to lung epithelium may prolong retention of therapeutic molecules within the lung and consequently yield higher overall bioavailability. To this end, we screened a library of structurally constrained peptides ('aptides') using phage-display technology and identified a high-affinity aptide for the mouse nicotinic acetylcholine receptor-alpha1 (nAChR-alpha1). The isolated aptide (APTnAChR alpha1) bound to its target protein with high affinity (Kd=47nM). Alexa 488 labeled APTnAChR-alpha1 showed preferential binding to nAChR-alpha1-positive mouse lung epithelial cells and mouse muscle cells. Furthermore, the aptide exhibited substantial binding in nAChR-alpha1-positive tissue sections of muscle, trachea and lung, but not in liver, kidney or spleen tissues, which are nAChR alpha1-negative. In an in vivo experiment, a high-intensity fluorescence signal was observed in the entire lung up to 50h after tracheal injection of Cy5.5 APTnAChR-alpha1, whereas most of the fluorescence signal from a Cy5.5-labeled scrambled peptide washed out within 20h after injection. Taken together, these results indicate that the high-affinity peptide for nAChR-alpha1 identified here bound tightly to lung epithelium and thus exhibited a long residence time in this tissue, suggesting that the peptide could be used for pulmonary delivery of active pharmaceuticals. PMID- 25025286 TI - Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury. AB - Restenosis often occurs at the site of vascular grafting and may become fatal for patients. Restenosis at anastomosis sites is due to neointimal hyperplasia (NH) and difficult to treat with conventional treatments. Such abnormal growth of smooth muscle cells in tunica media of vascular tissue can be reduced by delivering anti-proliferation drugs such as paclitaxel (PTX) to the inner vascular layer. Drug eluting stents (DES) or drug eluting balloon (DEB) have been developed to treat such vascular diseases. However, they are less efficient in drug delivery due to the drug loss to blood stream and inadequate to be applied to re-stenotic area in the presence of stent or anastomosis sites. Recently, we have introduced microneedle cuff (MNC) as perivascular delivery devices to achieve high delivery efficiency to tunica media. In this study, we investigated in vivo microneedle insertion and efficacy in treating NH using a rabbit balloon injury model. Microneedle shape was optimized for reliable insertion into tunica media layer. Uniform distribution of PTX in tunica media delivered by MNC devices was also confirmed. Animal study demonstrated significant NH reduction by MNC treatments and much higher delivery efficiency than flat type devices. PMID- 25025287 TI - [Calculation of standardised unit costs from a societal perspective for health economic evaluation]. AB - PURPOSE: Due to demographic aging, economic evaluation of health care technologies for the elderly becomes more important. A standardised questionnaire to measure the health-related resource utilisation has been designed. The monetary valuation of the resource use documented by the questionnaire is a central step towards the determination of the corresponding costs. The aim of this paper is to provide unit costs for the resources in the questionnaire from a societal perspective. METHODS: The unit costs are calculated pragmatically based on regularly published sources. Thus, an easy update is possible. RESULTS: This paper presents the calculated unit costs for outpatient medical care, inpatient care, informal and formal nursing care and pharmaceuticals from a societal perspective. CONCLUSION: The calculated unit costs can serve as a reference case in health economic evaluations and hence help to increase their comparability. PMID- 25025288 TI - [Relevance of quality of life as a quality indicator in guideline development]. AB - BACKGROUND: Guidelines provide systematically developed decision aids for medical treatment. Quality indicators are derived from recommendations of guidelines to promote the implementation of the guideline and to allow for quality management of both the guideline and the health care itself. OBJECTIVES: This study aims to describe the relevance of quality of life as a quality indicator in the development process of guidelines in the German context. METHODS: A systematic literature review was performed in the PubMed database, to highlight the current state of discussion on the use of quality indicators in the development process of guidelines. 90 articles were included in the analysis of the review. RESULTS: The focus of the evaluation of medical guidelines has changed over time. It started with the evaluation of the methodological quality. Currently, the evaluation of the effects of the guide-lines, especially the process quality but also the quality of results, is focused. Many articles merely mentioned that improving the quality of life - as well as reducing morbidity and mortality - is considered as an outcome parameter. Overall, it was obvious that quality of life is not yet considered as a quality indicator in the development of guidelines. CONCLUSIONS: A patient-oriented approach, taking into account the quality of life and not just factors of mortality and morbidity, is increasingly in demand. Therefore, quality of life should be respected in the primary studies underlying the guidelines as well as being a quality indicator. PMID- 25025289 TI - [Oral health status of students with and without disabilities in Erfurt, Germany]. AB - AIM: The aim of this study was to make a comparison of the oral health status of students with and without disabilities (Sw/D, Sw/oD) aged 6-18 years from the city of Erfurt. METHODS: 328 students with mental retardation (MR), physical disability (PD) and hearing impairment (HI) were examined according to WHO standard (1997). The control group consisted of 400 age-matched Sw/oD. Data analysis was performed in age groups 6-12 and 13-18 years. RESULTS: Caries prevalence of 6- to 12-year-old Sw/D (68.7%) was significantly higher than in Sw/oD (57%) (p=0.019).The caries experience of Sw/D was 2.3 dmft/0.5 DMFT and 1.6 dmft/0.4 DMFT of Sw/oD. PD had a lower restorative index than other Sw/D (p >= 0.023). There was no difference in caries prevalence and caries experience among 13- to 18-year-old Sw/D (51%; 1.9 DMFT) and Sw/oD (59%; 2.1 DMFT). MR had a lower prevalence of fissure sealants and less sealed teeth (p <= 0.042) and their periodontal health was inferior compared to other Sw/D. CONCLUSION: Intensive preventive measures should be intensified to compensate for oral health inequalities, particularly in MR. PMID- 25025290 TI - [Low-threshold support services for people with dementia--the viewpoint of volunteers]. AB - AIM OF THE STUDY: The aim of the study was to investigate the perspective of volunteers on low-threshold support services. The volunteers were asked to estimate their engagement in care and the constitution of these services in considera-tion of their employment position. METHODS: In an explorative cross sectional study we collected data using standardised questionnaires in 2 regions of North Rhine-Westphalia (Germany). The analysis was descriptive. RESULTS: The results show that the employment position differed: half of the volunteers were really honorary involved. The others were regularly salaried. In general all volunteers searched for a meaningful and fulfilling activity and benefitted from it. The aspects related to the constitution of the services (concerning the services in general, with organisational character, concerning the behaviour of the volunteer) were all important. The most important aspect was the needs of the people with dementia. These estimations hardly differed according to the employment position. CONCLUSION: The volunteers involved in low-threshold support services show a high commitment. They hold a lot of potential but they also have to be defended from excessive demands. Because of the salaried employment of the volunteers, the services providers have a planning reliability and can offer a continuous care. Thus shows a tendency towards a professionalisation of these voluntary workers. PMID- 25025291 TI - [Stress and Burnout Risk in Nursery School Teachers: Results from a Survey]. AB - This article presents results from a study of 834 nursery school teachers in Germany, investigating working conditions, stress, and stress-related health problems. In order to evaluate the extent of mental and psychosomatic troubles, as well as the risk of burnout, we used the standardised questionnaire "Burnout Screening Scales" (BOSS I). Data analysis yielded a high percentage of nursery school teachers who reported a remarkably high stress level; nearly 20% can be considered as a high-risk group for burnout. Poor staff conditions in many nurseries turned out to be the crucial stress source, along with large groups, insufficient teacher-child ratio, time pressure and multitasking. In the concluding discussion of the study results, we consider possible measures to reduce stress and to improve working conditions for nursery school teachers. PMID- 25025292 TI - [Need for information concerning medical rehabilitation of the federal german pension fund--findings of an online survey of general practitioners]. AB - AIM: General practitioners complain about information deficits, uncertainties and unclear requirements associated with medical rehabilitation. In this study General practitioners' specific information needs are identified and the preferred form for the presentation of information is determined. METHODS: In a secondary analysis of several focus groups with different stakeholders, rehabilitation specific aspects were identified for which General practitioners could have further information needs. Those were transferred into an online questionnaire. GPs in Schleswig-Holstein were invited to the online-survey via E Mail by different medical associations. RESULTS: A total of 194 questionnaires were available for analysis. In general, high information needs covering all rehabilitation topics in the questionnaire are evident. The highest information need is recognised for the following aspects: in which cases it makes sense to file an objection, which measures have to take place before it makes sense to file an objection and what the term "ambulant measures have been exhausted" exactly means. GPs clearly prefer a website as a means of informational source. Under the option of multiple replies 74.2% prefer a website, followed by the option of a brochure (44.8%) and further education (22.2%). CONCLUSION: General practitioners have high information needs regarding different aspects of rehabilitation which are not satisfied with existing sources of information. The development of a user-friendly website with comprehensible information on the required aspects seems necessary to increase the acceptance and understanding of medical rehabilitation among practitioners and therefore to optimise rehabilitation processes. PMID- 25025293 TI - [How do Prevention Projects Reach their Target Groups? Results of a Survey with Prevention Projects]. AB - AIM: The aim of this study was to assess methods used to access target groups in prevention projects funded within the prevention research framework by the German Federal Ministry of Education and Research. METHODS: A survey with prevention projects was conducted. Access strategies, communication channels, incentives, programme reach, and successful practical recruitment strategies were explored. RESULTS: 38 out of 60 projects took part in the survey. Most projects accessed their target group within structured settings (e. g., child day-care centers, schools, workplaces). Multiple communication channels and incentives were used, with written information and monetary incentives being used most frequently. Only few projects were able to report their programme reach adequately; programme reach was highest for programmes accessing the target groups in structured settings. The respondents viewed active recruitment via personal communication with the target group and key persons in the settings as the most successful strategy. CONCLUSION: The paper provides an overview on recruitment strategies used in current preven-tion projects. More systematic research on programme reach is necessary. PMID- 25025294 TI - [Implementing an Organised Colorectal Cancer Screening Programme in Germany: Opportunities and Challenges]. AB - BACKGROUND: Each year in Germany, about 65,000 people are diagnosed with colorectal cancer (CRC) and more than 25,000 people die of the disease. The majority of these cases could be avoided by a more effective screening programme. Recently, a law came into force that offers a great opportunity in this regard. It calls for introducing an organised CRC screening programme in Germany, which includes an invitation system as well as further measures for quality assurance and programme evaluation. To realise this opportunity, challenges of implementation need to be considered. The aim of this review article is to elaborate the challenges of an organised CRC screening in Germany in order to derive the need for action regarding successful implementation. METHODS: This review article is based on a selective literature search, including current guidelines and recommendations. RESULTS AND CONCLUSION: In the context of CRC screening, but also by colonoscopies performed for other indications (e.g., due to symptoms), precancerous lesions (adenomas) are detected and removed in a relevant proportion of the target population, which requires a surveillance examination after 3 or 5 years according to current recommendations. Therefore, an efficient invitation system for CRC screening should be designed to allow for a flexible interval depending on previous findings, which differs from mammography screening with its fixed interval. A prerequisite would be the standardised documentation of all colonoscopies irrespective of the indication, given that a substantial proportion of colonoscopies in Germany are performed outside of the screening program. Still, the work load regarding documentation could be less than for mammography screening. Another challenge in terms of organisation results from the parallel offer of 2 different screening tools (colonoscopy and faecal occult blood test). To realise the potential of an organised CRC screening, it seems important to devote sufficient time and resources for developing an efficient and feasible concept, while there might be interim options to avoid further delay regarding the initial invitation of the target population. Given that expertise from, amongst others, gastroenterology, epidemiology, clinical chemistry and health communication is required, an interdisciplinary approach appears essential. PMID- 25025295 TI - Elevated expression of IL-12 and IL-23 in patients with primary immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is an acquired autoimmune disorder. Both impaired platelet production and T-cell-mediated effects play a role in ITP. A T-helper1 (Th1) polarization of the immune response and up-regulation of Th17 cells have been demonstrated in ITP patients. Interleukin (IL)-12 and IL-23 produced by antigen presenting cells are essential for inducing and sustaining Th1 and Th17 effector cells via different pathways. However, less is known with regard to the levels of expression and synthesis of these two cytokines in patients with ITP. This was determined in this study in 46 patients with ITP as well as in 22 healthy controls. Our results showed that an increased expression of IL-12 p40, IL-12 p35, and IL-23 p19 mRNA was observed in bone marrow mononuclear cells and peripheral blood mononuclear cells of patients with ITP compared with controls. Consequently, higher levels of IL-12 and IL-23 were also found in bone marrow plasma and peripheral blood plasma in patients with ITP than in controls. Afterwards, a markedly higher level of IL-12 and IL-23 in bone marrow plasma or peripheral blood plasma was found in patients with chronic ITP than in patients with acute ITP. Furthermore, the peripheral blood plasma levels of IL-12 and IL 23 were negative correlated with platelet counts in ITP patients. Therefore, the augmented expression of IL-12 and IL-23 in patients with ITP may play an important role in the pathogenesis of this disease. PMID- 25025296 TI - Bending-induced symmetry breaking of lithiation in germanium nanowires. AB - From signal transduction of living cells to oxidation and corrosion of metals, mechanical stress intimately couples with chemical reactions, regulating these biological and physiochemical processes. The coupled effect is particularly evident in the electrochemical lithiation/delithiation cycling of high-capacity electrodes, such as silicon (Si), where on the one hand lithiation-generated stress mediates lithiation kinetics and on the other the electrochemical reaction rate regulates stress generation and mechanical failure of the electrodes. Here we report for the first time the evidence on the controlled lithiation in germanium nanowires (GeNWs) through external bending. Contrary to the symmetric core-shell lithiation in free-standing GeNWs, we show bending the GeNWs breaks the lithiation symmetry, speeding up lithaition at the tensile side while slowing down at the compressive side of the GeNWs. The bending-induced symmetry breaking of lithiation in GeNWs is further corroborated by chemomechanical modeling. In the light of the coupled effect between lithiation kinetics and mechanical stress in the electrochemical cycling, our findings shed light on strain/stress engineering of durable high-rate electrodes and energy harvesting through mechanical motion. PMID- 25025297 TI - Determinants of early introduction of solid, semi-solid or soft foods among infants aged 3-5 months in four Anglophone West African countries. AB - This study was conducted to explore and identify factors associated with the practice of early introduction of solid, semi-solid or soft foods among infants aged 3-5 months in four Anglophone West African countries. Data sources for the analyses were the latest Demographic and Health Survey datasets of the 4 countries, namely Ghana (GDHS, 2008), Liberia (LDHS, 2007), Nigeria (NDHS, 2013) and Sierra Leone (SLDHS, 2008). Multiple logistic regression methods were used to analyze the factors associated with early introduction of solid, semi-solid or soft foods among infants aged 3-5 months, using individual-, household- and community-level determinants. The sample consisted of 2447 infants aged 3-5 months from four Anglophone West African countries: 166 in Ghana, 263 in Liberia, 1658 in Nigeria and 360 in Sierra Leone. Multivariable analyses revealed the individual factors associated with early introduction of solid, semi-solid or soft foods in these countries. These included increased infant's age, diarrhea, acute respiratory infection and newborns perceived to be small by their mothers. Other predictors of early introduction of solid, semi-solid or soft foods were: mothers with no schooling, young mothers and fathers who worked in an agricultural industry. Public health interventions to improve exclusive breastfeeding practices by discouraging early introduction of solid, semi-solid or soft foods are needed in all 4 countries, targeting especially mothers at risk of introducing solid foods to their infants early. PMID- 25025299 TI - Association between Apolipoprotein B/Apolipoprotein A-1 and arterial stiffness in metabolic syndrome. AB - BACKGROUND: Apolipoprotein B/Apolipoprotein A-1 ratio (Apo B/Apo A-1) is known to be associated with atherosclerotic vascular disease. However, few studies have investigated the relationship between Apo B/Apo A-1 ratio and arterial stiffness, thus we investigated the relationships between Apo B/Apo A-1 and arterial stiffness in patients with metabolic syndrome (MetS). METHODS: 1252 subjects with MetS according to the Adult Treatment Panel III were enrolled in our study. Anthropometric profiles and serum concentrations of Apo B, Apo A-1, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), and high density lipoprotein cholesterol (HDL-C) were measured. Pulse wave velocity (PWV) was evaluated to assess arterial stiffness. RESULTS: The subjects were stratified into four groups according to their Apo B/Apo A-1 ratios. PWV gradually increased according to Apo B/Apo A-1 quartiles. After adjusting for age, arterial stiffness was significantly correlated with systolic blood pressure, diastolic blood pressure, FPG, homeostasis model assessment (HOMA-IR), Apo B and Apo B/Apo A-1. In multiple logistic regression analysis after adjusting for risk factors, Apo B/Apo A-1 ratio was a significant contributor to increased PWV. CONCLUSION: These results suggest that Apo B/Apo A-1 is independently associated with increased arterial stiffness in patients with MetS. PMID- 25025298 TI - Resveratrol increases nephrin and podocin expression and alleviates renal damage in rats fed a high-fat diet. AB - Resveratrol is well known for its anti-inflammation and anti-oxidant properties, and has been shown to be effective in alleviating the development of obesity. The purpose of this investigation was to analyze the effect of resveratrol on renal damage in obese rats induced by a high-fat diet (HFD) and its possible mechanisms. Male Sprague-Dawley rats were divided into three groups: control, HFD, and HFD plus resveratrol (treated with 100 mg/kg/day resveratrol). Body weight, serum and urine metabolic parameters, and kidney histology were measured. Meanwhile, the activities of nuclear factor-kappaB (NF-kappaB) and superoxide dismutase (SOD), the content of malondialdehyde (MDA), and the protein levels of tumor necrosis factor (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), nephrin and podocin in kidney were detected. Our work showed that resveratrol alleviated dyslipidemia and renal damage induced by HFD, decreased MDA level and increased SOD activity. Furthermore, the elevated NF-kappaB activity, increased TNF-alpha and MCP-1 levels, and reduced expressions of nephrin and podocin induced by HFD were significantly reversed by resveratrol. These results suggest resveratrol could ameliorate renal injury in rats fed a HFD, and the mechanisms are associated with suppressing oxidative stress and NF-kappaB signaling pathway that in turn up-regulate nephrin and podocin protein expression. PMID- 25025300 TI - Lack of genotypephenotype correlation in congenital adrenal hyperplasia due to a CYP21A2-like gene. AB - CONTEXT: Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, encoded by CYP21A2 gene, is an autosomal recessive disorder. The CYP21A2 gene, localized in a genetic unit defined RCCX module, is considered one of the most polymorphic of human genes. OBJECTIVES: We considered new evidences about the presence of a RCCX trimodular haplotype with a CYP21A2-like gene to explain the lack of a genotype-phenotype correlation in individuals of two different families. DESIGN AND METHODS: To verify gene duplication we used Multiplex Ligation Probe-Dependent Amplifications (MLPA) and to confirm the presence of a CYP21A2-like gene downstream TNXA gene we used previously described amplification and restriction strategy followed by the sequencing of the CYP21A2 gene downstream TNXB gene. RESULTS: The amplification strategy and restriction analysis of CYP21A1P/CYP21A2-TNXA PCR product in association with MLPA assay and sequencing of CYP21A2 gene downstream TNXB were able to identify the presence of the CYP21A2-like gene in healthy subjects of the two families, wherein the direct sequencing of CYP21A2 gene showed genotypes correlated to pathological phenotypes. CONCLUSIONS: The strategy suggested is useful to facilitate molecular testing in CAH patients, considering the new evidence about possible different haplotypes. PMID- 25025301 TI - Diagnostic features of retinal nerve fiber layer rotation in skew deviation using optical coherence tomography. AB - A 41-year-old woman with skew deviation had cyclotorsion of both eyes. This resulted in a falsely low probability plot of retinal nerve fiber layer thickness in adjacent clock hours on optical coherence tomography (OCT) due to displacement of the retinal nerve fiber layer peaks. Ocular cyclotorsion may cause misinterpretation of OCT probability plots. OCT retinal nerve fiber layer plots also may be used to objectively quantify the degree of ocular cyclotorsion. PMID- 25025303 TI - Crystallization, crystal structure, and isothermal melt crystallization kinetics of novel polyamide 6/SiO2 nanocomposites prepared using the sol-gel technique. AB - Polyamide 6/SiO2 (PA6/SiO2) nanocomposites with varying amounts of SiO2 were prepared by using a novel sol-gel technique. These nanocomposites were formed in situ by hydrolysis and through the condensation of tetraethoxysilane (TEOS) using formic acid with a small amount of water as the solvent for PA6. Observations of TGA showed that the thermal stability of PA6 nanocomposite was significantly improved compared to that of neat PA6. Microstructure development during the thermally induced crystallization of PA6/SiO2 nanocomposites was investigated with a combination of differential scanning calorimetry (DSC), FTIR spectroscopy, scanning electron microscopy (SEM), and AFM. FTIR spectroscopy was used to determine the crystal form of these nanocomposites, and it was concluded that SiO2 nanoparticles have the gamma-nucleating effect. The crystallinity of nanocomposites decreased with increasing TEOS loading as compared to that for neat PA6. SEM showed a very fine dispersion of nanoscale silica whereas SEM and Zetasizer proved the silica particle size was about 100-200 nm. The isothermal crystallization kinetics of these nanocomposites with increasing SiO2 content were investigated, and it was shown that the amount of SiO2 plays a significant role in crystallization kinetics. PMID- 25025302 TI - Alternative splicing of TAF6: downstream transcriptome impacts and upstream RNA splice control elements. AB - The TAF6delta pathway of apoptosis can dictate life versus death decisions independently of the status of p53 tumor suppressor. TAF6delta is an inducible pro-apoptotic subunit of the general RNA polymerase II (Pol II) transcription factor TFIID. Alternative splice site choice of TAF6delta has been shown to be a pivotal event in triggering death via the TAF6delta pathway, yet nothing is currently known about the mechanisms that promote TAF6delta splicing. Furthermore the transcriptome impact of the gain of function of TAF6delta versus the loss of function of the major TAF6alpha splice form remains undefined. Here we employ comparative microarray analysis to show that TAF6delta drives a transcriptome profile distinct from that resulting from depletion of TAF6alpha. To define the cis-acting RNA elements responsible for TAF6delta alternative splicing we performed a mutational analysis of a TAF6 minigene system. The data point to several new RNA elements that can modulate TAF6delta and also reveal a role for RNA secondary structure in the selection of TAF6delta. PMID- 25025304 TI - Genetic activation of mTORC1 signaling worsens neurocognitive outcome after traumatic brain injury. AB - Although the mechanisms that contribute to the development of traumatic brain injury (TBI)-related deficits are not fully understood, it has been proposed that altered energy utilization may be a contributing factor. The tuberous sclerosis complex, a heterodimer composed of hamartin/Tsc-1 and tuberin/Tsc-2, is a critical regulatory node that integrates nutritional and growth signals to govern energy using processes by regulating the activity of mechanistic Target of Rapamycin complex 1 (mTORC1). mTORC1 activation results in enhanced protein synthesis, an energy consuming process. We show that mice that have a heterozygous deletion of Tsc2 exhibit elevated basal mTORC1 activity in the cortex and the hippocampus while still exhibiting normal motor and neurocognitive functions. In addition, a mild closed head injury (mCHI) that did not activate mTORC1 in wild-type mice resulted in a further increase in mTORC1 activity in Tsc2(+/KO) mice above the level of activity observed in uninjured Tsc2(+/KO) mice. This enhanced level of increased mTORC1 activity was associated with worsened cognitive function as assessed using the Morris water maze and context discrimination tasks. These results suggest that there is a threshold of increased mTORC1 activity after a TBI that is detrimental to neurobehavioral performance, and interventions to inhibit excessive mTORC1 activation may be beneficial to neurocognitive outcome. PMID- 25025305 TI - Marker-based estimation of genetic parameters in genomics. AB - Linear mixed model (LMM) analysis has been recently used extensively for estimating additive genetic variances and narrow-sense heritability in many genomic studies. While the LMM analysis is computationally less intensive than the Bayesian algorithms, it remains infeasible for large-scale genomic data sets. In this paper, we advocate the use of a statistical procedure known as symmetric differences squared (SDS) as it may serve as a viable alternative when the LMM methods have difficulty or fail to work with large datasets. The SDS procedure is a general and computationally simple method based only on the least squares regression analysis. We carry out computer simulations and empirical analyses to compare the SDS procedure with two commonly used LMM-based procedures. Our results show that the SDS method is not as good as the LMM methods for small data sets, but it becomes progressively better and can match well with the precision of estimation by the LMM methods for data sets with large sample sizes. Its major advantage is that with larger and larger samples, it continues to work with the increasing precision of estimation while the commonly used LMM methods are no longer able to work under our current typical computing capacity. Thus, these results suggest that the SDS method can serve as a viable alternative particularly when analyzing 'big' genomic data sets. PMID- 25025307 TI - Protein damage and reactive oxygen species generation induced by the synergistic effects of ultrasound and methylene blue. AB - The sonodynamic damage to protein in the presence of methylene blue (MB) and the various influencing factors including ultrasonic irradiation time and MB concentration on the damage of protein were studied by fluorescence and absorption spectra. In addition, the mechanisms of the synergistic effects of ultrasound and MB were studied by oxidation-extraction photometry with several reactive oxygen species (ROS) scavengers. The results indicated that the damage of protein induced by the synergistic effects of ultrasound and MB were more serious than those that ultrasound or MB alone was applied. The damage of protein could be mainly due to the generation of ROS. The damage degree of protein increased with the increase of ultrasonic irradiation time and MB concentration because of the increased quantities of ROS generation. Both (1)O2 and .OH were the important mediators of the ultrasound-inducing protein damage in the presence of MB. PMID- 25025306 TI - Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation. AB - The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV 1BaL and HIV-1JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV 1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms. PMID- 25025308 TI - Ionothermal synthesis, properties and vibrational spectra of zinc (II) complex with nicotinamide. AB - The zinc (II) complex with nicotinamide, (C6H11N2)[ZnBr3(C6H6N2O)], was prepared under ionothermal condition by using the ionic liquid 1-ethyl-3-methylimidazolium bromide ([EMIM]Br) as a solvent. At the same time, [EMIM]Br also functions as a structure-directing agent, leading to a framework structure different from those obtained by the conventional methods. Single-crystal X-ray analysis revealed that the coordinated compound crystallizes in monoclinic space group P2(1)/c, and the Zn (II) ion is four-coordinated by one pyridine ring N atom and three bromide anions in a slightly distorted tetrahedron arrangement. The [EMIM](+) cations acting as the extra framework charge balancing species occupy the channels of this asymmetric unit. In the crystal structure, intermolecular NH?Br and NH?O hydrogen bonds link the molecules to form a supramolecular structure. In addition, this compound was further characterized by FT-IR and Raman spectroscopic techniques, and the observed important bands were assigned. Thermogravimetric analysis (TG), Differential Scanning Calorimetry (DSC) and fluorescent properties of solid samples were also studied at room temperature. PMID- 25025309 TI - Biogenic synthesis of SnO2 nanoparticles: evaluation of antibacterial and antioxidant activities. AB - Nanostructured semiconductors have been of special interest to scientific community due to their peculiar properties. The quantum size effect results in spectacular variation in the optical and vibrational characteristics of nanostructured materials compared to their bulk counterparts. The present work emphasizes an unexploited, cost effective, and environmentally benign method of synthesizing bioactive tin oxide nanoparticles of size from 2.1 nm to 4.1 nm using Saraca indica flower. The XRD pattern and HRTEM images of the samples revealed an increase in particle size with annealing temperature. Fine tuning band gap could be attained as evidenced by the shift of absorption band edge and photoluminescence emission. It is found that oxygen vacancies play an important role on PL emission. The synthesized nanoparticles exhibit antibacterial activity against gram negative bacteria Escherichia coli. The antioxidant activity is evaluated by scavenging free radicals of 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH). The efficiency of biogenic SnO2 nanoparticles as a promising antibacterial agent as well as an antioxidant for pharmaceutical applications is suggested. PMID- 25025310 TI - Room temperature phosphorescence study on the structural flexibility of single tryptophan containing proteins. AB - In this study, we have undertaken efforts to find correlation between phosphorescence lifetimes of single tryptophan containing proteins and some structural indicators of protein flexibility/rigidity, such as the degree of tryptophan burial or its exposure to solvent, protein secondary and tertiary structure of the region of localization of tryptophan as well as B factors for tryptophan residue and its immediate surroundings. Bearing in mind that, apart from effective local viscosity of the protein/solvent matrix, the other factor that concur in determining room temperature tryptophan phosphorescence (RTTP) lifetime in proteins is the extent of intramolecular quenching by His, Cys, Tyr and Trp side chains, the crystallographic structures derived from the Brookhaven Protein Data Bank were also analyzed concentrating on the presence of potentially quenching amino acid side chains in the close proximity of the indole chromophore. The obtained results indicated that, in most cases, the phosphorescence lifetimes of tryptophan containing proteins studied tend to correlate with the above mentioned structural indicators of protein rigidity/flexibility. This correlation is expected to provide guidelines for the future development of phosphorescence lifetime-based method for the prediction of structural flexibility of proteins, which is directly linked to their biological function. PMID- 25025311 TI - Enhanced 2-5 MUm emission in Ho3+/Yb3+ codoped halide modified transparent tellurite glasses. AB - Ho(3+)/Yb(3+) codoped TeO2-WO3-ZnO-ZnX2(X=F, Cl) glasses were prepared by melt quenching method. The absorption spectra, transmittance spectra, X-ray diffraction (XRD) curves, Raman spectra and mid-infrared fluorescence spectra were measured, along with the Judd-Ofelt intensity parameters, stimulated emission and absorption cross-sections were calculated to evaluate the effects of halide amount of the spectroscopic properties. It is shown that the introduction of an appropriate amount of halide can further improve the mid-infrared fluorescence intensity through an enhanced phonon-assisted energy transfer between Ho(3+)/Yb(3+) ions and the energy transfer mechanisms are investigated quantitatively in detail by calculating energy transfer microparameters and phonon contribution ratios. The results indicate that this kind of glasses is a promising material for mid-infrared optical fiber. PMID- 25025312 TI - Conformations of 2-thiouracil in the aqueous solution and its adsorption behavior on the gold substrates explored by DFT calculations and experimental methods. AB - 2-Thiouracil, a thio-derivative of uracil, may appear in various tautomeric forms due to the different positions of protons. In this paper, the adsorption behavior and conformations of 2-thiouracil on the gold substrates are inspected by means of surface-enhanced Raman scattering (SERS) and density functional theory (DFT) calculations. The results indicate that all the enhanced bands are assigned to in plane vibration modes. Besides, most of the bands related to N and S atoms are significantly enhanced and have obvious shifts in the SERS spectra. Furthermore, the CO stretching band at 1695 cm(-1) also appears in the SERS spectra. The theoretical SERS spectra of 2TU-Au4 and 2TU2-Au4 complexes agree well with the experimental SERS spectra of 2-thiouracil at 0.04 mM. Meanwhile, we calculate that the binding energies for 2TU2-Au4 and 2TU-Au4 are ca. 70 and 50 kcal/mol, respectively. Those results above imply that the 2TU and 2TU2 conformers can exist stably in the aqueous solution and both of them are vertically chemisorbed on the gold surfaces. For the 2TU, it is adsorbed on the gold surfaces through N1H position and the sulfur atom. While the 2TU2 adsorbed on the gold substrates through the N1 site and its deprotonated sulfur atom. PMID- 25025313 TI - Theoretical study on a series of iridium complexes with low efficiency roll-off property. AB - A series of heteroleptic cyclometalated Ir (III) complexes for OLEDs application have been investigated theoretically to explore their electronic structures and spectroscopic properties. The geometries, electronic structures, and the lowest lying singlet absorptions and triplet emissions of (piq)2Ir(acac) (labeled 1) and theoretically designed models (piq)2Ir(dpis) (labeled 2), (4Fpiq)2Ir(dpis) (labeled 3), (4F5M-piq)2Ir(dpis) (labeled 4), (4,5-2F-piq)2Ir(dpis) (labeled 5) and (5-F-piq)2Ir(dpis) (labeled 6) were investigated with density functional theory (DFT)-based approaches, where, piq=1-phenylisoquinolato, acac=acetylacetonate and dpis=diphenylimidodisilicate. Their structures in the ground and excited states have been optimized at the DFT/B3LYP/LANL2DZ and TDDFT/B3LYP/LANL2DZ levels, and the lowest absorptions and emissions were evaluated at B3LYP and M062X level of theory, respectively. Furthermore, the energy-transfer mechanism of these complexes also be analyzed here, and the result shown that the complexes 1-6 are having the low efficiency roll-off property. Except that, the oscillator strength analyze shown that the complexes 2 6, which were designed by theory, are suitable for OLED since their high oscillator strength property. PMID- 25025314 TI - Enhanced fluorescence quenching in an acridine orange - alizarin red system through matrine and its analytical application. AB - This study shows that alizarin red (AR) only slightly quenched fluorescence for acridine orange (AO) in an AR/AO mixed solution at pH=5-6. The reduced fluorescent signal was closely and linearly associated with the level of MT added to the system, which is the basis for a new quantitative MT assay method using the fluorescence quenching reaction in the AO-AR system. The results show that under optimal conditions, this method had a 14.9-43.5 mg L(-1) linear detection range with a 1.38 mg L(-1) detection limit and 1.24% precision. In addition, this method was used to determine the MT levels in the commercially available MT containing pesticides and suppositories, which showed a 96.6-103% recovery. Therefore, this method has multiple advantages, including simple and fast operation, high accuracy and low cost. Moreover, herein, we investigated the underlying mechanism in-depth using an ultraviolet (UV) spectroscopic technique. PMID- 25025315 TI - Micro-Raman spectroscopy and X-ray fluorescence spectrometry on the characterization of the Persian pigments used in the pre-seventeenth century wall paintings of Masjid-i Jame of Abarqu, central Iran. AB - The pigments used in the wall paintings of the Masjid-i Jame of Abarqu, central Iran, as less-known pigments used in the history of Persian painting, were investigated with micro-Raman spectroscopy, micro X-ray fluorescence (micro-XRF), scanning electron microscopy (SEM), and polarised light microscopy (PLM). The results showed that the green, red, and blue pigments were atacamite, red lead, and smalt mixed with natural ultramarine blue respectively applied on a white substrate composed of white huntite. Moreover, the blue smalt was identified to be used on the white huntite and under the paint layer in order to delineate the design of the wall paintings and to act as a rough sketch for the subsequent use of the other pigments. Glushinskite, as a less-reported mineral in historical wall paintings, was identified by micro-Raman spectroscopy and hypothesised to be associated with the degradation of the white huntite binder. Furthermore, micro Raman spectroscopy studies surprisingly revealed the mineral woodhouseite sparely mixed with the green pigment. This paper strongly suggests micro-Raman spectroscopy for identifying archaeological pigments and for diagnosing their deterioration products. Conducting scientific methods of analysis, the pigments identified in this study are reported for the first time to be used in Persian wall paintings. PMID- 25025316 TI - Spectroscopic characterization and solubility investigation on the effects of As(V) on mineral structure tooeleite (Fe6(AsO3)2SO4(OH)2.H2O). AB - Tooeleite is an unique ferric arsenite sulfate mineral, which has the potential significance of directly fixing As(III) as mineral trap. The tooeleite and various precipitates were hydrothermally synthesized under the different of initial As(III)/As(V) molar ratios and characterized by XRD, FTIR, XPS and SEM. The crystallinity of tooeleite decreases with the amount of As(V). The precipitate is free of any crystalline tooeleite at the level of that XRD could detect when the ratio of As(III)/As(V) of 7:3 and more. The characteristic bands of tooeleite are observed in 772, 340, 696 and 304 cm(-1), which are assigned to the nu1, nu2, nu3 and nu4 vibrations of AsO3(3-). These intensities of bands gradually decreases with the presence of As(V) and its increasing. An obviously wide band is observed in 830 cm(-1), which is the nu1 vibration of AsO4. The result of XPS reveals that the binding energies of As3d increase from 44.0 eV to 45.5 eV, which indicates that the amount of As(V) in the precipitates increases. The concentrations of arsenic released of these precipitates are 350-650 mg/L. The stability of tooeleite decreases by comparison when the presence of coexisting As(V) ions. PMID- 25025317 TI - Genetic variability and population divergence in the rare Fritillaria tubiformis subsp. moggridgei Rix (Liliaceae) as revealed by RAPD analysis. AB - Fritillaria tubiformis subsp. moggridgei Rix. is a rare alpine geophyte with shiny yellow flowers. This plant is sporadically distributed across the southwestern Alps where it is biogeographically close to F. tubiformis var. burnatii Planch. The latter has dark purple flowers and ranges in the majority of the Western and Central Alps. In order to develop appropriate strategies of conservation, a RAPD based analysis was conducted to study the genetic status of these taxa and the distribution of genetic variability of the subspecies by sampling seven populations distributed across the subspecies' range. Four populations of var. burnatii were chosen within this range and included in the genetic analysis. Some 264 individuals were analysed and 201 polymorphic loci were scored. Genetic diversity scored in the subspecies was in line with expectations for endemic species (He = 0.194). F. tubiformis var. burnatii showed lower intraspecific diversity (He = 0.173), notwithstanding a wider range than the subspecies. Most of the total phenotypic variation (about 83%) was allocated within populations, and significant lower proportions between taxa (6.45%) and between populations of the same taxon (10.64%). Moreover, PCoA analysis and Bayesian clustering separated populations into two genetically differentiated groups corresponding with the subspecific taxa. However, three populations ascribed to the subsp. moggridgei repeatedly showed genetic admixture with var. burnatii populations. Our findings suggest that: i) although the different flower colour, the two taxa are genetically very similar and share a consistent part of their gene pool, ii) the majority of genetic variability is allocated within populations rather than among them, iii) a representative amount of genetic diversity can be preserved by sampling from a restricted number of populations. The efficacy of RAPD markers in analysing genetic variation, and the contribution of the results to the preservation of biodiversity of the species, are discussed. PMID- 25025318 TI - Effect of exercise on balance, strength and reaction time in older people. AB - Twenty subjects enrolled to take part in an exercise programme (mean age = 62.5 years) and 20 control subjects (mean age = 65.5 years) underwent assessments of strength, reaction time, neuro-muscular control and body sway. The exercisers participated in one hour exercise sessions comprising a cardiorespiratory (walking) component and a gentle exercise component twice weekly for 20 weeks. All subjects were then re-tested for the same measures after the completion of the programme. The exercisers showed improved quadriceps strength, reaction time and reduced body sway when compared with the control group; the exercise group showing continued improvement throughout the programme in tests of body sway. The findings suggest that exercise can improve physical function in older people. PMID- 25025319 TI - The relationship between sitting balance and mobility outcome in stroke. AB - The purpose of this study was to identify the relationship between static sitting balance in the acute post stroke patient and gait outcome; and to determine the relationship between initial and six-week post stroke mobility. Fifty-two patients with cerebral infarcts had sitting balance and gait assessed on hospital admission. Gait was reassessed six weeks later using the Functional Independence Measure-Locomotion (FIM Locomotion) score. Sitting balance was positively correlated with gait outcome. In particular, lack of static sitting balance initially is correlated with dependent gait at six weeks post stroke. Consideration of infarct location and side of hemiplegia may further enhance the strength of the correlation. The FIM Locomotion was a useful assessment tool with strong correlation between initial and final FIM Locomotion scores. PMID- 25025320 TI - The relationship between upper trapezius muscle length and upper quadrant neural tissue extensibility. AB - The upper trapezius muscle and the nerves of the brachial plexus share common anatomical locations and orientations. Whether upper trapezius muscle length measurements could be influenced by upper quadrant neural tissue extensibility was the question investigated in this paper. Two groups of normal subjects were studied, one with lesser and one with greater upper quadrant neural extensibility, measured by the upper limb tension test. Results indicated that those with decreased neural extensibility had significantly less measured length of the upper trapezii. These results should direct clinicians to assess neural tissue extensibility prior to interpreting the results of length tests of the upper trapezius muscle. PMID- 25025321 TI - Straight leg raise test high reliability is not a motor memory artefact. AB - This study investigated whether the reported straight leg raise (SLR) test-retest reliability is an artefact of motor memory. Six SLR measurements were performed by one therapist on 16 subjects with a symptomatic SLR. Distance cues available to the subjects were manipulated by systematic variation of the starting position for each test. Angles at P1 (the angle at which pain was provoked) were measured with a gravitational goniometer No significant effect on P1 was observed due to either variation in starting position or repeated testing. The SLR procedure was found to be highly reliable, with an intraclass correlation coefficient (ICC) of 0.95. These results indicate that SLR reliability is not an artefact of memory for the movement involved in the test. PMID- 25025322 TI - EMG study of erector spinae and multifidus in two isometric back extension exercises. AB - Back exercises addressing deep muscles with a prime stabilising role such as multifidus are important in the rehabilitation of patients with low back pain. Electromyography of erector spinae and multifidus of 18 healthy subjects was investigated during prone arch and two isometric back extension exercises; trunk holding and leg holding. When compared with prone arch, both erector spinae and multifidus were recruited at a high level during trunk holding (76-79 per cent) and leg holding (66-68 per cent). Relative activity of erector spinae and multifidus was similar in different loading conditions and this implied they were working together as a single functional unit Further studies are needed to investigate the possibility of selective recruitment of individual lumbar muscles in back exercises. PMID- 25025323 TI - Learning from nature: introducing an epiphyte-host relationship in the synthesis of alloy nanoparticles by co-reduction methods. AB - This communication reports an epiphytic co-reduction method which can overcome the common tendency of sequential deposition in the synthesis of alloy nanoparticles. In this method the reduction of one of the metals (the epiphyte metal) is only turned-on and rendered more facile by the in situ generated fresh surfaces of the other metal (the host-metal). PMID- 25025324 TI - Royal brisbane and princess alexandra hospital physiotherapy departments: a survey. AB - The aim of this survey was to collect information about the patients treated by Physiotherapy, their conditions and the nature and duration of their physiotherapy treatment at two Brisbane public hospitals, Royal Brisbane Hospital (R.B.H.) and Princess Alexandra Hospital (P.A.H.), during 1972. PMID- 25025325 TI - Spirometry in a physiotherapy department. AB - Spirometry is used to provide information which will assist in determining the amount of pulmonary impairment. Tests can be quite elaborate and sophisticated, but physiotherapy departments in hospitals without a respiratory laboratory, can provide a good deal of information by using simple spirometry. PMID- 25025326 TI - Crisis and the physiotherapist. AB - Crisis is a term finding frequent usage in our everyday language. As such it conveys the meaning of a turning point, a period of change with the implication of stress and frequently upheaval. In psychological usage this meaning is defined more specifically, for crisis is used in a theoretical framework with many implications for health care professionals. PMID- 25025327 TI - A report on spina bifida. AB - The condition of Spina Bifida or Meningomyelocele, has become more prevalent in Queensland schools because of improved surgical measures developed since 1958. Many of the children are able to attend normal schools but some are in need of constant medical care. At Montrose Home for Crippled Children (run by the Queensland Society for Crippled Children) during the years 1970-74, twenty-seven Spina Bifida children have been admitted because of their physical needs. Most of these children are severely handicapped physically and moderately handicapped mentally. PMID- 25025328 TI - The home visit. AB - The home visit is in essence an investigation. It serves to provide an assessment of the patient's ability to function effectively and safely in his own home. Future goals of rehabilitation and methods of increasing the patient's independence may be determined from it. PMID- 25025329 TI - Effect of cafeteria diet history on cue-, pellet-priming-, and stress-induced reinstatement of food seeking in female rats. AB - BACKGROUND: Relapse to unhealthy eating habits is a major problem in human dietary treatment. The individuals most commonly seeking dietary treatment are overweight or obese women, yet the commonly used rat reinstatement model to study relapse to palatable food seeking during dieting primarily uses normal-weight male rats. To increase the clinical relevance of the relapse to palatable food seeking model, here we pre-expose female rats to a calorically-dense cafeteria diet in the home-cage to make them overweight prior to examining the effect of this diet history on cue-, pellet-priming- and footshock-induced reinstatement of food seeking. METHODS: Post-natal day 32 female Long-Evans rats had seven weeks of home-cage access to either chow only or daily or intermittent cafeteria diet alongside chow. Next, they were trained to self-administer normally preferred 45 mg food pellets accompanied by a tone-light cue. After extinction, all rats were tested for reinstatement induced by discrete cue, pellet-priming, and intermittent footshock under extinction conditions. RESULTS: Access to daily cafeteria diet and to a lesser degree access to intermittent cafeteria diet decreased food pellet self-administration compared to chow-only. Prior history of these cafeteria diets also reduced extinction responding, cue- and pellet-priming induced reinstatement. In contrast, modest stress-induced reinstatement was only observed in rats with a history of daily cafeteria diet. CONCLUSION: A history of cafeteria diet does not increase the propensity for cue- and pellet-priming induced relapse in the rat reinstatement model but does appear to make rats more susceptible to footshock stress-induced reinstatement. PMID- 25025330 TI - Effects of biochar on soil microbial biomass after four years of consecutive application in the north China Plain. AB - The long term effect of biochar application on soil microbial biomass is not well understood. We measured soil microbial biomass carbon (MBC) and nitrogen (MBN) in a field experiment during a winter wheat growing season after four consecutive years of no (CK), 4.5 (B4.5) and 9.0 t biochar ha(-1) yr(-1) (B9.0) applied. For comparison, a treatment with wheat straw residue incorporation (SR) was also included. Results showed that biochar application increased soil MBC significantly compared to the CK treatment, and that the effect size increased with biochar application rate. The B9.0 treatment showed the same effect on MBC as the SR treatment. Treatments effects on soil MBN were less strong than for MBC. The microbial biomass C?N ratio was significantly increased by biochar. Biochar might decrease the fraction of biomass N mineralized (KN), which would make the soil MBN for biochar treatments underestimated, and microbial biomass C?N ratios overestimated. Seasonal fluctuation in MBC was less for biochar amended soils than for CK and SR treatments, suggesting that biochar induced a less extreme environment for microorganisms throughout the season. There was a significant positive correlation between MBC and soil water content (SWC), but there was no significant correlation between MBC and soil temperature. Biochar amendments may therefore reduce temporal variability in environmental conditions for microbial growth in this system thereby reducing temporal fluctuations in C and N dynamics. PMID- 25025331 TI - Defining catastrophic costs and comparing their importance for adverse tuberculosis outcome with multi-drug resistance: a prospective cohort study, Peru. AB - BACKGROUND: Even when tuberculosis (TB) treatment is free, hidden costs incurred by patients and their households (TB-affected households) may worsen poverty and health. Extreme TB-associated costs have been termed "catastrophic" but are poorly defined. We studied TB-affected households' hidden costs and their association with adverse TB outcome to create a clinically relevant definition of catastrophic costs. METHODS AND FINDINGS: From 26 October 2002 to 30 November 2009, TB patients (n = 876, 11% with multi-drug-resistant [MDR] TB) and healthy controls (n = 487) were recruited to a prospective cohort study in shantytowns in Lima, Peru. Patients were interviewed prior to and every 2-4 wk throughout treatment, recording direct (household expenses) and indirect (lost income) TB related costs. Costs were expressed as a proportion of the household's annual income. In poorer households, costs were lower but constituted a higher proportion of the household's annual income: 27% (95% CI = 20%-43%) in the least poor houses versus 48% (95% CI = 36%-50%) in the poorest. Adverse TB outcome was defined as death, treatment abandonment or treatment failure during therapy, or recurrence within 2 y. 23% (166/725) of patients with a defined treatment outcome had an adverse outcome. Total costs >=20% of household annual income was defined as catastrophic because this threshold was most strongly associated with adverse TB outcome. Catastrophic costs were incurred by 345 households (39%). Having MDR TB was associated with a higher likelihood of incurring catastrophic costs (54% [95% CI = 43%-61%] versus 38% [95% CI = 34%-41%], p<0.003). Adverse outcome was independently associated with MDR TB (odds ratio [OR] = 8.4 [95% CI = 4.7-15], p<0.001), previous TB (OR = 2.1 [95% CI = 1.3-3.5], p = 0.005), days too unwell to work pre-treatment (OR = 1.01 [95% CI = 1.00-1.01], p = 0.02), and catastrophic costs (OR = 1.7 [95% CI = 1.1-2.6], p = 0.01). The adjusted population attributable fraction of adverse outcomes explained by catastrophic costs was 18% (95% CI = 6.9%-28%), similar to that of MDR TB (20% [95% CI = 14% 25%]). Sensitivity analyses demonstrated that existing catastrophic costs thresholds (>=10% or >=15% of household annual income) were not associated with adverse outcome in our setting. Study limitations included not measuring certain "dis-saving" variables (including selling household items) and gathering only 6 mo of costs-specific follow-up data for MDR TB patients. CONCLUSIONS: Despite free TB care, having TB disease was expensive for impoverished TB patients in Peru. Incurring higher relative costs was associated with adverse TB outcome. The population attributable fraction indicated that catastrophic costs and MDR TB were associated with similar proportions of adverse outcomes. Thus TB is a socioeconomic as well as infectious problem, and TB control interventions should address both the economic and clinical aspects of this disease. Please see later in the article for the Editors' Summary. PMID- 25025332 TI - Dissecting virus entry: replication-independent analysis of virus binding, internalization, and penetration using minimal complementation of beta galactosidase. AB - Studies of viral entry into host cells often rely on the detection of post-entry parameters, such as viral replication or the expression of a reporter gene, rather than on measuring entry per se. The lack of assays to easily detect the different steps of entry severely hampers the analysis of this key process in virus infection. Here we describe novel, highly adaptable viral entry assays making use of minimal complementation of the E. coli beta-galactosidase in mammalian cells. Enzyme activity is reconstituted when a small intravirion peptide (alpha-peptide) is complementing the inactive mutant form DeltaM15 of beta-galactosidase. The method allows to dissect and to independently detect binding, internalization, and fusion of viruses during host cell entry. Here we use it to confirm and extend current knowledge on the entry process of two enveloped viruses: vesicular stomatitis virus (VSV) and murine hepatitis coronavirus (MHV). PMID- 25025333 TI - Genetic targets of hydrogen sulfide in ventilator-induced lung injury--a microarray study. AB - Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection. PMID- 25025334 TI - Imidacloprid alters foraging and decreases bee avoidance of predators. AB - Concern is growing over the effects of neonicotinoid pesticides, which can impair honey bee cognition. We provide the first demonstration that sublethal concentrations of imidacloprid can harm honey bee decision-making about danger by significantly increasing the probability of a bee visiting a dangerous food source. Apis cerana is a native bee that is an important pollinator of agricultural crops and native plants in Asia. When foraging on nectar containing 40 ug/L (34 ppb) imidacloprid, honey bees (Apis cerana) showed no aversion to a feeder with a hornet predator, and 1.8 fold more bees chose the dangerous feeder as compared to control bees. Control bees exhibited significant predator avoidance. We also give the first evidence that foraging by A. cerana workers can be inhibited by sublethal concentrations of the pesticide, imidacloprid, which is widely used in Asia. Compared to bees collecting uncontaminated nectar, 23% fewer foragers returned to collect the nectar with 40 ug/L imidacloprid. Bees that did return respectively collected 46% and 63% less nectar containing 20 ug/L and 40 ug/L imidacloprid. These results suggest that the effects of neonicotinoids on honey bee decision-making and other advanced cognitive functions should be explored. Moreover, research should extend beyond the classic model, the European honey bee (A. mellifera), to other important bee species. PMID- 25025335 TI - Atomic layer deposition of a high-k dielectric on MoS2 using trimethylaluminum and ozone. AB - We present an Al2O3 dielectric layer on molybdenum disulfide (MoS2), deposited using atomic layer deposition (ALD) with ozone/trimethylaluminum (TMA) and water/TMA as precursors. The results of atomic force microscopy and low-energy ion scattering spectroscopy show that using TMA and ozone as precursors leads to the formation of uniform Al2O3 layers, in contrast to the incomplete coverage we observe when using TMA/H2O as precursors. Our Raman and X-ray photoelectron spectroscopy measurements indicate minimal variations in the MoS2 structure after ozone treatment at 200 degrees C, suggesting its excellent chemical resistance to ozone. PMID- 25025336 TI - Combined linkage and association studies show that HLA class II variants control levels of antibodies against Epstein-Barr virus antigens. AB - Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infection is associated with the development of several cancers, including Hodgkin lymphoma (HL). Elevated levels of anti-EBV antibodies have been associated with increased risk of HL. There is growing evidence that genetic factors control the levels of antibodies against EBV antigens. Here, we conducted linkage and association studies to search for genetic factors influencing either anti-viral capsid antigen (VCA) or anti-Epstein Barr nuclear antigen-1 (EBNA-1) IgG levels in a unique cohort of 424 individuals of European origin from 119 French families recruited through a Hodgkin lymphoma (HL) patient. No major locus controlling anti-VCA antibody levels was identified. However, we found that the HLA region influenced anti-EBNA-1 IgG titers. Refined association studies in this region identified a cluster of HLA class II variants associated with anti-EBNA-1 IgG titers (e.g. p = 5*10(-5) for rs9268403). The major allele of rs9268403 conferring a predisposition to high anti-EBNA-1 antibody levels was also associated with an increased risk of HL (p = 0.02). In summary, this study shows that HLA class II variants influenced anti-EBNA-1 IgG titers in a European population. It further shows the role of the same variants in the risk of HL. PMID- 25025340 TI - Condensed tannin changes induced by autoxidation: effect of the initial degree of polymerization and concentration. AB - Condensed tannins are a major class of polyphenols and play an important part in organoleptic properties of beverages. Because of their structure, they are chemically reactive. During food processing, reactions take place, leading to structural changes of the native structures to give modified tannins and pigments. Average degrees of polymerization (DPs) determined by standard depolymerization methods become irrelevant, because bonds created from oxidation are uncleavable. Small-angle X-ray scattering was used to determine the conformation of native and autoxidized tannins and assess the impact of tannins initial DP and concentration on changes induced by autoxidation. Different behaviors were observed: (i) slight increase of the DP when tannins were oxidized in dilute solutions; (ii) increase of the DP with tannins in concentrated solutions, leading to the formation of longer linear chains or branched macromolecules depending on the initial DP. PMID- 25025339 TI - Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5. AB - Fragment-based drug design is one of the most promising approaches for discovering novel and potent inhibitors against therapeutic targets. The first step of the process consists of identifying fragments that bind the protein target. The determination of the fragment binding mode plays a major role in the selection of the fragment hits that will be processed into drug-like compounds. Comparing the binding modes of analogous fragments is a critical task, not only to identify specific interactions between the protein target and the fragment, but also to verify whether the binding mode is conserved or differs according to the fragment modification. While X-ray crystallography is the technique of choice, NMR methods are helpful when this fails. We show here how the ligand observed saturation transfer difference (STD) experiment and the protein-observed 15N-HSQC experiment, two popular NMR screening experiments, can be used to compare the binding modes of analogous fragments. We discuss the application and limitations of these approaches based on STD-epitope mapping, chemical shift perturbation (CSP) calculation and comparative CSP sign analysis, using the human peroxiredoxin 5 as a protein model. PMID- 25025338 TI - Epidemiology of curable sexually transmitted infections among women at increased risk for HIV in northwestern Tanzania: inadequacy of syndromic management. AB - BACKGROUND: Curable, non-viral pathogens account for a significant burden of sexually transmitted infections (STIs), and there is established evidence that STIs increase both HIV acquisition and transmission. We investigated the prevalence, trends, and factors associated with Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum, and the performance of syndromic management, among a cohort of women working in bars, hotels, and other food and recreational facilities near large-scale mines in northwestern Tanzania. METHODS: HIV-negative women aged 18-44 years (N = 966) were enrolled and followed for 12 months in a microbicides feasibility study. We collected sociodemographic and behavioural data, performed clinical examinations, and tested for STIs, at enrolment and 3-monthly. Risk factors for STIs were investigated using logistic regression models with random effects. Sensitivity, specificity and predictive values of syndromic management were calculated. RESULTS: At enrolment, the prevalences of C. trachomatis, N. gonorrhoeae, T. vaginalis, and high-titre active syphilis were 111/956 (12%), 42/955 (4%), 184/945 (19%) and 46/965 (5%), respectively. There were significant decreases over time for C. trachomatis and T. vaginalis (OR trend per month: 0.94 [95% CI 0.91, 0.97]; and 0.95 [0.93, 0.98], respectively; both p<0.001). The majority of these infections were not diagnosed by the corresponding syndrome; therefore, most participants were not treated at the diagnosis visit. Syndromic management was poorly predictive of laboratory-diagnosed infections. We identified a number of risk factors for STIs, including low educational level, some sexual behaviours, and ever having been pregnant. CONCLUSIONS: This analysis demonstrates that the prevalences of curable STIs are high among women who work in food and recreational facilities in northwestern Tanzania. Most of these infections are missed by syndromic management. Accurate and affordable rapid-point-of-care tests and innovative interventions are needed to reduce the burden of STIs in this population which is at increased risk for HIV. PMID- 25025341 TI - Quantification of spatially differentiated resource footprints for products and services through a macro-economic and thermodynamic approach. AB - Although natural resources form the basis of our economy, they are not always used in a sustainable way. To achieve a more sustainable economic growth, resource consumption needs to be measured. Therefore, resource footprint frameworks (RFF) are being developed. To easily provide results, these RFF integrate inventory methodologies, at macrolevel mostly input-output (IO) models, with resource accounting methodologies, of which the Ecological Footprint is probably the best known one. The objective of this work is the development of a new RFF, in which a world IO-model (Exiobase), providing a global perspective, is integrated with the CEENE methodology (Cumulative Exergy Extraction from the Natural Environment), offering a more complete resource range: fossil fuels, metals, minerals, nuclear resources, water resources, land resources, abiotic renewable resources, and atmospheric resources. This RFF, called IO-CEENE, allows one to calculate resource footprints for products or services consumed in different countries as the exergy extracted from nature. The way the framework is constructed makes it possible to show which resources and countries contribute to the total footprint. This was illustrated by a case study, presenting the benefits of the framework's worldwide perspective. Additionally, a software file is provided to easily calculate results. PMID- 25025342 TI - Evaluation of different synchrotron beamline configurations for X-ray fluorescence analysis of environmental samples. AB - Synchrotron radiation X-ray fluorescence (SR-XRF) is a powerful elemental analysis tool, yet synchrotrons are large, multiuser facilities that are generally not amenable to modification. However, the X-ray beamlines from synchrotrons can be modified by simply including X-ray filters or removing monochromators to improve the SR-XRF analysis. In this study, we evaluated four easily applied beamline configurations for the analysis of three representative environmental samples, namely a thin aerosol sample, an intermediate thickness biological sample, and a thick rare earth mineral specimen. The results showed that the "white beam" configuration, which was simply the full, polychromatic output of the synchrotron, was the optimal configuration for the analysis of thin samples with little mass. The "filtered white beam" configuration removed the lower energy X-rays from the excitation beam so it gave better sensitivity for elements emitting more energetic X-rays. The "filtered white beam-filtered detector" configuration sacrifices the lower energy part of the spectrum (<15 keV) for improved sensitivity in the higher end (~26 to 48 keV range). The use of a monochromatic beam, which tends to be the standard mode of operation for most SR-XRF analyses reported in the literature, gave the least sensitive analysis. PMID- 25025343 TI - N-heterocyclic carbene-assisted, bis(phosphine)nickel-catalyzed cross-couplings of diarylborinic acids with aryl chlorides, tosylates, and sulfamates. AB - Efficient bis(phosphine)nickel-catalyzed cross-couplings of diarylborinic acids with aryl chlorides, tosylates, and sulfamates have been effected with an assistance of N-heterocyclic carbene (NHC) generated in situ from N,N' dialkylimidazoliums, e.g., N-butyl-N'-methylimidazolium bromide ([Bmim]Br), in toluene using K3PO4.3H2O as base. In contrast to bis(NHC)nickel-catalyzed conventional Suzuki coupling of arylboronic acids, mono(NHC)bis(phosphine)nickel species generated in situ from Ni(PPh3)2Cl2/[Bmim]Br displayed high catalytic activities in the cross-couplings of diarylborinic acids. The structural influences from diarylborinic acids were found to be rather small, while electronic factors from aryl chlorides, tosylates, and sulfamates affected the couplings remarkably. The couplings of electronically activated aryl chlorides, tosylates, and sulfamates could be efficiently effected with 1.5 mol % NiCl2(PPh3)2/[Bmim]Br as catalyst precursor to give the biaryl products in excellent yields, while 3-5 mol % loadings had to be used for the couplings of non- and deactivated ones. A small ortho-substitutent on the aromatic ring of aryl chlorides, tosylates, and sulfamates was tolerable. Applicability of the nickel-catalyzed cross-couplings in practical synthesis of fine chemicals has been demonstrated in process development for a third-generation topical retinoid, Adapalene. PMID- 25025344 TI - Seasonal incidence of medically attended respiratory syncytial virus infection in a community cohort of adults >=50 years old. AB - BACKGROUND: Diagnostic testing for respiratory syncytial virus (RSV) is not routinely performed in adults. We estimated medically attended RSV seasonal incidence in a community cohort of adults >=50 years old during four influenza seasons (2006-07 through 2009-10). METHODS: Patients seeking care for acute respiratory illness (ARI) were prospectively enrolled and tested for RSV by multiplex RT-PCR. Results from enrolled patients were used to estimate projected cases among non-enrolled patients with ARI. The seasonal incidence of medically attended RSV was the sum of actual and projected cases divided by the community cohort denominator. Since each enrollment period did not include the entire RSV season, incidence estimates were adjusted to account for the statewide proportion of RSV occurring outside the study enrollment period. RESULTS: There were 16,088 to 17,694 adults in the cohort each season and 164 RSV cases in all 4 seasons. The overall seasonal incidence of medically attended RSV was 154 episodes (95% CI, 132-180) per 10,000 persons; the incidence was highest in 2007-08 (179) and lowest in 2006-07 (110). Among persons 50-59, 60-69, and >=70 years old, RSV incidence was 124 (95% CI, 99-156), 147 (95% CI, 110-196), and 199 (95% CI, 153 258), respectively. CONCLUSIONS: The incidence of medically attended RSV increased with age and was similar during four seasons. PMID- 25025345 TI - Electric field-modulated non-ohmic behavior of carbon nanotube fibers in polar liquids. AB - We report a previously unseen non-ohmic effect in which the resistivity of carbon nanotube fibers immersed in polar liquids is modulated by the applied electric field. This behavior depends on the surface energy, dielectric constant, and viscosity of the immersion media. Supported by synchrotron SAXS and impedance spectroscopy, we propose a model in which the gap distance, and thus the conductance, of capacitive interbundle junctions is controlled by the applied field. PMID- 25025346 TI - Indication alerts intercept drug name confusion errors during computerized entry of medication orders. AB - BACKGROUND: Confusion between similar drug names is a common cause of potentially harmful medication errors. Interventions to prevent these errors at the point of prescribing have had limited success. The purpose of this study is to measure whether indication alerts at the time of computerized physician order entry (CPOE) can intercept drug name confusion errors. METHODS AND FINDINGS: A retrospective observational study of alerts provided to prescribers in a public, tertiary hospital and ambulatory practice with medication orders placed using CPOE. Consecutive patients seen from April 2006 through February 2012 were eligible if a clinician received an indication alert during ordering. A total of 54,499 unique patients were included. The computerized decision support system prompted prescribers to enter indications when certain medications were ordered without a coded indication in the electronic problem list. Alerts required prescribers either to ignore them by clicking OK, to place a problem in the problem list, or to cancel the order. Main outcome was the proportion of indication alerts resulting in the interception of drug name confusion errors. Error interception was determined using an algorithm to identify instances in which an alert triggered, the initial medication order was not completed, and the same prescriber ordered a similar-sounding medication on the same patient within 5 minutes. Similarity was defined using standard text similarity measures. Two clinicians performed chart review of all cases to determine whether the first, non-completed medication order had a documented or non-documented, plausible indication for use. If either reviewer found a plausible indication, the case was not considered an error. We analyzed 127,458 alerts and identified 176 intercepted drug name confusion errors, an interception rate of 0.14+/-.01%. CONCLUSIONS: Indication alerts intercepted 1.4 drug name confusion errors per 1000 alerts. Institutions with CPOE should consider using indication prompts to intercept drug name confusion errors. PMID- 25025347 TI - Inhaled interferon: a novel treatment for virus-induced asthma? PMID- 25025348 TI - The lipidome: a new player in chronic obstructive pulmonary disease pathophysiology? PMID- 25025349 TI - A new player in the game: epithelial cathepsin S in early cystic fibrosis lung disease. PMID- 25025350 TI - Ivacaftor: from bench to bedside... and back again. PMID- 25025351 TI - Wnt/beta-catenin and transforming growth factor-beta signaling in pulmonary fibrosis. A case for antagonistic pleiotropy? PMID- 25025352 TI - Pulmonary hypertension due to fibrotic lung disease: hidden value in a neutral trial. PMID- 25025353 TI - Sleep apnea and diabetes: good friends or something more? PMID- 25025354 TI - Endobronchial tuberculosis with anthracofibrosis. PMID- 25025355 TI - Neural respiratory drive and ventilation in patients with chronic obstructive pulmonary disease during sleep. PMID- 25025356 TI - Nuclear magnetic resonance-based metabolomics discriminates primary ciliary dyskinesia from cystic fibrosis. PMID- 25025357 TI - Inferior vena cava diameter may be misleading in detecting central venous pressure elevation induced by acute pulmonary hypertension. PMID- 25025358 TI - Patients with asthma demonstrate airway inflammation after exposure to concentrated ambient particulate matter. PMID- 25025359 TI - Practice guideline for pulmonary hypertension in sickle cell: direct evidence needed before universal adoption. PMID- 25025360 TI - Reply: Practice guideline for pulmonary hypertension in sickle cell: direct evidence needed before universal adoption. PMID- 25025361 TI - Vertebral erosion: an uncommon complication of tracheal tubes. PMID- 25025362 TI - Bronchial chloroma. PMID- 25025363 TI - Characterization of a meso-chiral isomer of a hexanuclear Cu(II) cage from racemization of the L-alanine Schiff base. AB - We are reporting structural characterization of two new hexanuclear cages (H3O)2[Cu3(MU3-OH)(MU3-NH3)(0.5)(L)3]2.8H2O (1) and (H3O)2[Cu3(MU3-OH)(MU3 H2O)(0.5)(L)3]2.8H2O (1a) where L(2-) is the dianionic form of the Schiff base of L-alanine and salicylaldehyde. The complex 1 has two C3 symmetric hydroxo bridged trinuclear halves joined by an ammonia or water molecule at the center through H bonding. Each of the trinuclear halves is enantiopure but of opposite chirality to the other half, making the hexanuclear unit a meso isomer. Temperature dependent magnetic measurements showed the presence of ferromagnetic interactions among trinuclear Cu(II) units, a rare occurrence among trinuclear Cu(II) complexes. Characterization of the LiHL showed it to be enantiopure. Addition of a base, monitored using optical rotation, showed that racemization occurs as a result of base addition. The racemization depends on the base as well as the temperature. Base or Cu(II) induced racemization of amino acid derivatives has been indicated in a number of cases in the past but structural characterization of the products or formation of this type of chiral hexanuclear architecture was never reported. Structures of the complex and the ligand have a number of interesting H-bonding situations. PMID- 25025364 TI - Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the International Society of Urological Pathology consensus conference. AB - Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology. PMID- 25025365 TI - Thecoma of the ovary: a report of 70 cases emphasizing aspects of its histopathology different from those often portrayed and its differential diagnosis. AB - Seventy thecomas of the ovary were evaluated to ascertain their histopathologic spectrum. The tumors occurred over a wide age range (average 49.6 y). Presentation in the form of pelvic or abdominal pain was uncommon, but postmenopausal bleeding was relatively frequent. All the tumors were unilateral, ranging up to 22.5 cm (average 4.9 cm) in greatest dimension. They were typically intact, uniformly solid, and yellow. Microscopic examination usually showed a predominant diffuse growth but was altered to varying degrees by hyaline plaques (37 cases), nodular growth (20 cases), calcification (20 cases), and keloid-like sclerosis (12 cases). Forty percent of the tumors had a minor component of fibroma. Reticulin stains typically showed an investment of single cells. The tumor cells characteristically had ill-defined cytoplasmic membranes and distinctive pale gray cytoplasm. Two tumors had degenerative so-called bizarre atypia. Fifteen tumors had nuclear grooves, but they were rarely conspicuous. The differential diagnosis is primarily with other sex cord-stromal neoplasms, particularly sclerosing stromal tumor, microcystic stromal tumor, steroid cell tumor, and adult granulosa cell tumor. The nodules of the first have a more heterogenous morphology than the uniform cell type of thecomas, and microcystic stromal tumors are distinguished because of microcysts and differing character of the tumor cells. Steroid cell tumors also have contrasting cytoplasmic features. Granulosa cell tumor with a prominent thecomatous component is the most clinically important differential and is largely solved by thorough sampling. Our experience indicates a relatively distinctive appearance of thecomas, which contrasts with the lipid-rich character often emphasized in the literature. Awareness of this and a spectrum of other findings should enable accurate interpretation of an almost invariably benign tumor. PMID- 25025366 TI - Glandular neoplasms of the urachus: a report of 55 cases emphasizing mucinous cystic tumors with proposed classification. AB - Published experience remains limited for glandular neoplasms of the urachus, especially mucinous cystic tumors. We reviewed 55 glandular urachal neoplasms to evaluate their clinical features and histopathologic spectrum and to devise a classification system for the mucinous cystic forms. Within the 55 cases studied, we observed 2 groups with differing clinical, gross, and histopathologic features. The first group, invasive, noncystic adenocarcinomas (n=24), had clinicopathologic features in accord with the known spectrum of urachal adenocarcinoma (mean age 50 y, female:male ratio 1.7, with recurrence or death from disease in 9/16 cases over a 45 mo mean follow-up). The second group, mucinous cystic tumors (n=31), morphologically resembled mucinous cystic tumors of the ovary and appeared classifiable by the same approach (mean age 47 y, female:male ratio 1.4) and included mucinous cystadenoma (n=4), mucinous cystic tumor of low malignant potential (n=22, including 2 cases with intraepithelial carcinoma), and mucinous cystadenocarcinoma with microscopic (n=4) or frank invasion (n=1). Follow-up information was available for 13 patients with mucinous cystic tumors (mean 41 mo); we observed no local recurrence or distant metastasis. This experience suggests that there is a distinct group of glandular, cystic tumors of the urachus that is classifiable in a manner similar to ovarian neoplasms and that has a favorable prognosis after complete excision. As with cystic neoplasms of other organs, rigorous sampling is recommended to identify potentially small foci of carcinoma that could be missed by inadequate sampling. Accordingly, classification based on methods other than complete surgical excision may be hazardous. PMID- 25025367 TI - Observations on the paper "sclerosing Sertoli cell tumor of the testis: a clinicopathologic study of 20 cases" by Kao et al. PMID- 25025368 TI - Best practices recommendations in the application of immunohistochemistry in the kidney tumors: report from the International Society of Urologic Pathology consensus conference. AB - Primary renal neoplasms comprise multiple distinct entities, some of which are well understood and others that are not. It is not uncommon for some of these entities to have overlapping morphologic features. Their clinical behavior is varied, ranging from highly malignant to benign, and metastatic renal cell carcinoma oftentimes enters into the differential diagnosis of tumors of unknown primary. In this age of personalized medicine, identifying biomarkers that can better predict clinical outcome and response to therapy is a pressing need. In 2013 the International Society of Urological Pathology held a meeting in which best practices recommendations on the use of immunohistochemical markers in urologic malignancies were discussed. In this review we make recommendations regarding immunohistochemical markers that are best suited to aid in establishing a diagnosis of renal primary, panels of antibodies that are most useful in classifying renal tumors, and the current status of prognostic and predictive biomarkers. Although no prognostic or predictive marker and set of markers have yet to be validated, ongoing research suggests that this fact is likely to change in the near future. PMID- 25025369 TI - Myelomastocytic leukemia: histopathological features, diagnostic criteria and differential diagnosis. AB - Myelomastocytic leukemia (MML) is an extremely rare myeloid overlap-neoplasm that belongs to the group of tryptase-positive (T+) myeloid neoplasms. Main differential diagnoses include aggressive systemic mastocytosis (ASM), in particular ASM in transformation; mast cell leukemia; T+ acute myeloid leukemia (T+ AML); acute basophilic leukemia and chronic basophilic leukemia. MML exhibits both proliferative and dysplastic features and is characterized by prominent differentiation into the mast cell lineage in an advanced myeloid neoplasm, usually primary or secondary AML. While the histological key feature of MML is a diffuse increase in neoplastic cells expressing mast cell-related antigens like tryptase and CD117 (KIT), the most important cytomorphological finding in bone marrow (BM) and peripheral blood (PB) is the metachromatically granulated blast cell (= metachromatic blast). In contrast to systemic mastocytosis (SM), MML neither shows activating point mutations at codon 816 of KIT nor the aberrant expression of CD25 by mast cells is seen. MML can only be diagnosed when tryptase staining is performed on BM biopsy specimens, PB and BM smears are investigated for presence of metachromatic blasts and other T+ leukemias have been excluded. PMID- 25025371 TI - Conditioning regimens in acute myeloid leukemia. AB - Current intensive consolidation chemotherapy for patients with acute myeloid leukemia (AML) produces median remission duration of 12-18 months, with less than 30% of patients surviving 5 years free of disease. Post-remission therapy is necessary to prevent relapse in most patients with AML; therefore, the aim of post-remission treatment is to eradicate the minimal residual disease. Nevertheless, the optimal form of treatment is still under debate. The choice among the possible approaches (intensive chemotherapy, autologous or allogeneic hematopoietic stem cell transplantation) relies on two main factors: the expected risk of relapse, as determined by biological features, and expected morbidity and mortality associated with a specific option. In this review, we focus on the different preparative regimens before autologous and allogeneic hematopoietic stem cell transplantation in patients with AML, stressing the importance of an adequate conditioning regimen as a mandatory element of a successful AML therapy, in both the allogeneic and the autologous transplant setting. PMID- 25025372 TI - Targeted therapies for cutaneous T-cell lymphomas. AB - Cutaneous T-cell lymphomas (CTCLs) comprise a clinicopathologically heterogeneous group of uncommon non-Hodgkin lymphomas that manifest primarily in the skin but also may involve lymph nodes, blood, bone marrow and viscera. CTCLs are generally considered incurable unless allogeneic stem cell transplantation is implemented. Goals of therapy are to control symptoms, maintain cosmesis and improve survival by maximally reducing the tumor burden. Current treatment consists of skin directed therapy for early stage disease and systemic therapy for advanced stage or refractory early stage disease. Despite the availability of a number of active systemic therapeutic strategies, including biological therapy, cytotoxic chemotherapy and extracorporeal photophoresis, there is an unmet need for targeted therapies, with favorable therapeutic indices, for the treatment of advanced and refractory CTCLs, which often render patients highly susceptible to infection. This review will discuss targeted therapy for the two most extensively studied subtypes of CTCL, mycosis fungoides and Sezary syndrome. PMID- 25025373 TI - Anemia in chronic kidney disease patients: treatment recommendations and emerging therapies. AB - Erythropoiesis-stimulating agents (ESA) and iron have been available since decades to treat anemia of chronic kidney disease (CKD). However, many grey areas surround the field. The optimal hemoglobin (Hb) target to aimed at with ESA, the general safety of ESA and boundaries to not be exceeded with iron supplementation are still to be clearly defined. New strategies to stimulate erythropoiesis and new iron molecules have been developed; the most promising approach is the manipulation of the hypoxia-inducible transcription factor (HIF) system. The regulation of activin A pathway is another option with good potential, also considering the additional advantage of increasing bone mass. New iron molecule for intravenous administration may be useful to reduce the number of doses to be administered. PMID- 25025374 TI - Robust Radiomics feature quantification using semiautomatic volumetric segmentation. AB - Due to advances in the acquisition and analysis of medical imaging, it is currently possible to quantify the tumor phenotype. The emerging field of Radiomics addresses this issue by converting medical images into minable data by extracting a large number of quantitative imaging features. One of the main challenges of Radiomics is tumor segmentation. Where manual delineation is time consuming and prone to inter-observer variability, it has been shown that semi automated approaches are fast and reduce inter-observer variability. In this study, a semiautomatic region growing volumetric segmentation algorithm, implemented in the free and publicly available 3D-Slicer platform, was investigated in terms of its robustness for quantitative imaging feature extraction. Fifty-six 3D-radiomic features, quantifying phenotypic differences based on tumor intensity, shape and texture, were extracted from the computed tomography images of twenty lung cancer patients. These radiomic features were derived from the 3D-tumor volumes defined by three independent observers twice using 3D-Slicer, and compared to manual slice-by-slice delineations of five independent physicians in terms of intra-class correlation coefficient (ICC) and feature range. Radiomic features extracted from 3D-Slicer segmentations had significantly higher reproducibility (ICC = 0.85+/-0.15, p = 0.0009) compared to the features extracted from the manual segmentations (ICC = 0.77+/-0.17). Furthermore, we found that features extracted from 3D-Slicer segmentations were more robust, as the range was significantly smaller across observers (p = 3.819e 07), and overlapping with the feature ranges extracted from manual contouring (boundary lower: p = 0.007, higher: p = 5.863e-06). Our results show that 3D Slicer segmented tumor volumes provide a better alternative to the manual delineation for feature quantification, as they yield more reproducible imaging descriptors. Therefore, 3D-Slicer can be employed for quantitative image feature extraction and image data mining research in large patient cohorts. PMID- 25025375 TI - Identification of pre-erythrocytic malaria antigens that target hepatocytes for killing in vivo and contribute to protection elicited by whole-parasite vaccination. AB - Pre-erythrocytic malaria vaccines, including those based on whole-parasite approaches, have shown protective efficacy in animal and human studies. However few pre-erythocytic antigens other than the immunodominant circumsporozoite protein (CSP) have been studied in depth with the goal of developing potent subunit malaria vaccines that are suited for use in endemic areas. Here we describe a novel technique to identify pre-erythrocytic malaria antigens that contribute to protection elicited by whole-parasite vaccination in the mouse model. Our approach combines immunization with genetically attenuated parasites and challenge with DNA plasmids encoding for potential protective pre erythrocytic malaria antigens as luciferase fusions by hydrodynamic tail vein injection. After optimizing the technique, we first showed that immunization with Pyfabb/f-, a P. yoelii genetically attenuated parasite, induces killing of CSP presenting hepatocytes. Depletion of CD8+ but not CD4+ T cells diminished the killing of CSP-expressing hepatocytes, indicating that killing is CD8+ T cell dependent. Finally we showed that the use of heterologous prime/boost immunization strategies that use genetically attenuated parasites and DNA vaccines enabled the characterization of a novel pre-erythrocytic antigen, Tmp21, as a contributor to Pyfabb/f- induced protection. This technique will be valuable for identification of potentially protective liver stage antigens and has the potential to contribute to the understanding of immunity elicited by whole parasite vaccination, as well as the development of effective subunit malaria vaccines. PMID- 25025370 TI - Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic. AB - Many patients with acute myeloid leukemia will eventually develop refractory or relapsed disease. In the absence of standard therapy for this population, there is currently an urgent unmet need for novel therapeutic agents. Targeted therapy with small molecule inhibitors represents a new therapeutic intervention that has been successful for the treatment of multiple tumors (e.g., gastrointestinal stromal tumors, chronic myelogenous leukemia). Hence, there has been great interest in generating selective small molecule inhibitors targeting critical pathways of proliferation and survival in acute myeloid leukemia. This review highlights a selective group of intriguing therapeutic agents and their presumed targets in both preclinical models and in early human clinical trials. PMID- 25025376 TI - tropiTree: an NGS-based EST-SSR resource for 24 tropical tree species. AB - The development of genetic tools for non-model organisms has been hampered by cost, but advances in next-generation sequencing (NGS) have created new opportunities. In ecological research, this raises the prospect for developing molecular markers to simultaneously study important genetic processes such as gene flow in multiple non-model plant species within complex natural and anthropogenic landscapes. Here, we report the use of bar-coded multiplexed paired end Illumina NGS for the de novo development of expressed sequence tag-derived simple sequence repeat (EST-SSR) markers at low cost for a range of 24 tree species. Each chosen tree species is important in complex tropical agroforestry systems where little is currently known about many genetic processes. An average of more than 5,000 EST-SSRs was identified for each of the 24 sequenced species, whereas prior to analysis 20 of the species had fewer than 100 nucleotide sequence citations. To make results available to potential users in a suitable format, we have developed an open-access, interactive online database, tropiTree (http://bioinf.hutton.ac.uk/tropiTree), which has a range of visualisation and search facilities, and which is a model for the efficient presentation and application of NGS data. PMID- 25025377 TI - Processive DNA demethylation via DNA deaminase-induced lesion resolution. AB - Base modifications of cytosine are an important aspect of chromatin biology, as they can directly regulate gene expression, while DNA repair ensures that those modifications retain genome integrity. Here we characterize how cytosine DNA deaminase AID can initiate DNA demethylation. In vitro, AID initiated targeted DNA demethylation of methyl CpGs when in combination with DNA repair competent extracts. Mechanistically, this is achieved by inducing base alterations at or near methyl-cytosine, with the lesion being resolved either via single base substitution or a more efficient processive polymerase dependent repair. The biochemical findings are recapitulated in an in vivo transgenic targeting assay, and provide the genetic support of the molecular insight into DNA demethylation. This targeting approach supports the hypothesis that mCpG DNA demethylation can proceed via various pathways and mCpGs do not have to be targeted to be demethylated. PMID- 25025379 TI - Geospatial analysis on the distributions of tobacco smoking and alcohol drinking in India. AB - BACKGROUND: Tobacco smoking and binge alcohol drinking are two of the leading risk factors for premature mortality worldwide. In India, studies have examined the geographic distributions of tobacco smoking and alcohol drinking only at the state-level; sub-state variations and the spatial association between the two consumptions are poorly understood. METHODOLOGY: We used data from the Special Fertility and Mortality Survey conducted in 1998 to examine the geographic distributions of tobacco smoking and alcohol drinking at the district and postal code levels. We used kriging interpolation to generate smoking and drinking distributions at the postal code level. We also examined spatial autocorrelations and identified spatial clusters of high and low prevalence of smoking and drinking. Finally, we used bivariate analyses to examine the spatial correlations between smoking and drinking, and between cigarette and bidi smoking. RESULTS: There was a high prevalence of any smoking in the central and northeastern states, and a high prevalence of any drinking in Himachal Pradesh, Arunachal Pradesh, and eastern Madhya Pradesh. Spatial clusters of early smoking (started smoking before age 20) were identified in the central states. Cigarette and bidi smoking showed distinctly different geographic patterns, with high levels of cigarette smoking in the northeastern states and high levels of bidi smoking in the central states. The geographic pattern of bidi smoking was similar to early smoking. Cigarette smoking was spatially associated with any drinking. Smoking prevalences in 1998 were correlated with prevalences in 2004 at the district level and 2010 at the state level. CONCLUSION: These results along with earlier evidence on the complementarities between tobacco smoking and alcohol drinking suggest that local public health action on smoking might also help to reduce alcohol consumption, and vice versa. Surveys that properly represent tobacco and alcohol consumptions at the district level are recommended. PMID- 25025378 TI - ERCC1 Cys8092Ala and XRCC1 Arg399Gln polymorphisms predict progression-free survival after curative radiotherapy for nasopharyngeal carcinoma. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) in DNA repair genes can alter gene expression and activity and affect response to cancer treatment and, correspondingly, survival. The present study was designed to evaluate the utility of the XRCC1 Arg399Gln and ERCC1 Cys8092Ala SNPs, measured in pretreatment biopsy samples, as predictors of response to radiotherapy in patients with non metastatic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: The study included 75 consecutive patients with stage II-IVA-B NPC. XRCC1 Arg399Glu and ERCC1 Cys8092Ala SNPs were identified from paraffin-embedded biopsy specimens via Sanger sequencing. Expression of p53 and pAkt protein was analyzed by immunohistochemical staining. Potential relationships between genetic polymorphisms and progression-free survival (PFS) were analyzed by using a Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. RESULTS: Multivariate analysis showed that carriers of the ERCC1 8092 Ala/Ala genotype [hazard ratio (HR) 1.882; 95% confidence interval (CI) 1.031-3.438; P = 0.039] and heavy smokers (>=20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR 2.019; 95% CI 1.010-4.036; P = 0.047) had significantly lower PFS rates. Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR 7.057; 95% CI 2.073 24.021; P = 0.002) or the ERCC1 Cys allele (HR 2.568; 95% CI 1.056-6.248; P = 0.038). CONCLUSIONS: The ERCC1 Cys8092Ala polymorphism is an independent predictor of response to radiotherapy for NPC, and the XRCC1 Arg399Glu mutation combined with smoking status seems to predict PFS as well. Our results further suggest a possible correlation between these genetic polymorphisms and p53 protein status on survival. PMID- 25025380 TI - Effects of an oxycodone conjugate vaccine on oxycodone self-administration and oxycodone-induced brain gene expression in rats. AB - Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination. PMID- 25025381 TI - Adipose tissue-derived mesenchymal stem cells in long-term dialysis patients display downregulation of PCAF expression and poor angiogenesis activation. AB - We previously demonstrated that mesenchymal stem cells (MSCs) differentiate into functional kidney cells capable of urine and erythropoietin production, indicating that they may be used for kidney regeneration. However, the viability of MSCs from dialysis patients may be affected under uremic conditions. In this study, we isolated MSCs from the adipose tissues of end-stage kidney disease (ESKD) patients undergoing long-term dialysis (KD-MSCs; mean: 72.3 months) and from healthy controls (HC-MSCs) to compare their viability. KD-MSCs and HC-MSCs were assessed for their proliferation potential, senescence, and differentiation capacities into adipocytes, osteoblasts, and chondrocytes. Gene expression of stem cell-specific transcription factors was analyzed by PCR array and confirmed by western blot analysis at the protein level. No significant differences of proliferation potential, senescence, or differentiation capacity were observed between KD-MSCs and HC-MSCs. However, gene and protein expression of p300/CBP associated factor (PCAF) was significantly suppressed in KD-MSCs. Because PCAF is a histone acetyltransferase that mediates regulation of hypoxia-inducible factor 1alpha (HIF-1alpha), we examined the hypoxic response in MSCs. HC-MSCs but not KD MSCs showed upregulation of PCAF protein expression under hypoxia. Similarly, HIF 1alpha and vascular endothelial growth factor (VEGF) expression did not increase under hypoxia in KD-MSCs but did so in HC-MSCs. Additionally, a directed in vivo angiogenesis assay revealed a decrease in angiogenesis activation of KD-MSCs. In conclusion, long-term uremia leads to persistent and systematic downregulation of PCAF gene and protein expression and poor angiogenesis activation of MSCs from patients with ESKD. Furthermore, PCAF, HIF-1alpha, and VEGF expression were not upregulated by hypoxic stimulation of KD-MSCs. These results suggest that the hypoxic response may be blunted in MSCs from ESKD patients. PMID- 25025382 TI - Epithelial-Myoepithelial Carcinoma of the Lacrimal Gland 14 Years After En Bloc Resection of a Pleomorphic Lacrimal Gland Adenoma. AB - Fourteen years after en bloc resection of an orbital pleomorphic adenoma, a 61 year-old female patient developed progressive left proptosis on the same side. A CT scan revealed a round, well-circumscribed, heterogeneously enhancing mass in the lacrimal fossa of the left orbit without calcification or bone erosion. An MRI scan showed a lesion that was hypointense on T1-weighted images and heterogeneously isointense on T2-weighted images. The tumor was completely resected through combined anterior and lateral orbitotomy. On histopathology, the specimen was identified as epithelial-myoepithelial carcinoma. After surgery, the patient received adjuvant therapy with irradiation of the orbit. At a 36-month follow-up evaluation, the patient remained tumor-free. Epithelial-myoepithelial carcinoma, a very uncommon tumor of the orbit, apparently behaves like a low grade malignancy and is associated with good survival rates. However, a good prognosis for survival is tentative at best, in part because of the rarity of the lesion. PMID- 25025383 TI - Fibrovascular ingrowth into porous polyethylene orbital implants (Medpor) after modified evisceration. AB - PURPOSE: To evaluate, using MRI, the extent and pattern of fibrovascular ingrowth into Medpor implants after modified evisceration. METHODS: Contrast T1-weighted images were performed in 21 patients within 1.5- to69-month intervals after modified evisceration with primary Medpor implantation. In 6 patients, the images were obtained separately following 1- and 5-minute delays after contrast administration. RESULTS: No grade I enhancement occurred in these series. Grade II was observed in 2 patients (9.09%), grade III in 8 patients (36.36%), grade IV in 9 patients (40.91%), and grade V in 3 patients (13.64%). Significant correlation existed between the grade of enhancement and the postevisceration interval (r = 0.483, p = 0.023 < 0.05). The images demonstrated an enhancement pattern that started at the unwrapped posterior pole and anterior location of rectus muscles with progressive centripetal vascularization toward the center of the implant. At the early stage of recovery, the fibrous connective tissue was thick in front of Medpor spheres. In the 5-minute delay images of 6 patients, 2 patients failed to exhibit further enhancement; 2 patients exhibited enlarged and homogeneous enhancement; and 2 patients revealed more intense enhancement patterns. The medical ethics committee of Zhongshan Ophthalmic Center approved the study. CONCLUSIONS: Fibrovascular ingrowth into Medpor implants was satisfactory after the modified evisceration and correlated with the duration of the implants. The double layers of sclera effectively prevented the implant extrusion and exposure. The authors recommend waiting at least 5 minutes before obtaining MR images after contrast administration. PMID- 25025384 TI - Anatomy of anterior ethmoidal foramen, medial canthal tendon, and lacrimal fossa for transcutaneous anterior ethmoidal nerve block in Japanese individuals. AB - PURPOSE: To examine the anatomical relationships of the anterior ethmoidal foramen (AEF), medial canthal tendon (MCT), and lacrimal fossa (LF) in Japanese individuals. METHODS: Thirty-eight orbits from 19 Japanese cadavers (7 men and 12 women; average age at death, 89.3 years) were used in this experimental anatomical study. The AEF, MCT, and superior border of the LF were exposed. The following distances were then measured: 1) from the point at the medial orbital rim directly anterior to the AEF to the superior border of the MCT (AEF-MCT), and 2) from the superior border of the LF to the superior border of the MCT (LF-MCT). RESULTS: (AEF-MCT) and (LF-MCT) distances were 9.40+/-1.92 (mean+/-standard deviation) and 4.21+/-1.18 mm, respectively. No values of (LF-MCT) exceeded the mean (AEF-MCT) (9.40 mm). CONCLUSIONS: The transcutaneous anterior ethmoidal nerve block can be reliably performed without injury to the lacrimal sac by inserting a needle approximately 9 mm superior to the superior border of the MCT. PMID- 25025385 TI - Injectable 5-FU with or without added steroid in periorbital skin grafting: initial observations. AB - PURPOSE: The authors describe their experience with postoperative injectable 5 fluorouracil (5-FU), with or without added low-dose and concentration steroid, in the particular patient subset undergoing eyelid skin grafting surgery. METHODS: A retrospective chart review (2011-2013) of patients who underwent eyelid skin grafting for various etiologies with adjunctive postoperative 5-FU (50 mg/ml) injections (with or without added kenalog 5 mg/ml) was performed. Injections were given 2 to 3 weeks postsurgery and as frequently as every 2 weeks for a total of up to 4 injections. At each visit, patients were evaluated for redness, swelling, wound healing, scar formation, tissue inflammation/atrophy, telangiectasis, and pigmentary disturbances. Patient interpretation of outcome was determined subjectively by asking if they were satisfied and objectively by their separate responses to specific questions graded on a Likert-type scale. Operating surgeon satisfaction was determined only by subjective clinical evaluation of final results. Finally, a graded evaluation of pre- and postoperative digital photographs by an independent facial plastic surgeon was added to quantitatively evaluate the surgical results. RESULTS: Nineteen patients with an average age of 66 years and follow up of 10 months are included. Surgical indications include reconstruction of cancer excision defects, repair of lower eyelid ectropion or retraction, benign eyelid lesion excision, and effacement of a canthal web. On average, patients had a total of 4 separate 0.3 to 0.5 ml 5-FU, or 5-FU/kenalog injections spaced 2 to 3 weeks apart. In 11 of 19 patients, the 5-FU injections were mixed with steroid. There were no cases of skin thinning, color/texture change, atrophy, telangiectasis, or infection after injection, and all patients had uneventful healing of their grafts. Eighty-nine percent of patients were satisfied with their outcome (graded 4.73/5) and the appearance of the skin graft (graded 4.79/5). In 95% of cases, the surgeon was satisfied with the surgical result. Independent surgeon assessment of outcome was graded (4.58/5). CONCLUSIONS: A 5-FU or 5-FU/kenalog (75%/25%) mixture can be injected safely after eyelid skin grafting surgery. Surgical results are good with minimal scarring, high patient and surgeon satisfaction, and few complications. Results are equally efficacious and complication-free with or without the addition of a steroid component to the injection mixture. PMID- 25025386 TI - Lower eyelid involutional ectropion repair with lateral tarsal strip and internal retractor reattachment with full-thickness eyelid sutures. AB - PURPOSE: To report a novel surgical technique for lower eyelid involutional ectropion repair using a lateral tarsal strip and internal retractor reattachment procedure involving full-thickness eyelid sutures. METHODS: A retrospective review was performed of patients who underwent repair of involutional ectropion via lateral tarsal strip and internal retractor reattachment with full-thickness eyelid sutures by 1 surgeon. Patients having concomitant or previous eyelid surgical procedures were excluded. Collected data included patient demographics, surgical outcomes, and length of follow up. RESULTS: Forty-one lower eyelids of 31 patients with involutional ectropion underwent surgical repair. There were 17 men and 14 women in the age range of 69 to 92 years (mean age 82.2+/-5.9 years). Surgical sites included 22 right and 19 left lower eyelids. Follow up ranged from 1 to 48 months with an average of 5.9 months. Surgical success with anatomical correction of involutional ectropion was achieved in 39 of 41 eyelids (95.1%). There were no perioperative or postoperative complications. Two of 41 (4.9%) eyelids had recurrence of ectropion 7 and 18 months after the procedure. CONCLUSIONS: This procedure combining lateral tarsal strip with internal retractor reattachment involving full-thickness eyelid sutures effectively addresses horizontal eyelid laxity and tarsal instability, providing an effective technique to correct involutional ectropion of the lower eyelid. PMID- 25025387 TI - Orbital Epithelioid Sarcoma: A Case Report. AB - Epithelioid sarcoma is a rare but often aggressive malignancy of soft tissue that usually occurs in young adults as a superficial lesion in the distal upper limbs. To date, there are only 4 case reports of epithelioid sarcoma primarily occurring in the orbit. Two of these patients were treated with primary exenteration only one of whom was alive 3 years after diagnosis. Radical surgical excision is thus the first treatment of choice for primary orbital epithelioid sarcoma. The authors present a patient with primary orbital epithelioid sarcoma who refused exenteration. Surgical debulking followed by local brachytherapy was performed. The patient remains tumor free 5 years after diagnosis. The literature remains limited regarding treatment options for primary orbital epithelioid sarcoma. However, based on reported cases and this case, the authors conclude that surgical excision combined with local iridium radiation therapy is an acceptable treatment when treating primary orbital epithelioid sarcoma. PMID- 25025388 TI - Secondary orbital ball implants after enucleation and evisceration: surgical management, morbidity, and long-term outcome. AB - PURPOSE: To investigate effectiveness of a simplified surgical technique for secondary ball implantation in anophthalmic sockets and to compare long-term results of secondary ball implantation in patients previously enucleated or eviscerated. METHODS: The study is a case series analysis of the clinical charts of 110 consecutive patients who underwent secondary ball implantation after enucleation or evisceration, from January 1998 to December 2011, under the care of 1 surgeon. Patients undergoing primary evisceration and implant exchange were excluded. Primary surgery was due to trauma in 48.8% patients, endophthalmitis and phthisis bulbi in 25.6%, tumors in 22.1%, and orbital vascular malformations in 3.5%. This study adheres to the principles outlined in the Declaration of Helsinki. RESULTS: Of 110 identified cases, 24 were excluded for insufficient follow-up (less than 2 years); mean follow-up was 6.4 years. Group A patients (previously enucleated) received a polyglactin mesh-wrapped implant. Group B patients (previously eviscerated) kept their own sclera as a secondary anterior capping on the polyglactin mesh-wrapped implant. There were 2 implant exposures (4.9%; 2 of 41) in group A. Hard palate graft was used to repair the exposed implant successfully. No exposure was noted in group B. No statistically significant between-group difference in exposure rate was found. CONCLUSIONS: Stable secondary ball implantation can be achieved long term, and a reliable surgical technique is the most important factor in predicting implant stability. In patients who had secondary implants following evisceration, sclera and polyglactin mesh may act as duplicate barriers between anterior surface of implants and overlying tissues. PMID- 25025389 TI - Dermis fat graft implantation after unilateral enucleation for retinoblastoma in pediatric patients. AB - PURPOSE: To evaluate the efficacy of dermis fat graft (DFG) as a primary implant technique in pediatric patients requiring unilateral enucleation due to retinoblastoma. METHODS: A retrospective chart review of 14 consecutive pediatric patients who underwent dermis fat graft implantation after unilateral enucleation for retinoblastoma by 1 surgeon (E.A.S.) was performed to evaluate graft efficacy with regard to orbital volume growth and any associated morbidity. Patients who received chemotherapy or external beam radiation were excluded. Demographic information was recorded. Serial MRIs were used to measure orbital volumes to compare the surgical and contralateral orbits over time. The main outcome measure was the difference in bony orbital volume between enucleated and contralateral, uninvolved orbits. Mann-Whitney U test was used to compare orbital volume measurements between surgical and nonsurgical orbits. Correlation testing was performed to determine the effect of age, sex, and follow-up time on the orbital volume changes. RESULTS: There was no statistical difference between the MRI volume measured for surgical and nonsurgical orbits over time. This was the case at all measured time points and for all ages and genders. All patients were under the age of 4 years at the time of surgery. The median difference in orbital volumes between surgical and nonsurgical orbits was -0.095 cm (range -1.26 to 1.01 cm; quartiles -0.32 to 0.07 cm; mean +/- SD, -0.144 +/- 0.0522 cm; 95% confidence interval, -0.247 to -0.0419 cm). The median follow-up time from surgery date to the most recent clinical examination was 38.5 months (range, 13 to 70 months; quartiles, 28.75 to 45.5 months; mean +/- standard deviation [SD], 38.43 +/- 17.21 months; 95% confidence interval, 29.41 to 47.45 months). CONCLUSIONS: In pediatric patients below 4 years of age with unilateral retinoblastoma treated with enucleation and primary dermis fat graft implantation, there was no statistically significant difference in bony orbital volume between the surgical and nonsurgical orbits during the follow-up period. PMID- 25025390 TI - Tick Infestation of the Eyelid With Histopathologic Characterization. AB - Ocular tick infestation is a rare occurrence. The authors report a case that is unique for being the first published example from New England, for its chronic presentation, and for the inclusion of histopathologic analysis in its diagnostic workup. A 75-year-old man was evaluated for a persistent eyelid growth secondary to an incompletely removed tick that had attached 6 months earlier. The lesion was completely excised, and a partially destroyed arthropod was observed embedded within the tissue. Light microscopy demonstrated a mixed granulomatous reaction. Given the disruption of the tick's anatomy, speciation could not be performed. The patient had an uneventful recovery. A corresponding review of tick bites to the eye is provided. PMID- 25025391 TI - Commentary: rituximab, adalimumab, etanercept, tocilizumab--are biologics the future for Graves' orbitopathy? AB - Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves disease and a rare disease in its severe expressions. Moderate-to-severe GO represents a therapeutic challenge. Established nonsurgical treatments include glucocorticoids (most commonly given intravenously), cyclosporine, and orbital radiotherapy. However, results are not always satisfactory, and a relevant proportion of GO patients need some kind of rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) once GO is inactivated. Biological agents have been used in several autoimmune disorders, with contrasting results. Current better understanding of the pathogenesis of GO allows us to identify pathways that might be the target of biologics. T and B cells, cytokines, and peroxisome proliferator-activated receptor-gamma might all be targeted by treatments. It is extremely difficult to design and perform sufficiently powered randomized controlled studies that may support the role of targeted therapies. For the time being, rituximab, a monoclonal antibody depleting CD20-positive B cells, appears the most promising agent, but so far its use relies on the results of small and uncontrolled studies. PMID- 25025392 TI - A cobalt-NHC complex as an improved catalyst for photochemical hydrogen evolution from water. AB - A macrocyclic N-heterocyclic carbene (NHC)-cobalt complex was found to act as an improved H2-evolving catalyst in a [Ru(bpy)3](2+)-sensitized photosystem using methylviologen as a redox acceptor (MV(2+) + e(-) -> MV(+), MV(2+) = N,N' dimethyl-4,4'-bipyridinium), which provides a driving force of only 150 meV for H2 evolution at pH 5.0. PMID- 25025393 TI - Use of floseal hemostatic matrix for control of hemostasis during laparoscopic cholecystectomy for acute cholecystitis: a multicenter historical control group comparison (the GLA study gelatin matrix for acute cholecystitis). AB - BACKGROUND: In patients with acute cholecystitis undergoing laparoscopic cholecystectomy, bleeding is a common complication that can reduce procedural visibility and worsen outcome. Insufficient hemostasis can also lead to postoperative bleeding that can, in rare cases, be fatal. Topical hemostatic agents are used to ensure adequate hemostasis during laparoscopic cholecystectomy. SUBJECTS AND METHODS: This prospective, open-label, nonrandomized, historical control group study investigated the use of Floseal((r)) (Baxter International, Inc., Deerfield, IL) hemostatic matrix as an adjunct to surgical techniques to achieve hemostasis of the resected areas in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. The primary end point was the rate of complete hemostasis 10 minutes after laparoscopic application of Floseal to the gallbladder bed. Secondary end points included complete hemostasis rates at 2, 4, and 6 minutes, surgery time, laparoscopic procedure to open laparotomy conversion rate, postoperative bleeding rate, and mortality and safety outcomes over the entire follow-up period. RESULTS: From April to November 2011, 101 consecutive patients were enrolled (51 men; mean age, 61.5+/-6.2 years). The historical control group of 100 age- and gender-matched patients with acute cholecystitis had undergone laparoscopic cholecystectomy without hemostatic agent. In the Floseal group, bleeding ceased within 10 minutes after laparoscopic application of the hemostatic agent to the gallbladder bed in all patients. The conversion rate was significantly lower in the Floseal group than in the control group (4 versus 12 patients, P<.05). CONCLUSIONS: Floseal in acute cholecystitis is safe, is effective in controlling bleeding, and results in a lower conversion rate compared with cholecystectomy without hemostatic agents. PMID- 25025394 TI - Mitoquinone restores platelet production in irradiation-induced thrombocytopenia. AB - Myelodysplastic syndromes (MDS) are hallmarked by cytopenia and dysplasia of hematopoietic cells, often accompanied by mitochondrial dysfunction and increases of reactive oxygen species (ROS) within affected cells. However, it is not known whether the increase in ROS production is an instigator or a byproduct of the disease. The present investigation shows that mice lacking immediate early responsive gene X-1 (IEX-1) exhibit lineage specific increases in ROS production and abnormal cytology upon radiation in blood cell types commonly identified in MDS. These affected cell lineages chiefly have the bone marrow as a primary site of differentiation and maturation, while cells with extramedullary differentiation and maturation like B- and T-cells remain unaffected. Increased ROS production is likely to contribute significantly to irradiation-induced thrombocytopenia in the absence of IEX-1 as demonstrated by effective reversal of the disorder after mitoquinone (MitoQ) treatment, a mitochondria-specific antioxidant. MitoQ reduced intracellular ROS production within megakaryocytes and platelets. It also normalized mitochondrial membrane potential and superoxide production in platelets in irradiated, IEX-1 deficient mice. The lineage-specific effects of mitochondrial ROS may help us understand the etiology of thrombocytopenia in association with MDS in a subgroup of the patients. PMID- 25025395 TI - Hyphal growth of phagocytosed Fusarium oxysporum causes cell lysis and death of murine macrophages. AB - Fusarium oxysporum is an important plant pathogen and an opportunistic pathogen of humans. Here we investigated phagocytosis of F. oxysporum by J774.1 murine cell line macrophages using live cell video microscopy. Macrophages avidly migrated towards F. oxysporum germlings and were rapidly engulfed after cell-cell contact was established. F. oxysporum germlings continued hyphal growth after engulfment by macrophages, leading to associated macrophage lysis and escape. Macrophage killing depended on the multiplicity of infection. After engulfment, F. oxysporum inhibited macrophages from completing mitosis, resulting in large daughter cells fused together by means of a F. oxysporum hypha. These results shed new light on the initial stages of Fusarium infection and the innate immune response of the mammalian host. PMID- 25025396 TI - Design and development of an instrument to measure overall lifestyle habits for epidemiological research: the Mediterranean Lifestyle (MEDLIFE) index. AB - OBJECTIVE: To design and develop a questionnaire that can account for an individual's adherence to a Mediterranean lifestyle including the assessment of diet and physical activity patterns, as well as social interaction. DESIGN: The Mediterranean Lifestyle (MEDLIFE) index was created based on the current Spanish Mediterranean food guide pyramid. MEDLIFE is a twenty-eight-item derived index consisting of questions about food consumption (fifteen items), traditional Mediterranean dietary habits (seven items) and physical activity, rest and social interaction habits (six items). Linear regression models and Spearman rank correlation were fitted to assess content validity and internal consistency. SETTING: A subset of participants in the Aragon Workers' Health Study cohort (Zaragoza, Spain) provided the data for development of MEDLIFE. SUBJECTS: Participants (n 988) of the Aragon Workers' Health Study cohort in Spain. RESULTS: Mean MEDLIFE score was 11.3 (sd 2.6; range: 0-28), and the quintile distribution of MEDLIFE score showed a significant association with each of the individual items as well as with specific nutrients and lifestyle indicators (intra-validity). We also quantified MEDLIFE correspondence with previously reported diet quality indices and found significant correlations (rho range: 0.44 0.53; P<0.001) for the Alternate Healthy Eating Index, the Alternate Mediterranean Diet Index and Mediterranean Diet Adherence Screener. CONCLUSIONS: MEDLIFE is the first index to include an overall assessment of lifestyle habits. It is expected to be a more holistic tool to measure adherence to the Mediterranean lifestyle in epidemiological studies. PMID- 25025399 TI - Dual-mode optical sensing of organic vapors and proteins with polydiacetylene (PDA)-embedded electrospun nanofibers. AB - Optical sensors capable of colorimetric visualization and/or fluorescence detection have shown tremendous potential for field technicians and emergency responders, owing to the portability and low cost of such devices. Polydiacetylene (PDA)-enhanced nanofibers are particularly promising due to high surface area, facile functionalization, simple construction, and the versatility to empower either colorimetric or fluorescence signaling. We demonstrate here a dual-mode optical sensing with electrospun nanofibers embedded with various PDAs. The solvent-dependent fluorescent transition of nanofibers generated a pattern that successfully distinguished four common organic solvents. The colorimetric and fluorescent sensing of biotin-avidin interactions by embedding biotinylated PCDA monomers into silica-reinforced nanofiber mats were realized for detection of biomolecules. Finally, a PDA-based nanofiber sensor array consisting of three monomers has been fabricated for the determination and identification of organic amine vapors using colorimetry and principal component analysis (PCA). The combination of PCA and the strategy of probing analytes in two different concentration ranges (ppm and ppth) led to successful analysis of all eight amines. PMID- 25025397 TI - Maternal magnesium deficiency in mice leads to maternal metabolic dysfunction and altered lipid metabolism with fetal growth restriction. AB - Inadequate magnesium (Mg) intake is a widespread problem, with over 50% of women of reproductive age consuming less than the Recommended Dietary Allowance (RDA). Because pregnancy increases the requirement for Mg and the beneficial effects of magnesium sulfate for preeclampsia/eclampsia and fetal neuroprotection are well described, we examined the outcomes of Mg deficiency during pregnancy. Briefly, pregnant Swiss Webster mice were fed either control or Mg-deficient diets starting on gestational day (GD) 6 through euthanasia on GD17. Mg-deficient dams had significantly reduced weight gain and higher plasma adipokines, in the absence of inflammation. Livers of Mg-deficient dams had significantly higher saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) and lower polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) (P < 0.0001) and arachidonic acid (AA) (P < 0.0001). Mechanistically, Mg deficiency was accompanied by enhanced desaturase and elongase mRNA expression in maternal livers along with higher circulating insulin and glucose concentrations (P < 0.05) and increased mRNA expression of Srebf1 and Chrebp, regulators of fatty acid synthesis (P < 0.05). Fetal pups exposed to Mg deficiency were growth restricted and exhibited reduced survival. Mg-deficient fetal livers showed lower MUFAs and higher PUFAs, with lower desaturase and elongase mRNA expression than controls. In addition, DHA concentrations were lower in Mg-deficient fetal brains (P < 0.05). These results indicate that Mg deficiency during pregnancy influences both maternal and fetal fatty acid metabolism, fetal growth and fetal survival, and support better understanding maternal Mg status before and during pregnancy. PMID- 25025401 TI - PAIN MECHANISMS - A REVIEW: I. Characteristics of the peripheral receptors. AB - This paper is the first in a series summarizing recent developments in our understanding of pain mechanisms. While neural mechanisms must exist for the two components (perception and aversion) of pain experience, the prime role of pain systems is still unclear. The major difficulties encountered in experimentally evaluating pain are considered briefly, as it is essential that these be appreciated by workers in this field. General sensory mechanisms are briefly summarized, including factors determining whether conscious awareness of a stimulus occurs and the acuity of stimulus site localization. Nociceptors ("pain" receptors) are considered in terms of their structural characteristics and fibre groups. Although it is still unclear precisely how nociceptors are activated, their known functional characteristics probably provide the basis for distinguishing stabbing from burning pain, and for the sensations associated with primary hyperalgesia. PMID- 25025400 TI - Improving co-amorphous drug formulations by the addition of the highly water soluble amino Acid, proline. AB - Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co amorphous drug-amino acid blends were prepared by ball milling and investigated for solid state characteristics, stability and the dissolution rate enhancement of NAP. All co-amorphous mixtures were stable at room temperature and 40 degrees C for a minimum of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP-TRP, through enhancing the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP-ARG. In comparison to crystalline NAP, binary NAP-TRP and NAP ARG, it could be shown that the highly soluble amino acid, PRO, improved the dissolution rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the solubility of the amino acid and potential interactions between the molecules are critical parameters to consider in the development of co-amorphous formulations. PMID- 25025402 TI - An holistic approach towards disabled persons and their rehabilitation. AB - Rehabilitation as a movement has grown out of the needs of disabled persons, which are different from those of the sick. Rehabilitation is developing into an holistic concept, which focuses on the whole person, not just on his or her physical or mental handicap. An holistic approach towards disabled persons and their rehabilitation is based on an awareness of the functional interdependence of psychological, physical, social and vocational factors in human health, illness and recovery. The physical, functional, psychological and social impact, which a stroke can have on a person, is described to illustrate the complexity of the disabling process, and the need for all rehabilitation team members to share holistic goals. The benefits of rehabilitation are maximized by an holistic approach, which aims at enabling persons with disabilities to function in society to the fullest physical, mental, social and vocational usefulness of which they are capable. PMID- 25025403 TI - Passive accessory movement at the elbow: a roentgenographic analysis. AB - Longitudinal movement of the radius, in relation to the ulna, occurring during abduction and adduction of the elbow, and during radial and ulnar deviation of the wrist, was examined roet-genographically on five students. A fixation device was designed to stabilize the humerus while the passive movements were carried out, and all measurements were done with the arm in 0 degrees extension. The average movement from full adduction to full abduction was 10.4 degrees and, at the same time, the radius moved an average of 1.6 mm distally in relation to the ulna. When the wrist was moved from full radial deviation to full ulnar deviation the radius moved an average of 0.1 mm in relation to the ulna. The importance of assessing passive accessory movements at the elbow in the examination and treatment of elbow lesions is discussed. PMID- 25025404 TI - Mild chlorodifluoroacylation of indoles via self-activation of sodium chlorodifluoroacetate. AB - A mild acylation of N-alkylindoles is reported using sodium chlorodifluoroacetate (SCDA) to synthesize useful chlorodifluoroketones. Friedel-Crafts reactivity of carboxylate salts is unusual and is not observed in similar electron-deficient acetate salts such as sodium trifluoroacetate. Mechanistic experiments indicate that the characteristic ability of SCDA to generate difluorocarbene is responsible for the reaction pathway via self-activation to form the active ester. PMID- 25025405 TI - Evidence-based update on tympanostomy tube placement for otitis media in children. PMID- 25025406 TI - Otologic manifestation of Samter triad. PMID- 25025407 TI - Large osteoma of the maxillary sinus accompanied by an unerupted tooth. PMID- 25025408 TI - Parathyroid adenoma. PMID- 25025409 TI - Pediatric rhabdomyosarcoma. PMID- 25025410 TI - Papillary thyroid cancer in a gravid woman. PMID- 25025411 TI - Ototoxicity in Nigeria: why it persists. AB - No therapy is currently available to reverse the serious damage that can be caused by ototoxic drugs, such as permanent hearing loss and balance disorders. Otolaryngologists in various regions of the world have developed strategies aimed at curtailing drug-induced ototoxicity, but similar efforts in most developing nations have yet to be well established. We conducted a study to document our experience in Nigeria. Our study population was made up of 156 patients-66 males and 90 females, aged 5 to 85 years (mean: 32.1 +/- 30.7)-who were diagnosed with drug-induced ototoxicity over a 3-year period. Tinnitus was the first and the predominant symptom in 140 patients (89.7%). The most common cause of drug induced ototoxicity among the 156 patients was injection of an unknown agent (n = 55 [35.3%]); among the known agents, the most common were chloramphenicol (n = 25 [16.0%]), chloroquine (n = 22 [14.1%]), and gentamicin (n = 20 [12.8%]). One pregnant woman experienced a miscarriage at 4 months after receiving intramuscular chloroquine, and another woman fell into a coma after receiving intramuscular streptomycin. Two agents that have not been linked to ototoxicity oxytocin and thiopentone sodium-were found to be ototoxic in our study (1 case each). Of the 312 ears, 31 (9.9%) showed normal audiometric patterns; on the other end of the spectrum, 155 ears (49.7%) had profound sensorineural hearing loss (SNHL). Mixed hearing loss was seen in 90 ears (28.8%). Hearing loss was bilaterally symmetrical in 127 patients (81.4%), bilaterally asymmetrical in 15 patients (9.6%), and unilateral in 14 patients (9.0%). Treatment was primarily medical; hearing aids were fitted for 7 patients (4.5%). Only 41 patients (26.3%) kept as many as 3 scheduled follow-up appointments. Ototoxicity remains prevalent in the developing countries of Africa. Numerous drugs and other agents are responsible, and management outcomes are difficult to ascertain. Thus, our emphasis must be placed on prevention if we are to minimize the potentially devastating effects of ototoxicity. PMID- 25025412 TI - Invasive primary aspergillosis of the larynx presenting as hoarseness and a chronic nonhealing laryngeal ulcer in an immunocompetent host: a rare entity. AB - Primary aspergillosis usually affects the paranasal sinuses, orbit, ear, and lower respiratory tract. Laryngeal aspergillosis usually occurs as a result of secondary invasion from the tracheobronchial tree, more commonly in immunocompromised hosts. Primary laryngeal localization of Aspergillus infection is seldom encountered. We report the case of an immunocompetent 42-year-old man who presented with hoarseness and a laryngeal ulcer of fairly long duration. A malignancy was initially suspected clinically, but a laryngoscopic biopsy led to a diagnosis of invasive primary laryngeal aspergillosis. No other focus of aspergillosis was found on x-ray and computed tomography. After identification of Aspergillus niger on culture, inquiries revealed no exposure to steroids, cytotoxic drugs, or irradiation, and workups for malignancy, human immunodeficiency virus infection, tuberculosis, and diabetes were negative. Although isolated laryngeal involvement is rare, aspergillosis may be considered in the differential diagnosis of a chronic nonhealing laryngeal ulcer that is clinically suggestive of a malignancy, even in an immunocompetent host. PMID- 25025413 TI - Survival characteristics of injected human cartilage slurry in a nude mouse model: a preliminary study. AB - We conducted a study to examine the viability, host response, and volume retention characteristics of drilled human septal cartilage slurry when injected into an athymic nude mouse model. We injected 0.2 ml of the slurry into the hind limbs of 6 mice. The mice were sequentially sacrificed over a period of 180 days. Histologic reviews of the hind limbs were performed to determine the viability of injected chondrocytes, host response, and volume retention. Specimens were obtained and histomorphologic analysis was performed at 1, 30, 90, and 180 days after injection. We identified viable cartilage throughout the study. Cartilage injection was well tolerated, and minimal inflammatory reaction occurred without significant adverse effects. The injected bolus of cartilage was found to have progressively dispersed throughout the muscle over time. Our findings warrant further investigation with a larger cohort of nude mice or possibly human subjects. PMID- 25025414 TI - Meningeal carcinomatosis in undifferentiated nasopharyngeal carcinoma: a case report. AB - Meningeal carcinomatosis is the tumoral invasion of the leptomeninges. It is caused by the spread of malignant cells throughout the subarachnoid space, which produces signs and symptoms due to multifocal involvement. Cranial nerve symptoms are the most common focal findings. The diagnosis is usually made by imaging and/or cytology. Head and neck cancers are the cause of approximately 2% of all cases of meningeal carcinomatosis; in very rare cases, they are caused by a nasopharyngeal carcinoma. We report a case of meningeal carcinomatosis that was caused by a recurrence of undifferentiated nasopharyngeal carcinoma. The patient, a 60-year-old woman, experienced no focal neurologic symptoms and exhibited no radiologic evidence of meningeal involvement. We also review the literature on meningeal carcinomatosis secondary to nasopharyngeal carcinoma. PMID- 25025415 TI - Transoral removal of a large parapharyngeal space neurofibroma with the Harmonic Scalpel. AB - We report the case of a 19-year-old man with neurofibromatosis type 1 who presented for evaluation of odynophagia, left-sided hemiparesis, multiple cafe au lait spots all over his body, and numerous subcutaneous and cutaneous neurofibromas. Imaging revealed the presence of two large neurofibromas-a 60 * 50 * 35-mm tumor in the left parapharyngeal space and an intradural tumor measuring 25 mm in diameter. We removed the larger tumor via a transoral route with the Harmonic Scalpel. The size of this tumor far exceeded the size of any other reported tumor removed in this manner. Various approaches to the parapharyngeal space have been described in the literature. To the best of our knowledge, this case represents the first report of a transoral removal of a huge parapharyngeal space neurofibroma with a Harmonic Scalpel. PMID- 25025416 TI - Primary cervical thoracic duct cyst: a case report and review of the literature. AB - Thoracic duct cysts are uncommon entities that are usually found in the thoracic segments of the thoracic duct. The presence of a thoracic duct cyst in the cervical area has been rarely reported. Etiologically, these cysts can arise either as a primary growth or secondary to trauma, obstruction, or inflammation. This entity was first described in 1964, and only 33 cases have been previously reported in literature. Of these, 16 cases involved a primary cyst. We report a new case of a primary thoracic duct cyst, and we discuss its presentation, diagnosis, and management, with an emphasis on meticulous surgical technique. We also review the relevant literature. PMID- 25025417 TI - Rhinosporidiosis: an unusual presentation. AB - Rhinosporidiosis is a chronic granulomatous disease that primarily affects the mucous membranes of the nose and nasopharynx. It is caused by Rhinosporidium seeberi. Clinically it presents as a reddish, bleeding, polypoid mass with a characteristic strawberry-like appearance on its surface, which is caused by the presence of mature sporangia. In the case described here, a 35-year-old man presented with a 6-month history of a slowly growing polypoid mass in his left nasal cavity. The surface of the mass was smooth, pale, and covered with nasal mucosa. It was attached to the nasal septum. Fine-needle aspiration cytology was suggestive of a parasitic cyst. The mass was excised with the use of local anesthesia. Histopathologic examination of the resected specimen revealed rhinosporidiosis. Prior to this diagnosis, the patient had not exhibited most of the typical clinical features that are suggestive of rhinosporidiosis. In the case of a nasal mass, a diagnosis of rhinosporidiosis is important to establish prior to any surgery because bleeding during and after surgery is usually profuse and can be life-threatening. The site of the excised mass should be cauterized to prevent recurrence. PMID- 25025418 TI - Angiolipoleiomyoma located in the earlobe. AB - Angiolipoleiomyoma (ALLM) is a solid tumor that is mostly derived from muscle tissue. It is often located in the kidneys of patients with tuberous sclerosis; ALLMs located outside the kidneys are very rare. Among the rare presentations are cutaneous ALLMs, which manifest as 1- to 4-cm asymptomatic, acquired, solitary, subcutaneous nodules that have a strong predilection for males. To the best of our knowledge, only 22 cases of ALLM of the skin have been previously reported in the literature; in 5 of these cases, the tumor was located on the ear. Histologically, tumoral proliferation is observed with smooth muscle, fat tissue, and vascular channels surrounded by a fibrous capsule; cellular atypia is not observed. We report the case of a 67-year-old man who presented for evaluation of a purplish nodular lesion that had been present on his right earlobe for 10 years. Analysis of an excisional biopsy specimen revealed a nodular formation that consisted mostly of thick-walled veins within a fibromyxoid stroma; smooth muscle tissue and fat globules were observed in places. The lesion was diagnosed as a cutaneous ALLM. PMID- 25025419 TI - Petrosquamosal sinus discovered during mastoidectomy, and its radiologic appearance on temporal bone CT: case report and brief review. AB - We report the case of a 47-year-old woman who underwent a mastoidectomy. Preoperative computed tomography demonstrated an unusually distended bony canal that passed through the superolateral portion of the right petrous bone. Intraoperatively, we identified the anomaly as a petrosquamosal sinus (PSS). This unusually dilated venous channel had arisen from the adjacent sigmoid sinus. A PSS is an emissary vein of the posterior fossa that courses along the petrosquamosal junction, connecting the sigmoid or transverse sinus with the extracranial venous system. While it usually regresses during fetal life, a dilated PSS occasionally persists into adulthood. Its anatomic course may lead to problematic bleeding during mastoidectomy. PMID- 25025420 TI - Acute vocal fold hemorrhage after phonosurgery. PMID- 25025421 TI - Endoscopic view of a middle meatal cyst. PMID- 25025422 TI - Leiomyosarcoma of the parapharyngeal space: a very rare entity. AB - Leiomyosarcoma of the head and neck is very rare, as only about 100 cases have been reported; of these, only 3 cases have been previously reported in the parapharyngeal space. We report the fourth such case, and we review the features of this entity. The patient was an 84-year-old woman who presented to the emergency department for treatment of an 18-month history of right-sided headache, a 6-month history of right-sided hearing loss and nasal obstruction, and a 2-month history of dysphagia. Physical examination revealed a bulge in the right side of the soft palate and the right lateral nasopharyngeal wall and complete obstruction of the right eustachian tube. Indirect laryngoscopy detected a bulge in the right lateral hypopharyngeal wall. Otoscopy revealed otitis media with effusion in the right ear. Imaging demonstrated a space-occupying lesion in the right parapharyngeal space that extended from the base of the skull to the level of the hypopharynx. Biopsy and histology identified the mass as a leiomyosarcoma. Metastasis to the brain was discovered shortly thereafter, and the patient died 10 months later. The unusual presentation of head and neck leiomyosarcoma requires a high index of suspicion and appropriate diagnostic imaging. Surgical excision is the recommended treatment when feasible; chemoradiotherapy does not appear to affect disease progression. PMID- 25025423 TI - Reinnervation of facial muscles with only a cross-facial nerve graft in a 25-year old patient with congenital facial palsy. AB - The standard method for managing chronic facial palsy is the two-stage free muscle flap. We report a case involving a 25-year-old patient who had facial palsy from her birth. Twelve months after the first stage of a cross-facial nerve graft, we found that the voluntary movements of her facial muscles had returned. Within the following 12 months, she gained complete recovery of her movements on the affected side, as confirmed by electromyography studies. This case demonstrates that neurotization of facial muscles in chronic facial palsy is possible. However, further studies are needed to define the trophic effects or trophic mediators that can restore function to atrophied facial muscles and to determine which patients might benefit from the cross-facial nerve graft procedure without the free-muscle graft procedure. PMID- 25025424 TI - Association analysis of GABRB3 promoter variants with heroin dependence. AB - GABRB3 encoding the beta3 subunit of GABAA receptor has been implicated in multiple neuropsychiatric disorders, including substance abuse. Previous studies reported that SNPs at the 5' regulatory region of GABRB3 could regulate GABRB3 gene expression and associated with childhood absence epilepsy (CAE). The study aimed to investigate whether SNPs at the 5' regulatory region of GABRB3 were associated with heroin dependence in our population. We first re-sequenced 1.5 kb of the 5'regulatory region of GABRB3 gene to examine the SNP profile in the genomic DNA of 365 control subjects. Then, we conducted a case-control association analysis between 576 subjects with heroin dependence (549 males, 27 females) and 886 controls (472 males, 414 females) by genotyping the rs4906902 as a tag SNP. We also conducted a reporter gene assay to assess the promoter activity of two major haplotypes derived from SNPs at this region. We detected 3 common SNPs (rs4906902, rs8179184 and rs20317) at this region that had strong pair-wise linkage disequilibrium. The C allele of rs4906902 was found to be associated with increased risk of heroin dependence (odds ratio:1.27, p = 0.002). Two major haplotypes (C-A-G and T-G-C) derived from these 3 SNPs accounted for 99% of this sample, and reporter gene activity assay showed that haplotype C-A-G that contained the C allele of the tag SNP rs4906902 had higher activity than haplotype T-G-C. Our data suggest that GABRB3 might be associated with heroin dependence, and increased expression of GABRB3 might contribute to the pathogenesis of heroin dependence. PMID- 25025425 TI - Facile synthesis of Ag-ZnO hybrid nanospindles for highly efficient photocatalytic degradation of methyl orange. AB - Highly photocatalytically active Ag nanoparticle decorated ZnO nanospindles were synthesized by a facile wet chemical method. The structural and optical properties of the as-synthesized materials were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and high resolution TEM (HRTEM) with energy dispersive X-ray spectroscopy, UV-visible absorption spectroscopy and Raman spectroscopy. The photocatalytic activity of these nanostructures was evaluated by analyzing sunlight driven degradation of methyl orange (MO) dye and it was observed that Ag nanoparticle modified ZnO nanospindles show significantly enhanced photocatalytic activity for degradation of MO, as compared to ZnO nanospindles. We attribute the observed enhanced photocatalytic activity of Ag nanoparticle decorated ZnO nanospindles to their improved sunlight utilization efficiency and the efficient suppression of recombination of photogenerated charge carriers due to the electron scavenging action of Ag nanoparticles and the interfacial electron transfers due to the Schottky junction between Ag nanoparticles and ZnO nanospindles. PMID- 25025426 TI - Effective melanin depigmentation of human and murine ocular tissues: an improved method for paraffin and frozen sections. AB - PURPOSE: The removal of excessive melanin pigments that obscure ocular tissue morphology is important to address scientific questions and for differential diagnosis of ocular tumours based on histology. Thus, the goal of the present study was to establish an effective and fast melanin bleaching method for paraffin and frozen mouse and human ocular tissues. METHODS: Paraffin-embedded and frozen ocular specimens from mice and human donors were subjected to bleaching employing two methods. The first employed potassium permanganate (KMnO4) with oxalic acid, and the second 10% hydrogen peroxide (H2O2). To determine optimal bleaching conditions, depigmentation was carried out at various incubation times. The effect of diluents used for 10% H2O2 was assessed using phosphate-buffered saline (PBS), and deionized water. Three different slide types and two fixatives, which were ice-cold acetone with 80% methanol, and 4% paraformaldehyde (PFA) were used to determine the optimal conditions for better tissue adherence during bleaching. All tissues were stained in hematoxylin and eosin for histological evaluation. RESULTS: Optimal bleaching was achieved using warm 10% H2O2 diluted in PBS at 65 degrees C for 120 minutes. Chromium-gelatin coated slides prevented tissue detachment. Adherence of cryosections was also improved with post-fixation using 4% PFA and overnight air-drying at RT after cryosectioning. Tissue morphology was preserved under these conditions. Conversely, tissues bleached in KMnO4/oxalic acid demonstrated poor depigmentation with extensive tissue damage. CONCLUSIONS: Warm dilute H2O2 at 65 degrees C for 120 minutes rapidly and effectively bleached both cryo- and paraffin sections of murine and human ocular tissues. PMID- 25025427 TI - Evidence-based nanoscopic and molecular framework for excipient functionality in compressed orally disintegrating tablets. AB - The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2-10 um2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. PMID- 25025428 TI - The surgeon's perspective: promoting and discouraging factors for choosing a career in surgery as perceived by surgeons. AB - BACKGROUND: The aim of this study was to identify the factors perceived by surgeons that promote surgery as an attractive or unattractive career choice for today's graduates. In addition, it examined whether the perspectives of surgeons in different professional situations converges. The content of work, contextual work conditions, and calling to this job are discussed in the context of choosing surgery as a career. METHODS: Eight hundred sixty-nine surgeons were asked to answer open-ended questions regarding the factors that promote surgery as an attractive or unattractive career choice for today's graduates. Four hundred ninety-two surgeons participated, and 1,525 statements were analyzed using Mayring's content-analyses method. Chi-square tests were used to analyze the differences among hierarchical positions. RESULTS: With respect to the factors that promote surgery as a profession, 40.8% (209/492) of the surgeons stated that surgery is a calling, 29.1% (149/492) of the surgeons provided at least one argument related to the positive task characteristics, and 12.9% (66/492) of the surgeons provided statements related to the positive contextual factors. With respect to the factors that discourage surgery as a profession, 45.7% (234/492) of the surgeons provided at least one argument related to the discouraging work characteristics, and 67.6% (346/492) of the surgeons provided problematic contextual characteristics. CONCLUSION: This study emphasizes the importance of the calling to surgery as an important factor for choosing surgery as a career. However, the extensive workload, training, and poor work-family balance have been identified as factors that discourage graduates from choosing surgery as a career. The identified positive factors could be used to attract and maintain graduates in surgical disciplines. PMID- 25025431 TI - Manual examination: is pain provocation a major cue for spinal dysfunction? AB - Evidence suggests that manual examination is reliable in the detection of dysfunctioned spinal segments. Clinical decisions are considered to relate to the presence of abnormal motion and tissue stiffness along with provocation of pain but there have been suggestions that pain is the major diagnostic cue. Pain provocation is important but reliance on pain could cause false positive joint dysfunction diagnoses. A single blind study was undertaken to test a manipulative physiotherapist's ability to differentiate painful and non painful cervical segments without the subject's verbal pain cues. Results indicated good agreement between the examiner and subjects for their independent nomination of most painful and painless segments, suggesting pain is not the only cue. PMID- 25025432 TI - Upper cervical spine flexor muscles: age related performance in asymptomatic women. AB - Isometric strength and endurance of the upper cervical flexor muscles were assessed in 54 moderately active asymptomatic females, with specific reference to anyage related differences. Subjects, chosen from asample of convenience, were categorised into three age groups, 20 - 25, 40 - 45 and 60 - 65 years. Strength (kiloponds (kp)) and endurance were measured by subjects flexing their chin against a metal bar to which strain gauges were attached. Endurance (seconds) was measured and defined as the time that subjects could hold atleast 50 percent of an initial maximal voluntary contraction (MVC). Normal values were established for the sample population. Mean strength values for the three age groups, 20 - 25, 40 - 45 and 60 - 65 years were 3.4, 3.5 and 3.4kp and endurance values were 65, 59 and 41 seconds respectively. There was no significant relationship between strength and age or endurance and age. PMID- 25025433 TI - Effect of exercise-induced fatigue on position sense of the knee. AB - Fatiguing isokinetic quadriceps exercises and the effect on the ability of 12 human subjects to reproduce knee angles was examined. The experimental and control procedures consisted of two separate test sessions conducted in sitting. Positioning was measured with a potentiometer. Accuracy was estimated by calculating the mean absolute error (AE) between five criterion and reproduction angles and the average directional or constant error (CE). Results showed a significant increase in target overshooting between the initial and final CE measurements on Day Two (experimental session) and Day One (control session). In contrast the control group showed no alteration in intrasession CE test performance. It is concluded that exercise-induced contractile fatigue can introduce bias into the encoding of positional information in a healthy knee. PMID- 25025429 TI - Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes. AB - We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non coding RNAs. We analysed 8929 regions harboring genes for potential long non coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co regulated with the closest protein coding gene. We compared the identified cis regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7*10(-7) to 9.5*10(-89). The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis. PMID- 25025430 TI - Gene expression profiling of the response to interferon beta in Epstein-Barr transformed and primary B cells of patients with multiple sclerosis. AB - The effects of interferon-beta (IFN-beta), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-beta. To identify gene expression changes and pathways induced by IFN-beta in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-beta exposure, with over 50 previously unrecognized as IFN-beta response genes. Pathways analysis demonstrated that IFN-beta affected LCLs in a similar manner to other cell types by activating known IFN-beta canonical pathways. Additionally, IFN beta increased the expression of innate immune response genes, while down regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-beta response genes in primary B cells. In this study new IFN-beta response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component. PMID- 25025434 TI - Clinical measures of balance and functional assessment in elderly persons. AB - The relationship between clinical measures of balance and function in elderly persons was the focus of this investigation. Sixty subjects were assessed on three clinical balance measures, the Balance Scale, the Self Paced Walk Test and the Falls Efficacy Scale and a measure of general function, the Functional Assessment Inventory. Results demonstrated significant relationships between all measures. The Balance Scale results were highly predictive of function and were predicted by scores on the Falls Efficacy Scale and the Self Paced Walk Test. Only the Self Paced Walk Test was able to discriminate between subjects on the basis of previously reported falls. On the basis of data from this sample of elderly people, it was concluded that the Balance Scale was the most appropriate clinical balance measure for use with older individuals. PMID- 25025435 TI - Quantitative gait analysis - comparison of rheumatoid arthritic and non-arthritic subjects. AB - This study quantified differences in the gait parameters of velocity and stride length at three different self selected speeds between 113 subjects with rheumatoid arthritis and 104 normal controls stratified for age and gender. Significant differences were found between the well-matched groups of females 50 64 and over 65 years of age at all three speeds for both gait parameters. Females younger than 50 years of age, however, differed from their controls only at normal and fast velocities. The gait of males appeared to be less affected by the disease as only males over 65 years of age differed significantly from their controls and then only at the fast self selected speed. These data provide a base from which to judge the efficacy of therapeutic intervention in the arthritic population. PMID- 25025436 TI - Ergonomics and the physiotherapist: a report on a research project on working postures. AB - In a series of lectures on biomechanical principles, Professor E. R. Tichauer, an authority on man-machine-task systems, stated: "Only a few years ago, the physical work load imposed on the individual employee was much heavier than is the case today, but it was, in many occupations, fairly evenly distributed over the entire musculo skeletal system. Today, the total energy demanded from man in the performance of an industrial task has often been reduced, but stress is concentrated on individual and small components of the worker's anatomy," The techniques for combating these new stresses are found in the science of ergonomics (Hopkins 1966). PMID- 25025437 TI - Physiotherapy in australia. AB - Tonight I plan to look back for a moment at the beginning of Physiotherapy in Australia, to discuss changes that have occurred primarily in education, and to think of our preparation for the future. PMID- 25025438 TI - 1,000 muscle injuries: a report. AB - In a little over two years Lewisham Hospital Sports Clinic treated 1,000 muscle injuries, representing 33% of the total patient load in that period. PMID- 25025439 TI - Low back pain and pain resulting from lumbar spine conditions: a comparison of treatment results. AB - In recent issues of the Medical Journal of Australia considerable interest has been shown in manipulation. Dr. B. Gard (1967) has suggested that statistical evidence be obtained from physiotherapy clinics as to the efficiency of manipulative treatment. A symposium was held in 1967 during which the chairman, Dr. Frank May introduced a panel of four speakers, Professor K. C. Bradley, Mr. C. EL Hembrow, Dr. W. Hargrave Wilson and Mr. A. Wright. May in summing up suggested that a new section of the Australian Medical Association be formed to promote interest in manipulative treatment. As a result of this a Victorian State Branch of the Australian Association of Physical Medicine has been formed to further the interest of manipulative treatment within the medical profession. PMID- 25025440 TI - The hamstring injury in Australian rules football. AB - To understand the nature of the torn hamstring injury in Australian Rules Football it is necessary to understand the action of this important muscle group during play. PMID- 25025441 TI - Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. AB - Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis. PMID- 25025442 TI - Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. AB - Mucosal alterations of the fallopian tube are generally thought to represent alterations of the native tubal mucosal epithelium, whether benign or malignant. The current paradigm implicating the fallopian tube fimbriae as the origin of most pelvic high-grade serous carcinomas (HGSCs) is based on the premise that HGSC growing within the tubal mucosa originated there. This has fueled proposals to redefine classification rules for assigning the primary site of origin on the basis of the presence or absence of HGSC in the tubal mucosa. The corollary is that it is unlikely for metastatic carcinoma to grow within fallopian tube mucosa. Evidence to support or refute this corollary is minimal, in part because the fallopian tubes historically have been ignored. This study reports the pattern and topography of 100 nongynecologic cancers that metastasized to the fallopian tubes. Most tumors were adenocarcinoma (87%), and the remainder included lymphomas, neuroendocrine tumors, and mesotheliomas. The most common primary origins of tumor were the colon (35%) and breast (15%). Gross evidence of a tubal nodule or mass was only seen in 35% of cases. Ovarian metastases were present in 95% of cases, although 23% did not exhibit gross evidence of metastasis. Tumor involved the fimbriae in 49% of cases, including 10% of cases in which the tumor was restricted to the fimbriae without involving the nonfimbriated portion of the tube. The anatomic distribution of metastases included the tubal mucosa (29%), submucosa (43%), muscularis (54%), serosa (76%), lymphovascular spaces (38%), intraluminal space (16%), and mesonephric remnants (39%). The most common architectural pattern of mucosal growth was a flat layer (22/29 cases), followed by varying degrees of stratification, tufting, and papillary growth. High-grade atypia was present in 18/29 cases of mucosal growth, resulting in patterns that resembled primary tubal HGSC. Accompanying growth in the tubal submucosa frequently produced a pseudoinvasive pattern mimicking invasive tubal HGSC. Immunohistochemical expression of p53 by 8/18 high-grade mucosal metastases further contributed to the resemblance to primary tubal HGSC. Bland cytology was present in 11/29 cases of mucosal growth, some of which also exhibited mucinous features, resulting in patterns that resembled either tubal mucinous metaplasia or nonmucinous tubal hyperplasia. Although uncommon, it is possible for metastases of nongynecologic cancers to grow within the mucosa of the fallopian tube and create a potential diagnostic pitfall. Intramucosal growth of a tumor in the fallopian tube is not pathognomonic of a primary tubal origin of the tumor. These findings may carry implications for proposed criteria using the status of the fallopian tube mucosa to assign primary origin of a gynecologic cancer. PMID- 25025443 TI - Expanding the morphologic spectrum of differentiated VIN (dVIN) through detailed mapping of cases with p53 loss. AB - The pathogenesis of vulvar squamous cell carcinoma follows 1 of 2 distinct pathways. A precursor lesion in the human papilloma virus-independent pathway, differentiated vulvar intraepithelial neoplasia (dVIN), was only recently characterized in detail and is infrequently diagnosed without an associated component of invasive carcinoma. Aberrant p53 immunostaining is frequently seen in dVIN, and in approximately 25% to 30% of cases it manifests as a complete loss or a p53-null pattern. The abrupt transition between p53 loss and basal p53 expression in lesional versus nonlesional epithelium allows clear demarcation between neoplastic and non-neoplastic epithelium. For this study, 14 specimens from 10 patients were identified from the pathology archives of 2 teaching hospitals on the basis of: (1) a diagnosis of dVIN, with or without invasive carcinoma; and (2) p53-null immunostaining pattern in lesional cells. Ten specimens had associated invasive carcinoma. All sections from each specimen that showed the specimen resection margin were stained for p53 and reviewed together with all hematoxylin and eosin sections. Detailed morphologic assessment of the p53-null epithelium was made and compared with the adjacent benign squamous epithelium. The status of the resection margins based on the original pathologic assessment was compared with that assessed with p53 immunohistochemistry. One specimen showed p53 loss in the invasive carcinoma but patchy basal positivity in the region originally diagnosed as dVIN, supporting interpretation as a benign hyperplastic focus, rather than dVIN. In the remaining 13 specimens the areas originally diagnosed as dVIN, as well as the associated invasive carcinoma (if present), were p53-null. In 8 of these specimens, on the basis of the presence of p53-null immunostaining and subtle morphologic abnormalities, dVIN was more extensive than originally recognized. The spectrum of morphologic changes in p53 null regions that were in continuity with areas originally recognized as dVIN were subtle and typically consisted of an abrupt change in maturation of the squamous epithelium (loss of keratohyaline granules and parakeratosis), tinctorial alterations in the keratinocytes, with cells containing more abundant eosinophilic cytoplasm, and minimal basal nuclear atypia. Margin status changed from negative to positive in 4 of 13 specimens and from focally to more extensively positive in an additional 3 specimens. In summary, the clonal in situ component of non-human papilloma virus vulvar squamous cell carcinoma can be characterized by very subtle morphologic abnormalities that may be misinterpreted as benign change. This results in underestimation of the extent of dVIN, and, as a result, resection margin involvement may be significantly underestimated. dVIN can also be overdiagnosed in areas of reactive change. Better tools for diagnosis of dVIN are needed; until such tools are developed the limitations in the current diagnosis of dVIN should be recognized. PMID- 25025444 TI - A novel chromogenic in situ hybridization assay for FGF23 mRNA in phosphaturic mesenchymal tumors. AB - Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT) are very rare tumors of bone and soft tissues. Most patients with PMT have long standing osteomalacia secondary to production of fibroblast growth factor 23 (FGF23), a hormone that inhibits phosphate reuptake within the renal proximal tubule. Previously, we have reported the detection of FGF23 mRNA in PMT by reverse transcription polymerase chain reaction (PCR); however, the low specificity and risk for nontumoral tissue contamination inherent in PCR-based methodology limit its clinical utility. We evaluated RNAscope as a semiquantitative method of in situ FGF23 mRNA detection in the diagnosis of PMT. Twenty-five PMTs (median 52 y, range 5 to 73 y) occurred in patients with tumor induced osteomalacia (TIO), manifesting as masses (mean 3.9 cm, range 1.4 to 12 cm) in various bones and soft tissues. FGF23 mRNA was positive in 96% (22/23) informative cases of PMT: 16 cases scored 3+; 5 scored as 2+; 1 scored as 1+. Among these cases, FGF23 mRNA was detected in 3 malignant PMTs along with their metastases. Forty control cases included aneurysmal bone cyst (N=4), chondromyxoid fibroma (N=8), high-grade osteosarcomas (N=8), and (nonfamilial) tumoral calcinosis, as well as miscellaneous cartilage-forming tumors or osteoid forming tumors and soft tissue tumors. All control cases were negative for FGF23 mRNA in the lesional cells. One aneurysmal bone cyst had rare FGF23 mRNA expressing osteocytes clustered around remodeled bone. One ovarian serous carcinoma in a patient with disseminated disease, elevated serum FGF23, and TIO was negative for FGF23 mRNA in the neoplastic cells. We conclude that RNAscope is a highly sensitive and specific, semiquantitative in situ hybridization method of FGF23 mRNA detection applicable to formalin-fixed, paraffin-embedded tissues. Detection of FGF23 expression is a valuable diagnostic adjunct, especially in patients with occult TIO. Compared with reverse transcription PCR, this method preserves tissue morphology and reduces "false positives" related to detection of endogenous FGF23 mRNA expression by osteocytes. PMID- 25025445 TI - Metastatic prostate adenocarcinoma to the penis: a series of 29 cases with predilection for ductal adenocarcinoma. AB - Twenty-nine men with metastatic prostate adenocarcinoma to the penis were identified at our institution between 1993 and 2013. Of the 29 patients, 19 had a prior history of adenocarcinoma of the prostate, and 8 of those had ductal features in the primary lesion. Sixteen of 29 revealed ductal features in the metastasis. Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis. Seven penile metastases were proven to be of prostatic origin solely by immunohistochemistry. Three cases were originally misdiagnosed as urothelial carcinoma upon review of the penile lesion. Other variant morphologies in the metastases included sarcomatoid carcinoma, small cell carcinoma, and adenosquamous carcinoma. In summary, prostate carcinoma involving the penis displays ductal features considerably more often than prostate cancer in general. Features that can cause difficulty in recognizing metastatic prostate adenocarcinoma to the penis include the unusual anatomic site for prostate cancer, poor differentiation, an increased prevalence of variant morphology, a long interval from the primary lesion, and, in some cases, no documented history of a primary prostatic lesion. Immunohistochemical analysis should be performed to rule out prostate carcinoma in penile/penile urethral tumors with morphology that differs from typical squamous or urothelial carcinoma. Even in the setting of metastatic disease, there is a critical need for an accurate diagnosis so that the appropriate therapy can be initiated, symptomatic relief can be provided, and long-term survival achieved in some cases, while at the same time avoiding penectomy for a misdiagnosis of a primary penile cancer. PMID- 25025446 TI - High-grade dysplasia versus carcinoma: east is east and west is west, but does it need to be that way? PMID- 25025447 TI - Granulomatosis with polyangiitis presenting as a renal tumor. AB - Inflammatory tumors of the kidney are uncommon and include primary inflammatory processes and systemic diseases such as sarcoidosis, IgG4 disease, and granulomatosis with polyangiitis (GPA). There are approximately 15 cases of the latter in the literature. Tumors in GPA are well described and have been reported in several organs including breast, orbit, mediastinum, central nervous system, and especially the lung. We report the case of a 48-year-old woman who presented with diffuse frontal headaches. Imaging showed both a cranial/sinus and renal mass. The pathology of the dura and nasal sinus biopsies were unrevealing. A nephrectomy was performed that demonstrated a discrete lesion with extensive necrosis, granulomatous inflammation, and crescentic pauci-immune glomerulonephritis, findings consistent with GPA. PMID- 25025448 TI - Profile of CD103 expression in T-cell neoplasms: immunoreactivity is not restricted to enteropathy-associated T-cell lymphoma. AB - Intestinal intraepithelial T lymphocytes express the alpha E subunit of integrin alphaEbeta7, which is detected by antibodies to CD103. Accordingly, within T-cell neoplasms, CD103 reactivity has most frequently been reported in enteropathy associated T-cell lymphomas, which are postulated to arise from intestinal intraepithelial T lymphocytes. However, prior studies of CD103 expression in T cell neoplasms have been limited by the requirement for fresh or frozen tissue, given the historic lack of an antibody to CD103 for use in paraffin-embedded sections. Thus, a thorough assessment of CD103 expression in a broad spectrum of T-cell neoplasms as categorized by the current classification system has not yet been performed. This study uses a newly described antibody to define the profile of CD103 immunoreactivity in paraffin sections of a wide variety of T-cell neoplasms (184 cases). Overall, 22 T-cell neoplasms (12%) were CD103 positive, including 7 of 15 gastrointestinal lymphomas (3.8% of total cases; 46% of gastrointestinal cases). In intestinal cases, CD103 positivity did not correlate with morphology, presence or absence of enteropathy, or immunohistochemical profile. A history of celiac disease was not documented in any case. Frequent but inconsistent reactivity was also noted for adult T-cell leukemia/lymphoma with 4 of 10 cases (40%) positive. In the remaining T-cell neoplasms representing most entities within the current World Health Organization classification, CD103 reactivity was sporadically observed in 11 of 159 cases (6.9%). CD103 positivity is an unusual feature in T-cell neoplasms and tends to occur in gastrointestinal lymphomas and adult T-cell leukemia/lymphoma but is not a consistent characteristic of these neoplasms. PMID- 25025449 TI - Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies. AB - The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (alphabeta-type T cell, gammadelta T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented. PMID- 25025450 TI - Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. AB - Primary mediastinal (thymic) large B-cell lymphoma (PMBL) and diffuse large B cell lymphoma (DLBCL) are tumors with distinct clinical and molecular characteristics that are difficult to distinguish by histopathologic and phenotypic analyses alone. Programmed cell death 1 ligand 2 (PD-L2) is a cell surface protein expressed by activated macrophages and dendritic cells that binds PD-1 on T cells to inhibit immune responses. Amplification and/or translocations involving chromosome 9p24.1, a region that includes PDCD1LG2-encoding PD-L2, is a common event in PMBL but not DLBCL and suggests that PD-L2 expression might be a distinguishing feature of PMBL. We developed an assay for the immunohistochemical detection of PD-L2 protein in fixed biopsy specimens (PD-L2 IHC), which we applied to a cohort of PMBLs and DLBCLs. For a subset of cases, we correlated the results of PD-L2 IHC with PDCD1LG2 copy number (CN) as determined by quantitative polymerase chain reaction. Twenty-three of 32 (72%) PMBLs but only 1 of 37 (3%) DLBCLs were positive by PD-L2 IHC. Among PMBLs with PDCD1LG2 CN gain, all were positive by PD-L2 IHC. One PMBL without CN gain was positive by PD-L2 IHC. When expressed in PMBL, PD-L2 was restricted to tumor cells and not detected on intratumoral macrophages. We conclude that PD-L2 protein is robustly expressed by the majority of PMBLs but only rare DLBCLs and often associated with PDCD1LG2 copy gain. PD-L2 IHC may serve as a useful ancillary test for distinguishing PMBL from DLBCL and for the rational selection of patients for therapeutic antibodies that inhibit PD-1 signaling. PMID- 25025451 TI - The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy. AB - Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (>=40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma. PMID- 25025453 TI - HIV health-care providers' burnout: can organizational culture make a difference? AB - One of the major challenges facing those working with people living with HIV (PLWH) is the increased potential for burnout, which results in increased turnover and reduces quality of care provided for PLWH. The goal of this study was to examine the relationship among HIV health-care providers' burnout (emotional exhaustion and depersonalization) and organizational culture including teamwork, involvement in decision-making, and critical appraisal. Health-care providers for PLWH (N = 47) in federally funded clinics in a southwestern state completed a cross-sectional survey questionnaire about their perceptions of organizational culture and burnout. The results of multiple regression analysis indicated that positive organizational culture (i.e., teamwork) was negatively related to emotional burnout (p < .005, R(2) = .18). Further negative organizational culture (i.e., critical appraisal) was positively related to depersonalization (p < .005, R(2) = .18). These findings suggest that effective organizational communication interventions might protect HIV health-care providers from burnout. PMID- 25025452 TI - Intranodal palisaded myofibroblastoma: another mesenchymal neoplasm with CTNNB1 (beta-catenin gene) mutations: clinicopathologic, immunohistochemical, and molecular genetic study of 18 cases. AB - Intranodal palisaded myofibroblastoma is a benign, lymph node-based myofibroblastic tumor of unknown pathogenesis. We report the clinicopathologic, immunohistochemical, and molecular genetic features of this rare entity. The study cohort consisted of 14 men and 4 women ranging in age from 31 to 65 (mean, 47; median 49) years with tumors arising in inguinal lymph nodes (n=15), a neck lymph node (n=1), and undesignated lymph nodes (n=2). Most individuals presented with a painless mass or lump. Possible trauma/injury to the inguinal region was documented in 4 cases. Tumors ranged in size from 1.0 to 4.2 (mean, 3.1; median; 3.0) cm. Microscopically, the process presented as a well-circumscribed, oftentimes pseudoencapsulated nodule (n=17) or nodules (n=1). Tumors consisted of a cellular proliferation of cytologically bland, spindled cells arranged in short fascicles and whorls within a finely collagenous (n=11) or myxocollagenous (n=7) matrix. In 12 tumors, scattered fibromatosis-like fascicles of spindled cells were noted. Histologic features characteristic of the process included nuclear palisades (n=16 cases), collagenous bodies (n=15), and perinuclear intracytoplasmic hyaline globules (n=10). Mitotic activity ranged from 0 to 8 (mean, 2; median, 1) mitotic figures/50 high-powered fields with no atypical division figures identified. Immunohistochemically, all tumors tested expressed smooth muscle actin and/or muscle-specific actin (n=5, each), and nuclear beta catenin and cyclin D1 (n=8, each). The latter 2 results prompted a screening for mutations in the beta-catenin gene glycogen synthase kinase-3 beta phosphorylation mutational "hotspot" region in exon 3 using polymerase chain reaction amplification and Sanger sequencing. Single nucleotide substitutions leading to missense mutations at the protein level were identified in 7 of 8 (88%) analyzed tumors and are responsible for the abnormal expression of beta catenin and cyclin D1. These results demonstrate that mutational activation of the beta-catenin gene is likely a pivotal event in the pathogenesis of intranodal palisaded myofibroblastoma. PMID- 25025454 TI - Diffusion of oxygen through cork stopper: is it a Knudsen or a Fickian mechanism? AB - The aim of this work is to identify which law governs oxygen transfer through cork: Knudsen or Fickian mechanism. This is important to better understand wine oxidation during post-bottling aging. Oxygen transfer through cork wafers is measured at 298 K using a manometric permeation technique. Depending on the mechanism, we can extract the transport coefficients. Increasing the initial pressure of oxygen from 50 to 800 hPa leads to a change in the values of the transport coefficients. This implies that oxygen transport through cork does not obey the Knudsen law. From these results, we conclude that the limiting step of oxygen transport through cork occurs in the cell wall following Fickian law. From the diffusion dependence's coefficients with pressure, we also extract by applying transition state theory an apparent activation volume of 45 +/- 4 nm(3). This high value indicates that oxygen molecules also diffuse from one site to another by passing through a gas phase. PMID- 25025455 TI - Circadian variation in human flexibility and grip strength. AB - The main aim of this study was to monitor changes in joint flexibility over 24 hours in 25 subjects. Measurements of finger tip to floor, lumbar flexion, lumbar extension, passive straight leg raising and glenohumeral lateral rotation at 90 degrees abduction were taken every two hours during the 24 hour cycle. The presence of circadian rhythms in flexibility were established by graphical analysis of the results. These were shown to exist in all measurements, the most strong being finger tip to floor and most weak glenohumeral lateral rotation. The study also investigated grip strength over 24 hours and disclosed a circadian pattern in which there was a considerable fall in strength during the early hours and a rapid rise after 0600 hours. PMID- 25025456 TI - The relationship of low back pain to postural changes during pregnancy. AB - To determine the nature of the postural changes in women during pregnancy, the degrees of lordosis, kyphosis and pelvic inclination in 34 pregnant women were measured progressively. The incidence of low back pain at each of the three occasions was also monitored. Analyses revealed that significant increases occurred in the lumbar and thoracic curvatures and that 82 percent of the women experienced back pain at some stage during their pregnancy. However, no significant relationship was revealed between posture and back pain and the study did not support the frequently made assertions that back pain in pregnancy is due to an increase in lordosis. PMID- 25025457 TI - Physiotherapists as managers: an analysis of tasks performed by head physiotherapists. AB - Knowledge of the activities performed by managers forms the basis for management training yet little is known of tasks performed by managers in the health service. A study was performed to identify the managerial role of three physiotherapists randomly selected from eleven physiotherapists in charge of large hospital departments who had taken part in a previous study to establish a profile of perceived tasks. Analysis revealed that the key roles of resource allocator, monitor and leader were similar to other middle managers, verbal contacts were typical of managers at all levels and clinical work caused role ambiguity. The study indicated areas where the head physiotherapist's performance could possibly be improved together with suggestions for management training and the selection of future head physiotherapists. PMID- 25025458 TI - Functional electrical stimulation of the extremities in the neurological patient: a review. AB - The use of functional electrical stimulation (FES) in the treatment of neurological conditions has an extensive history, one that has seen great advances in recent years. Developments in this area of rehabilitation are outlined and avenues for future research and clinical study suggested. The application of FES to the neurological patient may be of considerable benefit alongside conventional facilitatory/inhibitory techniques. The physiotherapist is ideally placed to participate in studies of this modality to determine its role in clinical practice. PMID- 25025459 TI - Electro-motor stimulation research methodology and reporting: a need for standardization. AB - The interest in electro-motor stimulation as a strengthening modality has prompted many recent studies. Unfortunately, ambiguity rather than clear directions for future research and clinical practice have emerged. Problems are identified with strength testing methods, and in non-standardized training programmes and stimulus parameters, suggesting the need for minimum requirements when reporting these studies. It is hoped that suggestions presented in this paper will result in more careful research designs, improved inter-study comparison and more appropriate clinical protocols. PMID- 25025460 TI - New physiotherapy graduates - are we satisfying their needs? AB - The importance of continuing education and meaningful experience for the physiotherapy graduate is readily acknowledged. It is especially important that new graduates are provided with appropriate opportunities for professional growth, so that they can consolidate and extend their theoretical knowledge and develop skill in its application. This paper raises some questions as to the seriousness with which these issues have been addressed and it highlights areas in which attention might be focussed to ensure the professional development of the new graduate and thereby the strengthening of physiotherapy practice. PMID- 25025461 TI - Single-molecule enzymatic conformational dynamics: spilling out the product molecules. AB - Product releasing is an essential step of an enzymatic reaction, and a mechanistic understanding primarily depends on the active-site conformational changes and molecular interactions that are involved in this step of the enzymatic reaction. Here we report our work on the enzymatic product releasing dynamics and mechanism of an enzyme, horseradish peroxidase (HRP), using combined single-molecule time-resolved fluorescence intensity, anisotropy, and lifetime measurements. Our results have shown a wide distribution of the multiple conformational states involved in active-site interacting with the product molecules during the product releasing. We have identified that there is a significant pathway in which the product molecules are spilled out from the enzymatic active site, driven by a squeezing effect from a tight active-site conformational state, although the conventional pathway of releasing a product molecule from an open active-site conformational state is still a primary pathway. Our study provides new insight into the enzymatic reaction dynamics and mechanism, and the information is uniquely obtainable from our combined time resolved single-molecule spectroscopic measurements and analyses. PMID- 25025463 TI - Tibial stress changes in new combat recruits for special forces: patterns and timing at MR imaging. AB - PURPOSE: To characterize the incidence, location, grade, and patterns of magnetic resonance (MR) imaging findings in the tibia in asymptomatic recruits before and after 4-month basic training and to investigate whether MR imaging parameters correlated with pretraining activity levels or with future symptomatic injury. MATERIALS AND METHODS: This study was approved by three institutional review boards and was conducted in compliance with HIPAA requirements. Volunteers were included in the study after they signed informed consent forms. MR imaging of the tibia of 55 men entering the Israeli Special Forces was performed on recruitment day and after basic training. Ten recruits who did not perform vigorous self training prior to and during service served as control subjects. MR imaging studies in all recruits were evaluated for presence, type, length, and location of bone stress changes in the tibia. Anthropometric measurements and activity history data were collected. Relationships between bone stress changes, physical activity, and clinical findings and between lesion size and progression were analyzed. RESULTS: Bone stress changes were seen in 35 of 55 recruits (in 26 recruits at time 0 and in nine recruits after basic training). Most bone stress changes consisted of endosteal marrow edema. Approximately 50% of bone stress changes occurred between the middle and distal thirds of the tibia. Lesion size at time 0 had significant correlation with progression. All endosteal findings smaller than 100 mm resolved or did not change, while most findings larger than 100 mm progressed. Of 10 control subjects, one had bone stress changes at time 0, and one had bone stress changes at 4 months. CONCLUSION: Most tibial bone stress changes occurred before basic training, were usually endosteal, occurred between the middle and distal thirds of the tibia, were smaller than 100 mm, and did not progress. These findings are presumed to represent normal bone remodeling. PMID- 25025462 TI - Oral microbiota distinguishes acute lymphoblastic leukemia pediatric hosts from healthy populations. AB - In leukemia, oral manifestations indicate aberrations in oral microbiota. Microbiota structure is determined by both host and environmental factors. In human hosts, how health status shapes the composition of oral microbiota is largely unknown. Taking advantage of advances in high-throughput sequencing, we compared the composition of supragingival plaque microbiota of acute lymphoblastic leukemia (ALL) pediatric patients with healthy controls. The oral microbiota of leukemia patients had lower richness and less diversity compared to healthy controls. Microbial samples clustered into two major groups, one of ALL patients and another of healthy children, with different structure and composition. Abundance changes of certain taxa including the Phylum Firmicutes, the Class Bacilli, the Order Lactobacillales, the Family Aerococcaceae and Carnobacteriaceae, as well as the Genus Abiotrophia and Granulicatella were associated with leukemia status. ALL patients demonstrated a structural imbalance of the oral microbiota, characterized by reduced diversity and abundance alterations, possibly involved in systemic infections, indicating the importance of immune status in shaping the structure of oral microbiota. PMID- 25025464 TI - Shear-wave elastography: a noninvasive tool for monitoring changing hepatic venous pressure gradients in patients with cirrhosis. AB - PURPOSE: To investigate whether liver stiffness ( LS liver stiffness ) and change in LS liver stiffness measurements ( DeltaLS change in LS ) at shear-wave elastography ( SWE shear-wave elastography ) correlates with the hepatic venous pressure gradient ( HVPG hepatic venous pressure gradient ) and to assess the feasibility of using SWE shear-wave elastography to estimate the change in HVPG hepatic venous pressure gradient ( DeltaHVPG change in HVPG ) in patients with portal hypertension. MATERIALS AND METHODS: Institutional review board approval was obtained, with waiver of informed consent. Between September 2010 and October 2012, 97 consecutive patients who were given a diagnosis of portal hypertension on the basis of HVPG hepatic venous pressure gradient measurement were included. Among these patients, 23 who underwent follow-up HVPG hepatic venous pressure gradient measurement to evaluate response to treatment were included in the follow-up group. The correlation between HVPG hepatic venous pressure gradient and LS liver stiffness was analyzed by using the Pearson correlation test. In the follow-up group, whether DeltaHVPG change in HVPG was correlated with DeltaLS change in LS was also evaluated. Thereafter, the areas under the receiver operating characteristic curves ( AUC area under the ROC curve s) were calculated to determine the diagnostic performances of DeltaLS change in LS and the second LS liver stiffness measurement after medical treatment and to compare their performances in association with clinical improvement and aggravation of portal hypertension. RESULTS: LS liver stiffness was moderately correlated with HVPG hepatic venous pressure gradient (r = 0.593) in the single-measurement group. There was also a strong correlation between DeltaLS change in LS and DeltaHVPG change in HVPG (r = 0.863). At comparison of the second LS liver stiffness measurement, DeltaLS change in LS showed no significant difference in AUC area under the ROC curve in patients with improvement (0.627 vs 0.794, P = .201) but showed higher AUC area under the ROC curve in association with aggravation of portal hypertension (0.925 vs 0.611, P = .026). CONCLUSION: Estimating DeltaHVPG change in HVPG by using SWE shear-wave elastography may be useful in patients with cirrhosis and portal hypertension. PMID- 25025465 TI - Platelet Activating Factor Receptor Activation Improves siRNA Uptake and RNAi Responses in Well-differentiated Airway Epithelia. AB - Well-differentiated human airway epithelia present formidable barriers to efficient siRNA delivery. We previously reported that treatment of airway epithelia with specific small molecules improves oligonucleotide uptake and facilitates RNAi responses. Here, we exploited the platelet activating factor receptor (PAFR) pathway, utilized by specific bacteria to transcytose into epithelia, as a trigger for internalization of Dicer-substrate siRNAs (DsiRNA). PAFR is a G-protein coupled receptor which can be engaged and activated by phosphorylcholine residues on the lipooligosaccharide (LOS) of nontypeable Haemophilus influenzae and the teichoic acid of Streptococcus pneumoniae as well as by its natural ligand, platelet activating factor (PAF). When well differentiated airway epithelia were simultaneously treated with either nontypeable Haemophilus influenzae LOS or PAF and transduced with DsiRNA formulated with the peptide transductin, we observed silencing of both endogenous and exogenous targets. PAF receptor antagonists prevented LOS or PAF-assisted DsiRNA silencing, demonstrating that ligand engagement of PAFR is essential for this process. Additionally, PAF-assisted DsiRNA transfection decreased CFTR protein expression and function and reduced exogenous viral protein levels and titer in human airway epithelia. Treatment with spiperone, a small molecule identified using the Connectivity map database to correlate gene expression changes in response to drug treatment with those associated with PAFR stimulation, also induced silencing. These results suggest that the signaling pathway activated by PAFR binding can be manipulated to facilitate siRNA entry and function in difficult to transfect well-differentiated airway epithelial cells. PMID- 25025466 TI - Designing Ago2-specific siRNA/shRNA to Avoid Competition with Endogenous miRNAs. AB - Relatively large amounts of transfected siRNA can compete for Ago proteins and thus compromise endogenous miRNA function, potentially leading to toxicities. Here, we show that shRNA can also perturb endogenous miRNA function similarly. More importantly, we also show that the problem can be solved by designing shRNAs in the context of pre-miR-451 structure with completely complementary stem, which significantly improves the Ago2 specificity. This shRNA was shown to be Ago2 specific, and maintain target-silencing ability while avoiding competition with endogenous miRNAs by not competing for Agos 1, 3, and 4. We conclude that modified pre-miR-451 structure provides a general platform to design shRNAs that significantly reduce perturbation of miRNA function. PMID- 25025468 TI - Temperature changes following quick icing: a brief investigation. AB - Quick icing has been reported as an easy and satisfactory method for facilitating muscle activity, even though the duration of stimulus is brief. The experiments described here attempted to evaluate whether application of ice to a limb for a short time could significantly alter the temperature of the skin to which the ice was applied and consequently lower the temperature of the underlying muscle. Normal subjects were used for the experiments and skin temperatures were measured at 30-second intervals after the completion of quick icing procedures. A 7 degrees C (mean) decrease of skin temperature was recorded during the first minute after icing, and skin temperatures remained significantly depressed during the next 4 minutes. It is proposed that this depression of skin temperature would be a sufficient stimulus to alter the excitability of spinal motor-neurons, in a manner similar to the excitability changes that occur when a limb is immersed in an ice-water bath. PMID- 25025467 TI - The detection of the methylated Wif-1 gene is more accurate than a fecal occult blood test for colorectal cancer screening. AB - BACKGROUND: The clinical benefit of guaiac fecal occult blood tests (FOBT) is now well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, also known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC. PATIENTS AND METHODS: We performed a cross-sectional study that included all consecutive subjects that were referred (from 2003 to 2007) for screening colonoscopies. Prior to colonoscopy, effluents (fresh stools, sera-S and urine-U) were harvested and FOBTs performed. Methylation levels were measured in stools, S and U for 3 genes (Wif1, ALX-4, and Vimentin) selected from a panel of 63 genes; Kras mutations and seven dominant and subdominant bacterial populations in stools were quantified. Calibration was assessed with the Hosmer Lemeshow chi-square, and discrimination was determined by calculating the C statistic (Area Under Curve) and Net Reclassification Improvement index. RESULTS: There were 247 individuals (mean age 60.8+/-12.4 years, 52% of males) in the study group, and 90 (36%) of these individuals were patients with advanced polyps or invasive adenocarcinomas. A multivariate model adjusted for age and FOBT led to a C-statistic of 0.83 [0.77-0.88]. After supplementary sequential (one-by-one) adjustment, Wif-1 methylation (S or U) and fecal microbiota dysbiosis led to increases of the C-statistic to 0.90 [0.84-0.94] (p = 0.02) and 0.81 [0.74-0.86] (p = 0.49), respectively. When adjusted jointly for FOBT and Wif-1 methylation or fecal microbiota dysbiosis, the increase of the C-statistic was even more significant (0.91 and 0.85, p<0.001 and p = 0.10, respectively). CONCLUSION: The detection of methylated Wif-1 in either S or U has a higher performance accuracy compared to guaiac FOBT for advanced colorectal neoplasia screening. Conversely, fecal microbiota dysbiosis detection was not more accurate. Blood and urine testing could be used in those individuals reluctant to undergo stool testing. PMID- 25025469 TI - Parent participation in paediatric physiotherapy home programmes. AB - Many studies attest to low levels of compliance behaviour by receivers of health care instructions. The present study investigated this problem in the context of physiotherapy. A questionnaire on parent participation was administered to 93 English-speaking mothers of young children receiving physiotherapy at eight Sydney hospitals or centres. The primary objective was to examine parents' perceptions of their compliance behaviour, frequency of execution in relation to family size or passing time, expectations of a programme, and importance attributed to the programme. It was found that mothers regarded home treatment programmes as substantially valuable, and not only devoted 2 hours each day to execution but continued to do this over many years, in spite of problems. One may conclude that English-speaking mothers who elect to keep their child in a physiotherapy programme in metropolitan Sydney appear eager to participate in the programme and cooperate with the physiotherapist. PMID- 25025470 TI - The importance of play in a child's early development. AB - A physiotherapist is concerned with the development or restoration of a quality of movement that enables the individual to take advantage of learning experiences and to perform activities of daily living. The paediatric physiotherapist is concerned with the development of children up to school age. PMID- 25025471 TI - PAIN MECHANISMS - A REVIEW: II. Afferent pain pathways. AB - This paper reviews some major advances in our understanding of the organization of afferent pain pathways, and relates these and other findings to the limited success rate achieved by various surgical interventions used in the treatment of chronic intractable pain. First-order pain afferents, many of which use the transmitter substance P, may enter the spinal cord via both the dorsal and ventral roots. After terminating superficially in the dorsal horn, information may apparently ascend to higher centres via numerous pathways, some of which are contralateral some ipsilateral. The preferred route to the primary somatosensory cortex appears to be the contralateral spinothalamic tract, but alternate pathways may be recruited following anterolateral cordotomy or thalamotomy. In addition to divergence of the central pain pathways and the presence of ventral root afferents, other factors considered that may contribute to surgical failure include denervation supersensitivity, the occurrence of prolonged spontaneous injury discharge, and divergence of the peripheral branches of nociceptive fibres. PMID- 25025472 TI - Using Natural Language Processing to Extract Abnormal Results From Cancer Screening Reports. AB - OBJECTIVES: Numerous studies show that follow-up of abnormal cancer screening results, such as mammography and Papanicolaou (Pap) smears, is frequently not performed in a timely manner. A contributing factor is that abnormal results may go unrecognized because they are buried in free-text documents in electronic medical records (EMRs), and, as a result, patients are lost to follow-up. By identifying abnormal results from free-text reports in EMRs and generating alerts to clinicians, natural language processing (NLP) technology has the potential for improving patient care. The goal of the current study was to evaluate the performance of NLP software for extracting abnormal results from free-text mammography and Pap smear reports stored in an EMR. METHODS: A sample of 421 and 500 free-text mammography and Pap reports, respectively, were manually reviewed by a physician, and the results were categorized for each report. We tested the performance of NLP to extract results from the reports. The 2 assessments (criterion standard versus NLP) were compared to determine the precision, recall, and accuracy of NLP. RESULTS: When NLP was compared with manual review for mammography reports, the results were as follows: precision, 98% (96%-99%); recall, 100% (98%-100%); and accuracy, 98% (96%-99%). For Pap smear reports, the precision, recall, and accuracy of NLP were all 100%. CONCLUSIONS: Our study developed NLP models that accurately extract abnormal results from mammography and Pap smear reports. Plans include using NLP technology to generate real-time alerts and reminders for providers to facilitate timely follow-up of abnormal results. PMID- 25025474 TI - Passive movement techniques for intra-articular and periarticular disorders. AB - Recent studies on the effects of passive movement on the maintenance of nutrition and the repair of articular cartilage are related to pain relief by passive movement treatment techniques. The techniques for patients with severe intra articular pain are described and compared with treatment techniques for patients with chronic intra-articular pain. The suggested importance of tensional forces in the maintenance of periarticular structures forms the basis for discussion of the passive treatment techniques utilized for patients with pain from ligamentous or capsular damage, or change, in both the recent and the chronic stage. PMID- 25025473 TI - Mutations of C-reactive protein (CRP) -286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk. AB - C-reactive protein (CRP) is an established marker of inflammation with pattern recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway. PMID- 25025475 TI - Career development of female physiotherapists: stage four of a longitudinal survey. AB - Career development of 62 female physiotherapists was surveyed 5 years after graduation, in this fourth stage of a longitudinal study: 87.1 per cent were currently employed. Job satisfaction was high as was work involvement. About half had specialized and the majority had attended short courses, workshops and seminars. Work pressure (too much to do and too little time) was the most frequently rated work stressor. The physiotherapists reported themselves being in good health, experiencing little role conflict and moderate satisfaction from various areas of their lives. As in previous surveys they indicated that they planned to have an average of 3 children and interrupt their careers while the children were young. PMID- 25025476 TI - Is asthma a psychosomatic illness? AB - In asthma the bronchial muscle is hyperirritable, making asthmatics susceptible to a wide variety of external and endogenous trigger factors normally experienced by us all. The level of hyperirritability determines the risk of developing bronchospasm on exposure to the trigger factors. Bronchial muscle tone is in part maintained by vagal nerves. Emotional factors can act as triggers for bronchospasm through these nerves, particularly in patients with the greatest hyperirritability. Asthma itself may arouse hostilities in parents, peers, and therapists. By definition asthma can therefore be considered psychosomatic, but because of current usage, this term does not help good medical management. The complex interplay between the organic abnormality in asthma and the psychosocial environment should always be carefully considered. PMID- 25025477 TI - How frequently do the results from completed US clinical trials enter the public domain?--A statistical analysis of the ClinicalTrials.gov database. AB - BACKGROUND: Achieving transparency in clinical trials, through either publishing results in a journal or posting results to the ClinicalTrials.gov (CTG) web site, is an essential public health good. However, it remains unknown what proportion of completed studies achieve public disclosure of results (PDOR), or what factors explain these differences. METHODS: We analyzed data from 400 randomly selected studies within the CTG database that had been listed as 'completed' and had at least four years in which to disclose results. Using Kaplan-Meier curves, we calculated times from completion to PDOR (defined as publishing the primary outcomes in a journal and/or posting results to CTG), and identified explanatory variables predicting these outcomes using Cox proportional hazards models. FINDINGS: Among the 400 clinical trials, 118 (29.5%) failed to achieve PDOR within four years of completion. The median day from study completion to PDOR among 282 studies (70.5%) that achieved PDOR was 602 days (mean 647 days, SD 454 days). Studies were less likely to achieve PDOR if at earlier stages (phase 2 vs. phase 3/4, adjusted HR 0.60, 95% CI 0.47-0.78), if they only included adult subjects (adjusted HR 0.61, 95% CI 0.45-0.83), involved randomization (adjusted HR 0.62, 95% CI 0.46-0.83), or had smaller sample sizes (<=50 subjects vs. >50, adjusted HR 0.60, 95% CI 0.44-0.83). Industry-funded studies were significantly less likely to be published than non-industry or blended studies (adjusted HR 0.49, 95% CI 0.36-0.66). CONCLUSIONS: A significant proportion of completed studies did not achieve PDOR within the four years of follow-up, particularly smaller studies at earlier stages of development with industry funding. This constitutes reporting bias and threatens the validity of the clinical research literature in the US. PMID- 25025478 TI - Treatment of a sulfate-rich groundwater contaminated with perchloroethene in a hydroponic plant root mat filter and a horizontal subsurface flow constructed wetland at pilot-scale. AB - A hydroponic plant root mat filter (HPRMF) was compared over 7months with a horizontal subsurface flow constructed wetland (HSSF CW) regarding the removal of perchloroethene (PCE) (about 2 mg L(-1)) from a sulfate- (850 mg L(-1)) and ammonia-rich (50 mg L(-1)) groundwater with a low TOC content. At a mean area specific inflow PCE load of 56 mg m(-2)d(-1), after 4m from inlet, the mean PCE removal during summer time reached 97% in the HPRMF and almost 100% in the HSSF CW. Within the first 2m in the HSSF CW metabolites like dichloroethenes, vinyl chloride and ethene accumulated, their concentrations decreased further along the flow path. Moreover, the tidal operation (a 7-d cycle) in the HSSFCW decreased the accumulation of PCE metabolites within the first 1m of the bed. The carcinogenic degradation metabolite vinyl chloride was not detected in the HPRMF. The smaller accumulation of the degradation metabolites in the HPRMF correlated with its higher redox potential. It can be concluded from this study that HPRMF appears an interesting alternative for special water treatment tasks and that tidal operation will show some positive effects on the removal of the accumulated PCE metabolites in HSSF CW. PMID- 25025479 TI - Interactions between anticancer trans-platinum compounds and proteins: crystal structures and ESI-MS spectra of two protein adducts of trans (dimethylamino)(methylamino)dichloridoplatinum(II). AB - The adducts formed between trans (dimethylamino)(methylamino)dichloridoplatinum(II), [t-PtCl2(dma)(ma)], and two model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease, were independently characterized by X-ray crystallography and electrospray ionization mass spectrometry. In these adducts, the Pt(II) center, upon chloride release, coordinates either to histidine or aspartic acid residues while both alkylamino ligands remain bound to the metal. Comparison with the cisplatin derivatives of the same proteins highlights for [t-PtCl2(dma)(ma)] a kind of biomolecular metalation remarkably different from that of cisplatin. PMID- 25025480 TI - A review of the effect of early intervention programmes on the developmental status of very preterm, very low birth weight infants. AB - Infants who are born prior to forty weeks gestation frequently demonstrate a rate of development which is different from that evidenced by their term born peers. This is true particularly for those infants who have no abnormalities which would interfere with their development but who are both very preterm (of 32 weeks gestation or less) and of very low weight at birth (1500 grams or less). Stimulation aimed at overcoming the negative aspects of preterm birth and enhancing the development of preterm born infants has been widely recommended. The evidence which supports the idea of such intervention is conflicting and based on inconclusive data. The purpose of this review is to identify those aspects of early stimulation programmes which have been of measurable benefit to preterm born subjects. From this basis it should be possible to isolate optimal forms of stimulation to guide those who seek to provide these infants with assistance designed to maximize their developmental potential. PMID- 25025481 TI - The Neuro-sensory Motor Developmental Assessment Part 1: Development and Administration of the Test. AB - The Neuro-sensory Motor Developmental Assessment (NSMDA) has been developed to meet the need for a progressive developmental assessment of infants and children. In this study a cohort of 148 preterm infants was assessed at 1, 4, 8, 12, and 24 months adjusted age. The results were used to classify the subjects as having normal, suspect or abnormal developmental status. The scores for each time were correlated with outcome scores at 24 months. Part One of this paper includes a description of the development and administration of the NSMDA. Longitudinal and cross correlations of scores were analysed and shown to be highly significant over the first two years of testing, thereby establishing the basis for validity and predictability of the NSMDA. PMID- 25025482 TI - The Neuro-Sensory Motor Developmental Assessment Part II: Predictive and Concurrent Validity. AB - The Neuro-sensory Motor Developmental Assessment (NSMDA) has been developed to meet the need for a progressive evaluation of infants and children. The content and administration of the NSMDA has been addressed in Part One of this paper. In this study the NSMDA was used to assess a cohort of 148 preterm infants at 1, 4, 8, 12, and 24 months. Results recorded at each assessment were compared with developmental outcome at 24 months. This paper provides statistical evidence of the NSMDA's validity. Verification in terms of predictive validity (sensitivity/specificity), and concurrent validity is described. Although early NSMDA scores were significantly correlated with outcome at two years, 8 months was found to be the optimal age for accurately discriminating between children who demonstrated normal or abnormal developmental status. PMID- 25025483 TI - A practical application of aspects of conductive education. AB - The philosophy and practice of Conductive Education is explored and the application of some of these principles to a residential/educational setting is investigated. Special attention is given to improving the efficiency and effectiveness of the existing service delivery for a group of twelve moderately to severely physically and intellectually disabled children aged between three and six years. Results obtained from evaluation of the task series are related to the child's ability to initiate movement and suggest improvement over time. Changes reported by team members such as improved communication, a positive environment, positive expectations and improved integration of treatment and services are discussed. Continued investigation is warranted. PMID- 25025484 TI - Legionnaires' disease: the wollongong experience. AB - Australia experienced its largest Legionnaires' disease epidemic in Wollongong, mid 1987. This paper presents an overview of Legionnaires' disease followed by details of the Wollongong epidemic including areas of particular interest to the physiotherapist, with comparisons of milder and severe cases. Unlike other epidemics, females outnumbered males. Predisposing factors of increasing age, cigarette smoking, respiratory and medical conditions were found. Except cigarette smoking, these factors and initial chest radiograph involving two or more zones, were significant features of the severe group. Patients in these categories require careful monitoring. Blood gases demonstrated consistent hypoxaemia and hypocapnoea. Seventy-eight per cent of cases recorded little or no sputum and implications for treatment are discussed. Impressions and fears of the epidemic are presented and recommendations made. PMID- 25025485 TI - Quality assurance: an integral part of private physiotherapy practice. AB - Quality Assurance has been defined as 'looking at what we do to and for our patients, thinking about it and deciding whether it comes up to acceptable standards, and if not, doing somet hing about it' (Legge 1984). Underlying the concept of Quality Assurance is the philosophy that the patient is the focus of physiotherapy, and he therefore expects and deserves optimum care (McCoy and Grant 1988). Greater marketplace competition from fringe health sciences, the rising cost of health care and the increasing sophistication of the health. consumer has increased the need to practise Quality Assurance to ensure optimal physiotherapy performance and outcomes (Vuori 1982). PMID- 25025486 TI - Tuberculosis in Papua New Guinea: from yesterday until today. AB - Little is known about the situation of tuberculosis in Papua New Guinea despite its high TB burden, emerging drug resistance and rising HIV co-infection. This review gives an overview on the current situation of TB in PNG and identifies knowledge gaps that should urgently be addressed in the future. PMID- 25025487 TI - Substrate activation in flavin-dependent thymidylate synthase. AB - Thymidylate is a critical DNA nucleotide that has to be synthesized in cells de novo by all organisms. Flavin-dependent thymidylate synthase (FDTS) catalyzes the final step in this de novo production of thymidylate in many human pathogens, but it is absent from humans. The FDTS reaction proceeds via a chemical route that is different from its human enzyme analogue, making FDTS a potential antimicrobial target. The chemical mechanism of FDTS is still not understood, and the two most recently proposed mechanisms involve reaction intermediates that are unusual in pyrimidine biosynthesis and biology in general. These mechanisms differ in the relative timing of the reaction of the flavin with the substrate. The consequence of this difference is significant: the intermediates are cationic in one case and neutral in the other, an important consideration in the construction of mechanism based enzyme inhibitors. Here we test these mechanisms via chemical trapping of reaction intermediates, stopped-flow, and substrate hydrogen isotope exchange techniques. Our findings suggest that an initial activation of the pyrimidine substrate by reduced flavin is required for catalysis, and a revised mechanism is proposed on the basis of previous and new data. These findings and the newly proposed mechanism add an important piece to the puzzle of the mechanism of FDTS and suggest a new class of intermediates that, in the future, may serve as targets for mechanism-based design of FDTS-specific inhibitors. PMID- 25025488 TI - Dynamic simulation of tibial tuberosity realignment: model evaluation. AB - This study was performed to evaluate a dynamic multibody model developed to characterize the influence of tibial tuberosity realignment procedures on patellofemoral motion and loading. Computational models were created to represent four knees previously tested at 40 degrees , 60 degrees , and 80 degrees of flexion with the tibial tuberosity in a lateral, medial and anteromedial positions. The experimentally loaded muscles, major ligaments of the knee, and patellar tendon were represented. A repeated measures ANOVA with post-hoc testing was performed at each flexion angle to compare data between the three positions of the tibial tuberosity. Significant experimental trends for decreased patella flexion due to tuberosity anteriorization and a decrease in the lateral contact force due to tuberosity medialization were reproduced computationally. The dynamic multibody modeling technique will allow simulation of function for symptomatic knees to identify optimal surgical treatment methods based on parameters related to knee pathology and pre-operative kinematics. PMID- 25025489 TI - (-)-Epigallocatechin-3-gallate modulates spinal cord neuronal degeneration by enhancing growth-associated protein 43, B-cell lymphoma 2, and decreasing B-cell lymphoma 2-associated x protein expression after sciatic nerve crush injury. AB - Our previous studies have established that (-)-epigallocatechin-3-gallate (EGCG) has both neuroprotective and -regenerative capacity after sciatic nerve injury. Moreover, this improvement was evident on the behavioral level. The aim of this study was to investigate the central effects of ECGC on spinal cord motor neurons after sciatic nerve injury. Our study showed that administering 50 mg/kg intraperitoneally i.p. of EGCG to sciatic nerve-injured rats improved their performance on different motor functions and mechanical hyperesthesia neurobehavioral tests. Histological analysis of spinal cords of EGCG-treated sciatic nerve-injured (CRUSH+ECGC) animals showed an increase in the number of neurons in the anterior horn, when compared to the naive, sham, and saline treated sciatic nerve-injured (CRUSH) control groups. Additionally, immunohistochemical study of spinal cord sections revealed that EGCG reduced the expression of glial fibrillary acidic protein and increased the expression of growth-associated protein 43, a marker of regenerating axons. Finally, EGCG reduced the ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 and increased the expression of survivin gene. This study may shed some light on the future clinical use of EGCG and its constituents in the treatment of peripheral nerve injury. PMID- 25025490 TI - Cytotoxicity of calcium rectorite micro/nanoparticles before and after organic modification. AB - Organically modified rectorite (OREC) micro/nanoparticles can be synthesized by organic modification from calcium rectorite (Ca(2+)-REC or REC), a common form of rectorite in nature. Although REC and OREC have potential applications in food packing and drug delivery, their cytotoxicity is not clear. In the present study, we investigated and compared the cytotoxicity of REC and OREC micro/nanoparticles in Chang liver cells, the human normal hepatic cells, and human hepatoma HepG2 cells. The interlayer spacing of OREC was enlarged after organic modification. After treatment with REC or OREC for 24 h at 1 and 5 MUg/mL, they were taken up by Chang liver cells. REC and OREC induced cytotoxicity in Chang liver and HepG2 cells at almost all doses (1, 2.5, 5, 7.5, and 10 MUg/mL) after 6, 24, and 48 h of treatment (P < 0.05 or P < 0.01). Compared with REC, OREC was more cytotoxic. However, there was no difference in the cytotoxicity of REC and OREC between the two cell lines. After treatment with REC or OREC at 7.5 and 10 MUg/mL for 24 h, the apoptotic and necrotic percentages of Chang liver cells were increased (P < 0.05 or P < 0.01). The levels of apoptosis-related proteins Bax, Bcl-2, and pro caspase-3 were all decreased in Chang liver cells after 24 h of exposure to REC or OREC at 5, 7.5, 10 MUg/mL. There was no change in the relative ratio of Bax/Bcl-2 after treatment, indicating that REC or OREC-induced apoptosis was not associated with Bax-related mitochondria-mediated apoptotic pathway. Our results suggested that OREC was more cytotoxic than REC, but the underlying mechanisms need further investigation. PMID- 25025491 TI - On the concept of postural muscles and posture in man. AB - Basic human posture should be derived from the principal movement pattern, namely gait. Since we stand on one leg for most of the time during walking, the stance on one leg should be considered to be the typical posture in man; the postural muscles are those which maintain this posture. PMID- 25025492 TI - Perceptual Trace Development during Motor Skill Acquisition in Stroke Patients. AB - The hypothesis that stroke patients could learn a perceptual motor skill by developing a strong perceptual trace with practice was tested. Ten spastic stroke patients and sixteen normal subjects were observed while they learned a novel self-paced linear displacement task. The criterion movement was the displacement of an object with the affected leg (in the case of stroke patients) and left leg (in normal subjects), to a designated target. Visual, auditory, kinesthetic as well as knowledge of result information was available to the subjects. The results showed that stroke patients were able to reduce their movement errors as a function of practice by developing and strengthening their perceptual trace. This technique may be adapated for the modification of the motor behaviour of stroke patients. PMID- 25025493 TI - Pain assessment. AB - The use of therapeutic measures which are designed primarily to modulate pain has high-lighted the need for an accurate and reliable method of pain assessment in the physiotherapy department. Some psychological considerations of pain are reviewed and different methods of pain assessment are described and discussed. The need for a practical pain assessment tool is emphasised in the ongoing assessment of the patient by the physiotherapist. A pain assessment model is proposed which can incorporate a Visual Analogue Scale, a record of analgesic intake and a record of the patient's activity level. These parameters can be recorded and displayed in graph form, which provides a clear picture of symptom relief and treatment effectiveness over a period of time. PMID- 25025495 TI - Nanoscopic vibrations of bacteria with different cell-wall properties adhering to surfaces under flow and static conditions. AB - Bacteria adhering to surfaces demonstrate random, nanoscopic vibrations around their equilibrium positions. This paper compares vibrational amplitudes of bacteria adhering to glass. Spring constants of the bond are derived from vibrational amplitudes and related to the electrophoretic softness of the cell surfaces and dissipation shifts measured upon bacterial adhesion in a quartz crystal-microbalance (QCM-D). Experiments were conducted with six bacterial strains with pairwise differences in cell surface characteristics. Vibrational amplitudes were highest in low ionic strength suspensions. Under fluid flow, vibrational amplitudes were lower in the direction of flow than perpendicular to it because stretching of cell surface polymers in the direction of flow causes stiffening of the polyelectrolyte network surrounding a bacterium. Under static conditions (0.57 mM), vibrational amplitudes of fibrillated Streptococcus salivarius HB7 (145 nm) were higher than that of a bald mutant HB-C12 (76 nm). Amplitudes of moderately extracellular polymeric substance (EPS) producing Staphylococcus epidermidis ATCC35983 (47 nm) were more than twice the amplitudes of strongly EPS producing S. epidermidis ATCC35984 (21 nm). No differences were found between Staphylococcus aureus strains differing in membrane cross-linking. High vibrational amplitudes corresponded with low dissipation shifts in QCM-D. In streptococci, the polyelectrolyte network surrounding a bacterium is formed by fibrillar surface appendages and spring constants derived from vibrational amplitudes decreased with increasing fibrillar density. In staphylococci, EPS constitutes the main network component, and larger amounts of EPS yielded higher spring constants. Spring constants increased with increasing ionic strength and strains with smaller electrophoretically derived bacterial cell surface softnesses possessed the highest spring constants. PMID- 25025496 TI - Fabrication of segmented Au/Co/Au nanowires: insights in the quality of Co/Au junctions. AB - Electrodeposition is a versatile method, which enables the fabrication of a variety of wire-like nanoarchitectures such as nanowires, nanorods, and nanotubes. By means of template-assisted electrodeposition, segmented Au/Co/Au nanowires are grown in anodic aluminum oxide templates from two different electrolytes. To tailor the properties of the cobalt segments, several electrochemical conditions are studied as a function of current density, pulse deposition, and pH. The morphology, crystal structure, and magnetic properties are accordingly investigated. Changes in the deposition conditions affect the cobalt electrocrystallization process directly. Cobalt tends to crystallize mainly in the hexagonal close-packed structure, which is the reason cobalt might not accommodate satisfactorily on the face-centered cubic Au surface or vice versa. We demonstrate that by modifying the electrolyte and the applied current densities, changes in the texture and the crystalline structure of cobalt lead to a good quality connection between dissimilar segments. In particular, lowering the bath pH, or using pulse plating at a high overpotential, produces polycrystalline fcc Co and thus well-connected Co/Au bimetallic junctions with smooth interface. These are crucial factors to be carefully considered taking into account that nanowires are potential building blocks in micro- and nanoelectromechanical systems. PMID- 25025494 TI - Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity. AB - Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS) injuries. Potential signaling mechanisms driving the conversion of astrocytes into "reactive" phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB). As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT) engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity induced astrogliosis both signal through STAT3 but appear to do so through different modules, perhaps localized to different cell types. PMID- 25025497 TI - Cervical goniometer. AB - A large number of orthopaedic casualties during the 1914-1918 war attracted the attention of various scientists towards the evaluation of range of motion at joints. PMID- 25025498 TI - The prosthetic problems of below knee amputees with flexion contractures. AB - It has always been difficult to provide the patient who has had a below knee amputation and has a fixed flexion contracture, with a suitable artificial limb. The adaptation of the Patellar Tendon Bearing (PTB) below knee prosthesis and the subsequent Supracondylar Variation (PTS) of this type of prosthesis has been applied to this problem. PMID- 25025499 TI - Heavy resistance exercise without apparatus. AB - A common problem in rehabilitation is the prescription of heavy-resistance exercise which requires little apparatus. Apparatus is often unavailable and always expensive. An attempt is made here to resolve the problem. Examples are described in which a common kitchen chair is the only necessary equipment. PMID- 25025500 TI - Operant behaviour and physiotherapy: establishing walking behaviour in a moderately retarded institutionalized boy. AB - The present study sets out the design of an operant conditioning programme which it was decided was the most appropriate form of physiotherapy for the patient, a moderately retarded institutionalized boy. PMID- 25025501 TI - Biofeedback in brain injury - an overview. AB - Biofeedback is the normal mechanism whereby an organism consciously monitors its behaviour and performance according to information received from its environment. PMID- 25025502 TI - The relationship of the vestibular and proprioceptive systems to dysfunction in verticality perception, posture and movement, after stroke. AB - The extent to which verticality perception influences posture and movement is of considerable importance to the physiotherapist. To determine the relative contributions of the vestibular and proprioceptive systems to visuo-spatial perception after stroke and the relationship of verticality perception to body alignment and utilisation of space during movement, a study was undertaken in the Department of Physiotherapy, University of Queensland. Forty stroke patients, divided into experimental groups on the basis of quality of verticality perception, were selected for study, while twenty two 'non-stroke' subjects, matched for age and sex, formed a control group. Measurements were taken of proprioception, body alignment, utilisation of space during movement, verticality perception and duration of post rotational nystagmus. Analyses of the correlations between these various modalities revealed those features which are of most significance to the perception of verticality, posture and movement of the stroke patient. From these results, implications for the physiotherapy management of the stroke patient with problems in verticality perception, body alignment and utilisation of space during movement, have been drawn. PMID- 25025503 TI - The anterior cruciate ligament : effect of passive movements. AB - A mercury strain guage was used to analyze the affects of passive movement techniques upon the anterior cruciate ligament. One post-mortem subject was studied. Posterior-anterior pressures, with knee flexed to 90 degrees and medially rotated, revealed the most significant displacement of the anterior cruciate. It is suggested that combined movements may play a significant role in treatment of the knee joint. PMID- 25025504 TI - Massage as an adjunct to meditation in the psychological treatment of cancer. AB - In the treatment of cancer by meditation the patient is led into a profoundly calm state of mind in which thought practically ceases. Talking alerts the patient and prevents this process. Massage can be used as a simple form of communication to help the patient towards this state of mind. Massage can also be used as an adjunct in teaching the cancer patient to transcend frustrations, discomfort and pain, and so reduce the level of anxiety. PMID- 25025505 TI - Regulation of postsynaptic plasticity genes' expression and topography by sustained dopamine perturbation and modulation by acute memantine: relevance to schizophrenia. AB - A relevant role for dopamine-glutamate interaction has been reported in the pathophysiology and treatment of psychoses. Dopamine and glutamate may interact at multiple levels, including the glutamatergic postsynaptic density (PSD), an electron-dense thickening that has gained recent attention as a switchboard of dopamine-glutamate interactions and for its role in synaptic plasticity. Recently, glutamate-based strategies, such as memantine add-on to antipsychotics, have been proposed for refractory symptoms of schizophrenia, e.g. cognitive impairment. Both antipsychotics and memantine regulate PSD transcripts but sparse information is available on memantine's effects under dopamine perturbation. We tested gene expression changes of the Homer1 and PSD-95 PSD proteins in models of sustained dopamine perturbation, i.e. subchronic treatment by: a) GBR-12909, a dopamine receptor indirect agonist; b) haloperidol, a D2R antagonist; c) SCH 23390, a dopamine D1 receptor (D1R) antagonist; and d) SCH-23390+haloperidol. On the last day of treatment, rats were acutely treated with vehicle or memantine. The Homer1a immediate-early gene was significantly induced by haloperidol and by haloperidol+SCH-23390. The gene was not induced by SCH-23390 per se or by GBR 12909. Expression of the constitutive genes Homer1b/c and PSD-95 was less affected by these dopaminergic paradigms. Acute memantine administration significantly increased Homer1a expression by the dopaminergic compounds used herein. Both haloperidol and haloperidol+SCH-23390 shifted Homer1a/Homer1b/c ratio of expression toward Homer1a. This pattern was sharpened by acute memantine. Dopaminergic compounds and acute memantine also differentially affected topographic distribution of gene expression and coordinated expression of Homer1a among cortical-subcortical regions. These results indicate that dopaminergic perturbations may affect glutamatergic signaling in different directions. Memantine may help partially revert dopamine-mediated glutamatergic dysfunctions. PMID- 25025506 TI - Head and neck free flap reconstruction in patients older than 80 years. AB - BACKGROUND: Free tissue transfer is a reliable method for reconstruction of head and neck defects. With the growing number of octogenarians in the population, it is important to understand how these patients respond to these procedures. METHODS: Through a retrospective chart review of patients who underwent a free flap reconstruction from 2000 to 2010 at an academic medical center, 48 patients, aged 80 years and older, were compared with a control group consisting of 97 similar patients, aged younger than 80 years. We compared the intensive care unit (ICU) length of stay, overall hospital stay, and the incidence of perioperative complications between the cohorts. RESULTS: The average length of stay in the ICU was significantly longer for the octogenarian group as compared with the younger group (101 vs. 41 hours, p-value = 0.007). The average length of hospital stay was not significantly different between the two groups (difference = 40 hours, p value = 0.102). The incidence of perioperative complication was 75% in the octogenarian group and 60% in the younger group (p-value = 0.095). There were two flap failures in the younger group, and none in the octogenarian group. There was a significantly higher rate of death within 30 days in the octogenarian group. CONCLUSIONS: Microvascular free tissue transfer is a reliable and safe method of reconstruction of head and neck defects in patients over 80 years of age. Patients should be counseled about the potential risks of increased incidence of medical complications, ICU length of stay, and rate of perioperative death when recommended to undergo free tissue transfer reconstruction. PMID- 25025507 TI - Magnetic Resonance Lymphangiography for the Study of Lymphatic System in Lymphedema. AB - BACKGROUND: Imaging of the lymphatic system is difficult because of its structural and anatomical characteristics, and the conventional diagnostic method, radionuclide-based imaging, has the disadvantage of poor resolution. Magnetic resonance (MR) imaging has been shown the capability of depicting lymphatic channels in lymphedema recently. The purpose of this study was to evaluate the imaging of MR lymphangiography (MRL) in diagnosis of limb lymphedema and its possible role in the microsurgical management of lymphedema. METHODS: A total of 710 patients with primary lymphedema (n = 378), secondary lymphedema (n = 332), were enrolled in the study. Contrast-enhanced lymphangiography was performed with 3.0 T MR unit (Philips Medical Systems, Best, The Netherlands) after intracutaneously injection of gadobenate dimeglumine. Kinetic of enhanced lymph flow within lymphatics and lymph nodes as well as the morphological abnormalities of lymphatic system were evaluated. RESULTS: MRL was able to display the detailed anatomical changes in the vessels and nodes. In primary lymphedema, there are three major types of lymphatic system malformation: (1) only lymph nodes affected, (2) only lymph vessels affected, and (3) both lymph vessels and lymph nodes affected. In secondary lymphedema MRL clearly demonstrated tortuous and dilated collecting lymphatics in lymphedemtous limbs. MRL also provided information concerning the functional status of lymph transport in lymphatic vessels and nodes by real-time visualization of enhanced lymph flow in lymphatic channels and within lymph nodes. CONCLUSION: Contrast MRL was capable of evaluating the anatomical and functional status of lymphatic vessels and lymph nodes in lymphedematous limb. This new imaging shows good potential for use in the diagnosis and surgical management of lymphedema. PMID- 25025508 TI - Resurfacing severe facial burn scars: an algorithm based on three different types of prefabricated expanded flaps. AB - BACKGROUND: In the reconstruction of facial burn scars, large, thin, color matching flaps are desirable due to aesthetic and functional demands. There have been many reports using prefabricated flaps to resurface facial skin lesions. However, an algorithm to select the most suitable treatment option for the individual patient is lacking. METHODS: An algorithm for facial resurfacing based on three types of prefabricated flaps from the cervical, periclavicular, and lateral thoracic area was setup, and 15 were patients treated accordingly. RESULTS: All 15 prefabricated flaps survived. Minor necrosis at the distal flap edge developed in three cases. After a follow-up of at least 6 months, all patients showed satisfactory aesthetic and functional outcomes. CONCLUSION: By individual selection of the most suitable option among these three types of prefabricated flaps, satisfactory resurfacing can be achieved for most facial burn scars. PMID- 25025509 TI - Clinical outcome following transfer of the supinator motor branch to the posterior interosseous nerve in patients with C7-T1 brachial plexus palsy. AB - BACKGROUND: In cases of C7-T1 brachial plexus palsy, a reliable method for the reconstruction of the finger and thumb extension was not established until the transfer of the supinator motor branch to the posterior interosseous nerve was proposed. The long-term outcome of this new technique requires evaluation due to the limited number of cases and the shorter follow-up period of the previous study. OBJECTIVE: This study aims to evaluate the long-term effect of the transfer of the supinator motor branch to the posterior interosseous nerve and to determine the recovery time course for this new technique. METHODS: A retrospective review was conducted in 10 patients with lower brachial plexus injuries who underwent transfer of the supinator motor branch. Patients were followed up postoperatively for a minimum of 24 months, with all patients scheduled to receive a physical examination and electrophysiological testing every 3 months for the first 2 years. RESULTS: Nine patients (90%) recovered to the Medical Research Council (MRC) grade 3 or better for the extensor digitorum communis. The electrophysiologically documented recovery began at an average of 5.7 months after surgery, with the average time required for the first finger extension being 9.1 months (range 5-18 months), and the average time required for achieving MRC grade 3 being 14.3 months (range 9-24 months). Moreover, no complications or loss of supination was observed in any patient. CONCLUSION: The supinator motor branch transfer is a safe procedure that yields recovery of finger extension in C7-T1 brachial plexus palsies with encouraging long-term outcomes. PMID- 25025510 TI - Open achilles tendon defects: a 12-year study on the injury mechanisms, reconstructions, and late complications. AB - BACKGROUND: Open injuries of the Achilles tendon, which can be complicated by skin and bone injuries, continue to be a great challenge for surgeons. This study aims to report our experience with treatment of open Achilles tendon defects, focusing on the injury mechanisms, soft tissue coverage and late complications. METHODS: A retrospective review was performed on 31 patients with open Achilles tendon defects between 1999 and 2011. The analyzed factors were injury mechanisms, surgeries, and long follow-up complications. The defect lengths of the Achilles tendons in the study ranged from 1 to 11 cm and the soft tissue defects ranged from 3 * 3 to 12 * 10 cm. Nine types of flaps were used for the coverage of concomitant skin defects. RESULTS: Motorcycle spoke injuries were the most common cause of injury. There was no complete flap loss or rerupture of the reconstructed Achilles tendon. At the latest follow-up, all limbs were preserved and all the patients had regained full walking abilities. The algorithm of one stage reconstruction was established, according to the defect length of the Achilles tendon and the defect size of skin. Late complications included maximum dorsiflexion loss and failure of heel raising ability on the single reconstructed foot. CONCLUSION: Open Achilles tendon defects are characteristic of concurrent skin and bone injuries and the reconstruction protocols of the different tissues should not be separated. PMID- 25025512 TI - The effect of ageing and strength training on skeletal muscle. AB - The present review describes several age related changes in the neuromuscular system of humans and animals which may underlie the marked strength decline of ageing muscle. Studies describing the effects of resistance training on the muscle strength of ageing humans and animals are also reviewed. From a survey of these studies, the strength decline with age appears to be due, in part, to a loss of muscle mass. While not conclusive, the effect of resistance training has been to attenuate the extent of the atrophy occurring with age, and to improve strength. A better understanding of the neuromuscular mechanisms of ageing, as well as the adaptive response of ageing mammalian muscle to resistance training, could enable physical therapists to critically evaluate the merits of strength training intervention for improving the physical ability of an ageing individual. PMID- 25025511 TI - Versatility of the thoracoacromial artery perforator flap in head and neck reconstruction. AB - BACKGROUND: The thoracoacromial artery perforator (TAAP) flap used in its pedicle or in the free microvascular variant is an emerging flap for use as a reconstructive option for the head and neck region. PATIENTS AND METHODS: Between 2006 and 2013, 17 patients with a mean age of 34 years (range, 17-59 years) underwent a TAAP flap procedure for reconstruction of postoncologic and posttraumatic head and neck defects. RESULTS: The pedicle TAAP flap was used to reconstruct neck (n = 5) and hypopharyngeal defects (n = 5); the free TAAP flap was used to resurface lower hemiface (n = 4), tongue (n = 1), and intraoral (n = 2) defects. The flap size ranged from 4.5 * 7 cm to 12 * 17 cm, with a mean thickness of 0.5 cm. The pectoralis major muscle was preserved in all of the cases. All of the patients healed uneventfully. The donor site was closed directly in four cases; a skin graft was used in four patients, and the donor site was covered by a local flap in one case. CONCLUSIONS: Our experience proved the consistent feasibility of the successful use of the TAAP flap for head and neck reconstructions resulting in adequate color matching, texture, and pliability in combination with limited anterior chest wall donor site morbidity. Its hairless nature ensures that this flap is a suitable primary option for inner lining reconstruction of oropharyngeal defects. PMID- 25025513 TI - Why choose to work in geriatrics? Factors which affect physiotherapists' decisions to work with older people. AB - The paper examines the factors which influence physiotherapists' decisions to practise geriatrics. Some 233 physiotherapists returned a questionnaire aimed at identifying the major issues which affected work preference. The questionnaire included items on previous work experience with older people, attitudes towards ageing and elderly clients, and professional issues which influence career choice. The results indicated that most physiotherapists preferred to work in areas other than geriatrics. The majority who practised geriatrics were females aged 41-65, employed part-time. The decision not to work in geriatrics appeared to be related to lack of work experience with older people and employment conditions. Greater negative bias towards elderly people was shown by physiotherapists without postgraduate education in gerontology. In addition, there was a perception amongst clinicians that gerontological physiotherapy offered few opportunities for professional advancement and lacked status. PMID- 25025514 TI - Motor assessment scale scores as a measure of rehabilitation outcome following stroke. AB - The purpose of this study was to investigate the outcome of rehabilitation following cerebrovascular accident (CVA) in one Sydney unit. This unit has implemented a philosophy of training based on a motor learning model for rehabilitation proposed by Carr and Shepherd (1987a and b). The proposed motor learning model stresses the need for task and context specific training of everyday actions. Data, including patient characteristics and Motor Assessment Scale (MAS) scores, were collected through a retrospective audit of all patients diagnosed as having a CVA and discharged from the unit during 1989. The major finding of this study was that, following rehabilitation within a multi disciplinary program, patients were able to improve their motor performance as demonstrated by changes in MAS scores. The measurement of outcome of rehabilitation for this unit has contributed to quality assurance by identifying motor tasks that warrant further emphasis in training in order to improve upon the reported outcome of rehabilitation. PMID- 25025515 TI - Strapping the shoulder in patients following a cerebrovascular accident (CVA): A pilot study. AB - This pilot study was undertaken to determine the effectiveness of a strapping technique to prevent the onset of shoulder pain in the hemiplegic upper limb of patients following a Cerebrovascular Accident (CVA). Eight patients with no voluntary movement in their hemiplegic upper limb were selected for inclusion within 48 hours of their admission to hospital. Four subjects were assigned to a strapping group and four were assigned to a non-strapping group. Each subject was assessed daily for the presence of shoulder pain utilising the Ritchie Articular Index, adapted for use with hemiplegic patients by Bohannon and LeFort (1986). The number of pain free days for each patient was recorded and a comparison made between the two groups. Results indicated that subjects in the strapping group experienced a significantly longer pain free period (mean=21 days) compared with the non-strapping group (mean=5.5 days). This pilot study demonstrated that strapping the affected shoulder following CVA did delay the onset of shoulder pain. However, further investigation with a larger study population is required to evaluate the effectiveness of the strapping technique against other factors. PMID- 25025516 TI - Predicting step time from step length and velocity. AB - This study was designed to investigate the relationship between step time and step length in a healthy population of young adults. The sample was composed of 10 females and 10 males with ages ranging from 19 to 25 years. The subjects walked along a resistive grid walkway at an audio-controlled cadence of 80 steps per minute. These trials consisted of two walks with asymmetrical step lengths (2/4 time), two walks with asymmetrical step times (3/4 time) and two in which the only constraint was the cadence. The results indicate that the values of average velocity and average step length can be used to calculate step time with reasonable accuracy in a symmetrical walking pattern, but not under conditions of induced step length or step time asymmetries. It is suggested that stride frequency rather than cadence be used, particularly when measurements are made from patients with asymmetrical walking patterns. PMID- 25025517 TI - A controlled double blind study comparing the effects of strong Burst Mode TENS and High Rate TENS on painful osteoarthritic knees. AB - This double blind, controlled study compared the changes in pain, stiffness, circumference and range of movement, produced by one 30 minute application of High Rate TENS, or strong Burst Mode TENS on chronic osteoarthritic knees. Both TENS applications were applied at strong, tolerable intensities for 30 minutes, over four acupuncture points around the knee. Pain, stiffness, circumference, and range of movement measurements were recorded immediately before and after the TENS applications. Length of continuation of pain relief and alteration in stiffness was reported by subjects. The study aimed to establish whether strong Burst Mode TENS produced significantly greater and longer lasting changes than those produced by High Rate TENS. The only significant change produced by strong Burst Mode when compared with High Rate TENS was on knee circumference. PMID- 25025518 TI - Development and optimization of an analytical system for volatile organic compound analysis coming from the heating of interstellar/cometary ice analogues. AB - This contribution presents an original analytical system for studying volatile organic compounds (VOC) coming from the heating and/or irradiation of interstellar/cometary ice analogues (VAHIIA system) through laboratory experiments. The VAHIIA system brings solutions to three analytical constraints regarding chromatography analysis: the low desorption kinetics of VOC (many hours) in the vacuum chamber during laboratory experiments, the low pressure under which they sublime (10(-9) mbar), and the presence of water in ice analogues. The VAHIIA system which we developed, calibrated, and optimized is composed of two units. The first is a preconcentration unit providing the VOC recovery. This unit is based on a cryogenic trapping which allows VOC preconcentration and provides an adequate pressure allowing their subsequent transfer to an injection unit. The latter is a gaseous injection unit allowing the direct injection into the GC-MS of the VOC previously transferred from the preconcentration unit. The feasibility of the online transfer through this interface is demonstrated. Nanomoles of VOC can be detected with the VAHIIA system, and the variability in replicate measurements is lower than 13%. The advantages of the GC-MS in comparison to infrared spectroscopy are pointed out, the GC-MS allowing an unambiguous identification of compounds coming from complex mixtures. Beyond the application to astrophysical subjects, these analytical developments can be used for all systems requiring vacuum/cryogenic environments. PMID- 25025519 TI - Acid-induced release of curcumin from calcium containing nanotheranostic excipient. AB - Poor water solubility is believed one of the most critical problems of numerous promising pharmaceutical ingredients in their successful clinical utilization. Nanomedicine holds considerable promise to address this challenge, because it extends the therapeutic window of hydrophobic drugs through nanonization approach. Recently, the integration of diagnostic agents with smart therapeutic nanocarriers is also an emerging research arena to simultaneously visualize diseased tissues, achieve site specific drug release and track the impact of therapy. In this study, we have developed a biocompatible smart theranostic nanosystem which transports a highly promising hydrophobic drug (curcumin) in response to mildly acidic environment. As calcium is a main constituent of human body, hence we exploited the reversible calcium chelate formation tendency of divalent calcium to load and unload curcumin molecules. Moreover, an emerging T1 contrast agent is also tethered onto the surface of nanocarrier to realize MRI diagnosis application. In-vitro cell experiments revealed a significantly high chemotherapeutic efficiency of curcumin nanoformulation (IC50; 1.67 MUg/mL), whereas free curcumin was found ineffective at the corresponding concentration (IC50; 29.72 MUg/mL). MR imaging test also validated the performance of resulting system. Our strategy can be extended for the targeted delivery of other hydrophobic pharmaceutical ingredients. PMID- 25025520 TI - [Study of codon 72 of p53 gene as a risk-factor in cervical cancer in Senegal]. AB - Beside human papilloma virus infection, several genetic factors have been involved in susceptibility to cervical cancer. The arginine allele at codon 72 in p53 tumor suppressor gene has been reported to be a risk-factor in different ethnic groups. Our aim was to study this polymorphism as a risk-factor in Senegal. We conducted a case-control association study by recruiting 30 patients with cervical cancer clinically followed up in the Curie Institute in Dakar, and 93 healthy female controls without diagnosed cervical cancer. For each individual, DNA was extracted from whole blood. The codon 72 polymorphism was genotyped by PCR-RFLP. We did not find any association between the arginine allele and susceptibility to cervical cancer in our population (P = 0.354). Moreover, any correlation between the arginine allele and histological lesions was observed. Even if we did not find any correlation between the arginine allele and susceptibility to cervical cancer, p53 as a tumor suppressor gene remains a good genetic marker in tumours biology. PMID- 25025521 TI - Visualization of phosphatidic acid fluctuations in the plasma membrane of living cells. AB - We developed genetically-encoded fluorescent sensors based on Forster Resonance Energy Transfer to monitor phosphatidic acid (PA) fluctuations in the plasma membrane using Spo20 as PA-binding motif. Basal PA levels and phospholipase D activity varied in different cell types. In addition, stimuli that activate PA phosphatases, leading to lower PA levels, increased lamellipodia and filopodia formation. Lower PA levels were observed in the leading edge than in the trailing edge of migrating HeLa cells. In MSC80 and OLN93 cells, which are stable cell lines derived from Schwann cells and oligodendrocytes, respectively, a higher ratio of diacylglycerol to PA levels was demonstrated in the membrane processes involved in myelination, compared to the cell body. We propose that the PA sensors reported here are valuable tools to unveil the role of PA in a variety of intracellular signaling pathways. PMID- 25025522 TI - Church-based social marketing to motivate older adults to take balance classes for fall prevention: cluster randomized controlled trial. AB - OBJECTIVE: Determine whether a church-based social marketing program increases older adults' participation in balance classes for fall prevention. METHODS: In 2009-10, 51 churches (7101 total members aged >= 60) in Colorado, U.S.A. were randomized to receive no intervention or a social marketing program. The program highlighted benefits of class participation (staying independent, building relationships), reduced potential barriers (providing convenient, subsidized classes), and communicated marketing messages through church leaders, trained "messengers," printed materials and church-based communication channels. Between group differences in balance class enrollment and marketing message recall among congregants were compared using Wilcoxon Two-Sample Test and regression models. RESULTS: Compared to 25 control churches, 26 churches receiving the social marketing program had a higher median proportion (9.8% vs. 0.3%; p<0.001) and mean number (7.0 vs. 0.5; IRR=11.2 [95%CI: 7.5, 16.8]) of older adult congregants who joined balance classes. Intervention church members were also more likely to recall information about preventing falls with balance classes (AOR=6.2; 95% CI: 2.6, 14.8) and availability of classes locally (AOR=7.7; 95% CI: 2.6, 22.9). CONCLUSIONS: Church-based social marketing effectively disseminated messages about preventing falls through balance classes and, by emphasizing benefits and reducing barriers and costs of participation, successfully motivated older adults to enroll in the classes. PMID- 25025524 TI - Electrochemical conversion of CO2 to fuels: tuning of the reaction zone using suitable functional groups in a solid polymer electrolyte. AB - The electrochemical reduction of gaseous CO2 is studied for the first time using sterically hindered bulky quaternary ammonium ions in a solid polymer matrix at room temperature and atmospheric pressure in a developed electrochemical reactor. Some new insights are found, leading to an effective reaction process. It is found that the reaction zone can be tuned to a great extent with the help of fixed functional groups attached to the solid polymer. To illustrate the concept, solid polymer electrolytes with the same backbone and different fixed functional groups are synthesized. It is found that only a change to the functional group in the membrane is needed to dramatically change the efficiency and selectivity of the reaction products. Suitable groups may increase the mass transfer of CO2 at the reaction interface and help as a co-catalyst. This work may open a new approach for the development of next generation processes for gaseous CO2 electroreduction to fuels, which is a present need. PMID- 25025523 TI - Nicotine reduction as an increase in the unit price of cigarettes: a behavioral economics approach. AB - Urgent action is needed to reduce the harm caused by smoking. Product standards that reduce the addictiveness of cigarettes are now possible both in the U.S. and in countries party to the Framework Convention on Tobacco Control. Specifically, standards that required substantially reduced nicotine content in cigarettes could enable cessation in smokers and prevent future smoking among current non smokers. Behavioral economics uses principles from the field of microeconomics to characterize how consumption of a reinforcer changes as a function of the unit price of that reinforcer (unit price=cost/reinforcer magnitude). A nicotine reduction policy might be considered an increase in the unit price of nicotine because smokers are paying more per unit of nicotine. This perspective allows principles from behavioral economics to be applied to nicotine reduction research questions, including how nicotine consumption, smoking behavior, use of other tobacco products, and use of other drugs of abuse are likely to be affected. This paper reviews the utility of this approach and evaluates the notion that a reduction in nicotine content is equivalent to a reduction in the reinforcement value of smoking-an assumption made by the unit price approach. PMID- 25025526 TI - Equity and Social Justice Within African American Breastfeeding Approaches. PMID- 25025525 TI - Stereodivergent approach to the avermectins based on "super silyl" directed aldol reactions. AB - A stereodivergent approach to the spiroketal fragment of the avermectins is described. The strategy utilizes a sequence of three aldol reactions directed by the tris(trimethylsilyl)silyl "super silyl" group. Central to this strategy is that each aldol reaction can be controlled to allow access to either diastereomer in high stereoselectivity, thereby affording 16 stereoisomers along the same linear skeleton. The aldol products can be transformed into spiroketals, including an advanced intermediate in the total synthesis of avermectin A1a. PMID- 25025527 TI - [Pd(C^N)(X)(PPh3)] palladacycles react with 2,4,6-trifluorophenyl boronic acid to give stable transmetallation products of the type [Pd(C^N)(2,4,6-F3C6H2)(PPh3)]. AB - Direct transmetallation between palladacyclic complexes and arylboronic acid occurs to give isolable transmetallation products. In THF, the reaction occurs <0.5 h. Prolonged reaction leads to the generation of a dinuclear Pd complex bearing bridging MU-hydroxo and MU-acetoxy ligands. Insight into precatalyst activation for Suzuki-Miyaura cross-couplings mediated by palladacycles has been gained, where acetate and N-imidate anions activate a neutral arylboronic acid. PMID- 25025528 TI - Single-step microfluidic fabrication of soft monodisperse polyelectrolyte microcapsules by interfacial complexation. AB - Common methods for fabrication of polyelectrolyte microcapsules rely on a multi step process. We propose a single-step approach to generate polyelectrolyte microcapsules with 1-2 MUm shells based on polyelectrolyte complexation across a water/oil droplet interface and study the effect of parameters controlling the polyelectrolyte complexation on shell thickness. PMID- 25025529 TI - The administration of atomoxetine during alcohol deprivation induces a time limited increase in alcohol consumption after relapse. AB - The administration of selective serotonin reuptake inhibitors (SSRIs) typically used as antidepressants increases alcohol consumption after an alcohol deprivation period in rats. However, the appearance of this effect after the treatment with selective noradrenaline reuptake inhibitors (SNRIs) has not been studied. In the present work we examined the effects of a 15-d treatment with the SNRI atomoxetine (1, 3 and 10 mg/kg, i.p.) in male rats trained to drink alcohol solutions in a 4-bottle choice test. The treatment with atomoxetine (10 mg/kg, i.p.) during an alcohol deprivation period increased alcohol consumption after relapse. This effect only lasted one week, disappearing thereafter. Treatment with atomoxetine did not cause a behavioral sensitized response to a challenge dose of amphetamine (1.5 mg/kg, i.p.), indicating the absence of a supersensitive dopaminergic transmission. This effect is markedly different from that of SSRI antidepressants that produced both long-lasting increases in alcohol consumption and behavioral sensitization. Clinical implications are discussed. PMID- 25025530 TI - Comparison of the different kinds of feeding on the level of fecal calprotectin. AB - BACKGROUND: Controversial results have been reported on the effect of type of feeding on the level of fecal calprotectin in infants. OBJECTIVE: To assess fecal calprotectin levels in breast fed or nonbreast fed healthy infants. DESIGN: A study was conducted to compare fecal calprotectin in infants who were exclusively breastfed compared to those who were not breastfed in Shanghai, China. Stool samples were collected and analyzed, and the fecal calprotectin concentration was determined using a commercially available enzyme-linked immunosorbent assay. The infant's weight and length were measured. Parents were asked to fill in a brief questionnaire, with questions about several clinical and sociodemographic factors. SUBJECTS: This study included 105 healthy infants aged 0-5 months. RESULTS: Stool samples were obtained from 105 healthy infants (63 boys, 42 girls) with a median age of 2.86 months (range 1-5.88). The median fecal calprotectin concentration was significantly higher in breast fed infants (377MUg/g, range 35 937MUg/g) than that in nonbreast fed ones (233MUg/g, range 37-895MUg/g) (p=0.001). A correlation was found that from 0 to 5 months, fecal calprotectin was negatively and significantly associated with age in both two kinds of feeding (breast fed: Spearman's rho -0.346, p=0.010; nonbreast fed: Spearman's rho 0.478, p<0.001). CONCLUSIONS: Our findings show that the kind of feeding influences the fecal calprotectin concentration and breast fed infants have higher levels than nonbreast fed ones in the first months of life. This may represent that human milk influences the gut mucosa by immunomodulating factors. PMID- 25025531 TI - A label-free double-amplification system for sensitive detection of single stranded DNA and thrombin by liquid chromatography-mass spectrometry. AB - A label-free double amplification system has been developed by using a ternary DNA probe containing the poly(adenine-thymine) sequence assisted by exonuclease III degradation. The method achieved more than 600-fold signal amplification and allowed sensitive detection of single-stranded DNA and thrombin at the pM level by using liquid chromatography/mass spectrometry. PMID- 25025533 TI - The anterior interlay myringoplasty: outcome and hearing results in anterior and subtotal tympanic membrane perforations. AB - OBJECTIVE: To describe a new technique, anterior interlay myringoplasty, to secure the anterior edge of a graft in tympanic membrane perforations with an anterior component. PATIENTS: Consecutive patients undergoing anterior interlay myringoplasty were identified from the prospective otology database of the senior author. INTERVENTION(S): A tympanomeatal flap is elevated from the posterior canal wall, the annulus is elevated, and the tympanic membrane (TM) dissected off the malleus handle. The anterior "pocket" is fashioned using the Hughes dissector to elevate the mucosa medially from the fibrous layer of the narrow anterior rim of the perforation leaving the anterior annulus undisturbed; the elevation of mucosa medially is continued into the Eustachian tube orifice, which is matched by the angulation of the Hughes. Releasing incisions are necessary through the mucosal layer allowing the posterior portion of the graft to lie as an underlay and secured between the TM and malleus handle. MAIN OUTCOME MEASURE(S): Primary outcomes of tympanic membrane perforation closure rates and hearing outcome averaged over frequency thresholds 0.5, 1, 2, and 4 kHz at 12 months. RESULTS: One hundred sixteen patients were included for analysis, and 50 were pediatric cases. The overall tympanic membrane perforation closure rate in all cases was 91% (105/116) at outpatient appointments closest to 12 months and a mean hearing threshold improvement of 9.98 dB (SD 9.63, range 43.8 dB improvement to 20 dB loss) was seen. CONCLUSION: The anterior interlay technique is a valuable method to achieve anterior support for a tympanic membrane graft and is associated with good closure rates and audiological outcomes. PMID- 25025534 TI - Cochlear Fistula as a Late Consequence of Tympanomastoidectomy. PMID- 25025532 TI - Population and demographic structure of Ixodes scapularis Say in the eastern United States. AB - INTRODUCTION: The most significant vector of tick-borne pathogens in the United States is Ixodes scapularis Say (the blacklegged tick). Previous studies have identified significant genetic, behavioral and morphological differences between northern vs. southern populations of this tick. Because tick-borne pathogens are dependent on their vectors for transmission, a baseline understanding of the vector population structure is crucial to determining the risks and epidemiology of pathogen transmission. METHODS: We investigated population genetic variation of I. scapularis populations in the eastern United States using a multilocus approach. We sequenced and analyzed the mitochondrial COI and 16S genes and three nuclear genes (serpin2, ixoderin B and lysozyme) from wild specimens. RESULTS: We identified a deep divergence (3-7%) in I. scapularis COI gene sequences from some southern specimens, suggesting we had sampled a different Ixodes species. Analysis of mitochondrial 16S rRNA sequences did not support this hypothesis and indicated that all specimens were I. scapularis. Phylogenetic analysis and analysis of molecular variance (AMOVA) supported significant differences between northern vs. southern populations. Demographic analysis suggested that northern populations had experienced a bottleneck/expansion event sometime in the past, possibly associated with Pleistocene glaciation events. CONCLUSIONS: Similar to other studies, our data support the division of northern vs. southern I. scapularis genetic lineages, likely due to differences in the demographic histories between these geographic regions. The deep divergence identified in some COI gene sequences highlights a potential hazard of relying solely on COI for species identification ("barcoding") and population genetics in this important vector arthropod. PMID- 25025535 TI - Spontaneous bone bed formation in cochlear implantation using the subperiosteal pocket technique. AB - OBJECTIVE: To show evidence of spontaneous bone pocket formation using the subperiosteal pocket technique for cochlear implantation surgery. STUDY DESIGN: Clinical capsule report. SETTING: University hospital. PATIENTS: We evaluated 8 pediatric revision cochlear implant patients who had previously undergone cochlear implantation using the subperiosteal pocket technique. The time between primary and revision surgery varied between 5 and 54 months. RESULTS: Spontaneous bone bed formation for the internal receiver stimulator and its electrodes was observed during revision surgeries in all patients. CONCLUSION: The subperiosteal pocket technique for cochlear implantation does not require pockets to be drilled in the skull, unlike the standard technique, because bone beds form spontaneously. PMID- 25025536 TI - Chemically assisted dissection by means of mesna in cholesteatoma surgery. AB - OBJECTIVE: To investigate whether the use of mesna (sodium 2 mercaptoethanesulfonate), a mucolytic agent capable of breaking disulfur bonds, reduces the frequency of residual cholesteatoma in canal wall up tympanomastoidectomy. STUDY DESIGN: Retrospective study. SETTING: Tertiary care otology and skull base centers. PATIENTS: Two hundred fourteen patients operated on by means of canal wall up tympanomastoidectomy for a middle ear cholesteatoma. INTERVENTIONS: Planned staged canal wall up tympanomastoidectomy. In the study group, the cholesteatoma removal was performed with the support of chemically assisted dissection by using mesna. In the control group, the dissection of the disease was performed by means of a traditional mechanical technique alone. MAIN OUTCOME MEASURES: Prevalence of residual cholesteatoma at the second-stage operation in the 2 groups of study. RESULTS: One hundred eight patients were treated with the ancillary use of mesna and one hundred six without chemically assisted dissection. A residual cholesteatoma was found in 12 (11.1%) of the 108 patients treated with chemically assisted dissection and in 26 (24.5%) of the 106 patients treated with mechanical dissection. After adjusting for potential confounders, CADISS procedure was associated with a significantly lower risk of having residual cholesteatoma (OR, 0.39; 95% CI, 0.18-0.84, p = 0.02). CONCLUSION: This study showed that chemically assisted dissection by using mesna represents a valid support in reducing the frequency of residual disease in cholesteatoma surgery. PMID- 25025537 TI - The transcanal transpromontorial corridor to treat cochlear schwannomas. PMID- 25025538 TI - Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment. AB - Dasatinib, which is an inhibitor of BCR-ABL and SRC family tyrosine kinases, is used for the treatment of patients with Philadelphia chromosome (Ph) positive leukemia, especially for those who develop resistance or who are intolerant to imatinib. The most common adverse effects attributed to its use are: myelosuppression, nausea, diarrhea, and peripheral edema. Hemorrhage, which could be gastrointestinal, genitourinary or central nervous system, is a less frequent adverse effect. In this case, we report a patient affected by precursor B-cell acute lymphoblastic leukemia (ALL) positive for the Ph chromosome translocation treated with the tyrosine kinase inhibitor (TKI) dasatinib. During the treatment with dasatinib the patient developed subdural hematoma (SDH). She did not have any head trauma, thrombocytopenia, coagulopathy or meningeal involvement, making dasatinib-induced platelet dysfunction the most likely cause of SDH. PMID- 25025539 TI - Copper-catalyzed aerobic decarboxylative sulfonylation of cinnamic acids with sodium sulfinates: stereospecific synthesis of (E)-alkenyl sulfones. AB - A copper-catalyzed aerobic decarboxylative sulfonylation of alkenyl carboxylic acids with sodium sulfinates is developed. This study offers a new and expedient strategy for stereoselective synthesis of (E)-alkenyl sulfones that are widely present in biologically active natural products and therapeutic agents. Moreover, the transformation is proposed to proceed via a radical process and exhibits a broad substrate scope and good functional group tolerance. PMID- 25025540 TI - Development of visual perception in the very young infant - a review. AB - This paper is addressed to the effects of experience on the developing nervous system of the very young infant. Particular attention is paid to visual and visual-motor development. PMID- 25025541 TI - The employed professional and trade unionism. AB - Trade unions are often in the news and their activities subject to much critical comment. Many professional people may feel that trade union activities and professional standards are in conflict. This paper argues that professional workers in employment can engage in trade union activity in a way which is compatible with professional standards of behaviour. Furthermore, it is suggested, greater involvement of professional workers in trade unions can be a creative and constructive force for better trade unions and better trade unionism. PMID- 25025542 TI - A medical rehabilitation programme for australia. AB - I began to write this paper in the hills North of Canton in China. It seemed appropriate to reflect on some of the differences and similarities between Chinese health services and ours. The outstanding similarity is that they set a high value on health. An outstanding difference lies in the reason they attach so much importance to the health of individuals and of the community. PMID- 25025543 TI - "Ethical principles and patient referral". AB - I am not a Philosopher by profession. I cannot claim to have a profound knowledge of the subject, "Ethics". But as a physiotherapist, I can claim to be concerned about the moral obligations of my profession to the public it serves; and it is from this basis that I feel qualified to speak. PMID- 25025544 TI - Psychiatric sequelae of head injury. AB - The psychiatric problems which may arise following head injury are common, occurring in from 10-77% of cases. The behaviours manifest often impede the progress of treatment causing frustration to the staff, and continuing distress to the patient. To assist in their understanding, I will present the sorts of problems which may arise, with reference to the course of the symptoms and behaviour and to their management. PMID- 25025545 TI - The role of the thoracic diaphragm. AB - The thoracic diaphragm is the principal muscle of inspiration and is present only in placentalia. Its dome-shaped musculo-fibrous septum separates the thorax from the abdominal cavity. PMID- 25025546 TI - Gels and lyotropic liquid crystals: using an imidazolium-based catanionic surfactant in binary solvents. AB - The self-assembly behavior of an imidazolium-based catanionic surfactant, 1-butyl 3-methylimidazolium dodecylsulfate ([C4mim][C12H25SO4]), was investigated in water-ethylammonium nitrate (EAN) mixed solvents with different volume ratios. It is particular interesting that this simple surfactant could not only form lyotropic liquid crystals (LLC) with multimesophases, i.e., normal hexagonal (H1), lamellar liquid crystal (Lalpha), and reverse bicontinuous cubic phase (V2), in the water-rich environment but also act as an efficient low-molecular weight gelator (LMWG) which gelated EAN-abundant binary media in a broad concentration range. The peculiar nanodisk cluster morphology of gels composed of similar bilayer units was first observed. FT-IR spectra and density functional theory (DFT) calculations reveal that strong H bonding and electrostatic interactions between EAN and the headgroups of [C4mim][C12H25SO4] are primarily responsible for gelation. The self-assembled gels displayed excellent mechanical strength and a thermoreversible sol-gel transition. It is for the first time that a rich variety of controllable ordered aggregates could be observed only by simply modulating the concentration of a single imidazolium-based catanionic surfactant or the ratio of mixed solvents. This environmentally friendly system is expected to have broad applications in various fields, such as materials science, drug delivery systems, and supramolecular chemistry. PMID- 25025547 TI - Quantitative evaluation of interaction force of fibrinogen at well-defined surfaces with various structures. AB - The effects of functional groups and structures at the surface of biomaterials on protein adsorption were examined using direct interaction force measurements. Three kinds of surface structures were evaluated: polymer brushes, self-assembled monolayers with low molecular weight compounds, and surfaces with conventional polymer coatings. These surfaces had various functional groups including phosphorylcholine (PC) group. The surface characterization demonstrated that surface wettability and flexibility depended on both the structure of the surface and the functional groups at the surface. The interactions of protein with these surfaces were evaluated by a force vs. distance curve using an atomic force microscope (AFM). We used fibrinogen as the protein, and the fibrinogen was immobilized on the surface of the AFM cantilever by a conventional technique. It was observed that the interaction force of fibrinogen was strongly related to surface hydrophobic nature and flexibility. That is, the interaction force increased with the increasing hydrophobic nature of the surface. The relationship between the amount of fibrinogen adsorbed on the surface and the interaction force showed good correlation in the range of fibrinogen adsorption from 0 to 250 ng/cm(2), that is, in a monolayered adsorption region. The interaction force decreased with increasing surface viscoelasticity. The most effective surface for preventing fibrinogen adsorption was the polymer brush surface with phosphorylcholine (PC) groups, that is, poly(2-methacryloyloxyethyl phosphorylcholine) brush. The interaction force of this sample was less than 0.1 nN and the amount of fibrinogen adsorbed on the surface was minimal. It was found that the evaluation of protein adsorption based on the interaction force measurement is useful for low-protein adsorption surfaces. It was demonstrated that an extremely hydrophilic and flexible surface could weaken the protein interactions at the surface, resulting in greater resistance to protein adsorption. PMID- 25025548 TI - Using videos to teach children inhaler technique: a pilot randomized controlled trial. AB - OBJECTIVE: This primary objective of this pilot randomized, controlled trial was to determine whether a brief video intervention delivered after a pediatric office visit could improve inhaler technique in children with asthma immediately and one month later. The intervention's effect on children's inhaler self efficacy and asthma control was also evaluated. METHODS: Children (n=91) ages 7 17 years with persistent asthma were recruited at two pediatric practices in North Carolina. Eligible children demonstrated their inhaler technique for metered dose inhalers (MDIs) either with or without a spacer. A trained research assistant used a validated inhaler technique checklist to record which steps children performed correctly. After a regularly scheduled office visit, children were randomized to watch either a 3-min MDI video (intervention group) or a nutrition video (control group) in English or Spanish. Children's technique was assessed again after watching the video and one month later. RESULTS: Children were primarily male (56%) and non-White (60%). When compared with the control group, children in the intervention group demonstrated a significant improvement in MDI technique post-intervention [mean=1.12 steps, 95% CI (0.73, 1.50)] but the improvement was not sustained at 1-month follow-up. The intervention did not lead to significant improvements in inhaler self-efficacy or asthma control. CONCLUSIONS: A brief video intervention offered during pediatric clinic visits can lead to immediate improvements in children's inhaler technique. Future studies should evaluate whether booster training videos can help maintain improvements in children's inhaler technique over time. PMID- 25025549 TI - A solitary wave-based sensor to monitor the setting of fresh concrete. AB - We present a proof-of-principle study about the use of a sensor for the nondestructive monitoring of strength development in hydrating concrete. The nondestructive evaluation technique is based on the propagation of highly nonlinear solitary waves (HNSWs), which are non-dispersive mechanical waves that can form and travel in highly nonlinear systems, such as one-dimensional particle chains. A built-in transducer is adopted to excite and detect the HNSWs. The waves are partially reflected at the transducer/concrete interface and partially transmitted into the concrete. The time-of-flight and the amplitude of the waves reflected at the interface are measured and analyzed with respect to the hydration time, and correlated to the initial and final set times established by the penetration test (ASTM C 403). The results show that certain features of the HNSWs change as the concrete curing progresses indicating that it has the potential of being an efficient, cost-effective tool for monitoring strengths/stiffness development. PMID- 25025550 TI - Correlation networks for identifying changes in brain connectivity during epileptiform discharges and transcranial magnetic stimulation. AB - The occurrence of epileptiform discharges (ED) in electroencephalographic (EEG) recordings of patients with epilepsy signifies a change in brain dynamics and particularly brain connectivity. Transcranial magnetic stimulation (TMS) has been recently acknowledged as a non-invasive brain stimulation technique that can be used in focal epilepsy for therapeutic purposes. In this case study, it is investigated whether simple time-domain connectivity measures, namely cross correlation and partial cross-correlation, can detect alterations in the connectivity structure estimated from selected EEG channels before and during ED, as well as how this changes with the application of TMS. The correlation for each channel pair is computed on non-overlapping windows of 1 s duration forming weighted networks. Further, binary networks are derived by thresholding or statistical significance tests (parametric and randomization tests). The information for the binary networks is summarized by statistical network measures, such as the average degree and the average path length. Alterations of brain connectivity before, during and after ED with or without TMS are identified by statistical analysis of the network measures at each state. PMID- 25025552 TI - Cell culture conditions: from outer space-like conditions to the mimicking of complex in vivo environments. PMID- 25025551 TI - The effectiveness of FES-evoked EMG potentials to assess muscle force and fatigue in individuals with spinal cord injury. AB - The evoked electromyographic signal (eEMG) potential is the standard index used to monitor both electrical changes within the motor unit during muscular activity and the electrical patterns during evoked contraction. However, technical and physiological limitations often preclude the acquisition and analysis of the signal especially during functional electrical stimulation (FES)-evoked contractions. Hence, an accurate quantification of the relationship between the eEMG potential and FES-evoked muscle response remains elusive and continues to attract the attention of researchers due to its potential application in the fields of biomechanics, muscle physiology, and rehabilitation science. We conducted a systematic review to examine the effectiveness of eEMG potentials to assess muscle force and fatigue, particularly as a biofeedback descriptor of FES evoked contractions in individuals with spinal cord injury. At the outset, 2867 citations were identified and, finally, fifty-nine trials met the inclusion criteria. Four hypotheses were proposed and evaluated to inform this review. The results showed that eEMG is effective at quantifying muscle force and fatigue during isometric contraction, but may not be effective during dynamic contractions including cycling and stepping. Positive correlation of up to r = 0.90 (p < 0.05) between the decline in the peak-to-peak amplitude of the eEMG and the decline in the force output during fatiguing isometric contractions has been reported. In the available prediction models, the performance index of the eEMG signal to estimate the generated muscle force ranged from 3.8% to 34% for 18 s to 70 s ahead of the actual muscle force generation. The strength and inherent limitations of the eEMG signal to assess muscle force and fatigue were evident from our findings with implications in clinical management of spinal cord injury (SCI) population. PMID- 25025553 TI - Current panorama of temporomandibular disorders' field in Brazil. AB - In 2012, the recognition of the specialty of Temporomandibular Disorders and Orofacial Pain completed ten years. Given this scenario, it is extremely important to track the current situation of this field of knowledge in Brazil, specifically in the area of research and training. We hope to discuss the importance of the recognition of this specialty and the inclusion of these subjects in undergraduate programs in Dentistry. OBJECTIVE: The objective of this study is to perform a bibliometric survey of researches regarding Temporomandibular Disorders and Orofacial Pain conducted in the country, determine the number of specialization courses in Orofacial Pain and the number of specialists in the field. METHODS: The bibliometric survey was conducted based on the Dissertations Portal of Coordination for the Improvement of Higher education Personnel (CAPES) and on PubMed. The panorama of the field of Orofacial Pain and Temporomandibular disorders in Brazil was determined by searching on the website of the Brazilian Council of Dentistry. RESULTS: We found 731 theses and dissertations with Temporomandibular Disorders and Orofacial Pain as the main subjects; 81 accredited/recognized Courses on Orofacial Pain and Temporomandibular Dysfunction completed; 8 accredited/recognized Specialization Courses on Orofacial Pain and Temporomandibular Dysfunction still in progress, and 1,064 registered specialists in Orofacial Pain and Temporomandibular Dysfunction in the Brazilian Council of Dentistry. Search in the PUBMED database yielded 576 articles published with the participation of Brazilian researchers as first authors and/or co-authors in the period from 2000 to 2013. From this amount, only 5 were published in Portuguese, while all the others were published in english. We can also notice that the number of published articles increases over time. CONCLUSION: The number of researches related to temporomandibular disorders has increased over the last ten years, as well as the number of specialization courses and the number of specialists, which represents a major breakthrough for this field of knowledge. PMID- 25025554 TI - Influence of time, toothpaste and saliva in the retention of Streptococcus mutans and Streptococcus sanguinis on different toothbrushes. AB - OBJECTIVES: The intraoral transmission of cariogenic and periodontopathogenic species seems to be facilitated by contaminated toothbrushes and other oral hygiene devices. The aim of this investigation was to analyze the in vitro retention and survival rate of Streptococcus mutans and Streptococcus sanguinis on different toothbrushes. The impacts of human saliva and antimicrobial toothpaste on these parameters were further evaluated. MATERIAL AND METHODS: Part I: Four toothbrushes (Colgate 360 degrees , Curaprox CS5460 ultra soft, elmex InterX, Trisa Flexible Head3) were contaminated by S. mutans DSM 20523 or S. sanguinis DSM 20068 suspensions for three minutes. Bacteria were removed from the toothbrushes after either three minutes (T0) or 24 hours (T24) of dry storage and grown on Columbia blood agar plates for the quantification of colony-forming units (CFUs). Part II: The effects of saliva from a caries-active or a caries inactive person and of toothpaste containing 0.12% chlorhexidine digluconate were also tested. RESULTS: Part I: After three minutes of dry storage, approximately one percent of the bacteria were still detectable on the toothbrushes. After 24 hours, S. sanguinis exhibited a more pronounced decrease in viable cell numbers compared with S. mutans but the differences were not significant (Kruskal-Wallis test, p>0.05). Part II: The addition of human saliva from a caries-active or caries-inactive person slightly increased the retention of both streptococcal species at T0. The use of toothpaste had no influence on the amount of viable streptococci at T0, but it reduced the microbial load after 24 hours of storage. There were only slight nonsignificant differences (p>0.05) between the four toothbrushes. CONCLUSIONS: In vitro bacterial retention and survival of S. sanguinis and S. mutans on different toothbrushes occurred. Within the limitations of this study, the use of human saliva or an antimicrobial toothpaste did not lead to significant differences in the microbial load on toothbrushes. PMID- 25025555 TI - Enamel crystals of mice susceptible or resistant to dental fluorosis: an AFM study. AB - OBJECTIVE: This study aimed to assess the overall apatite crystals profile in the enamel matrix of mice susceptible (A/J strain) or resistant (129P3/J strain) to dental fluorosis through analyses by atomic force microscopy (AFM). MATERIAL AND METHODS: Samples from the enamel matrix in the early stages of secretion and maturation were obtained from the incisors of mice from both strains. All detectable traces of matrix protein were removed from the samples by a sequential extraction procedure. The purified crystals (n=13 per strain) were analyzed qualitatively in the AFM. Surface roughness profile (Ra) was measured. RESULTS: The mean (+/-SD) Ra of the crystals of A/J strain (0.58+/-0.15 nm) was lower than the one found for the 129P3/J strain (0.66+/-0.21 nm) but the difference did not reach statistical significance (t=1.187, p=0.247). Crystals of the 129P3/J strain (70.42+/-6.79 nm) were found to be significantly narrower (t=4.013, p=0.0013) than the same parameter measured for the A/J strain (90.42+/-15.86 nm). CONCLUSION: enamel crystals of the 129P3/J strain are narrower, which is indicative of slower crystal growth and could interfere in the occurrence of dental fluorosis. PMID- 25025556 TI - Effect of root canal preparation, type of endodontic post and mechanical cycling on root fracture strength. AB - OBJECTIVE: To evaluate the impact of the type of root canal preparation, intraradicular post and mechanical cycling on the fracture strength of roots. MATERIAL AND METHODS: eighty human single rooted teeth were divided into 8 groups according to the instruments used for root canal preparation (manual or rotary instruments), the type of intraradicular post (fiber posts- FRC and cast post and core- CPC) and the use of mechanical cycling (MC) as follows: Manual and FRC; Manual, FRC and MC; Manual and CPC; Manual, CPC and MC; Rotary and FRC; Rotary, FRC and MC; Rotary and CPC; Rotary, CPC and MC. The filling was performed by lateral compactation. All root canals were prepared for a post with a 10 mm length, using the custom #2 bur of the glass fiber post system. For mechanical cycling, the protocol was applied as follows: an angle of incidence of 45 degrees , 37 degrees C, 88 N, 4 Hz, 2 million pulses. All groups were submitted to fracture strength test in a 45 degrees device with 1 mm/ min cross-head speed until failure occurred. RESULTS: The 3-way ANOVA showed that the root canal preparation strategy (p<0.03) and post type (p<0.0001) affected the fracture strength results, while mechanical cycling (p=0.29) did not. CONCLUSION: The root canal preparation strategy only influenced the root fracture strength when restoring with a fiber post and mechanical cycling, so it does not seem to be an important factor in this scenario. PMID- 25025557 TI - A microleakage study of gutta-percha/AH Plus and Resilon/Real self-etch systems after different irrigation protocols. AB - The development and maintenance of the sealing of the root canal system is the key to the success of root canal treatment. The resin-based adhesive material has the potential to reduce the microleakage of the root canal because of its adhesive properties and penetration into dentinal walls. Moreover, the irrigation protocols may have an influence on the adhesiveness of resin-based sealers to root dentin. OBJECTIVE: The objective of the present study was to evaluate the effect of different irrigant protocols on coronal bacterial microleakage of gutta percha/AH Plus and Resilon/Real Seal Self-etch systems. MATERIAL AND METHODS: One hundred ninety pre-molars were used. The teeth were divided into 18 experimental groups according to the irrigation protocols and filling materials used. The protocols used were: distilled water; sodium hypochlorite (NaOCl)+eDTA; NaOCl+H3PO4; NaOCl+eDTA+chlorhexidine (CHX); NaOCl+H3PO4+CHX; CHX+eDTA; CHX+ H3PO4; CHX+eDTA+CHX and CHX+H3PO4+CHX. Gutta-percha/AH Plus or Resilon/Real Seal Se were used as root-filling materials. The coronal microleakage was evaluated for 90 days against Enterococcus faecalis. Data were statistically analyzed using Kaplan-Meier survival test, Kruskal-Wallis and Mann-Whitney tests. RESULTS: No significant difference was verified in the groups using chlorhexidine or sodium hypochlorite during the chemo-mechanical preparation followed by eDTA or phosphoric acid for smear layer removal. The same results were found for filling materials. However, the statistical analyses revealed that a final flush with 2% chlorhexidine reduced significantly the coronal microleakage. CONCLUSION: A final flush with 2% chlorhexidine after smear layer removal reduces coronal microleakage of teeth filled with gutta-percha/AH Plus or Resilon/Real Seal SE. PMID- 25025558 TI - Effects of calcium hydroxide addition on the physical and chemical properties of a calcium silicate-based sealer. AB - Recently, various calcium silicate-based sealers have been introduced for use in root canal filling. The MTA Fillapex is one of these sealers, but some of its physicochemical properties are not in accordance with the ISO requirements. OBJECTIVE: The aim of this study was to evaluate the flowability, pH level and calcium release of pure MTA Fillapex (MTAF) or containing 5% (MTAF5) or 10% (MTAF10) calcium hydroxide (CH), in weight, in comparison with AH Plus sealer. MATERIAL AND METHODS: The flowability test was performed according to the ISO 6876:2001 requirements. For the pH level and calcium ion release analyses, the sealers were placed individually (n=10) in plastic tubes and immersed in deionized water. After 24 hours, 7 and 14 days, the water in which each specimen had been immersed was evaluated to determine the pH level changes and calcium released. Flowability, pH level and calcium release data were analyzed statistically by the ANOVA test (alpha=5%). RESULTS: In relation to flowability: MTAF>AH Plus>MTAF5>MTAF10. In relation to the pH level, for 24 h: MTAF5=MTAF10=MTAF>AH Plus; for 7 and 14 days: MTAF5=MTAF10>MTAF>AH Plus. For the calcium release, for all periods: MTAF>MTAF5=MTAF10>AH Plus. CONCLUSIONS: The addition of 5% CH to the MTA Fillapex (in weight) is an alternative to reduce the high flowability presented by the sealer, without interfering in its alkalization potential. PMID- 25025559 TI - Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB. AB - OBJECTIVE: The aim of this study was to evaluate a possible synergism between AGE RAGE and TLR4 signaling and the role of p38 MAPK and NF-kB signaling pathways on the modulation of the expression of inflammatory cytokines and proliferation of cells from the innate and adaptive immune response. MATERIAL AND METHODS: T lymphocyte (JM) and monocyte (U937) cell lines were stimulated with LPS and AGE BSA independently and associated, both in the presence and absence of p38 MAPK and NF-kB inhibitors. Proliferation was assessed by direct counting and viability was assessed by a biochemical assay of mitochondrial function. Cytokine gene expression for RAGe, CCL3, CCR5, IL-6 and TNF-alpha was studied by RT-PCR and RT qPCR. RESULTS: RAGE mRNA expression was detected in both cell lines. LPS and AGE BSA did not influence cell proliferation and viability of either cell line up to 72 hours. LPS and LPS associated with AGE induced expression of IL-6 and TNF alpha in monocytes and T cells, respectively. CONCLUSIONS: There is no synergistic effect between RAGE and TLR signaling on the expression of IL-6, TNF alpha , RAGE, CCR5 and CCL3 by monocytes and lymphocytes. Activation of RAGE associated or not with TLR signaling also had no effect on cell proliferation and survival of these cell types. PMID- 25025560 TI - Physical and chemical properties of orthodontic brackets after 12 and 24 months: in situ study. AB - OBJECTIVE: The aim of this article was to assess how intraoral biodegradation influenced the surface characteristics and friction levels of metallic brackets used during 12 and 24 months of orthodontic treatment and also to compare the static friction generated in these brackets with four different methods of the ligation of orthodontic wires. MATERIAL AND METHODS: Seventy premolar brackets as received from the manufacturer and 224 brackets that were used in previous orthodontic treatments were evaluated in this experiment. The surface morphology and the composition of the deposits found in the brackets were evaluated with rugosimetry, scanning electron microscopy, and energy dispersive X-ray spectroscopy. Friction was analyzed by applying tensile tests simulating sliding mechanics with a 0.019x0.025" steel wire. The static friction levels produced by the following ligation methods were evaluated: loosely attached steel ligature around all four bracket wings, steel ligature attached to only two wings, conventional elastomeric ligation around all 4 bracket wings, and non conventional Slide(r) elastomeric ligature. RESULTS: The results demonstrated the presence of biodegradation effects such as corrosion pits, plastic deformation, cracks, and material deposits. The main chemical elements found on these deposits were Carbon and Oxygen. The maximum friction produced by each ligation method changed according to the time of intraoral use. The steel ligature loosely attached to all four bracket wings produced the lowest friction levels in the new brackets. The conventional elastic ligatures generated the highest friction levels. The metallic brackets underwent significant degradation during orthodontic treatment, showing an increase in surface roughness and the deposit of chemical elements on the surface. CONCLUSION: The levels of static friction decreased with use. The non-conventional elastic ligatures were the best alternative to reduce friction. PMID- 25025561 TI - Assessment of quality of prescription by dental students. AB - OBJECTIVE: The main objective of this study was to evaluate changes in prescribing pattern of Dentistry students throughout academic course. METHODS: A case of non-complicated dental extraction was presented to all students that had completed their pharmacology coursework (from 4th semester to the last semester). The students were grouped according to year of study and were asked to prescribe paracetamol for pain control. A maximal score of 5 points was calculated from three subscores for identification of professional and patient (1.0 point), drug concentration, dosage, and quantity (1.5 points); and drug information, instructions, and warnings (2.5 points). The data were expressed as medians [95% confidence intervals (CIs)] and were compared using the Kruskal-Wallis test followed by Dunn's post hoc test. A p<0.05 value was considered statistically significant. A total of 92 students participated the study (2nd year, N=12; 3rd year, N=32; 4th year, N=28; 5th year, N=20). RESULTS: The quality of prescription showed improvement between 2nd-year students [2.0 (1.5-2.5)] and 4th-year students [3.2 (2.9-3.5), p<0.05]; 4th- and 5th-year students [3.6 (3.5-3.8)] performed similarly. Lack of information about pharmacological treatment, side effects, and administration route were the major deficiencies observed. CONCLUSION: Although Dentistry students present a general improvement in their prescribing performance, deficiencies remain even in advanced students. The data suggest that the teaching of good prescription practices should extend throughout the later phases of preprofessional dental education. PMID- 25025562 TI - Effect of veneering material on the deformation suffered by implant-supported fixed prosthesis framework. AB - Knowing how stresses are dissipated on the fixed implant-supported complex allows adequate treatment planning and better choice of the materials used for prosthesis fabrication. OBJECTIVES: The aim of this study was to evaluate the deformation suffered by cantilevered implant-supported fixed prostheses frameworks cast in silver-palladium alloy and coated with two occlusal veneering materials: acrylic resin or porcelain. MATERIAL AND METHODS: Two strain gauges were bonded to the inferior surface of the silver-palladium framework and two other were bonded to the occlusal surface of the prosthesis framework covered with ceramic and acrylic resin on each of its two halves. The framework was fixed to a metallic master model and a 35.2 N compression force was applied to the cantilever at 10, 15 and 20 mm from the most distal implant. The measurements of deformation by compression and tension were obtained. The statistical 2-way ANOVA test was used for individual analysis of the experiment variables and the Tukey test was used for the interrelation between all the variables (material and distance of force application). RESULTS: The results showed that both variables had influence on the studied factors (deformation by compression and tension). CONCLUSION: The ceramic coating provided greater rigidity to the assembly and therefore less distortion compared with the uncoated framework and with the resin coated framework. The cantilever arm length also influenced the prosthesis rigidity, causing higher deformation the farther the load was applied from the last implant. PMID- 25025563 TI - Brazilian minipig as a large-animal model for basic research and stem cell-based tissue engineering. Characterization and in vitro differentiation of bone marrow derived mesenchymal stem cells. AB - Stem cell-based regenerative medicine is one of the most intensively researched medical issues. Pre-clinical studies in a large-animal model, especially in swine or miniature pigs, are highly relevant to human applications. Mesenchymal stem cells (MSCs) have been isolated and expanded from different sources. OBJECTIVE: This study aimed at isolating and characterizing, for the first time, bone marrow derived MSCs (BM-MSCs) from a Brazilian minipig (BR1). Also, this aimed to validate a new large-animal model for stem cell-based tissue engineering. MATERIAL AND METHODS: Bone marrow (BM) was aspirated from the posterior iliac crest of twelve adult male BR1 under general anesthesia. MSCs were selected by plastic-adherence as originally described by Friedenstein. Cell morphology, surface marker expression, and cellular differentiation were examined. The immunophenotypic profile was determined by flow cytometry. The differentiation potential was assessed by cytological staining and by RT-PCR. RESULTS: MSCs were present in all minipig BM samples. These cells showed fibroblastic morphology and were positive for the surface markers CD90 (88.6%), CD29 (89.8%), CD44 (86.9%) and negative for CD34 (1.61%), CD45 (1.83%), CD14 (1.77%) and MHC-II (2.69%). MSCs were differentiated into adipocytes, osteoblasts, and chondroblasts as demonstrated by the presence of lipidic-rich vacuoles, the mineralized extracellular matrix, and the great presence of glycosaminoglycans, respectively. The higher gene expression of adipocyte fatty-acid binding protein (AP2), alkaline phosphatase (ALP) and collagen type 2 (COLII) also confirmed the trilineage differentiation (p<0.001, p<0.001, p=0.031; respectively). CONCLUSIONS: The isolation, cultivation, and differentiation of BM-MSCs from BR1 makes this animal eligible as a useful large-animal model for stem cell-based studies in Brazil. PMID- 25025564 TI - Frictional resistance of self-ligating versus conventional brackets in different bracket-archwire-angle combinations. AB - OBJECTIVE: To compare the influence of archwire material (NiTi, beta-Ti and stainless steel) and brackets design (self-ligating and conventional) on the frictional force resistance. MATERIAL AND METHODS: Two types of brackets (self ligating brackets - Smartclip, 3M/Unitek - and conventional brackets - Gemini, 3M/Unitek) with three (0, 5, and 10 degrees) slot angulation attached with elastomeric ligatures (TP Orthodontics) were tested. All brackets were tested with archwire 0.019"x0.025" nickel-titanium, beta-titanium, and stainless steel (Unitek/3M). The mechanical testing was performed with a universal testing machine eMIC DL 10000 (eMIC Co, Brazil). The wires were pulled from the bracket slots at a cross-head speed of 3 mm/min until 2 mm displacement. RESULTS: Self ligating brackets produced significantly lower friction values compared with those of conventional brackets. Frictional force resistance values were directly proportional to the increase in the bracket/ wire angulation. With regard to conventional brackets, stainless steel wires had the lowest friction force values, followed by nickel-titanium and beta-titanium ones. With regard to self ligating brackets, the nickel-titanium wires had the lowest friction values, significantly lower than those of other materials. CONCLUSION: even at different angulations, the self-ligating brackets showed significantly lower friction force values than the conventional brackets. Combined with nickel-titanium wires, the self-ligating brackets exhibit much lower friction, possibly due to the contact between nickel-titanium clips and wires of the same material. PMID- 25025565 TI - Caries-free subjects have high levels of urease and arginine deiminase activity. AB - OBJECTIVES: This study investigated the relationship between urease and arginine deiminase system (ADS) activities and dental caries through a cross-sectional study. MATERIAL AND METHODS: Urease and ADS activities were measured in saliva and plaque samples from 10 caries-free subjects and 13 caries-active. Urease activity was obtained from the ammonia produced by incubation of plaque and saliva samples in urea. ADS activity was obtained from the ammonia generated by the arginine-HCl and Tris-maleate buffer. Specific activity was defined as micromoles of ammonia per minute per milligram of protein. Shapiro-Wilk statistical test was used to analyze the distribution of the data, and Mann Whitney test was used to determine the significance of the data. RESULTS: The specific urease activity in saliva and plaque was significantly higher in individuals with low DMFT scores. ADS activity in saliva (6.050 vs 1.350, p=0.0154) and plaque (8.830 vs 1.210, p=0.025) was also higher in individuals with low DMFT scores. CONCLUSIONS: Caries-free subjects had a higher ammonia generation activity by urease and arginine deiminase system for both saliva and plaque samples than low caries-active subjects. High levels of alkali production in oral environment were related to caries-free subjects. PMID- 25025566 TI - Surgical techniques for the treatment of ankyloglossia in children: a case series. AB - This paper reports a series of clinical cases of ankyloglossia in children, which were approached by different techniques: frenotomy and frenectomy with the use of one hemostat, two hemostats, a groove director or laser. Information on the indications, contraindications, advantages and disadvantages of the techniques was also presented. Children diagnosed with ankyloglossia were subjected to different surgical procedures. The choice of the techniques was based on the age of the patient, length of the frenulum and availability of the instruments and equipment. All the techniques presented are successful for the treatment of ankyloglossia and require a skilled professional. Laser may be considered a simple and safe alternative for children while reducing the amount of local anesthetics needed, the bleeding and the chances of infection, swelling and discomfort. PMID- 25025567 TI - Cdh1 is an antagonist of the spindle assembly checkpoint. AB - The spindle assembly checkpoint (SAC) monitors unsatisfied connections of microtubules to kinetochores and prevents anaphase onset by inhibition of the ubiquitin ligase E3 anaphase-promoting complex or cyclosome (APC/C) in association with the activator Cdc20. Another APC/C activator, Cdh1, exists permanently throughout the cell cycle but it becomes active from telophase to G1. Here, we show that Cdh1 is partially active and mediates securin degradation even in SAC-active metaphase cells. Additionally, Cdh1 mediates Cdc20 degradation in metaphase, promoting formation of the APC/C-Cdh1. These results indicate that Cdh1 opposes the SAC and promotes anaphase transition. PMID- 25025568 TI - A Blk-p190RhoGAP signaling module downstream of activated Galpha13 functionally opposes CXCL12-stimulated RhoA activation and cell invasion. AB - Activation of the GTPase RhoA linked to cell invasion can be tightly regulated following Galpha13 stimulation. We have used a cellular model displaying Galpha13 dependent inhibition of RhoA activation associated with defective cell invasion to the chemokine CXCL12 to characterize the molecular players regulating these processes. Using both RNAi transfection approaches and protein overexpression experiments here we show that the Src kinase Blk is involved in Galpha13 activated tyrosine phosphorylation of p190RhoGAP, which causes RhoA inactivation and ultimately leads to deficient cell invasion. Characterization of molecular interplays between Galpha13, Blk and p190RhoGAP revealed that Blk binds Galpha13, and that Blk-mediated p190RhoGAP phosphorylation upon Galpha13 activation correlates with weakening of Galpha13-Blk association connected to increased Blk p190RhoGAP assembly. These results place Blk upstream of the p190RhoGAP-RhoA pathway in Galpha13-activated cells, overall representing an opposing signaling module during CXCL12-triggered invasion. In addition, analyses with Blk- or Galpha13-knockdown cells indicated that Blk can also mediate CXCL12-triggered phosphorylation of p190RhoGAP independently of Galpha13. However, even if CXCL12 induces the Blk-mediated GAP phosphorylation, the simultaneous stimulation of the guanine-nucleotide exchange factor Vav1 by the chemokine, as earlier reported, leads to a net increase in RhoA activation. Therefore, when Galpha13 is concurrently stimulated with CXCL12 there appears to be sufficient Blk activity to promote adequate levels of p190RhoGAP tyrosine phosphorylation to inactivate RhoA and to impair cell invasiveness. PMID- 25025569 TI - LGR5 regulates survival through mitochondria-mediated apoptosis and by targeting the Wnt/beta-catenin signaling pathway in colorectal cancer cells. AB - Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a newly identified surface marker of colorectal cancer stem cells (CSCs). Expression level of LGR5 is commonly elevated in human CRCs. Our previous study demonstrated that the elevated expression of LGR5 is associated with CRC initiation and progression. However, the role of LGR5 in CRC pathogenesis has not been sufficiently established. In this study, we aimed to characterize the role of LGR5 in CRC pathogenesis using the loss-of-function approach. Depletion of LGR5 suppressed the growth of several cultured CRC cells and caused an increase in the fraction of apoptotic cells, which were analyzed using Annexin V/PI staining and DNA fragmentation assay. Furthermore, depleting LGR5 induced apoptosis through the loss of mitochondrial membrane potential. Additionally, depletion of LGR5 suppressed beta-catenin nuclear translocation and blocked the activity of Wnt/beta-catenin signaling as manifested in the reduced expression of c-myc and cyclin D, two Wnt/beta-catenin targets in CRC cells. Treatment with Wnt3a considerably alleviated the growth inhibition and apoptotic cell death induced by LGR5 depletion in CRC cells. These data suggested that LGR5 regulates cell proliferation and survival by targeting the Wnt/beta-catenin signaling pathway. Thus, the findings of this study suggest that LGR5 plays a vital role in CRC pathogenesis and has the potential to serve as a diagnostic marker and a therapeutic target for CRC patients. PMID- 25025570 TI - Regulation of alternative splicing of CD44 in cancer. AB - CD44 is a hyaluronan binding cell surface signal transducing receptor that influences motility, cell survival and proliferation as well as the formation of tumor microenvironment. CD44 contains two variable regions encoded by variable exons. Alternative splicing, which is often deregulated in cancer, can produce various isoforms of CD44 with properties that may have different tissue specific effects and therefore even diverse effects on cancer progression. This review summarizes and puts together all major regulators of alternative splicing of CD44 in cancer that have been documented so far and that have an experimentally proved effect on CD44 isoform switching. It is important to better understand the mechanisms of alternative splicing of CD44, where all the variability of CD44 originates, to be able to explain the isoform switching and occurrence of variant isoforms of CD44 (CD44v) in cancer. PMID- 25025572 TI - Role of the guanine nucleotide exchange factor in Akt2-mediated plasma membrane translocation of GLUT4 in insulin-stimulated skeletal muscle. AB - The small GTPase Rac1 plays a key role in insulin-promoted glucose uptake mediated by the GLUT4 glucose transporter in skeletal muscle. Our recent studies have demonstrated that the serine/threonine protein kinase Akt2 is critically involved in insulin-dependent Rac1 activation. The purpose of this study is to clarify the role of the guanine nucleotide exchange factor FLJ00068 in Akt2 mediated Rac1 activation and GLUT4 translocation in mouse skeletal muscle and cultured myocytes. Constitutively activated FLJ00068 induced GLUT4 translocation in a Rac1-dependent and Akt2-independent manner in L6 myocytes. On the other hand, knockdown of FLJ00068 significantly reduced constitutively activated Akt2 triggered GLUT4 translocation. Furthermore, Rac1 activation and GLUT4 translocation induced by constitutively activated phosphoinositide 3-kinase were inhibited by knockdown of FLJ00068. In mouse gastrocnemius muscle, constitutively activated FLJ00068 actually induced GLUT4 translocation to the sarcolemma. GLUT4 translocation by constitutively activated FLJ00068 was totally abolished in rac1 knockout mouse gastrocnemius muscle. Additionally, we were successful in detecting the activation of Rac1 following the expression of constitutively activated FLJ00068 in gastrocnemius muscle by immunofluorescence microscopy using an activation-specific probe. Collectively, these results strongly support the notion that FLJ00068 regulates Rac1 downstream of Akt2, leading to the stimulation of glucose uptake in skeletal muscle. PMID- 25025571 TI - Molecular regulation of lysophosphatidic acid receptor 1 trafficking to the cell surface. AB - The lysophosphatidic acid receptor 1 (LPA1), a G-protein coupled receptor, regulates cell proliferation, migration, and cytokine release. Here, we investigate the molecular signature of LPA1 trafficking to the cell surface. The overexpressed LPA1 with a C-terminal V5 tag (LPA1-V5) is majorly expressed on the cell surface, while two deletion mutants (C320 and ?84-87) failed to be trafficked to the cell surface. Further, site-directed mutagenesis analysis of the LPA1 revealed that Ile325, Tyr85, and Leu87 within these two fragments regulate LPA1 maturation and trafficking to the cell surface. Over-expression of Sar1, a component of coat protein complex II (COPII), enhances glycosylation of LPA1 wild type, but not these mutants. The mutants of LPA1 are majorly localized in the endoplasmic reticulum (ER) and exhibit a higher binding affinity to heat shock protein 70 (Hsp70), when compared to the LPA1 wild type. Further, we found that all these mutants failed to increase phosphorylation of Erk, and the cytokine release in response to LPA treatment. These results suggest that Ile325, Tyr85, and Leu87 within LPA1 are essential for LPA1 protein properly folding in the ER. PMID- 25025575 TI - Acupuncture and physiotherapy - a decision for physiotherapists. AB - For many centuries our knowledge of Chinese achievements was limited to natural silk, cloissone, porcelain, jade, ivory and papier mache. Their philosophy and art of healing remained virtually unknown. PMID- 25025574 TI - Acidic pH increases cGMP accumulation through the OGR1/phospholipase C/Ca(2+)/neuronal NOS pathway in N1E-115 neuronal cells. AB - Neuronal NO synthase (nNOS)-mediated cGMP accumulation has been shown to affect a variety of neuronal cell activities, regardless of whether they are detrimental or beneficial, depending on the amount of their levels, under the physiological and pathological situations. In the present study, we examined the role of proton sensing G protein-coupled receptors (GPCRs), which have been identified as new pH sensors, in the acidic pH-induced nNOS/cGMP activity in N1E-115 neuronal cells. In this cell line, ovarian cancer G protein-coupled receptor 1 (OGR1) and G protein-coupled receptor 4 (GPR4) mRNAs are expressed. An extracellular acidic pH increased cGMP accumulation, which was inhibited by nNOS-specific inhibitors. Acidic pH also activated phospholipase C/Ca(2+) pathways and Akt-induced phosphorylation of nNOS at S1412, both of which have been shown to be critical regulatory mechanisms for nNOS activation. The acidic pH-induced activation of the phospholipase C/Ca(2+) pathway, but not Akt/nNOS phosphorylation, was inhibited by small interfering RNA specific to OGR1 and YM-254890, an inhibitor of Gq/11 proteins, in association with the inhibition of cGMP accumulation. Moreover cGMP accumulation was inhibited by 2-aminoethoxydiphenyl borate, an inhibitor of inositol 1,4,5-trisphosphate channel; however, it was not by wortmannin, a phosphatidylinositol 3-kinase inhibitor, which inhibited Akt/nNOS phosphorylation. In conclusion, acidic pH stimulates cGMP accumulation preferentially through the OGR1/Gq/11 proteins/phospholipase C/Ca(2+)/nNOS in N1E 115 neuronal cells. Akt-mediated phosphorylation of nNOS, however, does not appreciably contribute to the acidification-induced accumulation of cGMP. PMID- 25025573 TI - Ret finger protein mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. AB - Skeletal muscle atrophy results from the net loss of muscular proteins and organelles and is caused by pathologic conditions such as nerve injury, immobilization, cancer, and other metabolic diseases. Recently, ubiquitination mediated degradation of skeletal-muscle-specific transcription factors was shown to be involved in muscle atrophy, although the mechanisms have yet to be defined. Here we report that ret finger protein (RFP), also known as TRIM27, works as an E3 ligase in Pax7-induced degradation of MyoD. Muscle injury induced by sciatic nerve transection up-regulated RFP and RFP physically interacted with both Pax7 and MyoD. RFP and Pax7 synergistically reduced the protein amounts of MyoD but not the mRNA. RFP-induced reduction of MyoD protein was blocked by proteasome inhibitors. The Pax7-induced reduction MyoD was attenuated by RFP siRNA and by MG132, a proteasome inhibitor. RFPDeltaR, an RFP construct that lacks the RING domain, failed to reduce MyoD amounts. RFP ubiquitinated MyoD, but RFPDeltaR failed to do so. Forced expression of RFP, but not RFPDeltaR, enhanced Pax7 induced ubiquitination of MyoD, whereas RFP siRNA blocked the ubiquitination. Sciatic nerve injury-induced muscle atrophy as well the reduction in MyoD was attenuated in RFP knockout mice. Taken together, our results show that RFP works as a novel E3 ligase in the Pax7-mediated degradation of MyoD in response to skeletal muscle atrophy. PMID- 25025576 TI - What are you teaching and why? AB - What are Universities trying to produce by the end of the medical course? What is the purpose of our clinical education? It is easy enough to say that it is to produce "a good doctor", and perhaps we all know what that means although we might have differing interpretations of what constitutes a good doctor. Perhaps you know clearly what you mean when you graduate a good physiotherapist or a good speech therapist, but we have a lot of uncertainties about this, and about whether somebody who is reasonably good now will also be good in five years' or 10 years' time or even in one year's time when they are practising by themselves and not under our supervision. PMID- 25025577 TI - Haemophilia - its medical management. AB - The name haemophilia was coined by a German, Schonlein, about 150 years ago but it is only really in the last decade that the patient with this disorder in one of its more severe forms has had any real hope of leading something approaching a normal life. PMID- 25025578 TI - The patella tendon bearing brace. AB - In certain pathological conditions, the stress of weightbearing through the tibia and foot must be avoided. This may be because of (a) non-union or delayed union in fractures of the tibia. (b) pain in the ankle and foot. (c) chronic osteomyelitis in the tibia. (d) recovering fractured os calcis. (e) ulcerated areas on the foot. (f) traumatic loss of the heel pad. PMID- 25025579 TI - The significance of a midbrain syndrome in unconscious patients with severe head injury. AB - Recent advances in neurosurgical techniques and the development of specialized intensive care units have resulted in an increase in the numbers of patients surviving extensive brain damage. Renfrew (1971) and Symons (1961, 1967) have recently reviewed some aspects of the role of the physiotherapist in the management of patients falling within the category of "severe head injury", which encompasses a wide variety of patients with many different clinical and neurological problems. In the neurosurgical unit at the Royal Melbourne Hospital, we have treated a group of patients with severe head injury who have presented with signs which are predominantly characteristic of midbrain involvement. The dominance of these signs over other neurological signs which are indicative of brain damage, enables these patients to be classified as a separate clinical entity. This is of significance because the patients in this group follow a similar course in the unconscious state which presents difficulties in management for the physiotherapist. These difficulties require modification of the current techniques used in the treatment of head injuries. The scope of this paper is to describe the clinical features of this midbrain syndrome during the unconscious stage, highlighting the problems that these patients present and the techniques used in treating them. PMID- 25025580 TI - The changing physiology of middle age. AB - It is not easy to talk sensibly about middle age because there is real doubt as to whether it exists. It is something which rapidly recedes from us as we approach it and at the other end it blends confusingly into old age. During this century improvements in medical care and a general increase in living standards have led people to expect to retain good health until quite late in life. It is now unusual for a physician to attribute any illness merely to old age and he would be most unwise to do so in a patient under the age of 70. PMID- 25025581 TI - Life course impact of school-based promotion of healthy eating and active living to prevent childhood obesity. AB - BACKGROUND: The Alberta Project Promoting active Living and healthy Eating in Schools (APPLE Schools) is a comprehensive school health program that is proven feasible and effective in preventing obesity among school aged children. To support decision making on expanding this program, evidence on its long-term health and economic impacts is particularly critical. In the present study we estimate the life course impact of the APPLE Schools programs in terms of future body weights and avoided health care costs. METHOD: We modeled growth rates of body mass index (BMI) using longitudinal data from the National Population Health Survey collected between 1996-2008. These growth rate characteristics were used to project BMI trajectories for students that attended APPLE Schools and for students who attended control schools (141 randomly selected schools) in the Canadian province of Alberta. RESULTS: Throughout the life course, the prevalence of overweight (including obesity) was 1.2% to 2.8% (1.7 on average) less among students attending APPLE Schools relative to their peers attending control schools. The life course prevalence of obesity was 0.4% to 1.4% (0.8% on average) less among APPLE Schools students. If the APPLE Schools program were to be scaled up, the potential cost savings would be $33 to 82 million per year for the province of Alberta, or $150 to 330 million per year for Canada. CONCLUSIONS: These projected health and economic benefits seem to support broader implementation of school-based health promotion programs. PMID- 25025582 TI - The Boston Marathon bombing: after-action review of the Brigham and Women's Hospital emergency radiology response. AB - PURPOSE: To analyze imaging utilization and emergency radiology process turnaround times in response to the April 15, 2013, Boston Marathon bombing in order to identify opportunities for improvement in the Brigham and Women's Hospital (BWH) emergency operations plan. MATERIALS AND METHODS: Institutional review board approval was obtained with waivers of informed consent. Patient demographics, injuries, and outcomes were gathered, along with measures of emergency department (ED) imaging utilization and turnaround times, which were compared with operations from the preceding year by using the Wilcoxon rank sum test. Multivariate linear regression was used to assess contributors to examination cancellations. RESULTS: Forty patients presented to BWH after the bombing; 16 were admitted and 24 were discharged home. There were no fatalities. Ten patients required emergent surgery. Blast injury types included 13 (33%) primary, 20 (51%) secondary, three (8%) tertiary, and 19 (49%) quaternary. Thirty one patients (78%) underwent imaging in the ED; 57 radiographic examinations in 30 patients and 16 computed tomographic (CT) examinations in seven patients. Sixty-two radiographic and 14 CT orders were cancelled. Median time from blast to patient arrival was 97 minutes (interquartile range [IQR], 43-139 minutes), patient arrival to ED examination order, 24 minutes (IQR, 12-50 minutes), order to examination completion, 49 minutes (IQR, 26-70 minutes), and examination completion to available dictated text report, 75 minutes (IQR, 19-147 minutes). Examination completion turnaround times were significantly increased for radiography (52 minutes [IQR, 26-73 minutes] vs annual median, 31 minutes [IQR, 19-48 minutes]; P = .001) and decreased for CT (37 minutes [IQR, 26-50 minutes] vs annual median, 72 minutes [IQR, 40-129 minutes]; P = .001). There were no significant differences in report availability turnaround time (75 minutes [IQR, 19-147 minutes] vs annual median, 74 minutes [IQR, 35-127 minutes]; P = .34). CONCLUSION: The surge in imaging utilization after the Boston Marathon bombing stressed emergency radiology operations. Process analysis enabled identification of successes and opportunities for improvement in ongoing emergency operations planning. (c) RSNA, 2014. PMID- 25025583 TI - Guidelines-based diagnostic process does increase hospital delay in a cohort of colorectal cancer patients: a population-based study. AB - This is an investigation of factors determining hospital delay until treatment in an unrestricted population of colorectal cancer patients in the western part of the Netherlands. All patients with newly diagnosed colon (n=2146) and rectal carcinoma (n=1036) in the period 2006-2008 were included in analyses of inhospital delay (first hospital visit until first treatment >35 days). One-third of all patients were also available for analyses of prehospital delay (enrollment until first hospital visit >7 days). Patient, tumour and process factors predicting delay were examined in logistic regression models. The median prehospital and inhospital time intervals were 2 days [(p25-p75) 0-16] and 32 days (17-49), respectively, for colon cancer patients and 7 days (1-21) and 43 days (33-60) for rectal cancer patients. After adjustment for patient and tumour factors, colon and rectal cancer patients with first hospital visit before histological confirmation of cancer, complete diagnostic assessment or discussed in a multidisciplinary meeting had a higher probability of increased inhospital delay. Furthermore, first hospital visit before histological confirmation of cancer was associated with decreased prehospital delay in colon and rectal cancer patients. A guidelines-based diagnostic process (considered high quality of care) and multidisciplinary collaboration were associated with increased hospital delay in colorectal cancer patients. PMID- 25025584 TI - Synbiotic (Lactobacillus rhamnosus+Lactobacillus acidophilus+inulin) attenuates oxidative stress and colonic damage in 1,2 dimethylhydrazine dihydrochloride induced colon carcinogenesis in Sprague-Dawley rats: a long-term study. AB - The inexorable increase in the incidence of colorectal cancer has led to growing interest in its prevention by natural interventions. Thus, the present study was designed with the aim of delineating the antioxidative and antitumorigenic effects of synbiotics in experimental colon carcinogenesis. It was observed that administration of a synbiotic, before 1,2 dimethylhydrazine dihydrochloride (DMH) induced colon carcinogenesis in Sprague-Dawley rats, led to increased body weight and growth rate, and decreased tumor incidence compared with the DMH-only-treated group of animals. Most notably, the level of malondialdehyde, a measure of lipid peroxidation, decreased, and levels of the antioxidants, glutathione reductase, superoxide dismutase, and glutathione peroxidase increased in animals in the Lactobacillus acidophilus+DMH, inulin+DMH, and synbiotic+DMH groups compared with DMH-only-treated animals. Histopathological observations of the colon also documented fewer dysplastic changes and increased the number of goblet cells in the probiotic-treated, prebiotic-treated, and synbiotic-treated animals compared with DMH-only-treated animals. Taken together, the present study shows that the use of synbiotics is a better prophylactic strategy than the use of probiotic and prebiotic alone because of the greater increase in antioxidants associated with the higher degree of attenuation of DMH-induced tumorigenesis. PMID- 25025585 TI - A birth cohort analysis of the incidence of adenocarcinoma of the uterine cervix in the USA. AB - We investigated the incidence trends for adenocarcinoma (AC) of the cervix among individuals belonging to the 20-44-year age group in the USA and compared the observed birth cohort incidence patterns with the changing patterns of exposure to potential risk factors associated with AC of the cervix, such as infection with human papillomavirus, use of diethylstilbestrol (DES), obesity, and use of oral contraceptives. Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program for 1973-2010, we conducted age-period-cohort modeling to evaluate birth cohort patterns on incidence trends of AC of the cervix over time. The increase in the incidence of AC of the cervix started among those born around the mid 1940s and accelerated up until around the mid 1960s birth cohort in both whites and all races combined, regardless of the assumed period slope. There was a suggestion that the incidence rates of AC of the cervix slowed down after the 1975 birth cohort in both whites and all races combined. DES was used by millions of women in the USA as a synthetic estrogen between the years 1940 and 1971. This time period of DES use among pregnant women parallels the observed birth cohort trends in our study, whereby a notable acceleration in the incidence rates of AC of the cervix was observed among those born in the mid 1940s through the mid 1975s. Thus, our results appear to suggest that in-utero exposure to DES might be at least partly responsible for the observed incidence pattern of AC of the cervix as observed in this study. PMID- 25025586 TI - Optimal nasopharyngeal temperature probe placement. AB - BACKGROUND: Although the nasopharynx is a commonly used temperature-monitoring site during general anesthesia, it is unknown whether the position of nasopharyngeal temperature probes placed blindly by anesthesia practitioners is optimal. The purposes of this study were (1) to determine where the nasopharyngeal mucosa is in closest proximity to the internal carotid artery (ICA) and (2) to evaluate the tip position of nasopharyngeal temperature probes that were placed by anesthesiology residents and nurse anesthetists. METHODS: In the first phase of the study, we reviewed enhanced axial computed tomography images of 100 patients to determine where the nasopharyngeal mucosa was in closest proximity to the left or the right ICA. The distance from this point to the nares was then measured in the sagittal image. In the second phase of the study, nasendoscopy was used to evaluate the positioning of nasopharyngeal temperature probes placed by anesthesiology residents (244 patients) or nurse anesthetists (116 patients). Malpositioned probes were repositioned to an optimal location, and the temperature differences were recorded. RESULTS: In the computed tomography images, the mucosa in closest proximity to the ICA was in the upper, mid-, and lower nasopharynx in 60%, 38%, and 2% of patients, respectively. The average distances between the ICA and the nasopharyngeal mucosa in the upper portion were significantly shorter than those in the lower portion (female: 9.4 vs 16.8 mm, P < 0.001; male: 12.4 vs 18.8 mm, P < 0.001). The average distances (95% prediction interval) from the nares to the upper portion of the nasopharynx through the inferior meatus were 9.1 (8.1-10.2) cm in females and 9.7 (8.6-10.8) cm in males. Temperature probes were correctly positioned in the upper or mid nasopharynx by residents and nurses in 43% (95% confidence interval [CI], 37% 49%) and 41% (95% CI, 36%-50%), respectively. When the probe was inadvertently placed in the nasal cavity, the median (95% CI) temperature difference from the upper nasopharynx was 0.2 degrees C (0.15 degrees C-0.25 degrees C). CONCLUSIONS: The closest portion of the nasopharyngeal mucosa to the ICA is within the upper or mid-nasopharynx. The depth from the nares to the upper one-third of the nasopharynx is approximately 10 cm. Less than half of nasopharyngeal temperature probes placed blindly by practitioners were optimally positioned. PMID- 25025587 TI - Performance of Masimo rainbow acoustic monitoring for tracking changing respiratory rates under laryngeal mask airway general anesthesia for surgical procedures in the operating room: a prospective observational study. AB - BACKGROUND: Accurate monitoring of respiratory rate may be useful for the early detection of patient deterioration. Monitoring of respiratory rate in the operating room under general anesthesia by spirometry is technically straightforward and demonstrates high fidelity. Accurate measurement of the respiratory rate of an unattended patient outside the operating room is fraught with challenges. Monitors such as capnometry and thoracic impedance pneumography have significant drawbacks. Respiratory acoustic monitoring (RRaTM) is a new technology for respiratory rate monitoring, which has been demonstrated to provide accurate respiratory rates in patients recovering from anesthesia, but the performance of this RRa-enabled monitor under conditions of major respiratory rate variation has not been evaluated. METHODS: We enrolled 53 patients undergoing urologic procedures in the operating room under general anesthesia with a laryngeal mask airway, spontaneous ventilation, and no muscle relaxation in an observational study. Respiratory signals (RRa and in-circuit pneumotachograph) were stored for later analysis. Artifacts were excluded based on visual inspection of the raw respiratory waveforms. Instantaneous respiratory rates were obtained from the pneumotachograph signal using the Hilbert-Huang Transform. Instantaneous rate estimates (IREs) were compared with RRa by 3 methods. First, the mean delay between IREs and RRa was determined. Second, precision was obtained by Bland-Altman analysis for repeated measures. Third, for all disparities in rates exceeding 4 breaths per minute (bpm), the probability of persistent error was determined as a function of time, with 95% confidence intervals estimated by bootstrap analysis. RESULTS: Data were collected from 53 patients. Three patients were excluded due to missing data. There were no adverse events related to RRa monitoring. RRa demonstrated a median delay of 45 seconds (interquartile range 20 seconds) to detect a 1- bpm change in IREs. Bland-Altman revealed 95% limits of agreement of -2.1 to 2.2 bpm across the range of 7 to 48 bpm. Disparities in respiratory rate >4 bpm between the 2 methods did not persist beyond 160 seconds, and 90% of these differences resolved within 33 seconds (95% confidence interval 23-48 seconds). CONCLUSIONS: The data demonstrate that, under conditions of general anesthesia with a laryngeal mask airway and spontaneous ventilation, the RRa rapidly detects changes in respiratory rate, demonstrates minimal bias, and when errors in rate occur, these do not persist. The utility of this monitoring technology in detecting rate changes in unattended patients will require further study. PMID- 25025588 TI - Ropivacaine pharmacokinetics after local infiltration analgesia in hip arthroplasty. AB - In this study, we determined the plasma concentration of ropivacaine by liquid chromatography-mass spectrometry for 30 hours after local infiltration analgesia in 15 patients with elective hip arthroplasty. The 95% upper prediction bound of maximal unbound plasma concentration of ropivacaine was 0.032 mg/L. Side effects sufficient to stop an IV infusion have been reported at arterial concentrations of 0.34 to 0.85 mg/L. Alpha-1-acid glycoprotein did not correlate with the fraction of unbound ropivacaine during the first 24 hours after local infiltration analgesia. No signs or symptoms of systemic local anesthetic toxicity were observed. The Clopper-Pearson 95% upper confidence limit for adverse signs was 0.218. PMID- 25025589 TI - The Use of Computed Tomography in Assessing Muscle Cross-sectional Area, and the Relationship between Cross-sectional Area and Strength. AB - The estimation of muscle cross-sectional area (CSA) by anthropometric measurements is insensitive for objective clinical research. However computed tomography (CT) enables specific muscle imaging for accurate CSA determination. This study, involving 15 males with previous knee injuries, examined the repeatability of bilateral CT in calculating mid-thigh muscle densities (Houndsfield units: HU) and quadriceps atrophy. Significant differences between limbs in strength (p<0.0001), CSA (p<0.001) and HU (p<0.05) were observed. Prior to a four week electro-motor stimulation (EMS) programme, a significant correlation between force and quadriceps CSA existed which diminished over time. Neurogenic contributions to improved strength were demonstrated in the absence of increased CSA. These data suggest CSA is not a reliable predictor of strength potential in atrophic muscle. Computed tomography scanning provides an accurate, repeatable method for standardized tissue density and muscle CSA assessment. PMID- 25025590 TI - Normative isokinetic data on the ankle invertors and evertors. AB - To develop Australian normative data for ankle invertors and evertors, forty subjects aged between eighteen and thirty-four years were tested using Cybex II. Issues examined were the relationships between body weight and peak torque, peak torque values of evertors/invertors at specific velocities, and body weight and endurance. Mean absolute peak torque values at specific velocities and percentage changes in endurance performance at 120 degrees /sec were established. Results showed a significant correlation between body weight and absolute peak torque. Sex had a significant effect on these values. The ratio evertors/invertors had significant linearity with the test velocities indicating a constant ratio of these muscles, irrespective of velocity. No significant relationship was found between body weight and endurance. PMID- 25025591 TI - Shear accessory movements of the clavicular joints. AB - A study of the degree of accessory movements available in the sternoclavicular and acromioclavicular joints as a result of passive movement is presented. Using the common terms of hypomobility, normal and hypermobility and defining another set of terms - the pure, mixed and heterogenous triplets - findings based on a sample of 64 children indicate that the sternoclavicular joints, in comparison to the acromioclavicular joints, are decisively less mobile; are more uniformly constrained in their linear motions along the relevant anatomical planes; and exhibit a higher degree of left/right symmetry. The significance of these findings both from the biomechanical and clinical aspect is discussed. PMID- 25025592 TI - Repetitive strain injury: a diagnostic model and management guidelines. AB - A diagnostic model for understanding the group of patients described as having Repetitive Strain Injury (RSI) is outlined. Five diagnostic categories are suggested together with guidelines for the management of each group. The importance of viewing the patients in category 5, 'Non-Specific Regional Pain', as chronic pain patients is emphasized, together with a more detailed description of their management. PMID- 25025593 TI - Changes in the Characteristics of Physiotherapy Students in New South Wales over the Decade 1976-1986. AB - Responses to a survey comparing the backgrounds and career attitudes of incoming physiotherapy students in 1976 and 1986 indicated that female students in 1986 were more ambitious, more committed to full time careers, attached greater importance to professional recognition, pay and promotion, had more egalitarian attitudes toward women's role, had fewer romantic attachments and wanted fewer children. Responses of male students in 1986 revealed that they were older than women students, were somewhat more ambitious and conservative and were more concerned with their surroundings and freedom at work. PMID- 25025594 TI - Controlled release properties of zein-fatty acid blend films for multiple bioactive compounds. AB - To develop edible films having controlled release properties for multiple bioactive compounds, hydrophobicity and morphology of zein films were modified by blending zein with oleic (C18:1)Delta9, linoleic (C18:2)Delta(9,12), or lauric (C12) acids in the presence of lecithin. The blend zein films showed 2-8.5- and 1.6-2.9-fold lower initial release rates for the model active compounds, lysozyme (LYS) and (+)-catechin (CAT), than the zein control films, respectively. The change of fatty acid chain length affected both CAT and LYS release rates while the change of fatty acid double bond number affected only the CAT release rate. The film morphologies suggested that the blend films owe their controlled release properties mainly to the microspheres formed within their matrix and encapsulation of active compounds. The blend films showed antilisterial activity and antioxidant activity up to 81 MUmol Trolox/cm2. The controlled release of multiple bioactive compounds from a single film showed the possibility of combining application of active and bioactive packaging technologies and improving not only safety and quality but also health benefits of packed food. PMID- 25025595 TI - First photoswitchable neurotransmitter transporter inhibitor: light-induced control of gamma-aminobutyric acid transporter 1 (GAT1) activity in mouse brain. AB - Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be associated with low GABA levels. We have now developed a potent and subtype selective photoswitchable inhibitor of this transporter, which for the first time extends the photoswitch concept for the light-induced control of ligand affinity to active membrane transporters. The new inhibitor exhibited reduced activity upon irradiation with light, as demonstrated in GABA uptake assays and electrophysiological experiments with brain slices, and might be used as a tool compound for deepening the understanding of mGAT1 function in brain. PMID- 25025596 TI - Electrical safety: an Australian perspective. AB - Australia has an electricity mains supply that differs from those of most countries. Safety standards relating to both the mains supply and mains-powered apparatus also differ. This paper describes the mechanism of electric shock and methods of shock protection - core-balance relays, protected earth-free supplies and equipotential earthing are considered. Australian safety standards as applied to earthed mains-powered apparatus are summarized. Particular attention is given to class A and B treatment areas and electromedical apparatus having a patient circuit. Class A, B and Z patient circuits are described. PMID- 25025597 TI - SKIN TEMPERATURE, COLOUR, and WARMTH FELT, IN HYDROCOLLATOR PACK APPLICATIONS TO THE LUMBAR REGION. AB - The application of hydrocollator packs carries an inherent danger of overheating, which must be avoided. While a variety of temperatures and coverings for the packs has been reported, it has been stated that a bright red skin colour may be indicative of skin damage. It has also been stated that a therapeutically desirable rise in skin temperature would be one to over 40 degrees C during the treatment. In this study hydro-pack applications to the lumbar region of the back were assessed for onset of sensation after application, and at intervals thereafter for skin temperature, skin colour, and subjective sensation of warmth. The lack of co-relation found between these variables suggests that in clinical work an observation of the skin and also a subjective report, should be obtained at frequent intervals for at least the first nine minutes after application. The need for a rise in skin temperature above 40 degrees C is questioned. PMID- 25025598 TI - Work experiences of recent physiotherapy graduates. AB - Eighteen months after the completion of their training in 1978, 62 per cent of B App Sc (Cumb) graduates in physiotherapy responded to a questionnaire investigating their work experiences, attitudes and plans. All except 8 per cent were currently employed, and 15 per cent had experienced involuntary unemployment. Satisfaction with the job and career choice was high but there was least gratification regarding work aspects considered the most important. The most frequently cited work stressors were feelings of inadequacy, depression and irritation regarding patients and work overload. The majority of graduates planned to specialize and undertake further study. Many were undecided in their attitudes toward their profession and 39 per cent had not joined the Association. Some attitude changes had occurred since graduation. PMID- 25025599 TI - The team approach to the delivery of support services to teachers in educational settings. AB - As educational services accept responsibility for the provision of appropriate education for a wider range of disabled children, therapists and other support personnel will increasingly be called upon to work in an educational model. Team approaches - multidisciplinary, interdisciplinary or transdisciplinary - provide effective ways of organising staff to service the educational system. The therapists and other support professionals within the teams may work in at least three ways: traditionally; as a consultant; or as a resource person/information source. The advantages and disadvantages of each role are discussed. PMID- 25025600 TI - Charge transport and structural dynamics in carboxylic-acid-based deep eutectic mixtures. AB - Charge transport and structural dynamics in the 1:2 mol ratio mixture of lidocaine and decanoic acid (LID-DA), a model deep eutectic mixture (DEM), have been characterized over a wide temperature range using broad-band dielectric spectroscopy and depolarized dynamic light scattering. Additionally, Fourier transform infrared spectroscopy measurements were performed to assess the degree of proton transfer between the neutral parent molecules. From our detailed analysis of the dielectric spectra, we have determined that this carboxylic-acid based DEM is approximately 25% ionic at room temperature. Furthermore, we have found that the characteristic diffusion rate of mobile charge carriers is practically identical to the rate of structural relaxation at all measured temperatures, indicating that fast proton transport does not occur in LID-DA. Our results demonstrate that while LID-DA exhibits the thermal characteristics of a DEM, its charge transport properties resemble those of a protic ionic liquid. PMID- 25025602 TI - Polar metabolites of polycyclic aromatic compounds from fungi are potential soil and groundwater contaminants. AB - This study investigated the sorption to soil of water-soluble metabolites from polycyclic aromatic compounds (PACs). The soil fungus Cunninghamella elegans was used to produce PAC metabolites from two un-substituted PACs (phenanthrene, pyrene), three alkyl-substituted PACs (2-methylnaphthalene, 1-methylphenanthrene, 1-methylpyrene), and one sulfur-containing heterocyclic PAC (dibenzothiophene). Fifty-eight metabolites were tentatively identified; metabolites from the un substituted PACs were hydroxylated and sulfate conjugated, whereas metabolites from alkyl-substituted PACs were sulfate conjugated and either hydroxylated or oxidized to carboxylic acids at the methyl group. The metabolism of the sulfur containing heterocyclic PAC resulted in sulfate conjugates. The sorption of the PAC metabolites to three soils was determined using a batch equilibrium method, and partition coefficients (Kd's) were calculated for fourteen representative metabolites. Sulfate conjugated metabolites displayed Kd's below 70 whereas the metabolites with both a sulfate and a carboxylic acid group had Kd's below 2.8. The low Kd's of water-soluble PAC metabolites indicate high mobility in soil and a potential for leaching to surface- and groundwaters. PMID- 25025601 TI - Iyengar yoga for adolescents and young adults with irritable bowel syndrome. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic, disabling condition that greatly compromises patient functioning. The aim of this study was to assess the impact of a 6-week twice per week Iyengar yoga (IY) program on IBS symptoms in adolescents and young adults (YA) with IBS compared with a usual-care waitlist control group. METHODS: Assessments of symptoms, global improvement, pain, health related quality of life, psychological distress, functional disability, fatigue, and sleep were collected pre- and posttreatment. Weekly ratings of pain, IBS symptoms, and global improvement were also recorded until 2-month follow-up. A total of 51 participants completed the intervention (yoga = 29; usual-care waitlist = 22). RESULTS: Baseline attrition was 24%. On average, the yoga group attended 75% of classes. Analyses were divided by age group. Relative to controls, adolescents (14-17 years) assigned to yoga reported significantly improved physical functioning, whereas YA (18-26 years) assigned to yoga reported significantly improved IBS symptoms, global improvement, disability, psychological distress, sleep quality, and fatigue. Although abdominal pain intensity was statistically unchanged, 44% of adolescents and 46% of YA reported a minimally clinically significant reduction in pain following yoga, and one third of YA reported clinically significant levels of global symptom improvement. Analysis of the uncontrolled effects and maintenance of treatment effects for adolescents revealed global improvement immediately post-yoga that was not maintained at follow-up. For YA, global improvement, worst pain, constipation, and nausea were significantly improved postyoga, but only global improvement, worst pain, and nausea maintained at the 2-month follow-up. CONCLUSIONS: The findings suggest that a brief IY intervention is a feasible and safe adjunctive treatment for young people with IBS, leading to benefits in a number of IBS specific and general functioning domains for YA. The age-specific results suggest that yoga interventions may be most fruitful when developmentally tailored. PMID- 25025604 TI - Consistency of cervical and cervicothoracic posture in standing. AB - The reproducibility of cervical and cervicothoracic curvature in an unconstrained standing position was examined in 17 volunteers. Parameters investigated included three angles of cervical inclination (the angle between the horizontal and a line drawn between C2 and C7, C2 and T1, and C2 and T2 respectively), cervical lordosis, and cervicothoracic kyphosis. Reliability of these parameters for within-trial, between-trial (intraday), and between-day (one week apart) measures was calculated from lateral photographs using intraclass correlation coefficients ICC (2,1). All measures of cervical inclination were highly reproducible as was cervicothoracic kyphosis, but cervical lordosis had more variable reproducibility. These findings suggest that cervicothoracic kyphosis and cervical inclination are appropriate to use for determining the effects of intervention in either clinical practice or research. PMID- 25025603 TI - Transition from reciprocal cooperation to persistent behaviour in social dilemmas at the end of adolescence. AB - While human societies are extraordinarily cooperative in comparison with other social species, the question of why we cooperate with unrelated individuals remains open. Here we report results of a lab-in-the-field experiment with people of different ages in a social dilemma. We find that the average amount of cooperativeness is independent of age except for the elderly, who cooperate more, and a behavioural transition from reciprocal, but more volatile behaviour to more persistent actions towards the end of adolescence. Although all ages react to the cooperation received in the previous round, young teenagers mostly respond to what they see in their neighbourhood regardless of their previous actions. Decisions then become more predictable through midlife, when the act of cooperating or not is more likely to be repeated. Our results show that mechanisms such as reciprocity, which is based on reacting to previous actions, may promote cooperation in general, but its influence can be hindered by the fluctuating behaviour in the case of children. PMID- 25025605 TI - Strain at the subclavian artery during the upper limb tension test. AB - The manoeuvres of the upper limb tension test (ULTT) were described by Elvey (1983 and 1985) to identify the presence of a brachial plexus component in upper arm pain. A pilot study was undertaken to examine strain at the subclavian artery during the ULTT in two embalmed cadavers. Photographs of the artery segments were obtained at each step of the test and from these, strain scores were calculated. Results show that limb manoeuvres conducted with cervical contralateral lateral flexion produced more strain than with ipsilateral lateral flexion. Since cervical contralateral lateral flexion appears capable of increasing strain at the subclavian artery, further studies comparing strain at the artery with strain at cervical nerves are indicated. PMID- 25025606 TI - Measuring the endurance capacity of the cervical short flexor muscle group. AB - The role of the cervical short flexor muscles in maintaining head posture has been recognised recently. While a computerised device is available for measuring isometric performance of this muscle group, no clinical method is available. This paper reports on an inexpensive and time-efficient method of measuring the endurance capacity of the cervical short flexor muscle group in a clinical setting. The measurement is adapted from an exercise described and illustrated by Trott (1988). The measurements of cervical short-flexor endurance were reproducible over a one month interval. There was a systematic improvement in mean endurance capacity for both women and men and the possible causes of this are discussed. PMID- 25025607 TI - Another look at neurological rehabilitation. AB - Advances in neurophysiological research over the past 20 years have led to dramatic changes in the understanding of the neural control of movement. These newer concepts have directed attention towards possibilities for motor recovery previously discounted. They also imply that changes in health care delivery may be necessary in order to take advantage of the recovery process and achieve maximum potential. If the neurologically disabled are to benefit from the advances of science, and if physical therapy practitioners are to reach and maintain scientific credibility, some fundamental changes in clinical thinking and practice seem indicated. This article discusses some implications for the practice of physical therapy in neurology. PMID- 25025608 TI - Public perception of physiotherapy: implications for marketing. AB - A national telephone survey which randomly selected 510 members of the general public was undertaken in early 1992. The aim was to ascertain the public's perception of physiotherapy. The results of the survey revealed that physiotherapists were best known for their treatment of musculoskeletal conditions. There was very little awareness that physiotherapists provided specialist care for women and children. Location of the physiotherapist appeared to be an important factor, giving physiotherapists the potential to capitalise on tailoring service provision to their particular locality. Another important feature of physiotherapy service that was identified was the need for client centred care. Medical practitioners were found to be very important for referral and communication about physiotherapy. However it appears the public is unaware of the full range of physiotherapy services, which suggests that there is a need for appropriately focused marketing campaigns. PMID- 25025609 TI - Tailoring anti-platelet therapy--one size will not fit all. PMID- 25025610 TI - An analysis of TRITON-TIMI 38, based on the 12 month recommended length of therapy in the European label for prasugrel. AB - BACKGROUND: In TRITON-TIMI 38, patients with acute coronary syndromes were treated with prasugrel or clopidogrel, with aspirin, for a median of 14.5 (maximum of 15) months. Based on this trial, the EU label for prasugrel recommends treatment for up to 12 months and excludes patients with prior stroke/transient ischemic attack (TIA). Furthermore, the EU label recommends the 10 mg maintenance dose (MD) for patients with body weight >=60 kg and age <75 years. A lower MD of 5 mg is recommended for those with body weight <60 kg; although generally not recommended, 5 mg can be prescribed to patients >=75 years after individual risk-benefit evaluation. This paper presents the one-year outcome data for this '10 mg indicated cohort'. METHODS AND RESULTS: From the overall cohort of 13,608 patients in TRITON-TIMI 38, 10,804 fulfilled inclusion criteria for the 10 mg indicated cohort, of whom 22% had a history of diabetes, 73% an index diagnosis of unstable angina/non-ST-segment-elevation myocardial infarction (UA/NSTEMI), and 27% an index diagnosis of ST-segment-elevation myocardial infarction (STEMI). In this cohort at 12 months, those given prasugrel experienced significantly fewer ischemic events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, 7.8% vs 10.5%, hazard ratio (HR) = 0.73, p < 0.001, than those given clopidogrel, with a non-significant increase in non-coronary artery bypass graft (CABG) TIMI major bleeding, 1.7% vs 1.5%, HR = 1.15, p = 0.40; similarly, in the overall cohort these frequencies were 9.4% vs 11.4%, HR = 0.81, p < 0.001, for cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, and 2.2% vs 1.8%, HR = 1.24, p = 0.10, for non CABG TIMI major bleeding. There was a significant reduction in stent thrombosis in the prasugrel group, with similar mortality rates and no excess of strokes. CONCLUSIONS: Treatment with prasugrel according to EU label recommendations results in a significant 27% and 57% relative risk reduction (absolute risk reductions of 2.7% and 1.2%) in ischemic events and stent thromboses respectively compared with clopidogrel, with a 15% relative risk increase (absolute risk increase of 0.2%) for major bleeds (p = 0.40), and no excess of strokes. LIMITATIONS: Although restricted to 365 days of follow-up, this analysis encapsulates 1366 of 1424 (95.9%) of all primary endpoint events and 244 of 257 (94.9%) of all first non-CABG TIMI major bleeds reported in the pivotal manuscript. Furthermore, the 10 mg indicated cohort was not a pre-specified subgroup in the study protocol, but due to European labeling restrictions, results for all outcomes in this cohort are presented through 12 months. PMID- 25025612 TI - Probing the links between structure and magnetism in Sr(2-x)Ca(x)FeOsO6 double perovskites. AB - The synthesis, structure, and properties of the ordered double perovskites Sr2FeOsO6, Ca2FeOsO6, and SrCaFeOsO6 are reported. The latter two compounds have monoclinic P21/n symmetry and a(-)a(-)b(+) tilting of the octahedra, while Sr2FeOsO6 is tetragonal with I4/m symmetry and a(0)a(0)c(-) tilting. Magnetic measurements indicate and neutron powder diffraction studies confirm that Ca2FeOsO6 is a ferrimagnet with a Curie temperature of 350 K. The ferrimagnetism is retained if half of the Ca(2+) ions are replaced with larger Sr(2+) ions to form SrCaFeOsO6 (T(C) = 210 K). This substitution reduces the degree of octahedral tilting, but unlike most perovskites, the magnetic ordering temperature decreases as the Fe-O-Os bond angles approach a linear geometry. In contrast, Sr2FeOsO6 orders antiferromagnetically, as previously reported. X-ray absorption spectroscopy confirms the assignment of Fe(III) and Os(V) oxidation states for all three compounds. In these insulating double perovskites, the magnetic ground state is governed by a competition between the four-bond Fe-O-Os O-Fe antiferromagnetic superexchange coupling of Fe(III) ions and the two-bond Fe O-Os antiferromagnetic superexchange coupling between neighboring Fe(III) and Os(V) ions. When the Fe-O-Os bonds are linear, as they are in the c direction in Sr2FeOsO6, the four-bond coupling between Fe(III) ions prevails. The competition shifts in favor of antiferromagnetic coupling of Fe(III) and Os(V) as the Fe-O-Os bond angles bend in response to chemical pressure. PMID- 25025611 TI - Outcome prediction after mild and complicated mild traumatic brain injury: external validation of existing models and identification of new predictors using the TRACK-TBI pilot study. AB - Although the majority of patients with mild traumatic brain injury (mTBI) recover completely, some still suffer from disabling ailments at 3 or 6 months. We validated existing prognostic models for mTBI and explored predictors of poor outcome after mTBI. We selected patients with mTBI from TRACK-TBI Pilot, an unselected observational cohort of TBI patients from three centers in the United States. We validated two prognostic models for the Glasgow Outcome Scale Extended (GOS-E) at 6 months after injury. One model was based on the CRASH study data and another from Nijmegen, The Netherlands. Possible predictors of 3- and 6-month GOS E were analyzed with univariate and multi-variable proportional odds regression models. Of the 386 of 485 patients included in the study (median age, 44 years; interquartile range, 27-58), 75% (n=290) presented with a Glasgow Coma Score (GCS) of 15. In this mTBI population, both previously developed models had a poor performance (area under the receiver operating characteristic curve, 0.49-0.56). In multivariable analyses, the strongest predictors of lower 3- and 6-month GOS-E were older age, pre-existing psychiatric conditions, and lower education. Injury caused by assault, extracranial injuries, and lower GCS were also predictive of lower GOS-E. Existing models for mTBI performed unsatisfactorily. Our study shows that, for mTBI, different predictors are relevant as for moderate and severe TBI. These include age, pre-existing psychiatric conditions, and lower education. Development of a valid prediction model for mTBI patients requires further research efforts. PMID- 25025613 TI - New redox states observed in [FeFe] hydrogenases reveal redox coupling within the H-cluster. AB - Active [FeFe] hydrogenases can be obtained by expressing the unmaturated enzyme in Escherichia coli followed by incubation with a synthetic precursor of the binuclear [2Fe] subcluster, namely: [NEt4]2[Fe2(adt)(CO)4(CN)2] (adt = [S-CH2-NH CH2-S](2-)). The binuclear subsite Fe2(adt)(CO)3(CN)2 is attached through a bridging cysteine side chain to a [4Fe-4S] subcluster already present in the unmaturated enzyme thus yielding the intact native "H-cluster". We present FTIR electrochemical studies of the [FeFe] hydrogenase from Chlamydomonas reinhardtii, CrHydA1, maturated with the precursor of the native cofactor [Fe2(adt)(CO)4(CN)2](2-) as well as a non-natural variant [Fe2(pdt)(CO)4(CN)2](2 ) in which the bridging amine functionality is replaced by CH2. The obtained active enzyme CrHydA1(adt) shows the same redox states in the respective potential range as observed for the native system (E(ox/red) = -400 mV, E(red/sred) = -470 mV). For the Hox -> Hred transition the reducing equivalent is stored on the binuclear part, ([4Fe-4S](2+)Fe(II)Fe(I) -> [4Fe 4S](2+)Fe(I)Fe(I)), while the Hred -> Hsred transition is characterized by a reduction of the [4Fe-4S] part of the H-cluster ([4Fe-4S](2+)Fe(I)Fe(I) -> [4Fe 4S](+)Fe(I)Fe(I)). A similar transition is reported here for the CO inhibited state of the H-cluster: ([4Fe-4S](2+)Fe(I)Fe(II)CO -> [4Fe-4S](+)Fe(I)Fe(II)CO). An FTIR electrochemical study of the inactive variant with the pdt ligand, CrHydA1(pdt), identified two redox states H(pdt)-ox and H(pdt)-"red". Both EPR and FTIR spectra of H(pdt)-ox are virtually identical to those of the H(adt)-ox and the native Hox state. The H(pdt)-"red" state is also characterized by a reduced [4Fe-4S] subcluster. In contrast to CrHydA1(adt), the H(pdt)-ox state of CrHydA1(pdt) is stable up to rather high potentials (+200 mV). This study demonstrates the distinct redox coupling between the two parts of the H-cluster and confirms that the [4Fe-4S]H subsite is also redox active and as such an integral part of the H-cluster taking part in the catalytic cycle. PMID- 25025614 TI - Effect of disc degeneration on the muscle recruitment pattern in upright posture: a computational analysis. AB - Based on the sensor driving control mechanism model, the effect of disc degeneration on the trunk muscle recruitment (TMR) pattern was analysed in erect standing posture. A previously developed computational model was used for this analysis, with modifications incorporating the T12-L1 motion segment and additional muscle fascicles. To generate disc degeneration at three different levels (L3-L4, L4-L5, or L5-S1), the material properties of the ground matrix of the annulus and bulk modulus of the nucleus were reduced. The finite element method combined with an optimization technique was applied to calculate the muscle forces. Minimization of deviations in the averaged tensile stress in the annulus fibres at the outermost layer in the five discs was selected for muscle force calculations. The results indicated that the disc degeneration noticeably increased the activation of the superficial muscle (IT and R) even though there was no clear change in the longissimus thoracis. Unlike some of the superficial muscles, activation in the deep muscles (multifidus (ML, MS, MT), LL and Q) was decreased. The change in TMR pattern generated an intervertebral disc angle difference and nucleus pressure increased in the upper level. These differences are expected to be functional in that they reduce the stress at the degenerated disc by changing the muscle activation, which slows down the progress of disc degeneration. PMID- 25025615 TI - Translation of the facets during coupled motion in the cervical spine: a pilot study. AB - Facet movements in the mid-cervical spine (C2-C4) were examined on two cervical columns from preserved cadavers. The dissected columns were clamped to allow manual movement of one vertebra on the fixed vertebra beneath. Pins were inserted to mark the position of the facets, and movement changes recorded photographically; 160 measurements were taken from these photographs. The study showed that the facets of the free vertebra could be moved to either side in relation to the facets of the fixed vertebra. Furthermore during movements simulating lateral flexion and rotation, sideways translation of the facets was found to be part of the complex three dimensional motion. PMID- 25025616 TI - Designing a pulmonary rehabilitation programme. AB - Physiotherapists have an important role to play in the rehabilitation of patients with chronic obstructive pulmonary disease. Individually-tailored programmes including the following components, namely education, exercise, secretion removal, breathing 'training', home programmes, ventilatory muscle training, medications, support systems and counselling can provide subjective and objective benefits for these patients. A primary consideration is to involve patients in the planning, implementation and evaluation of the programme and to encourage them to develop self-help skills. Guidelines for designing a pulmonary rehabilitation programme are outlined,' and pertinent literature reviewed. PMID- 25025617 TI - Association between light exposure at night and insomnia in the general elderly population: the HEIJO-KYO cohort. AB - Chronic circadian misalignment between the internal and environmental rhythms, which is typically related to night-shift work and clock-gene variants, is associated with disruption of suprachiasmatic nucleus function and increased risk of insomnia. Under controlled laboratory conditions, light at night (LAN) suppresses melatonin secretion, delays the internal biological rhythm, and reduces sleepiness. Therefore, LAN exposure may cause circadian misalignment and insomnia, though it remains unclear in real-life situations whether LAN exposure is associated with insomnia. To evaluate an association between LAN exposure and sleep quality in home settings, we conducted a cross-sectional community-based study in 857 elderly individuals (mean age, 72.2 years). We evaluated bedroom light intensity using a light meter and subjectively and objectively measured sleep quality using the Pittsburgh Sleep Quality Index and an actigraph, respectively, along with urinary 6-sulfatoxymelatonin excretion. Compared with the lowest quartile group of LAN intensity, the highest quartile group revealed a significantly higher odds ratio (OR) for subjective insomnia in a multivariate model adjusted for age, gender, body mass index, daytime physical activity, urinary 6-sulfatoxymelatonin excretion, bedtime, rising time, and day length (adjusted OR, 1.61, 95% confidence interval, 1.05-2.45, p=0.029). In addition, higher OR for subjective insomnia was significantly associated with the increase in quartiles of LAN intensity (ptrend=0.043). Consistently, we observed significant association trends between the increase in quartiles of LAN intensity and poorer actigraphic sleep quality, including decreased sleep efficiency, prolonged sleep-onset latency, increased wake-after-sleep onset, shortened total sleep time, and delayed sleep-mid time in multivariate models adjusted for the covariates mentioned above (all ptrend<0.001). In conclusion, we demonstrated that LAN exposure in home settings is significantly associated with both subjectively and objectively measured sleep quality in a community-based elderly population. PMID- 25025618 TI - Bony and capsular determinants of glenohumeral 'locking' and 'quadrant' positions. AB - The anatomical relationships between the humerus and scapula were examined in the 'locking' and 'quadrant' positions of the glenohumeral joint together with capsular influences on the shape of the 'quadrant'. The glenohumeral joints of four embalmed cadavers were dissected to define capsular attachments and fibre directions. Selected bony and soft tissue landmarks were marked for reference. Four abduction angles were selected to represent 'locking' and parts of the 'quadrant'. A measuring board was designed to allow quantification and standardisation of all test positions. The results show that at 'locking', the postero-superior tip of the glenoid contacted the humeral head in all specimens. During the 'quadrant', a number of soft tissues around the joint were found to be either stretched or compressed. The capsule was found to influence the shape of the 'quadrant', and capsular stretch was noted anteriorly and interiorly. The findings are discussed in relation to clinical implications. PMID- 25025619 TI - The effect of training intensity on voluntary isometric strength improvement. AB - The effect of different training intensities on maximum voluntary isometric contraction (MVIC) strength was examined in a three week voluntary isometric exercise programme. Eighteen healthy university students were randomly assigned to one of three training groups: Low Intensity (LI), High Intensity (HI) and Maximal Effort (ME) groups. The LI and HI groups trained by producing voluntary isometric knee extension torques equivalent to 25% and 50% of MVIC strength, respectively. The ME group produced maximal effort contractions during training. Only the HI and ME groups demonstrated significant (p <.05) isometric strength gains. The HI group produced the greatest strength gain (45.8% of MVIC), followed by the ME group (31.3%) and the LI group (22.3%). No significant strength retention, cross transfer or isokinetic strength improvement were seen in any group. The strength improvements were of the same magnitude as those previously obtained using electro-motor stimulation at equivalent training intensities. PMID- 25025620 TI - Rehabilitation outcomes for elderly lower limb amputees. AB - The outcome following rehabilitation for 92 vascular amputees admitted to the Queen Elizabeth Geriatric Centre, Ballarat between 1 January 1982 and 31 December 1987 is presented. Data includes age, sex, concomitant disease, mortality, length of hospital stay and acceptance of prosthesis. Statistical analysis reveals no predictive factors for mobility levels attained by amputees other than amputation type, no predictive factors for acceptance of prostheses, and no predictive factors for total length of hospital stay. As a consequence, the Queen Elizabeth Geriatric Centre will continue the practice of admitting all amputees who wish to use artificial limbs to the prosthetic programme, regardless of age or concomitant disease. PMID- 25025621 TI - Adverse mechanical tension in the nervous system: a model for assessment and treatment. AB - The functional anatomy of the nervous system includes mechanisms to allow adaption to body movements. Injury or impairment of these mechanisms may lead to symptoms. Clinicians using tension tests as part of assessment and treatment have noted that altered nervous system movement and extensibility is a very frequent finding in many disorders. This paper describes a new model for assessment and treatment of mechanical disorders of the nervous system that is based on clinical observations and interpretations of anatomical, biomechanical and pathological literature. A broad approach is outlined which provides an insight into the possible mechanisms by which the nervous system can be responsible for symptom production. The concepts of intraneural and extraneural pathology are put forward and related to assessment and treatment. PMID- 25025622 TI - Minimal cerebral dysfunction in adults. AB - Awareness of minimal cerebral dysfunction (MCD) in children has increased in recent years and suitable management programmes have been developed. However, there has been less recognition that appropriate assessment and treatment might be provided for adults showing characteristic signs of MCD. A preliminary study was therefore carried out to ascertain the nature of the neurological deficits in adults presenting for assessment and to determine their responsiveness to treatment. A comparison of information relating to background features and neurological assessment with data collected from a reported study of MCD children revealed marked similarities between the two groups and demonstrated that major deficits in MCD children can continue to adulthood, creating functional difficulties in such important areas as reading, writing, spelling, memory and co ordination. PMID- 25025623 TI - A survey of work profiles and histories of physiotherapy graduates from the university of queensland. AB - The year 1988 marked the 50th anniversary of the commencement of physiotherapy education at the University of Queensland. A survey was conducted to record the work profiles and histories of Queensland graduates. Surveys were sent to 1,689 of the 1,897 graduates with a good response rate of 62.5 per cent. In 1987, 80 per cent of respondents were practising as physiotherapists, being reasonably evenly distributed between hospital practice, private practice and other more community based centres. With the exception of recent decade graduates, half of these predominantly female physiotherapists worked in a part-time capacity. The results of this survey do not reveal major manpower wastage. Although temporary absences from the profession for family reasons were common, only 15.1 per cent of all respondents have permanently withdrawn from the profession. PMID- 25025624 TI - Temporary tibial nerve block: adjunct to inhibitory plasters in the physiotherapy management of equinus in severely head injured children. AB - Spastic equinus, resulting from severe head injury in children, can greatly impede their rehabilitation. The use of a temporary tibial nerve block to negate the neurological component of the equinus, prior to the application of inhibitory plasters, is described and the rationale detailed. Subsequent physiotherapy management, including the application of the plasters, is discussed. Two clincal case studies are given to highlight the aspects involved. PMID- 25025625 TI - The Use of EMG Biofeedback in Quadriceps Strengthening Exercise for Rheumatoid Arthritis Patients: A Clinical Trial. AB - A clinical trial involving rheumatoid arthritis patients hospitalized due to an exacerbation of their disease, was initiated in order to determine whether EMG biofeedback when used in conjunction with isometric exercise enhanced quadriceps strengthening. The parameters of muscle bulk, strength and motor unit activity were measured before, during and after the trial to determine any improvements occurring. Results showed that in predominantly elderly patients there was no significant increase in quadriceps strengthening when EMG biofeed-back was used. Further, for subjects under 45 years of age, EMG biofeedback was not shown to effect significant improvement. PMID- 25025626 TI - A potent anti-thrombosis peptide (vasotab TY) from horsefly salivary glands. AB - Vasotab TY is a KGD (Lys-Gly-Asp)-containing peptide identified from salivary glands of the horsefly of Tabanus yao. We have previously reported that vasotab TY showed a strong vasodilator activity. In the present study, vasotab TY was found to inhibit platelet aggregation effectively. It completely inhibited platelet aggregation induced by adenosine diphosphate (ADP) at the concentration of 9.6MUg/ml. Vasotab TY significantly reduced thrombus weight in rat arteriovenous shunt model and inhibited thrombosis in carrageenan-induced mouse tail thrombosis model in vivo. Vasotab TY competitively bound to glycoprotein IIb/IIIa (GPIIb/IIIa) with eptifibatide, a well-known KGD-containing cyclic heptapeptide containing high specificity and high affinity for GPIIb/IIIa, suggesting that it is an antagonist of the fibrinogen receptor GPIIb/IIIa on the surface of platelet. The KGD motif in vasotab TY may facilitate the binding of it to GPIIb/IIIa. Vasotab TY showed a half-life of more than 1h in vivo. It showed little side effects including little bleeding, no hemolytic activity on human blood red cells and no cytotoxicity on human keratinocyte and THP-1 cells. Combined its vasodilator and platelet inhibitory functions, vasotab TY might be an excellent candidate for the development of clinical anti-thrombosis medicines. PMID- 25025627 TI - Radiographic and laboratory data ("the Megaprofile") can accurately guide medical management in the absence of stone analysis. AB - INTRODUCTION: Stone analysis is not always available, and recent studies reveal interlaboratory reporting differences, suggesting inaccurate reports. We sought to determine whether appropriate medical therapy could be made without stone analysis when imaging, history, and laboratory data were available. MATERIALS AND METHODS: One hundred stone formers (SFs) were categorized as calcium oxalate, calcium phosphate, uric acid, or struvite based on a single analysis. Age, gender, body mass index, comorbidities, serum chemistries, 24-hour urine, and imaging information were incorporated into a "Megaprofile." Radiographic details about patients' stones were recorded. Attenuation: Size ratios were calculated to predict stone composition. Stone composition data were then withheld and three urologists (S.L.B., S.S., and S.Y.N.) evaluated each Megaprofile, making nutritional and pharmacologic recommendations. Next, a repeat evaluation ensued with stone analyses. Recommendations were compared with the gold standard being those made using stone composition data. RESULTS: Without stone analysis, the panel recommended targeted nutrition therapy in 91% of cases, which remained unchanged once composition was revealed. Medication was prescribed in 68% of cases. Overall, therapy based on the Megaprofile without stone composition data was appropriate 93% of the time. In 7% of cases, therapy was changed after stone composition was revealed. In 21% of patients with recurrent urinary tract infections (UTIs), knowledge of stone composition altered therapy. CONCLUSIONS: Medical, laboratory, and radiographic data provide sufficient information to direct both nutritional and pharmacologic therapy in most SFs (93%), but those with recurrent UTIs may derive more benefit from stone analysis prior to directed medical therapy. PMID- 25025629 TI - Assessment of professional competence: the clinical teacher's responsibility. AB - The basic function of physiotherapy education is to develop a competent clinician. A student is prepared for this role by being exposed to a variety of educational experiences, of which the most influential occur during clinical practice. PMID- 25025628 TI - Functionalized anodic aluminum oxide membrane-electrode system for enzyme immobilization. AB - A nanoporous membrane system with directed flow carrying reagents to sequentially attached enzymes to mimic nature's enzyme complex system was demonstrated. Genetically modified glycosylation enzyme, OleD Loki variant, was immobilized onto nanometer-scale electrodes at the pore entrances/exits of anodic aluminum oxide membranes through His6-tag affinity binding. The enzyme activity was assessed in two reactions-a one-step "reverse" sugar nucleotide formation reaction (UDP-Glc) and a two-step sequential sugar nucleotide formation and sugar nucleotide-based glycosylation reaction. For the one-step reaction, enzyme specific activity of 6-20 min(-1) on membrane supports was seen to be comparable to solution enzyme specific activity of 10 min(-1). UDP-Glc production efficiencies as high as 98% were observed at a flow rate of 0.5 mL/min, at which the substrate residence time over the electrode length down pore entrances was matched to the enzyme activity rate. This flow geometry also prevented an unwanted secondary product hydrolysis reaction, as observed in the test homogeneous solution. Enzyme utilization increased by a factor of 280 compared to test homogeneous conditions due to the continuous flow of fresh substrate over the enzyme. To mimic enzyme complex systems, a two-step sequential reaction using OleD Loki enzyme was performed at membrane pore entrances then exits. After UDP Glc formation at the entrance electrode, aglycon 4-methylumbelliferone was supplied at the exit face of the reactor, affording overall 80% glycosylation efficiency. The membrane platform showed the ability to be regenerated with purified enzyme as well as directly from expression crude, thus demonstrating a single-step immobilization and purification process. PMID- 25025630 TI - Can and should physiotherapists specialize? AB - Physiotherapists with ability could specialize if they were given the opportunity. The issue to be faced is: Should physiotherapists specialize? Does the profession need a category called "specialist physiotherapist"? PMID- 25025631 TI - The joints of the shoulder girdle. AB - The long process of progression from quadruped to biped posture has demanded skeletal and muscular changes which have formed a distinct trend in those forms in which the forelimb has been freed for prehension. PMID- 25025632 TI - Spinal reflex incentive. AB - After graduation one tends to experiment with differing approaches to treatment of learnt patterns of conventional procedure. Spinal Reflex Incentive (S.R.I.) is a form of treatment which I have been using successfully for eight years. Its purpose is to gain voluntary movement after flaccid paralysis caused by an upper motor neuron lesion. PMID- 25025633 TI - A survey of recent knee injuries treated by physiotherapy. AB - The knee is not only the largest joint in the human body, but it is also the most complex (Romanes, 1969). It is an area of considerable importance to the physiotherapist, due to the fact that the knee is the site of frequent injury to both soft tissues and skeletal structures, with a predisposition to complications and a resulting pronounced functional deficit. If acute injuries are not managed correctly, permanent instability and pain may reduce the patient's functional capacity, while the rapid loss of muscle power in the quadriceps may predispose the knee to repeated trauma unless effective management is instituted. PMID- 25025634 TI - Physiotherapy and community medicine. AB - Community based health care should be oriented to local needs, preventive medicine and should be accessible to all. The bias in health care provision at large central institutions produces an uneven delivery of service dependent upon the nature of the disease. PMID- 25025635 TI - Use of inhibitory, weight-bearing plasters to increase movement in the presence of spasticity. AB - Spasticity of central origin following brain-damage prevents efficient functional movement. Inhibitory weight-bearing plasters can be applied to allow the patient to learn to move more normally while the spasticity is being controlled. This article is a summary of a case study where weight-bearing plasters were used with good results. PMID- 25025636 TI - The development and possible future of manipulative therapy in australia. AB - A brief synopsis of the development of manipulative therapy is given. An argument for specialisation and its concept to the consumer is advanced. PMID- 25025637 TI - On-chip monitoring of skeletal myoblast transplantation for the treatment of hypoxia-induced myocardial injury. AB - A comprehensive elucidation of the unexpected adverse events that occur in skeletal myoblast transplantation is fundamental for the optimization of myocardial therapeutic effects. However, a well-defined method to study the interactions between skeletal myoblasts and cardiomyocytes during the healing process is out of reach. Here, we describe a microfluidic method for monitoring the interactions between skeletal myoblasts and hypoxia-injured cardiomyocytes in a spatiotemporally-controlled manner, mimicking the in vivo cell transplantation process. A myocardial hypoxia environment was created using an oxygen consumption blocking reagent, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone. Meanwhile, the interactions between the skeletal L6 myoblasts and hypoxia-injured myocardium H9c2 cells were investigated, and the effects of a L6 conditional medium on H9c2 cells were comparatively analyzed by quantitatively measuring the morphological and pathophysiological dynamics of H9c2 cells. The results showed that skeletal myoblasts could repair hypoxia-injured H9c2 cells mainly through direct cell-to-cell interactions. This simple on-chip assay for investigating myocardial repair processes may provide avenues for the in vitro screening of drug-induced cardiotoxicity. PMID- 25025638 TI - Late positive potential (LPP) modulation during affective picture processing in preschoolers. AB - Research has demonstrated that late positive potential (LPP) is modulated by affective pictures in school-age children, adolescents and adults. However, little is known about such modulation in specific younger populations such as preschoolers. In this study, we examined whether LPP modulation during affective picture processing would also be observed in preschoolers as well as investigating the patterns of such modulation by using pictures which elicited emotional reactions of different valences. Twenty preschoolers (M age in months=61.00, SD=7.73) passively viewed pleasant, neutral and unpleasant pictures while their scalp event-related potentials (ERPs) were recorded. Results showed that in preschoolers pleasant and unpleasant pictures elicited significantly larger LPP amplitudes than neutral pictures, and this affective modulation of LPP amplitude emerged in the posterior region and gradually extended to the central and anterior regions. PMID- 25025639 TI - Peer review for physiotherapists in Australia: The concept of interpractice visits. AB - Peer review is a quality assurance tool which offers much to physiotherapists in the 1990s. It continues to be valuable when practised in both formal and informal settings. Over the last decade, peer review has been developed into several formalised processes, enabling physiotherapists to choose the most appropriate method of peer review to suit their mode of practice. The result is an opportunity for physiotherapists to share ideas for improvement in all aspects of physiotherapy practice in a non-threatening, positive environment. PMID- 25025640 TI - The influence of ankle strapping on wobbleboard performance, before and after exercise. AB - Twenty four uninjured female volunteers (mean age = 19.6 years) were utilised to study the effect of modified Gibney ankle strapping on proprioception before, during and after exercise, by measuring performance on an instrumented wobbleboard. Following a familiarisation session, testing was conducted on two occasions using a crossover research design, utilising strapped and unstrapped conditions. The time in contact, the number of contacts and the average time in contact that the wobbleboard made with a metal baseplate under the wobbleboard were recorded during a ten second test duration. Tests were conducted at the times of 0, 5, 10 and 15 minutes of a standardised exercise regime performed by the subjects. Results revealed that strapping had no significant effect on wobbleboard performance. Since the wobbleboard is widely accepted as a method of training as well as a clinical assessment of ankle proprioception, it could be inferred that strapping had no effect on proprioception before, during or after exercise. PMID- 25025641 TI - Blood pressure and heart rate responses to a standard lower limb isokinetic test. AB - In order to investigate the blood pressure and heart rate responses to a standard lower limb isokinetic test, 19 subjects between the ages of 20 and 30 were measured prior to, immediately post-exercise, and for four minutes into recovery. Although no direct comparisons were available, these values were found to reflect cardiovascular responses consistent with those seen in maximal treadmill testing. In addition, correlation studies demonstrated a nonsignificant relationship between systolic blood pressure and heart rate at all stages. Similarly, no significant relationship was found using scales of distress or perceived exertion. The implications of these findings are discussed in conjunction with relevant cardiovascular stress testing literature. Clinical recommendations include the implementation of a standardised screening procedure, a supervised cool-down phase and standard stress-testing precautions when undertaking maximal isokinetic testing. PMID- 25025642 TI - Techniques for active lumbar stabilisation for spinal protection: A pilot study. AB - Active protection of the lumbar spine is important in prevention of back strain during exercise. This EMG study investigated three common techniques used for lumbar stabilisation : posterior pelvic tilt, lower abdominal hollowing with lumbar spine flattening and abdominal bracing. The aim was to determine which method encouraged the best stability pattern. Muscle activity was measured in obliquus abdominis, upper and lower rectus abdominis and the lumbar erector spinae. Standardisation of muscle activity against that during maximally resisted trunk rotation (already shown to illustrate an appropriate stability pattern) allowed comparisons between exercise techniques in relation to their stabilisation pattern. Results indicated that posterior pelvic tilt demonstrated the least desirable stability pattern. Both abdominal hollowing and bracing provided a more suitable pattern. PMID- 25025643 TI - Load-displacement-time characteristics of the spine under posteroanterior mobilisation. AB - The load-displacement-time characteristics of the lumbarspine were obtained undersimulated central posteroanterior (PA) mobilisation. The instrumentation(the spinal mobiliser) consisted of a motor-driven force applicator and a pair of displacement transducers. The PA mobility of the L3, L4 and L5 segments of 28 young normal subjects (14 males and 14 females) was examined, and this was found to be dependent on spinal level but not on gender. At each level tested (except L5), greater movement was observed in the more caudal of the two segments adjacent to the mobilised vertebra. Finally, L4 was subjected to cyclic and sustained PA loadings, and to loadings at different rates. Viscoelastic behaviour such as creep and rate-dependency was observed, as was the preconditioning phenomenon. The results suggest that PA mobilisation produces more mechanical effects on the lower segment, and that the preconditioning and creep effects might explain the improvement in spinal mobility after mobilisation. PMID- 25025644 TI - Reliability of isokinetic torque measurements: A review of the literature. AB - Recently there has been increased interest in the use of isokinetic exercise by physiotherapists both in scientific research and clinical practice. Isokinetic exercise can be used for the assessment of muscle performance and for the treatment of impaired muscle performance. Fundamental to the use of isokinetic exercise is the establishment of reliable test protocols for each joint tested to ensure that the isokinetic measurements obtained from the several commercially available isokinetic dynamometers can be reliably reproduced. This paper reviews the literature available on the test-retest reliability of isokinetic torque measurements. PMID- 25025645 TI - A kinematic analysis of recovery of the ability to stand up following stroke. AB - The purpose of this study was to determine the change in some kinematic characteristics of standing up as patients recovered following stroke. Patients who have had a stroke resulting in a diagnosis of hemiplegia, but with no other involvement, were videotaped on two occasions; when they could first stand up independently and again when they could stand up and sit down three times in 10 seconds with no observable asymmetry. A kinematic analysis yielded angular displacement and velocity data from the affected hip and knee joints. The results indicate that the kinematic characteristics that changed significantly as the subjects improved their ability to stand up are related more to velocity than to angular displacement. Movement time decreased, peak angular velocities increased and the velocity profiles shifted towards normal. This implies that in the clinic, once a patient can stand up independently, improvement on this task will be promoted if motor training includes strategies that affect these temporal characteristics. PMID- 25025646 TI - [Implantation of a sulcus-fixated toric additive intraocular lens in a case of high astigmatism after a triple procedure]. AB - BACKGROUND: Residual refractive errors, especially high-grade astigmatism after penetrating keratoplasty, often lead to a significant loss of vision. If high anismetropia could not be corrected with glasses or contact lenses, different kinds of surgical procedures are available for visual rehabilitation (intraocular lens exchange, astigmatic keratotomy, Excimer laser treatment, intrastromal corneal ring segment implantation and additive intraocular lens implantation). Toric add-on IOLs are especially designed for sulcus implantation and correcting high astigmatism in pseudophakic eyes. All toric IOLs are individually manufactured according to subjective refraction and biometry. Depending on the underlying manufacturer high-grade astigmatism can be corrected with a cylindrical power up to + 30.0 D. CASE REPORT: A 74-year-old patient presented with endothelial decompensation and an uncorrected distance visual acuity (UDVA) of 1.0 logMAR for penetrating keratoplasty on the right eye due to a Fuchs endothelial dystrophy. Postoperatively, the uncorrected distance visual acuity improved to 0.8 logMAR, with pinhole correction to 0.5 logMAR. After removing the sutures a high and irregular corneal astigmatism of 21.0 D was found. The corrected distance visual acuity (CDVA) with a refraction of + 5.5 D sph, - 21.0 D cyl 90 degrees was 0.24 logMAR. Therefore an individually manufactured toric additive intraocular lens of + 25.0 D cylindrical and - 18.0 D spherical power for sulcus implantation was chosen and implanted uneventfully. Eight months after surgery refractive astigmatism was reduced significantly to - 0.75 D with an UDVA of 0.08 logMAR and a CDVA of 0.02 logMAR. During the 8-months follow-up period the additive IOL remained centered and no IOL rotation could be observed. CONCLUSION: Toric add-on IOLs are a safe and successful method for reducing high astigmatism and anisometropia after penetrating keratoplasty. One of the main advantages is the reversibility of the procedure by an explantation of the IOL. PMID- 25025647 TI - [A comparison of device-based diagnostic methods for keratoconus]. AB - PURPOSE: Due to the modern device-assisted diagnosis of keratoconus by topography, tomography and biomechanical properties of the cornea, a large number of parameters and indices are obtained as a result of clinical examinations. The aim of the present study was to investigate how modern screening methods support the diagnosis of keratoconus. PATIENTS AND METHODS: In this prospective study, 93 eyes of 93 keratoconus patients and 107 eyes of 107 healthy subjects (control group) were included. The keratoconus group contained 85 % males, whereas the distribution in the control group was balanced. The mean age was 35 +/- 12 years in the keratoconus group and 27 +/- 7 years in the control group. Exclusion criteria for both groups were previous eye surgery, cross-linking therapy, glaucoma, uveitis or other inflammatory diseases of the eye. All patients with a thyroid disorder were also excluded from the control group. All eyes were examined using the TMS-5 topographer, Pentacam and Ocular Response Analyzer (ORA). Based on receiver operator characteristics (ROC), the performance of various keratoconus indices was determined by means of the area under the curve (AUC). RESULTS: All parameters showed statistically highly significant differences between the keratoconus and control group (p <= 0.0001). The Surface Asymmetry Index (SAI) and the Keratoconus Severity Index (KSI) of TMS performed well with (mean value keratoconus group/mean value control group/AUC) SAI (2.43/0.36/0.969) and KSI (50.87/0.37/0.912). Pentacam parameters Index of Surface Variance (ISV) and Topographic Keratoconus Classification (TKC) were comparable to TMS parameters with ISV (90.05/15.77/0.969), TKC (2.23/0.00/0.940). ORA indices Corneal Hysteresis (CH), Corneal Resistance Factor (CRF) and Keratoconus Match Index (KMI) showed slightly poorer performance with CH (8.22/11.48/0.909), CRF (7.25/11.20/0.951), KMI (0.31/1.05/0.909). CONCLUSION: In this study, tomography and topography was more reliable in diagnosing keratoconus than evaluating the biomechanical properties of the cornea. SAI and KSI (TMS) as well as TKC and ISV (Pentacam) showed improved recognition rates compared to the KMI (ORA). However, individual parameters alone are not sufficient for the diagnosis of keratoconus. PMID- 25025648 TI - [Change of diagnoses at the fundus in the aera of pars plana vitrectomy]. PMID- 25025649 TI - [Clinical value of ab-interno trabecular surgery in the management of glaucoma]. AB - Ab-interno trabecular surgery does not damage sclera and conjunctiva in glaucoma patients and does not prejudice subsequent anti-glaucomatous filtration or drainage device surgery. As only trabecular resistance is surgically modified, the level of intraocular pressure (IOP) can usually not be reduced in the lower teens. Consequently, incisional ab-interno trabecular surgery is a valuable option in early glaucoma stages with moderate IOP elevation, especially in combination with cataract surgery. Ab-interno trabecular surgery is an insufficient surgical tool in normal pressure glaucoma, but also in glaucoma patients with very high IOP peaks. PMID- 25025650 TI - Lavage with allicin in combination with vancomycin inhibits biofilm formation by Staphylococcus epidermidis in a rabbit model of prosthetic joint infection. AB - BACKGROUND AND AIM: The present anti-infection strategy for prosthetic joint infections (PJI) includes the use of antibiotics and surgical treatments, but the bacterial eradication rates are still low. One of the major challenges is the formation of biofilm causing poor bacterial eradication. Recently it has been reported that allicin (diallyl thiosulphinate), an antibacterial principle of garlic, can inhibit bacteria adherence and prevent biofilm formation in vitro. However, whether allicin could inhibit biofilm formation in vivo is unknown. The aim of this study was to investigate the effects of allicin on biofilm formation, and whether allicin could potentiate the bactericidal effect of vancomycin in a rabbit PJI model. METHODS: A sterile stainless-steel screw with a sterile ultra high molecular weight polyethylene washer was inserted into the lateral femoral condyle of the right hind knee joint of rabbit, and 1 mL inoculum containing 104 colony-forming units of Staphylococcus epidermidis was inoculated into the knee joint (n = 32). Fourteen days later, rabbits randomly received one of the following 4 treatments using continuous lavages: normal saline, vancomycin (20 mcg/mL), allicin (4 mg/L), or allicin (4 mg/L) plus vancomycin (20 mcg/mL). Three days later, the washer surface biofilm formation was examined by scanning electron microscopy (SEM). The bacterial counts within the biofilm of implanted screws were determined by bacterial culture. RESULTS: The lowest number of viable bacterial counts of Staphylococcus epidermidis recovered from the biofilm was in the rabbits treated with allicin plus vancomycin (P<0.01 vs. all other groups). The biofilm formation was significantly reduced or undetectable by SEM in rabbits receiving allicin or allicin plus vancomycin. CONCLUSION: Intra-articular allicincan inhibit biofilm formation and enhance the bactericidal effect of vancomycin on implant surface in vivo. Allicin in combination with vancomycin may be a useful anti-infection strategy for the treatment of PJI. PMID- 25025651 TI - Quantitatively profiling the dissolution and redistribution of silver nanoparticles in living rats using a knotted reactor-based differentiation scheme. AB - Whether silver nanoparticles (AgNPs) degrade and release silver ions (Ag(+)) in vivo has remained an unresolved issue. To evaluate the biodistribution and dissolution behavior of intravenously administered AgNPs in living rats, we employed a knotted reactor (KR) device to construct a differentiation scheme for quantitative assessment of residual AgNPs and their released Ag(+) ions in complicated animal tissues; to do so, we adjusted the operating parameters of the KR, namely, the presence/absence of a rinse solution and the sample acidity. After optimization, our proposed differentiation system was confirmed to be tolerant to rat tissue and organ matrix and provide superior reliability of differentiating AgNPs/Ag(+) than the conventional centrifugal filtration method. We then applied this differentiation strategy to investigate the biodistribution and dissolution of AgNPs in rats 1, 3, and 5 days postadministration, and it was found that the administered AgNPs accumulated predominantly in the liver and spleen, then dissolved and released Ag(+) ions that were gradually excreted, resulting in almost all of the Ag(+) ions becoming deposited in the kidney, lung, and brain. Histopathological data also indicated that toxic responses were specifically located in the AgNP-rich liver, not in the Ag(+)-dominated tissues and organs. Thus, the full-scale chemical fate of AgNPs in vivo should be integrated into future assessments of the environmental health effects and utilization of AgNP-containing products. PMID- 25025652 TI - Kinetics and structural changes of Li-rich layered oxide 0.5Li2MnO3.0.5LiNi(0.292)Co(0.375)Mn(0.333)O2 material investigated by a novel technique combining in situ XRD and a multipotential step. AB - Li-rich layered oxide 0.5Li2MnO3.0.5LiNi0.292Co0.375Mn0.333O2 was prepared by an aqueous solution-evaporation route. X-ray powder diffraction (XRD) showed that the as-synthesized material was a solid solution consisting of layered alpha NaFeO2-type LiMO2 (M = Ni, Co, Mn) and monoclinic Li2MnO3. The superlattice spots in the selected area electron diffraction pattern indicated the ordering of lithium ions with transition metal (TM) ions in TM layers in this Li-rich layered oxide. Electrochemical performance testing showed that the as-synthesized material could deliver an initial discharge capacity of 267.7 mAh/g, with a capacity retention of 88.5% after 33 cycles. A new combination technique, multipotential step in situ XRD (MPS in situ XRD) measurement, was applied for the first time to investigate the Li-rich layered oxide. Using this approach, the relationships between kinetics and structural variations can be obtained simutaneously. In situ XRD results showed that the c parameter decreased from 3.70 to 4.30 V and increased from 4.30 to 4.70 V, whereas the a parameter underwent a decrease above 4.30 V during the first charge process. Below 3.90 V during the first discharge process, a slight decrease in the c parameter was found along with an increase in the a parameter. During the first charge process, the value of the coefficient of diffusion for lithium ions (DLi+) decreased to its mininum at 4.55 V, which might be associated with Ni(2+) migration, as indicated by both Ni occupancy in 3b sites (Ni3b%) in the Li(+) layers and complicated chemical reactions. Remarkably, a lattice distortion might occur within the local domain in the host stucture during the first discharge process, indicated by a slight splitting of the (003) diffraction peak at 3.20 V. PMID- 25025653 TI - Percutaneous use of ePTFE/FEP-covered metallic stent for palliation of malignant biliary obstruction. AB - INTRODUCTION: Placement of self-expanding metallic stents has been a standard palliative treatment for patients with inoperable biliary malignancy, aiming at improving quality of life via a minimally invasive procedure. This study aimed to evaluate the efficacy of percutaneous placement of expanded polytetrafluoroethylene/fluorinated ethylene propylene-covered metallic stents for palliation of inoperable biliary malignancy. MATERIAL AND METHODS: Between February 2012 and April 2013, 11 patients with inoperable malignant biliary obstruction were treated with stent implantation. Serum bilirubin and liver enzyme levels were measured before/immediately after stent placement and at one, three, and six months. Patient survival and stent patency were calculated using Kaplan-Meier analysis. RESULTS: No migration occurred. Patients showed clinical improvement immediately and one month after stent placement, with a significant reduction in mean serum bilirubin level (p < 0.05). At six months, bilirubin levels were <1.5 mg/dL in all cases. One patient developed acute liver failure four days after stent implantation, leading to death. Survival rates were 90% at three months and 70% at six months. Primary patency rates were 100%, 100%, and 90% at one, three, and six months, respectively. CONCLUSION: Percutaneous placement of expanded polytetrafluoroethylene/fluorinated ethylene propylene covered metallic stents offered an effective palliative therapy for patients with inoperable biliary malignancy. PMID- 25025654 TI - [Recent advances in patient-related outcome in gynaecological cancer]. AB - The evaluation of quality of life has become essential in gynecological oncology. Recent guidelines have been published to improve the collection, analysis and publication of the data quality of life that will make them more reliable, reproducible and integrate them into the final treatment decision. This year at ASCO, in breast cancer, the benefit of sentinel lymph node dissection compared to the quality of life has been demonstrated. New data on cognitive function in patients treated for breast cancer show the importance of the evaluation of these disorders especially among elderly patients who are at-risk populations. Medical strategies including targeted therapies can improve survival without impairing the quality of life, also with improved gastrointestinal symptoms in case of combination chemotherapy with bevacizumab in patients with ovarian cancer in a situation early recurrence. Similarly, the addition of a pathway inhibitor M- Tor (everolimus) with hormonal therapy does not induce degradation of the quality of life in women with metastatic breast cancer. PMID- 25025655 TI - Physicochemical modifications accompanying UV laser induced surface structures on poly(ethylene terephthalate) and their effect on adhesion of mesenchymal cells. AB - This work reports on the formation of different types of structures on the surface of polymer films upon UV laser irradiation. Poly(ethylene terephthalate) was irradiated with nanosecond UV pulses at 193 and 266 nm. The polarization of the laser beam and the irradiation angle of incidence were varied, giving rise to laser induced surface structures with different shapes and periodicities. The irradiated surfaces were topographically characterized by atomic force microscopy and the chemical modifications induced by laser irradiation were inspected via micro-Raman and fluorescence spectroscopies. Contact angle measurements were performed with different liquids, and the results evaluated in terms of surface free energy components. Finally, in order to test the influence of surface properties for a potential application, the modified surfaces were used for mesenchymal stem cell culture assays and the effect of nanostructure and surface chemistry on cell adhesion was evaluated. PMID- 25025656 TI - Making room for oxytocin in understanding depression. AB - Depression is accompanied by an array of neurobiological variations, including altered HPA axis activity, monoamine, growth factor and inflammatory immune functioning. In addition, a recent perspective has entertained the possible role for oxytocin in depressive disorders. Given the involvement of oxytocin in prosocial behaviors such as attachment, affiliation, trust, and social support seeking, it is not surprising this neuropeptide might be involved in the development or maintenance of depressive disorders. This view is supported by evidence that oxytocin interacts with various neuroendocrine, neurotransmitter, and inflammatory processes that have previously been implicated in depression. Thus, it might be profitable to consider the contribution of oxytocin in the context of several neurobiological changes provoked by stressors. The current review examines the relation between oxytocin and depression with a specific focus on the interactions between the oxytocinergic system and stressor-provoked biological and psychosocial responses. The possibility is also considered that oxytocin might increase the salience of social cues, such that positive or negative experiences result in exaggerated responses that may influence affective states. PMID- 25025657 TI - Food for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. AB - The last decades have shown a spectacular and partially unexplained rise in the prevalence of autism spectrum disorders (ASD). This rise in ASD seems to parallel changes in the dietary composition of fatty acids. This change is marked by the replacement of cholesterol by omega-6 (n-6) fatty acids in many of our food products, resulting in a drastically increased ratio of omega-6/omega-3 (n-6/n 3). In this context, we review the available knowledge on the putative role of fatty acids in neurodevelopment and describe how disturbances in n-6/n-3 ratios may contribute to the emergence of ASDs. Both clinical and experimental research is discussed. We argue that a change in the ratio of n-6/n-3, especially during early life, may induce developmental changes in brain connectivity, synaptogenesis, cognition and behavior that are directly related to ASD. PMID- 25025659 TI - The breath of life: an essay on the earliest history of respiration: part I. AB - The association of life with breath is as old as man himself. The evolution of concepts concerning the relationship of one to the other begins in the supernatural, and winds through mysticism, religion and philosophy to become the central theme, together with the problem of the mammalian innate heat, in the history of biology and physiology. For the present we shall look only at how the mind of man first began to grapple with this fundamental problem; in doing so, we shall see how he took his first tentative steps towards a scientific understanding of himself, the microcosm, and the universe, or macrocosm. PMID- 25025660 TI - Abnormalities in passive movement: diagrammatic representation. AB - "Geography would be incomprehensible without maps. They've reduced a tremendous muddle of facts into something you can read at a glance. Now I suspect [passive movement] is fundamentally no more difficult than geography. Except that it's about things in motion. If only somebody would invent a dynamic map." C. P. Snow(2.) PMID- 25025661 TI - Manipulation by physiotherapists. AB - Divergent opinions exist on whether or not physiotherapists should manipulate. The controversy can be simply resolved by pointing out that the past policy of withholding such tuition from physiotherapists has in no way diminished the public demand for manipulation; it has merely forced potential patients to the bonesetter. Even those doctors who resent the idea of physiotherapists manipulating must surely prefer its performance by trained personnel working under doctors' guidance to indiscriminate recourse to all sorts of largely untrained laymen without doctors' prior approval. Come what may, the patients are going to be manipulated; at least let this then be sought from trained physiotherapists who give treatment ethically to patients sent to them by doctors. PMID- 25025662 TI - The problems of photosensitivity. AB - The purpose of this paper is: 1. To define photosensitivity and photosensitizers. 2. To state the results of photosensitivity. 3. To discuss the mechanism of photosensitivity. 4. To indicate briefly specific conditions allied to photosensitivity. 5. To discuss the management of the problem (a) By medical means (briefly only) (b) By physical means with which the physiotherapist may be involved including: (i) spectrophotometry; (ii) results of experiments with filters and sun, and physical screens. 6. To describe experiments performed to check the properties of accepted sensitizers and desensitizers. PMID- 25025663 TI - A proposal for policy makers implementing baby-friendly care. PMID- 25025658 TI - Adolescent brain maturation and smoking: what we know and where we're headed. AB - Smoking is a leading cause of mortality and morbidity worldwide. Smoking initiation often occurs during adolescence. This paper reviews and synthesizes adolescent development and nicotine dependence literatures to provide an account of adolescent smoking from onset to compulsive use. We extend neurobiological models of adolescent risk-taking, that focus on the interplay between incentive processing and cognitive control brain systems, through incorporating psychosocial and contextual factors specific to smoking, to suggest that adolescents are more vulnerable than adults to cigarette use generally, but that individual differences exist placing some adolescents at increased risk for smoking. Upon smoking, adolescents are more likely to continue smoking due to the increased positive effects induced by nicotine during this period. Continued use during adolescence, may be best understood as reflecting drug-related changes to neural systems underlying incentive processing and cognitive control, resulting in decision-making that is biased towards continued smoking. Persistent changes following nicotine exposure that may underlie continued dependence are described. We highlight ways that interventions may benefit from a consideration of cognitive-neuroscience findings. PMID- 25025664 TI - Common genetic variation in the human CTF1 locus, encoding cardiotrophin-1, determines insulin sensitivity. AB - AIMS/HYPOTHESIS: Recently, cardiotrophin-1, a member of the interleukin-6 family of cytokines was described to protect beta-cells from apoptosis, to improve glucose-stimulated insulin secretion and insulin resistance, and to prevent streptozotocin-induced diabetes in mice. Here, we studied whether common single nucleotide polymorphisms (SNPs) in the CTF1 locus, encoding cardiotrophin-1, influence insulin secretion and insulin sensitivity in humans. METHODS: We genotyped 1,771 German subjects for three CTF1 tagging SNPs (rs1046276, rs1458201, and rs8046707). The subjects were metabolically characterized by an oral glucose tolerance test. Subgroups underwent magnetic resonance (MR) imaging/spectroscopy and hyperinsulinaemic-euglycaemic clamps. RESULTS: After appropriate adjustment, the minor allele of CTF1 SNP rs8046707 was significantly associated with decreased in vivo measures of insulin sensitivity. The other tested SNPs were not associated with OGTT-derived sensitivity parameters, nor did the three tested SNPs show any association with OGTT-derived parameters of insulin release. In the MR subgroup, SNP rs8046707 was nominally associated with lower visceral adipose tissue. Furthermore, the SNP rs1458201 showed a nominal association with increased VLDL levels. CONCLUSIONS: In conclusion, this study, even though preliminary and awaiting further confirmation by independent replication, provides first evidence that common genetic variation in CTF1 could contribute to insulin sensitivity in humans. Our SNP data indicate an insulin desensitizing effect of cardiotrophin-1 and underline that cardiotrophin-1 represents an interesting target to influence insulin sensitivity. PMID- 25025665 TI - Identification of natural compound inhibitors for multidrug efflux pumps of Escherichia coli and Pseudomonas aeruginosa using in silico high-throughput virtual screening and in vitro validation. AB - Pseudomonas aeruginosa and Escherichia coli are resistant to wide range of antibiotics rendering the treatment of infections very difficult. A main mechanism attributed to the resistance is the function of efflux pumps. MexAB OprM and AcrAB-TolC are the tripartite efflux pump assemblies, responsible for multidrug resistance in P. aeruginosa and E. coli respectively. Substrates that are more susceptible for efflux are predicted to have a common pharmacophore feature map. In this study, a new criterion of excluding compounds with efflux substrate-like features was used, thereby refining the selection process and enriching the inhibitor identification process. An in-house database of phytochemicals was created and screened using high-throughput virtual screening against AcrB and MexB proteins and filtered by matching with the common pharmacophore models (AADHR, ADHNR, AAHNR, AADHN, AADNR, AAADN, AAADR, AAANR, AAAHN, AAADD and AAADH) generated using known efflux substrates. Phytochemical hits that matched with any one or more of the efflux substrate models were excluded from the study. Hits that do not have features similar to the efflux substrate models were docked using XP docking against the AcrB and MexB proteins. The best hits of the XP docking were validated by checkerboard synergy assay and ethidium bromide accumulation assay for their efflux inhibition potency. Lanatoside C and diadzein were filtered based on the synergistic potential and validated for their efflux inhibition potency using ethidium bromide accumulation study. These compounds exhibited the ability to increase the accumulation of ethidium bromide inside the bacterial cell as evidenced by these increase in fluorescence in the presence of the compounds. With this good correlation between in silico screening and positive efflux inhibitory activity in vitro, the two compounds, lanatoside C and diadzein could be promising efflux pump inhibitors and effective to use in combination therapy against drug resistant strains of P. aeruginosa and E. coli. PMID- 25025666 TI - Development of a finite element model of decompressive craniectomy. AB - Decompressive craniectomy (DC), an operation whereby part of the skull is removed, is used in the management of patients with brain swelling. While the aim of DC is to reduce intracranial pressure, there is the risk that brain deformation and mechanical strain associated with the operation could damage the brain tissue. The nature and extent of the resulting strain regime is poorly understood at present. Finite element (FE) models of DC can provide insight into this applied strain and hence assist in deciding on the best surgical procedures. However there is uncertainty about how well these models match experimental data, which are difficult to obtain clinically. Hence there is a need to validate any modelling approach outside the clinical setting. This paper develops an axisymmetric FE model of an idealised DC to assess the key features of such an FE model which are needed for an accurate simulation of DC. The FE models are compared with an experimental model using gelatin hydrogel, which has similar poro-viscoelastic material property characteristics to brain tissue. Strain on a central plane of the FE model and the front face of the experimental model, deformation and load relaxation curves are compared between experiment and FE. Results show good agreement between the FE and experimental models, providing confidence in applying the proposed FE modelling approach to DC. Such a model should use material properties appropriate for brain tissue and include a more realistic whole head geometry. PMID- 25025667 TI - The glyco-stereoisomerism effect on hydrogelation of polymers interacting via dynamic covalent bonds. AB - This work explores, for the first time, the stereoisomerism effect of sugar units of glycopolymers on hydrogelation. Three glycopolymers with an identical main chain but different pendent sugar stereoisomers are employed. Hydrogelation of the glycopolymers occurs driven by the dynamic covalent bonds between the sugar units and the benzoboroxole (BOB)-containing polymer. We conclude that the gelation ability of the glycopolymers differs obviously as shown in the sequence, Man > Gal > Glc due to the corresponding difference in their sugar-BOB interaction ability. PMID- 25025668 TI - [Phylogenetic and molecular analysis of A/H1N1pdm influenza viruses isolated in the epidemic season 2012/2013 from hospitalised patients with -symptoms of influenza-like illness]. AB - AIM: To perform phylogenetic and molecular analysis of A/H1N1pdm influenza viruses isolated in the epidemic season 2012/2013 from hospitalised patients with symptoms of influenza-like illness (ILI). MATERIAL AND METHODS: The study set included 34 strains of the A/H1N1pdm influenza virus isolated in the Czech Republic in the epidemic season 2012/2013. The strains were analysed by partial or whole-genome sequencing. The genome segments were compared at the nucleotide and amino acid levels, absolute and percentage sequence identity were determined, and phylogenetic relations were identified. The last steps were the comparison of the H1 molecule with that of the most recent vaccine strain and identification of the genotypic structure and molecular markers linked to the pathogenicity and antiviral resistance. RESULTS: Phylogenetic analysis of the H1 molecule suggested that all 34 A/H1N1pdm isolates from the 2012/2013 season in the Czech Republic should be assigned to H1 group 6 divided into sublineages 6A and 6B. The comparison of the known antigenic regions of the H1 molecule with those in the most recent vaccine strain revealed two stable changes in antigenic regions Sb and Ca1. Furthermore, sporadic mutations were identified in antigenic regions Ca2, Cb, and Sb. Genotyping revealed co-circulation of two related but clearly distiguishable genotypes of A/H1N1pdm. All isolates showed sensitivity to oseltamivir. One strain consisted of two N1 sub-populations, one oseltamivir sensitive and the other oseltamivir resistant, in nearly equimolar proportions. CONCLUSION: All A/H1N1pdm isolates from the epidemic season 2012/2013 in the Czech Republic formed a phenotypically uniform group. At the nucleotide level, the divergence was relatively more pronounced and H1 sublineages and discrete genotypes were possible to identify. H1 molecules were highly identical to those of the vaccine strain A/California/7/2009 (H1N1) which showed that the current vaccine was protective enough. All strains were sensitive to oseltamivir; however, the selection of oseltamivir resistant N1 subpopulations was observed. PMID- 25025669 TI - Viral gastroenteritis in Eastern Bohemia Region of the Czech Republic. AB - PURPOSE: Acute gastroenteritis is one of the most common diseases in humans worldwide and represents a significant cause of mortality and morbidity. The majority of cases are of viral aetiology, evidence for which has been increasing in the past decade. Several studies on the prevalence in European countries of viral aetiology of gastroenteritis have been published in the last decade, but none from the Czech Republic. MATERIAL AND METHODS: In total 107 faeces samples obtained from patients hospitalised in the University Hospital in Hradec Kralove were examined by immunochromatographic tests using ROTA-ADENO Card Rapid-Viditest (VIDIA, Czech Republic) and RidaQuick Norovirus (R-Biopharm, Germany), and by an in-house Real-time PCR panel. RESULTS: Overall findings of viruses detected by PCR in the tested faeces samples were: rotaviruses in 29.9%, noroviruses in 14.0% and adenoviruses in 5.0%. Immunochromatographic antigen detection performed at lower sensitivity compared with PCR: rotaviruses in 28.0%, noroviruses in 4.7% and adenoviruses in 2.0%. Our findings demonstrate even lower sensitivity of the used immunochromatographic tests compared with manufacturers data. CONCLUSION: Our study has revealed limitations in immunochromatographic tests, especially in their sensitivity and the necessity for using another confirmatory method. We have set up real-time PCR in routine diagnosis of viral gastroenteritis in our hospital. PMID- 25025670 TI - Seroprevalence study of hepatitis E virus infection in two districts of the Czech Republic. AB - The aim of this work was to retrospectively examine serum samples from 230 people living in two districts in the Czech Republic in year 1989 (Znojmo and Jihlava) for the IgG antibodies against hepatitis E virus (HEV). For examination, commercial ELISA kit DIA.PRO was used and 13 seropositive persons were found, i.e. 5.7% of those examined. The seropositivity rate was higher in women (6.8%) than in men (3.7%), but the difference was not statistically significant. The age of examined persons did not reveal a significant effect on the seropositivity rate: mean age of seropositive subjects was 38.0 years while that of seronegative persons was 39.4 years. PMID- 25025671 TI - [An increase in the prevalence of syphilis in women in Eastern Bohemia - 30 years of surveillance]. AB - Epidemiological data on sexually transmitted infections in the Czech Republic has been carefully reported for many years. Here we present an analysis of regional data on syphilis spanning more than 30 years in eastern Bohemia. The epidemiological data were derived from the mandatory reporting of sexually transmitted diseases covering the period 1981-2011. The data showed a minimal incidence of cases in 1990 and an increasing trend thereafter. Two peaks in the incidence are apparent - within years 1995-1999 and 2003-2007. Interestingly, while before 1990 the numbers of positive men always exceeded those of women, their numbers equalized or even reversed within the two peaks. The results may also reflect trends in social change in the country after 1989. The analysis showed that the regional prevalence of syphilis in eastern Bohemia still remains low compared to some other regions of the Czech Republic. PMID- 25025672 TI - [Diagnosis of Clostridium difficile infections: comparative study of two immuno enzyme assays with confirmation by PCR and culture followed by PCR ribotyping]. AB - STUDY OBJECTIVE: Comparison of two commercially avail-able tests for the detection of Clostridium difficile Glutamate Dehydrogenase (GDH) and toxins A and B for their sensitivity and specificity. MATERIAL AND METHODS: Eighty-six stool samples from patients hospitalised in the Motol University Hospital were analysed. GDH and toxins A and B were assayed in parallel by two tests: C. difficile Quik Chek Complete(r) (Techlab, USA) and Liaison(r) C. difficile GDH and Toxins AalphaB (DiaSorin, USA). From the stool samples, nucleic acids were also isolated using the UltraClean(r) Fecal DNA kit (MoBio Laboratories, USA). The commercially available C. difficile Elite MGB(r) kit (Nanogen, Italy) was used for the polymerase chain reaction (PCR). Anaerobic culture on C. difficile selective medium (Oxoid) was performed for all positive samples at least in one test. Pure isolates were characterized by PCR ribotyping. RESULTS: Thirty-six (42%) samples were GDH negative and toxin A/B negative by both tests. Twenty (23%) samples were GDH positive and toxin A/B positive by both tests. Nine (10%) samples were GDH positive and toxin negative by both tests, but were positive by PCR. Eleven (13%) samples that were GDH positive and toxin negative by both tests remained negative by PCR. Six (7%) samples only were GDH positive and toxin positive by the Liaison(r) test alone. Four (5%) samples were GDH-positive by theLiaison(r) test alone. Culture failure was observed in 11 (13%) samples, of which seven were positive by PCR. PCR was inhibited in five (6%) samples. The following toxigenic ribotypes: AI-3, 001, 002, 012,014, 017, 020, 049, 054, 078, 176, 203, and 413 and non-toxigenic ribotypes: AI-34, AI-61, 010, 485, 495, and 596 were identified. CONCLUSION: The Liaison(r) test had seven percent higher sensitivity for the detection of toxins A/B. The two-step protocol of the tests is also cost-saving. The savings can be used e.g. for incorporating the PCR techniques into the diagnostic algorithm of the laboratory. PMID- 25025673 TI - Predicted strain coverage of a new protein-based meningococcal vaccine in the Czech Republic. AB - BACKGROUND: Recent data indicate that Neisseria meningitidis B strains cause about 70% of invasive meningococcal disease (IMD) cases in Europe and the availability of a vaccine effective against N. meningitidis B is desirable. A new protein-based MenB vaccine was licensed for use in Europe in January 2013. Meningococcal antigen typing system (MATS) was developed to predict strain coverage of this vaccine. Reports have recently been published for a European consortium, including aggregated data for the Czech Republic. The aim of this paper is to provide a detailed breakdown of MATS results for the Czech N. meningitidis B isolates. MATERIALS AND METHODS: One hundred and eight N. meningitidis B isolates from IMD collected in the Czech Republic during 2007-2010 were selected. MATS analysis was done according to the method previously published. RESULTS: Based on MATS analysis, the overall estimate of strain coverage of the new MenB vaccine for a panel of 108 Czech N. meningitidis B strains is 74% (95% CI: 59-87%). Thirty-nine strains (36%) are predicted to be covered by a single antigen and 41 strains (38%) by more than one antigen. For 28 strains (26%), no antigen coverage was found. CONCLUSIONS: MATS analysis showed that the new protein-based MenB vaccine could protect against a substantial proportion of IMD caused by N. meningitidis B in the Czech Republic. Continued detailed surveillance of IMD will be essential if the MenB vaccine is introduced to the country. PMID- 25025674 TI - [A point prevalence survey of healthcare-associated infections in the Slovak Republic - a part of the EU project]. AB - AIM: The aim of this survey was to estimate the prevalence of healthcare associated infections (HAI) in the Slovak Republic (SR), distribution of causative pathogens, and risk factors. METHODS: The point prevalence survey (PPS) of HAI in the SR was carried out in 40 acute care hospitals, according to a standardized methodology developed by the European Centre for Disease Prevention and Control (ECDC). Data were collected according to the standard protocol at the country, hospital, and patient levels. RESULTS: Of 8 397 patients included in the survey in the SR, 298 (3.5%) had HAI. The highest prevalence of HAI (12.4%) was found in the intensive care units (ICU) and Anaesthesiology and Intensive Care Medicine Units (AICMU). Nevertheless, intensive care medicine patients only represented 6.5% of all patients. The following six most common types of HAI accounted for 87.3% of all HAI: urinary tract infection (26.2%), pneumonia and other lower respiratory tract infections (22.0%), surgical site infection (15.7%), bloodstream infection (9.9%), infection of the eye, ear, and upper respiratory tract (8.3%), and skin and soft tissue infection (5.2%). The most often isolated pathogens were Escherichia coli (15.0%), Klebsiella spp. (12.5%), and Pseudomonas aeruginosa (10.8%). Of 8 397 surveyed patients, 60.5% had a medical device inserted: central vascular catheter (CVC)(3.4%), peripheral vascular catheter (PVC)(40.8%), urinary catheter (14.1%), or endotracheal tube (2.1%). The prevalence of HAI was higher in patients with than without a medical device inserted. CONCLUSION: By participating in the PPS, the SR has collected the most recent data on HAI and antimicrobial use in acute care hospitals. The adherence to the standard methods, standard definitions of HAI, and PPS protocol allows to repeat the survey, to analyse the HAI prevalence trend, and to take effective interventions. PMID- 25025675 TI - [Nosocomial transmission of listeriosis]. AB - Listeriosis is a severe and possibly fatal disease. Its incidence in the Czech Republic is low, with the most common vehicles of transmission being cheese, pastes, meat products, and salads. Nosocomial transmission is rare in the Czech Republic. Phylogenetic analysis and genotyping of isolated Listeria strains are very helpful in identifying the source of infection. A careful adherence to the preventive anti-epidemic measures in the health care institutions is still critically important. PMID- 25025676 TI - [Diversity of human Salmonella isolates in the South Moravian Region in 2009 2012]. AB - STUDY OBJECTIVE: To characterize the diversity of human Salmonella isolates from one of the administrative regions of the Czech Republic in a time horizon of four years using different typing methods. MATERIAL AND METHODS: The following phenotyping methods were used: serotyping, phage typing, and the disk diffusion method for antimicrobial susceptibility testing. Genotyping was performed using DNA macrorestriction analysis resolved by pulsed-field gel electrophoresis (PFGE). RESULTS: The most common serotypes involved in human cases of salmonellosis in the South Moravian Region were Salmonella Enteritidis, Salmonella Typhimurium, and monophasic Salmonella 4,[5],12:i:-. Phage typing revealed the predominance of phage type 8 in S. Enteritidis and changes in phage types of S. Typhimurium over years. The resistance levels in S. Typhimurium, monophasic Salmonella, and some other serotypes give increasing cause for concern about multidrug resistant strains as human pathogens. The study isolates were assigned to the complexes implicated in both local and international outbreaks. Isolates of serotype 9,12:l,v:- were identified for the first time in the Czech Republic. CONCLUSIONS: The diversity of the study isolates from 2009-2012 collected in the South Moravian Region suggests a high heterogeneity of the sources of human salmonellosis. However, the detection of several cases likely to be epidemiologically linked points out the need for careful typing of human isolates and their comparison with the strains of non-human origin. Higher resistance levels in some serotypes is behind the need for the surveillance of multidrug resistant strains. PMID- 25025677 TI - Post-mortem analysis of Candida albicans breakthrough infection during echinocandin treatment in haematopoietic stem cell transplant recipient. AB - We present case of a girl deceased due to Candida albicans breakthrough invasive infection during the echinocandin treatment after undergoing allogeneic haematopoietic stem cell transplant for relaps of acute myeloid leukaemia. Candida albicans generally susceptible to all antifungal drugs wasn't considered for potential resistance and conventional blood culture positivity was too late to reveal the resistance to echinocandins. Due to severe organ toxicities (liver, kidneys) she received echinocandin as an antifungal prophylaxis, no change was made for the treatment of Candida albicans infection. Later, the molecular analysis proved the mutation S645P known as being responsible for the echinocandin resistance. The post mortem analysis of fungal burden in autopsy samples showed very high levels of Candida DNA in gut, liver, spleen and kidneys. PMID- 25025678 TI - [Candida dubliniensis in clinical specimens and possibilities for identification]. AB - STUDY OBJECTIVE: The species Candida dubliniensis shares a wide range of phenotypic characteristics with Candida albicans, the most common yeast species isolated from clinical specimens. This is a considerable complication for the detection and identification of Candida dubliniensis from clinical specimens. The lack of data on the incidence of C. dubliniensis in the Czech Republic was the motivation behind the efforts to detect this pathogen in specimens analyzed at the Institute for Microbiology, Faculty of Medicine Masaryk University and St. Anne's Faculty Hospital in Brno. Another aim was to test the reliability of the culture methods used. MATERIAL AND METHODS: Altogether 2260 yeast isolates initially identified as C. albicans were analysed. To differentiate C. dubliniensis from C. albicans, four phenotypic methods were used: colour-based differentiation on CHROMagar Candida medium, culture on medium with 6.5% of NaCl, growth at 42 degrees C, and colony characteristics on Staib agar. To verify the results, the Bichro-Dubli Fumouze latex agglutination test and species-specific polymerase chain reactions (PCR) were used. RESULTS: Using phenotypic methods, latex agglutination, and PCR, 50 (2.2%) strains from the study set were assigned to C. dubliniensis. Most (31) C. dubliniensis isolates were recovered from the respiratory tract and the remaining others were three urine isolates, four stool isolates, one central venous catheter isolate, and one blood isolate. With the exception of colour-based differentiation on CHROMagar Candida medium showing a specificity of 85.5%, all the culture methods used have a high sensitivity and a high specificity. CONCLUSION: Identification of C. dubliniensis as C. albicans was confirmed in various clinical specimens, most often from the upper respiratory tract. The colour-based differentiation of C. dubliniensis from C. albicans on chromogenic CHROMagar Candida medium can only be recommended as a screening test for the differentiation of C. dubliniensis from other species of the genus Candida. The remaining three methods are highly reliable. The final identification should be based on a combination of these methods, with the species-specific PCR or latex agglutination test used for verification. PMID- 25025679 TI - [Natural antibodies against alpha(1,3) galactosyl epitope in the serum of cancer patients]. AB - BACKGROUND: Natural antibodies against saccharide antigens are found in the human serum; most of them are directed against alpha-galactosyl epitope (Galalpha1 3Galbeta1-4GlcNAc-R). Experimental and initial clinical studies show the potential for use of anti-galactosyl antibodies in the immunotherapy of cancer patients with glycolipids containing the alpha-galactosyl epitope. This therapeutic approach is based on the presence of these antibodies in the serum of cancer patients. Only scarce literature data is available on the incidence of these antibodies in cancer patients. Data is lacking on their amounts and isotype characteristics in different types of cancer. MATERIAL AND METHODS: An ELISA test with a polyacrylamide-conjugated synthetic disaccharide, Galalpha1-3Galbeta, has been designed for quantitative detection of anti-galactosyl IgM, IgG, and IgA antibody isotypes. This test was used to screen the sera from 57 patients with breast, colorectal, or panceatic cancer or malignant melanoma and from 145 healthy controls. RESULTS: The serum concentration of anti-galactosyl antibodies (anti-Gal) is gender dependent: anti-Gal IgM antibodies are present in higher titres in healthy women than in healthy men (p < 0.01). Patients with breast, colorectal, or pancreatic cancer or malignant melanoma had comparable serum levels of anti-Gal IgM, IgG, and IgA antibody isotypes to healthy controls. Male patients with colorectal cancer had higher anti-Gal IgA antibodies than healthy men (p< 0.01). CONCLUSION: Comparable concentrations and isotypes of anti galactosyl antibodies are found in the serum of cancer patients and healthy controls. PMID- 25025680 TI - [Cytolethal distending toxins]. AB - Cytolethal distending toxins (CDT) are intracellularly acting proteins which interfere with the eukaryotic cell cycle. They are produced by Gram-negative bacteria with affinity to mucocutaneous surfaces and could play a role in the pathogenesis of various mammalian diseases. The functional toxin is composed of three proteins: CdtB entering the nucleus and by its nuclease activity inducing nuclear fragmentation and chromatin disintegration, CdtA, and CdtC, the two latter being responsible for toxin attachment to the surface of the target cell. Cytotoxic effect of CDT leads to the cell cycle arrest before the cell enters mitosis and to further changes (cell distension and death, apoptosis) depending on the cell type. Thus, CDT may function as a virulence factor in pathogenic bacteria that produce it and thus may contribute to the initiation of certain diseases. Most important are inflammatory bowel diseases caused by intestinal bacteria, periodontitis with Aggregatibacter actinomycetemcomitans as the aetiologic agent and ulcus molle where Haemophilus ducreyi is the causative agent. PMID- 25025681 TI - [Evaluation of the importance of a ready-made, gentamicin-impregnated spacer in relation to bacteriological findings in patients with periprosthetic joint infections]. AB - BACKGROUND: Periprosthetic infection is a serious complication in total hip and knee arthroplasty. The complex therapeutic approach within two-stage reimplantation includes the use of antibiotic-impregnated spacers (temporary joint replacements). The aim of this paper was to evaluate bacteriological findings in selected patients with periprosthetic infection in whom a ready-made gentamicin-impregnated spacer was used to treat the infection. MATERIALS AND METHODS: Between 2008 and 2012, a ready-made, gentamicin-impregnated cement spacer was used in 24 patients to treat periprosthetic hip or knee infection within two-stage reimplantation. All components of the prosthesis and periprosthetic tissue samples were sent for microbiological examination at the first revision surgery, while at the second revision surgery, the spacer and surrounding tissue samples were sent in. In six patients with an inserted knee spacer, the level of gentamicin in the joint fluid was measured. Subsequently, the patients were regularly monitored. RESULTS: Twenty-two (92%) of 24 patients were bacteriologically positive by culture. The most commonly detected causative agents were coagulase-negative staphylococci. Other isolates were Staphylococcus aureus, Corynebacterium, anaerobic bacteria, and Salmonella serotype Enteritidis. Nineteen (76%) of 25 primary pathogens were gentamicin sensitive. Spacers from two patients were culture positive for coagulase-negative staphylococci that tested resistant to gentamicin. During the follow-up of at least two years, none of the patients developed another periprosthetic infection. CONCLUSION: The success rate of two-stage-reimplantation total hip and knee arthroplasty using ready-made, gentamicin-impregnated spacers was 100 % in our cohort of patients; no other periprosthetic infection was reported during the follow-up of at least two years. From the bacteriological results, it appears that the ready-made, gentamicin-impregnated spacer only covers 76 % of the range of the causative agents. The solution would be to use a spacer impregnated with a combination of vancomycin and gentamicin that would be effective against all cultured species. PMID- 25025682 TI - [Q fever - an occupational disease leading to disability - case report]. AB - Q fever is a zoonosis caused by the bacterium Coxiella burnetii. The infection results from inhalation of infected droplets or aerosols. The most frequent sources in the Czech Republic are sheep, horses, cattles, goats, and pigs. Frequently, the disease is deemed occupational, with male sex being a risk factor for its symptomatic form. Presented is a case of a 27-year-old male diagnosed with a chronic form of Q fever after six months of worsening symptoms. Even years later, his condition is manifested as osteoarthritis, granulomatous hepatitis, and microcytic hypochromic anemia. The source of infection was probably animal food stored in a facility where the patient was employed. He was recognized as having an occupational disease and being disabled, especially due to his severely impaired mobility. PMID- 25025683 TI - [Measles re-emerging in the Usti Region]. AB - A report is given of a measles outbreak in healthcare workers and the general population that occurred in February to March in Usti nad Labem. The source of infection was a man with a history of travel to India. The outbreak was primarily observed in the patients contacts and then spread widely to healthcare workers of the Masaryk Hospital in Usti nad Labem. The outbreak further reached the general population including family contacts of the patients. By the end of March 2014, 171 measles cases were reported, 68 (39.8%) of which in healthcare workers. Cases we confirmed by laboratory analysis of IgM antibodies and IgG antibody dynamics and, possibly, by R-PCR. In addition to standard preventive anti-epidemic measures, the healthcare workers of the Masaryk Hospital were vaccinated with an extra dose of the Priorix vaccine. Measles cases were most often reported in the population born in 1970-1980. This age group was the target population for an extra dose of the Priorix vaccine. General recommendations have been formulated based on the experience from the outbreak. PMID- 25025684 TI - The tumor-suppressive microRNA-135b targets c-myc in osteoscarcoma. AB - Osteosarcoma is the most common primary tumor of the bone. It leads to many deaths because of its rapid proliferation and metastasis. Recent studies have shown that microRNAs are important gene regulators that are involved in various cancer-related processes. In this study, we found that miR-135b was down regulated in both osteoscarcoma patient tumor tissues and osteoscarcoma cell lines in comparison to paired adjacent non-tumor bone tissue. We observed that a lower level of miR-135b was associated with metastasis. The ectopic expression of miR-135b markedly suppressed osteoscarcoma cell proliferation, migration, and invasion. Conversely, the inhibition of miR-135b expression dramatically accelerated cell proliferation, migration, and invasion. The forced expression of miR-135b in osteosarcoma cells resulted in a significant reduction in the protein level of c-Myc and repressed the activity of a luciferase reporter that contained the 3'-untranslated region of the c-Myc mRNA. These effects were abolished by the mutation of the predicted miR-135b-binding site, which indicates that c-Myc may be a miR-135b target gene. Moreover, the ectopic expression of c-Myc partially reversed the inhibition of cell proliferation and invasion that was caused by miR 135b. These data therefore suggest that miR-135b may function as a tumor suppressor to regulate osteosarcoma cell proliferation and invasion through a mechanism that targets the c-Myc oncogene. These findings indicate that miR-135b may play a role in the pathogenesis of osteosarcoma. PMID- 25025685 TI - The impact of an exercise therapy on psychosocial health of children with benign epilepsy: a pilot study. AB - OBJECTIVES: The purposes of the current study were to test the feasibility of exercise therapy for children with benign epilepsy with centrotemporal spikes (BECTS) and to collect pilot data about the impact of exercise therapy on neurocognitive, emotional, and behavioral outcomes. METHODS: Ten children with BECTS (9.7+/-1.42 years) participated in a therapeutic exercise program consisting of ten supervised exercise sessions and home-based exercises for five weeks. Electroencephalography (EEG), seizure frequency, and neurocognitive and psychological factors, including attention, executive function, depression, anxiety, behavioral problems, and quality of life, were assessed before and after the exercise program. RESULTS: No clinical symptoms were observed to worsen during the study, demonstrating that the exercise therapy was safe and also feasible. After five weeks of exercise therapy, significant improvements in neurocognitive domains such as simple visual and auditory attention, sustained attention, divided attention, psychomotor speed, and inhibition-disinhibition were observed. Furthermore, parent ratings of internalizing behavioral problems and social problems and mood-related well-being from quality of life improved after exercise therapy. Although not statistically significant, trends were noted toward improvement in children's self-reports of negative mood/somatization, parent reports of somatic complaints, and general health on a quality-of-life measure. CONCLUSIONS: A five-week structured exercise program was successfully implemented, with preliminary data suggesting beneficial impact on neurocognitive and psychobehavioral function. Exercise therapy should be further evaluated as a part of a comprehensive treatment program for children with benign epilepsy. PMID- 25025686 TI - Single-stranded DNA catalyzes hybridization of PCR-products to microarray capture probes. AB - Since its development, microarray technology has evolved to a standard method in the biotechnological and medical field with a broad range of applications. Nevertheless, the underlying mechanism of the hybridization process of PCR products to microarray capture probes is still not completely understood, and several observed phenomena cannot be explained with current models. We investigated the influence of several parameters on the hybridization reaction and identified ssDNA to play a major role in the process. An increase of the ssDNA content in a hybridization reaction strongly enhanced resulting signal intensities. A strong influence could also be observed when unlabeled ssDNA was added to the hybridization reaction. A reduction of the ssDNA content resulted in a massive decrease of the hybridization efficiency. According to these data, we developed a novel model for the hybridization mechanism. This model is based on the assumption that single stranded DNA is necessary as catalyst to induce the hybridization of dsDNA. The developed hybridization model is capable of giving explanations for several yet unresolved questions regarding the functionality of microarrays. Our findings not only deepen the understanding of the hybridization process, but also have immediate practical use in data interpretation and the development of new microarrays. PMID- 25025688 TI - Double emulsions from a capillary array injection microfluidic device. AB - A facile microfluidic device was developed by inserting an annular capillary array into a collection channel for single-step emulsification of double emulsions. By inserting multiple inner-phase solutions into the capillary array, multicomponent double emulsions or microcapsules with inner droplets of different content could also be obtained from the device. PMID- 25025687 TI - Keratinocyte antiviral response to Poly(dA:dT) stimulation and papillomavirus infection in a canine model of X-linked severe combined immunodeficiency. AB - X-linked severe combined immunodeficiency (XSCID) is caused by a genetic mutation within the common gamma chain (gammac), an essential component of the cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XSCID patients are most commonly treated with bone marrow transplants (BMT) to restore systemic immune function. However, BMT-XSCID humans and dogs remain at an increased risk for development of cutaneous papillomavirus (PV) infections and their associated neoplasms, most typically cutaneous papillomas. Since basal keratinocytes are the target cell for the initial PV infection, we wanted to determine if canine XSCID keratinocytes have a diminished antiviral cytokine response to poly(dA:dT) and canine papillomavirus-2 (CPV-2) upon initial infection. We performed quantitative RT-PCR for antiviral cytokines and downstream interferon stimulated genes (ISG) on poly(dA:dT) stimulated and CPV-2 infected monolayer keratinocyte cultures derived from XSCID and normal control dogs. We found that XSCID keratinocytes responded similarly to poly(dA:dT) as normal keratinocytes by upregulating antiviral cytokines and ISGs. CPV-2 infection of both XSCID and normal keratinocytes did not result in upregulation of antiviral cytokines or ISGs at 2, 4, or 6 days post infection. These data suggest that the antiviral response to initial PV infection of basal keratinocytes is similar between XSCID and normal patients, and is not the likely source for the remaining immunodeficiency in XSCID patients. PMID- 25025689 TI - The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex. AB - Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Abeta peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Abeta expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Abeta peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD. PMID- 25025690 TI - Sexual orientation and health among U.S. adults: national health interview survey, 2013. AB - OBJECTIVE: To provide national estimates for indicators of health-related behaviors, health status, health care service utilization, and health care access by sexual orientation using data from the 2013 National Health Interview Survey (NHIS). METHODS: NHIS is an annual multipurpose health survey conducted continuously throughout the year. Analyses were based on data collected in 2013 from 34,557 adults aged 18 and over. Sampling weights were used to produce national estimates that are representative of the civilian noninstitutionalized U.S. adult population. Differences in health-related behaviors, health status, health care service utilization, and health care access by sexual orientation were examined for adults aged 18-64, and separately for men and women. RESULTS: Based on the 2013 NHIS data, 96.6% of adults identified as straight, 1.6% identified as gay or lesbian, and 0.7% identified as bisexual. The remaining 1.1% of adults identified as ''something else,'' stated ''I don't know the answer,'' or refused to provide an answer. Significant differences were found in health related behaviors, health status, health care service utilization, and health care access among U.S. adults aged 18-64 who identified as straight, gay or lesbian, or bisexual. CONCLUSION: NHIS sexual orientation data can be used to track progress toward meeting the Healthy People 2020 goals and objectives related to the health of lesbian, gay, and bisexual persons. In addition, the data can be used to examine a wide range of health disparities among adults identifying as straight, gay or lesbian, or bisexual. PMID- 25025691 TI - Zyxin modulates the transmigration of Haemophilus influenzae to the central nervous system. AB - The mechanism by which Haemophilus influenzae causes meningitis is unclear. Previously, we established murine meningitis by intranasal instillation of H. influenzae as a cell-bound organism (CBO). In this study, we aimed to identify the molecules associated with inhibiting the transmigration of cells across the blood-brain barrier (BBB). Two-dimensional difference gel electrophoresis and protein identification by mass spectrometry were used for proteomic analysis. Analysis of the membranous extract from a tumor necrosis factor (TNF)-alpha treated human brain microvascular endothelial cell (HBMEC) monolayer revealed 41 differentially expressed proteins. Zyxin, which is thought to be essential for tight cell-to-cell junctions, decreased 1.8-fold in TNF-alpha-treated HBMECs. In addition, zyxin transcript levels decreased 1.5-fold in cells derived from TNF alpha-treated HBMECs. Intranasal instillation of CBOs in zyxin-deficient mice resulted in a significant higher mortality rate than in wild-type mice. Transmigration of CBOs across a HBMEC monolayer pretreated with TNF-alpha (1 ng/mL), interleukin (IL)-1beta (10 ng/mL), or lipopolysaccharide (LPS; 10 ng/mL) was assayed by counting CBOs that migrated from an upper chamber into a lower chamber. HBMEC pretreated with TNF-alpha exhibited significantly greater migration (P<0.01) than did control cells or cells treated with IL-1beta or LPS. Our findings highlight that zyxin is an important protein protecting the tight junction of the BBB against cell transmigration across the BBB. Finally, TNF alpha produced in respiratory infection when the primary infection reached the BBB caused decreased zyxin levels in BBB cell membranes. Furthermore, H. influenzae reaching the BBB as CBOs could transmigrate into cerebrospinal fluid across the zyxin-decreased BBB. PMID- 25025692 TI - Proteomic analysis reveals differences in tolerance to acid rain in two broad leaf tree species, Liquidambar formosana and Schima superba. AB - Acid rain (AR) is a serious environmental issue inducing harmful impacts on plant growth and development. It has been reported that Liquidambar formosana, considered as an AR-sensitive tree species, was largely injured by AR, compared with Schima superba, an AR-tolerant tree species. To clarify the different responses of these two species to AR, a comparative proteomic analysis was conducted in this study. More than 1000 protein spots were reproducibly detected on two-dimensional electrophoresis gels. Among them, 74 protein spots from L. formosana gels and 34 protein spots from S. superba gels showed significant changes in their abundances under AR stress. In both L. formosana and S. superba, the majority proteins with more than 2 fold changes were involved in photosynthesis and energy production, followed by material metabolism, stress and defense, transcription, post-translational and modification, and signal transduction. In contrast with L. formosana, no hormone response-related protein was found in S. superba. Moreover, the changes of proteins involved in photosynthesis, starch synthesis, and translation were distinctly different between L. formosana and S. superba. Protein expression analysis of three proteins (ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit, ascorbate peroxidase and glutathione-S-transferase) by Western blot was well correlated with the results of proteomics. In conclusion, our study provides new insights into AR stress responses in woody plants and clarifies the differences in strategies to cope with AR between L. formosana and S. superba. PMID- 25025693 TI - Variants in genes encoding pyrophosphate metabolizing enzymes are associated with Pseudoxanthoma elasticum. AB - OBJECTIVES: Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder characterized by progressive calcification and fragmentation of elastic fibers. Because of the great clinical variability between PXE patients the involvement of modifier genes was recently suggested. Therefore, we investigated the association of single nucleotide variants (SNVs) in selected candidate genes known to regulate cellular pyrophosphate metabolism. DESIGN AND METHODS: We used RLFP analyses to evaluate the distribution of SNVs in alkaline phosphatase (ALP), ectonucleotide pyrophosphatase 1 (ENPP1) and ankylosis (ANKH) in DNA samples from 190 German PXE patients and 190 age- and sex-matched healthy controls. Statistical analyses were performed using Fisher exact test and Bonferroni correction. RESULTS: The screening revealed three different SNVs in three genes, which were associated with PXE. The SNV c.1190-65C>A (rs1780329, minor allele frequency (MAF) patients: 0.17; controls: 0.11; P=0.04) in the ALP gene was significantly more frequent in PXE patients. Furthermore, PXE was highly associated with ANKH p.A98A genotype TT (P=0.0012), although the MAF was not different between patients and controls. After correction for multiple testing according to the Bonferroni method, one SNV in the ENPP1 gene (c.313+9G>T, rs7773477) remained significantly associated with PXE with significantly higher MAF values in the patient cohort (MAF: 0.04 vs. 0.00; P=0.0024) and a high association with PXE susceptibility (OR 27.96). CONCLUSION: Polymorphisms in ALP, ENPP1 and ANKH are important genetic risk factors contributing to PXE. PMID- 25025694 TI - Association between platelet reactivity and circulating platelet-derived microvesicles in patients with acute coronary syndrome. AB - High on-treatment platelet reactivity (HPR) to clopidogrel has been shown to increase the risk of cardiovascular events. Platelet-derived microvesicles (PMVs) may be prothrombotic and contribute to the risk of recurrent events observed in patients with HPR. However, PMVs may also serve as biomarkers and be used to assess platelet function. We investigated the association between platelet responses to clopidogrel (measured by whole blood impedance aggregometry) and circulating PMVs in patients with acute coronary syndrome (ACS). Blood samples were obtained at discharge from 200 patients with ACS who had undergone percutaneous coronary intervention (PCI). All patients were loaded with aspirin and clopidogrel before PCI. ADP-induced whole blood impedance aggregometry and measurement of PMVs were performed. Cut-off values for HPR and other reactivity (i.e. normal on-treatment reactivity, NPR and low on-treatment reactivity, LPR) to clopidogrel were set according to data from large prospective studies. We measured PMVs as phosphatidylserine and CD42a positive vesicles, together with CD62P or CD40L, using flow cytometry. ADP-induced platelet aggregation revealed that approximately 20% of patients had HPR. Levels of PMVs were almost two-fold higher in the HPR group compared with patients without HPR (for both CD42a- and CD62P-positive PMVs, p < 0.01). Furthermore, patients with LPR to clopidogrel had significantly fewer PMVs exposing CD62P than patients with HPR or those with NPR to clopidogrel. Patients with HPR during clopidogrel treatment have elevated levels of circulating PMVs, indicating ongoing platelet activation despite clopidogrel treatment. Moreover, in patients with LPR to clopidogrel, circulating PMV numbers are decreased. Taken together, our data suggest that PMVs are potential biomarkers of antiplatelet responses to clopidogrel. If PMVs also have prognostic value after, ACS should be tested in future studies. PMID- 25025696 TI - Rh(III)-catalyzed synthesis of sultones through C-H activation directed by a sulfonic acid group. AB - A new rhodium-catalyzed synthesis of sultones via the oxidative coupling of sulfonic acids with internal alkynes is described. The reaction proceeds via aryl C-H activation assisted by a sulfonic acid group. PMID- 25025695 TI - Directed evolution of an LBP/CD14 inhibitory peptide and its anti-endotoxin activity. AB - BACKGROUND: LPS-binding protein (LBP) and its ligand CD14 are located upstream of the signaling pathway for LPS-induced inflammation. Blocking LBP and CD14 binding might prevent LPS-induced inflammation. In previous studies, we obtained a peptide analog (MP12) for the LBP/CD14 binding site and showed that this peptide analog had anti-endotoxin activity. In this study, we used in vitro directed evolution for this peptide analog to improve its in vivo and in vitro anti endotoxin activity. METHODS: We used error-prone PCR (ep-PCR) and induced mutations in the C-terminus of LBP and attached the PCR products to T7 phages to establish a mutant phage display library. The positive clones that competed with LBP for CD14 binding was obtained by screening. We used both in vivo and in vitro experiments to compare the anti-endotoxin activities of a polypeptide designated P1 contained in a positive clone and MP12. RESULTS: 11 positive clones were obtained from among target phages. Sequencing showed that 9 positive clones had a threonine (T) to methionine (M) mutation in amino acid 287 of LBP. Compared to polypeptide MP12, polypeptide P1 significantly inhibited LPS-induced TNF-alpha expression and NF-kappaB activity in U937 cells (P<0.05). Compared to MP12, P1 significantly improved arterial oxygen pressure, an oxygenation index, and lung pathology scores in LPS-induced ARDS rats (P<0.05). CONCLUSION: By in vitro directed evolution of peptide analogs for the LBP/CD14 binding site, we established a new polypeptide (P1) with a threonine (T)-to-methionine (M) mutation in amino acid 287 of LBP. This polypeptide had high anti-endotoxin activity in vitro and in vivo, which suggested that amino acid 287 in the C terminus of LBP may play an important role in LBP binding with CD14. PMID- 25025697 TI - Regional anesthesia, time to hospital discharge, and in-hospital mortality: a propensity score matched analysis. AB - BACKGROUND AND OBJECTIVES: The anesthetic technique used during surgery can affect postoperative length of stay and outcomes, even after controlling for other clinically important factors. This study evaluated the impact of regional anesthesia (RA) compared with general anesthesia (GA) on the amount of time between leaving the operating room and hospital discharge and the odds of in hospital mortality. METHODS: Surgical patients admitted after surgery, who received RA, were matched to patients who received GA by propensity score in a 1:4 ratio. We measured the association between anesthetic technique and time to hospital discharge using Kaplan-Meier methods. In-hospital mortality was analyzed using a generalized estimating equation logistic regression model. RESULTS: A total of 5870 inpatient surgical cases were analyzed; 1174 cases received RA and 4696 cases received GA. The median time to hospital discharge among patients who received RA was 67.6 hours compared with 71.9 hours among patients who received GA (P < 0.0001). A total of 86 cases died in the hospital after surgery; 7 were in the RA cohort and 79 were in the GA cohort. Receiving RA during surgery was associated with 64% lesser odds of dying in the hospital (odds ratio, 0.36; 95% confidence interval, 0.16-0.75), when adjusting for the number of postoperative days spent in the hospital. CONCLUSIONS: The study data provide evidence that median time to discharge is shorter when RA is used instead of GA, controlling for other clinically important factors. Additionally, RA use during surgery was associated with a decrease in in-hospital mortality. When an appropriate option, RA may facilitate faster hospital discharge and improve patient outcomes. PMID- 25025698 TI - Synthesis and photophysical studies of a series of quinazoline chromophores. AB - The synthesis of a series of push-pull arylvinyl (styryl), aryl, and arylethynyl quinazoline derivatives by means of different straightforward protocols is reported. The photophysical properties of the compounds are described. The preparation of arylvinylquinazolines was performed by aldol condensation of the appropriate methylquinazoline and functionalized benzaldehyde. Suzuki and Sonogashira cross-coupling reactions were used to prepare the aryl and arylethynyl compounds, respectively, starting from chloroquinazolines. Optical studies revealed that all of the compounds reported here behave in a way similar to that of their pyrimidine counterparts, with absorption bands in the UV or visible region and the emission of green light upon irradiation. Large red shifts were observed in the fluorescence emission maxima upon increasing the solvent polarity. This strong emission solvatochromism suggests the formation of an intramolecular charge-separated emitting state. The materials can be easily and reversibly protonated at the nitrogen atoms of the heterocyclic ring, and this causes dramatic color changes. This phenomenon opens up the possibility of developing colorimetric pH sensors that can be efficiently modified a posteriori for specific applications. PMID- 25025699 TI - Effect of surfactants, gastric emptying, and dosage form on supersaturation of dipyridamole in an in vitro model simulating the stomach and duodenum. AB - The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different surfactants and comparison of dosage form (solution versus suspension) on the precipitation of dipyridamole revealed that crystal growth, rather than nucleation, is the rate-limiting step for the precipitation of dipyridamole. A linear dose-response relationship was found for the mean in vitro duodenal area under concentration-time curves (AUCinfinity) in the dose range of 25 mg to 100 mg (R(2) = 0.886). This is in agreement with the pharmacokinetic data of dipyridamole reported in the literature. The simulated stomach duodenum model can provide a reliable and discriminative screening tool for exploring the effect of different physiological variables or formulations on the supersaturation/precipitation kinetics of weakly basic drugs with solubility limited absorption. The amount of drug in solution in the duodenal compartment of the SSD correlates to bioavailability for the weakly basic drug, dipyridamole, which has solubility limited absorption and undergoes supersaturation/precipitation. PMID- 25025700 TI - Synthesis and characterization of dendritic star-shaped zwitterionic polymers as novel anticancer drug delivery carriers. AB - In this work, a novel dendritic star-shaped zwitterionic polymer, polyamidoamine graft-poly[3-dimethyl (methacryloyloxyethyl) ammonium propanesulfonate] (PAMAM-g PDMAPS), was synthesized. PAMAM dendrimers (generation 2, G2) were firstly prepared and then converted into the PAMAM-Br macroinitiator with 2 bromoisobutyryl bromide for ATRP. Finally, ATRP of zwitterionic DMAPS was carried out to obtain the dendritic star-shaped polymers PAMAM-g-PDMAPS with different PDMAPS chain lengths. Fourier transform-infrared spectroscopy, (1)H NMR, dynamic laser light scattering (DLS), and TEM were used to characterize the polymers. Encapsulation of adriamycin (ADR) by PAMAM-g-PDMAPS nanoparticles and ADR release behavior from ADR-loaded PAMAM-g-PDMAPS nanoparticles were investigated in detail. PAMAM-g-PDMAPS polymers, even starting from low-generation PAMAM core (G2), were found to show high loading efficiency for ADR because ADR existed not only within G2 PAMAM cores but also in PDMAPS layers. The release profile of ADR from ADR-loaded PAMAM-g-PDMAPS nanoparticles was pH-sensitive and could be controlled by the length of PDMAPS chains. Cell viability studies indicated that ADR-loaded PAMAM-g-PDMAPS could effectively restrain the growth of HepG2 cells and even kill them, whereas PAMAM-g-PDMAPS exhibited nontoxicity. All these results demonstrated that dendritic star-shaped zwitterionic polymers PAMAM-g PDMAPS are attractive candidates as anticancer drug delivery carriers. PMID- 25025701 TI - Sex differences in the chronic mild stress model of depression. AB - A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with 'chronic mild stress', 'chronic unpredictable stress' and 'chronic variable stress' as base terms and 'sex', 'gender', 'females' and 'depression' as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a 'silver bullet' in assessing the role of sex in the neurobiology of major depression. PMID- 25025702 TI - Neurological assessment of the preterm infant in the special care nursery and the diagnostic significance of the asymmetrical tonic neck reflex. AB - Neurological assessment at preterm age of 105 infants born at < 34 weeks gestation is discussed. The development of the asymmetrical tonic neck reflex (ATNR) was studied. There was no consistent post-menstrual age at which the 7 allocated grades occurred. The diagnostic significance of the preterm ATNR response for motor development (until 2 years) was considered. The incidence of an imposable reflex dominating spontaneous movement was significantly different (p<0.001) in the normal (n = 89) versus the abnormal development group (n = 16;13 having spastic cerebral palsy). The inclusion of observation of the quality of movement for this reflex could provide useful information in neurological assessment of preterm infants. PMID- 25025703 TI - A review of the histories of children with minimal cerebral dysfunction. AB - Although many factors have been thought to contribute to the development of minimal cerebral dysfunction (MCD), the aetiology of the condition has not been clearly specified. The existence of MCD can be associated with behavioural, emotional or educational problems, so that control of contributing factors can have important implications for the child. As part of a broad study of MCD carried out in the Department of Physiotherapy, University of Queensland, historical data were collected for 1,020 children who attended the MCD clinic. A comparison of the incidence of each of these factors with that in the normal population, highlighted a number of features which could bear further study. PMID- 25025704 TI - On the safe use of microwave and shortwave diathermy units. AB - Diathermy is a common treatment modality used to relieve pain through localized heating. This paper briefly discusses the mechanisms through which heat is generated in tissue and the absorption characteristics of the applied electromagnetic radiation. The adverse effects of this radiation are reviewed with particular emphasis on the current exposure limits for operators and non patients in the vicinity of diathermy devices. The newly introduced codes of practice for the 'Safe Use of Shortwave (Radiofrequency) and Microwave Diathermy' are also discussed. PMID- 25025705 TI - Assessment of the peripheral circulation: an update for practitioners. AB - This article describes the comprehensive assessment of the peripheral circulation. With greater understanding of haemodynamics and the mechanisms of circulatory dysfunction associated with disease and normal processes such as ageing, physical therapists are in a better position to assess and treat circulatory Impairment. Since adequate circulation is fundamental to function, circulatory assessment is an integral component of any assessment regardless of whether vascular dysfunction is a primary problem. Some tests that are performed in peripheral vascular laboratories are described, as well as those tests that can easily be performed by therapists. The interpretation of the results of these tests and the implications for more rational physical therapy treatment are described. PMID- 25025706 TI - Development of a course for final year physical therapy students. AB - This paper looks at the development and implementation of a course, Coordinated Rehabilitation, given in the final year of an existing three year B.Sc. curriculum in physical therapy. Preparatory developmental planning for the unit included a review of problem areas in medical curricula and the use of a content grid which facilitated integration of the course into the curriculum. Results of the grid, which gave information about the depth and sequence of material already covered, formed the basis of the course content. The objectives, structure and evaluation procedures are described, as well as the teaching strategies and learning activities selected for the students. The paper ends with a summary of students' reactions to the course. PMID- 25025707 TI - Decisions made by physiotherapists: a study of private practitioners in victoria. AB - This paper addresses the kinds of decisions physiotherapists in Victoria are making about their clients, including those presenting with referral and those presenting to the physiotherapist as first contact. A survey of private practitioners provided data concerning the incidences of primary contact practice, and the source and content of medical referrals. The incidence of primary contact practice and the management of these clients is documented and discussed with respect to the physiotherapists' referral relationship with medical practitioners. Medical referrals are described and the physiotherapists' compliance with treatment prescription is discussed. Implications for optimal decision-making are discussed in relation to biassed choice. PMID- 25025708 TI - Identification of distinct Bacillus thuringiensis 4A4 nematicidal factors using the model nematodes Pristionchus pacificus and Caenorhabditis elegans. AB - Bacillus thuringiensis has been extensively used for the biological control of insect pests. Nematicidal B. thuringiensis strains have also been identified; however, virulence factors of such strains are poorly investigated. Here, we describe virulence factors of the nematicidal B. thuringiensis 4A4 strain, using the model nematodes Pristionchus pacificus and Caenorhabditis elegans. We show that B. thuringiensis 4A4 kills both nematodes via intestinal damage. Whole genome sequencing of B. thuringiensis 4A4 identified Cry21Ha, Cry1Ba, Vip1/Vip2 and beta-exotoxin as potential nematicidal factors. Only Cry21Ha showed toxicity to C. elegans, while neither Cry nor Vip toxins were active against P. pacificus, when expressed in E. coli. Purified crystals also failed to intoxicate P. pacificus, while autoclaved spore-crystal mixture of B. thuringiensis 4A4 retained toxicity, suggesting that primary beta-exotoxin is responsible for P. pacificus killing. In support of this, we found that a beta-exotoxin-deficient variant of B. thuringiensis 4A4, generated by plasmid curing lost virulence to the nematodes. Thus, using two model nematodes we revealed virulence factors of the nematicidal strain B. thuringiensis 4A4 and showed the multifactorial nature of its virulence. PMID- 25025709 TI - The effect of experimental fusarium mycotoxicosis on microbiota diversity in porcine ascending colon contents. AB - The objective of the study was to determine the effect of exposure of pigs to the Fusarium mycotoxins zearalenone (ZEN) and deoxynivalenol (DON), administered together and separately, on the colon microbiota. An experiment was conducted for 42 days on gilts, randomly assigned to four groups and administered either ZEN, DON, ZEN+DON, or a placebo. The number of aerobic mesophilic bacteria, yeasts, molds, anaerobic Clostridium perfringens, fecal streptococci, Enterobacteriaceae, Escherichia coli, and lactic acid bacteria (LAB) were determined in the contents of the ascending colon. The influence of mycotoxins on the functional diversity of the colonic microbiota was assessed using EcoPlate tests (Biolog). Analysis revealed the predominance of LAB in all groups of pigs. Zearalenone, administered separately and together with DON, was found to have an adverse effect on mesophilic aerobic bacteria, but only after long exposure to this mycotoxin. During the six weeks of the experiment, the concentration of C. perfringens, E. coli, and other bacteria in the family Enterobacteriaceae was most considerably reduced in the experimental groups exposed to zearalenone, both separately and together with DON. Mycotoxins also affected the functional biodiversity of microorganisms. Both Shannon's diversity index and the number of catabolized substrates in Biolog plate (the R index) were much higher in the group subjected to mixed mycotoxicosis. PMID- 25025710 TI - Intraspecific variation of centruroides edwardsii venom from two regions of Colombia. AB - We report the first description studies, partial characterization, and intraspecific difference of Centruroides edwardsii, Gervais 1843, venom. C. edwardsii from two Colombian regions (Antioquia and Tolima) were evaluated. Both venoms showed hemolytic activity, possibly dependent of enzymatic active phospholipases, and neither coagulant nor proteolytic activities were observed. Venom electrophoretic profile showed significant differences between C. edwardsii venom from both regions. A high concentration of proteins with molecular masses between 31 kDa and 97.4 kDa, and an important concentration close or below 14.4 kDa were detected. RP-HPLC retention times between 38.2 min and 42.1 min, showed bands close to 14.4 kDa, which may correspond to phospholipases. RP-HPLC venom profile showed a well conserved region in both venoms between 7 and 17 min, after this, significant differences were detected. From Tolima region venom, 50 well defined peaks were detected, while in the Antioquia region venom, 55 well-defined peaks were detected. Larvicidal activity was only detected in the C. edwardsii venom from Antioquia. No antimicrobial activity was observed using complete venom or RP-HPLC collected fractions of both venoms. Lethally activity (carried out on female albino swiss mice) was detected at doses over 19.2 mg/kg of crude venom. Toxic effects included distress, excitability, eye irritation and secretions, hyperventilation, ataxia, paralysis, and salivation. PMID- 25025711 TI - Evaluation of rapid blood sample collection in the detection of circulating filarial antigens for epidemiological survey by rWbSXP-1 capture assay. AB - BACKGROUND: Lymphatic filariasis is a neglected tropical disease leading to profound disfiguring causing socio economic burden in the tropics. Current diagnosis strategies available during field surveys and epidemics are based on traditional microscopic detections and a few antigen/antibody assays. We have compared different sampling methodologies and standardized the highly sensitive and reliable rWbSXP-1 antigen detection assay to our new sampling methodology. METHODOLOGY: Samples collected as serum, whole blood, whole blood on filter paper and whole blood on microscopic slides from patients belonging to various clinical groups of filariasis [endemic normal(EN), chronic pathology(CP), microfilaraemic(MF) and non-endemic normal(NEN)] were collected and standardized the rWbSXP-1 antigen detection assay using monoclonal antibody raised against rWbSXP-1 protein. The whole blood collected on microscopic slide based sampling method was employed in the field and the presence of circulating filarial antigen (CFA) was assessed using the rWbSXP-1 assay. PRINCIPAL FINDINGS: The sampling methods were compared and no significant difference was observed for the detection of CFA (MF, P = 0.304, EN, P = 0.675, CP, P = 0.5698, NEN, P = 0.4494). Further the optimized sampling method was utilized to collect the 1106 samples from Polur, Tiruvannamalai. The rWbSXP-1 assay gave 98 antigen positive results whereas the microscopic method gave only 17. CONCLUSIONS: Four sampling methodologies were analyzed and the new sampling methodology of whole blood collected on microscopic slide was found to be convenient for the detection of CFA using rWbSXP-1 antigen detection assay. The 1106 samples from Polur were collected using the new method. The rWbSXP-1 antigen assay perceived a 7.32% increased result which was read as false negatives on the conventional microscopic staining method. This new sampling methodology coupled with the rWbSXP-1 antigen assay can be used in epidemiological surveys for lymphatic filariasis and the same sampling methodology can be expanded to other antigen based high affinity assays. PMID- 25025712 TI - Eggshell membrane-based biotemplating of mixed hemimicelle/admicelle as a solid phase extraction adsorbent for carcinogenic polycyclic aromatic hydrocarbons. AB - A new solid-phase extraction (SPE) format was demonstrated, based on eggshell membrane (ESM) templating of the mixed hemimicelle/admicelle of linear alkylbenzenesulfonates (LAS) as an adsorbent for the enrichment of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in environmental aqueous samples. The LAS mixed hemimicelle/admicelle formation and SPE of the target PAHs were conducted simultaneously by adding the organic target and LAS through a column filled with 500 mg of ESM. The effect of various factors, including LAS concentration, solution pH, ionic strength, and humic acid concentration on the recoveries of PAHs were investigated and optimized. The results showed that LAS concentration and solution pH had obvious effect on extraction of PAHs, and the recoveries of PAHs compounds decreased in the presence of salt and humic acid. Under the optimized analytical conditions, the present method could respond down to 0.1-8.6 ng/L PAHs with a linear calibration ranging from 0.02 to 10 MUg/L, showing a good PAHs enrichment ability with high sensitivity. The developed method was used satisfactorily for the detection of PAHs in environmental water samples. The mixed hemimicelle/admicelle adsorbent exhibited high extraction efficiency to PAHs and good selectivity with respect to natural organic matter and was advantageous over commercial C18 adsorbent, for example, high extraction yield, high breakthrough volume, and easy regeneration. PMID- 25025714 TI - Exploring health-related quality of life and social functioning in adolescents with inflammatory bowel diseases after attending camp oasis and participating in a Facebook group. AB - BACKGROUND: Youth with inflammatory bowel diseases are at risk for impaired health-related quality of life (HRQoL) and problems with social functioning. This study examined the impact of attending Camp Oasis (a disease-specific weeklong camp experience) on the HRQoL and social functioning of youth with inflammatory bowel diseases. Additionally, the study collected pilot data on whether a postcamp Facebook group contributed to maintenance or enhancement of these factors. METHODS: Twenty-one youth ages 14 to 17 years who attended Camp Oasis and were Facebook users participated. HRQoL and social functioning (i.e., social support and social connectedness) were assessed through validated youth-report questionnaires at precamp, postcamp, and post-Facebook group. The Facebook group was 8 weeks in duration and encouraged campers to continue interacting in a private, protected setting. RESULTS: Analyses of effect sizes (i.e., Cohen's d) indicated medium and statistically significant increases in HRQoL from precamp to postcamp (d = 0.40) and small increases in social functioning (d = 0.15-0.24). Additional improvements in social functioning were seen from postcamp to post Facebook group (d = 0.21-0.32), and overall improvements were observed in all domains (d = 0.17-0.52). CONCLUSIONS: Findings replicated those of previous research in documenting the value of Camp Oasis on enhancing HRQoL. Both the camp experience and the Facebook group contributed to improvements in youth social functioning. Thus, supplementing the camp experience with membership in an online community may enhance social functioning in adolescents with inflammatory bowel diseases. PMID- 25025715 TI - Diffusion-weighted magnetic resonance for assessing ileal Crohn's disease activity. AB - BACKGROUND: Endoscopy and imaging objectively assess Crohn's disease (CD) activity. Magnetic resonance enterography (MRE) uses no ionizing radiation, carries no significant morbidity, and is highly sensitive in revealing soft tissues inflammation. Diffusion-weighted imaging can distinguish intestinal inflammation from a lower diffusion of water molecules giving rise to a reduced apparent diffusion coefficient. The magnetic resonance index of activity score and, more recently, the Clermont score were recently developed for staging CD activity. The aim of this study was to compare the MRE scores and the Simple Endoscopic Score for CD in identifying ileal CD activity. METHODS: Fifty-five patients with ileal and ileocolonic CD were consecutively enrolled between June 2012 and June 2013. All patients underwent clinical examination, biochemical tests, MRE, and colonoscopy to assess disease activity. RESULTS: MRE assessed active ileal disease in 31 patients (56.3%). The Clermont score significantly correlated with the magnetic resonance index of activity score (r = 0.91; P < 0.0001) and the Simple Endoscopic Score for CD (r = 0.76; P < 0.0001). The apparent diffusion coefficient correlated with the Simple Endoscopic Score for CD (r = -0.63; P < 0.0001) especially in unoperated patients. CONCLUSIONS: The Clermont score and the apparent diffusion coefficient value can stage ileal CD, avoiding the need to use contrast agents. PMID- 25025716 TI - Sleep disturbances and inflammatory bowel disease. AB - With an estimated 70 million Americans suffering, sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many clinical research studies. Sleep is now also considered to be an important environmental and behavioral factor associated with the process of inflammation and the immune system. Increased sleepiness is considered part of the acute phase of response to tissue injury, and sleep loss activates inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha. Clinical studies in many immune-mediated diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis, have revealed an association of sleep disturbances with disease activity. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. The importance of sleep in inflammatory bowel disease has recently gained attention with some published studies demonstrating the association of sleep disturbances with disease activity, subclinical inflammation, and risk of disease relapse. A comprehensive review of sleep physiology and its association with the immune system is provided here. Experimental and clinical studies exploring this relationship in inflammatory bowel disease are reviewed, and the clinical implications of this relationship and future directions for research are also discussed. PMID- 25025713 TI - Cancer stem cells, cancer cell plasticity and radiation therapy. AB - Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms. PMID- 25025717 TI - Mucus layers in inflammatory bowel disease. AB - The intestinal epithelium is covered with mucus with the main structural building block being the densely O-glycosylated MUC2 mucin. The intestinal epithelium is exposed to ingested material, our digestive machinery, and large amounts of microorganisms. Mucus is the first line of defense and aids to limit exposure to all these threats to the epithelium. In the small intestine, mucus acts as a matrix, which contains antimicrobial products, such as defensins and immunoglobulin A that limit epithelial exposure to the luminal bacteria. In the colon, the stratified inner mucus layer acts as a physical barrier excluding bacteria from the epithelium. Bacterial penetration of this normally restricted zone is observed in many colitis models and also in patients with ulcerative colitis. Mucus defects that allow bacteria to reach the epithelium and to stimulate an immune system response can lead to the development of intestinal inflammation. The current state of our knowledge concerning the function of the mucus layers and the main mucin component, MUC2, in inflammatory bowel disease is described in this review. PMID- 25025718 TI - Dental acupuncture. AB - Recently the opportunity arose to perform certain operative dentistry on a patient using acupuncture as an analgesic. PMID- 25025719 TI - The physiotherapist in the obstetric team. AB - With the term obstetric physiotherapist coming into more frequent use, it seems opportune to examine what it means. PMID- 25025720 TI - Psychological factors modifying pain with particular reference to childbirth. AB - Pain is one of those strange concepts wherein we use the word daily, each and every one of us has some understanding and indeed personal experience of the concept, and yet it is an extremely difficult problem to define accurately what is meant by pain. This highlights the fact that pain is very much a subjective experience by an individual and, for this reason, we immediately strike problems in any scientific study because of the difficulty, indeed impossibility, of measuring accurately the inner experience of another individual. For many years, writers have discoursed on pain without ever attempting to define the concept. That there is an emotional component involved in pain has been recognised not only by physicians and other medical people, but by writers through the ages. Shakespeare says in Macbeth - "the labour we delight in physics pain", and again in Romeo and Juliet - "One fire burns out another's burning, one pain is lessened by another's anguish" - and in 1590 Montaigne wrote "we feel a cut from the surgeon's scalpel more than 10 blows of the sword in the heat of battle. The pains of childbirth considered so great both by doctors and by God are held in no account amongst entire nations. The wives of our Swiss infantry trudging after their husbands may be seen today carrying on the shoulder the infant which was yesterday in the womb." PMID- 25025721 TI - The use of natural childbirth methods in melbourne: patient opinion survey. AB - The effects of Natural Childbirth methods on labour pose problems of evaluation. Attempts have been made to measure their physical benefits and emotional advantages to the patient. However little is known about patient opinion of the use of preparation in labour and the attitudes which it engenders in them. PMID- 25025722 TI - Rhythmical intention as a method of treatment for the cerebral palsied patient. AB - Conductive Education as described by Cotton (1967, 1970) and Hari (1968) is the method of treatment introduced by Professor Andreas Peto at the State Institute for the Motor Disabled in Budapest. It is a system of treatment which does not separate the learning of intellectual, linguistic and functional skills into the usual areas of school, speech therapy, occupational therapy and physiotherapy. Instead the child approaches a total learning situation where the conductor is teacher/therapist and Rhythmical Intention is used as the method of learning all tasks. PMID- 25025723 TI - The treatment of joints by passive movement. AB - When physiotherapists think of joints being treated by passive movement they usually think of stretching, whereas the treatment of pain by this means is very little appreciated. Even with stretching techniques, many people think that stretching is carried out by taking the joint to the limit of its range and simply pushing; for example, they think that if a patient's shoulder is stiff, passive movement means merely taking his arm to the limit of elevation and then pushing it further into elevation. The intention of this paper is to explain how stretching is carried out, and to explain how passive movement treatment is applied in other joint situations with particular emphasis on the treatment of pain. PMID- 25025724 TI - The effect of postural drainage on the movement of the female diaphragm. AB - Twenty young, healthy females of average build were selected at random. PMID- 25025726 TI - Implications of neuro-developmental deviations in low birthweight and mechanically ventilated infants. AB - A condition described as transient dystonia which may have long term effects on the development of prematurely born infants has been reported in the literature. This study investigated the significance of this condition in 85 high risk infants. The infants were divided into those displaying dystonic and non-dystonic features at four months after expected date of delivery. Neuro-sensory motor status and the developmental quotient of each infant were assessed at 4, 12 and/or 18 months. The condition was present in 22 per cent of the group and developmental deviations were more marked in infants identified as dystonic compared with the non-dystonic. An increased percentage of normal responses by 18 months suggested that the condition may be transient. Implications for physiotherapy involve the recognition and selective treatment of dystonic infants. PMID- 25025727 TI - Physiotherapy in the treatment of hyperkinetic children. AB - The hyperkinetic syndrome is a feature of present times. This paper gives a brief survey of literature concerning the problem together with some details about causes, treatments, and methods of assessing the quantity and quality of the excessive movement. Although physiotherapists cannot treat the basic causes, they may give assistance by assessing the nature of the excessive movement and explaining this to teachers and parents, as well as helping with any co-existing clumsiness. PMID- 25025725 TI - Identification and Quantitation of Coding Variants and Isoforms of Pulmonary Surfactant Protein A. AB - Pulmonary surfactant protein A (SP-A), a heterooligomer of SP-A1 and SP-A2, is an important regulator of innate immunity of the lung. Nonsynonymous single nucleotide variants of SP-A have been linked to respiratory diseases, but the expressed repertoire of SP-A protein in human airway has not been investigated. Here, we used parallel trypsin and Glu-C digestion, followed by LC-MS/MS, to obtain sequence coverage of common SP-A variants and isoform-determining peptides. We further developed a SDS-PAGE-based, multiple reaction monitoring (GeLC-MRM) assay for enrichment and targeted quantitation of total SP-A, the SP A2 isoform, and the Gln223 and Lys223 variants of SP-A, from as little as one milliliter of bronchoalveolar lavage fluid. This assay identified individuals with the three genotypes at the 223 position of SP-A2: homozygous major (Gln223/Gln223), homozygous minor (Lys223/Lys223), or heterozygous (Gln223/Lys223). More generally, our studies demonstrate the challenges inherent in distinguishing highly homologous, copurifying protein isoforms by MS and show the applicability of MRM mass spectrometry for identification and quantitation of nonsynonymous single nucleotide variants and other proteoforms in airway lining fluid. PMID- 25025728 TI - A longitudinal study: concerning sensory-motor functioning in preschool and educational achievement in grades 1 and 2. AB - Two hundred and thirty-eight preschool children were divided into four groups according to the method of referral. Chi-square analysis following a clinical examination in the preschool showed highly significant differences between the groups, particularly in proprioceptive, vestibular and related functioning. Achievement and classroom behaviour in Grade 1, examined in a structured teacher interview, showed highly significant differences between the groups in general performance, english, mathematics, general knowledge and behavioural characteristics. Formal educational assessment in Grade 2 indicated a similar pattern, except that children referred by guidance and medical officers (group 4) deteriorated, and randomly sampled children with vestibular and proprioceptive dysfunction on the preschool examination (group 2) improved. PMID- 25025729 TI - An interim Australian version of the jebsen test of hand function. AB - An objective test of hand function, standardized for adults in the USA, has been adapted and standardized for the normal adult population of the Brisbane metropolitan area. Test items have been chosen to correspond as accurately as possible with the original test items, and all are readily available. The Australian version is quick to administer, and comprises eight test items, chosen to provide a broad sampling of hand function. Percentile norms are provided for dominant and non-dominant hands for men and women in various age-groups, ranging from 16 to 90 years. PMID- 25025730 TI - Research to optimise human performance. AB - The need for greater understanding of the factors which limit human movement and functional capacity and for determining effective methods for ensuring optimum performance has led to a wide range of related research studies. This paper draws on some of the research projects pursued or supervised by the author, to show the knowledge gained in aspects of movement capacity, muscle function and the influence of sensory motor deficits on movement and function. The inter relationship of the many factors influencing functional capacity emphasise the need to think broadly in research. Studies of effectiveness of physiotherapy and collection of data for ergonomic workplace design highlight the importance of both prevention and therapeutic care and demonstrate the contributions which physiotherapists can make through research to optimise human performance. PMID- 25025731 TI - The lumbar spine: structure, function, age changes and physiotherapy. AB - Increasing age brings about inevitable changes in the structure, shape and function of the human lumbar spine. The primary structural age change which occurs is a selective loss of the transversely oriented trabeculae within lumbar vertebrae, which causes them to become shorter, wider and more concave at their end-plate region. This in turn leads to a progressive alteration to the shape of the lumbar discs and, together with biochemical and histological change, brings about a reduction in spinal posture, flexibility and compliance and in the ability of the lumbar region to cope with sustained loading. This information is important for physiotherapists in their treatment of lumbar spinal disorders. PMID- 25025732 TI - Continuing education - does it make for a more competent practitioner? AB - It is more than two decades since mandatory continuing education (MCE) was introduced in the United States and barely a decade since some professional associations adopted MCE in Australia. The value of MCE as a means of maintaining or improving professional competence remains unclear. Despite there being no clear cut evidence of enhanced competence, no profession having adopted MCE has returned to a policy of voluntary continuing education. In Australia there appears to be a drift of health professions into mandatory continuing education. If MCE is adopted by the physiotherapy profession, what will the reasons be? The challenge is to clearly establish the links between continuing education, professional competence and health outcomes. PMID- 25025733 TI - Reflections on physiotherapy and the emerging science of movement rehabilitation. AB - Recent scientific advances in the field of human movement and its control have provided the impetus for developing new ways of thinking about the training and measurement of motor performance in individuals with movement dysfunction and are challenging traditional methods of practice. In this paper, the authors describe the process of importing knowledge from established fields of science to develop a more scientific framework for clinical practice. In addition, they present some of the results of their laboratory-based research into the control of the upper body and lower limbs in sit-to-stand and illustrate the process by which they have developed a protocol for optimising performance of sit-to-stand in training disabled individuals. PMID- 25025734 TI - Tissue temperature and blood flow: a research based overview of electrophysical modalities. AB - Tissue healing requires an adequate blood and oxygen supply. Physiotherapy heating modalities have traditionally been used to improve blood flow and more recently, electrical stimulation, magnetic fields and laser have been promoted for that purpose. Electrophysical modalities have been investigated for their influence on tissue temperature and blood flow. Ultrasound, hot packs and microwave irradiation increase tissue temperature with microwave providing the most clinically significant increase in blood flow. Ultrasound, laser, magnetic fields and comfortable sensory electrical stimulation do not produce significant changes in blood flow, whereas electrical stimulation which produces a motor response is effective. The most efficient and cost-effective physiotherapeutic method of increasing blood flow is by exercise. PMID- 25025735 TI - Paediatric physiotherapy: a review of some contributions made in Australia since 1954. AB - Paediatric practice in Australia has always attracted a significant number of therapists. In consideration of this input, it is reasonable to suppose that the literature published over the last 40 years might describe the contribution physiotherapists working in the paediatric area have made to the evolution of physiotherapy services in this time frame. A review of original articles published in the Australian Journal of Physiotherapy provides interesting information in support of this supposition. Two themes which have attracted significant research attention emerged and a brief examination of the series of papers which have contributed to understanding in these areas of practice is presented. PMID- 25025736 TI - Volatile organic compound identification and characterization by PCA and mapping at a high-technology science park. AB - High-technology industries have grown continuously in Taiwan and elsewhere in the world. Volatile organic compounds (VOCs) comprise the highest percentage of emissions in these industries. The objectives of this study were to identify VOC sources and to apportion their contributions by using a three-step approach. These included estimating concentration distributions, performing principal component analysis (PCA), and mapping concentration contours. The results showed that the dominant compound groups were aromatic and aliphatic compounds. The PCA resolved four emission sources: vehicular traffic, industrial solvents, waste water plants, and cleaning/degreasing agents. Spatial distributions showed that concentrations of vehicular traffic-related compounds (benzene and isooctane) were highest at the entrances to the science park, and strongly related to traffic volume, and that the emissions of industry-related compounds (xylene and ethylbenzene) were closest to the associated sources. This study provided an accurate, practical and efficient method of characterizing emission sources in an industrial complex. PMID- 25025737 TI - Discovery of 1H-indole-2-carboxamides as novel inhibitors of the androgen receptor binding function 3 (BF3). AB - To overcome resistance to conventional anti-androgens of human androgen receptor (AR), the allosteric site of the AR binding function 3 (BF3) was investigated as an alternative target for small molecule therapeutics. A library of 1H-indole-2 carboxamides were discovered as BF3 inhibitors and exhibited strong antiproliferative activity against LNCaP and enzalutamide-resistant prostate cancer cell lines. Several of the lead compounds may prove of particular benefit as a novel alternative treatment for castration-resistant prostate cancers. PMID- 25025738 TI - Subjective evaluation of physical and mental workload interactions across different muscle groups. AB - Both physical and mental demands, and their interactions, have been shown to increase biomechanical loading and physiological reactivity as well as impair task performance. Because these interactions have shown to be muscle-dependent, the aim of this study was to determine the sensitivity of the NASA Task Load Index (NASA TLX) and Ratings of Perceived Exertion (RPE) to evaluate physical and mental workload during muscle-specific tasks. Twenty-four participants performed upper extremity and low back exertions at three physical workload levels in the absence and presence of a mental stressor. Outcome measures included RPE and NASA TLX (six sub-scales) ratings. The findings indicate that while both RPEs and NASA TLX ratings were sensitive to muscle-specific changes in physical demand, only an additional mental stressor and its interaction with either physical demand or muscle groups influenced the effort sub-scale and overall workload scores of the NASA TLX. While additional investigations in actual work settings are warranted, the NASA TLX shows promise in evaluating perceived workload that is sensitive not only to physical and mental demands but also sensitive in determining workload for tasks that employ different muscle groups. PMID- 25025739 TI - Natural humic substances effects on the life history traits of Latonopsis australis SARS (1888) (Cladocera--Crustacea). AB - Cultivation medium is one of the first aspects to be considered in zooplankton laboratory cultivation. The use of artificial media does not concern to reproduce natural conditions to the cultivations, which may be achieved by using natural organic compounds like humic substances (HS). This study aimed to evaluate the effects of a concentrate of dissolved organic carbon (DOC) from the Negro River (NR(1)) and an extraction of humic acids (HA) from humus produced by Eisenia andrei on the life history traits of laboratory-based Latonopsis australis SARS (1888). A cohort life table approach was used to provide information about the effectiveness of NR and HA as supplements for the artificial cultivation of L. australis. Additionally, we seek to observe a maximization of L. australis artificial cultivation fitness by expanding the range of HS concentrations. The first experiment demonstrated that the females of L. australis reared under NR10 (mgDOCL(-1)) may have experienced an acceleration of the population life cycle, as the females have proportionally reproduced more and lived shorter than controls. By contrast, the use of the HA did not improve life history traits considered. The expansion of the concentration range (5, 10, 20 and 50 mgDOCL( 1)) corroborated the patterns observed on the first assay. Results for the fitness estimates combined with shorter lifespans than controls demonstrated trade-offs between reproductive output and female longevity reared under NR conditions, with NR20 been suggested as the best L. australis cultivation medium. This response might be associated with hormone-like effects. PMID- 25025740 TI - Evaluating wild grapevine tolerance to copper toxicity. AB - We evaluate copper tolerance and accumulation in Vitis vinifera ssp. sylvestris in populations from a copper contaminated site and an uncontaminated site, and in the grapevine rootstock "41B", investigating the effects of copper (0-23 mM) on growth, photosynthetic performance and mineral nutrient content. The highest Cu treatment induced nutrient imbalances and inhibited photosynthetic function, causing a drastic reduction in growth in the three study plants. Effective concentration was higher than 23 mM Cu in the wild grapevines and around 9 mM in the "41B" plants. The wild grapevine accessions studied controlled root Cu concentration more efficiently than is the case with the "41B" rootstock and must be considered Cu-tolerant. Wild grapevines from the Cu-contaminated site present certain physiological characteristics that make them relatively more suitable for exploitation in the genetic improvement of vines against conditions of excess Cu, compared to wild grapevine populations from uncontaminated sites. PMID- 25025741 TI - Molecular magnetic investigation of a family of octanuclear [Cu6Ln2] nanoclusters. AB - Reaction of in situ prepared acylhydrazone ligand with Ln(NO3)3.6H2O and Cu(OAc)2.H2O resulted in the formation of novel isostructural octanuclear Cu6Ln2 compounds (Ln = Dy (1), Tb (2), Gd (3), Y (4)) with an unprecedented octametallic structure, which can be described as an oblate wheel built up from two structurally similar Cu3 fragments linked together by two nodelike mononuclear lanthanide units. A detailed magnetic analysis reveals that the strong antiferromagnetic Cu...Cu interactions via the Cu-N-N-Cu-N-N-Cu linkage and the anticipated ferromagnetic Cu...Gd coupling makes an overall high-spin ground state in favor of the observation of significant magnetic caloric and SMM-like properties in the isotropic and anisotropic derivatives. PMID- 25025742 TI - A new raptorial dinosaur with exceptionally long feathering provides insights into dromaeosaurid flight performance. AB - Microraptorines are a group of predatory dromaeosaurid theropod dinosaurs with aerodynamic capacity. These close relatives of birds are essential for testing hypotheses explaining the origin and early evolution of avian flight. Here we describe a new 'four-winged' microraptorine, Changyuraptor yangi, from the Early Cretaceous Jehol Biota of China. With tail feathers that are nearly 30 cm long, roughly 30% the length of the skeleton, the new fossil possesses the longest known feathers for any non-avian dinosaur. Furthermore, it is the largest theropod with long, pennaceous feathers attached to the lower hind limbs (that is, 'hindwings'). The lengthy feathered tail of the new fossil provides insight into the flight performance of microraptorines and how they may have maintained aerial competency at larger body sizes. We demonstrate how the low-aspect-ratio tail of the new fossil would have acted as a pitch control structure reducing descent speed and thus playing a key role in landing. PMID- 25025743 TI - Management of late (>1 y) deep infection after spinal fusion: a retrospective cohort study. AB - BACKGROUND: The incidence of late infection published in the literature varies from 1% to 12% with varying definition of late infection (range, 3 mo to 1 y). Current evidence suggests implant removal and antibiotic therapy is necessary to clear these infections. A high incidence of late (>1 y) deep infection after instrumented spinal fusion was identified at our institution. We sought to evaluate the efficacy of our management of these patients. METHODS: A total of 1390 patients underwent instrumented spinal fusion from 2000 to 2009. Forty-two patients developed deep infection >1 year after index procedure (3%) and had surgical debridement. Clinical records and microbiology reports were reviewed for details of operative and postoperative management. RESULTS: Advanced imaging was only obtained in 6 patients (5 computed tomography, 1 magnetic resonance imaging). Offending organisms were identified in 39/42 patients, 27 of these grew Propionibacterium acnes. P. acnes grew in culture at a median of 6 days (range, 3 to 10 d), significantly longer than all other organisms, which grew in a median of 1 day (range, 0 to 8 d) (P<0.001). Implants were removed at the index hospitalization in 41 patients. Implant retention was attempted in 1 patient and failed. Primary closure was carried out in 37 patients; the remainder had undergone multiple debridements (4 planned, 1 unplanned). VAC closure was utilized in 2 patients. All patients were treated with organism-specific intravenous antibiotics and transitioned to oral antibiotics on average in 34 days (range, 2 to 186 d). Total length of antibiotic therapy was an average of 141 days (range, 34 to 413 d). CONCLUSIONS: P. acnes was the most common organism identified and took nearly 1 week to grow in culture. Treatment is generally successful with thorough debridement, removal of implants, and antibiotic treatment. LEVEL OF EVIDENCE: LEVEL III: retrospective comparative study. PMID- 25025744 TI - Effects of age, sex, and comorbidities on the pediatric outcomes data collection instrument (PODCI) in the general population. AB - BACKGROUND: The Pediatric Outcomes Data Collection Instrument (PODCI) is an outcomes assessment tool developed to allow measurement of health-related quality of life in children with disorders having musculoskeletal impact. The instrument was tested by Hunsaker and colleagues on a large population-based sample of children (n=5300), and partial results of that survey were published in 2002. Further publication of the findings did not occur. The PODCI was designed to collect data on age, sex, comorbidities, race and ethnicity, makeup of the household, and other demographic data that could have an impact on function and psychosocial issues. This retrospective study evaluated the impact of age, sex, and health/comorbid conditions on the subscales of the PODCI. METHODS: Using the database that was developed by Hunsaker and colleagues for the American Academy of Orthopaedic Surgeons, a 1-way multivariate analysis of variance was conducted to determine effects of prior comorbid condition versus no prior comorbid condition on the dependent variables of the PODCI Upper Extremity Function, Transfers and Basic Mobility, Sports and Physical Function, Comfort, and Happiness scales by parent respondent. A follow-up analysis of the health/comorbid condition, age, and sex of the child on the PODCI subscales using independent samples t tests was performed. RESULTS: Significant differences in the PODCI subscales of Transfers and Basic Mobility, Sports and Physical Function, Comfort, and Happiness occurred between children with a prior comorbid condition versus no prior reported comorbid condition. The sex of the child with a comorbid condition versus without a comorbidity appears to affect the PODCI subscale scores except for the Upper Extremity Function subscale. PODCI scales show an initial increase with age. Age at plateau varies, as do patterns of scores after plateau, with gradual decreases in quality-of-life scales. CONCLUSIONS: With further exploration of the population-based database, it was possible to confirm that age, sex, and comorbidities do have an impact on the levels of functional and psychosocial assessments done with the PODCI. Assessments done with the PODCI should include the assessment of, and potential correction for, these variables. LEVEL OF EVIDENCE: Prognostic studies level II retrospective. PMID- 25025745 TI - Fuzzy logic for personalized healthcare and diagnostics: FuzzyApp--a fuzzy logic based allergen-protein predictor. AB - The path to personalized medicine demands the use of new and customized biopharmaceutical products containing modified proteins. Hence, assessment of these products for allergenicity becomes mandatory before they are introduced as therapeutics. Despite the availability of different tools to predict the allergenicity of proteins, it remains challenging to predict the allergens and nonallergens, when they share significant sequence similarity with known nonallergens and allergens, respectively. Hence, we propose "FuzzyApp," a novel fuzzy rule based system to evaluate the quality of the query protein to be an allergen. It measures the allergenicity of the protein based on the fuzzy IF-THEN rules derived from five different modules. On various datasets, FuzzyApp outperformed other existing methods and retained balance between sensitivity and specificity, with positive Mathew's correlation coefficient. The high specificity of allergen-like putative nonallergens (APN) revealed the FuzzyApp's capability in distinguishing the APN from allergens. In addition, the error analysis and whole proteome dataset analysis suggest the efficiency and consistency of the proposed method. Further, FuzzyApp predicted the Tropomyosin from various allergenic and nonallergenic sources accurately. The web service created allows batch sequence submission, and outputs the result as readable sentences rather than values alone, which assists the user in understanding why and what features are responsible for the prediction. FuzzyApp is implemented using PERL CGI and is freely accessible at http://fuzzyapp.bicpu.edu.in/predict.php . We suggest the use of Fuzzy logic has much potential in biomarker and personalized medicine research to enhance predictive capabilities of post-genomics diagnostics. PMID- 25025746 TI - Facile estimation of catalytic activity and selectivities in copolymerization of propylene oxide with carbon dioxide mediated by metal complexes with planar tetradentate ligand. AB - Mechanistic studies were conducted to estimate (1) catalytic activity for PPC, (2) PPC/CPC selectivity, and (3) PPC/PPO selectivity for the metal-catalyzed copolymerization of propylene oxide with carbon dioxide [PPC: poly(propylene carbonate); CPC = cyclic propylene carbonate; PPO: poly(propylene oxide)]. Density functional theory (DFT) studies demonstrated that the DeltaG(crb) - DeltaG(epx) value should be an effective indicator for the catalytic activities [DeltaG(epx): dissociation energy of ethylene oxide from the epoxide-coordinating metal complex; DeltaG(crb): dissociation energy of methyl carbonate from the metal-carbonate complex]. In addition, metal complexes with a subthreshold DeltaG(epx) value were found to show low PPC/CPC selectivity. The PPC/PPO selectivity was related to the DeltaG(alk) - DeltaG(epx) value and steric environment around the metal center (DeltaG(alk): dissociation energy of alkoxide ligand from the metal center). Based on the mechanistic studies, two metal complexes were designed and applied to the copolymerization to support validity of these indicators. The results presented here should be useful for brand-new catalyst candidates since these indicators can be easily calculated by DFT method without computing transition states. PMID- 25025747 TI - Vertebral column development and its relation to adult pathology. AB - Normal notochordal and vascular attrition leaves weak spots in intervertebral discs through which intravertebral prolapse of disc material frequently occurs. Some varieties of prolapse cause somatic spinal pain. Asym-metrical and asynchronous growth of normal vertebral arches rotates thoracic vertebral bodies slightly to the left in infants and to the right in adolescents. Primary vascular asymmetry could cause the observed vertebral asymmetry. Luschka's joints develop in the cervical spine during childhood and give some protection against postero lateral disc prolapse, but cervical zygapophyseal joints give little protection to the disc in sagittal plane movements. The lumbar zygapophyseal joint plane changes from a coronal orientation in infants to a biplanar coronal and sagittal orientation in adults, which enables the joints to restrain both rotation and excessive flexion. This explains the observed pattern of stress related age changes in the joints. PMID- 25025748 TI - The innervation of the vertebral column. AB - The posterior elements of the vertebral column are innervated by branches of the dorsal rami of the spinal nerves, while the intervertebral discs and related ligaments are innervated by various branches of the ventral rami and sympathetic nervous system. A knowledge of this nerve supply forms the basis for a systematic classification of the possible sources of primary spinal pain, and the basis for several diagnostic techniques that use needles to provoke and anaesthetize putative sources of pain. In particular, the demonstration of a nerve supply to intervertebral discs vindicates the concept that these structures intrinsically may be sources of pain. PMID- 25025749 TI - Electromyographic studies of erectores spinae: symmetrical postures and sagittal trunk motion. AB - During standing, the electromyographic (EMG) activity of erectores spinae is minimal. However, this activity increases when an object is held in front of the body. The size of the EMG response to this loading is dependent on both the weight of the object and the position of its centre of mass relative to the lumbosacral junction. Interpretation of EMG results becomes complex when movements of large amplitude are involved. Problematically, erectores spinae become electrically silent during trunk flexion, at a position which requires high tension in post-vertebral structures. This emphasizes that EMG does not record the state of passive connective tissue tension, which is sufficient to support the vertebral column in some flexed postures. PMID- 25025750 TI - Age changes in the lumbar articular triad. AB - The articular triad of the intervertebral disc and the two synovial zygapophyseal joints at the same vertebral level, allows the spine its considerable mobility, while providing support and protection. The principal structural changes which occur to the elements of the articular triad in old age are an increase in the convexity, central height and horizontal intervertebral disc dimensions, and increased swelling and fibrillation of zygapophyseal joint cartilage with expansion of joint margins by osteophytes. These changes are directly responsible for the reduction in the ranges of all lumbar movements in old age. Advanced osteoarthrosis in old age is not accompanied by bony sclerosis, because of the generalized osteopenia of old age. PMID- 25025751 TI - Measurement of variations in lumbar zygapophyseal joint intracapsular pressure: a pilot study. AB - A pilot study using four subjects was conducted to investigate a proposed method of measuring 'in vivo' lumbar zygapophyseal intracapsular pressures. The authors were interested in establishing whether a resting pressure could be measured, and to observe pressure changes within the lumbar zygapophyseal capsules with fluid injection and with a range of active and passive movements including manipulative techniques. The results indicated that the apparatus could effectively measure intracapsular pressure changes on injection and lumbar movements. Significant pressure changes with specific localized manipulative therapy techniques were demonstrated. A resting intra-capsular pressure reading was not obtainable. Further controlled studies using this approach could provide valuable anatomical and clinical knowledge for the future. PMID- 25025752 TI - Correlation between the reduced circulating endothelial progenitor cell counts and elevated intraocular pressure-induced retinal ganglion cell apoptosis. AB - PURPOSE: To investigate the correlations between intraocular pressure (IOP) and circulating endothelial progenitor cells (EPCs), retinal ganglion cells (RGC) apoptosis and EPCs, and explore the possible role of EPCs in the elevated IOP induced RGC apoptosis. MATERIALS AND METHODS: A rat model of IOP elevation was induced by photocoagulation of the limbus vein and episcleral veins using a 532 nm green laser. Twenty rats were randomly assigned to normal control (NC) group, 30 rats were randomly assigned to sham-treated control (STC) group and 50 rats were randomly assigned to laser-treated (LT) group. The IOPs were measured with a Tono-pen XL tonometer. Hematoxylin-eosin staining was performed to observe the effects of IOP elevation on the structure of retina. Retinal apoptotic cells were determined by in situ TUNEL staining, and peripheral blood EPCs (CD34(+)/CD133(+)) were detected by flow cytometry. RESULTS: Compared with the NC group (9.9 +/- 1.2 mmHg), the IOPs in the LT group were 37.4 +/- 1.5, 31.8 +/- 4.1, 25.9 +/- 2.2, 23.1 +/- 3.6 and 22.4 +/- 3.0 mmHg on the third day, seventh day, third week, second month and third month, respectively, after the laser photocoagulation. There were significant differences in IOPs between the groups at the different time points (F = 110.02, p < 0.001). TUNEL analysis showed that only few apoptotic RGCs were found on the third and the seventh day after the laser treatment, and then many more apoptotic RGCs were found beginning on the third week after the laser treatment. The EPC counts were 121.3 +/- 22.4, 81.3 +/ 23.7, 46.1 +/- 15.8, 54.4 +/- 19.1 and 54.7 +/- 15.9 /2 * 10(5) mononuclear cells (MNCs) on the third day, seventh day, third week, second month and third month, respectively, after the laser photocoagulation, compared with the NC group (62.1 +/- 13.1)/2 * 10(5) MNCs. There were significant differences in EPC counts between the groups at the different time points (F = 22.09, p < 0.001). CONCLUSIONS: Elevated IOP-induced RGC apoptosis is associated with the reduced circulating EPC counts. PMID- 25025754 TI - A versatile tripodal Cu(I) reagent for C-N bond construction via nitrene-transfer chemistry: catalytic perspectives and mechanistic insights on C-H aminations/amidinations and olefin aziridinations. AB - A Cu(I) catalyst (1), supported by a framework of strongly basic guanidinato moieties, mediates nitrene-transfer from PhI?NR sources to a wide variety of aliphatic hydrocarbons (C-H amination or amidination in the presence of nitriles) and olefins (aziridination). Product profiles are consistent with a stepwise rather than concerted C-N bond formation. Mechanistic investigations with the aid of Hammett plots, kinetic isotope effects, labeled stereochemical probes, and radical traps and clocks allow us to conclude that carboradical intermediates play a major role and are generated by hydrogen-atom abstraction from substrate C H bonds or initial nitrene-addition to one of the olefinic carbons. Subsequent processes include solvent-caged radical recombination to afford the major amination and aziridination products but also one-electron oxidation of diffusively free carboradicals to generate amidination products due to carbocation participation. Analyses of metal- and ligand-centered events by variable temperature electrospray mass spectrometry, cyclic voltammetry, and electron paramagnetic resonance spectroscopy, coupled with computational studies, indicate that an active, but still elusive, copper-nitrene (S = 1) intermediate initially abstracts a hydrogen atom from, or adds nitrene to, C-H and C?C bonds, respectively, followed by a spin flip and radical rebound to afford intra- and intermolecular C-N containing products. PMID- 25025755 TI - Impact of low-grade adverse events on health-related quality of life in adult patients receiving imatinib or nilotinib for newly diagnosed Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase. AB - OBJECTIVE: Chronic myeloid leukemia (CML) treatment relies on tyrosine kinase inhibitors (TKIs), but their use can be associated with low-grade adverse events (AEs). This analysis aimed to identify the low-grade AEs which significantly impact the Health Related Quality of Life (HRQoL) of CML patients in chronic phase (CP) and to compare the incidence of such AEs among nilotinib- and imatinib treated patients. RESEARCH DESIGN AND METHODS: Data from the 48 month ENESTnd trial were used (N = 593 patients). HRQoL was assessed using generic (SF-36) and leukemia-specific (FACT-Leu) HRQoL surveys. AEs were categorized into 26 system organ classes. RESULTS: In the adjusted regression model, five low-grade AE categories - gastrointestinal disorders, blood and lymphatic system disorders, general disorders and administration site conditions, musculoskeletal disorders, and psychiatric disorders - significantly impaired at least one HRQoL score. The incidence rate of these five AE categories was either significantly lower for nilotinib than imatinib or not different between the two drugs. The AE categories with lower incidence for both nilotinib 300 mg BID and 400 mg BID versus imatinib 400 mg daily were gastrointestinal, blood and lymphatic system, and musculoskeletal; nilotinib 300 mg BID had lower incidence than imatinib for general disorders. LIMITATIONS: Low-grade AEs were grouped and analyzed by system organ class category, so the effect of some rare individual AEs on HRQoL may have been missed. CONCLUSIONS: The impact of low-grade AEs on HRQoL should be taken into account, along with other factors, when selecting the optimal treatment for patients newly diagnosed with CML-CP. PMID- 25025756 TI - First study of vitellogenesis of the broad fish tapeworm Diphyllobothrium latum (Cestoda, Diphyllobothriidea), a human parasite with extreme fecundity. AB - In the present study, the process of vitellogenesis of one of the most prolific organisms, the broad tapeworm, Diphyllobothrium latum, the causative agent of human diphyllobothriosis, was studied for the first time using transmission electron microscopy. Cytochemical staining with periodic acid-thiosemicarbazide silver proteinate for detection of glycogen was applied. Starting from the periphery toward the center of the vitelline follicle four stages of vitellocytes are differentiated: immature vitellocytes, early maturing vitellocytes, advanced maturing and mature vitellocytes. Differentiation into mature vitellocytes involves the formation of shell globule clusters containing shell globules, large amount of saturated lipid droplets and glycogen. A peculiar ultrastructural feature of D. latum vitellogenesis is the presence of lamellar bodies in the cytoplasm of mature vitellocytes. This feature is similar to that present in the closely related caryophyllideans and spathebothriideans. Despite the great similarity observed in the embryonic development of diphylobothriideans, caryophyllideans and spathebothriideans, and the fact that their vitellocytes share a feature not reported from other cestode groups, there are substantial differences in the morphology of vitelline clusters, types, amount and localization of their nutritive reserves. PMID- 25025757 TI - Molecular phylogenetic identification of Fasciola flukes in Nepal. AB - Eighty-one Fasciola flukes collected from 8 districts in Nepal were analyzed for their species identification on the basis of their spermatogenic status and nuclear ribosomal internal transcribed spacer 1 (ITS1) and for their phylogenetic relation with Fasciola flukes from other Asian countries on the basis of the mitochondrial NADH dehydrogenase subunit 1 (nad1) gene. Sixty-one flukes (75.3%) were aspermic Fasciola sp., and 20 flukes (24.7%) were identified as Fasciola gigantica. All of the aspermic flukes displayed the Fh/Fg type in ITS1, which was predominant in aspermic Fasciola sp. from China, and most (60 flukes) displayed the Fsp-ND1-N1 haplotype in the nad1, which had an identical nucleotide sequence to the major haplotype (Fg-C2) of the aspermic flukes from China. These results suggest that aspermic Fasciola sp. was introduced into Nepal from China. Furthermore, the results of the diversity indices, neutrality indices, and median joining network analysis with reference haplotypes from Asian countries suggest that aspermic Fasciola sp. rapidly expanded its distribution. In contrasts, F. gigantica displayed 10 nad1 haplotypes, which showed higher population diversity indices than the haplotypes of aspermic flukes, indicating that the F. gigantica population was clearly distributed in Nepal earlier than the aspermic Fasciola population. Although the F. gigantica haplotypes from Nepal formed a star-like phylogeny consisting of a main founder haplotype (Fg-ND1-N1), together with some F. gigantica haplotypes from Myanmar and Thailand, the Nepal population differed genetically from F. gigantica populations of neighboring countries as each country had distinct founder haplotype(s). PMID- 25025758 TI - Symptomatic subcapsular and perinephric hematoma following ureteroscopic lithotripsy for renal calculi. AB - OBJECTIVE: Ureteroscopic lithotripsy (URSL) is believed to be associated with less risk of symptomatic renal hematoma than extracorporeal shockwave lithotripsy (SWL) and percutaneous nephrolithotomy (PCNL). We sought to document the rate of and risk factors for this rare complication following URSL for renal calculi. METHODS: With Institutional Review Board approval, we reviewed 1087 cases of URSL performed between July 2009 and October 2012 for four surgeons. We identified cases for renal calculi complicated by symptomatic "hematoma" by searching electronic medical records of patients undergoing URSL with a web-based search tool and cross-referencing with a departmental quality improvement database for postoperative complications. Chi-squared tests were used to assess risk factors. RESULTS: Among 877 renal units exposed to URSL for renal calculi, 4 were complicated by symptomatic subcapsular hematomas (SH) and 3 by symptomatic perinephric hematomas (PH), yielding a 0.5% and 0.3% rate for each complication, respectively. Pain was the primary presenting symptom. Almost all cases presented within 24 to 48 hours postop. Two PH patients required postoperative blood transfusion. Four patients (two SH, two PH) were hospitalized for observation. Ureteral sheaths were used in two cases (one PH and one SH). There was no association with age, diabetes, body mass index (BMI), or operative duration (p values all>0.05). However, hematoma did correlate with female gender, preoperative hypertension, preoperative ureteral stenting, intraoperative ureteral sheath use, and postoperative ureteral stenting (all p-values<0.0001). CONCLUSIONS: While symptomatic hematoma is a complication of URSL, the rate of such outcome (0.8%) is far less than that reported by prior series with SWL and PCNL. This may partially be attributable to collection biases, where subclinical cases are not imaged, or anchoring biases, where clinicians attribute symptoms to another possible etiology. This outcome can be morbid, but can often be conservatively managed with observation. PMID- 25025759 TI - The neurophysiology of tone: the role of the muscle spindle and the stretch reflex. AB - The excitability of the stretch reflex is used as a measure of tone. The muscle spindle is the receptor for the stretch reflexes which may be phasic or tonic in nature. This paper provides a theoretical background through an overview of published studies as a basis for the under-standing of the contribution of the muscle spindle to both the phasic and tonic stretch reflexes. PMID- 25025760 TI - The treatment and management of duchenne muscular dystrophy at regency park centre, South australia. AB - This paper describes the treatment and management of boys with Duchenne Muscular Dystrophy at the Regency Park Centre for Young Disabled in Adelaide, South Australia. We have not been convinced that some of the active management programmes advocated else-where are effective. Our philosophies and practices reflect a relaxed environment which emphasises achievement and freedom of choice. PMID- 25025762 TI - An initial evaluation of eight abdominal exercises for their ability to provide stabilisation for the lumbar spine. AB - Eight abdominal strengthening exercises were investigated in order to evaluate their ability to promote stabilisation of the lumbar spine. Twenty-three healthy volunteers aged between 18 and 32 participated in the study. During each of the selected exercises, surface electromyography was used to measure the level of motor unit activity in the right upper rectus abdominis, the right lower rectus abdominis, the right oblique abdominis and right lumbar para-vertebral muscles. A formula, based on the relative importance of each muscle in the proposed stability pattern was devised and used to give a single 'stability' score in order to compare each of the eight exercises tested. Results indicated that the exercises which involved applied rotatory resistance to the trunk appeared to activate a more appropriate stability pattern for the lumbar spine. PMID- 25025761 TI - Association between reproductive factors and age-related macular degeneration in postmenopausal women: the Korea National Health and Nutrition Examination Survey 2010-2012. AB - PURPOSE: To examine the association between female reproductive factors and age related macular degeneration (AMD) in postmenopausal women. DESIGN: Nationwide population-based cross-sectional study. METHODS: A nationally representative dataset acquired from the 2010-2012 Korea National Health and Nutrition Examination Survey was analyzed. The dataset involved information for 4,377 postmenopausal women aged >=50 years with a fundus photograph evaluable for AMD in either eye. All participants were interviewed using standardized questionnaires to determine reproductive factors including menstruation, pregnancy, parity, lactation, and hormonal use. The association between reproductive factors and each type of AMD was investigated. RESULTS: The mean age of the study participants was 63.1+/-0.2 years. Mean ages at menarche and menopause were 16.1+/-0.0 and 49.2+/-0.1 years, respectively. The overall prevalence rates of early and late AMD were 11.2% (95% confidence interval [CI], 10.1-12.5) and 0.8% (95% CI, 0.5-1.2), respectively. When adjusted for age, neither smoking nor alcohol use was associated with the presence of any AMD or late AMD. Multivariate logistic regression analysis revealed age (OR, 1.12 per 1 year), duration of lactation (OR, 0.91 per 6 months), and duration of use of oral contraceptive pills (OCP) (OR, 1.10 per 6 months) as associated factors for late AMD. The other variables did not yield a significant correlation with the risk of any AMD or late AMD. CONCLUSION: After controlling for confounders, a longer duration of lactation appeared to protect against the development of late AMD. A longer duration of OCP use was associated with a higher risk of late AMD. PMID- 25025763 TI - The percentage of inspired oxygen at different flow rates during nebulisation. AB - The aim of this study was to determine the mean value for the fraction of inspired oxygen (FiO2) in normal subjects at oxygen flow rates of 2L/min, 4L/min and 6L/min during mouthpiece nebulisation. The FiO2 was defined as the fractional extraction of oxygen at the mouth. The variation in the FiO2 during normal and deep breathing was also studied in order to assess whether a significant difference in the FiO2 occurred. Breathing at a normal tidal volume, the values of the FiO2 were 27.5 per cent, 30.8 per cent and 34.9 per cent respectively. The values during deep breathing were 24.4 per cent, 27.9 per cent and 31.3 per cent respectively. It was clearly evident that the FiO2 during deep breathing was approximately 3 per cent less than that during normal tidal breathing. PMID- 25025764 TI - HIV infection and AIDS: A guide for physiotherapists. AB - Physiotherapists need to be informed about the nature of HIV infection and AIDS, both as care providers and in terms of occupational health and safety. An overview of the natural history of the human immunodeficiency virus and the consequences of infection is given. Safety procedures are outlined and the contribution that physiotherapists can make to the health maintenance of HIV infected patients is briefly described. PMID- 25025765 TI - Why do students enrol in the physiotherapy course? A study of students at SAIT. AB - This study used a questionnaire to determine the reasons students gave for enrolling in the course for Bachelor of Applied Science in Physiotherapy at the South Australian Institute of Technology, and the sources of information students had received about the profession. The most common reason given was that students felt the work would be interesting, satisfying and worthwhile; job availability and security, and a desire to help others also rated highly. Very few students had enrolled on the advice of parents, teachers or career guidance counsellors, although almost one-third had spoken to a counsellor. Working conditions were more important to the male students, while female students gave slightly more import to the desire to work with others. The age of the students had little effect on their reasons for entering the course. It is possible that some students did not have a full appreciation of the work of physiotherapists, nor their working conditions. Such a lack of knowledge may lead to students withdrawing from the course when they are enlightened. PMID- 25025766 TI - Genetic mutation analysis of human gastric adenocarcinomas using ion torrent sequencing platform. AB - Gastric cancer is the one of the major causes of cancer-related death, especially in Asia. Gastric adenocarcinoma, the most common type of gastric cancer, is heterogeneous and its incidence and cause varies widely with geographical regions, gender, ethnicity, and diet. Since unique mutations have been observed in individual human cancer samples, identification and characterization of the molecular alterations underlying individual gastric adenocarcinomas is a critical step for developing more effective, personalized therapies. Until recently, identifying genetic mutations on an individual basis by DNA sequencing remained a daunting task. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent sequencing platform, makes DNA sequencing cheaper, faster, and more reliable. In this study, we aim to identify genetic mutations in the genes which are targeted by drugs in clinical use or are under development in individual human gastric adenocarcinoma samples using Ion Torrent sequencing. We sequenced 737 loci from 45 cancer-related genes in 238 human gastric adenocarcinoma samples using the Ion Torrent Ampliseq Cancer Panel. The sequencing analysis revealed a high occurrence of mutations along the TP53 locus (9.7%) in our sample set. Thus, this study indicates the utility of a cost and time efficient tool such as Ion Torrent sequencing to screen cancer mutations for the development of personalized cancer therapy. PMID- 25025767 TI - De novo transcriptome assembly from inflorescence of Orchis italica: analysis of coding and non-coding transcripts. AB - The floral transcriptome of Orchis italica, a wild orchid species, was obtained using Illumina RNA-seq technology and specific de novo assembly and analysis tools. More than 100 million raw reads were processed resulting in 132,565 assembled transcripts and 86,079 unigenes with an average length of 606 bp and N50 of 956 bp. Functional annotation assigned 38,984 of the unigenes to records present in the NCBI non-redundant protein database, 32,161 of them to Gene Ontology terms, 15,775 of them to Eukaryotic Orthologous Groups (KOG) and 7,143 of them to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The in silico expression analysis based on the Fragments Per Kilobase of transcript per Million mapped reads (FPKM) was confirmed by real-time RT-PCR experiments on 10 selected unigenes, which showed high and statistically significant positive correlation with the RNA-seq based expression data. The prediction of putative long non coding RNAs was assessed using two different software packages, CPC and Portrait, resulting in 7,779 unannotated unigenes that matched the threshold values for both of the analyses. Among the predicted long non-coding RNAs, one is the homologue of TAS3, a long non-coding RNA precursor of trans-acting small interfering RNAs (ta-siRNAs). The differential expression pattern observed for the selected putative long non-coding RNAs suggests their possible functional role in different floral tissues. PMID- 25025768 TI - Inactivating UBE2M impacts the DNA damage response and genome integrity involving multiple cullin ligases. AB - Protein neddylation is involved in a wide variety of cellular processes. Here we show that the DNA damage response is perturbed in cells inactivated with an E2 Nedd8 conjugating enzyme UBE2M, measured by RAD51 foci formation kinetics and cell based DNA repair assays. UBE2M knockdown increases DNA breakages and cellular sensitivity to DNA damaging agents, further suggesting heightened genomic instability and defective DNA repair activity. Investigating the downstream Cullin targets of UBE2M revealed that silencing of Cullin 1, 2, and 4 ligases incurred significant DNA damage. In particular, UBE2M knockdown, or defective neddylation of Cullin 2, leads to a blockade in the G1 to S progression and is associated with delayed S-phase dependent DNA damage response. Cullin 4 inactivation leads to an aberrantly high DNA damage response that is associated with increased DNA breakages and sensitivity of cells to DNA damaging agents, suggesting a DNA repair defect is associated. siRNA interrogation of key Cullin substrates show that CDT1, p21, and Claspin are involved in elevated DNA damage in the UBE2M knockdown cells. Therefore, UBE2M is required to maintain genome integrity by activating multiple Cullin ligases throughout the cell cycle. PMID- 25025769 TI - Assembly of the type two secretion system in Aeromonas hydrophila involves direct interaction between the periplasmic domains of the assembly factor ExeB and the secretin ExeD. AB - The type two secretion system is a large, trans-envelope apparatus that secretes toxins across the outer membrane of many Gram-negative bacteria. In Aeromonas hydrophila, ExeA interacts with peptidoglycan and forms a heteromultimeric complex with ExeB that is required for assembly of the ExeD secretin of the secretion system in the outer membrane. While the peptidoglycan-ExeAB (PG-AB) complex is required for ExeD assembly, the assembly mechanism remains unresolved. We analyzed protein-protein interactions to address the hypothesis that ExeD assembly in the outer membrane requires direct interaction with the PG-AB complex. Yeast and bacterial two hybrid analyses demonstrated an interaction between the periplasmic domains of ExeB and ExeD. Two-codon insertion mutagenesis of exeD disrupted lipase secretion, and immunoblotting of whole cells demonstrated significantly reduced secretin in mutant cells. Mapping of the two codon insertions and deletion analysis showed that the ExeB-ExeD interaction involves the N0 and N1 subdomains of ExeD. Rotational anisotropy using the purified periplasmic domains of ExeB and ExeD determined that the apparent dissociation constant of the interaction is 1.19+/-0.16 uM. These results contribute important support for a putative mechanism by which the PG-AB complex facilitates assembly of ExeD through direct interaction between ExeB and ExeD. Furthermore, our results provide novel insight into the assembly function of ExeB that may contribute to elucidating the role of homologous proteins in secretion of toxins from other Gram negative pathogens. PMID- 25025770 TI - Dual fluorescent reporter pig for Cre recombination: transgene placement at the ROSA26 locus. AB - We are extending the Cre/loxP site-specific recombination system to pigs, focussing on conditional and tissue-specific expression of oncogenic mutations to model human cancers. Identifying the location, pattern and extent of Cre recombination in vivo is an important aspect of this technology. Here we report pigs with a dual fluorochrome cassette under the control of the strong CAG promoter that switches expression after Cre-recombination, from membrane-targeted tandem dimer Tomato to membrane-targeted green fluorescent protein. The reporter cassette was placed at the porcine ROSA26 locus by conventional gene targeting using primary mesenchymal stem cells, and animals generated by nuclear transfer. Gene targeting efficiency was high, and analysis of foetal organs and primary cells indicated that the reporter is highly expressed and functional. Cre reporter pigs will provide a multipurpose indicator of Cre recombinase activity, an important new tool for the rapidly expanding field of porcine genetic modification. PMID- 25025771 TI - Fast and sequence-specific palladium-mediated cross-coupling reaction identified from phage display. AB - Fast and specific bioorthogonal reactions are highly desirable because they provide efficient tracking of biomolecules that are present in low abundance and/or involved in fast dynamic process in living systems. Toward this end, classic strategy involves the optimization of substrate structures and reaction conditions in test tubes, testing their compatibility with biological systems, devising synthetic biology schemes to introduce the modified substrates into living cells or organisms, and finally validating the superior kinetics for enhanced capacity in tracking biomolecules in vivo--a lengthy process often mired by unexpected results. Here, we report a streamlined approach in which the "microenvironment" of a bioorthogonal chemical reporter is exploited directly in biological systems via phage-assisted interrogation of reactivity (PAIR) to optimize not only reaction kinetics but also specificity. Using the PAIR strategy, we identified a short alkyne-containing peptide sequence showing fast kinetics (k2=13,000+/-2000 M(-1) s(-1)) in a palladium-mediated cross-coupling reaction. Site-directed mutagenesis studies suggested that the residues surrounding the alkyne moiety facilitate the assembly of a key palladium-alkyne intermediate along the reaction pathway. When this peptide sequence was inserted into the extracellular domain of epidermal growth factor receptor (EGFR), this reactive sequence directed the specific labeling of EGFR in live mammalian cells. PMID- 25025772 TI - Lactate and the lactate-to-pyruvate molar ratio cannot be used as independent biomarkers for monitoring brain energetic metabolism: a microdialysis study in patients with traumatic brain injuries. AB - BACKGROUND: For decades, lactate has been considered an excellent biomarker for oxygen limitation and therefore of organ ischemia. The aim of the present study was to evaluate the frequency of increased brain lactate levels and the LP ratio (LPR) in a cohort of patients with severe or moderate traumatic brain injury (TBI) subjected to brain microdialysis monitoring to analyze the agreement between these two biomarkers and to indicate brain energy metabolism dysfunction. METHODS: Forty-six patients with an admission Glasgow coma scale score of <=13 after resuscitation admitted to a dedicated 10-bed Neurotraumatology Intensive Care Unit were included, and 5305 verified samples of good microdialysis data were analyzed. RESULTS: Lactate levels were above 2.5 mmol/L in 56.9% of the samples. The relationships between lactate and the LPR could not be adequately modeled by any linear or non-linear model. Neither Cohen's kappa nor Gwet's statistic showed an acceptable agreement between both biomarkers to classify the samples in regard to normal or abnormal metabolism. The dataset was divided into four patterns defined by the lactate concentrations and the LPR. A potential interpretation for these patterns is suggested and discussed. Pattern 4 (low pyruvate levels) was found in 10.7% of the samples and was characterized by a significantly low concentration of brain glucose compared with the other groups. CONCLUSIONS: Our study shows that metabolic abnormalities are frequent in the macroscopically normal brain in patients with traumatic brain injuries and a very poor agreement between lactate and the LPR when classifying metabolism. The concentration of lactate in the dialysates must be interpreted while taking into consideration the LPR to distinguish between anaerobic metabolism and aerobic hyperglycolysis. PMID- 25025773 TI - Detecting kinase activities from single cell lysate using concentration-enhanced mobility shift assay. AB - Electrokinetic preconcentration coupled with mobility shift assays can give rise to very high detection sensitivities. We describe a microfluidic device that utilizes this principle to detect cellular kinase activities by simultaneously concentrating and separating substrate peptides with different phosphorylation states. This platform is capable of reliably measuring kinase activities of single adherent cells cultured in nanoliter volume microwells. We also describe a novel method utilizing spacer peptides that significantly increase separation resolution while maintaining high concentration factors in this device. Thus, multiplexed kinase measurements can be implemented with single cell sensitivity. Multiple kinase activity profiling from single cell lysate could potentially allow us to study heterogeneous activation of signaling pathways that can lead to multiple cell fates. PMID- 25025775 TI - 5-Lipoxygenase activating protein (FLAP) dependent leukotriene biosynthesis inhibition (MK591) attenuates Lipid A endotoxin-induced inflammation. AB - The Lipid A moiety of endotoxin potently activates TLR-4 dependent host innate immune responses. We demonstrate that Lipid-A mediated leukotriene biosynthesis regulates pathogen-associated molecular patterns (PAMP)-dependent macrophage activation. Stimulation of murine macrophages (RAW264.7) with E. coli 0111:B4 endotoxin (LPS) or Kdo2-lipid A (Lipid A) induced inflammation and Lipid A was sufficient to induce TLR-4 mediated macrophage inflammation and rapid ERK activation. The contribution of leukotriene biosynthesis was evaluated with a 5 lipoxygenase activating protein (FLAP) inhibitor, MK591. MK591 pre-treatment not only enhanced but also sustained ERK activation for up to 4 hours after LPS and Lipid A stimulation while inhibiting cell proliferation and enhancing cellular apoptosis. Leukotriene biosynthesis inhibition attenuated inflammation induced by either whole LPS or the Lipid A fraction. These responses were regulated by inhibition of the key biosynthesis enzymes for the proinflammatory eicosanoids, 5 lipoxygenase (5-LO), and cyclooxygenase-2 (COX-2) quantified by immunoblotting. Inhibition of leukotriene biosynthesis differentially regulated TLR-2 and TLR-4 cell surface expression assessed by flow cytometry, suggesting a close mechanistic association between TLR expression and 5-LO associated eicosanoid activity in activated macrophages. Furthermore, MK591 pre-treatment enhanced ERK activation and inhibited cell proliferation after LPS or Lipid A stimulation. These effects were regulated in part by increased apoptosis and modulation of cell surface TLR expression. Together, these data clarify the mechanistic association between 5-lipoxygenase activating protein-mediated leukotriene biosynthesis and 5-LO dependent eicosanoid metabolites in mediating the TLR dependent inflammatory response after endotoxin exposure typical of bacterial sepsis. PMID- 25025776 TI - Looking beyond technology: an integrated approach to water, sanitation and hygiene in low income countries. PMID- 25025777 TI - Muscle magnetic resonance imaging of the lower limbs: valuable diagnostic tool in the investigation of childhood neuromuscular disorders. AB - Children presenting with neuromuscular symptoms are subject to exhaustive investigations. As it is noninvasive, muscle magnetic resonance imaging (MRI) is an important diagnostic tool in children, yet its impact has so far been mainly studied in small groups of genetically defined diseases, where specific MRI patterns are known. To assess the contribution of muscle MRI of the lower limbs in a diverse cohort of patients, we reviewed the diagnostic findings in 39 patients with a suspected neuromuscular disorder that underwent muscle MRI (28/39), biopsy (26/39), or both (18/39). MRI was performed without sedation in 26 of 28 patients at a mean age of 10 years (range, 1-27 years). In 10 of 28 cases (35%), MRI significantly contributed to the final diagnosis, and in 7 of 28 cases (25%), muscle MRI directly instructed genetic testing. These cases included Bethlem myopathy, laminopathy, calpainopathy, and RYR1-related myopathies. Muscle MRI serves as a valuable additional tool to guide diagnosis in suspected neuromuscular disorders in children, especially in cases with nonspecific biopsy findings. PMID- 25025779 TI - Phosphorylation of coat protein by protein kinase CK2 regulates cell-to-cell movement of Bamboo mosaic virus through modulating RNA binding. AB - In this study, we investigated the fine regulation of cell-to-cell movement of Bamboo mosaic virus (BaMV). We report that the coat protein (CP) of BaMV is phosphorylated in planta at position serine 241 (S241), in a process involving Nicotiana benthamiana casein kinase 2alpha (NbCK2alpha). BaMV CP and NbCK2alpha colocalize at the plasmodesmata, suggesting that phosphorylation of BaMV may be involved in its movement. S241 was mutated to examine the effects of temporal and spatial dysregulation of phosphorylation on i) the interactions between CP and viral RNA and ii) the regulation of cell-to-cell movement. Replacement of S241 with alanine did not affect RNA binding affinity but moderately impaired cell-to cell movement. A negative charge at position 241 reduced the ability of CP to bind RNA and severely interfered with cell-to-cell movement. Deletion of residues 240 to 242 increased the affinity of CP to viral RNA and dramatically impaired cell-to-cell movement. A threonine at position 241 changed the binding preference of CP toward genomic RNA and inhibited cell-to-cell movement. Together, these results reveal a fine regulatory mechanism for the cell-to-cell movement of BaMV, which involves the modulation of RNA binding affinity through appropriate phosphorylation of CP by NbCK2alpha. PMID- 25025778 TI - Characterization of a putative spindle assembly checkpoint kinase Mps1, suggests its involvement in cell division, morphogenesis and oxidative stress tolerance in Candida albicans. AB - In Saccharomyces cerevisiae MPS1 is one of the major protein kinase that governs the spindle checkpoint pathway. The S. cerevisiae structural homolog of opportunistic pathogen Candida albicans CaMPS1, is indispensable for the cell viability. The essentiality of Mps1 was confirmed by Homozygote Trisome test. To determine its biological function in this pathogen conditional mutant was generated through regulatable MET3 promoter. Examination of heterozygous and conditional (+Met/Cys) mps1 mutants revealed a mitosis specific arrest phenotype, where mutants showed large buds with undivided nuclei. Flowcytometry analysis revealed abnormal ploidy levels in mps1 mutant. In presence of anti-microtubule drug Nocodazole, mps1 mutant showed a dramatic loss of viability suggesting a role of Mps1 in Spindle Assembly Checkpoint (SAC) activation. These mutants were also defective in microtubule organization. Moreover, heterozygous mutant showed defective in-vitro yeast to hyphae morphological transition. Growth defect in heterozygous mutant suggest haploinsufficiency of this gene. qRT PCR analysis showed around 3 fold upregulation of MPS1 in presence of serum. This expression of MPS1 is dependent on Efg1 and is independent of other hyphal regulators like Ras1 and Tpk2. Furthermore, mps1 mutants were also sensitive to oxidative stress. Heterozygous mps1 mutant did not undergo morphological transition and showed 5 Fold reduction in colony forming units in response to macrophage. Thus, the vital checkpoint kinase, Mps1 besides cell division also has a role in morphogenesis and oxidative stress tolerance, in this pathogenic fungus. PMID- 25025780 TI - Inheritance of prehaustorial resistance to Puccinia graminis f. sp. avenae in barley (Hordeum vulgare L.). AB - Rust pathogens within the genus Puccinia cause some of the most economically significant diseases of crops. Different formae speciales of P. graminis have co evolved to mainly infect specific grass hosts; however, some genotypes of other closely related cereals can also be infected. This study investigated the inheritance of resistance to three diverse pathotypes of the oat stem rust pathogen (P. graminis f. sp. avenae) in the 'Yerong' ? 'Franklin' (Y/F) barley doubled haploid (DH) population, a host with which it is not normally associated. Both parents, 'Yerong' and 'Franklin', were immune to all P. graminis f. sp. avenae pathotypes; however. there was transgressive segregation within the Y/F population, in which infection types (IT) ranged from complete immunity to mesothetic susceptibility, suggesting the presence of heritable resistance. Both QTL and marker-trait association (MTA) analysis was performed on the Y/F population to map resistance loci in response to P. graminis f. sp. avenae. QTL on chromosome 1H ('Yerong' Rpga1 and Rpga2) were identified using all forms of analysis, while QTL detected on 5H ('Franklin' Rpga3 and Rpga4) and 7H (Rpga5) were only detected using MTA or composite interval mapping-single marker regression analysis respectively. Rpga1 to Rpga5 were effective in response to all P. graminis f. sp. avenae pathotypes used in this study, suggesting resistance is not pathotype specific. Rpga1 co-located to previously mapped QTL in the Y/F population for adult plant resistance to the barley leaf scald pathogen (Rhynchosporium secalis) on chromosome 1H. Histological evidence suggests that the resistance observed within parental and immune DH lines in the population was prehaustorial and caused by callose deposition within the walls of the mesophyll cells, preventing hyphal penetration. PMID- 25025781 TI - Comparative and functional analysis of the widely occurring family of Nep1-like proteins. AB - Nep1-like proteins (NLP) are best known for their cytotoxic activity in dicot plants. NLP are taxonomically widespread among microbes with very different lifestyles. To learn more about this enigmatic protein family, we analyzed more than 500 available NLP protein sequences from fungi, oomycetes, and bacteria. Phylogenetic clustering showed that, besides the previously documented two types, an additional, more divergent, third NLP type could be distinguished. By closely examining the three NLP types, we identified a noncytotoxic subgroup of type 1 NLP (designated type 1a), which have substitutions in amino acids making up a cation-binding pocket that is required for cytotoxicity. Type 2 NLP were found to contain a putative calcium-binding motif, which was shown to be required for cytotoxicity. Members of both type 1 and type 2 NLP were found to possess additional cysteine residues that, based on their predicted proximity, make up potential disulfide bridges that could provide additional stability to these secreted proteins. Type 1 and type 2 NLP, although both cytotoxic to plant cells, differ in their ability to induce necrosis when artificially targeted to different cellular compartments in planta, suggesting they have different mechanisms of cytotoxicity. PMID- 25025782 TI - beta-Aminobutyric acid (BABA)-induced resistance in Arabidopsis thaliana: link with iron homeostasis. AB - beta-Aminobutyric acid (BABA) is a nonprotein amino acid inducing resistance in many different plant species against a wide range of abiotic and biotic stresses. Nevertheless, how BABA primes plant natural defense reactions remains poorly understood. Based on its structure, we hypothesized and confirmed that BABA is able to chelate iron (Fe) in vitro. In vivo, we showed that it led to a transient Fe deficiency response in Arabidopsis thaliana plants exemplified by a reduction of ferritin accumulation and disturbances in the expression of genes related to Fe homeostasis. This response was not correlated to changes in Fe concentrations, suggesting that BABA affects the availability or the distribution of Fe rather than its assimilation. The phenotype of BABA-treated plants was similar to those of plants cultivated in Fe-deficient conditions. A metabolomic analysis indicated that both BABA and Fe deficiency induced the accumulation of common metabolites, including p-coumaroylagmatine, a metabolite previously shown to be synthesized in several plant species facing pathogen attack. Finally, we showed that the protective effect induced by BABA against Botrytis cinerea was mimicked by Fe deficiency. In conclusion, the Fe deficiency response caused by BABA could bring the plant to a defense-ready state, participating in the plant resistance against the pathogens. PMID- 25025783 TI - A longitudinal survey of the physical fitness of students at caulfield grammar school, 1969 - 1979 and its effect on other factors. AB - The results of physical fitness tests conducted at Caulfield Grammar School for the last nine years, 1969-1978. However concomitant with these results, other variables such as self esteem, academic performance etc, have been evaluated that perhaps show us that improving a person's level of fitness may also positively affect non-physical variables. It will not be my contention to justify physical education programmes on these grounds, because they need no other justification than that physical activity is a biological need and a pleasurable experience. But realistically it is the academics who control funds, staffing and timetables, so convincing these administrators that academic performance will not suffer from an increase in physical education time may have to be our tack. PMID- 25025784 TI - Therapeutic recreation - a conceptual criticism. AB - This paper has been written as a contribution to the attainment of integration in the field of special recreation. It is an attempt to conceptualise recreation for the disabled against a background of the therapeutic model in order to stimulate debate on the matter. The intention of the argument is to present a description of therapy' and 'recreation' current in Australian society; to show that these concepts are fundamentally different to one another; and to conclude that the concepts cannot be combined in the manner demanded by therapeutic recreation. PMID- 25025785 TI - Physiotherapy in the northern territory. AB - A brief history of health care in the Northern Territory is reviewed to indicate how the present state was derived. PMID- 25025786 TI - Pressure effects on the radical-radical recombination reaction of photochromic bridged imidazole dimers. AB - The bridged imidazole dimers are some of the attractive fast photochromic compounds which have potential applications to the ophthalmic lenses, real-time hologram and molecular machines. The strategy for expanding their photochromic properties such as the colour variation and tuning the decolouration rates has been vigorously investigated, but the insight into the structural changes along the photochromic reactions has not been demonstrated in detail. Here, we demonstrated the pressure dependence of the radical-radical recombination reaction of the bridged imidazole dimers. The radical-radical interaction can be controlled by applying high pressure. Our results give fundamental information about the molecular dynamics of the bridged imidazole dimers, leading to the development of new functional photochromic machines and pressure-sensitive photochromic materials. PMID- 25025787 TI - Exposure to arsenic and intra-chromosomal instability in blood. AB - The 450k Chip Analysis Methylation Pipeline (ChAMP) is a novel Illumina Infinium HumanMethylation450 BeadChip data processing algorithm that allows the analysis of copy number alterations (CNAs). With this pipeline we evaluated the prevalence of CNAs in peripheral blood leukocyte samples from healthy Argentinean Andean women with varying exposure to inorganic arsenic in drinking water. Arsenic exposure was assessed based on the sum concentrations of metabolites of inorganic arsenic in urine (U-As), which ranged from 10-663 MUg L(-1) with a median of 185 MUg L(-1). We used linear regression analysis to elucidate the association between U-As and the prevalence of CNAs. We found that increasing arsenic exposure was positively associated with the frequency of CNAs (p = 0.002), possibly in a dose-response relationship. Adjustment of the regression model for age and BMI of the subjects did not significantly change the effect estimate, although both covariates were significant predictors. Our results suggest that exposure to arsenic increases genomic instability in the form of CNAs. PMID- 25025788 TI - Haemodynamic stability of the ventilated intensive care patient: A review. AB - One of the major reasons for admission to an intensive care unit is haemodynamic instability. It is important for physiotherapists to recognize and predict haemodynamic instability when planning intervention in these patients. This paper reviews the existing literature on haemodynamic effects of physiotherapy in ventilated intensive care patients. Recommendations are made for further research, including multi-centre documentation, attainment of normal data and single case studies in this area. PMID- 25025789 TI - Dynamic pulmonary hyperinflation. AB - Hyperinflation is a compensatory mechanism which occurs in response to increased resistance of the airways. Hyperinflation allows for an increase in minute ventilation and improves the efficiency of the inspiratory intercostals. However, there are detrimental effects on the function of the diaphragm and the accessory muscles, which increase the work of breathing. The physiotherapist's inital goal is to enhance the action of the respiratory muscles and not to select strategies that will interfere with this compensatory mechanism. Once the underlying problem is stabilised, the physiotherapist may then use strategies which assist with the reversal of the problem. PMID- 25025790 TI - Sleep and respiration: Implications for pulmonary rehabilitation. AB - Despite the growing interest in the role of the inspiratory and accessory muscles of respiration in chronic respiratory disease, few therapists have considered the role sleep may play in the deterioration of a patient's clinical condition. A number of important physiological changes to respiration occur during sleep, which affect chest wall mechanics and gas exchange. The ensuing abnormalities caused by sleep hypoventilation and fragmentation can severely affect daytime function and wellbeing. Nocturnal nasal positive pressure ventilation (NIPPV) is now established as an effective means of preventing such changes in patients with chest wall and lung disease. Therapists involved in pulmonary rehabilitation programs must recognise the potential for nocturnal respiratory events to severely affect daytime function and understand the importance of reversing nocturnal respiratory failure in order to maximise the rehabilitation potential of patients. PMID- 25025791 TI - An evaluation of three elements of pulmonary rehabilitation. AB - In this study of 39 patients with severe chronic airflow limitation, an independent group design examined the effect on exercise performance of a six week program of leg muscle training, inspiratory muscle training and postural drainage. Exercise performance was reassessed at three months after the completion of the training program. MANOVA analysis of the 12-minute walking distance test showed a significant training effect (p < 0.001) with the largest effect occurring with leg muscle training (873 to 952 metres), a placebo response with postural drainage (886 to 925 metres) and minimal change with inspiratory muscle training (911 to 920 metres). There was a carry over effect at three months with leg muscle training, that was not seen in the other groups. PMID- 25025792 TI - The effects of exercise rehabilitation on perceived self-efficacy. AB - The influence of exercise rehabilitation on quality of life in patients with cardiac pathology, chronic airflow limitation and healthy controls was investigated. Eleven patients with cardiac pathology, 12 patients with chronic airflow limitation and 10 healthy controls participated in the research. They completed self-efficacy and happiness questionnaires prior to and following eight weeks of supervised exercise conditioning. Results demonstrated a significant improvement in physical efficacy in patients with cardiac pathology and chronic airflow limitation but not controls. Emotional efficacy improved significantly in healthy controls and patients with chronic airflow limitation but not those with cardiac pathology. Happiness was unchanged in all groups. PMID- 25025793 TI - EMG recordings of the respiratory muscles during unilateral and bilateral chest expansion. AB - Respiratory muscle (RM) EMG was recorded in 10 healthy adults during bilateral and voluntary unilateral inspiration. Each performed bilateral and unilateral inspiration at 50, 75 and 100 per cent of maximal inspiration (PI max) measured with a mouth pressure gauge. The obliquus externus abdominus (EAO) EMG was also recorded in five subjects. Results showed that RM and EAO activity on the expanding side was similar during all levels of effort. The RM activity on the non-contracting side during most submaximal efforts was higher than that on the same side during bilateral efforts but not during maximal effort. The increase in EMG could be due to cross-talk from EAO and latissimus dorsi, or co-activation of the internal intercostal muscles. Because RM activity at PI max was similar for unilateral and bilateral efforts, it was concluded that voluntary unilateral RM inhibition may not be possible during maximal effort. PMID- 25025794 TI - Peak expiratory flow rates produced with the Laerdal and Mapleson-C bagging circuits. AB - This study compared the peak expiratory flow rates (PEFR) at different inspiratory pause pressures (IPP) produced by the Mapleson-C circuit and the Laerdal self-inflating resuscitator. The difference in PEFR produced by the two circuits was significantly different at the lowest and the highest IPP studied (I3 and 38cm H20). The greatest differences in the mean expiratory flow rates produced was, however, only 0.07 litre sec(-7). The authors suggest that the choice of bagging circuit should depend on the experience and familiarity of the therapist with the circuit. PMID- 25025795 TI - The use of hypnosis for pain relief for patients with polyradiculoneuritis. AB - At the Royal Perth Hospital, pain during physiotherapy range of movement and muscle stretching exercises has been a significant problem for some patients who have had polyradiculoneuritis, otherwise known as the Guillain-Barre Syndrome (GBS). Anxiety often accompanies GBS and can exacerbate the experience of pain. Regular analgesics have failed to adequately control the patients' pain such that full range of movement has been impossible and soft tissue shortening has occurred. Recently, alternative pain control in the form of hypnotherapy has been used during physiotherapy sessions. Two case studies are presented as examples of the use of hypnotherapy at the Royal Perth Hospital. These describe the benefit of hypnotherapy for pain control in some patients who have GBS. PMID- 25025797 TI - Physiotherapy - a response to challenge. AB - What I propose to do tonight is to look briefly at the history of physiotherapy in Australia, the factors that have determined its development, and the present challenge to the profession. PMID- 25025796 TI - [Follow-up of endometrial cancer]. AB - Available data on appropriate follow-up in endometrial cancer highlight the need of well-conducted studies. Most recurrences tend to occur within three years and involve symptoms. Routine tests are not advocated without symptoms. In case of suspicious recurrence, TEP/CT seems to be the most sensitive and specific method. There is limited evidence to decide whether follow-up schedules with multiple visits result in survival benefits. An appropriate follow-up should be discussed based upon the risk of recurrence. Counselling on the potential symptoms of recurrence should be a major aim. PMID- 25025798 TI - Congenital abnormalities - what goes wrong in the embryo? AB - Most physiotherapists, in due course, are asked to take part in the management of a child with a congenital deformity. Involvement with such a child inevitably provokes the question "Why was this child born handicapped?" In other words, what went wrong in the embryo to result in this birth defect? PMID- 25025799 TI - Preventive physiotherapy in schools. AB - Discussion of preventive physiotherapy in schools should cover many issues-nearly all specialist fields. These should include anthropometry and ergonomics in relation to furniture design (Oxford, 1971), and in relation to the prevention of postural defects. Consideration of postural defects should also cover screening of ten to eleven year old girls for early detection of scoliosis. Asthma and other chest conditions, as well as general orthopaedic conditions, should also be included. PMID- 25025800 TI - Abnormal growth and development resulting from disease, trauma and deformity. AB - There are two concepts which interest me particularly in the field of paediatric physiotherapy. One is the prevention of abnormalities of growth and development; the other is the enrichment of development. PMID- 25025801 TI - Reappraisal of the early treatment of hemiplegia in adults. AB - The presence of large numbers of post stroke patients sitting in nursing homes in front of television is not a refutation of the value of rehabilitation, but a demonstration of a general attitude of medical and nursing staff to stroke, coupled with an unawareness of the importance of immediate referral from the medical practitioner. This attitude persists despite reference to the importance of early treatment in the literature. Following a survey in Belfast, Adams and Merrett (1961) wrote "the earlier physical retraining began the better". Sommerville (1968) and others similarly stress the importance of early treatment. PMID- 25025802 TI - Neck and back injuries in sport. AB - The Sports and Soft Tissue Injury Clinic is attached to the physiotherapy department of the Royal Perth (Rehabilitation) Hospital, and began in a small way in 1969. The clinic's patient load has increased by about one-third each year. We now treat about 200 patients per month. PMID- 25025803 TI - Acute locking of the cervical spine. AB - Acute locking of the cervical spine is a very clearly defined syndrome, occurring most commonly in adolescents. This syndrome is not to be confused with the locking of joints which can occur as a result of "loose bodies" or torn menisci. The syndrome has a typical history, protective deformity and a reasonably consistent site of pain. PMID- 25025804 TI - A study of the effectiveness of physiotherapy in the management of young children with minimal cerebral dysfunction. AB - Minimal cerebral dysfunction (MCD) is one of many terms used to describe the syndrome exhibited by children who demonstrate mild abnormalities on clinical neurological assessment. The neurological signs of minimal cerebral dysfunction are manifested in the nature of the reflex and automatic sensory responses as well as in the motor responses to specific stimulations. Those reactions which persist beyond the normal age for their integration, together with other mild signs of neurological dysfunction are also symptomatic of minimal cerebral dysfunction. PMID- 25025805 TI - Some aspects of acceleration extension syndromes. AB - Crowe (1928) first used the word whiplash to describe cervical strains which had been caused by extension type injuries due to sudden acceleration. They were found to heal very slowly and hence the word whiplash soon became synonymous with irreparable damage, continuous pain and residual disability. PMID- 25025806 TI - Problems of sensory integration in the mentally retarded child and their implications for the physiotherapist. AB - Affecting some 2.5-3.5% of the general population (Smith, 1971), mental retardation is an important national health, social and economic problem, with only four disabling conditions (cancer, arthritis, cardiac disease and mental illness) having higher incidence (Love, 1973). Of these conditions only mental retardation is prevalent in the early developmental period of life. PMID- 25025807 TI - Relaxation theory and practice. AB - This paper reviews the theoretical aspects of clinical use of relaxation and the problems inherent in its application in a hospital setting. It discusses the relative usefulness of relaxation procedures in various conditions. This includes the advantages versus the disadvantages of group practice, the use of audio casettes, specificity of instructions and interdisciplinary aspects of patient care. Some guidelines are provided for the practice of relaxation by physiotherapists. PMID- 25025808 TI - Postnatal survey. AB - It is widely accepted that part of the work of obstetric physiotherapists is to rehabilitate abdominal and pelvic floor muscles weakened by pregnancy and vaginal delivery. PMID- 25025810 TI - Bilateral lower limb amputation - an exercise in rehabilitation. AB - There is little need to stress the limitations imposed by functional deficits involving both lower limbs. At best the ability to walk on level surfaces is reduced and the ability to climb up and down is restricted. Older patients may become dependent on help for some of the normal activities of everyday life. Younger patients may be unable to earn a living. For both there is the fundamental loss of dignity associated with personal dependence. For the community there is the economic burden of an ever increasing number of people who are non-productive and require individual assistance. The numbers who are surviving amputation of both lower limbs is increasing, and the problem is therefore acquiring a degree of urgency. PMID- 25025809 TI - Promoter analysis of the gene encoding GDNF in murine Sertoli cells. AB - GDNF is a Sertoli-cell-derived factor that controls the balance between self renewal and differentiation of the spermatogonial stem cells. Although research in recent years has concentrated on the impact of GDNF on target germ cells rather little attention has been paid to the molecular control of GDNF expression in Sertoli cells. Here, we aimed to characterize the promoter region of the mouse gdnf gene active in Sertoli cells. We identified the transcriptional start sites and analyzed the promoter activity of the 5'-flanking regions. By in-silico analysis of evolutionarily conserved DNA sequences we identified several putative transcription factor-binding regions. Deletion analysis showed the involvement of the three CRE sites for basal and cAMP-induced expression of gdnf in murine Sertoli cells. These results provide the basis for future studies to analyze how hormonal or paracrine signals modulate the transcriptional activity of gdnf in Sertoli cells. PMID- 25025811 TI - Physiotherapy in a coronary care unit. AB - Most of the major hospitals throughout the world are opening coronary care units and the physiotherapist is expected to play a part in this new field of cardiac rehabilitation. The School of Physiotherapy in Sydney, together with the Occupational Therapists and Social Workers, was asked by the staff cardiologists in the professorial cardiac unit to submit a suitable cardiac rehabilitation programme which would be incorporated in a pilot study in coronary care to commence in the new year. PMID- 25025812 TI - Removal of plaster of paris by means of a schismostat. AB - The Schismostat is the result of experiments to remove plaster casts quickly and without fear of injury to the patient, with the emphasis on safety. Cutting equipment, particularly the blade of an electric saw, frequently causes damage. The Schismostat can be used on plasters as soon as they are applied, and it does not matter whether they are padded or not. The technique does require, however, that the plaster be applied in a particular manner. PMID- 25025813 TI - Breastfeeding, early brain development, and epigenetics--getting children off to their best start. PMID- 25025814 TI - Hydrogen peroxide inactivation of influenza virus preserves antigenic structure and immunogenicity. AB - The use of live virus in the laboratory requires additional precautions, such as personnel training and special equipment, in order to limit the transmission risk. This is a requirement which not all laboratories can fulfill. In this study, a viral inactivation method is introduced using hydrogen peroxide (H2O2), which maintains antigenicity. Three strains of influenza viruses were inactivated and the ex vivo cellular and humoral immune responses were further analyzed, by comparing them to live viruses, in ELISpot, Multiplex and ELISA assays. In all assays, the H2O2 inactivated viruses displayed comparable responses to the live viruses, suggesting that the inactivated viruses still elicited immunogenic responses even though inactivation was confirmed by lack of viral replication in MDCK cells. Taken together, this study demonstrates that influenza viruses inactivated with H2O2 retain immunogenicity and are able to both detect humoral and elicit cellular immune responses in vitro, which could reduce the need to handle live viruses in the laboratory. PMID- 25025815 TI - Simultaneous typing of nine avian respiratory pathogens using a novel GeXP analyzer-based multiplex PCR assay. AB - A new, rapid, and high-throughput GenomeLab Gene Expression Profiler (GeXP) analyzer-based multiplex PCR method was developed for simultaneous detection and differentiation of nine avian respiratory pathogens. The respiratory pathogens included in this study were avian influenza subtypes H5, H7, and H9, infectious bronchitis virus (IBV), Newcastle disease virus (NDV), infectious laryngotracheitis virus (ILTV), Mycoplasma gallisepticum (MG), Mycoplasma synoviae (MS) and Haemophilus paragallinarum (HPG). Ten pairs of primers were designed using conserved and specific sequence genes of AIV subtypes and respiratory pathogens from GenBank. Single and mixed pathogen cDNA/DNA templates were used to evaluate the specificity of the GeXP-multiplex assay. The corresponding specific DNA products were amplified for each pathogen. The specific DNA product amplification peaks of nine respiratory pathogens were observed on the GeXP analyzer. Non-respiratory avian pathogens, including chicken infectious anemia virus, fowl adenovirus, avian reovirus and infectious bursal disease virus, did not produce DNA products. The detection limit for the GeXP multiplex assay was determined to be 100 copies/MUl using various pre-mixed plasmids/ssRNAs containing known target genes of the respiratory pathogens. Further, GeXP-multiplex PCR assay was 100% specific when 24 clinical samples with respiratory infections were tested in comparison with conventional PCR method. The GeXP-multiplex PCR assay provides a novel tool for simultaneous detection and differentiation of nine avian respiratory pathogens. PMID- 25025816 TI - Development of a novel single step reverse genetics system for feline calicivirus. AB - The reverse genetics system is a useful tool to generate infectious virus. Feline calicivirus (FCV), a member of the genus Vesivirus in the family Caliciviridae, has a positive sense, single-stranded RNA genome. Two reverse genetics systems have been established for FCV; however, these methods need multi-steps to produce progeny infectious virus. In this study, a novel plasmid-based single step reverse genetics system for FCV has been developed. The plasmid carries FCV F4 strain genomic sequence with an introduced silent mutation. In addition, at the 5'- and 3'-end, a human elongation factor-1alpha promoter and a cis-acting hepatitis delta virus ribozyme following poly-A, were added, respectively. When the plasmid was transfected into Crandell-Rees feline kidney cells, progeny FCV was generated. The reverse genetics system-derived FCV (rFCV) showed similar growth kinetics and antigenic characteristics and had identical genomic terminals to those of the original FCV F4 strain. The presence of the introduced silent mutation in the rFCV genomic cDNA supported that the progeny virus was originated from the plasmid. This novel FCV reverse genetics system is simple and can be used to evaluate the functions of the viral genome, proteins, and phenotypic characterization of FCV strains in the future. PMID- 25025817 TI - A simple and efficient strategy for the de novo construction of greater-than genome-length hepatitis B virus replicons. AB - Hepatitis B virus (HBV) uses small covalently closed circular DNA for transcription and replication; linearization at any site would destruct at least one HBV open reading frame and interrupt the virus life cycle. Therefore, greater than-genome-length (GGL) HBV replicons have been widely used for HBV replication studies. However, the existing strategies for the de novo construction of GGL HBV replicons are too complex to implement, especially when multiple replicons need to be cloned. In this study, the pHBV-basic plasmid was constructed for efficient cloning of GGL HBV replicons; changing the orientation of the site for type IIs restriction enzyme SapI in this plasmid reduced the de novo construction of various GGL HBV replicons to only one to three steps. Furthermore, Q5 high fidelity DNA polymerase was found to be ideal for HBV genome amplification. In vitro experiments showed that the HBV replicon containing 1.31 genome copies replicated with better efficiency as evidenced by the titers of HBV DNA and HBsAg and HBeAg markers. The vector described in this study could serve as a powerful vehicle for in vitro and in vivo investigation of HBV replication. PMID- 25025818 TI - Towards personalized speech synthesis for augmentative and alternative communication. AB - Text-to-speech options on augmentative and alternative communication (AAC) devices are limited. Often, several individuals in a group setting use the same synthetic voice. This lack of customization may limit technology adoption and social integration. This paper describes our efforts to generate personalized synthesis for users with profoundly limited speech motor control. Existing voice banking and voice conversion techniques rely on recordings of clearly articulated speech from the target talker, which cannot be obtained from this population. Our VocaliD approach extracts prosodic properties from the target talker's source function and applies these features to a surrogate talker's database, generating a synthetic voice with the vocal identity of the target talker and the clarity of the surrogate talker. Promising intelligibility results suggest areas of further development for improved personalization. PMID- 25025819 TI - Purification, crystal structure determination and functional characterization of type III antifreeze proteins from the European eelpout Zoarces viviparus. AB - Antifreeze proteins (AFPs) are essential components of many organisms adaptation to cold temperatures. Fish type III AFPs are divided into two groups, SP isoforms being much less active than QAE1 isoforms. Two type III AFPs from Zoarces viviparus, a QAE1 (ZvAFP13) and an SP (ZvAFP6) isoform, are here characterized and their crystal structures determined. We conclude that the higher activity of the QAE1 isoforms cannot be attributed to single residues, but rather a combination of structural effects. Furthermore both ZvAFP6 and ZvAFP13 crystal structures have water molecules around T18 equivalent to the tetrahedral-like waters previously identified in a neutron crystal structure. Interestingly, ZvAFP6 forms dimers in the crystal, with a significant dimer interface. The presence of ZvAFP6 dimers was confirmed in solution by native electrophoresis and gel filtration. To our knowledge this is the first report of dimerization of AFP type III proteins. PMID- 25025820 TI - A 9 kDa antifreeze protein from the Antarctic springtail, Gomphiocephalus hodgsoni. AB - A 9 kDA antifreeze protein (AFP) was isolated and purified from the Antarctic springtail, Gomphiocephalus hodgsoni. By combining selective sampling procedures and a modified ice affinity purification protocol it was possible to directly isolate a single AFP protein without recourse to chromatographic separation techniques. Mass spectrometry identified a single 9 kDa component in the purified ice fraction. Intramolecular disulphide bonding was suggested by the presence of 12 cysteine residues. The specific amino acid composition is unique, particularly with regard to the presence of histidine (11.5%). But it also shows noticeable commonalities with insect AFPs in the abundance of cysteine (13.8%), while simultaneously hinting, through the presence of glycine (11.5%), that the metabolic building blocks of AFPs in Collembola may have a phylogenetically determined component. PMID- 25025821 TI - What's New in Shock, August 2014? PMID- 25025822 TI - Mirror, mirror on the wall, is off-pump better than on-pump at all? PMID- 25025823 TI - Achieving enhanced visible-light-driven photocatalysis using type-II NaNbO3/CdS core/shell heterostructures. AB - Expanding the light-harvesting range and suppressing the quick recombination of photogenerated charge carriers are of paramount significance in the field of photocatalysis. One possible approach to achieve wide absorption range is to synthesize type-II core/shell heterostructures. In addition, this system also shows great promise for fast separation of charge carriers and low charge recombination rate. Herein, following the surface functionalization method using 3-mercaptopropionic acid (MPA) as a surface functionalizing agent, we report on designing NaNbO3/CdS type-II core/shell heterostructures with an absorption range extending to visible range and explore the opportunity toward degradation of methylene blue (MB) dye as a model pollutant under visible light irradiation. Characterizations including X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), UV-vis diffuse reflectance spectrum (DRS), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), and Raman spectroscopy support the growth of CdS shell onto NaNbO3 nanorods. The resulting core/shell heterostructures unveiled high surface areas, enhanced light harvesting, and appreciably increased photocatalytic activity toward MB degradation compared to individual counterparts and the photocatalytic standard, Degussa P25, under visible light irradiation. The remarkably enhanced photocatalytic activity of core/shell heterostructures could be interpreted in terms of efficient charge separation owing to core/shell morphology and resulting type-II band alignment between NaNbO3 and CdS, which creates a step-like radial potential favoring the localization of one of the carriers in the core and the other in the shell. A plausible mechanism for the degradation of MB dye over NaNbO3/CdS core/shell heterostructures is also elucidated using active species scavenger studies. Our findings imply that hydroxyl radicals (OH(*)) play a crucial role in dictating the degradation of MB under visible light. This work highlights the importance of core/shell heterostructures in leading toward new paradigms for developing highly efficient and reusable photocatalysts for the destructive oxidation of recalcitrant organic pollutants. PMID- 25025824 TI - Evidence of two-state reactivity in alkane hydroxylation by Lewis-acid bound copper-nitrene complexes. AB - The behavior of the Lewis-acid adducts of two copper-nitrene [Cu(NR)](+) complexes in nitrene-transfer and H-atom abstraction reactions have been demonstrated to depend on the nature of the nitrene substituents. Two-state reactivity, in which a singlet ground state and a nearby triplet excited-state both contribute, provides a useful model for interpreting reactivity trends of the two compounds. PMID- 25025825 TI - Identification of differentially expressed genes potentially involved in the tolerance of Lotus tenuis to long-term alkaline stress. AB - Soil alkalinity is one of the most serious agricultural problems limiting crop yields. The legume Lotus tenuis is an important forage acknowledged by its ability to naturally grow in alkaline soils. To gain insight into the molecular responses that are activated by alkalinity in L. tenuis plants, subtractive cDNA libraries were generated from leaves and roots of these plants. Total RNAs of non stressed plants (pH 5.8; E.C. 1.2), and plants stressed by the addition of 10 mM of NaHCO3 (pH 9.0; E.C. 1.9), were used as source of the driver and the tester samples, respectively. RNA samples were collected after 14 and 28 days of treatment. A total of 158 unigenes from leaves and 92 unigenes from roots were obtained and classified into 11 functional categories. Unigenes from these categories (4 for leaves and 8 for roots), that were related with nutrient metabolism and oxidative stress relief were selected, and their differential expression analyzed by qRT-PCR. These genes were found to be differentially expressed in a time dependent manner in L. tenuis during the alkaline stress application. Data generated from this study will contribute to the understanding of the general molecular mechanisms associated to plant tolerance under long-term alkaline stress in plants. PMID- 25025826 TI - Synthesis of molecular tripods based on a rigid 9,9'-spirobifluorene scaffold. AB - The efficient synthesis of a new tripodal platform based on a rigid 9,9' spirobifluorene with three acetyl protected thiol groups in the positions 2, 3' and 6' for deposition on Au(111) surfaces is reported. The modular 9,9' spirobifluorene platform provides both a vertical arrangement of the molecular rod in position 7 and its electronic coupling to the gold substrate. To demonstrate the validity of the molecular design, the model compound 24 exposing a para-cyanophenylethynyl rod is synthesized. Our synthetic approach is based on a metal-halogen exchange reaction of 2-iodobiphenyl derivative and his subsequent reaction with 2,7-disubstituted fluoren-9-one to afford the carbinol 16. Further electrophilic cyclization and separation of regioisomers provided the corresponding 2,7,3',6'-tetrasubstituted 9,9'-spirobifluorene 17 as the key intermediate. The molecular structure of 17 was determined by single-crystal X ray diffraction crystallography. The self-assembly features of the target compound 24 were analyzed in preliminary UHV-STM experiments. These results already demonstrated the promising potential of the concept of the tripodal structure to stabilize the molecule on a Au(111) surface in order to control the spatial arrangement of the molecular rod. PMID- 25025827 TI - Optimization of pulse duration and pulse charge during transcutaneous electrical nerve stimulation. AB - The main effects and interaction of pulse duration and pulse charge on sensory, motor and painful stimulation were examined on six male subjects. Surface electrodes were placed over the triceps brachii muscle. Pulse duration was varied between 5 and 1000 us. Peak current, muscle torque and four excitatory responses were determined. Sequential order of sensory, motor and painful stimulation was evidenced. Selective excitation of these different physiological responses was easier and required less charge as pulse duration became shorter. The greatest non-painful torque was reached at 100 us pulse duration. The most suitable range for motor stimulation was 20 to 200 us. For painful stimulation, a 5 to 10 us duration was favoured. A range of 20 to 100 us was recommended for sensory stimulation. PMID- 25025828 TI - An evaluation of the need of the long-stay psychiatric patient for organised exercise. AB - Nine long-stay psychiatric patients, known to have had little organised exercise for some years, were involved in a programme of group physical activity for fourteen weeks following tests for body mobility as typified by range of head movement, length of stride and ability to raise the arms above the head. Positive physical gains were demonstrated relative to a non-exercising control group when tests were repeated at the end of the programme, and greatest benefit appeared to be derived by patients whose diagnosis included a degree of retardation or dementia. Every test subject exhibited some improvement in social behaviour, at least whilst in the group situation. PMID- 25025829 TI - Interferential fields in a fluid medium. AB - Field interaction between two applied interferential fields has been investigated in a homogenous water medium. Previous published theoretical explanations of interferential beats by Nemec (1967) and Hansjurgens (1974) used very simplistic assumptions for slowly varying fields. This present study describes the expected beating patterns without recourse to oversimplification. At each point in the medium two vector directions (Omega) and magnitudes (R) for 100 per cent beating are predicted to occur. Good agreement (r > 0.93) between predicted and measured values of R and Omega indicated the theoretical approach used was valid and in some cases gives different results than previous field distribution descriptions. PMID- 25025831 TI - Social and structural factors associated with vulnerability to HIV infection among young adults in South Africa. AB - There is increasing focus on social and structural factors following the marginal success of individual-level strategies for HIV prevention. While there is evidence of decreased HIV prevalence among young individuals in South Africa, there is still a need to monitor HIV incidence and prevalence in this vulnerable group as well as track and prevent high-risk sexual behavior(s). This study investigated the social and structural factors that shape the context of vulnerability to increased risk of exposure to HIV infection. A mixed-methods approach including qualitative and quantitative design components was employed. Young adults in the age group 18-24 were interviewed from four provinces in South Africa. The qualitative results produced strong support for the effectiveness of loveLife's HIV prevention programs. The household-based survey results showed that the strongest predictors of self-reported HIV infection (indicating a greater chance of being infected) using adjusted odds ratios (aOR) are: being diagnosed with an STI in a lifetime (aOR 13.68 95% Confidence Interval (CI) [4.61 40.56]; p < .001), inconsistent condom use (aOR 6.27 95% CI [2.08-18.84]; p < .01), and difficulty in accessing condoms (aOR 2.86 95% CI [1.04-7.88]; p < .05). The strongest predictors that indicated a decreased chance of being infected with the HI virus are: talking with partner about condom use in the past 12 months (aOR .08 95% CI [.02-.36]; p < .001) and having a grade 8 (aOR .04 95% CI [.01 .66]; p < .05) and higher educational level (aOR .04 95% CI [.01-.43]). These results show that social and structural factors serve as risk and protective factors for HIV prevention among young people. Intervention programs need to continue to focus on effective communication strategies and healthy relationships. Structural adjustments have to be made to encourage school attendance. Finally, social/health policies and health service delivery have to also be refined so that young people have access to youth friendly health services. PMID- 25025830 TI - Autologous platelet-rich plasma: a biological supplement to enhance adipose derived mesenchymal stem cell expansion. AB - Currently the use of non-autologous cell culture media (e.g., animal-derived or allogeneic serum) for clinical applications of mesenchymal stem cells (MSCs) is criticized by regulatory agencies. Autologous platelet-rich plasma (PRP) is proposed as a safer alternative medium supplement for adipose-derived mesenchymal stem cells (AT-MSC) culture. To study its efficiency on cell proliferation, AT MSCs were cultured for 10 days in media supplemented with different concentrations of autologous non-activated PRP (nPRP) or thrombin-activated PRP (tPRP) (1-60%). AT-MSC proliferation, cell phenotype, multipotency capacity, and chromosome stability were assessed and compared to AT-MSCs expanded in a classical medium supplemented with 10% of fetal bovine serum (FBS). Culture media supplemented with nPRP showed dose-dependent higher AT-MSC proliferation than did FBS or tPRP. Twenty percent nPRP was the most effective concentration to promote cell proliferation. This condition increased 13.9 times greater AT-MSC number in comparison to culture with FBS, without changing the AT-MSC phenotype, differentiation capacity, and chromosome status. We concluded that 20% autologous nPRP is a safe, efficient, and cost-effective supplement for AT-MSC expansion. It should be considered as an alternative to FBS or other nonautologous blood derivatives. It could serve as a potent substitute for the validation of future clinical protocols as it respects good manufacturing practices and regulatory agencies' standards. PMID- 25025833 TI - Steric congestion at, and proximity to, a ferrous center leads to hydration of alpha-nitrile substituents forming coordinated carboxamides. AB - The question of the conversion of nitrile groups into amides (nitrile hydration) by action of water in mild and eco-compatible conditions and in the presence of iron is addressed in this article. We come back to the only known example of hydration of a nitrile function into carboxamide by a ferrous [Fe(II)] center in particularly mild conditions and very efficiently and demonstrate that these unusual conditions result from the occurrence of steric stress at the reaction site and formation of a more stable end product. Two bis(cyano-substituted) (tris 2-pyridyl methyl amine) ligands have been prepared, and the structures of the corresponding FeCl2 complexes are reported, both in the solid state and in solution. These two ligands only differ by the position of the nitrile group on the tripod in the alpha and beta position, respectively, with respect to the pyridine nitrogen. In any case, intramolecular coordination is impossible. Upon action of water, the nitrile groups are hydrated however only if they are located in the alpha position. The fact that the beta-substituted beta-(NC)2TPAFeCl2 complex is not water sensitive suggests that the reaction proceeds in an intramolecular way at the vicinity of the metal center. In the bis alpha substituted alpha-(NC)2TPAFeCl2 complex, both functions are converted in a very clean fashion, pointing out that this complex exhibits ligand flexibility and is not deactivated after the first hydration. At a preparative scale, this reaction allows the one-pot conversion of the bis(cyano-substituted) tripod into a bis(amido-substituted) one in particularly mild conditions with a very good yield. Additionally, the XRD structure of a ferric compound in which the two carboxamido ligands are bound to the metal in a seven-coordinate environment is reported. PMID- 25025832 TI - Genomic analysis reveals selection for Asian genes in European pigs following human-mediated introgression. AB - The independent domestication of local wild boar populations in Asia and Europe about 10,000 years ago led to distinct European and Asian pig breeds, each with very different phenotypic characteristics. During the Industrial Revolution, Chinese breeds were imported to Europe to improve commercial traits in European breeds. Here we demonstrate the presence of introgressed Asian haplotypes in European domestic pigs and selection signatures on some loci in these regions, using whole genome sequence data. The introgression signatures are widespread and the Asian haplotypes are rarely fixed. The Asian introgressed haplotypes are associated with regions harbouring genes involved in meat quality, development and fertility. We identify Asian-derived non-synonymous mutations in the AHR gene that associate with increased litter size in multiple European commercial lines. These findings demonstrate that increased fertility was an important breeding goal for early nineteenth century pig farmers, and that Asian variants of genes related to this trait were preferentially selected during the development of modern European pig breeds. PMID- 25025834 TI - Rabbit hemorrhagic disease virus detected in Pico, Azores, Portugal, revealed a unique endemic strain with more than 17 years of independent evolution. AB - Rabbit hemorrhagic disease is caused by a calicivirus, rabbit hemorrhagic disease virus (RHDV), which is responsible for high mortality in domestic and wild European rabbits (Oryctolagus cuniculus). RHDV strains were sequenced from wild European rabbits (Oryctolagus cuniculus algirus) collected in the Azorean island of Pico, Portugal. Phylogenetic analyses showed that the Pico RHDV strains diverge from all of the others described so far, but cluster with the genogroups 1-5 (G1-G5). The genetic distance between the Pico RHDV sequences and each G1, G2 and G3-G5 genogroup (~0.08) is compatible with an RHDV introduction at least 17 years ago. Our results show that in Pico, RHDV is the outcome of an independent evolution from the original RHDV strain that appeared in its European rabbit population. These are the first sequences of RHDV obtained in the subspecies O. c. algirus, outside of its original region, the Iberian Peninsula. Furthermore, we discuss the risk of rabbit translocations from the Azores to the Iberian Peninsula, where the rabbit wild populations are suffering high mortalities. PMID- 25025835 TI - The role of the coat protein A-domain in p22 bacteriophage maturation. AB - Bacteriophage P22 has long been considered a hallmark model for virus assembly and maturation. Repurposing of P22 and other similar virus structures for nanotechnology and nanomedicine has reinvigorated the need to further understand the protein-protein interactions that allow for the assembly, as well as the conformational shifts required for maturation. In this work, gp5, the major coat structural protein of P22, has been manipulated in order to examine the mutational effects on procapsid stability and maturation. Insertions to the P22 coat protein A-domain, while widely permissive of procapsid assembly, destabilize the interactions necessary for virus maturation and potentially allow for the tunable adjustment of procapsid stability. Future manipulation of this region of the coat protein subunit can potentially be used to alter the stability of the capsid for controllable disassembly. PMID- 25025836 TI - Prospective and retrospective semantic processing: prediction, time, and relationship strength in event-related potentials. AB - Semantic context effects have variously been attributed to prospective processing - predictions about upcoming words - or to retrospective appreciation of relationships after reading both context and target. In two experiments, we altered the core variable distinguishing prospective from retrospective processing, namely time. Word pairs varying in strength of relationship were presented sequentially, to allow time for anticipation of the second word, or simultaneously. For both sorts of presentation, the amplitude of the N400 component of the event-related potential was graded from Unrelated to Moderate/Weak to Strong associates. Strong associates showed a temporal advantage over weaker associates - an earlier context effect - only during sequential presentation. Spatial distributions of the N400 context effects also differed for simultaneous versus sequential presentation. PMID- 25025837 TI - Development of lumbrical control in children aged four to six years. AB - This study was undertaken to provide data on the range and quality of movement performances in normal four, five and six year olds, when asked to demonstrate a simple lumbrical pattern of MCP flexion and IP extension in combination with wrist extension. The study also evaluated the ability to isolate individual movements of the thumb, third and fifth digits against the stable background posture. Lumbrical control appears poorly developed at four years, but improves from four to six years of age. The ability to isolate individual finger movements from the basic resting position improved across the three age levels. The results of this study revealed little difference between the performances of boys and girls, or between performances with either hand. PMID- 25025838 TI - Repeatability of three fine motor tests. AB - This study evaluated the repeatability of three fine motor tasks in normal children aged nine years. Using set procedures and well defined scoring categories, finger drumming, sequential finger/thumb opposition and finger tapping were shown to be repeatable quantitatively and qualitatively. Drumming and finger tapping (but not opposition) showed differences between hands, and movement in the easy direction was better than that in the difficult direction for drumming and opposition. Children demonstrate a preferred or easy direction of movement for drumming and for opposition, which must be considered when assessing hand function. This study has provided repeatability information for three tests, as well as baseline data against which children with motor impairment can be evaluated. PMID- 25025839 TI - Skier's thumb: a literature review. AB - Skier's thumb is defined as an acute injury to the ulnar collateral ligament of the metacarpophalangeal joint of the thumb. This review details the history, aetiology, epidemiology, anatomy, diagnosis, surgical and conservative treatment regimes, rehabilitation and current advances in the prevention of skier's thumb. It emphasises the importance of accurate diagnosis of skier's thumb, and appropriate referral of grade three ruptures for surgery. The need for research by physiotherapists which examines this common soft tissue injury is highlighted throughout the review. PMID- 25025840 TI - Patterns of improvement in neurological functioning of children with minimal cerebral dysfunction with physiotherapy intervention. AB - Sixty-four children with minimal cerebral dysfunction (MCD) were studied to evaluate the effectiveness of using a developmental physiotherapy approach to treatment. Assessments of the children's performance in major areas of neurological development were made initially and after six months. In addition, a twelve months assessment allowed a determination of whether early progress was maintained after cessation of treatment. Analyses of results revealed that physiotherapy treatment does ameliorate the neuro-developmental problems seen in children with MCD, and that beneficial effects are well established after six months. On cessation of treatment, the children maintained the better level of functioning for a further six months in comparison to the control group. Resolution of neurological problems after a relatively brief period of physiotherapy justifies this form of intervention for children with MCD. PMID- 25025841 TI - Water exercises for the frail elderly: a pilot programme. AB - With an ageing Australian population, exercise programmes for the elderly and frail elderly are becoming increasingly more important. It is suggested that gentle water exercise is the most appropriate form of activity for frail elderly, and therefore, a pilot programme was conducted and evaluated. The results show a statistically significant positive increase on a scale of affect on a pre- and post-programme questionnaire (F = 7.35, P <.05). Participants also reported other benefits from the programme. While no objective physical measurements were made the psychological benefits of the programme were identified as important factors motivating the frail elderly to commence, and maintain, regular physical activity, and ultimately be more independent in activities of daily living. PMID- 25025842 TI - Sensory and motor nerve conduction velocities following therapeutic ultrasound. AB - Nineteen healthy volunteers each received six, five-minute ultrasound treatments at sonation intensities of 0.0, 0.5, 1.0, 1.5, 2.0 and 2.5 W/cm(2), applied along the proximal forearm segment of the ulnar nerve, over an area of approximately 4.5 times the area of the ultasound application head. Sensory and motor nerve conduction velocities responded similarly, but not identically to ultrasound. All clinical intensities, with the exception of 0.5 W/cm(2) (p <0.10), were associated with significantly increased velocities. Subcutaneous tissue temperatures were directly related to sonation intensity, although significantly increased temperatures were not observed until 1.5 W/cm(2) intensity was used. The effectiveness of clinical applications of ultrasound in pain relief cannot be attributed to a decrease in nerve conduction velocity of the faster conducting A fibers, which are evaluated using standard nerve conduction techniques. PMID- 25025843 TI - What physiotherapists in private practice do: the effects of sex and training on clinical behaviour. AB - The past decade in Australia has witnessed the expansion of Graduate Diploma programmes designed for the practising clinician and it seemed timely to assess the effects of this type of post-graduate education. The objective of this study was to compare the clinical behaviour, defined as time allocation between different assessment and treatment procedures, of 16 generalist physiotherapists and 16 manipulative therapists. The results indicated some significant differences in the treatment choices and time allocation between qualifications groups, as well as some sex based differences. The implications of the findings are discussed with reference to decision making in clinical practice and the development of higher order clinical decision rules. PMID- 25025844 TI - Palpation examination of the posterior cervical spine: the ideal, average and abnormal. AB - The two purposes of this paper relate to Man in or beyond his fifth decade The first purpose is to detail the 'abnormalities' which can be found by palpation examination of the cervical spine posteriorly, and the second is to try to explain what the findings indicate. The 'Ideal' spine, the Abnormal' spine and three groups of the 'Average' spine are defined. The method of examining the cervical spine by palpation techniques is detailed. Discussion centres around what is normal for an ideal spine and the average spine and what it is that changes when the average spine becomes 'abnormal'. The associated 'new' and 'old' tissue changes are discussed in relation to the common findings in the Upper, Middle and Lower Cervical Spine. PMID- 25025845 TI - Pain relief with interferential therapy. AB - This paper considers some of the developments in knowledge and understanding of the phenomenon of pain. The 'pain-gate' theory and the descending pain suppression mechanisms are mentioned briefly. A number of mechanisms are suggested whereby interferential therapy may relieve pain. A brief description of the interferential stimulus and its potential for utilising the mechanisms described in earlier sections is given. Suggestions are made concerning the frequencies used for gaining this pain relieving effect. PMID- 25025846 TI - Scoliosis: a review. AB - School screening of adolescents reveals a high prevalence of mild rotational deformity. The objective of screening is to prevent serious deformity by regular review of these children, early recognition of progression and provision of spinal bracing for curves greater than 25 degrees . Two per cent of students screened in the age range 11-13 years have curves greater than 10 degrees but only two per thousand screened require active treatment. A programme of exercise combined with bracing until skeletal maturity is reached, obviates the need for major surgery. Indications for follow-up and treatment are reviewed, and some current concepts of the aetiology of idiopathic scoliosis are examined with particular emphasis on the relationship between scoliosis and growth. PMID- 25025848 TI - A study of the effect of antenatal physiotherapy coaching on labour pain in the nullipara. AB - An observational study was performed on nulliparous labour pain in an area with a low epidural rate which facilitated the comprehensive assessment of pain. Patients who had attended antenatal physiotherapy classes showed consistently less reaction to pain while experiencing the same level of perceived pain as the untrained. Duration of the first stage was the main factor associated with high pain levels. There was some evidence that training was particularly effective when there were fetal positional problems. PMID- 25025847 TI - Lack of ephrin receptor A1 is a favorable independent prognostic factor in clear cell renal cell carcinoma. AB - The EPH receptor tyrosine kinases and their cell-bound ligands, the ephrins, have been shown to be associated with cancer development and progression. In this study, mRNA and protein expression of the receptors EPHA1 and EPHA2 as well as of their ligand EFNA1 and their prognostic relevance in clear cell renal cell carcinoma was evaluated. Gene expression was measured in 75 cryo-preserved primary tumors and matched non-malignant renal specimens by quantitative PCR. Protein expression was analyzed by immunohistochemistry on tissue microarrays comprising non-malignant, primary tumors and metastatic renal tissues of 241 patients. Gene and protein expression of all three factors was altered in tumor specimens with EPHA1 and EPHA2 being generally diminished in tumors compared to normal renal tissue, whereas EFNA1 was commonly elevated. A positive EPHA1 and EPHA2 protein staining as well as a low EFNA1 protein level were significantly linked to more aggressive tumor features, but only a positive EPHA1 immunoreactivity was significantly associated with poor survival. In subgroup analyses, EPHA1 and EPHA2 protein levels were significantly higher in metastatic than in primary lesions. Patients with EPHA1/EPHA2-positive tumors or with tumors with positive EPHA1 and low EFNA1 immunoreactivity had the shortest survival rates compared to the respective other combinations. In a multivariate model, EPHA1 was an independent prognostic marker for different survival endpoints. In conclusion, an impaired EPH-ephrin signaling could contribute to the pathogenesis and progression of clear cell renal cell carcinoma. PMID- 25025849 TI - Problem list of stroke patients as identified in the problem orientated medical record. AB - In a retrospective study problem orientated physiotherapy records were examined on 156 consecutive stroke patients admitted to medical wards and referred to the physiotherapy department. The purpose of the study was to identify from the problem lists those problems physiotherapists are dealing with in stroke care. There were 1338 problems recorded, and these were divided into 16 clinically meaningful subgroups. Three of the sixteen subgroups accounted for 60.2 percent of all the problems recorded, namely lack of voluntary movement and mobility in general (25.7%), imbalance in muscle tone (19.5%), and problems in maintaining balance (15.0%). On discharge only 34.1 per cent of all problems were reported to be resolved. There was wide variation in the success rate claimed with different problems. PMID- 25025850 TI - Covert monitoring to promote consistency of walking performance: a case study. AB - A covert monitoring procedure was employed to encourage a stroke patient to 'self monitor' two parameters of her walking performance outside the physiotherapy department. The patient was aware that her walking would be monitored, but not of the identity of the monitors. After 12 days of covert monitoring, the two gait parameters, width of base and step length, were observed to be consistently within the specified limits. The covert monitoring procedure was thus successful in promoting consistent performance of a newly acquired gait beyond the physiotherapy department. PMID- 25025851 TI - Data Integration Protocol In Ten-steps (DIPIT): a new standard for medical researchers. AB - INTRODUCTION: The exponential increase in data, computing power and the availability of readily accessible analytical software has allowed organisations around the world to leverage the benefits of integrating multiple heterogeneous data files for enterprise-level planning and decision making. Benefits from effective data integration to the health and medical research community include more trustworthy research, higher service quality, improved personnel efficiency, reduction of redundant tasks, facilitation of auditing and more timely, relevant and specific information. The costs of poor quality processes elevate the risk of erroneous outcomes, an erosion of confidence in the data and the organisations using these data. To date there are no documented set of standards for best practice integration of heterogeneous data files for research purposes. Therefore, the aim of this paper is to describe a set of clear protocol for data file integration (Data Integration Protocol In Ten-steps; DIPIT) translational to any field of research. METHODS AND RESULTS: The DIPIT approach consists of a set of 10 systematic methodological steps to ensure the final data are appropriate for the analysis to meet the research objectives, legal and ethical requirements are met, and that data definitions are clear, concise, and comprehensive. This protocol is neither file specific nor software dependent, but aims to be transportable to any data-merging situation to minimise redundancy and error and translational to any field of research. DIPIT aims to generate a master data file that is of the optimal integrity to serve as the basis for research analysis. CONCLUSION: With linking of heterogeneous data files becoming increasingly common across all fields of medicine, DIPIT provides a systematic approach to a potentially complex task of integrating a large number of files and variables. The DIPIT protocol will ensure the final integrated data is consistent and of high integrity for the research requirements, useful for practical application across all fields of medical research. PMID- 25025852 TI - Ergogenic effect of a traditional natural powder: ghavoot. AB - Ghavoot is a traditional natural energizer in Iran. It is a mixture of different plant seeds that is traditionally used for its energogenic, analgesic, anti inflammatory, and anti-anxiety properties. Nevertheless, its ergogenic effect has never been studied. Twenty two healthy male students were randomly assigned to the experimental (n = 11) and control (n = 11) groups. Participants in the experimental group received ghavoot (34 g/dl) dissolved in 400 ml milk and the control group received 400 ml milk after 8 hr of fasting at 8 am on three days. Pretest measurements were taken one day before the supplementation and posttest carried out 1 hr after the last drink. The participants performed handgrip force, standing vertical jump, pull-up test, and 60-m speed tests. ANCOVA was carried out to find any differences between the two groups. In the experimental group, we found significant improvements in the handgrip force (p < 0.01), vertical jump (p < 0.001), pull-up test (p < 0.001), and 60-m speed test (p < 0.001). The effects of caffeine, antioxidants, and unsaturated fatty acids were previously investigated, but no supporting evidence is in accordance with our findings to prove the ergogenic effect of each component. However, the synergistic effect of the natural chemicals is expected to be responsible. PMID- 25025854 TI - Clinical and histological evaluation of socket grafting using different types of bone substitute in adult patients. AB - PURPOSE: This clinical and histological study evaluated the healing of extraction sockets after implantation of a biphasic calcium sulfate (CS) alone or in combination with a gamma-radiated human mineralized allograft. MATERIALS AND METHODS: Ten healthy adult patients participated in the study. A minimum of 2 teeth, per patient, extracted for different reasons were evaluated. Each socket was randomly filled to the crest with either (a) a biphasic CS or (b) large particulate gamma-radiated human mineralized allograft in combination with a biphasic CS. RESULTS: No complications during reentry of the socket site during bone core retrieval, such as inflammation/immunogenic response, were observed. Histological findings showed a mean new bone (NB) of 33% for sockets filled with biphasic CS and 31% for sockets filled with biphasic CS in combination with allograft material. There was no statistically significant difference in the percentage of NB and the presence of soft tissue between graft materials. CONCLUSION: Biphasic CS used alone or in combination with an allograft resulted in the same amount of NB formation in alveolar ridge preservation procedures. PMID- 25025853 TI - Synthesis, antimitotic and antivascular activity of 1-(3',4',5' trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles. AB - A new class of compounds that incorporated the structural motif of the 1 (3',4',5'-trimethoxtbenzoyl)-3-arylamino-5-amino-1,2,4-triazole molecular skeleton was synthesized and evaluated for their antiproliferative activity in vitro, interactions with tubulin, and cell cycle effects. The most active agent, 3c, was evaluated for antitumor activity in vivo. Structure-activity relationships were elucidated with various substituents on the phenyl ring of the anilino moiety at the C-3 position of the 1,2,4-triazole ring. The best results for inhibition of cancer cell growth were obtained with the p-Me, m,p-diMe, and p Et phenyl derivatives 3c, 3e, and 3f, respectively, and overall, these compounds were more or less as active as CA-4. Their vascular disrupting activity was evaluated in HUVEC cells, with compound 3c showing activity comparable with that of CA-4. Compound 3c almost eliminated the growth of syngeneic hepatocellular carcinoma in Balb/c mice, suggesting that 3c could be a new antimitotic agent with clinical potential. PMID- 25025855 TI - Comparative study of the sinus septa between dentulous and edentulous patients by cone beam computed tomography. AB - PURPOSE: The purpose of this study was to conduct radiographic comparison of maxillary septa in dentulous and edentulous patients using 3-dimensional cone beam computed tomography (CBCT). MATERIALS AND METHODS: From November- 2008 to August 2010, the CBCT of full dentulous 100 patients was conducted randomly at the Department of Radiology, Chonnam National University Dental Hospital. Septa in the maxillary sinus were analyzed. Also, CBCT of 51 patients with partial or full edentulous dentition on maxillary posterior area was obtained. The height of the maxillary sinus septa was measured from the sinus floor, the location divided by the anterior, middle, and posterior portion, and the direction was determined to be the buccopalatal, sagittal, and transverse course. RESULTS: In dentulous patients, sinus septa were found in 27% with 6.01 +/- 2.21 mm mean height. The mean age of these patients was 24 years and 9 months, and most septa were found in anterior portion with a buccopalatal course. In cases of edentulous patients, the prevalence of edentulous patients with septa was 25.8% with 5.30 +/- 1.90 mm mean height. The mean age of the patients was 63 years and 4 months, and most of septa were in the middle portion with a buccopalatal direction. CONCLUSION: There was no significant difference in the prevalence, incidence, height, location, and direction of maxillary sinus septa between dentulous and edentulous patients (P > 0.05). PMID- 25025856 TI - Comparison of surface modified zirconia implants with commercially available zirconium and titanium implants: a histological study in pigs. AB - INTRODUCTION: New biomaterials and their various surface modifications should undergo in vitro and in vivo evaluation before clinical trials. The objective of our in vivo study was to evaluate the biocompatibility of newly created zirconium implant surfaces after implantation in the lower jaw of pigs and compare the osseointegration of these dental implants with commercially available zirconium and titanium implants. MATERIALS AND METHODS: After a healing period of 12 weeks, a histological analysis of the soft and hard tissues and a histomorphometric analysis of the bone-implant contact (BIC) were performed. RESULTS: The implant surfaces showed an intimate connection to the adjacent bone for all tested implants. The 3 newly created zirconium implant surfaces achieved a BIC of 45% on average in comparison with a BIC of 56% from the reference zirconium implants and 35% from titanium implants. Furthermore, the new zirconium implants had a better attachment to gingival and bone tissues in the range of implant necks as compared with the reference implants. CONCLUSION: The results suggest that the new implants comparably osseointegrate within the healing period, and they have a good in vivo biocompatibility. PMID- 25025857 TI - Carbon film coating of abutment surfaces: effect on the abutment screw removal torque. AB - PURPOSE: To evaluate the effect of diamond-like carbon (DLC) coating of prefabricated implant abutment on screw removal torque (RT) before and after mechanical cycling (MC). MATERIALS AND METHODS: Fifty-four abutments for external hex implants were divided among 6 groups (n = 9): S, straight abutment (control); SC, straight coated abutment; SCy, straight abutment and MC; SCCy, straight coated abutment and MC; ACy, angled abutment and MC; and ACCy, angled coated abutment and MC. The abutments were attached to the implants by a titanium screw. RT values were measured and registered. Data (in Newton centimeter) were analyzed with analysis of variance and Dunnet test (alpha = 0.05). RESULTS: RT values were significantly affected by MC (P = 0.001) and the interaction between DLC coating and MC (P = 0.038). SCy and ACy showed the lowest RT values, statistically different from the control. The abutment coated groups had no statistical difference compared with the control. Scanning electron microscopy analysis showed DLC film with a thickness of 3 MUm uniformly coating the hexagonal abutment. CONCLUSION: DLC film deposited on the abutment can be used as an alternative procedure to reduce abutment screw loosening. PMID- 25025858 TI - Expression of SP7, RUNX1, DLX5, and CTNNB1 in human mesenchymal stem cells cultured on xenogeneic bone substitute as compared with machined titanium. AB - PURPOSE: The aim of this research was to investigate the gene expression profile of 4 transcription factors in human mesenchymal stem cells (hMSC) cultured with a xenogeneic bone substitute and a support of machined titanium. MATERIAL AND METHODS: In vitro studies were performed on hMSC cells, which grew in contact with cortical porcine bone and machined titanium disks for 10 days. RNA quantification for genes DLX5, CTNNB1, RUNX1, and SP7 was assessed by quantitative real-time polymerase chain reaction. For cells supported by titanium, immunocytochemistry of osteocalcin (OC) was also performed. RESULTS: In the osteoblast-induced cells (OIC), DLX5, CTNNB1, and RUNX1 were significantly upregulated (+2.38-, +3.51-, and +7.08-fold, respectively), whereas SP7 was downregulated (-26.32-fold). None of the genes seemed to be upregulated or downregulated by the corticocancellous porcine bone. In cells grown on titanium support, DLX5 and RUNX1 were respectively upregulated (+3.12-fold) and downregulated (-2.14-fold). For titanium support, the presence of both catenin beta-1 and OC was verified. CONCLUSION: The 2 genes RUNX1 and SP7 resulted differently expressed in cells cultured on metallic supports if compared with the expression recorded for OIC. An induction of the osteogenic phenotype was observed when cells were cultured on machined titanium, but not on xenogeneic material. PMID- 25025859 TI - Implants placed simultaneously with lateral window sinus augmentation using a putty alloplastic bone substitute for increased primary implant stability: a retrospective study. AB - INTRODUCTION: The aim of this retrospective study was to evaluate the primary stability of implants placed in significantly pneumatized maxillary sinuses with minimum residual bone height. MATERIALS AND METHODS: Seventeen patients who had been treated with simultaneous implant placement in sites with <5 mm of vertical bone height using a modified direct sinus lift technique were included. Implants placed in adjacent sites with at least 5 mm of bone height were included as quasi controls. RESULTS: A total of 30 implants were inserted with a maximum insertion torque number >20 N/cm. Logistic regression analysis failed to show any association between residual bone height and primary implant stability. Implant survival was 96.67% (29/30) during a mean follow-up of 15.74 months postloading. CONCLUSIONS: The diminished preoperative vertical dimensions of the residual ridges did not seem to negatively influence the osseointegration of implants placed in this study. The prerequisite for simultaneous sinus augmentation and implant placement is an adequate primary stability of the implant and not a fixed minimum bone height level. PMID- 25025860 TI - Mini-lateral windows for minimally invasive maxillary sinus augmentation: case series of a new technique. AB - OBJECTIVES: The purpose of this article was to introduce a new technique for minimally invasive lateral window sinus augmentation, developed to maximize the amount of residual lateral wall after the procedure. MATERIALS AND METHODS: Fourteen consecutive patients requiring maxillary sinus augmentation by a lateral approach and delayed implant placement were treated using standardized mini lateral windows. Before the procedure, the remaining height of alveolar bone was determined; 6 months after the procedure, the augmented height and augmented width were measured. The extent of the antrostomy was calculated using a gauge and compared with a conventional window size. RESULTS: A total of 15 maxillary sinus augmentation procedures were performed in 14 patients using this technique. Every patient received the planned implant treatment 6 months after the sinus augmentation procedure. The average residual bone height was 2.1 +/- 1.1 mm, the average augmented height was 13.4 +/- 3.4 mm, and the average augmented width was 19.0 +/- 5.5 mm. The average total area of the antrostomy was calculated to be 59.2 +/- 12.8 mm. CONCLUSIONS: The results of this case series study suggest that this technique allows for the achievement of a similar result as with conventional size windows, but with a significantly smaller total window area. PMID- 25025861 TI - Two-stage crestal sinus elevation by sequential drills in less than 4 mm of residual ridge height: a clinical and histologic case report. AB - PURPOSE: The aim of this work, the first human histologic case report of this technique, was a clinical and histologic evaluation of implant placed in a severely atrophic maxilla using a 2-stage crestal sinus elevation. CASE PRESENTATION: A 52-year-old woman required rehabilitation of an atrophic maxilla with a fixed implant-supported prosthesis. At the first surgery, a crestal sinus lift was performed using beta-tricalcium phosphate (beta-TCP), as radiographic tracer, and mineralized human bone allograft (MHBA) as grafting material. After 6 months, a bone core biopsy was taken, and 2 implants were placed in the augmented sites. Four months later, implants were exposed, and 2 splinted gold-porcelain crowns were delivered. Histology highlighted basal bone disappearance, replaced by a wide composite network (~50% vol/vol) of MHBA granules connected by newly formed bone, and osteoblastic activities. CONCLUSION: This case report demonstrates the possibility of executing a staged transcrestal sinus lift in atrophic situations. MHBA evidenced usefulness in maintaining bone volume. Histologic analyses confirmed the sound outcome of the graft augmentation. Additional studies would be beneficial to confirm or refute the reliability of this technique. PMID- 25025862 TI - Stabilization of beta-peptide helices by direct attachment of trifluoromethyl groups to peptide backbones. AB - The 14-helix structure of oligo-beta-peptides was significantly stabilized by direct attachment of CF3 groups to their backbones. Our studies indicate that this stabilization originates from the CF3-promoted increase in the intramolecular hydrogen-bonding ability of their backbone amides, leading to a novel strategy to stabilize peptide folding. PMID- 25025863 TI - Preoperative planning with noncontrast computed tomography in the prone and supine position for percutaneous nephrolithotomy: a practical overview. AB - OBJECTIVE: To evaluate kidney/adjacent organs positional changes in patients undergoing percutaneous nephrolithotomy (PCNL) using noncontrast computed tomography (NCCT) in prone and supine positions. METHODS: Patients scheduled PCNL were prospectively enrolled in the study and underwent NCCT in supine and in prone position (with boosters). Two imaginary lines for the posterior calyx of upper/mid/lower poles of both kidneys in prone and supine decubitus were considered and compared. Line I (LI): drawn horizontally in the coronal plane in contact with the posterior edge of the kidney. Line II (LII): drawn from the antero-lateral edge of the vertebra through the middle of the posterior calyx (ideal puncture line). Renal depth (d) was measured from LI to the anterior extremity of the vertebra. The maximum access angle (a) considered the window available in the axial plane to perform a secure approach to each calyx. RESULTS: Thirty-seven patients were analyzed; 56.7% were female; mean BMI was 28.3+/-4.9 kg/m(2). For the right kidney, prone position was associated with more organs crossed by LI (54.1% vs 18.9%; p<0.01) and LII (56.8% vs 27%; p=0.03) in the upper calyx. For the left kidney, LII crossed more organs in prone in the upper calyx (54.1% vs 29.7%; p=0.03). Both kidneys showed a tendency to be deeper in the supine position, which provided a wider access angle. CONCLUSIONS: Supine NCCT is not accurate to plan PCNL access in prone position. Prone decubitus is associated with more potential organ injuries in the upper pole. In supine, the kidney situates deeper in the abdomen but the access angle is wider than in prone. PMID- 25025864 TI - Preliminary anatomical and neurodevelopmental outcomes of intravitreal bevacizumab as adjunctive treatment for retinopathy of prematurity. AB - PURPOSE: To evaluate the two-year follow-up of patients with type 1 retinopathy of prematurity (ROP) who received intravitreal bevacizumab (IVB) as adjunctive treatment. MATERIALS AND METHODS: We conducted a longitudinal follow-up study of premature infants who received 0.625 mg IVB therapy in addition to standard laser photocoagulation therapy. For comparison of the ophthalmological and neurological assessment outcomes of these infants, a control group was formed with 13 birth weight- and gestational age-matched infants who were treated with laser therapy alone for type 1 ROP. The neurological status of the study group and the control group was examined systematically, and neurodevelopmental evaluation was assessed by the Bayley Scales of Infant Development (BSID-III). RESULTS: A total of 18 eyes of 13 infants were included in the study. Anatomical success was obtained in 14 eyes (78%) and retinal detachment was observed in 4 eyes (22%). At two years of age, no significant difference was found in terms of spherical or cylindrical refractive errors compared to the control group. In control group, 2/13 patients' and in study group, 3/13 patients' neurological examinations were abnormal. No significant difference was found in the mean cognitive, language or motor BSID III test scores of the groups. CONCLUSIONS: IVB appears to be useful for advanced ROP when laser treatment is precluded or not sufficient for preventing the progression of ROP. This pilot study indicates that IVB seems to contribute no further complications to the complications already present due to prematurity. PMID- 25025866 TI - Dream vs. reality: seven case-studies on the desirability and feasibility of cross-border hospital collaboration in Europe. AB - Despite being a niche phenomenon, cross-border health care collaboration receives a lot of attention in the EU and figures visibly on the policy agenda, in particular since the policy process which eventually led to the adoption of Directive 2011/24/EU. One of the underlying assumptions is that cross-border collaboration is desirable, providing justification to both the European Commission and to border-region stakeholders for promoting it. The purpose of this paper is to question this assumption and to examine the role of actors in pushing (or not) for cross-border collaboration. The analysis takes place in two parts. First, the EU policies to promote cross-border collaboration and the tools employed are examined, namely (a) use of European funds to sponsor concrete border-region collaboration projects, (b) use of European funds to sponsor research which gives visibility to cross-border collaboration, and (c) use of the European Commission's newly acquired legal mandate to encourage "Member States to cooperate in cross-border health care provision in border-regions" (Art. 10) and support "Member States in the development of European reference networks between health care providers and centres of expertise" (Art. 12). Second, evidence gathered in 2011-2013 from seven European border-regions on hospital cross-border collaboration is systematically reviewed to assess the reality of cross-border collaboration - can it work and when, and why do actors engage in cross-border collaboration? The preliminary findings suggest that while the EU plays a prominent role in some border-region initiatives, cross-border collaboration needs such a specific set of circumstances to work that it is questionable whether it can effectively be promoted. Moreover, local actors make use of the EU (as a source of funding, legislation or legitimisation) to serve their needs. PMID- 25025865 TI - Crowdsourcing for cognitive science--the utility of smartphones. AB - By 2015, there will be an estimated two billion smartphone users worldwide. This technology presents exciting opportunities for cognitive science as a medium for rapid, large-scale experimentation and data collection. At present, cost and logistics limit most study populations to small samples, restricting the experimental questions that can be addressed. In this study we investigated whether the mass collection of experimental data using smartphone technology is valid, given the variability of data collection outside of a laboratory setting. We presented four classic experimental paradigms as short games, available as a free app and over the first month 20,800 users submitted data. We found that the large sample size vastly outweighed the noise inherent in collecting data outside a controlled laboratory setting, and show that for all four games canonical results were reproduced. For the first time, we provide experimental validation for the use of smartphones for data collection in cognitive science, which can lead to the collection of richer data sets and a significant cost reduction as well as provide an opportunity for efficient phenotypic screening of large populations. PMID- 25025869 TI - Antibodies specific for carbamylated proteins precede the onset of clinical symptoms in mice with collagen induced arthritis. AB - OBJECTIVE: The immune response to post-translationally modified antigens is a key characteristic of rheumatoid arthritis. Carbamylation is such a posttranslational modification. Recently, we demonstrated that autoantibodies recognizing carbamylated proteins are present in sera of rheumatoid arthritis. The molecular mechanisms underlying the break of tolerance and hence the induction of anti-CarP antibody responses are unknown as well as their appearance in mouse models for systemic arthritis. Therefore we analyzed their appearance in the mouse collagen induced arthritis model. METHODS: collagen induced arthritis was induced by immunization with type II collagen in complete Freund's adjuvant. Arthritis severity was monitored by clinical scoring and anti-CarP antibody levels were determined by ELISA. RESULTS: Anti-CarP antibodies were detectable in mice with collagen induced arthritis. We did not detect ACPA in mice with collagen induced arthritis. The specificity of the antibodies for carbamylated proteins was confirmed by inhibition assays and immunoblotting. Injection with complete Freund's adjuvant without type II collagen could also induce anti-CarP antibodies, however, in mice with arthritis, the anti-CarP antibody response was stronger and developed more rapidly. The onset of collagen induced arthritis was preceded by an increase of anti-CarP IgG2a levels in the serum. CONCLUSION: In mice with collagen induced arthritis we did not observe an immune response against citrullinated antigens, but we did observe an immune response against carbamylated antigens. This anti-CarP response already appeared before disease onset, indicating that collagen induced arthritis can be used as an in vivo model to study anti-CarP antibodies. Our data also indicate that the tolerance to carbamylated proteins, in contrast to the response to citrullinated proteins, is easily broken and that arthritis boosts the immune response against these proteins. The anti-CarP response in mice with CIA can be used as a model for immune responses to post-translationally modified proteins. PMID- 25025868 TI - Clock genes in hypertension: novel insights from rodent models. AB - The circadian clock plays an integral role in the regulation of physiological processes, including the regulation of blood pressure. However, deregulation of the clock can lead to pathophysiological states including hypertension. Recent work has implicated the circadian clock genes in the regulation of processes in the heart, kidney, vasculature, and the metabolic organs, which are all critical in the regulation of the blood pressure. The goal of this review is to provide an introduction and general overview into the role of circadian clock genes in the regulation of blood pressure with a focus on their deregulation in the etiology of hypertension. This review will focus on the core circadian clock genes CLOCK, BMAL1, Per, and Cry. PMID- 25025870 TI - Patterns of user disclosure of complementary and alternative medicine (CAM) use. AB - OBJECTIVE: To investigate patterns of complementary and alternative medicine (CAM) use disclosure across medical and sociobehavioral factors and to provide a model that takes into account factors in explaining those patterns. SUBJECTS: A total of 21,849 CAM use episodes from 7347 respondents in the 2007 US National Health Interview Survey which involves the latest survey on CAM use. RESEARCH DESIGN: Respondents were a representative sample of US national population. Logistic hierarchical linear models specify how characteristics of users and their CAM use episodes influence user disclosure behaviors. RESULTS: At the individual level, users were more likely to disclose CAM use to health care professionals when they had health problems and when they were insured. At the episode level, CAM use episodes were more likely to be disclosed when they were intended to treat a specific medical condition and recommended by a health professional. Disclosure rates were high among most susceptible users (ie, sick people intending to treat specific conditions with CAM) and among the biologically based CAM modalities (eg, herbal supplements) that are most likely to produce adverse interactions with conventional biomedical treatments. CONCLUSIONS: User disclosure was affected not only by users' demographic and socioeconomic characteristics but also by episode-specific factors. Efforts to improve provider-user communication of CAM use should consider the varying effects of these factors. PMID- 25025871 TI - Physicians' anxiety due to uncertainty and use of race in medical decision making. AB - BACKGROUND: The explicit use of race in medical decision making is contested. Researchers have hypothesized that physicians use race in care when they are uncertain. OBJECTIVES: The aim of this study was to investigate whether physician anxiety due to uncertainty (ADU) is associated with a higher propensity to use race in medical decision making. RESEARCH DESIGN: This study included a national cross-sectional survey of general internists. SUBJECTS: A national sample of 1738 clinically active general internists drawn from the SK&A physician database were included in the study. MEASURES: ADU is a 5-item measure of emotional reactions to clinical uncertainty. Bonham and Sellers Racial Attributes in Clinical Evaluation (RACE) scale includes 7 items that measure self-reported use of race in medical decision making. We used bivariate regression to test for associations between physician characteristics, ADU, and RACE. Multivariate linear regression was performed to test for associations between ADU and RACE while adjusting for potential confounders. RESULTS: The mean score on ADU was 19.9 (SD=5.6). Mean score on RACE was 13.5 (SD=5.6). After adjusting for physician demographics, physicians with higher levels of ADU scored higher on RACE (+beta=0.08 in RACE, P=0.04, for each 1-point increase in ADU), as did physicians who understood "race" to mean biological or genetic ancestral, rather than sociocultural, group. Physicians who graduated from a US medical school, completed fellowship, and had more white patients scored lower on RACE. CONCLUSIONS: This study demonstrates positive associations between physicians' ADU, meanings attributed to race, and self-reported use of race in medical decision making. Future research should examine the potential impact of these associations on patient outcomes and health care disparities. PMID- 25025872 TI - 'Trust and teamwork matter': community health workers' experiences in integrated service delivery in India. AB - A comprehensive and integrated approach to strengthen primary health care has been the major thrust of the National Rural Health Mission (NRHM) that was launched in 2005 to revamp India's rural public health system. Though the logic of horizontal and integrated health care to strengthen health systems has long been acknowledged at policy level, empirical evidence on how such integration operates is rare. Based on recent (2011-2012) ethnographic fieldwork in Odisha, India, this article discusses community health workers' experiences in integrated service delivery through village-level outreach sessions within the NRHM. It shows that for health workers, the notion of integration goes well beyond a technical lens of mixing different health services. Crucially, they perceive 'teamwork' and 'building trust with the community' (beyond trust in health services) to be critical components of their practice. However, the comprehensive NRHM primary health care ideology - which the health workers espouse - is in constant tension with the exigencies of narrow indicators of health system performance. Our ethnography shows how monitoring mechanisms, the institutionalised privileging of statistical evidence over field-based knowledge and the highly hierarchical health bureaucratic structure that rests on top-down communications mitigate efforts towards sustainable health system integration. PMID- 25025873 TI - Climate-driven variation in the intensity of a host-symbiont animal interaction along a broad elevation gradient. AB - Gradients of environmental stress may affect biotic interactions in unpredictable ways responding to climate variation, depending on the abiotic stress tolerance of interacting partners. Here, we study the effect of local climate on the intensity of feather mites in six mountain passerines along a 1400 m elevational gradient characterized by shifting temperature and rainfall. Although obligatory symbionts of warm-blooded organisms are assumed to live in mild and homeothermic environments, those inhabiting external, non-blood-irrigated body portions of the host organism, such as feather mites, are expected to endure exposure to the direct influence of a fluctuating climate. As expected, feather mite intensity declined with elevation in all bird species, a pattern that was also found in cold-adapted passerines that have typical alpine habits. The elevation cline was mainly explained by a positive effect of the average temperature upon mite intensity in five of the six species studied. Precipitation explained less variance in mite intensity than average temperature, and showed a negative correlation in half of the studied species. We found no climate-driven migration of mites along the wings of birds, no replacement of mite species along elevation gradients and no association with available food resources for mites (estimated by the size of the uropygial gland). This study suggests that ectosymbionts of warm-blooded animals may be highly sensitive to climatic variation and become less abundant under stressful environmental conditions, providing empirical evidence of the decline of specialized biotic interactions among animal species at high elevations. PMID- 25025874 TI - Molecular excitons in a copper azadipyrrin complex. AB - Exciton coupling is investigated in a copper azadipyrrin complex, Cu(L-aza)2. Exciton coupling in Cu(L-aza)2 assuming a single pi-pi* state on the L-aza ligand fails to account for the electronic structure of Cu(L-aza)2, which displays two almost equal intensity transitions at 15 600 cm(-1) and 17 690 cm(-1). TD UB3LYP/6-31G(d) calculations suggest multiple pi-pi* transitions for the L-aza ligands and simple vector addition of the transition dipoles predicts two nearly orthogonal co-planar excitonic transitions that correctly reproduce the absorption band profile. Empirical modelling of absolute resonance Raman intensities using wavepacket dynamics confirms Cu(L-aza)2 has two equal intensity orthogonal exciton transitions. The phenyl substituents at the alpha- and gamma positions of the pyrrole rings play a central role in determining the orientation of the transition dipoles. Consequently the pi-pi* transitions for the L-aza ligands are oriented towards the substituent groups and are not in the plane of the pyrrole rings. Mode displacements in the Franck-Condon (FC) region obtained from the wavepacket model suggest that pyrrole ring and phenyl modes control the exciton FC dynamics. Our results suggest that Cu(L-aza)2 is an ideal model for theoretical, computational and experimental investigations of molecular excitons in molecular systems. PMID- 25025875 TI - Effects of movement and weightbearing on the glycosaminoglycan content of sheep articular cartilage. AB - Immobilised non-weightbearing joints show significant loss of proteoglycan. It is unclear whether this is due to a lack of compression, a lack of movement, or both. Evidence suggests that movement alone is insufficient to maintain proteoglycan levels. To investigate this problem, 20 sheep were divided into four groups and the right forelegs subjected to (1) normal weightbearing and movement, (2) movement without weightbearing, (3) weightbearing without movement and (4) non-weightbearing without movement. After one month, full thickness core samples of cartilage taken from the radio-carpal joints of both forelegs were analysed for glycosaminoglycan (GAG) content. Immobilised non-weightbearing joints showed a significant loss of GAG compared with the other groups. More importantly, movement alone without weightbearing was sufficient to maintain GAG content, as was weightbearing without movement. PMID- 25025876 TI - Continuous passive mobilisation following total knee replacement: A retrospective review. AB - A retrospective study of 87 total knee replacement (TKR) operations at the Royal Brisbane Hospital was undertaken in order to assess the effect of continuous passive mobilisation (CPM) of the knee on the post-operative course of the patients undergoing arthroplasty. Two mixed groups of patients with rheumatoid arthritis and osteoarthritis were compared. Forty-eight cases in which patients received CPM during their post-operative course were compared with 39 cases in which CPM was not used. Choice of treatment protocol was at the discretion of the surgeon in each case. The two groups did not differ significantly with regard to pre-operative or post-operative range of knee flexion, length of inpatient stay, or delay before the commencement of knee flexion after surgery. The CPM group was significantly older and this may have masked any beneficial effect of CPM on the measured outcomes. These results suggest that the use of CPM as applied in this study does not significantly alter the post-operative course or the range of movement on discharge. This finding is consistent with those of other studies. The difficulties inherent in this review and the possibilities for further prospective studies are discussed. PMID- 25025877 TI - Stretch-induced cervicobrachial pain syndrome. AB - The case records of 22 patients who presented with severe and persistent cervicobrachial pain were reviewed. The onset of their pain followed the performance of a forceful activity (lifting, pulling or pushing) using one or both arms in the outstretched position. Their symptoms and the findings on physical examination were both consistent with stretch-induced damage to neural tissues related to the painful upper limb. The predominant site of painful neural pathology appeared to be within the cervical spine. PMID- 25025878 TI - Normal lumbo-pelvic muscle lengths and their interrelationships in adolescent females. AB - Length indices of the erector spinae, abdominal, gluteal iliopsoas, rectus femoris and hamstring muscles were measured in 103 adolescent females. Means and standard deviations were calculated and the 95 per cent confidence intervals for the population and the 95 per cent individual tolerance limits were derived for each index. Analysis of the interrelationships of the muscle length indices using multiple correlation analysis revealed significant positive correlations between the lumbar erector spinae and iliopsoas and rectus femoris indices, between the abdominal and gluteal indices and between the iliopsoas and hamstring indices. Significant negative correlations exist between the lumbar erector spinae and gluteal indices, between the iliopsoas and abdominal indices and between the rectus femoris and hamstring indices. PMID- 25025879 TI - Some elementary guides for performing research into the effects of physiotherapy treatments. AB - If any profession is to survive, it cannot escape the necessity of continually subjecting its techniques to critical reappraisal. If a profession does not carry out research into its own methods, it is certain that it will come under challenge from other allied professions which do encourage research. This is already occurring with physiotherapy. In a recent International Seminar on Rehabilitation Medicine, Dr. J. V. Basmajian said: "I am persuaded that almost all therapeutic procedures in a rehabilitation department must be regarded as suspect; they may be either useless or harmful. I have little confidence in the scientific basis of any of them." PMID- 25025880 TI - Biomechanical problems affecting the spine. AB - The importance of bio-mechanics in the study of spinal problems is now more widely appreciated. PMID- 25025881 TI - A survey of antenatal education in australia. AB - There is increasing awareness of the need for ante-natal education for expectant parents. This role of education has traditionally gone to the physiotherapist, who first became involved when giving exercises to pregnant women in 1940. PMID- 25025882 TI - Positive physiotherapy following keller's operation. AB - It is stated that hallux valgus is the commonest of all deformities of the feet and that the operative procedures to correct this have a bad public reputation, though results are good (Wiles and Sweetnam, 1965). PMID- 25025883 TI - Report on the breville hohensonne 2020 impulse lamp. AB - Skin tests were carried out on 11 members in the Physiotherapy Department of Sydney Hospital using the Breville Hohensonne 2020 Impulse Lamp. As a test control, the same people were also tested with the Alpine air-cooled Sun Lamp, so that comparison could be made between the recognised first degree erythema of the person and the first degree erythema produced in test patches by the Impulse Lamp. PMID- 25025884 TI - Phosphorylation mimicking mutations of ALOX5 orthologs of different vertebrates do not alter reaction specificities of the enzymes. AB - 5-Lipoxygenase (ALOX5) plays a key role in the biosynthesis of pro-inflammatory leukotrienes whereas 15-lipoxygenases (ALOX15) have been implicated in the formation of pro-resolving eicosanoids (lipoxins, resolvins). Recently, it has been suggested that a phosphorylation mimicking mutant (Ser663Asp) of a stabilized variant of human ALOX5 exhibits dominant arachidonic acid 15 lipoxygenase activity (>95%). To test whether similar alterations in the reaction specificity can also be observed for ALOX5 orthologs of other species we expressed wildtype and phosphorylation mimicking mutants (Ser271Asp, Ser523Asp, Ser663Asp, Ser663Glu) of human, mouse and zebrafish ALOX5 in pro- and eukaryotic overexpression systems and characterized their reaction specificities. We found that neither of the phosphorylation mimicking mutants produced significant amounts of 15-hydroperoxyeicosatetraenoic acid and the 5-lipoxygenation/15 lipoxygenation ratio for all wildtype and mutant enzyme species was lower than 100:2. Taken together, this data suggest that phosphorylation of native ALOX5 orthologs of different vertebrates may not induce major alterations in the reaction specificity and thus may not inverse their biological activity. PMID- 25025885 TI - Charge carrier generation and transport in different stoichiometry APFO3:PC61BM solar cells. AB - In this paper we studied carrier drift dynamics in APFO3:PC61BM solar cells of varied stoichiometry (2:1, 1:1, and 1:4 APFO3:PC61BM) over a wide time range, from subpicoseconds to microseconds with a combination of ultrafast optical electric field probing and conventional transient integrated photocurrent techniques. Carrier drift and extraction dynamics are strongly stoichiometry dependent: the speed of electron or hole drift increases with higher concentration of PC61BM or polymer, respectively. The electron extraction from a sample with 80% PC61BM takes place during hundreds of picoseconds, but slows down to sub-microseconds in a sample with 33% PC61BM. The hole extraction is less stoichiometry dependent: it varies form sub-nanoseconds to tens of nanoseconds when the PC61BM concentration changes from 33% to 80%. The electron extraction rate correlates with the conversion efficiency of solar cells, leading to the conclusion that fast electron motion is essential for efficient charge carrier separation preventing their geminate recombination. PMID- 25025886 TI - Utility of intraoperative frozen section in the diagnosis of periprosthetic joint infection. AB - PURPOSE: Intraoperative frozen section (FS) is an effective diagnostic test for periprosthetic joint infection (PJI). We evaluated the diagnostic characteristics of single- and multiplex-site intraoperative FS, and evaluated the results of single-site FS combined with those of C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) for assessing PJI. METHODS: We studied 156 painful joint arthroplasties in 152 consecutive patients presenting for revision total joint arthroplasty due to PJI. Receiver operating characteristic analysis was used to determine the optimal cutoff values for CRP level, ESR, and intraoperative FS histopathology. Sensitivity, specificity, positive and negative predictive values, and accuracy of the diagnostic tests were assessed using a 2*2 table. RESULTS: We investigated the diagnostic utility of polymorphonuclear leukocyte number (PMN) per high-power field (HPF) on FS. Our data showed that 5 PMNs per HPF is a suitable diagnostic threshold, with a high accuracy in single- and multiplex-site FS. Five PMNs in any 1 of 5 sites had the highest sensitivity of 0.86 and a specificity of 0.96. Five PMNs in every 1 of 5 sites had greater diagnostic utility, with a specificity of 1; however, the sensitivity of this measure fell to 0.62. Five PMNs in single-site FS had a sensitivity of 0.70 and a specificity of 0.94. Five PMNs in single-site FS or CRP level >=15 mg/L increased the sensitivity to 0.92; however, the specificity decreased to 0.79. CONCLUSION: Compared with single-site FS, any 1 positive site on multiplex-site FS may improve sensitivity, while every 1 positive site on multiplex-site FS may improve specificity. Five PMNs in any 1 of 5 sites on FS has excellent utility for the diagnosis of PJI. Additional systematic large-scale studies are needed to verify this result. PMID- 25025888 TI - Hydrogen-dimer lines and electron waveguides in graphene. AB - The electronic and transport properties of graphene ribbons sandwiched between hydrogen dimer lines, of the kind recently realized by Nilsson et al., Carbon, 2012, 50, 2052, are investigated with the help of first principles methods. It is found that such lines of hydrogen atoms block conduction between neighboring channels and effectively allow the confinement of graphene charge carriers, thereby opening the possibility of imprinting nano-circuits in graphene by controlled hydrogenation. PMID- 25025887 TI - Conjugated polymer-assisted dispersion of single-wall carbon nanotubes: the power of polymer wrapping. AB - The future application of single-walled carbon nanotubes (SWNTs) in electronic (nano)devices is closely coupled to the availability of pure, semiconducting SWNTs and preferably, their defined positioning on suited substrates. Commercial carbon nanotube raw mixtures contain metallic as well as semiconducting tubes of different diameter and chirality. Although many techniques such as density gradient ultracentrifugation, dielectrophoresis, and dispersion by surfactants or polar biopolymers have been developed, so-called conjugated polymer wrapping is one of the most promising and powerful purification and discrimination strategies. The procedure involves debundling and dispersion of SWNTs by wrapping semiflexible conjugated polymers, such as poly(9,9-dialkylfluorene)s (PFx) or regioregular poly(3-alkylthiophene)s (P3AT), around the SWNTs, and is accompanied by SWNT discrimination by diameter and chirality. Thereby, the pi-conjugated backbone of the conjugated polymers interacts with the two-dimensional, graphene like pi-electron surface of the nanotubes and the solubilizing alkyl side chains of optimal length support debundling and dispersion in organic solvents. Careful structural design of the conjugated polymers allows for a selective and preferential dispersion of both small and large diameter SWNTs or SWNTs of specific chirality. As an example, with polyfluorenes as dispersing agents, it was shown that alkyl chain length of eight carbons are favored for the dispersion of SWNTs with diameters of 0.8-1.2 nm and longer alkyls with 12-15 carbons can efficiently interact with nanotubes of increased diameter up to 1.5 nm. Polar side chains at the PF backbone produce dispersions with increased SWNT concentration but, unfortunately, cause reduction in selectivity. The selectivity of the dispersion process can be monitored by a combination of absorption, photoluminescence, and photoluminescence excitation spectroscopy, allowing identification of nanotubes with specific coordinates [(n,m) indices]. The polymer wrapping strategy enables the generation of SWNT dispersions containing exclusively semiconducting nanotubes. Toward the applications in electronic devices, until now most applied approach is a direct processing of such SWNT dispersions into the active layer of network-type thin film field effect transistors. However, to achieve promising transistor performance (high mobility and on-off ratio) careful removal of the wrapping polymer chains seems crucial, for example, by washing or ultracentrifugation. More defined positioning of the SWNTs can be accomplished in directed self-assembly procedures. One possible strategy uses diblock copolymers containing a conjugated polymer block as dispersing moiety and a second block for directed self-assembly, for example, a DNA block for specific interaction with complementary DNA strands. Another strategy utilizes reactive side chains for controlled anchoring onto patterned surfaces (e.g., by interaction of thiol-terminated alkyl side chains with gold surfaces). A further promising application of purified SWNT dispersions is the field of organic (all-carbon) or hybrid solar cell devices. PMID- 25025889 TI - Risk factors for acute kidney injury following TA-TAVI or minimally invasive aortic valve replacement: which procedure is less kidney damaging in elderly patients? AB - BACKGROUND: Acute kidney injury (AKI) represents a major complication following aortic valve replacement in elderly patients. The aim of this study was to determine possible risk factors for AKI and to find the ideal strategy, minimally invasive valve replacement (MIS-AVR) or transapical valve implantation (TA-TAVI), regarding the postoperative renal outcome. METHODS: A total of 133 patients (age >= 75 years, 67 male) with severe aortic stenosis were included over 2 years: 42% were treated with MIS-AVR, 58% underwent TA-TAVI procedure. AKI was considered as a postprocedural 1.5* increase in creatinine or an increase of > 0.3 mg/dL/48 hours. Group differences were tested with chi-square or t-test. AKI risk assumption was analyzed in multiple multivariate logistic regression models. RESULTS: EuroSCORE II-related risk assumption was 8.7 +/- 6.9 for TA-TAVI and 4.5 +/- 5.7 for MIS-AVR (p < 0.001). The overall 30-day survival rate was 93%. Fifty eight patients developed a risk for AKI and 13 developed a manifest renal injury/failure. Logistic regression analysis revealed a higher AKI risk for TA TAVI (odds ratio, OR = 2.58; 95% confidence interval, CI = 1.18, 5.63; p = 0.017). EuroSCORE II (OR = 0.98; 95% CI = 0.92, 1.04; p = 0.433); preoperative creatinine (OR = 1.78; 95% CI = 0.67, 4.77; p = 0.249) and estimated glomerular filtration rate (OR = 1.00; 95% CI = 0.97, 1.02; p = 0.655) had no impact on AKI. A regression model adjusting for the variables age, gender, body mass index (BMI), diabetes, and procedure type revealed a higher AKI rate for male gender (OR = 2.41; 95% CI = 1.13, 5.11; p = 0.022). Operation time and radio-contrast media volume had no influence on the AKI-occurrence. There was no correlation between AKI and early mortality. CONCLUSION: A higher risk for AKI after TA-TAVI should be considered in the therapy decision, especially in elderly male patients because MIS-AVR still yields excellent results. PMID- 25025890 TI - Long-term outcomes after mitral valve repair for degenerative mitral regurgitation with persistent atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) adversely affects surgical outcomes of mitral valve surgery. However, the long-term impact of Maze procedure has not been clear yet. PATIENTS AND METHODS: We retrospectively investigated 159 patients who underwent mitral valve repair for degenerative mitral regurgitation with persistent AF between 1991 and 2010. The mean age of patients was 63.1 +/- 10.5 years. After we started performing Maze procedure in 2002, 65 patients underwent concomitant Maze procedure. The median follow-up time was 7.5 years. RESULTS: There was one operative death (0.63%). The overall survival rate was 91.0 +/- 2.6% at 5 years and 79.1 +/- 4.7% at 10 years. Survival was significantly better in patients who underwent Maze procedure than those who did not. The rate of freedom from AF in patients who underwent Maze procedure was 86.4 +/- 4.5% at 1 year and 81.1 +/- 5.6% at 5 years. The freedom rate from stroke was higher in patients who underwent Maze procedure than those who did not. Patients with postoperative AF had larger left ventricular systolic and diastolic diameters at follow-up and higher New York Heart Association functional class than patients without postoperative AF (1.4 +/- 0.5 vs. 1.1 +/- 0.3, p < 0.001). CONCLUSION: Maze procedure can have a positive effect on long-term survival, freedom from stroke, and cardiac function. PMID- 25025891 TI - Is Bilateral Pulmonary Lobectomy Feasible in Patients with Bilateral Lung Cancers? AB - BACKGROUND: While aggressive surgical resection is an acceptable strategy for bilateral lung cancers, there are still some controversies regarding the appropriate indications of bilateral pulmonary lobectomy. METHODS: Between 1996 and 2012, 21 patients underwent bilateral pulmonary lobectomy for bilateral lung cancers. Postoperative complications after bilateral pulmonary lobectomy were defined based on the Common Terminology Criteria for Adverse Event Version 4.0 (National Cancer Institute, USA). RESULTS: In this study, 21 patients underwent bilateral pulmonary lobectomy by staged surgery for bilateral lung cancers. Thirteen patients (62%) recovered without any complications after the second surgery. Among the eight (38%) patients with postoperative complications, four had relatively minor complications of grade 1 or 2. In contrast, postoperative complications were frequently observed in patients who underwent right lower lobectomy, were age >= 70 years, or had larger tumor size (p = 0.0041, 0.0195, 0.0324). The mean hospital stay after the second surgery was 8.0 days. In hospital mortality was found in five patients including three of respiratory failure. The median follow-up period for all patients was 40 months. The 5-year survival rate after bilateral pulmonary lobectomy was 61.7%. CONCLUSION: Although appropriate patient selection and careful perioperative management are mandatory, bilateral pulmonary lobectomy could be an acceptable procedure for patients with bilateral lung cancers. PMID- 25025893 TI - Management of the burned hand. AB - The hand appears to be the most common part of the body involved in burns as it is either used to shield the body from the burning agent or to extinguish the effects elsewhere on the body. The saying that "next to life there are hands" demonstrates the importance that is placed upon the use and need of one's hands in order to carry out everyday tasks of normal living. In order to manage burns to the hands, the effects of the injury and the aftermath must be understood and one must not only consider the hands, but the patient as a whole. The regime of treatment used at the Prince of Wales Burns Unit involving nursing care and physiotherapeutic techniques, is outlined, and the need for understanding of the pathophysiology of burns in order to correctly manage the burned hand is emphasised. PMID- 25025892 TI - Value of flexible bronchoscopy for the preoperative assessment of NSCLC diagnosed using percutaneous core needle biopsy. AB - BACKGROUND: We aimed to investigate the value of routine flexible bronchoscopy (FB) for the preoperative assessment of early-stage non-small cell lung cancer (NSCLC) diagnosed using percutaneous core needle biopsy (PCNB). METHODS: We enrolled 688 NSCLC patients who were treated at our hospital between January 2003 and December 2012 and who met the following criteria: (1) early-stage lung cancer (stage I or II); (2) lung cancer had been diagnosed using PCNB; and (3) no evidence of endobronchial disease in the airways other than the primary cancer site on both chest computed tomography (CT) and positron emission tomography-CT (PET-CT). All NSCLC patients were from the same tertiary referral center, where FB is routinely performed preoperatively for this disease, and their medical records were reviewed retrospectively. RESULTS: Of the 688 patients included in the study, 451 (65.6%) were male and the median age was 65 years. Pathology analysis revealed that adenocarcinoma was the most frequently observed cell type (516/688, 75.0%). The distribution of preoperative clinical staging for the 688 patients was (1) IA (54.5%, 375/688); (2) IB (22.1%, 152/688); (3) IIA (18.2%, 125/688); and (4) IIB (5.2%, 36/688). The majority of these patients (95.2%, 655/688) underwent surgical resection. Unsuspected malignant endobronchial lesion on FB was found in only two cases (0.3%), and the surgical strategy had to be modified for both of these patients. CONCLUSION: Preoperative FB is not beneficial for screening the airways of almost any patient with early-stage NSCLC, provided that neither PET-CT nor CT reveal any evidence of endobronchial malignant involvement other than at the primary cancer site. PMID- 25025894 TI - Recreational activities in community health care. AB - Recreation is a significant element of preventive health care, used by community health centres as an aid to rehabilitation, moderation of stress and maintenance of health. Although the amount of leisure available to the people is increasing, many are unable to take full advantage of it due to inadequate recreational education or other causes. Community health centres have an educative responsibility in this regard especially towards the unemployed. These centres organize therapeutic and socializing groups for patients in need. Examples are given. Recreational activities are also useful in the relief of stress, during breaks in production in work-places. The principles of safety need to be taught as an essential part of recreational education and the fitness of participants needs to be ensured by screening school children. The planning and erection of playground equipment needs supervision by competent professionals who exist in the community health centres. The conclusion recommends that safety check lists be available for all normal recreations and that everyone should receive adequate education to enable successful participation in recreational activities. PMID- 25025895 TI - "Recreation for the disabled from a consumer's point of view". AB - Recreation consists of an activity or experience usually chosen voluntarily by the participant, either because of the immediate satisfaction to be derived from it, or because the individual perceives some personal or social values to be achieved by it. It is usually enjoyable, and when it is conducted as part of organized community or agency services, it is designed to meet constructive and socially worthwhile goals of the individual participant, the group and society at large. PMID- 25025896 TI - Vitamin D supplementation in pregnancy: a systematic review. AB - BACKGROUND: It is unclear whether or not the current evidence base allows definite conclusions to be made regarding the optimal maternal circulating concentration of 25-hydroxyvitamin D [25(OH)D] during pregnancy, and how this might best be achieved. OBJECTIVES: To answer the following questions: (1) What are the clinical criteria for vitamin D deficiency in pregnant women? (2) What adverse maternal and neonatal health outcomes are associated with low maternal circulating 25(OH)D? (3) Does maternal supplementation with vitamin D in pregnancy lead to an improvement in these outcomes (including assessment of compliance and effectiveness)? (4) What is the optimal type (D2 or D3), dose, regimen and route for vitamin D supplementation in pregnancy? (5) Is supplementation with vitamin D in pregnancy likely to be cost-effective? METHODS: We performed a systematic review and where possible combined study results using meta-analysis to estimate the combined effect size. Major electronic databases [including Database of Abstracts of Reviews of Effects (DARE), Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR) and the Health Technology Assessment (HTA) database] were searched from inception up to June 2012 covering both published and grey literature. Bibliographies of selected papers were hand-searched for additional references. Relevant authors were contacted for any unpublished findings and additional data if necessary. Abstracts were reviewed by two reviewers. INCLUSION AND EXCLUSION CRITERIA: SUBJECTS: pregnant women or pregnant women and their offspring. EXPOSURE: either assessment of vitamin D status [dietary intake, sunlight exposure, circulating 25(OH)D concentration] or supplementation of participants with vitamin D or food containing vitamin D (e.g. oily fish). OUTCOMES: offspring - birthweight, birth length, head circumference, bone mass, anthropometry and body composition, risk of asthma and atopy, small for gestational dates, preterm birth, type 1 diabetes mellitus, low birthweight, serum calcium concentration, blood pressure and rickets; mother - pre-eclampsia, gestational diabetes mellitus, risk of caesarean section and bacterial vaginosis. RESULTS: Seventy-six studies were included. There was considerable heterogeneity between the studies and for most outcomes there was conflicting evidence. The evidence base was insufficient to reliably answer question 1 in relation to biochemical or disease outcomes. For questions 2 and 3, modest positive relationships were identified between maternal 25(OH)D and (1) offspring birthweight in meta-analysis of three observational studies using log-transformed 25(OH)D concentrations after adjustment for potential confounding factors [pooled regression coefficient 5.63 g/10% change maternal 25(OH)D, 95% confidence interval (CI) 1.11 to 10.16 g], but not in those four studies using natural units, or across intervention studies; (2) offspring cord blood or postnatal calcium concentrations in a meta-analysis of six intervention studies (all found to be at high risk of bias; mean difference 0.05 mmol/l, 95% CI 0.02 to 0.05 mmol/l); and (3) offspring bone mass in observational studies judged to be of good quality, but which did not permit meta-analysis. The evidence base was insufficient to reliably answer questions 4 and 5. LIMITATIONS: Study methodology varied widely in terms of study design, population used, vitamin D status assessment, exposure measured and outcome definition. CONCLUSIONS: The evidence base is currently insufficient to support definite clinical recommendations regarding vitamin D supplementation in pregnancy. Although there is modest evidence to support a relationship between maternal 25(OH)D status and offspring birthweight, bone mass and serum calcium concentrations, these findings were limited by their observational nature (birthweight, bone mass) or risk of bias and low quality (calcium concentrations). High-quality randomised trials are now required. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001426. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25025897 TI - Student-run free clinics and complementary curricula. PMID- 25025899 TI - A comment on the article on EPR in silver-alanine nanocomposites for radiation detection by Guidelli et al. in Nanoscale, 4, 2012. PMID- 25025898 TI - Inhibition of catalase by tea catechins in free and cellular state: a biophysical approach. AB - Tea flavonoids bind to variety of enzymes and inhibit their activities. In the present study, binding and inhibition of catalase activity by catechins with respect to their structure-affinity relationship has been elucidated. Fluorimetrically determined binding constants for (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) with catalase were observed to be 2.27*106 M(-1) and 1.66*106 M(-1), respectively. Thermodynamic parameters evidence exothermic and spontaneous interaction between catechins and catalase. Major forces of interaction are suggested to be through hydrogen bonding along with electrostatic contributions and conformational changes. Distinct loss of alpha-helical structure of catalase by interaction with EGCG was captured in circular dichroism (CD) spectra. Gallated catechins demonstrated higher binding constants and inhibition efficacy than non-gallated catechins. EGCG exhibited maximum inhibition of pure catalase. It also inhibited cellular catalase in K562 cancer cells with significant increase in cellular ROS and suppression of cell viability (IC50 54.5 uM). These results decipher the molecular mechanism by which tea catechins interact with catalase and highlight the potential of gallated catechin like EGCG as an anticancer drug. EGCG may have other non-specific targets in the cell, but its anticancer property is mainly defined by ROS accumulation due to catalase inhibition. PMID- 25025902 TI - Central nervous system contribution to mechanically produced motor and sensory responses. AB - Peripheral tissue pathology causes a rapid and enduring increase in the excitability of spinal cord neurones. This review examines some of the basic and clinical research which suggests that the central nervous system is capable of making a contribution to clinical signs and symptoms. Mechanically produced clinical responses of pain and movement behaviour may not always be indicative of their source or cause. Certain implications for physiotherapy are discussed. The actual systemic effects of mechanical stimuli, as used clinically by physiotherapists, need to be investigated. PMID- 25025903 TI - Pain or resistance - the manual therapists' dilemma. AB - Australian physiotherapists have been encouraged to collect interpret and use information related to spinal stiffness during the assessment and treatment of patients with spinal pain. This paper discusses some problems surrounding the interpretation of stiffness data and suggests an alternative approach to clinical practice that does not rely upon these tests. A review of the literature currently available suggests that considering stiffness may hinder rather than help treatment selection and patient management. PMID- 25025900 TI - Phylodynamic analysis reveals CRF01_AE dissemination between Japan and neighboring Asian countries and the role of intravenous drug use in transmission. AB - BACKGROUND: One major circulating HIV-1 subtype in Southeast Asian countries is CRF01_AE, but little is known about its epidemiology in Japan. We conducted a molecular phylodynamic study of patients newly diagnosed with CRF01_AE from 2003 to 2010. METHODS: Plasma samples from patients registered in Japanese Drug Resistance HIV-1 Surveillance Network were analyzed for protease-reverse transcriptase sequences; all sequences undergo subtyping and phylogenetic analysis using distance-matrix-based, maximum likelihood and Bayesian coalescent Markov Chain Monte Carlo (MCMC) phylogenetic inferences. Transmission clusters were identified using interior branch test and depth-first searches for sub-tree partitions. Times of most recent common ancestor (tMRCAs) of significant clusters were estimated using Bayesian MCMC analysis. RESULTS: Among 3618 patient registered in our network, 243 were infected with CRF01_AE. The majority of individuals with CRF01_AE were Japanese, predominantly male, and reported heterosexual contact as their risk factor. We found 5 large clusters with >=5 members and 25 small clusters consisting of pairs of individuals with highly related CRF01_AE strains. The earliest cluster showed a tMRCA of 1996, and consisted of individuals with their known risk as heterosexual contacts. The other four large clusters showed later tMRCAs between 2000 and 2002 with members including intravenous drug users (IVDU) and non-Japanese, but not men who have sex with men (MSM). In contrast, small clusters included a high frequency of individuals reporting MSM risk factors. Phylogenetic analysis also showed that some individuals infected with HIV strains spread in East and South-eastern Asian countries. CONCLUSIONS: Introduction of CRF01_AE viruses into Japan is estimated to have occurred in the 1990s. CFR01_AE spread via heterosexual behavior, then among persons connected with non-Japanese, IVDU, and MSM. Phylogenetic analysis demonstrated that some viral variants are largely restricted to Japan, while others have a broad geographic distribution. PMID- 25025901 TI - Strategic targeting of the PI3K-NFkappaB axis in cisplatin-resistant NSCLC. AB - Chemoresistance is a major therapeutic challenge to overcome in NSCLC, in order to improve the current survival rates of<15% at 5 years. We and others have shown increased PI3K signaling in NSCLC to be associated with a more aggressive disease, and a poorer prognosis. In this study, targeted inhibition of three strategic points of the PI3K-NFkappaB axis was performed with the aim of exploiting vulnerabilities in cisplatin-resistant NSCLC cells. Cisplatin resistant cell lines were previously generated through prolonged exposure to the drug. Expression of PI3K and NFkappaB pathway-related genes were compared between cisplatin-resistant cells and their matched parent cells using a gene expression array, qRT-PCR, DNA sequencing, western blot, and immunofluorescence. Targeted inhibition was performed using GDC-0980, a dual PI3K-mTOR inhibitor currently in Phase II clinical trials in NSCLC, and DHMEQ, an inhibitor of NFkappaB translocation which has been used extensively both in vitro and in vivo. Effects of the two inhibitors were assessed by BrdU proliferation assay and multiparameter viability assay. NFKBIA was shown to be 12-fold overexpressed in cisplatin-resistant cells, with no mutations present in exons 3, 4, or 5 of the gene. Corresponding overexpression of IkappaBalpha was also observed. Treatment with DHMEQ (but not GDC-0980) led to significantly enhanced effects on viability and proliferation in cisplatin-resistant cells compared with parent cells. We conclude that NFkappaB inhibition represents a more promising strategy than PI3K mTOR inhibition for treatment in the chemoresistance setting in NSCLC. PMID- 25025904 TI - Is walking aid height critical? AB - A study is reported in which 20 healthy subjects performed a non weight-bearing aided gait with elbow crutches. The crutches were adjusted to a conventional height and also to heights 2cm and 4cm above and below this setting. Temporospatial and kinetic data were acquired and the results indicated that no significant differences were demonstrated for most parameters across the various height settings. Only at the setting 4cm above conventional was there a significant increase in the abduction moment at the shoulder joint. The conclusion of the study was that height adjustment of elbow crutches with this gait was not a critical issue except at a height 4cm above the conventional setting, and that the subjective impression of the user regarding comfort was a good indicator of correctness of fit. PMID- 25025905 TI - Clinical diagnosis and management of minor shoulder instability. AB - The term minor instability refers to a condition in which chronic microtrauma involving the stabilising mechanisms of the glenohumeral joint leads to subluxation of the humeral head. The condition is commonly associated with athletes involved in repetitive high-velocity activities such as throwing or swimming. Minimal signs are found on physical examination of the shoulder joint but the patient presents with vague pain, catches of pain, apprehension with overhead movement or an impingement-like condition which appears resistant to treatment. The clinical examination findings which might alert the physiotherapist to the potential diagnosis of minor instability are reviewed. Following this, an approach to management with emphasis on establishing muscular control in the early stages of rehabilitation is presented. PMID- 25025906 TI - Stretching the truth. A review of the literature on muscle stretching. AB - The title of this review can be interpreted in two ways, reflecting the stage of development of knowledge regarding the neuromuscular events during short duration stretching of normal muscle. If current scientific theories are accepted as the truth, then the truth needs to be stretched a little to explain the findings from clinical trials in normal human subjects. Recent studies have shown quite high levels of electromyographic (EMG) activity in muscle undergoing stretching and also that proprioceptive neuromuscular facilitation (PNF) relaxation techniques actually increase EMG activity, yet paradoxically result in greater gains in range than those obtained from passive stretching techniques. These findings limit the somewhat simplistic notion of muscle relaxation during stretching, to achieve intramuscular connective tissue elongation. PMID- 25025907 TI - Peripheral articular mechanisms in pain production in osteoarthritis. AB - Osteoarthritis is a common disabling joint disease frequently resulting in considerable pain and discomfort. Although some progress has been made in terms of medical therapies designed to reduce osteoarthritic pain, the limitations of these therapies emphasise the need to explore alternative approaches to osteoarthritic pain management. This report summarises the major mechanisms of pain production in osteoarthritis and discusses the potential use of those exercises commonly used by physical therapists for relieving the pain associated with this disease. It is concluded that, in view of our limited understanding of the mechanisms of osteoarthritic pain production and the paucity of studies demonstrating the efficacy of exercise for reducing osteoarthritic pain, further basic and clinical research in this area is warranted. PMID- 25025908 TI - Isokinetic strength of the shoulder rotators in primary school boys. AB - Twenty boys aged between eight and 12 years were studied to determine the reliability of using an isokinetic dynamometer (KIN-COM) in evaluating shoulder rotation and to assess the relationship of anthropometric measures to isokinetic strength. Using a repeated measures design, each subject was asked to work the internal and external rotators of the glenohumeral joint of the dominant upper extremity concentrically and eccentrically at two speeds in random order on two separate occasions. Results showed no significant differences between the strength data collected on the two occasions. Internal rotators were found to be significantly stronger than the external rotators and the eccentric strength was significantly greater than the concentric strength. A significant relationship between the anthropometric measures (age, height and lean body weight) and the isokinetic strength was also demonstrated. PMID- 25025910 TI - Planning for clinical research. AB - The need to initiate research projects in physiotherapy is being recognized throughout the world, while a growing interest is being shown by physiotherapists in undertaking studies appropriate to the areas of medicine. Many writers have urged the profession to accept its responsibility for contributing to the advancement of knowledge and it is to be hoped that an increasing number of physiotherapists will respond to this challenge. PMID- 25025911 TI - Self-directed relaxation in daily living. AB - The purpose of this paper is to present a brief relaxation routine which can be easily learned and applied in daily living. PMID- 25025909 TI - Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients. AB - Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n = 355) and risperidone (n = 260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624 rs11013052-rs1409396) of PIP4K2A gene in incomplete responders (corrected p-value = 0.001; adjusted-OR = 3.19, 95%-CI = 1.46-6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub groups. MDR approach identified gene-gene interaction among BDNF_rs7103411 BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR = 7.91, 95%-CI = 4.08-15.36). While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in incomplete responders with low severity (OR = 4.09, 95%-CI = 2.09-8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of PIP4K2A gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway. PMID- 25025912 TI - Approach to the management of feeding problems in infancy. AB - The establishment and maintenance of satisfactory feeding is one of the basic concerns of those involved in caring for the infant. At first the baby's progress is measured in terms of his weight gain and growth, how well he takes his food and how contented he is. A little later, we anticipate his first smile, a growing awareness of his world, reaching and moving to explore and respond to it. Such new experiences as orange juice, cereal from a spoon, getting his first tooth, getting hands into his mouth, sucking his fingers, sitting up, babbling, eating strained foods, chewy foods - all mark milestones in the first year of life. When he is sick he goes "off his food". His well-being and progress are reflected in the feeding situation. PMID- 25025913 TI - Thoracic physiotherapy in paediatric intensive care. AB - Intensive care is the only area in paediatric physiotherapy in which the parents play little active part in treatment. In nearly every disease, whether thoracic, neurological or orthopaedic, the parents themselves carry out the treatment at home, and the therapist acts as teacher, supervisor and assessor. With inpatients, the parents must be taught to continue on discharge where the therapist leaves off. But in intensive care, the parents' role is to support the child emotionally while the therapist conducts the treatment. PMID- 25025914 TI - Preventive physiotherapy in industry. AB - Working time lost through industrial injury throughout Australia in 1973-4 amounted to some one and a quarter million man-weeks, costing in excess of one hundred million dollars, this figure being deduced from the total of claims under Workers' Compensation and Employers' Liability. About 28% of recorded injuries resulted directly from accidents during manual handling. A further 22% resulted from falling, slipping and tripping. In both classifications, sprains and strains were predominant. A relatively high occurrence of tenosynovitis and other soft tissue injuries, probably the result of repetitive motion and/or prolonged poor posture at work, were recorded. The implication is that over half of all industrial injuries are directly related to posture and body mechanics, the area in which physiotherapists are particularly interested and in which they are qualified to implement preventive action. PMID- 25025915 TI - Teamwork in community care. AB - What is teamwork? To some, it is like the battle cry of the innovators, the panacea of the jaded administrator or the latest fad in health care. I would like to help you look at it as a process whereby a group of people work together towards a common goal. It is cooperation and sharing. In the health care setting, it is a method whereby people who have been trained for different tasks contribute their various skills, expertise and differences in perception, to the management of problems of people needing health care. It is a co-operative effort directed towards meeting the health needs of a given community, hospital and beyond, in which the different professionals develop a working relationship in which they share and care, not only for their patients or clients, but for each other. PMID- 25025916 TI - Community care - the glebe approach. AB - The short history of Community Health Centres in Australia has been a stormy one. They have been seen as a threat by sections of the health care professionals. To some there is insecurity of roles and status, which can arise from the claims of emerging professions who are trying to establish their identities within the health-care team. To others, livelihood is threatened and health centres have been seen as the Labor Government's first steps towards nationalisation of Health. In this context it is interesting to note that regionalisation, including neighbourhood health centres, was a policy of the New South Wales Liberal Government long before it became Federal policy under a Labor Government. Questions of leadership, co-ordination and responsibility within health centres have also caused conflict. This has occurred at a time of rapid change, not only in health care delivery, but in the whole of society. It is no wonder people are confused. PMID- 25025917 TI - Problems of ethnic groups in our community. AB - In Australia there are many ethnic groups with varied social and traditional backgrounds. The English migrants, while being predominant in number, are considered to have the least problems, since their emotional and physical environment is similar to that of Australia. Migrants from Western Europe, while having an initial language problem, can be placed in the same category as the English migrant by virtue of Western Europe's comparable industrial and domestic conditions. PMID- 25025918 TI - Exercise as a bronchodilator. AB - In "Notes on Asthma" published in 1873, John Thorowgood stated that "daily exercise in the open air should not be neglected, and several cases testify to the effect of a steady walk in preventing an attack of asthma even when it already threatens". Similarly, Salter (1868) suggested that he was "puzzled by the fact" that exercise appeared to help some of his patients. From what we know today, it may be suggested that these patients were in fact, benefiting from the bronchodilation caused by exercise. PMID- 25025919 TI - Post-rotatory nystagmus in hyperactive children with spatial awareness problems. AB - In recent years a great deal of attention has been focused on the problems presented by children diagnosed as having "minimal cerebral dysfunction", a term which refers to children exhibiting mild clinical neurological symptoms. In 1973, Wender expanded this definition, pointing out that hyperactivity, short attention span, impulsivity, poor school work, perceptual-cognitive dysfunction and poor neurological functioning and coordination are among some of the cardinal features of minimal cerebral dysfunction. Recently, the various professional groups involved in the management of these children have become much more aware of their problems and, as a team, are endeavouring to provide better rationale for treatment procedures and management. PMID- 25025920 TI - Relaxation, the physiotherapist and the psychiatric patient. AB - This article discusses the role of relaxation training in psychiatric hospitals. Details of indications and contraindications are given. Interdisciplinary approach is stressed. Some ways in which physiotherapists may contribute to this area of patient care are suggested. PMID- 25025921 TI - The student selection process in three countries. AB - Of ninety institutions in three countries surveyed by a mail questionnaire, responses were received from 68 baccalaureate programmes in physiotherapy, a return rate of 76%. Selection criteria for all programmes were shown to be multiple, with the student's previous academic achievement used in every instance. A proportion of programmes indicated the use of objective measures of ability, interest and personality but rarely were these used in any combination. The majority of programmes use the interview, references, student's objectives and experience in physical therapy in combination. No respondents indicated specific weighting for any of these factors and the questionnaire did not seek this information specifically. PMID- 25025922 TI - Below knee temporary prosthesis. AB - There are definite advantages in using temporary prostheses. Their use reduces the length of time spent in hospital by amputee patients because stump conditioning and gait retraining is virtually completed by the time the patient receives his permanent prosthesis. PMID- 25025923 TI - Assessment of the value of positive pressure breathing apparatus in inducing cough. AB - In the last decade, numerous papers have discussed what has been called the indiscriminate use of intermittent positive pressure breathing therapy (IPPB) for the treatment of obstructive airways disease (Curtis et al., 1968; Loke and Anthonisen, 1974; Cheney et al., 1976; Baker, 1974; Murray, 1974; Barach and Segal, 1975; Sheldon and Gold, 1976; Dolovich et al., 1977). These papers have all failed to show any advantage of positive pressure breathing therapy, either in the acute or chronic stages of obstructive airways disease. IPPB apparatus is expensive, requires careful maintenance and cleaning and may lead to patient dependence. However, physiotherapists in this hospital gained the impression that patients who were receiving nebulisation with positive pressure appeared to cough more frequently, and to produce greater volumes of sputum, suggesting that IPPB apparatus may be a useful adjunct of physiotherapy. Therefore a study was designed to compare the effectiveness of nebulisation therapy, with and without positive pressure, on the production of cough and sputum volume in patients with chronic obstructive airways disease. PMID- 25025924 TI - The life cycle of the intervertebral discs and vertebral bodies: a review. AB - A review of the current concepts of growth, maturation and development of the vertebral bodies and intervertebral discs. PMID- 25025925 TI - A new concept in traction tables kaltenborn three dimensional treatment table. AB - The structure and use of the Kaltenborn Three Dimensional Couch is described. The couch is of particular value to therapists practising mobilization and manipulation of the spine but would be a valuable adjunct to any physiotherapist. Use of the couch has reduced treatment time and increased efficiency. PMID- 25025926 TI - Outcome following tranexamic acid exposure during breastfeeding. AB - OBJECTIVE: This study evaluated the outcome of infants exposed to tranexamic acid during lactation. SUBJECTS AND METHODS: A prospective, controlled observational study design was used. Mothers who contacted the Beilinson Teratology Information Service (BELTIS) regarding use of tranexamic acid while breastfeeding were followed up by phone interview. Data on lactation, neonatal symptoms, and outcomes at the age of 1-3 years were obtained. Mothers' breastfeeding while taking tranexamic acid and their infants were compared with those of a matched control group of breastfeeding mothers using a drug known to be safe during lactation (amoxicillin) and their infants. RESULTS: Follow-up was obtained for 28 of 32 women who sought advice regarding use of tranexamic acid during breastfeeding. Of the 28 women, six did not take the drug, and one refused to participate. The 21 remaining women (study group) were compared with 42 control women. A decreased amount of breastmilk was reported by one woman in the study group versus two women in the control group (p=1.0). Possible adverse drug effects were reported for one of 21 study group infants (restlessness) and for one of 42 control group infants (gastroesophageal reflux) (p=1.0). Growth below the 3rd percentile was found in one of 21 study group infants versus four of 42 control group infants (p=0.66). Development was normal for all study group infants. CONCLUSIONS: No increase in adverse long-term outcomes was found in infants exposed through breastfeeding to tranexamic acid. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women requiring treatment with tranexamic acid. PMID- 25025927 TI - The ERK/eIF4F/Bcl-XL pathway mediates SGP-2 induced osteosarcoma cells apoptosis in vitro and in vivo. AB - The aim of this study is to assess the molecular foundation of anti-tumor activity of SGP-2 in osteosarcoma cells. SGP-2 significantly blocks cell proliferation in human osteosarcoma U2OS cell model and inhibits tumor growth without causing apparent toxicity effect in mouse sarcoma S-180 cell-derived tumor model. Moreover, SGP-2 induces intrinsic apoptosis including the activation of caspase-3/7/9, the loss of mitochondrial transmembrane potential (DeltaPsim), and the release of cytochrome c from mitochondrion, controlled by the down regulation of B-cell lymphoma-extra large (Bcl-XL). Further research reveals that SGP-2 inhibits the assembly of eukaryotic initiation factor 4F (eIF4F) complex which is responsible for the decline of Bcl-XL. Finally, extracellular-signal regulated kinase (ERK) controls SGP-2 induced intrinsic apoptosis. Taken together, SGP-2 exerts anti-tumor effect through intrinsic apoptotic pathway controlled by ERK/eIF4F/Bcl-XL pathway. PMID- 25025928 TI - The physiotherapist and the acutely ill patient. AB - Nowadays acutely ill patients are nursed in intensive care units which have become the status symbol of the modern hospital. These units sometimes provide treatment which is more "intensive" than it is "caring" because the need for personal involvement of the staff with the patient may be subjugated to the needs of the monitors, respirators and other gadgetry. An array of knobs, dials and flashing lights is usually displayed prominently to impress the visitor and ensure that the ward acquires the full prestige value which such equipment merits. The staff, who have a considerable ego-investment in this electric paraphernalia, derive much satisfaction from its operation even when it is recording the terminal paroxysms of a dying patient. There is still wide debate in the medical literature as to whether these units can justify, in terms of gainful lives saved, their enormously expensive equipment, staff and expertise. Be all that as it may, there is no doubt that the intensive care unit has come to stay and we must all learn to work in them and, in particular, help the patients who are being processed by them to maintain a healthy outlook. Such patients may be well looked after physically but are often silently suffering psychological torture. PMID- 25025929 TI - Whiplash injuries of the cervical spine. AB - Whiplash injuries of the cervical spine are caused chiefly by road traffic accidents, but of course, to a lesser extent, occur in sport, in falls, and occasionally in industrial accidents. PMID- 25025930 TI - The short leg brace for ankle foot stability in adults. AB - When bracing of the ankle joint is indicated because of drop foot or spastic plantar flexors which prevent dorsiflexion, it is necessary to consider the foot not in isolation but in conjunction with the neighbouring joints, the other joints of the lower limb and even those of the trunk. Walking, running and jumping are highly complex and co-ordinated movements, and limitations on any one joint may derange neighbouring joints and cause disorders in weight bearing (Bowden, 1967). PMID- 25025931 TI - Developmental perceptual-motor disorders. AB - To understand or even begin to conceive the problems of the perceptually-motor handicapped is an enormous task. We have developed our personalities and abilities in a stable and meaningful environment and our security lies in our ability to manipulate and give meaning to this environment. Imagine the difficulties that are faced by a child with perceptual-motor problems. By this, we mean that he has problems with: (1) inaccurate or distorted input in the fields of vision, audition, proprioception, kineasthesia and tactility, (2) inaccurate integration of this input, (3) inaccurate motor output or inadequate responses. PMID- 25025932 TI - The conservative treatment of the acromioclavicular joint injury with special relation to physiotherapy treatment. AB - Injury to the acromioclavicular joint typically occurs when the point of the shoulder is speared into the ground. The clavicle tends to be displaced in the line of the action, resulting in a swelling in the acromioclavicular joint area, on the superior surface of the shoulder. The lateral and posterior section of the superior ligament is generally either strained or torn. It is probable the coraco clavicular ligament is also strained, but it is not obvious. PMID- 25025933 TI - Preparation of Au-Pt nanostructures by combining top-down with bottom-up strategies and application in label-free electrochemical immunosensor for detection of NMP22. AB - A novel label-free amperometric immunosensor for sensitive detection of nuclear matrix protein 22 (NMP22) was developed based on Au-Pt bimetallic nanostructures, which were prepared by combining top-down with bottom-up strategies. Nanoporous gold (NPG) was prepared by "top-down" dealloying of commercial Au/Ag alloy film. After deposition of NPG on an electrode, Pt nanoparticles (PtNPs) were further decorated on NPG by "bottom-up" electrodeposition. The prepared bimetallic nanostructures combine the merits of both NPG and PtNPs, and show a high electrocatalytic activity towards the reduction of H2O2. The label-free immunosensor was constructed by directly immobilizing antibody of NMP22 (anti NMP22) on the surface of bimetallic nanostructures. The immunoreaction induced amperometric response could be detected and negatively correlated to the concentration of NMP22. Bimetallic nanostructure morphologies and detection conditions were investigated to obtain the best sensing performance. Under the optimal conditions, a linear range from 0.01ng/mL to 10ng/mL and a detection limit of 3.33pg/mL were obtained. The proposed immunosensor showed high sensitivity, good selectivity, stability, reproducibility, and regeneration for the detection of NMP22, and it was evaluated in urine samples, receiving satisfactory results. PMID- 25025935 TI - Economic burden of amyotrophic lateral sclerosis: a Canadian study of out-of pocket expenses. AB - This study quantifies the 'out-of-pocket' expenses incurred by individuals with amyotrophic lateral sclerosis (ALS) and their families, explores cost-driving factors and describes the current state of financial support in a Canadian cohort. We performed structured cost-of-illness interviews with 50 consecutive ALS patients and family members detailing disease-specific factors, direct and indirect costs. Direct costs were divided into 'out-of-pocket' and 'government/non-profit organization (NPO) supported'. Results showed that the average annual direct cost per patient was $32,337, of which $19,574 (61%) was paid for out-of-pocket. The most significant direct cost was disease-related home renovations, which garnered minimal government or NPO support. The costs of mobility aids, medical expenses, and private personal support workers were also substantial. Higher out-of-pocket costs were associated with an ALS Functional Rating Scale gross motor subscore of <= 6 (p = 0.03), limb-predominant symptoms (p = 0.04) and > 4 h/week of personal support care (p = 0.005). Annual indirect costs (lost wages) for patients with ALS and family members providing care were $56,821. In conclusion, this study quantified the substantial personal economic impact of ALS as measured by non-reimbursed, out-of-pocket expenses. Mobilization of additional resources for ALS patients and families is required to soften the economic burden of this disabling disease. PMID- 25025936 TI - Isolated core training improves sprint performance in national-level junior swimmers. AB - PURPOSE: To quantify the effects of a 12-wk isolated core-training program on 50 m front-crawl swim time and measures of core musculature functionally relevant to swimming. METHODS: Twenty national-level junior swimmers (10 male and 10 female, 16+/-1 y, 171+/-5 cm, 63+/-4 kg) participated in the study. Group allocation (intervention [n=10], control [n=10]) was based on 2 preexisting swim-training groups who were part of the same swimming club but trained in different groups. The intervention group completed the core training, incorporating exercises targeting the lumbopelvic complex and upper region extending to the scapula, 3 times/wk for 12 wk. While the training was performed in addition to the normal pool-based swimming program, the control group maintained their usual pool-based swimming program. The authors made probabilistic magnitude-based inferences about the effect of the core training on 50-m swim time and functionally relevant measures of core function. RESULTS: Compared with the control group, the core training intervention group had a possibly large beneficial effect on 50-m swim time (-2.0%; 90% confidence interval -3.8 to -0.2%). Moreover, it showed small to moderate improvements on a timed prone-bridge test (9.0%; 2.1-16.4%) and asymmetric straight-arm pull-down test (23.1%; 13.7-33.4%), and there were moderate to large increases in peak EMG activity of core musculature during isolated tests of maximal voluntary contraction. CONCLUSION: This is the first study to demonstrate a clear beneficial effect of isolated core training on 50-m front-crawl swim performance. PMID- 25025934 TI - Endothelial cells in dengue hemorrhagic fever. AB - Therapies to prevent or reverse endothelial dysfunction and vascular leak found in dengue hemorrhagic fever (DHF) have not been identified. In this review we summarize dengue viruses and the spectrum of human disease and highlight evidence of endothelial cell dysfunction in DHF based on studies in patients and mouse and tissue culture models. Evidence suggests that both virus antigen and host immune response, can cause endothelial cell dysfunction and weaken endothelial barrier integrity. We suggest possible therapeutic interventions and highlight how therapies targeting altered endothelial function might be evaluated in animal models and in patients with DHF. PMID- 25025937 TI - Reply: To PMID 24418227. PMID- 25025938 TI - Re: The debate over robotics in benign gynecology. PMID- 25025939 TI - The relationship between primary cesarean delivery skin incision type and wound complications in women with morbid obesity: a response. PMID- 25025940 TI - Reply: To PMID 24657131. PMID- 25025941 TI - The fellowship effect: how the establishment of a fellowship in female pelvic medicine and reconstructive surgery affected resident vaginal hysterectomy training. AB - OBJECTIVE: We report on trends in resident-performed vaginal hysterectomies before and after the establishment of a female pelvic medicine and reconstructive surgery fellowship at Vanderbilt University Medical Center. STUDY DESIGN: We examined medical records and resident self-reports concerning all hysterectomies at our institution in an 8-year period: 4 years before fellowship and 4 years after. Route of hysterectomy, resident and fellow involvement, and division of attending surgeon were recorded from the electronic medical record. Resident Accreditation Council for Graduate Medical Education (ACGME) case log data were used to estimate the number of hysterectomies where residents reported themselves as the primary surgeon. RESULTS: During the 8-year period of this study, 3317 hysterectomies were performed at our institution, 41% (1371) before and 59% (1946) after fellowship. Prior to fellowship, 29% (393) were vaginal, 56% (766) were abdominal, and 15% (212) were laparoscopic/robotic. After addition of fellowship, 23% (449) were vaginal, 31% (597) were abdominal, and 46% (900) were laparoscopic/robotic. Of the total vaginal hysterectomies (TVH), there was resident involvement in 98.0% (385) cases before fellowship and 98.2% (441) cases after fellowship. From the ACGME case log data, the resident identified himself/herself as the primary surgeon in 388 cases before and 393 cases after fellowship. During this time period, medical records indicate a fellow was involved in 42% (189) of TVH, with resident involvement in all but 5 of these procedures. CONCLUSION: Frequency of resident involvement in TVH cases, either as primary surgeon or team member, remained constant after the addition of the female pelvic medicine and reconstructive surgery fellowship. PMID- 25025942 TI - Medical and obstetric complications among pregnant women with cystic fibrosis. AB - OBJECTIVE: The objective of this study was to estimate the nationwide prevalence of cystic fibrosis (CF) in pregnancy and determine what medical complications exist at delivery among pregnant women with CF. STUDY DESIGN: The Nationwide Inpatient Sample (NIS) was queried for all delivery-related discharges. Women with CF were identified by International Classification of Diseases, 9th revision, Clinical Modifications codes and compared with women without CF. The prevalence of selected severe medical complications was compared between the 2 groups (NIS years 2008-2010) using multivariable logistic regression and the linear change in prevalence of CF at delivery determined (NIS years 2000-2010). RESULTS: From 2000 to 2010, there was a significant linear increase in the prevalence of CF at delivery from 3.0 to 9.8 per 100,000 deliveries, in 2000 and 2010, respectively (R(2) = 0.92, P < .0001). From 2008-2010, there were 1119 deliveries to women with CF and 12,627,627 to women without CF. Women with CF were more likely to be white (P < .0001) and have diabetes (odds ratio [OR], 14.0; 95% confidence interval [CI], 11.8-16.7) or asthma (OR, 5.1; 95% CI, 4.3 6.1). Multivariable logistic regression demonstrated that women with CF were more likely to die (adjusted OR [aOR], 76.0; 95% CI, 31.6-183), require mechanical ventilation (aOR, 18.3; 95% CI, 10.8-31.2), or have pneumonia (aOR, 56.5; 95% CI, 43.2-74.1), acute renal failure (aOR, 17.3; 95% CI, 9.1-32.6), preterm labor (aOR, 2.2; 95% CI, 1.9-2.6), or an adverse composite CF outcome (aOR, 28.1; 95% CI, 21.8-36.3). CONCLUSION: Pregnant women with CF are more likely to die, require mechanical ventilation, and have infectious complications compared with women without CF, although the absolute risks are low and these events are relatively rare. PMID- 25025943 TI - Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA. PMID- 25025944 TI - Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety. AB - The purpose of this study was to assess the effectiveness of instituting a comprehensive protocol for the treatment of maternal hemorrhage within a large health care system. A comprehensive maternal hemorrhage protocol was initiated within a health care system with 29 different delivery units and with >60,000 annual births. Compliance with key elements of the protocol was assessed monthly by a dedicated perinatal safety nurse at each site and validated during site visits by system perinatal nurse specialist. Outcome variables were the total number of units of blood transfused and the number of puerperal hysterectomies. Three time points were assessed: (1) 2 months before implementation of the protocol, (2) a 2-month period that was measured at 5 months after implementation of the protocol, and (3) a 2-month period at 10 months after implementation. There were 32,059 deliveries during the 3 study periods. Relative to baseline, there was a significant reduction in blood product use per 1000 births (-25.9%; P < .01) and a nonsignificant reduction (-14.8%; P = .2) in the number of patients who required puerperal hysterectomy. Within a large health care system, the application of a standardized method to address maternal hemorrhage significantly reduced maternal morbidity, based on the need for maternal transfusion and peripartum hysterectomy. These data support implementation of standardized methods for postpartum care and treatment of maternal hemorrhage and support that this approach will reduce maternal morbidity. PMID- 25025945 TI - Alternative splicing in the fiddler crab cognate ecdysteroid receptor: variation in receptor isoform expression and DNA binding properties in response to hormone. AB - RXR cDNA cloning from three Uca species led to the identification of 4 conserved isoforms, indicative of alternative splicing in the hinge and ligand binding domains (LBD). Sequencing of overlapping clones from a Ucapugilator genomic library identified EcR isoforms matching previously identified cDNA variants; in addition, a cryptic exon in the LBD was detected and evidence for expression of this new isoform was obtained from next-generation sequencing. RNA-seq analysis also identified a new amino terminal EcR variant. EcR and RXR transcript abundance increases throughout ovarian maturation in U. pugilator, while cognate receptor transcript abundance remains constant in a related Indo-Pacific species with a different reproductive strategy. To examine if crab RXR LBD isoforms have different physical properties in vitro, electromobility shift assays were performed with different EcR isoforms. The cognate crab and fruit fly receptors differ in their responses to hormone. Ecdysteroids did not increase DNA binding for the crab heterodimers, while ecdysteroids stimulate binding for Drosophilamelanogaster EcR/USP heterodimers. In swapping experiments, UpEcR/USP heterodimers did not show ligand-responsive differences in DNA binding; both crab RXR LBD isoforms, however, conferred ligand-responsive increases in DNA binding with DmEcRs. These data indicate that both UpRXR LBD isoforms can heterodimerize with the heterologous DmEcR receptors and promote ligand and DNA binding. Unresponsiveness of the cognate receptors to ecdysteroid, however, suggest additional factors may be required to mediate endogenous, perhaps isoform specific, differences in EcR conformation, consistent with previously reported effects of UpRXR isoforms on UpEcR ligand-binding affinities. PMID- 25025946 TI - Size-dependent effects of nanoparticles on enzymes in the blood coagulation cascade. AB - Nanoparticles (NPs) are increasingly used in diagnostic and drug delivery. After entering the bloodstream, a protein corona will form around NPs. The size and curvature of NPs is one of the major characteristics affecting the composition of bound protein in the corona. Key initiators of the intrinsic pathway of blood coagulation, the contact activation complex, (Kallikrein, Factor XII, and high molecular weight Kininogen) have previously been identified on NPs surfaces. We show that the functional impact of carboxyl-modified polystyrene NPs on these initiators of the intrinsic pathway is size dependent. NPs with high curvature affect the enzymatic activity differently from NPs with low curvature. The size dependency is evident in full blood plasma as well as in solutions of single coagulation factors. NPs induce significant alteration of the enzymatic activity in a size-dependent manner, and enzyme kinetics studies show a critical role for NPs surface area and curvature. PMID- 25025947 TI - One-step preparation of mirror-like NiS nanosheets on ITO for the efficient counter electrode of dye-sensitized solar cells. AB - NiS nanosheets on ITO substrates were synthesized with in situ growth via a one step hydrothermal route, and exhibited an efficiency of 7.08% which was comparable to the solar cell based on the Pt electrode (7.01%) under the similar conditions. PMID- 25025949 TI - Maternal expectations and postpartum emotional adjustment in first-time mothers: results of a questionnaire survey. AB - OBJECTIVE: Several predictors of postpartum mood have been identified in the literature, but the role of maternal expectations in postpartum mental health remains unclear. The aim of this study was to identify whether maternal expectations during the postpartum hospital stay predict adjustment and depressive symptoms at 6 weeks postpartum. METHODS: The sample included 233 first time mothers recruited from the postpartum unit of a Midwestern hospital. Participants completed measures of maternal expectations and depressive symptoms (EPDS) at Time 1 (2 d postpartum) and completed EPDS and an Emotional Adjustment Scale (BaM-13) at Time 2 (6 weeks postpartum). RESULTS: A conditional relationship between the expectation that an infant's behavior will reflect maternal skill and Time 2 outcomes (BaM-13 and EPDS) was found, such that endorsing this belief predicted increased depression and poorer adjustment in those with higher (but not lower) Time 1 EPDS scores. Time 2 BaM-13 scores were also negatively predicted by expectations of self-sacrifice and positively predicted by expectations that parenthood would be naturally fulfilling. CONCLUSIONS: The expectations that new mothers hold about parenting soon after delivery are predictive of emotional adjustment in the early postpartum period, suggesting a role for discussion of expectations in future preventive strategies. PMID- 25025948 TI - Breaking of the phosphodiester bond: a key factor that induces hemolysis. AB - In-depth understanding the toxicity of nanomaterials in red blood cells (RBCs) is of great interest, because of the importance of RBCs in transporting oxygen in blood circulation. Although the toxic effects of nanoparticles in RBCs have been revealed, the conclusions from the literature are conflicting, and in particular, the toxic mechanism is still at the infant stage. Herein, we investigated the size-dependent toxicity of well-known CdTe semiconductor quantum dots (QDs) and revealed the exact toxic mechanism at the molecular level by confocal microscopy and Fourier transform infrared (FT-IR) spectroscopy techniques. We found that smaller mercaptosuccinic acid-capped CdTe QDs (MSA-QDs) with the green-emitting color could cause hemagglutination whereas the middle-size yellow-emitting MSA QDs induced the formation of stomatocytes and echinocytes and the bigger size red emitting MSA-QDs induced heavy hemolysis and the formation of lots of ghost cells. The FT-IR data proved that all the MSA-QDs were likely to bond to the RBCs membranes and caused the structural changes of lipid and protein in RBCs. But only the red-emitting MSA-QDs caused the breakage of the phosphodiester bond, which might cause the heavy hemolysis. To some extent, this is the first example that reveals the hemolysis mechanism at the molecular level. PMID- 25025951 TI - Physiotherapy at the XII Commonwealth Games Part I: Organization and Utilization of Services. AB - During the XII Commonwealth Games held in Brisbane in 1982, Australian physiotherapists provided a host service which treated nearly one thousand competitors and officials. This service, which was offered at both the Games Villages and Sporting Venues, required extensive planning over a two and a half year period. Appropriate staffing, equipment and space allocation was needed to cater for the wide variety of expected injuries. The services were well utilized which justified the efforts of the organizers and physiotherapists involved in the host team. PMID- 25025950 TI - Rapid prototyping amphiphilic polymer/hydroxyapatite composite scaffolds with hydration-induced self-fixation behavior. AB - Two major factors hampering the broad use of rapid prototyped biomaterials for tissue engineering applications are the requirement for custom-designed or expensive research-grade three-dimensional (3D) printers and the limited selection of suitable thermoplastic biomaterials exhibiting physical characteristics desired for facile surgical handling and biological properties encouraging tissue integration. Properly designed thermoplastic biodegradable amphiphilic polymers can exhibit hydration-dependent hydrophilicity changes and stiffening behavior, which may be exploited to facilitate the surgical delivery/self-fixation of the scaffold within a physiological tissue environment. Compared to conventional hydrophobic polyesters, they also present significant advantages in blending with hydrophilic osteoconductive minerals with improved interfacial adhesion for bone tissue engineering applications. Here, we demonstrated the excellent blending of biodegradable, amphiphilic poly(D,L-lactic acid)-poly(ethylene glycol)-poly(D,L-lactic acid) (PLA-PEG-PLA) (PELA) triblock co-polymer with hydroxyapatite (HA) and the fabrication of high-quality rapid prototyped 3D macroporous composite scaffolds using an unmodified consumer-grade 3D printer. The rapid prototyped HA-PELA composite scaffolds and the PELA control (without HA) swelled (66% and 44% volume increases, respectively) and stiffened (1.38-fold and 4-fold increases in compressive modulus, respectively) in water. To test the hypothesis that the hydration-induced physical changes can translate into self-fixation properties of the scaffolds within a confined defect, a straightforward in vitro pull-out test was designed to quantify the peak force required to dislodge these scaffolds from a simulated cylindrical defect at dry versus wet states. Consistent with our hypothesis, the peak fixation force measured for the PELA and HA-PELA scaffolds increased 6-fold and 15-fold upon hydration, respectively. Furthermore, we showed that the low-fouling 3D PELA inhibited the attachment of NIH3T3 fibroblasts or bone marrow stromal cells while the HA-PELA readily supported cellular attachment and osteogenic differentiation. Finally, we demonstrated the feasibility of rapid prototyping biphasic PELA/HA PELA scaffolds for potential guided bone regeneration where an osteoconductive scaffold interior encouraging osteointegration and a nonadhesive surface discouraging fibrous tissue encapsulation is desired. This work demonstrated that by combining facile and readily translatable rapid prototyping approaches with unique biomaterial designs, biodegradable composite scaffolds with well controlled macroporosities, spatially defined biological microenvironment, and useful handling characteristics can be developed. PMID- 25025952 TI - Physiotherapy at the XII Commonwealth Games Part II: Injuries and Management. AB - At the XII Commonwealth Games held in Brisbane in 1982, Australian physiotherapists as members of the host nation's medical division, treated the injuries of competitors from the ten sports contested. The nature and incidence of the injuries treated by the host physiotherapists is tabulated and comment is made regarding several significant features. Implications for the management skills of physiotherapists required either to travel with teams or work as host physiotherapists are made. Furthermore, the utilization of equipment is indicated. Overall the paper provides a resource to assist in future planning for such events in respect to physiotherapy manpower, expertise and equipment needs. PMID- 25025953 TI - 'Yes, but what about the Student?'. AB - Student evaluations of a simulated case conference in a rehabilitation setting were discussed and analysed, on the basis of the proposition that role-playing and simulated gaming are educational techniques of value in the training of health professionals. Eighteen fourth-year physiotherapy students responded positively in terms of insights gained from participation in a simulated group exercise. Students expressed interest in similar exercises to enable them to gain further insights into specific situations of relevance to their future professional lives. PMID- 25025954 TI - Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1beta, IL-1alpha and Th17-associated cytokines and decrease of Th1 and Th2 cytokines. AB - In order to clarify the inflammatory mechanism underlying familial Mediterranean fever (FMF), we aimed to evaluate the ex vivo cytokine profile of FMF patients during acute attacks and attack-free periods, and compare it with that of healthy controls. The study included 34 FMF patients, of whom 9 were studied during attack and remission and 24 healthy controls. Cytokine levels were evaluated by Luminex technology in serum and supernatants of PBMC (Peripheral Blood Mononuclear Cells) cultures with and without 24h stimulation of monocytes by LPS and T lymphocytes by anti-CD3/CD28 beads. Levels of IL-6 and TNF-alpha were higher in unstimulated and LPS-stimulated PBMC supernatants of FMF patients in crises compared to controls. In response to LPS stimulation, higher levels of IL 1beta and IL-1alpha were found in PBMC supernatants of patients during crises compared to those in remission and to controls. IFN-gamma and IL-4 levels were the lowest in unstimulated and anti-CD3/CD28 stimulated PBMCs supernatants of patients during crises compared to remission and controls. The Th17 cytokines IL 17 and IL-22 were respectively higher in anti-CD3/CD28 stimulated PBMC supernatants of FMF patients during and between crises compared to controls. Amongst cytokines tested in serum, only IL-6 and TNFalpha were enhanced in FMF patients. The ex vivo study represents an interesting approach to evaluate cytokines' involvement in FMF. Our results suggest an ongoing subclinical inflammation and define an elevated inflammatory cytokine signature, distinctly for M694V homozygous patients. The absence of spontaneous IL-1beta release by PBMCs reflects no constitutive activation of the inflammasome in FMF physiopathology. PMID- 25025955 TI - Does self-regulation capacity predict psychological well-being in physicians? AB - Despite increasing research on physician well-being, factors appearing to account for individual variation in levels of optimal functioning are largely unclear. One such factor could be self-regulation, which reflects how individuals effectively manage their thoughts, emotions and behaviours, and cope with adversity in their environment. The purpose of this study was to determine if self-regulation capacity could significantly predict psychological well-being in a sample of Canadian physicians. A total of 132 physicians completed the Scales of Psychological Well-Being and the short form of the Self-Regulation Questionnaire. Regression analyses confirmed the hypothesis that a significant amount of variance in levels of psychological well-being would be explained by self-regulation capacity. There was a particularly strong relationship between self-regulation capacity and the dimensions of purpose in life and environmental mastery, which suggests that physicians who effectively self-manage may be better able to preserve a sense of purpose and an adequate work-life balance in their daily life. Physicians today face consistently growing demands stemming from increasingly challenging work environments. Results of this study mark an important step in increasing our understanding of a potentially valuable skill that may help physicians to achieve well-being. PMID- 25025956 TI - Glucose-induced electrical activities and insulin secretion in pancreatic islet beta-cells are modulated by CFTR. AB - The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in beta-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca(2+) oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse beta-cells or RINm5F beta-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 beta-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in beta-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy. PMID- 25025958 TI - HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. AB - Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2 targeted therapies. In this article, we review the optimal sequence of HER2 targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development. PMID- 25025959 TI - Oestrogen receptors beta1 and betacx have divergent roles in breast cancer survival and lymph node metastasis. AB - BACKGROUND: The expression of oestrogen receptor (ER) alpha characterises a subset of breast cancers associated with good response to endocrine therapy. However, the clinical significance of the second ER, ERbeta1, and its splice variant ERbetacx is still unclear. METHODS: We here report an assessment of ERalpha, ERbeta1 and ERbetacx by immunohistochemistry using quantitative digital image analysis of 340 primary tumours and corresponding sentinel lymph nodes. RESULTS: No differences were seen in ER levels in primary tumours vs lymph node metastases. ERbeta1 and ERbetacx were equally distributed among age groups and tumour histological grades. Loss of ERbeta1 in the primary tumour was strongly associated with poor survival. Its prognostic impact was particularly evident in young patients and in high-grade tumours. The worst outcome was seen in the tumours lacking both ERalpha and ERbeta1. ERbetacx expression in the primary tumour correlated with a higher risk of lymph node metastasis, and with poor survival when expressed in sentinel node lymphocytes. CONCLUSIONS: Our study reveals highly significant although antagonising roles of ERbeta1 and ERbetacx in breast cancer. Consequently, we suggest that the histopathological assessment of ERbeta1 is of value as a prognostic and potentially predictive biomarker. PMID- 25025957 TI - BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3' diindolylmethane. AB - BACKGROUND: Haploinsufficiency may contribute to the development of breast cancer among women with a BRCA1 mutation. Thus, interventions that enhance BRCA1 expression may represent avenues for prevention. Studies have shown that 3,3' diindolylmethane (DIM) can upregulate BRCA1 expression in breast cancer cells. This has yet to be demonstrated in vivo. METHODS: We conducted a study to evaluate the ability of oral DIM to upregulate BRCA1 mRNA expression in white blood cells. A total of 18 women were enroled in the study, including 13 BRCA1 mutation carriers who received 300 mg per day of Rx Balance BioResponse DIM for 4 6 weeks (intervention group) and 5 BRCA1 mutation carriers who did not take DIM (control group). BRCA1 mRNA expression was assessed at baseline and at 4-6 weeks by real-time, quantitative PCR and the relative change in BRCA1 mRNA expression (that is, 2(-DeltaDeltaCT)) was calculated. RESULTS: The relative change in BRCA1 mRNA expression among women in the intervention group achieved borderline significance (P paired t-test=0.05). In the intervention group, BRCA1 mRNA expression increased in 10 of the participants, decreased in 2 and remained unchanged in 1 of the participants following DIM intervention (P sign test=0.02). On average, women in the intervention group experienced a 34% increase in BRCA1 mRNA expression (range -24 to 194%). There was no significant difference in the relative change in BRCA1 mRNA expression among women in the control group (P paired t-test=0.45). CONCLUSIONS: Under the tested conditions, oral DIM was associated with an increase in BRCA1 mRNA expression in women with a BRCA1 mutation. The possibility of mitigating the effect of an inherited deleterious BRCA1 mutation by increasing the physiologic expression of the gene and normalising protein levels represents a clinically important paradigm shift in the prevention strategies available to these high-risk women. Future studies with a larger sample size and higher doses of DIM are warranted. PMID- 25025960 TI - Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: a systematic literature review. AB - BACKGROUND: The immune system has a central role in controlling cancer, and factors that influence protective antitumour immunity could therefore have a significant impact on the course of malignant disease. Opioids are essential for the management of cancer pain, and preclinical studies indicate that opioids have the potential to influence these tumour immune surveillance mechanisms. The aim of this systematic literature review is to evaluate the clinical effects of opioids on the immune system of patients with cancer. METHODS: A systematic search of Ovid MEDLINE (PubMed) and Embase, Cochrane database and Web of Knowledge for clinical studies, which evaluated the effects of opioids on the immune system in patients with cancer, was performed. RESULTS: Five human studies, which have assessed the effects of opioids on the immune system in patients with cancer, were identified. Although all of these evaluated the effect of morphine on immunologic end points in patients with cancer, none measured the clinical effects. CONCLUSIONS: Evidence from preclinical, healthy volunteer and surgical models suggests that different opioids variably influence protective anti-tumour immunity; however, actual data derived from cancer populations are inconclusive and definitive recommendations cannot be made. Appropriately designed and powered studies assessing clinical outcomes of opioid use in people with cancer are therefore required to inform oncologists and others involved in cancer care about the rational use of opioids in this patient group. PMID- 25025961 TI - Elevated HOXB9 expression promotes differentiation and predicts a favourable outcome in colon adenocarcinoma patients. AB - BACKGROUND: Little is known about the tumour suppressive proteins and the underlying mechanisms that suppress colon cancer progression. Homeodomain containing transcription factor HOXB9 plays an important role in embryogenesis and cancer development. We here aim to uncover the potential role of HOXB9 in the regulation of colon adenocarcinoma progression including epithelial-to mesenchymal transition. METHODS: HOXB9 expression in colon adenocarcinoma cells and patients was analysed by western blot and immunohistochemistry separately. Correlation between HOXB9 expressions with patients' survival was assessed by Kaplan-Meier analysis. HOXB9-regulated target gene expression was determined by RNA sequencing in HOXB9-overexpressing colon adenocarcinoma cells. RESULTS: Elevated HOXB9 expression was identified in well-differentiated colon adenocarcinoma patients and was associated with a better overall patients' survival. Overexpression of HOXB9 inhibited colon adenocarcinoma cell growth, migration, invasion in vitro and tumour growth, liver as well as lung metastases in nude mice; whereas silencing HOXB9 promoted these functions. HOXB9 promoted colon adenocarcinoma differentiation via a mechanism that stimulates mesenchymal to-epithelial transition, involving downregulation of EMT-promoting transcriptional factors including Snail, Twist, FOXC2 and ZEB1 and upregulation of epithelial proteins including E-cadherin, claudins-1, -4, -7, occludin and ZO 1. CONCLUSIONS: HOXB9 is a novel tumour suppressor that inhibits colon adenocarcinoma progression by inducing differentiation. Elevated expression of HOXB9 predicts a longer survival in colon adenocarcinoma patients. PMID- 25025962 TI - Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer. AB - BACKGROUND: Over the past years, some members of the family of suppressor of cytokine signalling (SOCS) proteins have emerged as potential tumour suppressors. This study aimed at investigating the clinical significance of SOCS proteins in colorectal carcinoma (CRC). METHODS: We integrated publicly available microarray expression data on CRC in humans, analysed the expression pattern of SOCSs and assessed the predictive power of SOCS2 and SOCS6 for diagnostic purposes by generating receiver operating characteristic curves. Using laser microdissected patient material we assessed SOCS expression on RNA and protein levels as well as their methylation status in an independent CRC patient cohort. Finally, we investigated the prognostic value of SOCS2 and SOCS6. RESULTS: The meta-analysis as well as the independent patient cohort analysis reveal a stage-independent downregulation of SOCS2 and SOCS6 and identify both molecules as diagnostic biomarkers for CRC. We demonstrate a different methylation pattern within the SOCS2 promoter between tumour tissue and normal control tissue in 25% of CRC patients. Furthermore, early CRC stage patients with low expression of SOCS2 display significantly shorter disease-free survival. CONCLUSIONS: Our data offers evidence that SOCS2 and SOCS6 levels are reduced in CRC and may serve as diagnostic biomarkers for CRC patients. PMID- 25025963 TI - Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. AB - BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade >=3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m( 2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer. PMID- 25025964 TI - Intraperitoneal chemotherapy as adjuvant treatment to prevent peritoneal carcinomatosis of colorectal cancer origin: a systematic review. AB - BACKGROUND: Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) origin is associated with poor outcome. This systematic review evaluates the available evidence about adjuvant (hyperthermic) intraperitoneal chemotherapy ((H)IPEC) to prevent the development of PC. METHODS: A systematic search of literature was conducted in August 2013 in PubMed, Embase, and the Cochrane database for studies on (H)IPEC to prevent PC in patients who underwent curative surgery for primary CRC. RESULTS: Seven comparative studies and five cohort studies were selected. Treatment schedules varied between repeated fluoropyrimidine-based IPEC administration in the ambulatory setting to intra-operative (H)IPEC procedures using mitomycin-C or oxaliplatin. The reported rates of major complications related to adjuvant (H)IPEC was low. Four out of five evaluable comparative studies reported a significant difference in the incidence of PC in favour of (H)IPEC. All three comparative studies reporting on survival after intra operative (H)IPEC showed a significant survival benefit in favour of the experimental arm. Substantial heterogeneity in patient selection, treatment protocols, and treatment effect evaluation among studies was observed. CONCLUSIONS: The currently available evidence about adjuvant (H)IPEC in high-risk CRC is limited and subject to bias, but points towards improved oncological outcome and supports further randomised studies. PMID- 25025967 TI - Parenting practices and adolescent smoking in mainland China: the mediating effect of smoking-related cognitions. AB - This study examined the direct and indirect associations of general and smoking specific parenting practices with Chinese adolescents' smoking behaviors. Adolescents aged 14-17 years (N = 658) and their parents were recruited from three high schools in mainland China. Adolescents completed an anonymous online survey on their smoking behaviors, perceptions of parenting behaviors, and smoking-related cognitions including attitude, subjective norm, and perceived behavioral control. Parents completed a paper-and-pencil questionnaire on their parenting behaviors. Results indicated that psychological control and frequency of communication about smoking were positively linked to adolescent smoking through the mediation of two smoking-related cognitions-attitude and subjective norm. Parental knowledge of adolescent activities, disapproval of adolescent smoking, and home rules were negatively linked to adolescent smoking through the mediation of attitude and subjective norm. Results suggest that parenting practices and smoking-related cognitions are critical components to be incorporated in prevention and intervention programs for adolescent smoking in China. PMID- 25025965 TI - Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. AB - BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance associated pathways using global, unbiased techniques. METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model. CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser. PMID- 25025966 TI - Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex. AB - BACKGROUND: Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is a functional long non-coding RNA (lncRNA), which is highly expressed in several tumours, including colorectal cancer (CRC). Its biological function and mechanism in the prognosis of human CRC is still largely under investigation. METHODS: This study aimed to investigate the new effect mechanism of MALAT1 on the proliferation and migration of CRC cells in vitro and in vivo, and detect the expression of MALAT1, SFPQ (also known as PSF (PTB-associated splicing factor)), and PTBP2 (also known as PTB (polypyrimidine-tract-binding protein)) in CRC tumour tissues, followed by correlated analysis with clinicopathological parameters. RESULTS: We found that overexpression of MALAT1 could promote cell proliferation and migration in vitro, and promote tumour growth and metastasis in nude mice. The underlying mechanism was associated with tumour suppressor gene SFPQ and proto-oncogene PTBP2. In CRC, MALAT1 could bind to SFPQ, thus releasing PTBP2 from the SFPQ/PTBP2 complex. In turn, the increased SFPQ-detached PTBP2 promoted cell proliferation and migration. SFPQ critically mediated the regulatory effects of MALAT1. Moreover, in CRC tissues, MALAT1 and PTBP2 were overexpressed, both of which were associated closely with the invasion and metastasis of CRC. However, the SFPQ showed unchanged expression either in CRC tissues or adjacent normal tissues. CONCLUSIONS: Our findings implied that MALAT1 might be a potential predictor for tumour metastasis and prognosis. Furthermore, the interaction between MALAT1 and SFPQ could be a novel therapeutic target for CRC. PMID- 25025968 TI - Extensor strength in the anterior cruciate reconstructed knee. AB - Truncated range average torque (TRAT), peak torque (PT) and angle of peak torque (APT) in the knee extensor musculature of subjects with patellar tendon autograft anterior cruciate ligament reconstructions were compared with non-operated limbs two to four years following surgery. Twenty subjects were assessed using a Kin Com 500H isokinetic dynamometer at three velocities for both concentric and eccentric muscle actions. Results of TRAT for the knee extensors showed average concentric and eccentric deficits of 8.48 per cent and 6.73 per cent, respectively. Deficits in PT were 8.26 per cent concentrically and 7.96 per cent eccentrically. There was no difference in the APT for each action or velocity. Despite an accelerated rehabilitation program, significant residual deficits were evident. Continued strengthening of the knee extensor muscles is recommended. PMID- 25025969 TI - Ageing does not affect flexion relaxation of erector spinae. AB - Erector spinae (ES) activity during trunk flexion in 22 young (20-25 years) and 16 older (60-92 years) normal females was examined with surface EMG. The trunk movements and simultaneous EMG oscillograph of ES were recorded with two synchronised video cameras. The ES relaxed at the critical position (CP) which was 67 and 82 per cent of full trunk flexion for young and older subjects respectively. The vertebral movements to the CP were not different between groups, but the older subjects demonstrated more hip movement to the CP and less full trunk flexion range. The implications of these age related changes in trunk kinematics are yet to be developed with further clinical studies. PMID- 25025970 TI - Screen based keyboard operation: the adverse effects on the neural system. AB - The effect of screen based keyboard (SBK) operation on extensibility of the neural system was investigated using the radial nerve upper limb tension test (Butler 1991). Twenty-five female subjects (aged 17-55 years) including 15 SBK operators and 10 non-SBK operators who acted as a control were examined. Mean glenohumeral abduction in the upper limb tension test in the control group was 40 degrees. In the SBK operators, it was 27 degrees (right side) and 30 degrees (left side). Statistical analysis showed a significant difference between the groups. Results indicate that the normal mechanics of the neural system may be affected by SBK operation and that neural tension warrants consideration in the prevention and management of work related neck and upper limb disorders. PMID- 25025971 TI - Current perspectives on minimal cerebral dysfunction. AB - Children with minimal cerebral dysfunction (MCD) are a large client group for many paediatric physiotherapists. The increasing number of research papers published in the area of MCD are often complex and difficult to interpret because the children to whom they refer do not form an easily definable, homogeneous group and their prognosis is unclear. This review presents a summary of current findings about MCD and poses a number of questions about physiotherapy intervention. The need for physiotherapists to validate their role in the management of children with MCD is emphasised. PMID- 25025972 TI - Burnout in recently qualified physiotherapists in South Australia. AB - Burnout has been shown to be present in experienced physiotherapists and other health professionals, but the prevalence in recently graduated physiotherapists has not been established. This study used the Maslach Burnout Inventory to determine the prevalence of burnout in physiotherapists working in South Australia who had been qualified for less than five years. Sixty per cent of subjects were found to have moderate to high levels of emotional exhaustion, the key characteristic of burnout. High or moderate depersonalisations were recorded by 44 per cent of subjects. These levels were higher than those found in experienced physiotherapists (Solowij 1992). Burnout is related to attrition from the profession, absenteeism and reduced quality of care for patients, as well as physical and psychological symptoms. PMID- 25025973 TI - Experiences of childbirth: how effective is childbirth education? AB - Birth experiences of 94 primiparous women who had attended birth preparation classes, were compared to a control group of 22 women of similar age and parity who had not attended classes. The results revealed that in contrast to the control group, women who had attended classes were of higher socioeconomic status, were more likely to have the child's father present at birth, felt more prepared for the birth, and were somewhat more positive to the idea that women should have a choice between home birth and hospital birth However, there were no differences between the groups regarding the frequency of interventions in labour, the length of the labour, the pain experienced and their feelings of satisfaction. Thus, no substantial effect of childbirth education was evident in the management and experiences of the birth. PMID- 25025974 TI - Pregnancy and back pain among upper class nigerian women. AB - A study was conducted to look into the characteristics of back pain among pregnant upper class Nigerian women and to examine the reducing influence of antenatal physiotherapy. Of the 99 subjects who completed the questionnaire, 52 had attended antenatal physiotherapy and 47 had not. The results showed that a total of 89 (89.8%) had experienced back pain within the 'very mild' to 'severe' range; onset of pain was usually around the sixth and seventh month of pregnancy and was mostly felt in the evening. Increasing parity and age seemed to be associated with increasing back pain. Pain was aggravated by tiredness, and about one third of the subjects obtained relief by placing a small pillow behind their back when sitting. Subjects who attended antenatal physiotherapy fared significantly better than those who did not as regards the prevalence of back pain. PMID- 25025975 TI - The hydrogoniometer and assessment of gleno-humeral joint motion. AB - Inter-observer and intra-observer reliability tests have been investigated for the passive ranges of gleno-humeral abduction, lateral rotation with arm by the side and both lateral and medial rotation with the upper arm abducted to 90 degrees , using the Hydrogon-iometer. This device allows accurate quantification of gleno-humeral movement and is most appropriate for the Physiotherapy profession as an inexpensive, simple measuring device. PMID- 25025976 TI - The relevance of non-verbal skills in physiotherapy. AB - Non-verbal behaviour forms the major part of communication; responses in interactions are based on the subconscious perception and interpretation of non verbal messages. Through intuition and experience, most physiotherapists develop the skills necessary to aid their understanding of the behaviour and responses of patients. Increased awareness of non-verbal skills and the importance of their use will enhance both the physiotherapist-patient relationship and the quality of treatment. This paper discusses the relevance of these skills and the rationale for their implementation in a professional setting. PMID- 25025977 TI - The fetal heart response to static antenatal exercises in the supine position. AB - Continuous fetal heart rate traces were made in twenty-six low risk patients during static maternal exercises in the supine position, as prescribed in a hospital's antenatal education programme. Prior to exercise, fetal heart rate abnormalities were present in four patients. Three of these had an abnormal fetal outcome. During the exercises a further eight cases had reductions in fetal heart rate, variability or reactivity. An abnormal fetal outcome was recorded in two of these cases. The findings indicate uncertainty about the safety of antenatal exercises in the supine position in late pregnancy and, until further studies are available, it is prudent to advocate the practice of all antenatal exercises in a tilted position, and not at all where fetal compromise is suspected. PMID- 25025978 TI - Stimulation of bone healing with interferential therapy. AB - Methods of electrical stimulation of bone are reviewed for a comparison with the use of interference currents and for a consideration of the possible merits of various methods. A summary is given of results of treatment of 38 patients with delayed or non-union and predisposition to non-union, and the technique used with Interferential Therapy is described in detail. Results are also given of a study of the effects of stimulation on 11 patients with acute fractures of the tibial shaft, compared with 11 closely matched patients with similar acute fractures who did not receive Interferential Therapy. The advantages of surgically non-invasive techniques are emphasised and recommendations are made for the use of interference currents prophylactically in specific cases. PMID- 25025979 TI - Professional and personal attitudes of physiotherapy students toward disabled persons. AB - Form A of the Attitude Toward Disabled Persons (ATDP-A) scale was used to discover whether physiotherapy students distinguish between personal and professional attitudes toward people with disabilities. Forty fourth-year students successively completed two copies of the ATDP-A scale, one with their personal views and one with their professional views. A two-tailed t-test for correlated samples showed that the mean professional score was significantly greater (p < 0.05) than the mean personal score. Results are discussed in terms of inconsistencies in the research literature as well as implications for physiotherapy training programmes. PMID- 25025980 TI - The role of physiotherapy in a neonatal intensive care unit. AB - The role of physiotherapy in the neonatal intensive care unit has historically been mainly associated with the care of the neonate's lungs. Postural drainage coupled with percussion, vibrations and suction are all used in the physiotherapy management of neonatal respiratory disorders. At Monash Medical Centre all elective extubations are performed by the physiotherapist in accordance with the neonatal unit's protocol: this includes four hourly respiratory physiotherapy for the first 24 hours after extubation to ensure that post-extubation atelectasis does not occur. In addition to respiratory care, the physiotherapist is also engaged in the assessment and management of neonates with either neurological or musculoskeletal disorders. PMID- 25025981 TI - 3D Raman mapping of the collagen fibril orientation in human osteonal lamellae. AB - Chemical composition and fibrillar organization are the major determinants of osteonal bone mechanics. However, prominent methodologies commonly applied to investigate mechanical properties of bone on the micro scale are usually not able to concurrently describe both factors. In this study, we used polarized Raman spectroscopy (PRS) to simultaneously analyze structural and chemical information of collagen fibrils in human osteonal bone in a single experiment. Specifically, the three-dimensional arrangement of collagen fibrils in osteonal lamellae was assessed. By analyzing the anisotropic intensity of the amide I Raman band of collagen as a function of the orientation of the incident laser polarization, different parameters related to the orientation of the collagen fibrils and the degree of alignment of the fibrils were derived. Based on the analysis of several osteons, two major fibrillar organization patterns were identified, one with a monotonic and another with a periodically changing twist direction. These results confirm earlier reported twisted and oscillating plywood arrangements, respectively. Furthermore, indicators of the degree of alignment suggested the presence of disordered collagen within the lamellar organization of the osteon. The results show the versatility of the analytical PRS approach and demonstrate its capability in providing not only compositional, but also 3D structural information in a complex hierarchically structured biological material. The concurrent assessment of chemical and structural features may contribute to a comprehensive characterization of the microstructure of bone and other collagen based tissues. PMID- 25025982 TI - The reliability of selected techniques in clinical arthrometrics. AB - A number of studies which have examined reliability of spinal assessment procedures in manual therapy are reviewed. The tests examined were Passive Accessory Intervertebral Movements, Passive Physiological Intervertebral Movements, Straight Leg Raise and Forward Flexion. In general, tests of pain were found to be much more reproducible than tests of compliance. Straight Leg Raise and Forward Flexion tests were consistently more reliable than the Passive Intervertebral Movement tests. Possible explanations for these findings are advanced. The role of tests of compliance based on passive intervertebral movements in clinical decision-making may need to be re-examined. An appendix on reliability theory is included for the uninitiated reader. PMID- 25025983 TI - A CD8 T-cell epitope variant enhances immune targeting to a recombinant picornavirus vaccine antigen. AB - Recombinant virus vaccines are often less effective due to immunodominant responses against endogenous vector antigens. However, the use of small RNA virus vectors provides an opportunity to limit host exposure to endogenous virus antigens and focus immune responses on the desired vaccine antigen. Using the Daniel's strain of Theiler's murine encephalomyelitis virus, we have identified strategies to modulate responses to endogenous viral proteins by manipulating the host CD8+ T-cell repertoire prior to infection or through the use of mutations introduced into the virus genome. Both of these approaches enhance responses to vaccine antigens introduced into the picornavirus. However, the use of mutant immunodominant epitopes provides an opportunity for enhancing vaccine responses without further manipulation of the host. Using this strategy, we demonstrate that modification of the consensus MHC class I anchor residue within the virus genome can promote enhanced immunity to foreign antigens and self-antigens embedded in the virus genome. PMID- 25025984 TI - Highly selective directed arylation reactions via back-to-back dehydrogenative C H borylation/arylation reactions. AB - Dimeric rhodium N-heterocyclic carbene complexes are demonstrated to be effective catalyst precursors for directed C-H borylation reactions at room temperature. The reactions are highly selective for mono-borylation and can be combined with a one-pot Suzuki-Miyaura coupling to give C-H arylation products with exclusive selectivity for mono-arylation without the requirement for steric blocking groups. PMID- 25025985 TI - Diffusive public goods and coexistence of cooperators and cheaters on a 1D lattice. AB - Many populations of cells cooperate through the production of extracellular materials. These materials (enzymes, siderophores) spread by diffusion and can be applied by both the cooperator and cheater (non-producer) cells. In this paper the problem of coexistence of cooperator and cheater cells is studied on a 1D lattice where cooperator cells produce a diffusive material which is beneficial to the individuals according to the local concentration of this public good. The reproduction success of a cell increases linearly with the benefit in the first model version and increases non-linearly (saturates) in the second version. Two types of update rules are considered; either the cooperative cell stops producing material before death (death-production-birth, DpB) or it produces the common material before it is selected to die (production-death-birth, pDB). The empty space is occupied by its neighbors according to their replication rates. By using analytical and numerical methods I have shown that coexistence of the cooperator and cheater cells is possible although atypical in the linear version of this 1D model if either DpB or pDB update rule is assumed. While coexistence is impossible in the non-linear model with pDB update rule, it is one of the typical behaviors in case of the non-linear model with DpB update rule. PMID- 25025986 TI - The appetite regulatory effect of guggulsterones in rats: a repertoire of plasma hormones and neurotransmitters. AB - Guggulsterone or guggulipid is a steroidal constituent present in the neutral fraction of gum resin of Commiphora mukul, commonly known as guggul. The traditional uses of guggul-resin extract are well documented in the Ayurveda where it is prescribed to treat a variety of ailments including lipid-related disorders such as obesity and arteriosclerosis. The hypolipidemic activity of the extracts known since ancient times can be traced to the two closely related steroidal ketones, E-guggulsterone and Z-guggulsterone. In this study, we have investigated the dose dependent (100, 200, 400 mg/kg body weight) effect of guggulsterones on appetite regulating hormones [ghrelin, leptin, cholecystokinin (CCK)] and neurotransmitters (serotonin and dopamine), which play a major role in the energy homeostasis and thus influence obesity related factors. We have also studied its effect on food intake, body weight and plasma triglycerides and glucose in rats. Guggulsterones at the dose of 400 mg/kg body weight was able to significantly reduce food intake and limit body weight gain over a period of 15 days. It also significantly decreased the plasma ghrelin, glucose, triglyceride levels and increased plasma leptin, serotonin, dopamine levels, but did not show much effect on CCK levels. PMID- 25025987 TI - Impact of surgical experience on stone-free rates of ureteroscopy for single urinary calculi of the upper urinary tract: a matched-paired analysis of 600 patients. AB - INTRODUCTION: To evaluate the impact of surgical experience on ureteroscopic stone-free rates (SFR) and complication rates (CR) for the treatment of urinary calculi of the upper urinary tract. METHODS: We evaluated retrospectively, patients (n=300) having undergone ureteroscopy (URS) for single urinary calculi treated by residents (n=12) at our department over a 6-year period. These patients were matched according to age, gender, body-mass index, and stone side/size/site with patients (n=300) treated by consultants (n=5) of our department during the same period. Patient data, primary SFR, and CR were compared. RESULTS: The mean+/-standard deviation (range) stone size was 6.39+/ 3.26 (2-20) mm. The primary SFR after one URS procedure was 95.2% and did not differ between residents and consultants (95% vs 95.3%, p=0.489). The SFR were 95.9% and 98.5% for ureteral stones (p=0.125) and 93.2% and 89.3% for kidney stones (p=0.298) in the resident and consultant group, respectively. The SFR differed significantly between ureteral and kidney stones (97.2% vs 91.3%, p<=0.001). Perioperative complications occurred in a total of 63 patients (10.5%): Clavien 1: 3.8%, Clavien 2: 2%, Clavien 3a: 1.8%, and Clavien 3b: 2.8%, respectively. There were no differences in the total CR between residents (12%) and consultants (9%) (p=0.2116). However, the ureteral perforation rate was significantly higher in residents compared with consultants (4.3% vs 1.3%, p<=0.027). CONCLUSIONS: URS is a safe and efficacious procedure for the treatment of single urinary calculi. Resident status does not compromise the SFR after ureteroscopic treatment of single urinary calculi. However, the incidence of ureteral perforation was associated with surgeon's experience. PMID- 25025988 TI - Lithium in drinking water and suicide prevention: a review of the evidence. AB - Suicide is a serious public health problem worldwide, and many nations are committed to developing prevention programmes to reduce the incidence of suicide. To date, several strategies have been proposed for suicide prevention, both at the population and at the individual level, some of which may be pharmacological. In particular, a substantial amount of data show that lithium significantly reduces mortality in patients with mood disorders. Initiating from this evidence, some recent studies have investigated whether a relationship might exist between levels of lithium in drinking water and mortality rates for suicide in the general population. We have systematically reviewed all the articles published on this issue to date. The available literature indicates that higher lithium levels in drinking water may be associated with reduced risk of suicide in the general population. PMID- 25025989 TI - Pharmacogenetics of quetiapine in healthy volunteers: association with pharmacokinetics, pharmacodynamics, and adverse effects. AB - Quetiapine is an atypical antipsychotic used for treatment of schizophrenia. Variability in response to this drug may be associated with pharmacogenetics. The aim of this study was to identify genetic markers related to the pharmacokinetics, pharmacodynamics, and adverse effects of quetiapine. The study population comprised 79 healthy volunteers from two bioequivalence trials who were genotyped to identify polymorphisms in genes encoding enzymes, receptors, and transporters. Quetiapine plasma levels were quantified using high-performance liquid chromatography/mass spectrometry. Prolactin plasma levels were detected by indirect chemiluminescence. Possible adverse effects were recorded throughout the study. Factors with P value of 0.1 or less in the univariate analysis were included in a multiple regression analysis (logistic regression for adverse reactions). The area under the curve and clearance of quetiapine were affected by polymorphisms in CYP1A2 and DRD3, respectively. Men had a lower quetiapine area under the curve compared with women. Prolactin iC(max) was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms in CYP1A1 and CYP2C9 and somnolence. Several polymorphisms are responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals. PMID- 25025990 TI - The effect of collagen cross-linking procedure on the material of intracorneal ring segments. AB - PURPOSE: To assess the potential impact of corneal crosslinking treatment (365 nm ultraviolet (UV)A irradiation with riboflavin) on the material properties of Intracorneal Rings Segments (ICRS). MATERIALS AND METHODS: Material properties were studied using FT-IR spectroscopy and UV-Vis spectroscopy. Rings were examined: (1) after installation of riboflavin solution, (2) after irradiation with UV-A light and (3) after instillation of riboflavin solution followed by instillation and coeval irradiation. The experiments followed the standard corneal cross-linking (CXL) protocol of corneal crosslinking treatment. RESULTS: After instillation of riboflavin solution, a permanent intense yellow staining of the samples was observed. UV-Vis spectroscopy confirmed that a certain amount of riboflavin solution was absorbed into the samples after CXL procedure. FT-IR spectroscopic analysis showed alterations in the spectra of ICRS mainly at the 2800-3200 cm(-1) spectral region [modification in band intensities of CH(2) (2925 cm(-1)) and CH(3) (2950 cm(-1))]. CONCLUSIONS: Our results suggest crosslinking reaction in ICRS material. This should be taken into consideration prior to any CXL treatment of post ICRS-implanted cornea. PMID- 25025991 TI - New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer. AB - We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1 phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. PMID- 25025993 TI - Agonistic autoantibodies against the angiotensin AT1 receptor increase in unstable angina patients after stent implantation. AB - OBJECTIVES: Agonistic AT1 receptor autoantibodies have been described in patients with hypertension and preeclampsia. These autoantibodies could stimulate proliferation of vascular smooth muscle cells (VSMCs), which are involved in angiotensin II-induced vascular injury in cardiovascular disease. Hence, in this study, we explored the existence of agonistic AT1 receptor autoantibodies in unstable angina (UA) patients and the possible effects of them on the in-stent restenosis of these patients. METHODS: A total of 95 UA patients and 98 healthy volunteers were enrolled. The serum of each patient was analyzed for the presence of AT1 receptor autoantibodies by enzyme-linked immunosorbent assay. Their effects on VSMC proliferation and c-fos and c-jun expression were studied in vitro. RESULTS: AT1 receptor autoantibodies were detected in 34/95 patients with UA. The incidence was 10.2% in the control group and rose to 47.37% after stent implantation. In vitro, this autoantibody had agonist-like activity, shown as stimulation of VSMC proliferation and upregulation of c-fos and c-jun expression. These effects were similar to that of angiotensin II and could be weakened partly by the AT1-receptor blocker valsartan. CONCLUSION: Our findings show that the autoantibody from UA patients has similar agonistic activity to angiotensin II and might play a role in the pathogenesis of in-stent restenosis in these patients. PMID- 25025992 TI - Pioglitazone, a peroxisome proliferator-activated receptor gamma activator, suppresses coronary spasm. AB - OBJECTIVE: We examined whether a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, pioglitazone, suppresses coronary spasm. BACKGROUND: Patients with coronary spastic angina (CSA) also have endothelial dysfunction and inflammation. Activation of PPAR-gamma improves endothelial dysfunction and inflammation. PARTICIPANTS AND METHODS: The study participants included 73 consecutive CSA patients (47 men and 26 women, mean age 63.6+/-10.4 years) who were admitted to our institution with a suspicion of CSA because of episodes of chest discomfort occurring mostly at rest in whom coronary spasm was induced by an intracoronary acetylcholine injection and a repeat acetylcholine provocation injection was administered after 6 months of follow-up. Thirty-six of the patients were administered pioglitazone15-30 mg/day added on calcium channel blockers (CCBs) (pioglitazone group) and 37 were administered CCBs alone (control group). Clinical and laboratory data were also examined before and after 6 months of follow-up and the results between the two groups were compared. RESULTS: Coronary spasm was suppressed in 18/36 patients (50.0%) in the pioglitazone group (P<0.001) and 8/37 patients (21.6%) in the control group (P=0.008) after 6 months of treatment. Coronary spasm was thus significantly reduced in the pioglitazone group compared with the control group (P=0.011). The levels of total white blood cell count and high-sensitivity C-reactive protein decreased significantly (P<0.001 and P<0.001, respectively) in the pioglitazone group, whereas these levels did not differ in the control group (P=0.15 and 0.39, respectively) after the treatment. CONCLUSION: Pioglitazone added on CCBs significantly reduced coronary spasm compared with CCBs alone after 6 months of treatment. Pioglitazone may thus prove to be a novel therapy for coronary spasm. PMID- 25025994 TI - The ICAM-1 K469E polymorphism is associated with the risk of coronary artery disease: a meta-analysis. AB - BACKGROUND: The intercellular adhesion molecule-1 (ICAM-1) K469E polymorphism has been indicated to be correlated with coronary artery disease (CAD) susceptibility, but the results of studies are still debatable. Thus, a meta analysis was carried out. METHODS: Databases including PubMed, Embase, Web of Science, and CNKI were searched. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Eighteen studies with 3546 cases and 3852 controls were included in this meta-analysis. The association between the ICAM-1 K469E polymorphism and the risk of CAD was significant (OR=1.77; 95% CI, 1.52-2.05; P<0.01; I=27%). This result remained statistically significant when the adjusted ORs were combined (OR=1.95; 95% CI, 1.78-2.14; P<0.01; I=0%). When stratified by ethnicity, a significantly increased risk was observed in Whites (OR=1.75; 95% CI, 1.37-2.23; P<0.01; I=58%) and in Asians (OR=1.80; 95% CI, 1.45-2.24; P<0.01; I=0%). A significantly increased risk of myocardial infarction was observed (OR=2.24; 95% CI, 1.72-2.92; P<0.01; I=38%). CONCLUSION: In conclusion, this meta-analysis suggested that the ICAM-1 K469E polymorphism was a risk factor for CAD. PMID- 25025995 TI - Genetic risk of restenosis after percutaneous coronary interventions in the era of drug-eluting stents. AB - OBJECTIVES: Our previous studies identified three single nucleotide polymorphisms (SNPs), rs419598 in the interleukin-1 receptor antagonist gene (IL1RN), rs235326 in the CD18 gene (ITGB2), and rs5918 in the platelet glycoprotein IIIa gene (ITGB3), as risk factors for restenosis after placement of bare metal stents in coronary arteries. The aim of the present study was to determine whether these SNPs remain risk factors after drug-eluting stent implantation. PATIENTS AND METHODS: The study population included 2028 patients, who underwent drug-eluting stent implantation. The primary study endpoint was angiographic restenosis (diameter stenosis>=50% at the 6-month follow-up angiography) and clinical restenosis (target lesion revascularization at the 3-year follow-up). RESULTS: Angiographic restenosis was observed in 12.8% of the patients with genotype T/T, 14.6% with genotype T/C, and 13.0% with genotype C/C of IL1RN (P=0.60), in 13.1% of the patients with genotype C/C, 13.2% with genotype C/T, and 16.1% with genotype T/T of ITGB2 (P=0.53), and in 13.2% of the patients with genotype T/T, 14.8% with genotype T/C, and 9.6% with genotype C/C of ITGB3 (P=0.50). Clinical restenosis was present in 11.8% of the patients with genotype T/T, 12.5% with genotype T/C, and 9.9% with genotype C/C of IL1RN (P=0.63), in 13.3% of the patients with genotype C/C, 10.0% with genotype C/T, and 13.9% with genotype T/T of ITGB2 (P=0.07), and in 11.9% of the patients with genotype T/T, 12.1% with genotype T/C, and 10.2% with genotype C/C of ITGB3 (P=0.91). CONCLUSION: The SNPs rs419598 in IL1RN, rs235326 in ITGB2, and rs5918 in ITGB3, which have shown an association with restenosis after implantation of bare metal stents, were not related to restenosis after placement of drug-eluting stents. PMID- 25025996 TI - The extension-adduction test in chronic tennis elbow: Soft tissue components and joint biomechanics. AB - Lateral elbow pain in 25 patients with chronic tennis elbow was reproduced by passive extension-adduction (EA) tests. Standard EA tests were performed with the addition of passive wrist flexion and extension and also with the forearm in the pronated position. These modifications were chosen in order to evaluate the effect on pain of a change in the lateral articular and extra-articular tissues. Performing the EA test in pronation rather than supination produced no significant change. However, both wrist flexion and extension.produced significant increases in pain. These results suggest increased tension in lateral structures relevant to tennis elbow and point to a useful addition to the standard EA test. The increase in elbow pain on wrist extension suggests that abnormalities of neural tension may contribute to pain. The results also indicate that a good comparable sign may be demonstrated with the forearm either pronated or supinated. PMID- 25025997 TI - Reliability of a pedal goniometer for the assessment of ankle inversion in the plantarflexed position: Winner of the 1990 Beiersdorf Sports Physiotherapy Award. AB - A pedal goniometer was designed to measure the range of inversion of the ankle joint in 42 degrees of plantarflexion about an axis aligning more closely to that of the subtalar joint. The reliability of this instrument in assessing ankle inversion was examined. Repeated measurements of the full active range of movement of ankle inversion were made on 30 subjects. The values of the Pearson Correlation Coefficient for intra-tester and inter-tester reliability were r=0.96 and r=0.91 respectively. The high reliability demonstrated by this pedal goniometer will allow its use in areas such as assessment of joint position sense and evaluation of the effects of treatment modalities in rehabilitation. PMID- 25025998 TI - An isokinetic evaluation of trunk strength in elite female field hockey players. AB - A Kin-Corn dynamometer was used to evaluate trunk extensor and flexor strength in 11 elite female field hockey players. Average torques during maximal concentric and eccentric muscle actions through a range of movement from 25 degrees of extension to 30 degrees of flexion were measured at angular velocities of 30 degrees .s(-1) and 60 degrees .s(-1). Strength curve shape, average torque values and derived eccentric/concentric and trunk extensor/flexor ratios were analysed. The strength curves displayed greatest torques in the lengthened position for both muscle groups. Statistical analysis revealed no significant difference in strength between first and second test occasions (p=0.9920). Muscle action (eccentric versus concentric) and group (extensors versus flexors) were significant main effects (p <0.0001). There was no significant difference between torques at 30 degrees .s(-1) and 60 degrees .s(-1). The trunk extensor/flexor ratio approximated 1.75 for eccentric muscle action and 1.82 for concentric muscle actions. Gravity correction did not affect strength data but did affect strength curve shape. The results can be utilised to design individual prophylactic exercise programs for back pain. PMID- 25025999 TI - Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold. AB - BACKGROUND: Long-term Hodgkin lymphoma (HL) survivors have an increased risk of late cardiac morbidity and secondary lung cancer after chemotherapy and mediastinal radiotherapy. In this prospective study we investigate whether radiotherapy with deep inspiration breath-hold (DIBH) can reduce radiation doses to the lungs, heart, and cardiac structures without compromising the target dose. PATIENTS AND METHODS: Twenty-two patients (14 female, 8 male), median age 30 years (18-65 years), with supra-diaphragmatic HL were enrolled and had a thoracic PET/CT with DIBH in addition to staging FDG-PET/CT in free breathing (FB) and a planning CT in both FB and DIBH. For each patient an involved-node radiotherapy plan was done for both DIBH and FB, and the doses to the lungs, heart, and female breasts were recorded prospectively. Mean doses to the heart valves and coronary arteries were recorded retrospectively. Patients were treated with the technique yielding the lowest doses to normal structures. RESULTS: Nineteen patients were treated with DIBH and three with FB. DIBH reduced the mean estimated lung dose by 2.0 Gy (median: 8.5 Gy vs. 7.2 Gy) (p < 0.01) and the mean heart dose by 1.4 Gy (6.0 Gy vs. 3.9 Gy) (p < 0.01) compared to FB. The lung and heart V20Gy were reduced with a median of 5.3% and 6.3%. Mean doses to the female breasts were equal with FB and DIBH. CONCLUSION: DIBH can significantly decrease the estimated mean doses to the heart and lungs without lowering the dose to the target in radiotherapy for patients with mediastinal HL. PMID- 25026000 TI - Blood DNA methylation, nevi number, and the risk of melanoma. AB - Germline mutations determining increased cutaneous malignant melanoma (CMM) risk have been identified in familial and sporadic CMM cases, but they account only for a small proportion of CMM cases. Recent evidence suggests that germline epimutations (e.g. DNA methylation alterations), which can be inherited similarly to genomic mutations and can be detected in normal body cells (including blood), might increase susceptibility to cancer. The aim of the study was to identify germline epimutations of genes that were found to be mutated in familial CMM (p16, p14, CDK4, MC1R, hTERT), immune and inflammatory genes (ICAM-1, TNFalpha), DNA mismatch repair gene (MLH1), and repetitive elements (ALU, LINE-1, HERV-w). We measured DNA methylation using bisulfite pyrosequencing in peripheral blood mononuclear cells from 167 CMM cases and 164 sex-matched and age-matched controls. We used multivariable logistic regression models to evaluate the association between methylation levels and CMM status or presence of dysplastic nevi. We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFalpha [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18], CDK4 (OR=0.76, 95% CI=0.64-0.91), and MLH1 (OR=1.12, 95% CI=1.02-1.22). In control participants, the risk of developing dysplastic nevi was associated with methylation levels of TNFalpha (OR=0.81, 95% CI=0.69-0.95), hTERT (OR=0.90, 95% CI=0.82-0.99), and ALU (OR=1.56, 95% CI=1.02 2.39). Epimutations in CMM susceptibility genes and in genes involved in response to oxidative damage are associated with the risk of developing CMM or dysplastic nevi. Further studies measuring methylation levels of these genes in prospectively collected samples are warranted to further elucidate their role in the development and progression of CMM. PMID- 25026001 TI - Use of photochemiluminescence for the determination of antioxidant activities of carotenoids and antioxidant capacities of selected tomato products. AB - The purpose of this study was to compare the antioxidant activity of carotenoids to that of alpha-tocopherol by using a photochemiluminescence method (PCL). Comparisons to results obtained by using other established methods (alpha-TEAC, FRAP, DPPH, LPSC) were carried out. A relationship between the chemical structure of carotenoids and their antioxidant activity could be discussed. The number of conjugated double bonds and functional groups had a positive influence. Additionally, the lipophilic antioxidant capacities of selected tomato products were analyzed using PCL and alpha-TEAC. HPLC was used to identify and quantify contents of carotenoids, tocopherols, and tocotrienols. The raw material fresh tomatoes had the lowest antioxidant effect in both assays due to the lower carotenoid content. Tomato ketchup had the highest AOC in PCL, and tomato puree, in alpha-TEAC. The antioxidant capacities were mainly dependent on the water content of the samples. Furthermore, a concentration-dependent effect could be observed in both assays. PMID- 25026002 TI - Examination of CO2-SO2 solubility in water by SAFT1. Implications for CO2 transport and storage. AB - Removal of toxic gases like SO2 by cosequestration with CO2 in deep saline aquifers is a very attractive suggestion from environmental, human health and economic point of view. Examination of feasibility of this technique and forecasting the underlying fluid-rock interactions requires precise knowledge about the phase equilibria of the ternary mixture of SO2-CO2-H2O at conditions relevant to carbon capture and storage (CCS). In this study, a molecular-based statistical association fluid theory (SAFT1) model is applied to estimate the phase equilibria and aqueous phase density of mixtures. The molecules are modeled as associating segments while self-association is not allowed. The model is tested for different SO2 concentrations and for temperatures and pressures varying between 30-100 degrees C and ~6-30 MPa, respectively. Comparison of the results of this model against the available experimental data of binary systems demonstrates the capability of this equation of state, although, in contrast to the previous works, no temperature dependent binary interaction coefficient is applied. The results show that the total solubility of SO2 + CO2 in water varies exponentially with respect to SO2 concentrations, i.e., at low concentrations of SO2, total changes in solubility of the CO2 in water is negligible. PMID- 25026003 TI - Identification and expression analysis of zebrafish polypeptide alpha-N acetylgalactosaminyltransferase Y-subfamily genes during embryonic development. AB - Mucin-type glycosylation is one of the most common posttranslational modifications of secretory and membrane proteins and has diverse physiological functions. The initial biosynthesis of mucin-type carbohydrates is catalyzed by UDP-GalNAc: polypeptide alpha-N-acetylgalactosaminyltransferases (GalNAc-Ts) encoded by GALNT genes. Among these, GalNAc-T8, -T9, -T17, and -T18 form a characteristic subfamily called "Y-subfamily" and have no or very low in vitro transferase activities when assayed with typical mucin peptides as acceptor substrates. Although the Y-subfamily isozymes have been reported to be possibly involved in various diseases, their in vivo functions have not been reported. Here, we isolated zebrafish Y-subfamily galnt genes, and determined their spatial and temporal expressions during the early development of zebrafish. Our study demonstrated that all the Y-subfamily isozymes were well conserved in zebrafish with GalNAc-T18 having two orthologs, galnt18a and galnt18b, and with the other three isozymes each having a corresponding ortholog, galnt8, galnt9, and galnt17. The galnt8 was expressed in the cephalic mesoderm and hatching gland during early developmental stages, and differently expressed in the head, somatic muscles, and liver in the later stages. The other three orthologs also exhibited the characteristic expression patterns, although their expressions were generally strong in the nervous systems. In addition to the expression in the brain, galnt17 and galnt18a were expressed in the somitic muscles, and galnt18a and galnt18b in the notochord. These expression patterns may contribute to the functional analysis of the Y-subfamily, whose physiological roles still remain to be elucidated. PMID- 25026004 TI - Efficient decomposition of formaldehyde at room temperature over Pt/honeycomb ceramics with ultra-low Pt content. AB - Pt/honeycomb ceramic (Pt/HC) catalysts with ultra-low Pt content (0.005-0.055 wt%) were for the first time prepared by an impregnation of honeycomb ceramics with Pt precursor and NaBH4-reduction combined method. The microstructures, morphologies and textural properties of the resulting samples were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), and transmission electron microscopy (TEM). The obtained Pt/HC catalysts were used for catalytic oxidative decomposition of formaldehyde (HCHO) at room temperature. It was found that the as-prepared Pt/HC catalysts can efficiently decompose HCHO in air into CO2 and H2O at room temperature. The catalytic activity of the Pt/HC catalysts increases with increasing the Pt loading in the range of 0.005-0.013 wt%, and the further increase of the Pt loading does not obviously improve catalytic activity. From the viewpoint of cost and catalytic performance, 0.013 wt% Pt loading is the optimal Pt loading amount, and the Pt/HC catalyst with 0.013 wt% Pt loading also exhibited good catalytic stability. Considering practical applications, this work will provide new insights into the low-cost and large-scale fabrication of advanced catalytic materials for indoor air purification. PMID- 25026005 TI - [Does the hospital cost of care differ for inflammatory bowel disease patients with or without gastrointestinal infections? A case-control study]. AB - OBJECTIVE: Gastrointestinal Infections have been implicated as possible causes of exacerbation of inflammatory bowel disease (IBD) or risk factors for severe flares in general. The introduction of the G-DRG reimbursement system has greatly increased the pressure to provide cost effective treatment in German hospitals. Few studies have compared the costs of treating IBD patients with or without gastrointestinal infections and none of them have specifically considered the German reimbursement situation. METHODS: We performed a single center case control retrospective chart review from 2002 to 2011 of inpatients with IBD (Department of Internal Medicine IV, University Hospital Jena) with an exacerbation of their disease. The presence of gastrointestinal infections (Salmonella, Shigella, Campylobacter, Yersinia, adeno-, rota-, norovirus and Clostridium difficile) was assessed in all inpatients with Cohn's disease (CD) and ulcerative colitis (UC). IBD patients with gastrointestinal infections (n = 79) were matched for age to IBD patients who were negative for gastrointestinal pathogens (n = 158). Patient level costing (PLC) was used to express the total cost of hospital care for each patient; PLC comprised a weighted daily bed cost plus cost of all medical services provided (e. g., endoscopy, microbiology, pathology) calculated according to an activity-based costing approach. All costs were discounted to 2012 values. RESULTS: Gastrointestinal infections in IBD patients were not associated with an increase in mortality (0%); however, they were associated with 2.3-fold higher total hospital charges (6499.10 ? vs. 2817.00 ?; p = 0.001) and increased length of stay in hospital (14.5 vs. 9.4 days; p < 0.0001). Despite increased reimbursement by DRG for IBD patients with gastrointestinal infections compared to patients without infections (3833.90 ? vs. 2553.50 ?; p = 0.005), hospital care in these patients was substantially underfunded (deficit -2496.80 ? vs. -433.10 ?) because of increased length of stay with personnel costs, especially in UC. CONCLUSION: Inpatient hospital costs differ significantly for IBD patients with and without gastrointestinal infections, especially in ulcerative colitis, when care was provided in a single university hospital. PMID- 25026006 TI - Measurement of shear wave velocity using acoustic radiation force impulse imaging is not hampered by previous use of ultrasound contrast agents. AB - PURPOSE: To assess the inter-observer reproducibility of acoustic radiation force impulse imaging (ARFI) between 2 skilled physicians and to evaluate if ultrasound contrast agents (UCA) affect the measurement of shear wave velocity (SWV) using ARFI. PATIENTS AND METHODS: 53 patients (29 males, 24 females, 59 +/- 15 [22-84] years) who underwent contrast enhanced ultrasound (CEUS) examination were included. ARFI was performed on liver segment V by physicians A and B before CEUS, and by physician A within 4-6 minutes and 7-10 minutes after contrast injection. In a subgroup of 31 patients (15 males, 16 females, 57 +/- 18 [22-84] years), ARFI was also performed on focal liver lesions (FLL) by physician A before CEUS, and within 4-6 minutes and 7-10 minutes after contrast injection. RESULTS: The SWV values obtained by physician A and B before CEUS yielded an intra-class correlation coefficient value of 0.913 (95% CI, 0.849-0.950). No significant differences were shown between the SWV values of liver segment V in all 53 patients and of FLL in the subgroup of 31 patients obtained before CEUS and that of within 4-6 minutes and 7-10 minutes after contrast injection (all P > 0.05). CONCLUSION: ARFI showed excellent inter-observer reproducibility between 2 skilled physicians. UCA did not affect the measurement of SWV in both liver parenchyma and FLL, at least when performed 4 minutes after the contrast injection. ARFI may become an additional tool in the differential diagnosis of FLL. PMID- 25026007 TI - [Non-cirrhotic portal hypertension presented by acute upper gastrointestinal bleeding 7 years after oxaliplatin-chemotherapy]. AB - After having received adjuvant FOLFOX treatment consisting of oxaliplatin, folinic acid and fluoruracil following hemicolectomy in colon cancer 7 years ago, the findings of non-cirrhotic portal hypertension presented by acute upper gastrointestinal bleeding in a 49-year old woman were interpreted as oxaliplatin associated. Imaging techniques, hepatic venous pressure measurement and liver biopsy supported pre-sinusoidal damage due to NRH (nodular regenerative hyperplasia) as the underlying cause, even though histological findings were moderate. Following primary endoscopic treatment, a stable condition has thus far been achievable with standard drug therapy. PMID- 25026008 TI - [Cystic echinococcosis and hepatocellular carcinoma--a coincidence? A case report]. AB - INTRODUCTION: The coincidence of echinococcosis and hepatocellular carcinoma (HCC) is quite rare. We report the case of a 45-year-old man who was admitted to our hospital because of abdominal pain in the right upper quadrant and jaundice. Clinical features and diagnostics: There was no history of weight loss or fever. No abdominal mass was palpable. The laboratory reports showed increased transaminase levels. Ultrasonography revealed an inhomogenous, cystic lesion measuring 6 cm in diameter in the segments VI and VII. Serology for echinococcosis was negative, alpha-fetoprotein (AFP) was considerably increased. CT scan showed a solid mass of 3,7 cm in diameter adjacent to the cystic lesion. THERAPY AND COURSE: Anthelminthic therapy with albendazole caused a massive increase of cholestasis parameters and treatment had to be stopped. The simultaneous occurrence of serologically negative cystic echinococcosis and HCC was suspected and partial liver resection was performed. Histological examination confirmed both diagnoses and tumor resection in healthy tissue. 5 months after resection CT scan showed multicentric HCC affecting the whole liver. Palliative therapy with sorafenib was established. DISCUSSION: The coincidence of HCC and cystic echinococcosis in the non-cirrhotic liver of a young man is a rare event. Despite resection in healthy tissue multicentric HCC was diagnosed 5 months later. Only few cases of simultaneous occurrence of HCC and echinococcosis have been published so far. Some authors considered echinococcosis as a trigger for HCC. A causal link between both entities has not been demonstrated until now. PMID- 25026009 TI - [S2k guidelines diverticular disease/diverticulitis]. PMID- 25026011 TI - [Is mass eradication of Helicobacter pylori infection effective for preventing gastric cancer?]. PMID- 25026010 TI - [Results of a S2k-Consensus Conference of the German Society of Gastroenterolgy, Digestive- and Metabolic Diseases (DGVS) in conjunction with the German Coeliac Society (DZG) regarding coeliac disease, wheat allergy and wheat sensitivity]. PMID- 25026012 TI - [Begin of a new era in treating hepatitis C in Patients on the waiting list and after liver transplantation]. PMID- 25026013 TI - Aspects of applied physiology in chronic bronchitis and emphysema. AB - The terms chronic bronchitis and emphysema have been loosely applied in the literature to a wide spectrum of diseases characterised by chronic, irreversible airways obstruction. Their use as descriptive terms rather than specific diagnoses has hindered a proper understanding of the differences between the two diseases. The present paper is devoted primarily to the physiological aspects of chronic bronchitis and emphysema but to avoid confusion the two diseases will first be defined in terms of their clinical and pathological features. PMID- 25026014 TI - Physiotherapy for thoracic conditions: interstate panel: paper 1. AB - When we consider the rationale that forms the foundation for any aspect of thoracic physiotherapy, treatment will normally fall into two main categories - control of breathing and efficient coughing. PMID- 25026015 TI - Paper 2: coughing for the thoracic surgery patient. AB - Coughing is a mechanism designed to protect lung function. Together with normal ciliary action, it maintains patency of the airways. The cough is elicited by reflex stimulation of the cough-sensitive areas which are restricted to the upper airway down to the divisions from the main bronchi. Coughing may also be produced by conscious voluntary effort. PMID- 25026016 TI - Paper 3: the acutely distressed patient. AB - The acutely distressed patient is the one whose condition is deteriorating to the stage of respiratory failure or pulmonary insufficiency. I quote these definitions: Respiratory failure: "a failure to maintain normal blood gas homeostasis" (Sykes McNicol and Campbell, 1970); and pulmonary insufficiency: "when the lungs do not fully arterialise the blood passing through them, giving rise to lower than normal oxygen tensions and [/or] higher than normal carbon dioxide tensions in the arterial blood. These changes ... ultimately result in abnormal cellular function" (Robin and Bromberg 1966). PMID- 25026017 TI - Paper 4: breathing control with activity and the assessment of exercise tolerance. AB - Many patients with chronic airways disease are faced with the problem of an ever decreasing level of exercise tolerance associated with increasing dyspnoea and increasing recovery time from this dyspnoea. PMID- 25026018 TI - Cardiac rehabilitation: paper 1. AB - I intend to confine myself to rehabilitation as applied to ischaemic heart disease as this is by far the largest single cause of cardiac disability. In 1970, 20,515 males died of ischaemic heart disease out of a total of 62,828 male deaths (32.7%) and 13,424 females died of ischaemic heart disease out of a total of 50,220 female deaths (26.7%). PMID- 25026019 TI - Paper 2. AB - As with most rehabilitation programmes today, I believe that Cardiac Rehabilitation is best conducted as a team effort, each member making his own contribution, yet acting in a unified manner to ensure the very best will be done for the patient. PMID- 25026020 TI - Paper 3: physiotherapy at the work assessment centre, national heart foundation, melbourne. AB - The Centre has been using physiotherapy for assessment and training for the last eight years and currently we have 30 men attending twice weekly for exercise sessions. They usually attend from one to three months. The programme aims at three things: 1. to provide a bridge between sitting at home doing nothing and going back to competitive full-time employment; 2. to teach the patient what a reasonable amount of exercise feels like and that this amount is quite safe, and how to cope with any associated discomfort; 3. to establish an upper limit of performance, for example, recurrent angina may occur on lifting 60 lb. weights or less. This performance is then related to the patient's work situation and their physical capacity chart. PMID- 25026021 TI - Disability in brisbane caused by chronic disease. AB - Chronic diseases and the disabilities which they cause are the most important problem in Public Health. Ischaemic Heart Disease with its clinical manifestations of myocardial infarction and angina pectoris is a prime example of a chronic disease with acute complications which may lead either to death (ischaemic heart disease being the most common cause of death in Australia) or to permanent or semi-permanent invalidism. In the study of the epidemiology of chronic (disease there are certain problems encountered which are not faced in acute disease epidemiology. These include varying criteria for diagnosis (for example, what levels constitute normal blood pressure), the absence of an "incubation period" for the disease - when, for example, does arteriosclerosis begin in an individual - and a dearth of accurate incidence figures because most data on chronic disease are mortality data which, because of under reporting and incorrect diagnosis, may not give a true picture of the fatal effects of chronic disease. Death from cerebrovascular disease accounted for 1254 deaths per 10(6) population in Australia in 1970 yet hypertension only caused 139 deaths per 10(6). It is obvious that many death certificates recording stroke deaths do not mention hypertension which is a common cause of stroke. It can be seen that academic research into chronic disease epidemiology is fraught with many serious difficulties. PMID- 25026022 TI - Glutathione-triggered disassembly of dual disulfide located degradable nanocarriers of polylactide-based block copolymers for rapid drug release. AB - Reduction-responsive degradation based on disulfide-thiol chemistry is highly desirable in the development of self-assembled block copolymer nanocarriers for multifunctional polymer-based drug delivery applications. Most conventional approaches involve the incorporation of disulfide linkages at a single location. Herein, we report a new dual disulfide located degradable polylactide (PLA)-based block copolymer (DL-ssABP) synthesized by a combination of ring opening polymerization, facile coupling reactions, and controlled radical polymerization. The amphiphilic design of the DL-ssABP enables the formation of self-assembled micelles having disulfides positioned both in the hydrophobic PLA core and at the core/corona interface. The reductive response to glutathione as a cellular trigger results in the cleavage of the disulfide linkage at the interface shedding hydrophilic coronas as well as the disulfides in the PLA core causing disintegration of PLA cores. Such dual disulfide degradation process leads to a synergistically enhanced release of encapsulated anticancer drugs in cellular environments. These results, combined with flow cytometry and confocal laser scanning microscopy (CLSM) as well as cell viability measurements, suggest that DL-ssABP offers versatility in tumor-targeting controlled/enhanced drug delivery applications. PMID- 25026023 TI - Kinetics and mechanistic investigation into the possible activation of imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(III)], NAMI A, by 2-mercaptoethane sulfonate. AB - Imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(III)], NAMI A, is a promising antimetastatic prodrug with high specificity for metastatic cancer cells. Limited activity of NAMI-A against primary tumor suggests that its use in combination with other anticancer drug(s) might present a more desirable therapeutic outcome. The mechanism of activation and action of this prodrug is still largely unknown. The biological targets, as well, have not yet been delineated. The kinetics and mechanism of interaction of NAMI-A with 2 mercaptoethane sulfonate, MESNA, a chemoprotectant, have been studied spectrophotometrically under pseudo-first order conditions of excess MESNA. The reaction is characterized by initial reduction of NAMI-A and formation of dimeric MESNA as evidenced by electospray ionization mass spectrometry. A first order dependence on both NAMI-A and MESNA was obtained and a bimolecular rate constant of 0.71 +/- 0.06 M(-1) s(-1) was deduced. Activation parameters determined (DeltaS(?) = -178.12 +/- 0.28 J K(-1) mol(-1), DeltaH(?) = 20.64 +/- 0.082 kJ mol(-1) and DeltaG(?) = 75.89 +/- 1.76 kJ mol(-1) at 37 +/- 0.1 degrees C and pH 7.4) are indicative of formation of an associative intermediate prior to product formation and subsequent hydrolysis of the reduced complex. Our results suggest that MESNA might be able to activate the prodrug while still protecting against toxicity when given in a regimen involving NAMI-A and chemotherapy drug(s) that induce bladder and kidney toxicities. PMID- 25026024 TI - Influences of sex, age and education on attitudes towards gender inequitable norms and practices in South Sudan. AB - Prolonged conflict in South Sudan exacerbated gender disparities and inequities. This study assessed differences in attitudes towards gender inequitable norms and practices by sex, age and education to inform programming. Applying community based participatory research methodology, 680 adult respondents, selected by quota sampling, were interviewed in seven South Sudanese communities from 2009 to 2011. The verbally administered survey assessed attitudes using the Gender Equitable Men scale. Data were stratified by sex, age and education. Of 680 respondents, 352 were female, 326 were male and two did not report their sex. The majority of respondents agreed with gender inequitable household roles, but the majority disagreed with gender inequitable practices (i.e., early marriage, forced marriage and inequitable education of girls). Respondents who reported no education were more likely than those who reported any education to agree with gender inequitable practices (all p < 0.03) except for forced marriage (p = 0.07), and few significant differences were observed when these responses were stratified by sex and by age. The study reveals agreement with gender inequitable norms in the household but an overall disagreement with gender inequitable practices in sampled communities. The findings support that education of both women and men may promote gender equitable norms and practices. PMID- 25026025 TI - Combined movements in the cervical spine (c2-7) their value in examination and technique choice. AB - Treatment by passive movement has been shown to be a useful method when compared to other treatment procedures (Edwards 1969). It is however still empirical in nature. Part of the reason for this is because definite movement patterns related to pathology are still unclear. This can produce confusion when one is selecting a technique as very often there appears to be no relationship between the restricted movement the patient may exhibit and the technique chosen. It is suggested that detailed examination related to the combining of different movements will allow a more accurate choice of technique to be made. Under these circumstances the therapist should be able to predict the effect of a treatment technique. Progression of a treatment is also more logical as it depends on progressing the position of the joint to the position which is most painfull as the movement pattern improves, rather than increasing the vigour of the technique. PMID- 25026026 TI - Assessment of abdominal muscle exercises in non-pregnant, pregnant and postpartum subjects, using electromyography. AB - The purpose of this study was to analyse, by electromyographic technique, abdominal muscle activity in exercises commonly advocated as being effective in improving abdominal muscle performance. In general exercises from the lying position were found to involve the rectus abdominis and oblique muscles more than those exercises from standing, sitting or kneeling positions. Further, among exercises from lying, 'trunk on legs' and 'trunk plus legs' involved these muscles more than 'legs on trunk' exercises. With pregnancy and in the puerperium there was a change in the pattern of abdominal muscle involvement in exercises from the lying position, suggesting that the traditional division of exercise lists into 'antenatal' and 'postnatal' is not optimal: the demarcation "circumnatal" (around the time of birth) and "abnatal" (remote from the time of birth) would appear to be more appropriate. Details are given of the method of assessment of exercises, data analysis and interpretation of results. The findings have implications for the selection of exercises for clinical Use in obstetric physiotherapy. PMID- 25026027 TI - Hydrogen interactions with intrinsic point defects in hydrogen permeation barrier of alpha-Al2O3: a first-principles study. AB - It is crucial to understand hydrogen interactions with intrinsic point defects in the hydrogen permeation barrier (HPB) of alpha-Al2O3, finding underlying reasons for the not-so-low H-permeability of the barrier, and thereby produce samples with tailored defects for optimal performance. Using density functional theory (DFT), the formation energies of intrinsic point defects in an alpha-Al2O3 lattice, including extrinsic H-related defects (H(i), V(Al)-H complex, HO(i) and H(O)), in all possible charged states, are first calculated under HPB working conditions, to determine the dominant basic defect species for hydrogen. We find that the stable forms of H-related defects in alpha-Al2O3 are charged H interstitials (H(i)(q), where q is the charge state of the defect) and hydrogenation of the bulk V(Al)(3-) ([V(Al)(3-)-H(+)](q)), under hydrogen-rich conditions. As the system reaches equilibrium, H in alpha-Al2O3 is mainly present in the H(i)(+) state, and preferentially exists in the form of [V(Al)(3-)-H(+)] and H(O)(+). Migration processes of the dominant defects are further investigated, predicting that H(i)(+) is the predominant diffusion species in alpha-Al2O3. [V(Al)(3-)-H(+)](2-) and H(O)(+) can release trapped hydrogen during high temperature annealing, contributing to the H-transport in alpha-Al2O3. The formation energy is much higher than the migration energy for H(i)(+), suggesting that the migration of H(i)(+) is the bottleneck for creating low enough H permeation in alpha-Al2O3, and corresponding strategies for optimum H-suppressing performance for an alpha-Al2O3 HPB are proposed. PMID- 25026028 TI - Expression of CD55 on red blood cells of beta-thalassemia patients. AB - CD55 is a complement regulatory protein expressed by cells to protect them from bystander lysis by complement. It prevents the formation of C3/C5 convertase. In beta-thalassemia (beta-thal), the defective hemoglobin (Hb) production makes red blood cells (RBCs) lyse early and frequently. Loss of CD55 expression in those patients compromises the complement regulatory function, thereby accelerating RBC lysis. In this study, we aimed to evaluate the expression of CD55 on erythrocytes of beta-thal patients. Flow cytometry analysis of CD55 was conducted on RBCs of 21 beta-thalassemia major (beta-TM) patients, 11 beta-thalassemia intermedia (beta-TI) patients and 10 healthy volunteers. The results showed a significant decrease in CD55 expression in beta-TM (57.5 +/- 16.7%), while there was a slight decrease in beta-TI patients (81.8 +/- 3.8%) in comparison with that of the normal controls (88.7 +/- 0.8%). The diminished expression of CD55 was not accompanied by decrease in CD59 expression in beta-thal patients (97.2 +/- 2.3%). This could suggest a mechanism (could be genetic) responsible for low CD55 expression. It may be related to defective Hb genes in thalassemia, but it does not relate to cell membrane changes. PMID- 25026029 TI - Mitochondria are clamped to vacuoles for lipid transport. AB - In this issue of Developmental Cell, Elbaz-Alon et al. (2014) and Honscher et al. (2014) describe a contact site between mitochondria and the lysosome-like yeast vacuole named vCLAMP (vacuole and mitochondria patch). They show that vCLAMP plays a role in lipid exchange, thereby linking mitochondria to the endomembrane system. PMID- 25026030 TI - Live free or die: cell-cell adhesion regulates sensitivity to trail-induced apoptosis. AB - The ability of the death ligand TRAIL to induce tumor cell apoptosis has led to the development of TRAIL-based cancer therapies. Reporting recently in Molecular Cell, Lu et al. (2014) show that the basis for differential TRAIL responses involves clustering of death receptor complexes by E-cadherin and the actin cytoskeleton. PMID- 25026031 TI - Finding a common path: predicting gene function using inferred evolutionary trees. AB - Reporting in Cell, Li and colleagues (2014) describe an innovative method to functionally classify genes using evolutionary information. This approach demonstrates broad utility for eukaryotic gene annotation and suggests an intriguing new decomposition of pathways and complexes into evolutionarily conserved modules. PMID- 25026032 TI - Paternal nucleosomes: are they retained in developmental promoters or gene deserts? AB - Nucleosomes retained in spermatozoa may influence development and epigenetic inheritance. In this issue of Developmental Cell, Samans et al. (2014) and Carone et al. (2014) provide evidence for the predominant retention of sperm nucleosomes in gene deserts, necessitating a reevaluation of the prevailing notion claiming their enrichment over developmental promoters. PMID- 25026033 TI - With NuRD, HDACs Go "Nerdy". AB - Reporting in a recent issue of Neuron, Yamada et al. (2014) show that the histone deacetylase (HDAC)-containing NuRD complex plays a critical role in shutting down expression of specific synaptogenesis-related genes in the cerebellum, resulting in enhanced differentiation of presynaptic structures. This work suggests that HDACs in neurons acquire specificity through NuRD. PMID- 25026034 TI - Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. AB - Autophagy is an essential degradative pathway in neurons, yet little is known about mechanisms driving autophagy in highly polarized cells. Here, we use dual color live-cell imaging to investigate the neuron-specific mechanisms of constitutive autophagosome biogenesis in primary dorsal root ganglion (DRG) and hippocampal cultures. Under basal conditions, autophagosomes are continuously generated in the axon tip. There is an ordered assembly of proteins recruited with stereotypical kinetics onto the developing autophagosome. Plasma- or mitochondrial-derived membranes were not incorporated into nascent autophagosomes in the distal axon. Rather, autophagosomes are generated at double FYVE containing protein 1 (DFCP1)-positive subdomains of the endoplasmic reticulum (ER), distinct from ER exit sites. Biogenesis events are enriched distally; autophagosomes form infrequently in dendrites, the soma, or midaxon, consistent with a compartmentalized pathway for constitutive autophagy in primary neurons. Distal biogenesis may facilitate degradation of damaged mitochondria and long lived cytoplasmic proteins reaching the axon tip via slow axonal transport. PMID- 25026035 TI - Cellular metabolism regulates contact sites between vacuoles and mitochondria. AB - Emerging evidence suggests that contact sites between different organelles form central hubs in the coordination of cellular physiology. Although recent work has emphasized the crucial role of the endoplasmic reticulum in interorganellar crosstalk, the cooperative behavior of other organelles is largely unexplored. Here, we identify a contact site named vCLAMP (vacuole and mitochondria patch) that integrates mitochondria with the lysosome-like vacuole and thus the endocytic pathway. vCLAMPs depend on the vacuolar HOPS tethering complex subunit Vps39/Vam6 and the Rab GTPase Ypt7, which also participate in membrane fusion at the vacuole. Intriguingly, vCLAMPs are located proximal to the ER-mitochondria encounter structure (ERMES) complexes, and an increase in vCLAMPs can rescue the growth defect of ERMES mutants. Importantly, the persistence of vCLAMPs is regulated by phosphorylation of Vps39 and is strongly reduced during respiratory growth. The identification of this organelle contact site reveals a physical and metabolic interconnection between the endocytic pathway and mitochondria. PMID- 25026036 TI - A dynamic interface between vacuoles and mitochondria in yeast. AB - Cellular life depends on continuous transport of lipids and small molecules between mitochondria and the endomembrane system. Recently, endoplasmic reticulum mitochondrial encounter structure (ERMES) was identified as an important yet nonessential contact for such transport. Using a high-content screen in yeast, we found a contact site, marked by Vam6/Vps39, between vacuoles (the yeast lysosomal compartment) and mitochondria, named vCLAMP (vacuole and mitochondria patch). vCLAMP is enriched with ion and amino-acid transporters and has a role in lipid relay between the endomembrane system and mitochondria. Critically, we show that mitochondria are dependent on having one of two contact sites, ERMES or vCLAMP. The absence of one causes expansion of the other, and elimination of both is lethal. Identification of vCLAMP adds to our ability to understand the complexity of interorganellar crosstalk. PMID- 25026037 TI - Lack of effect of the apolipoprotein E epsilon4 genotype on cognition during healthy aging. AB - BACKGROUND: The apolipoprotein E (APOE) epsilon4 genotype is associated with an increased risk of Alzheimer's disease. In community surveys, older adults with this genotype have been found to have lower scores on neuropsychological tests than those who do not. It is possible that this is the consequence of subclinical changes in cognition in those persons who later develop dementia. The aim of this research was to determine whether the effect of APOE genotype on cognition would remain if those who subsequently became demented were retrospectively removed from the analysis of the baseline test data from a sample of healthy adults. METHOD: A sample of 241 nondemented persons over the age of 65 for whom APOE genotyping was available were administered a range of neuropsychological tests at baseline and were followed up 10 years later. RESULTS: Significant differences between the epsilon4-present and epsilon4-absent groups were found for the delayed recall trial of the Rey Auditory Verbal Learning Test and the Trail Making Test. When those participants known to have developed dementia during the follow-up period were excluded from the analysis of the baseline data these differences disappeared. A total of 113 nondemented survivors from the original sample were retested, and no difference was found in the rate of decline on any measure between the epsilon4-present and epsilon4-absent groups. CONCLUSIONS: It is likely that the reported effect of the epsilon4 APOE genotype on cognition is the consequence of the epsilon4-present group containing persons whose cognition is subtly affected by the early stages of a dementing process. It is also unlikely that the presence of the epsilon4 allele by itself leads to a significantly accelerated rate of cognitive decline in the nondemented elderly. PMID- 25026038 TI - Irrigation of root vegetables with treated wastewater: evaluating uptake of pharmaceuticals and the associated human health risks. AB - To meet mounting water demands, treated wastewater has become an important source of irrigation. Thus, contamination of treated wastewater by pharmaceutical compounds (PCs) and the fate of these compounds in the agricultural environment are of increasing concern. This field study aimed to quantify PC uptake by treated wastewater-irrigated root crops (carrots and sweet potatoes) grown in lysimeters and to evaluate potential risks. In both crops, the nonionic PCs (carbamazepine, caffeine, and lamotrigine) were detected at significantly higher concentrations than ionic PCs (metoprolol, bezafibrate, clofibric acid, diclofenac, gemfibrozil, ibuprofen, ketoprofen, naproxen, sulfamethoxazole, and sildenafil). PCs in leaves were found at higher concentrations than in the roots. Carbamazepine metabolites were found mainly in the leaves, where the concentration of the metabolite 10,11-epoxycarbamazepine was significantly higher than the parent compound. The health risk associated with consumption of wastewater-irrigated root vegetables was estimated using the threshold of toxicological concern (TTC) approach. Our data show that the TTC value of lamotrigine can be reached for a child at a daily consumption of half a carrot (~60 g). This study highlights that certain PCs accumulated in edible organs at concentrations above the TTC value should be categorized as contaminants of emerging concern. PMID- 25026039 TI - A psychophysical evaluation of manual stiffness discrimination. AB - One possible explanation for the poor reliability of clinical judgments of spinal stiffness is that humans do not possess a good ability to discriminate stiffness stimuli. This study sought to investigate this hypothesis by conducting stiffness discrimination tests on 72 subjects, using a mechanical device to provide the stiffness stimuli. The relative increment in stiffness needed so that two stimuli could be differentiated 75 per cent of the time was found to be 11 per cent when the pisiform grip was used to assess stiffness of stimuli in the range from 6 to 11 N/mm. Thus, by inference, other factors are more likely to be the cause of the poor reliability of clinical judgments of spinal stiffness. PMID- 25026040 TI - Muscle activation patterns during transfers in individuals with spinal cord injury. AB - The utility of functional electrical stimulation regimens depend on an understanding of movement strategies and muscle activation patterns. The purpose of this study was to describe the electromyographic (EMG) profiles of the lateral transfer in individuals with spinal cord injury. Two movement strategy groups were examined: translatory (n = 9) and rotatory (n = 4). Transfer event markers were identified from force platform data. EMG signal profiles (100ms Root Mean Square envelopes) of triceps and latissimus dorsi bilaterally were generated for each group. Rotatory movement strategy demonstrates greater muscle synchronisation than do individuals who translate. The results provide evidence of different phasic characteristics of muscle activity during the lateral transfer using two possible movement strategies. The implications for intervention regimens are discussed. PMID- 25026041 TI - Accuracy and reliability of physiotherapists in the interpretation of tape recorded lung sounds. AB - The effect of clinical experience on the accurate and reliable interpretation of auscultated lung sounds was examined by comparing 16 new graduates (Group A) with 16 experienced cardiopulmonary physiotherapists (Group B). Subjects listened to a tape comprising six different lung sounds, with each sound repeated three times in random order. Group B tended to be more accurate than Group A for five of the six sounds but the difference was significant only for the normal breath sound (chi(2) = 6.72, p = 0.01). Intra-rater reliability was poor; for any individual sound, a maximum of nine subjects recorded the same response on all three occasions. There were no significant inter-group differences in reliability. In conclusion, clinical experience had no significant effect on accuracy and reliability. PMID- 25026042 TI - Ultrasound imaging in rehabilitation. AB - Real-time ultrasound imaging is currently used extensively in medicine. It provides a safe, cost-effective and readily accessible method of examination of various organs and tissues. Furthermore, real-time ultrasound imaging has the potential to be of considerable benefit in rehabilitation. Possible applications in physiotherapy practice and research relate to measurement of muscle size and observation and monitoring of muscle contraction while it actually occurs. This may be useful for muscle rehabilitation and re-education, especially in the case of deep muscles, which are often difficult to assess. PMID- 25026043 TI - Parent satisfaction with the Minimal Motor Dysfunction Unit: a survey. AB - This study investigated parent satisfaction with the Minimal Motor Dysfunction Unit (MMDU), a service for clumsy children based in Adelaide. A questionnaire was developed and mailed to 102 parents whose children had attended the MMDU between 1991 and 1993. The response rate was 76 per cent. The level of parent satisfaction with the overall MMDU service was 86 per cent. Parents rated the processes of service delivery and the resulting outcomes as more important to them than structural aspects of the service. Based on parent comments, recommendations were made to assist in further improving the quality of the MMDU service. Parent satisfaction should be investigated as an outcome measure for other paediatric physiotherapy services. PMID- 25026044 TI - Hydrotherapy management of low back pain: a quality improvement project. AB - An audit of 81 patients referred to hydrotherapy for low back pain was carried out over 12 months. The audit recorded response to hydrotherapy in terms of area of pain; intensity of pain; range of motion and ability to perform activities of daily living; treatment frequency and duration; and hydrotherapy program content. Results showed a highly significant beneficial response (t(67) = 9.2, p < 0.001). Changes to the hydrotherapy service resulting from the study include improved documentation; standardised assessment; re-worked hydrotherapy program; and regular assessment of patients within planned time-frames. PMID- 25026045 TI - Catalytic control over the formation of supramolecular materials. AB - In this Perspective, we will discuss how the rate of formation of supramolecular materials can be drastically enhanced by catalytically controlling the rate of formation of their molecular building blocks, resulting in the formation of out of-equilibrium soft materials with enhanced mechanical properties. Also, the use of surface confined, patterned catalysts allows spatial control over self assembly, which can be applied to the formation of regular, micrometer sized hydrogel patterns. Catalysis has been applied for decades as an indispensable tool in the synthesis of both simple and highly complex molecules and polymers, ranging from milligram lab-scale to multi-ton industrial processes. However, despite being widespread in nature, until recently the use of catalysis to control the formation of supramolecular materials has remained limited. We will demonstrate the large potential of using catalysis as a tool in the construction of soft materials, illustrated by recent developments. PMID- 25026046 TI - Studies examining the relationship between the chemical structure of protoxin II and its activity on voltage gated sodium channels. AB - The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin comprises a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.7 and Nav1.2 channels were investigated. Other tail region modifications to this chimera explored the effects of tail length and tertiary structure on sodium channel activity. In addition, the activity of various C-terminal modifications of the native ProTx II was assayed and resulted in the identification of protoxin II-NHCH3, a molecule with greater potency against Nav1.7 channels (IC50=42 pM) than the original ProTx II. PMID- 25026047 TI - Crafty birds and fitness fiends: relationships of professional and leisure activities. AB - Stereotypes of therapists were found to contain a 'kernel of truth' in a survey comparing the active and passive leisure pursuits of female physiotherapy (N = 100) and occupational therapy (N = 107) graduates and undergraduates. Physiotherapists had relatively more active leisure patterns as adolescents and undergraduates. Occupational therapists had relatively passive leisure patterns that persisted after graduation. These findings support the spillover hypothesis of a work-leisure relationship. Following graduation physiotherapists adopted more passive leisure pursuits which supports the compensation theory of leisure. However, physiotherapy graduates felt deprived of sport and experienced less leisure satisfaction than occupational therapists. PMID- 25026048 TI - Communication and interpersonal Helping Skills: An Essential Component in Physiotherapy Education? AB - The rationale and content for an interdisciplinary communication and interpersonal helping skills programme taught to third year Physiotherapy students is described, noting in particular the need to integrate a general counselling model with specific interviewing and clinical skills required by Physiotherapists. A programme evaluation based on the participation of 97 students is described. Evaluation techniques included meetings of the independent evaluator with student representatives, and completion by students of several forms evaluating general and specific aspects of the programme. Overall, the results were positive and supportive of the rationale and content of the programme. A pre- and post-test design was used to assess outcome in terms of student priorities, results of which are discussed with reference to the measuring instrument's focus on ratings of performance as distinct from specific behaviours. Directives for the future development of the programme are highlighted. PMID- 25026049 TI - Towards the effective use of the specialist physiotherapist. AB - Physiotherapists in Australia have been able to become specialists by a process of specialisation since 1982. The process was designed to achieve certain aims with the majority of the profession supporting the aim of improving quality of care. The implications of the aims for appropriate utilisation of the specialist physiotherapist in today's Australian Society are discussed and a mode of practice is proposed. PMID- 25026050 TI - Thermal sensation and the skin sensation test: regional differences and their effects on the issue of reliability of temperature ranges. AB - This study assesses the differences in temperature sensitivity of skin areas. The subjects were required to associate the water content of test-tubes with the different heat sensations. The side of the test-tube was placed on the skin area and the temperature was matched with the subject's response. Analyses were limited to the warmth and cold sensations as generalizations can be made from these in terms of differences in the skin areas in heat perception. In the face, the temperature associated with warmth was significantly lower than in the forearm and the leg. This trend was different between the three areas in terms of the cold temperatures. The intra-individual difference suggests that results of skin sensation tests should be interpreted with some caution. PMID- 25026051 TI - An advanced lithium-ion battery based on a graphene anode and a lithium iron phosphate cathode. AB - We report an advanced lithium-ion battery based on a graphene ink anode and a lithium iron phosphate cathode. By carefully balancing the cell composition and suppressing the initial irreversible capacity of the anode in the round of few cycles, we demonstrate an optimal battery performance in terms of specific capacity, that is, 165 mAhg(-1), of an estimated energy density of about 190 Wh kg(-1) and a stable operation for over 80 charge-discharge cycles. The components of the battery are low cost and potentially scalable. To the best of our knowledge, complete, graphene-based, lithium ion batteries having performances comparable with those offered by the present technology are rarely reported; hence, we believe that the results disclosed in this work may open up new opportunities for exploiting graphene in the lithium-ion battery science and development. PMID- 25026052 TI - The motor performance of preschool-aged children after surgery for congenital heart disease. AB - This study compared the motor performance of preschool-aged children who had undergone surgery for congenital heart disease with that of a group of children matched for age, sex, preschool experience, racial and socio-economic background. Analysis of the results indicated that the performances of the children with congenital heart disease were significantly immature compared to the performances of the control children on the total assessment and in the areas of gross motor, muscle strength, fine motor, tone and postural reactions. Sex, age at first surgical intervention and presence of a cyanotic heart defect did not influence the performances of the study group children. Age at assessment and socio economic background were found to influence motor performances. The need for physiotherapists to be involved in the follow-up of children with congenital heart disease is supported. PMID- 25026053 TI - Effects of back care lessons on sitting and lifting by primary students. AB - This study investigated some of the effects of back care education. Four classes of students aged from 10 to 12 years were given three lessons structured to teach acceptable sitting posture, safe lifting techniques and sports injury prevention procedures. Data on the students' sitting postures and lifting skills were collected over a period of six weeks. The results of the study indicate that lessons on aspects of back care can have an immediate impact on students' sitting and lifting behaviours. Further research along the present lines is indicated to determine whether continued instruction and feedback over a longer interval would produce more durable changes. PMID- 25026054 TI - A survey of electromodality usage in private physiotherapy practices. AB - This study aimed to examine ownership and usage frequencies of electrotherapeutic modalities typically found in private physiotherapy practices in Brisbane. The survey included 73 practices, representing 70 per cent of the selected sample. Results revealed that ultrasound units were used more "frequently" than any other modality. Transcutaneous electrical nerve stimulation and interferential units were also used extensively. Short-wave diathermy units were found in more clinics than any other heating modality. Transcutaneous electrical nerve stimulation was the only modality to demonstrate a significant difference [p< 0:05) in "Frequent" usage between practitioners aged under 31 and those 31 and older. Overall, the majority of respondents (77.5 per cent) trained at the University of Queensland, a fact which may have influenced the identified trends. PMID- 25026055 TI - The effect of counterforce bracing on grip strength in tennis players with painful elbows. AB - Counterforce bracing is considered to change the mechanical origin of the forearm extensors, thereby decreasing the force of internally generated muscle tension. A clinical study was conducted of 19 tennis players complaining of elbow pain. Seventeen had previously used some form of counterforce bracing for symptomatic pain relief. In those with symptomatic arms, no significant difference in grip strength with or without the brace was identified. Similarly, no significant differences were recorded in the non-symptomatic arms, with or without the brace There was also no significant difference between the symptomatic and non symptomatic arms, when grip strength was compared with and without the brace. The frequent use of counterforce bracing suggests bracing may subjectively reduce symptoms of pain. However, the results of this study demonstrate that it has no effect on objective measures of grip strength. PMID- 25026057 TI - The relationship between the dynamic and static function of abdominal muscles. AB - Thirty-eight field force soldiers were studied to investigate the influence of training with repetitive dynamic curl-ups on the static holding capacity of abdominals for lumbopelvic control when load was progressively applied via lower limb movements. Results indicated that when high numbers of curl-ups (>51) were able to be performed continuously, the static capacity of the abdominals was higher (p <0.01). However, the ability to statically hold was found to be even more dependent on the speed at which the curl-up was performed (p <0.0001). Those regularly performing the curl-up at a rapid rate demonstrated decreased static abdominal function. The results suggest that when training the abdominals for a stability function, curl-up exercises should be performed at a slow controlled rate. PMID- 25026056 TI - Categorization by movement direction: retrieval-induced forgetting of motor sequences grouped by motion features. AB - We investigated the organized storage of motor sequences in memory by assuming that processes related to interference at retrieval are indicative of memory organization. Effects resulting from these processes, thus, would allow inferences on how motor sequences are represented and organized. Participants learned motor sequences that were categorized by the direction of the initial movement. The subsequent selective retrieval of a subset of sequences of one category resulted in retrieval-induced forgetting (RIF) for the non-retrieved sequences of the same category. RIF occurred in an explicit recall test (Experiment 1), as well in an implicit test assessing memory with novel cues (Experiment 2). The results suggest that RIF affected motor programmes and that other cues as the used effectors (here movement direction) can be used for the organization of procedural memory. Basic retrieval dynamics apparently operate within the declarative and procedural systems in a similar way. PMID- 25026058 TI - Adverse tension in the neural system. A preliminary study of tennis elbow. AB - This study investigated adverse tension in the neural system in 20 subjects suffering from unilateral symptoms of tennis elbow. A neural tissue tension test developed by Butler (1987 and 1991) was employed. Results indicated that the neural tissue was significantly less extensible in the arm with tennis elbow. Glenohumeral abduction range was on average 12 degrees less in the symptomatic arm when the test was performed with wrist and finger flexion and nine degrees less when the test incorporated wrist and finger extension. The test using wrist and finger flexion, which is considered to bias tension towards the radial nerve, reproduced the subjects' tennis elbow symptoms in 55 per cent of cases. These results suggest that adverse tension in neural structures may contribute to the pain. PMID- 25026059 TI - Postural alignment in standing: A repeatability study. AB - Interpretation of any postural changes over time relies on the knowledge that the person's perception of comfortable erect posture remains sufficiently constant. This study measured the repeatability of sagittal spinal alignment during one day, and the degree of variability in that alignment measured subsequently four, eight and 12 days, and 16 and 24 months later. Normal women, pregnant women and women with low back pain, in the age range of 15 to 34 years, were included in the study. Spinal curvature was determined using a clinometer, while an electro goniometer attached to callipers determined the degree of pelvic tilt. Results demonstrated that on any one day, a consistent postural alignment is assumed (in terms of spinal curvature and pelvic inclination) when an individual is asked to stand comfortably erect. In addition, in the normal, symptom-free, young adult subject, the perception of posture, and therefore postural alignment remains constant for at least two years. PMID- 25026060 TI - Evaluation of a buckle force transducer for measuring tissue tension. AB - A buckle force transducer, suitable for measuring forces in biological materials in situ, was investigated in order to establish its reliability as a force measuring instrument. Eleven separate materials varying in shape, size and mechanical properties, were tested. Each material was repeatedly loaded and unloaded. Calibration lines, relating the applied force and the output voltage, were calculated for each loading-unloading trial. For each material, deviations between trials were calculated as a percentage of the range of voltages recorded in the first trial of that material. These data were analysed to evaluate four parameters: test-retest reliability, the effect of skewed alignment, linearity of the instrument, and amount of hysteresis present. Results indicate that the buckle force transducer used is a highly reliable and consistent measuring instrument, which behaves in a linear manner and demonstrates acceptably small hysteresis. The implications for measuring forces in biological materials are discussed. PMID- 25026061 TI - The treatment of lymphoedema by Complex Physical Therapy. AB - Lymphoedema is a high protein oedema caused by a low output failure of the lymphatic system. Complex Physical Therapy is a conservative treatment which is designed to increase the transport capacity of the lymphatic system and remove the stagnant plasma proteins from the tissues. The treatment consists of massage, compression bandaging, an active exercise programme and care of the skin. Sometimes this is assisted by the use of a mercury compression pump and the prescription of one of the benzo pyrone drugs by the referring medical officer. The treatment is given daily for one hour, six days a week, usually over four weeks. At the completion of treatment, the limb is fitted with support hosiery. PMID- 25026062 TI - Educational programmes to develop clinical reasoning skills. AB - The role of physiotherapists has changed considerably over the last few decades. Autonomous professionals have replaced clinicians who applied technical skills under the direction of medical practitioners. The physiotherapy profession needs more than ever to produce clinicians who demonstrate competence in clinical reasoning and decision making. The challenge presented to all physiotherapists involved in teaching is to contribute to the development of clinicians who can use the complex skill of clinical reasoning in association with a sound clinical knowledge base. This paper discusses issues and strategies associated with achieving this goal. PMID- 25026063 TI - Programme evaluation: What we can learn from the United States experience. AB - The introduction of performance outcome measurement to Australian rehabilitation services is now on the agenda. The Functional Independence Measure (FIM) is being actively promoted as an appropriate system. This paper outlines the philosophy and evolution of the FIM in the United States of America (USA), and emphasises the positive aspects of accountability through global functional measurement. Physiotherapists are encouraged to be positive and innovative in their approach to the use of this accountability tool to ensure that physiotherapy continues to be seen as a primary discipline in the global functional context of the rehabilitation process. PMID- 25026065 TI - Combining single-molecule imaging and single-channel electrophysiology. AB - Combining simultaneous single-molecule fluorescence measurements of ion channel conformational change with single-channel electrophysiology would enable a direct link between structure and function. Such methods would help us to create a truly molecular "movie" of how these important biomolecules work. Here we review past and recent progress toward this goal. PMID- 25026066 TI - Spinal mobility and trunk muscle strength in elite hockey players. AB - Elite hockey players of both sexes from the Australian Institute of Sport were assessed for lumbar spine mobility, trunk flexion and back extensor muscle strength, hamstring flexibility and postural characteristics over a two year period. All the athletes were more mobile in rotation than the 'normal' West Australian population, and demonstrated flexible hamstrings and powerful back extensor muscles; trunk flexion was less strong initially, but improved after intervention in the form of a specific exercise programme, over the measurement period. A questionnaire disclosed that low back pain is a common complaint of hockey players, but rarely required intensive physical and medical treatment. The term 'hockey player's back' has been coined in recognition of the long flat thoracolumbar spine frequently noted in these subjects. PMID- 25026064 TI - The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes. AB - The critical importance of gastrointestinal microbes to digestion of dietary fiber in humans and other mammals has been appreciated for decades. Symbiotic microorganisms expand mammalian digestive physiology by providing an armament of diverse polysaccharide-degrading enzymes, which are largely absent in mammalian genomes. By out-sourcing this aspect of digestive physiology to our gut microbes, we maximize our ability to adapt to different carbohydrate nutrients on timescales as short as several hours due to the ability of the gut microbial community to rapidly alter its physiology from meal to meal. Because of their ability to pick up new traits by lateral gene transfer, our gut microbes also enable adaption over time periods as long as centuries and millennia by adjusting their gene content to reflect cultural dietary trends. Despite a vast amount of sequence-based insight into the metabolic potential of gut microbes, the specific mechanisms by which symbiotic gut microorganisms recognize and attack complex carbohydrates remain largely undefined. Here, we review the recent literature on this topic and posit that numerous, subtle variations in polysaccharides diversify the spectrum of available nutrient niches, each of which may be best filled by a subset of microorganisms that possess the corresponding proteins to recognize and degrade different carbohydrates. Understanding these relationships at precise mechanistic levels will be essential to obtain a complete understanding of the forces shaping gut microbial ecology and genomic evolution, as well as devising strategies to intentionally manipulate the composition and physiology of the gut microbial community to improve health. PMID- 25026067 TI - Evaluation of a temporary prosthetic insert in the rehabilitation of elderly ischaemic below-knee amputees: a pilot study. AB - The physiotherapy management of elderly, ischaemic below knee amputees is often compromised by delayed and/or complicated wound healing. Such patients are often unable to ambulate on a prosthesis for prolonged periods. Problems concommitant with immobilization such as weakness, contractures, and decreased morale tend to arise. This pilot study investigated the efficacy of incorporating a shaped Dunlopillo insert into a temporary prosthetic socket to allow the at risk group to ambulate as soon as the sutures were removed regardless of the state of wound healing. Two parameters were evaluated, namely wound healing and stump maturation. A total of eighteen subjects were observed in a control and an experimental group. Both wound healing (p < 0.05) and stump maturation (p < 0.05) were significantly enhanced by the inclusion of a Dunlopillo insert. PMID- 25026068 TI - The passive mechanical properties of muscle and their adaptations to altered patterns of use. AB - The length and stiffness of a relaxed muscle are determined by the mechanical properties of its intramuscular connective tissue and/or intracellular structures. Viscous deformation of these components of muscle is responsible for the increase in muscle length seen immediately after stretching, but this increase is transient. Lasting changes in muscle length can only be brought about by adaptations of the structure of muscle. An understanding of the nature of the stimulus for muscle to adapt can provide therapists with a theoretical basis for therapeutic intervention aimed at producing changes in muscle length. PMID- 25026069 TI - The effect of different electro-motor stimulation training intensities on strength improvement. AB - The effect of different training intensities of electro-motor stimulation (EMS) on strength gains produced in the quadriceps femoris muscle group was investigated. Twenty-four subjects were randomly assigned to one of three groups: Control (C), Low Intensity (LI) trained at 25% of their maximum voluntary isometric contraction (MVIC), and High Intensity (HI) trained at 50% of MVIC. Results indicated a significant strength improvement in both training groups (p<0.01) following a three-week EMS training program. The HI group showed significantly greater strength gains (48.5%) than the LI group (24.2%) (p<0.01). A significant carry-over effect was also demonstrated in a three-week follow-up period, specifically in the HI group. Positive isokinetic strength changes in the concentric mode were observed in both training groups. In addition, a significant cross transfer effect was demonstrated in the contralateral homologous muscle group (p<0.01) for both HI and LI groups. PMID- 25026070 TI - Scheuermann's Disease: A Review. AB - Scheuermann's disease (or more correctly, spinal osteochondrosis) is not confined to the thoracic spine: all parts of the spine may be affected. Major signs are endplate irregularity, more than 5 degrees vertebral wedging, and sagittal overgrowth. Minor signs are Schmorl's nodes, anterior flattening of the vertebral endplate, and anterior detachment of a ring apophysis. Symptoms are of little diagnostic value. Scheuermann's affects 20 per cent to 30 percent of the population; males and females equally. A hereditary predisposition is a major factor in the aetiology of Scheuermann's disease. There is evidence that this condition follows an autosomal dominant pattern of inheritance. Treatment consists of either exercises; bracing and exercises; or in very severe cases, surgery. PMID- 25026071 TI - Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion. AB - Current studies demonstrated that metformin is not only a hypoglycemic drug, but also a neuro-protective agent. However, the effect of metformin during ischemic brain injury is unclear. The aim of the present study is to explore the effect of metformin during ischemic brain injury. Adult male CD1 mice underwent 90min transient middle cerebral artery occlusion. Metformin (200mg/kg) was given at the time of reperfusion daily until sacrifice. Results showed that metformin treatment significantly reduced ischemia-induced brain atrophy volume compared to the control (p<0.05). Immunostaining results showed that the microvessel density in the peri-focal region of metformin treated mice was greatly increased compared to the control (p<0.05). Similarly, the numbers of BrdU+/DCX+ and nestin+ cells in the subventricular zone were increased in metformin treated mice compared to the control (p<0.05). Furthermore, we demonstrated that metformin treatment activated AMPK signaling pathway and promoted eNOS phosphorylation. Thus, we concluded that metformin promoted focal angiogenesis and neurogenesis and attenuated ischemia-induced brain injury in mice after middle cerebral artery occlusion, suggesting that metformin is a potential new drug for ischemic stroke therapy. PMID- 25026072 TI - Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage. AB - Ursolic acid (UA), a well-known anti-oxidative reagent, has been reported to protect the brain against ischemic stoke. However, the potential role of UA in protecting against early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The present study aimed to examine the effect of UA against EBI following SAH, and to demonstrate whether the effect is associated with its powerful antioxidant property. Male SD rats were divided into vehicle-treated sham, vehicle-treated SAH, and UA-treated SAH groups. The endovascular puncture model was used to induce SAH and all the rats were subsequently sacrificed at 48h after SAH. The results show that UA administration could significantly attenuate EBI (including brain edema, blood-brain barrier disruption, neural cell apoptosis, and neurological deficient) after SAH in rats and up-regulate the antioxidative levels in the rat cerebral cortex, suggesting that administration of UA in experimental SAH rats could alleviate brain injury symptom, potentially through its powerful antioxidant property. Hence, we concluded that UA might be a novel therapeutic agent for EBI following SAH. PMID- 25026073 TI - Anxiolytic-like effects and mechanism of (-)-myrtenol: a monoterpene alcohol. AB - The essential oil of Myrtus communis L. (Myrtaceae) and its compounds have been popularly used in numerous health disorders, including insomnia and nervous conditions, but their effects on central nervous system (CNS) have not been explored yet. We evaluated the anxiolytic-like effects and possible action mechanism of (-)-myrtenol (MYR), a monoterpenoid alcohol present in essential oil of M. communis L. Animal models of elevated plus maze (EPM), light-dark transition (LDT), open field and rotarod tests were used in the present study. MYR was administered in male rats. Diazepam was used as the standard drug (positive control) and flumazenil was used to elucidate the possible action mechanism. The results showed that none of the doses of MYR had effect on the resistance time in rotating bar, but caused reduction in the number of falls in rotarod tests when compared with a negative control. Similarly, MYR had no effect on the number of crossings, groomings or rearings in open field tests when compared with a negative control. However, in EPM and LDT tests, MYR significantly increased (p<0.001) the number of entries in open arms (F7,49=9.867), the time spent in open arms (F7,49=53.97) and the time spent in light compartment (F7,56=27.38), when compared with negative and positive controls, respectively. Flumazenil was able to reverse the effects of diazepam and MYR. These results suggest that MYR presents anxiolytic-like activity and that effect can be mediated by GABAergic transmission. PMID- 25026075 TI - Glycosylation and disulfide bond analysis of transiently and stably expressed clade C HIV-1 gp140 trimers in 293T cells identifies disulfide heterogeneity present in both proteins and differences in O-linked glycosylation. AB - The HIV-1 envelope protein (Env) mediates viral entry into host cells to initiate infection and is the sole target of antibody-based vaccine development. Significant efforts have been made toward the design, engineering, and expression of various soluble forms of HIV Env immunogen, yet a highly effective immunogen remains elusive. One of the key challenges in the development of an effective HIV vaccine is the presence of the complex set of post-translational modifications (PTMs) on Env, namely, glycosylation and disulfide bonds, that affect protein folding, epitope accessibility, and immunogenecity. Although these PTMs vary with expression systems, variations in Env's PTMs due to changes in the expression method are not yet well established. In this study, we compared the disulfide bond network and glycosylation profiles of clade C recombinant HIV-1 Env trimers, C97ZA012 gp140, expressed by stable and transient transfections using an integrated mass mapping workflow that combines collision induced dissociation (CID) and electron transfer dissociation (ETD). Site-specific analysis of the N- and O-glycosylation profiles revealed that C97ZA012 gp140 produced by both transfection methods displayed a high degree of similarity in N-glycosylation profiles and site occupancy except for one site. By contrast, different O glycosylation profiles were detected. Analysis of the disulfide bond networks of the Env revealed that both transfection methods yielded C97ZA012 gp140 adopting the expected disulfide bond pattern identified for the monomeric gp120 and gp41 as well as alternative disulfide bond patterns in the C1, V1/V2, and C2 regions. The finding that disulfide bonding is consistently heterogeneous in these proteins is perhaps the most significant outcome of these studies; this disulfide heterogeneity has been reported for multiple other recombinant gp140s, and it is likely present in most recombinantly expressed Env immunogens. PMID- 25026076 TI - The use of social media in endourology: an analysis of the 2013 World Congress of Endourology meeting. AB - OBJECTIVE: To examine the use of social media within Endourology by reporting on its utilization during the 2013 World Congress of Endourology (WCE) annual meeting. MATERIALS AND METHODS: Two social media platforms were analyzed for this study: Twitter (San Francisco, CA) and LinkedIn (Mountain View, CA). For Twitter, a third-party analysis service (Tweetreach) was used to quantitatively analyze all tweets with the hashtags #WCE2013 and #WCE13 during a 7-day period surrounding the WCE. Two reviewers independently classified tweet content using a predefined Twitter-specific classification system. Tweet sentiment was determined using sentiment analysis software (Semantria, Inc., Amherst, MA). Finally, the penetration of Twitter and LinkedIn within the WCE faculty was assessed by means of a manual search. RESULTS: During the study period, 335 tweets had the hashtag #WCE2013 or #WCE13. Content originated from 68 users resulting in a mean of 47 tweets/day and 4.9 tweets/contributor. Conference-related tweets had a reach of 38,141 unique Twitter accounts and an online exposure of 188,629 impressions. Physicians generated the majority of the content (63%), of which 55.8% were not attending the meeting. More tweets were informative (56.7%) versus uninformative (43.3%), and 17.9% had links to an external web citation. The mean sentiment score was 0.13 (range -0.90 to 1.80); 13.1%, 57.0%, and 29.9% of tweets were negative, neutral, and positive in sentiment, respectively. Of 302 WCE meeting faculty, 150 (49.7%) had registered LinkedIn accounts while only 52 (17.2%) had Twitter accounts, and only 19.2% tweeted during the meeting. CONCLUSIONS: Despite a relatively low number of Twitter users, tweeting about the WCE meeting dramatically increased its online exposure with dissemination of content that was mostly informative including engagement with physicians not attending the conference. While half of faculty at WCE 2013 had LinkedIn accounts, their social media footprint in Twitter was limited. PMID- 25026077 TI - Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation. AB - Roquin function in T cells is essential for the prevention of autoimmune disease. Roquin interacts with the 3' untranslated regions (UTRs) of co-stimulatory receptors and controls T-cell activation and differentiation. Here we show that the N-terminal ROQ domain from mouse roquin adopts an extended winged-helix (WH) fold, which is sufficient for binding to the constitutive decay element (CDE) in the Tnf 3' UTR. The crystal structure of the ROQ domain in complex with a prototypical CDE RNA stem-loop reveals tight recognition of the RNA stem and its triloop. Surprisingly, roquin uses mainly non-sequence-specific contacts to the RNA, thus suggesting a relaxed CDE consensus and implicating a broader spectrum of target mRNAs than previously anticipated. Consistently with this, NMR and binding experiments with CDE-like stem-loops together with cell-based assays confirm roquin-dependent regulation of relaxed CDE consensus motifs in natural 3' UTRs. PMID- 25026078 TI - The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double stranded RNA. AB - A conserved stem-loop motif of the constitutive decay element (CDE) in the 3' UTR of mRNAs is recognized by the ROQ domain of Roquin, which mediates mRNA degradation. Here we report two crystal structures of the Homo sapiens ROQ domain in complex with CDE RNA. The ROQ domain has an elongated shape with three subdomains. The 19-nt Hmgxb3 CDE is bound as a stem-loop to domain III. The 23-nt TNF RNA is bound as a duplex to a separate site at the interface between domains I and II. Mutagenesis studies confirm that the ROQ domain has two separate RNA binding sites, one for stem-loop RNA (A site) and the other for double-stranded RNA (B site). Mutation in either site perturbs the Roquin-mediated degradation of HMGXB3 and IL6 mRNAs in human cells, demonstrating the importance of both sites for mRNA decay. PMID- 25026080 TI - The journey of recovery and empowerment embraced by nature - clients' perspectives on nature-based rehabilitation in relation to the role of the natural environment. AB - This paper presents findings from real life situations, a longitudinal single case study on the role of natural environments in nature-based rehabilitation (NBR) for individuals with stress-related mental disorders, at the Alnarp Rehabilitation Garden in Sweden. A sample of 43 former clients voluntarily participated in semi-structured interview, and the data were analyzed according to interpretative phenomenological analysis (IPA). Three main superordinate themes were identified as the three phases of NBR-Prelude, Recuperating and Empowerment-explaining and illuminating the role of the natural environments in each phase. An explanatory model of NBR in this context is presented including the three phases of NBR, IRP supportive occupations and a pyramid of supporting environments. A new component of supportive environments was identified and herby named, Social quietness, an important component facilitating personal and intimate engagement with the natural environments. PMID- 25026079 TI - Structural basis for activity of highly efficient RNA mimics of green fluorescent protein. AB - GFP and its derivatives revolutionized the study of proteins. Spinach is a recently reported in vitro-evolved RNA mimic of GFP, which as genetically encoded fusions makes possible live-cell, real-time imaging of biological RNAs without resorting to large RNA-binding protein-GFP fusions. To elucidate the molecular basis of Spinach fluorescence, we solved the cocrystal structure of Spinach bound to its cognate exogenous chromophore, showing that Spinach activates the small molecule by immobilizing it between a base triple, a G-quadruplex and an unpaired G. Mutational and NMR analyses indicate that the G-quadruplex is essential for Spinach fluorescence, is also present in other fluorogenic RNAs and may represent a general strategy for RNAs to induce fluorescence of chromophores. The structure guided the design of a miniaturized 'Baby Spinach', and it provides a foundation for structure-driven design and tuning of fluorescent RNAs. PMID- 25026081 TI - Using benthic macroinvertebrate and fish communities as bioindicators of the Tanshui River basin around the greater Taipei area - multivariate analysis of spatial variation related to levels of water pollution. AB - After decades of strict pollution control and municipal sewage treatment, the water quality of the Tanshui River increased significantly after pollution mitigation as indicated by the River Pollution Index (RPI). The pollution level of the estuarine region decreased from severe pollution to mostly moderately impaired. The most polluted waters are presently restricted to a flow track length between 15-35 km relative to the river mouth. From July 2011 to September 2012, four surveys of fish and benthic macroinvertebrates were conducted at 45 sampling sites around the Tanshui River basin. The pollution level of all the study area indicated by the RPI could also be explained by the Family Biotic Index (FBI) and Biotic Index (BI) from the benthic macroinvertebrate community, and the Index of Biotic Integrity (IBI) of the fish community. The result of canonical correlation analysis between aquatic environmental factors and community structure indicated that the community structure was closely related to the level of water pollution. Fish species richness in the estuarine area has increased significantly in recent years. Some catadromous fish and crustaceans could cross the moderate polluted water into the upstream freshwater, and have re colonized their populations. The benthic macroinvertebrate community relying on the benthic substrate of the estuarine region is still very poor, and the water layer was still moderately polluted. PMID- 25026082 TI - Immigrants' access to health insurance: no equality without awareness. AB - The Czech government has identified commercial health insurance as one of the major problems for migrants' access to health care. Non-EU immigrants are eligible for public health insurance only if they have employee status or permanent residency. The present study examined migrants' access to the public health insurance system in Czechia. A cross-sectional survey of 909 immigrants from Ukraine and Vietnam was conducted in March and May 2013, and binary logistic regression was applied in data analysis. Among immigrants entitled to Czech public health insurance due to permanent residency/asylum, 30% were out of the public health insurance system, and of those entitled by their employment status, 50% were out of the system. Migrants with a poor knowledge of the Czech language are more likely to remain excluded from the system of public health insurance. Instead, they either remain in the commercial health insurance system or they simultaneously pay for both commercial and public health insurance, which is highly disadvantageous. Since there are no reasonable grounds to stay outside the public health insurance, it is concluded that it is lack of awareness that keeps eligible immigrants from entering the system. It is suggested that no equal access to health care exists without sufficient awareness about health care system. PMID- 25026083 TI - Genotypes and antibiotic resistances of Campylobacter jejuni isolates from cattle and pigeons in dairy farms. AB - Campylobacter jejuni is the most common food-borne zoonotic pathogen causing human gastroenteritis worldwide and has assumed more importance in Italy following the increased consumption of raw milk. Our objectives were to get an overview of genotypes and antibiotic resistances in C. jejuni isolated from milk, cattle feces, and pigeons in dairy herds of Northern Italy. flaB-typing was applied to 78 C. jejuni isolates, previously characterized by Multi-Locus Sequence Typing, and genotypic resistances towards macrolides and quinolones based on point mutations in the 23S rRNA and gyrA genes, respectively, were determined. flaB-typing revealed 22 different types with one of them being novel and was useful to further differentiate strains with an identical Sequence Type (ST) and to identify a pigeon-specific clone. Macrolide resistance was not found, while quinolone resistance was detected in 23.3% of isolates. A relationship between specific genotypes and antibiotic resistance was observed, but was only significant for the Clonal Complex 206. Our data confirm that pigeons do not play a role in the spread of C. jejuni among cattle and they are not responsible for milk contamination. A relevant number of bulk milk samples were contaminated by C. jejuni resistant to quinolones, representing a possible source of human resistant strains. PMID- 25026084 TI - Parent-child associations in pedometer-determined physical activity and sedentary behaviour on weekdays and weekends in random samples of families in the Czech Republic. AB - This study investigates whether more physically active parents bring up more physically active children and whether parents' level of physical activity helps children achieve step count recommendations on weekdays and weekends. The participants (388 parents aged 35-45 and their 485 children aged 9-12) were randomly recruited from 21 Czech government-funded primary schools. The participants recorded pedometer step counts for seven days (>=10 h a day) during April-May and September-October of 2013. Logistic regression (Enter method) was used to examine the achievement of the international recommendations of 11,000 steps/day for girls and 13,000 steps/day for boys. The children of fathers and mothers who met the weekend recommendation of 10,000 steps were 5.48 (95% confidence interval: 1.65; 18.19; p < 0.01) and 3.60 times, respectively (95% confidence interval: 1.21; 10.74; p < 0.05) more likely to achieve the international weekend recommendation than the children of less active parents. The children of mothers who reached the weekday pedometer-based step count recommendation were 4.94 times (95% confidence interval: 1.45; 16.82; p < 0.05) more likely to fulfil the step count recommendation on weekdays than the children of less active mothers. PMID- 25026087 TI - A trial of physiotherapy for symptoms in keyboard operating. AB - In An Earlier Study Ferguson (1969, 1971) noted occupational cramp in 22% of 263 male telegraphists examined in the Sydney office of a large communications undertaking. A further 6% had occupational myalgia, symptoms of which were also present in some subjects with cramp. At the time of that study all the telegraphists examined had been employed in the undertaking for at least seven years, and all had operated morse telegraphy before this mode was fully superseded by keyboard (teleprinter and telex) telegraphy some five years before. In those telegraphists subject of symptoms in operating, the disorder in many had been transferred from morse to keyboard operating. Though the muscle aching of the upper limb(s) in occupational myalgia can be directly related to continued performance of a repetitive task (Lundervold, 1958; Shigeta, 1974), even if the reason why some operators only are affected is a matter of conjecture, the cause of occupational cramp is still uncertain (Hunter, 1962). On present knowledge it could be considered as a functional incoordination of an accustomed skill, akin to a habit spasm. PMID- 25026086 TI - Inactivation of selected bacterial pathogens in dairy cattle manure by mesophilic anaerobic digestion (balloon type digester). AB - Anaerobic digestion of animal manure in biogas digesters has shown promise as a technology in reducing the microbial load to safe and recommended levels. We sought to treat dairy manure obtained from the Fort Hare Dairy Farm by investigating the survival rates of bacterial pathogens, through a total viable plate count method, before, during and after mesophilic anaerobic digestion. Different microbiological media were inoculated with different serial dilutions of manure samples that were withdrawn from the biogas digester at 3, 7 and 14 day intervals to determine the viable cells. Data obtained indicated that the pathogens of public health importance were 90%-99% reduced in the order: Campylobacter sp. (18 days) < Escherichia coli sp. (62 days) < Salmonella sp. (133 days) from a viable count of 10.1 * 103, 3.6 * 105, 7.4 * 103 to concentrations below the detection limit (DL = 102 cfu/g manure), respectively. This disparity in survival rates may be influenced by the inherent characteristics of these bacteria, available nutrients as well as the stages of the anaerobic digestion process. In addition, the highest p-value i.e., 0.957 for E. coli showed the statistical significance of its model and the strongest correlation between its reductions with days of digestion. In conclusion, the results demonstrated that the specific bacterial pathogens in manure can be considerably reduced through anaerobic digestion after 133 days. PMID- 25026088 TI - A simple method for examining post-rotatory nystagmus. AB - This paper is the report of a preliminary study undertaken to examine how normal five-year-old children respond to spinning with particular reference to post rotatory nystagmus. A simple method is described. PMID- 25026089 TI - Review of polypropylene orthoses carried out in new South wales. AB - Because of his inability to lift the forefoot the patient with dropped foot drags his toe along the ground or stubs it against minor obstructions. The problem may be localized to the foot and ankle but for the majority who suffer from central nervous system lesions there is an associated weakness of the knee and/or hip. PMID- 25026090 TI - An elaboration on holistic physiotherapy. AB - There seem to be as many ideas for the function of Community Health Care Centres as there are people who postulate them; nevertheless, such directed plurality looks vibrant and healthy, and may be worth the confusion engendered in initiates. The dilemma in mentioning Community Health Care Centres lies in the concept their name conjures. A simple clarification, however, establishes treatment-oriented and preventative concepts. The implication of the former would be that localized, co-ordinated care from a wide variety of professionals would be offered; of the latter, being far more broadly based, that recreational, social and educational activities would be provided, and that these would incorporate medical care. Physiotherapy will be included in both, and comments in this paper are directed toward the treatment-oriented concept, bearing generalization to the larger definition, and, with care, to our current situation. PMID- 25026091 TI - Mulberry leaf phenolics ameliorate hyperglycemia-induced oxidative stress and stabilize mitochondrial membrane potential in HepG2 cells. AB - To investigate the effect of phenolics in mulberry leaves (mulberry leaf phenolics; MLP) on hyperglycemia-induced oxidative stress and mitochondrial membrane potential (DeltaPsim) in HepG2 cells; we treated HepG2 with glucose [5.5 (N-Glc) or 50 mmol/L (Hi-Glc)] with or without MLP at 10 or 100 umol/L gallic acid equivalents and assessed level of reactive oxidant species (ROS), DeltaPsim, malondialdehyde (MDA) and nuclear factor-kappaB (NF-kappaB) activation. Hi-Glc induced oxidative damage was demonstrated by a series of increase in superoxides (560%, 0.5 h), MDA (400%, 24 h), NF-kappaB activation (474%, 4 h) and a wild fluctuation of DeltaPsim relative to the control cells (p <= 0.05). MLP treatments ameliorate Hi-Glc-induced negative effects by a 40% reduction in ROS production, 34-44% reduction in MDA production, over 35% inhibition of NF-kappaB activation, as well as exert protective effect on HepG2 cells from change in DeltaPsim. Our data show that MLP in vitro can protect hepatoctyes from hyperglycemia-induced oxidative damages. PMID- 25026092 TI - Who responds to placebos? Considering the "placebo personality" via a transactional model. AB - The placebo effect is now recognised as a genuine psychobiological phenomenon; however, the question of how it can be systematically harnessed to improve health outcomes is not yet clear. One issue that remains unresolved is why some respond to placebos and others do not. A number of traits have been linked to responding, but findings are scattered. In extending prior work, this paper offers three considerations. First, attempts to describe the placebo responder via a single personality trait may be limiting. A synthesis of findings to date suggests placebo responsiveness may reflect a two-faceted construct, with "inward" and "outward" orientation representing the different but related facets of placebo responsiveness. Second, the lack of theoretically driven research may be hindering progress. Personality measures rather than personality theory appear to be driving research and higher order traits are descriptive tools with limited use in predicting behaviour. A biologically based stimulus-response model of personality that considers how individuals respond to certain environmental cues may be more appropriate. Third, a transactional model of placebo responding in which dispositional characteristics interact with environmental contingencies is presented. Responsiveness may manifest in placebo environments where there is a match between an individual's biological trait-like response systems and environmental contingencies. This type of model may be useful in both research and clinical settings. Systematic consideration of how different individuals might respond to different placebo environments might facilitate identification of stable individual characteristics predictive of responding. The ability to determine who is responsive to placebo treatments, and in what context, may enable the matching of individual to treatment, thereby maximising the effectiveness of treatment and minimising possible iatrogenic harm. In the increasingly overtaxed modern health care industry, non-pharmacological treatment alternatives are of critical importance. PMID- 25026093 TI - The retrosplenial cortex is necessary for path integration in the dark. AB - An increasing amount of data indicates that the retrosplenial cortex (RSC) plays a role in navigation and spatial memory. Moreover, it has been suggested that the RSC integrates mnemonic spatial features of the environment with self-motion information therefore enabling accurate path integration in darkness. This hypothesis rests on data obtained from animals trained in spatial memory tasks involving the conjoint use of allothetic and idiothetic information [8]. We examined the contribution of the RSC when animals are submitted to a path integration task with minimal memory requirement in light and dark. We found that RSC-lesioned rats exhibited a path integration deficit in the dark but not in the light. This suggests that the RSC is important for path integration and incorporates visuospatial information to maintain path integration accuracy. PMID- 25026095 TI - Translating the impact of exercise on cognition: methodological issues in animal research. AB - Physical exercise and fitness have been proposed as potential factors that promote healthy cognitive aging. Some of the support for this hypothesis has come from animal research. Animal studies are also used to propose the physiological mechanisms underlying the cognitive performance improvement associated with exercise. In the present review and meta-analysis, we discuss several methodological problems that limit the contribution of animal studies to the understanding of the putative effects of exercise on cognitive aging. We suggest that the most likely measure to equate exercise intensity in rodent and humans may be oxygen consumption (VO2) because observed values are surprisingly similar in young and older rodents and humans. For practical reasons, several animal studies use young rodents kept in social isolation. We show that social isolation is associated with an enhanced impact of exercise on cognitive performance but not on some physiological measures thought to mediate the effect of exercise. Surprisingly, two months or more of exercise intervention appeared to be ineffective to promote cognitive performance compared to shorter durations. We argue that impact of exercise in socially isolated animals is explained by an alleviation of environmental impoverishment as much as an effect of physical exercise. It is possible that the introduction of exercise in rodents is partly mediated by environmental changes. It may explain why larger effects are observed for the shorter durations of exercise while much smaller effects are found after longer periods of exercise. PMID- 25026094 TI - Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice. AB - The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh).The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2h, 3h into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (MUg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug. PMID- 25026098 TI - Nano-scale characterization of binary self-assembled monolayers under an ambient condition with STM and TERS. AB - Gold surfaces were modified by benzyl-mercaptan (BM) and then partly replaced with benzenethiol (BT), which formed binary self-assembled monolayers (SAM). Initially BT randomly replaced BM in the monolayer, but at long exchange times >15 nm radius domains were observed with specific relative composition of BT and BM. PMID- 25026096 TI - Effects of mild to moderate sedation on saccadic eye movements. AB - Sedatives alter the metrics of saccadic eye movements. If these effects are nonspecific consequences of sedation, like drowsiness and loss of attention to the task, or differ between sedatives is still unresolved. A placebo-controlled multi-step infusion of one of three sedatives, propofol or midazolam, both GABA-A agonists, or dexmedetedomidine, an alpha2-adrenergic agonist, was adopted to compare the effects of these three drugs in exactly the same experimental conditions. 60 healthy human volunteers, randomly divided in 4 groups, participated in the study. Each infusion step, delivered by a computer-controlled infusion pump, lasted 20min. During the last 10min of each step, the subject executed a saccadic task. Target concentration was doubled at each step. This block was repeated until the subject was too sedated to continue or for a maximum of 6 blocks. Subjects were unaware which infusion they were receiving. A video eye tracker was used to record the movements of the right eye. Saccadic parameters were modeled as a function of block number, estimated sedative plasma concentration, and subjective evaluation of sedation. Propofol and midazolam had strong effects on the dynamics and latency of the saccades. Midazolam, and to a less extent, propofol, caused saccades to become increasingly hypometric. Dexmedetedomidine had less impact on saccadic metrics and presented no changes in saccadic gain. Suppression of the sympathetic system associated with dexmedetomidine has different effects on eye movements from the increased activity of the inhibitory GABA-A receptors by propofol and midazolam even when the subjects reported similar sedation level. PMID- 25026099 TI - Solid-state NMR shows that dynamically different domains of membrane proteins have different hydration dependence. AB - Hydration has a profound influence on the structure, dynamics, and functions of membrane and membrane-embedded proteins. So far the hydration response of molecular dynamics of membrane proteins in lipid bilayers is poorly understood. Here, we reveal different hydration dependence of the dynamics in dynamically different domains of membrane proteins by multidimensional magic angle spinning (MAS) solid-state NMR (ssNMR) spectroscopy using 121-residue integral diacylglycerol kinase (DAGK) in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG) lipid bilayers as a model system. The highly mobile and immobile domains of DAGK and their water accessibilities are identified site-specifically by scalar- and dipolar-coupling based MAS ssNMR experiments, respectively. Our experiments reveal different hydration dependence of the dynamics in highly mobile and immobile domains of membrane proteins. We demonstrate that the fast, large amplitude motions in highly mobile domains are not triggered until 20% hydration, enhanced at 20-50% hydration and unchanged at above 50% hydration. In contrast, motions on submicrosecond time scale of immobile residues are observed to be independent of the hydration levels in gel phase of lipids, and at the temperature near gel-liquid crystalline phase transition, amplitude of whole molecule rotations around the bilayer normal is dominated by the fluidity of lipid bilayers, which is strongly hydration dependent. The hydration dependence of the dynamics of DAGK revealed by this study provides new insights into the correlations of hydration to dynamics and function of membrane proteins in lipid bilayers. PMID- 25026097 TI - The influence of context on recognition memory in monkeys: effects of hippocampal, parahippocampal and perirhinal lesions. AB - This study further investigated the specific contributions of the medial temporal lobe structures to contextual recognition memory. Monkeys (Macaca mulatta) with either neurotoxic lesions of the hippocampus, aspiration lesions of the perirhinal cortex and parahippocampal areas TH/TF, or sham operations were tested on five conditions of a visual-paired comparison (VPC) task in which 3 dimensional objects were presented over multicolored backgrounds. In two conditions (Conditions 1 and 2: Context-changes), the sample object was presented on a new background during the retention tests, whereas in the three others (Conditions 3-5: No-context-changes) the sample object was presented over its familiar background. Novelty preference scores of control animals were weaker, but still significantly different from chance, in the Context-changes conditions than on the No-context-changes conditions. Animals in the three experimental groups showed strong preference for novelty on the No-context-change conditions, but weaker novelty preference on the Context-change conditions than controls. Thus, animals in all three lesion types had greater difficulty recognizing an object when its background was different from that used during encoding. The data are consistent with the view that the hippocampal formation, areas TH/TF, and perirhinal cortex contribute interactively to contextual memory processes. PMID- 25026100 TI - Oxygen transfer from an intramolecularly coordinated diaryltellurium oxide to acetonitrile. Formation and combined AIM and ELI-D analysis of a novel diaryltellurium acetimidate. AB - The reaction of the intramolecularly coordinated diaryltellurium(IV) oxide (8 Me2NC10H6)2TeO with acetonitrile proceeds with oxygen transfer and gives rise to the formation of the novel zwitterionic diaryltelluronium(IV) acetimidate (8 Me2NC10H6)2TeNC(O)CH3 (1) in 57% yield. Hydrolysis of 1 with hydrochloric acid affords acetamide and the previously known diarylhydroxytelluronium(IV) chloride [(8-Me2NC10H6)2Te(OH)]Cl. PMID- 25026101 TI - Disseminated Kaposi's sarcoma in patients with HIV infection correlates to high serum levels of IL-10. AB - Human herpesvirus 8 (HHV-8) is the etiologic agent of all Kaposi's sarcoma (KS), the outcome of which is associated with immuno-dysregulation, resulting in the abnormal production of inflammatory cytokines and chemokines. We quantified by enzyme-linked immunosorbent assay serum levels of interleukin (IL)-10, IL-17, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha from patients with KS-AIDS, classic KS, and human immunodeficiency virus (HIV) without KS. A correlation between HHV-8 molecular detection and cytokine production was also performed. We observed that IL-10 production was higher in patients with KS-AIDS when compared to those with classic KS or HIV. However, no significant differences were seen for IFN-gamma, TNF-alpha, or IL-17 production between studied groups. When patients with KS-AIDS were analyzed according to lesion topography, IL-10 levels were higher in patients with disseminated disease than those observed in patients with only cutaneous lesions or cutaneous and digestive and/or respiratory tract lesions. Finally, patients with KS-AIDS that presented viral DNA for HHV-8 in serum showed a higher production of IL-10 when compared with those patients with a negative result for nested polymerase chain reaction for the virus. The results presented here are the first to demonstrate that there exists a stratification of patients with KS-AIDS according to lesion topography where IL-10 levels are higher in those individuals with disseminated disease than those with only localized lesions. PMID- 25026102 TI - c-MRI findings after crystal meth abuse. AB - We describe a case of intoxication with N-methylamphetamine (Crystal-METH) after withdrawal. Crystal-METH abuse was associated with persisting neurological symptoms and impressive structural white matter alterations. Magnetic resonance imaging should be recommended to document the possible extensive changes in amphetamine abuse, which increases dramatically. PMID- 25026103 TI - A review of guidelines on home drug testing web sites for parents. AB - OBJECTIVES: To update and extend prior work reviewing Web sites that discuss home drug testing for parents, and assess the quality of information that the Web sites provide, to assist them in deciding when and how to use home drug testing. METHODS: We conducted a worldwide Web search that identified 8 Web sites providing information for parents on home drug testing. We assessed the information on the sites using a checklist developed with field experts in adolescent substance abuse and psychosocial interventions that focus on urine testing. RESULTS: None of the Web sites covered all the items on the 24-item checklist, and only 3 covered at least half of the items (12, 14, and 21 items, respectively). The remaining 5 Web sites covered less than half of the checklist items. The mean number of items covered by the Web sites was 11. CONCLUSIONS: Among the Web sites that we reviewed, few provided thorough information to parents regarding empirically supported strategies to effectively use drug testing to intervene on adolescent substance use. Furthermore, most Web sites did not provide thorough information regarding the risks and benefits to inform parents' decision to use home drug testing. Empirical evidence regarding efficacy, benefits, risks, and limitations of home drug testing is needed. PMID- 25026104 TI - Associations between problematic internet use and adolescents' physical and psychological symptoms: possible role of sleep quality. AB - OBJECTIVE: To evaluate the associations between problematic Internet use (PIU) and physical and psychological symptoms among Chinese adolescents, and to investigate the possible role of sleep quality in this association. METHODS: A cross-sectional school-based study was conducted in 4 cities in China. The Multidimensional Sub-health Questionnaire of Adolescents, the Pittsburgh Sleep Quality Index, and demographic variables were used to measure adolescents' physical and psychological symptoms and sleep quality, respectively, in 13,723 students (aged 12-20 years). Problematic Internet use was assessed by the 20-item Young Internet Addiction Test. Logistic regressions were used to evaluate the effects of sleep quality and PIU on physical and psychological symptoms, and to identify the mediating effect of sleep quality in adolescents. RESULTS: Prevalence rates of PIU, physical symptoms, psychological symptoms, and poor sleep quality were 11.7%, 24.9%, 19.8%, and 26.7%, respectively. Poor sleep quality was found to be an independent risk factor for both physical and psychological symptoms. The effects of PIU on the 2 health outcomes were partially mediated by sleep quality. CONCLUSIONS: Problematic Internet use is becoming a significant public health issue among Chinese adolescents that requires urgent attention. Excessive Internet use may not only have direct adverse health consequences but also have indirect negative effects through sleep deprivation. PMID- 25026105 TI - Role of the American College of Obstetricians and Gynecologists in supporting and encouraging breastfeeding. PMID- 25026106 TI - The slump test: examination and treatment. AB - The Slump test is becoming more widely accepted as an examination and treatment procedure for all levels of the vertebral column. The test is essential for a fuller recognition of the factors contributing to some patients' disorders. This paper describes the test, the normal pain response, predictable findings on examination, and use of the test in treatment. PMID- 25026107 TI - Therapeutic ultrasound: some historical background and development in knowledge of its effect on healing. AB - The origin and early clinical use of 'therapeutic' ultrasound are reviewed and theories about the mechanism of action of ultrasound are traced and discussed. Changes of emphasis which have taken place in the empirically-based use of ultrasound are described. Some experimental evidence about the effect of ultrasound on tissue healing in vivo is presented, which indicates the need for controlled clinical trials in physiotherapeutic practice. PMID- 25026108 TI - Motor stimulation with interferential currents. AB - The stimulation of motor nerves to produce muscle contraction in normally innervated muscles is a long established part of orthodox physiotherapy. Recently however, a revival of interest in the area has occurred, particularly in the U.S.A. Recent research has indicated that such stimulation can improve muscle strength, reduce muscle spasm and modulate spasticity, in addition to the more usual re-educative role of electrical stimulation. The concept of functional electrical stimulation (F.E.S.) seems destined to become an integral part of many programmes for the neurologically handicapped patient. This paper describes the technique of motor stimulation using interferential currents. The stimulating parameters and electrode placement are considered, along with a detailed explanation of the pre-modulated system of electrode arrangement. PMID- 25026109 TI - Criteria audit as a means of assessing the physiotherapy component of stroke rehabilitation. AB - A Physiotherapy Stroke Audit was conducted over a twelve month period on all stroke patients discharged from the rehabilitation wards of the Bendigo Home and Hospital for the Aged meeting the criteria. The audit method is described. Analysis of results revealed problem areas in documentation, outcome, complications and integrated care. A second audit was done over the following six months to assess the value of physiotherapy measures taken to improve outcome and integrated care and to lessen complications. A third audit is in process to accumulate objective information regarding stroke outcome and to test the effectiveness of a physiotherapy project to improve integrated care. PMID- 25026110 TI - The pursuit of knowledge: continuing education under scrutiny. AB - That physiotherapists recognise the need to pursue their professional knowledge is reflected in the large number of educational courses available. However, we know little of the involvement of the physiotherapy population in these programmes, or whether behavioural change is occurring as a result of participation. Many of the problems associated with continuing education are explored, particularly in the area of participation, motivation, isolation, and design of programmes. Some possible solutions are offered, together with suggestions for future programmes, designed to overcome these hypothetical problems. Above all, the author stresses the need for objective information as a pre-requisite for planning successful continuing education programmes. PMID- 25026111 TI - An in-service training programme for intern physiotherapists. AB - In-service education is one component or method of continuing education. This paper discusses the development of an in-service training programme for intern physiotherapists which is being conducted at the Prince Henry and Prince of Wales Hospitals in Sydney. The basic philosophy behind the programme is the proposition that the intern year for physiotherapists should be both a year of service and a total learning experience aimed at providing a transition between student training and independent professional responsibilities and capabilities. Accordingly the programme was planned to provide training for the interns which would assist them in developing clinical expertise in the tasks of a junior physiotherapist. The programme is proving to be a useful component of the overall learning experiences available to the 19 intern physiotherapists who are allocated to these hospitals each year. PMID- 25026112 TI - Mechanochemical lithiation of layered polysilane. AB - Lithiated polysilane was synthesized by the mechanochemical reaction of layered polysilane with metallic lithium. The resulting dark green powder formed a Si-Li bond on the surface and demonstrated electroconductivity. PMID- 25026113 TI - Influence of race/ethnicity, body mass index, and proximity of menopause on menstrual cycle patterns in the menopausal transition: the Study of Women's Health Across the Nation. AB - OBJECTIVE: Few studies have evaluated factors that influence menstrual cycle length (MCL) during the menopausal transition (MT), a life stage during which very long cycles become more likely to occur. The objective of this article was to assess how body mass index and race/ethnicity--factors associated with MCL in young women--influence MCL during the MT. METHODS: Study of Women's Health Across the Nation menstrual calendar substudy data of African-American, white, Chinese, and Japanese women were available for three sites (southeastern Michigan, Los Angeles, and northern California). Self-recorded monthly menstrual calendars with end-of-the-month questions on hormone therapy use and smoking were collected from 1996 to 2006. Height and weight were measured at annual study visits. We used quantile regression to model MCL at the 25th, 50th, 75th, and 90th percentiles with bootstrap sampling to construct 95% CIs. Models evaluated MCL with time indexed to the start of the MT (n = 963) and to the final menstrual period (n = 431). RESULTS: During the MT, increases in MCL occurred mostly at the right tail of the distribution, reflecting a lengthening of long menstrual cycles, not of the median MCL. After adjustment for smoking, education, physical activity, and time, Chinese and Japanese women had 1 day to 6 days longer MCLs compared with white women. Obese women had 1 day to 5 days longer MCLs compared with nonobese women. CONCLUSIONS: As occurs in younger women, menstrual characteristics during the MT are influenced by race/ethnicity and obesity. The long menstrual cycles characteristic of the MT are longer in obese women and in Chinese and Japanese women. PMID- 25026115 TI - Do menopausal symptoms continue after oral endocrine therapy for breast cancer? PMID- 25026114 TI - A potentially functional variant in the serotonin transporter gene is associated with premenopausal and perimenopausal hot flashes. AB - OBJECTIVE: An increase in the use of selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) to relieve menopausal hot flashes (HFs) has been observed recently. However, response to them has been heterogeneous. We hypothesized that this heterogeneity might be partially attributed to genetic variations in genes encoding the serotonin and/or norepinephrine transporters (SLC6A4 and SLC6A2). As a first step in testing the role of genetics in response to SSRIs/SNRIs, we examined the association between HFs and genetic variants within these two genes. METHODS: We tested 29 haplotype tagging single nucleotide polymorphisms within SLC6A4 and SLC6A2 for their association with HFs separately for European-American (396 cases and 392 controls) and African-American (125 cases and 81 controls) premenopausal and perimenopausal women. RESULTS: We found that the minor allele of SLC6A4_rs11080121 was associated with protection against HFs (odds ratio, 0.75; 95% CI, 0.60-0.94) only in European-American women. Bioinformatics analyses indicated that rs11080121 is fully correlated with rs1042173 in the 3' untranslated region of SLC6A4. The minor allele of rs1042173 seems to disrupt a conserved binding site for hsa-miR-590-3p microRNA. CONCLUSIONS: Disruption of a microRNA binding site leads to higher expression of SLC6A4, higher expression of SLC6A4 leads to depletion of serotonin in synaptic clefts, and depletion of serotonin triggers the presynaptic autoreceptor feedback mechanism to produce more serotonin, which is protective against HFs. This is the first study to test the association between HFs in both European-American and African-American premenopausal and perimenopausal women and genetic variants in two neurotransmitter transporter genes, SLC6A2 and SLC6A4. This information can be used in tailoring the pharmaceutical use of SSRIs/SNRIs for HF relief. PMID- 25026116 TI - "Beliefs about hot flashes drive treatment benefit". PMID- 25026117 TI - Vertebral body dimensions: an aid to diagnosis of severely progressive adolescent idiopathic scoliosis? AB - Following early diagnosis of Adolescent Idiopathic Scoliosis (AIS) it is very difficult to predict whether the curve will continue to increase and to what extent. A cross-sectional study was conducted to investigate the implications of depth and width dimensions of individual vertebral bodies in adolescents with mild and severely progressive soliosis. Results revealed a tendency for depth/width ratios in severe AIS to increase, and those with mild scoliosis to decrease from 13 to 15 years of age. This was proposed as a basis for an additional tool for diagnosis of severely progressive AIS. PMID- 25026118 TI - Precursors and possible effects of psychological stress. AB - The term stress can be used to refer to a generalised somatic response, involving hormonal activity, which renders an individual ready to react to a wide range of events. With continued stress there can result a wide range of pathological developments, including physical and psychological symptoms. This paper will review the social and psychological factors which appear to increase the stress response and will also examine some of the physical consequences of exposure to stress-inducing agents. Emphasis will be given to the possibilities that stress may result from common experiences of living in modern complex society. Individual differences need to be considered as moderators of stress, and also the means whereby people may be taught to cope with stress. PMID- 25026119 TI - Choices for childbirth: a survey of practice in melbourne maternity hospitals. AB - This paper describes a survey of childbirth practices in Melbourne hospitals. Information was collected from 27 of Melbourne's 34 hospitals with obstetric beds. The survey concentrated on aspects of the management of labour and the newborn where patients could expect to exercise a degree of choice. The survey found large variations in the degree of choice offered to patients in different categories of hospital on more than half the questionnaire items. Patients in large public hospitals were in general given the largest range of choice, followed by private hospital patients. Patient choice was very restricted in most small public hospitals. PMID- 25026120 TI - Creation of hydrophilic nitric oxide releasing polymers via plasma surface modification. AB - Herein, we describe the surface modification of an S-nitrosated polymer derivative via H2O plasma treatment, resulting in polymer coatings that maintained their nitric oxide (NO) releasing capabilities, but exhibited dramatic changes in surface wettability. The poly(lactic-co-glycolic acid)-based hydrophobic polymer was nitrosated to achieve a material capable of releasing the therapeutic agent NO. The NO-loaded films were subjected to low-temperature H2O plasma treatments, where the treatment power (20-50 W) and time (1-5 min) were varied. The plasma treated polymer films were superhydrophilic (water droplet spread completely in <100 ms), yet retained 90% of their initial S-nitrosothiol content. Under thermal conditions, NO release profiles were identical to controls. Under buffer soak conditions, the NO release profile was slightly lowered for the plasma-treated materials; however, they still result in physiologically relevant NO fluxes. XPS, SEM-EDS, and ATR-IR characterization suggests the plasma treatment resulted in polymer rearrangement and implantation of hydroxyl and carbonyl functional groups. Plasma treated samples maintained both hydrophilic surface properties and NO release profiles after storage at -18 degrees C for at least 10 days, demonstrating the surface modification and NO release capabilities are stable over time. The ability to tune polymer surface properties while maintaining bulk properties and NO release properties, and the stability of those properties under refrigerated conditions, represents a unique approach toward creating enhanced therapeutic biopolymers. PMID- 25026121 TI - Movement is life. AB - Starting in utero, where movement is essential for the development of normal joints, a pattern is set up which is repeated throughout life. The evolution of the species is mirrored in the development of the individual, and movement, exercise and neuromuscular development form a central theme. The major skeletal changed are related to the changes in age. The emergence of disease patterns, the progress of the ageing process and the factor influencing morbidity and mortality are discussed. The role of the therapist as an expert in exercise, both prophylactic and therapeutic, is emphasized and particular attention is paid to the widening opportunities outside the sphere of the traditional clinical setting. PMID- 25026122 TI - Biofeedback in treatment of stroke. AB - This paper presents a review of recent literature concerning the possible mechanisms by which EMG biofeedback treatment may aid in the rehabilitation of the stroke patient, and the practical application of this technique. Among the studies reviewed there is a general consensus that biofeedback training enables some patients, whose performance has previously plateaued, to gain a degree of control of hypertonic muscle groups and increased contraction in paretic groups thus improving function. However, there still remains a number of questions to be answered and limitations to be considered. PMID- 25026123 TI - Sensory and motor development of pre-term infants. AB - The neurological, sensory, motor and general developmental progress of 135 infants born more than 5 weeks before term was studied. Over a period of 12 months, 122 infants had post-term evaluations at one, four, eight and twelve months. These were carried out using both a standardized infant ability scale and a graded neurosensory and motor assessment. The abilities of the age adjusted pre term infants compared favourably with the standardized scale of expected age normal abilities. Developmental aspects of tactile, proprioceptive, vestibular and eye movement responses showed some interesting trends. There was some persistence of primitive motor reflexes and an apparent delay in the development of postural reactions. The achievement of the motor milestones such as sitting, crawling, standing and walking did fall within the wide limits of the normal range. Six per cent of the total group had definite neurological handicaps, 16 per cent responded inconsistently during one of the assessments and at 12 months, a further 11 per cent showed evidence of developmental delay. PMID- 25026124 TI - The influence of rice plow handle design and whole-body posture on grip force and upper-extremity muscle activation. AB - A previous job screening study revealed ergonomics risk factors in rice field plowing. This work motivated the present experimental investigation of the influence of plow handle design and farmer whole-body posture on grip force and arm muscle activity. A total of 24 experienced farmers performed a simulated plowing task, including walking on even and uneven ground while rolling a tiller equipped with conventional horizontal and proposed vertical handles. Results revealed the proposed handles, designed to promote neutral wrist posture, to increase upper-arm muscle use between 47% and 70% across ground types, as compared with conventional handles. The ratio of grip force to forearm muscle activity (or efficiency in muscle use) increased from 1.85 when using conventional handles on uneven ground to 2.16 when using the proposed handles with symmetrical body posture on even ground. However, participants perceived higher discomfort when using the proposed handles, as they were accustomed to the conventional design. PRACTITIONER SUMMARY: The findings of this work may be used to educate farmers on the potential for hand and arm injury in rice cultivation activities. Results may also provide a basis for redesign of existing tiller handles to promote neutral wrist posture, greater efficiency in muscle use and machine control. PMID- 25026126 TI - Two novel mutations in acid alpha-glucosidase gene in two patients with Pompe disease. AB - Pompe disease is an autosomal recessive lysosomal glycogen storage disorder (GSD) caused by acid alpha-glucosidase (GAA) deficiency. Pompe disease has a broad genotypic and phenotypic spectrum. The infantile-onset form is the most severe form and presents with hypotonia and cardiomyopathy in early infancy. The probands who died were found to have GSD type II based on clinical and biochemical findings. We report two families with Pompe disease in whom the parents' molecular analysis revealed two novel mutations: c.2045A>G (p.Q682R) and c.763C>T (p.Q255X). PMID- 25026125 TI - Clinical and molecular studies related to bone metabolism in patients with congenital adrenal hyperplasia. AB - Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency need glucocorticoid (GC) therapy, which alters bone mineral metabolism. We analyze clinical and biochemical parameters and different polymorphisms of candidate genes associated with bone mineral density (BMD) in CAH patients. The CAH patients treated with GC and healthy controls were studied. Anthropometric parameters, biochemical markers of bone turnover, and BMD were evaluated. Polymerase chain reaction technique was used to genotype different candidate genes. The 192-192 genotype frequency (IGF-I) was lower in poorly controlled patients than that from controls. In CAH patients, FF genotype (vitamin D receptor, VDR) correlated with lower lumbar spine BMD and there was a significant association between the 0-0 genotype (IGF-I) and high values of beta CrossLaps and a low total BMD. This study contributes to understanding of the association of genetic determinants of BMD with the variable response to GC treatment in CAH patients and demonstrates the usefulness of these genetic polymorphisms. PMID- 25026127 TI - Two heterozygous mutations of the AMH gene in a Japanese patient with persistent Mullerian duct syndrome. AB - Persistent Mullerian duct syndrome (PMDS) is an autosomal recessive disorder of sex development (DSD) characterized by the presence of Mullerian duct derivatives in 46, XY phenotypic males. To date, more than 50 different mutations of the anti Mullerian hormone gene (AMH) have been reported. Here, we report two novel mutations of AMH in a Japanese patient with PMDS. A 1-year-old male presented with bilateral cryptorchidism and normal male external genitalia. A laparoscopic surgery revealed a uterus and fallopian tubes. Serum AMH was very low. The patient's elder brother was also diagnosed as having PMDS at another hospital. Genetic analysis of AMH showed two novel mutations of p.N486T and p.V527L. Given that these two amino acids are well conserved among different species of AMH, the substitution of two amino acids might affect the normal function of AMH. In conclusion, PMDS should be included in differential diagnoses of cryptorchidism. PMID- 25026128 TI - Effect of trunk flexion speed on flexion relaxation of erector spinae. AB - Flexion relaxation of erector spinae (ES) has mainly been studied during slow trunk movements. Due to the viscoelastic properties of spinal ligaments, the ES activity may change at different movement speeds. Twenty-one normal females (20 25 years) were examined during slow, intermediate and natural speeds of trunk flexion. The movements and simultaneous ES surface EMG recordings were recorded by two synchronised video cameras. The ES relaxed at approximately 80 per cent of vertebral flexion at each speed, and no difference was found among the three speeds. This implies that either ES activity is independent of speed in the slow to natural functional speed range, or the flexion relaxation phenomenon is not related to changes in spinal ligamentous tension. PMID- 25026129 TI - Effects of age, gender and speed on three dimensional lumbar spine kinematics. AB - This article reports an investigation into the influences of gender, speed of motion and chronological age on the active movements of the lumbar spine. Data were collected from 100 able-bodied volunteers using an automated motion analysis system. Subjects performed movements at two self-selected speeds. Consistent patterns of motion coupling during the actions were detected and no significant gender-specific differences were observed. With advancing age, significant reductions in the ranges of forward and side flexion, but not axial rotation, were found. Age-related differences in the patterns of coupling between movements were also determined. The results of this study will provide therapists with data upon which to base judgments regarding movement restriction, particularly in older clients. PMID- 25026130 TI - Group exercise for subjects with osteoarthritis of the knee. AB - This study was designed to evaluate an established group exercise program at a large public hospital for subjects with osteoarthritis of the knee(s). Although quantitative gait analysis shows a clear difference between subjects with osteoarthritis of the knee(s) and asymptomatic controls, a significant effect of the group exercise program undertaken was not demonstrated, on either objectively measured gait parameters or subjectively reported pain and function. Possible reasons for this, together with an outline for a revised program and assessment procedure, are discussed. PMID- 25026131 TI - Post stroke recovery of balanced sitting and ambulation ability. AB - The primary aim of this retrospective audit was to determine whether sitting balance ability at initial physiotherapy assessment post stroke could predict ambulation ability at discharge. Also considered were the side affected by the stroke, sensory loss, dysphasia, whether they affected outcome and whether ambulation ability determined social destination at discharge. Forty stroke patients were treated during the 12-month study period. All patients received early physiotherapy treatment in the acute then rehabilitation wards. The average length of hospital stay was 47.7 +/- 28.2 [SD] days. All patients achieved independent sitting balance at discharge, with a significant improvement (p < 0.001) from initial assessment. Twenty-seven achieved independent ambulation by discharge. This was shown to have a significant (p < 0.001) relationship to early independent sitting balance but was not significantly related to side of stroke or sensory loss. PMID- 25026132 TI - Clinical indicators for physiotherapists. AB - Clinical indicators have recently been introduced into the Australian Council of Healthcare Standards (ACHS) Hospital Accreditation Programme. They offer a means of monitoring the process and outcome of care by determining flags of performance which are used for constant reassessment. This paper explores the benefits of developing clinical indicators specific to physiotherapy. It also identifies the steps preliminary to the development of indicators and gives examples of indicators currently being trialled by Australian physiotherapists. By taking the steps necessary to the development of indicators, physiotherapists in all types of practice will be in a better position to judge the effectiveness of their patient care. PMID- 25026133 TI - Quality of light - is laser necessary for effective photobiostimulation? AB - Is true laser, with its unique qualities of coherence, collimation and monochromaticity, necessary for effective photobiostimulation, or is a simpler form of light sufficient? Doubt has been cast on the importance of coherence and collimation in influencing biostimulation. It is hypothesised that monochromaticity (or singularity of wavelength) is the only characteristic of laser necessary for photostimulation. If wavelength is the important factor in phototherapy, the clinician must consider which wavelengths are capable of producing specific effects within living tissues. In addition, it is important to distinguish the quality of light provided by a unit and whether it will give the desired results without a large financial outlay. This article reviews the unique properties of laser, discusses their contribution to photobiostimulation and looks at apparatus which provide these properties. PMID- 25026134 TI - Factors affecting Low Level Laser Therapy. AB - Low Level Laser Therapy has been reported as causing many therapeutic reactions within living tissue, yet research studies have not been able to support conclusively the results which appear to occur clinically. If the physiotherapist accepts that light quality may have been a variable overlooked in previous studies, it is necessary to consider whether there are other factors which may have contributed to the variable and, at times, conflicting results. These factors include depth of penetration and resultant absorption. Factors such as power output, dose, pulse frequency and frequency of treatment will also influence the therapeutic action of laser. This review evaluates parameters common to most therapeutic lasers as well as other features including the multiple-diode probe. Issues which may help clinicians optimise their treatment when using Low Level Laser Therapy will be addressed. PMID- 25026135 TI - Perceptions of the clinical efficacy of laser therapy. AB - Adoption of therapeutic lasers has been widespread throughout Australia in recent years. A questionnaire survey was conducted amongst therapists in Victoria who were believed to have purchased this apparatus. The study sought to determine the extent of laser use in Victoria; the indications, techniques, dosage, expectations and outcomes; and the background knowledge about lasers possessed by the respondents. The elbow and shoulder were the most commonly treated regions; tendonitis and ligamentous lesions the most frequently treated disorders; pain relief and wound healing the most commonly expected effects; and 30mm the average expected penetration. Although 57.9 per cent of respondents attended one or more seminars prior to purchasing lasers, journals and other reading were given as the most valuable source of knowledge. PMID- 25026136 TI - Transcutaneous electrical nerve stimulation and chronic intractable angina pectoris. AB - The treatment trial being reported investigated whether the frequency and severity of pain in 11 patients with chronic intractable angina pectoris were decreased by TENS applied adjacent to T1 and T5 spinous processes. Pulse and blood pressure were measured before, during and after each treatment. Results showed a significant decrease in frequency and severity of pain. Rate pressure product was calculated to try to identify the mode of action. The mean RPP before TENS application, compared with the mean RPP at 30 minutes and at 90 minutes, was significantly reduced. It was concluded from these results that TENS should be considered as an adjunct to medical management in those patients with angina pectoris not satisfactorily controlled by optimal medication. PMID- 25026137 TI - Variability in human locomotion: are repeat trials necessary? AB - This study proposed to determine the extent to which multiple gait trials provide further information than that obtained from a single trial of walking. Gait data were collected using a video camera and force platform system on 10 subjects including a below knee amputee. The data supported several conclusions. If the purpose of gait research is to investigate and detail the kinematic and kinetic patterns of individual subjects, either during a single data collection session or across several sessions, then recording a single stride of normal gait per subject can be justified. However, if the purpose of the research is to produce population norms, then multiple strides per subject are necessary to obtain estimates of variability. PMID- 25026138 TI - The iliopsoas muscle and the lumbar spine. AB - The influence of the iliopsoas muscle length on postural and mobility characteristics of the lumbar spine was investigated in 60 normal male subjects. The passive physiological and accessory intervertebral movements were assessed. Measurements which provided estimations of the lumbar lordosis, lumbar extension and iliopsoas muscle length were also recorded. A difference was found in the iliopsoas muscle length with respect to the mobility of the passive physiological and accessory intervertebral movements at the L1-L2 and T12-L1 segments, and at the L2 and L1 levels respectively. As the iliopsoas muscle shortened, the intervertebral mobility increased. Furthermore, the iliopsoas muscle length showed a weak tendency toward a correlation with the lordosis and the lordosis tended to increase as the muscle shortened. No correlation was found between the iliopsoas muscle length and the range of lumbar extension. PMID- 25026139 TI - Effect of imposed auditory rhythms on human interlimb coordination. AB - A non-locomotor task was used to investigate human upper and lower extremity movement coordination. Eighteen normal adult subjects performed simultaneous clapping and foot-tapping in the seated position. Subjects performed the task at their preferred rate as well as at metronome rates of 1-4Hz. Temporal data and interlimb phase-linkage were analysed. Results of the temporal data indicated a reciprocal interaction among the upper and lower extremities. Most subjects also showed shifts in interlimb phase-linkage when they moved their limbs at metronome rates of higher than 1 Hz. These findings may suggest that the central nervous system (CNS) coordinates the self-paced movement of the extremities in the same way that it coordinates them under an externally-paced condition at slower rates. PMID- 25026140 TI - Anti-HIV activities of precisely defined, semirigid, carboxylated alternating copolymers. AB - Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. For both the IIIb and BaL HIV-1 strains, the lowest IC50 (0.095 and 0.23 MUg/mL, respectively) values were obtained with poly(4,4'-stilbenedicarboxylate alt-maleic acid) (DCSti-alt-MA). For JR-CSF and 92UG037, both tier 2 clinical isolates but different clades, DCSti-alt-MA exhibited the lowest IC50 (0.76 and 0.75 MUg/mL, respectively). Although DCSti-alt-MA had the lowest IC50 in MUg/mL for each strain, the other copolymers had IC50s less than 2-fold higher. Further, these copolymers achieved high selectivity indices (>100) for these clinical isolates. Polymer rigidity, as measured by the statistical segment length, emerged as a key property when comparing anti-HIV activities with those of other polyanions. A speculative illustration was proposed for possible modes of inhibition. PMID- 25026141 TI - Identification and developmental assessment of children with neurological impairment. AB - During foetal life, at birth and in the first few post-natal months, the brain is particularly vulnerable to damage. It is at this time that there is rapid development of the central nervous system, a merging of early primitive responses with more complex and later, highly integrated and adaptive responses, and the development of purposeful physical activities. PMID- 25026142 TI - Education of children with mild neurological dysfunction. AB - As one who is involved with the educational planning of children with disabling conditions, I am very conscious of the significance of the theme of this conference. Much of the work I have to do is involved in centres where a range of professionals have great responsibility in the treatment of children and where lines of communication are well-established, bridges are easily built between the professional islands. The greater cooperation and team work between professions working with children has had a marked impact of the understanding of children with special problems. A quick glance through the literature on special education reveals the contributions of disciplines outside education. PMID- 25026143 TI - Physical education - an important area within the education programme for children with learning disabilities. AB - In recent years, a great deal of attention has been given to the topic of children diagnosed as having learning disabilities. Controversy exists within and between the various professional groups that are concerned with diagnosis and/or treatment of the many faceted problems that exist within the area, but fortunately some progress is being made in understanding the problem and in understanding the complementary roles of the many professional groups involved. PMID- 25026144 TI - Degenerative disease affecting the nervous system. AB - The term "degenerative disease" is one which is rather widely used in relation to the nervous system and yet one which is rarely formally and carefully defined. The term appears to be applied to disorders of the nervous system which often occur in later life and which are of uncertain cause. In the Shorter Oxford Dictionary the word degeneration is defined as "a change of structure by which an organism, or an organ, assumes the form of a lower type". However this is not quite the sense in which the word is applied in human neuropathology, where it is conventional to restrict the use of the word to those organic disorders which are of uncertain or poorly understood cause and in which there is a deterioration or regression in the level of functioning of the nervous system. The concept of degenerative disorder is applied to other organs as well as to the brain, and as disease elsewhere in the body may affect the nervous system, it seems reasonable to include within the topic of degenerative disorder affecting the nervous system those conditions in which the nervous system is involved as a result of primary degenerations in other parts of the body. PMID- 25026145 TI - A facilitation and co-ordination therapy approach to the treatment of multiple sclerosis. AB - Facilitation and Co-ordination Therapy (F.A.C.T.) is the term applied to the modification of the techniques of Proprioceptive Neuromuscular Facilitation. These adaptations have been made to meet the needs of the patient with Multiple Sclerosis. It is simply one approach to physiotherapy treatment, on an intensive scale, for this condition of the nervous system. F.A.C.T. is not a rigid concept, but a flexible mechanism in which any form of treatment that is beneficial to the patient is employed. The treatment routine is based on the system used at the Kaiser Rehabilitation Centre, in Vallejo, California. The treatment consists of gait training, mat exercises, physical therapy and self-care activities. Some of the principles of the Bobath approach to treatment of neuromuscular disorders are incorporated in the F.A.C.T. programme. PMID- 25026146 TI - Nursing care of the domiciliary patient in queensland. AB - Community nursing is provided under many agencies within this State, and these nurses may be employed by either voluntary or official services. PMID- 25026147 TI - WESTERN DOMICILIARY CARE SERVICE: A report on the development and activities of a home care service associated with a teaching hospital. AB - Following the decision of the South Australian State Government to take advantage of the Commonwealth Home Care and Paramedical Services Acts of 1969, a detailed and co-ordinated plan for a pilot scheme was offered to the Director General of Medical Services for submission to the State and Commonwealth Governments for acceptance. Approval of the scheme was obtained late in 1970 and this was followed by the appointment of a committee to be responsible for the structuring and admistration of the scheme. PMID- 25026148 TI - Social work in domiciliary care. AB - The title of this paper is a very broad one, far too broad to cover here. There are so many facets to be considered and so many diverse groups in the community needing a service that a full day seminar would be needed to cover the role and the specific contribution of the social worker in all areas. PMID- 25026149 TI - Malignant melanoma in queensland. AB - Between July 1963 and December 1968, all cases of proven malignant melanoma occurring in Queensland were registered at the Research Unit of the Princess Alexandra Hospital as part of the Queensland Melanoma Project (Davis and Herron, 1966). During 1969, only selected teaching hospital cases were registered. In all, during the whole period, we have detailed records of 1,514 patients and these constitute the basis of this paper. In all cases, the microscopic diagnoses were reviewed by a panel of pathologists before the case was regarded as proven. PMID- 25026150 TI - The orthopaedic training programme in indonesia. AB - I was fortunate to visit Indonesia in association with the Orthopaedic Training Programme, firstly whilst on holiday in October 1970 and later as a volunteer in an advisory capacity in March 1971 at the request of the Indonesians involved in the Orthopaedic Training Programme. PMID- 25026151 TI - General physiotherapy in India. AB - I want to share with you briefly some of the problems I met during the 10 years I worked as a physiotherapist in the Christian Medical College Hospital, Ludhiana in north India. There I saw patients suffering from diseases that up till then I had only read about in textbooks. PMID- 25026152 TI - Physiotherapy in the treatment of endemic cretinism in the Western highlands of new Guinea. AB - Endemic cretinism describes a syndrome of developmental abnormalities which geographically coincide with severe iodine deficiency. PMID- 25026153 TI - Physiotherapy in Korea. AB - Korea is an ancient land, with a proud history of civilisation stretching back 43 centuries. It is a very beautiful country and its Japanese name "Chosun" or "Land of the Morning Calm" conjures up pictures of the morning mist floating down the narrow, winding terraced valleys, the rugged peaks above clear in the crisp, brilliant morning light. But it is also a tragic country as much of its history is of war - between Korea and her powerful neighbours, China and Japan, or between China and Japan, with Korea merely the battlefield. Intensely oriental, she is reaching to the West for all the advantages of modern civilisation which she was denied by the Japanese during their occupation from 1911-1945. Fiercely nationalistic, she is torn apart by the tragic division into North and South, along the 38th parallel, the result of the Korean War of 1949-1952. PMID- 25026154 TI - Superficial amygdala and hippocampal activity during affective music listening observed at 3 T but not 1.5 T fMRI. AB - The purpose of this study was to compare 3 T and 1.5 T fMRI results during emotional music listening. Stimuli comprised of psychoacoustically balanced instrumental musical pieces, with three different affective expressions (fear, neutral, joy). Participants (N=32) were split into two groups, one subjected to fMRI scanning using 3 T and another group scanned using 1.5 T. Whole brain t tests (corrected for multiple comparisons) compared joy and fear in each of the two groups. The 3 T group showed significant activity differences between joy and fear localized in bilateral superficial amygdala, bilateral hippocampus and bilateral auditory cortex. The 1.5 T group showed significant activity differences between joy and fear localized in bilateral auditory cortex and cuneus. This is the first study to compare results obtained under different field strengths with regard to affective processes elicited by means of auditory/musical stimulation. The findings raise concern over false negatives in the superficial amygdala and hippocampus in affective studies conducted under 1.5 T and caution that imaging improvements due to increasing magnetic field strength can be influenced by region-specific characteristics. PMID- 25026155 TI - A Bayesian approach to the creation of a study-customized neonatal brain atlas. AB - Atlas-based image analysis (ABA), in which an anatomical "parcellation map" is used for parcel-by-parcel image quantification, is widely used to analyze anatomical and functional changes related to brain development, aging, and various diseases. The parcellation maps are often created based on common MRI templates, which allow users to transform the template to target images, or vice versa, to perform parcel-by-parcel statistics, and report the scientific findings based on common anatomical parcels. The use of a study-specific template, which represents the anatomical features of the study population better than common templates, is preferable for accurate anatomical labeling; however, the creation of a parcellation map for a study-specific template is extremely labor intensive, and the definitions of anatomical boundaries are not necessarily compatible with those of the common template. In this study, we employed a volume-based template estimation (VTE) method to create a neonatal brain template customized to a study population, while keeping the anatomical parcellation identical to that of a common MRI atlas. The VTE was used to morph the standardized parcellation map of the JHU-neonate-SS atlas to capture the anatomical features of a study population. The resultant "study-customized" T1-weighted and diffusion tensor imaging (DTI) template, with three-dimensional anatomical parcellation that defined 122 brain regions, was compared with the JHU-neonate-SS atlas, in terms of the registration accuracy. A pronounced increase in the accuracy of cortical parcellation and superior tensor alignment were observed when the customized template was used. With the customized atlas-based analysis, the fractional anisotropy (FA) detected closely approximated the manual measurements. This tool provides a solution for achieving normalization-based measurements with increased accuracy, while reporting scientific findings in a consistent framework. PMID- 25026157 TI - BOLD matches neuronal activity at the mm scale: a combined 7T fMRI and ECoG study in human sensorimotor cortex. AB - High resolution BOLD fMRI has the potential to map activation patterns of small neuronal populations at the scale of cortical columns. However, BOLD fMRI does not measure neuronal activity, but only a correlate thereof, since it measures blood dynamics. To confirm that BOLD activation maps reflect neuronal population activity patterns, a direct comparison with neuro-electrophysiological data from the same cortical patch is necessary. Here, we compare BOLD activation patterns obtained with fMRI at 7 T to electrophysiological patterns obtained with implanted high density electrocorticography (ECoG) grids in the same patch of human sensorimotor cortex, and with similar resolution (1.5mm). We used high spatially sampled high-frequency broadband (HFB) power from ECoG, which reflects local neuronal population activity. The spatial distribution of 7 T BOLD activation matched the spatial distribution of ECoG HFB-power changes in the covered patch of sensorimotor cortex. BOLD fMRI activation foci were located within 1-3mm of the HFB-power ECoG foci. Both methods distinguished individual finger movement activation within a 1cm cortical patch, revealing a topographical medial to lateral layout for the little finger to index to thumb. These findings demonstrate that the BOLD signal at 7 T is strongly correlated with the underlying electrophysiology, and is capable of discriminating patterns of neuronal population activity at a millimeter scale. The results further indicate the utility of 7 T fMRI for investigation of intra-area organization of function and network dynamics. PMID- 25026156 TI - Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects. AB - Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2 * 2 * 2 mm(3), b = 700 s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test retest reproducibility. White matter b0 SNR reproducibility was on average 7 +/- 1% with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2-4% range for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios. PMID- 25026159 TI - The challenge of physiotherapy education in australia. AB - Before discussing the challenge facing Physiotherapy Education today let us look back at how this challenge was faced in the past. PMID- 25026158 TI - Regional distribution of lung compliance by image analysis of computed tomograms. AB - Computed tomography (CT) can yield quantitative information about volume distribution in the lung. By combining information provided by CT and respiratory mechanics, this study aims at quantifying regional lung compliance (CL) and its distribution and homogeneity in mechanically ventilated pigs. The animals underwent inspiratory hold maneuvers at 12 lung volumes with simultaneous CT exposure at two end-expiratory pressure levels and before and after acute lung injury (ALI) by oleic acid administration. CL and the sum of positive voxel compliances from CT were linearly correlated; negative compliance areas were found. A remarkably heterogeneous distribution of voxel compliance was found in the injured lungs. As the lung inflation increased, the homogeneity increased in healthy lungs but decreased in injured lungs. Image analysis brought novel findings regarding spatial homogeneity of compliance, which increases in ALI but not in healthy lungs by applying PEEP after a recruitment maneuver. PMID- 25026160 TI - Continuing education. AB - As the title suggests, education of the physiotherapist should be a continuing process which starts in undergraduate days and continues throughout the whole of the person's professional life. In the past there has been little co-ordination between these two stages of education and many of the advances to be seen in undergraduate education have not flowed through to the postgraduate sphere. Yet the continuing education of the physiotherapist is of great importance to the patient and the community, to the physiotherapist herself and to the profession as a whole. PMID- 25026161 TI - The recognition of overseas qualifications in australia. AB - Australian physiotherapists commonly regard themselves as members of a national profession. Many of us on occasion share a sense of community also with physiotherapists overseas. The concept of an Australiawide profession with a national approach to our international colleagues is an attractive one. It is, however, contradicted by the actual procedures for recognition of overseas qualifications in Australia. PMID- 25026162 TI - Is physiotherapy truly professional? AB - As the twentieth century draws to a close, there emerges a society which demands occupations to be clearly defined to ensure easy recognition, and hence a more efficiently organised labour force. This development has been assisted by the operation of professional bodies which lay down standards to be maintained by their members. Consequently, professional qualifications and capabilities are easily recognised by international bodies and mobility between countries is facilitated by clearly defined qualifications. PMID- 25026163 TI - The role of faculty development in physiotherapy education. AB - In recent years there has been a considerable change in the skills and qualifications necessary for faculty members in physiotherapy schools. The focus has shifted considerably from a primary emphasis on the clinical ability of all staff, toward the more universal scholastic goals of research, grants, publications, consultancies and teaching skills. From an absolute reliance on medical research, physiotherapy has had to learn how to go about its own research and apply it directly to treatment modalities and clinical programmes. These changes have had a profound and direct effect on the faculty of physiotherapy schools, while the profession as a whole struggles to come to terms with the change. As is the case in other long established professions, physiotherapy is learning to prize scholastic advancement and research as much as clinical excellence. PMID- 25026164 TI - The development of approaches to curriculum planning to meet academic and professional objectives. AB - The importance of developing a curriculum which satisfies the broad objectives of professional education has been recognized widely. The balance between enhancing scholarship and developing vocational skills, the importance of relevant evaluation of the curriculum, students and teachers and the place of research in current professional education are all matters worthy of consideration by those responsible for professional education. This paper reflects upon the historic attitudes to education and traces the changes in approach which have been necessary to ensure the provision of appropriate learning experiences for students seeking a professional education today. PMID- 25026165 TI - Physiotherapy clinical supervision: effectiveness and the use of models. AB - This paper reviews some of the literature which relates to physiotherapy clinical supervision. It explores the attitude of therapists to the role of student supervisor and their level of preparedness. Some behaviours for facilitating effective clinical supervision from recent studies of student preferences are presented. Appropriate models of the supervision process for physiotherapy students are given and a grid model is suggested as a possible method of simplifying and evaluating the complex and varied learning environments, interpersonal relationships and behaviours which occur in physiotherapy clinical placements. PMID- 25026166 TI - Student stress: an approach to coping at the interface between preclinical and clinical education. AB - The transition from preclinical to clinical education can provoke stress in students. This paper describes the nature of stress and outlines the use of a 'clinical coping workshop' at the University of Queensland, to identify and examine the particular stresses on physiotherapy students facing this transitional experience. Much of the stress experienced by students relates to the new behavioural responses required of them. It is suggested that negotiating an acceptable contract, related to student and tutor behaviour as much as to educational outcomes, can be helpful and is applicable in the clinical environment. Mutual expectations need to be openly shared in this process. PMID- 25026167 TI - Educational needs of health professionals in the treatment of chronic low back pain. AB - Behaviour Therapy is not used to a great extent in the physiotherapy management of chronic low back pain; yet the clinical research literature indicates that behavioural techniques may assist the maintenance of treatment gains. Two questionnaires were devised for hospital-based physiotherapy graduates to assess knowledge of behaviour therapy techniques and their relevance to physiotherapy management of the patient with chronic low back pain. Third-year undergraduate physiotherapy students who had just completed their Behaviour Therapy course at Cumberland College of Health Sciences, constituted the comparison group. Results showed that the graduates and physiotherapy students had comparable levels of knowledge. Both groups believed that the physiotherapist's use of behaviour therapy techniques was primarily for the purposes of improving the patient's daily activity and muscular state. Physiotherapy training for the management of this difficult patient group is discussed. PMID- 25026168 TI - A combined crossed molecular beams and ab initio investigation on the formation of vinylsulfidoboron (C2H311B32S). AB - We exploited crossed molecular beams techniques and electronic structure calculations to provide compelling evidence that the vinylsulfidoboron molecule (C2H3(11)B(32)S) - the simplest member of hitherto elusive olefinic organo sulfidoboron molecules (RBS) - can be formed via the gas phase reaction of boron monosulfide ((11)B(32)S) with ethylene (C2H4) under single collision conditions. The reaction mechanism follows indirect scattering dynamics via a barrierless addition of the boron monosulfide radical to the carbon-carbon double bond of ethylene. The initial reaction complex can either decompose to vinylsulfidoboron (C2H3(11)B(32)S) via the emission of a hydrogen atom from the sp(3) hybridized carbon atom, or isomerize via a 1,2-hydrogen shift prior to a hydrogen loss from the terminal carbon atom to form vinylsulfidoboron. Statistical (RRKM) calculations predict branching ratios of 8% and 92% for both pathways leading to vinylsulfidoboron, respectively. A comparison between the boron monosulfide ((11)B(32)S) plus ethylene and the boron monoxide ((11)BO) plus ethylene systems indicates that both reactions follow similar reaction mechanisms involving addition - elimination and addition - hydrogen migration - elimination pathways. Our experimental findings open up a novel pathway to access the previously poorly characterized class of organo-sulfidoboron molecules via bimolecular gas phase reactions, which are difficult to form through 'classical' organic synthesis. PMID- 25026170 TI - Exploring neighborhoods in the metagenome universe. AB - The variety of metagenomes in current databases provides a rapidly growing source of information for comparative studies. However, the quantity and quality of supplementary metadata is still lagging behind. It is therefore important to be able to identify related metagenomes by means of the available sequence data alone. We have studied efficient sequence-based methods for large-scale identification of similar metagenomes within a database retrieval context. In a broad comparison of different profiling methods we found that vector-based distance measures are well-suitable for the detection of metagenomic neighbors. Our evaluation on more than 1700 publicly available metagenomes indicates that for a query metagenome from a particular habitat on average nine out of ten nearest neighbors represent the same habitat category independent of the utilized profiling method or distance measure. While for well-defined labels a neighborhood accuracy of 100% can be achieved, in general the neighbor detection is severely affected by a natural overlap of manually annotated categories. In addition, we present results of a novel visualization method that is able to reflect the similarity of metagenomes in a 2D scatter plot. The visualization method shows a similarly high accuracy in the reduced space as compared with the high-dimensional profile space. Our study suggests that for inspection of metagenome neighborhoods the profiling methods and distance measures can be chosen to provide a convenient interpretation of results in terms of the underlying features. Furthermore, supplementary metadata of metagenome samples in the future needs to comply with readily available ontologies for fine-grained and standardized annotation. To make profile-based k-nearest-neighbor search and the 2D-visualization of the metagenome universe available to the research community, we included the proposed methods in our CoMet-Universe server for comparative metagenome analysis. PMID- 25026169 TI - Making the bend: DNA tertiary structure and protein-DNA interactions. AB - DNA structure functions as an overlapping code to the DNA sequence. Rapid progress in understanding the role of DNA structure in gene regulation, DNA damage recognition and genome stability has been made. The three dimensional structure of both proteins and DNA plays a crucial role for their specific interaction, and proteins can recognise the chemical signature of DNA sequence ("base readout") as well as the intrinsic DNA structure ("shape recognition"). These recognition mechanisms do not exist in isolation but, depending on the individual interaction partners, are combined to various extents. Driving force for the interaction between protein and DNA remain the unique thermodynamics of each individual DNA-protein pair. In this review we focus on the structures and conformations adopted by DNA, both influenced by and influencing the specific interaction with the corresponding protein binding partner, as well as their underlying thermodynamics. PMID- 25026171 TI - Subchronic toxicity of copper oxide nanoparticles and its attenuation with the help of a combination of bioprotectors. AB - In the copper metallurgy workplace air is polluted with condensation aerosols, which a significant fraction of is presented by copper oxide particles<100 nm. In the scientific literature, there is a lack of their in vivo toxicity characterization and virtually no attempts of enhancing organism's resistance to their impact. A stable suspension of copper oxide particles with mean (+/-SD) diameter 20+/-10 nm was prepared by laser ablation of pure copper in water. It was being injected intraperitoneally to rats at a dose of 10 mg/kg (0.5 mg per mL of deionized water) three times a week up to 19 injections. In parallel, another group of rats was so injected with the same suspension against the background of oral administration of a "bio-protective complex" (BPC) comprising pectin, a multivitamin-multimineral preparation, some amino acids and fish oil rich in omega-3 PUFA. After the termination of injections, many functional and biochemical indices for the organism's status, as well as pathological changes of liver, spleen, kidneys, and brain microscopic structure were evaluated for signs of toxicity. In the same organs we have measured accumulation of copper while their cells were used for performing the Random Amplification of Polymorphic DNA (RAPD) test for DNA fragmentation. The same features were assessed in control rats infected intraperitoneally with water with or without administration of the BPC. The copper oxide nanoparticles proved adversely bio-active in all respects considered in this study, their active in vivo solubilization in biological fluids playing presumably an important role in both toxicokinetics and toxicodynamics. The BPC proposed and tested by us attenuated systemic and target organs toxicity, as well as genotoxicity of this substance. Judging by experimental data obtained in this investigation, occupational exposures to nano scale copper oxide particles can present a significant health risk while the further search for its management with the help of innocuous bioprotectors seems to be justified. PMID- 25026172 TI - Joint identification of genetic variants for physical activity in Korean population. AB - There has been limited research on genome-wide association with physical activity (PA). This study ascertained genetic associations between PA and 344,893 single nucleotide polymorphism (SNP) markers in 8842 Korean samples. PA data were obtained from a validated questionnaire that included information on PA intensity and duration. Metabolic equivalent of tasks were calculated to estimate the total daily PA level for each individual. In addition to single- and multiple-SNP association tests, a pathway enrichment analysis was performed to identify the biological significance of SNP markers. Although no significant SNP was found at genome-wide significance level via single-SNP association tests, 59 genetic variants mapped to 76 genes were identified via a multiple SNP approach using a bootstrap selection stability measure. Pathway analysis for these 59 variants showed that maturity onset diabetes of the young (MODY) was enriched. Joint identification of SNPs could enable the identification of multiple SNPs with good predictive power for PA and a pathway enriched for PA. PMID- 25026173 TI - DADS suppresses human esophageal xenograft tumors through RAF/MEK/ERK and mitochondria-dependent pathways. AB - Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro-apoptotic effect of DADS on ECA109 cells was detected by Annexin V FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma. PMID- 25026174 TI - Induction of apurinic endonuclease 1 overexpression by endoplasmic reticulum stress in hepatoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Previous studies have noted the induction of endoplasmic reticulum stress or apurinic endonuclease 1 (APE1) expression in many tumors. Therefore, the aim of this study was to investigate the relationship between endoplasmic reticulum (ER stress) and APE1 in hepatocellular carcinoma. Here we investigate the expression of APE1 during ER stress in HepG2 and Huh-7 cell lines. Tunicamycin or brefeldin A, two ER stress inducers, increased APE1 and GRP78, an ER stress marker, expression in HepG2 and Huh-7 cells. Induction of APE1 expression was observed through transcription level in response to ER stress. APE1 nuclear localization during ER stress was determined using immunofluorescence assays in HepG2 cells. Furthermore, expression of Hepatitis B virus pre-S2? large mutant surface protein (pre-S2?), an ER stress-induced protein, also increased GRP78 and APE1 expression in the normal hepatocyte NeHepLxHT cell line. Similarly, tumor samples showed higher expression of APE1 in ER stress-correlated liver cancer tissue in vivo. Our results demonstrate that ER stress and HBV pre-S2? increased APE1 expression, which may play an important role in resistance to chemotherapeutic agents or tumor development. Therefore, these data provide an important chemotherapeutic strategy in ER stress and HBV pre-S2?-associated tumors. PMID- 25026175 TI - Copy number analysis of 24 oncogenes: MDM4 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer. AB - Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB) were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher's test p=0.023). Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p=0.041). Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients. PMID- 25026176 TI - Ficus carica polysaccharides promote the maturation and function of dendritic cells. AB - Various polysaccharides purified from plants are considered to be biological response modifiers and have been shown to enhance immune responses. Ficus carica L. is a Chinese traditional plant and has been widely used in Asian countries for its anti-tumor properties. Ficus carica polysaccharides (FCPS), one of the most essential and effective components in Ficus carica L., have been considered to be a beneficial immunomodulator and may be used in immunotherapy. However, the immunologic mechanism of FCPS is still unclear. Dectin-1 is a non-toll-like pattern recognition receptor, predominately expressed on dendritic cells (DCs). Activation of DCs through dectin-1 signaling can lead to the maturation of DC, thus inducing both innate and adaptive immune responses against tumor development and microbial infection. In our study, we found that FCPS could effectively stimulate DCs, partially through the dectin-1/Syk pathway, and promote their maturation, as shown by the up-regulation of CD40, CD80, CD86, and major histocompatibility complex II (MHCII). FCPS also enhanced the production of cytokines by DCs, including IL-12, IFN-gamma, IL-6, and IL-23. Moreover, FCPS treated DCs showed an enhanced capability to stimulate T cells and promote T cell proliferation. Altogether, these results demonstrate that FCPS are able to activate and maturate DCs, thereby up-regulating the immunostimulatory capacity of DCs, which leads to enhanced T cell responses. PMID- 25026177 TI - Differential regulation of the calpain-calpastatin complex by the L-domain of calpastatin. AB - Here we demonstrate that the presence of the L-domain in calpastatins induces biphasic interaction with calpain. Competition experiments revealed that the L domain is involved in positioning the first inhibitory unit in close and correct proximity to the calpain active site cleft, both in the closed and in the open conformation. At high concentrations of calpastatin, the multiple EF-hand structures in domains IV and VI of calpain can bind calpastatin, maintaining the active site accessible to substrate. Based on these observations, we hypothesize that two distinct calpain-calpastatin complexes may occur in which calpain can be either fully inhibited (I) or fully active (II). In complex II the accessible calpain active site can be occupied by an additional calpastatin molecule, now a cleavable substrate. The consequent proteolysis promotes the accumulation of calpastatin free inhibitory units which are able of improving the capacity of the cell to inhibit calpain. This process operates under conditions of prolonged [Ca(2+)] alteration, as seen for instance in Familial Amyotrophic Lateral Sclerosis (FALS) in which calpastatin levels are increased. Our findings show that the L-domain of calpastatin plays a crucial role in determining the formation of complexes with calpain in which calpain can be either inhibited or still active. Moreover, the presence of multiple inhibitory domains in native full-length calpastatin molecules provides a reservoir of potential inhibitory units to be used to counteract aberrant calpain activity. PMID- 25026178 TI - Sarcocystis cafferi n. sp. (Protozoa: Apicomplexa) from the African buffalo (Syncerus caffer). AB - Sarcocystis infections have been reported from the African buffalo ( Syncerus caffer ), but the species have not been named. Here we propose a new name Sarcocystis cafferi from the African buffalo. Histological examination of heart (92), skeletal muscle (36), and tongue (2) sections from 94 buffalos from the Greater Kruger National Park, South Africa, and a review of the literature revealed only 1 species of Sarcocystis in the African buffalo. Macrocysts were up to 12 mm long and 6 mm wide and were located in the neck muscles and overlying connective tissue. They were pale yellow; shaped like a lychee fruit stone or cashew nut; turgid or flaccid and oval to round (not fusiform). By light microscopy (LM) the sarcocyst wall was relatively thin. By scanning electron microscopy (SEM), the sarcocyst wall had a mesh-like structure with irregularly shaped villar protrusions (vp) that were of different sizes and folded over the sarcocyst wall. The entire surfaces of vp were covered with papillomatous structures. By transmission electron microscopy (TEM), the sarcocyst wall was up to 3.6 MUm thick and had highly branched villar protrusions that were up to 3 MUm long. The villar projections contained filamentous tubular structures, most of which were parallel to the long axis of the projections, but some tubules criss crossed, especially at the base. Granules were absent from these tubules. Longitudinally cut bradyzoites were 12.1 * 2.7 MUm in size, had a long convoluted mitochondrion, and only 2 rhoptries. Phylogenetic analysis of 18S rRNA and cytochrome C oxidase subunit 1 (cox1) gene sequences indicated that this Sarcocystis species is very closely related to, but distinct from, Sarcocystis fusiformis and Sarcocystis hirsuta. Thus, morphological findings by LM, SEM, and TEM together with molecular phylogenetic data (from 18S rRNA and cox1) confirm that the Sarcocystis species in the African buffalo is distinct from S. fusiformis and has therefore been named Sarcocystis cafferi. PMID- 25026179 TI - Optimal time discrimination. AB - In the temporal bisection task, participants categorize experienced stimulus durations as short or long based on their similarity to previously acquired reference durations. Reward maximization in this task requires integrating endogenous timing uncertainty as well as exogenous probabilities of the reference durations into temporal judgements. We tested human participants on the temporal bisection task with different short and long reference duration probabilities (exogenous probability) in two separate test sessions. Incorrect categorizations were not penalized in Experiment 1 but were penalized in Experiment 2, leading to different levels of stringency in the reward functions that participants tried to maximize. We evaluated the judgements within the framework of optimality. Our participants adapted their choice behaviour in a nearly optimal fashion and earned nearly the maximum possible expected gain they could attain given their level of endogenous timing uncertainty and exogenous probabilities in both experiments. These results point to the optimality of human temporal risk assessment in the temporal bisection task. The long categorization response times (RTs) were overall faster than short categorization RTs, and short but not long categorization RTs were modulated by reference duration probability manipulations. These observations suggested an asymmetry between short and long categorizations in the temporal bisection task. PMID- 25026180 TI - Cytocompatibility and cellular internalization mechanisms of SiC/SiO2 nanowires. AB - First evidence of in vitro cytocompatibility of SiC/SiO2 core-shell nanowires is reported. Different internalization mechanisms by adenocarcinomic alveolar basal epithelial cells, monocytic cell line derived from an acute monocytic leukemia, breast cancer cells, and normal human dermal fibroblasts are shown. The internalization occurs mainly for macropinocytosis and sporadically by direct penetration in all cell models considered, whereas it occurred for phagocytosis only in monocytic leukemia cells. The cytocompatibility of the nanowires is proved by the analysis of cell proliferation, cell cycle progression, and oxidative stress on the cells treated with NWs as compared to controls. Reactive oxygen species generation was detected as an early event that then quickly run out with a rapid decrease only in adenocarcinomic alveolar basal epithelial and human dermal fibroblasts cells. In all the cell lines, the intracellular presence of NWs induce the same molecular events but to a different extent: peroxidation of membrane lipids and oxidation of proteins. The NWs do not elicit either midterm (72 h) or long-term (10 days) cytotoxic activity leading to irreversible cellular damages or death. Our results are important in view of a possible use of SiC/SiO2 core-shell structures acting as biomolecule-delivery vectors or intracellular electrodes. PMID- 25026181 TI - Direct and self-reported measures of physical activity and sedentary behaviours by weight status in school-aged children: results from ISCOLE-Kenya. AB - BACKGROUND: Previous work has shown little association between self-report and directly measured physical activity. The objective of this study was to investigate the relationships between self-reported and directly assessed measures of physical activity and sedentary time by weight status in Kenyan children. METHODS: Direct assessment of body weight, physical activity and sedentary time of 563 children was collected through anthropometry and accelerometry, while self-reported assessment was achieved by administering a questionnaire. RESULTS: Under/healthy weight children had significantly higher directly measured mean daily minutes of moderate-to-vigorous physical activity (MVPA) compared to overweight/obese children (39 vs 20 minutes); had lower mean weekend-day minutes of sedentary time (346 vs 365 minutes); had a higher proportion who met accepted physical activity guidelines (15.3% vs 2.6%); and a higher number reported using active transportation to/from school (49.2% vs 32.4%). Self-reported time spent outside before and after school and active transport to/from school were significantly associated with mean weekday minutes of MVPA (r-value range = 0.12-0.36), but only for the under/healthy weight children. CONCLUSIONS: The results of this study found a number of differences in the accumulation of MVPA and sedentary time by weight status and weak-to-moderate correlations between self-report and direct measures of weekday and weekend-day physical activity among the under/healthy weight children. PMID- 25026182 TI - Non-verbal behaviour in same-sex and mixed-sex physiotherapist-patient interactions(1.). AB - Six male and six female physiotherapists were videotaped while treating male and female patients. The average duration of the therapist's gaze, smiling, touch, and speech, as well as the ratio of therapist's to patient's speech, were computed. It was found that these non-verbal behaviours differed as a function of sex of physiotherapist, sex of patient and point in the interaction. It was suggested that physiotherapists should increase their awareness of these behaviours in their interactions with patients. PMID- 25026183 TI - Personality characteristics of physiotherapy students. AB - Seventy-nine first year physiotherapy students from Lincoln Institute were matched for age and sex with a sample of fifty-two trainee teachers from Melbourne State College. The two samples were compared on personality dimensions as measured by Cattell's Sixteen Personality Factor Inventory. Statistical analysis revealed significant differences on five dimensions; Factors I, M, N, O and Q1. Compared to the teaching students the physiotherapy undergraduates were less tender-minded, more practical and conventional, more forthright, more self assured and more conservative. These results were reasonably consistent with other findings and had implications for professional behaviour and future training of physiotherapists. PMID- 25026184 TI - Male students in the health sciences: a comparison with female health science students and male university students. AB - Increasing numbers of males are entering the health sciences, particularly Physiotherapy. Fifteen males commencing such courses were compared with 252 female students and 30 male university students. Their backgrounds, career aspirations and attitudes were investigated in an attempt to explain their career choices and consider possible future effects on the health professions. Male health science students were older, came from large families of lower socio economic status and were more likely to aspire to leadership positions than female students. None of the characteristics of females who enter male-dominated occupations were found to distinguish males making atypical career choices. It is suggested that the findings have implications for the future of Physiotherapy, particularly in regard to leadership positions. PMID- 25026185 TI - Community knowledge of physiotherapy in a rural victorian town. AB - One hundred subjects (50 males and 50 females) were randomly selected from five different socioeconomic groups within a rural Victorian town. The subjects were asked to indicate from which of four therapy groups they would seek treatment for three specified medical conditions. The subjects indicated a significant preference to seek treatment from a physiotherapist rather than a chiropractor, an osteopath, or a faithhealer for all three conditions. The survey also asked questions about the activities of physiotherapists. In listing these activities many respondents appear to confuse the role of the physiotherapist with those of other health professionals such as nurses, occupational therapists, speech therapists, radiographers and psychologists. Of the sample 47% responded that they had sought treatment from a physiotherapist. It was found that these subjects had a significantly better knowledge of physiotherapy activities than those subjects who indicated no professional contact. PMID- 25026186 TI - Combining the techniques of physiotherapy and behaviour modification. AB - A severely retarded, hemiplegic child who was unable to walk unaided was given a combination of operant conditioning and physiotherapy to teach her the necessary skills for walking. Her progress was assessed daily using operant conditioning equipment and video tape records. The results suggest that behaviour modification offers both viable teaching techniques and methods of objective data collection and evaluation which can contribute to programmes of physiotherapy, occupational therapy, and speech therapy. PMID- 25026187 TI - A multidimensional approach to the assessment of pain. AB - The relative usefulness of various methods of assessment of pain is discussed. It is suggested that keeping an ongoing record of patients' pain is of value both to the patient and to the therapist. PMID- 25026188 TI - Uniform doping of metal oxide nanowires using solid state diffusion. AB - The synthesis of one-dimensional nanostructures with specific properties is often hindered by difficulty in tuning the material composition without sacrificing morphology and material quality. Here, we present a simple solid state diffusion method utilizing atomic layer deposition to controllably alter the composition of metal oxide nanowires. This compositional control allows for modification of the optical, electronic, and electrochemical properties of the semiconductor nanowires. Using this method and a novel process for manganese oxide atomic layer deposition, we produced manganese-doped rutile TiO2 nanowires and investigated their structural and photoelectrochemical properties. A homogeneous incorporation of the Mn dopant into the rutile lattice was observed, and the local chemical environment of the Mn was determined using X-ray absorption spectroscopy. The doping process resulted in a tunable enhancement in the electrocatalytic activity for water oxidation, demonstrating that this simple and general method can be used to control the properties of one-dimensional nanostructures for use in a variety of applications including solar-to-fuel generation. PMID- 25026189 TI - Effect of mitomycin, bevacizumab, and 5-Fluorouracil to inhibit urethral fibrosis in a rabbit model. AB - BACKGROUND AND PURPOSE: Mitomycin C (MMC), bevacizumab, and 5-fluorouracil (5-FU) are frequently used in cancer treatment. Each of these agents also exhibits antiproliferative properties in different tissues. We compared the efficacy of MMC, bevacizumab, and 5-FU may inhibit urethral fibrosis (UF) without statistically significant differences among them. MATERIALS AND METHODS: Forty male rabbits with traumatized urethras were divided into four groups: Group 1 (control), no medical treatment; group 2, MMC applied to the traumatized area; group 3, bevacizumab applied to the traumatized area; and group 4, 5-FU applied to the traumatized area. All animals were euthanized after 28 days to evaluate the presence of chronic inflammation and fibrosis. Tissue samples were subjected to hematoxylin and eosin and Masson trichrome staining to assess the presence of fibrosis, the state of the epithelium, and collagen density. RESULTS: The MMC and control groups showed the most significant difference in outcomes (P<0.001), followed by the bevacizumab (P=0.002) and 5-FU groups (P=0.005). No statistically significant difference was noted when all three treatment groups were compared with one another. Histopathologic examination revealed inflammatory cell infiltration in the connective tissue, irregular collagen bundles, increased fibroblasts, and a moderate degree of fibrosis in the control group. Compared with controls, all treatment groups exhibited mild fibrosis, less collagen bundle irregularity, and lower numbers of fibroblasts. CONCLUSION: MMC, bevacizumab, and 5-FU may inhibit UF. There were no statistically significant differences in the effectiveness among the three agents. PMID- 25026190 TI - Multiplex event-specific qualitative polymerase chain reaction for detecting three transgenic rice lines and application of a standard plasmid as a quantitative reference molecule. AB - The three most well-known genetically modified (GM) rice lines in China are TT51 1, KMD1, and KF6. The purposes of this study were to establish a multiplex event specific qualitative polymerase chain reaction (meqPCR) system for simultaneous detection of the three transgenic rice events and to construct a plasmid as the reference molecule for quantitative analysis. Event-specific primers for each event were selected or designed by focusing on the transgene borders between the inserted DNA and the flanking rice DNA. The developed meqPCR was anticipated to detect distinct amplicons as 454, 398, 301, and 250bp from KF6, KMD1, TT51-1, and the rice endogenous reference gene, respectively. The robustness of the meqPCR was tested with different levels of the three transgenic rice genomic DNAs, and the sensitivity threshold of the meqPCR was at least 50ng of 0.1% rice DNA for each event when the three transgenic rice events present and with other GM materials together. The constructed plasmid was evaluated using mixed samples with known GM contents in real-time quantitative PCR. The results indicated that the constructed plasmid was acceptable and suitable for GM rice quantitative analysis. PMID- 25026192 TI - Regioselective synthesis and molecular structure of the first derivative of praseodymium-containing metallofullerenes. AB - Regioselective cycloaddition of adamantylidene carbene to Pr@C(2v)(9)-C82 affords the first derivative of praseodymium-containing metallofullerenes. Single-crystal X-ray crystallographic data in combination with theoretical studies demonstrate that the addition is dictated by the single metal ion encapsulated inside the fullerene cage. PMID- 25026191 TI - Antifungal terpenoids from Hyalis argentea var. latisquama. AB - A detailed chemical study of the aerial parts and rhizomes of Hyalis argentea var. latisquama yielded a variety of sesqui- and diterpenes. In total, 26 compounds were isolated and identified, of which four are new, namely, two ent kaurenes (1 and 2), a diterpene lactone (3), and a lindenanolide (4). The previously reported compounds included a series of lindenanolides, guaianolides, elemanolides, and additional diterpenes. The antifungal activity of the isolated compounds was tested against Cryptococcus neoformans and Candida albicans. Among the isolated compounds, the lindenanolides were the only structural class that showed strong antifungal activity, and onoseriolide acetate (5) was the most active. On the other hand, the isolated guaianolides were only moderately active, while the diterpenes did not show significant antifungal activity. PMID- 25026193 TI - Amine-based solvents for exfoliating graphite to graphene outperform the dispersing capacity of N-methyl-pyrrolidone and surfactants. AB - Four organic amine-based solvents were discovered which enable direct exfoliation of graphite to produce high-quality and oxygen-free graphene nanosheets. These solvents outperform previously used solvents and additives such as N-methyl pyrrolidone and surfactants in terms of their dispersing capacity. The resulting dispersions allow the facile fabrication of zeolitic imidazolate framework (ZIF) graphene nanocomposites with remarkable CO2 storage capability. PMID- 25026194 TI - Movement dysfunction in patients with Parkinson's disease: A literature review. AB - Experimental evidence has shown that people with Parkinson's disease have deficits in the initiation and execution of movements. The delay in response initiation may be due to impairment in the organisation or translation of motor programs into muscle actions. The slowness in the execution of simple movements may result from inappropriate scaling of muscle activity, defective predictive function or defective memory for the computed forces. Extra slowness in the execution of complicated concurrent movements appears to be a result of deficits in switching from one program to another within a motor plan in sequential movements, or in superimposition of motor programs to form a motor plan in simultaneous movements. PMID- 25026195 TI - Weightbearing during comfortable stance in patients with stroke: Accuracy and reliability of measurements. AB - This study was designed to describe the accuracy and intrasession reliability of weightbearing measurements obtained with digital bathroom scales during comfortable bilateral upright stance in patients with stroke. The 20 subjects were all independently ambulatory with a unilateral assistive device. Their weightbearing during comfortable stance was measured over three trials. Analysis of variance revealed that the sum of the weightbearing measurements of the paretic and nonparetic sides did not differ significantly from total body weight. Thus, the measurements were considered accurate. Some variability in the weightbearing measurements was demonstrated with analysis of variance, which revealed significant differences between trials on both sides. Nevertheless, reliability as described by intraclass correlation coefficients was good (0.829 paretic side, 0.876 nonparetic side). Although such reliability is sufficient to justify clinical use, methods for increasing reliability should be examined. PMID- 25026196 TI - Ultrasound treatment for breast engorgement: A randomised double blind trial. AB - The aim of this study was to test the efficacy of thermal ultrasound therapy as a treatment for severe post partum breast engorgement. A randomised double-blind, placebo-controlled trial was conducted on 197 breasts. Two ultrasound machines of identical appearance were used. One was working normally, the other had the crystal replaced with a resistor producing surface heat only. Assessment of effectiveness was subjective, using visual analogue scales for pain and hardness, and objective, using tonometry. Results indicate that both the true and sham machines were effective in reducing subjectively perceived pain and hardness. However, the results of this study show that the effect cannot be attributed to the ultrasound component. PMID- 25026197 TI - Variation in the provision of cardiothoracic physiotherapy in Australian hospitals. AB - The chief physiotherapists of 47 Australian metropolitan public hospitals were asked about the hours of provision and organisation of cardiothoracic physiotherapy services. Forty three per cent provided physiotherapy services only during the day, 12 per cent during the day and evening, and 45 per cent provided 24-hour coverage. Variation among the states was found in the provision of cardiothoracic physiotherapy. Most hospitals which provided 24-hour coverage used on-call. Thirty three per cent of hospitals rostered staff to work during the evening and only 7 per cent had rostered night shifts. Differences could not be attributed to variations in hospital size. The implications of these findings for the physiotherapy profession and patient care are discussed and the need for further research highlighted. PMID- 25026198 TI - Grannies, elders, and friends: aging Aboriginal women in Toronto. AB - Based on a research project in Toronto, Canada, this article highlights the strengths and resiliency of 12 female Aboriginal Elders and seniors as they age together. For these women, being actively involved in their families and the Aboriginal community gives them a solid grounding in who they are, what their roles are and how they contribute to the whole. Of particular significance is the support and friendship the women offer each other through their commonalities, activities, and sense of humor. PMID- 25026199 TI - Utility of RNA-seq and GPMDB protein observation frequency for improving the sensitivity of protein identification by tandem MS. AB - Tandem mass spectrometry (MS/MS) followed by database search is the method of choice for protein identification in proteomic studies. Database searching methods employ spectral matching algorithms and statistical models to identify and quantify proteins in a sample. In general, these methods do not utilize any information other than spectral data for protein identification. However, considering the wealth of external data available for many biological systems, analysis methods can incorporate such information to improve the sensitivity of protein identification. In this study, we present a method to utilize Global Proteome Machine Database identification frequencies and RNA-seq transcript abundances to adjust the confidence scores of protein identifications. The method described is particularly useful for samples with low-to-moderate proteome coverage (i.e., <2000-3000 proteins), where we observe up to an 8% improvement in the number of proteins identified at a 1% false discovery rate. PMID- 25026200 TI - ColBioS-FlavRC: a collection of bioselective flavonoids and related compounds filtered from high-throughput screening outcomes. AB - Flavonoids, the vastest class of natural polyphenols, are extensively investigated for their multiple benefits on human health. Due to their physicochemical or biological properties, many representatives are considered to exhibit low selectivity among various protein targets or to plague high throughput screening (HTS) outcomes. The aim of this study is to highlight reliable, bioselective compounds sharing flavonoidic scaffolds in HTS experiments. A filtering scheme was applied to remove undesired flavonoids (and related compounds) from confirmatory PubChem bioassays. A number of 433 compounds addressing various protein targets form the core of the collection of bioselective flavonoids and related compounds (ColBioS-FlavRC). With an additional set of 2908 inactive related compounds, ColBioS-FlavRC offers the grounds for method optimization and validation. We exemplified the use of ColBioS FlavRC by pharmacophore modeling, subsequently (externally) validated for virtual screening purposes. The early enrichment capabilities of the pharmacophore hypotheses were measured by means of the median exponential retriever operating curve enrichment (MeROCE), a suited metric in comparative evaluations of virtual screening methods. ColBioS-FlavRC is available in the Supporting Information and is freely accessible for further studies. PMID- 25026201 TI - Effects of low doses of quercetin and genistein on oxidation and carbonylation in hemoglobin and myoglobin. AB - Protein-bound carbonyls have been shown to increase with age as well as in numerous diseases including rheumatoid arthritis, adult respiratory syndrome pulmonary fibrosis, diabetes, Parkinson's disease, and Alzheimer's just to mention a few. The effects of the flavonoids quercetin and genistein were investigated according to their ability to inhibit the oxidation of hemoglobin and myoglobin via the Fenton's pathway. Antioxidative activity of the flavonoids were determined by oxidizing hemoglobin and myoglobin in separate experiments with 50 MUM Fe(2+) and 0.01 mM hydrogen peroxide (H2O2) with and without quercetin and/or genistein. The samples were treated singly with either quercetin, genistein, or in combination at concentrations of 1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 MUM, respectively, dissolved in dimethyl sulfoxide (DMSO). Samples were then incubated in a water bath at 37 degrees C for 8, 12, and 24 hr, respectively. Levels of carbonylation were assayed by the protein carbonyl assay and the carbonyl levels quantified and expressed per mg of protein. The results indicate that protein carbonyls for samples treated with quercetin or genistein decreased in a dose-dependent manner compared to the controls. That of quercetin compared to genistein was more efficient in reducing the levels of protein carbonylation in hemoglobin and myoglobin, respectively. The combination of both flavonoids did show a gradual decrease in carbonyl compounds for only hemoglobin for all the doses and times tested. The results indicate that both flavonoids at low doses inhibited carbonylation in both hemoglobin and myoglobin and the inhibition may be attributed to the prevention of protein oxidation. PMID- 25026202 TI - Absence of furanocoumarins in Advantra Z(r) (Citrus aurantium, bitter orange) extracts. AB - Grapefruit (Citrus paradisi) juice is known for its ability to alter drug metabolism through inhibition of the cytochrome P450-3A4 (CYP3A4) system, and result in drug-food interactions that may be life threatening. The primary active ingredients in grapefruit responsible for these effects are the furanocoumarins bergapten, bergamottin, and 6',7'-dihydroxybergamottin (DHB). Bergamottin and DHB appear to be the most important in terms of adverse drug interactions. Furanocoumarins are present in the juices and fruits of other Citrus species including C. aurantium (bitter oranges). Bergapten is the predominant furanocoumarin in bitter orange. Bitter orange extracts are widely used in products associated with weight loss, sports performance, and energy production. Questions have been raised about the potential of bitter orange extracts to cause drug interactions. This study examined the furanocoumarin content of four standardized bitter orange extracts (Advantra Z(r)) by liquid chromatography-mass spectroscopy. The results indicated that the total furanocoumarin content of each of the four extracts was less than 20 MUg/g, amounts insufficient to exert significant effects on the metabolism of susceptible drugs in human subjects at the doses commonly used for these extracts. PMID- 25026203 TI - Prostate cancer cells alter the nature of their calcium influx to promote growth and acquire apoptotic resistance. AB - In this issue of Cancer Cell, Dubois and colleagues report a remodeling of calcium influx in prostate cancer cells. Prostate cancer cells can undergo an oncogenic switch from a calcium influx pathway capable of inducing apoptosis involving ORAI1 channels to a pro-proliferative calcium influx pathway involving ORAI1/3 heteromeric channels. PMID- 25026204 TI - Sox2: masterminding the root of cancer. AB - The transcription factor Sox2 is a master regulator that maintains stemness in embryonic stem cells and neural stem cells. Using elegant lineage tracing strategies and genetic reporter mouse models, two studies (one of which is by Vanner and colleagues in this issue of Cancer Cell) now demonstrate that rare Sox2-expressing cells are the founding cancer stem cell population driving tumor initiation and therapy resistance. PMID- 25026205 TI - Metabolic asymmetry in cancer: a "balancing act" that promotes tumor growth. AB - Profound metabolic differences between cancer cells and fibroblasts promote tumorigenesis. A study by Valencia and colleagues in this issue of Cancer Cell supports this assertion. They observed that metabolic asymmetry in prostate tumors drives aggressive disease with high p62 in anabolic cancer cells, but loss of p62 in catabolic fibroblasts. PMID- 25026206 TI - Promising rationally derived combination therapy with PI3K and CDK4/6 inhibitors. AB - In this issue of Cancer Cell, Vora and colleagues demonstrate that persistent CDK4 and pRB activation underlie acquired resistance to phosphatidylinositol 3 kinase (PI3K) inhibitors in breast cancer cell lines, suggesting that clinical evaluation of rational combination therapy with PI3K and CDK4/6 inhibitors to mitigate resistance to PI3K inhibition is warranted. PMID- 25026207 TI - RhoA mutations identified in diffuse gastric cancer. AB - The diffuse-type histologic variant of gastric cancer is characterized by highly invasive growth patterns and lack of cellular cohesion. Two recent studies have identified highly recurrent mutations of the gene encoding the small GTPase RhoA and suggest that RhoA activity may have a tumor suppressive role in this disease. PMID- 25026208 TI - Ibrutinib treatment of CLL: the cancer fights back. AB - Ibrutinib is a potent inhibitor of Bruton's tyrosine kinase (BTK). Studies published in the New England Journal of Medicine report that patients with chronic lymphocytic leukemia (CLL) have durable responses to ibrutinib, but they also describe the advent of bypass mutations that result in ibrutinib resistance and progressive disease. PMID- 25026209 TI - Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. PMID- 25026210 TI - Response to Chauhan et Al.: interstitial pressure and vascular collapse in pancreas cancer-fluids and solids, measurement and meaning. PMID- 25026211 TI - Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. AB - It is currently unclear whether Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at the plasma membrane or by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. We found that derepressed CRL4(DCAF1) promotes YAP- and TEAD-dependent transcription by ubiquitylating and, thereby, inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2-mutant tumors. We conclude that derepressed CRL4(DCAF1) promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus. PMID- 25026214 TI - The elusive rat model of conditioned placebo analgesia. AB - Recent research on human placebo analgesia has suggested the need for rodent models to further elucidate the neural substrates of the placebo effect. This series of 3 experiments therefore was performed in an attempt to develop a model of placebo analgesia in rats. In each study, female Sprague-Dawley rats received an L5 spinal nerve ligation to induce a neuropathic pain condition. Each rat then underwent a 4-day conditioning procedure in which an active analgesic drug or its vehicle (unconditioned stimulus) was associated with the following cues (conditioned stimuli): novel testing room (environmental), vanilla scent cue (olfactory), dim incandescent lighting (visual), restraint procedure/injection (tactile), and time of day and injection-test latency (temporal). The analgesics for each experiment were as follows: Experiment 1 used 90 mg/kg gabapentin, experiment 2 used 3mg/kg loperamide hydrochloride, and experiment 3 used 6 mg/kg morphine sulfate. On the following test day, half of the animals received the opposite treatment, resulting in 4 conditioning manipulations: drug/drug, drug/vehicle, vehicle/drug, and vehicle/vehicle. Nociceptive thresholds were assessed with the mechanical paw withdrawal threshold test each day after the conditioning procedure. In all 3 experiments, no significant differences were detected on test day between control and placebo groups, indicating a lack of a conditioned placebo analgesic response. Our results contrast with prior research that implies the existence of a reliable and robust response to placebo treatment. We conclude that placebo analgesia in rats is not particularly robust and that it is difficult to achieve using conventional procedures and proper experimental design. PMID- 25026215 TI - The effects of shift work and time of day on fine motor control during handwriting. AB - Handwriting is an elaborate and highly automatised skill relying on fine motor control. In laboratory conditions handwriting kinematics are modulated by the time of day. This study investigated handwriting kinematics in a rotational shift system and assessed whether similar time of day fluctuations at the work place can be observed. Handwriting performance was measured in two tasks of different levels of complexity in 34 shift workers across morning (6:00-14:00), evening (14:00-22:00) and night shifts (22:00-6:00). Participants were tested during all three shifts in 2-h intervals with mobile testing devices. We calculated average velocity, script size and writing frequency to quantify handwriting kinematics and fluency. Average velocity and script size were significantly affected by the shift work schedule with the worst performance during morning shifts and the best performance during evening shifts. Our data are of high economic relevance as fine motor skills are indispensable for accurate and effective production at the work place. PRACTITIONER SUMMARY: Handwriting is one of the most complex fine motor skills in humans, which is frequently performed in daily life. In this study, we tested handwriting repeatedly at the work place in a rotational shift system. We found slower handwriting velocity and reduced script size during morning shifts. PMID- 25026216 TI - A DFT + U study of acetylene selective hydrogenation over anatase supported PdaAgb (a + b = 4) cluster. AB - It is well known that the addition of Ag into Pd can promote the selectivity of acetylene hydrogenation to ethylene, and early theoretical studies focus on ideal single crystal model catalysts, so it is worth studying relatively realistic catalyst models, such as metal oxide supported PdAg systems. In this work, the reaction mechanisms for acetylene selective hydrogenation on the anatase TiO2(101) supported PdaAgb (a + b = 4) cluster are studied by density functional theory calculations with a Hubbard U correction. The results show that Ag addition to the Pd4 cluster reduces the interaction between the PdAg cluster and the support, and the possible reason is that the amount of electron transfer from the TiO2 support to the PdAg cluster decreases with increasing number of Ag atoms. Consequently the adsorption energies of acetylene and ethylene would become smaller on the anatase supported PdAg cluster as compared to that on the anatase supported Pd4 cluster, and this may help to enhance the selectivity of ethylene formation. Moreover, the reaction kinetics study of acetylene hydrogenation on anatase TiO2(101) supported PdAg cluster shows that the activation energy of the hydrogenation step is higher on the PdAg cluster than that on the pure Pd4 cluster, and thus reduces its catalytic activity. Importantly, the present calculation results suggested that the selectivity of ethylene formation, which is defined as the energy difference between the adsorption energy of ethylene and the barrier for its further hydrogenation, varies with the ratio of Pd/Ag in the PdAg cluster: the Pd3Ag system shows relatively low selectivity compared to that of the pure Pd4 cluster, whereas Pd2Ag2/PdAg3 displays higher selectivity than that of the pure Pd4 cluster. Furthermore, our present results demonstrated that the anatase support plays a key role in the acetylene hydrogenation processes: on one hand, it reduces the reaction activity of acetylene hydrogenation processes compared to the Pd2Ag2/Pd(111) and Pd2Ag2 clusters; on the other hand, it enhances the selectivity of ethylene due to its lower desorption energy. It was also found that the carbon species inside the Pd2Ag2 cluster has little effect on the catalytic selectivity towards ethylene formation, whereas the hydrogenation catalytic activity is enhanced significantly. Finally the role of the Pd2Ag2 anatase interface on the catalytic properties of acetylene hydrogenation was studied, and it was found that the interface can increase the activity of acetylene hydrogenation but the selectivity is not improved. PMID- 25026212 TI - Hematogenous metastasis of ovarian cancer: rethinking mode of spread. AB - Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3 neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis. PMID- 25026213 TI - Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression. AB - In selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the Lys48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer. PMID- 25026217 TI - Light-driven artificial enzymes for selective oxidation of guanosine triphosphate using water-soluble POSS network polymers. AB - The light-driven artificial enzymes were constructed to realize unnatural reactions concerning bio-significant molecules. In this manuscript, the guanosine triphosphate (GTP)-selective oxidation is reported using the network polymers composed of polyhedral oligomeric silsesquioxane (POSS). We synthesized the water soluble POSS network polymer containing the naphthyridine ligands to capture GTP inside the networks and the ruthenium complexes to oxidize the captured GTP under light irradiation. Initially, the binding affinities of the guanosine nucleosides to the naphthyridine ligand inside the POSS network polymer were evaluated from the emission quenching experiments. Accordingly, it was observed that the naphthyridine ligand can form the stable complex only with GTP (K(a) = 5.5 * 10(6) M(-1)). These results indicate that only GTP can be captured by the network polymer. Next, the photo-catalytic activity of the ruthenium complex-modified POSS network polymer was investigated. Finally, it was revealed that the network polymer can decompose GTP efficiently under light irradiation. This is the first example, to the best of our knowledge, to offer not only the GTP-selective host polymers but also the light-driven artificial enzyme for GTP oxidation. PMID- 25026218 TI - Prediction of protein structure classes by incorporating different protein descriptors into general Chou's pseudo amino acid composition. AB - Successful protein structure identification enables researchers to estimate the biological functions of proteins, yet it remains a challenging problem. The most common method for determining an unknown protein's structural class is to perform expensive and time-consuming manual experiments. Because of the availability of amino acid sequences generated in the post-genomic age, it is possible to predict an unknown protein's structural class using machine learning methods given a protein's amino-acid sequence and/or its secondary structural elements. Following recent research in this area, we propose a new machine learning system that is based on combining several protein descriptors extracted from different protein representations, such as position specific scoring matrix (PSSM), the amino-acid sequence, and secondary structural sequences. The prediction engine of our system is operated by an ensemble of support vector machines (SVMs), where each SVM is trained on a different descriptor. The results of each SVM are combined by sum rule. Our final ensemble produces a success rate that is substantially better than previously reported results on three well-established datasets. The MATLAB code and datasets used in our experiments are freely available for future comparison at http://www.dei.unipd.it/node/2357. PMID- 25026219 TI - Structural characteristics and mechanical and thermodynamic properties of nanocrystalline TiO2. PMID- 25026220 TI - Predictive value of early serum cytokine changes on long-term interferon beta-1a efficacy in multiple sclerosis. AB - BACKGROUND: In a previous study, we had evaluated short-term effects of interferon beta-1a (IFNB-1a) 44 MUg s.c. three times per week treatment on serum levels of IFN-gamma (IFNG), IL-23, IL-17, IL-10, IL-9, IL-4 and TGF-beta (TGFB) and found a reduction only in IL-17 and IL-23 levels after 2 months of treatment. METHODS: Using the same multiple sclerosis (MS) cohort, we assessed the predictive value of early cytokine level changes (difference between 2nd month and baseline levels as measured by ELISA) on the efficacy of long-term IFNB-1a treatment. RESULTS: The alteration in IFNG levels of patients without any relapse was statistically lower than that of patients having one or more relapses (p = 0.019, Student's t-test). When patients with or without expanded disability severity scale (EDSS) progression were compared, none of the cytokine level changes showed a significant difference between groups. IL-17 and IL-23 level changes did not predict relapse and EDSS progression in IFNB-1a-treated MS patients. CONCLUSION: Our results show that the predictive power of early IFNG measurement on relapse occurrence may potentially extend a time span of several years. PMID- 25026221 TI - Solution-processable low-voltage and flexible floating-gate memories based on an n-type polymer semiconductor and high-k polymer gate dielectrics. AB - High-performance low-voltage flash memories based on organic floating-gate field effect transistors are prepared by a solution process for the first time. Transistors with a high-mobility n-type polymer semiconductor, poly{[N,N(')-bis(2 octyldodecyl)naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2' bithiophene)}, and a high-k polymer gate dielectric, poly(vinylidene fluoride trifluoroethylene-chlorofluoroethylene) (k ~ 60), are successfully fabricated on flexible substrates. A thin layer of Au nanoparticles is embedded in the gate dielectric, which can store injected charge from the channel and result in a memory effect. The organic memories demonstrate high carrier mobilities (>0.3 cm(2)/(V s)), low program/erase voltages (+/-6 V), little degradation after 10(5) program/erase cycles, and good retention after 10(5) s, which suggest great promise in the application of nonvolatile memories in flexible electronics. PMID- 25026222 TI - Interferential therapy. AB - Interferential Therapy is a "new-comer" to the field of physical medicine, but it is gradually acquiring a particular identity. As the name implies, a current is generated within the tissues as a result of the interaction of two separate circuits. It can therefore be appreciated that four electrodes are required, two for each circuit. The two currents generated by the unit are medium frequency currents in the 4000 cycle per second range. One of these can be varied so that it is slightly out of phase with the other in such a way that a low frequency beat is generated where the two currents cross within the tissues, and this is equal to the difference between the two medium frequencies. The interferential current produced is an evenly alternating sinusoidal one, without polar effects (Diagram 1). Its frequency can be varied from 0 to 100 or 150, depending on the unit. It is evident that such a current can be made to scan the tissues more deeply, more accurately and more widely than the old sinusoidal current, depending on the way electrodes are placed, to determine where the low frequency current will be produced. Further, it has less superficial sensory effect, provided it is applied correctly. It is undoubtedly an effective therapy for controlling pain. PMID- 25026223 TI - An inpatient observation and comparison of the bennett's I.p.p.R. And aerosol methods of administering salbutamol. AB - Compared with aerosol administration the Bennett's Intermittent Positive Pressure Respirator (I.P.P.R.) has been the most favoured method of Salbutamol administration in hospitals for the treatment of asthma or Chronic Obstructive Airways Disease (C.O.A.D.). PMID- 25026224 TI - Physiotherapy and lung disease in children. AB - An understanding of normal development and normal function of the lung is essential to appreciate the physiological derangements which occur with lung disease. PMID- 25026225 TI - Patient referral and the physiotherapist. AB - In a radio interview earlier this year a chiropractor was asked: "What do you see as the role of physiotherapists?" His answer was interesting. "The physiotherapist is basically a second string practitioner. He is not a first contact practitioner; he doesn't directly contact the patient; he must go through the medical profession; and we feel that the physiotherapist could be used in a similar fashion by the chiropractor to provide massage and passive mobilization for the patient."(2.) PMID- 25026226 TI - Relaxation as a means of pain control. AB - The effectiveness of relaxation techniques as a means of increasing pain threshold and pain tolerance and of decreasing anxiety was tested. Forty-two physiotherapy students were divided into experimental and control groups and tested on pain threshold, pain tolerance and anxiety. The 21 experimental group subjects were given one session of relaxation and then re-tested. Their results showed that a single session of relaxation significantly increased their pain threshold and pain tolerance and decreased their anxiety about the situation. No such changes were noted when the control group was re-tested. PMID- 25026227 TI - Oxidation of isohumulones induces the formation of carboxylic acids by hydrolytic cleavage. AB - The degradation of isohumulones in mechanistic experiments was investigated. Incubation of trans-isohumulone in the presence of l-proline led to the formation of carboxylic acids and their corresponding proline amides. In the context of isohumulones unknown amides were verified first in model incubations and then in beer for the first time by comparison with authentic reference standards via LC MS analyses. Carboxylic acids and amides were formed preferably under oxidative conditions and increasing pH. Stable isotope experiments excluded the incorporation of molecular oxygen into carboxylic acids, strongly indicating a hydrolytic mechanism via beta-dicarbonyl cleavage. The proposed mechanism includes oxidation and thereby incorporation of molecular oxygen to the isohumulone ring structure followed by hydrolytic cleavage leading to acids and amides. PMID- 25026228 TI - Movement notation. AB - This paper will first discuss the reasons why people invent systems of movement notation and some of the problems they may encounter in so doing. A review of a few notation systems from the past will illustrate ways in which these problems have been tackled. Second, some detail will be given of a notation system which describes movement not only in terms of what is done but also how it is done. PMID- 25026229 TI - An introduction to benesh movement notation and its relevance to physiotherapy. AB - During the last few years attention has been concentrated on the analysis of movement in patients with disorders of the central nervous system. The phenomenon of movement has been looked at not as the operation of a mechanism made up of individual parts, but as the result of the integration of motor patterns in the central nervous system. The traditional neurological examination is inadequate for the assessment of movement patterns and as a result a specific method called "motoscopic" examination has been developed for this purpose. This has been described elsewhere (Milani Comparetti and Gidoni, 1967) and consists of the systematic visual observation of: (a) spontaneous posture and motor behaviour, (b) the performance of a series of movements as requested by the examiner (c) patterns of movement under certain stimulus conditions. PMID- 25026230 TI - ASSESSMENT PICTOGRAPHY: A Pictographic Assessment and Treatment Record. AB - The author's intention in developing assessment pictography (ASPI) was to provide a fully diagrammatic and freehand recording system with wide application in physiotherapy. In its present form ASPI allows recording of the results from five basic aspects of assessment and the recording of one area of treatment, as follows: Active Movement Test Movement tested. Starting position. Range of movement and estimated normal range. Pain during movement. Passive Movement Test Movement tested. Starting position. Range of movement and estimated normal range. Pain during movement. Abnormal resistance during movement. Muscle Strength Grading, Isometric Test "Movement" tested. Starting position. Intensity of muscle contraction. Pain during test. Functional Ability Test Activity tested. Level of ability. Passive Treatment Techniques Type of technique. Manner of delivery. Movement treated. PMID- 25026231 TI - Physiotherapy and ballet dancing. AB - The relationship of the physiotherapist to the athlete and dancer is twofold; he must be both teacher and healer. A teacher not only in exercise programmes, in the use of their tools of trade, their bodies and its bio-mechanics. A physiotherapist looking after ballet dancers must be a trained observer in movement and have an awareness of the movements that are required by a dancer. PMID- 25026232 TI - Sporting and industrial injuries. AB - Legally, sporting injuries are of two kinds-they may occur to the participants in a game or to spectators who are observing the progress of a sport. PMID- 25026233 TI - Some economic aspects of recreational injuries. AB - This paper deals with some basic features of accidents in recreation and will attempt to throw some light on their economic consequences. Let us examine sport as one aspect of recreation. As Williams (1973) put it, "Sport is a phenomenon of simple definition, but with well recognised features. It is essentially recreational, essentially physical, frequently competitive and always contrived." The number and type of participants has increased, along with the range of activities available. Classifications of sport, at best, are arbitrary but nevertheless are useful for analysis. These divisions may be land/air/water types; indoor/outdoor; team/individual; body contact/non-contact/vehicular; amateur/professional. Sports injuries are of two types, intrinsic or self inflicted (Williams, 1973) and extrinsic. Intrinsic injuries refer to those as a result of over-use (leading, for example, to stress fractures) and to specific incidents not involving outside agents. Extrinsic injuries are caused by contact with external objects and form the bulk of injuries sustained in body-contact, vehicular (horses, cars, skis) and environmental-type sports. Extrinsic injuries are generally more severe because greater forces and velocities are involved. Appendix 1 lists the main sporting activities according to location of sport; individual or team participation; likelihood of extensive body contact; and professional status. Professional players not only suffer loss of earning capacity but may reflect a bad investment for an entrepreneur or reduce spectator attendance and gate taking. It is apparent that team sports, having substantial body contact, face a higher risk of moderate to serious injury than do individual, non-contact sports, although major injuries can be sustained in the latter, for example, sprains and dislocations in athletics, golf, tennis, etc. Other sports must be classed as dangerous because of the nature of competition, for example, motor racing and flying. These particulars were collated during a survey on economic aspects of sport undertaken by the author in 1971-72 in Queensland. Some indication of the proportion of sport participants in the total Queensland population is given in Table 1. PMID- 25026234 TI - Physiotherapy and industrial injuries. AB - The Trade Union Clinic is situated centrally in the large industrial area west of Melbourne. It was established nine years ago by the Australasian Meat Industry Employees Union, to give adequate treatment to the large number of meat workers and others in the surrounding areas. PMID- 25026235 TI - "Don'T worry it's only pain": physiotherapy and sporting injuries. AB - The end result of any physiotherapeutic treatment should be rehabilitation of the patient, so that he may function in his chosen role in the community, be it sporting, wage earning, or within the family circle, as far as his physical and mental health allows. PMID- 25026236 TI - Rhizolysis: a physiotherapist's report. AB - In the Australian medical and paramedical fields considerable interest has been stirred by percutaneous rhizolysis, the procedure introduced here by Dr. W. E. Skyrme Rees, M.B., Ch.B., F.R.C.S. The technique itself comes under intensive scrutiny. In theory the technique is a "percutaneous bilateral section of the posterior primary rami", either lumbar or cervical. PMID- 25026237 TI - Acupuncture and physiotherapy. AB - Two months ago, while researching in Hong Kong, I was sent an Australian newspaper reporting a visit to Sydney by Professor Simpson, professor of Anaesthesia at London Hospital. He was quoted as having said; "Acupuncture seemed to have an exciting potential in medical science. It is going to have a very great impact in the practice of anaesthesia" and later, "The apparent success of acupuncture may be explained on the grounds that the needles distracted the patient's attention from the main course of pain". PMID- 25026238 TI - Anthropometry for the physiotherapist: arm reach boundaries for operation of cockpit controls. AB - The systematic measurement of body dimensions, using special instruments, is known as anthropometry and data produced by these measurements are used not only to determine the size and shape of equipment but also to define workspaces. If a workplace is being designed or improved to suit just one person, men only his individual measurements are required for the specifications. However, if the equipment or workspace is to be shared by many individuals of varying sizes and proportions, it is essential that measurements of a representative sample of the using population be taken. In the latter case, the data must be assembled and analysed so that the dimensions selected for design will be suitable for the majority of operators. If necessary, appropriate adjustments to cater for the range of sizes indicated by the measurements of the subject sample may be added to allow comfortable or posturally safe conditions for the total using population. Guides to equipment design using anthropometric data have been published by Damon, Stoudt and McFarland (1971) and Morgan, Cook, Chapanis and Lund (1963). PMID- 25026239 TI - Airways obstruction in children. AB - Over the past decade physiotherapy has played an increasingly important role in the treatment of airways obstruction. Obviously, the same basic principles of treatment apply to both children and adults-however, I wish to emphasise differences which exist, because of differences in years, from the neo-nate to the adolescent. PMID- 25026240 TI - Facilitation between extensor carpi radialis and pronator teres in humans: a study using a post-stimulus time histogram method. AB - Group I muscle afferents modulate the excitability of motor neurons through excitatory and inhibitory spinal reflexes. Spinal reflex relationships between various muscle pairs are well described in experimental animals but not in the human upper limb, which exhibits a fine control of movement. In the present study, spinal reflexes between the extensor carpi radialis (ECR) and pronator teres (PT) muscles were examined in healthy human subjects using a post-stimulus time histogram method. Electrical stimulation of low-threshold afferents of ECR nerves increased the motor neuron excitability in 31 of 76 PT motor units (MUs) in all eight subjects tested, while stimulation of low-threshold afferents of PT nerves increased the motor neuron excitability in 36 of 102 ECR MUs in all 10 subjects. The estimated central synaptic delay was almost equivalent to that of homonymous facilitation. Mechanical stimulation (MS) of ECR facilitated 16 of 30 PT MUs in all five subjects tested, while MS of PT facilitated 17 of 30 ECR MUs in all six subjects. These results suggest excitatory reflex (facilitation) between PT and ECR. Group I afferents should mediate the facilitation through a monosynaptic path. PMID- 25026241 TI - Physical aspects of planning for retirement. AB - The paper reviews evidence for the beneficial effects of aerobic exercise on the cardiovascular health of elderly persons. It makes a clear distinction between these benefits and those obtained with the anaerobic routines usually used with this group. It is suggested that physiotherapists have a role now and in the future in developing programmes for the growing number of older people in the community. The results obtained by some older exercisers who took part in one innovative programme run by the WAIT (Western Australian Institute of Technology) are briefly described. PMID- 25026242 TI - Therapeutic ultrasound in post-partum breast engorgement. AB - Two cases are described, one being breast engorgement 3 days after delivery, the other an incipient breast abscess occurring 4 months after delivery. Both were treated successfully with continuous ultrasound. PMID- 25026243 TI - MOTHERS SPEAK TO PROFESSIONALS: aspects of the NWAC meeting of mothers of disabled children significant to physiotherapists. AB - This paper summarizes the results of a conference attended by mothers of disabled children. A woman who has given birth to a disabled child belongs to one of the most disadvantaged groups in society. She faces physical, emotional and financial problems. She has little prospect of leading a normal life. She does not complain, and asks for very little-and not for herself but for her special child and her family. The major needs are for immediate, accurate, and honest information, sensitively presented, for appropriate support at the right time; for relief from the intense and intensive caring situation, and from the financial burdens of having a handicapped child. She asks for better community acceptance and a reduction of the intolerable isolation and discrimination as a result of being different. Finally, she would like to know that her child will be able to maintain, independently of herself, the lifestyle she has worked so hard to provide. PMID- 25026244 TI - The frequency of Th17 and Th22 cells in patients with colorectal cancer at pre operation and post-operation. AB - T helper 17 (Th17) and Th22 cells regulate the development of tumors. However, their roles in the development of colorectal cancer (CRC) are still unclear. A total of 49 patients with CRC and 18 healthy controls (HC) were evaluated for the percentages of circulating Th17 and Th22 cells by flow cytometry. The concentrations of serum interleukin-17A (IL-17A), IL-22 and carcinoembryonic antigen (CEA) were examined. The levels of IL-17A and IL-22 in tumors were determined by real-time PCR. We found that the percentages of Th17 and Th22 cells in the CRC patients were significantly lower than that in the HC and were associated negatively with the pathological stages of CRC. The levels of IL-17A and IL-22 mRNA transcripts were lower in the tumor tissues, particularly in the advanced CRC. After the tumor resection, the percentages of circulating Th17 and Th22 cells increased. These data suggest that decreased Th17 and Th22 responses may be associated with the development of CRC. PMID- 25026245 TI - Competitive displacement of sodium caseinate by low-molecular-weight emulsifiers and the effects on emulsion texture and rheology. AB - Low-molecular-weight (LMW) emulsifiers are used to promote controlled destabilization in many dairy-type emulsions in order to obtain stable foams in whippable products. The relation between fat globule aggregation induced by three LMW emulsifiers, lactic acid ester of monoglyceride (LACTEM), saturated monoglyceride (GMS), and unsaturated monoglyceride (GMU) and their effect on interfacial protein displacement was investigated. It was found that protein displacement by LMW emulsifiers was not necessary for fat globule aggregation in emulsions, and conversely fat globule aggregation was not necessarily accompanied by protein displacement. The three LMW emulsifiers had very different effects on emulsions. LACTEM induced shear instability of emulsions, which was accompanied by protein displacement. High stability was characteristic for emulsions with GMS where protein was displaced from the interface. Emulsions containing GMU were semisolid, but only low concentrations of protein were detected in the separated serum phase. The effects of LACTEM, GMS, and GMU may be explained by three different mechanisms involving formation of interfacial alpha-gel, pickering stabilization and increased exposure of bound casein to the water phase. The latter may facilitate partial coalescence. Stabilizing hydrocolloids did not have any effect on the LMW emulsifiers' ability to induce protein displacement. PMID- 25026246 TI - A novel oleanolic acid-loaded PLGA-TPGS nanoparticle for liver cancer treatment. AB - OBJECTIVES: Hepatocellular carcinoma is the third most common cause of cancer death. Oleanolic acid (OA) is a natural triterpenoid, has many important biological actions, including antitumor effect, but its poor solubility often leads to poor pharmacodynamics. The aim of our work is to make OA-loaded poly (lactide-co-glycolide)-d-alpha-tocopheryl polyethylene glycol 1000 succinate (PLGA-TPGS) nanoparticles (OPTN) to improve its efficacy to liver cancer and characterize it. METHODS: OPTN were prepared by ultrasonic emulsification-solvent evaporation technique using PLGA with or without the addition of TPGS (OPN). The coumarin-6-loaded nanoparticles were used as a fluorescence marker. The nanoparticles were characterized for surface morphology, surface charge, particle size, drug loading, encapsulation efficiency, in vitro drug-release, cellular uptake, cytotoxicity by human liver cancer cell line HepG2 cells, and therapeutic effect in vivo. KEY FINDINGS: The prepared nanoparticles were found to be spherical in shape. The in vitro drug-release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake and cytotoxicity of OPTN in the HepG2 cells compared with that of OPN. The treatment of OPTN group was better than OPN and FS groups in vivo. CONCLUSION: The results showed advantages of OPTN in terms of sustainable release and efficacy in liver cancer chemotherapy compared with OPN. OPTN could be acted as a novel and new dosage form to be used in cancer treatment study. PMID- 25026247 TI - Effects of preparing techniques and aging on dissolution behavior of the solid dispersions of NF/Soluplus/Kollidon SR: identification and classification by a combined analysis by FT-IR spectroscopy and computational approaches. AB - CONTEXT: Pharmaceutical solid dispersions are known to be seriously affected by issues of aging and processing. OBJECTIVE: This study investigated the spectral patterns in the solid dispersions (SD) of Nifedipine/Soluplus/Kollidon SR and the feasibility of the methodology in identification and evaluation of the solid dispersions. METHODS: The SD samples were prepared by hot melt extrusion (HMESD), solvent-evaporation (SESD), and fusion-cooling (FCSD). In order to distinguish the different SD samples, a combined analytical strategy by FT-IR spectrum, Raman spectrum, and computational approaches (PCA and HCA) were developed to investigate the spectral patterns of the solid dispersions. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), and dissolution test were employed as the reference characterization. The stability test under the accelerated condition was carried out to investigate the physical stability of the SDs. RESULT: For the three prepared SDs, the evident differences on the dissolution behaviors and the trend of aging was observed. By means of the combined analytical strategy, the samples could be successfully identified in terms of their preparing techniques. The strength of hydrogen bonding interaction between NF and polymers decreased in the order of HMESD > SESD > FCSD. The results of the stability test indicated that the similarity factor f2 value of dissolution profile decreased in the order of HMESD > SESD > FCSD. HMESD exhibited a tendency of minimal changing on both dissolution behavior and spectral patterns. CONCLUSION: The combined strategy suggested the possibility for identification of specific SDs in quality control and prediction of their trends on the aging. PMID- 25026248 TI - Kinetics and mechanism of sonochemical degradation of pharmaceuticals in municipal wastewater. AB - A series of six pharmaceuticals were degraded by continuous wave (CW) and pulsed wave (PW) ultrasound at 205 kHz using deionized water, wastewater effluent, and its isolated organic matter matrices. In deionized water, we observed that hydrophobicity is superior to diffusivity (D(W)) for predicting degradation kinetics. Enhancements in degradation kinetics by the PW mode were greatest for the highest DW (i.e., fluorouracil (5-FU)) and K(OW) (i.e., lovastatin (LOVS)) compounds, indicating that a pharmaceutical with either high diffusivity and low hydrophobicity or low diffusivity and high hydrophobicity benefits from additional time to populate the bubble-water interface during the silent cycle of PW ultrasound. Degradation of 5-FU and LOVS were inhibited by wastewater effluent to a greater extent than the other pharmaceuticals. In addition, a pulse enhancement (PE) for 5-FU and LOVS was not present in wastewater effluent. Irradiating 5-FU and LOVS in hydrophobic (HPO), transphilic (TPI), and hydrophilic (HPI) fractions of effluent organic matter (EfOM) showed that the TPI fraction reduced the PE the most, followed by the HPI and HPO fractions. The smaller size of the TPI over the HPO fraction and higher hydrophobicity of TPI over HPI implicate both size and hydrophobicity of EfOM in hindering degradation of pharmaceuticals. PMID- 25026249 TI - Examination of the cervical spine. AB - Examination of the cervical spine is discussed briefly in relation to history, neurological examination, vertebrobasilar insufficiency and x-rays. The general principles of examining cervical movements are presented. Details of the examination are discussed in more detail under the following headings: the upper cervical spine and its examination for cervical headache; the middle cervical spine with its examination being related to spondylosis/arthrosis; the middle and lower cervical spine and its examination related to wry neck, nerve root irritation or compression, and whiplash injury. PMID- 25026250 TI - Memory impairment in rehabilitation. AB - Memory impairment is a common problem in patients with physical disabilitiy of neurological origin. The important features of two types of memory and learning impairment, Amnesic Syndrome and Frontal Lobe Dysfunction, are briefly summarized. Emphasis is placed on the variability of signs and the possibility of new learning within these two classes of memory disorder. The learning requirements of different physiotherapy techniques are discussed in terms of the difficulties they present for the learning-impaired patient Some suggestions are made to assist in the identification of those patients with abnormalities of memory and learning. Several ways in which the rehabilitation program can be modified for patients with memory impairment are discussed. The implications for overall management of these "multi-disabled" patients is considered. A final suggestion is made concerning the value of neuropsychological referral within an interdisciplinary approach to the rehabilitation and management of neurological disability. PMID- 25026251 TI - Physical medicine over the last 40 years. AB - In medical rehabilitation, where we are primarily concerned with the treatment of physical disabilities of the locomotor system, physical methods of treatment play a very large part in the physical recovery of the patient. All my life I have been involved with this, and particularly with the work of physiotherapists, and it is useful to look back over the changes which have occurred in the last forty years - the main one of course has been the discarding of purely traditional methods and an attempt to use methods which have a scientific basis. But it is worth pointing out at this early stage that in doing this we can become a little pseudo-scientific, and perhaps most of all we tend to forget that no two people respond in the same manner, whether it be to physical treatment or to drugs; while we have general principles the best results are obtained only by studying each patient as an individual. Not least important is the rapport established between the patient and the therapist. PMID- 25026252 TI - Community attitudes toward physiotherapy and other health professions. AB - The present study was designed to assess community attitudes toward physiotherapy and five other health professions (osteopathy, acupuncture, chiropractic, naturopathy, and medicine). The study surveyed 100 people chosen from the Melbourne public on the basis of a stratified sampling procedure. In general, earlier findings were confirmed in that the community was found to be less than fully aware of the various functions of currently available health services. In addition, data were gathered on more specified issues including respondents' knowledge of their own and available insurance cover for physiotherapy; the effect of insurance cover on usage of physiotherapy; degree of awareness that a doctor's referral is no longer necessary before seeking physiotherapy; impressions concerning the relative amount of media coverage given to physiotherapy and other health professions; previous contact with, and degree of satisfaction with physiotherapy and other health professions; and respondents' likely preference among various professions for treatment of each of a wide variety of physical complaints. Overall, the results indicated that the health professions have a major task confronting them if they are to ensure that community attitudes are formulated on the basis of clear and accurate information concerning the total array of available health care. PMID- 25026253 TI - Physiotherapy aspects of overseas developments for children with developmental disabilities. AB - This paper describes the findings of a study tour investigating the provision of physiotherapy services for children with developmental disabilities. It was found that early intervention programmes were paramount, particularly in the U.S.A. Major trends, such as the use of transdisciplinary approaches, as well as the specific techniques evolving from them, including task analysis and the use of written behavioural objectives, should be noted and utilised by physiotherapists. Efforts to improve the lifestyle of the children and of their families were studied, including successful family support services in Norway. Finally, several recommendations relating to early intervention and to preschool and school services have been suggested. PMID- 25026254 TI - Continuing education in the health sciences. AB - Attitudes and preferences were surveyed in therapists undertaking an introductory continuing education unit in Psychology. The findings of the survey indicated clear support for continuing education in the health sciences. The survey also supplied an objective evaluation of how satisfactorily the unit was taught, and how effectively the unit achieved its aims, and provided information valuable for the planning of future continuing education programmes. PMID- 25026255 TI - Intracranial dynamics in pre-term infants and neonates: implications for physiotherapists. AB - The control of cerebral circulation and intracranial dynamics differs markedly in the pre-term and full term neonate from that in the adult. Immaturity can combine with several clinical conditions and iatrogenic factors to predispose the neonate to cerebral lesions, which may subsequently increase morbidity. As physiotherapists play an increasingly important role in neonatology, it is important to appreciate the immaturity of the nervous system and to recognise the risk factors for such conditions as peri-intraventricular haemorrhage and periventricular leucomalacia. This paper describes intracranial dynamics in the pre-term and full term infant and illustrates how these factors may interact with clinical conditions to cause cerebral lesions. Studies which examine the effect of respiratory physiotherapy on intracranial dynamics are reviewed and suggestions made for further research. PMID- 25026256 TI - Assessment of school students' needs for therapy services. AB - The development of a screening instrument to assess school students' needs for physiotherapy, occupational therapy and speech pathology is reported in this paper. Items for primary and secondary level students were generated by teachers and therapists to form a draft referral instrument for classroom teachers. Ninety six teachers in 18 metropolitan and country schools reviewed the four forms of the draft instrument with a total of 636 students. The results indicate that the draft Screening Instrument for Teacher Referral to Therapy Services in Schools (SRT) has face validity and utility in the educational setting. Plans to further refine the SRT items, and to conduct reliability and content validity studies are discussed. PMID- 25026257 TI - Towards a measurement of active muscle control for lumbar stabilisation. AB - No measure described to date reflects the ability of muscles to stabilise the lumbar spine. A static model was developed in supine crook lying, to measure active rotatory control with trunk loading in the sagittal plane via low, unilateral leg load. The hypothesis was that excessive lumbar movement indicates an inability of the stabilising muscles to automatically co-ordinate appropriate muscle force to support the spine. A computerised sensor was developed to monitor lumbar positional change. A rotatory stability index was calculated from pressure variations on taking leg load. Preliminary trials showed that this static model identified individuals with poor active rotatory control. Further development of the measurement model is warranted. PMID- 25026258 TI - Making inferences about muscle forces from clinical observations. AB - The analysis of movement dysfunction often requires that inferences be made about the muscle forces which occur during motor task performance. Physiotherapists probably use a range of different models of analysis to make inferences about such forces. These models differ in the degree to which they invoke simplifying assumptions about the non-muscle forces acting on body segments. In some circumstances even the most simple models of analysis will enable reasonable inferences to be made about muscle forces, but in other situations it may be very difficult to make reasonable inferences about muscle forces from clinical observations alone. PMID- 25026259 TI - Predicting return to work after rehabilitation for low back injury. AB - This study examined personal factors, diagnosis and delay in referral as possible influences on the return to work of workers after low back injury. These workers undertook rehabilitation programmes after WorkCover and workplace-based rehabilitation was introduced in NSW in July 1987. Using data from the NSW Commonwealth Rehabilitation Service, a Branch of the Commonwealth Department of Community Services and Health, a predictive model for return to work after rehabilitation was constructed. Factors which were associated with an increase in the likelihood of a return to work were younger age, fluency with English and early referral for rehabilitation. Severity of injury was not associated with the likelihood of returning to work. Although the data suggested that women returned to work more often than men, this difference was not statistically significant. PMID- 25026260 TI - Evaluation of physiotherapy using cost-utility analysis. AB - Limits on health care resources mean that resource allocation decisions should be guided by considerations of cost in relation to benefits. A method of economic evaluation, (cost-utility analysis) was used to evaluate the costs and benefits of a physiotherapy outpatient department. The quality of life of 56 patients was measured before and after physiotherapy intervention and the costs of the treatment compared with the benefits gained. Within the limitations of the study, physiotherapy was found to be good value for money compared with other health care interventions, with treatment for chronic conditions such as back pain, neck pain and osteoarthritis representing better value for money than treatment for acute conditions such as strains and sprains and fractures. PMID- 25026261 TI - Effect of water exercise on balance and related factors in older people. AB - Fifteen subjects enrolled to take part in a water exercise programme (mean age = 69.7 years) and 13 control subjects (mean age 72.6 years) underwent assessments of quadriceps and ankle dorsiflexion strength, reaction time, neuromuscular control, body sway, flexibility and joint pain. All subjects were then retested for the same measures after completion of the nine-week programme. The experimental subjects showed improved quadriceps strength and reduced body sway when compared with the control group. There was also a trend towards increased flexibility, improved reaction times and reduced joint pain in the experimental group. PMID- 25026262 TI - Implementation of international code of marketing breast-milk substitutes in China. AB - BACKGROUND: Breastmilk is the best source of nourishment for infants and young children, and breastfeeding is one of the most effective ways to ensure child health and survival. In May 1981, the World Health Assembly adopted the International Code of Marketing Breast-Milk Substitutes. Since then several subsequent resolutions have been adopted by the World Health Assembly, which both update and clarify the articles within the International Code (herein after the term "Code" refers to both the International Code and all subsequent resolutions). The Code is designed to regulate "inappropriate sales promotion" of breastmilk substitutes and instructs signatory governments to ensure the implementation of its aims through legislation. The Chinese Regulations of the Code were adopted by six government sectors in 1995. However, challenges in promotion, protection, and support of breastfeeding remain. This study aimed to monitor the implementation of the Code in China. SUBJECTS AND METHODS: Six cities were selected with considerable geographic coverage. In each city three hospitals and six stores were surveyed. The International Baby Food Action Network Interview Form was adapted, and direct observations were made. Research assistants administered the questionnaires to a random sample of mothers of infants under 6 months old who were in the outpatient department of the hospitals. In total, 291 mothers of infants, 35 stores, 17 hospitals, and 26 companies were surveyed. RESULTS: From the whole sample of 291 mothers, the proportion who reported exclusively breastfeeding their infant was 30.9%; 69.1% of mothers reported feeding their infant with commercially available formula. Regarding violations of the Code, 40.2% of the mothers reported receiving free formula samples. Of these, 76.1% received the free samples in or near hospitals. Among the stores surveyed, 45.7% were found promoting products in a way that violates the Code. Also, 69.0% of the labeling on the formula products did not comply with the regulations set out in the Code. CONCLUSIONS: As the social and economic developments continue, the interactions of more and more factors curb further success in breastfeeding. Support from all sectors of the society is needed in order to create a social environment to enable the promotion of breastfeeding, in addition to the efforts already made by the healthcare system. PMID- 25026263 TI - Dissolution mechanism of cellulose in N,N-dimethylacetamide/lithium chloride: revisiting through molecular interactions. AB - Understanding the interactions between solvent molecules and cellulose at a molecular level is still not fully achieved in cellulose/N,N-dimethylacetamide (DMAc)/LiCl system. In this paper, cellobiose was used as the model compound of cellulose to investigate the interactions in cellulose/DMAc/LiCl solution by using Fourier transform infrared spectroscopy (FTIR), (13)C, (35)Cl, and (7)Li nuclear magnetic resonance (NMR) spectroscopy and conductivity measurements. It was found that when cellulose is dissolved in DMAc/LiCl cosolvent system, the hydroxyl protons of cellulose form strong hydrogen bonds with the Cl(-), during which the intermolecular hydrogen bonding networks of cellulose is broken with simultaneous splitting of the Li(+)-Cl(-) ion pairs. Simultaneously, the Li(+) cations are further solvated by free DMAc molecules, which accompany the hydrogen bonded Cl(-) to meet electric balance. Thereafter, the cellulose chains are dispersed in molecular level in the solvent system to form homogeneous solution. This work clarifies the interactions in the cellulose/DMAc/LiCl solution at molecular level and the dissolution mechanism of cellulose in DMAc/LiCl, which is important for understanding the principle for selecting and designing new cellulose solvent systems. PMID- 25026264 TI - Ascophyllan purified from Ascophyllum nodosum induces Th1 and Tc1 immune responses by promoting dendritic cell maturation. AB - Marine-derived sulfated polysaccharides have been shown to possess certain anti virus, anti-tumor, anti-inflammatory and anti-coagulant activities. However, the in vivo immunomodulatory effects of marine-derived pure compounds have been less well characterized. In this study, we investigated the effect of ascophyllan, a sulfated polysaccharide purified from Ascophyllum nodosum, on the maturation of mouse dendritic cells (DCs) in vitro and in vivo. Ascophyllan induced up regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in bone marrow-derived DCs (BMDCs). Moreover, in vivo administration of ascophyllan promotes up-regulation of CD40, CD80, CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-alpha in spleen cDCs. Interestingly, ascophyllan induced a higher degree of co-stimulatory molecule up-regulation and pro-inflammatory cytokine production than fucoidan, a marine-derived polysaccharide with well-defined effect for promoting DC maturation. Ascophyllan also promoted the generation of IFN-gamma-producing Th1 and Tc1 cells in the presence of DCs in an IL-12-dependent manner. Finally, myeloid differentiation primary response 88 (MyD88) signaling pathway was essential for DC maturation induced by ascophyllan. Taken together, these results demonstrate that ascophyllan induces DC maturation, and consequently enhances Th1 and Tc1 responses in vivo. This knowledge could facilitate the development of novel therapeutic strategies to combat infectious diseases and cancer. PMID- 25026265 TI - The effect of polyunsaturated aldehydes on Skeletonema marinoi (Bacillariophyceae): the involvement of reactive oxygen species and nitric oxide. AB - Nitric oxide (NO) and reactive oxygen species (ROS) production was investigated in the marine diatom, Skeletonema marinoi (SM), exposed to 2E,4E/Z-decadienal (DECA), 2E,4E/Z-octadienal (OCTA), 2E,4E/Z-heptadienal (HEPTA) and a mix of these last two (MIX). When exposed to polyunsaturated aldehydes (PUA), a decrease of NO was observed, proportional to the PUA concentration (85% of the initial level after 180 min with 66 uM DECA). Only OCTA, HEPTA and MIX induced a parallel increase of ROS, the highest (2.9-times the control) with OCTA concentrations twice the EC50 for growth at 24 h (20 MUM). The synthesis of carotenoids belonging to the xanthophyll cycle (XC) was enhanced during exposure, suggesting their antioxidant activity. Our data provide evidence that specific pathways exist as a reaction to PUA and that they depend upon the PUA used and/or the diatom species. In fact, Phaeodactylum tricornutum (PT) produces NO in response to DECA, but not to OCTA. We advance the hypothesis that SM perceives OCTA and HEPTA as intra-population infochemicals (as it produces PUA), while PT (non-PUA producing species) perceives them as allelochemicals. The ability to produce and to use PUA as infochemicals may underlie ecological traits of different diatom species and modulate ecological success in natural communities. PMID- 25026267 TI - The Australian journal of physiotherapy oration: wholesome discontent - a spur to action. AB - That all discontent leads to progress is patently absurd, for there is the discontent born of self pity which can lead nowhere save to perdition. But discontent arising from a desire to better the status quo is worthy and has a fair claim to being the source and mainspring of all action that adds to the sum of human dignity. Lacking it, mankind would still be in the stone age, and his existence short, nasty and brutish as ever; possessed of it - and in every generation there are those in whom it is part of their very nature - he moves forward, and the firmament itself comes within his reach. PMID- 25026266 TI - Pseudaboydins A and B: novel isobenzofuranone derivatives from marine fungus Pseudallescheria boydii associated with starfish Acanthaster planci. AB - Two novel isobenzofuranone derivatives, pseudaboydins A (1) and B (2), along with five known compounds, including (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5 hydroxybenzofuran (3), (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5 methoxybenzofuran (4), 3,3'-dihydroxy-5,5'-dimethyldiphenyl ether (5), 3-(3 methoxy-5-methylphenoxy)-5-methylphenol (6) and (-)-regiolone (7), were isolated from the culture broth of the marine fungus, Pseudallescheria boydii, associated with the starfish, Acanthaster planci. Their structures were elucidated primarily based on NMR and MS data. The absolute configurations of 1-4 were determined by CD spectroscopy and single-crystal X-ray diffraction studies. The cytotoxic and antibacterial activities of 1-4 were evaluated. Pseudaboydin A (1) showed moderate cytotoxic activity against human nasopharyngeal carcinoma cell line HONE1, human nasopharyngeal carcinoma cell line SUNE1 and human glandular lung cancer cell line GLC82 with IC50 values of 37.1, 46.5 and 87.2 MUM, respectively. PMID- 25026268 TI - Sports medicine in the seventies. AB - One question which is frequently asked of me is "What is Sports Medicine?" A somewhat facetious friend has replied "It's a lurk designed to get a good parking spot at the football finals and a seat in the stand for the test match. There's even the bait of a free trip to the Olympic Games," he adds jealously. But whilst admitting that these statements can be true, there are many mundane tasks to be accomplished, usually in your own time, or that which, by rights, belongs to your family; many lectures to prepare and deliver, and much criticism to endure, when you fail to cure overnight, the football star's ruptured cruciate ligament or neurotic, spoilt temperament or both. PMID- 25026269 TI - The instant era: prostheses and performance, not porridge. AB - Anyone who has watched the removal of a limb in the operating theatre will have experienced the sinking feeling that accompanies the final irretrievable severance of the part. It is not difficult, therefore, to imagine the feelings of the patient who recovers from the anaesthetic minus a limb, in a deal of pain, and facing an incomprehensible future. PMID- 25026270 TI - Physiotherapy in intramuscular lesions. AB - Accidents will happen, even, it is said, in the best regulated circles. And accidents do happen, in motor cars, in industry, in the home, and in sport - in that order of occurrence. PMID- 25026271 TI - Canary in the coal mine: childhood obesity as an indicator of overall child health. PMID- 25026272 TI - Interdiffusion induced exchange coupling of L10-FePd/alpha-Fe magnetic nanocomposites. AB - One-pot synthesis of FePd and FePd/Fe2O3 (core/shell) nanoparticles via interdiffusion is reported for the first time. It was found that the size of FePd particles and Fe2O3 shell thickness could be controlled by the ligand and iron precursor amounts, respectively. These FePd/Fe2O3 particles can be reductively annealed at 500 degrees C to produce exchanged coupled L10-FePd/alpha-Fe magnetic nanocomposites. The effect of the phosphine ligand on magnetic characteristics of synthesized particles and final annealed nanocomposite is discussed. Finally, it was found that the magnetic properties of the final L10 FePd/alpha-Fe nanocomposites could be tuned by Fe2O3 shell thickness and can reach a coercivity (Hc) of up to 2.4 kOe and a saturation magnetization (Ms) of 141 emu/g. PMID- 25026273 TI - Design and establishment of a vector system that enables production of multifusion proteins and easy purification by a two-step affinity chromatography approach. AB - The LE (LguI/Eco81I)-cloning procedure allows a step-wise, directional fusion of multiple DNA-fragments into a vector by utilizing two restriction enzymes generating identical non-palindromic overhangs. This strategy was applied to produce heat-stable cellulase-fusion proteins containing up to five single moieties. Terminal affinity tags enable efficient purification using a simple two step approach. PMID- 25026274 TI - Further development of sample preparation and detection methods for O157 and the top 6 non-O157 STEC serogroups in cattle feces. AB - Shiga toxin-producing Escherichia coli (STEC) are food-borne pathogens responsible for outbreaks of human infections worldwide. Ruminant livestock harbor STEC in their intestinal tract, and through fecal contamination possess the potential to compromise the safety of food and water. As a human health safety risk, STEC detection methods on beef carcasses and trim are needed as mandated by the USDA-FSIS. In order to monitor STEC prior to harvest and human consumption, our goal was to evaluate and/or improve detection of seven STEC serogroups in cattle feces. In comparison to traditional approaches, sample processing methods in bovine feces were evaluated using a multi-factorial Latin square design which involved freezing or freeze drying feces. Autoclaved versus non-autoclaved feces were spiked with O26:H11 or O157:H7 serotypes in various dilutions and enriched for up to 6h. Each hour, enriched aliquots were compared using traditional culture methods and quantitative polymerase chain reaction (qPCR). Furthermore, a 7-serogroup multiplex PCR (mPCR) was developed to detect O26, O45, O103, O111, O121, O145 and O157 serogroups simultaneously. The diagnostic sensitivity of our mPCR assay following 6h enrichment was superior (10CFU/g across all serogroups) compared to a previously established PCR assay (10CFU/g for O26, and O103; >=10(4)CFU/g for all other serogroups). Obtaining viable isolates appeared to be limited by the efficiency of current immunomagnetic separation (IMS) methods, which ranged from 20 to 100% effectiveness at retrieving colonies depending on serogroup. After IMS, 70 putative STEC isolates were screened for Shiga toxin and attachment genes by mPCR. Sixty-five isolates contained one or both Shiga toxin genes. PMID- 25026275 TI - H-Ras regulation of TRAIL death receptor mediated apoptosis. AB - TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. Here we provide evidence demonstrating the role of H-Ras in TRAIL receptor mediated apoptosis. By analyzing the genome wide mRNA expression data of the NCI60 cancer cell lines, we found that H-Ras expression was consistently upregulated in TRAIL-resistant cell lines. By contrast, no correlation was found between TRAIL sensitivity and K-Ras expression levels or their mutational profiles. Notably, H-Ras upregulation associated with a surface deficiency of TRAIL death receptors. Selective inhibition of H-Ras activity in TRAIL-resistant cells restored the surface expression of both DR4 and DR5 without changing their total protein levels. The resulting cells became highly susceptible to both TRAIL and agonistic DR5 antibody, whereas K-Ras inhibition had little or no effect on TRAIL-induced apoptosis, indicating H-Ras plays a distinct role in the regulation of TRAIL death receptors. Further studies are warranted to determine the therapeutic potential of H-Ras-specific inhibitors in combination with TRAIL receptor agonists. PMID- 25026276 TI - Dietary energy balance modulates ovarian cancer progression and metastasis. AB - A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer. PMID- 25026277 TI - The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model. AB - NPM-ALK+ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK+ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK+ solid tumors. However, NPM-ALK+ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK+ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK+ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK+ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK+ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials. PMID- 25026278 TI - H-Prune through GSK-3beta interaction sustains canonical WNT/beta-catenin signaling enhancing cancer progression in NSCLC. AB - H-Prune hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3beta). Gsk-3beta is a negative regulator of canonical WNT/beta-catenin signaling. Here, we investigate the role of Gsk 3beta/h-Prune complex in the regulation of WNT/beta-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small cell lung cancer. PMID- 25026279 TI - Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice. AB - Acquired mutations in KIT are driver mutations in systemic mastocytosis (SM). Here, we tested the role of SHP2/PTPN11 phosphatase in oncogenic KIT signaling using an aggressive SM mouse model. Stable knock-down (KD) of SHP2 led to impaired growth, colony formation, and increased rates of apoptosis in P815 cells. This correlated with defects in signaling to ERK/Bim, Btk, Lyn, and Stat5 pathways in P815-KD cells compared to non-targeting (NT). Retro-orbital injections of P815 NT cells in syngeneic DBA/2 mice resulted in rapid development of aggressive SM within 13-16 days characterized by splenomegaly, extramedullary hematopoiesis, and multifocal liver tumors. In contrast, mice injected with P815 SHP2 KD cells showed less disease burden, including normal spleen weight and cellularity, and significant reductions in mastocytoma cells in spleen, bone marrow, peripheral blood and liver compared to NT controls. Treatment of human mast cell leukemia HMC-1 cells or P815 cells with SHP2 inhibitor II-B08, resulted in reduced colony formation and cell viability. Combining II-B08 with multi kinase inhibitor Dasatinib showed enhanced efficacy than either inhibitor alone in blocking cell growth pathways and cell viability. Taken together, these results identify SHP2 as a key effector of oncogenic KIT and a therapeutic target in aggressive SM. PMID- 25026280 TI - Top associated SNPs in prostate cancer are significantly enriched in cis expression quantitative trait loci and at transcription factor binding sites. AB - While genome-wide association studies (GWAS) have revealed thousands of disease risk single nucleotide polymorphisms (SNPs), their functions remain largely unknown. Recent studies have suggested the regulatory roles of GWAS risk variants in several common diseases; however, the complex regulatory structure in prostate cancer is unclear. We investigated the potential regulatory roles of risk variants in two prostate cancer GWAS datasets by their interactions with expression quantitative trait loci (eQTL) and/or transcription factor binding sites (TFBSs) in three populations. Our results indicated that the moderately associated GWAS SNPs were significantly enriched with cis-eQTLs and TFBSs in Caucasians (CEU), but not in African Americans (AA) or Japanese (JPT); this was also observed in an independent pan-cancer related SNPs from the GWAS Catalog. We found that the eQTL enrichment in the CEU population was tissue-specific to eQTLs from CEU lymphoblastoid cell lines. Importantly, we pinpointed two SNPs, rs2861405 and rs4766642, by overlapping results from cis-eQTL and TFBS as applied to the CEU data. These results suggested that prostate cancer associated SNPs and pan-cancer associated SNPs are likely to play regulatory roles in CEU. However, the negative enrichment results in AA or JPT and the potential mechanisms remain to be elucidated in additional samples. PMID- 25026281 TI - Discovery of selective inhibitors of Glutaminase-2, which inhibit mTORC1, activate autophagy and inhibit proliferation in cancer cells. AB - Glutaminase, which converts glutamine to glutamate, is involved in Warburg effect in cancer cells. Two human glutaminase genes have been identified, GLS (GLS1) and GLS2. Two alternative transcripts arise from each glutaminase gene: first, the kidney isoform (KGA) and glutaminase C (GAC) for GLS; and, second, the liver isoform (LGA) and glutaminase B (GAB) for GLS2. While GLS1 is considered as a cancer therapeutic target, the potential role of GLS2 in cancer remains unclear. Here, we discovered a series of alkyl benzoquinones that preferentially inhibit glutaminase B isoform (GAB, GLS2) rather than the kidney isoform of glutaminase (KGA, GLS1). We identified amino acid residues in an allosteric binding pocket responsible for the selectivity. Treatment with the alkyl benzoquinones decreased intracellular glutaminase activity and glutamate levels. GLS2 inhibition by either alkyl benzoquinones or GLS2 siRNA reduced carcinoma cell proliferation and anchorage-independent colony formation, and induced autophagy via AMPK mediated mTORC1 inhibition. Our findings demonstrate amino acid sequences for selective inhibition of glutaminase isozymes and validate GLS2 as a potential anti-cancer target. PMID- 25026282 TI - USP17 is required for clathrin mediated endocytosis of epidermal growth factor receptor. AB - Previously we have shown that expression of the deubiquitinating enzyme USP17 is required for cell proliferation and motility. More recently we reported that USP17 deubiquitinates RCE1 isoform 2 and thus regulates the processing of 'CaaX' motif proteins. Here we now show that USP17 expression is induced by epidermal growth factor and that USP17 expression is required for clathrin mediated endocytosis of epidermal growth factor receptor. In addition, we show that USP17 is required for the endocytosis of transferrin, an archetypal substrate for clathrin mediated endocytosis, and that USP17 depletion impedes plasma membrane recruitment of the machinery required for clathrin mediated endocytosis. Thus, our data reveal that USP17 is necessary for epidermal growth factor receptor and transferrin endocytosis via clathrin coated pits, indicate this is mediated via the regulation of the recruitment of the components of the endocytosis machinery and suggest USP17 may play a general role in receptor endocytosis. PMID- 25026283 TI - Clinical significance of phenotyping and karyotyping of circulating tumor cells in patients with advanced gastric cancer. AB - BACKGROUND: Karyotyping and phenotyping of circulating tumor cells (CTCs) in therapeutic cancer patients is of particular clinical significance in terms of both identifying chemo-resistant CTC subtypes and understanding CTC evolution. METHODS: The integrated subtraction enrichment (SET) and immunostaining fluorescence in situ hybridization (iFISH) platform was applied to detect and characterize CTCs in patients with advanced gastric cancer (AGC). Status of human epidermal growth factor receptor 2 (HER2) expressing and aneuploidy of chromosome 8 in CTCs enriched from the patients was examined by SET-iFISH following clinical chemotherapy or HER2-targeted therapy. CellSearch system was applied as a reference control. RESULTS: Phenotyping of CTCs in HER2 positive AGC patients demonstrated that HER2+ CTCs could be effectively eliminated in response to HER2 targeted therapy. Karytotyping of CTCs indicated that distinct CTCs with different ploidies of chromosomes 8 in AGC patients correlated to either sensitivity or resistance of paclitaxel or cisplatin-based chemotherapy. Examination of the copy number of chromosome 8 in CTCs provides a potential approach for predicting chemotherapeutic efficacy and monitoring chemo resistance. CONCLUSIONS: Phenotyping and karyotyping of the enriched CTCs upon ploidy of chromosome 8 or HER2 expression is of clinical potential for monitoring chemo-resistance and evaluating therapeutic efficacy for AGC patients. PMID- 25026284 TI - Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. AB - Mislocalization of proteins is a common feature of cancer cells. Since localization of proteins is tightly linked to its function, cancer cells can inactivate function of a tumor suppressor protein through mislocalization. The nuclear exportin CRM1/XPO 1 is upregulated in many cancers. Targeting XPO 1 can lead to nuclear retention of cargo proteins such as p53, Foxo, and BRCA1 leading to cell cycle arrest and apoptosis. We demonstrate that selective inhibitors of nuclear export (SINE) can functionally inactivate XPO 1 in prostate cancer cells. Unlike the potent, but toxic, XPO 1 inhibitor leptomycin B, SINE inhibitors (KPT 185, KPT-330, and KPT-251) cause a decrease in XPO 1 protein level through the proteasomal pathway. Treatment of prostate cancer cells with SINE inhibitors lead to XPO 1 inhibition, as evaluated by RevGFP export assay, leading to nuclear retention of p53 and Foxo proteins, consequently, triggering apoptosis. Our data reveal that treatment with SINE inhibitors at nanomolar concentrations results in decrease in proliferation and colonogenic capacity of prostate cancer cells by triggering apoptosis without causing any cell cycle arrest. We further demonstrate that SINE inhibitors can be combined with other chemotherapeutics like doxorubicin to achieve enhanced growth inhibition of prostate cancer cells. Since SINE inhibitors offer increased bioavailability, reduced toxicity to normal cells, and are orally available they can serve as effective therapeutics against prostate cancer. In conclusion, our data reveals that nucleocytoplasmic transport in prostate cancer can be effectively targeted by SINE inhibitors. PMID- 25026285 TI - CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome. AB - Malignant mesothelioma is a deadly tumor whose diagnosis and treatment remain very challenging. There is an urgent need to advance our understanding of mesothelioma biology and to identify new molecular markers for improving management of patients. CD157 is a membrane glycoprotein linked to ovarian cancer progression and mesenchymal differentiation. The common embryonic origin of ovarian epithelial cells and mesothelial cells and the evident similarities between ovarian and mesothelial cancer prompted us to investigate the biological role and clinical significance of CD157 in malignant pleural mesothelioma (MPM). CD157 mRNA and protein were detected in four of nine MPM cell lines of diverse histotype and in 85.2% of MPM surgical tissue samples (32/37 epithelioid; 37/44 biphasic). CD157 expression correlated with clinical aggressiveness in biphasic MPM. Indeed, high CD157 was a negative prognostic factor and an independent predictor of poor survival for patients with biphasic MPM by multivariate survival analysis (HR = 2.433, 95% CI 1.120-5.284; p = 0.025). In mesothelioma cell lines, CD157 gain (in CD157-negative cells) or knockdown (in CD157-positive cells) affected cell growth, migration, invasion and tumorigenicity, most notably in biphasic MPM cell lines. In these cells, CD157 expression was associated with increased activation of the mTOR signaling pathway, resulting in decreased platinum sensitivity. Moreover, a trend towards reduced survival was observed in patients with biphasic MPM receiving postoperative platinum-based chemotherapy. These findings indicate that CD157 is implicated in multiple aspects of MPM progression and suggest that CD157 expression could be used to stratify patients into different prognostic groups or to select patients that might benefit from particular chemotherapeutic approach. PMID- 25026286 TI - Surgery-induced wound response promotes stem-like and tumor-initiating features of breast cancer cells, via STAT3 signaling. AB - Inflammation is clinically linked to cancer but the mechanisms are not fully understood. Surgery itself elicits a range of inflammatory responses, suggesting that it could represent a perturbing factor in the process of local recurrence and/or metastasis. Post-surgery wound fluids (WF), drained from breast cancer patients, are rich in cytokines and growth factors, stimulate the in vitro growth of breast cancer cells and are potent activators of the STAT transcription factors. We wondered whether STAT signaling was functionally involved in the response of breast cancer cells to post-surgical inflammation. We discovered that WF induced the enrichment of breast cancer cells with stem-like phenotypes, via activation of STAT3. In vitro, WF highly stimulated mammosphere formation and self-renewal of breast cancer cells. In vivo, STAT3 signaling was critical for breast cancer cell tumorigenicity and for the formation of local relapse after surgery. Overall, we demonstrate here that surgery-induced inflammation promotes stem-like phenotypes and tumor-initiating abilities of breast cancer cells. Interfering with STAT3 signaling with a peri-surgical treatment was sufficient to strongly suppress this process. The understanding of the crosstalk between breast tumor-initiating cells and their microenvironment may open the way to successful targeting of these cells in their initial stages of growth and be eventually curative. PMID- 25026287 TI - MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. AB - We analysed the prognostic significance of minimal residual disease (MRD) level in adult patients with acute myeloid leukemia (AML) treated in the randomized gemtuzumab ozogamicin (GO) ALFA-0701 trial. Levels of WT1 and NPM1 gene transcripts were assessed using cDNA-based real-time quantitative PCR in 183 patients with WT1 overexpression and in 77 patients with NMP1 mutation (NPM1mut) at diagnosis. Positive WT1 MRD (defined as > 0.5% in the peripheral blood) after induction and at the end of treatment were both significantly associated with a higher risk of relapse and a shorter overall survival (OS). Positive NPM1mut MRD (defined as > 0.1% in the bone marrow) after induction and at the end of treatment also predicted a higher risk of relapse, but did not influence OS. Interestingly, the achievement of a negative NPM1mut MRD was significantly more frequent in patients treated in the GO arm compared to those treated in control arm (39 % versus 7% (p=0.006) after induction and 91% versus 61% (p=0.028) at the end of treatment). However, GO did not influence WT1 MRD levels. Our study supports the prognostic significance of MRD assessed by WT1 and NPM1mut transcript levels and show that NPM1 MRD is decreased by GO treatment. PMID- 25026288 TI - Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A2alpha via AKT in prostate cancer cells. AB - Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or loss-of function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A2alpha (cPLA2alpha) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. We examined whether AKT plays a role in promoting cPLA2alpha action in prostate cancer cells. We found a concordant increase in pAKT and cPLA2alpha levels in prostate tissue of prostate epithelial specific PTEN-knockout but not PTEN-wide type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA2alpha expression in PTEN mutated or deleted prostate cancer cells. An increase in AKT by Myr-AKT elevated cPLA2alpha protein levels, which could be diminished by inhibition of AKT phosphorylation without noticeable change in total AKT levels. pAKT levels had no influence on cPLA2alpha at mRNA levels but reduced cPLA2alpha protein degradation. Anti-AKT antibody co-immunoprecipitated cPLA2alpha and vice versa. Hence, AKT plays a role in enhancing cPLA2alpha protein stability in PTEN-null prostate cancer cells, revealing a link between oncogenic pathway and lipid metabolism. PMID- 25026289 TI - Microsatellite instability and ploidy status define three categories with distinctive prognostic impact in endometrioid endometrial cancer. AB - Microsatellite instability (MSI) and aneuploidy are inversely related phenomena. We tested whether ploidy status influences the clinical impact of MSI in endometrioid endometrial cancer (EEC). We analyzed 167 EECs for MSI and ploidy. Tumors were classified in three categories according to MSI and ploidy status. Associations with clinicopathological and molecular variables, survival, and treatment response were assessed. All MSI tumors (23%) were scored as diploid, and 14% of microsatellite stable (MSS) tumors presented aneuploidy. MSI tumors associated with older age at diagnosis, non-obesity, high histological grade, and advanced surgical stage. MSS-aneuploid tumors also associated with higher grade and advanced stage. In multivariate survival analysis MSI did not influence disease-free survival (DFS) or cancer-specific survival (CSS). However, when just diploid tumors were considered for the analysis, MSI significantly contributed to worse DFS and CSS, and the same was observed for aneuploidy when MSS tumors were analyzed alone. In diploid tumors, a differential response to postoperative radiotherapy (RT) was observed according to MSI, since it predicted poor DFS and CSS in the multivariate analysis. We conclude that ploidy status influences the clinical impact of MSI in EEC. Among diploid tumors those with MSI have poor clinical outcome and respond worse to RT. PMID- 25026290 TI - MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R. AB - We found that restoration of miR-100 expression resulted in accumulation of LC3B II and decrease of p62 in hepatocellular carcinoma (HCC) cells, whereas antagonism of miR-100 reduced the level of LC3B-II. Moreover, a significant correlation between miR-100 downregulation and p62 upregulation was observed in human HCC tissues, suggesting an autophagy-promoting effect of miR-100. Subsequent investigations disclosed that knockdown of Atg7 but not Beclin-1 attenuated the miR-100-induced LC3B-II elevation. Furthermore, miR-100 overexpression caused massive cell death, which was abrogated by both the Atg7 silencing and chloroquine treatment. Simultaneously, miR-100 expression led to increased fraction of cells with Annexin V-staining and loss of mitochondrial potential, implying that miR-100 may promote the Atg7-dependent autophagy and subsequent apoptotic cell death. Consistently, mouse xenograft models revealed that miR-100 inhibited the in vivo growth of HCC cells. We further showed that miR-100 suppressed the expression of mTOR and IGF-1R by binding to their 3' untranslated region, and knockdown of mTOR or IGF-1R phenocopied the pro autophagy effect of miR-100, indicating that miR-100 may promote autophagy by reducing mTOR and IGF-1R level. Collectively, our data uncover a new regulatory mechanism of autophagy and a novel function of miR-100, and provide a potential therapeutic target for HCC. PMID- 25026291 TI - Characterization of tumor-associated B-cell subsets in patients with colorectal cancer. AB - PURPOSE: A precise understanding of the mechanisms by which human immune cell subsets affect tumor biology will be critical for successful treatment of cancer using immunotherapeutic approaches. Recent evidence suggests that B cells can both promote and inhibit the development and progression of tumors. The aim of this study was to characterize the composition of the B-cell infiltrates in colorectal cancers (CRC) in order to gain further insight into the role of B cells in CRC. EXPERIMENTAL DESIGN: In this study we characterized B-cell subsets in primary tumors (n=38), metastases (n=6) and blood (n=46) of 51 patients with a diagnosis of CRC and blood of 10 healthy controls. B-cell subsets were analyzed by flow cytometry or immunohistochemistry. RESULTS: Peripheral blood of CRC patients contained a higher percentage of memory B cells than that of age-matched healthy controls. Furthermore, the percentage of B cells within tumors was higher than that in the peripheral blood of CRC patients while metastases were typically devoid of tumor-infiltrating B cells. Tumor-associated B cells were enriched for activated and terminally differentiated B cells. Relevant proportions of regulatory B cells could only be detected in advanced cancer and metastases. CONCLUSION: B cells constitute a significant proportion of the immune infiltrate in CRC. The B-cell infiltrate of primary CRC is characterized by an accumulation of terminally differentiated memory B cells or plasma cells suggestive of a specific immune response against the tumor. However advanced tumors and metastases are also infiltrated by a considerable number of regulatory B cells. PMID- 25026292 TI - Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition. AB - Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to RAD001. Thus, PI3K represents a novel potential target for PETs. We tested the impact of three novel PI3K inhibitors (BEZ235, BKM120 and BYL719) on proliferation of PET cells that are responsive (BON-1) or unresponsive (QGP-1) to RAD001. BEZ235 was the most efficient in inhibiting proliferation in PET cells. Furthermore, combined treatment with BEZ235 and RAD001 exhibited synergic effects and was also effective in BON-1 that acquired resistance to RAD001 (BON-1 RR). Analysis of PI3K/AKT/mTOR pathway showed that RAD001 and BEZ235 only partially inhibited mTOR-dependent phosphorylation of 4EBP1. By contrast, combined therapy with the two inhibitors strongly inhibited phosphorylation of 4EBP1, assembly of the translational initiation complex and protein synthesis. Thus, combined treatment with BEZ235 may represent suitable therapy to counteract primary and acquired resistance to RAD001 in PETs. PMID- 25026293 TI - Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-beta/Smad signaling pathway. AB - The transforming growth factor-beta (TGF-beta) signaling pathway is believed to contribute to carcinoma development by increasing cell invasiveness and metastasis and inducing the epithelial-to-mesenchymal transition (EMT). Protein phosphatase PPM1A has been reported to dephosphorylate TGF-beta-activated Smad2/3, thus inhibiting the TGF-beta signaling pathway. In this study, we investigated the role of PPM1A in bladder cancer. PPM1A protein expression was analyzed in 145 bladder cancer specimens. The loss of PPM1A expression was predictive of poor survival and high muscle-invasiveness. PPM1A was more commonly deficient among muscle-invasive relapse samples compared to primary tumors in twenty paired bladder cancer tissues. Functional studies indicated that blockade of PPM1A through lentivirus-mediated RNA interference significantly promoted urinary bladder cancer (BCa) cell motility, the EMT in vitro and metastasis in vivo, and these effects were dependent on the TGF-beta/Smad signaling pathway. The increase in p-Smad2/3 induced by TGF-beta1 correlated with the degree of PPM1A depletion in BCa cells, which resulted in an altered expression profile of TGF-beta-inducible genes. The correlations between PPM1A and biomarkers related to the TGF-beta signaling pathway and tumor invasion were also detected in BCa samples. These results demonstrate that loss of PPM1A is associated with the development of tumor invasion in bladder cancer patients. PMID- 25026294 TI - Acquisition of radioresistance in docetaxel-resistant human lung adenocarcinoma cells is linked with dysregulation of miR-451/c-Myc-survivin/rad-51 signaling. AB - Chemoresistant tumors usually fail to respond to radiotherapy. However, the mechanisms involved in chemo- and radiotherapy cross resistance are not fully understood. Previously, we have identified microRNA (miR)-451 as a tumor suppressor in lung adenocarcinoma (LAD). However, whether miR-451 plays critical roles in chemo- and radiotherapy cross resistance in LAD is unclear. Here, we established two docetaxel-resistant LAD cell models (SPC-A1/DTX and H1299/DTX), and showed that miR-451 was significantly downregulated in docetaxel-resistant LAD cells. Gain - and loss - of - function assays indicated that re-expression of miR-451 could reverse radioresistance of docetaxel-resistant LAD cells both in vitro and in vivo through promoting apoptosis and DNA double-strand breaks (DSBs). The proto-oncogene c-Myc was identified as a direct target of miR-451, and re-expression of miR-451 inhibited survivin and rad-51 expression by reducing the amount of c-Myc protein binding to their promoters. Silencing of c-Myc could phenocopy the effects of miR-451 upregulation, and restoration of c-Myc could partially rescue the effect of miR-451 upregulation on radiosensitivity of docetaxel-resistant LAD cells. Therefore, dysregulation of miR-451/c-Myc survivin/rad-51 signaling is responsible for radioresistance of docetaxel resistant LAD cells, and targeting it will be a potential strategy for reversing chemo- and radiotherapy cross resistance of LAD patients. PMID- 25026296 TI - MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. AB - Recent findings have revealed that dysregulated miRNAs contribute significantly to autophagy and chemoresistance. Pharmacologically targeting autophagy-related miRNAs is a novel strategy to reverse drug resistance. Here, we report a novel function of isoliquiritigenin (ISL) as a natural inhibitor of autophagy-related miR-25 in killing drug-resistant breast cancer cells. ISL induced chemosensitization, cell cycle arrest and autophagy, but not apoptosis, in MCF 7/ADR cells. ISL also promoted the degradation of the ATP-binding cassette (ABC) protein ABCG2 primarily via the autophagy-lysosome pathway. More importantly, miRNA 3.0 array experiments identified miR-25 as the main target of ISL in triggering autophagy flux. A mechanistic study validated that miR-25 inhibition led to autophagic cell death by directly increasing ULK1 expression, an early regulator in the autophagy induction phase. miR-25 overexpression was demonstrated to block ISL-induced autophagy and chemosensitization. Subsequent in vivo experiments showed that ISL had chemosensitizing potency, as revealed by an increase in LC3-II staining, the downregulation of ABCG2, a reduction in miR-25 expression and the activation of the miR-25 target ULK1. Overall, our results not only indicate that ISL acts as a natural autophagy inducer to increase breast cancer chemosensitivity, but also reveal that miR-25 functions as a novel regulator of autophagy by targeting ULK1. PMID- 25026295 TI - The NF1 gene revisited - from bench to bedside. AB - Neurofibromatosis type 1 (NF1) is a relatively common tumour predisposition syndrome related to germline aberrations of NF1, a tumour suppressor gene. The gene product neurofibromin is a negative regulator of the Ras cellular proliferation pathway, and also exerts tumour suppression via other mechanisms. Recent next-generation sequencing projects have revealed somatic NF1 aberrations in various sporadic tumours. NF1 plays a critical role in a wide range of tumours. NF1 alterations appear to be associated with resistance to therapy and adverse outcomes in several tumour types. Identification of a patient's germline or somatic NF1 aberrations can be challenging, as NF1 is one of the largest human genes, with a myriad of possible mutations. Epigenetic factors may also also contribute to inadequate levels of neurofibromin in cancer cells. Clinical trials of NF1-based therapeutic approaches are currently limited. Preclinical studies on neurofibromin-deficient malignancies have mainly been on malignant peripheral nerve sheath tumour cell lines or xenografts derived from NF1 patients. However, the emerging recognition of the role of NF1 in sporadic cancers may lead to the development of NF1-based treatments for other tumour types. Improved understanding of the implications of NF1 aberrations is critical for the development of novel therapeutic strategies. PMID- 25026297 TI - Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era. AB - Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in 'The Cancer Genome Atlas' (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 (p=0.031) and low PTEN (p=0.042) remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas. PMID- 25026298 TI - Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. AB - There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1. PMID- 25026299 TI - Specific delivery of microRNA93 into HBV-replicating hepatocytes downregulates protein expression of liver cancer susceptible gene MICA. AB - Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). To date, the lack of efficient in vitro systems supporting HBV infection and replication has been a major limitation of HBV research. Although primary human hepatocytes support the complete HBV life cycle, their limited availability and difficulties with gene transduction remain problematic. Here, we used human primary hepatocytes isolated from humanized chimeric uPA/SCID mice as efficient sources. These hepatocytes supported HBV replication in vitro. Based on analyses of mRNA and microRNA (miRNA) expression levels in HBV-infected hepatocytes, miRNA93 was significantly downregulated during HBV infection. MiRNA93 is critical for regulating the expression levels of MICA protein, which is a determinant for HBV-induced HCC susceptibility. Exogenous addition of miRNA93 in HBV-infected hepatocytes using bionanocapsules consisted of HBV envelope L proteins restored MICA protein expression levels in the supernatant. These results suggest that the rescued suppression of soluble MICA protein levels by miRNA93 targeted to HBV-infected hepatocytes using bionanocapsules may be useful for the prevention of HBV-induced HCC by altering deregulated miRNA93 expression. PMID- 25026300 TI - Low PKCalpha expression within the MRD-HR stratum defines a new subgroup of childhood T-ALL with very poor outcome. AB - Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCalphaS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCalpha potential as a prognostic biomarker, PKCalpha expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCalpha expression with the highest discrimination for incidence of relapse was identified. Patients with PKCalpha down-regulation, compared to patients with PKCalpha levels above the threshold, presented a markedly increased cumulative incidence of relapse (43.8% vs. 10.9%, P<0.001), as well as a worse 4-year overall survival (66% vs. 87.9%, P=0.002) and event-free survival (53.1% vs. 85.2%, P=0.002). In particular, low PKCalpha expression identified cases with extremely poor outcome within the high-risk minimal residual disease (MRD) stratum, their incidence of relapse being of 69% vs. 15% in the high PKCalpha levels group. In a multivariate analysis adjusting for main prognostic features, PKCalpha proved to be an independent prognostic factor related to incidence of relapse. Very high risk patients within the high-risk MRD stratum, identified by PKCalpha expression, could be proposed for experimental therapeutic protocols. PMID- 25026301 TI - High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients. AB - We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases tumorogenesis, induces epithelial-to-mesenchymal transition (EMT) and chemoresistance in SCLC. We sought to evaluate circulating HGF levels in SCLC patients and assess correlation with outcome and EMT features in the tumor. Serum samples from patients with SCLC were prospectively obtained at diagnosis, response evaluation and progression. HGF serum (sHGF) was quantified by ELISA. EMT markers and p-Met/Met were assayed by immunohistochemistry in tumor samples. Clinical data were prospectively recorder. One-hundred twelve patients were included. High baseline levels of sHGF were associated with shorter overall survival (p=0.006) and remained independently associated with survival in the multivariate analysis (p=0.016). For stage IV patients, an increase of sHGF levels at response evaluation (p=0.042) and at progression (p=0.003) were associated with poor outcome. sHGF levels were associated (p<0.05) with a mesenchymal phenotype in the tumor. In conclusion, high sHGF at diagnosis and increases during the course of the disease predict for poor outcome in SCLC patients and associate with EMT in the tumor. These data provide novel evidence on a role of sHGF in the adverse clinical behavior of SCLC and supports testing Met inhibitors in patients with high sHGF. PMID- 25026302 TI - Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury. AB - OBJECTIVE: Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value. Previously, we found that overexpression of profurin, the 83-amino acid prodomain of the proprotein convertase furin, lowered plasma HDL levels in wild-type mice. The question that remained was whether it had effects on apolipoprotein B (ApoB)-containing lipoproteins. METHODS: Adenovirus mediated overexpression of hepatic profurin in Ldlr(-/-)mice and wild-type mice were used to evaluate effects of profurin on ApoB-containing lipoproteins, atherosclerosis and vascular remodeling. RESULTS: Hepatic profurin overexpression resulted in a significant reduction in atherosclerotic lesion development in Ldlr(-/-)mice and a robust reduction in plasma LDL-c. Metabolic studies revealed lower secretion of ApoB and triglycerides in VLDL particles. Mechanistic studies showed that in the presence of profurin, hepatic ApoB, mainly ApoB100, was degraded by proteasomes. There was no effect on ApoB mRNA expression. Importantly, short-term hepatic profurin overexpression did not result in hepatic lipid accumulation. Blood vessel wall thickening caused by either wire-induced femoral artery injury or common carotid artery ligation was reduced. Profurin expression inhibited proliferation and migration in vascular smooth muscle cells in vitro. CONCLUSION: These results indicate that a profurin-based therapy has the potential to treat atherosclerosis by improving metabolic lipid profiles and reducing both atherosclerotic lesion development and pathological vascular remodeling. PMID- 25026303 TI - Bifidobacterium longum and Bifidobacterium breve isolates from preterm and full term neonates: comparison of cell surface properties. AB - We compared autoaggregation, surface hydrophobicity and Caco-2 cells adhesion capabilities of independent Bifidobacterium breve (n = 22) and Bifidobacterium longum (n = 25) strains isolated from preterm (n = 20) and full term neonates (n = 27). Concerning strains properties, a correlation between autoaggregation and surface hydrophobicity was found for B. longum (r = 0.40, p = 0.048), B. breve (r = 0.57, p = 0.005), and all strains independently of the species consideration (r = 0.46, p = 0.001). The absence of difference in adhesion capabilities between preterm and full term neonate strains suggests a strain-dependent property. However, B. longum strains from preterm neonates (n = 10) showed higher autoaggregation ability (p = 0.044). Additionally, independently of species consideration, preterm neonates strains showed lower surface hydrophobicity (p = 0.027). As far as species are considered, preterm neonate B. breve strains (n = 10) showed significantly lower surface hydrophobicity percentages (p = 0.043). Our results suggest the existence of variations in bifidobacteria membrane structure and/or composition that may reflect adaptation of these bacteria to the intestinal environment of either preterm or full term neonates. Such information is of interest when considering the use of bifidobacteria probiotic strains for modulation of preterm neonates gut microbiota. PMID- 25026304 TI - Tuning the underwater oleophobicity of graphene oxide coatings via UV irradiation. AB - Ultraviolet (UV) irradiation was utilized to gradually modify the chemistry and structure of graphene oxide (GO) flakes, as confirmed by XPS and AFM. Ultrathin GO coatings/membranes, made of UV-irradiated flakes, showed tunable underwater oleophobicity. UV-treated, superoleophobic GO membranes exhibited excellent antifouling capability for oil/water separation. PMID- 25026305 TI - Sports injuries and their management: what are the rugby league clubs providing? AB - Officials from nine of the twelve Sydney first grade rugby league football clubs were inter-viewed to determine what their clubs offered their athletes regarding sports injury management. This survey describes the different personnel used by the clubs, and their roles in injury treatment and physical conditioning programmes. It is concluded that some clubs are advancing in the areas of immediate injury treatment and injury prevention, but that the majority have deficiencies in their programmes related to these areas. It is also suggested that sports medical care and knowledge in this and similar sports would benefit by a greater involvement of a wider range of health professionals, to add to that already provided by medical doctors. PMID- 25026306 TI - Physiotherapy in leprosy. AB - Leprosy in the past has been shrouded in mystery and characterised by deformity. While much more is known of the disease today, allowing the majority of patients to be treated without undue difficulty, physiotherapy in lep-rosy has grown out of a need to prevent, minimise and correct deformities caused by the disease. This paper presents the aetiology of deformity in leprosy and outlines the role of physiotherapy in the management of leprosy patients with neuritis and permanent paralysis. It also describes physiotherapy in tendon transfer surgery and emphasises the need for a domicillary treatment programme to suit the leprosy endemic areas in the Northern Territory of Australia. PMID- 25026307 TI - Occupational physiotherapy in australia. PMID- 25026308 TI - A four year follow-up of infants with early signs of neuro-developmental deviation. AB - The transient and variable nature of abnormal or deviant neuro-developmental signs during the early post-term months of 'high risk' infants, has been recognized. Careful longitudinal follow-up of these children is indicated. This study investigates the neuro-sensory-motor and general developmental progress over four years, of a group of children who were identified as 'dystonic' at the adjusted age of four months. The developmental performance of these 15 children was compared with a matched group of children. The results indicated that at four years of age the 'dystonic' group of children were developmentally less competent and more variable in all areas assessed than their 'non-dystonic' peers. Only one child was ultimately diagnosed as cerebral palsy indicating the transient nature of quite marked early signs. The implications for possible problems at school emphasize the need for continued follow-up of this group of children. PMID- 25026309 TI - Electrode coupling media for transcutaneous electrical nerve stimulation. AB - In transcutaneous nerve stimulation current is supplied to the patient using surface electrodes which make electrical contact via wetted sponges or a conductive gel. This paper reports measurements of the electrical characteristics of ten commercially available gels. Five are recommended by the manufacturers as being suitable for electrode coupling only, three are recommended for ultrasound coupling only and two are designated 'dual purpose'. Marked differences in electrical conductivity are found. Both the dual purpose and ultrasound gels are found to be electrically inferior to 'electrode only' gels. The results are discussed in relation to different electrode types and in comparison with saline moistened sponges. PMID- 25026310 TI - Techniques and outcomes of combined inferior vena cava and visceral resection for benign and malignant disease. AB - BACKGROUND: Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contra-indication to curative surgery because of high surgical risks and poor long-term prognosis. Advances in surgical and anaesthetic techniques however have made this feasible. The aim of this study is to evaluate the outcome of combined IVC and visceral resection in a single institution. METHODS: A retrospective review of a prospectively maintained database was performed. Pre-operative clinicopathological data, operative details and post-operative outcomes including overall and disease-free survival were analysed. Clinicopathological data of patients over a seven-year period undergoing combined IVC and visceral resection was reviewed, including overall and disease-free survival. RESULTS: Between 2006 and 2012, 14 patients underwent IVC resection was accompanied by major hepatectomy (8), nephrectomy (6) and multivisceral resection (3). Post resection, the IVC was reconstructed primarily (3); with PTFE tube graft (9) or using a Gore-tex patch graft (2). All patients underwent a R0 resection. There were two postoperative deaths within 30 days. 6 patients had postoperative complications. There was 1 early and one late (after 6 months) IVC thrombosis. With a median follow up of 20 months (range 5-84 months), two patients died of tumour recurrence and ten are alive with (n = 5) or without (n = 5) disease. CONCLUSION: Combined IVC and visceral resection can be safely performed in selected patients. Surgery provides the possibility of negative margins, acceptable perioperative morbidity/mortality and prolonged survival. These factors combined with lack of alternative treatments justify this approach. However, specialist teams should perform the surgery preferably in centres with expertise in liver transplantation. PMID- 25026311 TI - The rationality of N3 classification in the 7th edition of the International Union Against Cancer TNM staging system for gastric adenocarcinomas: a case control study. AB - BACKGROUND: The 7th edition of the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) tumor-node-metastasis (TNM) classification system for gastric cancer is more detailed than the 6th edition with respect to tumor depth and lymph node metastasis. The purpose of this study was to evaluate the rationality of the 7th UICC/AJCC TNM classification system, focusing on N3 gastric cancers. METHODS: A total of 338 patients with N3 gastric cancer who underwent curative resection with >= 16 retrieved lymph nodes at two institutions between January 1997 and December 2007 were included in this study. Patients were divided into the N3a (n = 210) and N3b (n = 128) groups. Clinicopathologic characteristics and survival rates were compared between groups. RESULTS: No difference in clinicopathologic characteristics, including age (p = 0.989), sex (p = 0.382), tumor location (p = 0.124), surgery type (p = 0.909), depth of invasion (p = 0.313), histologic type (p = 0.111), and Lauren classification (p = 0.491), was observed between patients with N3a and N3b gastric cancer. However, overall survival (OS) rates of patients with N3a gastric cancer were greater than that of patients with N3b gastric cancer (5-year OS, 46% vs. 28%; 10-year OS, 33% vs. 19%; both p < 0.001). Five-year survival rates differed significantly between patients with T3N3a and T3N3b (p = 0.006) sub-stages and between those with T4aN3a and T4aN3b (p = 0.004) sub-stages. CONCLUSIONS: The results of this study support N3 sub-classification for gastric cancers, which warrant differential consideration according to TNM stage. PMID- 25026312 TI - Sweet escape: sialic acids in tumor immune evasion. AB - Sialic acids represent a family of sugar molecules derived from neuraminic acid that frequently terminate glycan chains and contribute to many biological processes. Already five decades ago, aberrantly high expression of sialic acids has been proposed to protect cancer cells from recognition and eradication by the immune system. Today, increased understanding at the molecular level demonstrates the broad immunomodulatory capacity of tumor-derived sialic acids that is, at least in part, mediated through interactions with immunoinhibitory Siglec receptors. Here we will review current studies from a sialic acid sugar perspective showing that tumor-derived sialic acids disable major killing mechanisms of effector immune cells, trigger production of immune suppressive cytokines and dampen activation of antigen-presenting cells and subsequent induction of anti-tumor immune responses. Furthermore, strategies to modulate sialic acid expression in cancer cells to improve cancer immunotherapy will be discussed. PMID- 25026313 TI - Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. AB - Inhibitors of poly(ADP-ribose) polymerases actualized the biological concept of synthetic lethality in the clinical practice, yielding a paradigmatic example of translational medicine. The profound sensitivity of tumors with germline BRCA mutations to PARP1/2 blockade owes to inherent defects of the BRCA-dependent homologous recombination machinery, which are unleashed by interruption of PARP DNA repair activity and lead to DNA damage overload and cell death. Conversely, aspirant BRCA-like tumors harboring somatic DNA repair dysfunctions (a vast entity of genetic and epigenetic defects known as "BRCAness") not always align with the familial counterpart and appear not to be equally sensitive to PARP inhibition. The acquisition of secondary resistance in initially responsive patients and the lack of standardized biomarkers to identify "BRCAness" pose serious threats to the clinical advance of PARP inhibitors; a feeling is also emerging that a BRCA-centered perspective might have missed the influence of additional, not negligible and DNA repair-independent PARP contributions onto therapy outcome. While regulatory approval for PARP1/2 inhibitors is still pending, novel therapeutic opportunities are sprouting from different branches of the PARP family, although they remain immature for clinical extrapolation. This review is an endeavor to provide a comprehensive appraisal of the multifaceted biology of PARPs and their evolving impact on cancer therapeutics. PMID- 25026315 TI - Endotracheal tube management in newborn infants with hyaline membrane disease. AB - Eighty-six intubated infants with hyaline membrane disease were randomized to have either 0.5 ml saline, or nothing inserted down the endotracheal tube (ETT) prior to 4-hourly suctioning. The aim of the study was to determine if routine saline instillation was of benefit in maintaining ETT patency. The endpoint was (1) when the staff caring for the patient considered the secretions were increasing with the likelihood of the ETT blocking, or (2) the tube was presumed blocked and on removal was blocked. For infants with a 2.5 mm ETT the mean hour of the endpoint was 13.5 if no saline was used and this was increased to 77.6 if saline was used (p<0.05). There was no difference with either a 3.0 or 3.5 mm ETT if saline was used or not. PMID- 25026314 TI - Photoredox alpha-vinylation of alpha-amino acids and N-aryl amines. AB - A new coupling protocol has been developed that allows the union of vinyl sulfones with photoredox-generated alpha-amino radicals to provide allylic amines of broad diversity. Direct C-H vinylations of N-aryl tertiary amines, as well as decarboxylative vinylations of N-Boc alpha-amino acids, proceed in high yield and with excellent olefin geometry control. The utility of this new allyl amine forming reaction has been demonstrated via the syntheses of several natural products and a number of established pharmacophores. PMID- 25026316 TI - The interrelation of spinal curves, pelvic tilt and muscle lengths in the adolescent female. AB - Thoracic kyphosis, lumbar lordosis and pelvic tilt were measured in standing in one hundred and three adolescent females, using a specially designed inclinometer. Indices of the muscle lengths (abdominals, erector spinae, iliopsoas, gluteals, rectus femoris and hamstrings) were measured using inclinometry and goniometry and expressed as angles of joint position. Multiple regression analysis revealed that the index of erector spinae length was negatively correlated with lumbar lordosis (r = - 0.24, p < 0.05). The abdominal length index was positively correlated with lumbar lordosis (r = 0.209, p < 0.05), and the hamstring length index was negatively correlated with lordosis (r = - 0.213, p < 0.05). No muscle length index was significantly related to pelvic tilt. A negative association between the degree of thoracic kyphosis and the abdominal length index was found (r = -0.245, p < 0.05). PMID- 25026317 TI - Acoustic output from therapeutic ultrasound units. AB - Reports of metered inaccuracy in 'therapeutic' ultrasound unit output have been made since 1962, but have tacitly been accepted, perhaps due to the universal lack of appropriate testing facilities. Factors of treatment selection subject to instrumental error include duration of application, operating frequency, intensity, pulsed output. Metered errors in space-averaged intensity are common and are the most difficult to detect without specialised equipment which is rarely available. Couplants, essential for ultrasound transmission, can be a source of acoustic power loss if incorrectly used. Beam profiles demonstrate the rapid spatial variations in the near (Fresnel) zone, necessitating soundhead movement during treatment. Ultrasound physics must be understood, but professional integrity should demand better output testing facilities and equipment for clinical treatment. PMID- 25026318 TI - A review of the use of electro-motor stimulation in human muscles. AB - The use of electrical stimulation in rehabilitation is a long established procedure for the management of a wide variety of musculoskeletal problems. This paper reviews important findings from studies on the electro-motor stimulation (EMS) of human muscles. It is particularly concerned with the results of EMS in normal subjects and in the rehabilitation setting, focusing on the stimulus parameters and training protocols used by various authors. A brief account is also given of some of the physiological effects of EMS on muscle. Attention is drawn to the urgent need for a more systematic approach to establish the optimal stimulation and training parameters. These factors must be considered when evaluating studies concerned with the efficacy of EMS-based rehabilitation programmes. PMID- 25026319 TI - The influence of unilateral electrical muscle stimulation on motor unit activity patterns in atrophic human quadriceps. AB - The efficacy of electrical muscle stimulation to restore motor function was investigated in fifteen males who described prior knee surgery/injury. Persisting strength imbalance between limbs related also to reduction in cross-sectional area of the affected quadriceps, as assessed by computed tomography of the midthigh. Subjects underwent a four-week programme of daily electro-motor stimulation with repeated assessment of force production by the knee extensors, correlated with surface electro-myography. Results showed no change in quadriceps cross-sectional area over the course of the study, however, significant improvements in force production for both limbs were achieved, accompanied by alteration in motor unit activity patterns to suggest that neural efficiency of motor unit activation (synchronization) may account for the improvements, as opposed to a marked morphological contribution. PMID- 25026320 TI - Torque production in human upper and lower limb muscles with voluntary and electrically stimulated contractions. AB - Two studies are reported in which the elbow flexor and extensor muscle groups and the quadriceps femoris muscle group in fifteen normal female subjects were tested under voluntary and electrically stimulated conditions. The torque produced during a maximum voluntary contraction (MVC) at each of six pre-determined joint angles was compared to the torque produced in maximum tolerated contractions (MTC) by two types of electrical stimulation (conventional interferential and high voltage stimulation). Results indicated a significant difference (p < 0.01) between the mean torque values produced by the MVC at all angles tested compared to the MTC. At the most favourable angle for producing an MTC, a mean torque of between 45 and 55% of an MVC for the elbow flexor and extensor muscles, and 65 to 74% for the quadriceps femoris muscle may be expected from both the high voltage and interferential stimulators. PMID- 25026321 TI - Maximum torque production in the quadriceps femoris muscle group using a variety of electrical stimulators. AB - A variety of electrical stimulators were used to produce a maximum tolerable contraction (MTC) in the non-dominant quadriceps femoris muscle group of 14 normal female subjects. This was compared to each subject's maximum voluntary contraction (MVC). A robotic dynamometer (Kin-Com) was used to control and measure joint angle and isometric torque production. Results indicated considerable variation in the torque produced by each subject under the different stimulation conditions. In general there were no significant differences in the force produced by each type of stimulator. However, significant differences were observed between all MTCs and MVC. Several subjects achieved a contraction under electrical stimulation in excess of their MVC. PMID- 25026322 TI - Origin of anomalous electronic circular dichroism spectrum of RuPt2(tppz)2Cl2(PF6)4 in acetonitrile. AB - We report a theoretical study of the structures, energetics, and electronic spectra of the Pt(II)/Ru(II) mixed-metal complex RuPt2(tppz)2Cl2(PF6)4 (tppz = 2,3,5,6-tetra(2-pyridyl)pyrazine) in acetonitrile. The hybrid B3LYP density functional theory and its TDDFT methods were used with a complete basis set (CBS) extrapolation scheme and a conductor polarizable continuum model (C-PCM) for solvation effects. Results showed that the trinuclear complex has four types of stable conformers and/or enantiomers. They are separated by high barriers owing to the repulsive H/H geometrical constraints in tppz. A strong entropy effect was found for the dissociation of RuPt2(tppz)2Cl2(PF6)n in acetonitrile. The UV visible and emission spectra of the complex were also simulated. They are in good agreement with experiments. In this work we have largely focused on exploring the origin of anomalous electronic circular dichroism (ECD) spectra of the RuPt2(tppz)2Cl2(PF6)4 complex in acetonitrile. As a result, a new mechanism has been proposed together with a clear illustration by using a physical model. PMID- 25026323 TI - The atypical antidepressant and neurorestorative agent tianeptine is a MU-opioid receptor agonist. AB - Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. However, in spite of three decades of basic and clinical investigations, the molecular target of tianeptine, as well as its mechanism of action, remains elusive. Herein, we report the characterization of tianeptine as a MU-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (K(i Human) of 383+/-183 nM and EC(50 Human) of 194+/-70 nM and EC(50 Mouse) of 641+/-120 nM for G-protein activation). Tianeptine was also a full delta-opioid receptor (DOR) agonist, although with much lower potency (EC(50 Human) of 37.4+/-11.2 MUM and EC(50 Mouse) of 14.5+/ 6.6 MUM for G-protein activation). In contrast, tianeptine was inactive at the kappa-opioid receptor (KOR, both human and rat). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions. PMID- 25026324 TI - Two consecutive births after ovarian preservation in a Gorlin syndrome patient. PMID- 25026325 TI - The changing role of the resident. AB - Over the past decade the growing acceptance of the concept of Team Medicine and the advent of Intensive Care Units has led to a change in the role of the physiotherapist. This change requires a round-the-clock physiotherapy service and demands that the therapist take increased personal responsibility for patients, as the treatment given is essential and indeed may be life-saving. PMID- 25026326 TI - Recollections of early resident physiotherapy. AB - The Physiotherapy staff establishment at the Royal Prince Alfred Hospital from 1933 until 1940 was one resident Chief Physiotherapist, two Junior Residents, and six full-time day staff (working a five and one-half day week). There was no Resident Staff at Royal North Shore Hospital during this period. PMID- 25026327 TI - Resident work at the royal north shore hospital: a.-Emergency plaster casts. AB - The emergency twenty-four hour service provided by the Physiotherapy Department at the Royal North Shore Hospital is chiefly concerned with Chest Management and Plaster of Paris application to fractures. PMID- 25026328 TI - B.-Care of the acute tetraplegic. AB - When a patient is admitted to the Spinal Unit of the Royal North Shore Hospital following a cervical cord injury, the physiotherapist begins treatment as soon as the diagnosis has been confirmed. She must have an exact knowledge of spinal cord levels so that she can assess the extent of diminished respiratory muscle power. The patient is lying on his back at this stage and may have had Blackburn calipers and traction applied. PMID- 25026329 TI - Physiotherapy for thoracic disease. AB - Physiotherapists have become important members of the treatment team for thoracic disease. PMID- 25026330 TI - The resident and the orthopaedic team. AB - The physiotherapist is an essential member of any orthopaedic team. PMID- 25026331 TI - Antiplasmodial activity of extracts of 25 cyanobacterial species from coastal regions of Tamil Nadu. AB - CONTEXT: Marine cyanobacteria offer considerable potential to isolate new antimalarials to meet a pressing need of our times. OBJECTIVE: To explore the antiplasmodial properties of marine cyanobacteria. MATERIALS AND METHODS: Cyanobacterial samples collected from the coastal regions of Tamil Nadu were identified using light microscopy, and the strains were cultivated in ASN-III medium. Organic extracts (0-100 ug mL(-1)) of 25 in vitro mass-cultivated cyanobacteria, prepared using methanol: chloroform mixture (1:1 v/v) were evaluated for their antiplasmodial activity against chloroquine-sensitive and resistant strains of Plasmodium falciparum by fluorescence-based SYBR Green I assay where chloroquine was used as a control. To detect the toxic effects of cyanobacterial extracts against red blood cells, the invasion, maturation, and growth rate of malarial parasites in cyanobacterial extracts pre-treated versus untreated erythrocytes were quantified microscopically. Mammalian cell line (HeLa) was used to determine cyanobacterial extract toxicity using the MTT assay. RESULTS: The extracts of Lyngbya aestuarii Liebm. ex Gomont CNP 1005 (C12) Oscillatoria boryana BDU 91451 (C22) and Oscillatoria boryana Bory ex Gomont BDU 141071 (C18) showed promising antiplasmodial activity (IC50 = 18, 18, and 51 MUg mL(-1) respectively) against Pf3D7. Pretreatment of red blood cells with IC100 of C12, C18, and C22 (40, 100, and 40 ugmL(-1), respectively) did not significantly influence the invasion, maturation, and growth rate of malarial parasites in comparison with untreated RBC controls suggesting a lack of toxicity to host cells. MTT assay based IC50 (>200 MUg mL(-1)) of these extracts against HeLa cell line also indicates their high selectivity against the malaria parasite. DISCUSSION AND CONCLUSION: These exploratory studies suggest the possibilities of development of new antimalarial compounds from marine cyanobacteria. PMID- 25026332 TI - Gastroprotective activity of polyphenolic-rich extract of Potentilla mooniana. AB - CONTEXT: Potentilla mooniana Wight. (Rosaceae) is a plant found in the Himalayan region where the root is traditionally used to treat stomach problems including gastric-ulcer. OBJECTIVE: To scientifically validate the gastro-protective effect and derive the possible mechanistic activity of the ethanol root extract from P. mooniana (EPM). MATERIALS AND METHODS: The gastroprotective effect of EPM (100 400 mg/kg, p.o.) was evaluated on both the physical (Pyloric ligation, PL; Cold restrain stress, CRS) and chemical (absolute ethanol, EtOH; aspirin, ASP) ulcerogens induced ulceration in rats. The mechanistic activity of EPM was tested on various gastric-ulcer parameters, namely gastric pH, volume, acid-pepsin output, DNA content, histamine level, H(+)K(+)-ATPase activity, mucus content, microvascular permeability, antioxidant markers, and gastric-histopathological study. RESULTS: EPM significantly reduces the ulcer score against all the four tested gastric-ulcer models. In the PL model, EPM showed significant reduction (p < 0.05) in acid-pepsin output and cell shedding; however, no significant effect was observed on gastric volume, cell proliferation, stomach glandular weight, and histamine levels. EPM (400 mg/kg, p.o.) when compared with ulcer control showed significant increase in gastric pH by 41.6% and decrease in H(+)K(+)-ATPase activity by 47.73%. In addition, EPM showed significant increase in mucus content by 58.60% and a decrease in the microvascular permeability of Evans Blue by 85.00%, justifying its protective effects. Furthermore, EPM also showed significant antioxidant activity and histopathologically possessed excellent cytoprotective effect. CONCLUSION: The gastro-protective effect of EPM is attributed mainly to the defensive mechanism owing to the presence of a good quantity of polyphenolic components. PMID- 25026333 TI - Evaluation of antidiabetic properties of cactus pear seed oil in rats. AB - CONTEXT: Cactus pear (Opuntia ficus-indica (L.) Mill. (Cactaceae)) is a medicinal plant widely used to treat diabetes. OBJECTIVE: This work investigates the hypoglycemic and antihyperglycemic effect of cactus pear seed oil (CPSO), its mechanism of action, and any toxic effects. MATERIALS AND METHODS: The hypoglycemic effect of CPSO was evaluated in groups of six healthy Wistar rats given 1 or 2 ml kg(-1) orally and compared with groups receiving glibenclamide (2 mg kg(-1)) or water. Glycemia was determined after 30, 60, 120, 240, and 360 min. The antihyperglycemic effect of CPSO was determined in healthy rats and in streptozotocin-induced diabetic rats (STZ); normal rats received 0.8 ml kg(-1) CPSO, while diabetic rats received 1 ml kg(-1) CPSO, their controls received water or 2 mg kg(-1) glibenclamide. For the antihyperglycemic effect evaluation, all the animals were fasted for 16 h before treatment and received glucose orally at 1 g kg(-1) 30 min after treatment; blood was taken after 30, 90, 150, and 210 min. Intestinal glucose absorption was estimated in rat jejunum perfused with a solution containing 5.55 mmol l(-1) glucose. Acute toxicity was determined in albino mice that received oral or intraperitoneal doses of 1, 3, or 5 ml kg(-1) CPSO. RESULTS: CPSO (p.o.) decreased postprandial hyperglycemia (60 min after glucose loading), 40.33% and 16.01%, in healthy and STZ-diabetic glucose-loaded rats, respectively. CPSO, also, significantly decreased intestinal glucose absorption by 25.42%. No adverse effects were seen in mice administered CPSO at up to 5 ml kg(-1). CONCLUSION: CPSO is antihyperglycemic. The effect can be explained partly by inhibition of intestinal glucose absorption. PMID- 25026334 TI - Xanthone-rich dichloromethane fraction of Securidaca inappendiculata, the possible antirheumatic material base with anti-inflammatory, analgesic, and immunodepressive effects. AB - CONTEXT: Securidaca inappendiculata Hassk. is an traditional Chinese medicine curing rheumatoid arthritis, but there is a lack of reports on material base research. OBJECTIVE: To find the active fraction of S. inappendiculata contributing the most to antirheumatic activity. MATERIALS AND METHODS: Prior to assays in vivo, mice were treated with different fractions from S. inappendiculata for 5 d at doses relative to 10, 5, and 2.5 g/kg of crude drug. Hot plate test and carrageenan-induced paw edema test were used to investigate analgesic and anti-inflammatory activities. PGE2 levels in inflammatory paws were determined by a colorimetric method. Carbon clearance test in vivo and lymphocyte transformation test in vitro were employed to assess the immune regulation activity. HPLC was used to explore the main compounds in the active fraction. RESULTS: All the fractions, especially the dichloromethane fraction (SID), alleviated inflammation. High dose of SID (112 mg/kg) inhibited paw swelling by 63.1%, and decreased PGE2 level to 38 ng/mL. The ethyl acetate fraction (SIE) and SID suppressed the carbon clearance rate (K = 0.044, 0.038 for high dose) efficiently. All fractions hindered the transformation and proliferation of lymphocyte, and prolonged the reaction time of rats in the hot plate test. The concentrations of two typical xanthones: 2-hydroxyl-1,7-dimethoxyl-xanthone and 1,7-dihydroxyl-xanthone in SID were 0.93% and 1.19%, respectively, by HPLC analysis. CONCLUSION: SID exhibited significant anti-inflammatory, analgesic, and immunodepressive effects in vivo and vitro, and deemed as the main material base for the antirheumatic activity. PMID- 25026335 TI - Antiviral and cytotoxic evaluation of coumarins from Prangos ferulacea. AB - CONTEXT: Prangos ferulacea (L.) Lindl. (Apiaceae) is a perennial plant found in the Middle-East, where it is commonly used as an antispasmodic and anti inflammatory agent. It is a rich source of coumarins. OBJECTIVE: To purify several coumarins from P. ferulacea and to screen their cytotoxicity and anti herpes activity. MATERIALS AND METHODS: Acetone extract of roots of P. ferulacea was subjected to several chromatographic separations to render pure coumarins (1 8). Anti-herpes virus effects of 1-7 were evaluated at concentration 2.5, 5, and 10 ugmL(-1), on a confluent monolayer of Vero cells infected with 25 PFU of HSV1. Cytotoxic effects of 1 and 2 were evaluated on an A2780S cell line using the MTT assay. The cells were exposed to a series of concentrations of coumarins (0.01 2.5 mM, 37 degrees C, 72 h). RESULTS: Compounds 1-8 were identified as osthole, isoimperatorin, oxypeucedanin, psoralen, oxypeucedanin hydrate, gosferol, oxypeucedanin methnolate, and pranferol. This is the first report of occurrence of 4 and 7 in this plant. Compound 1 showed a viability of 9.41% +/- 2.4 at 2.5 mM on A2780S cells (IC50 = 0.38 mM). The cell survival of 2 at 2.5 mM was 46.86% +/- 5.5 with IC50 equal to 1.1 mM. DISCUSSION AND CONCLUSION: Compound 1 shows cytotoxic effects on the A2780S cell line. Compound 2 is a cyclooxygenase-2 inhibitor and the A2780S cell line does not express COX-2 which may interpret the non-toxic effect of the compound on this cell line. None of the tested compounds showed an anti-HSV effect at non-toxic concentrations. PMID- 25026336 TI - Biological activity of clovers - free radical scavenging ability and antioxidant action of six Trifolium species. AB - CONTEXT: Clovers were chosen on the basis of traditional medicine recommendations, agricultural value, or available information on their promising chemical profiles. OBJECTIVE: This study evaluates and compares free radical scavenging and antioxidant properties of six clover species: Trifolium alexandrinum L. (Leguminosae), Trifolium fragiferum L., Trifolium hybridum L., Trifolium incarnatum L., Trifolium resupinatum var. majus Boiss., and Trifolium resupinatum var. resupinatum L. MATERIALS AND METHODS: Free radical scavenging activity of the extracts (1.5-50 ug/ml) was estimated by reduction of 1,1 diphenyl-2-picrylhydrazyl (DPPH(*)) and 2,2'-azino-bis(3-ethylbenzthiazoline-6 sulphonic) acid (ABTS(*)) radicals. The Trifolium extract effects on total antioxidant capacity of blood plasma were determined by the reduction of ABTS(*+) and DPPH(*) radicals, as well as with the use of the ferric reducing ability of plasma (FRAP) assay. RESULTS: The UPLC analysis of chemical profiles of the examined extracts showed the presence of three or four groups of phenolic substances, including phenolic acids, clovamides, isoflavones, and other flavonoids. The measurements of free radical scavenging and ferric reducing ability of the examined clover extracts revealed the strongest effect for T. alexandrinum. Furthermore, antioxidant activity assays in human plasma have shown protective effects of all extracts against peroxynitrite-induced reduction of total antioxidant capacity. CONCLUSIONS: Trifolium plants may be a rich source of bioactive substances with antioxidant properties. The examined extracts displayed free radical scavenging action and partly protected blood plasma against peroxynitrite-induced oxidative stress; however, the beneficial effects of T. alexandrinum and T. incarnatum seem to be slightly higher. PMID- 25026337 TI - Cytotoxicity of the compounds isolated from Pulsatilla chinensis saponins and apoptosis induced by 23-hydroxybetulinic acid. AB - CONTEXT: The rizoma of Pulsatilla chinensis (Bunge) Regel has been used as a traditional Chinese medicinal herb for thousands of years. Total saponins from P. chinensis can induce the apoptosis of solid cancer cells; however, their activity on chronic myeloid leukemia and the mechanisms remains unknown. OBJECTIVE: To study the activity of total saponins and the main active fractions from P. chinensis saponins on chronic myeloid leukemia, and to illustrate the mechanisms underlying the anticancer activities. MATERIALS AND METHODS: The cytotoxic activity were assayed by MTT; cell cycle arrest and apoptosis were tested by flow cytometry system; changes in the mitochondrial membrane potential were determined using JC-1; and the apoptosis signaling pathway was determined by western blotting. RESULTS: We demonstrated that total P. chinensis saponin displayed cytotoxic activity against K562 cell line. In addition, we identified 23 hydroxybetulinic acid (HBA), pulchinenoside A (PA), and anemoside B4 (AB4) from the total saponins, with the most cytotoxic compound HBA. Glycosylation at C3 and C28 of HBA significantly reduces its cytotoxicity. HBA could promote cell cycle arrest at S phase and induce apoptosis via intrinsic pathway. HBA disrupts mitochondrial membrane potential significantly (p < 0.01) and selectively downregulates the levels of Bcl-2, survivin and upregulates Bax, cytochrome C, cleaved caspase-9 and -3. DISCUSSION AND CONCLUSION: Total saponins from P. chinensis may be effective natural products against human chronic myelogenous leukemia; HBA is one of the bioactive components responsible for its anticancer activity, and could be further investigated as an alternative therapeutic drug for leukemia. PMID- 25026338 TI - Beneficial effect of Azadirachta indica on advanced glycation end-product in streptozotocin-diabetic rat. AB - CONTEXT: Both oxidation and hyperglycemia cause increased glycation and the formation of advanced glycation end-products (AGEs) which underlie the complications of diabetes. OBJECTIVE: The goal of this article is to determine the effect of the chloroform extract from leaves of Azadirachta indica A. Juss; (Meliaceae) (AI) on the formation of glycated protein. MATERIALS AND METHODS: Chloroform extract was subjected to in vitro bioassays to evaluate advanced glycation end-products formation. Bovine serum albumin (BSA)-glucose, BSA methylglyoxal, Amadori-rich protein, glycated hemoglobin, oxidation, and glycation of LDL were determined. Doses of AI of 200 mg/kg/d by oral gavage were administered once daily for 30 d, at streptozotocin-induced diabetic rats. After this period, renal damage (TBARS), glucose, methylglyoxal, glycolaldehyde, and tail tendon collagen were investigated. RESULTS AND DISCUSSION: AI exhibits protective action in BSA against glycation formation, GHb, protein levels, and LDL against glycation and oxidation. The renal glucose level decreases a 3.9 mg/g wet tissue. TBA-reactive substance showed a significant decrease to 1.82 mmol/mg protein. In addition, AI showed inhibitory activity against AGEs formation, methylglyoxal, and glycolaldehyde levels in kidney. Treatment with AI in rat tail tendon produced a reduction in cross-linking of collagen proteins. The antiglycation activities of A. indica were attributed in part to their antioxidant activity. AI alleviated oxidative stress under diabetic conditions through the inhibition of lipid peroxidation prevents the onset renal damage. CONCLUSION: We found that A. indica is an inhibitor AGE formation, and oxidative stress with a renoprotective effect, which are considered to play important roles in diabetic kidney disease. PMID- 25026339 TI - Acute oral toxicity of the ethyl acetate fraction of Orostachys japonicus in mice. AB - CONTEXT: Orostachys japonicus (Crassulaceae) is referred to as Wa-song in Korea. It is used as an anti-inflammatory, antifebrile, hemostatic, and anti cancer agent, and as an antidote. OBJECTIVE: The purpose of this study was to evaluate the acute toxicity of the ethyl acetate fraction of O. japonicus (OJE) after the oral administration in Balb/c mice of both sexes. MATERIALS AND METHODS: Mice were oral administered a single doses of 500, 1000, and 2000 mg/kg of body weight and were monitored for 14 d. Biochemical parameters [aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total protein (TP), globulin (GB), total cholesterol (TC), triglyceride (TG), blood urea nitrogen (BUN), and creatinine (CR)] and histopathological examination of liver were performed. RESULTS AND CONCLUSION: No animals died and no toxic changes were observed in clinical signs, body weight, and organ weight. The LD50 of orally administered OJE was higher than 2000 mg/kg/d in both sexes. No toxicological findings were found in biochemical parameters. In histophathological examination, neutrophilic infiltration was observed at a dose of 2000 mg/kg group in both sexes. These finding suggest that oral administration of OJE does not produce acute toxicity. Therefore, these results could provide satisfactory preclinical evidence of safety to launch clinical trials on standardized formulation of OJE to be a biohealth product. PMID- 25026340 TI - Interactions of the active components of Punica granatum (pomegranate) with the essential renal and hepatic human Solute Carrier transporters. AB - Abstract Context: Solute carrier transporters (SLCs) are membrane proteins responsible for cellular influx of various substances including many pharmaceutical agents; therefore, they largely impact on drug disposition and elimination in body. Punica granatum Linnaeus (Lythraceae), pomegranate, is a fruit with antidiabetic potential. Oleanolic acid (OA), ursolic acid (UA), and gallic acid (GA) are the major bioactive components of pomegranate. Co administration of these compounds with other drugs could result in altered drug pharmacokinetics, possibly due to competing for transporter proteins. OBJECTIVE: We investigated the interactions of these three compounds with the essential hepatic and renal SLC transporters. MATERIALS AND METHODS: Uptake of radiolabeled transporter model substrates was assessed in HEK293 cells over-expressing SLC transporters including the organic anion transporters (OATs), organic anion transporting polypeptides (OATPs) and organic cation transporters (OCTs), in the presence or absence of 10.0 uM UA, OA, or GA. Their IC50 values on specific SLC transporters were also evaluated using varying concentrations of the particular compound (ranging from 0.10 nM to 80.0 uM). RESULTS: Our results demonstrated UA could significantly inhibit OAT3 and OATP2B1 uptake (IC50: 18.9 +/- 8.20 uM and 11.0 +/- 5.00 uM, respectively) and GA has a pronounced inhibitory effect on OATP1B3 uptake (IC50: 1.60 +/- 0.60 MUM). DISCUSSION AND CONCLUSION: Our study reports the interactions of OA, UA, and GA with the essential SLC transporters. This information may contribute to elucidating the drug-drug/herb interactions involved with these three compounds and form the basis of therapeutic optimization when drugs are co-administered. PMID- 25026341 TI - Chemical constituents from Sedum aizoon and their hemostatic activity. AB - CONTEXT: Sedum aizoon L. (Crassulaceae) (SA) is widely used to treat various hemorrhages in folk medicine. However, its hemostatic constituents are not yet clear. OBJECTIVE: The chemical constituents of EtOAc fraction from SA and their hemostatic activity were investigated to provide a basis for the application in folk use. MATERIALS AND METHODS: The chemical constituents were isolated from the aerial parts of SA by column chromatography and identified by IR, MS, and NMR, then tested for hemostatic activity using the capillary method and coagulation assays including blood clotting time in vivo, and prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) in vitro at concentrations of 300.0, 100.0, and 30.0 ug/mL. RESULTS: Eleven compounds were identified as p-hydroxybenzoic acid (1), gallic acid (2), protocatechuic acid (3), vallinic acid (4), thymine (5), caffeic acid (6), 5,7-dihydroxy chromone (7), pyrogallol (8), quercetin (9), kaempferol (10), and luteolin (11). This is the first report of compounds 3-8 being isolated from this plant. Compounds 2 (300.0 and 100.0 ug/mL), 4 (100.0 ug/mL), and 11 (100.0 and 30.0 ug/mL) significantly reduced the clotting time (p < 0.01) with inhibition rates of 34.7, 24.5, 30.3, 25.9, and 36.6%, respectively. For further mechanism study, they also reduced PT (3.5, 2.5, 3.5, 3.5, and 3.8%, respectively), APTT (4.5, 3.3, 11.4, 8.5, and 11.1%, respectively), and TT (20.3, 3.8, 7.6, 6.1, and 10.3%, respectively). DISCUSSION AND CONCLUSION: SA produced hemostatic activity possibly related to the presence of gallic acid, vallinic acid, and luteolin, which may be potent candidates of hemostatic drug. PMID- 25026342 TI - In vivo anti-inflammatory and analgesic activities of strictosamide from Nauclea officinalis. AB - CONTEXT: Strictosamide is the main representative constituent of Nauclea officinalis Pierre ex Pitard (Rubiaceae), which has been used for a long time in China to treat diseases related to infection and inflammation, but its pharmacological activities are not well studied. OBJECTIVE: This work evaluates the anti-inflammatory and analgesic activities of strictosamide by in vivo experiments. MATERIALS AND METHODS: The anti-inflammatory activity was assessed in mice by models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema, acetic acid-elevated vascular permeability, and carboxymethylcellulose sodium (CMC-Na)-induced leukocyte migration. The analgesic activity was estimated in mice using acetic acid-induced writhing and hot-plate tests. Compound was injected to mice twice a day for 3 d at doses of 10, 20, and 40 mg/kg. RESULTS: At 20 and 40 mg/kg, strictosamide obviously decreased the TPA-induced mice ear edema (24.7 and 28.1% inhibition, respectively), and significantly inhibited acetic acid-stimulated peritoneal vascular permeability in mice (23.3 and 33.4% inhibition, respectively). It also significantly decreased the leukocytes in the mice peritoneal cavity induced by CMC-Na at all the tested doses (46.0, 49.1, and 58.7% inhibition, respectively). To acetic acid-induced writhing test in mice, strictosamide markedly prolonged the pain latency at 20 and 40 mg/kg and decreased the writhing counts at 40 mg/kg (49.7% inhibition). However, it did not obviously improve the pain threshold of mice in hot-plate test. DISCUSSION AND CONCLUSION: Strictosamide may have important effects on inflammation and inflammatory pain. The results provide scientific support for the role of strictosamide in the use of N. officinalis to treat inflammatory diseases. PMID- 25026343 TI - Eradication of methicillin-resistant Staphylococcus aureus infection by nanoliposomes loaded with gentamicin and oleic acid. AB - CONTEXT: Methicillin-resistant Staphylococcus aureus (MRSA) infection with its high incidence is responsible for nosocomial infections. MRSA strains resistant to multiple antibiotics have emerged increasingly. Recently, combination therapy and efficient drug delivery systems are developed to treat infections. OBJECTIVE: The aim of the present study was to evaluate antibacterial activities of combination of oleic acid and gentamicin against MRSA, in both free and liposomal forms, and in comparison with vancomycin. MATERIALS AND METHODS: The antibacterial activities against MRSA ATCC 43300 were assessed by the determination of minimum inhibitory concentration (MIC), MBC, and Fractional Inhibitory Concentration Index (FICI). The time-kill assays were performed to evaluate the potency of antibacterial agents. Nanoliposomal formulations of gentamicin, oleic acid, and combination of gentamicin with oleic acid were prepared by the dehydration-rehydration (DRV) method and characterized for size, zeta potential, and encapsulation efficiency. RESULTS: MIC values of gentamicin and oleic acid were 19.5 and >250 ug/ml, respectively. Synergetic effects were observed by the gentamicin and oleic acid combination; FICI was 0.5. Following incorporation of gentamicin into liposomal gentamicin and liposomal combination, the MIC values were reduced 15- and 27-fold, respectively. In comparison with vancomycin, liposomal combination was more effective in bacterial inhibition and killing. Liposomal combination was the most effective formula in time-kill study. DISCUSSION AND CONCLUSION: Liposomal formulation showed a higher antibacterial activity in comparison with the free forms and vancomycin. These carriers can improve antimicrobial activity as well as reducing the effective concentration required and inducing rapid bacterial clearance. PMID- 25026344 TI - Inhibitory effects of the ethyl acetate extract from bulbs of Scilla scilloides on lipoxygenase and hyaluronidase activities. AB - CONTEXT: Scilla scilloides Druce (Liliaceae) is a folk medicine to treat dermal inflammation; however, the medicinal properties of this plant have not been completely established. OBJECTIVE: The current study investigates the potent anti inflammatory effects of S. scilloides bulbs for its traditional usage using lipoxygenase and hyaluronidase as the inflammation model. To gain insight into the active constituents, nine homoisoflavones (1-9) were subsequently tested. MATERIALS AND METHODS: Lipoxygenase and hyaluronidase inhibition of ethyl acetate extract from the bulbs of this plant within 2000 ug/mL or homoisoflavones within 1000 uM were determined by colorimetric methods. RAW264.7 cells were incubated with 10 or 50 uM homoisoflavones plus lipopolysaccharide (LPS) for 24 h. The culture media were collected and analyzed for determination of the nitric oxide (NO) level by the colorimetric Griess method to measure the extent of inflammation. RESULTS: The extract exhibited inhibitory effects on lipoxygenase and hyaluronidase activities with IC50 values 31.5 and 169 ug/mL, respectively. Among the nine homoisoflavones tested, four (1 and 3-5) resulted in 79.3-97.9% higher lipoxygenase inhibition than 6.7-32.7% of the others at 500 uM. Calculated IC50 values indicated 5 as the compound responsible for strong lipoxygenase inhibition with 15.8 uM as the IC50 value. In the hyaluronidase assay, all homoisoflavones tested at 1000 uM demonstrated 16.2-58.0% inhibition. Incubating the cells in the presence of all nine homoisoflavones tested at 50 uM significantly suppressed the NO production, downward to 1.5-66.0%, in the LPS activated macrophage cells as a model. DISCUSSION AND CONCLUSION: These results may indicate a potential role of S. scilloides for anti-inflammatory purposes. PMID- 25026345 TI - DaoTan decoction (DTD) inhibits tumor necrosis factor-alpha (TNF-alpha)-induced expression of intercellular adhesion molecule-1 (ICAM-1), p53 and p21, in human umbilical vein endothelia cells (HUVECs). AB - CONTEXT: DTD is a Chinese herb prescription used for centuries to treat atherosclerosis or dizziness. Previous studies show that DTD could inhibit ICAM-1 expression induced by TNF-alpha. However, its mechanism has never been clearly described. OBJECTIVE: To examine the hypothesis that DTD might inhibit TNF-alpha induced ICAM-1 expression through regulating the expression of p53 and p21. MATERIALS AND METHODS: The rats were orally treated with DTD for 3 d (2.3 g/kg per day), and then the serum was collected. HUVECs were cultured and stimulated by TNF-alpha with or without DTD serum (5, 10, and 20%). The expression of ICAM-1 mRNA was examined by RT-PCR and the expression of p53 and p21 was examined by western blot analysis. RESULTS: The ICAM-1 mRNA levels induced by TNF-alpha were significantly reduced from 23 to 47%, and the expression of p53 and p21 mRNA levels were significantly reduced from 13 to 43% and 14 to 42%, as the concentration of DTD serum increased. In western blot, TNF-alpha-induced the expression of p53 and was inhibited from 15 to 53%, by DTD serum in a concentration-dependent manner. TNF-alpha-induced expression of p21 was inhibited from 2 to 37%, by DTD serum in a concentration-dependent manner. DISCUSSION AND CONCLUSION: DTD has a function of "dissolving phlegm", thus it is chosen for the treatment of atherosclerosis. This study demonstrated that DTD could significantly inhibit the expression of ICAM-1, p53 and p21, which are important factors of atherosclerosis. Therefore, the present study indicates the pharmacological basis for treatment of atherosclerosis with DTD. PMID- 25026346 TI - The protective effects of Cyperus rotundus on behavior and cognitive function in a rat model of hypoxia injury. AB - CONTEXT: Hypoxia injury (HI) with its long-term neurological complications is one of the leading causes of morbidity and mortality in the world. Currently, the treatment regimens for hypoxia are aimed only at ameliorating the damage without complete cure. The need, therefore, for novel therapeutic drugs to treat HI continues. OBJECTIVE: This study investigates the protective effects of the ethanol extract of Cyperus rotundus L. (Cyperaceae) (EECR), a medicinal plant used in Ayurvedic traditional medicine against sodium nitrite-induced hypoxia in rats. MATERIALS AND METHODS: We have evaluated the protective effect of 200 and 400 mg/kg of EECR against sodium nitrite-induced hypoxia injury in rats by assessing the cognitive functions, motor, and behavioral effects of EECR treatment along with the histological changes in the brain. By comparing the protective effects of standard drugs galantamine, a reversible cholinesterase inhibitor and pyritinol, an antioxidant nootropic drug against sodium nitrite induced hypoxia in rats, we have tested the protective ability of EECR. RESULTS: EECR at doses of 200 and 400 mg/kg was able to protect against the cognitive impairments, and the locomotor activity and muscular coordination defects, which are affected by sodium nitrite-induced hypoxia injury in rats. CONCLUSION: Based on our results, we suggest that the medicinal herb C. rotundus possesses a protective effect against sodium nitrite-induced hypoxia in rats. Further studies on these protective effects of EECR may help in designing better therapeutic regimes for hypoxia injury. PMID- 25026347 TI - Multi-constituent synergism is responsible for anti-inflammatory effect of Azadirachta indica leaf extract. AB - CONTEXT: Azadirachta indica A. Juss. (Meliaceaes) leaves have been used traditionally to treat swelling and rheumatism in Indian cultures. OBJECTIVE: To fractionate A. indica leaf extracts using bioactivity guided manner for identification of the active anti-inflammatory principles. MATERIALS AND METHODS: Polarity-gradient sequential extracts (petroleum ether, chloroform, methanol, and water) of A. indica leaves were screened for their anti-inflammatory potential using the carrageenan-induced rat paw edema model (1 g/kg). The chloroform extract was sequentially fractionated to obtain n-hexane (F-1), n-hexane chloroform (F-2), and chloroform (F-3) fractions and their inhibitory effect on rat paw edema was evaluated (500 mg/kg). Inhibitory effect of F-2 on granuloma formation, plasma interleukin (IL-1), and tumor necrosis factor (TNF-alpha) was assessed at the doses of 100, 200, and 400 mg/kg using the cotton pellet assay in rats. Three sub-fractions (SF-1, SF-2, and SF-3) were obtained upon chromatography of F-2, and their inhibitory effect on cyclooxygenase was assessed at 200 ug/mL concentration. The sub-fractions were subjected to gas chromatography-mass spectrometry (GC-MS). RESULTS: All the extracts showed significant anti-inflammatory effect; however, chloroform extract was the most effective against paw edema (53.25% inhibition). The three fractions of chloroform extract showed significant effect, while F-2 being the most potent (51.02%). F-2 demonstrated dose-dependent inhibition of granuloma and cytokines. Interestingly, all the sub-fractions of F-2 inhibited COX-1 and COX-2 with almost equal potential. GC-MS revealed that chemically the sub-fractions were totally different from each other. DISCUSSION AND CONCLUSION: Anti-inflammatory effect of A. indica is a result of cumulative and synergistic effects of diversified constituents with varying polarities that collectively exert the effect via suppression of cyclo-oxygenases and cytokines (IL-1 and TNF-alpha). PMID- 25026348 TI - Protective effects of Origanum vulgare ethanol extract against cyclophosphamide induced liver toxicity in mice. AB - Abstract Context: Despite its wide clinical use, cyclophosphamide (CP), an alkylating chemotherapeutic agent, possesses many adverse effects, including hepatotoxicity. Because Origanum vulgare L. (Lamiaceae) has antioxidative properties, it might protect against above-mentioned damage. OBJECTIVE: This study evaluated the protective effects of O. vulgare extract on CP-induced liver toxicity. MATERIALS AND METHODS: Mice were pretreated with aerial parts of O. vulgare ethanolic extract (intraperitoneally) at doses of 50, 100, 200, and 400 mg/kg for 7 consecutive days before the administration of a single 200 mg/kg intraperitoneal dose of CP 1 h after the last injection of O. vulgare. After 24 h, animals were anesthetized, blood samples and hepatic tissues were collected and used for biochemical and histological examination. RESULTS: Serum levels of hepatic markers were increased after CP treatment but restored in the O. vulgare pretreated groups. The serum ALT, AST, and ALP of the CP group were 196.49 +/- 3.82, 143.78 +/- 4.79, and 203.18 +/- 3.81 IU/l, respectively. However, pretreatment with 400 mg/kg O. vulgare significantly decreased the serum ALT, AST, and ALP to 52.49 +/- 2.18, 44.78 +/- 2.06, and 65.62 +/- 1.73 IU/l, respectively (p < 0.001). Histological examinations also confirmed the protective effects of O. vulgare against CP-induced liver toxicity. DISCUSSION AND CONCLUSION: Our results reveal that O. vulgare with high amount of flavonoids and phenolic compounds induces potent hepatoprotective mechanisms against CP. Therefore, O. vulgare might help defend the body against the side effects, particularly hepatic damages induced by chemotherapeutic agents. PMID- 25026349 TI - Anti-inflammatory potential of zootherapeutics derived from animals used in Brazilian traditional medicine. AB - CONTEXT: Animals are used for the treatment of diseases caused by inflammatory processes, although few studies evaluate their potential for these purposes. OBJECTIVES: To evaluate the anti-inflammatory potential of zootherapeutic products derived from vertebrates used in Brazilian traditional medicine. MATERIAL AND METHODS: The species analyzed were Tupinambis merianae, Iguana iguana, Crotalus durissus, Boa constrictor, and Euphractus sexcinctus. The methods used in anti-inflammatory assays were ear edema (topical) and paw (systemic). RESULTS: With regard to topical anti-inflammatory activity, the fat from T. merianae, C. durissus, I. iguana, B. constrictor, and E. sexcinctus reduced inflammation, while for systemic anti-inflammatory activity, only the fat and the skin of C. durissus, the skin of I. iguana and the fat from B. constrictor reduced inflammation. CONCLUSIONS: Studies should be conducted to evaluate the mechanisms of action for each product that demonstrated anti inflammatory activity as well as against other inflammatory processes. PMID- 25026350 TI - beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration. AB - CONTEXT: Propranolol, atenolol, and ICI118,551 are non-selective beta-adrenergic receptor (AR), beta1-AR, and beta2-AR antagonists, respectively. OBJECTIVE: We investigated the efficacy of propranolol, atenolol, and ICI118,551 on proliferation, migration, and invasion of non-stimulated breast (MCF7), colon (HT 29), and hepatocellular (HepG2) cancer cells. MATERIALS AND METHODS: beta-AR expression profiling of cells was performed by real time PCR. Cell proliferation was determined by MTT. Boyden chamber and scratch assays were performed to evaluate invasion and migration. RESULTS AND DISCUSSION: All cell lines expressed beta-ARs. ICI118,551 was the most cytotoxic, whereas atenolol was the least effective beta-AR antagonist for 24, 48, and 72 h. Cell invasion was inhibited by ICI118,551 (45, 46, and 50% for MCF7, HT29, and HepG2, respectively) and propranolol (72, 65, and 90% for MCF7, HT29, and HepG2, respectively). Propranolol, atenolol, and ICI118,551 reduced migration of MCF7, HT-29, and HepG2 cells to varying extents depending on the application concentration and duration. Propranolol and atenolol reduced migration of MCF7 and HT-29 in a concentration dependent manner, whereas migration of these cells decreased after 48 and 72 h of ICI118,551 applications. CONCLUSION: Beta2-AR antagonist seemed to be the most cytotoxic beta-blocker on non-stimulated cancer cells. Propranolol and ICI118,551 were more effective than atenolol in inhibiting invasion and migration of non stimulated MCF7 and HT-29 cells; ICI118,551 being the most potent. Concordantly, beta2-selective blockage seemed to be more effective for non-stimulated cells. Effect of the selective beta-AR antagonists showed variation depending on the concentration, incubation time, and histological origin of cells. PMID- 25026351 TI - Effects of rosmarinic acid on an experimental model of painful diabetic neuropathy in rats. AB - CONTEXT: Diabetic neuropathic (DN) pain is one of the diabetes complications. Rosmarinic acid (RA), a natural phenol antioxidant, shows some biological activities, including anti-inflammatory, analgesic, and anti-diabetic effects. OBJECTIVES: We investigated the efficacy of RA administration (10 and 30 mg/kg) on streptozotocin (STZ)-induced neuropathy in rats. MATERIAL AND METHODS: The animals received saline or RA (10 and 30 mg/kg, p.o.; once daily) for 8 weeks. DN was evaluated by the tail flick (TF) method, formalin test, and tactile allodynia. At the end, all rats were weighed and underwent plasma glucose measurement. RESULTS: There was an increase in licking time during both formalin test phases in diabetic animals (138.5 +/- 10.7 and 448.7 +/- 2.6 s) that was decreased by RA10 mg/kg (103.5 +/- 7.5 and 284.4 +/- 19 s) and RA 30 mg/kg (81.8 +/- 11 and 192.7 +/- 14 s). RA 30 mg/kg caused anti-nociception during the early phase in treated controls (52.1 +/- 6 s) than untreated controls (99.4 +/- 5.9 s). The TF latency in diabetics (2.9 +/- 0.1 s) was increased in RA10 and 30 mg/kg treated diabetics (5.3 +/- 0.4 and 6 +/- 0.86 s). The paw withdrawal threshold (PWT) of the diabetics (3.6 +/- 0.7 g) was increased after RA 10 and 30 mg/kg (13.8 +/- 0.3 and 14 +/- 0.4 g) treatment. RA did not induce a significant change in body weight and plasma glucose of rats. CONCLUSION: RA showed efficacy in amelioration of some aspects of DN. Therefore, RA makes a good candidate for DN treatment in clinical studies. PMID- 25026352 TI - beta-Amyrin and alpha-amyrin acetate isolated from the stem bark of Alstonia boonei display profound anti-inflammatory activity. AB - CONTEXT: Alstonia boonei De Wild (Apocyanaceae) is used in ethnomedicine for the management of malaria, ulcer, rhematic pain, toothache, and inflammatory disorders. OBJECTIVE: To investigate the anti-inflammatory potential of beta amyrin and alpha-amyrin acetate isolated from the stem bark of Alstonia boonei using animal models. MATERIALS AND METHODS: Chromatographic purification of the crude methanol extract led to the isolation and structure elucidation of beta amyrin and alpha-amyrin acetate. Their anti-inflammatory activities were evaluated in rodents using egg albumen-induced paw edema and xylene-induced ear edema models. The gastric ulcerogenic, in vivo leucocyte migration, and RBC membrane stabilization tests were also investigated. RESULTS: alpha-Amyrin acetate at 100 mg/kg showed significant (p < 0.05) inhibition of egg albumen induced paw edema with % inhibition of 40 at the 5th hour. Oral administration up to 100 mg/kg did not produce significant (p > 0.01) irritation of the gastric mucosa while significant (p < 0.01) ulceration was recorded for indomethacin at 40 mg/kg compared with the negative control. At 100 MUg/mL, both beta-amyrin and alpha-amyrin acetate inhibited heat-induced hemolysis to as much 47.2 and 61.5%, respectively, while diclofenac sodium (100 MUg/mL) evoked only 40.5% inhibition. Both compounds at 100 ug/ear produced significant (p < 0.01) inhibition of ear edema in mice by 39.4 and 55.5%, respectively. Also at 100 mg/kg (p.o.) alpha amyrin acetate evoked 60.3% reduction in total leucocyte count and significant (p < 0.05) suppression (47.9%) of neutrophil infiltration. DISCUSSION AND CONCLUSION: This study generally provided evidence of profound anti-inflammatory activity of beta-amyrin and alpha-amyrin acetate isolated from the Alstonia boonei stem bark. PMID- 25026353 TI - Antimicrobial activity of zinc oxide (ZnO) nanoparticle against Klebsiella pneumoniae. AB - CONTEXT: Zinc oxide nanoparticles (ZnO Nps) have potential application in piezoelectric nanogenerator and in biotechnology. OBJECTIVE: The antibacterial activity of ZnO Nps on Klebsiella pneumoniae (ATCC 70068) and mode of action of ZnO Nps was investigated. METHODS: ZnO Nps was synthesized by a precipitation method and characterized using scanning electron microscopy (SEM) and X-ray diffraction (XRD) methods. In vitro susceptibility of K. pnumoniae of the ZnO Nps was detected using the disk diffusion method, and the minimum inhibitory concentration (MIC) value was determined using the serial dilution method. The chemical and physical interaction between the cell envelope of K. pneumonia and ZnO Nps was investigated. The effect of ZnO Nps on the cytotoxic activities of K. pneumonia was investigated using a HEp-2 cell line. RESULTS: The MIC of ZnO Nps was found in 40 ug/ml. The standard growth curve showed that ZnO Nps of 0.75 mM inhibited K. pneumoniae after 4 h. The interaction with outer membrane protein (OMP) and lipoploysacharride (LPS) residues showed modulation in ~66 kDa and ~29 kDa proteins with the use of increasing concentrations of ZnO Nps. The amount of nucleic acid and protein released from the cells increased with the ZnO Nps concentration used. Importantly, the OD of the ZnO Nps-treated cells decreased within 30 min of incubation in the presence of SDS. ZnO Nps-treated K. pneumoniae were five-fold less infectious in the HEp-2 cell line at doses between 0.50 and 0.75 mM. DISCUSSION: These results suggest the potential antibacterial use of ZnO Nps against K. pneumoniae infections. PMID- 25026354 TI - Evaluation of the anti-diarrheal activity of Salvia connivens. AB - CONTEXT: Diarrheal disease is a leading cause of mortality and morbidity and accounts for 5-8 million deaths worldwide each year. Salvia connivens Epling (Lamiaceae) is used to treat sore throat, fevers, diarrhea, malaria, and also is used as an antipyretic. OBJECTIVE: The present study evaluates the efficacy of S. connivens in the treatment of diarrhea using animal models. MATERIALS AND METHODS: The anti-diarrheal effect of methanol extract of S. connivens was investigated on mice with castor oil, arachidonic acid (AA) or prostaglandin E2 (PGE2)-induced diarrhea. On Wistar rats, the activity was evaluated on the intestinal transit and Castor oil-induced enteropooling. RESULTS: The methanol extract at doses of 6.25, 12.5, 25, 50, 100, and 200 mg/kg on castor oil-induced diarrhea reduced the diarrhea by 32.3, 41.9, 67.7, 74.2, 83.3, and 100%, respectively. Additionally, this extract, at doses of 200 mg/kg, inhibited AA induced diarrhea by 100%. The methanol extract produced no effect on PGE2-induced diarrhea at the same doses. In Wistar rats, at dose of 200 mg/kg, the methanol extract inhibited intestinal transit and decreased the volume of intestinal secretion induced by castor oil. DISCUSSION: The methanol extract showed anti diarrheal effect on the animal models used. Phytochemical screening revealed the presence of alkaloids, tannins, and saponins which may be responsible for this effect. The extract did not cause any mortality or any visible signs of toxicity or differences in food and water uptake were seen. CONCLUSIONS: These results justify the use of S. connivens as an anti-diarrheal agent. PMID- 25026355 TI - Carbamazepine attenuates inducible nitric oxide synthase expression through Akt inhibition in activated microglial cells. AB - Abstract Background: Carbamazepine, which was developed primarily for the treatment of epilepsy, is now also useful for the treatment of non-epileptic disorders and inflammatory hyperalgesia. However, the mechanism of its anti neuroinflammatory action remains poorly understood. OBJECTIVE: This study elucidates the anti-neuroinflammatory capacity of carbamazepine on microglial activation and the relative mechanisms involved. MATERIALS AND METHODS: The microglial BV-2 cells were pretreated with carbamazepine for 15 min before activation by lipopolysaccharide (LPS). After LPS stimulation, the expression of inducible nitric oxide synthase (iNOS) was analyzed by Western blotting (WB) and reverse transcription-polymerase chain reaction. Signaling proteins and cyclooxygenase (COX)-2 were also evaluated by WB. The levels of nitrate and tumor necrosis factor (TNF)-alpha were analyzed by the Griess method and enzyme-linked immunosorbant assay, respectively. The formation of intracellular reactive oxygen species (ROS) was examined by fluorescent analysis. RESULTS: Carbamazepine strongly attenuated LPS-induced production of NO and iNOS protein at concentrations of 5, 10, and 20 MUM. Consistently, it could markedly suppress iNOS mRNA expression stimulated by LPS. Among the signaling pathways, LPS mediated IkappaBalpha degradation or JNK MAPK phosphorylation was not affected by carbamazepine. Interestingly, it was found that carbamazepine could concentration dependently inhibit LPS-activated phospho-Akt expression. Nevertheless, LPS induced ROS production was not affected by carbamazepine. Carbamazepine (20 MUM) affected either COX-2 expression or TNF-alpha production induced by LPS with approximately 70% and 51% inhibition, respectively. DISCUSSION AND CONCLUSION: Our findings showed that carbamazepine exerted selective inhibition on LPS induced microglial iNOS expression through the down-regulation of Akt activation, and thus may play a pivotal role of anti-neuroinflammation in its therapeutic efficacy. PMID- 25026356 TI - Comparison of the endothelial toxicity induced by short-term amiodarone and diazepam exposure in a human umbilical vein endothelial cell line (EVC304). AB - CONTEXT: Venous irritation is the most common side effect of intravenous therapy. Although many in vitro models have been developed to evaluate intravenous drug irritation, these models are not widely accepted. OBJECTIVES: The aim of this paper is to determine whether delayed or immediate cytotoxicity better reflects the in vivo venous irritation ranking. MATERIALS AND METHODS: We compared the endothelial toxicity induced by high-concentrations of amiodarone and diazepam after short-term exposure (20 min) in a human umbilical vein endothelial cell line (EVC304) by using five in vitro models: lactate dehydrogenase (LDH), glucose 6-phosphate dehydrogenase (G6PD), glutathione (GSH), adenosine triphosphate (ATP), and MTT assays. RESULTS: In the 24-h MTT assay, the IC50 of diazepam and amiodarone was 1.08 and 1.96 mM, respectively. In the 48-h MTT assay, the IC50 of diazepam and amiodarone was 1.114 and 1.128 mM, respectively. In the intracellular LDH and G6PD assays, the EC50 of diazepam was found to be 3.307 and 1.53 mM, while the values of amiodarone were 0.853 and 0.325 mM, respectively. In the intracellular ATP and GSH assays, the EC50 of diazepam was 0.905 and 1.283 mM, while the values of amiodarone were 0.040 and 0.326 mM, respectively. CONCLUSION: Both the results of intracellular macromolecule activities and micromolecule concentrations were similar to that observed in in vivo venous irritation studies. However, the delayed cytotoxicity rank from the MTT assay is inconsistent with the in vivo venous irritation rank, suggesting that initial toxicity, but not the delayed toxicity, is related to venous irritation. PMID- 25026357 TI - Salvia miltiorrhiza compounds protect the liver from acute injury by regulation of p38 and NFkappaB signaling in Kupffer cells. AB - CONTEXT: Salvia miltiorrhiza Bunge is a traditional Asian medicine used to treat cerebral and cardiac ischemia. However, the effects of the active compounds of S. miltiorrhiza on liver damage are unclear. OBJECTIVE: In this study, we tested the effects on acute liver injury of crude S. miltiorrhiza extracts from roots as well as neotanshinone B, dehydromiltirone, tanshinol A, tanshinone I, dihydrotanshinono I, neotanshinone A, cryptanshinono, tanshinone II A, and salvianolie acid B from purified S. miltiorrhiza extracts. MATERIALS AND METHODS: Various compounds or ethanol extract of S. miltiorrhiza (50, 100, and 200 mg/kg, p.o.) were administered to rats for five consecutive days. After acute carbon tetrachloride (CCl4)-induced liver injury by treatment of rats with a single dose of CCl4 (0.75 mL/kg, p.o), rat liver function was tested by measuring serum biochemical parameters. Serum cytokine concentrations were assessed by enzyme linked immunosorbent assay (ELISA). Expression of p38 and NFkappaB was evaluated by western blot. RESULTS: All S. miltiorrhiza components showed their effects on liver function from the dose from 50 to 200 mg/kg. At the dose of 200 mg/kg, they reduced serum levels of alkaline phosphatase (ALP) by 34-77%, alanine aminotransferase (ALT) by 30-57%, aspartate aminotransferase (AST) by 43-72%, creatine total bilirubin (BIL-T) by 33-81%, albumin (ALB) by 37-67%, indicating that S. miltiorrhiza extracts protected liver from CCl4-induced damage. Moreover, S. miltiorrhiza extracts at 200 mg/kg reduced the increase in the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) by 25-82%, interleukin-1 (IL-1) by 42-74% and interleukin-6 (IL-6) by 67-83%, indicating an effect on alleviating liver inflammation. Furthermore, in vitro, S. miltiorrhiza extracts inhibited p38 and NFkappaB signaling in Kupffer cells. This effect could be a main mechanism by which S. miltiorrhiza protects against acute liver toxicity. DISCUSSION AND CONCLUSION: Active compounds of S. miltiorrhiza protected the liver from CCl4 induced injury. Protection might have been due to inhibition of p38 and NFkappaB signaling in Kupffer cells, which subsequently reduced inflammation in the liver. PMID- 25026358 TI - Vitamin E: a potential therapy for gastric mucosal injury. AB - CONTEXT: Many scientific reports have shown the involvement of oxidative stress and inflammation as well as diminished gastroprotective substances in the pathogenesis of gastric lesions using various models. Therefore, treatment with antioxidants like tocopherol and tocotrienol may afford beneficial effects in attentuating the formation of the gastric lesions. OBJECTIVE: The aim of this work was to summarize documented reports on the effects of vitamin E on various models of gastric lesion. METHODS: A literature search was performed from databases in Medline (PubMed), Web of Science, ScienceDirect, and Googlescholar from June to December 2013. RESULTS AND CONCLUSION: The potential roles of tocopherol and tocotrienol in modifying the effects of ulcerogenic agents are discussed in this review. The protective effects of the vitamin E might involve ameliorating oxidative stress and inflammation as well as restoration of endogenous gastroprotective substances. This vitamin has the potential to be used as a therapy for gastric mucosal injury. PMID- 25026359 TI - Bioactivity-guided isolation and structural characterization of the antifungal compound, plumbagin, from Nepenthes gracilis. AB - CONTEXT: Despite several phytochemical studies of Nepenthes gracilis Korth (Nepenthaceae), the biological activities of this pitcher plant remain to be explored. OBJECTIVE: This study evaluates the antifungal activity of N. gracilis extracts, isolates, and characterizes its bioactive compound and evaluates the cytotoxicity of the isolated compound. MATERIALS AND METHODS: Fresh leaves of N. gracilis were sequentially extracted. The fungistatic and fungicidal activities of the extracts were evaluated against six species of fungi of medical importance using a colorimetric broth microdilution method. The most active extract was fractionated by liquid-liquid partitioning and further purified by a preparative thin layer chromatography. Structural elucidation was carried out using FT-IR, GC MS, and NMR. Cytotoxicity testing against rhesus monkey kidney epithelial cells (LLC-MK2) was assessed by a neutral red uptake (NRU) assay. RESULTS: The hexane extract, which showed the lowest minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), both at 20 MUg/mL against Candida albicans, Issatchenkia orientalis, and Trichophyton mentagrophytes, was subjected to bioactivity-guided fractionation. The isolated compound exhibited potent activity with the MIC values ranging from 2 to 31 MUg/mL against all the fungi. The active compound was identified as plumbagin (5-hydroxy-2-methyl-naphthalene 1,4-dione). The 50% cytotoxicity concentration (CC50) of plumbagin was 0.60 MUg/mL. DISCUSSION AND CONCLUSION: The selectivity indices of plumbagin against all the fungi were less than 1.0, indicating that plumbagin is more toxic to mammalian than fungal cells. This study provides information on the antifungal properties of N. gracilis leaf extracts, as well as the antifungal and cytotoxicity properties of plumbagin. PMID- 25026360 TI - Silymarin alleviates bleomycin-induced pulmonary toxicity and lipid peroxidation in mice. AB - CONTEXT: The application of bleomycin is limited due to its side effects including lung toxicity. Silymarin is a flavonoid complex isolated from milk thistle [Silybum marianum L. (Asteraceae)] which has been identified as an antioxidant and anti-inflammatory compound. OBJECTIVE: This study evaluates the effect of silymarin on oxidative and inflammatory parameters in the lungs of mice exposed to bleomycin. MATERIALS AND METHODS: BALB/c mice were divided into four groups of control, bleomycin (1.5 U/kg), bleomycin plus silymarin (50 and 100 mg/kg). After bleomycin administration, mice received 10 d intraperitoneal silymarin treatment. On 10th day, blood and lung samples were collected for measurement of oxidative and inflammatory factors. RESULTS: Silymarin led to a decrease in lung lipid peroxidation (0.19 and 0.17 nmol/mg protein) in bleomycin injected animals. Glutathione-S-transferase (GST) which was inhibited by bleomycin (32.4 nmol/min/mg protein) induced by higher dose of silymarin (41 nmol/min/mg protein). Silymarin caused an elevation in glutathione (GSH): 2.6 and 3.1 umol/g lung compare with bleomycin-injected animals 1.8 umol/g lung. Catalase (CAT) was increased due to high dose of silymarin (65.7 umol/min/ml protein) compare with bleomycin treated-mice. Myeloperoxidase (MPO) which was induced due to bleomycin (p < 0.05) reduced again by high dose of silymarin (0.51 U/min/mg protein). Bleomycin led to an increase in TNF-alpha and interleukin-6 (IL-6) (7.9 and 11.8 pg/ml). These parameters were reduced by silymarin (p < 0.05). CONCLUSIONS: Silymarin attenuated bleomycin induced-pulmonary toxicity. This protective effect may be due to the ability of silymarin in keeping oxidant antioxidant balance and regulating of inflammatory mediator release. PMID- 25026361 TI - Chemical composition and bioactivity of the volatile oil from leaves and stems of Eucalyptus cinerea. AB - CONTEXT: Eucalyptus cinerea F. Muell. ex Benth. (Myrtaceae) is a medium-sized tree cultivated in Egypt. OBJECTIVE: First, to determine the chemical composition of the volatile oil of the juvenile leaves and stems of E. cinerea to identify its chemotype. Second, to study the in vivo antioxidant activity and in vitro antimicrobial activity of the studied volatile oils against selected Gram positive, Gram-negative bacteria, yeast, and mycelia fungi. MATERIALS AND METHODS: The volatile oil was prepared by hydrodistillation and then identified by GC/MS analysis. Broth microdilution and agar dilution methods were applied for determining the MIC. The antioxidant activity was studied by determination of glutathione level in blood of alloxan-induced diabetic rats. RESULTS: The yield of the volatile oil hydrodistilled from the juvenile leaves and stems of E. cinerea was 4.5 and 0.5%, respectively. 1,8-Cineole was the major identified oxygenated monoterpenoid (84.55% and 60.15% in the juvenile leaves and stems, respectively). The antibacterial activity of the oil of the juvenile leaves was more potent against all the tested organisms than that of the stems. The (MIC) of volatile oil of the juvenile leaves against Escherichia coli, Pseudomonas aeruginosa, Streptococcus faecalis, Candida albicans, and Aspergillus flavus were 5.2, 5.6, 4, 4.8, and 12.8 MUg/ml, respectively. Also, the juvenile leaves' oil was more active as an antioxidant than that of the stems. They restored glutathione level by 33.7 +/- 1.1 and 29.6 +/- 0.7 mg/dl, respectively, compared with vitamin E (35.9 +/- 1.2 mg/dl) which was used as a reference. DISCUSSION AND CONCLUSION: RESULTS suggest that the volatile oil is 1,8-cineole chemotype. Moreover, the oil of the juvenile leaves of E. cinerea might find usefulness as a therapeutic agent following further development. PMID- 25026362 TI - Partial charge transfer contribution to the solvent isotope effect and photosensitized generation of singlet oxygen, O2(1Deltag), by substituted ruthenium(II) bipyridyl complexes in aqueous media. AB - The efficiency of singlet oxygen photosensitized by some ruthenium(ii) bipyridyl complex ions in aqueous media is reported in this study. Measurements were carried out in H2O and D2O. The effect of the deuterium isotope on the lifetime of (3)MLCT excited states of these complexes is studied in H2O and D2O. The deuterium isotope effect was discussed in terms of the vibronic coupling to the solvent in addition to the charge transfer to the solvent mechanism due to their dependence on the oxidation potential of the sensitizer. Quenching rate constants, kq, for quenching of the (3)MLCT states of these ruthenium complex ions by molecular oxygen were found to be in the range of (2.08-3.84) * 10(9) M( 1) s(-1) in H2O and (1.69-3.48) * 10(9) M(-1) s(-1) in D2O. The efficiency of singlet oxygen, O2((1)Deltag), production as a result of the (3)MLCT quenching by oxygen, f, is reported in D2O and found to be in the range 0.25-0.56. It has been found that the lifetime of the excited state is longer in D2O, tau, than in H2O, tau, which was related to partial charge transfer to the solvent in addition to the vibronic coupling mechanism. Mechanisms by which the excited states of these ruthenium complexes are quenched by molecular oxygen that shows the competition between charge transfer, non-charge transfer deactivation channels or energy transfer assisted charge transfer deactivation mechanisms are reported. PMID- 25026363 TI - Safety of robotic prostatectomy over time: a national study of in-hospital injury. AB - OBJECTIVE: To assess national trends of iatrogenic complications and associated burden of care among patients undergoing open and minimally invasive prostatectomy using a population-based cohort. METHODS: Using the nationally representative cohort, we identified patients who were diagnosed with prostate cancer, and underwent prostatectomy during 2001 and 2011. We determined the risk of iatrogenic complication and length of stay (LOS) over time among open and minimally invasive surgery (MIS) patients. Hierarchical multivariable logistic regression was performed to assess the changes over time and elucidate independent predictors of iatrogenic complications. RESULTS: We identified 556,932 and 219,434 prostate cancer patients undergoing open and minimally invasive prostatectomy. We found that iatrogenic complications for MIS were less frequent in later years (years 09-11 vs. year 01-02 odds ratio (OR), 0.21; 95% confidence intervals (CI), 0.09-0.40). MIS was associated with higher risk of iatrogenic complications in early period (years 01-02 OR, 3.81; 95% CI, 1.72 8.41), but lower risk in late period (years 09-11 OR 0.72 95% CI 0.61-0.86). Patients who experienced iatrogenic complications tended to have longer LOS (Median: Open vs. MIS, 4 days vs. 3 day) than those who didn't (Median: Open vs. MIS, 2 days vs. 1 day), regardless of procedure type. CONCLUSION: We found that minimally invasive prostatectomy is associated with lower risk of iatrogenic complications when compared with open surgery (OS). However, as "learning curve" is overcome over time, MIS becomes safer than OS. Iatrogenic complications are not benign and seem to be associated with higher burden of inpatient care. PMID- 25026364 TI - Cognitive processing of moral and social judgements: a comparison of offenders, students, and control participants. AB - Examining cognitive processes related to offenders' moral and social judgements is important in order to better understand their criminal behaviour. In the present study, 30 offenders, 30 students, and 24 control participants were administered the moral-conventional judgements computer task, which requires responding under strict time constraints. Participants read scenarios and were asked to judge whether the act was acceptable or unacceptable when rules were either assumed or removed. Additionally, participants completed an executive function (EF) task in order to examine the relation between EF and moral and social judgements. The findings revealed that, as expected, controls and students had faster reaction times (RTs) and a higher percentage of normative judgements than offenders. Additionally, offenders had a low percentage of normative judgements, particularly in the conventional rule removed condition. Finally, RTs of moral and conventional judgements in most conditions were related to EF among students but not controls or offenders. We conclude that offenders, as compared to controls and students, may rely more on rule-oriented responding and may rely less on EF when making moral and social judgements. PMID- 25026366 TI - Intraventricular hemorrhage on initial computed tomography as marker of diffuse axonal injury after traumatic brain injury. AB - Intraventricular hemorrhage (IVH) on initial computed tomography (CT) was reported to predict lesions of diffuse axonal injury (DAI) in the corpus callosum (CC) on subsequent magnetic resonance imaging (MRI). We aimed to examine the relationship between initial CT findings and DAI lesions detected on MRI as well as the relationship between the severity of IVH (IVH score) and severity of DAI (DAI staging). A consecutive 140 patients with traumatic brain injury (TBI) who underwent MRI within 30 days after onset were revisited. We reviewed their initial CT for the following six findings: Status of basal cistern, status of mid line shift, epidural hematoma, IVH, subarachnoid hemorrhage, and volume of hemorrhagic mass and IVH score were assigned in each patient. Based on MRI findings, patients were divided into DAI and non-DAI groups and were assigned a DAI staging. Then, to confirm that the IVH on initial CT predicts DAI lesions on MRI, we used multi-variate analysis of the six CT findings, including IVH, and examined the relationship between IVH score and DAI staging. The IVH detected on CT was the only predictor of DAI (p=0.0139). The IVH score and DAI staging showed significant positive correlation (p<0.0003). IVH score in DAI stage 3 (with DAI involving the brain stem; p=0.0025) or stage 2 (with DAI involving CC; p=0.0042) was significantly higher than that of DAI stage 0 (no DAI lesions). In conclusion, IVH on initial CT is the only marker of DAI on subsequent MRI, specifically severe DAI (stage 2 or 3). PMID- 25026365 TI - Zebrafish embryo model of Bartonella henselae infection. AB - Bartonella henselae (Bh) is an emerging zoonotic pathogen that has been associated with a variety of human diseases, including bacillary angiomatosis that is characterized by vasoproliferative tumor-like lesions on the skin of some immunosuppressed individuals. The study of Bh pathogenesis has been limited to in vitro cell culture systems due to the lack of an animal model. Therefore, we wanted to investigate whether the zebrafish embryo could be used to model human infection with Bh. Our data showed that Tg(fli1:egfp)(y1) zebrafish embryos supported a sustained Bh infection for 7 days with >10-fold bacterial replication when inoculated in the yolk sac. We showed that Bh recruited phagocytes to the site of infection in the Tg(mpx:GFP)uwm1 embryos. Infected embryos showed evidence of a Bh-induced angiogenic phenotype and an increase in the expression of genes encoding pro-inflammatory factors and pro-angiogenic markers. However, infection of zebrafish embryos with a deletion mutant in the major adhesin (BadA) resulted in little or no bacterial replication and a diminished host response, providing the first evidence that BadA is critical for in vivo infection. Thus, the zebrafish embryo provides the first practical model of Bh infection that will facilitate efforts to identify virulence factors and define molecular mechanisms of Bh pathogenesis. PMID- 25026367 TI - Distribution of APOE polymorphism in the "Paisa" population from northwest Colombia (Antioquia). AB - BACKGROUND: The apolipoprotein E (APOE) gene plays a pivotal role in cholesterol metabolism. Since the discovery of the APOE*2 and APOE*4 as the major susceptibility alleles for several diseases including dyslipidemia, atherosclerosis, coronary heart disease, late-onset and early Alzheimer's disease, the APOE genotype might be considered as a potential predictive factor for both epidemiological research and diagnosis. AIM: The aim of this study is to report on the polymorphism of the APOE gene in the "Paisa" population from northwest Colombia (Antioquia) to obtain a population baseline of the existing variation in this locus. METHOD: One thousand and one healthy voluntaries were genotyped for the APOE polymorphism using polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: The APOE*3/*3 genotype presented the highest frequency (66.33%) and the APOE*4/*4 had the lowest frequency (1.89%). Genotype frequencies comply with Hardy-Weinberg expectations. Allele frequencies obtained for APOE*2, APOE*3 and APOE*4 were 0.075 +/- 0.005 (95% CI = 0.063-0.086), 0.814 +/- 0.009 (0.797-0.831) and 0.111 +/- 0.007 (0.098-0.125), respectively. CONCLUSION: Although globally the high-to-low APOE frequency follows the E*3 > E*4 > E*2 trend, the present APOE frequency data is in disagreement with some reports from South-American countries. PMID- 25026369 TI - Enzymatic characterization of microbial isolates from lignocellulose waste composting: chronological evolution. AB - Successful composting is dependent upon microbial performance. An interdependent relationship is established between environmental and nutritional properties that rule the process and characteristics of the dominant microbial communities. To reach a better understanding of this relationship, the dynamics of major metabolic activities associated with cultivable isolates according to composting phases were evaluated. Ammonification (72.04%), amylolysis (35.65%), hemicellulolyis (30.75%), and proteolysis (33.61%) were the more frequent activities among isolates, with mesophilic bacteria and fungi as the prevalent microbial communities. Bacteria were mainly responsible for starch hydrolysis, while a higher percentage of hemicellulolytic and proteolytic isolates were ascribable to fungi. Composting seems to exert a functional selective effect on microbial communities by promoting the presence of specific metabolically dominant groups at each stage of the process. Moreover, the application of conglomerate analysis led to the statement of a clear correlation between the chronology of the process and characteristics of the associated microbiota. According to metabolic capabilities of the isolates and their density, three clear clusters were obtained corresponding to the start of the process, including the first thermophilic peak, the rest of the bio-oxidative stage, and the maturation phase. PMID- 25026370 TI - Analysis of substrate degradation, metabolite formation and microbial community responses in sand bioreactors treating winery wastewater: a comparative study. AB - There is a global need for the implementation of more cost-effective green technologies for the treatment of effluent from wineries. However, systems reliant on microbial biodegradation may be adversely affected by the highly seasonal character of cellar waste. In this study, the biodegradation of two different formulations of winery effluent in sand bioreactors was compared. The degradation of organic substrates and formation of metabolites was monitored by physicochemical analyses of pore water and final effluent samples. Changes in the bacterial community structures were detected using molecular fingerprinting. In wastewater with an overall COD of 2027 mg/L, a formulation with a high concentration of acetate (800 mg COD/L) was more recalcitrant to degradation than a formulation with a high concentration of glucose (800 mg COD/L). Ethanol, glucose and phenolics were degraded preferentially in the deeper layers of the sand bioreactors (average Eh 25 mV) than in the superficial layers (average Eh 102 mV). The redox status also played a pivotal role on the bacterial community composition. The study yielded valuable insight that can be utilized in the design (configuration and operation) of full scale sand bioreactors. PMID- 25026371 TI - Bacterial degradation of naproxen--undisclosed pollutant in the environment. AB - The presence of non-steroidal anti-inflammatory drugs (NSAIDs) in the environment is an emerging problem due to their potential influence on human health and biocenosis. This is the first report on the biotransformation of naproxen, a polycyclic NSAID, by a bacterial strain. Stenotrophomonas maltophilia KB2 transformed naproxen within 35 days with about 28% degradation efficiency. Under cometabolic conditions with glucose or phenol as a carbon source degradation efficiency was 78% and 40%, respectively. Moreover, in the presence of naproxen phenol monooxygenase, naphthalene dioxygenase, hydroxyquinol 1,2-dioxygenase and gentisate 1,2-dioxygenase were induced. This suggests that degradation of naproxen occurs by its hydroxylation to 5,7,8-trihydroxynaproxen, an intermediate that can be cleaved by hydroxyquinol 1,2-dioxygenase. The cleavage product is probably further oxidatively cleaved by gentisate 1,2-dioxygenase. The obtained results provide the basis for the use of cometabolic systems in the bioremediation of polycyclic NSAID-contaminated environments. PMID- 25026372 TI - Integrated water resources management and water users' associations in the arid region of northwest China: a case study of farmers' perceptions. AB - Water scarcity is a critical policy issue in the arid regions of northwest China. The local government has widely adopted integrated water resources management (IWRM), but lacks support from farmers and farm communities. We undertook a case study in the Minqin oasis of northwest China to examine farmers' responses to IWRM and understand why farmer water users' associations (WUAs) are not functioning effectively at the community level. Results of quantitative and qualitative surveys of 392 farmers in 27 administrative villages showed that over 70% of farmers disapprove of the IWRM market-based reforms. In particular, the failure of farmer WUAs can be attributed to overlapping organizational structures between the WUAs and the villagers' committees; mismatches between the organizational scale of the WUAs and practical irrigation management by the farmers themselves; marginalization of rural women in water decision-making processes; and the inflexibility of IWRM implementation. An important policy implication from this study is that rebuilding farmer WUAs is key to overcoming the difficulties of IWRM. The current water governance structure, which is dominated by administrative systems, must be thoroughly reviewed to break the vicious cycle of tension and distrust between farmers and the government. PMID- 25026373 TI - Significant N2 fixation by heterotrophs, photoheterotrophs and heterocystous cyanobacteria in two temperate estuaries. AB - Nitrogen (N) fixation is fueling planktonic production in a multitude of aquatic environments. In meso- and poly-haline estuaries, however, the contribution of N by pelagic N2 fixation is believed to be insignificant due to the high input of N from land and the presumed absence of active N2-fixing organisms. Here we report N2 fixation rates, nifH gene composition and nifH gene transcript abundance for key diazotrophic groups over 1 year in two contrasting, temperate, estuarine systems: Roskilde Fjord (RF) and the Great Belt (GB) strait. Annual pelagic N2 fixation rates averaged 17 and 61 mmol N m(-2) per year at the two sites, respectively. In RF, N2 fixation was mainly accompanied by transcripts related to heterotrophic (for example, Pseudomonas sp.) and photoheterotrophic bacteria (for example, unicellular diazotrophic cyanobacteria group A). In the GB, the first of two N2 fixation peaks coincided with a similar nifH-expressing community as in RF, whereas the second peak was synchronous with increased nifH expression by an array of diazotrophs, including heterotrophic organisms as well as the heterocystous cyanobacterium Anabaena. Thus, we show for the first time that significant planktonic N2 fixation takes place in mesohaline, temperate estuaries and that the importance of heterotrophic, photoheterotrophic and photosynthetic diazotrophs is clearly variable in space and time. PMID- 25026374 TI - Water fleas require microbiota for survival, growth and reproduction. AB - Microbiota have diverse roles in the functioning of their hosts; experiments using model organisms have enabled investigations into these functions. In the model crustacean Daphnia, little knowledge exists about the effect of microbiota on host well being. We assessed the effect of microbiota on Daphnia magna by experimentally depriving animals of their microbiota and comparing their growth, survival and fecundity to that of their bacteria-bearing counterparts. We tested Daphnia coming from both lab-reared parthenogenetic eggs of a single genotype and from genetically diverse field-collected resting eggs. We showed that bacteria free hosts are smaller, less fecund and have higher mortality than those with microbiota. We also manipulated the association by exposing bacteria-free Daphnia to a single bacterial strain of Aeromonas sp., and to laboratory environmental bacteria. These experiments further demonstrated that the Daphnia-microbiota system is amenable to manipulation under various experimental conditions. The results of this study have implications for studies of D. magna in ecotoxicology, ecology and environmental genomics. PMID- 25026376 TI - Engineering preferential adsorption of single-walled carbon nanotubes on functionalized ST-cut surfaces of quartz. AB - Horizontal alignment during synthesis of single-walled carbon nanotubes has been found experimentally along certain directions of well-defined quartz surfaces. The reasons for such alignment are here examined using first-principles computational analysis, as a function of structure and chemistry of the specific exposed facet, presence and location of OH and H functional groups, and degree of hydration of the surface. It is found that selective functionalization of low coordinated surface sites may cause exposure of low-coordinated Si atoms that bond strongly to nanotube walls. On the other hand, saturation of low-coordinated oxygen also favors carbon nanotube adhesion to the substrate. As found previously on bare silica surfaces, a chirality preference is confirmed on functionalized surfaces toward zigzag over armchair nanotubes. Magnetization effects on the surface originated by the presence of adsorbed functional groups are found to enhance adsorption of arm-chair nanotubes compared to that on clean surfaces. On the basis of the findings, it is suggested that surfaces may be engineered to favor horizontal adsorption of specific chiralities along preferential directions. PMID- 25026377 TI - Physiotherapy as a university subject in queensland. AB - The involvement of the University in the education of physiotherapists dates back to December, 1927, as far as I can ascertain from the relevant University files kindly made available by the Registrar, Doctor S. A. Rayner and the records officer, Mr. R. Stevenson. During that month preliminary discussions initiated by the Brisbane and South Coast Hospitals Board took place between Mr. J. D. Story, Senator of the University and Public Service Commissioner, Professor E. G. Goddard (Biology Department), Doctor J. B. M'Lean (General Medical Superintendent) and Mr. C. E. Chuter (Chairman, Brisbane and South Coast Hospitals Board). On January 23, 1928, there was a conference of interested parties. Those present were Doctor Lockhart Gibson, Professor Goddard and Professor T. Parnell (Physics Department), representing the University, Mr. C. E. Chuter, Mr. M. Baldwin, Doctor M'Lean, and Mr. H. Bolton representing the Hospitals Board, and Doctor Eustace Russell (President of the Australasian Massage Association, Queensland Branch). Professor Goddard was elected to the Chair. PMID- 25026375 TI - Modulation of Brahma expression by the mitogen-activated protein kinase/extracellular signal regulated kinase pathway is associated with changes in melanoma proliferation. AB - Brahma (BRM) and Brahma-related gene 1(BRG1) are catalytic subunits of SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes. BRM is epigenetically silenced in a wide-range of tumors. Mutations in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene occur frequently in melanoma and lead to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK1/2) pathway. We tested the hypothesis that BRM expression is modulated by oncogenic BRAF and phosphorylation of ERK1/2 in melanocytes and melanoma cells. Expression of oncogenic BRAF in melanocytes and melanoma cells that are wild-type for BRAF decreased BRM expression and increased BRG1 expression. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) or selective inhibition of BRAF in melanoma cells that harbor oncogenic BRAF increased BRM expression and decreased BRG1 expression. Increased BRM expression was associated with increased histone acetylation on the BRM promoter. Over-expression of BRM in melanoma cells that harbor oncogenic BRAF promoted changes in cell cycle progression and apoptosis consistent with a tumor suppressive role. Upon inhibition of BRAF(V600E) with PLX4032, BRM promoted survival. PLX4032 induced changes in BRM function were correlated with increased acetylation of the BRM protein. This study provides insights into the epigenetic consequences of inhibiting oncogenic BRAF in melanoma through modulation of SWI/SNF subunit expression and function. PMID- 25026378 TI - Relating passive movement treatment to some diagnoses. AB - When a patient is referred for treatment by passive movement, diagnosis is not the only factor which determines the kind of treatment movement to be used: the presenting symptoms and signs will also have much influence. There are, however, diagnoses which completely direct, or restrict, the kind of treatment to be used. The diagnosis of torn medial meniscus of the knee is one, particular manipulative techniques being required for this complaint. Another example is rheumatoid arthritis, in which the ligamentous tissue undergoes change and is weakened, thus restricting the strength of techniques. The importance of diagnosis can be seen from the above examples. PMID- 25026379 TI - Amputee gait. AB - The two types of lower limb prostheses most commonly seen today are the conventional Above-Knee and the Patellar-Tendon Bearing. I shall limit my discussion to the gait pattern and associated problems related to these prostheses. PMID- 25026380 TI - The care of the amputation stump. AB - The increasing incidence of amputation in the community, largely as the result of an increased longevity with its attendant senile gangrene (over 70% of peace-time amputations result from senile gangrene), is creating an awareness of the importance of adequate care of the amputation stump. It is essential therefore that the paramedical personnel and the surgeon should provide continuous supervision of the total treatment. PMID- 25026381 TI - Acupuncture. AB - Acupuncture has been used in China for at least 4,000 years and according to some authorities was said to have been devised about twenty-six centuries B.C. Its use in Britain dated back to the early years of the nineteenth century and indeed it was a subject which appeared on the pages of the first volume of the Lancet in 1823. It has also been used in France and elsewhere in Europe for about the same period of time in the treatment of diseases and of pain. In spite of such a long history it has never gained widespread acceptance in the West, a fact which in itself probably indicates that acupuncture has only limited application to modern medicine. Recent interest in the West in acupuncture stems from its use as a method of providing analgesia for surgical operations, a technique which was introduced to China in 1958. PMID- 25026382 TI - The effects of short wave diathermy, microwave and ultra sonics on demand pacemakers and ventrical inhibited pacemakers. AB - In 1971 tests were performed by Mrs. D. Bieri, Mrs. J. Heath of the School of Physio-therapy, New South Wales, and Dr. S. Hunyor of the Pacemaker Clinic, Royal Prince Alfred Hospital. Until this time there was no theory regarding diathermy on patients with implanted pacemakers. PMID- 25026383 TI - The distribution and characteristics of neck-arm pain in patients with and without a neurological deficit. AB - Neck and referred arm pain may arise from either somatic or neural tissues. Clinicians use the subjective nature of a patient's pain to aid the differentiation of the origin of the referred pain but little evidence has been presented to support the reliability of this practice. For this reason, 42 subjects with neck-arm pain were studied. They were subgrouped according to their neurological status in order to investigate whether differences existed between the groups in the descriptive nature and distribution of pain. Subjects with and without neurological signs were found to have no significant differences in the pain characteristics of area, region of greatest intensity, quality, depth and pain localization (p> .05). PMID- 25026384 TI - Isokinetic measures during concentric-eccentric cycles of the knee extensors. AB - The purpose of this study was to examine the peak and average torques produced by the knee extensors during continuous concentric-eccentric cycles at angular velocities of 45, 90, 135, and 180/s. Forty-one healthy females (mean age 26 years) were tested through the range of 80 to 10 flexion on a computerised dynamometer. Peak torques were significantly greater than average torques, and eccentric torques were significantly greater than concentric torques at all angular velocities (p < 0.01). As angular velocity increased, concentric peak and average torques decreased (-26% and -21%, respectively), whereas eccentric torques varied only slightly (3% and 5%, respectively). The extent to which eccentric testing may provide additional information about muscle performance and aid in clinical decisions requires further study. PMID- 25026385 TI - Lighting and the office environment: a review. AB - Lighting is one of several factors in an individual's working environment. The provision of 'good' lighting may assist in minimizing fatigue, which, if present, can inhibit a worker's efficiency. Fatigue must be addressed in many ways. For an operator of a visual display unit (VDU), lighting factors which may assist performance include a clear screen image without reflections or glare, appropriate ambient light and a view to look at There are also large differences in the needs of individuals of various ages. Recommendations about ambient lighting are conflicting. If tasks are screen-based only, lower levels than for general tasks are advocated. Appropriate lighting for any one situation must be determined after a thorough analysis of the task and the individual. PMID- 25026386 TI - Marketing physiotherapy services. AB - Marketing is now a vital issue for all sectors of the physiotherapy profession. Changing public attitudes to health care, increasing competition from many quarters, advances in medical science and progressive deregulation of the profession are some of the trends necessitating a marketing orientation. Marketing is essentially about the management of the relationship between physiotherapists and their clients, where clients may be patients, doctors, employers, rehabilitation providers or others. Marketing enables physiotherapists to increase their understanding of clients' needs and to use this information to improve the quality, delivery and value of their product. Marketing of physiotherapy services offers important benefits to the community, to those who refer patients to physiotherapists, to individual practitioners and to the profession itself. PMID- 25026387 TI - Frequency of use, awareness, and attitudes toward side effects of anabolic androgenic steroids consumption among male medical students in Iran. AB - This study was conducted to determine the frequency of anabolic-androgenic steroids consumption in male students studying at the university and their awareness, attitude, and role of sports activities; the present descriptive study was conducted on 271 volunteers in 2008. The data collected by self-report questionnaires was analyzed by descriptive inferential statistics. The prevalence of consumption was 3.3%, and it was significantly higher in those with a history of bodybuilding or athletic performance. The overall awareness rate was low, and the attitude was too optimistic. It seems that unawareness, incorrect attitude, and history of athletic performance increases the risk of consumption. PMID- 25026388 TI - Artificial Neural Networks: an overview and their use in the analysis of the AMPHORA-3 dataset. AB - The Artificial Adaptive Systems (AAS) are theories with which generative algebras are able to create artificial models simulating natural phenomenon. Artificial Neural Networks (ANNs) are the more diffused and best-known learning system models in the AAS. This article describes an overview of ANNs, noting its advantages and limitations for analyzing dynamic, complex, non-linear, multidimensional processes. An example of a specific ANN application to alcohol consumption in Spain, as part of the EU AMPHORA-3 project, during 1961-2006 is presented. Study's limitations are noted and future needed research using ANN methodologies are suggested. PMID- 25026389 TI - Synthesis and characterization of quantum dot nanoparticles bound to the plant volatile precursor of hydroxy-apo-10'-carotenal. AB - This study is focused on the synthesis and characterization of hydroxy-apo-10' carotenal/quantum dot (QD) conjugates aiming at the in vivo visualization of beta ionone, a carotenoid-derived volatile compound known for its important contribution to the flavor and aroma of many fruits, vegetables, and plants. The synthesis of nanoparticles bound to plant volatile precursors was achieved via coupling reaction of the QD to C27-aldehyde which was prepared from alpha-ionone via 12 steps in 2.4% overall yield. The formation of the QD-conjugate was confirmed by measuring its fluorescence spectrum to observe the occurrence of fluorescence resonance energy transfer. PMID- 25026391 TI - Mass-selective soft-landing of protein assemblies with controlled landing energies. AB - Selection and soft-landing of bionanoparticles in vacuum is potentially a preparative approach to separate heterogeneous mixtures for high-resolution structural study or to deposit homogeneous materials for nanotechnological applications. Soft-landing of intact protein assemblies however remains challenging, due to the difficulties of manipulating these heavy species in mass selective devices and retaining their structure during the experiment. We have developed a tandem mass spectrometer with the capability for controlled ion soft landing and ex situ visualization of the soft-landed particles by means of transmission electron microscopy. The deposition conditions can be controlled by adjusting the kinetic energies of the ions by applying accelerating or decelerating voltages to a set of ion-steering optics. To validate this approach, we have examined two cage-like protein complexes, GroEL and ferritin, and studied the effect of soft-landing conditions on the method's throughput and the preservation of protein structure. Separation, based on mass-to-charge ratio, of holo- and apo-ferritin complexes after electrospray ionization enabled us to soft land independently the separated complexes on a grid suitable for downstream transmission electron microscopy analysis. Following negative staining, images of the soft-landed complexes reveal that their structural integrity is largely conserved, with the characteristic central cavity of apoferritin, and iron core of holoferritin, surviving the phase transition from liquid to gas, soft-landing, and dehydration in vacuum. PMID- 25026390 TI - Target-independent prediction of drug synergies using only drug lipophilicity. AB - Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds ("drugs") previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms. PMID- 25026392 TI - Post-poliomyelitis sequelae: A pathophysiologic basis for management. AB - Management of the late sequelae of poliomyelitis is based on their underlying pathophysiology and on a limited number of research reports. The key elements of management including the history, assessment and possible interventions are described in this article. The indications for intervention and its parameters are determined on an individual basis to maximise the benefit-to-risk ratio. Heavy resistive or exhaustive exercise, for example, cannot be supported physiologically as a means of preserving function in most patients. However rest, pacing of activities, lifestyle modification, orthotic fitting, weight control, use of aids and devices should be of value. Despite the importance of rest, inactivity is associated with detrimental side effects which can be accentuated in the patient with the sequelae of poliomyelitis. Research is needed to establish criteria for prescribing therapeutic interventions including rest and low-intensity exercise for the post-poliomyelitis population. PMID- 25026393 TI - A survey of post-poliomyelitis sequelae: Manifestations, effects on people's lives and responses to treatment. AB - An Australia-wide questionnaire survey was conducted of 318 people who contracted polio between 1907 and 1962. It examined their medical histories, post-polio symptoms, effects of these symptoms on respondent's lives, and treatments found to be effective or ineffective. The average respondent was experiencing increasing muscle weakness, pain and fatigue. These imposed major restrictions on daily living activities and resulted in fear and depression. Physiotherapists were the allied health professionals most likely to be consulted. Physiotherapy was rated as providing considerable or some relief by a relatively high proportion (80 per cent) of clients but it also attracted criticism primarily due to vigorous exercise programs that increased fatigue and weakness. Aspects of the care of people with late effects of polio are discussed. PMID- 25026394 TI - Cardiovascular responses during histamine iontophoresis therapy. AB - The primary purpose of this study was to determine the effect of histamine iontophoresis on the cardiovascular system. Blood pressure and heart rate were monitored in 15 healthy males (ages 23-28 years) during histamine iontophoresis and direct current stimulation treatments. Cardiovascular responses were monitored before (for five minutes), during (for 20 minutes) and after (for five minutes) treatments. Blood pressure and heart rate did not change significantly (p > 0.05) from the baseline during either of the treatments, except in the fifth minute of the treatment when the systolic blood pressure during histamine iontophoresis was significantly lower than during direct current stimulation (p < 0.01). No other significant difference in the measured responses was noted. It was concluded that local administration of histamine dihydrochloride (1 per cent gel) into the skin by direct current for 20 minutes did not appreciably alter the blood pressure and heart rate responses. PMID- 25026395 TI - FTO-free counter electrodes for dye-sensitized solar cells using carbon nanosheets synthesised from a polymeric carbon source. AB - Highly conductive carbon nanosheets (CNSs) are fabricated using a polymeric carbon source and subsequently applied as the counter electrodes (CNS-CEs) for dye-sensitized solar cells (DSSCs). The CNSs have a similar structure to multilayered graphene, and their high electrical conductivity and electrocatalytic activity enable them to have a dual-function as both CEs and charge supporting electrodes. CNSs form a unique CE material that functions successfully while being metal- and fluorine doped tin oxide (FTO)-free and allowing DSSCs to achieve ~5% power conversion efficiency. The chemical structure, electrical properties, electrocatalytic activity, and work function of the CNS-CEs prepared under various conditions of carbonization are investigated, and their effects on the performance of the corresponding DSSCs are discussed. Carbonization temperature is shown to have influenced the size of graphitic domains and the presence of heteroatoms and functional groups in CNS-CEs. The change in the graphitic domain size has a marginal influence on the work function of the CNS-CEs and the overpotential for the reduction of the redox couples (I( )/I3(-)). However, the electrical conductivity of CNS-CEs and the charge transfer resistance at CE/electrolyte interfaces in the DSSCs are considerably influenced by the carbonization condition. Our study shows that CNSs serve as efficient, FTO free CE materials for DSSCs, and they are appropriate materials with which the effects of the chemical/physical properties of graphene-based materials on the electrode performance of various electrochemical devices may be studied. PMID- 25026396 TI - Multiporphyrinic cages: architectures and functions. PMID- 25026398 TI - Corrigendum. PMID- 25026397 TI - Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats. AB - Dexmedetomidine, a highly selective alpha2-adrenergic agonist, has been reported to attenuate isoflurane-induced cognitive impairment and neuroapoptosis. However, the underlying molecular mechanisms remain poorly understood. The aim of this study was to investigate whether mitogen-activated protein kinase (MAPK) pathway was involved in dexmedetomidine-induced neuroprotection against isoflurane effects. Seven-day-old (P7) neonatal Sprague-Dawley rats were pretreated with various concentrations of dexmedetomidine, and then exposed to 0.75% isoflurane or air for 6h. Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) was used to detect neuronal apoptosis in their hippocampus. Activated caspase-3, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinases (JNK), p38, phospho-ERK1/2, phospho-JNK and phospho-p38 proteins were detected by Western blotting in the hippocampus at the end of exposure. Also, P7 rats were pretreated with 75 MUg/kg dexmedetomidine alone, or given the ERK inhibitor U0126 before dexmedetomidine pretreatment, or pretreated with the p38 MAPK inhibitor SB203580 or JNK inhibitor SP600125 alone, and then exposed to 0.75% isoflurane for 6h. Isoflurane induced significant neuroapoptosis, increased the protein expression of phospho-JNK, phospho-c-Jun, phospho-p38 and phospho-nuclear factor-kappaB (NF-kappaB), decreased the level of phospho-ERK1/2 protein and reduced the ratio of Bcl-2/Bax in the hippocampus. Dexmedetomidine pretreatment inhibited isoflurane-induced neuroapoptosis and restored proteins expression of MAPK pathways and the Bcl-2/Bax ratio after isoflurane exposure. Moreover, SB203580 and SP600125 also partly attenuated the isoflurane-induced protein changes. However, U0126 did not reverse dexmedetomidine-induced neuroprotection. Our results indicate that the JNK and p38 pathways, not the ERK pathway are involved in dexmedetomidine-induced neuroprotection against isoflurane effects. PMID- 25026399 TI - The pain clinic. AB - The pain clinic is any group of medical and/or health professionals who are treating pain symptomatically. These clinics may be "open", where any doctor may refer patients, or "closed", where only specialists may refer patients. The patients are referred because of intractable pain, defined as pain of at least one month's duration, which has not been relieved by conventional techniques. Collaboration between the various specialists involved with the patients and between the other specialist clinics is of paramount importance. PMID- 25026400 TI - The role of passive mobilization in the immediate management of the fractured neck of humerus. AB - Conservative management, including an early introduction of pendular exercises to prevent shoulder stiffness, has always been advocated in the treatment of the fractured neck of humerus. However, the problem of glenohumeral joint stiffness can still be present many weeks after the fracture. It was proposed that the inclusion of passive mobilization in the treatment programme could lessen this problem. A method of passive mobilization which could be begun within the first few days post fracture, was used in a pilot study of 14 patients with fractures of the neck of humerus. Initial results indicated that with the inclusion of passive mobilization in an active treatment programme, good functional results could be obtained, while the period of rehabilitation and the number of treatments could also be substantially reduced. PMID- 25026401 TI - Preparation for retirement. AB - While the trend in Australia is towards earlier compulsory retirement, the United States Government has recently passed legislation which guarantees the rights of the elderly who wish to continue in employment to do so. This paper briefly discusses the concept of early retirement in the light of demographic trends which point to an increase in the proportion of elderly persons in the Australian population in the next few decades. Some of the needs of the elderly, as they themselves perceive them, are highlighted with special reference to a report commissioned by the Western Australian Council on the Ageing, and to a questionnaire completed by participants in the Western Australian Institute of Technology Activity Programme for the Over-60s. PMID- 25026402 TI - Physiotherapy services to special education in the Australian capital territory. AB - Child Health Physiotherapy Services in the A.C.T. have involvement with children in special education placements. The children range in age from birth to twelve years and exhibit neurological and developmental handicaps from minimal to profound. These services are provided to a number of different areas: an early intervention centre; three special schools for intellectually handicapped children; Junior Assessment Classes and Learning Centres in selected government schools; children with sensori-motor dysfunction from pre-schools and mainstream classes in primary schools. Children cannot be considered in isolation from the community in which they live. Physiotherapy is part of a total interaction to benefit the whole child by the family unit, doctors, other health professionals, teachers and counsellors. PMID- 25026403 TI - Negative disc exploration: positive canal signs. AB - It is common practice for those concerned with the treatment of patients with the many patterns of pain arising from the vertebral column to assess ranges of intervertebral joint movement and to associate with this assessment that of the behaviour of pain during the test movements. This clinical paper deals with the examination of movement of the pain sensitive structures in the vertebral canal (the dura mater and nerve root sleeves) and the clinical implications of restriction in range together with reproduction of the patient's pain. The possible clinical findings are considered in relation to low back pain, tethering of pain sensitive vertebral canal structures in pre and post laminectomy patients, the 'juvenile disc' patients and patients with headaches. PMID- 25026404 TI - Some thoughts on the mechanical anatomy of the female pelvis. AB - The obstetric significance of the female bony pelvis lies firstly, in its role during pregnancy wherein it protects the pelvic viscera and provides the point of attachment for the muscles of the abdominal walls, and secondly, during labour when the bony pelvis is the "immovable object" through which must pass the more pliable and compressible foetus. PMID- 25026405 TI - The physiology of labour. AB - The time of onset of labour is usually reasonably clear-cut and will be described by the patient as the onset of painful uterine contractions. The exact reason whereby the uterus changes from a retentive to an expulsive organ is not yet clearly understood. It probably is the summation of several factors: the drop in the hormone progesterone, either in absolute terms or relative to the level of oestrogen; attainment of a critical degree of distension and intrauterine pressure; a critical change in the consistency or sphincteric quality in the cervix; a critical build up of contractile protein in the uterine muscle cells and its increasing sensitivity to oxytocic hormone(s). PMID- 25026406 TI - Physiology of pregnancy. AB - Pregnancy commences with the fertilization of an ovum, and terminates thirty eight weeks later with the commencement of parturition. Once a month, approximately fourteen days before commencement of menstruation, an ovum is liberated from a mature graafian follicle. Fertilization usually occurs just before or soon after the ovum enters a fallopian tube. The zygote (fertilized ovum) takes approximately four days to pass down the tube, and on reaching the uterus it has divided several times to form the blastocyst. The blastocyst remains free in the uterus a further two to three days before being embedded in the endometrium (endothelial lining of the uterus). After ovulation the graafian follicle develops into the corpus luteum, a specialized endocrine structure. PMID- 25026407 TI - Psychological adjustments of pregnancy. AB - Reproduction in the human species is a universal phenomenon. This is such an obvious statement as to appear banal, and yet, considering the length of time that this phenomenon has been in operation, the gaps in our knowledge of the processes involved should be a cause of concern. Perhaps the fact that this phenomenon has been occurring for so many hundreds of thousands of years, has inspired an attitude of acceptance without enquiry. Certainly, there is an increasing body of medical knowledge as the result of many research enquiries into the physiological processes involved in pregnancy and the ways in which they may affect the mother and the foetus. Efforts have been made very successfully to reduce the level of maternal and infant mortality and morbidity, but surprisingly few studies have concerned themselves with the emotional aspects of this biological condition. Such studies, fortunately, are increasing and in the years to come, our knowledge of the psychological phenomena associated with child bearing will be more comprehensive than at the present time. Whilst in the last half century there has been a considerable body of speculative theory on the emotional aspects of pregnancy, it is only in comparatively recent years that attempts have been made in anything like a systematic or scientific way to study this particular aspect of child birth. This paper then must, of necessity, be something of a hotchpotch of current knowledge and current theories - some facts, some speculations - perhaps not as neatly tied up in a package deal as you would like. PMID- 25026408 TI - Analgesia and anaesthesia in labour. AB - In recent years, great advances have been made in the development of new drugs and techniques for the relief of pain in the obstetric patient. Many of the older drugs, if they have not already been discarded, are in the process of being discarded at the present time. I intend to describe the individual drugs that are useful in obstetrics today and briefly mention the part that I consider "psychoprophylaxis" (if I may use this term) has to play in present-day obstetric practice. PMID- 25026409 TI - Postnatal problems in obstetrics. AB - The following is a summary of some of the topics discussed. PMID- 25026410 TI - Harnessing entropic and enthalpic contributions to create a negative tone chemically amplified molecular resist for high-resolution lithography. AB - Here we present a new resist design concept. By adding dilute cross-linkers to a chemically amplified molecular resist, we synergize entropic and enthalpic contributions to dissolution by harnessing both changes to molecular weight and changes in intermolecular bonding to create a system that outperforms resists that emphasize one contribution over the other. We study patterning performance, resist modulus, solubility kinetics and material redistribution as a function of cross-linker concentration. Cross-linking varies from dilute oligomerization to creating a highly networked system. The addition of small amounts of cross-linker improves resist performance by reducing material diffusion and redistribution during development and stiffening the features to avoid pattern collapse. The new dilute cross-linking system achieves the highest resolution of a sensitive molecular glass resist at 20 nm half-pitch and line-edge roughness (LER) of 4.3 nm and can inform new resist design towards patterned feature control at the molecular level. PMID- 25026411 TI - Metal-organic framework derived hierarchical ZnO parallelepipeds as an efficient scattering layer in dye-sensitized solar cells. AB - Metal-organic frameworks (MOFs) have been used in the area of photovoltaic devices via a novel approach proposed here for the first time. Hierarchical ZnO parallelepipeds were prepared from a MOF precursor, which could then act as an effective light scattering layer in dye-sensitized solar cells, leading to significantly improved cell performance. PMID- 25026413 TI - Wavelet phase coherence analysis of the skin blood flow oscillations in human. AB - The wavelet phase coherence of oscillations in the peripheral blood flow of contralateral skin sites was studied in 20 healthy subjects. Skin perfusion was registered simultaneously on similar regions of the outer sides of the right and left forearms by the laser Doppler flowmetry technique. To estimate the reliability of the obtained wavelet phase coherence values we applied the comparative method using amplitude-adjusted Fourier transform surrogates. High median values (0.63 and 0.59) of the wavelet phase coherence were obtained for the frequency intervals of respiratory (0.145-0.6Hz) and cardiac (0.6-2Hz) rhythms in 18 and 20 participants, respectively. In all the 20 participants we detected high and reliable values (Me=0.72) of the wavelet phase coherence for skin blood flow oscillations in the myogenic interval (0.052-0.145Hz). Additionally, we demonstrated high wavelet phase coherence in the neurogenic (0.021-0.052Hz) and endothelial (0.0095-0.021Hz) intervals in 8 and 7 participants, respectively. The corresponding medians of the reliable wavelet phase coherence values for these intervals were 0.74 and 0.82. The obtained results suggest that the microvascular blood flow possesses not only the local mechanisms of generating low-frequency blood flow oscillations, but also a central mechanism, which is likely to synchronize low-frequency oscillations throughout the whole cardiovascular system. PMID- 25026414 TI - Decades of research in drug targeting to the upper gastrointestinal tract using gastroretention technologies: where do we stand? AB - A major constraint in oral controlled release drug delivery is that not all the drug candidates are absorbed uniformly throughout the gastrointestinal tract (GIT). Drugs having "absorption window" are absorbed in a particular portion of GIT only or are absorbed to a different extent in various segments of the GIT. Thus, only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. The drug must be released from the dosage form in solution form; otherwise, it is generally not absorbed. Hence, much research has been dedicated to the development of gastroretentive drug delivery systems that may optimize the bioavailability and subsequent therapeutic efficacy of such drugs, as these systems have unique properties to bypass the gastric emptying process. These systems show excellent in vitro results but fail to give desirable in vivo performance. During the last 2-3 decades, researchers from the academia and industries are giving considerable importance in this field. Unfortunately, till date, few so-called gastroretentive dosage forms have been brought to the market in spite of numerous academic publications. The manuscript considers strategies that are commonly used in the development of gastroretentive drug delivery systems with a special attention on various parameters, which needs to be monitored during formulation development. PMID- 25026412 TI - Role of lymphatic vasculature in regional and distant metastases. AB - In cancer, lymphatic vasculature has been traditionally viewed only as a transportation system for metastatic cells. It has now become clear that lymphatics perform many additional functions which could influence cancer progression. Lymphangiogenesis, induced at the primary tumor site and at distant sites, potently augments metastasis. Lymphatic endothelial cells (LECs) control tumor cell entry and exit from the lymphatic vessels. LECs also control immune cell traffic and directly modulate adaptive immune responses. This review highlights advances in our understanding of the mechanisms by which lymphatic vessels, and in particular lymphatic endothelium, impact metastasis. PMID- 25026415 TI - Surface-coated PLA nanoparticles loaded with temozolomide for improved brain deposition and potential treatment of gliomas: development, characterization and in vivo studies. AB - Hydrophobicity of PLA nanoparticles makes them a good substrate for macrophageal and reticulo-endothelial system uptake. Long-circulating properties can be imparted to these particles by coating them with hydrophilic stabilizers. Surface modified PLA nanoparticles loaded with anti-cancer agent temozolomide were fabricated by solvent evaporation method and coated with surface modifiers. Selection of the surface modifier was based upon uptake of nanoparticles by K9 cells (liver cells). The particles were prepared and characterized for various physicochemical properties using transmission electron microscopy, differential scanning calorimetry, powder X-ray diffraction and in vitro dissolution studies. In vitro BBB permeation studies were performed using the co-culture model developed by using Madin-Darby canine kidney and C6 glioma cells as endothelial and glial cells, respectively. In vitro C6 glioma cell cytotoxicity, cellular proliferation, cellular migration and cellular uptake studies due to developed nanoparticles was assessed. In vivo studies such as pharmacokinetics, qualitative and quantitative biodistribution studies were performed for the developed nanoparticles. Drug-loaded nanoparticles with entrapment efficiency of 50% were developed. PEG-1000 and polysorbate-80 coated nanoparticles were least taken up by the liver cells. Characterization of the nanoparticles revealed formation of spherical shape nanoparticles, with no drug and excipient interaction. In vivo pharmacokinetics of developed nanoparticles depicted enhancement of half-life, area under the curve and mean residence time of the drug. Qualitative and quantitative biodistribution studies confirmed enhanced permeation of the drug into the brain upon loading into nanoparticles with less deposition in the highly perfused organs like lung, liver, spleen, heart and kidney. PMID- 25026416 TI - Interactions of graphene oxide nanomaterials with natural organic matter and metal oxide surfaces. AB - Interactions of graphene oxide (GO) nanomaterials with natural organic matter (NOM) and metal oxide surfaces were investigated using a quartz crystal microbalance with dissipation monitoring (QCM-D). Three different types of NOM were studied: Suwannee River humic and fulvic acids (SRHA and SRFA) and alginate. Aluminum oxide surface was used as a model metal oxide surface. Deposition trends show that GO has the highest attachment on alginate, followed by SRFA, SRHA, and aluminum oxide surfaces, and that GO displayed higher interactions with all investigated surfaces than with silica. Deposition and release behavior of GO on aluminum oxide surface is very similar to positively charged poly-L-lysine-coated surface. Higher interactions of GO with NOM-coated surfaces are attributed to the hydroxyl, epoxy, and carboxyl functional groups of GO; higher deposition on alginate-coated surfaces is attributed to the rougher surface created by the extended conformation of the larger alginate macromolecules. Both ionic strength (IS) and ion valence (Na(+) vs Ca(2+)) had notable impact on interactions of GO with different environmental surfaces. Due to charge screening, increased IS resulted in greater deposition for NOM-coated surfaces. Release behavior of deposited GO varied significantly between different environmental surfaces. All surfaces showed significant release of deposited GO upon introduction of low IS water, indicating that deposition of GO on these surfaces is reversible. Release of GO from NOM-coated surfaces decreased with IS due to charge screening. Release rates of deposited GO from alginate-coated surface were significantly lower than from SRHA and SRFA-coated surfaces due to trapping of GO within the rough surface of the alginate layer. PMID- 25026417 TI - The treatment of back pain by spinal mobilization. AB - The treatment of the painful back is in a state of chaos. Perhaps with some thought and general cooperation from all interested bodies it may be possible to get some clarification of our ideas. A properly conducted trial of treatment is essential, with the final results as the only true guide to the efficiency of therapy. PMID- 25026418 TI - The management of rheumatoid arthritis. AB - Between two and three per cent of Australians suffer from rheumatoid arthritis, and in addition to the pain and disability experienced by the individual patient there is considerable cost to the community in terms of loss of work, cost of prescriptions and doctor's time. By an appreciation of the natural history of the disease and the potential value and disadvantages of the available treatment methods, these costs may be reduced. PMID- 25026419 TI - Clinical evaluation of the masman pressure unit in the reduction of limb oedema. AB - A clinical evaluation of the Masman Pressure Unit (M.P.U.) was undertaken in the Physiotherapy Department of Sydney Hospital to determine whether or not the M.P.U. was effective in reducing limb oedema. The study also investigated the pressures necessary to reduce oedema, the duration of treatment necessary, the duration of oedema relief, and how often treatment was necessary. PMID- 25026420 TI - A measurement of hand function in the normal child and the cerebral palsied child. AB - Although there are reports on hand function in normal children (Weiss and Flatt, 1971; Dickson and Calnan, 1972), there is little or no literature on the assessment of hand function in abnormal children. PMID- 25026421 TI - Observation and analysis of hemiplegic gait: stance phase. AB - People with hemiplegia resulting from cerebrovascular accident commonly demonstrate one or more deviations from the kinematics of normal gait. This paper presents a list of common kinematic deviations for which physiotherapists might look when making clinical observations of hemiplegic gait. A number of likely causes of those kinematic deviations are described, based on a review of the literature, biomechanical considerations and clinical observations. Particularly common and significant stance phase deviations are a decreased peak hip extension in late stance, increased or decreased peak lateral pelvic displacement, increased or decreased knee extension in early or mid stance and decreased plantarflexion at toe-off. The causes of these kinematic deviations lie in the inability to appropriately activate muscles and in the adaptive muscle shortening which commonly occurs following stroke. PMID- 25026422 TI - Observation and analysis of hemiplegic gait: swing phase. AB - Following hemiplegic stroke, many people present with one or more clinically significant kinematic deviations from normal gait. Significant kinematic deviations observed in swing phase include decreased peak hip flexion, decreased peak knee flexion, decreased knee extension for heel strike and decreased ankle dorsiflexion throughout swing. In this paper the causes of these kinematic deviations are discussed in terms of the forces produced by the inappropriate activation and adaptive shortening of particular muscle groups. PMID- 25026423 TI - Functional prediction post-stroke. AB - The ability of physiotherapists to accurately predict the recovery of motor function post-stroke (level) and the time required for this recovery (time) is a useful clinical skill. The degree of accuracy was investigated on eight functional tasks using ordinal assessment scales, in a prospective unblinded trial of 37 patients admitted sequentially to a stroke rehabilitation unit. The correlations between predicted and achieved performance for both level and time were statistically significant for all tasks. Prediction accuracy was better for level (ranging from 84 to 100 per cent +/- one level) than for time (ranging from 63 to 90 per cent +/- two weeks). When inaccurate, physiotherapists tended to be optimistic in predicting both level and time. Physiotherapists were able to predict independence accurately (independence predictive values ranging from 0.76 to 0.95). PMID- 25026424 TI - Attitudes toward people with disabilities of physiotherapists and members of the general population. AB - The Interaction with Disabled Persons (IDP) Scale is a new instrument developed to measure community attitudes towards people with disabilities. This article reports a section of the validation study for the IDP which took place between 1988 and 1990. It reports a comparison of performance on the IDP of a sample of 109 practising physiotherapists who responded to a questionnaire distributed by the Australian Physiotherapy Association and a sample of 4180 cases which covered a broad cross section of the Australian population. Results support hypotheses that members of the physiotherapist sample would be more positive in their attitudes and that positiveness of attitude is related to level of prior close contact with people with disabilities. PMID- 25026425 TI - Sideflexion induced lumbar spine conjunct rotation and its influencing factors. AB - Twenty motion segments from four male post mortem subjects with a mean age of 29 years were moved into the lumbar spine test positions of extension/left sideflexion, extension/right sideflexion, flexion/left sideflexion and flexion/right sideflexion Jheconjunct rotation (CR) that occurred was measured from a photographic record. The results indicated that the direction of the CR of the whole lumbar spine (ie between L1 and S1) was significantly different between the flexed and extended lumbar spine position. The direction of the CR was also significantly different between the different intervertebral motion segment levels. There was no relationship between CR and zygapophyseal joint geometry or intervertebral disc degeneration. PMID- 25026426 TI - Reported occurrence and nature of complications following manipulative physiotherapy in South Africa. AB - A questionnaire was utilised to establish the prevalence and nature of complications in South Africa following manipulative physiotherapy. Twenty-nine patients who received spinal manipulation presented with 52 complications. These are the only reported complications in an approximate total of 228,050 procedures applied. The majority (92 per cent) of these reported complications following cervical spine manipulation. Only minor complications were reported. Fifty-eight patients who received mobilisation to the cervical spine reported 129 post mobilisation complications. One patient suffered a cerebral vascular accident (CVA). The results of this survey show that spinal manipulation, as performed by physiotherapists in South Africa, is a relatively safe procedure. However, manipulative therapists should not be complacent when using cervical mobilisation and should be aware of potential risks. PMID- 25026427 TI - Developing a clinical indicator for obstructive mastitis. AB - Mastitis is a painful condition of the glands and ducts of the breast, which jeopardises breast feeding. It can occur in the puerperium and is associated with initial breast engorgement. It can also occur outside the puerperium and take several forms: mechanical, inflammatory and infective. The mechanical and inflammatory forms may be precursors of the infective form. In this clinical note, medium dose ultrasound therapy is suggested as a worthwhile intervention to reverse the early symptoms of blocked ducts or obstructive mastitis. Its use is indicated by its suggested anti-inflammatory and mechanical effects (Kitchen and Partridge 1990). PMID- 25026429 TI - Using surface electromyography in physiotherapy research. AB - Electromyography can be a useful tool for the physiotherapist to obtain information about the timing or magnitude of muscle activity when investigating the neuromuscular reflexes, muscle performance or patterns of movement. The quality of the signal recorded is dependent on the correct siting of electrodes, adequate skin preparation and the characteristics of the EMG machine itself. In order to accurately interpret the EMG data the user must be able to recognize artefacts which may distort the recording, and must also choose a processing technique which is appropriate for the particular application. This paper will review all these areas and provide an introduction to EMG techniques for the intending user. PMID- 25026430 TI - A survey of output characteristics of some new therapeutic ultrasound instruments manufactured in australia. AB - Seven newly purchased therapeutic ultrasound transducers were tested using a radiation pressure balance and steel baffles in compliance with Australian Standard Specification T40-1969. Total acoustic output at maximum meter settings, and effective transducer radiating areas were measured. Only one transducer demonstrated the output values nominated by the manufacturer. Two had an appropriate relationship between effective area and total output, though these values were not those stated by the manufacturer. The remaining four had effective radiating areas below the Australian Standards Association tolerance. Three of these had an otherwise acceptable power output and one had a very low output. These data substantiate the need for adequate testing facilities to be available for physiotherapists using ultrasound clinically. PMID- 25026431 TI - Muscle blood flow in peripheral vascular disease. AB - Physiotherapists are often involved in the post-operative management and rehabilitation of the lower limb amputee. Seldom, however, does one see the usual presentation of peripheral vascular disease - ischaemia of the muscles on exercise, ie: intermittent claudication. This article discusses a technique for demonstrating limitation in exercise blood flow - the basis of this symptom. Thallium 201 scanning is extensively used in demonstrating areas of reduced blood flow to one important muscle, the heart, and this technique can be extrapolated to the muscles of the leg. Twenty-two patients being studied with Thallium-201 for suspected coronary artery disease had the muscles of the lower limb scanned with a gamma camera. The photographs obtained form the basis of this article. PMID- 25026432 TI - The effect of neuropeptide Y on cell survival and neurotrophin expression in in vitro models of Alzheimer's disease. AB - Alzheimer's disease (AD) is a disorder characterized by the accumulation of abnormally folded protein fragments in neurons, i.e., beta-amyloid (Abeta) and tau protein, leading to cell death. Several neuropeptides present in the central nervous system (CNS) are believed to be involved in the pathophysiology of AD. Among them, neuropeptide Y (NPY), a small peptide widely distributed throughout the brain, has generated interest because of its role in neuroprotection against excitotoxicity in animal models of AD. In addition, it has been shown that NPY modulates neurogenesis. Interestingly, these latter effects are similar to those elicited by neurotrophins, which are critical molecules for the function and survival of neurons that degenerate during the course of AD. In this review we summarize the evidence for the involvement of NPY and neurotrophins in AD pathogenesis, and the similarity between them in CNS neurons. Finally, we recapitulate our recent in-vitro evidence for the involvement of neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the neuroprotective effect elicited by NPY in AD neuron-like models (neuroblastoma cells or primary cultures exposed to toxic concentrations of Abeta's pathogenic fragment 25-35), and propose a putative mechanism based on NPY-induced inhibition of voltage-dependent Ca(2+) influx in pre- and post-synaptic neurons. PMID- 25026434 TI - A nanoscale demonstration of hydrogen atom spillover and surface diffusion across silica using the kinetics of CO2 methanation catalyzed on spatially separate Pt and Co nanoparticles. AB - Hydrogen spillover is of great importance to understanding many phenomena in heterogeneous catalysis and has long been controversial. Here we exploit well defined nanoparticles to demonstrate its occurrence through evaluation of CO2 methanation kinetics. Combining platinum and cobalt nanoparticles causes a substantial increase in reaction rate, but increasing the spatial separation between discrete cobalt and platinum entities results in a dramatic ~ 50% drop in apparent activation energy, symptomatic of H atom surface diffusion limiting the reaction rate. PMID- 25026435 TI - Perceptual problems in neurology. AB - Physiotherapy has traditionally been concerned with muscle function. In dealing with patients with neurological disorders it may not be enough to have a thorough grasp of muscular innervation and musculoskeletal problems. We are all aware of the importance of the higher centres as manifested by motivation, courage, intelligence, the capacity to relax and so forth. This is the same for all patients. However, the perceptual problems which are unique to some neurological conditions may undermine the best efforts of a physiotherapist not familiar with them. The patient is the last person likely to be able to point out these problems because agnosia or unawareness is part of the picture. So the physiotherapist who hopes to succeed in this area must have expertise in methods of examination outside the traditional ones. PMID- 25026433 TI - Hyperfine and nuclear quadrupole tensors of nitrogen donors in the Q(A) site of bacterial reaction centers: correlation of the histidine N(delta) tensors with hydrogen bond strength. AB - X- and Q-band pulsed EPR spectroscopy was applied to study the interaction of the QA site semiquinone (SQA) with nitrogens from the local protein environment in natural abundance (14)N and in (15)N uniformly labeled photosynthetic reaction centers of Rhodobacter sphaeroides. The hyperfine and nuclear quadrupole tensors for His-M219 Ndelta and Ala-M260 peptide nitrogen (Np) were estimated through simultaneous simulation of the Q-band (15)N Davies ENDOR, X- and Q-band (14,15)N HYSCORE, and X-band (14)N three-pulse ESEEM spectra, with support from DFT calculations. The hyperfine coupling constants were found to be a((14)N) = 2.3 MHz, T = 0.3 MHz for His-M219 Ndelta and a((14)N) = 2.6 MHz, T = 0.3 MHz for Ala M260 Np. Despite that His-M219 Ndelta is established as the stronger of the two H bond donors, Ala-M260 Np is found to have the larger value of a((14)N). The nuclear quadrupole coupling constants were estimated as e(2)Qq/4h = 0.38 MHz, eta = 0.97 and e(2)Qq/4h = 0.74 MHz, eta = 0.59 for His-M219 Ndelta and Ala-M260 Np, respectively. An analysis of the available data on nuclear quadrupole tensors for imidazole nitrogens found in semiquinone-binding proteins and copper complexes reveals these systems share similar electron occupancies of the protonated nitrogen orbitals. By applying the Townes-Dailey model, developed previously for copper complexes, to the semiquinones, we find the asymmetry parameter eta to be a sensitive probe of the histidine Ndelta-semiquinone hydrogen bond strength. This is supported by a strong correlation observed between eta and the isotropic coupling constant a((14)N) and is consistent with previous computational works and our own semiquinone-histidine model calculations. The empirical relationship presented here for a((14)N) and eta will provide an important structural characterization tool in future studies of semiquinone-binding proteins. PMID- 25026436 TI - The bobath concept in the treatment of patients with brain damage. AB - Dr. and Mrs. Bobath have worked mainly with patients suffering from cerebral palsy, and with those who are hemiplegic as a result of a cerebro-vascular accident. However, their methods of treatment have been shown to be effective with a number of other disorders of brain function involving the sensorimotor system. The treatment they have developed is directed towards disorders of movement and disorders of tone. PMID- 25026437 TI - The relevance of measurement of physiological and structural parameters for rehabilitation. AB - For the past few weeks, the Physical Education Department of the University of Western Australia, in conjunction with the National Fitness Council of W.A., has undertaken the assessment of physical fitness levels of members of the public. Each person was required to produce a doctor's certificate which, among other things, stated precautions which should be catered for when prescribing an exercise programme. It was interesting to correlate the precautions written on the chart by the doctor and their interpretation by the individual. Usually the doctor's recommendation for care was interpreted by the subject to mean a distinct avoidance of any form of physical activity and served as a crutch for the abstinence of even normal household duties such as gardening or washing the car. PMID- 25026438 TI - Problems in the physiotherapy management of oesophageal surgery. AB - Those who started working in thoracic surgical units in the early 1950's have witnessed many changes. Over the years the emphasis has shifted from surgery for tuberculosis, to surgery for abnormalities of the heart, surgery for cancer of the lungs and surgery for a variety of conditions, both acquired and congenital, of the oesophagus. Some of the problems encountered in the physiotherapy management of this last group will be the subject of this paper. PMID- 25026439 TI - Modern management of acute myocardial infarction. AB - Coronary care units have led to a reduction in the mortality of patients with acute myocardial infarction (Goble et al., 1966; Killip and Kimball, 1967; MacMillan et al., 1967). Continuous electrocardiographic monitoring in patients with acute myocardial infarction has shown that cardiac arrhythmias are extremely common (Julian et al., 1964). The prompt and effective control of minor cardiac arrhythmias by appropriate anti-arrhythmic therapy, prevents the development of major cardiac arrhythmias and this is the chief benefit of the coronary care unit. To a lesser extent the successful resuscitation of patients with cardiac arrest contributes to the reduction in mortality. PMID- 25026440 TI - Compositional complexity of the mitochondrial proteome of a unicellular eukaryote (Acanthamoeba castellanii, supergroup Amoebozoa) rivals that of animals, fungi, and plants. AB - We present a combined proteomic and bioinformatic investigation of mitochondrial proteins from the amoeboid protist Acanthamoeba castellanii, the first such comprehensive investigation in a free-living member of the supergroup Amoebozoa. This protist was chosen both for its phylogenetic position (as a sister to animals and fungi) and its ecological ubiquity and physiological flexibility. We report 1033 A. castellanii mitochondrial protein sequences, 709 supported by mass spectrometry data (676 nucleus-encoded and 33 mitochondrion-encoded), including two previously unannotated mtDNA-encoded proteins, which we identify as highly divergent mitochondrial ribosomal proteins. Other notable findings include duplicate proteins for all of the enzymes of the tricarboxylic acid (TCA) cycle which, along with the identification of a mitochondrial malate synthase isocitrate lyase fusion protein, suggests the interesting possibility that the glyoxylate cycle operates in A. castellanii mitochondria. Additionally, the A. castellanii genome encodes an unusually high number (at least 29) of mitochondrion-targeted pentatricopeptide repeat (PPR) proteins, organellar RNA metabolism factors in other organisms. We discuss several key mitochondrial pathways, including DNA replication, transcription and translation, protein degradation, protein import and Fe-S cluster biosynthesis, highlighting similarities and differences in these pathways in other eukaryotes. In compositional and functional complexity, the mitochondrial proteome of A. castellanii rivals that of multicellular eukaryotes. BIOLOGICAL SIGNIFICANCE: Comprehensive proteomic surveys of mitochondria have been undertaken in a limited number of predominantly multicellular eukaryotes. This phylogenetically narrow perspective constrains and biases our insights into mitochondrial function and evolution, as it neglects protists, which account for most of the evolutionary and functional diversity within eukaryotes. We report here the first comprehensive investigation of the mitochondrial proteome in a member (A. castellanii) of the eukaryotic supergroup Amoebozoa. Through a combination of tandem mass spectrometry (MS/MS) and in silico data mining, we have retrieved 1033 candidate mitochondrial protein sequences, 709 having MS support. These data were used to reconstruct the metabolic pathways and protein complexes of A. castellanii mitochondria, and were integrated with data from other characterized mitochondrial proteomes to augment our understanding of mitochondrial proteome evolution. Our results demonstrate the power of combining direct proteomic and bioinformatic approaches in the discovery of novel mitochondrial proteins, both nucleus-encoded and mitochondrion-encoded, and highlight the compositional complexity of the A. castellanii mitochondrial proteome, which rivals that of animals, fungi and plants. PMID- 25026442 TI - Pain Control via the Dorso-Lumbar Sympathetic Outflow. AB - No acceptable scientific explanation has yet been found to account for the success of such remote treatments as acupuncture and connective tissue massage which do not conform to the recognized distribution of segmental reference. This paper is the result of clinical observations over the past seven years, revealing previously unsuspected effects from applying various treatments to the area of the sympathetic dorso-lumbar outflow for a wide variety of painful conditions. An hypothesis is offered which may account for those remote effects hitherto poorly understood. PMID- 25026441 TI - Comprehensive proteome analysis of the response of Pseudomonas putida KT2440 to the flavor compound vanillin. AB - Understanding of the molecular response of bacteria to precursors, products and environmental conditions applied in bioconversions is essential for optimizing whole-cell biocatalysis. To investigate the molecular response of the potential biocatalyst Pseudomonas putida KT2440 to the flavor compound vanillin we applied complementary gel- and LC-MS-based quantitative proteomics approaches. Our comprehensive proteomics survey included cytoplasmic and membrane proteins and led to the identification and quantification of 1614 proteins, corresponding to 30% of the total KT2440 proteome. 662 proteins were altered in abundance during growth on vanillin as sole carbon source as compared to growth on glucose. The proteome response entailed an increased abundance of enzymes involved in vanillin degradation, significant changes in central energy metabolism and an activation of solvent tolerance mechanisms. With respect to vanillin metabolism, particularly enzymes belonging to the beta-ketoadipate pathway including a transcriptional regulator and porins specific for vanillin uptake increased in abundance. However, catabolism of vanillin was not dependent on vanillin dehydrogenase (Vdh), as shown by quantitative proteome analysis of a Vdh deficient KT2440 mutant (GN235). Other aldehyde dehydrogenases that were significantly increased in abundance in response to vanillin may replace Vdh and thus may represent interesting targets for improving vanillin production in P. putida KT2440. BIOLOGICAL SIGNIFICANCE: The high demand for the flavor compound vanillin by the food and fragrance industry makes natural vanillin from vanilla pods a scarce and expensive resource rendering its biotechnological production economically attractive. Pseudomonas bacteria are metabolically very versatile and accept a broad range of hydrocarbons as carbon source making them suitable candidates for bioconversion processes. This work describes the impact of vanillin on the metabolism of the reference strain P. putida KT2440 on a proteome wide scale. The high proteome coverage of our proteomics survey allowed us to analyze the regulation of whole protein networks instead of single proteins. We were able to reconstruct the complete degradation pathway of vanillin and to monitor the changes in the energy metabolism of KT2440 induced by vanillin as sole carbon source. Vanillin dehydrogenase (Vdh) was not mandatory for vanillin degradation in KT2440 and may be substituted by other aldehyde dehydrogenases that were up-regulated in a wild-type as well as in a Vdh-deficient strain in the presence of vanillin. Aldehyde dehydrogenases, vanillin specific porins and efflux pump systems identified in study will be interesting targets for optimization of vanillin production in Pseudomonas bacteria. Furthermore, several mechanisms of solvent tolerance were induced by vanillin in KT2440. These include increased abundance of several efflux pump systems, chaperones as well as enzymes involved in cyclopropane fatty acid synthesis and trehalose formation. The present work will deepen the understanding of metabolism of aromatic compounds in P. putida and may lead to a more comprehensive understanding of solvent tolerance mechanisms in Gram-negative bacteria in general. Moreover, it will serve as a basis for further strain developments for a biotechnological production of vanillin in P. putida KT2440 or other Pseudomonas strains, highlighting the role of proteomics surveys as a powerful screening technology. PMID- 25026443 TI - Spinal manipulative therapy: review of some proposed mechanisms, and a new hypothesis. AB - Some of the claims for the effects, and mechanisms for the relief of pain of spinal origin, which have been attributed to spinal manipulative therapy are reviewed. Most of these are still to be adequately investigated experimentally; the few which have been specifically investigated have not been supported. It is hypothesized that an effective, albeit often temporary, decrease in patients' perception of pain may be a result of two ordered events. The first is inhibition of reflex muscle contraction which is maximally mediated by joint afferents with end of range passive joint movement. The second is a hysteresis effect for neural discharge in joint afferents which may be produced with maintained or repetitive end of range passive joint movement. PMID- 25026444 TI - Levator Scapulae Action during Shoulder Movement: A Possible Mechanism for Shoulder Pain of Cervical Origin. AB - The phenomenon of shoulder pain of cervical origin being reproduced on shoulder movement is clinically recognized. The action of the shoulder girdle muscles is a hypothetical cause of the cervical stress. This study examined the mode and degree of Levator Scapulae activity during shoulder activity. Electromyography and x-rays were used to measure levator scapulae activity and length. The results of the study show that levator scapulae contracts concentrically during the first 90 degrees of shoulder abduction and eccentrically during the second 90 degrees. The action of levator scapulae may be responsible for the application of force on the cervical spine during shoulder abduction. This force might cause cervical joint tissue distortion and pain if a pathological state was present. PMID- 25026445 TI - The effect of respiratory therapy on intracranial pressure in ventilated neurosurgical patients. AB - Considerable concern has been expressed about the effect of respiratory therapy on intracranial pressure (I.C.P.) in the acute stage of head injury. A study was performed to evaluate the effects of respiratory therapy techniques on the level of I.C.P. in neurosurgical patients. Twenty subjects were studied in both the paralysed and non-paralysed states. Their intracranial pressures were monitored during periods of no treatment (the control), during the application of individual respiratory techniques and during a complete respiratory treatment. Analyses revealed that total treatment time is a crucial factor in the level of I.C.P. Patients with a high resting I.C.P. are more vulnerable to large increases, prolonged manual hyperinflation raises I.C.P. level and suctioning, in particular, causes dramatic increases in I.C.P. PMID- 25026446 TI - Muscle Balance between Hamstrings and Quadriceps during Isokinetic Exercise. AB - The maximum flexor and extensor peak torques about the knee joint of 17 male and 17 female subjects were determined using a CYBEX isokinetic dynamometer. These values were used to evaluate the influence of changing joint angular-velocity on the ratio of peak hamstrings torque to peak quadriceps torque. Additionally, an assessment of the influence of gravity on the recorded peak torques, and thus the ratio, was made Values for the flexion-extension ratio corrected for gravity were found not significantly different at the measured joint angular-velocities whereas the values of the ratio not corrected for gravity were found significantly different at increasing joint angular-velocities It is necessary that the physiotherapist recognize the importance of the influence of gravity when recording forces developed in the vertical plane. PMID- 25026447 TI - Effects of cooling with simulated ice on skin temperature and nerve conduction velocity. AB - Commercially produced cold packs, which may be refrigerated to simulate ice packs, are preferred by many physiotherapists for cooling treatments. In the experiments described here, the efficiency of cold packs and ice packs was determined by measuring their effects on skin temperature and the conduction velocity of motor nerve fibres. Although the commercially available cold pack did alter the measured physiological variables, ice was found to be the more effective method of cooling superficial and possibly deep tissue. PMID- 25026448 TI - Old age and physical capacity: use it or lose it. AB - Increasing age is usually associated with a decline in the amount of habitual exercise activity of an individual in western society. While this reflects a decline in physical capacity, it is in large part due to socio-cultural pressures and expectations. The preservation of any function, intellectual or physical, is dependent upon the use that is made of that function, and the physiotherapist with a unique background in human movement and pathology has a vital role in the prescription and supervision of exercise with the elderly. Exercise has demonstrable effects on skeletal health and bone maintenance, muscle bulk and strength, the ranges of movements of joints, cartilage compliance, soft tissue extensibility, neuronal efficiency and cardiopulmonary fitness. This paper considers some of the physical aspects of ageing on body tissues together with the actual and potential role of physiotherapy in the health education and treatment of elderly people. PMID- 25026449 TI - An evaluation of school screening for scoliosis in Western australia. AB - This paper summarizes the results of research into the scoliosis screening programme undertaken in Western Australian schools over a three-year period from October 1976 to October 1979. It represents the follow-up operating in the spinal deformities clinics chiefly at the Princess Margaret Hospital for Children and also at the Royal Perth (Rehabilitation) Hospital giving details of numbers seen, sex and age relationship, necessity for review visits and active treatment required. The various treatments are outlined briefly. The optimum school levels at which screening should be carried out have emerged and the programme has been altered accordingly as from the beginning of 1980. This paper concludes that school screening for scoliosis is a worthwhile exercise in preventive medicine. PMID- 25026450 TI - The need for counselling of the male partner of a female mastectomy patient. AB - A survey was undertaken to investigate the need for counselling services to the partner of a mastectomy patient in terms of improving patient-partner relationships post-operatively. One hundred and two mastectomy patients, and their partners, were selected at random. Each was asked to complete, separately, anonymous questionnaires concerning any changes in their relationships following surgery. Particular areas of interest involved the reasons for such changes, what supportive measures had been available, and what supportive measures were needed. The effective response rates were 36 per cent for females and 22 per cent for males. Responses were computerised; the results obtained are listed, and discussed with a view to future needs. It is concluded that recognition of the need for psychological help to both patient and partner is essential, and the need for further research and counsellor training is urgent. PMID- 25026451 TI - Interferential therapy. AB - One hundred patients with a wide range of musculoskeletal conditions were treated by interferential therapy, using the Nemecrodyn '8' machine. No control group was used, but marked or complete improvement was achieved in a large percentage of the patients, especially those whose conditions had been of short duration. The use of the 'Vector system' enabled a wide area of treatment to be achieved. It was possible for certain patients to exercise while undergoing interferential therapy. Interferential therapy appears to be a most useful form of physiotherapy for many types of conditions, from immediate sports injuries to intransigent chronic conditions. PMID- 25026452 TI - Details of the excited-state potential energy surfaces of adenine by coupled cluster techniques. AB - EOM-CCSD and CC2-LR methods were used to study the potential energy surfaces of the three lowest excited states (two pipi* and an npi*) of adenine. The equilibrium structure could only be obtained for the S1 state, which has n-pi* character. It was shown that the topology of the coupled cluster surface is such that no minimum for the S2 and S3 states exists in the Franck-Condon region due to conical intersections between these low-lying states. To understand this topology, relevant cuts of the potential energy surfaces have also been calculated, and conical intersections have been located. Even a three-fold intersection between these three states was found. The crossings of these surfaces can be reached from the bright state barrierlessly without major change in the geometry. Therefore, these might play an important role in the ultrafast deactivation of adenine. PMID- 25026453 TI - [ONN]-type amine pyridine(s) phenolate-based oxovanadium(V) catalysts for ethylene homo- and copolymerization. AB - A series of oxovanadium(V) complexes containing amine pyridine(s) phenolate ligands [ONN] (2a-f) have been synthesized in high yields (68-83%) by reacting VO(O(n)Pr)3 with 1.0 equiv. of the ligands in CH2Cl2. These complexes were characterized by (1)H, (13)C and (51)V NMR spectroscopy and elemental analysis. X ray structural analysis for 2a, 2c and 2d revealed that these complexes adopt a six-coordinate distorted octahedral geometry around the vanadium center in the solid state. Upon treatment with Et2AlCl and CCl3COOEt, these complexes displayed high catalytic activities for ethylene polymerization even at elevated reaction temperatures, depending on ligand structures. The resulting polymers possessed high molecular weight and unimodal molecular weight distributions, indicative of the formation of a single catalytically active species during the polymerization catalysis. Excitingly, these vanadium(V) complexes could efficiently promote ethylene/norbornene copolymerization. The observed catalytic activity for the copolymerization was higher than that for ethylene homopolymerization. Moreover, the molecular weights of the resulting copolymers increased upon increasing the norbornene feed. These results indicated that introducing a suitable amount of norbornene into the system not only could accelerate the polymerization rate but also could restrain chain transfer reactions to some extent. PMID- 25026454 TI - Protein-leucine fed dose effects on muscle protein synthesis after endurance exercise. AB - Protein-leucine ingestion after strenuous endurance exercise accentuates muscle protein synthesis and improves recovery of muscle performance. PURPOSE: The objective of this study is to determine whether a low-dose protein-leucine blend ingested after endurance exercise enhances skeletal muscle myofibrillar protein fractional synthetic rate (FSR). METHOD: In a crossover design, 12 trained men completed 100 min of high-intensity cycling, then ingested either 70/15/180/30 g of protein/leucine/carbohydrate/fat (15LEU), 23/5/180/30 g of 5LEU, or 0/0/274/30 g of CON beverages in randomized order in four servings during the first 90 min of a 240-min recovery period. Muscle biopsies were collected at 30 and 240 min into recovery with FSR determined by L-[ring-13C6]phenylalanine incorporation and mTORC1 pathway phosphorylation by Western blot. RESULTS: The 33% (90% CL, +/-12%) increase in FSR with 5LEU (mean, SD: 0.080, 0.014%.h(-1)) versus CON (0.060, 0.012%.h(-1)) represented near-maximal FSR stimulation. Tripling protein-leucine dose (15LEU: 0.090, 0.11%.h(-1)) negligibly increased FSR (13%, +/-12% vs 5LEU). Despite similar FSR, mTORC1(Ser2448) phosphorylation only increased with 15LEU at 30 min, whereas p70S6K(Thr389), rpS6(Ser240/244), and 4E-BP1gamma(Ser112) phosphorylation increased with protein-leucine quantity at one or both time points. Plasma leucine and essential amino acid concentrations decreased during recovery in CON but increased with protein-leucine dose. Serum insulin was increased in 15LEU versus CON (60%, +/-20%) but was unaffected relative to 5LEU. Regression analysis revealed p70S6K-rpS6 phosphorylation moderately predicted FSR, but the associations with plasma leucine and essential amino acids were small. CONCLUSIONS: Ingesting 23 g of protein with 5 g of added leucine achieved near-maximal FSR after endurance exercise, an effect unlikely attributable to mTORC1-S6K-rpS6 signaling, insulin, or amino acids. Translating the effects of protein-leucine quantity on protein synthesis to optimizing adaptation and performance requires further research. PMID- 25026455 TI - Detection, Diversity, and Population Dynamics of Waterborne Phytophthora ramorum Populations. AB - Sudden oak death, the tree disease caused by Phytophthora ramorum, has significant environmental and economic impacts on natural forests on the U.S. west coast, plantations in the United Kingdom, and in the worldwide nursery trade. Stream baiting is vital for monitoring and early detection of the pathogen in high-risk areas and is performed routinely; however, little is known about the nature of water-borne P. ramorum populations. Two drainages in an infested California forest were monitored intensively using stream-baiting for 2 years between 2009 and 2011. Pathogen presence was determined both by isolation and polymerase chain reaction (PCR) from symptomatic bait leaves. Isolates were analyzed using simple sequence repeats to study population dynamics and genetic structure through time. Isolation was successful primarily only during spring conditions, while PCR extended the period of pathogen detection to most of the year. Water populations were extremely diverse, and changed between seasons and years. A few abundant genotypes dominated the water during conditions considered optimal for aerial populations, and matched those dominant in aerial populations. Temporal patterns of genotypic diversification and evenness were identical among aerial, soil, and water populations, indicating that all three substrates are part of the same epidemiological cycle, strongly influenced by rainfall and sporulation on leaves. However, there was structuring between substrates, likely arising due to reduced selection pressure in the water. Additionally, water populations showed wholesale mixing of genotypes without the evident spatial autocorrelation present in leaf and soil populations. PMID- 25026456 TI - Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves. AB - Interindividual variability in stable warfarin doses is largely attributed to VKORC1 and CYP2C9 variants. On the basis of a recent finding of the role of GATA4 in control of CYP2C9 expression, we tested a possible effect of GATA4 genotypes on variability in warfarin response using 201 Korean patients with prosthetic cardiac valves. Two single-nucleotide polymorphisms (SNPs), rs2645400 (G>T) and rs4841588 (G>T), were significantly associated with stable warfarin doses in patients carrying CYP2C9 wild-type homozygotes; homozygote carriers of these two SNPs required higher doses than those with other genotypes (5.94+/-1.73 versus 5.34+/-1.88 mg, P=0.026; 5.94+/-1.66 versus 5.37+/-1.92, P=0.036, respectively). Multivariate analysis showed that two GATA4 combinations, rs867858 (G>T)/rs10090884 (A>C) and rs2645400 (G>T)/rs4841588 (G>T), increased contribution to the overall warfarin dose variability from 36.4 to 40.9%. This study revealed that GATA4 can be predictive of stable warfarin dose and extended warfarin pharmacogenetics further to the regulation of CYP2C9 expression. PMID- 25026457 TI - EGFR ligands and DNA repair genes: genomic predictors of complete response after capecitabine-based chemoradiotherapy in locally advanced rectal cancer. AB - Epidermal growth factor receptor (EGFR) activation by radiation leads to increased cell proliferation and acts as a radioresistance mechanism. Neoadjuvant chemoradiation is the standard of care for locally advanced rectal cancer, and to date, no biomarkers of response have been found. We analyzed polymorphisms in the EGFR and its ligands, DNA repair genes and the thymidylate synthase in 84 stages II and III rectal cancer patients treated with neoadjuvant capecitabine plus radiotherapy. The rs11942466 polymorphism in the amphiregulin (AREG) gene region was associated with a pathological complete response (ypCR) (odds ratio: 0.26; 95% confidence interval: 0.06-0.79; P=0.014). The rs11615 C>T polymorphism in the ERCC1 gene also correlated with the ypCR as no patients with a C/C genotype achieved ypCR; P=0.023. This is the first work to propose variants within the AREG and the ERCC1 genes as promising predictive biomarkers of ypCR in rectal cancer. PMID- 25026458 TI - Longitudinal, 3D in vivo imaging of sebaceous glands by coherent anti-stokes Raman scattering microscopy: normal function and response to cryotherapy. AB - Sebaceous glands perform complex functions, and they are centrally involved in the pathogenesis of acne vulgaris. Current techniques for studying sebaceous glands are mostly static in nature, whereas the gland's main function-excretion of sebum via the holocrine mechanism-can only be evaluated over time. We present a longitudinal, real-time alternative-the in vivo, label-free imaging of sebaceous glands using Coherent Anti-Stokes Raman Scattering (CARS) microscopy, which is used to selectively visualize lipids. In mouse ears, CARS microscopy revealed dynamic changes in sebaceous glands during the holocrine secretion process, as well as in response to damage to the glands caused by cooling. Detailed gland structure, plus the active migration of individual sebocytes and cohorts of sebocytes, were measured. Cooling produced characteristic changes in sebocyte structure and migration. This study demonstrates that CARS microscopy is a promising tool for studying the sebaceous gland and its associated disorders in three dimensions in vivo. PMID- 25026459 TI - Differentiation of histidine tautomeric states using (15)N selectively filtered (13)C solid-state NMR spectroscopy. AB - The histidine imidazole ring in proteins usually contains a mixture of three possible tautomeric states (two neutral - tau and pi states and a charged state) at physiological pHs. Differentiating the tautomeric states is critical for understanding how the histidine residue participates in many structurally and functionally important proteins. In this work, one dimensional (15)N selectively filtered (13)C solid-state NMR spectroscopy is proposed to differentiate histidine tautomeric states and to identify all (13)C resonances of the individual imidazole rings in a mixture of tautomeric states. When (15)N selective 180 degrees pulses are applied to the protonated or non-protonated nitrogen region, the (13)C sites that are bonded to the non-protonated or protonated nitrogen sites can be identified, respectively. A sample of (13)C, (15)N labeled histidine powder lyophilized from a solution at pH 6.3 has been used to illustrate the usefulness of this scheme by uniquely assigning resonances of the neutral tau and charged states from the mixture. PMID- 25026460 TI - Analysis of aging in lager brewing yeast during serial repitching. AB - Serial repitching of brewing yeast inoculates is an important economic factor in the brewing industry, as their propagation is time and resource intensive. Here, we investigated whether replicative aging and/or the population distribution status changed during serial repitching in three different breweries with the same brewing yeast strain but different abiotic backgrounds and repitching regimes with varying numbers of reuses. Next to bud scar numbers the DNA content of the Saccharomyces pastorianus HEBRU cells was analyzed. Gene expression patterns were investigated using low-density microarrays with genes for aging, stress, storage compound metabolism and cell cycle. Two breweries showed a stable rejuvenation rate during serial repitching. In a third brewery the fraction of virgin cells varied, which could be explained with differing wort aeration rates. Furthermore, the number of bud scars per cell and cell size correlated in all 3 breweries throughout all runs. Transcriptome analyses revealed that from the 6th run on, mainly for the cells positive gene expression could be seen, for example up-regulation of trehalose and glycogen metabolism genes. Additionally, the cells' settling in the cone was dependent on cell size, with the lowest and the uppermost cone layers showing the highest amount of dead cells. In general, cells do not progressively age during extended serial repitching. PMID- 25026461 TI - Tiling patterns from ABC star molecules: 3-colored foams? AB - We present coarse-grained simulations of the self-assembly of 3-armed ABC star polyphiles. In systems of star polyphiles with two arms of equal length the simulations corroborate and expand previous findings from related miktoarm star terpolymer systems on the formation of patterns containing columnar domains whose sections are 2D planar tilings. However, the systematic variation of face topologies as the length of the third (unequal) arm is varied differs from earlier findings regarding the compositional dependence. We explore 2D 3-colored foams to establish the optimal patterns based on interfacial energy alone. A generic construction algorithm is described that accounts for all observed 2D tiling patterns and suggests other patterns likely to be found beyond the range of the simulations reported here. Patterns resulting from this algorithm are relaxed using Surface Evolver calculations to form 2D foams with minimal interfacial length as a function of composition. This allows us to estimate the interfacial enthalpic contributions to the free energy of related star molecular assemblies assuming strong segregation. We compare the resulting phase sequence with a number of theoretical results from particle-based simulations and field theory, allowing us to tease out relative enthalpic and entropic contributions as a function of the chain lengths making up the star molecules. Our results indicate that a richer polymorphism is to be expected in systems not dominated by chain entropy. Further, analysis of corresponding planar tiling patterns suggests that related two-periodic columnar structures are unlikely hypothetical phases in 4-arm star polyphile melts in the absence of sufficient arm configurational freedom for minor domains to form lens-shaped di-gons, which require higher molecular weight polymeric arms. Finally, we discuss the possibility of forming a complex tiling pattern that is a quasi-crystalline approximant for 3-arm star polyphiles with unequal arm lengths. PMID- 25026463 TI - Pectoralis major myofascial flap in salvage laryngectomy. AB - OBJECTIVE: The main purpose of this study was to evaluate the effect of the pectoralis major myofascial flap on pharyngocutaneous fistula formation and time to oral feeding. METHODS: This retrospective study reviewed 155 total laryngectomies. Patients were divided into two main groups. Group 1 included 110 patients who were treated primarily by total laryngectomy and group 2 comprised 45 patients who were treated by salvage laryngectomy with or without a pectoralis major myofascial flap. RESULTS: The use of a pectoralis major myofascial flap did not have a significant effect on pharyngocutaneous fistula formation in the salvage group (p = 0.376). When comparing the oral feeding day of patients with pharyngocutaneous fistula, a significant difference was observed between the salvage group with pectoralis major myofascial flap reinforcement and the salvage group without pectoralis major myofascial flap reinforcement (p = 0.004). DISCUSSION: Our study demonstrated that pectoralis major myofascial flap reinforcement did not decrease the rate of pharyngocutaneous fistula formation. Instead, it prevented the formation of large fistulas that would require surgical management, and showed a similar time to oral feeding and length of hospital stay to primary laryngectomy. PMID- 25026464 TI - Contrast constancy revisited: the perceived contrast of sinusoidal gratings above threshold. AB - The contrast sensitivity function of the human visual system, measured with sinusoidal luminance gratings, has an inverted U shape with a peak around 2-4 c/deg. Above threshold, it is thought that luminance gratings of equal physical contrasts but of distinguishably different spatial frequencies are all perceived as having similar contrasts, a phenomenon that has been termed contrast constancy. However, when suprathreshold contrast matches were measured for pairs of luminance gratings whose spatial frequencies were indistinguishable, the matching curves were not flat and followed a similar inverted U shape form as the contrast sensitivity function at threshold. It was therefore suggested that contrast constancy may only be revealed when matching the contrasts of clearly distinguishable spatial frequencies. Here, observers matched the perceived contrasts of suprathreshold luminance gratings of similar but visibly different spatial frequencies between 0.25 and 16 c/deg. The results show that, much like the contrast sensitivity function at threshold, observers are more sensitive to intermediate spatial frequencies (1-6 c/deg) than they are to either higher or to lower spatial frequencies. This tuning is evident when matching reference contrasts of 30-80%, implying a significant role in everyday vision. To demonstrate that these results were not due to local adaptation, the experiment was repeated with shorter stimulus duration, producing the same results. The extent of departure from contrast constancy found in the present study is compared to previously reported suprathreshold measurements. The results are also discussed with consideration to limitations with display apparatus such as monitor blur. PMID- 25026466 TI - Rational synthesis of low-polydispersity block copolymer vesicles in concentrated solution via polymerization-induced self-assembly. AB - Block copolymer self-assembly is normally conducted via post-polymerization processing at high dilution. In the case of block copolymer vesicles (or "polymersomes"), this approach normally leads to relatively broad size distributions, which is problematic for many potential applications. Herein we report the rational synthesis of low-polydispersity diblock copolymer vesicles in concentrated solution via polymerization-induced self-assembly using reversible addition-fragmentation chain transfer (RAFT) polymerization of benzyl methacrylate. Our strategy utilizes a binary mixture of a relatively long and a relatively short poly(methacrylic acid) stabilizer block, which become preferentially expressed at the outer and inner poly(benzyl methacrylate) membrane surface, respectively. Dynamic light scattering was utilized to construct phase diagrams to identify suitable conditions for the synthesis of relatively small, low-polydispersity vesicles. Small-angle X-ray scattering (SAXS) was used to verify that this binary mixture approach produced vesicles with significantly narrower size distributions compared to conventional vesicles prepared using a single (short) stabilizer block. Calculations performed using self-consistent mean field theory (SCMFT) account for the preferred self assembled structures of the block copolymer binary mixtures and are in reasonable agreement with experiment. Finally, both SAXS and SCMFT indicate a significant degree of solvent plasticization for the membrane-forming poly(benzyl methacrylate) chains. PMID- 25026465 TI - Modelling from the experimental developmental biologists viewpoint. AB - In this review we consider Reaction-Diffusion as the archetype of a model in developmental biology. We consider its history in relation to experimental work since it was first proposed in 1952 by Turing and revived in the 1970s by Meinhardt. We then discuss the most recent examples of experiments that address this model, including the challenges that remain in capturing the physico chemical manifestation of the model mechanism in a real developmental system. Finally we discuss the model's current status and use in the experimental community. PMID- 25026467 TI - Holding hands. AB - The hand, as much as the face, is an organ for expression of the emotions. PMID- 25026468 TI - Fingers, toes, palmar and plantar arches. AB - In vertebrates from Amphibia to Man there are striking similarities between thoracic and pelvic limbs, between hands and feet, between fingers and toes. Most standard textbooks of Human Anatomy describe the foot by pointing to similar features in the hand: the extensor apparatus of the toes, for instance, is usually dispatched in a few words as being the same as in the fingers, the axis of attachment of the interossei presenting the only difference. One concept, however, has evolved in reverse, starting in the foot, namely the arch. PMID- 25026469 TI - A more natural approach to movement in treatment. AB - It has long been traditional to teach the subjects of Anatomy and Kinesiology in a standardised way. For descriptive purposes, and for ease of management, bodily movements have been tidily divided into sectional compartments. Thus, flexion extension, abduction-adduction, medial and lateral rotation are descriptive terms, and refer to stylised rather than natural or habitual movements. These methods, together with the tremendous amount of time that students devote to the subjects, means that physiotherapists tend to think of movement mostly in relation to these terms, as movements about certain stylised axes, and in certain descriptive planes. Although this approach appears to be an acceptable introduction to the analysis and understanding of human movement, it would be desirable for students to understand, at an early stage, that habitual, natural movement does not follow this model, but rather cuts across and through it, modifying it considerably. PMID- 25026470 TI - Physiotherapy for paralysis. AB - This paper presents the conclusions obtained from clinical evidence which was gained whilst observing the muscle responses in patients affected by varying degrees of paralysis as a result of a cerebral vascular accident. PMID- 25026471 TI - Painful hemiplegic shoulder. AB - The painful hemiplegic shoulder is a phenomenon known to most physiotherapists, as are the problems it causes in the rehabilitation of these patients. PMID- 25026472 TI - Infrared spectroscopic markers of quinones in proteins from the respiratory chain. AB - In bioenergetic systems quinones play a central part in the coupling of electron and proton transfer. The specific function of each quinone binding site is based on the protein-quinone interaction that can be described by means of reaction induced FTIR difference spectroscopy, induced for example by light or electrochemically. The identification of sites in enzymes from the respiratory chain is presented together with the analysis of the accommodation of different types of quinones to the same enzyme and the possibility to monitor the interaction with inhibitors. Reaction induced FTIR difference spectroscopy is shown to give an essential information on the general geometry of quinone binding sites, the conformation of the ring and of the substituents as well as essential structural information on the identity of the amino-acid residues lining this site. This article is part of a Special Issue entitled: Vibrational spectroscopies and bioenergetic systems. PMID- 25026473 TI - Rhodium(III)-catalyzed olefinic C-H alkynylation of enamides at room temperature. AB - Rh(III)-catalyzed C-H olefinic alkynylation of enamides for the stereospecific construction of synthetically useful Z-type enynamides is reported. This protocol displays good functionality tolerance and operational simplicity thus providing an alternative synthetic opportunity for the ease of access to specific 1,3-enyne derivatives. PMID- 25026474 TI - Melanocyte biology and function with reference to oral melanin hyperpigmentation in HIV-seropositive subjects. AB - The color of normal skin and of oral mucosa is not determined by the number of melanocytes in the epithelium but rather by their melanogenic activity. Pigmented biopolymers or melanins are synthesized in melanosomes. Tyrosinase is the critical enzyme in the biosynthesis of both brown/black eumelanin and yellow/red pheomelanin. The number of the melanosomes within the melanocytes, the type of melanin within the melanosomes, and the efficacy of the transfer of melanosomes from the melanocytes to the neighboring keratinocytes all play an important role in tissue pigmentation. Melanin production is regulated by locally produced factors including proopiomelanocortin and its derivative peptides, particularly alpha-melanocyte-stimulating hormone (alpha-MSH), melanocortin 1 receptor (MC1R), adrenergic and cholinergic agents, growth factors, cytokines, and nitric oxide. Both eumelanin and pheomelanin can be produced by the same melanocytes, and the proportion of the two melanin types is influenced by the degree of functional activity of the alpha-MSH/MC1R intracellular pathway. The cause of HIV oral melanosis is not fully understood but may be associated with HIV-induced cytokine dysregulation, with the medications commonly prescribed to HIV-seropositive persons, and with adrenocortical dysfunction, which is not uncommon in HIV seropositive subjects with AIDS. The purpose of this article is to discuss some aspects of melanocyte biology and HIV-associated oral melanin hyperpigmentation. PMID- 25026475 TI - Rechargeable lithium-sulfur batteries. PMID- 25026476 TI - Model experimental study of scale invariant wetting behaviors in Cassie-Baxter and Wenzel regimes. AB - In this work, we discuss quantitatively two basic relations describing the wetting behavior of microtopographically patterned substrates. Each of them contains scale invariant topographical parameters that can be easily expressed onto substrates decorated with specifically designed micropillars. The first relation discussed in this paper describes the contact angle hysteresis of water droplets in the Cassie-Baxter regime. It is shown that the energy at the origin of the hysteresis, that has to be overcome for moving the triple line, can be invariantly expressed for hexagonal pillars by varying the pillars width and interpillar distance. Identical contact angle hystereses are thus measured on substrates expressing this scale invariance for pillar widths and interpillar distances ranging from 4 to 128 MUm. The second relation we discuss concerns the faceting of droplets spreading on microtopographically patterned substrates. It is shown in this case that the condition for pinning of the triple line can be fulfilled by simultaneously varying the height of the pillars and the interpillar distance, leading to faceted droplets of similar morphologies. The invariance of these two wetting phenomena resulting from the simultaneous and homothetic variation of topographical parameters is demonstrated for a wide range of pattern dimensions. Our results show that either of those two wetting behaviors can be simply achieved by the proper choice of a dimensionless ratio of topographical length scales. PMID- 25026477 TI - Ultra-low-cost and flexible paper-based microplasma generation devices for maskless patterning of poly(ethylene oxide)-like films. AB - This work presents the use of an ultra-low-cost and flexible paper-based microplasma array to perform maskless patterning of poly(ethylene oxide)-like (PEO-like) thin films with a feature size down to submillimeter scale. In this process, the liquid precursor was directly applied to the paper substrate, gradually vaporized, and dissociated in the microplasma cavity, which leads to plasma polymerization. The FTIR and XPS spectra of the deposited film confirm the PEO-like structures. The protein adsorption test using the absorption of fluorescence-labeled fibrinogen conjugates on the treated surface shows the deposited films possessed the antifouling property with decent pattern transfer fidelity defined by the geometry of the microplasma array. PMID- 25026478 TI - A modified upper limb tension test: An investigation of responses in normal subjects. AB - One of the modifications of the upper limb neural tissue tension test (Butler 1987) sequences the movements of scapula depression, elbow extension, glenohumeral internal rotation, forearm pronation, wrist and finger flexion or extension and glenohumeral abduction. This test is used in the clinical situation but no normative data have been established. Fifty normal subjects were tested for the normal sensory responses and for the range of glenohumeral abduction in both a wrist and finger flexion and extension position. For both tests, approximately 40 degrees of glenohumeral abduction was available in the final positions. Gender and side tested did not influence results. The test using wrist and finger flexion mainly produced a strong painful stretch over the radial aspect of the proximal forearm and elbow. In contrast no single area was predominant for the test using wrist and finger extension. Knowledge of these normal responses is necessary for clinical decision making of abnormality. PMID- 25026479 TI - A survey of gerontology articles in physiotherapy journals. AB - A total of 144 articles in the field of gerontology/geriatrics published between 1980-88 in leading physiotherapy journals in America, Australia, Canada, New Zealand and the United Kingdom were examined in terms of source of publication and authors, research design and possible professional practice implications. The study examines the subject content of what physiotherapists from different countries have published on ageing; documents the current literature reflecting professional practice achievements and research interest; and identifies gaps in topics included in the physiotherapy journals. The fact that articles on gerontology are underrepresented in physiotherapy journals is readily apparent. A trend towards publishing more data-based articles; a low percentage of articles written jointly by physiotherapists and other professionals; and limited collaboration as measured by joint publication between physiotherapists working in clinical settings and those working in tertiary institutions has also emerged. PMID- 25026480 TI - Intertester reliability of the Modified Anterior Drawer (Lachman) Test for anterior cruciate ligament laxity. AB - Eight therapists each examined 16 subjects (14 with documented ACL pathology, two normal subjects) in a single session. Instrumented anterior laxity measurements were performed bilaterally on all subjects prior to testing. Therapists assessed the degree of anterior tibial translation on a visual analogue scale, and indicated whether the nominated knee tested positive or negative using the Lachman test. Intertester reliability in assessing anterior translation was low. Correlation between the overall therapists' translation measurements and the arthrometer was moderate. Intertester reliability in indicating whether the nominated knee tested positive or negative was low. These findings suggest that greater expertise is necessary for therapists to reliably use the Lachman test as an assessment procedure in evaluation of the injured knee. PMID- 25026481 TI - Lumbar segmental instability: Manual assessment findings supported by radiological measurement (A case study). AB - Intervertebral instability is a condition which can potentially cause pain in the lumbar spine. This clinical paper considers a case study where a diagnosis of instability was made based on manipulative examination techniques and where this diagnosis was confirmed from lateral functional x-rays. This paper emphasises the importance of the examining therapist being on the look out for joint hypermobility as well as hypomobility in patients presenting with pain of spinal origin. PMID- 25026482 TI - Measurement of passive ankle dorsiflexion: Procedure and reliability. AB - The purpose of this study was to develop a reliable procedure to measure passive ankle dorsiflexion in the clinical setting. A known torque was applied to produce ankle dorsiflexion in a standardised testing position. Ankle angle was measured using skin surface markers and polaroid photography. The interrater reliability of this procedure was evaluated by having five testers each measure 15 subjects. It was found that the procedure was highly reliable; the Intraclass Correlation Coefficient for the combined group data was 0.97 and the percentage intertester agreement was 77 per cent. These results demonstrate that the measurement procedure has the potential to be a clinically useful means of evaluating the effect of physiotherapeutic intervention aimed at altering passive ankle dorsiflexion movement. PMID- 25026483 TI - Emergence of electric polarity in BiTeX (X = Br and I) monolayers and the giant Rashba spin splitting. AB - A number of graphene-like materials have been theoretically predicted and experimentally confirmed so far. Here, based on the first-principles calculations, we predict that stable BiTeX (X = Br and I) monolayers possess intrinsic large polar electric fields along the normal direction to the plane, making them two-dimensional polar systems. Moreover, we find that these novel monolayers with thicknesses of only 3.8 A can produce a giant Rashba spin splitting derived from their peculiarly polar atomic configurations. Furthermore, the Rashba parameters of BiTeX monolayers can be effectively modulated by applying strain, and are thus promising for wide applications in nanoelectronics. PMID- 25026486 TI - Changes in medical referrals to an outpatient physiotherapy department. AB - The information provided in 10 per cent of all written medical referrals received by a teaching hospital physiotherapy outpatient department in each of the years 1982 and 1989 was systematically analysed to identify any demonstrable changes in emphasis. Significant between year differences indicated fewer referrals containing a diagnosis in 1989 than in 1982, less emphasis on requests for physiotherapy modalities and a significant increase in more generalised requests and inclusion of aims of treatment. These results suggest that greater clinical autonomy is expected of physiotherapists by medical practitioners in this particular hospital setting, The method used in this study could be applied in future to monitor referral to physiotherapy to examine whether these results represent a real trend. PMID- 25026487 TI - Mandatory continuing professional education. A review. AB - Proponents of mandatory continuing professional education (MCPE) contend that continuing professional education is necessary to ensure clinical competence and prevent professional obsolescence. Opponents believe that MCPE is contrary to adult learning principles. Although the research demonstrates positive attitudes towards MCPE in those groups undertaking continuing education programmes, there has been insufficient quantitative research which examines whether continuing education results in enhancement of practitioner performance and improvement of patient care. Currently, there are no MCPE requirements in Australia for the general practice of physiotherapy. The recommendation for the physiotherapy profession is to address the immediate need for research into the relationship between continuing education and clinical competence. PMID- 25026485 TI - Changes in serum concentrations of maternal poly- and perfluoroalkyl substances over the course of pregnancy and predictors of exposure in a multiethnic cohort of Cincinnati, Ohio pregnant women during 2003-2006. AB - Data on predictors of gestational exposure to poly- and perfluoroalkyl substances (PFASs) in the United States are limited. To fill in this gap, in a multiethnic cohort of Ohio pregnant women recruited in 2003-2006, we measured perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and six additional PFASs in maternal serum at ~16 weeks gestation (N = 182) and delivery (N = 78), and in umbilical cord serum (N = 202). We used linear regression to examine associations between maternal serum PFASs concentrations and demographic, perinatal, and lifestyle factors. PFASs concentrations in maternal sera and in their infants' cord sera were highly correlated (Spearman rank correlation coefficients = 0.73-0.95). In 71 maternal-infant dyads, unadjusted geometric mean (GM) concentrations (95% confidence interval) (in MUg/L) in maternal serum at delivery of PFOS [8.50 (7.01-9.58)] and PFOA [3.43 (3.01-3.90)] were significantly lower than at 16 weeks gestation [11.57 (9.90-13.53], 4.91 (4.32 5.59), respectively], but higher than in infants' cord serum [3.32 (2.84-3.89), 2.85 (2.51-3.24), respectively] (P < 0.001). Women who were parous, with a history of previous breastfeeding, black, or in the lowest income category had significantly lower PFOS and PFOA GM concentrations than other women. These data suggest transplacental transfer of PFASs during pregnancy and nursing for the first time in a U.S. birth cohort. PMID- 25026488 TI - Posture of the head, shoulders and thoracic spine in comfortable erect standing. AB - Common clinical beliefs about the relationship between postural characteristics and pain are based on mainly anecdotal evidence. This study examined the reliability of physical characteristics of the head, shoulders and thoracic spine and identified relationships among them. Measurements were made from photographs of subjects in comfortable erect standing. A forward head position was related to the curvature of the upper thoracic spine, and a forward position of the shoulders to the tilt of the head in the sagittal plane and to upper cervical extension. The magnitude of the relationships, however, was of questionable clinical significance. No relationship was found between a forward head position and forward shoulders, nor between a forward head position and upper cervical spine extension. PMID- 25026489 TI - The meaning of mechanically produced responses. AB - The precise source and cause of mechanically evoked sensory and motor responses can sometimes be surprisingly difficult to identify. Accurate interpretation of these responses may be confounded by peripheral as well as central nervous system mechanisms. Examples of such peripheral nervous system mechanisms likely to be of relevance to therapists have been selected from basic and clinical research. Symptomatic relief has been inferred to endorse the diagnostic specificity of mechanical stimulation. The extent to which this would be valid for relief acquired by neurological means is discussed in terms of endogenous pain inhibitory systems. PMID- 25026490 TI - Mechanical stability, muscle strength and proprioception in the functionally unstable ankle. AB - Functional instability of the ankle is common following inversion sprain. Factors suggested as causes of this disability include mechanical instability of the talocrural joint, peroneal muscle weakness and motor incoordination due to impaired proprioception. This study documented physical examination characteristics of functionally unstable ankles relevant to these theories. Each ankle of 45 subjects with unilateral functional instability was examined. Mechanical stability was assessed by standard clinical instability tests. Evertor and inventor muscle strength was measured using the Cybex II dynamometer. The Uni axial Balance Evaluator (UBE) was used to assess dynamic control of the ankle and was considered capable of detecting unilaterally impaired proprioception. Mechanical instability was frequently absent in the functionally unstable ankles tested. Evertor muscle strength was similar in the normal and functionally unstable ankles. UBE results were consistent with the theory of impaired proprioception contributing to functional instability, but the need for further research is emphasised. PMID- 25026491 TI - Combined movements of the lumbar spine: examination and clinical significance. AB - The aim of this paper is to describe a method of examining the lumbar spine, incorporating the principle of combining movements and relating this to selection of technique. Almost all of the passive movement procedures used in the treatment of the lumbar spine are, in fact, procedures which involve combining or coupling different movements. The importance of examining the lumbar spine using the principles of combining movements is emphasised and it is suggested that this should be a central part of any planned examination. The importance of relating these movements to range and distribution of pain is considered in detail and the application of techniques, rotation in particular is described using positions which involve the combining of different movements. PMID- 25026492 TI - Biofeedback in strokes. AB - The effectiveness of biofeedback therapy, using the electromyograph, was compared with conventional physiotherapy treatments in eleven hemiparetic patients with severe disability of the upper limb. These were divided randomly into two groups, a group of six patients receiving biofeedback treatments and five receiving physiotherapy treatments with conventional techniques. The results showed greater improvements in the biofeedback group in most fields of testing, and the patients in this group had a greater degree of control over the patterns of movement in the upper limb and the relaxation of spastic muscle groups. It was concluded that a wide range of hemiparetic patients should benefit in some degree by treatment of this form. PMID- 25026493 TI - Report on a sensory programme for patients with sensory deficits. AB - Sensation and movement are seen to be linked together and sensation is often used as a means of improving movement function. The sensory programme is an attempt to focus on the sensory side of sensory/motor deficits, and involves the stimulation of touch, pressure, temperature and joint receptors, and also muscle spindles, in an effort to 're-educate' sensation. The programme described was tested on twenty patients. Although there was some improvement in sensation, motor improvement was more apparent and occurred earlier in treatment, some patients showing marked improvement in motor function after a relatively long (four to six months) period. The programme is seen as a useful technique to use in combination with other forms of treatment for patients with decreased sensation. It has lately been used for patients with hypersensitivity with some encouraging results. PMID- 25026494 TI - Some factors influencing the outcome of stroke rehabilitation. AB - The eventual outcome of a stroke patient's rehabilitation may depend as much upon his experiences following the stroke as upon the actual brain damage. Positive factorsinfluencing rehabilitation include the early stimulation of the body orienting mechanism in upright positions; the prevention of the development of spasticity; the therapist's understanding of the factors involved in learning a motor skill; the ability to analyse an everyday activity and find its missing or abnormal components an understanding of the current hypotheses about the effect of stimution upon the recovering brain. Negative factorsinclude a tendency to be obsessed with techniques of treatment rather than with a detailed analysis of the patient's problems; the perpetuation of certain 'myths' such as proximal to distal recovery of function, and practising movement in a neuro-developmental sequence despite the maturity of the adult patient's brain; a failure to understand the different physiological and behavioural mechanisms underlying apparently similar problems which leads to lack of cortical drive being confused with muscle weakness; the expectations of the therapist who expects a stroke patient will become spastic, will not recover functional use of his upper limb, and will need a quadripod stick in order not to fall over. PMID- 25026495 TI - Functional analysis of mutant FAM20C in Raine syndrome with FGF23-related hypophosphatemia. AB - Raine syndrome is an autosomal recessive disorder characterized by generalized osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Either homozygous or compound heterozygous mutations in family with sequence similarity 20, member C (FAM20C) have been reported to cause this syndrome. Recently, it was reported that fibroblast growth factor 23 (FGF23)-related hypophosphatemia was found in patients with non-lethal Raine syndrome, and Fam20c conditional knockout mice presented Fgf23-related hypophosphatemic rickets. To clarify the mechanism of how FAM20C regulates FGF23, we performed functional analysis of mutant FAM20C proteins reported in Raine syndrome. We analyzed 6 mutant FAM20C proteins (T268M, P328S, R408W, D451N, D478A, and R549W) for their distributions, kinase activities, and effects on dentin matrix protein (DMP1) promoter activity. We also analyzed the effect of Fam20c knockdown on Dmp1 and Fgf23 mRNA levels in UMR-106 cells. As a result, all the mutant FAM20C proteins showed decreased kinase activities compared to wild-type (WT) FAM20C, and most of them also showed impaired secretion. Overexpression of WT FAM20C increased DMP1 promoter activity in Saos-2 cells while mutant FAM20C did not. Fam20c knockdown decreased Dmp1 mRNA and increased Fgf23 mRNA in UMR-106 cells. In conclusion, our results suggest that FAM20C suppresses FGF23 production by enhancing DMP1 expression, and inactivating mutations in FAM20C cause FGF23-related hypophosphatemia by decreasing transcription of DMP1. PMID- 25026496 TI - iPS cell technologies and cartilage regeneration. AB - Articular cartilage covers the ends of bone and provides shock absorption and lubrication to the diarthrodial joints. Cartilage has a limited capacity for repair when injured, and there is a need for cell sources for chondrocytes that can be transplanted as part of a regenerative medicine approach. Induced pluripotent stem cells (iPSCs) have pluripotency and the potential for self renewal similar to embryonic stem cells (ESCs), but are not associated with the ethical issues that have plagued ESCs. Recent progress has made it possible to generate integration-free iPSCs and to differentiate iPSCs toward chondrocytes. An iPSC library prepared from donors homozygous for common HLA types is being developed, and will be able to provide allogeneic iPSC-derived chondrocytes at low cost that can cover the majority of the population. As an alternative approach, chondrocytic cells can be induced directly from dermal fibroblasts without going through the iPSC stage. Another important application of the iPSC technology is modeling cartilage diseases, such as skeletal dysplasia. Chondrogenically differentiated iPSCs generated from patients would recapitulate the pathology, and may serve as a useful platform both for exploring the disease mechanisms and for drug screening. This article is part of a Special Issue entitled "Stem Cells and Bone". PMID- 25026497 TI - A metal-free dyotropic-like rearrangement of 2-oxa allylic alcohols in the presence of organoboronic acids. AB - The first example of a dyotropic-like rearrangement of 2-oxa allylic alcohols in the presence of catalytic amounts of Selectfluor and DABCO was reported, which provides a facile access to organoboronates. This reaction represents an unprecedented dyotropic rearrangement consisting of cleavage of two vicinal bonds (one C-C bond and one C=C bond). PMID- 25026498 TI - Quality control in continuing education. AB - A quality continuing education programme may be seen as one which is of a high standard, relevant and viable. Efforts made to ensure the quality of continuing education should be directed towards these three ends. Where possible learners should be involved in programme planning, implementation and evaluation and should be encouraged to put their learning into practice. This paper will explore the issues and practicalities involved in attempts to ensure the quality of educational activities provided for qualified professionals by groups or bodies who are concerned with the professional development and quality of service of both individuals and professional groups. PMID- 25026499 TI - Spinal Pain Patients' Beliefs about Pain and Physiotherapy. AB - The lay public's medical knowledge is acquired from three sources: the lay consultation and referral service, the media, and the practitioner. Satisfaction with and continued utilization of a health care service may depend on congruence between patients' beliefs about the cause of illness and practitioners' conditions of care. The results of a recent survey indicate that the information to which patients with spinal pain had access, was inadequate for them to acquire accurate knowledge of the basis for their pain and physiotherapists' conditions of care. It is suggested that more accurate information on the mechanisms of spinal pain, volunteered by physiotherapists during the encounter, would be in the interests of the lay public and the physiotherapy profession. PMID- 25026500 TI - Private physiotherapy: characteristics of a sample of practitioners and their practices. AB - Responses to a questionnaire by 71 private practitioners indicated that the average practitioner was aged 38.6, graduated in 1967, had worked professionally for 14.8 years of which 8.8 years were spent in private practice. Some respondents (19 per cent) owned multiple practices, 48 per cent employed other therapists and 30 per cent had specialised practices. The average practice treated 93 patients a week in 40 minute consultations. The average respondent used 2.5 techniques from other areas of health care and owned 8 machines. Doctors referred 88 per cent of patients but 47.5 per cent of practitioners reported good effects from first contact status. Membership of professional associations was high. Female therapists were more likely to practice part-time and had less affiliations with community groups. PMID- 25026501 TI - Duplication and differentiation of common carp (Cyprinus carpio) myoglobin genes revealed by BAC analysis. AB - Two distinct myoglobin (mb) transcripts have been reported in common carp, Cyprinus carpio, which is a hypoxia-tolerant fish living in habitats with greatly fluctuant dissolved oxygen levels. Recombinant protein analysis has shown functional specialization of the two mb transcripts. In this work, analysis for mb-containing bacterial artificial chromosome (BAC) clones indicated different genome loci for common carp myoglobin-1 (mb-1) and myoglobin-2 (mb-2) genes. Fluorescence in situ hybridization (FISH) revealed that mb-1 and mb-2 are located on separate chromosomes. In both of the mb-1 and mb-2 containing BAC clones, gene synteny was well conserved with the homologous region on zebrafish chromosome 1, supporting that the common carp specific mb-2 gene originated from the recent whole genome duplication event in cyprinid lineage. Transcription factor binding sites search indicated that both common carp mb genes lacked specificity Protein 1 (Sp1) and myocyte enhancer factor-2 (MEF2) binding sites, which mediated muscle specific and calcium-dependent expression in the well-studied mb promoters. Potential hypoxia response elements (HREs) were predicted in the regulatory region of common carp mb genes. These characteristics of common carp mb gene regulatory region well interpreted the hypoxia-inducible, non-muscle expression pattern of mb-1. In the case of mb-2, a 10 bp insertion to the binding site of upstream stimulatory factor (USF), which was a co-factor of hypoxia inducible factor (HIF), might cause the non-response to hypoxia treatment of mb-2. The case of common carp mb gene duplication and subsequent differentiation in expression pattern and protein function provided an example for adaptive evolution toward aquatic hypoxia tolerance. PMID- 25026502 TI - Mitogenomic phylogeny of the Percichthyidae and Centrarchiformes (Percomorphaceae): comparison with recent nuclear gene-based studies and simultaneous analysis. AB - Delineation of the fish family Percichthyidae (Percomorphaceae) has a long and convoluted history, with recent morphological-based studies restricting species members to South American and Australian freshwater and catadromous temperate perches. Four recent nuclear gene-based phylogenetic studies, however, found that the Percichthyidae was not monophyletic and was nested within a newly discovered inter-familial clade of Percomorphaceae, the Centrarchiformes, which comprises the Centrarchidae and 12 other families. Here, we reexamined the systematics of the Percichthyidae and Centrarchiformes based on new mitogenomic information. Our mitogenomic results are globally congruent with the recent nuclear gene-based studies although the overall amount of phylogenetic signal of the mitogenome is lower. They do not support the monophyly of the Percichthyidae, because the catadromous genus Percalates is not exclusively related to the freshwater percichthyids. The Percichthyidae (minus Percalates) and Percalates belong to a larger clade, equivalent to the Centrarchiformes, but their respective sister groups are unresolved. Because all recent analyses recover a monophyletic Centrarchiformes but with substantially different intra-relationships, we performed a simultaneous analysis for a character set combining the mitogenome and 19 nuclear genes previously published, for 22 centrarchiform taxa. This analysis furthermore indicates that the Centrarchiformes are divided into three lineages and the superfamily Cirrhitoidea is monophyletic as well as the temperate and freshwater centrarchiform perch-like fishes. It also clarifies some of the relationships within the freshwater Percichthyidae. PMID- 25026503 TI - Charging dynamics of supercapacitors with narrow cylindrical nanopores. AB - We present a coarse-grained, continuum kinetic theory for charging supercapacitors with narrow cylindrical nanopores. The theory reveals that the occupancy of a nonpolarized pore and the energy barrier for ion-ion interdiffusion are the key issues controlling the different regimes of dynamic response. For 'ionophobic' pores, where the pore is empty at no applied voltage, charge density advances into the pore via diffusion-like dynamics. The mechanism of charging an 'ionophilic' pore is starkly different: for moderate ionophilicities, co-ions are expelled from the pore in a front-like manner, with significant 'congestion' at the pore entrance predicted for strong ionophilicity. We thus show that pore ionophilicity is detrimental to the speed of charging/discharging cycles, whereas making pores more ionophobic can substantially accelerate charging and cyclic recharging. PMID- 25026504 TI - Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6. AB - M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE2 and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE2/PPARdelta and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE2 or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE2 and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer. PMID- 25026506 TI - Osteoprotegerin independently predicts mortality in patients with stable coronary artery disease: the CLARICOR trial. AB - OBJECTIVES: To elucidate the prognostic power of serum osteoprotegerin (OPG) in patients with stable coronary artery disease (CAD). METHODS: Serum OPG levels were measured in the CLARICOR trial cohort of 4063 patients with stable CAD on blood samples drawn at randomization. The follow-up was 2.6 years for detailed cardiovascular events and 6 years for all-cause mortality. RESULTS: OPG levels were significantly increased in non-survivors (21%) compared to survivors (median [quartiles] 2092 ng/L [1636; 2800] compared to 1695 ng/L [1322; 2193, p < 0.0001]). The 2.6-year follow-up showed that OPG adds to the prediction of both cardiovascular and all-cause mortality in combination with clinical risk factors (HR [one log10 unit increase] 6.1 [95% CI 2.4-15.6, p = 0.0001]) and HR 6.5 [95% CI 3.4-12.5, p < 0.0001], respectively). Similar, in the 6-year follow-up, OPG was found to be a strong predictor for all-cause mortality. Importantly, OPG remained an independent predictor of mortality even after adjustment for both clinical and conventional cardiovascular risk markers (HR 2.5 [95% CI 1.6-3.9, p < 0.0001]). CONCLUSIONS: Serum OPG has a long-lasting independent predictive power as to all-cause mortality and cardiovascular death in patients with stable CAD. PMID- 25026507 TI - Development and validation of the diabetes knowledge assessment test for use in medical rehabilitation. AB - PURPOSE: To develop and validate the diabetes knowledge assessment test (DKAT), an assessment designed to measure diabetes knowledge of medical rehabilitation patients with or without diabetes. METHODS: Content validity methods were used to develop the DKAT, which was administered to rehabilitation patients to examine psychometric properties. RESULTS: Subjects were 75 inpatients (56% with diabetes; 45% male), and 75 outpatients (49% with diabetes; 69% male). The initial DKAT consisted of 49 items, which was reduced to 32 items based on psychometric criteria. Point-biserial item discrimination indices ranged from 0.26 to 0.61. Item difficulty indices ranged from 27 to 96%. Cronbach's alpha was 0.82. Known groups construct validity comparisons revealed that patients with diabetes obtained significantly higher DKAT scores than patients without diabetes (p = 0.01), supporting construct validity. Scores did not differ significantly by gender, educational attainment, age, or outpatient versus inpatient (all p > 0.05), further supporting construct validity. Confirmatory factor analysis identified two factors: "Complications" and "Risks-Symptoms-Management". CONCLUSIONS: Findings support claims that DKAT scores are valid and reliable for diabetes knowledge assessment across a range of rehabilitation conditions. It is appropriate for use with persons with or without diabetes engaging in rehabilitation services as an inpatient or outpatient. IMPLICATIONS FOR REHABILITATION: Medical rehabilitation patients represent an important population in which to assess core diabetes knowledge due to the extremely high prevalence of diabetes. We were unable to identify instruments with validity evidence aimed at assessing diabetes knowledge in rehabilitation populations, therefore undertook development of the DKAT. The DKAT represents a psychometrically promising assessment that can inform individuals at risk with the signs and symptoms of diabetes, as well as behavioral actions to reduce risk. The DKAT can also be used to identify those with a diagnosis of diabetes in need of formal diabetes education. PMID- 25026505 TI - Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis. AB - Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL+/+mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL 6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation. PMID- 25026508 TI - Does manual therapy provide additional benefit to breathing retraining in the management of dysfunctional breathing? A randomised controlled trial. AB - PURPOSE: Dysfunctional breathing (DB) is associated with an abnormal breathing pattern, unexplained breathlessness and significant patient morbidity. Treatment involves breathing retraining through respiratory physiotherapy. Recently, manual therapy (MT) has also been used, but no evidence exists to validate its use. This study sought to investigate whether MT produces additional benefit when compared with breathing retraining alone in patients with DB. METHODS: Sixty subjects with primary DB were randomised into either breathing retraining (standard treatment; n = 30) or breathing retraining plus MT (intervention; n = 30) group. Both the groups received standardised respiratory physiotherapy, which included: DB education, breathing retraining, home regimen, and audio disc. Intervention group subjects additionally received MT following further assessment. Data from 57 subjects were analysed. RESULTS: At baseline, standard treatment group subjects were statistically younger (41.7 + 13.5 versus 50.8 + 13.0 years; p = 0.001) with higher Nijmegen scores (38.6 + 9.5 versus 31.5 + 6.9; p = 0.001). However, no significant difference was found between the groups for primary outcome Nijmegen score (95% CI (-1.1, 6.6) p = 0.162), or any secondary outcomes (Hospital Anxiety & Depression Score, spirometry or exercise tolerance). CONCLUSION: Breathing retraining is currently the mainstay of treatment for patients with DB. The results of this study suggest MT provides no additional benefit in this patient group. IMPLICATIONS FOR REHABILITATION: Dysfunctional breathing (DB) is associated with significant patient morbidity but often goes unrecognised, leading to prolonged investigation and significant use of health care resources. Breathing retraining remains the primary management of this condition. However, physiotherapists are also using manual therapy (MT) as an adjunctive treatment for patients with DB. However, the results of this study suggest that MT provides no further benefit and cannot be recommended in the clinical management of this condition. PMID- 25026509 TI - Association between muscle power impairment and WHODAS 2.0 in older adults with physical disability in Taiwan. AB - PURPOSE: To explore the association between muscle power impairment and each World Health Organization Disability Assessment Schedule second edition (WHODAS 2.0) domain score among subjects with physical disability. METHODS: Subjects (>= 60 years) with physical disability related to neurological diseases, including 730 subjects with brain disease (BD) and 126 subjects with non-BD, were enrolled from a data bank of persons with disabilities from 1 July 2011 to 29 February 2012. Standardized WHODAS 2.0 scores ranging from 0 (least difficulty) to 100 (greatest difficulty) points were calculated for each domain. RESULTS: More than 50% of subjects with physical disability had the greatest difficulty in household activities and mobility. Muscle power impairment (adjusted odds ratios range among domains, 2.75-376.42, p < 0.001), age (1.38-4.81, p < 0.05), and speech impairment (1.94-5.80, p < 0.05) were associated with BD subjects experiencing the greatest difficulty in most WHODAS 2.0 domains. But a few associated factors were identified for the non-BD group in the study. CONCLUSIONS: Although the patterns of difficulty in most daily activities were similar between the BD and non-BD groups, factors associated with the difficulties differed between those two groups. Muscle power impairment, age and speech impairment were important factors associated with difficulties in subjects with BD-related physical disability. IMPLICATIONS FOR REHABILITATION: Older adults with physical disability often experience difficulties in household activities and mobility. Muscle power impairment is associated with difficulties in daily life in subjects with physical disability related to brain disease. Those subjects with brain disease who had older age, a greater degree of muscle power impairment, and the presence of speech impairment were at higher risk of experiencing difficulties in most daily activities. PMID- 25026510 TI - Back complaints among shearers in Western australia: a pilot study. AB - Thirty-two Western Australian shearers were surveyed in 1984 to determine the incidence of back problems. It was found that twenty-nine (90%) of the respondents surveyed either currently had back pain, or had suffered from back pain recently. The pain was almost exclusively of an intermittent nature, suggesting a mechanical problem. Most respondents had sought medical help for their problem. Very few shearers had been seen by physiotherapists in country areas. Shearing involves bending, twisting, lifting and dragging. It is considered that the heavy physical demand and static postures during the shearing process bear a strong relation to the incidence of back pain among shearers. A recently developed device called a 'Warrie Back Aid' was used by five of the respondents, who all reported considerable symptomatic relief. PMID- 25026511 TI - An ergonomic approach to retirement and ageing. AB - Advance planning and preparation for retirement organization are necessary for transitional ease, so that ageing persons are accepted as a normal and necessary community resource. Ageing people with increased leisure time perform useful voluntary work in which opportunities exist for study, activities and participation in mutual support groups. The needs of ageing people are similar to those of everyone but with some ergonomic intervention to supplement physical deficits. The interface between these needs and existing community caring service is considered. Adequate housing, accessibility to town facilities and transport, mobility and mental function, including decrements, are discussed. Recommendations are made for unification and funding of existing and desirable support services for ageing people. Inventories and check lists are included in the Appendices. PMID- 25026512 TI - Overseas observations of the physiotherapist in the work place. AB - A recent overseas study tour provided an opportunity for observation of the physiotherapist as one of a team concerned with health care in the workplace. This paper presents impressions gained during visits to some overseas institutions and industries in Scandinavia and the United Kingdom. A number of roles are possible for the physiotherapist in the workplace, but the nature of the contribution made varies between countries. The special features of physiotherapy practice in some overseas industries, the practical problems faced by the physiotherapist in implementing ergonomic principles and some of the solutions devised by physiotherapists are described. PMID- 25026513 TI - Work breaks for keyboard operators. AB - This paper aims to describe some of the current literature on work breaks and to discuss important issues related to work breaks for keyboard operators. The relationship between work breaks and fatigue is examined, as well as the relationship between fatigue and injury. From the present literature available, there is no evidence to support any particular work/rest regime to reduce fatigue. Physiological studies support the concept of short frequent pauses (micropauses) as being the most effective way of reducing neuromuscular fatigue. No universal regime will be suitable for every keyboard situation. Prescribed regimented work breaks have many disadvantages and should be avoided if possible in favour of work breaks that are spontaneous or designed into the work. PMID- 25026514 TI - Occupational overuse disorders in a university. AB - Many of the keyboard and technical staff of a University with a large component of research activity, have presented to the Health Service with discomfort in the neck, shoulders and upper limb. A description of the University organization is offered to suggest possible reasons for the high incidence. Strategies that were undertaken to confront the problem are presented. The advantages of prevention rather than intervention are yet again demonstrated. PMID- 25026515 TI - The role of the physiotherapist in the management of repetitive strain injury. AB - A review of current literature concerning the aetiology, diagnosis, role and involvement of physiotherapists in the treatment of repetitive strain injury (R.S.I.) is presented as a basis for investigation. To determine the modes of treatment used by physiotherapists in the management of R.S.I. and to analyse their efficacy, a questionnaire was designed. Forty centres were surveyed and the results are presented. Information concerning the most commonly encountered conditions, treatment given, and physiotherapists' opinions on prevention, patient education and further training in RSI management was also sought. An attempt is made to define the role of the physiotherapist in the recognition, treatment and education aspects of over-use injury, and recommendations for further research and physiotherapy involvement are presented. PMID- 25026516 TI - Domiciliary physiotherapy. AB - There is an increasing number of aged in our population and with the modern trend for early discharge from hospital, what is happening to the patient who needs physiotherapy, but is unable to attend the local clinic or hospital for treatment? How many domiciliary physiotherapists are there, and how much help is the district nurse receiving from her local physiotherapy department? PMID- 25026517 TI - Delegation of physiotherapy in the puerperium. AB - As obstetric techniques continue to improve, there is a decided swing in favour of an early discharge from hospital of an ever-increasing number of well mothers and babies. In some larger teaching maternity hospitals, women are being discharged 48-hours post partum, and in many cases these women return to a situation where immediate responsibility for full home duties is put upon them. In accordance with this growing tendency and the question of delegation of physiotherapy, perhaps the aims of physiotherapy in the puerperium should be reconsidered. The community is constantly being made more aware of the need for physical fitness, and so, as physiotherapists already involved with obstetric after-care, we have a very real responsibility to teach both new mothers and multiparas the absolute importance of specific post natal muscle re-education, the necessity for back care in lifting and in posture, the value and place of relaxation (that is, active muscle decontraction) in the often trying and stressing puerperium, and the need for a rapid return to a state of general physical fitness. PMID- 25026518 TI - The handicapped child at home. AB - The baby and small child are not able to perform consciously any adequate manoeuvres which will contribute positively to the correction of a disability. Thus the treatment of this age group is essentially passive or assistive active. Treatment attempting to achieve normal patterns of development is not a single "half hour period a day" approach but a "24 hour a day" plan of care and management. It is thus fundamental that success in treating the young child will depend on the child's parents and family. Since any child would be likely to spend most of the time with its mother, that child's future development is mostly in her hands, and any treatment of a child must be delegated very largely to the mother. PMID- 25026519 TI - Forty years on, or "play up! Play up! And play the game!". AB - "I have looked around for conclusive evidence to show that the people who go swimming, riding or climbing or playing football and so on, are in fact in some way a healthier part of the population, less liable to disease, more long lived." (Geiringer, 1971.). PMID- 25026520 TI - Home physiotherapy for the average patient. AB - The physiotherapist's work is most rewarding when the patient attends regularly for all the required treatments and exercises. This allows the physiotherapist to see the progress and to adjust the treatment accordingly to suit each individual patient. There is nothing more depressing than the patient who would benefit most from such physiotherapy, but who will not or cannot attend regularly for treatment. It is with this type of patient in mind that the physiotherapist must consider the alternatives which are available, to ensure the maximum return of function and the prevention of complications in the patient. PMID- 25026521 TI - Leprosy: ancient disease, modern challenge! AB - Alhough leprosy is a very ancient disease, it is only within the last few decades that it has come into the orbit of the physiotherapist. Yet today, the place of physiotherapy in the treatment of leprosy is being increasingly recognised. The cry, as in most fields, is that there are not enough physiotherapists to meet the need, and so there are thousands, perhaps more accurately, millions, of leprosy patients who are condemned to a life marred by crippling deformity, which could have been prevented if only ... there had been a physiotherapist available to teach others the techniques of re-education, and if only ... there was a physiotherapist available to do some research into more effective methods of treating the early signs of nerve damage and muscle weakness. If only ... there was a physiotherapist available to give advice and help to those who, with inadequate training, are now doing what they can do to prevent these unnecessary deformities. This is, I feel, the challenge to the physiotherapist-to teach and to research, because economically it would be impossible to maintain the number of physiotherapists needed to cope adequately with the number of patients. It is estimated that there are about 15 million leprosy patients in the world today, and estimating on the incidence of deformity in a sampling of 2,000 out-patients in the Republic of Korea, about 40 per cent of these have some motor paralysis, leading, if untreated, to deformity. The incidence of leprosy is highest in the underdeveloped and developing countries of Asia and Africa, where the economic structure is such that the health budget is inadequate to meet all the varied needs. It is in these same countries where tuberculosis and other infectious diseases are rife, and where the economic standing of both people and governments is low. PMID- 25026522 TI - Neurological processes of movement control: a review. AB - While an understanding of the control of movement is central to significant areas of physiotherapy practice, a complete grasp of the processes involved has proved to be both tantalizing and elusive. The complexity of integrative activity between sensory and motor systems appears to be beyond the reach of traditional methods of experiment. The resources of both psychophysical and neurophysiological methodology are even yet insufficiently refined to yield all that remains to be understood. PMID- 25026523 TI - Forces in the knee joint during exercise of the knee extensors. AB - What forces arise in the knee joint during the exercise of the quadriceps by extending the lower leg weighted with a de Lorme boot? How do these forces compare with those experienced in normal weight-bearing activities? PMID- 25026524 TI - Acupuncture in physiotherapy. AB - The introduction of the ancient Oriental practice of acupuncture into Western medicine has caused confusion amongst the health professionals, but it has captured the interest of the public. Confronted on one hand with the philosophy, art and science of thousands of years, and on the other with modern scientific theory and medical knowledge, and finding, initially and superficially, the two in diametric conflict, it is easy to understand why acupuncture is being considered with mixed emotions. However current research has led to recognition or confirmation of many of the ancient empirical observations by the very latest scientific technology (Riddle, 1974). PMID- 25026525 TI - Stimulus and response: some social indicators of the physiotherapy profession. AB - During 1975, a questionnaire was circulated to the members of the A.P.A. which was designed to build up a profile of physiotherapists and their attitudes towards their profession. The four major areas of enquiry were: (i) social and demographic characteristics (ii) coping mechanisms in relation to career and family (iii) educational and professional characteristics and attitudes (iv) employment characteristics and attitudes. PMID- 25026526 TI - The evaluation of physiotherapy in the treatment of stroke: a preliminary investigation. AB - For many years physiotherapists have treated patients suffering from cerebrovascular accident (C.V.A.). Probably no two treat these people in the same way, because we are all different; not only do we see things from a different point of view, depending on our own experience, but also we respond to each patient in a different way, and with a stroke patient always there is something different to feel. The amount of tone in a limb depends on the patient's emotional state, physical tiredness and activities immediately preceding the testing time. PMID- 25026527 TI - Rationale for the use of vibration in management of tactile defensive patients. AB - Physiotherapists use a variety of sensory stimulation techniques in the management of many clinical conditions including disorders of the central nervous system, peripheral nerve lesions and amputations. The rationale underlying these techniques is based on the neurophysiological effects of different types of sensory input onindividual receptors and the central nervous system as a whole. In recent years, neurophysiological research has necessitated a critical reappraisal of many old assumptions about the central nervous system. This paper examines the rationale for using vibration in the 'tactile defensive' patient and questions earlier conceptual models. Effects of vibratory stimulation on the nervous system are discussed, with some pertinent methodological considerations. PMID- 25026528 TI - Teamwork in the education of severely and profoundly handicapped cerebral palsy children. AB - A programme for severely and profoundly handicapped cerebral palsy children aged 5 to 9 years is described. The reasons for its establishment are discussed, together with the measures taken to establish its worth. Issues relevant to the organization of a team approach are presented. The study supports collaborative team efforts between therapy and teaching professions in the field, and also supports collaborative team efforts between university and clinical personnel, for the purpose of programme evaluation. PMID- 25026529 TI - DECISION MAKING IN RESEARCH AND CLINICAL PRACTICE: Part 1: The basis for decision. AB - This is the first part of a two-part paper. Part 1 describes the basis for decision making in research. The basic statistical procedures that provide the foundations for more advanced statistical techniques, the rationale underlying hypothesis testing, the nature of probability and its relevance to the normal curve, and the meaning of tests of significance and level of significance are discussed. These concepts provide the foundation for an understanding of the interpretation of decision rules and tests of significance, topics that will be discussed in Part II of the paper, to be published in a subsequent issue of this journal. All concepts and procedures are discussed in terms of their clinical relevance to the practising physical therapist. PMID- 25026530 TI - Interaction of anions with substituted buckybowls. The anion's nature and solvent effects. AB - Complexes formed by CN-substituted corannulene and sumanene with monovalent anions have been computationally studied to evaluate the effect of anion's nature and solvent upon the interaction. The results indicate that the most stable complex arrangement corresponds in all cases to the anion located by the center of the concave face of the bowl. All complexes are remarkably stable in the gas phase, with interaction energies ranging from -47 to -24 kcal/mol depending on the anion and the bowl considered. The order of stability for the different anion complexes in the gas phase is CO2H(-) > Cl(-) > Br(-) > NO3(-) ? ClO4(-) > BF4( ). Regarding the bowl employed, the intensity of the interaction is largest with the sumanene derivative substituted in the C-H aromatic groups. The weakest interactions are obtained with the sumanene derivative substituted in the CH2 groups, whereas complexes with the corannulene derivative give intermediate values. NO3(-) is oriented parallel to the bowl in the most stable complexes, whereas CO2H(-) prefers being oriented perpendicular to the bowl; ClO4(-) and BF4(-) arrange themselves with three bonds pointing to the bowl. These orientations are preferred on the basis of larger electrostatic and dispersion interactions. The preference of anions for the concave face of the bowl not only is mainly related to larger electrostatic interactions but also is because dispersion and induction are larger than in other arrangements considered. The presence of solvent modeled with a continuum model has a deep impact on the interaction energies already in solvents with low dielectric constant. All complexes remain stable, though energies in water hardly reach -7 kcal/mol. Br(-) complexes are the most stable in solvent, whereas CO2H(-) ones suffer a large penalty in solvent, becoming among the least stable complexes despite being the most stable in the gas phase. PMID- 25026531 TI - Alterations of platelet functions in children and adolescents with iron deficiency anemia and response to therapy. AB - Several changes in platelets have been reported in patients with iron-deficiency anemia (IDA), so a relationship between iron metabolism and thrombopoiesis should be considered. We aimed to study the alterations of platelet functions in patients with IDA by assessment of platelet aggregation with epinephrine, adenosine diphosphate (ADP) and ristocetin and by measuring platelet function analyzer-100 (PFA-100) closure time together with the effect of iron therapy on the same tests. A follow-up study was conducted in Ain Shams University Children's hospital in the period from June 2011 to June 2012 including 20 patients with confirmed IDA and 20 healthy age- and sex-matched control. Bleeding manifestations were reported. Laboratory analysis included complete blood count, assessment of iron status by measuring serum iron, TIBC and ferritin, assessment of platelet functions by PFA-100 closure time and platelet aggregation with collagen, ADP and ristocetin. Patients with IDA were treated by oral iron therapy 6 mg/kg/day of ferrous sulfate and post-therapeutic re-assessment was done. Mean age of IDA patients was 5.7 +/- 4.2 years. Bleeding manifestations were more common in patients group. Mean PFA-100 closure times (with epinephrine) were significantly longer in patients (179.1 +/- 86.4 seconds) compared to control group (115 +/- 28.5 seconds) (p < 0.05). Platelet aggregation by ADP (38.1 +/- 22.2%), epinephrine (19.7 +/- 14.2%) and ristocetin (58.8 +/- 21.4%) were significantly reduced in patients compared to control (62.7 +/- 6.2, 63.3 +/- 6.9, 73.8 +/- 8.3, respectively; p < 0.001). After treatment platelet aggregation tests induced by ADP (64.78 +/- 18.25%), and epinephrine (55.47 +/- 24%) were significantly increased in patients with IDA compared to before treatment (39.44 +/- 21.85%, 20.33 +/- 14.58%; p < 0.001). PFA-100 closure time as well showed significant decreased after treatment (118.4 +/- 27.242) compared to before treatment (186.2 +/- 90.35; p < 0.05). A negative correlation between platelet aggregation induced by ADP and mean values of serum ferritin before treatment (r = 0.042, p < 0.05) was found. A mutual effect is considered between iron deficiency and platelet functions. Subtle bleeding manifestations can occur in patients with IDA with delay in platelet aggregation and prolongation in PFA-100 closure times which can be reversed by iron therapy. PMID- 25026532 TI - Inefficiency of post-error adjustment in impulsive violent offenders. AB - Criminal offenders who show repeated impulsive violent behavior are often described as having impairments in both inhibitory control and error processing. A sample of such offenders was compared with controls using event-related potentials recorded during the performance of a combined flanker and stop-signal task with the aim of investigating the underlying mechanisms that may contribute toward such violent behavior by indexing conflict monitoring, error detection, and post-error processing. The results obtained indicated lower amplitude of the stop-signal N2 component for successfully inhibited trials, reflecting different degrees of inhibition in impulsive violent offenders, as well as a reduced Pe component over the parietal area, an indication of reduced awareness of errors. This is consistent with the behavioral data indicating a lack of post-error slowing compared with the control group. This suggests that these offenders have problems with error awareness, subjective error assessment processes, and the adjustment of future behavior. PMID- 25026533 TI - Remodeling of the piriform cortex after lesion in adult rodents. AB - Denervation of the piriform cortex by bulbotomy causes a series of important cellular changes in the inhibitory interneurons of layer I and transsynaptic apoptosis of a large number of pyramidal neurons in outer layer II within 24 h. In this study, we report that following the marked loss of neurons in outer layer II, the piriform cortex is reconstituted by the addition of newly formed neurons that restore the number to a preinjury level within 30 days. We provide evidence that the number of newly divided neuronal progenitors increases after injury and further show that a population of doublecortin-positive cells that resides in the piriform cortex decreases after injury. Taken together, these findings suggest that the piriform cortex has significant neurogenic potential that is activated following sensory denervation and may contribute toward the replacement of neurons in outer layer II. PMID- 25026534 TI - Spiders do not evoke greater early posterior negativity in the event-related potential as snakes. AB - It has been long believed that both snakes and spiders are archetypal fear stimuli for humans. Furthermore, snakes have been assumed as stronger threat cues for nonhuman primates. However, it is still unclear whether spiders hold a special status in human perception. The current study explored to what extent spider pictures draw early visual attention [as assessed with early posterior negativity (EPN)] when compared with insects similar to spiders. To measure the EPN, participants watched a random rapid serial presentation of pictures, which consisted of two conditions: spider condition (spider, wasp, bumblebee, beetle) and snake condition (snake, bird). EPN amplitudes revealed no significant difference between spider, wasp, bumblebee, and beetle pictures, whereas EPN amplitudes were significantly larger for snake pictures relative to bird pictures. In addition, EPN amplitudes were significantly larger for snake pictures relative to spider pictures. These results suggest that the early visual attentional capture of animate objects is stronger for snakes, whereas spiders do not appear to hold special early attentional value. PMID- 25026535 TI - Vascular accumulation of the small leucine-rich proteoglycan decorin in CADASIL. AB - Small penetrating brain artery thickening is a major feature of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Although affected fibrotic arteries of CADASIL have been shown to accumulate collagen, other components that compose pathological arterial walls remain incompletely characterized. We investigated the expression of decorin (DCN), the first collagen-binding small leucine-rich proteoglycan identified, in CADASIL. DCN was markedly upregulated in pathologically affected leptomeningeal and small penetrating arteries in CADASIL and was notably weaker in normal arteries from control brains. DCN protein was localized principally to the media and adventitia and only occasionally expressed in the intima. Immunoblotting of brain lysates showed a three-fold increase of DCN in CADASIL brains (compared with controls). Messenger RNA encoding DCN was five-fold increased in CADASIL. We conclude that DCN is the first identified proteoglycan to be identified in CADASIL arteries and may accumulate through transcriptional mechanisms. Additional studies are warranted to determine whether DCN localizes broadly to pathological small vessels in other cerebrovascular disorders. PMID- 25026536 TI - Advances in targeting nucleocapsid-nucleic acid interactions in HIV-1 therapy. AB - The continuing challenge of HIV-1 treatment resistance in patients creates a need for the development of new antiretroviral inhibitors. The HIV nucleocapsid (NC) protein is a potential therapeutic target. NC is necessary for viral RNA packaging and in the early stages of viral infection. The high level of NC amino acid conservation among all HIV-1 clades suggests a low tolerance for mutations. Thus, NC mutations that could arise during inhibitor treatment to provide resistance may render the virus less fit. Disruption of NC function provides a unique opportunity to strongly dampen replication at multiple points during the viral life cycle with a single inhibitor. Although NC exhibits desirable features for a potential antiviral target, the structural flexibility, size, and the presence of two zinc fingers makes small molecule targeting of NC a challenging task. In this review, we discuss the recent advances in strategies to develop inhibitors of NC function and present a perspective on potential novel approaches that may help to overcome some of the current challenges in the field. PMID- 25026537 TI - Differences and the relationship in default mode network intrinsic activity and functional connectivity in mild Alzheimer's disease and amnestic mild cognitive impairment. AB - There is evidence that the default mode network (DMN) functional connectivity is impaired in Alzheimer's disease (AD) and few studies also reported a decrease in DMN intrinsic activity, measured by the amplitude of low-frequency fluctuations (ALFFs). In this study, we analyzed the relationship between DMN intrinsic activity and functional connectivity, as well as their possible implications on cognition in patients with mild AD and amnestic mild cognitive impairment (aMCI) and healthy controls. In addition, we evaluated the differences both in connectivity and ALFF values between these groups. We recruited 29 controls, 20 aMCI, and 32 mild AD patients. To identify the DMN, functional connectivity was calculated by placing a seed in the posterior cingulate cortex (PCC). Within the DMN mask obtained, we calculated regional average ALFFs. Compared with controls, aMCI patients showed decreased ALFFs in the temporal region; compared with AD, aMCI showed higher values in the PCC but lower in the temporal area. The mild AD group had lower ALFFs in the PCC compared with controls. There was no difference between the connectivity in the aMCI group compared with the other groups, but AD patients showed decreased connectivity in the frontal, parietal, and PCC. Also, PCC ALFFs correlated to functional connectivity in nearly all subregions. Cognitive tests correlated to connectivity values but not to ALFFs. In conclusion, we found that DMN connectivity and ALFFs are correlated in these groups. Decreased PCC ALFFs disrupt the DMN functional organization, leading to cognitive problems in the AD spectrum. PMID- 25026538 TI - Circadian regulation of chloroplasts. AB - Circadian rhythms produce a biological measure of time that increases plant performance. The mechanisms that underlie this increase in productivity require investigation to provide information that will underpin future crop improvement. There is a growing body of evidence that a sophisticated signalling network interconnects the circadian oscillator and chloroplasts. We consider this in the context of circadian signalling to chloroplasts and the relationship between retrograde signalling and circadian regulation. We place circadian signalling to chloroplasts by sigma factors within an evolutionary context. We describe selected recent developments in the integration of light and circadian signals that control chloroplast gene expression. PMID- 25026539 TI - Chemotherapy-induced peripheral neuropathy #197. PMID- 25026540 TI - The effects of constant and diel-fluctuating temperature acclimation on the thermal tolerance, swimming capacity, specific dynamic action and growth performance of juvenile Chinese bream. AB - We investigated the effects of constant and diel-fluctuating temperature acclimation on the thermal tolerance, swimming capacity, specific dynamic action (SDA) and growth performance of juvenile Chinese bream (Parabramis pekinensis). The critical thermal maxima (CTmax), critical thermal minima (CTmin), lethal thermal maxima (LTmax), lethal thermal minima (LTmin), critical swimming speed (Ucrit) and fast-start escape response after 30 d acclimation to three constant temperatures (15, 20 and 25 degrees C) and one diel-fluctuating temperature (20+/-5 degrees C) were measured. In addition, feeding rate (FR), feeding efficiency (FE) and specific growth rate (SGR) were measured. The diel fluctuating temperature group showed lower CTmin than the 20 degrees C group but a similar CTmax, indicating a wider thermal scope. SDA linearly increased with the temperature. Temperature variation between 20 and 25 degrees C had little effect on either swimming or growth performance. However, fish in the 15 degrees C group exhibited much poorer swimming and growth performance than those in the 20 degrees C group. Ucrit decreased slightly under low acclimation temperature due to the pronounced improvement in swimming efficiency under cold temperature. Fish in the diel-fluctuating temperature group fed more but exhibited similar SGR compared to 20 degrees C group, possibly due in part to an increase in energy expenditure to cope with the temperature fluctuation. The narrower thermal scope and lower CTmax of Chinese bream together with the conservation of CTmax with temperature acclimation, suggests that local water temperature elevations may have more profound effects on Chinese bream than on other fish species in the Three Gorges Reservoir. PMID- 25026541 TI - Physiological and biochemical strategies for withstanding emersion in two galaxiid fishes. AB - The galaxiid fishes of the Southern hemisphere display variable tolerance to aerial exposure. Brown mudfish (Neochanna apoda), for example, pseudoaestivate, inhabiting moist soil for months at a time, whereas inanga (Galaxias maculatus) emerse under unfavourable water conditions, but only for periods of a few hours. This study sought to identify the physiological and biochemical strategies that determine emersion tolerance in these species. Nitrogenous waste excretion was measured before and after an experimental emersion period (14 days for mudfish, 6 h for inanga). Both species showed significantly elevated ammonia "washout" upon return to water, but no increase in plasma or muscle ammonia. Post-emersion urea levels were elevated in plasma and muscle in both fish, however the extent of the accumulation did not indicate significant de novo urea production. This was supported by the lack of carbamoyl phosphate synthetase activity in tissues. Consequently, mudfish metabolism was examined to determine whether changes in parameters such as oxygen consumption, carbon dioxide excretion, and/or altered metabolic costs (represented by the key ionoregulatory enzyme Na(+), K(+)-ATPase; NKA) could explain emersion tolerance. Oxygen consumption rates, already very low in immersed mudfish, were largely maintained over the course of emersion. Carbon dioxide excretion decreased during emersion, and a small, but significant, decrease in NKA was noted. These data suggest that the extended emersion capacity of mudfish may result from a generally low metabolic rate that is maintained throughout aerial exposure via cutaneous gas exchange, and which limits the production of potentially toxic nitrogenous waste. PMID- 25026542 TI - The molecular mechanism of aminopropylation of peptide-nucleotide antibiotic microcin C. AB - Translation inhibitor microcin C (McC) is a heptapeptide with an aspartate alpha carboxyl group linked to AMP via phosphoramidate bond. Modification of the McC phosphate by an aminopropyl moiety increases the biological activity by ~10-fold. Here, we determine the pathway of the aminopropylation reaction of McC. We show that the MccD enzyme uses S-adenosyl methionine to transfer 3-amino-3 carboxypropyl group onto a phosphate of an McC maturation intermediate consisting of adenylated heptapeptide. The carboxyl group is removed by the MccE enzyme, yielding mature McC. MccD is an inefficient enzyme that requires for its action the product of Escherichia coli mtn gene, a 5'-methylthioadenosine/S adenosylhomocysteine nucleosidase, which hydrolyses 5'-methylthioadenosine, the product of MccD-catalyzed reaction, thus stimulating the amino-3 carboxypropylation reaction. Both MccD and MccE are capable of modifying McC-like compounds with divergent peptide moieties, opening way for preparation of more potent peptidyl-adenylates. PMID- 25026543 TI - An approach to the problems of orofacial dysfunction in the adult. AB - The treatment of orofacial dysfunction is a part of physiotherapy which can often be neglected or missed entirely in a programme of rehabilitation. The face, tongue, palate and throat are areas which can be effectively treated in patients whose problem is one of muscle dysfunction. A knowledge of the muscles in these areas, combined with the physiotherapist's ability to re-train function and patience on the part of both therapist and patient will achieve the result of an improvement in this specialised area in exactly the same way as improvement occurs in any other part of the body. PMID- 25026544 TI - Physiotherapy programme for patients following a myocardial infarction. AB - The physiotherapy programme for a patient who has suffered a myocardial infarction is always under medical direction. It can be divided broadly into four parts: 1. The acute stage, in the Coronary Care Unit. 2. The semi-acute stage, in the ward attached to the Coronary Care Unit. 3. The convalescent stage, at home, returning twice weekly for Out-Patient treatment. 4. The maintenance programme, which will be carried out for the rest of the patient's life. PMID- 25026545 TI - Aspects of physiotherapy screening and its relevance in pre-school and special education. AB - A research project undertaken within the Department of Physiotherapy, University of Queensland (Steinberg, 1973) investigated the feasibility of establishing a pilot clinic for the study and treatment of very young children with minimal cerebral dysfunction. A neurodevelopmental approach to assessment and treatment was emphasised. PMID- 25026546 TI - A modification of the maitland roll top traction table. AB - This modification of the Maitland Roll Top Traction Table (Maitland, 1973) differs from the original as follows: 1. The two weight-bearing leaves are enclosed by a "guide frame" and the "U-piece" of the original is replaced by a hinged "gate" at the foot, which can be opened downwards for lumbar traction, or can be locked to restrain the leaves when the table is required for other purposes. 2. Four rollers of light steel replace the wooden dowels. 3. The modified table in use by the author is held by a floor peg, and is set up be between two walls 10' 6" apart which provide purchase points for traction. Alternatively, purchase at the head end can be taken by hooks attached to the table itself. 4. The design permits a six-foot plinth to be used. PMID- 25026547 TI - A study of cross-education in strength. AB - Cross-education has long been an area of interest. The term is credited to Scripture et al. (1894), who initiated the first series of studies in this area. These studies were mainly in the field of psychology and it was known that if a subject practised writing with one hand, skill was gained in writing with the other hand. DeLorme (1945), experimenting with adaption of weight-lifting procedures to the treatment of various disabilities of the skeletomuscular system, observed that unilateral exercise of the progressive-resistance type was associated with a concurrent development of increased strength in the symmetric muscle groups of the contralateral limb. Thus began the second series of studies, which were performed mainly by physicians and physical therapists. Hellebrandt, Parrish and Houtz (1947) suggested that neuromuscular cross-education may have a therapeutic use: where volitional control is defective, powerful isometric contraction may be evoked reflexly. Many theories have been put forward regarding the cause of cross-education of strength, none have yet been accepted to the exclusion of the others. In the opinion of this writer, it may be brought about in two ways: 1. By reflex isometric contractions occurring in the contralateral limb while the ipsilateral limb is being exercised. Hellebrandt et al. (ibid.) noticed that while subjects performed resisted knee extension exercises with one leg, the quadriceps of the other leg worked isometrically. Hansen (1961), Mathews et al. (1957) and Rarick and Larson (1962) have shown that isometric contractions will increase muscular strength. This possible cause of cross-education is referred to here as cross-training. 2. The skill learned by performing a strengthening exercise with one limb may bring about an increase in strength in the contralateral limb. Rasch and Morehouse (1957) found that subjects who trained isotonically in the standing position demonstrated a greater improvement in strength when they were tested in the familiar standing position rather than an unfamiliar lying position. They suggested that the gain recorded in the lying position was the true increase in strength, and that the difference between this score and the standing score was due to improvement in skill. This possible cause of cross-education will be referred to as cross-learning. PMID- 25026548 TI - Secondary structure of a conserved domain in an intron of influenza A M1 mRNA. AB - Influenza A virus utilizes RNA throughout infection. Little is known, however, about the roles of RNA structures. A previous bioinformatics survey predicted multiple regions of influenza A virus that are likely to generate evolutionarily conserved and stable RNA structures. One predicted conserved structure is in the pre-mRNA coding for essential proteins, M1 and M2. This structure starts 79 nucleotides downstream of the M2 mRNA 5' splice site. Here, a combination of biochemical structural mapping, mutagenesis, and NMR confirms the predicted three way multibranch structure of this RNA. Imino proton NMR spectra reveal no change in secondary structure when 80 mM KCl is supplemented with 4 mM MgCl2. Optical melting curves in 1 M NaCl and in 100 mM KCl with 10 mM MgCl2 are very similar, with melting temperatures ~14 degrees C higher than that for 100 mM KCl alone. These results provide a firm basis for designing experiments and potential therapeutics to test for function in cell culture. PMID- 25026550 TI - Down-regulation of Homer1b/c attenuates group I metabotropic glutamate receptors dependent Ca2+ signaling through regulating endoplasmic reticulum Ca2+ release in PC12 cells. AB - The molecular basis for group I metabotropic glutamate receptors (mGluR1 and 5) coupling to membrane ion channels and intracellular calcium pools is not fully understood. Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. In the present study, we demonstrate that Homer1b/c is constitutively expressed in PC12 cells, whereas Homer1a, the immediate early gene product, can be up-regulated by brain derived neurotrophic factor (BDNF) and glutamate. Knockdown of Homer1b/c using specific target small interfering RNA (siRNA) did not interfere the expression of mGluR1, mGluR5 and their downstream effectors, including inositol-1,4,5 trisphosphate receptors (IP3R), phospholipase C (PLC) and Gq proteins. By analyzing Ca(2+) imaging in PC12 cells, we demonstrated that Homer1b/c is an essential regulator of the Ca(2+) release from the endoplasmic reticulum (ER) induced by the activation of group I mGluRs, IP3R and ryanodine receptors (RyR). Furthermore, the group I mGluRs activation-dependent refilling of the Ca(2+) stores in both resting and depolarizing conditions were strongly attenuated in the absence of Homer1b/c. Together, our results demonstrate that in PC12 cells Homer1b/c is a regulator of group I mGluRs related Ca(2+) homeostasis that is essential for the maintenance of normal Ca(2+) levels in the ER. PMID- 25026549 TI - Integration of signals along orthogonal axes of the vertebrate neural tube controls progenitor competence and increases cell diversity. AB - A relatively small number of signals are responsible for the variety and pattern of cell types generated in developing embryos. In part this is achieved by exploiting differences in the concentration or duration of signaling to increase cellular diversity. In addition, however, changes in cellular competence-temporal shifts in the response of cells to a signal-contribute to the array of cell types generated. Here we investigate how these two mechanisms are combined in the vertebrate neural tube to increase the range of cell types and deliver spatial control over their location. We provide evidence that FGF signaling emanating from the posterior of the embryo controls a change in competence of neural progenitors to Shh and BMP, the two morphogens that are responsible for patterning the ventral and dorsal regions of the neural tube, respectively. Newly generated neural progenitors are exposed to FGF signaling, and this maintains the expression of the Nk1-class transcription factor Nkx1.2. Ventrally, this acts in combination with the Shh-induced transcription factor FoxA2 to specify floor plate cells and dorsally in combination with BMP signaling to induce neural crest cells. As development progresses, the intersection of FGF with BMP and Shh signals is interrupted by axis elongation, resulting in the loss of Nkx1.2 expression and allowing the induction of ventral and dorsal interneuron progenitors by Shh and BMP signaling to supervene. Hence a similar mechanism increases cell type diversity at both dorsal and ventral poles of the neural tube. Together these data reveal that tissue morphogenesis produces changes in the coincidence of signals acting along orthogonal axes of the neural tube and this is used to define spatial and temporal transitions in the competence of cells to interpret morphogen signaling. PMID- 25026551 TI - AS-2, a novel inhibitor of p53-dependent apoptosis, prevents apoptotic mitochondrial dysfunction in a transcription-independent manner and protects mice from a lethal dose of ionizing radiation. AB - In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated mice because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53 inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53 dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription dependent events than pifithrin-MU (PFTMU), an inhibitor of transcription independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also protected mice that had been exposed to a lethal dose of ionizing radiation. Our findings indicate that some types of bidentate 8HQ chelators could serve as radioprotectors with no substantial toxicity in vivo. PMID- 25026552 TI - Effects of epigenetic modificators in combination with small molecule inhibitors of receptor tyrosine kinases on medulloblastoma growth. AB - Epigenetic alterations and aberrant expression of genes controlling epigenetic mechanisms have been identified in several cancers, including medulloblastoma, the most common brain tumor in children. Here we show that combining drugs that inhibit two of the most important epigenetic factors, gene methylation and post translational modifications of protein histone-associated DNA, with small molecule inhibitors of receptor tyrosine kinases induces apoptosis. The histone deacetylation inhibitor, 4-phenylbutyrate (4-PB) and the demethylation agent, 5 Aza-2'deoxycytidine (5-Aza-dC) had minor effects on medulloblastoma cell cytotoxity in single agent treatment whereas a significant enhancement in cell cytotoxity was seen when these drugs were combined with Gleevec. Triple treatment of medulloblastoma cells with 4-PB, 5-Aza and Gleevec were associated with reduced DNA methyltransferase activity, reduced global methylation and induction of apoptosis. Taken together these results suggest that a combination of these drugs may be beneficial in the treatment of medulloblastoma. PMID- 25026553 TI - Evaluation of the steric impact of flavin adenine dinucleotide in Drosophila melanogaster cryptochrome function. AB - Photoreceptors are crucial components for circadian rhythm entrainment in animals, plants, fungi and cyanobacteria. Cryptochromes (CRYs) are flavin adenine dinucleotide (FAD) containing photoreceptors, and FAD is responsible for signal transduction, in contrast to photolyases where it promotes DNA-damage repair. In this work, we investigated an alternative role for FAD in CRY. We analyzed the Drosophila melanogaster CRY crystal structure by means of molecular dynamics, elucidating how this large co-factor within the receptor could be crucial for CRY structural stability. The co-factor appears indeed to improve receptor motility, providing steric hindrance. Moreover, multiple sequence alignments revealed that conserved motifs in the C-terminal tail could be necessary for functional stability. PMID- 25026554 TI - Protoplast: a more efficient system to study nucleo-cytoplasmic interactions. AB - Agrobacterium tumefaciens-mediated genetic transformation is a powerful tool for plant research, but it can be labor-intensive and time-consuming. Here, we report a protoplast-based approach to study nucleo-cytoplasmic interactions, such as cytoplasmic male sterility/fertility restoration (CMS/Rf) and organellar RNA editing. To test the system, we transfected the fertility restorer gene Rf5, which is involved in the rice HL-CMS/Rf system, into rice protoplasts prepared from the HL-CMS line. As the Rf5 protein accumulated in the transformed protoplasts, the CMS-associated transcripts were endonucleolytically cleaved. There were much lower levels of the CMS-associated protein ORFH79 in the transfected protoplasts than in the mock-transfected protoplasts. Next, we used a dsRNA-mediated gene silencing approach to down-regulate the pentatricopeptide protein gene MPR25, which participates in RNA editing of the organellar transcript nad5. The editing efficiency of mitochondrial transcripts of nad5 at nucleotide 1580 was much lower in the transfected protoplasts than in the mock transfected protoplasts. Together, these results show that protoplast is a simple and efficient system to study interactions between the nucleus and organelles. PMID- 25026555 TI - Cloning and characterization of the mouse JDP2 gene promoter reveal negative regulation by p53. AB - Jun dimerization protein 2 (JDP2) is a repressor of transcription factor AP-1. To investigate the transcriptional regulation of the JDP2 gene, we cloned the 5' flanking region of the mouse JDP2 gene. Primer extension analysis revealed a new transcription start site (+1). Promoter analysis showed that the region from nt 343 to nt +177 contains basal transcriptional activity. Interestingly, the tumor suppressor p53 significantly repressed the transcriptional activity of the JDP2 promoter. Given that JDP2 inhibits expression of p53, our results suggest a negative feedback loop between JDP2 and p53, and a direct link between JDP2 and a key oncogenic pathway. PMID- 25026556 TI - Superior stable sulfur cathodes of Li-S batteries enabled by molecular layer deposition. AB - For the first time, we report the employment of an ultrathin alucone film enabled by the molecular layer deposition technique to dramatically stabilize the sulfur cathodes for Li-S batteries. The alucone coated C/S cathode displayed over two times higher discharge capacity than the pristine one after 100 cycles, demonstrating a greatly prolonged cycle life. PMID- 25026557 TI - Localization of productively infected cells in the spleen and Peyer's patches of rhesus macaques during acute infection with SIVmac239Deltanef-enhanced green fluorescent protein. PMID- 25026558 TI - Efficient quantum dot light-emitting diodes by controlling the carrier accumulation and exciton formation. AB - The performances and spectroscopic properties of CdSe/ZnS quantum dot light emitting diodes (QD-LEDs) with inserting a thickness-varied 1,3,5-tris(N phenylbenzimidazole-2-yl)benzene (TPBi) layer between the QD emission layer and 4,4-N,N-dicarbazole-biphenyl (CBP) hole transport layer (HTL) are studied. The significant enhancement in device peak efficiency is demonstrated for the device with a 3.5 nm TPBi interlayer. The photoluminescence lifetimes of excitons formed within QDs in different devices are also measured to understand the influence of electric field on the QD emission dynamics process and device efficiency. All the excitons on QDs at different devices have nearly the same lifetime even though at different bias. The improvement of device performance is attributed to the separation of charge carrier accumulation interface from the exciton formation zone, which suppresses exciton quenching caused by accumulated carriers. PMID- 25026559 TI - Impact of lumbar spine posture on thoracic spine motion and muscle activation patterns. AB - Complex motion during standing is typical in daily living and requires movement of both the thoracic and lumbar spine; however, the effects of lumbar spine posture on thoracic spine motion patterns remain unclear. Thirteen males moved to six positions involving different lumbar (neutral and flexed) and thoracic (flexed and twisted) posture combinations. The thoracic spine was partitioned into three segments and the range of motion from each posture was calculated. Electromyographical data were collected from eight muscles bilaterally. Results showed that with a flexed lumbar spine, the lower-thoracic region had 14.83 degrees and 15.6 1 degrees more flexion than the upper- and mid-thoracic regions, respectively. A flexed lumbar spine significantly reduced the mid thoracic axial twist angle by 5.21 degrees compared to maximum twist in the mid thoracic region. Functional differences emerged across muscles, as low back musculature was greatest in maintaining flexed lumbar postures, while thoracic erector spinae and abdominals showed bilateral differences with greater activations to the ipsilateral side. Combined postures have been previously identified as potential injury modulators and bilateral muscle patterns can have an effect on loading pathways. Overall, changes in thoracic motion were modified by lumbar spine posture, highlighting the importance of considering a multi segmented approach when analyzing trunk motion. PMID- 25026560 TI - On the existence and characteristics of pi-beryllium bonds. AB - The existence of pi-beryllium bonds explains the stability of the complexes between ethylene and acetylene and BeX2 (X = H, F, and Cl) derivatives. These linkers involve a significant charge transfer from the pi(CC) bonding orbitals into the empty p orbitals of Be and to a much smaller degree into the sigma(BeH)* antibonding orbitals. The significant deformation of the BeX2 moiety and the slight deformation of the unsaturated hydrocarbon result in distortion energies as high as the dissociation energy of the complex. The pi-beryllium bonds are about four times stronger than conventional pi-hydrogen bonds and even stronger than the strongest pi-hydrogen bond reported to date in the literature. The topology of their electron density is characterized as being very flat in the bonding region between the pi-system and Be, which leads to topologically unstable structures close to catastrophe points. Among the functionals considered in our study M06 is the one that leads to values in better agreement with CCSD(T)/aug-cc-pVTZ calculations used as a reference. B3LYP underestimates some interactions, whereas M06-2X overestimates all of them. MP2 also yields good agreement with the CCSD(T) method. PMID- 25026561 TI - Interpersonal relationships in the physiotherapy clinical setting. AB - This paper consists of an introductory review of a limited portion of the literature pertaining to interpersonal relationships. As it placed particular emphasis on therapist-patient relationships, and their development in physiotherapy clinical affiliations, particular attention has been paid to aspects such as interpersonal communication and perception, observational learning, feedback and reiforcement. It appears that attempts to teach interpersonal relationship skills, although providing some positive results, are still far from efficient, and in fact the development of such programmes is still in its infancy. However interest in this area is growing and future contributions to its development are anxiously awaited by many. PMID- 25026562 TI - A description of two new instruments for measuring the ranges of sagittal and horizontal plane motions in the lumbar region. AB - Two new instruments, a lumbar spondylometer and a rotameter, for the measurement of sagittal and horizontal plane motion in the lumbar spine respectively, are described. They enable the clinician to more accurately measure and chart the progress of patients with low back problems. PMID- 25026563 TI - A study of the effects of different ultrasonic frequencies on experimental oedema. AB - This paper describes an investigation, undertaken at the University of Queensland, into the effect of different ultrasonic frequencies in "therapeutic" dosages on experimental oedema in rats, by means of due leakage estimation. Results indicate that ultra-sound is effective in limiting oedema, but further investigation is required to ascertain the means by which this is brought about. PMID- 25026564 TI - The role of intermittent positive pressure breathing in respiratory physiotherapy. AB - This article reviews the value and limitations of I.P.P.B. as opposed to other treatment methods available to the respiratory physiotherapist. In the treatment of patients with airways obstruction I.P.P.B. is presented as having a limited role. Alternative measures such as the use of simple nebulisation, relaxation therapy and manual methods to remove secretions are described as being preferable to I.P.P.B. in most cases. I.P.P.B. has some value in the early post-operative care of some patients undergoing surgery which results in limitation to spontaneous deep breathing postoperatively. However other methods, notably incentive spirometry should also be considered for these patients. In the treatment and prevention of respiratory complications associated with neuromuscular and skeletal disorders I.P.P.B. can play a significant role in counteracting the possible effects of hypoventilation. I.P.P.B. should be considered as one method among many which is available to the physiotherapist to assist in the treatment of respiratory complications associated with medical and surgical conditions. PMID- 25026565 TI - Graduating physiotherapists' perceptions of their career choice. AB - A survey of 72% of final year physiotherapy students at Cumberland College found that they were very satisfied with their career choice, few considered changing their occupation and changes in students' conceptions of physiotherapy had mostly been in a positive direction. They said that the most valued aspects of their career choice were the opportunity to accomplish something worthwhile, the friendliness of the people they worked with, and the opportunity to develop skills and abilities. Few students planned to leave the workforce but 69% hoped to be employed part-time during early childrearing. Some implications of such anticipated work patterns are discussed. PMID- 25026566 TI - Anti arthritic and anti inflammatory activity of a cytotoxic protein NN-32 from Indian spectacle cobra (Naja naja) venom in male albino rats. AB - The anti arthritic and anti inflammatory activity of NN-32, a cytotoxic protein from Indian spectacle cobra snake (Naja naja) venom has been studied in Freund's complete adjuvant (FCA) induced arthritis and carrageenan induced anti inflammatory model. NN-32 treatment showed significant decrease in physical and urinary parameters, serum enzymes, serum cytokines levels as compared to arthritic control group of rats. NN-32 treatment recovered carrageenan induced inflammation as compared to control group of rats. The findings showed that the cytotoxic protein NN-32 shares anti arthritic and anti inflammatory activity and thus NN-32 may target complex pathophysiological processes like cancer- arthritis inflammation. PMID- 25026567 TI - Physiotherapy, an adjunct to stellate ganglion and brachial plexus blocks for post-traumatic sympathetic dystrophy. AB - Reflex Sympathetic Dystrophy has been described under various different names such as Shoulder-hand Syndrome, Causalgia, Sudeck's Atrophy and several others (Bonica, 1973). However, the underlying pathophysiology seems to be similar in all and relates to an abnormality in sympathetic outflow to the limb as a primary disturbance. Therefore, the term Reflex Sympathetic Dystrophy appears to be an appropriate general term for all of these conditions. However, there are always quite diverse symptoms relating to disordered physiology outside the Sympathetic Nervous System as a result of pain and disuse. The presenting symptom in these patients is almost invariably a severe burning pain, which tends to divert the attention away from the abnormalities of sympathetic activity in the limb. PMID- 25026568 TI - Electro-analgesia. AB - Between May 1975 and March 1976, 19 patients with pain or hypersensitivity, or both, in the distribution of a peripheral nerve were treated with electro analgesia in the physiotherapy department of Sydney Hospital. The rationale for this treatment is the work of Melzack and Wall (1965). The current selected was that used by Meyer and Field (1972), a unidirectional square wave current with pulse length of 0.1 millisecond at a frequency of 100 Hertz. The machine used was a GRASS S48 stimulator, which is a highly accurate instrument. The electrodes were twin silver plates, 15 mm x 7 mm approximately, covered with lint mounted with a space of 2.5 cm on a piece of perspex (Fig. 1) or silver wire covered with lint for use on fingers. PMID- 25026569 TI - The role of the physiotherapist in accident prevention. AB - The physiotherapist is the Allied Health Professional who cares for the physical nature of the person and who plays a major part in the prevention of accidents and injuries. In the present context, we are concerned with the prevention of accidents of all kinds, including infections and illnesses, to people everywhere. PMID- 25026570 TI - An assessment method to evaluate the optimum treatment level of the head injury patient. AB - Rehabilitation of head injury patients is impossible without accurate and adequate assessment. Assessment should have a functional bias and be a continuing process to ensure that these patients are treated at their optimum level at all times. PMID- 25026571 TI - Relaxation. AB - The relaxed state, to me, is simply the state of being mentally and physically at ease. This does not necessarily mean a passive state, in a quiet place, day dreaming. It could mean an active state where the individual is working or playing in the day-to-day environment. To achieve this relaxed state the aim is to regulate the amount of stress so it does not exceed a determined level. Above this level, stress becomes counterproductive. We aim for the level of stress that is optimal for each individual at a particular time, performing a particular task. At this level the individual may be active or passive and still be relaxed. PMID- 25026572 TI - Thermal hydrolysis of waste activated sludge at Hengelo Wastewater Treatment Plant, the Netherlands. AB - The thermal hydrolysis process (THP) is a sludge treatment technique which affects anaerobic biodegradability, viscosity and dewaterability of waste activated sludge (WAS). In 2011 a THP-pilot plant was operated, connected to laboratory-scale digesters, at the water board Regge en Dinkel and in cooperation with Cambi A.S. and MWH Global. Thermal hydrolysis of WAS resulted in a 62% greater volatile solids (VS) reduction compared to non-hydrolysed sludge. Furthermore, the pilot digesters could be operated at a 2.3 times higher solids loading rate compared to conventional sludge digesters. By application of thermal sludge hydrolysis, the overall efficiency of the sludge treatment process can be improved. PMID- 25026573 TI - Monitoring the oxygen transfer efficiency of full-scale aeration systems: investigation method and experimental results. AB - This paper reports the results of a series of off-gas tests aimed at monitoring the evolution of the oxygen transfer efficiency in an urban wastewater treatment plant (3,500 population equivalent) located in Tuscany (Italy). The tests were conducted over a 2-year period starting with the testing of the aeration system. It was found that in the absence of membrane-panel cleaning operations, the oxygen transfer efficiency under standard conditions in process water (alphaSOTE) dropped from 18 to 9.5% in 2 years. This gives rise to a 40% increase in the wastewater treatment plant annual energy costs. The on-site chemical cleaning of the diffusers allowed for an almost total recovery of the transfer efficiency (alphaSOTE equal to 16%). The use of the off-gas method for monitoring the oxygen transfer efficiency over time is therefore essential for enabling correct planning of the cleaning operations of the diffusers and for cutting the energy consumption and operating costs of the aeration system. PMID- 25026574 TI - Inverse calculation of biochemical oxygen demand models based on time domain for the tidal Foshan River. AB - To simulate the variation of biochemical oxygen demand (BOD) in the tidal Foshan River, inverse calculations based on time domain are applied to the longitudinal dispersion coefficient (E(x)) and BOD decay rate (K(x)) in the BOD model for the tidal Foshan River. The derivatives of the inverse calculation have been respectively established on the basis of different flow directions in the tidal river. The results of this paper indicate that the calculated values of BOD based on the inverse calculation developed for the tidal Foshan River match the measured ones well. According to the calibration and verification of the inversely calculated BOD models, K(x) is more sensitive to the models than E(x) and different data sets of E(x) and K(x) hardly affect the precision of the models. PMID- 25026575 TI - Removal of methylene blue, a basic dye, from aqueous solutions using nano zerovalent iron. AB - In this research, the preparation of nanoparticles of Fe(0) (nano-zerovalent iron, NZVI) as adsorbent is discussed and the capability of adsorbing methylene blue (MB) is studied. The morphology of the adsorbent was evaluated with transmission electron microscopy. Batch studies were performed to delineate the influence of various experimental parameters such as pH, adsorbent dosage, initial dye concentration, temperature and contact time. Optimum conditions for MB removal were found to be pH 9.5, adsorbent dosage of 0.5 g L(-1) and equilibrium time of 1 min. The experimental equilibrium data were adjusted by the adsorption isotherms from Langmuir and Freundlich models, and their equilibrium parameters were determined. The adsorption of MB dye by NZVI obeyed both the Freundlich and Langmuir isotherm. The adsorption capacity of NZVI for MB in terms of monolayer adsorption was 208.33 mg g(-1). PMID- 25026576 TI - Evaluation of barrier materials for removing pollutants from groundwater rich in natural organic matter. AB - Permeable barriers are used for passive remediation of groundwater and can be constructed from a range of materials. The optimal material depends on the types of contaminants and physico-chemical parameters present at the site, as well as the hydraulic conductivity, environmental safety, availability, cost and long term stability of the material itself. The aim of the presented study was to test a number of materials for their ability to remove heavy metals and organic pollutants from groundwater with a high (140 mg L(-1)) content of natural organic matter (NOM). The following materials were included in the study: sand, peat, fly ash, iron powder, lignin and combinations thereof. Polluted water was fed into glass columns loaded with each sorbent and the contaminant removal efficiency of the material was evaluated through chemical analysis of the percolate. Materials based on fly ash and zero-valent iron were found to be the most effective for heavy metal removal, while fly ash and peat were the most effective for removing aliphatic compounds. Filtration through lignin and peat led to leaching of NOM. Although the leaching decreased over time, it remained high throughout the experiments. The results indicate that remediation of contaminated land at disused industrial sites is a complex task that often requires the use of mixed materials or a minimum of two sequential barriers. PMID- 25026577 TI - Deposit membrane fouling: influence of specific cake layer resistance and tangential shear stresses. AB - Cake fouling is the leading cause of membrane permeability decrease when filtering mixed liquor suspension containing high suspended solid concentrations. A simple model is proposed to simulate the cake resistance evolution with time by considering a macro-scale fouling linked only to the accumulation of particles on the membrane surface. This accumulation appears as the difference between the flux of deposited particles due to the filtration and the flux of particles detached from the membrane surface due to the tangential shear stresses caused by recirculation flow in the sidestream membrane bioreactor (MBR) or gas sparging close to the membrane surface for submerged MBR configuration. Two determining parameters were then highlighted: the specific cake resistance and the 'shear parameter'. Based on these parameters it is possible to predict model outputs as cake resistance and permeate flux evolution for short-time filtration periods. PMID- 25026578 TI - Application of three tailing-based composites in treating comprehensive electroplating wastewater. AB - Heavy metals and chemical oxygen demand (COD) are major challenging pollutants for most electroplating wastewater treatment plants. A novel composite material, prepared with a mixture of calcium and sodium compounds and tailings, was simply mixed by ratios and used to treat a comprehensive electroplating wastewater with influent COD, total copper (T-Cu), and total nickel (T-Ni) respectively as 690, 4.01, and 20.60 mg/L on average. Operational parameters, i.e. the contact time, pH, mass ratio of calcium and sodium compounds and tailings, were optimized as 30 min, 10.0, and 4:2:1. Removal rates for COD, T-Cu, and T-Ni could reach 71.8, 90.5, and 98.1%, respectively. No significant effect of initial concentrations on removal of T-Cu and T-Ni was observed for the composite material. The adsorption of Cu(II) and Ni(II) on the material fitted Langmuir and Freundlich isotherms respectively. Weight of waste sludge from the calcium/sodium-tailing system after reaction was 10% less than that from the calcium-tailing system. The tailing based composite is cost-effective in combating comprehensive electroplating pollution, which shows a possibility of applying the tailings in treating electroplating wastewater. PMID- 25026579 TI - Reduction of hexavalent chromium: photocatalysis and photochemistry and their application in wastewater remediation. AB - Hexavalent chromium present in wastewater discharge of galvanic industries is toxic to most microorganisms and potentially harmful to human health. This work examines the photochemical reduction of Cr(VI) with ethanol under ultraviolet (UV) and visible radiation, and photocatalytic reduction of Cr(VI) with TiO2 in the presence of ethanol under UV radiation. By means of different experimental designs, this study investigates the influence of the initial pH, ethanol amount, catalyst concentration and initial Cr(VI) concentration on total Cr(VI) reduction. The results obtained showed that photochemistry with ethanol under UV radiation (96.10%) was more efficient than photochemistry with ethanol under visible light (48.07%). Furthermore, photocatalysis with TiO2 in the presence of ethanol under UV radiation showed high values of total Cr(VI) reduction: 94.15%, under the optimal conditions established by the experimental design. Finally, experiments were carried out with wastewater discharge from an electroplating plant in its original concentration, and higher values of total Cr(VI) reduction were observed. PMID- 25026580 TI - Removal and retention of phosphorus by periphyton from wastewater with high organic load. AB - The total phosphorus (TP) removal efficiency from organic wastewater (pig farm and distillery wastewater) were estimated by using filamentous green algae (FGA) and benthic algal mats (BAM) treatment systems under laboratory conditions, and the contents of periphyton phosphorus fractions were determined by using a sequential extraction. The removal rates of TP reached 59-78% within the first 8 days of all treatment systems and could achieve average 80% during 30 day period, and the phosphorus removal rates by using BAM was higher than that of FGA. The ability of retention TP of periphyton enhanced gradually, the BAM TP contents were higher than that of FGA, the highest TP concentrations of BAM and FGA were 26.24 and 10.52 mg P g(-1).dry weight. Inorganic phosphorus (IP) always exceeded 67.5% of TP, but the organic phosphorus fraction only made up less than 20% of TP. The calcium-binding phosphorus (Ca-P) was the dominant fraction and its relative contribution to TP was more than 40%. The TP was also strongly and positively correlated with the IP and Ca-P (p < 0.01) in periphyton. It showed that the periphyton had a potential ability of rapid phosphorus removing and remarkable retention from wastewater with high load phosphorus. PMID- 25026581 TI - A pilot scale comparison of advanced oxidation processes for estrogenic hormone removal from municipal wastewater effluent. AB - This study investigates the oxidation of selected endocrine disrupting compounds (estrone, 17beta-estradiol, estriol and 17alpha-ethinylestradiol) during ozonation and advanced oxidation of biologically treated municipal wastewater effluents in a pilot scale. Selected estrogenic substances were spiked in the treated wastewater at levels ranging from 1.65 to 3.59 MUg . L(-1). All estrogens were removed by ozonation by more than 99% at ozone doses >=1.8 mg . L(-1). At a dose of 4.4 . mg L(-1) ozonation reduced concentrations of estrone, 17beta estradiol, estriol and 17alpha-ethinylestradiol by 99.8, 99.7, 99.9 and 99.7%, respectively. All tested advanced oxidation processes (AOPs) achieved high removal rates but they were slightly lower compared to ozonation. The lower removal rates for all tested advanced oxidation processes are caused by the presence of naturally occurring hydroxyl radical scavengers - carbonates and bicarbonates. PMID- 25026582 TI - Vertical flow constructed wetlands: kinetics of nutrient and organic matter removal. AB - The kinetics of organic matter and nutrient removal in a pilot vertical subsurface wetland with red ferralitic soil as substrate were evaluated. The wetland (20 m(2)) was planted with Cyperus alternifolius. The domestic wastewater that was treated in the wetland had undergone a primary treatment consisting of a septic moat and a buffer tank. From the sixth week of operation, the performance of the wetland stabilized, and a significant reduction in pollutant concentration of the effluent wastewater was obtained. Also a significant increase of dissolved oxygen (5 mg/l) was obtained. The organic matter removal efficiency was greater than 85% and the nutrient removal efficiency was greater than 75% in the vertical subsurface wetland. Nitrogen and biochemical oxygen demand (BOD) removal could be described by a first-order model. The kinetic constants were 3.64 and 3.27 d(-1) for BOD and for total nitrogen, respectively. Data on the removal of phosphorus were adapted to a second-order model. The kinetic constant was 0.96 (mg/l)(-1) d( 1). The results demonstrated the potential of vertical flow constructed wetlands to clean treated domestic wastewater before discharge into the environment. PMID- 25026583 TI - Analysis of extracellular polymeric substance (EPS) release in anaerobic sludge holding tank and its effects on membrane fouling in a membrane bioreactor (MBR). AB - Amongst sludge reduction strategies, the anaerobic side-stream sludge holding tank (SHT) is of particular interest because it has shown significant sludge reduction efficiency. However, due to the anaerobic and starving environment of the SHT, the release of extracellular polymeric substance (EPS) may be stimulated, and it may hamper the application of the SHT to the membrane bioreactor. In order to investigate the effect of sludge storage on EPS release, sludge samples from a pilot-scale sequencing batch reactor coupled with SHT was incubated in a series of bench-scale SHT reactors for different periods of time (0-24 h). The increase in EPS was not significant until 12 h of incubation (9.3%), while 40.9% of the increase was observed in the sample incubated for 24 h. The rapid increase in EPS concentration after 12 h indicates a greater rate of cell lysis than that with EPS consumption as substrate. Since inducing the initial stage of the endogenous phase within microorganisms is a key factor for the successful operation of the SHT for sludge reduction, the retention time for the SHT should be shorter than the time for the sudden increase in EPS release. PMID- 25026584 TI - Agar-encapsulated adsorbent based on leaf of platanus sp. to adsorb cadmium ion in water. AB - A low cost and environmentally friendly adsorbent was developed based on leaf of platanus sp. to adsorb cadmium ion in water. The adsorbent was modified with citric acid and then also encapsulated in agar for easy separation after the adsorption process. Parameters such as adsorbent dose, stirring time, solution pH and modification of the adsorbent with citric acid were investigated in a batch experiment in order to determine the optimum condition for Cd (II) adsorption. Based on the Langmuir isotherm adsorption model, the adsorption capacity of cadmium ion for raw adsorbent, modified adsorbent with citric acid and encapsulated adsorbent were 3.69, 15.31 and 6.89 mg/g, respectively. The high adsorption capacity after treatment with citric acid may be due to the increase in carboxylic content of the adsorbent surface and also the increase of surface area and pore volume of the adsorbent. With this high adsorption capacity for cadmium ion and an abundance of raw materials, this bio-adsorbent could be considered as a low cost adsorbent in the near future. PMID- 25026585 TI - Analysis of nitrogenous and algal oxygen demand in effluent from a system of aerated lagoons followed by polishing pond. AB - In this descriptive-analytical study, nitrogenous and algal oxygen demand were assessed for effluent from a system of facultative partially mixed lagoons followed by the polishing pond using 120 grab samples over 1 year. Filtered and non-filtered samples of polishing pond effluent were tested in the presence and absence of a nitrification inhibitor. Effective factors, including 5-day biochemical and chemical oxygen demand (BOD and COD), total suspended solids (TSS), dissolved oxygen, chlorophyll A, and temperature, were measured using standard methods for water and wastewater tests. The results were analyzed using repeated measures analysis of variance with SPSS version 16. Findings show that the annual mean of the total 5-day BOD in the effluent from the polishing pond consisted of 44.92% as the algal carbonaceous biochemical oxygen demand (CBOD), 43.61% as the nitrogenous biochemical oxygen demand (NBOD), and 11.47% as the soluble CBOD. According to this study, the annual mean ratios of algal COD and 5 day algal CBOD to TSS were 0.8 and 0.37, respectively. As the results demonstrate, undertaking quality evaluation of the final effluent from the lagoons without considering nitrogenous and algal oxygen demand would undermine effluent quality assessment and interpretation of the performance of the wastewater treatment plant. PMID- 25026586 TI - Removal of hazardous pharmaceutical dyes by adsorption onto papaya seeds. AB - Papaya (Carica papaya L.) seeds were used as adsorbent to remove toxic pharmaceutical dyes (tartrazine and amaranth) from aqueous solutions, in order to extend application range. The effects of pH, initial dye concentration, contact time and temperature were investigated. The kinetic data were evaluated by the pseudo first-order, pseudo second-order and Elovich models. The equilibrium was evaluated by the Langmuir, Freundlich and Temkin isotherm models. It was found that adsorption favored a pH of 2.5, temperature of 298 K and equilibrium was attained at 180-200 min. The adsorption kinetics followed the pseudo second-order model, and the equilibrium was well represented by the Langmuir model. The maximum adsorption capacities were 51.0 and 37.4 mg g(-1) for tartrazine and amaranth, respectively. These results revealed that papaya seeds can be used as an alternative adsorbent to remove pharmaceutical dyes from aqueous solutions. PMID- 25026587 TI - Study of constructed wetlands effluent disinfected with ozone. AB - The purpose of this research was to study the disinfection of sanitary effluent from constructed wetlands, evaluating the oxidation of organic matter, the formation of formaldehyde, as well as the efficiency of total coliforms and Escherichia coli inactivation. A constant flow of ozone was applied to the batch system in 5 and 10 mg.O3 L(-1) doses with contact times of 5 and 10 min. This study revealed that the average values of formaldehyde formation ranged between 259.00 and 379.00 MUg L(-1), which means that the values are within World Health Organization recommended values. The total coliforms and E. coli showed complete inactivation in almost all tests. The dose of ozone 5 mg.O3 L(-1) and contact time of 5 min were sufficient for a significant reduction of the concentration levels of pathogens in constructed wetlands effluent with similar characteristics, thus allowing for its agricultural reuse. PMID- 25026588 TI - Comparison of sludge treatment by O3 and O3/H2O2. AB - This work focuses on the comparison of sludge decomposition caused by ozone (O3) alone and by ozone/hydrogen peroxide (O3/H2O2). The content of carbonaceous organic materials, nitrogenous compounds and phosphoric substances in sludge supernatant were measured. The release of soluble chemical oxygen demand, total nitrogen (TN) and total phosphorus (TP) caused by O3/H2O2 treatment were more than by O3 alone. As a result, it can be concluded that the efficiency of sludge breakup in O3/H2O2 was better than that in O3 alone. However, a peak appeared in both systems for the biodegradable substances such as carbohydrate. Carbohydrate could be used as the carbon source for denitrification, and the releasing of TN and TP may become an additional burden for a subsequent biological system. So, it was of benefit for the enhancement of cryptic growth and cost reduction by raising and maintaining the content of biodegradable substance and reducing the concentrations of the nitrogenous and phosphoric substances as far as possible. Therefore, sludge treated by O3/H2O2 with lower O3 dose would be more suitable than O3 alone. PMID- 25026589 TI - Pilot trial study of a compact macro-filtration membrane bioreactor process for saline wastewater treatment. AB - Conventional membrane bioreactor (MBR) systems have increasingly been studied in recent decades. However, their applications have been limited due to their drawbacks such as low flux, membrane fouling, and high operating cost. In this study, a compact macro-filtration MBR (MfMBR) process was developed by using a large pore size membrane to mitigate the membrane fouling problem. A pilot trial of MfMBR process was set up and operated to treat 10 m(3)/day of saline wastewater within 4 h. The system was operated under an average permeate flux of 13.1 m(3)/(m(2).day) for 74 days. The average total suspended solids, total chemical oxygen demand, biological oxygen demand, total Kjeldahl nitrogen, and total nitrogen removal efficiencies achieved were 94.3, 83.1, 98.0, 93.1, and 63.3%, respectively, during steady-state operation. The confocal laser scanning microscopy image indicated that the backwash could effectively remove the bio cake and dead bacteria. Thus, the results showed that the MfMBR process, which is essentially a primary wastewater treatment process, had the potential to yield the same high quality effluent standards as the secondary treatment process; thereby suggesting that it could be used as an option when the economic budget and/or land space is limited. PMID- 25026590 TI - Linking the management of urban watersheds with the impacts on the receiving water bodies: the use of flow duration curves. AB - There is growing evidence that changes in the current hydrological behaviour of urbanising catchments are a major source of impacts on the downstream water bodies. However, current flow-rates are rarely considered in studies on urban stormwater management, usually focused on extreme flow-rates. We argue that taking into account receiving water bodies is possible with relatively small modifications in current practices of urban stormwater modelling, through the use of Flow duration curves (FDCs). In this paper, we discuss advantages and requirements of the use of FDCs. Then, we present an example of application comparing source control regulations over an urbanised catchment (178 ha) in Nantes, France. PMID- 25026591 TI - Biosorption of uranium(VI) from aqueous solution by biomass of brown algae Laminaria japonica. AB - The uranium(VI) adsorption efficiency of non-living biomass of brown algae was evaluated in various adsorption experimental conditions. Several different sizes of biomass were prepared using pretreatment and surface-modification steps. The kinetics of uranium uptake were mainly dependent on the particle size of the prepared Laminaria japonica biosorbent. The optimal particle size, contact time, and injection amount for the stable operation of the wastewater treatment process were determined. Spectroscopic analyses showed that uranium was adsorbed in the porous inside structure of the biosorbent. The ionic diffusivity in the biomass was the dominant rate-limiting factor; therefore, the adsorption rate was significantly increased with decrease of particle size. From the results of comparative experiments using the biosorbents and other chemical adsorbents/precipitants, such as activated carbons, zeolites, and limes, it was demonstrated that the brown algae biosorbent could replace the conventional chemicals for uranium removal. As a post-treatment for the final solid waste reduction, the ignition treatment could significantly reduce the weight of waste biosorbents. In conclusion, the brown algae biosorbent is shown to be a favorable adsorbent for uranium(VI) removal from radioactive wastewater. PMID- 25026592 TI - Combination of ion exchange and partial nitritation/Anammox process for ammonium removal from mainstream municipal wastewater. AB - In this study, a new technology of nitrogen removal from mainstream municipal wastewater is proposed. It is based on ammonium removal by ion exchange and regeneration of ion exchange material with 10-30 g/L NaCl solution with further nitrogen removal from spent regenerant by partial nitritation/Anammox process. Influence of regenerant strength on performance of ion exchange and biological parts of the proposed technology was evaluated. Moreover, the technology was tested in batch mode using pretreated municipal wastewater, strong acid cation (SAC) resin and partial nitritation/Anammox biomass. It was shown that with ion exchange it is possible to remove 99.9% of ammonium from wastewater while increasing the concentration of ammonium in spent regenerant by 18 times. Up to 95% of nitrogen from spent regenerant, produced by regeneration of SAC resin with 10 g/L NaCl solution, was removed biologically by partial nitritation/Anammox biomass. Moreover, the possibilities of integration of the technology into municipal wastewater treatment technology, and the challenges and advantages are discussed. PMID- 25026593 TI - Ultrasonic degradation of 1-H-benzotriazole in water. AB - This paper reports on the effect of different parameters of ultrasonic power, pollutant initial concentration, pH and the presence of co-existing chemical species (oxygen, nitrogen, ozone, and radical scavengers) on the ultrasonic degradation of the endocrine disruptor 1-H-benzotriazole. Increasing the 1-H benzotriazole initial concentration from 41.97 to 167.88 MUM increased the pollutant degradation rate by 40%. Likewise, a high applied ultrasonic power enhanced the extent of 1-H-benzotriazole removal and its initial degradation rate, which was accelerated in the presence of ozone and oxygen, but inhibited by nitrogen. The most favorable pH for the ultrasonic degradation was acidic media, reaching ~90% pollutant removal in 2 h. The hydroxyl free radical concentration in the reaction medium was proportional to the ultrasound power and the irradiation time. Kinetic models based on a Langmuir-type mechanism were used to predict the pollutant sonochemical degradation. It was concluded that degradation takes place at both the bubble-liquid interfacial region and in the bulk solution, and OH radicals were the main species responsible for the reaction. Hydroxyl free radicals were generated by water pyrolysis and then diffused into the interfacial region and the bulk solution where most of the solute molecules were present. PMID- 25026594 TI - New equation for the computation of flow velocity in partially filled pipes arranged in parallel. AB - This paper presents a new approach for the computation of flow velocity in pipes arranged in parallel based on an analytic development. The estimation of the flow parameters using existing methods requires trial and error procedures. The assessment of flow velocity is of great importance in flow measurement methods and in the design of drainage networks, among others. In drainage network design, the flow is mostly of free surface type. A new method is developed to eliminate the need for trial methods, where the computation of the flow velocity becomes easy, simple, and direct with zero deviation compared to Manning equation results and other approaches such as that have been considered as the best existing solutions. This research work shows that these approaches lack accuracy and do not cover the entire range of flow surface angles: 0 degrees <= theta <= 360 degrees . PMID- 25026595 TI - The regularity of wind-induced sediment resuspension in Meiliang Bay of Lake Taihu. AB - Contaminants released by wind-induced sediment resuspension could influence the water quality in shallow lakes. This study aims to reveal the quantitative relationship between wind speed (v) and sediment resuspension rate (r) in Meiliang Bay of Lake Taihu. The study was conducted in three steps. First, the in situ wind speed and current velocity were measured over a period of 2 days in Meiliang Bay to establish the relationship between wind and hydrodynamic conditions; second, an indoor experiment was conducted in a cylindrical simulator with sediment from the study area to determine sediment resuspension rates under different hydrodynamic conditions; and third, linkages between sediment resuspension and wind were determined. The average sediment resuspension rate was highly correlated with the wind speed (R(2) = 0.99), and was expressed by r = 20.72v(2.034) at wind speeds in the range of 0-14 m/s. The critical wind speed for sediment resuspension is about 7 m/s. Under these conditions, the average resuspension rate could reach 1,000 g/(m(2)d), with a total phosphorus release rate of 1.1 g/(m(2)d) and a total nitrogen release rate of 18.1 g/(m(2)d). PMID- 25026596 TI - A comparative study on the degradation of gallic acid by Aspergillus oryzae and Phanerochaete chrysosporium. AB - Recently, as an emerging persistent dissolved organic pollutant (DOP), gallic acid (GA) and its efficient decomposition methods have received global attention. The present work aimed to compare the effect of Aspergillus oryzae 5992 and Phanerochaete chrysosporium 40719 on degradation of different concentrations of GA. The A. oryzae grew well and achieved a GA removal rate up to 99% in media containing 1-4% GA, much higher than P. chrysosporium. The activity of laccase and lignin peroxidase excreted by A. oryzae was higher than that by P. chrysosporium in the presence of GA. Based on the results of high-performance liquid chromatography-electrospray ionization-mass spectrometry, three relevant intermediate metabolites were determined as progallin A, methyl gallate, and pyrogallic acid, implying that A. oryzae could not degrade GA unless the carboxyl in the molecule was protected or removed. In view of the ability of A. oryzae to accommodate a high concentration of GA and achieve a high removal rate, as well as the significantly different enzyme activities involved in GA degradation and the underlying mechanisms between the two fungal strains, A. oryzae is proven to be a superior strain for the degradation of DOP. PMID- 25026597 TI - Availability of the basal planes of graphene oxide determines whether it is antibacterial. AB - There are significant controversies on the antibacterial properties of graphene oxide (GO): GO was reported to be bactericidal in saline, whereas its activity in nutrient broth was controversial. To unveil the mechanisms underlying these contradictions, we performed antibacterial assays under comparable conditions. In saline, bare GO sheets were intrinsically bactericidal, yielding a bacterial survival percentage of <1% at 200 MUg/mL. Supplementing saline with <=10% Luria Bertani (LB) broth, however, progressively deactivated its bactericidal activity depending on LB-supplementation ratio. Supplementation of 10% LB made GO completely inactive; instead, ~100-fold bacterial growth was observed. Atomic force microscopy images showed that certain LB components were adsorbed on GO basal planes. Using bovine serum albumin and tryptophan as well-defined model adsorbates, we found that noncovalent adsorption on GO basal planes may account for the deactivation of GO's bactericidal activity. Moreover, this deactivation mechanism was shown to be extrapolatable to GO's cytotoxicity against mammalian cells. Taken together, our observations suggest that bare GO intrinsically kills both bacteria and mammalian cells and noncovalent adsorption on its basal planes may be a global deactivation mechanism for GO's cytotoxicity. PMID- 25026598 TI - Digestive enzymes from workers and soldiers of termite Nasutitermes corniger. AB - The digestive apparatus of termites may have several biotechnological applications, as well as being a target for pest control. This report discusses the detection of cellulases (endoglucanase, exoglucanase, and beta-glucosidase), hemicellulases (beta-xylosidase, alpha-l-arabinofuranosidase, and beta-d xylanase), alpha-amylase, and proteases (trypsin-like, chymotrypsin-like, and keratinase-type) in gut extracts from Nasutitermes corniger workers and soldiers. Additionally, the effects of pH (3.0-11.0) and temperature (30-100 degrees C) on enzyme activities were evaluated. All enzymes investigated were detected in the gut extracts of worker and soldier termites. Endoglucanase and beta-xylanase were the main cellulase and hemicellulase, respectively. Zymography for proteases of worker extracts revealed polypeptides of 22, 30, and 43kDa that hydrolyzed casein, and assays using protease inhibitors showed that serine proteases were the main proteases in worker and soldier guts. The determined enzyme activities and their response to different pH and temperature values revealed that workers and soldiers contained a distinct digestive apparatus. The ability of these termites to efficiently digest the main components of lignocellulosic materials stimulates the purification of gut enzymes. Further investigation into their biotechnological potential as well as whether the enzymes detected are produced by the termites or by their symbionts is needed. PMID- 25026599 TI - Troxerutin improves hepatic lipid homeostasis by restoring NAD(+)-depletion mediated dysfunction of lipin 1 signaling in high-fat diet-treated mice. AB - Recent evidences suggest that NAD(+) depletion leads to abnormal hepatic lipid metabolism in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD); however, the contributing mechanism is not well understood. Our previous study showed that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, effectively inhibited obesity, and normalized hyperglycemia and hyperlipidemia in high-cholesterol diet-induced diabetic mice. Here we investigated whether troxerutin improved hepatic lipid metabolism via preventing NAD(+) depletion in HFD-induced NAFLD mouse model and the mechanisms underlying these effects. Our results showed that troxerutin markedly prevented obesity, liver steatosis and injury in HFD-fed mice. Troxerutin largely suppressed oxidative stress-mediated NAD(+)-depletion by increasing nicotinamide phosphoribosyltransferase (NAMPT) protein expression and decreasing poly (ADP ribose) polymerase-1 (PARP1) protein expression and activity in HFD-treated mouse livers. Consequently, troxerutin remarkably restored Silent mating type information regulation 2 homolog1 (SirT1) protein expression and activity in HFD treated mouse livers. Therefore, troxerutin promoted SirT1-mediated AMP-activated protein kinase (AMPK) activation to inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling, which enhanced nuclear lipin 1 localization, lowered cytoplasmic lipin 1 localization and the ratio of hepatic Lpin 1beta/alpha. Ultimately, troxerutin improved lipid homeostasis by enhancing fatty acid oxidation and triglyceride secretion, and suppressing lipogenesis in HFD-fed mouse livers. In conclusion, troxerutin displayed beneficial effects on hepatic lipid homeostasis in HFD-induced NAFLD by blocking oxidative stress to restore NAD(+)-depletion-mediated dysfunction of lipin 1 signaling. This study provides novel mechanistic insights into NAFLD pathogenesis and indicates that troxerutin is a candidate for pharmacological intervention of NAFLD via restoring NAD(+) levels. PMID- 25026600 TI - Cancer and the twentieth century environment. AB - Cancers have been known from very early times. However, in the twentieth century, cancers have come to occupy an increasingly prominent position as causes of morbidity and mortality, and look large in the minds (and hearts) of contemporary men and women, especially in Western cultures. PMID- 25026601 TI - Physiotherapy at the montreal olympics. AB - Because of the good results that physiotherapy has achieved in the field of sports medicine, the need for a physiotherapist in the Olympic team could no longer be ignored. The Australia Sports Medicine Federation has wanted to include a physiotherapist since 1964 but was not successful until 1976. PMID- 25026602 TI - Health in the community. AB - Years ago, one of Mark Twain's characters summarized the attitude towards health held by the vast majority of Australians, when he stated "The only way to keep your health is to eat what you don't want, drink what you don't like, and do what you'd druther not". PMID- 25026603 TI - Aging: what abilities are lost? AB - Over the last decade most of us have become familiar with the terms "sexism" and "racism". PMID- 25026604 TI - Chondromalacia patellae. AB - Chondromalacia patellae is one of the most frequently encountered causes of knee pain in young people. The word chondromalacia is derived from the Greek words, chrondros, meaning cartilage and malakia, meaning softening. Hence chondromalacia patellae is a softening of the articular cartilage on the posterior surface of the patella. It may eventually lead to fibrillation, fissuring and erosion. PMID- 25026605 TI - Biomechanical problems: foot/spine relationships in youth. AB - It is accepted practice by the health professions to assess and treat many conditions as isolated problems. It is our intention to present to you a different approach to treatment. This is based on a total body assessment from analysing biomechanical faults and compensations in all body linkages. These biomechanical inadequacies are apparent at an early age and quite frequently at the initial weight-bearing stage. Sometimes the parents observe these changes but are frequently told the child will grow out of the odd shape and no total assessment or follow-up is carried out. Pain does not usually occur with these problems in the early stages and so there appears to be no reason for treatment. The opportunity for early assessment and treatment therefore, is often lost. However if the signs could be more widely recognized and at an early age and treatment instituted to correct any biomechanical faults then it should be possible for the health professions to make a real contribution in preventive health care and reduce the high incidence of many musculoskeletal problems which are so common and disabling in the community. PMID- 25026606 TI - The prevention of selected and imposed posture-caused injury. AB - It has been recognized for centuries that posture and health are interrelated. Poor health and injuries impose their own specific postures, and poor posture can contribute towards injury and poor health. The correlation between posture and health is not absolute. We can say that a certain posture will increase the probability of injury. Individual differences of age, sex, somatype, fitness, fatigue, load and frequency of posture adoption will dictate if injury will occur, or not, with any individual. There is no doubt that some postures are more stressful than others. The individual factors mentioned dictate whether the resulting strain is above or below the critical amount required for injury. PMID- 25026607 TI - Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. PMID- 25026608 TI - Strategies to prevent healthcare-associated infections through hand hygiene. PMID- 25026609 TI - An infection preventionist's view of the compendium of strategies to prevent healthcare-associated infections: structure, process, and outcome. PMID- 25026610 TI - A view from the joint commission perspective: updated compendium will continue to help reduce healthcare-associated infections. PMID- 25026611 TI - A compendium of strategies to prevent healthcare-associated infections in acute care hospitals: 2014 updates. AB - Since the publication of "A Compendium of Strategies to Prevent Healthcare Associated Infections in Acute Care Hospitals" in 2008, prevention of healthcare associated infections (HAIs) has become a national priority. Despite improvements, preventable HAIs continue to occur. The 2014 updates to the Compendium were created to provide acute care hospitals with up-to-date, practical, expert guidance to assist in prioritizing and implementing their HAI prevention efforts. They are the product of a highly collaborative effort led by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), the American Hospital Association (AHA), the Association for Professionals in Infection Control and Epidemiology (APIC), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise, including the Centers for Disease Control and Prevention (CDC), the Institute for Healthcare Improvement (IHI), the Pediatric Infectious Diseases Society (PIDS), the Society for Critical Care Medicine (SCCM), the Society for Hospital Medicine (SHM), and the Surgical Infection Society (SIS). PMID- 25026612 TI - Rising rates of carbapenem-resistant enterobacteriaceae in community hospitals: a mixed-methods review of epidemiology and microbiology practices in a network of community hospitals in the southeastern United States. AB - OBJECTIVE: Describe the epidemiology of carbapenem-resistant Enterobacteriaceae (CRE) and examine the effect of lower carbapenem breakpoints on CRE detection. DESIGN: Retrospective cohort. SETTING: Inpatient care at community hospitals. PATIENTS: All patients with CRE-positive cultures were included. METHODS: CRE isolated from 25 community hospitals were prospectively entered into a centralized database from January 2008 through December 2012. Microbiology laboratory practices were assessed using questionnaires. RESULTS: A total of 305 CRE isolates were detected at 16 hospitals (64%). Patients with CRE had symptomatic infection in 180 cases (59%) and asymptomatic colonization in the remainder (125 cases; 41%). Klebsiella pneumoniae (277 isolates; 91%) was the most prevalent species. The majority of cases were healthcare associated (288 cases; 94%). The rate of CRE detection increased more than fivefold from 2008 (0.26 cases per 100,000 patient-days) to 2012 (1.4 cases per 100,000 patient days; incidence rate ratio (IRR), 5.3 [95% confidence interval (CI), 1.22-22.7]; P = .01). Only 5 hospitals (20%) had adopted the 2010 Clinical and Laboratory Standards Institute (CLSI) carbapenem breakpoints. The 5 hospitals that adopted the lower carbapenem breakpoints were more likely to detect CRE after implementation of breakpoints than before (4.1 vs 0.5 cases per 100,000 patient days; P < .001; IRR, 8.1 [95% CI, 2.7-24.6]). Hospitals that implemented the lower carbapenem breakpoints were more likely to detect CRE than were hospitals that did not (3.3 vs 1.1 cases per 100,000 patient-days; P = .01). CONCLUSIONS: The rate of CRE detection increased fivefold in community hospitals in the southeastern United States from 2008 to 2012. Despite this, our estimates are likely underestimates of the true rate of CRE detection, given the low adoption of the carbapenem breakpoints recommended in the 2010 CLSI guidelines. PMID- 25026613 TI - Much to do about carbapenem-resistant Enterobacteriaceae: why supplementing surveillance may be the key to stopping spread. PMID- 25026614 TI - The use of rapid indicators for the detection of organic residues on clinically used gastrointestinal endoscopes with and without visually apparent debris. AB - BACKGROUND: Outbreaks of multidrug-resistant organisms have been linked to endoscope reprocessing lapses. Meticulous manual cleaning before high-level disinfection (HLD) is essential in reducing residual contamination that can interfere with HLD. Current reprocessing guidelines state that visual inspection is sufficient to confirm adequate cleaning. OBJECTIVE: Our aim was to evaluate contamination of clinically used endoscopes, using visual inspection and rapid indicator tests before and after manual cleaning. A second objective was to determine which rapid indicator instruments and methods could be used for quality improvement initiatives in endoscope reprocessing. DESIGN: Clinical use study of endoscope reprocessing effectiveness. SETTING: Tertiary care teaching hospital with an inpatient endoscopy center. METHODS: Researchers sampled endoscopes used for gastrointestinal procedures before and after manual cleaning. The external surfaces and 1 channel of each endoscope were visually inspected and tested with rapid indicators to measure protein, blood, and adenosine triphosphate (ATP) contamination levels. RESULTS: Multiple components were sampled during 37 encounters with 12 unique endoscopes. All bedside-cleaned endoscopes had high levels of ATP and detectable blood or protein, whether or not any residue was visible. Although there was no visible residue on any endoscopes after manual cleaning, 82% had at least 1 positive rapid indicator test. CONCLUSIONS: Relying solely on visual inspection of endoscopes prior to HLD is insufficient to ensure reprocessing effectiveness. For quality assurance initiatives, tests of different endoscope components using more than 1 indicator may be necessary. Additional research is needed to validate specific monitoring protocols. PMID- 25026615 TI - Monitoring of endoscope reprocessing: accumulating data but best practices remain undefined. PMID- 25026616 TI - Strategies to enhance adoption of ventilator-associated pneumonia prevention interventions: a systematic literature review. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is among the most lethal of all healthcare-associated infections. Guidelines summarize interventions to prevent VAP, but translating recommendations into practice is an art unto itself. OBJECTIVE: Summarize strategies to enhance adoption of VAP prevention interventions. METHODS: We conducted a systematic literature review of articles in the MEDLINE database published between 2002 and 2012. We selected articles on the basis of specific inclusion criteria. We used structured forms to abstract implementation strategies and inserted them into the "engage, educate, execute, and evaluate" framework. RESULTS: Twenty-seven articles met our inclusion criteria. Engagement strategies included multidisciplinary teamwork, involvement of local champions, and networking among peers. Educational strategies included training sessions and developing succinct summaries of the evidence. Execution strategies included standardization of care processes and building redundancies into routine care. Evaluation strategies included measuring performance and providing feedback to staff. CONCLUSION: We summarized and organized practical implementation strategies in a framework to enhance adoption of recommended evidence-based practices. We believe this work fills an important void in most clinical practice guidelines, and broad use of these strategies may expedite VAP reduction efforts. PMID- 25026617 TI - Surgical site infection risk factors identified for patients undergoing colon procedures, New York State 2009-2010. AB - BACKGROUND: Since 2007, New York State (NYS) hospitals have been required to report surgical site infections (SSIs) following colon procedures to the NYS Department of Health, using the National Healthcare Safety Network (NHSN). The purpose of this study was to identify risk factors for the development of SSIs in patients undergoing colon procedures. METHODS: NYS has been conducting validation studies at hospitals to assess the accuracy of the surveillance data reported by the participating hospitals. A sample of patients undergoing colon procedures in NYS hospitals were included in hospital-acquired infection program validation studies in 2009 and 2010. Medical chart reviews and on-site visits were performed to verify patient information reported and to evaluate additional risk factors for SSI. Bivariable and multivariable logistic regressions were performed. RESULTS: A total of 2,656 colon procedures were included in this analysis, including 698 SSI cases. Multivariable analysis indicated that SSI following colon procedure was associated with body mass index greater than 30 (odds ratio [OR], 1.48 [95% confidence interval (CI), 1.21-1.80]), male sex (OR, 1.34 [95% CI, 1.10-1.64]), American Society of Anesthesiologists physical classification score greater than 3 (OR, 1.33 [95% CI, 1.08-1.64]), procedure duration, transfusion (OR, 1.32 [95% CI, 1.05-1.66]), left-side colon surgical procedures, other gastroenterologic procedures, irrigation, hospital bed size greater than 500, and medical school affiliation. CONCLUSIONS: Male sex, obesity, transfusion, type of procedure, and prolonged duration were significant factors associated with overall infection risk after adjusting other factors. Additional factors not collected in the NHSN slightly improved prediction of SSIs. PMID- 25026618 TI - An economic model: value of antimicrobial-coated sutures to society, hospitals, and third-party payers in preventing abdominal surgical site infections. AB - BACKGROUND: While the persistence of high surgical site infection (SSI) rates has prompted the advent of more expensive sutures that are coated with antimicrobial agents to prevent SSIs, the economic value of such sutures has yet to be determined. METHODS: Using TreeAge Pro, we developed a decision analytic model to determine the cost-effectiveness of using antimicrobial sutures in abdominal incisions from the hospital, third-party payer, and societal perspectives. Sensitivity analyses systematically varied the risk of developing an SSI (range, 5%-20%), the cost of triclosan-coated sutures (range, $5-$25/inch), and triclosan coated suture efficacy in preventing infection (range, 5%-50%) to highlight the range of costs associated with using such sutures. RESULTS: Triclosan-coated sutures saved $4,109-$13,975 (hospital perspective), $4,133-$14,297 (third-party payer perspective), and $40,127-$53,244 (societal perspective) per SSI prevented, when a surgery had a 15% SSI risk, depending on their efficacy. If the SSI risk was no more than 5% and the efficacy in preventing SSIs was no more than 10%, triclosan-coated sutures resulted in extra expenditure for hospitals and third party payers (resulting in extra costs of $1,626 and $1,071 per SSI prevented for hospitals and third-party payers, respectively; SSI risk, 5%; efficacy, 10%). CONCLUSIONS: Our results suggest that switching to triclosan-coated sutures from the uncoated sutures can both prevent SSIs and save substantial costs for hospitals, third-party payers, and society, as long as efficacy in preventing SSIs is at least 10% and SSI risk is at least 10%. PMID- 25026619 TI - Cost analysis of strategies to reduce blood culture contamination in the emergency department: sterile collection kits and phlebotomy teams. AB - OBJECTIVE: Blood culture collection practices that reduce contamination, such as sterile blood culture collection kits and phlebotomy teams, increase up-front costs for collecting cultures but may lead to net savings by eliminating downstream costs associated with contamination. The study objective was to compare overall hospital costs associated with 3 collection strategies: usual care, sterile kits, and phlebotomy teams. DESIGN: Cost analysis. SETTING: This analysis was conducted from the perspective of a hospital leadership team selecting a blood culture collection strategy for an adult emergency department (ED) with 8,000 cultures drawn annually. METHODS: Total hospital costs associated with 3 strategies were compared: (1) usual care, with nurses collecting cultures without a standardized protocol; (2) sterile kits, with nurses using a dedicated sterile collection kit; and (3) phlebotomy teams, with cultures collected by laboratory-based phlebotomists. In the base case, contamination rates associated with usual care, sterile kits, and phlebotomy teams were assumed to be 4.34%, 1.68%, and 1.10%, respectively. Total hospital costs included costs of collecting cultures and hospitalization costs according to culture results (negative, true positive, and contaminated). RESULTS: Compared with usual care, annual net savings using the sterile kit and phlebotomy team strategies were $483,219 and $288,980, respectively. Both strategies remained less costly than usual care across a broad range of sensitivity analyses. CONCLUSIONS: EDs with high blood culture contamination rates should strongly consider evidence-based strategies to reduce contamination. In addition to improving quality, implementing a sterile collection kit or phlebotomy team strategy is likely to result in net cost savings. PMID- 25026620 TI - Changes in healthcare-associated Staphylococcus aureus bloodstream infections after the introduction of a national hand hygiene initiative. AB - BACKGROUND: Interventions that prevent healthcare-associated infection should lead to fewer deaths and shorter hospital stays. Cleaning hands (with soap or alcohol) is an effective way to prevent the transmission of organisms, but rates of compliance with hand hygiene are sometimes disappointingly low. The National Hand Hygiene Initiative in Australia aimed to improve hand hygiene compliance among healthcare workers, with the goal of reducing rates of healthcare associated infection. METHODS: We examined whether the introduction of the National Hand Hygiene Initiative was associated with a change in infection rates. Monthly infection rates for healthcare-associated Staphylococcus aureus bloodstream infections were examined in 38 Australian hospitals across 6 states. We used Poisson regression and examined 12 possible patterns of change, with the best fitting pattern chosen using the Akaike information criterion. Monthly bed days were included to control for increased hospital use over time. RESULTS: The National Hand Hygiene Initiative was associated with a reduction in infection rates in 4 of the 6 states studied. Two states showed an immediate reduction in rates of 17% and 28%, 2 states showed a linear decrease in rates of 8% and 11% per year, and 2 showed no change in infection rates. CONCLUSIONS: The intervention was associated with reduced infection rates in most states. The failure in 2 states may have been because those states already had effective initiatives before the national initiative's introduction or because infection rates were already low and could not be further reduced. PMID- 25026621 TI - Clostridium difficile infections in Veterans Health Administration acute care facilities. AB - OBJECTIVE: An initiative was implemented in July 2012 to decrease Clostridium difficile infections (CDIs) in Veterans Affairs (VA) acute care medical centers nationwide. This is a report of national baseline CDI data collected from the 21 months before implementation of the initiative. METHODS: Personnel at each of 132 data-reporting sites entered monthly retrospective CDI case data from October 2010 through June 2012 into a central database using case definitions similar to those of the National Healthcare Safety Network multidrug-resistant organism/CDI module. RESULTS: There were 958,387 hospital admissions, 5,286,841 patient-days, and 9,642 CDI cases reported during the 21-month analysis period. The pooled CDI admission prevalence rate (including recurrent cases) was 0.66 cases per 100 admissions. The nonduplicate/nonrecurrent community-onset not-healthcare-facility associated (CO-notHCFA) case rate was 0.35 cases per 100 admissions, and the community-onset healthcare facility-associated (CO-HCFA) case rate was 0.14 cases per 100 admissions. Hospital-onset healthcare facility-associated (HO-HCFA), clinically confirmed HO-HCFA (CC-HO-HCFA), and CO-HCFA rates were 9.32, 8.40, and 2.56 cases per 10,000 patient-days, respectively. There were significant decreases in admission prevalence (P = .0006, Poisson regression), HO-HCFA (P = .003), and CC-HO-HCFA (P = .004) rates after adjusting for type of diagnostic test. CO-HCFA and CO-notHCFA rates per 100 admissions also trended downward (P = .07 and .10, respectively). CONCLUSIONS: VA acute care medical facility CDI rates were higher than those reported in other healthcare systems, but unlike rates in other venues, they were decreasing or trending downward. Despite these downward trends, there is still a substantial burden of CDI in the system supporting the need for efforts to decrease rates further. PMID- 25026622 TI - Effectiveness of screening hospital admissions to detect asymptomatic carriers of Clostridium difficile: a modeling evaluation. AB - OBJECTIVE: Both asymptomatic and symptomatic Clostridium difficile carriers contribute to new colonizations and infections within a hospital, but current control strategies focus only on preventing transmission from symptomatic carriers. Our objective was to evaluate the potential effectiveness of methods targeting asymptomatic carriers to control C. difficile colonization and infection (CDI) rates in a hospital ward: screening patients at admission to detect asymptomatic C. difficile carriers and placing positive patients into contact precautions. METHODS: We developed an agent-based transmission model for C. difficile that incorporates screening and contact precautions for asymptomatic carriers in a hospital ward. We simulated scenarios that vary according to screening test characteristics, colonization prevalence, and type of strain present at admission. RESULTS: In our baseline scenario, on average, 42% of CDI cases were community-onset cases. Within the hospital-onset (HO) cases, approximately half were patients admitted as asymptomatic carriers who became symptomatic in the ward. On average, testing for asymptomatic carriers reduced the number of new colonizations and HO-CDI cases by 40%-50% and 10%-25%, respectively, compared with the baseline scenario. Test sensitivity, turnaround time, colonization prevalence at admission, and strain type had significant effects on testing efficacy. CONCLUSIONS: Testing for asymptomatic carriers at admission may reduce both the number of new colonizations and HO-CDI cases. Additional reductions could be achieved by preventing disease in patients who are admitted as asymptomatic carriers and developed CDI during the hospital stay. PMID- 25026623 TI - Infectious risk moments: a novel, human factors-informed approach to infection prevention. AB - We pilot tested a novel human factors-informed concept to identify infectious risk moments (IRMs) that occur with high frequency during routine intensive care. Following 30 observation-hours, 28 potential IRMs related to hand hygiene, gloves, and objects were expert rated. A comprehensive IRM inventory may provide valuable taxonomy for research, training, and intervention. PMID- 25026624 TI - Frequency of interactions and hand disinfections among anesthesiologists while providing anesthesia care in the operating room: induction versus maintenance. AB - We evaluated the behaviors of anesthesiologists during induction and maintenance of anesthesia. Contacts with surfaces occurred a mean (+/-standard error) of 154.8 +/- 7.7 and 60 +/- 3.1 times per hour during induction and maintenance, respectively (P < .0001). Hand hygiene events were 1.8 +/- 0.27 per hour during induction versus 1.19 +/- 0.27 during maintenance (P = .018). PMID- 25026625 TI - Effectiveness of an antimicrobial polymer to decrease contamination of environmental surfaces in the clinical setting. AB - We performed a real-world, controlled intervention to investigate use of an antimicrobial surface polymer, MSDS Poly, on environmental contamination. Pathogenic bacteria were identified in 18 (90%) of 20 observations in treated rooms and 19 (83%) of 23 observations in untreated rooms (P = .67). MSDS Poly had no significant effect on environmental contamination. PMID- 25026626 TI - Pseudo-outbreak of Phaeoacremonium parasiticum from a hospital ice dispenser. AB - In 31 patients, Phaeoacremonium parasiticum was recovered from bronchoscopy specimens (biopsies and aspirates). The pseudo-outbreak was caused by contaminated ice used to control hemorrhage during bronchoscopy and was associated with deficiencies in equipment cleaning. The bronchoscopy technique was modified, the ice dispenser was disinfected, bronchoscope reprocessing was improved, and there were no recurrences. PMID- 25026627 TI - Reduction in central line-associated bloodstream infections in patients with burns. PMID- 25026628 TI - Microbial contamination on used surgical instruments. PMID- 25026629 TI - Room decontamination using an ultraviolet-C device with short ultraviolet exposure time. PMID- 25026630 TI - Brucella abortus exposure during an orthopedic surgical procedure in New Mexico, 2010. PMID- 25026631 TI - Toward a standardized definition of healthcare-associated influenza? PMID- 25026632 TI - Reply to Vanhems et al. PMID- 25026633 TI - Colistin-resistant Klebsiella pneumoniae: report of a cluster of 24 cases from a new oncology center in eastern India. PMID- 25026634 TI - Fatal outbreak of polyclonal candidemia in a neonatal intensive care unit. PMID- 25026635 TI - Oral wounds and hepatitis B virus transmission. PMID- 25026637 TI - The impacts of neoadjuvant chemotherapy and of debulking surgery on survival from advanced ovarian cancer. AB - OBJECTIVES: Women with advanced ovarian cancer are treated with chemotherapy either before (neoadjuvant) or after surgery (primary debulking). The goal is to leave no residual disease post-surgery; for women treated with primary debulking surgery this has been associated with an improvement in survival. It has not been shown that the survival advantage conferred by having no residual disease post surgery is present for women who receive neoadjuvant chemotherapy. METHODS: We reviewed the records of 326 women with stage IIIc or IV serous ovarian cancer. We determined if they received neoadjuvant chemotherapy or primary debulking surgery and we measured the extent of residual disease post-surgery. We estimated seven year survival rates for women after various treatments. RESULTS: Women who had neoadjuvant chemotherapy were more likely to have no residual disease than women who had primary debulking surgery (50.1% versus 41.5%; p=0.03) but they experienced inferior seven-year survival (8.6% versus 41%; p<0.0001). Among women who had primary debulking surgery, those with no residual disease had much better seven-year survival than women who had any residual disease (73.6% versus 21.0%; p<0.0001). Women who had no residual disease after debulking surgery and who received intraperitoneal chemotherapy had a seven-year survival of 90%. CONCLUSIONS: Neoadjuvant chemotherapy should be reserved for ovarian cancer patients who are not candidates for primary debulking surgery. Among women with no residual disease after primary debulking surgery, intraperitoneal chemotherapy extends survival. PMID- 25026638 TI - Diagnostic accuracy of colposcopy in relation to human papillomavirus genotypes and multiple infection. AB - OBJECTIVE: The aim of this study is to evaluate the diagnostic accuracy of colposcopy for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in relation to the detection of human papillomavirus (HPV) type 16 and multiple HPV infection. METHODS: A cohort study of 2526 subjects attending a colposcopic service because of cytological abnormalities. HPV genotypes were identified using the INNO-LIPA genotyping system. RESULTS: The final colposcopic/pathological diagnoses were as follows: 1282 (50.8%) negative, 709 (28.1%) CIN1, 169 (6.7%) CIN2, 318 (12.6%) CIN3 and 48 (1.9%) invasive cervical cancer, respectively. Among women with ASCUS/LSIL, assuming any colposcopic abnormality as a cut-off, there were no significant differences in the sensitivities (83.8%, 95% CI=76-89.6 as compared to 84.1%, 95% CI=73.2-91.1, p=0.9) and ROC curves (0.61, 95% CI=0.58 0.65 as compared to 0.59, 95% CI=0.54-0.64, p=0.5) in the detection of CIN3+ lesions between subjects with single and multiple high-risk infection, and between subjects infected by HPV16 (83.1%, 95% CI=73.7-89.7, ROC=0.59, 95% CI=0.54-063) or other high-risk HPVs (84.7%, 95% CI=75.6-90.8, ROC=0.62, 95% CI=0.58-0.66, p=0.8 and p=0.6 compared to HPV16). After correction for confounders, the odds ratios of CIN3+ associated with any abnormal colposcopic findings were 2.47 (95%CI=1.44-4.23, p=0.001) among HPV16 positive, 3.34 (95% CI=2.16-5.42, p<0.001) among other high-risk HPVs and 1.3 (95% CI=0.72-2.48, p=0.36) among subjects with negative/low-risk HPVs. CONCLUSION: In routine clinical practice, multiple infection or HPV16 positivity did not affect colposcopic accuracy in the diagnosis of CIN3+ lesions. The sensitivity of colposcopy was poor among subjects who were uninfected or infected by low-risk HPV genotypes. PMID- 25026639 TI - A cautious view of putative precursors of serous carcinomas in the fallopian tubes of BRCA mutation carriers. AB - OBJECTIVE: To compare the frequency and distribution of candidate precursors of serous carcinoma in the fallopian tubes of BRCA mutation carriers to BRCA non mutation carriers (controls) at risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: 78 BRCA carriers (52 BRCA1, 26 BRCA2) and 23 controls underwent RRSO. Fallopian tubes were serially cross-sectioned, and adnexa were entirely submitted and examined by two gynecologic pathologists blinded to BRCA mutation status. The presence and location of serous tubal intraepithelial carcinoma (STIC), p53 overexpression (>= 6 consecutively stained nuclei), Ki67 overexpression, atypia/low grade dysplasia and epithelial hyperplasia were compared between BRCA carriers and controls. Patient age was dichotomized: <= 50 and >50 years. RESULTS: 9 (12%) BRCA carriers had occult carcinoma: 8 STIC and 1 stage IC tubal carcinoma with STIC. No occult carcinomas or STIC was seen in controls. STIC involved the distal tube in all cases and was multifocal in three cases. STIC was more common in women >50 (p=0.06). P53 overexpression was common in BRCA carriers (30%) and controls (43%) (p=0.5) and did not correlate with age. Only 5/9 (55%) of STIC exhibited p53 overexpression. 2 patients had Ki67 overexpression: both BRCA1 carriers with STIC. No difference in the frequency of atypia/low grade dysplasia or hyperplasia was observed between BRCA carriers and controls. CONCLUSIONS: STIC is the dominant precursor of serous fallopian tube carcinoma in BRCA carriers. There is insufficient evidence to support p53 overexpression alone as a putative precursor. Atypia/low grade dysplasia and epithelial hyperplasia are not pre-neoplastic lesions of serous fallopian tube carcinoma. PMID- 25026640 TI - Grafting hyaluronic acid onto gold surface to achieve low protein fouling in surface plasmon resonance biosensors. AB - Antifouling surfaces capable of reducing nonspecific protein adsorption from natural complex media are highly desirable in surface plasmon resonance (SPR) biosensors. A new protein-resistant surface made through the chemical grafting of easily available hyaluronic acid (HA) onto gold (Au) substrate demonstrates excellent antifouling performance against protein adsorption. AFM images showed the uniform HA layer with a thickness of ~10.5 nm on the Au surface. The water contact angles of Au surfaces decreased from 103 degrees to 12 degrees with the covalent attachment of a carboxylated HA matrix, indicating its high hydrophilicity mainly resulted from carboxyl and amide groups in the HA chains. Using SPR spectroscopy to investigate nonspecific adsorption from single protein solutions (bovine serum albumin (BSA), lysozyme) and complex media (soybean milk, cow milk, orange juice) to an HA matrix, it was found that ultralow or low protein adsorptions of 0.6-16.1 ng/cm(2) (e.g., soybean milk: 0.6 ng/cm(2)) were achieved on HA-Au surfaces. Moreover, anti-BSA was chosen as a model recognition molecule to characterize the immobilization capacity and the antifouling performance of anti-BSA/HA surfaces. The results showed that anti-BSA/HA sensor surfaces have a high anti-BSA loading of 780 ng/cm(2), together with achieving the ultralow (<3 ng/cm(2) for lysozyme and soybean milk) or low (<17 ng/cm(2) for cow milk and 10% blood serum) protein adsorptions. Additionally, the sensor chips also exhibited a high sensitivity to BSA over a wide range of concentrations from 15 to 700 nM. Our results demonstrate a promising antifouling surface using extremely hydrophilic HA as matrix to resist nonspecific adsorption from complex media in SPR biosensors. PMID- 25026641 TI - Reply: To PMID 23972109. PMID- 25026642 TI - Effects of methylphenidate on acute Math performance in children with ADHD. PMID- 25026643 TI - In memory of Patrik Rydberg. PMID- 25026644 TI - Understanding heliothine (Lepidoptera: Heliothinae) pests: what is a host plant? AB - Heliothine moths (Lepidoptera: Heliothinae) include some of the world's most devastating pest species. Whereas the majority of nonpest heliothinae specialize on a single plant family, genus, or species, pest species are highly polyphagous, with populations often escalating in size as they move from one crop species to another. Here, we examine the current literature on heliothine host-selection behavior with the aim of providing a knowledge base for research scientists and pest managers. We review the host relations of pest heliothines, with a particular focus on Helicoverpa armigera (Hubner), the most economically damaging of all heliothine species. We then consider the important question of what constitutes a host plant in these moths, and some of the problems that arise when trying to determine host plant status from empirical studies on host use. The top six host plant families in the two main Australian pest species (H. armigera and Helicoverpa punctigera Wallengren) are the same and the top three (Asteraceae, Fabaceae, and Malvaceae) are ranked the same (in terms of the number of host species on which eggs or larvae have been identified), suggesting that these species may use similar cues to identify their hosts. In contrast, for the two key pest heliothines in the Americas, the Fabaceae contains approximately 1/3 of hosts for both. For Helicoverpa zea (Boddie), the remaining hosts are more evenly distributed, with Solanaceae next, followed by Poaceae, Asteraceae, Malvaceae, and Rosaceae. For Heliothis virescens (F.), the next highest five families are Malvaceae, Asteraceae, Solanaceae, Convolvulaceae, and Scrophulariaceae. Again there is considerable overlap in host use at generic and even species level. H. armigera is the most widely distributed and recorded from 68 plant families worldwide, but only 14 families are recorded as a containing a host in all geographic areas. A few crop hosts are used throughout the range as expected, but in some cases there are anomalies, perhaps because host plant relation studies are not comparable. Studies on the attraction of heliothines to plant odors are examined in the context of our current understanding of insect olfaction, with the aim of better understanding the connection between odor perception and host choice. Finally, we discuss research into sustainable management of pest heliothines using knowledge of heliothine behavior and ecology. A coordinated international research effort is needed to advance our knowledge on host relations in widely distributed polyphagous species instead of the localized, piecemeal approaches to understanding these insects that has been the norm to date. PMID- 25026645 TI - Effects of green manure cover crops on Spodoptera litura (Lepidoptera: Noctuidae) populations. AB - Spodoptera litura (F.) is an important pest of numerous agro-economic crops, including green manure cover crops. In Taiwan, sesbania (Sesbanin roxburghii Merr.), sunn hemp (Crotalaria juncea L.), and rapeseed (Brassicae campestris L. variety chinensis) are the most popular green manure crops; sesbania and sunn hemp are commonly planted in warm seasons, whereas rapeseed is grown in the winter. In this study, life-table data for S. litura reared on these three green manures were collected to evaluate their roles as refuges of this pest. The net reproductive rate, intrinsic rate of increase, and finite rate of increase of S. litura were the highest when reared on sesbania (1428.1 offspring, 0.2327 d(-1), 1.2621 d(-1)), followed by sunn hemp (778.4 offspring, 0.2070 d(-1), 1.2300 d( 1)) and rapeseed (737.6 offspring, 0.2040 d(-1), 1.2263 d(-1)). The high growth rates on these green manure crops show that they can serve as potential breeding sites for S. litura. Population projection demonstrated the rapid growth of S. litura on sesbania, sunn hemp, and rapeseed as well. Because most growers have traditionally ignored pest management in green manure fields, the mass emergence of S. litura in these fields may cause unexpected infestations in nearby vegetable, corn, and peanut crops. This study shows that the use of green manures as sources of nutrients should be critically reassessed and an area-wide pest management program should be instituted by taking the population of S. litura in green manure fields into consideration. PMID- 25026646 TI - Extreme cold temperature to kill blueberry maggot (Diptera: Tephritidae) in reusable containers. AB - Pupae of the blueberry maggot, Rhagoletis mendax Curran (Diptera: Tephritidae), were subjected to -20 degrees C for 2, 4, 7, 10, and 15 d (control = 0 d at 4 degrees C) in fall 2011 and 2012 and were allowed to overwinter for at least 181 d at 4 degrees C. Mean adult emergence in the control was 64% in 2012 and 39% in 2013. No adults emerged in May 2012 from 500 pupae treated for > 2 d at -20 degrees C in fall 2011. Two adults emerged in May 2013 from 100 pupae treated for 2 d at -20 degrees C in fall 2012. No adults emerged in May 2013 from 400 pupae subjected to -20 degrees C for durations of 4, 7, 10, and 15 d. No adults emerged from larvae concealed in berries subjected to -20 degrees C for > 2 d. Exposure of larvae and pupae to cold temperatures (i.e., -20 degrees C) for > 2 d can be a valuable nonpesticidal method for killing R. mendax larvae and pupae associated with reusable containers. PMID- 25026647 TI - An EPG study of the probing behavior of adult Bemisia tabaci biotype Q (Hemiptera: Aleyrodidae) following exposure to cyantraniliprole. AB - Cyantraniliprole is a novel insecticide for control of multiple chewing and sucking insect pest species including the sweetpotato whitefly Bemisia tabaci (Gennadius), which is one of the most important polyphagous pests in tropical, subtropical, and Mediterranean regions. This study aims to evaluate the effects of cyantraniliprole on the probing behavior of B. tabaci on tomato. Electrical penetration graph data indicated that on plants treated with cyantraniliprole (foliar application), adult whiteflies of the genetic variant Q2 were not able to reach the phloem and consequently did not perform the activities represented by E1 and E2 waveforms, i.e., phloem salivation (during which inoculation of geminiviruses occurs) and phloem sap ingestion (during which geminiviruses are acquired by the whiteflies), respectively. The complete failure of B. tabaci biotype Q adults to feed from the phloem of tomato plants treated with cyantraniliprole could be explained by rapid cessation of ingestion because of the mode of action of this insecticide. Overall, these findings indicated that cyantraniliprole might represent a useful new tool for producers to protect tomato plants from damage by B. tabaci. PMID- 25026648 TI - Three-way interactions between the tomato plant, tomato yellow leaf curl virus, and Bemisia tabaci (Hemiptera: Aleyrodidae) facilitate virus spread. AB - Plant defense responses can greatly affect plant viruses and their herbivore vectors. The current article reports on plant defense responses involving jasmonic acid (JA), salicylic acid (SA), and proteinase inhibitor (PI) in the three-way interaction between tomato plants, tomato yellow leaf curl virus, and the whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). The results showed that feeding by viruliferous B. tabaci increases the longevity and fecundity of nonviruliferous B. tabaci that subsequently feed on the same plant. Feeding by nonviruliferous B. tabaci alone suppressed plant defense responses involving JA and PI but induced responses involving SA. Feeding by viruliferous B. tabaci increased the suppression of plant defenses involving JA and PI but did not increase responses involving SA. These results indicate that the interactive effects of tomato yellow leaf curl virus and B. tabaci on plants increase vector fitness and virus transmission by reducing plant defense. PMID- 25026649 TI - Effects of Bt cotton on Thrips tabaci (Thysanoptera: Thripidae) and its predator, Orius insidiosus (Hemiptera: Anthocoridae). AB - Laboratory studies were conducted to investigate tritrophic transfer of insecticidal Cry proteins from transgenic cotton to an herbivore and its predator, and to examine effects of these proteins on the predator's development, survival, and reproduction. Cry1Ac and Cry2Ab proteins from the bacterium Bacillus thuringiensis (Bt) produced in Bollgard-II (BG-II, Event 15985) cotton plants were acquired by Thrips tabaci Lindeman (Thysanoptera: Thripidae), an important sucking pest of cotton, and its generalist predator, Orius insidiosus (Say) (Hemiptera: Anthocoridae). The average protein titers in BG-II cotton leaves were 1,256 and 43,637 ng Cry1Ac and Cry2Ab per gram fresh leaf tissue, respectively. At the second trophic level, larvae of T. tabaci reared on BG-II cotton for 48-96 h had 22.1 and 2.1% of the Cry1Ac and Cry2Ab levels expressed in leaves, respectively. At the third trophic level, O. insidiosus that fed on T. tabaci larvae had 4.4 and 0.3% of the Cry1Ac and Cry2Ab protein levels, respectively, expressed in BG-II plants. O. insidiosus survivorship, time of nymphal development, adult weight, preoviposition and postoviposition periods, fecundity, and adult longevity were not adversely affected owing to consumption of T. tabaci larvae that had fed on BG-II cotton compared with non-Bt cotton. Our results indicate that O. insidiosus, a common predator of T. tabaci, is not harmed by BG-II cotton when exposed to Bt proteins through its prey. Thus, O. insidiosus can continue to provide important biological control services in the cotton ecosystem when BG-II cotton is used to control primary lepidopteran pests. PMID- 25026650 TI - Interactions between the entomopathogenic fungi Beauveria bassiana (Ascomycota: Hypocreales) and the aphid parasitoid Diaeretiella rapae (Hymenoptera: Braconidae) on Myzus persicae (Hemiptera: Aphididae). AB - The interactions between the entomopathogenic fungus Beauveria bassiana (Balsamo Crivelli) Vuillemin (Ascomycota: Hypocreales) and the aphid parasitoid Diaeretiella rapae McIntoch (Hymenoptera: Braconidae) were evaluated under laboratory conditions. Nymphs of Myzus persicae Sulzer (Hemiptera: Aphididae) were first exposed to parasitoid females for 24 h and then 0, 24, and 48 h afterwards sprayed with a solution of B. bassiana. Likewise, aphids were also sprayed with B. bassiana and then exposed to parasitoids at 0, 24, and 48 h afterwards. Parasitism rate varied from 13 to 66.5%, and were significantly lower in treatments where the two agents were exposed within a 0-24 h time interval compared with the control (without B. bassiana). Parasitoid emergence was negatively affected in treatments with B. bassiana spraying and subsequent exposure to D. rapae. Decreases in longevity of adult females of the D. rapae F1 generation were observed in treatments with B. bassiana spraying. The application of these two biological control agents can be used in combination on the control of M. persicae, wherein this use requires effective time management to avoid antagonistic interactions. PMID- 25026651 TI - Biology, life history, and laboratory rearing of Spathius galinae (Hymenoptera: Braconidae), a larval parasitoid of the invasive emerald ash borer (Coleoptera: Buprestidae). AB - Spathius galinae Belokobylskij & Strazanac is a recently described parasitoid of the emerald ash borer, Agrilus planipennis Fairmaire, in the Russian Far East, and is currently being considered for biocontrol introduction in the United States. Using A. planipennis larvae reared with freshly cut ash (Fraxinus spp.) sticks, we investigated the biology, life cycle, and rearing of S. galinae in the laboratory under normal rearing conditions (25 +/- 1 degrees C, 65 +/- 10% relative humidity, and a photoperiod of 16:8 [L:D] h). Our study showed that S. galinae took approximately 1 mo (29 d) to complete a single generation (from egg to adult) under the laboratory rearing conditions. After eclosion from eggs, larvae of S. galinae molted four times to reach the fifth instar, which then spun cocoons for pupation and development to adults. Adult female wasps had a median survival time of 7 wk with fecundity peaking 3 wk after emergence when reared in groups (of five females and five males) and 2 wk in single pairs. Throughout the life span, a single female S. galinae produced a mean (+/- SE) of 31 (+/- 3.0) progeny when reared in groups, and a mean (+/- SE) of 47 (+/- 5.3) progeny when reared in single pairs. Results from our study also showed that S. galinae could be effectively reared with A. planipennis larvae reared in both green (Fraxinus pennsylvanica Marshall) and tropical [Fraxinus uhdei (Wenzig) Lingelsh] ash sticks. However, the abortion (unemergence) rate of S. galinae progeny was much higher (20%) when reared with host larvae in green ash sticks than that (2.1%) in tropical ash sticks. PMID- 25026652 TI - Predation of the newly invasive pest Megacopta cribraria (Hemiptera: Plataspidae) in soybean habitats adjacent to cotton by a complex of predators. AB - The kudzu bug, Megacopta cribraria (F.) (Hemiptera: Plataspidae),is a newly invasive exotic insect found primarily on kudzu, but also on soybean, in the southeastern United States. We used molecular gut-content analysis to document predation on this pest by insects and spiders in soybean, and to detect remains of crop-specific alternative prey in predators' guts as markers of predator migration between soybean and adjacent cotton. M. cribraria was found exclusively on soybean. Eight native generalist predators over both crops screened positive by specific PCR for DNA of the pest: Geocoris punctipes (Say), Geocoris uliginosus (Say), Orius insidiosus (Say), Podisus maculicentris (Say), Hippodamia convergens Guerin-Meneville, Zelus renardii (Kolenati), Oxyopes salticus Hentz, and Peucetia viridans (Hentz); a ninth predator, the exotic Solenopsis invicta Buren, also screened positive for M. cribraria DNA. P. viridans was the only arthropod that tested positive for DNA of this invasive pest in only one crop, cotton. Two plant-feeding pentatomid species, Piezodorus guildinii (Westwood) and Thyanta custator (F.), were found exclusively on soybean, and another, Euschistus tristigmus (Say), was specific to cotton in the context of this study. Detection of predation on a combination of M. cribraria and P. guildinii and T. custator in cotton and M. cribraria and E. tristigmus in soybean demonstrated that these predators dispersed between crops. These results strongly support the use of soybean habitats adjacent to cotton as part of a conservation biological control strategy against M. cribraria. This is the first report documenting predation on this exotic pest in the field via molecular gut-content analysis. PMID- 25026653 TI - Evaluation for potential Trichogramma (Hymenoptera: Trichogrammatidae) strains for control of the striped stem borer (Lepidoptera: Crambidae) in the Greater Mekong Subregion. AB - Trichogramma species and strains differ significantly in host specificity and performance. Nine Trichogramma strains, six of them collected from paddy fields in the Greater Mekong Subregion, were evaluated for performance on eggs of the striped stem borer, Chilo suppressalis (Walker), in both laboratory and field tests to determine potential Trichogramma strains that can be used in an inundative release in an integrated pest management program. In the laboratory glass vial tests, all strains showed higher parasitism rates on 0-24-h eggs than on the two older age groups (24-48 and 48-72 h). Wasp emergence rate was also higher from parasitized 0-24-h striped stem borer eggs, while Trichogramma immature duration was significantly prolonged on 0-24-h striped stem borer eggs. Parasitism rates differed among Trichogramma strains, with Trichogramma chilonis Ishii CJ strain showing significantly higher parasitism rate than any other strains. In the field tests, parasitism of sentinel striped stem borer eggs by Trichogramma strains released at 50,000, 100,000, and 200,000 wasps per hectare was low, with marginal yet significant differences between strains. The highest parasitism was achieved by T. chilonis CJ strain at the high and medium release rates. Hence, it can be concluded that T. chilonis CJ strain released at 100,000 wasps per hectare may be a cost-effective control tactic for field releases targeting striped stem borer. PMID- 25026654 TI - Postharvest irradiation treatment for quarantine control of Drosophila suzukii (Diptera: Drosophilidae) in fresh commodities. AB - Irradiation is a postharvest quarantine treatment option for exported commodities such as stone fruits and small fruits to prevent movement of the new invasive pest spotted wing drosophila, Drosophila suzukii (Walker) (Diptera: Drosophilidae). The effects of irradiation on larval and pupal development and adult reproduction in D. suzukii were examined. Larvae (first, second, and third instars) and pupae (1-2-d-old, 3-5-d-old, and 7-8-d-old) on diet were irradiated at target doses of 20, 30, 40, and 50 Gy in replicated factorial experiments and survival to the adult stage was recorded. Tolerance to radiation increased with increasing age and developmental stage. Males and females were equally susceptible. A radiation dose of 40 Gy applied to first- and second-instar larvae prevented adult emergence. The late-stage pupa was the most radiation-tolerant stage that occurs in fruit, and individuals irradiated at this stage readily emerged as adults; therefore, prevention of F1 adults was the desired treatment response for large-scale validation tests with naturally infested fruit. In large scale tests, a radiation dose of 80 Gy applied to late-stage pupae in sweet cherries or grapes resulted in no production of F1 adults in > 33,000 treated individuals, which meets the zero tolerance requirement for market access. A minimum absorbed dose of 80 Gy is recommended for quarantine control of D. suzukii. PMID- 25026656 TI - Multiple quarantine treatment using bale compression and a three-day fumigation to control Hessian fly (Diptera: Cecidomyiidae) in exported hay. AB - A multiple quarantine treatment was developed to control Hessian fly puparia, Mayetiola destructor (Say), the stage of regulatory concern in exported hay. In a commercial test using 51.589 puparia, no insects survived to the adult stage after exposure to bale compression at 137 kg/cm2 and fumigation with 61 g/28.3 m3 hydrogen phosphide for 3d. The puparia were fumigated in infested wheat seedlings in cloth bags inside compressed timothy bales placed in different locations in three replicate freight containers in a heated building. Fumigant concentrations were 345-522 ppm on day 1; 580-824 ppm on day 2; and 680-861 ppm on day 3. Monitored temperatures were < 20 degrees C in all locations allowing the fumigation temperature to be established at > or = 20 degrees C. Copper detection plate corrosion values were severe inside the freight container doors, and moderate in the middle of bales in all locations, providing visual confirmation of exposure to hydrogen phosphide. Hydrogen phosphide residues in exposed hay bales were found in trace amounts, below the U.S. Environmental Protection Agency tolerance of 0.1 ppm for animal feeds. Timothy hay used in the commercial test is the representative species for all previously exported hay and straw species. The new multiple quarantine treatment is proposed for use with all previously tested bale sizes and wrapper styles for which 3-d fumigation data has been reported, and for bales and wrappers derived from those tested. PMID- 25026655 TI - Detection and genetic diversity of a heliothine invader (Lepidoptera: Noctuidae) from north and northeast of Brazil. AB - The cotton bollworm, Helicoverpa armigera (Hubner), was recently introduced in Brazil. During the 2012-2013 harvest, producers reported reduced yields up to 35% on major crops. The economic losses reached US$ 1 billion only in western Bahia, triggering a phytosanitary crisis. The deficiencies in existing taxonomic keys to deal with the morphologically indistinct larvae of H. armigera and the native Helicoverpa zea (Boddie) constrained the detection of new incursions of this heliothine invader. This study explored the identity of heliothine larvae that were found infesting soybean- and corn-growing areas from Roraima state, northern Brazil, through sequences of the mitochondrial cytochrome c oxidase subunit I gene. The inter- and intraspecies sequence variations of DNA barcodes in H. armigera and H. zea were analyzed. The genetic diversity and population structure of the specimens from Roraima and two populations from Piaui and Bahia states, northeastern Brazil, were assessed by adding the cytochrome c oxidase subunit II gene to the analysis. Owing to the lack of studies on genetic introgression for the two species, the suitability of using three different nuclear genes to distinguish the two species was also investigated. The results showed strong evidence that the heliothine larvae from north and northeast of Brazil are conspecific with H. armigera, suggesting that this invasive moth has already crossed the Amazon basin. Surveys in the north of South America should start as soon as possible to monitor the entry or spread of this moth in the Caribbean, Central America, and the United States. PMID- 25026657 TI - Potential pollinators of tomato, Lycopersicon esculentum (Solanaceae), in open crops and the effect of a solitary bee in fruit set and quality. AB - We identified native bees that are floral visitors and potential pollinators of tomato in Cerrado areas, described the foraging behavior of these species, and verified the influence of the visitation of a solitary bee on the quantity and quality of fruits. Three areas of tomato crops, located in Minas Gerais, Brazil, were sampled between March and November 2012. We collected 185 bees belonging to 13 species. Exomalopsis (Exomalopsis) analis Spinola, 1853 (Hymenoptera: Apidae) was the most abundant. Ten species performed buzz pollination. Apis mellifera L. 1758 (Hymenoptera: Apidae) and Paratrigona lineata (Lepeletier, 1836) (Hymenoptera: Apidae) could also act as pollinators. The fruit set and number of seeds obtained from the pollination treatment by E. analis were higher than those in the control group. Our results allowed the identification of potential tomato pollinators in Cerrado areas and also contributed information regarding the impact of a single species (E. analis) on fruit set and quality. Although most of the visiting bees show the ability for tomato pollination, there is an absence of adequate management techniques, and its usage is difficult with the aim of increasing the crop production, which is the case for E. analis. Species such as Melipona quinquefasciata, P. lineata, and A. mellifera, which are easy to handle, are not used for pollination services. Finally, it is suggested that a combination of different bee species that are able to pollinate the tomato is necessary to prevent the super-exploitation of only a single species for pollination services and to guarantee the occurrence of potential pollinators in the crop area. PMID- 25026658 TI - Does Athetis lepigone moth (Lepidoptera: Noctuidae) take a long-distance migration? AB - Athetis lepigone (Moschler), a new lepidopteran pest in China, has spread quickly to seven provinces since it was first reported causing damage on summer maize in Hebei province in 2005, Whether this species is a migrant or not remains unknown. The past 3 yr searchlight trapping on an island in the center of Bohai Gulf provided direct evidence that both male and female A. lepigone moths migrate across the Bohai Gulf waters in northern China because no host crops or A. lepigone larvae were found on this island. The four migration waves observed in this study represent high-altitude movements of the overwintering, first, second, and third generations of A. lepigone moths, respectively. Carbon isotope analysis showed that 1.76-5.44% of the tested A. lepigone moths originated from C4 plants, which provides additional evidence that this species is a migrant because there are no C4 plants on this small island. The 89.24-96.89% of tested A. lepigone moths originated from C3 plants were significantly higher than that from C4 plants in all generations, suggesting that maize fields are not the main host sites for A. lepigone. Few females were trapped in spring and early summer with relatively high mating frequency and more advanced ovarian development, suggesting that the migration of this species is not completely bound by the "oogenesis-flight syndrome." These findings reveal a new route for A. lepigone migrating to and from the northeastern agricultural region of China, and improve our knowledge of the migration ecology of A. lepigone. Further studies are needed to clarify the migration trajectories that will help in developing sound forecasting systems for this pest species. PMID- 25026659 TI - Seasonal migration of Ctenoplusia agnata (Lepidoptera: Noctuidae) over the Bohai Sea in northern China. AB - Ctenoplusia agnata (Staudinger) (Lepidoptera: Noctuidae) is an important polyphagous pest in East Asia. Previous studies showed that C. agnata moths possesses the potential to undertake long-distance migration; however, knowledge of whether or not the migration of C. agnata moths is a regular ecological behavior and what the pattern of seasonal migrations is in case of regular migration is currently lacking. In the current study, systemic monitoring of population dynamics of C. agnata was conducted by a searchlight trap on an island in the center of Bohai gulf in northern China, during 2003-2013. Our results provided strong evidence for the hypothesis that C. agnata is one of the pest species undertaking regular high altitude long-distance migration and we have depicted the seasonal migration pattern over the Bohai Sea. The first capture of C. agnata generally appeared in late April and early May, then the daily number of catches increased to high levels in late July and formed two waves of migration through August and early September, and finally, the moths disappeared in late October. The mean time from the earliest trapping to the latest trapping within a year was 141.0 +/- 3.0 days. The index of ovarian development of female C. agnata showed seasonal variability and suggested that its migratory flight may be independent of the degree of ovarian development and mating status. In addition, strong migration events took place in 2003, 2004, 2008, and 2010 (annual sum of catches > 10,000). The research result from this work is helpful for understanding the occurrence regularity of C. agnata and developing an integrated pest management strategy. PMID- 25026660 TI - Perching mate-locating strategy in Paysandisia archon (Lepidoptera: Castniidae): behavioral and morpho-physiological investigations. AB - We studied Paysandisia archon (Burmeister) (Lepidoptera: Castniidae: Castniinae) courtship behavior to provide a detailed qualitative and quantitative description of male and female behaviors. Moreover, to investigate the role of antennal olfaction and visual stimuli in mate-recognition, bioassays with antennectomized adults and dummies were performed. To assess the presence of a pheromone gland in the ovipositor, morphological (using light and scanning electron microscopic techniques), electrophysiological, and chemical investigations were carried out. We observed perching mate-locating behavior of P. archon males, with the female triggering the courtship sequence by approaching the perching male first. The stereotyped courtship sequence is made up of five main steps: female flight, pair flight, alighting close, copulation attempt, and clasping. Our findings suggest that visual cues are important in P. archon courtship behavior, and the role of chemical cues is also discussed. Moreover, we observed a higher antenna cleaning frequency in females than in males. Ovipositor extrusions during courtship appeared not to be related to calling behavior, and histological investigations showed no evidence of glandular tissues involved in sex pheromone production. The P. archon ovipositor consists of the eighth uromere, which forms the ovipositor base, and the 9th and 10th uromeres are fused together and connected to the base by an intersegmental membrane. Overall, 24 compounds were identified from extracts obtained from ovipositors: 9 compounds were detected only in extracts from the ovipositors of 24-h-old virgin females, and not from those of 1-h-old females. None of these compounds elicited any significant electrophysiological responses from male antennae. PMID- 25026661 TI - Effect of multiple endogenous biological factors on the response of the tephritids Anastrepha ludens and Anastrepha obliqua (Diptera: Tephritidae) to multilure traps baited with BioLure or NuLure in mango orchards. AB - The physiological state of an insect is likely the most important endogenous factor influencing resource-oriented behavior, and it varies considerably among individuals. Trials were conducted in mango orchards to study the effect of multiple endogenous biological factors on the response of two fly species, Anastrepha ludens (Loew) and Anastrepha obliqua Maquart (Diptera: Tephritidae), to BioLure and NuLure baits. The biological factors of the two fly species that were tested were the following: 1) fertility status-sterile (irradiated) and fertile flies; 2) two types of diets (only sugar and a 3:1 mixture of sugar and hydrolyzed yeast protein; 3) sex, and 4) two sexual maturity conditions (2-4- and 15-18-d-old flies, representing immature and sexually mature flies, respectively, and 2-4-d-old flies treated with methoprene as an artificially induced sexually state male condition). The laboratory-treated flies were released into three different mango orchards. The trials were conducted in four blocks per orchard using eight traps in each block (50:50 BioLure: NuLure). The traps were replaced every 2 d during the 12-d period and the flies per trap per day values were calculated. More protein-fed, fertile, female, immature, and A. obliqua flies were caught compared with the other flies tested. In addition, the traps baited with NuLure attracted more flies than those baited with BioLure. Interaction analyses indicated that the type of bait and the sexual maturity status were the most important factors affecting the responses of the flies. Our study demonstrated that lures attract only a small segment of the fly population, those that have a specific hunger for amino acids-immature flies-and those that were protein-starved. The implications for improved trapping system designs are discussed. PMID- 25026662 TI - Assessing the potential for establishment of western cherry fruit fly using ecological niche modeling. AB - Sweet cherries, Prunus avium (L.) L., grown in the western United States are exported to many countries around the world. Some of these countries have enforced strict quarantine rules and trade restrictions owing to concerns about the potential establishment and subsequent spread of western cherry fruit fly, Rhagoletis indifferens Curran (Diptera: Tephritidae), a major quarantine pest of sweet cherry. We used 1) niche models (CLIMEX and MaxEnt) to map the climatic suitability, 2) North Carolina State University-Animal and Plant Health Inspection Service Plant Pest Forecasting System to examine chilling requirement, and 3) host distribution and availability to assess the potential for establishment of R. indifferens in areas of western North America where it currently does not exist and eight current or potential fresh sweet cherry markets: Colombia, India, Indonesia, Malaysia, Taiwan, Thailand, Venezuela, and Vietnam. Results from niche models conformed well to the current distribution of R. indifferens in western North America. MaxEnt and CLIMEX models had high performance and predicted climatic suitability in some of the countries (e.g., Andean range in Colombia and Venezuela, northern and northeastern India, central Taiwan, and parts of Vietnam). However, our results showed no potential for establishment of R. indifferens in Colombia, Indonesia, Malaysia, Taiwan, Thailand, Venezuela, and Vietnam when the optimal chilling requirement to break diapause (minimum temperature < or = 3 degree C for at least 15 wk) was used as the criterion for whether establishment can occur. Furthermore, these countries have no host plant species available for R. indifferens. Our results can be used to make scientifically informed international trade decisions and negotiations by policy makers. PMID- 25026663 TI - Demographic analysis of the fitness of Problepsis superans (Lepidoptera: Geometridae) feeding on three ligustrum (Lamiales: Oleaceae) species. AB - Using the age-stage, two-sex life table, the effects of three ligustrum species, Ligustrum x vicaryi Hort., Ligustrum quihoui Carriere, and Ligustrum lucidum Aiton, on the fitness of Problepsis superans (Butler, 1885) (Lepidoptera: Geometridae) were assayed by considering life table parameters of P. superans at 27 +/- 1 degrees C, 70 +/- 5% relative humidity, and a photoperiod of 16:8 (L: D) h. The means and SEs of population parameters were calculated using the jackknife and bootstrap methods. The total developmental time of larval stage of P. superans on L. x vicaryi was significantly shorter than that on L. x vicaryi and L. quihoui, whereas higher fecundity was observed on L. x vicaryi. The highest value of the finite rate of increase was observed on L. x vicaryi. The intrinsic rate of increase of P. superans on L. x vicaryi, L. quihoui, and L. lucidum, was 0.147 +/- 0.004, 0.130 +/- 0.004, and 0.112 +/- 0.005, respectively, which differed significantly among the three ligustrum species. The net reproductive rate varied from 122.8 +/- 24.7 female offspring on L. lucidum to 242.2 +/- 36.2 female offspring on L. x vicaryi. The lowest mean generation time was observed on L. x vicaryi. The gross reproductive rate of P. superans on the three ligustrum species did not significantly differ. Based on growth and population parameters, the suitability of the three ligustrum species to P. superans is ranked from high to low in the order as L. x vicaryi, L. quihoui, and L. lucidum. PMID- 25026664 TI - Changes in nutritional composition of soybean seed caused by feeding of pentatomid (Hemiptera: Pentatomidae) and alydid bugs (Hemiptera: Alydidae). AB - Changes in protein, lipid, and carbohydrate content, and the weight loss of soybean seeds caused by the feeding of 6- to 7-d-old unmated male adults of the pentatomids Peizodorous hybneri (Gmelin) and Halymorpha halys (Stal), and an alydid, Riptortus pedestris (F.), were examined in the laboratory. Our goals were to determine which species had the greatest capacity to damage soybean seed and to measure the effect of that damage on the nutritional composition of soybean seed. Individuals of the three species were provided with a preweighed dry soybean seed and allowed to feed for 0, 4, 8, 12, 16, 20, and 24 d, after which the remaining seed was analyzed for any change in weight, protein, lipid, and carbohydrate concentration. Lipids, carbohydrates, and seed weights were reduced by bug feeding, and the reduction was directly proportional to feeding duration. H. halys was found to be the most voracious feeder, reducing soybean seed weight by 42% after 24 d of feeding. There was a significant interaction between species and feeding duration for changes in nutritional components. Seeds fed on by H. halys had the highest incremental increase in protein content (13%) after 24 d of feeding, followed by those fed on by R. pedestris and P. hybneri. However, carbohydrates and lipid content of the soybean seeds fed by the tested insect species were found to decrease significantly. Soybean pods at mature stages remain in the field for a long period, and findings of our study suggest that longer exposure of the mature soybean pods to these pest species in the field may lead to low-quality seeds and lower yields, and may even affect the germination potential of the seeds. PMID- 25026665 TI - Synergy of aggregation pheromone with methyl (E,E,Z) -2,4,6-decatrienoate in attraction of Halyomorpha halys (Hemiptera: Pentatomidae). AB - The reported male-produced aggregation pheromone of the brown marmorated stink bug, Halyomorpha halys (Stal) (Hemiptera: Pentatomidae), identified as a mixture of (3S,6S,7R,10S)-10,11-epoxy-1-bisabolen-3-ol and (3R, 6S, 7R, 10S)-10,11-epoxy 1-bisabolen-3-ol, offers new opportunities for its management. We found that black pyramid traps deployed along crop borders in Maryland and West Virginia, containing lures with both stereoisomers of this reported aggregation pheromone combined with methyl (E,E,Z)-2,4,6-decatrienoate (MDT) lures, attracted more adult and nymphal H. halys than either the aggregation pheromone or MDT alone. In season-long totals, combined lures acted synergistically by catching 1.9-3.2 times more number of adults, and 1.4-2.5 times more number of nymphs, than expected from an additive effect of the lures deployed individually. There were no significant differences in patterns of male and female captures. MDT alone was not significantly attractive to adults during most of the growing season, but became increasingly attractive to adults and especially nymphs in autumn. Mixed isomer lures containing eight stereoisomers of 10,11-epoxy-1-bisabolen-3-ol, including the two active stereoisomers, were as effective at catching adults and nymphs with or without MDT as were lures loaded only with the two active stereoisomers in the natural ratio ((3S, 6S, 7R, 10S)-10,11-epoxy-1-bisabolen-3 ol: (3R, 6S, 7R, 10S)-10,11-epoxy-1-bisabolen-3-ol) of 3.5:1. These results identify a combination of semiochemicals that is attractive season-long for detection, monitoring, and potential control of this polyphagous invasive pest of North America and Europe. PMID- 25026666 TI - A comparative life-table analysis of Sipha flava (Hemiptera: Aphididae) on two biofuel hosts, Miscanthus x giganteus and Saccharum spp. AB - Among the insects reported in biofuel crops, the yellow sugarcane aphid, Sipha flava (Forbes), is a potential pest of giant miscanthus, Miscanthus x giganteus Greef et Deu ex Hodkinson et Renvoize (M x g) and energy cane 'L79-1002', Saccharum spp. L. We studied the biology of S. flava on M x g and energy cane and estimated the development period, fecundity, longevity, intrinsic rate of increase, doubling time, reproductive value, and survivorship curves. To demonstrate the host suitability in a susceptible species, we studied the aphid life table on sorghum 'PL 18200,' Sorghum bicolor (L.) Moench. Life-table information was recorded under greenhouse conditions on the host plants. Our results suggested that both M x g and energy cane are suitable hosts for S. flava. We observed similar aphid development period on both hosts. Life-table estimates including longevity and fecundity suggested that M x g is a more suitable host for the aphid than energy cane. The intrinsic rate of increase for S. flava was lower on energy cane (0.231) than on M x g (0.258). PMID- 25026667 TI - The effect of male and female age on Lymantria dispar (Lepidoptera: Lymantriidae) fecundity. AB - Insects that reproduce sexually must locate a suitable mate, and many species have evolved efficient communication mechanisms to find each other. The number of reproductively viable individuals in a population can be an important constraint in the growth of populations. One factor that can affect insect fecundity is the age of mating adults, as fecundity tends to decline with age. Field observations collected annually on Lymantria dispar (L.) from 2001 to 2007 and 2009 consistently revealed a small proportion of egg masses (generally < 10% in each year) in which > 0 but < 5% of eggs were fertilized in an egg mass consisting of approximately 200-500 eggs. In these studies, male age was unknown but female age was fixed at < 24 h, which, according to previous studies on the effect of female L. dispar age on reproductive success, should have been optimal for fertilization. In this article, we analyzed field data (2001-2007 and 2009) to explore patterns in the occurrence of low-fertilized egg masses. We supplemented these data with laboratory experiments that examined the interacting role of male and female age, and multiple male matings. We observed that increases in male and female age reduce the rate of fertilization, which is furthermore reduced, as males mate multiple times as they age. This article highlights the importance of both female and male age at the time of mating in an invading species, with ramifications to low-density populations in this and other sexually reproducing insect species. PMID- 25026668 TI - Reduced-risk pest management programs for eastern U.S. peach orchards: effects on arthropod predators, parasitoids, and select pests. AB - We developed new integrated pest management programs for eastern U.S. peaches with minimal use of organophosphates. From 2002-2005, we assessed the ecological impacts of these reduced-risk programs versus grower standard conventional programs that still relied primarily on the use of organophosphorous and carbamate insecticides. Using a split-plot design replicated at four commercial Pennsylvania peach orchards, we quantified pesticide rates, environmental impact, and arthropod community response. We used Environmental Impact Quotient (EIQ) analysis based on the growers' pesticide records from each orchard to calculate seasonal cumulative EIQ field ratings for all years. Ecological effects of the reduced-risk and conventional program were also measured as the abundance and diversity of nontarget arthropod predators, parasitoids, and selected pest taxa. Pesticide inputs and EIQ values were substantially lower in reduced-risk programs compared with conventional spray programs. Arthropod arrays differed significantly between pest management programs: most beneficial predator and parasitoid taxa were positively associated with the reduced-risk program and negatively associated with the standard grower program. Regardless of the pest management program, we observed significant differences in species arrays in the peach tree canopy compared with the ground cover of the orchards, but the arthropod community did not differ among the field sites or based on distance from the edge of the orchard. We conclude that reduced-risk programs not only provide control comparable with that of conventional programs, but they also reduce negative environmental effects while conserving key arthropod biological control agents within eastern U.S. peach orchards. PMID- 25026669 TI - Antifungal agents against Aspergillus niger for rearing rice leaffolder larvae (Lepidoptera: Pyralidae) on artificial diet. AB - Mold contamination is an important issue in insect mass rearing. Frequently used antifungal agents such as sorbic acid and methylparaben have negative impact on many lepidopteran larvae, which might be one of the reasons for the difficulty in rearing rice leaffolder, Cnaphalocrocis medinalis (Guenee). In this study, 19 antifungal agents, including 7 food preservatives, 6 antifungal drugs, and 6 agricultural fungicides, were screened for their inhibitory activities on Aspergillus niger in diets. The results demonstrated that most of the tested chemicals are unsuitable as mold inhibitors in the diets of the rice leaffolder, and the rice leaffolder neonate is sensitive to sorbic acid and methylparaben. These two mold inhibitors at commonly used concentrations were shown to impact the survival of rice leaffolder larvae fed on artificial diets. Among the tested mold inhibitors, natamycin was the safest for the rice leaffolder larvae. Much higher larva survival was observed for the larvae fed on diets containing natamycin as an antifungal agent (59 and 72% at 200 and 400 ppm, respectively). Two agricultural fungicides, tebuconazole and azoxystrobin, are also potent as mold inhibitors when used in insect diets. The mixed use of natamycin and sorbic acid, or methylparaben, and the mixed use of sorbic acid and azoxystrobin resulted in significantly higher larva survival than sorbic acid + methylparaben. Natamycin + azoxystrobin and sorbic acid + tebuconazole resulted in larva survival similar to that of sorbic acid + methylparaben. The ternary combination of natamycin, sorbic acid, and methylparaben was the best combination for the rearing of rice leaffolder. PMID- 25026670 TI - Impact of corn earworm injury on yield of transgenic corn producing Bt toxins in the Carolinas. AB - Transgenic corn, Zea mays L., hybrids expressing insecticidal Cry proteins from Bacillus thuringiensis (Bt) and insecticide applications to suppress injury from Helicoverpa zea (Boddie) were evaluated in Florence, SC, and in Plymouth, NC, in 2012 and 2013. Based on kernel area injured, insecticide applications (chlorantraniliprole) every 3-4 d from R1 until H. zea had cycled out of corn reduced injury by 80-93% in Florence and 94-95% in Plymouth. Despite intensive applications of insecticide (13-18 per trial), limited injury still occurred in all treated plots in 2012, except in DKC 68-03 (Genuity VT Double PRO), based on kernels injured (both locations) and proportion of injured ears (Florence only). In 2013, ear injury was low in Plymouth, with no kernel injury in any insecticide treated plots, except P1498R (non-Bt) and P1498YHR (Optimum Intrasect). Injury in Florence in 2013 did not occur in treated plots of DKC 68-04 (non-Bt), DKC 68-03 (Genuity VT Double PRO), and N785-3111 (Agrisure Viptera). Yields were not significantly affected by insecticide treatment and were not statistically different among near-isolines with and without Bt traits. Yields were not significantly associated with kernel injury based on regression analyses. The value of using Bt corn hybrids to manage H. zea is discussed. PMID- 25026671 TI - Molecular markers for species identification of Hessian fly males caught on sticky pheromone traps. AB - Pheromone traps have been widely used to monitor insect population activity. However, sticky pheromone traps for the Hessian fly (Mayetiola destructor), one of the most destructive pests of wheat, have been used only in recent years. Hessian fly male adults are small and fragile, and preserving specimens during sorting of sticky pheromone traps is a challenge when intact specimens are often required to visually distinguish them from related insects such as fungus gnats. In this study, we have established a quick and reliable method based on polymerase chain reaction markers to correctly distinguish Hessian fly males from other closely related insects. Two Hessian fly-specific markers were established, one based on the trypsin gene MDP-10 and the other based on a gene encoding the salivary gland protein SSGP31-5. Both markers provided > 98% identification success of 110 Hessian fly samples prepared from single insects. The method should provide a useful tool to allow for identification of Hessian fly individuals on sticky pheromone traps or in other situations when Hessian fly eggs, larvae, pupae, and adults are difficult to distinguish from other insects. PMID- 25026672 TI - Efficiency and economic feasibility of pest control systems in watermelon cropping. AB - The aim of this work was to determine the efficiency and feasibility of two different watermelon pest control systems on pest infestations, natural enemies, and on the productivity and sustainability of watermelon cropping. Two independent experiments were carried out during the dry season of 2011. Both experiments were carried out using a randomized block experimental design, with three treatments; weekly application of pesticide (WAP), integrated pest management (IPM), and nonpesticide application (control); and four replicates. Arthropods sampling was performed every 2 d by direct counting at five randomly selected points in each plot. Samples were taken by beating the leaves from the apical portion of the plant against a white plastic tray. Arthropods that moved along the soil surface were sampled weekly using pitfall traps. Both WAP and IPM treatments negatively affected the arthropod population. We conclude that IPM is an attractive strategy for watermelon cropping both economically and environmentally because it provides the grower with an option to lower production cost, achieves the same production, and there is less need for pesticide application when compared with the prophylactic control treatment when pesticides are applied on a weekly basis. This has not been reported for watermelon before. PMID- 25026673 TI - Assessing the flight capabilities of the goldspotted oak borer (Coleoptera: Buprestidae) with computerized flight mills. AB - The goldspotted oak borer, Agrilus auroguttatus Schaeffer (Coleoptera: Buprestidae), is native to southern Arizona and is an invasive wood-boring beetle that has caused considerable mortality to native oak species in southern California. Assessing the dispersal capabilities of this woodborer may help to determine its potential environmental and economic risk within the invaded region, and possibly assist with the development of species-specific management strategies. The flight performance of A. auroguttatus adults under different age, mating, and nutritional status was assessed by tethering individuals to computerized flight mills for a 24-h trial period to collect information on total distance flown, flight times and velocities, number and duration of flight bouts, and postflight weight. The nutritional status and body size (i.e., elytron length) of A. auroguttatus adults had a significant influence on overall flight performance. Mating status and gender had no significant influence on total flight distance, duration, velocity, and flight bout time. Significant interactions between nutritional status and age were observed in the overall flight performance of A. auroguttatus, with decreased flight activity in old (approximately 6 d of age) starved individuals during a 24-h trial period. Overall, results of these flight mill assays indicate that A. auroguttatus is unable to disperse long distances across habitats that lack suitable oak hosts. This work supports the hypothesis that human-aided transportation via infested oak firewood from southern Arizona across the Sonoran desert likely caused the initial introduction, and subsequent satellite infestations of A. auroguttatus within southern California's native oak woodlands. PMID- 25026674 TI - An empirical predictive model for the spring emergence of Thecodiplosis japonensis (Diptera: Cecidomyiidae): model construction and validation on the basis of 25 years of field observation data. AB - The reliability of the empirical phenology model proposed by Nam et al. (2013) was tested using spring emergence data of Thecodiplosis japonensis Uchida et Inouye (Diptera: Cecidomyiidae) from 1986 to 2011 in Yeongcheon, Korea. First, the lower developmental threshold temperature (LDT) was estimated using spring emergence of T. japonensis and field temperatures. Then a degree-day model to predict spring emergence of T. japonensis was constructed, based on LDTs estimated from field observations and laboratory temperature-dependent development data. Based on field observations, the estimated LDT value for postdiapause development of T. japonensis was 6.1 degrees C, only 0.2 degrees C higher than that estimated from laboratory data. The explanatory power of the empirical degree-day model constructed on the basis of LDT from field observations was 87.2%, similar to the 87.0% of a degree-day model based on laboratory data, suggesting that both models had similar explanatory power. Furthermore, the predictions of median date of emergence in both models were only five days earlier than the observed median date in 2011. These results show that the empirical phenology model based on field observations is a reliable method for predicting the phenology of insects. PMID- 25026675 TI - Effects of forest type and management on native wood wasp abundance (Hymenoptera: Siricidae) in Mississippi, United States. AB - The United States has a rich fauna of native Siricidae (wood wasps), but they are rarely studied because they have limited economic impact. In 2004, a non-native wood-boring pest, Sirex noctilio F., was found established in North America. Because S. noctilio is an economically important pest in pine plantations throughout the Southern Hemisphere, interest in the ecology of American native wood wasp populations has increased. A study was conducted during fall 2011 to investigate the effects of forest stand type and characteristics on native wood wasp abundance, and to describe their flight phenology in northeastern Mississippi. In total, 609 native wood wasps were captured, consisting of 608 Sirex nigricornis F. and one Urocerus cressoni Norton. There were significant treatment and location effects that influenced wood wasp abundance. The flight period of wood wasps captured in our study (October-December) was similar to studies in the southeastern United States, but differed from results in Minnesota and the northeastern United States (June-October). Wood wasp abundance was significantly correlated with higher basal area, smaller tree diameter at breast height, and shorter trees, all indicators of forest stand stress. It appears proper silvicultural management of pine plantations may reduce native wood wasp population abundance in the southeastern United States, as it does to S. noctilio in the Southern Hemisphere. We propose implementing management models used for the southern pine beetle to reduce stand hazard of future infestations of native and invasive wood wasps. PMID- 25026676 TI - Demographic trends in mixed Bemisia tabaci (Hemiptera: Aleyrodidae) cryptic species populations in commercial poinsettia under biological control- and insecticide-based management. AB - Bemisia tabaci (Gennadius) is an economically important pest of agricultural and ornamental plants worldwide and is now widely recognized as a cryptic species complex. In North America, B. tabaci is a particularly important pest of greenhouse poinsettia. In poinsettia production, two cryptic species from the B. tabaci complex, Mediterranean and Middle East Minor 1, often infest crops simultaneously. Differences in pesticide susceptibility between these two cryptic species have the potential to influence growers' management decisions, including the use of biological control or insecticides, and the choice of insecticide active ingredient. However, the demographic behavior of mixed-species infestations in commercial greenhouses has yet to be investigated. We conducted a survey of B. tabaci populations in commercial greenhouses in Ontario, Canada, and provide evidence that under biological control-based management, Middle East Minor 1 can displace Mediterranean, whereas under insecticide-based management Mediterranean populations will persist. Furthermore, we comment on implications of this behavior on the management of B. tabaci, and comment on methods used to identify B. tabaci cryptic species. PMID- 25026677 TI - Pollen loads and specificity of native pollinators of lowbush blueberry. AB - The reproduction of lowbush blueberry (Vaccinium angustifolium Aiton) is closely tied to insect pollination, owing to self-incompatibility. Many species are known to have greater pollination efficiency than the introduced Apis mellifera L., commonly used for commercial purposes. In this study, we measured the pollen loads of several antophilous insect species, mostly Apoidea and Syrphidae, present in four lowbush blueberry fields in Lac-St-Jean, Quebec. To measure pollen loads and species specificity toward V. angustifolium, we net-collected 627 specimens of pollinators, retrieved their pollen loads, identified pollen taxa, and counted pollen grains. We found that the sizes of pollen loads were highly variable among species, ranging from a few hundred to more than 118,000 pollen grains per individual. Bombus and Andrena species in particular carried large amounts of Vaccinium pollen and thus may have greater pollination efficiency. Also, two species (Andrena bradleyi Viereck and Andrena carolina Viereck) showed nearly monolectic behavior toward lowbush blueberry. Finally, we identified alternative forage plants visited by native pollinators, notably species of Acer, Rubus, Ilex mucronata, Ledum groenlandicum, and Taraxacum. Protecting these flowering plants should be part of management practices to maintain healthy pollinator communities in a lowbush blueberry agroecosystem. PMID- 25026678 TI - Enhancement of insecticides against codling moth (Lepidoptera: Tortricidae) with L-aspartate in laboratory and field experiments. AB - The idea of enhancing insecticide efficacy against phytophagous insects with feeding stimulators was proposed as early as the 1960s, and a number of insect feeding stimulators based on sugars, molasses, and cottonseed extracts, biologically active at relatively high (5% and higher) concentrations, have been advocated. Here, we show that an acidic amino acid, L-aspartate, stimulates feeding in codling moth neonates at much lower concentrations and acts as an effective tank-mixed additive for increasing efficacy of insecticides, reducing fruit damage, and increasing yield of the fruit. In laboratory experiments, 1 mg/ml L-aspartate increased foliage consumption by 40-60% and, when added to Assail 30 SG, Baythroid XL, Delegate WG, or Carbaryl 80S, maintained its feeding stimulatory properties and reduced LD50(s) by approximately 10 times. In a 3-yr field trial, addition of L-aspartate to the aforementioned insecticides at 395 g/ha reduced fruit damage from approximately 6%, on average to < 1% for first generation codling moth, and from approximately 20 to approximately 5% for the second generation. Interestingly, addition of L-aspartate also increased the average weight of apples by 11-27%, as measured at the time of harvest. PMID- 25026679 TI - Evaluating irradiation dose for sterility induction and quality control of mass produced fruit fly Bactrocera tryoni (Diptera: Tephritidae). AB - The sterile insect technique has been routinely used to eradicate fruit fly Bactrocera tryoni (Froggatt) incursions. This study considers whether fly quality in a mass-rearing facility can be improved by reducing irradiation doses, without sacrificing reproductive sterility. Pupae were exposed to one of five target irradiation dose ranges: 0, 40-45, 50-55, 60-65, and 70-75 Gy. Pupae were then assessed using routine quality control measures: flight ability, sex ratio, longevity under nutritional stress, emergence, and reproductive sterility. Irradiation did not have a significant effect on flight ability or sex ratio tests. Longevity under nutritional stress was significantly increased at 70-75 Gy, but no other doses differed from 0 Gy. Emergence was slightly reduced in the 50-55, 60-65, and 70-75 Gy treatments, but 40-45 Gy treatments did not differ from 0 Gy, though confounding temporal factors complicate interpretation. Reproductive sterility remained acceptable (> 99.5%) for all doses--40-45 Gy (99.78%), 50-55 Gy (100%), 60-65 Gy (100%), and 70-75 Gy (99.99%). We recommend that B. tryoni used in sterile insect technique releases be irradiated at a target dose of 50-55 Gy, providing improved quality and undiminished sterility in comparison with the current 70-75 Gy standard while also providing a substantial buffer against risk of under dosing. PMID- 25026680 TI - Novel barriers to prevent dogwood borer (Lepidoptera: Sesiidae) and rodent damage in apple plantings. AB - We evaluated a combination of noninsecticidal alternatives to control trunk damaging dogwood borer, Synanthedon scitula (Harris), consisting of novel barrier technologies, used alone or in combination with mating disruption. Barrier formulations evaluated included fibrous barriers of nonwoven ethylene vinyl acetate (EVA) and nonfibrous barriers of rubberized paint (elastomer) used in building coatings. To examine efficacy of dogwood borer control in orchards, all barrier trials were replicated in field tests, both in combination with mating disruption and without it. Trunk inspections to determine whether mating disruption and barriers effectively reduced actual tree infestation showed pheromone disruption significantly reduced infestation compared with the untreated check, but was not as effective as trunk handgun sprays of chlorpyrifos. EVA trunk barriers were effective in preventing borer infestation compared with untreated trees. The elastomer did not differ from the check or the EVA treatment. There was no interaction between disruption and barrier treatments. Barrier field life and durability was assessed over 2 yr by comparing degradation over time due to weathering and other environmental effects including animal damage. The EVA persisted and remained more intact than the elastomer, but was in need of reapplication after 2 yr. Barriers were also screened for efficacy against voles in small-plot trials in nonorchard locations with known high vole pressure; they were tested either alone, combined with a repellent (thiram), or, in the case of the elastomer only, combined with an abrasive (sand). Only the EVA significantly lowered vole chewing damage relative to the untreated checks. PMID- 25026681 TI - Solanum habrochaites, a potential source of resistance against Bactericera cockerelli (Hemiptera: Triozidae) and "Candidatus Liberibacter solanacearum". AB - The potato psyllid, Bactericera cockerelli Sulc, also known as tomato psyllid, is a serious pest of solanaceous plants. Its host selection criteria are poorly understood. In this study, we tested whether the Solanum habrochaites (PI127826), a wild solanaceous plant known for its property to repel whiteflies, was repellent to potato psyllids. Using a combination of nonchoice assays and choice assays on different psyllid stages, we demonstrated that S. habrochaites is both repelling and toxic to potato psyllids compared with Solanum lycopersicum. However, those properties were not sufficient to avoid. transmission of the plant bacterial pathogen "Candidatus Liberibacter solanacearum" vectored by potato psyllids, the causative agent of potato zebra chip disease. However, a lower bacterial transmission rate to S. habrochaites was observed compared with S. lycopersicum. PMID- 25026682 TI - Influence of weeds on Argentine ant (Hymenoptera: Formicidae) and obscure mealybug (Hemiptera: Pseudococcidae) in a central California vineyard. AB - Obscure mealybug is a pest of grapes in the cool climate regions of coastal California, is found on some vineyard weeds, and is tended by the Argentine ant. A study was conducted at a vineyard in Arroyo Grande, CA, to evaluate the impact of weeds on ant activity on grapevines, and the role that ants and weeds have on obscure mealybug infestation in grape clusters. The incidence of the fungus Botrytis cinerea was recorded as well. Treatments were weed exclusion versus the presence of weeds, and ant exclusion versus the presence of ants. Ant activity was evaluated weekly using sugar-based monitoring stations, and mealybug infestation and Botrytis incidence of clusters were evaluated at harvest. Ant exclusion reduced the overall number of ant visits by 82%, and ants increased mealybug infestation of clusters by 53%. Ant activity was 33% higher in the weeds treatment, but there was no impact of weeds on mealybug infestation. We suggest that the higher ant activity recorded in the weeds treatment may have been an artifact of the sugar-based sampling method. Botrytis incidence was three times higher with ants, but did not differ between weeds and weed exclusion treatments. The study supports other research showing a relationship between mealybug infestation and the presence of ants, as well as the lack of impact of floor vegetation on mealybug infestation of grape clusters. It is the first report of a relationship between ants and Botrytis, although it is more likely that the higher Botrytis incidence found here is a result of increased mealybug density than a direct effect by ants. PMID- 25026683 TI - Durability of a novel durable bait for control of subterranean termites (Isoptera: Rhinotermitidae): results of five-year field aging studies. AB - A durable termite bait containing 0.5% noviflumuron was evaluated for physical durability, retention of active ingredient, consumption by termites, and toxicity to termites over 5 yr in field studies at locations in Indiana, Mississippi, and South Carolina. Plots in Indiana and Mississippi included both natural rainfall and irrigated plots, while plots in South Carolina received only natural rainfall. Samples collected every 3 mo for the first 4 yr were evaluated for consumption with a 7 d no-choice bioassay using Reticulitermes flavipes (Kollar). Consumption and toxicity of 5 yr samples were evaluated in similar bioassays conducted for 42 d. Durable baits received from field sites had some cracking, and a small amount of external flaking, but no major deterioration based on visual observation. There were no significant differences in noviflumuron concentration over the 5-yr period and no trend toward reduced concentrations of noviflumuron over time. Consumption of aged durable baits over 4 yr was variable, but termites usually consumed more aged durable bait than fresh durable bait and the differences were frequently significant. There were some exceptions, but termites consumed significantly more fresh durable bait than aged durable bait in only 4% of observations. When 5 yr samples were evaluated, consumption was lowest for fresh durable bait and termites consumed significantly more aged durable bait from irrigated plots in Indiana and from both natural and irrigated plots in Mississippi than fresh durable bait. Survival of termites fed blank durable bait was significantly higher than that for termites fed any of the baits containing noviflumuron and there were no significant differences in survival among the noviflumuron durable baits. Our results suggest that the bait would be durable for at least 5 yr and possibly longer under most environmental conditions. PMID- 25026684 TI - Effect of feeding status on mortality response of adult bed bugs (Hemiptera: Cimicidae) to some insecticide products. AB - Fresh and aged residual deposits of several insecticide products were tested against bed bug adults to determine if a recent bloodmeal affected their mortality response to the residues. The bed bugs with a recent bloodmeal survived significantly longer compared with the unfed ones on their exposure to fresh or aged residual deposits of chlorfenapyr and aged residual deposits of deltamethrin on a wooden substrate. Even though the survival time of fed bed bugs was significantly longer than that of unfed ones on their exposure to fresh residue of deltamethrin and aged residue of desiccant pyrethrin dust, these treatments resulted in similarly high final mortalities regardless of feeding status of the insects. Mortality responses of fed and unfed bed bugs were similar to fresh or aged residual deposits of imidacloprid + cyfluthrin combination and fresh residual deposits of desiccant pyrethrin dust. Topical application assays indicated that a recent bloodmeal significantly increased the bed bug's survival time for chlorfenapyr, but not for deltamethrin. Pyrethroid-resistant bed bugs also showed a similar increase in their survival time for chlorfenapyr after a bloodmeal. The comparison of mortality responses between fed and unfed bed bugs treated with similar amount of chlorfenapyr per fresh body weight indicated that increased body mass was not the primary cause for this bloodmeal-induced tolerance increase for chlorfenapyr. Because the surviving bed bugs can continue ovipositing, the effectiveness of chlorfenapyr residual deposits in bed bug harborages could be significantly affected by the feeding status of the adult bed bug populations. PMID- 25026685 TI - Influences of pyriproxyfen on fecundity and reproduction of the Pharaoh ant (Hymenoptera: Formicidae). AB - The effects of the juvenile hormone analog pyriproxyfen (at concentrations of 0.1, 0.5, and 1%) on egg production, number of ovarioles, and length of oocytes were examined in queens of the Pharaoh ant Monomorium pharaonis (L.). Pyriproxyfen significantly reduced egg production in queens from week 3 onwards. Queens that were exposed to 1% pyriproxyfen stopped producing eggs at week 8. After 8 wk, ovaries were dissected from all queens, and the number of ovarioles and the length of the largest oocytes were recorded. The ovaries of queens in treated colonies were smaller than those in untreated queens, and the number of ovarioles in the ovaries was significantly lower in all pyriproxyfen-treated queens. Queens treated with the highest concentrations of pyriproxyfen tended to have significantly shorter oocytes than untreated queens. Histological studies of the ovaries revealed that pyriproxyfen caused vacuolation in the ovarioles, thickening of the tunica propria, development of small eggs, and underdevelopment of nurse cells and the follicular epithelium. Exposure to pyriproxyfen reduced egg production and induced severe morphological changes in the ovaries of queens, and the effects increased with increased concentration of pyriproxyfen. PMID- 25026686 TI - Trehalase activity in fungus-growing termite, Odontotermes feae (Isoptera: Termitideae) and inhibitory effect of validamycin. AB - Trehalase is the hydrolytic enzyme that catalyzed the hydrolysis of trehalose to glucose. In this study, trehalase activity in the fungus-growing termite, Odontotermes feae Wasmann had been examined. Trehalase activity in digestive tract and carcass of O. feae was higher than that in wood-feeding termite, Coptotermes gestroi Wasmann. The intestinal tract of worker caste of O. feae was the main source of trehalase compared with that in salivary, fat body, and carcass. In particular, the highest activity was found in the midgut and hindgut parts. More specifically, the contents of midgut and hindgut had higher enzyme activity compared with that trehalase prepared from their epithelial tissue. The enzyme activity of gut trehalase in three different termite castes, worker, soldier, and reproductive, had been determined. The result showed that female alate had the highest activity, followed by worker, male alate, and soldier castes. Trehalose concentration in the reproductive caste was at lowest level, while soldier and worker contained the high trehalose concentration. This study indicates that high trehalase activity locates in the midgut and hindgut contents and change in trehalase activity in fungus-growing termite is caste-specific. Validamycin inhibited trehalase activity of O. feae in vivo and caused high mortality, indicating that this trehalase inhibitor is valuable tools for termite control. PMID- 25026687 TI - Monitoring of Bactrocera dorsalis (Diptera: Tephritidae) resistance to cyantraniliprole in the south of China. AB - The oriental fruit fly, Bactrocera dorsalis (Hendel), is a globally important economic insect pest that has evolved resistance to various types of insecticides. Cyantraniliprole (DuPont Cyazypyr) is a new anthranilic diamide insecticide registered to control lepidopteran and sucking insects. The susceptibility of field-collected populations of B. dorsalis to cyantraniliprole was assessed via a diet incorporation bioassay in adults. Based on the obtained LC50 values (ranging from 3.29 to 15.83 microg/g), all the testing populations, including ZZ (Fujian province), HH (Yunnan province), JM (Guangdong province), SY (Hainan province), HZ (Zhejiang province), YL (Guangxi province), SH (Shanghai), WH (Hubei province), and CS (Hunan province), were susceptible to cyantraniliprole, with the samples of WH (Hubei province) being the most tolerant (by 4.80-fold). Two (SY, Hainan province; CS, Hunan province) of the nine field collected populations of B. dorsalis showed a similar susceptibility to cyantraniliprole, while the remaining populations displayed narrow variations in tolerance compared with the laboratory strain. Synergist assays were performed to determine the potential detoxification mechanisms. Piperonyl butoxide showed significant synergism effects in lab, CS, and resistant strain. S,S,S tributylphorotrithioate and diethyl maleate also showed obvious synergism effects in resistant strain. A 19.44-fold increase in resistance to cyantraniliprole was observed after 14 generations of selection in the laboratory. The present work clarifies the baseline susceptibility and primary mechanisms of B. dorsalis to cyantraniliprole in the south China and established a cyantraniliprole-resistant strain as well. A sound resistance management strategy is also discussed in relation to the risk of susceptibility. PMID- 25026688 TI - Cross-resistance and baseline susceptibility of spirotetramat in Frankliniella occidentalis (Thysanoptera: Thripidae). AB - Western flower thrips, Frankliniella occidentalis (Pergande), is an economically important pest all over the world. New products against thrips are necessary, as there are few effective compounds exhibiting cross-resistance among them. Lethal effects, cross-resistance, and baseline susceptibility to spirotetramat were evaluated in this study. A new bioassay method for testing thrips against spirotetramat was developed. Spirotetramat showed a significant mortality effect on larvae after 7 d of exposure, but a low effect was observed on adults. Baseline results for larval instars showed LC50 values ranging from 11.59 to 49.81 mg AI/liter, with a low natural variability (3.2-fold). Cross-resistance studies showed overlapping confidence limits of the LC50 values for laboratory selected (against acrinathrin, methiocarb, formetanate, and spinosad) resistant and susceptible strains, and low resistance factors, from 0.5 to 1.9, suggesting no cross-resistance to conventional insecticides previously used. A slight ovicidal effect (21-40% reduction) was also detected. Despite presenting low effects on adults, spirotetramat showed high but slow efficacy on F. occidentalis larvae. Field populations in southeast Spain showed a consistent susceptibility to spirotetramat. Given the scarcity of effective products and the lack of cross resistance to other insecticides, spirotetramat can be considered as a good chemical tool to control F. occidentalis. PMID- 25026689 TI - Assessment of insecticide resistance of Lobesia botrana (Lepidoptera: Tortricidae) in Emilia-Romagna region. AB - The European grapevine moth, Lobesia botrana (Denis & Schiffermuller) (Lepidoptera: Tortricidae), is the key pest of vineyard, Vitis vinifera L. In Italy, failures in field chemical pest control have been recently reported. The susceptibility to insecticides indoxacarb, methoxyfenozide, and emamectin benzoate was then evaluated in a L. botrana population collected from a vineyard in Emilia-Romagna (northeastern Italy) where pest management programs achieved unsatisfactory results. The field trial showed that the indoxacarb efficacy toward L. botrana was very low in the two timings of application (7.9 and -1.5%) in comparison with untreated control, while the efficacy of methoxyfenozide (76.1%) and emamectin benzoate (88.8%) was high. The decreased efficacy of indoxacarb was also supported by the results of the laboratory bioassay on neonate L. botrana larvae, in which the resistance ratio was 72-fold in comparison with that of the susceptible strain. PMID- 25026690 TI - Susceptibility of the rice stem borer, Chilo suppressalis (Lepidoptera: Crambidae), to flubendiamide in China. AB - The rice stem borer, Chilo suppressalis (Walker), is an important rice pest in China, and has evolved resistance to several classes of insecticides. Flubendiamide is a phthalic diamide insecticide that shows selective insecticidal activity against lepidopterous insects. The susceptibility of 40 field populations of C. suppressalis, collected in 2011 and 2012 in seven provinces of south-eastern China, to flubendiamide was determined through rice seedling dipping bioassay method. Of these 40 populations, seven populations that were seldom exposed to flubendiamide were used to set up the baseline sensitivity, and the LC50 value was 0.092 mg/L. Variation in susceptibility among the 40 field populations was high (34-fold). The range of mean lethal concentration (LC50) values in response to this chemical was between 0.032 mg/L (FS11) and 1.090 mg/L (JH12) across the populations. Substantial variations of the susceptibility to flubendiamide were detected among different geographic populations. There was no significant difference observed between years for most populations, except for populations from Jinhua and Lujiang. Resistance ratios to the chemical ranged from 0.8 to 11.8, indicating that most colonies remained susceptible or showed certain decrease in susceptibility. It was found that 16 of the 40 populations had some level of resistance. However, moderate level of resistance was discovered in only one population from JH12 from Zhejiang province (11.8-fold). Other 15 populations showed low level of resistance (5.1-9.3-fold) to flubendiamide. These data are useful in future monitoring programs for detecting any changes in susceptibility as a result of using flubendiamide. PMID- 25026691 TI - Genetic structure and colonization history of the fruit fly Bactrocera tau (Diptera: Tephritidae) in China and Southeast Asia. AB - Bactrocera tau (Walker), a major invasive pest worldwide, was first described in Fujian (China) in 1849 and has dispersed to tropical and subtropical Asia and the South Pacific region. Few data are available on its colonization history and expansion processes. This pilot study attempted to reconstruct the colonization history and pathways of this pest in China and neighboring Southeast Asian countries based on mitochondrial DNA. Results of the study showed six genetic groups corresponding to geographical characteristics, although the pattern was relatively weak. Homogeneous genetic patterns were observed within southern and central China, and northern Vietnam. Continuous colonization from the coast of southern China to inland regions of China and northern Vietnam was suggested. Strong genetic structure was observed in western China, Thailand, and Laos. The isolation of four of the six groups was most probably attributable to major topographical barriers of western China. Yunnan acted as a contact zone of B. tau in China and neighboring Southeast Asia. The absence of isolation by distance and the overall low phylogeographic structure of B. tau suggested that long distance dispersal events and human activities could play a major role in the colonization and expansion patterns of B. tau. By analyzing the genetic diversity, gene flow, haplotype phylogeny, and demographic history of 23 fly populations, we hypothesized that B. tau could have been introduced long ago in southern China, from which it further expanded or that southern China could correspond to the native range of this species. PMID- 25026692 TI - Impact of temperatures on Hessian fly (Diptera: Cecidomyiidae) resistance in selected wheat cultivars (Poales: Poaceae) in the Great Plains region. AB - Changes in temperature can result in fundamental changes in plant physiology. This study investigated the impact of different temperatures from 14 to 26 degrees C on the resistance or susceptibility to the Hessian fly, Mayetiola destructor (Say), of selected wheat cultivars that are either currently popular in the Great Plains area or soon to be released to this region. We found that many wheat cultivars including 'Bill Brown,' 'Byrd,' 'Endurance,' 'Fuller,' 'GA 031257-10LE34,' and 'KS09H19-2-3' were susceptible to Hessian fly infestation at > or = 20 degrees C, but became resistant at a certain lower temperature, depending on different cultivars. These cultivars were classified as Hessian fly susceptible according to the traditional standards, and their impact on Hessian fly management needs to be reevaluated. However, many wheat cultivars that were resistant at < or = 20 degrees C became destabilized at a certain higher temperature. Phenotypic variations among the resistant cultivars at different temperatures were also observed, suggesting potential different resistance mechanisms. Studies on the genetic and molecular mechanisms associated with resistance at different temperatures are needed, which may lead to improved wheat cultivars with more durable resistance to Hessian fly infestation. PMID- 25026693 TI - Characterization of eight Russian wheat aphid (Hemiptera: Aphididae) biotypes using two-category resistant-susceptible plant responses. AB - Eight biotypes of the Russian wheat aphid, Diuraphis noxia (Kurdjumov), have been discovered in the United States since 2003. Biotypes are identified by the distinct feeding damage responses they produce on wheat carrying different Russian wheat aphid resistance genes, namely, from Dn1 to Dn9. Each Russian wheat aphid biotype has been named using plant damage criteria and virulence categories that have varied between studies. The study was initiated to compare the plant damage caused by all the eight known Russian wheat aphid biotypes, and analyze the results to determine how Russian wheat aphid virulence should be classified. Each Russian wheat aphid biotype was evaluated on 16 resistant or susceptible cereal genotypes. Plant damage criteria included leaf roll, leaf chlorosis, and plant height. The distribution of chlorosis ratings followed a bimodal pattern indicating two categories of plant responses, resistant or susceptible. Correlations were significant between chlorosis ratings and leaf roll (r(2) = 0.72) and between chlorosis ratings and plant height (r(2) = 0.48). The response of 16 cereal genotypes to feeding by eight Russian wheat aphid biotypes found RWA1, RWA2, RWA6, and RWA8 to differ in virulence, while Russian wheat aphid biotypes RWA3, RWA4, RWA5, and RWA7 produced similar virulence profiles. These biotypes have accordingly been consolidated to what is hereafter referred to as RWA3/7. Our results indicated that the five main biotypes RWA1, RWA2, RWA3/7, RWA6, and RWA8 can be identified using only four wheat genotypes containing Dn3, Dn4, Dn6, and Dn9. PMID- 25026694 TI - Efficacy of aerosol applications of methoprene and synergized pyrethrin against Tribolium castaneum adults and eggs. AB - Experiments were performed to determine the efficacy of a single aerosol application of the insecticides methoprene and piperonyl butoxide-synergized pyrethrin, alone or in combination, and the insecticide carrier, Isopar M, against Tribolium castaneum (Herbst), the red flour beetle. The initial test exposed adults to insecticide treatments and placed male/female pairs in flour. All adults exposed to synergized pyrethrin were knocked down for at least 24 h after exposure but they recovered. High adult survival and similar average numbers of living F1 progeny were produced regardless of treatment exposure. In a separate test, insecticide treatments were directly applied to newly laid eggs, which resulted in the suppression of egg hatch. Synergized pyrethrin was the most effective insecticide (P < or = 0.001) for suppressing egg hatch. The effect of flour on insecticide activity to eggs and consequent insect development was also evaluated. An amount of 0.01 g of flour in the exposure arena, 62-cm2 area, was not sufficient for individuals to develop beyond the early larval stages, regardless of the treatment. As the flour amount in the arena increased from 1 to 5 g, the number of eggs that could develop to the adult stage increased, but this number was significantly lower in the insecticide treatments than in the control or carrier treatments. The results of the later tests indicate a high efficacy of the insecticides alone or in combination on T. castaneum egg hatch and development to the adult stage. PMID- 25026695 TI - Molecular diagnostics of Drosophila suzukii (Diptera: Drosophilidae) Using PCR RFLP. AB - The invasive spotted wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), has become a serious pest in the United States. Identification of immature and poorly preserved specimens can be difficult. A molecular diagnostic method for distinguishing D. suzukii from other Drosophila spp. associated with fruit in the United States was developed. A 709-bp region of the mitochondrial DNA cytochrome oxidase I gene was amplified from D. suzukii collections in the United States and compared with sequences of other Drosophila taxa from GenBank. Based on DNA sequence polymorphisms, a polymerase chain reaction-restriction fragment length polymorphism analysis using the restriction enzyme Msp-I was found to differentiate D. suzukii from other Drosophila spp. in the United States. This technique can identify field-collected specimens from various sources and specimens regardless of life stage. This molecular diagnostic method will be useful for monitoring the spread of this economically important invasive insect. PMID- 25026696 TI - Type of intercept trap not important for capturing female Sirex noctilio and S. nigricornis (Hymenoptera: Siricidae) in North America. AB - Current detection tools for Sirex noctilio F. (Hymenoptera Siricidae) in North America are poor. To determine the importance of intercept trap type for capturing females of S. noctilio and its native congener, Sirex nigricornis F., in eastern North America, we report on seven trap comparison studies from different years and geographic locations. Among studies, total numbers of S. noctilio captured were low (mean of < or = 1 wasp per trap). Total numbers of S. nigricornis caught were generally greater, and ranged from a mean of 1-13 wasps per trap. Nearly all studies found no significant differences among intercept trap types in the number of woodwasps caught. For future studies, we recommend that either panel or 12-unit Lindgren funnel traps be used to catch S. noctilio or S. nigricornis in eastern North America. PMID- 25026697 TI - Profiling flavonoid cytotoxicity in human breast cancer cell lines: determination of structure-function relationships. AB - Flavonoids have been shown to be cytotoxic to cancer cells. However, the mechanism of cytotoxicity has not been clearly defined. It has previously been reported that HER2/ERBB2, the estrogen receptor, progesterone receptor, and p53 were required for flavonoid induced cytotoxicity in breast cancer cell lines. We have used a panel of breast cancer cell lines, known to contain as well as be deficient in these signaling pathways, to screen fourteen different flavonoids. Comparing the cytotoxicity for all flavonoids allows us to determine if a structure-functional relationship exists between cytotoxicity and flavonoid, and if a particular signaling pathway is required for cytotoxicity. We show that several flavonoids are cytotoxic to all cell lines including primary mammary epithelial cells tested. The cytotoxic flavonoids are also able to inhibit Mitochondrial Outer Membrane Permeability while at the same time stimulate ATP levels whereas the non-cytotoxic flavonoids are not able to do this. We also show that both cytotoxic and non-cytotoxic flavonoids can transverse the cell membrane to enter MDA-MB-231 cells at different levels. Finally, all flavonoids regardless of their cytotoxicity were able to induce some form of cell cycle arrest. We conclude that for flavonoids to be strongly cytotoxic, they must possess the 2,3 double bond in the C-ring and we believe the cytotoxicity occurs through mitochondrial poisoning in both cancer and normal cells. PMID- 25026698 TI - Induced production of new diterpenoids in the fungus Penicillium funiculosum. AB - The supplementation of a DNA methyltransferase inhibitor, 5-azacytidine (5-AZ), to the culture medium of Penicillium funiculosum, dramatically altered its metabolic profiles. Analysis of the culture broth extract led to the isolation of two new prenyleudesmane diterpenoids (1-2). The isolated compounds were further evaluated for their cytotoxic and antibacterial activities. Our findings confirmed that the use of chemical epigenetic modifiers is an effective technique for promoting the expression of silent biosynthetic pathways to produce unique secondary metabolites. PMID- 25026699 TI - Prediction of anticancer activity of diterpenes isolated from the paraiban flora through a PLS model and molecular surfaces. AB - The aim of this work was to predict the anticancer potential of 3 atisane, and 3 trachylobane diterpene compounds extracted from the roots of Xylopia langsdorffiana. The prediction of anticancer activity as expressed against PC-3 tumor cells was made using a PLS model built with 26 diterpenes in the training set. Significant statistical measures were obtained. The six investigated diterpenes were applied to the model and their activities against PC-3 cells were calculated. All the diterpenes were active, with atisane diterpenes showing the higher pICso values. In human prostate carcinoma PC-3 cells, the apoptosis mechanism is related to an inhibition of IKK/NF-KB. Antioxidant potential implies a greater electronic molecular atmosphere (increased donor electron capacity), which can reduce radical reactivity, and facilitate post donation charge accommodation. Molecular surfaces indicated a much greater electronic cloud over atisane diterpenes. PMID- 25026700 TI - Cladieunicellin J, a new hydroperoxyeunicellin from cladiella sp. AB - A new 6-hydroperoxyeunicellin diterpenoid, designated as cladieunicellin J (1), was isolated from an octocoral Cladiella sp., and its structure elucidated by spectroscopic methods. Compound 1 was found to exhibit cytotoxicity toward CCRF CEM human T-cell acute lymphoblastic leukemia. PMID- 25026701 TI - Triterpene saponins from the sea cucumber Stichopus chloronotus. AB - Sea cucumbers have been used as a dietary delicacy and important ingredient in Asian traditional medicine and functional foods over many centuries. Using combined chromatographic methods, six triterpene saponins (1-6), including a new compound, stichloroside F (1), were isolated from a methanol extract of the sea cucumber Stichopus chloronotus Brandt. Their structures were determined on the basis of spectroscopic (1H and 13C NMR, HSQC, HMBC, 1H-1lH COSY, ROESY) and FTICR MS data and by comparison with literature values. PMID- 25026702 TI - Ferulaldehyde and lupeol as direct and indirect antimicrobial compounds from Cordia gilletii (Boraginaceae) root barks. AB - Cordia gilletii De Wild (Boraginaceae), a medicinal plant used against infectious diseases in the Democratic Republic of Congo, was investigated for direct and indirect antimicrobial properties. On one hand, the methanol extract is active against many pathogenic bacteria, including resistant strains. Its bio-guided fractionation led to the isolation of ferulaldehyde; this compound showed antimicrobial and antioxidant properties that may support the activity we observed for the methanol extract and some of the traditional uses of C. gilletii. On the other hand, the n-hexane extract of root barks possesses indirect antimicrobial properties, enhancing the activity of antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). The fractionation of this extract led to the isolation of lupeol, which decreases the minimum inhibitory concentration of several antibiotics (4 to 8 fold) against MRSA and contributes to the effects observed for the raw n-hexane extract. PMID- 25026703 TI - New C20-diterpenoid alkaloids from Delphinium laxicymosum var pilostachyum. AB - From the whole herb of Delphinium laxicymosum var pilostachyum, three new C20 diterpenoid alkaloids, laxipilostine, laxipilosdine, and laxipilosline (1-3), were isolated, together with fourteen known diterpenoid alkaloids. Their structures were determined by extensively interpretation of their spectroscopic data (1D- and 2D-NMR, MS, and IR). PMID- 25026704 TI - Torrubiellone E, an antimalarial N-hydroxypyridone alkaloid from the spider pathogenic fungus Torrubiella longissima BCC 2022. AB - Torrubiellone E (1), a new N-hydroxypyridone alkaloid, was isolated from the spider pathogenic fungus Torrubiella longissima BCC 2022, together with the known compounds, torrubiellones A (2) and B (3), and JBIR-130 (4). Compound 1 exhibited antimalarial activity against Plasmodium falciparum K1 with an IC5 value of 3.2 microg/mL, while it also showed weak cytotoxic activities. PMID- 25026705 TI - Shoot accumulation kinetics and effects on herbivores of the wound-induced antioxidant indole alkaloid brachycerine of Psychotria brachyceras. AB - A major shoot-specific monoterpene indole alkaloid produced by Psychotria brachyceras, brachycerine, is regulated by either wounding or jasmonate application. Highest concentrations of the alkaloid are found in inflorescences, suggesting a defence role. Brachycerine has antimutagenic and antioxidant properties, capable of quenching singlet oxygen, hydroxyl radical, and superoxide. This study aimed at characterizing the putative role of brachycerine in P. brachyceras responses to wounding and herbivory. Damage to leaves increased the content of brachycerine locally. Wounding did not affect phenolics content in P brachyceras leaves, and no tannins were detected in the species. In generalist herbivore bioassays, neither brachycerine nor P. brachyceras extracts showed toxic effects. In vivo hydrogen peroxide staining assay showed less wound generated peroxide accumulation in alkaloid treated tissues. This pattern was confirmed in quantitative assays measuring tissue hydrogen peroxide concentrations. Data indicate that brachycerine is not a herbivore deterrent, but rather an indirect chemical defence, modulating oxidative stress caused by mechanical damage. PMID- 25026706 TI - Diastereoselective synthesis of (+)-pseudohygroline via proline-catalyzed alpha hydroxylation. AB - A highly diastereoselective total synthesis of (+)-pseudohygroline (1) starting from D-proline is described using Wittig olefination and MacMillan-alpha hydroxylation as key reactions. (+)-Pseudohygroline is an important molecule in alkaloid chemistry as it was prepared as part of the first chemical proof of the absolute stereochemistry of biosynthetically important (+)-hygroline (2) and (+) hygrine (3). PMID- 25026707 TI - Identification of nucleosides and nucleobases from cultured Cordyceps militaris. AB - Four nucleosides and seven nucleobases were isolated from the BuOH subfraction of the extract of cultured Cordyceps militaris; one of them, 6-acetylpurine (1) is a new natural compound. The structure of I was determined on the basis of HR-ESI MS, and I D and 2D NMR spectroscopic analysis. PMID- 25026708 TI - Orthosiphol A from the aerial parts of Orthosiphon aristatus is putatively responsible for hypoglycemic effect via alpha-glucosidase inhibition. AB - An infusion of Orthosiphon aristatus has long been used for diabetes therapy; however, the active principles remained unknown. Herein, we report the identification of the putative agents responsible for this antidiabetic activity using an a-glucosidase-guided isolation. Four flavonoids named sinensetin (1), salvigenin (2), tetramethylscutellarein (3) and 3,7,4'-tri-O-methylkaempferol (4), together with a diterpenoid named orthosiphol A (5), were characterized, based on analysis of their spectroscopic data. Flavonoids 3 and 4 inhibited yeast a-glucosidase with IC,o values of 6.34 and 0.75 mM, respectively, whereas orthosiphol A (5) selectively inhibited intestinal maltase with an IC5o, value of 6.54 mM. A kinetic investigation of 5 indicated that it retarded maltase function in a noncompetitive manner. PMID- 25026709 TI - Chemical components of Ardisia splendens leaves and their activity against coxsackie A16 viruses. AB - Using a combination of chromatographic methods, one new flavonol glycoside, myricetin 3,7-di-O-alpha-L-rhamnopyranoside (1), and nine known compounds myricitrin (2), quercetin 3,7-di-O-alpha-L-rhamnopyranoside (3), quercitrin (4), desmanthin-l (5), myricetin 3-O-(3"-O-galloyl)-alpha-L-rhamnopyranoside (6), (+) catechin (7), benzyl O-1-D-glucopyranoside (8), 2-phenylethyl O-beta-D glucopyranoside (9), and corilagin (10) were isolated from the leaves of Ardisia splendens Pit. Based on an in vitro test against Coxsackie viruses A16 by SRB assay, only compounds 2, 5, and 10 exhibited activity against Coxsackie viruses A16 with IC50 values of 40.1, 32.2, and 30.5 microM, respectively. This result suggested that compounds 2, 5, and 10 might be potential agents for treating hand, foot and mouth diseases. PMID- 25026710 TI - Glycosylation of quercetin with cultured plant cells and cyclodextrin glucanotransferase. AB - Quercetin was glucosylated by cultured plant cells of lpomoea batatas to its 3- and 7-O-beta-D-glucosides, and 3,7-O-beta-D-diglucoside. On the other hand, further glycosylation of quercetin 3-O-beta-D-glucoside by cyclodextrin glucanotransferase gave the 3-O-beta-maltoside, 3-O-beta-maltotrioside, and 3-O [beta-maltotetraosides of quercetin. PMID- 25026711 TI - Nectandra amazonum-derived flavonoids as COX-1 inhibitors: in vitro and docking studies. AB - The ability of eleven known flavonoids isolated from Nectandra amazonum (Lauraceae) was tested for in vitro PGHS (COX) inhibition. All test compounds exhibited a dose dependent activity at different levels, exhibiting selectivity towards COX-I inhibition. Autodock Vina was used to dock the compound structures within the active site of the PGHS-1 (PDB: 3N8V). In vitro results showed that chalcone and dihydrochalcone-related compounds exhibited reasonable inhibitory properties (IC50: 1.56-36.5 microM), with good correlation with docking results. Argl20 (or Tyr355) and Ser530 were found to be the key residues to dock the most active flavonoids, indicating such interaction might interfere with the formation of prostaglandin H2 in the active site of COX-I. PMID- 25026712 TI - New dihydrochalcone and propenamide from Lithocarpus polystachyus. AB - Two new compounds, (E)-4-(3, 4-dihydroxyphenyl)-N-(1 -hydroxy-2-(4-hydroxyphenyl) ethyl)-2-oxobut-3-enamide (1) and phloretin2-O-beta-apiofuranosyl (1-->06)-beta-D glucopyranoside (2) were isolated from Lithocarpus polystachyus Rehd. Their structures were determined on the basis of analysis of their 1D and 2D NMR spectroscopic and mass spectral data. PMID- 25026713 TI - Two new diphenylmethyl-substituted xanthones from Seicuridaca longepedunculata. AB - Two new diphenylmethyl-substituted xanthones, named muchimangins K (1) and L (2), have been isolated from the roots of Securidaca longepedunculata (Polygalaceae) collected in the Democratic Republic of Congo. Their structures were established by analyses of the spectral data, including 2D NMR spectra, to be 1 ,3,6,8 tetrahydroxy-2.5-dimethoxy-4-[ -(2,4,5-trimethoxyphenyl)-1-phenylmethyl]xanthone (1) and 1,3,6-trihydroxy-4,7-dimethoxy-2-[1-(2,4,5-trimethoxyphenyl)- 1 phenylmethyl]xanthone (2). PMID- 25026714 TI - Cytotoxic constituents from the Vietnamese fungus Xylaria schweinitzii. AB - Two new fungal pigments named schweinitzins A and B (1-2), together with (S) torosachrysone-8-O-methyl ether (3) and emodin-6,8-di-O-methyl ether (4) have been isolated from the methanolic extract of the fruit bodies of Xylaria schweinitzii (Xylariaceae) collected in Cuc Phuong national park, Ninh Binh province, Vietnam, by silica gel column chromatography and preparative HPLC. Their structures were elucidated by spectroscopic analysis such as IR, UV-Vis, 2D NMR and FT-ICR-MS. In addition, two compounds (1 and 3) showed strong cytotoxicity against all four cancer cell lines, KB (a human epidermal carcinoma), MCF7 (human breast carcinoma), SK-LU-I (human lung carcinoma) and HepG2 (hepatocellular carcinoma). PMID- 25026715 TI - Pro-inflammatory cytokines and nitric oxide inhibitory constituents from Cassia occidentalis roots. AB - The anti-inflammatory and cytotoxic activity of thirty-six extracts of nine Indian medicinal plants were determined by measuring the inhibition of production of nitric oxide (NO), interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Their cytotoxic activity against macrophages was determined by MTT assay. The ethyl acetate (EtOAc) extract of Cassia occidentalis L. (roots) (IC50 = 21.3 to 43.1 microg/mL) and Mimosa pudica (whole plant) (1C50= 31.7 to 47.2 microg/mL) and the dichloromethane (DCM) extract of Leucas cephalotes (whole plant) (IC50 = 46.8 to 49.3 microg/mL) exhibited significant anti-inflammatory activity by in vitro inhibition of the production of TNF-alpha, IL-1beta and NO in LPS stimulated RAW 264.7 cells. Furthermore, the five compounds isolated from the ethyl acetate extract of Cassia occidentalis roots were found to suppress LPS-induced IL-1beta, TNF-alpha and NO production in a concentration-dependent manner in these cells at 1C50 values ranging from 22.5 to 97.4 microM. Emodin and chrysophanol were also found active in inhibiting pro-inflammatory cytokines in vivo. These findings justify an ethnopharmacological use of C occidentalis roots as an effective herbal remedy for the treatment and prevention of inflammation and associated ailments. PMID- 25026716 TI - Identification and modulatory activity assessment of 2-hydroxy-3,4,6 trimethoxyacetophenone isolated from croton anisodontus mull. Arg.(euphorbiaceae). AB - The n-hexane extract of the stem bark of Croton anisodontus yielded 2-hydroxy 3,4,6-trimethoxyacetophenone, a well-known substance, but isolated from this species for the first time. The antimicrobial and modulatory activities of the compound towards Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, C. krusei and C. tropicalis strains were assessed. Antibiotics such as amikacin, gentamicin and neomycin were used in a sub-inhibitory concentration. Significant activity was observed towards P. aeruginosa and S. aureus 358, with p < 0.001 in association with amikacin. The present results place C anisodontus as an alternative source of 2-hydroxy-3,4,6 trimethoxyacetophenone with antibacterial potential. PMID- 25026717 TI - Bioactive metabolites produced by the endophytic fungus Phomopsis sp. YM355364. AB - A new compound, 16-acetoxycytosporone B (1), along with four known ones, dankasterone A (2), dankasterone B (3), 3beta,5alpha,9alpha-trihydroxy-(22E,24R) ergosta-7,22-dien-6-one (4), and cyclonerodiol oxide (5), were isolated from Phomopsis sp. YM355364, an endophytic fungus of Aconitum carmichaeli. Their structures were characterized by spectral analysis. Compound 2 exhibited significant inhibitory activity against influenza A/Thailand/Kan353/2004(H5N1) pseudovirus with all IC50 value of 3.56 microM. Compounds 1, 2, and 4 showed either moderate or weak antifungal activities against four pathogenic fungi. PMID- 25026718 TI - Phloroglucinol derivatives present an antidepressant-like effect in the mice tail suspension test (TST). AB - The antidepressant-like effects of phloroglucinol and seven synthetic related derivatives were investigated using the tail suspension test (TST) in mice. Compounds 2-methyl-1-[2,4,6-trihydroxy-3-(2-methylpropanoyl)phenyl] propan-l-one (5), 1-(2,4,6-trihydroxyphenyl)ethan-l-one (6), 1-(3-acetyl-2,4,6 trihydroxyphenyl)ethan-l-one (7), 2-methyl-1 -[2,4,6-trihydroxy-3-(2 methylpropanoyl)-5-{ [2,4,6-trihydroxy-3,5-bis(2-methylpropanoyl)phenyl]methyl phenyl] propan-1-one (9) and 1-{3-acetyl-5-[(3,5-diacetyl-2,4,6 trihydroxyphenyl)methyl]-2,4,6-trihydroxyphenyl}ethan-1-one (10), containing acyl groups, decreased the immobile behavior of mice treated orally with equimolar doses of imipramine 20 mg/kg, with no alterations in locomotor activity as assessed by the open-field test. These results suggest that these phloroglucinol derivatives could represent a new molecular model in the search for antidepressant drugs. PMID- 25026719 TI - A new ellagic acid glycoside and DNA topoisomerase IB inhibitory activity of saponins from Putranjiva roxburghii. AB - Chemical investigation of the stem bark and leaves of Putranjiva roxburghii has resulted in the isolation of a new ellagic acid glycoside (5) along with four saponins (1-4). The structures of the isolated compounds were established by detailed spectral analysis. Incidentally putranoside-A methyl ester (4) has been isolated for the first time from this species and the saponins (1-4) exhibited potent DNA topoisomerase IB inhibitory activity. PMID- 25026720 TI - Antioxidant activity and phenolic composition of Corylus colurna. AB - Corylus colurna L. (Turkish hazel), a common hazel species in Europe, could be considered as a source of pharmacologically important natural compounds, since other members of the Corylus genus have been reported to contain several constituents with beneficial biological activity. Nevertheless, its phytochemical exploration is still incomplete. In this study the potent antioxidant phenolic compounds in different parts of the plant were investigated. The phenolics in the leaves, bark, catkins and involucre of C. colurna possess notable scavenger activity on both DPPH and ABTS free radicals. The total polyphenol content shows significant correlation with the antioxidant activity of the samples. Twenty three phenolic compounds - hydroxycinnamic acid derivatives, flavonoid derivatives and diarylheptanoids - were characterized in the C. colurna extracts by LC-DAD, LC-ESI-TOF and LC-ESI-QQQ-MS. PMID- 25026721 TI - Glycosylation of artepillin C with cultured plant cells of Phytolacca americana. AB - Biotransformation of artepillin C was investigated using cultured plant cells as biocatalysts. Artepillin C was converted into its 4- and 9-beta-D-glucosides, and 4,9-beta-D-diglucoside by cultured cells of Phytolacca americana. In contrast, cultured lpomoea batatas cells glucosylated artepillin C to only its 4- and 9 beta-D-glucosides. PMID- 25026722 TI - Synthesis of substituted 1,3-diesters of glycerol using wittig chemistry. AB - 1,3-di-O-Cinnamoyl-glycerol is a natural compound isolated from a Jamaican medicinal plant commonly referred to as Ball moss (Tillandsia recurvata). The synthesis of this compound was achieved via a Wittig chemistry process. The synthetic approach started with acylation of a di-protected glycerol with cinnamoyl chloride, deprotection of the glycerol moiety, reaction of the primary alcohol with bromo acetylbromide followed by treatment with triphenyl phosphine to give the corresponding phosphonium bromide. The phosphonium bromide was then converted in situ to the Wittig reagent which is the basis for a novel route to 1,3-di-O-cinnamoyl glycerol. Four analogs were also synthesized, three of which are new and are being reported in this article for the first time. The new compounds include 3-(3,4-diemthoxy-phenyl)-acrylic acid 2-hydroxy-3-(3-ptolyl acryloyloxy)-propyl ester (3), 2-acetoxy-5-((E)-3-(3-((E)-3-(3,4 dimethoxyphenyl)acryloyloxy)-2-hydropropoxy)-3-oxoprop- 1-enyl)benzoic acid (4) and 4-((E)-3-(3-((E)-3-(3,4-dimethoxyphenyl)acryloyloxy)-2-hydropropoxy)-3 oxoprop-1-enyl)benzoic acid (5). The compounds showed no activity in our anticancer assay. PMID- 25026723 TI - In vitro cancer cell growth inhibition and antioxidant activity of Bombax ceiba (Bombacaceae) flower extracts. AB - The flowers of Bombax ceiba were investigated for their chemical composition, antioxidant effects and antiproliferative activity against seven human cancer cell lines. The antiproliferative responses of diethyl ether (DE) and light petroleum (PE) extracts were evaluated by sulforhodamine B (SRB) assay against MCF-7, HeLa, COR-L23, C32, A375, ACHN, and LNCaP cells in comparison with a human normal cell line, 142BR. Moreover, extracts were characterized by GC-MS analysis and tested for their antioxidant properties by different in vitro systems, namely DPPH, Fe-chelating activity and beta-carotene bleaching test. Both PE and DE extracts showed the highest antiproliferative activity against human renal adenocarcinoma (ACHN) in a concentration-dependent manner. PE extract showed the highest radical scavenging activity against the DPPH radical, while DE extract was more active in the beta-carotene bleaching test. The presence of beta sitosterol and some fatty acids may contribute to the bioactivity of B. ceiba flower extracts. PMID- 25026724 TI - Trichocladinols I-K, oxatricyclic and oxabicyclic polyketides from Trichocladium opacum. AB - Three new polyketides, trichocladinols I-K (1-3) with oxabicyclic (1 and 3) and oxatricyclic (2) skeletons, together with three knovwnl metabolites, massarilactone G (4), massarigenin D (5), and rosigenin (6), were isolated from the solid-substrate fermentation cultures of the ascomycete fungus Trichocladium opacum. The structures of the new compounds were elucidated primarily by analysis of NMR data. The absolute configurations of 1-3 were deduced from circular dichroism (CD) data. Compounds 1-3 were tested for cytotoxicity against five human carcinoma cell lines, HeLa, A549, MCF-7, HCT116, and T24. Compound I showed a weak cytotoxic effect against HeLa cells, but 2 and 3 were inactive. PMID- 25026725 TI - Hedyotis diffusa water extract diminished the cytotoxic effects of chemotherapy drugs against human breast cancer MCF7 cells. AB - Hedyotis diffusa is a Chinese herbal medicine widely used in combination with other herbal medicines such as Scutellaria barbata to treat various types of cancer. Late-stage and recurrent cancer patients usually use H. diffusa during chemotherapy in expecting to achieve additive or synergistic therapeutic effects. Several classes of active ingredients, including anthraquinones, iridoid glucosides and stigmasterols. have been isolated and characterized from H. diffusa. In the current study, we isolated alkaloid/flavonoid from H diffusa and showed that the crude alkaloid/flavonoid extract rather than its three major components possessed antitumor activity against human breast cancer cell line MCF7. Co-administration of H. diffusa water extract diminished the cytotoxicities of chemotherapy drugs doxorubicin, cyclophosphamide and docetaxel towards the MCF7 cells, implicating that H. diffusa should not be used during breast cancer chemotherapy. PMID- 25026726 TI - Composition and chemical variability of Eucalyptus bosistoana essential oil from Algerian Sahara. AB - The composition of eight oil samples isolated from leaves of Eucalyptus bosistoana F. Muell., acclimatized in Tamanrasset (southern Algeria, Saharan climate), has been investigated by GC (retention indices), GC-MS and 13C NMR spectroscopy. T wo groups may be distinguished. The five samples of group I have their composition dominated by p-cymene (32.0-39.5%), cryptone (11.5-15.6%), 1,8 cineole (7.8-10.5%) and spathulenol (6.8-16.5%). The three oil samples of group II contained mainly 1,8-cineole (55.3-63.9%) and alpha-pinene (11.6-12.1%). PMID- 25026727 TI - Volatile constituents of Melissa officinalis leaves determined by plant age. AB - The present study investigated changes in the content and chemical composition of the essential oil extracted by hydrodistillation from air-dried Melissa officinalis L. (lemon balm) leaves in the first and second year of plant growth. The lemon balm oil was analysed by GC-MS and GC-FID. The presence of 106 compounds, representing 100% of the oil constituents, was determined in the oil. The predominant components were geranial (45.2% and 45.1%) and neral (32.8% and 33.8%); their proportions in the examined samples of the oil obtained from one- and two-year-old plants were comparable. However, the age of lemon balm plants affected the concentration of other constituents and the proportions of the following compounds were subject to especially high fluctuations: citronellal (8.7% and 0.4%), geraniol (trace amounts and 0.6%), and geranyl acetate (0.5% and 3.0%), as well as, among others, isogeranial, E-caryophyllene, caryophyllene oxide, germacrene D, and carvacrol. The essential oil of two-year-old plants was characterized by a richer chemical composition than the oil from younger plants. PMID- 25026728 TI - Chemical composition and antibacterial activity of essential oil and extracts of Citharexylum spinosum flowers from Thailand. AB - The chemical composition and antibacterial and antioxidant activities of the essential oil and various solvent extracts of Citharexylum spinosum flowers are reported. The chemical compositions were determined by GC-MS with 151 volatile constituents identified. Methyl benzoate, piperitone, maltol, and maple furanone were the major constituents. All extracts were tested for their antibacterial activity against eight microorganisms. The flower oil had the greatest antibacterial activity against all bacterial strains (MIC values of 31.2 microg/mL), while the other solvent extracts had MIC values ranging from 31.2 to 1000 microg/mL. The essential oil had the highest antioxidant activity and total phenol content with IC50 values of 62.7 and 107.3 microg/mL, respectively. PMID- 25026729 TI - Antimicrobial activity of Ammodaucus leucotrichus fruit oil from Algerian Sahara. AB - Three fruit oil samples of Ammodaucus leucotrichus Cosson & Durieu from Algerian Sahara were obtained by hydrodistillation and analyzed by GC(RI), GC-MS and 13C NMR spectroscopy. The main compounds were perillaldehyde (87.0-87.9%) and limonene (7.4-8.2%). The antimicrobial effect of the essential oil was evaluated against bacteria, yeasts and filamentous fungi. High antibacterial activity was observed against Escherichia coli, Staphylococcus aureus. Enterobacter cloaceae, Bacillus cereus and Salmonella typhimurium, with MIC values between 0.5-1.0 microL/mL. Fungal strains were also sensitive to the essential oil (MIC values: 0.25-0.75 microL/mL).The most potent activity was observed against the filamentous fungi, Fusarium oxysporum and Aspergillusflavus (0.25-0.50 microL/mL). PMID- 25026730 TI - Anti-Legionella activity of essential oil of Satureja cuneifolia. AB - The essential oil of Satureja cuneifolia Ten. was characterized by a high concentration of the phenolic compounds carvacrol (21.3%) and thymol (9.2%). The in vitro activity of the essential oil against Legionela pneumophila serogroups (SG) I and 2-15 and Legionella spp. from different sources, using microdilution, showed that L. pneumofila is sensitive to the oil, with MICs ranging from 0.12 to 0.5%, v/v, and a MBC at 0.5 to 1%, v/v. The essential oil of S. cuneifolia was effective in the reduction of Legionellosis infections. PMID- 25026731 TI - In vitro cytotoxic activity guided essential oil composition of flowering twigs of Stevia rebaudiana. AB - The essential oil extracted by hydrodistillation from the flowering twigs of Stevia rebaudiana Bertoni (Asteraceae) was fractioned by chromatography. Forty three constituents were characterized with the help of GC, GC-MS and other spectroscopic techniques. The essential oil was found to be a complex mixture of mono- and sesqui-terpenes. The cytotoxicity of the essential oil and its fractions was evaluated by sulforhodamine B (SRB) based assay against two cancer cell types viz. C-6 (rat glioma cells) and CHOK1 (Chinese hamster ovary cells). The essential oil and its fractions showed promising cytotoxicity against both cell lines. The highest activity (95.6+/-0.6%) was show by the essential oil on the C-6 cell line at a concentration of 400 microg/mL, which was comparable with that of the standard drug vinblastin. PMID- 25026732 TI - Chemical composition and termiticidal activity of essential oils from different tissues of Chinese cedar (cryptomeria fortunei). AB - In this study antitermitic activities of essential oils from different tissues of Chinese cedar (Cryptomeria fortunei Hooibrenk) against Reticulitermnes chinensis were investigated. In addition, the yields of essential oils obtained by water distillation were compared and their constituents determined by GC-MS analyses. The yields of bark, sapwood, heartwood, and leaf essential oils of Chinese cedar were 0.9, 0.4, 1.0, and 1.5%, respectively. GC-MS analyses showed that the major compounds of bark, sapwood, heartwood, and leaf essential oils of Chinese cedar were ferruginol (30.6%), y-cadinene (18.3%), y-cadinene (31.0%), and kaurene (30.6%), respectively. Bioactivity tests against R. chinensis demonstrated that the leaf and heartwood essential oils had an excellent effect, and the LC) values after 5 days were 0.9 and 1.8 microL/mL (LC90=1.4 and 2.9 microL/mL), respectively. The results of this study showed that the leaf and heartwood essential oils of Chinese cedar might be considered as a potential source of a fine natural termiticide. PMID- 25026733 TI - Chemical composition and anti-inflammatory activity of Chamaecyparis obtusa f.formosana wood essential oil from Taiwan. AB - Chamaecyparis obtusa Siebold & Zucc. f.formosana Hayata (Cupressaceae) is one of the treasured conifers in Taiwan. In this study, the wood essential oil of the species was extracted and its anti-inflammatory bioactivities analyzed. The composition analysis of the essential oil yielded a total of 57 compounds with alpha-terpineol (19.4%), tau-muurolol (16.9%), borneol (16%), and alpha-cadinol (10.9%) predominating. The anti-inflammatory assays of the essential oil suggest that C obtusa f. formnosana wood oil has no cytotoxicity, and was capable of inhibiting the expressions of tumor necrosis factor (TNF-alpha), IL-6, IL-1, pro IL-1beta, NO, iNOS, and NLRP3 in murine macrophage cells. It was unable, however, to inhibit the expression of COX-2. Further investigation of the effect of the essential oil on the cellular signal transduction indicated that it was capable of inhibiting ERKI/2, JNKI/2 and p38; it also showed excellent inhibition against ROS. Thus, the overall results indicated that C. obtusa f.formnosana wood oil had very good anti-inflammatory efficacies. PMID- 25026734 TI - Chemical composition and anti-inflammation activity of essential oils from Citrus unshiu flower. AB - Though many essential oils from citrus peels are claimed to have several medicinal functions, the chemical composition and biological activities of the essential oils of Citrus flowers have not been well described. Therefore, this study intended to investigate the chemical composition and anti-inflammatory potential of essential oils from C. unshiu flower (CEO) to support its purported beneficial health effects. The chemical constituents of the CEO, analyzed by gas chromatography-mass spectrometry (GC-MS), included y-terpinene (24.7%), 2-beta pinene (16.6%), 1-methyl-2-isopropylbenzene (11.5%), L-limonene (5.7%), beta3 ocimene (5.6%), and alpha-pinene (4.7%). The effects of the CEO on nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages were also examined. The results indicate that the CEO is an effective inhibitor of LPS-induced NO and PGE2 production in RAW 264.7 cells. Additionally, CEO was shown to suppress the production of inflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6. Based on these results, CEO may be considered a potential anti-inflammatory candidate with human health benefits. PMID- 25026735 TI - Composition, antioxidant and antimicrobial activities of methanol extracts of some Acinos Miller species. AB - GC and GC/MS analyses of the methanol extracts obtained from the aerial parts of six Acinos Miller species from Serbia and Montenegro were performed. Seventy-four constituents, accounting for 84.9-99.0% of the total composition of the extracts, were identified. The common feature of the A. suaveolens, A. majoranifolius and A. alpinus methanol extracts was the high content of monoterpenes, while the common feature of the A. graveolens, A. arvensis and A. hungaricus methanol extracts was the prevalence of sesquiterpenes. The total flavonoids, polyphenols and tannins content, as well as antioxidant activity (FRAP and DPPH assay) of the methanolic extracts were investigated. The highest antioxidant activity was observed in the extract of A. alpinus which had high levels of all polyphenol classes examined. A disk diffusion method was used for the evaluation of the antimicrobial activities of the extracts against a panel of microorganisms (bacteria: Bacillus subtilis, Clostridium pyogenes, Enterococcus sp., Micrococcus flavus, Sarcina lutea, Staphylococcus aureus, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella enteritidis and Escherichia coli; fungi: Aspergillus niger, Candida albicans and Saccharomyces cerevisiae). The preliminary bioassay results indicated that the methanol extract of A. alpinus could be a possible source of antioxidant and antimicrobial compounds. PMID- 25026736 TI - [The tooth in all its facets]. PMID- 25026737 TI - [A dentist or denturist can be held liable for damages resulting from an unsuitable denture]. AB - The placement of a denture can lead to complaints. Sometimes these complaints are inherent in the condition of the patient's mouth, but sometimes the problems are the result of a defect in the denture itself for example because of an incorrect design. When, in such a case, the patient is harmed, the question arises as to whether and from whom he can claim compensation. If the patient succeeds in demonstrating that the denture is unsuitable, then the dentist or denturist can be held liable, provided the failure can be attributed to him, according to his culpability or under the law. PMID- 25026738 TI - [Treatment options in a child with trauma in the front 1]. PMID- 25026739 TI - [Treatment of a 56 year old patient with loose front teeth 1]. PMID- 25026740 TI - [Persistent pain following endodontic treatment]. AB - Dental pain is a very common pain in the orofacial area. Patients sometimes experience persistent pain following endodontic treatment. The cause of this pain can be found in the endodontically treated tooth itself when the pain persists after an inadequately performed treatment. Persistent pain is also possible after an apparently adequate endodontic treatment. Moreover the pain can have an odontogenic origin, in cases where the diagnostic procedure may have failed. A non-odontogenic cause can be located in proximate or more remote structures, which may be a question of systemic diseases or pain from neuropathic, neurovascular and/or psychogenic conditions. A thorough clinical examination forms the basis for the establishment of a valid diagnosis. PMID- 25026741 TI - [Dissertations 25 years after date 35. Periodontal disease in Down syndrome: an immunological disorder]. AB - In Down syndrome the prevalence of periodontal disease is high. Twentyfive years ago in a series of controlled experiments, based on an experimental gingivitis model, clinical, histological and immunological characteristics of a group children with Down syndrome and matched control children were evaluated. In the Down syndrome children the gingival inflammation occurred earlier and was more extensive. On the tissue level the early response was characterized by a polymorphonuclear leucocytes response. Chemotaxis assays were performed to rule out impaired function. It was found that random migration for the peripheral blood-polymorphonuclear leucocytes and chemotaxis in both groups of children were comparable; hence such a factor cannot be responsible the early polymorphonuclear leucocytes' response in the children with Down syndrome. The most striking feature in the group with Down syndrome was the delayed and impaired response of lymphocytes during plaque development compared to the controls. This impaired lymphocyte function was also observed in a pilot study on 1 child with Down syndrome. It showed a less pronounced T cell suppressor function and a lack of immune regulation. The high level of gingival inflammation in children with Down syndrome must therefore be related to their impaired adaptive immunity. PMID- 25026742 TI - [Dentistry and healthcare legislation 6. The effect of self-regulation in dental healthcare]. AB - Regulations which have been established by the professional community or by an organization of which a dentist is a member (self-regulation) have a more significant legal effect on dental care than many dentists realize. A dentist can only deviate from these regulations if he does so when motivated by the patient's best interests. Self-regulation can be relevant at the level of the professional community, the organization or the individual dentist. Self-regulation should satisfy a number of criteria if it is to be applicable to an entire professional community, specifically: it must be sufficiently authoritative, it must harmonize with existing laws and regulations and it must be easily accessible to both professionals and patients. The application of self-regulation is sometimes limited to a specific group, for example dentists who have signed a working agreement with a certain health insurance provider or who work in a certain institution. Self-regulation can entail liability not only on the part of the healthcare professional but also, in theory, on the part of those who establish the regulations. PMID- 25026743 TI - [Oral medicine 10. Pigmented lesions of the oral mucosa]. AB - Pigmented oral lesions may be due to the most diverse disorders. A distinction can be made between non-melanin-associated and melanin-associated pigmentations. Some lesions may be diagnosed on the basis of medical history and clinical research. In focal pigmented lesions, histological examination is necessary to establish a definitive diagnosis. Most disorders are benign but some may be malignant melanomas. PMID- 25026744 TI - [Kidney protection therapy in acute limb ischemia]. AB - Acute limb ischaemia is relatively frequent in the population (800:1 million, with about 1000 cases per year in Zachodniopomorskie province) and is a life threatening condition due to significant mortality (about 15%) and a high percentage of amputation (up to 25%). Early death is mainly caused by metabolic disorders associated with reperfusion syndrome following surgical revascularisation. Muscle injury caused by rhabdomyolysis leads to acute renal failure, cardiopulmonary insufficiency and generalised inflammatory reaction. Prompt treatment according to the current recommendations, including extensive fasciotomy and intensive and early nephroprotective and renal replacement therapy, offers the only chance to reduce early mortality in patients suffering from this disease. Differences in approach to the problem of renal replacement therapy presented by nephrologists/internists and surgeons are frequent and do not improve treatment outcome. The aim of this paper is to establish a standard consensus between the approach of the vascular surgeon, nephrologist and internist to achieve the best possible treatment outcomes in patients with acute limb ischaemia. PMID- 25026745 TI - [Analysis of the chosen parameters of metabolic status in patients with psoriasis]. AB - INTRODUCTION: Psoriasis is a chronic inflammatory dermatosis leading to the development of systemic inflammatory reaction. Previous data indicated the coexistence of psoriasis and the occurrence of metabolic disorders, with the common background of both processes determined by a chronic inflammation. The coexisting disorders, including type 2 diabetes, hypertension, heart ischemic disease, dislipidemia and obesity may have an important impact on intensity of psoriasis activity. MATERIAL AND METHODS: The analysis comprised of 82 randomly matched patients with various clinical forms of psoriasis, aged 17 to 81 years. In patients PASI and BSA indexes, BMI value and laboratory parameters of metabolic status (glucose and ureic acid levels, lipid fractions and CRP level in the serum) were evaluated. RESULTS: An average age in examined group was 54,3 years, an average time of presence of psoriasis symptoms was approximately 20 years. An average PASI value was 21,4; an average BSA value was 39.7%. The coexistence of type 2 diabetes was found in 14.6% of patients, hypertension in 42.7% and heart ischemic disease in 17%. Particularly large group of examined patients comprised persons with overweight (34.1%) and obesity (30.5%). Positive correlation between BSA and body weight, BSA and BMI value, BSA and abdominal circumference as well as positive correlation between PASI and body weight, PASI and BMI value, PASI and abdominal circumference were observed. Abnormal serum glucose levels were observed in 19.5% persons, ureic acid level in 2.9%, total cholesterol in 37.8% LDL cholesterol in 48.8%, and HDL cholesterol in 46.3%. CRP level was elevated in 43.9% patients. Positive correlation between BSA and ureic acid level, as well as PASI and ureic acid level was estimated. No correlation between PASI and the other laboratory parameters was found. CONCLUSIONS: The occurrence of metabolic syndrome is more common in patients with psoriasis in comparison to the general population. The extent and severity of psoriatic lesions correlate with high body weight, BMI and the level of ureic acid. PMID- 25026746 TI - [Polymorphisms in the oxidative stress-related genes and cancer risk]. AB - Oxidative damage induced by the generation of reactive oxygen species (ROS) is thought to be related to human cancer aetiology. Oxidative stress can result in DNA damage, including oxidized bases, formation of DNA adducts and DNA strand breaks, as well as lipid peroxidation, protein modification, membrane disruption and mitochondrial damage. The effect of reactive oxygen species is balanced by the antioxidant action ofnonenzymatic antioxidants (e.g. vitamins A, C, E, glutathione and flavonoids), as well as antioxidant enzymes. There are three main types of antioxidant defence enzymes: superoxide dismutases, catalase and glutathione peroxidases. A variety of cancer cells are known to have lower antioxidant enzyme activity when compared with their normal counterparts. Many studies have examined genetic variation in the genes coding for these enzymes and their relationship to cancer risk. Only a few genetic variants (single nucleotide polymorphisms--SNPs) in genes related to antioxidant defence were found to be associated with breast, prostate, lung, pancreatic, colorectal and bladder cancer. However, the results from these have been contradictory. Moreover, it is believed that environmental as well as genetic factors are implicated in the development of cancers, and consequently it is important to assess both genetic (including gene-gene association) and non-genetic (e.g. diet, supplementation, smoking and alcohol consumption) variability in the activities of defence enzymes in relation to cancer. In this review we focus on the biological function of antioxidant defence enzymes, and relationship between well-known SNPs in SOD1, SOD2, CAT, GPX1 and GPX4 genes and genetic susceptibility to cancer. PMID- 25026747 TI - [Self-concept in subjects after first heart attack, patients with selected dermatological diseases and healthy individuals]. AB - INTRODUCTION: This work is aimed at comparing the self-concept of individuals suffering from somatic diseases differing in the severity of symptoms and their visibility. MATERIAL AND METHODS: The study was carried out in three groups of subjects aged 30 to 65 years, with an even proportion of males and females: 160 dermatological patients, 160 patients after first heart attack and 160 healthy individuals. The structure and content of self-concept were measured with The Wheel Questionnaire by Ben Shalit. CONCLUSIONS: Somatically ill individuals revealed lower levels of self-acceptance and motivation for psychological change than healthy individuals, and they also possessed less self-knowledge then healthy subjects. These qualities of self-concept can diminish the adaptive abilities of ill persons. Therefore, the aims of psychological work with these patients should include enhancing their self-acceptance and willingness to change, as well as widening their self-awareness by encouraging reflection and exploration of various areas of experiencing and functioning. PMID- 25026748 TI - [Association between AIF-1 gene polymorphisms and response to rheumatoid arthritis treatment with sulphasalazine]. AB - INTRODUCTION: AIF-1 is an inflammatory cytokine influencing the immune system. There are increased levels of AIF-1 in the synovial fluid of patients with rheumatoid arthritis (RA). Sulfasalazine still remains the mainstay for the treatment of RA. It has an anti-inflammatory effect, inhibiting the action of inflammatory mediators. The aim of our study was to examine the association between AIF-1 (rs2269475:C>T, rs2736182:G>A, rs2259571:A>C) polymorphisms and response to sulfasalazine treatment in RA patients. MATERIAL: A total of 112 RA patients were enrolled in the study. RESULTS: There were no statistically significant associations between AIF-1 polymorphisms and response to sulphasalazine treatment. CONCLUSION: The results of this study suggest a lack of association between AIF-1 gene polymorphisms and response to sulphasalazine treatment. PMID- 25026749 TI - The evaluation of the treatment results in patients with a small closed pneumothorax. AB - INTRODUCTION: The aim of this study was to analyze the methods and results of the treatment of patients with a small closed pneumothorax. MATERIAL AND METHODS: The results of the treatment of 34 patients hospitalized for trauma in 2000-2010 due to a small closed pneumothorax were assessed. There were 23 men and 11 women. The age of the patients ranged from 20-84 years (av. 48.5). 15 patients had trauma affecting the right side, and 19 had left side trauma. In 10 cases the pneumothorax was associated with multiple trauma. In 24 cases fracture of the ribs (av. 3.4) was revealed in radiological examination. In 10 patients radiographs did not show fracture of the ribs (in 5 of these patients, a clinical trial indicated a fracture of one rib, not visible on x-ray). The size of the pneumothorax in chest radiographic anterior-posterior projection ranged from 0.5 2 cm (av. 1.2). Conservative treatment was monitored through radiological examination. RESULTS: In 33 patients spontaneous pneumothorax resorption was observed. In one patient it was necessary to apply pleural drainage due to the enlargement of the pneumothorax and the appearance of symptoms of respiratory failure. In one case it was necessary to puncture the pleural cavity to remove a hematoma occurring along with the pneumothorax. Good results of treatment were achieved in all cases. CONCLUSIONS: In conclusion, the conservative treatment of a small closed pneumothorax is effective in most cases. PMID- 25026750 TI - [Dihydropirymidine dehydrogenase (DPD)--a toxicity marker for 5-fluorouracil?]. AB - In proceedings relating to patients suffering from cancer, an important step is predicting response and toxicity to treatment. Depending on the type of cancer, physicians use the generally accepted schema of treatment, for example pharmacotherapy. 5-fluorouracil (5-FU) is the most widely used anticancer drug in chemotherapy for colon, breast, and head and neck cancer. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency, which is responsible for the metabolism of 5-FU, may experience severe side effects during treatment, and even death. In many publications the need for determining the activity of DPD is discussed, which would protect the patient from the numerous side effects of treatment. However, in practice these assays are not done routinely, despite the high demand. In most cases, a genetic test is used to detect changes in the gene encoding DPD (such as in the USA), but because of the large number of mutations the genetic test cannot be used as a screening test. Dihydropyrimidine dehydrogenase activity has been shown to have high variability among the general population, with an estimated proportion of at least 3-5% of individuals showing low or deficient DPD activity. In this publication we presents data about average dihydropirymidine dehydrogenase activity in various populations of the world (e.g. Japan, Ghana, Great Britain) including gender differences and collected information about the possibility of determination of DPD activity in different countries. Detection of reduced DPD activity in patients with planned chemotherapy will allow a lower dosage of 5-FU or alternative treatment without exposing them to adverse reactions. PMID- 25026751 TI - Effect of fluoride on sodium-proton exchanger activity, intracellular pH and calcium concentration in human non-stimulated platelets. AB - INTRODUCTION: Although the Na+/H+ exchanger (NHE) has been extensively investigated, studies on the effect of fluoride ions on the function of this protein are relatively few and controversial. The aim of this study was to analyze the effect of fluoride on the activity of the transmembrane NHE in human platelets. MATERIAL: The study material consisted of platelets in the form of platelet-rich plasma. CONCLUSIONS: Based on the obtained results, the following conclusions were formulated: fluoride may affect NHE activity in non-stimulated human platelets; changes in NHE activity depend on fluoride dose and exposure time; as fluoride concentration and/or exposure time is increased, NHE activity is inhibited; inhibition of NHE activity results in the accumulation of protons inside the platelets and a reduction in intracellular pH (intracellular acidification); the accumulation of protons inside the platelets is accompanied by an increase in intracellular calcium concentration. PMID- 25026752 TI - Diffuse trauma of the right lobe of the liver successfully treated without resection. Case report. AB - The victim of a motorcycle frontal crash was treated in a high reference teaching hospital for disruption of the right lobe of the liver (IV grade AAST/Moore). Primary packing, secondary biloma and abscess treatment including papillotomy and biliary stent, led, after 8 months, to cicatrisation of a damaged liver parenchyma. In conclusion, the authors stress that such injuries should be treated in highest level reference centres where all modern noninvasive interventional modalities are available, and that surgical resection is not always the operation of best choice. PMID- 25026753 TI - [Pemphigoid nodularis--diagnostic and therapeutic difficulties. A case report]. AB - The case of a 62-year-old female patient diagnosed with an extremely rare clinical variant of pemphigoid--nodular pemphigoid, imitating prurigo nodularis, is presented in the paper. In connection with the existence of the typical prurigo nodularis-like appearance in the patient, the diagnosis was maintained for several months. However, because of no response to the treatment and the remarkably chronic course of the disease, the patient was admitted to the Department in order to extend the diagnostics and verify the previous diagnosis. The direct and indirect immunofluorescence examinations performed on the patient enabled the final diagnosis of a rare variant of pemphigoid without typical blisters, and effective treatment was carried out. PMID- 25026754 TI - [Motor system physiotherapy of the masticatory organ]. AB - The motor system of the masticatory organ is a complex morphological and functional structure. Its dysfunctions are manifested by various symptoms within the masticatory apparatus and in distant organs. The paper presents a discussion on the physiotherapeutic procedure for the treatment of disorders in the motor system of the masticatory organ. Therapeutic methods are presented, including: massage, trigger point therapy, kinesitherapy, biofeedback, manual therapy, postural re-education, kinesiotaping, physical interventions (TENS, hyaluronidase iontophoresis, ultrasound, laser therapy, and magnetoledotherapy). The paper points out the role of a comprehensive approach to the patient in order to eliminate the cause of disorders, going beyond symptomatic treatment. PMID- 25026755 TI - [Evaluation of adaptation of FibreFill/Resilon post and Epiphany to the walls of the root canal. Scanning electron microscope study]. AB - BACKGROUND: The aim of the study was to evaluate the adaptation of sealer to the dentine and to the components of the post, i.e. the part made of composite reinforced with glass fibre and the part made of resilon. MATERIALS AND METHODS: The study was carried out on 7 extracted one-canal human teeth that were treated using Mtwo nickel-titanium instruments and an Endo IT Professional endodontic micromotor. The canals were rinsed with NaOCl, EDTA and chlorhexidine, and then filled with the Epiphany sealer and FibreFill posts. Next, tooth roots were cut along the frontal plane, to expose the entire lumen length of the filled canal, and inspected under the scanning electron microscope. RESULTS: SEM study demonstrated good adaptation of sealers to the walls of the root canals on their entire length, despite occasional gaps between the sealer and dentine. CONCLUSIONS: The results of preliminary studies suggest that FibreFill posts and Epiphany sealer are useful for canal filling. However, several-years' clinical follow-up is necessary for the complete evaluation of the system. PMID- 25026756 TI - [Cleanliness of the walls of root canals in teeth with incomplete development of root, rinsed with 2% chlorexidine. A SEM study]. AB - INTRODUCTION: The aim of the study was to evaluate the cleanliness of the walls of root canals with incomplete development of root, whose lumen was rinsed with 2% chlorhexidine solution during mechanical preparation. MATERIAL AND METHODS: Use was made of 8 maxillary premolar teeth with a single root canal and with incomplete development of the root apex (the teeth were removed during the growing stage for orthodontic reasons). The coronal and middle parts of the canals were instrumented using Gates-Glidden no. 3 and 4 drills, and the apical section with the help of Hedstroem size 50-80 files. During instrumentation of the canals irrigation was carried out using 2% chlorhexidine solution. Irrigating solution, volume 2 mL, was introduced into the canal with the use of a syringe and an endodontic needle after using each instrument, and 5 mL volume after complete instrumentation of the canal. RESULTS: Observations using a scanning electron microscope with x200 and x1000 magnification showed relatively effective removal of pulp remains and dentine chips, and the presence of a thick smear layer covering the canal walls throughout their length. Statistical analysis did not show significant differences in the degree of cleaning of particular sections of the canals. CONCLUSION: The presence of the smear layer in canals irrigated with chlorhexidine is evidence that it does not have properties for it to be dissolved, and this dictates the necessity of using chelating agents. PMID- 25026757 TI - Odontogenous sinus tract to the chin--case report. AB - This report describes the diagnosis, treatment and follow-up of a rare case of an odontogenic sinus tract to the chin. Despite the absence of caries, fillings, or crown damage, both lower central incisors were involved in a bony lesion. No history of any traumatic facial or dental injury was reported, and no orthodontic treatment with fixed appliances was performed. The findings on panoramic radiograph were incidental--the patient applied to the dental clinic due to a toothache in a lower first molar. The patient's history comprised seven-year-long unsuccessful dermatologic therapy. This included intraoral antibiotic and antihistamine intake, as well as topical antibiotic and steroid application. Endodontic treatment was proceeded, followed by recovery of the skin lesion. In the case of a single chronic suppurative or nodulocystic facial lesion, a dental clinical examination as well as a radiological assessment of the maxillary and mandibular dentition should be performed to exclude any odontogenic cause. PMID- 25026758 TI - The use of cortical screw anchorage for closing a space resulting from the loss of a lower molar--a case report. AB - Orthodontic microscrews are temporary implants providing skeletal anchorage, which may be used for en-masse incisor retraction, as well as for the protraction of posterior segments in order to close spaces without retracting anterior teeth. A patient, aged 16 was reported in whom a miniscrew of 9.5 mm length and 2 mm dimension was inserted distal to the lower left second premolar 2 months after extracting the first molar with periapical bone lesion after failed endodontic treatment. The lower third molar was mesialised using direct anchorage and a power arm to minimize mesial tipping. The space closed within 20 months, followed by a spontaneous eruption of the adjacent third molar. This treatment method constitutes a good alternative to third molar autotransplantation, allowing the avoidance of the risk of surgical procedure. PMID- 25026759 TI - The influence of age at menarche on the prevalence of disorders of the menstrual cycle among healthy university students. AB - INTRODUCTION: Many research findings indicate long-term health risks of early age at menarche. The aim of the present study was to determine the effects of early and late onset of menarche on menstrual disturbances and anthropometric measures among university students. MATERIAL AND METHODS: The research was carried out among 566 students of the Jagiellonian University. Measurements of the height, weight and waist circumference were taken for each person. The age at the first menstruation was assessed by a retrospective method based on information given by the students. Data related to the pattern of the menstrual cycle were gathered by a survey. RESULTS: The group featured an average age at menarche of 12.71, ranging between 10 and 17 years. The post--menarchal year was at least 5. According to percentiles, the females were divided into three groups of different puberty rate. Significant differences were observed in the pattern of menstrual cycles with relation to age at menarche. Among the early- and late-maturing group irregular cycles were more frequent than among those who reached puberty at the average age. The longest cycles and most frequent oligomenorrhoea were observed in the late-maturing group. There were no differences observed regarding the number of days with menstrual bleeding, although the early-maturing women more frequently declared that bleeding was profuse. Within the group of early-maturing students a significantly larger number declared to have suffered menstrual pain than in the other groups. More early-maturing students also complained of back pain and headaches during the menstrual cycle. CONCLUSION: Both early and late menarche might be related to menstrual dysfunction among young women. Menstrual disturbances were more prevalent among women who experienced menarche at a younger age. Moreover, in the early-maturing group overweight and obese states, as well as abdominal obesity, were frequent, and they are known as risk factors in many illnesses. PMID- 25026760 TI - The analysis of a personality profile of selected groups of nurses. AB - AIM: The analysis of a personality profile of selected groups of Polish nurses. MATERIAL AND METHODS: 72 nurses working in internal diseases departments and departments of surgery in Szczecin were investigated. To examine the personality profiles a diagnostic survey was used. It was based on an authorised Polish elaboration of Cattell's 16 Personality Factors Test. To examine their personality profile an authorised Polish elaboration of a diagnostic survey based on a standardized elaboration of personality profiles by Raymond B. Cattell was used. RESULTS: The analysis of the results indicated no significant differences between groups. The average sten scores from each of 16 examined factors were within the established limits. CONCLUSIONS: The personality profiles of the examined groups of nurses indicated a greater probability of the appearance of desirable features among the investigated people working in medical professions and demanding team cooperation, as well as relationship-building skills. Nurses, regardless of workplace, had personality traits indicating the need for education and improving occupational qualifications. PMID- 25026761 TI - [Evaluation of selected epidemiological risk factors for cancer of the lower gastrointestinal tract in middle Pomerania]. AB - INTRODUCTION: Cancer now represents the basic problem that modern medicine has difficulties dealing with both in Poland and around the world. In spite of the continuous development of science, more and better diagnostic techniques and new therapies based on the drugs acting selectively on cancer cells, the malignant cancer continues to be the first in women and the second in men, after heart disease, most common cause of death. According to data from the International Agency for Reserch of Cancer about 10 million people suffers from malignant cancer and the number of deaths due to this type of cancer has exceeded 6 million. If current trends do not change, until 2020 these figures can double. In a properly functioning organism the balance is maintained between the formation of new cells and tissues and apoptosis, a genetically programmed atrophy of cells. The formation of cancerous changes is the uncontrolled formation of new cells which anatomically should not occur in a particular location. These cells form tumours which can be divided into benign and malignant. Within the group of benign tumours, characteristic is that their cells are similar to the cells of a certain organ which has been affected by them. Organs are surrounded by connective tissue sac, and the cancers resulting from them mostly do not spread and their growth is slow. What is important for the patient is that they rarely are an imminent danger to life and they can be removed. Some types of benign tumours can become malignant. RESULTS AND CONCLUSIONS: Scientific studies have shown that colon cancer often derives from benign polyps and an early diagnosis and removal of pathological changes may prevent further mutations and the onset of cancer. Other studies have found a link between the incidence of cancer and smoking, physical activity, limiting alcohol consumption, or the use of certain drugs. Currently, it is believed that a high-fibre diet reduces the risk of developing cancer. The development of modern oncology, introduction and development of modern methods of genetic and imaging diagnosis as well as treatment (chemotherapy), have resulted in the need for an accurate determination of the biological structure of colon cancer. The introduction of modern diagnostic techniques in pathological anatomy, and, in particular, immunohistochemistry, has a significant impact on the understanding of new factors specific to cancer, considered as prognostic or predictive factors. Further development of medical science, including genetics and molecular biology, leads to a better understanding of the epidemiology of the colon cancer. The introduction of genetic DNA Microarray screening significantly affects the determination of the genetic profile of the specific population, which can cause the increased susceptibility to colon cancer. In the future this should allow the use of significantly more sensitive screening methods to separate the persons who are more susceptible to being affected (predictive diagnostics), and subsequently the introduction of efficient conduct associated with the introduction of a proper diet and the rules for promoting a healthy lifestyle, treatment methods in the occurrence of pathological lesions or early cancerous changes. PMID- 25026762 TI - [Levels of emotional intelligence and types of attachment among third year students of the Faculty of Health Science and the Faculty of Medicine--a comparative analysis]. AB - INTRODUCTION: For the purposes of this research attachment theory was incorporated into the concept of emotional intelligence. MATERIAL AND METHOD: The methodological starting point of this study was the assumption that the level of emotional intelligence and social competence is related to a steady feature, namely the type of attachment. Standardized questionnaires available in the Laboratory of Psychological Tests of the Polish Psychological Association were chosen to measure the level of emotional intelligence. However, the type of attachment was studied by Bartholomew's Self Description Test in my own translation. The study involved two groups of students, who were compared: 147 people from the Faculty of Health Sciences/Faculty of Nursing (nursing, midwifery, health promotion, cosmetology, emergency medicine, dietetics), and 181 people from the Faculty of Medicine (medicine), students in their second and third years of studies. A total of 328 people, aged 19-24, were tested. RESULTS: On the basis of the results it was stated that students of the Faculty of Health Sciences/Faculty of Nursing, as compared to students of the Faculty of Medicine, received significantly higher scores on the scale of the social competence scale, which investigated the efficiency of their behaviour in intimate situations. Moreover, statistical analysis proved that students of the Faculty of Health Sciences showed significantly higher scores than those studying at the Faculty of Medicine in the following fields: KKS-I subscale assessing social competencies in -conditioning effective behaviour in intimate situations, emotional intelligence measured with the INTE questionnaire,--awareness of their own emotional states and understanding their causes (DINEMO-I),--ability to recognize emotions in other people and understanding the reasons for the reactions expressed by them (DINEMO-Others)--emotional intelligence measured with the DINEMO questionnaire (DINEMO-general score). Women from both faculties showed higher social competence than men in the KKS-I, and higher emotional intelligence according to the INTE questionnaire and DINEMO: the overall result, DINEMO-Others and DINEMO-I (in the last scale, at level 0.065). Male students, from both faculties, showed significantly higher social competence in conditioning effectiveness of behaviour in situations requiring assertiveness (KKS-A). CONCLUSION: Taking into consideration the results of this study, the answer to the question of whether it is reasonable and necessary to develop skills among the examined students seems to be obvious. Indeed, assertive behaviours should be trained for at the Faculty of Health Sciences. At the same time skills related to EI--such as perceiving and processing emotional information, awareness of one's own and others' emotions, and associated social competencies in conditioning effective behaviours in intimate situations--should be trained for at the Faculty of Medicine. PMID- 25026763 TI - [Footwear according to the "business dress code", and the health condition of women's feet--computer-assisted holistic evaluation]. AB - BACKGROUND: According to the verdict of the Supreme Court in 2005, an employer may dismiss an employee if their conduct (including dress) exposes the employer to losses or threatens his interests. The aim of the study was a holistic assessment of the pleiotropic effects of high-heeled pointed shoes on the health condition of women's feet, wearing them at work, in accordance with the existing rules of the "business dress code". MATERIALS AND METHODS: A holistic multidisciplinary analysis was performed. It takes into account: 1) women employees of banks and other large corporations (82 persons); 2) 2D FEM computer model developed by the authors of foot deformed by pointed high-heeled shoes; 3) web site found after entering the code "business dress code". RESULTS: Over 60% of women in the office wore high-heeled shoes. The following has been found among people walking to work in high heels: 1) reduction in the quality of life in about 70% of cases, through periodic occurrence of pain and reduction of functional capacity of the feet; 2) increase in the pressure on the plantar side of the forefoot at least twice; 3) the continued effects the forces deforming the forefoot. CONCLUSIONS: 1. An evolutionary change of "dress code" shoes is necessary in order to lead to a reduction in non-physiological overload of feet and the consequence of their disability. 2. These changes are particularly urgent in patients with so-called "sensitive foot". PMID- 25026764 TI - [Evaluation of physical fitness in children of pre-school age including postural problems]. AB - BACKGROUND: Pre-school age is a period of intensive development when children shape their posture, habits and motor memory. In recent years an increased incidence of postural problems has been observed among children and adolescents. This process results from civilisation progress and sedentary life style. Most of the early-detected abnormalities are of a functional nature and are relatively easy to correct. However, if no preventive measures are taken, deformities of bones and joints may develop which are difficult to treat and result in serious health disorders. The aim of our study was to evaluate physical fitness in children of pre-school age depending on diagnosed postural problems. MATERIALS AND METHODS: The study included 64 children aged 6-7 years, in which abnormalities of body posture were diagnosed using the Wolanski method. The children were classified into two groups. Group 1 comprised children with abnormalities in the chest and shoulder girdle, and group 2 comprised children with lower limb abnormalities. Physical fitness was evaluated using the Modified Wroclaw Test for Physical Fitness by B. Sekita (1988). RESULTS: We found a statistically significant difference (p = 0.0148) between groups in a 20 m run. Test results demonstrated that dysfunctions of lower limbs influenced the times for longer distance runs, but no statistically significant difference was found between the groups for shuttle run times. Children from group 2 had lower long jump scores compared to group 1, but the difference was not statistically significant. A statistically significant difference (p = 0.0375) was found for medicine ball throw scores. Children from group 1 had higher scores. This can be explained by the higher number of boys in that group, who have greater physical strength than girls. RESULTS: Abnormalities of lower limbs in the studied group of children had a statistically significant influence on reduced physical fitness measured with the Sekita test. Abnormalities of the shoulder girdle and chest in the studied group of children had no effect on reduced physical fitness measured with the Sekita test. PMID- 25026765 TI - [Evaluation of the quality of life of patients undergoing rehabilitation for multiple sclerosis]. AB - INTRODUCTION: The aim of the study was to assess the quality of life in patients with multiple sclerosis who underwent complex rehabilitation, and to identify the aspect (psychological, physical or social) in which most improvement was achieved with respect to quality of life after complex rehabilitation. MATERIALS AND METHODS: The study was carried out from July to September 2010 at the Centre for the Rehabilitation of Patients with Multiple Sclerosis in Borne Sulinowo. The study group included 30 subjects with diagnosed multiple sclerosis. The study was based on a diagnostic survey--a questionnaire for direct survey. We used the reintegration to normal living index scale (RNLI) and expanded disability status scale. RESULTS: We found a statistically significant improvement in the assessment of the quality of life in patients who underwent complex rehabilitation (p = 0.000000). The analysis of individual aspects of the quality of life revealed a statistically significant improvement in all aspects: psychological (p = 0.000027), physical (p = 0.000090) and social (p = 0.000026). The difference in the assessment of the quality of life in the social aspect was 1.21, in the physical aspect - 1.16, and in the psychological aspect - 0.86. The greatest difference in the assessment of the quality of life was found for the social aspect, and the lowest in the psychological aspects. CONCLUSIONS: Complex rehabilitation improves the self--reported quality of life in patients with multiple sclerosis in all its aspects. After complex rehabilitation the highest scores were found for the assessment of the quality of life in the psychological aspect, but the greatest improvement in the quality of life was in the social aspect, proving the positive effects of sociotherapy. PMID- 25026766 TI - [Physiotherapist--profession known or unknown? Knowledge of the inhabitants of the West Pomeranian region of physiotherapy. Preliminary reports]. AB - INTRODUCTION: The aim of this study was to assess the knowledge of the inhabitants of the West Pomeranian region in terms of physiotherapy, and to highlight the need for action to expand public awareness of this topic. MATERIAL AND METHODS: A questionnaire survey involved a group of 267 adult men and women aged 18 to 78 years. All subjects were residents of West Pomerania. The questionnaire consists of 15 open and closed questions. Respondents provided answers to questions about physiotherapist competence, learning opportunities, and the availability of physiotherapy services. CONCLUSIONS: Knowledge about physiotherapy is insufficient. There is a great need to disseminate information about the profession of the physiotherapist. It is necessary to undertake further studies on a larger group of participants. PMID- 25026767 TI - [Evaluation of the quality of medical services by patients including selected sociodemographic variables]. AB - INTRODUCTION: Medical health care centres should aim at the application of a two dimensional concept of quality--technical quality and functional quality. Technical quality means the compliance with norms and technical requirements which apply to medical services that are provided to patients. This concerns medical standards, technology and the competence of medical staff. Functional quality, which means the subjective estimate of patients, is an additional benefit for the patient and it becomes the best competitive advantage in conditions of comparable technical levels of provided medical services. The patient will be satisfied with medical services if these elements are balanced. The aim of the study was the evaluation of the quality of functional services in a specialist outpatient clinic in the Szczecin area by patients. MATERIAL AND METHODS: 200 randomly-chosen patients of specialist outpatient clinics in Szczecin were asked to estimate the functional quality of services in specialist outpatient clinics. A questionnaire was used. The results were subjected to statistical analysis. RESULTS: Most of the patients--51.3% had confidence in their physician. 52.34% of the patients claimed that their doctor was not interested in their problems. Almost half of the respondents--47.92% stated that there was no telephone contact with their doctor. CONCLUSIONS: It is necessary to educate future physicians in problems of interpersonal communication. PMID- 25026768 TI - [Usefulness of the initial medical examination on matters relating to persons suspected of driving under the influence of amphetamine and its analogs or delta9 tetrahydrocannabinol based on the materials the Department of Forensic Medicine, Pomeranian Medical University in Szczecin]. AB - INTRODUCTION: Polish law forbids persons to drive under the influence of intoxicating substances, and those after the use of substances producing effects similar to alcohol. Therefore, there is a need to give an opinion based on a blood test, to establish whether or not the person from whom the blood was taken was under the influence of an intoxicating substance or after use of the drug while driving. Some authors reported that the final opinion should take into account chemical and toxicology test results identifying the parent compound and/or the metabolite only, but also the sampling time of the material to be analyzed in relation to the driving time, the result of the medical examination conducted prior to the collection of material for analysis, and the results of screening tests executed at the scene. Circumstances relating to the event, the findings and observations of third parties, and the testimony of the suspect are also relevant. The aim of this study was to evaluate the results of the medical examination in the evaluation of cases concerning driving by persons who were potentially under the influence of amphetamine and its analogs, or delta9 tetrahydrocannabinol, (delta9-THC) and conformity assessment of these results with the results of blood tests. An additional aim was to determine the factors considered by doctors when making their evaluation of patient's condition. MATERIAL AND METHODS: The study group consisted of 350 persons suspected of driving while under the influence of amphetamine and its analogs, and/or delta9 THC, from whom blood samples were taken to test amphetamine content or its analogues and/or delta9-tetrahydrocannabinol. Blood tests were carried out according to the existing procedure developed by the department. Blood samples were initially analyzed with immunochemical methods. Positive preliminary results were verified by gas chromatography-mass spectrometry. Statistical analysis was conducted with independent tests for multi-way tables, i.e. the Pearson chi2 test and the 2 x 2 tables Yates' correction was used for the low numbers. Comparison of mean concentrations of amphetamine and delta9-THC in the blood was performed using the U Mann-Whitney test. RESULTS: The analysis revealed a significant correlation between the symptoms and the results of the chemical-toxicological blood tests for mood only. There was no significant correlation between the results of toxicological and physical elements contained in the protocol of blood collection as the skin's appearance, speech, heart rate, pupil, pupil reaction to light, walking, lifting objects off the ground, the Romberg test, the finger-to nose test and orientation in the space time environment. In the analysis of the relationship between the medical assessment and physical elements significant relationships with the assessment of mood, pupils, pupil reaction to light and gait were found. A significant correlation between the prevalence of symptoms in terms of any/none and medical evaluation was found. CONCLUSIONS: 1. Preliminary medical examination based on the blood sampling protocol has no practical importance for determining whether a person is tested under the influence of amphetamines or its analogues and/or delta9-THC. 2. The confirmation of the state "under the influence of narcotics or psychotropics" should only be based on blood test results. 3. Doctors, when completing the blood collection report, are often guided by factors other than the test results when making assessment. 4. The low utility of the medical examination is affected by lack of standardization of test items. Doctors often find symptoms in a subjective manner. PMID- 25026769 TI - [Tuberculosis--a neverending story]. AB - It is estimated that over one third of the human population is now exposed or has been exposed in the past to Mycobacterium tuberculosis, and new infections occur in the world at a rate of one per second. The history of tuberculosis is long and very interesting, because before the isolation of mycobacteria and the finding of a cure, the disease mercilessly killed thousands of people and deprived doctors of hope. Robert Koch's momentous discovery was a major breakthrough in the fight against tuberculosis. Unfortunately, the disease has never been fully controlled. Tuberculosis is a chronic infectious disease localized in 90-95% of cases in the lungs, and therefore it is extremely difficult to diagnose unequivocally in paleopathological material. Only the form of osteo-arthritis leaves traces in archaeological material. The earliest evidence of tuberculosis (the location of the spine, Pott's disease) in the form of fossils is dated to before 8000 BC. Another very old trace is considered to be human remains from the Neolithic period (ca 5000 BC), found near Heidelberg, where changes in the thoracic spine are typical for spondylitis in tuberculosa. Constant growth in the incidence of new cases in the world can be observed today. Not everyone infected will develop the full-blown disease. The infection may remain dormant. However, one in ten latent infections will subsequently be activated, leading, if not treated, to the death of almost half of the patients. PMID- 25026770 TI - [Syphilis in the past and present]. AB - Syphilis is a specific inflammation which is extremely difficult to clearly diagnose in archaeological material. The origin of this disease is unclear. Most proponents hold the view that it comes from America, and that it was transmitted to Europe by sailors travelling with Columbus. In addition to the thesis of the American origin of syphilis is a suggestion that a mild form of syphilis existed in Europe before Columbus' expeditions. This form, until the end of the fifteenth century, began to spread epidemics. In Poland, the first officially reported case of the disease was described in 1495. Today, an increase in the incidence of new cases in Poland and globally can be observed. An increasing number of cases of congenital syphilis in newborns is also noted. This situation in Poland is connected with a change in the law in 2001, according to which only insured persons became entitled to free treatment. In view of the rising tide of the disease, and the appearance of advanced forms of the disease, in 2009 the free diagnosis, treatment, and follow up for all patients with syphilis was restored. PMID- 25026771 TI - [Acute kidney injury: progress in diagnosis and treatments. Editorial: Clinical importance of acute kidney injury]. PMID- 25026772 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: I. Acute kidney injury and acute renal failure]. PMID- 25026773 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: II. Epidemiology and pathophysiology of acute kidney injury]. PMID- 25026774 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: III. Approach to diagnosis; 1. Acute kidney injury definition and staging according to risk/injury/failure/loss/end-stage (RIFLE), acute kidney injury network (AKIN), and kidney disease: improving global outcomes (KDIGO) classifications]. PMID- 25026775 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: III. Approach to diagnosis; 2. Urinalysis and biomarker]. PMID- 25026776 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments: 1. Contrast-induced acute kidney injury]. PMID- 25026777 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments; 2. Acute kidney injury in intensive care unit]. PMID- 25026778 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments; 3. Drug induced AKI]. PMID- 25026779 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments; 4. Association of CKD and acute kidney injury]. PMID- 25026780 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments; 5. Exercise induced AKI]. PMID- 25026781 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments. 6. Acute kidney injury in hematological disorders]. PMID- 25026782 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments: 7. Kidney and lung crosstalk in acute kidney injury]. PMID- 25026783 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments; 8. Distant organ dysfunction associated with AKI]. PMID- 25026784 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: V. Prevention and treatments; 1. Prevention of acute kidney injury]. PMID- 25026785 TI - [Acute kidney injury : progress in diagnosis and treatments. Topics: V. Prevention and treatments; 2. Drug intervention in acute kidney injury]. PMID- 25026786 TI - [Acute kidney injury: progress in diagnosis and treatments. Topics: V. Prevention and treatments; 3. Renal replacement therapy for acute kidney injury]. PMID- 25026787 TI - [Discussion meeting on diagnosis and treatment of acute kidney injury (AKI)]. PMID- 25026788 TI - [Case report; Unilateral extracranial internal carotid artery vasospasm during the treatment for coronary vasospasm]. PMID- 25026789 TI - [Case report; A case of acquired hypocalciuric hypercalcemia due to autoantibody against the calcium-sensing receptor]. PMID- 25026790 TI - [Case report; A case of fulminant type 1 diabetes associated with drug-induced hypersensitivity syndrome]. PMID- 25026791 TI - [The cutting-edge of medicine; approach to medical treatment of esophago-gastric varices]. PMID- 25026792 TI - [Report from the 18th Tokai Chapter Educational Seminar: Inflammatory Disease]. PMID- 25026793 TI - [Series: For attending physicians; seeking to understand the diversity of medicine; efficiency and fairness in health care (overview)]. PMID- 25026794 TI - [Series: Physicians and disaster medical care; Third Stage, Management and education for disaster medicine: progress and problems related to the evacuation of Futaba Kosei Hospital as a result of the Fukushima Daiichi nuclear power plant accident]. PMID- 25026795 TI - [How does the physician interpret the patient's narrative as it relates to the physical exam?; Amnesia]. PMID- 25026796 TI - [Systemic autoimmune rheumatic diseases in 2013: problems of laboratory diagnosis]. AB - Progress in the laboratory diagnosis of systemic autoimmune rheumatic diseases (SRAD) is caused by the ever increasing clinical introduction of new highly productive methods for immune analysis using computer-aided systems and multiplex proteomic technologies. The urgent problem in the laboratory diagnosis of SRAD is the standardization of current methods for the detection of autoantibodies (autoAb), including the preparation of international reference materials for the calibration and external quality assessment of immunological assay. New autoAb technologies have a higher analytical validity than the previously used classical techniques immunodiffusion, agglutination, and immunofluorescence; however, their diagnostic sensitivity and specificity for SRAD have been poorly studied. Particular emphasis is laid on the standardization of the methods for examining antinuclear antibodies (ANAb), the major serologic marker of SRAD. According to the EULAR/ACR guidelines, indirect immunofluorescence reaction (IIFR) using human HEp-2 cells as substrate is the gold standard and a primary screening ANAb method. New methods for solid-phase analysis (enzyme immunoassay, multiplex test systems, etc.) cannot substitute the primary screening of ANAb using IIFR-HEp-2 as they identify antibodies to the limited number of antigens, increasing the number of false- negative results. The computer-aided systems for interpreting cell fluorescence tests contribute to the standardization and enhancement of the efficiency of detection of ANAb and other autoAb by IIFR. The use of complex diagnostic indices based on the multiparametric analysis of laboratory biomarkers in the serum makes it possible to most fully and objectively assess complex molecular mechanisms for the pathogenesis of SRAD, thus radically improving the early diagnosis, the estimation of the activity and severity of disease, the prediction of the outcomes of a pathological process and the response to treatment. PMID- 25026797 TI - [Association between bone mineral density and erosive and destructive changes in patients with rheumatoid arthritis: preliminary results]. AB - AIM: To obtain information on and to study an association between the erosive and destructive changes in the hand and foot joints, bone mineral density (BMD) in different parts of the skeleton and the X-ray alterations in the thoracic and lumbar vertebrae of patients with rheumatoid arthritis (RA). SUBJECTS AND METHODS: The investigation enrolled 66 women with a valid RA diagnosis, whose mean age was 51.6 +/- 9.6 years and the disease duration was 13.2 +/- 9.1 years. All the patients underwent clinical, laboratory, and X-ray studies assessing the progression of joint changes by the Sharp/van der Heijde method and estimating the vertebral body deformity index by the Genant technique, and BMD in 3 skeletal regions by dual-energy X-ray absorptiometry employing a Holovic Discovery A device. RESULTS: With X-ray higher-stage RA and higher Sharp total scores, regardless of age, there was a decrease in BMD in all skeletal areas and an increase in the number of patients with deformities of vertebrae and osteoporosis (OP) in at least one of the analyzed skeletal part. Thus, OP was found in 29% of the patients with Stages I and II RA and in 65% of those with Stages IV; deformities of vertebrae were in 12 and 22%, respectively. Comparative analysis of BMD and erosive and destructive changes in the patient groups different in age at onset of the disease has established that its young onset (from 16 to 30 years) and long duration have a negative effect on bone status. Femoral neck BMD in these patients is significantly lower than that in patients who were ill at older age (31-50 or over 50 years) (0.661 +/- 0.080, 0.739 +/- 0.111, and 0.713 +/- 0.120 g/cm2, respectively) and the Sharp total score was higher (181.1 +/- 91.3, 100.5 +/- 71.5 and 103.9 +/- 74.5, respectively). The patients' mean age in these groups at the study inclusion was 46.7 +/- 12.1, 51.9 +/- 6.7, and 60.3 +/- 3.3 years, respectively. CONCLUSION: With the longer disease duration, regardless of the age of patients with RA, there are increases in both Sharp total scores, X ray RA stage, and the number of patients with OP, deformities of thoracic and lumbar vertebrae (however, there is no evidence of significant differences), BMD decrease in all skeletal parts. PMID- 25026798 TI - [Diagnostic value of the determination of angiogenic factors and cytokine composition parameters in the serum and urine of patients with scleroderma systematica]. AB - AIM: To study the associations of the concentration of interleukins (IL) 1beta, 6, 8, 10, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha, vascular endothelial growth factor (VEGF) in the serum and urine with the clinical features of scleroderma systematica (SDS). SUBJECTS AND METHODS: The investigation enrolled 51 patients with a valid SDS diagnosis. The serum and urinary concentrations of interleukins, TNF-alpha, MCP-1, and VEGF were measured by solid-phase enzyme immunoassay. RESULTS: The patients with SDS were found to have higher serum and urine concentrations of proinflammatory cytokines and VEGF than in the comparison group. There were relationships between the levels of VEGF and proinflammatory cytokines and the disease duration, clinical forms, and clinical manifestation of SDS. CONCLUSION: Higher serum VEGF levels in patients with SDS may be used to estimate the magnitude of endothelial dysfunction. Estimation of serum IL-6 concentrations may be employed to determine the degree of sclerosis progression; that of MCP1 for the activity of fibrosing alveolitis. Quantitative analysis of urinary IL-6, IL-8, and VEGF levels in patients with SDS may be used to evaluate tubulointerstitial inflammation and to predict the development of interstitial fibrosis. PMID- 25026799 TI - [Cardiovascular diseases in patients with rheumatoid arthritis during long-term methotrexate therapy]. AB - AIM: To compare the prevalence of risk factors, clinical and subclinical manifestations of cardiovascular diseases (CVD) and their complications in methotrexate (MT)-treated and untreated patients with rheumatoid arthritis. SUBJECTS AND METHODS: The investigation enrolled 193 patients (168 women and 25 men) less than 60 years of age (mean age 49 [44; 53] years) with RA. The patients were divided into 2 groups: 1) 69 patients who received MT in a dose of 15.1 [10.2; 21] mg/week for at least 12 months (mean disease duration 25 [18; 48] months); 2) 124 patients who did not take MT. The patient groups were matched for age, gender, disease duration, RA activity, and the rate of rheumatoid factor (RF) seropositivity and extraarticular manifestations. RESULTS: Dyslipidemia was significantly less frequently identified in MT-treated patients (35/69 or 51%) than in MT-untreated ones (85/124 or 69%; p = 0.01). The serum from the patients treated with MT exhibited higher high-density lipoprotein cholesterol concentrations ((1.8 [0.9; 2.0] mmol/l) than in those untreated with MT (1.2 [1.0; 1.6] mmol/l; p = 0,047). In Group 1, hypertension (49%) and diabetes mellitus (3%) were slightly rare than in Group 2 (62 and 13%, respectively; p > 0.05). Carotid atherosclerotic plaques were found in 19 and 16% and intima-media thickness (IMT) enlargement was seen in 53 and 56% of the patients in Groups 1 and 2, respectively. Silent myocardial ischemia was diagnosed in every 10 patients; heart disease (exertional angina, myocardial infarction) was in every 5 patients in both groups. Aortocoronary bypass surgery was performed in 2 (3%) patients from those who received MT and had experienced MI and in one (1.6%) patient from the MT-untreated group. CONCLUSION: Long-term MT therapy was associated with the lower rate of dyslipidemia, but it failed to affect the incidence of CVD in patients with RA. PMID- 25026800 TI - [Bosentan: a considerable increase in the survival of patients with pulmonary hypertension associated with systemic rheumatic diseases]. AB - AIM: To evaluate the short-term efficacy of the nonselective endothelin receptor antagonist bosentan in the treatment of pulmonary hypertension (PH) associated with diffuse connective tissue diseases (CTD), as well as its effect on survival in both monotherapy and in combination with other PH-specific agents. SUBJECTS AND METHODS: The study included 20 CDT-associated PH patients who had been hospitalized in 2009-2013. All the patients had valid diagnoses of scleroderma systematica (SDS) (n = 18) or systemic lupus erythematosus (SLE) (n = 2). Bosentan was given in an initial dose of 62.5 mg/day twice for 4 weeks, then 125 mg/day twice. RESULTS: Eighteen patents completed therapy at 16 weeks. One patient with Functional Class (FC) IV PH associated with SDS died after 10 weeks of treatment because of PH progression; bosentan was discontinued in another patient following 4 weeks because of the enhanced activity of transaminases. The patients who had completed the investigation showed a significant FC decrease (from 2.9 +/- 1.0 to 2.4 +/- 1.0 following 16 weeks; p = 0.03), an increase in 6 minute walking distance (from 298 +/- 140 to 375 +/- 94 m; p < 0.002), a significant reduction in mean pulmonary artery pressure (from 48.2 +/- 15.0 to 42.8 +/- 12.0 mm Hg; p = 0.002), and pulmonary vascular resistance (PVR) (from 819 +/- 539 to 529 +/- 220 din/sec/cm(-5); p = 0.003). Right atrial pressure fell from 9.8 +/- 7.0 to 8.8 +/- 7.0 mm Hg; however, the changes were insignificant. There was a significant rise in cardiac index from 2.64 +/- 0.95 to 3.26 +/- 0.75 l/min/m2 (p = 0.005) and a significant decrease in uric acid levels from 562 +/- 254 to 469 +/- 194 micromol/l (p = 0.006). Overall 1-, 3-, and 5-year survival rates in patients with PH in the presence of CTD from PH onset were 100, 93, and 72%, respectively, in their treatment with endothelin receptor antagonists and differed significantly from the historical control group (87, 30, and 4%, respectively) when PH-specific therapy was unavailable. CONCLUSION: The survival of the bosentan-treated patients with SDS and PH becomes similar to that in the patients with classical SDS. Analysis of the findings revealed the association of survival with lower PVR at 16 weeks of bosentan therapy, which is indicative of the need for hemodynamic monitoring of therapeutic effectiveness. PMID- 25026801 TI - [Long-term follow-up of patients with refractory systemic lupus erythematosus during rituximab treatment]. AB - AIM: To evaluate the impact of anti-B-cell therapy on the clinical and immunological parameters of systemic lupus erythematosus (SLE) activity, on the time course of changes in these parameters during long-term follow-up, and on the tolerability of repeated rituximab (RTM) therapy cycles. SUBJECTS AND METHODS: RTM was given to 97 patients with high activity of SLE refractory to treatment with glucocorticosteroids (GCS) and cytostatics. The follow-up lasted 18 (12-36) months. The most common clinical manifestations of SLE were lupus nephritis (LN) (62%) and skin (33%) and nervous system (22.7%) involvements. Clinical SLE activity was assessed applying the SLE disease activity index 2000 (SLEDAI2K); therapeutic effectiveness was evaluated using indicators, such as partial response (PR), complete response (CR) and exacerbation. The exacerbation was classified as moderate and severe using the Selena-Sledai Flare index (SFI). RESULTS: Depletion was identified in 78% of the patients with SLE immediately after RTM therapy. During 3.5 years of follow-up, the effect of RTM was seen in 82% of the patients after repeated RMT therapy cycles (CR 56% and PR 28%). Exacerbations were observed in a total of 24 (24.7%) patients; the exacerbation lasted 12 (12-24) months after RTM therapy: of them 17.5% with LN and 7.2% with extrahepatic manifestations of SLE (exacerbations occurred 12 (12-24) and 18 (6 48) months after RMT therapy). In 24 exacerbated patients, B cells recovered at 6 (3-12) months. A year after RMT therapy, a group of 35 patients who were observed to have complete B cell depletion achieved CR statistically significantly more frequently than a group of 20 patients who had B-cell recovery (65.7 and 30% respectively, p = 0.03). CR was observed significantly more often in patients after repeated RTM therapy cycles than those who had received only one RTM therapy cycle (p = 0.02). The long-term follow-up showed a reduction in SLEDAI2K, normalization of laboratory values, and a decrease in the daily dose of GCS. Most patients tolerated well both the first and repeated RTM therapy cycles. CONCLUSION: According to the results of the long-term follow-up, RTM therapy is a highly effective treatment option for SLE patients in whom the previous standard therapy with GCS and cytostatics was previously ineffective. The 3.5-year follow up showed a good tolerability of RTM and revealed no increase in the risk of infectious complications or adverse reactions. PMID- 25026802 TI - [The specific features of gout in the elderly]. AB - AIM: To determine the specific feature of gout at its onset in the elderly. SUBJECTS AND METHODS: The investigation included 100 patients (74 men and 26 women) with primary gout on the basis of the criteria proposed by S. Wallace et al. (1977). The patients were divided into 2 groups: 1) 51 patients aged over 60 years; 2) 49 patients aged less than 60 years. In Groups 1 and 2, the mean age at gout onset was 66.1 +/- 4.8 and 41.6 +/- 10.0 years, respectively. A comparative retrospective analysis was made to analyze the detection rate for the site of onset gout, the pattern of arthritis, the number of tophus forms, the use of diuretics, small-dose acetylsalicylic acid (ASA), comorbidities, such as hypertension, type 2 diabetes mellitus (T2DM), obesity, chronic renal failure, coronary heart disease, chronic heart failure, and prior myocardial infarction. RESULTS: The disease duration in both groups averaged 8 years. In Groups 1 and 2, first metatarsophalangeal joint arthritis was diagnosed at its onset in 77 and 61%, respectively. In these groups, chronic arthritis was also diagnosed in 19 (37%) and 19 (39%). Examinations revealed tophi in 21 and 37% of cases in Groups 1 and 2, respectively. The administration of diuretics was recorded in 25 (49%) and 17 (35%) patients in these groups. Group 1 patients took low-dose ASA more frequently than Group 2 ones (19 (37%) and 7 (14%) patients, respectively; p = 0.013). Hypertension was identified in 23 (45%) examinees in Group 1 and 17 (40%) ones in Group 2. Both groups were matched for the number of patients with obesity (41 and 43%) and for that of patients with T2DM (15 and 10%, respectively). There were significant differences between the compared groups in the incidence of coronary heart disease, myocardial infarction, and chronic heart disease. CONCLUSION: The patients' age of gout onset does not affect substantial differences in the clinical features of gout with its comparable duration in the young and elderly patients. The main clinical features of gout are unique to both young and elderly patients. Cardiovascular diseases are more common at gout onset in the elderly. PMID- 25026803 TI - [Analgesia in hemophiliac patients during orthopedic surgery]. AB - AIM: To develop an effective and safe analgesic regimen (by minimizing the proportion of narcotic analgesics) in hemophiliac patients in the perioperative period during high-trauma surgeries (total knee and hip replacements). SUBJECTS AND METHODS: The prospective study included 24 patients aged 22 to 57 years (median age 38 years) with severe congenital hemophilia A (n = 22) and B (n = 2), who had undergone knee (n = 18) or hip (n = 6) replacements in the Hematology Research Center, Russian Ministry of Health of the Russian Federation, in 2013. Two analgesic regimens (a) paracetamol with trimeperidine; b) paracetamol and ketamine with trimeperidine) were used. To assess pain intensity, the authors used scoring scales: a visual analogue scale (VAS) and a numeric rating scale (NRS). The effect of paracetamol on hemostasis was evaluated on the basis of thromboelastogram and coagulogram readings. Possible paracetamol hepatotoxicity was assessed analyzing liver enzymes. RESULTS: An interview has shown that 66% of the hemophiliac patients regularly take analgesics for chronic pain syndrome, among them 29% use narcotic analgesics. It is difficult to achieve perioperative analgesia in these patients. The dosage of narcotics can be decreased (that of trimeperidine on an average from 80 to 45 mg/day) in the early postoperative period if non-narcotic analgesics, such as paracetamol 4 g/day, are incorporated into the analgesic regimen. Paracetamol promotes pain relief to moderate and mild (not more than 40-50 VAS scores and 3-4 NRS scores), without affecting hemostasis (the thromboelastogram readings differed statistically insignificantly; the coagulation index was 0.6-1.6) and without having a hepatotoxic effect. CONCLUSION: The systemic use of analgesics in hemophiliac patients considerably makes postoperative analgesia difficult. The use of paracetamol with trimeperidine within the first 24 hours after high-trauma surgeries in hemophiliac patients (even if they have hepatitis C) is rather effective and safe. PMID- 25026804 TI - [Differential diagnosis of rheumatic diseases and blood cancers involving the nasal cavity and accessory sinuses]. AB - AIM: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS). SUBJECTS AND METHODS: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis. RESULTS: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD. CONCLUSION: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4 RD. PMID- 25026805 TI - [Hormonal aspects of the development of obesity and metabolic syndrome in ethnic groups (by the population of the Chuvash Republic)]. AB - AIM: To study the specific features of the hormonal status in the development of obesity and metabolic syndrome (MS) in different ethnic groups. MATERIALS AND METHODS: The prevalence of obesity and MS was studied in Russian and Chuvash people, the relationship of MS to body mass index (BMI), the levels of insulin, dehydroepiandrosterone sulfate (DHEAS), and testosterone, and insulin resistance (IR) was assessed. RESULTS: The prevalence of obesity and MS depends on ethnicity and gender (these are more common in the Russians than in the Chuvashes, in the women than in the men). Overweight and obesity versus normal weight are characterized by the higher rate of MS, hyperinsulinemia, and low DHEAS concentrations. The obese men have decreased testosterone levels. The lower DHEAS levels are associated with the presence of MS (association factor +0.36) rather than with the development of obesity (association factor +0.07). In the Russians versus the Chuvashes, the development of MS is more frequently associated with the fall of DHEAS levels and less frequently with the development of IR. CONCLUSION: The incidence of MS increases with higher BMI, accompanies by IR and hyperinsulinemia. MS in the Russians is associated with the lower DHEAS concentration. PMID- 25026806 TI - [Clinical efficiency of combined therapy using adaptol for atopic dermatitis]. AB - AIM: To study the effect of the daytime anxiolytic adaptol on the efficiency and tolerability of combination treatment for atopic dermatitis (AD). SUBJECTS AND METHODS: Eighty patients with different clinical forms of AD were examined and then divided into 2 identical groups. The patients' mean age was 30.7 +/- 11.2 years; the mean disease duration was 20.2 +/- 12.8 years. Group 1 patients (n = 40) received standard treatment involving disintoxication therapy, prednisolone 30-60 mg/day, antihistamines, phototherapy (20 sessions), topical steroids and topical emollients. Group 2 patients (n = 40) took additionally adaptol as 3 tablets (1500 mg) daily. The efficiency of therapeutic measures was evaluated in 2 steps: by taking into account the changes in the scoring atopic dermatitis index (SCORAD) and the Dermatology Life Quality Index (DLQI) scores 4 weeks following the initiation of treatment and once more after 12 weeks. RESULTS: There was a tendency for the more pronounced decrease in SCORAD scores in Group 2 (using adaptol) versus Group 1 (standard treatment) to 9.8 +/- 2.57 and 10.8+ +/- 2.64, respectively. There were drops in SCORAD scores by 4.1 and 3.6 times, respectively. Twelve weeks after 12 weeks of treatment initiation was 7.1 +/- 2.13 scores in the adaptol group; on the contrary, this indicator increased slightly due to evolving recurrences and amounted to as many as 11.9 +/- 2.41 scores on the average. In Group 1, DLQI improved by 73% following 4 weeks and decreased by 1% after 12 weeks while in Group 2, it improved by 81% following 4 weeks and continued to improve up to 85% after 12 weeks. CONCLUSION: Comparison of examined dermatology indices in AD patients receiving standard treatment and treatment including adaptol gives proof to the great value and efficiency of using adaptol during an exacerbation and in the postrecurrence period. PMID- 25026807 TI - [Radiodiagnosis and knee joint replacement in hemophilic arthropathies in Kazakhstan residents]. AB - AIM: To assess complex radiodiagnosis and highly specialized medical care as knee joint replacement (KJR) to patients with hemophilic arthropathies (HA) who live in the Republic of Kazakhstan. SUBJECTS AND METHODS: The results of examination and treatment were analyzed in 40 patients with knee HA who were treated at the specialized Polytrauma Unit, Republican Research Center for Emergency Health Care. All patients with hemophilia A underwent joint X-ray study, computed tomography and magnetic resonance imaging (MRI), X-ray densitometry and ultrasound osteometry on admission and after KJR. RESULTS: Joint X-ray studies and computed tomography revealed that all the patients had Grades II-III arthroses with severe dysfunction of joints, their multiple involvements of different grades, which depended on the rate of recurrent hemarthrosis. Ultrasound study (USS) is the only mini-invasive method to control surgical hemostasis in hemophiliac patients after KJR. Osteodensitometry revealed osteopenia and osteoporosis in all the patients with hemophilia, which was a basis for prescribing calcium preparations in the early postoperative period for the prevention of instability of endoprosthetic components. We elaborated an algorithm for combination treatment in HA patients, which involved knee joint replacement. CONCLUSION: Highly specialized medical care to hemophilic patients and active introduction of the early surgical rehabilitation of the affected joint in their combination treatment contributed to the increased number of positive results, by restoring the quality of life in the patients: excellent, good, and satisfactory anatomic and functional results were obtained in 26.7, 51.1, and 22.2%, respectively. USS and MRI could evaluate joint changes in HA in detail, which plays an important role in the estimation of the course time of the disease, in the planning of endoprosthetic replacement, and in the timely prevention of severe complications of HA. Osteodensitometry makes it possible to monitor bone mineral density around the prosthesis and to postoperatively prevent endoprosthetic instability. PMID- 25026808 TI - [Panniculitides in an internist's practice]. AB - By panniculitides is meant a group of heterogeneous inflammatory diseases characterized by the involvement of subcutaneous adipose tissue. A diversity of their forms and variants of their course determines the need for careful patent examination to verify the diagnosis. The lecture gives a diagnostic algorithm and outlines principles in the differential diagnosis of panniculitides and its treatment approaches in current clinical practice. PMID- 25026809 TI - [The current classification of systemic vasculitides]. AB - Systemic vasculitides (SV) are severe multiorgan diseases whose early diagnosis and treatment can significantly improve prognosis. Improving the classification of SV may lead to a significant reduction in the likelihood of diagnostic errors. The presented paper deals with the results of the International Consensus Conference on the Nomenclature of SV (Chappel Hill, USA) in 2012. The nomenclature and definitions of the major forms of SV were revised and additional categories of vasculitis were included into the classification, by relying on the current trends in the practical use of terms, on the current ideas on the specific features of manifestations of diseases, and on achievements in studying the pathogenesis. PMID- 25026810 TI - [Meloxicam: the golden mean of nonsteroidal anti-inflammatory drugs]. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are most commonly used to treat acute and chronic pain in locomotor system (LMS) diseases. However, their administration may be accompanied by the development of dangerous complications as organic and functional disorders of the cardiovascular system (CVS) and gastrointestinal tract (GIT). Physicians have currently a wide range of NSAIDs at their disposal; but none of the representatives of this group can be considered the best. Thus, highly selective cyclooxygenase-2 inhibitors (Coxibs) are substantially safer for GIT; however, their use is clearly associated with the increased risk of severe cardiovascular events. Nonselective NSAIDs, such as naproxen or ketoprofen, are safer for CVS, but more frequently cause significant GIT organic and functional disorders. Moderately selective NSAIDs, such as meloxicam (movalis), conceivably could be the most acceptable choice for treating the majority of patients in this situation. This drug has been long and extensively used in global clinical practice and has gained the confidence of physicians and patients. The major benefits of meloxicam are its proven efficacy, convenient treatment regimen, relatively low risk of complications as organic and functional disorders of the GIT and CVD and good compatibility with low-dose aspirin. PMID- 25026811 TI - [Subclinical interstitial lung disease associated with rheumatoid arthritis]. AB - Interstitial lung disease (ILD) in rheumatoid arthritis (RA) is its extra articular manifestation. At the same time, ILD considerably worsens the prognosis of the disease. Mortality rates for interstitial pulmonary fibrosis are 6% of all cause mortality in RA patients. ILD can be identified by clinical examination only in 2-6% of cases, by plain chest X-ray in 1-6%, and by high-resolution computed tomography in 50-60%. The paper deals with subclinical ILD and discusses the state-of-the-art of investigations in this area. PMID- 25026812 TI - [Use of anti-B-cell therapy in case of antisynthetase syndrome as the severest subtype of polymyositis/dermatomyositis]. AB - Antisynthetase syndrome encompassing a symptom complex with severe interstitial lung disease is the severest subtype of polymyositis and dermatomyositis. The characteristic feature of antisynthetase syndrome is the insufficient efficiency of traditional therapy with glucocorticosteroids and cytostatics, which determines the prognosis of the disease and the need for new therapeutic approaches to treating these patients. PMID- 25026813 TI - [Cardiovascular diseases and osteoporosis: what is common?]. AB - The review analyzes the possible effect of cardiac drugs on the course of osteoporosis (OP). The fact that atherosclerosis and OP share the mechanisms of development, among which the enhanced activity of the sympathetic part of the autonomic nervous system and endothelial dysfunction are most important, is beyond question now. In this connection, beta-adrenoblockers, nebivolol in particular, attract attention. Nebivolol is known to be a selective beta1 adrenoblocker that has an additional vasodilator property, by stimulating the synthesis of nitric oxide. This may serve to increase bone mineral density and slow down the progression of OP. At the same time, most investigations in this area are retrospective therefore final conclusions call for randomized prospective studies that will be able to evaluate more objectively the effect of cardiac drugs on the prevention of OP or its progression delay. PMID- 25026814 TI - [The history of the Kazan School of Therapists (on the occasion of the 200th anniversary of the Kazan State Medical University)]. AB - The history of the Kazan School of Therapists numbers two centuries of scientific achievements and discoveries. German Professors F.H. Erdman and K.F. Fuks laid the groundwork for clinical teaching continued by Russian therapists N.A. Skandovsky, N.A. Vinogradov, A.P. Kazem-Bek, N.K. Goryaev, and other distinguished scientists. The prominent scientists of the 20th century made great contributions to the development of modern therapy; the names of M.N. Cheboksarov, Z.I. Malkin, A.G. Teregulov, and I.G. Salikhov are known and they are respected by the world medical public. PMID- 25026815 TI - [The clinical application of objective hearing monitoring technology in cochlear implants]. AB - OBJECTIVE: Compare the clinical characteristics and application value between elcetrically evoked stapedius responses and neural response telemetry. METHOD: Select number 1, 7, 11, 17, 22 electrodes from 21 cochlear implanting nucleus 24R cochlear implants, using NRT3.0 software provided by Cochlear corporation to test the threshold of elcetrically evoked stapedius responses and neural response telemetry during operation and subjective psychological physical test after operation repectively named elcetrically evoked stapedius responses threshold, electrically evokded compound aciton potentials threshold, and T-levels. Respectively study the correlations of ESRT, ECAP threshold, and T-levels. RESULT: The detection rates of ESRT, NRT, and T-levels were 96.19%, 93.33%, 100%. The mean thresholds of ESRT were 206.61 +/- 10. 74, 208.48 +/- 13.64, 205.52 +/- 14. 63, 203.76 +/- 12.97, 199.50 +/- 11.19; The mean thresholds of NRT were 184.11 +/- 6.35, 188.55 +/- 11.70, 187.00 +/- 12.29, 181.85 +/- 13.22, 179.00 +/- 10.50; The mean thresholds of T levels were 145.48 +/- 18.66, 148.62 +/- 8.22, 146.62 +/- 18.08, 142.52 +/- 13.11, 140.33 +/- 13.68. The mean thresholds of ESRT in each electrode were rather greater than that of T-levels. There is a high degree of consistency in the mean thresholds of ES RT, NRT and T-levels. The test time, test means, unilaterally detection rate during operation, ESR is better than NRT. All the electrodes were set as observation objects, the correlation of ESRT and NRT is 0.69, the correlation of NRT and T is 0.62, and the correlation of ESRT and T is 0.39. CONCLUSION: The application of elcetrically evoked stapedius responses and neural response telemetry during operation can rapidly estimate wether the implant is in good condition and the pathway is normal. Rather than neural response telemetry, elcetrically evoked stapedi us responses is more flexible, convienient, accurate and visual, while it is more objective superiority after operation especially for young children for the former detector. PMID- 25026816 TI - [Ten cases report of vascular compressive syndrome caused by the facial, acoustic nerves]. AB - OBJECTIVE: To search the features and the treatment of vascular compressive syndrome caused by the facial, acoustic nerves. METHOD: Ten cases of vascular compressive syndrome caused by the facial, acoustic nerves were included in the group,which were treated by microvascular decompression(MVD). Besides, the microanatomic relationship between the nerve and their adjacent vessel at the root exit zone (REZ) were observed under microscope or nasoendoscopy in MVD. RESULT: Tinnitus, vertigo and facial spasm disappeared after MVD in 7 cases (70%), improved in 2 cases (20%), and relapse in 1 case (10%). All cases were found out vessels compressing at the root zone of the facial nerve and the auditory nerve. CONCLUSION: The Clinical features of vascular compressive syndrome caused by the facial, acoustic nerves are facial spasm, tinnitus, and vertigo, for which microvascular decompression has a positive therapeutic effect as long as the diagnosis is correct. PMID- 25026817 TI - [Clinical analysis of ten cases of congenital middle ear cholesteatoma]. AB - OBJECTIVE: To investigate the clinical features and operation treatment of the congenital middle ear cholesteatoma. METHOD: A retrospective review of clinical and surgical records of 10 patients with congenital middle ear cholesteatoma were performed. All patients were treated by surgeries,5 of 10 cases deal with one stage tympanoplasty after drum exploration by external auditory meatus, 3 cases dealed with closed mastoidotympanectomy and tympanomastoidectomy, 2 cases dealed with open mastoidotympanectomy and tympanomastoidectomy. RESULT: The cholesteatomas were located at or around the posterior tympanum or mesotympanum in 5 patients, confined to the tympanic cavity and attic in 3 patients, advanced cholesteatoma that extended from the tympanic cavity into the mastoid antrum was seen in 2 patients. The mean postoperative PTA was 30 dB HL, the mean ABG was within 20 dB, after six months. No residual or recurrence of cholesteatoma was found. CONCLUSION: The congenital cholesteatoma often originates from the posterior or anterior of the middle ear, with hiding lesion, thus result in severe conductive hearing loss. Imaging examination plays an important role in diagnosing and treating of congenital cholesteatoma. Early stage surgical treatment can obtain a good hearing reconstruction effect. PMID- 25026818 TI - [Clinical analysis of 26 patients with relapsing polychondritis]. AB - OBJECTIVE: To discuss the clinical characteristics and early diagnosis and treatment of relapsing polychondritis(RP). METHOD: Twenty-six RP patients received the therapies of antibiotics, glucocorticosteroid, immunosuppressive agent,tracheotomy, tracheal sent implantation or non-invasive ventilation. RESULT: Twenty-six cases (88.5%) had auricle involvement, 20 cases (76.9%) had respiratory tract involvement, 18 cases (69.2%) had joints involvement, 10 cases (38.5%) had nose involvement, 6 cases (23.1%) had eyes involvement, 4 cases (15.4%) had cochlea and (or) vestibular involvement. Some patients with cardiac, vascular, kidney damage as well. One case died of severe pulmonary infection. One case died of respiratory failure. The symptoms of other 24 cases were stable or improved in different degrees. CONCLUSION: The clinical manifestations are diverse in RP patients, mainly in department of Otolaryngology, the prognoses of patients with airway involvement are worse, and it may improve the curative effect by an early diagnosis and a timely treatment. PMID- 25026819 TI - [The influence of congenital malformation of external and middle ear on the psychologic status of children patients]. AB - OBJECTIVE: This research focuses on the psychologic status of children patients with congenital malformation of external and middle ear by Achenbach's Child Behavior Checklist (CBCL) in order to explore the degree of the influence. METHOD: The 66 patients of 4-16 years old were assessed psychologic status with CBCL filled in by their parents according to their performance in half a year. Then calculated the detection rate of behav ioral disorders of these patients. Collected all patients' general information and Marx's grade of malformed ears. Then analyzed the relationship between the detection rate and these factors. RESULT: The detection rate of behavioral disorders of 4-16 years old patients, 21.21%, which is higher than that of Chinese norm. The Marx's grade and parents' mental stress relate with the behavioral disorders. In Logistic regression analysis, the value of Cox & Snell coefficient of the regression model is 0. 153. The detection rate of behavioral disorders in grade III patients (36.4%) is greater than that of grade II (4.3%), P = 0.004. CONCLUSION: Congenital malformation of external and middle ear has an absolute influence on the patients' psychologic status, but its effect is only about 15% parts of the multitudinous influential factors. And grade III patients carry a high-risk for behavioral disorders. PMID- 25026820 TI - [A retrospective study of 768 coblation treatment in children with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To investigate the therapeutic effects of 768 coblation treatment in children with obstructive sleep apnea-hypopnea syndrome. METHOD: A review of 768 coblation treatment in children with obstructive sleep apnea-hypopnea syndrome was presented with respect to the sleep monitoring results, therapeutic effects and complications. RESULT: The time of pseudomembrane ablate was 10-14 d after operation. There were 11 patients occurred Secondarily bleeding within 1 week and 21 patients lymphatic tissue hyperplasia compensatorily within half a year after operation. After operation 3 months, the sleep Monitoring results were improved remarkably (P < 0.01) and the symptoms of snore and choke improved. CONCLUSION: Coblation treatment in children with obstructive sleep apnea-hypopnea syndrome can reduce bleeding volume and improve obstruct syndrome apparently. The treatments of tonsils and adenoids differ with the characteristics of children and tympanotomy was fit for chil dren with secretory otitis media. PMID- 25026821 TI - [Effects of sleeping body posture on sleeping structure and respiratory events in patients with OSAHS]. AB - OBJECTIVE: To observe the effects of sleeping body posture on sleeping structure and respiratory events in patients with OSAHS. METHOD: We assessed the sleeping body position, the sleeping structure, position specific AHI and the Epworth Sleepiness Scale (ESS) in a total of 80 patients with Positional OSAHS. The patients were grouped according to AHI: mild OSAHS (5 < or = AHI <15), moderate (15 < or = AHI < 30) and severe (AHI > or = 30). The polysomnography data and clinical characteristics were compared between each group. RESULT: The severe OSAHS group, when compared with the mild and the moderate ones, had a significant different in REM%, NREM%, NREM LSaO2, RDI, S-AHI and L-AHI due to posture (P < 0.05). The severe and the mild OSAHS groups had significant different in MSaO2, LSaO2 due to posture (P < 0.05). The moderate and the mild OSAHS group had significant different in LSaO2, REM LSaO2 and RDI (P < 0.05). In all mild, moderate and severe groups, the LT% were higher than ST%, but the difference was not significant (P > 0.05). For mild-to-moderate groups, there was no correlation between the ESS and the AHI for any position different (P > 0.05). For severe group, the ESS was significantly correlated with L-AHI (r = 0.551; P < 0.01); the REM L-AHI and NREM L-AHI was also significantly correlated with ESS of severe group (r were 0.516 and 0.528, P < 0.01). CONCLUSION: The L-AHI, NREM L-AHI, REM L-AHI and NREM LSaO2 were considered to monitor the stability of OS-AHS, while REM LSaO2 were consider to clarify the severity of OSAHS. PMID- 25026822 TI - [Clinical analysis of esophageal perforation and neck abscess induced by esophageal foreign body]. AB - OBJECTIVE: To investigate the diagnosis and treatment of esophageal perforation and neck abscess induced by esophageal foreign body and to make a better solution for the disease. METHOD: Twenty-four cases with esophageal perforation and neck abscess induced by esophageal foreign body treated in our department were surgery under general anesthesia. The foreign bodies were removed via esophagoscope in 14 cases, thorocomy in 3 eral neck incision in 5; and no foreign bodies were found in 2 cases. RESULT: There were 16 cases complicated by abscess. Among these complications,there were 10 cases of periesophageal abscess,4 cases of neck abscess and 1 case of mediastinal abscess. In 24 patients, 21 cases cured and one died. One case was sent to the department of endocrinology because of hyperglycaemia and two cases were sent to the department of thoracic surgery for further treatment. CONCLUSION: Early diagnosis and treatment is the key to the management of esophageal perforation induced by esophageal foreign body. Thin section CT has a high value for the diagnosis and differential diagnosis in such patients. Once deep neck abscess is diagnosed, an early abscess surgical drainage, an appropriate antibiotics and a nutrition supporting treatment are effective for the patients. PMID- 25026823 TI - [The analysis of surgery effect of OSAHS children accompanied with sinusitis]. AB - OBJECTIVE: To discuss the clinical efficacy of adenoidectomy and tonsillectomy for the OSAHS children with sinusitis. METHOD: Reviewing 112 cases of children with OSAHS, in which the 80 patients without chronic sinusitis, 32 ones with chronic sinusitis. Among them, 103 cases of children with adenoidectomy, tonsil resection, 9 cases adenoidectomy only. We did questionnaire survey before and after surgeryand also did post-surgery clinical follow-up. RESULT: The effective rate was 90.0% for the OSAHS children without sinusitis after adenoid and tonsil ectomy surgery, while the effective rate was 46.9% for the ones with sinusitis, the efficiency was significant different in the two groups after surgery; the 16.1% children after tonsil ectomy surgery complained the incidence of pharyngeal foreign body sensation and pharyngeal lymphoid hyperplasia in children was 23.2%. CONCLUSION: The efficiency was aviable for the OSAHS children without sinusitis after surgery; The efficiency was not aviable enough for the OSAHS children with sinusitis after surgery, so the latter one need adjuvant drug treatment; We also should be attention to the pharyngeal foreign body sensation and the lymphoid hyperplasia in children after tonsillectomy. PMID- 25026824 TI - [Change of auditory brainstem response in hearing deprivation rat model induced by bilateral cochlears ablation]. AB - OBJECTIVE: To observe the change of auditory brainstem response (ABR) in hearing deprivation rat model induced by bilateral cochlears ablation at different time points. METHOD: Forty SD rats were randomly divided into four experiment groups including 2-week group, 4-week group, 6-week group, 8-week group and four control groups with 5 rats (n = 10) in each group. Then bilateral cochlears ablation was applied to experiment groups. The threshold value of ABR was measured at different time and latent period of each wave was compared. RESULT: The threshold of ABR in experiment group was elevated significantly. The latent period of each wave was pro longed significantly (P < 0.01). In experiment group, the threshold value of ABR in 2-week and 4-week group was significantly greater than that in 6 week group and 8-week group (P < 0.01). CONCLUSION: Bilateral cochlears ablation surgery could elevate the threshold of ABR and latent period of each wave prolonged. The effect of hearing deprivation became apparent after surgery for 4 weeks. PMID- 25026826 TI - [Meniere's disease in children aged 4-7 years]. PMID- 25026825 TI - [The expression of miR-183 family in the pathogenesis and development of noise induced deafness]. AB - OBJECTIVE: To detect the expression variation of microRNA-183 family in cochlea of animal model characterized by noise-induced deafness at various time points, and to explore the mechanisms responsible for noise-induced deafness. METHOD: Fifty mice were randomly divided into 5 groups. In the experimental group, 40 mice were exposed to 2-4 kHz narrow band noise at 100 dB SPL 6h per day for 3 consecutive days. The rest 10 mice served as the control group without receiving any noise. Auditory brainsterm response (ABR) were examined at the 1st, 7th, 14th and 28th day compaired with the ABR before the experiment,to confirm noise lead to the permanent threshold shift. The pathological damage processes of hair cell were detected by the basilar membrane stretched techniques. Real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) was apply to quantify the expression of microRNA183 family members. Statistical analysis was performed by the SPSS 17.0 software. RESULT: The hearing of mice in the experimental group was significantly less than that in the control group. In the experimental group, the hearing of mice exposed to noise were markedly less when compared with the one exposure to null-noise. The hearing in the 1st day group was least among experimental groups, and the followed one was mice in the 7th day group. No statistical difference were observed between the 14th and 28th day groups (P > 0.05). The results of surface preparation showed that the outer hair cells were chaotic, deformational, and their number decreased is time-dependent. The missing of the outer hair cells occurred mainly in the first and second rows, while the inner hair cells were not pronouncedly missing. The qRT-PCR showed that the expressions of the three genes (miR-183/96/182)in the 1st day and 7th day group with exposure to noise were less than in the control group (P < 0.01), while no significant difference was found between 1st day and 7th day group (P > 0.05). The expressions rised in the 14th day experimental groups, whereas the 28th day group's expressions of the three genes decreased markedly which were more than that in the 1st day and 7th day group (P < 0.01). CONCLUSION: After noise exposure for some time, the expressions of miRNA-183 family members have significant changes in animal model with noise-induced deafness, which indicated that the miRNA183 family members may play important roles in the pathogenesis and development of noise-induced deafness. PMID- 25026828 TI - [Canalplasty for stenosis or atresia of the external auditory canal]. AB - OBJECTIVE: To report the experience of canalplasty in treatment of stenosis or atresia of the external auditory canal. METHOD: A retrospective review was performed on 10 patients (10 ears) that underwent canalplasty. The lesions located in bony segment in 1 case, cartilaginous segment in 3 cases, both in cartilaginous and bony segments in 6 cases, in which 4 cases accompanied with the middle ear diseases. All patients received the canalplasty surgery, and tympanoplasty was applied simultaneously if the patient had otitis media. RESULT: Follow-up was conducted for 8-50 months respectively, 8 of the external auditory canal was wide and tympanic membrane gained a good shape, 2 case had stenosis or atresia reoccurrence after the operation. CONCLUSION: Appropriate approach and elimination of the lesions thoroughly are key points for the canalplasty. PMID- 25026827 TI - [Salvage surgery for recurrent laryngocarcinoma]. AB - OBJECTIVE: To study the curative effect and prognosis of salvage surgery performed for recurrent laryngocarcinoma. METHOD: The clinical data of 43 patients with salvage surgery for recurrent laryngocarcinoma hospitalized in Nanfang Hospital between 2003 and 2011 were analyzed retrospectively. Survival analysis was performed by using Kaplan-Meier method and prognosis factors were analyzed by Log-rank test. RESULT: After salvage surgery, 10 (23.3%) patients developed postoperative complications. Pharyngocutaneous fistula and infection occurred in 8 (18.6%) patients. Kaplan-Meier analysis showed that patients survived for 3-year (n = 32) and 5-year 25) after salvage surgery were 56.3% and 32.0% respectively. Univariate analysis indicated that clinical stage in the first diagnosis was significantly correlated with 3 year overall survival (P < 10.05). Local recurrence of laryngeal cavity group and preservation of laryngeal function group had a good prognosis respectively, but no sig nificant difference between them. CONCLUSION: Salvage surgery is a good choice for recurrent laryngeal carcinoma. Outcomes of these patients were correlated with clinical stages. Laryngeal function preserving surgery for local recurrent laryngeal carcinoma can achieve a expected curative effect and prognosis. PMID- 25026829 TI - [Analysis of personality characteristics of sudden deafness patients]. AB - OBJECTIVE: To Study the personality characteristics in patients with sudden deafness. METHOD: Thirty-eight sudden deafness patients and 45 healthy volunteers were assessed by Eysenck personality questionnaire (EPQ). RESULT: The standard scores of P, E, N dimensions of patients with sudden deafness were greater than healthy volunteers. The standard score in L dimensions of patients with sudden deafness was less than healthy volunteers. The difference of the standard score of P dimension revealed statistical significance (P < 0.05). The difference of the standard score of N dimension revealed statistical significance (P < 0.01). The difference of the standard scores of E, L dimensions revealed no statistical significance (P > 0.05). CONCLUSION: Sudden deafness patients have emotional instability and psychoticism personality characteristics. PMID- 25026830 TI - [Expression and significance of gene Rad52 in nasopharyngeal carcinoma]. AB - OBJECTIVE: To investigate the expression and clinical significance of Rad52, a homologous recombination repair gene, in tissues of nasopharyngeal carcinoma (NPC). METHOD: The expression of Rad52 was detected with three-step immunohistochemistry technique in tissues of 38 NPC patients and which have the corresponding paracancerous tissues. All of the Rad52 expression and clinical data (gender, age, clinical stage ) were compared and analyzed to conclude the relationship between them. RESULT: The Rad52 expressions were significantly different from NPC tissues to peri-NPC tissues (P < 0.05). It was found by Spearman analysis method that the Rad52 expression decreased with patients'clinical stages (P < 0.05), but has no significant relationship with gender, age, recurrence, and lymphonode metastasis (P > 0.05). The expression of Rad52 influenced the survival time of NPC patients significantly (P < 0.05). CONCLUSION: The Rad52 expression can be a useful prognostic and treatment factor for NPC patients. PMID- 25026831 TI - [Clinical analysis of 29 cases of cervical necrotizing fasciitis]. AB - OBJECTIVE: To study the experience of clinical features and treatment of deep cervical necrotizing fasciitis. METHOD: All 29 cases of cervical necrotizing fasciitis patients were diagnosed by CT, 12 cases underwent tracheostomies, lateral neck incisions and drainage operations, the other 17 patients underwent lateral neck incisions and drainage operations. Sequently washing, dressing changes and anti infection treatments were taken. RESULT: Twenty-eight cases were cured, 1 cases died. During a follow-up of half a year,no relapse. CONCLUSION: When patient was sufferd the cervical necrotizing fasciitis, surgical operation for exploration should be taken as soon as possible,and incision and drainage in the treatment of cervical abscess would obtain a satisfactory curative effect, which would prevent serious complications. PMID- 25026832 TI - [Clinical reseach of early laryngocarcinoma treatment by carbon dioxide laser microsurgery]. AB - OBJECTIVE: To define the oncologic efficacy of transoral endoscopic CO2 laser surgery in early glottic carci noma. METHOD: A retrospective study of 112 patients with laryngocarcinoma treated. Surgical treatment included endoscopic CO2 laser cordectomies according to the classification of the European Laryngological Society. After the patients were given the general anesthesia and oral intubation, the tumors in the study group were resected along the margin of the tumor under larynscope, and the safety margin was reserved as 3-5 mm. All the patients were followed-up for 12-62 months. RESULT: Eight relapses were detected in 112 cases of glottic laryngeal carcinoma after CO2 laser surgery. The local recurernce rate was 7.14% (8/112),of the rate for T1a, T1b and T2 were 0.89%, 0.89% and 5.04% respectively, with significant differences among groups (chi2 = 5.306, P < 0.01) . The rate of local recurrence rate of anterior commissure involvement was 7.14% and that was 7.14% when this site was not compromised by the tumor, which has no statistically significant differences (chi2 = 0.000, P > 0.01). CONCLUSION: According to our reaserch, endoscopic CO2 laser sur gery is an effective treatment for early laryngocarcinoma. PMID- 25026833 TI - [The application of retroauricular perforators flap in the external auditory canal-skin-defect repairing]. PMID- 25026834 TI - [Therapy of complication of cervical esophagus foreign body]. PMID- 25026835 TI - [Big osteoma of ethmoid sinus]. AB - Sinus osteoma is a common nasal and sinus disease, while the clinical cases of osteoma with a diameter greater than 30 millimeter are rarely seen. This paper reports a case of a 39-years-old male patient discovered with one-year long swelling pain in the right eye. The patients' right eye was mildly prominent and he suffered from hypopsia and diplopia. After CT scanned, he have ethmoid osteoma been discovered, besides, the right media rectus compression and orbital apex compression and consequent pathologically were diagnosed. The solid tumor ranged widely from the anterior skull base to the superior and interior orbital walls,and thus deprived the patient's complete surgical resection. As an attempt to prevent complications, most parts of the tumors were sur gically removed. PMID- 25026836 TI - [Applications of digital department in otolaryngology]. AB - OBJECTIVE: The aim of this study is to explore the applications of digital department in otolaryngology concern with the emergent and dangerous of otolaryngology diseases. METHOD: We have constructed digital otolaryngology head and neck surgery department on the basis of hospital information system, which is constructed under the guidance of the theories and methods of modern information integration technology, computer software technology, health informatics and network information technology. RESULT: The foundation of digital otolaryngology department can optimize digital workflow, improve work efficiency and eliminate the manual operation. CONCLUSION: Digital department in otolaryngology will promote the quality and upgrade the level of medical staff, it plays an important role in the hospital informationization. PMID- 25026837 TI - [The clinical characteristics and treatment progress of otitis media in children]. AB - Otitis media is a common problem in children, which may cause hearing loss and complications sometimes. This topic will review the definition, causes, types, clinical characteristics and treatments of each type of ear infections in children, by reading recently literatures. It is important to make an accurate diagnosis and choose a appropriate treatment of otitis media in children to avoid antibiotics abusing. Sometime some cases need operations, which are effective, especially in chronic suppurative otitis media and cholesteatoma, and we need further studying focuse on when do the operations and how to shoose them. PMID- 25026838 TI - [Diagnosis at a glance. Patient with advance stage HIV. Condyloma on the chin]. PMID- 25026839 TI - [The PARTNER study. HIV therapy as HIV prevention]. PMID- 25026841 TI - [Mississippi baby. Early therapy of newborn infants: permanent healing?]. PMID- 25026840 TI - [New HIV drugs. Pipeline stays well filled]. PMID- 25026842 TI - [Comparison of drug combinations. New strategies for initial HIV therapy]. PMID- 25026843 TI - [HIV/HCV coinfection. A good chance of recovery also for dually infected patients]. PMID- 25026844 TI - [Hepatitis C. An increase in interferon-free therapy]. PMID- 25026845 TI - [Preventing rebound viremia after ending ART. Long-term control]. PMID- 25026846 TI - [From fatal epidemic to chronic illness. How AIDS became manageable]. PMID- 25026847 TI - [AIDS in Africa. Change for the better with local programs]. PMID- 25026848 TI - [We have tamed HIV--let's stay doubly vigilant!]. PMID- 25026849 TI - [HIV infection and depression]. PMID- 25026850 TI - [Stigma related to HIV infection]. PMID- 25026851 TI - [Organic psychoses in HIV-infected patients--an interdisciplinary case report]. PMID- 25026852 TI - [Initial HIV therapy. ACTG 5257: convincing results for raltegravir compared with protease inhibitors]. PMID- 25026853 TI - [Eye exams in HIV patients]. PMID- 25026854 TI - [Simplification of antiviral therapy with single tablet regimens: advantages and disadvantages of modern ART]. PMID- 25026855 TI - [Management of late presenters with opportunistic diseases: when and how to start ART]. PMID- 25026856 TI - [Syphilis: the new epidemic among MSM]. PMID- 25026857 TI - [As simple and as compatible as possible. HIV patients profit from single tablet regimen]. PMID- 25026858 TI - [Increase of N. gonorrhoeae, Chlamydia trachomatis and Ureaplasma in HIV infected individuals]. PMID- 25026859 TI - [HIV infection. Compatibility of recent protease inhibitors in direct comparison the advantage of DRV]. PMID- 25026860 TI - [Therapy spectrum in hepatitis C extended. Newer NS3/4A protease inhibitor in chronic hepatitis C-GT1/4 infection]. PMID- 25026861 TI - [Anal cytology--a new recommended method for anal cancer screening in HIV positive patients]. PMID- 25026862 TI - [Integrase inhibitor in HIV therapy. Does dolutegravir set new standards?]. PMID- 25026863 TI - [HIV infection and AIDS from the health policy viewpoint. Savings and therapy superiority maintained - a contradiction in HIV therapy?]. PMID- 25026864 TI - Outcomes of polytrauma patients with diabetes mellitus. AB - BACKGROUND: The impact of diabetes mellitus in patients with multiple system injuries remains obscure. This study was designed to increase knowledge of outcomes of polytrauma in patients who have diabetes mellitus. METHODS: Data from the Trauma Audit and Research Network was used to identify patients who had suffered polytrauma during 2003 to 2011. These patients were filtered to those with known outcomes, then separated into those with diabetes, those known to have other co-morbidities but not diabetes and those known not to have any co morbidities or diabetes. The data were analyzed to establish if patients with diabetes had differing outcomes associated with their diabetes versus the other groups. RESULTS: In total, 222 patients had diabetes, 2,558 had no past medical co-morbidities (PMC), 2,709 had PMC but no diabetes. The diabetic group of patients was found to be older than the other groups (P <0.05). A higher mortality rate was found in the diabetic group compared to the non-PMC group (32.4% versus 12.9%), P <0.05). Rates of many complications including renal failure, myocardial infarction, acute respiratory distress syndrome, pulmonary embolism and deep vein thrombosis were all found to be higher in the diabetic group. CONCLUSIONS: Close monitoring of diabetic patients may result in improved outcomes. Tighter glycemic control and earlier intervention for complications may reduce mortality and morbidity. PMID- 25026865 TI - Collagen and hyaluronan at wound sites influence early polymicrobial biofilm adhesive events. AB - BACKGROUND: Wounds can easily become chronically infected, leading to secondary health complications, which occur more frequently in individuals with diabetes, compromised immune systems, and those that have suffered severe burns. When wounds become chronically infected, biofilm producing microbes are often isolated from these sites. The presence of a biofilm at a wound site has significant negative impact on the treatment outcomes, as biofilms are characteristically recalcitrant to removal, in part due to the formation of a protective matrix that shield residents organisms from inimical forces. Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) are two of the organisms most prevalently isolated from wound sites, and are of particular concern due to their elevated levels of antibiotic resistance, rapid growth, and exotoxin production. In order to understand the biofilm forming abilities of these microbes in a simulated wound environment we used a microtiter plate assay to assess the ability of these two organisms to bind to proteins that are typically found at wound sites: collagen and hyaluronan. RESULTS: Collagen and hyaluronan were used to coat the wells of 96-well plates in collagen:hyaluronan ratios of 0:1, 3:1, 1:1, 1:3, and 1:0 . P. aeruginosa and MRSA were inoculated as mono- and co cultures (1:1 and a 3:1 MRSA: P. aeruginosa). We determined that coating the wells with collagen and/or hyaluronan significantly increased the biofilm biomass of attached cells compared to an uncoated control, although no one coating formulation showed a significant increase compared to any other combination. We also noted that the fold-change increase for MRSA upon coating was greater than for P. aeruginosa. CONCLUSIONS: Our study suggests that the presence of collagen and/or hyaluronan at wound sites may be an important factor that influences the attachment and subsequent biofilm formation of notorious biofilm-formers, such as MRSA and P. aeruginosa. Understanding the kinetics of binding may aid in our comprehension of recalcitrant wound infection development, better enabling our ability to design therapies that would prevent or mitigate the negative outcomes associated with such infections. PMID- 25026866 TI - Accuracy of lung nodule volumetry in low-dose CT with iterative reconstruction: an anthropomorphic thoracic phantom study. AB - OBJECTIVE: The purpose of this study was to assess accuracy of lung nodule volumetry in low-dose CT with application of iterative reconstruction (IR) according to nodule size, nodule density and CT tube currents, using artificial lung nodules within an anthropomorphic thoracic phantom. METHODS: Eight artificial nodules (four diameters: 5, 8, 10 and 12 mm; two CT densities: -630 HU that represents ground-glass nodule and +100 HU that represents solid nodule) were randomly placed inside a thoracic phantom. Scans were performed with tube current-time product to 10, 20, 30 and 50 mAs. Images were reconstructed with IR and filtered back projection (FBP). We compared volume estimates to a reference standard and calculated the absolute percentage error (APE). RESULTS: The APE of all nodules was significantly lower when IR was used than with FBP (7.5 +/- 4.7% compared with 9.0 +/-6.9%; p < 0.001). The effect of IR was more pronounced for smaller nodules (p < 0.001). IR showed a significantly lower APE than FBP in ground-glass nodules (p < 0.0001), and the difference was more pronounced at the lowest tube current (11.8 +/- 5.9% compared with 21.3 +/- 6.1%; p < 0.0001). The effect of IR was most pronounced for ground-glass nodules in the lowest CT tube current. CONCLUSION: Lung nodule volumetry in low-dose CT by application of IR showed reliable accuracy in a phantom study. Lung nodule volumetry can be reliably applicable to all lung nodules including small, ground-glass nodules even in ultra-low-dose CT with application of IR. ADVANCES IN KNOWLEDGE: IR significantly improved the accuracy of lung nodule volumetry compared with FBP particularly for ground-glass (-630 HU) nodules. Volumetry in low-dose CT can be utilized in patient with lung nodule work-up, and IR has benefit for small, ground-glass lung nodules in low-dose CT. PMID- 25026867 TI - Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. AB - BACKGROUND: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. METHODS: We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. RESULTS: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. CONCLUSIONS: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD. PMID- 25026868 TI - Ethical issues that confront nurses in private hospitals in the Western Cape Metropolitan area. AB - BACKGROUND: Nurses are faced daily with a variety of ethical issues which could be as a result of budget cuts, target setting, the shortage of nurses and expertise. OBJECTIVES: The objectives of the study were to identify ethical issues related to patient care, to describe ethical issues related to patient diversity, rights and human dignity. To describe ethical issues related to caring in nursing and to the workplace environment. METHOD: A quantitative explorative descriptive research design was applied. A stratified sample of (n = 142/5%) was drawn from all nurses and caregivers (N = 2990) working in a selected group of eight private hospitals. Self-administered questionnaires were used to collect the data. Statistical tests were applied to determine statistical relationships between variables. RESULTS: RESULTS included (95%) of respondents provided safe and committed care to their patients, (99%) loved to care for their patients and (93%) believed in the Nurses' Pledge of Service. Fifty percent (50%) of the respondents indicated verbal abuse from patients and only (59%) experienced openness and transparency in the work environment. Analysis further identified that the caregivers did not respect the noble tradition of the profession and experienced the most verbal abuse. CONCLUSION: This study has identified ethical issues which may give rise to conflict within the workplace environment if not adequately addressed by management. The study further showed that the use of caregivers not regulated in nursing practice may pose as a threat to the safety of the patient. PMID- 25026869 TI - Assessment of the phytochemical constituents and antioxidant activity of a bloom forming microalgae Euglena tuba. AB - BACKGROUND: Unstable generation of free radicals in the body are responsible for many degenerative diseases. A bloom forming algae Euglena tuba growing abundantly in the aquatic habitats of Cachar district in the state of Assam in North-East India was analysed for its phytochemical contents, antioxidant activity as well as free radical scavenging potentials. RESULTS: Based on the ability of the extract in ABTS*+ radical cation inhibition and Fe3+ reducing power, the obtained results revealed the prominent antioxidant activity of the algae, with high correlation coefficient of its TEAC values to the respective phenolic and flavonoid contents. The extract had shown its scavenging activity for different free radicals and 41.89 +/- 0.41 MUg/ml, 5.83 +/- 0.07 MUg/ml, 278.46 +/- 15.02 MUg/ml and 223.25 +/- 4.19 MUg/ml were determined as the IC50 values for hydroxyl, superoxide, nitric oxide and hypochlorous acid respectively, which are lower than that of the corresponding reference standards. The phytochemical analysis also revealed that the phenolics, flavonoids, alkaloids, tannins and carbohydrates are present in adequate amount in the extract which was confirmed by HPLC analysis. CONCLUSIONS: The results showed that 70% methanol extract of the algae possesses excellent antioxidant and free radical scavenging properties. PMID- 25026870 TI - Yeast central nervous system infection in a critically ill patient: a case report. AB - INTRODUCTION: Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. CASE PRESENTATION: We describe the case of a 28-year-old Greek man with yeast central nervous system infection. CONCLUSIONS: Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients. PMID- 25026871 TI - A crew resource management program tailored to trauma resuscitation improves team behavior and communication. AB - BACKGROUND: Crew Resource Management (CRM) is a team-building communication process first implemented in the aviation industry to improve safety. It has been used in health care, particularly in surgical and intensive care settings, to improve team dynamics and reduce errors. We adapted a CRM process for implementation in the trauma resuscitation area. STUDY DESIGN: An interdisciplinary steering committee developed our CRM process to include a didactic classroom program based on a preimplementation survey of our trauma team members. Implementation with new cultural and process expectations followed. The Human Factors Attitude Survey and Communication and Teamwork Skills assessment tool were used to design, evaluate, and validate our CRM program. RESULTS: The initial trauma communication survey was completed by 160 team members (49% response). Twenty-five trauma resuscitations were observed and scored using Communication and Teamwork Skills. Areas of concern were identified and 324 staff completed our 3-hour CRM course during a 3-month period. After CRM training, 132 communication surveys and 38 Communication and Teamwork Skills observations were completed. In the post-CRM survey, respondents indicated improvement in accuracy of field to medical command information (p = 0.029); accuracy of emergency department medical command information to the resuscitation area (p = 0.002); and team leader identity, communication of plan, and role assignment (p = 0.001). After CRM training, staff were more likely to speak up when patient safety was a concern (p = 0.002). CONCLUSIONS: Crew Resource Management in the trauma resuscitation area enhances team dynamics, communication, and, ostensibly, patient safety. Philosophy and culture of CRM should be compulsory components of trauma programs and in resuscitation of injured patients. PMID- 25026872 TI - A global Delphi consensus study on defining and measuring quality in surgical training. AB - BACKGROUND: Evidence suggests that patient outcomes can be associated with the quality of surgical training. To raise the standards of surgical training, a tool to measure training quality is needed. The objective of this study was to define the elements of high-quality surgical training and methods to measure them. STUDY DESIGN: Modified Delphi methodology was used to achieve international expert consensus. Seventy statements about indicators and measures of training quality were developed based on themes from semi-structured interviews of surgeons. Eighty-three experts in surgical education from 13 countries were invited to complete an online survey ranking each statement on a 5-point Likert scale. Consensus was predefined as Cronbach's alpha >=0.80. Once consensus was achieved, statements ranked >=4 by >=80% of experts were used as themes to develop the Surgical Training Quality Assessment Tool (S-QAT). RESULTS: Fifty-three (64%) experts from 11 countries responded. Consensus was achieved after 2 rounds of voting (Cronbach's alpha = 0.930). Thirty-five statements were selected as themes for the Surgical Training Quality Assessment Tool. Statements defining training quality covered the following subjects: relationship between the trainer and trainee, operative exposure, supervision, feedback, structure and organization, and structured teaching programs. Consensus statements on measuring training quality included trainee feedback, trainer feedback, timetable structure, and trainee improvement. There was agreement that measuring training quality would have a positive effect on training. CONCLUSIONS: International expert consensus was achieved on defining and measuring high-quality surgical training. This has been translated into the (S-QAT) to evaluate surgical training programs. Competition created by comparing training quality might raise the standards of surgical education. PMID- 25026873 TI - Impact of negative clinical trial results for vertebroplasty on vertebral augmentation procedure rates. AB - BACKGROUND: Vertebroplasty and kyphoplasty are procedures for treating vertebral compression fractures (VCFs). In August 2009, 2 randomized trials in the New England Journal of Medicine found that vertebroplasty did not reduce pain or disability relative to a sham procedure among patients with osteoporotic VCFs. STUDY DESIGN: We evaluated quarterly trends in per capita rates of vertebroplasties and kyphoplasties using the Florida hospital inpatient discharge and ambulatory surgery center databases from 2005 to 2012, supplemented with physician specialty and population data. We reported trends by procedure type, patient diagnosis, and physician specialty. We modeled the procedures as interrupted time series with a break when the clinical trials were published, and estimated changes in procedure rates and health expenditures resulting from the trials. RESULTS: The trials led to a 51.5% decline in the per capita vertebroplasty rate and a 40.0% decline in the kyphoplasty rate (both results p < 0.010) compared with what procedure rates would have been without the trials. Vertebroplasty rates for interventional radiologists displayed no significant change; rates for surgeons and other specialists declined by 73.1% (p < 0.010). Overall, these changes imply nationwide health expenditure savings of just over $1 billion per year. CONCLUSIONS: Publication of negative clinical trial results led to moderate reductions in vertebroplasties and kyphoplasties for osteoporotic VCFs. However, vertebroplasty and kyphoplasty continue to be widely used to treat patients with osteoarthritis. Substantial differences in response across physicians suggest an important role for specialty society clinical guidelines in modulating how clinical evidence is incorporated into routine practice. PMID- 25026874 TI - Differences in hospital performance for noncancer vs cancer colorectal surgery. AB - BACKGROUND: Considerable hospital-to-hospital variations in surgical outcomes have been reported across surgical procedures. However, it is unclear whether hospital quality rankings are consistent for noncancer and cancer operations. We investigated the differences in hospital performance for noncancer and cancer colorectal resections at 52 hospitals participating in the Michigan Surgical Quality Collaborative (MSQC). STUDY DESIGN: Patients undergoing colorectal resections between 2008 and 2012 were identified. Hierarchical risk-adjusted models were used to evaluate hospital level 30-day morbidity, major morbidity, extended length-of-stay (LOS > 75(th) percentile), and mortality outcomes. Hospital performance, as ranked by observed-to-expected ratios, was compared by rank-order changes, interquartile ranges (IQR), and Spearman's correlations. RESULTS: Of the 19,990 colorectal resections, 7,292 (36.5%) were for cancer. We observed wide variations in all risk-adjusted 30-day outcomes between hospitals, but only weak correlations in cancer and noncancer performance within hospitals. Overall hospital performance in mortality after noncancer and cancer operations was not correlated (Spearman's rho: 0.02). Of the best performing hospitals in mortality after noncancer resections, 69% were reclassified to a worse quartile for cancer operations (median rank-change of 12.5 ranks [IQR 5 to 27]). Similarly, hospital performance in morbidity was only moderately correlated (rho: 0.59; p < 0.001). Of the hospitals with lowest morbidity rates for noncancer resections, 31% were reclassified. We noted a similar lack of relationship in major morbidity and extended LOS. CONCLUSIONS: A hospital's performance ranking in risk-adjusted outcomes after noncancer colorectal resections does not correlate to its performance for cancer-related colorectal resections. Indication for operation should be considered when leveraging risk-adjusted hospital outcomes for quality improvement efforts. PMID- 25026875 TI - Skin involvement and breast cancer: are T4b lesions of all sizes created equal? AB - BACKGROUND: Nonmetastatic, noninflammatory, invasive breast cancers with skin involvement (SI) are classified as T4b, regardless of size. This study evaluated disease-specific survival (DSS) to determine whether size should be considered for these lesions rather than grouping them all into stage III. STUDY DESIGN: Surveillance, Epidemiology, and End Results data linked to Medicare claims were reviewed. Skin involved and non-SI tumors were reclassified using the American Joint Committee on Cancer, 7(th) edition groupings using tumor size and nodal involvement alone without considering SI (neostage). Disease-specific survival was adjusted for demographics, histology, and treatment using competing risk methods with propensity score-based weighting and bootstrap standard errors. RESULTS: Among 924 SI patients diagnosed between 1992 and 2005, tumors were 0.1 to 2.0 cm, 2.1 to 5.0 cm, and >5.0 cm in 11.6%, 51.1%, and 37.3% of patients, respectively. There were no nodal metastases in 22.3%, 1 to 3 positive nodes in 31.7%, 4 to 9 positive in 28.6%, and >=10 positive in 17.4% of patients. For SI patients, adjusted 5-year DSS was 95.8% (95% CI, 95.6-96.0) for neostage I, declining progressively to 36.4% (95% CI, 33.8-39.2) for neostage IIIC patients. Adjusted 5-year DSS for SI and non-SI tumors (n = 66,185) was similar for neostage I, IIA, and IIB, and markedly lower for IIIA and IIIC. Adjusted DSS for SI IIIA was similar to non-SI IIIC. CONCLUSIONS: Noninflammatory SI breast cancers have widely varied DSS that differs by tumor size and nodal involvement and therefore should not all be stage III. Skin involvement should be subordinate to T and N groupings to classify SI with non-SI lesions having similar prognoses. PMID- 25026876 TI - Multiple listings as a reflection of geographic disparity in liver transplantation. AB - BACKGROUND: Geographic disparity in access to liver transplantation (LT) exists. This study sought to examine Model for End-Stage Liver Disease-era multiply listed (ML) LT candidate (ie, candidates who list at 2 or more LT centers to receive a liver transplant). STUDY DESIGN: Data on adult, primary, non-status 1 LT candidates (n = 59,557) listed from January 1, 2005 to December 31, 2011 were extracted from the United Network for Organ Sharing's Standard Transplant Analysis and Research files. Comparisons of ML vs singly listed LT candidates were performed, with additional analysis performed at the donor service area (DSA) and regional level, as well as assessment of the donor population used. RESULTS: There were 1,358 (2.3%) ML candidates during the 7-year study period. Multiply listed candidates compared with singly listed candidates were more often male, white, blood type O, nondiabetic, college educated, and privately insured. The odds of pursuing ML increased considerably as time on the waitlist increased. Of the ML candidates, 918 (67.6%) went on to receive a liver transplant (ML-LT), 767 (83.6%) at the secondary listing DSA, which was a median of 588 miles (range 229 to 1095 miles) from the primary listing DSA. When compared with the primary listing DSA, the secondary listing DSA had significantly lower match Model for End-Stage Liver Disease scores, as well as shorter wait times. Regional analysis demonstrated significantly higher odds for pursuing ML from LT candidates located within regions 1, 5, and 9. CONCLUSIONS: A small and distinctive cohort of LT candidates pursue ML, indicating willingness and means to travel to receive a liver transplant. Efforts toward equalizing LT access across regional disparities are warranted, and can help obviate the need for ML. PMID- 25026877 TI - Reduced red blood cell transfusion in cardiothoracic surgery after implementation of a novel clinical decision support tool. AB - BACKGROUND: Packed red blood cell (PRBC) transfusion can increase short- and long term adverse outcomes and health care costs. We compared the transfusion practices in cardiothoracic surgery before and after implementation of a novel clinical decision support (CDS) tool. STUDY DESIGN: The transfusion CDS tool was implemented within computerized provider order entry of a multi-institutional urban hospital system in September 2012. Data were queried for 12 months pre intervention and for another 12 months post-intervention to compare transfusion practices for all adult patients having isolated coronary artery bypass grafting (CABG) or isolated surgical aortic valve replacement (SAVR). RESULTS: The total number of patients undergoing either isolated CABG or isolated SAVR was 744 pre intervention and 765 post-intervention (p = 0.84). There was no significant difference in age (64 +/- 11.4 years vs 64.5 +/- 11.2 years, p = 0.37) or sex (30.2% vs 32.2% female, p = 0.42) between the 2 groups. The number of postoperative transfusions (374 [50.3%] vs 312 [40.8%], p < 0.001), postoperative PRBC units given (1.59 +/- 2.9 vs 1.25 +/- 2.5, p = 0.01), pre-transfusion hemoglobin level (8.09 +/- 1.5 g/dL vs 7.65 +/- 1.4 g/dL, p < 0.001), and incidence of surgical site infection (3.1% vs 1.1%; p = 0.005) were significantly reduced after implementation of the transfusion CDS tool. There were no significant differences in intraoperative transfusions (206 [27.7%] vs 180 [23.5%], p = 0.06), intraoperative PRBC units given (0.73 +/- 1.5 vs 0.65 +/- 1.4, p = 0.28), ICU length of stay (3.29 +/- 3.9 days vs 3.37 +/- 4.8 days, p = 0.74), or in-hospital mortality (1.3% vs 1.4%, p = 0.87). CONCLUSIONS: Implementation of a transfusion CDS tool was associated with lower pre transfusion hemoglobin levels, fewer transfusions, decreased infection rates, and decreased health care costs, without an increase in short-term mortality. PMID- 25026878 TI - Laparoscopy-assisted endoscopic full-thickness resection with basin lymphadenectomy based on sentinel lymph nodes for early gastric cancer. PMID- 25026879 TI - Association of radiographic morphology with early gastroesophageal reflux disease and satiety control after sleeve gastrectomy. AB - BACKGROUND: Variable gastric morphology has been identified on routine upper gastrointestinal series after laparoscopic sleeve gastrectomy. This test might give us useful information beyond the presence of leak and obstruction. The aim of this study is to standardize a morphologic classification of gastric sleeve based on water-soluble contrast upper gastrointestinal series, and to determine possible clinical implications. STUDY DESIGN: One hundred morbidly obese patients underwent laparoscopic sleeve gastrectomy and had routine upper gastrointestinal on postoperative day 1 or 2. Images were reviewed by 4 radiologists who were blinded to outcomes, and sleeve shape was classified as upper pouch, lower pouch, tubular, or dumbbell. Inter-observer agreement was calculated. Clinical outcomes including weight loss, satiety control, and reflux symptoms were recorded. Comparisons were determined by 1-way ANOVA and t-test. RESULTS: Mean age was 46 +/- 12 years and mean BMI was 45.1 +/- 6 kg/m(2). Overall inter-observer agreement level for the sleeve shape classification was 76.3%. Sleeve shapes were tubular in 37%, dumbbell in 32%, lower pouch in 22%, and upper pouch in 8%. Mean excess body weight loss at 1, 3, and 6 months was 16.8%, 29.9%, and 39.1%, respectively. Excess body weight loss was not associated with sleeve shape. Mean hunger score was 213 +/- 97, and patients with dumbbell shape had higher hunger scores (p = 0.003). Mean reflux score was 5.7 +/- 8. Upper pouch shape was associated with greater severity of reflux symptoms (p = 0.02). CONCLUSIONS: This study suggests a standardized radiographic classification of gastric sleeve morphology. Although sleeve shape is not correlated with weight loss, gastric sleeves with retained fundus result in lower satiety control and higher severity of reflux symptoms. An adequate resection of the gastric fundus might avoid this potential complication. PMID- 25026881 TI - Radiating Frohlich system as a model of cellular electromagnetism. AB - Oscillating polar entities inside the biological cells, most notably microtubules, are bound to emit electromagnetic radiation. This phenomenon is described by Frohlich kinetic equations expressing, in terms of quantum occupancy numbers of each discrete collective oscillatory mode, the balance between incoming metabolic energy flow and losses due to linear and non-linear interactions with the thermal environs of the oscillators. Hitherto, radiation losses have not been introduced as part of the balance; it was assumed that they were proportional to the modal occupation numbers. It is demonstrated that this formulation is incorrect and the radiation losses must be taken into account in the kinetic equations explicitly. Results of a numerical study of kinetic equations, enlarged in this sense, are presented for the case of three coupled oscillators which was shown to evince the essential attributes of the Frohlich systems. Oscillator eigenfrequencies were chosen, alternatively, to fall into the MHz and the THz frequency domains. It was found that large radiation levels destroy the main hallmark of the Frohlich systems, the energy condensation in the lowest frequency mode. The system then functions as a convertor of metabolic energy into radiation. At more moderate radiation levels, both energy condensation and significant radiation can coexist. Possible consequences for the cell physiology are suggested. PMID- 25026880 TI - The importance of the first complication: understanding failure to rescue after emergent surgery in the elderly. AB - BACKGROUND: Perioperative mortality in the elderly is high after emergency surgery and varies considerably among hospitals-an observation partially explained by differences in failure to rescue. We hypothesize that failure to rescue after certain types of complications underlies the disproportionately poor outcomes observed in elderly patients. STUDY DESIGN: We identified 23,217 patients undergoing emergent general or vascular surgery procedures at 41 hospitals within the Michigan Surgical Quality Collaborative between 2007 and 2012. Patients' first complications were identified and categorized by type. We compared failure to rescue rates at the patient-level between patients younger than 75 and 75 years of age and older. We then compared failure to rescue rates after specific complications across hospitals grouped in tertiles by risk adjusted 30-day mortality. RESULTS: Risk-adjusted failure to rescue rates were significantly higher in the elderly after a first infectious (21.7% vs 10.3%; p < 0.01) or pulmonary (38.2% vs 20.4%; p < 0.01) complication when compared with younger patients. At the hospital level, high-mortality centers failed to rescue elderly patients more frequently than low-mortality centers after a first infectious (35.6% vs 22.2%; p < 0.01) and pulmonary (24.3 vs 14.3; p < 0.01) complication. Failure to rescue rates after cardiovascular complications did not differ significantly across patient ages or tertiles of hospital mortality. CONCLUSIONS: Hospitals fail to rescue elderly patients at higher rates than younger patients after infectious and pulmonary complications. Efforts to recognize and manage these specific complications have the potential to improve emergency surgical care of the elderly in Michigan. PMID- 25026882 TI - Internal consistency and test-retest reliability of an instrumented functional reaching task using wireless electromyographic sensors. AB - The purpose of this study was to establish the internal consistency and test retest reliability of the electromyographic and accelerometric data sampled from the prime movers of the dominant arm during an antigravity, within-arm's length stand-reaching task without trunk restraint. Ten healthy young adults participated in two experimental sessions, approximately 7-10days apart. During each session, subjects performed 15 trials of both a flexion- and an abduction reaching task. Surface EMG and acceleration using wireless sensors were sampled from the anterior and middle deltoid. Reliability was established using Cronbach's alpha, intraclass correlation coefficients (ICC 2, k) and standard error of measurements (SEM) for electromyographic reaction time, burst duration and normalized amplitude along with peak acceleration. Results indicated high degrees of inter-trial and test-retest reliability for flexion (Cronbach's alpha range=0.92-0.99; ICC range=0.82-0.92) as well as abduction (Cronbach's alpha range=0.94-0.99; ICC range=0.81-0.94) reaching. The SEM associated with response variables for flexion and abduction ranged from 1.55-3.26% and 3.33-3.95% of means, respectively. Findings from this study revealed that electromyographic and accelerometric data collected from prime movers of the arm during the relatively functional stand-reaching task were highly reproducible. Given its high reliability and portability, the proposed test could have applications in clinical and laboratory settings to quantify upper limb function. PMID- 25026883 TI - Identification and antifungal activity of novel organic compounds found in cuticular and internal lipids of medically important flies. AB - Novel organic compounds found in the cuticular and internal lipids of medically important flies were identified. Uracil, 9-tricosene, 1-oleoyl glycerol, dimethyl suberate and butyl stearate were tested for their potential antifungal activity. Minimal inhibitory concentrations of the compounds against reference strains of fungi were determined. Uracil and dimethyl suberate slightly inhibited the growth of entomopathogenic fungi. The cuticular and internal lipids of Calliphora vicina, Calliphora vomitoria, Sarcophaga carnaria and Musca domestica were studied by gas chromatography (GC) combined with mass spectrometry (GC/MS). A comparison of the lipid extracts between the preimaginal and mature stages showed adults flies contained a higher total content of the identified components. Furthermore, their amounts distinctly predominated in the internal lipids of all the species. The amount of 9-tricosene was the highest in adults of C. vicina, while the larvae and pupae had a definitively lower amount of this compound. Uracil was found to be the most abundant component in extracts obtained from C. vomitoria especially in the internal lipids of adults. 1-oleoyl glycerol was detected in all of the examined species of flies. It was most abundant in the internal extracts isolated from the larvae of C. vicina and the pupae of C. vomitoria. Suberic acid dimethyl ester was found in the larval and pupal internal lipids of C. vicina and S. carnaria in low amounts. Butyl stearate was identified only in the internal lipids of the larvae and adults of houseflies. PMID- 25026885 TI - [Avoidable hospitalizations: the sole responsibility of primary care?]. AB - BACKGROUND: Avoidable hospitalizations are used as a performance indicator of primary care in many countries. We investigate here the validity and usefulness of this measure both at a global scale and for the French healthcare system. METHODS: A scoping study was performed to take a critical look at this concept. The different uses of avoidable hospitalizations as an indicator have already been reported in two recent systematic literature reviews. RESULTS: Rates of avoidable hospitalizations seem to be far more correlated with the socioeconomic attributes of patients than with primary care supply. The few studies conducted in France confirm this international trend. Several weaknesses have been spotted in the building of this indicator: the choice of conditions that can be considered as sources of avoidable hospitalizations, their identification among hospitalization disease codes, the quality of hospital coding procedures, the ecological bias in the data collection of illustrative variables. CONCLUSION: Guidelines for improvement of this indicator are provided. In particular, we discuss the possibility of its use at the scale of the whole healthcare system. PMID- 25026884 TI - A randomized trial of survey participation in a national random sample of general practitioners and gynecologists in France. AB - BACKGROUND: Healthcare professionals play a critical role in women's choice of contraceptive methods. However, national surveys on sexual and reproductive health (SRH) among physicians are rare and present low participation rates. We conducted a randomized trial to test for the effectiveness of three interventions to improve survey participation of private physicians delivering reproductive health services in France. METHODS: The study comprised a national random sample of 500 general practitioners and 500 gynecologists working in private offices. All received a postal invitation to participate either by completing a paper, phone or online questionnaire. Physicians were randomly assigned to six groups to test for the effect of three interventions: a non-monetary incentive in the form of a scientific book, telephone contact, and the possibility of completing the questionnaire by phone. RESULTS: Overall, 362 questionnaires were collected (26 online, 2 by phone) and 58 physicians were ineligible. The completion rate increased from 26.7% in physicians who received no intervention to 42.7% in those who received the book and a phone call. The phone call increased the completion rate by 11% percentage points (P=0.01), while the book had no significant effect. Results from multivariate logistic regressions also indicate that gynecologists (OR=1.6) and female physicians (OR=1.5) were more likely to participate than others. CONCLUSION: The results suggest that phone calls substantially increase participation of physicians in sexual and reproductive health surveys but have little impact on sampling distortion. Differentials in response rates by physicians' characteristics should be considered in future SRH studies among physicians. PMID- 25026886 TI - [Qualitative and quantitative comparisons of three individual deprivation scores for outpatients attending a free hospital care clinic in Paris]. AB - BACKGROUND: Inequality in health care is a growing problem, leading to the development of different tools for the assessment of individual deprivation. In France, three tools are mainly used: Epices (which stands for "score for the evaluation of social deprivation and health inequities among the centers for medical examination"), a score called "Handicap social" and a screening tool built for medical consultations by Pascal et al. at Nantes' hospital. The purpose of this study was to make a metrological assessment of those tools and a quantitative comparison by using them on a single deprived population. METHODS: In order to assess the metrological properties of the three scores, we used the quality criteria published by Terwee et al. which are: content validity, internal consistency, criterion validity, construct validity, reproducibility (agreement and reliability), responsiveness, floor and ceiling effects and interpretability. For the comparison, we used data from the patients who had attended a free hospital outpatient clinic dedicated to socially deprived people in Paris, during one month in 2010. The "Handicap social" survey was first filled in by the 721 outpatients before being recoded to allow the comparison with the other scores. RESULTS: While the population of interest was quite well defined by all three scores, other quality criteria were less satisfactory. For this outpatient population, the "Handicap social" score classed 3.2% as non-deprived (class 1), 32.7% as socially deprived (class 2) and 64.7% as very deprived (class 3). With the Epices score, the rates of deprivation varied from 97.9% to 100% depending on the way the score was estimated. For the Pascal score, rates ranged from 83.4% to 88.1%. On a subgroup level, only the Pascal score showed statistically significant associations with gender, occupation, education and origin. CONCLUSION: These three scores have very different goal and meanings. They are not interchangeable. Users should be aware of their advantages and disadvantages in order to use them wisely. Much remains to be done to fully assess their metrological performances. PMID- 25026887 TI - Immunophenotype and gene expression profile of mesenchymal stem cells derived from canine adipose tissue and bone marrow. AB - Veterinary adult stem cell therapy is an emerging area of basic and clinical research. Like their human counterparts, veterinary mesenchymal stem cells (MSCs) offer many potential therapeutic benefits. The characterization of canine-derived MSCs, however, is poorly defined compared to human MSCs. Furthermore, little consensus exists regarding the expression of canine MSC cell surface markers. To address this issue, this study investigated characteristics of cultured canine MSCs derived from both adipose tissue and bone marrow. The canine MSCs were obtained from donors of various breeds and ages. A panel of cell surface markers for canine MSCs was selected based on current human and canine literature and the availability of canine-reactive antibodies. Using flow cytometry, canine MSCs were defined to be CD90(+)CD44(+)MHC I(+)CD14(-)CD29(-)CD34(-)MHC II(-). Canine MSCs were further characterized using real-time RT-PCR as CD105(+)CD73(+)CD14(+)CD29(+)MHC II(+)CD45(-) at the mRNA level. Among these markers, canine MSCs differed from canine peripheral blood mononuclear cells (PBMCs) by the absence of CD45 expression at the mRNA level. A novel high throughput canine-specific PCR array was developed and used to identify changes in the gene expression profiles of canine MSCs. Genes including PTPRC, TNF, beta2M, TGFbeta1, and PDGFRbeta, were identified as unique to canine MSCs as compared to canine PBMCs. Our findings will facilitate characterization of canine MSCs for use in research and clinical trials. Moreover, the high-throughput PCR array is a novel tool for characterizing canine MSCs isolated from different tissues and potentially from different laboratories. PMID- 25026888 TI - LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria. AB - The innate immune-dependent bactericidal effects are critical for preventing microbial colonization in the urinary system. However, the mechanisms involved in establishing innate immune responses in kidney are not completely understood. Here we describe the role of a novel member of the LRR (leucine-rich repeat) class of transmembrane proteins, LRRC19 (LRR-containing 19) in eliminating uropathogenic bacteria. LRRC19 is predominantly expressed in human and mouse kidney tubular epithelial cells and LRRC19-deficient mice are more susceptible to uropathogenic Escherichia coli (UPEC) infection than wild-type or TLR4 knockout mice. Recognition of UPEC by LRRC19 induces the production of cytokines, chemokines and antimicrobial substances through TRAF2- and TRAF6-mediated NF kappaB and MAPK signalling pathways. Thus, LRRC19 may be a critical pathogen recognition receptor in kidney mediating the elimination of UPEC infection. PMID- 25026889 TI - Analysis of three strategies to increase screening coverage for cervical cancer in the general population of women aged 60 to 70 years: the CRICERVA study. AB - BACKGROUND: Cervical cancer is a frequently diagnosed cancer in women worldwide. Despite having easy preventive and therapeutic approaches, it is an important cause of mortality among women. METHODS: The CRICERVA study is a cluster clinical trial which assigned one of three interventions to the target population registered in Cerdanyola, Barcelona. Among the 5,707 resident women aged 60 to 70 years in the study area, women with no record of cervical cytology over the last three years were selected. The study included four arms: three interventions all including a pre-assigned date for screening visit and i) personalized invitation letter; ii) adding to i) an informative leaflet; and, iii) in addition to ii) a personalized appointment reminder phone call, and iv) no specific action taken (control group). Participants were offered a personal interview about social demographic characteristics and about screening attitudes. Cervical cytology and HPV DNA test (HC2) were offered as screening tests. In the case of screening positive in any of these tests, the women were followed up until a full diagnosis could be obtained. The effect size of each study arm was estimated as the absolute gain in coverage between the original coverage and the final coverage. RESULTS: From the intervention groups (4,775 women), we identified 3,616 who were not appropriately screened, of which 2,560 women answered the trial call and 1,376 were amenable to screening. HPV was tested in 920 women and cervical cytology in all 1,376. Overall, there was an absolute gain in coverage of 28.8% in the intervention groups compared to 6% in the control group. Coverage increased from 51.2% to 76.0% in strategy i); from 47.4% to 79.0% in strategy ii) and from 44.5% to 74.6% in strategy iii). Lack of information about the relevance of screening was the most important factor for not attending the screening program. CONCLUSIONS: The study confirms that actively contacting women and including a date for a screening visit, notably increased participation in the screening program. Efforts to improve health education in preventative activities are warranted. TRIAL REGISTRATION: Clinical Trials.gov Identifier NCT01373723. Registered 14 June 2011. PMID- 25026890 TI - Development of a training model for estimation of uterine size in early pregnancy. PMID- 25026891 TI - Direct observation of uterotonic drug use at public health facility-based deliveries in four districts in India. AB - OBJECTIVE: To describe intrapartum uterotonic drug use and related behaviors in public health facility-based deliveries and to describe drug storage conditions in associated pharmacies. METHODS: A descriptive study was conducted between August and November 2011 to document practices related to uterotonic administration and storage based on direct observation of deliveries at public health facilities in four Indian districts (n=97, n=89, n=91, and n=89) with contrasting maternal health and socioeconomic indicators. RESULTS: Uterotonic drug use before and after delivery was common among the 366 study participants. Labor augmentation rates ranged from 53.5%-93.0% of deliveries across districts, with many receiving multiple uterotonics and administration via intramuscular injection or intravenous push. Uterotonic use following delivery ranged from 78.6%-99.1% across districts, with correct use of uterotonics for postpartum hemorrhage prevention varying from 6.0%-8.8% in Uttar Pradesh and 41.2%-76.4% in Karnataka. Active management of the third stage of labor following Indian guidelines was less than 10% in all districts. Storage of uterotonics at room temperature was common. CONCLUSION: Given that labor augmentation is nearly routine and at odds with Indian guideline recommendations, rigorous research is needed to assess maternal and fetal outcomes of current versus guidelines-based practice. Active management of the third stage of labor as per Indian guidelines was minimal. PMID- 25026892 TI - Surgical management of great saphenous vein varicose veins: A meta-analysis. AB - PURPOSE: The purpose of this systematic review and meta-analysis is to synthesise the available evidence of randomised controlled trials comparing endovenous laser therapy to traditional open surgery, high ligation and stripping, for the treatment of great saphenous vein varicose veins in terms of clinical effectiveness, patient satisfaction and peri-operative complications. METHODS: MEDLINE, CINAHL, EMBASE and the Cochrane library were searched to identify eligible studies. All randomised controlled trials comparing endovenous laser therapy to high ligation and stripping that used ultrasound examination as an outcome measure and had follow up of one year or more were included. The Cochrane Collaboration's tool for assessing risk of bias was also used to assess the methodological quality of the included studies. Pooled risk ratios with 95% confidence intervals were used as the measure of effect for each dichotomous outcome. FINDINGS: Nine eligible publications relating to six randomised controlled trials were identified. The total enrolment of the studies was 1289 limbs. The clinical efficacy of endovenous laser therapy is comparable to that of surgery in the relatively short follow up period described in the studies. Meta analysis revealed a trend towards a higher risk of ultrasound recurrence after endovenous laser therapy at 12 months. Quality of life questionnaires reveal similar outcomes for endovenous laser therapy and surgery. There is low quality evidence to suggest surgery is associated with more pain, sensory complications and infection. CONCLUSION: Endovenous laser therapy is a safe alternative to traditional open surgery. There is some weak evidence to suggest that endovenous laser therapy has a higher risk of ultrasound-detected recurrence at 12 months following treatment compared to open surgery. However, it may be associated with less sensory complications, pigmentation and infection. PMID- 25026893 TI - What causes cerebral palsy? PMID- 25026894 TI - A temporary loop ileostomy affects renal function. AB - PURPOSE: The purpose of this study was to evaluate renal morbidity after a temporary loop ileostomy and to identify possible preoperative risk factors. METHOD: Consecutive patients at four hospitals serving 1,520,000 inhabitants who received a temporary loop ileostomy and underwent subsequent closure were identified and retrospectively studied from 1 January 2007 until 28 February 2010. Serum creatinine levels were obtained 1 week before index surgery and 1 week before closure of the loop ileostomy. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. RESULTS: Three hundred eight patients with median age of 64 were identified. The indication for the loop ileostomy was colorectal cancer (226), inflammatory bowel disease (41), diverticulosis (8), and other conditions (33). Median time until closure was 161 days (3-873). There was a decrease in eGFR at time of closure (89 vs. 83; p < 0.0001), and the number of patients with renal impairment (eGFR <60) increased (7.5 vs. 21 %, p < 0.0001). Preoperative risk factors for eGFR <60 at closure were age and hypertension. CONCLUSIONS: This study found that a loop ileostomy is associated with a reduced renal function for most patients, especially for older and hypertensive patients. This should be considered before constructing a loop ileostomy, and perhaps another stoma should be chosen if possible in patients at risk. Evaluation of medications before discharge and early and frequent postoperative follow-up could also reduce the risk of a reduced renal function. PMID- 25026895 TI - Mesoporous carbon originated from non-permanent porous MOFs for gas storage and CO2/CH4 separation. AB - Four nanoporous carbons prepared by direct carbonization of non-permanent highly porous MOF [Zn3(BTC)2 . (H2O)3]n without any additional carbon precursors. The carbonization temperature plays an important role in the pore structures of the resultant carbons. The Brunauer-Emmett-Teller (BET) surface areas of four carbon materials vary from 464 to 1671 m(2) g(-1) for different carbonization temperature. All the four carbon materials showed a mesoporous structure centered at ca. 3 nm, high surface area and good physicochemical stability. Hydrogen, methane and carbon dioxide sorption measurements indicated that the C1000 has good gas uptake capabilities. The excess H2 uptake at 77 K and 17.9 bar can reach 32.9 mg g(-1) and the total uptake is high to 45 mg g(-1). Meanwhile, at 95 bar, the total CH4 uptake can reach as high as 208 mg g(-1). Moreover the ideal adsorbed solution theory (IAST) prediction exhibited exceptionally high adsorption selectivity for CO2/CH4 in an equimolar mixture at 298 K and 1 bar (S(ads) = 27) which is significantly higher than that of some porous materials in the similar condition. PMID- 25026896 TI - International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. AB - Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties. PMID- 25026898 TI - Residual patient, anatomic, and surgical obstacles in treating active left-sided infective endocarditis. AB - OBJECTIVES: To identify and understand residual patient, anatomic, and surgical obstacles in treating active left-sided infective endocarditis (IE), we categorized the intraoperative pathologic entities in patients with left-sided IE and correlated the pathology (noninvasive vs invasive) and organism with IE context (affected valve, native vs prosthetic [PVE]) and surgical results. METHODS: From January 2002 to January 2011, 775 patients underwent surgery for active left-sided IE. Registries were queried, and endocarditis-related pathology was based on the echocardiographic findings and operative notes. Propensity adjustment and matching (55 pairs) were used for risk-adjusted outcome comparisons between the invasive aortic and mitral cases. RESULTS: A total of 395 patients had isolated aortic (PVE 59%, invasive 68%), 238 isolated mitral (PVE 29%, invasive 35%), and 142 combined aortic and mitral (PVE 44%, invasive 69%) IE. The 30-day survival was 92% and was similar for native valve endocarditis and PVE in all 3 valve combinations. Invasive versus noninvasive IE was associated with greater hospital mortality (11% vs 4.4%, P = .001). Patients with invasive IE had worse intermediate-term survival than those with noninvasive IE for mitral (P = .001) and aortic plus mitral (P = .02) IE but not for isolated aortic IE. This difference persisted in the matched patients. CONCLUSIONS: During the past decade, we have had low hospital mortality for surgically treated left-sided IE and have neutralized the added risk of PVE. However, outcomes remain worse for mitral versus aortic valve IE, with residual obstacles related to patient factors, inherent mitral valve anatomy in patients with invasive disease, and lack of an alternative mitral valve prosthesis optimal for IE. PMID- 25026897 TI - Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5 year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial. AB - BACKGROUND: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet. METHODS: From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation. RESULTS: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020). CONCLUSIONS: No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033. PMID- 25026899 TI - Mononuclear phagocyte accumulation in visceral tissue in HIV encephalitis: evidence for increased monocyte/macrophage trafficking and altered differentiation. AB - The invasion of circulating monocytes/macrophages (MPhi)s from the peripheral blood into the central nervous system (CNS) appears to play an important role in the pathogenesis of HIV dementia (HIV-D), the most severe form of HIV-associated neurocognitive disorders (HAND), often confirmed histologically as HIV encephalitis (HIVE). In order to determine if trafficking of monocytes/MPhis is exclusive to the CNS or if it also occurs in organs outside of the brain, we have focused our investigation on visceral tissues of patients with HIVE. Liver, lymph node, spleen, and kidney autopsy tissues from the same HIVE cases investigated in earlier studies were examined by immunohistochemistry for the presence of CD14, CD16, CD68, Ki-67, and HIV-1 p24 expression. Here, we report a statistically significant increase in accumulation of MPhis in kidney, spleen, and lymph node tissues in specimens from patients with HIVE. In liver, we did not observe a significant increase in parenchymal macrophage accumulation, although perivascular macrophage accumulation was consistently observed with nodular lesions in 4 of 5 HIVE cases. We also observed an absence of CD14 expression on splenic MPhis in HIVE cases, which may implicate the spleen as a potential source of increased plasma soluble CD14 in HIV infection. HIV-1 p24 expression was observed in liver, lymph node and spleen but not kidney. Interestingly, renal pathology suggestive of chronic tubulointerstitial nephritis (possibly due to chronic pyelonephritis), including tubulointerstitial scarring, chronic interstitial inflammation and focal global glomerulosclerosis, without evidence of HIV-associated nephropathy (HIVAN), was seen in four of eight HIVE cases. Focal segmental and global glomerulosclerosis with tubular dilatation and prominent interstitial inflammation, consistent with HIVAN, was observed in two of the eight cases. Abundant cells expressing monocyte/MPhi cell surface markers, CD14 and CD68, were also CD16(+) and found surrounding dilated tubules and adjacent to areas of glomerulosclerosis. The finding of co-morbid HIVE and renal pathology characterized by prominent interstitial inflammation may suggest a common mechanism involving the invasion of activated monocytes/MPhis from circulation. Monocyte/MPhi invasion of visceral tissues may play an important role in the immune dysfunction as well as comorbidity in AIDS and may, therefore, provide a high value target for the design of therapeutic strategies. PMID- 25026900 TI - Preventive antiretroviral therapy in non-thalassemia carrier infants exposed to mother-to-child transmission of HIV decreases cord and after delivery red blood production without altering the development of hemoglobin. AB - Antiretroviral (ARV) prophylaxis for prevention of mother to child transmission (MTCT) of HIV could affect hemoglobin (Hb) development of infants. A cross sectional descriptive study was conducted in 24 HIV-infected and 21 HIV uninfected pregnancies. ARV drugs were administered to HIV-infected pregnancies at 21 weeks of gestational age and at labor. Their infants received zidovudine (ZDV) until 4 weeks of age. Blood samples of ARV-exposed and - unexposed infants were collected at delivery, 1, 2 and 4 months of age. Molecular analyses for alpha-thalassemia-1 Southeast Asian (SEA) type deletion, beta-thalassemia mutations and Hb E were performed for excluding the thalassemia carrier infants. Hemoglobinopathy and Hb A, Hb F and Hb A2 were analyzed by using capillary electrophoresis (CE) while hematological parameters were measured using an automated blood counter. At delivery, 1 and 2 months of age, ARVexposed infants had significantly lower levels of RBC counts than ARV-unexposed infants (3.56 vs 4.90, 2.66 vs 4.62 and 3.01 vs 4.05 x10(12)/L; P <0.001, <0.001 and 0.001, respectively). At delivery, there was a trend for low hemoglobin level in the group of ARV-exposed infants as compared to the group of ARV-unexposed infants (149 vs 154 g/L; P = 0.09) and the significantly different levels were observed among the two groups at 1 and 2 months of age (89 vs 136 and 87 vs 110 g/L; P < 0.001 and 0.001, respectively). The development of Hb A, Hb F and Hb A2 levels from delivery to 4 months of age among the two groups was not significantly different. Therefore, ARV treatments for prevention of MTCT of HIV decreased RBC counts and hemoglobin but did not alter the development of Hb A, Hb F and Hb A2 of non-thalassemia carrier infants. PMID- 25026901 TI - [Graft reconstruction of flexor tendons]. AB - The improvement of primary flexor tendon repair has limited the indications of secondary repairs to neglected initial wound care and deficiencies in the surgical technique or rehabilitation. The surgical and rehabilitation care is complex and prolonged, requiring full cooperation of the patient. That is why the surgeon must evaluate patient's ability to integrate instructions and to comply with a long and demanding protocol. The functional needs of the patient are important in treatment decisions and the surgeon should not hesitate to use an appropriate surgical alternative (tenodesis, arthrodesis, tendon transfer, etc.). After a brief historical review, the authors discuss the indications, technical procedures and finally the results of one-stage and two-stage flexor tendon graft, which despite mixed results keep a real place in our current armamentarium. PMID- 25026902 TI - Magnetoresistance anomalies resulting from Stark resonances in semiconductor nanowires with a constriction. AB - Magnetotransport properties of a semiconductor nanowire with a constriction have been studied within the Landauer-Buttiker formalism in the presence of the axially oriented magnetic field at low temperatures. The one-electron quantum states in the nanowire have been calculated within the adiabatic approximation which takes into account the three-dimensional structure of the nanowire and allows us to study the effect of the transverse quantum states on the electronic current. The calculated current-voltage characteristics exhibit well pronounced peaks that result from the enhancement of the electron transmission by the Stark resonant states formed in the triangular quantum well near the constriction. The effect of the Stark resonances is clearly manifested in the magnetoresistance as a function of the drain-source voltage. The calculated magnetoresistance exhibits two interesting features: (i) rapid jumps at certain voltages, caused by the enhancement of the electron transmission by the Stark resonances, (ii) changes of sign that stem from the magnetic-field induced changes of the current-voltage characteristics slope. The influence of the constriction parameters (radius, length, smoothness of the potential barrier, position of the constriction in the nanowire) on the electronic current has also been analyzed. Since the effective potential barrier created by the constriction in the nanowire is similar to that generated by the negatively charged gate surrounding the nanowire, the presented results can also be applied to the description of the magnetoresistance in the gated nanowires. PMID- 25026903 TI - Copy number variations and genetic admixtures in three Xinjiang ethnic minority groups. AB - Xinjiang is geographically located in central Asia, and it has played an important historical role in connecting eastern Eurasian (EEA) and western Eurasian (WEA) people. However, human population genomic studies in this region have been largely underrepresented, especially with respect to studies of copy number variations (CNVs). Here we constructed the first CNV map of the three major ethnic minority groups, the Uyghur, Kazakh and Kirgiz, using Affymetrix Genome-Wide Human SNP Array 6.0. We systematically compared the properties of CNVs we identified in the three groups with the data from representatives of EEA and WEA. The analyses indicated a typical genetic admixture pattern in all three groups with ancestries from both EEA and WEA. We also identified several CNV regions showing significant deviation of allele frequency from the expected genome-wide distribution, which might be associated with population-specific phenotypes. Our study provides the first genome-wide perspective on the CNVs of three major Xinjiang ethnic minority groups and has implications for both evolutionary and medical studies. PMID- 25026904 TI - Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect. AB - Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects. PMID- 25026905 TI - Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia. AB - Variants in PORCN are a cause of Goltz-Gorlin syndrome or Focal Dermal Hypoplasia, an X-linked dominant disorder affecting heterozygous females and until now considered to be embryonic lethal in males. Exome sequencing was performed in a family in which two male siblings were characterized by microphthalmia and additional congenital anomalies including diaphragmatic hernia, spina bifida and cardiac defects. Surprisingly, we identified a maternally inherited variant in PORCN present in both males as well as in two female siblings. This represents the first finding of a PORCN variant in non mosaic males affected with Goltz-Gorlin syndrome. The apparently asymptomatic mother showed extreme skewing of X-inactivation (90%), an asymptomatic female sibling showed skewing of 88%, and the second female sibling affected with cutis aplasia of the scalp showed X-inactivation considered within the normal range. PMID- 25026906 TI - Comment on prediction of neonates' macrosomia with maternal lipid profile of healthy mothers by Mossayebi et al. PMID- 25026907 TI - Vaginal sampling of amniotic fluid in pPROM: a new technique for early detection of subclinical chorioamnionitis? PMID- 25026908 TI - Glycolipid sensing and innate immunity in paracoccidioidomycosis. AB - Distinct glycolipid profiles are described in microorganisms, which have been shown to modulate the innate immune system. We tested the hypothesis that glycosphingolipids from Paracoccidioides brasiliensis have immunomodulatory properties on monocytes and dendritic cells of two groups of healthy individuals, one cured of paracoccidioidomycosis in the past (CUR-I) and the other nonexposed to P. brasiliensis (HNE-I). Two classes of glycosphingolipids purified from yeast cells were evaluated: a neutral glycosphingolipid, monohexosylceramide (CMH), and acidic glycosylinositolphosphorylceramides (GIPCs). Both glycosphingolipids affected the functioning of innate immunity cells, interfering with the antigen presenting process: P. brasiliensis yeast cells phagocytosis, IL-10 secretion, and costimulatory molecules and recognition receptors expression by monocytes were altered, while dendritic cell antigen presentation to autologous T cells was markedly down-modulated as shown by reduced T-cell proliferative responses. The mechanisms by which CMH and GIPCs exert their effects differ since the target cells did not always respond similarly to the challenge with the glycosphingolipids. Moreover, CUR-I and HNE-I presented different responses to the glycosphingolipids. Differences not only in the glycosphingolipid structure (such as the polar head group or the ceramide moiety), but also in the innate immunity properties of CUR-I and HNE-I, may underlie these differences and contribute to individual's susceptibility or resistance to develop paracoccidioidomycosis. PMID- 25026909 TI - Melatonin facilitates extinction, but not acquisition or expression, of conditional cued fear in rats. AB - BACKGROUND: Previous studies have shown that melatonin is involved in the processes that contribute to learning and memory. At present study, we tested the effects of exogenous melatonin (2.5 mg/kg) on the acquisition, expression and extinction of cued fear in rats. RESULTS: Results showed that a single afternoon administration 30 min before conditioning has no effect on the acquisition of cued fear. Compared to rats injected with vehicle, rats injected with melatonin 30 min before extinction training presented a significant lower freezing during both extinction training and extinction test phases, however, freezing response did not differ for the initial four trials during extinction training. Melatonin injected immediately after extinction training was ineffective on extinction learning. CONCLUSIONS: These results suggest that melatonin, at the dose applied in this study, facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. These findings extend previous research on the melatonin effects on learning and memory and suggest that melatonin may serve as an agent for the treatment of anxiety disorders such as posttraumatic stress disorder (PTSD). PMID- 25026910 TI - Comparative study of CMR characteristics between arrhythmogenic right ventricular cardiomyopathy patients with/without syncope. AB - To compare cardiovascular magnetic resonance (CMR) characteristics between arrhythmogenic right ventricular cardiomyopathy (ARVC) patients with syncope and without syncope and explore CMR parameters related with syncope. A consecutive series of 80 patients with ARVC were divided in two groups according to history of syncope prior to CMR examinations. The biventricular function and volumes were calculated and indexed by body surface area. Fatty infiltration and late gadolinium enhancement (LGE) were self-quantitatively analyzed according to segmental model. Patients with syncope had statistically significant greater left ventricular end-diastolic volume index (LVEDVI) (79.6 +/- 23.0 vs. 69.0 +/- 17.9 mL/m(2), P = 0.030), right ventricular end-diastolic volume index (RVEDVI) (122.0 +/- 30.0 vs. 107.4 +/- 21.8 mL/m(2), P = 0.017), and LGE incidence (52.2 vs. 21.1 %, P = 0.006) than that of patients without syncope. Patients with syncope had a trend towards greater number of segments with LGE (8.6 +/- 4.2 vs. 6.6 +/- 3.1, P = 0.199) than that of patients without syncope in subgroup analyses of patients with LGE, but no statistical significance was reached. Multivariate regression analysis showed the presence of LGE was independently associated with syncope in patients with ARVC (odds ratios 8.827, 95 % confidence interval 1.945-40.068, P = 0.005). CMR is helpful in detection and management of the patients with ARVC. Patients with syncope had significantly higher LVEDVI, RVEDVI and LGE incidence, and larger studies with follow-up data are needed to elucidate the relationship between LGE and syncope in patients with ARVC. PMID- 25026911 TI - Screening coronary CT angiography: possibilities and pitfalls. PMID- 25026912 TI - Solvent effects on the photochemistry of 4-aminoimidazole-5-carbonitrile, a prebiotically plausible precursor of purines. AB - 4-Aminoimidazole-5-carbonitrile (AICN) was suggested as a prebiotically plausible precursor of purine nucleobases and nucleotides. Although it can be formed in a sequence of photoreactions, AICN is immune to further irradiation with UV-light. We present state-of-the-art multi-reference quantum-chemical calculations of potential energy surface cuts and conical intersection optimizations to explain the molecular mechanisms underlying the photostability of this compound. We have identified the N-H bond stretching and ring-puckering mechanisms that should be responsible for the photochemistry of AICN in the gas phase. We have further considered the photochemistry of AICN-water clusters, while including up to six explicit water molecules. The calculations reveal charge transfer to solvent followed by formation of an H3O(+) cation, both of which occur on the (1)pisigma* hypersurface. Interestingly, a second proton transfer to an adjacent water molecule leads to a (1)pisigma*/S0 conical intersection. We suggest that this electron-driven proton relay might be characteristic of low-lying (1)pisigma* states in chromophore-water clusters. Owing to its nature, this mechanism might also be responsible for the photostability of analogous organic molecules in bulk water. PMID- 25026913 TI - Systematic review and meta-analysis of the bone protective effect of phytoestrogens on osteoporosis in ovariectomized rats. AB - Phytoestrogens are candidate drugs for the treatment of osteoporosis. Many experiments have been designed to investigate the preventive effects of phytoestrogens for osteoporosis; however, it is easy for a single dissenting result from animal experiments to mislead clinical investigations. Herein, we use meta-analysis to assess the evidence for a protective effect of phytoestrogens on ovariectomized rat models of osteopenia. With respect to osteoporosis, PubMed and Web of Science were searched from January 2000 to March 2013 for relevant studies of phytoestrogens in ovariectomized rats. Two reviewers independently selected and assessed the studies. Data were aggregated using a random effects model. Meta analysis revealed that the phytoestrogen treatment group demonstrated a significantly higher femur bone mineral density and trabecular bone and lower bone turnover markers (serum alkaline phosphatase and serum osteocalcin) compared with the control ovariectomized group, thus showing a bone protective effect of phytoestrogens in ovariectomized rats. Subsequent sensitivity analyses indicated that the effect of phytoestrogens on serum alkaline phosphatase and serum osteocalcin are not robust. Despite the high heterogeneity in the systematic review of animal experiments, the present results indicated that phytoestrogens may offer the most potential for the prevention of bone loss by reducing the expected loss of trabecular bone and bone mineral density. Their effects are likely due to inhibition of bone resorption, but their benefits on bone formation are still unclear. Further studies are needed to assess the effect of phytoestrogens on bone formation and the efficacy and safety of individual phytoestrogens. PMID- 25026914 TI - Serum soluble receptor for advanced glycation end products correlates inversely with measures of adiposity in young adults. AB - Advanced glycation end products (AGEs) may promote inflammation by interacting with the receptor for advanced glycation end products. Serum soluble receptor for advanced glycation end products (sRAGE), a form of receptor for advanced glycation end products thought to mediate AGE's inflammatory properties, is decreased in diabetes mellitus and coronary artery disease. Evidence in older adults suggests that sRAGE is depressed in individuals without current disease who are obese; however, 2 studies have failed to find this correlation. We hypothesized that sRAGE would be inversely correlated with adiposity and positively correlated with inflammation, even in apparently healthy, young adults. By considering adults of body mass index (BMI) varying from normal weight to overweight and obese, we aimed to define how closely AGEs and sRAGE correlate with adiposity and other indicators of metabolic stress. Anthropometric measurements and fasting blood samples were obtained from participants (n = 69). Sera were analyzed for sRAGE, n-epsilon carboxy-methyl-lysine, a measure of AGEs, and high sensitivity C-reactive protein. High molecular weight adiponectin, glucose, insulin, total cholesterol, high-density lipoprotein, and triacylglycerol were also assessed (n = 32). Spearman rank correlations were used to evaluate the relationship among indicators of adiposity and biochemical indicators of metabolic health and inflammation. Factors inversely correlated with sRAGE include weight (Rs = -0.397; P = .001), waist circumference (-0.291; P = .015), and BMI (-0.3338; P = .004). High molecular weight adiponectin was positively correlated with sRAGE, and predictors of sRAGE included BMI and total cholesterol. This is the first time these associations have been found in a diverse population of young adults. PMID- 25026915 TI - Insulin resistance is not associated with thermogenic effect of a high-fat meal in obese children. AB - In adults, insulin resistance may decrease the thermogenic effect of food, contributing to weight gain. We aimed to determine the effect of insulin resistance on energy expenditure in children with long-standing obesity. We hypothesized that thermogenic effect of food would decrease with increasing insulin resistance. Energy expenditure was measured using whole room indirect calorimetry in obese children 7 to 18 years old. Participants were fed a high-fat meal with energy content equal to 35% of measured resting energy expenditure. Thermogenic effect of food was measured for 180 minutes posttest meal and expressed as a percent of calories consumed. Body composition was assessed using whole-body dual-energy x-ray absorptiometry. Fasting glucose, insulin, and hemoglobin A1C were measured. Complete data were available for 25 children (median age, 12.1 years; 52% male). As expected, a significant decrease in resting energy expenditure was observed with increasing Tanner stage (P = .02 by Kruskal-Wallis test). Insulin sensitivity, as determined by homeostasis model assessment index equation, did not significantly affect resting energy expenditure (P = .3) or thermogenic effect of food (P = .7) after adjustment for Tanner stage. In conclusion, our study did not find an association between insulin resistance and energy expenditure in obese children. PMID- 25026917 TI - Vitamin D intakes of children differ by race/ethnicity, sex, age, and income in the United States, 2007 to 2010. AB - The 2007-2010 National Health and Nutrition Examination Survey was used to estimate vitamin D intakes of children 1 to 18 years old in the United States by race/ethnicity, sex, age, and family using 24-hour dietary intake recalls and dietary supplement use questionnaires. We hypothesized that total, dietary, and supplemental vitamin D intakes of children would differ by race/ethnicity, sex, age, and income. Statistical analyses of weighted data were performed using Statistical Analysis Software (V 9.2) to estimate means +/- SE. Race and ethnic intake differences controlling for poverty income ratio (PIR), sex, and age were assessed by analysis of covariance. Total (dietary and supplement) vitamin D intake was greater in the high (7.9 +/- 0.3 MUg/d) vs the medium (6.5 +/- 0.3 MUg/d) income group, but not the low (7.2 +/- 0.2 MUg/d) PIR group. Total vitamin D intake of non-Hispanic (NH) white children (8.1 +/- 0.2 MUg/d) was greater than Hispanic (7.0 +/- 0.2 MUg/d) and NH black (5.9 +/- 0.2 MUg/d) children. Total vitamin D intake declined with age, and intake by boys was higher than girls. Only 17.4% of the children consumed supplements containing vitamin D. Overall, mean intake of vitamin D by all children in each age and ethnic group was lower than the estimated average requirement for vitamin D. Public health efforts should encourage consumption of foods high in vitamin D, expand the number of foods fortified, and target health messages to parents to increase use of vitamin D supplements by children. PMID- 25026918 TI - Breast-, complementary and bottle-feeding practices in Kenya: stagnant trends were experienced from 1998 to 2009. AB - The pattern of infant and young child feeding that provides the most benefit includes being put to the breast within an hour of birth, exclusive breastfeeding for 6 months, continued breastfeeding along with complementary foods up to 2 years of age or beyond, and avoidance of any bottle-feeding. However, since there are no published data from Kenya regarding trends in these feeding practices, this research undertook time trend estimation of these feeding practices using the 1998, 2003, and 2008-2009 Kenya Demographic and Health Survey and also examined the multivariate relationships between sociodemographic factors and feeding practices with data from 2008 to 2009. Logistic regression was used to test the significance of trends and to analyze sociodemographic characteristics associated with feeding practices. There was a significant decline in early initiation of breastfeeding among children in Central and Western provinces and those residing in urban areas. Trends in exclusive breastfeeding showed significant improvement in most sociodemographic segments, whereas trends in complementary feeding and breastfeeding remained stable. Bottle-feeding significantly decreased among children aged 12 to 23 months, as well as those living in Coast, Eastern, and Rift Valley provinces. In the multivariate analysis, the province was significantly associated with feeding practices, after controlling for child's size, birth order, and parity. The stagnant (and in some cases worsening) trends in early initiation of breastfeeding and complementary feeding with breastfeeding paint a worrisome picture of breastfeeding practices in Kenya; therefore, efforts to promote the most beneficial feeding practices should be intensified. PMID- 25026916 TI - A high-fiber, low-fat diet improves periodontal disease markers in high-risk subjects: a pilot study. AB - Periodontal disease is related to aging, smoking habits, diabetes mellitus, and systemic inflammation. However, there remains limited evidence about causality from intervention studies. An effective diet for prevention of periodontal disease has not been well established. The current study was an intervention study examining the effects of a high-fiber, low-fat diet on periodontal disease markers in high-risk subjects. Forty-seven volunteers were interviewed for recruitment into the study. Twenty-one volunteers with a body mass index of at least 25.0 kg/m(2) or with impaired glucose tolerance were enrolled in the study. After a 2- to 3-week run-in period, subjects were provided with a test meal consisting of high fiber and low fat (30 kcal/kg of ideal body weight) 3 times a day for 8 weeks and followed by a regular diet for 24 weeks. Four hundred twenty five teeth from 17 subjects were analyzed. Periodontal disease markers assessed as probing depth (2.28 vs 2.21 vs 2.13 mm; P < .0001), clinical attachment loss (6.11 vs 6.06 vs 5.98 mm; P < .0001), and bleeding on probing (16.2 vs 13.2 vs 14.6 %; P = .005) showed significant reductions after the test-meal period, and these improvements persisted until the follow-up period. Body weight (P < .0001), HbA1c (P < .0001), and high-sensitivity C-reactive protein (P = .038) levels showed improvement after the test-meal period; they returned to baseline levels after the follow-up period. In conclusion, treatment with a high-fiber, low-fat diet for 8 weeks effectively improved periodontal disease markers as well as metabolic profiles, at least in part, by effects other than the reduction of total energy intake. PMID- 25026919 TI - Black chokeberry juice (Aronia melanocarpa) reduces incidences of urinary tract infection among nursing home residents in the long term--a pilot study. AB - Urinary tract infection (UTI) is a major problem in nursing homes, and the mainstay of treatment is antibiotics. The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in specific nutrients, for example, cranberries, to prevent recurring UTI. Black chokeberry (Aronia melanocarpa [Michx] Elliott) is a rich source of phenolics, and thus, dietary intake of black chokeberry juice may reduce the incidences of UTI requiring medical treatment. In this pilot study, we examined the frequency of medically treated UTI among residents in 6 nursing homes who were offered black chokeberry juice or a placebo during a 6-month crossover intervention. The residents were offered a placebo drink for a 3-month period followed by chokeberry juice for the next 3 months (group A) or vice versa (group B). The juice was characterized by a high content of total phenolics (715 mg gallic acid equivalent, 100 mL(-1)), including B-type procyanidins, anthocyanins, and chlorogenic acids. Daily intake of chokeberry juice was 156 mL per resident in group A (n = 110) and 89 mL per resident in group B (n = 126). Urinary tract infection comprised 55% of all medically treated infections during the study period. The results revealed no immediate reduction in the frequency of UTI or the total use of antibiotics; however, during the subsequent 3-month period of juice administration, a reduction in antibiotics toward UTI was observed in both groups. The incidence of UTI was reduced by 55% in group A and 38% in group B. No changes in other infections or in use of prophylactics were observed. PMID- 25026920 TI - Dietary n-3 polyunsaturated fatty acids or soy protein isolate did not attenuate disease progression in a female rat model of autosomal recessive polycystic kidney disease. AB - Polycystic kidney disease (PKD) is an incurable genetic disorder that is characterized by multiple benign cysts. As PKD advances, cyst growth increases kidney volume, decreases renal function, and may lead to end-stage renal disease; however, in a PKD rat model, feeding soy protein isolate (SPI) reduced cyst proliferation and growth. The n-3 polyunsaturated fatty acids (PUFAs) are noted for their anti-inflammatory actions. Therefore, diet therapy could offer a potentially efficacious, safe, and cost-effective strategy for treating PKD. The objective of this study was to investigate the role of soy protein and/or n-3 PUFAs on PKD progression and severity in the rat model of autosomal recessive PKD. We hypothesized that the antiproliferative and anti-inflammatory actions associated with soy protein and n-3 PUFA supplementation will attenuate PKD progression in female PCK rats. For 12 weeks, young (age, 28 days) female PCK rats were randomly assigned (n=12/group) to 4 different diets: casein+/-corn oil, casein+/-soybean oil, SPI+/-soybean oil, or SPI+/-1:1 soybean/salmon oil (SPI+/ SB). The feeding of the different protein and lipid sources had no significant effect on relative kidney weight. Histologic evaluation showed no significant differences in cortical or medullary cyst size, interstitial inflammation, and fibrosis among diet groups. However, rats fed SPI+/-SB diet had cortical cyst obstruction and the highest (P<.01) serum blood urea nitrogen concentration. Rats fed SPI+/-SB diet had the highest (P<.001) renal docosahexaeonic acid, but there were no significant differences in renal tissue inflammation and proliferation gene expression among the diet groups. Based on these results, dietary soy protein and/or n-3 PUFAs did not attenuate disease progression or severity in the female PCK rat model of autosomal recessive PKD. PMID- 25026921 TI - Apple flavonols and n-3 polyunsaturated fatty acid-rich fish oil lowers blood C reactive protein in rats with hypercholesterolemia and acute inflammation. AB - Both quercetin glycosides and omega-3 polyunsaturated fatty acids (n-3 PUFA) are well established for their individual health benefits in ameliorating metabolic disease. However, their combined effects are not well documented. It was hypothesized that the beneficial properties of quercetin glycosides can be enhanced when provided in combination with n-3 PUFA. Therefore, the aim of the present study was to investigate the effects of apple flavonols (AF) and fish oil (FO), alone and in combination, on proinflammatory biomarkers and lipid profiles in rats fed a high-fat diet. Sixty male Wistar rats were randomly divided into 5 groups (n = 12) and fed a high-fat diet for 4 weeks. One of the 5 groups of rats was used as the high-fat control. The other 4 groups of rats were injected with lipopolysaccharide (LPS) (5 mg/kg body weight) intraperitoneally, 5 hours before euthanization. One of these 4 groups was used as the hypercholerolemic and inflammatory control (high-fat with lipopolysaccharide [HFL]), and the other 3 received AF (HFL + 25 mg/kg per day AF), FO (HFL + 1 g/kg per day FO), or the combination (HFL + AF + FO). Compared to the HFL group, the AF, FO, and AF + FO groups showed lower serum concentrations of interleukin-6 and C-reactive protein (CRP) levels. The AF, FO, and AF + FO also had lowered serum triacylglycerol and non-high-density lipoprotein cholesterol (HDL-C) concentrations, but higher HDL-C levels relative to the HFL group. An additive effect was observed on serum CRP in the AF + FO group as compared with the AF or FO groups. The results demonstrated that AF and FO inhibited the production of proinflammatory mediators and showed an improved efficacy to lower serum CRP when administered in combination, and they significantly improved blood lipid profiles in rats with diet-induced hyperlipidemia and LPS-induced acute inflammation. PMID- 25026922 TI - Type 2 diabetic conditions in Otsuka Long-Evans Tokushima Fatty rats are ameliorated by 5-aminolevulinic acid. AB - A precursor of protoporphyrin IX, 5-aminolevulinic acid (5-ALA) is used as a prodrug for photodiagnosis and photodynamic therapy. Recently, it has been shown that 5-ALA reduces glucose levels during fasting and after glucose loading in prediabetic subjects. We hypothesized that 5-ALA ameliorates diabetic conditions through mitochondrial changes in visceral adipose tissue. In order to explore the metabolic effects on the type 2 diabetic state, we administered ALA hydrochloride in combination with sodium ferrous citrate to Otsuka Long-Evans Tokushima Fatty (OLETF) rats at intragastric doses of 20 and 300 mg kg(-1) d(-1) for 6 weeks. The administration of 300 mg kg(-1) d(-1) of 5-ALA improved glucose intolerance, hypertriglyceridemia, and hyperleptinemia in OLETF rats more effectively than the administration of an equivalent dose of metformin, in accordance with reductions in food intake and body weight. Furthermore, the weight of the retroperitoneal fat tended to decrease and cellular mitochondrial content of the fat was markedly reduced by the 5-ALA administration, showing a positive correlation. These results suggest that 5-ALA ameliorates diabetic abnormalities in OLETF rats by reducing the visceral fat mass and mitochondrial content of adipocytes in a site specific manner. PMID- 25026923 TI - Low glycemic index vegan or low-calorie weight loss diets for women with polycystic ovary syndrome: a randomized controlled feasibility study. AB - The aim of this randomized pilot was to assess the feasibility of a dietary intervention among women with polycystic ovary syndrome (PCOS) comparing a vegan to a low-calorie (low-cal) diet. Overweight (body mass index, 39.9 +/- 6.1 kg/m(2)) women with PCOS (n = 18; age, 27.8 +/- 4.5 years; 39% black) who were experiencing infertility were recruited to participate in a 6-month randomized weight loss study delivered through nutrition counseling, e-mail, and Facebook. Body weight and dietary intake were assessed at 0, 3, and 6 months. We hypothesized that weight loss would be greater in the vegan group. Attrition was high at 3 (39%) and 6 months (67%). All analyses were conducted as intention-to treat and presented as median (interquartile range). Vegan participants lost significantly more weight at 3 months (-1.8% [-5.0%, -0.9%] vegan, 0.0 [-1.2%, 0.3%] low-cal; P = .04), but there was no difference between groups at 6 months (P = .39). Use of Facebook groups was significantly related to percent weight loss at 3 (P < .001) and 6 months (P = .05). Vegan participants had a greater decrease in energy (-265 [-439, 0] kcal/d) and fat intake (-7.4% [-9.2%, 0] energy) at 6 months compared with low-cal participants (0 [0, 112] kcal/d, P = .02; 0 [0, 3.0%] energy, P = .02). These preliminary results suggest that engagement with social media and adoption of a vegan diet may be effective for promoting short-term weight loss among women with PCOS; however, a larger trial that addresses potential high attrition rates is needed to confirm these results. PMID- 25026924 TI - Serum fructosamine and risk of type 2 diabetes mellitus among middle-age Finnish men: a 23-year population-based prospective study. AB - The aim of this study was to determine whether serum fructosamine is associated with the risk of type 2 diabetes mellitus (T2DM) in a cohort of middle-age Finnish men. Fructosamine and other cardiometabolic risk factors were measured in a sample of 2,520 subjects from the population-based Kuopio Ischemic Heart Disease study. Associations between baseline fructosamine levels and risk of T2DM involved Cox-regression analyses, progressively adjusted for potential confounders and mediators. Mean baseline age and fructosamine levels were 53 years and 267 umol/L, respectively. During a median follow-up of 23 years (interquartile range 18-25 years), 153 (6.1 %) new cases of T2DM were recorded. We observed an approximately "J-shaped" association between fructosamine values and T2DM risk, with a nadir at about 250 umol/L. In subjects with fructosamine >=250 umol/L, the hazard ratios per 1 standard deviation (28 umol/L) higher fructosamine levels resulted 1.20 (95 % CI 1.00-1.44; p = 0.046) in a model adjusted for age, body mass index, systolic blood pressure, serum high-density lipoprotein-cholesterol and family history T2DM. This association did not materially change upon further adjustment for C-reactive protein, physical activity, serum triglyceride and insulin resistance. However, no association was found when adjusting for baseline fasting plasma glucose (FPG). In this cohort of middle-age Finnish men, we found a "J-shaped" relationship between fructosamine and risk of T2DM, with a higher risk in subjects with baseline levels of fructosamine >=250 umol/L. Such an increased risk, however, was not independent from baseline FPG levels. PMID- 25026926 TI - Stone scattering during percutaneous nephrolithotomy: role of renal anatomical characteristics. AB - The purpose of this study was to evaluate how the upper calyx-lower calyx infundibular (ULI) angle influences intrarenal stone migration during percutaneous nephrolithotomy (PCNL) in patients with a solitary renal pelvis stone and significant hydronephrosis. 50 adult patients with a solitary renal pelvis stone larger than 20 mm were considered for PCNL with a pneumatic lithotriptor for stone fragmentation. Inclusion criteria were moderate to severe hydronephrosis and upper calyx infundibular width >10 mm, and access point was the lower calyx in all cases. The ULI angle as well as stone fragment migration from the renal pelvis toward the upper calyx was noted during the operation. To determine the "critical" angle above which the probability of stone migration would be increased significantly, receiver operating characteristic curve was used. Mean stone size was 33.8 +/- 13.2 mm. In 23 patients (46 %) the stone migrated toward the upper calyx during stone fragmentation. Mean ULI angle was significantly wider in patients whose stone migrated (120.2 +/- 20.5 versus 102.2 +/- 21.4, P = 0.004, 99 % CI = 6.04-29.9). A ULI angle of 117.5 degrees was the critical angle, above which the rate of stone migration rose significantly (P < 0.008). One-session stone-free rate was significantly higher in patients without stone migration (P = 0.03). In patients with a solitary renal pelvis stone and significant hydronephrosis, a wider ULI angle was associated with a greater likelihood of stone scattering which could potentially affect the outcome of PCNL with pneumatic lithotriptor. A cut-off angle of 117.5 degrees was the critical angle, above which access via a calyx other than the lower calyx (example: middle or upper calyx) seems advisable. PMID- 25026927 TI - Anatomic relations between the lateral collateral ligament and the radial head: implications for arthroscopic resection of the synovial fold of the elbow. AB - PURPOSE: The purpose of this study was to determine the anatomic relationship between the radial head and the lateral collateral ligament (LCL) and when the LCL would be at risk of iatrogenic injury during arthroscopic resection of the synovial fold. METHODS: Thirty-four formalin-fixed upper extremities were dissected. A projection of the LCL onto the radial head was marked with a needle. The percentage of the posterior border of the radial head overlaid by the LCL was digitally measured. A portion of the projection of the LCL was statistically correlated with the overall diameter of the radial head. RESULTS: The overall diameter of the radial head was 21.2 mm +/- 2.3. The proportionate projection of the medial border of the LCL onto the radial head was 5.3 +/- 1.6 mm on average. The lateral 25 % of the radial head was overlaid by the LCL with a maximum value of 40 % on average. The inter- and intraobserver reliability showed very good accordance with the digital measurements (r > 0.8). CONCLUSION: Care must be taken when performing a resection in the lateral 40 % of the radial head, whereas resection in the medial 60 % of the radial head appears to be safe. The LCL is an important stabiliser of the elbow joint, a lesion of which by undeliberate arthroscopic dissection may lead to joint instability. Iatrogenic injury to the LCL presumably can be prevented when respecting the given data. LEVEL OF EVIDENCE: Experimental study. PMID- 25026928 TI - Validation of the ArthroS virtual reality simulator for arthroscopic skills. AB - PURPOSE: Virtual reality simulator training has become important for acquiring arthroscopic skills. A new simulator for knee arthroscopy ArthroSTM has been developed. The purpose of this study was to demonstrate face and construct validity, executed according to a protocol used previously to validate arthroscopic simulators. METHODS: Twenty-seven participants were divided into three groups having different levels of arthroscopic experience. Participants answered questions regarding general information and the outer appearance of the simulator for face validity. Construct validity was assessed with one standardized navigation task. Face validity, educational value and user friendliness were further determined by giving participants three exercises and by asking them to fill out the questionnaire. RESULTS: Construct validity was demonstrated between experts and beginners. Median task times were not significantly different for all repetitions between novices and intermediates, and between intermediates and experts. Median face validity was 8.3 for the outer appearance, 6.5 for the intra-articular joint and 4.7 for surgical instruments. Educational value and user friendliness were perceived as nonsatisfactory, especially because of the lack of tactile feedback. CONCLUSION: The ArthroSTM demonstrated construct validity between novices and experts, but did not demonstrate full face validity. Future improvements should be mainly focused on the development of tactile feedback. It is necessary that a newly presented simulator is validated to prove it actually contributes to proficiency of skills. PMID- 25026929 TI - External rotation of the femoral component decreases patellofemoral contact stress in total knee arthroplasty. AB - PURPOSE: The purpose of this study was to investigate the relationship between patellofemoral (PF) contact stress in vivo and the alignment of the femoral component in patients after total knee arthroplasty (TKA). METHODS: Thirty knees with medial compartment osteoarthritis that underwent mobile-bearing TKA with modified gap technique were evaluated. Surgery was performed using a subvastus approach to eliminate the effect of the approach to muscle balance, with a computed tomography-based navigation system (Vector Vision 1.61; Brain Lab, Heimstetten, Germany). PF contact stress was measured by a Flexiforce pressure sensor (Nitta Co., Ltd., Osaka, Japan) intraoperatively, and the results were compared with the alignment of the femoral component after TKA. RESULTS: The PF contact stress was not correlated with sagittal and coronal alignment of the femoral component and patellar tracking, whereas rotational alignment of the femoral component was negatively correlated with PF contact stress (r = -0.718, p < 0.01). CONCLUSIONS: Regarding the alignment of the femoral component, only the rotational alignment of the femoral component was correlated with PF contact stress. PF contact stress decreased more as the femoral component rotated more externally. LEVEL OF EVIDENCE: Case control study, Level III. PMID- 25026930 TI - Roentgen stereophotogrammetric analysis: an effective tool to predict implant survival after an all-poly unicompartmental knee arthroplasty-a 10 year follow-up study. AB - PURPOSE: The main purpose of the present study was to determine long-term implant fixation of 15 unicompartmental knee arthroplasty (UKAs) with an all-poly tibial component using Roentgen stereophotogrammetric analysis (RSA) at a mean 10-year follow-up. The secondary purpose was to investigate whether the progressive loss of implant's fixation correlates with a reduction in Knee society score (KSS). METHODS: Fifteen non-consecutive patients with primary knee osteoarthritis received a UKA with an all-poly tibial component were assessed using KSS scores pre-operatively and post-operatively and RSA on day 2 after surgery, then at 3, 6, and 12 months and yearly thereafter. The mean last follow-up was 10 years. RESULTS: An increase in maximum total point motion (MTPM) values from 6 months to 1 year post-operatively was found respect to post-operative reference. Implants' displacement values were always <2 mm during the first 6 months, and then, two different trends were noticed in revised and non-revised implants. MTPM increase between 1 and 2 years of follow-up in non-revised UKAs was always <0.2 mm, whereas it was >0.2 mm in revised UKAs. A linear and negative correlation with statistical significance was found between MTPM and both clinical and functional KSS scores (p < 0.001). CONCLUSION: Also in a long-term follow-up evaluation, RSA is an effective tool to predict functional results after an all-poly UKA providing also a relevant predictive value at 1 year follow-up, and this can be very useful for both patients and surgeons. LEVEL OF EVIDENCE: Diagnostic studies, Level III. PMID- 25026932 TI - Increased shape and size offerings of femoral components improve fit during total knee arthroplasty. AB - PURPOSE: Contemporary total knee arthroplasty femoral component designs offer various degrees of fit amongst the global population. The purpose of this study was to assess component fit of contemporary femoral component design families against multiple ethnicities. METHODS: Using a multi-ethnic dataset including Caucasian, Indian, and Korean subjects, this study investigated component fit in six contemporary femoral component design families (A: PersonaTM, B: NexGen ((r)), C: Sigma ((r)), D: GENESISTM II, E: Triathlon ((r)), F: Vanguard ((r))). Component overhang/underhang was measured between the resected distal femur and its corresponding component size and compared across design families and ethnicities. The severity of overhang/underhang and propensity of downsizing due to clinically significant overhang were quantified for the overall dataset and each ethnicity. RESULTS: In all the overhang cases, Designs A and B had significantly lower component overhang than the other designs (p < 0.02). In all the underhang cases, Designs C and E had significantly greater underhang than the other designs (p < 0.01). Component design influenced the occurrence (% bones) of component downsizing due to clinically significant overhang (>3 mm), with the highest incidence observed in Designs D (20.5%) and F (17.7%), and the lowest incidence observed in Designs A (0%) and B (0.4%). Variation in component fit was significantly impacted by designs (p < 0.01) but not ethnicities (n.s.). CONCLUSIONS: The inclusion of multiple ML/AP shape offerings and the increased number of available sizes in Design A, as compared to other contemporary femoral component design families studied, result in improved femoral component fit across various ethnicities. PMID- 25026931 TI - No difference in mechanical alignment and femoral component placement between patient-specific instrumentation and conventional instrumentation in TKA. AB - PURPOSE: There is a rising interest in the use of patient-specific instrumentation (PSI) during total knee arthroplasty (TKA). The goal of this meta analysis was to compare PSI with conventional instrumentation (CI) in patients undergoing TKA. METHODS: A literature search was performed in PubMed, Embase, Springer, Ovid, China National Knowledge Infrastructure, and the Cochrane Library. A total of 10 randomized controlled studies involving 837 knees comparing outcomes of PSI TKAs with CI TKAs were included in the present analysis. Outcomes of interest included component alignment, surgical time, blood loss, and hospital stay. RESULTS: The results presented no significant differences between the two instrumentations in terms of restoring a neutral mechanical axis and femoral component placement. However, their differences have been noted regarding the alignment of the tibial component in coronal and sagittal planes. Also, 3 min less surgical time was used in PSI patients. CONCLUSIONS: Based on these findings, PSI appeared not to be superior to CI in terms of the post-operative mechanical axis of the limb or femoral component placement. Despite a statistical difference for operative duration, the benefit of a small reduction in surgical time with PSI is clinically irrelevant. LEVEL OF EVIDENCE: Therapeutic study (systematic review and meta-analysis), Level I. PMID- 25026933 TI - Speed, not magnitude, of knee extensor torque production is associated with self reported knee function early after anterior cruciate ligament reconstruction. AB - PURPOSE: To examine the magnitude and speed of knee extensor torque production at the initiation of advanced anterior cruciate ligament (ACL) reconstruction rehabilitation and the associations with self-reported knee function. METHODS: Twenty-eight subjects who were 12 weeks post-ACL reconstruction and 28 age- and sex-matched physically active controls participated in this study. Knee extensor torque was assessed bilaterally with an isokinetic dynamometer at 60 degrees /s. The variables of interest were peak torque, average rate of torque development, time to peak torque and quadriceps symmetry index. Knee function was assessed with the International Knee Documentation Committee Subjective Knee Form (IKDC SKF). RESULTS: Peak torque and average rate of torque development were lower on the surgical side compared to the non-surgical side and controls. Quadriceps symmetry index was lower in subjects with ACL reconstruction compared to controls. On the surgical side, average rate of torque development was positively correlated with IKDC-SKF score (r = 0.379) while time to peak torque was negatively correlated with IKDC-SKF score (r = -0.407). CONCLUSIONS: At the initiation of advanced ACL reconstruction rehabilitation, the surgical side displayed deficits in peak torque and average rate of torque development. A higher rate of torque development and shorter time to peak torque were associated with better self-reported knee function. The results suggest that the rate of torque development should be addressed during advanced ACL reconstruction rehabilitation and faster knee extensor torque generation may lead to better knee function. LEVEL OF EVIDENCE: III. PMID- 25026934 TI - Gait changes of the ACL-deficient knee 3D kinematic assessment. AB - PURPOSE: Static, one-dimensional testing cannot predict the behaviour of the anterior cruciate ligament (ACL)-deficient knee under realistic loading conditions. Currently, the most widely accepted method for assessing joint movement patterns is gait analysis. The purpose of the study was in vivo evaluation of the behaviour of the anterior cruciate ligament-deficient (ACLD) knees during walking, using 3D, real-time assessment tool. METHODS: Biomechanical data were collected prospectively on 30 patients with ACL rupture and 15 healthy subjects as a control group, with KneeKgTM System. Kinematic data were recorded in vivo during treadmill walking at self-selected speed. Flexion/extension, abduction/adduction, anterior/posterior tibial translation and external/internal tibial rotation were compared between groups. RESULTS: The ACLD patients showed a significant lower extension of the knee joint during stance phase (p < 0.05; 13.2 degrees +/- 2.1 degrees and 7.3 degrees +/- 2.7 degrees , for ACLD and control group, respectively). A significant difference in tibial rotation angle was found in ACLD knees compared to control knees (p < 0.05). The patients with ACLD rotated the tibia more internally (-1.4 degrees +/- 0.2 degrees ) during the mid stance phase, than control group (0.2 degrees +/- 0.3 degrees ). There was no significant difference in anteroposterior translation and adduction-abduction angles. CONCLUSION: Significant alterations of joint kinematics in the ACLD knee were revealed in this study by manifesting a higher flexion gait strategy and excessive internal tibial rotation during walking that could result in a more rapid cartilage thinning throughout the knee. The preoperative data obtained in this study will be useful to understand the post-ACL reconstruction kinematic behaviour of the knee. CLINICAL RELEVANCE: The findings in this study indicate that ACLD knee may adapt functionally to prevent excessive anterior-posterior translation but they fail to avoid rotational instability. PMID- 25026935 TI - Biomechanical comparison of three methods for distal Achilles tendon reconstruction. AB - PURPOSE: To compare the load at failure and stiffness associated with three surgical techniques for distal Achilles tendon reconstruction (AT). METHODS: Nine matched pairs of fresh-frozen human cadaveric ATs were divided into three groups. Distal AT reconstruction was performed using suture anchors or one of two lengths of tendon overlap (10 or 5 mm). Each tendon was loaded to failure. The load at failure (N), stiffness (N/mm), and mode of failure were recorded. Differences in load at failure and stiffness were analysed. RESULTS: Mean load at failure was significantly higher in the 10-mm group than in the 5-mm group (p < 0.05) or the suture-anchor group (p < 0.05). Load at failure did not differ significantly between the suture-anchor and 5-mm group, and stiffness did not differ significantly between any two groups. In the 10- and 5-mm groups, failure was caused by the grafts pulling out through the substance of the AT. Modes of failure varied in the suture-anchor group. CONCLUSIONS: The load at failure was higher in the 10-mm group than in the 5-mm and suture-anchor groups. Although all three surgical techniques provide sufficient primary load-bearing ability, the 10 mm tendon-overlap technique may be more conducive to early post-operative rehabilitation. PMID- 25026936 TI - Amplitude modulated S-tones can be superior to noise for tinnitus reduction. AB - PURPOSE: Recent evidence has suggested that amplitude modulated tones might have some advantages over broadband noise. METHOD: Fifty-six subjects listened to S Tones at a carrier frequency matched at the tinnitus pitch (amplitude modulation rate of 40 Hz) and to broadband noise. Subjects rated their tinnitus loudness before, during, and after a 120-s duration masker. RESULTS: The results suggested that S-Tones were generally more effective at reducing tinnitus loudness than noise. In about one third (21/56) of the subjects, there was no significant effect from any masker. In other subjects, 54.3% (19/35) showed a greater reduction for the S-Tones, 20% (7/35) showed a greater reduction with the noise, and 25.7% (9/35) showed similar performance between the 2 stimuli. The S-Tones showed a statistically significant benefit ( p < .01) versus noise at reducing the patient's tinnitus perception. Using low-level stimuli that were rated much softer than the subjects' baseline tinnitus, the S-Tones reduced the tinnitus loudness by 1.9 times the amount that noise did (about 28% on average, whereas the noise reduced the tinnitus by about 15%). CONCLUSION: S-Tones at the tinnitus pitch-match frequency are more likely to be effective than broadband noise at reducing tinnitus loudness. PMID- 25026937 TI - Functionalized graphene oxide as a nanocatalyst in dephosphorylation reactions: pursuing artificial enzymes. AB - The present study reports for the first time the use of a thiol-functionalized graphene oxide nanocatalyst with impressive activity (>10(5)-fold) in dephosphorylation reactions. The innovative and recyclable nanocatalyst has potential in designing artificial enzymes with targeted multifunctionalities and in detoxification of organophosphorus agents. PMID- 25026938 TI - Folic acid conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel for site specific delivery of hydrophobic drugs to cancer cells. AB - BACKGROUND: The hydrogel based system is found to be rarely reported for the delivery of hydrophobic drug due to the incompatibility of hydrophilicity of the polymer network and the hydrophobicity of drug. This problem can be solved by preparing semi-interpenetrating network of cross-linked polymer for tuning the hydrophilicity so as to entrap the hydrophobic drugs. The current study is to develop a folic acid conjugated cross-linked pH sensitive, biocompatible polymeric hydrogel to achieve a site specific drug delivery. For that, we have synthesized a folic acid conjugated PEG cross-linked acrylic polymer (FA-CLAP) hydrogel and investigated its loading and release of curcumin. The formed polymer hydrogel was then conjugated with folic acid for the site specific delivery of curcumin to cancer cells and then further characterized and conducted the cell uptake and cytotoxicity studies on human cervical cancer cell lines (HeLa). RESULTS: In this study, we synthesized folic acid conjugated cross-linked acrylic hydrogel for the delivery of hydrophobic drugs to the cancer site. Poly (ethyleneglycol) (PEG) diacrylate cross-linked acrylic polymer (PAA) was prepared via inverse emulsion polymerization technique and later conjugated it with folic acid (FA-CLAP). Hydrophobic drug curcumin is entrapped into it and investigated the entrapment efficiency. Characterization of synthesized hydogel was done by using Fourier Transform-Infrared spectroscopy (FT-IR), Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC). Polymerization and folate conjugation was confirmed by FT-IR spectroscopy. The release kinetics of drug from the entrapped form was studied which showed initial burst release followed by sustained release due to swelling and increased cross-linking. In vitro cytotoxicity and cell uptake studies were conducted in human cervical cancer (HeLa) cell lines. CONCLUSIONS: Results showed that curcumin entrapped folate conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel showed higher cellular uptake than the non folate conjugated form. So this can be suggested as a better delivery system for site specific release of hydrophobic cancer drugs. PMID- 25026939 TI - Effect of Smad pathway activation on podocyte cell cycle regulation: an immunohistochemical evaluation. AB - BACKGROUND: Mature podocytes are in cell cycle arrest and their inability to proliferate successfully is a consequence of negative cell-cycle regulators' expression, such as p57. Phosphorylated smad2/smad3 (pSmad2/3) is an intracellular heteromeric mediator of transforming growth factor beta (TGF-beta) signals and, together with co-activators such as P300, regulates gene transcription, including cell cycle regulator proteins. METHODS: In order to investigate Smad pathway activation and podocyte cell cycle regulation in glomerular injury, we studied the glomerular immunohistochemical expression of p57, pSmad2/3 and P300 in samples from 67 patients with various types of glomerulonephritis (GN) and 10 normal kidney tissue specimens. RESULTS: pSmad2/3 and p300 expression were found significantly increased in all glomerular cell types in both proliferative and nonproliferative GN, while a significant reduction in p57-positive podocytes was observed when compared to controls. Staining for p57 was found to inversely correlate to pSmad2/3 suggesting that glomerular Smad pathway activation is related to down-regulation of p57 expression in proliferative glomerulonephritis. To our knowledge, this is the first study that indicates a relation between the TGF-beta/Smad signalling pathway and the cell cycle regulatory protein p57 in human GN. CONCLUSION: The increased pSmad2/3 staining together with the reduced p57 expression found in biopsy specimens with intense interstitial inflammation, indicate a possible relation between interstitial inflammation, glomerular Smad pathway activation and podocyte cell-cycle deregulation. PMID- 25026940 TI - Graphic pathogeographies. AB - This paper focuses on the graphic pathogeographies in David B.'s Epileptic and David Small's Stitches: A Memoir to highlight the significance of geographic concepts in graphic novels of health and disease. Despite its importance in such works, few scholars have examined the role of geography in their narrative and structure. I examine the role of place in Epileptic and Stitches to extend the academic discussion on graphic novels of health and disease and identify how such works bring attention to the role of geography in the individual's engagement with health, disease, and related settings. PMID- 25026941 TI - The lack of antitumor effects of o,p'DDA excludes its role as an active metabolite of mitotane for adrenocortical carcinoma treatment. AB - Mitotane (o,p'DDD) is the most effective treatment of advanced adrenocortical carcinoma (ACC) but its mechanism of action remains unknown. Previous studies suggested that o,p'DDA may represent the active metabolite of mitotane. We aimed at reevaluating the potential role and pharmacological effects of o,p'DDA. Functional consequences of o,p'DDA exposure were studied on proliferation, steroidogenesis, and mitochondrial respiratory chain in human H295R and SW13 adrenocortical cells. Mitotane and its metabolites were quantified using high performance liquid chromatography combined to an ultraviolet detection in these cells treated with o,p'DDD or o,p'DDA and in human adrenal tissues. Dose-response curves up to 300 MUM showed that, as opposed to o,p'DDD, o,p'DDA did not inhibit cell proliferation nor alter respiratory chain complex IV activity, gene expression nor induce mitochondrial biogenesis, oxidative stress, or apoptosis. However, whereas mitotane drastically decreased expression of genes involved in steroidogenesis, o,p'DDA slightly reduced expression of some steroidogenic enzymes and exerts weak anti-secretory effects only at high doses. While o,p'DDD concentration was significantly reduced by 40 % in H295R cell supernatants after 48 h incubation, o,p'DDA levels remained unchanged suggesting that o,p'DDA was not efficiently transported into the cells. o,p'DDA was not detected in cell homogenates or supernatants after 48 h exposure to o,p'DDD, consistent with the absence of o,p'DDA production in these models. Finally, unlike o'p'DDD, we found that o,p'DDA content was undetectable in two ACC and one normal adrenal gland of mitotane-treated patients, suggesting a lack of cellular uptake and in situ production. Our results demonstrate that o,p'DDD, but not o,p'DDA, induces functional alterations in adrenal cells. PMID- 25026942 TI - Racial/Ethnic Disparities in Mental Health Care Utilization among U.S. College Students: Applying the Institution of Medicine Definition of Health Care Disparities. AB - OBJECTIVE: The authors apply the Institute of Medicine's definition of health care disparities to college students. METHODS: The analysis pools data from the first two waves of the Healthy Minds Study, a multicampus survey of students' mental health (N = 13,028). A probit model was used for any past-year service utilization, and group differences in health status were adjusted by transforming the entire distribution for each minority population to approximate the white distribution. RESULTS: Disparities existed between whites and all minority groups. Compared to other approaches, the predicted service disparities were greater because this method included the effects of mediating SES variables. CONCLUSIONS: Health care disparities persist in the college setting despite improved access and nearly universal insurance coverage. Our findings emphasize the importance of investigating potential sources of disparities beyond geography and coverage. PMID- 25026943 TI - Trainee interest in public psychiatry amidst implementation of the Affordable Care Act. PMID- 25026944 TI - Teaching an experiential mind-body method to medical students to increase interpersonal skills: a pilot study. AB - OBJECTIVE: The authors investigate whether inner relationship focusing increases self-awareness in medical students and, in the process, to give them experience with empathic listening. METHODS: Thirteen second-year medical students were randomized into experimental and control groups and surveyed pre-course and post course about their self-awareness and perceived comfort with clinical interpersonal skills. Subjects attended a 20-h course on inner relationship focusing, followed by 5 months of weekly sessions. Pre-course and post-course survey scores were averaged by group, and mean differences were calculated and compared using the two-sample t test. RESULTS: The experimental group showed improvement in all areas compared to the control group. Improvement in one area (comfort talking to patients about how recurring symptoms might relate to issues in their lives) reached statistical significance (P = 0.05). CONCLUSIONS: Inner relationship focusing is a potential tool to increase self-awareness and empathic listening in medical students. PMID- 25026945 TI - Preparing residents in training to become health-care leaders: a pilot project. AB - OBJECTIVE: The aim of this study is to describe a successful and exportable training module that addresses Next Accreditation System (NAS) behavioral milestones for leadership competencies. METHODS: A novel leadership training module, which required the creation of original business plans by teams of residents, was incorporated into a psychiatry PGY-2 training curriculum. RESULTS: In the creation and presentation of their business plans, the residents demonstrated competencies in the NAS functional domains of interpersonal and communication skills, professionalism, practice-based learning and improvement, and systems-based practice. Residents who responded with feedback after completing the course were very positive about their experience. CONCLUSIONS: The leadership training module described here allowed residents to acquire and demonstrate many of the competencies specified in leadership-oriented NAS milestones. The module did not require additional funding or a formal rotation or "track," is scalable to accommodate any number of residents and can be modified based on available local teaching resources. PMID- 25026946 TI - Building strengths with the Six Es of medication management. AB - The authors provide a template of focused skills drawn from various psychotherapy modalities for integration into follow-up psychopharmacology appointments. Titled the Six E model, this approach includes strategies to elicit an agenda, externalize the presenting problem, seek exceptions, engage empathetically, utilize enactments, and offer education. The template was trialed in a child and adolescent outpatient residency clinic under the guidance of two attendings. Qualitative feedback was solicited from fellows following utilization of the template. The Six E model was felt to improve structure and subjective satisfaction of patient, family, and provider participating in the brief appointments. PMID- 25026947 TI - Residency training in handoffs: a survey of program directors in psychiatry. AB - OBJECTIVE: The purpose of this study was to investigate how psychiatry programs are addressing the new Accreditation Council for Graduate Medical Education (ACGME) training requirements regarding transitions in patient care effective July 1, 2011. METHODS: An anonymous online survey was distributed to program directors of general psychiatry residencies within the USA. Survey questions pertaining to the 2011 ACGME handoff requirements focused on training modalities, assessment of competence, and oversight of appropriate handoff procedures. In addition, program directors were asked to share specific challenges in implementing the new handoff regulations as well as their view on how the new regulations would impact patient care. RESULTS: Of the 177 recipients, 108 completed at least part of the survey (61 % response rate). Only 11.4 % of programs indicated that they did not need to make any changes to their program in order to meet the new guidelines. Approximately a third of survey respondents reported that they did not yet have a formal curriculum in handoffs (32.4 %) and/or did not specifically assess competence at handoffs (30.5 %). Program directors cited the challenge of working with a variety of clinical settings with unique cultures, infrastructure, and policies and procedures and suggested that implementation and ownership of handoff training and assessment should be at the level of the clinical services. Despite these challenges, most program directors agreed that the new ACGME requirements would improve patient care and safety. CONCLUSIONS: The high frequency of programs without established handoff curricula or competence evaluations highlights the potential value of published resources and tools to provide standardized training and assessment in handoffs. The results also underscore the importance of developing training and assessment in close collaboration with the clinical services and recognizing the need to tailor handoff communications to address the types of transitions that occur within each clinical setting. PMID- 25026948 TI - The evolution of public psychiatry fellowships. AB - OBJECTIVE: The growth of Public Psychiatry Fellowships (PPFs) has reached a new developmental stage, providing a wide array of academic partnerships and educational opportunities in psychiatric leadership and administration. The authors examine the evolution of these programs and illustrate three distinct models. METHODS: Data from yearly surveys and discussions with PPF directors were used to identify key similarities and areas of divergence as the programs have evolved. RESULTS: The first period of program expansion took place 8-10 years ago when new programs were modeled on the Columbia PPF, and key elements of that program and the American Association of Community Psychiatrists (AACP) guidelines were incorporated broadly. Examples of multiple source (Columbia), single source (Yale and UCSF), and grant-funded programs (Alabama and UCSD) are presented. CONCLUSIONS: A review of the current status of PPFs reveals a diversity of structures and strategies for success, which can be attributed to the range of their funding sources. The advantages and potential disadvantages of those models are outlined with respect to the educational experience and opportunities for growth and sustainability. PMID- 25026949 TI - Comparison Between a Typical Undergraduate Psychiatry Program in China and Canada -an Approach to Inform Psychiatry Education Reform in China. AB - OBJECTIVE: Psychiatry as a field and undergraduate psychiatry education (UPE) specifically have historically been in the periphery of medicine in China, unlike the relatively central role they occupy in the West. During the current economic reform, Chinese undergraduate medical education (UME) is undergoing significant changes and standardization under the auspices of the national accreditation body. A comparative study, using Bereday's comparative education methodology and Feldmann's evaluative criteria as theoretical frameworks, to gain understanding of the differences and similarities between China and the West in terms of UPE can contribute to the UME reform, and specifically UPE development in China, and promote cross-cultural understanding. METHOD: The authors employed multi-sourced information to perform a comparative study of UPE, using the University of Toronto as a representative of the western model and Guangxi Medical University, a typical program in China, as the Chinese counterpart. RESULTS: Key contrasts are numerous; highlights include the difference in age and level of education of the entrants to medical school, centrally vs. locally developed UPE curriculum, level of integration with the rest of medical education, visibility within the medical school, adequacy of teaching resources, amount of clinical learning experience, opportunity for supervision and mentoring, and methods of student assessment. CONCLUSIONS: Examination of the existing, multi-sourced information reveals some fundamental differences in the current UPE between the representative Chinese and western programs, reflecting historical, political, cultural, and socioeconomic circumstances of the respective settings. The current analyses show some areas worthy of further exploration to inform Chinese UPE reform. The current research is a practical beginning to the development of a deeper collaborative dialogue about psychiatry and its educational underpinnings between China and the West. PMID- 25026950 TI - The Use of Simulation to Teach Suicide Risk Assessment to Health Profession Trainees-Rationale, Methodology, and a Proof of Concept Demonstration with a Virtual Patient. AB - OBJECTIVE: There is increasing use of educational technologies in medical and surgical specialties. Described herein is the development and application of an interactive virtual patient (VP) to teach suicide risk assessment to health profession trainees. We studied the effect of the following: (1) an interaction with a bipolar VP who attempts suicide or (2) completion of a video-teaching module on interviewing a bipolar patient, on medical students' proficiency in assessing suicide risk in standardized patients. We hypothesized that students who interact with a bipolar VP will be at least as likely to assess suicide risk, as their peers who completed a video module. METHODS: In a randomized, controlled study, we compared the frequency with which second-year students at the Medical College of Georgia asked suicide risk and bipolar symptoms questions by VP/video group. RESULTS: We recruited 67 students. The VP group inquired more frequently than the video group in 4 of 5 suicide risk areas and 11 of 14 other bipolar symptomatology areas. There were minimal to small effect sizes in favor of the VP technology. The students preferred the video over the VP as an educational tool (p = 0.007). CONCLUSIONS: Our study provides proof of concept that both VP and video module approaches are feasible for teaching students to assess suicide risk, and we present evidence about the role of active learning to improve communication skills. Depending on the learning context, interviewing a VP or observation of a videotaped interview can enhance the students' suicide risk assessment proficiency in an interview with a standardized patient. An interactive VP is a plausible modality to deliver basic concepts of suicide risk assessment to medical students, can facilitate individual preferences by providing easy access and portability, and has potential generalizability to other aspects of psychiatric training. PMID- 25026951 TI - Teaching a neuromedical-contextual approach to psychosomatic medicine. AB - The practice of psychosomatic medicine in the general hospital setting can be challenging, particularly for the inexperienced trainee. Guidance for how to approach a psychiatric consultation can be nonspecific or lacking altogether. In response, we offer a pedagogical model that emphasizes patient-specific neurological, medical, and contextual variables. A stepwise, "ABC" approach to psychiatric consultation is elaborated, beginning with collection of critical history ("Admission, Background, Consultation Question"), followed by both patient encounter ("Appearance, Behavior, Context") and actual patient examination ("Arousal, Brain/Body, Cognitive Assessment"), ultimately informing any given case formulation. Multiple clinical vignettes illustrate this approach and are offered for educational purposes in dissemination to trainees. PMID- 25026952 TI - One perspective on the value of journal editorship. PMID- 25026953 TI - The gradient technique improves success rates in intrauterine insemination cycles of unexplained subfertile couples when compared to swim up technique; a prospective randomized study. AB - PURPOSE: To compare the efficacy of gradient and swim-up semen preparation techniques on pregnancy rates in couples undergoing intrauterine insemination (IUI) cycles with low dose gonadotropin stimulation with the diagnosis of unexplained or mild male subfertility. METHODS: Two hundred and twenty three couples were randomized into swim up or gradient technique groups for sperm preperation. The clinical and on going pregnancy rates per cycle and per patient were evaluated. RESULTS: Both clinical and ongoing pregnancy rates per cycle were significantly higher in the "gradient" group (19% and 16.9%) in comparision with the "swim up" group (9.7% and 6.9%) (p < 0.05). Clinical pregnancy and on-going pregnancy rates per patient were higher in the "gradient" group (26.1% and 23.4%) when compared to the "swim up" group (15.2% and 10.7%), (p < 0.05). In the subgroup of 191 unexplained subfertile couples with 290 cycles; the "gradient" group also revealed significantly higher clinical and ongoing pregnancy rates per cycle (21.6% and 17.9%) when compared with the "swim up" group (10.3% and 7.1%) (p < 0.05). In total of 48 treatment cycles upon 32 couples with mild male factor subfertility no significant difference were found between the two sperm preparation techniques in terms of clinical (% 5.3 vs %6.9, p > 0.05) and ongoing (% 5.3 vs %6.9, p > 0.05) pregnancy rates per cycle. CONCLUSION: The gradient technique significantly improves clinical outcome in IUI cycles of unexplained subfertile couples when compared to swim up technique. In male subfertile patients, both techniques yield similar clinical outcomes. PMID- 25026954 TI - Dynamics of tear fluid desiccation on a glass surface: a contribution to tear quality assessment. AB - BACKGROUND: Fern-like crystalloids form when a microvolume of tear is allowed to dry out at ambient conditions on a glass surface. Presence of crystalloids in tear "microdesiccates" is used to evaluate patients with Dry-Eye disease. This study aims to examine morphologically the desiccation process of normal tear fluid and to identify changes associated with accelerated tear evaporation. Tear microdesiccates from healthy (Non-Dry Eye) and Dry Eye subjects were produced at ambient conditions. Microdesiccate formation was monitored continuously by dark field video microscopy. Additionally, accelerated desiccation of tear samples from healthy subjects was conducted under controlled experimental conditions. Particular morphological domains of tear microdesiccates and their progressive appearance during desiccation were compared. RESULTS: In normal tear microdesiccates, four distinctive morphological domains (zones I, II, III and transition band) were recognized. Stepwise formation of those domains is now described. Experimentally accelerated desiccation resulted in marked changes in some of those zones, particularly involving either disappearance or size reduction of fern-like crystalloids of zones II and III. Tear microdesiccates from Dry Eye subjects may also display those differences and be the expression of a more synchronous formation of microdesiccate domains. CONCLUSION: Morphological characteristics of tear microdesiccates can provide insights into the relative rate of tear evaporation. PMID- 25026955 TI - Optimal feeding systems for small-scale dairy herds in the North West Province, South Africa. AB - Land redistribution was legislated in 1994; it was designed to resolve historical imbalances inland ownership in South Africa. Between 2002 and 2006, a longitudinal observational studywas conducted with 15 purposively selected small scale dairy farmers in a land redistributionproject in Central North West Province. Four farmers left the project over the period. For thepurposes of this study, a small-scale dairy farm was defined as a farm that produces less than500 L of milk a day, irrespective of the number of cows or size of the farm. The study wasconducted in three phases. In the first phase, situational analysis using participatory ruralappraisal (PRA) and observation was used to outline the extent of the constraints and designappropriate interventions. Feeds that were used were tested and evaluated. In the secondphase, three different feeding systems were designed from the data obtained from PRA. Thesewere: (1) A semi intensive farm-based ration using available crops, pastures and crop residueswith minimal rations purchased. (2) An intensive, zero-grazing dairy system using a totalmixed ration. (3) A traditional, extensive or dual-purpose system, where the calf drank fromthe cow until weaning and milking was done only once a day. In the third phase, adoptionwas monitored. By July 2006, all remaining farmers had changed to commercially formulatedrations or licks and the body condition score of the cows had improved. It was concluded thatveterinary extension based on PRA and a holistic systems approach was a good option forsuch complex problems. Mentoring by commercial dairy farmers, veterinary and extensionservices appeared to be viable. Further research should be done to optimise the traditionalmodel of dairy farming, as this was relatively profitable, had a lower risk and was less labourintensive. PMID- 25026957 TI - No relation between CMV infection and mortality in the oldest old: results from the Belfrail study. AB - OBJECTIVE: previous studies have demonstrated an association between cytomegalovirus (CMV) infection and mortality in adults. In this prospective study, it was investigated whether these findings could be confirmed in the oldest old. METHODOLOGY: data obtained from a prospective observational cohort study (2008-2012) of 549 community-dwelling persons in Belgium aged 80 and older. RESULTS: seventy-six percent were anti-CMV seropositive of whom 37.5% had an anti CMV IgG titre in the highest tertile (>250 IU/ml). After a median time of follow up of 1,049 days, 127 deaths occurred. Cox proportional hazard models failed to show an association between CMV serostatus and all-cause mortality. Among persons seropositive for CMV, after adjusting for multiple confounders an anti-CMV in the highest tertile was statistically significantly associated with all-cause mortality (hazard ratio: 1.64, 95% confidence interval: 1.08, 2.48). CONCLUSION: in contrast to previous findings, a positive CMV serostatus was not associated with an increased risk for all-cause mortality in this cohort of very old people. This is probably the result of a survival effect. CMV seropositive subjects with high anti-CMV titres were at higher risk for all-cause mortality compared with other individuals. This may reflect CMV infection reactivation to be more common in the end stages of life. PMID- 25026960 TI - Clear cell carcinoma of the base of the tongue: case report and literature review. AB - OBJECTIVE: Clear cell carcinoma (CCC) is a rare, low-grade malignant neoplasm of minor salivary glands. Clear cell carcinoma is composed of monomorphic clear cells that contain glycogen within a hyalinized stroma. The microscopic diagnosis can be challenging, and the treatment strategy has not been established. METHODS: We report a case of a 56-year-old woman with CCC in the base of the tongue. A literature review, including 22 published cases and our case, was performed to clarify the clinical characteristics of CCC in the base of the tongue. RESULTS: The exophytic tumor showed no infiltration to the neighboring tissues. She underwent a local excision en bloc transorally and is free of the disease 15 months after surgery. In our review of 23 cases of CCC in the base of the tongue, 21 cases received surgical excision for the purpose of the primary treatment modality. The fact that the distinctive features of restricted site-related symptoms and the rare presentation of pain emerged was similar to previously reported cases of CCC. A relatively good prognosis was still indicated. CONCLUSION: We reveal the features of the unusual occurrence of CCC in the base of the tongue and consider the appropriate surgical approach for primary treatment. PMID- 25026961 TI - Endoscopic staple diverticulostomy for Zenker's diverticulum: review of experience in 337 cases. AB - OBJECTIVE: Surgical treatment of Zenker's diverticulum (ZD) has evolved over the previous 2 decades to a predominantly endoscopic approach. In this study, we review our experience with endoscopic staple-assisted diverticulostomy (ESD) for treatment of ZD from 2002 to 2011. METHODS: Retrospective chart review of 359 primary and revision ESD procedures performed on 337 unique patients between September 2002 and December 2011. Data were tabulated for age, sex, size of diverticulum, time to symptom recurrence, complications, and relief of symptoms. RESULTS: Of 337 attempted primary ESD procedures, 3.9% (N = 13) were aborted due to inadequate exposure. Of 324 patients who underwent primary ESD, 93.8% (N = 304) reported postoperative improvement of dysphagia symptoms. There was a 4.0% (N = 13) major complication rate. Patient-reported recurrence of symptoms occurred in 7.1% (N = 23) of primary ESD patients but was not significantly associated with diverticulum size (P = .9765). Twenty-one patients underwent revision ESD, with 95% (N = 20) of patients reporting improvement and 4.8% (N = 1) developing recurrent symptoms. CONCLUSION: Primary and revision ESD were shown to have similar success at relieving the symptoms of ZD, with low procedure abandonment and perioperative complication rates. Further patient follow-up is needed to determine the durability of symptom improvement and ZD recurrence rate following ESD. PMID- 25026958 TI - A20 deficiency causes spontaneous neuroinflammation in mice. AB - BACKGROUND: A20 (TNFAIP3) is a pleiotropic NFkappaB-dependent gene that terminates NFkappaB activation in response to inflammatory stimuli. The potent anti-inflammatory properties of A20 are well characterized in several organs. However, little is known about its role in the brain. In this study, we investigated the brain phenotype of A20 heterozygous (HT) and knockout (KO) mice. METHODS: The inflammatory status of A20 wild type (WT), HT and KO brain was determined by immunostaining, quantitative PCR, and Western blot analysis. Cytokines secretion was evaluated by ELISA. Quantitative results were statistically analyzed by ANOVA followed by a post-hoc test. RESULTS: Total loss of A20 caused remarkable reactive microgliosis and astrogliosis, as determined by F4/80 and GFAP immunostaining. Glial activation correlated with significantly higher mRNA and protein levels of the pro-inflammatory molecules TNF, IL-6, and MCP-1 in cerebral cortex and hippocampus of A20 KO, as compared to WT. Basal and TNF/LPS-induced cytokine production was significantly higher in A20 deficient mouse primary astrocytes and in a mouse microglia cell line. Brain endothelium of A20 KO mice demonstrated baseline activation as shown by increased vascular immunostaining for ICAM-1 and VCAM-1, and mRNA levels of E-selectin. In addition, total loss of A20 increased basal brain oxidative/nitrosative stress, as indicated by higher iNOS and NADPH oxidase subunit gp91phox levels, correlating with increased protein nitration, gauged by nitrotyrosine immunostaining. Notably, we also observed lower neurofilaments immunostaining in A20 KO brains, suggesting higher susceptibility to axonal injury. Importantly, A20 HT brains showed an intermediate phenotype, exhibiting considerable, albeit not statistically significant, increase in markers of basal inflammation when compared to WT. CONCLUSIONS: This is the first characterization of spontaneous neuroinflammation caused by total or partial loss of A20, suggesting its key role in maintenance of nervous tissue homeostasis, particularly control of inflammation. Remarkably, mere partial loss of A20 was sufficient to cause chronic, spontaneous low-grade cerebral inflammation, which could sensitize these animals to neurodegenerative diseases. These findings carry strong clinical relevance in that they question implication of identified A20 SNPs that lower A20 expression/function (phenocopying A20 HT mice) in the pathophysiology of neuroinflammatory diseases. PMID- 25026959 TI - IgG4- related disease: an orphan disease with many faces. AB - Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro inflammatory disorder (ORPHA284264). Although patients have been described more than 100 years ago, the systemic nature of this disease has been recognized in the 21st century only. Type 1 autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD. Typically, lymphoplasmacellular inflammation, storiform fibrosis and obliterative phlebitis are found in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. Consequently, diagnostic criteria for IgG4-RD have been proposed recently. Treatment is largely based on clinical experience and retrospective case series. Glucocorticoids are the mainstay of therapy, although adjunctive immunosuppressive agents are used in relapsing patients. This review summarizes current knowledge on clinical manifestations, pathophysiology and treatment of IgG4-RD. PMID- 25026962 TI - Antidiabetic, renal/hepatic/pancreas/cardiac protective and antioxidant potential of methanol/dichloromethane extract of Albizzia Lebbeck Benth. stem bark (ALEx) on streptozotocin induced diabetic rats. AB - BACKGROUND: Hypoglycemic and/or anti-hyperglycemic activities have been recorded with numerous plants, many of which are used as traditional herbal treatments of diabetes. Albizzia Lebbeck Benth. stem bark have been used in traditional medicine along with some preliminary reports on its hypoglycemic action. The aim of present investigation was to evaluate the antidiabetic and antioxidant activities of methanolic extract of stem bark of Albizzia Lebbeck Benth. in streptozotocin induced diabetic rats. METHODS: The powdered stem bark of Albizzia Lebbeck Benth.. was extracted with methanol (MeOH) using soxhlation method and subjected to phytochemical analysis. The methanol/dichloromethane extract of Albizzia Lebbeck Benth. (ALEx) was concentrated to dryness using Rotary Evaporator. Diabetes was experimentally induced in the rats by single intraperitoneal administration of Streptozotocin (60 mg/kg). They glycemic control was measured by the blood glucose, glycated heamoglobin and plasma insulin. The oxidative stress was evaluated in the liver and kidney by level of antioxidant markers and various biochemical parameters were assessed in diabetic control and extract treated rats. RESULTS: Streptozotocin induced diabetic rats depicted the increased blood glucose levels, total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), diminished level of high density lipoprotein cholesterol (HDL-c) level and perturb level of antioxidant markers. Oral administration of MeAL at a concentration of 100, 200, 300 and 400 mg/kg b.w daily for 30 days results a momentous decrease in fasting blood glucose, glycated heamoglobin and enhancement of plasma insulin level as compared with STZ induced diabetic rats. Furthermore, it significantly (p < 0.05) decreased the level of TC, TG, and LDL-c, VLDL-c. While it increases the level of HDL-c to a significant (p < 0.05) level. The treatment also resulted in a marked increase in reduced glutathione, glutathione Peroxidase, catalase and superoxide dismutase and diminished level of lipid peroxidation in liver and kidney of STZ induced diabetic rats. Histopathological studies suggest the diminution in the pancreatic, liver and cardiac muscle damage. CONCLUSION: Our research exertion clearly indicates the considerable antihyperglycemic, antihyperlipidemic, antioxidant & pancreas/renal/hepatic/cardiac protective action of ALEx. PMID- 25026964 TI - Examining Family Responses to Family Systems Nursing Interventions: An Integrative Review. AB - To add to the small, but growing, number of literature reviews of family interventions in health care, a systematic literature search of Family Systems Nursing intervention research resulted in the inclusion of 17 empirical research reports. Family Systems Nursing intervention research to date has primarily used qualitative methods and a few quasi-experimental designs using pre-post outcome measures. Families' responses to Family Systems Nursing interventions were categorized in this integrative review using the cognitive, affective, and behavioral domains of family functioning proposed by Wright and Leahey. Family response in the cognitive domain found improved understanding, capability, and enhanced coping. The affective response categories showed caring more about each other and the family, improved family emotional well-being, and improved individual emotional well-being. Finally, family responses in the behavioral domain comprised caring more for each other and the family, improvement in interactions within and outside family, and healthier individual behavior. These findings may guide the design of future family nursing intervention research and the selection of family outcome measures to examine the usefulness of Family Systems Nursing interventions. More intervention research using experimental and quasi-experimental designs is needed to strengthen the evidence for Family Systems Nursing practice. PMID- 25026963 TI - Neurological picture. Acute appearance of a carotid pseudoaneurysm during coughing. PMID- 25026965 TI - Attitudes of Registered and Licensed Practical Nurses About the Importance of Families in Surgical Hospital Units: Findings From the Landspitali University Hospital Family Nursing Implementation Project. AB - The purpose of this study was to examine attitudes of registered nurses and licensed practical nurses about the importance of the family in surgical hospital units before (T1) and after (T2) implementation of a Family Systems Nursing educational intervention based on the Calgary Family Assessment and Intervention Models. This study was part of the Landspitali University Hospital Family Nursing Implementation Project and used a nonrandomized, quasi-experimental design with nonequivalent group before and after and without a control group. There were 181 participants at T1 and 130 at T2. No difference was found in nurses' attitudes as measured by the Families Importance in Nursing Care-Nurses' Attitudes (FINC-NA) questionnaire, before and after the educational intervention. Attitudes toward families were favorable at both times. Analysis of demographic variables showed that age, work experience, and workplace (inpatient vs. outpatient units) had an effect on the nurses' attitudes toward families. The influence of work experience on attitudes toward family care warrants further exploration. PMID- 25026967 TI - Morphogenesis of filaments growing in flexible confinements. AB - Space-saving design is a requirement that is encountered in biological systems and the development of modern technological devices alike. Many living organisms dynamically pack their polymer chains, filaments or membranes inside deformable vesicles or soft tissue-like cell walls, chorions and buds. Surprisingly little is known about morphogenesis due to growth in flexible confinements--perhaps owing to the daunting complexity lying in the nonlinear feedback between packed material and expandable cavity. Here we show by experiments and simulations how geometric and material properties lead to a plethora of morphologies when elastic filaments are growing far beyond the equilibrium size of a flexible thin sheet they are confined in. Depending on friction, sheet flexibility and thickness, we identify four distinct morphological phases emerging from bifurcation and present the corresponding phase diagram. Four order parameters quantifying the transitions between these phases are proposed. PMID- 25026966 TI - Predictors of posttraumatic stress symptoms following childbirth. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) following childbirth has gained growing attention in the recent years. Although a number of predictors for PTSD following childbirth have been identified (e.g., history of sexual trauma, emergency caesarean section, low social support), only very few studies have tested predictors derived from current theoretical models of the disorder. This study first aimed to replicate the association of PTSD symptoms after childbirth with predictors identified in earlier research. Second, cognitive predictors derived from Ehlers and Clark's (2000) model of PTSD were examined. METHODS: N = 224 women who had recently given birth completed an online survey. In addition to computing single correlations between PTSD symptom severities and variables of interest, in a hierarchical multiple regression analyses posttraumatic stress symptoms were predicted by (1) prenatal variables, (2) birth-related variables, (3) postnatal social support, and (4) cognitive variables. RESULTS: Wellbeing during pregnancy and age were the only prenatal variables contributing significantly to the explanation of PTSD symptoms in the first step of the regression analysis. In the second step, the birth-related variables peritraumatic emotions and wellbeing during childbed significantly increased the explanation of variance. Despite showing significant bivariate correlations, social support entered in the third step did not predict PTSD symptom severities over and above the variables included in the first two steps. However, with the exception of peritraumatic dissociation all cognitive variables emerged as powerful predictors and increased the amount of variance explained from 43% to a total amount of 68%. CONCLUSIONS: The findings suggest that the prediction of PTSD following childbirth can be improved by focusing on variables derived from a current theoretical model of the disorder. PMID- 25026968 TI - Pancreaticoduodenectomy: expected post-operative anatomy and complications. AB - Pancreaticoduodenectomy is a complex, high-risk surgical procedure performed for tumours of the pancreatic head and other periampullary structures. The rate of perioperative mortality has decreased in the past number of years but perioperative morbidity remains high. This pictorial review illustrates expected findings in early and late post-operative periods, including mimickers of pathology. It aims to familiarize radiologists with the imaging appearances of common and unusual post-operative complications. These are classified into early non-vascular complications such as delayed gastric emptying, post-operative collections, pancreatic fistulae and bilomas; late non-vascular complications, for example, biliary strictures and hepatic abscesses; and vascular complications including haemorrhage and ischaemia. Options for minimally invasive image-guided management of vascular and non-vascular complications are discussed. Familiarity with normal anatomic findings is essential in order to distinguish expected post operative change from surgical complications or recurrent disease. This review summarizes the normal and abnormal radiological findings following pancreaticoduodenectomy. PMID- 25026969 TI - Absence of evidence ? evidence of absence: statistical analysis of inclusions in multiferroic thin films. AB - Assertions that a new material may offer particularly advantageous properties should always be subjected to careful critical evaluation, especially when those properties can be affected by the presence of inclusions at trace level. This is particularly important for claims relating to new multiferroic compounds, which can easily be confounded by unobserved second phase magnetic inclusions. We demonstrate an original methodology for the detection, localization and quantification of second phase inclusions in thin Aurivillius type films. Additionally, we develop a dedicated statistical model and demonstrate its application to the analysis of Bi(6)Ti(2.8)Fe(1.52)Mn(0.68)O18 (B6TFMO) thin films, that makes it possible to put a high, defined confidence level (e.g. 99.5%) to the statement of 'new single phase multiferroic materials'. While our methodology has been specifically developed for magnetic inclusions, it can easily be adapted to any other material system that can be affected by low level inclusions. PMID- 25026971 TI - Biological Research marks its 50th year by joining BioMed Central. PMID- 25026970 TI - Evolution of apomixis loci in Pilosella and Hieracium (Asteraceae) inferred from the conservation of apomixis-linked markers in natural and experimental populations. AB - The Hieracium and Pilosella (Lactuceae, Asteraceae) genera of closely related hawkweeds contain species with two different modes of gametophytic apomixis (asexual seed formation). Both genera contain polyploid species, and in wild populations, sexual and apomictic species co-exist. Apomixis is known to co-exist with sexuality in apomictic Pilosella individuals, however, apomictic Hieracium have been regarded as obligate apomicts. Here, a developmental analysis of apomixis within 16 Hieracium species revealed meiosis and megaspore tetrad formation in 1 to 7% of ovules, for the first time indicating residual sexuality in this genus. Molecular markers linked to the two independent, dominant loci LOSS OF APOMEIOSIS (LOA) and LOSS OF PARTHENOGENESIS (LOP) controlling apomixis in Pilosella piloselloides subsp. praealta were screened across 20 phenotyped Hieracium individuals from natural populations, and 65 phenotyped Pilosella individuals from natural and experimental cross populations, to examine their conservation, inheritance and association with reproductive modes. All of the tested LOA and LOP-linked markers were absent in the 20 Hieracium samples irrespective of their reproductive mode. Within Pilosella, LOA and LOP-linked markers were essentially absent within the sexual plants, although they were not conserved in all apomictic individuals. Both loci appeared to be inherited independently, and evidence for additional genetic factors influencing quantitative expression of LOA and LOP was obtained. Collectively, these data suggest independent evolution of apomixis in Hieracium and Pilosella and are discussed with respect to current knowledge of the evolution of apomixis. PMID- 25026972 TI - Random and targeted interventions for epidemic control in metapopulation models. AB - In general, different countries and communities respond to epidemics in accordance with their own control plans and protocols. However, owing to global human migration and mobility, strategic planning for epidemic control measures through the collaboration of relevant public health administrations is gaining importance for mitigating and containing large-scale epidemics. Here, we present a framework to evaluate the effectiveness of random (non-strategic) and targeted (strategic) epidemic interventions for spatially separated patches in metapopulation models. For a random intervention, we analytically derive the critical fraction of patches that receive epidemic interventions, above which epidemics are successfully contained. The analysis shows that the heterogeneity of patch connectivity makes it difficult to contain epidemics under the random intervention. We demonstrate that, particularly in such heterogeneously connected networks, targeted interventions are considerably effective compared to the random intervention. Our framework is useful for identifying the target areas where epidemic control measures should be focused. PMID- 25026973 TI - The utility of novel non-invasive technologies for remote hemodynamic monitoring in chronic heart failure. AB - Monitoring a patient's hemodynamic status may be a revolutionary way to aid a 'health maintenance' strategy in which the physician strives to therapeutically keep the patient in an ideal hemodynamic range. Currently, home telemonitoring employs a 'crisis-prevention' approach. This strategy is still based on easily acquired measures such as heart rate, weight and blood pressure--measurements that are useful to help implement guideline-directed therapy but provide little information about impending decompensation or the risk of hospitalisation. Current systems provide limited information to personalize and adapt medication therapy for heart failure. Several innovative technologies that can remotely monitor estimates of cardiovascular hemodynamics, such as cardiac index, systemic vascular resistance, augmentation index and added heart sounds may enable earlier detection of heart failure decompensation. This editorial presents an overview of the innovative technologies that are available for non-invasive hemodynamic monitoring and maybe adapted for home telemonitoring for chronic heart failure. PMID- 25026974 TI - Magnetoresistance of the high-pressure ferromagnetic phases (GaSb)2M (M=Cr,Mn). AB - For the first time magnetoresistance of the ferromagnetic high-pressure phases (GaSb)2M (M=Cr,Mn) has been measured in a wide range of temperature and magnetic field. It was found that the magnetic field dependencies of resistivity of both systems contain several contributions, including relatively smaller s-d exchange (Yosida-type) components in low fields and a quadratic positive term (PMR) in the low temperature region. The magnitude of the predominated negative term (NMR), which can be attributed to the quantum corrections effects, demonstrates a peak in the vicinity of Curie temperature. PMID- 25026975 TI - Tiopronin-induced membranous nephropathy: a case report. AB - BACKGROUND: Tiopronin, a glycine derivative extensively used to treat cystinuria and hepatic cell injury, can give rise to rare complications such as proteinuria and nephrotic syndrome. However, the pathological characteristics of this secondary nephropathy are poorly understood. Here, we report a case of tiopronin induced nephrotic syndrome. CASE PRESENTATION: A 65-year-old Chinese man with a history of myasthenia gravis admitted tiopronin for hepatoprotection therapy. After 3 months later, he presented with rapid weight gain, massive peripheral edema, and proteinuria in the nephrotic range. Laboratory findings included serum albumin (20 g/L), total protein (38 g/L), and total cholesterol (11.78 mmol/L). A 24-hour urine protein collection contained 8620 mg. Percutaneous renal biopsy revealed a uniformly thickened glomerular and rigid basement membrane with immunoglobulin G (IgG) and complement C3 deposited along the glomerular capillary wall. Withdrawal of tiopronin-induced proteinuria complete remission and clinical resolution of nephrotic syndrome. CONCLUSIONS: Potential risk of kidney injury exists with long-term tiopronin treatment. Membranous nephropathy was a common renal pathologic feature. Proteinuria in the nephrotic range may spontaneously remit after tiopronin withdrawal. Periodic urine analysis and patient follow-up are recommended with tiopronin therapy. PMID- 25026976 TI - Morphometric and phytochemical characterization of chaura fruits (Gaultheria pumila): a native Chilean berry with commercial potential. AB - BACKGROUND: For the first time, a morphometric characterization of chaura (Gaultheria pumila) fruits has been conducted between natural populations growing in the Villarrica National Park, Araucania Region, Chile. Chaura is a native Ericaceae from Chile that produces aromatic and tasty fruits which could be of agricultural interest. RESULTS: To influence the decision for a further domestication of G. pumila, both the fruit sizes (indicator of productivity) and the nutritional properties of the fruits have been determined from different subpopulations. Samples were a total of 74 plants and 15 fruits per plant which were randomly harvested following its natural distribution around the Villarrica volcano. Altogether, fresh weight, shape, color, diameter in the pole and the equatorial dimensions were determined as phenotypic traits of the G. pumila fruits. Meanwhile the total soluble solids, anthocyanin and pectin contents were calculated as nutritional traits of the Chaura fruits. Results showed a high phenotypic diversity between the sampled population with three main fruit shapes and three predominant colors. The round shapes were the most abundant, whereas a significant correlation was found among fruit size with weight and color. The highest fresh weight (597.3 mg), pole diameter (7.1 mm) and equatorial diameter (6.5 mm) were estimated in the pink color fruits. CONCLUSIONS: The total amount of anthocyanin was higher in red fruits, while the maximum pectin content was obtained in the round white fruits. Overall results must pave the way for a further domestication and introduction of the Chaura species in the agro productive system in Chile. PMID- 25026977 TI - Promoting family planning use after childbirth and desire to limit childbearing in Ethiopia. AB - BACKGROUND: In Ethiopia the average fertility rate in rural areas is about 6 children per woman, while it is 2.4 children per woman in urban areas. It is with this concept in mind that the investigators of this study wanted to correlate the promotion of after-child-birth-use of family planning and desire to limit childbearing in Ethiopia. Postpartum amenorrhea signifies the interval between childbirth and the return of menstruation. OBJECTIVES: The specific objective is to examine the desire to limit family size, along with cases of sterilized, fecund, postpartum amenorrhoea, declared in-fecund and menopausal women within the study area. METHODS: The study is based on the analysis of secondary data obtained from the 2011 Ethiopian Demographic and Health Survey (EDHS). This study is concentrated on couples because we need to know more about married people's desire to limit their family size. The bivariate, ANOVA, and multivariate analyses were used to analyse the association. RESULTS: The total number of respondents was 6,745 (78.3% rural and 21.7% urban), with 93.6% of them being currently married and 6.4% of them living with a partner. The mean duration of amenorrhea among women who gave birth in the five years preceding the survey is 16 months. Women with equal numbers of sons and daughters were found to be 75.4% (OR=0.25) less likely to desire more children, compared to women with more sons than daughters. CONCLUSION: Achievable resolutions include increasing females' ages at marriage, avoiding unwanted teenage pregnancies, completely eradicating home delivery, and inspiring young people to use modern methods of family planning to achieve Millennium Development Goals 4 & 5. PMID- 25026978 TI - A clinical classification acknowledging neuropsychiatric and cognitive impairment in Huntington's disease. AB - BACKGROUND: Involuntary movements, neuropsychiatric symptoms, and cognitive impairment are all part of the symptom triad in Huntington's disease (HD). Despite the fact that neuropsychiatric symptoms and cognitive decline may be early manifestations of HD, the clinical diagnosis is conventionally based on the presence of involuntary movements and a positive genetic test for the HD CAG repeat expansion. After investigating the frequencies of the triad manifestations in a large outpatient clinical cohort of HD gene-expansion carriers, we propose a new clinical classification. METHODS: In this cross-sectional study, 107 gene expansion carriers from a Danish outpatient clinic were recruited. All participants underwent neurological examination, psychiatric evaluation and neuropsychological testing. Participants were categorised according to motor symptoms, neuropsychiatric symptoms, the use of psychotropic medication, and cognitive impairment. RESULTS: Among the motor manifest HD gene-expansion carriers, 51.8% presented with the full symptom triad, 25.0% were defined as cognitively impaired in addition to motor symptoms, and 14.3% had neuropsychiatric symptoms along with motor symptoms. Only 8.9% had isolated motor symptoms. Among gene-expansion carriers without motor symptoms, 39.2% had neuropsychiatric symptoms, were cognitively impaired, or had a combination of the two. CONCLUSION: This is the first study to report the frequencies of both motor symptoms, cognitive impairment, and neuropsychiatric symptoms in HD gene expansion carriers in a national outpatient HD clinical cohort. We found that almost 40% of the gene-expansion carriers without motor symptoms had either neuropsychiatric symptoms, cognitive impairment or both, emphasising that these patients are not premanifest in psychiatric and cognitive terms, suggesting that the current clinical classification is neither necessarily suitable nor helpful for this patient group. Some premanifest gene-expansion carriers may have psychiatric and/or cognitive symptoms caused by reactive stress or other pathology than HD. Acknowledging this fact we, however, suggest classifying all HD gene-expansion carriers into three clinical categories: premanifest, non-motor manifest, and motor manifest. PMID- 25026979 TI - Incomplete reduction of branchial clefts in Mutton Merino lambs. AB - Congenital malformations of the branchial arches, clefts and grooves have not been previously reported in sheep. These defects may be due to infectious agents (especially viruses), toxins or genetic abnormalities. Defects were reported in two of a set of quadruplet lambs born prematurely to an eight-tooth Mutton Merino ewe. The lambs weighed between 2.0 kg and 2.5 kg; this is below the normal expected birth weight of 3.5 kg for quadruplet lambs, below which viability is compromised. The firstborn lamb was severely affected by bilateral oroauricular fistulae. The second lamb was unilaterally affected on the right, less severely than the first. The third lamb was normal and the fourth was mummified. The occurrence of another case in this small flock almost a decade earlier indicates that there could be genetic involvement. PMID- 25026980 TI - Alternative and antioxidant therapies used by a sample of infertile males in Jordan: a cross-sectional survey. AB - BACKGROUND: Complementary and alternative medicine (CAM) is frequently used in the Middle East, especially to treat chronic diseases such as infertility. We aimed to examine the prevalence, characteristics, and determinants of CAM use, particularly herbs and antioxidant therapies, among infertile males presenting for infertility evaluation in Jordan. METHODS: Demographic information, use of alternative and antioxidant therapies for infertility treatment, and patients' belief in efficacy and safety of the therapies used were collected using a face to-face questionnaire. Data were collected from 428 infertile male patients presenting at infertility clinics in Amman, the capital city of Jordan. The study was conducted between April 2013 and September 2013. RESULTS: Of the 428 men who completed the questionnaire, 184 (43%) used at least one of the alternative and antioxidant therapies specified in the questionnaire. Nutritional regime; vitamins, such as vitamins C and E; and medicinal herbs, such as ginger, saw palmetto, and ginseng were the most commonly used therapies reported. A correlation between the use of alternative and antioxidant therapies versus infertility duration was found. Additionally, the majority of males using CAM did not inform their health care providers about their usage. CONCLUSIONS: The high prevalence of CAM use among infertile male patients underscores the urge to assimilate CAM into the education and training of health professionals, as well as to improve infertile patients' knowledge of the safe use of CAM modalities. PMID- 25026981 TI - The effect of smoking on the duration of life with and without disability, Belgium 1997-2011. AB - BACKGROUND: Smoking is the single most important health threat yet there is no consistency as to whether non-smokers experience a compression of years lived with disability compared to (ex-)smokers. The objectives of the manuscript are (1) to assess the effect of smoking on the average years lived without disability (Disability Free Life Expectancy (DFLE)) and with disability (Disability Life Expectancy (DLE)) and (2) to estimate the extent to which these effects are due to better survival or reduced disability in never smokers. METHODS: Data on disability and mortality were provided by the Belgian Health Interview Survey 1997 and 2001 and a 10 years mortality follow-up of the survey participants. Disability was defined as difficulties in activities of daily living (ADL), in mobility, in continence or in sensory (vision, hearing) functions. Poisson and multinomial logistic regression models were fitted to estimate the probabilities of death and the prevalence of disability by age, gender and smoking status adjusted for socioeconomic position. The Sullivan method was used to estimate DFLE and DLE at age 30. The contribution of mortality and of disability to smoking related differences in DFLE and DLE was assessed using decomposition methods. RESULTS: Compared to never smokers, ex-smokers have a shorter life expectancy (LE) and DFLE but the number of years lived with disability is somewhat larger. For both sexes, the higher disability prevalence is the main contributing factor to the difference in DFLE and DLE. Smokers have a shorter LE, DFLE and DLE compared to never smokers. Both higher mortality and higher disability prevalence contribute to the difference in DFLE, but mortality is more important among males. Although both male and female smokers experience higher disability prevalence, their higher mortality outweighs their disability disadvantage resulting in a shorter DLE. CONCLUSION: Smoking kills and shortens both life without and life with disability. Smoking related disability can however not be ignored, given its contribution to the excess years with disability especially in younger age groups. PMID- 25026982 TI - Au137(SR)56 nanomolecules: composition, optical spectroscopy, electrochemistry and electrocatalytic reduction of CO2. AB - Au137(SR)56, a nanomolecule with a precise number of metal atoms and ligands, was synthesized. The composition was confirmed by MALDI and ESI mass spectrometry using three unique ligands (-SCH2CH2Ph, -SC6H13, and -SC4H9) and nano-alloys with Ag and Pd. The electrocatalytic properties were tested for CO2 reduction. PMID- 25026984 TI - Preparation of graphene supported Pt nanoparticles by a plasma approach and their application for methanol electro-oxidation: a comparison with chemical reduction. AB - A facile in situ plasma synthesis of graphene-based Pt nanoparticles is presented. For comparison, chemical reduction was also used. Ar plasma was capable of reducing Pt precursors into well dispersed Pt nanoparticles on graphene. The electrocatalytic activities of the two as-prepared catalysts were tested, and then they were used as anodes for methanol electro-oxidation in a DMFC. The catalyst prepared by the plasma approach showed higher catalytic activity for methanol electro-oxidation. The plasma technique is also suitable for the fabrication of other functional carbon based metal composites for their applications in multidisciplinary areas. PMID- 25026983 TI - Rewiring neural circuits by the insertion of ectopic electrical synapses in transgenic C. elegans. AB - Neural circuits are functional ensembles of neurons that are selectively interconnected by chemical or electrical synapses. Here we describe a synthetic biology approach to the study of neural circuits, whereby new electrical synapses can be introduced in novel sites in the neuronal circuitry to reprogram behaviour. We added electrical synapses composed of the vertebrate gap junction protein Cx36 between Caenorhabditis elegans chemosensory neurons with opposite intrinsic responses to salt. Connecting these neurons by an ectopic electrical synapse led to a loss of lateral asymmetry and altered chemotaxis behaviour. In a second example, introducing Cx36 into an inhibitory chemical synapse between an olfactory receptor neuron and an interneuron changed the sign of the connection from negative to positive, and abolished the animal's behavioural response to benzaldehyde. These data demonstrate a synthetic strategy to rewire behavioural circuits by engineering synaptic connectivity in C. elegans. PMID- 25026985 TI - Application of contrast-enhanced ultrasonography in the diagnosis of skeletal muscle crush injury in rabbits. AB - OBJECTIVE: To explore the diagnostic value of quantitative contrast-enhanced (CE) ultrasonography for crush injury in the hind limb muscles of rabbits. METHODS: A total of 120 New Zealand white rabbits were randomized to receive compression on the left hind limb for either 2 h (n = 56) or 4 h (n = 56) to induce muscle crush injury. Another eight animals were not injured and served as normal controls. CE ultrasonography parameters such as peak intensity (PI), ascending slop, descending slop and area under curve (AUC) were measured at 0.5, 2, 6 and 24 h and 3, 7 and 14 days after decompression. RESULTS: Compared with the uninjured muscles, reperfusion of the injured muscles showed early and high enhancement in CE ultrasonography images. The time-intensity curve showed a trend of rapid lift and gradual drop. The PI and AUC values differed significantly among the three groups and were positively correlated with serum and tissue biomarkers. Rabbits of the 4-h compression group showed significantly higher PI and AUC values, and serum and tissue parameters than the 2-h compression group at each time points. CONCLUSION: CE ultrasonography can effectively detect muscle crush injury and monitor dynamic changes of the injured muscles in rabbits. PI and AUC are promising diagnostic parameters for this disease. ADVANCES IN KNOWLEDGE: CE ultrasonography might play an important role in the pre-hospital and bedside settings for the diagnosis of muscle crush injury. PMID- 25026986 TI - Novel phthalamides containing sulfiliminyl moieties and derivatives as potential ryanodine receptor modulators. AB - To tackle the serious challenge of insect resistance and stricter environmental regulations, innovating a new eco-friendly insecticide is urgently required. A series of new phthalamides containing sulfiliminyl and sulfoximinyl moieties were designed and synthesized. In total, 30 new structures were characterized by 1H NMR spectra and HRMS. The bioassay results indicated that some title compounds exhibited excellent insecticidal activities against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)). 4a showed the same larvicidal level as that of commercial flubendiamide as a control. 7a and 9a exhibited outstanding activity against diamondback moth. The LC50 values of 7a and 9a were 8.33 * 10(-8) and 2.34 * 10(-8) mg L(-1), respectively, lower than that of flubendiamide (1.25 * 10(-7) mg L(-1)). The effects of 4a, 7a and 9a on intracellular calcium of neurons from the beet armyworm (Spodoptera exigua) indicated that these title compounds activate the receptor-operated calcium channel. The calcium ions efflux from the calcium store on endoplasmic reticulum (ER) when treated with novel compounds. The results of CoMFA calculation showed that N-cyanosulfilimines and N trifluoroacetylsulfoximines might be of importance to the larvicidal activity. The present work demonstrated that structures containing sulfiliminyl and sulfoximinyl moieties can be considered as lead compounds for the development of new insect ryanodine receptor modulators. PMID- 25026987 TI - Assessing the role of spatial correlations during collective cell spreading. AB - Spreading cell fronts are essential features of development, repair and disease processes. Many mathematical models used to describe the motion of cell fronts, such as Fisher's equation, invoke a mean-field assumption which implies that there is no spatial structure, such as cell clustering, present. Here, we examine the presence of spatial structure using a combination of in vitro circular barrier assays, discrete random walk simulations and pair correlation functions. In particular, we analyse discrete simulation data using pair correlation functions to show that spatial structure can form in a spreading population of cells either through sufficiently strong cell-to-cell adhesion or sufficiently rapid cell proliferation. We analyse images from a circular barrier assay describing the spreading of a population of MM127 melanoma cells using the same pair correlation functions. Our results indicate that the spreading melanoma cell populations remain very close to spatially uniform, suggesting that the strength of cell-to-cell adhesion and the rate of cell proliferation are both sufficiently small so as not to induce any spatial patterning in the spreading populations. PMID- 25026988 TI - Genomic imprinting: theories and data. PMID- 25026989 TI - Estimation of antioxidant, antimicrobial activity and brine shrimp toxicity of plants collected from Oymyakon region of the Republic of Sakha (Yakutia), Russia. AB - BACKGROUND: Several plants are reported to be produced various biological active compounds. Lichens from the extreme environments such as high altitude, high UV, drought and cold are believed to be synthesized unique types of secondary metabolites than the other one. Several human pathogenic bacteria and fungi have been muted into drug resistant strains. Various synthetic antioxidant compounds have posed carcinogenic effects. This phenomenon needs further research for new effective drugs of natural origin. This manuscript aimed to screen new source of biological active compounds from plants of subarctic origin. RESULTS: A total of 114 plant species, including 80 species of higher plants, 19 species of lichens and 15 species of mosses, were collected from Oymyakon region of the Republic of Sakha (Yakutia), Russia (6320'N, 14142'E-6315'N, 14227'E). Antimicrobial, DPPH free radical scavenging and brine shrimp (Artemia salina) toxicity of all crude extract were evaluated. The obtained result was analyzed and compared with commercial standards. A total of 28 species of higher plants showed very strong antioxidant activity (DPPH IC50, 0.45-5.0 MUg/mL), 13 species showed strong activity (DPPH IC50, 5-10 MUg/mL), 22 species showed moderate antioxidant activity (DPPH IC50,10-20 MUg/mL) and 17 species showed weak antioxidant activity (DPPH IC50 more than 20 MUg/mL). Similarly, 3 species of lichen showed strong antioxidant activity, one species showed moderate and 15 species showed weak DPPH reducing activity. In addition, 4 species of mosses showed moderate antioxidant activity and 11 species showed weak antioxidant activity. Similarly, extracts of 51 species of higher plants showed antimicrobial (AM) activity against Staphylococcus aureus and 2 species showed AM activity against Candida albicans. Similarly, 11 species of lichen showed AM activity against S. aureus and 3 species showed AM activity against Escherichia coli. One species of moss showed AM activity against S. aureus. And finally, one species of higher plant Rheum compactum and one species of lichen Flavocetraria cucullata showed the toxicity against Brine shrimp larvae in 100 MUg/mL of concentration. CONCLUSION: The experimental results showed that subarctic plant species could be potential sources of various biologically active natural compounds. PMID- 25026990 TI - Myocardial fibrosis as the first sign of cardiac involvement in a male patient with Fabry disease: report of a clinical case and discussion on the utility of the magnetic resonance in Fabry pathology. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging is increasingly used to assess myocardial involvement in patients with Fabry disease, an X linked lipid storage disorder. However, it is often proposed as an optional tool. A different cardiomyopathic disease progression between male and female patients was hypothesised in previous studies, as in female myocardial fibrosis was found without left ventricular (LV) hypertrophy, while myocardial fibrosis was always detected in association to LV hypertrophy in men. CASE PRESENTATION: A male Caucasian patient, 19 years old, diagnosed through a family-based molecular screening, presented with LGE of the LV inferolateral wall evidenced at the CMR, without LV hypertrophy, or other clinical signs of the disease. CONCLUSION: This is the first report of cardiac fibrosis as the first sign of organ involvement in a male patient with Fabry disease. This finding stresses the importance of performing CMR with LGE imaging for the initial staging and monitoring of Fabry patients of both genders. PMID- 25026991 TI - [Factors influencing course of hospitalization in patients with hip fractures: Complications, length of stay and hospital mortality]. AB - BACKGROUND: Time of surgery, age, sex, and co-morbidities influence the complication and mortality rate in patients with hip fractures. Patients with relevant co-morbidities, who were hospitalized at the weekend have a higher mortality rate. Complications prolong length of stay (LOS), which results in higher costs and shortage of bed capacity. OBJECTIVES: The influence of various factors on hospitalization with emphasis on complications, LOS, and clinical mortality should be observed. MATERIALS AND METHODS: Retrospectively, 242 patients with hip fractures (>64a) were observed. In addition to age and sex, time of hospitalization and surgery, intensive care therapy, hospital mortality, LOS, comorbidities, ASA, and complications were recorded. Times were assigned to the work week or the weekend or regular or on-call duty service. RESULTS: 29.8 % were hospitalized at the weekend, 66.1% on on-call duty, 24.1% were operated on the weekend, 67.4% on on-call duty. 86.3% were operated <48 h after admission. The mortality rate was 8.3%. Longer time to surgery results in more frequent intensive care therapy, prolongs the LOS, and increases overall complications. Advanced age increases mortality and LOS. A higher value of the ASA classification leads to increased mortality; co-morbidities lead to more frequent intensive care therapy. Surgical complications prolong LOS of 10.8d (86.4%). CONCLUSION: Hospitalization is influenced by age, ASA and co-morbidities as well as by time to surgery and operation in day or late and nighttime service. Early surgery and prevention of surgical complications reduce LOS. PMID- 25026992 TI - Cultural beliefs on disease causation in the Philippines: challenge and implications in genetic counseling. AB - The provision of culturally competent health care is an important professional issue recognized by the pioneer genetic counselors in the Philippines. Being an archipelago consisting of 7,107 islands, the Philippines has approximately 175 ethnolinguistic groups with their own unique cultural identity and health practices. The emphasis on culture in our genetic counseling training recognizes its crucial role in molding an individual's conceptualization of health, as well as other life aspects, especially since the Filipino culture is a mixture of indigenous as well as imported and borrowed elements. As part of this endeavor, we will describe in this paper seven common Filipino cultural beliefs: namamana, lihi, sumpa, gaba, pasma, namaligno, and kaloob ng Diyos. We will also share examples on how these common beliefs provide explanation as cause of illness and its implications in our genetic counseling profession. PMID- 25026993 TI - Modifiers of (CAG)(n) instability in Machado-Joseph disease (MJD/SCA3) transmissions: an association study with DNA replication, repair and recombination genes. AB - Twelve neurological disorders are caused by gene-specific CAG/CTG repeat expansions that are highly unstable upon transmission to offspring. This intergenerational repeat instability is clinically relevant since disease onset, progression and severity are associated with repeat size. Studies of model organisms revealed the involvement of some DNA replication and repair genes in the process of repeat instability, however, little is known about their role in patients. Here, we used an association study to search for genetic modifiers of (CAG)n instability in 137 parent-child transmissions in Machado-Joseph disease (MJD/SCA3). With the hypothesis that variants in genes involved in DNA replication, repair or recombination might alter the MJD CAG instability patterns, we screened 768 SNPs from 93 of these genes. We found a variant in ERCC6 (rs2228528) associated with an expansion bias of MJD alleles. When using a gene-gene interaction model, the allele combination G-A (rs4140804-rs2972388) of RPA3-CDK7 is also associated with MJD instability in a direction-dependent manner. Interestingly, the transcription-coupled repair factor ERCC6 (aka CSB), the single-strand binding protein RPA, and the CDK7 kinase part of the TFIIH transcription repair complex, have all been linked to transcription-coupled repair. This is the first study performed in patient samples to implicate specific modifiers of CAG instability in humans. In summary, we found variants in three transcription-coupled repair genes associated with the MJD mutation that points to distinct mechanisms of (CAG)n instability. PMID- 25026994 TI - Through the patient's eyes: the value of a comprehensive brain tumor center. AB - Since the founding of the Tumor Section of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) in 1984 much in neurosurgical oncology has changed. More than 40,000 papers have been published on glioma since the arrival of the AANS/CNS Tumor Section. Increasingly, research is focusing on more patient-centered care and quality of life. Preliminary work suggests that a greater emphasis on the patient and caregiver's experience of disease is crucial. Also, the provision of hope and appropriate information and communication with health care providers helps to lessen anxiety and promote improved quality of life. Lastly, our patients need a mechanism for continued symptom control and psychosocial support throughout their experience of this disease. An excellent venue for providing these facets of neurooncological patient care is the multidisciplinary brain tumor board and symptom management team. Herein, we present the philosophy and practice of the Hermelin Brain Tumor Center at the Henry Ford Health System as one type of approach to caring for the patient with a malignant glioma. The authors are aware of several brain tumor centers that share our philosophy and approach to patient care. Our comments are not meant to be exclusive to our experience and should be interpreted as representative of the growing movement in neurosurgery to provide comprehensive, multidisciplinary, patient-centered care. PMID- 25026995 TI - Analyzing temozolomide medication errors: potentially fatal. AB - The EORTC-NCIC regimen for glioblastoma requires different dosing of temozolomide (TMZ) during radiation and maintenance therapy. This complexity is exacerbated by the availability of multiple TMZ capsule strengths. TMZ is an alkylating agent and the major toxicity of this class is dose-related myelosuppression. Inadvertent overdose can be fatal. The websites of the Institute for Safe Medication Practices (ISMP), and the Food and Drug Administration (FDA) MedWatch database were reviewed. We searched the MedWatch database for adverse events associated with TMZ and obtained all reports including hematologic toxicity submitted from 1st November 1997 to 30th May 2012. The ISMP describes errors with TMZ resulting from the positioning of information on the label of the commercial product. The strength and quantity of capsules on the label were in close proximity to each other, and this has been changed by the manufacturer. MedWatch identified 45 medication errors. Patient errors were the most common, accounting for 21 or 47% of errors, followed by dispensing errors, which accounted for 13 or 29%. Seven reports or 16% were errors in the prescribing of TMZ. Reported outcomes ranged from reversible hematological adverse events (13%), to hospitalization for other adverse events (13%) or death (18%). Four error reports lacked detail and could not be categorized. Although the FDA issued a warning in 2003 regarding fatal medication errors and the product label warns of overdosing, errors in TMZ dosing occur for various reasons and involve both healthcare professionals and patients. Overdosing errors can be fatal. PMID- 25026996 TI - Patterns of care in adult medulloblastoma: results of an international online survey. AB - The literature on medulloblastoma in adults is generally limited to case reports and retrospective series, and there is no accepted standard of care. The Cooperative Trials Group for Neuro-Oncology (COGNO) sought to determine the range and consistency of clinicians' approaches to management as a basis for future trials. We aimed to identify current treatment strategies for adult medulloblastoma through an online survey launched at the 2012 Society of Neuro Oncology meeting and by email invitation. Clinicians who had treated at least one adult patient with medulloblastoma, primitive neuroectodermal tumor (PNET), or pineoblastoma in the preceding year were asked about their most recent patient and invited to discuss their approach to a typical clinical scenario. Between November 2012 and January 2013, 45 clinicians (11 medical oncologists, 8 radiation oncologists, 5 pediatric oncologists, and 21 others) from Australia (24), United States (3), Europe (4) and other countries (14) completed the survey. Responding clinicians had treated 54 cases in the past 12 months. The most common histological type was medulloblastoma (64%), then PNET (20%). Most patients were male (68%), and had high-risk disease (65%). Complete surgical resection in 56 and 32% had molecular testing. Radiotherapy was predominantly cranio-spinal (92%) and given mostly post-resection (80%). Combination chemotherapy was more common than single-agent chemotherapy. The choice of chemotherapy varied considerably. There is substantial variation in the treatment of adult medulloblastoma, most pronounced in the choice of chemotherapeutic agents, highlighting the need for further collaborative research to guide evidence-based treatment strategies. PMID- 25026998 TI - Prognostic significance of WT1 expression in soft tissue sarcoma. AB - BACKGROUND: Soft tissue sarcomas (STS) are rare. We evaluated the WT1 protein expression level in various types of STS and elucidated the value of WT1 as a prognostic factor and a possible therapeutic target. METHODS: Immunohistochemical staining for WT1 was performed in 87 cases of STS using formalin-fixed, paraffin embedded blocks. The correlation between WT1 expression and clinicopathological factors was analyzed. Survival analysis was conducted in 67 patients. We assessed the validity of WT1 immunohistochemistry as an index of WT1 protein expression using Western blot analysis. RESULTS: WT1 expression was noted in 47 cases (54.0%). Most rhabdomyosarcomas and malignant peripheral nerve sheath tumors showed WT1 expression (91.7% and 71.4%, respectively; P = 0.005). WT1 expression was related to higher FNCLCC histologic grade and AJCC tumor stage. In the group with high grade STS, strong WT1 expression was correlated with better survival (P = 0.025). The immunohistochemical results were correlated quantitatively with the staining score and the concentration of the Western blot band. CONCLUSIONS: This study demonstrates that various types of STS show positive immunostaining for WT1 and that WT1 expression has a prognostic significance. So STS should be considered candidates for WT1 peptide--based immunotherapy. PMID- 25026999 TI - Anatomical study of phrenic nerve course in relation to neck dissection. AB - The present study sought to clarify the course of the phrenic nerve and its correlation with anatomical landmarks in the neck region. We examined 17 cadavers (30 sides). In each, the phrenic nerves was dissected from the lateral side of the neck, and its position within the triangle formed by the mastoid process and sternal and acromial ends of the clavicle was determined. The point where the phrenic nerve arises in the posterior triangle was found to be similar to the point where the cutaneous blanches of the cervical plexus emerge at the middle of the posterior border of the sternocleidomastoid muscle. In the supraclavian triangle, the phrenic nerve crosses the anterior border of the anterior scalene muscle near Erb's point where the superficial point is 2-3 cm superior from the clavicle and posterior border of the sternocleidomastoid muscle. The phrenic nerve arises in the posterior triangle near the nerve point, then descends to the anterior surface of the anterior scalene muscle in the supraclavian triangle. It is necessary to be aware of the supraclavian triangle below Erb's point during neck dissection procedures. PMID- 25026997 TI - The novel immunotherapeutic molecule T11TS modulates glioma-induced changes of key components of the immunological synapse in favor of T cell activation and glioma abrogation. AB - T-cell-mediated immune responses are typically low in conditions of malignant glioma which has been known to cause marked immunesuppression and dysregulate major T-cell signaling molecules. Thus, T-cell-based immunotherapies are currently in vogue in the treatment of malignant glioma. The novel glycopeptide, T11TS/S-LFA-3/S-CD58 has previously been shown by our group to be highly efficacious in glioma abrogation in in vivo and in vitro conditions. This glycopeptide ligands to the costimulatory CD2 molecule on T-cells, causing profound immune stimulation leading to glioma abrogation, suggesting probable involvement of T11TS in modulation of the T-cell signaling pathway. The present study offers a multi-targeted approach towards repair of some of the key components of the immunological synapse at the T-cell-APC interface and is therefore the first of its kind to offer a holistic model of restoration of immunological synapse components so as to trigger T-cells towards activation against glioma. The study thus indicates that the totally dysregulated molecular events at the immunological synapse in glioma are restored back to normal levels with the administration of T11TS, which finally culminates in glioma abrogation. The present study thus delineates an important T-cell signaling approach whereby T11TS acts as an anti-neoplastic agent, thus helping to chart out newer avenues in the fight against gliomas. PMID- 25027000 TI - Influence of the phase function in generalized diffuse reflectance models: review of current formalisms and novel observations. AB - Diffuse reflectance spectroscopy, which has been demonstrated as a noninvasive diagnostic technique, relies on quantitative models for extracting optical property values from turbid media, such as biological tissues. We review and compare reflectance models that have been published, and we test similar models over a much wider range of measurement parameters than previously published, with specific focus on the effects of the scattering phase function and the source detector distance. It has previously been shown that the dependence of a forward reflectance model on the scattering phase function can be described more accurately using a variable, gamma, which is a more predictive variable for reflectance than the traditional anisotropy factor, g. We show that variations in the reflectance model due to the phase function are strongly dependent on the source-detector separation, and we identify a dimensionless scattering distance at which reflectance is insensitive to the phase function. Further, we evaluate how variations in the phase function and source-detector separation affect the accuracy of inverse property extraction. By simultaneously fitting two or more reflectance spectra, measured at different source-detector separations, we also demonstrate that an estimate of gamma can be extracted, in addition to the reduced scattering and absorption coefficients. PMID- 25027001 TI - Mueller matrix polarimetry for differentiating characteristic features of cancerous tissues. AB - Polarization measurements allow one to enhance the imaging contrast of superficial tissues and obtain new polarization sensitive parameters for better descriptions of the micro- and macro- structural and optical properties of complex tissues. Since the majority of cancers originate in the epithelial layer, probing the morphological and pathological changes in the superficial tissues using an expended parameter set with improved contrast will assist in early clinical detection of cancers. We carry out Mueller matrix imaging on different cancerous tissues to look for cancer specific features. Using proper scattering models and Monte Carlo simulations, we examine the relationship between the microstructures of the samples, which are represented by the parameters of the scattering model and the characteristic features of the Mueller matrix. This study gives new clues on the contrast mechanisms of polarization sensitive measurements for different cancers and may provide new diagnostic techniques for clinical applications. PMID- 25027003 TI - Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra. AB - We are reporting on an experimental investigation of a movable diffuse reflectance spectroscopy system to extract diagnostically relevant optical properties of two-layered tissue phantoms simulating mucosae that are covered with stratified squamous epithelium. The reflectance spectra were measured at multiple sourcedetector separations using two imaging fiber bundles in contact with the phantoms, one with its optical axis perpendicular to the sample surface (perpendicular probe) and the other with its distal end beveled and optical axis tilted at 45 deg (oblique probe). Polystyrene microspheres and purified human hemoglobin were used to make tissue phantoms whose scattering and absorption properties could be well controlled and theoretically predicted. Monte Carlo simulations were used to predict the reflectance spectra for system calibration and an iterative curve fitting that simultaneously extracted the top layer reduced scattering coefficient, thickness, bottom layer reduced scattering coefficient, and hemoglobin concentration of the phantoms. The errors of the recovered parameters ranged from 7% to 20%. The oblique probe showed higher accuracy in the extracted top layer reduced scattering coefficient and thickness than the perpendicular probe. The developed system and data analysis methods provide a feasible tool to quantify the optical properties in vivo. PMID- 25027002 TI - Target-to-background enhancement in multispectral endoscopy with background autofluorescence mitigation for quantitative molecular imaging. AB - Fluorescence molecular imaging with exogenous probes improves specificity for the detection of diseased tissues by targeting unambiguous molecular signatures. Additionally, increased diagnostic sensitivity is expected with the application of multiple molecular probes. We developed a real-time multispectral fluorescence reflectance scanning fiber endoscope (SFE) for wide-field molecular imaging of fluorescent dye-labeled molecular probes at nanomolar detection levels. Concurrent multichannel imaging with the wide-field SFE also allows for real-time mitigation of the background autofluorescence (AF) signal, especially when fluorescein, a U.S. Food and Drug Administration approved dye, is used as the target fluorophore. Quantitative tissue AF was measured for the ex vivo porcine esophagus and murine brain tissues across the visible and nearinfrared spectra. AF signals were then transferred to the unit of targeted fluorophore concentration to evaluate the SFE detection sensitivity for sodium fluorescein and cyanine. Next, we demonstrated a real-time AF mitigation algorithm on a tissue phantom, which featured molecular probe targeted cells of high-grade dysplasia on a substrate containing AF species. The target-to-background ratio was enhanced by more than one order of magnitude when applying the real-time AF mitigation algorithm. Furthermore, a quantitative estimate of the fluorescein photodegradation (photobleaching) rate was evaluated and shown to be insignificant under the illumination conditions of SFE. In summary, the multichannel laser-based flexible SFE has demonstrated the capability to provide sufficient detection sensitivity, image contrast, and quantitative target intensity information for detecting small precancerous lesions in vivo. PMID- 25027004 TI - [Microbiome and nutrition. The way to a future therapy for chronic inflammatory bowel diseases?]. AB - The complex microbiome of the human gut contains an excessive amount of genetic information that is more than 100-fold larger than the human genome. In patients with inflammatory bowel disease diversity of the gut microbiome is significantly reduced and moreover specific phyla are overrepresented or underrepresented. However, the functional capacity of the microflora to generate certain metabolic products containing lipids or amino acids- and more complex regulatory substances is more important that the mere annotation of the microorganisms. Modern pharmacological approaches target the functional capacity and constitution of the microbiome. An important strategy is the development of controlled release formulations that deliver defined lipid, carbohydrate or amino acid products derived from nutritional components targeting gut areas distal to the absorption zones of the upper gastrointestinal tract. PMID- 25027005 TI - [Prevention of prostate cancer. Long-term results of the Prostate Cancer Prevention Trial (PCPT)]. PMID- 25027006 TI - Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. AB - Although the majority of Alzheimer's disease (AD) cases are sporadic, about 5% of cases are inherited in an autosomal dominant pattern as familial AD (FAD) and manifest at an early age. Mutations in the presenilin 1 (PSEN1) gene account for the majority of early-onset FAD. Here, we describe the generation of virus-free human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of patients harboring the FAD PSEN1 mutation A246E and fibroblasts from healthy age matched controls using nonintegrating episomal vectors. We have differentiated these hiPSC lines to the neuronal lineage and demonstrated that hiPSC-derived neurons have mature phenotypic and physiological properties. Neurons from mutant hiPSC lines express PSEN1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of amyloid precursor protein (APP) indicated by an increase in beta-amyloid (Abeta)42/Abeta40 ratio. FAD hiPSCs harboring disease properties can be used as humanized models to test novel diagnostic methods and therapies and explore novel hypotheses for AD pathogenesis. PMID- 25027008 TI - Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy. AB - BACKGROUND: During the last few years it has been shown in several laboratories that Celecoxib (Cx), a non-steroidal anti-inflammatory agent (NSAID) normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant to chemotherapeutical drugs used in cancer have not been described. RESULTS: Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM), inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF) production and cell proliferation in the tumor. CONCLUSION: The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs) and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects. PMID- 25027009 TI - MiR-302c inhibits tumor growth of hepatocellular carcinoma by suppressing the endothelial-mesenchymal transition of endothelial cells. AB - Endothelial cells (ECs) are critical for angiogenesis, and microRNA plays important roles in this process. In this study, we investigated the function and mechanism of miR-302c in the process of endothelial-mesenchymal transition (EndMT) in ECs. When miR-302c was overexpressed in HUVECs, the motility of the HUVECs was weakened; the expression levels of EndMT markers were also changed: vascular endothelial (VE)-cadherin was up-regulated, whereas beta-catenin, FSP1, and alpha-SMA were down-regulated. Further in vivo and in vitro experiments showed that the growth of HCC was inhibited when co-cultured or co-injected with HUVECs overexpressing miR-302c. On the contrary, when miR-302c was suppressed in HUVECs, the opposite results were observed. Reporter assays showed that miR-302c inhibited metadherin (MTDH) expression through directly binding to its 3'UTR. In addition, compared to ECs isolated from normal liver tissues of HCC patients, ECs isolated from tumor tissues expressed markedly low levels of miR-302c but high levels of MTDH. These results suggest that EC-specific miR-302c suppresses tumor growth in HCC through MTDH-mediated inhibition of EndMT. MTDH and miR-302c might provide a new strategy for anti-angiogenic therapy in HCC. PMID- 25027010 TI - Optic nerve involvement of Waldenstrom's macroglobulinemia: with autopsy findings. AB - Waldenstrom's macroglobulinemia (WM) is an indolent chronic lymphoproliferative disorder within the spectrum of lymphoplasmacytic lymphoma (LPL), characterized by a proliferation of plasmacytoid lymphocytes and the production of monoclonal IgM. Although, peripheral neurologic complications commonly occurs due to hyperviscosity in WM, central nervous system (CNS) involvement is very rare. Herein, we present the case of a 67-year-old man who initially presented with progressive visual loss and was diagnosed as WM/LPL with a very aggressive clinical course. He underwent chemotherapy with high dose methotrexate (MTX) plus cytarabine (Ara-C). However, he died and findings of a subsequent autopsy revealed the presence of lymphoplasmacytoid cells in the optic nerve. PMID- 25027011 TI - Hippocrates: the forefather of neurology. AB - Hippocrates is one of the most influential medical doctors of all times. He started observing and experimenting in times of mysticism and magic. He carried a holistic and humanitarian approach to the patient with examination as the principal approach-inspection, palpation and auscultation are still the most important tools in diagnosing algorithms of today. He had immense experience with the human body most likely due to numerous wound treatments he had performed; some even believe he performed autopsies despite the negative trend at the time. Hippocrates identified the brain as the analyst of the outside world, the interpreter of consciousness and the center of intelligence and willpower. Interestingly, Hippocrates was aware of many valid concepts in neurology; his treatise On the Sacred Disease was the most important for understanding neurology and epilepsy. His other ideas pioneered modern day neurology mentioning neurological diseases like apoplexy, spondylitis, hemiplegia, and paraplegia. Today, 10 % of neurological Pubmed and 7 % of neuroscience Scopus reviews mention Corpus Hippocraticum as one of the sources. Therefore, Hippocrates may be considered as the forefather of neurology. PMID- 25027013 TI - Stump appendicitis: a rare and unusual complication after appendectomy. Case report and review of the literature. AB - INTRODUCTION: Stump appendicitis is a rare but important complication that can occour after an open or laparoscopic appendectomy. Although it represents a recognized serious condition that should not be overlooked, it is not often considered by surgeons within the differential diagnoses faced with a patient presenting right iliac fossa abdominal pain, particularly those who present a previous history of appendectomy. MATERIAL OF STUDY: A comprehensive review of English literature was performed and 87 cases of stump appendicitis were identified. Each case was charted based on 10 variables and data were analyzed. One original case of stump appendicitis after open appendectomy treated at our institution is also described and taken as a model. DISCUSSION: Several factors may contribute to the etiology of stump appendicitis, mainly related to the length of the residual tissue after appendectomy. A delay in diagnosis, possibly misled by a previous history of appendectomy, represents a risk of complications and possible stump perforation. The imaging studies, especially CT scan, seem to be helpful tools in getting the earliest possible diagnosis. CONCLUSION: Surgeons should be aware of the occurrence of this rare but dangerous entity, in order to avoid a delay in diagnosis and in the appropriate therapeutic choice. We want to emphasize also the technical recommendations to be respected in course of appendectomy. KEY WORDS: Appendectomy, Appendicular residue, Diagnosis, Stump appendicitis. PMID- 25027012 TI - The association between the LRRK2 G2385R variant and the risk of Parkinson's disease: a meta-analysis based on 23 case-control studies. AB - Clinical diagnosis of Parkinson's disease (PD) is essential but misdiagnosis of PD-like diseases is quite common. LRRK2 G2385R variants have been extensively examined for the association to the risk of Parkinson's disease. However, results from different studies are inconsistent. The purpose of this meta-analysis was to assess the association between the LRRK2 G2385R variants and the risk of PD. A systematic literature search was performed for 6 databases up to January of 2014 to identify case-control studies involving LRRK2 G2385R variants and the risk of PD. A total of 12,915 cases and 12,451 controls in 23 case-control studies were included in this meta-analysis. The results indicated that the variant A allele carriers (GA + AA) increased risk of PD when compared with the homozygote GG (GA + AA vs. GG: OR = 2.4, 95 % CI = 1.97 to 2.92, P < 0.00001). In the subgroup analysis by ethnicity, increased risks were identified among Chinese (OR = 2.69, 95 % CI = 2.1-3.45, P < 0.00001) as well as in non-Chinese (OR = 2.17, 95 % CI 1.75-2.69, P < 0.00001). In the subgroup analysis by age of onset, significant associations were found in both later-onset PD (LOPD) and early-onset PD (EOPD) cases. And there was no significant difference of the allele frequency between patients with LOPD and EOPD (OR = 1.18, 95 % CI = 0.77-1.80, P = 0.45). Our results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD. Meanwhile, it is possible that age is not the risk factor to facilitate G2385R gene mutation. PMID- 25027014 TI - Stigma and mental health treatment of adolescents with depression in jordan. AB - Stigma is a fundamental barrier to seeking and engaging in mental health treatment for individuals managing depression. This study examines stigma perceptions of mental health treatment for Arab adolescents managing depression using a vignette survey completed by adults in public spaces in Amman, Jordan (n = 108). The vignette was systematically changed across four different conditions that varied the described youth's gender and whether or not they were receiving treatment for their depression. Two-way ANOVAs found that gender and receipt of mental health treatment influenced perceptions of stigma. Seeking treatment, however, did not increase perceived stigma, and receiving mental health treatment rather than no treatment was found as more likely to be a helpful approach for both males and females. Findings indicate that personal level stigma may have greater effects on females whereas public stigma may exert more influence on males. Participants endorsed that adolescents with depression are most likely to be helped when a family sought treatment rather than not seeking treatment. Findings also indicate that the community seems to appreciate the need for treatment and the likelihood of benefiting from formal mental health services. PMID- 25027015 TI - A qualitative exploration of service users' information needs and preferences when receiving a serious mental health diagnosis. AB - Helpful strategies for communicating news of a serious mental health diagnosis are poorly understood. This study explored service users' preferences for how they would like clinicians to deliver such news when a diagnosis of mental illness is made. Qualitative interviews were conducted with forty-five individuals identifying with serious mental illness in eleven community based mental health facilities. Inductive thematic analysis resulted in eight primary themes. Five themes related to the structure and content of the discussion; including a focus on information exchange, using an individualized collaborative partnership paradigm, addressing stigma, balancing hope with realism, and recognizing the dynamic nature of diagnosis. The remaining themes related to the involvement of others; including the importance of clinicians' communication and relationship skills, involvement and education of carers, and offering an opportunity for peer support. The product of the synthesis of themes is a step wise model for communicating news of mental health diagnosis. PMID- 25027016 TI - Study of oleanolic acid on the estrodiol production and the fat production of mouse preadipocyte 3T3-L1 in vitro. AB - The women during the menopause period have an increased tendency for the obesity, which represents the more fat production than during the premenopausal period. Although this is not beneficial overall, it could provide a compensatory source for the estrogen production for the menopausal women. So it would be meaningful to find an agent that could inhibit the fat production while does not disturb the total estrogen production by fat tissues. In the present study, the effect of oleanolic acid (OA) on the fat production and the total estrogen production of the differentiating mouse preadipocyte 3T3-L1 as well as the mechanisms behind those effects were preliminarily investigated. The cell line 3T3-L1 was chosen as the model cell because it is usually used for the research about the obesity. During the induced differentiation of 3T3-L1 cells, cells were intervened continuously with OA. The fat production was determined with the oil red staining assay and the total estrogen production was measured with the ELISA assay. Finally, the expression patterns for important genes of the fat production and the estrogen production were studied, respectively with the real-time fluorescence quantitative PCR (qPCR). The results showed that for the differentiating 3T3-L1 cells, OA could significantly inhibit the fat production and did not disturb the total estrogen production significantly. In the mechanism studies, OA was found to significantly down-regulate ACC, the key gene for fat synthesis, which could explain the inhibitory effect of OA on the fat production; OA was also found to significantly up-regulate CYP11A1, CYP17, CYP19, the key genes for the estrogen synthesis and significantly down-regulate CYP1A1, the key gene for the estrogen decomposition, which preliminarily explained the lack of the effect of OA on the total estrogen production. In conclusion, OA was found able to inhibit the fat production while maintaining the total estrogen level and the mechanisms for the above findings were preliminarily clarified, which suggests that OA may be useful to treat the menopausal obesity. PMID- 25027017 TI - Developing and using expert systems and neural networks in medicine: a review on benefits and challenges. AB - Complicacy of clinical decisions justifies utilization of information systems such as artificial intelligence (e.g. expert systems and neural networks) to achieve better decisions, however, application of these systems in the medical domain faces some challenges. We aimed at to review the applications of these systems in the medical domain and discuss about such challenges. Following a brief introduction of expert systems and neural networks by representing few examples, the challenges of these systems in the medical domain are discussed. We found that the applications of expert systems and artificial neural networks have been increased in the medical domain. These systems have shown many advantages such as utilization of experts' knowledge, gaining rare knowledge, more time for assessment of the decision, more consistent decisions, and shorter decision making process. In spite of all these advantages, there are challenges ahead of developing and using such systems including maintenance, required experts, inputting patients' data into the system, problems for knowledge acquisition, problems in modeling medical knowledge, evaluation and validation of system performance, wrong recommendations and responsibility, limited domains of such systems and necessity of integrating such systems into the routine work flows. We concluded that expert systems and neural networks can be successfully used in medicine; however, there are many concerns and questions to be answered through future studies and discussions. PMID- 25027018 TI - The impact of acute kidney injury on the long-term risk of stroke. AB - BACKGROUND: The incidence of acute kidney injury (AKI) requiring dialysis in hospitalized patients is increasing; however, information on the long-term incidence of stroke in patients surviving to discharge after recovering from AKI after dialysis has not been reported. METHODS AND RESULTS: Patients that survived after recovery from dialysis-requiring AKI during index hospitalizations from 1999 to 2008 were identified in nationwide administrative registries. The risk of de novo stroke and death were analyzed with time-varying Cox proportional hazard models. The results were validated by a critical care database. We enrolled 4315 patients in the AKI-recovery group (men, 57.7%; mean age, 62.8+/-16.8 years) and matched 4315 control subjects as the non-AKI group by propensity scores. After a median follow-up period of 3.36 years, the incident stroke rate was 15.6 per 1000 person-years. The AKI-recovery group had higher risk (hazard ratio: 1.25; P=0.037) and higher severity of stroke events than the non-AKI group, regardless of progression to subsequent chronic kidney disease. The rate of incident stroke was not statistically different in those with diabetes alone (without AKI) and in those with AKI alone (without diabetes) after hospital discharge (P=0.086). Furthermore, the risk of mortality in the AKI-recovery group was higher than in the non-AKI group (hazard ratio: 2.4; P<0.001). CONCLUSIONS: The patients who recovered from AKI had a higher incidence of developing incident stroke and mortality than the patients without AKI, and the impact was similar to diabetes. Our results suggest that a public health initiative is needed to enhance postdischarge follow-up of renal function and to control the subsequent incidence of stroke among patients who recover from AKI after dialysis. PMID- 25027019 TI - Laparoscopic extravesical vesicovaginal fistula repair: our technique and 15-year experience. AB - INTRODUCTION AND HYPOTHESIS: Two types of laparoscopic vesicovaginal fistula (VVF) repairs, the traditional transvesical (O'Conor) and extravesical techniques, dominate the literature. We present our 15-year experience of primary and recurrent cases of VVF utilizing an extravesical technique, which we first described in 1999. METHODS: An IRB approved retrospective study revealed 44 female patients with either primary or recurrent VVF. Laparoscopic extravesical repair was performed without an omental flap in the majority of cases. A three layer closure technique was performed utilizing a double-layer bladder closure and a single-layer vaginal closure followed by bladder testing. A suprapubic catheter was utilized for 2-3 weeks postoperatively for bladder decompression. RESULTS: A review of our experience reveals a 97 % (32 out of 33) cure for primary VVF and 100 % (11 out of 11) rate for recurrent fistulas, with an overall cure rate of 98 % (43 out of 44) at a mean follow-up of 17.3 months (range 3-64). An omental flap was not utilized in 98 % of patients (43 out of 44), with a success rate of 98 % (42 out of 43). The mean estimated blood loss was 39 mL (range 0-450), mean hospital stay was 1.1 days (range 1-3), and none of the patients suffered any major intra- or postoperative complications. None of the patients required a conversion to open laparotomy. CONCLUSIONS: Based upon our experience we believe that performing laparoscopic extravesical VVF repair using a three-layer closure technique without an interposition omentum is a safe, effective, minimally invasive technique with excellent cure rates in an experienced surgeon's hands. PMID- 25027020 TI - Vaginal hysterectomy: past, present, and future. AB - Vaginal hysterectomy is the oldest and least invasive of the hysterectomy techniques and fulfills the evidence-based requirements as the preferred route of hysterectomy for benign gynecologic disease. Currently, vaginal hysterectomy is commonly utilized for treating uterine prolapse, but despite proven safety and effectiveness, the use of vaginal hysterectomy for treating non-prolapse conditions has been and remains underutilized in surgical practice. Improving the use of vaginal hysterectomy in the future will likely depend on addressing the key issues of training and maintaining skills in the technique and increasing awareness of the scientific evidence supporting its use. PMID- 25027021 TI - A prospective observational study of lower urinary tract symptoms before and after surgical removal of a large pelvic mass. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the impact of the surgical removal of a large pelvic mass on preexisting lower urinary tract symptoms (LUTS) and function. METHODS: This was a prospective study of planned surgical management of women with a large pelvic mass (uterine or ovarian mass >= 7 cm on pelvic ultrasound) who also reported bothersome LUTS (urinary frequency, urgency, incontinence and/or voiding dysfunction). Assessment included structured history and examination, completion of the short forms of the Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7), a 3-day bladder diary and multi-channel urodynamics (UDS) at baseline and 3 months postoperatively. The primary outcome was a reduction in the total mean scores of the UDI-6 and IIQ-7. Secondary outcomes were a change in bladder diary and UDS parameters. Univariate analysis and paired t test were used in the statistical analysis. RESULTS: Twenty-nine women underwent surgical management of a pelvic mass. The most common preoperative urinary symptom was urinary urgency. Two women had overt urinary retention that resolved completely postoperatively. All women completed pre- and postoperative UDI-6 and IIQ-7. The UDI-6 and IIQ-7 demonstrated a highly significant reduction in the mean total scores of 66%, signifying symptom and quality of life improvement. Bladder diary parameters showed significant reductions in daytime urinary frequency and stress incontinence episodes. Maximum and average voided volumes increased by a mean of 60 ml. Only 14 women underwent postoperative UDS. CONCLUSIONS: This study provides evidence that the majority of LUTS present preoperatively improve significantly or resolve completely following removal of a >= 7-cm pelvic mass. PMID- 25027022 TI - The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy. AB - BACKGROUND: To study the expression of D2R, MGMT and VEGF for clinical significance in pituitary adenomas, and to predict the potential curative medical therapy of dopamine agonists, temozolomide and bevacizumab on pituitary adenomas. METHODS: Immunohistochemistry and western blot were performed to detect the expression of expression of D2R, MGMT and VEGF in pituitary adenoma tissue samples. The ratio of high expression of D2R, MGMT or VEGF in different subtypes of PA was compared by the use of chi-squared tests. The relationships between D2R, MGMT and VEGF expression were assessed by the Spearman rank correlation test. The association between their expression and clinical parameters was analyzed using a chi-squared test, or Fisher's exact probability test when appropriate. RESULTS: The data showed that in 197 different histological subtypes of pituitary adenomas (PAs), 64.9% of them were D2R high expression, 86.3% were MGMT low expression and 58.9% were VEGF high expression. D2R high expression existed more frequently in PRL- and GH- secreting PAs. MGMT low expression existed in all PA subtypes. VEGF high expression existed more frequently in PRL, ACTH, FSH secreting and non-functioning PAs. The data of western blot also support the results. Spearman's rank correlation analysis showed that expression of MGMT was positively associated with D2R (r = 0.154, P = 0.031) and VEGF (r = 0.161, P = 0.024) in PAs, but no correlation was showed between D2R and VEGF expression (r = -0.025, P = 0.725 > 0.05). The association between their expression and clinical parameters was analyzed using a chi-squared test, or Fisher's exact probability test when appropriate, but the result showed no significant association. CONCLUSIONS: PRL-and GH-secreting PAs exist high expression of D2R, responding to dopamine agonists; Most PAs exist low expression of MGMT and high expression of VEGF, TMZ or bevacizumab treatment could be applied under the premise of indications. PMID- 25027023 TI - Phenanthrene and phenylpropanoid constituents from the roots of Cymbidium Great Flower 'Marylaurencin' and their antimicrobial activity. AB - Two new phenanthrenes, and one new phenylpropanoid, named ephemeranthoquinone C (1), and marylaurencinols C (2) and D (3), were isolated from the roots of Cymbidium Great Flower 'Marylaurencin', respectively. These structures were determined on the basis of 2D NMR experiments. The compounds were tested for antimicrobial activity against Bacillus subtilis, Klebsiella pneumoniae, and Trichophyton rubrum. PMID- 25027024 TI - Transcriptional activation of a geranylgeranyl diphosphate synthase gene, GGPPS2, isolated from Scoparia dulcis by treatment with methyl jasmonate and yeast extract. AB - A cDNA clone, designated SdGGPPS2, was isolated from young seedlings of Scoparia dulcis. The putative amino acid sequence of the translate of the gene showed high homology with geranylgeranyl diphosphate synthase (GGPPS) from various plant sources, and the N-terminal residues exhibited the characteristics of chloroplast targeting sequence. An appreciable increase in the transcriptional level of SdGGPPS2 was observed by exposure of the leaf tissues of S. dulcis to methyl jasmonate, yeast extract or Ca(2+) ionophore A23187. In contrast, SdGGPPS1, a homologous GGPPS gene of the plant, showed no or only negligible change in the expression level upon treatment with these stimuli. The truncated protein heterologously expressed in Escherichia coli in which the putative targeting domain was deleted catalyzed the condensation of farnesyl diphosphate and isopentenyl diphosphate to liberate geranylgeranyl diphosphate. These results suggested that SdGGPPS2 plays physiological roles in methyl jasmonate and yeast extract-induced metabolism in the chloroplast of S. dulcis cells. PMID- 25027025 TI - Electronic Health Records (EHRs) in the oncology clinic: how clinician interaction with EHRs can improve communication with the patient. PMID- 25027026 TI - Antifungal and cytotoxicity activities of the fresh xylem sap of Hymenaea courbaril L. and its major constituent fisetin. AB - BACKGROUND: The great potential of plants as Hymenaea courbaril L (jatoba) has not yet been throughly explored scientifically and therefore it is very important to investigate their pharmacological and toxicological activities to establish their real efficacy and safety. This study investigated the cytotoxicity of xylem sap of Hymenaea courbaril L and its bioactivity against the fungi Cryptococcus neoformans species complex and dermatophytes. METHODS: The fresh xylem sap of H. courbaril was filtered resulting in an insoluble brown color precipitate and was identified as fisetin. In the filtrate was identified the mixture of fisetinediol, fustin, 3-O-methyl-2,3-trans-fustin and taxifolin, which were evaluated by broth microdilution antifungal susceptibility testing against C. neoformans species complex and dermatophytes. The fresh xylem sap and fisetin were screened for cytotoxicity against the 3T3-A31 cells of Balb/c using neutral red uptake (NRU) assay. RESULTS: The fresh xylem sap and the fisetin showed higher in vitro activity than the filtrate. The xylem sap of H. courbaril inhibited the growth of dermatophytes and of C. neoformans with minimal inhibition concentration (MIC) < 256 MUg/mL, while the fisetin showed MIC < 128 MUg/mL for these fungi. Fisetin showed lower toxicity (IC50 = 158 MUg/mL) than the fresh xylem sap (IC50 = 109 MUg/mL). CONCLUSION: Naturally occurring fisetin can provide excellent starting points for clinical application and can certainly represent a therapeutic potential against fungal infections, because it showed in vitro antifungal activity and low toxicity on animal cells. PMID- 25027027 TI - Microfluidic molecular assay platform for the detection of miRNAs, mRNAs, proteins, and posttranslational modifications at single-cell resolution. AB - Cell signaling is a dynamic and complex process. A typical signaling pathway may begin with activation of cell surface receptors, leading to activation of a kinase cascade that culminates in induction of messenger RNA (mRNA) and noncoding microRNA (miRNA) production in the nucleus, followed by modulation of mRNA expression by miRNAs in the cytosol, and end with production of proteins in response to the signaling pathway. Signaling pathways involve proteins, miRNA, and mRNAs, along with various forms of transient posttranslational modifications, and detecting each type of signaling molecule requires categorically different sample preparation methods such as Western blotting for proteins, PCR for nucleic acids, and flow cytometry for posttranslational modifications. Since we know that cells in populations behave heterogeneously,(1) especially in the cases of stem cells, cancer, and hematopoiesis, there is need for a new technology that provides capability to detect and quantify multiple categories of signaling molecules in intact single cells to provide a comprehensive view of the cell's physiological state. In this Technology Brief, we describe our automated microfluidic platform with a portfolio of customized molecular assays that can detect nucleic acids, proteins, and posttranslational modifications in single intact cells with >95% reduction in reagent requirement in under 8 h. PMID- 25027028 TI - Application of geographical information system (GIS) technology in the control of Buruli ulcer in Ghana. AB - BACKGROUND: Buruli ulcer (BU) disease is a chronic debilitating skin disease caused by Mycobacteriumulcerans. It is associated with areas where the water is slow-flowing or stagnant. Policy makers take the necessary strategic and policy decisions especially where to target interventions based on available evidence including spatial distribution of the disease. Unfortunately, there is limited information on the spatial distribution of BU in Ghana. The aim of the study was to use Geographical Information System (GIS) technology to show the spatial distribution and hot spots of BU in Greater Accra and Eastern Regions in Ghana. The information could then be used by decision makers to make the necessary strategic and policy decisions, especially where to target intervention. METHODS: We conducted a community case search and spatial mapping in two districts in Eastern region (Akuapem South and Suhum- Kraboa-Coaltar) and two districts in Greater Accra region (Ga West and Ga South Municipalities) of Ghana to identify the spatial distribution of BU cases in the communities along the Densu River. These municipalities are already known to the Ministry of Health as having high case load of BU. Structured questionnaires on demographic characteristics, environmental factors and general practices were administered to the cases.Using the E-trex Garmin Geographical Positioning System (GPS), the location of the case patient was marked along with any important attributes of the community. ArcGIS was used to generate maps showing BU distribution and hot spots. RESULTS: Two hundred and fifty-seven (257) probable BU patients were enrolled in the study after the case search. These cases and their houses (or homes) were located with the GPS. The GIS maps generated showed a varying distribution of BU in the various communities. We observed clustering of BU patients downstream of the Densu River which had hitherto not been observed. CONCLUSIONS: There is clustering of BU in areas where the river was most contaminated. The identified hot spots for BU should be targeted for interventions by policy makers to ensure effective control of BU in Ghana. PMID- 25027031 TI - Hierarchical growth of curved organic nanowires upon evaporation induced self assembly. AB - Self-assembly of a TTF derivative capable of forming self-assembled monolayers at the surface of graphite displays hierarchical growth of multilayers and concentric nanorings upon evaporation of the solvent as observed by AFM. PMID- 25027030 TI - Sevelamer is cost effective versus calcium carbonate for the first-line treatment of hyperphosphatemia in new patients to hemodialysis: a patient-level economic evaluation of the INDEPENDENT-HD study. AB - BACKGROUND: The recent multicenter, randomized, open-label INDEPENDENT study demonstrated that sevelamer improves survival in new to hemodialysis (HD) patients compared with calcium carbonate. The objective of this study was to determine the cost-effectiveness of sevelamer versus calcium carbonate for patients new to HD, using patient-level data from the INDEPENDENT study. STUDY DESIGN: Cost-effectiveness analysis. SETTING AND POPULATION: Adult patients new to HD in Italy. MODEL, PERSPECTIVE, TIMEFRAME: A patient-level cost-effectiveness analysis was conducted from the perspective of the Servizio Sanitario Nazionale, Italy's national health service. The analysis was conducted for a 3-year time horizon. The cost of dialysis was excluded from the base case analysis. INTERVENTION: Sevelamer was compared to calcium carbonate. OUTCOMES: Total life years (LYs), total costs, and the incremental cost per LY gained were calculated. Bootstrapping was used to estimate confidence intervals around LYs, costs, and cost-effectiveness and to calculate the cost-effectiveness acceptability curve. RESULTS: Sevelamer was associated with a gain of 0.26 in LYs compared to calcium carbonate, over the 3-year time horizon. Total drug costs were ?3,282 higher for sevelamer versus calcium carbonate, while total hospitalization costs were ?2,020 lower for sevelamer versus calcium carbonate. The total incremental cost of sevelamer versus calcium carbonate was ?1,262, resulting in a cost per LY gained of ?4,897. The bootstrap analysis demonstrated that sevelamer was cost effective compared with calcium carbonate in 99.4 % of 10,000 bootstrap replicates, assuming a willingness-to-pay threshold of ?20,000 per LY gained. LIMITATIONS: Data on hospitalizations was taken from a post hoc retrospective chart review of the patients included in the INDEPENDENT study. Patient quality of life or health utility was not included in the analysis. CONCLUSIONS: Sevelamer is a cost effective alternative to calcium carbonate for the first-line treatment of hyperphosphatemia in new to HD patients in Italy. PMID- 25027032 TI - A highly unradiogenic lead isotopic signature revealed by volcanic rocks from the East Pacific Rise. AB - Radiogenic isotopes in oceanic basalts provide a window into the different geochemical components defining the composition of Earth's mantle. Here we report the discovery of a novel geochemical signature in volcanic glasses sampled at a sub-kilometre scale along the East Pacific Rise between 15 degrees 37'N and 15 degrees 47'N. The most striking aspect of this signature is its unradiogenic lead ((206)Pb/(204)Pb=17.49, (207)Pb/(204)Pb=15.46 and (208)Pb/(204)Pb=36.83). In conjunction with enriched Sr, Nd and Hf signatures, Pb isotopes depict mixing lines that trend away from any known mantle end-members. We suggest that this unradiogenic lead component sampled by magmatic melts corresponds to a novel upper mantle reservoir that should be considered in the Pb isotope budget of the bulk silicate Earth. Major, trace element and isotope compositions are suggestive of an ancient and lower continental origin for this unradiogenic lead component, possibly sulphide-bearing pyroxenites that were preserved even after prolonged stirring within the ambient upper mantle. PMID- 25027033 TI - Synthesis of N,N,O-chelate zinc and aluminum complexes and their catalysis in the ring-opening polymerization of epsilon-caprolactone and rac-lactide. AB - Zinc and aluminum complexes supported by N,N,O-chelate ligands were synthesized and characterized. The zinc complexes [Zn(Et){2-{OC(R(1))=CH}-6-(3,5 Me2C3HN2)C5H3N}]2 (R(1) = Ph, 1a; R(1) = Bu(t), 1b) were synthesized by reaction of ligand precursors 2-{R(1)C(O)CH2}-6-(3,5-Me2C3HN2)C5H3N (R(1) = Ph, HL(1); R(1) = Bu(t), HL(2)) with ZnEt2. The aluminum complexes [Al(R)2{2-{OC(Ph)=CH}-6 (3,5-Me2C3HN2)C5H3N}] (R = Me, 2a; R = Et, 2b) were synthesized by reaction of HL(1) with AlMe3 or AlEt3. Similar treatment of the ligand precursor 2 {Ph2C(OH)CH2}-6-(3,5-Me2C3HN2)C5H3N (HL(3)) with AlMe3 or AlEt3 afforded aluminum complexes [Al(R)2{2-{OC(Ph)2CH2}-6-(3,5-Me2C3HN2)C5H3N}] (R = Me, 3a; R = Et, 3b). The complexes were characterized by (1)H and (13)C{(1)H} NMR spectroscopy, elemental analyses and single crystal X-ray diffraction (for 1a, 1b, 2b and 3a). All the complexes are active to catalyze the ring-opening polymerization of epsilon-caprolactone in the presence of BnOH, leading to polycaprolactone with good molecular weight control and relatively narrow molecular weight distribution. The zinc complexes/BnOH showed good catalytic activity for the ring opening polymerization of rac-lactide, displaying good molecular weight control and very narrow molecular weight distributions. The PLA catalyzed by complex 1a/BnOH showed somewhat hetero-stereoselectivity with Pr up to 0.73 when the polymerization was performed in THF at 0 degrees C. Complex 1a/BnOH also catalyzed block copolymerization of epsilon-CL and rac-LA with good molecular weight control of the polymer. Kinetic studies of the polymerization reactions were performed. PMID- 25027034 TI - Embolization of percutaneous transhepatic portal venous access tract with N-butyl cyanoacrylate. AB - OBJECTIVE: To evaluate the safety and feasibility of N-butyl cyanoacrylate (N BCA) embolization of percutaneous transhepatic portal venous access tract and to establish an appropriate technique. METHODS: 40 consecutive patients underwent percutaneous transhepatic portal venous intervention for various reasons. Embolization of percutaneous transhepatic portal venous access tract was performed after the procedure in all of the patients using N-BCA and Lipiodol(r) (Lipiodol Ultra Fluide; Laboratoire Guerbet, Aulnay-sous-Bois, France) mixture. Immediate ultrasonography and fluoroscopy were performed to evaluate perihepatic haematoma formation and unintended embolization of more than one segmental portal vein. Follow-up CT was performed, and haemoglobin and haematocrit levels were checked to evaluate the presence of bleeding. RESULTS: Immediate haemostasis was achieved in all of the patients, without development of perihepatic haematoma or unintended embolization of more than one segmental portal vein. Complete embolization of percutaneous access tract was confirmed in 39 out of 40 patients by CT. Seven patients showed decreased haemoglobin and haematocrit levels. Other complications included mild pain at the site of embolization and mild fever, which resolved after conservative management. 16 patients died during the follow up period owing to progression of the underlying disease. CONCLUSION: Embolization of percutaneous transhepatic portal vein access tract with N-BCA is feasible and technically safe. With the appropriate technique, N-BCA can be safely used as an alternate embolic material since it is easy to use and inexpensive compared with other embolic materials. ADVANCES IN KNOWLEDGE: This is the first study to investigate the efficacy of N-BCA for percutaneous transhepatic portal venous access tract embolization. PMID- 25027035 TI - Effects of aerobic exercise during hemodialysis on physical functional performance and depression. AB - Previous studies have concluded that exercise training is beneficial to patients on hemodialysis (HD). Results, however, have shown that differences in the type, intensity, and frequency of physical exercise lead to variability in its effects on physical functional performance and depression. Further research is thus warranted. Our aim was to evaluate the effects of aerobic exercise on physical functional performance and depression during HD. Using a pretest-posttest control group design, we recruited HD patients and nonrandomly assigned them to an exercise group (n = 13) that completed a 12-week aerobic exercise program during HD or a control group (n = 11) that did no exercise during HD. The primary outcome measures were physical functional performance, as evaluated by the 6-min walk test and the sit-to-stand test, and depression, as evaluated by the Beck Depression Inventory II. The secondary outcome measures were albumin and triglyceride levels and hematocrit. Results revealed significant between-group differences in physical functional performance and depression but not in albumin level, hematocrit, or triglyceride level. Findings suggest that exercise may play a critical role in physical functional performance and may decrease depression. Exercise should be encouraged and performed during HD in HD centers. PMID- 25027036 TI - Fatigue and physical activity after myocardial infarction. AB - BACKGROUND: Fatigue is prevalent after myocardial infarction (MI) and is a barrier to physical activity (PA). Because PA is an important health behavior in preventing or delaying recurrent MIs, examining the influence of biophysical markers and fatigue on PA is important as a prerequisite to developing effective interventions. OBJECTIVE: This study compared PA in 34 men and 38 women, aged 65 and older, 6-8 months post MI, and examined the influence of biophysiological measures and fatigue on PA in this sample. METHODS: Using a cross-sectional descriptive correlational design, adults completed a demographic form that included documentation of blood pressure, heart rate, height and weight; the Revised Piper Fatigue Scale (RPFS), and the Community Healthy Activities Model Program for Seniors Physical Activity Questionnaire for Older Adults, and blood collection for measurement of hemoglobin (Hgb), interleukin-6, and B-natriuretic peptide. RESULTS: There were no differences in frequency of PA between older men and older women; however, men reported a higher intensity of PA (p = .011). When controlling for sex, age, and biophysiological measures, the RPFS significantly explained 16% of the variance in the frequency of PA (p = .03), with no individual subscale serving as a significant predictor. The RPFS behavior/severity subscale explained 31% of the variance in energy expended on all PA (p < .001) and 40% of the variance in energy expended on moderate intensity PA (p < .001). CONCLUSION: The older adults participating in this study did not participate in the recommended levels of PA, and fatigue significantly influenced PA post MI. PMID- 25027037 TI - STAT1 plays a role in TLR signal transduction and inflammatory responses. AB - Activation of the Toll-like receptor (TLR) family of innate immune sensors stimulates multiple signal transduction pathways. Previous studies have suggested that TLR2, TLR4 and TLR9 induce serine phosphorylation of Signal Transducers and Activators of Transcription-1 (STAT1) at residue 727 (S727), although its role in TLR signaling was unclear. We report here that STAT1 rapidly undergoes phosphorylation following TLR4 challenge with lipopolysaccharide (LPS) in a model of LPS hypersensitivity in vivo. Importantly, genetic ablation of STAT1 protected against LPS-induced lethality suggesting that STAT1 may have a key role in TLR induced inflammation. We have found that multiple TLRs induce Ser727 phosphorylation of STAT1, which is dependent on MyD88 and TRIF signaling, but independent of interferon (IFN) regulatory factor (IRF)-3, IRF7 and the IFN receptor complex, suggesting that activation is a direct TLR response rather than autocrine activation via IFN. Importantly, we found that STAT1 interacts with tumor necrosis factor (TNF) receptor-associated factor-6 (TRAF6), a key mediator of TLR signaling after TLR challenge and that following activation, STAT1 translocates to the nucleus. Critically, macrophages generated from mice in which the S727 residue was replaced with alanine (STAT1 S727A mice) display significantly reduced TNFalpha protein production, but not reduced interleukin-6 or RANTES protein in response to multiple TLR challenges, as compared with wild type macrophages. These results clearly demonstrate cross-talk between the TLR and JAK/STAT signaling pathways with direct recruitment of STAT1 by TRAF6 and that the direct activation of STAT1 by TLR signaling suggests a crucial role for STAT1 in TLR-induced inflammation. PMID- 25027038 TI - The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT. AB - Over the last decade, the significance of the homeostatic CC chemokine receptor-7 and its ligands CC chemokine ligand-19 (CCL19) and CCL21, in various types of cancer, particularly mammary carcinoma, has been highlighted. The chemokine receptor CCX-CKR is a high-affinity receptor for these chemokine ligands but rather than inducing classical downstream signalling events promoting migration, it instead sequesters and targets its ligands for degradation, and appears to function as a regulator of the bioavailability of these chemokines in vivo. Therefore, in this study, we tested the hypothesis that local regulation of chemokine levels by CCX-CKR expressed on tumours alters tumour growth and metastasis in vivo. Expression of CCX-CKR on 4T1.2 mouse mammary carcinoma cells inhibited orthotopic tumour growth. However, this effect could not be correlated with chemokine scavenging in vivo and was not mediated by host adaptive immunity. Conversely, expression of CCX-CKR on 4T1.2 cells resulted in enhanced spontaneous metastasis and haematogenous metastasis in vivo. In vitro characterisation of the tumourigenicity of CCX-CKR-expressing 4T1.2 cells suggested accelerated epithelial-mesenchymal transition (EMT) revealed by their more invasive and motile character, lower adherence to the extracellular matrix and to each other, and greater resistance to anoikis. Further analysis of CCX-CKR-expressing 4T1.2 cells also revealed that transforming growth factor (TGF)-beta1 expression was increased both at mRNA and protein levels leading to enhanced autocrine phosphorylation of Smad 2/3 in these cells. Together, our data show a novel function for the chemokine receptor CCX-CKR as a regulator of TGF-beta1 expression and the EMT in breast cancer cells. PMID- 25027039 TI - Anthropometric characteristics of Iranian military personnel and their changes over recent years. AB - BACKGROUND: In most armies, clothes, equipment and weapons are designed according to the physical characteristics and anthropometric data of soldiers. OBJECTIVE: To study the anthropometric characteristics of Iranian army force and their changes over recent years. METHODS: 12 635 Iranian military personnel aged between 18 and 30 years with tenure of <10 years who were normally engaged in educational military activities and soldiers were enrolled in this study, which was conducted in 2010. RESULTS: The military personnel had a mean+/-SD stature of 174.1+/-6.3 cm and sitting height of 89.7+/-3.8 cm. They had a mean weight of 70.0 kg, and body mass index of 23.3 kg/m2. CONCLUSION: The stature of Iranian army has increased by 14 mm during the last 15 years. The stature was less than those of the western countries and 3-4 cm more than those of East Asian personnel. The body mass index has had an increasing trend. PMID- 25027040 TI - Morbidity profile of child labor at gem polishing units of Jaipur, India. AB - BACKGROUND: There are millions of working children worldwide. Several causes are suggested for this social evil of which poverty plays a significant role in whether a child will work. OBJECTIVE: To determine the morbidity profile in the working children of gem polishing units of Jaipur, India and assess some of its associated socio-economic factors. METHODS: The present cross-sectional study included 586 gem polishing working children. Using interview, the demographic characteristics, occupational and clinical history of participants were recorded. The reason for taking up the job, income from the job and their desire to attend the school were also asked to assess the social causes of child labor in this region. RESULTS: The mean+/-SD age of the working children was 11.3+/-5.3 years. In most of the instances, parents compelled the child to take up the job. Supposed to increase the family income substantially, the child labor activity failed to do so. On the other hand, the children suffered from several occupational health problems like eyestrain, headache, gastrointestinal complaints (eg, abdominal pain, nausea, vomiting, and diarrhea), musculoskeletal symptoms (e.g., back pain, pain in limbs, neck pain, and joint pains) and skin diseases (e.g., scabies, dermatitis). CONCLUSION: It seems that the social factors forcing the children to work in the studied region, result in deterioration of their health and affect their growth. PMID- 25027041 TI - Respiratory diseases in agate grinding workers in Iran. AB - BACKGROUND: Agate is a hard silica stone with bands of various colors, which is used in jewelry. The agate grinding workers are exposed to silica dust. OBJECTIVE: To determine the prevalence of respiratory diseases in agate grinding workers and the associated factors. METHODS: In this cross-sectional study, 170 agate grinding workers from Mashhad, northeastern Iran, were examined. Medical and occupational history for respiratory illnesses was taken using respiratory questionnaire of the national program of silicosis control, lung examination, spirometry and chest radiography. Chest x-rays were interpreted according to the International Labor Office (ILO) classification system, 2000. RESULTS: The mean+/ SD of age and work duration of the participants were 31.2+/-10.1 and 13+/-8.2 years, respectively. The prevalence of silicosis among agate workers was 12.9% (95% CI: 7.9%-18.0%); 18 workers had simple and 4 had complicated silicosis. There was a significant (p<0.05) relationship between contracting silicosis and exposure duration. 20 (11.7%) workers had symptoms consistent with chronic bronchitis and 8 (4.7%) showed asthma and asthma-like symptoms. The most frequent disorder observed in spirometry was the restrictive pattern (n=43, 30%). In the agate grinders, clinical and spirometry findings did not match with radiological findings. CONCLUSION: Agate grinding workers are at increased risk for respiratory diseases, specifically for silicosis and chronic bronchitis. The disease is related to silica dust exposure, poor ventilation and inappropriate personal protection. PMID- 25027042 TI - Incense and joss stick making in small household factories, Thailand. AB - BACKGROUND: Incense and joss stick are generally used in the world. Most products were made in small household factories. There are many environmental and occupational hazards in these factories. OBJECTIVE: To evaluate the workplace environmental and occupational hazards in small household incense and joss stick factories in Roi-Et, Thailand. METHODS: Nine small household factories in rural areas of Roi-Et, Thailand, were studied. Dust concentration and small aerosol particles were counted through real time exposure monitoring. The inductively coupled plasma optical emission spectrometry (ICP-OES) was used for quantitative measurement of heavy metal residue in incense products. RESULTS: Several heavy metals were found in dissolved dye and joss sticks. Those included barium, manganese, and lead. Rolling and shaking processes produced the highest concentration of dust and aerosols. Only 3.9% of female workers used personal protection equipment. CONCLUSION: Dust and chemicals were major threats in small household incense and joss stick factories in Thailand. Increasing awareness towards using personal protection equipment and emphasis on elimination of environmental workplace hazards should be considered to help the workers of this industry. PMID- 25027043 TI - Knowledge, attitude and practice of dentists towards prophylaxis after exposure to blood and body fluids. AB - BACKGROUND: Post-exposure prophylaxis plays an important role in prevention of bloodborne diseases after occupational exposures. OBJECTIVE: To evaluate the knowledge, attitude and practice of dentists towards post-exposure prophylaxis. METHODS: In a cross-sectional study, 140 dentists in Shiraz were selected through a systematic randomized sampling. They filled out a self-made questionnaire including 30 knowledge, 4 attitude and 10 practice questions. Mean of knowledge and percentage of various items of attitude and practice were reported. RESULTS: The mean+/-SD knowledge score of dentists was 18.5+/-6.2. Knowledge had a significant relationship with the level of education (p<0.001), attending infection control seminars (p<0.001), and working in public clinics (p<0.001). A total of 63 (43%) dentists believed that immediate washing of the exposed area has no effect on the prevention of hepatitis and AIDS. Of the studied dentists, 13%, 11%, and 34% believed that prophylaxis after exposure to patients' blood had no effect on prevention of human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus infections, respectively. Only 170 (53%) exposed dentists immediately washed the exposed area and only 43 (13.4%) of them evaluated the source patient for risk factors of hepatitis and AIDS. CONCLUSION: Knowledge, attitude and practice of dentists working in Shiraz towards postexposure prophylaxis are not desirable. Interventions to raise their awareness are therefore warranted. PMID- 25027044 TI - Injection safety among primary health care workers in Jazan Region, Saudi Arabia. AB - BACKGROUND: Occupational exposure to percutaneous injuries is a substantial source of infections with blood-borne pathogens among health-care workers. Few studies evaluated injection safety practices in Saudi Arabia. OBJECTIVE: To examine the structure and process of injection safety at primary health care level in Jazan health district, to evaluate knowledge, attitudes, and practices of primary health care physicians and nurses towards injection safety, and to determine the incidence of needle stick injuries among health care workers in Jazan region, Saudi Arabia. METHODS: A cross-sectional study was conducted in Jazan primary health care centers (PHCCs), Saudi Arabia from September 2011 to March 2012. Data were collected using an observational checklist and data collection sheet. Jazan city health district was chosen at random from the 14 health sectors in Jazan region. All the 33 (10 urban, and 23 rural) PHCCs of Jazan city were included in this study to get the predetermined sample size of health care workers. 200 health care workers (HCWs) were recruited (29% physicians, and 71% nurses). RESULTS: Syringes in the PHCCs were disposable (100%), individually packed (92%), and available at all volumes (98%). Methods of safe disposal of needles and sharps were also operated through contracting with professional companies in 84.8% of instances. Urban PHCCs had more posts for injection safety promotion than rural centers (p=0.02). Continuous Medical Education (CME) programs on infection control were present in only 60% of PHCCs. At least 95% of HCWs in Jazan believed that sharp objects should be kept in a puncture-proof container, kept in a closed container, or disposed by a professional company. More than 80% of HCWs washed their hands by soap and water and cleaned them by alcohol before giving injection, and also got the three doses of hepatitis B vaccine.The rate of needle stick injury in the past year was 14%, without a significant difference between nurses and physicians (p=0.8). CONCLUSION: Jazan PHCCs have reasonable facilities that prevent needle-stick injuries. We need to design and implement more educational programs on safety injection, and increase promotion of safety injection posters, especially in rural PHCCs. PMID- 25027045 TI - The toxic effects of silver nanoparticles on blood mononuclear cells. AB - BACKGROUND: Nanoparticles have become one of the leading technologies over the past two years. The extensive use of nanoparticles has raised great concern about their occupational fate and biological effects. With an increase in the production and use of nanomaterial, it is more likely to get exposed to them occupationally and environmentally. OBJECTIVE: To assess the toxicity of silver nanoparticles on human mononuclear cells. METHODS: In this in vitro experimental study, suspensions of blood mononuclear cells from 10 young healthy men were incubated with 10-nm silver nanoparticles in different concentrations (range: 1 500 MUg/mL) for 6 and 24 hours by MTT assay. Positive and negative controls were used for comparison. RESULTS: After 6 hours of exposure, 10.9% to 48.4% of the cells died. After 24 hours of exposure, the rate ranged from 56.8% to 86.3%. Regardless of the exposure time, the maximum cytotoxicity was observed at the concentration of 500 MUg/mL of silver nanoparticles. By increasing the exposure time to 24 hours, the cytotoxicity of nanoparticles substantially increased at all concentrations. Cell death was significantly higher when compared to the controls (p<0.01). CONCLUSION: Silver nanoparticles possess both time- and dose dependent cytotoxicity and can thus be considered as very toxic for mononuclear cells. PMID- 25027046 TI - Comments on Uranium concentration in groundwater in Hisar City, India. PMID- 25027047 TI - Efficient asymmetric synthesis of N-protected-beta-aryloxyamino acids via regioselective ring opening of serine sulfamidate carboxylic acid. AB - First regioselective ring opening of serine derived cyclic sulfamidate by hard nucleophiles like ArONa is developed, where beta-elimination of serine sulfamidate ester by stronger nucleophiles is overcome by reversal of the electronic effect of the carboxylate anion. This method provides easy and direct access to a variety of N-Boc- and N-PMB protected beta-aryloxy-alpha-amino acids with complete retention of enantiopurity in moderate to high yields. PMID- 25027048 TI - Comparison of two alternative study designs in assessment of medicines utilisation in neonates. AB - BACKGROUND: Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use. METHODS: A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation. RESULTS: Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93). CONCLUSION: The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates. PMID- 25027049 TI - Myocardial ischemia in a patient with peripheral vascular disease, an arteriovenous fistula, and patent coronary artery bypass grafts. AB - Patients with coronary artery disease often have concurrent peripheral vascular disease. The presence of concurrent vascular pathologies can pose unique challenges among patients who have undergone coronary artery bypass grafting utilizing the left internal mammary artery. We describe a patient with peripheral vascular disease and prior history of coronary artery bypass grafting, who presented with recurrent anginal symptoms and an abnormal stress test despite the absence of significant residual unrevascularized coronary artery disease. Additional evaluation led to the identification of an ipsilateral severe subclavian stenosis with a concomitant ipsilateral upper extremity arteriovenous fistula. Patient's symptoms resolved with the treatment of the underlying vascular lesions. PMID- 25027050 TI - Seed germination of Agave species as influenced by substrate water potential. AB - BACKGROUND: Plants of Agave spp. perform Crassulacean acid metabolism (CAM) and are highly drought-tolerant, but little is known concerning seed germination under low water availability. The aim of this study was to assess the effect of substrate water potential (PsiW) on seed germination and contrast hydrotime parameters of seven valuable and commercially-important Agave species from different geographical distributions and climatic regions of Mexico. Our hypothesis was that seed germination of Agave species is not affected by low water availability independently of seed biomass and the climate of their distribution area. RESULTS: Seed germination (at 25 degrees C and in the dark) between 85 and 100% for all species occurred within 80-180 h at -0.03 MPa and 250 430 h at -1.0 MPa. Seed germination at -1.5 MPa declined to less than 50% (p < 0.05) for A. asperrima and A. cupreata but did not change significantly for A. americana var. marginata, A. lechuguilla and A. striata, although they showed the lowest mean base water potential (-2.01 to -2.64 MPa). Seed germination of 40% Agave species, from arid and semi-arid climates in this study, was not affected by the lower PsiW. CONCLUSION: Germination of seeds of Agave species is moderately affected by low water availability, is partially dependent of their ecological distribution, and is independent of seed mass. PMID- 25027051 TI - Echinoderm regeneration: an in vitro approach using the crinoid Antedon mediterranea. AB - Among echinoderms, crinoids are well known for their remarkable regenerative potential. Regeneration depends mainly on progenitor cells (undifferentiated or differentiated), which migrate and proliferate in the lesion site. The crucial role of the "progenitor" elements involved in the regenerative processes, in terms of cell recruitment, sources, and fate, is a central problem in view of its topical interest and biological implications. The spectacular regenerative potential of crinoids is used to replace lost internal and external organs. In particular, the process of arm regeneration in the feather star Antedon mediterranea is the regeneration model most extensively explored to date. We have addressed the morphological and functional characterization of the cell phenotypes responsible for the arm regenerative processes by using an in vitro approach. This represents the first successful attempt to culture cells involved in crinoid regeneration. A comparison of these results with others from previous in vivo investigations confirms the diverse cell types contributing to regeneration and underscores their involvement in migration, proliferation, and dedifferentiation processes. PMID- 25027052 TI - RNA-binding protein research with transcriptome-wide technologies in neural development. AB - An increasing number of studies have demonstrated that neural RNA-binding proteins (nRNABPs) participate in several steps of neural development through post-transcriptional regulation of their RNA targets (Grabowski Curr Opin Genet Dev 21:388-394, 2011). Classical genetics and in vitro biochemical approaches have identified several important RNA targets of nRNABPs linked to cell-fate decision and neuronal functions. In recent years, new technologies, such as unbiased in vivo protein-RNA interaction approaches, high-throughput sequencing cross-linked immunoprecipitation (HITS-CLIP), microarrays, RNAseq and others, have been developed. The use of these with genetics has succeeded in defining a dynamic range of RNA targets of RNABPs at the transcriptome-wide level. This new platform also provides the mechanistic insights into a specific biological function of nRNABPs. This review highlights the discoveries and challenges of the interplay between the nRNABPs and their biological functions in neural development. PMID- 25027053 TI - Interrelationships between sirtuin 1 and transcription factors p53 and NF-kappaB (p50/p65) in the control of ovarian cell apoptosis and proliferation. AB - The roles of the mTOR system enzyme sirtuin 1 (SIRT1), the transcription factor p53 and the nuclear factor kappaB (NF-kappaB) and their interrelationships in the control of ovarian function have not been well studied. We examine, in vitro, the involvement of SIRT1, p53 and the p65 and p50 subunits of NFkappaB and their interrelationships in the control of the apoptosis and proliferation of porcine ovarian granulosa cells. Monolayers of primary granulosa cells were transfected with cDNA constructs encoding SIRT1, p53, p65 or p50 alone or were co-transfected with gene constructs for SIRT1 together with p53, p65 or p50. The accumulation of SIRT1, markers of proliferation (mitogen-activated protein kinase or extracellular-signal-regulated kinases 1,2) and a marker of apoptosis (caspase 3) was detected by immunocytochemistry. Transfection of cells with a SIRT1 gene construct alone promoted the accumulation of SIRT1 and decreased the accumulation of proliferation markers but did not affect the marker of apoptosis. Transfection of cells with gene constructs encoding p53, p50 or p65 decreased the expression of proliferation markers but not the apoptosis marker. Co-transfection of cells with SIRT1 cDNA changed the action of p65 on cell proliferation from inhibitory to stimulatory. SIRT1 overexpression induced the pro-apoptotic action of p53 and p50 but not of p65 constructs. Thus, SIRT1, p53 and NF-kappaB are involved in the control of both the proliferation and the apoptosis of ovarian cells. These novel data on the cross-talk between the mTOR/SIRT1 system and the transcription factors p53 and NF-kappaB show both the inhibitory (proliferation) and stimulatory (apoptosis) influences of SIRT1 on transcription factor action in ovarian cells. PMID- 25027054 TI - Who is paying your doctor? PMID- 25027055 TI - Sublobar resection versus lobectomy in solid-type, clinical stage IA, non-small cell lung cancer. AB - BACKGROUND: Recent studies have demonstrated that sublobar resection is not inferior to lobectomy for peripheral early lung cancer with ground-glass opacification. However, the effect of sublobar resection on solid-type early lung cancer is controversial. The aim of this study was to compare clinical outcomes of patients who have undergone sublobar resection or lobectomy for solid-type, early-stage, non-small cell lung cancer (NSCLC). METHODS: This study was a retrospective review of the records of patients who underwent lobectomy or sublobar resection between March 2000 and September 2010 for clinical stage IA NSCL. Patients with pure ground-glass opacities or death within 30 days after surgery were excluded. Disease-free interval, survival, and prognostic factors were analyzed. RESULTS: Thirty-one patients and 133 patients underwent sublobar resection and lobectomy, respectively. There were significant differences in age (P < 0.001), cardiovascular disease (P = 0.001), and diffusing capacity of the lung for carbon monoxide (DLCO) (P < 0.001). The patients with lobectomy had a significantly longer disease-free interval (P < 0.001) and survival (P = 0.001). By multivariate analysis, sublobar resection (P = 0.011), lymphatic vessel invasion (P = 0.006), and number of positive lymph nodes (P = 0.028) were predictors for survival. Sublobar resection (P < 0.001), visceral pleural invasion (P = 0.002), and lymphatic vessel invasion (P < 0.001) were predictors for disease-free interval. CONCLUSIONS: Lobectomy should remain the standard surgical procedure for solid-type, clinical stage IA, NSCLC. PMID- 25027056 TI - The clinical significance of potentially curative resection for gastric cancer following the clearance of free cancer cells in the peritoneal cavity by induction chemotherapy. AB - PURPOSE: The aim of this study was to evaluate the significance of the conversion of the peritoneal cytology from positive to negative following induction chemotherapy in relation to the prognosis after subsequent resection for gastric cancer. METHODS: This retrospective study was conducted using a prospectively maintained database. A total of 47 patients with free cancer cells in the peritoneal cavity, as evaluated by staging laparoscopy, but no other evidence of distant metastasis, who underwent induction chemotherapy followed by surgery were enrolled in the study. Then, the clinicopathological factors and survival in the study subjects were assessed. RESULTS: The median survival time and 5-year overall survival rate of the 47 study participants were 20.4 months and 25.0 %, respectively. In 23 of the patients, the peritoneal cytology converted from positive to negative after the induction chemotherapy, and a microscopically margin-negative gastrectomy was performed. The median survival time of 30.4 months and the 5-year survival rate of 34.6 % of these patients was significantly more favorable than the corresponding values of 15.0 months and 17.6 % in the patients who had persistently positive cytology (P = 0.03). CONCLUSION: Based on our findings, the clearance of free cancer cells in the peritoneal cavity by induction chemotherapy improves the prognosis of patients following subsequent gastrectomy. PMID- 25027057 TI - The utility of biomarkers in differentiating bacterial from non-bacterial lower respiratory tract infection in hospitalized children: difference of the diagnostic performance between acute pneumonia and bronchitis. AB - The aim of this study is to investigate the utility of several biomarkers in differentiating bacterial community-acquired lower respiratory tract infection (CA-LRTI) from non-bacterial CA-LRTI in children and the difference of their diagnostic performance between pneumonia and bronchitis. A retrospective cohort study composed of 108 pediatric patients hospitalized for CA-LRTI was performed during 2010-2013. Based on the findings of chest X-ray and sputum samples, patients were divided into 4 categories, group of bacterial pneumonia or bronchitis, and non-bacterial (viral or etiology-unknown) pneumonia or bronchitis. Peripheral white blood cell and neutrophil counts, and serum C reactive protein (CRP) and procalcitonin (PCT) levels were compared among the 4 groups. Finally, 54 patients were the subject of this study. In the patients with pneumonia, serum CRP and PCT levels were significantly elevated in the group of bacterial pneumonia (CRP: p = 0.02, PCT: p = 0.0008). The area under the receiver operating characteristic curve for PCT for distinguishing between bacterial and non-bacterial pneumonia was the largest, and sensitivity, specificity, positive predictive value and negative predictive value of PCT were best among 4 markers. On the other hand, in the patients with bronchitis, neutrophil count was significantly decreased in non-bacterial bronchitis whereas no significant differences of WBC count, CRP level or PCT level were seen. In conclusion, PCT was the most useful marker to differentiate bacterial pneumonia whereas neutrophil count contributed most to the discrimination of bacterial bronchitis. The diagnostic performance of biomarkers may be different between pneumonia and bronchitis. PMID- 25027058 TI - Is epicardial adipose tissue an epiphenomenon or a new player in the pathophysiology of atrial fibrillation? PMID- 25027059 TI - Sphere formation permits Oct4 reprogramming of ciliary body epithelial cells into induced pluripotent stem cells. AB - Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by defined sets of transcription factors. We previously described reprogramming of monolayer-cultured adult mouse ciliary body epithelial (CE) cells by Oct4 and Klf4, but not with Oct4 alone. In this study, we report that Oct4 alone is sufficient to reprogram CE cells to iPS cells through sphere formation. Furthermore, we demonstrate that sphere formation induces a partial reprogramming state characterized by expression of retinal progenitor markers, upregulation of reprogramming transcription factors, such as Sall4 and Nanog, demethylation in the promoter regions of pluripotency associated genes, and mesenchymal to epithelial transition. The Oct4-iPS cells maintained normal karyotypes, expressed markers for pluripotent stem cells, and were capable of differentiating into derivatives of all three embryonic germ layers in vivo and in vitro. These findings suggest that sphere formation may render somatic cells more susceptible to reprogramming. PMID- 25027060 TI - Role of the Programmed Death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease. AB - Programmed death-1 (PD-1) belongs to the CD28 family of co-stimulatory and co inhibitory molecules and regulates adaptive immunity. This molecule induces the development of regulatory T cells, T cell tolerance, or apoptosis. We examined the role of PD-1 pathway in Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mice. Up-regulation of PD-1 and PD-1 ligand-1 (PD-L1) mRNA expression in bone marrow-derived dendritic cells were induced by TMEV infection in vitro. Furthermore, PD-1 and PD-L1 mRNA expression was increased in the spinal cords of the TMEV-infected mice in vivo. Treatment with a blocking monoclonal antibody (mAb) against PD-1, especially during the effector phase, resulted in significant deterioration of the TMEV-IDD both clinically and histologically. Flow cytometric analysis revealed a dramatically increase of CD4(+) T cells producing Th1 cytokines such as IFN-gamma and TNF alpha in the spinal cord of anti-PD-1 mAb-treated mice. These results indicate that the PD-1 pathway plays a pivotal regulatory role in the development of TMEV IDD. PMID- 25027061 TI - Antibodies to neural and non-neural autoantigens in Japanese patients with CNS demyelinating disorders. AB - Anti-aquaporin 4 (AQP4) antibodies (Abs) are essential in neuromyelitis optica spectrum disorders (NMOSD), but the relationship between CNS demyelinating disorders (CNSDD) and other neural Abs remains unclear. Here we screened anti neural Abs in the sera of 70 Japanese CNSDD patients. While two had only demyelinating events among three anti-N-methyl-d-aspartate receptor (NMDAR) Ab positive subjects, the other subject who also had anti-AQP4 Abs experienced episodes of anti-NMDAR encephalitis and of NMOSD. Major lesions in the three anti contactin-associated protein 2 Ab-positive subjects were infratentorial, including one co-carrying anti-AQP4 Abs. Thus, autoantibodies can be clinically silent, but multiple autoantibodies may participate in the pathogenesis. PMID- 25027062 TI - Metabolic syndrome, diabetes, and cardiovascular risk in HIV. AB - HIV infection and its treatment have been associated with adipose tissue changes and disorders of glucose and lipid metabolism. The proportion of HIV-infected adults over the age of 50 is also growing placing HIV-infected adults at particular risk for metabolic perturbations and cardiovascular disease. The metabolic syndrome in HIV-infected adults has been increasingly studied but whether HIV is associated with greater risk remains unclear, likely because of the interplay of host, viral and antiretroviral factors that are associated with the components of the metabolic syndrome. The relationship between HIV and diabetes mellitus (DM) risk has also been debated. While the Framingham Risk Score is a well-accepted measure of 10-year cardiovascular risk in the general population, it may not accurately predict risk in the HIV setting due to HIV related factors such as inflammation that are not accounted for. We summarize the recent literature on metabolic syndrome, DM, and cardiovascular risk in HIV infected adults. PMID- 25027063 TI - A counterweight is not necessary to implement simple, natural and comfortable single-leg cycle training. PMID- 25027064 TI - Bone formation is suppressed with multi-stressor military training. AB - PURPOSE: To determine the effects of US Army Ranger Training, an 8-week, physically demanding program (energy expenditure of 2,500-4,500 kcal/day) with energy restriction (deficit of 1,000-4,000 kcal/day) and sleep deprivation (<4 h sleep/night) on bone metabolism. METHODS: Blood was collected from 22 men (age 24 +/- 4 years) before and after training. Follow-up measurements were made in a subset of 8 subjects between 2 and 6 weeks after training. Serum was analyzed for bone formation biomarkers [bone alkaline phosphatase (BAP) and osteocalcin (OCN)], bone resorption biomarkers [C-telopeptide cross-links of type I collagen (CTX) and tartrate-resistant acid phosphatase (TRAP5b)], calcium, parathyroid hormone (PTH), and vitamin D 25(OH)D increased significantly by 37.3 +/- 45.2 % with training [corrected]. A repeated-measures ANOVA with time as the only factor was used to analyze data on the subset of 8 subjects who completed follow-up data collection. RESULTS: BAP and OCN significantly decreased by 22.8 +/- 15.5% (pre 41.9 +/- 10.1; post 31.7 +/- 7.8 ng/ml) and 21.0 +/- 23.3% (pre 15.0 +/- 3.5; post 11.3 +/- 2.1 ng/ml), respectively, with training, suggesting suppressed bone formation. OCN returned to baseline, while BAP remained suppressed 2-6 weeks post training. TRAP5b significantly increased by 57.5 +/- 51.6% (pre 3.0 +/- 0.9; post 4.6 +/- 1.4 ng/ml) from pre- to post-training, suggesting increased bone resorption, and returned to baseline 2-6 weeks post-training. PTH Increased significantly by 37.3 +/- 45.2% with training. No changes in CTX, calcium, or PTH were detected. CONCLUSIONS: These data indicate that multi-stressor military training results in increased bone resorption and suppressed bone formation, with recovery of bone metabolism 2-6 weeks after completion of training. PMID- 25027065 TI - Effects of lactation length and boar contact in early lactation on expression of oestrus in multiparous sows. AB - The ability to stimulate a fertile oestrus during early lactation provides an opportunity to increase piglet weaning age whilst maintaining 2.4 litters per sow per year. This study evaluated the effects of boar contact beginning on day 7 of lactation and lactation length on lactation oestrus induction and subsequent reproductive output in multiparous sows (parity 2.9 +/- 0.16; mean +/- SEM; range 2-6). Large White * Landrace multiparous sows were allocated to one of four treatment groups; weaning at 26 days post-partum and no boar contact (control); weaning at 26 days and boar contact (BC); weaning at 7 days and boar contact (BC+short lactation (SL)); and weaning at 7 days and no boar contact (SL). Control and SL sows were taken for a short walk daily during which a backpressure test was performed in the absence of a boar. Oestrus expression within 26 days of farrowing was significantly higher in BC (67%) and BC+SL (93%) sows than control (11%) and SL (13%) sows (P<0.05). Of sows mated within 26 days of farrowing, there was no difference in the number of piglets born alive or stillborn. Therefore, boar contact is an effective method to stimulate oestrus within 26 days of farrowing in both lactating and weaned sows. PMID- 25027066 TI - Resistance to first-line antituberculosis drugs in Spain, 2010-2011. RETUBES Study. AB - INTRODUCTION: The magnitude of current resistance to antituberculosis drugs in Spain is unknown. The objective of this study is to describe resistance to first line antituberculosis drugs and determine the associated factors. METHODS: Prospective multicenter study of adult tuberculosis patients with positive Mycobacterium tuberculosis culture and antibiogram including first-line drugs in 32 hospitals and one out-patient center of the Spanish Health System between 2010 and 2011. RESULTS: A total of 519 patients, 342 Spanish nationals and 177 (34.1%) foreigners were studied. Drug resistance was found in 48 (9.2%), of which 35 (6.7%) were isoniazid-resistant. There were 10 (1.9%) multiresistant cases and no strain was extremely resistant. Initial isoniazid resistance was detected in 28 of the 487 (5.7%) antituberulosis-naive patients, most of whom were foreigners (P<.01). Acquired resistance was seen in 7 (22.6%) previously treated cases. Multiresistance was initial in 6 cases (1.2%) and acquired in another 4 (12.9%). Factors associated with initial isoniazid resistance were immigrant status and group cohabitation OR=2.3; 95%CI: .98-5.67 and OR=2.2; 95%CI: 1.05-7.07 respectively). The factor associated with acquired resistance to isoniazid was age below 50 years (P=.03). CONCLUSIONS: The rate of initial isoniazid resistance is greater than estimated, probably due to the increase in immigration during recent years, suggesting that systematic national monitoring is required. Immigrants and those who cohabit in groups have a higher risk of isoniazid resistance. PMID- 25027069 TI - Comparison of the Verigene Clostridium difficile, Simplexa C. difficile Universal Direct, BD MAX Cdiff, and Xpert C. difficile assays for the detection of toxigenic C. difficile. AB - We compared the Verigene Clostridium difficile test (Nanosphere, Northbrook, IL, USA), the Simplexa C. difficile Universal Direct (Focus Diagnostics, Cypress, CA, USA), the BD MAX Cdiff (Becton Dickinson, Franklin Lakes, NJ, USA), and the Xpert C. difficile (Cepheid, Sunnyvale, CA, USA) assays for the detection of toxigenic C. difficile. One hundred and ninety deidentified, remnant diarrheal specimens were included in this study. After resolution of discordant results by toxigenic culture, the Xpert C. difficile assay displayed the highest sensitivity (100%), with a specificity of 98.8%. The sensitivity and specificity were 95.2% and 99.4% and 87% and 100% for the Verigene CDF and Simplexa Universal Direct assays, respectively. Finally, the BD MAX assay showed a sensitivity of 87% and a specificity of 98.8%. Despite differences in the overall performance of these assays, these results support the routine use of these platforms for the detection of toxigenic C. difficile in the clinical laboratory. PMID- 25027067 TI - Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update. AB - The effect of hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD). AAT deficiency (AATD) is defined as a serum concentration lower than 35% of the expected mean value or 50 mg/dl (determined by nephelometry). It is associated in over 95% of cases with Pi*ZZ genotypes, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles. A systematic qualitative review was made of 107 articles, focusing mainly on an active search for AATD in COPD patients and intravenous (iv) treatment with AAT. On the basis of this review, the consultant committee of the Spanish Registry of Patients with AATD recommends that all COPD patients be screened for AATD with the determination of AAT serum concentrations, and when these are low, the evaluation must be completed with phenotyping and, on occasions, genotyping. Patients with severe AATD COPD should receive the pharmacological and non pharmacological treatment recommended in the COPD guidelines. There is enough evidence from large observational studies and randomized placebo-controlled clinical trials to show that the administration of iv AAT reduces mortality and slows the progression of emphysema, hence its indication in selected cases that meet the inclusion criteria stipulated in international guidelines. The administration of periodic infusions of AAT is the only specific treatment for delaying the progression of emphysema associated with AATD. PMID- 25027070 TI - Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. AB - The mechanisms that contribute to the development of diabetes complications remain unclear. A defective reaction of tissues to hypoxia has recently emerged as a new pathogenic mechanism and consists of a complex repression of hypoxia inducible factor (HIF), which is the main regulator of the adaptive response to hypoxia. This paper discusses the mechanisms by which hyperglycaemia contributes to HIF repression in diabetes. Furthermore, a comprehensive analysis of the functional relevance of these new findings to the development of chronic diabetes complications is provided, along with examples from animal models and clinics. PMID- 25027071 TI - Is a single positive blood culture for Enterococcus species representative of infection or contamination? AB - Data on the clinical outcomes of patients with a single compared with multiple positive blood cultures for Enterococcus species is limited. We undertook a retrospective cohort study in adults with at least one positive blood culture for Enterococcus species in a single institution. Clinical outcomes included death and elimination of infection. We included 471 positive blood cultures from 206 enterococcal positive blood culture episodes in 189 patients. Multiple positive blood cultures for Enterococcus species occurred in 110/206 (53.4 %) episodes; 31.6 % of patients had diabetes mellitus; 42.9 % of patients had solid or hematologic malignancy; 26.5 % of patients were solid organ transplant recipients; hospital-acquired and healthcare-associated acquisition represented 55.3 % and 33.0 % of episodes, respectively. Thirty-five patients died and 110 episodes of enterococcal bloodstream infection were successfully treated. In the multivariable analysis, multiple positive blood cultures were not statistically significantly associated with an increased likelihood of in-hospital death [odds ratio (OR) 1.00, 95 % confidence interval (CI) 0.42-2.40] or elimination (OR 1.41, 95 % CI 0.76-2.64) compared with single positive blood cultures. Hematologic malignancy and diabetes mellitus were independently associated with in-hospital death (OR 2.83, 95 % Cl 1.02-7.82; OR 2.79, 95 % Cl 1.16-6.70, respectively). Infectious disease consultation was associated with a greater likelihood of elimination (OR 2.50, 95 % Cl 1.32-4.72). The clinical outcomes of patients with single versus multiple positive blood cultures with Enterococcus species were similar in our institution. Further studies should examine efficient methods to detect contamination versus true infection. PMID- 25027073 TI - Towards better hypertension management in India. PMID- 25027074 TI - Obesity--a risk factor or a disease: What can exercise do for obese children? PMID- 25027072 TI - Targeting CCR5 for anti-HIV research. AB - Highly active antiretroviral therapy (HAART) is the only approach for human immunodeficiency virus (HIV) infection treatment at present. Although HAART is effective in controlling the progression of infection, it is impossible to eradicate the virus from patients. The patients have to live with the virus. Alternative ways for the cure of HIV infection have been investigated. As the major co-receptor for HIV-1 infection, C-C motif chemokine receptor 5 (CCR5) is naturally an ideal target for anti-HIV research. The first CCR5 antagonist, maraviroc, has been approved for the treatment of HIV infection. Several other CCR5 antagonists are in clinical trials. CCR5 delta32 is a natural genotype, conferring resistance to CCR5 using HIV-1 strains. Gene therapy research targeting this mutant has been conducted for HIV infection treatment. A Berlin patient has been cured of HIV infection by the transplantation of stem cells from a CCR5 delta32 genotype donor. The infusion of an engineered zinc finger nuclease (ZFN)-modified autologous cluster of differentiation 4 (CD4) T cells has been proved to be a promising direction recently. In this study, the anti-HIV research targeting CCR5 is summarized, including CCR5 antagonist development, stem cell transplantation, and gene therapy. PMID- 25027075 TI - Progeria: a rare genetic premature ageing disorder. AB - Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs. PMID- 25027077 TI - Need for a nomogram of renal sizes in the Indian population- findings from a single centre sonographic study. AB - BACKGROUND & OBJECTIVES: Renal size is an important parameter used in the diagnosis and follow up of renal diseases. However, while making decisions, clinicians must be aware of the dependence of these dimensions on the ethnicity of the individual, independent of anthropometric indices. There is no established nomogram for renal sizes in the Indian population. The aim of this study was to assess the applicability of oft-quoted ranges of normal renal sizes in our population. METHODS: Renal dimensions including length, width and parenchymal thickness were sonographically measured in 140 individuals with no renal disease. Analysis was done for differences due to age, gender and laterality. The correlation of renal dimensions with anthropometric parameters like weight, height, body mass index (BMI) and body surface area (BSA) was analyzed. RESULTS: The means of length, width and parenchymal thickness of all 280 kidneys of 140 patients were 9.65 +/- 0.63, 4.5 +/- 0.42 and 2.04 +/- 0.2 cm, respectively. There was a significant difference in parenchymal thickness between the right and left kidneys, while there was no significant right-left difference in length or width. Gender-wise analysis showed significant differences between male and female renal breadths but not length and parenchymal thickness. Age group-wise analysis showed significant decrease in renal length and parenchymal thickness beyond the seventh decade. There was a moderate positive correlation of bilateral renal length with body weight and BSA, and a weak positive correlation with body height and BMI. INTERPRETATION & CONCLUSIONS: Renal sizes in our population are in contrast to commonly quoted normal values in literature. Conclusions about renal sizes need to be made with reference to nomograms and should not be based upon data from other populations. We also present formulae whereby to derive renal sizes from anthropometric indices in our population. PMID- 25027076 TI - Human mammaglobin in breast cancer: a brief review of its clinical utility. AB - Human mammaglobin is a member of the uteroglobin proteins family that has recently been tested as a specific marker for breast cancer. While low levels may be seen in normal breast tissue, expression is increased dramatically in breast cancer and is correlated with higher grade. Detection in blood and body fluids is also correlated with cancer metastasis, and its levels with prognosis. This promises to be a useful screen for early detection of breast cancer, especially in high risk individuals. Mammoglobin has also been used for immunotherapeutic targeting of breast cancer cells. However, there are some controversies regarding its diagnostic efficacy and prognostic value, which warrant further study. PMID- 25027078 TI - Changes in clinical & biochemical presentations of primary hyperparathyroidism in India over a period of 20 years. AB - BACKGROUND & OBJECTIVES: With the advent of serum chemistry autoanalyzer and routine estimation of serum calcium as a part of annual physical examination, there has been a dramatic change in the presentation of primary hyperparathyroidism (PHPT) from symptomatic to asymptomatic disease in the United States. However, such trend has not been documented from India. We carried out this retrospective study to analyse the changes in clinical presentations of PHPT patients over a period of two decades in a tertiary care centre in north India. METHODS: This retrospective study included patients with PHPT treated at a single centre of north India between March 1990 and October 2010. Two decades were divided into four different time periods, i.e. 1990 to 1994, 1995 to 1999, 2000 to 2004 and 2005 to 2010. Clinical presentations, biochemical parameters and surgical outcomes were compared between different time periods using appropriate statistical methods. RESULTS: Data of 202 patients with PHPT with male: female ratio of 3:7 were analyzed. There was a rise in the number of cases of PHPT diagnosed in the last decade compared to the previous decade (28 cases vs 174 cases, P<0.001). Change in the mean age, male: female ratio, lag time for the diagnosis of PHPT and clinical presentations of PHPT (predominance of bone and stone symptoms) did not differ across different time periods. Non-significant decrease in serum calcium levels at the time of diagnosis of PHPT and a significant, decline in the serum alkaline phosphatase levels (P<0.01) were found in the last decade, however, iPTH levels were higher in the last decade ( P <0.05). There was no change in the site and size of parathyroid adenoma in the two decades, however, postoperative symptomatic hypocalcemia was less frequent in the last decade. INTERPRETATION & CONCLUSIONS: The findings of this retrospective analysis show that the PHPT still remains symptomatic disease with increasing awareness over the last two decades in our center. There was not much change in the clinical presentation, in the past two decades. PMID- 25027079 TI - A 4-compartment model based validation of air displacement plethysmography, dual energy X-ray absorptiometry, skinfold technique & bio-electrical impedance for measuring body fat in Indian adults. AB - BACKGROUND & OBJECTIVES: Many methods are available for measuring body fat of an individual, each having its own advantages and limitations. The primary objective of the present study was to validate body fat estimates from individual methods using the 4-compartment (4C) model as reference. The second objective was to obtain estimates of hydration of fat free mass (FFM) using the 4C model. METHODS: The body fat of 39 adults (19 men and 20 women) aged 20-40 yr was estimated using air displacement plethysmography (ADP), dual energy X-ray absorptiometry (DEXA), 4-skinfold technique and bio-electrical impedance (BIA). Total body water was estimated using isotope dilution method. RESULTS: All the methods underestimated body fat when compared to 4C model, except for DEXA and the mean difference from the reference was lowest for DEXA and ADP. The precision of the fat mass estimated from 4C model using the propagation of error was 0.25 kg, while the mean hydration factor obtained by the 4C model was found to be 0.74 +/- 0.02 in the whole group of men and women. INTERPRETATIONS & CONCLUSION: The results of the present study suggest that DEXA and ADP methods can provide reasonably accurate estimates of body fat, while skinfold and bio-electrical impedance methods require the use of population specific equations. PMID- 25027080 TI - Profile of inhalant users seeking treatment at a de-addiction centre in north India. AB - BACKGROUND & OBJECTIVES: Inhalants are substances whose chemical vapors are inhaled to produce euphoric, disinhibiting, and exciting effects. Data on inhalant abuse in India are relatively scarce. We report the demographic and clinical profile of inhalant users among the treatment seekers at a Drug De addiction and Treatment Centre in north India. METHODS: The records of treatment seekers at the Drug De-addiction and Treatment Centre, over 10 years (2002-2011) were scanned to identify 92 cases reporting inhalant use. Of these 92 cases, the complete record files were available for 87 (94.6%) cases. These case files were reviewed and the relevant data were collected and analyzed. RESULTS: Over the study period of 10 years, the number of cases with inhalant abuse per year rose steadily to peak at 20 cases (4.08% of new cases) in 2006 and then stabilized at 1-3 per cent of new cases annually. Of the 87 cases studied, all were males with a mean age of 18.9+/-4.12 yr, mean education of 9.8+/-3.42 yr and mean family income of Rs. 7676+/-7343.15 (median: Rs. 5000). Majority of subjects were unmarried (89.7%), urban resident (79.3%), and from a nuclear family (78.2%). About half of the subjects were students (50.6%). The most common inhalant used was typewriter correction fluid (73.6%) followed by typewriter diluent fluid (19.5%) and glue (6.9%). The most common reason for initiation was curiosity. The mean age of onset of inhalant use was 16.3+/-4.22 yr. Most subjects fulfilled the criteria for inhalant dependence (85.1%). Psychiatric co-morbidity and the family history of substance dependence were present in 26.4 and 32.9 per cent subjects, respectively. Majority of the subjects reported drug related problems, occupation and finance being the worst affected. Interpretations & conclusions: Our results showed that the inhalant users were mostly urban youth belonging to middle socio economic class families. The principal sources of inhalant abuse were the commonly available substances like typewriter correction fluids and majority of the subjects initiated it out of curiosity. Nearly three-fourth of the subjects used some other substance of abuse in addition, tobacco being the most common. In view of associated drug related problems, there is a need for strategies to prevent this emerging health care problem. PMID- 25027081 TI - Role of computed tomography (CT) scan in staging of cervical carcinoma. AB - BACKGROUND & OBJECTIVES: Staging of cervical carcinoma is done clinically using International Federation of Obstetrics and Gynecology (FIGO) guidelines. It is based on physical examination findings and also includes results of biopsy, endoscopy and conventional radiological tests like chest radiograph, intravenous urography and barium enema. These conventional radiological investigations have largely been replaced by computed tomography (CT) and magnetic resonance imaging (MRI) at present. FIGO staging system does not consider CT and MRI mandatory; however, use of these modalities are encouraged. This prospective study was conducted to determine the role of CT in staging work up in women diagnosed with cervical carcinoma. METHODS: Fifty three women diagnosed with cervical carcinoma were evaluated with contrast enhanced CT scan of abdomen and pelvis. CT scan images were especially evaluated to determine tumour size, invasion of parmetrium, pelvic walls, rectum, urinary bladder and ureters, pelvic or retroperitoneal lymphadenopathy and distant metastases. CT findings were associated with clinical findings and staging, including findings from cystoscopy and sigmoidoscopy. RESULTS: There was a poor agreement between clinical and CT staging of cervical carcinoma. Primary tumour was demonstrated on CT in 36 (70%) of 53 patients. CT underestimated the parametrial, vaginal and pelvic wall invasion when compared with physical examination. CT overestimated the urinary bladder and rectal invasion when compared with cysto-sigmoidoscopy, however, CT had 100 per cent negative predictive value (NPV) to exclude bladder and rectal involvement. CT detection of lymph node enlargement and lung metastases influenced the management. INTERPRETATION & CONCLUSIONS: Our findings show that CT scan does not reliably correlate with clinical FIGO staging of cervical cancer. However, it can detect urinary obstruction as well as nodal or distant metastases and thus improves the clinical FIGO staging. PMID- 25027082 TI - Copy number polymorphism of glutathione-S-transferase genes (GSTM1 & GSTT1) in susceptibility to lung cancer in a high-risk population from north-east India. AB - BACKGROUND & OBJECTIVES: Genetic polymorphisms in glutathione-S-transferase genes ( GSTM1 and GSTT1 ) have been studied intensively for their potential role in lung cancer susceptibility. However, most of the studies on association between the polymorphisms and lung cancer do not distinguish between genotypes with one or two copies of the genes. The present study investigates the gene dosage effects of GSTT1 and GSTM1 copy number and their environmental interactions to examine the association of lung cancer risk with trimodular genotypes of the GSTs in a high-risk population from north-east India. METHODS: A total of 154 lung cancer cases and 154 age and sex matched controls from the high risk region of north-east India were analyzed by multiplex real-time PCR to determine the trimodal genotypes (+/+, +/- and -/-) in both the genes ( GSTM1 and GSTT1 ). RESULTS: No significant association and gene dosage effect of GSTM1 gene copy number with lung cancer risk ( P trend =0.13) were found. However, absence of GSTT1 conferred 68 per cent (OR=0.32;95%CI=0.15-0.71;P=0.005) reduced risk compared to the two copy number of the gene. t0 here was evidence of gene dosage effect of GSTT1 gene ( P trend =0.006). Tobacco smoking was a major environmental risk factor to lung cancer (OR=3.03;95%CI=1.73-5.31;P<0.001). However, its interaction with null genotype of GSTT1 conferred significant reduced risk to lung cancer (OR=0.30;95%CI=0.10-0.91;P=0.03). Further in only tobacco smokers, null genotype was associated with increased reduced risk [0.03(0.001-0.78)0.03; P trend =0.006]. No effect modification of GSTM1 was observed with lung cancer risk by environmental risk factors. INTERPRETATION & CONCLUSIONS: The results suggest that absence of GSTT1 null genotype may be associated with a reduced risk of lung cancer and the effect remains unchanged after interaction with smoking. PMID- 25027083 TI - Associations between androgen receptor CAG & GGN repeat polymorphism & recurrent spontaneous abortions in Chinese women. AB - BACKGROUND & OBJECTIVES: Recurrent spontaneous abortion (RSA) is a reproductive problem that occurs in women in reproductive age with a frequency of 1-3 per cent. Previous studies have reported high levels of serum androgens to be associated with RSAs. At the molecular level, the effect of androgens is mediated through the activation of the androgen receptor (AR). The CAG and GGN repeat polymorphisms of the AR gene are associated with the AR activity. We hypothesize that the AR CAG/GGN repeat polymorphism may be associated with levels of serum androgens. Thus, this study as undertaken to evaluate the relationship between CAG/GGN repeats in exon 1 of the AR gene in women with RSAs. METHODS: This case control study was performed in Ningxia, PR China, including 149 women with RSAs and 210 controls. The CAG and GGN repeats of the AR gene were genotyped using a PCR-based assay and were analyzed using Peak Scanner Software v1.0 to determine the CAG/GGN repeat length. RESULTS: CAG repeats ranged from 15 to 29 in the RSA patients, compared to 14 to 35 in the control group. The median value of CAG repeats was 22 for the RSA group and 24 for control group. The total AR CAG alleles (<=22 repeats), shorter AR CAG alleles (<=22 repeats), and biallelic means (<=22.5 repeats) were significantly different in the RSA group in comparison to the control group ( P <0.001, P <0.01). The median value of the GGN repeats was 23 for the cases and 22 for controls. The total number of AR GGN alleles (<=23 repeats) was significantly different in the RSA group compared to the control group ( P <0.5). There was no difference between the RSA group and the control groups in regards to shorter alleles, longer alleles, and biallelic means. INTERPRETATION & CONCLUSIONS: Our observation suggests that the CAG and GGN repeat length is shorter in women with RSAs as compared with controls and that shorter CAG and GGN repeats may be pathogenic for RSAs in Chinese women. Further studies need to be done in different ethnic populations. PMID- 25027084 TI - Association of interleukin-10 with hepatitis B virus (HBV) mediated disease progression in Indian population. AB - BACKGROUND & OBJECTIVES: Interleukin (IL)-10, an anti-inflammatory Th2 cytokine, is one of the key coordinators of the inflammatory responses involved. The present study was designed to evaluate the impact of IL-10 (-819/-592) genotypes, haplotypes, mRNA and the protein levels with risk for hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) development in India. METHODS: A total of 390 subjects (145 controls, 62 inactive HBV-carriers, 64 chronic-active HBV patients, 60 HBV related cirrhotics and 59 HBV- HCC subjects) were enrolled in the study. Allele specific (AS)-PCR, ELISA and RT-PCR methods were used for assessing polymorphism, spontaneous blood levels and the mRNA expression, respectively of IL-10. RESULTS: The study revealed that the CC/TA genotype acted as a risk factor for cirrhosis (OR a =2.02; P<0.05) and the subsequent HCC development (OR a =2.20; P<0.05), with controls as reference. However, no significant association was found between the two haplotypes (CC and TA) observed and HCC risk. Moreover, the IL-10 protein and mRNA levels in peripheral blood mono nuclear cells (PBMCs) showed a significant elevation as the disease progressed to cirrhosis. But, no variation was observed in the IL-10 levels in subjects with different IL-10 genotypes. INTERPRETATION & CONCLUSIONS: These preliminary results suggest a strong association of IL10 (-819/-592) with the HBV infection mediated disease progression, from inactive carrier state to malignancy, in Indian population. PMID- 25027085 TI - Induction of resistant mutants of Salmonella enterica serotype Typhi under ciprofloxacin selective pressure. AB - BACKGROUND & OBJECTIVES: Infection with Salmonella enterica serovar Typhi (hereafter S. Typhi) is an important public health problem in India. There has been an increase in the number of reported clinical failures to ciprofloxacin treatment but the data on possible mechanism of failure are limited. One mechanism that has been widely reported and found associated with ciprofloxacin resistance, is the mutations in target genes in QRDR (quinolone resistance determining region). It is hypothesized that mutations in DNA gyrase or topoisomerase IV result in therapeutic failure under selective pressure of antibiotic while the patient is on treatment. We undertook in vitro sequential selection studies to expose the clinical isolates of S. Typhi to different concentration of ciprofloxacin to study the role of antibiotic selective pressure in the development of mutations in QRDR. METHODS: Total 26 clinical isolates were divided in to two parts: part I included six isolates obtained from three patients with relapse of enteric fever and part II included 20 isolates with different ciprofloxacin MIC levels. For in vitro induction of mutation experiment, five S. Typhi isolates were selected which included three NAS (nalidixic acid sensitive) and 2 NAR (nalidixic acid resistant) S. Typhi. These isolates were grown under increasing concentrations of ciprofloxacin and mutations acquired in QRDR of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) were investigated by sequencing. RESULTS: For the isolates included in the part I of the study, it was found that the MIC to ciprofloxacin increased in the isolates obtained during the relapse of enteric fever as compare to the first isolate. All isolates had single mutation in gyrA gene at S83 without additional mutation in the second isolate. In the second part of the study, the nine isolates with varying MICs to ciprofloxacin also had single mutation in gyrA gene at S83 and another six had triple mutations, two mutations in gyrA gene (at S83 and D87) and one mutation in parC gene (at S80). In in vitro induction of mutation experiment, all mutated isolates showed triple mutation (two mutation in gyrA and one in parC gene) while no mutations were found in wild isolates. INTERPRETATION & CONCLUSIONS: Upon exposure to the step-wise increased concentration of ciprofloxacin, isolates become more tolerant to the ciprofloxacin and showed 2-4 fold higher MICs without new mutation after 8 MUg/ml. So the accumulation of mutations under continuous ciprofloxacin pressure and tolerance of the mutant isolates led to the clinical failure. These results also suggested that there could be another mechanism responsible for resistance. PMID- 25027086 TI - Entomological investigations into an epidemic of Japanese encephalitis (JE) in northern districts of West Bengal, India (2011-2012). AB - BACKGROUND & OBJECTIVES: Japanese encephalitis (JE) is one of the most important arboviral diseases of human beings with outbreaks in many parts of Southeast Asia including India. We present the entomological findings of an outbreak occurred in northern part of West Bengal during 2011-2012 with special emphasis on the role of JE vectors in different seasons. METHODS: Adult mosquito collections were made with the help of mouth aspirators, aided by flash lights during day time resting inside human and animal habitations as indoor, and resting outside field grasses, bushes, underneath of culverts and bridges as outdoor, and in and around the pig enclosures and cattle sheds during dusk period in JE affected villages from Cooch Behar, Dakshin Dinajpur, Darjeeling and Jalpaiguri districts in North West Bengal. In all study villages, a long handled with enamel bowl dipper was used to obtain immature stages of mosquitoes from various breeding habitats. RESULTS: A total of 19 different types of mosquito breeding habitats were examined for vectors of JE. From these habitats, 23.7 per cent were positive for breeding during the study period. Overall, nine different species were recorded through emergence, but none was positive for JE virus when subjected for detection of virus. Adult mosquitoes of more than 50 per cent of the potential JE vector species obtained through dusk and the rest through indoor and outdoor collections in all seasons. Altogether, 27 different species were recorded. Most of these were JE vectors. INTERPRETATION & CONCLUSIONS: Our results showed that in addition to Cx. vishnui subgroup, detection of JE virus antigen in Cx. quinquefasciatus indicated the possible maintenance of JE virus in nature through poor vector mosquitoes throughout the year. Since, all potential vector species reported elsewhere in India were also found in this region and fluctuated in density in different seasons, a proper integrated vector control programme needs to be implemented to control JE transmission. PMID- 25027087 TI - Serratia odorifera mediated enhancement in susceptibility of Aedes aegypti for chikungunya virus. AB - BACKGROUND & OBJECTIVES: The susceptibility of the mosquito to the invading pathogen is predominantly dictated by the complex interactions between the mosquito midgut and the surface proteins of the invading pathogen. It is well documented that the midgut microbiota plays an important role in determining the susceptibility of the mosquito to the pathogen. In the present study, we investigated the influence of Serratia odorifera, an endogenous cultivable midgut inhabitant of Aedes aegypti on the chikungunya virus (CHIKV) susceptibility to this mosquito. METHODS: Ae. aegypti females free of gutflora were co-fed with CHIKV and either of the two midgut inhabitants namely, S. odorifeara and Microbacterium oxydans. CHIKV dissemination was checked on 10 th day post feeding (DPF) using indirect immunoflurescence assay and plaque assay. CHIKV interacting proteins of the mosquito midgut were identified using virus overlay protein binding assay and MALDI TOF/TOF analysis. RESULTS: The observations revealed that co-feeding of S. odorifera with CHIKV significantly enhanced the CHIKV susceptibility in adult Ae. aegypti, as compared to the mosquitoes fed with CHIKV alone and CHIKV co-fed with another midgut inhabitant, M. oxydans. Virus overlay protein binding assay (VOPBA) results revealed that porin and heat shock protein (HSP60) of Ae. aegypti midgut brush border membrane fraction interacted with CHIKV. INTERPRETATION & CONCLUSIONS: The results of this study indicated that the enhancement in the CHIKV susceptibility of Ae. aegypti females was due to the suppression of immune response of Ae. aegypti as a result of the interaction between S. odorifera P40 protein and porin on the gut membrane. PMID- 25027088 TI - Isolation of Chandipura virus (Vesiculovirus: Rhabdoviridae) from Sergentomyia species of sandflies from Nagpur, Maharashtra, India. AB - BACKGROUND & OBJECTIVES: An outbreak of acute encephalitis syndrome was reported from Vidarbha region of Maharashtra s0 tate, India, during July 2012. Anti-IgM antibodies against Chandipura virus (CHPV) were detected in clinical samples. Sandfly collections were done to determine their role in CHPV transmission. METHODS: Twenty nine pools of Sergentomyia spp. comprising 625 specimens were processed for virus isolation in Vero E6 cell line. Diagnostic RT-PCR targeting N gene was carried out with the sample that showed cytopathic effects (CPE). The PCR product was sequenced, analysed and the sequences were deposited in Genbank database. RESULTS: CPE in Vero E6 cell line infected with three pools was detected at 48 h post infection. However, virus could be isolated only from one pool. RT-PCR studies demonstrated 527 nucleotide product that confirmed the agent as CHPV. Sequence analysis of the new isolate showed difference in 10-12 nucleotides in comparison to earlier isolates. INTERPRETATION & CONCLUSIONS: This is perhaps the first isolation of CHPV from Sergentomyia spp. in India and virus isolation during transmission season suggests their probable role in CHPV transmission. Further studies need to be done to confirm the precise role of Sargentomyia spp. in CHPV transmission. PMID- 25027089 TI - Low vaccine efficacy of mumps component among MMR vaccine recipients in Chennai, India. AB - Introduction of MMR vaccine was believed to have resulted in a decline in the incidence of measles, mumps and rubella infections. However, recent reports suggest the re-emergence of mumps infection worldwide in the vaccinated populations. It was proposed that the reason for this re-emergence was poor efficacy of MMR vaccine. The present study was aimed to investigate mumps infection in MMR vaccinated and non-vaccinated populations in Chennai, India. Blood samples were collected from acute mumps cases (n=74, 42<12 yr age, 54% males) and investigated for IgM antibody against mumps, IgG antibody against measles, mumps and rubella viruses by ELISA. Sixty seven (91%) patients had received MMR vaccine. All the 67 vaccinated cases were positive for parotitis, and mumps IgM. However, only 10 (15%) were positive for IgG. All samples (100%) were positive for rubella and measles IgG. These findings showed the occurrence of mumps infection among MMR vaccinated individuals in Chennai, India. The MMR vaccine failed to generate anti-mumps IgG. The reason may be low vaccine efficacy of the mumps component of the MMR vaccine used. PMID- 25027090 TI - Rapid detection of Brucella by an automated blood culture system at a tertiary care hospital of north India. PMID- 25027091 TI - Rare manifestation of multiple endocrine neoplasia type 2A & cutaneous lichen amyloidosis in a family with RET gene mutation. PMID- 25027092 TI - Pathogenicity of avian influenza H11N1 virus isolated from wild aquatic bird Eurasian Spoonbill (Platalea leucorodia). PMID- 25027093 TI - 18F FDG PET/CT identifies unsuspected bilateral adrenal histoplasmosis in an elderly immuno compromised patient. PMID- 25027094 TI - Triple torus palatinus. PMID- 25027095 TI - Doxorubicin induces sarcoplasmic reticulum calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats. AB - This study aims to explore the changes in calcium regulation in the sarcoplasmic reticulum (SR) during doxorubicin (DOX) treatment. Sprague-Dawley rats were treated with intravenous DOX (1.5 mg/kg) twice weekly for 12 treatments. The hemodynamic changes, myocardial oxidative stress, levels of cardiac toxicity markers, and calcium handling of the myocardial SR were observed. When the accumulation of DOX reached 12 mg/kg, (1) heart weight, left ventricular mass, and lung congestion increased significantly, and ascites appeared; (2) SBP, DBP, MAP, +dP/dt, -dP/dt, and LVSP decreased significantly, and LVEDP increased (p < 0.01); (3) the iNOS activity and MDA and NO concentrations significantly increased, while the SOD decreased (p < 0.05 or 0.01); (4) the serum level of the AST, LDH CPK, cTnI, and BNP increased significantly (p < 0.01); (5) during DOX treatment, the rat SR Ca(2+) absorption function and Ca(2+)-stimulated ATPase activity declined dramatically, as did the SERCA2 and phospholamban levels (p < 0.01). As expected, all these changes became evident with DOX accumulation in vivo (p < 0.05 or 0.01). In conclusion, DOX induces SR calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats. PMID- 25027096 TI - Effects and mechanism of action of ligustrazine on isoprenaline-induced cardiomyocyte hypertrophy. AB - The aim of the study is to explore the effects and mechanism of the action of ligustrazine on isoprenaline-induced cardiomyocyte hypertrophy. Primary culture of neonatal rat cardiomyocytes was used as the model, and isoprenaline was used to induce cardiomyocyte hypertrophy. Effects of different dosages of ligustrazine polysaccharide on the cardiomyocyte were observed. RT-PCR was used to detect the expression of atrial natriuretic factor (ANP) mRNA, and Western blot analysis was used to detect the CaN protein level in cardiomyocytes. After treating with ligustrazine, the significant increase of MDA content and decrease of SOD activity were inhibited in supernatant. Compared to the control group, ANP mRNA in isoprenaline-treated cardiomyocytes was significantly increased (P < 0.05); compared to the isoprenaline group, ANP mRNA was significantly decreased in all ligustrazine groups (P < 0.01). In all ligustrazine groups, the CaN expression was inhibited in isoprenaline-treated cardiomyocytes in a dose-dependent manner. In conclusion, ligustrazine has protective effects on isoprenaline-induced neonatal rat cardiomyocyte, which may be related to the decrease of CaN expression. PMID- 25027097 TI - Editorial overview: Host pathogens. PMID- 25027098 TI - The Vigileo-FloTracTM system: arterial waveform analysis for measuring cardiac output and predicting fluid responsiveness: a clinical review. PMID- 25027099 TI - Why the new severe aortic insufficiency after mitral and tricuspid valve repair? PMID- 25027100 TI - A dilated structure in the left atrium. PMID- 25027101 TI - Randomized trial of fish oil infusion to prevent atrial fibrillation after cardiac surgery: data from an implantable continuous cardiac monitor. AB - OBJECTIVE: To test the hypothesis that perioperative OMEGA-3 polyunsaturated fatty acid infusion would reduce the incidence of postoperative atrial fibrillation in patients after coronary artery bypass grafting as assessed by an implantable continuous cardiac monitor. DESIGN: Prospective, randomized, double blind, placebo-controlled study. SETTING: Tertiary cardiothoracic referral center. PARTICIPANTS: Thirty-nine patients with coronary artery disease who underwent surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were assigned randomly to receive either OMEGA-3 polyunsaturated fatty acids (200 mg/kg/day starting before anesthesia induction for 24 hours followed by 100 mg/kg/day for 7 days) or placebo. The primary outcome was freedom from atrial fibrillation at 2-year follow-up. Reveal((r)) cardiac monitor was implanted subcutaneously in all patients. Data from the cardiac monitor were collected on the 10th day and 3, 6, 12, and 24 months postoperatively. MEASUREMENT AND MAIN RESULTS: Postoperative atrial fibrillation developed in 4 (19%) patients in the control group and in 5 (27.8%) patients in the study group at 10-day follow-up (p = 0.88). At 2-year follow-up, 5 (27.8%) patients in the control group and 6 (35.3%) patients in the study group had atrial fibrillation (p = 0.9). Atrial fibrillation duration predicted risk of cardiovascular hospitalization at the 2 year follow-up (regression coefficient estimate = 0.24, standard error 0.02, p<0.0001; R(2) = 0.74). CONCLUSIONS: Infusion of OMEGA-3 polyunsaturated fatty acids failed to prevent the occurrence of atrial fibrillation in 2 years after coronary artery bypass grafting surgery. The cumulative atrial fibrillation duration registered by the continuous cardiac monitor at the 2-year follow-up was a significant predictor of an adverse outcome. PMID- 25027102 TI - Perioperative management of the Wolff-Parkinson-White syndrome. PMID- 25027103 TI - Elevated levels of angiopoietin-2 as a biomarker for respiratory failure after cardiac surgery. AB - OBJECTIVES: Angiopoietin-1 and angiopoietin-2 are important factors in regulating endothelial vascular permeability. This study evaluated perioperative changes in serum levels of angiopoietin-1 and -2 in patients undergoing cardiac surgery. DESIGN: Measurement of serum levels of angiopoietin-1 and angiopoietin-2 in samples collected during a previously conducted prospective, multicenter, observational study. SETTING: Three university hospitals. PARTICIPANTS: Eighty four adult patients undergoing cardiac surgery. INTERVENTION: Serum levels of angiopoietins were measured at baseline, immediately after surgery, and the day after surgery (POD-1). MEASUREMENTS AND MAIN RESULTS: Serum levels of angiopoietin-2 were elevated by POD-1 (median 3.3 ng/mL, interquartile range [IQR] 2.5-4.6 ng/mL) compared with baseline (median 1.6 ng/mL, IQR 1.3-2.1 ng/mL, p < 0.0001), and angiopoietin-1 levels were decreased immediately after surgery (baseline median 23.2 ng/mL, IQR 10.2-32.8 ng/mL; postoperative median 8.0 ng/mL, IQR 1.5-13.2 ng/mL, p<0.0001). Angiopoietin-2 levels on POD-1 in patients undergoing off-pump coronary artery bypass grafting were significantly lower than those in patients undergoing aortic surgery (p = 0.0009) and valve surgery (p = 0.008). Angiopoietin-2 levels on POD-1 had a predictive performance of the area under the curve (AUC) of the receiver operating characteristic curve 0.74 for mechanical ventilation>3 days. Angiopoietin-1 levels and the angiopoietin 2/angiopoietin-1 ratio showed lower predictive performance (AUC values 0.58 and 0.68, respectively). CONCLUSIONS: Angiopoietin-2 serum levels were elevated after cardiac surgery. Elevated angiopoietin-2 had a good predictive performance for respiratory failure after cardiac surgery, perhaps reflecting the severity of lung dysfunction related to postoperative increases in vascular permeability. PMID- 25027104 TI - Current use of ultrasound transmission gel for transesophageal echocardiogram examinations: a survey of cardiothoracic anesthesiology fellowship directors. AB - OBJECTIVE: Ultrasound transmission gel (USTG) is used routinely to enhance the image quality during transesophageal echocardiogram examinations. Ultrasound gel is manufactured in both sterile and non-sterile preparations, and both preparations have been used during transesophageal echocardiograms in the United States. The United States Food and Drug Administration (FDA) currently recommends that all transesophageal echocardiogram (TEE) examinations be performed using sterile ultrasound gel. The authors sought to identify if anesthesiology departments with cardiothoracic fellowship programs follow current FDA recommendations of using sterile ultrasound gel during TEE examination. DESIGN: Survey. SETTING: Survey of cardiothoracic fellowship directors. The majority of fellowship directors practice in academic hospitals although the practice site was not addressed in the survey. PARTICIPANTS: Fellowship directors volunteered to participate in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survey responses were tallied using the website, www.surveymonkey.com, and 56% of respondents do not currently follow the current FDA recommendations. CONCLUSIONS: A majority of cardiothoracic program director respondents to the authors' survey do not utilize single-use sterile packets of USTG for TEE examinations. While the infectious risk of USTG used for TEE examinations from multiple-use containers versus single-use sterile containers has not been established clearly, a change in practice to follow the current FDA recommendations may be advised. PMID- 25027105 TI - In response to Dr. Kanchi Muralidhar. PMID- 25027106 TI - In-hospital mortality and morbidity after robotic coronary artery surgery. AB - OBJECTIVES: The objective of this study was to assess the impact of robotic approaches on outcomes of coronary bypass surgery. DESIGN: Retrospective national database analysis. SETTING: United States hospitals. PARTICIPANTS: A weighted sample of 484,128 patients undergoing isolated coronary artery surgery identified from the Nationwide Inpatient Sample from 2008 through 2010. INTERVENTIONS: Robotically assisted coronary artery bypass surgery versus conventional bypass surgery. MEASUREMENTS AND MAIN RESULTS: Robotic approaches were used in 2,582 patients (0.4%). Patients undergoing robotic surgery were less likely to be female (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.87), present with acute myocardial infarction (OR 0.53, 95% CI 0.38-0.73), or have cerebrovascular disease (OR 0.41, 95% CI 0.23-0.71) compared to patients undergoing conventional surgery. In 59% of robotic cases, a single bypass was performed, and 2 bypasses were performed in 25% of cases. After adjusting for comorbidity, reduced postoperative stroke (0.0% v 1.5%, p = 0.045) and transfusion (13.5% v 24.4%, p = 0.001) rates were observed in patients who underwent robotic single-bypass surgery compared to conventional surgery. In patients undergoing multiple bypass grafts, higher mortality (1.1% v 0.5%), and cardiovascular complications (12.2% v 10.6%) were observed when robotic assistance was used, but the differences were not statistically significant (p = 0.5). The mean number of robotic cases carried out annually at institutions sampled was 6. CONCLUSIONS: Robotic assistance is associated with lower rates of postoperative complications in highly selected patients undergoing single coronary artery bypass surgery, but the benefits of this approach are reduced in patients who require multiple coronary artery bypass grafts. PMID- 25027107 TI - Inflammatory factors in the circulation of patients with active rheumatoid arthritis stimulate osteoclastogenesis via endogenous cytokine production by osteoblasts. AB - SUMMARY: The combination of cytokines present in the circulation of patients with active rheumatoid arthritis might contribute to the generalized bone loss that commonly occurs in these patients, by directly inhibiting osteoblast proliferation and differentiation, but especially by enhancing endogenous cytokine (i.e., receptor activator of nuclear factor-kappa B ligand (RANKL) and interleukin-6 (IL)-6) production by osteoblasts, thereby stimulating osteoclastogenesis. INTRODUCTION: Generalized bone loss, as occurs in patients with rheumatoid arthritis (RA), is related to elevated levels of circulating cytokines. Individual cytokines have deleterious effects on proliferation and differentiation of osteoblast cell lines, but little is known about the effect of the interaction between inflammatory factors in the circulation of patients with active RA on human osteoblast function, including their communication towards other bone cells. We investigated whether serum from patients with active RA enhances cytokine production by osteoblasts, thereby effectively altering osteoblast-stimulated osteoclastogenesis. METHODS: Serum was obtained from 20 patients with active RA (active RA sera) and from the same patients in clinical remission (remission RA sera). To determine osteoclastogenesis, RA serum pretreated primary human osteoblast cultures were established in direct contact with human osteoclast precursors in the presence or absence of osteoprotegerin (OPG) or IL-6 inhibitor. RESULTS: Compared to remission RA sera, active RA sera inhibited osteoblast proliferation and differentiation in vitro as demonstrated by a reduced DNA content and gene expression of KI-67, collagen type 1, osteopontin, and osteocalcin. Active RA sera inhibited OPG expression and enhanced RANKL and IL-6 expression but did not alter IL-8 expression in osteoblasts. IL-1beta, IL-17, and tumor necrosis factor-alpha (TNF-alpha) expression were undetectable. In coculture, active RA sera treatment of osteoblasts stimulated while addition of OPG or IL-6 inhibitory antibodies significantly reduced the number of osteoclasts. CONCLUSION: Active RA sera contain circulating factors, likely cytokines and chemokines, that might contribute to bone loss by directly inhibiting osteoblast proliferation and differentiation, but especially, these factors modulate endogenous cytokine production by osteoblasts, thereby affecting osteoclastogenesis. PMID- 25027108 TI - The measurement of bone mineral density of bilateral proximal humeri using DXA in patients with unilateral rotator cuff tear. AB - We propose that the measurement of the bone mineral density (BMD) of the proximal humerus be standardized using the dual energy X-ray absorptiometry (DXA) in patients supposed to undergo rotator cuff repair surgery as well as those with the fracture of the proximal humerus as the BMD of the proximal humerus is decreased in these patients. INTRODUCTION: We propose that the measurement of the BMD of the proximal humerus be standardized using the DXA in patients who are supposed to undergo rotator cuff repair surgery as well as those with the fracture of the proximal humerus. METHODS: We conducted the prospective study in 213 patients with unilateral rotator cuff tear but without contralateral shoulder pain or disease. In these patients, we preoperatively measured the BMD of the bilateral proximal humeri with a repeat measurement in 20 patients. We predefined three regions of interest (ROIs) in the proximal humerus with the consideration of the rotator cuff repair surgery as well as proximal humeral fractures. RESULTS: The measurement of the BMD of the proximal humerus using the DXA showed excellent reliability (intraclass correlation coefficient > .90). BMD values of all three ROIs in the affected shoulder were significantly lower than those in asymptomatic shoulder (all p < 0.05). In female patients, the BMD values of ROIs in bilateral shoulder were significantly lower than those in male patients (all p < 0.001). In multiple regressions, however, there were no significant correlations between other clinical characteristics, except for the gender, and the BMD of GT in the affected shoulder. CONCLUSIONS: It is imperative that the bone quality of the proximal humerus be accurately evaluated prior to surgery in patients who are supposed to undergo rotator cuff repair using suture anchors as well as in those with proximal humeral fractures. This is because the BMD of the proximal humerus is decreased in these patients. PMID- 25027109 TI - Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized, placebo controlled trial. AB - The effect of an investigational oral calcitonin tablet upon bone mineral density (BMD) of the spine was investigated in postmenopausal women with low bone mass and at increased risk of fracture. Compared to placebo, calcitonin tablets increased lumbar spine BMD. This agent may provide an additional choice for patients. INTRODUCTION: An investigational oral salmon calcitonin preparation was previously shown to increase lumbar spine BMD in postmenopausal women with osteoporosis. Our objective was to evaluate the use of this agent in postmenopausal women with low bone mass and at increased fracture risk but not meeting BMD criteria for osteoporosis. METHODS: Treatment-naive women were randomized to receive oral recombinant salmon calcitonin tablets or placebo once daily for 1 year. Dual-energy X-ray absorptiometry was performed at baseline and at study weeks 28 and 54. CTx-1, a bone resorption marker, was obtained at the same time points. Subjects returned periodically for tolerability assessment and adverse event (AE) recording. RESULTS: One hundred twenty-nine women in the USA were randomized, 86 to calcitonin and 43 to placebo. Calcitonin recipients experienced a significant increase from baseline in lumbar spine BMD; the difference compared with placebo was significant. Dosing at bedtime or with dinner was equally effective. CTx-1 was suppressed in calcitonin recipients but not in placebo subjects. Gastrointestinal AEs were common, but the overall safety profile was comparable between groups. CONCLUSIONS: Oral calcitonin may provide a useful therapeutic alternative for some women with low bone mass. PMID- 25027110 TI - Bone status and fractures in 85 adults with Wilson's disease. AB - Wilson's disease is characterized by copper deposition, especially in the liver and central nervous system. We assessed the prevalent fractures and bone mineral density (BMD) and related risk factors in 85 patients. BMD was normal, but patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk for fractures. INTRODUCTION: Wilson's disease (WD) is characterized by copper deposition, especially in the liver and central nervous system. Two studies showed a high prevalence of osteoporosis in WD patients. We wanted to assess the prevalent fractures and bone mineral density (BMD) and to identify risk factors for bone loss and fractures in a large group of WD patients. METHODS: In this prospective cross-sectional survey at National center of reference for WD, we included 85 patients, 47 women, and 38 men, with a mean age of 35 +/- 10 years, and mean time from diagnosis to study of 21 +/- 9 years; 57 (67%) patients had neurological signs. Peripheral fractures, prevalent radiological vertebral fractures (VFx), and dual-energy X-ray absorptiometry BMD measurements at the femoral neck (FN) and lumbar spine (LS) were studied. RESULTS: Mean LS and FN Z-score was normal (-0.37 +/- 1.20 at LS and -0.06 +/- 1.20 at FN). BMI <19 kg/m(2) and amenorrhea were associated with low BMD. Prevalent peripheral fractures were noted in 43 (51%) and VF in 7 (8%) patients. Severity of neurological involvement and male sex was associated with peripheral fractures, whereas older age, severe neurological involvement, and low BMD and Z score values were associated with VF. CONCLUSION: Our data showing normal BMD overall do not support routine bone status evaluation in adults with WD. However, patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk factors for fractures and may require specific monitoring. PMID- 25027111 TI - Reference equations for ultrasound bone densitometry of the radius in Central European children and adolescents. AB - Bone density measurements are important for evaluation and follow-up of children with alterations in their mineral status (increased risk for fractures and osteoporosis subsequently). Interpretation of these measurements relies on the availability of appropriate reference equations. We developed gender-specific, age-dependent reference values of bone density for Central European children. INTRODUCTION: In recent years, there has been an increasing demand for the measurement of bone density in children exposed to an increased risk of early alterations in their bone status. These values must be compared to an adequate reference population. The aim of the present study was to create reference equations of radial speed of sound (SOS) for Central European children and adolescents. METHODS: In this cross-sectional study, SOS values were measured at the distal third of the radius in 581 Swiss children and adolescents (321 girls and 260 boys) aged 6 to 16 years using the Sunlight Omnisense(r) 7000P quantitative ultrasound system. RESULTS: Gender-specific reference equations for SOS values were derived by polynomial regression and combined a cubic dependence of age and a linear dependence of height. The fitted SOS curves in our study population show a plateau period in both genders for younger ages followed by an increase phase beginning at the age of 12 in girls and 14 in boys. Neither the reported level of physical activity nor additional sport nor self-reported calcium intake influenced the reference equations. CONCLUSIONS: Our results show a good agreement with similar studies using the same measurement technique on other body parts, suggesting a wide applicability of the obtained reference curves over different European populations. PMID- 25027112 TI - Effects of hip abductor muscle forces and knee boundary conditions on femoral neck stresses during simulated falls. AB - Through experiments that simulated sideways falls with a mechanical hip impact simulator, we demonstrated the protective effect of hip abductor muscle forces in reducing peak stresses at the femoral neck and the corresponding risk for hip fracture. INTRODUCTION: Over 90% of hip fractures are due to falls, and an improved understanding the factors that separate injurious and non-injurious falls (via their influence on the peak stress generated at the femoral neck) may lead to improved risk assessment and prevention strategies. The purpose of this study was to measure the effect of muscle forces spanning the hip, and knee boundary conditions, on peak forces and estimated stresses at the femoral neck during simulated falls with a mechanical system. METHODS: We simulated hip abductor muscle forces and knee boundary conditions with a mechanical hip impact simulator and measured forces and stresses at the femoral neck during sideways falls. RESULTS: Peak compressive and tensile stresses, shear force, bending moment, and axial force are each associated with hip abductor muscle forces and knee boundary conditions (p < 0.0005). When muscle force increased from 400 to 1,200 N, peak compressive and tensile stresses decreased 24 and 56%, respectively. These effects were similar to the magnitude of decline in fracture strength associated with osteoporosis and arose from the tension-band effect of the muscle in reducing the bending moment by 37%. Furthermore, peak compressive and tensile stresses averaged 40 and 51% lower, respectively, in the free knee than fixed knee condition. CONCLUSIONS: Contraction of the hip abductor muscles at the moment of impact during a fall, and landing with the knee free of constraints, substantially reduced peak compressive and tensile stresses at the femoral neck and risk for femoral fracture in a sideways fall. PMID- 25027113 TI - Altered distribution of the EphA4 kinase in hippocampal brain tissue of patients with Alzheimer's disease correlates with pathology. AB - Synaptic dysfunction occurs early in the progression of Alzheimer's disease (AD) and correlates with memory decline. There is emerging evidence that deregulation of Erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinases (RTK) signaling contributes to the aberrant synaptic functions associated with neurodegeneration. The Eph receptor A4 is highly expressed in human adult hippocampal brain tissue and was previously linked to cognitive impairment in a transgenic mouse model for AD. Whether EphA4 levels are altered in AD brain remains elusive. Therefore we investigated the protein levels and localization of EphA4 in human hippocampus derived from AD (n = 29) as well as non-demented control cases (n = 19). The total EphA4 protein levels were not changed in AD patients compared to control cases. However, immunohistochemical localization of EphA4 revealed an altered distribution in AD compared to control hippocampus. EphA4 immunoreactivity was observed in plaque-like structures in AD cases. Double labelling with phosphorylated tau and amyloid beta indicates that EphA4 co localizes with neuritic plaques in AD. This altered distribution pattern was observed at early stages (Braak stage II) and correlates with the hallmarks of AD pathology suggesting a reduced availability of EphA4 that is likely to contribute to synaptic dysfunction that occurs early in AD. PMID- 25027114 TI - CD117 expression influences proliferation but not survival in canine mammary tumours. AB - CD117 is a transmembrane tyrosine kinase receptor encoded by the c-Kit proto oncogene. The immunohistochemical expression of CD117 was examined in 49 specimens of canine mammary glands (eight normal/hyperplastic, 11 benign tumours and 30 malignant tumours). Expression was assessed as: (1) presence or absence of CD117; (2) membrane, cytoplasmic, or both, distributions; and (3) percentage of CD117-labelled cells. None of these three immunohistochemical parameters was correlated with the type of mammary tissue (i.e. normal, benign or malignant), histotypes or histological stage of malignant tumours, or survival. An association was observed between Ki67 index and all three CD117 labelling parameters only for malignant tumours, with a significant increase in proliferative activity in tumours expressing CD117, mainly with both cytoplasmic and membrane expression. PMID- 25027115 TI - The highest prognostic impact of LDH among International Prognostic Indices (IPIs): an explorative study of five IPI factors among patients with DLBCL in the era of rituximab. AB - Although the International Prognostic Index (IPI) is considered as the current standard prognostication system for diffuse large B-cell lymphoma (DLBCL), prognostic heterogeneity is suggested to exist among the patients within the same IPI risk group. Hence, we investigated the pattern of distribution and prognostic impact of five IPI factors within the same IPI score. We retrospectively reviewed the medical records of 387 patients newly diagnosed as pathologically proven DLBCL between February 2002 and February 2010. We classified patients to IPI risk scores and categorized them according to the combinations of IPI. Then, we explored the frequency of five IPI factors and analyzed the correlation between these subgroups and efficacy outcomes: complete response (CR), event-free survival (EFS), and overall survival (OS). Survival estimates by IPI score in this cohort corresponded to the classic IPI. Elevated serum level of lactate dehydrogenase (LDH) was the most prevalently distributed factor throughout the scores, and patients with elevated serum level of LDH tended to have lower CR, inferior EFS, and/or OS irrespective of IPI scores. Particularly, among the subgroups of IPI score of 2, elevated serum level of LDH was significantly associated with inferior CR (73.1 vs 95.2 %), 3-year EFS (57 vs 87 %), and 3-year OS (58 vs 82 %). In addition, the higher serum level of LDH, particularly above 2,000 IU/L, was significantly correlated with the inferior survival outcomes (3 year EFS 78.0 vs 58.5 vs 45.5 vs 20.0 %, 3-year OS 86.0 vs 66.2 vs 58.2 vs 40.0 %). In conclusion, among five factors of IPI, elevated serum level of LDH seems to be the most frequently distributed and, more importantly, the most relevant IPI factor with the highest prognostic impact. These findings still warrant further validation in larger cohorts. PMID- 25027116 TI - Assessment of changes in the BRCA2 and P53 genes in breast invasive ductal carcinoma in northeast Brazil. AB - BACKGROUND: BRCA protein interacts with at least 13 different proteins that have been implicated with cancer susceptibility and loss of BRCA function is correlated to sensitivity to DNA crosslinking agents in preclinical models. RESULTS: BRCA2 methylation frequency was 44%, p53 Pro22 allele frequency was 32% and heterozygous frequency of Arg/Pro72 genotype was 60% which could be associated as risk factor for metastasis (p = 0.046 OR = 4.190). Regarding to polymorphism of codon 249 the frequency of Arg249 allele presented 82% which was considered not statistically significant. CONCLUSIONS: There was not statistical significance to BRCA2 promoter methylation with any parameters chosen. However, our findings suggest that patients who present heterozygous genotype at codon 72 of p53 gene may have a major susceptibility to any type of metastasis and this could serve as potential auxiliary biomarker for poor prognosis. PMID- 25027117 TI - A guide into the evolving knowledge of bariatric and metabolic surgery. PMID- 25027118 TI - Size-tunable and monodisperse Tm3+/Gd3+-doped hexagonal NaYbF4 nanoparticles with engineered efficient near infrared-to-near infrared upconversion for in vivo imaging. AB - Hexagonal NaYbF4:Tm(3+) upconversion nanoparticles hold promise for use in high contrast near-infrared-to-near-infrared (NIR-to-NIR) in vitro and in vivo bioimaging. However, significant hurdles remain in their preparation and control of their morphology and size, as well as in enhancement of their upconversion efficiency. Here, we describe a systematic approach to produce highly controlled hexagonal NaYbF4:Tm(3+) nanoparticles with superior upconversion. We found that doping appropriate concentrations of trivalent gadolinium (Gd(3+)) can convert NaYbF4:Tm(3+) 0.5% nanoparticles with cubic phase and irregular shape into highly monodisperse NaYbF4:Tm(3+) 0.5% nanoplates or nanospheres in a pure hexagonal phase and of tunable size. The intensity and the lifetime of the upconverted NIR luminescence at 800 nm exhibit a direct dependence on the size distribution of the resulting nanoparticles, being ascribed to the varied surface-to-volume ratios determined by the different nanoparticle size. Epitaxial growth of a thin NaYF4 shell layer of ~2 nm on the ~22 nm core of hexagonal NaYbF4:Gd(3+) 30%/Tm(3+) 0.5% nanoparticles resulted in a dramatic 350 fold NIR upconversion efficiency enhancement, because of effective suppression of surface-related quenching mechanisms. In vivo NIR-to-NIR upconversion imaging was demonstrated using a dispersion of phospholipid-polyethylene glycol (DSPE-PEG)-coated core/shell nanoparticles in phosphate buffered saline. PMID- 25027119 TI - Implementing the Resource in Clinic Program in primary care delivery: a team based dyad approach. AB - Alberta's Primary Care Networks (PCNs) bring together family physicians and other health professionals to provide local, comprehensive, and readily accessible primary care services to patients. The Edmonton North PCN, one of the largest in the province, piloted the Resource in Clinic (RIC) Program with objectives to increase efficiencies in the use of physician time, increase physician workplace satisfaction, increase unattached/orphan patient access, and decrease patient wait times. An evaluation of the RIC Program employed surveys (completed by physicians with RICs, RIC staff, and patients), log chart recording, and physician billing data and cost analysis. The findings indicated high satisfaction with the model, increased physician visits, and improved access for patient with comorbidities. The study did not demonstrate increased number of patients or new patients, nor could conclusions be drawn related to patient wait times. PMID- 25027122 TI - The Smiths: W. Blair Bruce. PMID- 25027123 TI - Guideline addresses care for prostate cancer survivors. PMID- 25027124 TI - Statin use may stop when illness is terminal, study says. PMID- 25027134 TI - Quality reporting that addresses disparities in health care. PMID- 25027135 TI - The transformation of diagnostic radiology in the ACO era. PMID- 25027136 TI - A piece of my mind. The M&M game. PMID- 25027137 TI - Advancing telecare for pain treatment in primary care. PMID- 25027138 TI - Declining stroke incidence and improving survival in US communities: evidence for success and future challenges. PMID- 25027139 TI - Telecare collaborative management of chronic pain in primary care: a randomized clinical trial. AB - IMPORTANCE: Chronic musculoskeletal pain is among the most prevalent, costly, and disabling medical disorders. However, few clinical trials have examined interventions to improve chronic pain in primary care. OBJECTIVE: To determine the effectiveness of a telecare intervention for chronic pain. DESIGN, SETTING, AND PARTICIPANTS: The Stepped Care to Optimize Pain Care Effectiveness (SCOPE) study was a randomized trial comparing a telephone-delivered collaborative care management intervention vs usual care in 250 patients with chronic (>=3 months) musculoskeletal pain of at least moderate intensity (Brief Pain Inventory [BPI] score >=5). Patients were enrolled from 5 primary care clinics in a single Veterans Affairs medical center from June 2010 through May 2012, with 12-month follow-up completed by June 2013. INTERVENTIONS: Patients were randomized either to an intervention group (n = 124) or to a usual care group whose members received all pain care as usual from their primary care physicians (n = 126). The intervention group received 12 months of telecare management that coupled automated symptom monitoring with an algorithm-guided stepped care approach to optimizing analgesics. MAIN OUTCOMES AND MEASURES: Primary outcome was the BPI total score, which ranges from 0 ("no pain") to 10 ("pain as bad as you can imagine") and for which a 1-point change is considered clinically important. Secondary pain outcomes included BPI interference and severity, global pain improvement, treatment satisfaction, and use of opioids and other analgesics. RESULTS: Overall, mean (SD) baseline BPI scores in the intervention and control groups were 5.31 (1.81) and 5.12 (1.80), respectively. Compared with usual care, the intervention group had a 1.02-point lower (95% CI, -1.58 to -0.47) BPI score at 12 months (3.57 vs 4.59). Patients in the intervention group were nearly twice as likely to report at least a 30% improvement in their pain score by 12 months (51.7% vs 27.1%; relative risk, 1.9 [95% CI, 1.4 to 2.7]), with a number needed to treat of 4.1 (95% CI, 3.0 to 6.4) for a 30% improvement. Secondary pain outcomes also improved. Few patients in either group required opioid initiation or dose escalation. CONCLUSIONS AND RELEVANCE: Telecare collaborative management increased the proportion of primary care patients with improved chronic musculoskeletal pain. This was accomplished by optimizing nonopioid analgesic medications using a stepped care algorithm and monitoring. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00926588. PMID- 25027140 TI - Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial. AB - IMPORTANCE: Primary Sjogren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited. OBJECTIVE: To evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjogren syndrome: dryness, pain, and fatigue. DESIGN, SETTING, AND PARTICIPANTS: From April 2008 to May 2011, 120 patients with primary Sjogren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome), and week 48. The last follow-up date for the last patient was May 15, 2012. INTERVENTIONS: Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue. RESULTS: At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group. CONCLUSIONS AND RELEVANCE: Among patients with primary Sjogren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00632866. PMID- 25027141 TI - Stroke incidence and mortality trends in US communities, 1987 to 2011. AB - IMPORTANCE: Prior studies have shown decreases in stroke mortality over time, but data on validated stroke incidence and long-term trends by race are limited. OBJECTIVE: To study trends in stroke incidence and subsequent mortality among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort from 1987 to 2011. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 14,357 participants (282,097 person-years) free of stroke at baseline was facilitated in 4 different US communities. Participants were recruited for the purpose of studying all stroke hospitalizations and deaths and for collection of baseline information on cardiovascular risk factors (via interviews and physical examinations) in 1987-1989. Participants were followed up (via examinations, annual phone interviews, active surveillance of discharges from local hospitals, and linkage with the National Death Index) through December 31, 2011. The study physician reviewers adjudicated all possible strokes and classified them as definite or probable ischemic or hemorrhagic events. MAIN OUTCOMES AND MEASURES: Trends in rates of first-ever stroke per 10 years of calendar time were estimated using Poisson regression incidence rate ratios (IRRs), with subsequent mortality analyzed using Cox proportional hazards regression models and hazard ratios (HRs) overall and by race, sex, and age divided at 65 years. RESULTS: Among 1051 (7%) participants with incident stroke, there were 929 with incident ischemic stroke and 140 with incident hemorrhagic stroke (18 participants had both during the study period). Crude incidence rates were 3.73 (95% CI, 3.51-3.96) per 1000 person-years for total stroke, 3.29 (95% CI, 3.08-3.50) per 1000 person-years for ischemic stroke, and 0.49 (95% CI, 0.41-0.57) per 1000 person-years for hemorrhagic stroke. Stroke incidence decreased over time in white and black participants (age-adjusted IRRs per 10-year period, 0.76 [95% CI, 0.66-0.87]; absolute decrease of 0.93 per 1000 person-years overall). The decrease in age adjusted incidence was evident in participants age 65 years and older (age adjusted IRR per 10-year period, 0.69 [95% CI, 0.59-0.81]; absolute decrease of 1.35 per 1000 person-years) but not evident in participants younger than 65 years (age-adjusted IRR per 10-year period, 0.97 [95% CI, 0.76-1.25]; absolute decrease of 0.09 per 1000 person-years) (P = .02 for interaction). The decrease in incidence was similar by sex. Of participants with incident stroke, 614 (58%) died through 2011. The mortality rate was higher for hemorrhagic stroke (68%) than for ischemic stroke (57%). Overall, mortality after stroke decreased over time (hazard ratio [HR], 0.80 [95% CI, 0.66-0.98]; absolute decrease of 8.09 per 100 strokes after 10 years [per 10-year period]). The decrease in mortality was mostly accounted for by the decrease at younger than age 65 years (HR, 0.65 [95% CI, 0.46-0.93]; absolute decrease of 14.19 per 100 strokes after 10 years [per 10 year period]), but was similar across race and sex. CONCLUSIONS AND RELEVANCE: In a multicenter cohort of black and white adults in US communities, stroke incidence and mortality rates decreased from 1987 to 2011. The decreases varied across age groups, but were similar across sex and race, showing that improvements in stroke incidence and outcome continued to 2011. PMID- 25027142 TI - Time elapsed after ischemic stroke and risk of adverse cardiovascular events and mortality following elective noncardiac surgery. AB - IMPORTANCE: The timing of surgery in patients with recent ischemic stroke is an important and inadequately addressed issue. OBJECTIVE: To assess the safety and importance of time elapsed between stroke and surgery in the risk of perioperative cardiovascular events and mortality. DESIGN, SETTING, AND PARTICIPANTS: Danish nationwide cohort study (2005-2011) including all patients aged 20 years or older undergoing elective noncardiac surgeries (n=481,183 surgeries). EXPOSURES: Time elapsed between stroke and surgery in categories and as a continuous measure. MAIN OUTCOMES AND MEASURES: Risk of major adverse cardiovascular events (MACE; including ischemic stroke, acute myocardial infarction, and cardiovascular mortality) and all-cause mortality up to 30 days after surgery. Odds ratios (ORs) were calculated by multivariable logistic regression models. RESULTS: Crude incidence rates of MACE among patients with (n = 7137) and without (n = 474,046) prior stroke were 54.4 (95% CI, 49.1-59.9) vs 4.1 (95% CI, 3.9-4.2) per 1000 patients. Compared with patients without stroke, ORs for MACE were 14.23 (95% CI, 11.61-17.45) for stroke less than 3 months prior to surgery, 4.85 (95% CI, 3.32-7.08) for stroke 3 to less than 6 months prior, 3.04 (95% CI, 2.13-4.34) for stroke 6 to less than 12 months prior, and 2.47 (95% CI, 2.07-2.95) for stroke 12 months or more prior. MACE risks were at least as high for low-risk (OR, 9.96; 95% CI, 5.49-18.07 for stroke <3 months) and intermediate-risk (OR, 17.12; 95% CI, 13.68-21.42 for stroke <3 months) surgery compared with high-risk surgery (OR, 2.97; 95% CI, 0.98-9.01 for stroke <3 months) (P = .003 for interaction). Similar patterns were found for 30-day mortality: ORs were 3.07 (95% CI, 2.30-4.09) for stroke less than 3 months prior, 1.97 (95% CI, 1.22-3.19) for stroke 3 to less than 6 months prior, 1.45 (95% CI, 0.95-2.20) for stroke 6 to less than 12 months prior, and 1.46 (95% CI, 1.21 1.77) for stroke 12 months or more prior to surgery compared with patients without stroke. Cubic regression splines performed on the stroke subgroup supported that risk leveled off after 9 months. CONCLUSIONS AND RELEVANCE: A history of stroke was associated with adverse outcomes following surgery, in particular if time between stroke and surgery was less than 9 months. After 9 months, the associated risk appeared stable yet still increased compared with patients with no stroke. The time dependency of risk may warrant attention in future guidelines. PMID- 25027144 TI - The need to revisit VTE quality measures. PMID- 25027145 TI - Erosive plaque on scrotum. PMID- 25027143 TI - Does this adult patient have early HIV infection?: The Rational Clinical Examination systematic review. AB - IMPORTANCE: Timely identification of human immunodeficiency virus (HIV) infection in adults can contribute to reduced mortality and likelihood of further HIV transmission. During the first 6 months after infection, known as early HIV infection, patients often report a well-described constellation of symptoms and signs. However, the literature examining utility of the clinical examination in identifying early infection has not been systematically assessed. OBJECTIVE: To assess the accuracy of symptoms and signs in identifying early HIV infection among adults. DATA SOURCES: We searched MEDLINE and EMBASE (1981-May, 2014) for articles investigating symptoms and signs of early HIV infection in adults and searched reference lists of retrieved articles. STUDY SELECTION: We retained original studies that compared symptoms and signs among patients with early HIV infection in comparison to HIV-negative individuals. DATA EXTRACTION AND SYNTHESIS: Data were extracted and used to calculate sensitivity, specificity, and likelihood ratios (LRs), and meta-analysis was used to calculate summary LRs. RESULTS: Of 1356 studies, 16 studies included data that were eligible for meta analysis and included a total of 24,745 patients and 1253 cases of early HIV infection. Symptoms that increased the likelihood of early HIV infection the most included genital ulcers (LR, 5.4; 95% CI, 2.5-12), weight loss (LR, 4.7; 95% CI, 2.1-7.2), vomiting (LR, 4.6; 95% CI, 2.5-8.0), and swollen lymph nodes (LR, 4.6; 95% CI, 1.3-8.0). No symptoms had an LR that was 0.5 or lower, but the absence of recent fever (LR, 0.74; 95% CI, 0.64-0.84) slightly decreased the likelihood of early HIV infection. The presence of lymphadenopathy on physical examination was the most useful sign (LR, 3.1; 95% CI, 1.0-5.2). No sign had an LR of 0.5 or less, but the absence of lymphadenopathy slightly decreased the likelihood of early HIV infection (LR, 0.70, 95% CI, 0.49-0.92). Using data from studies that considered combinations of findings (range of possible findings, 4-17), the summary LR for individuals with 0 findings was 0.47 (95% CI, 0.38-0.58). CONCLUSIONS AND RELEVANCE: The limited utility of the clinical examination to detect or rule out early HIV infection highlights the importance of routine testing for HIV infection among adults. PMID- 25027146 TI - Physician registration for deceased organ donation. PMID- 25027147 TI - Guidelines for managing high blood pressure. PMID- 25027148 TI - Guidelines for managing high blood pressure. PMID- 25027149 TI - Guidelines for managing high blood pressure. PMID- 25027150 TI - Guidelines for managing high blood pressure--reply. PMID- 25027151 TI - Interpreting whole-genome sequencing. PMID- 25027152 TI - Interpreting whole-genome sequencing--reply. PMID- 25027153 TI - Addressing suicide risk in emergency department patients. PMID- 25027154 TI - Addressing suicide risk in emergency department patients. PMID- 25027156 TI - Some medical aspects of vacation time. PMID- 25027157 TI - Design of a randomised acupuncture trial on functional neck/shoulder stiffness with two placebo controls. AB - BACKGROUND: Functional neck/shoulder stiffness is one of the most well-known indications for acupuncture treatment in Japan. There is little evidence for the effectiveness of acupuncture treatment for functional neck/shoulder stiffness. Research using two different placebos may allow an efficient method to tease apart the components of real acupuncture from various kinds of 'non-specific' effects such as ritual with touch or ritual alone. Herein, we describe a protocol of an ongoing, single-centre, randomised, placebo-controlled trial which aims to assess whether, in functional neck/shoulder stiffness, acupuncture treatment with skin piercing has a specific effect over two types of placebo: skin-touching plus ritual or ritual alone. METHODS: Six acupuncturists and 400 patients with functional neck/shoulder stiffness are randomly assigned to four treatment groups: genuine acupuncture penetrating the skin, skin-touch placebo or no-touch placebo needles in a double-blind manner (practitioner-patient blinding) or no treatment control group. Each acupuncturist applies a needle to each of four acupoints (Bladder10, Small Intestine14, Gallbladder21 and Bladder42) in the neck/shoulder to 50 patients. Before, immediately after and 24 hours after the treatment, patients are asked about the intensity of their neck/shoulder stiffness. After the treatment, practitioners and patients are asked to guess whether the treatment is "penetrating", "skin-touch" or "no-touch" or to record "cannot identify the treatment". DISCUSSION: In addition to intention-to-treat analysis, we will conduct subgroup analysis based on practitioners' or patients' guesses to discuss the efficacy and effectiveness of treatments with skin piercing and various placebo controls. The results of practitioner and patient blinding will be discussed. We believe this study will further distinguish the role of different components of acupuncture. TRIAL REGISTRATION: Current Controlled Trial ISRCTN76896018. PMID- 25027158 TI - Quality of life in mothers of children with cerebral palsy: The role of children's gross motor function. AB - Four hundred and twenty-four Iranian mothers of children with cerebral palsy (CP) were recruited using the convenience sampling approach in a cross-sectional study. The researchers assessed the quality of life (QOL) in mothers according to the gross motor function levels and types of CP. The evaluation was done using a well-validated Persian version of the 36-item Short Form Health Survey (SF-36) questionnaire. In 2012, demographic data and clinical relevant information were also collected in rehabilitation clinics affiliated to Tehran University of Medical Sciences. The results indicated that the mean score for the study sample on physical component summary (PCS) and mental component summary (MCS) was 39.21 and 41.23, respectively. This suggests that participants considered themselves to have a low QOL (p < .05). The mean PCS scores for SF-36 were significantly different between mothers having CP children of different age, levels of motor function, and CP types (p < .05 and p < .01, respectively). The results indicate that mothers of children with CP suffer from poor physical and mental health. Therefore, particular attention should be paid to the QOL in mothers of children with CP, and rehabilitation professionals should offer supportive strategies to promote aspects of their QOL. PMID- 25027159 TI - A year of celebration at Mayo Clinic. PMID- 25027160 TI - Review on modeling anti-antibody responses to monoclonal antibodies. AB - Monoclonal antibodies (mAbs) represent a therapeutic strategy that has been increasingly used in different diseases. mAbs are highly specific for their targets leading to induce specific effector functions. Despite their therapeutic benefits, the presence of immunogenic reactions is of growing concern. The immunogenicity identified as anti-drug antibodies (ADA) production due to the continuous administration of mAbs may affect the pharmacokinetics (PK) and/or the pharmacodynamics (PD) of mAbs administered to patients. Therefore, the immunogenicity and its clinical impact have been studied by several authors using PK modeling approaches. In this review, the authors try to present all those models under a unique theoretical mechanism-based framework incorporating the main considerations related to ADA formation, and how ADA may affect the efficacy or toxicity profile of some therapeutic biomolecules. PMID- 25027161 TI - Prooxidant-antioxidant balance in patients with traumatic brain injury. AB - Brain trauma is an important cause of mortality and disability among young people worldwide. One of the mechanisms of post-traumatic secondary brain damage is related to free radical release and oxidative stress (OS). OS is the consequence of an imbalance between pro-oxidants and antioxidants in favor of pro-oxidants. This imbalance may lead to macromolecule damage including lipid peroxidation, protein crosslinking, DNA damage and changes in growth and function of cells in brain. Free radical release and subsequent lipid peroxidation are early events following neural tissues injury and are associated with hypo-perfusion, edema, and disruption of axonal guidance. In this study, we determined the prooxidant antioxidant balance (PAB) in patients with brain injury, and its correlation with number of demographic and clinical parameters. Sera from 98 patients with traumatic brain and 100 healthy subjects were collected. The serum PAB was measured. Age, sex, GCS (Glasgow coma scale), mechanism of injury, brain lesions found on CT scan and lesions in other parts of the body, caused by trauma, were determined. A significantly higher PAB value was observed in the patient group (138.97 +/- 15.9 HK unit) compared to the controls (60.82 +/- 12.6 HK) (P = 0.001). In the patient group, there was no significant correlation of PAB with GCS, brain lesion characteristic, mechanism of injury, other accompanying traumatic injury, age and gender. When patients were classified into three groups according to GCS: group 1 (GCS>13, n = 28, PAB serum value = 138.51 +/- 62.66 HK), group 2 (GCS between 8 and 12, n = 29, PAB serum value = 162.7 +/- 50.6 HK) and group 3 (GCS <8, n = 41, PAB serum value = 155.56 +/- 58.21 HK); there was no significant difference between groups. The serum PAB values were higher in patients with traumatic brain injury, although this was not associated with the extent of injury. PMID- 25027162 TI - Myoclonus as the main presentation of Epstein-Barr virus encephalitis. PMID- 25027163 TI - Effects of visual span on reading speed and parafoveal processing in eye movements during sentence reading. AB - The visual span (or ''uncrowded window''), which limits the sensory information on each fixation, has been shown to determine reading speed in tasks involving rapid serial visual presentation of single words. The present study investigated whether this is also true for fixation durations during sentence reading when all words are presented at the same time and parafoveal preview of words prior to fixation typically reduces later word-recognition times. If so, a larger visual span may allow more efficient parafoveal processing and thus faster reading. In order to test this hypothesis, visual span profiles (VSPs) were collected from 60 participants and related to data from an eye-tracking reading experiment. The results confirmed a positive relationship between the readers' VSPs and fixation based reading speed. However, this relationship was not determined by parafoveal processing. There was no evidence that individual differences in VSPs predicted differences in parafoveal preview benefit. Nevertheless, preview benefit correlated with reading speed, suggesting an independent effect on oculomotor control during reading. In summary, the present results indicate a more complex relationship between the visual span, parafoveal processing, and reading speed than initially assumed. PMID- 25027165 TI - Migrants to pay 150% of NHS costs for their care. PMID- 25027164 TI - Color-detection thresholds in rhesus macaque monkeys and humans. AB - Macaque monkeys are a model of human color vision. To facilitate linking physiology in monkeys with psychophysics in humans, we directly compared color detection thresholds in humans and rhesus monkeys. Colors were defined by an equiluminant plane of cone-opponent color space. All subjects were tested on an identical apparatus with a four-alternative forced-choice task. Targets were 2 degrees square, centered 2 degrees from fixation, embedded in luminance noise. Across all subjects, the change in detection thresholds from initial testing to plateau performance ("learning") was similar for +L - M (red) colors and +M - L (bluish-green) colors. But the extent of learning was higher for +S (lavender) than for -S (yellow-lime); moreover, at plateau performance, the cone contrast at the detection threshold was higher for +S than for -S. These asymmetries may reflect differences in retinal circuitry for S-ON and S-OFF. At plateau performance, the two species also had similar detection thresholds for all colors, although monkeys had shorter reaction times than humans and slightly lower thresholds for colors that modulated L/M cones. We discuss whether these observations, together with previous work showing that monkeys have lower spatial acuity than humans, could be accounted for by selective pressures driving higher chromatic sensitivity at the cost of spatial acuity amongst monkeys, specifically for the more recently evolved L - M mechanism. PMID- 25027166 TI - Efficient, solvent-free hydrogenation of alpha-angelica lactone catalysed by Ru/C at atmospheric pressure and room temperature. AB - The hydrogenation of alpha-angelica lactone was investigated over Ru/C. A mild protocol was developed, which resulted in full conversion and 96% selectivity toward gamma-valerolactone. The reaction network was investigated and alpha angelica lactone was employed in the one-pot conversion into 2 methyltetrahydrofuran, demonstrating its superiority as a platform molecule in potential biorefinery schemes. PMID- 25027167 TI - Combined effects of smoking and interleukin-6 and C-reactive protein genetic variants on endothelial function, inflammation, thrombosis and incidence of coronary artery disease. PMID- 25027168 TI - The effect of percutaneous renal denervation on muscle sympathetic nerve activity in hypertensive patients. AB - OBJECTIVE: The rationale of percutaneous renal denervation (RDN) is based on extensive studies suggesting that renal nerves contribute to hypertension and that they comprise a sensible treatment target. Muscle sympathetic nerve activity (MSNA) is considered to be one of the few reliable methods to quantify central sympathetic activity. The aim of this current study is to determine the effect of RDN on MSNA in a standardized fashion. METHODS: MSNA was determined in 13 patients before and 6months after RDN. Anti-hypertensive medication was stopped before MSNA. If cessation of medication was considered unsafe, a patient was instructed to use the exact same medication on both occasions. RESULTS: Ten sets of MSNA recordings were of good quality for analysis. Mean age was 57 +/- 3 years and mean eGFR was 85 +/- 18 mL/min/1.73 m(2). MSNA was determined twice during a medication free interval in 5 patients; 1 patient used the exact same medication twice, and 4 patients used different drugs. Mean BP changed from 206 +/- 7 over 116 +/- 4 mmHg, to 186 +/- 6 over 106 +/- 3 mmHg, 6 months after RDN (p=0.06 for systolic BP, p=0.04 for diastolic BP). Mean resting heart rate did not change (p=0.44). MSNA did not change after RDN: 37 +/- 4 bursts/min and 43 +/- 4 bursts/min (p=0.11) at baseline and after RDN, respectively. In the 6 patients with standardized medication use during the MSNA sessions, results were comparable. CONCLUSIONS: Treatment with RDN did not result in a change in MSNA. Changes in BP did not correlate with changes in MSNA. PMID- 25027169 TI - Measurement of absolute copy number variation reveals association with essential hypertension. AB - BACKGROUND: The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. METHODS: Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. RESULTS: A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). CONCLUSIONS: Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension. PMID- 25027170 TI - Split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck cancer patients-final results of a randomized clinical trial. AB - OBJECTIVE: Evaluation of the efficacy and toxicity of split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck (H&N) cancer patients. METHODS: We enrolled 101 patients (39 in CHA-CHA and 37 in conventional (Conv.) arm completed the treatment). The CHA-CHA arm patients were irradiated twice a day, 7 days a week, using a fraction dose (fd) of 1.6 Gy up to 64 Gy with an 8-day gap in midterm. Patients in the control (Conv.) arm group were irradiated with a fd of 2 Gy, five times a week to a total dose of 72 74 Gy in the overall treatment time of 50-53 days. Quality of life (QOL) and acute mucosal reaction were evaluated during radiotherapy (RT). After RT, we followed the effect of treatment, QOL, performance status and adverse effects of radiation. For statistical analysis mainly a hierarchical multilevel modelling was used. RESULTS: QOL was most deteriorated in the CHA-CHA arm; the CHA-CHA scheme also caused a relatively stronger acute injury. There were no significant differences in late adverse effects. In the CHA-CHA arm in 35% and in Conv. arm in 30% of patients, disease was controlled during follow-up. Tumour regression 1 year after the treatment was significantly better in the CHA-CHA arm. However, the overall survival rate analysis did not show significant difference between both arms. CONCLUSION: Despite differences in treatment results, we cannot conclude that split-course accelerated hyperfractionated irradiation is superior to conventionally fractionated RT as a sole treatment for advanced H&N cancer patients. ADVANCES IN KNOWLEDGE: Obtained results in the context of published data support the statement that altered fractionations alone do not give an advantage for advanced H&N cancer patients. PMID- 25027172 TI - Non-toxigenic penicillin-resistant cutaneous C. diphtheriae infection: a case report and review of the literature. AB - Here, we report a case of non-toxigenic Corynebacterium diphtheriae in a previously healthy 14-year-old girl that was acquired in Ethiopia and presented locally. This is the first clinical case of penicillin-resistant C. diphtheriae in the UK. This is significant finding because penicillin is the recommended first-line agent for the prophylaxis against and treatment of C. diphtheriae in patients who are not allergic to penicillin. PMID- 25027171 TI - Neurotrophin receptors expression in mesial temporal lobe epilepsy with and without psychiatric comorbidities and their relation with seizure type and surgical outcome. AB - Epilepsy and psychiatric comorbidities are frequently associated, but their common biological substrate is unknown. We have previously reported altered structural elements and neurotrophins (NTs) expression in mesial temporal lobe epilepsy (MTLE) patients with psychiatric comorbidities. NTs receptors can regulate neurotransmission and promote neuroplasticity, being important candidates in the regulation and manifestation of psychopatological states and seizure-related events. MTLE hippocampi of subjects without psychiatric history, MTLE + major depression, MTLE + interictal psychosis derived from epilepsy surgery, and control necropsies were investigated for p75(NTR), TrkB, TrkA, and TrkC immunohistochemistry. Increased expression of p75(NTR), decreased TrkA, unaltered TrkC, and complex alterations involving TrkB expression were seen in MTLE groups. Increased TrkB expression in patients without complete seizure remission and in those with secondarily generalized seizures was seen. Decreased p75(NTR) expression associated with interictal psychosis, and increased TrkB in those with psychosis or major depression was also reported, although their p75(NTR)/TrkB ratios were lower than in MTLE without psychiatric comorbidities. Our results provide evidence of alterations in expression of NTs receptors in the epileptogenic hippocampus that are differentially modulated in presence of psychiatric comorbidities. As already explored in animal models, even in chronic human MTLE increased TrkB expression, among other NT receptors alterations, may play a major role in seizure type, frequency and surgery outcome. PMID- 25027173 TI - New insights into the chemistry of di- and trimetallic iron dithiolene derivatives. Structural, Mossbauer, magnetic, electrochemical and theoretical studies. AB - Reaction of Fe3(CO)12 with 1,2-dithiolene HSC6H2Cl2SH affords a mixture of complexes [Fe2(CO)6(MU-SC6H2Cl2S)] 1, [Fe2(SC6H2Cl2S)4] 2 and [Fe3(CO)7(MU3 SC6H2Cl2S)2] 3. In the course of the reaction the trimetallic cluster 3 is first formed and then converted into the known dinuclear compound 1 to afford finally the neutral diiron tetrakis(dithiolato) derivative 2. Compounds 2 and 3 have been studied by Mossbauer spectroscopy, X-ray crystallography and theoretical calculations. In compound 2 the metal atoms are in an intermediate-spin Fe(III) state (S(Fe) = 3/2) and each metal is bonded to a bridging dithiolene ligand and a non-bridging thienyl radical (S = 1/2). Magnetic measurements show a strong antiferromagnetic coupling in complex 2. Cyclic voltammetry experiments show that the mixed valence trinuclear cluster 3 undergoes a fully reversible one electron reduction. Additionally, compound 3 behaves as an electrocatalyst in the reduction process of protons to hydrogen. PMID- 25027174 TI - Impact of different privacy conditions and incentives on survey response rate, participant representativeness, and disclosure of sensitive information: a randomized controlled trial. AB - BACKGROUND: Anonymous survey methods appear to promote greater disclosure of sensitive or stigmatizing information compared to non-anonymous methods. Higher disclosure rates have traditionally been interpreted as being more accurate than lower rates. We examined the impact of 3 increasingly private mailed survey conditions-ranging from potentially identifiable to completely anonymous-on survey response and on respondents' representativeness of the underlying sampling frame, completeness in answering sensitive survey items, and disclosure of sensitive information. We also examined the impact of 2 incentives ($10 versus $20) on these outcomes. METHODS: A 3X2 factorial, randomized controlled trial of 324 representatively selected, male Gulf War I era veterans who had applied for United States Department of Veterans Affairs (VA) disability benefits. Men were asked about past sexual assault experiences, childhood abuse, combat, other traumas, mental health symptoms, and sexual orientation. We used a novel technique, the pre-merged questionnaire, to link anonymous responses to administrative data. RESULTS: Response rates ranged from 56.0% to 63.3% across privacy conditions (p = 0.49) and from 52.8% to 68.1% across incentives (p = 0.007). Respondents' characteristics differed by privacy and by incentive assignments, with completely anonymous respondents and $20 respondents appearing least different from their non-respondent counterparts. Survey completeness did not differ by privacy or by incentive. No clear pattern of disclosing sensitive information by privacy condition or by incentive emerged. For example, although all respondents came from the same sampling frame, estimates of sexual abuse ranged from 13.6% to 33.3% across privacy conditions, with the highest estimate coming from the intermediate privacy condition (p = 0.007). CONCLUSION: Greater privacy and larger incentives do not necessarily result in higher disclosure rates of sensitive information than lesser privacy and lower incentives. Furthermore, disclosure of sensitive or stigmatizing information under differing privacy conditions may have less to do with promoting or impeding participants' "honesty" or "accuracy" than with selectively recruiting or attracting subpopulations that are higher or lower in such experiences. Pre-merged questionnaires bypassed many historical limitations of anonymous surveys and hold promise for exploring non-response issues in future research. PMID- 25027175 TI - Nanoparticle uptake by airway phagocytes after fungal spore challenge in murine allergic asthma and chronic bronchitis. AB - BACKGROUND: In healthy lungs, deposited micrometer-sized particles are efficiently phagocytosed by macrophages present on airway surfaces; however, uptake of nanoparticles (NP) by macrophages appears less effective and is largely unstudied in lung disease. Using mouse models of allergic asthma and chronic obstructive pulmonary disease (COPD), we investigated NP uptake after challenge with common biogenic ambient air microparticles. METHODS: Bronchoalveolar lavage (BAL) cells from diseased mice (allergic asthma: ovalbumin [OVA] sensitized and COPD: Scnn1b-transgenic [Tg]) and their respective healthy controls were exposed ex vivo first to 3-MUm fungal spores of Calvatia excipuliformis and then to 20-nm gold (Au) NP. Electron microscopic imaging was performed and NP uptake was assessed by quantitative morphometry. RESULTS: Macrophages from diseased mice were significantly larger compared to controls in OVA-allergic versus sham controls and in Scnn1b-Tg versus wild type (WT) mice. The percentage of macrophages containing AuNP tended to be lower in Scnn1b-Tg than in WT mice. In all animal groups, fungal spores were localized in macrophage phagosomes, the membrane tightly surrounding the spore, whilst AuNP were found in vesicles largely exceeding NP size, co-localized in spore phagosomes and occasionally, in the cytoplasm. AuNP in vesicles were located close to the membrane. In BAL from OVA-allergic mice, 13.9 +/- 8.3% of all eosinophils contained AuNP in vesicles exceeding NP size and close to the membrane. CONCLUSIONS: Overall, AuNP uptake by BAL macrophages occurred mainly by co-uptake together with other material, including micrometer-sized ambient air particles like fungal spores. The lower percentage of NP containing macrophages in BAL from Scnn1b-Tg mice points to a change in the macrophage population from a highly to a less phagocytic phenotype. This likely contributes to inefficient macrophage clearance of NP in lung disease. Finally, the AuNP containing eosinophils in OVA-allergic mice show that other inflammatory cells present on airway surfaces may substantially contribute to NP uptake. PMID- 25027176 TI - Raman spectroscopic study of the repair of surgical bone defects grafted or not with biphasic synthetic micro-granular HA + beta-calcium triphosphate irradiated or not with lambda850 nm LED light. AB - The handling of bone losses due to different etiologic factors is difficult and many techniques are aim to improve repair, including a wide range of biomaterials and, recently, photobioengineering. This work aimed to assess, through Raman spectroscopy, the level of bone mineralization using the intensities of the Raman peaks of both inorganic (~960, ~1,070, and 1,077 cm(-1)) and organic (~1,454 and ~1,666 cm(-1)) contents of bone tissue. Forty rats were divided into four groups each subdivided into two subgroups according to the time of sacrifice (15 and 30 days). Surgical bone defects were made on the femur of each animal with a trephine drill. On animals of group clot, the defect was filled only by blood clot, on group LED, the defect filled with the clot was further irradiated. On animals of groups biomaterial and LED + biomaterial, the defect was filled by biomaterial and the last one was further irradiated (lambda850 +/- 10 nm, 150 mW, Phi ~ 0.5 cm(2), 20 J/cm(2)-session, 140 J/cm(2)-treatment) at 48-h intervals and repeated for 2 weeks. At both 15th and 30th days following sacrifice, samples were taken and analyzed by Raman spectroscopy. At the end of the experimental time, the intensity of hydroxyapatite (HA) (~960 cm(-1)) were higher on group LED + biomaterial and the peaks of both organic content (~1,454 and ~1,666 cm(-1)) and transitional HA (~1,070 and ~1,077 cm(-1)) were lower on the same group. It is concluded that the use of LED phototherapy associated to biomaterial was effective in improving bone healing on bone defects as a result of the increasing deposition of HA measured by Raman spectroscopy. PMID- 25027177 TI - Comparison of the change in the dimension of the pulmonary vein ostia immediately after pulmonary vein isolation for atrial fibrillation-open irrigated-tip catheters versus non-irrigated conventional 4 mm-tip catheters. AB - INTRODUCTION: A difference in the lesion formation between open irrigated-tip (OITC) and non-irrigated 4-mm-tip catheters (NITC) may result in a difference in the dimension of the pulmonary vein (PV) ostia after PV isolation of atrial fibrillation (AF). This study evaluated the difference using intracardiac echocardiography (ICE) before and immediately after an extensive encircling PV isolation (EPVI) with an OITC and with an NITC. METHODS AND RESULTS: We studied 100 consecutive patients (OITC group, 54; NITC group, 46) who received EPVI. Changes in the vessel, lumen, and wall thickness areas of the PVs were evaluated at the PV ostia by ICE. There were no significant differences in the baseline characteristics and acute success rate of the EPVI between the OITC and NITC groups. The energy delivered to achieve EPVI was higher in the OITC group than that in the NITC group (34,967 +/- 13,222 J vs. 28,300 +/- 10,614 J; p=0.01). After the ablation, the reduction in the vessel and lumen cross-sectional areas was significantly smaller in the OITC group than that in the NITC group (-9.05 +/ 28.4 % vs. -21.2 +/- 28.8 %, p<0.001; -8.76 % vs. -17.7 +/- 26.9 %, p=0.003). The wall thickness area slightly decreased in the OITC group, but increased in the NITC group (-2.96 +/- 38.4 % vs. 10.5 +/- 76.6 %, p=0.591). During a median follow-up of 234 days, there was no significant difference in the AF recurrence after the initial ablation procedure between the two groups. CONCLUSION: Greater PV ostial narrowing occurred with the NITC than OITC immediately after the EPVI. PV ostial wall edema was noted with only the NITC. These findings suggested that an OITC might reduce any acute PV narrowing and wall edema as compared with an NITC. PMID- 25027178 TI - Dentin sialophosphoprotein: a regulatory protein for dental pulp stem cell identity and fate. AB - The dentin sialophosphoprotein (dspp) transcript is expressed during tooth development as a DSPP precursor protein, which then undergoes cleavage to form mature dentin sialoprotein (DSP) and phosphophoryn (PP) proteins. Previous studies using DSPP-knockout (KO) mice have reported that these animals have hypomineralized teeth, thin dentin, and a large dental pulp chamber, similar to those from patients with dentinogenesis imperfecta III. However, there is no information about factors that regulate dental pulp stem cell lineage fate, a critical early event in the odontoblast-dentin mineralization scheme. To reveal the role of DSPP in odontoblast lineage differentiation during tooth development, we systematically examined teeth from wild-type (wt) and DSPP-KO C57BL/6 mice between the ages of postnatal day 1 and 3 months. We found developmental abnormalities not previously reported, such as circular dentin formation within dental pulp cells and altered odontoblast differentiation in DSPP-KO mice, even as early as 1 day after birth. Surprisingly, we also identified chondrocyte-like cells in the dental pulp from KO-mice teeth. Thus, these studies that compare wt and DSPP-KO mice suggest that the expression of DSPP precursor protein is required for normal odontoblast lineage differentiation and that the absence of DSPP allows dental pulp cells to differentiate into chondrocyte-like cells, which could negatively impact pulpal wound healing and tissue regeneration. PMID- 25027179 TI - Principles of nutrition in Islamic and traditional Persian medicine. AB - Nutrition has a crucial role in maintaining body health. Eating and drinking has a special place in Islamic doctrine and traditional Persian medicine. Traditional Persian medicine is a holistic medicine and provides great attention to the spiritual aspects of life as well as somatic aspects to maintain human health. In this view, people are not going to eat and drink for pleasure but to maintain a good life and physical health, due to daily tasks, as well as observing moral aspects of a human life and spiritual satisfaction. PMID- 25027180 TI - A high ratio of ADP-TRAP induced platelet aggregation is associated more strongly with increased mortality after coronary stent implantation than high conventional ADP induced aggregation alone. AB - OBJECTIVE: This study aimed to evaluate whether a high relative ADP induced aggregation (r-ADP-agg) is associated with an increased mortality in patients after coronary stent implantation. BACKGROUND: Several trials were not able to improve clinical outcome by adapting platelet inhibition in patients after coronary stent implantation and high platelet reactivity (HPR). Platelet monitoring is complex and conventional definition of adenosindiphosphate (ADP) induced aggregation alone might not transfer the whole picture of adequate platelet inhibition in vivo. METHODS: In a prospective single-centre observational trial multiple electrode aggregometry was performed in whole blood of patients after stent implantation. r-ADP-agg was defined as the ADP-thrombin receptor activating peptide ratio to reflect an individual degree of P2Y12 dependent platelet inhibition with a cut-off value for HPR of >= 50%. The primary end point was mortality. RESULTS: Follow-up was completed in 176 of 184 patients (96%) with a mean follow-up time of 3.7 years. 35 (20 %) patients revealed an r ADP-agg >= 50%. An r-ADP-agg >= 50% was associated with an increased mortality [unadjusted hazard ratio (HR) 7.006 (2.561-19.17); p = 0.0001]. In a multivariable Cox regression analysis mortality was independently associated with an r-ADP-agg >= 50% [HR 3.324 (1.542-7.165); p = 0.0022], ACS-setting [HR 3.249 (1.322-7.989); p = 0.0102] and severely reduced LV function [HR 5.463 (2.098 14.26); p = 0.0005]. CONCLUSION: An r-ADP-agg >= 50% is associated with an increased mortality in patients after coronary stent implantation. Furthermore, r ADP-agg might represent a better tool to predict clinical outcome than the conventional ADP induced platelet aggregation alone. PMID- 25027181 TI - Age estimation from the sternal end of the fourth rib: a study of the validity of Iscan's Method in Tunisian male population. AB - The aim of this study was to assess the fourth rib phase Iscan method on a Tunisian sample. One hundred and eight (108) specimens of sternal ends of fourth ribs of Tunisian male population were collected during forensic autopsies performed in the Department of Forensic Medicine and Pathology of the University Hospital Fattouma Bourguiba of Monastir. Two operators, independently, assigned each rib to Iscan's phase. The data obtained by the two operators were analyzed using SPSS 17.0 and MedCalc. The repeatability and accuracy of Iscan method was tested by kappa coefficient (kappa), for each operator. Spearman correlation coefficient (R), between estimated Iscan phase and Iscan phase relative to chronological age, was good with values of 0.758 (CI: 0.664-0.828) and 0.717 (CI: 0.611-0.798) for operator 1 and operator 2, respectively. The perfect agreement, between Iscan phase related to chronological age and Iscan phase estimated by both operators, was found for phases fewer than 5. Intra-observer agreement was highest for both operators with kappa value of 0.73 for operator 1 and 0.71 for operator 2. The estimation of the observers fell within one phase from the ideal and there was minimal disparity. A good accuracy between operator 1 and operator 2 was found (kappa=0.747, p=0.057). In order to improve the results, we have pooled ages in five new phases. The correlation, between new age groups and Iscan phase estimated by both operators, was moderate. We conclude that Iscan method can be applicable in Tunisian population with a good correlation for age ranges under 39years. PMID- 25027182 TI - Vulvar cancer and sentinel lymph nodes: a new standard of care? AB - The treatment of early-stage vulvar cancer has remained surgical over time. Fortunately, less invasive surgical options have emerged, decreasing the significant morbidity associated with treatment. In the past decade, sentinel lymph node (SLN) dissection alone in select patients with vulvar cancer has been shown to be safe, feasible and has decreased surgical morbidity. In addition, multiple recent studies have reported low groin recurrence rates in women that underwent SLN dissection alone, which are similar to groin recurrence rates seen among women that underwent complete inguinal lymph node dissection. We believe SLN dissection should be the standard of care in select patients at institutions with surgeons experienced in the SLN technique. We feel caution should be used when performing SLN dissections in large vulvar lesions and in midline lesions. Further information is needed regarding the appropriate treatment of positive sentinel lymph nodes and, in particular, on the management of micrometastases. PMID- 25027183 TI - A one night stand? Reproductive excursions of female roe deer as a breeding dispersal tactic. AB - Breeding dispersal, defined as the net movement between successive breeding sites, remains a poorly understood and seldom reported phenomenon in mammals, despite its importance for population dynamics and genetics. In large herbivores, females may be more mobile during the breeding season, undertaking short-term trips (excursions) outside their normal home range. If fertilisation occurs, leading to gene flow of the male genome, this behaviour could be considered a form of breeding dispersal from a genetic point of view. Here, we investigated ranging behaviour of 235 adult roe deer using intensive GPS monitoring in six populations across Europe within the EURODEER initiative. We show that excursions are common from June to August among females, with 41.8% (vs. 18.1% of males) making at least one excursion. Most individuals performed only one excursion per season and departure dates for females were concentrated in time, centred on the rutting period, suggesting a link with reproduction. The distance females travelled during excursions was significantly greater than the site-specific average diameter of a male home range, while travel speed decreased once they progressed beyond this diameter, indicating search behaviour or interaction with other male(s) outside the resident male's territory. Because adults are normally highly sedentary, the potential for mating with relatives is substantial; hence, we conclude that rut excursions could be an alternative tactic enabling females to avoid mating with a closely related male. To understand better the ultimate drivers at play, it will be crucial to explore the genetic causes and consequences of this behaviour. PMID- 25027186 TI - Postchemotherapy lymphadenectomy in patients with metastatic urothelial carcinoma: long-term efficacy and implications for trial design. AB - BACKGROUND: The contribution of postchemotherapy pelvic (PLND) or retroperitoneal lymphadenectomy (RPLND) on survival in patients with advanced and metastatic UC is still unclear. PATIENTS AND METHODS: Between September 1986 and May 2012, 157 patients with locally advanced or metastatic UC received first-line chemotherapy consisting of mMVAC (modified methotrexate, vinblastine, doxorubicin, and cisplatin), according to our policy. Patients with subdiaphragmatic nodal disease and/or local recurrence only and who experienced at least stable disease (SD) were selected. Fifty-nine patients were identified, 28 of whom underwent surgery, 31 started consolidation chemotherapy with or without radiotherapy or observation. The prognostic effect of candidate factors on survival was evaluated using Cox proportional hazard regression models. RESULTS: A total of 14 PLND and 14 RPLND patients were identified after they had achieved a complete response (CR; n = 7) or a partial response (PR) and SD (n = 21). Median follow-up was 88 months (interquartile range, 24-211 months). Median PFS was 18 (95% confidence interval [CI], 11-not estimated) and 11 (95% CI, 5-19) months, respectively, in favor of the surgical cohort and curves were statistically different (log-rank test, P = .009). In multivariate analysis, postchemotherapy surgery was significantly prognostic for PFS and OS and response to chemotherapy (PR and SD vs. CR) was prognostic for PFS and trended to significance for OS. A model including these 2 factors showed bootstrap-corrected Harrel C statistics for PFS and OS of 0.65 and 0.68, respectively. CONCLUSION: In well selected patients with UC like those who achieved a clinical benefit with chemotherapy and had nodal metastatic disease, there was a survival advantage in removal of disease residuals. PMID- 25027185 TI - Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth. AB - BACKGROUND: Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 +/- 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method. RESULTS: The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype. CONCLUSIONS: These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet. PMID- 25027187 TI - Life satisfaction in adult survivors of childhood brain tumors. AB - Adult survivors of childhood brain tumors experience multiple, significant, lifelong deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors' physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggest some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population-based matched controls. Chi-square tests, t tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated that life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors' general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population. PMID- 25027188 TI - Music therapy services in pediatric oncology: a national clinical practice review. AB - This article presents the results of a national clinical practice review conducted in Australia of music therapy services in pediatric oncology hospitals. Literature specifically related to music therapy and symptom management in pediatric oncology is reviewed. The results from a national benchmarking survey distributed to all music therapists working with children with cancer in Australian pediatric hospitals are discussed. Patient and family feedback provided from a quality improvement activity conducted at a major pediatric tertiary hospital is summarized, and considerations for future growth as a profession and further research is proposed. PMID- 25027189 TI - A novel fluorescence probe for estimation of cysteine/histidine in human blood plasma and recognition of endogenous cysteine in live Hct116 cells. AB - A new Cu(II)-complex is used as a "Turn-On" luminescence probe for specific detection of endogenous Cys in live Hct116 cells and Cys present in human blood plasma without any interference from other amino acids, especially GSH and Hcy. Difference in the mechanistic pathway for Cys and His recognition is discussed. PMID- 25027190 TI - Chemical and structural stability of lithium-ion battery electrode materials under electron beam. AB - The investigation of chemical and structural dynamics in battery materials is essential to elucidation of structure-property relationships for rational design of advanced battery materials. Spatially resolved techniques, such as scanning/transmission electron microscopy (S/TEM), are widely applied to address this challenge. However, battery materials are susceptible to electron beam damage, complicating the data interpretation. In this study, we demonstrate that, under electron beam irradiation, the surface and bulk of battery materials undergo chemical and structural evolution equivalent to that observed during charge-discharge cycling. In a lithiated NiO nanosheet, a Li2CO3-containing surface reaction layer (SRL) was gradually decomposed during electron energy loss spectroscopy (EELS) acquisition. For cycled LiNi(0.4)Mn(0.4)Co(0.18)Ti(0.02)O2 particles, repeated electron beam irradiation induced a phase transition from an layered structure to an rock-salt structure, which is attributed to the stoichiometric lithium and oxygen removal from 3a and 6c sites, respectively. Nevertheless, it is still feasible to preserve pristine chemical environments by minimizing electron beam damage, for example, using fast electron imaging and spectroscopy. Finally, the present study provides examples of electron beam damage on lithium-ion battery materials and suggests that special attention is necessary to prevent misinterpretation of experimental results. PMID- 25027191 TI - Letter in response to Picillo et al., in relation to Szewczyk-Krolikowski et al.: the influence of age and gender on motor and non-motor features of early Parkinson's disease: initial findings from the Oxford Parkinson disease Center (OPDC) discovery cohort. PMID- 25027192 TI - An electronic tool for systematic reporting of fractures on skeletal surveys in suspected child abuse: prototype development and physician feedback. AB - OBJECTIVE: To describe a skeletal survey data entry and compilation tool and assess physician attitudes toward this reporting approach. BACKGROUND: Narrative skeletal survey reports are highly variable and prone to inconsistencies with potential adverse impact on patients. MATERIALS AND METHODS: The prototype skeletal survey data entry and compilation tool was developed and introduced into clinical practice at a large urban children's hospital. Pediatric radiologists and child protection team (CPT) pediatricians completed a survey of reporting preferences. Skeletal survey reports between March 1, 2013, and March 1, 2014, were reviewed to assess use of the tool. RESULTS: The survey response rate was 70% (14/20) for radiologists and 100% (4/4) for CPT pediatricians. Among responding radiologists, 54.5% (6/11) indicated that a skeletal survey data entry and compilation tool was helpful for skeletal surveys with >3 fractures; 80% (8/10) of responding radiologists indicated that tabulated data from prior skeletal survey was helpful when interpreting a follow-up skeletal survey with >3 fractures; 90.9% (10/11) of radiologists thought the tool improved report organization; 72.7% (8/11) thought it improved accuracy. Most radiologists (11/12, 91.7%) and 100% (4/4) of CPT clinicians preferred reports with both free text and a tabulated fracture list for testifying in court when >3 fractures were present. The tool was used in the reporting of 14/23 (61%) skeletal surveys with >3 fractures during a 1-year period. A case example using the application is presented. CONCLUSION: Most radiologists and CPT physicians at our center prefer skeletal survey reports with tabulated data and narrative description; 91.7% (11/12) of radiologists and all CPT clinicians prefer this approach for testifying in court when >3 fractures are present. PMID- 25027193 TI - Novel diffusion tensor imaging technique reveals developmental streamline volume changes in the corticospinal tract associated with leg motor control. AB - BACKGROUND: Diffusion tensor imaging (DTI) has expanded our knowledge of corticospinal tract (CST) anatomy and development. However, previous developmental DTI studies assessed the CST as a whole, overlooking potential differences in development of its components related to control of the upper and lower extremities. The present cross-sectional study investigated age-related changes, side and gender differences in streamline volume of the leg- and hand related segments of the CST in children. SUBJECTS AND METHODS: DTI data of 31 children (1-14 years; mean age: 6+/-4 years; 17 girls) with normal conventional MRI were analyzed. Leg- and hand-related CST streamline volumes were quantified separately, using a recently validated novel tractography approach. CST streamline volumes on both sides were compared between genders and correlated with age. RESULTS: Higher absolute streamline volumes were found in the left leg related CST compared to the right (p=0.001) without a gender effect (p=0.4), whereas no differences were found in the absolute hand-related CST volumes (p>0.4). CST leg-related streamline volumes, normalized to hemispheric white matter volumes, declined with age in the right hemisphere only (R=-.51; p=0.004). Absolute leg-related CST streamline volumes showed similar, but slightly weaker correlations. Hand-related absolute or normalized CST streamline volumes showed no age-related variations on either side. CONCLUSION: These results suggest differential development of CST segments controlling hand vs. leg movements. Asymmetric volume changes in the lower limb motor pathway may be secondary to gradually strengthening left hemispheric dominance and is consistent with previous data suggesting that footedness is a better predictor of hemispheric lateralization than handedness. PMID- 25027194 TI - Nebulized fentanyl vs intravenous morphine for ED patients with acute limb pain: a randomized clinical trial. AB - OBJECTIVE: Intravenous morphine has been used as a common method of pain control in emergency care. Nebulized fentanyl is also an effective temporary substitute. This study was designed to compare the effectiveness of nebulized fentanyl with intravenous (IV) morphine on management of acute limb pain. METHODS: This was a placebo-controlled, double-blind randomized clinical trial. Ninety emergency department patients with moderate to severe pain aged 15 to 50 years were blocked randomized and enrolled in this study. Forty-seven patients in the experimental group received nebulized fentanyl (4 MUg/kg) and IV normal saline as placebo, and the remaining 43 patients in the control group received IV morphine (0.1 mg/kg) and nebulized normal saline as placebo. All participants' pain scores were assessed by Numerical Rating Scale before and after intervention at 5-, 10-, 15-, 30-, 45-, and 60-minute intervals. Patients' vital sign and possible adverse effects were recorded respectively. Finally, all participants were assessed for their satisfaction. RESULTS: The mean initial pain score in the experimental group was 8.7 and 8.4 in the control group (P = .1). Pain relief in both groups after 5 and 10 minutes were similar (P = .72). Although the pain relief was significantly greater with fentanyl at 15 minutes, this difference is not clinically significant. Pain management in both groups was successful and was more than 3 scores reduction in Numerical Rating Scale. Patient satisfaction in both groups was similar. No adverse effects were reported in the experimental group. CONCLUSION: This study suggests that nebulized fentanyl is a rapid, safe, and effective method for temporary control of acute limb pain in emergency department patients. PMID- 25027195 TI - Fascia iliaca compartment block in the reduction of dislocation of total hip arthroplasty. PMID- 25027196 TI - Decision making on management of adult patients with acute appendicitis. PMID- 25027197 TI - Pitfalls of the ultrasound diagnosis of pneumothorax. PMID- 25027198 TI - Successful management of heat stroke associated with multiple-organ dysfunction by active intravascular cooling. AB - Heat stroke is a life-threatening condition requiring immediate initiation of rapid and effective cooling. We report successful cooling with initial intravascular cooling use that rapidly achieved the target temperature with continued normothermia thereafter. A 39-year-old previously healthy man collapsed on a hot, humid day and presented with a disturbance of consciousness. On initial examination, Glasgow Coma Scale score was 6/15, and his body temperature was 40.7 degrees C. He was therefore intubated, and fluid resuscitation was initiated. A Cool Line catheter (Asahi KASEI ZOLL Medical, Tokyo, Japan) was inserted, and aggressive cooling was started using the intravascular balloon-catheter system (The Thermogard XP system; Asahi KASEI ZOLL Medical) within 32 minutes of arrival. His core temperature reached 38.8 degrees C after 17 minutes of intravascular cooling at an average cooling rate of 0.10 degrees C/min. Further investigation revealed impaired liver function and renal failure. His hemodynamic condition was stabilized, and no vasoactive agents were administrated during hospitalization. The cooling catheter was removed on day 2 of admission, and no bleeding, infection, or thrombosis associated with catheter placement was observed. Blood and urine cultures remained negative. Extubation was performed on day 3, and he was discharged on day 5 without further complication or sequelae. It is essential in the treatment of heat stroke to cool as quickly as possible and to provide cardiovascular support. In patients with severe heat stroke and multiple-organ dysfunction, initial use of the active intravascular cooling technique is warranted for aggressive cooling. PMID- 25027199 TI - Occurrence of pneumomediastinum due to dental procedures. AB - The occurrence of pneumomediastinum and massive subcutaneous emphysema due to dental procedures is quite rare. We present a case of pneumomediastinum and massive subcutaneous emphysema that occurred during third molar tooth extraction with air-turbine handpiece. PMID- 25027200 TI - Saddle pulmonary emboli mimicking pulmonary artery dissection. AB - Pulmonary embolism (PE) can be a potentially fatal condition and requires early diagnosis. It is a frequently underdiagnosed, underestimated, and undertreated disease because of various features and nonspecific clinical presentation. Laboratory D-dimer test, lung scan, and echocardiography can help in making the diagnosis. Recently, computed tomography has been most common used for the diagnosis. We report a case of pulmonary embolism mimicking pulmonary artery dissection by initially using images from computed tomography. Further evaluation of the computed tomographic images using coronal plane confirmed the diagnosis of pulmonary embolism. Because the treatment modalities are completely different between the 2 diseases, we emphasize that 2 different orthogonal planes are necessary for diagnosis using computed tomographic image examination. PMID- 25027201 TI - Caspase-3-mediated splenic lymphocyte apoptosis in a porcine model of cardiac arrest. AB - BACKGROUND: Postresuscitation immunologic dysfunction contributes to the low survival rate after successful resuscitation, but its mechanism remains poorly understood. The mitochondrial apoptosis pathway is initiated by the Bcl-2/Bax controlled and caspase-3-mediated pathway, this study investigated whether mitochondrial pathway-mediated splenic lymphocyte apoptosis is involved in the postresuscitation immunosuppression in a porcine model of cardiac arrest. METHODS: Twenty-eight Wuzhishan miniature pigs were randomly divided into 2 groups: return of spontaneous circulation (ROSC; n = 22) and sham-operated (n = 6). Return of spontaneous circulation was initiated after 8 minutes of untreated ventricular fibrillation. After successful ROSC, CD4(+) and CD8(+) lymphocyte subsets were determined by flow cytometry. Surviving pigs were randomly assigned to be humanely killed at 24 and 72 hours after ROSC (n = 8 per group). Spleens were removed for histopathologic analysis, Western blotting, quantitative real time polymerase chain reaction, and terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling assay. RESULTS: A high degree of splenic lymphocyte apoptosis was observed in the ROSC group. Expression of Bax and activated caspase-3 was markedly increased in splenic tissue, whereas Bcl-2 was significantly decreased in the post-ROSC group compared with the sham-operated group (P < .05) at 24 and 72 hours after ROSC. The messenger RNA levels of activated caspase-3 of splenic tissue were significantly elevated at 24 and 72 hours after ROSC. CONCLUSION: These results demonstrates that Bcl-2/Bax and caspase-3-mediated mitochondrial apoptosis signaling pathway may contribute to abnormal splenic lymphocyte apoptosis, which may be one of the main pathologic mechanisms of postresuscitation disturbance of immunologic function in a porcine model of cardiac arrest. PMID- 25027202 TI - Boarding is associated with higher rates of medication delays and adverse events but fewer laboratory-related delays. AB - BACKGROUND: Hospital crowding and emergency department (ED) boarding are large and growing problems. To date, there has been a paucity of information regarding the quality of care received by patients boarding in the ED compared with the care received by patients on an inpatient unit. We compared the rate of delays and adverse events at the event level that occur while boarding in the ED vs while on an inpatient unit. METHODS: This study was a secondary analysis of data from medical record review and administrative databases at 2 urban academic teaching hospitals from August 1, 2004, through January 31, 2005. We measured delayed repeat cardiac enzymes, delayed partial thromboplastin time level checks, delayed antibiotic administration, delayed administration of home medications, and adverse events. We compared the incidence of events during ED boarding vs while on an inpatient unit. RESULTS: Among 1431 patient medical records, we identified 1016 events. Emergency department boarding was associated with an increased risk of home medication delays (risk ratio [RR], 1.54; 95% confidence interval [CI], 1.26-1.88), delayed antibiotic administration (RR, 2.49; 95% CI, 1.72-3.52), and adverse events (RR, 2.36; 95% CI, 1.15-4.72). On the contrary, ED boarding was associated with fewer delays in repeat cardiac enzymes (RR, 0.17; 95% CI, 0.09-0.27) and delayed partial thromboplastin time checks (RR, 0.54; 95% CI, 0.27-0.96). CONCLUSION: Compared with inpatient units, ED boarding was associated with more medication-related delays and adverse events but fewer laboratory-related delays. Until we can eliminate ED boarding, it is critical to identify areas for improvement. PMID- 25027203 TI - Considerations for tetanus infection in an adult with a protective tetanus antibody level. PMID- 25027204 TI - Concentration gradient focusing and separation in a silica nanofluidic channel with a non-uniform electroosmotic flow. AB - The simultaneous concentration gradient focusing and separation of proteins in a silica nanofluidic channel of various geometries is investigated experimentally and theoretically. Previous modelling of a similar device [Inglis et al., Angew. Chem. Int. Ed., 2011, 50, 7546] assumed a uniform velocity profile along the length of the nanochannel. Using detailed numerical analysis incorporating charge regulation and viscoelectric effects, we show that in reality the varying axial electric field and varying electric double layer thickness caused by the concentration gradient, induce a highly non-uniform velocity profile, fundamentally altering the protein trapping mechanism: the direction of the local electroosmotic flow reverses and two local vortices are formed near the centreline of the nanochannel at the low salt concentration end, enhancing trapping efficiency. Simulation results for yellow/red fluorescent protein R-PE concentration enhancement, peak focusing position and peak focusing width are in good agreement with experimental measurements, validating the model. The predicted separation of yellow/red (R-PE) from green (Dyl-Strep) fluorescent proteins mimics that from a previous experiment [Inglis et al., Angew. Chem. Int. Ed., 2011, 50, 7546] conducted in a slightly different geometry. The results will inform the design of new class of matrix-free particle focusing and separation devices. PMID- 25027206 TI - Hepatocellular carcinoma surveillance: a national survey of current practices in the USA. AB - BACKGROUND: The incidence rate of hepatocellular carcinoma (HCC) in the USA is rapidly rising. Surveillance using biannual ultrasound (US) is recommended, but actual practices are unknown. AIM: To determine current HCC surveillance practices among gastroenterology and hepatology providers in the USA. METHODS: A 21-question electronic survey was emailed to 12,485 gastroenterology and hepatology providers in the USA. The survey contained questions concerning provider background, surveillance practices, and opinions. Pearson chi-square and multivariate logistic regression tests were used to analyze the data. RESULTS: We received 777 responses (6.2% response rate); 656 were eligible for analysis. 92% place cirrhotic patients under surveillance independent of etiology, 79% exclusively use a 6-month interval, and 77% use alpha-fetoprotein. While 93% use US, only 36% use US exclusively and 60% use two or more imaging modalities. Providers from transplant centers favor using additional imaging modalities, instead of only US. Multivariate analysis showed transplant center providers who allocate more time to patient care (OR 1.96, p = 0.004) and see more cirrhotic patients (OR 2.07, p = 0.033) have increased odds of using additional imaging modalities. CONCLUSIONS: Participating providers reported very high rates of surveillance utilization and use of a biannual interval. It is likely that the sample is composed of providers who are very engaged and informed about HCC surveillance. However, their surveillance imaging practices largely deviated from practice guidelines, which all recommend only using US. Providers affiliated with transplant centers tend to use additional imaging modalities such as computed tomography and MRI, instead of US only. PMID- 25027207 TI - Angioleiomyoma, a rare intracranial tumor: 3 case report and a literature review. AB - Three cases of intracranial angioleiomyoma (ALM) in our neurosurgery center are reported in detail. ALM is a benign soft tissue tumor comprised of mature smooth muscle cells and a prominent vascular component, which is extremely rare as a primary intracranial lesion. Altogether, only 12 cases were recorded in the literature to date, to the best of our knowledge. Case 1 is the second report of intra-sella ALM, a 51-year-old woman presented with visual deterioration for 2 months. An MRI showed an intra-sella 3-cm tumor, partially flame-like, enhanced with gadolinium. Using microscopic endonasal transsphenoidal approach, the tumor was completely resected with great difficulty. At 11 days post-surgery, she died of a sudden catastrophic nasal hemorrhage. An angiography revealed a pseudo aneurysm of ICA (internal carotid artery). Case 2 is a 49-year-old man who presented with weakness of the lower limbs for 1 year. A large subtentorial mass was found affixed to the torcular and straight sinus, which was partially flame like, dramatically enhanced as in case 1. Case 3 is that of a 77-year-old man. An ALM mass was revealed in the diploe of left temporal bone, and had eroded the inner table. Immunohistochemical workup confirmed the diagnosis of angioleiomyoma in all 3 cases. The radiology, operation, and complication of surgery in each case were discussed. In conclusion, intracranial ALMs are extremely rare, usually located ex-neuro axis (such as in our cases), in the sella, in posterior fossa, or in the skull. Magnetic resonance imaging (MRI) revealed a special feature of flame-like partial enhancement that may be helpful to distinguish ALM from pituitary tumors or meningiomas, and should result in the consideration of this rare tumor entity early on in the diagnostic process. A definitive diagnosis depends on histological analyses. The resection of ALM in certain locations is difficult and risky because of the rich blood supply. PMID- 25027205 TI - Differential regulation of EGFR-MAPK signaling by deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) in colon cancer. AB - A high-fat diet coincides with increased levels of bile acids. This increase in bile acids, particularly deoxycholic acid (DCA), has been strongly associated with the development of colon cancer. Conversely, ursodeoxycholic acid (UDCA) may have chemopreventive properties. Although structurally similar, DCA and UDCA present different biological and pathological effects in colon cancer progression. The differential regulation of cancer by these two bile acids is not yet fully understood. However, one possible explanation for their diverging effects is their ability to differentially regulate signaling pathways involved in the multistep progression of colon cancer, such as the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway. This review will examine the biological effects of DCA and UDCA on colon cancer development, as well as the diverging effects of these bile acids on the oncogenic signaling pathways that play a role in colon cancer development, with a particular emphasis on bile acid regulation of the EGFR-MAPK pathway. PMID- 25027208 TI - Studies on assessment methods of malignant ascites residue and changes of verapamil concentration in intraperitoneal perfusion chemotherapy. AB - PURPOSE: To establish a simple method for estimating residual peritoneal ascites in order to determine the optimum verapamil (VRP) initial concentration in the intraperitoneal perfusion chemotherapy. METHODS: (1) Pelvic size of adults was assessed by measuring distance from the superior margin of pubic symphysis to the connecting line of two anterior superior spine (SL) and to the midpoint of the line (SM) in 172 adults; (2) 35 postoperative gastric or colon cancer patients with indications for use of preventive intraperitoneal chemotherapy were infused with 1,000-1,250 mL 0.9 % normal saline solution for about 15 min and used for perfusate detection by moving along the midpoint of connecting line of two anterior superior spine after 5 min of infusion; (3) The VRP concentration in ascites was detected by liquid chromatography. RESULTS: The distance between two anterior superior spines for adult were 29.6 +/- 2.6 cm and the distance from the superior margin of pubic symphysis to the midpoint between two anterior superior spines was 10.6 +/- 1.9 cm. When the total intraperitoneal infusion fluid was 1,000-1,250 mL, it could be detected by B-mode ultrasonic device at 0.1-0.3 cm directly below the midpoint of two anterior superior spines. The VRP reversal concentration of drug resistance could maintain for 90 min when the residual ascites volume was within the range of 1,000-1,250 mL. CONCLUSIONS: Detection of liquid at the position directly below or above the midpoint of two anterior superior spines by B-mode ultrasonic device in patients in erect position could be a simple method for estimation of ascites volume (liquid found at 0.1-0.3 cm directly below the midpoint of two anterior superior spines suggested that ascites volume was smaller than 1,000-1,250 mL). The method could be used for determination of VRP initial concentration for IPC treatment. PMID- 25027209 TI - [Gut feeling in youth health care: 2 cases]. AB - BACKGROUND: Dutch Youth health care is an easily accessible service where parents can ask for support for the healthy development of their children. The majority of the screenings and medical examinations show no abnormalities. Sometimes there is doubt about the severity of symptoms: the line between healthy variation and diseases or abnormalities can be rather fine. CASE DESCRIPTION: Patient A, a 3 month-old baby, showed signals of hypotonia and growth deficit while breastfeeding. Additional nutrition restored his growth and muscle tone. Patient B, a 4-week-old baby, displayed severe hypotonia. This appeared to be based on Werdnig-Hoffman disease. He died at the age of 4 months. CONCLUSION: Distinguishing conditions in the normal range from rare and severe conditions is daily work for every physician and is based on knowledge and experience. Combining symptoms and signs is essential. The youth health care physician sees mostly healthy children and is aware of the great variation within that group. This makes the youth health care physician an expert in distinguishing conditions in the normal range from rare and severe conditions. PMID- 25027210 TI - [Survey among gynaecologists and surgeons on rectocele]. AB - OBJECTIVE: Provide insight into how gynaecologists and surgeons name, diagnose and treat a rectocele and identify the differences between these two professional groups. DESIGN: Questionnaire survey. METHODS: We sent an online survey with 16 multiple-choice questions to gynaecologists and surgeons from two national working groups. RESULTS: There is no discernible consensus on nomenclature, diagnostics and treatment. Gynaecologists and surgeons each choose their own approach. CONCLUSION: It is in the patient's interest to draw up a joint guideline; however, multidisciplinary cooperation is only possible if gynaecologists and surgeons speak the same language. PMID- 25027211 TI - [An acute vomiting infant with profuse diarrhoea: enterocolitis due to non-IgE mediated cow's milk allergy]. AB - BACKGROUND: Food protein-induced enterocolitis is a manifestation of non-IgE mediated cow's milk allergy, characterized by acute vomiting and profuse diarrhoea. This reaction is often not recognized as cow's milk allergy. CASE DESCRIPTION: We present a 6-week-old, formula-fed girl with frequent vomiting, diarrhoea and failure to thrive. These symptoms disappeared after giving cow's milk-free formula. Forty-five minutes after the last dose in a non-blinded provocation test with cow's milk, she developed profuse diarrhoea and vomiting, resulting in hypovolemic shock. No specific IgE against cow's milk was found. CONCLUSION: Unusual in this case is the severe but relatively late reaction to the provocation test. In an acutely ill infant with vomiting, diarrhoea and pallor - which can even result in shock - food protein-induced enterocolitis as manifestation of non-IgE-mediated allergy must be considered. These symptoms start as late as 2 to 3 hours after exposure and disappear after withdrawal of the causal product. PMID- 25027212 TI - [Treatment of injuries of the Chopart joint]. AB - BACKGROUND: Injuries to the Chopart joint of the tarsal foot are relatively rare, difficult to recognize and are associated with significant long term morbidity. CASE DESCRIPTION: A 16-year-old boy attended the emergency department after a forklift truck ran over his left foot. Physical examination and X-ray evaluation revealed a fracture of the Chopart joint with a navicular bone fracture and dislocation of the calcaneo-cuboidal joint. Operative open reduction and internal fixation was performed. One year after operative treatment, the patient was able to play sport without functional impairment. CONCLUSION: Adequate evaluation on initial presentation of the injury and additional investigations are imperative for the treatment of patients with Chopart joint injuries. Adequate operative reduction and fixation at an early stage will result in good functional recovery. PMID- 25027213 TI - [Guideline for febrile children in the hospital setting; relevance for general practitioners and paediatricians]. AB - Febrile children pose the diagnostic dilemma of distinguishing those with serious infections from the vast majority with self-limiting diseases at an early stage. Alarm symptoms can aid in assessing the probability of serious infections in febrile children. The combined absence of alarm symptoms is useful in ruling out serious infections. CRP and PCT values are important diagnostic markers in febrile children in hospital settings. Children without any alarm symptoms and low inflammatory markers can be treated conservatively, provided there are good instructions on reassessment. Children with amber alarm symptoms or mildly elevated inflammatory markers in whom a serious infection cannot be ruled out require clinical observation or ambulant follow-up; empirical parenteral antibiotic treatment should also be considered and easily accessible. Children with red alarm symptoms or highly elevated inflammatory markers deserve clinical observation. In children < 3 months, empirical parenteral antibiotic treatment is also indicated. PMID- 25027214 TI - [Is this the end for double RAAS inhibition?]. AB - Recently, the VA NEPHRON-D study was stopped early due to insignificant effects and increased adverse events. This was the last in a series of trials on the value of dual versus single blockade of the renin-angiotensin-aldosterone system in patients at risk for renal or cardiovascular complications. From these studies, the picture has emerged that dual blockade is hardly effective and increases the risk of hyperkalaemia and renal failure. Background use of beta blockers - little recognised indirect renin inhibitors - may play a role in the detrimental effects of dual blockade. Aldosterone antagonists in combination with one of the RAAS inhibitors may confer some benefit, but have not been studied sufficiently. For now, combining ACE inhibitors, angiotensin receptor blockers and aliskiren is to be discouraged. PMID- 25027215 TI - [Gastrointestinal amyloidosis in a patient with multiple myeloma]. AB - BACKGROUND: Gastrointestinal amyloidosis is characterized by deposition of amyloid in the gastrointestinal mucosa. This can cause an increased risk of malabsorption, obstruction, gastrointestinal bleeding and perforations. CASE DESCRIPTION: A 52-year-old male presented with rectal bleeding. Endoscopic evaluation revealed non-specific red and purple lesions in the sigmoid colon. Histological results were inconclusive. Six weeks later this patient presented at the emergency room with an intestinal perforation. He also had newly developed renal insufficiency. Further analysis led to the diagnosis of multiple myeloma. After 3 doses of bortezomib and dexamethasone the patient was admitted with abdominal pain and rectal bleeding. Revision of our earlier sigmoid biopsies revealed gastrointestinal amyloidosis. The patient died 4 months after initial presentation. CONCLUSION: Gastrointestinal amyloidosis is a rare disease. Due to non-specific symptoms, diagnosis can easily be missed in patients who have not been diagnosed previously with amyloidosis or a related disease. PMID- 25027216 TI - [Embryonic health and preconception care: importance for current and future generations]. AB - Embryonic growth and development differ between pregnancies. Constitutional maternal characteristics and environmental influences affect embryonic size. Slowed embryonic growth is associated with an increased risk of gestational complications such as foetal growth restriction. A child who was small when an embryo is also at more risk of having an adverse cardiovascular risk profile at 6 years of age. The importance of embryonic health means that preconception care needs to be generally available. PMID- 25027217 TI - [Aortic valve replacement and screening for frailty]. AB - The prevalence of aortic stenosis is increasing due to aging of the general population. Transcatheter aortic valve implantation (TAVI) is an alternative for surgical aortic valve replacement (AVR) for high-risk patients. Cardiac scoring systems have been developed to predict the risk of adverse outcomes following surgery, but currently they do not include frailty parameters, and frail patients have an increased risk of adverse health outcomes. Preoperative frailty correlates with adverse outcomes, mortality and functional decline in patients undergoing TAVI; by identifying these patients it is possible to counteract symptoms of frailty by implementing tailored intervention by the geriatrician. The Comprehensive Geriatric Assessment (CGA) is a tool used to detect frailty. Based on the current literature, we highly recommend performing a CGA and a minimum of a Timed Up and Go test, a mini nutritional assessment and serum albumin measurements in patients aged > 70 years undergoing a TAVI or surgical AVR, in order to aim reducing the accompanying risks of the intervention. PMID- 25027218 TI - [A hockey player with displacement of the wrist]. AB - A 17-year-old boy had a painful left wrist after he fell while playing hockey. Examination showed volar displacement of the distal part of the ulna; the ulnar styloid prominence was absent. X-rays showed isolated volar displacement of the distal ulna. The diagnosis 'distal radio-ulnar joint dislocation' was made. Treatment consisted of K-wire fixation and an upper arm cast. He reached functional recovery. PMID- 25027219 TI - [The placebo effect: is the wish father to the thought?]. AB - The placebo effect remains an interesting topic for research. Recently, a systematic review estimated the percentage of responders after various placebo interventions in studies assessing prophylactic treatment for migraine. The authors report that after oral, pharmacologic placebos, 22% of patients reported an attack frequency reduction of > 50% and that after sham acupuncture, this percentage was 38%. In this commentary the methodological issues of the paper are discussed, and the conclusion is that in research into placebo effects the wish might be father to the thought. PMID- 25027220 TI - [A neonate with a vaginal cyst]. AB - During the physical examination of a full-term neonate we noticed a stalked, fluid-filled appendix, attached to the posterior vagina wall. A 'hymenal tag' was diagnosed: an innocent, self-limiting phenomenon caused by maternal oestrogens. PMID- 25027221 TI - [Give general practitioner a central role during the chronic phase after stroke]. AB - In February 2014 an update of a systematic review was published on the effectiveness of physical therapy after stroke. This review shows that the quality and quantity of the scientific basis for physical therapy interventions in rehabilitation after stroke have increased significantly, which confirms the relevance of physical therapy in multidisciplinary stroke care. As far as physical therapy is concerned, implementation of the results of this review and organisation or reorganisation of care so that it is accessible to all patients is a major challenge. We propose that the general practitioner should be given a central role in the care of patients during the chronic phase after stroke. PMID- 25027222 TI - [A girl with hypopigmented skin lesions]. AB - A 9-year-old girl visited the department of Dermatology with an asymptomatic hypopigmented skin eruption on her upper legs, groins and trunk since 7 years. Histopathological analysis established the diagnosis of hypopigmented mycosis fungoides, a rare subtype of cutaneous T-cell lymphoma which is most commonly seen at younger age. The lesions are successfully treated with clobetasol 0.05% ointment 4 days a week. PMID- 25027223 TI - Orbitofrontal cortex volume and brain reward response in obesity. AB - BACKGROUND/OBJECTIVES: What drives overconsumption of food is poorly understood. Alterations in brain structure and function could contribute to increased food seeking. Recently, brain orbitofrontal cortex (OFC) volume has been implicated in dysregulated eating but little is known how brain structure relates to function. SUBJECTS/METHODS: We examined obese (n=18, age=28.7+/-8.3 years) and healthy control women (n=24, age=27.4+/-6.3 years) using a multimodal brain imaging approach. We applied magnetic resonance and diffusion tensor imaging to study brain gray and white matter volume as well as white matter (WM) integrity, and tested whether orbitofrontal cortex volume predicts brain reward circuitry activation in a taste reinforcement-learning paradigm that has been associated with dopamine function. RESULTS: Obese individuals displayed lower gray and associated white matter volumes (P<0.05 family-wise error (FWE)- small volume corrected) compared with controls in the orbitofrontal cortex, striatum and insula. White matter integrity was reduced in obese individuals in fiber tracts including the external capsule, corona radiata, sagittal stratum, and the uncinate, inferior fronto-occipital, and inferior longitudinal fasciculi. Gray matter volume of the gyrus rectus at the medial edge of the orbitofrontal cortex predicted functional taste reward-learning response in frontal cortex, insula, basal ganglia, amygdala, hypothalamus and anterior cingulate cortex in control but not obese individuals. CONCLUSIONS: This study indicates a strong association between medial orbitofrontal cortex volume and taste reinforcement-learning activation in the brain in control but not in obese women. Lower brain volumes in the orbitofrontal cortex and other brain regions associated with taste reward function as well as lower integrity of connecting pathways in obesity (OB) may support a more widespread disruption of reward pathways. The medial orbitofrontal cortex is an important structure in the termination of food intake and disturbances in this and related structures could contribute to overconsumption of food in obesity. PMID- 25027225 TI - Against the onslaught of endemic carbapenemase-producing Klebsiella pneumoniae, the war is being lost on the Irish Front. PMID- 25027224 TI - Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin. AB - BACKGROUND/OBJECTIVES: Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state. METHODS: Adult male C57BL/6J, apelin knock-out (KO) or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure, mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses. RESULTS: In HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P<0.05), accelerated glucose oxidation (P<0.05) and mitochondrial damage. Treatment of HFD-fed mice with apelin for 4 weeks prevented pressure overload-induced decline in FA metabolism (P<0.05) and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose (P<0.01), improved glucose tolerance (P<0.05) and preserved cardiac function (P<0.05) in HFD-fed mice subjected to pressure overload. In apelin KO HFD-fed mice, spontaneous cardiac dysfunction is associated with reduced FA oxidation (P<0.001) and increased glucose oxidation (P<0.05). In isolated cardiomyocytes, apelin stimulated FA oxidation in a dose-dependent manner and this effect was prevented by small interfering RNA sirtuin 3 knockdown. CONCLUSIONS: These data suggest that obesity-related decline in cardiac function is associated with defective myocardial energy metabolism and mitochondrial abnormalities. Furthermore, our work points for therapeutic potential of apelin to prevent myocardial metabolic abnormalities in heart failure paired with obesity. PMID- 25027226 TI - Tuberculosis screening in a dialysis unit: detecting latent tuberculosis infection is only half the problem. AB - Patients with chronic kidney disease are at increased risk of tuberculosis. We describe the events that occurred when we encountered a patient receiving haemodialysis with pulmonary tuberculosis. Nine (of 41) patients dialysing at the same time as the index case had a positive interferon-gamma release assay (IGRA) and were offered therapy for latent tuberculosis infection (LTBI). Patients with an initial negative IGRA were rescreened at six months, identifying a further three IGRA-positive patients. All patients were then rescreened at 12 months. No new IGRA-positive cases were identified and no staff or patients developed active disease. Only five of the 12 IGRA-positive patients completed LTBI therapy. PMID- 25027227 TI - Transportation fuel production by combination of LDPE thermal cracking and catalytic hydroreforming. AB - Fuel production from plastics is a promising way to reduce landfilling rates while obtaining valuable products. The usage of Ni-supported hierarchical Beta zeolite (h-Beta) for the hydroreforming of the oils coming from LDPE thermal cracking has proved to produce high selectivities to gasoline and diesel fuels (>80%). In the present work, the effect of the Ni loading on Ni/h-Beta is investigated in the hydroreforming of the oils form LDPE thermal cracking. h-Beta samples were impregnated with Ni nitrate, calcined and reduced in H2 up to 550 degrees C to achieve different Ni contents: 1.5%, 4%, 7% and 10%. Larger and more easily reducible metal particles were obtained on Ni 7%/h-Beta and Ni 10%/h-Beta. Hydroreforming tests were carried out in autoclave reactor at 310 degrees C, under 20 bar H2, for 45 min. Ni content progressively increased the amount of gases at the expenses of diesel fractions, while gasoline remained approximately constant about 52-54%. Maximum selectivity to automotive fuels (~81%) was obtained with Ni 7%/h-Beta. Ni loading also enhanced olefins saturation up to Ni 7%/h-Beta. High cetane indices (71-86) and octane numbers (89-91) were obtained over all the catalysts. Regarding the different studied Ni contents, Ni 7%/h-Beta constitutes a rather promising catalyst for obtaining high quality fuels from LDPE thermal cracking oils. PMID- 25027228 TI - Rapid discrimination of plastic packaging materials using MIR spectroscopy coupled with independent components analysis (ICA). AB - Plastic packaging wastes increased considerably in recent decades, raising a major and serious public concern on political, economical and environmental levels. Dealing with this kind of problems is generally done by landfilling and energy recovery. However, these two methods are becoming more and more expensive, hazardous to the public health and the environment. Therefore, recycling is gaining worldwide consideration as a solution to decrease the growing volume of plastic packaging wastes and simultaneously reduce the consumption of oil required to produce virgin resin. Nevertheless, a major shortage is encountered in recycling which is related to the sorting of plastic wastes. In this paper, a feasibility study was performed in order to test the potential of an innovative approach combining mid infrared (MIR) spectroscopy with independent components analysis (ICA), as a simple and fast approach which could achieve high separation rates. This approach (MIR-ICA) gave 100% discrimination rates in the separation of all studied plastics: polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), polystyrene (PS) and polylactide (PLA). In addition, some more specific discriminations were obtained separating plastic materials belonging to the same polymer family e.g. high density polyethylene (HDPE) from low density polyethylene (LDPE). High discrimination rates were obtained despite the heterogeneity among samples especially differences in colors, thicknesses and surface textures. The reproducibility of the proposed approach was also tested using two spectrometers with considerable differences in their sensitivities. Discrimination rates were not affected proving that the developed approach could be extrapolated to different spectrometers. MIR combined with ICA is a promising tool for plastic waste separation that can help improve performance in this field; however further technological improvements and developments are required before it can be applied at an industrial level given that all tests presented here were performed under laboratory conditions. PMID- 25027229 TI - Effectiveness of an intervention designed to optimize statins use: a primary prevention randomized clinical trial. AB - BACKGROUND: Although hypercholesterolemia is considered a cardiovascular risk factor, in isolation it is not necessarily sufficient cause for a cardiovascular event. To improve event prediction, cardiovascular risk calculators have been developed; the REGICOR calculator has been validated for use in our population. The objective of this project is to develop an intervention with general practitioners (GPs) and evaluate its impact on prescription adequacy of cholesterol-lowering drugs in primary prevention of cardiovascular disease and in controlling the costs associated with this disease. METHODS: This nonblinded, cluster-randomized clinical trial analyzes data from primary care electronic medical records (ECAP) and other databases. Inclusion criteria are patients aged 35 to 74 years with no known cardiovascular disease and a new prescription for cholesterol-lowering drugs during the 2-year study period. Dependent variables include the following: RETIRA, defined as new cholesterol-lowering drugs initiated during the year preceding the intervention, considered inadequate, and withdrawn during the study period; EVITA, defined as new cholesterol-lowering drugs initiated during the study period and considered inadequate; COST, defined as the total cost of inadequate new treatments prescribed; and REGISTER, defined as the recording of cardiovascular risk factors. Independent variables include the GP's quality-of-care indicators and randomly assigned study group (intervention vs control), patient demographics, and clinical variables. Aggregated descriptive analysis will be done at the GP level and multilevel analysis will be performed to estimate the intervention effect, adjusted for individual and GP variables. DISCUSSION: The study objective is to generate evidence about the effectiveness of implementing feedback information programs directed to GPs in the context of Primary Care. The goal is to improve the prescription adequacy of lipid-lowering therapies for primary prevention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01997671. November 28, 2013. PMID- 25027230 TI - LMA Supreme for neonatal resuscitation: study protocol for a randomized controlled trial. AB - BACKGROUND: The most important action in the resuscitation of a newborn in the delivery room is to establish effective assisted ventilation. The face mask and endotracheal tube are the devices used to achieve this goal. Laryngeal mask airways that fit over the laryngeal inlet have been shown to be effective for ventilating newborns at birth and should be considered as an alternative to facemask ventilation or endotracheal intubation among newborns weighing >2,000 g or delivered >=34 weeks' gestation. A recent systematic review and meta-analysis of supraglottic airways in neonatal resuscitation reported the results of four randomized controlled trials (RCTs) stating that fewer infants in the group using laryngeal mask airways required endotracheal intubation (1.5%) compared to the group using face masks (12.0%). However, there were methodological concerns over all the RCTs including the fact that the majority of the operators in the trials were anesthesiologists.Our hypothesis is based on the assumption that ventilating newborns needing positive pressure ventilation with a laryngeal mask airway will be more effective than ventilating with a face mask in a setting where neonatal resuscitation is performed by midwives, nurses, and pediatricians. The primary aim of this study will be to assess the effectiveness of the laryngeal mask airway over the face mask in preventing the need for endotracheal intubation. METHODS/DESIGN: This will be an open, prospective, randomized, single center, clinical trial. In this study, 142 newborns weighing >1,500 g or delivered >=34 weeks gestation needing positive pressure ventilation at birth will be randomized to be ventilated with a laryngeal mask airway (LMA SupremeTM, LMA Company, UK - intervention group) or with a face mask (control group). PRIMARY OUTCOME: Proportion of newborns needing endotracheal intubation. SECONDARY OUTCOMES: Apgar score at 5 minutes, time to first breath, onset of the first cry, duration of resuscitation, death or moderate to severe hypoxic-ischemic encephalopathy within 7 days of life. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01963936 (October 11, 2013). PMID- 25027231 TI - Challenges and opportunities of a paperless baseline survey in Sri Lanka. AB - BACKGROUND: Personal digital assistants (PDAs) have been shown to reduce costs associated with survey implementation and digitisation, and to improve data quality when compared to traditional paper based data collection. Few studies, however, have shared their experiences of the use of these devices in rural settings in Asia. This paper reports on our experiences of using a PDA device for data collection in Sri Lanka as part of a large cluster randomised control trial. FINDINGS: We found that PDAs were useful for collecting data for a baseline survey of a large randomised control trial (54,000 households). We found that the PDA device and survey format was easy to use by inexperienced field staff, even though the survey was programmed in English. The device enabled the rapid digitisation of survey data, providing a good basis for continuous data quality assurance, supervision of staff and survey implementation. An unexpected advantage was the improved community opinion of the research project as a result of the device, because the use of the technology gave data collectors an elevated status amongst the community. In addition the global positioning system (GPS) functionality of the device allowed precise mapping of households, and hence distinct settlements to be identified as randomisation clusters. Future users should be mindful that to save costs the piloting should be completed before programming. In addition consideration of a local after-care service is important to avoid costs and time delays associated with sending devices back to overseas providers. DISCUSSION: Since the start of this study, PDA devices have rapidly developed and are increasingly used. The use of PDA or similar devices for research is not without its problems; however we believe that the universal lessons learnt as part of this study are even more important for the effective utilisation of these rapidly developing technologies in resource poor settings. PMID- 25027232 TI - Molecular detection of Rickettsia species in Amblyomma ticks collected from snakes in Thailand. AB - Some reptile ticks are potential vectors of pathogens such as spotted fever group (SFG) rickettsiae. Here, we report for the first time in detail the molecular evidence, DNA sequences and phylogenetic studies, for the presence of Rickettsia spp. in Amblyomma ticks (Amblyomma helvolum and Amblyomma varanense) from snakes in Thailand. A total of 24 tick samples was collected from 4 snake species and identified. A phylogenetic analysis inferred from the partial sequences of the gltA gene indicated that the Rickettsia spp. from 2 Amblyomma helvolum and 1 Amblyomma varanense belong to the same group as the SFG rickettsiae, which are closely related to Rickettsia raoultii strains. In contrast, there was 1 Rickettsia sp. from Amblyomma helvolum grouped into the same clade with other SFG rickettsiae (Rickettsia tamurae, Rickettsia monacensis, and a Rickettsia endosymbiont of Amblyomma dubitatum from Brazil). However, another Rickettsia sp. from Amblyomma varanense was closely related to Rickettsia bellii and Rickettsia sp. strain RDa420 from Thailand. In addition, from phylogenetic results based on the 16S rRNA gene and a concatenated tree of the 3 genes (gltA, ompA, and ompB), we found what may be a novel SFG rickettsia species closely related to Rickettsia raoultii (from both Amblyomma varanense and Amblyomma helvolum). In conclusion, our findings are the first report on the presence of novel SFG rickettsiae in 2 snake tick species, Amblyomma varanense and Amblyomma helvolum in Thailand and in south-eastern Asia. PMID- 25027233 TI - Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) nymphs: an ultrastructural study of the integument and midgut. AB - This is an ultrastructural study of two important organs of ticks: the integument, covering the body and involved in the molting process, and the midgut, the first organ to have contact with the ingested host blood. The integument of Rhipicephalus sanguineus sensu lato freshly engorged nymphs consists of a layer of epidermal cells rich in organelles and a cuticle, subdivided in epicuticle and procuticle. The latter presents two distinct regions: the exocuticle (with several pore canals) and the endocuticle (secreted in highly organized overlaid lamellae). The midgut of R. sanguineus sensu lato freshly engorged nymphs consists of an epithelial wall formed by two types of cells: the generative cells, with few organelles; and the digestive cells, with several endosomes, digestive vacuoles, hematin residual bodies, and small drops of lipid. PMID- 25027234 TI - Low prevalence of Borrelia bavariensis in Ixodes ricinus ticks in southeastern Austria. AB - Borrelia bavariensis was recently described as a distinct genospecies among the B. burgdorferi sensu lato complex. The prevalence of B. bavariensis in Austria, a highly endemic area for tick-transmitted pathogens, is scarcely characterized. To investigate the prevalence of B. bavariensis in Ixodes ricinus ticks we reevaluated the results of a study conducted in 518 ticks from southeastern Austria collected in 2002 and 2003. The presence of B. burgdorferi s.l.-specific DNA in ticks was analyzed by a PCR for the outer surface protein A (ospA) gene. Borrelia species were differentiated by restriction fragment length polymorphism (RFLP) analysis, and samples positive for B. bavariensis were further analyzed by multilocus sequence analysis. Two of 133 (1.5%) B. burgdorferi s.l.-positive I. ricinus ticks were infected with B. bavariensis. Both specimens were coinfected with the OspA serotype 5 of B. garinii. Borrelia bavariensis is present; however, seem to be rare in I. ricinus ticks in southeastern Austria. PMID- 25027235 TI - Selected spices and their combination modulate hypercholesterolemia-induced oxidative stress in experimental rats. AB - BACKGROUND: Effect of aqueous extracts of Allium sativum (garlic), Zingiber officinale (ginger), Capsicum fructensces (cayenne pepper) and their mixture on oxidative stress in rats fed high Cholesterol/high fat diet was investigated. Rats were randomly distributed into six groups (n=6) and given different dietary/spice treatments. Group 1 standard rat chow (control), group 2, hypercholesterolemic diet plus water, and groups 3, 4, 5, 6, hypercholesterolemic diet with 0.5 ml 200 mg . kg-1 aqueous extracts of garlic, ginger, cayenne pepper or their mixture respectively daily for 4 weeks. RESULTS: Pronounced oxidative stress in the hypercholesterolemic rats evidenced by significant (p<0.05) increase in MDA levels, and suppression of the antioxidant enzymes system in rat's liver, kidney, heart and brain tissues was observed. Extracts of spices singly or combined administered at 200 mg.kg-1 body weight significantly (p<0.05) reduced MDA levels and restored activities of antioxidant enzymes. CONCLUSIONS: It is concluded that consumption of garlic, ginger, pepper, or their mixture may help to modulate oxidative stress caused by hypercholesterolemia in rats. PMID- 25027236 TI - Toxic influence of silver and uranium salts on activated sludge of wastewater treatment plants and synthetic activated sludge associates modeled on its pure cultures. AB - Toxic impact of silver and uranium salts on activated sludge of wastewater treatment facilities has been studied. Some dominating cultures (an active nitrogen fixer Agrobacterium tumifaciens (A.t) and micromyces such as Fusarium nivale, Fusarium oxysporum, and Penicillium glabrum) have been isolated and identified as a result of selection of the activated sludge microorganisms being steadiest under stressful conditions. For these cultures, the lethal doses of silver amounted 1, 600, 50, and 300 ug/l and the lethal doses of uranium were 120, 1,500, 1,000, and 1,000 mg/l, respectively. A.tumifaciens is shown to be more sensitive to heavy metals than micromyces. Synthetic granular activated sludge was formed on the basis of three cultures of the isolated micromyces steadiest against stress. Its granules were much more resistant to silver than the whole native activated sludge was. The concentration of silver causing 50 % inhibition of synthetic granular activated sludge growth reached 160-170 MUg/l as far as for the native activated sludge it came only to 100-110 MUg/l. PMID- 25027237 TI - Analysis of particle size reduction on overall surface area and enzymatic hydrolysis yield of corn stover. AB - Particle size of lignocellulose materials is an important factor for enzymatic hydrolysis efficiency. In this study, corn stover was milled and sieved into different size fractions from 1.42, 0.69, 0.34, to 0.21 mm, and the corresponding enzymatic hydrolysis yields were 24.69, 23.96, 25.34, and 26.97 %, respectively. The results indicate that the hydrolysis yield is approximately constant with changing corn stover particle sizes in the experimental range. The overall surface area and the inner pore size measurement show that the overall specific surface area was less than 2 % with the half reduction of particle size due to the greater inner pore surface area. The scanning electron microscope photographs gave direct evidence of the much greater inner pore surface area of corn stover particles. This result provided a reference when a proper size reduction of lignocellulose materials is considered in biorefining operations. PMID- 25027239 TI - Gold nanorod-enhanced light emission in quantum-dot-doped polymer nanofibers. AB - One-dimensional nanomaterials have attracted great interest in both fundamental research and technological applications because they can function as device elements and be used to effectively generate, guide, and detect light. Here we report a gold nanorod-enhanced light emission in quantum-dot-doped polymer nanofibers. By incorporating gold nanorods into quantum-dot-doped polymer nanofiber, a 67% increment in 600 nm red light emission efficiency was obtained with an extinction coefficient of 100 cm(-1), a low excitation power operation of 100 nW, and a 100 min increment in photostability. PMID- 25027238 TI - Correlates of exposure to secondhand smoke (SHS) at home among non-smoking adults in Bangladesh: findings from the ITC Bangladesh survey. AB - BACKGROUND: Exposure to secondhand smoke (SHS) is a serious global public health problem. Understanding the correlates of SHS exposure could guide the development of evidence based SHS exposure reduction interventions. The purpose of this study is to describe the pattern of and factors associated with SHS exposure among non smoking adults in Bangladesh. METHODS: Data come from adult non-smokers who participated in the second wave (2010) of the International Tobacco Control Policy (ITC) Evaluation Bangladesh Survey conducted in all six administrative divisions of Bangladesh. A structured questionnaire gathered information on participants' demographic characteristics, pattern of SHS exposure, SHS knowledge, and attitudes towards tobacco control. Exposure to SHS at home was defined as non-smokers who lived with at least one smoker in their household and who reported having no home smoking ban. The data were analyzed using chi-square tests and logistic regression procedures. RESULTS: The SHS exposure rate at home among the participants (N=2813) was 43%. Several sociodemographic and attitudinal factors were associated with SHS exposure. Logistic regression analyses identified eight predictors of SHS exposure: being female (OR=2.35), being aged 15-24 (OR=2.17), being recruited from Dhaka slums (OR=5.19) or non-tribal/non border areas outside Dhaka (OR=2.19) or tribal/border area (OR=4.36), having lower education (1-8 years: OR=2.45; illiterate: OR=3.00, having higher monthly household income (5000 to <10,000 Taka: OR=2.34; 10,000 Taka or more: OR=2.28), having a father who smoked in the past or currently smokes (OR=2.09), having lower concern about the harms of tobacco on children (unconcerned OR=3.99; moderate concern OR=2.26), and not knowing the fact that SHS causes lung cancer in non-smokers (OR=2.04). CONCLUSIONS: Almost half of non-smoking Bangladeshi adults are exposed to SHS at home. The findings suggest the need for comprehensive tobacco control measures that would improve public understanding about health hazards of SHS exposure at home and encourage educational initiatives to promote smoke-free homes. Interventions should deliver targeted messages to reach those in the low socioeconomic status group. PMID- 25027240 TI - Highlights in basic autonomic neuroscience: insular cortex injury leads to cardiovascular dysfunction. PMID- 25027241 TI - Chemoreflex control of the cardiovascular system remains altered after recovery from low protein diet early in life. AB - This study aimed to evaluate the cardiovascular component of the arterial chemoreflex in rats recovered from low protein diet. Male Fischer rats were randomly divided into control and recovered (R-PR) groups after weaning. R-PR rats were fed with low protein diet for 35days and recovered under normal protein diet for 70days. Control rats received normal protein diet for 105days. Arterial chemoreflex was elicited by intravenous injection of KCN. Results showed that pressor response of the chemoreflex was increased in R-PR. Data suggest that protein restriction may alter cardiovascular response to chemical activation of the chemoreflex after recovery. PMID- 25027243 TI - The effect of a detonation nanodiamond coating on the thermal decomposition properties of RDX explosives. AB - A well-dispersed and uniformly shaped detonation nanodiamond (DND) was produced and coated over micron scale RDX in various amounts to form four kinds of DND coating composites (NDRs). In order to confirm the optimal coating amount and its effect on the thermal properties, the thermal decomposition and kinetics were studied by DSC, TG and DPTA techniques. The critical temperature of thermal explosion (Tb) and the self accelerating decomposition temperature (T(SADT)) both exhibit an interesting volcano-shaped changing trend and rank in an increasing order of NDR4 < NDR1 < RDX < NDR3 < NDR2. This indicates that the DND coating amount, ranging from 1/7 to 1/5, provides NDRs with better thermal safety than RDX. The thermolytic kinetic parameters (Ea and A) and activation thermodynamic parameters (DeltaS(?), DeltaH(?) and DeltaG(?)) are sorted in the following order: NDR1 < NDR4 < NDR2 < NDR3. The gas emission and reaction rate constant of the initial thermal decomposition have the same order. The results show that the DND coating could improve the reactivity of the NDRs and the effect is proportional to the coating amount. However, excessive coating that is more than 1/3 conversely hinders decomposition and gas diffusion, like a layer of protective shell. The isoconversional activation energy (Ea) varies with the conversion extent (alpha) at the initial stage of alpha = 0.1-0.5, which indicates that the thermal decomposition of the NDRs is a multi-step process including the secondary reaction or catalytic reaction. However, the Ea values are almost independent of alpha when alpha = 0.6-0.9, with the mean values in an increasing order of NDR1 < NDR4 < NDR2 < NDR3. PMID- 25027244 TI - Base-promoted synthesis of coumarins from salicylaldehydes and aryl-substituted 1,1-dibromo-1-alkenes under transition-metal-free conditions. AB - Facile synthesis of coumarin via the tandem reaction of salicylaldehyde with aryl substituted 1,1-dibromo-1-alkene was developed. This new protocol proceeds smoothly under mild and transition-metal-free conditions, it allows rapid access to coumarins containing various heteroatoms that are more difficult to prepare by traditional methods. Based on the isolated intermediate of 4-(diethylamino)-3 phenylchroman-2-one and detailed mechanistic studies, a credible tandem pathway was proposed. PMID- 25027245 TI - Adult stem cells from the hyaluronic acid-rich node and duct system differentiate into neuronal cells and repair brain injury. AB - The existence of a hyaluronic acid-rich node and duct system (HAR-NDS) within the lymphatic and blood vessels was demonstrated previously. The HAR-NDS was enriched with small (3.0-5.0 MUm in diameter), adult stem cells with properties similar to those of the very small embryonic-like stem cells (VSELs). Sca-1(+)Lin(-)CD45(-) cells were enriched approximately 100-fold in the intravascular HAR-NDS compared with the bone marrow. We named these adult stem cells "node and duct stem cells (NDSCs)." NDSCs formed colonies on C2C12 feeder layers, were positive for fetal alkaline phosphatase, and could be subcultured on the feeder layers. NDSCs were Oct4(+)Nanog(+)SSEA-1(+)Sox2(+), while VSELs were Oct4(+)Nanog(+)SSEA-1(+)Sox2( ). NDSCs had higher sphere-forming efficiency and proliferative potential than VSELs, and they were found to differentiate into neuronal cells in vitro. Injection of NDSCs into mice partially repaired ischemic brain damage. Thus, we report the discovery of potential adult stem cells that may be involved in tissue regeneration. The intravascular HAR-NDS may serve as a route that delivers these stem cells to their target tissues. PMID- 25027246 TI - Biomineralization mediated by anaerobic methane-consuming cell consortia. AB - Anaerobic methanotrophic archaea (ANME) play a significant role in global carbon cycles. These organisms consume more than 90% of ocean-derived methane and influence the landscape of the seafloor by stimulating the formation of carbonates. ANME frequently form cell consortia with sulfate-reducing bacteria (SRB) of the family Deltaproteobacteria. We investigated the mechanistic link between ANME and the natural consortium by examining anaerobic oxidation of methane (AOM) metabolism and the deposition of biogenetic minerals through high resolution imaging analysis. All of the cell consortia found in a sample of marine sediment were encrusted by a thick siliceous envelope consisting of laminated and cementing substances, whereas carbonate minerals were not found attached to cells. Beside SRB cells, other bacteria (such as Betaproteobacteria) were found to link with the consortia by adhering to the siliceous crusts. Given the properties of siliceous minerals, we hypothesize that ANME cell consortia can interact with other microorganisms and their substrates via their siliceous envelope, and this mechanism of silicon accumulation may serve in clay mineral formation in marine sedimentary environments. A mechanism for biomineralization mediated by AOM consortia was suggested based on the above observations. PMID- 25027247 TI - Current state of the art brachytherapy treatment planning dosimetry algorithms. AB - Following literature contributions delineating the deficiencies introduced by the approximations of conventional brachytherapy dosimetry, different model-based dosimetry algorithms have been incorporated into commercial systems for (192)Ir brachytherapy treatment planning. The calculation settings of these algorithms are pre-configured according to criteria established by their developers for optimizing computation speed vs accuracy. Their clinical use is hence straightforward. A basic understanding of these algorithms and their limitations is essential, however, for commissioning; detecting differences from conventional algorithms; explaining their origin; assessing their impact; and maintaining global uniformity of clinical practice. PMID- 25027248 TI - Successful term delivery after laparoscopic resection of a non-communicating rudimentary horn in a patient with a unicornuate uterus: a case report. AB - Unicornuate uterus accompanied by a non-communicating rudimentary horn is a rare uterine malformation. If a embryo is implanted into the rudimentary horn, continuation of pregnancy is difficult due to the risk of uterine rupture. We recently performed laparoscopic resection of the right rudimentary horn after two right rudimentary horn pregnancies in a woman, in whom a normal pregnancy occurred in the left unicornuate uterus, leading to successful delivery of a baby. This case is presented herein. The diagnostic procedures leading to identification of this rare malformation were prompted by inability to remove uterine contents during surgery performed after a diagnosis of missed abortion. A right rudimentary horn pregnancy, which had occurred twice, was treated with methotrexate. To prevent further pregnancy in the right rudimentary horn, resection of this rudimentary horn was planned and successfully implemented under laparoscopic guidance. This surgical procedure is usually difficult, but fertility could be preserved by employing minimally invasive surgery, involving the use of a LigaSureTM Vessel Sealing System to avoid ligation and assure virtually no bleeding. Soon after surgery, a natural pregnancy in the left unicornuate uterus was confirmed. Intrauterine fetal growth was normal, and transvaginal delivery at term was possible. PMID- 25027249 TI - Successful treatment of penetrating chest injury caused by a crossbow. AB - A 67-year-old man presented with a crossbow injury sustained in a suicide attempt during which he fixed the crossbow to a table. Although he retired to bed without treatment on the day of the initial injury, his pain increased the following day, and he was admitted to our hospital. On arrival, his vital signs were stable and a 10-mm diameter crossbow arrow that had penetrated the right anterior chest remained in place. Chest computed tomography revealed suspected damage to the right middle lobe, diaphragm, and liver. A right anterior thoracotomy was performed with partial resection of the middle lobe, diaphragm repair, and arrest of hepatic bleeding. There were no complications, and his postoperative course was uneventful. On day 12 after surgery, he was transferred to the psychiatry department of another hospital for treatment of his depression. PMID- 25027250 TI - Intraperitoneal residual contrast agent from hysterosalpingography detected following cesarean section. AB - Residual contrast agent from hysterosalpingography was detected in the abdominal cavity in a patient who had undergone Cesarean section. It is believed that magnetic resonance imaging alone would be sufficient to distinguish such medium from a foreign body in such cases. PMID- 25027251 TI - Establishment of highly metastatic cell line (Lu10) from murine mammary carcinoma cell line MCH66 and biological characteristics of Lu10. AB - OBJECTIVE: Mouse mammary cancer cell line MCH66 shows invasion-independent metastasis. To elucidate this metastatic mechanism, the biological characteristics putatively related to metastasis were analyzed using several cell lines with different metastatic abilities derived from MCH66. METHODS: Metastatic capacity, invasive activity, growth property, and mRNA expressions of factors associated with endothelial cell proliferation were comparatively analyzed in MCH66 and its sublines. RESULTS: Lu10 subline exhibited higher metastatic potential to the lungs and lymph nodes (100%) than MCH66 or Lu1 subline (0/5, 0/5 each). The growth rate was almost identical between Lu10 and MCH66, and Lu10 revealed weaker invasive activity in vitro than MCH66. In Lu10 tumors in mice, well-developed sinusoidal blood vessels and dilated lymphatics were noted compared with in Lu1 tumors. Accordingly, Lu10 showed higher expression of vascular endothelial growth factor (VEGF)-C, -D, platelet-derived growth factor (PDGF)-B and pleiotrophin than Lu1, while the expression of other growth factors such as VEGF-A, midkine, angiogenin, hepatocyte growth factor, PDGF-A, and basic fibroblast growth factor remained unchanged between Lu1 and Lu10. CONCLUSION: These data indicate that high invasiveness and rapid growth are not required for this metastatic process, and some angiogenic mediators are involved in blood borne and lymphatic metastasis. PMID- 25027252 TI - Visibility of ultrasound-guided echogenic needle and its potential in clinical delivery of regional anesthesia. AB - OBJECTIVE: Ultrasound-guided regional anesthesia is recommended for nerve block due to its safety and reliability. Needle visualization is important when inserting needles into tissues in close proximity to target nerves. For safety reasons, the tip of the standard-type needle for application of nerve block is thinner than that of an interventional needle for insertion into intra-abdominal organs, and this makes it harder to determine its precise position. The purpose of this study was to evaluate the performance of an insulated echogenic needle under ultrasound guidance in phantoms and in the routine anesthetic management of patients undergoing elective surgery. METHODS: Needles with a 21-G diameter were inserted into Blue PhantomTM (Advanced Medical Technologies, LLC, WA) and chicken breast phantoms at angles of 15, 30, 45, 60, and 75 degrees relative to the surface. The needle was scanned by ultrasound using a TiTANTM (SonoSite, WA, USA). Visualization was compared between an insulated needle with corner cube reflectors (CCR-type: Hakko, Japan) and an insulated standard needle (S-type: Hakko, Japan). Both types of needle were also used to deliver regional anesthesia in patients with an ASA classification of PS1-2 undergoing elective surgery. RESULTS: The tip of CCR appeared as 3 bright points under ultrasound, and was more hyperechoic than S. The CCR-type needle was clearly visible under ultrasound at insertion angles of 15, 30, and 45 degrees, and was consistently more hyperechoic than S. However, at steeper angles of > 60 degrees, visibility was poorer. In delivering clinical regional nerve block, CCR was usually more hyperechoic than S, allowing the nerve block points targeted to be accessed with greater ease. CONCLUSIONS: The better visibility of the tip of CCR indicates that it is superior to S in the clinical delivery of peripheral nerve block. PMID- 25027253 TI - Case of combined paratracheal air cyst and accessory cardiac bronchus. AB - Paratracheal air cyst (PTAC) is rather frequently detected on thoracic multi detector computed tomography (MDCT) in daily practice. Accessory cardiac bronchus (ACB) is a rare anomaly; however, the incidence rate is increasing with the use of recent high quality MDCT scanners. We report a case of combined PTAC and ACB that was incidentally detected by MDCT. Three dimensional CT images revealed anatomical details. PMID- 25027254 TI - Effectiveness of a community pharmacy weight management programme. AB - BACKGROUND: Obesity is a growing problem in England with one quarter of the adult population being obese and around 60 % being overweight or obese. Given the high costs of treating obesity-related conditions such as coronary heart disease and type-2 diabetes the UK Government aims to reduce obesity through public health services including those provided by community pharmacists. OBJECTIVE: To evaluate the effectiveness of a community pharmacy weight management clinic in assisting obese patients to reduce their weight. SETTING: Community pharmacies across four Primary Care Trusts in England. METHODS: Retrospective analysis of data collected by pharmacies providing weight management programmes. The service involved measurement with provision of advice and support. Data analysis consisted of frequency counts, percentages and means with standard deviations (SD) for demographic and biometric variables. Paired t tests were used to compare weight, waist circumference and blood pressure at 3 and 6 months. MAIN OUTCOME MEASURE: Weight change at 3 months. RESULTS: 281 patients attended the programme across four Primary Care Trusts. Three-quarters were female, mean age 52.8 years (SD +/- 14.4) and mean baseline weight 96.3 kg (SD +/- 15.7). At 3 months patients had lost weight (mean change = -3.07 kg) and waist circumference (mean change = -3.87 cm), but there was no difference in blood pressure. After 6 months weight and waist circumference were further reduced from baseline (mean change = 4.59 kg, -4.79 cm respectively) and there was a reduction in blood pressure (mean change systolic = -9.5 mmHg; diastolic = -4.7 mmHg). CONCLUSION: The study has demonstrated that reductions in weight and waist circumference can be achieved in patients who participate in a community pharmacy weight management programme. PMID- 25027255 TI - Completeness of patient records in community pharmacies post-discharge after in patient medication reconciliation: a before-after study. AB - BACKGROUND: Transfer of discharge medication related information to community pharmacies could improve continuity of care. This requires for community pharmacies to accurately update their patient records when new information is transferred. An instruction manual that specifies how to document information regarding medication changes and clinical information (i.e. allergies/contraindications) could support community pharmacies. OBJECTIVE: To explore the effect of instruction manuals sent to community pharmacies on completeness of their patient records. SETTING: A before-after study was performed (July 2009-August 2010) in the St Lucas Andreas Hospital, a general teaching hospital in Amsterdam, The Netherlands. METHODS: Patients discharged from the cardiology and respiratory ward were included consecutively. The intervention consisted of a training session for community pharmacies regarding documentation problems and faxing an instruction manual to community pharmacies specifying how to document discharge information in their information system. Usual care consisted of faxing a discharge medication overview to community pharmacies without additional instructions. Two weeks after discharge the medication records of community pharmacies were collected by fax. These were compared with the initial discharge overviews regarding completeness of medication changes (i.e. explicit explanation that medication had been changed) and clinical information documentation. MAIN OUTCOME MEASURE OUTCOMES: were the number and percentage of completely documented medication changes (either needing to be dispensed or not) and clinical information items. The sample size was calculated at 107 patients per measurement period. Multivariable logistic regression was used for analysis. RESULTS: Two hundred and eighteen patients (112 before-106 after) were included. Completeness of medication changes documentation increased marginally after the intervention (46.6 vs 56.3 %, adjusted Odds Ratio 1.4 [95 % confidence interval 1.07-1.83]). Documentation increased when medication was actually dispensed by the community pharmacy. No significant improvements were seen for allergy and contraindication documentation. CONCLUSION: The intervention is insufficient to increase the completeness of documentation by community pharmacies as marginal improvements were achieved. Future studies should evaluate whether electronic infrastructures may help in achieving updated medication records to improve continuity of pharmaceutical care. PMID- 25027256 TI - Comparative acute toxicity of gallium(III), antimony(III), indium(III), cadmium(II), and copper(II) on freshwater swamp shrimp (Macrobrachium nipponense). AB - BACKGROUND: Acute toxicity testing were carried out the freshwater swamp shrimp, Macrobrachium nipponense, as the model animal for the semiconductor applied metals (gallium, antimony, indium, cadmium, and copper) to evaluate if the species is an suitable experimental animal of pollution in aquatic ecosystem. RESULTS: The static renewal test method of acute lethal concentrations determination was used, and water temperature was maintained at 24.0 +/- 0.5 degrees C. Data of individual metal obtained from acute toxicity tests were determined using probit analysis method. The median lethal concentration (96-h LC50) of gallium, antimony, indium, cadmium, and copper for M. nipponense were estimated as 2.7742, 1.9626, 6.8938, 0.0539, and 0.0313 mg/L, respectively. CONCLUSIONS: Comparing the toxicity tolerance of M. nipponense with other species which exposed to these metals, it is obviously that the M. nipponense is more sensitive than that of various other aquatic animals. PMID- 25027257 TI - Teaching tracheal intubation: Airtraq is superior to Macintosh laryngoscope. AB - BACKGROUND: Tracheal intubation with Macintosh laryngoscope is taught to medical students as it is a lifesaving procedure. However, it is a difficult technique to learn and the consequences of intubation failure are potentially serious. The Airtraq optical laryngoscope is a relatively novel intubation device, which allows visualization of the glottic plane without alignment of the oral, pharyngeal, and tracheal axes, possessing advantages over Macintosh for novice personnel. We introduced a teaching mode featured with a progressive evaluation scheme for preparation and performance of tracheal intubation with medical students in this prospective randomized crossover trial who had no prior airway management experience to find the superior one. METHODS: Twenty-six medical students of the 8-year programme in the 6th year participated in this trial, when they did their one-week rotation in the department of anaesthesiology. Each of the students intubated 6 patients, who were scheduled for surgeries under general anaesthesia, each laryngoscope for 3 patients respectively. One hundred and forty nine consecutive patients scheduled for surgical procedures requiring tracheal intubation were enrolled. Patients were randomly allocated to undergo tracheal intubation using Macintosh (n = 75) or Airtraq (n =74) laryngoscope. The progressive evaluation scheme was applied to each intubation attempt. RESULTS: Intubation success rate was significantly higher in Airtraq group than Macintosh group (87.8% vs. 66.7%, P < 0.05). Duration of glottis exposure was significantly shorter in Airtraq group compared to Macintosh group (50 +/- 19 s vs. 81 +/- 27 s, P < 0.001). A grade I Cormack and Lehane glottic view was obtained in 94.6% of patients in the Airtraq group versus 32% of patients in the Macintosh group (P <0.001). Duration of intubation in Airtraq group was significantly shorter (68 +/ 21 s vs. 96 +/- 22 s, P < 0.05) compared to Macintosh group. CONCLUSIONS: Airtraq laryngoscope is easier to master for novice personnel with a higher intubation success rate and shorter intubation duration compared with the Macintosh laryngoscope. TRIAL REGISTRATION: Trial registration number is ChiCTR TRC-13003987, approval date Dec 12, 2013. PMID- 25027258 TI - N-Sulfonic acid poly(4-vinylpyridinium) hydrogen sulfate as an efficient and reusable solid acid catalyst for one-pot synthesis of xanthene derivatives in dry media under ultrasound irradiation. AB - N-Sulfonic acid poly(4-vinylpyridinium) hydrogen sulfate catalyzed efficiently the synthesis of xanthene derivatives under ultrasonic irradiation at room temperature, which has prompted various concerns involving cost and environmental persistence. This methodology shows the effect of presence of anion hydrogen sulfate as an important and effective factor on the promotion of the one-pot multi-components and condensation reactions. The catalyst can be recovered by simple filtration and used for several times without a significant loss of catalytic activity. PMID- 25027259 TI - Preparation of ultrafine cubic Sb2O3 crystals under ultrasonic. AB - The processes and conditions for ultrasonic preparation of cubic Sb2O3 crystals under ultrasonic by neutralizing Sb4O5Cl2 with ammonium hydroxide were researched. The effects of ultrasonic power, time and temperature as well as ratio of Sb4O5Cl2 to water on the crystal form and particle size of Sb2O3 were investigated by X-ray diffraction, scanning electron microscopy and laser particle size analyzer. Cubic Sb2O3 crystals were prepared by being sonicated at 100W and 20 degrees C for 30min. The particles were cubic-like, with the average size of 0.777MUm. PMID- 25027260 TI - Three new sesquiterpenoids from cultures of the basidiomycete Conocybe siliginea. AB - Three new sesquiterpenoids (1-3), along with four known compounds (4-7), were isolated from cultures of the fungus Conocybe siliginea. The structures of new compounds were elucidated using spectroscopic methods. The known compounds were identified by comparing their spectroscopic data with those reported in the literature. All new compounds were evaluated for cytotoxicity against five human cancer cell lines, but none of them possesses significant activity (IC50>40MUM). PMID- 25027261 TI - The association between adolescent sexting, psychosocial difficulties, and risk behavior: integrative review. AB - When a sexting message spreads to an unintended audience, it can adversely affect the victim's reputation. Sexting incidents constitute a potential school safety risk. Just as with other types of adolescent risk behavior, school nurses might have to initiate the first response when a sexting episode arises, but a school nurse's role goes beyond intervention. They can also play an important role in the prevention of sexting and its related risks. This article reviews the links between adolescent sexting, other types of risk behavior, and its emotional and psychosocial conditions. Seven databases were examined and nine studies remained for further review. The review of the literature shows that adolescent sexting is cross sectionally associated with a range of health-risk behaviors. Youth who engage in sexting are also found to experience peer pressure and a range of emotional difficulties. The results can guide school nurse education and practice. PMID- 25027262 TI - Hashimoto's encephalopathy: a brief review. AB - Hashimoto's encephalopathy (HE) is a syndrome of altered mental status, hallucinations, delusional thinking, and often, epileptic seizures. It is diagnosed by the clinical syndrome, the presence of elevated titers of antithyroid antibodies, the lack of another diagnosis based on clinical evaluation, and the response to corticosteroid and other immunosuppressant treatment. This review discusses the symptoms, pathophysiology, and treatment of HE. The disorder is important to recognize because aggressive treatment may bring about a favorable clinical outcome. The disorder has a relatively benign prognosis, compared with many of the entities for which it can be mistaken. PMID- 25027263 TI - Injecting under pressure: the pain of low CSF pressure headache responsive to botulinum toxin injections. AB - Low intracranial pressure headaches can, at times, be refractory to treatment including multiple blood patches and preventative medications. Imaging studies are often unable to demonstrate a cerebrospinal fluid leak that is causing headache and other associated symptoms. Onabotulinum toxin A (BTX) injection is a treatment that has proven efficacy for the treatment of chronic migraine and potentially other headache disorders. We report a patient with a long standing history of refractory low pressure headaches with brain imaging that demonstrated brain sag, and no CSF leak could be identified. She received no sustained benefit from numerous blood patches, and was unresponsive or intolerant to multiple preventative medications. With BTX treatment, the patient continued to have daily headaches, but her pain intensity improved from an average 7/10 to 3/10. This benefit has been sustained over 7 years. This case suggests that BTX may be an effective treatment for headaches due to low intracranial pressure. It also suggests that the beneficial effects of BTX in the treatment of headaches occur through a direct modulation of the nociceptive system rather than merely induction of pericranial muscle relaxation. PMID- 25027265 TI - Topiramate for weight reduction in adolescents with severe obesity. AB - BACKGROUND: Medications for use as an adjunct to lifestyle modification therapy (LSM) for severe adolescent obesity are limited. Topiramate results in weight reduction in adults with obesity, but has not been studied in adolescents. OBJECTIVE: To examine the effect of topiramate plus LSM on body mass index (BMI) reduction in adolescents with severe obesity. METHODS: Data for this retrospective chart review were collected from patients attending a pediatric weight management program who were treated with LSM plus topiramate for 3 months minimum. Mean BMI percent change from baseline was evaluated using t-tests. RESULTS: Twenty-eight patients (mean age 15.2 +/- 2.5 years, mean baseline BMI 46.2 +/- 10.3 kg/m(2)) were identified for inclusion. The 6-month percent change in BMI was -4.9, 95% confidence interval (-7.1, -2.8), P < .001. CONCLUSIONS: Topiramate with concurrent LSM was associated with clinically meaningful BMI reduction in adolescents with severe obesity. Randomized controlled clinical trials examining efficacy and safety of topiramate for severe obesity in adolescents are needed. PMID- 25027264 TI - Neuromyelitis optica spectrum disorders. AB - Since the discovery of aquaporin 4-IgG, a sensitive and highly specific biomarker of neuromyelitis optica (NMO), a wide range of syndromes have been recognized as being associated with this condition. This observation has led to new proposed terminology for the entire disorder, NMO spectrum disorders (NMOSD). The discovery of a pathogenic autoantibody and its target antigen has also facilitated basic research into the immunopathogenesis of the disease. Key advances include establishment of passive transfer animal models demonstrating the pathogenic potential of the autoantibody and confirming an important role of complement suggested by immunopathology of NMO brain lesions and of B-cell subsets, plasmablasts in particular. These discoveries have led to phase 1 clinical trials of targeted immunotherapy with potential for improved efficacy and less toxicity than current empiric immunosuppressant medications used to treat NMOSD. Randomized clinical trials are beginning to assess the efficacy and safety of a variety of immunotherapies in NMOSD. Therapeutic options are likely to increase, and improved outcomes in NMOSD patients are anticipated. PMID- 25027266 TI - Umbilical stalk elevation technique for safer Veress needle insertion in obese patients: a case-control study. AB - OBJECTIVE: The purpose of this retrospective study was to compare our umbilical stalk elevation (USE) technique with the classic Veress needle (VN) technique in obese patients. STUDY DESIGN: The USE technique was performed on 40 patients. One control per case was randomly selected from among those undergoing the classic VN technique using a random number table. In USE technique, a 12 mm skin incision was created at the superior crease of the umbilical fold, and the underlying subcutaneous adipose tissue was bluntly dissected using the tip of a fine clamp until the umbilical stalk was isolated at the inferior and central part of the incision. Next, the umbilical stalk was covered and held by a towel clip, and the abdominal wall was elevated by upward traction. The VN was then inserted nearly perpendicular to the incision and turned toward the pelvis immediately after resistance to the needle had been lost. A post-hoc power analysis was performed. RESULTS: The number of attempts was significantly lower in the USE laparoscopy group than in the classic laparoscopy group (1.2 +/- 0.4 vs. 2.1 +/- 0.7, respectively; P<0.001). The USE technique group had a slightly shorter abdominal entry time than did the classic technique group (328.52 +/- 63.71 vs. 434.95 +/- 124.10s; P<0.001). Six (7.5%) failed insufflations occurred in our study (5 patients in the classic group vs. 1 patient in the USE group (P=0.10). CONCLUSION: Our novel USE technique can be an effective means of establishing pneumoperitoneum in obese patients undergoing gynecologic laparoscopic procedures. PMID- 25027267 TI - Home based educational intervention to improve perinatal outcomes for a disadvantaged community: a randomised control trial. AB - OBJECTIVES: Pregnancy, labour, and delivery involve risk for mothers and infants. This study tested the effectiveness of a home-based programme to improve perinatal outcomes among socially disadvantaged women. The hypothesis was that the intervention group who received education and support during pregnancy would have better perinatal outcomes than the control group. STUDY DESIGN: This is a randomised controlled trial. Pregnant women from a disadvantaged community in Dublin, Ireland were eligible for participation in Preparing for Life, a home visiting early intervention programme. 233 participants were recruited and assigned to an intervention (n=115) and control (n=118) group using an unconditional probability randomisation strategy. Maternity hospital records were available for 206 participants (nintervention=106; ncontrol=100). Consent to access records was not provided by 9 participants, records were missing for 17 participants and 1 record was excluded due to miscarriage. The intervention group were prescribed an average of ten prenatal home visits from a trained mentor. Mentors provided information on healthy prenatal behaviours and the birthing experience using tip sheets and social support. The control group received care as usual including the opportunity to attend standard antenatal classes. The outcomes included neonatal (Apgar scores, birth weight, gestational age and prematurity) and maternal (labour onset method and delivery method) outcomes. Statistical analyses were conducted using t -tests, tests of proportions, regression, logistic regression and permutation testing. RESULTS: There were no differences on any of the neonatal outcomes or the majority of the maternal outcomes. Two secondary results were found such that there was an increase in the rate of spontaneous onset of labour in the intervention group compared to the control group (69.8% v 58.0%; OR 1.67, 95% CI=0.94, 2.97; p<0.05) and there was a reduction in caesarean section rates in the intervention group compared to the control group (15.1% v 25.0%; OR 0.53, 95% CI=0.27, 1.07; p<0.05). CONCLUSIONS: This prenatal home visiting programme had no impact on neonatal outcomes, yet there was suggestive evidence that it prepared women for birth, and potentially led to increased spontaneous onset of labour and reduced caesarean section. Further studies are required to test these observation generating hypotheses. Trial registration ISRCTN04631728- http://www.controlled trials.com/ISRCTN04631728/ PMID- 25027268 TI - Healthy excuses and the need for more research. PMID- 25027269 TI - Surgical repair of complete atrio-ventricular canal: one more approach? PMID- 25027270 TI - Abnormal fibrous band from the left atrium to the left ventricle causing mitral regurgitation. PMID- 25027271 TI - Surgical management of infective endocarditis: an analysis of early and late outcomes. AB - OBJECTIVES: To review our experience of surgical management of infective endocarditis (IE) over a 13-year period and analyse the outcomes and associated prognostic factors. METHODS: A retrospective review was conducted for 191 consecutive patients who underwent surgery for native and prosthetic valve endocarditis (PVE) between January 2000 and December 2012. Surgical outcomes were reviewed to include survival and postoperative complications. Follow-up was complete for 172 of 179 patients (96.1%) surviving to hospital discharge, with a mean follow-up of 6.6 +/- 3.7 years. RESULTS: Mean age was 47.4 +/- 14.9 years with 113 (63.9%) males. Native valve endocarditis was present in 177 patients (92.7%). Sixty-three patients (33.0%) presented with embolic complications. The brain was the most common site of embolism, involving 25 patients (13.1%). Streptococcus viridans was the most common infective organism, isolated in 68 patients (35.7%), followed by Staphylococcus aureus in 30 patients (15.7%). Eighty-seven patients (45.5%) had active endocarditis at the time of surgery. The mitral valve was infected in 136 patients (71.2%), the aortic valve in 66 (34.6%), the tricuspid valve in 29 (15.2%) and multiple valves in 38 (19.9%). Nineteen patients (9.9%) were intravenous drug users (IVDU). Twelve IVDUs (63.2%) suffered from tricuspid valve IE, compared with 7 of 162 patients (4.3%) in the non-IVDU population (P < 0.001). The most common indication for early surgery was intractable cardiac failure. Twelve patients (6.3%) died during the hospital stay for surgical treatment of IE. Logistic multivariate analysis identified preoperative creatinine clearance and stroke as independent predictors of in hospital mortality. Overall 10-year survival and freedom from valve-related reoperation were 74.8 and 90.3%, respectively. Age, PVE, S. aureus endocarditis and postoperative left ventricular ejection fraction (LVEF) <=45% were factors influencing long-term survival. CONCLUSIONS: Surgical management of endocarditis continues to be challenging and is associated with significant morbidity and mortality. This report of 191 patients who underwent valve surgery for IE shows that in-hospital mortality is influenced by preoperative renal function and stroke at the time of presentation. The optimal timing for surgery in patients with stroke remains controversial. Long-term survival was negatively influenced by increasing age, moderate to severely impaired LVEF, prosthetic valve IE and S. aureus infection. PMID- 25027272 TI - Indian government must spend more on healthcare, salaries, and infrastructure. PMID- 25027273 TI - Accounting for length-bias and selection effects in estimating the distribution of menstrual cycle length. AB - Prospective pregnancy studies are a valuable source of longitudinal data on menstrual cycle length. However, care is needed when making inferences of such renewal processes. For example, accounting for the sampling plan is necessary for unbiased estimation of the menstrual cycle length distribution for the study population. If couples can enroll when they learn of the study as opposed to waiting for the start of a new menstrual cycle, then due to length-bias, the enrollment cycle will be stochastically larger than the general run of cycles, a typical property of prevalent cohort studies. Furthermore, the probability of enrollment can depend on the length of time since a woman's last menstrual period (a backward recurrence time), resulting in selection effects. We focus on accounting for length-bias and selection effects in the likelihood for enrollment menstrual cycle length, using a recursive two-stage approach wherein we first estimate the probability of enrollment as a function of the backward recurrence time and then use it in a likelihood with sampling weights that account for length-bias and selection effects. To broaden the applicability of our methods, we augment our model to incorporate a couple-specific random effect and time independent covariate. A simulation study quantifies performance for two scenarios of enrollment probability when proper account is taken of sampling plan features. In addition, we estimate the probability of enrollment and the distribution of menstrual cycle length for the study population of the Longitudinal Investigation of Fertility and the Environment Study. PMID- 25027274 TI - Testing calibration of risk models at extremes of disease risk. AB - Risk-prediction models need careful calibration to ensure they produce unbiased estimates of risk for subjects in the underlying population given their risk factor profiles. As subjects with extreme high or low risk may be the most affected by knowledge of their risk estimates, checking the adequacy of risk models at the extremes of risk is very important for clinical applications. We propose a new approach to test model calibration targeted toward extremes of disease risk distribution where standard goodness-of-fit tests may lack power due to sparseness of data. We construct a test statistic based on model residuals summed over only those individuals who pass high and/or low risk thresholds and then maximize the test statistic over different risk thresholds. We derive an asymptotic distribution for the max-test statistic based on analytic derivation of the variance-covariance function of the underlying Gaussian process. The method is applied to a large case-control study of breast cancer to examine joint effects of common single nucleotide polymorphisms (SNPs) discovered through recent genome-wide association studies. The analysis clearly indicates a non additive effect of the SNPs on the scale of absolute risk, but an excellent fit for the linear-logistic model even at the extremes of risks. PMID- 25027275 TI - Black yeast diversity on creosoted railway sleepers changes with ambient climatic conditions. AB - The environmental isolation of opportunistic pathogenic black yeasts, which are responsible for a wide spectrum of human infections, is essential to understanding the ecology of clinical fungi. Extreme outdoor environments polluted with aromatic hydrocarbons support the growth of black yeasts in unlikely places, such as railway sleepers. However, there are limited data concerning the diversity of these fungi growing on polluted railway sleepers. In this investigation, we examined 845 railway sleeper samples, obtained from 11 Turkish cities representing altitudes from 25 to 1,893 m, and inoculated the samples onto mycological media for the isolation of black yeasts. Ninety-four samples (11.1 %) yielded positive results for black yeast, with creosoted oak sleepers having a significantly higher number of isolates than concrete sleepers (p < 0.05). Identification based on the ribosomal DNA (rDNA) internal transcribed spacer region revealed the highest prevalence of Exophiala phaeomuriformis, followed by Exophiala dermatitidis, Exophiala heteromorpha, Exophiala xenobiotica, and Exophiala crusticola. This study revealed that railway sleepers harboring black yeasts were predominantly (>75 %) populated with thermophilic species. We observed that altitude might have a significant effect on species diversity. Briefly, E. phaeomuriformis exhibited growth over a wide altitude range, from 30 to 1,893 m. In contrast, E. dermatitidis had a remarkable aversion to low altitudes and exhibited maximum growth at 1,285 m. In conclusion, we speculate that one can predict what species will be found on railway sleepers and their probability and that species diversity primarily depends on sleeper type and altitude height. We believe that this study can contribute new insights into the ecology of black yeasts on railway sleepers and the railway factors that influence their diversity. PMID- 25027276 TI - Bacterial diversity in the rhizosphere of cucumbers grown in soils covering a wide range of cucumber cropping histories and environmental conditions. AB - Rhizosphere microorganisms in soils are important for plant growth. However, the importance of rhizosphere microorganisms is still underestimated since many microorganisms associated with plant roots cannot be cultured and since the microbial diversity in the rhizosphere can be influenced by several factors, such as the cropping history, biogeography, and agricultural practice. Here, we characterized the rhizosphere bacterial diversity of cucumber plants grown in soils covering a wide range of cucumber cropping histories and environmental conditions by using pyrosequencing of bacterial 16S rRNA genes. We also tested the effects of compost addition and/or bacterial inoculation on the bacterial diversity in the rhizosphere. We identified an average of approximately 8,883 reads per sample, corresponding to around 4,993 molecular operational taxonomic units per sample. The Proteobacteria was the most abundant phylum in almost all soils. The abundances of the phyla Bacteroidetes, Actinobacteria, Firmicutes, Acidobacteria, and Verrucomicrobia varied among the samples, and together with Proteobacteria, these phyla were the six most abundant phyla in almost all analyzed samples. Analyzing all the sample libraries together, the predominant genera found were Flavobacterium, Ohtaekwangia, Opitutus, Gp6, Steroidobacter, and Acidovorax. Overall, compost and microbial amendments increased shoot biomass when compared to untreated soils. However, compost addition decreased the bacterial alpha-diversity in most soils (but for three soils compost increased diversity), and no statistical effect of microbial amendment on the bacterial alpha-diversity was found. Moreover, soil amendments did not significantly influence the bacterial beta-diversity. Soil organic content appeared more important than compost and microbial amendments in shaping the structure of bacterial communities in the rhizosphere of cucumber. PMID- 25027278 TI - Assessment of spatial uncertainty in computed tomography-based Gamma Knife stereotactic radiosurgery process with automated positioning system. AB - BACKGROUND: In this study, we assessed the geometric accuracy of an automated positioning system in Gamma Knife (GK) surgery. Specifically, we looked at the total spatial uncertainty over the entire treatment range of GK stereotactic radiosurgery (SRS) procedures in both the GK model C and the Perfexion (PFX). METHODS: An originally-developed phantom and a radiochromic film were used for obtaining actual dose distributions. The phantom, with inserted films on different axial planes (z = 60, 75, 100, 125, 140 mm), sagittal planes (x = 60, 75, 100, 125, 140 mm), and coronal planes (y = 60, 75, 100, 125, 140 mm), was placed on a Leksell skull frame. Computed tomography (CT) was then performed with a stereotactic localizer box attached to the frame, and dose planning was made using the Leksell GammaPlan treatment planning system. The phantom finally received beam delivery using a single shot of a 4-mm collimator helmet. The discrepancy between the planned shot position and the irradiated center position was evaluated by a dedicated film analysis software. RESULTS: The total uncertainty of CT-based GK SRS was less than 1 mm for almost all measured points over the stereotactic space in both the model C and the PFX. In addition, the geometric accuracy of the automated positioning system was estimated to be less than 0.1 mm and equal to 0.5 mm in the central and peripheral areas, respectively. CONCLUSIONS: We confirmed that the total spatial uncertainties of both the GK model C and the PFX are acceptable for clinical use. PMID- 25027277 TI - Population dynamics of Vibrio and Pseudomonas species isolated from farmed Tasmanian Atlantic salmon (Salmo salar L.): a seasonal study. AB - Vibrio and Pseudomonas species have been shown to be part of the normal microbiota of Atlantic salmon (Salmo salar L.), with some strains causing disease in fish. The factors affecting their prevalence and persistence in the salmon gut, however, have not been well studied. In this study, we collected 340 Vibrio and 150 Pseudomonas isolates from the hindgut of farmed Tasmanian Atlantic salmon, fed with two commercially available diets. Samples were collected every 6 8 weeks between July 2011 and May 2012. Isolates from selective agar were initially identified using biochemical tests and confirmed using genus-specific primers and 16S ribosomal RNA (16S rRNA) sequencing. Random amplified polymorphic DNA (RAPD) PCR was used to type both Pseudomonas and Vibrio; the latter was further typed using a biochemical fingerprinting method (PhP-RV plates). We observed low species diversity with strains comprising Vibrio ichthyoenteri/Vibrio scophthalmi, Vibrio crassostreae/Vibrio splendidus, Aliivibrio finisterrensis, Photobacterium phosphoreum and Pseudomonas fragi. Out of 340 Vibrio isolates, 238 (70 %) belonged to 21 clonal types and were found predominantly during summer when water temperatures reached 15 to 21 degrees C. Of these, the four major clonal types were found in multiple samples (70 %). P. fragi, on the other hand, was only found during the colder water temperatures and belonged to 18 clonal types. The presence of both groups of bacteria and their clonal types were independent of the fish diets used, suggesting that the water temperature was the main factor of the prevalence and persistence of these bacteria in the gut of Atlantic salmon. PMID- 25027279 TI - Treatment of urological complications in more than 1,000 kidney transplantations: the role of interventional radiology. AB - PURPOSE: The aim of this study is to evaluate the efficacy and safety of interventional radiology procedures in the treatment of major urological complications after kidney transplantation. MATERIALS AND METHODS: Between 2000 and 2010, 1,146 kidney transplants were performed at our institution. A total of 146 major complications occurred, including 77 obstructions, 36 leaks and 33 associated perigraft fluid collections. Percutaneous treatment was carried out in 118/146 complications in 91 patients. In the case of stenosis-obstruction and fistulas (104 complications), the first therapeutic step was placement of a nephrostomy catheter, followed by balloon ureteroplasty, placement of external internal catheters and double-J stents; 14/33 collections were drained under ultrasound guidance. RESULTS: In all 118 percutaneous interventions, we were able to place a nephrostomy or drainage catheter, with a technical success rate of 100 %. The long-term success rate was 49.6 %: in 57/115 (three patients were lost to follow-up) we obtained the complete resolution of the complication. The procedure related mortality rate was 0 %. There was only one major complication and the rate of minor complications was 14.4 %. CONCLUSIONS: Interventional radiology is the first choice option in the treatment of urological complications after kidney transplantation. PMID- 25027280 TI - Lymph node involvement in colon cancer patients decreases with age; a population based analysis. AB - BACKGROUND: The variation in nodal involvement between age groups has not been thoroughly studied in colon cancer, but it may affect strategies for extent of resection in elderly patients. The objective of our study was to compare nodal involvement in colon cancer patients, with a focus on surgical staging practices in the elderly. METHODS: We extracted data from the Surveillance, Epidemiology and End Results registry on 208,077 patients diagnosed with stage I-III colon adenocarcinoma between 2000 and 2010. Patients undergoing colon resection, patients with adequate staging with >=12 lymph nodes examined (LNE, n = 114,351) and with node-positive cancers were compared in age groups using chi-squared test. Relative risk (RR) of node-positive cancer was compared in a multivariable log-linear model, and relative survival in a flexible parametric model. RESULTS: While the rates of colon resection were similar in all age groups, older patients were significantly less likely to have >=12 LNE (P < 0.0001). When adequately staged, older patients had a significantly lower proportion of node-positive cancers (P < 0.0001). Survival was better in patients with >=12 LNE, with no significant difference in the benefit between the age groups (P = 0.25). CONCLUSIONS: When adequately staged, older patients are less likely to have node positive colon cancer, which may help them avoid adjuvant chemotherapy. Since the survival benefit of adequate nodal staging is similar in every age group, the guidelines for extent of resection and pathological examination should be diligently adhered to in all patients undergoing curative surgery, regardless of age. PMID- 25027281 TI - Effect of velocity on microdroplet fluorescence quantified by laser-induced fluorescence. AB - Microdroplets generated inside microfluidic devices have been widely used as miniaturized chemical and biological reactors allowing important reductions in experimental fluid volumes and making it possible to carry out high-throughput assays. Laser-induced fluorescence (LIF) is commonly used to detect and quantify the product, marker or cell content inside each individual droplet. In this work, we employed this technique to characterize the response of in-flow microdroplets filled with fluorescein dye at different laser powers and flow velocities. Using two parallel laser beams closely focused inside a microchannel we determined the microdroplet velocities and showed that the droplet fluorescence intensity decreases exponentially with reducing velocities because of the effects of photobleaching. In contrast, the fluorescence intensity increases linearly with laser power in the 4-10 mW range. When LIF is used for microdroplet measurements it is important to consider not just the fluorophore concentration but also the droplet velocity and laser power in the development of quantitative assays. PMID- 25027282 TI - Hematopoietic myeloid cell differentiation diminishes nucleotide excision repair. AB - Myeloid cell differentiation is the process by which stem cells develop into mature monocytes or granulocytes. This process is achieved by the sequential activation of variety of genes. Disruption of this process can result in immunodeficiency, bone marrow failure syndrome, or leukemia. Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation and can be treated by a combination of all-trans retinoic acid (ATRA) and anthracycline. This treatment can induce leukemic cell differentiation, leading to extremely high remission rates. XAB2, a molecule involved in nucleotide excision repair (NER), is downregulated during granulocyte differentiation and shows reduced expression in NB4 APL-derived cells in vitro. Differentiation of APL by ATRA treatment reduced XAB2 expression levels in vivo. These observations suggest that cellular differentiation is associated with reduced NER activity and provides new insights into combined differentiation induction. NB4 cells were more susceptible than the immature myeloid leukemic cell lines, Kasumi-3 and Kasumi-1, to the DNA interstrand crosslinking agent cisplatin. PMID- 25027283 TI - Metabolism of aflatoxins: key enzymes and interindividual as well as interspecies differences. AB - Aflatoxins are potent hepatocarcinogen in animal models and suspected carcinogen in humans. The most important aflatoxin in terms of toxic potency and occurrence is aflatoxin B1 (AFB1). In this review, we mainly summarized the key metabolizing enzymes of AFB1 in animals and humans. Moreover, the interindividual and the interspecies differences in AFB1 metabolism are highly concerned. In human liver, CYP3A4 plays an important role in biotransforming AFB1 to the toxic product AFB1 8,9-epoxide. In human lung, CYP2A13 has a significant activity in metabolizing AFB1 to AFB1-8,9-epoxide and AFM1-8,9-epoxide. The epoxide of AFB1-8,9-epoxide could conjugate with glutathione to reduce the toxicity by glutathione-S transferase (GST). In poultry species, CYP2A6, CYP3A37, CYP1A5, and CYP1A1 are responsible for bioactivation of AFB1. There are interindividual variations in the rate of activation of aflatoxins in various species, and there are also differences between children and adults. The age and living regions are important factors affecting resistance of species to AFB1. The rate of AFB1-8,9-epoxide formation and its conjugation with glutathione are key parameters in interspecies and interindividual differences in sensitivity to the toxic effect of AFB1. This review provides an important information for key metabolizing enzymes and the global metabolism of aflatoxins in different species. PMID- 25027284 TI - An expressive therapy group disclosure intervention for women living with HIV improves social support, self-efficacy, and the safety and quality of relationships: a qualitative analysis. AB - Women living with HIV (WLHIV) face high rates of morbidity and mortality. HIV disclosure interventions have been identified as a promising but under-evaluated approach for WLHIV to improve their health and well-being. The Medea Project is an expressive therapy group intervention that was first developed to help incarcerated women develop the confidence and skills to tell their stories publicly in theatrical performances. The intervention was subsequently adapted as a community-based disclosure intervention for WLHIV. Our study describes an analysis of the impact of the Medea Project on the lives of the WLHIV who participated. All participating WLHIV publicly disclosed their HIV status during the performances. Five impact themes emerged from the data: sisterhood, catharsis, self-acceptance, safer and healthier relationships, and gaining a voice. Our study identifies a voluntary, effective, and broadly beneficial disclosure intervention for women living with HIV. PMID- 25027285 TI - Development of an NPM1/MLF1 D-FISH probe set for the detection of t(3;5)(q25;q35) identified in patients with acute myeloid leukemia. AB - The t(3;5)(q25;q35) NPM1/MLF1 fusion has an incidence of approximately 0.5% in acute myeloid leukemia (AML) and has an intermediate prognosis at diagnosis. We have developed a dual-color, dual-fusion fluorescence in situ hybridization (D FISH) assay to detect fusion of the MLF1 and NPM1 genes. A blinded investigation was performed using 25 normal bone marrow specimens and 26 bone marrow samples from patients with one or more metaphases with a t(3;5)(q21-q25;q31-q35) or a der(5)t(3;5)(q21-q25;q31-q35) previously identified by chromosome analysis. Once unblinded, the results indicate our D-FISH method identified NPM1/MLF1 fusion in 15 of the 26 fully evaluated patient samples. Excluding three samples with a single abnormal t(3;5) metaphase, 15 of 17 (88%) patient samples with a balanced t(3;5) demonstrated NPM1/MLF1 fusion, and 0 of 6 patient samples with a der(5)t(3;5) demonstrated NPM1/MLF1 fusion, suggesting only the balanced form of this 3;5 translocation as observed by karyotype is associated with NPM1/MLF1 fusion. Overall, the FISH results demonstrated five different outcomes (NPM1/MLF1 fusion, MLF1 disruption, MLF1 duplication, NPM1 deletion, and normal), indicating significant molecular heterogeneity when the 3;5 translocation is identified. The development of this sensitive D-FISH strategy for the detection of NPM1/MLF1 fusion adds to the AML FISH testing repertoire and is effective in the detection of this translocation at diagnosis as well as monitoring residual disease in AML patients. PMID- 25027286 TI - Controlling on-demand gastric acidity in obese subjects: a randomized, controlled trial comparing a single dose of 20 mg rabeprazole and 20 mg omeprazole. AB - BACKGROUND: Obesity is associated with a risk of gastroesophageal reflux disease. The pharmacodynamic efficacy of proton pump inhibitors has not been specifically evaluated in obese subjects. The aim of this study was to compare the antisecretory response to a single oral dose of 20 mg rabeprazole, 20 mg omeprazole and placebo in obese subjects. METHODS: Gastric pH was monitored for 24 hours on three separate occasions in eighteen H. pylori-negative, asymptomatic obese subjects. Subjects were given omeprazole, rabeprazole or placebo in a randomized order and in a double-blind fashion. The main analysis criterion was 24-h percent of time post dose with intragastric pH above 3; secondary criteria were percentage of time above pH 4, median pH, [H+] concentrations and nocturnal acid breakthrough (NAB). Results were analyzed using linear mixed models and Wilks test comparing variances. RESULTS: 24-h median [IQ] percentages of time with gastric pH above 3 and 4 were higher with rabeprazole than omeprazole (46 [37-55] vs. 30 [15-55] %, 9 [5-11] % for placebo) but the differences did not reach statistical significance (p = 0.11 and 0.24, respectively). Median acid concentrations were significantly lower with rabeprazole than with omeprazole and placebo (22 [14-53] vs. 54 [19-130] and 95 [73-170] mmoles/l, p < 0.01) for all periods. The number of NAB was significantly lower with rabeprazole than with omeprazole (median 1 [1,2] vs. 2 [1-3], p = 0.04). Variances of 24-h data (pH above 3 and 4, median pH, [H+] concentrations) were significantly lower with rabeprazole than with omeprazole (p < 0.0001). CONCLUSIONS: In asymptomatic obese subjects the gastric antisecretory response to a single dose of rabeprazole and omeprazole was strong and not significantly different between drugs despite a significantly more homogeneous response with rabeprazole. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01136317. PMID- 25027288 TI - Seasonality and dietary requirements: will eating seasonal food contribute to health and environmental sustainability? AB - Eating more seasonal food is one proposal for moving towards more sustainable consumption patterns, based on the assumption that it could reduce the environmental impact of the diet. The aim of the present paper is to consider the implications of eating seasonal food on the different elements of sustainability (i.e. health, economics, society), not just the environment. Seasonality can be defined as either globally seasonal (i.e. produced in the natural production season but consumed anywhere in the world) or locally seasonal (i.e. produced in the natural production season and consumed within the same climatic zone). The environmental, health, economic and societal impact varies by the definition used. Global seasonality has the nutritional benefit of providing a more varied and consistent supply of fresh produce year round, but this increases demand for foods that in turn can have a high environmental cost in the country of production (e.g. water stress, land use change with loss of biodiversity). Greenhouse gas emissions of globally seasonal food are not necessarily higher than food produced locally as it depends more on the production system used than transportation. Eating more seasonal food, however, is only one element of a sustainable diet and should not overshadow some of the potentially more difficult dietary behaviours to change that could have greater environmental and health benefits (e.g. reducing overconsumption or meat consumption). For future guidelines for sustainable diets to be realistic they will need to take into account modern lifestyles, cultural and social expectations in the current food environment. PMID- 25027287 TI - Temporal regulation of mRNAs for select bone morphogenetic proteins (BMP), BMP receptors and their associated SMAD proteins during bovine early embryonic development: effects of exogenous BMP2 on embryo developmental progression. AB - BACKGROUND: We previously demonstrated embryotrophic actions of maternal (oocyte derived) follistatin during bovine early embryogenesis. Classical actions of follistatin are attributed to inhibition of activity of growth factors including activins and bone morphogenetic proteins (BMP). However, temporal changes in BMP mRNA in early bovine embryos and the effects of exogenous BMP on embryo developmental progression are not understood. The objectives of present studies were to characterize mRNA abundance for select BMP, BMP receptors and BMP receptor associated SMADs during bovine oocyte maturation and early embryogenesis and determine effects of addition of exogenous BMP protein on early development. METHODS: Relative abundance of mRNA for BMP2, BMP3, BMP7, BMP10, SMAD1, SMAD5, ALK3, ALK6, ALK2, BMPR2, ACVR2A and ACVR2B was determined by RT-qPCR analysis of germinal vesicle (GV) and in vitro matured metaphase II (MII) oocytes and in vitro produced embryos collected at pronuclear, 2-cell (C), 4C, 8C, 16C, morula and blastocyst stages. Effects of addition of recombinant human BMP2 (0, 1, 10 and 100 ng/ml) during initial 72 h of embryo culture on early cleavage (within 30 h post insemination), total cleavage, development to 8C-16C and blastocyst stages and blastocyst mRNA abundance for markers of inner cell mass (NANOG) and trophectoderm (CDX2) were also determined. RESULTS: Abundance of mRNA for BMP2, BMP10, SMAD1, SMAD5, ALK3, ALK2, BMPR2 and ACVR2B was elevated in MII oocytes and/or pronuclear stage embryos (relative to GV) and remained elevated through the 8C -16C stages, whereas BMP3, BMP7 and ALK2 mRNAs were transiently elevated. Culture of embryos to the 8C stage in the presence of alpha-amanitin resulted in increased abundance for all of above transcripts examined relative to untreated 8C embryos. Effects of addition of exogenous BMP2 on early cleavage rates and rates of development to 8C-16C and blastocyst stages were not observed, but BMP2 treatment increased blastocyst mRNA for CDX2 and NANOG. CONCLUSIONS: Abundance of maternally derived mRNAs for above BMP system components are dynamically regulated during oocyte maturation and early embryogenesis. Exogenous BMP2 treatment does not influence progression to various developmental endpoints, but impacts characteristics of resulting blastocysts. Results support a potential role for BMPs in bovine early embryogenesis. PMID- 25027289 TI - Childhood obesity: the impact on long-term risk of metabolic and CVD is not necessarily inevitable. AB - The worldwide prevalence of overweight and obesity in the adult population is estimated to be 35%. These trends are reflected in childhood obesity prevalence, and the potential impact of early-onset obesity is of great concern. The aim of this review was to investigate the long-term implications of childhood obesity for metabolic and cardiovascular health, focusing on the independent contribution of childhood obesity to adult disease risk, as distinct from associations mediated by tracking of obesity across the lifespan. The data systematically reviewed provide little evidence to suggest that childhood overweight and obesity are independent risk factors for metabolic and cardiovascular risk during adulthood. Instead, the data demonstrate that the relationships observed are dependent on tracking of BMI between childhood and adulthood, alongside persistence of dietary patterns and physical activity. Adjustment for adult BMI uncovers unexpected negative associations between childhood BMI and adult disease, suggesting a protective effect of childhood obesity at any given level of adult BMI. Further work is required to explain these findings, both in terms of pathways and statistical artefacts. To conclude, it must be stressed that it is not suggested that childhood obesity is without negative consequence. Childhood obesity is clearly associated with a range of adverse physical and psychological outcomes. However, the data are important in supporting a positive message that the long-term consequences of childhood obesity are avoidable; and that there remains opportunity for intervention across the lifespan. This nuance in understanding long-term risk is important when considering the effectiveness of interventions at different stages of the lifespan. PMID- 25027290 TI - DNA methylation, ageing and the influence of early life nutrition. AB - It is well established that genotype plays an important role in the ageing process. However, recent studies have suggested that epigenetic mechanisms may also influence the onset of ageing-associated diseases and longevity. Epigenetics is defined as processes that induce heritable changes in gene expression without a change in the DNA nucleotide sequence. The major epigenetic mechanisms are DNA methylation, histone modification and non-coding RNA. Such processes are involved in the regulation of tissue-specific gene expression, cell differentiation and genomic imprinting. However, epigenetic dysregulation is frequently seen with ageing. Relatively little is known about the factors that initiate such changes. However, there is emerging evidence that the early life environment, in particular nutrition, in early life can induce long-term changes in DNA methylation resulting in an altered susceptibility to a range of ageing associated diseases. In this review, we will focus on the changes in DNA methylation that occur during ageing; their role in the ageing process and how early life nutrition can modulate DNA methylation and influence longevity. Understanding the mechanisms by which diet in early life can influence the epigenome will be crucial for the development of preventative and intervention strategies to increase well-being in later life. PMID- 25027292 TI - Five questions that need answering when considering the design of clinical trials. AB - Evidence suggests that research protocols often lack important information on study design, which hinders external review. The study protocol should provide an adequate explanation for why the proposed study methodology is appropriate for the question posed, why the study design is likely to answer the research question, and why it is the best approach. It is especially important that researchers explain why the treatment difference sought is worthwhile to patients, and they should reference consultations with the public and patient groups and existing literature. Moreover, the study design should be underpinned by a systematic review of the existing evidence, which should be included in the research protocol. The Health Research Authority in collaboration with partners has published guidance entitled 'Specific questions that need answering when considering the design of clinical trials'. The guidance will help those designing research and those reviewing it to address key issues. PMID- 25027293 TI - Assisting with sex, drugs and rock & roll. PMID- 25027291 TI - Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: etiological contribution to complex regional pain syndromes (Part II). AB - Cumulating evidence indicated that nerve injury-associated cellular and molecular changes play an essential role in contributing to the development of pathological pain, and more recent findings implicated the critical role of epigenetic mechanisms in pain-related sensitization in the DRG subsequent to nerve injury. In this part of the dyad review (Part II), we reviewed and paid special attention on the etiological contribution of DGR gene expression modulated by epigenetic mechanisms of CRPS. As essential effectors to different molecular activation, we first discussed the activation of various signaling pathways that subsequently from nerve injury, and in further illustrated the fundamental and functional underpinnings of nerve injury-induced pain, in which we argued for the potential epigenetic mechanisms in response to sensitizing stimuli or injury. Therefore, understanding the specific mediating factors that influence individual epigenetic differences contributing to pain sensitivity and responsiveness to analgesics possesses crucial clinical implications. PMID- 25027294 TI - Pathophysiological functions of adrenomedullin and natriuretic peptides in patients with primary aldosteronism. AB - To measure the plasma concentrations of adrenomedullin (ADM),atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP), and investigate their pathophysiological functions in patients with primary aldosteronism (PA). Between June 2006 and December 2012, we recruited 25 patients with untreated PA, 30 patients with untreated low-renin essential hypertension (EH), and 35 healthy control subjects. The plasma concentrations of ADM, ANP, and BNP were measured in all the subjects. After 4 weeks of effective antihypertensive therapy with slow release nifedipine, the three peptides were measured again in the PA and low renin EH subjects. Unilateral laparoscopic adrenalectomy was performed in all the PA patients; 2 weeks after surgery, the three peptides were measured again. The PA patients had significantly higher plasma concentrations of ADM, ANP, and BNP than the low-renin EH and control subjects. The low-renin EH and control subjects significantly differed in the concentrations of the three peptides between low renin EH and control subjects. ADM was the most important peptide associated with aldosterone or blood pressure in the PA patients. Plasma ADM concentration was not only correlated with plasma aldosterone concentrations, but also with systolic and diastolic blood pressures, and plasma ANP and BNP concentrations in the PA patients. By contrast, ADM concentration was not related to blood urea nitrogen levels, serum creatinine levels, and glomerular filtration rates. After antihypertensive treatment, the concentrations of the three peptides significantly decreased in the low-renin EH patients, but remained unchanged in the PA subjects. However, these concentrations significantly decreased 2 weeks after laparoscopic adrenalectomy in the PA subjects. ADM, ANP, and BNP possibly participate in the mechanisms counteracting further elevation of blood pressure or plasma volume expansion resulting from aldosterone hypersecretion in PA patients. An ADM/aldosterone local regulatory mechanism may be involved in regulating adrenal adenoma functions. PMID- 25027295 TI - Meta-analysis of the association of ADIPOQ G276T polymorphism with insulin resistance and blood glucose. AB - Insulin resistance (IR) is a major risk for the development of type 2 diabetes (T2D). Numerous studies have been conducted to determine the relationship of ADIPOQ G276T with IR and blood glucose, but the results are conflicting. We conducted a meta-analysis in this work to further investigate such an association. Published works were retrieved from PubMed and Embase databases. A pooled standardized mean difference (SMD) with 95 % confidence interval (CI) was calculated under a dominant model using a random effect model. Twenty-five studies involving 7,480 subjects were included in the meta-analysis. A significant association of G276T polymorphism with homeostasis model assessment insulin resistance index (HOMA-IR) was observed after excluding studies with obvious heterogeneity by performing influence analysis (SMD = -0. 08, 95 % CI 0.15 to -0.01, p = 0.019) and Galbraith plot analysis (SMD = -0.08, 95 % CI -0.14 to -0.02, p = 0.005). In the subgroup analysis, Asians with TG/TT genotypes were found to have a significantly decreased degree of HOMA-IR (SMD = -0.13, 95 % CI 0.20 to -0.07, p < 0.001). The association of G276T with IR or blood glucose for the subgroups (obese, male, and T2D) was also significant. However, the results may not be reliable for small sample sizes. The current meta-analysis suggested that the G276T polymorphism may genetically affect IR using HOMA-IR as an index, and the effect of this polymorphism on IR particularly exists in Asians. PMID- 25027297 TI - Comment on Deng et al. entitled "meta-analysis of methylcobalamin alone and in combination with prostaglandin E1 in the treatment of diabetic peripheral neuropathy". PMID- 25027296 TI - The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. AB - About 10-15 % of adult gastrointestinal stromal tumors (GISTs) and 85 % of pediatric GISTs do not have mutations in the KIT or PDGFRA genes and are generally classified as KIT/PDGFRA wild type (WT). Recent studies have shown that this group of KIT/PDGFRA WT GISTs is quite heterogeneous in terms of clinical phenotype, genetic etiology, and molecular pathways. Succinate dehydrogenase subunit (SDH)-deficient GISTs, which include tumors that are part of multiple endocrine neoplasia syndromes, are the newest group of KIT/PDGFRA WT GIST to be molecularly elucidated. This review aims to describe the different genetic subgroups of KIT/PDGFRA WT GIST, with a special focus on the SDH-deficient GIST. PMID- 25027298 TI - Acute oral toxicity and anti-inflammatory activity of hydroalcoholic extract from Lampaya medicinalis Phil in rats. AB - BACKGROUND: Algesia and inflammation are related with several pathological conditions. It is known that many drugs available for the treatment of these problems cause unwanted side effects. This study was aimed at evaluating acute toxicity and anti-inflammatory activity of Lampaya medicinalis Phil. (Verbenaceae) widely used in the folk medicine of Northern Chile against rheumatism, arthritis and body joints pain. RESULTS: Oral administration of hydroalcoholic extract (HAE) at the highest dose of 3000 mg/ Kg body weight resulted in no mortalities or evidence of significant behavioral changes. Histological examination revealed normal architecture and no significant adverse effects were observed on the liver, kidney, heart, lung or ovaries and testicles. The results suggest that the oral administration of hydroalcoholic extract (HAE) from Lampaya medicinalis did not produce any toxic effect in rats. Hydroalcoholic extract (HAE) significantly inhibited the carrageenan-induced rat paw edema in dose - response relationship, at test doses of 37.5, 75, 150 and 300 mg/Kg body weight. Maximum inhibition (61.98 +/- 2.69%) was noted at 300 mg/Kg after 2 h of drug treatment carrageenan induced paw edema, whereas indomethacin produced 47.90 +/- 1.16% of inhibition. The inhibitory values of edema at 3 h postcarrageenan were 31.04 +/- 0.75%, 40.51 +/- 2.36%, 48.97 +/- 1.14% and 56.87 +/- 0.41% for 37.5, 75, 150, and 300 mg/kg of extract respectively. Indomethacin (10 mg/Kg) gave a percentage inhibition of 49.44 +/- 1.44. HAE (300 and 150 mg/kg) induced an anti-inflammatory effect greater than (or comparable) with the effect of indomethacin from 2nd to 4th hours of the experiment. CONCLUSIONS: Our results reveal for first time that compounds contained in the hydroalcoholic extract of Lampaya medicinalis Phil exert anti-inflammatory effect and the oral administration is safe and non toxic up to dose level 3000 mg/kg body weight. The anti-inflammatory activity may be associated with the presence of flavonoids. These findings also justify the traditional use of the plant for treating pain. PMID- 25027299 TI - Insights into the evolution and domain structure of Ataxin-2 proteins across eukaryotes. AB - BACKGROUND: Ataxin-2 is an evolutionarily conserved protein first identified in humans as responsible for spinocerebellar ataxia type 2 (SCA2). The molecular basis of SCA2 is the expansion of a polyglutamine tract in Ataxin-2, encoding a Lsm domain that may bind RNA and a PAM2 motif that enables interaction with the poly (A) binding protein. Although the association with SCA2 has been verified, a detailed molecular function for Ataxin-2 has not been established. RESULTS: We have undertaken a survey of Ataxin-2 proteins across all eukaryotic domains. In eukaryotes, except for vertebrates and land plants, a single ortholog was identified. Notably, with the exception of birds, two Ataxin-2 genes exist in vertebrates. Expansion was observed in land plants and a novel class lacking the LsmAD domain was identified. Large polyQ tracts appear limited to primates and insects of the orders Hymenoptera and Diptera. A common feature across Ataxin-2 orthologs is the presence of proline-rich motifs, formerly described in the human protein. CONCLUSION: Our analysis provides valuable information on the evolution and domain structure of Ataxin-2 proteins. Proline-rich motifs that may mediate protein interactions are widespread in Ataxin-2 proteins, but expansion of polyglutamine tracts associated with spinocerebellar ataxia type 2, is present only in primates, as well as some insects. Our analysis of Ataxin-2 proteins provides also a source to examine orthologs in a number of different species. PMID- 25027300 TI - Serious complication of postextubation laryngeal oedema treated by corticosteroids: septic cricoid chondronecrosis. PMID- 25027301 TI - Transparent magnesium aluminate spinel: a prospective biomaterial for esthetic orthodontic brackets. AB - Adult orthodontics is recently gaining popularity due to its importance in esthetics, oral and general health. However, none of the currently available alumina or zirconia based ceramic orthodontic brackets meet the esthetic demands of adult patients. Inherent hexagonal lattice structure and associated birefringence limits the visible light transmission in polycrystalline alumina and make them appear white and non transparent. Hence focus of the present study was to assess the feasibility of using magnesium aluminate (MgAl2O4) spinel; a member of the transparent ceramic family for esthetic orthodontic brackets. Transparent spinel specimens were developed from commercially available white spinel powder through colloidal shaping followed by pressureless sintering and hot isostatic pressing at optimum conditions of temperature and pressure. Samples were characterized for chemical composition, phases, density, hardness, flexural strength, fracture toughness and optical transmission. Biocompatibility was evaluated with in-vitro cell line experiments for cytotoxicity, apoptosis and genotoxicity. Results showed that transparent spinel samples had requisite physico-chemical, mechanical, optical and excellent biocompatibility for fabricating orthodontic brackets. Transparent spinel developed through this method demonstrated its possibility as a prospective biomaterial for developing esthetic orthodontic brackets. PMID- 25027302 TI - Sequential assembly of 3D perfusable microfluidic hydrogels. AB - Bottom-up tissue engineering provides a promising way to recreate complex structural organizations of native organs in artificial constructs by assembling functional repeating modules. However, it is challenging for current bottom-up strategies to simultaneously produce a controllable and immediately perfusable microfluidic network in modularly assembled 3D constructs. Here we presented a bottom-up strategy to produce perfusable microchannels in 3D hydrogels by sequentially assembling microfluidic modules. The effects of agarose-collagen composition on microchannel replication and 3D assembly of hydrogel modules were investigated. The unique property of predefined microchannels in transporting fluids within 3D assemblies was evaluated. Endothelial cells were incorporated into the microfluidic network of 3D hydrogels for dynamic culture in a house-made bioreactor system. The results indicated that the sequential assembly method could produce interconnected 3D predefined microfluidic networks in optimized agarose-collagen hydrogels, which were fully perfusable and successfully functioned as fluid pathways to facilitate the spreading of endothelial cells. We envision that the presented method could be potentially used to engineer 3D vascularized parenchymal constructs by encapsulating primary cells in bulk hydrogels and incorporating endothelial cells in predefined microchannels. PMID- 25027303 TI - Antibiotic eluting clay mineral (Laponite(r)) for wound healing application: an in vitro study. AB - Different materials in form of sponge, hydrogel and film have been developed and formulated for treating and dressing burn wounds. In this study, the potential of Laponite, a gel forming clay, in combination with an antimicrobial agent (mafenide), as a wound dressing material was tested in vitro. Laponite/mafenide (Lap/Maf) hydrogel was formulated in three different ratios of Lap/Maf 1:1, 1:2, 1:3. Laponite/mafenide/alginate (Lap/Maf/Alg) film was also formulated by combining Lap/Maf gel (1:1) with alginate. Intercalation rate of mafenide into the layers of Laponite nanoparticles and physico-chemical properties, including wound dressing characteristics of materials were studied using various analytical methods. Furthermore, the degradation of materials and the release profile of mafenide were investigated in simulated wound exudates fluid and antibacterial effectiveness of the eluted mafenide was tested on a range of bacterial species. The cytotoxicity of materials was also evaluated in skin fibroblast culture. The results showed that mafenide molecules were intercalated between the nano-sized layers of Laponite. The eluted mafenide showed active antibacterial effects against all three tested bacteria. All intercalated mafenide released from Lap/Maf 1:1 and 1:2 gel formulations and nearly 80% release from 1:3 formulation during test period. No significant difference was observed in release profile of mafenide between Lap/Maf/Alg film and Lap/Maf formulations. Wound dressing tests on Lap/Maf/Alg film showed it is a breathable dressing and has capacity to absorb wound exudates. The study showed that prepared Lap/Maf composite has the potential to be used as an antibiotic eluting gel or film for wound healing application. Additionally, Laponite has shown benefits in wound healing processes by releasing Mg(2+) ions and thereby reducing the cytotoxic effect of mafenide on fibroblast cells. PMID- 25027304 TI - Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting beta2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers. METHODS: In this randomized, double-blind, 4 period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 MUg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 MUg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1). RESULTS: All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P<.001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters (P <= .049) except 24-hour trough FEV1 at 28.8 MUg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0-14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO). CONCLUSIONS: This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 MUg total daily dose, or 57.6 MUg twice daily based on comparisons with the active comparator. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182. PMID- 25027305 TI - Addendum to BASOII Trial report. PMID- 25027306 TI - Clinico-pathological characteristics of different types of immunodeficiency associated smooth muscle tumours. AB - Rare Epstein-Barr virus (EBV)+ smooth muscle tumours (SMT) manifest typically under immunosuppression. Three major subtypes are known: human immunodeficiency virus-associated (HIV-SMT), after transplantation (PTSMT) or associated with congenital immunodeficiency syndromes (CI-SMT). So far, there are no analyses which compare the clinico-pathological characteristics of all three subtypes. Case reports and case series on these three tumour types were collected (1990 2012). Meta-data analysis was performed for identification of similarities and differences. A total of 73 HIV-SMT, 66 PTSMT and 9 CI-SMT were evaluated. There was a slight female predominance (55-67%). Children were affected nearly equally in HIV-SMT (33%) and PTSMT (35%), while all CI-SMT occurred in children. HIV-SMT manifested preferentially in the central nervous system, gut/liver, skin, lungs/larynx/pharynx and adrenal glands. PTSMT were predominantly found in the liver, lungs/larynx/pharynx, gut/spleen and brain. CI-SMT were often found in lungs/larynx, brain, liver, adrenal glands and spleen. Antecedent EBV+ lymphoproliferations manifested more often in PTSMT. In all three tumour subtypes, survival analyses did not show any significant differences regarding surgical therapeutic approaches, the occurrence of multiple tumours, tumour size or sarcoma-like histological features. HIV-SMT had the poorest overall survival, which might be attributed to HIV-associated infectious complications. PMID- 25027307 TI - A highly-sensitive anti-Mullerian hormone assay improves analysis of ovarian function following chemotherapy for early breast cancer. AB - AIM: Anti-Mullerian hormone (AMH) shows promise as a biomarker of the ovarian reserve but current assays are insufficiently sensitive to allow assessment of this post-chemotherapy in most women. We have assessed a new highly sensitive AMH assay (Ansh picoAMH) in the evaluation of ovarian activity in women with very low ovarian reserve after chemotherapy. METHODS: A prospective cohort and an independent validation cohort of premenopausal women with early breast cancer (eBC) were recruited at the time of diagnosis (combined n=98), and ovarian reserve markers 2-5 years later following chemotherapy were assessed in relation to menstrual activity. RESULTS: The picoAMH assay had a limit of detection of 7.5 pg/ml. AMH clearly distinguished women with ongoing menses from those with amenorrhoea at 2 years after diagnosis (mean 522 +/- 169 versus 8.9 +/- 1.3 pg/ml, P<0.0001) with high predictive value for continuing menses or amenorrhoea for the subsequent 3 years. AMH was detectable in more women than using a previous assay (P=0.004). Other markers of the ovarian reserve (follicle stimulating hormone (FSH), inhibin B) were also of discriminatory value but to lesser extents. This finding was validated in a second, independent cohort of women treated for eBC. CONCLUSION: The 10-fold increased assay sensitivity showed very clear distinction between groups based on ovarian activity with excellent prediction of future menses or amenorrhoea. This will improve assessment of post chemotherapy ovarian function in women and may aid treatment decisions. PMID- 25027308 TI - Reactive oxygen species initiate a metabolic collapse in hippocampal slices: potential trigger of cortical spreading depression. AB - Excessive accumulation of reactive oxygen species (ROS) underlies oxidative damage. We find that in hippocampal slices, decreased activity of glucose-based antioxidant system induces a massive, abrupt, and detrimental change in cellular functions. We call this phenomenon metabolic collapse (MC). This collapse manifested in long-lasting silencing of synaptic transmission, abnormal oxidation of NAD(P)H and FADH2 associated with immense oxygen consumption, and massive neuronal depolarization. MC occurred without any preceding deficiency in neuronal energy supply or disturbances of ionic homeostasis and spread throughout the hippocampus. It was associated with a preceding accumulation of ROS and was largely prevented by application of an efficient antioxidant Tempol (4-hydroxy 2,2,6,6-tetramethylpiperidine-1-oxyl). The consequences of MC resemble cortical spreading depression (CSD), a wave of neuronal depolarization that occurs in migraine, brain trauma, and stroke, the cellular initiation mechanisms of which are poorly understood. We suggest that ROS accumulation might also be the primary trigger of CSD. Indeed, we found that Tempol strongly reduced occurrence of CSD in vivo, suggesting that ROS accumulation may be a key mechanism of CSD initiation. PMID- 25027309 TI - Moderately elevated intracranial pressure after diffuse traumatic brain injury is associated with exacerbated neuronal pathology and behavioral morbidity in the rat. AB - Traumatic brain injury (TBI)-induced elevated intracranial pressure (ICP) is correlated with ensuing morbidity/mortality in humans. This relationship is assumed to rely mostly on the recognition that extremely elevated ICP either indicates hematoma/contusions capable of precipitating herniation or alters cerebral perfusion pressure (CPP), which precipitates global ischemia. However, whether subischemic levels of elevated ICP without hematoma/contusion contribute to increased morbidity/mortality remains unknown. To address this knowledge gap, we utilized a model of moderate diffuse TBI in rats followed by either intraventricular ICP monitoring or manual ICP elevation to 20 mm Hg, in which CPP was above ischemic levels. The effects of ICP elevation after TBI on acute and chronic histopathology, as well as on behavioral morbidity, were evaluated. ICP elevation after TBI resulted in increased acute neuronal membrane perturbation and was also associated with reduced neuronal density at 4 weeks after injury. Somatosensory hypersensitivity was exacerbated by ICP elevation and was correlated to the observed neuronal loss. In conclusion, this study indicates that morbidity and increased neuronal damage/death associated with elevated ICP can occur without concurrent global ischemia. Therefore, understanding the pathologies associated with subischemic levels of elevated ICP could lead to the development of better therapeutic strategies for the treatment and management of TBI patients. PMID- 25027310 TI - Regulatory pathways affecting vascular stabilization via VE-cadherin dynamics: insights from zebrafish (Danio rerio). AB - The endothelial-specific transmembrane glycoprotein, vascular endothelial (VE) cadherin, is required for the organization of a stable vascular endothelium. A number of cerebrovascular disorders are associated with mutations in genes that otherwise regulate vascular integrity through VE-cadherin dynamics. Hence, identification and characterization of regulatory pathways contributing to endothelial cell-cell adhesion is of clinical relevance, particularly in the treatment of aneurysms and cerebral cavernous malformations. The zebrafish (Danio rerio) have recently emerged as a powerful paradigm for studies geared toward elucidating the etiology of cerebrovascular disorders, principally in uncovering the genetic and mechanistic basis controlling endothelial adhesive barrier function. PMID- 25027311 TI - Shock waves associated with electric pulses affect cell electro-permeabilization. AB - New features of cell electro-permeabilization are obtained by using high field (several tens of kV/cm) with short (sub-microsecond, nanosecond) pulse duration. Arcing appears as a main safety problem when air gaps are present between electrodes. A new applicator design was chosen to obtain a closed chamber where high field pulses could be delivered in a safe way with very short pulse duration. The safety issue of the system was validated under millisecond, microsecond and nanosecond pulses. The closed chamber applicator was then checked for its use under classical electro-mediated permeabilization and electro-gene transfer (EGT). A 20 times decrease in gene expression was observed compared with classical open chambers. It was experimentally observed that shock waves were present under the closed chamber configuration of the applicator. This was not the case with an open chamber design. Electropulsation chamber design plays a role on pulsing conditions and in the efficiency of gene electro transfer. PMID- 25027312 TI - Linking crystal structure with temperature-sensitive vibrational modes in calcium carbonate minerals. AB - We demonstrate a correlation between how an IR-active vibrational mode responds to temperature changes and how it responds to crystallinity differences. Infrared (IR) spectroscopy was used to track changes in carbonate-related vibrational modes in three different CaCO3 polymorphs (calcite, aragonite, and vaterite) and CaMg(CO3)2 (dolomite) during heating. Of the three characteristic IR-active carbonate modes, the in-plane bending mode (nu4) shows the most pronounced changes with heating in polymorphs that have planar carbonate arrangements (calcite, aragonite, and dolomite). In contrast, this mode is virtually unchanged in vaterite, which has a canted arrangement of carbonate units. We correlate these trends with recent studies that identified the nu4 mode as most susceptible to changes related to crystallinity differences in calcite and amorphous calcium carbonate. Thus, our results suggest that studies of packing arrangements could provide a generalizable approach to identify the most diagnostic vibrational modes for tracking either temperature-dependent or crystallinity-related effects in IR-active solids. PMID- 25027313 TI - Magnetic resonance imaging of traumatic brain injury: a pictorial review. AB - Traumatic brain injury (TBI) is a significant source of major morbidity and mortality in blunt trauma patients. Computed tomography (CT) is the primary imaging modality of choice for patients with potential brain injury in the acute setting, with magnetic resonance imaging (MRI) playing a role in evaluating equivocal CT findings and may help with determining long-term prognosis and recovery. MRI is being utilized more commonly in the acute and subacute setting of TBI; therefore, radiologists should be familiar with the MRI appearance of the various manifestations of TBI. Here, we review the imaging of common intracranial injuries with illustrative cases comparing CT and MRI. PMID- 25027316 TI - Perampanel, an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models. AB - Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3 yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 MUM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 MUM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients. PMID- 25027317 TI - Intranasal administration as a route for drug delivery to the brain: evidence for a unique pathway for albumin. AB - A variety of compounds will distribute into the brain when placed at the cribriform plate by intranasal (i.n.) administration. In this study, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the blood-brain barrier, to distribute into the brain after i.n. administration. We labeled bovine serum albumin with [(125)I] ([(125)I]Alb) and studied its uptake into 11 brain regions and its entry into the blood from 5 minutes to 6 hours after i.n. administration. [(125)I]Alb was present throughout the brain at 5 minutes. Several regions showed distinct peaks in uptake that ranged from 5 minutes (parietal cortex) to 60 minutes (midbrain). About 2-4% of the i.n. [(125)I]Alb entered the bloodstream. The highest levels occurred in the olfactory bulb and striatum. Distribution was dose-dependent, with less taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid-phase stimulator PMA (phorbol 12-myristate 13-acetate), but inhibitors to receptor-mediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered the distribution of radioactive leptin given by i.n. administration, decreasing uptake into the blood and by the cerebellum and increasing uptake by the hypothalamus. We conclude that [(125)I]Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid-phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration. PMID- 25027318 TI - Deficiency of Ube3a in Huntington's disease mice brain increases aggregate load and accelerates disease pathology. AB - Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of CAG repeats in the gene encoding huntingtin. Mutant huntingtin undergoes proteolytic processing and its N-terminal fragment containing polyglutamine repeat accumulates as inclusion not only in nucleus but also in cytoplasm and neuronal processes. Here, we demonstrate that removal of ubiquitin ligase Ube3a selectively from HD mice brain resulted in accelerated disease phenotype and shorter lifespan in comparison with HD mice. The deficiency of Ube3a in HD mice brain also caused significant increase in global aggregates load, and these aggregates were less ubiquitinated when compared with age-matched HD mice. These Ube3a-maternal deficient HD mice also showed drastic reduction of DARPP-32, a dopamine-regulated phoshphoprotein in their striatum. These results emphasize the crucial role of Ube3a in the progression of HD and its immense potential as therapeutic target. PMID- 25027319 TI - Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies. AB - Disturbances of lipid metabolism have been implicated in psychiatric illnesses. We previously reported an association between the gene for fatty acid binding protein 7 (FABP7) and schizophrenia. Furthermore, we identified and reported several rare non-synonymous polymorphisms of the brain-expressed genes FABP3, FABP5 and FABP7 from schizophrenia and autism spectrum disorder (ASD), diseases known to part share genetic architecture. Here, we conducted further studies to better understand the contribution these genes make to the pathogenesis of schizophrenia and ASD. In postmortem brains, we detected altered mRNA expression levels of FABP5 in schizophrenia, and of FABP7 in ASD and altered FABP5 in peripheral lymphocytes. Using a patient cohort, comprehensive mutation screening identified six missense and two frameshift variants from the three FABP genes. The two frameshift proteins, FABP3 E132fs and FABP7 N80fs, formed cellular aggregates and were unstable when expressed in cultured cells. The four missense mutants with predicted possible damaging outcomes showed no changes in intracellular localization. Examining ligand binding properties, FABP7 S86G and FABP7 V126L lost their preference for docosahexaenoic acid to linoleic acid. Finally, mice deficient in Fabp3, Fabp5 and Fabp7 were evaluated in a systematic behavioral test battery. The Fabp3 knockout (KO) mice showed decreased social memory and novelty seeking, and Fabp7 KO mice displayed hyperactive and anxiety related phenotypes, while Fabp5 KO mice showed no apparent phenotypes. In conclusion, disturbances in brain-expressed FABPs could represent an underlying disease mechanism in a proportion of schizophrenia and ASD sufferers. PMID- 25027321 TI - Genome-wide association and admixture analysis of glaucoma in the Women's Health Initiative. AB - We report a genome-wide association study (GWAS) and admixture analysis of glaucoma in 12 008 African-American and Hispanic women (age 50-79 years) from the Women's Health Initiative (WHI). Although GWAS of glaucoma have been conducted on several populations, this is the first to look at glaucoma in individuals of African-American and Hispanic race/ethnicity. Prevalent and incident glaucoma was determined by self-report from study questionnaires administered at baseline (1993-1998) and annually through 2005. For African Americans, there was a total of 658 prevalent cases, 1062 incident cases and 6067 individuals who never progressed to glaucoma. For our replication cohort, we used the WHI Hispanics, including 153 prevalent cases, 336 incident cases and 2685 non-cases. We found an association of African ancestry with glaucoma incidence in African Americans (hazards ratio 1.62, 95% CI 1.023-2.56, P = 0.038) and in Hispanics (hazards ratio 3.21, 95% CI 1.32-7.80, P = 0.011). Although we found that no previously identified glaucoma SNPs replicated in either the WHI African Americans or Hispanics, a risk score combining all previously reported hits was significant in African-American prevalent cases (P = 0.0046), and was in the expected direction in the incident cases, as well as in the Hispanic incident cases. Additionally, after imputing to 1000 Genomes, two less common independent SNPs were suggestive in African Americans, but had too low of an allele frequency in Hispanics to test for replication. These results suggest the possibility of a distinct genetic architecture underlying glaucoma in individuals of African ancestry. PMID- 25027320 TI - SUCLG2 identified as both a determinator of CSF Abeta1-42 levels and an attenuator of cognitive decline in Alzheimer's disease. AB - Cerebrospinal fluid amyloid-beta 1-42 (Abeta1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Abeta1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Abeta1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5*10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 * 10(-5)), with the strongest effect being observed in APOE-epsilon4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 * 10( 3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Abeta1-42. PMID- 25027322 TI - The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease. AB - Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 * 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 * 10(-7) and 3.70 * 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants. PMID- 25027323 TI - Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma. AB - Gain-of-function mutations in the olfactomedin domain of the MYOC gene facilitate the toxic accumulation of amyloid-containing myocilin aggregates, hastening the onset of the prevalent ocular disorder primary open-angle glaucoma. Aggregation of wild-type myocilin has been reported in other glaucoma subtypes, suggesting broader relevance of misfolded myocilin across the disease spectrum, but the absence of myocilin does not cause disease. Thus, strategies aimed at eliminating myocilin could be therapeutically relevant for glaucoma. Here, a novel and selective Grp94 inhibitor reduced the levels of several mutant myocilin proteins as well as wild-type myocilin when forced to misfold in cells. This inhibitor rescued mutant myocilin toxicity in primary human trabecular meshwork cells. Mechanistically, in vitro kinetics studies demonstrate that Grp94 recognizes on pathway aggregates of the myocilin olfactomedin domain (myoc-OLF), accelerates rates of aggregation and co-precipitates with myoc-OLF. These results indicate that aberrant myocilin quaternary structure drives Grp94 recognition, rather than peptide motifs exposed by unfolded protein. Inhibition of Grp94 ameliorates the effects of Grp94-accelerated myoc-OLF aggregation, and Grp94 remains in solution. In cells, when wild-type myocilin is driven to misfold and aggregate, it becomes a client of Grp94 and sensitive to Grp94 inhibition. Taken together, the interaction of Grp94 with myocilin aggregates can be manipulated by cellular environment and genetics; this process can be exploited with Grp94 inhibitors to promote the clearance of toxic forms of myocilin. PMID- 25027324 TI - Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients. AB - It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-Delta52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials. PMID- 25027325 TI - Selective demethylation and altered gene expression are associated with ICF syndrome in human-induced pluripotent stem cells and mesenchymal stem cells. AB - Immunodeficiency, centromeric instability and facial anomalies type I (ICF1) syndrome is a rare genetic disease caused by mutations in DNA methyltransferase (DNMT) 3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1-iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1-iPSCs relevant to ICF syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to MSCs, we find virtually all CG hypomethylated regions remained hypomethylated when compared with either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 syndrome. GEO accession number: GSE46030. PMID- 25027326 TI - Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder. AB - Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches. PMID- 25027327 TI - Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. AB - Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1alpha, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor kappaB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. PMID- 25027328 TI - Deficiency of patched 1-induced Gli1 signal transduction results in astrogenesis in Swedish mutated APP transgenic mice. AB - Normally, sonic hedgehog (Shh) signaling induces high levels of Patched 1 (Ptc1) and its associated transcription factor Gli1 with genesis of specific neuronal progeny. But their roles in the neural stem cells (NSCs), including glial precursor cells (GPCs), of Alzheimer's disease (AD) are unclear. Here, we show that Ptc1 and Gli1 are significantly deficits in the hippocampus of an aged AD transgenic mouse mode, whereas these two molecules are highly elevated at young ages. Our similar findings in autopsied AD brains validate the discovery in AD mouse models. To examine whether Abeta peptides, which are a main component of the amyloid plaques in AD brains, affected Ptc1-Gli1 signaling, we treated GPCs with Abeta peptides, we found that high dose of Abeta1-42 but not Abeta1-40 significantly decreased Ptc1-Gli1, while Shh itself was elevated in hippocampal NSCs/GPCs. Furthermore, we found that deficits of Ptc1-Gli1 signaling induced NSCs/GPCs into asymmetric division, which results in an increase in the number of dividing cells including transit-amplifying cells and neuroblasts. These precursor cells commit to apoptosis-like death under the toxic conditions. By this way, adult neural precursor cell pool is exhausted and defective neurogenesis happens in AD brains. Our findings suggest that Ptc1-Gli1 signaling deregulation resulting abnormal loss of GPCs may contribute to a cognition decline in AD brains. The novel findings elucidate a new molecular mechanism of adult NSCs/GPCs on neurogenesis and demonstrate a regulatory role for Ptc1-Gli1 in adult neural circuit integrity of the brain. PMID- 25027331 TI - Reconsolidation allows fear memory to be updated to a less aversive level through the incorporation of appetitive information. AB - The capacity to adapt to new situations is one of the most important features of memory. When retrieved, memories may undergo a labile state that is sensitive to modification. This process, called reconsolidation, can lead to memory updating through the integration of new information into a previously consolidated memory background. Thus reconsolidation provides the opportunity to modify an undesired fear memory by updating its emotional valence to a less aversive level. Here we evaluated whether a fear memory can be reinterpreted by the concomitant presentation of an appetitive stimulus during its reactivation, hindering fear expression. We found that memory reactivation in the presence of appetitive stimuli resulted in the suppression of a fear response. In addition, fear expression was not amenable to reinstatement, spontaneous recovery, or rapid reacquisition. Such effect was prevented by either systemic injection of nimodipine or intra-hippocampal infusion of ifenprodil, indicating that memory updating was mediated by a reconsolidation mechanism relying on hippocampal neuronal plasticity. Taken together, this study shows that reconsolidation allows for a 're-signification' of unwanted fear memories through the incorporation of appetitive information. It brings a new promising cognitive approach to treat fear-related disorders. PMID- 25027333 TI - Dual-source CT imaging of multiple giant coronary and axillary aneurysms in a child with Kawasaki disease. AB - Peripheral arterial aneurysms are a feature of Kawasaki disease (KD), and very little information has been published on this feature. Failure to recognize this important complication can lead to severe consequences such as peripheral gangrene. We present the case of a 2-year-old girl, diagnosed with KD at 11 months of age, who developed multiple giant aneurysms in the bilateral axillary arteries and right coronary artery. Imaging findings from dual-source computed tomography are described in this report. PMID- 25027330 TI - Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans. AB - Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain <10% of the phenotypic variance in height. We searched for novel associations between height and common (minor allele frequency, MAF >=5%) or infrequent (0.5% < MAF < 5%) variants across the exome in African Americans. Using a reference panel of 1692 African Americans and 471 Europeans from the National Heart, Lung, and Blood Institute's (NHLBI) Exome Sequencing Project (ESP), we imputed whole-exome sequence data into 13 719 African Americans with existing array-based GWAS data (discovery). Variants achieving a height-association threshold of P < 5E-06 in the imputed dataset were followed up in an independent sample of 1989 African Americans with whole-exome sequence data (replication). We used P < 2.5E-07 (=0.05/196 779 variants) to define statistically significant associations in meta-analyses combining the discovery and replication sets (N = 15 708). We discovered and replicated three independent loci for association: 5p13.3/C5orf22/rs17410035 (MAF = 0.10, beta = 0.64 cm, P = 8.3E-08), 13q14.2/SPRYD7/rs114089985 (MAF = 0.03, beta = 1.46 cm, P = 4.8E-10) and 17q23.3/GH2/rs2006123 (MAF = 0.30; beta = 0.47 cm; P = 4.7E-09). Conditional analyses suggested 5p13.3 (C5orf22/rs17410035) and 13q14.2 (SPRYD7/rs114089985) may harbor novel height alleles independent of previous GWAS identified variants (r(2) with GWAS loci <0.01); whereas 17q23.3/GH2/rs2006123 was correlated with GWAS-identified variants in European and African populations. Notably, 13q14.2/rs114089985 is infrequent in African Americans (MAF = 3%), extremely rare in European Americans (MAF = 0.03%), and monomorphic in Asian populations, suggesting it may be an African-American-specific height allele. Our findings demonstrate that whole-exome imputation of sequence variants can identify low-frequency variants and discover novel variants in non-European populations. PMID- 25027332 TI - Impaired cognition after stimulation of P2Y1 receptors in the rat medial prefrontal cortex. AB - We hypothesize that cortical ATP and ADP accumulating in the extracellular space, eg during prolonged network activity, contribute to a decline in cognitive performance in particular via stimulation of the G protein-coupled P2Y1 receptor (P2Y1R) subtype. Here, we report first evidence on P2Y1R-mediated control of cognitive functioning in rats using bilateral microinfusions of the selective agonist MRS2365 into medial prefrontal cortex (mPFC). MRS2365 attenuated prepulse inhibition of the acoustic startle reflex while having no impact on startle amplitude. Stimulation of P2Y1Rs deteriorated performance accuracy in the delayed non-matching to position task in a delay dependent manner and increased the rate of magazine entries consistent with both working memory disturbances and impaired impulse control. Further, MRS2365 significantly impaired performance in the reversal learning task. These effects might be related to MRS2365-evoked increase of dopamine observed by microdialysis to be short-lasting in mPFC and long lasting in the nucleus accumbens. P2Y1Rs were identified on pyramidal cells and parvalbumin-positive interneurons, but not on tyrosine hydroxylase-positive fibers, which argues for an indirect activation of dopaminergic afferents in the cortex by MRS2365. Collectively, these results suggest that activation of P2Y1Rs in the mPFC impairs inhibitory control and behavioral flexibility mediated by increased mesocorticolimbic activity and local disinhibition. PMID- 25027334 TI - Endometrial carcinoma in women 40 year old or younger: a case report and literature review. AB - Endometrial cancer is the most frequent gynecologic cancer. Although it mainly occurs in menopausal women, it can hit younger patients as well. Only few cases of affected women under the age of 30 are reported. A case of a 23-year-old patient with endometrioid carcinoma grade II-III is presented. Hysterectomy is considered the standard treatment and it could represent a problem for those young women who desire to preserve fertility. A conservative management can be offered to these patients when the tumor is well differentiated and advanced stage is excluded. Several studies are available in literature about fertility sparing approach. Progestin treatment, combined or not with hysteroscopic ablation seem to be the most validated conservative management. Anyhow this treatment is not free risk, because it is not always effective and disease progression during or after treatment is possible. Then a strict evaluation and selection of patients before starting treatment is mandatory. PMID- 25027335 TI - Transvaginal three-dimensional color power Doppler ultrasound and cervical MVD measurement in the detection of cervical intraepithelial neoplasia. AB - OBJECTIVE: To explore the potential correlation between three-dimensional color power Doppler ultrasound (3D-CPA) parameters and high-grade cervical lesions and early cervical cancer microvessel density (MVD) and investigate the role of transvaginal three-dimensional power Doppler ultrasonography in the detection of cervical intraepithelial neoplasia. PATIENTS AND METHODS: Totally 90 subjects were randomly divided into three groups: the control group (n = 30, including patients with chronic cervicitis), the high-grade cervical intraepithelial neoplasia (CIN) group (n = 30, mainly CIN II-III), and the early cervical cancer group (stage Ia-IIa) (n = 30). All patients received preoperative 3D-CPA, and the cervical blood flow was graded. The cervical and intra-mass parameters including vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were measured. The immunohistochemistry of the anti-CD34 monoclonal antibody was performed for the post-operative specimens obtained from each group. The MVD of the tumors was calculated. The difference of each parameter was compared among these three groups, and the correlations between the ultrasound vascular parameters and MVD were analyzed. The high-grade CIN group was followed up for 6 months after the loop electrosurgical excision procedure (LEEP) conization surgery with 3D-CPA. RESULTS: Compared with the other two groups, the early cervical cancer group had significantly higher VI, FI, and VFI parameters (p < 0.01). Compared with the control group, all of the three parameters of the high grade CIN group were significantly higher (p < 0.01). The MVD values increased from the control group to the high-grade CIN group, and in turn to the cervical cancer group, with significant differences between each pair (p < 0.05). MVD was positively correlated with the ultrasound parameters VI and VFI (r = 0.723, r = 0.692). There were significant differences among the three groups in terms of vascular morphology and type. However, the ultrasound parameters and vascular types were not significantly different between the postoperative CIN group and the control group. CONCLUSIONS: 3D-CPA can be used to assess blood flow in the cervix. It is particularly useful for the early diagnosis of cervical cancer and CIN and for the postoperative follow-up of CIN. PMID- 25027336 TI - Evaluation of chronic rhinosinusitis management using the SNOT-22 in adult cystic fibrosis patients. AB - OBJECTIVES: Sinonasal disease (SND) is a common finding in subjects with Cystic Fibrosis (CF). Even though it does not play a key role in the life expectancy of these patients, it increases the morbidity rate of CF, with deterioration of the quality of life and of general health status. The aim of this study is the evaluation of the impact of sinonasal disease and Extensive Endoscopic Sinus Surgery (eESS) on the quality of life (QOL) of CF patients by means of the 22 item Sino-Nasal Outcome Test (SNOT-22) and define if there is a correlation between SNOT-22 and the Lund-Mackay score. PATIENTS AND METHODS: We performed a prospective study in 33 CF patients with medically refractory SND. The extent of polyposis was graded both endoscopically and on computed tomography images in accordance with the Lund-Mackay score. All patients underwent eESS. The SNOT was administered in order to assess the quality of life related to SND both before surgery and during follow-up at 6 months, 1 year and 2 years postoperatively. RESULTS: The SNOT-22 and Lund-Mackay score showed a remarkable mean improvement during follow-up. The differences between the initial examination and last score were significant (p < 0.001), but there was no statistic correlation between SNOT 22 and Lund-Mackay. CONCLUSIONS: More attention should be paid to sinonasal symptoms in CF patients and SNOT-22 is a simple and effective tool for this purpose. This score is also important for indicating the outcome of the eESS procedure. In all patients SNOT showed a significant improvement in QoL. PMID- 25027337 TI - Acral Lentiginous Melanoma - misdiagnosis, referral delay and 5 years specific survival according to site. AB - OBJECTIVES: Acral lentiginous melanoma (ALM) is a defined histopathological entity with peculiar clinical-pathological features and is the most common subtype of malignant melanoma in acral locations. The 5-year survival rate is lower than that for all cutaneous malignant melanoma overall (80.3% versus 91.3%). Controversy exists in the literature as to whether this worse prognosis is attributable to a more aggressive biological nature or to difficult-to-see sites and consequent advanced stage at the time of diagnosis. The main purpose of the study was to explore any prognostic difference according to upper limb or lower limb localizations, based on the hypothesis that upper limb localizations might receive attention sooner than lower limb localizations. PATIENTS AND METHODS: A cohort longitudinal study was performed through a retrospective review of all patients consecutively referred to our Unit with histological confirmation of ALM. Data were collected from a 10 year period between 1996 and 2006 to allow determination of 5 year survival statistics. RESULTS: Out of 87 patients included in the study, 32 were men (37%) and 55 were women 63%. The average number of months it took for patients to present was 62 months with a mode of 12 months. Overall 5 year survival was 80% and a multivariate analysis showed that the most reliable prognostic indicators are the Breslow's thickness and the margins of complete excision. When controlling the survival rates for Breslow thickness, the values were similar to the reported rates indicated in the recent literature for cutaneous malignant melanoma. CONCLUSIONS: The higher aggressiveness of ALM was noticed to be attributable to a later stage and more advanced thickness at diagnosis. No significant difference was found between upper and lower limb localization in terms of prognosis. PMID- 25027338 TI - LigaSure(r) versus clamp tie technique for thyroid surgery; decreased operative time versus increased inflammatory effect: a prospective randomized study. AB - OBJECTIVE: The aim of this study was to compare the LigaSure(r) Small Jaw Instrument (LSJI) with the conventional clamp-and-tie (CT) technique in thyroid surgery regarding complication rates (hematoma, hypocalcemia and recurrent nerve palsy), the duration of the operative procedure, and systemic and local inflammatory effects. PATIENTS AND METHODS: Fifty-four consecutive patients were randomized prospectively into two groups, a Conventional Clamp-Tie (CT) group and a LigaSure(r) Vessel Sealing System (LVSS) Group. Pre- and postoperative blood plasma samples were taken to measure the tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), calcium, parathormon, CRP levels and WBC, as well as the lymphocyte subset (CD3, CD4, CD8, CD16/56, CD19) counts. The drain fluid samples were collected after the removal of the drains to measure the levels of IL-6 and TNF-alpha. RESULTS: Both groups showed significant changes regarding peripheral blood CD3+, CD4+, and CD8+ T cell levels (p < 0.05). In the LVSS group, the level of CD16+56+ NK cells showed a significant decrease compared with the CT group (p < 0.05). The IL-6 and TNF-alpha levels in the drainage fluid were significantly higher in the LVSS group. CONCLUSIONS: We demonstrated that LSJI can decrease operative time. Although the systemic inflammatory effect of LSJI remains inconclusive, the local inflammatory effect was significant, which could cause early and late postoperative problems. PMID- 25027339 TI - Multicenter, double-blind, randomized clinical trial of parenterally administered Cefoselis versus Cefepime for the treatment of acute bacterial infections. AB - AIM: This study aims to evaluate the clinical efficacy and safety of intravenous Cefoselis injection for the treatment of acute moderate and severe bacterial infections. PATIENTS AND METHODS: A multicenter, double-blind, randomized clinical trial was carried out using Cefepime as control. Patients received 1.0 g of either Cefoselis or Cefepime for moderate infections or 2.0 g for severe infections at an interval of 12 hours for 7 to 14 days. A total of 276 patients (138 with Cefoselis, 138 with Cefepime) with respiratory or urinary tract infections were enrolled in the study. Up to 137 and 124 patients receiving Cefoselis and 132 and 125 patients receiving Cefepime were eligible for the ITT (intent to treat) and PP (per protocol) analyses, respectively. RESULTS: At the end of the treatment, the cure rates and effective rates were 59.68% (74/124) and 93.55% (116/124) with Cefoselis, and 56.00% (74/124) and 90.40% (116/124) with Cefepime. The bacterial eradication rates of the two groups were 90.32% and 93.85%, respectively. No statistical differences were observed on the above mentioned parameters between the two groups (all p > 0.05). Adverse events, mainly mild aminotransferase elevation and mild leukopenia, were observed in 11.59% (16/138) and 13.77% (19/138) of patients with Cefoselis and Cefepime, respectively (p > 0.05). CONCLUSIONS: Cefoselis is an effective and safe choice against acute moderate and severe respiratory infections and UTI (urinary tract infection). PMID- 25027340 TI - Comparison of plasma antioxidant levels in middle-aged and old male with idiopatic osteoporosis: preliminary data. AB - OBJECTIVES: With the purpose of evaluating the role of oxidative stress (OS) in male idiopatic osteoporosis, we have evaluated plasma total antioxidant capacity (TAC) in patients classified according to age (< 65 or >= 65 yrs), with normal hormone values and in age-matched healthy control subjects. PATIENTS AND METHODS: TAC was evaluated with a colorimetric method, using the system metamyoglobin-H2O2 and the chromogen ABTS; the latency time (LAG, sec) in the appearance of ABTS radical species is proportional to antioxidant content of the system. RESULTS: We found slightly increased LAG values in middle-aged patients, compared with age matched controls, probably expression of a compensatory mechanism to OS; on the contrary aged patients showed significantly lower LAG values in comparison with age-matched controls, suggesting a defective compensatory mechanism and, therefore, a risk for oxidative damage. CONCLUSIONS: OS could be a possible mechanism underlying male osteoporosis, both in middle-aged and aged patients, but compensatory mechanisms seem to be defective in the last group. PMID- 25027341 TI - Characterization and improvement of phenol-sulfuric acid microassay for glucose based glycogen. AB - OBJECTIVES: Phenol-sulfuric acid reagent is used to measure the concentration of glyco-polymers and -conjugates. There are several uncertainties on glycogen measurement in the tissues. We aimed to improve phenol-sulfuric reagent for microassay of glucose based-glycogen in small tube or microplate. MATERIALS AND METHODS: The condition of the reaction was optimized and scaled down for both small tube and microplate application. RESULTS: The color intensity was found to be a function of all components of the assay mixture, that is, the amount of sugar and phenol together with the volume of total water and acid. The absorbance increased in the range of 4-10 mg of phenol and reached the plateau between 10-16 mg per 1 mL of acid. The color intensity was a linear function of total water volume (sugar-water- phenol). The sensitivity increased eight times as total water volume was changed from 50 up to 400 uL. The curve for acid volume peaked at about 1 mL. The optimal assay condition was determined to be 13 mg of phenol (200 uL 6.5%), 400-425 uL of total water volume (100 uL of sugar, 100 uL water) for 1 mL of acid. The initial spontaneous high temperature is essential the reaction to proceed and any handling gives inconsistent results and decreases the precision and sensitivity of the method. The values were scaled down by a factor of 0.5 for tube application and reading in cuvet or microplate and by 0.2 or 0.15 for microplate application. CONCLUSIONS: The results indicated that phenol sulfuric acid reagent could be scaled down to 1.0, 0.5 and 0.20, 0.15 mL of sulfuric acid for microassay of glucose based-glycogen. PMID- 25027342 TI - Blood glucose fluctuation aggravates lower extremity vascular disease in type 2 diabetes. AB - OBJECTIVES: Lower-extremity vascular diseases are important complication of diabetes. In the present study, we investigated the influence of blood glucose fluctuation in type 2 diabetes-associated lower-extremity vascular diseases, and explore the possible mechanism. PATIENTS AND METHODS: Patients with type 2 diabetes was assigned to Group B (without lower-extremity vascular disease) and group C (with lower-extremity vascular disease). Healthy subjects (Group A) served as normal controls. All patients received dynamic blood glucose monitoring for 72 h. The mean amplitude of glycemic excursion (MAGE) and the largest amplitude of glycemic excursion (LAGE) were estimated. The levels of von Willebrand factor (vWF), ischemia-modified albumin (IMA), glycosylated hemoglobin (HbA1c), and biochemical indices were examined, and the lower-extremity vascular diseases were scored in patients from group C. RESULTS: Groups B and C have higher systolic blood pressure (SBP), total cholesterol (TC) level, high-density lipoprotein cholesterol (HDL-C) level, HbA1c level, and vWF level and lower IMA level than those in Group A (p < 0.05). Elevated MAGE and LAGE were observed in groups B and C as compared with Group A. Correlation analysis revealed that the score of lower-extremity vascular diseases was associated with MAGE, LAGE, SBP, LDL-C, vWF, HbA1c, and IMA (p < 0.05). Stepwise multiple-linear regression analysis revealed that lower-extremity vascular diseases were involved with MAGE, IMA, and vWF. CONCLUSIONS: Enhanced fluctuation in patients with type 2 diabetes may promote the occurrence and development of lower-extremity vascular diseases through aggravating vascular endothelial injury. PMID- 25027343 TI - MiR-126 inhibits the invasion of gastric cancer cell in part by targeting Crk. AB - OBJECTIVE: Accumulating evidence has shown that microRNAs (miRNAs) are aberrantly expressed in human gastric cancer and crucial to tumorigenesis. Herein, we identified the role of miR-126 in human gastric cancer (GC) growth and development in vitro. MATERIALS AND METHODS: MiR-126 expression was investigated in GC tissue samples and cell lines by real-time PCR. Crystal violet test and Transwell assay were conducted to explore the effects of miR-126 on the proliferation and invasion of human GC cell lines, respectively. The impaction of miR-126 over expression on putative target Crk (v-crk sarcoma virus CT10 oncogene homolog) was subsequently confirmed via Western blot. Crk specific siRNA was used to suppress Crk expression. RESULTS: MiR-126 expression was frequently and markedly downregulated (p < 0.05) in human gastric cancer tissues. Overexpression of miR-126 inhibited GC cells invasion but did not affect its proliferation in vitro. Moreover, overexpression of miR-126 significantly decreased (p < 0.05) the protein levels of Crk, which has previously been identified as a direct target of miR-126. Knockdown of Crk also markedly suppressed GC cells invasion. CONCLUSIONS: Our results demonstrated that overexpression of miR-126 inhibited GC cells invasion in part by targeting Crk. These findings suggested that miR-126 played major roles in the malignant behavior of GC and it might be a promising therapeutic target of GC. PMID- 25027344 TI - Cluster of differentiation 24 monoclonal antibody induces apoptosis in the osteosarcoma cells. AB - OBJECTIVES: Cluster of differentiation 24 (CD24) was overexpressed in osteosarcoma and positive CD24 expression correlates significantly with distant metastasis invasion and poor survival in osteosarcomas. We, therefore, suggested that CD24 would be a new molecular target for therapeutic strategies. In the present study, we aimed to investigate the effects of CD24 down-regulation using monoclonal antibodies (mAb) on apoptosis in osteosarcoma cells in vitro and in vivo. MATERIALS AND METHODS: Osteosarcoma MG-63 cells were treated with Anti-CD24 mAb, and the effects on growth and apoptosis were evaluated in vitro and in vivo. RESULTS: Anti-CD24 mAb could induce the apoptosis of cultured MG63 cells and anti CD24 mAb treatment inhibited the tumor growth after cancer cell grafting and enhanced the cell apoptosis inside the tumor tissue. CONCLUSIONS: The findings showed that anti-CD24 mAb targeting therapy provides a new avenue toward treating osteosarcoma. PMID- 25027345 TI - Oncostatin-M as a novel biomarker in colon cancer patients and its association with clinicopathologic variables. AB - OBJECTIVE: The aim of this study was to evaluate preoperative serum oncostatin M (OSM) concentration as a diagnostic marker in colon cancer patients and its association with clinicopathologic variables. PATIENTS AND METHODS: Preoperative serum OSM concentrations were measured in 100 colon cancer patients and 70 healthy volunteers by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum OSM concentrations were significantly higher in colon cancer patients than in controls (p < 0.001). Serum OSM concentrations increased significantly with higher T stage (p < 0.001) and were significantly higher in patients with increased tumor burden, lymphovascular involvement, and lymph node and distant metastasis (p < 0.001 for each). CONCLUSIONS: To our knowledge, this is the first report showing that elevated OSM concentration was associated with colon cancer and its clinicopathologic variables, including invasion and metastasis. These findings indicate that serum OSM may serve as a novel biomarker in the diagnosis of colon cancer. PMID- 25027346 TI - Meta-analysis of the differentially expressed colorectal cancer-related microRNA expression profiles. AB - OBJECTIVES: Unique microRNAs (miRNAs) have been identified in colorectal cancer in recent studies which can be used to accurately diagnose the presence of colorectal cancer and help predict disease recurrence. Differential expression of specific miRNAs in tissues or blood offers the prospect of their use in early detection and screening for colorectal cancer. However, the experiments under different environments would produce different results. The purpose of this study was to get a reliable result on differentially expressed miRNAs related to colorectal cancer by integrating different studies. MATERIALS AND METHODS: A meta analysis was performed to review three miRNA microarray datasets from three published literatures that compared the microRNAs expression profiles in colorectal cancer tissues with those in normal colorectal tissues. The R VennDiagram package was applied to identify the overlapping miRNAs with differential expression among these three studies. RESULTS: A total of 175 differentially expressed miRNAs were reported in the three miRNA expression profiling studies that compared colorectal cancer tissues with normal tissues, of which 25 miRNAs were reported at least by two studies including 15 up-regulated miRNAs and 10 down-regulated miRNAs. Among the 25 miRNAs, 15 ones were differentially expressed between early stage colorectal cancer and normal tissues including 11 up-regulated miRNAs and 4 down-regulated miRNAs, of which hsa-miR 195 (down-regulated) and hsa-miR-20a (up-regulated) were shared by these three studies. CONCLUSIONS: The 15 differentially expressed miRNAs, especially hsa-miR 195 and hsa-miR-20a may be used as potential biomarkers for early detection and screening of colorectal cancer. PMID- 25027347 TI - Effect of glutamine on intestinal barrier function following liver transplantation in rats. AB - OBJECTIVES: Glutamine is an important fuel for intestinal mucosal epithelial cells, and it promotes intestinal mucosal cell differentiation and proliferation. Most liver transplantation (LT) patients suffer from intestinal barrier dysfunction. Whether enteral glutamine supplementation has beneficial effects on intestinal barrier function following LT is not known. We investigated the effect of glutamine (Gln) supplementation on NF-kappaB and on the intestinal barrier in rats after an allogenic LT with concomitant immunosuppressive therapy. MATERIALS AND METHODS: Inbred Sprague-Dawley rats (n=40) receiving allogenic LT were randomly divided into Gln and control groups (n=20, each). Gln group rats were administered Gln (0.4 g/kg.day) by gastric infusion for 6 days, while control rats received saline. Ten rats from each group were sampled for basal parameters on the 3rd day, prior to LT. The remaining 10 from each group were sampled after receiving LT. Twenty inbred Sprague-Dawley rats were selected as donors. The 20 recipients underwent orthotopic LT after 3 days of treatment and were given immunosuppressive therapy for 6 days post-operation. They were euthanized for sample collection on the 7th day. NF-kappaB protein in the intestinal mucosa, portal plasma Gln, endotoxin and TNF-alpha levels, ileocecal sIgA content, bacterial translocation and mucosal ultrastructure were assessed. RESULTS: On the postoperative day 6, the Gln group had increased plasma Gln and ileocecal sIgA (secretory IgA). Gln group also showed improvement in mucosal microvilli structure and had reduced levels of intestinal mucosal NF-kappaB, portal endotoxin and TNF-alpha and decreased bacterial translocation as compared to the control group. CONCLUSIONS: Parenteral supplementation of glutamine ameliorated mucosal injury during allogenic LT, and improved intestinal barrier function. These findings suggest that glutamine supplementation may be an effective therapy to ensure successful recovery from liver transplantation. PMID- 25027329 TI - Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. AB - Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 * 10(-39); Region 3: rs2853677, P = 3.30 * 10(-36) and PConditional = 2.36 * 10( 8); Region 4: rs2736098, P = 3.87 * 10(-12) and PConditional = 5.19 * 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 * 10(-6); and Region 6: rs10069690, P = 7.49 * 10(-15) and PConditional = 5.35 * 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 * 10(-18) and PConditional = 7.06 * 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. PMID- 25027348 TI - Management of acute dyarrhea: current and future trends. AB - Acute diarrhea is a very common symptom, which may recognize different causes and is basically the expression of an altered homeostasis of the bowel, which overcame current classifications. When approaching patients with acute diarrhea, we should firstly check body temperature and vital parameters and secondly provide a general medical examination mainly focused on the abdomen, in order to exclude surgical causes of diarrhea, such as acute appendicitis, diverticulitis, intestinal occlusion and others. Another important aspect is the assessment of the level of hydration in order to provide the right amount of fluids. There is no current indication for the administration of loperamide in infectious diarrhea, but there is a strong rationale for new class of drugs, which may be defined as "mucous regenerators", such as gelatin tannate. Further studies are needed on this matter in order to test the effect of gelatin tannate in adult patients with acute diarrhea. PMID- 25027349 TI - Lunasin as a promising health-beneficial peptide. AB - Lunasin, a 43 amino acid polypeptide originally isolated from soybean, is known to produce multiple health benefits, including anti-hypertension, antioxidant activity, cancer prevention or therapy, anti-inflammation, hypocholesterolemic activity, anti-obesity and immunomodulation. These effects are believed to be due to its unique structure that includes a putative helical region, an Arg-Gly-Asp (RGD) motif and an Asp-rich carboxyl terminus. The focus of this article is to summarize the discovery, characterization and biological activities of lunasin, which will provide a reference for the future development and utilization of lunasin, and a basis for exploring the underlying mechanisms of these health beneficial functions. PMID- 25027350 TI - The protective effect of infliximab on cisplatin-induced intestinal tissue toxicity. AB - OBJECTIVE: Cisplatin (CP) is a popular chemotherapeutic agent. However, high doses of CP may lead to severe side effects to the gastrointestinal system. The aim of this study was to investigate the protective effects of infliximab on small intestine injury induced by high doses of CP. MATERIALS AND METHODS: The A total of 30 rats were equally divided into three groups, including sham (C), cisplatin (CP), and cisplatin + infliximab (CPI). The CP group was treated with 7 mg/kg intraperitoneal cisplatin, and a laparotomy was performed 5 days later. The CPI group received 7 mg/kg infliximab intraperitoneally, were administered 7 mg/kg cisplatin 4 days later, and a laparotomy was performed 5 days after receiving cisplatin. Histopathological and immunohistochemical analysis of small intestine tissue sections were performed, and superoxide dismutase, malondialdehyde, and TNF-alpha levels were measured. RESULTS: Histopathological evaluation revealed that the CP group had damage in the epithelium and connective tissue, but this damage was significantly improved in the CPI group (p < 0.05). In addition, these histopathological findings were confirmed by biochemical analyses. CONCLUSIONS: These results suggest that infliximab is protective against the adverse effects of CP. PMID- 25027351 TI - Evaluation of genotyping methods and the relative cost of pharmacogenomics. AB - Recently, several methods to assess the quality of cost-effectiveness, cost utility and cost-benefit in the pharmacogenomic field have become available. A relevant example is the National Institute for Health and Clinical Excellence (NICE). NICE forms a diverse clinical Advisory committee, which stimulates Pharma and Academic communities to produce a robust set of data, including the design and data source, for economic models of personalized healthcare. Personalized medicine includes genomic tests of each patients and their disease into their clinical treatments, so as minimize toxicity and maximize benefits. It is well known that Pharmacogenomics (PG) tests, performed before drug treatment, lower overall medical costs and provide higher quality of life and longer life expectancy. In this issue relative costs of genotyping methods and platforms, were evaluated by "manually cured criteria" due to lack of specific guidelines. Finally, with the progress made in this scenario over the next five years, health decision-making may able to accelerating the translation of genetic technologies into routine clinical laboratory. PMID- 25027352 TI - Mipomersen is a promising therapy in the management of hypercholesterolemia: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: By inhibiting apolipoprotein B (ApoB) synthesis, mipomersen can significantly reduce ApoB-containing lipoproteins in hypercholesterolemic patients. OBJECTIVE: This study sought to ascertain both the extent to which mipomersen can decrease ApoB-containing lipoproteins and the safety of mipomersen therapy. METHODS: Studies were identified through PubMed, CENTRAL, Embase, Clinical Trials, reviews, and reference lists of relevant papers. The efficacy endpoints were the changes in low-density lipoprotein cholesterol (LDL-C), non high-density lipoprotein cholesterol (non-HDL-C), ApoB, and lipoprotein (a) [Lp(a)]. The safety endpoints were the incidence of injection-site reactions, flu like symptoms, and elevated transaminases. RESULTS: Six randomized controlled trials with 444 patients were included in the analysis. Compared with the placebo group, patients who received mipomersen therapy had a significant reduction in LDL-C (33.13%), as well as a reduction in non-HDL-C (31.70%), ApoB (33.27%), and LP(a) (26.34%). Mipomersen therapy was also associated with an obvious increase in injection-site reactions with an odds ratio (OR) of 14.15, flu-like symptoms with an OR of 2.07, and alanine aminotransferase levels >= 3 * the upper limit of normal with an OR of 11.21. CONCLUSIONS: Mipomersen therapy is effective for lowering ApoB-containing lipoproteins in patients with severe hypercholesterolemia. Future studies exploring how to minimize side effects of mipomersen therapy are needed. PMID- 25027353 TI - Represcription of low-dose acetylsalicylic acid after discontinuation in patients receiving treatment for secondary cardiovascular disease prevention in the UK. AB - In this retrospective database study, carried out using The Health Improvement Network, a UK primary care database, we followed up patients who were prescribed low-dose acetylsalicylic acid (ASA) (75-300 mg/day) for the secondary prevention of cardiovascular disease in 2000-2007, and who discontinued therapy for a period of at least 90 days during that time (n = 11,565). We assessed the incidence of, and factors associated with, ASA represcription. Patients were followed up from the first day after their initial 90-day period of discontinuation (start date) until ASA represcription, death, or the end of the study period (31 December 2010). Hazard ratios for factors associated with represcription were calculated using Cox regression models. The cumulative incidence of ASA represcription was 85.2% over the entire follow-up period, and 63.5% of all represcriptions were received in the first 6 months after patients' start dates. Factors significantly associated with a reduced likelihood of ASA represcription included being aged 75 84 years, cardiovascular and gastrointestinal comorbidities (in particular, atrial fibrillation and high overall gastrointestinal risk), adverse drug reactions experienced during therapy, and use of gastroprotective or cardiovascular medications (most notably warfarin). Factors significantly associated with an increased likelihood of ASA represcription included obesity, diabetes mellitus, stable angina, depression, and use of non-steroidal anti inflammatory drugs. In conclusion, approximately 85% of patients who discontinued low-dose ASA therapy were subsequently represcribed ASA during the study period. Comorbidities and comedication use affected represcription rates. PMID- 25027354 TI - Thymidine phosphorylase gene variant, platelet counts and survival in gastrointestinal cancer patients treated by fluoropyrimidines. AB - The predictive value of thymidine phosphorylase gene variants (TP, also called platelet-derived endothelial cell growth factor) and thrombocytosis were controversial and worthy of further study in gastrointestinal cancer (GIC) patients. We screened all of the common missense single nucleotide polymorphisms (MAF >= 0.1) in fluoropyrimidines (FU) pathway genes (including TP, TS, ENOSF1 and DPD). Three of them were selected and genotyped using Sequenom MassARRAY in 141 GIC patients. TP expression was assessed by immunohistochemistry. Our aim was to evaluate the prognostic significance of studied genes and platelet counts in GIC patients. Multivariate analyses indicated in rs11479-T allele carriers, platelet counts negatively correlated to overall survival. In addition, T allele of TP: rs11479 was associated with higher TP expression in cancer tissues. We suggest TP: rs11479 variant combined with platelet counts may be useful prognostic makers in GIC patients receiving first-line FU chemotherapy and thrombopoietin factor should be used with caution in the rs11479 T allele bearing patients. PMID- 25027355 TI - [4-point internal fixator stabilization of a sacral insufficiency fracture]. AB - Sacral insufficiency fractures develop due to a discrepancy between physiological load and load-bearing capacity. Besides osteoporosis as the main predisposing factor, other diseases lead to a loss of the bony elastic resistivity and therefore are able to cause these characteristic bilateral sacral stress fractures. Most patients complain of low back pain and show difficulties in mobilization.The non-operative therapy is based on analgesics and pain-adapted mobilization. Due to the noticeable functional deficit and persistent discomfort, surgery is necessary in many cases. Various operative methods are available, without significant differences regarding stability. We present the case of a 56 year-old man, in whom the progression of B-cell chronic lymphocytic leukemia (B CLL) led to the development of osteolysis in the posterior pelvic ring and caused a sacral insufficiency fracture. Due to the progressive deterioration of mobilization and the persistent severe pain, we decided to stabilize the posterior pelvic ring. After surgery the patient could be mobilized and the pain was significantly reduced. PMID- 25027356 TI - [The surgically treated gunshot injury. Securing evidence in hospitals without primary participation of police or legal medicine]. AB - Against the background of a problematic reconstruction of a hunting accident, the question arises how such cases can be handled in hospitals and how exhibits can be adequately dealt with. After evaluating a questionnaire on current conditions of securing evidence in cases of surgically treated gunshot wounds from 26 surgical institutions in Mecklenburg-Western Pomerania and in consideration of the certified advanced training in the field of legal medicine, recommendations are given regarding the securing of evidence within the clinical setting without primary involvement of police or legal medicine. PMID- 25027357 TI - Hispanics/Latinos and the HIV continuum of care in the Southern USA: a qualitative review of the literature, 2002-2013. AB - Hispanics/Latinos are disproportionately affected by HIV infection, but access HIV care less often than non-Hispanic whites in the USA. The majority of new HIV diagnoses among Hispanics/Latinos occur in the southern USA; however, data are lacking regarding factors associated with HIV care access for Hispanics/Latinos in the South. We conducted a qualitative review of peer-reviewed articles using the HIV continuum of care framework to assess HIV care for Hispanics/Latinos in the US South. We identified 13 studies conducted in southern states that were informed by the continuum of care: testing and diagnosis of HIV infection (n = 9); linkage and retention in care (n = 2); and prescription of and adherence to ART (n = 2). Barriers to health care access included stigma, lack of Spanish speaking health-care providers, and fear of deportation. Facilitators to health care access included provider endorsement of HIV tests and regular health care. Innovative solutions (e.g., patient navigators), tailored strategies (e.g., community outreach) and organizational-level interventions (e.g., increasing provider endorsement of HIV tests) can improve access for Hispanics/Latinos in the South. PMID- 25027358 TI - Convergence accommodation to convergence CA/C ratio: convergence versus divergence. AB - AIM: To determine whether the convergence accommodation to convergence (CA/C) ratio during divergence with base-in (BI) prisms is of a similar or different magnitude to that measured during convergence with base-out (BO) prisms. METHODS: Eighteen participants with normal binocular single vision were recruited. The participants viewed a pseudo-Gaussian target, which consisted of a light emitting diode (LED) behind a diffusing screen at 40 cm. After 5 minutes of dark adaptation, the refractive status of the eye was measured without any prism using a Shin-Nippon SRW-5000 autorefractor. The participant held the selected prism (5Delta or 10Delta BO or BI, counterbalanced) in front of their right eye and obtained a single, fused image of the target while refractive measures were taken with each. A 30-second rest period was given between measurements. The mean age of the participants was 20.6+/-3.22 years. RESULTS: The mean CA/C ratios for the 5Delta BO, 10Delta BO, 5Delta BI, and 10Delta BI were 0.108 (+/-0.074) D/Delta, 0.110 (+/-0.056) D/Delta, 0.100 (+/-0.090) D/Delta, and 0.089 (+/-0.055) D/Delta, respectively. A 2-factor repeated measures ANOVA found that the CA/C ratio did not significantly change with differing levels of prism-induced convergence and divergence (p=0.649). CONCLUSIONS: Change in accommodation induced by manipulating vergence is similar whether convergence or divergence are induced. The CA/C ratio did not show any change with differing levels of prism-induced convergence and divergence. PMID- 25027359 TI - Plaques and tangles as well as Lewy-type alpha synucleinopathy are associated with formed visual hallucinations. AB - OBJECTIVE: Previous research has linked complex or formed visual hallucinations (VH) to Lewy-type alpha-synucleinopathy (LTS) in neocortical and limbic areas. As Alzheimer's disease pathology often co-occurs with LTS, we questioned whether this pathology - amyloid plaques and neurofibrillary tangles - might also be linked to VH. METHODS: We performed a semi-quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), or dementia with Lewy bodies (DLB). 173 subjects including 50 with VH and 123 without VH - were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini-mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities. RESULTS: A significant relationship was found between the density of LTS and the presence of VH in PD, AD, and DLB. Plaque and tangle densities also were associated with VH in PD (p = .003 for plaque and p = .004 for tangles) but not in AD, where densities were high regardless of the presence of hallucinations. Furthermore, with DLB cases excluded, comorbidity of PD and AD was significantly more prevalent among subjects + VH than subjects -VH (p < .001). CONCLUSION: These findings suggest that both AD and PD neuropathology contribute to the pathogenesis of VH. Incident VH could be predictive of concomitant AD/PD pathology even when criteria are not met for a second diagnosis. PMID- 25027360 TI - Sarcophaga (Liosarcophaga) dux (Diptera: Sarcophagidae): A flesh fly species of medical importance. AB - BACKGROUND: Although tropical climate of Thailand is suitably endowed with biodiversity of insects, flies of medical importance is not well investigated. Using information from literature search, fly survey approach and specialist's experience, we review database of Sarcophaga (Liosarcophaga) dux Thomson (Diptera: Sarcophagidae), one of the priorities flesh fly species of medical importance in Thailand. RESULTS: This review deals with morphology, bionomics and medical involvement. Important morphological characteristics of egg, larva, puparia and adult were highlighted with illustration and/or micrographs. Search pertaining to molecular analysis used for fly identification and developmental rate of larvae were included. Medical involvement of larvae was not only myiasis producing agent in humans and animals, but associated with human death investigations. CONCLUSIONS: This information will enable us to accurate identify this species and to emphasis the increase medically important scene in Thailand. PMID- 25027361 TI - Cat and dog exposure and respiratory morbidities in cystic fibrosis. AB - OBJECTIVE: To understand the triggers that may impact respiratory health in cystic fibrosis (CF), including the effects of pets, because environmental factors contribute to one-half of the variation in lung function in patients with CF. STUDY DESIGN: A total of 703 subjects with CF were recruited through the US CF Twin-Sibling Study. Questionnaires were used to determine the presence/absence of cats and dogs in households with a child with CF. Questionnaires, chart review, and US CF Foundation Patient Registry data were used to track respiratory and infection outcomes. RESULTS: Within the sample, 47% of subjects reported owning a dog, and 28% reported owning a cat. After adjustment for demographic factors, dog ownership was not associated with any adverse clinical outcomes, and cat ownership was associated an increased risk in developing nasal polyps (aOR 1.66; P = .024) compared with noncat owners. Subjects who owned both cats and dogs were twice as likely to report wheezing compared with other subjects (aOR: 2.01; P = .009). There were no differences in prevalence and age of acquisition for the common CF respiratory pathogens Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus between cat/dog owners and noncat/dog owners. CONCLUSIONS: Cat ownership was associated with a greater frequency of developing nasal polyps and combined cat-dog ownership was associated with a greater rate of wheezing. Prospective studies are needed to confirm these associations and the potential psychosocial benefits of cat and/or dog ownership. PMID- 25027363 TI - Unmasking a mask-like face. PMID- 25027362 TI - Viral respiratory tract infections in the neonatal intensive care unit: the VIRIoN-I study. AB - OBJECTIVE: To determine the frequency of respiratory viral infections among infants who were evaluated for late-onset sepsis in the neonatal intensive care units (NICUs) of Parkland Memorial Hospital, Dallas, Texas; and Women & Infants Hospital, Providence, Rhode Island. STUDY DESIGN: Prospective cohort study conducted from January 15, 2012 to January 31, 2013. Infants in the NICU were enrolled if they were inborn, had never been discharged home, and were evaluated for sepsis (at >72 hours of age) and antibiotic therapy was initiated. Infants had a nasopharyngeal specimen collected for detection of respiratory viruses by multiplex polymerase chain reaction within 72 hours of the initiation of antibiotic therapy. Their medical records were reviewed for demographic, clinical, radiographic, and laboratory data until NICU discharge. RESULTS: During the 13-month study, 8 of 100 infants, or 8 (6%) of the 135 sepsis evaluations, had a respiratory virus detected by polymerase chain reaction (2, enterovirus/rhinovirus; 2, rhinovirus; 2, coronaviruses; and 2, parainfluenza-3 virus). By bivariate analysis, the infants with viral detection were older (41 vs 11 days; P = .007), exposed to individuals with respiratory tract viral symptoms (37% vs 2%; P = .003), tested for respiratory viruses by provider (75% vs 11%; P < .001), and had lower total neutrophil counts (P = .02). In multivariate regression analysis, the best predictor of viral infection was the caregivers' clinical suspicion of viral infection (P = .006). CONCLUSIONS: A total of 8% of infants, or 6% of all NICU sepsis evaluations, had a respiratory virus detected when evaluated for bacterial sepsis. These findings argue for more respiratory viral testing of infants with suspected sepsis using optimal molecular assays to establish accurate diagnoses, prevent transmission, and inform antibiotic stewardship efforts. PMID- 25027364 TI - Dermal melanocytosis: more than meets the eye. PMID- 25027365 TI - New synthetic method of 8-oxocoptisine starting from natural quaternary coptisine as anti-ulcerative colitis agent. AB - Quaternary coptisine (1), a natural bioactive quaternary protoberberine alkaloid (QPA), was treated with potassium ferricyanide in aqueous solution of 5 N sodium hydroxide leading to the acquisition of 8-oxocoptisine (2) with much higher yield than reported in the literature. This is the first report of the oxidation of a natural QPA by applying potassium ferricyanide as an oxidant. 8-Oxocoptisine showed significant anti-ulcerative colitis efficacy in vitro with EC50 value being 8.12 * 10(- 8) M. PMID- 25027366 TI - Impact of case volume on outcomes of ureteroscopy for ureteral stones: the clinical research office of the endourological society ureteroscopy global study. AB - BACKGROUND: The Clinical Research Office of the Endourological Society (CROES) undertook the Ureteroscopy Global Study to establish a prospective global database to examine the worldwide use of ureteroscopy (URS) and to determine factors affecting outcome. OBJECTIVE: To investigate the influence of case volume on the outcomes of URS for ureteral stones. DESIGN, SETTING, AND PARTICIPANTS: The URS Global Study collected prospective data on consecutive patients with urinary stones treated with URS at 114 centres worldwide for 1 yr. Centres were identified as low or high volume based on the median overall annual case volume. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pre- and intraoperative characteristics, and postoperative outcomes in patients at low- and high-volume centres were compared. The relationships between case volume and stone-free rate (SFR), stone burden, complications, and hospital stay were explored using multivariate regression analysis. RESULTS AND LIMITATIONS: Across all centres, the median case volume was 67; 58 and 56 centres were designated as low volume and high volume, respectively. URS procedures at high-volume centres took significantly less time to conduct. Mean SFR was 91.9% and 86.3% at high- and low volume centres, respectively (p<0.001); the adjusted probability of a stone-free outcome increased with increasing case volume (p<0.001). Patients treated at a high-volume centre were less likely to need retreatment, had shorter postoperative hospital stay, were less likely to be readmitted within 3 mo, and had fewer and less severe complications. At case volumes approximately >200, the probability of complications decreased with increasing case volume (p=0.02). The study is limited by the heterogeneity of participating centres and surgeons and the inclusion of patients treated by more than one approach. CONCLUSIONS: In the treatment of ureteral stones with URS, high-volume centres achieve better outcomes than low-volume centres. Several outcome measures for URS improve with an increase in case volume. PATIENT SUMMARY: Outcomes following treatment of ureteral stones by ureteroscopy (URS) were studied in a large group of patients at centres worldwide. The proportion of successful procedures (ie, those in which patients became stone free) increased as the annual volume of URS at a hospital increased. Hospital stays were shorter and postoperative complications were less likely at high-volume hospitals. We conclude that for URS, the best outcomes are seen in patients treated at high-volume hospitals. PMID- 25027367 TI - Editorial: epigenetics. PMID- 25027368 TI - In vitro methods in drug transporter interaction assessment. AB - Drug transporter proteins recruit to pharmacological barrier tissues and profoundly affect the ADME properties of a large number of drugs. In vitro assays optimized for drug transporters have grown into routine tools in the determination of molecular level interactions as well as prediction of barrier penetration and system level pharmacokinetics. Regulatory position mandates increasing interest in the application of these assays during drug development. PMID- 25027369 TI - What does a picture tell? In vivo imaging of ABC transporter function. AB - Activity of ABC transporters in tumor tissue or at the blood-brain barrier is believed to be responsible for treatment failure of substrate drugs. As this mechanism will not be present in every single patient, diagnostic tools to study transporter function are urgently needed. Many efforts were made over the past years to improve in vivo quantification of ABC transporter function by molecular imaging techniques. This includes development of new positron emitting tracers, but also the evaluation of modified experimental protocols using already existing tracers. In addition to imaging of transporter function in healthy animals or volunteers, results from disease models or human patients are covered in this review. PMID- 25027370 TI - Histone H2B ubiquitination: signaling not scrapping. AB - Monoubiquitination of histone H2B has emerged as an important chromatin modification with roles not only in transcription but also in cell differentiation, DNA repair or mRNA processing. Recently, the genome-wide distribution of histone H2B ubiquitination in different organisms has been reported. In this review we discuss the mechanisms regulating H2B ubiquitination and its downstream effectors as well as the suggested functions for this mark in light of these recent studies.: PMID- 25027371 TI - Epigenetic drugs that do not target enzyme activity. AB - While the installation and removal of epigenetic post-translational modifications or 'marks' on both DNA and histone proteins are the tangible outcome of enzymatically catalyzed processes, the role of the epigenetic reader proteins looks, at first, less obvious. As they do not catalyze a chemical transformation or process as such, their role is not enzymatic. However, this does not preclude them from being potential targets for drug discovery as their function is clearly correlated to transcriptional activity and as a class of proteins, they appear to have binding sites of sufficient definition and size to be inhibited by small molecules. This suggests that this third class of epigenetic proteins that are involved in the interpretation of post-translational marks (as opposed to the creation or deletion of marks) may represent attractive targets for drug discovery efforts. This review mainly summarizes selected publications, patent literature and company disclosures on these non-enzymatic epigenetic reader proteins from 2009 to the present. PMID- 25027372 TI - Environmental stressors and the epigenome. AB - Epigenetic modification and transgenerational transfer of phenotype at the individual or population level, particularly in response to environmental change, is at the forefront of biological investigation. The plasticity of this process allows an organism to respond to changes in environmental conditions, potentially conferring a survival advantage. In this review, we discuss epigenetic transgenerational phenomena in the specific context of environmental stressors including hypoxia and environmental toxicants.: PMID- 25027373 TI - Transmembrane drug transporter - taxonomy, assays, and their role in drug discovery. PMID- 25027374 TI - Transporter taxonomy - a comparison of different transport protein classification schemes. AB - Currently, there are more than 800 well characterized human membrane transport proteins (including channels and transporters) and there are estimates that about 10% (approx. 2000) of all human genes are related to transport. Membrane transport proteins are of interest as potential drug targets, for drug delivery, and as a cause of side effects and drug-drug interactions. In light of the development of Open PHACTS, which provides an open pharmacological space, we analyzed selected membrane transport protein classification schemes (Transporter Classification Database, ChEMBL, IUPHAR/BPS Guide to Pharmacology, and Gene Ontology) for their ability to serve as a basis for pharmacology driven protein classification. A comparison of these membrane transport protein classification schemes by using a set of clinically relevant transporters as use-case reveals the strengths and weaknesses of the different taxonomy approaches. PMID- 25027375 TI - Transporter assays and assay ontologies: useful tools for drug discovery. AB - Transport proteins represent an eminent class of drug targets and ADMET (absorption, distribution, metabolism, excretion, toxicity) associated genes. There exists a large number of distinct activity assays for transport proteins, depending on not only the measurement needed (e.g. transport activity, strength of ligand-protein interaction), but also due to heterogeneous assay setups used by different research groups. Efforts to systematically organize this (divergent) bioassay data have large potential impact in Public-Private partnership and conventional commercial drug discovery. In this short review, we highlight some of the frequently used high-throughput assays for transport proteins, and we discuss emerging assay ontologies and their application to this field. Focusing on human P-glycoprotein (Multidrug resistance protein 1; gene name: ABCB1, MDR1), we exemplify how annotation of bioassay data per target class could improve and add to existing ontologies, and we propose to include an additional layer of metadata supporting data fusion across different bioassays. PMID- 25027376 TI - Genetic variations of bile salt transporters. AB - Bile salt transporters directly or indirectly influence biological processes through physicochemical or signalling properties of bile salts. The coordinated action of uptake and efflux transporters in polarized epithelial cells of the liver, biliary tree, small intestine and kidney determine bile salt concentrations in different compartments of the body. Genetic variations of bile salt transporters lead to clinical relevant phenotypes of varying severity ranging from a predisposition for drug-induced liver injury to rapidly progressing end-stage liver disease. This review focuses on the impact of genetic variations of bile salt transporters including BSEP, NTCP, ASBT and OSTalpha/beta and discusses approaches for transporter analysis. PMID- 25027377 TI - Computational models for predicting the interaction with ABC transporters. AB - There is strong evidence that ATP-binding cassette (ABC) transporters play a critical role in the pharmacokinetic and pharmacodynamic properties of many drugs and xenobiotics. Due to their pharmacological role, several computational approaches have been developed to understand and predict the interaction between ABC transporters and their ligands. Here, we provide an overview of the current state of the art of the ligand-based models that, derived from the transport and inhibitory activities of a set of ligands, have been published for ABC transporters. PMID- 25027378 TI - Restricting CNS penetration of drugs to minimise adverse events: role of drug transporters. AB - Some drug discovery approaches can benefit from restricting the access of compounds to the central nervous system (CNS) to minimise the risk of side effects. Designing compounds that act as substrates for efflux transporters in the blood-brain barrier can achieve CNS restriction without significantly impairing absorption in the intestine. In vitro assays can be deployed to optimise a balance between passive permeability and active efflux via the ABC family transporters P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2) whilst in vivo estimates of distribution of unbound concentrations of drug are needed to understand pharmacologically relevant exposure in peripheral and central compartments. This strategy can deliver significant CNS restriction whilst retaining good oral bioavailability, cell penetration and pharmacological activity. The possible risks of targeting P-gp and BCRP in orally delivered drugs are discussed. PMID- 25027379 TI - Pharmacological correction of misfolding of ABC proteins. AB - The endoplasmic reticulum (ER) quality control system distinguishes between correctly and incorrectly folded proteins to prevent processing of aberrantly folded conformations along the secretory pathway. Non-synonymous mutations can lead to misfolding of ABC proteins and associated disease phenotypes. Specific phenotypes may at least partially be corrected by small molecules, so-called pharmacological chaperones. Screening for folding correctors is expected to open an avenue for treatment of diseases such as cystic fibrosis and intrahepatic cholestasis. PMID- 25027380 TI - The controversial world of sirtuins. AB - The controversy around sirtuins and their functions in aging has drawn in the past few years as much attention, if not more, from the scientific community and the public as they did when first proposed as the key conserved aging regulators in eukaryotes. With some of the basic observations on sirtuin longevity promoting functions being questioned in popular model systems, researchers are wondering if this family of conserved enzymes still holds strong potential as therapeutic targets. This review examines the several controversial issues around sirtuins and their functions in aging, calorie restriction, as well as age-related diseases in light of recent studies in mammalian systems and discusses whether modulators of sirtuins still hold the secret of life.: PMID- 25027381 TI - A high throughput flow cytometric assay platform targeting transporter inhibition. AB - This review highlights the concepts, recent applications and limitations of High Throughput Screening (HTS) flow cytometry-based efflux inhibitory assays. This platform has been employed in mammalian and yeast efflux systems leading to the identification of small molecules with transporter inhibitory capabilities. This technology offers the possibility of substrate multiplexing and may promote novel strategies targeting microbial efflux systems. This platform can generate a comprehensive dataset that may support efforts to map the interface between chemistry and transporter biology in a variety of pathogenic systems. PMID- 25027382 TI - Automatic patient-customised 3D reconstruction of human costal cartilage from lung MDCT dataset. AB - PURPOSE: The costal cartilage is a prominent feature of the anterior chest wall that is subject to developmental and acquired abnormalities. A fully automatic algorithm to reconstruct the human costal cartilage from multidetector computed tomography (MDCT) images was developed and tested. METHODS: The reconstruction algorithm includes three steps: (1) estimation of length, curvature and end points for each costal cartilage centre-line, (2) costal cartilage cross-section area approximation, and (3) transformation of the estimated cross-section to the centre-line into a cylindrical coordinate system. Four different models were as follows: circle, vertical ellipse, horizontal ellipse and a non-geometric shape have been assumed for the cross-section. Shape estimates were based on each patient's dataset, so the algorithm is patient-specific and anatomically faithful. MDCT datasets from 15 patients were evaluated with the automated algorithm and the results compared with reference masks provided by an experienced radiologist. RESULTS: The costal cartilage reconstruction result and the reference mask were visually consistent. Based on evaluation results, the circular model cross-section with area of twice M (mean area of all rib cross sections in the mid-coronal plane) had the highest Dice similarity coefficient (DSC = 77.5%) with only 2.12 mm registration distance. CONCLUSION: Costal cartilage 3D morphology can be extracted from MDCT scans with an automated method, using a circular cross-section with area equal to twice M. PMID- 25027383 TI - The Medical Vestment and Surgical Instruments of Saint Cosmas and Damian on Sinai Icons From the Seventh to the Eighteenth Century. AB - The iconography of the doctor saints Cosmas and Damian and the artistic representations of their miracles are important sources for the history of medicine. Within the sphere of physician-saints, Cosmas and Damian have the greatest number of iconographic depictions in Byzantine and Post-Byzantine art. In most of their representations, they wear long robes as a sort of professional mantles and carry surgical instruments and boxes indicating their status as doctors. The progress of Byzantine surgery could be attested by these objects, some of them mentioned in collections of miracle stories and documented in medical sources. PMID- 25027384 TI - Internal consistency of the readiness for interprofessional learning scale in German health care students and professionals. AB - BACKGROUND: The implementation of a bachelor degree in "Interprofessional Health Care" at the University of Heidelberg, Germany has fostered the need to evaluate the impact of this innovative programme. The Readiness for Interprofessional Learning Scale (RIPLS) was developed by Parsell and Bligh (1999) to assess student's attitudes towards interprofessional education. The RIPLS consists of 19 items and four subscales were identified by McFadyen (J Interprof Care19:595-603, 2005): "teamwork and collaboration", "negative professional identity", "positive professional identity" and "roles and responsibilities". The RIPLS has been translated into a number of languages and used in a variety of different educational settings. A German version of the RIPLS was not available. Aim of the study was the translation of the RIPLS into German and testing of internal consistency. METHODS: The RIPLS was translated to German according to international guidelines and its psychometric properties were assessed in two online surveys with two different samples a) health care graduates and b) health care students. Descriptive analysis (mean, SD, corrected item-total correlation) of the Readiness for Interprofessional Learning Scale - German (RIPLS-D) was performed for item characteristics and Cronbach's Alpha was calculated for internal consistency of overall and subscales of the RIPLS-D. RESULTS: Each sample consisted of 76 datasets. Reliability for the RIPLS-D overall scale was 0.83 in both samples. The subscales displayed internal consistency between 0.42 and 0.88. Corrected item-total correlation showed low values in two subscales in the sample of graduates. CONCLUSIONS: While the overall RIPLS-D scale is reliable, several subscales showed low values and should be used with caution to measure readiness for interprofessional learning in the German health care context. Internal consistency of the instrument does not seem to be given in health care professionals at different stages of their professional career. In particular the sub-scale "roles and responsibilities" was problematic. For these reasons, the RIPLS-D cannot be recommended for use to assess this concept. PMID- 25027385 TI - Sodium selective erythrocyte glycocalyx and salt sensitivity in man. AB - Negatively charged surfaces of erythrocytes (RBC) reflect properties of the endothelial glycocalyx. Plasma electrolytes counteract these charges and thus control the repulsive forces between RBC and endothelium. Although Na(+) is supposed to exert a rather high affinity to the RBC surface, a direct comparison between Na(+) and K(+) in counteracting the RBC surface has been never made. Therefore, we measured Na(+)/K(+) selectivity of the RBC surface in 20 healthy volunteers applying the previously published salt blood test (SBT). It turned out that the Na(+)/K(+) selectivity ratio of the RBC glycocalyx is on average 6.1 +/- 0.39 (ranging from 3 to 9 in different individuals). Considering standard plasma Na(+) and K(+) concentrations, binding probability of Na(+)/K(+) at the RBC surface is about 180:1. The SBT reveals that plasma K(+) counteracts only about 7% of the negative charges in the RBC glycocalyx. As an in vivo proof of principle, a volunteer's blood was continuously tested over 6 months while applying a glycocalyx protective polyphenol-rich natural compound (hawthorn extract). It turned out that RBC Na(+) sensitivity (the inverse of Na(+) buffer capacity) decreased significantly by about 25% while Na(+)/K(+) selectivity of the RBC glycocalyx declined only slightly by about 8 %. Taken together, (i) plasma Na(+) selectively buffers the negative charges of the RBC glycocalyx, (ii) the contribution of K(+) in counteracting these negative surface charges is small, and (iii) natural polyphenols applied in vivo increase RBC surface negativity. In conclusion, low plasma Na(+) is supposed to favor frictionless RBC slipping through blood vessels. PMID- 25027387 TI - Quantification of pharmaceutical peptides using selenium as an elemental detection label. AB - The aim of the present work was to demonstrate how selenium labelling of a synthetic cell-penetrating peptide may be employed in evaluation of stability and quantitative estimation of cellular uptake by inductively coupled plasma mass spectrometry (ICP-MS). Two analogues of the cell-penetrating peptide, penetratin, were synthesized, one with selenomethionine (SeMet) added at the N-terminal of the peptide (N-PenM(Se)) and the other with the internal methionine (Met) replaced with SeMet (i-PenM(Se)). The purity of the synthesized peptides was 92% for N-PenM(Se) and 89% for i-PenM(Se) as determined by liquid chromatography (LC) ICP-MS. The selenium-labelled peptides were investigated by cell uptake studies in HeLa WT cells. The stability of the peptides was monitored in water, cell medium and during cell uptake studies. Total uptake of selenium was quantified by flow injection (FI)-ICP-MS. Speciation analysis of cell samples by LC-ICP-MS showed mainly uptake of the intact peptides, while the amount of intact peptides in cell lysates was semi-quantitatively determined. The selenium-containing penetratin analogues were to some extent degraded in pure cell medium, while an extensive degradation was observed during cell uptake studies. The major degradation products were determined by LC-electrospray ionization mass spectrometry (ESI-MS). The labelling method in combination with FI-ICP-MS, LC-ICP MS and LC-ESI-MS techniques provided detailed information on the fate of penetratin in cellular uptake studies. Most pharmaceutical peptides, including penetratin, are synthetic analogues of endogenous peptides, and incorporation of selenium may improve the critical assessment of the native drug or drug delivery candidate early in the drug development process. PMID- 25027386 TI - Glutathione and redox signaling in substance abuse. AB - Throughout the last couple decades, the cause and consequences of substance abuse has expanded to identify the underlying neurobiological signaling mechanisms associated with addictive behavior. Chronic use of drugs, such as cocaine, methamphetamine and alcohol leads to the formation of oxidative or nitrosative stress (ROS/RNS) and changes in glutathione and redox homeostasis. Of importance, redox-sensitive post-translational modifications on cysteine residues, such as S glutathionylation and S-nitrosylation could impact on the structure and function of addiction related signaling proteins. In this commentary, we evaluate the role of glutathione and redox signaling in cocaine-, methamphetamine- and alcohol addiction and conclude by discussing the possibility of targeting redox pathways for the therapeutic intervention of these substance abuse disorders. PMID- 25027388 TI - Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats. AB - AIMS/HYPOTHESIS: Although the initial healing stage involves a re epithelialization in humans, diabetic foot ulceration (DFU) has been investigated using rodent models with wounds on the thigh skin, in which a wound contraction is initiated. In this study, we established a rodent model of DFU on the plantar skin and evaluated the therapeutic efficacy of bone-marrow-derived mesenchymal stem cells (BM-MSCs) in this model. METHODS: The wounds made on the hind paws or thighs of streptozotocin induced diabetic or control rats were treated with BM MSCs. Expression levels of phosphorylated focal adhesion kinase (pFAK), matrix metaroprotease (MMP)-2, EGF, and IGF-1, were evaluated in human keratinocytes, which were cultured in conditioned media of BM-MSCs (MSC-CM) with high glucose levels. RESULTS: Re-epithelialization initiated the healing process on the plantar, but not on the thigh, skin. The therapy utilizing BM-MSCs ameliorated the delayed healing in diabetic rats. In the keratinocytes cultured with MSC-CM, the decreased pFAK levels in the high glucose condition were restored, and the MMP2, EGF, and IGF-1 levels increased. CONCLUSIONS/INTERPRETATION: Our study established a novel rat DFU model. The impaired healing process in diabetic rats was ameliorated by transplantation of BM-MSCs. This amelioration might be accounted for by the modification of keratinocyte functions. PMID- 25027389 TI - A practical method to measure GFR in people with type 1 diabetes. AB - AIMS: Improved early diagnostic methods are needed to identify risk for kidney disease in people with type 1 diabetes. We hypothesized that glomerular filtration rate (GFR) measured by iohexol clearance in dried blood spots (DBS) on filter paper would be comparable to plasma (gold-standard) and superior to estimated GFR (eGFR) and, second, that adjustment for ambient blood glucose would improve accuracy and precision of GFR measurement. METHODS: GFR was measured by iohexol clearance in plasma, DBS, and as estimated by the CKD-Epidemiology Collaboration equations in 15 adults with type 1 diabetes at two visits, one euglycemic and one hyperglycemic. RESULTS: GFR measured by DBS was more comparable and less biased than GFR cystatin C, serum creatinine, and both combined. GFR was higher during hyperglycemia. Correction for between visit glycemia statistically significantly reduced bias and mean squared error for GFR measured by DBS as compared to gold-standard during euglycemia. CONCLUSIONS: Iohexol clearance measured with DBS performed better than eGFR methods. Correction for ambient blood glucose improved precision and accuracy of GFR measurement. This method is more convenient than the gold-standard GFR method and may improve screening and diagnostic capabilities in people with type 1 diabetes, especially when GFR is >60ml/min/1.73m(2). PMID- 25027390 TI - NNT is highly misleading when assessing chronic disease prevention. PMID- 25027392 TI - Ultrahigh responsivity and external quantum efficiency of an ultraviolet-light photodetector based on a single VO2 microwire. AB - We demonstrated a single microwire photodetector first made using a VO2 microwire that exhibted high responsivity (Rlambda) and external quantum efficiency (EQE) under varying light intensities. The VO2 nanowires/microwires were grown and attached on the surface of the SiO2/Si(100) substrate. The SiO2 layer can produce extremely low densities of long VO2 microwires. An individual VO2 microwire was bonded onto the ends using silver paste to fabricate a photodetector. The high resolution transmission electron microscopy image indicates that the nanowires grew along the [100] axis as a single crystal. The critical parameters, such as Rlambda, EQE, and detectivity, are extremely high, 7069 A W(-1), 2.4 * 10(10)%, and 1.5 * 10(14) Jones, respectively, under a bias of 4 V and an illumination intensity of 1 MUW cm(-2). The asymmetry in the I-V curves results from the unequal barrier heights at the two contacts. The photodetector has a linear I-V curve with a low dark current while a nonlinear curves was observed under varing light intensities. The highly efficient hole-trapping effect contributed to the high responsivity and external quantum efficiency in the metal-oxide nanomaterial photodetector. The responsivity of VO2 photodetector is 6 and 4 orders higher than that of graphene (or MoS2) and GaS, respectively. The findings demonstrate that VO2 nanowire/microwire is highly suitable for realizing a high-performance photodetector on a SiO2/Si substrate. PMID- 25027391 TI - Treatment recommendations for patients with Waldenstrom macroglobulinemia (WM) and related disorders: IWWM-7 consensus. AB - Waldenstrom macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged. PMID- 25027393 TI - Significance of estrogen receptor subtypes in breast tumorigenesis and progression. AB - The aim of the study was to investigate the effects of estrogen receptor (ER) subtypes (ERalpha and ERbeta) on breast cancer development and progression. The expression level of ERalpha and ERbeta in breast cancer tissues and paired normal breast tissues were detected by Western blot analysis and immunohistochemistry (IHC) staining. The features of ERalpha and ERbeta status in cancer tissues or normal breast tissues and the correlations between clinicopathological characteristics and prognosis were analyzed. The expression levels of ERalpha and ERbeta in breast cancer tissues are significantly lower than those in the paired normal tissues. The expression of ERbeta is decreased more than that of ERalpha. ERalpha expression levels in cancer tissues are associated with tumor diameter, tumor-node-metastasis (TNM) stage, and progesterone receptor (PR) status. However, ERbeta expression levels in cancer tissues are not correlated with clinicopathological factors of patients with breast cancer. In conclusion, ER subtypes might play different roles in the development of breast cancer. PMID- 25027395 TI - Seminal plasma protein in renal cell carcinoma: expression of semenogelin I is a predictor for cancer progression and prognosis. AB - The incidence of renal cell carcinoma (RCC) has been steadily rising each year. There are currently few recognized biomarkers for the diagnosis and prognosis of RCC. We investigated semenogelin I (Sg I) expression and its clinical significance in patients with RCC. The expression levels of Sg I and its protein were measured by qPCR and Western blotting, respectively. Immunohistochemistry was used to investigate the protein expression of Sg I in RCC and normal renal tissue from 53 patients. The Kaplan-Meier method and log-rank test were used to evaluate the data. By qRCR (p < 0.01) and Western blot, the level of Sg I expression in benign tissues was higher than that in RCC tissues. Expression of Sg I was observed in 30 (57 %) RCC cases, which was significantly lower than that observed in benign renal tissues from the same patients [Sg I positive in 53 (100 %) cases (p < 0.0001)] by immunohistochemistry. There was an inverse relation between Sg I expression and clinical stage (pT1-2 vs pT3-4, p < 0.0001). Patients with Sg I-negative tumor had a significantly higher risk of recurrence (Kaplan Meier and log-rank tests, p < 0.0001). There was low Sg I expression in RCC. Sg I expression has potential value in predicting cancer progression and prognosis. These findings support the use of Sg I as a novel biomarker for RCC. PMID- 25027394 TI - MiR-137 regulates epithelial-mesenchymal transition in gastrointestinal stromal tumor. AB - Activation of the epithelial-to-mesenchymal transition (EMT) endows extraordinary invasive capability of cancer cells and causes of treatment failure and metastasis in gastrointestinal stromal tumor (GIST); however, the molecular mechanisms governing GIST invasion remain largely unknown. MicroRNAs (miRNAs) have been shown to play critical roles in cell motility and invasion, which promotes us to study the biological functions of miR-137 in the EMT of GIST. We have found that miR-137 was dramatically downregulated in clinical specimen of GIST. Using an in silico analysis approach, Twist1, a key regulator gene of EMT, has been identified as the target of miR-137. Quantitative RT-PCT and western blot were used to confirm that miR-137 directly targeted on Twist1 and repressed Twist1 expression in GIST-H1 human gastrointestinal stromal tumor cell line. Further, miR-137 was found to increase expression of E-cadherin and cytokeratin, but suppress expression of N-cadherin and vimentin. In vitro experiments have shown that miR-137 enhanced the epithelial cell morphology, decreased GIST cell migration, activated G1 cell cycle arrest, and induced cell apoptosis. These results suggest a novel mechanism that miR-137 regulates EMT and inhibits cell migration via Twist1 downregulation. Therefore, miR-137 may function as anti migration and anti-metastasis in GIST and our study provides a potential approach for developing miR-137-based therapeutic strategy for GIST. PMID- 25027396 TI - Quantitative assessment of the diagnostic role of MUC1 in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma has the worst prognosis of any gastrointestinal cancer, with the mortality approaching the incidence. Early detection is crucial for improving patient prognosis. We therefore performed a meta-analysis to assess the diagnostic performance of MUC1 for pancreatic ductal adenocarcinoma (PDAC). A comprehensive search was performed to retrieve relevant studies on detecting immunohistochemical expression of MUC1 in the diagnosis of PDAC. Data on accuracy of included studies were extracted for further heterogeneity exploring, statistical pooling, and SROC (summary receiver operating characteristics) analyzing using the Meta-DiSc 1.4 and STATA 12.0 software. Seventeen studies were se1ected with 1,363 patients involved. The heterogeneity (except for threshold effect) was found in these studies. The pooled sensitivity and specificity were 0.83 (95 % confidence interval (CI), 0.81-0.86) and 0.63 (95 % CI, 0.59-0.66), respectively. The pooled positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 3.02 (95 % CI, 1.95-4.70) and 0.21 (95 % CI, 0.13-0.32), respectively. The pooled diagnostic odds ratio (DOR) was 20.44 (95 % CI, 9.53 43.85). The area under of SROC curve was 0.8879 and the Q index was 0.8185. This meta-analysis indicates that MUC1 assay plays an important role in the diagnosis of PDAC. PMID- 25027397 TI - MicroRNAs as novel biomarkers in the diagnosis of non-small cell lung cancer: a meta-analysis based on 20 studies. AB - The detection of microRNAs (miRNAs), particularly those obtained from the bloodstream, is an emerging method for diagnosing human cancers, including non small cell lung cancer (NSCLC). However, studies on the accuracy of miRNAs detection in diagnosing NSCLC have yield inconsistent conclusions, making it necessary to conduct a meta-analysis to systematically evaluate the diagnostic value of miRNAs in the diagnosis of NSCLC. The Medline, Embase, Chinese National Knowledge Infrastructure (CNKI), and Sinomed electronic databases were searched to identify all related articles evaluating the diagnostic value of miRNAs for NSCLC. A bivariate regression model was used to calculate the pooled diagnostic accuracy estimates. A total of 20 articles were included in this meta-analysis, involving 1,563 NSCLC patients and 1,060 healthy controls. Overall, our bivariate random effects meta-analysis yielded area under curve (AUC) of 0.85 (95 % CI: 0.82-0.88) with sensitivity of 76 % (95 CI: 72-80) and specificity of 80 % (95 % CI: 77-84) for the use of miRNAs in differentiating NSCLC patients from healthy controls. In addition, subgroup and meta-regression analyses revealed that a combination of multiple miRNAs (AUC, sensitivity, and specificity of 0.89, 81, and 84, respectively) had a higher diagnostic accuracy than single miRNA-based assays (AUC, sensitivity, and specificity of 0.81, 73, and 77 %, respectively). Furthermore, a comparison of miRNAs expression patterns between blood and sputum samples provides additional evidence that miRNAs obtained from blood (AUC, sensitivity, and specificity of 0.86, 78, and 80 %, respectively) are more credible diagnostic biomarkers than those from sputum (AUC, sensitivity, and specificity of 0.79, 66, and 79 %, respectively). In summary, the current meta analysis suggests that the detection of miRNAs may be used in the future as an initial screening test for NSCLC, particularly, the detection of a combination of multiple miRNAs, which is a more comprehensive indicator than individual miRNAs. PMID- 25027398 TI - Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7. AB - Verrucarin A (VA), an active constituent of pathogenic fungus Myrothecium verrucaria, which has the ability to inhibit the growth of breast cancer cells. However, the mechanism by which VA exerts its inhibitory potential remains elusive. Here, we demonstrated that VA inhibited the growth of MCF-7 breast cancer cells, increased the levels of reactive oxygen species (ROS), and subsequently induced mitochondrial membrane potential (Deltapsim) loss, leading to the increase of Bax/Bcl-2 ratio, cytochrome c release, caspase activation, PARP degradation, and apoptosis. VA effectively increased the phosphorylation of p38MAPK and diminished the phosphorylation of ERK/Akt. In addition, VA caused cell cycle deregulation through the induction of p21 and p53. Furthermore, ROS scavenger (n-acetyl-L-cysteine) and p38MAPK inhibitor (SB202190) effectively abrogated the VA-induced cell cycle deregulation and apoptosis. Conversely, U0126, an ERK1/2 inhibitor, enhanced the VA-induced apoptotic signals. Taken together, our results suggest that VA-induces apoptosis and cell cycle deregulation in MCF-7 cells through ROS-dependent p38MAPK activation. PMID- 25027399 TI - Cytochrome P450 1B1 polymorphisms and risk of renal cell carcinoma in men. AB - The cytochrome P450 1B1 (CYP1B1) enzyme activates xenobiotics to reactive forms as well as convert estradiol to 4-hydroxy-estradiol that has been shown to play a role in the carcinogenesis process of the kidney in male but not female animals. Prior reports show polymorphic variants of CYP1B1 to alter catalytic activity, and thus, we hypothesize that polymorphisms of the CYP1B1 gene are involved in the malignant transformation of the renal cell in men. The genetic distributions of five CYP1B1 polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism in 480 normal healthy subjects and 403 sporadic renal cell carcinoma cases. All subjects were Caucasian men. The sites evaluated were codons 48 (C -> G, Arg -> Gly, rs10012), 119 (G -> T, Ala -> Ser, rs1056827), 432 (C -> G, Leu -> Val, rs1056836), 449 (C -> T, Asp, rs1056837), and 453 (A -> G, Asn -> Ser, rs1800440). A trend was demonstrated for the 432 Val/Val (chi2, P = 0.06) and 449 T/T (chi2, P = 0.1) genotypes to play a protective role against renal cancer. Odds ratio (95 % confidence interval) for Val/Val compared to Leu/Leu at codon 432 was 0.65 (0.44-0.95) and T/T compared to C/C at codon 449 was 0.67 (0.45-0.99). Codons 432 and 449 were observed to be linked (D = 0.24), and haplotype involving 432 Val and 449 T was significantly reduced in cancer cases (P = 0.04). No association was found, however, when analyzing polymorphic sites with clinical stage of cancer. These results demonstrate polymorphisms of CYP1B1 to be associated with renal carcinogenesis and are of importance in understanding their role in the pathogenesis of renal cell carcinoma. PMID- 25027400 TI - Effects of leptin and leptin receptor gene polymorphisms on lung cancer. AB - Leptin (LEP), an adipocyte-derived cytokine, has been reported to participate in carcinogenesis. Elevated levels of systemic and pulmonary LEP are associated with diseases related to lung injury and lung cancer. The purpose of the present study was to investigate if the LEP and leptin receptor (LEPR) gene polymorphisms are associated with lung cancer in a cohort of Turkish population. One hundred and sixty-two lung cancer patients and 130 healthy controls were included in the study. The genotypes of LEP gene -2548G > A and LEPR gene Q223R polymorphisms were determined using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) analysis. The genotype frequencies of LEP -2548G > A polymorphism showed statistically significant differences between lung cancer patients and controls (p = 0.007). GA + AA genotypes and A allele of LEP -2548G > A polymorphism was found to be susceptibility factors for lung cancer (p = 0.003, odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.32-4.10; p = 0.003, OR 1.65, 95 % CI 1.18-2.29, respectively). The genotype and allele frequencies of LEPR Q223R polymorphism did not show any statistically significant differences between lung cancer patients and controls (p = 0.782 and p = 0.762, respectively). Although AA-QQ and AA-QR combined genotypes of LEP -2548G > A-LEPR Q223R loci were significantly higher in lung cancer patients (p = 0.020 and p = 0.047, respectively), GG-QQ, GG-QR, and AA-RR combined genotypes were significantly higher in control group. As a result, susceptibility effects of LEP -2548G > A polymorphism alone or in combination with LEPR Q223R polymorphism on lung cancer were observed. Further studies are necessary to prove the association of LEP and LEPR gene polymorphisms with lung cancer. PMID- 25027401 TI - Secreted protein acidic and rich in cysteine inhibits the growth of human pancreatic cancer cells with G1 arrest induction. AB - Aberrant secreted protein acidic and rich in cysteine (SPARC) expression has been reported to play an important role in the tumor development. However, the pattern and the role of SPARC in pancreatic cancer remain largely unknown. Therefore, we further deciphered the role of SPARC played in pancreatic cancer. We first evaluated the SPARC expression in human pancreatic cancer tissues and pancreatic cancer cells. Then we forced expression and silenced SPARC expression in pancreatic cancer cell lines MIA PaCa2 and PANC-1, respectively, using lentivirus vectors. We characterized the stable cells in vitro. In this study, we found that SPARC expression was weak in cancer cells in specimens which negatively correlated with the expression level of phosphorylated pRB and poorer outcome. Moreover, our results demonstrated that SPARC negatively regulated pancreatic cell growth in vitro. Furthermore, we disclosed that the activation of p53 and p27(Kip1) may involve in the effect of SPARC on pancreatic cancer cells. SPARC is downregulated in pancreatic cancer cells and retards the growth of pancreatic cancer cell. Taken together, these results indicate SPARC may be a potential target for pancreatic cancer therapy. PMID- 25027402 TI - Clinical significance of serum ferritin in elderly patients with primary lung carcinoma. AB - This study determined the levels of serum ferritin (SF) and carcinoembryonic antigen (CEA) in elderly patients with advanced primary lung cancer (PLC), and aimed to investigate the correlation between the SF level and clinical characteristics and compare the positive rates of SF and CEA levels in PLC patients and those in normal subjects. The SF and CEA levels of 69 elderly cases of advanced PLC and 63 elderly controls were determined by electrochemiluminescence method. The correlation between each independent clinicopathological characteristic and levels of SF and CEA was calculated. The positive rates of SF and CEA levels in PLC patients and those in normal subjects were compared. The results revealed that the level of SF in controls was significantly lower than those in patients with advanced LC (145.04 +/- 141.77 vs. 293.57 +/- 274.95 ng/ml, t = -3.845, P = 0.000). There was a statistically significant difference between SF level and gender, smoking, and regional lymph node metastasis, respectively (P < 0.05). The positive rate of SF combining with CEA was significantly higher than those of SF and CEA alone in patients with advanced PLC. High serum level of SF is helpful for diagnosing PLC in elderly patients and indicates poor prognosis. PMID- 25027403 TI - MiR-7-5p is frequently downregulated in glioblastoma microvasculature and inhibits vascular endothelial cell proliferation by targeting RAF1. AB - The aberrant expression of microRNAs (miRNAs) is always associated with tumor development and progression. Microvascular proliferation is one of the unique pathologic features of glioblastoma (GBM) . In this study, the microvasculature from GBM or normal brain tissue derived from neurosurgeries was purified and total RNA was isolated from purified microvasculature. The difference of miRNA expression profiles between glioblastoma microvasculature and normal brain capillaries was investigated. It was found that miR-7-5p in GBM microvessels was significantly reduced compared with that in normal brain capillaries. In the in vitro experiments, overexpression of miR-7-5p significantly inhibited human umbilical vein endothelial cell proliferation. Forced expression of miR-7-5p in human umbilical vein endothelial cells in vitro significantly reduced the protein level of RAF1 and repressed the activity of the luciferase, a reporter vector carrying the 3'-untranslated region of RAF1. These findings indicate that RAF1 is one of the miR-7-5p target genes. Furthermore, a significant inverse correlation between miR-7-5p expression and RAF1 protein level in GBM microvasculature was found. These data suggest that miR-7-5p functions as a tumor suppressor gene to regulate GBM microvascular endothelial cell proliferation potentially by targeting the RAF1 oncogene, implicating an important role for miR-7-5p in the pathogenesis of GBM. It may serve as a guide for the antitumor angiogenesis drug development. PMID- 25027404 TI - Nitidine chloride induces apoptosis, cell cycle arrest, and synergistic cytotoxicity with doxorubicin in breast cancer cells. AB - Medicinal plant extracts have been widely used for cancer treatment. Nitidine chloride (NC) is a natural bioactive alkaloid that has recently been reported to have diverse anticancer properties. We aimed to investigate the cytotoxic effects of NC and the effectiveness of combinatorial treatment including NC and doxorubicin in breast cancer cells. Using MTT and flowcytometry assays, we found that NC induced cell growth inhibition and G2/M cell cycle arrest in a time- and dose-dependent manner both in MCF-7 and MDA-MB-231 breast cancer cell lines. Cancer cell growth inhibition was associated with increased levels of the p53 and p21 proteins. Apoptosis induction by NC treatment was confirmed by JC-1 mitochondrial membrane potential, annexin V-positive cell, and TUNEL staining. Using western blot analysis, we found that NC upregulated the pro-apoptotic proteins Bax, cleaved caspase-9 and -3 and cleaved PARP and that it downregulated the anti-apoptotic proteins Bcl-2 and PARP. By using the PI3K/Akt inhibitor LY294002, we further demonstrated that NC-induced apoptosis might be Akt-specific or dependent. In addition, NC exhibited a synergistic effect with doxorubicin on the growth inhibition of the human breast cancer cell lines MCF-7 and MDA-MB-231. Our study demonstrated the anticancer effect of NC on breast cancer and highlighted the potential clinical application of NC. PMID- 25027405 TI - MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA. AB - Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4 2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT 263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC. PMID- 25027406 TI - C-reactive protein genetic polymorphisms increase susceptibility to HBV-related hepatocellular carcinoma in a Chinese population. AB - Chronic inflammation has been implicated in the etiology of hepatocellular carcinoma (HCC). The C-reactive protein (CRP) genetic polymorphisms affected serum CRP concentrations and elevation of CRP has been considered as the hallmark of acute and chronic inflammation. In this study, we investigated the association between CRP genetic polymorphisms and HBV-related HCC risk in a Chinese population. Two polymorphisms in the CRP gene (rs3093059 and rs2794521) were examined in 192 HBV-related HCC patients, 277 non-HCC patients with HBV infection, and 192 healthy controls using polymerase chain reaction-restriction fragment length polymorphism method. DNA direct sequencing was performed to validate the results of genotyping. We found that there were significant differences in the genotype and allele frequencies of the CRP gene rs3093059 polymorphism between the HBV-related HCC patients and the non-HCC patients with HBV infection. The rs3093059 TC genotype was associated with a significant increased HCC risk as compared with the TT genotype (odds ratio (OR) = 1.98, 95 % confidence interval (CI) 1.32-2.95, P = 0.001). The rs3093059 C allele was correlated with a significant increased HCC risk as compared with the T allele (OR = 1.65, 95 % CI 1.16-2.30, P = 0.005). Furthermore, the rs3093059 TC combined with CC genotypes were found to correlate with a significant increased HCC risk compared with the TT genotype in dominant model (OR = 1.92, 95 % CI 1.29-2.82, P = 0.001). However, we did not find any significant effect of CRP rs2794521 polymorphism on HCC risk in this population. In haplotype analysis between HBV related HCC patients and non-HCC patients with HBV infection, the TC haplotype was found correlated with a significant increased HCC risk (OR = 1.750, 95 % CI 1.234-2.480, P = 0.001). The results suggested that the CRP rs3093059 polymorphism may contribute to increased HCC risk in HBV-infected patients in the Chinese population. Further large and well-designed studies in diverse ethnic populations are needed to confirm our results. PMID- 25027407 TI - Evaluation of preoperative serum markers for individual patient prognosis in stage I-III rectal cancer. AB - Several independent serum biomarkers have been proposed as prognostic and/or predictive markers for colorectal cancer (CRC). To this date, carcinoembryonic antigen (CEA) remains the only recommended serological CRC biomarker. The present retrospective analysis investigates the prognostic value of several serum markers. A total of 256 patients with rectal cancer underwent surgery for curative intent in a university cancer center between January 1988 and June 2007. Preoperative serum was retrospectively analyzed for albumin, alkaline phosphatase (aP), beta-human chorionic gonadotropin, bilirubin, CA 125, cancer antigen 19-9, cancer antigen 72-4 (CA 72-4), CEA, CRP, CYFRA 21-1, ferritin, gamma-glutamyl transpeptidase, glutamate oxaloacetate transanunase, glutamate pyruvate transaminase, hemoglobin, haptoglobin, interleukin-6, interleukin-8, creatinine, lactate-dehydrogenase, serum amyloid A (SAA), and 25-hydroxyvitamin D. Cancer specific survival (CSS) and disease-free survival (DFS) were estimated. Median follow-up time was 8.4 years. Overall 3- and 5-year CSS was 88.6 and 78.9 %, respectively. DFS rates were 72.8 % (3 years) and 67.5 % (5 years). Univariate analysis of CSS indicated aP, CA 72-4, CEA, and SAA as prognostic factors, while aP, CEA, and SAA were also prognostic with regard to DFS. Multivariate analysis confirmed SAA together with T and N stage as prognostic factors. According to UICC stage, CEA and SAA add prognostic value in stages II and III with regard to DFS and CSS, respectively. The combined use of CEA and SAA is able to identify patients with favorable and poor prognosis. In addition to tumor baseline parameters, routine analysis of SAA together with CEA provided markedly improved prognostic value on CSS and DFS in resected rectal cancer. PMID- 25027408 TI - Patient-physician role relationships and patient activation: the moderating effects of race and ethnicity. AB - The goals of this article were to empirically describe how racial and ethnic minorities compare with Whites in terms of their role relationships with physicians and examine how differences in those relationships are associated (positively or negatively) with patient activation for minority groups, relative to Whites. Based on analysis of survey data collected from a random sample of 8,140 individuals with chronic illness, we found that both Blacks and Hispanics generally perceive their role relationships with physicians to be less equitable than do Whites and that the benefits to minorities from more equitable role relationships with physicians are not uniform across dimensions of patient physician relationships or racial and ethnic subgroups. Based on these findings, we submit that race and ethnicity should be considered in the development and assessment of tailored interventions to improve activation. PMID- 25027410 TI - A systematic review of factors affecting children's right to health in cluster randomized trials in Kenya. AB - Following the South African case, Treatment Action Campaign and Others v Minister of Health and Others, the use of 'pilot' studies to investigate interventions already proven efficacious, offered free of charge to government, but confined by the government to a small part of the population, may violate children's right to health, and the negative duty on governments not to prevent access to treatment. The applicants challenged a government decision to offer Nevirapine in a few pilot sites when evidence showed Nevirapine significantly reduced HIV transmission rates and despite donor offers of a free supply. The government refused to expand access, arguing they needed to collect more information, and citing concerns about long-term hazards, side effects, resistance and inadequate infrastructure. The court ruled this violated children's right to health and asked the government to immediately expand access. Cluster randomized trials involving children are increasingly popular, and are often used to reduce 'contamination': the possibility that members of a cluster adopt behavior of other clusters. However, they raise unique issues insufficiently addressed in literature and ethical guidelines. This case provides additional crucial guidance, based on a common human rights framework, for the Kenyan government and other involved stakeholders. Children possess special rights, often represent a 'captive' group, and so motivate extra consideration. In a systematic review, we therefore investigated whether cluster trial designs are used to prevent or delay children's access to treatment in Kenya or otherwise inconsistently with children's right to health as outlined in the above case. Although we did not find state sponsored cluster trials, most had significant public sector involvement. Core obligations under children's right to health were inadequately addressed across trials. Few cluster trials reported rationale for cluster randomization, offered post- trial access or planned to implement successful interventions. A small number of trials may have unnecessarily evaluated proven interventions, offered their control arm trial conditions worse than local standards of care or evaluated interventions ostensibly worse than local standards of care. Further research is required to establish if children's right to health in cluster trials is well understood and to explain why some obligations are unmet. PMID- 25027409 TI - Examining the role of patient experience surveys in measuring health care quality. AB - Patient care experience surveys evaluate the degree to which care is patient centered. This article reviews the literature on the association between patient experiences and other measures of health care quality. Research indicates that better patient care experiences are associated with higher levels of adherence to recommended prevention and treatment processes, better clinical outcomes, better patient safety within hospitals, and less health care utilization. Patient experience measures that are collected using psychometrically sound instruments, employing recommended sample sizes and adjustment procedures, and implemented according to standard protocols are intrinsically meaningful and are appropriate complements for clinical process and outcome measures in public reporting and pay for-performance programs. PMID- 25027411 TI - The epidemiology and treatment of anal fissures in a population-based cohort. AB - BACKGROUND: Anal fissure (AF) is regarded as a common problem, but there are no published epidemiologic data, nor information on current treatment. The purpose of this study was to examine the incidence, associated comorbidities, and treatment of AF in a population-based cohort. METHODS: We conducted a retrospective analysis of all persons who were enrolled in one large regional managed care system and treated for AF during calendar years 2005-2011. All persons aged 6 years or older who had a clinic, hospitalization, or surgical procedure associated with AF were identified from utilization data. To identify comorbidities associated with AF, each case was matched by age and gender to 3 controls. RESULTS: There were 1,243 AF cases, including 721 (58%) females and 522 (42%) males; 150 (12%) of the cases occurred in children aged 6-17 years. The overall annual incidence was 0.11% (1.1 cases per 1000 person-years), but ranged widely by age [0.05% in patients 6-17 years to 0.18% in patients 25-34 years]. The incidence also varied by sex, and was significantly higher among females 12 24 years, and among males 55-64 years (P < 0.001). Comorbidities associated with AF included chronic constipation (prevalence 14.2% vs 3.6%), hypothyroidism (14.7% vs 10.4%), obesity (13.0% vs 7.7%), and solid tumors without metastasis (5.2% vs 3.7%) (P < 0.001 for all comparisons). A total of 448 were dispensed a topical prescription medication, 31 had botulinum toxin injection, and only 13 had lateral internal sphincterotomy. CONCLUSIONS: AF is a common clinical problem, and the incidence varies substantially by age and sex. Constipation, obesity, and hypothyroidism are associated comorbidities. Most patients are prescribed topical treatments, although it appears that many prescriptions are never filled. Surgical interventions for AF including botulinum toxin and lateral internal sphincterotomy are uncommon. PMID- 25027413 TI - Letter regarding "In consideration of subspecialty training in forensic anthropology for pathologists". PMID- 25027412 TI - Frontobasal gray matter loss is associated with the TREM2 p.R47H variant. AB - A rare heterozygous TREM2 variant p.R47H (rs75932628) has been associated with an increased risk for Alzheimer's disease (AD). We aimed to investigate the clinical presentation, neuropsychological profile, and regional pattern of gray matter and white matter loss associated with the TREM2 variant p.R47H, and to establish which regions best differentiate p.R47H carriers from noncarriers in 2 sample sets (Spanish and Alzheimer's Disease Neuroimaging Initiative, ADNI1). This was a cross-sectional study including a total number of 16 TREM2 p.R47H carriers diagnosed with AD or mild cognitive impairment, 75 AD p.R47H noncarriers and 75 cognitively intact TREM2 p.R47H noncarriers. Spanish AD TREM2 p.R47H carriers showed apraxia (9 of 9) and psychiatric symptoms such as personality changes, anxiety, paranoia, or fears more frequently than in AD noncarriers (corrected p = 0.039). For gray matter and white matter volumetric brain magnetic resonance imaging voxelwise analyses, we used statistical parametric mapping (SPM8) based on the General Linear Model. We used 3 different design matrices with a full factorial design. Voxel-based morphometry analyses were performed separately in the 2 sample sets. The absence of interset statistical differences allowed us to perform joint and conjunction analyses. Independent voxel-based morphometry analysis of the Spanish set as well as conjunction and joint analyses revealed substantial gray matter loss in orbitofrontal cortex and anterior cingulate cortex with relative preservation of parietal lobes in AD and/or mild cognitive impairment TREM2 p.R47H carriers, suggesting that TREM2 p.R47H variant is associated with certain clinical and neuroimaging AD features in addition to the increased TREM2 p.R47H atrophy in temporal lobes as described previously. The high frequency of pathologic behavioral symptoms, combined with a preferential frontobasal gray matter cortical loss, suggests that frontobasal and temporal regions could be more susceptible to the deleterious biological effects of the TREM2 variant p.R47H. PMID- 25027414 TI - Cardiac fibroma presenting as sudden unexpected death in an adolescent. PMID- 25027415 TI - Head injuries in falls from a standing height: do fractures of the orbital roof matter? A prospective autopsy study. AB - PURPOSE: The aim of this study was to analyze the occurrence and characteristics of orbital roof fractures, periorbital hematoma, conjunctival hemorrhage, orbital roof discoloration, and concomitant head injuries in falls from a standing height. METHODS: A prospective autopsy study was performed over a 4-year period (from 2010 to 2013). Subjects who had died due to traumatic brain injury caused by falls from a standing height were included in the study. RESULTS: Fifty cases of ground level falls were recorded. This group consisted of 39 men and 11 women, with an average age of 67.3 +/- 13.6 years, and median age of 70 years. Skull fractures originating in the proximity of impact site were found in 47 of 50 individuals, and 22 had isolated orbital roof fractures not connected to the fracture line. Bluish discoloration of the orbital roof was noted in 19 subjects, 14 had periorbital hematomas, and 12 had blotchy or purpura-like conjunctival hemorrhages. CONCLUSIONS: Isolated orbital roof fractures in falls from a standing height are easily detected using a standard autopsy technique, with special regard to careful removal of the dura in the anterior cranial fossa. Our study shows that orbital roof fractures can occur in accidental falls from a standing height and may not be associated with concomitant skull fractures and brain injuries. PMID- 25027416 TI - Unusual patterned skin lesions caused by postmortem fungal activity. PMID- 25027417 TI - Antibiotic consumption and its influence on the resistance in Enterobacteriaceae. AB - BACKGROUND: Increasing bacterial resistance to antibiotics is one of the most serious problems in current medicine. An important factor contributing to the growing prevalence of multiresistant bacteria is application of antibiotics. This study aimed at analyzing the development of resistance of Enterobacteriaceae to selected beta-lactam, fluoroquinolone and aminoglycoside antibiotics in the University Hospital Olomouc and assessing the effect of selection pressure of these antibiotics. METHODS: For the period between 1 January 2000 and 31 December 2011, resistance of Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Proteus mirabilis to third- and fourth-generation cephalosporins, meropenem, piperacillin/tazobactam, fluoroquinolones and aminoglycosides was retrospectively studied. For the assessment of selection pressure of antibiotics, a parameter of defined daily dose in absolute annual consumption (DDDatb) based on the ATC/DDD classification and in relative annual consumption (RDDDatb) as the number of defined daily doses per 100 bed-days was used. The relationship between frequency of strains resistant to a particular antibiotic and antibiotic consumption was assessed by linear regression analysis using Spearman's correlation. The level of statistical significance was set at p < 0.05. RESULTS: A total of 113,027 isolates from the Enterobacteriaceae family were analyzed. There was a significant effect of selection pressure of the primary antibiotic in the following cases: piperacillin/tazobactam in Klebsiella pneumoniae, gentamicin in Klebsiella pneumoniae and Escherichia coli and amikacin in Escherichia coli and Enterobacter cloacae. Also, there was significant correlation between resistance to ceftazidime and consumption of piperacillin/tazobactam in Klebsiella pneumoniae and Escherichia coli. No relationship was found between consumption of third- and fourth-generation cephalosporins and resistance to ceftazidime or between fluoroquinolone consumption and resistance to ciprofloxacin. CONCLUSION: The study showed the effects of both direct and indirect selection pressure on increasing resistance to gentamicin, amikacin, piperacillin/tazobactam and ceftazidime. Given the fact that no correlation was found between resistance to fluoroquinolones and consumption of either primary or secondary antibiotics, we assume that the increasing resistance to fluoroquinolones is probably due to circulation of resistance genes in the bacterial population and that this resistance was not affected by reduced use of these antibiotics. PMID- 25027420 TI - [Consensus on the diagnosis and treatment of multiple organ dysfunction syndrome in the elderly by experts of traditional Chinese medicine and western medicine (protocol)]. PMID- 25027419 TI - Serology as a diagnostic tool for predicting initialPseudomonas aeruginosa acquisition in children with cystic fibrosis. AB - RATIONALE: Pseudomonas aeruginosa (Pa) serology could potentially be a useful adjunct to respiratory culture methods for the detection of initial or early Pa infection in patients with cystic fibrosis (CF). OBJECTIVE: To evaluate the utility of Pa serology to predict Pa isolation from respiratory (generally oropharyngeal) cultures in the subsequent 6 or 12 months among young children with CF from whom Pa had never been previously cultured. Pa serology was also evaluated in a group of healthy controls. METHODS: Children <= 12 years of age without prior isolation of Pa from respiratory cultures participating in the Early Pseudomonal Infection Control EPIC Observational Study (EPIC OBS) had annual serum samples for measurement of antibodies against alkaline protease, elastase and exotoxin A using a commercial kit; controls had a single serum sample. Logistic regression with generalized estimating equations was used to characterize associations between log10 serum antibody titers and first isolation of Pa from a respiratory culture within the subsequent 6 or 12 months, with adjustment for sex and age. Receiver operating characteristic curves were used to optimize antibody titer cutpoints by age group. The diagnostic properties of each antibody were estimated using these optimized cutpoints. RESULTS: Pa serology was evaluated in 582 children with CF (2084 serum samples) and 94 healthy controls. There was substantial overlap between serum antibody titers among controls, CF patients who did not acquire Pa (N = 261) and CF patients who did acquire Pa (N = 321). The maximum positive predictive value for first Pa positive culture within the ensuing 6 months was 76.2% and maximum negative predictive value was 72.1% for any antigen or combination of antigens; values were similar for 12 months. CONCLUSIONS: Pa serology does not appear useful for predicting first Pa positive oropharyngeal culture among young CF patients. PMID- 25027418 TI - Impact of alginate-producing Pseudomonas aeruginosa on alveolar macrophage apoptotic cell clearance. AB - Pseudomonas aeruginosa infection is a hallmark of lung disease in cystic fibrosis. Acute infection with P. aeruginosa profoundly inhibits alveolar macrophage clearance of apoptotic cells (efferocytosis) via direct effect of virulence factors. During chronic infection, P. aeruginosa evades host defense by decreased virulence, which includes the production or, in the case of mucoidy, overproduction of alginate. The impact of alginate on innate immunity, in particular on macrophage clearance of apoptotic cells is not known. We hypothesized that P. aeruginosa strains that exhibit reduced virulence impair macrophage clearance of apoptotic cells and we investigated if the polysaccharide alginate produced by mucoid P. aeruginosa is sufficient to inhibit alveolar macrophage efferocytosis. Rat alveolar or human peripheral blood monocyte (THP-1) derived macrophage cell lines were exposed in vitro to exogenous alginate or to wild type or alginate-overproducing mucoid P. aeruginosa prior to challenge with apoptotic human Jurkat T-lymphocytes. The importance of LPS contamination and that of structural integrity of alginate polymers was tested using alginate of different purities and alginate lyase, respectively. Alginate inhibited alveolar macrophage efferocytosis in a dose- and time-dependent manner. This effect was augmented but not exclusively attributed to lipopolysaccharide (LPS) present in alginates. Alginate-producing P. aeruginosa inhibited macrophage efferocytosis by more than 50%. A mannuronic-specific alginate lyase did not restore efferocytosis inhibited by exogenous guluronic-rich marine alginate, but had a marked beneficial effect on efferocytosis of alveolar macrophages exposed to mucoid P. aeruginosa. Despite decreased virulence, mucoid P. aeruginosa may contribute to chronic airway inflammation through significant inhibition of alveolar clearance of apoptotic cells and debris. The mechanism by which mucoid bacteria inhibit efferocytosis may involve alginate production and synergy with LPS, suggesting that alginate lyase may be an attractive therapeutic approach to airway inflammation in cystic fibrosis and other chronic obstructive pulmonary diseases characterized by P. aeruginosa colonization. PMID- 25027421 TI - [Interpretation of the international guidelines for definition and clinical management of intra-abdominal hypertension and abdominal compartment syndrome in children, 2013]. PMID- 25027422 TI - [The effect of reactive oxygen species regulation of expression of Bcl-2 and Bax in apoptosis of human umbilical vein endothelial cell induced by heat stress]. AB - OBJECTIVE: To observe the effect of heat stress-induced reactive oxygen species (ROS) burst on the regulation of expression of Bcl-2 and Bax in human umbilical vein endothelial cell (HUVEC) apoptosis induced by heat stress, and explore the pathogenesis of vascular endothelial damage caused by severe heat stroke. METHODS: HUVEC heat stress model was reproduced. Cells of heat stress group were incubated at either 39, 41, or 43 centigrade for 2 hours, then all the cells were further incubated at 37 centigrade and 5% CO2 for 24 hours. Before heat stress, cells of 43 centigrade heat stress group were pretreated with 10 MUmol/L MnTMPyP, which was a specific scavenger of ROS, for 1 hour. Cells of control group were incubated at 37 centigrade and 5% CO2. The amount of ROS was assayed with 2', 7' dichlorofluorescin diacetate (DCFH-DA) and dihydroethidium (DHE) staining. Apoptosis was determined by using staining with Hoechst33258. The mRNA expressions of Bcl-2 and Bax were determined by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of Bcl-2, Bax, caspase-3 were analyzed by Western Blot. In addition, the effect of MnTMPyP on heat stress induced apoptosis was also studied. RESULTS: Compared with control group, there was no obvious change in cells after 39 centigrade heat stress. With the increase in heat stress temperature up to 41 centigrade and 43 centigrade, viability of cells showed a lowering trend, with a burst of ROS, and an increase of mRNA and protein of Bax, and the protein of caspase-3 was significantly increased, the mRNA and protein of Bcl-2 were significantly decreased in a temperature-dependent manner. These changes were marked in 43 centigrade heat stress group as compared with those of the control group [cell viability: (46.00+/-4.00)% vs. (96.33+/ 1.53)%, t=20.164, P=0.001; ROS (fluorescence relative value): 400.67+/-12.10 vs. 99.33+/-4.04, t=32.909, P=0.001; Bax mRNA (A value): 3.03+/-0.15 vs. 1.00+/-0.00, t=23.056, P=0.001; Bax protein (gray value): 3.97+/-0.21 vs. 1.00+/-0.00, t=24.684, P=0.001; caspase-3 protein (gray value): 4.80+/-0.20 vs. 1.00+/-0.00, t=32.909, P=0.001; Bcl-2 mRNA(A value): 0.42+/-0.30 vs. 1.00+/-0.00, t=33.072, P=0.001; Bcl-2 protein (gray value): 0.39+/-0.25 vs. 1.00+/-0.00, t=42.212, P=0.001]. It was shown that pre-condition with the antioxidant MnTMPyP significantly decreased the heat stress-induced expression of Bax, caspase-3, and apoptosis, and the expression of Bcl-2 was elevated [Bax mRNA (A value): 2.00+/ 0.20 vs. 3.33+/-0.25, t=7.184, P=0.002; Bax protein (gray value): 2.03+/-0.25 vs. 3.23+/-0.25, t=5.840, P=0.004; caspase-3 protein (gray value): 2.07+/-0.21 vs. 5.00+/-0.20, t=17.600, P=0.001; Bcl-2 mRNA(A value): 0.71+/-0.40 vs. 0.42+/-0.26, t=8.126, P=0.002; Bcl-2 protein (gray value): 0.57+/-0.31 vs. 0.40+/-0.06, t=5.091, P=0.007]. CONCLUSIONS: A burst in an increase of ROS plays an important role on heat stress-induced HUVEC apoptosis, and the mechanism is probably related to the expressions of Bcl-2 and Bax. The vascular endothelial cells apoptosis may be one of the pathogenetic factor in severe heat stroke. PMID- 25027423 TI - [Monitoring and control of pan-drug resistant Acinetobacter baumannii colonization and infection in a medical intensive care unit]. AB - OBJECTIVE: To describe the monitoring and control of pan-drug resistant Acinetobacter baumannii (XDRABA) colonization and infection in a medical intensive care unit (ICU), and to summarize the effective measures of surveillance of nosocomial infection and control. METHODS: Nonsurgical patients admitted to medical ICU of Peking University People's Hospital from September 2009 to April 2013 with length of ICU stay over 48 hours were surveyed. Number of cases of colonization and infection of XDRABA per month was recorded, and the clinical features of patients with XDRABA colonization and infection were observed. The control of XDRABA colonization and infection was divided into three stages: (1) Outbreak stage, from September 2009 to August 2010, the infection control measures included stringent hand hygiene and surface disinfection, use of disposable ventilator tubes and improvement in antibiotics use. (2) Environmental control stage, from September 2010 to April 2012, the infection control measures consisted of on-the-spot investigation, isolation of patients with XDRABA colonization and infection, tubes terminal environment disinfection. (3) Microbial screening stage, from May 2012 to April 2013, throat, nose and axillary swabs were obtained when the patients admitted. RESULTS: From 2009 September to 2013 April there was a total of 193 patients colonized or infected with XDRABA, and 64 patients died (mortality rate was 33.2%), and 133 (68.9%) patients were on mechanical ventilation. Patients with XDRABA colonization and infection had severer illness [acute physiology and chronic health evaluation II (APACHEII) score 20.3+/-6.7], longer ICU stay [(34.6+/-13.8) days]. In outbreak stage, number of cases with XDRABA colonization and infection was 5-9 per month. In environmental control stage, case number of XDRABA colonization and infection was 3-6 per month. In microbial screening stage, case number of XDRABA colonization and infection, which were already present, was 2-4 per month, and they were mainly admitted from emergency department (59.5%). The number of cases of ICU acquired XDRABA colonization and infection decreased from 2-3 to 0-1 per month. CONCLUSIONS: To control the colonization and infection of XDRABA, monitoring of microorganism, hand hygiene, isolation of patients with XDRABA colonization and infection, and stringent environment disinfection were very necessary. PMID- 25027424 TI - [A prospective randomized controlled trial on effect of norvancomycin tube sealing for prevention of central venous catheter-related infection in critical patients]. AB - OBJECTIVE: To evaluate the clinical value of tube-sealing with norvancomycin and heparin saline mixture for prevention of central venous catheter-related infection (CRI). METHODS: A prospective randomized controlled trial was performed. 120 patients who were admitted to department of critical care medicine from January 2012 to January 2014 were included, with their subclavian vein catheterization installation time longer than 48 hours, age over 18 years and younger than 80 years, and acute physiology and chronic health evaluation II (APACHE II) score reaching 10-29. The patients were divided into two groups using a random number table, and finally 116 patients were enrolled. Norvancomycin and heparin saline mixture were used for tube sealing in the intervention group (n=56), while only heparin saline was used in the control group (n=60). The incidence of CRI, catheter correlated spectrum of pathogens, adverse events, mortality, hospital day, catheter retention time, and hospital costs were compared between two groups. RESULTS: (1) There was no significant difference in the incidence of CRI between intervention group and control group [7.14% (4/56) vs. 8.33% (5/60), chi(2)=0.058, P=1.000]. There was no catheter pathogenic colonization in the intervention group, but there were 2 cases of catheter pathogenic colonization in control group. (2) A total of 7 pathogens were found in two groups. Three cases with pathogenic bacteria was found in the intervention group, with 1 case of Pseudomonas aeruginosa, 1 case Acinetobacter baumannii, and 1 case fungi. Staphylococcus aureus, Staphylococcus epidermidis, fungi, and Acinetobacter baumannii was found in the control group, with 1 case of each. There was no significantly statistical difference between two groups (all P>0.05), but there was a decreasing trend of Gram-positive cocci infection in the intervention group. (3) There was no significant difference in the catheter thrombosis, local bleeding or hematoma, catheter dislocation and other adverse events between intervention group and control group [21.43% (12/56) vs. 23.33% (14/60), chi(2)=0.060, P=0.806]. (4) There were no significant differences in mortality [7.14% (4/56) vs. 8.33% (5/60), chi(2)=0.058, P=1.000], hospital day (35.9+/-15.2 days vs. 34.1+/-16.3 days, t=16.330, P=0.620), catheter retention time (25.0+/-4.5 days vs. 24.5+/-5.1 days, t=26.427, P=2.560) and cost of hospitalization (10 thousand Yuan: 3.42+/-1.22 vs. 3.72+/-1.30, t=13.215, P=1.560) between intervention group and control group. CONCLUSIONS: For patients with central venous catheter, application norvancomycin with heparin saline mixture for tube sealing did not reduce the incidence of CRI, the incidence of adverse events and mortality, does not reduce hospitalization time, catheter retention time and hospital costs, but may reduce the catheter colonization and infection of Gram-positive bacteria. PMID- 25027425 TI - [Clinical research for trough value of serum vancomycin in critical patients]. AB - OBJECTIVE: To observe the changes in serum vancomycin trough concentration, and explore its optimal dosage in critical patients. METHODS: A retrospective study was conducted. Data of 66 patients who used vancomycin during July 2010 to May 2012 in surgical intensive care unit (SICU) of the First Affiliated Hospital of Sun Yat-Sen University were collected and analyzed. According to the endogenous creatinine clearance rate (CCr), the patients were divided into two groups: CCr normal group (>=70 mL/min) and CCr lowered group (<70 mL/min). The distribution of vancomycin serum trough concentration between two groups, relationship between vancomycin serum trough concentrations and CCr, and the influence of vancomycin serum trough concentrations on the prognosis was analyzed. The difference between actual dosage and the recommended dosage in guideline was compared between two groups. RESULTS: 119 times of vancomycin serum trough concentration in 66 patients were enrolled, and it was found that only 20.17% (24/119) reached the target concentration (15-20 mg/L), 45.38% (54/119)<15 mg/L and 34.45% (41/119) >20 mg/L. Vancomycin serum trough concentration in CCr normal group (55 cases) was (13.11+/-6.84) mg/L, among them 65.5% (36/55) attained lower trough concentrations (<15 mg/L). In the subgroup with 15-20 mg/L trough serum concentrations, vancomycin doses were significantly lower than that of recommendation (1.95+/-0.61 g/d vs. 2.73+/-0.32 g/d, F=1.739, P=0.001). Vancomycin serum trough concentration in CCr lowered group (64 cases) was (20.49+/-8.12) mg/L, with 51.5% (33/64) of them showed higher trough concentrations (>20 mg/L). In the subgroup with 15-20 mg/L vancomycin trough serum concentration, vancomycin doses were higher than that of recommendation (1.08+/-0.49 g/d vs. 0.78+/-0.19 g/d, F=11.294, P=0.062). There was no significant difference in 28-day mortality between patients with targeting trough serum concentrations and those without [22.2% (4/18) vs. 18.8% (9/48), chi(2)=0.009, P=0.924]. Serum creatinine [odds ratio (OR)=1.001, 95% confidence interval (95%CI): 0.990-1.012, P=0.000], vancomycin doses (OR=0.600, 95%CI: 0.251 1.434, P=0.003), age (OR=0.985, 95%CI: 0.955-1.015, P=0.015) and body mass index (OR=1.013, 95%CI: 0.967-1.062, P=0.022) were found to be correlated to serum trough concentrations by multiple linear regression analysis. CONCLUSIONS: The rate of vancomycin serum trough concentrations reaching the standard is low in critical patients, so constant monitoring is necessary. Creatinine, vancomycin dosage, age and body mass index show a relatively significant influence on the serum trough concentrations, and they should be taken into consideration in dosage to be given. PMID- 25027426 TI - [Significance of the ratio of plasma vascular endothelial growth factor level to platelet count in the prognosis of patients with sepsis]. AB - OBJECTIVE: To investigate the clinical value of the ratio of plasma vascular endothelial growth factor level to platelet count (VEGF/PLT) in predicting 28-day prognosis in patients with sepsis. METHODS: A prospective cohort study was conducted. From September 2009 to March 2013, 164 sepsis patients in Intensive Care Unit (ICU) of Guangdong General Hospital were included for study. Patients with age younger than 18 years old, the illness already reaching final stage of chronic diseases, suffering from two or more organs dysfunction within 3 days, acute pancreatitis without infection, or less than 28 days of expected survival time were excluded. Finally, 135 patients were included in the further analysis. Peripheral blood samples were collected at admission. Routine blood tests were done, and then VEGF levels in plasma were measured by enzyme linked immunosorbent assay (ELISA). Acute physiology and chronic health evaluation II (APACHEII) scores were recorded every day for 7 days. Patients' prognosis was assessed during the following 28 days. The patients were divided into 28-day survival group and non-survival group. Comparison between two groups was done by single factor analysis. Spearman rank correlation was used to analyze the correlation between VEGF levels and PLT. Mutivariate logistic regression analysis was performed to identify the independent risk factor for 28-day prognosis. Receiver operating characteristic curve (ROC curve) was plotted, and the effect of related indexes on predicting 28-day survival was evaluated by area under ROC curve (AUC). RESULTS: There were no significant differences in VEGF (471.73+/-198.34 ng/L vs. 383.49+/-266.54 ng/L, t=-1.918, P=0.057), PLT (220.40+/-127.60*10(9)/L vs. 246.42+/-100.72*10(9)/L, t=1.275, P=0.204), leucocyte counts (12.48+/ 4.62*10(9)/L vs. 13.70+/-5.97*10(9)/L, t=1.063, P=0.292), mean arterial pressure (86.50+/-12.04 mmHg vs. 91.03+/-13.10 mmHg, t=1.557, P=0.123) and blood lactic acid (1.79+/-1.30 mmol/L vs. 1.50+/-0.60 mmol/L, t=-1.768, P=0.079) at admission between the non-survival group (n=42) and survival group (n=93). VEGF/PLT (2.59+/ 1.44 vs. 1.73+/-1.13, t=-3.756, P=0.000) as well as APACHEII scores (15.50+/-4.50 vs. 13.28+/-4.61, t=-2.022, P=0.045) of the non-survival group were significantly higher than those of survival group, and oxygenation index (PaO2/FiO2) of the non survival group was significantly lower than that of survival group (32.38+/-11.12 kPa vs. 37.04+/-10.97 kPa, t=2.278, P=0.024). Correlation analysis showed that the concentration of VEGF was positively correlated with PLT (r=0.271, P=0.001). It was shown by multivariate logistic regression analysis that only VEGF/PLT was the independent risk factor in predicting 28-day prognosis in patients with sepsis [odds ratio (OR) was 1.591, 95% confidence interval (95%CI) 1.164-2.175, P=0.004]. AUC of VEGF/PLT was 0.704+/-0.047 (P=0.000, 95%CI: 0.611-0.797) for predicting 28-day survival. The optimal cut-off point was 1.32, and the sensitivity and specificity were 81.0% and 48.4 %,respectively. CONCLUSIONS: VEGF/PLT can be used as one of the indicators to predict 28-day survival in patients with sepsis. PMID- 25027427 TI - [The significance of serum N-terminal pro-brain natriuretic peptide levels for prognosis of patients in intensive care unit]. AB - OBJECTIVE: To assess the significance of elevated serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in predicting 30-day mortality rate for patients in intensive care unit (ICU). METHODS: A retrospective study was conducted. The clinical data of 480 patients admitted to ICU in Tianjin First Center Hospital from June 2012 to October 2013 were studied. The characteristics of patients were recorded, the acute physiology and chronic health evaluationII ( APACHEII) score was calculated, and the routine blood tests, blood biochemistry, and serum NT-proBNP level within 24 hours after admission were determined. Patients were divided into non-survival and survival groups according to 30-day outcome, and the characteristics and clinical parameters were compared between two groups, and single factor analysis affecting prognosis was analyzed. All patients were divided into four groups according to four percentile method as NT proBNP<280 ng/L (group Q1), 280 ng/L<=NT-proBNP<1 200 ng/L (group Q2), 1 200 ng/L<=NT-proBNP<1 990 ng/L (group Q3), 1 990 ng/L<=NT-proBNP<4 700 ng/L (group Q4). A Cox regression analysis was used to test the independence of the predictors. A receiver operator characteristic curve (ROC curve) was plotted to compare the power of APACHEII score and NT-proBNP in predicting the outcome. Kaplan-Meier analysis was used to assess survival rate among different NT-proBNP patients. RESULTS: By single factor analysis it was shown that age, APACHEII score, creatinine, NT-proBNP and severe infection were those influencing the outcome. NT-proBNP 1 200-4 700 ng/L (groups Q3 and Q4) and APACHEII score>20 were independent risk factors for predicting outcome [relative risk (RR) for group Q3 was 3.624, 95% credibility interval (95%CI) was 1.258-10.138; RR for group Q4 was 5.059, 95%CI was 3.202-9.993; RR for APACHEII score>20 was 2.987, 95%CI was 1.345 5.823]. The area under the ROC curve (AUC) for APACHEII score and serum NT-proBNP was similar, and it was 0.831 (95%CI 0.778-0.884) and 0.876 (95%CI 0.827-0.925), respectively. The cut-off value of NT-proBNP for predicting mortality was 1 250 ng/L. Kaplan-Meier analysis showed that groups of Q2, Q3 and Q4 had lower cumulative survival rate compared with group Q1 (26.5%, 25.4%, 16.2% vs. 29.6%), and group Q4 showed most significant extent of lowering of survival rate (chi(2)=122.920, P<0.05). CONCLUSIONS: Elevated NT-proBNP level in ICU patients signify severity of the disease, and it is an independent predictor of death of ICU patients. PMID- 25027428 TI - [Inhibitory effect of kukoamine B on lung inflammatory responses in mice with sepsis]. AB - OBJECTIVE: To investigate the inhibitory effect of kukoamine B (KB) on lung inflammatory responses in mice with sepsis and its possible molecular mechanism. METHODS: Twenty-eight male mice were randomly divided into control group (n=8), lipopolysaccharide (LPS) group (n=10), and LPS + KB group (n=10). Sepsis model was reproduced by intra-peritoneal injection of 20 mg/kg LPS, while equivalent normal saline was given in control group, and 20 MUg/kg KB was injected through caudal vein 4 hours after LPS challenge in LPS + KB group. After 8 hours of LPS challenge, the concentration of LPS in plasma and the activity of myeloperoxidase (MPO) in the lung tissue were determined. The contents of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta(IL-1beta) in plasma, alveolar lavage fluid and lung tissue homogenates were assessed by enzyme linked immunosorbent assay (ELISA). The activation of nuclear factor-KappaB (NF-KappaB) and the expression of inducible nitric oxide synthase (iNOS) in lung tissue were determined by Western Blot. The pathological changes in lung tissues were observed with hematoxylin-eosin (HE) staining. The expression of intercellular adhesion molecule-1 (ICAM-1) in lung tissue was determined by immunohistochemistry. RESULTS: Compared with control group, the concentration of LPS in plasma (1 155.650+/-147.149 kEU/L vs. 31.390+/-18.859 kEU/L), MPO activity (1.177+/-0.093 U/g vs. 0.775+/-0.166 U/g), NF-KappaB activity (gray value: 1.557+/-0.105 vs. 0.824+/-0.032) and the expression of iNOS (gray value: 0.650+/ 0.129 vs. 0.392+/-0.097) were significantly increased in LPS group (all P<0.05). After KB intervention, the concentration of LPS (624.461+/-149.012 kEU/L), MPO activity (0.919+/-0.023 U/g), NF-KappaB activity (1.127+/-0.074) and the expression of iNOS (0.425+/-0.066) were significantly lowered (all P<0.05). Compared with control group, the contents of TNF-alpha (47.325+/-13.864 ng/L vs. 6.534+/-0.544 ng/L, 13.382+/-2.231 ng/L vs. 3.748+/-0.692 ng/L, 31.127+/-7.399 ng/L vs. 14.948+/-4.673 ng/L) and IL-1beta (74.329+/-11.890 ng/L vs. 29.921+/ 6.487 ng/L, 9.422+/-2.674 ng/L vs. 1.105+/-0.364 ng/L, 528.509+/-32.073 ng/L vs. 109.945+/-13.561 ng/L) in plasma, alveolar lavage fluid and lung tissue homogenates were obviously enhanced in LPS group (all P<0.05). With KB intervention, the contents of TNF-alpha (20.331+/-7.789 ng/L, 7.145+/-1.202 ng/L, 15.966+/-2.946 ng/L) and IL-1beta (57.707+/-8.098 ng/L, 2.212+/-0.878 ng/L, 426.154+/-11.270 ng/L) were markedly reduced (plasma TNF-alpha: F=16.052, P=0.002; IL-1beta: F=20.649, P=0.000; lung tissue homogenates TNF-alpha: F=31.134, P=0.001; IL-1beta: F=22.792, P=0.002; alveolar lavage fluid TNF-alpha: F=10.013, P=0.009; IL-1beta: F=319.857, P=0.000). In addition, leukocyte infiltration to the lung tissue was attenuated, and the expression of ICAM-1 was reduced by KB in histological examination. CONCLUSIONS: KB, as a neutralizer of LPS, can inhibit the release of inflammatory mediators, reduce the pulmonary inflammatory response and protect the function of lung in septic mice. PMID- 25027429 TI - [Effect of alpha-melanocyte stimulating hormone and its novel analogue on the production of tissue factor pathway inhibitor in mice with endotoxemia]. AB - OBJECTIVE: To evaluate the effect of alpha-melanocyte stimulating hormone (alpha MSH) and its novel analogue STY39 on the production of tissue factor pathway inhibitor (TFPI) in mice with endotoxemia. METHODS: Female BALB/c mice were randomly divided into eight groups with 9 mice in each group. Endotoxemia was reproduced by intraperitoneal injection of lipopolysaccharide (LPS, 25 MUg/kg) and D-galactosamine (D-Gal, 100 mg/kg). The animals of the control group were given phosphate buffered solution (PBS) instead. In the experimental groups, the mice were injected intraperitoneally with 2.5 mg/kg alpha-MSH or STY39 at 1, 2 or 3 hours following LPS injection. The orbital blood was collected at different time points, and tissues of lung, liver, and kidney were collected 8 hours after the administration of LPS. The plasma TFPI levels were determined by enzyme linked immunosorbent assay (ELISA), and the expression of TFPI mRNA in different tissues was determined with reverse transcription-polymerase chain reaction (RT PCR). RESULTS: The plasma TFPI levels began to increase (11.84+/-1.55 MUg/L) in the endotoxemia mice 4 hours after LPS challenge and reached the peak (23.49 +/- 1.12 MUg/L) at 8 hours. alpha-MSH or STY39 treatment at 1, 2 or 3 hours after LPS challenge could significantly increase the TFPI content, with the best drug effect at 1 hour after LPS challenge (the blood was collected 8 hours after LPS challenge, alpha-MSH group: 58.79+/-2.67 MUg/L vs. 28.49+/-1.69 MUg/L, STY39 group: 71.08+/-2.13 MUg/L vs. 28.49+/-1.69 MUg/L, both P<0.01), and the effect of STY39 was better than that of alpha-MSH (P<0.01). A small amount of TFPI mRNA expression was observed in each tissue of the healthy mice. After LPS challenge, TFPI mRNA expression was increased in all the tissues, especially in the lung, liver and kidney. alpha-MSH or STY39 treatment at 1 hour after LPS challenge could significantly up-regulate the expression of TFPI mRNA in the lung and liver (A value, alpha-MSH in lung: 51.10+/-2.89 vs. 32.43+/-2.51, STY39 in lung: 72.11+/-3.48 vs. 32.43+/-2.51; alpha-MSH in liver: 43.21+/-2.12 vs. 29.29+/-2.06, STY39 in liver: 66.82+/-1.76 vs. 29.29+/-2.06, both P<0.01). The treatment with STY39 at 1 hour after LPS challenge could significantly up-regulate the expression of TFPI mRNA in the kidney (A value: 45.21+/-1.80 vs. 30.44+/-2.23, P<0.01), but the treatment with alpha-MSH had no obvious effect (A value: 24.61+/ 1.98 vs. 30.44+/-2.23, P>0.05). The enhancing effect of early administration of STY39 on TFPI mRNA expression in the lung, liver and kidney tissues of endotoxemia mice was more powerful than that of alpha-MSH (all P<0.01). CONCLUSIONS: The early administration of alpha-MSH or STY39 may up-regulate TFPI production in the mice with endotoxemia, and the effect of STY39 is superior to alpha-MSH. PMID- 25027430 TI - [Analysis of components of mesenteric lymph in rats with severe intraperitoneal infection]. AB - OBJECTIVE: To investigate the components of mesenteric lymph of the rats with severe intraperitoneal infection, and inquire into the effect of intestinal lymphatic pathway in severe intraperitoneal infection. METHODS: Twenty-four male Wistar rats were randomly divided into two groups according to random number table method, namely model group and sham group with 12 rats in each group. The rat model of severe intraperitoneal infection was reproduced by injecting artificial gastric juice and E.coli intraperitoneally. Mesenteric lymph in both groups was collected 4 hours after the reproduction of the model, and white blood cells were counted and classified. The levels of endotoxin, alkaline phosphatase (AKP), lactate dehydrogenase (LDH), creatine kinase (CK), glutamine transferase (GST), protein and cytokines of mesenteric lymph were determined. RESULTS: Compared with the sham group, there was an increase in the neutrophil ratio in mesenteric lymph (0.167+/-0.004 vs. 0.610+/-0.006, t=33.520, P<0.001), however the percentage of both macrophages (0.009+/-0.001 vs. 0.020+/-0.004, t=-6.677, P<0.001) and lymphocytes (0.824+/-0.005 vs. 0.921+/-0.004, t=-31.471, P<0.001) was decreased in model group. Compared with sham group, the levels of endotoxin (0.346+/-0.022 kEU/L vs. 0.186+/-0.001 kEU/L, t=18.103, P<0.001), AKP [U (king unit): 13.97+/-5.55 vs. 3.76+/-0.18, t=4.503, P=0.006], LDH (2 827.45+/-1 940.32 U/L vs. 712.68+/-14.09 U/L, t=2.670, P=0.044), CK (2.19+/-1.21 kU/L vs. 0.70+/ 0.01 kU/L, t=3.035, P=0.029), GST (12.33+/-6.53 kU/L vs. 1.36+/-0.39 kU/L, t=4.105, P=0.009) were all significantly elevated. The concentration of protein (4.40+/-0.48 g/L vs. 2.84+/-0.16 g/L, t=6.882, P=0.001), tumor necrosis factor alpha (TNF-alpha: 499.39+/-76.36 ng/L vs. 180.90+/-70.98 ng/L, t=7.483, P<0.001), interleukin-6 (IL-6: 13.74+/-0.78 MUg/L vs. -0.07+/-0.07 MUg/L, t=52.972, P<0.001), intercellular adhesion molecule-1 (ICAM-1: 2 754.19+/-221.48 ng/L vs. 1 362.85+/-393.43 ng/L, t=6.891, P<0.001) and monocyte chemo-attractant protein-1 (MCP-1: 28.23+/-1.77 MUg/L vs. 24.87+/-1.15 MUg/L, t=3.561, P=0.007) and high mobility group protein-1 (HMGB-1: 1 392.78+/-572.42 ng/L vs. 564.17+/-21.32 ng/L, t=3.543, P=0.016) in mesenteric lymph in model group were significantly higher than those in sham group. CONCLUSIONS: Intestinal lymphatic pathway maybe the early pathway for the production of remote organ injury caused by severe intraperitoneal infection. PMID- 25027431 TI - [N-terminal pro-B-type natriuretic peptide value for prediction of mortality among critically ill patients in different age groups in intensive care unit]. AB - OBJECTIVE: To investigate N-terminal pro-B-type natriuretic peptide (NT-proBNP) cutoff value for the mortality in different age groups in critically ill patients. METHODS: A retrospective study was conducted. 295 patients admitted to the intensive care unit (ICU) of 401st Hospital of PLA from January 2011 to October 2012 were divided into two groups according to age [group with age<65 years old (n=105) and group with age>= 65 years old (n=190)]. The concentrations of serum NT-proBNP, hematocrit (HCT), procalcitonin (PCT), C-reactive protein(CRP), serum creatinine(SCr), estimated glomerular filtration rate (eGFR), acute physiology and chronic health evaluationII (APACHEII) score and probability of survival (PS) were recorded within 24 hours. The primary outcome was ICU mortality. Receiver operator characteristic curve (ROC curve) was used to evaluate the value of NT-proBNP for predicting the mortality. RESULTS: (1) There were no significant differences in the length of stay in ICU, mechanical ventilation rate, the mortality, the incidence of cardiovascular disease, digestive disease, neurologic disease, and the number of patients having received operation, HCT, PCT and CRP between the two groups (all P>0.05). The percentage of the male, the APACHEII score, the percentage of respiratory disease, and NT proBNP in group with age>=65 years old were higher than those of the group with age<65 years old [the percentage of the male: 51.6% vs. 33.0%, chi (2)=9.093, P=0.003; APACHEII score: 22.94+/-8.10 vs. 19.44+/-8.51, Z=-3.259, P=0.001; the percentage of respiratory disease: 29.47% vs. 17.14%, chi(2)=5.472, P=0.024; NT proBNP: 5 859.00 (2 050.75, 23 802.75) ng/L vs. 2 882.00 (275.15, 6 236.00) ng/L, Z=-5.514, P=0.000]; PS, the percentage of patients having multiple injuries and other diseases and eGFR in group with age>=65 years old were lower than those of the group with age <65 years old [PS: 59.0 (31.5,79.0)% vs. 70.0 (40.0, 84.0)%, Z=-3.431, P=0.001; the percentage of multiple injuries: 0.53% vs. 17.14%, chi(2)=30.987, P=0.000; the percentage of other disease: 5.79% vs. 13.33%, chi(2)=4.962, P=0.030; eGFR (ml*min(-1)*1.73 m(-2)): 81.07 (45.77, 131.80) vs. 95.54 (33.64, 165.55), Z=-2.214, P=0.027]. (2) The area under the ROC curve (AUC) [95% confidence interval (95%CI)] of NT-proBNP in patients with age<65 years old was significantly higher than that of group with age>=65 years old and the entire group [0.825 (0.738-0.892) vs. 0.664 (0.592-0.731) and 0.725 (0.670-0.775), Z1= 2.835, P1=0.005; Z2=-1.995, P2=0.046]. (3) The sensitivity (76.10% vs. 64.10%), specificity (82.35% vs. 67.12%), positive predictive value (90.0% vs. 75.8%), and negative predictive value (62.2% vs. 53.8%) with cutoff value of NT-proBNP (2 882 ng/L) in group with age<65 years old were significantly higher than those with NT proBNP cutoff value (6 062 ng/L) in group with age>=65 years old. CONCLUSIONS: NT proBNP cutoff value in different age groups for the prediction of mortality in the critically ill patients maybe more objective and accurate. PMID- 25027432 TI - [Effect of hydrocortisone sodium succinate on serum tumor necrosis factor-alpha and interleukin-10 in septic shock]. PMID- 25027433 TI - [The kinetic change in leucocyte, serum procalcitonin and C-reactive protein in patient with sepsis]. PMID- 25027434 TI - [Advance in the research regarding the effect of glycogen synthase kinase 3 in sepsis]. PMID- 25027435 TI - [Application of micro RNA in clinical practice of sepsis]. PMID- 25027436 TI - [Advances in the study of clinical manifestations and pathogenesis of sepsis induced myocardial depression]. PMID- 25027437 TI - Antiphospholipid antibodies during 6-month treatment with infliximab: a preliminary report. AB - BACKGROUND: The introduction of tumor necrosis factor (TNF) antagonists (adalimumab, infliximab, and etanercept) was a major advance and was highly important and beneficial in most rheumatoid arthritis (RA) patients. The adverse effects of this treatment are infrequent, but include opportunistic intracellular infection (especially the reactivation of latent Mycobacterium tuberculosis); exacerbation of demyelinating disorders; and the production of various types of antibodies such as antinuclear antibodies (ANA) or double-stranded DNA autoantibodies (dsDNA) and antiphospholipid antibodies (aPL) such as anti cardiolipin antibodies (aCL) and anti-B2GP-I antibodies (B2GP-I). The aim of the study was to determine the prevalence of aCL and B2GP-I in IgM and IgG classes, using ELISA tests, during 6 months of follow-up in patients with refractory RA successfully treated with infliximab. MATERIAL/METHODS: We determined the prevalence of aCL and B2GP-I in IgM and IgG classes, using ELISA tests, during 6 months of follow-up in patients with refractory RA successfully treated with infliximab. RESULTS: We observed a statistically important increase only in the group of B2GP-I IgM (p<0.05). There are contradictory results concerning the ability of infliximab to induce aPL, but most authors confirm this phenomenon. CONCLUSIONS: Further investigations are needed to determine if the new aPL appears in patients with beta2-GPI gene polymorphisms such as leucine-to-valine substitution at position 247, which can lead to a conformational changes in beta2 GPI protein, leading to aPL synthesis. The role of aPL in pathogenesis of APS is still unclear, but we should remember the immunogenic aspect of TNF antagonist treatment. Therefore, we recommend early detection of aPL and observation of the patient, paying special attention to signs and symptoms of thromboembolism. PMID- 25027438 TI - The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6. AB - The Hippo signaling pathway regulates tissue growth in Drosophila through the transcriptional coactivator Yorkie (Yki). How Yki activates target gene transcription is poorly understood. Here, we identify Nuclear receptor coactivator 6 (Ncoa6), a subunit of the Trithorax-related (Trr) histone H3 lysine 4 (H3K4) methyltransferase complex, as a Yki-binding protein. Like Yki, Ncoa6 and Trr are functionally required for Hippo-mediated growth control and target gene expression. Strikingly, artificial tethering of Ncoa6 to Sd is sufficient to promote tissue growth and Yki target expression even in the absence of Yki, underscoring the importance of Yki-mediated recruitment of Ncoa6 in transcriptional activation. Consistent with the established role for the Trr complex in histone methylation, we show that Yki, Ncoa6, and Trr are required for normal H3K4 methylation at Hippo target genes. These findings shed light on Yki mediated transcriptional regulation and uncover a potential link between chromatin modification and tissue growth. PMID- 25027439 TI - Insect endosymbiont proliferation is limited by lipid availability. AB - Spiroplasma poulsonii is a maternally transmitted bacterial endosymbiont that is naturally associated with Drosophila melanogaster. S. poulsonii resides extracellularly in the hemolymph, where it must acquire metabolites to sustain proliferation. In this study, we find that Spiroplasma proliferation specifically depletes host hemolymph diacylglyceride, the major lipid class transported by the lipoprotein, Lpp. RNAi-mediated knockdown of Lpp expression, which reduces the amount of circulating lipids, inhibits Spiroplasma proliferation demonstrating that bacterial proliferation requires hemolymph-lipids. Altogether, our study shows that an insect endosymbiont acquires specific lipidic metabolites from the transport lipoproteins in the hemolymph of its host. In addition, we show that the proliferation of this endosymbiont is limited by the availability of hemolymph lipids. This feature could limit endosymbiont over-proliferation under conditions of host nutrient limitation as lipid availability is strongly influenced by the nutritional state. PMID- 25027441 TI - Effects of blastomere biopsy on post-natal growth and behavior in mice. AB - STUDY QUESTION: Does blastomere biopsy (BB) of preimplantation embryos induce long-term effects on their growth and post-natal behavior? SUMMARY ANSWER: BB induces long-term effects on body weight and behavior in male mice. WHAT IS KNOWN ALREADY: BB is an essential technique for performing preimplantation genetic diagnosis (PGD), a screening test that can detect genetic abnormalities of embryos before their transfer in utero. There is limited understanding of the post-natal consequences and safety of BB. STUDY DESIGN, SIZE, DURATION: Offspring who had a BB performed as embryos, as well as control offspring, were examined for body and neurological development and subjected to a screening battery of behavioral tests, designed to model symptoms of psychiatric disorders. At least 12 mice were used for each test over the course of 16 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos were subjected to a single BB at the 8-cell stage and then cultured in vitro until the blastocyst stage (BB group). Two control groups were created, one consisting of embryos cultured in vitro without any manipulation (in vitro control (IVC) group) and one of embryos developed entirely in vivo (in vivo group). Embryos from in vitro groups (BB and IVC) were transferred to pseudo-pregnant female mice at the blastocyst stage. Body growth parameters and developmental landmarks of the resulting offspring were observed during their entire lifespan. Furthermore, validated behavioral tests were used to assess early communicative functions, startle reflex, and anxiety- and depression-like behaviors. MAIN RESULTS AND THE ROLE OF CHANCE: We found that male mice derived from BB exhibited peculiar behavioral alterations and changes in body weight. BB-derived male mice showed increased body weight with respect to both controls as early as the second week of life. Adult males displayed decreased times of immobility in the tail suspension test (P < 0.05) and deficits in habituation to, and pre-pulse inhibition of, the startle reflex (P < 0.05). BB did not affect communicative skills and anxiety-like responses. LIMITATIONS, REASONS FOR CAUTION: Extrapolation of these results to humans requires caution as the culture protocols used in human clinics could be better established than in mice research. Furthermore species-specific neurodevelopmental features could be a source of differences between mice and humans in the effects of BB. WIDER IMPLICATIONS OF THE FINDINGS: Our data demonstrate that BB affects long-term programming of post-natal development and behavior in mice, suggesting that PGD procedures could be a risk factor for late onset, neurodevelopmental and metabolic disease predisposition. Thus, in light of our observations, long-term follow-up in humans or other primates generated after BB is needed. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the European Research Council (FP7/2007-2013)/Programme IDEAS GA no. 210103 to G.E.P. European Research Council - Programme FP7-KBBE-2012.1.3-04, GA no. 312097 Acronym: FECUND to G.E.P.; MIUR/CNR, Programme FIRB. GA n. B81J12002520001 Acronym: GenHome to P.L. The authors are participating in the COST action FA 1201 'Epiconcept' Epigenetic and Periconception Environment. No competing interests are declared. PMID- 25027440 TI - Laser ablation of Dbx1 neurons in the pre-Botzinger complex stops inspiratory rhythm and impairs output in neonatal mice. AB - To understand the neural origins of rhythmic behavior one must characterize the central pattern generator circuit and quantify the population size needed to sustain functionality. Breathing-related interneurons of the brainstem pre Botzinger complex (preBotC) that putatively comprise the core respiratory rhythm generator in mammals are derived from Dbx1-expressing precursors. Here, we show that selective photonic destruction of Dbx1 preBotC neurons in neonatal mouse slices impairs respiratory rhythm but surprisingly also the magnitude of motor output; respiratory hypoglossal nerve discharge decreased and its frequency steadily diminished until rhythm stopped irreversibly after 85+/-20 (mean +/- SEM) cellular ablations, which corresponds to ~15% of the estimated population. These results demonstrate that a single canonical interneuron class generates respiratory rhythm and contributes in a premotor capacity, whereas these functions are normally attributed to discrete populations. We also establish quantitative cellular parameters that govern network viability, which may have ramifications for respiratory pathology in disease states. PMID- 25027442 TI - Current approaches and future role of high content imaging in safety sciences and drug discovery. AB - High content imaging combines automated microscopy with image analysis approaches to simultaneously quantify multiple phenotypic and/or functional parameters in biological systems. The technology has become an important tool in the fields of safety sciences and drug discovery, because it can be used for mode-of-action identification, determination of hazard potency and the discovery of toxicity targets and biomarkers. In contrast to conventional biochemical endpoints, high content imaging provides insight into the spatial distribution and dynamics of responses in biological systems. This allows the identification of signaling pathways underlying cell defense, adaptation, toxicity and death. Therefore, high content imaging is considered a promising technology to address the challenges for the "Toxicity testing in the 21st century" approach. Currently, high content imaging technologies are frequently applied in academia for mechanistic toxicity studies and in pharmaceutical industry for the ranking and selection of lead drug compounds or to identify/confirm mechanisms underlying effects observed in vivo. A recent workshop gathered scientists working on high content imaging in academia, pharmaceutical industry and regulatory bodies with the objective to compile the state-of-the-art of the technology in the different institutions. Together they defined technical and methodological gaps, proposed quality control measures and performance standards, highlighted cell sources and new readouts and discussed future requirements for regulatory implementation. This review summarizes the discussion, proposed solutions and recommendations of the specialists contributing to the workshop. PMID- 25027443 TI - Does the speed of the treadmill influence the training effect in people learning to walk after stroke? A double-blind randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of high-speed treadmill training and progressive treadmill training for stroke patients. DESIGN: A double-blind, randomized controlled trial. SETTING: Inpatient rehabilitation hospital. PARTICIPANTS: A total of 61 ambulatory stroke patients. INTERVENTIONS: Patients in both groups underwent treadmill training for 30 minutes with conventional intervention. The progressive training group (n = 31) was trained to walk on a treadmill with a stepwise increase of speed over the treatment period. The high speed training group (n = 30) trained to begin at 1.2-1.3 m/s, which is faster than the mean speed of stroke patients. All participants underwent 20 training sessions for five weeks. MAIN MEASURES: Timed up-and-go test, 10-m walk test, 6 minute walk test, and both step lengths and cadence. RESULTS: There were significant improvements in the results of the timed up-and-go test (-1.96 vs. 5.02 seconds), 10-m walk test (0.30 vs. 0.47 m/s), 6-minute walk test (38.35 vs. 64.40 m), and in the step length of the affected side (0.14 vs. 0.19 m) and the unaffected side (0.10 vs. 0.12 m) in the high-speed training group compared with those in the progressive training group (p < 0.05). Step width was not changed in either group (p > 0.05). CONCLUSION: These results suggest that high-speed training is an effective method for improving the walking ability of stroke patients. PMID- 25027444 TI - Can the Alexander Technique improve balance and mobility in older adults with visual impairments? A randomized controlled trial. AB - OBJECTIVE: To investigate the impact of Alexander Technique lessons on balance and mobility in older adults with visual impairments. DESIGN: Randomized assessor blinded controlled trial with intervention and usual care control groups. SETTING: Participants' homes. SUBJECTS: A total of 120 community-dwellers aged 50+ with visual impairments. INTERVENTION: Twelve weeks of Alexander lessons and usual care. MAIN OUTCOME MEASURES: Short Physical Performance Battery items were primary outcomes at 3 months and secondary outcomes at 12 months. Additional secondary outcomes were postural sway, maximal balance range and falls over 12 months. RESULTS: Between-group differences in primary outcomes were not significant. The intervention group reduced postural sway on a firm surface with eyes open at 3 months after adjusting for baseline values (-29.59 mm, 95%CI 49.52 to -9.67, P < 0.01). Planned sub-group analyses indicated a greater intervention effect among past multiple-fallers (2+) than non-multiple fallers for gait speed (P = 0.02) and step length (P < 0.01) at 3 months and chair stand at 12 months (P < 0.01). There was a non-significant reduction in falls rate (IRR = 0.64, 95%CI 0.34 to 1.15, P = 0.13) and injurious falls (IRR = 0.61, 95% CI 0.28 to 1.30, P = 0.20) in the intervention group compared to the control group. CONCLUSION: The intervention did not have a significant impact on the primary outcomes but benefits for the intervention group in postural sway, trends towards fewer falls and injurious falls and improved mobility among past multiple-fallers suggest further investigation of the Alexander Technique is warranted. PMID- 25027445 TI - Risk factors for the second contralateral hip fracture in elderly patients: a systematic review and meta-analysis. AB - OBJECTIVES: To achieve a quantitative and comprehensive conclusion concerning the risk factors for the second contralateral hip fracture in elderly patients with initial hip fractures. DATA SOURCES: This search was applied to Medline, Embase, Cochrane central database (all up to April 2014). METHODS: All the studies on bilateral hip fractures in elderly patients published in English were reviewed and qualities of included studies were assessed using the Newcastle-Ottawa Scale. All the data were carefully and independently abstracted by two reviewers, any disagreement was settled by discussion. Data was pooled and a meta-analysis completed. RESULTS: A total of 13 case-control studies were identified for the meta-analysis. The significant risk factors were female (odds ratio (OR), 1.30; 95% confidence interval (CI), 1.02-1.64), living in institutions (OR, 2.53; 95% CI, 1.33-4.85), osteoporosis (OR, 10.02; 95% CI, 5.41-18.57), low vision (OR, 2.09; 95% CI, 1.06-4.12), dementia (OR, 2.02; 95% CI, 1.54-2.65), dizziness (OR, 2.87; 95% CI, 1.42-5.87) cardiac diseases (OR, 1.33; 95% CI, 1.00-1.78) and respiration diseases (OR, 2.58; 95% CI, 1.22-5.47). No significant difference was found in admission age between patients with the unilateral hip fracture and the first hip fracture of bilateral hip groups (standardized mean difference, 0.02, 95% CI, -0.30 to 0.35]. CONCLUSIONS: Patients involved with female, living in institutions, osteoporosis, low vision, dizziness, dementia, respiration diseases and cardiac diseases were at risk for a second contralateral hip fracture after the initial hip fracture. PMID- 25027446 TI - Effectiveness of rehabilitation interventions in improving emotional and functional status in hearing or visually impaired older adults: a systematic review with meta-analyses. AB - OBJECTIVE: To assess the effectiveness of non-equipment based rehabilitation interventions for older adults with an age-related hearing or visual impairment. DATA SOURCES: We searched PubMed, EMBASE, PsychInfo, CINAHL, and the Cochrane Central Register of Controlled Trials. REVIEW METHODS: Two authors independently assessed trial eligibility, extracted data and assessed methodological quality. Controlled studies with more than 80% of participants aged >= 55 years and with rehabilitation interventions either separately or in combination with technical device provision were included. Meta-analyses were undertaken for the primary outcomes: emotional status, functional status, self-efficacy and social participation. All studies were categorized into 3 subgroups of intervention approaches (cognitive restructuring, education, and problem-solving), and subgroup analysis was performed. RESULTS: Fourteen studies were identified: six on hearing impairment and eight on visual impairment, involving 1622 sensory impaired participants (mean age 70). Methodological quality of the studies was modest. Eight studies offered data for meta-analysis. No significant effects in favour of interventions on either emotional or functional status, self-efficacy, or social participation were found. In the subgroup analysis, only the problem solving approach showed a positive effect on emotional status. CONCLUSIONS: This review found no effects of non-equipment based rehabilitation interventions on emotional and functional status, self-efficacy, and social participation. However, subgroup analysis showed problem-solving as a potential effective approach for positively affecting emotional status. PMID- 25027447 TI - Nitratireductor shengliensis sp. nov., isolated from an oil-polluted saline soil. AB - Two Gram-negative, non-motile, short-rod-shaped bacterial isolates, designated 110399(T) and 110248, were isolated from an oil-polluted saline soil in Shengli Oilfield, Eastern China. The two strains shared 99.9 % 16S rRNA gene sequence similarity with the DNA-DNA relatedness value being 80.0 %. They were both capable to grow at 20-40 degrees C, pH 7-9, and 1-9 % (w/v) NaCl with the optimum growth happened at 30 degrees C, pH 8, and 2-6 % (w/v) NaCl. The phylogenetic analysis based on 16S rRNA gene sequences revealed that the two strains were members of Nitratireductor and most closely related to Nitratireductor pacificus pht-3B(T) and N. basaltis J3(T) with the 16S rRNA gene sequence similarities being 97.1 and 97.0 %. The DNA-DNA relatedness between the novel strains and two type strains were below 27 +/- 7 %. The strains 110399(T) and 110248 also differed from N. pacificus and N. basaltis in nitrate reduction, salt tolerance, enzyme activities, and utilization of carbon sources. The major cellular fatty acids of strain 110399(T) were C19:0omega8c cyclo (10.5 %) and Summed Feature 8 (C18:1omega7c and/or C18:1omega6c, 41.5 %) which are typical in the genus Nitratireductor. The predominant ubiquinone was Q-10. The genome DNA G+C content of strain 110399(T) and 110248 was 61.1 and 61.7 mol%. On the basis of genetic, phenotypic, and chemotaxonomic analyses, strains 110399(T) and 110248 represent a novel species within the genus Nitratireductor, for which the name Nitratireductor shengliensis sp. nov. is proposed. The type strain is 110399(T) (=CGMCC 1.12519(T) = LMG 27405(T)). PMID- 25027448 TI - Seohaeicola nanhaiensis sp. nov., a moderately halophilic bacterium isolated from the benthic sediment of South China Sea. AB - An aerobic, Gram-staining negative, non-motile, and rod-shaped bacterial strain, SS011A0-7#2-2(T), was isolated from the sediment of South China Sea with the depth of 1,500 m. Optimum growth occurred at pH 8.0, 30 degrees C, and 6 % (w/v) NaCl. Strain SS011A0-7#2-2(T) did not synthesize bacteriochlorophyll a or carotenoid, neither possess photosynthesis genes. Its genome DNA G+C content was 67.9 mol%. It contained Q-10 as the predominant ubiquinone and C18:1 omega7c (52.3 %) as the major fatty acid. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, unidentified phospholipid, and unidentified aminolipid. The 16S rRNA gene sequence analysis revealed that it was closely related to Seohaeicola saemankumensis SD-15(T), Phaeobacter gallaeciensis BS 107(T) and Roseovarius pacificus 81-2(T) in Rhodobacteraceae, with the 16S rRNA gene sequence similarities being 96.5, 95.7, and 95.6 %, respectively. However, the phylogeny of the 16S rRNA gene sequences revealed that strain SS011A0-7#2-2(T) was a member of the genus Seohaeicola. Strain SS011A0-7#2-2(T) was moderately halophilic which was different from Seohaeicola saemankumensis SD-15(T), and it showed the enzyme activities and carbon source spectrum significantly different from Seohaeicola saemankumensis SD-15(T). As its physiological and chemotaxinomic properties were different from those of Seohaeicola saemankumensis SD-15(T), strain SS011A0-7#2-2(T) represents a novel species of the genus Seohaecola. The name Seohaeicola nanhaiensis sp. nov. is proposed, with strain SS011A0-7#2-2(T) (=LMG 27733(T) = CGMCC 1.12759(T)) as the type strain. PMID- 25027449 TI - Validation of drinking water disinfection by-product exposure assessment for rural areas in the National Children's Study. AB - The objective of this study was to provide evidence to evaluate the proposed National Children's Study (NCS) protocol for household water sampling in rural study areas. Day-to-day variability in total trihalomethane (TTHM) concentrations in community water supplies (CWS) in rural areas was determined, and the correlation between TTHM concentrations from household taps and CWS monitoring reports was evaluated. Daily water samples were collected from 7 households serviced by 7 different CWS for 15 days. Coefficients of variation for TTHM concentration over 15 days ranged from 8% to 20% depending on the household. Correlations were tested between TTHM household concentrations and the closest date- and location-matched CWS monitoring reports for the 15-day mean (R=0.85, P<0.01). To simulate the NCS-proposed protocol, correlations were tested for 30 additional NCS household samples (polynomial fit: R=0.74, P=0.04). CWS reported TTHM concentrations >50 MUg/l corresponded to measured NCS household concentrations ranging from 2 to 60 MUg/l. TTHM concentrations were higher in CWS than NCS samples (11.2+/-3.2 MUg/l, mean difference+/-SE, P<0.01). These results show that in rural areas there is high variability within households and poor correlation at higher concentrations, suggesting that TTHM concentrations from CWS monitoring reports are not an accurate measure of exposure in the household. PMID- 25027450 TI - Mouthing activity data for children aged 7 to 35 months in Taiwan. AB - Young children's mouthing activities thought to be among the most important exposure pathways. Unfortunately, mouthing activity studies have only been conducted in a few countries. In the current study, we used videotaping and computer-based translating method to obtain mouthing activity data for 66 children aged 7-35 months in Taiwan. The median indoor hand-to-mouth and object to-mouth frequencies were 8.91 and 11.39 contacts/h, respectively. The median indoor hand-to-mouth and object-to-mouth hourly contact durations were 0.34 and 0.46 min/h, respectively. The indoor object-to-mouth activities were significantly and negatively correlated with age. Children aged 12 to <24 months in the current study had lower indoor hand-to-mouth and object-to-mouth frequencies than children of same age group in the United States. We also found that indoor mouthing duration with pacifier was significantly and negatively correlated with indoor mouthing duration with other non-dietary objects. The results of the current study indicate that the mouthing behaviors may be different between different countries or populations with different ethnic or lifestyle characteristics. We conclude that using hand-to-mouth frequency values from the current literature may not be most reliable for estimating non-dietary exposures of young children living in Taiwan or even in other similar Asian countries. PMID- 25027451 TI - Mechanistic insights into the link between inflammation and cardiovascular disease: rheumatoid arthritis as a human model of inflammation. PMID- 25027452 TI - Coronary artery calcium testing: exploring the need for a randomized trial. PMID- 25027453 TI - From molecular imaging to pathogenesis and vice versa.... PMID- 25027454 TI - Achieving very-low-dose radiation exposure in cardiac computed tomography, single photon emission computed tomography, and positron emission tomography. PMID- 25027455 TI - Imaging challenges in secondary mitral regurgitation: unsolved issues and perspectives. PMID- 25027456 TI - Novel imaging of coronary artery anomalies to assess their prevalence, the causes of clinical symptoms, and the risk of sudden cardiac death. PMID- 25027457 TI - Neointimal proliferation is associated with clinical restenosis 2 years after fully bioresorbable vascular scaffold implantation. PMID- 25027458 TI - Unusually efficient pyridine photodissociation from Ru(II) complexes with sterically bulky bidentate ancillary ligands. AB - The introduction of steric bulk to the bidentate ligand in [Ru(tpy)(bpy)(py)](2+) (1; tpy = 2,2':2',6"-terpyridine; bpy = 2,2'-bipyridine; py = pyridine) to provide [Ru(tpy)(Me2bpy)(py)](2+) (2; Me2bpy = 6,6'-dimethyl-2,2'-bipyridine) and [Ru(tpy)(biq)(py)](2+) (3; biq = 2,2'-biquinoline) facilitates photoinduced dissociation of pyridine with visible light. Upon irradiation of 2 and 3 in CH3CN (lambdairr = 500 nm), ligand exchange occurs to produce the corresponding [Ru(tpy)(NN)(NCCH3)](2+) (NN = Me2bpy, biq) complex with quantum yields, Phi500, of 0.16(1) and 0.033(1) for 2 and 3, respectively. These values represent an increase in efficiency of the reaction by 2-3 orders of magnitude as compared to that of 1, Phi500 < 0.0001, under similar experimental conditions. The photolysis of 2 and 3 in H2O with low energy light to produce [Ru(tpy)(NN)(OH2)](2+) (NN = Me2bpy, biq) also proceeds rapidly (lambdairr > 590 nm). Complexes 1-3 are stable in the dark in both CH3CN and H2O under similar experimental conditions. X-ray crystal structures and theoretical calculations highlight significant distortion of the planes of the bidentate ligands in 2 and 3 relative to that of 1. The crystallographic dihedral angles defined by the bidentate ligand, Me2bpy in 2 and biq in 3, and the tpy ligand were determined to be 67.87 degrees and 61.89 degrees , respectively, whereas only a small distortion from the octahedral geometry is observed between bpy and tpy in 1, 83.34 degrees . The steric bulk afforded by Me2bpy and biq also result in major distortions of the pyridine ligand in 2 and 3, respectively, relative to 1, which are believed to weaken its sigma-bonding and pi-back-bonding to the metal and play a crucial role in the efficiency of the photoinduced ligand exchange. The ability of 2 and 3 to undergo ligand exchange with lambdairr > 590 nm makes them potential candidates to build photochemotherapeutic agents for the delivery of drugs with pyridine binding groups. PMID- 25027459 TI - The effect of triclosan coated sutures on rate of surgical site infection after hip and knee replacement: a protocol for a double-blind randomised controlled trial. AB - BACKGROUND: 187,000 hip and knee joint replacements are performed every year in the National Health Service (NHS). One of the commonest complications is surgical site infection (SSI), and this represents a significant burden in terms of patient morbidity, mortality and cost to health services around the world. The aim of this randomised controlled trial (RCT) is to determine if the addition of triclosan coated sutures to a standard regimen can reduce the rate of SSI after total knee replacement (TKR) and total hip replacement (THR). METHODS: 2400 patients due to undergo a total hip or knee replacement are being recruited into this two-centre RCT. Participants are recruited before surgery and randomised to either standard care or intervention group. Participants, outcome assessors and statistician are blind to treatment allocation throughout the study. The intervention consists of triclosan coated sutures vs. standard non-coated sutures. The primary outcome is the Health protection Agency (HPA) defined superficial surgical site infection at 30 days. Secondary outcomes include HPA defined deep surgical site infection at 12 months, length of hospital stay, critical care stay, and payer costs. DISCUSSION: To date there are no orthopaedic randomised controlled trials on this scale assessing the effectiveness of a surgical intervention, particularly those that can be translated across the surgical specialities. The results from this trial will inform evidence-based recommendations for suture selection in the management of patients undergoing total hip or knee replacement. If triclosan coated sutures are found to be an effective intervention, implementation into clinical practice could improve long term outcomes for patients undergoing hip and knee replacement. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 17807356. PMID- 25027460 TI - Association of serum total bilirubin levels with diastolic dysfunction in heart failure with preserved ejection fraction. AB - BACKGROUND: Left ventricular diastolic dysfunction is one of the main characteristics of heart failure patients with a preserved left ventricular ejection fraction. As bilirubin is regarded as an important endogenous antioxidant molecule, serum total bilirubin levels were compared between heart failure patients with a preserved left ventricular ejection fraction and normal controls in this study. We recruited 327 heart failure patients with a preserved left ventricular ejection fraction and 200 healthy controls. Patients were divided into 4 subgroups by their comprehensive echocardiographic manifestations, 1-mild, 2-moderate, 3-severe (reversible restrictive), 4-severe (fixed restrictive). Total bilirubin levels were compared using stepwise multiple regressions adjusted for selected factors. RESULTS: After adjusting for gender, age, smoking, systolic blood pressure, diastolic blood pressure, total cholesterol and triglyceride, serum total bilirubin levels were significantly lower in the heart failure group compared with the control group (P < 0.01). Patients in the subgroup (4-severe) showed significantly (P < 0.05) lower levels of total bilirubin when compared with the subgroup (1-mild). CONCLUSIONS: TB level was negatively correlated with left ventricular diastolic dysfunction in heart failure patients with a preserved left ventricular ejection fraction, which might provide a new insight into the complicated mechanisms of heart failure with a preserved left ventricular ejection fraction. PMID- 25027461 TI - Biologic therapy with or without topical treatment in psoriasis: what does the current evidence say? AB - Biologic therapy represents a relatively new class of drugs which have revolutionized the treatment of psoriasis and are used with increasing frequency in order to control this chronic, systemic inflammatory disease. However, it is unclear what role there is for combination therapy of biologics with traditional topical agents. The purpose of this article is to assess the literature on the role of topical agents as adjuvants to biological treatments in the treatment of psoriasis and identify areas for further research. A MEDLINE search was performed in order to identify English-language publications from 1996 to 2014 examining combination biologic therapy with topical medications in the treatment of psoriasis. Data from these clinical studies are summarized and the outcomes are discussed. In general, the addition of adjuvant topical therapy to systemic biologic therapy allowed for a reduction in dosage and side effects of both agents, maintenance of initial response to biologics, treatment of recalcitrant lesions in partial responders, and potential acceleration of response to biologic therapies. The current data, though limited, suggest that using topical therapies as adjunct treatment to biologics is a well tolerated and effective means of controlling psoriasis and improving quality of life for patients. However, the treating physician should remain attentive to signs of adverse events and seek opportunities to reduce the dose or treatment frequency during chronic use. PMID- 25027462 TI - [The usefulness of MRI and MR angiography in the diagnosis of Moyamoya disease in children]. PMID- 25027463 TI - [Topiramate in substance-related and addictive disorders]. AB - BACKGROUND: Drug treatments used in substance use disorders are not effective in all patients. OBJECTIVE: To assess the effectiveness of topiramate use in the treatment of substance use disorders. INFORMATION SOURCES: Medline database from January 1966 to December 2013, Cochrane database and clinicaltrials.gov. SELECTION OF STUDIES: We used keywords topiramate, addiction, substance abuse, alcohol, tobacco, nicotine, cocaine, methamphetamine, opiate, heroin, benzodiazepine, cannabis, bulimia nervosa, binge eating disorder, gambling. All clinical trials were included. Animal trials, laboratory tests, reviews, answers to writers, case-reports, case series and publications unrelated to the topic were excluded. Twenty-eight articles investigating the efficacy of topiramate in substance use were included. RESULTS: In alcohol-related disorder, several trials and a meta-analysis showed a reduction of days of consumption. In a single-center trial on tobacco-related disorder, topiramate was not found effective in reducing the carbon monoxide expired. In cocaine-related disorder, one single-center trial showed a reduction of days of consumption and two single-center trials have found a trend in favour of topiramate. In alcohol and cocaine co-dependency, a single center trial found a trend in favour of topiramate. In methamphetamine-related disorder, a multicenter trial found a trend in favour of topiramate. In bulimia nervosa, two single-center trials showed a reduction in binge eating and compensatory behaviours. In binge eating disorder, several trials showed a reduction of binge eating and weight. In gambling, one single-center trial did not show any significant results. There were no randomized controlled trials found in opioid-related disorder, benzodiazepines-related disorder, and cannabis related disorder. LIMITATIONS: Definition of abstinence and methods to assess the efficacy of topiramate differed between trials. The methodological quality of included trials was variable, especially with no double-blind procedure in eight trials. CONCLUSION: Topiramate showed interest mainly in alcoholism, binge eating disorder and bulimia nervosa. No definitive conclusions can be reached for other substance use disorders such as nicotine dependence, cocaine dependence, amphetamine dependence or cannabis dependence and for gambling. PMID- 25027464 TI - Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary Working Group. AB - Systemic sclerosis per se should not be considered as an a priori contraindication for a pre-transplantation assessment in patients with advanced interstitial lung disease and/or pulmonary hypertension. For lung or heart-lung transplantation, a multidisciplinary approach, adapting the pre-transplant assessment to systemic sclerosis and optimizing systemic sclerosis patient management before, during and after surgery should improved the short- and long term prognosis. Indications and contraindications for transplantation have to be adapted to the specificities of systemic sclerosis. A special focus on the digestive tract involvement and its thorough evaluation are mandatory before transplantation in systemic sclerosis. As the esophagus is almost always involved, isolated gastro-oesophageal reflux disease, pH metry and/or manometry abnormalities should not be a systematic per se contraindication for pre transplantation assessment. Corticosteroids may be harmful in systemic sclerosis as they are associated with acute renal crisis. A low dose corticosteroids protocol for immunosuppression is therefore advisable in systemic sclerosis. PMID- 25027465 TI - Monitoring retention in care: using multiple laboratory tests as an indicator for HIV medical care. AB - Retention in care is an important strategy for HIV prevention. Unfortunately, surveillance systems were not designed to capture face-to-face visits with HIV health care providers to assess retention in care. Instead, HIV-related laboratory tests are used as a surrogate measure. This study estimated the sensitivity (90%) and specificity (28%) of two HIV-related laboratory tests separated by at least 90 days for two face-to-face visits among people receiving HIV-related health care in Oregon. Overall accuracy of the surrogate was good but slightly overestimated the proportion of people living with HIV/AIDS actually retained in care. PMID- 25027466 TI - The effect of age on the changes in bone mineral density and osteoporosis detection rates in Han Chinese men over the age of 50. AB - OBJECTIVE: To examine the relationship between age and BMD at different skeletal sites and osteoporosis (OP) detection rates in Han Chinese men over 50 years and to assess the diagnostic value of the OSTA. METHODS: A retrospective analysis of 1488 men over 50 was carried out and group comparisons were made. RESULTS: BMDs at total hip and femoral neck decreased with age (p < 0.01) and were negatively correlated with age by liner correlation analysis (r = -0.36, -0.30; p all <0.05). The detection rates of OP and osteopenia were 10.08% and 43.21% respectively, which increased with age, and significantly higher among over 70 years old than under 70 individuals (47.75% versus 35.56%; 14.88% versus 1.99%; p all <0.01). The detection rate at the femoral neck was similar to the overall detection rate. Sensitivities of OSTA index at a cutoff value of -1 and -4 were 87.33% and 52.0% respectively, and the specificities were 56.20% and 87.59%. CONCLUSION: BMDs at femoral neck and total hip decrease with age. Detection rates of OP increase with age. Bilateral femoral neck BMD measurement can improve detection rates of OP. OSTA is a useful screening tool for OP in Han Chinese men over 50 years. PMID- 25027467 TI - Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies. AB - There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3 aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies. PMID- 25027468 TI - Copper-catalyzed arylsulfonylation of N-arylsulfonyl-acrylamides with arylsulfonohydrazides: synthesis of sulfonated oxindoles. AB - A copper-catalyzed arylsulfonylation of N-arylsulfonyl-acrylamides with sulfonylhydrazides through a tandem radical process was developed. This methodology provided an alternative strategy for the synthesis of sulfonated oxindoles by forming C-S, C-N and C-C bonds in a single operation. PMID- 25027469 TI - Evaluation of invasiveness in single-site laparoscopic colectomy, using "the PainVisionTM system" for quantitative analysis of pain sensation. AB - BACKGROUND: Single-site laparoscopic colectomy (SLC) is increasingly performed for colon cancer. There are few reports on invasiveness in SLC. This study aimed to evaluate the postoperative pain from SLC, as compared to conventional multiport laparoscopic colectomy (MLC). METHODS: We compared postoperative pain among patients from the SLC group (n = 11) with those from the MLC group (n = 11) who underwent laparoscopic surgery for colon cancer at our institution between May and October 2013. Patients were specifically matched for gender, age, body mass index, tumor size, and performance status. Postoperative pain was evaluated at rest and during mobilization, using a visual analog scale (VAS) on postoperative days (PODs) 1-7, and by postoperative frequency of analgesics; pain intensity was evaluated at rest, using the Pain VisionTM system on PODs 1-7. Other operative outcomes of the two groups were also recorded. RESULTS: Patient demographics, operative outcomes, time duration before first flatus, and C reactive protein and WBC count on POD 1 showed no significant differences between groups. Results of sequential VAS during mobilization until POD 7 were significantly less in the SLC group than in the MLC group (p = 0.009). However, sequential VAS at rest did not differ between the two groups (p = 0.11). Measured with the Pain VisionTM system, the difference in pain intensity at rest was statistically significant for the postoperative period (p = 0.003). Total requests for analgesics until POD 7 were reduced in the SLC group compared to that in the MLC group, but lacked statistical significance (three vs. seven, respectively, p = 0.07). CONCLUSIONS: In both quantitative and objective measurements using the Pain VisionTM system, SLC significantly reduced postoperative pain. SLC is a promising procedure, associated with less invasiveness than MLC. PMID- 25027470 TI - Bipolar sealing of lung parenchyma: tests in an ex vivo model. AB - BACKGROUND: Almost every pulmonary lobe resection requires cutting the lung parenchyma in the area of a lung fissure. A monopolar cutter or stapler is often used for this purpose. The seal should be absolutely airtight to prevent post operative pulmonary fistulas. In the present study, the bipolar sealing technique was evaluated regarding air tightness of the seals during normal ventilation and its burst pressure in an ex vivo animal model. MATERIALS AND METHODS: The investigations were carried out on paracardial lung lobes obtained from heart lung preparations taken from freshly killed pigs at a slaughter house. In the laboratory, each individual lobe was perfused with Ringer's solution at body temperature and protectively ventilated through a tube (frequency: 20 1/min, p insp = 20 mbar, PEEP +5 mbar). Non-anatomic resection was carried out in the periphery of the lung lobe. The two control groups (12 lobes per group; Group 1 stapler, Group 2-parenchyma suture) were compared to three groups in which different bipolar sealing instruments were used. They were Group 3-MARSEAL((r)) 10 mm (KLS Martin, Tuttlingen); Group 4-MARSEAL((r)) 5 mm; and Group 5 MARCLAMP((r)) (KLS Martin, Tuttlingen). The SealSafe((r)) G3 electric current was used in all cases. Ventilation was continued for 20 min following parenchymal resection. Parenchymal sealing was then judged visually in a water bath and given a score (0-3). Burst pressure (mbar) was measured by increasing the inspiration pressure stepwise. Group mean values were compared (nonparametric Mann-Whitney U test, p < 0.005). RESULTS: Parenchymal seals were airtight under ventilation throughout the observation period in all groups. Mean burst pressures were as follows: Group 1: 47.1 +/- 6.2 mbar; Group 2: 32.9 +/- 3.9 mbar; Group 3: 38.8 +/ 2.2 mbar; Group 4: 25.0 +/- 6.4 mbar; and Group 5: 32.9 +/- 5.8 mbar. Group 1, the stapler group, thus exhibited the highest burst pressures. Burst pressures for Group 3 were significantly greater than those for Group 2 (p < 0.006). Burst pressures for groups 2 and 5 were similar (p = 0.97). However, the burst pressures for Group 4 were significantly lower than those for Group 2 (p < 0.001). CONCLUSION: MARSEAL((r)) 10 mm and MARCLAMP((r)) achieved adequate burst pressures compared to the two control groups and thus might be suitable for clinical use. PMID- 25027471 TI - Endoscopic or laparoscopic approach for hepatolithiasis in the era of endoscopy in China. AB - BACKGROUND: Many endoscopic procedures have been used to treat hepatolithiasis, including as laparoscopic hepatectomy (LH), laparoscopic intrahepatic duct exploration (LIDE), and endoscopic retrograde cholangiopancreatography (ERCP). However, long-term results of such treatments are rarely reported. The series aimed to evaluate the immediate outcomes and long-term results of these treatments and their optimal indications. METHODS: From January 2002 to April 2010, a total of 124 continuous patients with hepatolithiasis were primarily treated with endoscopic surgery, including LH (LH group, n = 37), LIDE (LIDE group n = 41), and ERCP (ERCP group, n = 46) at our two institutes. These cases were retrospectively reviewed. The patients' demographic variables, operative outcomes, complete clearance rate, and cholangitis recurrence rate were analyzed. RESULTS: Complete stone clearance was achieved in 94.6 % of LH, 78.0 % of LIDE, and 67.4 % of ERCP patients. After a median follow-up period of 5.0 years (rang 2 8 years), we observed stone recurrence in 26.6 % (33/124) of patients and recurrent cholangitis in 24.2 % (30/124) of patients. Stricture, stones in both lobes, and non-hepatectomy treatments were significant risk factors for incomplete stone clearance on multivariate analysis. In addition, recurrent cholangitis was associated with non-hepatectomy therapy, Sphincter of Oddi dysfunction, residual stones, and intrahepatic bile strictures. CONCLUSION: In this study with 2-8 years of follow-up, residual stones, biliary stricture, Sphincter of Oddi dysfunction, and ERCP therapy were associated with recurrent stones and/or cholangitis after treatment, indicating that the modification of Sphincter of Oddi function and maintaining its normal pressure are very important. PMID- 25027472 TI - Technical description and feasibility of laparoscopic adrenal contouring using fluorescence imaging. AB - BACKGROUND: Identification of adrenal glands from the surrounding structures during laparoscopic surgery can be challenging especially in obese individuals. This can increase the chances for hemorrhage and conversion to open surgery. We present the first report of fluorescent infrared visualization of the adrenal glands in a large animal model. METHODS: Five adult Yorkshire pigs were utilized for the study, in compliance with the animal study regulations. After an intravenous bolus administration of 3 mL of indocyanine green (ICG), visualization was performed with a xenon/infrared light source and a laparoscope with a charge-coupled filter device. Activation of the device was done with a foot pedal. Images were analyzed using histogram software and the difference of enhancement was statistically analyzed using unpaired two-tailed t test. RESULTS: The right adrenal glands were visualized in all five animals immediately after administering ICG. Fluorescence facilitated demarcation of adrenal gland tissue from surrounding adipose tissue. Peritoneum and fat was visualized in black color. Adrenal enhancement lasted for 4 h in all cases. The mean value for adrenal fluorescence using histogram count was 71.75 pixels, and for adrenal xenon was 168.87 pixels (p = 0.0002; 95 % CI -130.93 to -0.63). The mean value for fat fluorescence using histogram count was 5.54 pixels and fat xenon was 187.15 pixels (p = 0.0001; 95 % CI -199.39 to -163.82). Although there was no significant difference between adrenal and fat enhancement with xenon light (p = 0.24; 95 % CI -15.53 to 52.09), the difference became significant between adrenal and fat fluorescence (p = 0.0001; 95 % CI 48.51-83.9). CONCLUSION: Fluorescence imaging appears to be a feasible and easy method to differentiate adrenal glands from the surrounding tissue in a large animal model. Further studies are necessary to investigate the real application of this method during laparoscopic adrenalectomy in humans. PMID- 25027473 TI - The mobility and human oral bioaccessibility of Zn and Pb in urban dusts of Estarreja (N Portugal). AB - Twenty-one samples of urban dust were collected from Estarreja city (Portugal). The main objective of this work was to assess the potential availability of Pb and Zn present dust samples from Estarreja city via the oral ingestion exposure route using a combination of geochemical tests: (a) using sequential extraction to identify the fractionation of the Pb and Zn within the geochemical components that make up the dust and (b) in vitro bioaccessibility (BA) measurements to identify which components are the source(s) of the bioaccessible fraction (Bf). These samples were analysed for their quasi-total contents of Pb and Zn by inductively coupled plasma mass spectrometry, for their element solid-phase distribution using selective sequential extraction method and for the Bfs of these elements using a physiologically based extraction test. The study showed that the concentrations of Zn were higher than Pb, but both are site-specific. The sequential extraction test shows that the exchangeable and acid-soluble phases are important bearing phases for Pb and Zn. The BA test showed that a high proportion of the total concentration is available for absorption into the human body (ranges from 22.5 to 84.1% for Pb and 28.7 to 86.3% for Zn). PMID- 25027474 TI - Convergent evolution of IL-6 in two leporids (Oryctolagus and Pentalagus) originated an extended protein. AB - Interleukin 6 (IL-6) is a class-I helical cytokine with a broad spectrum of biological activities and a gene structure conserved throughout vertebrates, with five coding exons. IL-6 from European rabbits belonging to the subspecies Oryctolagus cuniculus cuniculus was previously shown to differ from other mammals by extending an additional 27 amino acids. However, in other leporids (Sylvilagus spp and Lepus spp) that diverged from the European rabbit ~12 million years ago this mutation was not present. In this study, we extended the study of IL-6 for the Oryctolagus cuniculus algirus subspecies and five additional lagomorphs' genera (Brachylagus, Bunolagus, Pentalagus, Romerolagus, and Ochotona). We confirmed the presence of the mutated stop codon in both O. c. cuniculus and O. c. algirus. We found that the typical stop codon is present in Sylvilagus bachmani and Lepus europaeus, in agreement with previous reports, but also in Bunolagus, Brachylagus, and Ochotona. Remarkably, in Pentalagus we detected a deletion of the stop codon causing an extension of IL-6 for 17 extra residues. Our results indicate that the IL-6 extension in those species occurred by two independent events: one occurred between 2 and 8 million years ago in the ancestral of the Oryctolagus subspecies, and the other occurred in a Pentalagus ancestral at a maximum of 9 million years ago. The absence of this IL-6 extension in Bunolagus, sister genus of Oryctolagus, shows that this evolutionary event happened by convergence suggesting some functional relevance. PMID- 25027475 TI - Use of phage display technique in treatment of HNSCC. PMID- 25027477 TI - Tin-decorated ruthenium nanoparticles: a way to tune selectivity in hydrogenation reaction. AB - Two series of ruthenium nanoparticles stabilized either by a polymer (polyvinylpyrrolidone; Ru/PVP) or a ligand (bisdiphenylphosphinobutane; Ru/dppb) were reacted with tributyltin hydride [(n-C4H9)3SnH] leading to tin-decorated ruthenium nanoparticles, Ru/PVP/Sn and Ru/dppb/Sn. The Sn/Ru molar ratio was varied in order to study the influence of the surface tin content on the properties of these new nanoparticles, by comparison with Ru/PVP and Ru/dppb. Besides HRTEM and WAXS analyses, spectroscopic techniques (IR, NMR and Mossbauer) combined with theoretical calculations and a simple catalytic test (styrene hydrogenation) allowed us to evidence the formation of MU(3)-bridging "SnR" groups on the ruthenium surface as well as to rationalize their influence on surface chemistry and catalytic activity. PMID- 25027476 TI - Transcriptome analysis of Acidovorax avenae subsp. avenae cultivated in vivo and co-culture with Burkholderia seminalis. AB - Response of bacterial pathogen to environmental bacteria and its host is critical for understanding of microbial adaption and pathogenesis. Here, we used RNA-Seq to comprehensively and quantitatively assess the transcriptional response of Acidovorax avenae subsp. avenae strain RS-1 cultivated in vitro, in vivo and in co-culture with rice rhizobacterium Burkholderia seminalis R456. Results revealed a slight response to other bacteria, but a strong response to host. In particular, a large number of virulence associated genes encoding Type I to VI secretion systems, 118 putative non-coding RNAs, and 7 genomic islands (GIs) were differentially expressed in vivo based on comparative genomic and transcriptomic analyses. Furthermore, the loss of virulence for knockout mutants of 11 differentially expressed T6SS genes emphasized the importance of these genes in bacterial pathogenicity. In addition, the reliability of expression data obtained by RNA-Seq was supported by quantitative real-time PCR of the 25 selected T6SS genes. Overall, this study highlighted the role of differentially expressed genes in elucidating bacterial pathogenesis based on combined analysis of RNA-Seq data and knockout of T6SS genes. PMID- 25027478 TI - Predicting clinical outcome using brain activation associated with set-shifting and central coherence skills in Anorexia Nervosa. AB - BACKGROUND: Patients with Anorexia Nervosa (AN) have neuropsychological deficits in Set-Shifting (SS) and central coherence (CC) consistent with an inflexible thinking style and overly detailed processing style, respectively. This study investigates brain activation during SS and CC tasks in patients with AN and tests whether this activation is a biomarker that predicts response to treatment. METHODS: FMRI data were collected from 21 females with AN while performing an SS task (the Wisconsin Card Sort) and a CC task (embedded figures), and used to predict outcome following 16 weeks of treatment (either 16 weeks of cognitive behavioral therapy or 8 weeks cognitive remediation therapy followed by 8 weeks of cognitive behavioral therapy). RESULTS: Significant activation during the SS task included bilateral dorsolateral and ventrolateral prefrontal cortex and left anterior middle frontal gyrus. Higher scores on the neuropsychological test of SS (measured outside the scanner at baseline) were correlated with greater DLPFC and VLPFC/insula activation. Improvements in SS following treatment were significantly predicted by a combination of low VLPFC/insula and high anterior middle frontal activation (R squared = .68, p = .001). For the CC task, visual and parietal cortical areas were activated, but were not significantly correlated with neuropsychological measures of CC and did not predict outcome. CONCLUSION: Cognitive flexibility requires the support of several prefrontal cortex resources. As previous studies suggest that the VLPFC is important for selecting context-appropriate responses, patients who have difficulties with this skill may benefit the most from cognitive therapy with or without cognitive remediation therapy. The ability to sustain inhibition of an unwanted response, subserved by the anterior middle frontal gyrus, is a cognitive feature that predicts favorable outcome to cognitive treatment. CC deficits may not be an effective predictor of clinical outcome. PMID- 25027479 TI - Tailored exercise program reduces symptoms of upper limb work-related musculoskeletal disorders in a group of metalworkers: A randomized controlled trial. AB - Work-related musculoskeletal disorders (WRMDs) are a leading cause of work related disability and loss of productivity in the developed countries; these disorders may concur with the indirect costs of an illness or injury included losses of potential output. Literature on workplace physical activity program provided a mixed but positive impact on health and important worksite outcomes. Therefore, programs of physical activity organized and performed in the workplace could reveal as essential tool to reduce musculoskeletal symptoms. This investigation aimed to assess the effectiveness of a tailored physical activity program, performed in a work-environment, to reduce the symptoms in upper extremities and neck with the novelty in personalizing the approach applied to the exercise protocol, basing on pain and disability levels, to reduce the onset and symptoms in upper extremity and neck WRMDs increasing upper-limb strength and flexibility. 68 metalworkers were recruited, 34 were randomly allocated to an intervention group (IG), while the other 34 to a control group. Primary outcomes concerned pain symptoms measured with visual analog scales while disability was measured by DASH (Disability of the Arm, Shoulder and Hand), and NPDS-I (Neck Pain and Disability Scale) questionnaires. Grip strength, upper-limb mobility, neck and shoulder range of motion were also assessed. After the 9-month intervention, IG reduced pain symptoms on neck, shoulders, elbows and on wrists. Grip strength and upper-limb mobility improved as well as scores on questionnaires. This protocol suggests that performing a tailored physical activity program is beneficial to reduce pain and disability on upper-limb WRMDs. PMID- 25027480 TI - The TESS reverse shoulder arthroplasty without a stem in the treatment of cuff deficient shoulder conditions: clinical and radiographic results. AB - BACKGROUND: Reverse total shoulder arthroplasty (RSA) is a recent concept that enables good functional outcomes in cases of massive rotator cuff tear and cuff tear arthropathy. Design parameters influence the functional results and complications. The purpose of this study is to present the results of a novel RSA, the Total Evolutive Shoulder System (TESS; Biomet, Warsaw, IN, USA), based on a reverse corolla without a stem. METHODS: We enrolled 101 patients with 105 RSAs in a prospective study, with a minimum follow-up period of 24 months. The analysis concerned 91 RSAs in 87 patients (61 men and 26 women), with a mean age of 73 years, at a mean follow-up of 41 months (range, 24-69 months). RESULTS: Ninety-six percent of patients rated their satisfaction as good or excellent. Mean flexion was 143 degrees (range, 90 degrees -170 degrees ), and mean external rotation was 39 degrees (range, 20 degrees -70 degrees ). The Constant score improved from 40 points preoperatively to 68 points at last follow-up (P < .001). The mean American Shoulder and Elbow Surgeons score was 24 points. The mean neck-shaft angle was 154 degrees (range, 142 degrees -165 degrees ). Inferior scapular notching occurred in 17 cases (19%). The notching rate was higher when the glenometaphyseal angle increased (P < .001), when the inferior tilt decreased (P = .003), and when the neck-shaft angle increased. There was no evidence of component loosening. CONCLUSION: TESS RSA provided encouraging midterm results with favorable outcomes and a low rate of complications. The stemless TESS with a reverse corolla is a reliable, less invasive system. PMID- 25027481 TI - Stemless shoulder arthroplasty: current status. AB - BACKGROUND: Since the original Neer humeral replacement in the 1950s, the standard primary anatomic total shoulder arthroplasty design has slowly evolved. Most recently, the humeral stem has become progressively shorter to help combat stem-related complications. Currently, there are several companies who have developed and marketed a stemless humeral arthroplasty component. MATERIALS AND METHODS: Manufacturers' data for 5 stemless shoulder arthroplasty components currently on the market were analyzed and reviewed. A literature review of short term results for stemless shoulder arthroplasty was completed. RESULTS: Of the stemless shoulder arthroplasty systems available on the market, 3 are currently undergoing clinical trials in the United States. The Tornier Simpliciti (Tornier, Edina, MN, USA) clinical trial began in 2011. The study with 2-year minimum follow-up results is scheduled for completion in November 2014. The Arthrex Eclipse (Arthrex, Naples, FL, USA) clinical trial was started in January 2013. The tentative study completion date is 2017. The Biomet Nano (Biomet, Warsaw, IN, USA) clinical trial began in October 2013 and also has a tentative completion date of 2017. No other clinical trial is currently under way in the United States. Early results for stemless shoulder arthroplasty indicate clinical results similar to standard stemmed shoulder arthroplasty. Radiographic analysis indicates implant stability without migration or subsidence at 2- to 3-year minimum follow-up.. CONCLUSIONS: Several stemless shoulder arthroplasty implants are available outside the United States. Early clinical and radiographic results are promising, but well-designed clinical studies and midterm results are lacking. Three clinical trials are currently under way in the United States with initial availability for use anticipated in 2015. PMID- 25027482 TI - Ocular gene transfer in the spotlight: implications of newspaper content for clinical communications. AB - BACKGROUND: Ocular gene transfer clinical trials are raising hopes for blindness treatments and attracting media attention. News media provide an accessible health information source for patients and the public, but are often criticized for overemphasizing benefits and underplaying risks of novel biomedical interventions. Overly optimistic portrayals of unproven interventions may influence public and patient expectations; the latter may cause patients to downplay risks and over-emphasize benefits, with implications for informed consent for clinical trials. We analyze the news media communications landscape about ocular gene transfer and make recommendations for improving communications between clinicians and potential trial participants in light of media coverage. METHODS: We analyzed leading newspaper articles about ocular gene transfer (1990 2012) from United States (n = 55), Canada (n = 26), and United Kingdom (n = 77) from Factiva and Canadian Newsstand databases using pre-defined coding categories. We evaluated the content of newspaper articles about ocular gene transfer for hereditary retinopathies, exploring representations of framing techniques, research design, risks/benefits, and translational timelines. RESULTS: The dominant frame in 61% of stories was a celebration of progress, followed by human-interest in 30% of stories. Missing from the positive frames were explanations of research design; articles conflated clinical research with treatment. Conflicts-of-interest and funding sources were similarly omitted. Attention was directed to the benefits of gene transfer, while risks were only reported in 43% of articles. A range of visual outcomes was described from slowing vision loss to cure, but the latter was the most frequently represented even though it is clinically infeasible. Despite the prominence of visual benefit portrayals, 87% of the articles failed to provide timelines for the commencement of clinical trials or for clinical implementation. CONCLUSIONS: Our analysis confirms that despite many initiatives to improve media communications about experimental biotechnologies, media coverage remains overly optimistic and omits important information. In light of these findings, our recommendations focus on the need for clinicians account for media coverage in their communications with patients, especially in the context of clinical trial enrolment. The development of evidence-based communication strategies will facilitate informed consent and promote the ethical translation of this biotechnology. PMID- 25027483 TI - Heart donation after circulatory determination of death: ethically acceptable? PMID- 25027484 TI - Venous thromboembolism. 30-year risk of death after VTE. PMID- 25027485 TI - Rehabilitation. Smartphone-based cardiac rehabilitation--a first RCT. PMID- 25027486 TI - Acute coronary syndromes. Quality of care for STEMI in China. PMID- 25027487 TI - Global availability of cardiac rehabilitation. AB - Cardiovascular disease (CVD) is the most-prevalent noncommunicable disease and leading cause of death globally. Over 80% of deaths from CVD occur in low-income and middle-income countries (LMICs). To limit the socioeconomic impact of CVD, a comprehensive approach to health care is needed. Cardiac rehabilitation delivers a cost-effective and structured exercise, education, and risk reduction programme, which can reduce mortality by up to 25% in addition to improving a patient's functional capacity and lowering rehospitalization rates. Despite these benefits and recommendations in clinical practice guidelines, cardiac rehabilitation programmes are grossly under-used compared with revascularization or medical therapy for patients with CVD. Worldwide, only 38.8% of countries have cardiac rehabilitation programmes. Specifically, 68.0% of high-income and 23% of LMICs (8.3% for low-income and 28.2% for middle-income countries) offer cardiac rehabilitation programmes to patients with CVD. Cardiac rehabilitation density estimates range from one programme per 0.1 to 6.4 million inhabitants. Multilevel strategies to augment cardiac rehabilitation capacity and availability at national and international levels, such as supportive public health policies, systematic referral strategies, and alternative models of delivery are needed. PMID- 25027489 TI - Immune enhancement activities of silk lutein extract from Bombyx mori cocoons. AB - BACKGROUND: Declining immune function poses an important clinical challenge worldwide and supplementation with natural products that possessing immune enhancing properties is a promising approach for preventing or delaying immune function decline. Cocoons from yellow silkworms are a significant source of lutein, and this unexplored silk extract could be a viable alternative source for dietary lutein. This study assessed immunomodulatory activities of the silk lutein extract. Female BALB/c mice orally received lutein, either as silk or marigold extracts (10 or 20 mg/kg daily), or vehicle only (1% tween 80 in PBS pH 7.4) for 4 weeks. Natural killer (NK) cell activity, specific antibody production, lymphocyte subpopulations, mitogen-induced lymphocyte proliferation, and cytokine production were examined. RESULTS: Silk lutein extract increased NK cell activity, and the effect was dose-related whereas marigold lutein extract was ineffective. Silk lutein extract dose-dependently enhanced antibody production in pre-immunized mice but marigold lutein extract had no effect. Feeding with silk lutein extract increased the populations of CD3+ and CD4 + CD3 + cells. Silk lutein extract also stimulated concanavalin A- and lipopolysaccharide-induced proliferations of T and B lymphocytes, respectively. Moreover, silk lutein extract increased IL-2 and IFN-gamma production while the effect of marigold lutein extract was undetectable. CONCLUSIONS: Together, silk lutein extract enhanced both innate and adaptive immune functions. This preparation may prove to be an effective supplement for strengthened immunity. PMID- 25027490 TI - Study links vasectomy to small raised risk of aggressive prostate cancer. PMID- 25027491 TI - The clinical development program of lixisenatide: a once-daily glucagon-like Peptide-1 receptor agonist. AB - Lixisenatide (AVE0010) is a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes. Phase II dose-finding and pharmacodynamic studies identified the 20 ug once-daily dose as having the optimum combination of efficacy, convenience and tolerability. Lixisenatide was prospectively investigated in a series of 11 multinational, randomised, controlled phase III trials (GLP-1 agonist AVE0010 in paTients with type 2 diabetes mellitus for Glycemic cOntrol and sAfety evaLuation [GetGoal] programme) that included a direct head-to-head study with exenatide. The GetGoal programme established the efficacy and safety profile of lixisenatide 20 ug once daily across the spectrum of patients with type 2 diabetes, including patients not treated with anti-diabetic agents, those failing on oral agents and as an adjunct to basal insulin therapy. The main efficacy endpoints were met in all studies, with the baseline to endpoint reductions in HbA1c consistently ranging from 0.7% to 1.0%. In a head-to-head comparison with exenatide 10 MUg twice daily, lixisenatide 20 MUg once daily was non-inferior for HbA1c reduction, achieved with threefold fewer patients with symptomatic hypoglycemia events and better gastrointestinal tolerability. Three randomised trials of lixisenatide treatment added to basal insulin showed significantly improved glycemic control over placebo, with pronounced postprandial glucose reductions and good tolerability. Discontinuations for adverse events were consistently low, ranging from 2.5% to 10.4%. As the provision of individualized care moves center stage in diabetes management, lixisenatide with once-daily dosing, a single maintenance dose and fixed-dose pens offers an important treatment option for type 2 diabetes. PMID- 25027488 TI - The role of heat shock proteins in atherosclerosis. AB - Atherosclerosis is a chronic, multifactorial disease that starts in youth, manifests clinically later in life, and can lead to myocardial infarction, stroke, claudication, and death. Although inflammatory processes have long been known to be involved in atherogenesis, interest in this subject has grown in the past 30-40 years. Animal experiments and human analyses of early atherosclerotic lesions have shown that the first pathogenic event in atherogenesis is the intimal infiltration of T cells at arterial branching points. These T cells recognize heat shock protein (HSP)60, which is expressed together with adhesion molecules by endothelial cells in response to classic risk factors for atherosclerosis. Although these HSP60-reactive T cells initiate atherosclerosis, antibodies to HSP60 accelerate and perpetuate the disease. All healthy humans develop cellular and humoral immunity against microbial HSP60 by infection or vaccination. Given that prokaryotic (bacterial) and eukaryotic (for instance, human) HSP60 display substantial sequence homology, atherosclerosis might be the price we pay for this protective immunity, if risk factors stress the vascular endothelial cells beyond physiological conditions. PMID- 25027492 TI - Fear of e-Health records implementation? AB - As our world is dominated by Information Communication and Technologies (ICT), governments of many leading countries have decided to implement ICT in their health systems. The first step is the digitalisation of medical records (e-Health Records or EHRs). In order to reduce concerns that health systems encountered, EHRs are supposed to prevent duplicated prescriptions and hospitalisations, ineffective transferability of medical records, lack of communication in clinical assessments, etc. They are also expected to improve the relationship between health providers and patients. At first sight, EHR seems to offer considerable potential for assisting health policies, enabling the development of new tools to facilitate coordination and cooperation among health professionals and promoting a new approach to sharing medical information. However, as discussed in this article, recent debates have shown that EHR presents pros and cons (technical, financial, social) that governments need to clarify urgently. PMID- 25027493 TI - Auricular acupuncture for primary care treatment of low back pain and posterior pelvic pain in pregnancy: study protocol for a multicentre randomised placebo controlled trial. AB - BACKGROUND: About 45% of all pregnant women suffer low back pain and/or pelvic girdle pain (LBPGP). This study seeks to evaluate the effect of auricular acupuncture on LBPGP compared with placebo auricular acupuncture and with standard obstetric care in the field of primary health care. METHODS AND DESIGN: This study will be a four-parallel-arm, multicentre, randomised, placebo controlled trial. A total of 212 pregnant women (24 to 36 weeks' gestation), aged at least 17 years, with LBPGP, will be randomly assigned to the verum auricular acupuncture plus standard obstetric care group (VAAc), to the non-specific auricular acupuncture plus standard obstetric care group (NSAAc), to the non specific placebo auricular acupuncture plus standard obstetric care group (PAAc), or the standard obstetric care group (SOC). The VAAc, NSAAc, and PAAc groups will receive treatment at three auricular acupuncture points (specific points for the VAAc group or non-specific ones for the NSAAc and PAAc groups), once a week for 2 weeks; the SOC group will receive only standard obstetric care during the same period. The primary outcome will be the reduction in pain intensity, according to the visual analogue scale (iVAS), at 2 weeks after the start of treatment. The secondary outcomes will be functional status with respect to LBPGP (according to the Roland-Morris disability questionnaire), health-related quality of life (SF12) at 2 weeks after the start of treatment, and iVAS at 12 and 48 weeks postpartum. DISCUSSION: This trial will implement a high-quality methodology and may provide evidence for the efficacy, safety, and specificity of auricular acupuncture as a treatment for pregnant women with LBPGP. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41033073 (date 20/03/2014). PMID- 25027494 TI - Somatic cell mutations caused by 365 nm LED-UVA due to DNA double-strand breaks through oxidative damage. AB - Evidence is accumulating indicating that UVA (320-400 nm ultraviolet light) plays an important role in photo-carcinogenesis. UVA is thought to produce reactive oxygen species in irradiated cells through photo-activation of inherent photosensitizers, and was recently reported to cause DNA double-strand breaks (DSBs) in exposed cells. We have investigated the involvement of UVA in mutations and DNA damage in somatic cells using Drosophila melanogaster larvae. Using the Okazaki Large Spectrograph, we previously observed that longer wavelength UVA (>330 nm) was more mutagenic in post-replication repair-deficient D. melanogaster (mei-41) than in the nucleotide excision repair-deficient strain (mei-9). LED light has recently been developed as a high-dose-rate UVA source. LED-UVA light (365 nm) was also more mutagenic in mei-41 than in mei-9. The mei-41 gene was shown to be an orthologue of the human ATR gene, which is involved in the repair of DSBs through phosphorylation of histone H2AX. In order to estimate the extent to which oxidative damage contributes to mutation, we established a new D. melanogaster strain (urate-null mutant) that is sensitive to oxidative damage and has a marker to detect somatic cell mutations. When somatic cell mutations were examined using this strain, LED-UVA was mutagenic in the urate-null strain at doses that were non-mutagenic in the urate-positive strain. In an effort to investigate the generation of DSBs, we examined the presence of phosphorylated histone H2AvD (H2AX D. melanogaster homologue). At high doses of LED-UVA (>800 kJ m(-2)), levels of phosphorylated H2AvD (gamma-H2AvD) increased significantly in the urate-null strain. Moreover, the level of gamma-H2AvD increased in the excision repair-deficient strain but not in the ATR-deficient strain following UVA-irradiation. These results supported the notion that the generation of gamma H2AvD was mediated by the function of the mei-41 gene. It was reported that ATR functions on DSB repair in D. melanogaster. Taken together, we propose a possible pathway for UVA-induced mutation, whereby DNA double-strand breaks resulting from oxidative stress might be responsible for UVA-induced mutation in somatic cells of D. melanogaster larvae. PMID- 25027495 TI - A multiresidue screen for the analysis of toxicants in bovine rumen contents. AB - Analysis of rumen contents is helpful in solving poisoning cases when ingestion of a toxic substance by cattle or other ruminant animals is suspected. The most common technique employs extraction of the sample with organic solvent followed by clean-up method(s) before analysis with gas chromatography-mass spectrometry equipped with a library of mass spectra to help identify unknowns. A rapid method using magnesium sulfate, primary secondary amine, and C18 sorbents following principles of QuEChERS to clean up rumen contents samples is reported herein. The method was validated to analyze fortified bovine rumen contents to detect commonly found organophosphorus pesticides, carbamates, and several other compounds such as atropine, 4-aminopyridine, caffeine, scopolamine, 3-chloro-4 methylaniline, strychnine, metaldehyde, and metronidazole. For each compound, the ratio of 2 ions from the mass spectrum was monitored in fortified rumen contents. The ion ratio of fortified sample was compared with the ion ratio of standard sample spectrum and was found to be within 20%, with the exception of aldicarb and 4-aminopyridine with ion ratio of 26% and 29%, respectively. Usefulness of the method was demonstrated by not only analyzing bovine rumen contents but also canine and avian gastrointestinal contents submitted for organic chemical screening. PMID- 25027497 TI - Use of an automated system for detection of canine serum antibodies against Ehrlichia canis glycoprotein 36. AB - Ehrlichia canis is the most common cause of monocytotropic ehrlichiosis in dogs around the world. The purpose of the present study was to validate a new automated fluorescence system (Accuplex4TM BioCD system; Antech Diagnostics, Lake Success, New York) to detect antibodies against the E. canis immunodominant glycoprotein 36 (gp36). Sera and blood samples (ethylenediamine tetra-acetic acid) were collected from mixed sex beagles ( n = 8) on days 0, 3, 7, 10, 14, 17, 21, 28, 42, 49, 56, 63, 70, 77, 84, and 98 after intravenous inoculation with culture-derived E. canis. Sera were assayed using the Accuplex4 BioCD system (Accuplex4), an E. canis indirect fluorescent antibody test (IFAT), and a commercially available kit. A complete blood cell count and a proprietary E. canis polymerase chain reaction (PCR) were performed on each blood sample. On the day thrombocytopenia was first detected for each dog, E. canis DNA was amplified from blood of all dogs. At those times, E. canis antibodies were detected in 7 of 8 dogs by the Accuplex4, 1 of 8 dogs by the commercial kit, and 4 of 8 dogs by IFAT. Ehrlichia canis DNA was amplified from blood before seroconversion in any antibody assay for 6 dogs. Antibodies against gp36 were detected by Accuplex4 within 3 days of PCR-positive test results and were detected up to 25 days sooner than the commercial kit. After starting doxycycline treatment, E. canis DNA was no longer amplified by PCR assay, but serum antibodies remained detectable by all assays. PMID- 25027496 TI - Molecular, biological, and antigenic characterization of a Border disease virus isolated from a pig during classical swine fever surveillance in Japan. AB - In the current study, molecular, biological, and antigenic analyses were performed to characterize Border disease virus (BDV) strain FNK2012-1 isolated from a pig in 2012 in Japan. The complete genome comprises 12,327 nucleotides (nt), including a large open reading frame of 11,685 nt. Phylogenetic analysis revealed that FNK2012-1 was clustered into BDV genotype 1 with ovine strains. FNK2012-1 grew in porcine, bovine, and ovine primary cells and cell lines, but grew better in bovine and ovine cells than in porcine cells. Specific pathogen free pigs inoculated with FNK2012-1 did not show any clinical signs. Noninoculated contact control pigs also did not show clinical signs and did not seroconvert. The results suggest that FNK2012-1 may be of ruminant origin and is poorly adapted to pigs. Such observations can provide important insights into evidence for infection and transmission of BDV, which may be of ruminant origin, among pigs. PMID- 25027498 TI - New pancreatic adenocarcinoma in a Crohn's patient treated with tumor necrosis factor (TNF) inhibitors for 6 months. PMID- 25027499 TI - Legionella control in the water system of antiquated hospital buildings by shock and continuous hyperchlorination: 5 years experience. AB - BACKGROUND: To control the presence of Legionella in an old hospital water system, an integrated strategy of water disinfection-filtration was implemented in the university hospital Umberto I in Rome. METHODS: Due to antiquated buildings, hospital water system design and hospital extension (38 buildings), shock hyperchlorination (sodium hypochlorite, 20-50 ppm of free chlorine at distal points for 1-2 h) followed by continuous hyperchlorination (0.5-1.0 mg/L at distal points) were adopted, and microbiological and chemical monitoring of the water supply was carried out in the university hospital (December 2006 December 2011). RESULTS: Overall, 1308 samples of cold <20 degrees C (44.5%), mixed >=20 degrees C <= 45 degrees C (37.7%) and hot >45 degrees C (17.8%) water were collected, determining residual free chlorine (0.43 +/- 0.44 mg/L), pH (7.43 +/- 0.29) and trihalomethanes (8.97 +/- 18.56 MUg/L). Legionella was isolated in 102 (9.8%) out of 1.041 water samples without filters (L. pneumophila sg 1 17.6%, L. pneumophila sg 2-14 28.4%, L. non pneumophila 53.9%), and in none of the 267 samples with filters. Legionella was recovered in 23 buildings out of 38 and 29 samples (28.4%) exceeded 103 cfu/L. When considering the disinfection treatment Legionella was isolated: before shock hyperchlorination (21.1%), 15 days after shock hyperchlorination (7.8%), 30 days after shock hyperchlorination (3.5%), during continuous hyperchlorination (5.5%) and without continuous hyperchlorination (27.3%). Continuous hyperchlorination following the shock treatment achieved >70% reduction of positive samples, whereas no continuous hyperchlorination after shock treatment was more frequently associated to Legionella isolation (OR 6.41; 95% CI 3.10-13.26; p <0.001). Independent risk factors for Legionella isolation were: residual free chlorine <0.5 mg/L (OR 13.0; 95% CI 1.37 - 123.2; p <0.03), water T degrees >=20 degrees C <= 45 degrees C (OR 12.0; 95% CI 1.28 - 111.48; p <0.03) and no continuous hyperchlorination after shock treatment (OR 10.3; 95% CI 1.06 - 100.05; p <0.05). CONCLUSIONS: Shock and continuous hyperchlorination achieved significant Legionella reduction, but effective chlorine levels (>0.5 < 1.0 mg/L) deteriorated water quality (organoleptic and chemical). However, shock and continuous hyperchlorination remains a valid-term option in old buildings with no water system rational design, managing problems due to hospital extension and absence of a proper hot water recirculation system. PMID- 25027501 TI - Reply: occipital bending in depression. PMID- 25027502 TI - Occipital bending in depression. PMID- 25027503 TI - Impact of brain tumour location on emotion and personality: a voxel-based lesion symptom mapping study on mentalization processes. AB - Patients affected by brain tumours may show behavioural and emotional regulation deficits, sometimes showing flattened affect and sometimes experiencing a true 'change' in personality. However, little evidence is available to the surgeon as to what changes are likely to occur with damage at specific sites, as previous studies have either relied on single cases or provided only limited anatomical specificity, mostly reporting associations rather than dissociations of symptoms. We investigated these aspects in patients undergoing surgery for the removal of cerebral tumours. We argued that many of the problems described can be ascribed to the onset of difficulties in one or more of the different levels of the process of mentalizing (i.e. abstracting and reflecting upon) emotion and intentions, which impacts on everyday behaviour. These were investigated in terms of (i) emotion recognition; (ii) Theory of Mind; (iii) alexithymia; and (iv) self maturity (personality disorder). We hypothesized that temporo/limbic areas would be critical for processing emotion and intentions at a more perceptual level, while frontal lobe structures would be more critical when higher levels of mentalization/abstraction are required. We administered four different tasks, Task 1: emotion recognition of Ekman faces; Task 2: the Eyes Test (Theory of Mind); Task 3: Toronto Alexithymia Scale; and Task 4: Temperament and Character Inventory (a personality inventory), both immediately before and few days after the operation for the removal of brain tumours in a series of 71 patients (age range: 18-75 years; 33 female) with lesions located in the left or right frontal, temporal and parietal lobes. Lobe-based and voxel-based analysis confirmed that tasks requiring interpretation of emotions and intentions at more basic (less mentalized) levels (Tasks 1 and 2) were more affected by temporo/insular lesions, with emotion recognition (Task 1) being maximally impaired by anterior temporal and amygdala lesions and Task 2 (found to be a 'basic' Theory of Mind task involving only limited mentalization) being mostly impaired by posterior temporoparietal lesions. Tasks relying on higher-level mentalization (Tasks 3 and 4) were maximally affected by prefrontal lesions, with the alexithymia scale (Task 3) being mostly associated with anterior/medial lesions and the self maturity measure (Task 4) with lateral prefrontal ones. PMID- 25027504 TI - The forest for the trees. Comment on "Toward a computational framework for cognitive biology: unifying approaches from cognitive neuroscience and comparative cognition" by W.T. Fitch. PMID- 25027500 TI - State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology. AB - Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain- are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing. PMID- 25027505 TI - Learning, epigenetics, and computation: an extension on Fitch's proposal. Comment on "Toward a computational framework for cognitive biology: unifying approaches from cognitive neuroscience and comparative cognition" by W. Tecumseh Fitch. PMID- 25027506 TI - Technical features of the INCRAFTTM AAA Stent Graft System. AB - The INCRAFT(r) AAA Stent Graft System is the advanced endovascular aneurysm repair (EVAR) technology for the treatment of infrarenal abdominal aneurysms. This new system is designed to address the unmet needs of current endografts by combining unique features and adding new refinements compared to existing endografts delivered through a flexible 14-Fr ultra-low system. The INCRAFT(r) AAA Stent Graft System introduces innovative features without deviating from proven stent-graft design principles. It is a three-piece modular system, made of low porosity polyester and segmented nitinol stents. However, the introduction of cap-free delivery and partial proximal repositioning enhances the ability of the device to better match individual aortoiliac anatomy with a high deliverability and placement accuracy in a easy to use system. Moreover, the INCRAFT(r) System allows a "customization" of the implant during the procedure with bilateral in situ length adjustment features. The present data from the ongoing clinical trials confirm excellent results with this system, but postmarket studies will be necessary to verify the effectiveness of this system in the real-world setting. PMID- 25027507 TI - Fruit and vegetable consumption of U.S. Youth, 2009-2010. AB - KEY FINDINGS: Data from the National Health and Nutrition Examination Survey, 2009-2010. More than three-quarters of youth aged 2-19 years (77.1%) consumed fruit on a given day. Almost 92% of youth aged 2-19 years consumed vegetables on a given day. Nine out of 10 children aged 2-5 years consumed fruit, while only 6 out of 10 adolescents consumed fruit on a given day. More children aged 2-5 years than adolescents consumed vegetables on a given day. The Dietary Guidelines for Americans (DGA), 2010 encourage Americans, including youth, to increase their consumption of fruits and vegetables. Individuals are encouraged to "eat a variety of vegetables, especially dark-green and red and orange vegetables." Fruits and vegetables are sources of many under-consumed nutrients and consuming fruits and vegetables is associated with a decreased risk of chronic disease (1 3). This report examines the percentage of youth aged 2-19 years who consumed fruits and vegetables on a given day in 2009-2010, using data from one 24-hour dietary recall interview. PMID- 25027508 TI - Null allele, allelic dropouts or rare sex detection in clonal organisms: simulations and application to real data sets of pathogenic microbes. AB - BACKGROUND: Pathogens and their vectors are organisms whose ecology is often only accessible through population genetics tools based on spatio-temporal variability of molecular markers. However, molecular tools may present technical difficulties due to the masking of some alleles (allelic dropouts and/or null alleles), which tends to bias the estimation of heterozygosity and thus the inferences concerning the breeding system of the organism under study. This is especially critical in clonal organisms in which deviation from panmixia, as measured by Wright's FIS, can, in principle, be used to infer both the extent of clonality and structure in a given population. In particular, null alleles and allelic dropouts are locus specific and likely produce high variance of Wright's FIS across loci, as rare sex is expected to do. In this paper we propose a tool enabling to discriminate between consequences of these technical problems and those of rare sex. METHODS: We have performed various simulations of clonal and partially clonal populations. We introduce allelic dropouts and null alleles in clonal data sets and compare the results with those that exhibit increasing rates of sexual recombination. We use the narrow relationship that links Wright's FIS to genetic diversity in purely clonal populations as assessment criterion, since this relationship disappears faster with sexual recombination than with amplification problems of certain alleles. RESULTS: We show that the relevance of our criterion for detecting poorly amplified alleles depends partly on the population structure, the level of homoplasy and/or mutation rate. However, the interpretation of data becomes difficult when the number of poorly amplified alleles is above 50%. The application of this method to reinterpret published data sets of pathogenic clonal microbes (yeast and trypanosomes) confirms its usefulness and allows refining previous estimates concerning important pathogenic agents. CONCLUSION: Our criterion of superimposing between the FIS expected under clonality and the observed FIS, is effective when amplification difficulties occur in low to moderate frequencies (20-30%). PMID- 25027509 TI - Apoptotic cells subjected to cold/warming exposure disorganize apoptotic microtubule network and undergo secondary necrosis. AB - Apoptotic microtubule network (AMN) is organized during apoptosis, forming a cortical structure beneath the plasma membrane which plays a critical role in preserving cell morphology and plasma membrane integrity. The aim of this study was to examine the effect of cold/warming exposure on apoptotic microtubules and plasma membrane integrity during the execution phase of apoptosis. We demonstrated in camptothecin-induced apoptotic H460 cells that cold/warming exposure disorganized apoptotic microtubules and allowed the access of active caspases to the cellular cortex and the cleavage of essential proteins in the preservation of plasma membrane permeability. Cleavage of cellular cortex and plasma membrane proteins, such as alpha-spectrin, paxilin, focal adhesion kinase and calcium ATPase pump (PMCA-4) involved in cell calcium extrusion resulted in increased plasma permeability and calcium overload leading apoptotic cells to secondary necrosis. The essential role of caspase-mediated cleavage in this process was demonstrated because the addition of the pan-caspase inhibitor z-VAD during cold/warming exposure that induces AMN depolymerization avoided the cleavage of cortical and plasma membrane proteins and prevented apoptotic cells to undergo secondary necrosis. Likewise, apoptotic microtubules stabilization by taxol during cold/warming exposure also prevented cellular cortex and plasma membrane protein cleavage and secondary necrosis. Furthermore, microtubules stabilization or caspase inhibition during cold/warming exposure was also critical for proper phosphatidylserine externalization and apoptotic cell clearance by macrophages. These results indicate that cold/warming exposure of apoptotic cells induces secondary necrosis which can be prevented by both, microtubule stabilization or caspase inhibition. PMID- 25027510 TI - An alternative certification examination ("ACE") in surgery. AB - BACKGROUND: Medical graduates are required to be competent in many domains of professional practice when joining the health care workforce. Current undergraduate examination methods robustly assess up to 5 of these 8 required skills. This study sought to evaluate an alternative certification examination ("ACE") in assessing all of the 8 required domains in surgical cases. METHODS: A total of 143 final-year medical students were invited to participate in an "ACE" in February 2013. In total, 137 students, 95.8% of the class, agreed to participate. The "ACE" format consisted of 4 sequential patient encounters observed by 2 independent examiners. It assessed all the 8 required domains of professional practice. The examiners and the students evaluated this examination format using a Likert scale and free-text comments. RESULTS: The "ACE" assessed all the 8 domains. The inclusion of a patient safety measure to avoid an egregious error in the pass criteria resulted in 27 (18.9%) students failing to meet them. The correlation of grades between the independent examiners in the "ACE" was strong at a Cronbach alpha of 0.907 (CI: 0.766-1). The "ACE" format was reported as an acceptable examination methodology by the examiners for formative or summative assessment of surgical cases at the end of a primary medical degree. CONCLUSION: The "ACE" format is standardized, is integrative, and has excellent interrater reliability. Inclusion of a patient safety measure as pass criteria appears to increase specificity. The "ACE" shows potential as an alternative examination to the traditional long case examination and objective structured clinical examination in assessing all the 8 domains of professional practice. PMID- 25027511 TI - "Same as it ever was"--only different: a successful ACGME innovative project to equip PGY I residents to take at-home call. AB - OBJECTIVE: Establish a competency-based system for advancement of postgraduate year (PGY) I residents to take at-home call, with indirect and direct supervision available. DESIGN: Application of an innovative project approved by the ACGME to equip PGY I residents to take at-home call was successful. Formal education of PGY I residents with a variety of modalities included the successful completion of the Fundamentals of Surgery Curriculum and a structured 12-week curriculum, which focused on medical knowledge, patient care, systems-based practice, and skills lab scenarios. Residents were responsible for inpatient care during the day with direct supervision. Patient care logs (PCLs) were maintained by the resident for patient encounters. The PGY I residents were evaluated with faculty and senior resident review of the PCLs, a written examination, nurse mock pages, and oral proficiency examinations. The decision to permit the resident to take at home call was determined by the Clinical Competency Committee (CCC). SETTING: Independent academic medical center with 3 categorical surgical residents per year. PARTICIPANTS: Categorical PGY I surgery residents from 2013 to 2014. RESULTS: Residents completed the structured program and successfully passed the oral and written examinations. The CCC determined that the residents were able to take at-home call starting in October of the PGY I year. The number and type of patients were monitored with specified limitations and ongoing maintenance and review of PCLs. A formal backup system, with senior resident and faculty availability by phone or physical presence, was used. CONCLUSION: We present an Accreditation Council for Graduate Medical Education-approved innovative project, which appears to have been successful in implementing at-home call for PGY I residents. This enables the progressive development of PGY I residents and assists our CCC in the development of competency-based milestones for advancement. The effect of this project is significant for those residency programs where incorporation of at-home call is possible. PMID- 25027512 TI - Inspiring tomorrow's surgeons: the benefits of student surgical society membership?? AB - OBJECTIVES: To assess the perceived value of medical school student surgical society membership and its effect on determining future career aspirations. DESIGN: Cross-sectional survey. SETTING: Three UK medical school student surgical societies. PARTICIPANTS: Undergraduate and postgraduate students. RESULTS: Of 119 students, 60 (50.4%) completed the survey. Of the respondents, 62.3% indicated that the surgical society had increased their awareness and knowledge about the different surgical specialties. Of the respondents who had decided on a career in surgery before joining the society, 67.6% stated that participating in society events had better prepared them for the career. Plastic surgery (13.3%), general surgery (11.7%), and neurosurgery (11.7%) were the 3 most popular specialties for future careers. Surgical skills workshops (21.9%), conferences (21.1%), and careers talks (16.4%) were chosen by students as the most useful career-guiding events organized by surgical societies. CONCLUSION: Participation in medical school surgical societies is perceived as a valuable part of undergraduate and postgraduate medical education in aiding students to decide on future careers. PMID- 25027513 TI - A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias. AB - The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10 mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES containing CALM-AF10 transcription factor. PMID- 25027514 TI - A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis. AB - Despite improvements in therapy amyloid light-chain (AL) amyloidosis, there are few studies comparing different regimens. Here we present a matched comparison with 69 patients in each cohort examining upfront therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) vs cyclophosphamide, thalidomide and dexamethasone (CTD). On an intention-to-treat basis, the overall response rates were 71.0% vs 79.7% in the CVD and CTD arms, respectively, (P=0.32). A higher complete response (CR) rate was observed in the CVD arm (40.5%) vs CTD (24.6%), P=0.046. One-year overall survival (OS) was 65.2% and 66.7% for CVD and CTD, respectively (P=0.87). The median progression-free survival (PFS) was 28.0 and 14.0 m for CVD and CTD, respectively (P=0.039). In a landmark analysis assessing outcomes performed at 6 months, the CR rate with CVD was 59.6% vs 34.0% for CTD (P=0.03). The 1-year OS was 96% with CVD and 92% with CTD (P=0.40). The median PFS with CVD was not reached and was 19.2 m with CTD, P=0.028). In summary, both regimens are unable to overcome the high rate of early deaths in AL amyloidosis. However, CVD correlates with improved depth of response and superior PFS supporting its use in the frontline setting. Further optimisation and better supportive-care strategies are required to increase the proportion of patients fully benefiting from therapy. PMID- 25027515 TI - Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. AB - Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses. PMID- 25027516 TI - Does ruxolitinib improve survival of persons with MPN-associated myelofibrosis? Should it? PMID- 25027517 TI - Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. AB - Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials. This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer. Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML. Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy. Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic. PMID- 25027518 TI - Genomic and epigenomic co-evolution in follicular lymphomas. AB - Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma, we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstructed phylogenetic trees of the evolution by taking advantage of the activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array-based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co evolution in FL. PMID- 25027519 TI - Renal function-adjusted contrast volume redefines the baseline estimation of contrast-induced acute kidney injury risk in patients undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Age, estimated glomerular renal function (eGFR), and ejection fraction are preprocedural predictors of contrast-induced acute kidney injury (CI AKI) after primary percutaneous coronary intervention. The effect of renal function-adjusted contrast volume (CV) remains not totally explored, and a threshold has not yet been established. METHODS AND RESULTS: Logistic regression and receiver-operating characteristic curve analyses were used to assess whether CV/eGFR was an independent predictor of CI-AKI. The increased discriminative value of CV/eGFR over the preprocedural model based on age, eGFR, and ejection fraction was examined using the net reclassification improvement analysis. Of 470 patients enrolled, we observed 25 (5.3%) cases of CI-AKI. Patients with CI-AKI had received a higher renal function-adjusted CV (CV/eGFR 3.62 versus 1.96; P<0.001), and CI-AKI incidence was higher (15%; P<0.001) in patients in the highest quartile of CV/eGFR, corresponding to the cutoff indicated by the receiver-operating characteristic curve (>2.5; area under the curve, 0.77). At multivariable analysis, CV/eGFR above the cutoff (odds ratio, 5.57; P=0.002) remained an independent predictor of CI-AKI. The model with CV/eGFR demonstrated a statistically significantly net reclassification improvement of 0.23 (P=0.021) over the baseline preprocedural model, largely driven by a correct decrease in risk estimates for patients not experiencing CI-AKI, with a likelihood ratio chi(2) of 5.973 (P=0.029). CONCLUSIONS: CV remains a key risk factor for CI-AKI after primary percutaneous coronary intervention and our study supports the need for minimizing CV, independently from baseline preprocedural risk. A CV restricted to no more than twice and a half the baseline eGFR might be valuable in reducing the risk of CI-AKI. PMID- 25027520 TI - Factors associated with vascular complications in patients undergoing balloon expandable transfemoral transcatheter aortic valve replacement via open versus percutaneous approaches. AB - BACKGROUND: Vascular complications after transfemoral transcatheter aortic valve replacement are common and associated with significant morbidity and mortality. Little is known about the effect of access approach on vascular complications. METHODS AND RESULTS: Between 2007 and 2013, 331 patients underwent transfemoral transcatheter aortic valve replacement via open surgical (OS) or fully percutaneous (PC) approaches. Patient data and clinical outcomes were collected. Valve Academic Research Consortium-defined vascular complications were noted. Multivariable analysis with propensity matching was performed, and vascular complications, mortality, and length of stay were assessed. One hundred twenty patients were treated with the OS approach and 211 patients via the PC approach. There were fewer major vascular complications (11% versus 20%; P=0.03) and shorter length of stay (7.5 versus 9.9 days; P=0.003) in the PC group when compared with those in the OS group. In multivariable analysis, vascular complications were more likely in women (odds ratio, 2.2; P=0.02) and with increasing differences between sheath outer diameter and minimal artery diameter (overall vascular complications: odds ratio, 1.4; P=0.02 and major vascular complications: odds ratio, 2.0; P<0.001). Propensity-matched analysis demonstrated no difference in vascular complications between the OS and the PC groups (22% versus 19%; P=0.73) but significantly reduced length of stay in the PC group (7.9 versus 10.0 days; P=0.04). CONCLUSIONS: Transfemoral transcatheter aortic valve replacement performed via the PC route is associated with similar risk of vascular complications and significantly lower postprocedural length of stay than the OS route. The degree of sheath oversizing with respect to iliofemoral minimal artery diameter and female sex are associated with vascular complications regardless of access approach. PMID- 25027521 TI - Role of berberine in ameliorating Schistosoma mansoni-induced hepatic injury in mice. AB - BACKGROUND: Schistosomiasis is caused by helminth parasites of the genus Schistosoma. Berberine chloride (BER), an isoquinoline alkaloid, has been used in vivo for its antiparasitic, antioxidant and hepatoprotective properties. In this study, the protective effect of BER and praziquantel has been compared for the extent of schistosomiasis-induced oxidative stress in hepatic tissue of mice. RESULTS: S. mansoni was able to induce inflammation and injury to the liver, evidenced (i) by an increase in inflammatory cellular infiltrations, dilated sinusoids and vacuolated hepatocytes, (ii) by decreased levels of alanine and aspartate aminotransferases and increased levels of alkaline phosphatase, gamma glutamyl transferase in the liver homogenate, (iii) by increased production of nitric oxide and thiobarbituric acid reactive substances, and (iv) by lowered glutathione levels and decreased activities of catalase and superoxide dismutase, respectively. All these infection-induced parameters were significantly altered during BER treatment. In particular, berberine counteracted the S. mansoni induced loss of glutathione and the activities of catalase and superoxide dismutase. CONCLUSION: Based on these results, it is concluded that berberine could ameliorate pre-existing liver damage and oxidative stress conditions due to schistosomiasis. PMID- 25027522 TI - Inhaled insulin product approved. PMID- 25027523 TI - Psychiatric provider status for pharmacist helps community treatment effort. PMID- 25027524 TI - Pharmacists improve diabetes care. PMID- 25027526 TI - White House summit tackles opioid abuse. PMID- 25027528 TI - Multiple mini-interviews for pharmacy residency candidates. PMID- 25027529 TI - Potential pitfalls of basing specific antibiotic therapy on rapid susceptibility reporting. PMID- 25027530 TI - Potential pitfalls of basing specific antibiotic therapy on rapid susceptibility reporting. PMID- 25027531 TI - Pharmacist-managed protocol to implement simvastatin labeling changes in a family medicine clinic. PMID- 25027532 TI - Perioperative management of bariatric surgery patients. AB - PURPOSE: The perioperative management of bariatric surgery patients is described. SUMMARY: Obesity and anatomical changes create unique challenges for clinicians when caring for bariatric surgery patients. Common bariatric surgery procedures performed include Roux-en-Y gastric bypass, sleeve gastrectomy, and adjustable gastric banding. Pain management in the acute postoperative period depends on careful dosing of opioid agents and the use of adjunctive agents. Prevention and management of infectious complications include appropriate surgical prophylaxis, monitoring and rapid treatment of suspected intra-abdominal infections, and detection and treatment of Helicobacter pylori infection. Venous thromboembolism (VTE) prophylaxis and treatment are complicated by obesity, and the use of pharmacologic agents must be balanced with bleeding risk. Bleeding is a serious complication that should be closely monitored in the immediate postoperative period. Blood products remain first-line therapy for the treatment of bleeding in this population. Acute differences in drug absorption as well as emerging hormonal changes necessitate the immediate postoperative adjustment of chronic medications to ensure both safety and efficacy. Pharmacists are valuable members of interprofessional teams for bariatric surgery patients because they provide expertise on the availability of dosage forms and dosage modification to ensure that patient pharmacotherapy is not interrupted; assist in the management of hypertension, diabetes, and psychotropic medications; and ensure appropriate antimicrobial prophylaxis and VTE prophylaxis and treatment dosages. CONCLUSION: The management of patients in the perioperative period of bariatric surgery requires appropriate selection and dosing of medications for pain management and treatment of infectious complications, VTE, bleeding, and other chronic diseases. PMID- 25027534 TI - Safety and efficacy of colchicine therapy in the prevention of recurrent pericarditis. AB - PURPOSE: A review of published data on the safety and efficacy of colchicine therapy for primary and secondary prevention of pericarditis is presented. SUMMARY: Colchicine has been used effectively as an antiinflammatory agent for gout and has shown promise as a treatment for acute and recurrent pericarditis. Several small studies have indicated that colchicine can decrease pericarditis symptom persistence at 72 hours and pericarditis recurrence rates at 18 months compared with conventional therapy (corticosteroids and aspirin or ibuprofen). A review of pooled data from four prospective randomized trials concluded that colchicine is safe and efficacious for the management of acute and recurrent pericarditis, with the results indicating lower rates of the respective primary and secondary endpoints of recurrent disease and symptom persistence in colchicine-treated patients. A separate meta-analysis of five studies found a reduced risk of pericarditis with colchicine use, suggesting that the drug may have clinical utility in both primary and secondary prevention. The accumulated evidence suggests that treatment with colchicine in the context of pericarditis is safe and well tolerated, with gastrointestinal intolerance being the most common adverse event documented in the clinical trials to date. CONCLUSION: Based on a review of the literature, prevention of recurrent pericarditis with colchicine can be considered a safe and effective option, though some patients have experienced gastrointestinal intolerance. Due to evidence that corticosteroids may potentially exacerbate the risk of relapse, colchicine may be a safer and preferable option. PMID- 25027533 TI - Pharmacotherapy for alcoholic patients with alcoholic liver disease. AB - PURPOSE: An update on pharmacotherapy for achieving and maintaining abstinence and mitigating hepatic damage in patients with alcoholic liver disease (ALD) is presented. SUMMARY: Currently there are limited pharmacotherapy options for managing ALD, which encompasses a broad spectrum of disorders ranging from steatosis and alcoholic hepatitis to fibrosis, cirrhosis, and hepatocellular cancer. Individual variation in the severity, presentation, and complex pathologenesis of ALD defines barriers to effective treatment. Scoring of disease severity using validated assessment instruments should guide treatment approaches; abstinence and proper nutrition continue to be the cornerstones of management. A literature search (through December 31, 2013) identified no reports of randomized controlled trials using Food and Drug Administration (FDA)-approved medications for the treatment of alcohol dependence in ALD-spectrum disorders. Disulfiram, acamprosate, and naltrexone (oral and intramuscular), while approved by FDA for treatment of alcohol dependence, are not currently approved for use in patients with ALD. Baclofen (also not FDA-approved for use in ALD) is the only medication available in the United States with demonstrated safety and efficacy in reducing alcoholic behavior that has been formally tested in clinical trials in patients with ALD. Pharmacotherapy of alcoholic hepatitis using glucocorticoids or pentoxifylline has shown promise, but these options are reserved for severe ALD only. CONCLUSION: Although various treatments have been investigated for ALD in patients with alcoholism, complete abstinence from alcohol is currently the only recommended form of hepatoprotection for the entire spectrum of ALD diagnoses. PMID- 25027535 TI - Glycopyrrolate for treatment of clozapine-induced sialorrhea in adults. AB - PURPOSE: Four cases in which glycopyrrolate was used to treat clozapine-induced sialorrhea (CIS) are reported. SUMMARY: Glycopyrrolate is an antimuscarinic agent that can be used preoperatively to inhibit drooling and excessive secretions of the respiratory tract. The outcomes of four patients who received glycopyrrolate for the treatment of CIS are described. The Thomas-Stonell and Greenberg Drooling Severity and Frequency Scale (DSFS) was used retrospectively to rate patients' drooling. Glycopyrrolate was effective in alleviating CIS in cases 1-3. Two patients (cases 1 and 4) exhibited severe drooling, which caused their clothing, hands, and objects to consistently become wet. One patient (case 1) responded well to glycopyrrolate and was restarted on the medication when CIS returned after discontinuation of the drug. While another patient (case 3) displayed a similar response to therapy for CIS as the patient described in case 1, this patient did not experience the psychosocial complications as did the patient in case 1, possibly due to the use of glycopyrrolate as the initial treatment of choice. The patient in case 2 experienced moderate but frequent drooling. Thioridazine's high anticholinergic potential may have contributed to this patient's lower baseline DSFS score compared with the scores of the other three patients, or it could have augmented initial symptom improvement. CIS continued in the patient described in case 4 despite treatment with glycopyrrolate, with only mild improvement in the severity and frequency of drooling. CONCLUSION: Glycopyrrolate was effective in alleviating symptoms in three of four patients with CIS. In a fourth patient, the degree of improvement was unknown due to documentation discrepancies; however, mild improvement was noted initially. PMID- 25027536 TI - Visual compatibility of defibrotide with selected drugs during simulated Y-site administration. AB - PURPOSE: The visual compatibility of a solution of defibrotide (the only drug recommended for treatment and prophylaxis of hepatic venoocclusive disease) with solutions of various drugs commonly administered in bone marrow transplant procedures was studied. METHODS: Solutions of 43 drug products in concentrations typically used in clinical practice were evaluated in 1:1 mixtures with defibrotide solution in glass tubes kept at room temperature. The evaluated products included antiinfectious, corticoid, sedative, analgesic, and cardiovascular agents widely used for hematopoietic stem cell transplantation and other marrow transplant procedures; in most cases, test solutions were prepared via dilution in or reconstitution with sterile water, 0.9% sodium chloride injection, or 5% dextrose injection. The mixtures were visually observed immediately after manual mixing and at specified time points (60, 150, and 240 minutes). Visual compatibility was defined as the absence of color change, haze, fibers, particles, gas generation, and precipitate formation. The effect of mixing order on visual compatibility was ascertained. RESULTS: Of the 43 tested drug solutions, 36 were found to be visually compatible with the defibrotide solution over the entire four-hour study period. Solutions of 7 drugs (amikacin, furosemide, midazolam, mycophenolate mofetil, nicardipine, tobramycin, and vancomycin) were visually incompatible with defibrotide solution. In some cases, evidence of incompatibility was observed intermittently or was dependent on mixing order. CONCLUSION: Defibrotide solution was found to be visually compatible with solutions of 36 i.v. products that are likely to be coadministered with the drug in a bone marrow transplant unit. Seven drug solutions were visually incompatible with defibrotide solution. PMID- 25027537 TI - Teaching and learning curriculum programs: recommendations for postgraduate pharmacy experiences in education. AB - PURPOSE: Recommendations for the development and support of teaching and learning curriculum (TLC) experiences within postgraduate pharmacy training programs are discussed. SUMMARY: Recent attention has turned toward meeting teaching- and learning-related educational outcomes through a programmatic process during the first or second year of postgraduate education. These programs are usually coordinated by schools and colleges of pharmacy and often referred to as "teaching certificate programs," though no national standards or regulation of these programs currently exists. In an effort to describe the landscape of these programs and to develop a framework for their basic design and content, the American Association of Colleges of Pharmacy Pharmacy Practice Section's Task Force on Student Engagement and Involvement, with input from the American Society of Health-System Pharmacists, reviewed evidence from the literature and conference proceedings and considered author experience and expertise over a two year period. The members of the task force created and reached consensus on a policy statement and 12 recommendations to guide the development of best practices of TLC programs. The recommendations address topics such as the value of TLC programs, program content, teaching and learning experiences, feedback for participants, the development of a teaching portfolio, the provision of adequate resources for TLC programs, programmatic assessment and improvement, program transparency, and accreditation. CONCLUSION: TLC programs provide postgraduate participants with valuable knowledge and skills in teaching applicable to the practitioner and academician. Postgraduate programs should be transparent to candidates and seek to ensure the best experiences for participants through systematic program implementation and assessments. PMID- 25027538 TI - Improving pharmacist documentation of clinical interventions through focused education. AB - PURPOSE: The impact of a focused education initiative to increase pharmacists' documentation of clinical interventions is described. SUMMARY: A focused education initiative was developed to increase the consistency of pharmacists' documentation of clinical interventions in order to achieve pharmacy goals and to demonstrate the value of pharmacy services at Carolinas Medical Center in Charlotte, North Carolina. Education was provided through weekly pharmacy newsletter publications, weekly huddles, and monthly staff meetings. Pharmacy clinical specialists were tasked with providing examples of activities that should be documented as interventions, reviewing the selection of intervention categories to best capture the specific activity, and emphasizing the need for appropriate documentation. Monthly progress was monitored, and results were posted publicly to incentivize staff and assist with accountability. Increases in the number of clinical interventions was reported at monthly pharmacy staff meetings to reinforce the value of this process. The total number of pharmacy clinical interventions increased from an average of 12,493 per month in the first quarter of 2012 to an average of 27,978 per month in the second quarter of 2013, representing a 120% improvement. Associated cost-avoidance dollars also increased proportionally, such that the average cost-avoidance dollars in the second quarter of 2013 was $1.5 million per month. In addition, the pharmacy department far exceeded the health system's division of pharmacy targets for established quality indicators. Effects were sustained during the 12 months after completion of the education initiative. CONCLUSION: Implementation of a focused pharmacist education initiative led to increased numbers of clinical interventions reported and increased documentation of costs avoided. PMID- 25027539 TI - Sterile product compounding using an i.v. compounding workflow management system at a pediatric hospital. AB - PURPOSE: Patient safety enhancements achieved through the use of an automated i.v. compounding workflow management system are reported. SUMMARY: Automated systems integrating barcode verification of ingredients and the capture of serial images of all steps of the admixture process have the potential to improve the accuracy of parenteral i.v. medication dose preparation. About 18 months after the implementation of such a system at a large pediatric hospital, a retrospective analysis of dose preparation outcomes was conducted to evaluate the effectiveness of the i.v. workflow manager in detecting compounding errors and to categorize detected errors. In verifying the accuracy of 425,683 medication doses prepared during the approximately 13-month evaluation period, dispensing pharmacists detected preparation or documentation errors affecting 2,900 doses (0.68%); 1,223 of those doses (0.29%) required reworking, and 1,677 (0.4%) were rejected and destroyed. Roughly 23% of the detected errors were classified as undetectable via the pharmacy's previous verification practices, with 167 errors judged to pose the potential for adverse drug events resulting in moderate (n=146) or severe (n=21) harm. Among the reworked and rejected doses, 43.8% and 31.3%, respectively, were due to newly emergent problems not seen with traditional paper-based verification systems; however, most of these errors involved blurry or missing images and were not judged to be clinically significant. CONCLUSION: Implementation of an i.v. workflow management system that integrates barcode verification, automated calculations, and image-capture capabilities led to increased detection of errors in the sterile product compounding process. PMID- 25027540 TI - Editorial: Prof. Wokyung Sung and pathways in biological physics. PMID- 25027541 TI - PICVib: an accurate, fast and simple procedure to investigate selected vibrational modes and evaluate infrared intensities. AB - The generalization of the PICVib approach [M. V. P. dos Santos et al., J. Comput. Chem., 2013, 34, 611] for calculating infrared intensities is shown to be successful and to preserve all interesting features of the procedure such as easiness of implementation and parallelization, flexibility, treatment of large systems and at high theoretical levels. It was tested and validated for very diverse molecular systems: XH3 (D3h), YH4 (D4h), conformers of RDX, S(N)2 and E2 reaction product complexes, the [W(dppe)2(NNC5H10)] complex, carbon nanotubes, and hydrogen-bonded complexes (H2O...HOH, MeHO...HOH, MeOH...OH2, MeOH...OHMe) including the guanine-cytosine pair. The PICVib shows an excellent overall performance for calculating infrared intensities of localized normal modes and even mixed vibrations, whereas care must be taken for vibrations involving intermolecular interactions. DFT functionals are still the best combination with high level ab initio methods such as CCSD and CCSD(T). PMID- 25027542 TI - Influence of glucocorticoids on the osteogenic differentiation of rat bone marrow derived mesenchymal stem cells. AB - BACKGROUND: Glucocorticoid has been used extensively in clinical applications, because of its several pharmacologic actions, which include immunosuppression, anti-inflammation, anti-shock, and relief of asthma. However, the long-term or high-dose application of glucocorticoid can induce adverse effects such as osteoporosis, which is known in this case as glucocorticoid-induced osteoporosis (GIOP). It is a secondary osteoporosis that results in easy fracturing, and even disability. Therefore it became a thorny issue. METHODS: The rat model of glucocorticoid-induced osteoporosis (GIOP) was replicated to isolate BMSCs. Rats were assigned into four groups: normal, normal induction, GIOP, and GIOP induction. The growth cycle was monitored by using flow cytometry. Osteogenic differentiation was compared by using alkaline phosphatase (ALP) staining with a modified calcium cobalt method. The quantitative detection of osteoprotegerin and the receptor activator of nuclear factor kappa-B ligand (RANKL) was conducted by using enzyme-linked immunoassay. Finally, renal Klotho mRNA expression was assessed by using RT-PCR. RESULTS: BMSC proliferation was reduced in GIOP rats. The ALP-positive expression of normal BMSCs to the osteogenic induction solution was stronger than that of BMSCs from GIOP rats (P < 0.01). Osteoprotegerin expression was significantly higher in the normal induction group than in the normal, GIOP (P < 0.01), and GIOP induction groups (P < 0.05). RANKL expression was significantly higher in the normal induction group than in the other groups (P < 0.01) and significantly higher in the normal group than in the GIOP and GIOP induction groups (P < 0.01). RT-PCR analysis showed that renal Klotho mRNA expression was significantly reduced in the GIOP group compared with the normal group (P < 0.01). CONCLUSION: BMSC proliferation, osteogenic differentiation, and reactive activity to an osteogenic inductor were reduced in GIOP rats. Klotho mRNA expression decreased during GIOP induction. PMID- 25027543 TI - Simultaneous versus staged hepatic resection for colorectal metastases with an intact primary cancer. PMID- 25027544 TI - A new paradigm, a follow-up letter to the editor of the journal of arthroplasty. PMID- 25027546 TI - Ethical objections against including life-extension costs in cost-effectiveness analysis: a consistent approach. AB - One of the major ethical concerns regarding cost-effectiveness analysis in health care has been the inclusion of life-extension costs ("it is cheaper to let people die"). For this reason, many analysts have opted to rule out life-extension costs from the analysis. However, surprisingly little has been written in the health economics literature regarding this ethical concern and the resulting practice. The purpose of this work was to present a framework and potential solution for ethical objections against life-extension costs. This work found three levels of ethical concern: (i) with respect to all life-extension costs (disease-related and -unrelated); (ii) with respect to disease-unrelated costs only; and (iii) regarding disease-unrelated costs plus disease-related costs not influenced by the intervention. Excluding all life-extension costs for ethical reasons would require-for reasons of consistency-a simultaneous exclusion of savings from reducing morbidity. At the other extreme, excluding only disease-unrelated life extension costs for ethical reasons would require-again for reasons of consistency-the exclusion of health gains due to treatment of unrelated diseases. Therefore, addressing ethical concerns regarding the inclusion of life-extension costs necessitates fundamental changes in the calculation of cost effectiveness. PMID- 25027545 TI - Effects of orthognathic surgery on pharyngeal airway and respiratory function during sleep in patients with mandibular prognathism. AB - The aim of this study was to determine changes in overnight respiratory function and craniofacial and pharyngeal airway morphology following orthognathic surgery. The subjects were 40 patients in whom mandibular prognathism was corrected by orthognathic surgery: a one-jaw operation in 22 patients and a two-jaw operation in 18 patients. Morphological changes were studied using cone beam computed tomography immediately before surgery and at more than 6 months after surgery, and the apnoea-hypopnoea index (AHI) was measured with a portable polysomnography system. Pharyngeal airway volume was decreased significantly after surgery, especially in the one-jaw operation group. AHI was not changed significantly after surgery in either group, although AHI in one patient in the one-jaw operation group was increased to 19 events/h. There was no significant change in pharyngeal airway morphology in that patient, but he was obesity class 1 and was 54 years old. In conclusion, some patients who are obese, have a large amount of mandibular setback, and/or are of relatively advanced age may develop sleep disordered breathing after mandibular setback; a two-jaw operation should therefore be considered in skeletal class III patients who have such risks because it decreases the amount of pharyngeal airway space reduction caused by mandibular setback surgery. PMID- 25027547 TI - Clinical and genetic analyses of a Chinese female with 17alpha-hydroxylase/17,20 lyase deficiency. AB - AIMS: 17alpha-Hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive disease caused by CYP17 gene mutations. This disease is clinically characterised by hypertension, hypokalaemia, sexual infantilism in females or pseudohermaphroditism in males, and adrenal hyperplasia. This study aims to investigate a rare case of 17OHD accompanied by both cystic ovaries and massive adrenal mass. METHODS: This study performed clinical, hormonal, radiological and genetic analyses. Blood samples were collected from the patient for the genetic test. Genomic DNA was extracted from peripheral blood leukocytes, and the coding sequence abnormalities of CYP17 were assessed using polymerase chain reaction and direct sequencing analysis. RESULTS: The genetic analysis of CYP17 revealed compound heterozygous mutations in the individual. One was a mis-sense mutation of c.1226 C > G, which changes codon 409 in exon 7 from proline (CCG) to arginine (CGG). Another was a mutation of p.Val311Asp,fs,330X, which was first reported in a compound heterozygote mutation of Y329fs and V311fs from a Chinese patient. CONCLUSION: This study presented a rare case of 17OHD accompanied by both cystic ovaries and massive adrenal mass. This study obtained significant information on the genotype-phenotype correlation of 17OHD. PMID- 25027548 TI - Novel transgenic rice-based vaccines. AB - Oral vaccination can induce both systemic and mucosal antigen-specific immune responses. To control rampant mucosal infectious diseases, the development of new effective oral vaccines is needed. Plant-based vaccines are new candidates for oral vaccines, and have some advantages over the traditional vaccines in cost, safety, and scalability. Rice seeds are attractive for vaccine production because of their stability and resistance to digestion in the stomach. The efficacy of some rice-based vaccines for infectious, autoimmune, and other diseases has been already demonstrated in animal models. We reported the efficacy in mice, safety, and stability of a rice-based cholera toxin B subunit vaccine called MucoRice CTB. To advance MucoRice-CTB for use in humans, we also examined its efficacy and safety in primates. The potential of transgenic rice production as a new mucosal vaccine delivery system is reviewed from the perspective of future development of effective oral vaccines. PMID- 25027549 TI - Food allergy and the oral immunotherapy approach. AB - Food allergy represents an increasing health problem, with children being the most affected population. The symptoms can appear within minutes or hours of ingesting the offending food, producing skin manifestations, respiratory, gastrointestinal and anaphylactic reactions in the severe forms. Food allergy is established by the loss of tolerance to food proteins, and is characterized by an altered balance of regulatory T (Treg) cells and the shift to Th2 type cytokines in the intestinal lamina propria. We have described the contribution of different factors in establishing oral tolerance, such as the antigenic exposition route, the gut microenvironment, and the timing of the food introduction. Apart from avoiding the food, immunotherapy is the only intervention which produces oral desensitization to food proteins. Among the underlying immunological mechanisms of oral immunotherapy (OIT) are the changes in humoral immunity (a decrease of allergen-specific IgE and an increase of allergen-specific IgG4) and cellular changes such as the increased number of FoxP3(+) Treg cells. At present, the experiences of OIT with various foods are offering promising results. OIT appears to be safe producing low adverse reactions, and effective in inducing desensitization in most subjects with food allergy. PMID- 25027550 TI - Strain-induced phase transition and electron spin-polarization in graphene spirals. AB - Spin-polarized triangular graphene nanoflakes (t-GNFs) serve as ideal building blocks for the long-desired ferromagnetic graphene superlattices, but they are always assembled to planar structures which reduce its mechanical properties. Here, by joining t-GNFs in a spiral way, we propose one-dimensional graphene spirals (GSs) with superior mechanical properties and tunable electronic structures. We demonstrate theoretically the unique features of electron motion in the spiral lattice by means of first-principles calculations combined with a simple Hubbard model. Within a linear elastic deformation range, the GSs are nonmagnetic metals. When the axial tensile strain exceeds an ultimate strain, however, they convert to magnetic semiconductors with stable ferromagnetic ordering along the edges. Such strain-induced phase transition and tunable electron spin-polarization revealed in the GSs open a new avenue for spintronics devices. PMID- 25027551 TI - How do bacteraemic patients present to the emergency department and what is the diagnostic validity of the clinical parameters; temperature, C-reactive protein and systemic inflammatory response syndrome? AB - OBJECTIVE: Although blood cultures are often ordered based on the presence of fever, it is a clinical challenge to identify patients eligible for blood cultures. Our aim was to evaluate the diagnostic value of temperature, C-reactive protein (CRP), and Systemic Inflammatory Response Syndrome (SIRS) to identify bacteraemic patients in the Medical Emergency Department (MED). METHODS: A population-based cohort study including all adult patients at the MED at Odense University Hospital between August 1st 2009 - August 31st 2011. RESULTS: 11,988 patients were admitted to the MED within the study period. Blood cultures were performed on 5,499 (45.9%) patients within 2 days of arrival, of which 418 (7.6%) patients were diagnosed with bacteraemia. This corresponded to 3.5% of all patients. 34.1% of the bacteraemic patients had a normal rectal temperature (36.0 degrees -38.0 degrees C) recorded at arrival, 32.6% had a CRP < 100 mg/L and 28.0% did not fulfil the SIRS criteria.For a temperature cut-point of >38.0 degrees C sensitivity was 0.64 (95% CI 0.59-0.69) and specificity was 0.81 (0.80 0.82) to identify bacteraemic patients. CONCLUSION: One third of the acute medical bacteraemic patients had a normal temperature at arrival to the MED. A normal temperature combined with a CRP < 100 mg/L and no SIRS criteria, ruled out bacteraemia. PMID- 25027552 TI - Radiation plus docetaxel and cisplatin in locally advanced pancreatic carcinoma: a non-comparative randomized phase II trial. AB - BACKGROUND: We performed a randomized, non-comparative phase II study evaluating docetaxel in combination with either daily continuous (protracted IV) 5 fluorouracil or cisplatin administered weekly, concurrent to radiotherapy in the treatment of locally advanced pancreatic carcinoma. Results of the docetaxel plus cisplatin regimen are reported. METHODS: Forty chemotherapy-naive patients with locally advanced pancreatic carcinoma were randomly assigned to receive 5 fluorouracil and docetaxel or docetaxel 20mg/m(2) and cisplatin 20mg/m(2)/week, plus concurrent radiotherapy for 6 weeks. The radiation dose to the primary tumour was 54Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate. RESULTS: 51 patients from 7 centres were included in the docetaxel-cisplatin treatment group. Six-month non-progression rate was 39% (95% confidence interval: 26-53). Median overall survival was 9.6 months (95% confidence interval: 2.4-60.7); 6 complete and 8 partial responses were obtained. Six patients survived more than 2 years after their inclusion in the trial. Grade >=3 toxicity was reported in 63% of patients; no treatment-related death occurred. Severe toxicities were mainly anorexia (22%), vomiting (20%) and fatigue (24%). CONCLUSIONS: Despite inadequate efficacy according to the main end point, this regimen gave a satisfactory rate of objective response (27%) with tolerable toxicity. PMID- 25027553 TI - Histological responses to downy mildew in resistant and susceptible grapevines. AB - Downy mildew in grapevines, caused by Plasmopara viticola, is a very serious disease throughout the grape-producing nations, especially in more humid climates. Downy mildew mainly affects the cultivated varieties of Vitis vinifera. A promising way to minimize or eliminate P. viticola infections is by the adoption of resistant cultivars. Chinese wild grapevines are reported to possess resistance to many fungal diseases. In this study, three Chinese wild grapevines (Vitis pseudoreticulata Baihe-35-1, Vitis davidii var. cyanocarpa Langao-5, and Vitis piasezkii Liuba-8) and a European cultivated variety (V. vinifera cv. Pinot noir) were inoculated with P. viticola, and a histological survey was undertaken. Macroscopic observations revealed no sporulation in V. piasezkii Liuba-8, little sporulation in V. pseudoreticulata Baihe-35-1 and V. davidii var. cyanocarpa Langao-5, but serious sporulation in V. vinifera cv. Pinot noir. Aniline blue staining indicated callose deposition in V. pseudoreticulata Baihe-35-1, V. davidii var. cyanocarpa Langao-5, and V. piasezkii Liuba-8. Cells with distinctive fluorescence were also observed in V. pseudoreticulata Baihe-35-1. After staining with 3,3-diaminobenzidine, production of H2O2 was observed early on, after infection in V. davidii var. cyanocarpa Langao-5 and V. piasezkii Liuba 8. No H2O2 accumulation was observed in V. vinifera cv. Pinot noir. It is concluded that V. piasezkii Liuba-8 should be classified as "highly resistant" to downy mildew, V. pseudoreticulata Baihe-35-1 and V. davidii var. cyanocarpa Langao-5 as "resistant," and V. vinifera Pinot noir as "susceptible." The possible roles of stomatal callose deposition in the defense r6eactions of the mildew-resistant grapevines are discussed. PMID- 25027554 TI - The experience of adjusting to a diagnosis of non-epileptic attack disorder (NEAD) and the subsequent process of psychological therapy. AB - PURPOSE: Research suggests psychological therapy as the treatment of choice for individuals diagnosed with NEAD. This study explored the experience of adjusting to a diagnosis of NEAD and engagement with therapy through a qualitative methodology. METHOD: Semi-structured interviews were conducted with 6 people with a diagnosis of NEAD and analysed using thematic analysis. RESULTS: Six master themes were generated, with four discussed. Two themes were not discussed due to previous coverage in the literature and their less direct relevance to the service context. Theme 1: 'understanding NEAD' incorporated participants' evolving understanding of the diagnosis and their reflections on this. Theme 2: 'I can't deal with you' centres on participants' accounts of relationships with professionals in the context of NEAD. Theme 3: 'experiences of psychological therapy' reflected participants' experience of being referred to psychology and gaining a deeper understanding of themselves through therapy. Theme 4: 'adjusting to life with NEAD' explores participants' views on living with NEAD and their expectations for the future. CONCLUSION: This study extended previous research by highlighting the impact of how the diagnosis is received and understood on engagement in therapy. Improving awareness of NEAD amongst healthcare professionals is of key importance in reducing stigma and encouraging engagement in therapy. PMID- 25027555 TI - Seizures and EEG pattern in the 22q13.3 deletion syndrome: clinical report of six Italian cases. AB - PURPOSE: The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a rare genetic disorder characterized by hypotonia, severely impaired development of speech and language, autistic-like behaviour, and minor dysmorphic features. Neurologic problems may include seizures of different types, such as febrile, generalized tonic-clonic, focal, and absence seizures. No peculiar EEG features have been associated with 22q13 deletion syndrome to date. In order to verify if a peculiar clinical and EEG pattern is present in 22q13.3 deletion syndrome, we studied six Italian patients with this chromosome abnormality. METHOD: Array CGH analysis was carried out in the six subjects (1 male, 5 females, age range 11-30 years, median 19.5). They underwent a complete general and neurologic examinations. The EEG study consisted of at least one awake and one nap-sleep video-EEG recordings and evaluation of other EEGs performed elsewhere. RESULTS: Three subjects suffered from myoclonic or generalized tonic clonic seizures with a rather benign course; all showed multifocal paroxysmal abnormalities on EEG recording, predominant over the frontal-temporal regions, activated during sleep. CONCLUSION: 22q13.3 deletion syndrome seems to be associated, at least in a subgroup of patients, with a peculiar clinical and EEG pattern, characterized by a childhood epilepsy with a rather benign evolution and with multifocal paroxysmal EEG abnormalities activated by sleep. PMID- 25027556 TI - Lynx1 supports neuronal health in the mouse dorsal striatum during aging: an ultrastructural investigation. AB - Nicotinic acetylcholine receptors have been shown to participate in neuroprotection in the aging brain. Lynx protein modulators dampen the activity of the cholinergic system through direct interaction with nicotinic receptors. Although lynx1 null mutant mice exhibit augmented learning and plasticity, they also exhibit macroscopic vacuolation in the dorsal striatum as they age, detectable at the optical microscope level. Despite the relevance of the lynx1 gene to brain function, little is known about the cellular ultrastructure of these age-related changes. In this study, we assessed degeneration in the dorsal striatum in 1-, 3-, 7-, and 13-month-old mice, using optical and transmission electron microscopy. We observed a loss of nerve fibers, a breakdown in nerve fiber bundles, and a loss of neuronal nuclei in the 13-month-old lynx1 null striatum. At higher magnification, these nerve fibers displayed intracellular vacuoles and disordered myelin sheaths. Few or none of these morphological alterations were present in younger lynx1 null mutant mice or in heterozygous lynx1 null mutant mice at any age. These data indicate that neuronal health can be maintained by titrating lynx1 dosage and that the lynx1 gene may participate in a trade-off between neuroprotection and augmented learning. PMID- 25027557 TI - Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimerization. AB - FOXP1, FOXP2, and FOXP4 are three members of the FOXP gene subfamily of transcription factors involved in the development of the central nervous system. Previous studies have shown that the transcriptional activity of FOXP1/2/4 is regulated by homo- and heterodimerization. However, their transcriptional gene targets in the developing brain are still largely unknown. FOXP2 regulates the expression of many genes important in embryonic development, including WNT and Notch signaling pathways. In this study, we investigate whether dimerization of FOXP1/2/4 leads to differential expression of ten known FOXP2 target genes (CER1, SFRP4, WISP2, PRICKLE1, NCOR2, SNW1, NEUROD2, PAX3, EFNB3, and SLIT1). FOXP1/2/4 open-reading frames were stably transfected into HEK293 cells, and the expression level of these FOXP2 target genes was quantified using real-time polymerase chain reaction. Our results revealed that the specific combination of FOXP1/2/4 dimers regulates transcription of various FOXP2 target genes involved in early neuronal development. PMID- 25027558 TI - Bayesian network and mechanistic hierarchical structure modeling of increased likelihood of developing intractable childhood epilepsy from the combined effect of mtDNA variants, oxidative damage, and copy number. AB - Despite that mutations in mitochondrial DNA (mtDNA) have been associated with major epilepsy syndromes, the role of mtDNA instability and mitochondrial dysfunction in epileptogenesis has not been comprehensively examined. In the present study, we investigated the role of mtDNA copy number, oxidative damage, and mtDNA variants as independent or combined risk factors for the development of intractable childhood epilepsy. We analyzed mtDNA copy number and oxidative damage by quantitative polymerase chain reaction (PCR), and mtDNA variants by dot blot in brain tissue specimens collected from 21 pediatric intractable epilepsy patients and 11 non-epileptic patients. Bayesian network and mechanistic hierarchical structure Markov chain Monte Carlo (MCMC) modeling were used to analyze the relationship between these variables. The combined effects of oxidative mtDNA damages and mtDNA copy number produced more significant correlation with epilepsy than that of mtDNA copy number alone with epilepsy. Epilepsy patients showed significant correlations with mtDNA single nucleotide polymorphisms (SNPs)--A1555G, G3196A, T3197C, G9952A, A10006G, A10398G, cortical dysplasia status, oxidative mtDNA damage and relative mtDNA copy number. Comparison of 12 mechanistic structure models suggested that female children who have the wild type allele 10398A and variant allele 9952A, and high mtDNA copy number and oxidative stress have increased probability of developing intractable epilepsy. Estimation of nuclear genes controlling mitochondrial biogenesis, cortical dysplasia, and the effect of the environment using MCMC method showed that these latent variables had a very significant contribution in the development of intractable epilepsy. These data suggest that mitochondrial genetics play a significant role in the pathogenesis of epilepsy in children, and findings of this study may guide the prospects for targeting mitochondria for therapeutic treatment of childhood intractable epilepsy. PMID- 25027559 TI - KHSRP participates in manganese-induced neurotoxicity in rat striatum and PC12 cells. AB - Manganese (Mn) is an essential micronutrient. However, exposure to high doses of Mn may lead to a neurological disease known as manganism, which is characterized by marked brain neuronal loss. K-homology splicing regulator protein (KHSRP) is a multifunctional RNA-binding protein and has been implicated in the regulation of multiple cellular signaling associated with neuronal apoptosis and survival, such as p38 mitogen-activated protein kinase (MAPK), nuclear factor kappaB (NF kappaB), and Wnt/beta-catenin pathways. In the present study, the role of KHSRP in Mn-induced neurotoxicity was investigated in vivo using a rat model of chronic Mn exposure and in vitro using differentiated PC12 cell cultures. Western blot and immunohistochemical analyses showed a significant upregulation of KHSRP in rat striatum following Mn exposure. Immunofluorescent labeling indicated that KHSRP was localized mainly in neurons. Terminal deoxynucleotidyl transferase mediated biotinylated-dUTP nick end labeling (TUNEL) assay showed that KHSRP was mainly distributed in apoptotic neurons. Increased KHSRP expression was positively correlated with the upregulation of several apoptosis-related proteins, such as p53, bax, and active caspase-3. In addition, significant co localization of KHSRP and active caspase-3 in neurons after Mn exposure was also observed, suggesting a potential involvement of KHSRP in the regulation of Mn induced striatal neuronal apoptosis. Importantly, interference with KHSRP apparently decreased the level of p53 and attenuated Mn-induced neuronal apoptosis. Taken together, these results indicate that upregulation of KHSRP may be involved in the pathological process underlying Mn neurotoxicity via the modulation of p53 signaling. PMID- 25027560 TI - Voluntary exercise promotes beneficial anti-aging mechanisms in SAMP8 female brain. AB - Regular physical exercise mediates health and longevity promotion involving Sirtuin 1 (SIRT1)-regulated pathways. The anti-aging activity of SIRT1 is achieved, at least in part, by means of fine-tuning the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway by preventing the transition of an originally pro-survival program into a pro-aging mechanism. Additionally, SIRT1 promotes mitochondrial function and reduces the production of reactive oxygen species (ROS) through regulating peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), the master controller of mitochondrial biogenesis. Here, by using senescence-accelerated mice prone 8 (SAMP8) as a model for aging, we determined the effect of wheel-running as a paradigm for long-term voluntary exercise on SIRT1-AMPK pathway and mitochondrial functionality measured by oxidative phosphorylation (OXPHOS) complex content in the hippocampus and cortex. We found differential activation of SIRT1 in both tissues and hippocampal specific activation of AMPK. These findings correlated well with significant changes in OXPHOS in the hippocampal, but not in the cerebral cortex, area. Collectively, the results revealed greater benefits of the exercise in the wheel running intervention in a murine model of senescence, which was directly related with mitochondrial function and which was mediated through the modulation of SIRT1 and AMPK pathways. PMID- 25027561 TI - Structure and dynamics of potassium chloride in aqueous solution. AB - The structure and dynamics of potassium chloride in aqueous solution over a wide range of concentrations-and in particular beyond saturation-are studied using molecular dynamics simulations to help shed light on recent experimental studies of nonphotochemical laser-induced nucleation (NPLIN). In NPLIN experiments, the duration, t, of the laser pulse (with wavelength 1064 nm) is found to influence the occurrence of crystal nucleation in supersaturated KCl(aq): if t is less than about 5 ps, no crystal nucleation is observed; if t is greater than about 100 ps, crystal nucleation is observed, and with a known dependence on laser power. Assuming that the laser acts on spontaneously formed solute clusters, these observations suggest that there are transient structures in supersaturated solutions with relaxation times on the scale of 5-100 ps. Ion-cluster formation and ion-cluster lifetimes are calculated according to various criteria, and it is found that, in the supersaturated regime, there are indeed structures with relaxation times of up to 100 ps. In addition, the ion dynamics in this regime is found to show signs of collective behavior, as evidenced by stretched exponential decay of the self-intermediate scattering function. Although these results do not explain the phenomenon of NPLIN, they do provide insights into possible relevant dynamical factors in supersaturated aqueous solutions of potassium chloride. PMID- 25027562 TI - Inflammatory myofibroblastic tumor of the bladder - an unexpected case coexisting with an ovarian teratoma. AB - Inflammatory myofibroblastic tumors (IMTs) mainly occur in children and young adults, usually in the first two decades of life. IMT-type tumors belong to neoplasms of an intermediate biologic potential with considerable rate of local recurrence and in some cases that able to create metastases. Presented case is the first IMT coexisting with the other neoplasm. In our paper we are going to present a peculiar case of an IMT of the bladder coexisting with an ovarian teratoma, and to discuss its pathogenesis, histological picture and differential diagnosis. A 19-year-old female was admitted to the Gynecological Department and during the surgery, two independent, non-adjacent tumors were found. To settle the diagnosis, a FISH examination with the ALK1 break apart probe was carried out. It confirmed the rearrangement of the chromosome 2p23. Morphologic and immunophenotypic similarities between an IMT and other malignant tumors of the bladder may lead to diagnostic errors and an unnecessary radical cystectomy as a result. The therapy of choice is only total excision of the tumor. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1937487606122622. PMID- 25027563 TI - Nosocomial infections with metallo-beta-lactamase-producing Pseudomonas aeruginosa: molecular epidemiology, risk factors, clinical features and outcomes. AB - BACKGROUND: Metallo-beta-lactamases (MBLs) have emerged as one of the most important bacterial resistance mechanisms because of their ability to hydrolyse virtually all beta-lactam agents. MBL-producing Pseudomonas aeruginosa (MBL-PA) are an important cause of nosocomial infections, particularly in intensive care units (ICUs), where they are associated with serious infections and present a significant clinical risk. AIM: To assess the molecular epidemiology, risk factors and outcomes of nosocomial infections caused by MBL-PA in a teaching hospital in Southern Brazil. METHODS: From January 2001 to December 2008, 142 carbapenem-resistant P. aeruginosa strains were isolated from distinct clinical samples from hospitalized patients. These isolates were screened for MBLs, and underwent polymerase chain reaction, sequencing and pulsed-field gel electrophoresis (PFGE). Patients infected with carbapenem-resistant MBL-PA were considered as cases, and patients infected with non-MBL-PA were considered as controls. FINDINGS: Eighty-four of 142 patients with positive carbapenem resistant P. aeruginosa cultures met the criteria of the Centers for Disease Control and Prevention for infection. Fifty-eight patients were infected with MBL PA (69%) and 26 patients were infected with non-MBL-PA (31%). Multi-variate analysis revealed that ICU stay [P = 0.003, odds ratio (OR) 4.01, 95% confidence interval (CI) 1.15-14.01] and urinary tract infection (P = 0.001, OR 9.67, 95% CI 1.72-54.48) were important risk factors for MBL-PA infection. Patients infected with MBL-PA showed faster onset of infection (P = 0.002) and faster progression to death (P = 0.04). CONCLUSIONS: These results showed the severity of MBL-PA infections, and demonstrated the urgent need for strategies to improve infection control measures to prevent an increase in these nosocomial infections. PMID- 25027564 TI - The value of text messages to increase response rates for post-discharge surgical site infection surveillance. PMID- 25027566 TI - Electrochemically induced Fenton reaction of few-layer MoS2 nanosheets: preparation of luminescent quantum dots via a transition of nanoporous morphology. AB - Electrochemically induced Fenton (electro-Fenton) reaction was used for efficient and controllable preparation of hydroxyl radicals, leading to the generation of luminescent quantum dots through etching of as-exfoliated MoS2 nanosheets. Morphologic changes of MoS2 nanosheets during the electro-Fenton reaction were monitored using transmission electron microscopy, showing that etching of MoS2 nanosheets induced by hydroxyl radicals resulted in rapid homogeneous fracturing of the sheets into small dots via a transition of nanoporous morphology. The as generated dots with vertical dimensional thickness of ca. 0.7 nm and plane size of ca. 5 nm were demonstrated to be MoS2 quantum dots (MoS2-QDs), and their photoluminescence properties were explored based on quantum confinement, edge effect, and intrinsic characteristics. Moreover, the degree of etching and the concomitant porosity of MoS2 nanosheets could be conveniently tuned via the electro-Fenton reaction time, resulting in a new morphology of nanoporous MoS2 nanosheets, with potential new applications in various significant areas. PMID- 25027567 TI - Extracavitary primary effusion lymphoma initially presenting with hemophagocytic lymphohistocytosis. PMID- 25027568 TI - Monosomal karyotype predicts adverse prognosis in patients diagnosed with chronic myelomonocytic leukemia: a single-institution experience. AB - INTRODUCTION: Cytogenetic abnormalities have a significant prognostic effect in many hematologic neoplasms. Monosomal karyotype (MK), a newly recognized cytogenetic category, has been reported to be a marker of poor prognosis in patients with myelodysplastic syndromes and myelofibrosis, but its effect in chronic myelomonocytic leukemia (CMML) remains relatively unknown. PATIENTS AND METHODS: A retrospective study of cases diagnosed with CMML found a total of 262 patients. Patient characteristics, cytogenetic data, and survival were analyzed. RESULTS: Cytogenetic analysis found diploidy in 167 patients (64%). Trisomy 8 was the most frequent cytogenetic abnormality at 8% (22), followed by complex karyotype (CK) at 5% (14), (-)7 at 4% (10), and MK at 3% (7, of which 6 [86%] were also CK). Median overall survival was statistically significantly worse in MK-positive cases than in MK-negative cases (MK(+) vs. MK(-)). Patients with MK(+) only or CK(+)MK(+) did worse than any other group. CONCLUSION: MK is a rare entity but can predict statistically significantly shorter overall survival among all other cytogenetic categories. PMID- 25027569 TI - Clinical features of patients with Philadelphia-negative myeloproliferative neoplasms complicated by portal hypertension. AB - BACKGROUND: Portal hypertension has been reported to afflict 7% to 18% of patients with Philadelphia-negative MPNs, with complications of variceal bleeding and ascites. The clinical features and outcomes of these patients are unclear. PATIENTS AND METHODS: In this multicenter retrospective study, we evaluated the clinical features of 51 patients with MPNs complicated by PHTN. RESULTS: The diagnosis of underlying MPN was most frequently PV (39%) and primary MF (35%), followed by post-PV MF (18%), ET (4%), and post-ET MF (4%). Frequency of Janus Kinase 2 V617F mutation appears as expected in the underlying MPN. Thrombosis within the splanchnic circulation was prevalent in patients with polycythemia compared with other MPNs (76% vs. 26%; P = .0007). CONCLUSION: PV and MF patients have a greater incidence of PHTN in our population, with thrombosis contributing to PHTN development in PV patients. Patients with splanchnic circulation thrombosis are potential candidates for screening for PHTN. These data might be useful for developing screening strategies for early detection of PHTN in patients with MPN. PMID- 25027570 TI - Anti-biofilm, anti-hemolysis, and anti-virulence activities of black pepper, cananga, myrrh oils, and nerolidol against Staphylococcus aureus. AB - The long-term usage of antibiotics has resulted in the evolution of multidrug resistant bacteria. Unlike antibiotics, anti-virulence approaches target bacterial virulence without affecting cell viability, which may be less prone to develop drug resistance. Staphylococcus aureus is a major human pathogen that produces diverse virulence factors, such as alpha-toxin, which is hemolytic. Also, biofilm formation of S. aureus is one of the mechanisms of its drug resistance. In this study, anti-biofilm screening of 83 essential oils showed that black pepper, cananga, and myrrh oils and their common constituent cis nerolidol at 0.01 % markedly inhibited S. aureus biofilm formation. Furthermore, the three essential oils and cis-nerolidol at below 0.005 % almost abolished the hemolytic activity of S. aureus. Transcriptional analyses showed that black pepper oil down-regulated the expressions of the alpha-toxin gene (hla), the nuclease genes, and the regulatory genes. In addition, black pepper, cananga, and myrrh oils and cis-nerolidol attenuated S. aureus virulence in the nematode Caenorhabditis elegans. This study is one of the most extensive on anti-virulence screening using diverse essential oils and provides comprehensive data on the subject. This finding implies other beneficial effects of essential oils and suggests that black pepper, cananga, and myrrh oils have potential use as anti virulence strategies against persistent S. aureus infections. PMID- 25027571 TI - Response of phyllosphere bacterial communities to elevated CO2 during rice growing season. AB - The phyllosphere, the aerial parts of terrestrial plants, represents the largest biological interface on Earth. This habitat is colonized by diverse microorganisms that affect plant health and growth. However, the community structure of these phyllosphere microorganisms and their responses to environmental changes, such as rising atmospheric CO2, are poorly understood. Using a massive parallel pyrosequencing technique, we investigated the feedback of a phyllosphere bacterial community in rice to elevated CO2 (eCO2) at the tillering, filling, and maturity stages under nitrogen fertilization with low (LN) and high application rates (HN). The results revealed 9,406 distinct operational taxonomic units that could be classified into 8 phyla, 13 classes, 26 orders, 59 families, and 120 genera. The family Enterobacteriaceae within Gammaproteobacteria was the most dominant phylotype during the rice growing season, accounting for 61.0-97.2 % of the total microbial communities. A statistical analysis indicated that the shift in structure and composition of phyllosphere bacterial communities was largely dependent on the rice growing stage. eCO2 showed a distinct effect on the structure of bacterial communities at different growth stages, and the most evident response of the community structure to eCO2 was observed at the filling stage. eCO2 significantly increased the relative abundance of the most dominant phylotype (Enterobacteriaceae) from 88.6 % at aCO2 (ambient CO2) to 97.2 % at eCO2 under LN fertilization at the filling stage, while it significantly decreased the total relative abundance of other phylotypes from 7.48 to 1.35 %. Similarly, higher value for the relative abundance of the most dominant family (Enterobacteriaceae) and lower value for the total relative abundance of other families were observed under eCO2 condition at other growth stages and under different N fertilizations, but the difference was not statistically significant. No consistent response pattern was observed along growth stages that could be attributed to N treatments. These results provide useful insights into our understanding of the response of a phyllosphere bacterial community to eCO2 with regards to the diversity, composition, and structure during rice growing seasons. PMID- 25027572 TI - High-level expression and characterization of recombinant acid urease for enzymatic degradation of urea in rice wine. AB - Ethylcarbamate, a carcinogenic compound, is formed from urea and ethanol in rice wine, and enzymatic elimination of urea is always attractive. In the present work, we amplified the acid urease gene cluster ureABCEFGD from Lactobacillus reuteri CICC6124 and constructed robust Lactococcus lactis cell factories for the production of acid urease. The titer of the recombinant acid urease was increased from 1,550 to 11,560 U/L by optimization of the cultivation process. Meanwhile, the enzyme showed satisfied properties toward urea elimination in the rice wine model system. By incubating the enzyme (50 U/L) at 20 degrees C for 60 h, about 95.8% of urea in rice wine was removed. Interestingly, this acid urease also exhibited activity toward ethylcarbamate. The results demonstrated that this recombinant acid urease has great potential in the elimination of urea in rice wine. PMID- 25027573 TI - Patients eligible for treatment with simeprevir in a French center. AB - BACKGROUND: Simeprevir (Olysio((r))), a second-wave protease inhibitor recently approved for the treatment of chronic hepatitis C, is not indicated in patients with genotype 1a strain harboring the Q80K protease mutation. Phase 2 and 3 studies on this molecule mainly focused on North American patients and the prevalence of Q80K is particularly high in the USA (around 50%). The prevalence of this mutation in other parts of the world is currently unknown. OBJECTIVES: The purpose of our study was to perform a detection of this mutation in a single PCR technique and to study the prevalence of this Q80K mutation in a non U.S. population. We can thus estimate the proportion of HCV positive patients who can be treated with simeprevir. STUDY DESIGN: We conducted a meta-analysis of response rates in the presence or absence of this mutation in randomized trials and then describe a simple and reliable method to detect this mutation. We also examined bilirubin levels in our cohort of 95 HCV genotype 1a patients. RESULTS: Ten patients (10.5%) had a Q80K mutation and 12 patients exhibited bilirubin levels above the upper limit of normal at baseline. In our cohort, 21 patients (22%) were therefore ineligible for treatment with simeprevir. The prevalence of this mutation seems to be much lower in European patients. CONCLUSION: In conclusion, before considering treatment with simeprevir, physicians must be able to screen for the Q80K mutation. PMID- 25027574 TI - Variable expression of the forgotten oncogene E5 in HPV-positive oropharyngeal cancer. AB - BACKGROUND: The role of the HPV E6/E7 oncogenes in head and neck squamous cell cancer (HNSCC) has been studied extensively, but the role of the viral E5 protein remains poorly understood. Studies in cervical cancer indicate that E5 increases epidermal growth factor receptor (EGFR) recycling to the cell surface and enhances growth factor signal transduction. OBJECTIVE: This study was designed to examine the relationship between HPV E5, EGFR, and survival in HPV-positive HNSCC. STUDY DESIGN: A retrospective search of the London Health Sciences Centre pathology database was performed to identify oropharyngeal cancer samples. HPV E5 and EGFR expression was measured by reverse transcriptase real-time PCR. RESULTS: The majority of oropharyngeal tumor samples (59/82, 72%) were HPV-16 positive. Among the HPV-positive tumors, highly variable E5 expression was detected from early polycistronic transcripts. Tumors with high E5 expression levels had significantly higher EGFR levels (p=0.03). High E5 levels were correlated with improved recurrence-free survival, but not overall survival (p=0.02 and 0.71, respectively), whereas high EGFR was strongly associated with decreased recurrence-free and overall survival (p<0.001 and 0.006 respectively). Multivariate analysis revealed E5 and EGFR to be the strongest predictors of recurrence-free survival (p<0.01). CONCLUSIONS: HPV E5-encoded transcripts are variably expressed in HPV-positive HNSCC and this is correlated with EGFR expression in HPV-positive OPC. However, E5 and EGFR independently predict recurrence-free survival in opposing manners. These findings require further validation to determine if E5 and EGFR are useful biomarkers to stratify treatment intensity for patients with HPV-positive HNSCC. PMID- 25027575 TI - Metabolomics in pediatric nephrology: emerging concepts. AB - Metabolomics, the latest of the "omics" sciences, refers to the systematic study of metabolites and their changes in biological samples due to physiological stimuli and/or genetic modification. Because metabolites represent the downstream expression of genome, transcriptome, and proteome, they can closely reflect the phenotype of an organism at a specific time. As an emerging field in analytical biochemistry, metabolomics has the potential to play a major role in monitoring real-time kidney function and detecting adverse renal events. Additionally, small molecule metabolites can provide mechanistic insights into novel biomarkers of kidney diseases, given the limitations of the current traditional markers. The clinical utility of metabolomics in the field of pediatric nephrology includes biomarker discovery, defining as yet unrecognized biological therapeutic targets, linking of metabolites to relevant standard indices and clinical outcomes, and providing a window of opportunity to investigate the intricacies of environment/genetic interplay in specific disease states. PMID- 25027576 TI - Clinicopathological characteristics and outcomes of pediatric patients with systemic small blood vessel vasculitis. AB - BACKGROUND: Systemic small blood vessel vasculitis (SSV) is uncommon among pediatric patients, and the predictive value of the new histopathological classification for SSV in terms of renal outcomes in these patients is unknown. METHODS: The study cohort comprised 38 pediatric patients and 285 adult patients with SSV who were treated in a medical center between 1993 and 2012. RESULTS: Children accounted for 11.8 % of all patients with SSV diagnosed during the study period. In contrast to the adult patients, the pediatric patients were predominantly female (73.7 vs. 51.9 %; P < 0.05). The prevalence of skin purpura was higher and pulmonary symptoms were less common among pediatric patients than among adult ones (36.8 vs. 13.7 %, P < 0.01 and 26.3 vs. 46.0 %, P < 0.05, respectively). Subtype was correlated with the baseline levels of serum creatinine and treatment response among patients with SSV and was found to have a tendency to predict end-stage renal disease (ESRD) among pediatric patients (hazard ratio 2.273, P < 0.01). The probability of progressing to ESRD was highest in pediatric patients with the sclerotic glomerulonephritis subtype, followed by the mixed, crescentic and focal glomerulonephritis subtypes (in descending order of probability) (P < 0.01). CONCLUSIONS: Estimated histopathological classification has a prognostic value for renal outcome and response to therapy in children with SSV. PMID- 25027577 TI - Identification of Giovanni Battista Morgagni remains following historical, anthropological, and molecular studies. AB - Morgagni died on December 5, 1771, 89 years old, and was buried in Saint Maxim Church in Padua, where his wife and five of his 15 children, four daughters, and one son were already buried. In 1868 and 1900, the tomb was opened to identify Morgagni. Among the remains of several adult individuals, two skulls considered of very old persons were identified and replaced in an earthenware jar inside the sepulcher. In 2011, we opened the tomb and found the remains described during the first two identifications, but additionally, we found the skulls fragments of three very young individuals which could have been Morgagni's children. An anthropological analysis confirmed that one of the skulls inside the earthenware jar belonged to the oldest individuals ("senilis") between those found in the tomb. A genetic analysis proved a kinship between this skull and the fragments of young individuals (one male and two females), supporting the hypothesis that they were Morgagni and his children. In conclusion, thanks to the interaction between historical studies, anthropological research, and molecular analysis that reinforce each other, we can assume that the skull is Giovanni Battista Morgagni's and that the series of skull fragments are from his children who were buried together with their parents. PMID- 25027578 TI - Primary gammadelta T cell lymphoma of the lung: report of a case with features suggesting derivation from intraepithelial gammadelta T lymphocytes. AB - T cell lymphoma of gammadelta T cell origin is a rare disease that mainly involves extranodal sites and shows aggressive clinical behavior. Here, we report a case of primary gammadelta T cell lymphoma of the lungs with epitheliotropism in the respiratory epithelium, a feature somewhat reminiscent of what is observed in enteropathy-associated T cell lymphoma. A 63-year-old man presented with chest pain and dyspnea on exertion, weight loss, and general weakness. On a positron emission tomography (PET) scan, multiple hypermetabolic lesions were found in both lungs. Microscopic examination of the wedge lung biopsy revealed nodular infiltration of monomorphic, medium- to large-sized atypical lymphocytes with round nuclei, coarse chromatin, and a variable amount of clear to eosinophilic cytoplasm. Of note, intraepithelial lymphocytosis by atypical lymphoid cells was observed in the respiratory epithelium within and around the nodule. Immunohistochemically, the tumor cells were CD3+, TCRbetaF1-, TCRgamma+, CD5-, CD7+, CD20-, CD79a-, CD30-, CD4-, CD8-, CD10-, BCL6-, CD21-, CD56+, CD57-, and CD138-, and expressed cytotoxic molecules. Epstein-Barr virus (EBV) was not detected by an in situ hybridization assay for EBV-encoded RNA. Interestingly, CD103 was expressed by a subset of tumor cells, especially those infiltrating the epithelium. T cell clonality was detected by multiplex PCR analysis of TRG and TRD gene rearrangements. After 2 months of systemic chemotherapy, PET scan showed regression of the size and metabolic activity of the lesions. This case represents a unique gammadelta T cell lymphoma of the lungs showing epitheliotropism by CD103+ gammadelta T cells that is suggestive of tissue resident gammadelta T cells as the cell of origin. PMID- 25027579 TI - Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma. AB - The most common subtype of renal cell carcinoma is the clear cell type (ccRCC), accounting for 75 % of cases. Inactivation of VHL gene is thought to be an early event in ccRCC carcinogenesis. Our intention was to assess whether VHL mutational status might provide useful predictive or prognostic information in patients with ccRCC. VHL messenger RNA (mRNA) expression was analyzed by in situ hybridization and its protein by immunohistochemistry on a tissue microarray containing samples from 148 cases. This was validated by qRT-PCR on 62 cases, for which RNA was available. The mutation status was assessed in 91 cases by Sanger sequencing. VHL was found mutated in 57 % of cases, with missense mutations in 26 %, nonsense in 5 %, splice site in 13 %, deletions in 39 %, indels in 8 %, duplications in 8 %, and insertions in 2 % of the cases. The prevalence of mutations by exon was the following: exon 1, 47 %; exon 2, 27 %; and exon 3, 13 %. VHL protein was expressed in a high number of cases (80 %), but significant correlations were not found between protein expression, clinical data, and survival. Importantly, of the 91 samples evaluated by sequencing, 45 were mutated, and 87 % of those were strongly positive. We found 32 novel mutations in the VHL gene in ccRCC. The presence of mutations was not concordant with mRNA or protein expression. Nonsense mutations of the VHL gene appear to be related with poorer prognosis and survival. PMID- 25027580 TI - Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different. AB - An HPV infection is involved in the etiology of about 25 % of head and neck squamous cell carcinomas (HNSCC). It has been postulated that a strong antitumoral immune response in HPV-positive tumors represents an important underlying mechanism for their good response to therapy. Recently, the Warburg phenomenon has returned to the center of attention because it affects antitumoral immune response and response to therapy. Accumulation of tumor cell-derived lactate inhibits cytotoxic T cells, as these, analogous to cancer cells, depend on glycolysis and lactate secretion for fulfillment of energy needs. Sparse information exists on the Warburg effect in HNSCC. This study aimed to characterize the metabolic and immunological features of HPV-negative and HPV positive HNSCC. An immunohistochemical analysis of oropharyngeal carcinomas showed an enhanced antitumoral immune response (CD8/CD4 ratio) together with increased levels of proteins involved in transmembranous metabolite transportation (GLUT1 and CD147) and respiratory metabolism (COX5B) in HPV positive tumors as compared to HPV-negative tumors. mRNA and Western blot analyses of an HPV-positive and HPV-negative HNSCC cell line revealed metabolic characteristics similar to the in vivo situation. Additionally, the HPV-negative cell line showed stronger extracellular lactate accumulation. In contrast, the HPV-positive cell line presented with better adaption to lactic acidosis suggesting an ability to metabolize lactate. Our results indicate that HPV positive and HPV-negative carcinomas do not only differ in terms of tumor immune microenvironment, but also in terms of tumor metabolism, characterized by an increased glucose and respiratory metabolism together with decreased lactate accumulation in HPV-positive HNSCC. Therefore, targeting metabolic pathways could represent a promising adjunct in the therapy of HPV-positive HNSCC. PMID- 25027581 TI - Clinically relevant quality measures for risk factor control in primary care: a retrospective cohort study. AB - BACKGROUND: Assessment of the proportion of patients with well controlled cardiovascular risk factors underestimates the proportion of patients receiving high quality of care. Evaluating whether physicians respond appropriately to poor risk factor control gives a different picture of quality of care. We assessed physician response to control cardiovascular risk factors, as well as markers of potential overtreatment in Switzerland, a country with universal healthcare coverage but without systematic quality monitoring, annual report cards on quality of care or financial incentives to improve quality. METHODS: We performed a retrospective cohort study of 1002 randomly selected patients aged 50-80 years from four university primary care settings in Switzerland. For hypertension, dyslipidemia and diabetes mellitus, we first measured proportions in control, then assessed therapy modifications among those in poor control. "Appropriate clinical action" was defined as a therapy modification or return to control without therapy modification within 12 months among patients with baseline poor control. Potential overtreatment of these conditions was defined as intensive treatment among low-risk patients with optimal target values. RESULTS: 20% of patients with hypertension, 41% with dyslipidemia and 36% with diabetes mellitus were in control at baseline. When appropriate clinical action in response to poor control was integrated into measuring quality of care, 52 to 55% had appropriate quality of care. Over 12 months, therapy of 61% of patients with baseline poor control was modified for hypertension, 33% for dyslipidemia, and 85% for diabetes mellitus. Increases in number of drug classes (28-51%) and in drug doses (10-61%) were the most common therapy modifications. Patients with target organ damage and higher baseline values were more likely to have appropriate clinical action. We found low rates of potential overtreatment with 2% for hypertension, 3% for diabetes mellitus and 3-6% for dyslipidemia. CONCLUSIONS: In primary care, evaluating whether physicians respond appropriately to poor risk factor control, in addition to assessing proportions in control, provide a broader view of the quality of care than relying solely on measures of proportions in control. Such measures could be more clinically relevant and acceptable to physicians than simply reporting levels of control. PMID- 25027582 TI - Antidepressant-like activity of magnesium in the olfactory bulbectomy model is associated with the AMPA/BDNF pathway. AB - RATIONALE: Numerous studies suggest agents that act on glutamatergic transmission as potential antidepressants. Preclinical and clinical evidence suggests that magnesium, an N-methyl-D-aspartate receptor blocker, may be useful in the treatment of depression. OBJECTIVE: The aim of this study was to investigate the effects of magnesium on behavior; protein levels of GluN2A, GluN2B [N-methyl-D aspartate receptor (NMDAR) subunits], GluA1 [alpha-amino-3-hydroxy-5 methyl-4 isoxazolepropionic acid (AMPA) subunit], phospho-Ser-831-GluA1 (P-S831), phospho Ser-845-GluA1 (P-S845), and brain-derived neurotrophic factor (BDNF); and messenger RNA (mRNA) levels of GluN2A and GluN2B in different brain areas in the olfactory bulbectomy (OB) model of depression in rats. METHODS: Magnesium was administered once daily for 14 days at three doses (10, 15, and 20 mg/kg, intraperitoneal) to sham and OB rats. Following treatment, open field and passive avoidance tests were performed in the sham and OB rats. After 24 h, the hippocampus, the prefrontal cortex (PFC), and the amygdala of rats treated with the most active dose (15 mg/kg) were harvested, and the protein and mRNA levels were determined. RESULTS: Chronic administration of magnesium (15 and 20 mg/kg) reduced the number of trials required to learn passive avoidance and reduced the OB-induced hyperactivity. OB increased the P-S845 level in the hippocampus, which was reduced by magnesium treatment. Magnesium significantly increased the levels of BDNF, GluN2B, P-S831, and P-S845 protein (and mRNA) primarily in the PFC and the hippocampus in OB rats. CONCLUSION: For the first time, the present results demonstrate the antidepressant-like activity of magnesium in the OB animal model of depression and indicate the potential involvement of the AMPA/BDNF pathway in this activity. PMID- 25027583 TI - On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. AB - RATIONALE: Several studies have suggested the inhibitory control of adenosine (A)2A receptor stimulation in cocaine-induced behavioral actions. OBJECTIVES: A combination of systemic or local drug injections and in vivo neurochemical analysis investigated A2A receptors in cocaine and food reward. METHODS: Rats, trained to self-administer cocaine or food, were tested with the selective A2A receptor antagonists KW 6002 and SCH 58261 or the selective A2A receptor agonist CGS 21680. Extracellular dopamine, glutamate, and GABA levels in the nucleus accumbens and ventral pallidum were determined following intra-accumbal CGS 21680 administration during cocaine self-administration. RESULTS: Neither KW 6002 nor SCH 58261 (0.25-1 mg/kg) altered cocaine self-administration (0.125-0.5 mg/kg/infusion), while CGS 21680 (0.2-0.4 mg/kg) produced a downward shift in the cocaine dose-response curve under a fixed ratio schedule of reinforcement and decreased the cocaine breaking point. CGS 21680 blocked also operant responding for food, while the A2A receptor antagonists were inactive. Local steady-state infusion of CGS 21680 (10 MUM) during cocaine self-administration increased the active level pressing that was accompanied with reduced dopamine and increased GABA in the nucleus accumbens in the absence of changes in GABA and glutamate levels in the ventral pallidum. Pretreatment with systemic KW 6002 counteracted the increases in number of cocaine infusions seen after intra-accumbal administration of CGS 21680. CONCLUSION: The findings support a role of A2A receptors in modulating goal-maintained behaviors. They also indicate that increased accumbal GABA release involving an antagonistic A2A-D2 receptor interaction can participate in mediating the inhibitory effects of the A2A agonist on cocaine reward. PMID- 25027586 TI - Non-inferiority of creatinine excretion rate to urinary L-FABP and NGAL as predictors of early renal allograft function. AB - BACKGROUND: We evaluated accuracy of urinary liver type fatty acid-binding protein (L-FABP) for prediction of early allograft function and compared it to neutrophil gelatinase associated lipocalin (NGAL), diuresis and urinary creatinine excretion rate (UCr). METHODS: Urine samples from 71 consecutive patients were taken 4, 10, 24 and 48 h after transplantation. We classified recipients into two groups: immediate graft function (IGF), with more than 70% reduction of serum Cr at 7th day post-transplant, and delayed graft function (DGF)/slow graft function (SGF) group (DGF--the need for hemodialysis procedure in the first week, SGF--less than 70% reduction of serum Cr in the first week). RESULTS: Thirty-one recipients had IGF and 40 had DGF/SGF. L-FABP was only useful 48 h post-transplant with ROC AUC of 0.85 (95% C.I. 0.74-0.92); NGAL 24 h post transplant had ROC AUC of 0.82 (0.7-0.91). Sensitivity, specificity, PPV and NPV for prediction of DGF/SGF with L-FABP > 9.5 mg/mmol Cr and NGAL > 33.1 MUg/mmol Cr were: 86, 80, 83 and 83% (L-FABP), and 68, 93, 91, and 73% (NGAL). The difference in urine output between the groups was largest 4 h post-transplant (p = 0.001), later on the difference diminished. There were no significant differences in ROC AUC between L-FABP at 48 h, NGAL at 24 h, urine output at 4 h and UCr excretion rate at 10 h post-transplant. UCr < 0.56 mmol/h 10 h post transplant predicted DGF/SGF with 94% sensitivity, 84% specificity, 89% PPV and 91% NPV, ROC AUC was 0.9. Classification tree with urine output 4 h and UCr 10 h post-transplant accurately predicted 89% of outcomes. When L-FABP or NGAL were added, the prediction was accurate in 92 or 90%, respectively. CONCLUSIONS: L FABP is comparable to NGAL for prediction of first week allograft function, however UCr and diuresis were non-inferior. PMID- 25027587 TI - Chemically mediated group formation in soil-dwelling larvae and pupae of the beetle Trypoxylus dichotomus. AB - Many insects form groups through interactions among individuals, and these are often mediated by chemical, acoustic, or visual cues and signals. In spite of the diversity of soil-dwelling insects, their aggregation behaviour has not been examined as extensively as that of aboveground species. We investigated the aggregation mechanisms of larvae of the Japanese rhinoceros beetle Trypoxylus dichotomus, which live in groups in humus soil. In two-choice laboratory tests, 2nd- and 3rd-instar larvae gathered at conspecific larvae irrespective of the kinship. The ablation of maxillae, which bear chemosensilla, abolished aggregation behaviour. Intact larvae also exhibited aggregation behaviour towards a larval homogenate. These results suggest that larval aggregation is mediated by chemical cues. We also demonstrated that the mature larvae of T. dichotomus built their pupal cells close to a mesh bag containing a conspecific pupal cell, which indicated that larvae utilize chemical cues emanating from these cells to select the pupation site. Thus, the larvae of T. dichotomus may use chemical cues from the conspecifics in two different contexts, i.e. larval aggregation and pupation site selection. Using conspecific cues, larvae may be able to choose suitable locations for foraging or building pupal cells. The results of the present study highlight the importance of chemical information in belowground ecology. PMID- 25027585 TI - Effects of pitavastatin versus atorvastatin on the peripheral endothelial progenitor cells and vascular endothelial growth factor in high-risk patients: a pilot prospective, double-blind, randomized study. AB - BACKGROUND: Circulating endothelial progenitor cells (EPCs) reflect endothelial repair capacity and may be a significant marker for the clinical outcomes of cardiovascular disease. While some high-dose statin treatments may improve endothelial function, it is not known whether different statins may have similar effects on EPCs.This study aimed to investigate the potential class effects of different statin treatment including pitavastatin and atorvastatin on circulating EPCs in clinical setting. METHODS: A pilot prospective, double-blind, randomized study was conducted to evaluate the ordinary dose of pitavastatin (2 mg daily) or atorvastatin (10 mg daily) treatment for 12 weeks on circulating EPCs in patients with cardiovascular risk such as hypercholesterolemia and type 2 diabetes mellitus (T2DM). Additional in vitro study was conducted to clarify the direct effects of both statins on EPCs from the patients. RESULTS: A total of 26 patients (19 with T2DM) completed the study. While the lipid-lowering effects were similar in both treatments, the counts of circulating CD34+KDR+EPCs were significantly increased (from 0.021 +/- 0.015 to 0.054 +/- 0.044% of gated mononuclear cells, P < 0.05) only by pitavastatin treatment. Besides, plasma asymmetric dimethylarginine level was reduced (from 0.68 +/- 0.10 to 0.53 +/- 0.12 MUmol/L, P < 0.05) by atorvastatin, and plasma vascular endothelial growth factor (VEGF) level was increased (from 74.33 +/- 32.26 to 98.65 +/- 46.64 pg/mL, P < 0.05) by pitavastatin. In the in vitro study, while both statins increased endothelial nitric oxide synthase (eNOS) expression, only pitavastatin increased the phosphorylation of eNOS in EPCs. Pitavastatin but not atorvastatin ameliorated the adhesion ability of early EPCs and the migration and tube formation capacities of late EPCs. CONCLUSIONS: While both statins similarly reduced plasma lipids, only pitavastatin increased plasma VEGF level and circulating EPCs in high-risk patients, which is probably related to the differential pleiotropic effects of different statins. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT01386853. PMID- 25027588 TI - An opilioacarid mite in Cretaceous Burmese amber. AB - A fossil opilioacarid mite (Parasitiformes: Opilioacarida) in Burmese amber is described as ?Opilioacarus groehni sp. nov. This ca. 99 Ma record (Upper Cretaceous: Cenomanian) represents only the third fossil example of this putatively basal mite lineage, the others originating from Eocene Baltic amber (ca. 44-49 Ma). Our new record is not only the oldest record of Opilioacarida, but it is also one of the oldest examples of the entire Parasitiformes clade. The presence of Opilioacarida-potentially Opiloacarus-in the Cretaceous of SE Asia suggests that some modern genus groups were formerly more widely distributed across the northern hemisphere, raising questions about previously suggested Gondwanan origins for these mites. PMID- 25027589 TI - Hours lying down per day and mortality from all-causes and cardiovascular disease: the HUNT Study, Norway. AB - Time spent sitting has been positively associated with mortality in several studies, whereas time lying down per day has not been extensively studied. The authors prospectively examined the association between hours lying down per day and risk of death from all-causes and from cardiovascular disease among 39,175 persons aged 20-79 years in the population-based HUNT Study in Norway. Adjusted hazard ratios (HRs) with 95 % confidence intervals (CIs) were obtained from Cox regression, using people lying down for 7 h per day as reference. During a median follow-up of 12.3 years a total of 2,659 persons died (851 from cardiovascular disease). People lying 11-18 h per day had a HR of 1.60 (95 % CI 1.29, 1.98) for death from all causes and a HR of 1.91 (95 % CI 1.35, 2.71) for cardiovascular death. Analyses stratified by leisure time physical activity showed a positive association with cardiovascular mortality also among physically active people, with HRs of 1.38 (95 % CI 0.97, 1.96) and 1.84 (95 % CI 1.07, 3.16) among people lying down 10 and 11-18 h per day, respectively. In this large prospective study, excessive hours lying down per day were associated with increased all-cause and cardiovascular mortality, even among physically active persons. PMID- 25027590 TI - Evaluation of seasonal antioxidant activity and total phenolic compounds in stems and leaves of some almond (Prunus amygdalus L.) varieties. AB - BACKGROUND: This study aimed to determine the seasonal changes of total antioxidant activity and phenolic compounds in samples taken from leaves (April, July, October) and stems (April, July, October, January) of some almond (Prunus amygdalus L.) varieties (Nonpareil, Ferragnes and Texas). RESULTS: It was indicated that antioxidant activity and phenolic compounds in leaves and stems of Nonpareil, Ferragnes and Texas showed seasonal differences. Antioxidant activity IC50 of these varieties reached the highest value in April for leaves whereas in October for stems. The highest level of total phenolic compounds was in January for stems while in October for leaves. CONCLUSIONS: These results showed that total antioxidant activity and phenolics in leaves and stems of almond varieties changed according to season and plant organ. PMID- 25027591 TI - Breast cancer: Improving cancer detection rates. PMID- 25027592 TI - Genetics: Driver genes are mutated early in the course of oesophageal adenocarcinoma. PMID- 25027593 TI - Pancreatic cancer: CONKO conquers. PMID- 25027594 TI - Supporter of assisted dying law fears wrecking tactics by opponents. PMID- 25027595 TI - TM4SF5-mediated protein-protein networks and tumorigenic roles. AB - Transmembrane 4 L six family member 5 (TM4SF5), as a membrane glycoprotein with 4 transmembrane domains, is similar to the tetraspanins in terms of membrane topology and plays important roles in tumorigenesis and tumor metastasis. Especially, TM4SF5 appears to form a massive protein-protein complex consisting of diverse membrane proteins and/or receptors in addition to cytosolic signaling molecules to regulate their signaling activities during the pathological processes. TM4SF5 is shown to interact with integrins alpha2, alpha5, and beta1, EGFR, IL6R, CD151, focal adhesion kinase (FAK), and c-Src. This review focuses on the significance of the interactions with regards to TM4SF5-positive tumorigenesis and metastasis. PMID- 25027596 TI - Tight junction protein 1 is regulated by transforming growth factor-beta and contributes to cell motility in NSCLC cells. AB - Tight junction protein 1 (TJP1), a component of tight junction, has been reported to play a role in protein networks as an adaptor protein, and TJP1 expression is altered during tumor development. Here, we found that TJP1 expression was increased at the RNA and protein levels in TGF-beta-stimulated lung cancer cells, A549. SB431542, a type-I TGF-beta receptor inhibitor, as well as SB203580, a p38 kinase inhibitor, significantly abrogated the effect of TGF-beta on TJP1 expression. Diphenyleneiodonium, an NADPH oxidase inhibitor, also attenuated TJP1 expression in response to TGF-beta in lung cancer cells. When TJP1 expression was reduced by shRNA lentiviral particles in A549 cells (A549-sh TJP1), wound healing was much lower than in cells infected with control viral particles. Taken together, these data suggest that TGF-beta enhances TJP1 expression, which may play a role beyond structural support in tight junctions during cancer development. PMID- 25027597 TI - Endothelial dysfunction in patients with chronic venous disease: an evaluation based on the flow-mediated dilatation test. AB - AIM: The vascular system constitutes a functional whole, and it has been assumed that the arterial endothelium and the venous endothelium are organs integral to internal secretion. Despite previous studies concerning the potential role of endothelial cells in the development of chronic venous disease (CVD), there is still no direct clinical confirmation of endothelial dysfunction in CVD patients. The aim of this study was to document the presence of endothelial cell dysfunction in a clinical setting in CVD patients. METHODS: In this study, the flow-mediated dilatation (FMD) test was performed in 131 patients with CVD (at stages C0s-C3 according to the CEAP classification) and 84 healthy volunteers. With the help of a precise algorithm, all the patients with other confirmed factors that could potentially influence endothelial activity were excluded from the examination. RESULTS: FMD test values were lower in the CVD group (median: 7.87 +/- 3.31%) compared to the control group (median: 12.06 +/- 3.94%) (p<0.05). With sex separation and partition into two age groups (20-40 and 41-60 yrs.), characteristic, significant FMD value differences were obtained. In the statistical analysis, the clinical severity of CVD negatively correlated with the FMD value. CONCLUSION: According to the FMD test results, endothelial dysfunction was observed in patients with CVD. The change in the endothelial activity observed in this examination correlates with the clinical severity of chronic venous disease. PMID- 25027598 TI - Impaired central arterial elasticity in young adults born with intrauterine growth restriction. AB - BACKGROUND: Intrauterine growth retardation and prematurity at birth constitute risk factors for future cardiovascular adverse events. Some previous reports have highlighted that subjects born preterm may develop peripheral arterial dysfunction. However, central (aortic) arterial distensibility has not yet been fully investigated in these subjects. METHODS: Sixty subjects were enrolled: thirty were high grade ex-preterm subjects (10 males [M] and 20 females [F], aged 17-28, mean 20.1+/-2.5 years). They were compared with 30 healthy, age-matched subjects born at term (C, 10 M and 20 F). Central aortic elasticity was assessed non-invasively by calculating two indexes derived from echocardiographic and blood pressure measures: aortic root distensibility and aortic stiffness index. RESULTS: Aortic distensibility was significantly lower (P<0.0001), and aortic stiffness index was significantly higher (P<0.0001) in former preterm individuals than in controls. The above stated indexes were correlated with birth weight (r=0.78, P<0.0001 and r=-0.41, P=0.02, respectively), as well as with gestational age (r=0.54, P=0.002 and r=-0.37, P=0.04, respectively). When excluding the influence of body mass index, intrauterine growth restriction - expressed as birth weight - remains the only determinant of impaired central arterial elasticity. CONCLUSIONS: Since aortic distensibility usually impairs in time, former preterm subjects appear to have a "vascular age" older than their healthy born at term peers. This finding may have important implications for cardiovascular morbidity in later life. PMID- 25027599 TI - Acute and mid-term outcomes after treatment of multiple, recurrent restenoses of the lower limb arteries. AB - AIM: Recanalization of long segmental occlusions of femoropopliteal arteries can be achieved by angioplasty and implantation of nitinol stents with high procedural success rates. However, due to recurrent in-stent restenoses (ISR) some patients need repeated interventions and their intermediate success rates are uncertain. METHODS: Patients who were treated in our center from March 2008 through February 2011 due to symptomatic ISR (as determined by Duplex sonography) were retrospectively included in the study. After endovascular treatment of their ISR, they were prospectively evaluated with regard to recurrent ISR of the target lesions. RESULTS: A total of 36 limbs (=lesions) in 32 patients (69% male, mean age 69+/-9 years) were successfully treated by balloon-angioplasty. Adjunctive cutting balloons and drug eluting balloons were used in 78% and 8%, respectively. Mean follow-up was 326 days. Recurrent ISR occurred in 10 (28%) lesions, while 26 (78%) lesions showed no recurrence of ISR. In a multivariate logistic regression analysis, age, gender, cardiovascular risk factors, renal failure and medication with cilostazol were not significantly associated with recurrent ISR. Moreover, the number of previous interventions of the target lesions was not an independent predictor of recurrent ISR. CONCLUSION: Patients with multiple recurrences of ISR seem to have the same prospects of acute and mid-term success for endovascular treatment as those with first presentation of ISR. However, this observation has to be confirmed by prospective, large scale studies with a longer follow-up period to determine the significance of endovascular intervention within the scope of different revascularization approaches for treatment of recurrent ISR. PMID- 25027600 TI - Selective high ligation of the sapheno-femoral junction decreases the neovascularization and the recurrent varicose veins in the operated groin. AB - AIM: High ligation (HL) and stripping of GSV can be distinguished in Babcock's radical ligation (RHL), and selective (SHL): the new technique consists to ligate the SFJ keeping some of the tributary veins. The study analyzes the neovascularization and recurrence incidence in the groin after the SHL. METHODS: A retrospective study performed in a center specialized in venous surgery in Italy, it included 360 patients underwent unilateral varicose vein surgery from January 2001 to December 2008 (210 females and 150 males, mean aged 51.9 years, range 18 to 75 years, the limbs were 222 rights and 138 lefts), CEAP classification was C2,s. Operative technique was standardised to SFJ ligation with the SHL, the GSV was stripped to the level of the knee, multiple phlebectomies were performed and the ligation of the incontinent perforating veins was performed if it was necessary. All patients had a venous reflux from terminal valve of SFJ and the femoral valves were continent. All patients were submitted to clinical examination of the lower limbs and Duplex Scanning (DS) in the pre/postoperative period every year after surgery and by two independent operator in 2013. The follow-up is from 5 years for the patients operated in 2008 to 12 years for the patients operated in 2001. RESULTS: The neovascularizations and recurrencies in the groin were founded in 7 patients, the incidence is 1.9% of the total cases. The GSV stump and the left tributaries were open to venous flow, it was no venous reflux from the groin, no venous thrombosis of the GSV stump were detected. CONCLUSION: The SHL of the SFJ is a reliable technique, decreasing the incidence of neovascularizations and recurrent varicose veins in the operated groin. PMID- 25027601 TI - Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells. AB - The vitamin A metabolite all-trans retinoic acid (RA) is an important determinant of intestinal immunity. RA primes dendritic cells (DCs) to express CD103 and produce RA themselves, which induces the gut-homing receptors alpha4beta7 and CCR9 on T cells and amplifies transforming growth factor (TGF)-beta-mediated development of Foxp3(+) regulatory T (Treg) cells. Here we investigated the effect of RA on human DCs and subsequent development of T cells. We report a novel role of RA in immune regulation by showing that RA-conditioned human DCs did not substantially enhance Foxp3 but induced alpha4beta7(+) CCR9(+) T cells expressing high levels of interleukin (IL)-10, which were functional suppressive Treg cells. IL-10 production was dependent on DC-derived RA and was maintained when DCs were stimulated with toll-like receptor ligands. Furthermore, the presence of TGF-beta during RA-DC-driven T-cell priming favored the induction of Foxp3(+) Treg cells over IL-10(+) Treg cells. Experiments with naive CD4(+) T cells stimulated by anti-CD3 and anti-CD28 antibodies in the absence of DCs emphasized that RA induces IL-10 in face of inflammatory mediators. The data thus show for the first time that RA induces IL-10-producing Treg cells and postulates a novel mechanism for IL-10 in maintaining tolerance to the intestinal microbiome. PMID- 25027602 TI - IFI16: At the interphase between innate DNA sensing and genome regulation. AB - DNA carries the genetic code, and is also a potent stimulator of innate immune responses. IFI16 is a member of the family of PYHIN proteins and is composed of a PYRIN domain involved in homotypic protein-protein interactions and two HIN domains mediating DNA binding. PYHIN proteins have been described to possess functions as innate pattern recognition receptors or transcriptional regulators. Interestingly, it is now emerging that IFI16, which exhibits both nuclear and cytosolic location, possesses both of these functions. In this review we discuss the current literature on IFI16 and propose key questions now facing this field of research. We propose that IFI16 plays a central role in the close interaction between the innate immune system and cellular regulation of the genome. PMID- 25027603 TI - Robertsonian chromosomes and the nuclear architecture of mouse meiotic prophase spermatocytes. AB - BACKGROUND: The nuclear architecture of meiotic prophase spermatocytes is based on higher-order patterns of spatial associations among chromosomal domains from different bivalents. The meiotic nuclear architecture depends on the chromosome characteristics and consequently is prone to modification by chromosomal rearrangements. In this work, we consider Mus domesticus spermatocytes with diploid chromosome number 2n = 40, all telocentric, and investigate a possible modification of the ancestral nuclear architecture due to the emergence of derived Rb chromosomes, which may be present in the homozygous or heterozygous condition. RESULTS: In the 2n = 40 spermatocyte nuclei random associations mediated by pericentromeric heterochromatin among the 19 telocentric bivalents ocurr at the nuclear periphery. The observed frequency of associations among them, made distinguishable by specific probes and FISH, seems to be the same for pairs that may or may not form Rb chromosomes. In the homozygote Rb 2n = 24 spermatocytes, associations also mediated by pericentromeric heterochromatin occur mainly between the three telocentric or the eight metacentric bivalents themselves. In heterozygote Rb 2n = 32 spermatocytes all heterochromatin is localized at the nuclear periphery, yet associations are mainly observed among the three telocentric bivalents and between the asynaptic axes of the trivalents. CONCLUSIONS: The Rb chromosomes pose sharp restrictions for interactions in the 2n = 24 and 2n = 32 spermatocytes, as compared to the ample possibilities for interactions between bivalents in the 2n = 40 spermatocytes. Undoubtedly the emergence of Rb chromosomes changes the ancestral nuclear architecture of 2n = 40 spermatocytes since they establish new types of interactions among chromosomal domains, particularly through centromeric and heterochromatic regions at the nuclear periphery among telocentric and at the nuclear center among Rb metacentric ones. PMID- 25027604 TI - Expression, purification, and characterization of rhTyrRS. AB - BACKGROUND: Aminoacyl-tRNA synthetases (AARSs) catalyze the first step of protein synthesis. Emerging evidence indicates that AARSs may have additional functions, playing a role in signal transduction pathways regulating thrombopoiesis and inflammation. Recombinant human tyrosyl-tRNA synthetase (rhTyrRS) is engineered with a single amino acid substitution that unmasks its cytokine activity. An industrial production method that provides high yield as well as high purity, quality, and potency of this protein is required for preclinical research. RESULTS: We expressed codon-optimized rhTyrRS in Escherichia coli under fermentation conditions. Soluble protein was purified by a three-step purification method using cation exchange chromatography, gel filtration chromatography, and anion exchange chromatography. We also established a method to test the biological activity of rhTyrRS by measuring aminoacylation and IL-8 release in rhTyrRS-treated HL-60 cells. CONCLUSIONS: The characterization of purified rhTyrRS indicated that this protein can be used in pharmacodynamic and pharmacokinetic studies. PMID- 25027605 TI - Molecular dynamics study of the dominant-negative E219K polymorphism in human prion protein. AB - Human prion diseases are associated with misfolding or aggregation of the Human Prion Protein (HuPrP). Missense mutations in the HuPrP gene, contribute to conversion of HuPrP(C) to HuPrP(Sc) and amyloid formation. Based on our previous comprehensive study, three missense mutations, from two different functional groups, i.e. disease-related mutations, and protective mutations, were selected and extensive molecular dynamics simulations were performed on these three mutants to compare their dynamics and conformations with those of the wildtype HuPrP. In addition to simulations of monomeric forms of mutants, in order to study the dominant-negative effect of protective mutation (E219K), 30-ns simulations were performed on E219K-wildtype and wildtype-wildtype dimeric forms. Our results indicate that, although after 30-ns simulations the global three dimensional structure of models remain fairly intact, the disease-related mutations (V210I and Q212P) introduce local structural changes, i.e. close contact changes and secondary structure changes, in addition to global flexibility changes. Furthermore, our results support the loss of hydrophobic interaction due to the mutations in hydrophobic core that has been reported by previous NMR and computational studies. On the other hand, this protective mutation (E219K) results in helix elongation, and significant increases of overall flexibility of E219K mutant during 30-ns simulation. In conclusion, the simulations of dimeric forms suggest that the dominant-negative effect of this protective mutation (E219K) is due to the incompatible structures and dynamics of allelic variants during conversion process. PMID- 25027606 TI - Novel treatments with small molecules in psoriatic arthritis. AB - Current treatment options for patients with active psoriatic arthritis (PsA) include synthetic disease-modifying antirheumatic drugs and biologic agents. Propelled by increased understanding of immunopathogenesis of PsA, new therapeutic agents targeting different biologic pathways have been evaluated. This article discusses novel small-molecule, orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA. This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase (JAK) inhibitors. Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA. Tofacitinib, an oral inhibitor of JAK3, JAK1, and, to a lesser degree, JAK2, approved for the treatment of rheumatoid arthritis in several countries, has demonstrated positive results in psoriasis in phase II studies. Studies in PsA are ongoing. With these new developments, treatment options will continue to improve in the future. PMID- 25027609 TI - Detection of Anaplasma platys in dogs and Rhipicephalus sanguineus group ticks by a quantitative real-time PCR. AB - Anaplasma platys is an obligate intracellular, tick-borne pathogen of dogs, which causes canine infectious cyclic thrombocytopenia (CICT). The vector role of Rhipicephalus sanguineus group ticks has been only suggested, but definitive evidence is lacking. This study aimed to detect and quantify A. platys DNA in infected dogs and in their respective ticks through a quantitative real-time PCR assay. From March to May 2009, blood and tick samples from dogs residing in a CICT-endemic area were collected and molecularly analysed. Differences (p<0.05) were detected in the bacterial load between tick nymphs (3.5 * 10(-2)+/- 2.5 * 10(-2)) and adults (female: 1.2 * 10(-1) +/- 1.1 * 10(-1); male: 9.3 * 10(-2)+/- 1.2 * 10(-2)) and between unengorged (1.1 * 10(-1) +/- 2.8 * 10(-2)) and partially or fully engorged ticks (1.9 * 10(-1) +/- 2.7 * 10(-2)). No difference was found between ticks collected from positive (1.1 * 10(-1)+/- 0.6 * 10(-1)) and negative (1.2 * 10(-1) +/- 0.3 * 10(-1)) dogs (p>0.05). The mean bacterial load detected in positive dogs was lower than that in their respective ticks (p>0.05). This study provides circumstantial evidence of the putative role of Rhipicephalus sp. I as a vector of this pathogen. PMID- 25027610 TI - The European wildcats (Felis silvestris silvestris) as reservoir hosts of Troglostrongylus brevior (Strongylida: Crenosomatidae) lungworms. AB - The increasing reports of Troglostrongylus brevior lungworm in domestic cats from Italy and Spain raised questions on its factual distribution and on the role wildcats play as reservoirs of these parasites. Carcasses of 21 wildcats were collected in natural parks of southern Italy (i.e., Catania, Sicily n=5 and Matera, Basilicata n=16) and biometrically and genetically identified as Felis silvestris silvestris, but two as hybrids. Troglostrongylus brevior and Eucoleus aerophilus lungworms were found in 15 (71.4%) and 7 (33.3%) individuals, respectively, being five (23.8%) co-infected by the two species. Both lungworms showed an aggregated distribution in the host population, assessed by k-index (i.e., 0.69 for T. brevior and 0.42 for E. aerophilus). Although no statistical significant difference was recorded among age, gender and geographical location of wildcats, a larger rate of infection by T. brevior was assessed in yearlings (85.7%) than adults (64.3%). This is the first epidemiological study reporting T. brevior infection in the European wildcat and discusses the potential threat this may represent for the conservation of this endangered species of felids. In addition, given the large frequency of lungworm infection herein recorded, the role of wildcats as reservoir hosts of these parasites to domestic cats is discussed. PMID- 25027611 TI - The adulticide effect of a combination of doxycycline and ivermectin in Dirofilaria immitis-experimentally infected dogs is associated with reduction in local T regulatory cell populations. AB - In a previous study, dogs experimentally infected with Dirofilaria immitis were treated with either ivermectin or doxycycline or a combination of both. The adulticide effect was significantly higher in the dogs treated with both drugs and was similar to that observed in dogs treated with melarsomine hydrochloride. In the present study, lung tissue samples from these dogs were evaluated for the presence of T regulatory (Foxp3+) cells by immunohistochemistry. Cells were enumerated for each dog in the four groups and compared with untreated controls. There was a significantly lower number of Treg cells in those dogs treated with a combination of both drugs when compared either to the control group or to the other groups treated with either drug alone or with melarsomine. These results suggest that successful adulticide effects of doxycycline and ivermectin are associated with a decrease in immune regulation towards the parasite. PMID- 25027612 TI - Volume of fluids administered during resuscitation for severe sepsis and septic shock and the development of the acute respiratory distress syndrome. AB - PURPOSE: The purpose of this study was to examine the association between the volume of intravenous (IV) fluids administered in the resuscitative phase of severe sepsis and septic shock and the development of the acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: This was a retrospective cohort study of adult patients admitted with severe sepsis and septic shock at a large academic public hospital. The relationship between the volume of IV fluids administered and the development of ARDS was examined using multivariable logistic regression analysis. RESULTS: Among 296 patients hospitalized for severe sepsis and septic shock, 75 (25.3%) developed ARDS. After controlling for confounding variables, there was no significant association between the volume of IV fluids administered in the first 24 hours of hospitalization and the development of ARDS (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.95 1.18). Serum albumin (OR, 0.52; 95% CI, 0.31-0.87) and Acute Physiology and Chronic Health Evaluation II score (OR, 1.08; 95% CI, 1.04-1.13) on admission were the most informative covariates for the development of ARDS in the regression model. CONCLUSIONS: For patients hospitalized for severe sepsis and septic shock, fluid administration to improve end-organ perfusion should remain the top priority in early resuscitation despite the potential risk of inducing ARDS. PMID- 25027613 TI - Calf muscle venous thrombosis: a review of the clinical implications and therapy. AB - Calf muscle veins have been demonstrated to be one of the most frequent areas that develop deep venous thrombosis (DVT), both as an isolated finding and in combination with proximal DVT. Calf muscle venous thrombosis (CMVT) has been shown to be more frequently associated with localized calf tenderness, and when left untreated, a proportion tend to propagate proximally and may lead to pulmonary embolism. Imaging with duplex venous scanning is fairly sensitive in the diagnosis of CMVT. Treatment recommendations for CMVT are variable with some studies showing clear clinical benefit of anticoagulation therapy and others showing no benefit. PMID- 25027614 TI - Heart failure caused by renal arteriovenous fistula with giant renal artery aneurysms. AB - We encountered an extremely rare case of a renal arteriovenous fistula (AVF) with 2 giant renal artery aneurysms (RAAs) in a 75-year-old woman who presented with congestive heart failure and pulmonary hypertension. A chest x-ray revealed cardiomegaly with a cardiothoracic ratio (CTR) of 65%. Computed tomography showed 2 giant left RAAs (diameter, 45 * 40 mm(2) and 75 * 60 mm(2)) associated with an AVF, dilated inferior vena cava, and dilated pulmonary arteries. A radical nephrectomy was performed through a transverse laparotomy after the left renal vein, and arteries were dissected from the inferior vena cava and aorta, respectively. The patient's postoperative course was uneventful, and her condition improved. Her cardiomegaly was ameliorated, as manifested by a decrease in CTR to 57% and the absence of volume overload. PMID- 25027615 TI - Pharmacokinetic profile of dextromethorphan hydrobromide in a syrup formulation in children and adolescents. AB - BACKGROUND: Dextromethorphan hydrobromide (DM) is a widely used antitussive. This study determined, for the first time, the basic pharmacokinetic profile of DM and its active metabolite, dextrorphan (DP) in children and adolescents. METHODS: Thirty-eight male and female subjects at risk for developing an upper respiratory tract infection (URTI), or symptomatic with cough due to URTI, were enrolled in this single-dose, open-label study: ages 2-5 years (Group A, n = 8), 6-11 years (Group B, n = 17), 12-17 years (Group C, n = 13). Subjects were genotyped for cytochrome P450 (CYP) 2D6 polymorphisms and characterized as poor (PM) or non poor metabolizers (non-PM). Groups A and B were dosed using an age-weight dosing schedule (DM range 7.5-24.75 mg); a 30-mg dose was used for Group C. RESULTS: Average exposures to total DP increased as age group increased, and average exposure to DM was highest in the adolescent group. One subject in that group was a PM. The terminal half-life (t 1/2) values were longer in the adolescent group due in part to the single PM subject. No relationship between body weight and pharmacokinetic parameters was noted. CONCLUSIONS: This is the first evaluation of the pharmacokinetic characteristics of DM in children and adolescents. A single dose of DM in this population was safe, and well tolerated at all doses tested. The data are used to model and compare pediatric DM exposures with those of adults. PMID- 25027616 TI - Intra-rater and inter-rater reliabilities of real-time acceleration gait analysis system. AB - PURPOSE: The purposes of this study were to construct a real-time acceleration gait analysis system equipped with software to analyse real-time trunk acceleration during walking and to examine the intra-rater and inter-rater reliabilities of the this system. METHODS: This system has been comprised of an accelerometer, an acceleration amplifier, a transmitter, two foot switches, a receiver and a personal computer installed with the real-time acceleration analysis software. The acceleration signals received were analysed using the real time acceleration analysis software, and gait parameters were calculated. The subjects were 20 healthy individuals and two raters. The intra-rater and inter rater reliabilities of the measurement results obtained from this system were examined by performing intraclass correlation coefficients (ICC) and Bland-Altman analysis. RESULTS: The intra-rater and inter-rater ICCs ranged from 0.61 to 0.92 in any gait parameters. In the Bland-Altman analysis, neither fixed nor proportional bias was found in any of the gait parameters. CONCLUSIONS: From the ICC and Bland-Altman analysis results, the gait measurement using this system clearly demonstrates that the intra-rater and inter-rater measurements had good reproducibility. Owing to this system, we can improve the clinical efficiency of gait analysis and gait training for physiotherapy. Implication for Rehabilitation This study focused on the advantage of a gait analysis method using an accelerometer and constructed a gait analysis system that calculates real-time gait parameters from trunk acceleration measurements during walking. The gait analysis using this system has good intra-rater and inter-rater reliabilities, and using this system can improve the clinical efficiency of gait analysis and gait training. PMID- 25027617 TI - Neuroanatomical differences between men and women in help-seeking coping strategy. AB - Help seeking (HS) is a core coping strategy that is directed towards obtaining support, advice, or assistance as means of managing stress. Women have been found to use more HS than men. Neural correlates of sex differences have also been reported in prefrontal-limbic system (PLS) regions that are linked to stress and coping, yet structural differences between men and women relating to HS in the PLS are still unknown. Thus, the association between gray matter volume (GMV) and HS was investigated using voxel-based morphometry (VBM) in a large healthy sample (126 men and 156 women). Results indicated women reported more HS than men did. VBM results showed that the relation between HS scores and GMV differed between men and women in regions of the bilateral orbitofrontal cortex extending to the subgenual anterior cingulate cortex(OFC/sgACC). Among women, higher HS scores were associated with smaller GMV in these areas while a positive correlation between GMV and HS scores was observed among men. These results remained significant after controlling for general intelligence, stress, anxiety and depression. Thus, this study suggested that structural differences between men and women are correlated to characteristic brain regions known to be involved in the PLS which is considered critical in stress regulation. PMID- 25027618 TI - A routine method for cloning, expressing and purifying Abeta(1-42) for structural NMR studies. AB - Nuclear magnetic resonance (NMR) is a key technology in the biophysicist's toolbox for gaining atomic-level insight into structure and dynamics of biomolecules. Investigation of the amyloid-beta peptide (Abeta) of Alzheimer's disease is one area where NMR has proven useful, and holds even more potential. A barrier to realizing this potential, however, is the expense of the isotopically enriched peptide required for most NMR work. Whereas most biomolecular NMR studies employ biosynthetic methods as a very cost-effective means to obtain isotopically enriched biomolecules, this approach has proven less than straightforward for Abeta. Furthermore, the notorious propensity of Abeta to aggregate during purification and handling reduces yields and increases the already relatively high costs of solid phase synthesis methods. Here we report our biosynthetic and purification developments that yield pure, uniformly enriched 15N and 13C15N Abeta(1-42), in excess of 10 mg/L of culture media. The final HPLC-purified product was stable for long periods, which we characterize by solution-state NMR, thioflavin T assays, circular dichroism, electrospray mass spectrometry, and dynamic light scattering. These developments should facilitate further investigations into Alzheimer's disease, and perhaps misfolding diseases in general. PMID- 25027619 TI - [Perioperative haemodynamic complications of ectopia cordis]. PMID- 25027620 TI - [Outbreak of hand, foot and mouth disease with onychomadesis caused by Coxsackie virus A16 in Granada]. AB - INTRODUCTION: Due to the significant increase in the number of cases of hand, foot and mouth disease (HFMD) among pre-school children population during late 2011 and early 2012. A study has been proposed with the aim of describing the HFMD outbreak and analyzing the risk factors associated with suffering onychomadesis. PATIENTS AND METHODS: A descriptive and analytical case-control study was designed. The study population was 376 children between 6 and 36 months old, living in the Basic Health Catchment area of Peligros (Granada). The study inclued an epidemiological survey of 28 cases and paired controls in order to collect data on the time, person and place, and implementing preventive actions and family health education. Finally a microbiological viral study of stool samples was made. RESULTS: There were 64% of girls with average age 20.8 months. The clinical signs fornd were, fever (75%), vesicular palmar eruption (71%), plantar eruption (68%), erosive stomatitis (64%), and nail loss (46%). The risk of getting sick was 14 times greater for those children attending a childcare centre and had contact with sick cases (OR 13.8; 95% CI; 3.79-50.18). The average time since onset of symptoms and onychomadesis was 52 days, and its appearance was linked to the presence of ulcers in mouth (P=.006). Five samples were positive to enteroviruses Coxsackie A16. CONCLUSION: There was an outbreak of HFMD detected by pediatricians and families. The cases presented with marked clinical symptoms, and the nail loss (onychomadesis) generated a social alarm. The cause of the outbreak was an enterovirus Coxsackie A16 transmitted among sick cases and through childcare centres. PMID- 25027621 TI - [Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene]. AB - Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory. PMID- 25027622 TI - [Atypical cardiac tamponade due to central venous catheter. Can we prevent it?]. PMID- 25027623 TI - A modified technique for fixation of chronic instability of the distal tibiofibular syndesmosis using a wire and button. AB - Distal tibiofibular syndesmosis injury accounts for 1% to 11% of soft tissue injuries of the ankle. Some acute syndesmotic injuries will fail to heal effectively owing to inadequate treatment or misdiagnosis, eventually resulting in chronic instability, which can destroy the stability of the ankle joint. Various surgical techniques have been described for fixation of the syndesmosis. Among the existing methods, the suture button has the advantage of allowing for physiologic micromotion at the syndesmosis by maintaining the reduction and preventing the risk of screw breakage. However, the "relatively" long suture between buttons can gradually relax under continuous loading, resulting in fixation failure, which we have termed electric wire phenomenon. In the present report, we have described a modified technique for flexible fixation using the Endobutton CL ULTRA fixation device by tricortical fixation, instead of quadricortical fixation, to allow for robust and reliable fixation of the distal tibiofibular syndesmosis. The modified technique is devoid of the concern regarding the use of screw fixation and can reduce the risk of displacement or elongation and skin irritation associated with the suture button. PMID- 25027625 TI - Ethnobotanical and economic value of Ravenala madagascariensis Sonn. in Eastern Madagascar. AB - BACKGROUND: Known worldwide as the "traveler's tree", the Malagasy endemic species Ravenala madagascariensis Sonn. (Strelitziaceae) is considered as an iconic symbol of Madagascar. It is a widespread species in the eastern part of the country with four different varieties which are well represented in Ambalabe community. All of them are used for different purposes and the species represents an important cultural value in the lives of the local population. However, uses of Ravenala are only generally well known by local population. Thus, in this study, we report on the different uses of Ravenala and its importance to the Ambalabe local people. METHODS: Semi-structured interviews among 116 people, 59 men and 57 women with ages ranging from 17 to 84 years old, free listing and market surveys were conducted in order to collect the vernacular names, the uses of Ravenala madagascariensis and the price of plant parts sold in local market. Then, the uses were categorized according to Camara-Leret et al. classification. RESULTS: Different parts of the plant are currently used by local population, which are grouped as heart, trunk, leaves, petioles and rachis. Seven categories of use were recorded, most cited include: human food, utensils and tools, and house building. The most commonly used parts are trunk, heart, leaves and petioles for which the price varies between $3-15. Uses mentioned for construction (floor, roofs and wall), human food and utensils and tools are the most frequent and salient for local population. But the use of the plant as first materials for house building is revealed to be the most important for them. CONCLUSIONS: Ravenala madagascariensis is very important to the Ambalabe communities because for local population, it represents the Betsimisaraka cultural and traditional use of the plant for house building. Moreover, none of its parts are discarded. The harvest and sale of R. madagascariensis for building materials can also provide an additional source of income to the family. Besides, using Ravenala in house construction reduces the use of slow growing trees and contributes to the sustainable use of natural forest resources. PMID- 25027624 TI - Protein overexpression of CIRP and TLR4 in oral squamous cell carcinoma: an immunohistochemical and clinical correlation analysis. AB - Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy. Here, we evaluated the expression of cold-inducible RNA-binding protein (CIRP) and toll-like receptors 4 (TLR4) in OSCC tissues with immunohistochemistry. Using biostatistical methods designed to assess the impact of the expression of CIRP and TLR4 on the prognosis of patients with OSCC and relate that expression to the clinicopathological characteristics of these patients. For the first time, we demonstrated that the expression of CIRP and TLR4 was increased in OSCC and that high levels of CIRP or TLR4 expression were associated with a short survival rate. In addition, we were surprised to find that the levels of expression of CIRP and TLR4 were very similar. The goal of this study was to evaluate whether these two genes may provide clues as to the regulatory mechanisms of OSCC, serve as prognostic markers and establish a new direction for further studies of these biological mechanisms. PMID- 25027626 TI - Baseline serum interleukin-34 levels independently predict radiographic progression in patients with rheumatoid arthritis. AB - The aim of our observational study was to investigate the clinical significance of interleukin (IL)-34, a novel osteoclastogenic cytokine, for predicting structural damage in patients with rheumatoid arthritis (RA). Serum IL-34 levels were measured in 100 RA patients, 36 patients with ankylosing spondylitis (AS), and 59 gender- and age-matched healthy individuals using an enzyme-linked immunosorbent assay. We also measured IL-34 concentrations in synovial fluid (SF) samples from 18 RA patients and 19 osteoarthritis (OA) patients. Progression of structural damage was assessed in 81 patients with RA by plain radiographs using the modified Sharp/van der Heijde score (SHS) at baseline and after an average 1.6-year follow-up period. Serum IL-34 levels were significantly higher in patients with RA (p < 0.001) or AS (p < 0.001) than in healthy controls. SF IL-34 levels were also significantly higher in RA patients than in OA patients (p < 0.001). In RA, serum IL-34 levels were associated with rheumatoid factor positivity (p = 0.01), current smoking (p < 0.01), erythrocyte sedimentation rate (p = 0.01), and C-reactive protein levels (p < 0.01), but not with disease activity score 28. DeltaSHS/year was positively correlated with serum IL-34 levels (r = 0.443, p < 0.001). In multivariate logistic regression analyses, serum IL-34 level was an independent risk factor for radiographic progression. These results suggest that IL-34, a novel osteoclastogenic cytokine, plays a role in RA-associated joint damage and is a potential biomarker for predicting subsequent radiographic progression in patients with RA. PMID- 25027627 TI - [The use of social healthcare resources and informal care characteristics care of immobilised homecare patients]. AB - OBJECTIVE: To describe the use of social healthcare resources by immobilised patients and informal care characteristics and the level/degree of satisfaction with home care services. METHOD: Descriptive observational study carried out in primary care. The target group were 369 randomly selected immobilised home care patients in the area of Albacete, Spain. The variables included were: socio demographic data of the patient and carer; the use of social healthcare resources; perceived social support (DUKE-UNK questionnaire); family function (APGAR questionnaire); nursing care and home care services satisfaction (SATISFAD 10 questionnaire). RESULTS: 66.9% of immobilised homecare patients have high dependency and 18.6% have bedsores. The majority of informal carers are women (83.1%) with an average of 57.7 years of age (DE 15.1). The average intensity of care is 15.7 hours per day (DE 8.5) and the average length of care is 5 years. The average number of visits from nurses per month is 2.1 (DE 2.1), although this measurement is higher in patients with bedsores or multiple diseases. The most widely used social health care resources are telephone care (34.2%) and home care (20.3%), for which 65.6% of immobilised homecare patients receive dependency benefits. Overall satisfaction with home care is of a high degree. CONCLUSION: Musculoskeletal disorders is the main reason for immobilisation in home care patients. Most informal carers are older women. The length and intensity of care is high and the main support comes from healthcare professionals. Patients make limited use of social healthcare resources. PMID- 25027628 TI - Constructing an alternative wheat karyotype using barley genomic DNA. AB - The established karyotype was generated by genomic in situ hybridization (GISH) using total barley genomic DNA as labelled probe on mitotic metaphase bread wheat chromosomes. GISH produced specific banding signals on 16 of the 21 chromosome pairs. The following chromosomes showed distinctive banding patterns: 2A, 3A, 4A, 5A, 6A, 7A, 1D, 2D, 7D and all of the B chromosomes. The remaining chromosomes showed either faint bands or no hybridization signals at all. The in situ hybridization patterns corresponded to the GAA-satellite sequence, which is similar to the N-banding pattern in wheat. In situ hybridization by labelling total barley genomic DNA made it possible to identify most of the bread wheat chromosomes. The present paper describes a GISH-banding method for hexaploid wheat chromosomes. It is a valuable alternative method for fast chromosome selection without using FISH repetitive DNA clones. PMID- 25027629 TI - What is crop heterosis: new insights into an old topic. AB - Heterosis (or hybrid vigor) refers to a natural phenomenon whereby hybrid offspring of genetically diverse individuals out-perform their parents in multiple traits including yield, adaptability and resistances to biotic and abiotic stressors. Innovations in technology and research continue to clarify the mechanisms underlying crop heterosis, however the intrinsic relationship between the biological basis of heterosis remain unclear. In this review, we aim to provide insight into the molecular genetic basis of heterosis by presenting recent advances in the 'omics' of heterosis and the role of non-coding regions, particularly in relation to energy-use efficiency. We propose that future research should focus on integrating the expanding datasets from different species and hybrid combinations, to mine key heterotic genes and unravel interactive 'omics' networks associated with heterosis. Improved understanding of heterosis and the biological basis for its manipulation in agriculture should help to streamline its use in enhancing crop productivity. PMID- 25027631 TI - Dihydroartemisinin inhibits activation of the Toll-like receptor 4 signaling pathway and production of type I interferon in spleen cells from lupus-prone MRL/lpr mice. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by various immunological abnormalities. Dihydroartemisinin (DHA), a metabolite of artemisinin, has been recently reported to exhibit immunosuppressive properties. The present study aims to determine the effects of DHA on spleen cell activation triggered by lipopolysaccharide (LPS) and investigate the effects of DHA on LPS-induced activation of the Toll-like receptor 4 (TLR4)/interferon regulatory factor (IRF) signaling pathway. Spleen cells from lupus-prone MRL/lpr mice were isolated, prepared and cultured. Cells were treated with LPS alone or LPS with DHA, and spleen cell proliferation was analyzed using MTS assay. Protein expressions of TLR4, IRF3, and IRF7 were analyzed by Western blot. IRF3 phosphorylation was also determined. Gene expression levels of IFN-alpha and IFN-beta were measured using real-time PCR, and protein levels in cells' supernatants were determined by ELISA. DHA was found to inhibit LPS-induced spleen cell proliferation, decrease LPS-induced protein expression of TLR4, and inhibit IRF3 phosphorylation. Furthermore, LPS significantly induced IRF3 expression and slightly increased IRF7 expression in the nucleus of spleen cells, which was accompanied by enhanced IFN-alpha and IFN beta production. DHA inhibited the effects of LPS in spleen cells of MRL/lpr mice. Taken together, the data obtained reveal that DHA inhibits LPS-induced cell activation possibly by suppressing the TLR4/IRF/IFN pathway in spleen cells of MRL/lpr mice. These data suggest that DHA has the potential therapeutic utility for the treatment of SLE. PMID- 25027632 TI - Together but apart: Caring for a spouse with dementia resident in a care facility. AB - This longitudinal, exploratory study was designed to better understand the lived experience of spousal caregivers age 60 and older providing care to partners with Alzheimer's disease and related dementias resident in a care facility. Twenty eight spousal caregivers were interviewed up to three times over a period of 2 years, and long-term care facility staff from four locations across British Columbia (BC), Canada participated in four focus groups. Thematic analysis of interview and focus group transcripts revealed a central, unifying theme 'together but apart'. The results identify key targets for policy makers and service providers to support positive health and well-being outcomes for spousal caregivers providing care to their partners diagnosed with Alzheimer's disease and related dementia and living in care facilities. PMID- 25027633 TI - Establishing a community of practice for dementia champions (innovative practice). AB - This discussion paper considers the currently evolving roles of dementia champions and describes an initiative designed to support their activities. The aim of this initiative was to establish a county-wide group that has a shared group identity and sufficient critical mass that is able to identify and implement dementia training and development needs for the health and social care workforce. The approach used to achieve this aim was a Dementia Champion Community of Practice Project, which involved dementia leads in various NHS Trusts. Whilst this approach might be effective at practitioner level, the Dementia Champion Community of Practice Project experience suggests that if such initiatives are to be sustainable they need to be strategically placed within networks that can bring together service providers, educators and commissioners. PMID- 25027634 TI - Solution processed polydimethylsiloxane/gold nanostar flexible substrates for plasmonic sensing. AB - Gold nanostars can display tunable optical properties in the visible and near IR, which lead to strong electromagnetic field enhancement at their tips. We report generalized application of gold nanostars for ultrasensitive identification of molecules, based on both localized surface plasmon resonance (LSPR) and surface enhanced Raman scattering (SERS). We address the requirements of plasmonic sensors, related to sufficiently large areas where nanoparticles are uniformly immobilized with high density, as well as mechanical flexibility, which offers additional advantages for real-world applications. Gold nanostar monolayers were thus immobilized on transparent, flexible polydimethylsiloxane substrates, and their refractive index sensitivity and SERS performance were studied. The application of such substrates for LSPR based molecular sensing is demonstrated via detection of a model analyte, mercaptoundecanoic acid. We further demonstrate SERS-based pesticide detection on fruit skin, by simply covering the fruit surface with the flexible plasmonic substrate, at the area where the target molecule is to be detected. The transparency of the substrate allows SERS detection through backside excitation, thereby facilitating practical implementation. PMID- 25027635 TI - Synaptic Vesicle Endocytosis and Endosomal Recycling in Central Nerve Terminals: Discrete Trafficking Routes? AB - Synaptic vesicle (SV) retrieval from the presynaptic plasma membrane occurs via a variety of different and complementary modes. The dominant retrieval mode during high-intensity stimulation is activity-dependent bulk endocytosis (ADBE). ADBE involves the generation of endosomes direct from the plasma membrane which then donate membrane and cargo to form SVs that replenish the reserve SV pool. Recent evidence has suggested that ADBE may involve an additional endosomal processing step to produce a mature, functional SV. This suggests that ADBE may utilize key molecules or indeed whole pathways from classical endocytic recycling routes that are ubiquitous across all cell types. This review will assess the current evidence for a contribution of endocytic recycling to the SV life cycle, with a particular focus on ADBE. In doing so it highlights points where both routes may either converge or exploit existing mechanisms to ensure efficient generation of SVs during high-intensity stimulation. PMID- 25027630 TI - Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy. AB - The Big Potassium (BK) ion channel is commonly known by a variety of names (Maxi K, KCNMA1, slo, stretch-activated potassium channel, KCa1.1). Each name reflects a different physical property displayed by this single ion channel. This transmembrane channel is found on nearly every cell type of the body and has its own distinctive roles for that tissue type. The BKalpha channel contains the pore that releases potassium ions from intracellular stores. This ion channel is found on the cell membrane, endoplasmic reticulum, Golgi and mitochondria. Complex splicing pathways produce different isoforms. The BKalpha channels can be phosphorylated, palmitoylated and myristylated. BK is composed of a homo-tetramer that interacts with beta and gamma chains. These accessory proteins provide a further modulating effect on the functions of BKalpha channels. BK channels play important roles in cell division and migration. In this review, we will focus on the biology of the BK channel, especially its role, and its immune response towards cancer. Recent proteomic studies have linked BK channels with various proteins. Some of these interactions offer further insight into the role that BK channels have with cancers, especially with brain tumors. This review shows that BK channels have a complex interplay with intracellular components of cancer cells and still have plenty of secrets to be discovered. PMID- 25027636 TI - Predictive chromosomal clusters of synchronous and metachronous brain metastases in clear cell renal cell carcinoma. AB - Synchronous (early) and metachronous (late) brain metastasis (BM) events of sporadic clear cell renal cell carcinoma (ccRCC) (n = 148) were retrospectively analyzed using comparative genomic hybridization (CGH). Using oncogenetic tree models and cluster analyses, chromosomal imbalances related to recurrence-free survival until BM (RFS-BM) were analyzed. Losses at 9p and 9q appeared to be hallmarks of metachronous BM events, whereas an absence of detectable chromosomal changes at 3p was often associated with synchronous BM events. Correspondingly, k means clustering showed that cluster 1 cases generally exhibited low copy number chromosomal changes that did not involve 3p. Cluster 2 cases had a high occurrence of -9p/-9q (94-98%) deletions, whereas cluster 3 cases had a higher frequency of copy number changes, including loss at chromosome 14 (80%). The higher number of synchronous cases in cluster 1 was also associated with a significantly shorter RFS-BM compared with clusters 2 and 3 (P = 0.02). Conversely, a significantly longer RFS-BM was observed for cluster 2 versus clusters 1 and 3 (P = 0.02). Taken together, these data suggest that metachronous BM events of ccRCC are characterized by loss of chromosome 9, whereas synchronous BM events may form independently of detectable genetic changes at chromosomes 9 and 3p. PMID- 25027637 TI - The prognostic significance of an inv(3)(q21q26.2) in addition to a t(9;22)(q34;q11.2) in patients treated with tyrosine kinase inhibitors. AB - In chronic myelogenous leukemia, BCR-ABL1 positive detection of cytogenetic abnormalities in addition to the t(9;22) is thought to portend a poor prognosis; however, not all abnormalities associated with the t(9;22) have the same impact. Inv(3) defines a group of aggressive neoplasms with poor response to conventional treatment options. In this study, four cases with the t(9;22) and inv(3) treated with tyrosine kinase inhibitors (TKI) were investigated. In three cases, the inv(3) was not detected at the initial diagnosis and the patients initially responded to TKI therapy; the inv(3) was detected at blast crisis in all three cases, and one case had both abnormalities at the initial presentation, but this case presented as acute myeloid leukemia. In all cases, detection of an inv(3) was associated with a high blast count and a lack of response to treatment regimens including TKI. All patients died within months from the detection of inv(3). This indicates that cases with the t(9;22) and inv(3) have a clinical course similar to that of cases with an inv(3) and no other therapeutically targetable abnormality. PMID- 25027638 TI - Kager's fat pad inflammation associated with HIV infection and AIDS: MRI findings. AB - OBJECTIVE: To describe magnetic resonance imaging (MRI) features of Kager's fat pad inflammation in HIV-positive patients with lipodystrophy due to protease inhibitor treatment and posterior ankle pain. METHODS: A case-control, cross sectional study; group 1 included 14 HIV-positive patients using protease inhibitors, presenting lipodystrophy syndrome and having posterior ankle pain; group 2 (CGHIV-) included 112 HIV-negative patients without lipodystrophy syndrome who were being evaluated for posterior ankle pain; group 3 (CGHIV + 1) included 23 HIV-positive patients not using a protease inhibitor, without lipodystrophy syndrome and with posterior ankle pain; group 4 (CGHIV + 2) comprised 18 HIV-positive patients who were being treated with a protease inhibitor and had lipodystrophy syndrome but did not have posterior ankle pain. Images were evaluated for the presence of edema by two radiologists who were blinded to clinical features. Fisher's exact test was used to evaluate differences among the groups. Interobserver variation was tested using Cohen's kappa (kappa) statistic. RESULTS: The presence of edema within Kager's fat pad was strongly associated with symptoms in HIV-positive patients who had lipodystrophy (p <= 0.0001). Concordance between observers was excellent (kappa > 0.9). CONCLUSION: MRI findings of Kager's fat pad inflammation related to HIV/AIDS is a source of symptoms in HIV patients with posterior ankle pain using protease inhibitors and having lipodystrophy syndrome. PMID- 25027639 TI - Genetic ablation of VIAAT in glycinergic neurons causes a severe respiratory phenotype and perinatal death. AB - Both glycinergic and GABAergic neurons require the vesicular inhibitory amino acid transporter (VIAAT) for synaptic vesicle filling. Presynaptic GABA concentrations are determined by the GABA-synthesizing enzymes glutamate decarboxylase (GAD)65 and GAD67, whereas the presynaptic glycine content depends on the plasma membrane glycine transporter 2 (GlyT2). Although severely impaired, glycinergic transmission is not completely absent in GlyT2-knockout mice, suggesting that other routes of glycine uptake or de novo synthesis of glycine exist in presynaptic terminals. To investigate the consequences of a complete loss of glycinergic transmission, we generated a mouse line with a conditional ablation of VIAAT in glycinergic neurons by crossing mice with loxP-flanked VIAAT alleles with a GlyT2-Cre transgenic mouse line. Interestingly, conditional VIAAT knockout (VIAAT cKO) mice were not viable at birth. In addition to the dominant respiratory failure, VIAAT cKO showed an umbilical hernia and a cleft palate. Immunohistochemistry revealed an almost complete depletion of VIAAT in the brainstem. Electrophysiology revealed the absence of both spontaneous glycinergic and GABAergic inhibitory postsynaptic currents from hypoglossal motoneurons. Our results demonstrate that the deletion of VIAAT in GlyT2-Cre expressing neurons also strongly affects GABAergic transmission and suggest a large overlap of the glycinergic and the GABAergic neuron population during early development in the caudal parts of the brain. PMID- 25027640 TI - The effects of transcranial direct current stimulation in patients with neuropathic pain from spinal cord injury. AB - OBJECTIVE: Transcranial direct current stimulation (tDCS) has demonstrated efficacy for reducing neuropathic pain, but the respective mechanisms remain largely unknown. The current study tested the hypothesis that pain reduction with tDCS is associated with an increase in the peak frequency spectrum density in the theta-alpha range. METHODS: Twenty patients with spinal cord injury and bilateral neuropathic pain received single sessions of both sham and anodal tDCS (2 mA) over the left primary motor area (M1) for 20 min. Treatment order was randomly assigned. Pre- to post-procedure changes in pain intensity and peak frequency of electroencephalogram spectral analysis were compared between treatment conditions. RESULTS: The active treatment condition (anodal tDCS over M1) but not sham treatment resulted in significant decreases in pain intensity. In addition, consistent with the study hypothesis, peak theta-alpha frequency (PTAF) assessed from an electrode placed over the site of stimulation increased more from pre- to post-session among participants in the active tDCS condition, relative to those in the sham tDCS condition. Moreover, we found a significant association between a decrease in pain intensity and an increase in PTAF at the stimulation site. CONCLUSIONS: The findings are consistent with the possibility that anodal tDCS over the left M1 may be effective, at least in part, because it results in an increase in M1 cortical excitability, perhaps due to a pain inhibitory effect of motor cortex stimulation that may influence the descending pain modulation system. Future research is needed to determine if there is a causal association between increased left anterior activity and pain reduction. SIGNIFICANCE: The results provide new findings regarding the effects of tDCS on neuropathic pain and brain oscillation changes. PMID- 25027641 TI - Normative data and long-term test-retest reliability of the triple stimulation technique (TST) in multiple sclerosis. AB - OBJECTIVES: Transcranial magnetic stimulation is useful for the assessment of cortico-spinal tract integrity in multiple sclerosis (MS). An advanced approach is the triple stimulation technique (TST), utilizing a combination of central and peripheral stimuli, reducing individual response variability. Although TST measures have been implemented in longitudinal studies, basic methodological data on temporal properties of abnormal TST values in MS are sparse. METHODS: Normative TST data were obtained from 48 healthy participants. Longitudinal measures were derived from 17 MS-patients (relapsing-remitting: N=10; clinically isolated syndrome: N=7) prior to, three and twelve months following therapy initiation. Intraclass correlations were used to examine test-retest reliability. Complementary, patient ambulation and cognition were assessed. RESULTS: Patient TST parameters were abnormal, involving excellent test-retest reliability and stable mean values. Cognitive and motor performance improved. CONCLUSIONS: Results are the first to show that abnormal TST values in MS, reflecting diagnostic utility, are highly reliable in a long-term follow-up. Methodological properties are adequate for a longitudinal implementation of TST. Parameters were insensitive to alterations in cognitive/motor functioning. Sensitivity may be verified in subgroups with different treatment regimes. SIGNIFICANCE: Results provide new normative data, support diagnostic utility of TST measures in MS, and confirm their long-term robustness. PMID- 25027643 TI - Use of titanium dioxide nanoparticles biosynthesized by Bacillus mycoides in quantum dot sensitized solar cells. AB - BACKGROUND: One of the major challenges of nanotechnology during the last decade has been the development of new procedures to synthesize nanoparticles. In this context, biosynthetic methods have taken hold since they are simple, safe and eco friendly. RESULTS: In this study, we report the biosynthesis of TiO2 nanoparticles by an environmental isolate of Bacillus mycoides, a poorly described Gram-positive bacterium able to form colonies with novel morphologies. This isolate was able to produce TiO2 nanoparticles at 37 degrees C in the presence of titanyl hydroxide. Biosynthesized nanoparticles have anatase polymorphic structure, spherical morphology, polydisperse size (40-60 nm) and an organic shell as determined by UV-vis spectroscopy, TEM, DLS and FTIR, respectively. Also, conversely to chemically produced nanoparticles, biosynthesized TiO2 do not display phototoxicity. In order to design less expensive and greener solar cells, biosynthesized nanoparticles were evaluated in Quantum Dot Sensitized Solar Cells (QDSSCs) and compared with chemically produced TiO2 nanoparticles. Solar cell parameters such as short circuit current density (ISC) and open circuit voltage (VOC) revealed that biosynthesized TiO2 nanoparticles can mobilize electrons in QDSSCs similarly than chemically produced TiO2. CONCLUSIONS: Our results indicate that bacterial extracellular production of TiO2 nanoparticles at low temperatures represents a novel alternative for the construction of green solar cells. PMID- 25027644 TI - [Pediatric intraspinal neoplasms]. AB - With an overall incidence of 10% of all central nervous system tumors, spinal tumors are relatively rare in children. The majority of these tumors are astrocytomas and ependymomas (70%) followed by rare non-glial tumor entities, such as gangliogliomas. They can be differentiated into intramedullary, extramedullary intradural and extramedullary extradural tumors according to their occurrence within the anatomical intraspinal compartments. The clinical presentation is generally unspecific. Longer lasting back pain or a gradually worsening scoliosis are often the first signs of the disease. Neurological deficits, such as gait disturbances and paresis often occur after a time delay. In rare cases increased intracranial pressure has been reported.Knowledge concerning potential organ manifestations, resulting complications and typical radiological presentation, especially in magnetic resonance imaging are mandatory for adequate diagnosis and treatment of affected patients. PMID- 25027645 TI - Long-term sequelae of severe sepsis: cognitive impairment and structural brain alterations - an MRI study (LossCog MRI). AB - BACKGROUND: The number of patients with cognitive impairment after sepsis or septic shock is high. However, the underlying neurophysiological basis of sepsis induced cognitive impairment is not fully understood. METHODS/DESIGN: This is a prospective, controlled observational study. We are in the process of recruiting 25 survivors of severe sepsis or septic shock who will be investigated with functional MRI (fMRI), T1-weighted MRI und Diffusion Tensor Imaging (DTI) as well as Magnetoencephalography (MEG). Furthermore, patients will undergo neuropsychological evaluation using the DemTect and the clock drawing tests. In addition, verbal and declarative memory is assessed by the Verbal Learning and Memory Test. The primary aim is to determine the volumetry of the amygdala and the hippocampus. The secondary aim is to analyze the relationship between cognitive tests and MEG, and the (f)MRI results. Moreover, a between-group comparison will be evaluated to an age-matched group of healthy controls. DISCUSSION: In a previous MEG study, we observed a significant slowing of the prominent background activity in sepsis survivors and hepatic encephalopathy patients in particular shortly after discharge from the ICU. Intriguingly, the rhythmic brain activity after visual flickering stimulation was altered in sepsis survivors in comparison to age-matched healthy volunteers. We propose that this desynchronization is based on affected underlying neuronal responses between various interconnected brain regions. The current project will analyze whether the modifications are related to a damage of the fibers connecting different brain regions or to a disturbance of the functional interaction between different brain regions or even due to an atrophy of certain brain regions. TRIAL REGISTRATION: "Langzeitfolgen nach schwerer Sepsis: Kognitive Beeintrachtigungen und strukturelle Veranderungen am Gehirn, eine MRT Studie"; German Clinical Trials Register (DRKS00005484). PMID- 25027646 TI - Roles of apoplastic peroxidases in plant response to wounding. AB - Apoplastic class III peroxidases (EC 1.11.1.7) play key roles in the response of plants to pathogen infection and abiotic stresses, including wounding. Wounding is a common stress for plants that can be caused by insect or animal grazing or trampling, or result from agricultural practices. Typically, mechanical damage to a plant immediately induces a rapid release and activation of apoplastic peroxidases, and an oxidative burst of reactive oxygen species (ROS), followed by the upregulation of peroxidase genes. We discuss how plants control the expression of peroxidases genes upon wounding, and also the sparse information on peroxidase-mediated signal transduction pathways. Evidence reviewed here suggests that in many plants production of the ROS that comprise the initial oxidative burst results from a complex interplay of peroxidases with other apoplastic enzymes. Later responses following wounding include various forms of tissue healing, for example through peroxidase-dependent suberinization, or cell death. Limited data suggest that ROS-mediated death signalling during the wound response may involve the peroxidase network, together with other redox molecules. In conclusion, the ability of peroxidases to both generate and scavenge ROS plays a key role in the involvement of these enigmatic enzymes in plant stress tolerance. PMID- 25027647 TI - Accurate genome relative abundance estimation for closely related species in a metagenomic sample. AB - BACKGROUND: Metagenomics has a great potential to discover previously unattainable information about microbial communities. An important prerequisite for such discoveries is to accurately estimate the composition of microbial communities. Most of prevalent homology-based approaches utilize solely the results of an alignment tool such as BLAST, limiting their estimation accuracy to high ranks of the taxonomy tree. RESULTS: We developed a new homology-based approach called Taxonomic Analysis by Elimination and Correction (TAEC), which utilizes the similarity in the genomic sequence in addition to the result of an alignment tool. The proposed method is comprehensively tested on various simulated benchmark datasets of diverse complexity of microbial structure. Compared with other available methods designed for estimating taxonomic composition at a relatively low taxonomic rank, TAEC demonstrates greater accuracy in quantification of genomes in a given microbial sample. We also applied TAEC on two real metagenomic datasets, oral cavity dataset and Crohn's disease dataset. Our results, while agreeing with previous findings at higher ranks of the taxonomy tree, provide accurate estimation of taxonomic compositions at the species/strain level, narrowing down which species/strains need more attention in the study of oral cavity and the Crohn's disease. CONCLUSIONS: By taking account of the similarity in the genomic sequence TAEC outperforms other available tools in estimating taxonomic composition at a very low rank, especially when closely related species/strains exist in a metagenomic sample. PMID- 25027648 TI - Assessment of outcome following the use of recombinant human bone morphogenetic protein-2 for spinal fusion in the elderly population. AB - INTRODUCTION: Although the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion has been fairly studied in the general population, relatively little research has been conducted on its use in the elderly patient demographic despite this population's growth. The authors sought to examine the clinical efficacy, complication rate, and cost-effectiveness of rhBMP-2 use in elderly patients undergoing spinal fusion surgery. EVIDENCE ACQUISITION: We conducted a systematic review of the published literature for elderly patients that underwent spinal fusion surgery with the use of rhBMP-2. A systematic search was performed utilizing the PUBMED and MEDLINE databases in order to identify all papers dealing with recombinant human Bone Morphogenic Protein-2 use in patients over the age of 60 years. EVIDENCE SYNTHESIS: Twenty-five papers were identified that met our inclusion criteria. While successful fusion, improvement in pain, and improved quality of life were encountered in elderly patients who were treated with fusions surgery along with rhBMP-2, there were several complications that were encountered including seroma formation, pleural effusions, and bone non union. CONCLUSIONS: The literature demonstrated that BMP serves as a potent osteoinductive agent in the elderly with similar efficacy to bone autograft. Although use of BMP showed mixed results and had higher initial costs, when taken into account with complication correction and costs, BMP usage appears to be more economically beneficial overall. Future studies are needed to clarify the clinical significance of the complications encountered in elderly patients treated with rhBMP-2. Future research can assist in developing recommendations which can minimize these risks in the elderly patient demographic. PMID- 25027650 TI - Translation. DENR-MCT1 reinitiates translation. AB - Translation reinitiation of open reading frames (ORFs) located after upstream ORFs is dependent on the DENR-MCT1 complex, which regulates a specific set of mRNAs. PMID- 25027651 TI - Stem cells. Ovary surface stem cells repair ovulatory wounds. AB - LGR5+ epithelial stem cells that sustain ovary repair and homeostasis are located throughout the ovary surface. PMID- 25027652 TI - Plant biology informs drug discovery. AB - Michael Rape provides a striking example of how basic research - in this case in the plant sciences - can be unexpectedly informative for drug development. PMID- 25027649 TI - Regulation of microRNA biogenesis. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, and their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are ~22 nucleotides in length, and they are produced by two RNase III proteins- Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging. PMID- 25027653 TI - Linear ubiquitin chains: NF-kappaB signalling, cell death and beyond. AB - Ubiquitylation is a versatile post-translational modification. Met1-linked linear ubiquitin chains are involved in nuclear factor-kappaB signalling and cell death, and dysfunctions in linear ubiquitylation underlie chronic inflammation. Recent identification of deubiquitylating enzymes and binding domains that are specific for linear ubiquitin chains suggests new physiological roles for linear ubiquitin chains. Moreover, the ligase required for linear ubiquitylation has a crucial role in the pathogenesis of some malignancies. Structural and functional analyses of the conjugation and deconjugation of linear ubiquitin chains have enabled the development of new probes to study the roles of linear chain ubiquitylation. PMID- 25027654 TI - Apoptosis. DR5 unfolds ER stress. AB - ER stress induces apoptosis through DR5, which is regulated by the UPR factors PERK and IRE1alpha. PMID- 25027656 TI - Creating a sustainable health promotion workforce in Australia: a health promoting approach to professionalisation. PMID- 25027658 TI - Observing Pt nanoparticle formation at the atomic level during polyol synthesis. AB - This study investigated the synthesis of platinum nanoparticles (Pt NPs) in ethylene glycol using low cost and low toxicity chemicals as reducing (ascorbic acid) and stabilizing agents (polyvinylpyrrolidone and sodium citrate). By monitoring the changes in the local chemical environment of the Pt atoms in real time by in situ dispersive X-ray absorption spectroscopy, it is observed that the NP formation kinetics involved three different stages within 3 h 30 min of the reaction: a reduction-nucleation burst, followed by diffusion-limited Ostwald ripening growth and subsequent stabilization of the NPs. The resulting Pt NPs were analyzed by transmission electron microscopy and X-ray diffraction, revealing a monodisperse average size distribution of 2.7 +/- 0.5 nm, characterized by highly crystalline and stable Pt clusters, showing no significant aging for at least nine months. PMID- 25027655 TI - Illuminating cell signalling with optogenetic tools. AB - The light-based control of ion channels has been transformative for the neurosciences, but the optogenetic toolkit does not stop there. An expanding number of proteins and cellular functions have been shown to be controlled by light, and the practical considerations in deciding between reversible optogenetic systems (such as systems that use light-oxygen-voltage domains, phytochrome proteins, cryptochrome proteins and the fluorescent protein Dronpa) are well defined. The field is moving beyond proof of concept to answering real biological questions, such as how cell signalling is regulated in space and time, that were difficult or impossible to address with previous tools. PMID- 25027659 TI - Fluorescence quenching of fluoroquinolone antibiotics by 4-hydroxy-TEMPO in aqueous solution. AB - The fluorescence quenching of norfloxacin, danofloxacin, enrofloxacin and levofloxacin, belonging to a group of fluoroquinolone antibiotics, by 4-hydroxy TEMPO was studied in aqueous solutions with the use of steady-state, time resolved fluorescence spectroscopy as well as UV-VIS absorption spectroscopy methods. In order to understand the mechanism of quenching the absorption and fluorescence emission spectra of all fluoroquinolone antibiotics studied as well as decreases of their fluorescence were registered as a function of the 4-hydroxy TEMPO concentration. No deviations from a linearity in the Stern-Volmer plots (determined from both, steady-state and time-resolved measurements) were observed. The fluorescence quenching mechanism was proved to be totally dynamic, what was additionally confirmed by the registration of Stern-Volmer plots at 5 temperatures ranging from 15 to 55 degrees C. On the basis of theoretical calculations of fluoroquinolones' molecular radii and ionization potentials the mechanism of electron transfer was rejected. It seems that the fluorescence quenching is diffusion-limited and is caused by the increase of nonradiative processes, such as internal conversion or intersystem crossing. The Stern-Volmer quenching constants and bimolecular quenching constants were determined at the room temperature for all fluoroquinolone antibiotics studied. PMID- 25027660 TI - Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I. AB - Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases (LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serotypes of adeno-associated viruses (AAV) such as AAV9 provides a potential platform for stable and efficient delivery of enzymes to the CNS. We evaluated the safety and efficacy of intrathecal delivery of AAV9 expressing alpha-l-iduronidase (IDUA) in a previously described feline model of mucopolysaccharidosis I (MPS I). A neurological phenotype has not been defined in these animals, so our analysis focused on the biochemical and histological CNS abnormalities characteristic of MPS I. Five MPS I cats were dosed with AAV9 vector at 4-7 months of age and followed for 6 months. Treated animals demonstrated virtually complete correction of biochemical and histological manifestations of the disease throughout the CNS. There was a range of antibody responses against IDUA in this cohort which reduced detectable enzyme without substantially reducing efficacy; there was no evidence of toxicity. This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic. PMID- 25027662 TI - Strategies to maintain skeletal muscle mass in the injured athlete: nutritional considerations and exercise mimetics. AB - The recovery from many injuries sustained in athletic training or competition often requires an extensive period of limb immobilisation (muscle disuse). Such periods induce skeletal muscle loss and consequent declines in metabolic health and functional capacity, particularly during the early stages (1-2 weeks) of muscle disuse. The extent of muscle loss during injury strongly influences the level and duration of rehabilitation required. Currently, however, efforts to intervene and attenuate muscle loss during the initial two weeks of injury are minimal. Mechanistically, muscle disuse atrophy is primarily attributed to a decline in basal muscle protein synthesis rate and the development of anabolic resistance to food intake. Dietary protein consumption is of critical importance for stimulating muscle protein synthesis rates throughout the day. Given that the injured athlete greatly reduces physical activity levels, maintaining muscle mass whilst simultaneously avoiding gains in fat mass can become challenging. Nevertheless, evidence suggests that maintaining or increasing daily protein intake by focusing upon the amount, type and timing of dietary protein ingestion throughout the day can restrict the loss of muscle mass and strength during recovery from injury. Moreover, neuromuscular electrical stimulation may be applied to evoke involuntary muscle contractions and support muscle mass maintenance in the injured athlete. Although more applied work is required to translate laboratory findings directly to the injured athlete, current recommendations for practitioners aiming to limit the loss of muscle mass and/or strength following injury in their athletes are outlined herein. PMID- 25027661 TI - A cationic nanoemulsion for the delivery of next-generation RNA vaccines. AB - Nucleic acid-based vaccines such as viral vectors, plasmid DNA, and mRNA are being developed as a means to address a number of unmet medical needs that current vaccine technologies have been unable to address. Here, we describe a cationic nanoemulsion (CNE) delivery system developed to deliver a self amplifying mRNA vaccine. This nonviral delivery system is based on Novartis's proprietary adjuvant MF59, which has an established clinical safety profile and is well tolerated in children, adults, and the elderly. We show that nonviral delivery of a 9 kb self-amplifying mRNA elicits potent immune responses in mice, rats, rabbits, and nonhuman primates comparable to a viral delivery technology, and demonstrate that, relatively low doses (75 ug) induce antibody and T-cell responses in primates. We also show the CNE-delivered self-amplifying mRNA enhances the local immune environment through recruitment of immune cells similar to an MF59 adjuvanted subunit vaccine. Lastly, we show that the site of protein expression within the muscle and magnitude of protein expression is similar to a viral vector. Given the demonstration that self-amplifying mRNA delivered using a CNE is well tolerated and immunogenic in a variety of animal models, we are optimistic about the prospects for this technology. PMID- 25027663 TI - Physiological and biochemical characterization of egg extract of black widow spiders to uncover molecular basis of egg toxicity. AB - BACKGROUND: Black widow spider (L. tredecimguttatus) has toxic components not only in the venomous glands, but also in other parts of the body and its eggs. It is biologically important to investigate the molecular basis of the egg toxicity. RESULTS: In the present work, an aqueous extract was prepared from the eggs of the spider and characterized using multiple physiological and biochemical strategies. Gel electrophoresis and mass spectrometry demonstrated that the eggs are rich in high-molecular-mass proteins and the peptides below 5 kDa. The lyophilized extract of the eggs had a protein content of 34.22% and was shown to have a strong toxicity towards mammals and insects. When applied at a concentration of 0.25 mg/mL, the extract could completely block the neuromuscular transmission in mouse isolated phrenic nerve-hemidiaphragm preparations within 12.0 +/- 1.5 min. Using whole-cell patch-clamp technique, the egg extract was demonstrated to be able to inhibit the voltage-activated Na+, K+ and Ca2+ currents in rat DRG neurons. In addition, the extract displayed activities of multiple hydrolases. Finally, the molecular basis of the egg toxicity was discussed. CONCLUSIONS: The eggs of black widow spiders are rich in proteinous compounds particularly the high-molecular-mass proteins with different types of biological activity The neurotoxic and other active compounds in the eggs are believed to play important roles in the eggs' toxic actions. PMID- 25027665 TI - Should research fraud be a crime? PMID- 25027664 TI - Porphyromonas gingivalis infection increases osteoclastic bone resorption and osteoblastic bone formation in a periodontitis mouse model. AB - BACKGROUND: Porphyromonas gingivalis has been shown to invade osteoblasts and inhibit their differentiation and mineralization in vitro. However, it is unclear if P. gingivalis can invade osteoblasts in vivo and how this would affect alveolar osteoblast/osteoclast dynamics. This study aims to answer these questions using a periodontitis mouse model under repetitive P. gingivalis inoculations. METHODS: For 3-month-old BALB/cByJ female mice, 10(9) CFU of P. gingivalis were inoculated onto the gingival margin of maxillary molars 4 times at 2-day intervals. After 2 weeks, another 4 inoculations at 2-day intervals were applied. Calcein was injected 7 and 2 days before sacrificing animals to label the newly formed bone. Four weeks after final inoculation, mice were sacrificed and maxilla collected. Immunohistochemistry, micro-CT, and bone histomorphometry were performed on the specimens. Sham infection with only vehicle was the control. RESULTS: P. gingivalis was found to invade gingival epithelia, periodontal ligament fibroblasts, and alveolar osteoblasts. Micro-CT showed alveolar bone resorption and significant reduction of bone mineral density and content in the infected mice compared to the controls. Bone histomorphometry showed a decrease in osteoblasts, an increase in osteoclasts and bone resorption, and a surprisingly increased osteoblastic bone formation in the infected mice compared to the controls. CONCLUSIONS: P. gingivalis invades alveolar osteoblasts in the periodontitis mouse model and cause alveolar bone loss. Although P. gingivalis appears to suppress osteoblast pool and enhance osteoclastic bone resorption, the bone formation capacity is temporarily elevated in the infected mice, possibly via some anti-microbial compensational mechanisms. PMID- 25027666 TI - Clinically isolated syndromes and the relationship to multiple sclerosis. AB - The most common presentation of multiple sclerosis (MS) is with a clinically isolated syndrome (CIS) affecting the optic nerves, brainstem or spinal cord. Two thirds of patients with CIS will have further episodes of neurological dysfunction and convert to relapsing-remitting MS, while the remaining patients have a monophasic illness, at least clinically. Abnormalities on a baseline MRI scan predict the subsequent development of MS in patients with CIS. In the long term, about 80% of patients with an abnormal MRI convert to MS compared with 20% with a normal MRI. For patients who develop MS the long term prognosis is varied. After 20 years, almost half will have developed secondary progressive MS, while around one third have a benign disease course with little physical disability. Disease-modifying treatments delay conversion to MS in selected CIS patients with abnormal MRI but an effect on long term disability has not been demonstrated. In this review we discuss recent advances in the diagnosis, management and prognostication of patients with CIS. PMID- 25027667 TI - Factors associated with early recurrence at the first evaluation of patients with transient ischemic attack. AB - We aimed to identify factors easily collected at admission in patients with transient ischemic attack (TIA) that were associated with early recurrence, so as to guide clinicians' decision-making about hospitalization in routine practice. From September 2011 to January 2013, all TIA patients who were referred to the University Hospital of Dijon, France, were identified. Vascular risk factors and clinical information were collected. The etiology of the TIA was defined according to the results of complementary examinations performed at admission as follows: large artery atherosclerosis (LAA-TIA) TIA, TIA due to atrial fibrillation (AF-TIA), other causes, and undetermined TIA. Logistic regression analyses were performed to identify factors associated with any recurrence at 48 hours (stroke or TIA). Among the 312 TIA patients, the etiology was LAA-TIA in 33 patients (10.6%), AF-TIA in 57 (18.3%), other causes in 23 (7.3%), and undetermined in 199 (63.8%). Early recurrence rates were 12.1% in patients with LAA-TIA, 5.3% in patients with AF-TIA, 4.3% in patients with another cause of TIA, and 1.0% in patients with undetermined TIA. In multivariable analysis, the LAA etiology was independently associated with early recurrence (odds ratio [OR]: 12.03; 95% confidence interval [CI]: 1.84-78.48, p=0.009). A non-significant trend was also observed for AF-TIA (OR: 3.82; 95% CI: 0.40-36.62, p=0.25) and other causes (OR: 3.73; 95% CI: 0.30-46.26, p=0.31). A simple initial assessment of TIA patients in the emergency room would be helpful in targeting those with a high risk of early recurrence and who therefore need to be hospitalized. PMID- 25027668 TI - Quality of life in indigenous and non-indigenous older adults: assessing the CASP 12 factor structure and identifying a brief CASP-3. AB - PURPOSE: We assessed whether the original three-factor structure of the older adult CASP-12 Quality of Life (QOL) scale was stable for both indigenous and non indigenous older adult populations in the same non-European country (i.e. New Zealand). METHOD: A total of 3076 New Zealanders aged 50-84 (Maori = 1,130; non Maori sample = 1,946) completed a postal survey for the first data collection wave of the New Zealand Longitudinal Study of Ageing in 2010. The survey included the CASP-12, a chronic health conditions checklist, CES-D-10, de Jong Gierveld loneliness scale, and the WHOQOL single-item QOL indicator. RESULTS: Exploratory factor analysis revealed that the CASP-12 responses resulted in a revised two factor structure for both Maori and non-Maori we called the NZCASP-11, which included a new three-item global indicator of QOL (CASP-3) that consistently cross-loaded on both factors. Confirmatory factor analysis supported the NZCASP 11 factor structure over the original CASP-12 model, and further assessment validated both the utility of the NZCASP-11 as an indicator of QOL in New Zealand and illustrated the utility of the CASP-3 as a brief screen for global QOL. CONCLUSION: While CASP items coalesce to provide a robust QOL indicator of indigenous and non-indigenous QOL in a single-country setting, the actual factor structure underpinning this CASP indicator (i.e. the NZCASP-11) is not entirely reflective of that found in the United Kingdom. Furthermore, we revealed that three CASP items (i.e. the CASP-3) may reflect a stable brief indicator of QOL applicable for assessing QOL across cultures within a single setting. PMID- 25027670 TI - Patient-reported outcomes and health-related quality of life in prostate cancer treated with a single fraction of high dose rate brachytherapy combined with hypofractionated external beam radiotherapy. AB - AIMS: High dose rate (HDR) brachytherapy offers a highly conformal approach to radiotherapy delivery, enabling dose escalation. We report our experience using a combined HDR boost and external beam radiotherapy (EBRT) approach and its associated toxicity and effect on quality of life. MATERIALS AND METHODS: Patients with intermediate- or high-risk prostate cancer were treated with a single fraction HDR boost and EBRT between July 2008 and March 2010. Patient reported toxicity data were collected at baseline and regular intervals after radiotherapy using International Prostate Symptom Score and Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales (LENT-SOMA) questionnaires; health-related quality of life data were captured by the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Ninety-five patients received an HDR boost of 12.5 Gy followed by EBRT delivered as 37.5 Gy in 15 fractions over 3 weeks. The International Prostate Symptom Score peaked 6 weeks after radiotherapy (median value: 9). The LENT-SOMA bladder/urethra mean baseline score was 0.35 and peaked 6 weeks after radiotherapy (mean = 0.59). Difficulties with urinary flow and frequency were the most common reported symptoms. LENT-SOMA rectum/bowel mean scores at baseline were 0.24 and peaked after 6 months (mean = 0.37). Bowel urgency was the most common reported toxicity. EPIC urinary scores returned to baseline values at 6 months and bowel median scores recovered after 24 months. There were no statistically significant associations between patient or dosimetric parameters and patient-reported outcomes. CONCLUSION: A combined HDR boost and hypofractionated EBRT regimen offers a well-tolerated method of dose escalation with acceptable levels of patient-reported toxicity. PMID- 25027671 TI - Undesirable effects related to oral antineoplastic drugs: comparison between patients' internet narratives and a national pharmacovigilance database. AB - BACKGROUND: The Internet is changing the way people learn about health and illness. Over the previous decade, the oral antineoplastic (OAN) agents have changed patient management allowing more ambulatory care. In this regard, websites could be an interesting source of data about OAN-induced adverse events (AEs). OBJECTIVE: The aim of the study was to describe the characteristics of AEs, as reported on websites by patients exposed to OAN agents, and to compare these to those recorded in the French pharmacovigilance database (FPVD). METHODS: We performed a retrospective study to collect AEs reported by patients in five of the best-known website forums in France over 1 year (2011). For each report, we recorded demographic data, cancer type, drug involved and AEs. The same analysis was done in the FPVD for OAN-induced adverse drug reactions (ADRs). RESULTS: A total of 202 AEs were identified in website posts and 1,448 ADRs were found in the FPVD. The most cited drugs in websites were protein kinase inhibitors (n = 88, 43.5%) and hormone antagonists (n = 61, 30.2%). More musculoskeletal disorder reports were found in the patient websites compared with the FPVD (16.34 vs. 4.70%, p < 0.001). As for skin disorders, we collected fewer reports in the patient website forums than in the FPVD (13.37 vs. 22.17%, p = 0.004). AEs reported in the patient websites were less serious (n = 10, 4.95%) than ADRs recorded in the FPVD (n = 999, 68.99%) (p < 0.001). CONCLUSIONS: AEs reported in the website forums are considered by patients to be relevant enough to be shared. Data from patient websites could be used as a source of data to detect AEs alongside conventional pharmacovigilance. PMID- 25027672 TI - GST-M1 is transcribed moreso than AKR7A2 in AFB1-exposed human monocytes and lymphocytes. AB - Glutathione-S-transferases (GST) and aldo-keto reductases (AKR) are key aflatoxin (AF)-detoxifying enzymes. In this study, the expression of GST-M1, GST-T1, AKR 7A2, and AKR-7A3 genes in human monocytes and lymphocytes was analyzed after in vitro exposure to 10 or 100 ng AFB1/ml for 2 h. Unlike in pilot studies that showed that all four examined genes were present in HepG2 cells, in lymphocytes and monocytes, only GST-M1 and AKR-7A2 were detected. In fact, the induced expression of both GST-M1 and AKR-7A2 genes in human monocytes was moreso than that seen in AFB1-exposed lymphocytes. In addition, analyses of the effects of the exposures on cell cycle status were performed as, in cells lacking adequate detoxification capacities, it would be expected the cells would arrest at checkpoints in the cell cycle or progress to apoptotic/necrotic states. The results here indicated that only the high dose of AFB1 led to a change in cell cycle profiles and only in the monocytes (i.e. cells in S phase were significantly reduced). In general, the results here strongly suggest that human immune cell lineages appear to be able to increase their expression of AFB1 detoxifying enzymes (albeit to differing degrees) and, as a result, are able to counter potential toxicities from AFB1 and (likely) its metabolites. PMID- 25027673 TI - Evaluation of anti-cancer and immunomodulatory effects of carnosol in a Balb/c WEHI-164 fibrosarcoma model. AB - Agents that destroy tumor cells and simultaneously boost host anti-tumor immunity are of keen interest in cancer therapy. In the present study, the effect of carnosol on anti-tumor immunity in a Balb/c mouse model of fibrosarcoma was evaluated. Carnosol was administered intraperitoneally daily (at 5 or 10 mg/kg/day, for 7 days) to tumor-bearing mice (i.e. 7 days after initial injection of tumor cells). Another group of tumor-bearing mice was treated with 20 mg cyclophosphamide/kg/d (positive control); a final group received vehicle only (vehicle control). After an initial measure on Day 0, tumor size was measured twice during the 7-day treatment period. One day after the final treatment with vehicle/carnosol (i.e. Day 7), the mice had their tumors measured and then were euthanized to permit their spleen and tumor to be harvested for isolation of, respectively, splenocytes and tumor-associated lymphocytes. Using these materials, spontaneous and mitogen-induced release of interleukin (IL)-4, IL-10, and interferon (IFN)-gamma, lymphocyte proliferation, and the absolute numbers/relative percentages of splenic and tumor-associated T-regulatory (Treg) and other T-lymphocyte sub-sets were evaluated. The results showed that carnosol at both doses significantly suppressed tumor growth and caused depletion of splenic and tumor-associated Treg cells. It also caused relative (vs control mouse cell values) decreases in splenocyte spontaneous/inducible production of IL 4 and IL-10 and increases in IFNgamma and cell proliferation. Carnosol at either dose did not cause changes in the percentages of CD4(+) or CD8(+) lymphocytes in the spleen or in tumor-associated lymphocyte populations. The observed increases in IFNgamma, decreases in IL-10 and IL-4 production, and reductions in splenic/tumor-associated Treg cell levels might be signs reflecting the potential anti-tumor activity of carnosol. Based on the findings here, it is asserted that carnosol is a likely candidate - after more complete toxicologic evaluation - for eventual use as an anti-cancer therapeutic. PMID- 25027674 TI - Development of a fluorescence-based in vivo phagocytosis assay to measure mononuclear phagocyte system function in the rat. AB - The mononuclear phagocyte system (MPS) which provides protection against infection is made up of phagocytic cells that engulf and digest bacteria or other foreign substances. Suppression of the MPS may lead to decreased clearance of pathogenic microbes. Drug delivery systems and immunomodulatory therapeutics that target phagocytes have a potential to inhibit MPS function. Available methods to measure inhibition of MPS function use uptake of radioactively-labeled cells or labor-intensive semi-quantitative histologic techniques. The objective of this work was to develop a non-radioactive quantitative method to measure MPS function in vivo by administering heat-killed E. coli conjugated to a pH-sensitive fluorescent dye (Bioparticles((r))). Fluorescence of the Bioparticles((r)) is increased at low pH when they are in phagocytic lysosomes. The amount of Bioparticles((r)) phagocytosed by MPS organs in rats was determined by measuring fluorescence intensity in livers and spleens ex vivo using an IVIS((r)) Spectrum Pre-clinical In Vivo Imaging System. Phagocytosis of the particles by peripheral blood neutrophils was measured by flow cytometry. To assess method sensitivity, compounds likely to suppress the MPS [clodronate-containing liposomes, carboxylate-modified latex particles, maleic vinyl ether (MVE) polymer] were administered to rats prior to injection of the Bioparticles((r)). The E. coli particles consistently co-localized with macrophage markers in the liver but not in the spleen. All of the compounds tested decreased phagocytosis in the liver, but had no consistent effects on phagocytic activity in the spleen. In addition, administration of clodronate liposomes and MVE polymer increased the percentage of peripheral blood neutrophils that phagocytosed the Bioparticles((r)). In conclusion, an in vivo rat model was developed that measures phagocytosis of E. coli particles in the liver and may be used to assess the impact of test compounds on MPS function. Still, the detection of inhibition of splenic macrophage function will require further assay development. PMID- 25027675 TI - Percutaneous cerclage wiring followed by intramedullary nailing for subtrochanteric femoral fractures: a technical note with clinical results. AB - BACKGROUND: Although intramedullary nailing is an ideal treatment for subtrochanteric femoral fractures, it is technically challenging in fractures extending into the nail entry area and/or involving the lesser trochanter. Although the application of circumferential wire may facilitate reduction in these situations, its use remains controversial due to possible blood supply disturbances to underlying bone. In the present study, we evaluated complex subtrochanteric fractures treated by percutaneous cerclage wiring followed by intramedullary (IM) nailing for anatomical fracture reduction and union. METHODS: Twelve patients (mean age 48.3 years) with an unstable subtrochanteric fracture were prospectively treated. Indications of percutaneous cerclage wiring followed by IM nailing were a fracture extending proximally into the nail entry area deemed difficult to treat by anatomical reconstruction by IM nailing or a fracture with long oblique or spiral component. One or two cerclage wires were percutaneously applied for the temporary reduction of main fragments, and then, a cephalo-medullary or a reconstruction nail was fixed. We assessed radiologic results (union time, alignment), functional results, and complications. RESULTS: All 12 cases healed, without a bone graft, at an average of 19.1 weeks after surgery (range 16-24). In 11 cases, acceptable alignment was achieved (mean, valgus 0.3 degrees extension 0.6 degrees ) with minimal leg-length discrepancy; the other exhibited 1 cm of shortening. All patients were able to return to pre injury activity levels, and median Merle d'Aubigne score was 16.9 (15-18). No infection or implant-related complication was encountered to latest follow-up (minimum 12 months postoperatively). CONCLUSION: Temporary reduction by percutaneous wiring offers a means of satisfactory nailing in difficult subtrochanteric femoral fractures, and affords anatomical reconstruction and favorable bony union. PMID- 25027676 TI - A single dose of platelet-rich plasma improves the organization and strength of a surgically repaired rotator cuff tendon in rats. AB - INTRODUCTION: Rotator cuff tear (RCT) is a common cause of pain and disability among adults. Platelet-rich plasma (PRP) is a fraction of whole blood containing concentrated growth factors and proteins important for tissue healing. This study aimed at investigating the effects of local autologous PRP injection on repaired rotator cuff (RC) tendon repair in rats. METHODS: Following experimental RCT and suturing, 44 Wistar rats were randomly allocated into two groups: (1) RC repair only (controls); (2) RC repair + PRP administration-shoulders were treated with intra-articular PRP immediately after the repair. Animals were killed after 3 weeks and tendon, were tested biomechanically in tension (12 rats/group). The remaining tendons (10 rats/group) were stained using hematoxylin and eosin and Picro-sirius Red. Histological analysis evaluated the cellular aspects of the repair tissue. RESULTS: PRP administration following experimental RC tear and suture resulted in a significantly higher maximal load (p < 0.001) and stiffness (p < 0.005) as compared to non-treated animals. Bonar score of PRP-treated tendons was significantly better (p = 0.018) than the control group. Collagen birefringence was significantly higher in PRP shoulders (p = 0.002), indicating improved organization. Vascularity scores were similar in both groups. CONCLUSION: Application of a single dose autologous PRP in adjunct to surgical repair resultes in improved tendon-to-bone healing, assessed by histological and biomechanical testing in a rat model of acute RCT, when tested at 3 weeks compared to controls. Further studies will be essential to determine the role of PRP in clinical practice. PMID- 25027677 TI - Does immobilization after arthroscopic rotator cuff repair increase tendon healing? A systematic review and meta-analysis. AB - INTRODUCTION: To determine whether immobilization after arthroscopic rotator cuff repair improved tendon healing compared with early passive motion. MATERIALS AND METHODS: A systematic electronic literature search was conducted to identify randomized controlled trials (RCTs) comparing early passive motion with immobilization after arthroscopic rotator cuff repair. The primary outcome assessed was tendon healing in the repaired cuff. Secondary outcome measures were range of motion (ROM) and American Shoulder and Elbow Surgeons (ASES) shoulder scale, Simple Shoulder Test (SST), Constant, and visual analog scale (VAS) for pain scores. Pooled analyses were performed using a random effects model to obtain summary estimates of treatment effect with 95% confidence intervals. Heterogeneity among included studies was quantified. RESULTS: Three RCTs examining 265 patients were included. Meta-analysis revealed no significant difference in tendon healing in the repaired cuff between the early-motion and immobilization groups. A significant difference in external rotation at 6 months postoperatively favored early motion over immobilization, but no significant difference was observed at 1 year postoperatively. In one study, Constant scores were slightly higher in the early-motion group than in the immobilization group. Two studies found no significant difference in ASES, SST, or VAS score between groups. CONCLUSION: We found no evidence that immobilization after arthroscopic rotator cuff repair was superior to early-motion rehabilitation in terms of tendon healing or clinical outcome. Patients in the early-motion group may recover ROM more rapidly. LEVEL OF EVIDENCE: Level II; systematic review of levels I and II studies. PMID- 25027678 TI - Hydrogen bonding in bulk heterojunction solar cells: a case study. AB - Small molecules with dithieno[3,2-b;2',3'-d]thiophene as central building block and octyl cyanoacetate and octyl cyanoacetamide as different terminal building blocks have been designed and synthesized. The amide containing small molecule can form intermolecular hydrogen bonding between N-H...O = C of the amide group. The photovoltaic properties and active layer morphologies of the two molecules in bulk heterojunction solar cells are compared to study the influence of hydrogen bonding on the active layer morphology. New methanofullerene compound containing amide group has also been synthesized and compared with conventional fullerene electron acceptors. PMID- 25027679 TI - Severe secondary bone marrow aplasia due to methotrexate in a patient with late onset rheumatoid arthritis. PMID- 25027681 TI - Introduction to special section "Topics on metal cluster assembly in enzymes". PMID- 25027680 TI - Elemental anomalies in the hippocampal formation after repetitive electrical stimulation: an X-ray fluorescence microscopy study. AB - Our previous studies carried out on the pilocarpine model of seizures showed that highly resolved elemental analysis might be very helpful in the investigation of processes involved in the pathogenesis of epilepsy, such as excitotoxicity or mossy fiber sprouting. In this study, the changes in elemental composition that occurred in the hippocampal formation in the electrical kindling model of seizures were examined to determine the mechanisms responsible for the phenomenon of kindling and spontaneous seizure activity that may occur in this animal model. X-ray fluorescence microscopy was applied for topographic and quantitative analysis of selected elements in tissues taken from rats subjected to repetitive transauricular electroshocks (ES) and controls (N). The detailed comparisons were carried out for sectors 1 and 3 of the Ammon's horn (CA1 and CA3, respectively), the dentate gyrus (DG) and hilus of DG. The obtained results showed only one statistically significant difference between ES and N groups, namely a higher level of Fe was noticed in CA3 region in the kindled animals. However, further analysis of correlations between the elemental levels and quantitative parameters describing electroshock-induced tonic and clonic seizures showed that the areal densities of some elements (Ca, Cu, Zn) strongly depended on the progress of kindling process. The areal density of Cu in CA1 decreased with the cumulative (totaled over 21 stimulation days) intensity and duration of electroshock-induced tonic seizures while Zn level in the hilus of DG was positively correlated with the duration and intensity of both tonic and clonic seizures. PMID- 25027682 TI - Thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant chemotherapy and radical cystectomy. AB - OBJECTIVES: Patients receiving cisplatin are at high risk of thromboembolic events (TEEs). The objective of this study was to assess the effect of cisplatin based neoadjuvant chemotherapy (NCT) on the incidence of perioperative TEEs in patients undergoing radical cystectomy. METHODS AND MATERIALS: We analyzed a consecutive sample of 202 patients with urothelial carcinoma treated with radical cystectomy between 2005 and 2013. Data were collected retrospectively by reviewing medical records. Median follow-up was 16.9 months. Events of interest were defined as venous or arterial TEEs occurring from the date of diagnosis to 30 days after surgery. TEE incidence among patients treated with NCT and cystectomy was compared with that among patients treated with cystectomy alone using Fisher exact test and Cox proportional hazards regression. Proportional hazards regression was also used to assess whether TEE is a predictor of cancer progression and survival. RESULTS: Of 202 patients, 17 (8.4%) developed a TEE, including 8 of 42 (19.1%) treated with NCT and cystectomy and 9 of 160 (5.6%) treated with cystectomy alone (risk ratio = 3.39, 95% CI: 1.39-8.24). After adjustment for observation time, there remained an association between treatment with NCT and risk of TEE (hazard ratio = 2.40; 95% CI: 0.92-6.27; P = 0.07). Overall, 7 events occurred before cystectomy and 10 occurred postoperatively. Among patients treated with NCT, 6 of 8 events occurred before cystectomy. Detection of TEE was clinically significant as preoperative TEE was found to be an independent predictor of progression and cancer-specific mortality (adjusted hazard ratio = 3.91, 95% CI: 1.34-11.45). The main limitations of our study are its retrospective data collection and small absolute number of events. CONCLUSIONS: TEE occurs commonly in patients with urothelial carcinoma undergoing NCT. Preoperative TEE is an independent predictor of progression and cancer specific mortality. PMID- 25027683 TI - Extent of lymph node dissection and recurrence-free survival after radical cystectomy: a meta-analysis. AB - INTRODUCTION: Lymph node dissection (LND) at the time of radical cystectomy (RC) is the standard of care in the treatment of muscle-invasive bladder cancer. However, no final consensus about its optimal extent has been reached. METHODS: We conducted a meta-analysis to determine the effect of the extent of LND on 5 year recurrence-free survival and its complication rates in patients undergoing RC. A systematic search of MEDLINE, PubMed, and EMBASE has been performed. All studies published until June 2013 and providing information on 5-year recurrence free survival were included in the analysis. RESULTS: We analyzed the recurrence free survival data of 11 studies on standard or extended LND or both in patients undergoing RC. The extended (above the bifurcation of iliac vessels) LND showed a significant trend toward a higher proportion of lymph node-positive patients (odds ratio = 1.39; 95% CI: 0.96-2.00; P = 0.08). Including all studies that compare extended with standard LND, the overall odds ratio for the 5-year recurrence-free survival is 1.63 (95% CI: 1.28-2.07, P<0.001), showing a strong and statistical significant survival benefit for the group of patients who underwent extended LND. Moreover, the weighted average 5-year recurrence-free survival rate of all existing studies on standard LND is significantly different from the ones reporting extended LND rates. No differences in perioperative mortality or complication rates were reported. CONCLUSION: The present meta analysis provides evidence to the positive effect of extended LND on recurrence free survival and its diagnostic benefit in patients undergoing RC. Patients who underwent extended LND did not suffer from higher complication rates or perioperative mortality. PMID- 25027684 TI - Clinical features of leiomyosarcoma of the urinary bladder: analysis of 183 cases. AB - INTRODUCTION: Experience with management of urinary bladder leiomyosarcoma (LMS) is rare. Therefore, to better elucidate the disease characteristics of urinary bladder LMS, we utilized a large population-based cancer registry to examine the epidemiology, natural history, pathological characteristics, prognostic factors, and treatment outcomes. MATERIAL AND METHODS: The Surveillance, Epidemiology, and End Results database (1973-2010) was used to identify cases by tumor site and histology codes. The association between clinical and demographic characteristics and long-term survival was examined. RESULTS: A total of 183 histologically confirmed cases were identified between 1973 and 2010. The annual age-adjusted incidence rate was 0.23 cases per 1,000,000 and did not significantly change over time. Median age of the patients was 65 years (interquartile range: 47-78 y). Of the patients with a known pathologic tumor stage (n = 164), 50% had a regional or distant disease. Overall, 63.2% of patients with known histologic grade (n = 106), had poorly differentiated or undifferentiated histology. Most patients (92.9%) received cancer-directed surgery (CDS), with 34.4% having radical or partial cystectomy. Only 7.7% of patients received radiation therapy in combination with surgery. The median disease-specific survival was 46 months. Five- and 10-year cancer-specific survival rates were 47%, and 35%, respectively. On multivariate analysis, a worse outcome was associated with an undifferentiated tumor grade, distant disease, and failure to undergo CDS. CONCLUSION: This series represents the largest cohort of LMS of the urinary bladder studied to date. LMS commonly presented as high grade and advanced stage with a poor prognosis. Reduced disease-specific survival was associated with increasing age, undifferentiated tumor grade, distant disease, and failure to undergo CDS. PMID- 25027685 TI - Critical analysis of the 2010 TNM classification in patients with lymph node positive bladder cancer: influence of lymph node disease burden. AB - OBJECTIVES: In 2010, a new TNM staging system was published by American Joint Committee on Cancer, changing the nodal classification to include the presence of common iliac lymph node (LN) involvement as N3 category. The objective of this study was to define the capability of the current TNM nodal classification to separate patients with different prognostic stages and to evaluate the effect of LN disease burden. METHODS AND MATERIALS: A total of 93 patients with metastatic LNs after radical cystectomy and extended LN dissection for urothelial carcinoma of the bladder between 1999 and 2012 were included. The median follow-up was 21.5 months. The correlation between N3 and indicators of LN disease burden was analyzed using the Spearman correlation coefficient. Recurrence-free survival (RFS) and overall survival (OS) analysis was performed using the Kaplan-Meier and Cox proportional hazards methods. RESULTS: The presence of N3 disease was associated with higher number of metastatic LNs (7 vs. 2, P<0.01); however, this was highly variable and correlation coefficients between common iliac metastatic LNs and other lymphatic disease burden indicators demonstrated weak association (0.39-0.63). Patients with N1 lesions were found to have a distinct RFS and OS (P<0.01 and P = 0.01, respectively). A trend toward worse RFS (P = 0.07) and OS (P = 0.08) was observed in patients with N3 lesions. However, no difference in RFS or OS was found between patients with N2 and N3 lesions (P = 0.83 and 0.50, respectively). CONCLUSIONS: The N3 category in the current TNM classification defines a group of patients with high but heterogeneous disease burden. This may be the explanation for its lack of prognostic stratification when compared with N2 category bladder cancer. PMID- 25027686 TI - Low preoperative lymphocyte-monocyte ratio (LMR) represents a potentially poor prognostic factor in nonmetastatic clear cell renal cell carcinoma. AB - OBJECTIVES: To explore the potential prognostic significance of the lymphocyte monocyte ratio (LMR) in patients with nonmetastatic renal cell carcinoma (RCC), as the LMR has been repeatedly proposed to have a negative effect on patient's survival in various hematological and solid cancers. However, findings about LMR's prognostic significance in RCC have not been reported yet. METHODS AND MATERIALS: We retrospectively evaluated the prognostic significance of the LMR in a cohort comprising 678 patients with nonmetastatic clear cell RCC, who were operated between 2000 and 2010 with curative radical or partial nephrectomy at a single tertiary academic center. Preoperative LMR was calculated 1 day before surgical intervention. Patients were categorized using an LMR cutoff of 3.0. Cancer-specific survival (CSS), metastasis-free survival, and overall survival were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the LMR, multivariate Cox regression models were applied. Additionally, the influence of the LMR on the predictive accuracy of the Leibovich prognosis score was determined using the Harrell concordance index (c index) and decision curve analysis. RESULTS: Low LMR was statistically significantly associated with older patients (>=65 y), high tumor grade (G3+G4), advanced pathologic T category (pT3+pT4), the presence of histologic tumor necrosis, and male gender (P<0.05). Multivariate analysis identified a low LMR as an independent prognostic factor for patients' CSS (hazard ratio = 2.33; 95% CI: 1.10-4.94; P = 0.027). The estimated c-index was 0.83 using the Leibovich prognosis score and 0.86 when the LMR was added. CONCLUSIONS: Regarding CSS of patients with RCC, a decreased LMR represents an independent prognostic factor. Adding the LMR to well-established prognostic models, such as the Leibovich prognosis score, might improve their predictive ability. PMID- 25027687 TI - Increased preoperative levels of plasma fibrinogen and D dimer in patients with renal cell carcinoma is associated with poor survival and adverse tumor characteristics. AB - BACKGROUND AND OBJECTIVE: The relationship between renal cell carcinoma (RCC) and coagulation/fibrinolysis system has been described in several studies. The aim of this study was to investigate the role of 4 different coagulation/fibrinolysis factors on the prediction of histopathologic and survival prognosis in patients with RCC. PATIENTS AND METHODS: Data from 128 patients who underwent surgical intervention between March 2006 and January 2011 for RCC were evaluated in this prospective study. Blood samples were collected from all patients on the morning of the operation to measure the plasma fibrinogen, D-dimer, coagulation factor VII, and antithrombin 3 levels. The relationships of these factors in the demographic, clinical, and histopathologic outcomes were analyzed using the Student t, Mann-Whitney U, Kruskal-Wallis, and one-way analysis of variance tests. Receiver operating curve analyses were performed to determine the optimal cutoff level for fibrinogen and d dimer, both of which had a strong relation with the clinical and histopathologic parameters. Disease-free survival (DFS), cancer specific survival (CSS), and overall survival (OS) were assessed using the Kaplan Meier method. Multivariate Cox regression analyses (forward stepwise logistic regression) were performed to examine the independent prognostic values on survival outcomes. RESULTS: Increased plasma fibrinogen and d-dimer levels were associated with tumor size (P = 0.004 and 0.106), nuclear grade (P<0.001 and<0.001), TNM category (P<0.001 and 0.029), and metastasis (P<0.001 and 0.032). Both increased plasma fibrinogen and d-dimer levels predicted decreased DFS (P = 0.027 and 0.04), CSS (P = 0.007 and 0.043), and OS (P = 0.014 and 0.001) rates based on Kaplan-Meier analyses. Furthermore, multivariate analyses demonstrated that fibrinogen independently predicted poor DFS (hazard ratio [HR] = 2.52; 95% CI: 1.04-6.31; P = 0.029) and CSS (HR = 3.89; 95% CI: 1.13-13.40; P = 0.032), whereas d dimer had negative independent prognostic value on OS (HR = 4.01; 95% CI: 1.54-10.50; P = 0.005). CONCLUSIONS: Increased plasma fibrinogen levels accurately predict poor histopathologic and survival outcomes and may be an effective independent prognostic factor in patients with RCC. Moreover, d dimer may serve as a copredictive factor in conjunction with fibrinogen. PMID- 25027688 TI - Lymphopenia is an independent predictor of inferior outcome in papillary renal cell carcinoma. AB - PURPOSE: Lymphopenia as a likely index of poor systemic immunity is an independent predictor of inferior outcome in patients with clear cell renal cell carcinoma (RCC). We sought to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in a cohort of patients with papillary RCC (PRCC). MATERIALS AND METHODS: A prospectively maintained, renal cancer database was analyzed. Patients with preoperative ALC, within 3 months before surgery, were eligible for the study. Those with multifocal or bilateral renal tumors were excluded. Correlations between ALC and age, gender, smoking, Charlson comorbidity index, pathologic T category, PRCC subtype, and TNM stage were evaluated. Differences in overall survival (OS) and cancer-specific survival by ALC status were assessed using the log-rank test and cumulative incident estimators, respectively. Cox proportional hazards model was used for multivariable analyses. RESULTS: A total of 192 patients met the inclusion criteria. As a continuous variable, preoperative ALC was associated with higher TNM stage (P = 0.001) and older age (P = 0.01). As a dichotomous variable, lymphopenia (<1,300 cells/ul) was associated with higher TNM stage (P = 0.003). On multivariable analyses, controlling for covariates, after a median follow-up of 37.3 months, lymphopenia was associated with inferior OS (hazard ratio = 2.3 [95% CI: 1.2-4.3], P = 0.011) and trended to significance for cancer-specific survival (P = 0.071). Among patients with nonmetastatic disease and lymphopenia, OS at 37.5 months was shorter compared with those with normal ALC (83% vs. 93%, P = 0.0006). CONCLUSIONS: In patients with PRCC, lymphopenia is associated with lower survival independent of TNM stage, age, and histology. ALC may provide an additional preoperative prognostic factor. PMID- 25027690 TI - Depicting Changes in Multiple Symptoms Over Time. AB - Ridit analysis, an acronym for Relative to an Identified Distribution, is a method for assessing change in ordinal data and can be used to show how individual symptoms change or remain the same over time. The purposes of this article are to (a) describe how to use ridit analysis to assess change in a symptom measure using data from a longitudinal study, (b) give a step-by-step example of ridit analysis, (c) show the clinical relevance of applying ridit analysis, and (d) display results in an innovative graphic. Mean ridit effect sizes were calculated for the frequency and distress of 64 symptoms in lung transplant patients before and after transplant. Results were displayed in a bubble graph. Ridit analysis allowed us to maintain the specificity of individual symptoms and to show how each symptom changed or remained the same over time. The bubble graph provides an efficient way for clinicians to identify changes in symptom frequency and distress over time. PMID- 25027689 TI - Initial experience with electronic tracking of specific tumor sites in men undergoing active surveillance of prostate cancer. AB - OBJECTIVES: Targeted biopsy, using magnetic resonance (MR)-ultrasound (US) fusion, may allow tracking of specific cancer sites in the prostate. We aimed to evaluate the initial use of the technique to follow tumor sites in men on active surveillance of prostate cancer. METHODS AND MATERIALS: A total of 53 men with prostate cancer (all T1c category) underwent rebiopsy of 74 positive biopsy sites, which were tracked and targeted using the Artemis MR-US fusion device (Eigen, Grass Valley, CA) from March 2010 through January 2013. The initial biopsy included 12 cores from a standard template (mapped by software) and directed biopsies from regions of interest seen on MR imaging (MRI). In the repeat biopsy, samples were taken from sites containing cancer at the initial biopsy. Outcomes of interest at second MR-US biopsy included (a) presence of any cancer and (b) presence of clinically significant cancer. RESULTS: All cancers on initial biopsy had either Gleason score 3+3 = 6 (n = 63) or 3+4 = 7 (n = 11). At initial biopsy, 23 cancers were within an MRI target, and 51 were found on systematic biopsy. Cancer detection rate on repeat biopsy (29/74, 39%) was independent of Gleason score on initial biopsy (P = not significant) but directly related to initial cancer core length (P<0.02). Repeat sampling of cancerous sites within MRI targets was more likely to show cancer than resampling of tumorous systematic sites (61% vs. 29%, P = 0.005). When initial cancer core length was>=4 mm within an MRI target, more than 80% (5/6) of follow-up tracking biopsies were positive. An increase of Gleason score was uncommon (9/74, 12%). CONCLUSIONS: Monitoring of specific prostate cancer-containing sites may be achieved in some men using an electronic tracking system. The chances of finding tumor on repeat specific-site sampling was directly related to the length of tumor in the initial biopsy core and presence of tumor within an MRI target; upgrading of Gleason score was uncommon. Further research is required to evaluate the potential utility of site-specific biopsy tracking for patients with prostate cancer on active surveillance. PMID- 25027691 TI - Designed alpha-sheet peptides inhibit amyloid formation by targeting toxic oligomers. AB - Previous studies suggest that the toxic soluble-oligomeric form of different amyloid proteins share a common backbone conformation, but the amorphous nature of this oligomer prevents its structural characterization by experiment. Based on molecular dynamics simulations we proposed that toxic intermediates of different amyloid proteins adopt a common, nonstandard secondary structure, called alpha sheet. Here we report the experimental characterization of peptides designed to be complementary to the alpha-sheet conformation observed in the simulations. We demonstrate inhibition of aggregation in two different amyloid systems, beta amyloid peptide (Abeta) and transthyretin, by these designed alpha-sheet peptides. When immobilized the alpha-sheet designs preferentially bind species from solutions enriched in the toxic conformer compared with non-aggregated, nontoxic species or mature fibrils. The designs display characteristic spectroscopic signatures distinguishing them from conventional secondary structures, supporting alpha-sheet as a structure involved in the toxic oligomer stage of amyloid formation and paving the way for novel therapeutics and diagnostics.DOI: http://dx.doi.org/10.7554/eLife.01681.001. PMID- 25027693 TI - Important role of SUMOylation of Spliceosome factors in prostate cancer cells. AB - Sentrin/SUMO (small ubiquitin-like modifier)-specific proteases (SENPs) have been implicated in the development of prostate cancer. However, due to the low abundance of SUMO-modified proteins and high activity of SENPs, the SUMO substrates affected by SENPs in prostate cancer cells are largely unknown. Here, we identified SI2, a novel cell-permeable SENP-specific inhibitor, by high throughput screening. Using SI2 as a way of inhibiting the activity of SENPs and the SUMO stably transfected PC3 cells as a prostate cancer model, in combination with the stable isotope labeling with amino acids (SILAC) quantitative proteomic technique, we identified more than 900 putative target proteins of SUMO, in which 231 proteins were further subjected to bioinformatic analysis. In the highly enriched spliceosome pathway, we validated that USP39, HSPA1A, and HSPA2 were novel target proteins of SUMO. Furthermore, we demonstrated that K6, K16, K29, K51, and K73 were the SUMOylation sites of USP39. Mutation of these SUMO modification sites of USP39 further promoted the proliferation-enhancing effect of USP39 on prostate cancer cells. This study provides the SUMOproteome of PC3 cells and reveals that SUMOylation of spliceosome factors may be implicated in the pathogenesis of prostate cancer. Optimization of SI2 for isotype-specific SENP inhibitors warrants further investigation. PMID- 25027694 TI - Anchoring durum wheat diversity in the reality of traditional agricultural systems: varieties, seed management, and farmers' perception in two Moroccan regions. AB - BACKGROUND: Traditional agrosystems are the places were crop species have evolved and continue to evolve under a combination of human and environmental pressures. A better knowledge of the mechanisms underlying the dynamics of crop diversity in these agrosystems is crucial to sustain food security and farmers' self-reliance. It requires as a first step, anchoring a description of the available diversity in its geographical, environmental, cultural and socio-economic context. METHODS: We conducted interviews with farmers cultivating durum wheat in two contrasted traditional agrosystems of Morocco in the Pre-Rif (163 farmers) and in the oases of the Atlas Mountains (110 farmers). We documented the varietal diversity of durum wheat, the main characteristics of the farms, the farming and seed management practices applied to durum wheat, and the farmers' perception of their varieties. RESULTS: As expected in traditional agrosystems, farmers largely practiced diversified subsistence agriculture on small plots and relied on on farm seed production or informal seed exchange networks. Heterogeneity nevertheless prevailed on many variables, especially on the modernization of practices in the Pre-Rif region. Fourteen (resp. 11) traditional and 5 (resp. 3) modern varieties were identified in the Pre-Rif region (resp. in the Atlas Mountains). The majority of farmers grew a single variety, and most traditional varieties were distributed in restricted geographical areas. At the farm level, more than half of the varieties were renewed in the last decade in the Pre-Rif, a more rapid renewal than in the Atlas Mountain. Modern varieties were more prevalent in the Pre-Rif region and were integrated in the traditional practices of seed production, selection and exchange. They were clearly distinguished by the farmers from the landraces, the last ones being appreciated for their quality traits. CONCLUSIONS: The surveyed traditional agrosystems constitute open, dynamic and heterogeneous entities. We suggest that competing factors could favour or limit the cultivation of improved varieties and the erosion of original durum wheat diversity. This first description opens the way to focused further investigations, including complementing variety names with cultural, genetic and phenotypic information and unravelling the multidimensional factors and consequences of modern variety adoption. PMID- 25027695 TI - [Changes in clinic-epidemiological characteristics of new cases of HIV-1 infection in Castellon (Spain), and its impact on delayed presentation (1987 2011)]. AB - OBJECTIVE: To describe the trend of the clinical and epidemiological characteristics of a cohort of HIV-1 infected patients in Castellon (Spain), and its impact on the delayed presentation. METHODS: Data from HIV-1 infected outpatients presenting for care for the first time between 1987 and 2011 were retrospectively analyzed. RESULTS: There have been significant changes in the characteristics of the 1001 newly presented patients during the period studied. An increase in the mean age was observed (increasing from about 30 years before 1996, to approximately 35 after the 2000-2002 period), as well as an increase in the percentage of immigrants (<2% before 1997, to 50% in the 2009-2011 period), and a decline in the proportion of intravenous drug use as the main transmission route (changing from being 92.3% before 1988 to below 20% after the 2003-2005 period), together with a decrease in the proportion of hepatitis-C coinfection. The rate of late presentation has not significantly changed, being 47.1% in the period studied. Factors associated with this late presentation were: older age, hospital diagnosis, an increased delay between estimated infection time and diagnosis, and between diagnosis and initial presentation. CONCLUSIONS: The epidemiology of HIV-1 infection in our area has dramatically changed since the beginning of the disease. The increasing delay between estimated infection time and diagnosis is an important cause of the lack of variation in the late presentation rate, and highlights the low impact of early diagnosis strategies. PMID- 25027696 TI - [In vitro susceptibility of rapidly growing mycobacteria biofilms against different antimicrobials]. PMID- 25027692 TI - The quantitative architecture of centromeric chromatin. AB - The centromere, responsible for chromosome segregation during mitosis, is epigenetically defined by CENP-A containing chromatin. The amount of centromeric CENP-A has direct implications for both the architecture and epigenetic inheritance of centromeres. Using complementary strategies, we determined that typical human centromeres contain ~400 molecules of CENP-A, which is controlled by a mass-action mechanism. This number, despite representing only ~4% of all centromeric nucleosomes, forms a ~50-fold enrichment to the overall genome. In addition, although pre-assembled CENP-A is randomly segregated during cell division, this amount of CENP-A is sufficient to prevent stochastic loss of centromere function and identity. Finally, we produced a statistical map of CENP A occupancy at a human neocentromere and identified nucleosome positions that feature CENP-A in a majority of cells. In summary, we present a quantitative view of the centromere that provides a mechanistic framework for both robust epigenetic inheritance of centromeres and the paucity of neocentromere formation.DOI: http://dx.doi.org/10.7554/eLife.02137.001. PMID- 25027697 TI - [Pruritic dermatitis after hiking in the mountains]. PMID- 25027698 TI - The pellino e3 ubiquitin ligases recognize specific phosphothreonine motifs and have distinct substrate specificities. AB - The four mammalian Pellinos (Pellinos 1, 2, 3a, and 3b) are E3 ubiquitin ligases that are emerging as critical mediators for a variety of immune signaling pathways, including those activated by Toll-like receptors, the T-cell receptor, and NOD2. It is becoming increasingly clear that each Pellino has a distinct role in facilitating immune receptor signaling. However, the underlying mechanisms by which these highly homologous proteins act selectively in these signaling pathways are not clear. In this study, we investigate whether Pellino substrate recognition contributes to the divergent functions of Pellinos. Substrate recognition of each Pellino is mediated by its noncanonical forkhead-associated (FHA) domain, a well-characterized phosphothreonine-binding module. Pellino FHA domains share very high sequence identity, so a molecular basis for differences in substrate recognition is not immediately apparent. To explore Pellino substrate specificity, we first identify a high-affinity Pellino2 FHA domain binding motif in the Pellino substrate, interleukin-1 receptor-associated kinase 1 (IRAK1). Analysis of binding of the different Pellinos to a panel of phosphothreonine-containing peptides derived from the IRAK1-binding motif reveals that each Pellino has a distinct phosphothreonine peptide binding preference. We observe a similar binding specificity in the interaction of Pellinos with a number of known Pellino substrates. These results argue that the nonredundant roles that Pellinos play in immune signaling are in part due to their divergent substrate specificities. This new insight into Pellino substrate recognition could be exploited for pharmacological advantage in treating inflammatory diseases that have been linked to the aberrant regulation of Pellinos. PMID- 25027699 TI - Shape-controlled synthesis of NiCo2S4 and their charge storage characteristics in supercapacitors. AB - In this work, a facile hydrothermal approach for the shape-controlled synthesis of NiCo2S4 architectures is reported. Four different morphologies, urchin-, tube , flower-, and cubic-like NiCo2S4 microstructures, have been successfully synthesized by employing various solvents. The obtained precursors and products have been characterized by X-ray diffraction, field-emission scanning electron microscopy and transmission electron microscopy. It is revealed that the supersaturation of nucleation and crystal growth is determined by the solvent polarity and solubility, which can precisely control the morphology of NiCo2S4 microstructures. The detailed electrochemical performances of the various NiCo2S4 microstructures are investigated by cyclic voltammetry and galvanostatic charge discharge measurements. The results indicate that the tube-like NiCo2S4 exhibits promising capacitive properties with high capacitance and excellent retention. Its specific capacitance can reach 1048 F g(-1) at the current density of 3.0 A g(-1) and 75.9% of its initial capacitance is maintained at the current density of 10.0 A g(-1) after 5000 charge-discharge cycles. PMID- 25027700 TI - Is cardiorespiratory fitness a determinant of cardiomyopathy in the setting of type 2 diabetes? AB - OBJECTIVE: The aim of this study was to determine whether high fitness attenuates the defects in left ventricular (LV) structure, function and triglyceride (TG) content in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Patients (n = 74) with T2DM and >=1 additional cardiac risk factor were recruited to participate in this cross-sectional study. Outcome measures of interest were LV structure and function by magnetic resonance imaging (MRI) and myocardial TG content by (1)H-magnetic resonance spectroscopy (MRS). The primary exposure variable was cardiorespiratory fitness defined by peak oxygen consumption scaled to fat-free mass (FFM; VO2peak-FFM). RESULTS: Mean age was 53.5 years; 42.9% were women and mean glycosylated haemoglobin (HbA1c) was 8.0% with the mean duration of T2DM 8.2 years. VO2peak-FFM was crudely associated with both LV end systolic (r = 0.35, p = 0.002) and diastolic volumes (r = 0.32, p = 0.004), but not with ejection fraction (r = -0.15, p = 0.206), myocardial TG (r = -0.04, p = 0.734) or early diastolic peak filling rate (PFR; r = -0.01, p = 0.887). In multiple linear regression analyses, among measures of LV structure/function, VO2peak-FFM was independently associated only with LV end-diastolic volume (EDV) (beta = 1.037, p = 0.038). CONCLUSION: In individuals with T2DM at increased cardiovascular (CV) risk, cardiorespiratory fitness is not associated with LV morphology, function or myocardial TG content. PMID- 25027701 TI - Thiamin supplementation does not reduce the frequency of adverse events after anti-malarial therapy among patients with falciparum malaria in southern Laos. AB - BACKGROUND: In a recent study one third of Lao patients presenting with uncomplicated Plasmodium falciparum malaria had biochemical evidence of thiamin deficiency, which was associated with a higher incidence of adverse events. Thiamin supplementation might, therefore, reduce adverse events in this population. METHODS: An exploratory, double-blind, parallel group, placebo controlled, superiority trial of thiamin supplementation in patients of all ages with uncomplicated and severe falciparum malaria was conducted in Xepon District, Savannakhet Province, southern Laos. Patients were randomly assigned to either oral thiamin 10 mg/day for 7 days immediately after standard anti-malarial treatment then 5 mg daily until day 42, or identical oral placebo. RESULTS: After interim analyses when 630 patients (314 in thiamin and 316 in placebo groups) had been recruited, the trial was discontinued on the grounds of futility. On admission biochemical thiamin deficiency (alpha >= 25%) was present in 27% of patients and 9% had severe deficiency (alpha > 31%). After 42 days of treatment, the frequency of thiamin deficiency was lower in the thiamin (2%, 1% severe) compared to the placebo (11%, 3% severe) groups (p < 0.001 and p = 0.05), respectively. Except for diarrhoea, 7% in the placebo compared to 3% in the thiamin group (p = 0.04), and dizziness on day 1 (33% vs 25%, p = 0.045), all adverse events were not significantly different between the groups (p > 0.05). Clinical, haematological, and parasitological responses to treatment did not differ significantly between the two groups. CONCLUSION: Thiamin supplementation reduced biochemical thiamin deficiency among Lao malaria patients following anti malarial drug treatment, but it did not reduce the frequency of adverse events after anti-malarial therapy or have any detected clinical or parasitological impact. TRIAL REGISTRATION: ISRCTN 85411059. PMID- 25027702 TI - Metabolic engineering of Escherichia coli for the production of riboflavin. AB - BACKGROUND: Riboflavin (vitamin B2), the precursor of the flavin cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is used commercially as an animal feed supplement and food colorant. E. coli is a robust host for various genetic manipulations and has been employed for efficient production of biofuels, polymers, amino acids, and bulk chemicals. Thus, the aim of this study was to understand the metabolic capacity of E. coli for the riboflavin production by modification of central metabolism, riboflavin biosynthesis pathway and optimization of the fermentation conditions. RESULTS: The basic producer RF01S, in which the riboflavin biosynthesis genes ribABDEC from E. coli were overexpressed under the control of the inducible trc promoter, could accumulate 229.1 mg/L of riboflavin. Further engineering was performed by examining the impact of expression of zwf (encodes glucose 6-phosphate dehydrogenase) and gnd (encodes 6-phosphogluconate dehydrogenase) from Corynebacterium glutamicum and pgl (encodes 6-phosphogluconolactonase) from E. coli on riboflavin production. Deleting pgi (encodes glucose-6-phosphate isomerase) and genes of Entner Doudoroff (ED) pathway successfully redirected the carbon flux into the oxidative pentose phosphate pathway, and overexpressing the acs (encodes acetyl-CoA synthetase) reduced the acetate accumulation. These modifications increased riboflavin production to 585.2 mg/L. By further modulating the expression of ribF (encodes riboflavin kinase) for reducing the conversion of riboflavin to FMN in RF05S, the final engineering strain RF05S-M40 could produce 1036.1 mg/L riboflavin in LB medium at 37 degrees C. After optimizing the fermentation conditions, strain RF05S-M40 produced 2702.8 mg/L riboflavin in the optimized semi-defined medium, which was a value nearly 12-fold higher than that of RF01S, with a yield of 137.5 mg riboflavin/g glucose. CONCLUSIONS: The engineered strain RF05S-M40 has the highest yield among all reported riboflavin production strains in shake flask culture. This work collectively demonstrates that E. coli has a potential to be a microbial cell factory for riboflavin bioproduction. PMID- 25027704 TI - Novel loss-of-function PRRT2 mutation causes paroxysmal kinesigenic dyskinesia in a Han Chinese family. AB - BACKGROUND: Mutations in proline-rich transmembrane protein 2 (PRRT2) are a cause of paroxysmal kinesigenic dyskinesia (PKD). In this study, we investigated the PRRT2 gene mutation in a Chinese Han family with PKD and study the pathogenesis of the mutation with PRRT2 gene. METHODS: Peripheral venous blood was taken from the family members. Sanger sequencing was used for novel mutation sequencing. For the pathogenesis with the novel mutation was analyzed by bioinformatics, real time PCR, subcellular localization and Western blot. RESULTS: The Sanger sequencing showed a novel mutation, c.186-187delGC, a deletion mutation, in exon 2 of the PRRT2 gene, the frameshift mutation generated a truncated protein that was stably expressed in transfected Human embryonic kidney (HEK) 293 cells. A subcellular localization assay in COS-7 cells with GFP-tagged protein showed nuclear localization for the mutant protein while the wild-type protein was localized in membranes. Co-transfection of HEK293 cells with wild-type and mutant expression plasmids cells did not influence mRNA or protein expression from the wild-type plasmid. CONCLUSIONS: Our findings demonstrated that the c.186-187delGC mutation resulted in a truncated protein from the PRRT2 gene to involve in PKD pathogenesis with haploinsufficiency. The results extend the mutation spectrum of the PRRT2 gene and provide a new example for studying the pathogenesis of the mutated PRRT2 gene. PMID- 25027705 TI - Antiviral medications for the treatment of hepatitis B and C infection and their effects on kidney function. AB - Over the last decade, treatment options for chronic hepatitis B and hepatitis C infection have markedly evolved. Several Food and Drug Administration-approved drugs are now available for the treatment of chronic hepatitis B, including immunomodulators (standard and pegylated interferon alpha), nucleoside analogues (lamivudine, entecavir and telbivudine) and nucleotide analogues (adefovir dipivoxil and tenofovir). For hepatitis C, the FDA-approved therapies include peginterferon-alpha, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir with expected approval of more agents in the foreseeable future. Some of these antiviral medications have been reported to have nephrotoxic effects, particularly with long-standing therapy, although the exact mechanism has not been fully elucidated. Secondary forms of glomerulonephritis that can be associated with hepatitis B and hepatitis C viral infection can further complicate the evaluation of renal failure in this population. Knowledge of the different antiviral medications and their potential nephrotoxic effects is crucial, since early identification and substitution to a different agent with withdrawal of the offending medication, may result in recovery or stabilization of renal function. Close monitoring of renal function while taking new antiviral medications is recommended, as some of the nephrotoxic effects may only appear after long-term use. PMID- 25027706 TI - Stimulated production of steroids in Inonotus obliquus by host factors from birch. AB - Steroids was considered as one of the bioactive components in Inonotus obliquus, while this kind of secondary metabolites are less accumulated in cultured mycelia. In this study, effect of extracts from bark and core of host-related species, birch (Betula platyphylla Suk.), on steroid production of I. obliquus in submerged culture were evaluated. The results showed that all dosages (0.01 and 0.1 g/L) of aqueous extracts and methanol extracts from birch bark and birch core possessed significantly stimulatory effect on steroid production of I. obliquus (P < 0.05). Among the eight extracts, the aqueous extract (0.01 g/L) from birch bark gave the highest steroid production (225.5 +/- 8.7 mg/L), which is 97.3% higher than that of the control group. The aqueous extract (0.01 and 0.1 g/L) from birch bark could simultaneously stimulated mycelial growth and steroid content, while the methanol extract from birch bark only elevated the steroid content. High performance liquid chromatography analysis showed that productions of betulin, ergosterol, cholesterol, lanosterol, stigmasterol, and sitosterol in I. obliquus simultaneously increased in the presence of aqueous extract and methanol extract from birch bark. The results presented herein indicate that extracts from birch bark could act as an inducer for steroid biosynthesis of I. obliquus. PMID- 25027707 TI - Femtogram detection of horseradish peroxidase by a common desktop scanner. AB - We report an image-based detection of horseradish peroxidase (HRP) by different color spaces. The results show excellent correlation between color saturation and absorbance (Pearson correlation coefficient; 0.9868) with respect to HRP. The present method can detect 185 and 46.45 fg/ml of HRP using o-phenylenediamine dihydrochloride and 3,3',5,5'-tetramethylbenzidine as chromogenic substrates respectively. PMID- 25027708 TI - Expression and characterization of an M cell-specific ligand-fused dengue virus tetravalent epitope using Saccharomyces cerevisiae. AB - A fusion construct (Tet-EDIII-Co1) consisting of an M cell-specific peptide ligand (Co1) at the C-terminus of a recombinant tetravalent gene encoding the amino acid sequences of dengue envelope domain III (Tet-EDIII) from four serotypes was expressed and tested for binding activity to the mucosal immune inductive site M cells for the development of an oral vaccine. The yeast episomal expression vector, pYEGPD-TER, which was designed to direct gene expression using the glyceraldehyde-3-phosphate dehydrogenase (GPD) promoter, a functional signal peptide of the amylase 1A protein from rice, and the GAL7 terminator, was used to clone the Tet-EDIII-Co1 gene and resultant plasmids were then used to transform Saccharomyces cerevisiae. PCR and back-transformation into Escherichia coli confirmed the presence of the Tet-EDIII-Co1 gene-containing plasmid in transformants. Northern blot analysis of transformed S. cerevisiae identified the presence of the Tet-EDIII-Co1-specific transcript. Western blot analysis indicated that the produced Tet-EDIII-Co1 protein with the expected molecular weight was successfully secreted into the culture medium. Quantitative Western blot analysis and ELISA revealed that the recombinant Tet-EDIII-Co1 protein comprised approximately 0.1-0.2% of cell-free extracts (CFEs). In addition, 0.1 0.2 mg of Tet-EDIII-Co1 protein per liter of culture filtrate was detected on day 1, and this quantity peaked on day 3 after cultivation. In vivo binding assays showed that the Tet-EDIII-Co1 protein was delivered specifically to M cells in Peyer's patches (PPs) while the Tet-EDIII protein lacking the Co1 ligand did not, which demonstrated the efficient targeting of this antigenic protein through the mucosal-specific ligand. PMID- 25027709 TI - What parameters from 18F-FDG PET/CT are useful in evaluation of adrenal lesions? AB - PURPOSE: Prior studies have suggested that (18)F-FDG PET/CT can help characterize adrenal lesions and differentiate adrenal metastases from benign lesions. The aim of this study was to assess the value of (18)F-FDG PET/CT for the differentiation of malignant from benign adrenal lesions. METHODS: This retrospective study included 85 patients (47 men and 38 women, age 63.8 +/- 10.8 years) who had undergone (18)F-FDG PET/CT (60 min after injection 300 - 370 MBq (18)F-FDG; Biograph 64 scanner) for evaluation of 102 nonsecreting adrenal masses. For semiquantitative analysis, the maximum standardized uptake value (SUVmax), adrenal to liver (T/L) SUVmax ratio, mean CT attenuation value and tumour diameter were measured in all lesions and compared with the pathological findings. RESULTS: Malignant adrenal tumours (68% of evaluated tumours) had a significantly higher mean SUVmax (13.0 +/- 7.1 vs. 3.7 +/- 3.0), a higher T/L SUVmax ratio (4.2 +/- 2.6 vs. 1.0 +/- 0.9), a higher CT attenuation value (31.9 +/- 16. 7 HU vs. 0.2 +/- 25.8 HU) and a greater diameter (43.6 +/- 23.7 mm vs. 25.6 +/- 13.3 mm) than benign lesions. The false-positive findings were tuberculosis and benign phaeochromocytoma. Based on ROC analysis, a T/L SUVmax ratio >1.53, an adrenal SUVmax >5.2, an attenuation value >24 HU and a tumour diameter >30 mm were chosen as the optimal cut-off values for differentiating malignant from benign tumours. The areas under the ROC curves for the selected cut-off values were 0.96, 0.96, 0.88 and 0.77, respectively. A multivariate logistic regression model revealed that the T/L SUVmax ratio was an independent prognostic factor for malignancy (p < 0.001); a CT attenuation value of >25 HU and a tumour diameter >30 mm had no additional individual importance in the diagnosis of malignancy. CONCLUSION: Using a T/L SUVmax ratio >1.53 and an adrenal SUVmax >5.2 in (18)F-FDG PET/CT led to high diagnostic sensitivity, specificity and negative predictive value for characterizing adrenal tumours. The diagnostic accuracies of the two parameters were comparable, but T/L SUVmax ratio was an independent predictor of malignancy. PMID- 25027710 TI - 2014 update on non-small cell lung cancer (excluding diagnosis). AB - Lung cancer (LC) is a major public health issue because of its frequency, but especially because of the severity of this disease. The epidemiology has changed with an increased incidence in non-smokers and women. The ATS/ERS/IASLC classification of adenocarcinomas was modified in 2011, and they are now the most frequent histological subtype. More than half the cases of LC are diagnosed at the metastatic stage. Biopsies must provide tissue samples that are quantitatively large enough and of a good enough quality for diagnosis and to search for biomarkers. When the cancer seems to be localized, precise staging must be obtained. Treatment is based on the TNM classification. In localized stages, lobectomy associated with lymph node dissection is the standard therapy. Intraoperative chemotherapy improves survival in case of lymph node infiltration. Stereotactic radiation therapy and radiofrequency can be considered as specific cases. In cases with local progression, treatment is more controversial. In the presence of metastases, the goal is not a cure, but improving survival and quality of life. Numerous advances have been made with personalized treatment, (in particular in relation to the histological type and oncogenic addiction in tumors, access to new drugs, and improved management). Clinical research in thoracic cancer is very active. The fight against tobacco should remain a priority. PMID- 25027711 TI - Chemopreventive effects of curcumin on chemically induced mouse skin carcinogenesis in BK5.insulin-like growth factor-1 transgenic mice. AB - The insulin-like growth factor-1 (IGF-1) signaling pathway is strongly associated with the risk of various cancers, and its inhibition has emerged as a potent anticancer strategy. Accumulating evidence from in vitro studies has shown that curcumin is a potent inhibitor of the IGF-1 signaling pathway. However, direct evidence that curcumin modulates IGF-1-induced tumorigenesis in a physiological system has not been reported. Therefore, in this study, we assessed the anticarcinogenic activity of curcumin on skin cancer by using BK5.IGF-1 transgenic (Tg) mice that overexpress IGF-1 in the skin epidermis. In 7,12 dimethylbenz(a)anthracene (DMBA)-tetradecanoyl phorbol-13-acetate (TPA) two-stage skin carcinogenesis, a curcumin diet (0.02% wt/wt) fed for 14 wk remarkably reduced mouse skin tumor multiplicity by 53%, epidermal hyperplasia and proliferation compared to the control diet group. TPA-induced phosphorylation of Akt, S6 kinase (S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) in mouse skin was lower in the curcumin group than in the control group. Curcumin treatment inhibited IGF-1-induced phosphorylation of the IGF-1 receptor, insulin receptor substrate-1, Akt, S6K, and 4EBP1 in the mouse keratinocyte cell line, C50 in a dose-dependent manner. Taken together, these data suggest that curcumin exerts significant anticarcinogenic activity in skin cancer through the inhibition of IGF-1 signaling. PMID- 25027712 TI - Lysosome sorting of beta-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor. AB - The integral membrane protein LIMP-2 has been a paradigm for mannose 6-phosphate receptor (MPR) independent lysosomal targeting, binding to beta glucocerebrosidase (beta-GCase) and directing it to the lysosome, before dissociating in the late-endosomal/lysosomal compartments. Here we report structural results illuminating how LIMP-2 binds and releases beta-GCase according to changes in pH, via a histidine trigger, and suggesting that LIMP-2 localizes the ceramide portion of the substrate adjacent to the beta-GCase catalytic site. Remarkably, we find that LIMP-2 bears P-Man9GlcNAc2 covalently attached to residue N325, and that it binds MPR, via mannose 6-phosphate, with a similar affinity to that observed between LIMP-2 and beta-GCase. The binding sites for beta-GCase and the MPR are functionally separate, so that a stable ternary complex can be formed. By fluorescence lifetime imaging microscopy, we also demonstrate that LIMP-2 interacts with MPR in living cells. These results revise the accepted view of LIMP-2-beta-GCase lysosomal targeting. PMID- 25027713 TI - [Fractal geometry in the objective grading of prostate carcinoma]. AB - BACKGROUND: A possible approach to objectively classify complex patterns in tumor tissue is a mathematical and statistical investigation of the distribution of cell nuclei as a geometric representation of cancer cells by fractal dimensions. Both the existence and changes in the fractal structure of tumor tissue have important consequences for the objective system of tumor grading. In addition, the complexity of growth in different carcinomas or their intercellular interactions can be compared to each other. RESULTS: We present a theoretical introduction into fractal geometry as well as in the computer algorithms based upon the Renyi family of fractal dimensions. Finally, a geometric model of prostate cancer is introduced and the relationship between geometric patterns of prostate tumor and the fractal dimensions of the Renyi family are explained. PMID- 25027714 TI - [Friedrich Berthold Reinke (1862-1919) : Rostock anatomist and describer of Reinke's crystals in the testis and Reinke's space in the larynx]. AB - The 95th anniversary of the anatomist Friedrich Berthold Reinke's death is 19 May 2014. This an excellent moment to remember his anatomical research. Two structures which he discovered and first described continue to be associated with his name: Reinke crystals of testicular Leydig cells and Reinke's space in the larynx. Reinke's crystals are crystalline protein aggregates within interstitial Leydig cells which are probably associated with testosterone production. They are pathognomonic for Leydig cell tumours. PMID- 25027716 TI - High pressure does not counterbalance the advantages of open techniques over closed techniques during heated intraperitoneal chemotherapy with oxaliplatin. AB - BACKGROUND: Heated intraperitoneal chemotherapy (HIPEC) treats residual microscopic disease after cytoreductive surgery. In experimental models, the open HIPEC technique has shown a higher and more homogenous concentration of platinum in the peritoneum than achieved using the closed technique. A 25-cm H2O pressure enhances the penetration of oxaliplatin. Because pressure is easier to set up with the closed technique, high pressure may counterbalance the drawbacks of this technique versus open HIPEC, and a higher pressure may induce a higher penetration. Because higher concentration does not mean deeper penetration, a study of tissues beneath the peritoneum is required. Finally, achieving a deeper penetration (and a higher concentration) raises the question of the passage of drugs through the surgical glove and the surgeon's safety. METHODS: Four groups of pigs underwent HIPEC with oxaliplatin (150 mg/L) for 30 minutes in open isobaric pressure and pressure at 25 cm H2O, and closed pressure at 25 and 40 cm H2O. Systemic absorption and peritoneal mapping of the concentration of platinum were analyzed, as well as in the retroperitoneal tissue and the surgical gloves. RESULTS: Blood concentrations were higher in open groups. In the parietal surfaces, the concentrations were not different between the isobaric and the closed groups (47.08, 56.39, and 48.57 mg/kg, respectively), but were higher in the open high-pressure group (85.93 mg/kg). In the visceral surfaces, they were lower in the closed groups (3.2 and 3.05 mg/kg) than in the open groups (7.03 and 9.56 mg/kg). Platinum concentrations were similar in the deep retroperitoneal tissue when compared between isobaric and high-pressure procedures. No platin was detected in the internal aspect of the gloves. CONCLUSION: The use of high pressure during HIPEC does not counterbalance the drawbacks of closed techniques. The tissue concentration of oxaliplatin achieved with the open techniques is higher, even if high pressure is applied during a closed technique. Open 25 cm H2O HIPEC achieved the highest tissue penetration of oxaliplatin, but did not enhance the depth of oxaliplatin penetration. High pressure did not enhance the risk of HIPEC. PMID- 25027717 TI - The structure of selective dinucleotide interactions and periodicities in D melanogaster mtDNA. AB - BACKGROUND: We found a strong selective 3-sites periodicity of deviations from randomness of the dinucleotide (DN) distribution, where both bases of DN were separated by 1, 2, K sites in prokaryotes and mtDNA. Three main aspects are studied. I) the specific 3 K-sites periodic structure of the 16 DN. II) to discard the possibility that the periodicity was produced by the highly nonrandom interactive association of contiguous bases, by studying the interaction of non contiguous bases, the first one chosen each I sites and the second chosen J sites downstream. III) the difference between this selective periodicity of association (distance to randomness) of the four bases with the described fixed periodicities of base sequences. RESULTS: I) The 16 pairs presented a consistent periodicity in the strength of association of both bases of the pairs; the most deviated pairs are those where G and C are involved and the least deviated ones are those where A and T are involved. II) we found significant non-random interactions when the first nucleotide is chosen every I sites and the second J sites downstream until I=J=76. III) we showed conclusive differences between these internucleotide association periodicities and sequence periodicities. CONCLUSIONS: This relational selective periodicity is different from sequence periodicities and indicates that any base strongly interacts with the bases of the residual genome; this interaction and periodicity is highly structured and systematic for every pair of bases. This interaction should be destroyed in few generations by recurrent mutation; it is only compatible with the Synthetic Theory of Evolution and agrees with the Wright's adaptive landscape conception and evolution by shifting balanced adaptive peaks. PMID- 25027718 TI - Efficient generation of sFat-1 transgenic rabbits rich in n-3 polyunsaturated fatty acids by intracytoplasmic sperm injection. AB - N-3 polyunsaturated fatty acids (n-3 PUFAs) have their first double bond at the third carbon from the methyl end of the fatty-acid chain and had been proven to be beneficial to human health. However, mammals cannot produce n-3 PUFAs by themselves because they lack the n-3 fatty-acid desaturase (Fat-1) gene. Thus, the possibility of producing sFat-1 transgenic rabbits was explored in this study. The transgenic cassette of pPGK1-sFat-1-CMV-EGFP was constructed and transgenic rabbit embryos were produced by intracytoplasmic sperm injection (ICSI). When 123 EGFP-positive embryos at the 2-8-cell stage were transplanted into the oviduct of four oestrous-synchronised recipients, two of them became pregnant and gave birth to seven pups. However, transfer of embryos into the uterus of oestrous-synchronised recipients and oviduct or uterus of oocyte donor rabbits did not result in pregnancy. The integration of the sFat-1 gene was confirmed in six of the seven live pups by PCR and Southern blot. The expression of the sFat-1 gene in the six transgenic pups was also detected by reverse transcription polymerase chain reaction (RT-PCR). Gas chromatography-mass spectrometry analysis revealed that transgenic rabbits exhibited an ~15-fold decrease in the ratio of n-6:n-3 PUFAs in muscle compared with wild-type rabbits and non-transgenic rabbits. These results demonstrate that sFat-1 transgenic rabbits can be produced by ICSI and display a low ratio of n-6:n-3 PUFAs. PMID- 25027719 TI - The mysterious Spotted Green Pigeon and its relation to the Dodo and its kindred. AB - BACKGROUND: The closely related and extinct Dodo (Raphus cucullatus) and Rodrigues Solitaire (Pezophaps solitaria), both in the subfamily Raphinae, are members of a clade of morphologically very diverse pigeons. Genetic analyses have revealed that the Nicobar Pigeon (Caloenas nicobarica) is the closest living relative of these birds, thereby highlighting their ancestors' remarkable migration and morphological evolution. The Spotted Green Pigeon (Caloenas maculata) was described in 1783 and showed some similarities to the Nicobar Pigeon. Soon however the taxon fell into obscurity, as it was regarded as simply an abnormal form of the Nicobar Pigeon. The relationship between both taxa has occasionally been questioned, leading some ornithologists to suggest that the two may in fact be different taxa. Today only one of the original two specimens survives and nothing is known about the origin of the taxon. Due to its potential close relationship, the Spotted Green Pigeon may hold clues to the historical migration, isolation and morphological evolution of the Dodo and its kindred. RESULTS: We use ancient DNA methodologies to investigate the phylogeny and authenticity of the Spotted Green Pigeon. A novel extraction method with the ability to retain and purify heavily fragmented DNA is used to investigate two feathers from the sole surviving specimen. Maximum Likelihood phylogenetic analyses reveal that the Spotted Green Pigeon is a unique lineage and together with the Nicobar Pigeon, is basal to the Dodo and Rodrigues Solitaire. CONCLUSIONS: The distance observed for the Spotted Green Pigeon and Nicobar Pigeon is larger than that observed within other Pigeon species, indicating that the Spotted Green pigeon is a unique taxon, thereby also indicating it is a genuine addition to the list of extinct species. The phylogenetic placement of the Spotted Green Pigeon indicates that the ancestors of both Caloenas and therefore Raphinae displayed and shared the following traits: ability of flight, semi-terrestrial habits and an affinity towards islands. This set of traits supports the stepping stone hypothesis, which states that the Raphinae got to their respective localities by island hopping from India or Southeast Asia. PMID- 25027720 TI - Enantiomeric-selective determination of pyrethroids: application to human samples. AB - Recently, some works point out the bioaccumulation of pyrethroids in humans. Given the chiral properties of pyrethroids, our goal in this work was to develop a gas chromatography (GC)-MS-MS methodology for the enantioselective analysis of six common pyrethroids. For the first time, we separate the enantiomers of bifenthrin, cyhalothrin, cyfluthrin, cypermethrin, permethrin and tetramethrin in a single analysis of less than 75 min and with resolutions greater than 0.58 in all cases. The developed method proved to be reproducible (with relative standard deviations under 3%) and sensitive (with instrumental limits of detection from 4 to 49 fg) enough to evaluate the enantiomeric distribution of these pyrethroids. The developed methodology was applied to commercial insecticides and human breast milk samples. Some potential selective bioaccumulation for cyhalothrin, cyperpermethrin and tetramethrin was described in humans. PMID- 25027721 TI - Simultaneous determination of bufadienolides and phenolic compounds in sea squill (Drimia maritima (L.) Stearn) by HPLC-DAD-MSn as a means to differentiate individual plant parts and developmental stages. AB - Mediterranean sea squill (Drimia maritima (L.) Stearn) is used in the production of medicinal products. Current HPLC methods comprise tedious sample clean-up and have been merely focused on the analysis of cardiac glycosides, whereas a thorough characterization of D. maritima considering both the latter compound class and more hydrophilic secondary metabolites in one HPLC run has not been performed so far. Consequently, a novel HPLC-DAD-MS(n) method has been developed allowing the simultaneous determination of both cardiac glycosides and phenolic compounds, which is characterized by simplified sample preparation. This method was applied to characterize sea squill, revealing a complex profile of its extractive compounds derived from the two classes. Furthermore, the potential of the method reported here to quantitate the predominant compounds, i.e., dihydroquercetin derivatives and bufadienolides, was demonstrated. The occurrence of phenolic compounds, not described for sea squill so far, and of characteristic compounds specific to individual plant parts or vegetation stages was further addressed. The data revealed that classification of various vegetation phases based on quantitative evaluation of bufadienolides and dihydroquercetin derivatives applying principal component analysis (PCA) appears possible. Thus, the methodology presented here forms the basis for future routine application in quality control of raw materials and pharmaceutical preparations derived from sea squill. This will allow systematic comparison of different plant parts, vegetation stages and origins based on an extended sample set. PMID- 25027722 TI - The potential of the Child Health Utility 9D Index as an outcome measure for child dental health. AB - BACKGROUND: The Child Health Utility 9D (CHU9D) is a relatively new generic child health-related quality of life measure (HRQoL)-designed to be completed by children-which enables the calculation of utility values.The aim is to investigate the use of the CHU9D Index as an outcome measure for child dental health in New Zealand. METHOD: A survey was conducted of children aged between 6 and 9 years attending for routine dental examinations in community clinics in Dunedin (New Zealand) in 2012. The CHU9D, a HRQoL, was used, along with the Child Perceptions Questionnaire (CPQ), a validated oral health-related quality of life (OHRQoL) measure. Socio-demographic characteristics (sex, age, ethnicity and household deprivation) were recorded. Dental therapists undertook routine clinical examinations, with charting recorded for each child for decayed, missing and filled deciduous teeth (dmft) at the d3 level. RESULTS: One hundred and forty 6-to-9-year-olds (50.7% female) took part in the study (93.3% participation rate). The mean d3mft was 2.4 (SD = 2.6; range 0 to 9). Both CHU9D and CPQ detected differences in the impact of dental caries, with scores in the expected direction: children who presented with caries had higher scores (indicating poorer OHRQoL) than those who were free of apparent caries. Children with no apparent caries had a higher mean CHU9D score than those with caries (indicating better HRQoL). The difference for the CPQ was statistically significant, but for CHU9D the difference was not significant. When the two indices were compared, there was a significant difference in mean CHU9D scores by the prevalence of CPQ and subscale impacts with children experiencing no impacts having mean CHU9D scores closer to 1.0 (representing perfect health). CONCLUSION: The CHU9D may be useful in dental research. Further exploration in samples with different caries experience is required. The use of the CHU9D in child oral health studies will enable the calculation of quality-adjusted life years (QALYs) for use in economic evaluation. PMID- 25027723 TI - Recent advances to improve fermentative butanol production: genetic engineering and fermentation technology. AB - Butanol has recently attracted attention as an alternative biofuel because of its various advantages over other biofuels. Many researchers have focused on butanol fermentation with renewable and sustainable resources, especially lignocellulosic materials, which has provided significant progress in butanol fermentation. However, there are still some drawbacks in butanol fermentation in terms of low butanol concentration and productivity, high cost of feedstock and product inhibition, which makes butanol fermentation less competitive than the production of other biofuels. These hurdles are being resolved in several ways. Genetic engineering is now available for improving butanol yield and butanol ratio through overexpression, knock out/down, and insertion of genes encoding key enzymes in the metabolic pathway of butanol fermentation. In addition, there are also many strategies to improve fermentation technology, such as multi-stage continuous fermentation, continuous fermentation integrated with immobilization and cell recycling, and the inclusion of additional organic acids or electron carriers to change metabolic flux. This review focuses on the most recent advances in butanol fermentation especially from the perspectives of genetic engineering and fermentation technology. PMID- 25027724 TI - Microbial transformations of halolactones with p-menthane system. AB - Biologically active piperitone-derived racemic iodo-, bromo- and chlorolactones (1-3) were transformed with the use of microbial enzymatic systems. Four strains of filamentous fungi Absidia glauca AM254, Absidia cylindrospora AM336, Mortierella vinaceae AM149 and Nigrospora oryzae AM8 transformed halolactones (1 3) to four new halohydroxylactones (4-7). In all biotransformations the hydroxy group was incorporated in inactivated methine carbon atom at isopropyl substituent. In N. oryzae AM8 culture the bromolactone with additional hydroxy group in alpha-position, relative to CO bond in gamma-lactone ring, was also formed as a product. The structures of new compounds were established on the basis of spectral data. PMID- 25027730 TI - Sleep quality and facial pain in fibromyalgia syndrome. AB - AIMS: This study aims to evaluate the sleep conditions in fibromyalgia syndrome and the influence of the temporomandibular disorders (TMDs) and fibromyalgia association in self-reported sleep quality. METHODOLOGY: Forty female patients with fibromyalgia (FMS) were compared with 40 healthy women [control group (CG)]. Three questionnaires were used (i.e. RDC/TMD to diagnose TMD and to determine pain intensity and disability and Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) to assess sleep conditions). Statistical analyses were performed using the Wilcoxon-Mann-Whitney test to ordinal variables, Student's t-test to obtain the quantitative total scores of PSQI and chronic pain classification, Spearman's rho to determine the correlation between facial pain and quality sleep, and Fisher's exact test for other variables. RESULTS: A moderate correlation between facial pain intensity and low sleep quality was found (rho = 0.56; P<0.0001); however, TMD and FMS association did not show worse sleep quality (P>0.05). Excessive daytime sleepiness was more prevalent in FMS (37.5%; P<0.0001) besides having the worst sleep quality (PSQI = 12.72) compared with CG (PSQI = 4.62). CONCLUSION: Fibromyalgia patients experience intense facial pain in addition to poor sleep and high disabilities. TMD and FMS association do not appear to worsen this condition; however, facial pain intensity was correlated with low sleep quality. PMID- 25027731 TI - The role of occlusal factors on the occurrence of temporomandibular disorders. AB - AIMS: The aim of this study was to investigate the relationship between occlusal factors and temporomandibular disorders (TMD). METHODOLOGY: One hundred patients were selected among those who sought medical or dental care in public practice in Recife, Brazil. The presence of malocclusions and absence of five or more posterior teeth were evaluated by the clinical exam. TMD diagnosis was given using Research Diagnostic Criteria (RDC/TMD). Statistics were carried out using Fisher and Mann-Whitney methods with 5% significance level, as well as multiple logistic regression analysis. RESULTS: The sample was mainly comprised of women (83%), individuals over 30 years old (57%) and singles (53%). The percentage of TMD and malocclusion in total sample was 42% and 50%, respectively, while in TMD subjects, malocclusion was present in 38.1%. There was no association between TMD and the occlusal factors studied. CONCLUSION: It can be concluded that malocclusion and loss of five or more posterior teeth does not contribute to TMD. PMID- 25027732 TI - Spatiotemporal patterns of current source density in the prefrontal cortex of a behaving monkey. AB - One of the fundamental missions of neuroscience is to explore the input and output properties of neuronal networks to reveal their functional significance. However, it is technically difficult to examine synaptic inputs into neuronal circuits in behaving animals. Here, we conducted current source density (CSD) analysis on local field potentials (LFPs) recorded simultaneously using a multi contact electrode in the prefrontal cortex (PFC) of a behaving monkey. We observed current sink task-dependent spatiotemporal patterns considered to reflect the synaptic input to neurons adjacent to the recording site. Specifically, the inferior convex current sink in the PFC was dominant during the delay period, whereas the current sink was prominent in the principal sulcus during the sample cue and test cue periods. Surprisingly, sulcus current sink patterns were spatially periodic, which corresponds to the columnar structure suggested by previous anatomical studies. The approaches used in the current study will help to elucidate how the PFC network performs executive functions according to its synaptic input. PMID- 25027733 TI - Noncoding RNAs in the regulation of DNA replication. AB - Noncoding RNAs (ncRNAs) have crucial roles in epigenetic, transcriptional, and post-transcriptional regulation. Recent studies have begun to reveal a role of ncRNAs in DNA replication. Here, we review the roles of ncRNAs in regulating different aspects of DNA replication in prokaryotic and eukaryotic systems. We speculate that ncRNAs might function to guide the origin recognition complex (ORC) to chromosomal DNA during replication initiation in higher eukaryotes. PMID- 25027734 TI - Demographic, cognitive, affective, and behavioral variables associated with overweight and obesity in low-active girls. AB - This study examined personal, cognitive, affective, and behavioral variables related to body mass index (BMI) among 73 6th and 7th grade girls, and differences between categories of healthy weight, overweight, and obese in the variables. BMI was correlated with barriers to physical activity, enjoyment of physical activity, light physical activity, moderate to vigorous physical activity, vigorous physical activity, and sedentary time. As compared to obese girls, those who were non-obese perceived greater enjoyment of physical activity, engaged in more light and vigorous physical activity, and had fewer minutes/hour of sedentary time. Findings can inform interventions. PMID- 25027735 TI - Complication rates and reduction potential of palmar versus dorsal locking plate osteosynthesis for the treatment of distal radius fractures. AB - BACKGROUND: The aim of this study was to evaluate the complication rates of volar versus dorsal locking plates and postoperative reduction potential after distal radius fractures. MATERIALS AND METHODS: For this study 285 distal radius fractures (280 patients/59.4 % female) treated with locked plating were retrospectively evaluated. The mean age of the patients was 54.6 years (SD 17.4) and the mean follow-up was 33.2 months (SD 17.2). The palmar approach was used in 225 cases and the dorsal approach in 60 cases (95 % type C fractures). RESULTS: Adequate reduction was achieved with both approaches, regardless of fracture severity. In the dorsal group, the complications and implant removal rates were significantly higher and the operative time was also longer. CONCLUSIONS: Based on these facts, we advocate the palmar locking plate for the vast majority of fractures. In cases of complex multifragmentary articular fractures where no compromise in reduction is acceptable, and with the biomechanical equality of palmar and dorsal plating remaining unproven, dorsal plating may still be considered. LEVEL OF EVIDENCE: Therapeutic level IV. PMID- 25027737 TI - Effect of management practices and animal age on incidence of mastitis in Nili Ravi buffaloes. AB - Buffalo is an economically important dairy animal in South Asia but mostly ignored in research priorities. In this retrospective study, the effect of management practices and age of animal on the incidence of mastitis in Nili Ravi buffaloes was investigated. A total of 1,560 quarters of buffaloes (n = 390) were screened by visual examination of the udder and milk (clinical mastitis) and California mastitis test (subclinical mastitis). Household data was collected on a predesigned questionnaire and analyzed. The prevalence of subclinical mastitis, clinical mastitis, and blind quarters was 41.8, 13.6, and 9.7 %, respectively. The highest prevalence was noted in the hind quarters and left side as compared to that in the forequarters and right side. This data significantly (p < 0.05) supported the idea that larger herd size has more chances of mastitis, with the highest prevalence (40, 32, and 27 %) in the large, medium, and small herds, respectively. Stage of lactation was significantly (p < 0.01) involved in mastitis, and the highest incidence (43.3 %) was noted in early lactation. Milk production of lactating buffaloes that ranged 6-10 l/day showed a higher rate of mastitis occurrence (p < 0.05). The cleanliness condition of a farm also contributed significantly. Animal age significantly affected the incidence of mastitis. Results revealed that age of the animal has a positive correlation (R (2) = 0.772) with mastitis. This study concluded that some factors alone or in combination with other factors influence significantly the occurrence of mastitis, and to minimize the infection, these factors should be considered. The outcome of the study will be valuable for policy-making for positive management practices and implementation of preventive measures. PMID- 25027738 TI - Identification and molecular analysis of infectious bursal disease in broiler farms in the Kurdistan Regional Government of Iraq. AB - The present study was undertaken to characterize field isolates of infectious bursal disease virus (IBDV). The identification was done using reverse transcription-polymerase chain reaction (RT-PCR) and partial sequencing of the VP2 gene. Pooled bursal samples were collected from commercial broiler farms located in the Kurdistan Regional Government (KRG) of Iraq. The genetic material of the IBDV was detected in 10 out of 29 field samples. Sequences of the hypervariable VP2 region were determined for 10 of these viruses. Molecular analysis of the VP2 gene of five IBDVs showed amino acid sequences consistent with the very virulent (vv) IBDV. Two samples were identified as classic vaccine viruses, and three samples were classic vaccine viruses that appear to have mutated during replication in the field. Phylogenetic analysis showed that all five field IBDV strains of the present study were closely related to each other. On the basis of nucleotide sequencing and phylogenetic analysis, it is very likely that IBD-causing viruses in this part of Iraq are of the very virulent type. These IBDVs appear to be evolving relative to their type strains. PMID- 25027739 TI - HOTAIR: a cancer-related long non-coding RNA. AB - Long non-coding RNA was dismissed as merely transcriptional "noise" in the past decades. Numerous researches have shown that lncRNAs regulated gene expression at the epigenetic level. Moreover, lncRNAs played important roles in proliferation, apoptosis and invasiveness of tumor cells, and participated in metastatic capacity of cancers. Recent studies revealed HOX transcript antisense RNA, a lncRNA with regulatory functions of transcription, could bind PRC2 and LSD1/CoREST/REST complexes and direct to the specific gene sites, resulted in H3K27 methylation and H3K4 demethylation and ultimately gene silencing. Aberrant HOTAIR expression was associated with various sites of cancers such as breast, hepatocellular, gastric, colorectal, pancreatic et al; and affected survival and prognosis of cancer patients. In this review, we introduce an overall view of HOTAIR by describing the known molecular mechanisms and potential functions of HOTAIR and summarizing the latest progresses on the research of HOTAIR in various human cancers. PMID- 25027740 TI - In vitro and in vivo studies of antitumor effects of the recombinant immunotoxin MSH-PE38KDEL on melanoma. AB - MSH-PE38KDEL is a chimeric molecule composed of MSH, and fused to a truncated mutant form of Pseudomonas exotoxin (PE38KDEL). Our study aims to evaluate the specific cytotoxicity of recombinant immunotoxin MSH-PE38KDEL on melanoma cells A875 and B16 in vitro, as well as its inhibition of metastatic melanoma in vivo. MSH-PE38KDEL was expressed in Escherichia coli, and greater than 90% purity was obtained. The purified MSH-PE38KDEL was found to be selectively cytotoxic to MSH receptor-positive melanoma cells in vitro. The specific cytotoxicity of recombinant MSH-PE38KDEL to A875 and B16 was over 85% by cell viability assay; however, MSH-PE38KDEL had no cytotoxicity to the human 2BS cells. The anti-tumor activity of MSH-PE38KDEL was evaluated in mice with induced melanoma through intra-tumor or intravenous administration. The results showed that 90% melanoma growths were inhibited, and 40% of the tumors were disappeared completely. Histopathology results showed MSH-PE38KDEL can effectively inhibit intrahepatic metastasis. In conclusion, MSH-PE38KDEL had cytotoxic effects on MSH receptor positive melanoma cells, and causes significant tumor growth inhibition. These results support a possible new approach for the treatment of melanoma. PMID- 25027741 TI - Co-mutated pathways analysis highlights the coordination mechanism in glioblastoma multiforme. AB - The mutation of cancer represents a high heterogeneity characteristic, setting a big obstacle in the mechanism study of it. In this study, we explored the distributions of mutated genes in pathways in glioblastoma multiforme (GBM), and constructed networks of co-mutated pathway pairs under the false discovery rate (FDR) control. By comparing the mutation frequencies, a total of 50 mutated genes were screened with the frequency > 3, and TP53, PTEN, and EGFR were the top 3 genes. By KEGG enrichment, 18 pathways of the mutation gene spectrum of GBM were enriched. These pathways were further studied to explore the coordination between pathways, co-mutated pathway pairs, such as mismatch repair/vascular smooth muscle contraction, mismatch repair/long-term depression, mismatch repair/dopaminergic synapse, and TGF-beta signaling pathway/retrograde endocannabinoid signaling pathway were enriched in the network under FDR < 0.01; and cell cycle/p53 signaling was a co-mutated pathway pairs in the network under FDR < 0.05. Meanwhile, the samples overlap levels of enriched pathways were calculated for further confirming of the co-mutated pathway model. By the co mutated pathway analysis, the coordination mechanism of cancer can be explored, and it may provide basis for the pathogenesis and combined therapy study of cancer. PMID- 25027742 TI - Up front hepatectomy for metastatic rectal carcinoma - reversed, liver first approach. Early experience with 15 patients. AB - Timing and sequence of therapeutic interventions in patients with colorectal cancer (CRC) and synchronous liver metastases is a matter of ongoing discussion. The aim of this report is to show the feasibility and safety of a reversed strategy in patients with up front resectable synchronous liver metastases. Consecutive series of 15 patients with locally advanced rectal carcinoma and liver synchronous metastases where up front liver resection was carried out as an initial intervention is presented. Local treatment of both, metastatic disease and primary tumor, was preferred. Liver resection was followed by neoadjuvant (preoperative) concomitant radiochemotherapy (RCT) for local pelvic disease control and subsequent resection of rectum. Systemic adjuvant chemotherapy was placed at the end of the entire treatment cycle. All 15 patients after up front hepatectomy were able to proceed with their treatment plan. 14 patients completed their RCT for primary tumor and subsequent rectal resection was successfully carried out. In 12 of them. 3 patients showed complete clinical response on cross sectional imaging and a careful "wait-and-see" policy was adopted for them. In two patients metastatic disease progression was noticed during the treatment cycle.Liver first approach in patients with up front resectable colorectal liver metastases (CRLM) is safe and feasible. Local neoadjuvant treatment after CRLM resection may result in preoperative downsizing or even complete clinical response of the primary tumor. Reversed strategy may to a degree eliminate negative oncologic impact of surgical complications after rectal surgery as CRLM has been already addressed. PMID- 25027744 TI - High TBX2 expression predicts poor prognosis in non-small cell lung cancer. AB - Deregulated expression of T-box2 (TBX2) has been implicated in malignancies. However, the expression pattern and the role of TBX2 in non-small cell lung cancer (NSCLC) remain unclear. The aim of this study was to explore the clinical value of TBX2 in patients with NSCLC. We examined TBX2 expression in 40 NSCLC tissues and matched adjacent noncancerous tissues by quantitative RT-PCR (qRT PCR) and Western blotting. Furthermore, the TBX2 protein expression was analyzed by immunohistochemistry in 416 NSCLC samples. Kaplan-Meier method and multivariate Cox regression model were used to evaluate the prognostic value of TBX2 expression in NSCLC for disease survival. The expression of TBX2 was significantly elevated in NSCLC tissues as compared with adjacent non-cancerous tissues (P<0.001). The high expression of TBX2 in NSCLC was significantly correlated with lymph node metastasis and tumor node metastasis (TNM) stage. Kaplan-Meier survival analysis revealed that high expression of TBX2 correlated with poor prognosis of NSCLC patients (P<0.01). Multivariate analysis showed that TBX2 expression was an independent prognostic marker for overall survival of NSCLC patients (HR=2.21, 95%CI=1.349-3.905, P=0.0015). Our results suggest that high TBX2 expression is associated with poor prognosis of NSCLC patients, and TBX2 may be a prognostic biomarker for NSCLC. PMID- 25027743 TI - PIK3CA mutations are a predictor of docetaxel plus epirubicin neoadjuvant chemotherapy clinical efficacy in breast cancer. AB - This study proposed to investigate the relationship of PIK3CA somatic mutations, the most common activating mutations in human breast cancer (BC), and the efficacy of neoadjuvant chemotherapy (NCT).Using a novel liquid chip technology,PIK3CA DNA somatic mutations and HER2, PTEN, EGFR mRNA expression profiles were analyzed in formalin fixed paraffin embedded samples of 93 BC patients treated with epirubicin plus docetaxel NCT.PIK3CA mutations were found in 30 patients (32.3%), in which the point mutations of E542K, E545K, H1047L and H1047R were 4.3, 9.7, 4.3 and 14.0%respectively. The PIK3CA mutations were significantly associated with patients' clinical response; 27 of 30 PIK3CA mutated patients had either a partial or complete response (p=0.002). Multivariate analysis further confirmed that, after adjustments for age, disease stages and NCT cycles, PIK3CA was associated with clinical response (Odds Ration 0.126, 95% CI [0.029,0.691]). However, there was no significant difference between PIK3CA mutations in pathological complete response (pCR,7 /92) and non pCR group. Furthermore, no EGFR, KRAS and BRAF mutations were detected in any of the 93 samples. Our data for the first time suggested that PIK3CA mutation status may be a predictor for better understanding clinical response to the combination of epirubicin and docetaxel NCT in patients with BC. PMID- 25027745 TI - Visualising dual downregulation of insulin-like growth factor receptor-1 and vascular endothelial growth factor-A by heat shock protein 90 inhibition effect in triple negative breast cancer. AB - PURPOSE: Triple negative breast cancer (TNBC) is biologically characterised by heterogeneous presence of molecular pathways underlying it. Insulin-like growth factor receptor-1 (IGF-1R) expression and vascular endothelial growth factor-A (VEGF-A) have been identified as key factors in these pathways in TNBC. In this study, we aimed at in vivo PET imaging the effect of heat shock protein (Hsp) 90 inhibition by means of NVP-AUY922 on these pathways, with zirconium-89 ((89)Zr) labelled antibodies targeting IGF-1R and VEGF-A. MATERIALS AND METHODS: In vitro NVP-AUY922 effects on cellular IGF-1R expression and VEGF-A secretion were determined in MCF-7 and MDA-MB-231 cell lines. Moreover human TNBC bearing MDA-MB 231 mice received 50mg/kg NVP-AUY922 or vehicle q3d intraperitoneally for 21days. PET scans with (89)Zr-MAB391 and (89)Zr-bevacizumab for visualisation of IGF-1R and VEGF-A were performed before and during treatment. Ex vivo biodistribution and correlative tissue analyses were performed. RESULTS: NVP-AUY922 treatment reduced IGF-1R expression and VEGF-A excretion in both cell lines. Hsp90 inhibition lowered tumour uptake on (89)Zr-MAB391-PET by 37.3% (P<0.01) and on (89)Zr-bevacizumab-PET by 44.4% (P<0.01). This was confirmed by ex vivo biodistribution with a reduction of 41.3% injected dose (ID)/g for (89)Zr-MAB391 and 37.8% ID/g for (89)Zr-bevacizumab, while no differences were observed for other tissues. This coincided with reduced IGF-1R expression and mean vessel density in the NVP-AUY922 treated tumours. CONCLUSION: (89)Zr-MAB391 and (89)Zr bevacizumab PET reflect effect of Hsp90 inhibitors and can therefore potentially be used to monitor therapeutic effects of Hsp90 inhibitor therapy in TNBC. PMID- 25027746 TI - Developmental changes in decision making under risk: The role of executive functions and reasoning abilities in 8- to 19-year-old decision makers. AB - Previous studies have shown that children and adolescents often tend toward risky decisions despite explicit knowledge about the potential negative consequences. This phenomenon has been suggested to be associated with the immaturity of brain areas involved in cognitive control functions. Particularly, "frontal lobe functions," such as executive functions and reasoning, mature until young adulthood and are thought to be involved in age-related changes in decision making under explicit risk conditions. We investigated 112 participants, aged 8 19 years, with a frequently used task assessing decisions under risk, the Game of Dice Task (GDT). Additionally, we administered the Modified Card Sorting Test assessing executive functioning (categorization, cognitive flexibility, and strategy maintenance) as well as the Ravens Progressive Matrices assessing reasoning. The results showed that risk taking in the GDT decreased with increasing age and this effect was not moderated by reasoning but by executive functions: Particularly, young persons with weak executive functioning showed very risky decision making. Thus, the individual maturation of executive functions, associated with areas in the prefrontal cortex, seems to be an important factor in young peoples' behavior in risky decision-making situations. PMID- 25027747 TI - Parenteral iron as a cause of hypophosphataemia. PMID- 25027748 TI - Understanding the origin of band gap formation in graphene on metals: graphene on Cu/Ir(111). AB - Understanding the nature of the interaction at the graphene/metal interfaces is the basis for graphene-based electron- and spin-transport devices. Here we investigate the hybridization between graphene- and metal-derived electronic states by studying the changes induced through intercalation of a pseudomorphic monolayer of Cu in between graphene and Ir(111), using scanning tunnelling microscopy and photoelectron spectroscopy in combination with density functional theory calculations. We observe the modifications in the band structure by the intercalation process and its concomitant changes in the charge distribution at the interface. Through a state-selective analysis of band hybridization, we are able to determine their contributions to the valence band of graphene giving rise to the gap opening. Our methodology reveals the mechanisms that are responsible for the modification of the electronic structure of graphene at the Dirac point, and permits to predict the electronic structure of other graphene-metal interfaces. PMID- 25027749 TI - The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients. AB - BACKGROUND: Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis. METHODS: In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human beta Defensin 2 (HbetaD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention. RESULTS: During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean +/- SD 19.82 +/- 19.55 days vs. 13.82 +/- 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HbetaD2 levels were higher for NAC group (at day 3). CONCLUSION: High dose of NAC administration not only did not improve patients' outcome, but also raised the risk of inflammation and was associated with increased serum creatinine. PMID- 25027750 TI - Calcipotriol counteracts betamethasone-induced decrease in extracellular matrix components related to skin atrophy. AB - The calcipotriol/betamethasone dipropionate fixed-combination gel is widely used for topical treatment of psoriasis vulgaris. It has been hypothesized that calcipotriol counteracts glucocorticoid-induced skin atrophy which is associated with changes in the extracellular matrix (ECM). To elucidate the combined effects of calcipotriol and betamethasone on key ECM components, a comparative study to the respective mono-treatments was carried out. The effect on collagen I synthesis, matrix metalloproteinase (MMP) secretion, and hyaluronic acid (HA) production was investigated in primary human fibroblast and keratinocyte cultures as well as in a human skin explant model. We show that calcipotriol counteracts betamethasone-induced suppression of collagen I synthesis. Similarly, calcipotriol and betamethasone have opposing effects on MMP expression in both fibroblasts and keratinocytes. Moreover, calcipotriol is able to restore betamethasone-impaired HA synthesis in keratinocytes and prevent betamethasone induced epidermal thinning in minipigs upon treatment with the calcipotriol/betamethasone gel. In summary, our results show for the first time in primary human skin cultures that calcipotriol reduces early signs of betamethasone-induced skin atrophy by modulation of key ECM components. These results indicate that the calcipotriol component of the fixed-combination gel counteracts the atrophogenic effects of betamethasone on the skin. PMID- 25027751 TI - Luteal phase support with gonadotropin-releasing hormone agonist. PMID- 25027752 TI - Human death caused by a giant anteater (Myrmecophaga tridactyla) in Brazil. AB - The fatal outcome of a defensive attack by a giant anteater (Myrmecophaga tridactyla) is reported. The attack occurred while the victim was hunting, and his dogs cornered the adult anteater, which assumed an erect, threatening position. The hunter did not fire his rifle because of concern about accidentally shooting his dogs. He approached the animal armed with a knife, but was grabbed by its forelimbs. When his sons freed him, he had puncture wounds and severe bleeding in the left inguinal region; he died at the scene. Necroscopic examination showed femoral artery lesions and a large hematoma in the left thigh, with death caused by hypovolemic shock. A similar case is cited, and recommendations are made that boundaries between wildlife and humans be respected, especially when they coinhabit a given area. PMID- 25027753 TI - Long-term monitoring of oxygen saturation at altitude can be useful in predicting the subsequent development of moderate-to-severe acute mountain sickness. AB - OBJECTIVE: The use of pulse oximetry (Spo2) to identify subjects susceptible to acute mountain sickness (AMS) is the subject of debate. To obtain more reliable data, we monitored Spo2 for 24 hours at altitude to investigate the ability to predict impending AMS. METHODS: The study was conducted during the climb from Alagna (1154 m) to Capanna Regina Margherita (4559 m), with an overnight stay in Capanna Gnifetti (3647 m). Sixty subjects (11 women) were recruited. Each subject was fitted with a 24-hour recording finger pulse oximeter. The subjects rode a cable car to 3275 m and climbed to 3647 m, where they spent the night. RESULTS: In the morning, 24 subjects (6 women) had a Lake Louise Questionnaire score (LLS) >= 3 (AMS(+)), and 15 subjects (4 women) exhibited moderate-to-severe disease (LLS >= 5 = AMS(++)). At Alagna, Spo2 did not differ between the AMS(-) and AMS(+) subjects. At higher stations, all AMS(+) subjects exhibited a significantly lower Spo2 than did the AMS(-) subjects: at 3275 m, 85.4% vs 87.7%; resting at 3647 m, 84.5% vs 86.4%. The receiver operating characteristics curve analysis resulted in a rather poor discrimination between the AMS(-) subjects and all of the AMS(+) subjects. With the cutoff LLS >= 5, the sensitivity was 86.67%, the specificity was 82.25%, and the area under the curve was 0.88 (P < .0001) for Spo2 <= 84% at 3647 m. CONCLUSIONS: We conclude that AMS(+) subjects exhibit a more severe and prolonged oxygen desaturation than do AMS(-) subjects starting from the beginning of altitude exposure, but the predictive power of Spo2 is accurate only for AMS(++). PMID- 25027754 TI - Recombinant DNA technology for melanoma immunotherapy: anti-Id DNA vaccines targeting high molecular weight melanoma-associated antigen. AB - Anti-idiotypic MK2-23 monoclonal antibody (anti-Id MK2-23 mAb), which mimics the high molecular weight melanoma-associated antigen (HMW-MAA), has been used to implement active immunotherapy against melanoma. However, due to safety and standardization issues, this approach never entered extensive clinical trials. In the present study, we investigated the usage of DNA vaccines as an alternative to MK2-23 mAb immunization. MK2-23 DNA plasmids coding for single chain (scFv) MK2 23 antibody were constructed via the insertion of variable heavy (V H) and light (V L) chains of MK2-23 into the pVAC-1mcs plasmids. Two alternative MK2-23 plasmids format V H/V L, and V L/V H were assembled. We demonstrate that both polypeptides expressed by scFv plasmids in vitro retained the ability to mimic HMW-MAA antigen, and to elicit specific anti-HMW-MAA humoral and cellular immunoresponses in immunized mice. Notably, MK2-23 scFv DNA vaccines impaired the onset and growth of transplantable B16 melanoma cells not engineered to express HMW-MAA. This pilot study suggests that optimized MK2-23 scFv DNA vaccines could potentially provide a safer and cost-effective alternative to anti-Id antibody immunization, for melanoma immunotherapy. PMID- 25027755 TI - Nutrient partitioning of Merino sheep divergently selected for genetic difference in resistance to Haemonchus contortus. AB - This research was designed to determine if divergent genetic selection for resistance to Haemonchus contortus had produced correlated changes in the metabolism of amino-nitrogen in the absence or presence of H. contortus infection. Partitioning of amino acid-nitrogen between tissues was determined in 42 Merino weaner wethers from the CSIRO Haemonchus selection flock, increased resistance to Haemonchus (IRH), decreased resistance to Haemonchus (DRH) and random bred control (C) selection lines. Weaner wethers were fed a restricted diet (9.8 MJ ME/kgDM, 86 gMP/kg DM) calculated to allow a gain of 125 g/d bodyweight throughout the experimental period and were either worm-free or trickle infected with H. contortus. At 8 weeks post-infection animals were injected with (15)N-labelled duckweed directly into the abomasums. Animals were euthanased at either 6 or 24h after the injection to collect tissue samples for calculation of percentage recovery of (15)N in tissue and to determine abomasal worm counts. Worm egg count and worm counts at week 8 of infection were lower in animals from the IRH line. IRH animals had a lower N digestibility, increased oxidation of amino acids and lower N balance but whole-body protein flux was unaffected. Amino acid metabolism, as assessed from (15)N uptake and excretion in response to H. contortus infection, differed between IRH and DRH animals. In IRH animals a greater recovery of (15)N in the thymus and abomasal smooth muscle indicated greater partitioning of amino acids towards the immune response. In DRH animals an increased recovery of (15)N in the spleen, in response to infection, may be a possible adaptation. It appears that divergent selection for worm egg count has not been associated with symmetrical changes in amino acid metabolism, but rather the partitioning of amino acid resources reflects each selection line's independent response to infection. PMID- 25027756 TI - Sequence-specific DNA interactions with calixarene-based langmuir monolayers. AB - The interactions of an amphiphilic calixarene, namely p-guanidino-dodecyloxy calix[4]arene, 1, self-assembled as Langmuir monolayers, with short double stranded DNA, were investigated by surface pressure-area (pi-A) isotherms, surface ellipsometry and Brewster angle microscopy (BAM). Three DNA 30mers were used as models, poly(AT), poly(GC) and a random DNA sequence with 50% of G:C base pairs. The interactions of these model DNA duplexes with 1-based Langmuir monolayers were studied by measuring compression isotherms using increasing DNA concentrations (10(-6), 10(-5), 10(-4), and 5 * 10(-4) g L(-1)) in the aqueous subphase. The isotherms of 1 showed an expansion of the monolayer with, interestingly, significant differences depending on the duplex DNA sequence studied. Indeed, the interactions of 1-based monolayers with poly(AT) led to an expansion of the monolayer that was significantly more pronounced that for monolayers on subphases of poly(GC) and the random DNA sequence. The structure and thickness of 1-based Langmuir monolayers were investigated by BAM and surface ellipsometry that showed differences in thickness and structure between a monolayer formed on pure water or on a DNA subphase, with here again relevant dissimilarities depending on the DNA composition. PMID- 25027757 TI - [Atorvastatin inhibits the atherosclerotic lesion induced by tumor necrosis factor-like weak inducer of apoptosis in apolipoprotein E deficient mice]. AB - AIM: Interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) with its receptor Fn14 accelerates atherosclerotic plaque development in ApoE deficient mice (ApoE KO). In this work, an analysis has been made on the effect of an HMG-CoA reductase inhibitor, atorvastatin, on atherosclerotic plaque development accelerated by TWEAK in ApoE KO mice. MATERIALS AND METHODS: Eight week-old ApoE KO mice were fed with a high cholesterol diet for 4 weeks. The animals were then randomized into 3 groups: mice injected i.p. with saline, recombinant TWEAK (10 MUg/kg/twice a week), or recombinant TWEAK plus atorvastatin (1 mg/kg/day) for 4 weeks. The lesion size, cellular composition, lipid and collagen content were analyzed, as well as inflammatory response in atherosclerotic plaques present in aortic root of mice. RESULTS: TWEAK treated mice showed an increase in atherosclerotic plaque size, as well as in collagen/lipid ratio compared with control mice. In addition, macrophage content, MCP-1 and RANTES expression, and NF-kappaB activation were augmented in atherosclerotic plaques present in aortic root of TWEAK treated mice compared with control mice. Treatment with atorvastatin prevented all these changes induced by TWEAK in atherosclerotic lesions. Atorvastatin treatment also decreased Fn14 expression in the atherosclerotic plaques of ApoE KO mice. CONCLUSIONS: Atorvastatin prevents the pro-atherogenic effects induced by TWEAK in ApoE KO mice, which could be related to the inhibition of Fn14 expression. The results of this study provide new information on the beneficial effects of statin treatment in cardiovascular diseases. PMID- 25027759 TI - Occurrence of antibiotic resistance in bacteria isolated from seawater organisms caught in Campania Region: preliminary study. AB - BACKGROUND: Environmental contamination by pharmaceuticals is a public health concern: drugs administered to humans and animals are excreted with urine or faeces and attend the sewage treatment. The main consequences of use and abuse of antibiotics is the development and diffusion of antibiotic resistance that has become a serious global problem. Aim of the study is to evaluate the presence of antimicrobial residues and to assess the antimicrobial resistance in bacteria species isolated from different wild caught seawater fish and fishery products. RESULTS: Three antibiotic substances (Oxytetracicline, Sulfamethoxazole and Trimethoprim) were detected (by screening and confirmatory methods) in Octopus vulgaris, Sepia officinalis and Thais haemastoma. All Vibrio strains isolated from fish were resistant to Vancomycin (VA) and Penicillin (P). In Vibrio alginolyticus, isolated in Octopus vulgaris, a resistance against 9 antibiotics was noted. CONCLUSIONS: Wild caught seawater fish collected in Gulf of Salerno (Campania Region), especially in marine areas including mouths of streams, were contaminated with antibiotic-resistant bacteria strains and that they might play an important role in the spread of antibiotic-resistance. PMID- 25027760 TI - Altered expression pattern of Nrf2/HO-1 axis during accelerated-senescence in HIV 1 transgenic rat. AB - Chronic oxidative stress plays a central role in the pathogenesis of many diseases, including HIV-1 associated disorders. Concomitantly with the decline of endogenous antioxidant systems, it was reported that HIV-1-related proteins increase the production of radical species in cells and tissues that are not directly infected by the virus. In the context of HIV-1 infection, the role of Nrf2, a key transcription factor that contributes to the maintenance of cellular redox homeostasis, remains largely uncharacterized. One of the major stress responsive player regulated by Nrf2 is the antioxidant enzyme HO-1. The Nrf2/HO-1 axis constitutes a crucial cell survival mechanism to counteract oxidative stress and inflammation. The present study aims to investigate the age-related patterns of Nrf2 and HO-1 in different brain regions and tissues of HIV-1 transgenic rat. Since HIV-1 induces an accelerated aging and the redox imbalance may actively promote senescence, we also evaluated the senescence phenotype-switching by quantifying levels of beta-galactosidase activity. Our results showed changes in gene expression, with different trends depending on the brain regions and tissues examined. However, compared to age-matched controls, we observed in HIV-1 transgenic rats a significant reduction in the protein levels of Nrf2 and HO-1, suggesting a weakening in the protection exerted by Nrf2/HO-1 system. Moreover, we show that senescence occurs more rapidly in HIV-1 transgenic rats than in control animals. To our knowledge this is the first in vivo report showing the involvement of Nrf2/HO-1 pathway in a rat model of HIV-1. PMID- 25027758 TI - Differential expression of miR-139, miR-486 and miR-21 in breast cancer patients sub-classified according to lymph node status. AB - PURPOSE: Therapeutic decisions in breast cancer are increasingly guided by prognostic and predictive biomarkers. Non-protein-coding microRNAs (miRNAs) have recently been found to be deregulated in breast cancers and, in addition, to be correlated with several clinico-pathological features. One of the most consistently up-regulated miRNAs is miR-21. Here, we specifically searched for differentially expressed miRNAs in high-risk breast cancer patients as compared to low-risk breast cancer patients. In the same patients, we also compared miR-21 expression with the expression of its presumed target PTEN. METHODS: Both microarray and RT-qPCR techniques were used to assess miRNA expression levels in lymph node-positive and -negative human invasive ductal carcinoma tissues. Simultaneously, PTEN protein expression levels were assessed using immunohistochemistry. RESULTS: miR-486-5p and miR-139-5p were found to be down regulated in patients with lymph node metastases, whereas miR-21 was found to be up-regulated in patients with a positive lymph node status. miR-21 expression levels were found to significantly correlate with tumour size (r = 0.403, p = 0.009; Spearman's rank), whereas no relation was found between miR-21 and PTEN expression levels (Kruskal-Wallis test). CONCLUSION: Down-regulation of miR-486 5p and miR-139-5p, in conjunction with up-regulation of miR-21, may represent a useful signature for the identification of high-risk breast cancer patients. PMID- 25027761 TI - Lost in translation: mice, men and cutaneous immunity in old age. AB - Translational research programs offer incredible opportunities to bring cutting edge science into clinical practice. To facilitate these medical advances, funding agencies are increasingly focusing on a translational "payoff" within grant applications and larger programs. As this is the underlying promise of biomedical research-delivering advances to public health to improve the quality of life-such strategic initiatives are paramount. However, the process of taking experimental observations between model systems and human subjects can be extraordinarily frustrating. We brought together the collective expertise of our mouse and human immunology research programs to reverse engineer a clinical observation into a mouse model system. Our goal was to model (in mice) the age related impaired delayed-type hypersensitivity response observed in humans, and then evaluate the efficacy of interventions to improve cutaneous immunity. We report here on what worked, what didn't, and what we learned along the way. PMID- 25027762 TI - Na4La2(CO3)5 and CsNa5Ca5(CO3)8: two new carbonates as UV nonlinear optical materials. AB - Two nonlinear optical crystal carbonates (Na4La2(CO3)5 and CsNa5Ca5(CO3)8 were successfully synthesized by hydrothermal method, and both of them crystallized in the same noncentrosymmetric hexagonal space group P63mc (No. 186). The structure of Na4La2(CO3)5 consists of a three-dimensional network made up of [CO3] triangles as well as irregular [Na(0.67)La(0.33)O10] and [NaO8] polyhedra. The structure of CsNa5Ca5(CO3)8 can be described as the standing-on-edge [CO3] groups connect the adjacent infinite [CaCO3]infinity layers in the ab plane to construct a framework with four types of channels running parallel to [010]. The Na, Cs, and [Na(0.67)Ca(0.33)] atoms reside in these channels. The measurement of second harmonic generation (SHG) by the method adapted from Kurtz and Perry indicated that Na4La2(CO3)5 and CsNa5Ca5(CO3)8 were phase-matchable in the visible region and exhibited SHG responses of approximately 3 and 1 * KH2PO4 (KDP). Meanwhile, they exhibited wide transparent region with short UV cutoff edge at about 235 and 210 nm, respectively, suggesting that these crystals as NLO materials may have potential applications in the UV region. PMID- 25027763 TI - Sharpening rhomboid specificity by dimerisation and allostery. PMID- 25027764 TI - Phytohormone dynamics associated with gall insects, and their potential role in the evolution of the gall-inducing habit. AB - While plant galls can be induced by a variety of organisms, insects produce the most diverse and complex galls found in nature; yet, how these galls are formed is unknown. Phytohormones have long been hypothesized to play a key role in gall production, but their exact role, and how they influence galls, has been unclear. Research in the past decade has provided better insight into the role of plant hormones in gall growth and plant defenses. We review and synthesize recent literature on auxin, cytokinins, and abscisic, jasmonic, and salicylic acids to provide a broader understanding of how these phytohormones might effect gall production, help plants defend against galls, and/or allow insects to overcome host-plant defenses. After reviewing these topics, we consider the potential for phytohormones to have facilitated the evolution of insect galls. More specialized research is needed to provide a mechanistic understanding of how phytohormones operate in gall-insect-plant interactions, but current evidence strongly supports phytohormones as key factors determining the success and failure of insect galls. PMID- 25027765 TI - Moving from recycling to waste prevention: A review of barriers and enables. AB - Current European waste policy does not mainly aim to treat waste streams but rather place in the foreground of interest the complete supply chain of a product. Waste prevention and re-use do have the highest priority and they take effect before the end-of-life phase of a product or a material is reached. Recycling only takes the third place whereas recovery and disposal represent the least favourable options. Recycling can help to decrease the consumption of primary resources but it does not tackle the causes but only the symptoms. In principle, recycling processes require energy and will generate side streams (i.e. waste). Furthermore, there are insuperable barriers and the practice is far from 100% recycling. The philosophy of waste prevention and re-use is completely different since they really tackle the causes. It is self-evident that a decrease of waste will also decrease the consumption of resources, energy and money to process the waste. However, even if European legislation is proceeding in the right direction, a clear decrease in waste generation did not occur up to now. Unfortunately, waste generation represents a positive factor of economic growth. Basically, waste generation is a huge business and numerous stakeholders are not interested to reduce waste. More sophisticated incentives are required to decouple economic growth from waste generation. PMID- 25027766 TI - Addressing nutritional gaps with multivitamin and mineral supplements. AB - A balanced and varied diet is the best source of essential vitamins and minerals; however, nutrient deficiencies occur, including in populations with bountiful food supplies and the means to procure nutrient-rich foods. For example, the typical American diet bears little resemblance to what experts recommend for fruit, vegetables, and whole grains, which serve as important sources of an array of vitamins and minerals. With time, deficiencies in one or more micronutrients may lead to serious health issues. A common reason people take multivitamin and mineral (MVM) supplements is to maintain or improve health, but research examining the effectiveness of MVMs in the prevention of certain chronic conditions is ongoing. In addition to the utility of MVMs for filling in relatively small but critical nutritional gaps, which may help prevent conditions such as anemia, neural tube defects, and osteoporosis, some evidence supports possible benefits of MVM supplementation with regard to cancer prevention (particularly in men) and prevention or delay of cataract, as well as some aspects of cognitive performance. Unlike some single-vitamin supplements, MVM supplements are generally well tolerated and do not appear to increase the risk of mortality, cerebrovascular disease, or heart failure. The potential benefits of MVM supplements likely outweigh any risk in the general population and may be particularly beneficial for older people. PMID- 25027767 TI - Identifying USPs regulating immune signals in Drosophila: USP2 deubiquitinates Imd and promotes its degradation by interacting with the proteasome. AB - BACKGROUND: Rapid activation of innate immune defences upon microbial infection depends on the evolutionary conserved NF-kappaB dependent signals which deregulation is frequently associated with chronic inflammation and oncogenesis. These signals are tightly regulated by the linkage of different kinds of ubiquitin moieties on proteins that modify either their activity or their stability. To investigate how ubiquitin specific proteases (USPs) orchestrate immune signal regulation, we created and screened a focused RNA interference library on Drosophila NF-kappaB-like pathways Toll and Imd in cultured S2 cells, and further analysed the function of selected genes in vivo. RESULTS: We report here that USP2 and USP34/Puf, in addition to the previously described USP36/Scny, prevent inappropriate activation of Imd-dependent immune signal in unchallenged conditions. Moreover, USP34 is also necessary to prevent constitutive activation of the Toll pathway. However, while USP2 also prevents excessive Imd-dependent signalling in vivo, USP34 shows differential requirement depending on NF-kappaB target genes, in response to fly infection by either Gram-positive or Gram negative bacteria. We further show that USP2 prevents the constitutive activation of signalling by promoting Imd proteasomal degradation. Indeed, the homeostasis of the Imd scaffolding molecule is tightly regulated by the linkage of lysine 48 linked ubiquitin chains (K48) acting as a tag for its proteasomal degradation. This process is necessary to prevent constitutive activation of Imd pathway in vivo and is inhibited in response to infection. The control of Imd homeostasis by USP2 is associated with the hydrolysis of Imd linked K48-ubiquitin chains and the synergistic binding of USP2 and Imd to the proteasome, as evidenced by both mass spectrometry analysis of USP2 partners and by co-immunoprecipitation experiments. CONCLUSION: Our work identified one known (USP36) and two new (USP2, USP34) ubiquitin specific proteases regulating Imd or Toll dependent immune signalling in Drosophila. It further highlights the ubiquitin dependent control of Imd homeostasis and shows a new activity for USP2 at the proteasome allowing for Imd degradation. This study provides original information for the better understanding of the strong implication of USP2 in pathological processes in humans, including cancerogenesis. PMID- 25027768 TI - Short- and long-term efficacy of cholinesterase inhibitors in older adults with alzheimer's disease and mixed dementia: results of a 21-month observational study. AB - AIM: The high cost of cholinesterase inhibitors (ChEIs) makes it crucial for the clinician to accurately identify subjects who will benefit from treatment. In Italy ChEI efficacy is assessed after 3 months, but this time interval may not be enough to know whether to continue or abandon the treatment. The aim of the study was to establish whether identifying responders (R) to ChEI on the strength of a 3--month treatment suffices to predict long--term stability in patients with dementia. METHODS: For the study, 336 patients with dementia treated with ChEIs were assessed. They were considered as R when Mini--Mental State Examination (MMSE) score was stable or improved after 3 or 9 months of ChEIs, and as persistently stable if MMSE score dropped by <2 points in 21 months. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were calculated to test response at 3 or 9 months vis--a--vis 21 months persistent stability. RESULTS: For response assessment at 3 months, sensitivity was 0.83 and specificity 0.58, whereas at 9 months sensitivity was 0.84 and specificity 0.73. When age, sex, years of education, ChEI type, and antipsychotic/antidepressant drugs were included in the linear regression model with long--term variations in MMSE score, only MMSE variations between 0--3 and 0--9 months were significantly associated with long--term stability. CONCLUSION: in Italian patients, assessing response later on (after 6--9 months of treatment instead of 3) seems better able to distinguish between patients who will or will not benefit in the long--term from ChEI treatment. PMID- 25027769 TI - Assessment of visual fixation in vegetative and minimally conscious states. AB - BACKGROUND: Visual fixation plays a key role in the differentiation between vegetative state/unresponsive wakefulness (VS/UWS) syndrome and minimally conscious state (MCS). However, the use of different stimuli changes the frequency of visual fixation occured in patients, thereby possibly affecting the accuracy of the diagnosis. In order to establish a standardized assessment of visual fixation in patients in disorders of consciousness (DOC), we compared the frequency of visual fixation elicited by mirror,a ball and a light. METHOD: Visual fixation was assessed in eighty-one post-comatose patients diagnosed with a MCS or VS/UWS. Occurrence of fixation to different stimuli was analysis used Chi-square testing. RESULT: 40 (49%) out of the 81 patients showed fixation to visual stimuli. Among those, significantly more patients (39, 48%) had visual fixation elicited by mirror compared to a ball (23, 28%) and mirror compared to a light (20, 25%). CONCLUSION: The use of a mirror during the assessment of visual fixation showed higher positive response rate, compared to other stimuli in eliciting a visual fixating response. Therefore, fixation elicited by a mirror can be a very sensitive and accurate test to differentiate the two disorders of consciousness. PMID- 25027770 TI - Personal, social and environmental correlates of active transport to school among adolescents in Otago, New Zealand. AB - OBJECTIVES: With increasingly sedentary lifestyles, opportunities for physical activity such as active transport to school need to be promoted in adolescents. This study examines personal, social and environmental correlates of active transport to school among adolescents including sociodemographics, behavioural patterns, motivational factors, perceived barriers, peer support, family resources, school characteristics, urban/rural setting, distance to school and neighbourhood safety perceptions. DESIGN: Cross-sectional study. METHODS: In 2009 and 2011, 2018 secondary school students (age: 14.8+/-1.3 years; 73% urban; 53% boys) from 22 out of 24 schools from Otago, New Zealand completed the Otago School Students Lifestyle Survey. Multivariate binary logistic regression models were used to compare active transport to school correlates in students using active transport to school versus bus and car users (motorised transport). RESULTS: Overall, 37% of students used active transport to school, 24% bus, and 39% car. Compared to motorised transport users, active transport to school users were more likely to live closer to school (1.4+/-1.4 active transport to school vs. 8.3+/-8.4km motorised transport; p<0.001). In a multivariate analysis, shorter distance to school (OR (95%CI) (0.03 (0.01-0.05)), younger age (0.85 (0.78-0.92)), fewer vehicles (0.66 (0.49-0.89)) and fewer screens (0.53 (0.35 0.82)) per household, meeting screen time guidelines (1.74 (1.22-2.50)), opportunity to chat with friends (2.26 (1.58-3.23)), nice scenery (1.69 (1.14 2.50)), and parental perceptions of active transport to school safety (2.32 (1.25 4.30)) were positively associated with active transport to school, while perceived time constraints (0.46 (0.29-0.72)) and attending girls-only school (0.51 (0.35-0.75)) had a negative association with active transport to school. CONCLUSIONS: Future active transport to school interventions in adolescents should focus on encouraging active transport to school, reiterating its social benefits, and addressing parental safety concerns around active transport to school. PMID- 25027771 TI - Effects of Kinesio((r)) taping on skeletal muscle strength-A meta-analysis of current evidence. AB - OBJECTIVES: The purpose of this study was to test whether certain applications of Kinesio tapes might facilitate contraction and increase muscle strength in healthy adults. DESIGN: A meta-analysis of studies investigating the efficacy of Kinesio tapes application was performed. METHODS: The scientific databases Pubmed and Google Scholar were systematically searched for appropriate articles. Descriptive statistics were extracted to calculate measures of effect size (Pearson's r) and estimate the overall population effect. The methodological quality of the included studies was assessed using a specific quality appraisal tool. In addition, the included studies were grouped according to the muscle groups examined, to test whether Kinesio tapes effects were dependent on the area of application. RESULTS: A total of 19 studies, comprising data of 530 subjects and 48 pairwise comparisons of muscle strength were included. The methodological quality of these studies ranged from moderate to good. While substantial variability of individual effect sizes was observed, the overall population effect (r=0.05, CI: -0.23 to 0.34) suggests that, on average, the potential to increase strength by application of Kinesio tapes is negligible. Comparisons between studies grouped by the muscle groups examined showed that the effects of Kinesio tapes are not muscle-group dependent. CONCLUSIONS: While the application of Kinesio tapes may have some therapeutic benefits, the usage of these tapes does not promote strength gains in healthy adults. PMID- 25027772 TI - The relationship between the piriformis muscle, low back pain, lower limb injuries and motor control training among elite football players. AB - OBJECTIVES: Australian Football League (AFL) players have a high incidence of back injuries. Motor control training to increase lumbopelvic neuromuscular control has been effective in reducing low back pain (LBP) and lower limb injuries in elite athletes. Control of pelvic and femoral alignment during functional activity involves the piriformis muscle. This study investigated (a) the effect of motor control training on piriformis muscle size in AFL players, with and without LBP, during the playing season, and (b) whether there is a relationship between lower limb injury and piriformis muscle size. DESIGN: Stepped-wedge intervention. METHODS: 46 AFL players participated in a motor control training programme consisting of two 30min sessions per week over 7-8 weeks, delivered across the season as a randomised 3 group single-blinded stepped wedge design. Assessment of piriformis muscle cross-sectional area (CSA) involved magnetic resonance imaging (MRI) at 3 time points during the season. Assessment of LBP consisted of player interview and physical examination. Injury data were obtained from club records. RESULTS: An interaction effect for Time, Intervention Group and LBP group (F=3.7, p=0.03) was found. Piriformis muscle CSA showed significant increases between Times 1 and 2 (F=4.24, p=0.046), and Times 2 and 3 (F=8.59, p=0.006). Players with a smaller increase in piriformis muscle CSA across the season had higher odds of sustaining an injury (OR=1.08). CONCLUSIONS: Piriformis muscle size increases across the season in elite AFL players and is affected by the presence of LBP and lower limb injury. Motor control training positively affects piriformis muscle size in players with LBP. PMID- 25027773 TI - Relation of major depression to survival after coronary artery bypass grafting. AB - The primary aim was to study the association between preoperative depression and long-term survival after coronary artery bypass grafting (CABG). Our secondary objective was to analyze the association between depression and cardiovascular events or all-cause mortality. In a nationwide, population-based, cohort study, all patients who underwent CABG in Sweden from 1997 to 2008 were included from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Individual level data were cross-linked from other national Swedish registers. Depression status and outcomes were obtained from the National Patient Register. The study population was 56,064 patients who underwent primary, isolated, nonemergent CABG. We identified 324 patients (0.6%) with depression before CABG. During a mean follow-up of 7.5 years, 114 patients (35%) with depression died, compared with 13,767 patients (25%) in the control group. Depression was significantly associated with increased mortality and the combined end point of death or rehospitalization for myocardial infarction, heart failure, or stroke (multivariate-adjusted hazard ratios [95% confidence intervals] 1.65 [1.37 to 1.99] and 1.61 [1.38 to 1.89], respectively). In conclusion, we found a strong and significant association between depression and long-term survival in patients with established ischemic heart disease who underwent CABG. Depression was also associated with an increased risk for a combination of death or rehospitalization for heart failure, myocardial infarction, or stroke. PMID- 25027774 TI - Effects of Xinfeng Capsule on the expression of platelet derived growth factor in synovium of adjuvant arthritis rats. AB - OBJECTIVE: To observe the effects of Xinfeng Capsule (, XFC) on platelet parameters in peripheral blood and expression of platelet derived growth factor (PDGF) in synovium of adjuvant arthritis (AA) rats. METHODS: A total of 40 male Sprague-Dawley (SD) rats were randomized into 5 groups: normal control (NC), AA model control (MC), methotrexate (MTX) treatment, Tripterygium wilfordii polycoride tablet (TPT) treatment, and XFC treatment. Excluding the NC group, the AA model was induced by intracutaneous injection of 0.1 mL Freund's complete adjuvant in the right hind limb. Induction of AA and the effects of drug treatments were assessed by voix pedis swelling, arthritis index (AI), body mass, and the pathological changes of joints and cartilage with a light microscopy. Platelet parameters in peripheral blood were detected with an automated hematology analyzer. PDGF in synovium was detected with immunohistochemical methods and PDGF mRNA expression in synovium was detected with reverse transcription polymerase chain reaction. RESULTS: Compared with the NC group, the MC group had significantly increased voix pedis swelling, AI, platelet (PLT) and plateletcrit (PCT) in peripheral blood and PDGF as well as PDGF mRNA in synovium (all P<0.01) and the joint cartilage was also highly degenerated. Compared with the MC group, the 3 treated groups had significantly decreased voix pedis swelling, AI, PLT, PCT, PDGF, and PDGF mRNA (P<0.01). The body mass in the XFC group was significantly higher than those in MTX and TPT groups (P <0.05). The levels of PLT, PCT, PDGF, and PDGF mRNA in the XFC group showed a decreasing tendency with no significant difference compared with the MTX and TPT groups (P >0.05). PDGF and PDGF mRNA of AA rats were positively correlated with voix pedis swelling, AI, PLT, and PCT (P <0.05 or P <0.01). CONCLUSIONS: The expression and biosynthesis of PDGF increase in the synovium of AA rats and correlate with voix pedis swelling, AI, PLT, and PCT. XFC can decrease the levels of PDGF, PDGF mRNA, PLT, and PCT, thereby mitigating inflammation induced by platelet activation and reducing voix pedis swelling and the AI in AA rats. PMID- 25027775 TI - 3D niche microarrays for systems-level analyses of cell fate. AB - The behaviour of mammalian cells in a tissue is governed by the three-dimensional (3D) microenvironment and involves a dynamic interplay between biochemical and mechanical signals provided by the extracellular matrix (ECM), cell-cell interactions and soluble factors. The complexity of the microenvironment and the context-dependent cell responses that arise from these interactions have posed a major challenge to understanding the underlying regulatory mechanisms. Here we develop an experimental paradigm to dissect the role of various interacting factors by simultaneously synthesizing more than 1,000 unique microenvironments with robotic nanolitre liquid-dispensing technology and by probing their effects on cell fate. Using this novel 3D microarray platform, we assess the combined effects of matrix elasticity, proteolytic degradability and three distinct classes of signalling proteins on mouse embryonic stem cells, unveiling a comprehensive map of interactions involved in regulating self-renewal. This approach is broadly applicable to gain a systems-level understanding of multifactorial 3D cell-matrix interactions. PMID- 25027776 TI - Trend analysis in water quality of Al-Wehda Dam, north of Jordan. AB - Temporal status and trends in water quality of Al-Wehda Dam, Jordan, from 2006 to 2012 indicate that the dam is subject to a combination of impacts from rainstorm and agricultural runoffs. It also revealed that mineral dissolution, sediment load, rainfall events, evaporation, and water-level fluctuation are the major contributors to variations in water quality. The water chemistry of the impounded Al-Wehda Reservoir showed that Na, Ca, Mg, HCO3, and Cl are the principal ions, reflecting the dominance of carbonate weathering, with some contribution of silicates. The pH values showed a cyclic pattern with highest values observed in the spring seasons. Total dissolved solids (TDS), Ca, Mg, and HCO3 are primarily related to leaching and evaporation, with elevated levels that occurred in the rainy winter months. In contrast, seasonal patterns in Na, K, Cl, and NH4-N contents showed decreased values in winter. Peaks in NO3-N observed in winter are strongly associated with agricultural runoff. Fluctuations in chlorophyll-a level were coincided with low ratio of total nitrogen (TN) to total phosphorus (TP). Seasonal variations in organic matter content were also apparent, with peaks that generally occurred in spring through early fall corresponding with high algal growth. On an annual basis, the vast majority of water quality data have generally declined, particularly, in 2011. However, it is not clear whether these decreases are related to change in management practices within the Yarmouk basin, or protective measures have been implemented. Comparison of in-lake and post-dam water quality from 2009 to 2011 showed variation in concentrations, where Ca, HCO3, NO3-N, Mg, and TDS showed relatively greater post-dam values than in-lake water, whereas pH, Na, Cl, K, COD, BOD5, and chlorophyll-a were consistently lower in post-dam water. This comparison emphasizes the importance of self purification capacity of Al-Wehda Dam in reducing some contaminants. PMID- 25027777 TI - Pharmaceuticals as emerging organic contaminants in Umgeni River water system, KwaZulu-Natal, South Africa. AB - The occurrences of pharmaceuticals and personal care products as emerging organic contaminants (EOCs) have been reported in several countries of the world except from African countries. This study was therefore conducted to investigate the occurrence of nine antibiotics, five antipyretics, atenolol, bezafibrate, and caffeine in wastewater and surface water samples from the Umgeni River. The water samples were extracted with solid-phase extraction using hydrophilic-lipophilic balance (HLB) and C-18 cartridges for the acidic and neutral drugs, respectively. The quantification was carried out with high-performance liquid chromatography diode array detector (HPLC-DAD) using the standard addition method. The method limits of detections were in the range of 0.14-0.97 MUg/L while the recoveries were between 53.8 and 108.1 %. The wastewater had 100 % occurrence of the analytes studied, with caffeine having the highest concentration at 61 +/- 5 MUg/L and nalidixic acid being the most observed antibiotic at 31 +/- 3 MUg/L. The waste treatment process reduced the influent concentrations by 43.0-94.2 % before discharge except for atenolol removal that is lower. The concentrations of the analytes were lower in the surface water with most compounds having concentrations below 10 MUg/L except acetaminophen and atenolol. The estuary mouth and Blue Lagoon had the highest concentrations of some of the compounds in surface water which depict downstream load. The factors governing the fate and mobility of these compounds in this environment are not fully understood yet and will require further studies. PMID- 25027778 TI - Simultaneous determination of hydroxylamine and phenol using a nanostructure based electrochemical sensor. AB - The electrochemical oxidation of hydroxylamine on the surface of a carbon paste electrode modified with carbon nanotubes and 2,7-bis(ferrocenyl ethyl)fluoren-9 one is studied. The electrochemical response characteristics of the modified electrode toward hydroxylamine and phenol were investigated. The results showed an efficient catalytic activity of the electrode for the electro-oxidation of hydroxylamine, which leads to lowering its overpotential. The modified electrode exhibits an efficient electron-mediating behavior together with well-separated oxidation peaks for hydroxylamine and phenol. Also, the modified electrode was used for determination of hydroxylamine and phenol in some real samples. PMID- 25027779 TI - Elemental analysis of aerosols in Tehran's atmosphere using PIXE and identification of pollution sources. AB - In this study, the proton-induced X-ray emission (PIXE) technique has been applied to measure the elemental composition and concentrations of particulate matter of 220 samples of aerosols in Tehran's atmosphere within a 450-day time interval starting from March 2009 and ending in June 2010, covering all four seasons. PIXE analysis shows the samples are comprised of various elements including Al, Si, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Br, Rb, Sr, and Pb. Also, to obtain more information about the sources of pollution and to identify the major sources of urban particulate matter, principal component analysis (PCA) was used. Furthermore, micro-PIXE was performed to study individual aerosols in some samples. Results revealed that the concentration of elements originating from vehicle emissions increases three times in winter; whereas the concentration of elements with soil origin remains constant. Based on wind rose maps, it is inferred that the high concentrations of the elements Al, Si, K, Ca, Ti, Mn, and Fe are associated with natural dust brought by winds into Tehran from the west. PMID- 25027780 TI - Multi-model ensemble simulation and projection in the climate change in the Mekong River Basin. Part I: temperature. AB - This paper evaluates the performance of the Coupled Model Intercomparison Project phase 5 (CMIP5) in simulating annual and decadal temperature in the Mekong River Basin from 1950 to 2005. By use of Bayesian multi-model averaging method, the future projection of temperature variation under different scenarios are also analyzed. The results show, the performances of climate model are more accurate in space than time, the model can catch the warming characteristics in the Mekong river Basin, but the accuracy of simulation is not good enough. Bayesian multi model averaging method can improve the annual and decadal temperature simulation when compared to a single result. The projected temperature in Mekong River will increase by 0.88 degrees C/100 year, 2.15 degrees C/100 year and 4.96 degrees C/100 year for the RCP2.6, RCP4.5, and RCP8.5 scenarios, respectively, over the twenty-first century. The findings will be beneficial for local people and policy maker to formulate regional strategies against the potential menaces of warming scenarios. PMID- 25027781 TI - Non-apoptotic role of caspase-3 in synapse refinement. AB - Caspases, a family of cysteine proteases, mediate programmed cell death during early neural development and neurodegeneration, as well as following neurotoxic insults. Notably, accumulating lines of evidence have shown non-apoptotic roles of caspases in the structural and functional plasticity of neuronal circuits under physiological conditions, such as growth-cone dynamics and axonal/dendritic pruning, as well as neuronal excitability and plasticity. Here, we summarize recent progress on the roles of caspases in synaptic refinement. PMID- 25027782 TI - Particle-size distribution of airborne poly- and perfluorinated alkyl substances. AB - Eleven particle-size-segregated samples were taken to investigate the particle size distribution of perfluoroalkyl substances (PFASs) using two five stage impactors in parallel. Samples were extracted with methanol and detected by HPLC/MS-MS. Investigation yielded reproducible results for the parallel samples over the entire sampling period. Particle-size distribution varied between perfluorooctane sulfonate (PFOS) and other perfluoroalkyl sulfonates (PFSAs), perfluorooctane carboxylate (PFOA) and other perfluoroalkyl carboxylates (PFCAs) and n-methyl-perfluorooctanesulfonamido ethanol (MeFOSE). Whereas PFOA and MeFOSE were predominantly observed in smallest size fraction (<0.14MUm), maximum PFOS mass fractions were observed in the coarser size fractions between 1.38 and 3.81MUm. The reason for this different behaviour remained unclear and indicated a complex atmospheric PFAS processing and sampling which should be further investigated and optimized, respectively. PMID- 25027784 TI - Dietary exposures to eight metallic contaminants of the Hong Kong adult population from a total diet study. AB - Dietary exposures to eight metallic contaminants, aluminium (Al), antimony (Sb), cadmium (Cd), lead (Pb), methylmercury (MeHg), nickel (Ni), tin (Sn) and vanadium (V), of the Hong Kong adult population were estimated using the total diet study (TDS) approach. The estimated mean exposures of Al (0.60 mg kg(-1) bw week(-1)), Sb (0.016-0.039 ug kg(-1) bw day(-1)), Cd (8.3 ug kg(-1) bw month(-1)), Pb (0.21 ug kg(-1) bw day(-1)), MeHg (0.74 ug kg(-1) bw week(-1)), Ni (3.1 ug kg(-1) bw day(-1)), Sn (0.029-0.031 mg kg(-1) bw week(-1)) and V (0.13 ug kg(-1) bw day( 1)) were well below the relevant health-based guidance values (HBGVs) where available. However, dietary exposures to MeHg of women aged 20-49 years (child bearing age) accounted for 150% of the provisional tolerable weekly intake (PTWI) and to Al and Cd of some high consumers were found exceeding or approaching the HBGVs. The major food contributors of MeHg were fish and seafood (90%), of Al were non-alcoholic beverages including tea (33%), and of Cd were vegetables (36%). MeHg exposure during pregnancy was a public health concern in Hong Kong due to potential health risks to the foetus. Results suggest that there is a need to continue monitoring the exposures to metallic contaminants, especially Al, Cd and MeHg, of the Hong Kong population. PMID- 25027783 TI - Effect of chlorocholine chlorid on phenolic acids accumulation and polyphenols formation of buckwheat plants. AB - BACKGROUND: Effect of chlorocholine chloride (CCC) on phenolic acids composition and polyphenols accumulation in various anatomical parts (stems, leaves and inflorescences) of common buckwheat (Fagopyrum esculentum Moench) in the early stages of vegetation period were surveyed. RESULTS: Treatment of buckwheat seeds with 2% of CCC has been increased content of total phenolics in the stems, leaves and inflorescences. On analyzing the different parts of buckwheat plants, 9 different phenolic acids - vanilic acid, ferulic acid, trans-ferulic acid, chlorogenic acid, salycilic acid, cinamic acid, p-coumaric acid, p-anisic acid, methoxycinamic acid and catechins were identified. The levels of identified phenolic acids varied not only significantly among the plant organs but also between early stages of vegetation period. Same changes as in contents of chlorogenic acid, ferulic acid, trans-ferulic acid were found for content of salycilic acid. The content of these phenolic acids has been significant increased under effect of 2% CCC treatment at the phase I (formation of buds) in the stems and at the phase II (beginning of flowering) in the leaves and then inflorescences respectively. The content of catechins as potential buckwheat antioxidants has been increased at the early stages of vegetation period after treatment with 2% CCC. CONCLUSIONS: The obtained results suggest that influence of CCC on the phenolics composition can be a result of various mechanisms of CCC uptake, transforming and/or its translocation in the buckwheat seedlings. PMID- 25027785 TI - Education scholarship in emergency medicine part 1: innovating and improving teaching and learning. AB - As emergency medicine (EM) education evolves, a more advanced understanding of education scholarship is required. This article is the first in a series of three articles that reports the recommendations of the 2013 education scholarship consensus conference of the Academic Section of the Canadian Association of Emergency Physicians. Adopting the Canadian Association for Medical Education's definition, education scholarship (including both research and innovation) is defined. A rationale for why education scholarship should be a priority for EM is discussed. PMID- 25027787 TI - Education scholarship in emergency medicine part 3: a "how-to" guide. AB - Successful emergency medicine (EM) education scholarship requires a systematic approach that includes searching the (grey) literature, mobilizing resources, adopting frameworks to focus the innovation, integrating a component of program evaluation, and disseminating the innovation via traditional and emerging avenues. This paper provides direction for EM teachers and educators looking to transform their education innovation into scholarship. Recommendations on producing EM education scholarship from the 2013 consensus conference of the Academic Section of the Canadian Association of Emergency Physicians are presented. PMID- 25027788 TI - CAEP/ACMU 2014 Scientific Abstracts, May 31-June 4, 2014, Ottawa, Ontario. PMID- 25027789 TI - Education scholarship in emergency medicine part 2: supporting and developing scholars. AB - Emergency medicine (EM) is defined, in part, by clinical excellence across an immense breadth of content and the provision of exemplary bedside teaching to a wide variety of learners. The specialty is also well-suited to a number of emerging areas of education scholarship, particularly in relation to team-based learning, clinical reasoning, acute care response, and simulation-based teaching. The success of EM education scholarship will be predicated on systematic, collective attention to providing the infrastructure for this to occur. Specifically, as a new generation of emergency physicians prepares for education careers, academic organizations need to develop means not only to identify potential scholars but also to mentor, support, and encourage their careers. This paper summarizes the supporting literature and presents related recommendations from a 2013 consensus conference on EM education scholarship led by the Academic Section of the Canadian Association of Emergency Physicians. PMID- 25027790 TI - Identification and characterization of three chemosensory receptor families in the cotton bollworm Helicoverpa armigera. AB - BACKGROUND: Chemosensory receptors including olfactory receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs) play a central role in sensing chemical signals and guiding insect behaviours, and are potential target genes in insect pest control. The cotton bollworm Helicoverpa armigera is one of the most destructive pest species that can feed on over 200 different plant species. This diversity of host plants is likely linked to a complex chemosensory system. Here we built on previous work to characterize crucial chemosensory tissues linked to environmental interactions including larval antennae, larval mouthparts and larval fat bodies, as well as male and female adult heads, male and female adult tarsi, and female abdomens. RESULTS: Using transcriptome sequencing, Trinity RNA seq assemblies and extensive manual curation, we identified a total of 91 candidate chemosensory receptors (60 candidate ORs, 10 GRs and 21 IRs). Thirty five of these candidates present full-length transcripts. First, we performed in silico differential expression analysis on different sequenced tissues. Further, we created extensive expression profiles using reverse transcription (RT)-PCR on a variety of adult and larval stages. We found that the expression profile of HarmOR51 was limited to adult male antenna suggesting a role in mating that was further supported by a phylogenetic analysis clustering it into the pheromone receptor clade. HarmOR51 in calcium imaging analysis did not show responses to either of the two H. armigera sex pheromone components (Z9-16:Ald or Z11-16:Ald) inviting a future detailed study. In addition, we found four novel HarmORs (OR1, 53, 54 and 58) that appeared to be larvae-antennal specific. Finally, our expression profiling showed that four "divergent" HarmIRs (IR2, 7d.1, 7d.2 and 7d.3) were expressed in both adult and larval antennae, suggesting a functional divergence from their Drosophila homologues. CONCLUSIONS: This study explored three chemoreceptor superfamily genes using a curated transcriptomic approach coupled with extensive expression profiling and a more limited functional characterization. Our results have now provided an extensive resource for investigating the chemoreceptor complement of this insect pest, and meanwhile allow for targeted experiments to identify potential molecular targets for pest control and to investigate insect-plant interactions. PMID- 25027791 TI - Implementation of specific motor expertise during a mental rotation task of hands. AB - Mental rotation of the hands classically induces kinesthetic effects according to the direction of the rotation, with faster response times to the hands' medial rotations compared with lateral rotations, and is thus commonly used to induce engagement in motor imagery (MI). In the present study, we compared the performances of table tennis players (experts on hand movements), who commonly execute and observe fast hand movements, to those of soccer players (non-experts on hand movements) on a mental rotation task of hands. Our results showed a significant effect of the direction of rotation (DOR) confirming the engagement of the participants in MI. In addition, only hand movement experts were faster when the task figures corresponded to their dominant hand compared with the non dominant hand, revealing a selective effect of motor expertise. Interestingly, the effect of the DOR collapsed in hand movement experts only when the task figures corresponded to their dominant hand, but it is noteworthy that lateral and medial rotations of the right-hand stimuli were not faster than medial rotations of the left-hand stimuli. These results are discussed in relation to possible strategies during the task. Overall, the present study highlights the embodied nature of the mental rotation task of hands by revealing selective effects of motor expertise. PMID- 25027792 TI - Sensorimotor synchronization with audio-visual stimuli: limited multisensory integration. AB - Understanding how we synchronize our actions with stimuli from different sensory modalities plays a central role in helping to establish how we interact with our multisensory environment. Recent research has shown better performance with multisensory over unisensory stimuli; however, the type of stimuli used has mainly been auditory and tactile. The aim of this article was to expand our understanding of sensorimotor synchronization with multisensory audio-visual stimuli and compare these findings to their individual unisensory counterparts. This research also aims to assess the role of spatio-temporal structure for each sensory modality. The visual and/or auditory stimuli had either temporal or spatio-temporal information available and were presented to the participants in unimodal and bimodal conditions. Globally, the performance was significantly better for the bimodal compared to the unimodal conditions; however, this benefit was limited to only one of the bimodal conditions. In terms of the unimodal conditions, the level of synchronization with visual stimuli was better than auditory, and while there was an observed benefit with the spatio-temporal compared to temporal visual stimulus, this was not replicated with the auditory stimulus. PMID- 25027793 TI - Altered CD8(+) T cell frequency and function in tuberculous lymphadenitis. AB - CD8(+) T cells secreting Type1 and Type 17 cytokines and cytotoxic molecules play a major role in immunity and protection against pulmonary tuberculosis (PTB), although their role in tuberculous lymphadenitis (TBL) is not well known. To identify the distribution and function of CD8(+) T cells expressing Type1, Type 2 and Type 17 cytokines and cytotoxic molecules in TBL, we examined baseline and mycobacterial-antigen specific immune responses in the whole blood of individuals with PTB and compared them with TBL. TBL is characterized by elevated frequencies of baseline and mycobacterial-antigen stimulated CD8(+) T cells expressing Type 1 (IL-2 and TNFalpha) and Type 17 (IL-17A and IL-17F) cytokines in comparison to PTB individuals. In contrast, TBL individuals exhibited diminished frequency of CD8(+) T cells expressing perforin, granzyme B and CD107a. The blockade of IL-1R and IL-6R during antigenic stimulation resulted in significantly diminished frequencies of CD8(+) T cells expressing Type 1 and Type 17 cytokines in TBL. Therefore, our data suggest that TBL is characterized by an IL-1 and IL-6 dependent expansion of CD8(+) T cells expressing Type 1 and Type 17 cytokines as well as altered frequencies of cytotoxic molecules, reflecting an important association of these cells with the pathogenesis of TBL. PMID- 25027794 TI - Specific appetite, energetic and metabolomics responses to fat overfeeding in resistant-to-bodyweight-gain constitutional thinness. AB - BACKGROUND: Contrasting with obesity, constitutional thinness (CT) is a rare condition of natural low bodyweight. CT exhibits preserved menstruation in females, no biological marker of undernutrition, no eating disorders but a bodyweight gain desire. Anorexigenic hormonal profile with high peptide tyrosine tyrosine (PYY) was shown in circadian profile. CT could be considered as the opposite of obesity, where some patients appear to resist diet-induced bodyweight loss. OBJECTIVE: The objective of this study was to evaluate appetite regulatory hormones in CTs in an inverse paradigm of diet-induced weight loss. METHODS: A 4 week fat overfeeding (2640 kJ excess) was performed to compare eight CT women (body mass index (BMI)<17.5 kg m(-)(2)) to eight female controls (BMI 18.5-25 kg m(-)(2)). Appetite regulatory hormones profile after test meal, food intake, bodyweight, body composition, energy expenditure and urine metabolomics profiles were monitored before and after overfeeding. RESULTS: After overfeeding, fasting total and acylated ghrelin were significantly lower in CTs than in controls (P=0.01 and 0.03, respectively). After overfeeding, peptide tyrosine tyrosine (PYY) and glucagon-like-peptide 1 both presented earlier (T15 min vs T30 min) and higher post-meal responses (incremental area under the curve) in CTs compared with controls. CTs failed to increase bodyweight (+0.22+/-0.18 kg, P=0.26 vs baseline), contrasting with controls (+0.72+/-0.26 kg, P=0.03 vs baseline, P=0.01 vs CTs). Resting energy expenditure increased in CTs only (P=0.031 vs baseline). After overfeeding, a significant negative difference between total energy expenditure and food intake was noticed in CTs only (-2754+/-720 kJ, P=0.01). CONCLUSION: CTs showed specific adaptation to fat overfeeding: overall increase in anorexigenic hormonal profile, enhanced post prandial GLP-1 and PYY and inverse to controls changes in urine metabolomics. Overfeeding revealed a paradoxical positive energy balance contemporary to a lack of bodyweight gain, suggesting yet unknown specific energy expenditure pathways in CTs. PMID- 25027795 TI - Long-term changes in the ghrelin-CB1R axis associated with the maintenance of lower body weight after sleeve gastrectomy. AB - OBJECTIVES: In the hypothalamus, the molecular actions of receptors for growth hormone secretagogue (ghrelin) receptor-GHSR, leptin receptor-b (LEPRb), Melanocortin-4 receptor (MC4R) and Cannabinoid-1 receptor (CB1R) regulate energy homeostasis and body weight. We hypothesized that the acute loss of stomach tissue upon sleeve gastrectomy (SG), performed to treat obesity, imposes modulations on the expression of these receptors in the brain to sustain weight loss. METHODS: Rats, induced to obesity with high-fat diet were randomized to SG- or sham-operation groups and killed at 30 or 90 days post surgery, when the expression of Ghrl, Mboat4 and Cnr1 in the stomach, and Ghsr, Leprb, Mc4r and Cnr1 in distinct brain areas was assessed by reverse transcription-PCR and western blotting. RESULTS: SG acutely reduced body weight and fat mass and suppressed the remnant stomach mRNA levels of preproghrelin and ghrelin O acyltransferase, which correlated well with long-term decreases in CB1R mRNA. In the hypothalamus, increases in GHSR and decreases in CB1R and LEPRb by 30 days were followed by further downregulation of CB1R and an increase in MC4R by 90 days. CONCLUSIONS: Post SG, acyl-ghrelin initiates a temporal hierarchy of molecular events in the gut-brain axis that may both explain the sustained lower body weight and suggest intervention into the cannabinoid pathways for additional therapeutic benefits. PMID- 25027797 TI - The relevance of methane emissions from beef production and the challenges of the Argentinean beef production platform. AB - The livestock sector faces the challenge to respond to the growing demand for animal protein from an expanding population while reducing environmental impact through GHG emissions. Globally about 2.836 million tons of CO2-eq were emitted by the beef production sector equivalent to 46,2 kg CO2-eq per kg carcass weight (CW). From the 1.485 million cattle head spread out over the world, 82% are on extensive grazing systems while only 18% are on high productive intensive systems. Among the top ten beef exporter countries, five are located in Latin America accounting a quarter of the global stock and two of them, Argentina and Uruguay, produce on temperate pastures under grazing systems. In Argentina, the livestock area was reduced in favor of increasing the grain cropping area, which took place in the last two decades. Production systems were intensified to maintain cattle stock. Cattle programs changed from 100% pasture to pasture supplemented with cereal grains and conserved forages, and confinement on grain feeding for fattening was incorporated. Due to land sharing competition with cash crops, no increment of cattle stock is expected therefore improving production efficiency appears as the only way to increase beef production while reducing methane emissions intensity. Beef produced on intensive grazing systems on supplemented pastures maintained organoleptic, nutritional and lipid profile than that of beef produced on pure grazing systems. PMID- 25027798 TI - Pre- and post-harvest interventions to reduce pathogen contamination in the U.S. beef industry. AB - Significant effort has been targeted at reducing the risk of pathogens in U.S. beef products since the mid-1990s. These efforts were focused on Escherichia coli O157:H7 after it was declared an adulterant in ground beef or its components. Post-harvest interventions applied to hides and carcasses by beef processors resulted in significant progress. Effective pre-harvest approaches proved hard to identify and implement. Six additional pathogenic E. coli serogroups were made adulterants in some beef products in 2012 and discussion regarding Salmonella is ongoing. Success to date has resulted from the combination of regulatory, research, and industry efforts to reduce the presence of pathogens in beef. PMID- 25027799 TI - WITHDRAWN: Primary CNS lymphoma and high-grade glioma: differentiation using perfusion and proton spectroscopic MR imaging. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25027800 TI - Magnetic resonance and diffusion-weighted imaging in categorization of uterine sarcomas: correlation with pathological findings. AB - OBJECTIVES: We investigated the utility of magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in the categorization of uterine sarcoma (US) and compared them with pathological findings. METHODS: The baseline and MRI characteristics were recorded and compared across the subtypes of USs. RESULTS: There were no differences in the conventional or DWI signals among the four subtypes of US, except in the heterogeneity of T2-weighted imaging. A difference in the mean apparent diffusion coefficient value for USs and uterine fibroids differed significantly (P=.019). CONCLUSIONS: MRI characteristics showed no specific differences between any subtypes of US. PMID- 25027801 TI - Development of radamide analogs as Grp94 inhibitors. AB - Hsp90 isoform-selective inhibition is highly desired as it can potentially avoid the toxic side-effects of pan-inhibition. The current study developed selective inhibitors of one such isoform, Grp94, predicated on the chimeric and pan-Hsp90 inhibitor, radamide (RDA). Replacement of the quinone moiety of RDA with a phenyl ring (2) was found to be better suited for Grp94 inhibition as it can fully interact with a unique hydrophobic pocket present in Grp94. An extensive SAR for this scaffold showed that substitutions at the 2- and 4-positions (8 and 27, respectively) manifested excellent Grp94 affinity and selectivity. Introduction of heteroatoms into the ring also proved beneficial, with a 2-pyridine derivative (38) exhibiting the highest Grp94 affinity (K(d)=820 nM). Subsequent cell-based assays showed that these Grp94 inhibitors inhibit migration of the metastatic breast cancer cell line, MDA-MB-231, as well as exhibit an anti-proliferative affect against the multiple myeloma cell line, RPMI 8226. PMID- 25027802 TI - Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies. AB - Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s>10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K(i) value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII. PMID- 25027803 TI - A combined numerical and experimental framework for determining permeability properties of the arterial media. AB - The medial layer of the arterial wall may play an important role in the regulation of water and solute transport across the wall. In particular, a high medial resistance to transport could cause accumulation of lipid-carrying molecules in the inner wall. In this study, the water transport properties of medial tissue were characterised in a numerical model, utilising experimentally obtained data for the medial microstructure and the relative permeability of different constituents. For the model, a new solver for flow in porous materials, based on a high-order splitting scheme, was implemented in the spectral/hp element library nektar++ and validated. The data were obtained by immersing excised aortic bifurcations in a solution of fluorescent protein tracer and subsequently imaging them with a confocal microscope. Cuboidal regions of interest were selected in which the microstructure and relative permeability of different structures were transformed to a computational mesh. Impermeable objects were treated fictitiously in the numerical scheme. On this cube, a pressure drop was applied in the three coordinate directions and the principal components of the permeability tensor were determined. The reconstructed images demonstrated the arrangement of elastic lamellae and interspersed smooth muscle cells in rat aortic media; the distribution and alignment of the smooth muscle cells varied spatially within the extracellular matrix. The numerical simulations highlighted that the heterogeneity of the medial structure is important in determining local water transport properties of the tissue, resulting in regional and directional variation of the permeability tensor. A major factor in this variation is the alignment and density of smooth muscle cells in the media, particularly adjacent to the adventitial layer. PMID- 25027804 TI - The effect of pentoxifylline on penile cavernosal tissues in ischemic priapism induced rat model. AB - INTRODUCTION: Priapism is defined as persisting (>4 h), painful and abnormal tumescence that can occur without sexual stimulation. Three subtypes priapisms are seen-the non-ischemic priapism, intermittent and the ischemic priapism. In ischemic priapism, there is an abnormality in the veno-occlusive mechanism, resulting in venous stasis and accumulation of deoxygenated blood within the penile cavernosal tissue. Cavernosal tissue necrosis develops after extended period of ischemia and is eventually replaced by fibrotic tissue. It may results in erectile dysfunction if not treated promptly. Although, standard treatment of the ischemic priapism is penile aspiration and intracavernosal alpha-adrenergic agents, new oral agents have been investigated to reduce the cavernosal damage. In this study, the effect of different doses of pentoxifylline on cavernosal tissues was evaluated. MATERIALS AND METHODS: Thirty-six male Wistar albino rats, age 5.5-6 months and weighing 250-300 g, were used in this study. The rats were randomly divided into five groups. In Group 1 (n = 7), the control group, only penectomy was performed. In Group 2 (n = 8), after 1 h of ischemic priapism, penectomy was performed. Group 3 (n = 7) received daily a 10 mg oral pentoxifylline for 4 weeks after 1 h of ischemic priapism, group 4 (n = 7) received a daily 30 mg oral pentoxifylline for 4 weeks after 1 h of ischemic priapism, and group 5 (n = 7) received a daily 100 mg oral pentoxifylline for 4 weeks after 1 h of ischemic priapism. At the completion of a 4-week period, penile tissues were obtained. Before penile tissues were obtained, intracavernosal pressures measured with electrical field stimulation and smooth muscle collagen ratio were evaluated pathologically. RESULTS: Electrical field stimulation-induced intracavernosal relaxation decreased in group 2 compared with group 1 (p < 0.05). Electrical field stimulation-induced relaxation enhanced in the group 3, 4 and 5 compared to group 2 (p < 0.05). In group 2, the collagen density was significantly higher than group 1. Administration of pentoxifylline reduced the collagen density caused by ischemic priapism in groups 3, 4 and 5 compared with group 2. CONCLUSION: The results of the present study showed that ischemic priapism caused damage in the penile tissues of rats, and treatment with pentoxifylline reduced the harmful effects of ischemic priapism. PMID- 25027805 TI - Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis. AB - PURPOSE: Calcineurin inhibitors (CNI) associated nephrotoxicity remains a risk factor for long-term graft dysfunction after renal transplantation. Everolimus is a mammalian target of rapamycin inhibitor and exhibits synergistic immunosuppressive activity with CNI to permit CNI-reduction. We conducted a systematic review to compare the efficacy of everolimus-based CNI sparing and standard CNI regimens in renal transplantation recipients. METHODS: We searched PubMed and Web of Science databases to identify relevant randomized controlled trials. Glomerular filtration rate (GFR), biopsy-proven acute rejection (BPAR), death or graft loss and incidence of adverse events were the major estimates of renal function, efficacy, and tolerability of the two regimens. RESULTS: Seven studies providing data for 2,067 patients were included. Six of the seven studies used cyclosporine as the CNI. The patients were divided into two groups: everolimus-based CNI sparing (elimination and minimization) group and standard CNI group. Everolimus-based regimen was associated with increased GFR [P = 0.02; weighted mean difference (WMD) 4.83 mL/min], decreased serum creatinine (P = 0.004; WMD -9.94 MUmol/L) and no more death or graft loss [P = 0.72; relative risk (RR) 1.07]. CNI-minimization was not associated with increased BPAR (P = 0.25; RR 0.85) while CNI-elimination was associated with more BPAR Grade 1 (P < 0.00001; RR 4.20). Use of everolimus reduced the risk of CMV infection (P = 0.0002; RR 0.47). There was a higher risk of discontinuation of everolimus (P < 0.00001; RR 1.69) and non-fatal adverse events (P < 0.00001; RR 1.73) in patients on the everolimus based CNI sparing regimens. CONCLUSIONS: Everolimus-based CNI sparing regimen could optimize long-term graft function without leading to more death or graft loss. Although CNI elimination was associated with higher risk of BPAR, everolimus use with CNI minimization did not increase the risk of acute rejections. Use of everolimus was associated with reduction in the incidence of CMV infection, but there was a higher risk of discontinuation of this drug and other non-fatal adverse events. PMID- 25027806 TI - Molecular interactions and solubilization of structurally related meso-porphyrin photosensitizers by amphiphilic block copolymers (Pluronics). AB - The influence of four Pluronics block copolymers (i.e. F68, P123, F127, and L44) on the aggregation and solubilization of five structurally related meso tetraphenyl porphyrin photosensitizers (PS) as model compounds for use in Photodynamic Therapy of cancer (PDT) was evaluated. Interactions between the PSs and Pluronics were studied at micromolar concentration by means of UV-Vis absorption spectrometry and by kinematic viscosity (upsilon) and osmolarity measurements at millimolar concentrations. Pluronic micelles were characterized by size and zeta potential (zeta) measurements. The morphology of selected PS Pluronic assemblies was studied by atomic force microscopy (AFM). While hydrophobic 5,10,15,20-Tetrakis(4-hydroxyphenyl) porphine (THPP) seemed to be solubilized in the Pluronic micellar cores, amphiphilic di(monoethanolammonium) meso-tetraphenyl porphine disulphonate (TPPS2a) was likely bound to the micellar palisade layer. Hydrophilic PSs like 5,10,15,20-Tetrakis (4 trimethylaniliniumphenyl) porphine (TAPP) seemed to form complexes with Pluronic unimers and to be distributed among the micellar coronas. TPPS2a aggregated into a network which could be broken at Pluronic concentration [Formula: see text] cmc, but would reconstitute in the presence of tonicity adjusting agents, e.g. sodium chloride (NaCl) or glucose. PMID- 25027808 TI - Implementation of a multidisciplinary infectious diseases team in a tertiary hospital within an Antimicrobial Stewardship Program. AB - BACKGROUND: In January 2011, as part of an antimicrobial stewardship program the Antimicrobial Management Team (AMT) at the Ghent University Hospital initiated a multidisciplinary Infectious Diseases Team (MIT) consisting of infectious diseases physicians, clinical microbiologists, and clinical pharmacists. The aim of this study is to describe the type and acceptance rate of recommendations provided by the MIT. METHOD: Prospective, observational study in a tertiary care, university teaching hospital with 1062 beds in non-consecutive hospitalized adult patients, excluding intensive care units and paediatrics. RESULTS: The MIT communicated 432 recommendations in 87 days observed. Of the 293 patients for whom a recommendation was made, the median age was 57 years (range: 16-91 years) and 169 (57.7%) were male. Skin or soft tissue infections (14%), respiratory tract infections (13%), infections without known focus (11%), abdominal infections (11%), and bone infections (8%) were most common. Recommendations were made to perform additional clinical investigation(s) [N = 137 (27%)], to adjust the dose of an antimicrobial drug [N = 42 (8%)], to stop an antimicrobial drug [N = 104 (21%)], to switch from a parenteral to an oral drug [N = 39 (8%)] or to initiate an antimicrobial drug [N = 178 (36%)], with an acceptance rate of 73.0%, 83.3%, 81.7%, 76.9%, and 84.0%, respectively. CONCLUSIONS: The MIT formulated about five recommendations a day primarily focusing on pharmacotherapy, but also on clinical investigations. In both fields, a high acceptance rate was observed. PMID- 25027809 TI - Factors affecting cellulose hydrolysis based on inactivation of adsorbed enzymes. AB - The rate of enzymatic hydrolysis of cellulose reaction is known to decrease significantly as the reaction proceeds. Factors such as reaction temperature, time, and surface area of substrate that affect cellulose conversion were analyzed relative to their role in a mechanistic model based on first order inactivation of adsorbed cellulases. The activation energies for the hydrolytic step and inactivation step were very close in magnitude: 16.3 kcal mol(-1) for hydrolysis and 18.0 kcal mol(-1) for inactivation, respectively. Therefore, increasing reaction temperature would cause a significant increase in the inactivation rate in addition to the catalytic reaction rate. Vmax,app was only 20% or less of the value at 72 h compared to at 2h as a result of inactivation of adsorbed cellulases, suggesting prolonged hydrolysis is not an efficient way to improve cellulose hydrolysis. Hydrolysis rate increased with corresponding increases in available substrate surface binding area. PMID- 25027810 TI - An alternative feedstock of corn meal for industrial fuel ethanol production: delignified corncob residue. AB - Delignified corncob residue is an industrial solid waste from xylose production using corncob as feedstock. In this study, delignified corncob residue was used as the feedstock of ethanol production by simultaneous saccharification and fermentation (SSF) and the optimal fermentation performance was investigated under various operation conditions. The ethanol titer and yield reached 75.07 g/L and 89.38%, respectively, using a regular industrial yeast strain at moderate cellulase dosage and high solids loading. A uniform SSF temperature of 37 degrees C at both prehydrolysis and SSF stages was tested. The fermentation performance and cost of delignified corncob residue and corn meal was compared as feedstock of ethanol fermentation. The result shows that the delignified corncob residue is competitive to corn meal as ethanol production feedstock. The study gives a typical case to demonstrate the potential of intensively processed lignocellulose as the alternative feedstock of corn meal for industrial fuel ethanol production. PMID- 25027811 TI - Altered regulation of protein kinase a activity in the medial prefrontal cortex of normal and brain-injured animals actively engaged in a working memory task. AB - Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is required for short- and long-term memory. In contrast, enhanced PKA activity has been shown to impair working memory, a prefrontal cortex (PFC)-dependent, transient form of memory critical for cognition and goal-directed behaviors. Working memory can be impaired after traumatic brain injury (TBI) in the absence of overt damage to the PFC. The cellular and molecular mechanisms that contribute to this deficit are largely unknown. In the present study, we examined whether altered PKA signaling in the PFC as a result of TBI is a contributing mechanism. We measured PKA activity in medial PFC (mPFC) tissue homogenates prepared from sham and 14-day postinjury rats. PKA activity was measured both when animals were inactive and when actively engaged in a spatial working memory task. Our results demonstrate, for the first time, that PKA activity in the mPFC is actively suppressed in uninjured animals performing a working memory task. By comparison, both basal and working memory-related PKA activity was elevated in TBI animals. Inhibition of PKA activity by intra-mPFC administration of Rp-cAMPS into TBI animals had no influence on working memory performance 30 min postinfusion, but significantly improved working memory when tested 24 h later. This improvement was associated with reduced glutamic acid decarboxylase 67 messenger RNA levels. Taken together, these results suggest that TBI-associated working memory dysfunction may result, in part, from enhanced PKA activity, possibly leading to altered expression of plasticity-related genes in the mPFC. PMID- 25027813 TI - Sertoli-Leydig cell tumor in a 12-year-old girl: a review article and case report. AB - BACKGROUND: The Sertoli and Leydig cell tumor is an unusual neoplasm that belongs to the sex cord-stromal tumors. Generally these tumors are associated with good prognosis. These tumors usually present virilizing symptoms such as oligomenorrhea or amenorrhea, hirsutism, voice raucity, laryngeal protuberance and clitoromegaly. CASE PRESENTATION: A 12 year old girl referred acute abdominal pain with no other clinical manifestations. An abdominal ultrasound showed a semisolid mass suggestive of ovarian tumor. The diagnosis was confirmed by a computed tomography. A unilateral salpingo oophorectomy was performed and the pathologist reported a Sertoli-Leydig tumor with intermediate differentiation. The outcome was excellent. CONCLUSIONS: These tumors represent a rare condition in children. However, they can occur at any age, therefore it is important to acknowledge the clinical manifestations, diagnostic approach and therapeutic options. In this case the patient presented unusual symptoms which makes it more interesting. PMID- 25027812 TI - Highly efficient targeted mutagenesis in one-cell mouse embryos mediated by the TALEN and CRISPR/Cas systems. AB - Since the establishment of embryonic stem (ES) cell lines, the combined use of gene targeting with homologous recombination has aided in elucidating the functions of various genes. However, the ES cell technique is inefficient and time-consuming. Recently, two new gene-targeting technologies have been developed: the transcription activator-like effector nuclease (TALEN) system, and the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein (Cas) system. In addition to aiding researchers in solving conventional problems, these technologies can be used to induce site-specific mutations in various species for which ES cells have not been established. Here, by targeting the Fgf10 gene through RNA microinjection in one-cell mouse embryos with the TALEN and CRISPR/Cas systems, we produced the known limb-defect phenotypes of Fgf10-deficient embryos at the F0 generation. Compared to the TALEN system, the CRISPR/Cas system induced the limb-defect phenotypes with a strikingly higher efficiency. Our results demonstrate that although both gene targeting technologies are useful, the CRISPR/Cas system more effectively elicits single-step biallelic mutations in mice. PMID- 25027814 TI - Progranulin shows cytoprotective effects on trophoblast cells in vitro but does not antagonize TNF-alpha-induced apoptosis. AB - AIMS: The glycoprotein progranulin directly binds to TNF-receptors and thereby can antagonize the inflammatory effects of TNF-alpha. Here we analyzed the impact of both cytokines on cytotoxicity and viability of trophoblast cells. METHODS: Isolated villous first trimester human trophoblast cells and the human choriocarcinoma cell line BeWo were treated with recombinant human progranulin and TNF-alpha. Analyses were performed by LDH- and MTT-assay and measurement of caspase-8-activity. RESULTS: Progranulin treatment showed some cytoprotective effects on isolated trophoblast cells. However, TNF-alpha-induced apoptosis was not antagonized by addition of progranulin. Effects were similar, but more pronounced in BeWo cells. CONCLUSION: The cytoprotective activity of progranulin on trophoblast cells in vitro was only weak and of doubtful biologic relevance. It was not able to antagonize TNF-alpha. Future studies should focus on possible paracrine activities of progranulin. PMID- 25027815 TI - Hyperparathyroid crisis presenting with hyperemesis gravidarum. AB - PURPOSE: Primary hyperparathyroidism during pregnancy is a rare condition, and the diagnosis may be confounded by pregnancy related conditions. Since the appropriate management reduces the maternal and fetal complications; differential diagnosis becomes quite crucial. METHOD: Clinical course of a patient with hyperparathyroid crisis will be discussed with the review of the literature. A 22 year- old, (gravida 2, para 1) woman was presented with hyperparathyroid crisis at the 11th weeks' gestation. She was hospitalized twice due to hyperemesis gravidarum. When she was admitted to the hospital for the third time due to increased vomiting and weight-loss, serum biochemistry panel was performed and it revealed severe hypercalcemia that serum Ca was 17.59 mg/dl, and she was referred to our hospital as parathyroid crisis. Maternal hypercalcemia was resolved after urgent parathyroidectomy. She was diagnosed as preeclampsia at the 30 weeks' gestation and delivered a male infant weighing 1,090 g at 33 weeks' gestation with APGAR scores 6 at 1 min, and 7 at min 5, without evidence of neonatal hypocalcemia or tetany. RESULTS: Urgent parathyroidectomy is the definite treatment in symptomatic patients with hyperparathyroidism during pregnancy. Resolving maternal hypercalcemia prevents neonatal tetany and hypocalcemia. CONCLUSION: Hyperemesis may lead to hypercalcemic crisis in patients with hyperparathyroidism, so serum Ca level should be checked in patients with hyperemesis gravidarum especially who detoriate rapidly. Although they share some common pathogenetic mechanisms, there is not enough evidence for attributing preeclampsia to primary hyperparathyroidism. PMID- 25027816 TI - Comment to "win not by numbers, but by skill". PMID- 25027817 TI - Response to "screening depression during and after pregnancy using the EPDS". PMID- 25027818 TI - Screening cytomegalovirus, rubella and toxoplasma infections in pregnant women with unknown pre-pregnancy serological status. AB - PURPOSE: To determine the prevalence of acute cytomegalovirus (CMV), rubella and T. gondii infections among pregnant women who had no serological status tested for these microorganisms prior to pregnancy in a metropolitan area. METHODS: A cross-sectional study was undertaken between January 2009 and January 2013 in 1,258 women presenting for their first antenatal visit (between 6 and 11 weeks of gestation). All women were tested for IgG and IgM antibodies. Subsequently, avidity test was utilized for inconclusive results. They were followed until delivery and all newborns were examined by a pediatrician. RESULTS: Presence of IgM antibody positivity alone was not detected in any women. Avidity test excluded primary infection in 15 out of 16 (93.7 %) women who were positive for both IgG and IgM antibodies. Amniocentesis was performed in one case with borderline IgG avidity for T. gondii. No primary infections were detected in any newborn for the infections screened. The prevalences of IgG antibodies were 95 % for rubella, 84.1 % for CMV and 23.1 % for T. gondii. CONCLUSIONS: Assessment of IgG and IgM antibodies followed by IgG avidity testing for inconclusive results may be an acceptable approach in pregnant women with unknown serological status prior to pregnancy. Utilization of IgG avidity as a supplemental test prevented unnecessary intervention in IgG and IgM antibodies positive patients. No primary infection was detected for CMV, rubella and T. gondii infections in the urban population screened. PMID- 25027819 TI - Response to: microsurgical principles should be considered in studies addressing adhesion prevention: Caglar et al. (2014). PMID- 25027820 TI - Would it be too late? A retrospective case-control analysis to evaluate maternal fetal outcomes in advanced maternal age. AB - PURPOSE: To evaluate maternal-fetal outcomes in women of advanced maternal age (AMA; >35 years old) and women of physiological maternal age as controls (C; <35 years old). METHODS: Single-center, retrospective case-control analysis, from January 1 to December 31, 2013. For each group, we evaluated obstetric history, number of twin pregnancies, delivery mode, incidence of obstetric diseases and neonatal outcomes (5-min Apgar score, neonatal weight, meconium stained fluid rate, admission to the neonatal intensive care unit rate, and incidence of congenital malformations). Data are presented as n (%) and analyzed with chi (2) test and Fisher exact test (when required). A p value < 0.05 was considered statistically significant. Moreover, we calculated the odds ratio (OR), with confidence interval (CI) at 95 %. RESULTS: We enrolled 1,347 pregnant women, 210 (15.6 %) in AMA and 1,137 (84.4 %) C. AMA patients showed a higher rate of previous (anamnestic) spontaneous abortion (SA; p = 0.001; OR = 2.10) and previous (anamnestic) voluntary pregnancy termination (p = 0.022; OR = 1.59), iterative cesarean section (p = 0.026; OR = 2.33), SA (p = 0.001; OR = 12.82), preterm delivery (p = 0.001; OR = 69.84), congenital malformations (p = 0.036; OR = 3.94). In C there was a greater number of nulliparous (p = 0.009; OR = 0.52) and vaginal deliveries (p = 0.025; OR = 0.41). There were not any statistically significant differences between the two groups for twin pregnancies (p = 0.862; OR = 0.97), first cesarean section (p = 0.145; OR = 0.95), other obstetric diseases and neonatal outcomes. CONCLUSION: AMA could be considered an important risk factor only for SA and PTD and does not influence neonatal outcomes except for congenital malformations. PMID- 25027821 TI - Do follicular fluid gelatinase levels affect fertilization rates and oocyte quality? AB - BACKGROUND: Matrix metalloproteinase-2 and -9, known as gelatinases, are considered to be essential for tissue remodelling during the reproductive process. However, their role in reproduction is unclear. AIMS: In the present study, we aimed to investigate the relationship between follicular fluid gelatinase levels and oocyte quality and fertilization, and to compare the activities of gelatinase levels with different drug stimulation protocols. METHODS: We evaluated 60 women with unexplained infertility who underwent in vitro fertilization (IVF) treatment. Thirty patients underwent a gonadotropin releasing hormone (GnRH) agonist protocol and 30 underwent a GnRH antagonist protocol. Follicular fluid was obtained during oocyte retrieval. Oocyte quality was determined using light microscopy, and oocytes were considered to be fertilized when two pronuclei were present. Gelatinase activities were measured using commercial enzyme-linked immunosorbent assay kits. The study was partially supported by the Scientific Research Unit of Suleyman Demirel University (Protocol Number: 3620-TU1-13), and all procedures were conducted with the approval of the Suleyman Demirel University Local Ethics Board. Statistical analyses of the data were performed using the independent t test, Fisher exact test, Mann-Whitney U test, one-way ANOVA, and posthoc least significant difference. RESULTS: Follicular fluid gelatinase levels were significantly higher for agonist drug administration (p = 0.001), and a positive correlation was observed between matrix metalloproteinase-9 levels and oocyte grade (p = 0.01). Moreover, a positive relationship between matrix metalloproteinase-9 levels and fertilization was observed (p = 0.02). CONCLUSION: Follicular fluid gelatinase activities, particularly MMP-9 activity, might be a predictor of oocyte quality and IVF success. PMID- 25027822 TI - Secondary bacterial infections in influenza virus infection pathogenesis. AB - Influenza is often complicated by bacterial pathogens that colonize the nasopharynx and invade the middle ear and/or lung epithelium. Incidence and pathogenicity of influenza-bacterial coinfections are multifactorial processes that involve various pathogenic virulence factors and host responses with distinct site- and strain-specific differences. Animal models and kinetic models have improved our understanding of how influenza viruses interact with their bacterial co-pathogens and the accompanying immune responses. Data from these models indicate that considerable alterations in epithelial surfaces and aberrant immune responses lead to severe inflammation, a key driver of bacterial acquisition and infection severity following influenza. However, further experimental and analytical studies are essential to determining the full mechanistic spectrum of different viral and bacterial strains and species and to finding new ways to prevent and treat influenza-associated bacterial coinfections. Here, we review recent advances regarding transmission and disease potential of influenza-associated bacterial infections and discuss the current gaps in knowledge. PMID- 25027823 TI - The natural history of ADP-ribosyltransferases and the ADP-ribosylation system. AB - Catalysis of NAD(+)-dependent ADP-ribosylation of proteins, nucleic acids, or small molecules has evolved in at least three structurally unrelated superfamilies of enzymes, namely ADP-ribosyltransferase (ART), the Sirtuins, and probably TM1506. Of these, the ART superfamily is the most diverse in terms of structure, active site residues, and targets that they modify. The primary diversification of the ART superfamily occurred in the context of diverse bacterial conflict systems, wherein ARTs play both offensive and defensive roles. These include toxin-antitoxin systems, virus-host interactions, intraspecific antagonism (polymorphic toxins), symbiont/parasite effectors/toxins, resistance to antibiotics, and repair of RNAs cleaved in conflicts. ARTs evolving in these systems have been repeatedly acquired by lateral transfer throughout eukaryotic evolution, starting from the PARP family, which was acquired prior to the last eukaryotic common ancestor. They were incorporated into eukaryotic regulatory/epigenetic control systems (e.g., PARP family and NEURL4), and also used as defensive (e.g., pierisin and CARP-1 families) or immunity-related proteins (e.g., Gig2-like ARTs). The ADP-ribosylation system also includes other domains, such as the Macro, ADP-ribosyl glycohydrolase, NADAR, and ADP-ribosyl cyclase, which appear to have initially diversified in bacterial conflict-related systems. Unlike ARTs, sirtuins appear to have a much smaller presence in conflict related systems. PMID- 25027827 TI - Formation of protein and protein-gold nanoparticle stabilized microbubbles by pressurized gyration. AB - A one-pot single-step novel process has been developed to form microbubbles up to 250 MUm in diameter using a pressurized rotating device. The microbubble diameter is shown to be a function of rotational speed and working pressure of the processing system, and a modified Rayleigh-Plesset equation has been derived to explain the bubble-forming mechanism. A parametric plot is constructed to identify a rotating speed and working pressure regime, which allows for continuous bubbling. Bare protein (lysozyme) microbubbles generated in this way exhibit a morphological change, resulting in microcapsules over a period of time. Microbubbles prepared with gold nanoparticles at the bubble surface showed greater stability over a time period and retained the same morphology. The functionalization of microbubbles with gold nanoparticles also rendered optical tunability and has promising applications in imaging, biosensing, and diagnostics. PMID- 25027824 TI - Arginase I levels are decreased in the plasma of pediatric patients with atopic dermatitis. AB - BACKGROUND: Serum arginase levels have been shown to be elevated in conditions, such as trauma, cancer, chronic wounds, pregnancy, and diabetes. This also has been found to be true in atopic diseases, such as asthma and allergic rhinitis. OBJECTIVE: To study arginase activity in patients with atopic dermatitis (AD). METHODS: In this pilot study, arginase activity levels in 15 pediatric patients with AD were compared with those in controls to determine whether arginase levels in AD are altered as in patients with other atopic diseases. RESULTS: In contrast to the other diseases studied, arginase activity was found to be decreased in granulocytes and in the plasma of patients with AD compared with controls. This finding was coupled with a trend toward higher L-arginine plasma levels. CONCLUSION: In AD, a different mechanism of arginine metabolism seems to be stimulated, leading to the formation of nitric oxide pathway components causing suppression of the arginase pathway and impairment in skin hydration, collagen synthesis, and wound healing. PMID- 25027828 TI - Basic investigation into the present burn care system in China: burn units, doctors, nurses, beds and special treatment equipment. AB - OBJECTIVE: The aim of the study was to survey the current burn units in China to understand the burn care system in the country and supply basic data for the National Burn Repository of China (NBRC) and further research. METHOD: A questionnaire was developed and sent to burn unit directors in China via e-mail, which was followed up with reminder text messages to obtain information for the study. RESULTS: Of the 405 hospitals from the 31 provinces in mainland China that responded to the questionnaire, 63.7% of the responses came from Grade 3A hospitals, and the most popular model of organisation was the Burns and Plastic Surgery arrangement (63.0%). An average of 9.43+/-0.351 doctors work in each burn unit with 70.4% of all units having 4-11 doctors. The ratio of chief surgeon to associate chief surgeon to attending surgeon to resident surgeon and surgeon assistant was 1:1.8:2.2:2.3. An average of 30% of all doctors in each burn unit held postgraduate degrees, and more than 90% of all surgeons held a bachelor's degree or higher. There were 16.48+/-0.637 nurses per burn unit, 56.5% of burn units had 8-15 nurses, and the ratio of chief nurse to associate chief nurse to supervisor nurse to nurse practitioner to junior nurse was 1:11.8:57.0:82.1:86.1. More than 80% of all nurses had received a college education or above. However, only 30% of nurses held bachelor's degrees or higher, while only 0.66% of nurses had received postgraduate degrees. A total of 39.91+/-1.50 beds were available in each burn unit and 45% of burn units had 20-39 beds. Up to 70% of the total beds were prepared for patients with burn, and more than 10% of the beds were specifically for patients with severe burn. The ratios of doctors to nurses, beds to doctors, beds to nurses, and beds to doctors and nurses were 0.64+/-0.01, 4.48+/-0.12, 2.67+/-0.09, and 1.66+/-0.06, respectively. The workload of each doctor and nurse was most heavy in units with 40-59 beds. In addition, we estimated that there were 0.05, 0.5, 0.8, and 1.9 burn units, burn doctors, nurses, and beds, respectively, per 100,000 members of the population in mainland China. Chinese burn units lack special burn treatments, nursing equipment, and operation apparatuses. CONCLUSION: To the best of our knowledge, this is the first survey of the present burn care system in China. These results confirm that the burn care system is not equivalent to the national power of this country and the system lacks a great number of trained burn professionals. Burn doctors and nurses bear a heavy burden of work. This report supplies basic data to spur further research. We propose creating a burn unit registration system and a special database in China. PMID- 25027829 TI - An Italian initiative to prevent corruption in health and social care. PMID- 25027831 TI - Perspective image comprehension depends on both visual and proprioceptive information. AB - Proprioceptive information can supplement visual information in the comprehension of ambiguous perspective images. The importance of proprioceptive information in unambiguous perspective image comprehension is untested, however. We explored the role of proprioception in perspective image comprehension using three experiments in which participants took or imagined taking an upward- or downward-oriented posture and then made judgments about images viewed from below or viewed from above. Participants were faster and more accurate in their judgments when their actual or simulated posture was consistent with the posture implied by the perspective of the image they were judging. These results support a role for proprioception in the comprehension of unambiguous perspective images as well as ambiguous perspective images. PMID- 25027830 TI - Depressive symptoms and alcohol correlates among Brazilians aged 14 years and older: a cross-sectional study. AB - BACKGROUND: The associations between depressive symptoms and alcohol-related disorders, drinking patterns and other characteristics of alcohol use are important public health issues worldwide. This study aims to study these associations in an upper middle-income country, Brazil, and search for related socio-demographic correlations in men and women. METHODS: A cross-sectional study was conducted between November 2005 and April 2006. The sample of 3,007 participants, selected using a multistage probabilistic sampling method, represents the Brazilian population aged 14 and older. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and alcohol dependence was assessed using the Composite International Diagnostic Interview. Associations assessed using bi-variate analysis were tested using Rao-Scott measures. Gender specific multinomial logistic regression models were developed. RESULTS: Among the participants with alcohol dependence, 46% had depressive symptoms (17.2% mild/moderate and 28.8% major/severe; p < 0.01); 35.8% (p = 0.08) of those with alcohol abuse and 23.9% (p < 0.01) of those with a binge-drinking pattern also had depressive symptoms. Alcohol abstainers and infrequent drinkers had the highest prevalence of major/severe depressive symptoms, whereas frequent heavy drinkers had the lowest prevalence of major/severe depressive symptoms. In women, alcohol dependence and the presence of one or more problems related to alcohol consumption were associated with higher risks of major/severe depressive symptoms. Among men, alcohol dependence and being >=45 years old were associated with higher risks of major/severe depressive symptoms. CONCLUSIONS: In Brazil, the prevalence of depressive symptoms is strongly related to alcohol dependence; the strongest association was between major/severe depressive symptoms and alcohol dependence in women. This survey supports the possible association of biopsychosocial distress, alcohol consumption and the prevalence of depressive symptoms in Brazil. Investing in education, social programs, and care for those with alcohol dependence and major/severe depressive symptoms, especially for such women, and the development of alcohol prevention policies may be components of a strategic plan to reduce the prevalence of depression and alcohol problems in Brazil. Such a plan may also promote the socio-economic development of Brazil and other middle-income countries. PMID- 25027832 TI - Brain imaging findings and social/emotional problems in Israeli children with neurofibromatosis type 1. AB - A potential association between brain MRI findings and social/emotional difficulties in children with neurofibromatosis type 1 (NF1) was examined. Twenty eight children with NF1 filled in the Strengths and Difficulties Questionnaire (SDQ), and possible associations between their responses and findings in their brain MRI were sought. T2 bright foci were identified in MRI scans of 24 patients (85 %). There were no associations between the presence of the bright foci in any specific brain region and any of the SDQ scores for the emotional/behavioral measures. Male patients had significantly abnormal SDQ scores and peer problems. Patients with abnormal SDQ scores were younger than those with normal SDQ scores (mean 13.2 years vs 14.3 years, respectively; p = 0.23). A comparison of the scores obtained in ours and in another group of 11 children with NF1 yielded a significant difference between the groups. CONCLUSION: We believe that the lack of correlation between the MRI findings and the social/emotional parameters of the SDQ is another demonstration of the marked clinical variability characteristic of NF1. PMID- 25027833 TI - Don't miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation. AB - Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ = 58). CONCLUSION: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis. PMID- 25027834 TI - Expression profile of maize microRNAs corresponding to their target genes under drought stress. AB - Microarray assay of four inbred lines was used to identify 303 microRNAs differentially expressed under drought stress. The microRNAs were used for bioinformatics prediction of their target genes. The majority of the differentially expressed microRNA families showed different expression profiles at different time points of the stress process among the four inbred lines. Digital gene expression profiling revealed 54 genes targeted by 128 of the microRNAs differentially expressed under the same stress conditions. The differential expression of miR159 and miR168 was further validated by locked nucleic acid northern hybridization. These results indicated that miR159 and miR168, as well as numerous other microRNAs, play critical roles in signaling pathways of maize response to drought stress. However, the level of the post transcriptional regulation mediated by microRNAs had different responses among genotypes, and the gene expression related to signaling pathways under drought stress is also regulated, possibly by multiple mechanisms. PMID- 25027835 TI - Paraoxonase 1 polymorphisms within a Mississippi USA population as possible biomarkers of enzyme activities associated with disease susceptibility. AB - Paraoxonase (PON1) hydrolyzes paraoxon (PO) and diazoxon (DZO), active metabolites of insecticides parathion and diazinon. The PON1 gene has single nucleotide polymorphisms (SNPs) including a codon 192 arginine (R) to glutamine (Q) and methionine (M) to leucine (L) at codon 55. Hydrolysis of PO (POase), DZO (DZOase), dihydrocoumarin (lactonase), and phenyl acetate (arylesterase) were evaluated for associations with race, gender, age, and PON1 55/192 SNP genotypes. Variables were analyzed both individually and in combination. QQ individuals had higher lactonase (p < 0.001) than RR individuals. This might partially explain why predominantly RR African Americans have higher rates of coronary disease than predominantly QQ Caucasians. Significant (p < 0.001) differences in arylesterase were seen among genotypes with QQ and MM lowest whereas RR and LL were highest. This opposes the prevailing belief that arylesterase is unaffected by genotype and suggests that this activity cannot be used to quantify PON1 protein. PMID- 25027836 TI - An evaluation of the use of oral contrast media in abdominopelvic CT. AB - OBJECTIVES: To evaluate the diagnostic efficacy of different oral contrast media (OCM) for abdominopelvic CT examinations performed for follow-up general oncological indications. The objectives were to establish anatomical image quality criteria for abdominopelvic CT; use these criteria to evaluate and compare image quality using positive OCM, neutral OCM and no OCM; and evaluate possible benefits for the medical imaging department. METHODS: Forty-six adult patients attending a follow-up abdominopelvic CT for general oncological indications and who had a previous abdominopelvic CT with positive OCM (n = 46) were recruited and prospectively placed into either the water (n = 25) or no OCM (n = 21) group. Three radiologists performed absolute visual grading analysis (VGA) to assess image quality by grading the fulfilment of 24 anatomical image quality criteria. RESULTS: Visual grading characteristics (VGC) analysis of the data showed comparable image quality with regards to reproduction of abdominal structures, bowel discrimination, presence of artefacts, and visualization of the amount of intra-abdominal fat for the three OCM protocols. CONCLUSION: All three OCM protocols provided similar image quality for follow-up abdominopelvic CT for general oncological indications. KEY POINTS: * Positive oral contrast media are routinely used for abdominopelvic multidetector computed tomography * Experimental study comparing image quality using three different oral contrast materials * Three different oral contrast materials result in comparable CT image quality * Benefits for patients and medical imaging department. PMID- 25027837 TI - Diagnostic accuracy of two-dimensional shear wave elastography for the non invasive staging of hepatic fibrosis in chronic hepatitis B: a cohort study with internal validation. AB - OBJECTIVES: To determine the accuracy of two-dimensional shear wave elastography (2D-SWE) for noninvasive staging of hepatic fibrosis in chronic hepatitis B (CHB). METHODS: Patients with CHB infection who underwent liver biopsy were consecutively included. Receiver-operating characteristic (ROC) curves were constructed to assess the overall accuracy and identify optimal cutoff values. RESULTS: Three hundred three patients were analysed. The diagnostic performance characteristics were determined for the first 202 patients (the index cohort) and were validated on the next 101 patients (validation cohort). The areas under the ROC curves for significant fibrosis, severe fibrosis and cirrhosis were all greater than 0.90 and did not differ significantly between the index and validation cohorts. Using the cutoff values generated from the index cohort, the validation cohort 2D-SWE had negative predictive values of 82.6 % (95 % confidence interval [CI]: 68.4 % - 92.3 %) for significant fibrosis, 95.1 % (95 % CI: 86.3 % - 99.0 %) for severe fibrosis and 97.4 % (95 % CI: 90.8 % - 99.7 %) for cirrhosis. The positive predictive values were 83.6 % (95 % CI: 71.2 % - 92.2 %), 65.0 % (95 % CI: 48.1 - 79.5 %) and 60.0 % (95 % CI: 38.7 % - 78.9 %), respectively. CONCLUSION: The 2D-SWE showed good diagnostic accuracy in staging liver fibrosis in patients with CHB infection and assisted in excluding liver fibrosis and cirrhosis. KEY POINTS: * Two-dimensional shear wave elastography showed good diagnostic accuracy in assessing liver fibrosis. * Diagnostic performance did not differ significantly between the index and validation cohorts. * Two-dimensional shear wave elastography assisted in excluding liver fibrosis and cirrhosis. PMID- 25027838 TI - Left atrial dysfunction in type 2 diabetes mellitus: insights from cardiac MRI. AB - OBJECTIVES: The left atrium (LA) modulates left ventricular filling through reservoir, conduit and booster pump functions. Only limited data exist on LA involvement in type 2 diabetes mellitus (DM2). This study sought to assess LA function in asymptomatic DM2 with cardiac MRI. We hypothesized that cardiac MRI can detect LA dysfunction in asymptomatic DM2. METHODS: Forty-five patients with asymptomatic DM2 and 24 normoglycaemic controls were studied. MRI cine imaging was performed to measure LA maximal and minimal volumes. A flow-sensitive phase contrast gradient-echo sequence was used for flow measurements perpendicular to the orifice of the mitral valve, to quantify active LA stroke volume. LA total, passive and active emptying volumes and fractions were calculated. RESULTS: LA reservoir function, namely LA total ejection fraction, was significantly greater in controls compared to patients with DM2 (62.2 +/- 5.2 vs 57.0 +/- 7.6 %, P = 0.004). LA passive ejection fraction was also greater in the controls (26.2 +/- 9.5 vs 16.1 +/- 11.0 %, P < 0.001). Regarding parameters of LA booster pump function, LA active ejection fraction was not significantly different between groups. DM2 was demonstrated to be an independent determinant of LA function. CONCLUSIONS: Cardiac MRI enables the detection of LA dysfunction in asymptomatic DM2, characterized by a reduction in LA reservoir and conduit functions. KEY POINTS: * Evaluation of left atrial function is feasible with cardiac MRI * Type 2 diabetes mellitus is associated with left atrial dysfunction * Left atrial function modulates left ventricular filling. PMID- 25027839 TI - (1)H-MRS is useful to reinforce the suspicion of primary central nervous system lymphoma prior to surgery. AB - OBJECTIVES: To assess whether (1)H-MRS may be useful to reinforce the radiological suspicion of PCNSL. METHODS: In this retrospective study, we included 546 patients with untreated brain tumours in which single-voxel spectroscopy at TE 30 ms and 136 ms had been performed. The patients were split into two subgroups: "training set" and "test set." Differences between PCNSL and five other types of intracranial tumours were assessed in the test set of patients using the Mann-Whitney U nonparametric test and cut-off values for pair wise comparisons defined by constructing receiver operating characteristic curves. These thresholds were used to construct classifiers for binary comparison between PCNSL and non-PCNSL. The performance of the obtained classifiers was assessed in the independent test set of patients. RESULTS: Significant differences were found between PCNSL and the other groups evaluated. All bilateral comparisons performed in the test set obtained accuracy values above 70 % (71-89 %). Lipids were found to be useful to discriminate between PCNSL and glioblastoma/metastasis at short TE. Myo-inositol resonance was found to be very consistent for discriminating between PCNSL and astrocytomas at short TE. CONCLUSIONS: (1)H-MRS is useful to reinforce diagnostic suspicion of PCNSL on MRI. KEY POINTS: * (1) H-MRS can be used to reinforce the diagnostic suspicion of PCNSL. * Lipids can be used to discriminate between PCNSL and GB/MET. * Myo inositol resonance can be used to discriminate between PCNSL and astrocytomas. PMID- 25027840 TI - Automatic exposure control in CT: the effect of patient size, anatomical region and prescribed modulation strength on tube current and image quality. AB - OBJECTIVES: To study the effect of patient size, body region and modulation strength on tube current and image quality on CT examinations that use automatic tube current modulation (ATCM). METHODS: Ten physical anthropomorphic phantoms that simulate an individual as neonate, 1-, 5-, 10-year-old and adult at various body habitus were employed. CT acquisition of head, neck, thorax and abdomen/pelvis was performed with ATCM activated at weak, average and strong modulation strength. The mean modulated mAs (mAsmod) values were recorded. Image noise was measured at selected anatomical sites. RESULTS: The mAsmod recorded for neonate compared to 10-year-old increased by 30 %, 14 %, 6 % and 53 % for head, neck, thorax and abdomen/pelvis, respectively, (P < 0.05). The mAsmod was lower than the preselected mAs with the exception of the 10-year-old phantom. In paediatric and adult phantoms, the mAsmod ranged from 44 and 53 for weak to 117 and 93 for strong modulation strength, respectively. At the same exposure parameters image noise increased with body size (P < 0.05). CONCLUSIONS: The ATCM system studied here may affect dose differently for different patient habitus. Dose may decrease for overweight adults but increase for children older than 5 years old. Care should be taken when implementing ATCM protocols to ensure that image quality is maintained. KEY POINTS: * ATCM efficiency is related to the size of the patient's body. * ATCM should be activated without caution in overweight adult individuals. * ATCM may increase radiation dose in children older than 5 years old. * ATCM efficiency depends on the protocol selected for a specific anatomical region. * Modulation strength may be appropriately tuned to enhance ATCM efficiency. PMID- 25027841 TI - Diagnostic accuracy of segmental enhancement inversion for the diagnosis of renal oncocytoma using biphasic computed tomography (CT) and multiphase contrast enhanced magnetic resonance imaging (MRI). AB - OBJECTIVES: Segmental enhancement inversion (SEI) is a controversial imaging finding reportedly specific for the diagnosis of renal oncocytoma. The purpose of this study was to re-evaluate SEI using biphasic CT and multiphase MRI. METHODS: With research ethics board approval, a retrospective analysis of patients with resection or biopsy of oncocytoma or chromophobe renal cell carcinoma (Ch-RCC) between 2008-2012 was performed. Twenty-four patients with oncocytoma and 13 patients with Ch-RCC underwent CT, while 13 patients with oncocytoma and 10 patients with Ch-RCC underwent MRI. Two blinded radiologists reviewed the CT and MRI studies independently in separate sessions to assess for SEI. A third radiologist established consensus. Interobserver variability was calculated and diagnostic accuracy was compared using ROC and the Fisher exact test. RESULTS: There was no difference in detection of SEI between oncocytoma and Ch-RCC at CT [both readers (p = 0.65, 0.5) and consensus review (p = 0.29)] or MRI [both readers (p = 0.64, 0.74) and consensus review (p = 0.53)]. The interobserver variability at CT (K = 0.28-0.33) and MRI (K = 0.25-0.44) was fair. The sensitivity and specificity for diagnosis of oncocytoma were 21 % and 92 % at CT and 15 % and 90 % at MRI. CONCLUSION: SEI is not useful for the diagnosis of renal oncocytoma with CT or MRI. KEY POINTS: * SEI was detected in a minority of renal oncocytomas and chromophobe RCC. * Interobserver agreement for segmental enhancement inversion was only fair. * SEI is not useful for diagnosing renal oncocytoma with CT or MRI. PMID- 25027842 TI - LincRNAs MONC and MIR100HG act as oncogenes in acute megakaryoblastic leukemia. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are recognized as pivotal players during developmental ontogenesis and pathogenesis of cancer. The intronic microRNA (miRNA) clusters miR-99a ~ 125b-2 and miR-100 ~ 125b-1 promote progression of acute megakaryoblastic leukemia (AMKL), an aggressive form of hematologic cancers. The function of the lncRNA hostgenes MIR99AHG (alias MONC) and MIR100HG within this ncRNA ensemble remained elusive. RESULTS: Here we report that lncRNAs MONC and MIR100HG are highly expressed in AMKL blasts. The transcripts were mainly localized in the nucleus and their expression correlated with the corresponding miRNA clusters. Knockdown of MONC or MIR100HG impeded leukemic growth of AMKL cell lines and primary patient samples. The development of a lentiviral lncRNA vector to ectopically express lncRNAs without perturbing their secondary structure due to improper termination of the viral transcript, allowed us to study the function of MONC independent of the miRNAs in cord blood hematopoietic stem and progenitor cells (HSPCs). We could show that MONC interfered with hematopoietic lineage decisions and enhanced the proliferation of immature erythroid progenitor cells. CONCLUSIONS: Our study reveals an unprecedented function of lncRNAs MONC and MIR100HG as regulators of hematopoiesis and oncogenes in the development of myeloid leukemia. PMID- 25027844 TI - Cystic fibrosis. AB - Cystic Fibrosis used to be considered rare and inevitably fatal in early childhood. We now know it is the most common genetic disease in man, and while it is the most serious of all childhood chest conditions, more and more children are reaching adolescence and adult life, owing to early diagnosis and modern methods of treatment. Occasional cases are now being diagnosed later in life-in adolescence and even adult life. PMID- 25027843 TI - Secular trends in pregnancy weight gain in German women and their influences on foetal outcome: a hospital-based study. AB - BACKGROUND: Increasing rates of overweight have been reported. In Germany, women of childbearing age are especially affected. Those women are at increased risks of several peri- and postnatal complications. The purpose of this study was to carry out Germany's first study in terms of secular trends of overweight and weight gain during pregnancy related to foetal clinical outcomes (birth weight, Apgar score and umbilical blood pH). METHODS: A database maintained by a large regional university hospital in Cologne, Germany was used to evaluate clinical routine data from 1996 to 2012. 11771 women (23.5 +/- 5.4 years; 18-48 years), who gave birth to a live singleton child (>2000 gram) were included. Recommended weight gain during pregnancy was based on IOM guidelines: Total weight gain range for underweight (initial BMI < 18.5 kg/m2) is 12.5-18 kg/ 28-40 lbs respectively, for normal-weight (initial BMI 18.5 -24.9 kg/m2) is 11.5-16 kg/ 25-35 lbs respectively, for overweight (initial BMI 25.0-29.9 kg/m2) is 7-11.5 kg/ 15-25 lbs respectively and for obese (initial BMI >= 30.0 kg/m2) is 5-9 kg/ 11-20 lbs respectively.A one-way variance analysis was employed to test for differences in particular factors in various groups. Multiple linear regression analysis was used to model impact factors. RESULTS: Over the second analysed period (2005 2012), the number of women with high weight gain increased from 33.8% to 42.9% (p <0.001). 54.5% overweight and 57.7% obese women were affected (p <0.001). Women with high weight gain were 54.5% significantly more likely to give birth to an infant >= 4000 grams than women with normal (31.7%) or low weight gain (13.8%, p < 0.001). Women with normal weight gain had significantly better foetal outcomes in terms of the Apgar score at 5 min and umbilical cord blood pH. CONCLUSION: These data confirm an increase in maternal weight gain before and during pregnancy. An excessive weight gain is accompanied by macrosomia, lower Apgar scores and pH-value. Women should therefore be advised about the risks of obesity before and during pregnancy as well as excessive maternal weight gain during pregnancy. PMID- 25027845 TI - The development or re-establishment of movement in patients with abnormal vision. AB - It is a most surprising fact that the study of movement in relation to vision has almost totally evaded scientific investigation up to a few years ago. As I stated in 1964, the problem presented itself to me as soon as I entered a school for the blind. Why, if blindness was their only handicap did these children present such a picture of physical abnormality, poor posture, awkward gait and a vast range of neurological symptoms reminiscent of almost every disease of the nervous system? In 1966, Dr. Irwin Siegel, consultant orthopaedist to the Chicago Institute for the Visually Handicapped wrote, "Two years ago I blindfolded myself and took a step-as an orthopaedist I had treated many posture problems, but always in sighted patients. The blindfold changed this, for with one step I entered a world where posture, balance and mobility were not governed by sight." If not by sight, then by what? PMID- 25027846 TI - History, basis and techniques of connective tissue massage. AB - Connective Tissue Massage has been practiced as a therapeutic procedure for three decades. In Germany, its country of origin, as in most parts of Europe, it is an integral part of Physiotherapy and is taught at every training school. The medical practitioner has accepted C.T.M. as a manual form of neural therapy and prescribes it freely for the benefit of his patients. In English speaking countries C.T.M. is almost unknown, its slow acceptance being due to the following reasons: 1. Our present day knowledge makes it impossible to account on a scientific basis for ail the effects gained by the application of C.T.M. 2. The misleading name "Connective tissue massage", by emphasizing the word massage makes the treatment suspect to the medical practitioner and the physiotherapist. PMID- 25027847 TI - The conservative management of scoliosis in children and adolescents, and the use of the milwaukee brace. AB - Many children and adolescents with scoliosis are referred to the physiotherapist for conservative treatment. These scolioses include all types, congenital, idiopathic and paralytic curves in the infantile, juvenile and adolescent age groups. PMID- 25027848 TI - The contribution of lifestyle coaching of overweight patients in primary care to more autonomous motivation for physical activity and healthy dietary behaviour: results of a longitudinal study. AB - BACKGROUND: Combined lifestyle interventions (CLIs) have been advocated as an effective instrument in efforts to reduce overweight and obesity. The odds of maintaining higher levels of physical activity (PA) and healthier dietary behaviour improve when people are more intrinsically motivated to change their behaviour. To promote the shift towards more autonomous types of motivation, facilitator led CLIs have been developed including lifestyle coaching as key element. The present study examined the shift in types of motivation to increase PA and healthy dieting among participants of a primary care CLI, and the contribution of lifestyle coaching to potential changes in motivational quality. METHODS: This prospective cohort study included participants of 29 general practices in the Netherlands that implemented a CLI named 'BeweegKuur'. Questionnaires including items on demographics, lifestyle coaching and motivation were sent at baseline and after 4 months. Aspects of motivation were assessed with the Behavioural Regulation and Exercise Questionnaire (BREQ-2) and the Regulation of Eating Behaviour Questionnaire (REBS). We performed a drop out analysis to identify selective drop-out. Changes in motivation were analysed with t-tests and effect size interpretations (Cohen's d), and multivariate regression analysis was used to identify predictors of motivational change. RESULTS: For physical activity, changes in motivational regulation were fully in line with the tenets of Self Determination Theory and Motivational Interviewing: participants made a shift towards a more autonomous type of motivation (i.e. controlled types of motivation decreased and autonomous types increased). Moreover, an autonomy supportive coaching style was generally found to predict a larger shift in autonomous types of motivation. For healthy dietary behaviour, however, except for a small decrease in external motivation, no favourable changes in different types of motivation were observed. The relation between coaching and motivation appeared to be influenced by the presence of physical activity guidance in the programme. CONCLUSIONS: Motivation of participants of a real life primary care CLI had changed towards a more autonomous motivation after 4 months of intervention. Autonomy-supportive lifestyle coaching contributed to this change with respect to physical activity. Lifestyle coaching for healthy diet requires thorough knowledge about the problem of unhealthy dieting and solid coaching skills. PMID- 25027849 TI - Amelioration of lipid profile and level of antioxidant activities by epigallocatechin-gallate in a rat model of atherogenesis. AB - AIM: Improperly balanced, highly processed diets rich in calories, carbohydrates and fat are considered to contribute to oxidative stress induced hypercholesterolaemic atherosclerosis. The aim of our study was to test whether the antioxidant component epigallocatechin gallate (EGCG) may ameliorate the atherosclerotic effect of high fat diet in rats. METHODS: A disease model for atherosclerosis was designed by formulating atherogenic diet and fed to Wistar rats for 30 days. The treatment trial was made by administration of EGCG (100 mg/kg) for six or 12 days. The lipid profile, antioxidant status and tissue morphometric analysis were performed. RESULTS: A significant increase in serum levels of total cholesterol, triglycerides and lipoprotein cholesterol fractions and cardiac risk ratio were observed in atherogenic diet fed rats than that of normal diet-fed rats. EGCG treated atherogenic diet fed rats resulted a reduction in total cholesterol, triglycerides, low-density and very low-density lipoprotein cholesterol fractions, and an increase in high-density lipoprotein cholesterol compared to untreated-atherogenic diet fed rats. A significant decrease in lipid peroxidation, increased mean levels of non-enzymatic antioxidants and enzymatic antioxidants was measured in EGCG administered rats, compared with those in untreated-disease model. CONCLUSION: Morphometric analysis and the activity of cardiac marker enzymes demonstrated that EGCG was effective in limiting atherogenic tissue damage in aortic layers, and ameliorated the lipid profile. This preliminary study suggests EGCG may be useful as a novel therapeutic component for treating atherosclerosis and thus warrants further detailed investigation. PMID- 25027851 TI - One or three species in Megadenia (Brassicaceae): insight from molecular studies. AB - Megadenia Maxim. is a small genus of the Brassicaceae endemic to East Asia with three disjunct areas of distribution: the eastern edge of the Qinghai-Tibetan Plateau, the Eastern Sayan Mountains in southern Siberia, and Chandalaz Ridge in the southern Sikhote-Alin Mountains. Although distinct species (M. pygmaea Maxim., M. bardunovii Popov, and M. speluncarum Vorob., Vorosch. and Gorovoj) have been described from each area, they have lately been reduced to synonymy with M. pygmaea due to high morphological similarity. Here, we present the first molecular study of Megadenia. Using the sequences of 11 noncoding regions from the cytoplasmic (chloroplast and mitochondrial) and nuclear genomes, we assessed divergence within the genus and explored the relationships between Megadenia and Biscutella L. Although M. bardunovii, M. speluncarum, and M. pygmaea were found to be indiscernible with regard to the nuclear and mitochondrial markers studied, our data on the plastid genome revealed their distinctness and a clear subdivision of the genus into three lineages matching the three described species. All of the phylogenetic analyses of the chloroplast DNA sequences provide strong support for the inclusion of Megadenia and Biscutella in the tribe Biscutelleae. A dating analysis shows that the genus Megadenia is of Miocene origin and diversification within the genus, which has led to the three extant lineages, most likely occurred during the Early-Middle Pleistocene, in agreement with the vicariance pattern. Given the present-day distribution, differences in habitat preferences and in some anatomical traits, and lack of a direct genealogical relationship, M. pygmaea, M. bardunovii, and M. speluncarum should be treated as distinct species or at least subspecies. PMID- 25027850 TI - Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome. AB - Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post translational modifications, and HSF2 steers the formation of atypical alcohol specific HSF1-HSF2 heterocomplexes. This perturbs the in vivo binding of HSF2 to heat shock elements (HSEs) in genes that control neuronal migration in normal conditions, such as p35 or the MAPs (microtubule-associated proteins, such as Dclk1 and Dcx), and alters their expression. In the absence of HSF2, migration defects as well as alterations in gene expression are reduced. Thus, HSF2, as a sensor for alcohol stress in the fetal brain, acts as a mediator of the neuronal migration defects associated with FASD. PMID- 25027853 TI - Biliary dysplasia in primary sclerosing cholangitis harbors cytogenetic abnormalities similar to cholangiocarcinoma. AB - Grading criteria for biliary dysplasia associated with primary sclerosing cholangitis (PSC) have been recently described. Although a dysplasia to cholangiocarcinoma (CCA) sequence is implied, supportive data are lacking. Seventeen liver explants with biliary dysplasia from patients with PSC were selected. Formalin-fixed, paraffin-embedded blocks from each patient were evaluated to identify areas of normal/reactive biliary epithelium, intestinal metaplasia, low-grade dysplasia, high-grade dysplasia, and CCA. Areas of interest were assessed for chromosomal alteration with fluorescence in situ hybridization using probes directed to locus 9p21 and centromeres 3, 7, and 17. The cutoffs for calling probe copy number abnormalities for polysomy, single locus gain, and homozygous 9p21 loss were established by receiver operating characteristic curve analysis. Of 4 areas of intestinal metaplasia, 19 low-grade dysplasias, 19 high grade dysplasias, and 5 CCAs, 0%, 11%, 58%, and 40% displayed polysomy and 0%, 0%, 16%, and 40% exhibited homozygous 9p21 loss as the most severe abnormality, respectively. Patients with prior or current CCA were more likely to display polysomy in dysplasia than patients without CCA (70% versus 14%; P = .05); however, high-grade dysplasia was proportionally more common in the CCA associated dysplasia group. Polysomy and homozygous 9p21 loss are detected in biliary dysplasia and CCA. These findings support a dysplasia-carcinoma sequence in PSC patients and suggest that fluorescence in situ hybridization analysis could help refine the grading of biliary dysplasia in these patients. PMID- 25027852 TI - Identification of platelet function defects by multi-parameter assessment of thrombus formation. AB - Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC 2)>GPIb>alpha6beta1, alphaIIbbeta3>alpha2beta1>CD36, alpha5beta1, alphavbeta3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency. PMID- 25027854 TI - Genome-wide analysis of DNA methylation patterns in horse. AB - BACKGROUND: DNA methylation is an epigenetic regulatory mechanism that plays an essential role in mediating biological processes and determining phenotypic plasticity in organisms. Although the horse reference genome and whole transcriptome data are publically available the global DNA methylation data are yet to be known. RESULTS: We report the first genome-wide DNA methylation characteristics data from skeletal muscle, heart, lung, and cerebrum tissues of thoroughbred (TH) and Jeju (JH) horses, an indigenous Korea breed, respectively by methyl-DNA immunoprecipitation sequencing. The analysis of the DNA methylation patterns indicated that the average methylation density was the lowest in the promoter region, while the density in the coding DNA sequence region was the highest. Among repeat elements, a relatively high density of methylation was observed in long interspersed nuclear elements compared to short interspersed nuclear elements or long terminal repeat elements. We also successfully identified differential methylated regions through a comparative analysis of corresponding tissues from TH and JH, indicating that the gene body regions showed a high methylation density. CONCLUSIONS: We provide report the first DNA methylation landscape and differentially methylated genomic regions (DMRs) of thoroughbred and Jeju horses, providing comprehensive DMRs maps of the DNA methylome. These data are invaluable resource to better understanding of epigenetics in the horse providing information for the further biological function analyses. PMID- 25027855 TI - First report of in vitro selection of RNA aptamers targeted to recombinant Loxosceles laeta spider toxins. AB - BACKGROUND: Loxoscelism is the envenomation caused by the bite of Loxosceles spp. spiders. It entails severe necrotizing skin lesions, sometimes accompanied by systemic reactions and even death. There are no diagnostic means and treatment is mostly palliative. The main toxin, found in several isoforms in the venom, is sphingomyelinase D (SMD), a phospholipase that has been used to generate antibodies intended for medical applications. Nucleic acid aptamers are a promising alternative to antibodies. Aptamers may be isolated from a combinatorial mixture of oligonucleotides by iterative selection of those that bind to the target. In this work, two Loxosceles laeta SMD isoforms, Ll1 and Ll2, were produced in bacteria and used as targets with the aim of identifying RNA aptamers that inhibit sphingomyelinase activity. RESULTS: Six RNA aptamers capable of eliciting partial but statistically significant inhibitions of the sphingomyelinase activity of recombinant SMD-Ll1 and SMD-Ll2 were obtained: four aptamers exert ~17% inhibition of SMD-Ll1, while two aptamers result in ~25% inhibition of SMD-Ll2 and ~18% cross inhibition of SMD-Ll1. CONCLUSIONS: This work is the first attempt to obtain aptamers with therapeutic and diagnostic potential for loxoscelism and provides an initial platform to undertake the development of novel anti Loxosceles venom agents. PMID- 25027856 TI - Late-onset subcutaneous scalp calcifications in a patient with pseudo pseudohypoparathyroidism. AB - Ectopic calcifications and even bone formation have been linked to GNAS gene mutations. A 51-year-old Caucasian female had been diagnosed of pseudo pseudohypoparathyroidism (PPHP) in 1989. She has always had normal serum parathyroid hormone, calcium, and phosphorus levels. A non-contrast computed tomography of the head was done in 2013 and it showed finely speckled subcutaneous calcifications in the high convexity of the head. Cutaneous exploration did not show any abnormality. We herein report an unusual case of late-onset scalp calcifications in a patient with PPHP. PMID- 25027857 TI - Xanthogranulomatous inflammation of the perimetrium with infiltration into the uterine myometrium in a postmenopausal woman: a case report. AB - BACKGROUND: Xanthogranulomatous inflammation is an uncommon form of chronic inflammation that is destructive to the normal tissue of affected organs. Although xanthogranulomatous endometritis and xanthogranulomatous salpingitis of the female genital tract has been described previously, to the best of our knowledge, this is the first report of xanthogranulomatous inflammation with infiltration into the uterine myometrium from the perimetrium without endometritis. CASE PRESENTATION: A 68-year-old Japanese woman with intermittent lower abdominal pain and low-grade fever who was initially treated with antibiotics underwent hysterectomy due to abscess formation in the posterior wall of the myometrium and perimetrium (the outer serosal layer of the uterus). Histopathological findings revealed that the abscess was caused by xanthogranulomatous inflammation with the granulation tissue and chronic inflammatory cells that consisted of focal and sheets of foam cells. The inflammation destroyed the perimetrial elastic lamina, and the myometrium was deeply infiltrated by the xanthoma cells. Neither endometritis nor salpingitis was coexistent with the xanthogranulomatous inflammation. CONCLUSION: The patient was diagnosed as xanthogranulomatous inflammation, most likely arising from the perimetrium. Our findings suggest that the perimetrium, as well as the endometrium and adnexae, is one of the origins of xanthogranulomatous inflammation in female genital tract. PMID- 25027858 TI - Considering the human implications of new and emerging technologies in the area of human security. PMID- 25027859 TI - Responsibility for crashes of autonomous vehicles: an ethical analysis. AB - A number of companies including Google and BMW are currently working on the development of autonomous cars. But if fully autonomous cars are going to drive on our roads, it must be decided who is to be held responsible in case of accidents. This involves not only legal questions, but also moral ones. The first question discussed is whether we should try to design the tort liability for car manufacturers in a way that will help along the development and improvement of autonomous vehicles. In particular, Patrick Lin's concern that any security gain derived from the introduction of autonomous cars would constitute a trade-off in human lives will be addressed. The second question is whether it would be morally permissible to impose liability on the user based on a duty to pay attention to the road and traffic and to intervene when necessary to avoid accidents. Doubts about the moral legitimacy of such a scheme are based on the notion that it is a form of defamation if a person is held to blame for causing the death of another by his inattention if he never had a real chance to intervene. Therefore, the legitimacy of such an approach would depend on the user having an actual chance to do so. The last option discussed in this paper is a system in which a person using an autonomous vehicle has no duty (and possibly no way) of interfering, but is still held (financially, not criminally) responsible for possible accidents. Two ways of doing so are discussed, but only one is judged morally feasible. PMID- 25027861 TI - Liquid crystalline assembly of rod-coil diblock copolymer and homopolymer blends by dissipative particle dynamics simulation. AB - Liquid crystalline assembly of rod-coil diblock copolymers blended with coil or rod homopolymers is investigated by dissipative particle dynamics simulation, considering systematically the effect of the interactions between rods and coils, the volume fraction and length of the added coil or rod homopolymers. The addition of coil or rod homopolymers induces disorder-order or order-liquid crystalline transition. In rod-coil/coil blends, the solubilization of homopolymers will saturate at a certain amount of homopolymers and then the excess homopolymers will be segregated into the central regions of coil block domains, forming "wet-dry mixture" lamellae. The solubility capacity decreases with increasing homopolymer length, determined by the competition between the mixing entropy and the elastic entropy. In rod-coil/rod blends, due to the orientational interactions between rods, the length matched rod homopolymers directly interdigitate with rod blocks with less entropy loss, thus prompting the formation of a bilayer liquid crystalline phase. The rod domain spacing Dr remains unchanged and conversely the coil domain spacing Dc becomes thin, to occupy more interfacial area. With the addition of shorter rod homopolymers, the overall lamellar spacing D of blends monotonically increases with the volume fraction of homopolymers, similar to the case of rod-coil/coil blends. Generally, rod homopolymers have a more significant impact on the liquid crystalline assembly of the blends, compared with the coil homopolymers. Our results indicate that blending with coil or rod homopolymers into a rod-coil system is an effective method to induce liquid crystal phase transition and control the phase spacing of the ordered structure. PMID- 25027860 TI - The 'Magic Light': A Discussion on Laser Ethics. AB - Innovations in technology and science form novel fields that, although beneficial, introduce new bio-ethical issues. In their short history, lasers have greatly influenced our everyday lives, especially in medicine. This paper focuses particularly on medical and para-medical laser ethics and their origins, and presents the complex relationships within laser ethics through a three dimensional matrix model. The term 'laser' and the myth of the 'magic light' can be identified as landmarks for laser related ethical issues. These ethical issues are divided into five major groups: (1) media, marketing, and advertising; (2) economic outcomes; (3) user training; (4) the user-patient/client relationship; and (5) other issues. In addition, issues arising from two of the most common applications of lasers, laser eye surgery and laser tattoo removal, are discussed. The aim of this paper is to demonstrate that the use of medical and para-medical lasers has so greatly influenced our lives that the scientific community must initiate an earnest discussion of medical laser ethics. PMID- 25027862 TI - Population-based analysis of treatment modalities and survival for clinically localized small-cell carcinoma of the prostate. AB - BACKGROUND: Small-cell carcinoma of the prostate is an aggressive cancer whose rarity has prevented the development of a consensus management approach. The objective of the current study was to determine the treatment patterns and evaluate factors affecting overall survival for patients with localized small cell carcinoma of the prostate. METHODS: After querying the National Cancer Database, we identified all patients diagnosed with localized small-cell carcinoma of the prostate between 1998 and 2011 (n=287). Using Kaplan-Meier curves and Cox regression analyses, we assessed the effect of treatment and clinical stage on overall survival. RESULTS: Treatments included radiation therapy in 46% (n=131), chemotherapy in 38% (n=107), androgen deprivation therapy (ADT) in 22% (n=63) and radical prostatectomy in 13% (n=38). Median overall survival was 14.8 months. Upon multivariate analysis, local therapy (radical prostatectomy or radiation therapy) was associated with improved survival (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.14-0.38, P<0.001). Advanced clinical stage predicted worse survival among all men (cT3: HR 2.83, 95% CI 1.27 6.32, P=0.011; cT4: HR 3.26, 95% CI 1.50-7.07, P=0.003) and men who received local therapy (cT3: HR 4.67, 95% CI 1.41-15.44, P=0.012; cT4: HR 4.01, 95% CI 1.14-14.08, P=0.03) but not among men who received no local therapy (cT3: HR 1.64, 95% CI 0.51-5.27, P=0.4; cT4: HR 2.35, 95% CI 0.74-7.48, P=0.15). Age, receipt of chemotherapy and ADT, and clinical stage T2 disease (compared with T1) did not predict survival. CONCLUSION: Men with localized small-cell carcinoma of the prostate have a poor overall survival. Local therapy may represent a suitable and underused modality for select patients. PMID- 25027863 TI - Impact of NADiA ProsVue PSA slope on secondary treatment decisions after radical prostatectomy. AB - BACKGROUND: Selecting appropriate candidates for postprostatectomy radiotherapy is challenging, because adverse pathological features cannot accurately predict clinical recurrence. Biomarkers that identify residual disease activity may assist clinicians when counseling patients on the risks, benefits and costs of secondary treatment. NADiA ProsVue PSA slope results <=2.0 pg ml(-1) month(-1) are predictive of a reduced risk of clinical recurrence; however, its clinical utility has not yet been studied. METHODS: We prospectively enrolled men treated by radical prostatectomy in a multicenter, institutional review board-approved clinical trial. At postsurgical follow-up, investigators (N=17) stratified men into low-, intermediate- or high-risk groups for prostate cancer recurrence based on clinicopathological findings and other factors. Investigators documented their initial treatment plan for each subject and serially collected three serum samples for ProsVue testing. After the ProsVue result was reported, investigators recorded whether or not the initial treatment plan was changed. The proportion of cases referred for secondary treatment before and after ProsVue was reported, and the significance of the difference determined. RESULTS: Complete assessments were reported for 225 men, 128 (56.9%) of whom were stratified into intermediate- and high-risk groups. Investigators reported that they would have referred 41/128 (32.0%) at-risk men for secondary treatment. However, after results were known, they referred only 15/128 (11.7%) men. The difference in proportions (-20.3%, 95% confidence interval (CI) -29.9 to -10.3%) is significant (P<0.0001). Odds of a referral was significantly reduced after results were reported (odds ratio 0.28, 95% CI 0.15-0.54, P<0.0001). CONCLUSIONS: Knowledge of a ProsVue result had significant impact on the final treatment plan. A ProsVue result ?2.0 pg ml(-1) month(-1) significantly reduced the proportion of men at risk of recurrence who otherwise would have been referred for secondary treatment. PMID- 25027864 TI - Pineal region masses--imaging findings and surgical approaches. AB - The anatomy of the pineal region is complex. Despite advances in surgical techniques since the first reported successful pineal region surgery in the early 20th century, pineal region surgery remains challenging owing to the proximity of deep cerebral veins and dorsal midbrain structures critical for vision. In this article, we review the relevant surgical anatomy of the pineal region and discuss historically important and current surgical approaches. We describe specific imaging features of pineal region masses that may affect surgical planning and review neoplastic and nonneoplastic masses that occur in the pineal region. PMID- 25027865 TI - In vivo studies: comparing the administration via and the impact on the biodistribution of radiopharmaceuticals. AB - The use of in vivo assay to determine the biodistribution and subsequent inter comparison with human parameters has been used since the dawn of science. The use of this type of test admits the metabolic equity among animals for inter comparison. Thus, the use of Wistar rats in particular is quite frequent. Regarding routes of administration, there are three ways to test priority: jugular vein, intraocular (eye plexus) and caudal; there is a consensus that these three pathways behave in the same way, or at least very similar. Biodistribution studies of drugs, especially radiopharmaceuticals, have been using randomly any of these pathways believed to be effective in their likeness without worrying about your real analytic equity. In this study, we performed in vivo assay in 8 Wistar rats using 99mTc -labeled Herceptin to review the route of administration on the biodistribution result. Thus, four mice were injected via the intraocular (eye plexus), and four were injected via tail (caudal plexus). The results were quite disparate and call the attention of the scientific community to reassess the protocols for animal experiments, in order to have uniformity and fairness between the data and may represent a test for human inter comparison of more reliable and trustworthy way. PMID- 25027866 TI - The PEGylated liposomal doxorubicin improves the delivery and therapeutic efficiency of 188Re-Liposome by modulating phagocytosis in C26 murine colon carcinoma tumor model. AB - Liposome in delivering radionuclide for cancer therapy has been expansively studied; however, liposome itself can be deliberately entrapped and destroyed by the reticuloendothelial system, causing an insufficiency of the drug delivery, which in turn would restrict the effectiveness of the drug. In this study, mice with subcutaneous implantation of C26 murine colon cancer received an experimental treatment regimen in which mice took delivery of PEGylated liposomal doxorubicin (LipoDox) first, after a three-day interval, of Rhenium-188 encapsulated into PEGylated liposome ((188)Re-Liposome) subsequently and by which suppressed the functioning of reticuloendothelial system for the short term. The data showed that based upon the biodistribution assay and the evaluation of the therapeutic efficacy, (188)Re-Liposome was more sufficiently delivered to tumor sites in mice with this treatment regimen than mice without the regimen, and that cancer mortalities in mice with the treatment regimen were much lower than the mortalities in mice without the regimen. Taken together, a new strategy proposed in this study significantly improved both the (188)Re-Liposome delivery and the effectiveness of (188)Re-Liposome, suggesting that the strategy can be an ideal treatment for cancer. PMID- 25027867 TI - In vitro evidence that the pastoral Artemisia campestris species exerts an anthelmintic effect on Haemonchus contortus from sheep. AB - Occurrence of anthelmintic resistant strains of helminths is increasing. The aim of this study was to evaluate the in vitro anthelmintic activity of Artemisia campestris in comparison to albendazole against Haemonchus contortus of sheep. In this respect, in vitro anthelmintic activities of crude aqueous and crude ethanolic extracts of aerial parts of A. campestris were investigated on eggs and adults of Haemonchus contortus. Chemical analyses revealed that overall profile of both extracts samples were dominated by flavonoids among them quercetin and apigenin derivatives were the most abundant phenolics constituents. Both extract types completely inhibited egg hatching at a concentration close to 2 mg/ml. Lethal concentration 50% of A. campestris ethanolic and aqueous extracts were 0.83 and 1.00 mg/ml respectively (p < 0.05). The ethanolic extract showed better in vitro activity against adult parasites than the aqueous extract in terms of the paralysis and/or death of the worms at different hours post-treatment. Dose dependent activity was also observed for both extract. After 8 and 24 h of exposure, the ethanolic extract induced 91.3 and 100% mortality at the highest tested concentration respectively, while the aqueous extract induced 3.22 and 70.96% at the same concentration respectively.To our knowledge, these results depict for the first time that A. campestris possesses in vitro anti-Haemonchus contortus properties. PMID- 25027869 TI - Circulating immune mediators are closely linked in adult-onset type 1 diabetes as well as in non-diabetic subjects. AB - Relationships between circulating immune mediators (cytokines, chemokines and growth factors) and a beta cell destructive autoimmune process in adult-onset type 1 diabetes are poorly elucidated. We measured serum levels of immune mediators in type 1 diabetic patients in the context of ongoing deterioration of endogenous insulin secretion. Levels of 27 immune mediators were measured in 34 GADA (glutamic acid decarboxylase antibodies) positive type 1 diabetic patients, aged 27.4 +/- 1.2 years at a mean of 7 weeks after diagnosis (designated 0 month) and 6 months later. Endogenous insulin secretion was assessed by C-peptide glucagon stimulation tests during 12 months. Additional data (for baseline analysis) was obtained in 9 GADA positive type 1 diabetic subjects and in 43 non diabetic age- and sex-matched subjects. In general, the levels of immune mediators displayed large inter- but small intra-individual differences with only minor changes observed between measurements at 0 month and at 6 months. Levels of the majority of immune mediators were strongly and positively correlated to each other not only in the diabetic, but also in the non-diabetic subjects. Body weight (BMI) was positively associated with levels of IL-1 ra, IL-2, IL-4, IL-6, IL-17, Basic FGF, GCSF, IFN gamma and MIP-1 alpha. Adjustment for BMI removed most associations to C-peptide. When adjusted for BMI, levels at 0 month for Basic FGF and MIP-1 alpha were inversely associated with the percentage decline in stimulated C-peptide from 0 to 12 months (nominally p < 0.05). We conclude that associations between different immune mediators are strikingly but not exclusively tied in autoimmune diabetes. BMI is a major confounder in the analysis of associations to autoimmunity. Associations of beta cell decline to individual immune mediators need confirmation in further studies. PMID- 25027870 TI - 'Stepping in' or 'stepping back': how first year nursing students begin to learn about person-centred care. AB - BACKGROUND: The concept of person-centred care has gained international recognition over the last decade and forms one of the key concepts of our Nursing Quality Improvement Curricular Framework. OBJECTIVES: This study aimed to investigate nursing students' learning about person-centred care during the first year of their programme. METHODS: Qualitative thematic analysis of a section of placement learning documents from two consecutive cohorts of students from all fields of nursing (n=405), supplemented by three focus group discussions. RESULTS: Two conceptual categories of student approaches to learning emerged. Firstly, 'stepping back', or learning from a distance about how nurses provide care, often through reading case notes and care plans; second, 'stepping in', learning about the patient as a person by direct interaction with service users. Evidence of reflection on the patient's experience of care was limited. These results have resonance with existing pedagogical theories around preferences for active or passive styles of learning. The potential for clinical mentors to build student confidence and encourage direct engagement with patients was highlighted. CONCLUSIONS: Students are aware of the concepts, principles and professional values of person-centred care from early in their programme; however, the majority tend to be preoccupied by learning about what nurses 'do', rather than 'how patients experience care'. Development towards a more person-centred approach may require targeted support from mentors to help students gain confidence and begin reflecting on how patients experience care. PMID- 25027871 TI - The evidence-based practice profiles of academic and clinical staff involved in pre-registration nursing students' education: a cross sectional survey of US and UK staff. AB - BACKGROUND: Competency in evidence-based practice (EBP) is a requirement for graduate nurses. Despite a growing body of research exploring the EBP profiles of students, little research has explored the EBP profiles of nurse educators. OBJECTIVES: To explore: the differences/similarities in the EBP profiles of US and UK clinical and academic faculty; the barriers nurse educators experience when teaching EBP; the impact of postgraduate education on EBP profile and; what nurse educators perceive "success" in implementing and teaching EBP to be. DESIGN: A cross-sectional online survey design was employed. SETTINGS: Two Universities delivering undergraduate nursing education in the US and UK, in partnership with large hospital systems, small community hospitals, community settings, and independent sector health organisations. PARTICIPANTS: Eighty-one nurse educators working in academic and clinical contexts in the US and UK (US academic=12, US clinical=17, UK academic=9, UK clinical=43) were recruited opportunistically. METHODS: Participants were emailed a weblink to an online survey, comprising demographic questions, the Evidence-Based Practice Questionnaire and open-ended questions about EBP barriers, facilitators and successes. RESULTS: Quantitative results indicated that academic faculty scored significantly higher on knowledge and skills of EBP, than clinical faculty, but revealed no other significant differences on EBP use or attitudes, or between US and UK professionals. Participants with postgraduate training scored significantly higher on EBP knowledge/skills, but not EBP attitudes or use. Qualitative findings identified key themes relating to EBP barriers and facilitators, including: Evidence-, organisational-, and teaching-related issues. Perceptions of successes in EBP were also described. CONCLUSIONS: Nurse educators working in the UK and US face similar EBP barriers to teaching and implementation, but view it positively and use it frequently. Clinical staff may require extra support to maintain their EBP knowledge and skills in comparison to staff working in academic contexts. PMID- 25027872 TI - Atrial natriuretic peptide locally counteracts the deleterious effects of cardiomyocyte mineralocorticoid receptor activation. AB - BACKGROUND: The endocrine balance between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone system is critical for the maintenance of arterial blood pressure and volume homeostasis. This study investigated whether a cardiac imbalance between ANP and aldosterone, toward increased mineralocorticoid receptor (MR) signaling, contributes to adverse left ventricular remodeling in response to pressure overload. METHODS AND RESULTS: We used the MR-selective antagonist eplerenone to test the role of MRs in mediating pressure overload induced dilatative cardiomyopathy of mice with abolished local, cardiac ANP activity. In response to 21 days of transverse aortic constriction, mice with cardiomyocyte-restricted inactivation (knockout) of the ANP receptor (guanylyl cyclase [GC]-A) or the downstream cGMP-dependent protein kinase I developed enhanced left ventricular hypertrophy and fibrosis together with contractile dysfunction. Treatment with eplerenone (100 mg/kg/d) attenuated left ventricular hypertrophy and fully prevented fibrosis, dilatation, and failure. Transverse aortic constriction induced the cardiac expression of profibrotic connective tissue growth factor and attenuated the expression of SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) in knockout mice, but not in controls. These genotype dependent molecular changes were similarly prevented by eplerenone. ANP attenuated the aldosterone-induced nuclear translocation of MRs via GC-A/cGMP dependent protein kinase I in transfected HEK 293 (human embryonic kidney) cells. Coimmunoprecipitation and fluorescence resonance energy transfer experiments demonstrated that a population of MRs were membrane associated in close interaction with GC-A and cGMP-dependent protein kinase I and, moreover, that aldosterone caused a conformational change of this membrane MR/GC-A protein complex which was prevented by ANP. CONCLUSIONS: ANP counter-regulates cardiac MR activation in hypertensive heart disease. An imbalance in cardiac ANP/GC-A (inhibition) and aldosterone/MR signaling (augmentation) favors adverse cardiac remodeling in chronic pressure overload. PMID- 25027875 TI - The next phase in safe staffing battle is crucial. PMID- 25027874 TI - Bridge-to-decision therapy with a continuous-flow external ventricular assist device in refractory cardiogenic shock of various causes. AB - BACKGROUND: Mortality for refractory cardiogenic shock remains high. In this patient cohort, there have been mixed results in mechanical circulatory support device use as a bridge-to-decision therapy. We evaluated a continuous-flow external ventricular assist device (VAD), CentriMag VAD (Thoratec Corp., Pleasanton, CA), in patients with various causes of refractory cardiogenic shock. METHODS AND RESULTS: This is a retrospective review of adult patients who underwent surgical CentriMag VAD insertion as bridge-to-decision therapy. From January 2007 through June 2012, 143 patients received CentriMag VAD. The cause of refractory cardiogenic shock was failure of medical management in 71 patients, postcardiotomy shock in 37, graft failure post-heart transplantation in 22, and right ventricular failure post-implantable left VAD in 13. Mean age was 52+/-16 years, and 71% were in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 1. Among 158 device runs, device configuration was BiVAD in 67%, isolated right VAD in 26%, and isolated left VAD in 8%. Median duration of support was 14 days (interquartile range, 8-26). Survival was 69% at 30 days and 49% at 1 year. The next destination after the CentriMag VAD was myocardial recovery in 30%, device exchange to an implantable VAD in 15%, and heart transplantation in 18%. The failure of medical management and the graft failure post-heart transplantation groups had higher 30-day survival compared with the postcardiotomy shock group. Major bleeding events occurred in 33% and cerebrovascular accidents in 14%. There was no CentriMag pump failure or thrombosis. CONCLUSIONS: Bridge-to-decision therapy with CentriMag VAD is feasible in a variety of refractory cardiogenic shock settings. Patients with postcardiotomy shock have inferior survival. PMID- 25027873 TI - Heart failure with anemia: novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes. AB - BACKGROUND: Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia. METHODS AND RESULTS: In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia-HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF. CONCLUSIONS: Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00834691. PMID- 25027877 TI - NICE calls for use of 'red flags' to trigger immediate review of care. PMID- 25027882 TI - New end of life guidance could lead to conflict with patients' interests. PMID- 25027887 TI - Nurses could be more vulnerable if DH plans on restraint go through. PMID- 25027889 TI - Introduction of standards of care will make safe staffing levels law. PMID- 25027893 TI - Identifying the nutritional needs of dementia patients is essential. PMID- 25027899 TI - Type 2 diabetes. PMID- 25027900 TI - Keeping infection control in hand. AB - Despite huge progress in recent years, rates of healthcare-associated infections in the NHS remain 'unacceptable and avoidable', according to NICE. Its new quality standard addresses priority areas such as hand hygiene, antibiotics and catheters. In this article, front line nurses discuss attempts at infection prevention and control. PMID- 25027901 TI - Don't cross the line from professional to personal. AB - The draft code requires nurses and midwives to maintain clear professional boundaries with patients and their families, avoiding personal, emotional and sexual relationships. Maintaining these boundaries can be complex, but it helps to share difficult experiences with colleagues, reflecting on where the boundaries should sit. PMID- 25027902 TI - Curtains hide risks to health and hygiene. AB - Curtains around hospital beds can harbour pathogens that pose an infection risk to patients and staff. A recent study by researchers at a Nottingham hospital identified curtains as a potential source of an outbreak of group A streptococcus (GAS) infection. Good hand hygiene is crucial to reduce the risks of contamination. PMID- 25027916 TI - Climate change may be debatable, but promoting sustainability is not. PMID- 25027917 TI - Stakeholder meeting will discuss concerns on sharing patient data. PMID- 25027918 TI - Is work being done to compare mentoring across NHS trusts? PMID- 25027919 TI - There is no such thing as a UK or British National Health Service. PMID- 25027922 TI - Safe moving and handling of patients: an interprofessional approach. AB - A gap in the medical undergraduate curriculum on safe moving and handling of patients was identified, and a project to enhance moving and handling education for undergraduates in various healthcare disciplines was undertaken. A team of nurses, doctors, physiotherapists and e-learning professionals developed a cross discipline e-learning resource, piloted with medical and nursing students at Queen's University Belfast. One outcome of the project was the development of a deeper recognition of the common curriculum across healthcare disciplines. PMID- 25027923 TI - Alcohol-related liver disease. AB - Alcohol is one of the three leading causes of liver disease in the developed world. Patients with alcohol-related liver disease are often cared for in general wards and hospitals, rather than specialist centres. This may be a result of the number of patients being admitted or a lack of referral to specialist services by healthcare professionals. The financial cost of caring for patients with alcohol related injuries is continuing to rise. This article explores the mechanisms of liver injury caused by alcohol; the risk factors associated with alcohol-related liver disease; assessment tools used to identify patients with alcohol use disorders; withdrawal from alcohol; chronic liver disease; and issues surrounding transplantation. The importance of the nursing role in assessing and monitoring patients undergoing withdrawal from alcohol, information giving and advice on the prevention of alcohol-related liver injury, and supporting patients with alcohol related liver injury is highlighted. PMID- 25027924 TI - Topical treatments. PMID- 25027925 TI - Remedial action in the management of wound-related pain. AB - Wound-related pain, particularly following wound care interventions, is a concern to all involved in wound management. However, little is understood about how remedial action to manage such pain can affect healthcare provision, particularly in terms of resources. This article describes a Delphi study - a process of gaining expert consensus in a particular area - identifying the main factors influenced by the presence of pain at wound dressing change. It was found that the presence of pain influences the choice and frequency of analgesia, use of anxiolytic medications, frequency of dressing change and the environment in which care is provided. These results can help clinicians to understand the close relationship that exists between pain and clinical intervention, and the implications for resource management. PMID- 25027926 TI - Wound care considerations in neonates. AB - Wound care management is a complex issue when caring for the neonate. An understanding of the anatomy and physiology of neonatal skin is necessary to recognise and prevent any potential problems. Effective wound care is a dynamic process based on accurate assessment and the setting of realistic goals. Knowledge of the specific characteristics of neonatal skin and the wound healing process is required when determining appropriate treatment and selecting wound care products. PMID- 25027934 TI - Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-alpha induced nuclear factor-kappa B (NF-kappaB) activation. AB - The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22beta-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-kappaB and IKKbeta inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub micromolar activity against TNF-alpha induced activation of NF-kappaB and exhibited inhibition of IKKbeta in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 MUM. The Western blot analysis further showed that the suppression of NF kappaB activity by the lead analog 11 was due to the inhibition of IkappaBalpha degradation, a natural inhibitor of NF-kappaB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKbeta. PMID- 25027933 TI - Inhibition of prostaglandin E(2) production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation. AB - The discovery of potent inhibitors of prostaglandin E2 (PGE2) synthesis in recent years has been proven to be an important game changer in pharmaceutical industry. It is known that excessive production of PGE2 triggers a vast array of biological signals and physiological events that contributes to inflammatory diseases such as rheumatoid arthritis, atherosclerosis, cancer, and pain. In this Letter, we report the synthesis of a series of minor prenylated chalcones and flavonoids which was found to be significantly active in suppressing the PGE2 production secreted by lipopolysaccharide-induced mouse macrophage cells (RAW 264.7). Among the compounds tested, 14b showed a dose-response inhibition of PGE2 production with an IC50 value of 2.1 MUM. The suppression upon PGE2 secretion was not due to cell death since 14b did not reduce the cell viability in close proximity to the PGE2 inhibition concentration. The obtained atomic coordinates for the single crystal XRD of 14b was then applied in the docking simulation to determine the potential important binding interactions with murine COX-2 and mPGES-1 putative binding sites. PMID- 25027935 TI - Protolichesterinic acid derivatives: alpha-methylene-gamma-lactones as potent dual activators of PPARgamma and Nrf2 transcriptional factors. AB - PPARgamma and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of alpha,beta-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPARgamma and Nrf2 activation evaluation. Among them, two alpha-methylene-gamma-lactones were identified as potent dual activators of PPARgamma and Nrf2 in macrophages. PMID- 25027936 TI - Synthesis and evaluation of triazole linked glycosylated 18beta-glycyrrhetinic acid derivatives as anticancer agents. AB - A series of glycosyl triazol linked 18beta-glycyrrhetinic acid (GA) derivatives have been synthesized using 1,3-dipolar cycloaddition reaction of per-O acetylated glycosyl azide derivatives (4a-h) with propargyl ester of 18beta glycyrrhetinic acid (GA) (2 and 3) following the concept of 'Click chemistry'. The synthesized triazole derivatives were de-O-acetylated to furnish compounds (7a-h and 8a-c) with free hydroxyl groups in the carbohydrate moieties, which were evaluated for their anticancer potential against human cervical cancer cells (HeLa) and normal kidney epithelial (NKE) cells. GA (1), compound 7d, compound 7g and compound 8c showed promising anticancer activities. PMID- 25027937 TI - Design and synthesis of 3-isoxazolidone derivatives as new Chlamydia trachomatis inhibitors. AB - Chlamydia trachomatis (Ct) is a bacterial human pathogen responsible for the development of trachoma, the worldwide infection leading to blindness, and is also a major cause of sexually transmitted diseases. As iron is an essential metabolite for this bacterium, iron depletion presents a promising strategy to limit Ct proliferation. The aim of this study is to synthesize 3-isoxazolidone derivatives bearing known chelating moieties in an attempt to develop new bactericidal anti-Chlamydiaceae molecules. We have investigated the paths by which these new compounds affect Ct serovar L2 development in HeLa cells, in the presence or absence of exogenously added iron. The iron-chelating properties of these molecules were also determined. Our data reveal important bactericidal effects which are distinguishable from those due to iron chelation. PMID- 25027938 TI - Synthesis and receptor binding in trans-CD ring-fused A-CD estrogens: comparison with the cis-fused isomers. AB - Ligands which selectively activate only one of the estrogen receptors, ERalpha or ERbeta, are current pharmaceutical targets. Previously, we have reported on substituted cis A-CD ligands in which the B-ring of the steroidal structure has been removed and cis refers the stereochemistry of the CD ring junction as compared to trans in estradiol. These compounds often showed good potency and selectivity for ERbeta. Here we report the synthesis and binding affinities for a similar series of trans A-CD ligands, and compare them to the cis-series. Counterintuitively, trans A-CD ligands, which are structurally more closely related to the natural ligand estradiol, show weaker binding and less beta selectivity than their cis-counterparts. PMID- 25027939 TI - Design and synthesis of gamma-butyrolactone derivatives as potential spermicidal agents. AB - A series of gamma-butyrolactone derivatives has been designed and synthesized from commercially available 2-acetyl butyrolactone (3-acetyldihydrofuran-2(3H) one, 1) by aminoalkylating its active methylene followed by condensation with different aldehydes. Compounds having amino group were further converted to their respective tartrate salts and were evaluated for spermicidal activity against human sperm in vitro. Compounds showing appreciable spermicidal activity at ?0.5% [3c, 4d (0.5%); 2c, 3d (0.1%); 2d, 4c (0.05%)] were tested for safety studies against human cervical (HeLa) cell line. These compounds were found safer than, Nonoxynol-9. One of the two most active compounds was also found to be the safest (IC50=961 MUg/ml; 4c), while the second compound exhibited lower safety against HeLa (IC50=269 MUg/ml; 2d). The compound 4c significantly reduced the number of free thiols on human sperm. All the compounds were inactive against Trichomonas vaginalis. PMID- 25027940 TI - Identification of arylsulfonamides as ExoU inhibitors. AB - ExoU is a potent virulence factor of Pseudomonas aeruginosa and is considered a potential therapeutic target. In order to discover novel ExoU inhibitors, we screened an in-house chemical library utilizing a yeast-based screening system. Some sulfonamides displayed significant activity without nonspecific cytotoxicity. We describe a series of sulfonamides as novel ExoU inhibitors, along with a brief structure-activity relationship. PMID- 25027941 TI - Vertical-scar skin pattern with laterally-based dermal flaps for direct, implant breast reconstruction following risk-reducing skin-sparing mastectomy in macromastia. PMID- 25027942 TI - Acquired cutis laxa: diagnostic and therapeutic considerations. PMID- 25027943 TI - Avoiding and identifying errors and other threats to the credibility of health economic models. AB - Health economic models have become the primary vehicle for undertaking economic evaluation and are used in various healthcare jurisdictions across the world to inform decisions about the use of new and existing health technologies. Models are required because a single source of evidence, such as a randomised controlled trial, is rarely sufficient to provide all relevant information about the expected costs and health consequences of all competing decision alternatives. Whilst models are used to synthesise all relevant evidence, they also contain assumptions, abstractions and simplifications. By their very nature, all models are therefore 'wrong'. As such, the interpretation of estimates of the cost effectiveness of health technologies requires careful judgements about the degree of confidence that can be placed in the models from which they are drawn. The presence of a single error or inappropriate judgement within a model may lead to inappropriate decisions, an inefficient allocation of healthcare resources and ultimately suboptimal outcomes for patients. This paper sets out a taxonomy of threats to the credibility of health economic models. The taxonomy segregates threats to model credibility into three broad categories: (i) unequivocal errors, (ii) violations, and (iii) matters of judgement; and maps these across the main elements of the model development process. These three categories are defined according to the existence of criteria for judging correctness, the degree of force with which such criteria can be applied, and the means by which these credibility threats can be handled. A range of suggested processes and techniques for avoiding and identifying these threats is put forward with the intention of prospectively improving the credibility of models. PMID- 25027944 TI - Preferences for oral anticoagulants in atrial fibrillation: a best-best discrete choice experiment. AB - BACKGROUND: Atrial fibrillation (AF) is recognised as a growing clinical and public health problem in many countries, owing to disability and death from stroke associated with the condition, high hospitalisation costs and an increasing prevalence with ageing populations. Under-treatment with oral anticoagulants has been a significant challenge of treatment, historically related to patient concerns over the safety and convenience of warfarin, which until recently was the only oral anticoagulant available. OBJECTIVES: The aim of this study is to examine: (1) patient preferences for attributes of warfarin and the new oral anticoagulants (dabigatran, rivaroxaban, apixaban) in AF; (2) which attributes are most important; and (3) whether current under-treatment is likely to improve with the new oral anticoagulants. METHODS: This study was conducted in Melbourne, Australia, with members of the general public with or without AF aged >=40 years, where those without AF proxy for newly-diagnosed patients. Participants completed a computerised best-best discrete choice experiment (and follow-up interview) as if they had AF with a moderate-to-high risk of stroke. Choice data were modelled using mixed rank-ordered logit. Relative value was explored via estimation of marginal rates of substitution with predicted probability analysis used to simulate potential uptake of oral anticoagulants. RESULTS: Seventy-six participants were recruited and completed the study. Efficacy (stroke risk) was more important than safety (bleed risk, antidote), which were both considerably more important than convenience factors (blood tests, dose frequency, drug or food interactions). Cost was also important. Predicted use of the new oral anticoagulants (and under-treatment of AF) using simulation, given moderate-to-high risk of stroke, is 25 % (52 %), 54 % (29 %) and 70 % (21 %) assuming a market price of AUD$120/month, AUD$30/month (subsidised price) and AUD$30/month with an antidote, respectively. CONCLUSIONS: Based on the study sample and the modelled attributes, the overall profiles of the new oral anticoagulants were preferred to warfarin as their cost decreased. Public subsidisation and the development of antidotes (such as vitamin K for warfarin) for the new oral anticoagulants may have a positive effect on the under treatment of AF. PMID- 25027945 TI - Effects of sevoflurane and desflurane on otoacoustic emissions in humans. AB - Otoacoustic emissions (OAEs) are non-invasive, easy to apply and objective test methods which are widely used to determine the presence of hearing in audiology clinics. Under certain circumstances, the study should be applied under general anesthesia. The aim of this study was to determine the influence of new short acting inhalation agents, desflurane and sevoflurane, on OAE in humans. These short-acting agents are widely used in general anesthesia. Thirty-one healthy patients who underwent septoplasty and turbinoplasty surgery were included in this study. Unpremedicated patients were anesthetized and monitored by a standard protocol except the inhalation agents. Desflurane and sevoflurane were added to the inhaled gas mixture at ~1MAC, 5-6 % and 1.5-2 %, respectively. Transient evoked otoacoustic emissions and distortion product otoacoustic emissions measured in both ears of each patient preoperatively in the operating room before induction, 5 min after induction, after the completion of surgical procedure while the anesthetic agents are still given and 1 h after surgery in the ward. Between-group and within-group comparisons and correlations with hemodynamic parameters were performed for statistical analysis. The measurements of 26 ears in desflurane group and 28 ears in sevoflurane group were evaluated. There were no differences in initial measurements between groups (p > 0.05). Both groups presented significant decrease in intraoperative measurements and changes in time were statistically significant (p < 0.05). The changes in OAEs were similar to changes in systemic blood pressures. Correlation between OAEs and systemic blood pressures were significant (p < 0.05). In conclusion, sevoflurane and desflurane decreased OAEs around 2-3 dB; OAEs are still measurable under inhalation agents. This provides some findings about the OAE status of patient, but the evaluations should be done with the impact of anesthetic agents in mind. PMID- 25027946 TI - Establishment and characterization of an experimental mouse model of allergic rhinitis. AB - Allergic rhinitis (AR) is a common worldwide disease. Animal studies on AR were adopted in various investigations. However, animal studies simply aimed at establishing an animal model for AR have been seldom seen. The purpose of this study was to introduce an easy-to-establish experimental mouse model of AR. To develop a mouse model of AR, 38 Balb/c mice were randomly assigned to two groups. Mice in the study group were sensitized by intraperitoneal (IP) injection of ovalbumin (OVA) on day 1 and 6, followed by continuous inhalation (IH) of OVA solution for 1 week (day 8-14) using a newly designed inhalation box. The control group mice received sensitization of IP normal saline and IH sterilized distilled water instead of OVA. Before and after sensitization, the frequencies of nasal symptoms (sneezing, nasal rubbing) were recorded and the serum levels of total immunoglobulin E (IgE) were evaluated using ELISA. Finally, the murine nasal mucosal tissues were stained by Giemsa solution to estimate the degree of mast cell infiltration. After sensitization by IP and IH OVA, the study group showed significant phenotypic changes including increased sneezing and rubbing. Pathological and cytological findings also confirmed significant elevated serum total IgE titer and local mast cell infiltration in the study group statistically. We successfully developed a workable experimental animal model for AR that was more easily sensitized using our new-designed inhalation box, with less stress and more precisely to be observed. PMID- 25027947 TI - Self-assembled tunable photonic hyper-crystals. AB - We demonstrate a novel artificial optical material, the "photonic hyper-crystal", which combines the most interesting features of hyperbolic metamaterials and photonic crystals. Similar to hyperbolic metamaterials, photonic hyper-crystals exhibit broadband divergence in their photonic density of states due to the lack of usual diffraction limit on the photon wave vector. On the other hand, similar to photonic crystals, hyperbolic dispersion law of extraordinary photons is modulated by forbidden gaps near the boundaries of photonic Brillouin zones. Three dimensional self-assembly of photonic hyper-crystals has been achieved by application of external magnetic field to a cobalt nanoparticle-based ferrofluid. Unique spectral properties of photonic hyper-crystals lead to extreme sensitivity of the material to monolayer coatings of cobalt nanoparticles, which should find numerous applications in biological and chemical sensing. PMID- 25027948 TI - Prominent response with helical tomotherapy in recurrent ameloblastic carcinoma of maxillary sinus: a case report. AB - INTRODUCTION: Ameloblastoma is a benign but locally aggressive tumor of odontogenic epithelial tissue. Reports of radiotherapy treatment modalities are limited in the literature. CASE PRESENTATION: A thirty-five year old male presented with complaints of headache radiating to his face for about six months and impaired vision. The patient's Positron Emission Tomography (PET) showed a mass in the left maxillary sinus extending to the nasal cavity and invading the adjacent tissues. An R2 (macroscopic residual tumor) surgical resection performed to debulk the tumor. Due to the recurrence and residual mass, the patient was treated with helical tomotherapy. At 2 months post-radiotherapy, patient's vision returned to normal. PET scan showed a significant reduction in lesion size 12 months post-radiation. CONCLUSION: In cases of ameloblastic carcinoma with, post surgical recurrence or patients not suitable for surgical treatment, helical tomotherapy can be an effective treatment option. PMID- 25027950 TI - In situ diazonium-modified flexible ITO-coated PEN substrates for the deposition of adherent silver-polypyrrole nanocomposite films. AB - In this paper, we report a simple and versatile process of electrografting the aryl multilayers onto indium tin oxide (ITO)-coated flexible poly(ethylene naphthalate) (PEN) substrates using a diazonium salt (4-pyrrolylphenyldiazonium) solution, which was generated in situ from a reaction between the 4-(1H-pyrrol-1 yl)aniline precursor and sodium nitrite in an acidic medium. The first aryl layer bonds with the ITO surface through In-O-C and Sn-O-C bonds which facilitate the formation of a uniform aryl multilayer that is ~8 nm thick. The presence of the aryl multilayer has been confirmed by impedance spectroscopy as well as by electron-transfer blocking measurements. These in situ diazonium-modified ITO coated PEN substrates may find applications in flexible organic electronics and sensor industries. Here we demonstrate the application of diazonium-modified flexible substrates for the growth of adherent silver/polpyrrole nanocomposite films using surface-confined UV photopolymerization. These nanocomposite films have platelet morphology owing to the template effect of the pyrrole-terminated aryl multilayers. In addition, the films are highly doped (32%). This work opens new areas in the design of flexible ITO-conductive polymer hybrids. PMID- 25027949 TI - ACE for all - a molecular perspective. AB - Angiotensin-I converting enzyme (ACE, EC 3.4.15.1) is a zinc dependent dipeptidyl carboxypeptidase with an essential role in mammalian blood pressure regulation as part of the renin-angiotensin aldosterone system (RAAS). As such, it has long been targeted in the treatment of hypertension through the use of ACE inhibitors. Although ACE has been studied since the 1950s, only recently have the full range of functions of this enzyme begun to truly be appreciated. ACE homologues have been found in a host of other organisms, and are now known to be conserved in insects. Insect ACE homologues typically share over 30 % amino acid sequence identity with human ACE. Given that insects lack a mammalian type circulatory system, they must have crucial roles in other physiological processes. The first ACE crystal structures were reported during the last decade and have enabled these enzymes to be studied from an entirely different perspective. Here we review many of these key developments and the implications that they have had on our understanding of the diverse functions of these enzymes. Specifically, we consider how structural information is being used in the design of a new generation of ACE inhibitors with increased specificity, and how the structures of ACE homologues are related to their functions. The Anopheles gambiae genome is predicted to code for ten ACE homologues, more than any genome studied so far. We have modelled the active sites of some of these as yet uncharacterised enzymes to try and infer more about their potential roles at the molecular level. PMID- 25027951 TI - Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug drug interactions. AB - The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies. PMID- 25027952 TI - Erratum to: En bloc transurethral resection with 2-micron continuous-wave laser for primary non-muscle-invasive bladder cancer: a randomized controlled trial. PMID- 25027953 TI - The molecular life of diatoms. PMID- 25027954 TI - Information about diabetogenic effect of statins is inadequate in France. PMID- 25027955 TI - Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Emerging evidence indicates that alteration of epigenetics might be a key event in HNSCC progression. Abnormal expression of histone methyltransferase G9a, which contributes to transcriptional repression of tumor suppressors, has been implicated in promoting cancerous malignancies. However, its role in HNSCC has not been previously characterized. In this study, we elucidate the function of G9a and its downstream mechanism in HNSCC. METHODS: We investigated the clinical relevance of G9a in HNSCC using immunohistochemistry (IHC) staining. In vitro cell proliferation and tumorigenesis ability of G9a-manipulated HNSCC cells were examined with MTT assays, clonogenic assays, and soft agar assays. We examined different routes of cell death in HNSCC cells induced by G9a-depletion or enzymatic inhibition by immunoblot, flow cytometry, fluorescent and transmission electron microscopy analysis. Specific targets of G9a were identified by affymetrix microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Lastly, functions of G9a in vivo were confirmed with a xenograft tumor model. RESULTS: G9a expression is positively correlated to proliferation marker Ki-67 and to poor prognosis in HNSCC patients. Genetic or pharmacological inhibition of G9a reduced cell proliferation without inducing necrosis or apoptosis. Instead, autophagic cell death was the major consequence, and our investigation of mechanisms suggested it is mediated via the dual specificity phosphatase-4 (DUSP4) dependent ERK inactivation pathway. An orthotopic tumor model further confirmed the growth inhibiting effect and induction of autophagy that followed suppression of G9a. CONCLUSIONS: In this study, we provide evidence that G9a confers the survival advantage of HNSCC. Genetic or pharmacological inhibition of G9a induces autophagic cell death; this finding provides a basis for new therapeutic targets for treating HNSCC. PMID- 25027956 TI - CrossTalk proposal: elevated loop gain is a consequence of obstructive sleep apnoea. PMID- 25027957 TI - CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea. PMID- 25027958 TI - Rebuttal from Magdy Younes. PMID- 25027959 TI - Rebuttal from J. E. Orr, B. A. Edwards and A. Malhotra. PMID- 25027960 TI - Politics and physiology: Hermann Rein and the Nobel Prize 1933-1953. PMID- 25027961 TI - The ROAD to a focused view of airway smooth muscle and inflammatory cells in asthmatic sensitization: a tribute to Newman Stephens. PMID- 25027962 TI - On the limits of cerebral oxygen extraction. PMID- 25027963 TI - Abraham Guz (1929-2014). PMID- 25027965 TI - Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol. AB - BACKGROUND: Non-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK's National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials. METHODS/DESIGN: NIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down's syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk >= 1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7-10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals. DISCUSSION: The results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice. NIHR PORTFOLIO NUMBER: 13865. PMID- 25027966 TI - The activating effect of IFN-gamma on monocytes/macrophages is regulated by the LIF-trophoblast-IL-10 axis via Stat1 inhibition and Stat3 activation. AB - Interferon gamma (IFN-gamma) and leukemia inhibitory factor (LIF) are key gestational factors that may differentially affect leukocyte function during gestation. Because IFN-gamma induces a pro-inflammatory phenotype in macrophages and because trophoblast cells are principal targets of LIF in the placenta, we investigated whether and how soluble factors from trophoblast cells regulate the effects of IFN-gamma on macrophage activation. IFN-gamma reduces macrophage motility, but enhances Stat1 activation, pro-inflammatory gene expression and cytotoxic functions. Soluble factors from villous cytotrophoblasts (vCT+LIF cells) and BeWo cells (BW/ST+LIF cells) that were differentiated in the presence of LIF inhibit macrophage Stat1 activation but inversely sustain Stat3 activation in response to IFN-gamma. vCT+LIF cells produce soluble factors that induce Stat3 activation; this effect is partially abrogated in the presence of neutralizing anti-interleukin 10 (IL-10) antibodies. Moreover, soluble factors from BW/ST+LIF cells reduce cell proliferation but enhance the migratory responses of monocytes. In addition, these factors reverse the inhibitory effect of IFN-gamma on monocyte/macrophage motility. BW/ST+LIF cells also generate IFN-gamma-activated macrophages with enhanced IL-10 expression, but reduced tumor-necrosis factor alpha (TNF-alpha), CD14 and CD40 expression as well as impaired cytotoxic function. Additional assays performed in the presence of neutralizing anti-IL-10 antibodies and exogenous IL-10 demonstrate that reduced macrophage cytotoxicity and proliferation, but increased cell motility result from the ability of trophoblast IL-10 to sustain Stat3 activation and suppress IFN-gamma-induced Stat1 activation. These in vitro studies are the first to describe the regulatory role of the LIF-trophoblast-IL-10 axis in the process of macrophage activation in response to pro-inflammatory cytokines. PMID- 25027968 TI - A new cytosolic DNA-recognition pathway for DNA-induced inflammatory responses. PMID- 25027967 TI - TH17 cells in human recurrent pregnancy loss and pre-eclampsia. AB - T helper 17 (TH17) cells have been identified as a new lineage of helper T cells and have been shown to be important in host defense against extracellular infectious agents, autoimmune disease and chronic inflammatory diseases. Recently, TH17 cells have also been shown to participate in successful pregnancy, as well as in the pathogenesis of diseases of pregnancy, such as recurrent spontaneous abortion (RSA) and pre-eclampsia (PE). Here, we review our current knowledge of TH17 cells in human RSA and PE. We also discuss how the local uterine microenvironment affects the differentiation of TH17 cells and the mechanisms that regulate TH17 cells during pregnancy. Research into TH17 cells will not only advance our understanding of TH17-related pregnancy complications, but will also facilitate the design of novel therapies for reproductive diseases. PMID- 25027970 TI - Audit of healthy lifestyle behaviors among patients with diabetes and hypertension attending ambulatory health care services in the United Arab Emirates. AB - BACKGROUND: Knowledge is limited on healthy lifestyle behaviors and their associations with glycemic and blood pressure control among patients with diabetes and hypertension in the United Arab Emirates (UAE). OBJECTIVE: To examine healthy lifestyle behaviors and their associations with glycemic and blood pressure control among patients with hypertension and diabetes, and improvement after the implementation of an intervention in a Chronic Disease Program. SUBJECTS: All patients with diabetes or hypertension attending seven primary health care centers in Al Ain, UAE during a designated three-week period in July and August 2009. METHOD: Nurses conducted an audit of patients' adherence to health lifestyle behaviors related to meal planning, smoking, exercise, blood glucose and blood pressure monitoring at home, and foot and eye exams in the Chronic Disease Program clinics after a self-management intervention. A perceived knowledge score and discussion scores (based on the frequency the patients discuss diabetes and hypertension management issues with their providers) were calculated. Data were analyzed using linear regression and odds ratios. RESULTS: Patients reported acceptable rates of adherence to healthy lifestyle behaviors, including a low smoking rate (6% in males), following a meal plan and exercising (88.6% and 78.7%, respectively). Among patients with diabetes, 59% tested their blood glucose levels at least once a week compared to only 15.3% of those with hypertension monitoring their blood pressure levels at home. Only 33% of the participants were following the current physical activity recommendations. Healthy lifestyle behaviors fell into the following clusters: meal planning with exercise (odds ratio (OR): 8.9 [3.3-23.7]), meal planning with foot exams (OR: 10.6 [3.4-32.9]) and exercising and foot exams (OR: 5.2 [1.9-14.2]). CONCLUSION: This practice-based audit provides an essential assessment for future interventions to improve adherence to healthy life style behaviors among patients with diabetes and hypertension attending primary health clinics in the UAE. PMID- 25027969 TI - Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis. AB - Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-alpha receptor knockout (IFNAR(-/-)) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Ralpha) or PD-L1 were i.p. injected. We found that CD8(+) T cells in IFNAR(-/-) mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-gamma production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR(-/-) and control mice. Injection of PD-L1-specific mAb in IFNAR(-/-) mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR(-/-) mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8(+) T cells in vitro. Accordingly, blocking IL 7R signaling in vivo resulted in increased PD-1 expression on CD8(+) T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL 7 production maintains antiviral CD8(+) T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis. PMID- 25027971 TI - Cancer prevention in Africa: a review of the literature. AB - Cancer is an emerging crisis in Africa. Cancer was the seventh leading cause of death in 2004. If not controlled, cancer incidence in Africa is expected to reach 1.28 million cases annually and claim 970,000 lives yearly by 2030. This paper presents a review of the literature on current cancer prevention approaches in Africa, and consists of cancer prevention studies conducted in African countries (e.g. South Africa and Nigeria) from PubMed, Scopus, and CINAHL databases. Common female cancers in Africa are breast and cervical cancer while prostate cancer is the most common neoplasm among African males. Other common cancers are liver, colorectal, and non-Hodgkin's lymphoma. Mortality related to these cancers comes as a result of delays in screening and treatment, unfamiliarity with cancer and cancer prevention, inaccessibility and unaffordability of care, and inefficiency of healthcare systems. Cancer prevention efforts are deficient because many governments lack cancer prevention and control policies. Also contributing to the lack of cancer prevention and control policies are low levels of awareness, scarce human and financial resources, and inadequacy of cancer registries. Overall, governments grapple with limited funds and competing healthcare priorities. As cancer continues to increase in Africa, the need for rigorous interdisciplinary research on cancer etiology and monitoring in Africa has never been timelier. Cost-effective cancer prevention programs, coordination of donor funding, advocacy, and education should be aggressively pursued. The call for more collaborative approaches in research and policy is urgently needed. PMID- 25027972 TI - MicroRNAs in cancer: biomarkers, functions and therapy. AB - The emergence of microRNAs has been one of the defining developments in cancer biology over the past decade, and the explosion of knowledge in this area has brought forward new diagnostic and therapeutic opportunities. The importance of microRNAs in cancer has been underlined by the identification of alterations in microRNA target binding sites and the microRNA processing machinery in tumor cells. Clinical trials utilizing microRNA profiling for patient prognosis and clinical response are now underway, and the first microRNA mimic entered the clinic for cancer therapy in 2013. In this article we review the potential applications of microRNAs for the clinical assessment of patient outcome in cancer, as well as in cancer monitoring and therapy. PMID- 25027973 TI - A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. AB - BACKGROUND: The aim of this study was to compare the efficacy of hepatic arterial infusion chemotherapy (HAIC) and sorafenib in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). METHODS: A total of 110 patients were observed between February 2008 and May 2013 in seven Korean centers. Fifty patients were treated with HAIC, and 60 patients were treated with sorafenib. RESULTS: The disease control rate in the HAIC was significantly higher than that in the sorafenib group (p < 0.001), although there was no significant difference in the objective response rate (p = 0.214). The median overall survival (OS) was significantly longer in the HAIC group than in the sorafenib group (7.1 vs. 5.5 months, p = 0.011). The median time to-progression (TTP) was also significantly longer in the HAIC group than in the sorafenib group (3.3 vs. 2.1 months, p = 0.034). In the multivariate analysis, tumor diameter (>= 10 cm) and the absence of combined loco-regional treatment were significant prognostic factors influencing OS (p = 0.002 and p = 0.010, respectively) and TTP (p = 0.017 and p = 0.006, respectively). The treatment modality tended to be a significant prognostic factor for survival (p = 0.052), but not for tumor progression (p = 0.121). CONCLUSIONS: HAIC is comparable with sorafenib in terms of OS and TTP in advanced HCC patients with PVTT. HAIC shows more favorable treatment responses compared with sorafenib. Therefore, HAIC might be an alternative treatment modality to sorafenib in advanced HCC patients with PVTT. PMID- 25027974 TI - The prospective relationship between sedentary time and cardiometabolic health in adults at increased cardiometabolic risk - the Hoorn Prevention Study. AB - BACKGROUND: Sedentary time has been identified as an important and independent risk factor for the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) in adults. However, to date most studies have focused on TV time, few also included other sedentary behaviours such as computer use and reading, and most studies had a cross-sectional design. We aimed to examine the prospective relationship between time spent on sedentary behaviours in different domains with individual and clustered cardiometabolic risk in adults. METHODS: Longitudinal data of 622 adults aged 30-50 years (42% males) at increased cardiometabolic risk were used. Leisure time TV viewing, computer use, reading and other sedentary activities (e.g. passive transport) were assessed using a subscale of the Activity Questionnaire for Adolescents and Adults (AQuAA), and summed into overall sedentary behaviour (min/day). Weight and blood pressure were measured, waist-to-hip ratio and BMI calculated, and fasting plasma levels of glucose, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides determined. T2DM risk score was estimated according to the ARIC formula and CVD mortality risk according to the SCORE formula. RESULTS: Generalized Estimating Equation analysis demonstrated that over a two-year period higher levels of overall sedentary time and TV time were weakly but negatively associated with one out of 13 studied cardiometabolic risk factors (i.e. HDL cholesterol). CONCLUSION: Overall sedentary time, as well as sedentary time in different domains, was virtually not related with cardiometabolic risk factors. PMID- 25027975 TI - Changes of periprosthetic bone density after a cementless short hip stem: a clinical and radiological analysis. AB - PURPOSE: The purpose of this study was to examine the concept of proximal load initiation of a total short-stemmed hip arthroplasty (Metha BBraun, Aesculap, Tuttlingen, Germany) on the basis of bone variations by means of osteodensitometric dual energy X-ray absorptiometry and radiologic measurements. METHODS: After power analysis 40 patients were included in this study. DXA examination, radiological and clinical follow-up was performed pre-operatively and postoperatively. Socio-demographic relevancies of bone progression and radiological changes were raised epidemiologically and clinically. RESULTS: Improvement of the Harris hip score from 54.7 points preoperative to 96.7 points postoperative was detected (p < 0.01). Loss of summarized overall net average bone mass density (netavg BMD) could only be manifested after six months compared to the netavg BMD of the postoperative measurement (p < 0.01). After six and 12 months BMD atrophy was shown mainly in regions of interest (ROI) 1, 4 and 7. Positive correlations between changes of BMD and age, male sex and BMI were detectable. No stem had to be revised. CONCLUSIONS: The Metha implant shows excellent osseointegration at the coated area of the stem without factors of aseptic loosening in the short term. This study shows that parameters like age, sex and BMI influence BMD progression and stress shielding. Metha implant shows excellent results especially in young patients with good bone stock. PMID- 25027976 TI - Management of severe periacetabular bone loss combined with pelvic discontinuity in revision hip arthroplasty. AB - PURPOSE: Revision of failed total hip arthroplasty with massive acetabular bone loss resulting in pelvic discontinuity represents a rare but challenging problem. The objective of this study was to present short to mid-term results of revision total hip arthroplasty with a custom-made acetabular implant in a consecutive series of patients with pelvic discontinuity. METHODS: We retrospectively reviewed 18 consecutive patients with massive acetabular bone loss (Paprosky Type 3B) resulting in pelvic discontinuity reconstructed with revision total hip arthroplasty using a custom-made acetabular component. The prosthesis was created on the basis of a thin-cut 1-mm computed tomography (CT) scan of the pelvis. Initial stability of the implant was obtained by screw fixation. Harris hip score and sequential radiographs were used to evaluate the clinical and radiographic results. RESULTS: At an average follow up of 30 months (range 17-62 months) 16 of 18 (88.9%) custom-made implants were considered radiographically stable without signs of acetabular migration of more than 2 mm in the horizontal or vertical direction, implant rotation or screw breakage. Complications included two periprosthetic joint infections treated with explantation of the implant. Three patients had recurrent dislocations postoperatively. The mean Harris hip score improved from 28 +/- 12 points preoperatively to 69 +/- 13 points at the time of last follow up. CONCLUSION: Treatment of acetabular bone loss and pelvic discontinuity with a custom-made acetabular component can provide a durable solution with good clinical and radiographic results. PMID- 25027977 TI - Excluding infections in arthroplasty using leucocyte esterase test. AB - PURPOSE: Periprosthetic joint infections remain a major challenge for the surgeon in modern arthroplasty. The decision on how to handle a case is often difficult due to the variety of clinical presentations. The aim of this study was to establish the leucocyte esterase test as an intra-operative rapid diagnostic tool in an unclear infected or aseptic situation. METHODS: In the setting of 364 endoprosthetic joint procedures on knee, hip and shoulder, we aspirated synovial fluid before performing capsulotomy. We performed a leucocyte esterase test. The results were correlated with the pre-operative synovial fluid aspirations, the laboratory blood sample parameters (C-reactive protein, white blood cells) and the intra-operative histopathological and microbiological findings. RESULTS: The leucocyte esterase test has a sensitivity of 100% and a specificity of 96.5%. The positive predictive value was 82% and the negative predictive value was 100%. Correlation with conventional methods such as serum C-reactive protein and serum white blood cells is given. The histopathological evaluation confirmed the microbiological results in all but three cases. CONCLUSIONS: Based on our results and the current literature, we recommend the leucocyte esterase test as a useful tool in the diagnosis of periprosthetic joint infection. PMID- 25027978 TI - Predictors associated with nonunion and symptomatic malunion following non operative treatment of displaced midshaft clavicle fractures--a systematic review of the literature. AB - PURPOSE: The aim of this study was to survey existing literature in order to identify all reported predictors associated with nonunion or symptomatic malunion in adult patients with displaced midshaft clavicle fractures treated non operatively. METHOD: A systematic literature search in Medline was carried out in order to identify publications in English, reporting on predictors for nonunion and malunion in adults with displaced midshaft clavicle fractures. After applying inclusion and exclusion criteria, eight publications were included in this systematic review. RESULTS: A total of 2,117 midshaft clavicle fractures were included in the eight publications. All publications reported on predictors for nonunion but none were found to report on predictors for malunion. The studies were characterized by different definitions for nonunion and symptomatic malunion if at all present. A total of 13 potential factors associated with nonunion were identified, six of these (displacement, comminution, shortening, age, gender and smoking) were reported as predictors for nonunion. Outcome definitions varied among the studies. CONCLUSION: The included publications varied greatly in design, sample size, and quality. Based on the present literature most of the predictors were found to be of limited evidence, however displacement seems to be the most likely factor that can be used to predict for nonunion. Treating all clavicle fractures with displacement surgically would inevitably lead to overtreatment, which is why future studies need to focus on predictive factors in order to differentiate between patients that would benefit from surgery and those who would not. PMID- 25027979 TI - Gender-specific outcome after implantation of low-contact-stress mobile-bearing total knee arthroplasty with a minimum follow-up of ten years. AB - PURPOSE: The study aim was an analysis of gender-specific outcome differences after implantation of the low-contact-stress (LCS) mobile-bearing total knee arthroplasty (TKA) with a minimum follow-up of ten years. METHODS: We retrospectively analysed 138 prostheses in 108 patients (82 women and 26 men) using our hospital database and a minimum follow-up of ten years (mean 14, range 11-23). Data was extracted with respect to quality of life, clinical outcome parameters [range of motion (ROM), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, visual analogue scale (VAS), Knee Society Score (KSS), and complications. RESULTS: At follow-up, we observed no statistically significant differences in all outcome parameters between female and male patients after LCS TKA, except for VAS score, which revealed no clinical relevance due to the low difference (1.53 vs 1.03, p = 0.043). CONCLUSIONS: Ten years after implantation of the LCS TKA, gender did not influence its beneficial outcome. PMID- 25027980 TI - The use of postoperative suction drainage in total knee arthroplasty: a systematic review. AB - PURPOSE: The purpose of this systematic review and meta-analysis of randomised controlled trials is to assess the effectiveness of no drainage when compared to drainage in total knee arthroplasty, in terms of recovery of knee flexion, reduction in swelling, length of hospital stay and haemoglobin levels following TKA. METHODS: Six randomised controlled trials were included. RESULTS: There is no significant difference between the individuals who receive a drain and those who do not across any of the measures examined (p < 0.05). This analysis demonstrates no statistical difference in ROM [mean difference 0.03 degrees (95 %CI -1.51 to 1.45, p = 0.64, I(2) = 0 %)]. , nor in knee circumference [mean difference 1.63 cm (95 % CI -1.07 - 4.34 cm, p = 0.34), [I(2) = 0.12]. CONCLUSION: The finding raises the possibility that drains are not required to assist in recovery following TKA. PMID- 25027981 TI - Reply to comment on Agarwal et al.: Does initial Pirani score and age influence number of Ponseti casts in children? PMID- 25027983 TI - Functional restriction and a new balance between proximal and distal gut: the tools of the real metabolic surgery. PMID- 25027982 TI - Long-term effects of laparoscopic Roux-en-Y gastric bypass on diabetes mellitus, hypertension and dyslipidaemia in morbidly obese patients. AB - BACKGROUND: Severely obese patients have an increased risk for developing metabolic complications such as type 2 diabetes mellitus (T2DM), dyslipidaemia (DL) and hypertension (HT). The aim of the present study is to research the effect of a primary laparoscopic Roux-en-Y gastric bypass (LRYGB) on T2DM, HT and DL in the long-term. METHODS: Fifty-two out of 89 (58 %) adult severely obese patients with T2DM who had received a LRYGB between January 2000 and December 2008 were evaluated. Primary outcome of evaluation was remission of T2DM according to the definition of 2009 consensus statement. Complete remission was defined as achievement fasting plasma glucose (FPG) of <5.6 mmol/l (<100.8 mg/dL) and HbA1c <42 mmol/mol (<6.0 %)) without glucose-lowering medication for at least 1 year. Partial remission was defined as a FPG of 5.6-6.9 mmol/l (100.8-124.2 mg/dL) and HbA1c 42-48 mmol/mol (6.0-6.5 %), without glucose-lowering medication for at least 1 year. Remission of T2DM was considered if the patient met the criteria for complete or partial remission. Secondary outcomes were remission of HT, DL and changes in medication use. RESULTS: Patients had a mean age of 47.5 +/ 9.6 years, body mass index of 46.6 +/- 6.4 kg/m(2) and a mean duration of T2DM of 6.1 +/- 5.4 years at the time of surgery. The mean post-operative follow-up period was 6.9 +/- 2.3 years. At the end of the follow-up, mean weight loss was 60 +/- 24 % excess weight loss (EWL) and 26 +/- 10 % total body weight loss (TBWL). Mean HbA1c level had significantly decreased from 64.8 +/- 19.7 mmol/mol to 46.4 +/- 12.9 mmol/l (p < 0.0001). Overall medication use was reduced from 85 % to 37 % of the patients (p < 0.0001), while the number of insulin users was reduced from 40 % to 6 % (p < 0.0001). Nineteen percent of the patients had a relapse of T2DM during follow-up. Pre-operative HbA1ac level (odds ratio 0.911, p = 0.020) and duration of T2DM (odds ratio 0.637, p = 0.010) were independent risk factors for failed remission of T2DM. The number of patients with HT was significantly reduced from 73 % to 54 % (p = 0.042), and number of patients with DL was non-significantly decreased from 71 % to 54 % (p = 0.068). CONCLUSIONS: The laparoscopic RYGB operation results in a sustained EWL of 60 % (26 % TBWL) with 52 % long-term remission of T2DM. However, 19 % of the patients had a relapse of their T2DM. Furthermore, HT and DL improved markedly. PMID- 25027984 TI - If You Can Answer Why, You Have a Good Chance at Success! PMID- 25027985 TI - Static Versus Dynamic Musculoskeletal Ultrasound for Detection of Plantar Plate Pathology. AB - : Musculoskeletal ultrasound (US) is a common modality used to examine plantar plate pathology. Comparison of the diagnostic accuracy of static versus dynamic ultrasound has not been previously published. The objective of this study was to prospectively compare the value of using preoperative static and dynamic ultrasound findings to diagnose plantar plate pathology using intraoperative inspection as the standard of reference. Patients attending a single foot and ankle specialty clinic from August 2012 to June 2013 with clinically suspected plantar plate pathology that was unresponsive to conservative care served as the study population. Static and dynamic ultrasound exams were performed by a single experienced rater and compared to intraoperative findings. The overall accuracy, sensitivity, specificity, positive predictive value and negative predictive value were determined for static and dynamic ultrasound exams. Thirty-six patients (45 lesser metatarsophalangeal joints) were included in this analysis. Of the 36 patients, 29 were females and 7 were males with average age of 57.9 +/- 7.8 years (range, 38-73). There were 38 plantar plate tears (84.4%) noted on intraoperative examination. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for the static US exam were 80.0%, 81.6%, 71.4%, 93.9%, and 41.7%, respectively. The same values for the dynamic US exam were 88.9%, 100%, 28.6%, 88.3%, and 100%, respectively. Static and dynamic ultrasound techniques are each highly sensitive methods for assessing plantar plate pathology. However, the sensitivity and accuracy of the exam is best when dynamic assessment of the plantar plate is employed. Caution should be used when relying solely on static images to diagnose subtle injuries in this area of the foot. LEVELS OF EVIDENCE: Diagnostic Level II, Prospective. PMID- 25027986 TI - Association Between Smoking and Wound Infection Rates Following Calcaneal Fracture Fixation. AB - : Fixation of displaced, intra-articular calcaneal fractures has shown to improve outcome, but wound complications can be devastating for the patient. While smoking remains a factor associated with poor outcome, evidence is still somewhat contradictory. We studied the association of smoking and wound complication after calcaneal fracture fixation. In addition, we evaluated infection rates and association with age of patient, delay in surgery, tourniquet time, and Sanders classification. We conducted a retrospective cohort study in a teaching hospital from 2004 to 2011 evaluating a single surgeon series of calcaneal open reduction internal fixation via an extensile lateral approach. Patient demographics, mechanism of injury, history preexisting medical comorbidity, smoking status, soft tissue condition, delay in surgery, tourniquet time, presence of superficial or deep infection, and treatment of any infection were noted. Superficial and deep infection rate were 11.6% and 2.9%, respectively. Smokers had an increased rate of 12.5% and 6.25%, respectively. Most infections settled with antibiotics, and only 2 cases required surgical debridement. In conclusion, all the deep infections occurred in smokers whose surgery was delayed for more than 14 days. We found no increase in the rate of wound complications in association with age of patient, Sanders grading, or tourniquet time. LEVELS OF EVIDENCE: Prognostic Level III, retrospective comparative cohort study. PMID- 25027987 TI - Charcot Arthropathy: Operative and Nonoperative Management. PMID- 25027990 TI - Water-induced correlation between single ions imaged at the solid-liquid interface. AB - When immersed into water, most solids develop a surface charge, which is neutralized by an accumulation of dissolved counterions at the interface. Although the density distribution of counterions perpendicular to the interface obeys well-established theories, little is known about counterions' lateral organization at the surface of the solid. Here we show, by using atomic force microscopy and computer simulations, that single hydrated metal ions can spontaneously form ordered structures at the surface of homogeneous solids in aqueous solutions. The structures are laterally stabilized only by water molecules with no need for specific interactions between the surface and the ions. The mechanism, studied here for several systems, is controlled by the hydration landscape of both the surface and the adsorbed ions. The existence of discrete ion domains could play an important role in interfacial phenomena such as charge transfer, crystal growth, nanoscale self-assembly and colloidal stability. PMID- 25027988 TI - Getting ready for building: signaling and autophagosome biogenesis. AB - Autophagy is the main cellular catabolic process responsible for degrading organelles and large protein aggregates. It is initiated by the formation of a unique membrane structure, the phagophore, which engulfs part of the cytoplasm and forms a double-membrane vesicle termed the autophagosome. Fusion of the outer autophagosomal membrane with the lysosome and degradation of the inner membrane contents complete the process. The extent of autophagy must be tightly regulated to avoid destruction of proteins and organelles essential for cell survival. Autophagic activity is thus regulated by external and internal cues, which initiate the formation of well-defined autophagy-related protein complexes that mediate autophagosome formation and selective cargo recruitment into these organelles. Autophagosome formation and the signaling pathways that regulate it have recently attracted substantial attention. In this review, we analyze the different signaling pathways that regulate autophagy and discuss recent progress in our understanding of autophagosome biogenesis. PMID- 25027989 TI - On the resilience of remote traumatic memories against exposure therapy-mediated attenuation. AB - How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Despite the fact that traumatic memories are often not readily amenable to immediate intervention, surprisingly few studies have investigated treatment options for remote traumata in animal models. The few that have unanimously concluded that exposure therapy-based approaches, the most successful behavioral intervention for the attenuation of recent forms of traumata in humans, fail to effectively reduce remote fear memories. Here, we provide an overview of these animal studies with an emphasis on why remote traumatic memories might be refractory to behavioral interventions: A lack of neuroplasticity in brain areas relevant for learning and memory emerges as a common denominator of such resilience. We then outline the findings of a recent study in mice showing that by combining exposure therapy-like approaches with small molecule inhibitors of histone deacetylases (HDACis), even remote memories can be persistently attenuated. This pharmacological intervention reinstated neuroplasticity to levels comparable to those found upon successful attenuation of recent memories. Thus, HDACis-or any other agent capable of heightening neuroplasticity-in conjunction with exposure therapy-based treatments might constitute a promising approach to overcome remote traumata. PMID- 25027992 TI - Communication: separable potential energy surfaces from multiplicative artificial neural networks. AB - We present a potential energy surface fitting scheme based on multiplicative artificial neural networks. It has the sum of products form required for efficient computation of the dynamics of multidimensional quantum systems with the multi configuration time dependent Hartree method. Moreover, it results in analytic potential energy matrix elements when combined with quantum dynamics methods using Gaussian basis functions, eliminating the need for a local harmonic approximation. Scaling behavior with respect to the complexity of the potential as well as the requested accuracy is discussed. PMID- 25027991 TI - Expression and prognostic role of SGTA in human breast carcinoma correlates with tumor cell proliferation. AB - Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) was reported to be implicated in various cellular processes and involved in control of cell cycle regulation and transcription. It may play a critical role in oncogenesis. In this study, to investigate the potential roles of SGTA in breast cancer, expression patterns, interaction and the correlation with clinical/prognostic factors of SGTA and Ki-67 were examined among patients with breast cancer. Immunohistochemistry and Western blot analysis were performed for SGTA in 100 breast carcinoma samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine the prognostic significance. We found that SGTA was overexpressed in breast carcinoma compared with the adjacent normal tissues. High expression of SGTA was positively associated with histological grade (P = 0.002) and Ki-67 (P = 0.001). Univariate analysis showed that SGTA expression was associated with a poor prognosis (P = 0.002). Kaplan-Meier survival curves of the study population showed that high expression level of SGTA significantly correlated with short-term survival. While in vitro, SGTA depletion by small interfering RNA inhibited cell proliferation and cell cycle in breast cancer cell lines. Western blot analyses showed that SGTA depletion decreased cyclin A, cyclin B and CDK2, whereas increased p27 levels. Additionally, treatment of phosphatidylinositol 3-kinase inhibitor LY294002 could arrest cells growth and diminish SGTA expression. These results suggested that SGTA overexpression was involved in the pathogenesis of breast cancer which might serve as a future target for novel treatment in breast cancer. PMID- 25027993 TI - Efficient algorithms for semiclassical instanton calculations based on discretized path integrals. AB - Path integral instanton method is a promising way to calculate the tunneling splitting of energies for degenerated two state systems. In order to calculate the tunneling splitting, we need to take the zero temperature limit, or the limit of infinite imaginary time duration. In the method developed by Richardson and Althorpe [J. Chem. Phys. 134, 054109 (2011)], the limit is simply replaced by the sufficiently long imaginary time. In the present study, we have developed a new formula of the tunneling splitting based on the discretized path integrals to take the limit analytically. We have applied our new formula to model systems, and found that this approach can significantly reduce the computational cost and gain the numerical accuracy. We then developed the method combined with the electronic structure calculations to obtain the accurate interatomic potential on the fly. We present an application of our ab initio instanton method to the ammonia umbrella flip motion. PMID- 25027994 TI - Complex absorbing potentials within EOM-CC family of methods: theory, implementation, and benchmarks. AB - A production-level implementation of equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) for electron attachment and excitation energies augmented by a complex absorbing potential (CAP) is presented. The new method enables the treatment of metastable states within the EOM-CC formalism in a similar manner as bound states. The numeric performance of the method and the sensitivity of resonance positions and lifetimes to the CAP parameters and the choice of one electron basis set are investigated. A protocol for studying molecular shape resonances based on the use of standard basis sets and a universal criterion for choosing the CAP parameters are presented. Our results for a variety of pi(*) shape resonances of small to medium-size molecules demonstrate that CAP-augmented EOM-CCSD is competitive relative to other theoretical approaches for the treatment of resonances and is often able to reproduce experimental results. PMID- 25027995 TI - The complex chemical Langevin equation. AB - The chemical Langevin equation (CLE) is a popular simulation method to probe the stochastic dynamics of chemical systems. The CLE's main disadvantage is its break down in finite time due to the problem of evaluating square roots of negative quantities whenever the molecule numbers become sufficiently small. We show that this issue is not a numerical integration problem, rather in many systems it is intrinsic to all representations of the CLE. Various methods of correcting the CLE have been proposed which avoid its break down. We show that these methods introduce undesirable artefacts in the CLE's predictions. In particular, for unimolecular systems, these correction methods lead to CLE predictions for the mean concentrations and variance of fluctuations which disagree with those of the chemical master equation. We show that, by extending the domain of the CLE to complex space, break down is eliminated, and the CLE's accuracy for unimolecular systems is restored. Although the molecule numbers are generally complex, we show that the "complex CLE" predicts real-valued quantities for the mean concentrations, the moments of intrinsic noise, power spectra, and first passage times, hence admitting a physical interpretation. It is also shown to provide a more accurate approximation of the chemical master equation of simple biochemical circuits involving bimolecular reactions than the various corrected forms of the real-valued CLE, the linear-noise approximation and a commonly used two moment closure approximation. PMID- 25027996 TI - Fast variance reduction for steady-state simulation and sensitivity analysis of stochastic chemical systems using shadow function estimators. AB - We address the problem of estimating steady-state quantities associated to systems of stochastic chemical kinetics. In most cases of interest, these systems are analytically intractable, and one has to resort to computational methods to estimate stationary values of cost functions. In this work, we introduce a novel variance reduction algorithm for stochastic chemical kinetics, inspired by related methods in queueing theory, in particular the use of shadow functions. Using two numerical examples, we demonstrate the efficiency of the method for the calculation of steady-state parametric sensitivities and evaluate its performance in comparison to other estimation methods. PMID- 25027997 TI - Embedded-cluster calculations in a numeric atomic orbital density-functional theory framework. AB - We integrate the all-electron electronic structure code FHI-aims into the general ChemShell package for solid-state embedding quantum and molecular mechanical (QM/MM) calculations. A major undertaking in this integration is the implementation of pseudopotential functionality into FHI-aims to describe cations at the QM/MM boundary through effective core potentials and therewith prevent spurious overpolarization of the electronic density. Based on numeric atomic orbital basis sets, FHI-aims offers particularly efficient access to exact exchange and second order perturbation theory, rendering the established QM/MM setup an ideal tool for hybrid and double-hybrid level density functional theory calculations of solid systems. We illustrate this capability by calculating the reduction potential of Fe in the Fe-substituted ZSM-5 zeolitic framework and the reaction energy profile for (photo-)catalytic water oxidation at TiO2(110). PMID- 25027998 TI - New tools for the systematic analysis and visualization of electronic excitations. I. Formalism. AB - A variety of density matrix based methods for the analysis and visualization of electronic excitations are discussed and their implementation within the framework of the algebraic diagrammatic construction of the polarization propagator is reported. Their mathematical expressions are given and an extensive phenomenological discussion is provided to aid the interpretation of the results. Starting from several standard procedures, e.g., population analysis, natural orbital decomposition, and density plotting, we proceed to more advanced concepts of natural transition orbitals and attachment/detachment densities. In addition, special focus is laid on information coded in the transition density matrix and its phenomenological analysis in terms of an electron-hole picture. Taking advantage of both the orbital and real space representations of the density matrices, the physical information in these analysis methods is outlined, and similarities and differences between the approaches are highlighted. Moreover, new analysis tools for excited states are introduced including state averaged natural transition orbitals, which give a compact description of a number of states simultaneously, and natural difference orbitals (defined as the eigenvectors of the difference density matrix), which reveal details about orbital relaxation effects. PMID- 25027999 TI - New tools for the systematic analysis and visualization of electronic excitations. II. Applications. AB - The excited states of a diverse set of molecules are examined using a collection of newly implemented analysis methods. These examples expose the particular power of three of these tools: (i) natural difference orbitals (the eigenvectors of the difference density matrix) for the description of orbital relaxation effects, (ii) analysis of the one-electron transition density matrix in terms of an electron-hole picture to identify charge resonance and excitonic correlation effects, and (iii) state-averaged natural transition orbitals for a compact simultaneous representation of several states. Furthermore, the utility of a wide array of additional analysis methods is highlighted. Five molecules with diverse excited state characteristics are chosen for these tasks: pyridine as a prototypical small heteroaromatic molecule, a model system of six neon atoms to study charge resonance effects, hexatriene in its neutral and radical cation forms to exemplify the cases of double excitations and spin-polarization, respectively, and a model iridium complex as a representative metal organic compound. Using these examples a number of phenomena, which are at first sight unexpected, are highlighted and their physical significance is discussed. Moreover, the generality of the conclusions of this paper is verified by a comparison of single- and multireference ab initio methods. PMID- 25028000 TI - Magnetizability and rotational g tensors for density fitted local second-order Moller-Plesset perturbation theory using gauge-including atomic orbitals. AB - In this paper, we present theory and implementation of an efficient program for calculating magnetizabilities and rotational g tensors of closed-shell molecules at the level of local second-order Moller-Plesset perturbation theory (MP2) using London orbitals. Density fitting is employed to factorize the electron repulsion integrals with ordinary Gaussians as fitting functions. The presented program for the calculation of magnetizabilities and rotational g tensors is based on a previous implementation of NMR shielding tensors reported by S. Loibl and M. Schutz [J. Chem. Phys. 137, 084107 (2012)]. Extensive test calculations show (i) that the errors introduced by density fitting are negligible, and (ii) that the errors of the local approximation are still rather small, although larger than for nuclear magnetic resonance (NMR) shielding tensors. Electron correlation effects for magnetizabilities are tiny for most of the molecules considered here. MP2 appears to overestimate the correlation contribution of magnetizabilities such that it does not constitute an improvement over Hartree-Fock (when comparing to higher-order methods like CCSD(T)). For rotational g tensors the situation is different and MP2 provides a significant improvement in accuracy over Hartree Fock. The computational performance of the new program was tested for two extended systems, the larger comprising about 2200 basis functions. It turns out that a magnetizability (or rotational g tensor) calculation takes about 1.5 times longer than a corresponding NMR shielding tensor calculation. PMID- 25028001 TI - Bowl breakout: escaping the positive region when searching for saddle points. AB - We present a scheme improving the minimum-mode following method for finding first order saddle points by confining the displacements of atoms to the subset of those subject to the largest force. By doing so it is ensured that the displacement remains of a local character within regions where all eigenvalues of the Hessian matrix are positive. However, as soon as a region is entered where an eigenvalue turns negative all atoms are released to maintain the ability of determining concerted moves. Applying the proposed scheme reduces the required number of force calls for the determination of connected saddle points by a factor two or more compared to a free search. Furthermore, a wider distribution of the relevant low barrier saddle points is obtained. Finally, the dependency on the initial distortion and the applied maximal step size is reduced making minimum-mode guided searches both more robust and applicable. PMID- 25028002 TI - Novel type of chimera spiral waves arising from decoupling of a diffusible component. AB - Spiral waves composed of coherent traveling waves surrounding a core containing stochastically distributed stationary areas are found in numerical simulations of a three-variable reaction-diffusion system with one diffusible species. In the spiral core, diffusion of this component (w) mediates transitions between dynamic states of the subsystem formed by the other two components, whose dynamics is more rapid than that of w. Diffusive coupling between adjacent sites can be "on" or "off" depending on the subsystem state. The incoherent structures in the spiral core are produced by this decoupling of the slow diffusive component from the fast non-diffusing subsystem. The phase diagram reveals that the region of incoherent behavior in chimera spirals grows drastically, leading to modulation and breakup of the spirals, in the transition zones between 1(n-1) and 1(n) local mixed-mode oscillations. PMID- 25028003 TI - Multipole plasmon excitations of C60 dimers. AB - We study the multipole plasmon mode frequencies of a pair of C60 molecules by means of the linearized hydrodynamic theory for electronic excitations on the each C60 surface. We apply the two-center spherical coordinate system for mathematical convenience and find an explicit form of the surface plasmon energies. Numerical result shows when approaching the two C60 molecules, the coupling between the bare plasmon modes leads to the appearance of additional modes having energies that are different from those of the isolated C60 molecules. PMID- 25028004 TI - Assessment of density functional theory based DeltaSCF (self-consistent field) and linear response methods for longest wavelength excited states of extended pi conjugated molecular systems. AB - Computational investigation of the longest wavelength excitations in a series of cyanines and linear n-acenes is undertaken with the use of standard spin conserving linear response time-dependent density functional theory (TD-DFT) as well as its spin-flip variant and a DeltaSCF method based on the ensemble DFT. The spin-conserving linear response TD-DFT fails to accurately reproduce the lowest excitation energy in these pi-conjugated systems by strongly overestimating the excitation energies of cyanines and underestimating the excitation energies of n-acenes. The spin-flip TD-DFT is capable of correcting the underestimation of excitation energies of n-acenes by bringing in the non dynamic electron correlation into the ground state; however, it does not fully correct for the overestimation of the excitation energies of cyanines, for which the non-dynamic correlation does not seem to play a role. The ensemble DFT method employed in this work is capable of correcting for the effect of missing non dynamic correlation in the ground state of n-acenes and for the deficient description of differential correlation effects between the ground and excited states of cyanines and yields the excitation energies of both types of extended pi-conjugated systems with the accuracy matching high-level ab initio multireference calculations. PMID- 25028005 TI - Orbital-dependent second-order scaled-opposite-spin correlation functionals in the optimized effective potential method. AB - The performance of correlated optimized effective potential (OEP) functionals based on the spin-resolved second-order correlation energy is analysed. The relative importance of singly- and doubly- excited contributions as well as the effect of scaling the same- and opposite- spin components is investigated in detail comparing OEP results with Kohn-Sham (KS) quantities determined via an inversion procedure using accurate ab initio electronic densities. Special attention is dedicated in particular to the recently proposed scaled-opposite spin OEP functional [I. Grabowski, E. Fabiano, and F. Della Sala, Phys. Rev. B 87, 075103 (2013)] which is the most advantageous from a computational point of view. We find that for high accuracy, a careful, system dependent, selection of the scaling coefficient is required. We analyse several size-extensive approaches for this selection. Finally, we find that a composite approach, named OEP2-SOSh, based on a post-SCF rescaling of the correlation energy can yield high accuracy for many properties, being comparable with the most accurate OEP procedures previously reported in the literature but at substantially reduced computational effort. PMID- 25028006 TI - Derivative couplings between TDDFT excited states obtained by direct differentiation in the Tamm-Dancoff approximation. AB - Working within the Tamm-Dancoff approximation, we calculate the derivative couplings between time-dependent density-functional theory excited states by assuming that the Kohn-Sham superposition of singly excited determinants represents a true electronic wavefunction. All Pulay terms are included in our derivative coupling expression. The reasonability of our approach can be established by noting that, for closely separated electronic states in the infinite basis limit, our final expression agrees exactly with the Chernyak Mukamel expression (with transition densities from response theory). Finally, we also validate our approach empirically by analyzing the behavior of the derivative couplings around the T1/T2 conical intersection of benzaldehyde. PMID- 25028007 TI - An ionic concentration and size dependent dielectric permittivity Poisson Boltzmann model for biomolecular solvation studies. AB - By considering the influence of volume exclusion on the solvent dielectric, a variable dielectric Poisson-Boltzmann (VDPB) model is explored for molecular solvation studies by using a dielectric as an explicit function of ionic sizes and concentrations. A finite element method is adopted and an iterative strategy is introduced to numerically solve the VDPB equation. According to our computations, the current dielectric model can result in considerable differences compared with the traditional Poisson-Boltzmann (PB) solutions, especially for those systems with highly charged biomolecule and/or under high salt concentration condition. The model to certain extent captures the fact of dielectric decrement of electrolyte solutions, which is especially remarkable in the vicinity of molecules. Counter-ion concentration very near the molecular surface in VDPB calculation is found higher than that in PB. The new dielectric model may also influence the charge compensation behavior near biomolecular surface. For a spherical cavity solvated in a concentrated ionic solution, charge inversion is observed in VDPB, which does not occur with the traditional PB model. Besides, the solvation energy predicted by VDPB will always be greater than that by PB. Moreover, differing from PB, the VDPB also allows non-monotonous dependencies of solvation energy on ionic strength. PMID- 25028008 TI - Ring polymer dynamics for rigid tops with an improved integrator. AB - When working in curved spaces, such as those created with the introduction of holonomic constraints, or those generated from the parameters of Lie groups, the presence of a non-uniform metric significantly alters the Ring Polymer Molecular Dynamics from its Cartesian space counterpart. The presence of a nonuniform metric causes difficulties manifested in significant long-time energy drift for the common integrators, which should be absent in a good algorithm. Using a new integrator developed with the aid of the variational principle, we implement a version of Ring Polymer Molecular Dynamics adapted to curved spaces [S. Wolf and E. Curotto, J. Chem. Phys. 137, 014109 (2012)], specifically testing a symmetric ellipsoid of inertia mapped by stereographic projection coordinates. We find that the algorithm conserves the energy without long-term energy drift and converges quadratically in the time step. To test this implementation of Ring Polymer Molecular Dynamics, we compute the position-position autocorrelation function for a rigid ammonia molecule in an external field, for several values of the Trotter number. PMID- 25028009 TI - Irreversible thermodynamics of open chemical networks. I. Emergent cycles and broken conservation laws. AB - In this paper and Paper II, we outline a general framework for the thermodynamic description of open chemical reaction networks, with special regard to metabolic networks regulating cellular physiology and biochemical functions. We first introduce closed networks "in a box", whose thermodynamics is subjected to strict physical constraints: the mass-action law, elementarity of processes, and detailed balance. We further digress on the role of solvents and on the seemingly unacknowledged property of network independence of free energy landscapes. We then open the system by assuming that the concentrations of certain substrate species (the chemostats) are fixed, whether because promptly regulated by the environment via contact with reservoirs, or because nearly constant in a time window. As a result, the system is driven out of equilibrium. A rich algebraic and topological structure ensues in the network of internal species: Emergent irreversible cycles are associated with nonvanishing affinities, whose symmetries are dictated by the breakage of conservation laws. These central results are resumed in the relation a + b = s(Y) between the number of fundamental affinities a, that of broken conservation laws b and the number of chemostats s(Y). We decompose the steady state entropy production rate in terms of fundamental fluxes and affinities in the spirit of Schnakenberg's theory of network thermodynamics, paving the way for the forthcoming treatment of the linear regime, of efficiency and tight coupling, of free energy transduction, and of thermodynamic constraints for network reconstruction. PMID- 25028010 TI - A MATLAB-based finite-element visualization of quantum reactive scattering. I. Collinear atom-diatom reactions. AB - We restate the application of the finite element method to collinear triatomic reactive scattering dynamics with a novel treatment of the scattering boundary conditions. The method provides directly the reactive scattering wave function and, subsequently, the probability current density field. Visualizing these quantities provides additional insight into the quantum dynamics of simple chemical reactions beyond simplistic one-dimensional models. Application is made here to a symmetric reaction (H+H2), a heavy-light-light reaction (F+H2), and a heavy-light-heavy reaction (F+HCl). To accompany this article, we have written a MATLAB code which is fast, simple enough to be accessible to a wide audience, as well as generally applicable to any problem that can be mapped onto a collinear atom-diatom reaction. The code and user's manual are available for download from http://www2.chem.umd.edu/groups/alexander/FEM. PMID- 25028011 TI - Tensor hypercontracted ppRPA: reducing the cost of the particle-particle random phase approximation from O(r(6)) to O(r(4)). AB - In recent years, interest in the random-phase approximation (RPA) has grown rapidly. At the same time, tensor hypercontraction has emerged as an intriguing method to reduce the computational cost of electronic structure algorithms. In this paper, we combine the particle-particle random phase approximation with tensor hypercontraction to produce the tensor-hypercontracted particle-particle RPA (THC-ppRPA) algorithm. Unlike previous implementations of ppRPA which scale as O(r(6)), the THC-ppRPA algorithm scales asymptotically as only O(r(4)), albeit with a much larger prefactor than the traditional algorithm. We apply THC-ppRPA to several model systems and show that it yields the same results as traditional ppRPA to within mH accuracy. Our method opens the door to the development of post Kohn Sham functionals based on ppRPA without the excessive asymptotic cost of traditional ppRPA implementations. PMID- 25028012 TI - A new broadband homonuclear mixing pulse for NMR with low applied power. AB - Broadband homonuclear mixing pulses with low radiofrequency power are essential for NMR spectroscopy of proteins and small molecules, especially for emerging applications in high field NMR. We have analytically designed a mixing pulse with high bandwidth-to-power ratio, using our recently developed multi-frame method. Here, we compare the new pulse, NF4 (mixing in the fourth nutating frame), to the best currently available sequence, focusing on the low-power regime. We use simulations and experiments to compare the two pulses' relaxation properties and bandwidth, and demonstrate that NF4 has approximately 1.35 times higher bandwidth, with similar effective relaxation. Therefore, NF4 is a good choice for broadband homonuclear mixing, particularly when the available radiofrequency power is limited. PMID- 25028014 TI - Thermal radiation of laser heated niobium clusters Nb(+)(N), 8 ? N ? 22. AB - The thermal radiation from small, laser heated, positively charged niobium clusters has been measured. The emitted power was determined by the quenching effect on the metastable decay, employing two different experimental protocols. The radiative power decreases slightly with cluster size and shows no strong size to-size variations. The magnitude is 40-50 keV/s at the timescale of several microseconds, which is the measured crossover time from evaporative to radiative cooling. PMID- 25028013 TI - Differential cross sections for intermediate-energy electron scattering from alpha-tetrahydrofurfuryl alcohol: excitation of electronic-states. AB - We report on measurements of differential cross sections (DCSs) for electron impact excitation of a series of Rydberg electronic-states in alpha tetrahydrofurfuryl alcohol (THFA). The energy range of these experiments was 20 50 eV, while the scattered electron was detected in the 10 degrees -90 degrees angular range. There are currently no other experimental data or theoretical computations against which we can directly compare the present measured results. Nonetheless, we are able to compare our THFA DCSs with earlier cross section measurements for Rydberg-state electronic excitation for tetrahydrofuran, a similar cyclic ether, from Do et al. [J. Chem. Phys. 134, 144302 (2011)]. In addition, "rotationally averaged" elastic DCSs, calculated using our independent atom model with screened additivity rule correction approach are also reported. Those latter results give integral cross sections consistent with the optical theorem, and supercede those from the only previous study of Milosavljevic et al. [Eur. Phys. J. D 40, 107 (2006)]. PMID- 25028015 TI - O2(b(1)Sigma(+)(g), upsilon = 0, 1) relative yields in O((1)D) + O2 energy transfer. AB - Energy transfer from O((1)D) to O2 is the main source of O2(b(1)Sigma(+)(g) in vibrational levels upsilon = 0 and 1 in the Earth's thermosphere. Knowledge of the relative yields for O2(b(1)Sigma(+)(g) production in upsilon = 0 and 1 is essential for a reliable interpretation and modeling of the O2 atmospheric band emissions (b(1)Sigma(+)(g) - X (3)Sigma(-)(g) from these two vibrational levels. We report laboratory measurements of the relative yields at room temperature. In the experiments, O2(b(1)Sigma(+)(g), upsilon = 0, 1) is generated by O((1)D) + O2 collisions following partial photodissociation of O2 at 157.6 nm. O2(b(1)Sigma(+)(g), upsilon = 0, 1) emission detection is used to monitor the temporal evolution of the vibrational level populations. The measured fractional yield for upsilon = 1 is 0.8 +/- 0.1, in contrast with the results of previous studies that indicated dominant O2(b(1)Sigma(+)(g), upsilon = 0) production. A revision is warranted of the values used for these relative yields in atmospheric models. PMID- 25028016 TI - Rotationally resolved state-to-state photoelectron study of niobium carbide radical. AB - By employing the two-color visible (VIS)-ultraviolet (UV) laser photoexcitation scheme and the pulsed field ionization-photoelectron (PFI-PE) detection, we have obtained rovibronically selected and resolved photoelectron spectra for niobium carbide cation (NbC(+)). The fully rotationally resolved state-to-state VIS-UV PFI-PE spectra thus obtained allow the unambiguous assignments of rotational photoionization transitions, indicating that the electronic configuration and term symmetry of NbC(+)(X) ground state are ...10sigma(2) 5pi(4) 11sigma(2) (X(1)Sigma(+)). Furthermore, the rotational analysis of these spectra yields the ionization energy of NbC [IE(NbC)] to be 56,369.2 +/- 0.8 cm(-1) (6.9889 +/- 0.0001 eV) and the rotation constant B0 (+) = 0.5681 +/- 0.0007 cm(-1). The latter value allows the determination of the bond distance r0 (+) = 1.671 +/- 0.001 A for NbC(+)(X(1)Sigma(+)). Based on conservation of energy, the IE(NbC) determined in the present study along with the known IE(Nb) gives the difference of 0 K bond dissociation energies (D0's) for NbC(+) and NbC, D0(NbC(+)) - D0(NbC) = -1855.4 +/- 0.9 cm(-1) (-0.2300 +/- 0.0001 eV). The energetic values and the B0 (+) constant determined in this work are valuable for benchmarking state-of-the art ab initio quantum calculations of 4d transition metal-containing molecules. PMID- 25028017 TI - Theoretical oxidation state analysis of Ru-(bpy)3: influence of water solvation and Hubbard correction in first-principles calculations. AB - Oxidation state is a powerful concept that is widely used in chemistry and materials physics, although the concept itself is arguably ill-defined quantum mechanically. In this work, we present impartial comparison of four, well recognized theoretical approaches based on Lowdin atomic orbital projection, Bader decomposition, maximally localized Wannier function, and occupation matrix diagonalization, for assessing how well transition metal oxidation states can be characterized. Here, we study a representative molecular complex, tris(bipyridine)ruthenium. We also consider the influence of water solvation through first-principles molecular dynamics as well as the improved electronic structure description for strongly correlated d-electrons by including Hubbard correction in density functional theory calculations. PMID- 25028018 TI - Infrared spectroscopy of the acetyl cation and its protonated ketene isomer. AB - [C2,H3,O](+) ions are generated with a pulsed discharge in a supersonic expansion containing methyl acetate or acetone. These ions are mass selected and their infrared spectra are recorded via laser photodissociation and the method of argon tagging. Computational chemistry is employed to investigate structural isomers and their spectra. The acetyl cation (CH3CO(+)) is the global minimum and protonated ketene (CH2COH(+)) is the next lowest energy isomer (+176.2 kJ/mol). When methyl acetate is employed as the precursor, the infrared spectrum reveals that only the acetyl cation is formed. Partially resolved rotational structure reveals rotation about the C3 axis. When acetone is used as the precursor, acetyl is still the most abundant cation, but there is also a minor component of protonated ketene. Computations reveal a significant barrier to interconversion between the two isomers (+221 kJ/mol), indicating that protonated ketene must be obtained via kinetic trapping. Both isomers may be present in interstellar environments, and their implications for astrochemistry are discussed. PMID- 25028019 TI - The dependence of homogeneous nucleation rate on supersaturation. AB - The claim that classical nucleation theory (CNT) correctly predicts the dependence on supersaturation of the steady-state rate of homogeneous nucleation is reexamined in light of recent experimental studies of nucleation of a range of substances, including water, argon, nitrogen, and several 1-alcohols. Based on these studies (which include, for water, a compilation of nine different studies), it is concluded that the dependence of nucleation rate on supersaturation is not correctly predicted by CNT. It is shown that CNT's incorrect prediction of the supersaturation dependence of nucleation rate is due to its incorrect prediction of the Gibbs free energy change associated with formation of small clusters from the monomer vapor, evaluated at the substance's equilibrium vapor pressure, even though that free energy change is itself a function only of temperature. PMID- 25028020 TI - Production of cold beams of ND3 with variable rotational state distributions by electrostatic extraction of He and Ne buffer-gas-cooled beams. AB - The measurement of the rotational state distribution of a velocity-selected, buffer-gas-cooled beam of ND3 is described. In an apparatus recently constructed to study cold ion-molecule collisions, the ND3 beam is extracted from a cryogenically cooled buffer-gas cell using a 2.15 m long electrostatic quadrupole guide with three 90 degrees bends. (2+1) resonance enhanced multiphoton ionization spectra of molecules exiting the guide show that beams of ND3 can be produced with rotational state populations corresponding to approximately T(rot) = 9-18 K, achieved through manipulation of the temperature of the buffer-gas cell (operated at 6 K or 17 K), the identity of the buffer gas (He or Ne), or the relative densities of the buffer gas and ND3. The translational temperature of the guided ND3 is found to be similar in a 6 K helium and 17 K neon buffer-gas cell (peak kinetic energies of 6.92(0.13) K and 5.90(0.01) K, respectively). The characterization of this cold-molecule source provides an opportunity for the first experimental investigations into the rotational dependence of reaction cross sections in low temperature collisions. PMID- 25028021 TI - On the room-temperature phase diagram of high pressure hydrogen: an ab initio molecular dynamics perspective and a diffusion Monte Carlo study. AB - The finite-temperature phase diagram of hydrogen in the region of phase IV and its neighborhood was studied using the ab initio molecular dynamics (MD) and the ab initio path-integral molecular dynamics (PIMD). The electronic structures were analyzed using the density-functional theory (DFT), the random-phase approximation, and the diffusion Monte Carlo (DMC) methods. Taking the state-of the-art DMC results as benchmark, comparisons of the energy differences between structures generated from the MD and PIMD simulations, with molecular and dissociated hydrogens, respectively, in the weak molecular layers of phase IV, indicate that standard functionals in DFT tend to underestimate the dissociation barrier of the weak molecular layers in this mixed phase. Because of this underestimation, inclusion of the quantum nuclear effects (QNEs) in PIMD using electronic structures generated with these functionals leads to artificially dissociated hydrogen layers in phase IV and an error compensation between the neglect of QNEs and the deficiencies of these functionals in standard ab initio MD simulations exists. This analysis partly rationalizes why earlier ab initio MD simulations complement so well the experimental observations. The temperature and pressure dependencies for the stability of phase IV were also studied in the end and compared with earlier results. PMID- 25028022 TI - Reversible amorphous-crystalline phase changes in a wide range of Se(1-x)Te(x) alloys studied using ultrafast differential scanning calorimetry. AB - The reversible amorphous-crystalline phase change in a chalcogenide material, specifically the Se1-xTex alloy, has been investigated for the first time using ultrafast differential scanning calorimetry. Heating rates and cooling rates up to 5000 K/s were used. Repeated reversible amorphous-crystalline phase switching was achieved by consecutively melting, melt-quenching, and recrystallizing upon heating. Using a well-conditioned method, the composition of a single sample was allowed to shift slowly from 15 at. %Te to 60 at. %Te, eliminating sample-to sample variability from the measurements. Using Energy Dispersive X-ray Spectroscopy composition analysis, the onset of melting for different Te concentrations was confirmed to coincide with the literature solidus line, validating the use of the onset of melting Tm as a composition indicator. The glass transition Tg and crystallization temperature Tc could be determined accurately, allowing the construction of extended phase diagrams. It was found that Tm and Tg increase (but Tg/Tm decrease slightly) with increasing Te concentration. Contrarily, the Tc decreases substantially, indicating that the amorphous phase becomes progressively unfavorable. This coincides well with the observation that the critical quench rate to prevent crystallization increases about three orders of magnitude with increasing Te concentration. Due to the employment of a large range of heating rates, non-Arrhenius behavior was detected, indicating that the undercooled liquid SeTe is a fragile liquid. The activation energy of crystallization was found to increase 0.5-0.6 eV when the Te concentration increases from 15 to 30 at. % Te, but it ceases to increase when approaching 50 at. % Te. PMID- 25028023 TI - An electronic criterion for assessing intrinsic brittleness of metallic glasses. AB - Bulk metallic glasses (BMGs) are characterized by a number of remarkable physical and mechanical properties. Unfortunately, these same materials are often intrinsically brittle, which limits their utility. Consequently, considerable effort has been expended searching for correlations between the phenomenologically complex mechanical properties of metallic glasses and more basic properties, such correlations might provide insight into the structure and bonding controlling the deformation properties of BMGs. While conducting such a search, we uncovered a weak correlation between a BMG's work function and its susceptibility to brittle behavior. We argue that the basis for this correlation is a consequence of a component of the work function - the surface dipole - and a fundamental bond property related to the shape of the charge density at a bond critical point. Together these observations suggest that simple first principle calculations might be useful in the search for tougher BMGs. PMID- 25028024 TI - Liquid-state polaron theory of the hydrated electron revisited. AB - The quantum path integral/classical liquid-state theory of Chandler and co workers, created to describe an excess electron in solvent, is re-examined for the hydrated electron. The portion that models electron-water density correlations is replaced by two equations: the range optimized random phase approximation (RO-RPA), and the Donley, Rajasekaran, and Liu (DRL) approximation to the "two-chain" equation, both shown previously to describe accurately the static structure and thermodynamics of strongly charged polyelectrolyte solutions. The static equilibrium properties of the hydrated electron are analyzed using five different electron-water pseudopotentials. The theory is then compared with data from mixed quantum/classical Monte Carlo and molecular dynamics simulations using these same pseudopotentials. It is found that the predictions of the RO-RPA and DRL-based polaron theories are similar and improve upon previous theory, with values for almost all properties analyzed in reasonable quantitative agreement with the available simulation data. Also, it is found using the Larsen, Glover, and Schwartz pseudopotential that the theories give values for the solvation free energy that are at least three times larger than that from experiment. PMID- 25028025 TI - Lithium hydroxide, LiOH, at elevated densities. AB - We discuss the high-pressure phases of crystalline lithium hydroxide, LiOH. Using first-principles calculations, and assisted by evolutionary structure searches, we reproduce the experimentally known phase transition under pressure, but we suggest that the high-pressure phase LiOH-III be assigned to a new hydrogen bonded tetragonal structure type that is unique amongst alkali hydroxides. LiOH is at the intersection of both ionic and hydrogen bonding, and we examine the various ensuing structural features and their energetic driving mechanisms. At P = 17 GPa, we predict another phase transition to a new phase, Pbcm-LiOH-IV, which we find to be stable over a wide pressure range. Eventually, at extremely high pressures of 1100 GPa, the ground state of LiOH is predicted to become a polymeric structure with an unusual graphitic oxygen-hydrogen net. However, because of its ionic character, the anticipated metallization of LiOH is much delayed; in fact, its electronic band gap increases monotonically into the TPa pressure range. PMID- 25028026 TI - The effect of substrate on thermodynamic and kinetic anisotropies in atomic thin films. AB - Glasses have a wide range of technological applications. The recent discovery of ultrastable glasses that are obtained by depositing the vapor of a glass-forming liquid onto the surface of a cold substrate has sparked renewed interest in the effects of confinements on physicochemical properties of liquids and glasses. Here, we use molecular dynamics simulations to study the effect of substrate on thin films of a model glass-forming liquid, the Kob-Andersen binary Lennard-Jones system, and compute profiles of several thermodynamic and kinetic properties across the film. We observe that the substrate can induce large oscillations in profiles of thermodynamic properties such as density, composition, and stress, and we establish a correlation between the oscillations in total density and the oscillations in normal stress. We also demonstrate that the kinetic properties of an atomic film can be readily tuned by changing the strength of interactions between the substrate and the liquid. Most notably, we show that a weakly attractive substrate can induce the emergence of a highly mobile region in its vicinity. In this highly mobile region, structural relaxation is several times faster than in the bulk, and the exploration of the potential energy landscape is also more efficient. In the subsurface region near a strongly attractive substrate, however, the dynamics is decelerated and the sampling of the potential energy landscape becomes less efficient than the bulk. We explain these two distinct behaviors by establishing a correlation between the oscillations in kinetic properties and the oscillations in lateral stress. Our findings offer interesting opportunities for designing better substrates for the vapor deposition process or developing alternative procedures for situations where vapor deposition is not feasible. PMID- 25028027 TI - Structural, vibrational, and elastic properties of a calcium aluminosilicate glass from molecular dynamics simulations: the role of the potential. AB - We study a calcium aluminosilicate glass of composition (SiO2)0.60(Al2O3)0.10(CaO)0.30 by means of molecular dynamics. To this end, we conduct parallel simulations, following a consistent methodology, but using three different potentials. Structural and elastic properties are analyzed and compared to available experimental data. This allows assessing the respective abilities of the potentials to produce a realistic glass. We report that, although all these potentials offer a reasonable glass structure, featuring tricluster oxygen atoms, their respective vibrational and elastic predictions differ. This allows us to draw some general conclusions about the crucial role, or otherwise, of the interaction potential in silicate systems. PMID- 25028028 TI - Diffusion affected magnetic field effect in exciplex fluorescence. AB - The fluorescence of the exciplex, (1)[D(+delta)A(-delta)], formed at contact of photoexcited acceptor (1)A(*) with an electron donor (1)D, is known to be very sensitive to an external magnetic field, reducing the spin conversion efficiency in the resulting geminate radical ion pair, (1, 3)[D(+)...A(-)]. The relative increase of the exciplex fluorescence in the highest magnetic field compared to the lowest one, known as the magnetic field effect, crucially depends on the viscosity of the solvent. This phenomenon first studied experimentally is at first reproduced here theoretically. The magnetic field effect is shown to vanish in both limits of high and low solvent diffusivity reaching a maximum in between. It is also very sensitive to the solvent dielectric constant and to the exciplex and radical-ion pair conversion rates. PMID- 25028029 TI - Ultrafast pump-probe and 2DIR anisotropy and temperature-dependent dynamics of liquid water within the E3B model. AB - Recently, Tainter et al. [J. Chem. Phys. 134, 184501 (2011)] reparameterized a new rigid water model (E3B) that explicitly includes three-body interactions in its Hamiltonian. Compared to commonly used water models such as SPC/E and TIP4P, the new model shows better agreement with experiment for many physical properties including liquid density, melting temperature, virial coefficients, etc. However, the dynamics of the E3B model, especially as a function of temperature, has not been systematically evaluated. Experimental nonlinear vibrational spectroscopy is an ideal tool to study the dynamics of matter in condensed phases. In the present study, we calculate linear and nonlinear vibrational spectroscopy observables for liquid water using the E3B model at five temperatures: 10, 30, 50, 70 and 90 degrees C. Specifically, we calculate absorption and Raman spectra and pump-probe anisotropy for HOD in H2O at all temperatures, frequency-resolved pump-probe anisotropy for HOD in both H2O and D2O at 30 degrees C, and 2DIR anisotropy for HOD in D2O at 30 degrees C. In all cases, we find reasonable agreement with experiment, and for the ultrafast spectroscopy our results are a significant improvement over those of the SPC/E model. A likely reason for this improvement is that the three-body interaction terms in the E3B model are able to model cooperative hydrogen bonding. We also calculate rotational and frequency relaxation times at all temperatures, and fit the results to the Arrhenius equation. We find that the activation energy for hydrogen-bond switching in liquid water is 3.8 kcal/mol, which agrees well with the experimental value of 3.7 kcal/mol obtained from anisotropy decay experiments. PMID- 25028030 TI - Simulating the vibrational spectra of ionic liquid systems: 1-ethyl-3 methylimidazolium acetate and its mixtures. AB - The vibrational spectra of the ionic liquid 1-ethyl-3-methylimidazolium acetate and its mixtures with water and carbon dioxide are calculated using ab initio molecular dynamics simulations, and the results are compared to experimental data. The new implementation of a normal coordinate analysis in the trajectory analyzer TRAVIS is used to assign the experimentally observed bands to specific molecular vibrations. The applied computational approaches prove to be particularly suitable for the modeling of bulk phase effects on vibrational spectra, which are highly important for the discussion of the microscopic structure in systems with a strong dynamic network of intermolecular interactions, such as ionic liquids. PMID- 25028031 TI - Critical point of gas-liquid type phase transition and phase equilibrium functions in developed two-component plasma model. AB - A two-component plasma model, which we called a "shelf Coulomb" model has been developed in this work. A Monte Carlo study has been undertaken to calculate equations of state, pair distribution functions, internal energies, and other thermodynamics properties. A canonical NVT ensemble with periodic boundary conditions was used. The motivation behind the model is also discussed in this work. The "shelf Coulomb" model can be compared to classical two-component (electron-proton) model where charges with zero size interact via a classical Coulomb law. With important difference for interaction of opposite charges: electrons and protons interact via the Coulomb law for large distances between particles, while interaction potential is cut off on small distances. The cut off distance is defined by an arbitrary E parameter, which depends on system temperature. All the thermodynamics properties of the model depend on dimensionless parameters E and gamma = betae(2)n(1/3) (where beta = 1/kBT, n is the particle's density, kB is the Boltzmann constant, and T is the temperature) only. In addition, it has been shown that the virial theorem works in this model. All the calculations were carried over a wide range of dimensionless E and gamma parameters in order to find the phase transition region, critical point, spinodal, and binodal lines of a model system. The system is observed to undergo a first order gas-liquid type phase transition with the critical point being in the vicinity of E(crit) ~ 13(T(*)(crit) ~ 0.076), gamma(crit) ~ 1.8(v(*)(crit) ~ 0.17), P(*)(crit) ~ 0.39, where specific volume v* = 1/gamma(3) and reduced temperature T(*) = E(-1). PMID- 25028032 TI - Dynamics of H2 Eley-Rideal abstraction from W(110): sensitivity to the representation of the molecule-surface potential. AB - Dynamics of the Eley-Rideal (ER) abstraction of H2 from W(110) is analyzed by means of quasi-classical trajectory calculations. Simulations are based on two different molecule-surface potential energy surfaces (PES) constructed from Density Functional Theory results. One PES is obtained by fitting, using a Flexible Periodic London-Eyring-Polanyi-Sato (FPLEPS) functional form, and the other by interpolation through the corrugation reducing procedure (CRP). Then, the present study allows us to elucidate the ER dynamics sensitivity on the PES representation. Despite some sizable discrepancies between both H+H/W(110) PESs, the obtained projectile-energy dependence of the total ER cross sections are qualitatively very similar ensuring that the main physical ingredients are captured in both PES models. The obtained distributions of the final energy among the different molecular degrees of freedom barely depend on the PES model, being most likely determined by the reaction exothermicity. Therefore, a reasonably good agreement with the measured final vibrational state distribution is observed in spite of the pressure and material gaps between theoretical and experimental conditions. PMID- 25028033 TI - The interaction of organic adsorbate vibrations with substrate lattice waves in methyl-Si(111)-(1 * 1). AB - A combined helium atom scattering and density functional perturbation theory study has been performed to elucidate the surface phonon dispersion relations for both the CH3-Si(111)-(1 * 1) and CD3-Si(111)-(1 * 1) surfaces. The combination of experimental and theoretical methods has allowed characterization of the interactions between the low energy vibrations of the adsorbate and the lattice waves of the underlying substrate, as well as characterization of the interactions between neighboring methyl groups, across the entire wavevector resolved vibrational energy spectrum of each system. The Rayleigh wave was found to hybridize with the surface rocking libration near the surface Brillouin zone edge at both the M-point and K-point. The calculations indicated that the range of possible energies for the potential barrier to the methyl rotation about the Si-C axis is sufficient to prevent the free rotation of the methyl groups at a room temperature interface. The density functional perturbation theory calculations revealed several other surface phonons that experienced mode splitting arising from the mutual interaction of adjacent methyl groups. The theory identified a Lucas pair that exists just below the silicon optical bands. For both the CH3- and CD3-terminated Si(111) surfaces, the deformations of the methyl groups were examined and compared to previous experimental and theoretical work on the nature of the surface vibrations. The calculations indicated a splitting of the asymmetric deformation of the methyl group near the zone edges due to steric interactions of adjacent methyl groups. The observed shifts in vibrational energies of the -CD3 groups were consistent with the expected effect of isotopic substitution in this system. PMID- 25028034 TI - Pressure-driven variations of hydrogen bonding energy in ammonium azide (NH4N3): IR absorption and Raman scattering studies. AB - In this study, high pressure infrared (IR) absorption and Raman scattering studies for ammonium azide (NH4N3) were carried out at room temperature up to 20 GPa and 22 GPa, respectively. For comparison and further assignment, the vibrational spectra at ambient conditions were calculated using CASTEP code, particularly for the far- and mid-IR modes. The recorded vibrational data consistently indicated a pressure-induced phase transition at 2.9 GPa. All observed vibrational modes maintained their identities at the high pressure phase, indicating that NH4N3 was still presented in the form of ammonium cations and azide anions linked by the hydrogen bond (N-H?N). Above 2.9 GPa, the relative magnitude of the torsional mode weakened and the N-H symmetric stretch displayed a redshift, indicating strengthened hydrogen bonding energy. The opposite effects were observed above 12 GPa, where the relative magnitude of the torsional mode strengthened and the N-H symmetric stretch reverted to a blueshift, indicating weakened hydrogen bonding energy. It can be concluded that the hydrogen bonding energy exhibited a weakening (0-2.9 GPa), strengthening (2.9-12 GPa), and then again weakening (12-22 GPa) phenomena with the increasing of compression. The hydrogen bonding energy changing with the increase of pressure can be ascribed to a phase transition at 2.9 GPa and a rotational or bending behavior of azide ions at 12 GPa. PMID- 25028035 TI - Toward tailorable surfaces: a combined theoretical and experimental study of lanthanum niobate layered perovskites. AB - A comprehensive theoretical investigation of the MLaNb2O7 (M = H, Li, Na, K, Rb, and Cs) series of ion-exchangeable layered perovskite is presented. These perovskites are in particular interesting in view of their potential applications as inorganic supports for the design of new hybrid inorganic-organic proton conductors. In particular, their structural and electronic properties have been investigated by periodic calculations in the framework of Density Functional Theory, using different exchange-correlation functionals. A general very good agreement with the available experimental (XRD, NPD, and EXAFS) data has been found. The structure of the protonated HLaNb2O7 form has also been further clarified and a new tetragonal space group is proposed for this compound, better reproducing the experimental cell parameters and yielding to a more realistic picture of the system. The electronic investigation highlighted that all the compounds considered are very similar to each other and that the interaction between interlayer cations and perovskite slabs is purely ionic, except for the proton that is, instead, covalently bound. PMID- 25028036 TI - Aris-Taylor dispersion in tubes with dead ends. AB - This paper deals with transport of point Brownian particles in a cylindrical tube with dead ends in the presence of laminar flow of viscous fluid in the cylindrical part of the tube (Poiseuille flow). It is assumed that the dead ends are identical and are formed by spherical cavities connected to the cylindrical part of the tube by narrow necks. The focus is on the effective velocity and diffusivity of the particles as functions of the mean flow velocity and geometric parameter of the tube. Entering a dead end, the particle interrupts its propagation along the tube axis. Later it returns, and the axial motion continues. From the axial propagation point of view, the particle entry into a dead end and its successive return to the flow is equivalent to the particle reversible binding to the tube wall. The effect of reversible binding on the transport parameters has been previously studied assuming that the particle survival probability in the bound state decays as a single exponential. However, this is not the case when the particle enters a dead end, since escape from the dead end is a non-Markovian process. Our analysis of the problem consists of two steps: First, we derive expressions for the effective transport parameters in the general case of non-Markovian binding. Second, we find the effective velocity and diffusivity by substituting into these expressions known results for the moments of the particle lifetime in the dead end [L. Dagdug, A. M. Berezhkovskii, Yu. A. Makhnovskii, and V. Yu. Zitserman, J. Chem. Phys. 127, 224712 (2007)]. To check the accuracy of our theory, we compare its predictions with the values of the effective velocity and diffusivity obtained from Brownian dynamics simulations. The comparison shows excellent agreement between the theoretical predictions and numerical results. PMID- 25028037 TI - Dynamic mean field theory for lattice gas models of fluids confined in porous materials: higher order theory based on the Bethe-Peierls and path probability method approximations. AB - Recently we have developed a dynamic mean field theory (DMFT) for lattice gas models of fluids in porous materials [P. A. Monson, J. Chem. Phys. 128(8), 084701 (2008)]. The theory can be used to describe the relaxation processes in the approach to equilibrium or metastable states for fluids in pores and is especially useful for studying system exhibiting adsorption/desorption hysteresis. In this paper we discuss the extension of the theory to higher order by means of the path probability method (PPM) of Kikuchi and co-workers. We show that this leads to a treatment of the dynamics that is consistent with thermodynamics coming from the Bethe-Peierls or Quasi-Chemical approximation for the equilibrium or metastable equilibrium states of the lattice model. We compare the results from the PPM with those from DMFT and from dynamic Monte Carlo simulations. We find that the predictions from PPM are qualitatively similar to those from DMFT but give somewhat improved quantitative accuracy, in part due to the superior treatment of the underlying thermodynamics. This comes at the cost of greater computational expense associated with the larger number of equations that must be solved. PMID- 25028038 TI - First principles studies of proton conduction in KTaO3. AB - KTaO3 (KTO) is a useful prototypical perovskite for examining the mechanisms of proton transport in perovskites. Previously, Gomez et al. [J. Chem. Phys. 126, 194701 (2007)] reported density functional theory (DFT) calculations describing proton hopping in defect-free KTO. We use DFT calculations to extend that work in two directions, namely, understanding isotope effects in low and high temperature proton transport and the role of native point defects in KTO. At cryogenic temperatures, quantum tunneling plays a vital role in the net hopping of protons in KTO. At the elevated temperature characteristic of applications involving proton-conducting perovskites, tunneling is negligible but zero point energy effects still lead to non-negligible isotope effects for H(+), D(+), and T(+). We also use DFT to characterize the populations of relevant point defects in KTO as a function of experimental conditions, and to examine the migration of protons that are close in proximity to these defects. This information gives useful insight into the overall transport rates of protons through KTO under a variety of external environments. We also assess the overall diffusivity of protons in KTO at various ranges of oxygen vacancy concentrations by performing kinetic Monte Carlo simulations. PMID- 25028039 TI - Adapting SAFT-gamma perturbation theory to site-based molecular dynamics simulation. II. Confined fluids and vapor-liquid interfaces. AB - In this work, a new classical density functional theory is developed for group contribution equations of state (EOS). Details of implementation are demonstrated for the recently-developed SAFT-gamma WCA EOS and selective applications are studied for confined fluids and vapor-liquid interfaces. The acronym WCA (Weeks Chandler-Andersen) refers to the characterization of the reference part of the third-order thermodynamic perturbation theory applied in formulating the EOS. SAFT-gamma refers to the particular form of "statistical associating fluid theory" that is applied to the fused-sphere, heteronuclear, united-atom molecular models of interest. For the monomer term, the modified fundamental measure theory is extended to WCA-spheres. A new chain functional is also introduced for fused and soft heteronuclear chains. The attractive interactions are taken into account by considering the structure of the fluid, thus elevating the theory beyond the mean field approximation. The fluctuations of energy are also included via a non local third-order perturbation theory. The theory includes resolution of the density profiles of individual groups such as CH2 and CH3 and satisfies stoichiometric constraints for the density profiles. New molecular simulations are conducted to demonstrate the accuracy of each Helmholtz free energy contribution in reproducing the microstructure of inhomogeneous systems at the united-atom level of coarse graining. At each stage, comparisons are made to assess where the present theory stands relative to the current state of the art for studying inhomogeneous fluids. Overall, it is shown that the characteristic features of real molecular fluids are captured both qualitatively and quantitatively. For example, the average pore density deviates ~2% from simulation data for attractive pentadecane in a 2-nm slit pore. Another example is the surface tension of ethane/heptane mixture, which deviates ~1% from simulation data while the theory reproduces the excess accumulation of ethane at the interface. PMID- 25028040 TI - Peptide-induced membrane curvature in edge-stabilized open bilayers: a theoretical and molecular dynamics study. AB - Peptide- or protein-induced curvatures of lipid membranes may be studied in molecular dynamics (MD) simulations. In these, membranes are usually modeled as infinitely extended bilayers by using periodic boundary conditions. However, the enforced periodicity results in an underestimation of the bending power of peptides, unless the patch size is much larger than the induced curvature radii. In this letter, we propose a novel approach to evaluate the bending power of a given distribution and/or density of peptides based on the use of flat open-edged lipid patches. To ensure long-lived metastable structures, the patch rim is stabilized in MD simulations by a local enrichment with short-chain lipids. By combining the theory of continuum elastic media with MD simulations, we prove that open-edged patches evolve from a planar state to a closed vesicle, with a transition rate that strongly depends on the concentration of lipid soluble peptides. For close-to-critical values for the patch size and edge energy, the response to even small changes in peptide concentration adopts a transition-like behavior (buckling instability). The usage of open-edged membrane patches amplifies the bending power of peptides, thereby enabling the analysis of the structural properties of membrane-peptide systems. We applied the presented method to investigate the curvature induced by aggregating beta -amyloid peptides, unraveling a strong sensitivity of membrane deformation to the peptide concentration. PMID- 25028041 TI - Phase diagram of mixtures of colloids and polymers in the thermal crossover from good to theta solvent. AB - We determine the phase diagram of mixtures of spherical colloids and neutral nonadsorbing polymers in the thermal crossover region between the theta point and the good-solvent regime. We use the generalized free-volume theory, which takes into account the polymer-concentration dependence of the depletion thickness and of the polymer compressibility. This approach turns out to be quite accurate as long as q = Rg/Rc ? 1 (Rg is the radius of gyration of the polymer and Rc is the colloid radius). We find that, close to the theta point, the phase diagram is not very sensitive to solvent quality, while, close to the good-solvent region, changes of the solvent quality modify significantly the position of the critical point and of the binodals. We also analyze the phase behavior of aqueous solutions of charged colloids and polymers, using the approach proposed by Fortini et al. [J. Phys.: Condens. Matter 17, 7783 (2005)]. PMID- 25028042 TI - Coarse-grained molecular simulations of membrane adhesion domains. AB - We use a coarse-grained molecular model of supported lipid bilayers to study the formation of adhesion domains. We find that this process is a first order phase transition, triggered by a combination of pairwise short range attractive interactions between the adhesion bonds and many-body Casimir-like interactions, mediated by the membrane thermal undulations. The simulation results display an excellent agreement with the recently proposed Weil-Farago two-dimensional lattice model, in which the occupied and empty sites represent, respectively, the adhesion bonds and unbound segments of the membrane. A second phase transition, into a hexatic phase, is observed when the attraction between the adhesion bonds is further strengthened. PMID- 25028043 TI - Brownian cluster dynamics with short range patchy interactions: its application to polymers and step-growth polymerization. AB - We present a novel simulation technique derived from Brownian cluster dynamics used so far to study the isotropic colloidal aggregation. It now implements the classical Kern-Frenkel potential to describe patchy interactions between particles. This technique gives access to static properties, dynamics and kinetics of the system, even far from the equilibrium. Particle thermal motions are modeled using billions of independent small random translations and rotations, constrained by the excluded volume and the connectivity. This algorithm, applied to a single polymer chain leads to correct static and dynamic properties, in the framework where hydrodynamic interactions are ignored. By varying patch angles, various local chain flexibilities can be obtained. We have used this new algorithm to model step-growth polymerization under various solvent qualities. The polymerization reaction is modeled by an irreversible aggregation between patches while an isotropic finite square-well potential is superimposed to mimic the solvent quality. In bad solvent conditions, a competition between a phase separation (due to the isotropic interaction) and polymerization (due to patches) occurs. Surprisingly, an arrested network with a very peculiar structure appears. It is made of strands and nodes. Strands gather few stretched chains that dip into entangled globular nodes. These nodes act as reticulation points between the strands. The system is kinetically driven and we observe a trapped arrested structure. That demonstrates one of the strengths of this new simulation technique. It can give valuable insights about mechanisms that could be involved in the formation of stranded gels. PMID- 25028044 TI - Brownian dynamics simulations of nanosheet solutions under shear. AB - The flow-induced conformation dynamics of nanosheets are simulated using a Brownian Dynamics (BD) formulation applied to a bead-rod sheetlike molecular model. This is the first-ever use of BD to simulate flow-induced dynamics of two dimensional structures. Using this framework, we simulate dilute suspensions of coarse-grained nanosheets and compute conformation dynamics for simple shear flow. The data show power law scaling relationships between nanosheet parameters (such as bending moduli and molecular weight) and the resulting intrinsic viscosity and conformation. For nonzero bending moduli, an effective dimension of 2.77 at equilibrium is calculated from the scaling relationship between radius of gyration and molecular weight. We also find that intrinsic viscosity varies with molecular weight with an exponent of 2.12 +/- 0.23; this dependence is significantly larger than those found for linear polymers. Weak shear thinning is observed at high Weissenberg number (Wi). This simulation method provides a computational basis for developing manufacturing processes for nanosheet-derived materials by relating flow forces and nanosheet parameters to the resulting material morphology. PMID- 25028045 TI - Effects of knot type in the folding of topologically complex lattice proteins. AB - The folding properties of a protein whose native structure contains a 52 knot are investigated by means of extensive Monte Carlo simulations of a simple lattice model and compared with those of a 31 knot. A 52 knot embedded in the native structure enhances the kinetic stability of the carrier lattice protein in a way that is clearly more pronounced than in the case of the 31 knot. However, this happens at the expense of a severe loss in folding efficiency, an observation that is consistent with the relative abundance of 31 and 52 knots in the Protein Data Bank. The folding mechanism of the 52 knot shares with that of the 31 knot the occurrence of a threading movement of the chain terminus that lays closer to the knotted core. However, co-concomitant knotting and folding in the 52 knot occurs with negligible probability, in sharp contrast to what is observed for the 31 knot. The study of several single point mutations highlights the importance in the folding of knotted proteins of the so-called structural mutations (i.e., energetic perturbations of native interactions between residues that are critical for knotting but not for folding). On the other hand, the present study predicts that mutations that perturb the folding transition state may significantly enhance the kinetic stability of knotted proteins provided they involve residues located within the knotted core. PMID- 25028049 TI - Experimental and mathematical analysis of in vitro Pitavastatin hepatic uptake across species. AB - 1. To investigate the non-linear kinetics of in vitro hepatocyte uptake across species, the OATP substrate Pitavastatin was used as a probe. 2. Experiments were conducted at AstraZeneca (Alderley Park, Macclesfield) using freshly isolated rat, dog and human hepatocytes, utilising the "oil spin" methodology described by Hassen et al. (1996). Very few mechanistic models have previously been used to characterise the uptake process. 3. Here two candidate pharmacokinetic non-linear compartmental models are proposed. Both models have been shown to be structurally identifiable and distinghishable previously, which establishes that all unknown parameters could be identified from the experimental observations available and that input/output relationships for both the candidate models were structurally different. 4. A kinetic modelling software package, FACSIMILE (MCPA Software, Faringdon, UK), was used to obtain numerical solutions for the system equations and for parameter estimation. Model fits gave good agreement with the in vitro data and suggest the current widely accepted assumption that the rate of diffusion across the hepatocyte cell membrane is the same at both 4 degrees C and 37 degrees C is not valid, at least for Pitavastatin. Although this finding has already been proposed, this is the first time it is comprehensively debunked using statistical testing. PMID- 25028050 TI - Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. AB - BACKGROUND: The microbiota of the mammalian gastrointestinal (GI) tract consists of diverse populations of commensal bacteria that interact with host physiological function. Dysregulating these populations, through exogenous means such as antibiotics or dietary changes, can have adverse consequences on the health of the host. Studies from laboratories such as ours have demonstrated that exposure to psychological stressors disrupts the population profile of intestinal microbiota. To date, such studies have primarily focused on prolonged stressors (repeated across several days) and have assessed fecal bacterial populations. It is not known whether shorter stressors can also impact the microbiota, and whether colonic mucosa-associated populations can also be affected. The mucosa associated microbiota exist in close proximity to elements of the host immune system and the two are tightly interrelated. Therefore, alterations in these populations should be emphasized. Additionally, stressors can induce differential responses in anxiety-like behavior and corticosterone outputs in variant strains of mice. Thus, whether stressor exposure can have contrasting effects on the colonic microbiota in inbred C57BL/6 mice and outbred CD-1 mice was also examined. RESULTS: In the present study, we used high throughput pyrosequencing to assess the effects of a single 2-hour exposure to a social stressor, called social disruption (SDR), on colonic mucosa-associated microbial profiles of C57BL/6 mice. The data indicate that exposure to the stressor significantly changed the community profile and significantly reduced the relative proportions of two genera and one family of highly abundant intestinal bacteria, including the genus Lactobacillus. This finding was confirmed using a quantitative real time polymerase chain reaction (qPCR) technique. The use of qPCR also identified mouse strain-specific differences in bacterial abundances. L. reuteri, an immunomodulatory species, was decreased in stressor-exposed CD-1 mice, but not C57BL/6 mice. CONCLUSIONS: These data illustrate that stressor exposure can affect microbial populations, including the lactobacilli, that are closely associated with the colonic mucosa. Because the lactobacilli can have beneficial effects on human health, stressor-induced reductions of their population could have important health implications. PMID- 25028052 TI - Impact of forest fragment size on between-group encounters in lion-tailed macaques. AB - Between-group encounters are an obvious outcome of intergroup competition. Between-group encounters in primates range from avoidance to fatally aggressive. The prevailing hypotheses explain such encounters as mate defense strategy by males and resource defense strategy by females. However, the rate and nature of between-group encounters may also be influenced by habitat and demographic characteristics. We studied the effect of forest fragment size on group encounters in lion-tailed macaques in the Western Ghats of southern India. The encounter rate decreased as the fragment size increased. Group density and home range overlap correlated positively with the encounter rate. The aggressive encounters were more in the relatively medium-sized fragment where the observed frequency of between-group encounters was higher than the expected frequency than in the small fragment and the large forest complex. Together, these results indicate a complex pattern of effects of fragment size on between-group encounters in primates. PMID- 25028053 TI - Predicting the settlement of coarse granular materials under vertical loading. AB - Granular materials are widely used in industrial processes despite their complex and poorly understood mechanical behaviour both in static and dynamic regimes. A prototypical example is the settlement and compaction of a granular bed under vibrational loading. The elementary mechanisms of this process are still unclear and there is presently no established theory or methodology to predict the settlement and its statistical variability. By means of a parametric study, carried out on a full-scale track, and a critical analysis of density relaxation laws, we introduce a novel settlement model in coarse granular materials under cyclic loading. Our extensive experimental data indicate that the settlement process is governed by three independent parameters strongly correlated with the vibration intensity and initial packing fraction. We show that the mean settlement is well predicted by the model with its parameter values extracted from experimental data. PMID- 25028051 TI - McArdle disease: a unique study model in sports medicine. AB - McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called 'second wind' phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities. Patients have been traditionally advised by clinicians to refrain from exercise, yet sports medicine and careful exercise prescription are their best allies at present because no effective enzyme replacement therapy is expected to be available in the near future. As of today, although unable to restore myophosphorylase deficiency, the 'simple' use of exercise as therapy seems probably more promising and practical for patients than more 'complex' medical approaches. PMID- 25028054 TI - Safety of e-cigarettes still needs to be proved. PMID- 25028055 TI - [Endolifter, a new tool for safe and rapid submucosal endoscopic dissection]. AB - BACKGROUND: The effectiveness of endoscopic submucosal dissection (ESD) is similar to that of surgery in the treatment of early lesions. The technique requires a high level of technical skill. Training on biologic models and the mastering of accessories facilitate ESD. AIMS: The aim was to evaluate the usefulness of the Endolifter in facilitating tissue exposure during ESD in an in vivo porcine model performed at the experimental surgery laboratory of the School of Medicine at the Universidad de Sao Paulo in Brazil. MATERIAL AND METHOD: A study with an experimental design employing an in vivo porcine model was conducted on 5 Yorkshire pigs weighing 20-25kg. ESDs were performed using the Endolifter. Mucosal layer dissection was carried out with a dual knife and IT knife and all the endoscopic procedures were performed by a single expert endoscopist. RESULTS: A total of 25 ESDs were performed, with a technical success rate of 100%. The mean dissection time was 12.34min (range: 10.40-14.50 min) and the mean lesion size was 2.7cm (range: 2.3-3.2cm). There were no episodes of bleeding or perforations during the procedures. CONCLUSIONS: The Endolifter enables rapid and effective ESDs to be carried out. It is an applicable and easy to-use device that can be manipulated by a single operator. PMID- 25028056 TI - Effect of miscarriage history on maternal-infant bonding during the first year postpartum in the first baby study: a longitudinal cohort study. AB - BACKGROUND: Miscarriage, the unexpected loss of pregnancy before 20 weeks gestation, may have a negative effect on a mother's perception of herself as a capable woman and on her emotional health when she is pregnant again subsequent to the miscarriage. As such, a mother with a history of miscarriage may be at greater risk for difficulties navigating the process of becoming a mother and achieving positive maternal-infant bonding with an infant born subsequent to the loss. The aim of this study was to examine the effect of miscarriage history on maternal-infant bonding after the birth of a healthy infant to test the hypothesis that women with a history of miscarriage have decreased maternal infant bonding compared to women without a history of miscarriage. METHODS: We completed secondary analysis of the First Baby Study, a longitudinal cohort study, to examine the effect of a history of miscarriage on maternal-infant bonding at 1 month, 6 months, and 12 months after women experienced the birth of their first live-born baby. In a sample of 2798 women living in Pennsylvania, USA, we tested our hypothesis using linear regression analysis of Shortened Postpartum Bonding Questionnaire (S-PBQ) scores, followed by longitudinal analysis using a generalized estimating equations model with repeated measures. RESULTS: We found that women with a history of miscarriage had similar S-PBQ scores as women without a history of miscarriage at each of the three postpartum time points. Likewise, longitudinal analysis revealed no difference in the pattern of maternal-infant bonding scores between women with and without a history of miscarriage. CONCLUSIONS: Women in the First Baby Study with a history of miscarriage did not differ from women without a history of miscarriage in their reported level of bonding with their subsequently born infants. It is important for clinicians to recognize that even though some women may experience impaired bonding related to a history of miscarriage, the majority of women form a healthy bond with their infant despite this history. PMID- 25028057 TI - Methanol extract from Vietnamese Caesalpinia sappan induces apoptosis in HeLa cells. AB - BACKGROUND: This study evaluated the cytotoxic activity of extracts from Caesalpinia sappan heartwood against multiple cancer cell lines using an MTT cell viability assay. The cell death though induction of apoptosis was as indicated by DNA fragmentation and caspase-3 enzyme activation. RESULTS: A methanol extract from C. sappan (MECS) showed cytotoxic activity against several of the cancer cell lines. The most potent activity exhibited by the MECS was against HeLa cells with an IC50 value of 26.5 +/- 3.2 MUg/mL. Treatment of HeLa cells with various MECS concentrations resulted in growth inhibition and induction of apoptosis, as indicated by DNA fragmentation and caspase-3 enzyme activation. CONCLUSION: This study is the first report of the anticancer properties of the heartwood of C. sappan native to Vietnam. Our findings demonstrate that C. sappan heartwood may have beneficial applications in the field of anticancer drug discovery. PMID- 25028058 TI - Conservative treatment using a newly designed custom-made wrist splint for ulnocarpal abutment syndrome. AB - BACKGROUND: Immobilization of the wrist joint with a splint is an established approach for ulnar-sided pain due to ulnocarpal abutment syndrome. However, patients have a tendency to stop wearing the splints because of its inconvenience and there have been no reports based on splint therapy. OBJECTIVE: We investigated the usefulness of a newly designed custom-made aluminum splint for ulnar-sided wrist pain. STUDY DESIGN: This was a cohort study of the aluminum splint therapy for the patients who had been primarily treated with a conventional splint but ceased to use it because of the inconvenience in activities of daily living. METHODS: The subjects included 10 female patients (mean age = 44.2 years). The outcome was assessed using the visual analogue scale score for pain, the disabilities of the arm, shoulder and hand score, range of motion of the wrist, and the grip strength. The mean follow-up period after wearing the aluminum splint was 8.8 months. RESULTS: All parameters, including the visual analogue scale pain and disabilities of the arm, shoulder and hand scores, improved significantly (p < 0.05) following use of the aluminum splint relative to the pretreatment scores. Seven patients continued to use the aluminum splint, and three of the seven had complete remission from related pain. CONCLUSION: Constant use of the aluminum splint during the study period was associated with improvement in the ulnar-sided wrist pain scores, which reconfirmed that increased adherence to splint use in daily activities is an important intentional behavioral strategy. CLINICAL RELEVANCE: Although the custom splint is effective for alleviation of wrist pain in ulnocarpal abutment syndrome, continuity of splint use is a key element of conservative treatment. This study showed that a splint that patients were willing to wear in their daily life was a useful device for alleviation of pain. PMID- 25028059 TI - A genetic epidemiology approach to cyber-security. AB - While much attention has been paid to the vulnerability of computer networks to node and link failure, there is limited systematic understanding of the factors that determine the likelihood that a node (computer) is compromised. We therefore collect threat log data in a university network to study the patterns of threat activity for individual hosts. We relate this information to the properties of each host as observed through network-wide scans, establishing associations between the network services a host is running and the kinds of threats to which it is susceptible. We propose a methodology to associate services to threats inspired by the tools used in genetics to identify statistical associations between mutations and diseases. The proposed approach allows us to determine probabilities of infection directly from observation, offering an automated high throughput strategy to develop comprehensive metrics for cyber-security. PMID- 25028060 TI - The effects of cognitive impairment on nursing home residents' emergency department visits and hospitalizations. AB - BACKGROUND: Little is known about the relationship of cognitive impairment (CI) in nursing home (NH) residents and their use of emergency department (ED) and subsequent hospital services. METHODS: We analyzed 2006 Medicare claims and resident assessment data for 112,412 Medicare beneficiaries aged >65 years residing in US nursing facilities. We estimated the effect of resident characteristics and severity of CI on rates of total ED visits per year, then estimated the odds of hospitalization after ED evaluation. RESULTS: Mild CI predicted higher rates of ED visits relative to no CI, and ED visit rates decreased as severity of CI increased. In unadjusted models, mild CI and very severe CI predicted higher odds of hospitalization after ED evaluation; however, after adjusting for other factors, severity of CI was not significant. CONCLUSIONS: Higher rates of ED visits among those with mild CI may represent a unique marker in the presentation of acute illness and warrant further investigation. PMID- 25028061 TI - Effects of particle softness on shear thickening of microgel suspensions. AB - A series of microgel particles composed of a polystyrene (PS) core and a thermo sensitive poly(N-isopropylacrylamide) (PNIPAM) shell with different shell thicknesses were investigated to elucidate the effect of microgel softness on its shear thickening behavior. Since the softness of the microgels increases with decreasing temperature through the volume phase transition effect of PNIPAM shell, the measured softness parameter, n, which is derived from the Zwanzig Mountain equation, was used to measure and describe the combined influences of temperature and shell thickness. Confocal microscopy is used to investigate the interaction potential between microgel particles with different softness parameters. According to the obtained results, the softness parameter can provide an estimate for the shear thickening behavior of microgel suspensions, at least semi-quantitatively. PMID- 25028062 TI - Melleolides induce rapid cell death in human primary monocytes and cancer cells. AB - The melleolides are structurally unique and bioactive natural products of the basidiomycete genus Armillaria. Here, we report on cytotoxic effects of melleolides from Armillaria mellea towards non-transformed human primary monocytes and human cancer cell lines, respectively. In contrast to staurosporine or pretubulysin that are less cytotoxic for monocytes, the cytotoxic potency of the active melleolides in primary monocytes is comparable to that in cancer cells. The onset of the cytotoxic effects of melleolides was rapid (within <1 h), as compared to the apoptosis inducer staurosporine, the protein biosynthesis inhibitor cycloheximide, and the DNA transcription inhibitor actinomycin D (>5 h, each). Side-by-side comparison with the detergent triton X-100 and staurosporine in microscopic and flow cytometric analysis studies as well as analysis of the viability of mitochondria exclude cell lysis and apoptosis as relevant or primary mechanisms. Our results rather point to necrotic features of cell death mediated by an as yet elusive but rapid mechanism. PMID- 25028063 TI - Experiences of critical incidents among female and male firefighters. AB - BACKGROUND: A critical incident is defined as an event stressful enough to overwhelm the usually effective coping skills of an individual. Firefighters are frequently exposed to critical incidents that might have consequences for individuals and their performance in organization. AIM: The aim of this study was to describe experiences of critical incidents among female and male Swedish firefighters. METHOD: In all 180 participants (16 women, 164 men) who had been involved in up to 25 critical incidents during the last year responded to a survey describing critical incidents experienced in the past year. A qualitative content analysis identified several areas for improvement in firefighters' working conditions. RESULTS: Female firefighters were terse in describing their experiences, while the men described their experiences of critical events more vividly. The critical incidents described by the firefighters concerned such overwhelming situations as traffic accidents, huge fires, and other fatal incidents such as drownings and suicides. Risk of delay due to lack of equipment training and lack of medical education was mentioned. Lack of resources and organizational problems was mentioned as causing risks of failure. Several firefighters expressed frustration over being assaulted and threatened, or exposed to other kinds of violence. Not knowing how close, physically or mentally, one can get to people during ongoing rescue can lead to unsuccessful operations. CONCLUSIONS: Gender patterns should always be taken into account, making it possible for all firefighters to express and reflect on existentially tough experiences. Education needs to focus more on medical and mental health issues. Firefighters were sometimes exposed to the difficult challenge of violence and assault during rescue operations. The complexity of this problem needs to be highlighted, not only in firefighter organizations, but also in society in general. PMID- 25028064 TI - Bonding and spectroscopic properties of complexes of SO2-O2 and SO2-N2 and its atmospheric consequences. AB - van der Waals complexes of sulfur dioxide (SO2) with oxygen (O2) and nitrogen (N2) have been investigated by using MP2 and aug-cc-pVXZ (X = D, T) basis set. Two minimum structures with symmetry C1 and Cs have been located at the intermolecular potential energy surface (IPES) of the complex of SO2-O2. Stacked Cs structure of SO2-O2 is found to have greater stability than C1 structure. In the case of SO2-N2, one minimum structure with Cs symmetry has been characterized. In this study, CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ and interaction energy calculation at complete basis set (CBS) limit has been employed for better energetic description. The natural bond orbital (NBO) calculation demonstrates the bonding in terms of charge transfer from X-atom lone pair of X2 (X = O or N) to the antibonding SO orbital of SO2. The strength of various intra and inter bonds in the complexes were calculated in terms of electron density at bond critical points (BCP) using quantum theory of atoms in molecules (QTAIM). Frequency calculations for these complexes show a number of interactions induced by low frequency modes in the far IR region. Symmetry adapted calculation were also computed for the complexes and is established that the ratio of dispersion to induction effect is large for the most stable conformers. The atmospheric implications are also discussed for these complexes. PMID- 25028066 TI - Chronic histiocytic intervillositis: outcome, associated diseases and treatment in a multicenter prospective study. AB - Introduction: In this prospective multicenter study, we aimed to describe (1) the outcome of pregnancy in the case of previous chronic histiocytic intervillositis (CHI), (2) the immunological findings and associated diseases, (3) the treatments, and (4) the factors associated with pregnancy loss. METHODS: We prospectively included all patients with a prior CHI with ongoing pregnancy between 2011 and 2013. RESULTS: Twenty-four women (age 34+/-5 years) were included in this study. An autoimmune disease was present in seven (29%) cases. Twenty-one prospective pregnancies were treated. The number of live births was more frequent comparatively to the previous obstetrical issues (16/24 versus 24/76; p=0.003). Most of the pregnancies were treated (88%), whereas only 13% of previous pregnancies were treated (p<0.05). No difference was found with respect to the pregnancy outcome in the different treatment regimens. In univariate analyses, a prior history of intrauterine death and intrauterine growth restriction and the presence of CHI in prospective placentas were associated with failure to have a live birth. DISCUSSION: In this multicenter study, we show the frequency of the associated autoimmune diseases in CHI, as well as the presence of autoantibodies without characterized autoimmune disease. The number of live births increased from 32% to 67% in the treated pregnancies. Despite the treatment intervention, the risk of preterm delivery remained at 30%. Last, we show that the recurrence rate of an adverse pregnancy outcome persisted at 30% despite treatment intervention. CONCLUSION: CHI is associated with high recurrence rate and the combined regimen seems to be necessary, in particular, in the presence of previous intrauterine death. PMID- 25028065 TI - Reliability, validity and treatment sensitivity of the Schizophrenia Cognition Rating Scale. AB - Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r=-0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P<.001). These data suggest that the SCoRS has potential as a clinically relevant measure in clinical trials aiming to improve cognition in schizophrenia, and may be useful for clinical practice. The weaknesses of the SCoRS include its reliance on informant information, which is not available for some patients, and reduced validity when patient's self-report is the sole information source. PMID- 25028067 TI - Preoperative administration of 0.2% chlorhexidine mouthrinse reduces the risk of bacteraemia associated with intra-alveolar tooth extraction. AB - The aim of the study was to investigate the effect of preoperative 0.2% chlorhexidine mouthwash on the risk of bacteraemia following routine intra alveolar tooth extraction. The study was a randomized controlled clinical study of 101 subjects who underwent intra-alveolar dental extractions under local anaesthesia. Subjects were randomly assigned to either chlorhexidine or a control group. The chlorhexidine group had 0.2% chlorhexidine mouthwash administered for 1 min before any dental manipulation, and the control group had a mouthrinse of sterile water. Blood samples were collected at baseline, 1 min and 15 min after the dental extractions. Subculture and further identification of the isolated bacteria were performed by conventional microbiological techniques. There was a statistically significant difference in the incidence of bacteraemia between the control group (52.4%) and chlorhexidine group (27.1%) (P = 0.012). Bacteraemia was most frequently detected at 1 min after extraction (33.3%). Of the 30 subjects who had positive blood culture at 1 min, bacteraemia persisted in 8 (26.7%) of the subjects after 15 min. Bacteria isolated included Staphylococcus aureus, Actinomycetes naesulendi, Prevotella species, Streptococcus spp., and Acinetobacter iwoffii. Routine use of 0.20% chlorhexidine mouthwash before dental extraction is recommended to reduce the risk of bacteraemia following tooth extraction. PMID- 25028068 TI - Biomechanical analysis of fractures in the mandibular neck (collum mandibulae). AB - After treatment of fractures in the neck of the mandible by means of immobilization of the dentition, often more or less severe manifestations of malocclusion remain. It was hypothesized that this is caused by an altered articulation in the jaw joint on the affected side. Furthermore, it was hypothesized that an anteriorly displaced condyle, as observed frequently as a side effect of the treatment, is caused by pull of the lateral pterygoid muscle, despite maxillomandibular fixation. Intervention experiments were performed in silico to test these hypotheses. With a biomechanical model of the human masticatory system alterations were applied mimicking a fractured mandibular neck and configurations that had been observed after healing. It was predicted that the altered articulation in the jaw joint caused asymmetrical jaw movements despite symmetrical muscle activation. The jaw was predicted to close with an open bite similar to clinical observations. The predicted laterodeviations, however, were not in accordance with clinical observations. Despite maxillo mandibular fixation the lateral pterygoid muscle was able to pull the mandibular condyle out of its fossa in anterior direction. Consequently, despite some methodological limitations, in general the predictions corroborated the hypotheses. PMID- 25028069 TI - [Femtosecond laser in cataract surgery. A critical appraisal]. AB - BACKGROUND: The use of femtosecond lasers (FSL) is increasingly spreading in cataract surgery. Potential advantages over standard manual cataract surgery are the superior precision of corneal incisions and capsular openings as well as the reduction of ultrasound energy for lens nucleus work-up. Exact positioning and dimensioning of the anterior capsular opening should help reduce decentration and tilt of the intraocular lens (IOL) optics and thus achieve better target refraction. Together with the possibility to correct low-grade corneal astigmatism by precise arcuate incision, FSL technology is expected to convert cataract surgery from a purely curative into a refractive procedure. METHODS: Apart from own experiences this review article critically analyses the pertinent literature published so far as well as congress presentations and personal reports of other FSL surgeons. The advantages and disadvantages are scrutinized with regard to their impact on the surgical and refractive results and compared with those experienced by the authors with manual cataract surgery over several decades. Economic and healthcare political aspects are also addressed. RESULTS: The use of FSL surgery improves the precision and reproducibility of corneal incisions and the capsular opening and reduces the amount of ultrasound energy required for lens nucleus work-up. However, the clinical benefits must be put into perspective due to the subsequent surgical manipulation of the incisions (during lens emulsification, aspiration and IOL injection), the lacking possibility to visualize the crystalline lens equator as the reference for correct capsulotomy centration and the relativity of ultrasound energy consumption on the corneal endothelial trauma. This is of particular relevance against the background of the significantly higher costs. Conversely, tears of the anterior capsule edge which, apart from interfering with correct IOL positioning, may entail serious complications presently occur more frequently with all FSL instruments. From the economic and healthcare political viewpoint, thought should be given to the possible acquisition of the cataract surgical business by the industry or investors, as cataract surgery is a high-volume standardized procedure with enormous future potential. This could fundamentally change our currently decentralized and individualized structures and subsequently the steam of patient and make surgeons largely dependent or superfluous. PMID- 25028070 TI - [Quo vadis neuroimaging? The eye as window to the brain. Current options and future perspectives]. AB - A possible manifestation site for multiple sclerosis (MS) is the optic nerve which clinically presents as optic neuritis. In recent years studies have shown that MS patients have a reduced retinal nerve fiber layer (RNFL) thickness. The literature and own investigations could show that MS patients have a thinning of the RNFL (especially in temporal quadrants) with reduction of the total macular volume and this alteration is also correlated with the severity of the disease. Neuromyelitis optica (monophasic) shows an extreme thinning of the RNFL with severe reduction in vision. In neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, a thinning of the RNFL is also present mostly in all quadrants. Amyotrophic lateral sclerosis and schizophrenia do not show alterations of the retinal layers with optical coherence tomography. PMID- 25028071 TI - [Protective glasses. Personal eye protection for professional use]. AB - Several activities in the occupational environment or in leisure time implicate an increased risk of eye injuries. Many injuries could be prevented by wearing adequate eye protection devices; however, the selection of appropriate eye protection devices requires considerations of different attributes in order to achieve a maximum of protection efficiency. This article provides an overview on the three basic types of eye protection device, introduces the classification regarding optical and protective properties and gives some additional advice on the selection of protective eyewear beyond the current standard regulations. PMID- 25028072 TI - The role of total and cartilage-specific estrogen receptor alpha expression for the ameliorating effect of estrogen treatment on arthritis. AB - INTRODUCTION: Estrogen (E2) delays onset and decreases severity of experimental arthritis. The aim of this study was to investigate the importance of total estrogen receptor alpha (ERalpha) expression and cartilage-specific ERalpha expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis. METHODS: Mice with total (total ERalpha-/-) or cartilage-specific (Col2alpha1-ERalpha-/-) inactivation of ERalpha and wild type (WT) littermates were ovariectomized, treated with E2 or placebo, and induced with antigen-induced arthritis (AIA). At termination, knees were collected for histology, synovial and splenic cells were investigated by using flow cytometry, and splenic cells were subjected to a T-cell proliferation assay. RESULTS: E2 decreased synovitis and joint destruction in WT mice. Amelioration of arthritis was associated with decreased frequencies of inflammatory cells in synovial tissue and decreased splenic T-cell proliferation. E2 did not affect synovitis or joint destruction in total ERalpha-/- mice. In Col2alpha1-ERalpha-/- mice, E2 protected against joint destruction to a similar extent as in WT mice. In contrast, E2 did not significantly ameliorate synovitis in Col2alpha1-ERalpha /- mice. CONCLUSIONS: Treatment with E2 ameliorates both synovitis and joint destruction in ovariectomized mice with AIA via ERalpha. This decreased severity in arthritis is associated with decreased synovial inflammatory cell frequencies and reduced splenic T-cell proliferation. ERalpha expression in cartilage is not required for estrogenic amelioration of joint destruction. However, our data indicate that ERalpha expression in cartilage is involved in estrogenic effects on synovitis, suggesting different mechanisms for the amelioration of joint destruction and synovitis by E2. PMID- 25028074 TI - Risk factors for acute kidney injury in aortic arch surgery with selective cerebral perfusion and mild hypothermic lower body circulatory arrest. AB - OBJECTIVES: Previous studies have reported a high incidence of acute kidney injury (AKI) after thoracic aortic surgery. However, the incidence of AKI in patients undergoing total arch replacement (TAR) with selective cerebral perfusion (SCP) and mild hypothermic lower body circulatory arrest (mild HLBCA) with a tympanic temperature of 25 degrees C remains unknown. We studied AKI incidence and associated risk factors, as defined by the Acute Kidney Injury Network (AKIN). METHODS: We examined 116 consecutive patients with aortic arch aneurysm undergoing non-emergency TAR. Our surgical method is standardized to use systemic cooling of the tympanic membrane temperature to 25 degrees C for circulatory arrest, followed by SCP and myocardial protection by cold blood cardioplegia. Anastomoses were sequentially constructed at the distal arch, the proximal root, the left sub-clavian artery, the left carotid artery and the right brachiocephalic artery. Bladder temperature was generally around 30 degrees C at the start of lower body circulatory arrest (mild HLBCA) until reperfusion of the distal aorta. The incidence of AKI was investigated, with multivariate analysis of its risk factors. RESULTS: The mean operation time, cardiopulmonary bypass (CPB) time, mild HLBCA time and SCP time were 270.6 +/- 72.5, 151.0 +/- 46.4, 53.1 +/- 20.1 and 99.0 +/- 28.4 min, respectively. Hospital mortality occurred in 2 cases (1.7%). AKI occurred in 50 cases (43.1%); of which, 2 cases required renal replacement therapy (RRT). However, AKI had subsided in 44 cases by discharge. For contemporary perspective, the incidence of AKI was 32.8% in off pump coronary bypass grafting and 38.9% in aortic valve replacement. Multivariate analysis of risk factors for AKI identified chronic kidney disease (CKD) (eGFR <60 ml/min/1.73 m(2)) and mild HLBCA time >60 min. CONCLUSIONS: Our method of TAR was associated with low mortality and low rate of kidney injury by discharge. However, prolonged mild HLBCA and preoperative CKD might need additional consideration. PMID- 25028073 TI - Evaluation of felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions. AB - OBJECTIVE: To evaluate felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions (PK-DDIs) involving cytochrome P450 (CYP) enzymes and P glycoprotein (P-gp). METHODS: Felodipine extended-release 10 mg was administered daily to six healthy subjects for 7 days (days 1-7). Subjects were administered a modified Inje cocktail comprising the selective probe substrates caffeine 100 mg (CYP1A2), losartan 25 mg (CYP2C9), omeprazole 20 mg (CYP2C19), dextromethorphan 30 mg (CYP2D6), midazolam 2 mg (CYP3A) and digoxin 250 MUg (P-gp) on day 0 (prior to felodipine exposure) and day 7 (after felodipine exposure). Plasma samples were collected over 24 h and drug concentrations measured by UPLC-MS/MS. RESULTS: The geometric means of the area under the plasma concentration-time curve ratios (probe AUC after felodipine exposure/probe AUC prior to felodipine exposure) and 95% confidence intervals for each probe were: caffeine 0.91 (0.64-1.30), losartan 1.05 (0.95-1.15), omeprazole 1.17 (0.78-1.76), dextromethorphan 1.46 (1.00-2.12), midazolam 1.23 (0.99-1.52) and digoxin 1.01 (0.89-1.15). CONCLUSION: Felodipine may be a weak in vivo inhibitor of CYP3A and CYP2D6 but is unlikely to act as a significant perpetrator of PK-DDIs. PMID- 25028075 TI - Combined operative technique with anterior surgical approach and video-assisted thoracoscopic surgical lobectomy for anterior superior sulcus tumours. AB - Video-assisted thoracoscopic surgery (VATS) has been widely used, but surgical resections of superior sulcus tumours remain challenging because of their anatomical location. For such cases, less-invasive procedures, such as the anterior transcervical-thoracic and transmanubrial approaches, have been widely performed because of their excellent visualization of the subclavian vessels. Recently, a combined operative technique with an anterior surgical approach and VATS for anterior superior sulcus tumours has been introduced. Herein, we report three cases of anterior superior sulcus tumours successfully resected by surgical approaches combined with a VATS-based lobectomy. In all cases, operability was confirmed by VATS, and upper lobectomies with hilar and mediastinal lymph node dissections were performed. Subsequently, dissections of the anterior inlet of the tumours were performed using the transmanubrial approach in two patients and the anterior trans-cervical-thoracic approach in one patient. Both approaches provided excellent access to the anterior inlet of the tumour and exposure of the subclavian vessels, resulting in radical resection of the tumour with concomitant resection of the surrounding anatomical structures, including the chest wall and vessels. In conclusion, VATS lobectomy combined with the anterior surgical approach might be an excellent procedure for the resection of anterior superior sulcus tumours. PMID- 25028076 TI - Evaluation of bilateral pulmonary artery banding for initial palliation in single ventricle neonates and infants: risk factors for mortality before the bidirectional Glenn procedure. AB - OBJECTIVES: Bilateral pulmonary artery banding is considered as 'first-stage' palliation for neonates who have hypoplastic left heart syndrome. This study aimed to identify risk factors that influence outcome before the bidirectional Glenn operation. METHODS: This retrospective evaluation involved 30 consecutive patients with hypoplastic left heart syndrome, or a variant, who underwent bilateral pulmonary artery banding between August 2005 and December 2011 at our institution. Clinical echocardiographic, operative and catheter examination data were reviewed. RESULTS: This study included 9 patients with hypoplastic left heart syndrome and 21 patients with variants. Bilateral pulmonary artery banding was performed at a median age of 7 days. Finally, 19 patients had the bidirectional Glenn operation performed (Group A), and the remaining 11 patients died before the bidirectional Glenn procedure (Group NA). Catheter evaluations before the bidirectional Glenn procedure were carried out at 97 +/- 34 days. The mean pulmonary venous wedge pressure was significantly lower (Group A: 13.1 +/- 3.1 mmHg vs Group NA: 22.9 +/- 3.7 mmHg, P <0.01), systemic ventricular ejection fraction was higher (54.4 +/- 10.7 vs 41.7 +/- 9.9%, P <0.05), systemic ventricular end-diastolic pressure was lower (6.1 +/- 2.4 vs 10.5 +/- 3.6 mmHg, P <0.05) and the rate of patients with more than mild systemic atrioventricular valve regurgitation was lower in Group A than in Group NA (15.7 vs 62.5%, P <0.05). Multivariate logistic regression analysis showed that mean pulmonary venous wedge pressure was the most significant predictor of attaining the bidirectional Glenn anastomosis (odds ratio: 2.35, P <0.01). CONCLUSIONS: Postoperative atrioventricular valve regurgitation, cardiac function and mean pulmonary venous wedge pressure are closely correlated with mortality after bilateral pulmonary artery banding. Additional treatments, including operations, are considered to maintain cardiac function and not to raise pulmonary venous wedge pressure before the bidirectional Glenn procedure. PMID- 25028077 TI - Obesity and the liver: nonalcoholic fatty liver disease. AB - The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) parallels the rise of obesity and its complications. NAFLD is a common cause of cirrhosis and a leading indication for liver transplant. Genetic susceptibility, dietary composition, and exercise habits influence the development of NAFLD, and insulin resistance results in widespread metabolic perturbations with a net effect of triglyceride accumulation in the liver. Some patients will develop hepatocyte cellular injury and fibrosis of the liver, which can progress to cirrhosis and require liver transplant. Treatments targeting the pathophysiological mechanisms of NAFLD exist, but carry some potential risk and are not universally effective. Weight loss and lifestyle changes remain the most effective and safest approach, but sustainable change is difficult for most patients to achieve. Future work will continue to focus on developing effective and safe interventions to prevent the development of advanced liver disease, whereas efforts in the public health domain continue to combat obesity. PMID- 25028078 TI - Dreams, reality and memory: confabulations in lucid dreamers implicate reality monitoring dysfunction in dream consciousness. AB - INTRODUCTION: Dreams might represent a window on altered states of consciousness with relevance to psychotic experiences, where reality monitoring is impaired. We examined reality monitoring in healthy, non-psychotic individuals with varying degrees of dream awareness using a task designed to assess confabulatory memory errors - a confusion regarding reality whereby information from the past feels falsely familiar and does not constrain current perception appropriately. Confabulatory errors are common following damage to the ventromedial prefrontal cortex (vmPFC). Ventromedial function has previously been implicated in dreaming and dream awareness. METHODS: In a hospital research setting, physically and mentally healthy individuals with high (n = 18) and low (n = 13) self-reported dream awareness completed a computerised cognitive task that involved reality monitoring based on familiarity across a series of task runs. RESULTS: Signal detection theory analysis revealed a more liberal acceptance bias in those with high dream awareness, consistent with the notion of overlap in the perception of dreams, imagination and reality. CONCLUSIONS: We discuss the implications of these results for models of reality monitoring and psychosis with a particular focus on the role of vmPFC in default-mode brain function, model-based reinforcement learning and the phenomenology of dreaming and waking consciousness. PMID- 25028079 TI - Behavioural phenotyping of male growth hormone-releasing hormone (GHRH) knockout mice. AB - OBJECTIVE: GH-releasing hormone (GHRH) is a key regulator of GH secretion. The role of GH in anxiety is somewhat contradictory. The aim of this study is to elucidate the consequences of lack of GHRH on emotional behaviour in a mouse model of GH deficiency due to removal of the GHRH gene (GHRH knock out, GHRHKO). DESIGN: Homozygous GHRHKO and wild type male mice were utilized for this study. The emotional behaviour was measured through a battery of behavioural tests (locomotor activity/open field, light-dark exploration, elevated plus maze, forced swim test, tail suspension test). To correlate the emotional behaviour with brain neurochemistry, we evaluated thyrotropin-releasing hormone (TRH) gene expression in hypothalamic tissue by real-time PCR, and the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) in prefrontal cortex by HPLC analysis. RESULTS: GHRHKO mice showed increased exploratory activity. In the open field test (P<0.005), light-dark box (P<0.005) and elevated plus maze (P<0.05), GHRHKO mice demonstrated a decrease in anxiety related behaviour. In addition, GHRHKO mice showed reduced immobility time with respect to control in forced swim test and tail suspension test (P<0.0001). The gene expression of hypothalamic TRH (P<0.05) was increased, while NE levels in prefrontal cortex were decreased compared to control (P<0.05). CONCLUSION: These results suggest that in male mice GHRH deficiency brings about an increased physical activity and decreased anxiety- and depression-related behaviour, possibly related to increased TRH and decreased NE levels in the brain. PMID- 25028081 TI - Screening for hemoglobin Bart's disease among fetuses at risk at mid-pregnancy using the fetal cardiac diameter to biparietal diameter ratio. AB - BACKGROUND: All sonomarkers used to screen for fetal hemoglobin (Hb) Bart's disease need high expertise, preventing them from being widely used. Fetal cardiac diameter to biparietal diameter (C/B) ratio is a simple marker which has never been evaluated for its effectiveness. Therefore, we conducted this study to evaluate the effectiveness of C/B ratio in predicting fetal Hb Bart's disease among fetuses at risk. METHODS: Fetuses at risk of Hb Bart's disease scheduled for diagnostic cordocentesis at 18 to 22 weeks of pregnancy were prospectively enrolled. All underwent ultrasound for fetal biometry and cardio-STIC acquisition for subsequent off-line analysis. Cardio-STIC volume datasets (VDS) were analyzed for cardiac diameter measurement and C/B ratio was calculated by the authors who did not know the fetal diagnosis. Final diagnosis of Hb Bart's disease was based on fetal blood Hb typing. RESULTS: Of 131 pregnancies enrolled to the study, 11 were excluded because of poor quality VDS. The remaining 120 were available for analysis. C/B ratio was significantly higher in the fetuses with Hb Bart's disease than that in the unaffected ones (53.16% vs 41.68%, P < 0.001). C/B ratio could detect fetuses with Hb Bart's disease with sensitivity of 91.5% and specificity of 77.6% (AUC ROC 0.929), using a cut-off point of greater than 45%. CONCLUSIONS: Among fetuses at risk, C/B ratio measurement at mid-pregnancy, using cut-off point of 45%, could effectively differentiate fetuses with Hb Bart's disease from unaffected fetuses. PMID- 25028082 TI - Effect of 12-month intervention with lipid-based nutrient supplements on physical activity of 18-month-old Malawian children: a randomised, controlled trial. AB - BACKGROUND/OBJECTIVES: This study measured the effects of dietary supplementation with lipid-based nutrient supplements (LNSs) on 18-month-old children's physical activity. SUBJECTS/METHODS: In a randomised, controlled, outcome-assessor blinded trial 1932 six-month-old children from Malawi received one of five interventions daily from 6-18 months of age: 10-g milk-LNS, 20-g milk-LNS, 20-g non-milk-LNS, 40-g milk-LNS or 40-g non-milk-LNS, or received no intervention in the same period (control). The control group received delayed intervention with corn-soy blend from 18-30 months. Physical activity was measured over 1 week by ActiGraph GT3X+ accelerometer at 18 months. Main outcome was mean vector magnitude accelerometer counts/15 s. Analyses were restricted to children with valid accelerometer data on at least 4 days with minimum 6 h of wearing time per day. RESULTS: Of the 1435 children recruited to this substudy, 1053 provided sufficient data for analysis. The mean (s.d.) vector magnitude accelerometer counts in the total sample were 307 (64). The difference (95% CI) in mean accelerometer counts, compared with the control group, was 8 (-6 to 21, P=0.258) in 10-g milk-LNS, 3 (-11 to 17, P=0.715) in 20-g milk-LNS, 5 (-8 to 19, P=0.445) in 20-g non-milk-LNS, 10 (-3 to 23, P=0.148) in 40-g milk-LNS and 2 (-12 to 16, P=0.760) in 40-g non-milk-LNS groups. CONCLUSIONS: Provision of 10-40 g doses of LNS daily for 12 months did not increase physical activity of Malawian toddlers. PMID- 25028083 TI - Predictors of vitamin D status in subjects that consume a vitamin D supplement. AB - BACKGROUND/OBJECTIVE: Although dietary supplement use has increased significantly among the general population, the interplay between vitamin D supplementation and other factors that influence vitamin D status remains unclear. The objective of this study was to identify predictor variables of vitamin D status in free-living subjects to determine the extent to which vitamin D supplements and other factors influence vitamin D status. SUBJECTS/METHODS: This was a retrospective, cross sectional study involving 743 volunteers. Serum 25-hydroxy-vitamin D (25(OH)D) level and the variables diet, supplement usage, latitude of residence, ethnicity, age and body mass index (BMI) were used to predict vitamin D status in a summer and winter cohort. RESULTS: Supplemental vitamin D3 consumption was the most significant positive predictor, whereas BMI was the most significant negative predictor, of vitamin D status in each cohort. Other positive predictors were fortified beverage and dairy consumption in the summer and winter cohort, respectively. Negative predictors were: African American, Asian and Hispanic race in the summer; latitude of residence >36 degrees N, Asian and Hispanic ethnicity in the winter. Mean(+/- s.d.) 25(OH)D levels were 101.1 (+/- 42.1) and 92.6 (+/- 39.0) nmol/l in summer and winter, respectively. Comparing non-supplement vs supplement users, approximately 38 vs 2.5% in the winter and 18 vs 1.4% in the summer had vitamin D levels <50 nmol/l. CONCLUSIONS: Vitamin D supplementation was the most significant positive predictor of vitamin D status. Collectively, these data point to the practicality of utilizing vitamin D supplements to reduce hypovitaminosis D in adults throughout the United States. PMID- 25028084 TI - Healthy diet indicator and mortality in Eastern European populations: prospective evidence from the HAPIEE cohort. AB - BACKGROUND/OBJECTIVES: Unhealthy diet has been proposed as one of the main reasons for the high mortality in Central and Eastern Europe (CEE) and the former Soviet Union (FSU) but individual-level effects of dietary habits on health in the region are sparse. We examined the associations between the healthy diet indicator (HDI) and all-cause and cause-specific mortality in three CEE/FSU populations. SUBJECTS/METHODS: Dietary intakes of foods and nutrients, assessed by food frequency questionnaire in the Health, Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) cohort study, were used to construct the HDI, which follows the WHO 2003 dietary recommendations. Among 18 559 eligible adult participants (age range: 45-69 years) without a history of major chronic diseases at baseline, 1209 deaths occurred over a mean follow-up of 7 years. The association between HDI and mortality was estimated by Cox regression. RESULTS: After adjusting for covariates, HDI was inversely and statistically significantly associated with cardiovascular disease (CVD) and coronary heart disease (CHD) mortality, but not with other cause-specific and all-cause mortality in the pooled sample. Hazard ratios per one standard deviation (s.d.) increase in HDI score were 0.95 (95% confidence interval=0.89-1.00, P=0.068), 0.90 (0.81-0.99, P=0.030) and 0.85 (0.74-0.97, P=0.018) for all-cause, CVD and CHD mortality, respectively. Population attributable risk fractions for low HDI were 2.9% for all-cause, 14.2% for CVD and 10.7% for CHD mortality. CONCLUSIONS: These findings support the hypothesis that unhealthy diet has had a role in the high CVD mortality in Eastern Europe. PMID- 25028085 TI - Associations between diet quality and mental health in socially disadvantaged New Zealand adolescents. AB - BACKGROUND/OBJECTIVES: To examine the relationship between diet quality and mental health in an ethnically diverse adolescent population in New Zealand. SUBJECTS/METHODS: Cross-sectional, population-based study design. Data were available at baseline for 4249 students. Responses from self-reported dietary questionnaires were used to assess diet quality; healthy eating and unhealthy eating were assessed as two separate scales. Mental health was assessed by the emotional subscale of the PedsQL instrument. RESULTS: Eating a healthy diet was significantly associated with better emotional health (P<0.001) and eating an unhealthy diet was significantly associated with greater emotional distress (P<0.001), after controlling for age, ethnicity and gender. The healthy and unhealthy eating scales were independently related to mental health scores. CONCLUSIONS: These findings contribute to a growing body of literature that diet quality is associated with mental health in adolescents. Further research is warranted to determine whether improvements to the diets of adolescents can have meaningful improvements to mental well-being. PMID- 25028086 TI - Association of red blood cell n-3 polyunsaturated fatty acids with plasma inflammatory biomarkers among the Quebec Cree population. AB - BACKGROUND/OBJECTIVES: We examined the prevalence of elevated plasma high sensitivity C-reactive protein (hs-CRP) concentrations and associations with red blood cell (RBC) long-chain n-3 polyunsaturated fatty acids (LCn-3PUFA) in the James Bay Cree population from the province of Quebec (Canada). SUBJECTS/METHODS: A total of 744 Cree adults (18-91 years) from seven communities of Eastern James Bay were included in these cross-sectional analyses. Associations between RBC LCn 3PUFA and proinflammatory markers (hs-CRP, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha)) were assessed by using multivariate general linear models with adjustment for sex, age and waist circumference. An arbitrary inflammation score was defined based on the sum of the quartiles of hs-CRP, IL-6 and TNF-alpha concentrations (range=3-12). RESULTS: Elevated hs-CRP concentrations (>3 mg/l) were present in 46.9% (95% confidence interval (CI) 43.3 50.5) of the James Bay Cree population. RBC docosapentaenoic acid (DPAn-3; C22:5n 3) was inversely associated with hs-CRP, TNF-alpha and the inflammation score (all P trend<0.02), whereas eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3) in RBC were not associated with inflammation (all P trend>0.18). Among participants with RBC DPAn-3 levels above the median of the population, odds ratio of having an elevated inflammation score (>=9) was 0.67 (95% CI, 0.48 0.93) compared with participants below the median. CONCLUSIONS: RESULTS indicate that low-grade systemic inflammation is highly prevalent and that higher RBC DPAn 3 levels are associated with a lower risk of systemic inflammation in the James Bay Cree population. PMID- 25028087 TI - Judgments of others' heights are biased toward the height of the perceiver. AB - We examined how observers use one aspect of their own morphology, height, when judging the physical characteristics of other people. To address this, participants judged the heights of people as they walked past. We tested the hypothesis that differences between participant and target height account for systematic patterns of variability and bias in height estimation. Height estimate error and error variability increased as the difference between participant height and target height increased, suggesting that estimates are scaled to observers' heights. Furthermore, participants' height estimates were biased toward two standards, demonstrating classic category effects. First, estimates were biased toward participants' own heights. Second, participants biased height estimates toward the average height of the target distribution. These results support past research on using both the body and categorical information to estimate target properties but extend to real-world situations involving interactions with moving people, such as height judgments provided during eyewitness testimony. PMID- 25028088 TI - Sapronosis: a distinctive type of infectious agent. AB - Sapronotic disease agents have evolutionary and epidemiological properties unlike other infectious organisms. Their essential saprophagic existence prevents coevolution, and no host-parasite virulence trade-off can evolve. However, the host may evolve defenses. Models of pathogens show that sapronoses, lacking a threshold of transmission, cannot regulate host populations, although they can reduce host abundance and even extirpate their hosts. Immunocompromised hosts are relatively susceptible to sapronoses. Some particularly important sapronoses, such as cholera and anthrax, can sustain an epidemic in a host population. However, these microbes ultimately persist as saprophages. One-third of human infectious disease agents are sapronotic, including nearly all fungal diseases. Recognition that an infectious disease is sapronotic illuminates a need for effective environmental control strategies. PMID- 25028089 TI - Discovering a vaccine against neosporosis using computers: is it feasible? AB - A vaccine is urgently needed to prevent cattle neosporosis. This infectious disease is caused by the parasite Neospora caninum, a complex biological system with multifaceted life cycles. An in silico vaccine discovery approach attempts to transform digital abstractions of this system into adequate knowledge to predict candidates. Researchers need current information to implement such an approach, such as understanding evasion mechanisms of the immune system, type of immune response to elicit, availability of data and prediction programs, and statistical models to analyze predictions. Taken together, an in silico approach involves assembly of an intricate jigsaw of interdisciplinary and interdependent knowledge. In this review, we focus on the approach influencing vaccine development against Neospora caninum, which can be generalized to other pathogenic apicomplexans. PMID- 25028090 TI - Expanding Integrated Vector Management to promote healthy environments. AB - Integrated Vector Management (IVM) strategies are intended to protect communities from pathogen transmission by arthropods. These strategies target multiple vectors and different ecological and socioeconomic settings, but the aggregate benefits of IVM are limited by the narrow focus of its approach; IVM strategies aim only to control arthropod vectors. We argue that IVM should encompass environmental modifications at early stages - for instance, infrastructural development and sanitation services - to regulate not only vectors but also nuisance biting arthropods. An additional focus on nuisance biting arthropods will improve public health and quality of life and minimize social-disparity issues fostered by pests. Optimally, IVM could incorporate environmental awareness and promotion of control methods proactively to reduce threats of serious pest situations. PMID- 25028091 TI - Comparison of HRRT and HR+ scanners for quantitative (R)-[11C]verapamil, [11C]raclopride and [11C]flumazenil brain studies. AB - PURPOSE: This study was conducted to directly compare the high-resolution research tomograph (HRRT) (high-resolution brain) and HR+ (standard whole-body) positron emission tomography (PET) only scanners for quantitative brain studies using three tracers with vastly different tracer distributions. PROCEDURES: Healthy volunteers underwent successive scans on HR+ and HRRT scanners (in random order) using either (R)-[(11)C]verapamil (n = 6), [(11)C]raclopride (n = 7) or [(11)C]flumazenil (n = 7). For all tracers, metabolite-corrected plasma-input functions were generated. RESULTS: After resolution matching, HRRT-derived kinetic parameter values correlated well with those of HR+ for all tracers (intraclass correlation coefficients >=0.78), having a good absolute interscanner test-retest variability (<=15 %). However, systematic differences can be seen for HRRT-derived kinetic parameter values (range -13 to +15 %). CONCLUSION: Quantification of kinetic parameters based on plasma-input models leads to comparable results when spatial resolution between HRRT and HR+ data is matched. When using reference-tissue models, differences remain that are likely caused by differences in attenuation and scatter corrections and/or image reconstruction. PMID- 25028092 TI - Focusing on delayed clearance for identifying small-sized metastatic lung tumors using synchrotron radiation angiography with a highly sensitive receiver. AB - OBJECTIVES: To detect metastatic lung tumors of less than 1 mm in size by focusing on the clearance of contrast material using synchrotron radiation (SR) angiography characterized by high spatial resolution and high-sensitivity receiver. METHODS: C6 cells, derived from rat glioma cells, were injected to the rat tail vein. Two weeks after injection, the rats underwent SR angiography using a high-gain avalanche rushing amorphous photoconductor (HARP) receiver of extra high sensitivity with high contrast resolution. The 256-grayscale value was employed in the analysis of images. RESULTS: 19 nodules were identified in images. The tumors were confirmed histopathologically. The average tumor size was 621+/-193 um. The clearance curve of the densities was expressed as a logarithm function. Tumors showed delayed clearance of contrast material, taking up to 28 s, compared with arteries, which cleared rapidly at 8 s. In 256 grayscale, the distance was 50. This gap in density clearance made it possible to identify tumors. CONCLUSIONS: SR angiography with a HARP receiver provides high sensitivity and spatial resolution and makes it possible to diagnose metastatic lung tumors of less than 1 mm in size by focusing on differences in the clearance times of contrast material. PMID- 25028093 TI - Surgical technique of double valve replacement in a patient with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is an inherited connective tissue disorder. Left ventricle dilation and valve insufficiency are complications in patients with OI and such patients are at high risk of mortality and complications related to bleeding and tissue friability during cardiac surgery. Valve dehiscence due to extreme friability of the annulus is a major complication of cardiac valve replacement with OI. We describe OI in a male patient who underwent double valve replacement with mechanical valves using a tissue protective method to prevent valve dehiscence. PMID- 25028094 TI - Trends in meat science and technology: the future looks bright, but the journey will be long. AB - With an increasing world population, an increase in affluence and a substantial growth in the demand for high quality protein, the meat sector faces a fantastic but challenging century. New scientific knowledge, technology and creative minds are the main ingredients in order to reach out for this great opportunity. Efficiency all the way from breeding and farming to processing and dispatch is crucial for success. Technology has brought us far, and there is still a huge potential for increased efficiency by implementing best practices on a global scale. New challenges include: hyper flexible automation, more accurate and faster measurement systems and meeting special consumer demands already at the production line. Systems for optimal animal welfare will be even more important and sustainability is no longer a consumer trend but a license to operate. The scientific meat society must provide knowledge and technology so we together can reach out for a seemingly bright future. PMID- 25028097 TI - Nocturia and nocturnal polyuria are symptoms of obstructive sleep apnoea. PMID- 25028095 TI - Nicotine-mediated invasion and migration of non-small cell lung carcinoma cells by modulating STMN3 and GSPT1 genes in an ID1-dependent manner. AB - BACKGROUND: Inhibitor of DNA binding/Differentiation 1 (ID1) is a helix loop helix transcription factor that lacks the basic DNA binding domain. Over expression of ID1 has been correlated with a variety of human cancers; our earlier studies had shown that reported ID1 is induced by nicotine or EGF stimulation of non-small cell lung cancer (NSCLC) cells and its down regulation abrogates cell proliferation, invasion and migration. Here we made attempts to identify downstream targets of ID1 that mediate these effects. METHODS: A microarray analysis was done on two different NSCLC cell lines (A549 and H1650) that were transfected with a siRNA to ID1 or a control, non-targeting siRNA. Cells were stimulated with nicotine and genes that were differentially expressed upon nicotine stimulation and ID1 depletion were analyzed to identify potential downstream targets of ID1. The prospective role of the identified genes was validated by RT-PCR. Additional functional assays were conducted to assess the role of these genes in nicotine induced proliferation, invasion and migration. Experiments were also conducted to elucidate the role of ID1, which does not bind to DNA directly, affects the expression of these genes at transcriptional level. RESULTS: A microarray analysis showed multiple genes are affected by the depletion of ID1; we focused on two of them: Stathmin-like3 (STMN3), a microtubule destabilizing protein, and GSPT1, a protein involved in translation termination; these proteins were induced by both nicotine and EGF in an ID1 dependent fashion. Overexpression of ID1 in two different cell lines induced STMN3 and GSPT1 at the transcriptional level, while depletion of ID1 reduced their expression. STMN3 and GSPT1 were found to facilitate the proliferation, invasion and migration of NSCLC cells in response to nAChR activation. Attempts made to assess how ID1, which is a transcriptional repressor, induces these genes showed that ID1 down regulates the expression of two transcriptional co repressors, NRSF and ZBP89, involved in the repression of these genes. CONCLUSIONS: Collectively, our data suggests that nicotine and EGF induce genes such as STMN3 and GSPT1 to promote the proliferation, invasion and migration of NSCLC, thus enhancing their tumorigenic properties. These studies thus reveal a central role for ID1 and its downstream targets in facilitating lung cancer progression. PMID- 25028096 TI - Inhalation of ultrafine carbon particles alters heart rate and heart rate variability in people with type 2 diabetes. AB - BACKGROUND: Diabetes may confer an increased risk for the cardiovascular health effects of particulate air pollution, but few human clinical studies of air pollution have included people with diabetes. Ultrafine particles (UFP, <=100 nm in diameter) have been hypothesized to be an important component of particulate air pollution with regard to cardiovascular health effects. METHODS: 17 never smoker subjects 30-60 years of age, with stable type 2 diabetes but otherwise healthy, inhaled either filtered air (0-10 particles/cm3) or elemental carbon UFP (~107 particles/cm3, ~50 ug/m3, count median diameter 32 nm) by mouthpiece, for 2 hours at rest, in a double-blind, randomized, crossover study design. A digital 12-lead electrocardiogram (ECG) was recorded continuously for 48 hours, beginning 1 hour prior to exposure. RESULTS: Analysis of 5-minute segments of the ECG during quiet rest showed reduced high-frequency heart rate variability with UFP relative to air exposure (p = 0.014), paralleled by non-significant reductions in time-domain heart rate variability parameters. In the analysis of longer durations of the ECG, we found that UFP exposure increased the heart rate relative to air exposure. During the 21- to 45-hour interval after exposure, the average heart rate increased approximately 8 beats per minute with UFP, compared to 5 beats per minute with air (p = 0.045). There were no UFP effects on cardiac rhythm or repolarization. CONCLUSIONS: Inhalation of elemental carbon ultrafine particles alters heart rate and heart rate variability in people with type 2 diabetes. Our findings suggest that effects may occur and persist hours after a single 2-hour exposure. PMID- 25028098 TI - Healthcare workers' experiences of HIV testing in Tshwane, South Africa. AB - BACKGROUND: In an era when antiretroviral (ARV) therapy has become part of the Human Immunodeficiency Virus (HIV) prevention strategy, early testing and introduction to ARVs iscritical for improving public health outcomes in general and, in particular, the lives of people living with HIV. South Africa has the highest number of people living with HIV as compared with the rest of the world. Initiated voluntary HIV counselling and testing and provider initiated counselling and testing (PICT) are required in order to increase the uptake of HIV testing. OBJECTIVES: To explore and describe the experiences of healthcare workers who are themselves in need of HIV testing. METHOD: A descriptive, exploratory design was used. In-depth interviews were conducted with the 26 healthcare workers who were involved in HIV testing in the Tshwane district of South Africa. The participants were sampled purposively from two healthcare settings. A thematic framework was used for data analysis. RESULTS: There was a complication with regard to PICT as healthcare workers felt they could not initiate HIV testing for themselves and or their work colleagues without their confidentiality being compromised. This was complicated further by both the perceived and actual fear of stigmatisation and discrimination. It was difficult for qualified staff to support and encourage the uptake of HIV testing by students nurses as this was seen, albeit incorrectly, as targeting the students in a negative manner. CONCLUSION: There is a need for accessible HIV testing policies for healthcare workers in order to increase access to HIV testing and prevent the progression of the disease. PMID- 25028099 TI - Interleukin-20 promotes airway remodeling in asthma. AB - Previous studies have demonstrated that interleukin-20 (IL-20) is a pro inflammatory cytokine, and it has been implicated in psoriasis, lupus nephritis, rheumatoid arthritis, atherosclerosis, and ulcerative colitis. Little is known about the effects of IL-20 in airway remodeling in asthma. The aim of our study was to demonstrate the function of IL-20 in airway remodeling in asthma. To identify the expression of IL-20 and its receptor, IL-20R1/IL-20R2, in the airway epithelium in bronchial tissues, bronchial biopsy specimens were collected from patients and mice with asthma and healthy subjects and stained with specific antibodies. To characterize the effects of IL-20 in asthmatic airway remodeling, we silenced and stimulated IL-20 in cell lines isolated from mice by shRNA and recombinant protein approaches, respectively, and detected the expression of alpha-SMA and FN-1 by Western blot analysis. First, overexpression of IL-20 and its receptor, IL-20R1/IL-20R2, was detected in the airway epithelium collected from patients and mice with asthma. Second, IL-20 increased the expression of fibronectin-1 and alpha-SMA, and silencing of IL-20 in mouse lung epithelial (MLE)-12 cells decreased the expression of fibronectin-1 and alpha-SMA. IL-20 may be a critical cytokine in airway remodeling in asthma. This study indicates that targeting IL-20 and/or its receptors may be a new therapeutic strategy for asthma. PMID- 25028101 TI - Evaluation of IL-8 nasal lavage levels and the effects of nasal involvement on disease severity in patients with stable chronic obstructive pulmonary disease. AB - Interleukin 8 (IL-8) is used to evaluate the severity of inflammation in the airways. The aim of this study was to evaluate patients with chronic obstructive pulmonary disease (COPD) for the presence of upper respiratory tract involvement by questioning patients regarding nasal symptoms and by measuring levels of IL-8 in nasal lavage material. A total of 47 COPD patients and 23 healthy controls were enrolled in this study. Pulmonary function tests were performed for all participants who were asked to complete a Sinonasal Outcome Test-20 (SNOT-20) questionnaire on the same day, as a measure of quality of life. Median IL-8 level in nasal lavage specimens of COPD patients with stable disease was higher than that of healthy controls. An increase in cigarette pack-years was significantly associated with an increase in nasal IL-8 levels. Similarly, IL-8 levels correlated positively with stage of COPD. A significant link between number of visits to the emergency department and stage of disease was observed. Patients with COPD had a significantly higher mean SNOT-20 severity score compared to healthy controls. Proper management of sinonasal disease may help to decrease the number of COPD attacks and consequently improve quality of life. PMID- 25028102 TI - Inhibition of peripheral nociceptors by aminoglycosides produces analgesia in inflammatory pain models in the rat. AB - Aminoglycosides (AGs) modulate nociceptors and ionic channels expressed in sensory neurons. The AG applied in situ could be useful to alleviate hyperalgesia in animal models of inflammatory pain. We tested streptomycin (ST) and neomycin (NEO) as analgesic agents applied in situ in rat paw inflammation caused by formalin or carrageenan administration. The action of ST and NEO on the action potential discharge produced by acidic stimuli in isolated dorsal root ganglion neurons was also studied in current-clamp recordings. In the formalin test, ST and NEO significantly reduced the nociceptive behaviour. ST reduced the N-(4 methyl-2-quinazolinyl)-guanidine (GMQ)-induced nociceptive behaviour, and NEO diminished the hyperalgesia to thermonociception and mechanonociception produced by CAR. In the current-clamp experiments, ST and NEO reduced the generation of action potentials when an acidic solution was applied. We conclude that ST and NEO produce analgesia to inflammatory pain, an effect that is due in part to the inhibition of ASIC activation in sensory neurons. PMID- 25028100 TI - Improvement of bioavailability and anti-inflammatory potential of curcumin in combination with emu oil. AB - The purpose of the present study is to evaluate the effect of emu oil on bioavailability of curcumin when co-administered and to evaluate the property that enhances the anti-inflammatory potential of curcumin. Oral bioavailability of curcumin in combination with emu oil was determined by measuring the plasma concentration of curcumin by HPLC. The anti-inflammatory potential was evaluated in carrageenan-induced paw edema model (acute model) and in Freund's complete adjuvant (FCA)-induced arthritis model (chronic model) in male SD rats. The anti inflammatory potential of curcumin in combination with emu oil has been significantly increased in both acute and chronic inflammatory models as evident from inhibition of increase in paw volume, arthritic score, and expression of pro inflammatory cytokines. The increased anti-inflammatory activity in combination therapy is due to enhanced bioavailability (5.2-fold compared to aqueous suspension) of curcumin by emu oil. Finally, it is concluded that the combination of emu oil with curcumin will be a promising approach for the treatment of arthritis. PMID- 25028103 TI - Genetic variants of interleukin 17A are functionally associated with increased risk of age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Interleukin 17 (IL 17) is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. In the current study, we examined two single nucleotide polymorphisms (SNPs), rs2275913G/A and rs3748067C/T, in the IL-17A gene between AMD patients and healthy controls. Results showed that rs2275913AA genotype and rs3748067TT genotype were associated with increased susceptibility to AMD (hazard ratio [HR], 1.75; 95 % confidence interval [CI], 1.07 to 3.02; P=0.023, and HR, 2.12; 95 % CI, 1.26 to 4.01; P=0.004; data were adjusted for age and sex). Next, we investigated the functional relevance of the two SNPs. In vitro stimulated peripheral blood mononuclear cells (PBMCs) from subjects possessing the rs2275913AA genotype produced significantly more IL-17 than those with the GG genotype. However, PBMCs with rs3748067TT genotype revealed significantly higher IL-17 production than those with rs3748067CC genotype only in AMD patients but not in controls. These data indicate IL-17A polymorphisms are associated with increased risk of AMD probably by affecting gene expression. PMID- 25028104 TI - The relationship between inflammatory marker levels and pulmonary tuberculosis severity. AB - We aimed to investigate the correlation between red cell distribution width (RDW), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and other inflammatory markers with pulmonary tuberculosis (PTB) severity. Seventy patients with active pulmonary tuberculosis were compared with 50 age matched and gender-matched healthy controls. The mean age of PTB patients was 50.4 +/- 21.8 years. There were no differences in terms of age, gender, and smoking history between PTB patients and controls. Patients with advanced PTB had a significantly higher white blood cell count, neutrophil count, RDW, NLR, and C reactive protein when compared to patients with mild to moderate PTB. RDW (17.7 versus 15.7 %, p=0.002) and NLR (4.7 versus 3.1, p=0.009) values were higher in patients with advanced PTB as opposed to patients with mild to moderate PTB. NLR and RDW levels may be used as markers of inflammation to help clinically manage patients with TB and to determine disease severity. PMID- 25028105 TI - CORR Insights (r): What are the patterns of prophylactic postoperative oral antibiotic use after foot and ankle surgery? PMID- 25028106 TI - Revisions of monoblock metal-on-metal THAs have high early complication rates. AB - BACKGROUND: A relatively high percentage of monoblock metal-on-metal total hip arthroplasties (THAs) undergo early revision. Revision of these THAs poses challenges unique to this implant type. The early complications after these revisions remain unreported as do the clinical and demographic factors associated with these complications. QUESTIONS/PURPOSES: We describe (1) the frequency of early complications after revision of monoblock metal-on-metal THA; and (2) the clinical and demographic factors associated with complications. METHODS: A review of our institution's total joint registry identified 107 patients who underwent 114 revisions of monoblock metal-on-metal THAs. Mean patient age at revision was 60 years (range, 17-84 years), and 65% of the patients were women. Mean followup after revision was 14 months (range, 0-122 months). Revision diagnoses included metallosis (51%), aseptic loosening (27%), infection (7%), pain (6%), malposition (4%), instability (3%), iliopsoas impingement (2%), and periprosthetic fracture (1%). Major complications (instability, infection, aseptic loosening, and wound complications) were documented and included in the analysis. Minor postoperative complications such as urinary tract infection were excluded. RESULTS: Twenty three of 114 procedures (20%) involved at least one early complication after revision of monoblock metal-on-metal THA with 18 (16%) undergoing at least one additional subsequent surgery. The most common complications included aseptic loosening (6%), deep infection (6%), dislocation (4%), and acetabular fracture (3%). Patients who sustained a complication after revision surgery were older on average than those who did not (66 years versus 58 years, p=0.003). There were no differences in complication rate with respect to sex, time to revision, or revision diagnosis. CONCLUSIONS: Complications and reoperations occur frequently after revision for failed monoblock metal-on-metal THA (20% and 16%, respectively), and older patients appear to be at greater risk for complications after these revisions. Aseptic loosening, deep infection, and instability are all of great concern after revision and surgeons should be aware of these potential complications when undertaking revision of these THAs. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 25028108 TI - CORR Insights(r): The alpha-defensin test for periprosthetic joint infection outperforms the leukocyte esterase test strip. PMID- 25028109 TI - The combination of rhytidoplasty and fractional CO2 laser therapy in the treatment of facial aging. AB - BACKGROUND: Facial aging is a natural biological process with symptoms such as sagging tissue, accentuated lines, furrows, wrinkles, dyschromias, and loss of facial volume. Rhytidectomy alone often fails to achieve a patient's expected goals, which is why there is a high demand for adjunct laser skin treatment. METHODS: From January 2007 to February 2013, a total of 80 patients with skin types Fitzpatrick I-IV underwent large undermined cutaneous flap rhytidectomy and superficial muscular aponeurotic system (SMAS) plicature plus hyaluronic acid injection on the nasolabial folds and lips and concomitant Lumenis UltraPulse CO2 Active FX total ablation mode resurfacing of nonundermined skin. The undermined skin was treated with a fractional laser using different energies depending on the type of skin. Patients were evaluated at 5, 10, 15, 30, 60, and 90 days after the operation. At the last evaluation patients completed a specific questionnaire about satisfaction. RESULTS: Complications included expansive hematomas (5 %), partial necrosis (1.25 %), bacterial infection (1.25 %), herpetic infection (1.25 %), hypertrophic scar (1.25 %), and spot hyperchromia (1.25 %). 95 % of patients were extremely satisfied, 3.75 % were satisfied, and only 1.25 % were unsatisfied. CONCLUSION: The combination of subcutaneous flap rhytidectomy and SMAS plicature with fractional laser resurfacing plus hyaluronic acid injection is a safe procedure with low incidence of major complications and improves patient satisfaction. PMID- 25028110 TI - Combined alloplastic implant and autologous dermis graft for nasal augmentation rhinoplasty in Asians. PMID- 25028107 TI - Minorities are less likely to receive autologous blood transfusion for major elective orthopaedic surgery. AB - BACKGROUND: Surgeons commonly arrange for patients to perform autologous blood donation before elective orthopaedic surgery. Understanding sociodemographic patterns of use of autologous blood transfusion can help improve quality of care and cost containment. QUESTIONS/PURPOSES: We sought to determine whether there were (1) racial disparities, (2) insurance-based disparities, or (3) income-based disparities in autologous blood use. Additionally, we evaluated the combined effect of (4) race and insurance and (5) race and income on autologous blood use, and we compared ratios of autologous with allogeneic blood use. METHODS: Of the more than 3,500,000 patients undergoing major elective orthopaedic surgery identified in the Nationwide Inpatient Sample between 2008 and 2011, 2.4% received autologous blood transfusion and 12% received allogeneic blood transfusion. Multivariable logistic regression was performed to determine the influence of race, insurance status, and income on autologous blood use. RESULTS: Compared with white patients, Hispanic patients had lower odds of autologous blood use for elective hip (odds ratio [OR], 0.75; 95% CI, 0.69-0.82) and knee arthroplasties (OR, 0.71; 95% CI, 0.67-0.75). Black patients had lower odds of receiving autologous blood transfusion for hip arthroplasty (OR, 0.78; 95% CI, 0.74-0.83). Compared with the privately insured, uninsured and publicly insured patients were less likely to receive autologous blood for total joint arthroplasty and spinal fusion. Patients with low and medium income were less likely to have autologous blood transfusion for total joint arthroplasty and spinal fusion compared with high-level income earners. Even at comparable income and insurance levels with whites, Hispanic and black patients tended to be less likely to receive autologous blood transfusion. Ratios of autologous to allogeneic blood use were lower among minority patients. CONCLUSIONS: Historically disadvantaged populations receive fewer autologous blood transfusions for elective orthopaedic surgery. Whether the differential use is attributable to patient preference or unequal access to this practice should be investigated further. LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 25028111 TI - Anatomical study of the mandibular angle and body in wide mandibular angle cases. AB - BACKGROUND: Mandibular angle reduction surgery is widely used for aesthetic purposes. Because inferior alveolar nerve injury is a common complication of this surgery, the anatomical location of this nerve must be known before surgery. This study investigated the relative location of the inferior alveolar nerve in mesofacial and brachyfacial groups. METHODS: Panoramic views of patients were divided into Groups A (gonial angle < 120 degrees ) and B (gonial angle > 120 degrees ). For the analysis, the magnification of each image was standardized and the following parameters were measured: (1) gonial angle; (2) distance from the alveolar ridge at the center of the first and second premolars and first and second molars to (a) the inferior margin of the inferior alveolar canal and (b) the inferior margin of the mandible; (3) distance from the posterior alveolar ridge to the gonial angle and to (a) on the same line; (4) size of the first and second molars. RESULTS: Statistical analysis showed that there were no significant differences (P > 0.05) between Group A and Group B with respect to the distance from the alveolar ridge to the inferior alveolar canal in the first premolar, second premolar, and first molar. The differences between Group A and Group B with respect to the distance from the alveolar ridge to the inferior margin of the mandible for the second premolar, first molar, second molar and gonial angle were 0.7, 1.5, 2.8, and 7.0 mm, respectively (P < 0.05). The differences between Group A and Group B with respect to the distances from the inferior margin of the inferior alveolar canal to the inferior margin of the mandible for the same landmarks were 0.7, 1.1, 1.3, and 5.7 mm, respectively (P < 0.05). CONCLUSION: The difference in length from the alveolar ridge to the mandibular canal between the two groups was minimal, but the length to the gonial angle differed significantly. These results will help reduce inferior alveolar nerve injury during mandibular angle reduction surgery. PMID- 25028112 TI - Platelet-rich plasma mixed-fat grafting: a reasonable prosurvival strategy for fat grafts? AB - BACKGROUND: One of the most interesting developments in practical applications of fat grafting in recent years is the use of prosurvival strategies to improve maintenance of volume. Platelet-rich plasma (PRP) plays a decisive role in the repair and regeneration of different tissues via the activation and secretion of a great variety of growth factors and other cytokines stored in the alpha granules of the platelets. This review aimed to assess the efficacy of PRP mixed fat grafting as a prosurvival strategy for fat grafts. METHODS: Online searches of the Cochrane Library and MEDLINE until January 2014 were conducted. The review included studies with at least one clinical end point in which the effect of PRP on the absorption and viability of the fat graft could be assessed. RESULTS: The review comprised 6 preclinical studies with a control group and 9 clinical studies of humans. It also included comparative studies performed with other prosurvival strategies for fat grafts, such as combination with the stromal vascular fraction and second-generation PRP, also called "platelet-rich fibrin." The results indicate that PRP may have a dose-dependent positive effect on fat grafts and suggest low complication rates. CONCLUSIONS: The development of new growth factor delivery systems or cell therapies to enrich fat grafts is an area that merits further research. PMID- 25028113 TI - Ethical issues in Chinese aesthetic surgery. AB - Guided by the medical ethics principles of "four principles plus scope," Chinese aesthetic medical practitioners have proposed some extremely valuable ethical principles combined with the construction of aesthetic medicine and the requirements of clinical practice such as the principle of general nonmaleficence, the principle of local minimal invasiveness, the principle of informed consent, and the principle of respect and confidentiality. Chinese aesthetic surgical ethics provide valuable guidance for the practice of aesthetic medicine. Adherence to the ethics of Chinese aesthetic surgery provides an essential guide for the practice of aesthetic medicine in China. These principles protect both the medical practitioner and the patient, helping them to avoid unnecessary risks and disputes and ultimately promoting the sustainable development of aesthetic medicine. PMID- 25028114 TI - Reply to "pseudolymphoma on tattoos". PMID- 25028115 TI - The correction of alar-columella web deformities in unilateral cleft-lip nasal deformities with web graft technique. AB - BACKGROUND: Among the many secondary deformities in cleft-lip nose, the alar columella web is unsightly and is a recurrent deformity. The purpose of this article is to revisit the correction of alar web deformity in patients with cleft lip nasal deformities and to introduce our web graft technique. METHODS: Thirteen patients with alar webbing underwent surgery between June 2012 and February 2013. The age range of the patients at the time of surgery was 14-29 years. An open rhinoplasty incision, including a reverse-U incision, was made and cartilage work was performed. After the cleft side was equalized with the dome angle of the healthy side, we used contralateral alar or auricular cartilage grafts as a stiff batten to stabilize the converted web skin. The web graft was fixed to the cleft side web skin's inner side with at least three sutures to maintain the tucking of the vestibular skin. The follow-up period ranged from 1 to 20 months. RESULTS: The postoperative frontal and basal views showed that the nostrils and columella had better shape. Most patients demonstrated correction of the drooping alar rim and satisfactory symmetry of the nostrils. CONCLUSION: A web graft supports the vestibular lining of the reverse-U incision and increases the strength of the new concavity of the tucked skin. We expect that a long-lasting concave web contour could be achieved with this technique. PMID- 25028116 TI - Evidence-based medicine in aesthetic medicine and surgery: reality or fantasy? AB - The goal of evidence-based medicine (EBM) is for health-care professionals to incorporate existing medical evidence into clinical practice to achieve the greatest possible outcomes. The theory of EBM has been employed since the 11th century and has evolved dramatically into the modern application used by practicing physicians today. There are five levels of evidence currently used to evaluate if certain techniques, methods, and surgical procedures are the "best" to be used in practice. Despite the outlined format of EBM, plastic surgeons have difficulty applying EBM in clinical practice because of the influence of expert opinion and the subjective nature of outcomes. This article explores the function of EBM in aesthetic plastic surgery. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25028117 TI - Role of antioxidants in dermal aging: an in vitro study by q-RT-PCR. AB - BACKGROUND: Reactive oxygen species production is the final step in skin aging. These unstable molecules can damage and destroy DNA, proteins, and membrane phospholipids. The aim of this study was to test the in vitro effect of an antioxidant precursor, N-acetylcysteine (NAC), on human dermal fibroblasts. NAC alone and a solution of NAC and amino acids together, used in aesthetic medicine as intradermal injection treatment, were tested. METHODS: The expression levels of some connective related genes (HAS1, HYAL1, ELN, ELANE, DSP, GDF6, and IGF1) were analyzed on cultures of dermal fibroblasts using real-time reverse transcription polymerase chain reaction (real time RT-PCR). RESULTS: All genes were upregulated after 24 h of treatment. CONCLUSIONS: An interesting effect of gene induction by administration of NAC and amino acids in vitro was demonstrated. Upregulation of elastin-, hyaluronic acid-, and GDF6-encoding genes supports the evidence of clinical improvement induced by NAC biostimulation in the prevention and correction of skin aging. PMID- 25028118 TI - Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients. AB - PURPOSE: We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy. METHODS: The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5'-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3'-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations' results were correlated with disease control rate, progression-free survival (PFS) and overall survival. RESULTS: Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality. CONCLUSION: The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non squamous NSCLC patients. PMID- 25028119 TI - Circulating tumor cell detection in high-risk non-metastatic prostate cancer. AB - PURPOSE: The detection of circulating tumor cells (CTCs) provides important prognostic information in men with metastatic prostate cancer. We aim to determine the rate of detection of CTCs in patients with high-risk non-metastatic prostate cancer using the CellSearch(r) method. METHOD: Samples of peripheral blood (7.5 mL) were drawn from 36 men with newly diagnosed high-risk non metastatic prostate cancer, prior to any initiation of therapy and analyzed for CTCs using the CellSearch(r) method. RESULTS: The median age was 70 years, median PSA was 14.1, and the median Gleason score was 9. The median 5-year risk of progression of disease using a validated nomogram was 39 %. Five out of 36 patients (14 %, 95 % CI 5-30 %) had CTCs detected in their circulation. Four patients had only 1 CTC per 7.5 mL of blood detected. One patient had 3 CTCs per 7.5 mL of blood detected, which included a circulating tumor microemboli. Both on univariate analysis and multivariate analysis, there were no correlations found between CTC positivity and the classic prognostic factors including PSA, Gleason score, T-stage and age. CONCLUSION: This study demonstrates that patients with high-risk, non-metastatic prostate cancer present infrequently with small number of CTCs in peripheral blood. This finding is consistent with the limited literature available in this setting. Other CTC isolation and detection technologies with improved sensitivity and specificity may enable detection of CTCs with mesenchymal phenotypes, although none as yet have been validated for clinical use. Newer assays are emerging for detection of new putative biomarkers for prostate cancer. Correlation of disease control outcomes with CTC detection will be important. PMID- 25028120 TI - Organic acids, sugars, vitamin C content and some pomological characteristics of eleven hawthorn species (Crataegus spp.) from Turkey. AB - BACKGROUND: The Hawthorn (Crateagus sp.) mostly occurs around the temperate region of the world with a high number of species, producing a fruit with numerous beneficial effects for human health. The aim of the study was to determine organic acid and sugar contents in the fruit of a number of hawthorn species grown in Erzincan province of Turkey. RESULTS: Citric acid was the predominant organic acid in all hawthorn species and C. pseudoheterophylla had the highest citric acid content (23.688 g/100 g). There were not statistically significant differences among hawthorn species (except C. atrosanguinea Pojark) in terms of fumaric acid content. C.pontica C.Koch had a higher content of vitamin C (9.418 mg/100 g) compared to other species. Fructose was the predominant sugar component in all species and C. monogyna subsp. monogyna Joiq had the highest fructose content (18.378 g/100 g). CONCLUSIONS: The high fruit quality of the studied species indicates the importance of this fruit in human nutrition as a natural source. The study revealed that there were differences in terms of fruit characteristics among hawthorn species and thus better quality hawthorn genotypes can be selected within the species. Hence, this study is considered to be a valuable reference for forthcoming studies. The high fruit quality of the studied species indicates the importance of this fruit in human nutrition as a natural source. PMID- 25028121 TI - Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a fatal degenerative muscle disease resulting from mutations in the dystrophin gene. Increased oxidative stress and altered Ca(2+) homeostasis are hallmarks of dystrophic muscle. While impaired autophagy has recently been implicated in the disease process, the mechanisms underlying the impairment have not been elucidated. Here we show that nicotinamide adenine dinucleotide phosphatase (Nox2)-induced oxidative stress impairs both autophagy and lysosome formation in mdx mice. Persistent activation of Src kinase leads to activation of the autophagy repressor mammalian target of rapamycin (mTOR) via PI3K/Akt phosphorylation. Inhibition of Nox2 or Src kinase reduces oxidative stress and partially rescues the defective autophagy and lysosome biogenesis. Genetic downregulation of Nox2 activity in the mdx mouse decreases reactive oxygen species (ROS) production, abrogates defective autophagy and rescues histological abnormalities and contractile impairment. Our data highlight mechanisms underlying the pathogenesis of DMD and identify NADPH oxidase and Src kinase as potential therapeutic targets. PMID- 25028122 TI - Understanding cervical cancer: an exploration of lay perceptions, beliefs and knowledge about cervical cancer among the Acholi in northern Uganda. AB - BACKGROUND: Cervical cancer is the most common cancer affecting women in Uganda; yet community understanding of the disease is limited. We explored community perceptions, beliefs and knowledge about the local names, causes, symptoms, course, treatment, and prognosis of cervical cancer in order to inform targeted interventions to promote early help-seeking. METHODS: Twenty four focus group discussions (FGD) with men and women aged 18 - 59 years and ten key informant interviews with persons aged >= 60 years were conducted at two sites in Gulu district between May and June 2012. A semi-structured interview guide informed by Kleinman's illness explanatory model and literature on community awareness of cervical cancer was used to collect data. Data analysis was supported with use of ATLAS.ti 6.1 in coding, organizing and tracking data segments. We used content analysis technique in data analysis and organised data into a structured format under distinct themes and categories. RESULTS: Cervical cancer was known by the local name "two remo", meaning "an illness that manifests with bleeding." Respondents believed that early onset of sexual activity, multiple male sexual partners and multi-parity cause cervical cancer. Respondents in half of FGDs also reported that use of condoms and family planning pills and injections cause cervical cancer. Symptoms of cervical cancer reported included vaginal bleeding, watery vaginal discharge and lower abdominal and waist pain. Respondents in most of the FGDs and key informants perceived cervical cancer as a chronic illness and that it can be treated with both modern and traditional medicines. The majority thought that cervical cancer treatment was supportive; the illness is not curable. CONCLUSIONS: While some lay beliefs about the causes of cervical cancer suggest some understanding of aetiology of the disease, other perceived causes particularly those related to use of family planning and condoms are potentially hurtful to public health. Awareness campaigns to promote early help-seeking for cervical cancer symptoms need to be culturally-sensitive and context-specific; and include messages on symptoms, risk factors, course, treatment and prognoses. PMID- 25028123 TI - Switchable scattering meta-surfaces for broadband terahertz modulation. AB - Active tuning and switching of electromagnetic properties of materials is of great importance for controlling their interaction with electromagnetic waves. In spite of their great promise, previously demonstrated reconfigurable metamaterials are limited in their operation bandwidth due to their resonant nature. Here, we demonstrate a new class of meta-surfaces that exhibit electrically-induced switching in their scattering parameters at room temperature and over a broad range of frequencies. Structural configuration of the subwavelength meta-molecules determines their electromagnetic response to an incident electromagnetic radiation. By reconfiguration of the meta-molecule structure, the strength of the induced electric field and magnetic field in the opposite direction to the incident fields are varied and the scattering parameters of the meta-surface are altered, consequently. We demonstrate a custom designed meta-surface with switchable scattering parameters at a broad range of terahertz frequencies, enabling terahertz intensity modulation with record high modulation depths and modulation bandwidths through a fully integrated, voltage controlled device platform at room temperature. PMID- 25028124 TI - The breath of life: an essay on the earliest history of respiration: part ii. AB - It is to ancient Greek civilization that we must look for the first groping steps towards a naturalistic concept of respiration, although we shall not, of course, expect to find one which is consistent with modern views. Nearly a millennium before Christ, Homer wrote of the gods as more less predictable and very human beings, deserving more of admiration and emulation than worship; they took a fairly commonsense view of man's earthly pursuits, and left him a measure of control over his own destiny. From this relatively disrespectful state-by comparison with primitive or Old Testament views-it is but a stage to a rationalistic view of the universe, that is, to science, and this step was taken about three centuries later (6th century B.C.) by Thales, Anaximander and Anaximenes. We cannot pause to consider their views in detail, nor can we digress, as strictly we should, to consider the emerging relationship between philosophy and science. Suffice it to say that these first philosopher-scientists sought to explain the universe and life in rational terms, basing their rationalizations-we might say extrapolations-on certain specific observations of natural phenomena. The latter were concerned, in the main, with the interrelationships of basic substances (ultimately regarded as the four elements) such as fire, earth, air and water. Water, for example, could be condensed to form earth, or rarefied to form mist and vapour. PMID- 25028125 TI - Factorial trials as a method of studying physiotherapy. AB - This article discusses the need for research in the field of physiotherapy, and the difficulties involved in carrying out this type of research. It describes a factorial trial, and the advantages of using it in physiotherapy. The appendix is a letter from a statistician, and discusses some of these advantages in more detail. PMID- 25028126 TI - A neurological assessment chart. AB - A uniform method of assessing patients with neurological disorders is a growing problem. So often patients transfer from one hospital to another and the progress notes which are forwarded are too scant, non-existent, or meaningless because of differing grading systems for assessment. As more knowledge is gained about neurological disorders it has become more apparent that a uniform chart or grading system would be of great value. During the last two years the Neurological Study Group of the Victorian Physiotherapy Postgraduate Society has compiled this neurological assessment chart in an effort to solve the problem. PMID- 25028127 TI - Parkinson's disease: recent trends in physiotherapy. AB - Parkinson's disease, paralysis ajitans or "shaking palsy" is characterized by rigidity, tremor, and akinesia. PMID- 25028128 TI - Movements of the cervical spine. AB - During an investigation of the available published literature on radiological studies of the movements of the cervical spine, a number of facts were collected which elaborate on the traditional and brief explanation of movement given by most anatomy texts. PMID- 25028129 TI - Accumulation of humic-like fluorescent dissolved organic matter in the Japan Sea. AB - Major fraction of marine dissolved organic matter (DOM) is biologically recalcitrant, however, the accumulation mechanism of recalcitrant DOM has not been fully understood. Here, we examine the distributions of humic-like fluorescent DOM, factions of recalcitrant DOM, and the level of apparent oxygen utilization in the Japan Sea. We find linear relationships between these parameters for the deep water (>200 m) of the Japan Sea, suggesting that fluorescent DOM is produced in situ in the Japan Sea. Furthermore, we find that the amount of fluorescent DOM at a given apparent oxygen utilization is greater in the deep water of the Japan Sea than it is in the North Pacific, where the highest level of fluorescent DOM in the open ocean was previously observed. We conclude that the repeated renewal of the deep water contributes to the accumulation of fluorescent DOM in the interior of the Japan Sea. PMID- 25028130 TI - Electrical stimulation using sine waveform prevents unloading-induced muscle atrophy in the deep calf muscles of rat. AB - The aim of this study was to compare the effects of electrical stimulation by using rectangular and sine waveforms in the prevention of deep muscle atrophy in rat calf muscles. Rats were randomly divided into the following groups: control, hindlimb unloading (HU), and HU plus electrical stimulation (ES). The animals in the ES group were electrically stimulated using rectangular waveform (RS) on the left calves and sine waveform (SS) on the right calves, twice a day, for 2 weeks during unloading. HU for 2 weeks resulted in a loss of the muscle mass, a decrease in the cross-sectional area of the muscle fibers, and overexpression of ubiquitinated proteins in the gastrocnemius and soleus muscles. In contrast, electrical stimulation with RS attenuated the HU-induced reduction in the cross sectional area of muscle fibers and the increase of ubiquitinated proteins in the gastrocnemius muscle. However, electrical stimulation with RS failed to prevent muscle atrophy in the deep portion of the gastrocnemius and the soleus muscles. Nevertheless, electrical stimulation with SS attenuated the HU-induced muscle atrophy and the up-regulation of ubiquitinated proteins in both gastrocnemius and soleus muscles. This indicates that SS was more effective in the prevention of deep muscle atrophy than RS. Since the skin muscle layers act like the plates of a capacitor, separated by the subcutaneous adipose layer, the SS can pass through this capacitor more easily than the RS. Hence, SS can prevent the progressive loss of muscle fibers in the deep portion of the calf muscles. PMID- 25028132 TI - Demise of the academic student lecture: an inevitable trend in the digital age. PMID- 25028131 TI - Dynamic dialog between cytokeratin 18 and annexin A1 in breast cancer: a transcriptional disequilibrium. AB - Cytokeratins (CKs) constitute the cytoskeletal network and are regulated by post translational modifications, acting not only as a mechanical support, but also in cell signaling and regulatory processes. Signaling is mediated by CK-associated proteins, such as Annexin A1 (ANXA1), a ligand of the CK18/CK8 complex. ANXA1 has a pivotal role in cellular and immunological responses, and together with CK18 have been implicated in several processes related to malignant transformation in breast cancer (BC). Our aim was to demonstrate how their interaction might be linked to BC development. We investigated transcript levels, protein expression and distribution for both targets in breast tissues of 92 patients (42 BCs and 50 benign diseases) using qPCR and immunohistochemistry, respectively. ANXA1 and CK18 mRNAs were inversely correlated, and their ratio in each TNM stage significantly differentiated BC from benign diseases (OR=5.62). These differences did not mirror tissue protein levels, but a significant dichotomous protein distribution in tumor tissues was observed, differing from the expected co localization observed during cell homeostasis. The disequilibrium of transcriptional levels between ANXA1/CK18 and alterations in their tissue distribution are present either in initial events or tumor progression, which suggest a critical event in BC. The broken dialog between ANXA1 and CK18 in normal breast tissues may play a critical role in BC development, and together may be used as combined targets for BC diagnostics. PMID- 25028133 TI - Infrared LED light therapy influences the expression of fibronectin and tenascin in skin wounds of malnourished rats--a preliminary study. AB - The aim of this investigation was to evaluate the effect of infrared (lambda 846+/-20nm) LED irradiation on the expression profile of the extracellular matrix protein components, tenascin and fibronectin on skin wounds induced in well nourished and malnourished rats. Eighteen albino rats (21 days old) were randomly divided into a well-nourished group (standard diet) and a malnourished group (regional basic diet). After receiving the diet for 70 days, skin wounds were created and the animals were subdivided into three groups: well-nourished control (n=6), malnourished control (n=6), and malnourished+LED irradiated (lambda 846+/ 20nm, 100mW, 4J/cm(2)) (n=6). The animals were sacrificed 3 and 7 days after injury and histological sections were immunostained for both proteins. They were examined for the presence, intensity, distribution and pattern of immunolabeling. At 3 days, the distribution of tenascin was shown to be greater in the wound bed of malnourished animals compared to the well-nourished group. The intensity and distribution of tenascin was shown to be lower in the malnourished LED irradiated group compared to the malnourished control. There was a significant difference regarding the presence of fibronectin in the malnourished and well-nourished groups after 7 days (p=0.03). The intensity of fibronectin was slight (100%) in the irradiated group and moderate to intense in the malnourished control group. The results of the present study indicate that infrared LED irradiation modulates positively the expression of tenascin and particularly fibronectin. PMID- 25028135 TI - Cerebral blood flow and oxygenation in infants after birth asphyxia. Clinically useful information? AB - The term 'luxury perfusion' was coined nearly 50 years ago after observation of bright-red blood in the cerebral veins of adults with various brain pathologies. The bright-red blood represents decreased oxygen extraction and hence the perfusion is 'luxurious' compared to oxygen needs. Gradual loss of cellular energy charge during the hours following severe birth asphyxia was observed twenty years later by sequential cranial magnetic resonance spectroscopy. This led to the concept of delayed energy failure that is linked to mitochondrial dysfunction and apoptotic cell death. Abnormally increased perfusion and lack of normal cerebral blood flow regulation are also typically present, but whether the perfusion abnormalities at this secondary stage are detrimental, beneficial, or a mere epiphenomenon remains elusive. In contrast, incomplete reoxygenation of the brain during and following resuscitation is likely to compromise outcome. The clinical value of cerebral oximetry in this context can only be examined in a randomised clinical trial. PMID- 25028134 TI - Electrochemical selection and characterization of a high current-generating Shewanella oneidensis mutant with altered cell-surface morphology and biofilm related gene expression. AB - BACKGROUND: Shewanella oneidensis MR-1 exhibits extracellular electron transfer (EET) activity that is influenced by various cellular components, including outer membrane cytochromes, cell-surface polysaccharides (CPS), and regulatory proteins. Here, a random transposon-insertion mutant library of S. oneidensis MR 1 was screened after extended cultivation in electrochemical cells (ECs) with a working electrode poised at +0.2 V (vs. Ag/AgCl) to isolate mutants that adapted to electrode-respiring conditions and identify as-yet-unknown EET-related factors. RESULTS: Several mutants isolated from the enrichment culture exhibited rough morphology and extraordinarily large colonies on agar plates compared to wild-type MR-1. One of the isolated mutants, designated strain EC-2, produced 90% higher electric current than wild-type MR-1 in ECs and was found to have a transposon inserted in the SO_1860 (uvrY) gene, which encodes a DNA-binding response regulator of the BarA/UvrY two-component regulatory system. However, an in-frame deletion mutant of SO_1860 (?SO_1860) did not exhibit a similar level of current generation as that of EC-2, suggesting that the enhanced current generating capability of EC-2 was not simply due to the disruption of SO_1860. In both EC-2 and ?SO_1860, the transcription of genes related to CPS synthesis was decreased compared to wild-type MR-1, suggesting that CPS negatively affects current generation. In addition, transcriptome analyses revealed that a number of genes, including those involved in biofilm formation, were differentially expressed in EC-2 compared to those in ?SO_1860. CONCLUSIONS: The present results indicate that the altered expression of the genes related to CPS biosynthesis and biofilm formation is associated with the distinct morphotype and high current generating capability of strain EC-2, suggesting an important role of these genes in determining the EET activity of S. oneidensis. PMID- 25028137 TI - Blood stem cell donation: a model for worldwide cooperation in transplantation. PMID- 25028136 TI - Non-invasive assessment of neonatal brain oxygen metabolism: A review of newly available techniques. AB - Because oxidative metabolism is the primary form of energy production in the brain, the amount of oxygen consumed by the brain, denoted by a physiological parameter termed cerebral metabolic rate of oxygen (CMRO2), represents a key marker for tissue viability and brain function. Quantitative assessment of cerebral oxygen metabolism in the neonate may provide an important marker in better understanding normal brain development and in making diagnosis and treatment decisions in neonatal brain injuries. Measurement of CMRO2 in humans has been a challenging task, particularly in neonates. Recently, several promising techniques have been proposed to quantify neonatal CMRO2 and the purpose of this article is to provide a technical review of these techniques. Among these, we will focus the review on the NIRS optic based methods and MRI methods which are non-invasive, have been applied in normal and sick newborns and show great potentials. Potential clinical prospects of CMRO2 techniques are discussed in the context of their advantages, challenges and limitations. PMID- 25028138 TI - Creation and validation of the Singapore birth nomograms for birth weight, length and head circumference based on a 12-year birth cohort. AB - INTRODUCTION: Both gestation and birth weight have significant impact on mortality and morbidity in newborn infants. Nomograms at birth allow classification of infants into small for gestational age (SGA) and large for gestational age (LGA) categories, for risk stratification and more intensive monitoring. To date, the growth charts for preterm newborn infants in Singapore are based on the Fenton growth charts, which are constructed based on combining data from various Western growth cohorts. Hence, we aim to create Singapore nomograms for birth weight, length and head circumference at birth, which would reflect the norms and challenges faced by local infants. MATERIALS AND METHODS: Growth parameters of all babies born or admitted to our unit from 2001 to 2012 were retrieved. Following exclusion of outliers, nomograms for 3 percentiles of 10th, 50th, and 90th were generated for the gestational age (GA) ranges of 25 to 42 weeks using quantile regression (QR) combined with the use of restricted cubic splines. Various polynomial models (second to third degrees) were investigated for suitability of fit. The optimum QR model was found to be a third degree polynomial with a single knotted cubic spline in the mid-point of the GA range, at 33.5 weeks. Check for goodness of fit was done by visual inspection first. Next, check was performed to ensure the correct proportion: 10% of all cases fall above the upper 90th percentile and 10% fall below the lower 10th percentile. Furthermore, an alternative formula-based method of nomogram construction, using mean, standard deviation (SD) and assumption of normality at each gestational age, was used for counterchecking. RESULTS: A total of 13,403 newborns were included in the analysis. The new infant-foetal growth charts with respect to birth weight, heel-crown length and occipitofrontal circumference from 25 to 42 weeks gestations with the 10th, 50th and 90th were presented. CONCLUSION: Nomograms for birth weight, length and head circumference at birth had significant impact on neonatal practice and validation of the Singapore birth nomograms against Fenton growth charts showed better sensitivity and comparable specificity, positive and negative predictive values. PMID- 25028139 TI - Osteogenic sarcoma in children and young adults. AB - INTRODUCTION: More than 80% of children with osteogenic sarcoma (OS) relapse and 35% to 40% of them die within the first 2 years after diagnosis due to relapse. We investigated the incidence, treatment modalities used and the outcome of patients with OS treated in Singapore. MATERIALS AND METHODS: Patients with OS treated in Department of Paediatrics KK Women's and Children's Hospital (KKH) and National University Hospital (NUH) between January 1994 and June 2011 were reviewed. Chemotherapy was as per the European Osteosarcoma Intergroup (EOI) and as per the Memorial Sloan-Kettering Cancer Centre's (MSKCC) T12 protocols. Overall and event-free (EFS) 5-year survivals were calculated using Kaplan-Meier analysis and Cox proportional hazards regression analysis. RESULTS: Of 66 patients with OS, 19 (29%) of them presented with metastatic OS. The median age of diagnosis was 12.1 years with 5-year overall survival of 61.7% (95% CI, 48.1 to 75.3). The 5-year overall survival for those with non-metastatic and metastatic OS was 73.1% (95% CI, 58.1 to 88.1) and 34.7% (95% CI, 8.7 to 60.7, P=0.007) respectively. The 5-year overall survival for those treated as per the MSKCC T12 and EOI was 72.4% (95% CI, 52.6 to 92.2) and 54.3% (95% CI, 36.3 to 72.3, P=0.087) respectively. After controlling for confounding factors, patients with non-metastatic OS had higher 5-year EFS (HR, 0.228, 95% CI, 0.096 to 0.541, P=0.001) and overall survival (HR, 0.294, 95% CI, 0.121 to 0.713, P=0.007) compared to those with metastatic OS. Non-metastatic OS patients treated as per EOI regimen had lower 5-year EFS (HR, 2.397, 95% CI, 1.012 to 6.678, P=0.047) compared to those treated per MSKCC T12 regimen. CONCLUSION: Multidrug combination chemotherapy including high-dose methotrexate (HD-MTX) and a multidisciplinary team approach introduced in 2003 in Singapore is well tolerated and can be safely delivered. The survival benefit between the 2 regimens still needs to be explored. PMID- 25028140 TI - Neonatal Diabetes in a Singapore Children's Hospital: Molecular Diagnoses of Four Cases. AB - INTRODUCTION: Neonatal diabetes (ND) presents below 6 months of age, and is caused by a genetic defect in glucose homeostasis. Molecular genetic diagnosis can identify the exact molecular aetiology and guide clinical management. The objective of this study was to identify ND among children with diabetes in a major children's hospital in Singapore and to characterise their molecular and clinical features. MATERIALS AND METHODS: The study identified all infants below 6 months of age who presented with diabetes to our centre from January 2008 to December 2010. It also reviewed diabetes database comprising 662 patients, to identify those who were diagnosed with diabetes below 6 months of age between January 1997 and December 2010. Four patients (3 females and 1 male) were identified and their molecular aetiology was investigated. RESULTS: A molecular aetiology was found in each of the 4 patients identified. Two patients (Patient 1 and 2) had permanent ND (PND). Patient 1 who has KCNJ11/R201H mutation was successfully switched from insulin to oral glibenclamide and Patient 2 who has a novel mutation INS/C109Y continues to be treated with insulin. Two patients (Patient 3 and 4) had transient ND (TND) and no longer require insulin or any other intervention to maintain normoglycaemia. Patient 3 has a novel mutation ABCC8/F1182S and Patient 4 has a paternal duplication on chromosome 6q24. CONCLUSION: This study identified 4 cases of ND in our cohort of diabetes children and confirmed their molecular diagnosis. Molecular genetic testing for these children led to accurate diagnosis and appropriate management. PMID- 25028141 TI - Surgeon-Performed Ultrasound-Guided Fine-Needle Aspiration Cytology (SP-US-FNAC) Shortens Time for Diagnosis of Thyroid Nodules. AB - INTRODUCTION: Ultrasound-guided fine-needle aspiration cytology (US-FNAC) of thyroid nodules is an important diagnostic procedure. In most hospitals, patients are referred to radiologists for US-FNAC, but this often results in a long waiting time before results are available. Surgeon-performed US-FNAC (SP-US-FNAC) during the initial patient consultation attempts to reduce the waiting time but it is not known whether this is as accurate as radiologist-performed US-FNAC (RP US-FNAC). The aim of this study is to compare the clinical efficiency between SP US-FNAC and RP-US-FNAC. MATERIALS AND METHODS: A retrospective study was performed on patients from the Department of General Surgery, Tan Tock Seng Hospital (TTSH) who underwent an US-FNAC from August 2011 to May 2012. All cases of SP-US-FNAC were performed by a single surgeon. This study compared the rates of positive diagnoses achieved by SP-US-FNAC and RPUS- FNAC as well as the time interval to reach a cytological diagnosis by each group. RESULTS: A total of 40 cases of SP-US-FNAC and 72 cases of RP-US-FNAC were included in the study. SP-US FNAC resulted in 28 (70%) positive diagnoses and 12 (30%) nondiagnoses while RP US-FNAC resulted in 47 (65.3%) positive diagnoses and 25 (34.7%) non-diagnoses. These results were comparable (P=0.678). The median time taken to reach a cytological diagnosis was 1 working day for SP-US-FNAC and 29.5 working days for RP-US-FNAC resulting in a shorter interval to reaching a cytological diagnosis for SP-US-FNAC (P<0.001). CONCLUSION: In the workup of thyroid nodules, SP-US FNAC is as accurate as RP-US-FNAC but significantly reduces the time taken to reach a cytological diagnosis. This leads to greater clinical efficiency in the management of patients with thyroid nodules, which in turn leads to other benefits such as decreased patient anxiety and increased patient satisfaction. PMID- 25028142 TI - Chikungunya in Singapore--the battle continues. PMID- 25028143 TI - Implications of morbid obesity and surgery for the obese. PMID- 25028144 TI - Haemoglobin E-beta Thalassaemia in Singapore. PMID- 25028145 TI - Treatment-related Acute Myeloid Leukaemia After Temozolomide for Glioblastoma Multiforme. PMID- 25028146 TI - A rash in an elderly woman. Diagnosis: Leukaemia cutis (cutaneous leukaemic infiltrates). PMID- 25028147 TI - Early outcomes of extra-thoracic debranching thoracic endovascular aortic repair for distal aortic arch disease. AB - Thoracic endovascular aortic repair (TEVAR) combined with supra-aortic debranching is a promising approach for distal aortic arch disease, especially in high-risk patients. Most debranching TEVAR procedures for distal arch pathologies can now be performed by using extra-thoracic bypass and endovascular repair, without intra-thoracic manipulation needing sternotomy or thoracotomy. To compare the early outcomes of extra-thoracic debranching TEVAR with those of conventional arch replacement, we retrospectively reviewed data from 20 high-risk patients with distal aortic arch disease who underwent extra-thoracic debranching TEVAR and 16 patients who underwent total arch replacement from March 2009 to November 2011. Patient demographics, operative data, and outcomes in each group were evaluated and compared. The mean follow-up period was 22.4 +/- 12.7 months. In the extra-thoracic debranching TEVAR group, primary technical success was achieved in all cases. One patient (5 %) died of low cardiac output syndrome within 30 days after surgery. Two patients had perioperative morbidities (10 %); both had a stroke during the procedure. No endoleak or graft migration was observed, and all bypass grafts remained patent. No patient had paraplegia, a new aortic event, or surgical site infection. In conclusion, the early outcomes of extra-thoracic debranching TEVAR in high-risk patients with distal aortic arch disease were satisfactory and encouraging, compared with conventional arch replacement. Extra-thoracic debranching TEVAR has the advantage of less invasiveness and no possibility of sternal infection. PMID- 25028148 TI - Comparison of neovascularization in dermal substitutes seeded with autologous fibroblasts or impregnated with bFGF applied to diabetic foot ulcers using laser Doppler imaging. AB - A bilayered artificial dermis (AD) composed of an upper silicone sheet and a lower collagen sponge has been widely applied for skin defects. After application, fibroblasts and capillaries infiltrate the AD and the collagen sponge is replaced by host dermal tissue within a few weeks. However, this delay and the high incidence of infection are concerns regarding the use of AD in the treatment of chronic ulcers. In this study, we compared the neovascularization of conventional AD seeded with autologous fibroblasts (cultured dermis: CD) and collagen/gelatin sponge (CGS), which is a novel artificial dermis capable of sustained release of basic fibroblast growth factor (bFGF) after application using laser Doppler imaging (LDI). CD (n = 5) and CGS impregnated with bFGF (n = 6) were applied to diabetic foot ulcers after debridement. Perfusion units (PUs) were measured just after, and 1, 2 and 3 weeks after application, and complete healing rates within 16 weeks were compared. No significant differences in PUs were seen 1, 2 and 3 weeks after application and in healing rates within 16 weeks between the two groups. This study suggested that CD and CGS treatments were effective, but there were no significant differences between them in the treatment of diabetic ulcers . PMID- 25028149 TI - Antineoplastic activity of monocrotaline against hepatocellular carcinoma. AB - Plants are fantastic sources for present day life saving drugs. Monocrotaline a natural ligand exhibits dose-dependent cytotoxicity with potent antineoplastic activity. This study was intended to disclose the therapeutic potential of monocrotaline against hepatocellular carcinoma. The in silico predictions have highlighted the antineoplastic potential, druglikeness and biodegradability of monocrotaline. The in silico docking study has provided an insight and evidence for the antineoplastic activity of monocrotaline against p53, HGF and TREM1 proteins which play a threatening role in causing hepatocellular carcinoma. The mode of action of monocrotaline was determined experimentally by in vitro techniques such as XTT assay, NRU assay and whole cell brine shrimp assay have further supported our in silico studies. The in vitro cytotoxicity of monocrotaline was proved at IC50 24.966 ug/mL and genotoxicity at 2 X IC50 against HepG2 cells. Further, the credible druglike properties with non mutagenicity, non-toxic on mammalian fibroblast and the potential antineoplastic activity through in vitro experimental validations established monocrotaline as a novel scaffold for liver cancer with superior efficacy and lesser side effects. PMID- 25028150 TI - Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells. AB - Poly-ADP-ribose-polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replication-dependent and more profound in HR-deficient tumors. Here, we present a new mode of PARPi-mediated radiosensitization which was observed in four out of six HR-proficient tumor cell lines (responders) investigated, but not in normal cells. This effect is replication-independent, as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin. We showed that responders are radiosensitized by Olaparib because their DSB-repair is switched to PARP1-dependent end-joining (PARP1-EJ), as evident by (i) the significant increase in the number of residual gammaH2AX foci following irradiation with 3Gy and treatment with Olaparib, (ii) the enhanced enrichment of PARP1 at the chromatin after 3Gy and (iii) the inhibition of end-joining activity measured by a specific reporter substrate upon Olaparib treatment. This is the first study which directly demonstrates the switch to PARP1-EJ in tumor cells and its contribution to the response to Olaparib as a radiosensitizer, findings which could widen the scope of application of PARPi in tumor therapy. PMID- 25028151 TI - Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib, axitinib, cediranib or regorafenib: an updated systematic review and comparative meta-analysis. AB - BACKGROUND: We performed a systematic review and comparative meta-analysis of cardiovascular toxicities associated with sunitinib, axitinib, cediranib or regorafenib; oral multi tyrosine kinase inhibitors. PATIENTS AND METHODS: Eligible studies included randomized phase II and III trials of patients with solid tumors on sunitinib, axitinib, cediranib or regorafenib describing daily events of hypertension, left ventricular dysfunction, bleeding or thrombosis. RESULTS: Patients treated with these four agents had a significantly increased risk of all-grade hypertension and bleeding. The RR of all-grade hypertension, bleeding, thrombosis and cardiac dysfunction were 2.78 (95% CI 2.03-3.81; p<0.00001), 1.93 (95% CI 1.41-2.64; p<0.00001), 0.85 (95% CI 0.60-1.19; p=0.50), 2.36 (95% CI 0.95-5.87; p=0.06), respectively. Exploratory subgroup analysis showed no effect of the agent used (sunitinib vs. axitinib vs. cediranib) in the risk of hypertension; while for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib. CONCLUSIONS: Our meta-analysis has demonstrated that sunitinib, axitinib, cediranib and regorafenib are associated with a higher risk of developing all grade and high grade hypertension compared with control. While for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib. Clinicians should be aware of these risks and perform regular cardiovascular monitoring. PMID- 25028152 TI - The Shark that does not bite: an Australian rubber glove distraction technique for distressed children. PMID- 25028153 TI - Development of a non-dairy probiotic fermented product based on almond milk and inulin. AB - A new fermented almond "milk" that combined the properties of both almonds and probiotics was considered to cover the current versatile health-promoting foods' demand. Almond milk fermentation with probiotic Lactobacillus reuteri and Streptococcus thermophilus was studied by using a Central Composite design with response surface methodology, and different factors (glucose, fructose, inulin and starters) were optimised to assure high probiotic survivals in the final product. The optimal formulation was physicochemically characterised throughout cold storage (28 days) and both probiotic survivals to in vitro digestion and proteolysis were quantified. Results showed that a high probiotic population (>10(7) cfu/mL) was obtained in the previously optimised almond milk throughout storage time, which correspond to the addition of 0.75 g of glucose/100 mL, 0.75 g of fructose/100 mL, 2 g/100 mL inulin and 6 mL/100 mL inoculum. Glucose was used as the main nutrient and the production of mannitol by L. reuteri was detected. The fermentation process increased the viscosity values, forming a weak gel structure, whose physical properties hardly changed. Probiotic bacteria notably survived (51%) to the in vitro digestion, surely related to the inulin presence, which would add value to the developed product by enhancing the potential health benefits of its consumption. PMID- 25028154 TI - Cross-cultural perception of six commercial olive oils: A study with Spanish and US consumers. AB - A cross-cultural study was conducted with Spanish and US consumers to gain an insight into the preferred characteristics of olive oils in both countries. Six commercial olive oils (four samples from Spain and two samples from the US) were analyzed by a highly trained panel (descriptive analysis) and also by two consumers' groups (100 consumers from Spain and 100 from the US). Demographic, acceptability, and Just-About-Right data were collected to study the preferences of both groups, and the relationships with descriptive data were explored to determine the drivers of like/dislike. The Spanish extra virgin olive oils and the imported US extra virgin olive oil were characterized by having bitter, pungent, and more green notes, and were preferred by the Spanish consumers. The US consumers liked the bland Spanish refined olive oil, and the Californian olive oil that was characterized by fruity, floral, and sweet notes. The results showed that the Spanish consumers were more aware about olive oil quality in general than their US counterparts, maybe because of a higher usage of the product in Spain. The present study provides essential data which might help producers in designing and promoting olive oils matching US consumers' requirements, an emerging market for this Mediterranean product. PMID- 25028155 TI - Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia. AB - Neurodevelopmental processes are widely believed to underlie schizophrenia. Analysis of brain texture from conventional magnetic resonance imaging (MRI) can detect disturbance in brain cytoarchitecture. We tested the hypothesis that patients with schizophrenia manifest quantitative differences in brain texture that, alongside discrete volumetric changes, may serve as an endophenotypic biomarker. Texture analysis (TA) of grey matter distribution and voxel-based morphometry (VBM) of regional brain volumes were applied to MRI scans of 27 patients with schizophrenia and 24 controls. Texture parameters (uniformity and entropy) were also used as covariates in VBM analyses to test for correspondence with regional brain volume. Linear discriminant analysis tested if texture and volumetric data predicted diagnostic group membership (schizophrenia or control). We found that uniformity and entropy of grey matter differed significantly between individuals with schizophrenia and controls at the fine spatial scale (filter width below 2mm). Within the schizophrenia group, these texture parameters correlated with volumes of the left hippocampus, right amygdala and cerebellum. The best predictor of diagnostic group membership was the combination of fine texture heterogeneity and left hippocampal size. This study highlights the presence of distributed grey-matter abnormalities in schizophrenia, and their relation to focal structural abnormality of the hippocampus. The conjunction of these features has potential as a neuroimaging endophenotype of schizophrenia. PMID- 25028156 TI - Left fronto-temporal dysconnectivity within the language network in schizophrenia: an fMRI and DTI study. AB - Schizophrenia is a mental disorder characterized by language disorders. Studies reveal that both a functional dysconnectivity and a disturbance in the integrity of white matter fibers are implicated in the language process in patients with schizophrenia. Here, we investigate the relationship between functional connectivity within a language-comprehension network and anatomical connectivity using fiber tracking in schizophrenia. We hypothesized that patients would present an impaired functional connectivity in the language network due to anatomical dysconnectivity. Participants comprised 20 patients with DSM-IV schizophrenia and 20 healthy controls who were studied with functional magnetic resonance imaging and diffusion tensor imaging. The temporal correlation coefficient and diffusion values between the left frontal and temporal clusters, belonging to the language network, were individually extracted, in order to study the relationships of anatomo-functional connectivity. In patients, functional connectivity was positively correlated with fractional anisotropy, but was negatively correlated with radial diffusivity and/or mean diffusivity, in the left arcuate fasciculus and part of the inferior occipitofrontal fasciculus, determined as the fronto-temporal tracts. Our findings indicate a close relationship between functional and anatomical dysconnectivity in patients with schizophrenia. The disturbance in the integrity of the left fronto-temporal tracts might be one origin of the functional dysconnectivity in the language comprehension network in schizophrenia. PMID- 25028157 TI - Living Alone During Cancer Treatment: An Exploration of Patients' Experiences. AB - The social environment is an important determinant in the overall experience of having cancer. The purpose of this article is to identify how patients experience living alone during their cancer treatment. Using qualitative methods based on grounded theory techniques, we interviewed a sample of 32 cancer patients. Living alone was an ambiguous experience during cancer treatment: patients experienced both a lack of support as well a gain in privacy, freedom, and know-how. Living alone was also seen as a constitutive element of the patients' identity. Consequently, patients saw living alone as either a threat or as a resource for their adjustment to cancer treatment. These divergent meanings of living alone did share one common attribute, which was that staying independent was their key goal during cancer treatment. Health care providers should be attentive to the heterogeneous aspects of the experience of living alone when critically appraising the independence of patients. PMID- 25028158 TI - Science of the Particular: An Advocacy of Naturalistic Case Study in Health Research. AB - Case studies can provide us with in-depth understanding of a single demarcated entity. Cases can be corporations and clinics, but are usually people. There are several approaches to case study. Naturalistic case study constitutes the science of the particular. The aim of naturalistic case study is to understand with minimum intervention the particularity of a case in its ordinary situation from multiple perspectives. Naturalistic case study relies on a humanistic commitment to study the world from the human perspective. The purpose here is to illuminate how five key features of naturalistic case study can be used in health research. Case studies are of use in various disciplines. In this article we show that the naturalistic case study can have extraordinary value in health research, and is useful from a variety of perspectives. We do so by presenting a case report of a 92-year-old resident moving to a care center. PMID- 25028159 TI - Re-examination of the taxonomic status of Enterobacter helveticus, Enterobacter pulveris and Enterobacter turicensis as members of the genus Cronobacter and their reclassification in the genera Franconibacter gen. nov. and Siccibacter gen. nov. as Franconibacter helveticus comb. nov., Franconibacter pulveris comb. nov. and Siccibacter turicensis comb. nov., respectively. AB - Recently, a taxonomical re-evaluation of the genus Enterobacter, based on multi locus sequence typing (MLST) analysis, has led to the proposal that the species Enterobacter pulveris, Enterobacter helveticus and Enterobacter turicensis should be reclassified as novel species of the genus Cronobacter. In the present work, new genome-scale analyses, including average nucleotide identity, genome-scale phylogeny and k-mer analysis, coupled with previously reported DNA-DNA hybridization values and biochemical characterization strongly indicate that these three species of the genus Enterobacter are not members of the genus Cronobacter, nor do they belong to the re-evaluated genus Enterobacter. Furthermore, data from this polyphasic study indicated that all three species constitute two new genera. We propose reclassifying Enterobacter pulveris and Enterobacter helveticus in the genus Franconibacter gen. nov. as Franconibacter pulveris comb. nov. (type strain 601/05(T) = LMG 24057(T) = DSM 19144(T)) and Franconibacter helveticus comb. nov. (type strain 513/05(T) = LMG 23732(T) = DSM 18396(T)), respectively, and Enterobacter turicensis in the genus Siccibacter gen. nov. as Siccibacter turicensis comb. nov. (type strain 508/05(T) = LMG 23730(T) = DSM 18397(T)). PMID- 25028160 TI - Expert clinical reasoning and pain assessment in mechanically ventilated patients: A descriptive study. AB - BACKGROUND: Pain assessment in mechanically ventilated patients is challenging, because nurses need to decode pain behaviour, interpret pain scores, and make appropriate decisions. This clinical reasoning process is inherent to advanced nursing practice, but is poorly understood. A better understanding of this process could contribute to improved pain assessment and management. OBJECTIVE: This study aimed to describe the indicators that influence expert nurses' clinical reasoning when assessing pain in critically ill nonverbal patients. METHODS: This descriptive observational study was conducted in the adult intensive care unit (ICU) of a tertiary referral hospital in Western Switzerland. A purposive sample of expert nurses, caring for nonverbal ventilated patients who received sedation and analgesia, were invited to participate in the study. Data were collected in "real life" using recorded think-aloud combined with direct non participant observation and brief interviews. Data were analysed using deductive and inductive content analyses using a theoretical framework related to clinical reasoning and pain. RESULTS: Seven expert nurses with an average of 7.85 (+/-3.1) years of critical care experience participated in the study. The patients had respiratory distress (n=2), cardiac arrest (n=2), sub-arachnoid bleeding (n=1), and multi-trauma (n=2). A total of 1344 quotes in five categories were identified. Patients' physiological stability was the principal indicator for making decision in relation to pain management. Results also showed that it is a permanent challenge for nurses to discriminate situations requiring sedation from situations requiring analgesia. Expert nurses mainly used working knowledge and patterns to anticipate and prevent pain. CONCLUSIONS: Patient's clinical condition is important for making decision about pain in critically ill nonverbal patients. The concept of pain cannot be assessed in isolation and its assessment should take the patient's clinical stability and sedation into account. Further research is warranted to confirm these results. PMID- 25028161 TI - Polymorphisms in TLR1, TLR6 and TLR10 genes and the risk of Graves' disease. AB - Graves' disease (GD) is postulated to be caused by the combined effects of susceptibility genes and environmental triggers. Toll-like receptors (TLRs) play a role in the activation of innate and adaptive immune responses in mammalians. The aim of this study was to evaluate the potential association of polymorphisms in TLR1, TLR6 and TLR10 genes with GD in Chinese Cantonese population. Seven single nucleotide polymorphisms (i.e. rs4833095 and rs5743565 in TLR1; rs5743808 in TLR6; and rs4504265, rs11466655, rs11096957 and rs10856839 in TLR10) were evaluated in 332 GD patients and 351 unrelated controls from Chinese Cantonese population. SNP rs5743565 in TLR1 conferred a protective effect against GD. The minor allele G of rs5743565 decreased the risk of GD in all cases (odds ratio; ORG vs. A=0.72 (0.58-0.91); p=0.005; ptrend=0.004) and early onset patients (ORG vs. A=0.72 (0.56-0.91); p=0.007; ptrend=0.006). This study provided evidence that genetic variation rs5743565 in TLR1 might be associated with the decreased susceptibility of GD. PMID- 25028162 TI - Towards an ethical theory in disaster situations. AB - Health Care professionals working in disaster situations have to face urgent choices which diverge from their normal deontological ethos and are more utilitarian. Such is the triage system used to choose whom to treat. Instead of entering a crisis these professionals should be thought that ethics is not harmonizable to all situations and that there are situations in which saving as many lives as possible mean sacrificing others. This calls for defining a perimeter zone in which such choices occur, and a time frame (a space-time niche) in which it ought to be considered ethical and legitimate to use such value laden choices. PMID- 25028163 TI - We need to stop pretending that everything is OK with the Indian healthcare system. PMID- 25028164 TI - A computer-generated animated face stimulus set for psychophysiological research. AB - Human faces are fundamentally dynamic, but experimental investigations of face perception have traditionally relied on static images of faces. Although naturalistic videos of actors have been used with success in some contexts, much research in neuroscience and psychophysics demands carefully controlled stimuli. In this article, we describe a novel set of computer-generated, dynamic face stimuli. These grayscale faces are tightly controlled for low- and high-level visual properties. All faces are standardized in terms of size, luminance, location, and the size of facial features. Each face begins with a neutral pose and transitions to an expression over the course of 30 frames. Altogether, 222 stimuli were created, spanning three different categories of movement: (1) an affective movement (fearful face), (2) a neutral movement (close-lipped, puffed cheeks with open eyes), and (3) a biologically impossible movement (upward dislocation of eyes and mouth). To determine whether early brain responses sensitive to low-level visual features differed between the expressions, we measured the occipital P100 event-related potential, which is known to reflect differences in early stages of visual processing, and the N170, which reflects structural encoding of faces. We found no differences between the faces at the P100, indicating that different face categories were well matched on low-level image properties. This database provides researchers with a well-controlled set of dynamic faces, controlled for low-level image characteristics, that are applicable to a range of research questions in social perception. PMID- 25028166 TI - A high-risk patient with long-QT syndrome with no response to cardioselective beta-blockers. AB - We present a case of a high-risk 19-year-old female with long-QT syndrome (LQTS) with compound mutations. She had a history of aborted cardiac arrest and syncope and had received treatment with propranolol for 15 years. However, because she developed adult-onset asthma we tried to switch propranolol, a nonselective beta blocker, to beta-1-cardioselective agents, bisoprolol and metoprolol. These resulted in both a markedly prolonged corrected QT interval and the development of LQTS-associated arrhythmias. Eventually, propranolol was reinitiated at a higher dose with the addition of verapamil, and she has had no further cardiac or asthmatic events for 5 years. PMID- 25028165 TI - Hybrid therapy in the management of atrial fibrillation. AB - Atrial fibrillation is the most common sustained arrhythmia. Because of the sub optimal outcomes and associated risks of medical therapy as well as the recent advances in non-pharmacologic strategies, a multitude of combined (hybrid) algorithms have been introduced that improve efficacy of standalone therapies while maintaining a high safety profile. Antiarrhythmic administration enhances success rate of electrical cardioversion. Catheter ablation of antiarrhythmic drug-induced typical atrial flutter may prevent recurrent atrial fibrillation. Through simple ablation in the right atrium, suppression of atrial fibrillation may be achieved in patients with previously ineffective antiarrhythmic therapy. Efficacy of complex catheter ablation in the left atrium is improved with antiarrhythmic drugs. Catheter ablation followed by permanent pacemaker implantation is an effective and safe treatment option for selected patients. Additional strategies include pacing therapies such as atrial pacing with permanent pacemakers, preventive pacing algorithms, and/or implantable dual chamber defibrillators are available. Modern hybrid strategies combining both epicardial and endocardial approaches in order to create a complex set of radiofrequency lesions in the left atrium have demonstrated a high rate of success and warrant further research. Hybrid therapy for atrial fibrillation reviews history of development of non-pharmacological treatment strategies and outlines avenues of ongoing research in this field. PMID- 25028168 TI - First clinical experience of the looped Inoue balloon technique for antegrade percutaneous balloon aortic valvuloplasty. AB - Balloon aortic valvuloplasty (BAV) has played a limited role in the management of patients with severe aortic stenosis. However, BAV is being performed more frequently these days with the emergence of transcatheter aortic valve implantation (TAVI). We previously described a technique named "looped Inoue balloon technique" to simplify the antegrade transvenous BAV by making a loop in the left atrium using two stylets. We present a case in which the looped Inoue balloon technique was successfully applied. The patient was an 83-year-old woman with progressive dyspnea due to severe aortic stenosis. The aortic valve area was 0.39 cm(2) with a mean transvalvular gradient of 46 mmHg. The patient was deemed high risk for surgical aortic valve replacement or TAVI in view of the multiple comorbidities and frailty. Antegrade BAV using the looped Inoue balloon technique was performed. The procedure was successful without any complications. The post procedural aortic valve area increased to 1.15 cm(2) with a mean pressure gradient of 23 mmHg. This is the first report of clinical use of the looped Inoue balloon technique for antegrade BAV. PMID- 25028167 TI - Effects of the endothelin receptor antagonist bosentan on hemodynamics and exercise capacity in Japanese patients with mildly symptomatic pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) trial has mostly enrolled patients with World Health Organization functional class (WHO FC) III or IV. However, PAH is rapidly progressive in nature even in patients with less severe forms at diagnosis. Following the recent studies in Western population, here we assessed the efficacy of bosentan in Japanese patients with WHO FCII PAH. In this open label trial, bosentan 125 mg twice daily was administered for 12 weeks in 16 patients, and a hemodynamic evaluation was performed. Treatment was continued for a further 12 weeks, where the effect on exercise capacity was assessed in 13 patients. In 16 patients, mean pulmonary arterial pressure decreased from 40.4 +/ 10.4 to 35.6 +/- 12.6 mmHg (p = 0.018) and cardiac index increased from 2.54 +/- 0.73 to 2.96 +/- 0.82 L/min/m(2) (p = 0.023). Thus, pulmonary vascular resistance decreased from 792 +/- 565 to 598 +/- 558 dyn.sec/cm(5) (p = 0.006). In 13 patients followed up for 24 weeks, 6-min walking distance increased from baseline at Week 12 (p = 0.003) and Week 24 (p = 0.011). All patients were mildly symptomatic at baseline with dyspnea index (Borg scale) of 2.50 +/- 1.58 and the specific activity scale (SAS) of 5.0 +/- 1.4 METs. These values remained unchanged throughout the study. These results suggest that bosentan treatment was beneficial for Japanese patients with WHO FC II PAH and treatment should be started in the early stage of the disease. PMID- 25028169 TI - Cardiopulmonary resuscitation can be futile and sometimes worse in dying patients. PMID- 25028170 TI - Does CPAP therapy alter urinary albumin level in adult patients with moderate to severe obstructive sleep apnea syndrome? AB - BACKGROUND: Urinary albumin is a marker of cardiovascular morbidity and mortality, and also it has been viewed as a marker for vascular endothelial dysfunction in both the kidneys and systemic vasculature. Lowering urinary albumin is associated with fewer cardiovascular and renal diseases. We investigated the change in urinary albumin after 1 month of continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea syndrome (OSAS). METHODS: Eighteen patients (four females) in the middle-age group with moderate to severe OSAS were enrolled, who received and were compliant to CPAP therapy. Patients did not have a systemic disease or use a medication that could influence urinary albumin. Blood and urine samples were obtained in the morning after polysomnography and after 1 month of CPAP therapy to measure urinary albumin excretion and urinary albumin-to-creatinine ratio. RESULTS: Urinary albumin excretion (UAE) and urinary albumin/creatinine ratio (UACR) decreased significantly after 1 month of CPAP therapy: UAE at baseline and 1 month, 50 (1.1 174.8) and 22.7 (4.1-55.9); UACR, 27 (18.5-51.6) and 10.6 (4.3-43.1). UAE alteration was significantly associated with proportion of sleep time spent below an SaO2 of 90%. Serum creatinine, serum total cholesterol, and creatinine clearance also decreased after 1 month of CPAP therapy. CONCLUSION: Albuminuria is not rare in patients with OSAS and can be corrected after CPAP therapy. Determination of urinary albumin level is a simple, inexpensive, and noninvasive method that could be a promising biomarker to identify a high-risk population in patients with OSAS who may benefit from closer medical follow-up and preventive therapy. PMID- 25028171 TI - Obstructive sleep apnea should be treated in patients with idiopathic pulmonary fibrosis. AB - STUDY OBJECTIVES: The most recent idiopathic pulmonary fibrosis (IPF) guidelines include obstructive sleep apnea (OSA) among the IPF-associated comorbidities. Furthermore, they recognize the paucity of studies related to continuous positive airway pressure(CPAP) treatment in this patient group and call for intensive research in this field. Our aim was to assess the effect of CPAP treatment on sleep and overall life quality parameters, morbidity, and mortality in IPF patients with OSA. METHODS: Ninety-two treatment-naive, newly diagnosed, consecutive IPF patients underwent overnight-attended polysomnography (PSG). In those patients with an apnea-hypopnea index (AHI) of >=15, therapy with CPAP was initiated. Patients were divided into poor and good CPAP compliance groups. All subjects completed multiple quality-of-life and sleep instruments before CPAP initiation and at 1 year after the start of CPAP treatment. RESULTS: The good CPAP compliance group (37 patients) showed statistically significant improvement in all quality-of-life and sleep instruments after 1 year's CPAP treatment. The poor CPAP compliance group (18 patients) showed significant changes of smaller strength only in a minority of the used instruments. During the 24-month follow up period after CPAP initiation, three patients from the CPAP poor compliance group died, whereas all patients from the good CPAP compliance group remained alive. CONCLUSION: Early OSA recognition and treatment is crucial in a fatal disease such as IPF. Effective CPAP treatment in IPF patients with OSA results in a significant improvement in daily living activities and quality of sleep and life. Good CPAP compliance appears to improve mortality. PMID- 25028172 TI - A functional EGF+61 polymorphism is associated with severity of obstructive sleep apnea. AB - BACKGROUND: Involvement of epidermal growth factor (EGF) is reported in diseases caused by hypoxia. Its functional polymorphism may alter its transcription, affecting EGF expression, contributing to obstructive sleep apnea (OSA). OBJECTIVE: The aim of this study was to investigate associations of EGF+61 polymorphism and risk of OSA. METHODS: Two hundred two participants were enrolled in this case-control study. DNA was extracted from peripheral blood, and EGF 61A/G polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: No significant association between EGF 61 A/G polymorphism and risk of OSA was observed in any of the gene models tested (AA vs. GG: OR = 0.97, 95% CI = 0.37-2.55; P = 0.95). However, compared with GG genotype, AG genotype associated with decreased risk of severe OSA (AG vs. GG: OR = 0.32, 95% CI = 0.11-0.94). CONCLUSIONS: Our study showed that AG genotype has a protective effect on OSA patients against severe disease, although EGF 61A/G polymorphisms have no role on the risk of the disease. Additional large studies should further validate our findings. PMID- 25028173 TI - Effects of surgical weight loss for treating obstructive sleep apnea. AB - PURPOSE: Weight loss has been reported to reduce the severity of obstructive sleep apnea (OSA), particularly in the obese population. However, prospective studies with polysomnography (PSG) for the precise evaluation of OSA are lacking especially in Asian countries. We evaluated the effects of surgical weight loss for treating OSA using PSG data obtained before and after surgery. METHODS: We performed a prospective study analyzing the clinical and PSG data obtained from our cohort of bariatric surgical candidates with moderate to severe OSA, as confirmed by preoperative PSG. The patients underwent follow-up PSG at least 12 months after bariatric surgery (laparoscopic Roux-en-Y gastric bypass). RESULTS: Of the 47 patients (70.1%) with moderate to severe OSA among 67 patients who underwent preoperative PSG, 10 patients underwent postoperative PSG. The mean apnea-hypopnea index (AHI) of these 10 patients significantly reduced from 51.0+/ 34.2 to 9.3+/-12.9 events/h, while their mean body mass index (BMI) loss was from 39.9+/-8.3 to 26.9+/-4.4 kg/m2. Although the severity of OSA improved considerably, OSA resolution was achieved in only five patients (50%). When compared to the patients who achieved OSA resolution, the patients with residual OSA showed a tendency to have lower minimum arterial oxygen saturation (SaO2) levels and higher supine AHI values in preoperative PSG. CONCLUSIONS: Surgical weight loss resulted in the significant improvement of OSA associated with obesity. However, OSA remained in a considerable proportion of patients even after substantial weight loss. We recommend that postoperative PSG be considered for the evaluation of residual OSA, especially in patients with low minimum SaO2 levels and high supine AHI in preoperative PSG. PMID- 25028174 TI - Jewish holidays and their associated medical risks. AB - Religiosity is inherent in human cultures. Being different in many aspects, all have rules regarding appropriate behavior and rituals. Celebrations of social events and of holidays prevail in all major religions. These include code of dress, prayers, special food and activities which may have negative health implications. The Jewish religion is 'blessed' with an abundance of holidays each with its unique health implications. In this paper we provide an outline of the character of these festivals and possible medical repercussions on those celebrating them. Observant members of the Jewish religion and teams treating this population should be knowledgeable of potentially associated risks. Pre holiday periods should be specifically targeted for educational and preventive activity in order diminish injury or morbidity. PMID- 25028175 TI - Health of children born through artificial oocyte activation: a pilot study. AB - Artificial oocyte activation (AOA) has shown to improve fertility in severe male infertility following intracytoplasmic sperm insemination (ICSI). However, the effect of AOA on the health status of children has not been studied. This pilot historical cohort study aims to evaluate physical and mental health of 79 and 89 children from 275 and 406 couples undergoing ICSI-AOA using ionomycin and conventional ICSI, respectively. The outcomes assessed were clinical pregnancy, abortion, type of delivery, and health of children (major birth defect, mental and behavior status). No significant differences were observed between the ICSI AOA and the ICSI groups for these parameters, and the rate of major birth defects were not significantly different between the 2 groups. In this study, AOA has not imposed a greater risk on physical and mental health of children born through AOA, but for such a solid conclusion, further trails with higher number of cases are required and conclusions drawn are limited to this study. PMID- 25028176 TI - Gestational diabetes mellitus upregulates vitamin D receptor in extravillous trophoblasts and fetoplacental endothelial cells. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is often accompanied by low maternal vitamin D, that is, calcitriol (1,25[OH]2 vitamin D3), levels. Here, we tested the hypothesis that the placental vitamin D receptor (VDR) is regulated by calcitriol and altered in GDM with distinct changes in different placental cell types. Specifically, we aimed to localize VDR in human term placentas from normal and GDM pregnancies, to quantify its cellular expression and to study in vitro its regulation by its physiological agonist calcitriol. STUDY DESIGN: Placental tissue slides of 80 patients (40 with GDM/40 controls) were double stained for VDR and human leukocyte antigen G to identify extravillous trophoblasts (EVTs). Staining intensity was semiquantified. Quantitative real time-polymerase chain reaction and Western blotting measured VDR messenger RNA (mRNA) and protein in decidual tissue. The trophoblast cell line BeWo was used to study in vitro VDR regulation by calcitriol (0.01, 0.1, and 1 nmol/mL). RESULTS: Vitamin D receptor protein and mRNA levels are upregulated (P < .05) in EVT (1.8-fold) as well as in placental endothelium (5.8-fold) of patients with GDM. Expression of VDR is regulated by calcitriol in a bimodal manner: high doses (0.1 and 1 nmol/mL) caused downregulation, whereas the low dose (0.01 nmol/mL) resulted in VDR upregulation. CONCLUSION: Vitamin D receptor is upregulated in EVT and endothelium of GDM placentas. This could be due to low maternal vitamin D levels in patients with GDM because in vitro low calcitriol doses upregulate VDR in trophoblast cells. PMID- 25028177 TI - Quality-of-life benefits of catheter ablation of persistent atrial fibrillation: a reanalysis of data from the SARA study. AB - AIMS: The recently published SARA study was a prospective, multi-centre randomized controlled trial that compared CA to antiarrhythmic drug therapy (ADT) in 146 patients with persistent atrial fibrillation (AF). The study found that recurrence of AF or atrial flutter occurred significantly less often in the CA arm compared to the ADT arm (29.6% vs. 56.3%, p = 0.002). Despite this clear superiority in terms of efficacy, the authors were not able to demonstrate a corresponding Quality of Life (QoL) improvement. We sought to investigate this apparent disparity using alternative analytical methods. METHODS AND RESULTS: We were able to show that a high coefficient of variation existed for all QoL measures at each time point which may explain the lack of statistical difference originally reported. We reanalyzed the raw QoL data from the SARA study using paired sample t-tests for the change in QOL for individual patients between baseline and 12 month (final) follow up. For patients randomized to ADT the difference in QoL after 12 months was not significant for any of the four QoL domains (global, physical, psychological and sexual) whereas for patients randomized to CA all comparisons were significant (global, p < 0.001; physical, p = 0.001; psychological, p < 0.001; sexual, p = 0.003). CONCLUSION: In the SARA study, after 12 months' follow up, CA significantly improved QoL for patients with persistent AF whereas medical therapy had no appreciable effect. PMID- 25028178 TI - Can time-based decay explain temporal distinctiveness effects in task switching? AB - In task switching, extending the response-cue interval (RCI) reduces the switch cost--the detriment to performance when switching compared to repeating tasks. This reduction has been used as evidence for the existence of task-set decay processes. Recently, this has been challenged by the observation of sequential dependencies on the RCI effect: switch cost is only reduced at longer RCIs when the previous trial had a short RCI. This trial-wise variation of RCI is thought to affect the temporal distinctiveness (TD) of a previous task's episodic trace, affecting the probability of its automatic retrieval on the current trial; importantly, TD is thought to be independent of the current trial's RCI. The present study highlights a dependency between the current RCI and TD, and demonstrates that a decay model can reproduce some patterns of data attributed to TD. Further, the decay account makes a strong prediction when TD is held constant: repetition response times should slow as the RCI increases, and switch response times should be facilitated. This prediction was tested via re-analysis of extant data and three experiments. The re-analysis provided some evidence for the decay account, but Experiments 1 and 2 report slowing for task repetition and switch trials, which cannot be explained by a task-set decay process. Experiment 3, which utilized tasks requiring perceptual judgements, showed small evidence for decay. We conclude that the data are largely consistent with the TD account and that the evidence for decay of higher-level task-sets is not convincing. PMID- 25028179 TI - Analysis of dynein intermediate chains, light intermediate chains and light chains in a cohort of hereditary peripheral neuropathies. AB - The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort. PMID- 25028180 TI - Metformin enhances nitric oxide production and diminishes Rho kinase activity in rats with hyperlipidemia. AB - BACKGROUND: Rho kinase over-activation is associated with nitric oxide (NO) reduction and atherosclerosis. Metformin is favorable for endothelial function improvement and cardiovascular outcomes. Whether cardio-protective effect of metformin is associated with Rho kinase activity is unknown. METHODS: Hyperlipidemia model of rats were established accordingly. Thereafter, medical interventions in terms of atorvastatin, metformin or combined therapy were administered for 4 weeks. Laboratory parameters were compared among each groups at initial, 6 weeks of high-fat and high-cholesterol diet administration, and 4 weeks of medical intervention. Lineal regression analyses were performed. RESULTS: No significant difference of laboratory parameters was observed initially. Six weeks of high-fat and high-cholesterol diet administration, serum levels of cholesterol, C-reactive protein (CRP) level, and Rho kinase activity were significantly increased while NO production was concomitantly reduced in comparison to the sham group. After 4 weeks of medical intervention, CRP level and Rho kinase activity were profoundly diminished while NO production was significantly enhanced in the atorvastatin and metformin groups, and these benefits were further enhanced with combined therapy. Lineal regression analyses showed that Rho kinase activity was negatively correlated with NO production but positively correlated with CRP level. CONCLUSION: In rats with hyperlipidemia, metformin and atorvastatin therapy is favorable for NO production and CRP reduction, which might be associated with Rho kinase activity decrease. PMID- 25028181 TI - Changes in large-scale chromatin structure and function during oogenesis: a journey in company with follicular cells. AB - The mammalian oocyte nucleus or germinal vesicle (GV) exhibits characteristic chromatin configurations, which are subject to dynamic modifications through oogenesis. Aim of this review is to highlight how changes in chromatin configurations are related to both functional and structural modifications occurring in the oocyte nuclear and cytoplasmic compartments. During the long phase of meiotic arrest at the diplotene stage, the chromatin enclosed within the GV is subjected to several levels of regulation. Morphologically, the chromosomes lose their individuality and form a loose chromatin mass. The decondensed configuration of chromatin then undergoes profound rearrangements during the final stages of oocyte growth that are tightly associated with the acquisition of meiotic and developmental competence. Functionally, the discrete stages of chromatin condensation are characterized by different level of transcriptional activity, DNA methylation and covalent histone modifications. Interestingly, the program of chromatin rearrangement is not completely intrinsic to the oocyte, but follicular cells exert their regulatory actions through gap junction mediated communications and intracellular messenger dependent mechanism(s). With this in mind and since oocyte growth mostly relies on the bidirectional interaction with the follicular cells, a connection between cumulus cells gene expression profile and oocyte developmental competence, according to chromatin configuration is proposed. This analysis can help in identifying candidate genes involved in the process of oocyte developmental competence acquisition and in providing non invasive biomarkers of oocyte health status that can have important implications in treating human infertility as well as managing breeding schemes in domestic mammals. PMID- 25028182 TI - Ultrastructure of the epididymis and vas deferens of agoutis at different stages of sexual development. AB - The agouti (Dasyprocta spp.) is a rodent found predominantly in the Brazilian Caatinga and has importance as an alternative source of protein. In this study, the objective was to describe the ultrastructure of components of sperm pathways, especially the epididymis and vas deferens, during sexual development of agoutis kept in captivity. Segments of the vas deferens and epididymis of 8 agouti males at different stages of sexual development (prepubescent, prepubertal, pubescent, and adult) were fixed in glutaraldehyde. The following laboratory procedures were performed: histology following the standard protocol for semithin cut (toluidine blue), and transmission electron microscopy. This was a pioneer study in which it was observed that the epididymis of agoutis is composed of principal, basal, halogen, apical, and clean cells. During prepubescent and prepubertal stages, clean cells were observed in addition to principal, basal, and halogen cells. Once puberty was reached, apical cells were also present, and clean cells were no longer visible. This epithelial change during sexual development is possibly due to physiological functions. The interaction between these cells supports this, and age probably influenced the change. With regard to the vas deferens, this study was also a pioneer to note that before pubescence there were two muscle layers, differing from older animals, which had three muscle layers. This may be due to lack of sperm transit in younger animals. We concluded that the pseudostratified stereociliated epithelium of the epididymis and vas deferens of agoutis kept in captivity undergo morphological and functional changes during sexual development. PMID- 25028184 TI - Physiotherapy for patients with spina bifida cystica. AB - The condition Spina Bifida Cystica is characterised by a cystic swelling in the mid-line of the back, with an underlying defect in the posterior arches of several vertebrae and generally, involvement of the spinal cord (95% of all cases). Whilst the lesion may occur at any level of the spine, it is the lumbar and lumbo sacral regions which are most commonly affected. PMID- 25028183 TI - Evaluation of a regional monitoring program's statistical power to detect temporal trends in forest health indicators. AB - Forests are socioeconomically and ecologically important ecosystems that are exposed to a variety of natural and anthropogenic stressors. As such, monitoring forest condition and detecting temporal changes therein remain critical to sound public and private forestland management. The National Parks Service's Vital Signs monitoring program collects information on many forest health indicators, including species richness, cover by exotics, browse pressure, and forest regeneration. We applied a mixed-model approach to partition variability in data for 30 forest health indicators collected from several national parks in the eastern United States. We then used the estimated variance components in a simulation model to evaluate trend detection capabilities for each indicator. We investigated the extent to which the following factors affected ability to detect trends: (a) sample design: using simple panel versus connected panel design, (b) effect size: increasing trend magnitude, (c) sample size: varying the number of plots sampled each year, and (d) stratified sampling: post-stratifying plots into vegetation domains. Statistical power varied among indicators; however, indicators that measured the proportion of a total yielded higher power when compared to indicators that measured absolute or average values. In addition, the total variability for an indicator appeared to influence power to detect temporal trends more than how total variance was partitioned among spatial and temporal sources. Based on these analyses and the monitoring objectives of the Vital Signs program, the current sampling design is likely overly intensive for detecting a 5 % trend.year(-1) for all indicators and is appropriate for detecting a 1 % trend.year(-1) in most indicators. PMID- 25028185 TI - Discussion on the use of weight bearing plasters in the reduction of hypertonicity. AB - The following discussion is based on the results recorded over a period of four years at the New Farm Centre of the Queensland Spastic Welfare League. PMID- 25028186 TI - VIBRATORY MOTOR STIMULATION: A Preliminary Report. AB - At the annual meeting of the Australian Association of Neurologists in 1964, J. W. Lance-from the Division of Neurology, Prince Henry Hospital, Sydney, and the School of Medicine, University of New South Wales-made one of the earliest reports on the effects of low amplitude, high frequency, sinusoidal stretch on human skeletal muscle (Lance, 1965). This effect consists of an involuntary asynchronous motor unit contraction in the muscle subjected to the mechanical vibration, with reciprocal relaxation of the prime antagonists. Hagbarth and Eklund (1966a) termed this response the tonic vibration reflex (TVR). This author has coined the term vibratory motor stimulation (VMS) to describe the use of mechanical vibration for the purpose of eliciting the TVR or its correlates. PMID- 25028187 TI - Frozen shoulder - an effective method of treatment. AB - Although there has been a considerable amount of material published on the pathology and the probable aetiology of the frozen shoulder, the same cannot be said of suggestions for an effective method of physical treatment for all stages of the condition. Some authors claim that exercises mar the recovery process (Cyriax, 1957). Others have found that the condition runs a self-limiting course of anything up to three years, and any physical treatment is "notoriously unsuccessful" in altering this pattern (Crisp and Hume Kendall, 1955). However, all agree that the recovery of frozen shoulders, treated or untreated, is prolonged, and in the acute phase of the condition, physiotherapy plays no part in the treatment of pain (Cyriax, Ibid., Crisp and Hume Kendall, Ibid., Stening, 1961). PMID- 25028188 TI - Women's maternity care needs and related service models in rural areas: A comprehensive systematic review of qualitative evidence. AB - BACKGROUND: Understanding the needs of rural women in maternity care and service models available to them is significant for the development of effective policies and the sustainability of rural communities. Nevertheless, no systematic review of studies addressing these needs has been conducted. OBJECTIVES: To synthesise the best available evidence on the experiences of women's needs in maternity care and existing service models in rural areas. METHODS: Literature search of ten electronic databases, digital theses, and reference lists of relevant studies applying inclusion/exclusion criteria was conducted. Selected papers were assessed using standardised critical appraisal instruments from JBI-QARI. Data extracted from these studies were synthesised using thematic synthesis. FINDINGS: 12 studies met the inclusion criteria. There were three main themes and several sub-themes identified. A comprehensive set of the maternity care expectations of rural women was reported in this review including safety (7), continuity of care (6) and quality of care (6), and informed choices needs (4). In addition, challenges in accessing maternity services also emerged from the literature such as access (6), risk of travelling (9) and associated cost of travel (9). Four models of maternity care examined in the literature were medically led care (5), GP-led care (4), midwifery-led care (7) and home birth (6). CONCLUSION: The systematic review demonstrates the importance of including well-conducted qualitative studies in informing the development of evidence-based policies to address women's maternity care needs and inform service models. Synthesising the findings from qualitative studies offers important insight for informing effective public health policy. PMID- 25028189 TI - Impact of having a high-risk pregnancy on future postpartum contraceptive method choice. AB - BACKGROUND: To compare the knowledge and preference of preconceptional contraception to future postpartum contraceptive method choice in high-risk pregnancies. RESEARCH QUESTION: Does a high-risk pregnancy condition affect future postpartum contraceptive method choice? METHOD: Women hospitalised at the High Risk Pregnancy unit of a tertiary research and training hospital were asked to complete a self-reported questionnaire that included demographic characteristics, presence of unintended pregnancy, contraceptive method of choice before the current pregnancy, plans for contraceptive use following delivery and requests for any contraceptive counselling in the postpartum period. FINDINGS: A total of 655 pregnant women were recruited. The mean age, gravidity and parity of the women were 27.48 +/- 6.25 years, 2.81 +/- 2.15 and 1.40 +/- 1.77, respectively. High-risk pregnancy indications included 207 (31.6%) maternal, 396 (60.5%) foetal and 52 (7.9%) uterine factors. All postpartum contraceptive choices except for combined oral contraceptives (COCs) usage were significantly different from preconceptional contraceptive preferences (p<0.001). High-risk pregnancy indications, future child bearing, ideal number of children, income and education levels were the most important factors influencing postpartum contraceptive choices. While the leading contraceptive method in the postpartum period was long-acting reversible contraceptive methods (non-hormonal copper intrauterine device Cu-IUD, the levonorgestrel-releasing intrauterine system (LNG IUS) (40%), the least preferred method was COCs use (5.2%) and preference of COCs use showed no difference between the preconceptional and postpartum periods (p=0.202). Overall 73.7% of the women wanted to receive contraceptive counselling before their discharge. CONCLUSION: A high-risk pregnancy condition may change the opinion and preference of contraceptive use, and also seems to affect the awareness of family planning methods. PMID- 25028190 TI - In vitro toxicity of grey MTA in comparison to white MTA on human periodontal ligament fibroblasts. AB - AIM: This was to define and compare the in vitro toxicity of grey MTA with that of white MTA on cultured human periodontal ligament (PDL) fibroblasts. METHODS: PDL cells were obtained from sound first permanent molars and cultured in Dulbecco's Modified Eagle's Medium. Cultures were subjected to different concentrations of grey and white MTA (0.5, 5, 50 and 500 ug/ml) for 24 h at 37 degrees C. Cells that were not exposed to grey or white MTA served as the negative control. In vitro toxicity was assessed using MTT assay. STATISTICS: The results were compared using ANOVA and Tukey statistical tests (p < 0.05). RESULTS: White MTA presented higher in vitro toxicity than grey MTA. However, the differences were almost insignificant (p > 0.05). CONCLUSION: Both colours of MTA are biocompatible since they were both able to preserve PDL fibroblasts for up to 24 h. MTA is as a promising alternative in pulpotomy of primary teeth. PMID- 25028191 TI - Expression of vimentin and survivin in clear cell renal cell carcinoma and correlation with p53. AB - PURPOSE: This study focuses on investigating the expression correlation of vimentin, survivin and p53 in clear cell renal cell carcinoma (ccRCC) and the clinical significance. METHODS: The mRNA and protein expression levels of the vimentin, survivin and p53 were determined in ccRCC and adjacent normal renal tissues, using quantitative real-time-polymerase chain reaction (qRT-PCR) and Western blot. We detected the expression and localization of vimentin, survivin and p53 protein in ccRCC by immunohistochemistrical SP method and analyzed the relationships among clinical pathologic parameters and patient prognosis. RESULTS: The expression of vimentin and survivin was significantly increased in ccRCC compared with adjacent normal renal tissues, which were positively correlated with the pathological grade and clinical stage (P < 0.05). p53 was highly expressed in ccRCC compared with normal tissues (P < 0.05), which was not positively correlated with the pathological grade and clinical stage (P > 0.05). Furthermore, univariate and multivariate analysis showed that high expression levels of vimentin and survivin were independent prognostic indicators for ccRCC. The levels of vimentin and survivin were positively correlated in ccRCC (r = 0.428, P < 0.01). CONCLUSIONS: Reliable basis about biological behavior and prognosis judgments of ccRCC can be provided by combining detection of vimentin and survivin. Foundation and new ideas for gene therapy of ccRCC may be provided by further studying the relationship among vimentin, survivin and p53 in ccRCC. PMID- 25028192 TI - Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: A meta-analysis. AB - AIMS: Several polymorphisms have been identified in TNFSF15, while their roles in the incidence of ulcerative colitis (UC) and Crohn's disease (CD) are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk. METHOD: Databases were searched until 31 January 2014 for eligible studies on TNFSF15 polymorphisms. Data were extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95% CIs) were calculated. RESULTS: Fifteen studies with 8903 CD patients, 4687 UC patients and 12 606 controls were included. Except for rs4263839 polymorphism, significant associations were found between the rest six TNFSF15 polymorphisms and CD risk (rs3810936: OR = 2.10, 95% CI, 1.47-3.00; rs6478108: OR = 2.19, 95% CI, 1.53 3.13; rs4979462: OR = 1.89, 95% CI, 1.42-2.52; rs6478109: OR = 2.00, 95% CI, 1.39 2.88; rs7848647: OR = 1.54, 95% CI, 1.15-2.06; rs7869487: OR = 1.51, 95% CI, 1.06 2.17). And we found rs3810936, rs6478108 and rs6478109 polymorphism were significantly associated with UC risk (rs3810936: OR = 1.19, 95% CI, 1.06-1.34; rs6478108: OR = 1.16, 95% CI, 1.06-1.26; rs6478109: OR = 1.16, 95% CI, 1.03 1.32). According to the subgroup analysis by ethnicity, except for rs4263839 in Caucasian and rs4979462 in Asian, all the rest investigated TNFSF15 polymorphisms were associated with CD risk and rs3810936 and rs7848647 polymorphism in Asian as well as rs6478108 polymorphism in Caucasian were associated with UC risk. CONCLUSION: This meta-analysis indicated that most of the seven TNFSF15 polymorphisms (except for rs4263839) were risk factors contributed to CD and UC susceptibility. The differences in ethnicity did not influence the risk obviously. PMID- 25028193 TI - A robust HIV-1 viral load detection assay optimized for Indian sub type C specific strains and resource limiting setting. AB - BACKGROUND: Human Immunodeficiency Virus Type 1 (HIV-1) viral load testing at regular intervals is an integral component of disease management in Acquired Immunodeficiency Syndrome (AIDS) patients. The need in countries like India is therefore an assay that is not only economical but efficient and highly specific for HIV-1 sub type C virus. This study reports a SYBR Green-based HIV-1 real time PCR assay for viral load testing and is designed for enhanced specificity towards HIV-1 sub type C viruses prevalent in India. RESULTS: Linear regression of the observed and reference concentration of standards used in this study generated a correlation coefficient of 0.998 (p<0.001). Lower limit of detection of the test protocol was 50 copies/ml of plasma. The assay demonstrated 100% specificity when tested with negative control sera. The Spearman coefficient of the reported assay with an US-FDA approved, Taqman probe-based commercial kit was found to be 0.997. No significant difference in viral load was detected when the SYBR Green based assay was used to test infected plasma stored at -20 degrees C and room temperature for 7 days respectively (Wilcoxon signed rank test, p=0.105). In a comparative study on 90 pretested HIV-1 positive samples with viral loads ranging from 5,000-25,000 HIV-1 RNA copies/ml and between two commercial assays it was found that the later failed to amplify in 13.33% and 10% samples respectively while in 7.77% and 4.44% samples the copy number values were reduced by >0.5 log value, a figure that is considered clinically significant by physicians. CONCLUSION: The HIV-1 viral load assay reported in this study was found to be robust, reliable, economical and effective in resource limited settings such as those existing in India. PCR probes specially designed from HIV-1 Subtype C specific nucleotide sequences originating from India imparted specificity towards such isolates and demonstrated superior results when compared to two similar commercial assays widely used in India. PMID- 25028195 TI - Single-layer centrifugation separates spermatozoa from diploid cells in epididymal samples from gray wolves, Canis lupus (L.). AB - Sperm samples may be used for assisted reproductive technologies (e.g., farmed or endangered species) or as a source of haploid DNA or sperm-specific RNA. When ejaculated spermatozoa are not available or are very difficult to obtain, as is the case for most wild endangered species, the epididymides of dead animals (e.g., animals that have been found dead, shot by hunters or poachers, or that that require euthanasia in zoological collections) can be used as a source of sperm. Such epididymal sperm samples are usually contaminated with cellular debris, erythrocytes, leukocytes, and sometimes also bacteria. These contaminants may be sources of reactive oxygen species that damage spermatozoa during freezing or contribute undesired genetic material from diploid cells. We used single-layer centrifugation through a colloid formulation, Androcoll-C, to successfully separate wolf epididymal spermatozoa from contaminating cells and cellular debris in epididymal samples harvested from carcasses. Such a procedure may potentially be applied to epididymal sperm samples from other species. PMID- 25028196 TI - An unusual cause of bilateral massive peripheral edema in a young male with type 1 diabetes mellitus. AB - The present article demonstrates an unusual case of bilateral massive peripheral edema caused by neurogenic areflexic bladder in diabetes mellitus type 1. A 28 year-old patient with diabetes type 1 treated for a number of years was referred to the department of internal medicine because of massive edema of his lower limbs. Blood samples revealed increased concentrations of glucose (21.2 mmol/L) and glycated hemoglobin (8.5%). The computed tomography examination of abdomen and pelvis confirmed enlargement of the bladder, with smooth external contour and normal wall thickness. In addition, computed tomography demonstrated bilateral compression of the iliac veins caused by the enlarged bladder. This case highlights the importance of keeping a broad differential diagnosis in mind for patients with diabetes and massive peripheral edema. Neurogenic bladder should be considered in the differential diagnosis, especially for patients with poor glycemia control and long-standing diabetes complicated by diabetic neuropathy. PMID- 25028197 TI - Design and development of culture-specific pictograms for type 2 diabetes mellitus education and counselling. PMID- 25028198 TI - Surface wrinkling on polydimethylsiloxane microspheres via wet surface chemical oxidation. AB - Here we introduce a simple low-cost yet robust method to realize spontaneously wrinkled morphologies on spherical surfaces. It is based on surface chemical oxidation of aqueous-phase-synthesized polydimethylsiloxane (PDMS) microspheres in the mixed H2SO4/HNO3/H2O solution. Consequently, curvature and overstress sensitive wrinkles including dimples and labyrinth patterns are successfully induced on the resulting oxidized PDMS microspheres. A power-law dependence of the wrinkling wavelength on the microsphere radius exists. The effects of experimental parameters on these tunable spherical wrinkles have been systematically investigated, when the microspheres are pre-deposited on a substrate. These parameters include the radius and modulus of microspheres, the mixed acid solution composition, the oxidation duration, and the water washing post-treatment. Meanwhile, the complicated chemical oxidation process has also been well studied by in-situ optical observation via the microsphere system, which represents an intractable issue in a planar system. Furthermore, we realize surface wrinkled topographies on the whole microspheres at a large scale, when microspheres are directly dispersed in the mixed acid solution for surface oxidation. These results indicate that the introduced wet surface chemical oxidation has the great potential to apply to other complicated curved surfaces for large-scale generation of well-defined wrinkling patterns, which endow the solids with desired physical properties. PMID- 25028199 TI - Disturbing findings about the risk of suicide and psychiatric hospitals. PMID- 25028202 TI - Sex trafficking awareness and associated factors among youth females in Bahir Dar town, North-West Ethiopia: a community based study. AB - BACKGROUND: Sex trafficking is a contemporary issue in both developed and developing countries. The number of trafficked women and young girls has increased globally. Females aged 18-25 are the most targeted group of trafficking. Although the problem is evident in Ethiopia, there are no studies that explored sex trafficking awareness among females. Therefore, the aim of this study was to assess sex trafficking awareness and associated factors among youth females in Bahir Dar town, North-West Ethiopia. METHODS: A community based cross sectional study design was employed to collect data from February 1st-30th 2012 from a total of 417 youth females. The participants in the study were selected using systematic random sampling techniques. A structured Amharic questionnaire was used to collect data. Data were entered, cleaned and analyzed using SPSS 16.0. Descriptive statistics were used to describe data. Logistic regression analysis was used to identify factors associated with sex trafficking awareness. RESULT: Two hundred forty-nine (60%) of the participants reported that they had heard or read about sex trafficking. Television (64%), friends (46%) and radio (39%) were the most frequently mentioned sources of information about sex trafficking. About 87% and 74% of the participants mentioned friends and brokers respectively as mediators of sex trafficking. Having TV at home (AOR = 2. 19, 95% CI: 1.31-3.67), completing grade 10 or more (AOR = 2. 22, 95% CI: 1.18-4.17), taking training on gender issues (AOR = 3. 59, 95% CI: 2.11-6.10) and living together with parents (AOR = 3. 65, 95% CI: 1.68-7.93) were factors found associated with sex trafficking awareness. CONCLUSION: In this study, sex trafficking awareness was low among youth females. Having TV at home, living together with someone and being trained on gender issues were predictors of sex trafficking awareness. Therefore, providing education about sex trafficking will help to increase sex trafficking awareness among youth females. PMID- 25028200 TI - Mortality of people suffering from mental illness: a study of a cohort of patients hospitalised in psychiatry in the north of France. AB - BACKGROUND: The mortality of people suffering from psychiatric illnesses is far higher than that of the general population, all categories of diagnosis combined; mortality statistics can be used as an index of quality of care. The aim of this study was to assess the all-cause mortality in psychiatric patients covering all diagnostic groups. METHODS: The living or deceased status of 4,417 patients of majority age hospitalised in a public mental health establishment between 2004 and 2007 were requested from French National Institute for Statistics and Economic Studies on 1st January 2011. The cause of death of those people who had died was obtained from French National Institute for Health and Medical Research and comparative standardized mortality ratios (SMR) were established from the population in a region of northern France of the same age in 2006. RESULTS: The study population was made up of 54% men and 46% women, median age 41 and 45 years old, respectively. Four hundred and seventy-three people died during the period studied. The SMR were 421 for men (95% CI 378-470) and 330 for women (95% CI 281 388). The highest SMRs were found in patients aged 35-54, with a 20-time higher mortality risk than the general population of the same age. CONCLUSION: Our study confirms the considerably higher mortality in psychiatric patients than in general population, particularly in mean age and mostly due to an unnatural cause. PMID- 25028203 TI - An integrative review of South African cancer nursing research published from 2002-2012. AB - BACKGROUND: This integrative review aimed to quantify the publication output of South African cancer nursing research conducted between 2002 and 2012 and to identify key trends relevant to cancer nurse researchers. OBJECTIVES: To describe the publication output of cancer nursing research in terms of the journals of publication, authors, focus, participants and methods used, to explore whether the published work was funded and to assess the quality of the studies published. METHODS: An integrative review was conducted using the key words South Africa in combination with cancer nursing and oncology nursing to search the databases Pubmed, PsycINFO, CINAHL, Sabinet, Web of Science, Medline and OvidSP. A data extraction sheet was developed to document the required information from each paper and all publications were reviewed independently by the authors. RESULTS: A total of 181 publications for potential inclusion were identified and 26 papers were included in this review. Cervical cancer, specifically the prevention of this disease, was the most popular diagnostic focus and theme of investigation. Most of the studies were descriptive and none of the studies met the criteria of the highest quality. CONCLUSION: Nursing added to the body of knowledge regarding the primary and secondary prevention of cancer. There is a need for work on both men and women diagnosed withthe most common cancers, as well as the family and care giver. There is also a need for multidisciplinary work using complex interventions focusing on symptom management to improve patient outcomes. PMID- 25028204 TI - A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells. AB - Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure-function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G protein-coupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity. PMID- 25028206 TI - Antimalarial efficacy of dynamic compound of plumbagin chemical constituent from Plumbago zeylanica Linn (Plumbaginaceae) against the malarial vector Anopheles stephensi Liston (Diptera: Culicidae). AB - In the present investigation, the effective root compound of plumbagin of Plumbago zeylanica (Plumbaginaceae) was evaluated for chemical constituent and antimalarial effect against the fourth instar larvae of Anopheles stephensi Liston (Diptera). In the chromatographic analyses of root compound with Rf value of 0.788 and NMR analyses also revealed that the effective compound contain naphthoquinone plumbagin were identified as the major chemical constituent. Larval mortality was observed after 3 h of exposure period. The plumbagin compound showed remarkable larvicidal activity against A. stephensi (LC50 32.65 and LC9072.27 ppm). Histopathological effects of compound was observed in the treated larvae. Based on the results, the plumbagin compound of P. zeylanica can be considered as a new source of natural larvicide for the control of malarial vector. PMID- 25028207 TI - Comparative analysis of the diagnostic performance of adult, cercarial and egg antigens assessed by ELISA, in the diagnosis of chronic human Schistosoma mansoni infection. AB - Total IgG ELISA was assessed comparing soluble adult worm (SWA), cercarial (SCA), and egg antigens (SEA) using sera of chronic schistosomiasis patients in two different concentrations (1/50 and 1/100). This response showed reactivity against all antigens. Concerning 1/100 serum concentration the SWA gave the best sensitivity (100%) followed by SCA (86.6%) and SEA (80%). The best specificity was obtained from SCA (94.11%) with an equivalent result from the SWA and SEA (76.47%). Concerning the 1/50 serum concentration, the SWA gave the best sensitivity (100%) with an equivalent result from the SCA and SEA (80%). The best specificity was obtained from SEA (82.35%) followed by SCA (76.47%) then SWA (64.7%). The best AUC value (0.992) was that for SWA indicating its high ability to predict the disease in comparison to (0.914) for SCA and 0.871 for SEA in serum dilution 1/100. The highest AUC value (0.955) was that for SWA in comparison to (0.914) for SEA and (0.88) for SCA in serum dilution 1/50. Comparison between the AUCs from the three mentioned antigens revealed highly significant differences when the data were analyzed by ROC. Each antigen showed a highly statistically significant correlation within its optical density values at both concentrations; 1/100 and 1/50. Comparing the two concentrations in each antigen revealed a non significant correlation obtained from the SWA which signifies a near outcome from both concentrations while the SCA and SEA showed a highly significant difference between the two concentrations. In conclusion, for the diagnosis of chronic schistosomiasis mansoni, total IgG reactivity revealed the best sensitivity by SWA. There was a difference in the type of antigen showing best specificity results between SCA and SEA according to serum concentration used. PMID- 25028208 TI - Description of Cloacina atthis sp. nov. from the stomach of the euro (Macropus robustus) (Marsupialia: Macropodidae) from Western Australia based on morphological and molecular criteria. AB - A new species of strongyloid nematode from the genus Cloacina (Chabertiidae: Cloacininae) is described from the stomach of the hill kangaroo or euro (Macropus robustus) (Marsupialia: Macropodidae) from Western Australia. Cloacina atthis sp. nov. was found only in euros from the Pilbara region in the northwest of Western Australia, in spite of extensive collecting of the same host species from around the Australian continent. C. atthis is most closely related to Cloacina clymene, a species found in the same host species but only in the eastern half of the continent; the two species differ in minor morphological features (the shape of the wall of the buccal capsule, spicule lengths, the degree of sclerotisation of the gubernaculum and the shape of the vagina) as well as in differences in the internal transcribed spacers of ribosomal DNA. This study highlights the importance of using molecular methods when investigating the apparently disjunct distributions of strongyloid nematodes. PMID- 25028209 TI - Presence of ecto-protein tyrosine phosphatase activity is vital for survival of Setaria cervi, a bovine filarial parasite. AB - The ecto protein tyrosine phosphatases (PTP) are known to play a crucial role in the pathogenesis and survival of the intracellular parasites. However, their presence and role in filarial parasites is still unknown. We found a significant amount of tyrosine phosphatase activity in the surface antigen fraction extracted from Setaria cervi (S. cervi), a bovine filarial parasite. An antibody designed against the conserved catalytic core of human protein tyrosine phosphatases, PTP1B cross reacted with a 63 kDa band in the surface antigen. We detected a significant amount of PTP activity in the intact S. cervi adult parasites as well as microfilariae in this study for the first time. This PTP may be localized on the surface of the parasite with an exposed active site available for the external substrates. The PTP activity was also inhibited by sodium orthovanadate and phenyl arsine oxide, specific inhibitors of PTP in both the life stages. The Km and Vmax for PTP in the adult parasites and microfilariae were determined to be 2.574 +/- 0.14 mM; 206.3 +/- 2.75 MUM Pi/h/two parasites and 5.510 +/- 0.59 mM; 62.27 +/- 2.27 MUM Pi/h/10(6) parasites respectively using O-P-L-Tyrosine as substrate. Interestingly, a positive correlation was observed between the inhibition in PTP activity and reduction in the motility/ viability of the parasites when they were subjected to the specific PTP inhibitors (Orthovanadate and Phenyl arsine oxide) for 4 h in the KRB maintenance medium. The activity was also significantly inhibited in the parasites exposed to antifilarial drug/compounds for e.g. Diethylcarbamazine, Acetylsalicylic Acid and SK7, a methyl chalcone. Therefore suggesting a possible role played by PTP in the survival of the parasite, its interaction with the host as well as in the screening of newly synthesized antifilarials/drugs. PMID- 25028210 TI - Comparative studies on the proteomic expression patterns in the third- and fifth stage larvae of Angiostrongylus cantonensis. AB - Angiostrongylus cantonensis is an important zoonotic parasite causing eosinophilic meningitis and eosinophilic meningoencephalitis in humans. In this study, the protein expression profiles of the infective third- and pathogenic fifth-stage larvae (L3 and L5) of this parasite were compared by proteomic techniques. Isolated protein samples were separated by two-dimensional gel electrophoresis (2-DE), stained with silver nitrate, and analyzed by matrix assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Proteins from L5 were mainly at pH 5-7 and with molecular weight (MW) 40-100 kDa, whereas those from L3 were at pH 5-6 and with 5-35 kDa. Of 100 protein spots identified, 33 were from L3 whereas 67 from L5 and 63 had known identities, whereas 37 were hypothetical proteins. There were 15 spots of stress proteins, and HSP60 was the most frequently found heat stress proteins in L5. More binding and protein transport-related proteins were found in L5 including peptidylprolyl isomerase (cyclophilin)-like 2, serum albumin, preproalbumin precursor, and dilute class unconventional myosin. L3 had a higher expression of cytoskeleton and membrane proteins than L5. In addition, four protein spots were identified in the sera of the rat host by Western blot analysis. The present proteomic study revealed different protein expression profiles in L3 and L5 of A. cantonensis. These changes may reflect the development of L3 from the poikilothermic snails to L5 in the homoeothemic rats. This information may be useful for the finding of stage-specific proteins and biomarker for diagnosis of angiostrongyliasis. PMID- 25028211 TI - Development of a milk and serum ELISA test for the detection of Teladorsagia circumcincta antibodies in goats using experimentally and naturally infected animals. AB - Teladorsagia circumcincta is among the most important gastrointestinal parasites in small ruminants and the predominant species in Southern European goats. Parasite control is largely based on metaphylactic/preventative treatments, which is often seen as non-sustainable anymore. The reasons are increased consumer demand to reduce chemicals in livestock production and anthelmintic resistance against the common drugs. This study aimed at the development of a T. circumcincta-enzyme-linked immunosorbent assay (ELISA) specifically for goats. Samples were obtained from goats raised parasite-free or infected experimentally. Sampling continued during the following pasture season and housing period. The sensitivity for the use in bulk milk samples as an indicator of T. circumcincta infection levels in grazing goats was examined. The ELISA enables clear differentiation of negative and positive animals. With a specificity of 100% negative cut-off values for serum and milk were 0.294 and 0.228 (sensitivity, 95%). Positive cut-off values (sensitivity, 90%) were 0.606 (serum) and 0.419 (milk), while a sensitivity of 95% resulted in 0.509 and 0.363, respectively. The grey-zone between negative/positive cut-offs was introduced to deal with animals in pre-patency and decreasing antibody levels after infection. There was no cross reactivity for Trichostrongylus colubriformis and Cooperia oncophora while for Haemonchus contortus and Fasciola hepatica it cannot be fully excluded currently. In bulk milk samples, 5% of the milk had to be contributed from animals infected with T. circumcincta to be detected as positive. The results derived from experimentally and naturally infected as well as parasite naive animals indicate the potential of the ELISA to be used in targeted anthelmintic treatment regimes in goats. PMID- 25028213 TI - Measurement-based model of a wide-bore CT scanner for Monte Carlo dosimetric calculations with GMCTdospp software. AB - The aim of this work was to create a model of a wide-bore Siemens Somatom Sensation Open CT scanner for use with GMCTdospp, which is an EGSnrc-based software tool dedicated for Monte Carlo calculations of dose in CT examinations. The method was based on matching spectrum and filtration to half value layer and dose profile, and thus was similar to the method of Turner et al. (Med. Phys. 36, pp. 2154-2164). Input data on unfiltered beam spectra were taken from two sources: the TASMIP model and IPEM Report 78. Two sources of HVL data were also used, namely measurements and documentation. Dose profile along the fan-beam was measured with Gafchromic RTQA-1010 (QA+) film. Two-component model of filtration was assumed: bow-tie filter made of aluminum with 0.5 mm thickness on central axis, and flat filter made of one of four materials: aluminum, graphite, lead, or titanium. Good agreement between calculations and measurements was obtained for models based on the measured values of HVL. Doses calculated with GMCTdospp differed from the doses measured with pencil ion chamber placed in PMMA phantom by less than 5%, and root mean square difference for four tube potentials and three positions in the phantom did not exceed 2.5%. The differences for models based on HVL values from documentation exceeded 10%. Models based on TASMIP spectra and IPEM78 spectra performed equally well. PMID- 25028212 TI - Ultrastructure of immature stages of Cochliomyia macellaria (Diptera: Calliphoridae), a fly of medical and veterinary importance. AB - Cochliomyia macellaria (Diptera: Calliphoridae) is known as the secondary screwworm because it causes secondary or facultative myiasis when the larvae feed on necrotic tissues. This fly has a significant medical and veterinary importance since it has been reported to transport eggs of Dermatobia hominis (human botfly), which can cause significant economic losses to livestock. Since this screwworm has been collected colonizing both pig carcasses and human cadavers, it is considered one of the most important species for forensic entomology studies. Scanning electron microscopy (SEM) gives detailed information on the morphological characteristics which can help identify the immature forms of the flies. The aim of this study was to describe and analyze the morphological characteristics of the eggs, all the larval instars, and the puparia of Cochliomyia macellaria using SEM. The egg is ellipsoid and the dorsal surface is concave. The islands inside the median area had no anastomosis, but some perforations could be observed. From the second larval instar onwards, besides the intersegmental spines, other bands of spines were observed at the abdominal segments. Two spiracular openings were visible on the first and second larval instars, which were not expected. These characteristics are specific to Cochliomyia genus. The number and the general aspect of the spine tips in the cephalic region, the intersegmental bands on the abdomen, and the number of the spiracular openings could together help identify C. macellaria. PMID- 25028214 TI - Single level lumbar laminectomy alters segmental biomechanical behavior without affecting adjacent segments. AB - BACKGROUND: Degenerative lumbar spinal stenosis causes neurological symptoms due to neural compression. Lumbar laminectomy is a commonly used treatment for symptomatic degenerative spinal stenosis. However, it is unknown if and to what extent single level laminectomy affects the range of motion and stiffness of treated and adjacent segments. An increase in range of motion and a decrease in stiffness are possible predictors of post-operative spondylolisthesis or spinal failure. METHODS: Twelve cadaveric human lumbar spines were obtained. After preloading, spines were tested in flexion-extension, lateral bending, and axial rotation. Subsequently, single level lumbar laminectomy analogous to clinical practice was performed at level lumbar 2 or 4. Thereafter, load-deformation tests were repeated. The range of motion and stiffness of treated and adjacent segments were calculated before and after laminectomy. Untreated segments were used as control group. Effects of laminectomy on stiffness and range of motion were tested, separately for treated, adjacent and control segments, using repeated measures analysis of variance. FINDINGS: Range of motion at the level of laminectomy increased significantly for flexion and extension (7.3%), lateral bending (7.5%), and axial rotation (12.2%). Range of motion of adjacent segments was only significantly affected in lateral bending (-7.7%). Stiffness was not affected by laminectomy. INTERPRETATION: The increase in range of motion of 7-12% does not seem to indicate the use of additional instrumentation to stabilize the lumbar spine. If instrumentation is still considered in a patient, its primary focus should be on re-stabilizing only the treated segment level. PMID- 25028215 TI - Predicting drug metabolism by CYP1A1, CYP1A2, and CYP1B1: insights from MetaSite, molecular docking and quantum chemical calculations. AB - Recently, CYP1 enzymes are documented for selective metabolism of anticancer leads in cancer prevention and/or progression. Elucidation of specificity of substrates/inhibitors of CYP1 isoforms plays a vital role in design of more selective and potent anticancer leads. However, an area of concern is the broad range of substrate specificities and planar nature of substrates with limited dataset which makes it difficult to predict their site of metabolism (SOM) accurately. In the present study, various models for prediction of site of metabolism in case of CYP1A1, CYP1A2, and CYP1B1 substrates were developed using MetaSite, molecular docking, and quantum chemical descriptors. The predictive accuracy of MetaSite, molecular docking, and quantum chemical descriptors in identifying experimental site of metabolism was analyzed at three levels; top rank, top three ranks, and top five ranks. Two quantum chemical descriptors, chemical hardness and local nucleophilicity are proposed for the prediction of CYP-mediated SOM for the first time. The predictive accuracy shown by chemical hardness at top three ranks was 83.3, 85.7, and 84.6 % for CYP1A1, CYP1A2 and CYP1B1, respectively, whereas local nucleophilicity gave poor predictions of 50, 42.8, and 46.2 %, respectively. The predictability of chemical hardness descriptor outperformed at all three levels of ranks for CYP1A1, CYP1A2, and CYP1B1. Hence, we propose chemical hardness as an useful quantum chemical descriptor for prediction of metabolically vulnerable prints in CYP1A1, CYP1A2, and CYP1B1 mediated metabolism and support the optimization efforts in drug discovery and development programs. PMID- 25028216 TI - Management of traumatic cataract in adults at a reference center in Mexico City. AB - The purpose of the study was to determine the clinical presentation, mode of injury, surgical, and postoperative outcomes in adult patients with traumatic cataract. This is a clinical, observational, and retrospective study with review of records of patients in the period 2010-2012. Eighty patients were included, of whom 67 (83.75 %) were male. The mean age at presentation was 46 years (range 18 82 years). Sixty-four patients (80 %) had a closed-globe blunt ocular trauma and 16 (20 %) had an open-globe penetrating trauma. Seventy-seven (96.25 %) patients underwent phacoemulsification; 13.7 % (n = 11) required placement of capsular tension rings and 22.5 % (n = 18) automated anterior vitrectomy. In 53 % of the cases the intraocular lens (IOL) was placed in the capsular bag. Forty-seven patients (58.75 %) achieved a best-corrected visual acuity of 20/40 or better. In 57 (71.25 %) the final refraction was obtained, with a mean spherical equivalent of -0.56D (range -3.50D to +2.00 D). The improvement in visual acuity was significantly higher when the IOL was placed in the capsular bag compared to when it was placed in the sulcus (average difference of 0.667, p = 0.001). The most common mechanism of trauma is closed globe. Phacoemulsification was the procedure most common performed, with the IOL placed most commonly in the capsular bag. The final best-corrected visual acuity in most patients was 20/40 or better. Placing the IOL in the capsular bag represented an improvement in visual acuity compared to placement in the sulcus. PMID- 25028217 TI - Activated leukocyte cell adhesion molecule (ALCAM/CD166) expression in head and neck squamous cell carcinoma (HNSSC). AB - Activated leukocyte cell adhesion molecule (ALCAM/CD166) is expressed in a number of malignancies (e.g. prostate, breast, squamous cell carcinoma of the esophagus, lung and head and neck tumors). Based on studies in which ALCAM showed prognostic relevance in several carcinomas, it has been discussed as a potential therapeutic target. We evaluate its expression in head and neck squamous cell carcinomas (HNSCCs). A tissue microarray was constructed from more than 400 HNSCCs. Slides were analyzed by immunohistochemistry for ALCAM. Membranous and cytoplasmic ALCAM positivity were rated separately. The tumors were combined into (a) cases with membranous staining and (b) cases with cytoplasmic staining, independently from membranous/cytoplasmic co-expression. We found staining in 70.3% of interpretable HNSCCs. Pure membranous staining was found in 12.4% of tumors, with cytoplasmic positivity in 40.1% of cases, and membranous/cytoplasmic co-expression in 17.9%. No significant association between ALCAM positivity and clinical parameters was found. No significant association between ALCAM expression and survival data was observed for all tumors. The frequent expression of ALCAM (70.3%) in head and neck squamous cell carcinomas does not support an important role for HNSCC biology. The increased levels of ALCAM suggest the existence of a therapeutic window for potential anti-ALCAM therapies. PMID- 25028219 TI - Saudi Medical Journal 35 year anniversary. PMID- 25028218 TI - Cancer survivors' self-efficacy to self-manage in the year following primary treatment. AB - PURPOSE: Cancer survivors are increasingly expected to manage the consequences of cancer and its treatment for themselves. There is evidence that self-efficacy is important for successful self-management and that this can be enhanced with support. The purpose of this study was to assess self-efficacy to manage problems in the year following primary treatment. METHODS: This cross-sectional online survey included cancer survivors who had completed their treatment within the past 12 months. Self-efficacy was assessed and variables expected to be associated with self-efficacy were measured using validated scales including quality of life, well-being, illness perceptions, depression and social support. RESULTS: One hundred eighty-two respondents (mean age 50; 81% female) completed the survey. They had been treated for a range of cancers; most commonly breast (45%). Self-efficacy scores varied between individuals and according to the illness-related task to be managed. Respondents were least confident in managing fatigue and most confident in accessing information about their cancer. Individuals most likely to report low self-efficacy were women, those experiencing higher levels of pain and/or depression, lower well-being scores, lower socio-economic status, low levels of social support, or a more negative perception of cancer. CONCLUSIONS: Self-efficacy to self-manage problems faced as a consequence of cancer and its treatment can vary widely in the year following treatment. Fatigue may be particularly difficult to manage. IMPLICATIONS FOR CANCER SURVIVORS: Variations in self-efficacy highlight the importance of assessing specific problems faced and people's confidence to manage them in order to tailor appropriate self-management support. PMID- 25028220 TI - The battle against respiration-induced organ motion in external beam radiotherapy. AB - The latter 2 decades of the last century have witnessed significant improvements in external beam radiotherapy (EBRT), moved primarily by the advances in imaging modalities and computer-based treatment planning. These advancements lead to introducing the addition of a fourth-dimension, time, to the three-dimensional geometry in EBRT. The new era in EBRT presents challenges and opportunities to compensate for the effect of respiratory-induced target motion and improve treatment output. A number of these methods have been investigated, some of them already clinically approved and some still under development. Thus, there has been an increasing amount of literature in the area of respiratory motion compensation in EBRT. One criticism in most of the literature is that, it is either unorganized, or provides limited information. A few literature reviews provide a comprehensive overview regarding this fast growing area of study. The literature review here will provide an up to date summary of these publications. PMID- 25028221 TI - Early endoscopic retrograde cholangiopancreatography in mild gallstone pancreatitis with deranged liver function test. A 7-year experience in central Saudi Arabia. AB - OBJECTIVE: To determine the use of liver function tests (LFTs) as a selection tool for preoperative endoscopic retrograde cholangiopancreatography (ERCP) in patients with mild gallstone pancreatitis. METHODS: All patients admitted with mild gallstone pancreatitis with deranged LFTs in King Saud Medical City, Riyadh, Kingdom of Saudi Arabia between January 2006 and February 2013 were studied retrospectively. Patients' demography, symptoms, laboratory values, imaging studies, ERCP findings, complications and its treatment, surgical intervention, intraoperative and postoperative findings, mortality, and outpatient follow up were collected and analyzed. RESULTS: A total of 245 patients were admitted as mild gallstone pancreatitis with admission day deranged LFTs. Pre-operative ERCP was performed in 74 patients based on admission day LFTs (Group A). Endoscopic retrograde cholangiopancreatography was normal in 65 patients, revealed stones in 5, and sludge in 4 patients. Six patients developed ERCP complications. Endoscopic retrograde cholangiopancreatography was deferred in 171 patients (Group B) until the LFTs were repeated in 3-4 days. Liver function tests remained persistently high in 8 patients. They were submitted to preoperative ERCP, which revealed stones (n=5) and sludge (n=3). Patients with normalized LFTs (n=163) were not submitted to ERCP. Three of them developed gallstone related complications. CONCLUSION: Patients admitted with predicted mild gallstone pancreatitis, deranged LFTs, and no evidence of cholangitis should not be submitted to ERCP unless a repeat LFT within 3-4 days shows persistently deranged LFTs. This will reduce unnecessary ERCP and its complications. PMID- 25028222 TI - The effects of diazepam on blood pressure levels in cataract surgery. AB - OBJECTIVE: To evaluate the effects of oral diazepam on blood pressure (BP) alterations in patients that underwent cataract surgery under topical anesthesia. METHODS: A total of 147 patients that underwent phacoemulsification surgery under topical anesthesia, were reviewed retrospectively. The study took place in the Department of Ophthalmology, Adnan Menderes University Medical Faculty, Aydin, Turkey, between January 2011 and July 2013. Patients were divided into 2 groups: Group 1: received 5 mg diazepam per oral one hour prior to surgery, and Group 2 (control group): none administered preoperatively. The BP readings of all patients were scanned through their files. Five readings were chosen for statistical analysis. The first reading was taken in the ophthalmology ward on the morning of the operation, the second was taken in the premedication room just before the surgery, 2 readings were taken intraoperatively and recorded as third and fourth values, and the fifth reading was recorded from those taken in the ophthalmology ward after surgery. RESULTS: Group 1 had a mean age of 62.17 +/- 10.01 years, while the Group 2 had a mean age of 64.31 +/- 10.88 years. There were no differences between the 2 groups by means of systolic and diastolic BP levels measured preoperatively in the ophthalmology ward. Intraoperative systolic and diastolic BP levels were significantly higher in Group 2 (p<0.001). CONCLUSION: Elevated BP can undermine surgical outcomes; and may lead to unforeseen complications. To prevent the elevation of BP to risky levels in the intraoperative period, diazepam administration may be beneficial, even in normotensive patients. PMID- 25028223 TI - The incidence of leukemia in Saudi Arabia. Descriptive epidemiological analysis of data from the Saudi Cancer Registry 2001-2008. AB - OBJECTIVE: To describe the epidemiological data of leukemia cases diagnosed from 2001 to 2008 among male and female Saudis, including the frequency and percentage of cases, the crude incidence rate (CIR), and the age-standardized incidence rate (ASIR) stratified by leukemia subtype, region, and year of diagnosis. METHODS: This is a retrospective descriptive epidemiological analysis of all Saudi leukemia cases recorded in the Saudi Cancer Registry SCR between January 2001 and December 2008. The study was carried out in 2013 to investigate the pattern of leukemia in the Saudi population. Descriptive statistics and Poisson regression model were used. RESULTS: A total of 3852 leukemia cases were registered in the SCR between January 2001 and December 2008. The region of Riyadh, Saudi Arabia had the highest overall ASIR among Saudi males at 5.2 per 100,000 males, followed by both the Eastern region and Northern region at 4.9 per 100,000 males. Furthermore, the region of Najran recorded the highest overall ASIR among Saudi females at 4.5 per 100,000 females. However, Jazan had the lowest average ASIRs of leukemia in Saudi Arabia. CONCLUSION: There was a slight increase in the CIRs and ASIRs of leukemia in Saudi Arabia between 2001 and 2008. Riyadh, the Eastern region, and the Northern region had the highest overall ASIRs of leukemia among Saudi males, and Najran had the highest overall ASIRs of leukemia among Saudi females; while Jazan had the lowest rates among the Saudi population. PMID- 25028224 TI - Prevalence of chronic obstructive pulmonary disease in Saudi Arabia. AB - OBJECTIVE: To assess the prevalence of epidemiologically defined chronic obstructive pulmonary disease (COPD) in Saudi Arabia. METHODS: This cross sectional, observational, population-based survey of COPD was conducted between June 2010 and December 2011 across the country of Saudi Arabia. A total of 56,000 randomly selected telephone numbers were called, which identified 10,001 eligible subjects; of whom 9,779 agreed to participate. A screening questionnaire included 6 questions related to cigarette consumption and water-pipe use was administered to each participant. Subjects with positive screening results were invited to provide input for a detailed COPD questionnaire. RESULTS: The adjusted proportion of subjects who reported a current, or past smoking history was 27.9%. Gender specific smoking rates adjusted by age were 38.7% (95% confidence interval [CI]: 37.5-39.9%) in men, and 7.4% (95% CI: 6.5-8.3%) in women. The epidemiological definition of symptomatic COPD was met by a total of 249 subjects. The age and gender-adjusted prevalence of COPD was 2.4% (95% CI: 2.1-2.7%). Overall, COPD was more frequently documented (p<0.0001) in men (3.5% [95% CI: 3-4%]) than in women (1% [95% CI: 0.7-1.3%]). CONCLUSION: The prevalence of epidemiologically defined COPD in the general population of Saudi Arabia is 2.4%, which is lower than that reported in industrialized countries. PMID- 25028225 TI - Changing epidemiology of tuberculosis detected by an 8-year retrospective laboratory study in a tertiary teaching hospital in central Saudi Arabia. AB - OBJECTIVE: To study the laboratory diagnosis of tuberculosis (TB), and relate the findings to its epidemiology in Central Saudi Arabia. METHODS: This retrospective study was carried out at the Department of Pathology/Microbiology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between January 2003 and December 2010. Data were retrieved from the hospital information system on laboratory findings. After adjustment, 9,405 specimens were studied. The specimens were stained by Ziehl-Neelsen (ZN), auramine-rhodamine, and cultured in Bactec alert 960, and Lowenstein-Jensen media. Mycobacterium tuberculosis (M. tuberculosis) complex and non-tuberculous mycobacteria were differentiated by ProbTec system and p-nitrobenzoate medium. The BACTEC MGIT 960 SIRE kit was used for susceptibility testing. RESULTS: A total of 568 (6%) specimens grew M. tuberculosis complex, and 87% were from Saudis with an incidence rate of 55.6/100,000 of TB. Time to positive growth in the Bactec liquid medium was directly related to the acid fast bacilli smear load. Most of the positive patients were from the 18-35 years age group. The percentage of multidrug resistance was 0.7%. CONCLUSION: Most patients (87%) were Saudis showing an incident rate of 55.6/100,000. An increase of TB cases was noticed in the 18-35 age group. Resistance to isoniazid was 10.6%, 1% to Rifampicin, 2-8% to Ethambutol, and streptomycin was 6%. PMID- 25028226 TI - Acute Toxoplasma gondii infection in children with reactive hyperplasia of the cervical lymph nodes. AB - OBJECTIVE: To determine the seroprevalence of Toxoplasma gondii (T. gondii) in children with reactive hyperplasia of the cervical lymph nodes. METHODS: This cross-sectional prospective study was conducted in Khartoum Children Emergency Hospital, Khartoum, Sudan between January 2010 and April 2011. Eighty children with cervical lymphadenopathy were selected using random sampling. Their lymph nodes were aspirated for cytology, and a blood sample was collected from all patients for routine laboratory analysis and T. gondii IgG and IgM antibodies. RESULTS: Among 80 children with cervical lymphadenopathy, 60 (75%) had non specific reactive hyperplasia. The seroprevalence of T. gondii among children with cervical lymphadenopathy was 27.5% (n=22), and the seropositivity of acute T. gondii among those with reactive hyperplasia was 36.7% (n=22/60). Lymph nodes in the T. gondii positive group were mobile and warm (p<0.05). The clinical features and laboratory tests were insignificant predictors of acute T. gondii infection with reactive hyperplasia of the cervical lymph nodes. CONCLUSION: The prevalence of acute T. gondii infection is high among children with non-specific reactive hyperplasia of the cervical lymph nodes. Routine laboratory studies are not helpful in the diagnosis of T. gondii infection with reactive hyperplasia of the lymph nodes however, serological studies may be requested prior to invasive procedures. PMID- 25028227 TI - Knowledge and attitude of healthcare professionals toward medication pregnancy category systems in Saudi hospitals. AB - OBJECTIVE: To assess the knowledge and attitudes of healthcare professionals (HCPs) toward systems used in describing the safety of medications use during pregnancy. METHODS: A cross-sectional self-administered survey was conducted in 4 tertiary hospitals in Riyadh, Saudi Arabia between March and May 2012. The targeted HCPs were physicians and pharmacists. The survey was validated and contained 4 main sections. Descriptive statistics were used to report responses to the survey's questions. RESULTS: A total of 393 HCPs responded to the survey, with a response rate of 97%. Half of the respondents were physicians. Of the participants, 60% were males. Most respondents (66%) stated that they have prescribed/dispensed a drug that may cause teratogenicity. Moreover, 87% of the respondents (48% pharmacists and 39% physicians) were aware of the Food and Drug Administration (FDA) pregnancy category, and most (72%) found it helpful. Only 11% of the participants strongly agree to use the European Medicine Agency (EMA) system for pregnancy category system as their main reference. CONCLUSION: In general, HCPs in Saudi Arabian hospitals have good knowledge of and attitudes toward pregnancy category systems, with more familiarity with the FDA system. The FDA system is preferred over the EMA system. PMID- 25028228 TI - Assessment of health-related quality of life among adolescents with type 1 diabetes mellitus in Saudi Arabia. AB - OBJECTIVE: To evaluate the health-related quality of life (HRQoL) for adolescents with type 1 diabetes mellitus (T1DM). METHODS: A cross-sectional study was conducted among 214 adolescents (13-18 years) with T1DM at the Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia from June to September 2013. Respondents were selected by their availability during routine visits to outpatient clinics, and interviewed using the Arabic translated version of the Pediatric Quality of Life Inventory 3.0 Diabetes Module (PedsQL 3.0 DM) independently. RESULTS: Female gender, multiple daily injection (MDI), longer duration of T1DM (>7 years), diabetic ketoacidosis (DKA) and adolescents with >7 HbA1c level had at least one poor HRQoL outcome. Multivariate linear regression analysis showed that age, treatment type (MDI), DKA, and >7 HbA1c were independent influencing factors for subscale diabetes symptoms, whereas >7 HbA1c was the independent influencing factor for treatment barriers and overall HRQoL. The DKA was the independent influencing factor for the subscale of worry, and female gender was the independent influencing factor for the subscale of communication. CONCLUSION: Female gender, age, treatment type, >7 HbA1c, and DKA are the strongest determinants for lower HRQoL for at least one subscale of the PedsQL 3.0 DM. PMID- 25028229 TI - Improving door-to-doctor and door-to-analgesia time in a tertiary teaching hospital emergency department through a novel 'Red Box' system. AB - OBJECTIVE: To evaluate the effectiveness of a new patient flow system, 'The Red Box' on the quality of patient care in respect of the time taken for the care to be delivered to the patient. METHODS: A pre-post study was conducted looking at the door-to-doctor (DTD) and door-to-analgesia (DTA) times for cases presenting to the Emergency Department (ED) of a tertiary teaching hospital 'The National University of Malaysia Medical Center' between the periods of July and September 2005 against July and September 2008. Demographic data, ED presentation time, time seen by first doctor, and time first analgesia given were collected in both periods and analyzed. RESULTS: A total of 1,000 cases were enrolled. Group A (pre Red Box) and group B (post-Red Box) comprised 500 cases each. The mean DTD time for group A was 29 minutes (SD +/- 3 minutes) and for group B was 3 minutes (SD +/- 1 minute), with a 98.8% reduction (p<0.001). For DTA time, group A recorded a mean of 46 minutes (SD +/- 3 minutes), and group B recorded a mean of 9 minutes (SD +/- 2 minutes), an 80.4% reduction (p<0.001). CONCLUSION: The implementation of a red box system improved the quality of emergency patient care in the ED of a tertiary teaching hospital as evidenced by significant reductions in DTD and DTA time. PMID- 25028230 TI - Illicit drug abuse affects periodontal health status. AB - OBJECTIVE: To determine periodontal health status among drug addicts in Jeddah, Kingdom of Saudi Arabia. METHODS: Drug addiction recovery patients were recruited from Al-Amal Rehabilitation Hospital, Jeddah, Kingdom of Saudi Arabia between October and December 2012. A questionnaire was used to determine socio demographic data, oral hygiene measures, and previous drug abuse. Full periodontal charting was carried out including probing depth, recession, attachment loss, bleeding on probing, and plaque index. RESULTS: A total of 57 male patients participated in the study. Cannabis was the drug of choice of most (66.7%) of the subjects, followed by amphetamines (52.6%), alcohol (43.9%), heroin (35.1%), and 8.8% reported using cocaine. All participants had some form of periodontitis with moderate chronic periodontitis affecting 60% of the sample, while mild periodontitis affected 29.1%, and severe periodontitis affected 10.9% of the sample. Cocaine and heroin users showed higher mean clinical attachment loss compared with non-users (p<0.05). Pocket depths of 5-6 mm were found in more than half of the sample. Cocaine users had the highest percentage (80%) of pocket depths that ranged from 5-6 mm. CONCLUSION: Illicit drug use, especially heroin and cocaine, is associated with more severe forms of periodontitis. PMID- 25028231 TI - Prevalence of manufacturing defects in latex examination gloves used in selected dental practices in central Saudi Arabia. AB - OBJECTIVE: To assess the defect rates in latex examination gloves used in selected dental practices in Riyadh, Saudi Arabia. METHODS: In this cross sectional study, a total of 796 latex examination gloves were collected from 5 governmental hospitals and 5 private dental practices between April 2012 and May 2012. The gloves were assessed for presence of defects visually (VT) and using water inflation test (WIT). One and 2 sample t-tests were used to assess significant differences in defect rates among each latex brand, and between governmental hospitals and private dental practices. RESULTS: Defects in latex gloves were more likely to be identified using WIT compared with VT (20.2% versus 4.3%, p=0.000). Using WIT, examined latex gloves had a defect rate approximately 8 times the acceptable quality level of 2.5% (20.2%, p=0.000). Using WIT, gloves used in private dental practices had significantly higher defect rates compared with governmental dental clinics (25.6% versus 14.6%, p=0.006). CONCLUSION: Most latex examination gloves used in the sampled governmental dental clinics and private dental practices in Riyadh had significantly higher preexisting defect rates than acceptable standard levels. PMID- 25028232 TI - Validation of the postgraduate hospital educational environment measure at a Saudi university medical school. AB - OBJECTIVE: The English version of the postgraduate hospital educational environment measure (PHEEM) was evaluated to determine its psychometric properties, validity, and internal consistency. The instrument was used to measure the clinical learning environment in the hospital setting of a Saudi university medical school. METHODS: This cross-sectional study was performed in a Saudi medical school between June and August 2012. The postgraduate hospital educational environment measure was administered to interns (house officers) and residents rotating at a Saudi university hospital. Means and mean ranks were calculated. The effects of training stage (intern versus resident) and gender (male versus female) on the PHEEM scores were estimated. Construct validity was measured using exploratory factor analysis, and internal consistency was measured using Cronbach's alpha. RESULTS: In this study, 193 interns and residents responded to the PHEEM. The response rate was 100%. The internal consistency of the 40-item questionnaire was 0.936 (Cronbach's alpha) with a maximum score of 160. The PHEEM mean score was 89.21 +/- 21.6. CONCLUSION: The PHEEM is a valid and highly reliable instrument that can be applied to measure the educational environment among interns and residents in hospital-based clerkships. The hospital training environment was positive, and the interns were more satisfied than the residents. Gender had no influence on the perceptions of the hospital's educational environment. PMID- 25028233 TI - Primary Ewing's sarcoma of the anterior fontanelle in a neonate. AB - Primary cranial Ewing's sarcoma is extremely rare. We present a case of primary Ewing's sarcoma of the skull in a neonate that involved the anterior fontanelle and was very aggressive in nature. Even with radical surgery, the patient had early recurrence within 2 months of surgery and ultimately died. Detailed radiological and pathological findings are described. PMID- 25028234 TI - Bilateral iliopsoas abscess associated with right hip septic arthritis in a neonate. AB - Iliopsoas abscess is a very rare pathology in the neonatal period. There is a lack of reports in the literature on bilateral psoas abscess with hip joint arthritis. We report a case of bilateral iliopsoas abscess with concomitant right hip septic arthritis, caused by methicillin-resistant Staphylococcus aureus in a 28-day-old male infant. The baby presented with bilateral diffuse swelling of the groins and upper thighs. He was treated successfully by ultrasound-guided percutaneous drainage along with systemic antibiotic therapy. Clinical improvement was observed within 24-48 hours of drainage. PMID- 25028235 TI - Cecum perforation due to biliary stent migration. AB - The endoscopic placement of biliary stents for benign and malignant biliary disease has been performed for over a decade. Several complications of stent placement have been described such as pancreatitis, hemorrhage, cholangitis, and perforation. Migration of biliary stents is a rare event, which can cause severe complications such as gastrointestinal tract perforation. We report the case of a 26-year-old woman with a cecum perforation due to biliary stent migration. We present the second case of cecal perforation related to the migration of a biliary stent. PMID- 25028236 TI - Delayed presentation of Morel-Lavallee lesion. AB - Closed degloving skin lesions of the limbs are uncommon, and diagnosis may be missed at the time of acute trauma. Usually, they are associated with pelvic fractures but may occur in absence of any bony injury. When this closed internal degloving occurs over the greater trochanter, it is known as a Morel-Lavallee lesion. We report a case of unusually delayed presentation of Morel-Lavallee lesion treated successfully by debridement, packing, and delayed closure. PMID- 25028237 TI - Alcoholic liver disease. Are there any differences between China and Western countries in clinical features? AB - OBJECTIVE: To investigate the clinical features of alcoholic liver disease (ALD) in hospitalized Chinese patients, and their differences compared with western countries. METHODS: Four hundred and eight hospitalized patients with ALD at First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, from January 2008 to December 2010 were studied retrospectively. Clinical data were analyzed and compared with western countries through literature review. RESULTS: The patients with ALD accounted for 7.8% of all hospitalized patients with liver diseases. These patients comprised 400 men and 8 women, aged between 45 and 55 years. Among the patients, there were 318 patients with alcoholic cirrhosis (77.9%), 48 patients with alcoholic hepatitis (11.8%), 9 patients with fatty liver (2.2%), and 33 patients with mild alcoholic injury (8.1%). The abstinence rate in these patients was 37.7%. Logistic-regression analysis showed that daily intake amount, duration of drinking, drinking hard liquors and smoking were the risk factors for alcoholic cirrhosis, but abstinence was the favorable factor for treatment. Compared with western countries, Chinese patients had a lower constituent ratio of ALD among liver diseases, lower proportions of females, and rate of concomitant hepatitis C infection; but the drinking status, clinical manifestations, and abstinence rate were similar between them. CONCLUSION: There are differences as well as similarities between China and western countries in the clinical features of ALD. PMID- 25028238 TI - Etiological profile of Omani women with recurrent pregnancy loss. AB - OBJECTIVE: To define the different causes of recurrent pregnancy loss (RPL) among Omani women. METHODS: This retrospective study included all women with RPL seen between June 2006 and March 2012 in the RPL outpatient clinic in Sultan Qaboos University hospital, Muscat, Oman. The data were collected from the Hospital Information System by screening the electronic records of these patients. The sample size gathered during the study period was 290 women. RESULTS: One hundred and forty (48%) of the examined patients had an identifiable cause for RPL, while in 150 (52%), no cause was identified. The most common causes were immunological factors (35.4%) and the least common were environmental factors (1.7%). Other causes implicated included: chromosomal abnormalities (8%), anatomical factors (9.4%), endocrine disorders (29.8%), infectious causes (3%), and thrombotic causes (12.7%). CONCLUSION: Recurrent pregnancy loss is prevalent among Omani women. The etiological profile of RPL in Omani women is consistent with that reported elsewhere according to previously published studies, with minor variations. PMID- 25028239 TI - The perception of otolaryngology-related diseases among parents of children with Down syndrome in Jeddah, Saudi Arabia. AB - OBJECTIVE: To assess the perception of otolaryngology-related diseases among parents of children with Down syndrome (DS). METHODS: A cross-sectional survey design. A questionnaire was distributed to parents of children with DS. The parents were attending an event aiming to raise awareness that was organized on World Down Syndrome Day on the 21st of March 2013, organized by Princess Al Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. The complete dates of study were March to May 2013. RESULTS: Questionnaires were completed and perceptions regarding 10 common otolaryngology-related diseases were obtained from 78 parents. The data shows that most of the parents were not familiar with these otolaryngology-related diseases. CONCLUSION: Many parents were not aware of some of the otolaryngology related conditions affecting children with DS, and did not have regular follow up. Perception was highly affected by the presence of the condition in the children. Awareness of otolaryngology-related diseases affecting children with DS should be raised. PMID- 25028240 TI - Formative assessment in health professional education. PMID- 25028241 TI - An unusual case of bezoar from Sudan. PMID- 25028243 TI - [Current state of knowledge and developments in the prophylaxis and acute treatment of migraine]. AB - For the acute treatment of the headache phase of a migraine attack, a variety of different pharmacotherapeutic treatment options exist. These range from nonspecifically acting non-opioid analgesics (e.g., paracetamol) and nonsteroidal anti-inflammatory substances (e.g., acetylsalicylic acid, ibuprofen, naproxen, diclofenac) to agents specifically interfering with the serotonin system (ergot alkaloids such as ergotamine and its derivatives, triptans). In patients with significant emesis co-occurring during an attack, additional antiemetics such as metoclopramide or domperidone may be administered. In migraine prophylaxis, largely divergent agents, e.g., beta-adrenoceptor antagonists, Ca-antagonists, or anticonvulsants, are commonly used. The diversity of these compounds may help the treating physician to tailor prophylactic treatment to the patient's individual needs. The treatment success of the individual patient is difficult to predict both in acute and prophylactic migraine treatment. Apart from contraindications or associated side effects of a particular substance, the individual patient's response to treatment is therefore a major determinant in selecting the suitable medication. PMID- 25028242 TI - Perspectives on the simulation of protein-surface interactions using empirical force field methods. AB - Protein-surface interactions are of fundamental importance for a broad range of applications in the fields of biomaterials and biotechnology. Present experimental methods are limited in their ability to provide a comprehensive depiction of these interactions at the atomistic level. In contrast, empirical force field based simulation methods inherently provide the ability to predict and visualize protein-surface interactions with full atomistic detail. These methods, however, must be carefully developed, validated, and properly applied before confidence can be placed in results from the simulations. In this perspectives paper, I provide an overview of the critical aspects that I consider being of greatest importance for the development of these methods, with a focus on the research that my combined experimental and molecular simulation groups have conducted over the past decade to address these issues. These critical issues include the tuning of interfacial force field parameters to accurately represent the thermodynamics of interfacial behavior, adequate sampling of these types of complex molecular systems to generate results that can be comparable with experimental data, and the generation of experimental data that can be used for simulation results evaluation and validation. PMID- 25028244 TI - Can genetics improve precision of therapy in diabetes? AB - Diabetes mellitus is a lifelong, incapacitating disease affecting multiple organs. Presently, type 2 diabetes (T2D) can neither be prevented nor cured and the disease is associated with devastating chronic complications. These complications impose an immense burden on the quality of life of patients and account for about 12% of direct health care costs in Europe. Genetic analysis will increase our understanding of this heterogeneous disease and may help offer more personalized treatment. PMID- 25028246 TI - Hydrocephalus in patients with closed neural tube defects. AB - BACKGROUND: Hydrocephalus is common in patients with open neural tube defects (NTDs), but association with closed NTDs has rarely been reported. We describe three patients with untreated closed NTDs who required surgery for hydrocephalus. CASE REPORTS: Case 1: A full-term newborn presented with a skin-covered midline lumbar spine lipoma. Magnetic resonance imaging (MRI) scan demonstrated a lipomyelomeningocele. An ultrasound at birth showed mild ventriculomegaly but cerebrospinal fluid diversion was not offered because his fontanelle was soft. He was lost to follow-up and then presented at age 6 months with signs and symptoms of hydrocephalus. An endoscopic third ventriculostomy and choroid plexus coagulation were performed, and the lipomyelomeningocele was subsequently repaired electively. Case 2: A full-term neonate presented with a skin-covered midline lumbar spine lesion consistent with a meningocele on MRI scan. He was additionally noted to have macrocephaly, a full fontanelle, and ventriculomegaly on MRI scan. At age 2 days, an endoscopic third ventriculostomy and choroid plexus coagulation were performed. A ventriculoperitoneal shunt was required 1 month later. Three months after birth, an elective spinal cord untethering procedure was performed. Case 3: A neonate presented with a midline lumbar skin tag. An MRI scan demonstrated a lipomyelomeningocele, and surgery was planned electively. On preoperative evaluation at age 3 months, the patient had a tense fontanelle. The surgery was postponed, and a ventriculoperitoneal shunt was placed after imaging studies revealed hydrocephalus. CONCLUSION: Patients with closed NTDs should be assessed for clinical signs and symptoms of hydrocephalus because of this rare but possible association. PMID- 25028247 TI - The effects of antiepileptic drugs on vascular risk factors: a narrative review. AB - PURPOSE: Epilepsy is associated with increased cardiovascular disease (CVD) morbidity and mortality. The exact causes of this link are not clearly defined. The role of antiepileptic drugs (AEDs) in influencing CVD risk in patients with epilepsy remains controversial. A link between epilepsy, AEDs and cardiac arrhythmias has been proposed and may be responsible for sudden unexpected death in epilepsy (SUDEP). METHODS: We searched MEDLINE up to December 1, 2013 for relevant publications using combinations of keywords. We also examined the reference list of articles identified by this search and selected those we judged relevant. These were included in this narrative review. RESULTS: AEDs may exert both beneficial and adverse cardiovascular effects. This narrative review considers the influence of AEDs on some predictors of vascular risk [i.e. weight, insulin resistance, metabolic syndrome, lipids, lipoprotein (a), C-reactive protein, homocysteine, vitamins, coagulation factors, uric acid, carotid intima media thickness, markers of oxidative status and matrix metalloproteinase-9]. Certain AEDs can also have pro-arrhythmic properties. CONCLUSIONS: AEDs may exert different effects on various established and emerging predictors of vascular risk. Furthermore, pharmacokinetic interactions between AEDs and drugs used to reduce vascular risk (e.g. statins) need to be better documented. Whether this knowledge, in terms of individualizing antiepileptic and CVD prevention treatment, will prove to be relevant in clinical practice remains to be established. PMID- 25028248 TI - The role of product inhibition as a yield-determining factor in enzymatic high solid hydrolysis of pretreated corn stover. AB - Industrially, enzymatic hydrolysis of lignocellulose at high solid content is preferable over low solids due to a reduction in processing costs. Unfortunately, the economic benefits are counteracted by a linear decrease in yield with solid content, referred to as the "solid effect" in the literature. In the current study, we investigate the contribution of product inhibition to the solid effect (7-33 % solids). Product inhibition was measured directly by adding glucose to high-solid hydrolysis samples and indirectly through variation of water content and beta-glucosidase concentration. The results suggest that the solid effect is mainly controlled by product inhibition under the given experimental conditions (washed pretreated corn stover as substrate). Cellobiose was found to be approximately 15 times more inhibitory than glucose on a molar scale. However, considering that glucose concentrations are at least 100 times higher than cellobiose concentrations under industrial conditions, glucose inhibition of cellulases is suggested to be the main cause of the solid effect. PMID- 25028245 TI - Munc18c: a controversial regulator of peripheral insulin action. AB - Insulin resistance, a hallmark of impaired glucose tolerance and type 2 diabetes (T2D), arises from dysfunction of insulin action and subsequent glucose uptake by peripheral tissues, predominantly skeletal muscle and fat. Exocytosis of glucose transporter (GLUT4)-containing vesicles facilitated by soluble NSF (N ethylmaleimide-sensitive factor) attachment receptor (SNARE) protein isoforms, and Munc18c (mammalian homolog of Unc-18c) mediates this glucose uptake. Emerging evidences, including recent human clinical studies, point to pivotal roles for Munc18c in peripheral insulin action in adipose and skeletal muscle. Intriguing new advances are also initiating debates regarding the molecular mechanism(s) controlling Munc18c action. The objective of this review is therefore to present a balanced perspective of new continuities and controversies surrounding the regulation and requirement for Munc18c in the regulation of peripheral insulin action. PMID- 25028249 TI - Familial risk of cerebral palsy: population based cohort study. AB - OBJECTIVE: To investigate risks of recurrence of cerebral palsy in family members with various degrees of relatedness to elucidate patterns of hereditability. DESIGN: Population based cohort study. SETTING: Data from the Medical Birth Registry of Norway, linked to the Norwegian social insurance scheme to identify cases of cerebral palsy and to databases of Statistics Norway to identify relatives. PARTICIPANTS: 2,036,741 Norwegians born during 1967-2002, 3649 of whom had a diagnosis of cerebral palsy; 22,558 pairs of twins, 1,851,144 pairs of first degree relatives, 1,699,856 pairs of second degree relatives, and 5,165,968 pairs of third degree relatives were identified. MAIN OUTCOME MEASURE: Cerebral palsy. RESULTS: If one twin had cerebral palsy, the relative risk of recurrence of cerebral palsy was 15.6 (95% confidence interval 9.8 to 25) in the other twin. In families with an affected singleton child, risk was increased 9.2 (6.4 to 13) fold in a subsequent full sibling and 3.0 (1.1 to 8.6)-fold in a half sibling. Affected parents were also at increased risk of having an affected child (6.5 (1.6 to 26)-fold). No evidence was found of differential transmission through mothers or fathers, although the study had limited power to detect such differences. For people with an affected first cousin, only weak evidence existed for an increased risk (1.5 (0.9 to 2.7)-fold). Risks in siblings or cousins were independent of sex of the index case. After exclusion of preterm births (an important risk factor for cerebral palsy), familial risks remained and were often stronger. CONCLUSIONS: People born into families in which someone already has cerebral palsy are themselves at elevated risk, depending on their degree of relatedness. Elevated risk may extend even to third degree relatives (first cousins). The patterns of risk suggest multifactorial inheritance, in which multiple genes interact with each other and with environmental factors. These data offer additional evidence that the underlying causes of cerebral palsy extend beyond the clinical management of delivery. PMID- 25028250 TI - Treatment and functional outcome of patients with cystoid macular edema: a single center experience. AB - The aim of this study was to describe a single-center experience in the treatment and follow-up of cystoid macular edema patients. Clinical records of all patients with cystoid macular edema followed up in the Rheumatologic and Ophthalmological Unit of our center between 1993 and 2013 were retrospectively evaluated. The outcome was assessed by visual acuity and optical coherence tomography status during follow-up. Comparisons were made by Fisher's exact test (p < 0.05 significant). In this study 16 eyes in 9 patients were analyzed. Our study includes mainly post-uveitic (78 %) cases with a high prevalence of human leukocyte antigen B51 (67 %). Systemic immunosuppressive therapy was prescribed in 87 % of cases. The most frequently used drugs were cyclosporine, interferon alpha, and infliximab. The first two molecules appeared respectively the most used as the first option and the one with the longest survival on treatment. Interferon-alpha was the most effective drug in contrasting visual acuity loss compared to the majority of drugs, but significantly more effective than mycophenolate (p = 0.01) in reducing macular edema. At the end of follow-up, 50 % of patients showed a significant visual loss, while 88 % did not present macular edema. In our small cohort, interferon-alpha is the most promising drug in contrasting visual acuity loss in cystoid macular edema. Visual prognosis remains severe in these patients. PMID- 25028252 TI - The effect of damage to optical pathways on posture and movement. AB - Of all man's senses, his ability to see is undoubtedly the most important. It is through vision that we derive pleasure from television, movies and ballet, that we can enjoy the convenience of driving a motor vehicle and maintain the ability to protect ourselves from other lethal weapons on our roads. Memory, dreams, imagination, sound, smell and taste all have visual associations. We judge time, in seconds, days or seasons by what we see. Memory in particular is based to a large extent on visual experiences, and those who lose vision can still recall its highlights and understand its meaning. Those who are born blind must have great difficulty in understanding seemingly simple things we take for granted, such as the meaning of light and dark, the concepts of colour, the beauty of sunsets, and the information imparted by various facial expressions. We with vision can observe a small degree of contraction of the orbicularis oris which changes an insulting remark into a humorous one. PMID- 25028251 TI - Maternal reflective functioning among mothers with childhood maltreatment histories: links to sensitive parenting and infant attachment security. AB - This study examined relationships among maternal reflective functioning, parenting, infant attachment, and demographic risk in a relatively large (N = 83) socioeconomically diverse sample of women with and without a history of childhood maltreatment and their infants. Most prior research on parental reflective functioning has utilized small homogenous samples. Reflective functioning was assessed with the Parent Development Interview, parenting was coded from videotaped mother-child interactions, and infant attachment was evaluated in Ainsworth's Strange Situation by independent teams of reliable coders masked to maternal history. Reflective functioning was associated with parenting sensitivity and secure attachment, and inversely associated with demographic risk and parenting negativity; however, it was not associated with maternal maltreatment history or PTSD. Parenting sensitivity mediated the relationship between reflective functioning and infant attachment, controlling for demographic risk. Findings are discussed in the context of prior research on reflective functioning and the importance of targeting reflective functioning in interventions. PMID- 25028253 TI - Birth order and age as factors in emotionally-triggered asthma. AB - It has been observed by Gibson (1966) that the incidence of bronchial asthma is 7% to 9% of the total population of school children in Tasmania. PMID- 25028254 TI - A clinical study of the value of a mixture of nitrous oxide and oxygen as an analgesic in relief of pain following thoracic surgery and its usage physiotherapeutically. AB - When patients have been subjected to thoracic and abdominal surgery, the ability to cough and ventilate the lungs adequately is inhibited post-operatively by pain and apprehension. The use of anaesthetic agents to relieve pain on stretching the incision has been investigated previously, particularly with patients following abdominal surgery. PMID- 25028255 TI - The effects of faradism under pressure on venous pressure. AB - Deep vein thrombosis was found at postmortem in patients treated by bed rest for myocardial infarction. We were asked to include deep calf massage to our programmed treatments of such patients in an attempt to prevent thromboses. On discussion, our Electrotherapy Department suggested that faradism under pressure might be more effective than deep calf massage. We were aware that many authorities in electrotherapy considered that cardiac disease is a contraindication to faradism under pressure as it is said to increase venous return. PMID- 25028256 TI - Compositional studies and biological activities of some mash bean (Vigna mungo (L.) Hepper) cultivars commonly consumed in Pakistan. AB - BACKGROUND: In recent years, the desire to adopt a healthy diet has drawn attention to legume seeds and food products derived from them. Mash bean is an important legume crop used in Pakistan however a systematic mapping of the chemical composition of mash bean seeds is lacking. Therefore seeds of four mash bean (Vigna mungo (L.) Hepper, family Leguminoseae) cultivars (NARC-Mash-1, NARC Mash-2, NARC-Mash-3, NARC-Mash-97) commonly consumed in Pakistan have been analyzed for their chemical composition, antioxidant potential and biological activities like inhibition of formation of advanced glycation end products (AGE) activity and tyrosinase inhibition activity. RESULTS: The investigated cultivars varied in terms of biochemical composition to various extents. Mineral composition indicated potassium and zinc in highest and lowest amounts respectively, in all cultivars. The amino acid profile in protein of these cultivars suggested cysteine is present in lowest quantity in all cultivars while fatty acid distribution pattern indicated unsaturated fatty acids as major fatty acids in all cultivars. All cultivars were found to be rich source of tocopherols and sterols. Fourier transform infrared spectroscopy (FTIR) fingerprints of seed flour and extracts indicated major functional groups such as polysaccharides, lipids, amides, amines and amino acids. Results indicated that all investigated cultivars possessed appreciable antioxidant potential. CONCLUSIONS: All cultivars are rich source of protein and possess sufficient content of dietary fiber, a balanced amino acid profile, low saturated fatty acids and antioxidant capacity that rationalizes many traditional uses of seeds of this crop besides its nutritional importance. The collected data will be useful for academic and corporate researchers, nutritionists and clinical dieticians as well as consumers. If proper attention is paid, it may become an important export commodity and may fetch considerable foreign exchange for Pakistan. PMID- 25028257 TI - Electron spin manipulation and readout through an optical fiber. AB - The electron spin of nitrogen--vacancy (NV) centers in diamond offers a solid state quantum bit and enables high-precision magnetic-field sensing on the nanoscale. Implementation of these approaches in a fiber format would offer unique opportunities for a broad range of technologies ranging from quantum information to neuroscience and bioimaging. Here, we demonstrate an ultracompact fiber-optic probe where a diamond microcrystal with a well-defined orientation of spin quantization NV axes is attached to the fiber tip, allowing the electron spins of NV centers to be manipulated, polarized, and read out through a fiber optic waveguide integrated with a two-wire microwave transmission line. The microwave field transmitted through this line is used to manipulate the orientation of electron spins in NV centers through the electron-spin resonance tuned by an external magnetic field. The electron spin is then optically initialized and read out, with the initializing laser radiation and the photoluminescence spin-readout return from NV centers delivered by the same optical fiber. PMID- 25028258 TI - Dispersant Corexit 9500A and chemically dispersed crude oil decreases the growth rates of meroplanktonic barnacle nauplii (Amphibalanus improvisus) and tornaria larvae (Schizocardium sp.). AB - Our knowledge of the lethal and sublethal effects of dispersants and dispersed crude oil on meroplanktonic larvae is limited despite the importance of planktonic larval stages in the life cycle of benthic invertebrates. We determined the effects of Light Louisiana Sweet crude oil, dispersant Corexit 9500A, and dispersant-treated crude oil on the survival and growth rates of nauplii of the barnacle Amphibalanus improvisus and tornaria larvae of the enteropneust Schizocardium sp. Growth rates of barnacle nauplii and tornaria larvae were significantly reduced after exposure to chemically dispersed crude oil and dispersant Corexit 9500A at concentrations commonly found in the water column after dispersant application in crude oil spills. We also found that barnacle nauplii ingested dispersed crude oil, which may have important consequences for the biotransfer of petroleum hydrocarbons through coastal pelagic food webs after a crude oil spill. Therefore, application of chemical dispersants increases the impact of crude oil spills on meroplanktonic larvae, which may affect recruitment and population dynamics of marine benthic invertebrates. PMID- 25028259 TI - The combined oral contraceptive pill -- recent developments, risks and benefits. AB - The introduction of the birth control pill as an effective, coitally-independent method of contraception was a public health milestone of the last century. Over time, combined oral contraception (COC) formulations and pill-taking regimens have evolved with improved safety and tolerability while maintaining contraceptive efficacy. In addition to protection against pregnancy, use of combined oral contraception confers a number of significant non-contraceptive benefits to users. COC use is also associated with well-studied risks. Common side effects are generally self-limiting and improve with increasing duration of use while serious adverse events, including venous thromboembolism, are rare among healthy COC users. Contraceptive decision-making should include consideration of both the risks and benefits of a given method versus the real consequences of unintended pregnancy. PMID- 25028260 TI - The effects of early life lead exposure on the expression of interleukin (IL) 1beta, IL-6, and glial fibrillary acidic protein in the hippocampus of mouse pups. AB - The present study was undertaken to investigate the effects of maternal lead (Pb) exposure on the expression of interleukin (IL) 1beta, IL 6, and glial fibrillary acidic protein (GFAP) in hippocampus of mice offspring. Pb exposure initiated from the beginning of gestation to weaning. Lead acetate (PbAc) administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1, 0.5 and 1% groups ,respectively. On the postnatal day 21, the Pb levels in their blood and hippocampus were determined by graphite furnace atomic absorption spectrometry. The expression of IL 1beta, IL 6, and GFAP in hippocampus was measured by immunohistochemistry and Western blotting. The Pb levels in blood and hippocampus of all Pb-exposed groups were significantly higher than that of the control group (p < 0.05). The expression of IL-1beta, IL 6, and GFAP was increased in Pb-exposed groups in comparison with the control group (p < 0.05). The high expression of IL-1beta, IL-6, and GFAP in the hippocampus of pups may contribute to the neurotoxicity associated with maternal Pb exposure. PMID- 25028261 TI - Evaluation of gatifloxacin for its potential to induce antioxidant imbalance and retinopathy in rabbits. AB - Gatifloxacin, a fluoroquinolone antibiotic, has been reported to produce several adverse reactions. In the present investigation, gatifloxacin administered at the dose rate of 10 and 20 mg kg(-1) body weight per day, respectively, for 21 consecutive days, was evaluated for its potential to induce antioxidant status alterations and retinal damage in rabbits. A significant alteration in the antioxidant status of rabbits particularly in the high-dose group was observed which is indicated by decreased activity of superoxide dismutase and levels of blood glutathione with a concomitant increase in the activity of catalase, glutathione peroxidase, and glutathione S-transferase enzymes. The activity of glutathione reductase differed nonsignificantly between groups throughout the study period. The levels of malondialdehyde were elevated in the high-dose group. The histopathological examination of eyeball tunics revealed clumping of nuclei of the retinal outer nuclear layer in the gatifloxacin-treated groups. The results from this study indicate that repeated gatifloxacin administration produces a dose-dependent oxidative stress and retinopathy. PMID- 25028262 TI - EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells. AB - The most widespread neoplasm of the pleura is malignant pleural mesothelioma (MPM) with low prevalence rate. The mechanistic target of rapamycin signaling pathway, inhibited by RAD001, was shown to be deregulated in MPM development and considered a novel target for the MPM therapy. The EF24, a curcumin analog, also affects several signaling pathways and kills cancer cells as a single agent or in combination with classical drugs. We aimed to evaluate possible effects of RAD001, EF24, cisplatin, and oxaliplatin treatments on both malignant pleural mesothelioma (MSTO-211H) and nonmalignant mesothelial (Met-5A) cell lines. The effects of the agents on MSTO-211H and Met-5A cells were evaluated in terms of cell viability, cytotoxicity, DNA synthesis rate, quantitation of apoptotic DNA fragmentation, and cleaved caspase 3 levels. Moreover, quantitative messenger RNA (mRNA) analysis of apoptotic (CASP9) and antiapoptotic (BCL2L1 and BCL2) genes were also performed. We found that both EF24 and RAD001 alone treatments decreased only MSTO-211H cell viability, but cisplatin and oxaliplatin affected both cell lines. Pretreatment with EF24 or RAD001 followed by cisplatin increased the effects of cisplatin alone application. EF24 and RAD001 pretreatment decreased DNA fragmentation rate when compared with cisplatin alone treatment in Met-5A cells. Sequential treatments resulted in a significant increase of CASP9 mRNA expression in MSTO-211H cells but not in Met-5A cells. Our preliminary results suggest that pretreatment with EF24 or RAD001 may reduce cytotoxic effect of cisplatin on nonmalignant mesothelial cells and increase cell death response of MPM cells. Further analyses using animal models are needed to confirm these findings in vivo. PMID- 25028263 TI - Probiotic Properties of Lactobacillus crispatus 2,029: Homeostatic Interaction with Cervicovaginal Epithelial Cells and Antagonistic Activity to Genitourinary Pathogens. AB - Lactobacillus crispatus 2029 isolated upon investigation of vaginal lactobacilli of healthy women of reproductive age was selected as a probiotic candidate. The aim of the present study was elucidation of the role of L. crispatus 2029 in resistance of the female reproductive tract to genitourinary pathogens using cervicovaginal epithelial model. Lactobacillus crispatus 2029 has surface layers (S-layers), which completely surround cells as the outermost component of their envelope. S-layers are responsible for the adhesion of lactobacilli on the surface of cervicovaginal epithelial cells. Study of interactions between L. crispatus 2029 and a type IV collagen, a major molecular component of epithelial cell extracellular matrix, showed that 125I-labeled type IV collagen binds to lactobacilli with high affinity (Kd = (8.0 +/- 0.7) * 10(-10) M). Lactobacillus crispatus 2029 consistently colonized epithelial cells. There were no toxicity, epithelial damage and apoptosis after 24 h of colonization. Electronic microscope images demonstrated intimate association between L. crispatus 2029 and epithelial cells. Upon binding to epithelial cells, lactobacilli were recognized by toll like 2/6 receptors. Lactobacillus crispatus induced NF-kappaB activation in epithelial cells and did not induce expression of innate immunity mediators IL-8, IL-1beta, IL-1alpha and TNF-alpha. Lactobacillus crispatus 2029 inhibited IL-8 production in epithelial cells induced by MALP-2 and increased production of anti inflammatory cytokine IL-6, maintaining the homeostasis of female reproductive tract. Lactobacillus crispatus 2029 produced H2O2 and provided wide spectrum of antagonistic activity increasing colonization resistance to urinary tract infections by bacterial vaginosis and vulvovaginal candidiasis associated agents. PMID- 25028264 TI - [The role of the community stroke rehabilitation nurse]. PMID- 25028265 TI - Potential for reducing air-pollutants while achieving 2 degrees C global temperature change limit target. AB - This study analyzes the potential to reduce air pollutants while achieving the 2 degrees C global temperature change limit target above pre-industrial levels, by using the bottom-up optimization model, AIM/Enduse[Global]. This study focuses on; 1) estimating mitigation potentials and costs for achieving 2 degrees C, 2.5 degrees C, and 3 degrees C target scenarios, 2) assessing co-benefits of reducing air pollutants such as NOx, SO2, BC, PM, and 3) analyzing features of sectoral attributions in Annex I and Non-Annex I groups of countries. The carbon tax scenario at 50 US$/tCO2-eq in 2050 can reduce GHG emissions more than the 3 degrees C target scenario, but a higher carbon price around 400 US$/tCO2-eq in 2050 is required to achieve the 2 degrees C target scenario. However, there is also a co-benefit of large reduction potential of air pollutants, in the range of 60-80% reductions in 2050 from the reference scenario while achieving the 2 degrees C target. PMID- 25028266 TI - ABC transporters as differentiation markers in glioblastoma cells. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumour, characterized by a high aggressivity, a huge heterogeneity attending a hierarchical model and resistance to therapy. Drug resistance has been correlated with the presence of the ABC efflux transporters which are able to exclude drugs for the cellular cytoplasm. In the nucleus of the GBM, initiating cells (ICs) can self-renew and give rise to cancer stem cells, which differ to the side population cells and the different cellular subtypes that form the mass around them. The ICs do not express or express ATP binding cassette (ABC) at very low levels, but this expression may increase with the differentiation process. We suggest that the differentiation process may be responsible of chemoresistance of the GBM cells. We compared three ABC transporters expression: ABCA1, MRP4 and MRP5, in the ICs obtained from 9 patients with GBM and their respective differentiated GBM cells. We show an overexpression of the three ABC transporters in the differentiated GBM cells in comparison to ICs. IMPLICATIONS OF THE HYPOTHESIS: The blockade of these ABC transporters could help to improve the drug effectivity and thus reduce the tumour growth and prevent the tumour recurrence. PMID- 25028267 TI - Microsatellite markers for Lycium ruthenicum (Solananeae). AB - We developed microsatellite markers in Lycium ruthenicum, a desert plant widely distributed in northwestern China. In order to investigate its population genetic structure, genetic diversity, and its evolutionary history, we have isolated 11 novel microsatellite loci primers and characterized them in 24 individuals from 3 populations of L. ruthenicum using the combined biotin capture technique. For these microsatellites, one to seven alleles per locus were identified. The observed heterozygosities ranged from 0 to 0.958, meanwhile the expected heterozygosities ranged from 0 to 0.841. These microsatellite markers could be first useful for population level studies like genetic diversity and structure in this species. PMID- 25028268 TI - Biological characteristics of rat dorsal root ganglion cell and human vascular endothelial cell in mono- and co-culture. AB - This study aimed to evaluate the biological activity of rat dorsal root ganglion cell (DRGC) and human vascular endothelial cell (HMVEC) in mono- and co-culture. Expression levels of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) mRNA were measured by quantitative real-time RT-PCR (qRT-PCR). Western blot analysis was used to identify VEGF and NGF protein expressions. Cell injury was assessed by measuring cell viability with methylthiazol tetrazolium (MTT) assay. The results showed that VEGF and NGF mRNA levels in the HMVEC+DRGC group were significantly higher than those in the DRGC and HMVEC groups (all p < 0.05). There were also greater increases in both VEGF and NGF protein expressions in the HMVEC+DRGC group than those in the DRGC and HMVEC groups (all p < 0.05). The results of MTT analysis revealed significant differences in cell viability among the HMVEC+DRGC group and the DRGC and HMVEC groups (all p < 0.05). In summary, our findings provide evidence that DRGC and HMVEC in co-culture may exhibit greater biological activity than DRGC in mono-culture. PMID- 25028269 TI - A second chance at EMR: the avulsion technique to complete resection within areas of submucosal fibrosis. PMID- 25028270 TI - Salvage cryotherapy in portal hypertensive gastropathy. PMID- 25028271 TI - Closure of a perforated duodenal ulcer by over-the-scope clip. PMID- 25028272 TI - Three late adverse events of choledochoduodenostomy of which the endoscopist should be aware: direct retrograde cholangioscopy is helpful for diagnosis and therapy. PMID- 25028273 TI - Dead-end ducts: rendezvous techniques for reconnecting the obstructed pancreas. PMID- 25028274 TI - A comparison of oral sulfate solution with sodium picosulfate: magnesium citrate in split doses as bowel preparation for colonoscopy. AB - BACKGROUND: There are few data comparing U.S. Food and Drug Administration approved low-volume bowel preparations for colonoscopy. OBJECTIVE: To compare oral sulfate solution (OSS) with sodium picosulfate plus magnesium citrate (SP+MC) for bowel cleansing efficacy. DESIGN: Single-blind, randomized, controlled trial. SETTING: Ten U.S. centers. PATIENTS: Outpatients undergoing colonoscopy for routine indications. INTERVENTIONS: Patients were randomized to undergo bowel preparation with OSS or SP+MC. Both preparations were given in split doses. MAIN OUTCOME MEASUREMENTS: Cleansing efficacy on a 4-point scale from excellent (4) to poor (1). RESULTS: Among 338 randomized patients who took preparation, OSS resulted in a higher rate of successful (excellent or good) preparation (94.7% vs 85.7%; P = .006) and more excellent preparations (54% vs 26%; P < .001) compared with SP+MC. There was no difference between OSS and SP+MC in treatment-emergent adverse events. SP+MC had better scores for nausea, but the differences were small. LIMITATIONS: The preparation grading scale has been used in previous studies and has regulatory acceptance but has not been formally validated. CONCLUSION: The U.S. Food and Drug Administration-approved split-dose regimen of OSS provides superior bowel cleansing compared with the approved split dose regimen of SP+MC. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01786629.). PMID- 25028275 TI - Endoscopic strangulation techniques for treatment of upper GI mucosal and submucosal lesions. PMID- 25028276 TI - Single-session EUS-guided transgastric ERCP in the gastric bypass patient. PMID- 25028277 TI - Successful closure of a Billroth II duodenal stump leak with fistulization to the colon by use of stacked over-the-scope clips. PMID- 25028278 TI - [Principles of orthopedic treatment of flaccid paralysis]. AB - BACKGROUND: Flaccid paralysis is the result of many different causes presenting with a multitude of symptoms ranging from affecting only the efferent pathways up to involvement of both the afferent and efferent loops of the peripheral neuoromotor system. The peripheral distribution corresponds to the damage. OBJECTIVES: The functional limitations of flaccid paralysis are the result of a permanent or progressive muscular weakness and ensuing contractures, deformities and instabilities which require compensatory and adaptive mechanisms from the patient to cope with these impairments. MATERIAL AND METHODS: Compensatory mechanisms are required for gait problems as well as for impaired standing, sitting ability and to optimize the use of the upper extremities. For setting therapeutic indications as well as for the treatment of the patients the causes of the functional deficits and the compensatory efforts from the patient must be considered. A list of the more common problems helps in this respect. RESULTS: Every treatment should be subdivided into preventive and therapeutic measures. Preventive options mostly consist of conservative methods while manifest deformities and instabilities are usually treated by combined therapeutic approaches, i.e. surgical and conservative. The correct straightening of the leg axes and joints, balancing and support of the musculature by tendon transfers and bony stabilizations followed by appropriate orthotic devices are the essential therapeutic principles. CONCLUSION: The basis of any management of functional problems in flaccid paralysis has to consider the pathomechanics of the primary deformities and the weakness as well as the compensatory mechanisms which allow the patient to achieve the functional goals. Neither surgery nor orthotic devices alone can fulfil the detailed requirements of a functional improvement. Instead a combination of both will succeed in most cases and is known as surgical-orthotic integration. PMID- 25028279 TI - [Spinal cord injury: still an interdisciplinary challenge [corrected]]. AB - INTRODUCTION: Spinal cord injuries with symptoms of paraplegia remain incurable even 5000 years after the first description. However, the treatment of the residual paralysis and sensory deficits at the level of or below the spinal injury has made great progress. METHODS: This study involved a selective literature review with an emphasis on historical development, epidemiology, classification, acute and secondary rehabilitation after spinal cord injury with specific aspects of hand surgery in tetraplegia, decubitus treatment and urological specialist care, taking the experiences in a specialized center for spinal cord injuries into account. RESULTS: Modern comprehensive management started in the 1940s led by Sir Ludwig Guttmann. Early operative decompression and stabilization of spinal injuries is safe and can reduce secondary damage to the spinal cord but definitive evidence is lacking. Operative approaches provide advantages for the patient compared to conservative therapy, e.g. being able to be immediately transferred to a specialized center. Epidemiologically, the proportion of women and the average age has increased during the past decades, as well as the percentage of patients with tetraplegia. Common sequelae of spinal cord injuries include disorders of the digestive and urogenital system, autonomic regulation, chronic pain as well as swallowing and breathing restrictions. Frequent complications, such as thrombosis and pulmonary embolism, heterotopic ossification, decubitus ulcers, contractures, neuropathic pain and spasticity can impede rehabilitation. The general objective of rehabilitation and life-long care of patients with spinal cord injuries is to achieve the greatest possible autonomy, mobility, integration, employability and quality of life. A partial recovery of arm and grip function by surgical muscle or nerve transposition, joint stabilization and tenodesis can reliably support these goals in approximately 70 % of patients with tetraplegia. CONCLUSION: Spinal cord injuries require holistic interdisciplinary therapy from the beginning and regular life long comprehensive and specific orthopedic examinations are also required to maintain the best possible level of independence. PMID- 25028280 TI - [Bilateral spastic cerebral palsy with ambulatory ability (diplegia): pathophysiology, state of the art of conservative and surgical treatment and rehabilitation]. AB - BACKGROUND: Infantile cerebral palsy is one of the most common diseases resulting in chronic disability and is mostly concomitant with impairment in the ability to walk. DISEASE PATTERN: Muscle contractions typically develop during the growth phase with subsequent joint contracture and instability as well as bone deformities to various extents. From a biomechanical viewpoint the gait impairment is due to a lever arm dysfunction. THERAPEUTIC STRATEGIES: The therapy concept is multimodal and involves conservative as well as operative measures. The objectives are to lower the muscle tonus, to avoid muscle and joint contractures and bone deformities and to correct already fixed malformations in order to achieve the best possible function for the patient. Complicated multilevel operations are often necessary to achieve this aim. CONCLUSION: Extensive knowledge on the biomechanics of gait and the pathobiomechanics of spastic bilateral cerebral palsy are necessary to carry out surgery. Using instrumental gait analyses the biomechanical relationships can be analyzed better and complicated operations can be planned with greater precision. PMID- 25028281 TI - [Bilateral spastic paresis without the ability to walk]. AB - BACKGROUND: Developmental disorders and severe damage to major parts of the brain cause loss of motor, sensor, cognitive and mental function. These disorders cannot be medically treated in a sufficiently curative manner and are likely to develop into severe disability in children and adults. THERAPY: Medical nursing care and treatment aims to achieve the best possible quality of life by a lack of pain, ability to communicate, autonomy, and activities of daily life. As part of the team neuro-orthopedic surgeons have to analyze the orthostatic effects of motor functional disorders in order to set up a treatment plan that includes preventive and palliative treatment options by movement therapy, orthotic, medicinal, and surgical interventions. CONCLUSION: Pain and severe progressive deformities, such as contracture of extremity joints, hip dislocation, and spinal deformity must be prevented as far as possible. Activities of daily life should be enhanced by balancing and promoting muscle power and stabilizing weak and unstable parts of the body when possible. PMID- 25028282 TI - [Conservative treatment of idiopathic scoliosis with effective braces: early response to trunk asymmetry may avoid curvature progress]. AB - Vertical posture of the growing child requires minute central nervous control mechanisms in order to maintain symmetry of the torso in its various activities. Scoliosis describes a constant deviation in the frontal, transverse and sagittal planes from the dynamic symmetry of the trunk. Early intervention with effective bracing, physiotherapy and sports can reverse curve progression during growth spurts, once these are identified in screening. Modern braces have a derotating and reducing effect (mirror effect) on asymmetric body volumes, thus influencing the growing torso and restoring lasting symmetry. Recent data support the use of braces to reverse progressing scoliosis. PMID- 25028283 TI - Improving teacher-child relationship quality and teacher-rated behavioral adjustment amongst externalizing preschoolers: effects of a two-component intervention. AB - The school-based Playing-2-gether is a 12-week intervention with two components aimed at decreasing child externalizing behavior through improving teacher-child interactions. The first component is rooted in attachment theory and aimed at enhancing teacher-child relationship quality, and the second is based on learning theory and aimed at improving teachers' behavior management. In this three-wave randomized study, effects of Playing-2-gether on the teacher-child relationship quality and on teacher-rated child behavioral adjustment were investigated. To this aim, 175 dyads consisting of male preschoolers with relatively high levels of externalizing problem behavior and their teachers were randomly assigned to Playing-2-gether (n = 89) or an education-as-usual control condition (n = 86). Teacher-rated questionnaires were collected at pre-test, after the first intervention component, and at post-test. At post-test, the intervention group showed a larger decrease in teacher-child conflict, child conduct problems, and child hyperactivity/inattention. Supplementary analyses showed that all positive effects were already visible after the first intervention component and that teacher-child conflict, child conduct problems and hyperactivity/inattention did not further reduce during the second component. In addition, an increase in closeness was found following the first component, but subsequently disappeared at post-test. PMID- 25028284 TI - Irritable and defiant sub-dimensions of ODD: their stability and prediction of internalizing symptoms and conduct problems from adolescence to young adulthood. AB - Emerging research has identified sub-dimensions of oppositional defiant disorder irritability and defiance - that differentially predict internalizing and externalizing symptoms in preschoolers, children, and adolescents. Using a theoretical approach and confirmatory factor analyses to distinguish between irritability and defiance, we investigate the associations among these dimensions and internalizing (anxiety and depression) and externalizing problems (conduct problems) within and across time in a community-based sample of 662 youth (342 females) spanning ages 12 to 18 years old at baseline. On average, irritability was stable across assessment points and defiance declined. Within time, associations of irritability with internalizing were consistently stronger than associations of irritability with conduct problems. Defiance was similarly associated within time with both internalizing and conduct problems in mid adolescence, but was more highly related to internalizing than to conduct problems by early adulthood (ages 18 to 25). Over time, increasing irritability was related to changes in both internalizing and conduct problems; whereas increases in defiance predicted increases in conduct problems more strongly than internalizing symptoms. Increases in both internalizing and conduct problems were also associated with subsequent increases in both irritability and defiance. Sex differences in these associations were not significant. PMID- 25028285 TI - [Vitamin D status in 6- to 10-year-old children: a French multicenter study in 326 children]. AB - OBJECTIVE: To assess the vitamin D status of children aged 6-10years in the French general population for whom no guidelines have yet been defined due to insufficient data. METHOD: The study was conducted during two winters with very different sunshine levels: 5 March to 17 April 2012 and 8 January to 16 April 2013 in 20 then 22 centers. Three hundred children (60 children for each year of age) attending an ambulatory care unit or outpatient department for a reason unrelated to vitamin D status were included at the end of winter in 20 hospital centers (ten centers in the northern half of France above latitude 46-47 degrees N/Lille: 50 degrees N and ten centers in the southern half of France below latitude 46-47 degrees N/Marseille: 43 degrees N). Centralized 25 hydroxyvitamin D (25(OH)D), alkaline phosphatase (ALP), and parathormone (PTH) assays were performed on leftover blood samples. The currently accepted normal range for 25(OH)D was used to define the following categories: <=25nmol/L: severe vitamin D deficiency, 25nmol/L100nmol/L: high vitamin D status. A standardized questionnaire was used to collect the child's characteristics, use of a vitamin D supplement, and milk and dairy product intake. The cumulative number of hours of sunshine over the 90days prior to inclusion in each center was obtained from the Meteo-France weather bureau. RESULTS: 25(OH)D assays were performed in 326 children; more than 95% of children received milk and dairy products and 38% had received a vitamin D supplement since starting the school year: 3.1% of children in the overall population presented severe vitamin D deficiency, 34.4% presented vitamin D deficiency, 53.1% had a sufficient vitamin D status, and 9.5% had a 25(OH)D concentration >100nmol/L with no impact on serum calcium and urinary calcium. Children living in the north of France generally had lower 25(OH)D levels than children living in the south of France. In the non-supplemented population (n=188), 5.3% of children presented severe vitamin D deficiency, 45.2% presented vitamin D deficiency and 48.4% had sufficient 25(OH)D levels. The percentage of children with severe vitamin D deficiency or vitamin D deficiency was twofold higher during the winter with poor sunshine compared to the sunnier winter with a less marked north/south difference. No case of severe vitamin D deficiency was observed in the supplemented population (n=119); 10-15% of children presented vitamin D deficiency and 22.7% had a 25(OH)D concentration >100nmol/L, while remaining within the acceptable range. Two cases of hypervitaminosis without hypercalcemia were identified: one after an unknown loading dose with a calcium/creatinine ratio in the normal range (0.8); for the second one, no additional information could be obtained. Vitamin D supplementation considerably reduced the north/south difference and the Winter1/Winter2 difference. A child not receiving a vitamin D supplement had a ninefold higher risk of vitamin D deficiency at the end of winter than a child receiving a vitamin D supplement (OR=8.8; 95%CI, 4.6-16.8). CONCLUSION: At least one-third of children aged 6-10years presented deficient 25(OH)D levels. None of the children receiving a vitamin D supplement presented severe vitamin D deficiency, only a small number of children presented vitamin D deficiency (n=16 (13.4%)), and no signs of overload were observed, while one half of non supplemented children (n=95 (50.5%)) presented at least vitamin D deficiency at the end of winter. These results support the need for vitamin D supplementation during winter in children aged 6-10years. PMID- 25028286 TI - Supine craniospinal irradiation using a proton pencil beam scanning technique without match line changes for field junctions. AB - PURPOSE: To propose and validate a craniospinal irradiation approach using a proton pencil beam scanning technique that overcomes the complexity of the planning associated with feathering match lines. METHODS AND MATERIALS: Ten craniospinal irradiation patients had treatment planned with gradient dose optimization using the proton pencil beam scanning technique. The robustness of the plans was evaluated by shifting the isocenter of each treatment field by +/-3 mm in the longitudinal direction and was compared with the original nonshifted plan with metrics of conformity number, homogeneity index, and maximal cord doses. An anthropomorphic phantom study using film measurements was carried out on a plan with 5-cm junction length. To mimic setup errors in the phantom study, fields were recalculated with isocenter shifts of 1, 3, 5, and 10 mm longitudinally, and compared with the original plans and measurements. RESULTS: Uniform dose coverage to the entire target volumes was achieved using the gradient optimization approach with averaged junction lengths of 6.7 +/- 0.5 cm. The average conformity number and homogeneity index equaled 0.78 +/- 0.03 and 1.09 +/- 0.01, respectively. Setup errors of 3 mm per field (6 mm in worst-case scenario) caused on average 4.6% lower conformity number 2.5% higher homogeneity index and maximal cord dose of 4216.1 +/- 98.2 cGy. When the junction length was 5 cm or longer, setup errors of 6 mm resulted in up to 12% dosimetric deviation. Consistent results were reached between film measurements and planned dose profiles in the junction area. CONCLUSIONS: Longitudinal setup errors directly reduce the dosimetric accuracy of the proton craniospinal irradiation treatment with matched proton pencil beam scanning fields. The reported technique creates a slow dose gradient in the junction area, which makes the treatment more robust to longitudinal setup errors compared to conventional feathering methods. PMID- 25028287 TI - 2,4-Dinitrophenol: a threat to Chinese body-conscious groups. AB - 2,4-Dinitrophenol (2,4-DNP), a yellowish compound, has historically been used in the manufacture of dyes, explosives, and fungicides. As it uncouples mitochondrial oxidative phosphorylation, the compound was also used as an antiobesity agent early in the past century. The compound was subsequently banned by the United States Food and Drug Administration in 1938 due to its potentially fatal adverse effects, including hyperthermia, cataract, agranulocytosis, hepatoxicity, nephrotoxicity, and cardiotoxicity. However, the popularity of 2,4 DNP as a slimming aid has appeared to increase again in recent years. The Hong Kong Hospital Authority Toxicology Reference Laboratory recently confirmed two cases of self-administered 2,4-DNP with different clinical presentations to hospitals in the area. Here we describe those two cases, in an attempt to underscore the potential of misuse of this substance by body-conscious groups among the Chinese population. PMID- 25028288 TI - Nonpalpable intramuscular hemangioma treated with hookwire localization and excision. AB - BACKGROUND: The local recurrence rate after surgical excision of intramuscular hemangioma reported is between 18% and 61%. The aim of this study was to review the clinical outcome and local recurrence rate after surgical excision of nonpalpable intramuscular hemangioma using preoperative ultrasound-guided hookwire localization. METHODS: We performed ultrasound-guided hookwire localization before excision surgery for nonpalpable intramuscular hemangioma in 37 cases between January 1997 and 2011. There were 20 females and 17 males, with a mean age of 30.2 years (range, 17-49 years). The mean localization procedure time was 10.6 minutes (range, 3-20 minutes). RESULTS: The average operation time was 48.6 minutes (range, 30-80 minutes). The average length of the excision wound was 5 cm (range, 4-11 cm), and the average hospital stay was 2.5 days (range, 2-4 days). The postoperative therapeutic report confirmed the diagnosis of intramuscular hemangioma. The average tumor size was 2.11 cm and all excision margins were free in all specimens. After the mean follow-up of 92.9 months (range, 14-179 months), one of the 37 patients had local recurrence (recurrence rate 2.7%). CONCLUSION: The use of ultrasound-guided hookwire localization before excision surgery is safe and effective in treating nonpalpable intramuscular hemangioma and could provide a better cosmetic result and functional recovery. PMID- 25028289 TI - Impact of carotid stenting in dizzy patients with carotid stenosis. AB - BACKGROUND: Little is known about the impact of severe carotid stenosis on health related quality of life (HRQoL). The aim of this study was to assess the effects of carotid stenting (CAS) on HRQoL in dizzy patients with carotid stenosis. METHODS: Patients with symptomatic (>=60%) or asymptomatic (>=80%) severe carotid stenosis and who complained of dizziness and received CAS were recruited. Two HRQoL questionnaires-a generic survey, the 36-item Short-Form Health Survey and a disease-specific instrument, the Dizziness Handicap Inventory-served as outcome measures. Patients were followed 1 week prior to CAS and 6 months postprocedurally. RESULTS: CAS was performed in 178 consecutive patients, 61 of whom complained of dizziness. Forty-one patients (67.2%, 34 male; mean age, 73.3 +/- 10.5 years; range, 47-87 years) completed the study. Twenty asymptomatic volunteers (17 male; mean age, 70.3 +/- 9.3 years; range, 54-84 years) served as normal controls. Compared to controls, patients tallied lower scores in the overall total and three subscales (physical, functional, and emotional) of the Dizziness Handicap Inventory (p < 0.01). Similar findings were noted in seven out of eight domains of the 36-item Short-Form Health Survey score. After 6 months, CAS resulted in significantly improved HRQoL (role physical, bodily pain, general health, social function, and role emotional) in these patients. CONCLUSION: CAS resulted in improved HRQoL in patients with severe carotid stenosis who experienced dizziness. PMID- 25028290 TI - Damage induced by paracetamol compared with N-acetylcysteine. AB - BACKGROUND: This study investigated the effect of thiamine pyrophosphate (TPP) on oxidative liver damage induced in rats with high-dose paracetamol. METHODS: Rats for this experiment were divided into the following groups: healthy control, paracetamol control, thiamine + paracetamol, TPP + paracetamol, and N acetylcysteine + paracetamol. Oxidant and antioxidant parameters and liver function test levels were compared between the groups. RESULTS: The results show that TPP and N-acetylcysteine with paracetamol equally prevented a rise in oxidants such as malondialdehyde and nitric oxide. They also prevented a decrease in enzymatic and nonenzymatic antioxidants such as glutathione, glutathione peroxidase, glutaredoxin, glutathione S-transferase, superoxide dismutase, and catalase in the rat liver. CONCLUSION: Thiamine pyrophosphate and N acetylcysteine had a similar positive effect on oxidative damage caused by paracetamol hepatotoxicity. These findings show that TPP may be beneficial in paracetamol hepatotoxicity. PMID- 25028291 TI - New grading of moyamoya disease using color-coded parametric quantitative digital subtraction angiography. AB - BACKGROUND: Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by idiopathic progressive stenosis or the occlusion of the intracranial arteries. Digital subtraction angiography (DSA) is the reference diagnostic imaging modality for MMD. Use of the conventional Suzuki grading remains the gold standard for evaluating the severity of MMD. In this study, we propose a quantitative method using color-coded parametric quantitative DSA (QDSA) to improve prediction of the severity of MMD. METHODS: Eighteen DSA examinations from 18 patients with MMD and 14 control participants were included. All patients with MMD underwent DSA and dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI). QDSA was used to determine the delay time of maximal opacification (Td) between the internal carotid artery and the M2 segment of the middle cerebral artery. The time-to-peak (TTP) was measured in the medial frontal, lateral frontal, parietal, and occipital lobes from the DSC-PWI. The relative TTP (rTTP) values were then obtained by subtracting the TTP of the cerebellum. RESULTS: The Td was significantly longer in the patients with MMD presenting with infarction than in the control group. The Td significantly correlated with the angiographic Suzuki grading system and showed closer correlation with prolonged rTTP in the medial frontal, lateral frontal, and parietal regions compared with Suzuki grading. CONCLUSION: The Td significantly correlated with conventional angiographic grading and with the status of hemodynamic impairment in patients with MMD. QDSA and Td measurements can provide a simple and quantitative angiographic grading system for patients with MMD. PMID- 25028292 TI - Measurement of fetal maxillary and mandibular angles for first-trimester prenatal screening among Taiwanese women. AB - BACKGROUND: Early fetal structure evaluation is crucial. Fetal abnormalities might indicate chromosomal anomalies or abnormal fetal growth. The aim of this study was to establish the appropriate reference range of maxillary and mandibular angles among the Taiwanese population at 11(+0)-13(+6) weeks of gestation in normal singleton pregnancy as reference values for prenatal ultrasonographic examinations. METHODS: Fetal ultrasonographic data on maxillary angles and mandibular angles at a gestational age ranging from 11(+0) weeks to 13(+6) weeks were recorded in this study. Maternal background and pregnancy outcome were obtained from hospital records. RESULTS: A total of 87 patients were included in this study. Maxillary and mandibular angles were successfully recorded in 87 (100%) and 84 (96.6%) patients, respectively. The mean maternal age was 31 (range, 19-41) years, with a corresponding gestational age of 12(+4) (range, 11(+0)-13(+6)) weeks. The maxillary and mandibular angles were 79.9 degrees +/- 15.6 degrees and 71.0 degrees +/- 12.8 degrees , respectively. First-degree correlation was not found to exist between gestational age and maxillary and mandibular angles. CONCLUSION: Normative data for ultrasonographic measurements of maxillary and mandibular angles among the Taiwanese population are presented. Our results may serve as reference values in congenital anomaly screening during prenatal examination. PMID- 25028293 TI - Persistent renal hyperparathyroidism caused by intrathyroidal parathyroid glands. AB - Renal hyperparathyroidism usually occurs in chronic renal failure patients on regular dialysis. However, renal hyperparathyroidism resulting from intrathyroidal parathyroid glands is an uncommon condition. We herein present the case of a 35-year-old woman who has been on hemodialysis for 20 years. She had renal hyperparathyroidism with generalized weakness and bone pain for 2 years. The patient initially underwent parathyroidectomy at a local institution, during which two large parathyroid glands were resected from the right side (no parathyroid glands were found on the left side); however, the surgical procedure was unsuccessful, and the patient had persistent renal hyperparathyroidism after the operation. She was then transferred to our hospital and ectopic intrathyroidal parathyroid glands were localized by neck ultrasonography and technetium-99m sestamibi scans with single-photon emission computed tomography imaging preoperatively. A left thyroid lobectomy was performed and two intrathyroidal parathyroid glands were found. The patient recovered uneventfully and her symptoms resolved. Therefore, clinicians should be aware of the possibility of renal hyperparathyroidism resulting from intrathyroidal parathyroid glands in cases where the renal hyperparathyroidism persists after parathyroidectomy. PMID- 25028294 TI - Management and clinical outcomes of intraocular foreign bodies with the aid of orbital computed tomography. AB - BACKGROUND: Computed tomography (CT) is known to be the first-line imaging method for patients with or suspect to have intraocular foreign bodies (IOFBs). The purpose of this study is to evaluate clinical outcomes in the management of IOFBs with the aid of CT. METHODS: Retrospective chart review of patients who received orbital CT prior to the removal of an IOFB between January 2000 and December 2010 was carried out. Patients with an IOFB who did not receive an operation or those without a preoperation CT examination were excluded. Twenty patients with a mean age of 37 years were selected. The duration between injury and surgery ranged from hours to 4 months. Detailed information and ophthalmologic examination results including patient history, visual acuity (VA), slit-lamp examination, fundoscopic examination, operation notes and bacterial culture results were recorded for all patients. The orbital CT images were performed with multidetector CT scanners with a 2-3.75 mm slice thickness. RESULTS: This study found 18 patients (90%) with only one IOFB on CT image, in which only nine IOFBs were discovered on clinical assessment. The CT image failed to discover the IOFB in two patients who had tiny iron dust fragments located in the cornea stroma or embedded in the lens. Preoperative determination of the IOFB size and location was helpful in the decision-making of the route of extraction. Further, there was a correlation between clinical presentation about vitreous hemorrhage and the development of postoperative retinal detachment (Fisher's exact test, p = 0.029). The presence of positive bacterial cultures was also found to be associated with decreased VA (Fisher's exact test, p = 0.047). The injured eyes were anatomically preserved in all patients. However, two patients had loss of light perception. Eleven patients (55%) had improved VA of more than two lines on Snellen's chart, seven patients worsened, and two patients retained the same initial VA. CONCLUSION: Multidetector CT plays an important role in the detection, localization, size measurement, and surgical approach towards the extraction of the IOFB. The presence of vitreous hemorrhage is a predictive factor for postoperative retinal detachment, and positive bacterial cultures result in poorer visual outcomes. PMID- 25028295 TI - Pain can be reduced by the cooperation of surgeons and other participants. PMID- 25028296 TI - Mast cell leukemia: an extremely rare disease. AB - Systemic mastocytosis is characterized by pathologic proliferation and accumulation of mast cells in at least one extracutaneous organ such as liver, spleen, bone marrow, or lymph nodes. The clinical features are highly variable depending on impairment of the involved organ systems. It often raises diagnostic challenges. Here we report a case of a 78-year-old patient with mast cell leukemia. The literature is reviewed regarding the diagnosis and updated management of this rare disease. PMID- 25028297 TI - The use of transjugular intrahepatic portosystemic stent shunt (TIPS) in the management of portal hypertensive bleeding. AB - Acute esophageal variceal hemorrhage is a terrible complication of portal hypertension and. rebleeding is very common in survivors of acute variceal bleeding. Traditional medical management options include the use of vasoconstrictor, balloon tamponade, and endoscopic therapy. Though endoscopic therapy has achieved successful hemostasis in the majority of acute variceal bleeding episodes, the outcome is usually dismal when such therapy fails. Transjugular intrahepatic portosystemic stent shunt (TIPS) was invented to decompress portal hypertension, but is now widely used in Western countries to treat patients with refractory variceal hemorrhage or refractory ascites. By contrast, TIPS has not been commonly used in Asia. In this article, I have reviewed the role of TIPS in the management of portal hypertensive bleeding, which will hopefully be useful for clinicians facing variceal bleeding that is not amenable to endoscopic therapies. PMID- 25028298 TI - Lymphovascular space invasion and tumor differentiation are predictors for postoperative recurrence in patients with pathological stage I nonsmall cell lung cancer. AB - BACKGROUND: We investigated factors predicting postoperative recurrence in patients with pathological Stage I nonsmall cell lung cancer (NSCLC). METHODS: All patients with clinical Stage I NSCLC who underwent surgical resection at Tri Service General Hospital in Taiwan between January 2002 and June 2006 were reviewed retrospectively. All study patients underwent standard staging workups. We reviewed the records of 261 patients with an average follow-up of 93 months; we then included 179 patients with pathological Stage I. RESULTS: Two hundred sixty-one patients with clinical Stage I NSCLC were eligible. There were no significant differences in sex, tumor histopathology, location, and age between the two groups (recurrence and nonrecurrence), except for tumor differentiation (p = 0.002), survival rate (p < 0.001), lymphovascular space invasion (LVSI; p = 0.007), advanced pathology stage (p = 0.022), maximum standard uptake value (SUVmax; p = 0.027), tumor size (p < 0.011), and carcinoembryonic antigen (CEA) levels (p = 0.013). Overall survival was significantly related to postoperative recurrence (p < 0.001) in patients with pathological Stage I, in whom recurrences developed in 11.17%. Only 179 patients with pathological Stage I NSCLC, including 20 patients with postoperative recurrences, were selected. Tumor differentiation (odds ratio 3.581, p = 0.058) and LVSI (odds ratio 5.374, p = 0.020) were independent factors predicting recurrence. CONCLUSION: Tumor differentiation and LVSI were predictors of postoperative relapse for patients with pathological stage I NSCLC. Risk factors of postoperative recurrence in patients with pathological Stage I NSCLC may enable us to optimize the patient selection for postoperative adjuvant therapies to prevent possibly occult micrometastases. PMID- 25028299 TI - [C-Section: little but enough information to put a stop to the inadequacy]. PMID- 25028300 TI - [C-section rate in low-risk women: a useful indicator to compare hospitals attending deliveries with different risks]. AB - BACKGROUND: the C-section rate has been criticized as a performance indicator for not considering that different hospitals manage deliveries with diverse risks. In this work we explore the characteristics of a new indicator restricted to low C section risk deliveries. METHODS: retrospective cohort of all births (n=214,611) in all public hospitals during 2005-2010 in the Valencia Region, Spain (source: minimum basic dataset). A low-risk subpopulation consisting of women under-35, no history of c-section, between 37 and 41 gestational weeks, and with a single fetus, with cephalic presentation and normal weight (2500-3999 g) was constructed. We analyzed variability in the new indicator, its correlation with the crude indicator and, using multilevel logistic regression models, the presence of residual risks. RESULTS: a total of 117 589 births (58.4% of the whole deliveries) were identified as low C-section risk. The c-section rate in these women was 11.9% (24.4% for all deliveries) ranging between hospitals from 7.0% to 28.9%. The c-section rate in low-risk and total deliveries correlated strongly (r=0.88). The remaining risks in the population of low risk did not alter the hospital effect on the c-section rate. CONCLUSION: the percentage of C section in low risk women include a high volume of deliveries, correlated with the crude indicator and residual risks are not differentially influenced by hospitals, being a useful indicator for monitoring the quality of obstetric care in the National Health System. PMID- 25028301 TI - [Response bias in a population postal survey on Health-Related Quality of Life (sf-12v2)]. AB - BACKGROUND: the bias associated with the low response rate may limit the economic advantage of population surveys by mail. The factors associated with non-response were estimated with an emphasis on Health-Related Quality of Life (HRQoL). METHODS: people who had answered to the Health Survey Murcia-2007 2007 (>= 18 years), realized by telephone, were sent another postal questionnaire four months later. Both evaluations included information about HRQoL: SF-12v2 (by phone) and EQ-5D (postal). A logistic regression was realized to identify baseline factors (sociodemographic factors, health-related behaviors and HRQoL-physical component summary (PCS) and mental component summary (MCS) of the SF-12v2) associated with non-response to the postal survey. RESULTS: 2,078 individuals (61.5%) did not answer. Multivariate analysis: non-response was associated with marital status, more likely not to respond if it was not married: widower OR: 2,24; IC95% 0,61/0,88; separate/divorced 1,69; 1,10/2,59-; single 1,53; 1,23/1,90 ) and inversely with age (25-34 years OR: 0,95; IC95% 0,69/1,29; 35-44 years 0,60; 0,43/0,85; 45-54 years 0,42; 0,29/0,60; 55-64 years 0,29; 0,20/0,43; 65-74 years 0,17; 0,11/0,26-;>=75 years 0,15; 0,09/0,23) and educational level (low-OR: 0,65; IC95% 0,48/0,86; intermediate 0,41; 0,30/0,57; high-0,22; 0,16/0,30). It was also associated with HRQoL, but differentially for PCS (those with intermediate scores have less probability of not answering OR: 0.73; 95% CI: 0.61/0.88) than for the MCS (the persons in the highest tertile were more likely to not answering 1.47; 1.22/1.78. CONCLUSION: the HRQoL influences the non- response to the postal surveys, leading to an overrepresentation of individuals with middle physical health and low mental health, which it adds small magnitude bias in the estimation of population HRQoL. PMID- 25028302 TI - [Epidemiological analysis of tuberculous lymphadenopathy in a District of Barcelona: proposal of a diagnostic algorithm]. AB - BACKGROUND: Barcelona (Spain) has experienced a dramatic change in its demography, which is reflected in the local epidemics of tuberculous lymphadenopathy (TL). The objective of the study is to analyze the associated risk factors to TL in a district of Barcelona with an incidence above 50 cases per 10,000 inhabitants/year, which will help to construct a diagnostic algorithm. METHODS: single-centre retrospective cohort study of all cases of TL diagnosed between 1990 and 2009. Due to the demographic changes, we analyzed 2 separate study periods (1990-1999 and 2000-2009). Socio-demographic, clinical and diagnostic features were assessed and compared between both cohorts and the algorithm was constructed with these results. Data was obtained from all the patients diagnosed with TL in Hospital del Mar (Barcelona) and was sent to the Public Health Agency of Barcelona. RESULTS: in the first study period, 152 patients had TL (73.7% Spanish-born) and in the second study period 147 (70.7% immigrants). In the first period, the percentage of male immigrants was 70.5% and 57.1% were younger than 35 years old but in the second study period, there was a 58.1% of Spanish-born female patients and 69.8% above 35 years old. The percentage of HIV co-infection decreased from 69.9% to 44.2% in the second period but use of immunosuppressive treatment increased to 9.3% in Spanish-born patients. Multivariate analysis showed intravenous drug use (OR 8.2; 95%CI: 3.4 19.8) and immigrant status (OR 4.8; 95%CI: 2.7-8.3) as risk factors associated to TL. CONCLUSION: male immigrants arriving from areas with high burden of TB, younger than 35 years old and Spanish-born women, older than 35 years old, with HIV infection (although with a lower proportion than before year 2000) or receiving immunosuppressive treatment, are the groups with an increased risk of TL in our district. PMID- 25028303 TI - [Estimating the burden of disease due to permanent disability in Spain during the period 2009-2012]. AB - BACKGROUND: Permanent disability (PD) is a major social and economic burden. The aim of this study was to determine the burden of disease due to PD. METHODS: Using data from the Continuous Working Life Sample (CWLS) -a random sample consisting of 4% of the active members affiliated to the Social Security (SS) System in Spain (1.1 million members) which data come from administrative registries from the SS- the diagnosis of PD (2009-2012) was established from the information on the temporary sickness absence (TSA) episodes from 2009. The diagnoses were imputed if two criteria were fulfilled: long duration of TSA and short period of time between the TSA episode and PD. The burden of disease was estimated for cases with an established diagnosis of PD by using the potential years of working life lost (PYWLL), estimated as the difference between the legal retirement age (65 years) and the age at the start of a PD. RESULTS: In the CWLS, 163,135 (13.6%9 individuals suffered a TSA episode in 2009, out of which 4,738 were granted a PD pension in the period of 2009-2012. The diagnosis was established for 3,073 (64.9%) cases. A large percentage of PD was produced by musculoskeletal (27.4%) and mental disorders (11.6%), likewise these diagnoses produced more PYWLL due to a PD: 11,086 (26.5%) and 7,052 (16.9%), respectively. Mental disorders produced PD at younger ages (median= 49 years of age). CONCLUSION: Mental and musculoskeletal disorders represent a major burden of disease produced by PD and measured by PYWLL. The diagnoses of PD should become available in order to estimate with more accuracy the PYWLL produced by PD and specific diagnoses. PMID- 25028304 TI - [Referrals and sex of physicians and patients: a gender analysis, Andalussia, Spain]. AB - BACKGROUND: It has been identified differences of medical care practice in primary care related to physician's sex. Simultaneously, there are gender inequalities in the assignment of health resources. Both aspects give rise to an increasing growing interest in the management and provision of health services. OBJECTIVES: To examine the differences in the referral practice made by female and male primary care physicians working in health centers in Andalusia, to consider whether there are disparities in referrals received by men and women, and to examine the interaction between patient's sex and physician's sex. METHODS: Observational, cross-sectional, and multicenter study. POPULATION: 4 health districts in Andalucia and their physicians. SAMPLE: 382 physicians. MEASUREMENTS: referral rate per visit (RV), referral rate per patient quota (RQ), patient's sex, physician: sex, age, postgraduate family medicine specialty, size of the patient quota by sex, mean number of patients/day by sex, mean age of the patient quota by sex, and proportion of men in the quota. Health center: urban / rural, size of the team, enrolled population, and postgraduate family medicine specialty's accreditation. SOURCES: databases of health districts. PERIOD OF STUDY: 2010. ANALYSIS: Bivariate and multivariate multilevel analysis of the referral rate per visit with mixed Poisson model. RESULTS: In 2010 382 physicians made 129,161 referrals to specialized care. The RQ was 23.47 and the RV was 4.92. The RQ in women and men was 27.23 and 19.78 for women physicians, being 27.37 and 19.51 for male physicians. The RV in women and men was 4.92 and 5.48 for women physicians, being 4.54 and 4.93 for male physicians. CONCLUSION: There are no differences in referral according to physician's sex. However, there are signs that might indicate the existence of gender inequality, and women patient received less referrals. There are no physician-patient's sex interaction. PMID- 25028305 TI - [Smoking prevalence and associated factors during pregnancy in Andalucia 2007 2012]. AB - BACKGROUND: Smoking during pregnancy is the most important preventable perinatal health problem. The aim of this research is to determine smoking prevalence in pregnant women at different times of pregnancy in Andalucia, using biochemical validation methods and to explore factors associated with it. METHODS: Cross sectional study. The study population was pregnant women followed in andalusian public health centers. A random sample of 40 health centers, stratified by number of pregnancies was collected, with 1813 pregnant enrolled in 3 independent samples (beginning and end of pregnancy, postpartum). The smoke exposure was measured by urinary cotinine, self-report and carbon monoxide in exhaled air. Control variables were socio-demographic, obstetric and related to smoking habit. A logistic regression was performed to explore factors associated with pregnancy smoking. RESULTS: The mean prevalence in the whole sample was 21.6%, which was lower at the end of pregnancy (15.6%) and postpartum (16.7%) than at the beginning (30.3%). Daily smokers fell from 56.3% before pregnancy to 14% at the end (according to selfreport). Most of the quitters gave up before pregnancy (21.8%) or when they noticed they were pregnant (23.6%). Deception rate was 19.6%, varying according to gestational age and the amount of tobacco consumed. Younger age (OR: 0.956, CI 0.92-0.99), be exposed to second hand smoke at home (OR: 3.48, CI 2.6 to 4.7), a higher level of consumption before pregnancy (6-10 OR 13.1 CI 3 to 56.9,> 10 OR 25.1 CI 5.8 to 109.6), greater gestational age at measurement (end OR: 0.5 CI: 0.4-0.8; immediate postpartum OR 0.4 CI 0.3-0.6) and lower educational level (no education and first grade compared to university OR: 1.98, CI 1.22 to 3.22) were identified as factors associated. CONCLUSION: Consumption variations with gestational age compel to indicate the time of measurement in prevalence studies. The profile of the pregnant smoker was being young, poorly educated, exposed to tobacco smoke at home and with a previous history of heavy smoking. PMID- 25028306 TI - [Differences in cesarean sections between spontaneous and induced labour]. AB - BACKGROUND: The induction of labour (IOL) may be associated with complications for pregnant women. The aim was to assess the differences in the number of caesarean sections between spontaneous or induced labour. METHODS: Historical groups from 841 women with induced labour and 2,534 women with an spontaneous onset of labour over a three- year period (from 2009 to 2011). They were carried out in "Mancha Centro" Hospital (Alcazar de San Juan). It was used a multivariate analysis through binary logistic regression to control confounding variables. RESULTS: The prevalence of IOL was 22,9%. The most frequent indications were: Premature Rupture of Membranes (22,7%), bad- controlled Diabetes (22,5%). It was reported a relation between induced labour and cesarean section risk due to parity (nulliparous OR= 2.68, IC 95%: 2.15- 3.34 and multiparous OR= 2.10, IC 95%: 1.72- 2.57). Postterm pregnancy (37,1%), pathological monitor (35.3%) and hypertensive diseases of pregnancy (34%) reported the highest risks of cesarean section. The IOL was related to other factors: a long- time length first -stage of labour (OR= 6.00; IC 95%: 4.02- 8.95), use of epidural analgesia (OR= 3.10; IC 95%: 2.24- 4.29) and blood transfusion needs (OR= 3.33; IC 95%: 1.70- 9.67). CONCLUSION: Independently of parity, The IOL increases the risk to: have a longer duration first- stage, use epidural analgesia, need a blood transfusion and have a cesarean section. This relation is stronger when induction is due to postterm pregnancy, pathological monitor or hypertensive diseases. No relation was found among induced labour and second- stage duration, episiotomy, perineal tears, excessive blood loss or uterine rupture. PMID- 25028307 TI - [Sociodemographic and clinical data predicting unplanned pregnancy in young 13 to 24 years, Spain]. AB - BACKGROUND: Unplanned pregnancy (UP) is still a public health problem. This study aims at finding out the sexual behaviours and contraceptive practices related to UP in young women. METHODS: 583 women between the ages of 13 and 24 years old were assisted in the contraception office in 2012. Dependent variable: UP. Independent variables: sociodemographic, sexual behaviours and contraceptive practices. Bivariate analysis, chi-squared and Student's t tests. Multivariate analysis, binary logistic regression. RESULTS: 174 (29.8%) young girls had had a UP. The risk of UP increased in immigrant women (OR 2.858 [CI 95% 1.808-4.519]), in less educated young women (OR 2.343 [CI 95% 1.361-4.035]), in those who did not use a safe contraceptive method in their first coitus (OR 3.043 [CI 95% 1.900 4.875]), in those who stated problems with the use of methods (OR 2.092 [CI 95% 1.267-3.454]) and in those who attend irregularly the consultation (OR 2.063 [CI 95% 1.275-3.339]). There is no relationship with age (teenagers/young). The model is considered acceptable: Hosmer-Lemeshow is not significant and its discrimination power is at 77%. CONCLUSION: Predictors of unplanned pregnancy in young women are: immigrant women, less educated young women, not using use a safe contraceptive method in their first coitus, stated problems with the use of methods and attend the consultation irregularly. PMID- 25028308 TI - [Attitudes of medical students about influenza vaccination]. AB - BACKGROUND: Vaccination coverage against seasonal influenza virus among healthcare personnel is low. The aim of this study was to know the reasons for which the medical students have intention to be vaccinated against influenza when they become healthcare workers (HCWs), and to identify its determining factors. METHODS: A cross-sectional study was performed during the 2011-2012 school year. It included all enrolled medical students from a Spanish University. The information (intention to be vaccinated, reasons and 8 questions about knowledge of influenza vaccine) was obtained by a self-administered questionnaire. Absolute and relative frequencies were calculated and the associations were then evaluated using a Chi-square test and logistic regression. RESULTS: 654 students of the 1130 (57.9%) completed the questionnaire. 63.0% had intention to be vaccinated. The main reasons to have intention to be vaccinated were: belief that vaccination is convenient (68.2%), to avoid transmitting influenza to patients (65.5%), and to avoid getting influenza from patients (64.8%). The main reasons for not having intention to be vaccinated were: low risk of influenza (41.7%) and to avoid shots/medication (27.7%). Knowledge that the vaccine is recommended for HCWs was associated with the intention (p= 0.000). CONCLUSION: Intention to get vaccinated was high regarding current coverage; thus, it is needed to investigate why the coverages against influenza among Spanish physicians are usually low. The level of knowledge has left room for improvement and knowing that the vaccine is recommended for HCWs was associated with the intention. PMID- 25028309 TI - [G_Clinic questionnaire to assess job satisfaction in the clinical management units, Spain]. AB - BACKGROUND: Job satisfaction of nurses is a determinant factor in the quality and organizational adaptation of clinical management models in the current socio economic context. The aim of this study was to construct and validate a questionnaire to measure job satisfaction of nurses in the Clinical Management Units in the Andalusian Public Health System. METHODS: Clinimetric and cross sectional study with a sample of 314 nurses of two university hospitals from Seville. Nurses were surveyed in 2011, from March to June. We used the Font Roja questionnaire adapted to our study variables. We performed analyses of correlations, reliability and construct validity, using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to test the a priori model. RESULTS: The end questionnaire consists of 10 items, whose internal consistency was 0.75, with a percentage of variance explaining of 63.67%. CFA confirmed 4 dimensions (work environment, work relationships, motivation, and recognition): significant chi2 (p < .001); chi2/gl = 2.013; GFI= 0.958, RMR = 0.055 y RMSEA = 0.057; AGFI = 0.927, NFI = 0.878, TLI = 0.902, CFI =0.933 e IFI = 0.935; AIC = 132.486 y ECVI = 0.423. CONCLUSION: This new questionnaire (G_Clinic) improves clinimetric values of the Font Roja questionnaire, because it reduces the number of items, improves the reliability of the dimensions, increases the value of variance explained, and allows knowing job satisfaction of nurses in clinical managementt. PMID- 25028311 TI - Preparation of visible light-driven g-C3N4@ZnO hybrid photocatalyst via mechanochemistry. AB - C3N4@ZnO hybrid materials with visible light photocatalytic performance have been prepared by facile mechanical milling. The dispersion of conjugated molecule g C3N4 on the surface of ZnO improved during mechanical process, and the multilayer hybrid structure of g-C3N4@ZnO materials with remarkable visible light photocatalytic activity was formed by ball milling. The photocatalytic activity and photocurrent intensity of g-C3N4@ZnO under visible light irradiation was 3.0 and 2.0 times higher than those of pure C3N4, respectively. The great enhancement of visible light response originates from the increase of separation and immigration efficiency of photogenerated electron-hole pairs. Furthermore, a synergistic photocatalysis mechanism between ZnO and g-C3N4 was proposed. The enhanced visible light photocatalytic properties originate from the injection of excited electrons from the LUMO of C3N4 to the CB of ZnO. However, the photocatalytic activity of the photocatalyst is much lower than that of ZnO under UV light, which is caused by the lattice defect of ZnO formed during milling. PMID- 25028310 TI - Cervicovaginal atresia with hematometra: restoring menstrual and sexual function by utero-coloneovaginoplasty. AB - BACKGROUND: Cervicovaginal atresia is a rare Mullerian anomaly. The management of cervicovaginal atresia has evolved from historical recommendations of hysterectomy to various reconstructive procedures more recently. The latter carries a risk of significant morbidity and unknown fertility. We present our experience in the management of this complex anomaly. METHODS: Twenty patients with cervicovaginal atresia were operated in our hospital from January 2004 through December 2013. The details of their anatomical variations and functional outcomes were analyzed. RESULTS: Eighteen out of twenty patients had cervical agenesis. Two patients had cervical hypoplasia. All patients underwent utero coloneovaginoplasty. Post operatively, all patients have regular menstrual cycles. One patient is married, sexually active and has satisfactory coital function. One patient had a bowel anastomotic leak that required a diversion ileostomy. Two patients developed mild stenosis. One patient has mild neovaginal mucosal prolapse. No patient has developed pyometra. CONCLUSION: Patients with cervicovaginal atresia need to be counselled about the various reconstructive options available and the potential risks. Social and economic factor play a significant role in determining the plan of management. For patients from conservative societies, utero-coloneovaginoplasty provides a safe conduit for the passage of menstrual flow and coitus, at the cost of permanent infertility. PMID- 25028312 TI - Microbiology and visual outcomes of culture-positive bacterial endophthalmitis in Oxford, UK. AB - PURPOSE: To review the microbiology of culture-positive cases of bacterial endophthalmitis, and to correlate this with visual outcomes. METHOD: Case notes were reviewed for culture-positive cases of bacterial endophthalmitis over a period from November 1999 to June 2012. Cases were identified retrospectively using a local database. The Fisher exact test was used for statistical analysis. RESULTS: Of the 47 cases of culture-positive bacterial endophthalmitis identified, 81 % occurred postoperatively, 11 % followed intravitreal injection, 6 % had an endogenous source and 2 % followed ocular trauma. Eighty-seven percent of bacteria cultured were Gram-positive. The most commonly identified organisms were coagulase-negative Staphylococci (47 %) and Streptococcus spp. (30 %). Patients were treated with intravitreal vancomycin and either amikacin or ceftazidime. All Gram-negative isolates were sensitive to aminoglycosides and ceftazidime, and all Gram-positive isolates were vancomycin-sensitive. Final visual acuity (VA) was 6/12 or better in 41 % of cases and counting fingers (CF) or worse in 30 %. Endophthalmitis caused by Streptococcus spp. was associated with a poorer final VA (OR for CF or worse = 14.9, P < 0.01). Cases caused by coagulase-negative Staphylococci had a better visual outcome (OR for VA of 6/12 or better = 5.7, P = 0.013). Five eyes were eviscerated or enucleated. Infection with Haemophilus influenzae was strongly associated with this outcome (OR = 57, P < 0.01). CONCLUSION: Over the time period of this study there was no evidence of emerging resistance to empirical antibiotics which are commonly used for the treatment of bacterial endophthalmitis. Infection with coagulase-negative Staphylococci was associated with a good visual outcome, whilst infection with Streptococcus spp. or Haemophilus influenzae was associated with a poor visual outcome. PMID- 25028313 TI - ILM peeling technique influences the degree of a dissociated optic nerve fibre layer appearance after macular hole surgery. AB - PURPOSE: We sought to assess the effect of two different internal limiting membrane [ILM] peeling techniques carried out during surgery for idiopathic macular holes on the postoperative extent of a dissociated optic nerve fibre layer appearance [DONFL]. METHODS: We collected prospective data of surgical records, videos, and pre- and postoperative imaging of a consecutive series of patients undergoing surgery for idiopathic macular hole with one of two surgeons. One surgeon used a forceps pinch-peel technique to peel the ILM, whereas the other surgeon used a diamond dusted membrane scraper. The extent of any DONFL was measured using spectral domain optical coherence tomography and blue reflectance imaging at three months postoperatively. A proportion of the ILMs removed were examined with transmission electron microscopy. RESULTS: Fifty-seven patients were studied, with 41 in the forceps group and 16 in the scraper group. The groups were well matched, with no significant difference in any preoperative parameters. Some degree of DONFL was observed on the 3-month blue reflectance images in 88 % of the forceps group and 100 % of the scraper group [p = 0.14]. There was a significant difference in the total number of depressions in the nerve fibre layer typical of DONFL on OCT between the two groups [p = 0.001], and general regression analysis showed that the peeling technique used had the only significant association with the degree of DONFL observed. Electron microscopy showed large patches of cellular debris on the retinal side of the peeled ILM in 3 out of 4 cases in the scraper group and 1 out of 12 cases in the forceps group. CONCLUSION: ILM peeling technique and possibly other surgeon-specific factors appear to influence the extent of DONFL observed after ILM peeling macular hole surgery. PMID- 25028314 TI - Removal of malachite green dye from wastewater by different organic acid-modified natural adsorbent: kinetics, equilibriums, mechanisms, practical application, and disposal of dye-loaded adsorbent. AB - Natural adsorbent (Cinnamomum camphora sawdust) modified by organic acid (oxalic acid, citric acid, and tartaric acid) was investigated as a potential adsorbent for the removal of hazardous malachite green (MG) dye in aqueous media in a batch process. The extent of MG adsorption onto modified sawdust increased with increasing organic acid concentrations, pH, contact time, and temperature but decreased with increasing adsorbent dosage and ionic strength. Kinetic study indicated that the pseudo-second-order kinetic model could best describe the adsorption kinetics of MG. Equilibrium data were found to fit well with the Langmuir model, and the maximum adsorption capacity of the three kinds of organic acid-modified sawdust was 280.3, 222.8, and 157.5 mg/g, respectively. Thermodynamic parameters suggested that the sorption of MG was an endothermic process. The adsorption mechanism, the application of adsorbents in practical wastewater, the prediction of single-stage batch adsorption system, and the disposal of depleted adsorbents were also discussed. PMID- 25028315 TI - Development of Lymantria dispar affected by manganese in food. AB - We studied the response of gypsy moth (Lymantria dispar (Linnaeus) (Lepidoptera: Lymantriidae)) to the content of manganese in food in the laboratory breeding of caterpillars. The food of the caterpillars {Betula pendula Roth (Fagales: Betulaceae) leaves} was contaminated by dipping in the solution of MnCl2 . 4H2O with manganese concentrations of 0, 0.5, 5 and 10 mg ml(-1), by which differentiated manganese contents (307; 632; 4,087 and 8,124 mg kg(-1)) were reached. Parameters recorded during the rearing were as follows: effect of manganese on food consumption, mortality and length of the development of caterpillars, pupation and hatching of imagoes. At the same time, manganese concentrations were determined in the offered and unconsumed food, excrements, and exuviae of the caterpillars, pupal cases and imagoes by using the AAS method. As compared with the control, high manganese contents in the food of gypsy moth caterpillars affected the process of development particularly by increased mortality of the first instar caterpillars (8 % mortality for caterpillars with no Mn contamination (T0) and 62 % mortality for subjects with the highest contamination by manganese (T3)), by prolonged development of the first-third instar (18.7 days (T0) and 27.8 days (T3)) and by increased food consumption of the first-third instar {0.185 g of leaf dry matter (T0) and 0.483 g of leaf dry matter (T3)}. The main defence strategy of the caterpillars to prevent contamination by the increased manganese content in food is the translocation of manganese into frass and exuviae castoff in the process of ecdysis. In the process of development, the content of manganese was reduced by excretion in imagoes to 0.5 % of the intake level even at its maximum inputs in food. PMID- 25028316 TI - Displacement and competitive sorption of organic pollutants on multiwalled carbon nanotubes. AB - Displacement of lindane presorbed on the pristine and OH-functionalized multiwalled carbon nanotubes (MWCNTs) by phenanthrene, naphthalene, and atrazine, and competition of these compounds with lindane on the aforementioned sorbents were investigated. Displacement of lindane presorbed on MWCNTs by atrazine, naphthalene, and phenanthrene, and competitive sorption effect of these chemicals with lindane on MWCNTs followed the same order: atrazine > naphthalene > phenanthrene. The lowest competition and displacement of lindane by phenanthrene were mainly because of the strong interactions between these two chemicals, whereas interaction of lindane with atrazine and naphthalene was quite low. The more pronounced displacement of lindane by atrazine than naphthalene and higher competitive sorption of lindane with atrazine than with naphthalene can be ascribed to the larger molecular volume of atrazine; thus, the steric hindrance effect is higher relative to naphthalene. This study is valuable for evaluating influence of the coexisting organic compounds on sorption of primary solute towards MWCNTs in the environment. PMID- 25028317 TI - Sequential anaerobic/aerobic digestion for enhanced sludge stabilization: comparison of the process performance for mixed and waste sludge [corrected]. AB - Sequential anaerobic-aerobic digestion has been demonstrated as a promising alternative for enhanced sludge stabilization. In this paper, a feasibility study of the sequential digestion applied to real waste activated sludge (WAS) and mixed sludge is presented. Process performance is evaluated in terms of total solid (TS) and volatile solid (VS) removal, biogas production, and dewaterability trend in the anaerobic and double-stage digested sludge. In the proposed digestion lay out, the aerobic stage was operated with intermittent aeration to reduce the nitrogen load recycled to the wastewater treatment plant (WWTP). Experimental results showed a very good performance of the sequential digestion process for both waste and mixed sludge, even if, given its better digestibility, higher efficiencies are observed for mixed sludge. VS removal efficiencies in the anaerobic stage were 48 and 50% for waste and mixed sludge, respectively, while a significant additional improvement of the VS removal of 25% for WAS and 45% for mixed sludge has been obtained in the aerobic stage. The post-aerobic stage, operated with intermittent aeration, was also efficient in nitrogen removal, providing a significant decrease of the nitrogen content in the supernatant: nitrification efficiencies of 90 and 97% and denitrification efficiencies of 62 and 70% have been obtained for secondary and mixed sludges, respectively. A positive effect due to the aerobic stage was also observed on the sludge dewaterability in both cases. Biogas production, expressed as Nm(3)/(kgVSdestroyed), was 0.54 for waste and 0.82 for mixed sludge and is in the range of values reported in the literature in spite of the low anaerobic sludge retention time of 15 days. PMID- 25028318 TI - Tire tread wear particles in ambient air--a previously unknown source of human exposure to the biocide 2-mercaptobenzothiazole. AB - Urban particulate matter (PM), asphalt, and tire samples were investigated for their content of benzothiazole and benzothiazole derivates. The purpose of this study was to examine whether wear particles, i.e., tire tread wear or road surface wear, could contribute to atmospheric concentrations of benzothiazole derivatives. Airborne particulate matter (PM10) sampled at a busy street in Stockholm, Sweden, contained on average 17 pg/m(3) benzothiazole and 64 pg/m(3) 2 mercaptobenzothiazole, and the total suspended particulate-associated benzothiazole and 2-mercaptobenzothiazole concentrations were 199 and 591 pg/m(3), respectively. This indicates that tire tread wear may be a major source of these benzothiazoles to urban air PM in Stockholm. Furthermore, 2 mercaptobenzothiazole was determined in urban air particulates for the first time in this study, and its presence in inhalable PM10 implies that the human exposure to this biocide is underestimated. This calls for a revision of the risk assessments of 2-mercaptobenzothiazole exposure to humans which currently is limited to occupational exposure. PMID- 25028319 TI - Sorption of chlorimuron-ethyl on montmorillonite clays: effects of exchangeable cations, pH, and ionic strength. AB - Sorption interaction of chlorimuron-ethyl with montmorillonite clays was investigated under varied types of exchangeable cation, pH, and ionic strength conditions. Chlorimuron-ethyl sorption on bentonites exhibited pronounced cation dependency, and the sorption ability increased as the sequence Ca(2+)- < Na(+)- < Al(3+)- < Fe(3+)-bentonite, due to different sorption mechanisms, whereas the cation dependency was influenced by the clay type and much weaker for montmorillonites. The decrease of pH at the range of 4.0-6.0 prominently increased sorption of chlorimuron-ethyl on all cation-exchanged montmorillonite clays, and nearly a neglected sorption (about 2 %) can be observed at pH over 7.0. In the presence of CaCl2, sorption of chlorimuron-ethyl on Fe(3+)-bentonite was promoted because of complexion of Ca(2+) and the surface of Fe(3+)-bentonite. However, as the concentration of CaCl2 increased, chlorimuron-ethyl sorption on Ca(2+)- and Fe(3+)-exchanged bentonite decreased, suggesting that Ca bridging was not the prevailing mechanism for sorption of chlorimuron-ethyl on these clays. Furthermore, chlorimuron-ethyl sorption was relatively sensitive to pH, and the change of pH may obscure effect of other factors on the sorption, so it was quite necessary to control pH at a constant value when the effect of other factor was being studied. PMID- 25028320 TI - Advanced multivariate analysis to assess remediation of hydrocarbons in soils. AB - Accurate monitoring of degradation levels in soils is essential in order to understand and achieve complete degradation of petroleum hydrocarbons in contaminated soils. We aimed to develop the use of multivariate methods for the monitoring of biodegradation of diesel in soils and to determine if diesel contaminated soils could be remediated to a chemical composition similar to that of an uncontaminated soil. An incubation experiment was set up with three contrasting soil types. Each soil was exposed to diesel at varying stages of degradation and then analysed for key hydrocarbons throughout 161 days of incubation. Hydrocarbon distributions were analysed by Principal Coordinate Analysis and similar samples grouped by cluster analysis. Variation and differences between samples were determined using permutational multivariate analysis of variance. It was found that all soils followed trajectories approaching the chemical composition of the unpolluted soil. Some contaminated soils were no longer significantly different to that of uncontaminated soil after 161 days of incubation. The use of cluster analysis allows the assignment of a percentage chemical similarity of a diesel contaminated soil to an uncontaminated soil sample. This will aid in the monitoring of hydrocarbon contaminated sites and the establishment of potential endpoints for successful remediation. PMID- 25028321 TI - The effect of environmental remediation on the cesium-137 levels in white-tailed deer. AB - Due to activities involving nuclear energy research during the latter half of the 1900 s, environmental contamination in the form of elevated cesium-137 levels was observed within the Brookhaven National Laboratory, a US Department of Energy facility. Between the years 2000 and 2005, the laboratory carried out a major soil cleanup effort to remove cesium-137 from contaminated sites. In this study, we examine the effectiveness of the cleanup effort by comparing the levels of cesium-137 in the meat of white-tailed deer found within and around the laboratory. Results suggest that the cleanup was effective, with mean concentration of cesium-137 in the meat from within the laboratory decreasing from 2.04 Bq/g prior to 1.22 Bq/g after cleanup. At the current level, the consumption of deer would not pose any human health hazard. Nevertheless, statistically higher levels of cesium-137 were detected in the deer within the laboratory as opposed to levels found in deer 1 mi beyond the laboratory site. PMID- 25028322 TI - Seeds' physicochemical traits and mucilage protection against aluminum effect during germination and root elongation as important factors in a biofuel seed crop (Ricinus communis). AB - We determined the length, volume, dry biomass, and density in seeds of five castor bean cultivars and verified notable physicochemical trait differences. Seeds were then subjected to different toxic aluminum (Al) concentrations to evaluate germination, relative root elongation, and the role of root apices' rhizosphere mucilage layer. Seeds' physicochemical traits were associated with Al toxicity responses, and the absence of Al in cotyledons near to the embryo was revealed by Al-hematoxylin staining, indicating that Al did not induce significant germination reduction rates between cultivars. However, in the more sensitive cultivar, Al was found around the embryo, contributing to subsequent growth inhibition. After this, to investigate the role of mucilage in Al tolerance, an assay was conducted using NH4Cl to remove root mucilage before or after exposure to different Al concentrations. Sequentially, the roots were stained with hematoxylin and a quantitative analysis of staining intensity was obtained. These results revealed the significant contribution of the mucilage layer to Al toxicity responses in castor bean seedlings. Root growth elongation under Al toxicity confirmed the role of the mucilage layer, which jointly indicated the differential Al tolerance between cultivars and an efficient Al exclusion mechanism in the tolerant cultivar. PMID- 25028323 TI - Translocation analysis and safety assessment in two water spinach cultivars with distinctive shoot Cd and Pb concentrations. AB - A pot experiment was conducted to investigate the translocation of cadmium (Cd) and lead (Pb) and assess the safety of edible parts in two cultivars of water spinach (Ipomoea aquatica Forsk.) contrasting in shoot Cd and Pb concentrations. A low-Cd-Pb cultivar (QLQ) and a high-Cd-Pb cultivar (T308) were grown in five soils with different concentrations of Cd and Pb. The results showed that QLQ had lower Cd and Pb concentrations in stems and leaves and higher root Cd concentration than T308 did. Root Pb concentration of T308 dramatically increased with increasing soil Pb concentration and was higher than that of QLQ in the highest Pb treatment. The root-to-stem Cd translocation ability in T308 was 2.3 3.0-fold higher than that in QLQ. Nevertheless, there was no significant difference in root-to-stem Pb translocation between QLQ and T308. The bioconcentration factors (BCFs) for Cd and Pb in the two cultivars remained stable in different Cd or Pb treatments, which were attributable to the homeostatic control mechanisms of Cd and Pb in water spinach. PMID- 25028324 TI - Acid-base physiology response to ocean acidification of two ecologically and economically important holothuroids from contrasting habitats, Holothuria scabra and Holothuria parva. AB - Sea cucumbers are dominant invertebrates in several ecosystems such as coral reefs, seagrass meadows and mangroves. As bioturbators, they have an important ecological role in making available calcium carbonate and nutrients to the rest of the community. However, due to their commercial value, they face overexploitation in the natural environment. On top of that, occurring ocean acidification could impact these organisms, considered sensitive as echinoderms are osmoconformers, high-magnesium calcite producers and have a low metabolism. As a first investigation of the impact of ocean acidification on sea cucumbers, we tested the impact of short-term (6 to 12 days) exposure to ocean acidification (seawater pH 7.7 and 7.4) on two sea cucumbers collected in SW Madagascar, Holothuria scabra, a high commercial value species living in the seagrass meadows, and H. parva, inhabiting the mangroves. The former lives in a habitat with moderate fluctuations of seawater chemistry (driven by day-night differences) while the second lives in a highly variable intertidal environment. In both species, pH of the coelomic fluid was significantly negatively affected by reduced seawater pH, with a pronounced extracellular acidosis in individuals maintained at pH 7.7 and 7.4. This acidosis was due to an increased dissolved inorganic carbon content and pCO2 of the coelomic fluid, indicating a limited diffusion of the CO2 towards the external medium. However, respiration and ammonium excretion rates were not affected. No evidence of accumulation of bicarbonate was observed to buffer the coelomic fluid pH. If this acidosis stays uncompensated for when facing long-term exposure, other processes could be affected in both species, eventually leading to impacts on their ecological role. PMID- 25028325 TI - Response of duckweed to various concentrations of selenite. AB - The uptake of Se(IV) and its effects on the physiological and biochemical characteristics of duckweed (Lemna minor L.) have been studied. Duckweed plants were cultivated in controlled conditions for 7 weeks in different concentrations of Na selenite: 0.5, 1, 2, 5 (exposed 42 days) and 10 mg Se L(-1) (survived 7-21 days). The addition of 1 mg Se L(-1) did not negatively affect photochemical efficiency whilst respiratory potential increased in weeks 2-4 compared to control. The addition of 1 mg Se(IV) L(-1) increased the amount of chlorophyll a in weeks 3 and 4 and the amount of carotenoids in weeks 1, 3 and 5. Concentrations of 2 and 5 mg Se L(-1) negatively affected photochemical efficiency in weeks 3 and 4, and increased respiratory potential in comparison to the control in weeks 1-4, whilst beyond week 4, the respiratory potential decreased. Plants exposed to the highest concentration of Se(IV) had to be replaced twice during the experiment because they were dying. That was reflected in photochemical efficiency as well as in respiratory potential, which decreased in time. The content of Se in duckweed increased with the increasing concentration of Se: plants growing in 0.5 mg Se L(-1) contained 0.9 mg Se g(-1) DM and plants exposed to 5 mg Se L(-1) contained 5.8 mg Se g(-1) DM. The group of plants exposed to 10 mg Se L(-1) for 21 days contained 19.5 mg Se g(-1) DM. Our study revealed that duckweed absorbed high amount of Se(IV) from the water. PMID- 25028326 TI - Effect of Zn toxicity on root morphology, ultrastructure, and the ability to accumulate Zn in Moso bamboo (Phyllostachys pubescens). AB - The effects of zinc (Zn) on seed germination and growth of Moso bamboo (Phyllostachys pubescens) were investigated. Under zinc stress, the seed germination rate did not show significant difference from that of the control. Hydroponics experiments indicated that Moso bamboo had a strong ability to accumulate Zn in the shoot and it reached its maximum value in the shoot at 100 MUM Zn. The root Zn concentration ranged from 2,329.29 to 8,642.51 mg kg(-1), with the root Zn concentration at 10 MUM Zn being 58.23 times that of the control. The root morphology parameters slightly increased at the lower Zn treatments, while growth restriction was evident at higher Zn treatments. Root ultrastructural studies revealed that the cell structure, root tips, and organelles were significantly changed under Zn stress as compared to those of the control. Some abnormalities were evident in the cell walls, vacuoles, mitochondria, plasmalemma, tonoplast, and xylem parenchyma of root cells. While Moso bamboo seems a suitable candidate for phytoremediation, its metal remediation ability should be further explored in future investigations. PMID- 25028327 TI - Influence of organic and inorganic flocculants on the formation of PCDD/Fs during sewage sludge incineration. AB - Flocculants are widely used to improve the properties of sludge dewatering in industrial wastewater treatment. However, there have been no studies conducted on the influence of flocculants on the formation of polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) during sewage sludge incineration. This paper selected three typical kinds of flocculants, including polyacrylamide (PAM), poly ferric chloride (PFC), and polyaluminum chloride (PAC) flocculant, to study their influences on the formation of PCDD/Fs during sewage sludge incineration. The results indicated that PAM flocculant, which is an organic flocculant, inhibited the formation of PCDD/Fs in sewage sludge incineration, while inorganic flocculant, such as PFC and PAC flocculant, promoted the formation. The most probable explanation is that the amino content in the PAM flocculant acted as an inhibitor in the formation of PCDD/Fs, while the chlorine content, especially the metal catalyst in the PFC and PAC flocculants, increased the formation rate. The addition of flocculants nearly did not change the distribution of PCDD/F homologues. The PCDFs contributed the most toxic equivalent (TEQ) value, especially 2, 3, 4, 7, 8-PeCDF. Therefore, the use of inorganic flocculants in industrial wastewater treatment should be further assessed and possibly needs to be strictly regulated if the sludge is incinerated. From this aspect, a priority to the use of organic flocculants should be given. PMID- 25028329 TI - Acoustic characteristics of different target vowels during the laryngeal telescopy. AB - OBJECTIVE: The aim of this study was to investigate the acoustic characteristics of target vowels phonated in normal voice persons while performing laryngeal telescopy. The acoustic characteristics are compared to show the extent of possible difference to speculate their impact on phonation function. METHODS: Thirty-four male subjects aged 20-39 years with normal voice were included in this study. The target vowels were /i/ and /E/. Recording of voice samples was done under natural phonation and during laryngeal telescopy. The acoustic analysis included the parameters of fundamental frequency, jitter, shimmer and noise-to-harmonic ratio. RESULTS: The sound of a target vowel /E/ was perceived identical in more than 90% of the subjects by the examiner and speech language pathologist during the telescopy. Both /i/ and /E/ sounds showed significant difference when compared with the results under natural phonation. There was no significant difference between /i/ and /E/ during the telescopy. CONCLUSION: The present study showed that change in target vowels during laryngeal telescopy makes no significant difference in the acoustic characteristics. The results may lead to the speculation that the phonation mechanism was not affected significantly by different vowels during the telescopy. This study may suggest that in the principle of comfortable phonation, introduction of the target vowels /i/ and /E/ is practical. PMID- 25028330 TI - Examination of the lumbar spine. AB - "Physiotherapy as a Positive Science" is the theme of this Congress. If different forms of physiotherapy for the lumbar spine are to be evaluated, examination must be more accurate than is normally accepted at present. Only by reference to a sound foundation based on accurate examination can the theme become reality. PMID- 25028328 TI - Triazole-induced toxicity in developing rare minnow (Gobiocypris rarus) embryos. AB - Using rare minnow (Gobiocypris rarus) at early-life stages as experimental models, the developmental toxicity of five widely used triazole fungicides (myclobutanil, fluconazole, flusilazole, triflumizole, and epoxiconazole) were investigated following exposure to 1-15 mg/L for 72 h. Meanwhile, morphological parameters (body length, body weight, and heart rate), enzyme activities (superoxide dismutase (SOD), glutathione S-transferase (GST), adenosine triphosphatase (ATPase), and acetyl cholinesterase (AChE)), and mRNA levels (hsp70, mstn, mt, apaf1, vezf1, and cyp1a) were also recorded following exposure to 0.2, 1.0, and 5.0 mg/L for 72 h. Results indicated that increased malformation and mortality, decreased body length, body weight, and heart rate provide a concentration-dependent pattern; values of 72 h LC50 (median lethal concentration) and EC50 (median effective concentration) ranged from 3 to 12 mg/L. Most importantly, the results of the present study suggest that even at the lowest concentration, 0.2 mg/L, five triazole fungicides also caused notable changes in enzyme activities and mRNA levels. Overall, the present study points out that those five triazole fungicides are highly toxic to the early development of G. rarus embryos. The information presented in this study will be helpful in better understanding the toxicity induced by triazole fungicides in fish embryos. PMID- 25028331 TI - Changing patterns in physiotherapy education in South australia. AB - In 1969 arrangements were completed for transfer of the Diploma in Physiotherapy (offered by The University of Adelaide since 1945) to the South Australian Institute of Technology. This transfer was the result of recommendations by the Martin Committee in its report on Tertiary Education in Australia. PMID- 25028332 TI - Outline of a technique for the treatment of soft tissue lesions of the shoulder involving the rotator cuff. AB - It is with diffidence that I present this paper, because I have no doubt that many of you work on the same principle, using different techniques. I began to study this problem years ago, after frequently observing patients being instructed, ordered or implored not to raise the shoulder while abducting the arm. I made the same request, until I became convinced that the patient was being asked to achieve a mechanical impossibility. By experiment I found what appeared to me to be the best way of controlling the head of the humerus during the movement. PMID- 25028334 TI - Surgeon who referred girlfriend to gynaecologist has suspension revoked. PMID- 25028335 TI - Experience with sandwich liner and its high rate of failure. AB - BACKGROUND: Composite ceramic with polyethylene backing was introduced to enhance the quality of ceramic articulation, but the liner's high rate of ceramic fracture has brought serious concern. In this study, the authors investigated the failure rate of sandwich liner in long-term follow-up patients at single institution. METHODS: In this series, we retrospectively reviewed 134 patients (143 hips), and six patients (6.2%) were found to have liner fracture. They were compared to nonfracture patients to identify the associating factors. General patient characteristics were obtained through review of charts. All patients were implanted with SPH Contact acetabular cup and sandwich liner. Function (Harris hip score) and activity (Devane score) were recorded preoperatively and at final follow-up. Radiologically, inclination and abduction angles were measured for comparison. RESULTS: The study did not show any statistical differences between fracture and nonfracture groups in age, weight or body mass index. Side, type of stem used and radiologic parameters were not also significantly different. The operation had significantly improved function and activity postoperatively in both groups, but no statistical significance was noted between the two groups exception to preoperative Harris hip score. On inspection, retrieved ceramic heads and liners showed substantial metal transfer on their surfaces, and linear wears were evident on the ceramic heads. CONCLUSIONS: Compared to other studies, our series also experienced high rate of sandwich liner fracture. Though its use was generally discontinued, it is worrisome to note that failure rate of the liner will substantially increase over time. PMID- 25028337 TI - Steadily improving survival in lung cancer. AB - BACKGROUND: National data demonstrate minimal improvement in survival for patients diagnosed with lung cancer despite a number of apparent advances during the past 3 decades. We wished to know how demographic characteristics, staging, therapy, and survival have changed over time for patients with lung cancer who were accessioned to the cancer registry of a large community hospital in southern California. PATIENTS AND METHODS: Clinical features and survival data were collected on patients diagnosed during each of the successive 6-year eras of 1986 to 1991 (n = 812), 1992 to 1997 (n = 1072), 1998 to 2003 (n = 1209), and 2004 to 2009 (n = 1365). RESULTS: Median survival improved from 11 to 13 to 16 to 26 months and overall 5-year survival steadily improved from 16.5% to 19.1% to 24.0% to 31.1%. The proportion of patients with localized disease at diagnosis increased from 18.4% to 24.1% to 24.9% to 31.6%. Improvements in relative survival were much greater than have occurred nationally. Other obvious trends over time were increasing age of patients, increasing proportions with diagnoses of adenocarcinoma with concomitant decreases in squamous cell and small cell histologies, and decreases in the proportion of large cell carcinoma with reciprocal increases in neuroendocrine diagnoses. The use of chemotherapy for patients with local disease tripled in the most recent era. CONCLUSION: Survival has steadily improved for patients in this community who were diagnosed with lung cancer. The explanations for this improvement are multifactorial, but include earlier stage at diagnosis, decreases in histologic types associated with active smoking, and increased use of systemic therapies. PMID- 25028336 TI - Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer. AB - Prostate cancer is the most commonly diagnosed cancer disease in men in the Unites States and its management remains a challenge in everyday oncology practice. Thus, advanced therapeutic strategies are required to treat prostate cancer patients. Curcumin (CUR) is a promising anticancer agent for various cancer types. The objective of this study was to evaluate therapeutic potential of novel poly(lactic-co-glycolic acid)- CUR nanoparticles (PLGA-CUR NPs) for prostate cancer treatment. Our results indicate that PLGA-CUR NPs efficiently internalize in prostate cancer cells and release biologically active CUR in cytosolic compartment of cells for effective therapeutic activity. Cell proliferation (MTS), clonogenic, and Western blot analyses reveal that PLGA-CUR NPs can effectively inhibit proliferation and colony formation ability of prostate cancer cells than free CUR. PLGA-CUR NPs showed superior tumor regression compared to CUR in xenograft mice. Further investigations reveal that PLGA-CUR NPs inhibit nuclear beta-catenin and AR expression in cells and in tumor xenograft tissues. It also suppresses STAT3 and AKT phosphorylation and leads to apoptosis via inhibition of key anti-apoptotic proteins, Mcl-1, Bcl-xL and caused induction of PARP cleavage. Additionally, significant downregulation of oncogenic miR21 and up-regulation of miR-205 was observed with PLGA-CUR NPs treatment as determined by RT-PCR and in situ hybridization analyses. A superior anti-cancer potential was attained with PSMA antibody conjugated PLGA-CUR NPs in prostate cancer cells and a significant tumor targeting of (131)I labeled PSMA antibody was achieved with PLGA-CUR NPs in prostate cancer xenograft mice model. In conclusion, PLGA-CUR NPs can significantly accumulate and exhibit superior anticancer activity in prostate cancer. PMID- 25028338 TI - Neurocognitive function after (chemo)-radiotherapy for head and neck cancer. AB - Radical radiotherapy has a pivotal role in the treatment of head and neck cancer (HNC) and cures a significant proportion of patients while simultaneously sparing critical normal organs. Some patients treated with radical radiotherapy for HNC receive significant radiation doses to large volumes of brain tissue. In fact, intensity-modulated radiotherapy techniques for HNC have been associated with a net increase in irradiated brain volumes. The increasing use of chemoradiotherapy for HNC has additionally exposed this patient population to potential neurotoxicity due to cytotoxic drugs. Patients with HNC may be particularly at risk for adverse late brain effects after (chemo)-radiotherapy, such as impaired neurocognitive function (NCF), as risk factors for the development of HNC, such as smoking, excess alcohol consumption and poor diet, are also associated with impaired NCF. The relatively good survival rates with modern treatment for HNC, and exposure to multiple potentially neurotoxic factors, means that it is important to understand the impact of (chemo)-radiotherapy for HNC on NCF, and to consider what measures can be taken to minimise treatment-related neurotoxicity. Here, we review evidence relating to the late neurotoxicity of radical (chemo) radiotherapy for HNC, with a focus on studies of NCF in this patient population. PMID- 25028339 TI - Nicotine dependence, "background" and cue-induced craving and smoking in the laboratory. AB - BACKGROUND: Nicotine dependence has been associated with higher "background" craving and smoking, independent of situational cues. Due in part to conceptual and methodological differences across past studies, the relationship between dependence and cue-reactivity (CR; e.g., cue-induced craving and smoking) remains unclear. METHODS: 207 daily smokers completed six pictorial CR sessions (smoking, negative affect, positive affect, alcohol, smoking prohibitions, and neutral). Individuals rated craving before (background craving) and after cues, and could smoke following cue exposure. Session videos were coded to assess smoking. Participants completed four nicotine dependence measures. Regression models assessed the relationship of dependence to cue-independent (i.e., pre-cue) and cue-specific (i.e., pre-post cue change for each cue, relative to neutral) craving and smoking (likelihood of smoking, latency to smoke, puff count). RESULTS: Dependence was associated with background craving and smoking, but did not predict change in craving across the entire sample for any cue. Among alcohol drinkers, dependence was associated with greater increases in craving following the alcohol cue. Only one dependence measure (Wisconsin Inventory of Smoking Dependence Motives) was consistently associated with smoking reactivity (higher likelihood of smoking, shorter latency to smoke, greater puff count) in response to cues. CONCLUSION: While related to cue-independent background craving and smoking, dependence is not strongly associated with laboratory cue-induced craving under conditions of minimal deprivation. Dependence measures that incorporate situational influences on smoking correlate with greater cue-provoked smoking. This may suggest independent roles for CR and traditional dependence as determinants of smoking, and highlights the importance of assessing behavioral CR outcomes. PMID- 25028341 TI - The tyrosine hydroxylase 2 (TH2) system in zebrafish brain and stress activation of hypothalamic cells. AB - Two tyrosine hydroxylases (TH1 and TH2) are found in teleost fish, but no antibodies are available for TH2 protein to analyze the detailed structure of the system. We generated antibodies targeting TH2 and used them to characterize the TH2-producing cells in larval and adult zebrafish brain. The rabbit antisera reliably detected two bands corresponding to TH1 and TH2 close to 55 kDa in brain homogenates. The antisera detected neurons in brain nuclei which express th1 and th2 mRNA; knockdown of th2 expression by morpholino oligonucleotide injection abolished both the th2 mRNA signal and immunoreactivity with the rabbit antisera in TH2 cells. Double staining of samples with the rabbit antiserum made against TH2 and a monoclonal antibody which detects only TH1 allowed identification of cell groups expressing either one of the proteins. Cell groups in preoptic area, anterior, intermediate, and posterior part of the paraventricular organ contained neurons stained with the new TH2 antisera but not with the characterized monoclonal TH1 antibody. Neurons immunoreactive for TH2 and 5-HT were distinct. In situ hybridization for the mRNA of the immediate early gene c-fos combined with TH1/TH2 immunohistochemistry was used to characterize the cells of the zebrafish brain reacting to handling stress and a noxious chemical stimulus. Strong upregulation of c-fos expression was detected in hypothalamic nuclei containing TH2 cells, but few of the c-fos-expressing cells were positive for TH2, suggesting that these stressors do not directly activate a large proportion of TH2 cells. PMID- 25028340 TI - Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin. AB - Metazoan parasites typically induce a type 2 immune response, characterized by T helper 2 (Th2) cells that produce the cytokines IL-4, IL-5 and IL-13 among others. The type 2 response is host protective, reducing the number of parasites either through direct killing in the tissues, or expulsion from the intestine. Type 2 immunity also protects the host against damage mediated by these large extracellular parasites as they migrate through the body. At the center of both the innate and adaptive type 2 immune response, is the IL-4Ralpha that mediates many of the key effector functions. Here we highlight the striking overlap between the molecules, cells and pathways that mediate both parasite control and tissue repair. We have proposed that adaptive Th2 immunity evolved out of our innate repair pathways to mediate both accelerated repair and parasite control in the face of continual assault from multicellular pathogens. Type 2 cytokines are involved in many aspects of mammalian physiology independent of helminth infection. Therefore understanding the evolutionary relationship between helminth killing and tissue repair should provide new insight into immune mechanisms of tissue protection in the face of physical injury. PMID- 25028342 TI - Slow to fast muscle transformation following heterochronous isotransplantation is influenced by host thyroid hormone status. AB - We studied the effect of regeneration, altered innervation and thyroid hormone (TH) levels on fiber type transitions in slow soleus (SOL) muscles grafted (GRAFT) into host extensor digitorum longus (EDLh) muscles of euthyroid (EU), hyperthyroid (HT) and hypothyroid (HY) Lewis strain rats. SOL muscles were excised from 3-week to 4-week-old inbred Lewis rats and intramuscularly transplanted into EDLh muscles of 2-month-old female rats of the same strain. The proportions of type 1, 2A, 2X and 2B fibers of GRAFT were determined by immunohistochemistry and compared with those of EDLh muscle and EDL and SOL muscles of the unoperated contralateral hind limb. After an average regeneration period of 6-7 months and after being reinnervated by the "fast" peroneal nerve of EDLh muscle, GRAFT was transformed into a fast muscle. However, the extent of GRAFT transformation varied with different TH states. In the EU rats, GRAFT contained about 95 % of fast fibers, among which type 2X and 2B fibers predominated (about 75 %). The transition toward fast muscle phenotype was more pronounced in HT status, where the fastest type 2B fibers predominated. On the contrary, in HY status, the slow to fast transformation was less pronounced, as GRAFT contained less type 2B and 2X but more type 2A and 1 fibers. We conclude that the type of innervation is the crucial factor for the slow to fast fiber type transitions in GRAFT, but the extent of muscle transformation is further modulated by altered TH status. PMID- 25028343 TI - Proliferating pancreatic beta-cells upregulate ALDH. AB - High levels of aldehyde dehydrogenase (ALDH) activity have been regarded as a specific feature of progenitor cells and stem cells. Hence, as an indicator of ALDH activity, aldefluor fluorescence has been widely used for the identification and isolation of stem and progenitor cells. ALDH activity was recently detected in embryonic mouse pancreas, and specifically and exclusively in adult centroacinar and terminal duct cells, suggesting that these duct cells may harbor cells of endocrine and exocrine differentiation potential in the adult pancreas. Here, we report the presence of aldefluor+ beta-cells in a beta-cell proliferation model, partial pancreatectomy. The aldefluor+ beta-cells are essentially all positive for Ki-67 and expressed high levels of cell-cycle activators such as CyclinD1, CyclinD2, and CDK4, suggesting that they are mitotic cells. Our data thus reveal a potential change in ALDH activity of proliferating beta-cells, which provides a novel method for the isolation and analysis of proliferating beta-cells. Moreover, our data also suggest that aldefluor lineage tracing is not a proper method for analyzing progenitor or stem activity in the adult pancreas. PMID- 25028345 TI - Leukocyte telomere length and late-life depression. AB - OBJECTIVE: Depressive disorders have been associated with increased risk for aging-related diseases, possibly as a consequence of accelerated cellular aging. Cellular aging, indexed by telomere length (TL) shortening, has been linked to depression in adults younger than 60 years; however, it remains unclear whether this is the case in late-life depression (age >60 years). The objective of this study was to assess differences in TL between persons with current late-life depression and never-depressed comparisons and to examine the association between characteristics of late-life depression and TL. METHODS: In this cross-sectional study using the Netherlands Study of Depression in Older Persons, 355 persons with current late-life depression and 128 never-depressed comparisons, aged 60-93 years (mean age [SD]: 70.5 [7.4] years, 65% women), were recruited through primary care and mental healthcare. Late-life depression was established using a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based structured psychiatric interview. Leukocyte TL, expressed in base pairs (bp), was determined in fasting blood samples by performing quantitative polymerase chain reaction. RESULTS: Mean TL did not differ between depressed persons (bp [SD]: 5,035 [431]) and never-depressed (bp [SD]: 5,057 [729]) comparisons. Further, TL was not associated with severity, duration, and age at onset of depression; comorbid anxiety disorders; anxiety symptoms; apathy severity; antidepressant use; benzodiazepine use; cognitive functioning; and childhood trauma. CONCLUSION: Late-life depression was not associated with increased cellular aging. This absent association, which contradicts observations in younger adults, may be due to the potential larger heterogenic nature of late-life depression and lifetime cumulative exposure to other TL-damaging factors, possibly overruling effects of late-life depression. PMID- 25028346 TI - Health campaigning group calls for action on corruption in India. PMID- 25028344 TI - Models of care for late-life depression of the medically ill: examples from chronic obstructive pulmonary disease and stroke. AB - Depression worsens most treatment outcomes in medically ill older adults. Chronic medical illnesses weaken and demoralize patients and compromise their ability to adhere to treatments requiring consistency and effort. Acute medical illnesses create a psychosocial storm that finds patients and their ecosystem unprepared. We describe two intervention models that can be used to target and personalize treatment in depressed, chronically, or acutely medically ill older adults. The Personalized Adherence Intervention for Depression and COPD (PID-C) is a model intervention for depressed patients with chronic medical illnesses. It targets patient-specific barriers to treatment engagement and aims to shift the balance in favor of treatment participation. PID-C led to higher remission rates of depression, reduction in depressive symptoms, and reduction in dyspnea-related disability. The addition of problem-solving training enables patients to use resources available to them and hopefully improve their outcomes. Ecosystem focused therapy (EFT) is a model intervention for depression developing in the context of an acute medical event. It was developed for patients with poststroke depression (PSD) and targets five areas, part of the "psychosocial storm" originating from the patient's sudden disability and the resulting change in the patient's needs and family's life. A preliminary study suggests that EFT is feasible and efficacious in reducing depressive symptoms and signs and disability in PSD. PMID- 25028347 TI - Does more education lead to better health habits? Evidence from the school reforms in Australia. AB - The current study provides new empirical evidence on the causal effect of education on health-related behaviors by exploiting historical changes in the compulsory schooling laws in Australia. Since World War II, Australian states increased the minimum school leaving age from 14 to 15 in different years. Using differences in the laws regarding minimum school leaving age across different cohorts and across different states as a source of exogenous variation in education, we show that more education improves people's diets and their tendency to engage in more regular exercise and drinking moderately, but not necessarily their tendency to avoid smoking and to engage in more preventive health checks. The improvements in health behaviors are also reflected in the estimated positive effect of education on some health outcomes. Our results are robust to alternative measures of education and different estimation methods. PMID- 25028348 TI - Heart failure risk: effects of red meat, processed red meat, (and enhanced red meat?). PMID- 25028349 TI - GLP-1 agonist therapy for advanced heart failure with reduced ejection fraction: design and rationale for the functional impact of GLP-1 for heart failure treatment study. PMID- 25028351 TI - Management of a patient with eosinophilic myocarditis and normal peripheral eosinophil count: case report and literature review. PMID- 25028352 TI - Letter by Dalzell regarding article, "outcomes of patients with peripartum cardiomyopathy who received mechanical circulatory support: data from the interagency registry for mechanically assisted circulatory support". PMID- 25028350 TI - Molecular and cellular basis of viable dysfunctional myocardium. PMID- 25028353 TI - Vitamin D and macular thickness in the elderly: an optical coherence tomography study. AB - PURPOSE: Vitamin D insufficiency is associated with age-related macular degeneration. Our objective was to determine whether low serum 25-hydroxyvitamin D (25OHD) concentration was associated with macular thickness among older adults with no signs of macular dysfunction. METHODS: Sixty-two French older community dwellers with no patent macular dysfunction (mean +/- SD, 71.2 +/- 5.0 years; 45.2% female) included in the Gait and Alzheimer Interaction Tracking (GAIT) study (ClinicalTrials.gov number, NCT01315717) were separated into two groups according to serum 25OHD level (i.e., insufficient < 50 nmol/L or sufficient >= 50 nmol/L). The macular thickness was measured on 1000 MUm central macula with optical coherence tomography, and further binarized according to normal values of macular thickness (i.e., 267.74 MUm for males, and 255.60 MUm for females). Age, sex, number of comorbidities, cognitive disorders, body mass index, mean arterial pressure, visual acuity, intraocular pressure, serum calcium concentration and season of testing were considered as potential confounders. RESULTS: The mean serum 25OHD concentration was 61.2 +/- 26.3 nmol/L. Patients with vitamin D insufficiency had a reduced macular thickness compared to those without (232.9 +/ 40.4 MUm vs. 253.3 +/- 32.1 MUm, P = 0.042). After adjustment for potential confounders, vitamin D insufficiency was associated with a decreased macular thickness (beta = -59.4 MUm, P = 0.001). Consistently, the participants with vitamin D insufficiency had a 3.7-fold higher risk of having abnormally low macular thickness compared with those with sufficient 25OHD level (P = 0.042). CONCLUSIONS: Vitamin D insufficiency was associated with reduced macular thickness among older patients with no patent macular dysfunction. This implies that vitamin D insufficiency may be involved in macular thinning, and provides a scientific base for vitamin D replacement trials in age-related macular degeneration. PMID- 25028354 TI - Dynamic responses in retinal vessel caliber with flicker light stimulation in eyes with diabetic retinopathy. AB - PURPOSE: This study investigated the responses of retinal vessels to flickering light in diabetic patients with various stages of diabetic retinopathy (DR). METHODS: This cross-sectional observational study evaluated adult subjects with diabetes mellitus. The Dynamic Vessel Analyzer (DVA) was used to measure retinal vascular dilatation in response to diffuse illuminance flicker. Diabetic retinopathy was graded from retinal photography. RESULTS: There were 279 subjects in total, with a mean age of 59.9 +/- 9.2 years. The majority were male (73%) and the mean HbA1c level and mean duration of diabetes were 7.7% +/- 1.4% and 13.9 +/ 10.4 years, respectively. After adjustments for age, sex, smoking, duration of diabetes, HbA1c, hypertension, and hyperlipidemia, the responses of both retinal arterioles and venules to flicker stimulation decreased continuously with increasing stages of diabetic retinopathy (P = 0.008 and <0.001, respectively). Subjects with reduced arteriolar dilation responses were more likely to have any DR (odds ratio, OR, 1.20, [95% confidence interval (CI), 1.01-1.45], P = 0.045, per SD decrease). Subjects with reduced venular dilation responses were more likely to have any DR, moderate DR, or vision-threatening DR (OR: 1.27 [1.04 1.53], P = 0.02; OR: 1.27 (1.06-1.49), P = 0.007; and OR: 1.51 (1.14-1.50), P = 0.002; per SD decrease, respectively). CONCLUSIONS: The responses of retinal arterioles and venules to flickering light are reduced in subjects with DR, and decrease progressively with more severe stages of DR. PMID- 25028355 TI - Intermediate filaments in the human extraocular muscles. AB - PURPOSE: To investigate the distribution of the intermediate filament (IF) proteins desmin, vimentin, and nestin in human extraocular muscles (EOMs). METHODS: Healthy adult EOM samples were serially sectioned (5 and 1 MUm) and processed for immunohistochemistry, with specific antibodies (Abs) against desmin, vimentin, and nestin and different myosin heavy chains (MyHCs), including the newly characterized Ab MYH7b against MyHC slow tonic. The distribution of desmin was also studied in EOMs at 16 to 18 weeks of gestation. RESULTS: Desmin was present in the vast majority of muscle fibers. Notably, muscle fibers that contained MyHC slow tonic were either unlabeled or very weakly labeled with three different Abs against desmin. These muscle fibers had normal cytoarchitecture and intact basement membrane. In fetal muscle, desmin was also absent or weak in myotubes containing MyHC slow tonic. Nestin was detected in a large proportion of muscle fibers in the orbital layer and to some extent also in the global layer, whereas no muscle fibers contained vimentin. Desmin and nestin were enriched at neuromuscular junctions, as in limb muscle. In contrast, some myotendinous junctions lacked desmin or nestin. CONCLUSIONS: The human EOMs differed significantly from the other muscles in the body with respect to their IF composition. Desmin, hitherto regarded as a ubiquitous muscle cytoskeletal protein, was absent or only present in trace amounts in a subset of normal muscle fibers in adult and fetal EOMs. Nestin, normally downregulated early in the postnatal period, was present in a high proportion of adult muscle fibers. PMID- 25028356 TI - Higher order ocular aberrations and their relation to refractive error and ocular biometry in children. AB - PURPOSE: The interaction between higher order ocular aberrations (HOA) and refractive error is not yet fully understood. This study investigated HOA in relation to refractive error and ocular biometric parameters in a population with a high prevalence of ametropia. METHODS: The HOA were investigated in two cohorts of Caucasian children aged 9 to 10 and 15 to 16 years (n = 313). These aberrations were measured for a 5-mm pupil with the IRX3 aberrometer. Cycloplegic refractive error and ocular biometry measures, including axial length and corneal curvature, also were assessed with the Shin-Nippon SRW-5000 auto-refractor and Zeiss IOLMaster, respectively. Participants were divided into refractive groups for analysis of HOA. RESULTS: The magnitude of total HOA was higher in this population at 0.27 MUm (interquartile range [IQR], 0.22-0.32 MUm) than other HOA reported in the literature. The profile of HOA was not significantly different across the two age cohorts or across refractive groups, nor did spherical aberration differ significantly with age (Z40 = 0.07 MUm for both cohorts). Multivariate linear regression analysis demonstrated spherical aberration was significantly related to axial length (but not refractive grouping), with longer eyes having less positive values of fourth order and root mean square (RMS) spherical aberration. CONCLUSIONS: This study found no significant difference in HOA across refractive groups. The current study also highlights the importance of knowledge of axial length when analyzing HOA. PMID- 25028357 TI - The effect of photocoagulation in ischemic areas to prevent recurrence of diabetic macular edema after intravitreal bevacizumab injection. AB - PURPOSE: This study aimed to investigate whether targeted retinal photocoagulation (TRP) for nonperfused areas (NPAs) could have a preventive effect on the recurrence of diabetic macular edema (DME) after intravitreal injection of bevacizumab (IVB). METHODS: Eyes in the IVB group received 1.25 mg IVB, and eyes in the IVB+TRP group received 1.25 mg IVB combined with TRP of NPAs. Two weeks before IVB administration, grid/focal photocoagulation (PC) had been performed in both groups. After IVB treatment, the best corrected visual acuity (BCVA) and central retinal thickness (CRT), determined by optical coherence tomography, were measured every month for 6 months. RESULTS: Fifty-two patients with DME were enrolled and randomized to an IVB group (n = 26) and an IVB+TRP group (n = 26). After IVB, the CRT decreased temporally, and the CRT significantly increased at 2 months and thereafter in the IVB group but did not increase significantly in the IVB+TRP group. Maximum increase in CRT after IVB was significantly correlated with the width of NPAs in the IVB group (P = 0.0368), but not in the IVB+TRP group. Best corrected visual acuity in the IVB+TRP group was significantly better than that in the IVB group 5 and 6 months after treatment (P < 0.05). CONCLUSIONS: Targeted retinal photocoagulation for NPAs was effective to maintain the reduced CRT after grid/focal PC and IVB for patients with DME. These results suggest that retinal ischemia is associated with the pathogenesis of recurrence of DME after IVB. ( www.umin.ac.jp/ctr number, UMIN000007566.). PMID- 25028358 TI - Corneal wound healing, a newly identified function of CAP37, is mediated by protein kinase C delta (PKCdelta). AB - PURPOSE: The neutrophil-derived granular protein, CAP37, an innate immune system molecule, has antibiotic and immunomodulatory effects on host cells, including corneal epithelial cells. We previously showed that CAP37 modulates corneal epithelial cell migration, adhesion, and proliferation, and that protein kinase C delta (PKCdelta) mediates CAP37-induced chemotaxis of these cells. The objective of this study was to investigate the hypothesis that CAP37 facilitates corneal wound healing through the PKC signaling pathway. METHODS: The standard "scratch" assay performed on monolayers of corneal epithelial cells was used to measure the in vitro effect of CAP37 on wound closure. In vivo wound healing in response to CAP37 was measured using a mouse corneal epithelium abrasion model. In vitro and in vivo wound closure were monitored over 48 hours. The PKCdelta was visualized during wound closure in cell monolayers and corneal epithelium by immunohistochemistry. The importance of PKCdelta in CAP37-induced corneal wound healing was assessed by siRNA. RESULTS: We found that CAP37 accelerated wound closure in vitro and in vivo. Maximal closure occurred with concentrations of CAP37 between 250 and 500 ng/mL. Topical applications on mouse cornea led to re epithelialization of the cornea by 24 hours. Immunohistochemistry of in vitro and in vivo wounds revealed a local increase of PKCdelta along the wound edge in CAP37-treated cell monolayers and corneas, compared to untreated controls. CAP37 induced corneal wound healing was significantly reduced in vivo upon treatment with PKCdelta siRNA. CONCLUSIONS: These findings support the hypothesis that CAP37 facilitates corneal wound healing through the activation of PKCdelta. PMID- 25028359 TI - Development and evaluation of porcine atelocollagen vitrigel membrane with a spherical curve and transplantable artificial corneal endothelial grafts. AB - PURPOSE: To develop a collagen vitrigel (CV) optimized as a corneal endothelial cell (CEC) carrier and create an artificial corneal endothelial graft. METHODS: We first developed a flat-shaped collagen vitrigel for regenerative medicine (CV RM) using porcine atelocollagen and ultraviolet (UV) irradiation. The optimal UV amount was determined by measuring the CV-RM transparency under various irradiating conditions. The collagen vitrigel for corneal endothelial regenerative treatment (CV-CERT), a transparent porcine atelocollagen with a curved shape, was made using spherically curved molds and UV irradiation. The membrane permeability of the CV-CERT was tested in vitro. The biocompatibility, transparency, and adhesiveness of the CV-CERT were evaluated in rabbit eyes. We also developed a culture technique for distributing human CECs on the curved CV CERT. RESULTS: The optimal amount of UV irradiation for CV-RM transparency was 2400 mJ/cm(2). Membrane permeability of CV-CERT at day 5 was higher than that of commercially available CV (P = 0.032). The CV-CERT was transparent and biocompatible in rabbit corneas for up to 4 months. The CV-CERT remained attached to the rabbit corneal posterior surface, whereas the flat-shaped CV-RM, differing only in shape from the CV-CERT, dislocated soon after surgery. Human CECs seeded on the CV-CERT using our technique were evenly distributed with a single layer structure and a mean cell density of 2650 +/- 100 cells/mm(2). CONCLUSIONS: We developed a transparent and biocompatible porcine-derived atelocollagen vitrigel membrane with a spherical curvature. A transplantable artificial endothelial graft was created by combining cultured human CECs and the CV-CERT. PMID- 25028361 TI - Serine Proteinase Inhibitor SERPINA3K Suppresses Corneal Neovascularization via Inhibiting Wnt Signaling and VEGF. AB - Purpose: To evaluate the anti-neovascularization effects and investigate the possible mechanisms of SERPINA3K, a member of serine proteinase inhibitor family, using a specific rat model of suture-induced corneal neovascularization. Methods: A rat corneal suture model was set up and SERPINA3K was topically administered three times daily for 7 days. The clinical indications were evaluated on day 2, 5 and 7, including area of neovascularization and inflammation index. The eyeballs were collected after day 7 and the following examinations were performed: histological investigation, immunostaining, western blot and quantitative real time polymerase chain reaction (PCR) assay. Wnt3a, a Wnt pathway ligand, was added to cultured Human Umbilical Vein Endothelial Cells (HUVEC), followed by detecting cell migration and western blot. Meanwhile, an in vitro VEGF165 stimulated HUVEC model was applied and the following measurements were conducted: cell proliferation, cell migration and tube formation. Results: SERPINA3K significantly suppressed corneal neovascularization and inhibited corneal inflammation. SERPINA3K downregulated the levels of beta-catenin, non-pi-beta catenin and transcription factor 4 (TCF4), but upregulated the level of pi-beta catenin of the corneas induced by suture. SERPINA3K also decreased the gene expression and protein level of VEGF. Meanwhile, induction of Wnt3a increased the cell migration, activated the Wnt signaling and upregulated VEGF in cultured HUVEC, which were antagonized by SERPINA3K. In addition, SERPINA3K significantly inhibited VEGF165-induced cell proliferation and migration of HUVEC, SERPINA3K also specifically suppressed the VEGF165-induced tube formation of HUVEC. Conclusions: SERPINA3K has therapeutic potential for corneal neovascularization. The underlying mechanism may be through inhibiting Wnt signaling pathway and VEGF. PMID- 25028360 TI - Ultrastructural changes associated with dexamethasone-induced ocular hypertension in mice. AB - PURPOSE: To determine whether dexamethasone (DEX)-induced ocular hypertension (OHT) in mice mimics the hallmarks of steroid-induced glaucoma (SIG) in humans, including reduced conventional outflow facility (C), increased extracellular matrix (ECM), and myofibroblasts within the outflow pathway. METHODS: Osmotic mini-pumps were implanted subcutaneously into C57BL/6J mice for systemic delivery of DEX (3-4 mg/kg/d, n = 31 mice) or vehicle (n = 28). IOP was measured weekly by rebound tonometry. After 3 to 4 weeks, mice were euthanized and eyes enucleated for ex vivo perfusion to measure C, for electron microscopy to examine the trabecular meshwork (TM) and Schlemm's canal (SC), or for immunohistochemistry to examine type IV collagen and alpha-smooth muscle actin. The length of basement membrane material (BMM) was measured along the anterior-posterior extent of SC by electron microscopy. Ultrastructural changes in BMM of DEX-treated mice were compared against archived human SIG specimens. RESULTS: Dexamethasone increased IOP by 2.6 +/- 1.6 mm Hg (mean +/- SD) over 3 to 4 weeks and decreased C by 52% +/- 17% versus controls. Intraocular pressure elevation correlated with decreased C. Dexamethasone treatment led to increased fibrillar material in the TM, plaque like sheath material surrounding elastic fibers, and myofibroblasts along SC outer wall. The length of BMM underlying SC was significantly increased in mice with DEX and in humans with SIG, and in mice decreased C correlated with increased BMM. CONCLUSIONS: Dexamethasone-induced OHT in mice mimics hallmarks of human SIG within 4 weeks of DEX treatment. The correlation between reduced C and newly formed ECM motivates further study using DEX-treated mice to investigate the pathogenesis of conventional outflow obstruction in glaucoma. PMID- 25028362 TI - Lack of paraoxonase 1 alters phospholipid composition, but not morphology and function of the mouse retina. AB - PURPOSE: Biochemical and genetic analyses established a contribution of lipid metabolism to AMD pathology. Paraoxonase 1 (PON1) is an antioxidative protein involved in high density lipoprotein (HDL) function and was found to be associated with AMD. Here, we used Pon1(-/-) mice to study the influence of PON1 on retinal physiology and to reveal the potential impact of PON1 on AMD etiology. METHODS: Laser capture microdissection served to isolate single retinal layers. Retinal function was assessed by ERG. Retinal and RPE morphology were monitored by fundus imaging, fluorescein angiography, light and transmission electron microscopy, and immunofluorescence microscopy. Levels of mRNA and composition of phospholipid species were determined by real-time PCR and LC-MS, respectively. RESULTS: Adult (8 weeks old) Pon1(-/-) mice displayed normal retinal function and morphology, but their retinas contained reduced amounts of lysophosphatidylcholines (LPCs) compared to controls. Aged (12 months old) Pon1( /-) animals did not show any morphologic or molecular signs of photoreceptor or RPE degeneration, or of accelerated aging. Photoreceptors of Pon1(-/-) and control mice were similarly susceptible to light damage. CONCLUSIONS: Results indicated that PON1 is not essential for normal development, function, ageing, and the defense against light damage of the mouse retina. Reduced levels of LPCs in eyes of Pon1(-/-) mice may reflect a decreased activity of phospholipase A2 or altered antioxidative activity in aged eyes. PMID- 25028363 TI - In vitro and in vivo evaluation of novel ciprofloxacin-releasing silicone hydrogel contact lenses. AB - PURPOSE: The purpose of this study was to evaluate ciprofloxacin-releasing silicone hydrogel contact lens materials in vitro and in vivo for the treatment of microbial keratitis. METHODS: Model silicone hydrogel contact lens materials were manufactured using a molecular imprinting technique to modify ciprofloxacin release kinetics. Various contact lens properties, including light transmission and surface wettability, were determined, and the in vitro ciprofloxacin release kinetics elucidated using fluorescence spectrophotometry. The materials then were evaluated for their ability to inhibit Pseudomonas aeruginosa growth in vitro and in an in vivo rabbit model of microbial keratitis. RESULTS: Synthesized lenses had similar material properties to commercial contact lens materials. There was a decrease in light transmission in the shorter wavelengths due to incorporation of the antibiotic, but over 80% light transmission between 400 and 700 nm. Modified materials released for more than 8 hours, significantly longer than unmodified controls (P < 0.05). In vivo, there was no statistically significant difference between the number of colony-forming units (CFU) recovered from corneas treated with eye drops and those treated with one of two modified contact lenses (P > 0.05), which is significantly less than corneas treated with unmodified control lenses or those that received no treatment at all (P < 0.05). CONCLUSIONS: These novel contact lenses designed for the extended release of ciprofloxacin may be beneficial to supplement or augment future treatments of sight-threatening microbial keratitis. PMID- 25028364 TI - Stimulants and Cannabis Use Among a Marginalized Population in British Columbia, Canada: Role of Trauma and Incarceration. AB - High rates of substance use, especially cannabis and stimulant use, have been associated with homelessness, exposure to trauma, and involvement with the criminal justice system. This study explored differences in substance use (cannabis vs. stimulants) and associations with trauma and incarceration among a homeless population. Data were derived from the BC Health of the Homeless Study (BCHOHS), carried out in three cities in British Columbia, Canada. Measures included sociodemographic information, the Maudsley Addiction Profile (MAP), the Childhood Trauma Questionnaire (CTQ), and the Mini International Neuropsychiatric Interview (MINI) Plus. Stimulant users were more likely to be female (43%), using multiple substances (3.2), and engaging in survival sex (14%). Cannabis users had higher rates of lifetime psychotic disorders (32%). Among the incarcerated, cannabis users had been subjected to greater emotional neglect (p < .05) and one in two cannabis users had a history of lifetime depressive disorders (p < .05). Childhood physical abuse and Caucasian ethnicity were also associated with greater crack cocaine use. One explanation for the results is that a history of childhood abuse may lead to a developmental cascade of depressive symptoms and other psychopathology, increasing the chances of cannabis dependence and the development of psychosis. PMID- 25028366 TI - High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma. AB - Neuroblastoma is a pediatric cancer with significant genomic and biologic heterogeneity. p16 and ARF, two important tumor-suppressor genes on chromosome 9p21, are inactivated commonly in most cancers, but paradoxically overexpressed in neuroblastoma. Here, we report that exon gamma in p16 is also part of an undescribed long noncoding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single-exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue, but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16, and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced-stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease. PMID- 25028367 TI - USP9X downregulation renders breast cancer cells resistant to tamoxifen. AB - Tamoxifen is one of the most widely used endocrine agents for the treatment of estrogen receptor alpha (ERalpha)-positive breast cancer. Although effective in most patients, resistance to tamoxifen is a clinically significant problem and the mechanisms responsible remain elusive. To address this problem, we performed a large scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells to identify candidate resistance genes. In this manner, we found that loss of function in the deubiquitinase USP9X prevented proliferation arrest by tamoxifen, but not by the ER downregulator fulvestrant. RNAi-mediated attenuation of USP9X was sufficient to stabilize ERalpha on chromatin in the presence of tamoxifen, causing a global tamoxifen-driven activation of ERalpha-responsive genes. Using a gene signature defined by their differential expression after USP9X attenuation in the presence of tamoxifen, we were able to define patients with ERalpha-positive breast cancer experiencing a poor outcome after adjuvant treatment with tamoxifen. The signature was specific in its lack of correlation with survival in patients with breast cancer who did not receive endocrine therapy. Overall, our findings identify a gene signature as a candidate biomarker of response to tamoxifen in breast cancer. PMID- 25028368 TI - Is there subclinical synovitis in patients with palindromic rheumatism in the intercritical period? a clinical and ultrasonographic study according to anticitrullinated protein antibody status. AB - OBJECTIVE: To investigate the presence of subclinical synovitis by ultrasound (US) and the clinical phenotype in patients with palindromic rheumatism (PR) according to anticitrullinated protein antibody (ACPA) status. METHODS: Fifty four patients with PR were studied. Clinical, demographic, serological, and therapeutic characteristics were compared in ACPA-positive and ACPA-negative patients. US searching for synovial hypertrophy (SH) and power Doppler signal (PDUS) in 22 joints of the hands was performed in the intercritical period. The results were compared according to ACPA status and with a healthy control group (n = 30). In 10 patients, US was performed during the joint attack. RESULTS: Most patients were female (63%) with a mean disease duration of 11.6 +/- 10.7 years. Thirty-six patients (66.7%) were ACPA-positive. ACPA-positive patients had a shorter duration of attacks, a younger age, and less knee involvement at disease onset. US examination showed SH grade >= 1 in 79.6% of patients with PR and 50% of controls. Significant US results (SH >= 2 or PDUS) were observed in 2.7% and 1.4% of joints assessed and in 33% and 25.9% of patients with PR, respectively. Only 4 patients (7.4%) had US active synovitis (SH >= 2 plus PDUS) in at least 1 joint. US assessment showed no significant differences between ACPA-positive and ACPA-negative patients. PDUS was observed in 7 out of 10 patients during attacks. CONCLUSION: Some differences emerged in the clinical phenotype of PR according to ACPA status. Most patients with PR do not have US subclinical synovitis in the intercritical period, even those who are ACPA-positive. PMID- 25028369 TI - Comparison of lifts versus tape measure in determining leg length discrepancy. AB - OBJECTIVE: To evaluate the validity (accuracy) and reliability of 2 commonly used clinical methods, 1 indirect (lifts) and 1 direct (tape measure), for assessment of leg length discrepancy (LLD) in comparison to radiograph. METHODS: Twenty subjects suspected of having LLD participated in this study. Two clinical methods, 1 direct using a tape measure and 1 indirect using lifts, were standardized and carried out by 4 examiners. Difference in height of the femoral heads on standing pelvic radiograph was measured and served as the gold standard. RESULTS: The intraclass correlation coefficient assessing interobserver reliability was 0.737 for lifts and 0.477 for tape measure. The remainder of the analysis is based on the average of the measurements by the 4 examiners. Pearson correlation coefficients were 0.93 for the lifts and 0.75 for the tape measure method. Paired sample t tests showed difference in means of 2 mm (p = 0.051) for lifts and -5 mm (p = 0.007) for tape measure compared with radiograph. Sensitivity and specificity were 55% and 89% for lifts and 45% and 56% for tape measure, respectively, using > 5 mm as the definition for LLD. The wrong leg was identified as being shorter in 1 out of 20 subjects using lifts versus 7 out of 20 using tape measure. CONCLUSION: The indirect standing method of LLD measurement using lifts had superior validity, interobserver reliability, and specificity in comparison with radiograph over the direct supine method using tape measure. Both clinical methods underestimated LLD compared with radiograph. PMID- 25028370 TI - Longterm retention rate and risk factor for discontinuation due to insufficient efficacy and adverse events in Japanese patients with rheumatoid arthritis receiving etanercept therapy. AB - OBJECTIVE: Assessing retention rate and risk factor for drug discontinuation is important for drug evaluation. We examined a 3-year retention rate and the risk factor for discontinuation due to insufficient efficacy (IE) and adverse events (AE) in Japanese patients with rheumatoid arthritis (RA) who are receiving etanercept (ETN). METHODS: Data were collected from 588 patients treated with ETN as a first biologic from the Tsurumai Biologics Communication Registry. Baseline characteristics for the incidence of both IE and AE were analyzed using the Cox proportional-hazards regression model. Patients were divided into groups based on age and concomitant methotrexate (MTX). Drug retention rates were calculated using the Kaplan-Meier method and compared among groups using the log-rank test. RESULTS: ETN monotherapy without concomitant MTX [MTX(-)] was significantly related to a higher incidence of discontinuation due to IE [hazard ratio (HR) = 2.226, 95% CI 1.363-3.634]. Older age and MTX(-) were significantly related to a higher incidence of discontinuation due to AE [HR = 1.040, 1.746, 95% CI 1.020 1.060, 1.103-2.763, respectively]. The MTX(-)/>= 65 years group had the lowest retention rate (p < 0.001). The discontinuation rate due to IE was lower in the MTX(+)/< 65 years group compared to < 65 years/MTX(-), >= 65 years/MTX(-) group (p = 0.006, p < 0.001, respectively). The discontinuation rate due to AE was highest in the MTX(-)/>= 65 years group (p < 0.001). CONCLUSION: Our findings suggest that the risk of discontinuation due to IE was high in the patients who did not use concomitant MTX and that the risk of discontinuation due to AE was high in elderly patients who did not use concomitant MTX. PMID- 25028371 TI - The effect of different remission definitions on identification of predictors of both point and sustained remission in rheumatoid arthritis treated with anti-TNF therapy. AB - OBJECTIVE: Predictors of remission in rheumatoid arthritis (RA) have been defined in cross-sectional analyses using the 28-joint Disease Activity Score (DAS28), but not with newer composite disease activity measures or using the more clinically relevant state of sustained remission. We have evaluated predictors of remission using cross-sectional and longitudinal durations of disease state, and by applying additional definitions of remission [American College of Rheumatology/European League Against Rheumatism Boolean, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI)]. METHODS: Individuals in the Alberta Biologics Pharmacosurveillance Program were classified for the presence of remission (point and/or sustained > 1 yr) by each of the 4 definitions. Multivariate models were constructed including all available variables in the dataset and refined to optimize model fit and predictive ability to calculate OR for remission. RESULTS: Nonsmoking status independently predicted point remission by all definitions (OR range 1.20-2.71). Minority ethnicity decreased odds of remission by DAS28 (OR 0.13) and CDAI (OR 0.09) definitions. Male sex was associated with DAS28 remission (OR 2.85), whereas higher baseline physician global (OR 0.67) and erythrocyte sedimentation rate values (OR 0.98) decreased odds of DAS28 remission. Higher baseline patient global score (OR 0.77) and swollen joint counts (OR 0.93) were negative predictors for CDAI remission. Higher baseline Health Assessment Questionnaire (OR 0.62) reduced odds for remission by the SDAI definition, and educational attainment increased these odds (OR 2.13). Sustained remission was negatively predicted by baseline physician global for the DAS28 (OR 0.80), and higher tender joint count (OR 0.96) for the CDAI. CONCLUSION: We demonstrate the influence of duration of remission state and remission definition on defining independent predictors for remission in RA requiring anti-tumor necrosis factor therapy. These predictors offer improved applicability for modern rheumatology practice. PMID- 25028372 TI - Association of anticyclic citrullinated peptide antibodies and/or rheumatoid factor status and clinical presentation in early arthritis: results from the ESPOIR cohort. AB - OBJECTIVE: To compare the initial clinical, biological, and radiographic findings of early arthritis by positivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide antibodies (anti-CCP), and to validate a patient profile based on this serologic information. METHODS: The ESPOIR cohort comprises patients presenting synovitis of at least 2 joints for 6 weeks to 6 months. Patients underwent testing for IgM rheumatoid factor (IgM-RF) and anti-CCP2 antibodies and were divided into 4 groups: RF- and anti-CCP- (group 1), RF+ and anti-CCP- (group 2), RF- and anti-CCP+ (group 3), RF+ and anti-CCP+ (group 4). We compared the groups in terms of clinical, biological, and radiographic features (baseline scores and 6-month and 12-month progression). RESULTS: Of the 813 recruited patients, 406 (50%) were in group 1, 91 (11.2%) in group 2, 34 (4.1%) in group 3, and 281 (34.6%) in group 4. Mean baseline erythrocyte sedimentation rate and C-reactive protein were higher for anti-CCP+ groups (groups 3 and 4) than for other groups (p < 0.001), and van der Heijde-modified Sharp score for radiographs was higher for group 4 than for other groups (p < 0.001). Clinical presentation was not consistently associated with serologic profile. Radiographic progression at 1 year was higher for anti-CCP+ groups than other groups (p < 0.001). CONCLUSION: The phenotype of patients with early arthritis with or without anti-CCP and/or RF positivity did not correspond to a particular clinical presentation. However, baseline acute-phase reactants and short-term radiographic progression were high in patients with anti-CCP positivity, which may be associated with the inflammatory process and progressive disease in patients with early arthritis. PMID- 25028373 TI - Tumor necrosis factor-alpha promoter -308/238 polymorphism association with less severe disease in ankylosing spondylitis is unrelated to serum TNF-alpha and does not predict TNF inhibitor response. AB - OBJECTIVE: Despite the clinical efficacy of tumor necrosis factor inhibitors (TNFi), the manner in which TNF-alpha contributes to disease in patients with ankylosing spondylitis (AS) remains unresolved. We investigated the relationship between TNF-alpha gene promoter region polymorphism, serum TNF-alpha levels, and clinical phenotype. METHODS: We did a cross-sectional and longitudinal cohort study in TNFi-naive patients with AS (n = 335). Clinical data and biological samples were collected during a research visit with genotyping for TNF-alpha -238 A/G and -308 A/G performed by Taqman RT-PCR and TNF levels determined by sandwich ELISA. Longitudinal TNF levels were monitored in unselected patients (n = 61). RESULTS: TNF-alpha -308 GA/AA genotype was present in 14% and TNF-alpha -238 GA/AA genotype in 1% of patients. TNF-alpha -308 GA/AA genotype was associated with a reduced risk of uveitis and better spinal function, while TNF-alpha -238 GA/AA genotype was associated with later age of onset and lower erythrocyte sedimentation rate (ESR). Serum TNF-alpha level was lower in patients with AS (151 pg/ml) than in controls (263 pg/ml), because more patients with AS had undetectable serum TNF-alpha (66 vs 25%, p < 0.001). TNFi treatment did not influence serum TNF-alpha. There was no effect of TNF-alpha -308/-238 or HLA-B27 genotype on serum TNF-alpha or subsequent initiation of TNFi. CONCLUSION: TNF alpha -238 or -308 GA/AA genotypes in patients with AS are associated with signs of less severe disease. Serum TNF-alpha is, however, undetectable in two-thirds of patients with AS and is not influenced by TNF-alpha promoter genotype or TNFi therapy. These data suggest a more significant role for TNF-alpha at local sites of inflammation in AS than through systemic effects. PMID- 25028374 TI - Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus. AB - OBJECTIVE: To elucidate the potential role of follicular helper T cells (TFH) and interleukin 10 (IL-10)+ B cells in the development of systemic lupus erythematosus (SLE). METHODS: The numbers of peripheral blood CD27+, CD38+, CD86+, CD95+, IL-10+ B cells, and inducible T cell costimulator (ICOS)+, programmed death-1 (PD-1)+, IL-21+, CXCR5+CD4+ TFH-like cells were examined in 23 patients with new onset SLE and 20 healthy controls (HC). RESULTS: In comparison with HC, significantly reduced numbers of CD19+ and IL-10+ B cells, but increased numbers of CD27(high), CD86+, CD95+ B cells, CXCR5+CD4+, ICOS+, PD-1+, and IL-21+ TFH-like cells were detected, which were accompanied by higher levels of serum IL 21, but lower levels of IL-10 in the patients. Treatment with anti-SLE therapy modulated the imbalance of different subsets of B and TFH-like cells. The levels of serum IL-21 and IL-10 were positively correlated with the numbers of CD4+CXCR5+ TFH-like and CD19+CD5+CD1d+ B cells in the patients, respectively. The numbers of CD27(high) B cells were correlated positively with IL-21+ TFH-like cells, but negatively with IL-10+ B cells. The values of SLE Disease Activity Index, C3, and erythrocyte sedimentation rate were correlated positively with serum IL-21, but negatively with IL-10 in those patients. CONCLUSION: Our data indicate that the imbalance of IL-21+ TFH-like, CD27(high), and IL-10+ B cells may be associated with the pathogenesis of SLE, and levels of serum IL-21 and IL 10 may be valuable for evaluating disease activity in SLE. PMID- 25028375 TI - Consistently Good clinical response in patients with early axial spondyloarthritis after 3 years of continuous treatment with etanercept: longterm data of the ESTHER trial. AB - OBJECTIVE: In patients with early active axial spondyloarthritis (axSpA) with a disease duration of < 5 years, the longterm efficacy of 3 years of continuous etanercept (ETN) treatment was assessed. METHODS: In a previously reported ESTHER trial, patients with axSpA were randomized to treatment with ETN (n = 40) versus sulfasalazine (SSZ; n = 36) in the first year. We analyzed the clinical, laboratory, and magnetic resonance imaging (MRI) response in the pooled dataset of patients (study population; n = 61), including patients with ankylosing spondylitis (AS, n = 31) and nonradiographic axSpA (nr-axSpA, n = 30) who were continuously treated with ETN for 3 consecutive years. Data were analyzed using the last observation carried forward and completer analysis. RESULTS: In the entire group of patients in the study population (n = 61), the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.7 (+/- 1.3) at baseline to 2.6 (+/- 2.4) at Year 3. The Ankylosing Spondylitis Disease Activity Score (ASDAS) decreased from 3.4 (+/- 0.8) to 1.5 (+/- 1.0). Also, mean values for MRI spine and sacroiliac joint scores showed a significant decrease. Response rates in the nr-axSpA group were similar and at least as good compared to the AS group for all outcome measures. When comparing remission stages, we found that ASDAS inactive disease correlated better with C-reactive protein and MRI remission than with Assessment of SpondyloArthritis international Society partial remission. CONCLUSION: There was a consistent and sustained clinical response in patients with early axSpA treated with ETN over 3 years. ClinicalTrials.gov registration number NCT00844142. PMID- 25028376 TI - Function of N-terminal pro-brain natriuretic peptide in Takayasu arteritis disease monitoring. AB - OBJECTIVE: Increased levels of N-terminal pro-brain natriuretic peptide (NT proBNP) are associated with cardiovascular morbidity and mortality. Inflammation may also affect levels of NT-proBNP. We investigated the relationship of NT proBNP with inflammation, disease activity, disease severity, and progression of Takayasu arteritis (TA). METHODS: Plasma levels of NT-proBNP were determined in 68 patients with TA and in 90 control subjects. Disease activity and disease severity in patients with TA were defined according to the National Institutes of Health and Ishikawa's criteria, respectively. RESULTS: NT-proBNP levels were higher in patients with active disease (915.0 +/- 328.0 pmol/l) and patients in remission (618.2 +/- 243.4 pmol/l) than in controls (427.2 +/- 81.4 pmol/l) (p < 0.001). Patients with severe TA showed significantly higher NT-proBNP levels than those with mild-moderate TA (924.0 +/- 332.4 pmol/l vs 653.8 +/- 269.1 pmol/l; p = 0.001). In patients with longitudinal data, NT-proBNP levels at the active phase were significantly higher than those at the stable phase (944.1 +/- 216.7 pmol/l vs 552.1 +/- 178.2 pmol/l; p = 0.001). Inflammatory markers, including C reactive protein, erythrocyte sedimentation rate, and white blood cell count, were independently associated with NT-proBNP levels after adjustment for other confounding factors (R(2) adjusted = 0.307, p = 0.001). CONCLUSION: NT-proBNP levels were significantly increased in patients with active TA exhibiting complications. NT-proBNP levels were independently associated with inflammation. These results indicate that NT-proBNP may be a useful marker to assess the status, severity, and progression of TA. PMID- 25028377 TI - Work productivity loss and fatigue in psoriatic arthritis. AB - OBJECTIVE: To explore the relationship between fatigue and work productivity loss (WPL) in people with psoriatic arthritis (PsA). METHODS: Data were collected from participants in the Utah Psoriasis Initiative Arthritis registry between January 2010 and May 2013. WPL was measured with the 8-item Work Limitations Questionnaire. Fatigue was assessed with question 1 from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI#1), "How would you describe the overall level of fatigue/tiredness you have experienced?" and with question 1 from the Psoriatic Arthritis Quality of Life Questionnaire (PsAQOL#1) "I feel tired whatever I do." Psoriatic activity was evaluated with tender joint count (TJC), swollen joint count (SJC), dactylitis count, enthesitis count, inflammatory back pain (IBP), physician global assessment, body surface area, and psoriasis pain and itch. RESULTS: Among 107 participants, work productivity was reduced by 6.7%, compared to benchmark employees without limitations. Fatigue was reported by 54 patients (50.5%) on PsAQOL#1, and 64 (60.0%) were classified as high fatigue by BASDAI#1. TJC, SJC, enthesitis count, IBP, and depressed mood were highest or most frequent in participants reporting fatigue. After adjustments for psoriatic activity and depressed mood, WPL was associated with fatigue, as measured by PsAQOL#1 (p = 0.01) and BASDAI#1 (p = 0.002). CONCLUSION: WPL was associated with fatigue, and the association was not entirely explained by the evaluated musculoskeletal, cutaneous, or psychiatric manifestations of PsA. PMID- 25028378 TI - Circulating concentrations of the novel adipokine chemerin are associated with cardiovascular disease risk in rheumatoid arthritis. AB - OBJECTIVE: Depending on physiological context, the adipokine chemerin can reduce or enhance cardiovascular risk. We investigated whether chemerin concentrations represent cardiovascular disease risk in rheumatoid arthritis (RA). METHODS: We assessed ELISA-determined chemerin concentrations and those of 4 early endothelial activation molecules as well as angiopoietin 2, which mediates angiogenesis and thereby contributes to advanced atherosclerosis, the common carotid artery intima-media thickness (cIMT), and carotid artery plaque by ultrasound in 236 patients (114 black and 122 white) with RA. Relationships were identified in potential confounder and mediator-adjusted mixed regression models. RESULTS: Mean (SD) chemerin and median (interquartile range) angiopoietin 2 concentrations were 114 (35) ng/ml and 2560 (2044-3341) pg/ml, respectively; the mean (SD) cIMT was 0.708 (0.110) mm, and 40.3% of patients had plaque. Chemerin concentrations were not related to those of early endothelial activation molecules, but associated with those of angiopoietin 2 [beta SE = 0.002 (0.0004), p < 0.0001] and plaque [OR 1.006 (95% CI 1.00-1.013), p = 0.05] in all patients. The presence of major conventional cardiovascular risk factors, generalized and abdominal obesity, and RA severity markers modified the independent chemerin cardiovascular risk relations (interaction p < 0.05). Consequently, chemerin concentrations were associated with cIMT in those with but not without overweight or generalized obesity and abdominal obesity [beta SE = 0.001 (0.0003), p = 0.005 and 0.001 (0.0001), p = 0.001 vs -0.001 (0.0004), p = 0.2 and -0.0002 (0.0004), p = 0.6, respectively], and with plaque in those without but not with generalized obesity [OR 1.008 (95% CI) 1.000-1.016, p = 0.03 vs 1.003 (0.990-1.017), p = 0.6, respectively]. The beta (SE) for the chemerin-intima-media thickness relations in patients with overweight or generalized obesity and abdominal obesity were larger than in those without these characteristics (p < 0.0001 and = 0.04, respectively). CONCLUSION: Chemerin is associated with endothelial activation and atherosclerosis in RA. Adiposity influences the chemerin-atherosclerotic phenotype relations in RA. PMID- 25028379 TI - Rilonacept for gout flare prevention in patients receiving uric acid-lowering therapy: results of RESURGE, a phase III, international safety study. AB - OBJECTIVE: To evaluate the safety and efficacy of once-weekly subcutaneous rilonacept 160 mg for prevention of gout flares in patients initiating or continuing urate-lowering therapy (ULT). METHODS: This phase III study was conducted in the United States, South Africa, Europe, and Asia. Adults (n = 1315, 18-80 yrs) with gout, who were initiating or continuing ULT, were randomized to treatment with weekly subcutaneous injections of rilonacept 160 mg or placebo for 16 weeks followed by a 4-week safety followup. The primary endpoint was safety, assessed by adverse events (AE) and laboratory values. Efficacy was a secondary endpoint. RESULTS: Demographic and clinical characteristics were similar between treatments; predominantly male (87.8%), mean age 52.7 +/- 11.3 years. Patients with >= 1 AE were 66.6% with rilonacept versus 59.1% placebo, with slightly more AE-related withdrawals with rilonacept (4.7% vs 3.0%) because of the greater incidence of injection site reactions (15.2% rilonacept, 3.3% placebo). Serious AE were similar in both groups, as were serious infections (0.9% placebo, 0.5% rilonacept); no tuberculosis or opportunistic infections occurred. Most common AE were headache, arthralgia, injection site erythema, accidental overdose, and pain in extremity. Of the 6 deaths, only 1 in the placebo group was considered treatment-related. At Week 16, rilonacept resulted in 70.3% fewer gout flares per patient (p < 0.0001), fewer patients with >= 1 and >= 2 gout flares (p < 0.0001), and 64.9% fewer gout flare days (p < 0.0001) relative to placebo. CONCLUSION: Weekly subcutaneous administration of rilonacept 160 mg showed no new safety signals. The safety profile was consistent with previous studies. Rilonacept also significantly reduced the risk of gout flares. Clinicaltrials.gov identifier NCT00856206; EudraCT No. 2008-007784-16. PMID- 25028380 TI - Systemic sclerosis and the risk of tuberculosis. AB - OBJECTIVE: Pulmonary involvement is common in patients with systemic sclerosis (SSc), and this condition causes substantial morbidity and mortality. Disrupted immunity from the disease or associated medication may render such patients subject to tuberculosis (TB) infection. However, the relationship between SSc and TB has not yet been investigated. METHODS: Using the Taiwan National Health Insurance Research Database, 838 patients with SSc diagnosed in Taiwan during 2000-2006 were identified and followed for emergence of TB infection. Incidence rate ratios (IRR) of TB compared to 8380 randomly selected age-, sex-, and comorbidity-matched controls without SSc were calculated. The Cox proportional hazards model was used for multivariate adjustment to identify independent risk factors for TB infection. RESULTS: The risk of TB infection was higher in the SSc cohort than in controls (IRR 2.81, 95% CI 1.36-5.37; p = 0.004), particularly for pulmonary TB (IRR 2.53, 95% CI 1.08-5.30; p = 0.022). Other independent risk factors for TB infection in patients with SSc were age >= 60 years [hazard ratio (HR) 3.52, 95% CI 1.10-11.33; p = 0.035] and pulmonary hypertension (PH; HR 6.06, 95% CI 1.59-23.17; p = 0.008). Mortality did not differ for SSc patients with or without TB. CONCLUSION: In this nationwide study, the incidence of TB infection was significantly higher among patients with SSc than in controls without SSc. Special care should be taken in managing patients with SSc who are at high risk for TB, especially those aged >= 60 years or who also have PH. PMID- 25028381 TI - Effect of remission definition on healthcare cost savings estimates for patients with rheumatoid arthritis treated with biologic therapies. AB - OBJECTIVE: Sustained remission in rheumatoid arthritis (RA) results in healthcare utilization cost savings. We evaluated the variation in estimates of savings when different definitions of remission [2011 American College of Rheumatology/European League Against Rheumatism Boolean Definition, Simplified Disease Activity Index (SDAI) <= 3.3, Clinical Disease Activity Index (CDAI) <= 2.8, and Disease Activity Score-28 (DAS28) <= 2.6] are applied. METHODS: The annual mean healthcare service utilization costs were estimated from provincial physician billing claims, outpatient visits, and hospitalizations, with linkage to clinical data from the Alberta Biologics Pharmacosurveillance Program (ABioPharm). Cost savings in patients who had a 1-year continuous period of remission were compared to those who did not, using 4 definitions of remission. RESULTS: In 1086 patients, sustained remission rates were 16.1% for DAS28, 8.8% for Boolean, 5.5% for CDAI, and 4.2% for SDAI. The estimated mean annual healthcare cost savings per patient achieving remission (relative to not) were SDAI $1928 (95% CI 592, 3264), DAS28 $1676 (95% CI 987, 2365), and Boolean $1259 (95% CI 417, 2100). The annual savings by CDAI remission per patient were not significant at $423 (95% CI -1757, 2602). For patients in DAS28, Boolean, and SDAI remission, savings were seen both in costs directly related to RA and its comorbidities, and in costs for non-RA-related conditions. CONCLUSION: The magnitude of the healthcare cost savings varies according to the remission definition used in classifying patient disease status. The highest point estimate for cost savings was observed in patients attaining SDAI remission and the least with the CDAI; confidence intervals for these estimates do overlap. Future pharmacoeconomic analyses should employ all response definitions in assessing the influence of treatment. PMID- 25028382 TI - Are rheumatoid arthritis patients discernible from other early arthritis patients using 1.5T extremity magnetic resonance imaging? a large cross-sectional study. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is increasingly used in rheumatoid arthritis (RA) research. A European League Against Rheumatism (EULAR) task force recently suggested that MRI can improve the certainty of RA diagnosis. Because this recommendation may reflect a tendency to use MRI in daily practice, thorough studies on the value of MRI are required. Thus far no large studies have evaluated the accuracy of MRI to differentiate early RA from other patients with early arthritis. We performed a large cross-sectional study to determine whether patients who are clinically classified with RA differ in MRI features compared to patients with other diagnoses. METHODS: In our study, 179 patients presenting with early arthritis (median symptom duration 15.4 weeks) underwent 1.5T extremity MRI of unilateral wrist, metacarpophalangeal, and metatarsophalangeal joints according to our arthritis protocol, the foot without contrast. Images were scored according to OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) by 2 independent readers. Tenosynovitis was also assessed. The main outcome was fulfilling the 1987 American College of Rheumatology (ACR) criteria for RA. Test characteristics and areas under the receiver-operator characteristic curves (AUC) were evaluated. In subanalyses, the 2010 ACR/EULAR criteria were used as outcome, and analyses were stratified for anticitrullinated protein antibodies (ACPA). RESULTS: The ACR 1987 criteria were fulfilled in 43 patients (24.0%). Patients with RA had higher scores for synovitis, tenosynovitis, and bone marrow edema (BME) than patients without RA (p < 0.05). ACPA-positive patients had more BME (median scores 6.5 vs. 4.25, p = 0.016) than ACPA-negative patients. For all MRI features, the predictive value for the presence of RA was low (< 50%). For all MRI features the AUC were < 0.70. Patients who fulfilled ACR/EULAR 2010 criteria but not ACR87 criteria for RA had less synovitis than patients who were positive for RA according to both sets of criteria (p = 0.029). CONCLUSION: Although patients with RA had higher scores of MRI inflammation and ACPA-positive patients had more BME, the severity of MRI inflammation assessed according to RAMRIS does not accurately differentiate patients with RA from other early arthritis patients. PMID- 25028383 TI - Joint damage progression in patients with rheumatoid arthritis in clinical remission: do biologics perform better than synthetic antirheumatic drugs? AB - OBJECTIVE: Randomized controlled studies have demonstrated protective advantages of biologic therapies over the synthetic disease-modifying antirheumatic drugs (DMARD) in slowing joint damage progression in patients with rheumatoid arthritis (RA). This effect appears to be largely independent of the clinical disease control. We measured the rate of radiographic progression in patients with RA in clinical remission treated with synthetic versus biologic DMARD. METHODS: This is an observational cohort study of patients with RA in clinical remission, nested within the Swiss Clinical Quality Management in Rheumatoid Arthritis (SCQM-RA) Registry. The primary study outcome was the rate of radiographic progression (Ratingen erosion score), and a secondary outcome was functional disability [Health Assessment Questionnaire-Disability Index (HAQ-DI)] progression. We compared the rate of progression between synthetic and biologic DMARD using a multivariate regression model for longitudinal data, adjusting for potential confounders. RESULTS: A total of 2055 patients in the SCQM-RA registry were in remission at least once from 1999 to 2012 and met the study inclusion criteria. Baseline characteristics of patients in remission receiving synthetic and biologic DMARD were not significantly different in terms of prognostic factors for joint damage progression. During followup, erosion progression differed significantly between the 2 groups [1.4% (95% CI: 1.1-1.6) vs 0.9% (95% CI: 0.5 1.2) of progression over 3 years, respectively, p < 0.001], with less damage progression in patients treated with biologic DMARD than with synthetic DMARD. This difference remained significant after adjusting for confounding factors. The evolution of the HAQ-DI score was also statistically better in the biologic group (p < 0.001). CONCLUSION: This observational study confirms that the rate of structural damage progression in clinical remission is decreased taking biologics compared to synthetic DMARD. However, while the difference is statistically significant it is probably not relevant from a clinical perspective. PMID- 25028384 TI - Effect of human immunodeficiency virus infection on disease activity in rheumatoid arthritis: a retrospective study in South Africans. AB - OBJECTIVE: To determine the effect of human immunodeficiency virus (HIV) infection on disease activity in rheumatoid arthritis (RA). METHODS: A retrospective records review of patients who contracted HIV infection subsequent to RA diagnosis (HIV group), compared to an HIV-negative group of patients with RA (control group), for 28-joint Disease Activity Score (DAS28) scores at initial presentation (T0) and last clinic visit (TL), and at diagnosis of HIV infection (TH) in the HIV group. RESULTS: Of 1712 patients with RA, 85 were HIV-positive (4.9%), 43 of them contracting HIV subsequent to RA diagnosis. The mean (SD) age, RA disease duration, and duration following diagnosis of HIV were 47.1 (10.1), 10.5 (8.4), and 2.9 (2.0) years, respectively, for the HIV group. Both the HIV and control groups showed similar improvement in joint counts and C-reactive protein (CRP) at visit TL, in spite of methotrexate (MTX) being withdrawn in most patients in the HIV group by visit TL (11.6% in the HIV group were still taking MTX vs 83.7% in the control group, p = 0.0002), but a minority (13.9%) had ongoing moderate to high disease activity at visit TL. In the HIV group, the mean DAS28-erythrocyte sedimentation rate (ESR) and DAS28-CRP scores were similar at baseline, but at visits TH and TL the mean DAS28-ESR scores were significantly higher than the mean DAS28-CRP scores (31% and 31.8%, p < 0.0005 and p < 0.004, respectively), mainly resulting from ESR increase following HIV seroconversion. CONCLUSION: Disease activity improved in most patients in the HIV group in spite of stopping the MTX as the "anchor drug." The DAS28-ESR overestimates disease activity compared to the DAS28-CRP in the setting of HIV infection. PMID- 25028385 TI - The epidemic of pre-diabetes: the medicine and the politics. PMID- 25028386 TI - Neighborhood Characteristics and ADHD: Results of a National Study. AB - OBJECTIVE: We examined the association of neighborhood social and physical characteristics with ADHD, accounting for individual and family factors. METHOD: The 2007 National Survey of Child Health, a nationally representative data set, was used (N = 64,076). Three neighborhood scales were generated: social support, amenities, and disorder. Logistic and ordinal logistic regressions were conducted to examine the association of these scales with ADHD diagnosis and severity while adjusting for individual and family characteristics. RESULTS: Eight percent had a child with ADHD: 47% described as mild, 40% moderate, and 13% severe. In adjusted models, lower neighborhood support was associated with increased ADHD diagnosis (odds ratio [OR] = 1.66 [1.05, 2.63]) and severity (OR = 3.74 [1.71, 8.15]); neighborhood amenities or disorder were not significantly associated. Poor parental mental health was associated with ADHD prevalence and severity. CONCLUSION: Neighborhood social support is a potential area of intervention for children with ADHD and their caregivers. Research challenges and opportunities are discussed. PMID- 25028387 TI - A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension. AB - AIMS: Pulmonary arterial hypertension (PAH) is characterized by the development of unique neointimal lesions in the small pulmonary arteries, leading to increased right ventricular (RV) afterload and failure. Novel therapeutic strategies are needed that target these neointimal lesions. Recently, the transcription factor Egr-1 (early growth response protein 1) was demonstrated to be up-regulated early in experimental neointimal PAH. Its effect on disease development, however, is unknown. We aimed to uncover a novel role for Egr-1 as a molecular inductor for disease development in PAH. METHODS AND RESULTS: In experimental flow-associated PAH in rats, we investigated the effects of Egr-1 down-regulation on pulmonary vascular remodelling, including neointimal development, and disease progression. Intravenous administration of catalytic oligodeoxynucleotides (DNA enzymes, DNAzymes) resulted in down-regulation of pulmonary vascular Egr-1 expression. Compared with vehicle or scrambled DNAzymes, DNAzymes attenuated pulmonary vascular remodelling, including the development of occlusive neointimal lesions. Selective down-regulation of Egr-1 in vivo led to reduced expression of vascular PDGF-B, TGF-beta, IL-6, and p53, resulting in a reduction of vascular proliferation and increased apoptosis. DNAzyme treatment further attenuated pulmonary vascular resistance, RV systolic pressure, and RV hypertrophy. In contrast, in non-neointimal PH rodents, DNAzyme treatment had no effect on pulmonary vascular and RV remodelling. Finally, pharmacological inhibition of Egr-1 with pioglitazone, a peroxisome proliferator activated receptor-gamma ligand, attenuated vascular remodelling including the development of neointimal lesions. CONCLUSIONS: These results indicate that Egr-1 governs pulmonary vascular remodelling and the development of characteristic vascular neointimal lesions in flow-associated PAH. Egr-1 is therefore a potential target for future PAH treatment. PMID- 25028388 TI - Spotlight on HDL biology: new insights in metabolism, function, and translation. PMID- 25028389 TI - Mechanical, degradation and cytocompatibility properties of magnesium coated phosphate glass fibre reinforced polycaprolactone composites. AB - Retention of mechanical properties of phosphate glass fibre reinforced degradable polyesters such as polycaprolactone and polylactic acid in aqueous media has been shown to be strongly influenced by the integrity of the fibre/polymer interface. A previous study utilising 'single fibre' fragmentation tests found that coating with magnesium improved the fibre and matrix interfacial shear strength. Therefore, the aim of this study was to investigate the effects of a magnesium coating on the manufacture and characterisation of a random chopped fibre reinforced polycaprolactone composite. Short chopped strand non-woven phosphate glass fibre mats were sputter coated with degradable magnesium to manufacture phosphate glass fibre/polycaprolactone composites. The degradation behaviour (water uptake, mass loss and pH change of the media) of these polycaprolactone composites as well as of pure polycaprolactone was investigated in phosphate buffered saline. The Mg coated fibre reinforced composites revealed less water uptake and mass loss during degradation compared to the non-coated composites. The cations released were also explored and a lower ion release profile for all three cations investigated (namely Na(+), Mg(2+) and Ca(2+)) was seen for the Mg coated composite samples. An increase of 17% in tensile strength and 47% in tensile modulus was obtained for the Mg coated composite samples. Both flexural and tensile properties were investigated and a higher retention of mechanical properties was obtained for the Mg coated fibre reinforced composite samples up to 10 days immersion in PBS. Cytocompatibility study showed both composite samples (coated and non-coated) had good cytocompatibility with human osteosarcoma cell line. PMID- 25028390 TI - Ablation of driver domains during persistent atrial fibrillation: a call for more understanding. PMID- 25028391 TI - Driver domains in persistent atrial fibrillation. AB - BACKGROUND: Specific noninvasive signal processing was applied to identify drivers in distinct categories of persistent atrial fibrillation (AF). METHODS AND RESULTS: In 103 consecutive patients with persistent AF, accurate biatrial geometry relative to an array of 252 body surface electrodes was obtained from a noncontrast computed tomography scan. The reconstructed unipolar AF electrograms acquired at bedside from multiple windows (duration, 9+/-1 s) were signal processed to identify the drivers (focal or reentrant activity) and their cumulative density map. The driver domains were catheter ablated by using AF termination as the procedural end point in comparison with the stepwise-ablation control group. The maps showed incessantly changing beat-to-beat wave fronts and varying spatiotemporal behavior of driver activities. Reentries were not sustained (median, 2.6 rotations lasting 449+/-89 ms), meandered substantially but recurred repetitively in the same region. In total, 4720 drivers were identified in 103 patients: 3802 (80.5%) reentries and 918 (19.5%) focal breakthroughs; most of them colocalized. Of these, 69% reentries and 71% foci were in the left atrium. Driver ablation alone terminated 75% and 15% of persistent and long-lasting AF, respectively. The number of targeted driver regions increased with the duration of continuous AF: 2 in patients presenting in sinus rhythm, 3 in AF lasting 1 to 3 months, 4 in AF lasting 4 to 6 months, and 6 in AF lasting longer. The termination rate sharply declined after 6 months. The mean radiofrequency delivery to AF termination was 28+/-17 minutes versus 65+/-33 minutes in the control group (P<0.0001). At 12 months, 85% patients with AF termination were free from AF, similar to the control population (87%,); P=not significant. CONCLUSIONS: Persistent AF in early months is maintained predominantly by drivers clustered in a few regions, most of them being unstable reentries. PMID- 25028392 TI - Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate. AB - Trehalose dimycolate, an unusual glycolipid in the outer membrane of Mycobacterium tuberculosis, stimulates macrophages by binding to the macrophage receptor mincle. This stimulation plays an important role both in infection by mycobacteria and in the use of derivatives of mycobacteria as adjuvants to enhance the immune response. The mechanism of trehalose dimycolate binding to the C-type carbohydrate-recognition domain in human mincle has been investigated using a series of synthetic analogs of trehalose dimycolate and site-directed mutagenesis of the human protein. The results support a mechanism of binding acylated trehalose derivatives to human mincle that is very similar to the mechanism of binding to bovine mincle, in which one glucose residue in the trehalose headgroup of the glycolipid is ligated to the principle Ca(2+)-binding site in the carbohydrate-recognition domain, with specificity for the disaccharide resulting from interactions with the second glucose residue. Acyl chains attached to the 6-OH groups of trehalose enhance affinity, with the affinity dependent on the length of the acyl chains and the presence of a hydrophobic groove adjacent to the sugar-binding sites. The results indicate that the available crystal structure of the carbohydrate-recognition domain of human mincle is unlikely to be in a fully active conformation. Instead, the ligand binding conformation probably resembles closely the structure observed for bovine mincle in complex with trehalose. These studies provide a basis for targeting human mincle as a means of inhibiting interactions with mycobacteria and as an approach to harnessing the ability of mincle to stimulate the immune response. PMID- 25028393 TI - Meeting report on EMBO workshop: glycobiology and glycochemistry, applications to human health and disease. PMID- 25028394 TI - Connecting model species to nature: predator-induced long-term sensitization in Aplysia californica. AB - Previous research on sensitization in Aplysia was based entirely on unnatural noxious stimuli, usually electric shock, until our laboratory found that a natural noxious stimulus, a single sublethal lobster attack, causes short-term sensitization. We here extend that finding by demonstrating that multiple lobster attacks induce long-term sensitization (>=24 h) as well as similar, although not identical, neuronal correlates as observed after electric shock. Together these findings establish long- and short-term sensitization caused by sublethal predator attack as a natural equivalent to sensitization caused by artificial stimuli. PMID- 25028395 TI - Contralateral disconnection of the rat prelimbic cortex and dorsomedial striatum impairs cue-guided behavioral switching. AB - Switches in reward outcomes or reward-predictive cues are two fundamental ways in which information is used to flexibly shift response patterns. The rat prelimbic cortex and dorsomedial striatum support behavioral flexibility based on a change in outcomes. The present experiments investigated whether these two brain regions are necessary for conditional discrimination performance in which a switch in reward-predictive cues occurs every three to six trials. The GABA agonists baclofen and muscimol infused into the prelimbic cortex significantly impaired performance leading rats to adopt an inappropriate turn strategy. The NMDA receptor antagonist D-AP5 infused into the dorsomedial striatum or prelimbic cortex and dorsomedial striatum contralateral disconnection impaired performance due to a rat failing to switch a response choice for an entire trial block in about two out of 13 test blocks. In an additional study, contralateral disconnection did not affect nonswitch discrimination performance. The results suggest that the prelimbic cortex and dorsomedial striatum are necessary to support cue-guided behavioral switching. The prelimbic cortex may be critical for generating alternative response patterns while the dorsomedial striatum supports the selection of an appropriate response when cue information must be used to flexibly switch response patterns. PMID- 25028396 TI - The role of age on dose-limiting toxicities in phase I dose-escalation trials. AB - PURPOSE: Elderly oncology patients are not enrolled in early-phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients, resulting in a disproportionate number of dose-limiting toxicities (DLT). Recent single-institution studies provide conflicting data on the relationship between age and DLT. EXPERIMENTAL DESIGN: We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients' dose levels were described as a percentage of maximum tolerated dose, the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables. RESULTS: Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (P < 0.05). There was no association between dose level administered and age (P = 0.57). CONCLUSIONS: This analysis of phase I dose-escalation trials, involving more than 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. Although increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels. PMID- 25028397 TI - Impaired mitochondrial function in human placenta with increased maternal adiposity. AB - The placenta plays a key role in regulation of fetal growth and development and in mediating in utero developmental programming. Obesity, which is associated with chronic inflammation and mitochondrial dysfunction in many tissues, exerts a programming effect in pregnancy. We determined the effect of increasing maternal adiposity and of fetal sex on placental ATP generation, mitochondrial biogenesis, expression of electron transport chain subunits, and mitochondrial function in isolated trophoblasts. Placental tissue was collected from women with prepregnancy BMI ranging from 18.5 to 45 following C-section at term with no labor. Increasing maternal adiposity was associated with excessive production of reactive oxygen species and a significant reduction in placental ATP levels in placentae with male and female fetuses. To explore the potential mechanism of placental mitochondrial dysfunction, levels of transcription factors regulating the expression of genes involved in electron transport and mitochondrial biogenesis were measured. Our in vitro studies showed significant reduction in mitochondrial respiration in cultured primary trophoblasts with increasing maternal obesity along with an abnormal metabolic flexibility of these cells. This reduction in placental mitochondrial respiration in pregnancies complicated by maternal obesity could compromise placental function and potentially underlie the increased susceptibility of these pregnancies to fetal demise in late gestation and to developmental programming. PMID- 25028398 TI - Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study. AB - OBJECTIVE: Serum lipase activities above the threefold upper reference limit indicate acute pancreatitis. We investigated whether high lipase activity-within the reference range and in the absence of pancreatitis-are associated with genetic single nucleotide polymorphisms (SNP), and whether these identified SNPs are also associated with clinical pancreatitis. METHODS: Genome-wide association studies (GWAS) on phenotypes 'serum lipase activity' and 'high serum lipase activity' were conducted including 3966 German volunteers from the population based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genome-wide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients. RESULTS: Initial discovery GWAS detected SNPs within or near genes encoding the ABO blood group specifying transferases A/B (ABO), Fucosyltransferase-2 (FUT2), and Chymotrypsinogen-B2 (CTRB2), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR=1.49; p=0.012) and ABO blood-type-B (OR=2.48; p=7.29*10(-8)) with high lipase activity levels. In pancreatitis patients, significant associations were found for FUT-2 non-secretor status (OR=1.53; p=8.56*10(-4)) and ABO-B (OR=1.69, p=1.0*10(-4)) with chronic pancreatitis, but not with acute pancreatitis. Conversely, carriers of blood group O were less frequently affected by chronic pancreatitis (OR=0.62; p=1.22*10(-05)) and less likely to have high lipase activity levels (OR=0.59; p=8.14*10(-05)). CONCLUSIONS: These are the first results indicating that ABO blood type-B as well as FUT2 non-secretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects. PMID- 25028399 TI - Tolerization of inflammatory gene expression. AB - Lipopolysaccharide (LPS) is a potent inducer of inflammation. However, in a phenomenon known as LPS tolerance, prolonged exposure to LPS reprograms the host response to subsequent LPS reexposure. Proinflammatory cytokine production is suppressed, while production of antimicrobial genes is increased. In vivo models suggest that LPS tolerance dramatically reduces susceptibility to septic shock, while keeping the capacity for clearance of certain pathogens intact. These observations imply that artificial induction of tolerance may be an attractive means to intervene in the progression of sepsis and other inflammatory diseases. However, the underlying mechanisms that govern the tolerogenic response remain poorly understood, hindering efforts to evaluate LPS tolerance induction as a therapeutic approach. Recent advances indicate that chromatin modifications and microRNA mediators may be particularly important in the tolerogenic response. In this review, we discuss possible mechanisms to account for the phenomenon of LPS tolerance, with particular emphasis on the role of newly identified mediators. PMID- 25028400 TI - Dissection of signaling in inflammation: three novel inflammatory regulators. AB - Uncontrolled inflammation is a feature of autoimmune diseases and autoinflammatory syndromes and may promote tumorigenesis. Thus, identifying molecules that regulate the signaling pathways triggering, mediating, and suppressing inflammation could be helpful in developing new therapeutic approaches for these debilitating diseases. In this review, we present new information on three molecules with important roles in controlling inflammation: MALT1, Ariadne-2, and acetylcholine. We summarize our current state of knowledge of how these molecules function, and how they are involved in pathways of NF kappaB activation or vagal nerve stimulation associated with inflammation. PMID- 25028401 TI - Programmed cell death 1-directed immunotherapy for enhancing T-cell function. AB - T-cell exhaustion is a unique state that appears during many chronic infections and cancer and is characterized by loss of proliferative capacity and effector function. Complex mechanisms are involved in this T-cell dysfunction but an inhibitory receptor, PD-1, has been identified as a major regulator of T-cell exhaustion. Blockade of the PD-1 pathway can reinvigorate exhausted T cells, resulting in better control of chronic infections and cancer. Notably, recent clinical studies have revealed that PD-1-directed immunotherapy is highly effective in cancer patients, demonstrating that PD-1 is a promising therapeutic target in humans. In this review, we summarize our current understanding of the epigenetic regulation of PD-1 expression in T cells and discuss potential combination therapy with PD-1 blockade toward developing more effective treatment for chronic infections and cancer. PMID- 25028406 TI - Laryngopyocoele presenting with acute airway obstruction. AB - A 66-year-old woman was transferred to the emergency department with a left-sided neck lump and fever. She was stridulous with reduced consciousness level and required immediate intubation to protect her airway. CT imaging showed a fluid filled and air-filled lesion in the left side of the neck; the diagnosis was later confirmed as an infected laryngocoele. She underwent ultrasound guided drainage of the lesion with successful reduction of the neck lump. Following elective tracheostomy she was weaned from ventilation. Subsequent direct endoscopy and biopsy showed no evidence of malignancy or other lesion. She was discharged with permanent tracheostomy to be sustained until definitive surgical resection of the laryngocoele. PMID- 25028407 TI - Spontaneous tumour lysis syndrome associated with contrast dye iohexol use in mantle cell lymphoma. AB - We describe a case of a 73-year-old man who presented with right-sided abdominal pain associated with palpable mass. Initial laboratory examination was normal except lactate dehydrogenase level. Subsequent CT image showed situs inversus and splenic mass with multiple lymph nodes enlargement. Biopsy taken from the splenic mass demonstrated mantle cell lymphoma. Staging CT examination was performed with intravenous contrast, and patient developed altered mental status, respiratory failure and acute kidney injury requiring intensive care unit care. Laboratory examination revealed hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia, which are consistent with spontaneous tumour lysis syndrome. The patient was successfully treated with rasburicase and haemodialysis, and completed the first course of chemotherapy without further complications. PMID- 25028408 TI - The truncation artefact in patients with a high body mass index on myocardial perfusion SPECT. PMID- 25028409 TI - Frank's sign: a coronary artery disease predictor. PMID- 25028410 TI - Preoperative biliary decompression preceding pancreaticoduodenectomy with plastic or self-expandable metallic stent. AB - BACKGROUND AND AIMS: The rainage (PBD) prior to pancreaticoduodenectomy (PD) is controversial. If PBD is required, large bore self-expandable metallic stents (SEMS) are thought to maintain better drainage and have fewer postoperative complications than plastic stents. The confirming evidence is scarce. The aim of the study was to compare outcomes of surgery in patients who underwent PBD with SEMS or plastic stents deployed at endoscopic retrograde cholangiopancreatography (ERCP). MATERIAL AND METHODS: This is a retrospective study of 366 patients having had PD during 2000-2009. Preceding endoscopic PBD was performed in 191 patients and nine had had percutaneous transhepatic drainage (PTD). At the time of operation, 163 patients had a plastic stent and 28 had SEMS. Due to stent exchanges, 176 plastic stents and 29 SEMS were placed in all. RESULTS AND CONCLUSIONS: The stent failure rate was 7.4% for plastic stents and 3.4% for SEMS (p = 0.697). A bilirubin level under 50 umol/L was reached by 80% of the patients with plastic stents and by 61% of the patients with SEMS (p = 0.058). A postoperative infection complication and/or a pancreatic fistula was found in 26% while using plastic stents and in 25% using SEMS (p = 1.000). In unstented patients with biliary obstruction, the bile juice was sterile significantly more often than in endoscopically stented patients (100% vs 1%, p < 0.001). When the stented and unstented patients were compared regarding postoperative infection complications, there was no significant difference between the groups (p = 0.365). Plastic stents did not differ from SEMS regarding the stent failure rate, bilirubin level decrease, amount of bacteria in the bile juice, or postoperative complications when used for PBD. The significantly higher price of SEMS suggests their use in selected cases only. PMID- 25028411 TI - Lessons from primary PCI practice for the next decade. AB - Primary percutaneous coronary intervention (PPCI) is the reperfusion treatment of choice for acute ST-elevation myocardial infarction with studies having demonstrated improved outcomes with PPCI over thrombolysis. Its use has increased substantially over the last decade, overtaking thrombolytic therapy in many countries. This has been paralleled with advances in adjunctive technology and pharmacological therapy to further improve outcome, but challenges remain for PPCI practitioners. The evidence behind PPCI is reviewed at every stage of the patient's journey. PMID- 25028412 TI - BNP during exercise: a novel use for a familiar biomarker in aortic stenosis. PMID- 25028413 TI - Childhood headache attributed to airplane travel: a case report. AB - Headache attributed to airplane flights is a rare form of headache disorder. This case study describes an 11-year-old girl with recurrent, severe, frontal headaches occurring during airplane travel. The episodes were associated with dizziness and facial pallor but no additional symptoms and showed spontaneous resolution on landing. Blood tests and imaging revealed no abnormalities. The present case fulfils the criteria for airplane headache recently included in the revised edition of the International Classification of Headache Disorders (ICHD III Beta). Only a few cases of airplane headache have been reported in children. To our knowledge, this is the fourth case. We review the current literature on this rare syndrome and discuss various proposed pathophysiological mechanisms. PMID- 25028414 TI - A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers. AB - Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5 mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures. PMID- 25028415 TI - Early modified functional hemispherectomy in a young infant with Ohtahara syndrome and hemimegalencephaly. AB - We report on the youngest infant treated with modified functional hemispherectomy at the age of 5 months for Ohtahara syndrome and hemimegalencephaly as underlying pathology, and we depict the favorable outcome regarding seizure control and psychomotor development. These results highlight the potential usefulness of early surgery in such conditions. PMID- 25028416 TI - West syndrome in a patient with Schinzel-Giedion syndrome. AB - Schinzel-Giedion syndrome is a rare recognizable malformation syndrome defined by characteristic facial features, profound developmental delay, severe growth failure, and multiple congenital anomalies. The causative gene of Schinzel Giedion syndrome, SETBP1, has been identified, but limited cases have been confirmed by molecular analysis. We present a 9-month-old girl affected by West syndrome with Schinzel-Giedion syndrome. Congenital severe hydronephrosis, typical facial features, and multiple anomalies suggested a clinical diagnosis of Schinzel-Giedion syndrome. Hypsarrhythmia occurred at 7 months of age and was temporarily controlled by adrenocorticotropic hormone (ACTH) therapy during 5 weeks. SETBP1 mutational analysis showed the presence of a recurrent mutation, p.Ile871Thr. The implications in management of Schinzel-Giedion syndrome are discussed. PMID- 25028417 TI - Mitochondrial genetics and disease. AB - Mitochondrial disease resulting in reduced bioenergetic output can be due to mutations in either nuclear DNA-encoded or mitochondrial DNA-encoded gene products. We summarize some of the underlying principles of mitochondrial genetics that impact the diagnosis and pathogenesis of mitochondrial disorders. In addition, we present a brief overview of a new frontier in the field, namely, mitochondrial "dynamics," which controls organellar fusion, fission, trafficking, and positioning, and exerts mitochondrial "quality control" by maintaining organellar integrity and viability. Analysis of mutations in gene products associated with this latter area has opened up new vistas in the study of disorders associated with compromised energy production. PMID- 25028418 TI - ZEB2 gene mutation and duplication of 22q11.23 in Mowat-Wilson syndrome. AB - Mowat-Wilson syndrome is a recently delineated multiple congenital anomaly syndrome characterized by a distinctive facial appearance in association with intellectual disability, microcephaly, agenesis of the corpus callosum, seizures, congenital heart disease, Hirschsprung disease, short stature, and genitourinary anomalies. We report a 2-year-10-month-old white female with this syndrome caused by mutations in the ZEB2 gene, and in addition a duplication of the 22q11.23, a previously undocumented occurrence. PMID- 25028419 TI - An atypical presentation of an extremely late stent thrombosis after more than 7 years (2634 days) of DES implantation in a patient without obvious risk factors on regular dual antiplatelet therapy. AB - Very late stent thrombosis is a rare complication of percutaneous coronary intervention in the era of dual antiplatelet therapy. The risk factors for stent thrombosis are drug default, age, diabetes, renal dysfunction, left ventricular dysfunction, smoking or procedure-related factors and complications. We are describing the case of a 55-year-old non-smoker patient without the conventional risk factors for stent thrombosis maintaining good compliance with dual antiplatelet (aspirin and clopidogrel) drugs in standard doses. The patient had a history of having received a Cypher stent more than 7 years (2634 days) ago in the left circumflex artery for the management of in-stent restenosis of a bare metal stent implanted previously. He was referred with acute stent thrombosis with an atypical presentation of non-ST elevation myocardial infarction having unexplainable spontaneous resolution of electrocardiographic changes. The patient was successfully managed with newer generation drug-eluting stents reimplantation. The presence of acute onset of symptoms and thrombus containing soft lesion as documented during intervention supported the diagnosis of acute stent thrombosis. To the best of our knowledge this case is one of the longest duration of presentation with acute stent thrombosis after stent implantation ever reported in literature and is also unique in its unusual mode of presentation. PMID- 25028420 TI - Angiographic suppression of the artery of Adamkiewicz by venous hypertension resolving after embolization in a case of spinal epidural arteriovenous fistula. AB - A case of complete angiographic suppression of the artery of Adamkiewicz and anterior spinal artery in a patient with a spinal epidural arteriovenous fistula (AVF) is reported. Slow flow AVFs typically present with progressive myelopathy secondary to spinal venous hypertension (SVH). The lack of a normal venous phase during angiography and its restoration after treatment is commonly observed with these lesions, yet a similar phenomenon seems exceptional at the arterial level. Right T11 intercostal artery angiograms obtained before and after treatment of a left L4 epidural AVF documented the initial suppression of the artery of Adamkiewicz and anterior spinal artery, and their normal appearance immediately after correction of the SVH by embolization. This report confirms that SVH can angiographically suppress prominent and functionally important spinal arteries, re-emphasizing the potential role played by secondary arterial changes in SVH induced myelopathy. This hemodynamic phenomenon also represents a potential pitfall during diagnostic and therapeutic endovascular procedures. PMID- 25028421 TI - Conservative management of persistent facial cutaneous sinus tract with a dental origin. AB - Facial and cervical area sinus tracts can be odontogenic or non-odontogenic, and so clinicians should be aware that lesions with a dental origin can be confused with dermatological lesions. We describe three cases of cutaneous lesions of dental origin that were initially misdiagnosed as being dermatological in origin. Multiple unsuccessful treatments were attempted but the lesions failed to heal. However, conservative endodontic intervention resulted in complete resolution of the causative periapical lesions within a short period, making surgery unnecessary. Dental aetiology, as part of a differential diagnosis, must be considered in such oro-facial lesions. PMID- 25028422 TI - Multisubstrate isotope labeling and metagenomic analysis of active soil bacterial communities. AB - Soil microbial diversity represents the largest global reservoir of novel microorganisms and enzymes. In this study, we coupled functional metagenomics and DNA stable-isotope probing (DNA-SIP) using multiple plant-derived carbon substrates and diverse soils to characterize active soil bacterial communities and their glycoside hydrolase genes, which have value for industrial applications. We incubated samples from three disparate Canadian soils (tundra, temperate rainforest, and agricultural) with five native carbon ((12)C) or stable isotope-labeled ((13)C) carbohydrates (glucose, cellobiose, xylose, arabinose, and cellulose). Indicator species analysis revealed high specificity and fidelity for many uncultured and unclassified bacterial taxa in the heavy DNA for all soils and substrates. Among characterized taxa, Actinomycetales (Salinibacterium), Rhizobiales (Devosia), Rhodospirillales (Telmatospirillum), and Caulobacterales (Phenylobacterium and Asticcacaulis) were bacterial indicator species for the heavy substrates and soils tested. Both Actinomycetales and Caulobacterales (Phenylobacterium) were associated with metabolism of cellulose, and Alphaproteobacteria were associated with the metabolism of arabinose; members of the order Rhizobiales were strongly associated with the metabolism of xylose. Annotated metagenomic data suggested diverse glycoside hydrolase gene representation within the pooled heavy DNA. By screening 2,876 cloned fragments derived from the (13)C-labeled DNA isolated from soils incubated with cellulose, we demonstrate the power of combining DNA-SIP, multiple-displacement amplification (MDA), and functional metagenomics by efficiently isolating multiple clones with activity on carboxymethyl cellulose and fluorogenic proxy substrates for carbohydrate-active enzymes. Importance: The ability to identify genes based on function, instead of sequence homology, allows the discovery of genes that would not be identified through sequence alone. This is arguably the most powerful application of metagenomics for the recovery of novel genes and a natural partner of the stable-isotope-probing approach for targeting active-yet uncultured microorganisms. We expanded on previous efforts to combine stable isotope probing and metagenomics, enriching microorganisms from multiple soils that were active in degrading plant-derived carbohydrates, followed by construction of a cellulose-based metagenomic library and recovery of glycoside hydrolases through functional metagenomics. The major advance of our study was the discovery of active-yet-uncultivated soil microorganisms and enrichment of their glycoside hydrolases. We recovered positive cosmid clones in a higher frequency than would be expected with direct metagenomic analysis of soil DNA. This study has generated an invaluable metagenomic resource that future research will exploit for genetic and enzymatic potential. PMID- 25028423 TI - Toxoplasma gondii ingests and digests host cytosolic proteins. AB - The protozoan parasite Toxoplasma gondii resides within a nonfusogenic vacuole during intracellular replication. Although the limiting membrane of this vacuole provides a protective barrier to acidification and degradation by lysosomal hydrolases, it also physically segregates the parasite from the host cytosol. Accordingly, it has been suggested that T. gondii acquires material from the host via membrane channels or transporters. The ability of the parasite to internalize macromolecules via endocytosis during intracellular replication has not been tested. Here, we show that Toxoplasma ingests host cytosolic proteins and digests them using cathepsin L and other proteases within its endolysosomal system. Ingestion was reduced in mutant parasites lacking an intravacuolar network of tubular membranes, implicating this apparatus as a possible conduit for trafficking to the parasite. Genetic ablation of proteins involved in the pathway is associated with diminished parasite replication and virulence attenuation. We show that both virulent type I and avirulent type II strain parasites ingest and digest host-derived protein, indicating that the pathway is not restricted to highly virulent strains. The findings provide the first definitive evidence that T. gondii internalizes proteins from the host during intracellular residence and suggest that protein digestion within the endolysosomal system of the parasite contributes to toxoplasmosis. Importance: Toxoplasma gondii causes significant disease in individuals with weak immune systems. Treatment options for this infection have drawbacks, creating a need to understand how this parasite survives within the cells it infects as a prelude to interrupting its survival strategies. This study reveals that T. gondii internalizes proteins from the cytoplasm of the cells it infects and degrades such proteins within a digestive compartment within the parasite. Disruption of proteins involved in the pathway reduced parasite replication and lessened disease severity. The identification of a novel parasite ingestion pathway opens opportunities to interfere with this process and improve the outcome of infection. PMID- 25028424 TI - A Mycobacterium tuberculosis cytochrome bd oxidase mutant is hypersensitive to bedaquiline. AB - The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significantly by inhibiting cytochrome bd oxidase, a non-proton-pumping terminal oxidase. BDQ was instantly bactericidal against a cytochrome bd oxidase null mutant of M. tuberculosis, and the rate of killing was increased by more than 50%. We propose that this exclusively bacterial enzyme should be a high-priority target for new drug discovery. Importance: A major drawback of current TB chemotherapy is its long duration. New drug regimens with rapid killing kinetics are desperately needed. Our study demonstrates that inhibition of a nonessential bacterial enzyme greatly improves the efficacy of the latest TB drug bedaquiline and emphasizes that screening for compounds with synergistic killing mechanisms is a promising strategy. PMID- 25028426 TI - Recovery of a medieval Brucella melitensis genome using shotgun metagenomics. AB - Shotgun metagenomics provides a powerful assumption-free approach to the recovery of pathogen genomes from contemporary and historical material. We sequenced the metagenome of a calcified nodule from the skeleton of a 14th-century middle-aged male excavated from the medieval Sardinian settlement of Geridu. We obtained 6.5 fold coverage of a Brucella melitensis genome. Sequence reads from this genome showed signatures typical of ancient or aged DNA. Despite the relatively low coverage, we were able to use information from single-nucleotide polymorphisms to place the medieval pathogen genome within a clade of B. melitensis strains that included the well-studied Ether strain and two other recent Italian isolates. We confirmed this placement using information from deletions and IS711 insertions. We conclude that metagenomics stands ready to document past and present infections, shedding light on the emergence, evolution, and spread of microbial pathogens. Importance: Infectious diseases have shaped human populations and societies throughout history. The recovery of pathogen DNA sequences from human remains provides an opportunity to identify and characterize the causes of individual and epidemic infections. By sequencing DNA extracted from medieval human remains through shotgun metagenomics, without target-specific capture or amplification, we have obtained a draft genome sequence of an ~700-year-old Brucella melitensis strain. Using a variety of bioinformatic approaches, we have shown that this historical strain is most closely related to recent strains isolated from Italy, confirming the continuity of this zoonotic infection, and even a specific lineage, in the Mediterranean region over the centuries. PMID- 25028425 TI - Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes. AB - Immune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress--a phenomenon we term stress pathway interference--lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy. Importance: The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance. PMID- 25028427 TI - Conditionally rare taxa disproportionately contribute to temporal changes in microbial diversity. AB - Microbial communities typically contain many rare taxa that make up the majority of the observed membership, yet the contribution of this microbial "rare biosphere" to community dynamics is unclear. Using 16S rRNA amplicon sequencing of 3,237 samples from 42 time series of microbial communities from nine different ecosystems (air; marine; lake; stream; adult human skin, tongue, and gut; infant gut; and brewery wastewater treatment), we introduce a new method to detect typically rare microbial taxa that occasionally become very abundant (conditionally rare taxa [CRT]) and then quantify their contributions to temporal shifts in community structure. We discovered that CRT made up 1.5 to 28% of the community membership, represented a broad diversity of bacterial and archaeal lineages, and explained large amounts of temporal community dissimilarity (i.e., up to 97% of Bray-Curtis dissimilarity). Most of the CRT were detected at multiple time points, though we also identified "one-hit wonder" CRT that were observed at only one time point. Using a case study from a temperate lake, we gained additional insights into the ecology of CRT by comparing routine community time series to large disturbance events. Our results reveal that many rare taxa contribute a greater amount to microbial community dynamics than is apparent from their low proportional abundances. This observation was true across a wide range of ecosystems, indicating that these rare taxa are essential for understanding community changes over time. Importance: Microbial communities and their processes are the foundations of ecosystems. The ecological roles of rare microorganisms are largely unknown, but it is thought that they contribute to community stability by acting as a reservoir that can rapidly respond to environmental changes. We investigated the occurrence of typically rare taxa that very occasionally become more prominent in their communities ("conditionally rare"). We quantified conditionally rare taxa in time series from a wide variety of ecosystems and discovered that not only were conditionally rare taxa present in all of the examples, but they also contributed disproportionately to temporal changes in diversity when they were most abundant. This result indicates an important and general role for rare microbial taxa within their communities. PMID- 25028428 TI - Apoptosis-like death, an extreme SOS response in Escherichia coli. AB - In bacteria, SOS is a global response to DNA damage, mediated by the recA-lexA genes, resulting in cell cycle arrest, DNA repair, and mutagenesis. Previously, we reported that Escherichia coli responds to DNA damage via another recA-lexA mediated pathway resulting in programmed cell death (PCD). We called it apoptosis like death (ALD) because it is characterized by membrane depolarization and DNA fragmentation, which are hallmarks of eukaryotic mitochondrial apoptosis. Here, we show that ALD is an extreme SOS response that occurs only under conditions of severe DNA damage. Furthermore, we found that ALD is characterized by additional hallmarks of eukaryotic mitochondrial apoptosis, including (i) rRNA degradation by the endoribonuclease YbeY, (ii) upregulation of a unique set of genes that we called extensive-damage-induced (Edin) genes, (iii) a decrease in the activities of complexes I and II of the electron transport chain, and (iv) the formation of high levels of OH through the Fenton reaction, eventually resulting in cell death. Our genetic and molecular studies on ALD provide additional insight for the evolution of mitochondria and the apoptotic pathway in eukaryotes. Importance: The SOS response is the first described and the most studied bacterial response to DNA damage. It is mediated by a set of two genes, recA lexA, and it results in DNA repair and thereby in the survival of the bacterial culture. We have shown that Escherichia coli responds to DNA damage by an additional recA-lexA-mediated pathway resulting in an apoptosis-like death (ALD). Apoptosis is a mode of cell death that has previously been reported only in eukaryotes. We found that E. coli ALD is characterized by several hallmarks of eukaryotic mitochondrial apoptosis. Altogether, our results revealed that recA lexA is a DNA damage response coordinator that permits two opposite responses: life, mediated by the SOS, and death, mediated by the ALD. The choice seems to be a function of the degree of DNA damage in the cell. PMID- 25028430 TI - Editorial. PMID- 25028429 TI - Cryptococcus gattii in North American Pacific Northwest: whole-population genome analysis provides insights into species evolution and dispersal. AB - The emergence of distinct populations of Cryptococcus gattii in the temperate North American Pacific Northwest (PNW) was surprising, as this species was previously thought to be confined to tropical and semitropical regions. Beyond a new habitat niche, the dominant emergent population displayed increased virulence and caused primary pulmonary disease, as opposed to the predominantly neurologic disease seen previously elsewhere. Whole-genome sequencing was performed on 118 C. gattii isolates, including the PNW subtypes and the global diversity of molecular type VGII, to better ascertain the natural source and genomic adaptations leading to the emergence of infection in the PNW. Overall, the VGII population was highly diverse, demonstrating large numbers of mutational and recombinational events; however, the three dominant subtypes from the PNW were of low diversity and were completely clonal. Although strains of VGII were found on at least five continents, all genetic subpopulations were represented or were most closely related to strains from South America. The phylogenetic data are consistent with multiple dispersal events from South America to North America and elsewhere. Numerous gene content differences were identified between the emergent clones and other VGII lineages, including genes potentially related to habitat adaptation, virulence, and pathology. Evidence was also found for possible gene introgression from Cryptococcus neoformans var. grubii that is rarely seen in global C. gattii but that was present in all PNW populations. These findings provide greater understanding of C. gattii evolution in North America and support extensive evolution in, and dispersal from, South America. Importance: Cryptococcus gattii emerged in the temperate North American Pacific Northwest (PNW) in the late 1990s. Beyond a new environmental niche, these emergent populations displayed increased virulence and resulted in a different pattern of clinical disease. In particular, severe pulmonary infections predominated in contrast to presentation with neurologic disease as seen previously elsewhere. We employed population-level whole-genome sequencing and analysis to explore the genetic relationships and gene content of the PNW C. gattii populations. We provide evidence that the PNW strains originated from South America and identified numerous genes potentially related to habitat adaptation, virulence expression, and clinical presentation. Characterization of these genetic features may lead to improved diagnostics and therapies for such fungal infections. The data indicate that there were multiple recent introductions of C. gattii into the PNW. Public health vigilance is warranted for emergence in regions where C. gattii is not thought to be endemic. PMID- 25028431 TI - Recurrent urethral fibroepithelial polyps in a golden retriever. AB - A 2 yr old castrated male golden retriever was referred multiple times over a period of 7.5 yr for stranguria, pollakiuria, urinary incontinence and urinary outflow obstructions due to urethral polyps. Diagnostic imaging modalities used to identify polyps included abdominal ultrasound, excretory urography, double contrast retrograde urethrocystograms, and urethrocystoscopy, which revealed multiple filling defects within the proximal and prostatic urethra. Multiple cystotomies and endourologic procedures were performed to remove the multiple fibroepithelial polyps within the proximal and prostatic urethra. Urinary incontinence resulted from treatments, but did respond to phenylpropanolamine. Medical treatment consisted of a nonsteroidal anti-inflammatory drug, which appeared to decrease the recurrence of the polyps over time. Urethral polyps are an uncommon cause of urinary outflow obstruction and do not usually recur after removal. This case illustrates an uncommon clinical presentation and the difficulties encountered in treatment over an expanded time frame. PMID- 25028432 TI - Radiographic and ultrasonographic findings of uterine neoplasms in nine dogs. AB - The records of nine female intact dogs with histologically confirmed uterine tumors were reviewed retrospectively, and the related radiographic and ultrasonographic signs of the lesions detected were recorded. Radiography revealed a soft-tissue opacity between the urinary bladder and colon in six of seven dogs with uterine body and/or cervical tumors, and a soft-tissue opacity in the midventral abdomen in two dogs with uterine horn tumors. Ultrasonography revealed masses in all dogs with uterine body/cervical tumors and could delineate the origin of the mass in one of two dogs with uterine horn tumors. The mass was characterized ultrasonographically as solid in three dogs (all leiomyomas), solid with cystic component in four dogs (two adenocarcinomas, one leiomyoma, and one fibroleiomyoma), and cystic in two (both leiomyomas). Hyperechoic foci in the mass were observed in three dogs. Ultrasonography was a useful method for demonstrating uterine body and/or cervical tumors. However, it was not possible to ascertain sonographically that a mass originated in a uterine horn unless there was associated evidence of uterine horn to which the mass could be traced. The ultrasonographic appearance of uterine tumors was variable, and the type of neoplasm could only be determined by taking biopsies of the mass. PMID- 25028433 TI - Point-of-care blood gases, electrolytes, chemistries, hemoglobin, and hematocrit measurement in venous samples from pet rabbits. AB - Point-of-care testing is an attractive option in rabbit medicine, because it permits rapid analysis of a panel of electrolytes, chemistries, blood gases, hemoglobin, and hematocrit, requiring only 65 MUL of blood. The purpose of this study was to evaluate the performance of a portable clinical analyzer for measurement of pH, partial pressure of CO2, Na, chloride, potassium, blood urea nitrogen, glucose, hematocrit, and hemoglobin in healthy and diseased rabbits. Blood samples obtained from 30 pet rabbits were analyzed immediately after collection by the portable clinical analyzer (PCA) and immediately thereafter (time <20 sec) by a reference analyzer. Bland-Altman plots and Passing-Bablok regression analysis were used to compare the results. Limits of agreement were wide for all the variables studied, with the exception of pH. Most variables presented significant proportional and/or constant bias. The current study provides sufficient evidence that the PCA presents reliability for pH, although its low agreement with a reference analyzer for the other variables does not support their interchangeability. Limits of agreement provided for each variable allow researchers to evaluate if the PCA is reliable enough for their scope. To the authors' knowledge, the present is the first report evaluating a PCA in the rabbit. PMID- 25028434 TI - Gastrointestinal perforation associated with endoscopy in cats and dogs. AB - Gastrointestinal endoscopy is a minimally invasive diagnostic tool for cats and dogs with signs of gastrointestinal disease. This retrospective study examined the case records of six cats and one dog diagnosed with perforation secondary to gastrointestinal endoscopy. Gastrointestinal perforation occurred in 1.6% of cats and 0.1% of dogs that underwent endoscopy during the 17 yr study period (from 1993 to 2010). It can be difficult to predict what animals are at risk for gastrointestinal perforation but possible risk factors suggested by this study include small intestinal infiltrative disease in cats and preexisting gastrointestinal ulceration in both cats and dogs. Overall, gastrointestinal endoscopy is associated with a low rate of gastrointestinal perforation. PMID- 25028435 TI - Abdominal chronic expanding hematoma causing iron-deficiency anemia in a dog. AB - A 2 yr old spayed female mixed-breed Irish wolfhound was referred for assessment of anemia and slowly progressing abdominal distention. At the time of admission, the dog had marked anemia and thrombocytosis, a decreased serum iron concentration, and a normal coagulation profile. An ultrasound examination showed a massive fluid-filled cavitated structure in the abdominal cavity. Paracentesis of that structure yielded a large amount of hemorrhagic fluid with an iron concentration >24 times greater than the serum iron concentration, consistent with chronic sequestration of iron, leading to iron-deficiency anemia. Blood transfusions and incomplete surgical removal of the structure allowed short-term stabilization of the patient, but the dog was euthanized 17 days postsurgery for lethargy and continued abdominal distention. Histopathological evaluation of the structure was consistent with a chronic expanding hematoma. To the authors' knowledge, this is the first reported case of intra-abdominal chronic expanding hematoma in a dog. It is also unique given its features of iron-deficiency anemia caused by internal blood loss. PMID- 25028436 TI - Assessment of a veterinary dipstick for determination of urine protein/creatinine ratio in canines. AB - The urine protein/creatinine ratio (UPC) is a widely used screening test of glomerular barrier function. It usually requires sending urine samples to a distant laboratory, which is costly and time consuming. A point-of-care urine dipstick that could accurately measure UPC would increase test utility and utilization. The objective of this study was to determine if there was good correlation and agreement between UPC as measured by a dipstick and a laboratory analyzer. Thirty-one canines undergoing UPC measurement as part of a diagnostic workup were included in the study. A total of 2 mL of urine was collected via cystocentesis. Urine was applied to the dipstick then presented to two blinded reviewers to analyze. The remaining urine was submitted to a clinical pathology laboratory for analysis. UPC data from the dipsticks and the analyzer was converted into an ordinal scale. Correlation and agreement between the individual reviews and the analyzer was calculated. Agreement between reviewers was substantial; however, correlation and agreement between the individual reviews and the analyzer was low. On the basis of this information, use of this veterinary urinary dipstick to determine UPC cannot be recommended at this time. PMID- 25028437 TI - Common confounders of dietary elimination trials contain the antigens soy, pork, and beef. AB - Nutritionists and dermatologists recommend avoiding flavored over-the-counter (OTC) products and medications during dietary elimination trials because those products are thought to contain common proteins that may confound the trial. The objective of this study was to determine if there are soy, pork, and beef antigens in flavored OTC products and medications and, if so, could those antigens be identified. Seven products, three OTC products and four veterinary therapeutics, were tested using enzyme-linked immunosorbent assays (ELISA) for the presence of soy, pork, and beef antigens, in addition to positive and negative controls. All OTC test products produced ELISA results in agreement with their ingredient lists. ELISA testing of veterinary therapeutic products did not agree with either their ingredient lists or product inserts because of other ingredients not listed. Veterinarians should contact manufacturers of oral therapeutics prior to prescribing them to determine other ingredients. Likewise, manufacturers should be contacted regarding "natural and artificial flavors." Lastly, gelatin capsules may contain either beef or pork proteins and should not be administered during a trial. In conclusion, flavored medications contain the common antigens soy, pork, and beef although they may or may not be listed on the ingredient list or product insert. PMID- 25028438 TI - Mural endocarditis caused by Corynebacterium mustelae in a dog with a VSD. AB - A 6 yr old female spayed large Munsterlander was evaluated following a 3 wk history of lethargy, inappetence, intermittent fever, and a recent change to the timing of her previously diagnosed heart murmur. Physical examination revealed marked dehydration, lethargy, and a grade 5/6 to-and-fro heart murmur that was auscultated best at the right sternal border. The dog was febrile, and echocardiography revealed a large, mobile, vegetative lesion in the right ventricular outflow tract associated with a ventricular septal defect (VSD). Mild aortic insufficiency was present. Corynebacterium mustelae (C. mustelae) was isolated from a pooled blood culture. Treatment of infective endocarditis (IE) was initiated along with supportive care, and the patient was discharged 9 days later. The dog remained without clinical signs 132 days after discharge. VSD is rarely mentioned as a predisposing factor for development of IE in veterinary literature; however, this report highlights that dogs with a VSD may be at risk for IE. To the authors' knowledge, this is the first documented case of a canine infection with C. mustelae. Infection with C. mustelae in this case represents a novel agent for IE in the dog. PMID- 25028439 TI - Resolution of polyneuropathy in a hypothyroid dog following thyroid supplementation. AB - An 8 yr old male golden retriever was evaluated because of chronic, progressive, multiple neurologic signs. Physical examination showed marked obesity and facial swelling with a "tragic facial expression." Neurologic evaluation revealed the dog had multiple cranial nerve deficits and lower motor neuron signs in the pelvic limbs. Serum biochemical analysis and thyroid function tests were consistent with hypothyroidism. A biopsy from the common peroneal nerve revealed a loss of myelinated fibers, inappropriately thin myelinated fibers, and resolving subperineurial edema. The diagnosis of polyneuropathy associated with hypothyroidism was made. Levothyroxine therapy was initiated. Response to levothyroxine treatment was slow, with most neurologic abnormalities persisting for >6 wk. However, the dog made a full neurologic recovery within 6 mo. Although the occurrence of polyneuropathy in dogs resulting from hypothyroidism has been controversial, the study authors demonstrated that hypothyroid polyneuropathy can occur in dogs as documented in humans. This is the first report describing long term follow-up information together with detailed pathological features of hypothyroid polyneuropathy in a dog. In hypothyroid polyneuropathy, the response to thyroid replacement may be slow, but a recovery can be expected if treatment is initiated before peripheral nerve fiber loss becomes severe. PMID- 25028440 TI - Systematic review of surgical treatments for cranial cruciate ligament disease in dogs. AB - Surgery for cranial cruciate ligament disease is often recommended; however, it is unclear if one procedure is superior. The aim of this systematic review was to answer the a priori question, "Is there a surgical procedure that will allow a consistent return to normal clinical function in dogs with cranial cruciate ligament disease and is that procedure superior to others?" A systematic literature search was performed through September 2013. Peer reviewed publication in the English language and 6 mo of postoperative follow-up were required. In total, 444 manuscripts were identified and reviewed, and 34 met the inclusion criteria. Two studies provided level 1, 6 provided level 2, 6 provided level 3, and 20 provided level 4 evidence relative to the study question. The most common surgical procedures included tibial plateau leveling osteotomy (TPLO, n = 14), lateral extracapsular suture (n = 13), tibial tuberosity advancement (n = 6). The strength of the evaluated evidence most strongly supports the ability of the TPLO in the ability to return dogs to normal function. It also provided strong support that functional recovery in the intermediate postoperative time period was superior following TPLO compared with lateral extracapsular suture. There was insufficient data to adequately evaluate other surgical procedures. PMID- 25028441 TI - Copperhead (Agkistrodon contortrix) envenomation of dogs: 52 cases (2004-2011). AB - Copperhead envenomation is common within the US, and no studies exist describing the clinical course of copperhead envenomation in dogs. Almost all treatment decisions regarding those bites are extrapolated from retrospective studies evaluating the clinical course of rattlesnake bites. Because copperheads and rattlesnakes produce venom with different potency, assumptions that treatment of the different envenomations should be similar may be incorrect. The purpose of this retrospective study was to evaluate the clinical course of copperhead envenomation in dogs and administered treatments. Medical records of 52 dogs treated for copperhead envenomation were reviewed, and owners were contacted regarding outcome. The most common clinical signs associated with copperhead envenomation included swelling, pain, and ecchymosis. Clinicopathological abnormalities (e.g., thrombocytopenia, elevated clotting times, leukocytosis) were mild, and red blood cell morphology changes and coagulopathies were rare. Most dogs were treated with antimicrobials, analgesics, and fluid therapy. No dogs in this study required the use of antivenin and all survived to discharge. This study found that the clinical course after copperhead envenomation is generally limited to local rather than systemic illness. Copperhead envenomation in dogs is largely self-limiting and responsive to supportive care with hospitalization for monitoring. PMID- 25028442 TI - Paragonimosis in a cat and the temporal progression of pulmonary radiographic lesions following treatment. AB - A 16 mo old cat presented with a 5 mo history of dyspnea, coughing, and gagging. Radiographic findings revealed seven nodules measuring 1-3 cm distributed multifocally in the lungs. Examination of feces revealed large numbers of eggs of Paragonimus kellicotti. Two fenbendazole treatment regimens (28 mg/kg per os q 12 hr for 21 days) and prednisone were required to eliminate the infection. Resolution of pulmonary nodules was monitored for 8 mo following successful treatment, and four lesions were still partially visible at 8 mo. PMID- 25028443 TI - Mortal harm and the antemortem experience of death. PMID- 25028444 TI - Von Willebrand factor drives the association between elevated factor VIII and poor outcomes in patients with ischemic stroke. AB - BACKGROUND AND PURPOSE: Despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few studies have examined the relationship of these factors with acute ischemic stroke (AIS). We sought to determine whether concurrent elevation in FVIII and vWF was associated with adverse events and outcomes. METHODS: From our prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October 2013 were included if both FVIII and vWF were measured during admission. The primary outcome was the modified Rankin Scale score on discharge. RESULTS: Among 1453 cases in our stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9%) had FVIII-/vWF-, 16 patients (10.8%) had FVIII+/vWF-, and 51 patients (34.5%) had FVIII+/vWF+. In the fully adjusted model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio, 8.6; 95% confidence interval, 1.58 46.85; P=0.013) and neuroworsening (odds ratio, 3.2; 95% confidence interval, 1.18-8.73; P=0.022) than patients with FVIII-/vWF-. Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had increased odds of poor functional outcome (modified Rankin Scale>2; odds ratio, 2.87; 95% confidence interval, 1.16-7.06; P=0.021) than patients with FVIII-/vWF-. CONCLUSIONS: Concurrent FVIII/vWF elevation predicts higher odds of inpatient complications, neuroworsening, and worse functional outcomes for patients with AIS compared with patients with normal levels. Our findings suggest that FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS. PMID- 25028445 TI - Morphology of susceptibility vessel sign predicts middle cerebral artery recanalization after intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: We aimed to evaluate the predictive value of susceptibility vessel sign (SVS) burden and morphology in middle cerebral artery recanalization. METHODS: We retrospectively examined clinical and imaging data from 72 consecutive patients with acute ischemic stroke with middle cerebral artery occlusion and examined the association of recanalization with SVS length and shape. RESULTS: None of the patients with a middle cerebral artery SVS >20 mm in length achieved recanalization. For patients with a relatively short SVS (length <20 mm), irregular shape was a strong independent predictor for no recanalization (odds ratio, 6.891; 95% confidence interval, 1.441-32.950; P=0.016). CONCLUSIONS: Irregular shape and long length (>20 mm) of SVS decrease the potential to recanalize the occluded middle cerebral artery with intravenous thrombolysis. PMID- 25028446 TI - Clinical features and outcomes of spinal cord arteriovenous malformations: comparison between nidus and fistulous types. AB - BACKGROUND AND PURPOSE: As a result of the rarity of spinal cord arteriovenous malformations (AVM), there are only a few series available that describe clinical features, outcome after treatment, and natural history of these lesions. In this article, we aim to describe our experience with both nidus- and fistulous-type spinal cord AVMs. METHODS: Forty-four consecutive patients with spinal cord AVMs were retrospectively reviewed. There were 26 patients with a nidus-type and 18 patients with a fistulous-type AVM. Treatments were performed with embolization (n=23), surgery (n=13), combined embolization-surgery (n=3), or conservative management (n=5). Clinical features, radiological findings, treatment results, and clinical outcomes were assessed. RESULTS: Patients with nidus-type AVMs were younger at presentation and more often presented with hemorrhage, with a higher proportion of hematomyelia than fistulous-type AVMs (P<0.05). Progression of clinical presentation from hemorrhage to congestive myelopathy during follow-up was noted in 5 patients, all of which had AVMs of the nidus type. Complete obliteration could be achieved more often in the fistulous type (72%) than in the nidus type (27%). Improved or stable clinical status at last follow-up was noted in 100% of fistulous-type and 77% of nidus-type patients. Long-term clinical deterioration was noted in 6 of 26 patients with nidus-type (23%) AVMs and was related to recurrent bleeding (n=3) or progressive venous congestion (n=3). Overall rebleed rate after presentation with hemorrhage was 7 in 145.5 patient years (4.8%/y) if the lesion was not treated, 3 in 102 patient-years (2.9%/y) after partial treatment, and 0 in 47.5 patient-years (0%) after complete treatment. CONCLUSIONS: Nidus and fistulous spinal cord AVMs have different clinical features and obliteration rates, which may affect their long-term prognosis. PMID- 25028447 TI - Socioeconomic status inconsistency and risk of stroke among Japanese middle-aged women. AB - BACKGROUND AND PURPOSE: Little research has been conducted to examine the effect of inconsistencies in socioeconomic status on cardiovascular health. In particular, no studies have been reported in Asian countries, including Japan, which is thought to have high socioeconomic status inconsistency among women. METHODS: We examined the effect of status inconsistency between education level and occupation on stroke risk in a prospective 20-year study of 14 742 middle aged Japanese women included in the prospective Japan Public Health Center-based (JPHC) Study Cohort I in 1990. Status inconsistency between education level and occupation was determined (qualified, overqualified, and underqualified), and the association with risk of stroke was examined. Cox proportional regression analysis was used to determine hazard ratios, which were adjusted for age, marital status, and geographical area. RESULTS: Adjusted hazard ratio for stroke in overqualified compared with qualified women was 2.06 (95% confidence interval, 1.13-3.78). Adjusted hazard ratios for stroke among highly educated manual workers and workers in service industry were 3.47 (95% confidence interval, 1.54 7.84) and 3.21 (95% confidence interval, 1.49-6.90), respectively, when compared with highly educated professionals/managers. CONCLUSIONS: High academic qualifications without an appropriate job could be a risk factor for stroke among Japanese women. Our result suggests that status inconsistency could be a potential explanation for the increased stroke risk among highly educated women. PMID- 25028449 TI - Cerebral microbleeds: is antithrombotic therapy safe to administer? PMID- 25028448 TI - Risk score to predict hospital-acquired pneumonia after spontaneous intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: We aimed to develop a risk score (intracerebral hemorrhage-associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. METHODS: The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer-Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. RESULTS: The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively. A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0.72-0.77) and validation (AUROC, 0.76; 95% confidence interval, 0.71-0.79) cohorts. The ICH-APS A was more sensitive for patients with length of stay >48 hours (AUROC, 0.78; 95% confidence interval, 0.75-0.81) than those with length of stay <48 hours (AUROC, 0.64; 95% confidence interval, 0.55-0.73). The ICH-APS-A was well calibrated (Hosmer-Lemeshow test) in the derivation (P=0.20) and validation (P=0.66) cohorts. Similarly, a 26-point ICH-APS-B was established. The ICH-APS-A and ICH APS-B were not significantly different in discrimination and reclassification for SAP after ICH. CONCLUSION: The ICH-APSs are valid risk scores for predicting SAP after ICH, especially for patients with length of stay >48 hours. PMID- 25028450 TI - Trends in 10-year survival of patients with stroke hospitalized between 1980 and 2000: the Minnesota stroke survey. AB - BACKGROUND AND PURPOSE: We report on trends in poststroke survival, both in the early period after stroke and over the long term. We examine these trends by stroke subtype. METHODS: The Minnesota Stroke Survey is a study of all hospitalized patients with acute stroke aged 30 to 74 years in the Minneapolis-St Paul metropolis. Validated stroke events were sampled for survey years 1980, 1985, 1990, 1995, and 2000 and subtyped as ischemic or hemorrhagic by neuroimaging for survey years 1990, 1995, and 2000. Survival was obtained by linkage to vital statistics data through the year 2010. RESULTS: There were 3773 acute stroke events. Age-adjusted 10-year survival improved from 1980 to 2000 (men 29.5% and 46.5%; P<0.0001; women 32.6% and 50.5%; P<0.0001). Ten-year ischemic stroke survival (n=1667) improved from 1990 to 2000 (men 35.3% and 50%; P=0.0001; women 38% and 55.3%; P<0.0001). Ten-year hemorrhagic stroke survival showed a trend toward improvement, but this (n=489) did not reach statistical significance, perhaps because of their smaller number (men 29.7% and 45.8%; P=0.06; women 39.2% and 49.6%; P=0.2). Markers of stroke severity including unconsciousness or major neurological deficits at admission declined from 1980 to 2000 while neuroimaging use increased. CONCLUSIONS: These poststroke survival trends are likely because of multiple factors, including more sensitive case ascertainment shifting the case mix toward less severe strokes, improved stroke care and risk factor management, and overall improvements in population health and longevity. PMID- 25028452 TI - Case finding advantage of HIV rapid tests in community settings: men who have sex with men in 12 programme areas in China, 2011. AB - We sought to describe the advantage of rapid tests over ELISA tests in community based screening for HIV among men who have sex with men (MSM) in urban areas of China. Data of 31,406 screening tests conducted over six months in 2011 among MSM across 12 areas were analyzed to compare the differences between those receiving rapid testing and ELISA. Rapid tests accounted for 45.8% of these screening tests. The rate of being screened positive was 7.2% among rapid tests and 5.3% for ELISA tests (chi(2 )= 49.161, p < 0.001). This advantage of rapid test in HIV case finding persisted even when socio-demographic, behavioural, screening recruitment channel and city were controlled for in logistic regression (exp[beta] = 1.42, p < 0.001, 95% CI = 1.27,1.59). MSM who received rapid tests, compared with those tested by ELISA, were less likely to use condoms during last anal sex (50.8% vs. 72.3%, chi(2 )= 1706.146, p < 0.001), more likely to have multiple sex partners (55.7% vs. 49.5%, chi(2 )= 238.188, p < 0.001) and less likely to have previously undergone HIV testing (38.8% vs. 54.7%, chi(2 )= 798.476, p < 0.001). These results demonstrate the robustness of the advantage of rapid tests over traditional ELISA tests in screening for MSM with HIV infection in cooperation with community-based organizations in urban settings in China. PMID- 25028451 TI - Deficiency of the ferrous iron transporter FeoAB is linked with metronidazole resistance in Bacteroides fragilis. AB - BACKGROUND: Metronidazole is the most commonly used antimicrobial for Bacteroides fragilis infections and is recommended for prophylaxis of colorectal surgery. Metronidazole resistance is increasing and the mechanisms of resistance are not clear. METHODS: A transposon mutant library was generated in B. fragilis 638R (BF638R) to identify the genetic loci associated with resistance to metronidazole. RESULTS: Thirty-two independently isolated metronidazole-resistant mutants had a transposon insertion in BF638R_1421 that encodes the ferrous transport fusion protein (feoAB). Deletion of feoAB resulted in a 10-fold increased MIC of metronidazole for the strain. The metronidazole MIC for the feoAB mutant was similar to that for the parent strain when grown on media supplemented with excess iron, suggesting that the increase seen in the MIC of metronidazole was due to reduced cellular iron transport in the feoAB mutant. The furA gene repressed feoAB transcription in an iron-dependent manner and disruption of furA resulted in constitutive transcription of feoAB, regardless of whether or not iron was present. However, disruption of feoAB also diminished the capacity of BF638R to grow in a mouse intraperitoneal abscess model, suggesting that inorganic ferrous iron assimilation is essential for B. fragilis survival in vivo. CONCLUSIONS: Selection for feoAB mutations as a result of metronidazole treatment will disable the pathogenic potential of B. fragilis and could contribute to the clinical efficacy of metronidazole. While mutations in feoAB are probably not a direct cause of clinical resistance, this study provides a key insight into intracellular metronidazole activity and the link with intracellular iron homeostasis. PMID- 25028453 TI - HSV oropharyngeal shedding among HIV-infected children in Tanzania. AB - Herpes simplex virus (HSV) oral shedding has not been studied among HIV-positive children in Africa. We sought to evaluate longitudinal oral HSV reactivation in HIV-positive and -negative children. Twenty HIV-positive antiretroviral-naive and 10 HIV-negative children aged 3-12 years in Tanzania were followed prospectively for 14 days. Oral swabs were collected daily and submitted for HSV DNA PCR analysis. Clinical data were collected via chart review and daily diaries. HSV DNA was detected in 10 (50%) of HIV-positive and 4 (40%) of HIV-negative children. Children who shed HSV had virus detected in a median of 21.4% of samples; shedding was intermittent. Median CD4 count among HIV-infected children was 667 cells/uL in those with positive HSV DNA and 886 cells/uL in those who were negative (p = 0.6). Of the HIV-positive children reporting prior sores, five (83%) had positive HSV swabs, whereas the one HIV-negative child with prior sores did not have a PCR-positive swab. HSV is detected frequently in children with and without HIV. HIV-infected children reporting oral sores have a high rate of HSV detection. Given the proven strong interactions between HIV and HSV, further study of co-infection with these viruses is warranted in children. PMID- 25028454 TI - Decreased glutathione and low catalase activity contribute to oxidative stress in children with alpha-1 antitrypsin deficiency. AB - BACKGROUND: Recent investigations in animal models have revealed oxidative stress and oxidative damage in the pathogenesis of alpha-1 antitrypsin deficiency (AATD). However, no data are available on the oxidative stress status and antioxidant enzyme activity in these patients. This study was aimed to analyse the oxidative stress profile and enzymatic antioxidant defence mechanisms in children with AATD. METHODS: Oxidative stress parameters and the activity of the main antioxidant enzymes were prospectively measured in serum of fifty-one children diagnosed with AATD and thirty-eight control individuals. RESULTS: Oxidative stress was increased in the serum of children with intermediate- (MZ; SZ) and high-risk (ZZ) phenotypes for developing AATD-related emphysema and/or liver disease. When compared with the control group, intermediate- and high-risk groups showed significantly lower total glutathione and reduced glutathione levels, decreased catalase activity and increased glutathione peroxidase activity leading to an accumulation of hydrogen peroxide that would explain the significantly increased levels of oxidative stress biomarkers observed in these patients. No differences were observed between the control (MM) and the low-risk (MS; SS) groups. A gradation in oxidative stress parameters was observed when patients were compared among themselves, in that the expression of the Z allele produces a higher oxidative stress status in homozygous (ZZ) than in heterozygous (MZ; SZ) patients. CONCLUSIONS: Increased oxidative stress, together with reduced antioxidant defence are involved in the pathophysiology of AATD at early stages, opening up a new rationale for the use of antioxidant therapies in the treatment of the disease. PMID- 25028455 TI - Pulmonary vascular volumes and airways obstruction in SCD patients. PMID- 25028456 TI - Physicians' human papillomavirus vaccine recommendations in the context of permissive guidelines for male patients: a national study. AB - BACKGROUND: Little is known about physicians' human papillomavirus (HPV) vaccine recommendations for males while the Advisory Committee on Immunization Practices' (ACIP) permissive guidelines for male vaccination were in effect. The purpose of this study was to examine and explore factors associated with U.S. physicians' HPV vaccine recommendations to early (ages 11-12), middle (13-17), and late adolescent/young adult (18-26) males. METHODS: Nationally representative samples of family physicians and pediatricians were selected in 2011 (n = 1,219). Physicians reported the frequency with which they recommended HPV vaccine to male patients ["always" (>75% of the time) vs. other] for each age group. Statistically significant predictors of vaccine recommendation were identified using multivariable logistic regression. RESULTS: The prevalence of physicians reporting they "always" recommended HPV vaccination for males was 10.8% for ages 11 to 12, 12.9% for ages 13 to 17, and 13.2% for ages 18 to 26. Pediatrician specialty and self-reported early adoption of new vaccines were significantly associated with recommendation for all patient age groups. In addition, physician race and patient payment method were associated with physician recommendations to patients ages 11 to 12, and patient race was associated with recommendations to ages 13 to 17 and 18 to 26. CONCLUSIONS: Less than 15% of physicians surveyed reported "always" recommending HPV vaccine to male patients following national guidelines for permissive vaccination. Vaccine financing may have affected physicians' vaccine recommendations. IMPACT: If these recommendation practices continue following the ACIP's routine recommendation for males in October 2011, then interventions designed to increase recommendations should target family physicians and possibly use early adopters to encourage support of HPV vaccination guidelines. PMID- 25028457 TI - Factors associated with adherence to an end-of-study biopsy: lessons from the prostate cancer prevention trial (SWOG-Coordinated Intergroup Study S9217). AB - BACKGROUND: The Prostate Cancer Prevention Trial (PCPT) was a 7-year randomized, double-blind, placebo-controlled trial of the efficacy of finasteride for the prevention of prostate cancer with a primary outcome of histologically determined prevalence of prostate cancer at the end of 7 years. METHODS: A systematic modeling process using logistic regression identified factors available at year 6 that are associated with end-of-study (EOS) biopsy adherence at year 7, stratified by whether participants were ever prompted for a prostate biopsy by year 6. Final models were evaluated for discrimination. At year 6, 13,590 men were available for analysis. RESULTS: Participants were more likely to have the EOS biopsy if they were adherent to study visit schedules and procedures and/or were in good health (P < 0.01). Participants at larger sites and/or sites that received retention and adherence grants were also more likely to have the EOS biopsy (P < 0.05). CONCLUSIONS: Our results show good adherence to study requirements 1 year before the EOS biopsy was associated with greater odds that a participant would comply with the invasive EOS requirement. IMPACT: Monitoring adherence behaviors may identify participants at risk of nonadherence to more demanding study end points. Such information could help frame adherence intervention strategies in future trials. PMID- 25028459 TI - Characterization of uncultured giant rod-shaped magnetotactic Gammaproteobacteria from a freshwater pond in Kanazawa, Japan. AB - Magnetotactic bacteria (MTB) are widespread aquatic bacteria, and are a phylogenetically, physiologically and morphologically heterogeneous group, but they all have the ability to orientate and move along the geomagnetic field using intracellular magnetic organelles called magnetosomes. Isolation and cultivation of novel MTB are necessary for a comprehensive understanding of magnetosome formation and function in divergent MTB. In this study, we enriched a giant rod shaped magnetotactic bacterium (strain GRS-1) from a freshwater pond in Kanazawa, Japan. Cells of strain GRS-1 were unusually large (~13*~8 um). They swam in a helical trajectory towards the south pole of a bar magnet by means of a polar bundle of flagella. Another striking feature of GRS-1 was the presence of two distinct intracellular biomineralized structures: large electron-dense granules composed of calcium and long chains of magnetosomes that surround the large calcium granules. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that this strain belongs to the Gammaproteobacteria and represents a new genus of MTB. PMID- 25028458 TI - The RcsCDB regulatory system plays a crucial role in the protection of Salmonella enterica serovar Typhimurium against oxidative stress. AB - Dps, the most abundant protein during the stationary growth phase, in Salmonella enterica is required for resistance to reactive oxygen species produced by the host during infection. It has been reported that in Salmonella dps expression is controlled by RpoS and Fur proteins. However, the regulation and function of Dps remain to be resolved. In the present work we demonstrate that activation of the complex RcsCDB regulatory system increases dps expression during exponential growth of Salmonella. In addition, we show that such dps upregulation produces high levels of H2O2 resistance. This phenotype allows the bacteria to avoid reactive oxygen species killing at early stages of growth, thus protecting its genetic material. PMID- 25028460 TI - Plasticity of fimbrial genotype and serotype within populations of Bordetella pertussis: analysis by paired flow cytometry and genome sequencing. AB - The fimbriae of Bordetella pertussis are required for colonization of the human respiratory tract. Two serologically distinct fimbrial subunits, Fim2 and Fim3, considered important vaccine components for many years, are included in the Sanofi Pasteur 5-component acellular pertussis vaccine, and the World Health Organization recommends the inclusion of strains expressing both fimbrial serotypes in whole-cell pertussis vaccines. Each of the fimbrial major subunit genes, fim2, fim3, and fimX, has a promoter poly(C) tract upstream of its -10 box. Such monotonic DNA elements are susceptible to changes in length via slipped strand mispairing in vitro and in vivo, which potentially causes on/off switching of genes at every cell division. Here, we have described intra-culture variability in poly(C) tract lengths and the resulting fimbrial phenotypes in 22 recent UK B. pertussis isolates. Owing to the highly plastic nature of fimbrial promoters, we used the same cultures for both genome sequencing and flow cytometry. Individual cultures of B. pertussis contained multiple fimbrial serotypes and multiple different fimbrial promoter poly(C) tract lengths, which supports earlier serological evidence that B. pertussis expresses both serotypes during infection. PMID- 25028462 TI - Feasibility of universal HIV testing in an outpatient clinic. PMID- 25028461 TI - A concentration addition model to assess activation of the pregnane X receptor (PXR) by pesticide mixtures found in the French diet. AB - French consumers are exposed to mixtures of pesticide residues in part through food consumption. As a xenosensor, the pregnane X receptor (hPXR) is activated by numerous pesticides, the combined effect of which is currently unknown. We examined the activation of hPXR by seven pesticide mixtures most likely found in the French diet and their individual components. The mixture's effect was estimated using the concentration addition (CA) model. PXR transactivation was measured by monitoring luciferase activity in hPXR/HepG2 cells and CYP3A4 expression in human hepatocytes. The three mixtures with the highest potency were evaluated using the CA model, at equimolar concentrations and at their relative proportion in the diet. The seven mixtures significantly activated hPXR and induced the expression of CYP3A4 in human hepatocytes. Of the 14 pesticides which constitute the three most active mixtures, four were found to be strong hPXR agonists, four medium, and six weak. Depending on the mixture and pesticide proportions, additive, greater than additive or less than additive effects between compounds were demonstrated. Predictions of the combined effects were obtained with both real-life and equimolar proportions at low concentrations. Pesticides act mostly additively to activate hPXR, when present in a mixture. Modulation of hPXR activation and its target genes induction may represent a risk factor contributing to exacerbate the physiological response of the hPXR signaling pathways and to explain some adverse effects in humans. PMID- 25028464 TI - The role of postoperative factors in surgical site infections: time to take notice. AB - Surgical site infections (SSIs) continue to occur, in many instances despite high compliance with best practice measures primarily revolving around pre- and intraoperative periods. Postoperative factors have traditionally been considered to play a relatively minor role in the causation of SSIs. An increasing body of evidence, however, suggests that many SSIs occur as a result of pathogens gaining access to surgical wounds either hematogenously, through drains, or through slowly healing wounds due to systemic anticoagulation or other factors, particularly in the setting of high compliance with standard perioperative antibiotic prophylaxis. Evidence also supports frequent acquisition of methicillin-resistant Staphylococcus aureus (MRSA) during the postoperative period. These findings, coupled with lack of clear efficacy of various pre- and intraoperative interventions such as MRSA decolonization and use of vancomycin for prophylaxis against this organism, should force us to consider the important role that postoperative factors may play in the causation of SSIs in the current era. PMID- 25028463 TI - Sputum culture conversion with moxifloxacin-containing regimens in the treatment of patients with newly diagnosed sputum-positive pulmonary tuberculosis in South India. AB - BACKGROUND: Rapid sputum culture conversion at 2 months indicates the sterilizing capacity and potential of regimens to shorten duration of tuberculosis treatment. We compared results of sputum culture conversion by moxifloxacin and control regimens and identified factors affecting sputum culture positivity after 2 months of treatment. METHODS: Human immunodeficiency virus-uninfected adults with newly diagnosed smear-positive pulmonary tuberculosis were randomized to receive a 3- or 4-month moxifloxacin regimen (moxifloxacin [M], isoniazid [H], rifampicin [R], pyrazinamide [Z], ethambutol [E]) or the control regimen (RHZE thrice weekly). Bacteriological assessments were done at 15, 30, 45, and 60 days of treatment. Because all patients in the moxifloxacin groups received 2 months of daily RHZEM, they were grouped together for analysis. Statistical methods included chi(2) test and logistic regression analysis. RESULTS: Sputum culture conversion was analyzed in 780 (616 in the moxifloxacin group and 164 in the control group) of 801 enrolled patients. Ninety-five percent of 590 patients in the moxifloxacin group and 81% of 151 patients in the control group had negative sputum cultures at month 2 (P < .001). The control regimen, age (>=35 years), initial sputum culture grade (2+ or 3+), and male sex were significantly associated with higher odds of positive sputum cultures at 2 months. CONCLUSIONS: A 5-drug daily regimen with moxifloxacin results in significantly higher sputum culture conversion in the first 2 months compared with a thrice-weekly, 4-drug regimen in patients with newly diagnosed sputum-positive pulmonary tuberculosis. PMID- 25028465 TI - Veterinarians' attitudes to chronic pain in dogs. AB - Veterinary surgeons in the UK were invited to complete an internet survey concerning their attitudes to chronic pain in dogs. UK veterinary surgeons numbering 215 completed surveys in full along with 48 worldwide specialists in anaesthesia and 37 worldwide specialists in oncology. Osteoarthritis, dental and aural disease, vertebral and spinal cord conditions, neoplasia and skin conditions were considered important causes of chronic pain in dogs. UK practitioners used significantly fewer classes of analgesic drugs regularly than either category of specialist. The major barriers to adequate treatment of chronic pain were reported as difficulties with pain assessment, expense of drugs, and difficulties with owner compliance. Illustrations of six common neoplastic conditions were used and scored for pain according to prior experience by practitioners. All six conditions were consistently described as involving some degree of pain with primary bone tumour and oral tumour, causing severe pain and moderate to severe pain, respectively. Years since graduation and specialist status affected the pain scores attributed to the conditions. There was a significant correlation between the pain score attributed to the illustrated condition, and the tendency to administer analgesia. PMID- 25028466 TI - Feline hyperthyroidism reported in primary-care veterinary practices in England: prevalence, associated factors and spatial distribution. AB - Feline hyperthyroidism is a commonly diagnosed endocrinopathy that can have a substantial deleterious impact on the welfare of affected cats. This study aimed to estimate the prevalence, associated factors and geographical distribution for feline hyperthyroidism in England, using primary-care veterinary practice clinical data from the VetCompass Animal Surveillance Project. Prevalence was estimated from the overall cat cohort. Associated factor analysis used an age matched, nested, case-control design with multivariable logistic regression. There were 2,276 cases of feline hyperthyroidism identified from 95,629 cats attending 84 practices from September 2009 to December 2011. Cases were aged 6-25 years. 3.7 per cent of cases and 9.9 per cent of controls were purebred, 56.4 per cent of cases and 56.5 per cent of controls were female, and 88.1 per cent of cases and 86.0 per cent of controls were neutered. The apparent prevalence was 2.4 per cent (95% CI 2.3 to 2.5 per cent) overall, and 8.7 per cent (95% CI 8.3 to 9.0 per cent) in cats aged 10 years or above. Burmese (OR 0.15, 95% CI 0.07 to 0.32, P<0.0001), Persian (OR 0.17, 95% CI 0.08 to 0.33, P<0.0001), Siamese (OR 0.4, 95% CI 0.21 to 0.75, P=0.004) and purebred cats overall (OR 0.33, 95% CI 0.25 to 0.42, P< 0.0001) had lower odds of feline hyperthyroidism than non purebred cats. Insured cats had increased odds (OR 1.78, 95% CI 1.56 to 2.03, P< 0.001). There was little evidence of spatial variation. This study highlights feline hyperthyroidism as a high-prevalence disease in England, and reports reduced odds of diagnosis in certain breeds and purebred cats overall. PMID- 25028467 TI - Inner workings: face processing. PMID- 25028469 TI - Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. AB - Well-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are among the most common subtypes of soft tissue sarcomas. Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients. The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in more than 95% of WD/DDLPS. In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts. We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma (RB) phosphorylation and dramatically decreased liposarcoma cell growth. Cell-cycle analysis demonstrated arrest at G0-G1. siRNA mediated knockdown of RB rescued the inhibitory effects of LEE011, demonstrating that LEE011 decreased proliferation through RB. Oral administration of LEE011 to mice bearing human liposarcoma xenografts resulted in approximately 50% reduction in tumor (18)F-fluorodeoxyglucose uptake with decreased tumor biomarkers, including RB phosphorylation and bromodeoxyuridine incorporation in vivo. Continued treatment inhibited tumor growth or induced regression without detrimental effects on mouse weight. After prolonged continuous dosing, reestablishment of RB phosphorylation and cell-cycle progression was noted. These findings validate the critical role of CDK4 in maintaining liposarcoma proliferation through its ability to inactivate RB function, and suggest its potential function in the regulation of survival and metabolism of liposarcoma, supporting the rationale for clinical development of LEE011 for the treatment of WD/DDLPS. PMID- 25028470 TI - Quinacrine overcomes resistance to erlotinib by inhibiting FACT, NF-kappaB, and cell-cycle progression in non-small cell lung cancer. AB - Erlotinib is a tyrosine kinase inhibitor approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest because many tumors express wild type (wt) EGFR or develop a second-site EGFR mutation. To test drug combinations that could improve the efficacy of erlotinib, we combined erlotinib with quinacrine, which inhibits the FACT (facilitates chromatin transcription) complex that is required for NF-kappaB transcriptional activity. In A549 (wtEGFR), H1975 (EGFR-L858R/T790M), and H1993 (MET amplification) NSCLC cells, this drug combination was highly synergistic, as quantified by Chou-Talalay combination indices, and slowed xenograft tumor growth. At a sub-IC50 but more clinically attainable concentration of erlotinib, quinacrine, alone or in combination with erlotinib, significantly inhibited colony formation and induced cell-cycle arrest and apoptosis. Quinacrine decreased the level of active FACT subunit SSRP1 and suppressed NF-kappaB-dependent luciferase activity. Knockdown of SSRP1 decreased cell growth and sensitized cells to erlotinib. Moreover, transcriptomic profiling showed that quinacrine or combination treatment significantly affected cell-cycle related genes that contain binding sites for transcription factors that regulate SSRP1 target genes. As potential biomarkers of drug combination efficacy, we identified genes that were more strongly suppressed by the combination than by single treatment, and whose increased expression predicted poorer survival in patients with lung adenocarcinoma. This preclinical study shows that quinacrine overcomes erlotinib resistance by inhibiting FACT and cell-cycle progression, and supports a clinical trial testing erlotinib alone versus this combination in advanced NSCLC. PMID- 25028471 TI - Direct inhibition of choline kinase by a near-infrared fluorescent carbocyanine. AB - Choline kinase alpha (ChoK) expression is increasingly being recognized as an important indicator of breast cancer prognosis; however, previous efforts to noninvasively measure ChoK status have been complicated by the spectral limitations of in vivo magnetic resonance spectroscopy (MRS) and the complex network of enzymes involved in choline metabolism. The most effective ChoK inhibitors are symmetric and contain quaternary ammonium groups within heterocyclic head groups connected by an aliphatic spacer. Characterization of these bis-pyridinium and bis-quinolinium compounds has led to phase I clinical trials to assess small-molecule inhibitors of ChoK for solid tumor treatment. We report the development of a novel carbocyanine dye, JAS239, whose bis-indolium structure conforms to the parameters established for ChoK specificity and whose spacer length confers fluorescence in the near-infrared (NIR) window. Fluorimetry and confocal microscopy were used to demonstrate that JAS239 rapidly enters breast cancer cells independent of the choline transporters, with accumulation in the cytosolic space where ChoK is active. Radio-tracing and (1)H MRS techniques were used to determine that JAS239 binds and competitively inhibits ChoK intracellularly, preventing choline phosphorylation while inducing cell death in breast cancer cell lines with similar efficacy to known ChoK inhibitors. Fluorescent molecules that report on ChoK status have potential use as companion diagnostics for noninvasive breast tumor staging, because NIR fluorescence allows for detection of real-time probe accumulation in vivo. Furthermore, their ability as novel ChoK inhibitors may prove effective against aggressive, therapy resistant tumors. PMID- 25028472 TI - Contrasting genetic structure between two begomoviruses infecting the same leguminous hosts. AB - Begomoviruses are whitefly-transmitted, ssDNA plant viruses and are among the most damaging pathogens causing epidemics in economically important crops worldwide. Wild/non-cultivated plants play a crucial epidemiological role, acting as begomovirus reservoirs and as 'mixing vessels' where recombination can occur. Previous work suggests a higher degree of genetic variability in begomovirus populations from non-cultivated hosts compared with cultivated hosts. To assess this supposed host effect on the genetic variability of begomovirus populations, cultivated (common bean, Phaseolus vulgaris, and lima bean, Phaseolus lunatus) and non-cultivated (Macroptilium lathyroides) legume hosts were sampled from two regions of Brazil. A total of 212 full-length DNA-A genome segments were sequenced from samples collected between 2005 and 2012, and populations of the begomoviruses Bean golden mosaic virus (BGMV) and Macroptilium yellow spot virus (MaYSV) were obtained. We found, for each begomovirus species, similar genetic variation between populations infecting cultivated and non-cultivated hosts, indicating that the presumed genetic variability of the host did not a priori affect viral variability. We observed a higher degree of genetic variation in isolates from MaYSV populations than BGMV populations, which was explained by numerous recombination events in MaYSV. MaYSV and BGMV showed distinct distributions of genetic variation, with the BGMV population (but not MaYSV) being structured by both host and geography. PMID- 25028474 TI - Gauging the quality of qualitative research in adapted physical activity. AB - Qualitative inquiry is increasingly being used in adapted physical activity research, which raises questions about how to best evaluate its quality. This article aims to clarify the distinction between quality criteria (the what) and strategies (the how) in qualitative inquiry. An electronic keyword search was used to identify articles pertaining to quality evaluation published between 1995 and 2012 (n=204). A five phase systematic review resulted in the identification of 56 articles for detailed review. Data extraction tables were generated and analyzed for commonalities in terminology and meanings. Six flexible criteria for gauging quality were formulated: reflexivity, credibility, resonance, significant contribution, ethics, and coherence. Strategies for achieving the established criteria were also identified. It is suggested that researchers indicate the paradigm under which they are working and guidelines by which they would like readers to evaluate their work as well as what criteria can be absent without affecting the research value. PMID- 25028473 TI - Impact of the rtI187V polymerase substitution of hepatitis B virus on viral replication and antiviral drug susceptibility. AB - A high prevalence of the rtI187V polymerase substitution of hepatitis B virus (HBV) was detected in nucleoside/nucleotide-analogue-naive and -treated chronic hepatitis B (CHB) patients. We aimed at assessing the replicative capacity and susceptibility to lamivudine (LAM) and adefovir (ADV) in vitro of HBV harbouring rtI187V alone or in conjunction with LAM- or ADV-resistant mutations. The reverse transcriptase region of HBV isolates was directly sequenced from a cohort of 300 CHB patients from China. Replication-competent HBV constructs containing rtI187V and combined with LAM-resistant (rtM204I, rtL180M/rtM204V) mutations were generated, and compared with WT, LAM-resistant single (rtM204I) or double (rtL180M/rtM204V) and ADV-resistant (rtN236T) clones. In a Chinese cohort of 300 CHB patients, 8.7 % (26/300) showed substitution of rtI187 with V. Of note, the rtI187V prevalence in HBV genotype B was significantly higher than that in HBV genotype C (95.2 vs 4.8 %). In vitro phenotypic assays showed that the viruses bearing the rtI187V substitution had impaired replication efficacy when compared with the WT and the virus carrying rtI187V combined with LAM-resistant single or double mutations showed even more significantly impaired replicative capacities. Furthermore, rtI187V HBV remained susceptible towards treatment with LAM or ADV in vitro whereas the combination of the rtI187V substitution with LAM-resistant mutations rendered HBV resistant to LAM but still sensitive to ADV. Our study revealed that the rtI187V substitution in the HBV polymerase frequently occurred in CHB patients, particularly those with HBV genotype B. However, the emergence of the rtI187V substitution significantly impaired viral replication but without affecting drug sensitivity in vitro. PMID- 25028475 TI - Practicum in adapted physical activity: a Dewey-inspired action research project. AB - The purpose of this study was to investigate what adapted physical activity (APA) students learn from their practicum experiences. One cohort of APA students participated, and data were generated from an action research project that included observations, reflective journals, and a focus group interview. The theoretical framework for the study was Dewey's and Wackerhausen's theories of reflections. The findings show the objects of students' reflections, the kind of conceptual resources they draw on while reflecting, and their knowledge interests. In addition, two paradoxes are identified: the tension between reflecting from and on own values, and how practicum as a valued experience of reality can become too difficult to handle. In conclusion, we reflect on how practicum learning can be facilitated. PMID- 25028476 TI - Barriers to and facilitators of sports participation in people with visual impairments. AB - We examined barriers to and facilitators of sports participation in people with visual impairments. Participants registered at Royal Visio, Bartimeus, and the Eye Association were invited to complete a questionnaire (telephone or online). Six hundred forty-eight of the invited participants (13%) completed the questionnaire, and 63% of the respondents reported sports participation. Walking (43%), fitness (34%), and cycling (34%) were frequently mentioned sports. Costs, lack of peers/buddies, and visual impairment were negatively associated with sports participation, whereas higher education and computer (software) use were positively associated. The most important personal barrier was visual impairment; transport was the most important environmental barrier. Active participants also mentioned dependence on others as a personal barrier. The most important personal facilitators were health, fun, and social contacts; support from family was the most important environmental facilitator. To improve sports participation in people with visual impairments, the emphasis in a sports program should be on the positive aspects of sports, such as fun, health, and social contacts. PMID- 25028477 TI - Say what you mean: rethinking disability language in Adapted Physical Activity Quarterly. AB - Adapted Physical Activity Quarterly (APAQ) currently mandates that authors use person-first language in their publications. In this viewpoint article, we argue that although this policy is well intentioned, it betrays a very particular cultural and disciplinary approach to disability: one that is inappropriate given the international and multidisciplinary mandate of the journal. Further, we contend that APAQ's current language policy may serve to delimit the range of high-quality articles submitted and to encourage both theoretical inconsistency and the erasure of the ways in which research participants self-identify. The article begins with narrative accounts of each of our negotiations with disability terminology in adapted physical activity research and practice. We then provide historical and theoretical contexts for person-first language, as well as various other widely circulated alternative English-language disability terminology. We close with four suggested revisions to APAQ's language policy. PMID- 25028478 TI - Physical activity patterns in adults who are blind as assessed by accelerometry. AB - The main purpose of our study was to quantify, by using accelerometry, daily physical activity (PA) in adults with visual impairments. Sixty-three adults (34.9% women) who are blind (18-65 years) wore an accelerometer for at least 3 days (minimum of 10 hr per day), including 1 weekend day. Nineteen participants (~30%) reached the recommendation of 30 min per day of PA, when counting every minute of moderate or greater intensity. No one achieved that goal when considering bouts of at least 10 min. No differences were found between genders in PA measures. Chronological age, age of blindness onset, and body mass index were not associated with PA. We conclude that adults who are blind have low levels of PA and are considerably less active compared with the general population. Health promotion strategies should be implemented to increase daily PA for people with visual impairments. PMID- 25028481 TI - G-protein betagamma subunit dimers modulate kidney repair after ischemia reperfusion injury in rats. AB - Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G protein betagamma subunit (Gbetagamma) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gbetagamma activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P < 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P < 0.05) the number of proliferating cell nuclear antigen-positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P < 0.05) S-phase cell cycle entry compared with vehicle treated cells as determined by 5'-bromo-2'-deoxyuridine incorporation. Taken together, these data suggest that Gbetagamma signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury. PMID- 25028482 TI - Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics. AB - The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na(+) currents were recorded using the patch clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 MUM) and its optical isomers had a similar IC50 [40 and 47 MUM for the (+) and (-) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 MUM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na(+) channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders. PMID- 25028483 TI - Identification of Kv11.1 isoform switch as a novel pathogenic mechanism of long QT syndrome. AB - BACKGROUND: The KCNH2 gene encodes the Kv11.1 potassium channel that conducts the rapidly activating delayed rectifier current in the heart. The relative expression of the full-length Kv11.1a isoform and the C-terminally truncated Kv11.1a-USO isoform plays an important role in regulation of channel function. The formation of C-terminal isoforms is determined by competition between the splicing and alternative polyadenylation of KCNH2 intron 9. It is not known whether changes in the relative expression of Kv11.1a and Kv11.1a-USO can cause long-QT syndrome. METHODS AND RESULTS: We identified a novel KCNH2 splice site mutation in a large family. The mutation, IVS9-2delA, is a deletion of the A in the AG dinucleotide of the 3' acceptor site of intron 9. We designed an intron containing full-length KCNH2 gene construct to study the effects of the mutation on the relative expression of Kv11.1a and Kv11.1a-USO at the mRNA, protein, and functional levels. We found that this mutation disrupted normal splicing and resulted in exclusive polyadenylation of intron 9, leading to a switch from the functional Kv11.1a to the nonfunctional Kv11.1a-USO isoform in HEK293 cells and HL-1 cardiomyocytes. We also showed that IVS9-2delA caused isoform switch in the mutant allele of mRNA isolated from patient lymphocytes. CONCLUSIONS: Our findings indicate that the IVS9-2delA mutation causes a switch in the expression of the functional Kv11.1a isoform to the nonfunctional Kv11.1a-USO isoform. Kv11.1 isoform switch represents a novel mechanism in the pathogenesis of long-QT syndrome. PMID- 25028484 TI - A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation. AB - BACKGROUND: Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Because missense mutations in the NKX2-5 homeodomain (DNA-binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knockin model. METHODS AND RESULTS: We generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg->Gly (R52G). All the heterozygous neonatal Nkx2-5(+/R52G) mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein malformation of the tricuspid valve, and perimembranous and muscular ventricular septal defects. In addition, P10 Nkx2 5(+/R52G) mice demonstrated atrial sepal anomalies, with significant increase in the size of the interatrial communication and fossa ovalis, and decrease in the length of the flap valve compared with control Nkx2-5(+/+) or Nkx2-5(+/-) mice. CONCLUSIONS: The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) is highly penetrant and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knockin mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain. PMID- 25028486 TI - Dynamical coupling of plasmons and molecular excitations by hybrid quantum/classical calculations: time-domain approach. AB - The presence of plasmonic material influences the optical properties of nearby molecules in untrivial ways due to the dynamical plasmon-molecule coupling. We combine quantum and classical calculation schemes to study this phenomenon in a hybrid system that consists of a Na(2) molecule located in the gap between two Au/Ag nanoparticles. The molecule is treated quantum-mechanically with time dependent density-functional theory, and the nanoparticles with quasistatic classical electrodynamics. The nanoparticle dimer has a plasmon resonance in the visible part of the electromagnetic spectrum, and the Na(2) molecule has an electron-hole excitation in the same energy range. Due to the dynamical interaction of the two subsystems the plasmon and the molecular excitations couple, creating a hybridized molecular-plasmon excited state. This state has unique properties that yield e.g. enhanced photoabsorption compared to the freestanding Na(2) molecule. The computational approach used enables decoupling of the mutual plasmon-molecule interaction, and our analysis verifies that it is not legitimate to neglect the back coupling effect when describing the dynamical interaction between plasmonic material and nearby molecules. Time-resolved analysis shows nearly instantaneous formation of the coupled state, and provides an intuitive picture of the underlying physics. PMID- 25028485 TI - Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study. AB - BACKGROUND: Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT. METHODS AND RESULTS: A total of 1961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds >=2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8*10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response (P=0.03) and diastolic BP response (P=4.6*10(-5)). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with systolic BP response to CPT (P=4.0*10(-5) and 2.7*10(-4), respectively), and variants in genes MCM8 and STK35 were associated with mean arterial pressure response to CPT (P=1.5*10(-5) and 5.0*10(-5), respectively). CONCLUSIONS: Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2, and STK35 in this region. Additional work is warranted to confirm these findings. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov; Unique identifier: NCT00721721. PMID- 25028487 TI - Substrate engineering in stabilizing epitaxial MgO(1 1 1) polar ultrathin films: first-principles calculations. AB - Growing MgO(1 1 1) polar ultrathin films (PUFs) on heterogeneous substrates is technologically challenging. By using first-principles calculations, we show that while the O-termination of the supported PUF can be perfectly passivated by H adatoms, the compensation of the Mg-termination at the interface is the key to the stabilization. Proper charge transfer across the interface is highly required, which is dominated by the work function difference between the two surfaces that form the interface. Taking Ag(1 1 1) as an example, we propose that a thin Pt buffer layer can increase the work function of the substrate,and improve the PUF quality significantly. PMID- 25028488 TI - Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells. AB - Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day. Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbalpha YFP reporter expression. In principle, such synchrony may be caused by either unidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters. These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer. PMID- 25028489 TI - A system-level model for the microbial regulatory genome. AB - Microbes can tailor transcriptional responses to diverse environmental challenges despite having streamlined genomes and a limited number of regulators. Here, we present data-driven models that capture the dynamic interplay of the environment and genome-encoded regulatory programs of two types of prokaryotes: Escherichia coli (a bacterium) and Halobacterium salinarum (an archaeon). The models reveal how the genome-wide distributions of cis-acting gene regulatory elements and the conditional influences of transcription factors at each of those elements encode programs for eliciting a wide array of environment-specific responses. We demonstrate how these programs partition transcriptional regulation of genes within regulons and operons to re-organize gene-gene functional associations in each environment. The models capture fitness-relevant co-regulation by different transcriptional control mechanisms acting across the entire genome, to define a generalized, system-level organizing principle for prokaryotic gene regulatory networks that goes well beyond existing paradigms of gene regulation. An online resource (http://egrin2.systemsbiology.net) has been developed to facilitate multiscale exploration of conditional gene regulation in the two prokaryotes. PMID- 25028490 TI - Intercellular network structure and regulatory motifs in the human hematopoietic system. AB - The hematopoietic system is a distributed tissue that consists of functionally distinct cell types continuously produced through hematopoietic stem cell (HSC) differentiation. Combining genomic and phenotypic data with high-content experiments, we have built a directional cell-cell communication network between 12 cell types isolated from human umbilical cord blood. Network structure analysis revealed that ligand production is cell type dependent, whereas ligand binding is promiscuous. Consequently, additional control strategies such as cell frequency modulation and compartmentalization were needed to achieve specificity in HSC fate regulation. Incorporating the in vitro effects (quiescence, self renewal, proliferation, or differentiation) of 27 HSC binding ligands into the topology of the cell-cell communication network allowed coding of cell type dependent feedback regulation of HSC fate. Pathway enrichment analysis identified intracellular regulatory motifs enriched in these cell type- and ligand-coupled responses. This study uncovers cellular mechanisms of hematopoietic cell feedback in HSC fate regulation, provides insight into the design principles of the human hematopoietic system, and serves as a foundation for the analysis of intercellular regulation in multicellular systems. PMID- 25028491 TI - A new species of Alwisia (Myxomycetes) from New South Wales and Tasmania. AB - Based on a morphological investigation of a series of specimens collected in New South Wales and Tasmania and a phylogeny constructed with partial 18S ribosomal RNA gene sequences, we describe a new species Alwisia lloydiae; the fourth species within the recently revalidated genus Alwisia. This new species is characterized by short ovate sporothecae with mostly free stalks, morphologically resembling the recently described A. morula. However, the new species possesses a tubular capillitium that suggests an affinity with A. bombarda. The capillitium of the new species is ornamented with globular warts, and this feature separates it from all other members of the genus. PMID- 25028492 TI - Genomic characterization of three unique Dehalococcoides that respire on persistent polychlorinated biphenyls. AB - Fastidious anaerobic bacteria play critical roles in environmental bioremediation of halogenated compounds. However, their characterization and application have been largely impeded by difficulties in growing them in pure culture. Thus far, no pure culture has been reported to respire on the notorious polychlorinated biphenyls (PCBs), and functional genes responsible for PCB detoxification remain unknown due to the extremely slow growth of PCB-respiring bacteria. Here we report the successful isolation and characterization of three Dehalococcoides mccartyi strains that respire on commercial PCBs. Using high-throughput metagenomic analysis, combined with traditional culture techniques, tetrachloroethene (PCE) was identified as a feasible alternative to PCBs to isolate PCB-respiring Dehalococcoides from PCB-enriched cultures. With PCE as an alternative electron acceptor, the PCB-respiring Dehalococcoides were boosted to a higher cell density (1.2 * 10(8) to 1.3 * 10(8) cells per mL on PCE vs. 5.9 * 10(6) to 10.4 * 10(6) cells per mL on PCBs) with a shorter culturing time (30 d on PCE vs. 150 d on PCBs). The transcriptomic profiles illustrated that the distinct PCB dechlorination profile of each strain was predominantly mediated by a single, novel reductive dehalogenase (RDase) catalyzing chlorine removal from both PCBs and PCE. The transcription levels of PCB-RDase genes are 5-60 times higher than the genome-wide average. The cultivation of PCB-respiring Dehalococcoides in pure culture and the identification of PCB-RDase genes deepen our understanding of organohalide respiration of PCBs and shed light on in situ PCB bioremediation. PMID- 25028493 TI - Discovery of coesite and stishovite in eucrite. AB - Howardite-eucrite-diogenite meteorites (HEDs) probably originated from the asteroid 4 Vesta. We investigated one eucrite, Bereba, to clarify a dynamic event that occurred on 4 Vesta using a shock-induced high-pressure polymorph. We discovered high-pressure polymorphs of silica, coesite, and stishovite originating from quartz and/or cristobalite in and around the shock-melt veins of Bereba. Lamellar stishovite formed in silica grains through a solid-state phase transition. A network-like rupture was formed and melting took place along the rupture in the silica grains. Nanosized granular coesite grains crystallized from the silica melt. Based on shock-induced high-pressure polymorphs, the estimated shock-pressure condition ranged from ~8 to ~13 GPa. Considering radiometric ages and shock features, the dynamic event that led to the formation of coesite and stishovite occurred ca. 4.1 Ga ago, which corresponds to the late heavy bombardment period (ca. 3.8-4.1 Ga), deduced from the lunar cataclysm. There are two giant impact basins around the south pole of 4 Vesta. Although the origin of HEDs is thought to be related to dynamic events that formed the basins ca. 1.0 Ga ago, our findings are at variance with that idea. PMID- 25028494 TI - Intraoperative mass spectrometry of tumor metabolites. PMID- 25028495 TI - Comparative proteomic study reveals 17beta-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17beta-hydroxysteroid dehydrogenase-13 (17beta-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17beta-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17beta-HSD family plays an important role in lipid metabolism, 17beta HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17beta-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus-mediated hepatic overexpression of human 17beta-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17beta-HSD13 as a pathogenic protein in the development of NAFLD. PMID- 25028496 TI - Strigolactones regulate rice tiller angle by attenuating shoot gravitropism through inhibiting auxin biosynthesis. AB - Tiller angle, a key agronomic trait for achieving ideal plant architecture and increasing grain yield, is regulated mainly by shoot gravitropism. Strigolactones (SLs) are a group of newly identified plant hormones that are essential for shoot branching/rice tillering and have further biological functions as yet undetermined. Through screening for suppressors of lazy1 (sols), a classic rice mutant exhibiting large tiller angle and defective shoot gravitropism, we identified multiple SOLS that are involved in the SL biosynthetic or signaling pathway. We show that SL biosynthetic or signaling mutants can rescue the spreading phenotype of lazy1 (la1) and that SLs can inhibit auxin biosynthesis and attenuate rice shoot gravitropism, mainly by decreasing the local indoleacetic acid content. Although both SLs and LA1 are negative regulators of polar auxin transport, SLs do not alter the lateral auxin transport of shoot base, unlike LA1, which is a positive regulator of lateral auxin transport in rice. Genetic evidence demonstrates that SLs and LA1 participate in regulating shoot gravitropism and tiller angle in distinct genetic pathways. In addition, the SL-mediated shoot gravitropism is conserved in Arabidopsis. Our results disclose a new role of SLs and shed light on a previously unidentified mechanism underlying shoot gravitropism. Our study indicates that SLs could be considered as an important tool to achieve ideal plant architecture in the future. PMID- 25028497 TI - Right sizes of nano- and microstructures for high-performance and rigid bulk thermoelectrics. AB - In this paper, we systematically investigate three different routes of synthesizing 2% Na-doped PbTe after melting the elements: (i) quenching followed by hot-pressing (QH), (ii) annealing followed by hot-pressing, and (iii) quenching and annealing followed by hot-pressing. We found that the thermoelectric figure of merit, zT, strongly depends on the synthesis condition and that its value can be enhanced to ~ 2.0 at 773 K by optimizing the size distribution of the nanostructures in the material. Based on our theoretical analysis on both electron and thermal transport, this zT enhancement is attributed to the reduction of both the lattice and electronic thermal conductivities; the smallest sizes (2 ~ 6 nm) of nanostructures in the QH sample are responsible for effectively scattering the wide range of phonon wavelengths to minimize the lattice thermal conductivity to ~ 0.5 W/m K. The reduced electronic thermal conductivity associated with the suppressed electrical conductivity by nanostructures also helped reduce the total thermal conductivity. In addition to the high zT of the QH sample, the mechanical hardness is higher than the other samples by a factor of around 2 due to the smaller grain sizes. Overall, this paper suggests a guideline on how to achieve high zT and mechanical strength of a thermoelectric material by controlling nano- and microstructures of the material. PMID- 25028498 TI - Insulin-like peptide 5 is an orexigenic gastrointestinal hormone. AB - The gut endocrine system is emerging as a central player in the control of appetite and glucose homeostasis, and as a rich source of peptides with therapeutic potential in the field of diabetes and obesity. In this study we have explored the physiology of insulin-like peptide 5 (Insl5), which we identified as a product of colonic enteroendocrine L-cells, better known for their secretion of glucagon-like peptide-1 and peptideYY. i.p. Insl5 increased food intake in wild type mice but not mice lacking the cognate receptor Rxfp4. Plasma Insl5 levels were elevated by fasting or prolonged calorie restriction, and declined with feeding. We conclude that Insl5 is an orexigenic hormone released from colonic L cells, which promotes appetite during conditions of energy deprivation. PMID- 25028499 TI - Proteome-wide remodeling of protein location and function by stress. AB - Protein location and function can change dynamically depending on many factors, including environmental stress, disease state, age, developmental stage, and cell type. Here, we describe an integrative computational framework, called the conditional function predictor (CoFP; http://nbm.ajou.ac.kr/cofp/), for predicting changes in subcellular location and function on a proteome-wide scale. The essence of the CoFP approach is to cross-reference general knowledge about a protein and its known network of physical interactions, which typically pool measurements from diverse environments, against gene expression profiles that have been measured under specific conditions of interest. Using CoFP, we predict condition-specific subcellular locations, biological processes, and molecular functions of the yeast proteome under 18 specified conditions. In addition to highly accurate retrieval of previously known gold standard protein locations and functions, CoFP predicts previously unidentified condition-dependent locations and functions for nearly all yeast proteins. Many of these predictions can be confirmed using high-resolution cellular imaging. We show that, under DNA damaging conditions, Tsr1, Caf120, Dip5, Skg6, Lte1, and Nnf2 change subcellular location and RNA polymerase I subunit A43, Ino2, and Ids2 show changes in DNA binding. Beyond specific predictions, this work reveals a global landscape of changing protein location and function, highlighting a surprising number of proteins that translocate from the mitochondria to the nucleus or from endoplasmic reticulum to Golgi apparatus under stress. PMID- 25028501 TI - Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial. AB - BACKGROUND: Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients with World Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay. METHODS: Here, we retrospectively investigated the diagnostic and prognostic performance of these algorithms in comparison to individual marker testing and patient outcome in the biomarker cohort (n = 115 patients) of the NOA-04 trial. RESULTS: Concordance for IDH and 1p/19q status was very high: In 92% of samples, the HM450 and reference data agreed. In discordant samples, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of biological phenotype by the HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of samples than conventional methylation-specific PCR, with 87 of 91 G-CIMP tumors predicted as MGMT promoter-methylated. Pyrosequencing of discordant samples confirmed the HM450 assessment in 14 of 17 cases. CONCLUSIONS: G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing. PMID- 25028504 TI - Looking forward: an update to the CCR instructions for authors. PMID- 25028502 TI - Comparison of endovascular treatment approaches for acute ischemic stroke: cost effectiveness, technical success, and clinical outcomes. AB - INTRODUCTION: The use of mechanical thrombectomy for the treatment of acute ischemic stroke has significantly advanced over the last 5 years. Few data are available comparing the cost and clinical and angiographic outcomes associated with available techniques. The aim of this study is to compare the cost and efficacy of current endovascular stroke therapies. METHODS: A single-center retrospective review was performed of the medical record and hospital financial database of all ischemic stroke cases admitted from 2009 to 2013. Three discrete treatment methodologies used during this time were compared: traditional Penumbra System (PS), stent retriever with local aspiration (SRLA) and A Direct Aspiration first Pass Technique (ADAPT). Statistical analyses of clinical and angiographic outcomes and costs for each group were performed. RESULTS: 222 patients (45% men) underwent mechanical thrombectomy. Successful revascularization was defined as Thrombolysis In Cerebral Infarction (TICI) 2b/3 flow, which was achieved in 79% of cases with PS, 83% of cases with SRLA, and 95% of cases with ADAPT. The average total cost of hospitalization for patients was $51,599 with PS, $54,700 with SRLA, and $33 ,11 with ADAPT (p<0.0001). Average times to recanalization were 88 min with PS, 47 min with SRLA, and 37 min with ADAPT (p<0.0001). Similar rates of good functional outcomes were seen in the three groups (PS 36% vs SRLA 43% vs ADAPT 47%; p=0.4). CONCLUSIONS: The ADAPT technique represents the most technically successful yet cost-effective approach to revascularization of large vessel intracranial occlusions. PMID- 25028505 TI - Molecular pathways: connecting fibrosis and solid tumor metastasis. AB - Pathologic organ fibrosis is a condition that can affect all major tissues and is typically ascribed to the excessive accumulation of extracellular matrix components, predominantly collagens. It typically leads to compromise of organ function and subsequent organ failure, and it is estimated that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. PMID- 25028508 TI - Are we ready for a blood-based test to detect colon cancer? PMID- 25028506 TI - A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast. AB - PURPOSE: Local transdermal therapy to the breast may achieve effective target organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in situ (DCIS). METHODS: Twenty-seven pre- and postmenopausal women were randomized to 4-OHT (4 mg/day) or oral-T (20 mg/day) for 6 to 10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography/tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGFI), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined. RESULTS: Posttherapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P <= 0.03 in both, between-group P = 0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (P = 0.0003), whereas mean breast adipose tissue concentrations of 4 OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P = 0.88). There were significant increases in plasma SHBG, factor VIII, and von Willebrand factor and a significant decrease in plasma IGFI with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. CONCLUSIONS: The antiproliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention. PMID- 25028509 TI - A mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-dependent transcriptional program controls activation of the early growth response 1 (EGR1) gene during amino acid limitation. AB - Amino acid (AA) limitation in mammalian cells triggers a collection of signaling cascades jointly referred to as the AA response (AAR). In human HepG2 hepatocellular carcinoma, the early growth response 1 (EGR1) gene was induced by either AA deprivation or endoplasmic reticulum stress. AAR-dependent EGR1 activation was discovered to be independent of the well characterized GCN2-ATF4 pathway and instead dependent on MEK-ERK signaling, one of the MAPK pathways. ChIP showed that constitutively bound ELK1 at the EGR1 proximal promoter region was phosphorylated after AAR activation. Increased p-ELK1 binding was associated with increased de novo recruitment of RNA polymerase II to the EGR1 promoter. EGR1 transcription was not induced in HEK293T cells lacking endogenous MEK activity, but overexpression of exogenous constitutively active MEK in HEK293T cells resulted in increased basal and AAR-induced EGR1 expression. ChIP analysis of the human vascular endothelial growth factor A (VEGF-A) gene, a known EGR1 responsive gene, revealed moderate increases in AAR-induced EGR1 binding within the proximal promoter and highly inducible binding to a site within the first intron. Collectively, these data document a novel AA-activated MEK-ERK-ELK1 signaling mechanism. PMID- 25028510 TI - Peptide-dependent conformational fluctuation determines the stability of the human leukocyte antigen class I complex. AB - In immune-mediated control of pathogens, human leukocyte antigen (HLA) class I presents various antigenic peptides to CD8(+) T-cells. Long-lived peptide presentation is important for efficient antigen-specific T-cell activation. Presentation time depends on the peptide sequence and the stability of the peptide-HLA complex (pHLA). However, the determinant of peptide-dependent pHLA stability remains elusive. Here, to reveal the pHLA stabilization mechanism, we examined the crystal structures of an HLA class I allomorph in complex with HIV derived peptides and evaluated site-specific conformational fluctuations using NMR. Although the crystal structures of various pHLAs were almost identical independent of the peptides, fluctuation analyses identified a peptide-dependent minor state that would be more tightly packed toward the peptide. The minor population correlated well with the thermostability and cell surface presentation of pHLA, indicating that this newly identified minor state is important for stabilizing the pHLA and facilitating T-cell recognition. PMID- 25028511 TI - Roles for N-terminal extracellular domains of nicotinic acetylcholine receptor (nAChR) beta3 subunits in enhanced functional expression of mouse alpha6beta2beta3- and alpha6beta4beta3-nAChRs. AB - Functional heterologous expression of naturally expressed mouse alpha6*-nicotinic acetylcholine receptors (malpha6*-nAChRs; where "*" indicates the presence of additional subunits) has been difficult. Here we expressed and characterized wild type (WT), gain-of-function, chimeric, or gain-of-function chimeric nAChR subunits, sometimes as hybrid nAChRs containing both human (h) and mouse (m) subunits, in Xenopus oocytes. Hybrid malpha6mbeta4hbeta3- (~ 5-8-fold) or WT malpha6mbeta4mbeta3-nAChRs (~ 2-fold) yielded higher function than malpha6mbeta4 nAChRs. Function was not detected when malpha6 and mbeta2 subunits were expressed together or in the additional presence of hbeta3 or mbeta3 subunits. However, function emerged upon expression of malpha6mbeta2mbeta3(V9'S)-nAChRs containing beta3 subunits having gain-of-function V9'S (valine to serine at the 9'-position) mutations in transmembrane domain II and was further elevated 9-fold when hbeta3(V9'S) subunits were substituted for mbeta3(V9'S) subunits. Studies involving WT or gain-of-function chimeric mouse/human beta3 subunits narrowed the search for domains that influence functional expression of malpha6*-nAChRs. Using hbeta3 subunits as templates for site-directed mutagenesis studies, substitution with mbeta3 subunit residues in extracellular N-terminal domain loops "C" (Glu(221) and Phe(223)), "E" (Ser(144) and Ser(148)), and "beta2-beta3" (Gln(94) and Glu(101)) increased function of malpha6mbeta2*- (~ 2-3-fold) or malpha6mbeta4* (~ 2-4-fold)-nAChRs. EC50 values for nicotine acting at malpha6mbeta4*-nAChR were unaffected by beta3 subunit residue substitutions in loop C or E. Thus, amino acid residues located in primary (loop C) or complementary (loops beta2-beta3 and E) interfaces of beta3 subunits are some of the molecular impediments for functional expression of malpha6mbeta2beta3- or malpha6mbeta4beta3-nAChRs. PMID- 25028512 TI - Transforming growth factor (TGF)-beta-activated kinase 1 (TAK1) activation requires phosphorylation of serine 412 by protein kinase A catalytic subunit alpha (PKACalpha) and X-linked protein kinase (PRKX). AB - TGF-beta-activated kinase 1 (TAK1) is a key kinase in mediating Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) signaling. Although TAK1 activation involves the phosphorylation of Thr-184 and Thr-187 residues at the activation loop, the molecular mechanism underlying the complete activation of TAK1 remains elusive. In this work, we show that the Thr-187 phosphorylation of TAK1 is regulated by its C-terminal coiled-coil domain-mediated dimerization in an autophosphorylation manner. Importantly, we find that TAK1 activation in mediating downstream signaling requires an additional phosphorylation at Ser-412, which is critical for TAK1 response to proinflammatory stimuli, such as TNF alpha, LPS, and IL-1beta. In vitro kinase and shRNA-based knockdown assays reveal that TAK1 Ser-412 phosphorylation is regulated by cAMP-dependent protein kinase catalytic subunit alpha (PKACalpha) and X-linked protein kinase (PRKX), which is essential for proper signaling and proinflammatory cytokine induction by TLR/IL 1R activation. Morpholino-based in vivo knockdown and rescue studies show that the corresponding site Ser-391 in zebrafish TAK1 plays a conserved role in NF kappaB activation. Collectively, our data unravel a previously unknown mechanism involving TAK1 phosphorylation mediated by PKACalpha and PRKX that contributes to innate immune signaling. PMID- 25028513 TI - beta-III Tubulin fragments inhibit alpha-synuclein accumulation in models of multiple system atrophy. AB - Multiple system atrophy (MSA) is a neurodegenerative disease caused by alpha synuclein aggregation in oligodendrocytes and neurons. Using a transgenic mouse model overexpressing human alpha-synuclein in oligodendrocytes, we previously demonstrated that oligodendrocytic alpha-synuclein inclusions induce neuronal alpha-synuclein accumulation and progressive neuronal degeneration. alpha Synuclein binds to beta-III tubulin, leading to the neuronal accumulation of insoluble alpha-synuclein in an MSA mouse model. The present study demonstrates that alpha-synuclein co-localizes with beta-III tubulin in the brain tissue from patients with MSA and MSA model transgenic mice as well as neurons cultured from these mice. Accumulation of insoluble alpha-synuclein in MSA mouse neurons was blocked by the peptide fragment beta-III tubulin (residues 235-282). We have determined the alpha-synuclein-binding domain of beta-III tubulin and demonstrated that a short fragment containing this domain can suppress alpha synuclein accumulation in the primary cultured cells. Administration of a short alpha-synuclein-binding fragment of beta-III tubulin may be a novel therapeutic strategy for MSA. PMID- 25028514 TI - Cytosolic nucleotides block and regulate the Arabidopsis vacuolar anion channel AtALMT9. AB - The aluminum-activated malate transporters (ALMTs) form a membrane protein family exhibiting different physiological roles in plants, varying from conferring tolerance to environmental Al(3+) to the regulation of stomatal movement. The regulation of the anion channels of the ALMT family is largely unknown. Identifying intracellular modulators of the activity of anion channels is fundamental to understanding their physiological functions. In this study we investigated the role of cytosolic nucleotides in regulating the activity of the vacuolar anion channel AtALMT9. We found that cytosolic nucleotides modulate the transport activity of AtALMT9. This modulation was based on a direct block of the pore of the channel at negative membrane potentials (open channel block) by the nucleotide and not by a phosphorylation mechanism. The block by nucleotides of AtALMT9-mediated currents was voltage dependent. The blocking efficiency of intracellular nucleotides increased with the number of phosphate groups and ATP was the most effective cellular blocker. Interestingly, the ATP block induced a marked modification of the current-voltage characteristic of AtALMT9. In addition, increased concentrations of vacuolar anions were able to shift the ATP block threshold to a more negative membrane potential. The block of AtALMT9 mediated anion currents by ATP at negative membrane potentials acts as a gate of the channel and vacuolar anion tune this gating mechanism. Our results suggest that anion transport across the vacuolar membrane in plant cells is controlled by cytosolic nucleotides and the energetic status of the cell. PMID- 25028515 TI - Different mechanisms regulate expression of zebrafish myelin protein zero (P0) in myelinating oligodendrocytes and its induction following axonal injury. AB - Zebrafish CNS axons regenerate robustly following injury; it is thought that CNS oligodendrocytes contribute to this response by expressing growth-promoting molecules. We characterized the mpz gene, which encodes myelin protein zero and is up-regulated in oligodendroglia following axonal injury. The 2.5-kb mpz mRNA is expressed from a single TATA box promoter. Four independent Tg(mpz:egfp) transgenic zebrafish lines, in which GFP was expressed under the mpz promoter and 10 kb of genomic 5'-flanking sequence, showed transgene expression in CNS oligodendrocytes from larval development through adulthood. Following optic nerve crush injury, the mpz:egfp transgene was strongly up-regulated in oligodendrocytes along the regenerating retinotectal projection, mirroring up regulation of endogenous mpz mRNA. GFP-expressing oligodendroglia were significantly more abundant in the regenerating optic pathway, resulting from both transgene induction in oligodendroglial precursors and the birth of new cells. Up-regulation of the mpz:egfp transgene was not dependent on axonal regeneration, suggesting that the primary signal may be axonal loss, debris, or microglial infiltration. Deletion experiments indicated that an oligodendroglial enhancer located in the region from -6 to -10 kb with respect to the mpz transcriptional start site is dissociable from the cis-regulatory element mediating the mpz transcriptional response to axonal injury, which is located between -1 and -4 kb. These data show that different mechanisms regulate expression of zebrafish mpz in myelinating oligodendrocytes and its induction following axonal injury. The underlying molecular events could potentially be exploited to enhance axonal repair following mammalian CNS injury. The transgenic lines and cis-regulatory constructs reported here will facilitate identification of the relevant signaling pathways. PMID- 25028516 TI - Parallel in-register intermolecular beta-sheet architectures for prion-seeded prion protein (PrP) amyloids. AB - Structures of the infectious form of prion protein (e.g. PrP(Sc) or PrP-Scrapie) remain poorly defined. The prevalent structural models of PrP(Sc) retain most of the native alpha-helices of the normal, noninfectious prion protein, cellular prion protein (PrP(C)), but evidence is accumulating that these helices are absent in PrP(Sc) amyloid. Moreover, recombinant PrP(C) can form amyloid fibrils in vitro that have parallel in-register intermolecular beta-sheet architectures in the domains originally occupied by helices 2 and 3. Here, we provide solid state NMR evidence that the latter is also true of initially prion-seeded recombinant PrP amyloids formed in the absence of denaturants. These results, in the context of a primarily beta-sheet structure, led us to build detailed models of PrP amyloid based on parallel in-register architectures, fibrillar shapes and dimensions, and other available experimentally derived conformational constraints. Molecular dynamics simulations of PrP(90-231) octameric segments suggested that such linear fibrils, which are consistent with many features of PrP(Sc) fibrils, can have stable parallel in-register beta-sheet cores. These simulations revealed that the C-terminal residues ~124-227 more readily adopt stable tightly packed structures than the N-terminal residues ~90-123 in the absence of cofactors. Variations in the placement of turns and loops that link the beta-sheets could give rise to distinct prion strains capable of faithful template-driven propagation. Moreover, our modeling suggests that single PrP monomers can comprise the entire cross-section of fibrils that have previously been assumed to be pairs of laterally associated protofilaments. Together, these insights provide a new basis for deciphering mammalian prion structures. PMID- 25028517 TI - The three Mycobacterium tuberculosis antigen 85 isoforms have unique substrates and activities determined by non-active site regions. AB - The three isoforms of antigen 85 (A, B, and C) are the most abundant secreted mycobacterial proteins and catalyze transesterification reactions that synthesize mycolated arabinogalactan, trehalose monomycolate (TMM), and trehalose dimycolate (TDM), important constituents of the outermost layer of the cellular envelope of Mycobacterium tuberculosis. These three enzymes are nearly identical at the active site and have therefore been postulated to exist to evade host immunity. Distal to the active site is a second putative carbohydrate-binding site of lower homology. Mutagenesis of the three isoforms at this second site affected both substrate selectivity and overall catalytic activity in vitro. Using synthetic and natural substrates, we show that these three enzymes exhibit unique selectivity; antigen 85A more efficiently mycolates TMM to form TDM, whereas C (and to a lesser extent B) has a higher rate of activity using free trehalose to form TMM. This difference in substrate selectivity extends to the hexasaccharide fragment of cell wall arabinan. Mutation of secondary site residues from the most active isoform (C) into those present in A or B partially interconverts this substrate selectivity. These experiments in combination with molecular dynamics simulations reveal that differences in the N-terminal helix alpha9, the adjacent Pro(216)-Phe(228) loop, and helix alpha5 are the likely cause of changes in activity and substrate selectivity. These differences explain the existence of three isoforms and will allow for future work in developing inhibitors. PMID- 25028518 TI - Inactivation of the Mycobacterium tuberculosis antigen 85 complex by covalent, allosteric inhibitors. AB - The rise of multidrug-resistant and totally drug-resistant tuberculosis and the association with an increasing number of HIV-positive patients developing tuberculosis emphasize the necessity to find new antitubercular targets and drugs. The antigen 85 (Ag85) complex from Mycobacterium tuberculosis plays important roles in the biosynthesis of major components of the mycobacterial cell envelope. For this reason, Ag85 has emerged as an attractive drug target. Recently, ebselen was identified as an effective inhibitor of the Ag85 complex through covalent modification of a cysteine residue proximal to the Ag85 active site and is therefore a covalent, allosteric inhibitor. To expand the understanding of this process, we have solved the x-ray crystal structures of Ag85C covalently modified with ebselen and other thiol-reactive compounds, p chloromercuribenzoic acid and iodoacetamide, as well as the structure of a cysteine to glycine mutant. All four structures confirm that chemical modification or mutation at this particular cysteine residue leads to the disruption of the active site hydrogen-bonded network essential for Ag85 catalysis. We also describe x-ray crystal structures of Ag85C single mutants within the catalytic triad and show that a mutation of any one of these three residues promotes the same conformational change observed in the cysteine modified forms. These results provide evidence for active site dynamics that may afford new strategies for the development of selective and potent Ag85 inhibitors. PMID- 25028519 TI - Indian hedgehog signaling regulates transcription and expression of collagen type X via Runx2/Smads interactions. AB - Indian hedgehog (Ihh) is essential for chondrocyte differentiation and endochondral ossification and acts with parathyroid hormone-related peptide in a negative feedback loop to regulate early chondrocyte differentiation and entry to hypertrophic differentiation. Independent of this function, we and others recently reported independent Ihh functions to promote chondrocyte hypertrophy and matrix mineralization in vivo and in vitro. However, the molecular mechanisms for these actions and their functional significance are still unknown. We recently discovered that Ihh overexpression in chondrocytes stimulated the expression of late chondrocyte differentiation markers and induced matrix mineralization. Focusing on collagen type X (Col10alpha1) expression and transcription, we observed that hedgehog downstream transcription factors GLI Kruppel family members (Gli) 1/2 increased COL10A1 promoter activity and identified a novel Gli1/2 response element in the 250-bp basic promoter. In addition, we found that Ihh induced Runx2 expression in chondrocytes without up regulating other modulators of chondrocyte maturation such as Mef2c, Foxa2, and Foxa3. Runx2 promoted Col10alpha1 expression in cooperation with Ihh. Further analyses using promoter assays, immunofluorescence, and binding assays showed the interaction of Gli1/2 in a complex with Runx2/Smads induces chondrocyte differentiation. Finally, we could demonstrate that Ihh promotes in vitro matrix mineralization using similar molecular mechanisms. Our data provide an in vitro mechanism for Ihh signaling to positively regulate Col10alpha1 transcription. Thus, Ihh signaling could be an important player for not only early chondrocyte differentiation but maturation and calcification of chondrocytes. PMID- 25028520 TI - Regulation of protein phosphatase 1I by Cdc25C-associated kinase 1 (C-TAK1) and PFTAIRE protein kinase. AB - Protein phosphatase 1I (PP-1I) is a major endogenous form of protein phosphatase 1 (PP-1) that consists of the core catalytic subunit PP-1c and the regulatory subunit inhibitor 2 (I-2). Phosphorylation of the Thr-72 residue of I-2 is required for activation of PP-1I. We studied the effects of two protein kinases identified previously in purified brain PP-1I by mass spectrometry, Cdc25C associated kinase 1 (C-TAK1) and PFTAIRE (PFTK1) kinase, for their ability to regulate PP-1I. Purified C-TAK1 phosphorylated I-2 in reconstituted PP-1I (PP-1c. I-2) on Ser-71, which resulted in partial inhibition of its ATP-dependent phosphatase activity and inhibited subsequent phosphorylation of Thr-72 by the exogenous activating kinase GSK-3. In contrast, purified PFTK1 phosphorylated I-2 at Ser-86, a site known to potentiate Thr-72 phosphorylation and activation of PP 1I phosphatase activity by GSK-3. These findings indicate that brain PP-1I associates with and is regulated by the associated protein kinases C-TAK1 and PFTK1. Multisite phosphorylation of the I-2 regulatory subunit of PP-1I leads to activation or inactivation of PP-1I through bidirectional modulation of Thr-72 phosphorylation, the critical activating residue of I-2. PMID- 25028521 TI - The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-kappaB signaling. AB - Inactivating mutations of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH) have been linked to an aggressive variant of hereditary kidney cancer (hereditary leiomyomatosis and renal cell cancer). These tumors accumulate markedly elevated levels of fumarate. Fumarate is among a growing list of oncometabolites identified in cancers with mutations of genes involved in intermediary metabolism. FH-deficient tumors are notable for their pronounced accumulation of the transcription factor hypoxia inducible factor-1alpha (HIF 1alpha) and aggressive behavior. To date, HIF-1alpha accumulation in hereditary leiomyomatosis and renal cell cancer tumors is thought to result from fumarate dependent inhibition of prolyl hydroxylases and subsequent evasion from von Hippel-Lindau-dependent degradation. Here, we demonstrate a novel mechanism by which fumarate promotes HIF-1alpha mRNA and protein accumulation independent of the von Hippel-Lindau pathway. Here we demonstrate that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1alpha promoter through non canonical signaling via the upstream Tank binding kinase 1 (TBK1). Consistent with these data, inhibition of the TBK1/p65 axis blocks HIF-1alpha accumulation in cellular models of FH loss and markedly reduces cell invasion of FH-deficient RCC cancer cells. Collectively, our data demonstrate a novel mechanism by which pseudohypoxia is promoted in FH-deficient tumors and identifies TBK1 as a novel putative therapeutic target for the treatment of aggressive fumarate-driven tumors. PMID- 25028522 TI - Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. AB - Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on whole-body insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans. PMID- 25028523 TI - Hepatic ABCA1 expression improves beta-cell function and glucose tolerance. AB - Low HDL is a risk factor for the development of type 2 diabetes. Hepatic ABCA1 is the rate-limiting protein in HDL biogenesis, and mice lacking hepatic ABCA1 (ABCA1(-l/-l)) have very low plasma HDL concentrations. To investigate the role of hepatic ABCA1 in glucose tolerance and beta-cell function, we used ABCA1(-l/ l) mice, which showed impaired glucose tolerance without changes in insulin sensitivity. Insulin secretion was reduced following glucose gavage. Ex vivo, glucose stimulated insulin secretion from beta-cells from wild-type (WT) and ABCA1(-l/-l) mice was similar. Insulin secretion was, however, reduced upon addition of ABCA1(-l/-l) serum to the medium compared with WT serum, whereas islets lacking beta-cell ABCA1 were not affected differently by ABCA1(-l/-l) or WT serum. After high-fat feeding, WT and ABCA1(-l/-l) mice showed no difference in glucose tolerance or insulin secretion, and serum from ABCA1(-l/-l) and WT mice fed a high-fat diet did not affect insulin secretion differently. We conclude that hepatic ABCA1 improves glucose tolerance by improving beta-cell function through both HDL production and interaction with beta-cell ABCA1. The beneficial effect of hepatic ABCA1 is decreased under metabolic stress. Increasing hepatic ABCA1 may represent a novel therapeutic strategy for improving glucose homeostasis in diabetes. PMID- 25028524 TI - Increased intraretinal PO2 in short-term diabetic rats. AB - In diabetic retinopathy, neovascularization is hypothesized to develop due to hypoxia in the retina. However, evidence for retinal hypoxia is limited, and the progressive changes in oxygenation are unknown. The objective of this study was to determine if retinal hypoxia occurs early in the development of diabetes. Intraretinal oxygen (PO2) profiles were recorded with oxygen-sensitive microelectrodes in control and diabetic Long-Evans rats at 4 and 12 weeks after induction of diabetes. Diabetes did not affect oxygen consumption in the photoreceptors in either dark or light adaptation. Oxygenation of the inner retina was not affected after 4 weeks of diabetes, although vascular endothelial growth factor levels increased. At 12 weeks, average inner retinal PO2, normalized to choriocapillaris PO2, was higher in diabetic rats than in age matched controls, which was opposite to what was expected. Thus retinal hypoxia is not a condition of early diabetes in rat retina. Increased inner retinal PO2 may occur because oxygen consumption decreases in the inner retina. PMID- 25028526 TI - Impact of language barriers on complications and mortality among immigrants with diabetes: a population-based cohort study. AB - OBJECTIVE: Our objective was to examine the effect of language barriers on the risk of acute and chronic complications of diabetes and on mortality among immigrants. RESEARCH DESIGN AND METHODS: Linked health and immigration databases were used to identify 87,707 adults with diabetes who immigrated to Ontario, Canada, between 1985 and 2005. These individuals were included in our cohort and stratified by language ability at the time of their immigration application. Primary end points included: one or more emergency department visit or hospitalization for 1) hypo- or hyperglycemia, skin and soft tissue infection, or foot ulcer and 2) a cardiovascular event or death between April 1, 2005, and February 29, 2012. RESULTS: Our cohort was followed up for a median of 6.9 person years. Immigrants with language barriers were older (mean age, 49 +/- 15 vs. 42 +/- 13 years; P < 0.001), more likely to have immigrated for family reunification (66% vs. 38%, P < 0.001), had less education (secondary school or less and no education, 82% vs. 53%; P < 0.001), and a higher use of health care (mean visits, 8.6 +/- 12.1 vs. 7.8 +/- 11.2; P < 0.001). Immigrants with language barriers were not found to have higher adjusted rates of diabetes complications (acute complications: hazard ratio [HR] 0.99, 95% CI 0.93-1.05; cardiovascular events or death: HR 0.95, 95% CI 0.91-0.99). Significant predictors included older age, being unmarried, living in a rural neighborhood, and having less education. Immigrants who were older (>=65 years) and who had arrived through family reunification had a lower risk of cardiovascular events or death (HR 0.88, 95% CI 0.81-0.96). CONCLUSIONS: In a heterogenous immigrant population with universal insurance, language barriers were not found to increase the risk of diabetes complications. However, their effect may vary based on age at time of landing, education level, marital status, and neighborhood of settlement. PMID- 25028525 TI - Islet-1 Is essential for pancreatic beta-cell function. AB - Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal beta-cell by performing physiological and morphometric analyses of a tamoxifen inducible, beta-cell-specific Isl-1 loss-of-function mouse: Isl-1(L/L); Pdx1 CreER(Tm). Ablating Isl-1 in postnatal beta-cells reduced glucose tolerance without significantly reducing beta-cell mass or increasing beta-cell apoptosis. Rather, islets from Isl-1(L/L); Pdx1-CreER(Tm) mice showed impaired insulin secretion. To identify direct targets of Isl-1, we integrated high-throughput gene expression and Isl-1 chromatin occupancy using islets from Isl-1(L/L); Pdx1 CreER(Tm) mice and betaTC3 insulinoma cells, respectively. Ablating Isl-1 significantly affected the beta-cell transcriptome, including known targets Insulin and MafA as well as novel targets Pdx1 and Slc2a2. Using chromatin immunoprecipitation sequencing and luciferase reporter assays, we found that Isl 1 directly occupies functional regulatory elements of Pdx1 and Slc2a2. Thus Isl-1 is essential for postnatal beta-cell function, directly regulates Pdx1 and Slc2a2, and has a mature beta-cell cistrome distinct from that of pancreatic endocrine progenitors. PMID- 25028527 TI - A rare case of an EML4-ALK-rearranged lung adenocarcinoma missed by in situ hybridization but detected by RT-PCR. PMID- 25028528 TI - Message in a bottle: decoding medication injury patterns in the gastrointestinal tract. AB - Medication injury in the gastrointestinal tract (GIT) is a rapidly evolving topic. Increasing endoscopy together with an ageing population, polypharmacy, and a burgeoning drug industry offer heightened opportunities to observe the unintended side effects of therapeutic ingestants. In this review, we emphasise the most commonly encountered medication injuries involving the GIT, as well as emerging agents and mimics. While topics are organised by organ system, the reader should keep in mind that injury patterns are generally not site-specific. As such, awareness of these major morphologic patterns can be translated to multiple tissue sites to more broadly facilitate the diagnostic process. PMID- 25028529 TI - LPS-challenged TNFalpha production, prostaglandin secretion, and TNFalpha/TNFRs expression in the endometrium of domestic cats in estrus or diestrus, and in cats with pyometra or receiving medroxyprogesterone acetate. AB - Progesterone (P4) derivatives which are commonly used to block the cyclicity of domestic cats disturb the endocrine balance in the endometrium. The aims of this study were (i) to examine whether lipopolysaccharide (LPS) is responsible for enhancement of tumor necrosis factor-alpha (TNFalpha) secretion by the feline endometrial epithelial and stromal cells in vitro, (ii) to know whether immunolocalization of TNFalpha/TNFR1 and TNFR2 differs in cats at estrus or diestrus, receiving medroxyprogesterone acetate and suffering from pyometra, and (iii) to determine if TNFalpha-challenged prostaglandin secretion is stopped by prostaglandin synthases inhibitors. A total of 37 domestic adult cats in estrus or diestrus, receiving octane medroxyprogesterone or having clinical symptoms of pyometra, were enrolled in this study. The results obtained showed a distinct increase in LPS-challenged TNFalpha secretion in endometrial epithelial, but not stromal cells. TNFalpha augmented PG secretion was blocked by phospholipase A2 (PLA2) and cyclooxygeanase-2 (COX-2), but not by mitogen-activated protein kinase (MAPK) inhibitor. TNFalpha/TNFR1 and 2 protein expressions were limited mostly to the surface and glandular epithelium. TNFalpha/TNFRs protein was upregulated in the inflammatory uterus and hence may be involved in development of pathologic changes in the endometrial glands in cats receiving exogenous P4 as a hormonal contraceptive. PMID- 25028530 TI - Evaluating choroidal thickness in diabetic retinopathy. PMID- 25028532 TI - Effect of intravitreal aflibercept injection for age-related macular degeneration with a retinal pigment epithelial tear refractory to intravitreal ranibizumab injection. AB - BACKGROUND: The purpose of this study was to evaluate the effects of intravitreal aflibercept injection for age-related macular degeneration (AMD) with a retinal pigment epithelial (RPE) tear after intravitreal ranibizumab injection (IVR) which finally became resistant to additional IVR. METHODS: We reviewed the medical records of AMD patients with RPE tears after intravitreal ranibizumab injection who were treated with intravitreal aflibercept injection after acquisition of resistance to additional IVR. RESULTS: One eye from three patients, aged 66, 77, and 78 years, was evaluated. All cases started treatment with IVR for AMD. RPE tear developed 1, 4, and 3 months after the first IVR, respectively. Additional IVR was performed seven, seven, and nine times over 10, 19, and 21 months, respectively, but all cases finally became resistant to IVR. Intravitreal aflibercept injection was performed four times, six times, and once over 8, 9, and 6 months, respectively. At the last visit, all patients had complete resolution of subretinal and intraretinal fluid. CONCLUSION: Continued intravitreal aflibercept injection may be beneficial to manage AMD with RPE tear which has become resistant to additional IVR. PMID- 25028533 TI - Correlation between optic nerve head structural parameters and glaucomatous visual field indices. AB - We examined associations between optic nerve head structural parameters and glaucomatous visual field indices. The study population included patients with glaucomatous optic neuropathy who were evaluated at Aichi Medical University, Nagakute, Aichi, Japan, from October 2010 to January 2011. A total of 57 eyes from 33 patients were assessed. We measured visual field using a Humphrey field analyzer, peripapillary retinal nerve fiber layer thickness (RNFL-T), and Bruch's membrane opening-minimum rim width (BMO-MRW) using spectral domain optical coherence tomography, and rim area with referring three-dimensional photography. Spearman's rank correlation coefficients were calculated between the threshold of visual sensitivity or total deviation of visual field and the following five optic nerve head structural parameters: RNFL-T length, BMO-MRW length, rim area, and calculated RNFL-T and BMO-MRW volumes (each length multiplied by rim area). The Akaike information criterion was calculated to determine which structural parameter was the best predictor of each visual field index. Threshold of visual sensitivity had correlation coefficients of 0.23 with global sector of RNFL-T, 0.32 with BMO-MRW, 0.14 with rim area, 0.21 with RNFL-T volume, and 0.26 with BMO MRW volume. The correlation coefficients for each parameter with total deviation of visual field were 0.22, 0.33, 0.28, 0.36, and 0.37, respectively. The Akaike information criterion of BMO-MRW showed the smallest values in analyses of both threshold of visual sensitivity and total deviation. The present results show that RNFL-T volume and BMO-MRW volume were more strongly correlated with total deviation than BMO-MRW, but BMO-MRW appeared to be the best predictor of the two glaucomatous visual field indices. PMID- 25028531 TI - Ranibizumab for the treatment of degenerative ocular conditions. AB - Degenerative ocular conditions, such as age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, and myopic degeneration, have become a major public health problem and a leading cause of blindness in developed countries. Anti-vascular endothelial growth factor (VEGF) drugs seem to be an effective and safe treatment for these conditions. Ranibizumab, a humanized monoclonal antibody antigen-binding fragment, which inhibits all biologically active isoforms of VEGF-A, is still the gold standard treatment for the majority of these pathological entities. In this review, we present the results of the most important clinical trials concerning the efficacy and safety of ranibizumab for the treatment of degenerative ocular conditions. PMID- 25028534 TI - Non steroidal anti-inflammatory drugs in the prevention of cystoid macular edema after uneventful cataract surgery. AB - BACKGROUND: Cystoid macular edema (CME) remains an important complication after cataract surgery. There is no consensus about how to prevent this frequent complication. The purpose of this study was to conceive an effective anti inflammatory strategy using nonsteroidal anti-inflammatory drugs (NSAIDs) together with regular treatment with corticosteroids to prevent CME and improve visual acuity after cataract surgery in patients without risk factors. MATERIALS AND METHODS: We searched the PubMed, Cochrane, and Google Scholar databases focused on prospective, controlled, randomized, double-blind clinical trials published in the last 10 years, with a minimum follow-up of 4 weeks. RESULTS: A total of nine clinical trials, one systematic review, and two reviews satisfied our search criteria. Most studies highlighted that NSAIDs are as powerful as corticosteroids to diminish postoperative inflammation, and demonstrated an additional benefit when used in combination with standard corticosteroid postsurgical therapy. In addition, the use of NSAIDs in the perioperative period seems to significantly improve the outcome after surgery and helps prevent CME in low-risk patients. CONCLUSION: The prophylactic use of NSAIDs in combination with the standard postoperative steroid scheme appears to be a positive course of action for preventing CME after cataract surgery. We suggest a therapeutic scheme based on the administration of one drop four times a day, beginning the day before surgery and for 4 weeks after the procedure. It is also advisable to administer one drop every 15 minutes in the hour prior to surgery in order to obtain better anti-inflammatory efficacy. PMID- 25028535 TI - Quetiapine for acute bipolar depression: a systematic review and meta-analysis. AB - BACKGROUND: Precise estimated risks and benefits of quetiapine for acute bipolar depression are needed for clinical practice. OBJECTIVE: To systematically review the efficacy and the tolerability of quetiapine, either as monotherapy or combination therapy, for acute bipolar depression. METHODS: We included all randomized, controlled trials (RCTs) comparing quetiapine with other treatments, including placebo, in patients with acute bipolar depression (bipolar I or II disorder, major depressive episode). Published and unpublished RCTs were identified using the Cochrane Central Register of Controlled Trials, MEDLINE, Web of Knowledge, CINAHL, PsycINFO, the EU Clinical Trials Register database, and ClinicalTrials.gov. The primary outcome was the change scores of depression rating scales. RESULTS: Eleven RCTs (n=3,488) were included. Two of them were conducted in children and adolescents. The change in depression scores was significantly greater in the quetiapine group compared with the placebo group (mean difference, [MD] =-4.66, 95% confidence interval [CI] -5.59 to -3.73). The significant difference was observed from week 1. Compared with placebo, quetiapine had higher incidence rates of extrapyramidal side effects, sedation, somnolence, dizziness, fatigue, constipation, dry mouth, increased appetite, and weight gain but lower risks of treatment-emergent mania and headache. Quetiapine treatment was associated with significant improvement of clinical global impression, quality of life, sleep quality, anxiety, and functioning. CONCLUSION: Quetiapine monotherapy is effective for acute bipolar depression and the prevention of mania/hypomania switching. Its common adverse effects are extrapyramidal side effects, sedation, somnolence, dizziness, fatigue, constipation, dry mouth, increased appetite, and weight gain. The lower risk of headache in quetiapine-treated patients with acute bipolar depression should be further investigated. The evidence for the use of quetiapine combined with mood stabilizers in children and adolescents with acute bipolar depression is too small to support the clinical practice. PMID- 25028536 TI - Novel nanocrystal formulation of megestrol acetate has improved bioavailability compared with the conventional micronized formulation in the fasting state. AB - BACKGROUND: Megestrol acetate is an effective treatment for improving appetite and increasing body weight in patients with cancer-associated anorexia. However, Megace oral suspension (OS), a micronized formulation of megestrol acetate, has low bioavailability in the fasting state. To overcome this limitation, a nanocrystal formulation has been developed. This study was performed to evaluate the pharmacokinetics and tolerability of the nanocrystal formulation and to compare them with those of Megace OS in the fed and fasting states. METHODS: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in three parts in 93 healthy subjects. A single 625 mg/5 mL oral dose of a nanocrystal formulation was administered in the fasting and fed states (part I). In parts II and III, a single 625 mg/5 mL oral dose of the nanocrystal formulation or Megace OS 800 mg/20 mL was given in the fed and fasting states, respectively. Blood samples were collected for up to 120 hours post dose for pharmacokinetic analysis. Tolerability was evaluated throughout the entire study period. RESULTS: The nanocrystal formulation of megestrol acetate was rapidly absorbed in both the fed and fasting states. In the fed state, systemic exposure was comparable between the nanocrystal formulation of megestrol acetate and Megace OS. In the fasting state, however, the peak plasma concentration and area under the plasma concentration-time curve to the last measurable concentration of megestrol acetate was 6.7-fold and 1.9-fold higher, respectively, for the nanocrystal formulation than for Megace OS. No serious adverse events were reported. CONCLUSION: Systemic exposure to megestrol acetate is less affected by lack of concomitant food intake when it is administered using the nanocrystal formulation. The nanocrystal formulation of megestrol acetate could be more effective in treating patients with cachexia or anorexia. PMID- 25028537 TI - Assessing the potential impact of non-proprietary drug copies on quality of medicine and treatment in patients with relapsing multiple sclerosis: the experience with fingolimod. AB - BACKGROUND: Fingolimod is a once-daily oral treatment for relapsing multiple sclerosis, the proprietary production processes of which are tightly controlled, owing to its susceptibility to contamination by impurities, including genotoxic impurities. Many markets produce nonproprietary medicines; assessing their efficacy and safety is difficult as regulators may approve nonproprietary drugs without bioequivalence data, genotoxic evaluation, or risk management plans (RMPs). This assessment is especially important for fingolimod given its solubility/bioavailability profile, genotoxicity risk, and low-dose final product (0.5 mg). This paper presents an evaluation of the quality of proprietary and nonproprietary fingolimod variants. METHODS: Proprietary fingolimod was used as a reference substance against which eleven nonproprietary fingolimod copies were assessed. The microparticle size distribution of each compound was assessed by laser light diffraction, and inorganic impurity content by sulfated ash testing. Heavy metals content was quantified using inductively coupled plasma optical emission spectrometry, and levels of unspecified impurities by high-performance liquid chromatography. Solubility was assessed in a range of solvents at different pH values. Key information from the fingolimod RMP is also presented. RESULTS: Nonproprietary fingolimod variants exhibited properties out of proprietary or internationally accepted specifications, including differences in particle size distribution and levels of impurities such as heavy metals. For microparticle size and heavy metals, all tested fingolimod copies were out-of specification by several-fold magnitudes. Proprietary fingolimod has a well defined RMP, highlighting known and potential mid- to long-term safety risks, and risk-minimization and pharmacovigilance procedures. CONCLUSION: Nonproprietary fingolimod copies produced by processes less well controlled than or altered from proprietary production processes may reduce product reproducibility and quality, potentially presenting risks to patients. Safety data and risk-minimization strategies for proprietary fingolimod may not apply to the nonproprietary fingolimod copies evaluated here. Market authorization of nonproprietary fingolimod copies should require an appropriate RMP to minimize risks to patients. PMID- 25028538 TI - Instruments to assess patient satisfaction after teleconsultation and triage: a systematic review. AB - BACKGROUND: Patient satisfaction is crucial for the acceptance, use, and adherence to recommendations from teleconsultations regarding health care requests and triage services. OBJECTIVES: Our objectives are to systematically review the literature for multidimensional instruments that measure patient satisfaction after teleconsultation and triage and to compare these for content, reliability, validity, and factor analysis. METHODS: We searched Medline, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO for literature on these instruments. Two reviewers independently screened all obtained references for eligibility and extracted data from the eligible articles. The results were presented using summary tables. RESULTS: We included 31 publications, describing 16 instruments in our review. The reporting on test development and psychometric characteristics was incomplete. The development process, described by ten of 16 instruments, included a review of the literature (n=7), patient or stakeholder interviews (n=5), and expert consultations (n=3). Four instruments evaluated factor structure, reliability, and validity; two of those four demonstrated low levels of reliability for some of their subscales. CONCLUSION: A majority of instruments on patient satisfaction after teleconsultation showed methodological limitations and lack rigorous evaluation. Users should carefully reflect on the content of the questionnaires and their relevance to the application. Future research should apply more rigorously established scientific standards for instrument development and psychometric evaluation. PMID- 25028539 TI - Associations between the 2007 Medicare reimbursement reduction for bone mineral density testing and osteoporosis drug therapy patterns of female Medicare beneficiaries. AB - OBJECTIVE: To examine how drug therapy patterns for osteoporosis have changed after the Medicare Physician Fee Schedule (MPFS) reimbursement reduction in 2007, in relation to follow-up bone mineral density (BMD) testing status. METHODS: We used a retrospective temporal shift design to examine changes in drug therapy patterns before (Phase 1: January 1, 2005-December 31, 2006) and after (Phase 2: July 1, 2007-June 30, 2009) the MPFS reimbursement reduction in 2007, Cleveland, OH, USA. Participants were osteoporotic older women in Phase 1 (n=1,340) and Phase 2 (n=1,437). The main outcomes were a) adherence, b) adjustment, c) occurrence of an extended gap, and d) restarting drug therapy after an extended gap. Follow-up BMD testing status by study phase and location were also analyzed. RESULTS: BMD testing rates at physicians' offices decreased from 64.5% in Phase 1 to 58.4% in Phase 2 (P=0.02); however, testing rates in hospital outpatient settings increased (from 20.8% to 24.5%). There were also decreases in drug therapy adjustment from 15.9% in Phase 1 to 11.6% in Phase 2 (odds ratio [OR]: 0.73; P<0.01) and in restarting drug therapy after an extended gap (55.4% in Phase 1 and 43.6% in Phase 2; OR: 0.76; P<0.01). CONCLUSION: There were no changes in the overall rate of follow-up BMD testing. The rates of drug adjustments and restarting drug therapy after an extended gap did decrease. These decreases were more evident when follow-up BMD testing was not performed. PMID- 25028540 TI - Effect of a structured, active, home-based cancer-treatment program for the management of patients on oral chemotherapy. AB - INTRODUCTION: The advent of oral chemotherapy agents has had a strong impact on several aspects of the management of cancer patients, including survival rates, health-care expenditure, and health-related quality of life. However, access to care and adherence to oral chemotherapy are central to optimal outcomes. PATIENTS AND METHODS: In this multicenter observational study, we assessed the effect of the "Active Home Care" initiative - a structured, active, home-based cancer treatment program - on quality of life, health-care utilization, and patient adherence and satisfaction using self-administered questionnaires. Sixty-two patients treated with oral chemotherapy (capecitabine, vinorelbine, imatinib, sunitinib, sorafenib, temozolomide, ibandronate) were enrolled in the program. Weekly home visits were scheduled, each one with a trained nurse who delivered the home-based chemotherapy and reviewed patients' compliance and treatment toxicity. An oncologist evaluated patients and modified the dosage of oral chemotherapy based on toxicity reported during the previous cycle at bi-weekly visits. RESULTS: A total of 460 home visits were performed between April 2012 and February 2013. The Active Home Care initiative was associated with significant improvements in physical functioning and symptoms, and reductions in the access to cancer facilities. Satisfaction with oral chemotherapy and care received was high. All patients reported having taken their medications according to their prescription, and no patient reported difficulties in managing the oral chemotherapy regimen. CONCLUSION: The Active Home Care program was associated with improvements in the quality of life of patients and caregivers, better adherence to treatment, and the effective management of therapy and cancer related symptoms. Home-based cancer treatment may also optimize the utilization of health-care resources. PMID- 25028541 TI - Bromfenac ophthalmic solution for the treatment of postoperative ocular pain and inflammation: safety, efficacy, and patient adherence. AB - Ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used by clinicians to manage ocular inflammation and pain following cataract surgery. Over the past decade, the US Food and Drug Administration has approved multiple topical NSAIDs for these purposes, including several reformulated products. One of these medications, bromfenac ophthalmic solution, has a long and extensive history, with proven efficacy and safety in patients following cataract surgery. The evolution of bromfenac ophthalmic solution over the years has involved either lowering the concentration of the active ingredient or extending the dosing interval to improve patient adherence/compliance. This review will focus on the history and progression of bromfenac ophthalmic solution and report the available patient preference and adherence data regarding this ocular NSAID throughout its evolution. PMID- 25028542 TI - Reasoning Exercises in Assisted Living: a cluster randomized trial to improve reasoning and everyday problem solving. AB - PURPOSE OF THE STUDY: Assisted living (AL) residents are at risk for cognitive and functional declines that eventually reduce their ability to care for themselves, thereby triggering nursing home placement. In developing a method to slow this decline, the efficacy of Reasoning Exercises in Assisted Living (REAL), a cognitive training intervention that teaches everyday reasoning and problem solving skills to AL residents, was tested. DESIGN AND METHODS: At thirteen randomized Midwestern facilities, AL residents whose Mini Mental State Examination scores ranged from 19-29 either were trained in REAL or a vitamin education attention control program or received no treatment at all. For 3 weeks, treated groups received personal training in their respective programs. RESULTS: Scores on the Every Day Problems Test for Cognitively Challenged Elders (EPCCE) and on the Direct Assessment of Functional Status (DAFS) showed significant increases only for the REAL group. For EPCCE, change from baseline immediately postintervention was +3.10 (P<0.01), and there was significant retention at the 3 month follow-up (d=2.71; P<0.01). For DAFS, change from baseline immediately postintervention was +3.52 (P<0.001), although retention was not as strong. Neither the attention nor the no-treatment control groups had significant gains immediately postintervention or at follow-up assessments. Post hoc across-group comparison of baseline change also highlights the benefits of REAL training. For EPCCE, the magnitude of gain was significantly larger in the REAL group versus the no-treatment control group immediately postintervention (d=3.82; P<0.01) and at the 3-month follow-up (d=3.80; P<0.01). For DAFS, gain magnitude immediately postintervention for REAL was significantly greater compared with in the attention control group (d=4.73; P<0.01). IMPLICATIONS: REAL improves skills in everyday problem solving, which may allow AL residents to maintain self-care and extend AL residency. This benefit is particularly important given the growing population of AL residents at risk for cognitive and self-care decline. PMID- 25028543 TI - Cross-cultural adaptation and reliability testing of the Tilburg Frailty Indicator for optimizing care of Polish patients with frailty syndrome. AB - BACKGROUND: Frail older people are at high risk of developing adverse outcomes, such as disability, mortality, hospitalization, and institutionalization. Previous research suggests that the Tilburg Frailty Indicator (TFI) is a valid and reliable instrument for measuring frailty. The aim of this study was to adapt and to test the reliability of the Polish version of the TFI. METHOD: A standard guideline was used for translation and cultural adaptation of the English version of the TFI into Polish. The study included 100 Polish patients (mean age 68.2+/ 6.5 years), among them 42 men and 58 women. Cronbach's alpha was used for analysis of the internal consistency of the TFI. RESULTS: The mean total TFI score was 6.7+/-3.1. Forty patients scored >=5, which corresponded to being frail. Cronbach's alpha reliability coefficients of the instrument ranged from 0.68 to 0.72 and item-total correlation ranged from 0.12 to 0.52. CONCLUSION: The TFI is valid and reproducible for assessment of frailty syndrome among a Polish population. The Polish adaptation of the TFI proved a useful and fast tool for assessing frailty. PMID- 25028544 TI - Electrospun vancomycin-loaded coating on titanium implants for the prevention of implant-associated infections. AB - The objectives of this work were to develop an antibiotic coating on the surface of a titanium plate to determine its antibacterial properties in vitro and in vivo. To prepare vancomycin-coated titanium implants, we adopted the electrospinning nanotechnique. The surface structure of the coating implants was observed using a scanning electron microscope. An elution method and a high pressure liquid chromatography assay were used to characterize the release behavior of vancomycin from the coating. The antibacterial efficacy and the cytotoxicity of the coated titanium implants on osteoblasts were investigated in vitro. In addition, X-ray, white blood cell count, C-reactive protein, erythrocyte sedimentation rate, and pathological examination were performed to validate its antimicrobial efficacy in vivo. The antibiotic coating released 82.7% (approximately 528.2 MUg) of total vancomycin loading in the coating in vitro. The release behavior of vancomycin from nanofiber coatings exhibited a biphasic release pattern with an initial burst on day 1, followed by a slow and controlled release over 28 days. There was no cytotoxicity observed in vitro for the vancomycin-loaded coating. The vancomycin-coated titanium implants were active in treating implant-associated infection in vivo. Thus, vancomycin-coated titanium implants may be a promising approach to prevent and treat implant associated infections. PMID- 25028545 TI - In vivo anticancer evaluation of the hyperthermic efficacy of anti-human epidermal growth factor receptor-targeted PEG-based nanocarrier containing magnetic nanoparticles. AB - Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with (99m)Tc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431 human tumor cell line. Following radiolabeling with (99m)Tc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma. PMID- 25028546 TI - Safety evaluation of poly(lactic-co-glycolic acid)/poly(lactic-acid) microspheres through intravitreal injection in rabbits. AB - Poly(lactic-co-glycolic acid) (PLGA) and/or poly(lactic-acid) (PLA) microspheres are important drug delivery systems. This study investigated eye biocompatibility and safety of PLGA/PLA microspheres through intravitreal injection in rabbits. Normal New Zealand rabbits were randomly selected and received intravitreal administration of different doses (low, medium, or high) of PLGA/PLA microspheres and erythropoietin-loaded PLGA/PLA microspheres. The animals were clinically examined and sacrificed at 1, 2, 4, 8, and 12 weeks postadministration, and retinal tissues were prepared for analysis. Retinal reactions to the microspheres were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end staining and glial fibrillary acidic protein immunohistochemistry. Retinal structure changes were assessed by hematoxylin and eosin staining and transmission electron microscopy. Finally, retinal function influences were explored by the electroretinography test. Terminal deoxynucleotidyl transferase mediated dUTP nick end staining revealed no apoptotic cells in the injected retinas; immunohistochemistry did not detect any increased glial fibrillary acidic protein expression. Hematoxylin and eosin staining and transmission electron microscopy revealed no micro- or ultrastructure changes in the retinas at different time points postintravitreal injection. The electroretinography test showed no significant influence of scotopic or photopic amplitudes. The results demonstrated that PLGA/PLA microspheres did not cause retinal histological changes or functional damage and were biocompatible and safe enough for intravitreal injection in rabbits for controlled drug delivery. PMID- 25028547 TI - Sinoporphyrin sodium, a novel sensitizer, triggers mitochondrial-dependent apoptosis in ECA-109 cells via production of reactive oxygen species. AB - BACKGROUND: Sonodynamic therapy (SDT) is a promising method that uses ultrasound to activate certain chemical sensitizers for the treatment of cancer. The purpose of this study was to investigate the sonoactivity of a novel sensitizer, sinoporphyrin sodium (DVDMS), and its sonotoxicity in an esophageal cancer (ECA 109) cell line. METHODS: The fluorescence intensity of DVDMS, hematoporphyrin, protoporphyrin IX, and Photofrin II was detected by fluorescence microscopy and flow cytometry. Generation of singlet oxygen was measured using a 1, 3 diphenylisobenzofuran experiment. A 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay was used to examine cell viability. Production of reactive oxygen species (ROS) and destabilization of the mitochondrial membrane potential were assessed by flow cytometry. Apoptosis was analyzed using Annexin PE/7-amino-actinomycin D staining. Confocal microscopy was performed to assess mitochondrial damage and identify release of cytochrome C after treatment. Western blots were used to determine expression of oxidative stress-related and apoptosis-associated protein. Ultrastructural changes in the cell were studied by scanning electron microscopy. RESULTS: DVDMS showed higher autofluorescence intensity and singlet oxygen production efficiency compared with other photosensitizers in both cancerous and normal cells. Compared with hematoporphyrin, DVDMS-mediated SDT was more cytotoxic in ECA-109 cells. Abundant intracellular ROS was found in the SDT groups, and the cytotoxicity induced by SDT was effectively remitted by ROS scavengers. DVDMS located mainly to the mitochondria of ECA-109 cells, which were seriously damaged after exposure to SDT. Release of cytochrome C, an increased rate of apoptosis, and activated apoptosis protein were detected in the SDT group. In addition, relatively severe cell damage was observed on scanning electron microscopy after treatment with DVDMS and SDT. CONCLUSION: These results suggest that DVDMS could be activated by ultrasound, and that DVDMS mediates SDT-induced mitochondrial-dependent apoptosis in ECA-109 cells via production of ROS. PMID- 25028548 TI - Antitumor effect of iRGD-modified liposomes containing conjugated linoleic acid paclitaxel (CLA-PTX) on B16-F10 melanoma. AB - In the present study, we prepared a novel delivery system of iRGD (CRGDK/RGPD/EC) modified sterically stabilized liposomes (SSLs) containing conjugated linoleic acid-paclitaxel (CLA-PTX). The anti-tumor effect of iRGD-SSL-CLA-PTX was investigated on B16-F10 melanoma in vitro and in vivo. The in vitro targeting effect of iRGD-modified SSLs was investigated in a real-time confocal microscopic analysis experiment. An endocytosis-inhibition assay was used to evaluate the endocytosis pathways of the iRGD-modified SSLs. In addition, the in vitro cellular uptake and in vitro cytotoxicity of iRGD-SSL-CLA-PTX were evaluated in B16-F10 melanoma cells. In vivo biodistribution and in vivo antitumor effects of iRGD-SSL-CLA-PTX were investigated in B16-F10 tumor-bearing mice. The induction of apoptosis by iRGD-SSL-CLA-PTX was evaluated in tumor-tissue sections. Real time confocal microscopic analysis results indicated that the iRGD-modified SSLs internalized into B16-F10 cells faster than SSLs. The identified endocytosis pathway of iRGD-modified SSLs indicated that energy- and lipid raft-mediated endocytosis played a key role in the liposomes' cellular uptake. The results of the cellular uptake experiment indicated that the increased cellular uptake of CLA-PTX in the iRGD-SSL-CLA-PTX-treated group was 1.9-, 2.4-, or 2.1-fold compared with that in the CLA-PTX group after a 2-, 4-, or 6-hour incubation, respectively. In the biodistribution test, the CLA-PTX level in tumor tissues from iRGD-SSL-CLA-PTX-treated mice at 1 hour (1.84+/-0.17 MUg/g) and 4 hours (1.17+/-0.28 MUg/g) was 2.3- and 2.0-fold higher than that of CLA-PTX solution at 1 hour (0.79+/-0.06 MUg/g) and 4 hours (0.58+/-0.04 MUg/g). The value of the area under the curve for the first 24 hours in the tumors of iRGD-SSL-CLA-PTX-treated mice was significantly higher than that in the SSL-CLA-PTX and CLA-PTX solution treated groups (P<0.01). The in vivo antitumor results indicated that iRGD-SSL CLA-PTX significantly inhibited the growth of B16-F10 tumors compared with the SSL-CLA-PTX or CLA-PTX solution-treatment groups (P<0.01). The results of tumor cell apoptosis showed that tumors from the iRGD-SSL-CLA-PTX-treated group exhibited more advanced cell apoptosis compared with the control, CLA-PTX solution-, and SSL-CLA-PTX-treated groups. In conclusion, the antitumor effect of iRGD-SSL-CLA-PTX was confirmed on B16-F10 melanoma in vitro and in vivo. PMID- 25028550 TI - Lubricin as a novel nanostructured protein coating to reduce fibroblast density. AB - Excessive fibroblast adhesion and proliferation on the surface of medical implants (such as catheters, endotracheal tubes, intraocular lenses, etc) can lead to major postsurgical complications. This study showed that when coated on tissue culture polystyrene, lubricin, a nanostructured mucinous glycoprotein found in the synovial fluid of joints, decreased fibroblast density for up to 2 days of culture compared to controls treated with phosphate buffered saline (PBS). When examining why, similar antifibroblast density results were found when coating tissue culture polystyrene with bovine submaxillary mucin (BSM), an even smaller protein closely related to the central subregion of lubricin. Additionally, results from this study demonstrated that in contrast to BSM or controls (PBS-coated and non-coated samples), lubricin was better at preserving the health of nonadherent or loosely adherent fibroblasts; fibroblasts that did not adhere or loosely adhered on the lubricin-coated tissue culture polystyrene adhered and proliferated well for up to an additional day when they were reseeded on uncoated tissue culture polystyrene. In summary, this study provides evidence for the promise of nanostructured lubricin (and to a lesser extent BSM) to inhibit fibroblast adhesion and growth when coated on medical devices; lubricin should be further explored for numerous medical device applications. PMID- 25028549 TI - Preparation and characterization of Tamoxifen citrate loaded nanoparticles for breast cancer therapy. AB - BACKGROUND: Four formulations of Tamoxifen citrate loaded polylactide-co glycolide (PLGA) based nanoparticles (TNPs) were developed and characterized. Their internalization by Michigan Cancer Foundation-7 (MCF-7) breast cancer cells was also investigated. METHODS: Nanoparticles were prepared by a multiple emulsion solvent evaporation method. Then the following studies were carried out: drug-excipients interaction using Fourier transform infrared spectroscopy (FTIR), surface morphology by field emission scanning electron microscopy (FESEM), zeta potential and size distribution using a Zetasizer Nano ZS90 and particle size analyzer, and in vitro drug release. In vitro cellular uptake of nanoparticles was assessed by confocal microscopy and their cell viability (%) was studied. RESULTS: No chemical interaction was observed between the drug and the selected excipients. TNPs had a smooth surface, and a nanosize range (250-380 nm) with a negative surface charge. Drug loadings of the prepared particles were 1.5%+/ 0.02% weight/weight (w/w), 2.68%+/-0.5% w/w, 4.09%+/-0.2% w/w, 27.16%+/-2.08% w/w for NP1-NP4, respectively. A sustained drug release pattern from the nanoparticles was observed for the entire period of study, ie, up to 60 days. Further, nanoparticles were internalized well by the MCF-7 breast cancer cells on a concentration dependent manner and were present in the cytoplasm. The nucleus was free from nanoparticle entry. Drug loaded nanoparticles were found to be more cytotoxic than the free drug. CONCLUSION: TNPs (NP4) showed the highest drug loading, released the drug in a sustained manner for a prolonged period of time and were taken up well by the MCF-7 breast cancer cell line in vitro. Thus the formulation may be suitable for breast cancer treatment due to the good permeation of the formulation into the breast cancer cells. PMID- 25028551 TI - Improvement of verbal fluency in patients with diffuse brain injury over time. AB - BACKGROUND: Diffuse axonal injury (DAI), a common cause of neurological sequelae in patients with traumatic brain injury (TBI), is considered one of the most prevalent forms of primary neuronal injury in patients with severe TBI. Cognitive deficits induced by DAI can persist over time, especially following moderate or severe injuries. The aim of the present study was to compare verbal fluency (VF) performance at 6 and 12 months after the trauma in a same group of patients with DAI. METHODS: Eighteen patients with moderate to severe DAI and 17 healthy volunteers were enrolled. All DAI participants had sustained a TBI at least 6 months prior to the start of the study, were between 18 and 50 years of age, and had at least 4 years of education. The VF test was administered within an extensive neuropsychological test battery. We evaluated the same patients at 6 months (DAI1 group) and 12 months (DAI2 group) and compared the results of neuropsychological tests with a control group of healthy volunteers who were matched to patients for sex, age, and educational level. RESULTS: In comparison to controls, the DAI1 group produced significantly fewer words. The DAI2 group produced significantly more semantic words than DAI1 (P<0.05) and demonstrated a trend towards the production of more clusters for letter A (P=0.09) and total words generated in a phonemic test (P=0.09). No significant differences were observed between DAI2 and the control group in the total number of words generated in phonetic FAS or semantic fluency scores. CONCLUSION: The present findings may be useful in the construction of a management plan for long-term TBI rehabilitation that considers the trauma of each patient. Further, our results suggest the VF test is a suitable instrument for the assessment of cognitive difficulties following TBI. PMID- 25028552 TI - Brain meningioma with initial manifestation similar to cervical radiculopathy: a case report. AB - Meningiomas are the most common benign brain tumors, and are characterized by slow growth and a long asymptomatic period. Once the tumor becomes symptomatic, the various presentations may be related to the location and compression of adjacent structures. Meningioma is primarily treated through surgical intervention, and thus earlier diagnosis is likely to result in better prognosis. The symptoms of the meningioma may mimic other diseases, making precise diagnosis difficult, which will then delay treatment. We report a case of brain meningioma that showed initial signs and symptoms similar to cervical radiculopathy. The symptoms extended gradually, and the ultimate diagnosis of meningioma was confirmed based on brain-image studies. After brain-tumor excision, postoperation radiotherapy, and aggressive rehabilitation, the patient was able to perform better in daily activities. PMID- 25028553 TI - Cost-effectiveness analysis on the use of rFSH + rLH for the treatment of anovulation in hypogonadotropic hypogonadal women. AB - BACKGROUND: Hypogonadotropic hypogonadal women are characterized by ovarian functionality deficiency, caused by low concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). To recover reproduction functionality, recommended therapies for ovarian induction involve injections of FSH and LH medications. OBJECTIVE: Since important differences exist between recombinant and urinary gonadotropin therapies in terms of efficacy and cost, the objective of this study was to develop a cost-effectiveness model to compare recombinant FSH (rFSH) + recombinant LH (rLH) and highly purified human menopausal gonadotropin (HP-HMG). METHODS: A Markov model was developed, considering three cycles of therapy; probability of pregnancy and miscarriage were considered, and the efficacy was evaluated in terms of pregnancy occurrence. The perspective of the model was that of the Italian Health Service, so only direct cost (drugs, specialist visits, patient examinations, and hospitalizations) were included. RESULTS: rFSH + rLH is associated with a higher total cost (?3,453.50) and higher efficacy (0.87) compared with HP-HMG (?2,719.70 and 0.50). rFSH + rLH generated an incremental cost effectiveness ratio equal to ?2,007.30 compared to HP-HMG; the average cost per pregnancy is estimated to be ?3,990.00 for recombinant strategy and ?5,439.80 for urinary strategy. Results of probabilistic sensitivity analysis were consistent with the abovementioned findings. CONCLUSION: Despite the higher acquisition cost in comparison to HP HMG, rFSH + rLH resulted in a higher pregnancy rate, which makes it the recommended choice when considering cost-effectiveness of LH in supporting FSH induced follicular gonadotropins in hypogonadotropic hypogonadal women. PMID- 25028554 TI - Icosapent ethyl for the treatment of severe hypertriglyceridemia. AB - Hypertriglyceridemia is a highly prevalent lipid abnormality and it is associated with atherosclerosis, with a growing body of evidence linking elevated triglycerides (TGs) with cardiovascular disease. The current major omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) combination, lowers serum TGs while often increasing levels of low-density lipoprotein cholesterol. Icosapent ethyl is an omega-3 polyunsaturated fatty acid with a 96% pure ethyl ester of EPA that has been recently approved for lowering TG levels in patients with very high TGs (>=500 mg/dL), and it does so without significantly affecting serum low-density lipoprotein cholesterol. The potential benefits of omega-3 fatty acid therapy for dyslipidemias will be discussed, including the potential pros and cons of EPA alone versus the more common and readily available EPA/DHA combination therapy. PMID- 25028555 TI - Update on ranolazine in the management of angina. AB - Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndrome)-TIMI (Thrombolysis In Myocardial Infarction) 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost effective due to its ability to decrease angina-related hospitalizations and improve quality of life. PMID- 25028556 TI - Epidemiology of stroke in a rural community in Southeastern Nigeria. AB - BACKGROUND: The prevalence and incidence of stroke vary from community to community worldwide. Nonetheless, not much is known about the current epidemiology of stroke in rural Nigeria and indeed Africa. METHODS: We carried out a two-phase door-to-door survey in a rural, predominantly low-income, community in Anambra, Southeastern Nigeria. We used a modified World Health Organization (WHO) protocol for detecting neurological diseases in the first phase, and a stroke-specific questionnaire and neurological examination in the second phase. An equal number of sex- and age-matched stroke-negative subjects were examined. RESULTS: We identified ten stroke subjects in the study. The crude prevalence of stroke in rural Nigeria was 1.63 (95% confidence interval [CI] 0.78 3.00) per 1,000 population. The crude prevalence of stroke in males was 1.99 (95% CI 0.73-4.33) per 1,000, while that for females was 1.28 (95% CI 0.35-3.28) per 1,000 population. The peak age-specific prevalence of stroke was 12.08 (95% CI 3.92-28.19) per 1,000, while after adjustment to WHO world population, the peak was 1.0 (95% CI 0.33-2.33) per 1,000. CONCLUSION: The prevalence of stroke was found to be higher than previously documented in rural Nigeria, with a slightly higher prevalence in males than females. This is, however, comparable to data from rural Africa. PMID- 25028557 TI - There's more than one way to skin a fruit: formation and functions of fruit cuticles. AB - As with all aerial plant organs, fleshy fruits are encased in a hydrophobic cuticle that must fulfil multiple functions, including limiting desiccation and preventing microbial infection, which in the case of fruits maintains palatability and promotes seed dispersal. Fruit cuticles have many features in common with those of vegetative organs, but also have unique characteristics, including the fact that they are often astomatous, thicker than those of most leaves, and can be relatively easily isolated. These attributes provide a valuable experimental system to address questions related to cuticle structure, function, and the relationships between composition, architecture, permeability, and biomechanical properties. Here we provide an overview of insights into cuticle biology that have resulted from studies of those of fleshy fruits, as well as the diversity and dynamic nature of fruit cuticle composition and architecture, the environmental factors that influence those features, and the roles that they play in fruit ontogeny. PMID- 25028558 TI - Role of plant hormones and their interplay in development and ripening of fleshy fruits. AB - Plant hormones have been extensively studied for their roles in the regulation of various aspects of plant development. However, in the last decade important new insights have been made into their action during development and ripening, in both dry and fleshy fruits. Emerging evidence suggests that relative functions of plant hormones are not restricted to a particular stage, and a complex network of more than one plant hormone is involved in controlling various aspects of fruit development. Though some areas are extensively covered, considerable gaps in our knowledge and understanding still exist in the control of hormonal networks and crosstalk between different hormones during fruit expansion, maturation, and various other aspects of ripening. Here, we evaluate the new knowledge on their relative roles during tomato fruit development with a view to understand their mechanism of action in fleshy fruits. For a better understanding, pertinent evidences available on hormonal crosstalk during fruit development in other species are also discussed. We envisage that such detailed knowledge will help design new strategies for effective manipulation of fruit ripening. PMID- 25028559 TI - Integration of multidisciplinary technologies for real time target visualization and verification for radiotherapy. AB - The current practice of radiotherapy examines target coverage solely from digitally reconstructed beam's eye view (BEV) in a way that is indirectly accessible and that is not in real time. We aimed to visualize treatment targets in real time from each BEV. The image data of phantom or patients from ultrasound (US) and computed tomography (CT) scans were captured to perform image registration. We integrated US, CT, US/CT image registration, robotic manipulation of US, a radiation treatment planning system, and a linear accelerator to constitute an innovative target visualization system. The performance of this algorithm segmented the target organ in CT images, transformed and reconstructed US images to match each orientation, and generated image registration in real time mode with acceptable accuracy. This image transformation allowed physicians to visualize the CT image-reconstructed target via a US probe outside the BEV that was non-coplanar to the beam's plane. It allowed the physicians to remotely control the US probe that was equipped on a robotic arm to dynamically trace and real time monitor the coverage of the target within the BEV during a simulated beam-on situation. This target visualization system may provide a direct remotely accessible and real time way to visualize, verify, and ensure tumor targeting during radiotherapy. PMID- 25028560 TI - Mapping lymph nodes in cancer management - role of (99m)Tc-tilmanocept injection. AB - Two decades ago, lymphatic mapping of sentinel lymph nodes (SLN) was introduced into surgical cancer management and was termed sentinel node navigated surgery. Although this technique is now routinely performed in the management of breast cancer and malignant melanoma, it is still under investigation for use in other cancers. The radioisotope technetium ((99m)Tc) and vital blue dyes are among the most widely used enhancers for SLN mapping, although near-infrared fluorescence imaging of indocyanine green is also becoming more commonly used. (99m)Tc tilmanocept is a new synthetic radioisotope with a relatively small molecular size that was specifically developed for lymphatic mapping. Because of its small size, (99m)Tc-tilmanocept quickly migrates from its site of injection and rapidly accumulates in the SLN. The mannose moieties of (99m)Tc-tilmanosept facilitate its binding to mannose receptors (CD206) expressed in reticuloendothelial cells of the SLN. This binding prevents transit to second-echelon lymph nodes. In Phase III trials of breast cancer and malignant melanoma, and Phase II trials of other malignancies, (99m)Tc-tilmanocept had superior identification rates and sensitivity compared with blue dye. Trials comparing (99m)Tc-tilmanocept with other (99m)Tc-based agents are required before it can be routinely used in clinical settings. PMID- 25028561 TI - Clinicopathological and biological significance of aberrant activation of glycogen synthase kinase-3 in ovarian cancer. AB - BACKGROUND: Glycogen synthase kinase-3 (GSK-3) plays an important role in human cancer. The aim of this study is to evaluate the clinicopathological significance of expression of GSK-3alpha/beta and pGSK-3alpha/beta(Tyr279/216) in patients with epithelial ovarian cancer and to investigate whether GSK-3 inhibition can influence cell viability and tumor growth of ovarian cancer. METHODS: Immunohistochemistry was used to examine expression of GSK-3alpha/beta and pGSK 3alpha/beta(Tyr279/216) in 71 human epithelial ovarian cancer tissues and correlations between protein expression, and clinicopathological factors were analyzed. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay following exposure of ovarian carcinoma cells to pharmacological inhibitors of GSK-3 or GSK-3 small interfering RNA. In vivo validation of tumor growth inhibition was performed with xenograft mice. RESULTS: The expression levels of GSK-3alpha/beta and pGSK 3alpha/beta(Tyr279/216) in ovarian cancers were significantly higher than those in benign tumors. High expression of GSK-3alpha/beta was more likely to be found in patients with advanced International Federation of Gynecology and Obstetrics (FIGO) stages and high serum cancer antigen 125. Higher expression of pGSK 3alpha/beta(Tyr279/216) was associated with advanced FIGO stages, residual tumor mass, high serum cancer antigen 125, and poor chemoresponse. Worse overall survival was revealed by Kaplan-Meier survival curves in patients with high expression of GSK-3alpha/beta or pGSK-3alpha/beta(Tyr279/216). Multivariate analysis indicated that FIGO stage, GSK-3alpha/beta expression, and pGSK 3alpha/beta(Tyr279/216) expression were independent prognostic factors for overall survival. GSK-3 inhibition by lithium chloride, 4-benzyl-2-methyl-1,2,4 thiadiazolidine-3,5-dione (TDZD-8), or GSK-3 small interfering RNA can decrease viability of SKOV3 and SKOV3-TR30 ovarian cancer cells. Additionally, lithium chloride-treated SKOV3 xenograft mice had a significant reduction in tumor growth compared with control-treated animals. CONCLUSION: Our findings suggest that overexpression and aberrant activation of GSK-3 may contribute to progression and poor prognosis in ovarian cancer. Inhibition of GSK-3 may be a potential therapy for ovarian cancer. PMID- 25028562 TI - Incidence rate of non-Hodgkin's lymphomas among males in Saudi Arabia: an observational descriptive epidemiological analysis of data from the Saudi Cancer Registry, 2001-2008. AB - BACKGROUND: This study describes epidemiological data of non-Hodgkin's lymphoma (NHL) diagnosed from 2001 to 2008 among Saudi men. MATERIALS AND METHODS: Retrospective data from all NHL cancer cases among Saudi men recorded in the Saudi Cancer Registry (SCR) between January 2001 and December 2008 were used. Descriptive statistics, analysis of variance, Poisson regression, and simple linear regression were also used. RESULTS: In total, 2,555 new cases of NHL were recorded between January 2001 and December 2008. The region of Riyadh, Saudi Arabia had the highest overall age-standardized incidence rate (ASIR) at 7.8, followed by the Eastern region at 6.8, and Makkah at 6.1 per 100,000 men; however, Jazan, Hail, and Baha had the lowest average ASIRs at 2.5, 3.7, and 3.9 per 100,000 men, respectively. The incidence-rate ratio for the number of NHL cases was significantly higher in Riyadh (4.68, 95% confidence interval [CI] 4.11 5.32), followed by Makkah (4.47, 95% CI 3.94-5.07), and the Eastern region of Saudi Arabia (3.27, 95% CI 2.90-3.69) than that in the reference region of Jazan. Jouf had the highest changes in the ASIRs of NHL among Saudi men from 2001 and 2008 (5.0 per 100,000 men). CONCLUSION: A significant increase in the crude incidence rate and ASIR for NHL in Saudi Arabia between 2001 and 2008 was found. Riyadh, the Eastern region, and Makkah had the highest overall ASIR in Saudi Arabia. Jazan, Hail, and Baha had the lowest rates. Additionally, Riyadh, Makkah, and the Eastern region had the highest incidence-rate ratio for the number of NHL cases. Finally, Jouf had the highest changes in crude incidence rate and ASIR from 2001 to 2008. Further analytical studies are needed to determine the potential risk factors of NHL among Saudi men. PMID- 25028563 TI - The importance of catastrophizing for successful pharmacological treatment of peripheral neuropathic pain. AB - OBJECTIVE: Catastrophizing may be a negative predictor of pain-related outcomes. We evaluated the impact of catastrophizing upon success of first-line pharmacotherapy in the management of neuropathic pain (NeP) due to peripheral polyneuropathy. METHODS: Patients with confirmed NeP with NeP Visual Analog Scale (VAS) pain severity score >=4 (0-10 scale) completed the Coping Strategies Questionnaire (CSQ) catastrophizing subscale at baseline. Pharmacological therapy consisting of first-line agents gabapentin, pregabalin, or a tricyclic antidepressant was initiated. Other measures examined included the Karnofsky Performance Scale, Beck Depression Inventory, EuroQol Quality of Life Health Questionnaire, and Modified Brief Pain Inventory. At 3 and 6 months, questionnaires were repeated and adverse effect reporting was completed. Outcome measures assessed were pharmacotherapy success (>=30% relief of NeP) and tolerability over 6 months of follow-up. Bivariate relationships using Pearson product-moment correlations were examined for baseline CSQ catastrophizing subscale score and the change in the NeP VAS scores and medication discontinuation. RESULTS: Sixty-six patients were screened, 62 subjects participated, and 58 subjects (94%) completed the final follow-up visit. Greater catastrophizing was associated with poor pain relief response and greater likelihood of discontinuation of pharmacotherapy, reports of greater disability, and impaired quality of life. Duration of pain was negatively associated with likelihood of pharmacotherapy success. CONCLUSION: Catastrophizing exerts maladaptive effects on outcomes with pharmacotherapy in NeP patients. Detection of catastrophizing during clinical visits when pharmacological therapy is being considered can be a predictive factor for patient outcomes. PMID- 25028564 TI - Factors associated with adherence to antiretroviral therapy in HIV-infected patients in Kathmandu District, Nepal. AB - PURPOSE: There are a high number of HIV-infected patients receiving antiretroviral therapy (ART) in the Kathmandu District of Nepal, but information on adherence and factors influencing it are scarce in this population. The present study aimed to estimate ART adherence among HIV-infected patients in the Kathmandu District of Nepal, and to determine the factors associated with ART adherence. PATIENTS AND METHODS: This study included 316 HIV-infected patients attending three ART centers in the Kathmandu District. Information on sociodemographic characteristics, socioeconomic status, and ART use for the previous 7 days was collected via interview. Participants were considered adherent if they reported taking >=95% of their ART as prescribed. The association between explanatory variables and ART adherence was measured using logistic regression and reported as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Male participants accounted for 64.6% (n=204). Overall ART adherence was 86.7%. ART adherence in men and women were 84.3% and 91.1%, respectively. Age (OR 1.04; 95% CI 1.00-1.09), travel time to ART centers (OR 1.38; 95% CI 1.12-1.71), history of illegal drug use (OR 3.98; 95% CI 1.71-9.24), and adverse effects (OR 4.88; 95% CI 1.09-21.8), were all independently and negatively associated with ART adherence. Use of reminder tools (OR 3.45; 95% CI 1.33-8.91) was independently and positively associated with ART adherence. CONCLUSION: The observed ART adherence in this study is encouraging. Travel time to ART centers, self-reported adverse effects, illegal drug use, and not using reminder tools were the major determinants of ART adherence. Interventions that take these factors into account could further improve ART adherence. PMID- 25028565 TI - Incidence rate of ovarian cancer cases in Saudi Arabia: an observational descriptive epidemiological analysis of data from Saudi Cancer Registry 2001 2008. AB - PURPOSE: This study provides descriptive epidemiological data, such as the percentage of cases diagnosed, crude incidence rate (CIR), and age-standardized incidence rate (ASIR) of ovarian cancer in Saudi Arabia from 2001-2008. PATIENTS AND METHODS: A retrospective descriptive epidemiological analysis of all ovarian cancer cases recorded in the Saudi Cancer Registry (SCR) from January 2001 December 2008 was performed. The data were analyzed using descriptive statistics, analysis of variance tests, Poisson regression, and simple linear modeling. RESULTS: A total of 991 ovarian cancer cases were recorded in the SCR from January 2001-December 2008. The region of Riyadh had the highest overall ASIR at 3.3 cases per 100,000 women, followed by the Jouf and Asir regions at 3.13 and 2.96 cases per 100,000 women. However, Hail and Jazan had the lowest rates at 1.4 and 0.6 cases per 100,000 women, respectively. Compared to Jazan, the incidence rate ratio for the number of ovarian cancer cases was significantly higher (P<0.001) in the Makkah region at 6.4 (95% confidence interval [CI]: 4.13-9.83), followed by Riyadh at 6.3 (95% CI: 4.10-9.82), and the eastern region of Saudi Arabia at 4.52 (95% CI: 2.93-6.98). The predicted annual CIR and ASIR for ovarian cancer in Saudi Arabia could be defined by the equations 0.9 + (0.07* years) and 1.71 + (0.09* years), respectively. CONCLUSION: We observed a slight increase in the CIRs and ASIRs for ovarian cancer in Saudi Arabia from 2001-2008. Riyadh, Jouf, and Asir had the highest overall ASIR, while Jazan and Hail had the lowest rates. Makkah, Riyadh, and the eastern region of Saudi Arabia had the highest incidence rate ratio for the number of ovarian cancer cases. Further analytical studies are required to determine the potential risk factors of ovarian cancer among Saudi women. PMID- 25028566 TI - Transcriptional regulation of human hydroxysteroid sulfotransferase SULT2A1 by LXRalpha. AB - The nuclear receptor liver X receptor (LXR) plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. In this study, we uncovered a function of LXRalpha (NR1H3) in regulating the human hydroxysteroid sulfotransferase SULT2A1, a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. We showed that activation of LXR induced the expression of SULT2A1 at mRNA, protein, and enzymatic levels. A combination of promoter reporter gene and chromatin immunoprecipitation assays showed that LXRalpha transactivated the SULT2A1 gene promoter through its specific binding to the -500- to -258-base pair region of the SULT2A1 gene promoter. LXR small interfering RNA knockdown experiments suggested that LXRalpha, but not LXRbeta, played a dominant role in regulating SULT2A1. In primary human hepatocytes, we found a positive correlation between the expression of SULT2A1 and LXRalpha, which further supported the regulation of SULT2A1 by LXRalpha. In summary, our results established human SULT2A1 as a novel LXRalpha target gene. The expression of LXRalpha is a potential predictor for the expression of SULT2A1 in human liver. PMID- 25028567 TI - The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. AB - Milk thistle (Silybum marianum) extracts are widely used as a complementary and alternative treatment of various hepatic conditions and a host of other diseases/disorders. The active constituents of milk thistle supplements are believed to be the flavonolignans contained within the extracts. In vitro studies have suggested that some milk thistle components may significantly inhibit specific cytochrome P450 (P450) enzymes. However, determining the potential for clinically significant drug interactions with milk thistle products has been complicated by inconsistencies between in vitro and in vivo study results. The aim of the present study was to determine the effect of a standardized milk thistle supplement on major P450 drug-metabolizing enzymes after a 14-day exposure period. CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5 activities were measured by simultaneously administering the four probe drugs, caffeine, tolbutamide, dextromethorphan, and midazolam, to nine healthy volunteers before and after exposure to a standardized milk thistle extract given thrice daily for 14 days. The three most abundant falvonolignans found in plasma, following exposure to milk thistle extracts, were silybin A, silybin B, and isosilybin B. The concentrations of these three major constituents were individually measured in study subjects as potential perpetrators. The peak concentrations and areas under the time-concentration curves of the four probe drugs were determined with the milk thistle administration. Exposure to milk thistle extract produced no significant influence on CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5 activities. PMID- 25028568 TI - Fluorescence resonance energy transfer-based real-time polymerase chain reaction method without DNA extraction for the genotyping of F5, F2, F12, MTHFR, and HFE. AB - Blood samples are extensively used for the molecular diagnosis of many hematological diseases. The daily practice in a clinical laboratory of molecular diagnosis in hematology involves using a variety of techniques, based on the amplification of nucleic acids. Current methods for polymerase chain reaction (PCR) use purified genomic DNA, mostly isolated from total peripheral blood cells or white blood cells (WBC). In this paper we describe a real-time fluorescence resonance energy transfer-based method for genotyping directly from blood cells. Our strategy is based on an initial isolation of the WBCs, allowing the removal of PCR inhibitors, such as the heme group, present in the erythrocytes. Once the erythrocytes have been lysed, in the LightCycler((r)) 2.0 Instrument, we perform a real-time PCR followed by a melting curve analysis for different genes (Factors 2, 5, 12, MTHFR, and HFE). After testing 34 samples comparing the real-time crossing point (CP) values between WBC (5*10(6) WBC/mL) and purified DNA (20 ng/MUL), the results for F5 Leiden were as follows: CP mean value for WBC was 29.26+/-0.566 versus purified DNA 24.79+/-0.56. Thus, when PCR was performed from WBC (5*10(6) WBC/mL) instead of DNA (20 ng/MUL), we observed a delay of about 4 cycles. These small differences in CP values were similar for all genes tested and did not significantly affect the subsequent analysis by melting curves. In both cases the fluorescence values were high enough, allowing a robust genotyping of all these genes without a previous DNA purification/extraction. PMID- 25028569 TI - Teaching teamwork: an evaluation of an interprofessional training ward placement for health care students. AB - The establishment of interprofessional teamwork training in the preprofessional health care curriculum is a major challenge for teaching faculties. Interprofessional clinical placements offer an opportunity for teamwork education, as students in various professions can work and learn together. In this sequential, mixed-method study, focus group and survey techniques were used to evaluate students' educational experiences after 2-week ward-based interprofessional clinical placements. Forty-five senior nursing, medicine, and other health care students cared for patients in hospital wards under professional supervision, with nursing-medicine student "teams" leading care. Thirty-six students attended nine exit focus groups. Five central themes that emerged about training were student autonomy and workload, understanding of other professional roles, communication and shared knowledge, interprofessional teamwork/collaboration, and the "inner circle", or being part of the unit team. The learning environment was described as positive. In a postplacement satisfaction survey (n=38), students likewise rated the educational experience highly. In practicing teamwork and collaboration, students were able to rehearse their future professional role. We suggest that interprofessional clinical placements be regarded as an essential learning experience for senior preprofessional students. More work is needed to fully understand the effect of this interactive program on students' clinical learning and preparation for practice. PMID- 25028570 TI - Prognostic impact of standard laboratory values on outcome in patients with sudden sensorineural hearing loss. AB - BACKGROUND: Aim of the present study was to evaluate prognostic factors, in particular standard laboratory parameters, for better outcome after idiopathic sudden sensorineural hearing loss (SSNHL). METHODS: Using a retrospective review, 173 patients were included presenting between 2006 and 2009 with unilateral SSNHL, >=30 dB bone conduction in three succeeding frequencies between 0.125 to 8 kHz in pure tone audiometry (PTA), and a time interval between first symptoms and diagnostics <= 4 weeks. Hearing gain of <10 dB versus >=10 dB in the affected ear in 6PTA values was the primary outcome criterion. Univariate and multivariate statistical tests were used to analyze predictors for better outcome. RESULTS: The initial hearing loss was 50.6 +/- 27.2 dB. The absolute hearing gain was 15.6 +/- 20.1 dB. Eighty-one patients (47%) had a final hearing gain of >=10 dB. Low frequency hearing loss (p <0.0001); start of inpatient treatment <4 days after onset (p = 0.018); first SSNHL (versus recurrent SSNHL, p = 0.001); initial hearing loss >= 60 dB (p < 0.0001); an initial quick value lower than the reference values (p = 0.040); and a pretherapeutic hyperfibrinogenemia (p = 0.007) were significantly correlated to better outcome (>=10 dB absolute hearing gain). Multivariate analysis revealed that first SSNHL (p = 0.004), start of treatment <4 days after onset (p = 0.015), initial hearing loss >= 60 dB (p = 0.001), and hyperfibrinogenemia (p = 0.032) were independent prognostic factors for better hearing recovery. CONCLUSION: Better hearing gain in patients with hyperfibrinogenemia might be explained by the rheological properties of the applied therapy and supports the hypothesis that SSNHL is caused in part by vascular factors. PMID- 25028571 TI - Towards a standardised approach for evaluating guidelines and guidance documents on palliative sedation: study protocol. AB - BACKGROUND: Sedation in palliative care has received growing attention in recent years; and so have guidelines, position statements, and related literature that provide recommendations for its practice. Yet little is known collectively about the content, scope and methodological quality of these materials. According to research, there are large variations in palliative sedation practice, depending on the definition and methodology used. However, a standardised approach to comparing and contrasting related documents, across countries, associations and governmental bodies is lacking. This paper reports on a protocol designed to enable thorough and systematic comparison of guidelines and guidance documents on palliative sedation. METHODS AND DESIGN: A multidisciplinary and international group of palliative care researchers, identified themes and clinical issues on palliative sedation based on expert consultations and evidence drawn from the EAPC (European Association of Palliative Care) framework for palliative sedation and AGREE II (Appraisal Guideline Research and Evaluation) instrument for guideline assessment. The most relevant themes were selected and built into a comprehensive checklist. This was tested on people working closely with practitioners and patients, for user-friendliness and comprehensibility, and modified where necessary. Next, a systematic search was conducted for guidelines in English, Dutch, Flemish, or Italian. The search was performed in multiple databases (PubMed, CancerLit, CNAHL, Cochrane Library, NHS Evidence and Google Scholar), and via other Internet resources. Hereafter, the final version of the checklist will be used to extract data from selected literature, and the same will be compiled, entered into SPSS, cleaned and analysed systematically for publication. DISCUSSION: We have together developed a comprehensive checklist in a scientifically rigorous manner to allow standardised and systematic comparison. The protocol is applicable to all guidelines on palliative sedation, and the approach will contribute to rigorous and systematic comparison of international guidelines on any challenging topic such as this. Results from the study will provide valuable insights into common core elements and differences between the selected guidelines, and the extent to which recommendations are derived from, or match those in the EAPC framework. The outcomes of the study will be disseminated via peer-reviewed journals and directly to appropriate audiences. PMID- 25028572 TI - Examination of the leaf proteome during flooding stress and the induction of programmed cell death in maize. AB - BACKGROUND: Maize is a major economic crop worldwide, with substantial crop loss attributed to flooding. During a stress response, programmed cell death (PCD) can be an effective way for plants better adapt. To identify flooding stress related PCD proteins in maize leaves, proteomic analysis was performed using two dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mass spectrometry. RESULTS: Comparative proteomics was combined with physiological and biochemical analysis of maize leaves under flooding stress. Fv/Fm, qP, qN and relative water content (RWC) were found to be altered in response to flooding stress, with an increase in H2O2 content noted in vivo. Furthermore, DNA ladder detection indicated that PCD had occurred under flooding treatment. The maize leaf proteome was analyzed via 2D-DIGE gel, with a total of 32 differentially expressed spots isolated, 31 spots were successfully identified via MALDI-TOF/TOF MS which represent 28 proteins. The identified proteins were related to energy metabolism and photosynthesis, PCD, phytohormones and polyamines. To better characterize the role of translationally controlled tumor protein (TCTP) in PCD during a stress response, mRNA expression was examined in different plants by stress-induced PCD. These included heat stress induced rice protoplasts, Tobacco Mosaic Virus infected tobacco leaves and dark induced rice and Arabidopsis thaliana leaves, all of which showed active PCD, and TCTP expression was increased in different degrees. Moreover, S-adenosylmethionine synthase 2 (SAMS2) and S-adenosylmethionine decarboxylase (SAMDC) mRNA expression were also increased, but ACC synthase (ACS) and ACC oxidase (ACO) mRNA expression were not found in maize leaves following flooding. Lastly, ethylene and polyamine concentrations were increased in response to flooding treatment in maize leaves. CONCLUSIONS: Following flooding stress, the photosynthetic systems were damaged, resulting in a disruption in energy metabolism, with the noted photosynthetic decline also possibly attributed to ROS production. The observed PCD could be regulated by TCTP with a possible role for H2O2 in TCTP induction under flooding stress. Additionally, increased SAMS2 expression was closely associated with an increased polyamine synthesis during flooding treatment. PMID- 25028573 TI - Proteomic analysis of Cucumis sativus cotyledons after glucohexaose treatment as a part of ROS accumulation related resistance mechanism. AB - BACKGROUND: Glucohexaose is a safe farm chemical used for pathogen prevention, which can induce systemic acquired resistance in cucumber. RESULTS: We found that glucohexaose treatment of cucumber plant induced an accumulation of the reactive oxidative species (ROS). Histochemistry showed sharp increases in O(2-) and H2O2 5 h after glucohexaose treatment. After 5 h, the O(2-) content decreased to a normal level, but the H2O2 content remained at a high level 10 h after glucohexaose treatment. And antioxidant enzymes were also changed after glucohexaose treatment. We also investigated the relationship between ROS accumulation and glucohexaose-induced proteome alteration using 2D electrophoresis coupled with MS/MS. 54 protein spots, which enhanced expression under glucohexaose treatment but suppressed the expression by application of DPI and DMTU, have been identified. CONCLUSION: Our study showed the accumulation of ROS is a part of mechanism of glucohexaose induced resistance in cucumber cotyledons. The up-regulated proteins identified by MS such as PP2C and antioxidation proteins are important in ROS signaling. It will be interesting to find out the regulatory mechanism underlying the induction of these proteins via ROS, and provide some clues to the mechanism of glucohexaose-induced resistance. PMID- 25028574 TI - Comparative secretome analysis of Streptomyces scabiei during growth in the presence or absence of potato suberin. AB - BACKGROUND: Suberin is a recalcitrant plant biopolymer composed of a polyphenolic and a polyaliphatic domain. Although suberin contributes to a significant portion of soil organic matter, the biological process of suberin degradation is poorly characterized. It has been suggested that Streptomyces scabiei, a plant pathogenic bacterium, can produce suberin-degrading enzymes. In this study, a comparative analysis of the S. scabiei secretome from culture media supplemented or not with potato suberin was carried out to identify enzymes that could be involved in suberin degradation. METHODS: S. scabiei was grown in the presence of casein only or in the presence of both casein and suberin. Extracellular proteins from 1-, 3- and 5-day-old supernatants were analyzed by LC-MS/MS to determine their putative functions. Real-time RT-PCR was performed to monitor the expression level of genes encoding several proteins potentially involved in suberin degradation. RESULTS: The effect of suberin on the extracellular protein profile of S. scabiei strain has been analyzed. A total of 246 proteins were found to be common in the data sets from both casein medium (CM) and casein suberin medium (CSM), whereas 124 and 139 proteins were detected only in CM or CSM, respectively. The identified proteins could be divided into 19 functional groups. Two functional groups of proteins (degradation of aromatic compounds and secondary metabolism) were only associated with the CSM. A high proportion of the proteins found to be either exclusively produced, or overproduced, in presence of suberin were involved in carbohydrate metabolism. Most of the proteins included in the lipid metabolism class have been detected in CSM. Apart from lipid metabolism proteins, other identified proteins, particularly two feruloyl esterases, may also actively participate in the breakdown of suberin architecture. Both feruloyl esterase genes were overexpressed between 30 to 340 times in the presence of suberin. CONCLUSION: This study demonstrated that the presence of suberin in S. scabiei growth medium induced the production of a wide variety of glycosyl hydrolases. Furthermore, this study has allowed the identification of extracellular enzymes that could be involved in the degradation of suberin, including enzymes of the lipid metabolism and feruloyl esterases. PMID- 25028575 TI - PhosFox: a bioinformatics tool for peptide-level processing of LC-MS/MS-based phosphoproteomic data. AB - BACKGROUND: It is possible to identify thousands of phosphopeptides and -proteins in a single experiment with mass spectrometry-based phosphoproteomics. However, a current bottleneck is the downstream data analysis which is often laborious and requires a number of manual steps. RESULTS: Toward automating the analysis steps, we have developed and implemented a software, PhosFox, which enables peptide level processing of phosphoproteomic data generated by multiple protein identification search algorithms, including Mascot, Sequest, and Paragon, as well as cross-comparison of their identification results. The software supports both qualitative and quantitative phosphoproteomics studies, as well as multiple between-group comparisons. Importantly, PhosFox detects uniquely phosphorylated peptides and proteins in one sample compared to another. It also distinguishes differences in phosphorylation sites between phosphorylated proteins in different samples. Using two case study examples, a qualitative phosphoproteome dataset from human keratinocytes and a quantitative phosphoproteome dataset from rat kidney inner medulla, we demonstrate here how PhosFox facilitates an efficient and in-depth phosphoproteome data analysis. PhosFox was implemented in the Perl programming language and it can be run on most common operating systems. Due to its flexible interface and open source distribution, the users can easily incorporate the program into their MS data analysis workflows and extend the program with new features. PhosFox source code, implementation and user instructions are freely available from https://bitbucket.org/phintsan/phosfox. CONCLUSIONS: PhosFox facilitates efficient and more in-depth comparisons between phosphoproteins in case-control settings. The open source implementation is easily extendable to accommodate additional features for widespread application use cases. PMID- 25028576 TI - The First Reported Case of Colonic Infection Caused by Candida tropicalis and a Review of the Literature. AB - Lower gastrointestinal tract infections caused by Candida species are rarely reported, and Candida albicans is the only pathogen that has been identified. The author reports a first case of colonic candidiasis caused by Candida tropicalis in a 55-year-old female with diabetes mellitus type 2, diffuse large B-cell lymphoma and neutropenia induced by chemotherapy. Diarrhea and fever were the presenting symptoms. Diagnosis was made based on deep tissue involvement on colonoscopy with biopsy and positive hemoculture. This alerted the physician to be aware of Candida non-albicans as a cause of colonic infection. Fungal culture should always be done to identify specific Candida species, leading to appropriate antifungal therapy. A review of the literature on colonic candidiasis is also presented here. PMID- 25028577 TI - Successful retrieval of a retained capsule endoscope with single incision laparoscopic surgery. AB - Capsule endoscopy (CE) is commonly used for examining and diagnosing gastrointestinal disease, especially small bowel disease. Capsule retention is a well-known and significant complication of CE and requires surgical or endoscopic removal. Most reports described the retrieval of retained CE via laparotomy. We report a case of successful retrieval of the capsule using single incision laparoscopic surgery. PMID- 25028578 TI - A case of plummer-vinson syndrome showing rapid improvement of Dysphagia and esophageal web after two weeks of iron therapy. AB - Plummer-Vinson syndrome (PVS) is a rare entity characterized by upper esophageal webs and iron deficiency anemia. We report a case of PVS whose esophageal web was rapidly improved by iron therapy. A 77-year-old woman was admitted to our hospital with complaints of dysphagia, vomiting, shortness of breath and weight loss for 1 month. Physical examination revealed conjunctival pallor, koilonychia, angular cheilitis and smooth tongue, and laboratory findings were consistent with microcytic hypochromic anemia with iron deficiency. Gastrointestinal endoscopy and barium-swallow esophagography detected a web that prevented passage of the endoscope into the upper portion of the esophagus. The patient received oral iron therapy daily; the hemoglobin concentration rose to 8.9 g/dl and the complaints of dysphagia were dramatically improved after 2 weeks, with improvement of luminal stenosis confirmed by gastrointestinal endoscopy and barium-swallow esophagography. The PVS described in this report had a distinct clinical course, showing very rapid improvement of dysphagia and esophageal web after 2 weeks of oral iron therapy. PMID- 25028579 TI - High-dose toremifene for fulvestrant-resistant metastatic breast cancer: a report of two cases. AB - INTRODUCTION: Hormone receptor (HR)-positive metastatic breast cancer (MBC) is usually treated with hormone therapy. In postmenopausal females, aromatase inhibitors (AIs) are usually used as first-line therapy, and fulvestrant is used subsequently. The optimal treatment beyond fulvestrant has not been established. We experienced two cases in which high-dose toremifene (hdTOR) was effective after the failure of AIs and fulvestrant. CASE 1: A 73-year-old female with HR positive left breast cancer (T2N1M0) underwent preoperative chemotherapy and mastectomy with axillary dissection. Computed tomography (CT) revealed liver tumors in S7 (23 mm) and S8 (25 mm) during adjuvant letrozole therapy, so fulvestrant was started. The tumors initially decreased in size (23 and 22 mm), but then progressed (36 and 25 mm). Treatment was changed to hdTOR, and the tumors shrunk to 26 mm (S7) and 24 mm (S8), and she was stable for 6 months while receiving hdTOR. CASE 2: An 81-year-old female with HR-positive left breast cancer (T2N1M0) underwent left mastectomy and axillary dissection. CT revealed liver tumors in S7 (20 mm) and S8 (11 mm) during adjuvant letrozole therapy, so fulvestrant treatment was started. The tumor in S7 shrunk (13 mm), but the tumor in S8 slightly progressed (13 mm), and both tumors progressed (14 and 18 mm) after 6 months. Treatment was changed to hdTOR, and the tumors slightly shrunk (12 and 14 mm) after 6 months. hdTOR has been continued for 9 months. CONCLUSION: hdTOR was effective for MBC after multiple hormone therapies, likely because it acts via a different mechanism of action. PMID- 25028580 TI - Clinical and echographic long-term follow-up of a retinal macrocyst: a case report. AB - The purpose of this paper is to report the case of a 62-year-old male diagnosed with a retinal macrocyst secondary to a long-standing retinal detachment in his right eye. At fundoscopy examination, an oval, elevated retinal lesion in the superior nasal quadrant was noted. Ultrasonography was performed, with a B-mode echography showing an oval, anechoic image and a standardized A-mode echography with a reflectivity spike higher than 98%, which was compatible with a retinal macrocyst. The patient refused surgical treatment for the retinal detachment and was followed for 14 months with stable visual acuity and no clinical or echographic changes. PMID- 25028581 TI - Expression of ABCG2 (BCRP) in mouse models with enhanced erythropoiesis. AB - Haem is a structural component of numerous cellular proteins which contributes significantly to iron metabolic processes in mammals but its toxicity demands that cellular levels must be tightly regulated. Breast Cancer Resistance Protein (BCRP/ABCG2), an ATP Binding Cassette G-member protein has been shown to possess porphyrin/haem efflux function. The current study evaluated the expression and regulation of Abcg2 mRNA and protein levels in mouse tissues involved in erythropoiesis. Abcg2 mRNA expression was enhanced in bone marrow hemopoietic progenitor cells from mice that were treated with phenylhydrazine (PHZ). Abcg2 mRNA expression was increased particularly in the extramedullary haematopoietic tissues from all the mice models with enhanced erythropoiesis. Haem oxygenase (ho1) levels tended to increase in the liver of mice with enhanced erythropoiesis and gene expression patterns differed from those observed in the spleen. Efflux of haem biosynthetic metabolites might be dependent on the relative abundance of Abcg2 or ho1 during erythropoiesis. Abcg2 appears to act principally as a safety valve regulating porphyrin levels during the early stages of erythropoiesis and its role in systemic haem metabolism and erythrophagocytosis, in particular, awaits further clarification. PMID- 25028583 TI - Development of the motivation to change lifestyle and health behaviours for dementia risk reduction scale. AB - BACKGROUND AND AIMS: It is not yet understood how attitudes concerning dementia risk may affect motivation to change health behaviours and lifestyle. This study was designed to develop a reliable and valid theory-based measure to understand beliefs underpinning the lifestyle and health behavioural changes needed for dementia risk reduction. METHODS: 617 participants aged >=50 years completed a theory-based questionnaire, namely, the Motivation to Change Lifestyle and Health Behaviours for Dementia Risk Reduction (MCLHB-DRR) scale. The MCLHB-DRR consists of 53 items, reflecting seven subscales of the Health Belief Model. RESULTS: Confirmatory factor analysis was performed and revealed that a seven-factor solution with 27 items fitted the data (comparative fit index = 0.920, root-mean square error of approximation = 0.047) better than the original 53 items. Internal reliability (alpha = 0.608-0.864) and test-retest reliability (alpha = 0.552-0.776) were moderate to high. Measurement of invariance across gender and age was also demonstrated. CONCLUSIONS: These results propose that the MCLHB-DRR is a useful tool in assessing the beliefs and attitudes of males and females aged >=50 years towards dementia risk reduction. This measure can be used in the development and evaluation of interventions aimed at dementia prevention. PMID- 25028584 TI - Nephrectomy in autosomal dominant polycystic kidney disease: a patient with exceptionally large, still functioning kidneys. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is characterized by progressive cyst formation in both kidneys, often leading to end-stage kidney disease. Indications for surgical removal of an ADPKD kidney include intractable pain, hematuria, infection, or exceptional enlargement and small abdominal cavity hampering implantation of a donor kidney. We report the case of an extraordinarily large ADPKD kidney weighing 8.7 kg (19.3 lb) with a maximal length of 48 cm (19 inch), and with cysts filled with both clear and bloody fluid. PMID- 25028582 TI - Occupational exposure to mineral turpentine and heavy fuels: a possible risk factor for Alzheimer's disease. AB - BACKGROUND: The association between solvents and Alzheimer's disease (AD) has been the subject of several studies. Yet, only few studies have examined the various solvents separately, and the controls have rarely been monitored long enough. For these reasons and others, we believe that further studies are required. OBJECTIVES: The objective of this study was to identify solvents associated with the clinicoradiological diagnostic of AD or mixed-type dementia (MD). METHODS: A retrospective case-control study was performed in 156 patients followed up at the Memory Diagnostic Center of Bertinot Juel Hospital (France). The inclusion criteria were known occupation(s), a Mini-Mental State Examination (MMSE) score >=10 at the first visit, a neuropsychological evaluation performed and a diagnosis established in our Memory Diagnostic Center. The diagnostics were crossed with 9 solvents belonging to two classes of solvents. Exposure was evaluated using French national job-exposure matrices. RESULTS: Certain petroleum based solvents and fuels (i.e. mineral turpentine, diesel fuel, fuel oil and kerosene) were associated with a diagnosis of AD or MD. This association was still significant after adjustment for age, sex and education (adjusted OR: 6.5; 95% CI: 2-20). CONCLUSION: Occupational exposure to mineral turpentine and heavy fuels may be a risk factor for AD and MD. PMID- 25028585 TI - Neonatal sepsis with multi-organ failure and treated with a new dialysis device specifically designed for newborns. AB - Neonatal sepsis due to E. coli is often complicated by multiple organ failure (MOF) and a high mortality risk. We report the case of a term newborn discharged in good condition who suddenly fell into septic shock after 11 days and required immediate resuscitation, volume expansion and a high-dosage amine infusion. Extremely severe metabolic acidosis, disseminated intravascular coagulation (DIC) with diffuse bleeding, and unstable hemodynamic status with oliguria turned into strict anuria, and the patient became anuric. The presence of DIC, with gastric and intestinal bleeding, rendered peritoneal dialysis impossible. Continuous renal replacement therapy (CRRT) was started with the new dialysis machine CARPEDIEM((r)) (Cardio-Renal Pediatric Dialysis Emergency Machine), available on a trial-basis in our center, after the surgical placement of jugular double-lumen central venous catheters. A 'ready to use' neonatal kit with a low-priming volume of the extracorporeal circuit allowed a prompt hemofiltration start. The filtration CRRT was continuously performed for 48 h, then intermittently (12 h/day) for 2 more days and interrupted on day 5 for diuresis reprisal. Acute kidney injury and multi-organ failure resolved after 5 days. The child survived without neurological damage, with a normal renal function and a normal development at 9 months follow-up. In conclusion, a prompt CRRT start with this specifically designed neonatal device allowed a progressive stabilization of hemodynamics, a better control of acidosis, a reduction of amine requirement, a gradual control of fluid overload and a rapid improvement of MOF, DIC as well as a resolution of the acute kidney injury. The device also allowed the extension of CRRT in the neonatal age. PMID- 25028586 TI - Bladder Cancer versus Hemorrhagic Cystitis: A Case of Mistaken Identity in a 34 Year-Old Male Undergoing Therapy for Granulomatosis with Polyangiitis. AB - A 34-year-old male was referred for management of bladder cancer noted on workup for gross hematuria and new-onset irritative voiding symptoms. The patient's history was significant for recently diagnosed granulomatosis with polyangiitis for which he was undergoing treatment with oral cyclophosphamide and corticosteroids. Cystoscopy revealed lesions suspicious for malignancy, but the patient was diagnosed with hemorrhagic cystitis secondary to BK virus infection upon cytology review, and immunostaining confirmed a polyomavirus infection of the urothelium. The patient's symptoms resolved after a modification of his immunosuppressive regimen, and antiviral therapy was ultimately unnecessary. Though symptomatic BK virus infection of the genitourinary tract is common in immunosuppressed transplant patients, its occurrence in a patient undergoing immunomodulation for an autoimmune disease has not been reported yet. This case illustrates the potential for active BK virus infections in atypical patient populations and underscores the importance of rigorous hematuria workup, particularly in patients with multiple risk factors. PMID- 25028587 TI - Detection of melanoma metastases in resected human lymph nodes by noninvasive multispectral photoacoustic imaging. AB - Objective. Sentinel node biopsy in patients with cutaneous melanoma improves staging, provides prognostic information, and leads to an increased survival in node-positive patients. However, frozen section analysis of the sentinel node is not reliable and definitive histopathology evaluation requires days, preventing intraoperative decision-making and immediate therapy. Photoacoustic imaging can evaluate intact lymph nodes, but specificity can be hampered by other absorbers such as hemoglobin. Near infrared multispectral photoacoustic imaging is a new approach that has the potential to selectively detect melanin. The purpose of the present study is to examine the potential of multispectral photoacoustic imaging to identify melanoma metastasis in human lymph nodes. Methods. Three metastatic and nine benign lymph nodes from eight melanoma patients were scanned ex vivo using a Vevo LAZR((c)) multispectral photoacoustic imager and were spectrally analyzed per pixel. The results were compared to histopathology as gold standard. Results. The nodal volume could be scanned within 20 minutes. An unmixing procedure was proposed to identify melanoma metastases with multispectral photoacoustic imaging. Ultrasound overlay enabled anatomical correlation. The penetration depth of the photoacoustic signal was up to 2 cm. Conclusion. Multispectral three-dimensional photoacoustic imaging allowed for selective identification of melanoma metastases in human lymph nodes. PMID- 25028588 TI - Duodenal chromogranin a cell density as a biomarker for the diagnosis of irritable bowel syndrome. AB - Background and Aim. Chromogranin A (CgA) is a common marker for endocrine cells. The density of duodenal CgA cells is reduced in patients with irritable bowel syndrome (IBS). Methods. The present study was undertaken to evaluate the density of duodenal CgA as a biomarker for the diagnosis of IBS. Two hundred and three patients with IBS were recruited (180 females and 23 males; mean age, 36 years; range, 18-66 years). The control group comprised 86 healthy subjects without gastrointestinal complaints (77 females and 9 males; mean age, 38 years; range, 18-67 years). Biopsy samples were taken from the duodenum during gastroscopy. Sections from these biopsy samples were immunostained for CgA using the avidin biotin complex (ABC) method. CgA cell density was quantified by computerized image analysis. Results. The CgA cell density was lower in IBS-total and in all of the IBS subgroups than in the controls. The sensitivity and specificity for a cutoff of <200 cells/mm(2) were 86% and 95%, respectively. Conclusion. The duodenal CgA cell density seems to be a good biomarker for the diagnosis of IBS. It is an inexpensive, simple, and easy-to-use method that does not require sophisticated equipment or considerable experience. PMID- 25028589 TI - A large cardiac mass: diagnosis of caseous mitral annular calcification and determining optimum management strategy. AB - A 64-year-old woman with dizziness and blurry vision underwent an evaluation for a possible stroke with a head-neck CT scan and a transthoracic echocardiogram. The head-neck CT scan was unremarkable, but the echocardiogram was notable for a 2.0 * 2.3 cm heterogeneous echodensity attached to the mitral valve. After a transesophageal echocardiogram and chest CT scan, the mass was determined to be a caseous mitral annular calcification, CMAC. This entity is a rare variant of MAC with an estimated prevalence of 0.068%. Echocardiographic techniques can distinguish CMAC from other intracardiac masses such as tumor, cyst, or abscess. CMAC is associated with cerebrovascular accidents; however, optimal treatment is controversial given the rarity of this clinical finding. Management strategies should be tailored based on the patient's presentation, risk factors, and overall clinical circumstances. PMID- 25028590 TI - Chinese herbal medicine bushen qinggan formula for blood pressure variability and endothelial injury in hypertensive patients: a randomized controlled pilot clinical trial. AB - Background. Blood pressure variability (BPV) independent of average blood pressure is related to cardiovascular damage. Meanwhile, BPV is also associated with measures of endothelial injury. Decoction, a traditional used form of Traditional Chinese Medicine (TCM), is inconvenient to prepare, carry, and store. Dispensing granules is now developing as an alternative to decoction, but the evidence supporting its clinical efficacy the same as decoction remains unclear. Objective. To examine the therapeutic effects on mean blood pressure (MBP), blood pressure variability, and endothelial function by giving Bushen Qinggan Formula, a compound Chinese Herbal Medicine and also to evaluate the difference in efficacy between decoction and granule. Methods. A total of 150 patients with hypertension were enrolled and randomly assigned to receive the placebo, Bushen Qinggan decoction, or Bushen Qinggan granule in addition to the standard medications (amlodipine-5 mg/d) for the treatment of essential hypertension (EH). The outcome was the reduction in the MBP and BPV and also included changes in the endothelial markers including endothelin-1 (ET-1) and nitric oxide (NO) after 8 weeks of treatment. Results. Compared with the control group, the Bushen Qinggan decoction and granule groups had significant improvement (P < 0.01) in BPV and endothelial founction. The level of BPV and endothelial function between decoction and granule group had no significant difference (P > 0.05). Conclusion. Based on the standard treatment, Bushen Qinggan Formula further improved BPV and endothelial function. The efficacy of Bushen Qinggan decoction and granule is similar in improving BPV and endothelial function. However, no significant antihypertensive effects could be demonstrated. PMID- 25028591 TI - The effect of 1,8-cineole inhalation on preoperative anxiety: a randomized clinical trial. AB - The aim of this study was to investigate the effect of inhalation of eucalyptus oil and its constituents on anxiety in patients before selective nerve root block (SNRB). This study was a randomized controlled trial carried out in 62 patients before SNRB. The patients were randomized to inhale limonene, 1,8-cineole, or eucalyptus oil, each at concentrations of 1% vol/vol in almond oil or almond oil (control). Anxiety-visual analog scale (A-VAS), state-trait anxiety inventory (STAI), profile of mood states (POMS), pain-visual analog scale (P-VAS), blood pressure, and pulse rate were measured before and after inhalation prior to SNRB. Measures of anxiety, including A-VAS (P < 0.001), STAI (P = 0.005), and POMS (P < 0.001), were significantly lower in 1,8-cineole than in the control group and significantly greater in 1,8-cineole than in the eucalyptus group in A-VAS. P-VAS was significantly lower after than before inhalation of limonene, 1,8-cineole, and eucalyptus, despite having no significant difference in the four groups compared with control group. 1,8-Cineole, a major constituent of eucalyptus, was effective in decreasing anxiety before SNRB. The present findings suggest that inhalation of 1,8-cineole may be used to relieve anxiety before, during, and after various operations, in addition to SNRB. PMID- 25028592 TI - Prolonged Diuretic Activity and Calcium-Sparing Effect of Tropaeolum majus: Evidence in the Prevention of Osteoporosis. AB - Although several studies indicate high effectiveness in the use of the hydroethanolic extract from Tropaeolum majus (HETM) as a diuretic, the impact of its prolonged use in the presence of low estrogen levels remains unclear. Thus, the aim of this study was to investigate the diuretic effects of prolonged administration of HETM in ovariectomized rats and their interrelationship between calcium excretion and bone turnover. Forty-two female Wistar rats were ovariectomized (OVX) and treated orally with different doses of HETM (3, 30, and 300 mg/kg) for 4 weeks. On the first day of treatment and at weekly intervals for four weeks the diuretic activity was evaluated. Electrolyte concentrations and creatinine levels were estimated from urine sample of each rat. The serum lipids, urea, creatinine, and osteocalcin were also measured at the end of the experiment. The data revealed that the HETM was able to sustain its diuretic effect after prolonged treatment. Moreover, its use has not affected the urinary calcium or potassium excretion, reduces lipid levels, and maintains osteocalcin levels similarly to untreated rats. These findings support the potential of HETM as a candidate to be used in clinical conditions in which the renal loss of calcium is not desired. PMID- 25028593 TI - Medical image segmentation based on a hybrid region-based active contour model. AB - A novel hybrid region-based active contour model is presented to segment medical images with intensity inhomogeneity. The energy functional for the proposed model consists of three weighted terms: global term, local term, and regularization term. The total energy is incorporated into a level set formulation with a level set regularization term, from which a curve evolution equation is derived for energy minimization. Experiments on some synthetic and real images demonstrate that our model is more efficient compared with the localizing region-based active contours (LRBAC) method, proposed by Lankton, and more robust compared with the Chan-Vese (C-V) active contour model. PMID- 25028594 TI - Cost of care and antibiotic prescribing attitudes for community-acquired complicated intra-abdominal infections in Italy: a retrospective study. AB - INTRODUCTION: Complicated intra-abdominal infections (cIAIs) are a common cause of morbidity worldwide, and in spite of improvements in patient care, therapeutic failure still occurs, impacting in-hospital resource consumption. This study aimed to assess the costs associated with the treatment of community-acquired cIAIs, from the Italian National Health Service perspective. METHODS: This retrospective study analyzed the charts of patients who were discharged from four Italian university hospitals between January 1 and December 31, 2009 with a primary diagnosis of community-acquired cIAIs. Patient characteristics, diagnosis, surgical procedure, antibiotic therapy, and length of hospital stay were all recorded and the cost of total hospital care was estimated. Costs were calculated in Euros at 2009 values. RESULTS: The records of 260 patients (mean age 48.9 years; 57% males) were analyzed. The average cost of care for a patient hospitalized due to cIAI was ?4385 (95% CI 3650-5120), with an average daily cost of ?419 (95% CI 378-440). Antibiotic therapy represented just under half (44.3%) of hospitalization costs. The strongest predictor of the increase in hospital costs was clinical failure: patients who clinically failed received an average of 8.2 additional days of antibiotic therapy and spent 11 more days in hospital compared with patients who responded to first-line therapy (both p < 0.05 vs. patients who were successfully treated). Furthermore, they incurred ?5592 in additional hospitalization costs (2.88 times the cost associated with clinical success) with 53% (?2973) of the additional costs attributable to antibiotic therapy. Overall, antibiotic appropriateness rate was 78.8% (n = 205), and was significantly higher in patients receiving combination therapy compared with those treated with monotherapy (97.3% vs. 64.6%). CONCLUSION: The results of this study suggest that hospitals need to be aware of the clinical and economic consequences of antibiotic therapy of cIAIs and to reduce overall resource use and costs by improving the rate of success with appropriate initial empiric therapy. PMID- 25028595 TI - A non-syndromic intellectual disability associated with a de novo microdeletion at 7q and 18p, microduplication at Xp, and 18q partial trisomy detected using chromosomal microarray analysis approach. AB - BACKGROUND: Chromosome abnormalities that segregate with a disease phenotype can facilitate the identification of disease loci and genes. The relationship between chromosome 18 anomalies with severe intellectual disability has attracted the attention of cytogeneticists worldwide. Duplications of the X chromosome can cause intellectual disability in females with variable phenotypic effects, due in part to variations in X-inactivation patterns. Additionally, deletions of the 7qter region are associated with a range of phenotypes. RESULTS: We report the first case of de novo microdeletion at 7q and 18p, 18q partial trisomy, microduplication at Xp associated to intellectual disability in a Brazilian child, presenting a normal karyotype. Karyotyping showed any chromosome alteration. Chromosomal microarray analysis detected a de novo microdeletion at 18p11.32 and 18q partial trisomy, an inherited microdeletion at 7q31.1 and a de novo microduplication at Xp22.33p21.3. CONCLUSIONS: Our report illustrates a case that presents complex genomic imbalances which may contribute to a severe clinical phenotypes. The rare and complex phenotypes have to be investigated to define the subsets and allow the phenotypes classification. PMID- 25028596 TI - The Mbd1-Atf7ip-Setdb1 pathway contributes to the maintenance of X chromosome inactivation. AB - BACKGROUND: X chromosome inactivation (XCI) is a developmental program of heterochromatin formation that initiates during early female mammalian embryonic development and is maintained through a lifetime of cell divisions in somatic cells. Despite identification of the crucial long non-coding RNA Xist and involvement of specific chromatin modifiers in the establishment and maintenance of the heterochromatin of the inactive X chromosome (Xi), interference with known pathways only partially reactivates the Xi once silencing has been established. Here, we studied ATF7IP (MCAF1), a protein previously characterized to coordinate DNA methylation and histone H3K9 methylation through interactions with the methyl DNA binding protein MBD1 and the histone H3K9 methyltransferase SETDB1, as a candidate maintenance factor of the Xi. RESULTS: We found that siRNA-mediated knockdown of Atf7ip in mouse embryonic fibroblasts (MEFs) induces the activation of silenced reporter genes on the Xi in a low number of cells. Additional inhibition of two pathways known to contribute to Xi maintenance, DNA methylation and Xist RNA coating of the X chromosome, strongly increased the number of cells expressing Xi-linked genes upon Atf7ip knockdown. Despite its functional importance in Xi maintenance, ATF7IP does not accumulate on the Xi in MEFs or differentiating mouse embryonic stem cells. However, we found that depletion of two known repressive biochemical interactors of ATF7IP, MBD1 and SETDB1, but not of other unrelated H3K9 methyltransferases, also induces the activation of an Xi linked reporter in MEFs. CONCLUSIONS: Together, these data indicate that Atf7ip acts in a synergistic fashion with DNA methylation and Xist RNA to maintain the silent state of the Xi in somatic cells, and that Mbd1 and Setdb1, similar to Atf7ip, play a functional role in Xi silencing. We therefore propose that ATF7IP links DNA methylation on the Xi to SETDB1-mediated H3K9 trimethylation via its interaction with MBD1, and that this function is a crucial feature of the stable silencing of the Xi in female mammalian cells. PMID- 25028597 TI - Development and validation of a new high-throughput method to investigate the clonality of HTLV-1-infected cells based on provirus integration sites. AB - Transformation and clonal proliferation of T-cells infected with human T-cell leukemia virus type-I (HTLV-1) cause adult T-cell leukemia. We took advantage of next-generation sequencing technology to develop and internally validate a new methodology for isolating integration sites and estimating the number of cells in each HTLV-1-infected clone (clone size). Initial analysis was performed with DNA samples from infected individuals. We then used appropriate controls with known integration sites and clonality status to confirm the accuracy of our system, which indeed had the least errors among the currently available techniques. Results suggest potential clinical and biological applications of the new method. PMID- 25028598 TI - Correlates of foot pain severity in adults with hallux valgus: a cross-sectional study. AB - BACKGROUND: Hallux valgus (HV) is highly prevalent and associated with progressive first metatarsophalangeal joint subluxation and osteoarthritis. The link between structural HV deformity and foot pain is unclear. This study investigated possible explanatory factors surrounding foot pain in HV, including radiographic HV angle and signs of joint degeneration. METHODS: Participants were 60 adults (53 female) with HV aged 20 to 75 years. Participant demographics and a range of radiographic, clinical and functional measures were considered potential correlates of foot pain. Self-reported foot pain (visual analogue scales and a dichotomous definition) was considered the dependent variable. Multivariate modelling was used to determine which characteristics and measures explained pain, with univariate analyses first used to screen potential variables. RESULTS: Approximately 20 to 30% of the variance in foot pain associated with HV could be explained by patient characteristics such as poorer general health status, lower educational attainment and increased occupational physical activity levels, in combination with some dynamic physical characteristics such as hallux plantarflexion weakness and reduced force-time integral under the second metatarsal during gait. Neither increasing lateral deviation of the hallux (HV angle) nor presence of first metatarsophalangeal joint osteoarthritis was associated with foot pain. CONCLUSIONS: This study shows that passive structural factors, including HV angle, do not appear to be significant correlates of foot pain intensity in HV. Our data demonstrate the importance of considering patient characteristics such as general health and physical activity levels when assessing foot pain associated with HV. PMID- 25028599 TI - KIFCI, a novel putative prognostic biomarker for ovarian adenocarcinomas: delineating protein interaction networks and signaling circuitries. AB - BACKGROUND: Amplified centrosomes in cancers are recently garnering a lot of attention as an emerging hub of diagnostic, prognostic and therapeutic targets. Ovarian adenocarcinomas commonly harbor supernumerary centrosomes that drive chromosomal instability. A centrosome clustering molecule, KIFC1, is indispensable for the viability of extra centrosome-bearing cancer cells, and may underlie progression of ovarian cancers. METHODS: Centrosome amplification in low and high- grade serous ovarian adenocarcinomas was quantitated employing confocal imaging. KIFC1 expression was analyzed in ovarian tumors using publically-available databases. Associated grade, stage and clinical information from these databases were plotted for KIFC1 gene expression values. Furthermore, interactions and functional annotation of KIFC1 and its highly correlated genes were studied using DAVID and STRING 9.1. RESULTS: Clinical specimens of ovarian cancers display robust centrosome amplification and deploy centrosome clustering to execute an error-prone mitosis to enable karyotypic heterogeneity that fosters tumor progression and aggressiveness. Our in silico analyses showed KIFC1 overexpression in human ovarian tumors (n = 1090) and its upregulation associated with tumor aggressiveness utilizing publically-available gene expression databases. KIFC1 expression correlated with advanced tumor grade and stage. Dichotomization of KIFC1 levels revealed a significantly lower overall survival time for patients in high KIFC1 group. Intriguingly, in a matched-cohort of primary (n = 7) and metastatic (n = 7) ovarian samples, no significant differences in KIFC1 expression were detectable, suggesting that high KIFC1 expression may serve as a marker of metastases onset. Nonetheless, KIFC1 levels in both primary and matched metastatic sites were significantly higher compared to normal tissue . Ingenuity based network prediction algorithms combined with pre-established protein interaction networks uncovered several novel cell-cycle related partner genes on the basis of interconnectivity, illuminating the centrosome clustering independent agenda of KIFC1 in ovarian tumor progression. CONCLUSIONS: Ovarian cancers display amplified centrosomes, a feature of aggressive tumors. To cope up with the abnormal centrosomal load, ovarian cancer cells upregulate genes like KIFC1 that are known to induce centrosome clustering. Our data underscore KIFC1 as a putative biomarker that predicts worse prognosis, poor overall survival and may serve as a potential marker of onset of metastatic dissemination in ovarian cancer patients. PMID- 25028600 TI - Genome sequencing, annotation and comparative genomic analysis of Shigella dysenteriae strain SD1D. AB - BACKGROUND: Shigellosis is an acute form of gastroenteritis caused by the bacteria belonging to the genus Shigella. It is the most common cause of morbidity and mortality in children. Shigella belongs to the family Enterobactericeae, which is a Gram-negative and rod shaped bacterium. In the present study, we report the draft genome of Shigella dysenteriae strain SD1D, which was isolated from the stool sample of a healthy individual. RESULTS: Based on 16S rRNA gene sequence and phylogenetic analysis, the strain SD1D was identified as Shigella dysenteriae. The draft genome of SD1D consisted of 45, 93, 159 bp with a G + C content of 50.7%, 4, 960 predicted CDSs, 75 tRNAs and 2 rRNAs. The final assembly contained 146 contigs of total length 45, 93, 159 bp with N50 contig length of 77, 053 bp; the largest contig assembled measured 3, 85, 550 bp. CONCLUSIONS: We have for the first time performed the whole genome sequencing of Shigella dysenteriae strain SD1D. The comparative genomic analysis revealed several genes responsible for the pathogenesis, virulence, defense, resistance to antibiotics and toxic compounds, multidrug resistance efflux pumps and other genomic features of the bacterium. PMID- 25028601 TI - Effects of high-fat diet and the anti-diabetic drug metformin on circulating GLP 1 and the relative number of intestinal L-cells. AB - BACKGROUND: Elevated serum free fatty acids (FFAs) contribute to the pathogenesis of type-2-diabetes (T2D), and lipotoxicity is observed in many cell types. We recently showed that simulated hyperlipidemia induces lipoapoptosis also in GLP-1 secreting L-cells in vitro, while metformin confers lipoprotection. The aim of this study was to determine if a high fat diet (HFD) reduces the number of enteroendocrine L-cells and/or GLP-1 plasma levels in a rodent model, and potential effects thereupon of metformin treatment. METHODS: C57/Bl6 mice received control/HFD for 12-weeks, and oral administration of metformin/saline for the last 14 days. Blood glucose, glycosylated hemoglobin and plasma insulin and GLP-1 were determined before and after treatment with metformin using ELISAs. GLP-1-immunopositive cells in intestinal tissue sections were quantified using immunohistochemistry. RESULTS: A HFD increased blood glucose, glycosylated hemoglobin, and fasting plasma insulin (33%, 15% and 70% increase, respectively), in conjunction with reduced oral glucose tolerance, indicating the manifestation of insulin resistance. Metformin counteracted these adverse effects, while also reducing prandial plasma FFAs. The number of GLP-1-positive cells was indicated to be reduced (55% reduction of the number of GLP-1-positive cells, p = 0.134), while there was a trend toward increased prandial plasma GLP-1 despite reduced food intake following a HFD. CONCLUSION: HFD-fed mice rapidly develop insulin resistance. Metformin exerts beneficial glucose lowering effects, and is indicated to improve the incretin response. Albeit no significant effect, a HFD tends to reduce the number of GLP-1-positive cells. However, considering concurrent normal or increased plasma GLP-1, any reduction in the number of GLP-1 positive cells, probably does not contribute to development of the glucose intolerance, but may contribute to progression of the diabetic state through eventual loss of a functional incretin response. PMID- 25028602 TI - Antioxidant supplement inhibits skeletal muscle constitutive autophagy rather than fasting-induced autophagy in mice. AB - In this study, we tested the hypothesis that NAC administration leads to reduced oxidative stress and thus to decreased expression of autophagy markers in young mice. Our results reveal that NAC administration results in reduced muscle mRNA levels of several autophagy markers, including Beclin-1, Atg7, LC3, Atg9, and LAMP2. However, NAC supplement fails to block the activation of skeletal muscle autophagy in response to fasting, because fasting significantly increases the mRNA level of several autophagy markers and LC3 lipidation. We further examined the effects of NAC administration on mitochondrial antioxidant capacity in fed and 24-hour fasted mice. Our results clearly show that NAC administration depresses the expression of manganese superoxide dismutase (MnSOD) and TP53 induced glycolysis and apoptosis regulator (TIGAR), both of which play a predominant antioxidant role in mitochondria by reducing ROS level. In addition, we found no beneficial effect of NAC supplement on muscle mass but it can protect from muscle loss in response to fasting. Collectively, our findings indicate that ROS is required for skeletal muscle constitutive autophagy, rather than starvation-induced autophagy, and that antioxidant NAC inhibits constitutive autophagy by the regulation of mitochondrial ROS production and antioxidant capacity. PMID- 25028603 TI - Neuromuscular activity of Bothrops fonsecai snake venom in vertebrate preparations. AB - The neuromuscular activity of venom from Bothrops fonsecai, a lancehead endemic to southeastern Brazil, was investigated. Chick biventer cervicis (CBC) and mouse phrenic nerve-diaphragm (PND) preparations were used for myographic recordings and mouse diaphragm muscle was used for membrane resting potential (RP) and miniature end-plate potential (MEPP) recordings. Creatine kinase release and muscle damage were also assessed. In CBC, venom (40, 80 and 160MUg/ml) produced concentration- and time-dependent neuromuscular blockade (50% blockade in 85+/-9 min and 73+/-8 min with 80 and 160MUg/ml, respectively) and attenuated the contractures to 110MUM ACh (78-100% inhibition) and 40mM KCl (45-90% inhibition). The venom-induced decrease in twitch-tension in curarized, directly-stimulated preparations was similar to that in indirectly stimulated preparations. Venom (100 and 200MUg/ml) also caused blockade in PND preparations (50% blockade in 94+/-13 min and 49+/-8 min with 100 and 200MUg/ml, respectively) but did not alter the RP or MEPP amplitude. In CBC, venom caused creatine kinase release and myonecrosis. The venom-induced decrease in twitch-tension and in the contractures to ACh and K(+) were abolished by preincubating venom with commercial antivenom. These findings indicate that Bothrops fonsecai venom interferes with neuromuscular transmission essentially through postsynaptic muscle damage that affects responses to ACh and KCl. These actions are effectively prevented by commercial antivenom. PMID- 25028604 TI - A gene expression estimator of intramuscular fat percentage for use in both cattle and sheep. AB - BACKGROUND: The expression of genes encoding proteins involved in triacyglyceride and fatty acid synthesis and storage in cattle muscle are correlated with intramuscular fat (IMF)%. Are the same genes also correlated with IMF% in sheep muscle, and can the same set of genes be used to estimate IMF% in both species? RESULTS: The correlation between gene expression (microarray) and IMF% in the longissimus muscle (LM) of twenty sheep was calculated. An integrated analysis of this dataset with an equivalent cattle correlation dataset and a cattle differential expression dataset was undertaken. A total of 30 genes were identified to be strongly correlated with IMF% in both cattle and sheep. The overlap of genes was highly significant, 8 of the 13 genes in the TAG gene set and 8 of the 13 genes in the FA gene set were in the top 100 and 500 genes respectively most correlated with IMF% in sheep, P-value = 0. Of the 30 genes, CIDEA, THRSP, ACSM1, DGAT2 and FABP4 had the highest average rank in both species. Using the data from two small groups of Brahman cattle (control and Hormone growth promotant-treated [known to decrease IMF% in muscle]) and 22 animals in total, the utility of a direct measure and different estimators of IMF% (ultrasound and gene expression) to differentiate between the two groups were examined. Directly measured IMF% and IMF% estimated from ultrasound scanning could not discriminate between the two groups. However, using gene expression to estimate IMF% discriminated between the two groups. Increasing the number of genes used to estimate IMF% from one to five significantly increased the discrimination power; but increasing the number of genes to 15 resulted in little further improvement. CONCLUSION: We have demonstrated the utility of a comparative approach to identify robust estimators of IMF% in the LM in cattle and sheep. We have also demonstrated a number of approaches (potentially applicable to much smaller groups of animals than conventional methods) to using gene expression to rank animals for IMF% within a single farm/treatment, or to estimate differences in IMF% between two farms/treatments. PMID- 25028605 TI - Ledipasvir/Sofosbuvir administration achieves very high rate of viral clearance in patients with HCV genotype 1 infection without cirrhosis, regardless of ribavirin co-administration or length of treatment. PMID- 25028606 TI - Intensive glucose-lowering results in increased cardiovascular mortality in younger but not older individuals with type 2 diabetes. PMID- 25028607 TI - Evidence base needs among clinicians. PMID- 25028608 TI - Characterization of the nasopharyngeal microbiota in health and during rhinovirus challenge. AB - BACKGROUND: The bacterial communities of the nasopharynx play an important role in upper respiratory tract infections (URTIs). Our study represents the first survey of the nasopharynx during a known, controlled viral challenge. We aimed to gain a better understanding of the composition and dynamics of the nasopharyngeal microbiome during viral infection. METHODS: Rhinovirus illnesses were induced by self-inoculation using the finger to nose or eye natural transmission route in ten otherwise healthy young adults. Nasal lavage fluid samples (NLF) samples were collected at specific time points before, during, and following experimental rhinovirus inoculation. Bacterial DNA from each sample (N = 97 from 10 subjects) was subjected to 16S rRNA sequencing by amplifying the V1-V2 hypervariable region followed by sequencing using the 454-FLX platform. RESULTS: This survey of the nasopharyngeal microbiota revealed a highly complex microbial ecosystem. Taxonomic composition varied widely between subjects and between time points of the same subject. We also observed significantly higher diversity in not infected individuals compared to infected individuals. Two genera - Neisseria and Propionibacterium - differed significantly between infected and not infected individuals. Certain phyla, including Firmicutes, Actinobacteria, and Proteobacteria, were detected in all samples. CONCLUSIONS: Our results reveal the complex and diverse nature of the nasopharyngeal microbiota in both healthy and viral-challenged adults. Although some phyla were common to all samples, differences in levels of diversity and selected phyla were detected between infected and uninfected participants. Deeper, species-level metagenomic sequencing in a larger sample is warranted. PMID- 25028609 TI - The effect of work characteristics on dermatologic symptoms in hairdressers. AB - OBJECTIVES: Hairdressers in Korea perform various tasks and are exposed to health risk factors such as chemical substances or prolonged duration of wet work. The objective of this study is to provide descriptive statistics on the demographics and work characteristics of hairdressers in Korea and to identify work-related risk factors for dermatologic symptoms in hairdressers. METHODS: 1,054 hairdressers were selected and analyzed for this study. Independent variables were exposure to chemical substances, the training status of the hairdressers, and the main tasks required of them, and the dependent variable was the incidence of dermatologic symptoms. The relationships between work characteristics and dermatologic symptoms were evaluated by estimating odds ratios using multiple logistic regression analysis. RESULTS: Among the 1,054 study subjects, 212 hairdressers (20.1%) complained of dermatologic symptoms, and the symptoms were more prevalent in younger, unmarried or highly educated hairdressers. The main tasks that comprise the majority of the wet work were strictly determined by training status, since 96.5% of staff hairdressers identified washing as their main task, while only 1.5% and 2.0% of master and designer hairdressers, respectively, identified this as their main task. Multiple logistic regressions was performed to estimate odds ratios. While exposure to hairdressing chemicals showed no significant effect on the odds ratio for the incidence of dermatologic symptoms, higher odds ratios of dermatologic symptoms were shown in staff hairdressers (2.70, 95% CI: 1.32 - 5.51) and in hairdressers who perform washing as their main task (2.03, 95% CI: 1.22 - 3.37), after adjusting for general and work characteristics. CONCLUSIONS: This study showed that the training status and main tasks of hairdressers are closely related to each other and that the training status and main tasks of hairdressers are related to the incidence of dermatologic symptoms. This suggests that in the future, regulations on working conditions and health management guidelines for hairdressers should be established. PMID- 25028610 TI - Treatment outcomes in a decentralized antiretroviral therapy program: a comparison of two levels of care in north central Nigeria. AB - Background. Decentralization of antiretroviral therapy (ART) services is a key strategy to achieving universal access to treatment for people living with HIV/AIDS. Our objective was to assess clinical and laboratory outcomes within a decentralized program in Nigeria. Methods. Using a tiered hub-and-spoke model to decentralize services, a tertiary hospital scaled down services to 13 secondary level hospitals using national and program guidelines. We obtained sociodemographic, clinical, and immunovirologic data on previously antiretroviral drug naive patients aged >=15 years that received HAART for at least 6 months and compared treatment outcomes between the prime and satellite sites. Results. Out of 7,747 patients, 3729 (48.1%) were enrolled at the satellites while on HAART, prime site patients achieved better immune reconstitution based on CD4+ cell counts at 12 (P < 0.001) and 24 weeks (P < 0.001) with similar responses at 48 weeks (P = 0.11) and higher rates of viral suppression (<400 c/mL) at 12 (P < 0.001) and 48 weeks (P = 0.03), but similar responses at 24 weeks (P = 0.21). Mortality was 2.3% versus 5.0% (P < 0.001) at prime and satellite sites, while transfer rate was 8.7% versus 5.5% (P = 0.001) at prime and satellites. Conclusion. ART decentralization is feasible in resource-limited settings, but efforts have to be intensified to maintain good quality of care. PMID- 25028611 TI - Anxiety, automatic negative thoughts, and unconditional self-acceptance in rheumatoid arthritis: a preliminary study. AB - Objectives. This research was carried out in two stages: the objectives of the first stage were (1) to identify the existing relationships between the level of anxiety, the frequency of automatic negative thoughts, and unconditional self acceptance and (2) to capture the existing differences regarding these variables between people diagnosed with rheumatoid arthritis and those with no such medical history. Methods. The sample made up of 50 subjects filled out the following three questionnaires: the Hamilton Anxiety Scale, the Automatic Thoughts Questionnaire, and the Unconditional Self-Acceptance Questionnaire. Results. Psychological anxiety is positively correlated with automatic negative thoughts, while unconditional self-acceptance is negatively correlated with both psychological anxiety and somatic anxiety as well as with automatic negative thoughts. All studied variables were significantly different in rheumatoid arthritis as compared to the control population. Conclusions. The results showed the presence to a greater extent of anxiety and automatic negative thoughts, along with reduced unconditional self-acceptance among people with rheumatoid arthritis. Intervention on these variables through support and counseling can lead to reducing anxiety and depression, to altering the coping styles, and, implicitly, to improving the patients' quality of life. PMID- 25028613 TI - Iatrogenic Ascending Aorta Dissection during Diagnostic Coronary Angiography: Rare but Life-Threatening. AB - Dissection of the ascending aorta is a very rare but life-threatening complication during diagnostic angiography. We present a case of an elderly woman who underwent an elective diagnostic coronary angiography, complicated with an iatrogenic ascending aorta dissection that did not involve the coronary arteries but originated 4 cm distal of the aortic valve. The patient developed cardiogenic shock due to acute pericardial tamponade and so immediate, life-saving cardiac surgery with implantation of a supracoronary graft was successfully performed. A biopsy from the excised aorta showed loss of smooth muscle cells and accumulation of basophilic ground substance, clear features of cystic media necrosis. This is believed to be the underlying cause of the dissection besides a nonselective injection of the right coronary artery. PMID- 25028612 TI - Protective effects of Ginkgo biloba extract EGb 761 against noise trauma-induced hearing loss and tinnitus development. AB - Noise-induced hearing loss (NIHL) and resulting comorbidities like subjective tinnitus are common diseases in modern societies. A substance shown to be effective against NIHL in an animal model is the Ginkgo biloba extract EGb 761. Further effects of the extract on the cellular and systemic levels of the nervous system make it a promising candidate not only for protection against NIHL but also for its secondary comorbidities like tinnitus. Following an earlier study we here tested the potential effectiveness of prophylactic EGb 761 treatment against NIHL and tinnitus development in the Mongolian gerbil. We monitored the effects of EGb 761 and noise trauma-induced changes on signal processing within the auditory system by means of behavioral and electrophysiological approaches. We found significantly reduced NIHL and tinnitus development upon EGb 761 application, compared to vehicle treated animals. These protective effects of EGb 761 were correlated with changes in auditory processing, both at peripheral and central levels. We propose a model with two main effects of EGb 761 on auditory processing, first, an increase of auditory brainstem activity leading to an increased thalamic input to the primary auditory cortex (AI) and second, an asymmetric effect on lateral inhibition in AI. PMID- 25028614 TI - Serum Free Light Chain Only Myeloma with Cytoplasmic IgM. AB - In the past decade, the serum free light chain (FLC) immunoassays have become widely available enabling greater sensitivity in the diagnosis and management of monoclonal light chain diseases. Here, we describe a rare case of serum free light chain only myeloma with cytoplasmic IgM. A 75-year-old woman presented with a progressively worsening lumbosacral pain. FDG PET/CT images showed increased FDG uptake in the sacral mass, vertebral bodies, and ribs. Laboratory data found hypogammaglobulinemia and the bone marrow aspirate revealed only 2.2% of plasma cells. The serum and urine protein electrophoresis did not detect a monoclonal band. However, the serum FLC immunoassays reported an abnormal kappa/lambda ratio (0.001) indicating the presence of monoclonal lambda FLC. The sacral tumor biopsy revealed proliferation of plasma cells and immunohistochemical staining showed that the plasma cells were positive for CD138, IgM, and lambda light chain but negative for CD20. This case may have previously been described as a nonsecretory IgM myeloma but recently would be identified as free light chain only myeloma. The immunohistochemical and genetic features of the clonal plasma cells in free light chain only myeloma need to be further investigated to better understand the relevance and incidence of this myeloma type. PMID- 25028615 TI - Young maternal age and old paternal age induce similar risk of mental disorders in offspring. PMID- 25028617 TI - Malignant Pelvic Pheochromocytoma Presenting as NonFunctioning Kidney and Accelerated Hypertension: A Rare Presentation. AB - Paragangliomas are neuroendocrine tumors that arise from sympathetic nerve ganglia. They can develop anywhere from the neck to the pelvis, but are most commonly found in the abdomen, particularly at the aortic bifurcation or in the periaortic region. Malignant paragangliomas account for 29-40% of cases. We report a case of 36-year hypertensive female presented with and right flank pain and accelerated hypertension. On evaluation she was diagnosed to have non unctioning kidney due to malignant pelvic paraganglioma with right ureteric encasement. We believe our case is one of the first reported in literature as rare presentation of malignant paraganglioma presenting as nonfunctioning kidney and accelerated hypertension. PMID- 25028616 TI - Mycobacterium fortuitum and Polymicrobial Peritoneal Dialysis-Related Peritonitis: A Case Report and Review of the Literature. AB - Mycobacterium fortuitum is a ubiquitous, rapidly growing nontuberculous mycobacterium (NTM). It is the most commonly reported NTM in peritoneal dialysis (PD) associated peritonitis. We report a case of a 52-year-old man on PD, who developed refractory polymicrobial peritonitis necessitating PD catheter removal and shift to hemodialysis. Thereafter, M. fortuitum was identified in the PD catheter culture and in successive cultures of initial peritoneal effluent and patient was treated with amikacin and ciprofloxacin for six months with a good and sustained clinical response. Months after completion of the course of antibiotics, the patient successfully returned to PD. To our knowledge, this is the first reported case of M. fortuitum peritonitis in the field of polymicrobial PD peritonitis. It demonstrates the diagnostic yield of pursuing further investigations in cases of refractory PD peritonitis. In a systematic review of the literature, only 20 reports of M. fortuitum PD peritonitis were identified. Similar to our case, a delay in microbiological diagnosis was frequently noted and the Tenckhoff catheter was commonly removed. However, the type and duration of antibiotic therapy varied widely making the optimal treatment unclear. PMID- 25028618 TI - Indirect inguinal hernia containing a fallopian tube and ovary in a reproductive aged woman. AB - An indirect inguinal hernia containing an incarcerated fallopian tube and ovary is extremely rare in adult females. The current report describes a woman of reproductive years presenting with an irreducible indirect hernia which required the surgical intervention of a general surgeon as well as counseling regarding future fertility by a gynecologist. The diagnosis was made by physical and sonographic examination and was confirmed by CT scan and surgical intervention. We suggest a multimodel and multidisciplinary approach in order to safely and efficiently preserve ovarian and fertility function in young women who present with an inguinal hernia containing reproductive organs. PMID- 25028619 TI - Racial/Ethnic differences in poststroke rehabilitation outcomes. AB - Background. Significant racial and ethnic disparities in stroke incidence, severity, and morbidity have been consistently reported; however, less is known about potential differences in poststroke rehabilitation outcomes. Objective. To examine racial and ethnic differences in poststroke rehabilitation outcomes. Methods. We completed an in-depth search of Medline and several major journals dedicated to publishing research articles on stroke, rehabilitation, and racial ethnic patterns of disease over a 10-year period (2003-2012). We identified studies that reported rehabilitation outcomes and the race or ethnicity of at least two groups. Results. 17 studies involving 429,108 stroke survivors met inclusion criteria for the review. The majority (94%) of studies examined outcomes between Blacks and Whites. Of those studies examining outcomes between Blacks and Whites, 59% showed that Blacks were generally less likely to achieve equivalent functional improvement following rehabilitation. Blacks were more likely to experience lower FIM gain or change scores (range: 1-60%) and more likely to have lower efficiency scores (range: 5-16%) than Whites. Conclusions. Black stroke survivors appear to generally achieve poorer functional outcomes than White stroke survivors. Future studies are warranted to evaluate the precise magnitude of these differences, whether they go beyond chance, and the underlying contributory mechanisms. PMID- 25028621 TI - Cardiovascular and renal medicine, an expanding territory. PMID- 25028620 TI - Advances in diagnosis of respiratory diseases of small ruminants. AB - Irrespective of aetiology, infectious respiratory diseases of sheep and goats contribute to 5.6 percent of the total diseases of small ruminants. These infectious respiratory disorders are divided into two groups: the diseases of upper respiratory tract, namely, nasal myiasis and enzootic nasal tumors, and diseases of lower respiratory tract, namely, peste des petits ruminants (PPR), parainfluenza, Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, caprine arthritis encephalitis virus, caseous lymphadenitis, verminous pneumonia, and many others. Depending upon aetiology, many of them are acute and fatal in nature. Early, rapid, and specific diagnosis of such diseases holds great importance to reduce the losses. The advanced enzyme-linked immunosorbent assays (ELISAs) for the detection of antigen as well as antibodies directly from the samples and molecular diagnostic assays along with microsatellites comprehensively assist in diagnosis as well as treatment and epidemiological studies. The present review discusses the advancements made in the diagnosis of common infectious respiratory diseases of sheep and goats. It would update the knowledge and help in adapting and implementing appropriate, timely, and confirmatory diagnostic procedures. Moreover, it would assist in designing appropriate prevention protocols and devising suitable control strategies to overcome respiratory diseases and alleviate the economic losses. PMID- 25028623 TI - Cardiovascular and non-cardiovascular mortality in dialysis patients: where is the link? AB - Over the past decade, the research agenda in dialysis has been dominated by studies on risk factors associated with cardiovascular mortality. It has now become increasingly clear that in dialysis patients, non-cardiovascular causes of death are increased to the same extent as cardiovascular mortality, and therefore research efforts in this area deserve an equally prominent place on the nephrology research agenda. As previous research has suggested an association between cardiovascular disease and infections, more research on potential links between the causal pathways of cardiovascular events and infections is also warranted. PMID- 25028622 TI - The complexity of the cardio-renal link: taxonomy, syndromes, and diseases. AB - Bidirectional mechanisms exist that link diseases affecting the heart and kidney. This link is complex and remains poorly understood; therefore, charting the shared territory of cardiovascular (CV) and renal medicine poses major problems. Until now, no convincing rationale for delineating new syndromes existed. The multiple connections of the arterial system and the heart and kidney with other systems, from energy and protein balance to the musculoskeletal, clearly require special focus and rigorous framing. Nephrologists have yet to fully understand why the application of dialysis has had only limited success in halting the parallel burdens of CV and non-CV death in patients with end-stage renal disease. Cardiologists, intensivists, and nephrologists alike should settle whether and when extracorporeal ultrafiltration benefits patients with decompensated heart failure. These sparse but interconnected themes spanning from the basic science clinical transition phase to clinical science, epidemiology, and medical technology already form the basis for the young discipline of 'CV and renal medicine'. PMID- 25028624 TI - Targets of new immunosuppressants in renal transplantation. AB - Although current immunosuppression is highly effective in avoiding acute rejection, it is associated with nephrotoxicity, cardiovascular morbidity, infection, and cancer. Thus, new drugs dealing with new mechanisms, as well as minimizing comorbidities, are warranted in renal transplantation. Few novel drugs are currently under investigation in Phase I, II, or III clinical trials. Belatacept is a humanized antibody that inhibits T-cell co-stimulation and has shown encouraging results in Phase II and III trials. Moreover, two new small molecules are under clinical development: AEB071 or sotrastaurin (a protein kinase C inhibitor) and CP-690550 or tasocitinib (a Janus kinase inhibitor). Refinement in selecting the best combinations for the new and current immunosuppressive agents is probably the main challenge for the next few years. PMID- 25028626 TI - Sixteen per cent of women have depression symptoms in the year after childbirth and are more likely to report physical symptoms, including tiredness and back pain. AB - Implications for practice and research: The importance of physical and mental health in the postnatal period has been recognised in this study and in other research. Postnatal visiting has declined in the UK and satisfaction with postnatal care is low compared to other aspects of maternity care. Further research should focus on cost-effective strategies to improve this. PMID- 25028625 TI - Pharmacogenetics of tacrolimus: ready for clinical translation? AB - Tacrolimus (Tac) exhibits an interindividual pharmacokinetic variability that affects the dose required to reach the target concentration in blood. Tac is metabolized by two enzymes of the cytochrome P450 family, CYP3A5 and CYP3A4. The effect of the CYP3A5 genotype on Tac bioavailability has been demonstrated, and the main determinant of this pharmacogenetic effect is a single-nucleotide polymorphism (SNP) in intron 3 of CYP3A5 (6986 A>G; SNP rs776746; also known as CYP3A5*3). The mean dose-adjusted blood Tac concentration was significantly higher among CYP3A5*3 homozygotes than that of carriers of the wild-type allele (CYP3A5*1). In a recent prospective study, a group of kidney transplant patients received a Tac dose either according to the CYP3A5 genotype (the adapted group) or according to the standard regimen (the control group). All patients received induction therapy with mycophenolate mofetil, corticosteroids, and either basiliximab or intravenous anti-thymocyte globulin. Patients in the adapted-dose group required 3-8 days (median 6 days) to reach the target range compared with 3 25 days (median 7 days) in the control group (P=0.001). The total number of dose modifications was also lower in the adapted-dose group. This study also suggested that the CYP3A5 genotype might contribute minimally to the reduction of early acute rejection. However, additional studies are necessary to determine whether the pharmacogenetic approach could help reduce the necessity for induction therapy and co-immunosuppressors. PMID- 25028627 TI - Biology of stem cells: an overview. AB - Stem cells are defined as precursor cells that have the capacity to self-renew and to generate multiple mature cell types. Only after collecting and culturing tissues is it possible to classify cells according to this operational concept. This difficulty in identifying stem cells in situ, without any manipulation, limits the understanding of their true nature. This review aims at presenting, to health professionals interested in this area, an overview on the biology of embryonic and adult stem cells, and their therapeutic potential. PMID- 25028628 TI - The potential use of stem cells derived from human amniotic fluid in renal diseases. AB - Amniotic fluid (AF) contains a variety of cell types derived from fetal tissues that can easily grow in culture. These cells can be obtained during amniocentesis for prenatal screening of fetal genetic diseases, usually performed during the second trimester of pregnancy. Of particular interest, some expanded sub populations derived from AF cells are capable of extensive self-renewal and maintain prolonged undifferentiated proliferation, which are defining properties of stem cells. These human AF stem cells (hAFSCs) exhibit multilineage potential and can differentiate into the three germ layers. They have high proliferation rates and express mesenchymal and embryonic markers, but do not induce tumor formation. In this study, hAFSCs derived from amniocentesis performed at 16-20 weeks of pregnancy were isolated, grown in culture, and characterized by flow cytometry and by their potential ability to differentiate into osteogenic, adipogenic, and chondrogenic lineages. After 4-7 passages, 5 * 105 hAFSCs were inoculated under the kidney capsule of Wistar rats that were subjected to an experimental model of chronic renal disease, the 5/6 nephrectomy model (Nx). After 30 days, Nx rats treated with hAFSCs displayed significant reductions in blood pressure, proteinuria, macrophages, and alpha-smooth muscle actin expression compared with Nx animals. These preliminary results suggest that hAFSCs isolated and expanded from AF obtained by routine amniocentesis can promote renoprotection in the Nx model. Considering that the AF cells not used for fetal karyotyping are usually discarded, and that their use does not raise ethical issues, they may represent an alternative source of stem cells for cell therapy and regenerative medicine. PMID- 25028631 TI - Work Group Membership. PMID- 25028629 TI - Potential of mesenchymal stem cells in the repair of tubular injury. AB - Current interventions for the treatment of acute kidney injury (AKI) are not satisfactory, and it is time to approach new strategies in order to definitely take a step forward. At its beginning, cell therapy was innovative and promising. We have shown that mesenchymal stem cells (MSCs), isolated from human and murine bone marrow (BM), behave as an efficacious tool for the treatment of cisplatin induced AKI in mice in terms of amelioration of renal function and structure, and animal survival. Although the mechanism has not been completely elucidated, we have provided data showing that BM-MSC-mediated renal recovery involves the release at the site of injury of the growth factor, insulin-like growth factor-1. Several biological effects have been observed in renal tissues of mice treated with BM-MSCs, including increased cell proliferation, hemodynamic changes, and cell apoptosis reduction. In the same experimental model, we have tested the effect of MSCs isolated from cord blood (CB-MSCs), which, similar to BM-MSCs, not only ameliorated renal function but also protected animals from death to a remarkably higher extent. Animals receiving CB-MSCs showed reduction of oxidative stress and activation of AKT prosurvival pathway in tubular cells. These results hold great promise for future studies in patients with AKI. PMID- 25028632 TI - KDIGO Board Members. PMID- 25028633 TI - Foreword. PMID- 25028635 TI - Chapter 1: Introduction. PMID- 25028637 TI - Methods for guideline development. PMID- 25028636 TI - Chapter 3: Steroid-sensitive nephrotic syndrome in children. PMID- 25028638 TI - Chapter 3: Assessment of lipid status in children with CKD. PMID- 25028639 TI - Rational approaches to the treatment of hypertension: drug therapy-monotherapy, combination, or fixed-dose combination? AB - Blood pressure (BP) control is inadequate worldwide. Many clinical trials suggest that BP is not satisfactorily controlled using monotherapy in most patients. Free drug or fixed-dose combinations are other therapeutic options. The advantages and disadvantages for different treatment approaches are discussed in this review. PMID- 25028640 TI - Hypertension in women. AB - Hypertension is the most common modifiable risk factor for cardiovascular disease, the leading cause of death in both men and women. The prevalence and severity of hypertension rise markedly with age, and blood pressure control becomes more difficult with aging in both genders, particularly in women. In addition, there are forms of hypertension that occur exclusively in women, e.g., hypertension related to menopause, oral contraceptive use, or pregnancy (e.g., chronic hypertension, gestational hypertension, pre-eclampsia or eclampsia). Randomized controlled trials show that antihypertensive therapy provides similar reductions in major cardiovascular events in men and women. Therefore, gender should not influence decisions on selection of blood pressure lowering therapies, except for consideration of gender-specific side effects or contraindications for use in women who are or may become pregnant. This article reviews the prevalence, awareness, treatment, and control of hypertension in women, as well as recent guidelines for management of hypertension in women. PMID- 25028641 TI - Novel strategies for treatment of resistant hypertension. AB - Resistant hypertension, defined as blood pressure (BP) remaining above goal despite the use of 3 or more antihypertensive medications at maximally tolerated doses (one ideally being a diuretic) or BP that requires 4 or more agents to achieve control, occurs in a substantial proportion (>10%) of treated hypertensive patients. Refractory hypertension is a recently described subset of resistant hypertension that cannot be controlled with maximal medical therapy (?5 antihypertensive medications of different classes at maximal tolerated doses). Patients with resistant or refractory hypertension are at increased cardiovascular risk and comprise the target population for novel antihypertensive treatments. Device-based interventions, including carotid baroreceptor activation and renal denervation, reduce sympathetic nervous system activity and have effectively reduced BP in early clinical trials of resistant hypertension. Renal denervation interrupts afferent and efferent renal nerve signaling by delivering radiofrequency energy, other forms of energy, or norepinephrine-depleting pharmaceuticals through catheters in the renal arteries. Renal denervation has the advantage of not requiring general anesthesia, surgical intervention, or device implantation and has been evaluated extensively in observational proof-of principle studies and larger randomized controlled trials. It has been shown to be safe and effective in reducing clinic BP, indices of sympathetic nervous system activity, and a variety of hypertension-related comorbidities. These include impaired glucose metabolism/insulin resistance, end-stage renal disease, obstructive sleep apnea, cardiac hypertrophy, heart failure, and cardiac arrhythmias. This article reviews the strengths, limitations, and future applications of novel device-based treatment, particularly renal denervation, for resistant hypertension and its comorbidities. PMID- 25028642 TI - How to determine 'dry weight'? AB - Sodium and fluid retention in dialysis patients is associated with hypertension and vascular changes that may ultimately lead to serious cardiovascular complications. Achieving and maintaining dry weight appears to be an effective but forgotten strategy in controlling and maintaining normal blood pressure among hypertensive patients on dialysis. A crucial question is how to determine 'dry weight'. Normotension without the use of antihypertensive medications in conjunction with a cardio-thoracic index below 48% is the most important criterion showing that the dry weight is achieved. PMID- 25028643 TI - Pharmacological and non-pharmacological treatment of hypertension in dialysis patients. AB - Hypertension is very common in dialysis patients. The most important cause of hypertension is hypervolemia. Fluid restriction and volume management with standard hemodialysis are effective strategies to achieve dry weight and blood pressure control without use of antihypertensive drugs. If the captopril test is positive, a renin-angiotensin system blocker should be started. The pre-dialysis blood pressure goal in hemodialysis patients should be <140/90 mm Hg initially and <130/80 mm Hg at 3-6 months of dialysis. PMID- 25028644 TI - Calcimimetics and outcomes in CKD. AB - In the past decade, several experimental studies demonstrated an inhibitory effect of calcimimetics on the progression of vascular calcification in animals with chronic kidney disease (CKD), in keeping with the expression of the calcium sensing receptor (CaR) in vascular tissue. In addition, calcimimetics were also found to prevent the arterial remodeling caused by CKD and to slow the progression of atherosclerosis in uremic rats and mice, respectively. The mode of action of these CaR modulators could be both via a better control of secondary hyperparathyroidism and direct effects on the vessel wall. Two main clinical trials, ADVANCE and EVOLVE, recently evaluated in patients with CKD stage 5D the effects of the calcimimetic cinacalcet on the progression of vascular calcification and hard cardiovascular outcomes, respectively. Both trials missed their respective primary end point by intent-to-treat analysis although by other prespecified analyses, including adjustment for baseline characteristics, there was strong suggestive evidence in favor of reductions in risk, in agreement with numerous experimental studies. Further clinical trials are needed to settle this issue definitively. PMID- 25028645 TI - Serum HDL-C level of Iranian adults: results from sixth national Surveillance of Risk Factors of Non-Communicable Disease. AB - BACKGROUND: Reduced level of high-density lipoprotein-cholesterol (HDL-C) is shown to be in association with the risk of coronary artery disease (CAD), metabolic syndrome, and chronic renal disease. Lack of a national representative research for assessing the level of HDL-C among Iranian adults, which is essential for health policy makers, was the motivation for this study. METHODS: HDL-C levels of 4,803 Iranian adults aged 25-64 years old were measured by sixth national Surveillance of Risk Factors of Non-Communicable Disease (SuRFNCD) in 2011. Data were entered into STATA 12 software and were analyzed using fractional polynomial model and other statistical methods. RESULTS: In average, Iranian adult women had 5.8 +/- 0.3 mg/dL higher HDL-C level than men. The analysis showed that the HDL-C levels will be changed at most 3 mg/dL from the age of 25 to 64 years. Furthermore, it was shown that approximately half of the men and one third of the women had HDL-C level less than 40 mg/DL. Also HDL-C level of more than 60% of the women was less than 50 mg/dL. CONCLUSIONS: High level of HDL-C among Iranian adults was shown in this study which can be a major reason of increasing incidence of heart diseases in Iran. Hence, formulating policy regulations and interventions in Iranian lifestyle to reduce HDL-C levels should be among top priorities for health politicians. PMID- 25028646 TI - Aberrant DNA methylation patterns in diabetic nephropathy. AB - BACKGROUND: The aim of this study was to evaluate whether global levels of DNA methylation status were associated with albuminuria and progression of diabetic nephropathy in a case-control study of 123 patients with type 2 diabetes- 53 patients with albuminuria and 70 patients without albuminuria. METHODS: The 5 methyl cytosine content was assessed by reverse phase high pressure liquid chromatography (RP-HPLC) of peripheral blood mononuclear cells to determine individual global DNA methylation status in two groups. RESULTS: Global DNA methylation levels were significantly higher in patients with albuminuria compared with those in normal range of albuminuria (p = 0.01). There were significant differences in global levels of DNA methylation in relation to albuminuria (p = 0.028) and an interesting pattern of increasing global levels of DNA methylation in terms of albuminuria severity. In patients with micro- and macro albuminuria, we found no significant correlations between global DNA methylation levels and duration of diabetes (p > 0.05). In both sub groups, there were not significant differences between global DNA methylation levels with good and poor glycaemic control (p > 0.05). In addition, in patients with albuminuria, no differences in DNA methylation levels were observed between patients with and without other risk factors including age, gender, hypertension, dyslipidaemia and obesity. CONCLUSIONS: These data may be helpful in further studies to develop novel biomarkers and new strategies for clinical care of patients at risk of diabetic nephropathy. PMID- 25028647 TI - Abnormal COX2 protein expression may be correlated with poor prognosis in oral cancer: a meta-analysis. AB - BACKGROUND: The prognostic significance of COX2 for survival of patients with oral cancer remains controversial. Thus, the meta-analysis was performed in order to identify COX2 expression impact on prognosis of oral cancer. METHOD: Relevant literatures were searched using the following electronic databases without any language restrictions: Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and CBM. Version 12.0 STATA software (Stata Corporation, College Station, Texas, USA) was used for the current meta-analysis. Odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence interval (95% CI) were also calculated to clarify the correlation between COX2 expression and prognosis of oral cancer. RESULTS: Final analysis of 979 oral cancer patients from 12 clinical cohort studies was performed. The meta-analysis results show that COX2 expression in cancer tissues was significantly higher than those in normal and benign tissues (all P < 0.05). Combined HR of COX2 suggests that positive COX2 expression has a shorter overall survival (OS) than those of negative COX2 expression (P < 0.05). CONCLUSION: The meta-analysis study shows that elevated COX2 expression may be associated with the pathogenesis of oral cancer and with a worse prognosis in oral cancer patients. PMID- 25028648 TI - Ultrasonographic fetal growth charts: an informatic approach by quantitative analysis of the impact of ethnicity on diagnoses based on a preliminary report on Salentinian population. AB - Clear guidance on fetal growth assessment is important because of the strong links between growth restriction or macrosomia and adverse perinatal outcome in order to reduce associated morbidity and mortality. Fetal growth curves are extensively adopted to track fetal sizes from the early phases of pregnancy up to delivery. In the literature, a large variety of reference charts are reported but they are mostly up to five decades old. Furthermore, they do not address several variables and factors (e.g., ethnicity, foods, lifestyle, smoke, and physiological and pathological variables), which are very important for a correct evaluation of the fetal well-being. Therefore, currently adopted fetal growth charts are inadequate to support the melting pot of ethnic groups and lifestyles of our society. Customized fetal growth charts are needed to provide an accurate fetal assessment and to avoid unnecessary obstetric interventions at the time of delivery. Starting from the development of a growth chart purposely built for a specific population, in the paper, authors quantify and analyse the impact of the adoption of wrong growth charts on fetal diagnoses. These results come from a preliminary evaluation of a new open service developed to produce personalized growth charts for specific ethnicity, lifestyle, and other parameters. PMID- 25028649 TI - Sequence-based appraisal of the genes encoding neck and carbohydrate recognition domain of conglutinin in blackbuck (Antilope cervicapra) and goat (Capra hircus). AB - Conglutinin, a collagenous C-type lectin, acts as soluble pattern recognition receptor (PRR) in recognition of pathogens. In the present study, genes encoding neck and carbohydrate recognition domain (NCRD) of conglutinin in goat and blackbuck were amplified, cloned, and sequenced. The obtained 488 bp ORFs encoding NCRD were submitted to NCBI with accession numbers KC505182 and KC505183. Both nucleotide and predicted amino acid sequences were analysed with sequences of other ruminants retrieved from NCBI GenBank using DNAstar and Megalign5.2 software. Sequence analysis revealed maximum similarity of blackbuck sequence with wild ruminants like nilgai and buffalo, whereas goat sequence displayed maximum similarity with sheep sequence at both nucleotide and amino acid level. Phylogenetic analysis further indicated clear divergence of wild ruminants from the domestic ruminants in separate clusters. The predicted secondary structures of NCRD protein in goat and blackbuck using SWISSMODEL ProtParam online software were found to possess 6 beta-sheets and 3 alpha-helices which are identical to the result obtained in case of sheep, cattle, buffalo, and nilgai. However, quaternary structure in goat, sheep, and cattle was found to differ from that of buffalo, nilgai, and blackbuck, suggesting a probable variation in the efficiency of antimicrobial activity among wild and domestic ruminants. PMID- 25028650 TI - In vitro ultrastructural changes of MCF-7 for metastasise bone cancer and induction of apoptosis via mitochondrial cytochrome C released by CaCO3/Dox nanocrystals. AB - Bones are the most frequent site for breast cancer cells to settle and spread (metastasise); bone metastasis is considered to have a substantial impact on the quality of patients with common cancers. However, majority of breast cancers develop insensitivity to conventional chemotherapy which provides only palliation and can induce systemic side effects. In this study we evaluated the effect of free Dox and CaCO3/Dox nanocrystal on MCF-7 breast cancer using MTT (3-[4, 5 dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide), neural red, and lactate dehydrogenase colorimetric assays while DNA fragmentation and BrdU genotoxicity were also examined. Apoptogenic protein Bax, cytochrome C, and caspase-3 protein were analysed. Morphological changes of MCF-7 were determined using contrast light microscope and scanning and transmission electron microscope (SEM and TEM). The findings of the analysis revealed higher toxicity of CaCO3/Dox nanocrystal and effective cells killing compared to free Dox, morphological changes such as formation of apoptotic bodies, membrane blebbing, and absent of microvilli as indicated by the SEM analysis while TEM revealed the presence of chromatin condensation, chromosomal DNA fragmentation, cell shrinkage, and nuclear fragmentation. Results of TUNEL assay verified that most of the cells undergoes apoptosis by internucleosomal fragmentation of genomic DNA whereas the extent of apoptotic cells was calculated using the apoptotic index (AI). Therefore, the biobased calcium carbonate nanocrystals such as Dox carriers may serve as an alternative to conventional delivery system. PMID- 25028651 TI - Biopolymeric formulations for biocatalysis and biomedical applications. AB - Three gel disks formulations prepared using chitosan (Chito) or polyethylenimine (PEI) followed by glutaraldehyde were prepared for biocatalysis and biomedical applications. The carriers have been used to immobilize lactase covalently and it was evaluated in terms of enzyme loading capacity and enzyme kinetics (km and Vmax). The Km of the Chito formulation was almost half that of the PEI formulations, which is favored in industries. On the other hand, the gel disks were evaluated in terms of their swelling kinetics and the gels' morphology using SEM. The mechanism of the three gels' swelling was also studied and it was found to be non-Fickian, where the mechanism of transport depends on both the diffusion and polymer relaxation, which are controlling the overall rate of water uptake. The Chito formulation was 2-5 folds and PEI formulations were 33-62 folds in terms of the swelling rate constant and the diffusion rate, respectively. These results were highly supported by the SEM. This study will help scientists to design the right polymer network for enzymes immobilization as well as control the surface area and the swelling power of the polymers for different applications such as drug delivery systems and tissue engineering. PMID- 25028652 TI - Circadian system development and plasticity. PMID- 25028654 TI - Combination of the auxins NAA, IBA, and IAA with GA3 improves the commercial seed tuber production of potato (Solanum tuberosum L.) under in vitro conditions. AB - The study compared the effects of 1.0 * MS medium containing various concentrations of alpha-naphthaleneacetic acid (NAA), indole-3-acetic acid (IAA), and indole-3-butyric acid (IBA), alone or in combination with gibberellic acid (GA3) in micropropagation of three potato (Solanum tuberosum L.) cultivars Pasinler, Granola, and Caspar using binodal stem cuttings. The results testified improved regeneration on 1.0 * MS medium containing variants of NAA, IAA, and IBA plus GA3 on all cultivars. The minimum days to shoot induction on three cultivars ranged 4.25-5 d on 1.0 * MS medium containing 0.25 mg L(-1) GA3 + 1 mg L(-1) NAA. The longest shoots (11.8 cm), maximum number of nodes (13.50), and maximum number of leaves (11.00) were recorded on cv. Caspar on 1.0 * MS medium containing 1 mg L(-1) NAA + 0.25 mg L(-1) GA3. The minimum time to root induction (12.25 d) was noted on cv. Pasinler on the same medium. All of the regenerated shoots could be easily rooted. The results showed that the combined effect of various concentrations of NAA, IAA, and IBA plus GA3 was more pronounced compared to the auxins used alone. The results of this research are of significant importance for potato breeders. PMID- 25028653 TI - From innate to adaptive immune response in muscular dystrophies and skeletal muscle regeneration: the role of lymphocytes. AB - Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD). We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease. PMID- 25028655 TI - Pepsinogen II can be a potential surrogate marker of morphological changes in corpus before and after H. pylori eradication. AB - BACKGROUND: The aim of this investigation is to study the relationship between gastric morphology and serum biomarkers before and after Helicobacter pylori eradication. METHODS: First-degree relatives of gastric cancer patients underwent gastroscopy before and 2.5 years after H. pylori eradication. The morphological changes in two categories (normal to mild and moderate to severe) were compared with level of pepsinogens I and II before eradication (n = 369), after eradication (n = 115), and in those with persistent infection (n = 250). RESULTS: After eradication, pepsinogen I decreased to 70% and pepsinogen II to 45% of the previous values. Unlike pepsinogen II and pepsinogen I to II ratio that were affected by the severity of inflammation and atrophy in corpus in all groups, pepsinogen I generally did not change. After eradication, subjects with high mononuclear infiltration in corpus had lower pepsinogen I (54 versus 77.1 MU/mL), higher pepsinogen II (9.4 versus 6.9 MU/mL), and lower ratio (7.9 versus 11.6) than those without (P < 0.05). CONCLUSION: Pepsinogen II is a good marker of corpus morphological changes before and after H. pylori eradication. PMID- 25028656 TI - Effect of autologous platelet rich fibrin on the healing of experimental articular cartilage defects of the knee in an animal model. AB - The effect of autologous platelet rich fibrin (PRF), a second generation platelet product, on the healing of experimental articular cartilage lesions was evaluated in an animal model. Full thickness cartilage lesions with a diameter of 6 mm and depth of 5 mm were created in the weight bearing area of femoral condyles of both hind limbs in 12 adult mixed breed dogs. Defects in the left hind limb of each dog were repaired by PRF implantation whereas those in the right hind limb were left empty. The animals were euthanized at 4, 16, and 24 weeks following surgery and the resultant repair tissue was investigated macroscopically and microscopically. The results of macroscopic and histological evaluations indicated that there were significant differences between the PRF treated and untreated defects. In conclusion, the present study indicated that the use of platelet rich fibrin as a source of autologous growth factors leads to improvement in articular cartilage repair. PMID- 25028657 TI - Relationship between spectral-domain optical coherence tomography and standard automated perimetry in healthy and glaucoma patients. AB - OBJECTIVE: To evaluate the relationship between spectral-domain optical coherence tomography (OCT) and standard automated perimetry (SAP) in healthy and glaucoma individuals. METHODS: The sample comprised 338 individuals divided into 2 groups according to intraocular pressure and visual field outcomes. All participants underwent a reliable SAP and imaging of the optic nerve head with the Cirrus OCT. Pearson correlations were calculated between threshold sensitivity values of SAP (converted to linear scale) and OCT parameters. RESULTS: Mean age did not differ between the control and glaucoma groups (59.55 +/- 9.7 years and 61.05 +/- 9.4 years, resp.; P = 0.15). Significant differences were found for the threshold sensitivities at each of the 52 points evaluated with SAP (P < 0.001) and the peripapillary retinal nerve fiber layer (RNFL) thicknesses, except at 3 and 9 clock-hour positions between both groups. Mild to moderate correlations (ranging between 0.286 and 0.593; P < 0.001) were observed between SAP and most OCT parameters in the glaucoma group. The strongest correlations were found between the inferior RNFL thickness and the superior hemifield points. The healthy group showed lower and weaker correlations than the glaucoma group. CONCLUSIONS: Peripapillary RNFL thickness measured with Cirrus OCT showed mild to moderate correlations with SAP in glaucoma patients. PMID- 25028658 TI - Antibacterial activity of leaf extracts of Baeckea frutescens against methicillin resistant Staphylococcus aureus. AB - This study was based on screening antibacterial activity of the ethanol extract of Baeckea frutescens L. against MRSA clinical isolates, analyzes the potential antibacterial compound, and assesses the cytotoxicity effect of the extract in tissue culture. Leaves of Baeckea frutescens L. were shade dried, powdered, and extracted using solvent ethanol. Preliminary phytochemical screening of the crude extracts revealed the presence of alkaloids, flavonoids, steroids, terpenoids, phenols, and carbohydrates. The presence of these bioactive constituents is related to the antibacterial activity of the plant. Disc diffusion method revealed a high degree of activity against microorganisms. The results confirm that Baeckea frutescens L. can be used as a source of drugs to fight infections caused by susceptible bacteria. PMID- 25028659 TI - The gene-gene interaction of INSIG-SCAP-SREBP pathway on the risk of obesity in Chinese children. AB - BACKGROUND: Childhood obesity has become a global public health problem in recent years. This study aimed to explore the association of genetic variants in INSIG SCAP-SREBP pathway with obesity in Chinese children. METHODS: A case-control study was conducted, including 705 obese cases and 1,325 nonobese controls. We genotyped 15 single nucleotide polymorphisms (SNPs) of five genes in INSIG-SCAP SREBP pathway, including insulin induced gene 1 (INSIG1), insulin induced gene 2 (INSIG2), SREBP cleavage-activating protein gene (SCAP), sterol regulatory element binding protein gene 1 (SREBP1), and sterol regulatory element binding protein gene 2 (SREBP2). We used generalized multifactor dimensionality reduction (GMDR) and logistic regression to investigate gene-gene interactions. RESULTS: Single polymorphism analyses showed that SCAP rs12487736 and rs12490383 were nominally associated with obesity. We identified a 3-locus interaction on obesity in GMDR analyses (P = 0.001), involving 3 genetic variants of INSIG2, SCAP, and SREBP2. The individuals in high-risk group of the 3-locus combinations had a 79.9% increased risk of obesity compared with those in low-risk group (OR = 1.799, 95% CI: 1.475-2.193, P = 6.61 * 10(-9)). CONCLUSION: We identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect. PMID- 25028660 TI - Histological, histochemical, and protein changes after induced malocclusion by occlusion alteration of Wistar rats. AB - Although disorders of the stomatognathic system are common, the mechanisms involved are unknown. Our objective was to study the changes in the masseter muscles after unilateral exodontia. Molar extraction was performed on Wistar rats (left side), and the animals were sacrificed after either 14 or 26 days. The masseter muscle was processed for histological analysis, conventional and in situ zymography, and immunohistochemistry. The morphological analysis showed unique and specific characteristics for the experimental group. By conventional zymography no significant values of 72 kDa MMP-2 (P < 0.05) were found in both of the sides of masseter muscle after 14 and 26 days of unilateral extraction. The in situ zymography showed gelatinolytic activity on all deep masseter muscles, with significant increase on the contralateral side after 14 and 26 days (P < 0.05). The immunohistochemistry demonstrated greater expression of MMP-2 than MMP 9 and MMP-14 in all masseter muscles and there were few differences in the staining of 4 TIMPs. This knowledge about morphology and molecular masticatory muscle remodeling following environmental interventions can be used to develop clinically successful treatments. PMID- 25028662 TI - On macroscopic quantum phenomena in biomolecules and cells: from Levinthal to Hopfield. AB - In the context of the macroscopic quantum phenomena of the second kind, we hereby seek for a solution-in-principle of the long standing problem of the polymer folding, which was considered by Levinthal as (semi)classically intractable. To illuminate it, we applied quantum-chemical and quantum decoherence approaches to conformational transitions. Our analyses imply the existence of novel macroscopic quantum biomolecular phenomena, with biomolecular chain folding in an open environment considered as a subtle interplay between energy and conformation eigenstates of this biomolecule, governed by quantum-chemical and quantum decoherence laws. On the other hand, within an open biological cell, a system of all identical (noninteracting and dynamically noncoupled) biomolecular proteins might be considered as corresponding spatial quantum ensemble of these identical biomolecular processors, providing spatially distributed quantum solution to a single corresponding biomolecular chain folding, whose density of conformational states might be represented as Hopfield-like quantum-holographic associative neural network too (providing an equivalent global quantum-informational alternative to standard molecular-biology local biochemical approach in biomolecules and cells and higher hierarchical levels of organism, as well). PMID- 25028661 TI - Downregulation of transketolase activity is related to inhibition of hippocampal progenitor cell proliferation induced by thiamine deficiency. AB - In animal experiments, hippocampal neurogenesis and the activity of thiamine dependent transketolase decrease markedly under conditions of thiamine deficiency. To further investigate the effect of thiamine deficiency on the proliferation of hippocampal progenitor cells (HPCs) and the potential mechanisms involved in this effect, we cultured HPCs in vitro in the absence of thiamine and found that proliferation and transketolase activity were both significantly repressed. Furthermore, specific inhibition of transketolase activity by oxythiamine strongly inhibited HPC proliferation in a dose-dependent manner. However, thiamine deficiency itself inhibited the proliferation to a greater degree than did oxythiamine. Taken together, our results suggest that modulation of transketolase activity might be one of the mechanisms by which thiamine regulates the proliferation of hippocampal progenitor cells. PMID- 25028663 TI - Hepatocellular carcinoma: carcinogenesis, establishment, progression, and therapies. PMID- 25028664 TI - p53 abnormalities and potential therapeutic targeting in multiple myeloma. AB - p53 abnormalities are regarded as an independent prognostic marker in multiple myeloma. Patients harbouring this genetic anomaly are commonly resistant to standard therapy. Thus, various p53 reactivating agents have been developed in order to restore its tumour suppressive abilities. Small molecular compounds, especially, have gained popularity in its efficacy against myeloma cells. For instance, promising preclinical results have steered both nutlin-3 and PRIMA-1 into phase I/II clinical trials. This review summarizes different modes of p53 inactivation in myeloma and highlights the current p53-based therapies that are being utilized in the clinic. Finally, we discuss the potential and promise that the novel small molecules possess for clinical application in improving the treatment outcome of myeloma. PMID- 25028665 TI - Tumor necrosis factor-alpha -308 G>A polymorphism, adherence to Mediterranean diet, and risk of overweight/obesity in young women. AB - The present study was conducted in order to (i) characterize the adherence to the Mediterranean diet (MD) pattern and fatty acids (FAs) intakes and (ii) explore interactions between TNFA -308 G>A polymorphism and adherence to MD and FAs intakes, respectively, on overweight/obesity risk. From 2010 to 2013, 380 healthy women were enrolled, and MD score (MDS) and FAs intakes were evaluated by a Food Frequencies Questionnaire in relation to nutritional status. TNFA -308 G/A polymorphism was characterized using PCR-RFLP. A total of 32.6% of women were overweight or obese. Lower mean MDS values were more observed in the younger age group than in the older age group (3.60 versus 4.45). The risk of being overweight/obese was 3.5-fold increased due to poor adherence to MD and was about twofold increased in less educated women. Furthermore, younger age was associated with poor adherence to MD. No evidence for an independent effect of the polymorphism on overweight/obesity risk was found. There was no evidence of biological interaction from the gene-diet interaction analyses. Young women, less educated and with poor adherence to MD, are a target group for the nutritional interventions that aimed to control the obesity risk, thus improving the adherence to MD and particularly the intake of unsaturated FAs. PMID- 25028666 TI - Growth kinetics and mechanistic action of reactive oxygen species released by silver nanoparticles from Aspergillus niger on Escherichia coli. AB - Silver Nanoparticles (AgNPs), the real silver bullet, are known to have good antibacterial properties against pathogenic microorganisms. In the present study AgNPs were prepared from extracellular filtrate of Aspergillus niger. Characterization of AgNPs by UV-Vis spectrum reveals specific surface plasmon resonance at peak 416 nm; TEM photographs revealed the size of the AgNPs to be 20 55 nm. Average diameter of the produced AgNPs was found to be 73 nm with a zeta potential that was -24 mV using Malvern Zetasizer. SEM micrographs showed AgNPs to be spherical with smooth morphology. EDS revealed the presence of pure metallic AgNPs along with carbon and oxygen signatures. Of the different concentrations (0, 2.5, 5, 10, and 15 MUg/mL) used 10 MUg/mL were sufficient to inhibit 10(7) CFU/mL of E. coli. ROS production was measured using DCFH-DA method and the the free radical generation effect of AgNPs on bacterial growth inhibition was investigated by ESR spectroscopy. This paper not only deals with the damage inflicted on microorganisms by AgNPs but also induces cell death through the production of ROS released by AgNPs and also growth kinetics of E. coli supplemented with AgNPs produced by A. niger. PMID- 25028667 TI - Adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion in mice. AB - Adrenomedullin was originally isolated from pheochromocytoma cells and reduces insulin resistance by decreasing oxidative stress. White matter lesions induced by aging and hyperglycemia play a crucial role in cognitive impairment in poststroke patients. Here, we examine whether adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion. Adrenomedullin heterozygous, wild-type young/aged mice were subjected to prolonged hypoperfusion. Prolonged cerebral hypoperfusion followed by immunohistochemical analysis was used to evaluate white matter injury. After prolonged hypoperfusion, white matter damage progressed in a time-dependent manner in AM(+/-) group compared with the wild-type group. The number of oligodendrocyte progenitor cells gradually increased after prolonged hypoperfusion, whereas oligodendrocytes decreased following a transient increase, but the ratio of increase was mild in the AM(+/-) group (P < 0.05). Oxidative stress was detected in oligodendrocytes, with a larger increase in the AM(+/-) group (P < 0.05). Aged mice showed the same tendency, but white matter damage was worse, especially in the aged AM(+/-) group. Our results demonstrated that white matter injury was increased in adrenomedullin deficiency, which induced oxidative stress. White matter injury was more exacerbated because of hyperglycemia in aged AM(+/-) group. Adrenomedullin may be an important target in the control of ischemic white matter injury. PMID- 25028668 TI - Ceftriaxone, a beta-lactam antibiotic, modulates apoptosis pathways and oxidative stress in a rat model of neuropathic pain. AB - PURPOSE: In our previous study, ceftriaxone, a beta-lactam antibiotic, elicited antinociceptive effects in the chronic constriction injury (CCI) of neuropathic pain. In this study, we assessed apoptosis and oxidative stress in the spinal cord of neuropathic rats treated with ceftriaxone. METHODS: 45 male Wistar rats were divided as naive, sham, normal saline-treated CCI rats, and CCI animals treated with the effective dose of ceftriaxone. Involvement of Bax, Bcl2, and caspases 3 and 9, important contributors of programmed cell death (apoptosis), was determined using western blotting at days 3 and 7. The markers of oxidative stress including malondialdehyde (MDA) and reduced glutathione (GSH) were measured on days 3 and 7. RESULTS: Increased Bax/Bcl2 ratio and cleaved active forms of caspases 3 and 9 were observed in the spinal cord of CCI rats on day 3. Ceftriaxone attenuated the increased levels of Bax and cleaved forms of caspases 3 and 9, while it increased Bcl2 levels. Bax and active forms of caspases declined by day 7. Consequently, comparison among groups showed no difference at this time. CCI enhanced MDA and decreased GSH on days 3 and 7, while ceftriaxone protected against the CCI-induced oxidative stress. CONCLUSION: Our results suggest that ceftriaxone, an upregulator/activator of GLT1, could concomitantly reduce oxidative stress and apoptosis and producing its new analogs lacking antimicrobial activity may represent a novel approach for neuropathic pain treatment. PMID- 25028669 TI - Geometric analysis of alloreactive HLA alpha-helices. AB - Molecular dynamics (MD) is a valuable tool for the investigation of functional elements in biomolecules, providing information on dynamic properties and processes. Previous work by our group has characterized static geometric properties of the two MHC alpha-helices comprising the peptide binding region recognized by T cells. We build upon this work and used several spline models to approximate the overall shape of MHC alpha-helices. We applied this technique to a series of MD simulations of alloreactive MHC molecules that allowed us to capture the dynamics of MHC alpha-helices' steric configurations. Here, we discuss the variability of spline models underlying the geometric analysis with varying polynomial degrees of the splines. PMID- 25028671 TI - Second- and further-line therapy with erlotinib in patients with advanced non small-cell lung cancer in daily clinical practice. AB - INTRODUCTION: The aim of this retrospective study was to examine effect of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) in second line and further therapy in daily clinical practice. METHODS: Patients with histologically or cytologically proven NSCLC (n = 84) treated with erlotinib in second-line (n = 34), third-line (n = 36), and more-line therapy (n = 14) were examined for progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of therapy, and adverse effects. RESULTS: Median PFS of all lines was 83 days (CI 70.0-96.0), OS was 7 months (CI 4.7-9.3), DCR was 66.2% (CI 55-77%), and 1-year survival rate was 33% (CI 22-43%), with no significant difference between therapy lines. Median duration of treatment was 76 days (IQR 39-139.5). Patients with epidermal growth factor receptor mutation (EGFR-M) reached the highest PFS (204 days), as did patients with good performance status (ECOG 0-1: 94 versus ECOG 2-3: 65 days, P = 0.035). Patients with EGFR-M also revealed a DCR of 100%. The most frequent side effects were rash (69%) and diarrhoea (41%), without any significant difference between therapy lines. In 24 patients, the treatment dose was reduced and in 18, the therapy was paused. CONCLUSION: Erlotinib works in all therapy lines without any significant differences in efficacy and side effects. PMID- 25028672 TI - Similarity measure and entropy of fuzzy soft sets. AB - Soft set theory, proposed by Molodtsov, has been regarded as an effective mathematical tool to deal with uncertainties. Recently, uncertainty measures of soft sets and fuzzy soft sets have gained attentions from researchers. This paper is devoted to the study of uncertainty measures of fuzzy soft sets. The axioms for similarity measure and entropy are proposed. A new category of similarity measures and entropies is presented based on fuzzy equivalence. Our approach is general in the sense that by using different fuzzy equivalences one gets different similarity measures and entropies. The relationships among these measures and the other proposals in the literatures are analyzed. PMID- 25028670 TI - Regulation of mitochondrial genome inheritance by autophagy and ubiquitin proteasome system: implications for health, fitness, and fertility. AB - Mitochondria, the energy-generating organelles, play a role in numerous cellular functions including adenosine triphosphate (ATP) production, cellular homeostasis, and apoptosis. Maternal inheritance of mitochondria and mitochondrial DNA (mtDNA) is universally observed in humans and most animals. In general, high levels of mitochondrial heteroplasmy might contribute to a detrimental effect on fitness and disease resistance. Therefore, a disposal of the sperm-derived mitochondria inside fertilized oocytes assures normal preimplantation embryo development. Here we summarize the current research and knowledge concerning the role of autophagic pathway and ubiquitin-proteasome dependent proteolysis in sperm mitophagy in mammals, including humans. Current data indicate that sperm mitophagy inside the fertilized oocyte could occur along multiple degradation routes converging on autophagic clearance of paternal mitochondria. The influence of assisted reproductive therapies (ART) such as intracytoplasmic sperm injection (ICSI), mitochondrial replacement (MR), and assisted fertilization of oocytes from patients of advanced reproductive age on mitochondrial function, inheritance, and fitness and for the development and health of ART babies will be of particular interest to clinical audiences. Altogether, the study of sperm mitophagy after fertilization has implications in the timing of evolution and developmental and reproductive biology and in human health, fitness, and management of mitochondrial disease. PMID- 25028673 TI - Assessment of total phenolic, antioxidant, and antibacterial activities of Passiflora species. AB - This study focused on total phenolic content (TPC) and antioxidant and antibacterial activities of the leaves and stems of Passiflora quadrangularis, P. maliformis, and P. edulis extracted using three solvents: petroleum ether, acetone, and methanol. The maximum extraction yields of antioxidant components from the leaves and stems were isolated using methanol extracts of P. edulis (24.28%) and P. quadrangularis (9.76%), respectively. Among the leaf extracts, the methanol extract of P. maliformis had the significantly highest TPC and the strongest antioxidant activity, whereas among the stem extracts, the methanol extract of P. quadrangularis showed the highest phenolic amount and possessed the strongest antioxidant activity. The antibacterial properties of the Passiflora species were tested using the disc diffusion method against 10 human pathogenic bacteria. The largest inhibition zone was observed for the methanol extract of P. maliformis against B. subtilis. Generally, extracts from the Passiflora species exhibit distinct inhibition against Gram-positive but not Gram-negative bacteria. Based on the generated biplot, three clusters of bacteria were designated according to their performance towards the tested extracts. The present study revealed that methanol extracts of the Passiflora contain constituents with significant phenolic, antioxidant, and antibacterial properties for pharmaceutical and nutraceutical uses. PMID- 25028674 TI - The use of artificial neural network for prediction of dissolution kinetics. AB - Colemanite is a preferred boron mineral in industry, such as boric acid production, fabrication of heat resistant glass, and cleaning agents. Dissolution of the mineral is one of the most important processes for these industries. In this study, dissolution of colemanite was examined in water saturated with carbon dioxide solutions. Also, prediction of dissolution rate was determined using artificial neural networks (ANNs) which are based on the multilayered perceptron. Reaction temperature, total pressure, stirring speed, solid/liquid ratio, particle size, and reaction time were selected as input parameters to predict the dissolution rate. Experimental dataset was used to train multilayer perceptron (MLP) networks to allow for prediction of dissolution kinetics. Developing ANNs has provided highly accurate predictions in comparison with an obtained mathematical model used through regression method. We conclude that ANNs may be a preferred alternative approach instead of conventional statistical methods for prediction of boron minerals. PMID- 25028676 TI - Advances in perioperative management. PMID- 25028677 TI - Doubly fed induction generator wind turbines with fuzzy controller: a survey. AB - Wind energy is one of the extraordinary sources of renewable energy due to its clean character and free availability. With the increasing wind power penetration, the wind farms are directly influencing the power systems. The majority of wind farms are using variable speed wind turbines equipped with doubly fed induction generators (DFIG) due to their advantages over other wind turbine generators (WTGs). Therefore, the analysis of wind power dynamics with the DFIG wind turbines has become a very important research issue, especially during transient faults. This paper presents fuzzy logic control of doubly fed induction generator (DFIG) wind turbine in a sample power system. Fuzzy logic controller is applied to rotor side converter for active power control and voltage regulation of wind turbine. PMID- 25028675 TI - An empirical study of different approaches for protein classification. AB - Many domains would benefit from reliable and efficient systems for automatic protein classification. An area of particular interest in recent studies on automatic protein classification is the exploration of new methods for extracting features from a protein that work well for specific problems. These methods, however, are not generalizable and have proven useful in only a few domains. Our goal is to evaluate several feature extraction approaches for representing proteins by testing them across multiple datasets. Different types of protein representations are evaluated: those starting from the position specific scoring matrix of the proteins (PSSM), those derived from the amino-acid sequence, two matrix representations, and features taken from the 3D tertiary structure of the protein. We also test new variants of proteins descriptors. We develop our system experimentally by comparing and combining different descriptors taken from the protein representations. Each descriptor is used to train a separate support vector machine (SVM), and the results are combined by sum rule. Some stand-alone descriptors work well on some datasets but not on others. Through fusion, the different descriptors provide a performance that works well across all tested datasets, in some cases performing better than the state-of-the-art. PMID- 25028678 TI - Determination of the Kothe-Toeplitz duals over the non-Newtonian complex field. AB - The important point to note is that the non-Newtonian calculus is a self contained system independent of any other system of calculus. Therefore the reader may be surprised to learn that there is a uniform relationship between the corresponding operators of this calculus and the classical calculus. Several basic concepts based on non-Newtonian calculus are presented by Grossman (1983), Grossman and Katz (1978), and Grossman (1979). Following Grossman and Katz, in the present paper, we introduce the sets of bounded, convergent, null series and p-bounded variation of sequences over the complex field C* and prove that these are complete. We propose a quite concrete approach based on the notion of Kothe Toeplitz duals with respect to the non-Newtonian calculus. Finally, we derive some inclusion relationships between Kothe space and solidness. PMID- 25028679 TI - Semiconductor-based photocatalytic, photoelectrochemical, and photovoltaic solar energy conversion. PMID- 25028680 TI - Efficient dynamic replication algorithm using agent for data grid. AB - In data grids scientific and business applications produce huge volume of data which needs to be transferred among the distributed and heterogeneous nodes of data grids. Data replication provides a solution for managing data files efficiently in large grids. The data replication helps in enhancing the data availability which reduces the overall access time of the file. In this paper an algorithm, namely, EDRA using agents for data grid, has been proposed and implemented. EDRA consists of dynamic replication of hierarchical structure taken into account for the selection of best replica. Decision for selecting the best replica is based on scheduling parameters. The scheduling parameters are bandwidth, load gauge, and computing capacity of the node. The scheduling in data grid helps in reducing the data access time. The distribution of the load on the nodes of data grid is done evenly by considering scheduling parameters. EDRA is implemented using data grid simulator, namely, OptorSim. European Data Grid CMS test bed topology is used in this experiment. The simulation results are obtained by comparing BHR, LRU, No Replication, and EDRA. The result shows the efficiency of EDRA algorithm in terms of mean job execution time, network usage, and storage usage of node. PMID- 25028681 TI - Two-layer fragile watermarking method secured with chaotic map for authentication of digital Holy Quran. AB - This paper presents a novel watermarking method to facilitate the authentication and detection of the image forgery on the Quran images. Two layers of embedding scheme on wavelet and spatial domain are introduced to enhance the sensitivity of fragile watermarking and defend the attacks. Discrete wavelet transforms are applied to decompose the host image into wavelet prior to embedding the watermark in the wavelet domain. The watermarked wavelet coefficient is inverted back to spatial domain then the least significant bits is utilized to hide another watermark. A chaotic map is utilized to blur the watermark to make it secure against the local attack. The proposed method allows high watermark payloads, while preserving good image quality. Experiment results confirm that the proposed methods are fragile and have superior tampering detection even though the tampered area is very small. PMID- 25028682 TI - Novel back propagation optimization by Cuckoo Search algorithm. AB - The traditional Back Propagation (BP) has some significant disadvantages, such as training too slowly, easiness to fall into local minima, and sensitivity of the initial weights and bias. In order to overcome these shortcomings, an improved BP network that is optimized by Cuckoo Search (CS), called CSBP, is proposed in this paper. In CSBP, CS is used to simultaneously optimize the initial weights and bias of BP network. Wine data is adopted to study the prediction performance of CSBP, and the proposed method is compared with the basic BP and the General Regression Neural Network (GRNN). Moreover, the parameter study of CSBP is conducted in order to make the CSBP implement in the best way. PMID- 25028683 TI - Chinese stomatological association (CSA). PMID- 25028684 TI - Review of casein phosphopeptides-amorphous calcium phosphate. AB - Casein phosphopeptides-amorphous calcium phosphate (CPP-ACP) is a bioactive agent with a base of milk products, which has been formulated from two parts: casein phosphopeptides (CPP) and amorphous calcium phosphate (ACP). CPP was produced from milk protein casein and has a remarkable ability to stabilize calcium phosphate in solution and to substantially increase the level of calcium phosphate in dental plaque. CPP-ACP buffers the free calcium and phosphate ion activities, thereby helping to maintain a state of supersaturation with respect to tooth enamel, reducing demineralisation and promoting remineralisation. The free calcium and phosphate ions move out of the CPP, enter the enamel rods and reform onto apatite crystals. Laboratory, animal and human studies have shown that CPP-ACP inhibits cariogenic activity. CPP-ACP is useful in the treatment of white spot lesions, hypomineralised enamel, mild fluorosis, tooth sensitivity and erosion, and prevents plaque accumulation around brackets and other orthodontic appliances. CPP-ACP also facilitates a normal post-eruptive maturation process and is ideal for protecting primary teeth at a time when oral care is difficult. CPP-ACP has commercial potential as an additive to foods, soft drinks and chewing gum, as well as additive to toothpastes and mouthwashes to control dental caries. PMID- 25028685 TI - Dynamic implant valve approach for dental implant procedures. AB - OBJECTIVE: To present the results of our current research involving the dynamic implant valve approach (DIVA) in cases with human patients. METHODS: The new kind of implant was designed with an internal sealing screw that might serve for drug delivery system and possible endoscopic direct observation via its channel. The DIVA was used in cases when the implant insertion should be combined with the maxillary sinus floor lifting and/or bone augmentation procedure. A total of 63 patients (female n = 31, male n = 32, age range 33-67 years old, mean age 49 years old) were treated with DIVA and 218 new type implants were inserted. RESULTS: Out of 218 inserted implants, 146 implants were inserted in the maxilla with bone level < 5 mm, and 72 implants were inserted in the maxilla with bone level > 5 mm. The number of implants per patients varied from one to eight. The failure consisted of seven implants (3.2%) in five patients. No correlation was found between failure cases and the bone density or quality. Follow up (4 to 18 months) showed that in 211 cases (96.8%), the implantation was totally successful both from objective clinical, imaging (cone beam computed tomography) and subjective patients' viewpoints. CONCLUSION: The new dynamic implant valve approach simplified dental implantation procedure and postoperative treatment. The implant with an inner sealing screw could be considered for use in cases when elevation of the maxillary sinus membrane is needed, as well as in cases when bone augmentation procedures or future treatment might be suspected. PMID- 25028686 TI - Mineralised Collagen Scaffolds Loaded with Stromal Cell-derived Factor-1 Improve Mandibular Bone Regeneration. AB - OBJECTIVE: To create an in situ matrix environment conducive to stem cells from host bone marrow to promote bone regeneration. METHODS: Three-dimensional porous, mineralised collagen (MC) scaffolds were prepared using a freeze-drying process. The microstructure of scaffolds was observed by field emission scanning electron microscopy. The Bose BioDynamic test system was applied to examine their mechanical properties in wet conditions. The effect of scaffolds loaded with stromal cellderived factor-1alpha (SDF-1alpha) on migration of stem cells was assessed using a 24-well transwell system. SDF-1alpha-loaded scaffolds were implanted in the critical size defect in rats and histological staining was used to evaluate the new bone formation. RESULTS: Mechanical testing showed that the MC scaffold featured an increased Young's modulus compared with the pure collagen (Col) scaffold in wet conditions. In addition, the MC scaffold loaded with SDF 1alpha chemokine improved bone marrow stromal cells' migration. When implanted in mandibular bone defects with 5 mm diameter, the MC scaffolds containing SDF 1alpha significantly improved the formation of new bone and blood capillaries within the scaffolds, compared with the SDF-1alpha-loaded Col scaffolds and the control group. CONCLUSION: The mineralised collagen scaffolds loaded with SDF 1alpha, which creates a matrix environment conducive to stem cell migration, can be exploited to improve bone self-repair as an alternative to contemporary cell seeding approaches. PMID- 25028687 TI - Accuracy of computer-guided implant surgery by a CAD/CAM and laser scanning technique. AB - OBJECTIVES: To explore the method of manufacturing an implant surgery template with a computer-aided design/computer-aided manufacturing (CAD/CAM) technique and evaluate its precision in clinical cases. METHODS: Patients referred to the 2nd Dental Center of Peking University who were partially edentulous, were enrolled and scanned with cone beam computed tomography (CBCT). Diagnostic casts were laser scanned to record the configuration of the patients' dentition and mucosae. CBCT and laser scanning data were subsequently loaded into Simplant software. Implant positions were planned in the software with a computer-aided design technique, and surgical templates were fabricated with a rapid prototyping technique. These templates were used to guide implant placement surgery. RESULTS: The mean value of linear deviation was 1.00 mm (range 0 to 2.16 mm) for implant shoulder and 1.26 mm (range 0.51 to 2.86 mm) for the implant apex. The mean angular deviation was 4.74 degress (0.37 to 10.28 degrees). Deviations were higher in the posterior region than anterior. The tooth-supported template provided higher precision than did the tooth/ mucosa-supported template, but no statistically significant difference was found. CONCLUSION: Computer-guided implant surgery with the CAD/CAM technique provides dentists with a good platform for preoperative planning, precise implant insertion, and ideal rehabilitation. The protocol of this three-dimensional laser scanning technique can provide precision comparable to that of double-scanning. PMID- 25028688 TI - Three-dimensional analysis using finite element method of anterior teeth inclination and center of resistance location. AB - OBJECTIVE: To locate the centre of resistance of consolidated units of four and six anterior teeth during retraction. METHODS: Twelve three-dimensional (3D) models were designed in SolidWorks of the anterior segment with four and six teeth and their supporting structure. A proper force system was applied in each model to retract the teeth bodily. The exact location of the centre of resistances (CRes) was determined. It was found that the path of CRes change in four-tooth and six-tooth units according to the anterior teeth torque. RESULTS: A posterior shift of the CRes by increasing the inclination of teeth was shown. However, vertical position has a fluctuant behaviour. First it moves apically, then it moves incisally. Furthermore, results suggest that in en masse retraction, translation can be achieved with a smaller amount of moment-to-force ratio than in four-incisor retraction. In other words, for bodily retraction of anterior incisor segments, we should apply force in a more apical position. CONCLUSION: Different anterior torques between 7 and 35 degrees, cannot affect the CRes position dramatically. The area of CRes shifting is 0.92 mm (anterioposteriorly) x 0.74 mm (superior-inferiorly) in the six-tooth unit in the teeth model and 0.85 mm (anterioposteriorly) x 0.82 mm (superior-inferiorly) in the teeth and bone model. In the four-tooth model, the area of CRes shifting is 0.97 mm (anterioposteriorly) x 0.93 mm (superior-inferiorly) in tooth model and 0.77 mm (anterioposteriorly) x 0.87 mm (superior-inferiorly) in the teeth and bone model. PMID- 25028689 TI - Short-term Efficacy of Agents Containing KNO3 or CPP-ACP in Treatment of Dentin Hypersensitivity. AB - OBJECTIVE: To evaluate the short-term efficacy of agents containing KNO3 or casein phosphopeptide- amorphous calcium phosphate (CPP-ACP) in the treatment of dentin hypersensitivity. METHODS: UltraEZ, containing KNO3 and MI Paste, containing CPP-ACP were applied in this study. The dentin hypersensitivity of 102 subjects was established by a tactile stimulus with a Yeaple preasure probe, and the degree of hypersensitivity was measured using a visual analogue scale (VAS). The patients were divided into four groups: A, B, C and D, using a random number table. UltraEZ, a placebo of UltraEZ, MI Paste, and a placebo of MI Paste were applied to group A, B, C and D respectively for 2 weeks. Dentin hypersensitivity was measured using VAS before the treatment (baseline), on day 2, 7, and 14 during the treatment, and on day 30 and 60 posttreatment. RESULTS: The efficacy of UltraEZ on dentin hypersensitivity was significantly better than that of the corresponding placebo group on day 7 during the treatment, whereas the efficacy of MI Paste exhibited better than that of the placebo group on day 14 during the treatment. However, there were no differences between the efficacy of the two agents on day 14 during the treatment, day 30 or day 60 posttreatment. CONCLUSION: Both UltraEZ and MI Paste had a significant effect on dentin hypersensitivity. UltraEZ showed quicker effects than MI Paste, but MI Paste had a greater sustained action after treatment than UltraEZ. PMID- 25028690 TI - Ankylosis of temporomandibular joint caused by psoriatic arthritis: a report of four cases with literature review. AB - Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. PsA is often confused with other diseases such as osteoarthritis and rheumatoid arthritis. PsA involving temporomandibular joints (TMJs) are uncommon: only 19 articles with 43 cases have been documented in the literature. TMJ ankylosis caused by PsA is rare, with only six cases having been reported. The authors present four cases of ankylosis of the TMJ secondary to PsA and review the literature. The findings of this study suggest that more attention should be paid to psoriasis patients with TMJ symptoms and proper treatment should be taken to prevent irreversible TMJ damage. PMID- 25028691 TI - Kissing molars and hyperplastic dental follicles: report of a case and literature review. AB - "Kissing" molars are impacted permanent molars that have occlusal surfaces contacting each other in a single follicular space, with roots pointing in opposite directions. It is deemed to be appropriate to medically investigate mucopolysaccharidosis (MPS) in patients presenting with kissing molars as kissing molars have been linked with MPS. The case of bilateral occurrence of kissing molars in an 18-year-old woman is described. Pathological analysis of the follicular tissue suggested hyperplastic dental follicles. Therefore, this case report analysed the association of impacted permanent teeth with hyperplastic dental follicles, following the review of seven documented reports describing such association. PMID- 25028692 TI - Disparity in the persistence of high-risk human papillomavirus genotypes between African American and European American women of college age. AB - BACKGROUND: Cervical cancer incidence and mortality rates are higher in African Americans than in European Americans (white, non-Hispanic of European ancestry). The reasons for this disparity are not known. METHODS: We recruited a population based longitudinal cohort of 326 European American and 113 African American female college freshmen in Columbia, South Carolina, to compare clearance of high risk human papillomavirus (HR-HPV) infection between ethnicities. HPV testing and typing from samples obtained for Papanicolaou testing occurred every 6 months. RESULTS: African American participants had an increased risk of testing positive for HR-HPV, compared with European American participants, but the frequency of incident HPV infection was the same in African American and European American women. Thus, exposure to HPV could not explain the higher rate of HPV positivity among African American women. The time required for 50% of participants to clear HR-HPV infection was 601 days for African American women (n = 63) and 316 days for European American women (n = 178; odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08-2.53). African American women were more likely than European American women to have an abnormal result of a Papanicolaou test (OR, 1.58; 95% CI, 1.05-2.39). CONCLUSIONS: We propose that the longer time to clearance of HR HPV among African American women leads to increased rates of abnormal results of Papanicolaou tests and contributes to the increased rates of cervical cancer observed in African American women. PMID- 25028694 TI - Repurposing of prochlorperazine for use against dengue virus infection. AB - The increasing prevalence of dengue virus (DENV) infection presents serious disease and economic burdens in countries where dengue epidemics are occurring. Despite the clinical importance, no DENV vaccine or anti-DENV drug is available. In this study, we found that prochlorperazine (PCZ), a dopamine D2 receptor (D2R) antagonist approved to treat nausea, vomiting, and headache in humans has potent in vitro and in vivo antiviral activity against DENV infection. PCZ can block DENV infection by targeting viral binding and viral entry through D2R- and clathrin-associated mechanisms, respectively. Administration of PCZ immediately or 6 hours after DENV infection in a Stat1-deficient mouse model completely protected against or delayed lethality. Overall, PCZ showed a previously unknown antiviral effect against DENV infection, and D2R may play a role in the DENV life cycle. Prophylactic and/or therapeutic treatment with PCZ might reduce viral replication and relieve the clinical symptoms of patients with dengue. PMID- 25028693 TI - Regulation of oxidative stress by methylation-controlled J protein controls macrophage responses to inflammatory insults. AB - Mitochondria contribute to macrophage immune function through the generation of reactive oxygen species, a byproduct of the mitochondrial respiratory chain. MCJ (also known as DnaJC15) is a mitochondrial inner membrane protein identified as an endogenous inhibitor of respiratory chain complex I. Here we show that MCJ is essential for the production of tumor necrosis factor by macrophages in response to a variety of Toll-like receptor ligands and bacteria, without affecting their phagocytic activity. Loss of MCJ in macrophages results in increased mitochondrial respiration and elevated basal levels of reactive oxygen species that cause activation of the JNK/c-Jun pathway, lead to the upregulation of the TACE (also known as ADAM17) inhibitor TIMP-3, and lead to the inhibition of tumor necrosis factor shedding from the plasma membrane. Consequently, MCJ-deficient mice are resistant to the development of fulminant liver injury upon lipopolysaccharide administration. Thus, attenuation of the mitochondrial respiratory chain by MCJ in macrophages exquisitely regulates the response of macrophages to infectious insults. PMID- 25028695 TI - An engagement factor for caregiver radiation dose assessment with radioiodine treatment. AB - This study aims to suggest ways to better manage thyroid cancer patients treated with high- and low-activity radioiodine ((131)I) by assessing external radiation doses to family members and caregivers and the level of radiation in the surrounding environment. The radiation doses to caregivers of 33 inpatients (who were quarantined in the hospital for 2-3 d after treatment) and 31 outpatients who received radioiodine treatment after thyroidectomy were measured using passive thermoluminescence dosemeters. In this study, 33 inpatients were administered high-activity (100-200 mCi) (131)I, and 31 outpatients were administered low-activity (30 mCi) (131)I. The average doses to caregivers were measured at 0.61 mSv for outpatients and 0.16 mSv for inpatients. The total integrated dose of the recovery (recuperation) rooms where the patients stayed after release from hospital was measured to be 0.83 mSv for outpatients and 0.23 mSv for inpatients. To reflect the degree of engagement between the caregiver and the patient, considering the duration and distance between two during exposure, the authors used the engagement factor introduced by Jeong et al. (Estimation of external radiation dose to caregivers of patients treated with radioiodine after thyroidectomy. Health Phys 2014; 106: :466-474.). This study presents a new engagement factor (K-value) of 0.82 obtained from the radiation doses to caregivers of both in- and out-patients treated with high- and low-activity radioiodine, and based on this new value, this study presented a new predicted dose for caregivers. A patient treated with high-activity radioiodine can be released after 24 h of isolation, whereas outpatients treated with low-activity radioiodine should be isolated for at least 12 h. PMID- 25028696 TI - Increasing the sensitivity of microfluidics based immunoassays using isotachophoresis. AB - We have developed a microfluidic device that enhances the sensitivity of protein immunoassays by preconcentrating the protein sample using isotachophoresis (ITP). Two approaches were followed to study the sensitivity gain achieved that way. The first approach was using antibody-coated magnetic beads loaded into a microchannel to capture the proteins within the ITP sample zone. The second was to directly bind the antibodies to the microchannel surface. The use of ITP increased the sensitivity of both the direct and the bead-based immunoassay and lowered the model protein's detection limit. Our setup also uses electrokinetic injection for sample charging, thereby sparing the need for integrating mechanical components such as pumps or valves and reducing the complexity of the setup. This work demonstrates the feasibility of using ITP as a preconcentration mechanism of proteins in immunoassays. The protein was concentrated by a factor of 100 and the assay's limit of detection was in the picomolar range. ITP can be applied to any sample of mixed content, separating and preconcentrating the desired analyte before it reaches the detection region with immobilized antibodies, without the need for separating and concentrating the sample in an independent step. PMID- 25028697 TI - The relationship between emotional suppression and psychological distress in breast cancer patients after surgery. AB - OBJECTIVE: The purpose of this study was to examine the relationship between emotional suppression and psychological distress in breast cancer patients after surgery. We examined this relationship using questionnaires at the first visit to the breast cancer outpatient clinic at our hospital and after surgery, as well as interviews after surgery. METHODS: A total of 31 breast cancer patients were asked to complete the Courtauld Emotional Control Scale and the Profile of Mood States at their first visit to the outpatient clinic. Patients were also asked to complete the Profile of Mood States between 1 and 6 months after surgery. Trained clinical psychologists conducted the interviews, asking patients to speak freely about their current anxieties, worries and thoughts. Based on the median Courtauld Emotional Control Scale score of 42 points, participants were divided into emotional suppression and emotional expression groups. RESULTS: The Total Mood Disturbance score, as well as each of the subscale (except vigor) scores of the Profile of Mood States, were significantly higher in the emotional suppression group than the emotional expression group. The emotional suppression group expressed significantly more negative emotions and fewer positive emotions than the emotional expression group. CONCLUSIONS: Patients with emotional suppression felt and expressed more psychological distress after surgery. This finding highlights the need for medical staff to comprehend the psychological traits of breast cancer patients, including emotional suppression, in the early stages of breast cancer in order to provide adequate psychological support. PMID- 25028698 TI - A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. AB - Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor. PMID- 25028699 TI - Vibrational spectroscopic methods for cytology and cellular research. AB - The use of vibrational spectroscopy, FTIR and Raman, for cytology and cellular research has the potential to revolutionise the approach to cellular analysis. Vibrational spectroscopy is non-destructive, simple to operate and provides direct information. Importantly it does not require expensive exogenous labels that may affect the chemistry of the cell under analysis. In addition, the advent of spectroscopic microscopes provides the ability to image cells and acquire spectra with a subcellular resolution. This introductory review focuses on recent developments within this fast paced field and highlights potential for the future use of FTIR and Raman spectroscopy. We particularly focus on the development of live cell research and the new technologies and methodologies that have enabled this. PMID- 25028700 TI - Global in vivo terminal amino acid labeling for exploring differential expressed proteins induced by dialyzed serum cultivation. AB - Taking advantage of reliable metabolic labeling and accurate isobaric MS2 quantification, we developed a global in vivo terminal amino acid labeling (G IVTAL) strategy by combining metabolic labeling and isotopic dimethyl labeling for quantifying tryptic peptides. With G-IVTAL, the scale of qualitative and quantitative data can be increased twofold compared with in vivo termini amino acid labeling (IVTAL) in which Lys-N and Arg-C are used for digestion. As a result, up to 81.78% of the identified proteins have been confidently quantified in G-IVTAL-labeled HepG2 cells. Dialyzed serum has been used in most SILAC studies to ensure complete labeling. However, dialysis requires the removal of low molecular weight hormones, cytokines, and cellular growth factors, which are essential for the cell growth of certain cell lines. To address the influence of dialyzed serum in HepG2 growth, the G-IVTAL strategy was applied to quantify the expression differences between dialyzed serum- and normal serum-cultured HepG2 cells. Finally, we discovered 111 differentially expressed proteins, which could be used as references to improve the reliability of the SILAC quantification. Among these, by using western blotting, the differential expressions of MTDH, BCAP31, and GPC3 were confirmed as being influenced by dialyzed serum. The experimental results demonstrate that the G-IVTAL strategy is a powerful tool to achieve accurate and reliable protein quantification. PMID- 25028701 TI - Identification and discrimination of binding sites of an organoruthenium anticancer complex to single-stranded oligonucleotides by mass spectrometry. AB - We here report the identification of the binding sites of an organometallic ruthenium anticancer complex [(eta(6)-biphenyl)Ru(en)Cl](+) (1) to single stranded oligodeoxynucleotides (ODNs) 5'-CCCA4G5C6CC-3' (I) and 5'-CCC3G4A5CCC-3' (II) by mass spectrometry. The MS analysis of exonuclease ladders demonstrated that the 5'-exonuclease bovine spleen phosphodiesterase digestion of I and II mono-ruthenated by complex 1 was arrested solely at A4 and partially at C3 and G4, respectively, and that the 3'-exonuclease snake venom phosphodiesterase digestion of the ruthenated ODNs was arrested solely at G5 and G4, respectively, due to the ruthenation. These results did not allow unambiguous identification of ruthenation sites on the metallated ODNs. In contrast, tandem mass spectrometry analysis with CID fragmentation of the mono-ruthenated ODNs provided sequential and complementary [a(i) - B]/wi fragments, leading to unambiguous identification of G5 in I and G4 in II as the ruthenation sites on the ODN adducts, which is in line with the high selectivity of the complex towards guanine base as reported previously. These findings suggest that caution should be raised with regard to the identification of the binding sites of metal complexes, in particular complexes with bulky ligands, like biphenyl in complex 1, to DNA by MS analysis of exonuclease ladders of the metallated adducts, because the bulky ligands may adopt such an orientation that they block the exonuclease cleavage of the 5'- or 3'-side phosphodiester bonds adjacent to the binding sites, leading to digestion stalling at the nucleotides before the binding sites. PMID- 25028702 TI - Dendronized supramolecular polymers. AB - Supramolecular polymers formed from topological building blocks pave a new avenue for creating novel supramolecular structures and functional materials. Dendronized supramolecular polymers (DSPs) combine the topological characteristics of dendronized polymers and a dynamic nature from supramolecular chemistry, and are promising for the formation of supramolecular structures and functional assemblies. These topological supramolecular polymers have a characteristic cylindrical shape, high rigidity, multivalency, as well as inherent thickness. These structural characteristics make them ideal candidates for supramolecular assembly. DSPs can be formed through non-covalent interactions, such as hydrogen bonding, pi-pi stacking, and metal coordination, and classified into main-chain, side-chain and block types. This feature article will summarize methodologies for the preparation of homo- and block DSPs with a focus on their supramolecular structure formation. Particular attention is put on the structural effects of DSPs on their supramolecular assembly. PMID- 25028703 TI - Maternal genotype and severe preeclampsia: a HuGE review. AB - Severe preeclampsia is a common cause of maternal and perinatal morbidity worldwide. The disease clusters in families; however, individual genetic studies have produced inconsistent results. We conducted a review to examine relationships between maternal genotype and severe preeclampsia. We searched the MEDLINE and Embase databases for prospective and retrospective cohort and case control studies reporting associations between genes and severe preeclampsia. Four reviewers independently undertook study selection, quality assessment, and data extraction. We performed random-effects meta-analyses by genotype and predefined functional gene group (thrombophilic, vasoactive, metabolic, immune, and cell signalling). Fifty-seven studies evaluated 50 genotypes in 5,049 cases and 16,989 controls. Meta-analysis showed a higher risk of severe preeclampsia with coagulation factor V gene (proaccelerin, labile factor) (F5) polymorphism rs6025 (odds ratio = 1.90, 95% confidence interval: 1.42, 2.54; 23 studies, I(2) = 29%), coagulation factor II (thrombin) gene (F2) mutation G20210A (rs1799963) (odds ratio = 2.01, 95% confidence interval: 1.14, 3.55, 9 studies, I(2) = 0%), leptin receptor gene (LEPR) polymorphism rs1137100 (odds ratio = 1.75, 95% confidence interval: 1.15, 2.65; 2 studies, I(2) = 0%), and the thrombophilic gene group (odds ratio = 1.87, 95% confidence interval: 1.43, 2.45, I(2) = 27%). There were no associations with other gene groups. There was moderate heterogeneity between studies and potential for bias from poor-quality genotyping and inconsistent definition of phenotype. Further studies with robust methods should investigate genetic factors that might potentially be used to stratify pregnancies according to risk of complications. PMID- 25028704 TI - Glenoid bone loss in the setting of an anterior labroligamentous periosteal sleeve avulsion tear. AB - BACKGROUND: Glenoid bone loss is a factor that has been inversely associated with the success of shoulder instability repair. Recently, patients with an anterior labroligamentous periosteal sleeve avulsion (ALPSA) lesion have also been identified as having a higher failure rate after surgical repair. PURPOSE: To determine differences in the amount of glenoid bone loss and to compare demographic factors of instability in patients with and without ALPSA tears. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Over a 3-year period, all patients (N = 83) who were treated for anterior shoulder instability at a single institution were reviewed retrospectively. A total of 39 (47%) were identified as having an ALPSA lesion and 44 (53%) as having no ALPSA tear. Glenoid bone loss was determined in 2 ways: (1) radiographically by 3-dimensional computed tomography (3D CT) (humeral head digitally subtracted by 3 blinded observers) and (2) with arthroscopic techniques at the time of surgery. Demographic data such as the time from the initial instability event to advanced imaging and surgery were noted. These data were then analyzed with the Student t test to determine any significant differences between the 2 groups. RESULTS: The patients with an ALPSA lesion had more preoperative instability events than those without (8.2 vs 3.6, respectively; P = .04). The mean glenoid bone loss measured by 3D CT was 12.7% (range, 0%-22.3%) for those with ALPSA tears versus 6.25% (range, 0%-23.1%) for those without (P = .002). The mean duration of total instability for those with ALPSA tears was 42.9 months versus 46.3 months for those without (P = .95). Lastly, the mean bone loss based on arthroscopic measures was 11.4% for patients with ALPSA tears and 4.3% for those without ALPSA tears (P = .017). From the existing magnetic resonance imaging/arthrography scans reviewed, 82% of patients could be correctly identified as having an ALPSA lesion. CONCLUSION: Patients with anterior shoulder instability who have an ALPSA lesion have nearly twice the amount of glenoid bone loss as those with a standard Bankart tear (no ALPSA lesion). Patients with ALPSA lesions had statistically more instability events, and this may be an additional factor in either developing an ALPSA lesion or glenoid bone loss or both. PMID- 25028705 TI - Letter to the editor on 'Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited-disease small cell lung cancer'. PMID- 25028706 TI - Reply to the letter to the editor 'Still a long way to go to achieve multidisciplinarity for the benefit of patients: commentary on the ESMO position paper' by Valentini et al. PMID- 25028707 TI - Disease-regulated local IL-10 gene therapy diminishes synovitis and cartilage proteoglycan depletion in experimental arthritis. AB - OBJECTIVES: Rheumatoid arthritis is a chronic destructive autoimmune disease, but the course is unpredictable in individual patients. An attractive treatment would provide a disease-regulated therapy that offers personalised drug delivery. Therefore, we expressed the anti-inflammatory interleukin-10 (IL-10) gene under the control of inflammation-dependent promoters in a mouse model of arthritis. METHODS: Proximal promoters of S100a8, Cxcl1, Mmp13, Saa3, IL-1b and Tsg6 were selected by whole-genome expression analysis of inflamed synovial tissues from arthritic mice. Mice were injected intraarticularly in knee joints with lentiviral vectors expressing a luciferase reporter or the therapeutic protein IL 10 under control of the Saa3 or Mmp13 promoter. After 4 days, arthritis was induced by intraarticular injection of streptococcal cell walls (SCW). At different time points after arthritis induction, in vivo bioluminescent imaging was performed and knee joints were dissected for histological and RNA analysis. RESULTS: The disease-regulated promoter-luciferase reporter constructs showed different activation profiles during the course of the disease. The Saa3 and Mmp13 promoters were significantly induced at day 1 or day 4 after arthritis induction respectively and selected for further research. Overexpression of IL-10 using these two disease-inducible promoters resulted in less synovitis and markedly diminished cartilage proteoglycan depletion and in upregulation of IL 1Ra and SOCS3 gene expression. CONCLUSIONS: Our study shows that promoters of genes that are expressed locally during arthritis can be candidates for disease regulated overexpression of biologics into arthritic joints, as shown for IL-10 in SCW arthritis. The disease-inducible approach might be promising for future tailor-made local gene therapy in arthritis. PMID- 25028708 TI - Subsets of RP105-negative plasmablasts in IgG4-related disease. PMID- 25028709 TI - How important is confidentiality in sexual health clinics? A survey of patients across 51 clinics in England. PMID- 25028710 TI - An evaluation of a dedicated chronic pelvic pain syndrome clinic in genitourinary medicine. PMID- 25028711 TI - A reaudit of the management of syphilis in pregnancy in a large inner London hospital. PMID- 25028712 TI - Empiric NSU treatment needs updating. PMID- 25028714 TI - Retraction. PMID- 25028715 TI - BASHH patient survey on changes to the confidentiality laws: the importance of phrasing and order of survey questions. PMID- 25028716 TI - Killing the Killer: PARC/CUL9 promotes cell survival by destroying cytochrome C. AB - Balanced amounts of apoptotic cell death are essential for health; its deregulation plays key roles in neurodegeneration, autoimmunity, and cancer. Mitochondria orchestrate apoptosis through a process called mitochondrial outer membrane permeabilization (MOMP). After MOMP, mitochondrial cytochrome c is released into the cytoplasm, where it binds the adaptor molecule APAF1, triggering caspase protease activation and cell death. In this issue of Science Signaling, Deshmukh and colleagues define a new survival mechanism downstream of mitochondrial permeabilization. Specifically, they identify proteasomal degradation of cytochrome c as a major determinant of cell survival. In an unbiased approach, PARC (also known as CUL9) was found to be the ubiquitin ligase responsible for the ubiquitination and proteasomal degradation of cytochrome c. The consequences of this survival process may be double-edged because both cancer cells and postmitotic cells use PARC/CUL9-mediated cytochrome c degradation to ensure cell survival. Ultimately, differential targeting of this process may promote survival of postmitotic tissue or enhance tumor-specific killing. PMID- 25028717 TI - The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. AB - The ability to withstand mitochondrial damage is especially critical for the survival of postmitotic cells, such as neurons. Likewise, cancer cells can also survive mitochondrial stress. We found that cytochrome c (Cyt c), which induces apoptosis upon its release from damaged mitochondria, is targeted for proteasome mediated degradation in mouse neurons, cardiomyocytes, and myotubes and in human glioma and neuroblastoma cells, but not in proliferating human fibroblasts. In mouse neurons, apoptotic protease-activating factor 1 (Apaf-1) prevented the proteasome-dependent degradation of Cyt c in response to induced mitochondrial stress. An RNA interference screen in U-87 MG glioma cells identified p53 associated Parkin-like cytoplasmic protein (PARC, also known as CUL9) as an E3 ligase that targets Cyt c for degradation. The abundance of PARC positively correlated with differentiation in mouse neurons, and overexpression of PARC reduced the abundance of mitochondrially-released cytosolic Cyt c in various cancer cell lines and in mouse embryonic fibroblasts. Conversely, neurons from Parc-deficient mice had increased sensitivity to mitochondrial damage, and neuroblastoma or glioma cells in which PARC or ubiquitin was knocked down had increased abundance of mitochondrially-released cytosolic Cyt c and decreased viability in response to stress. These findings suggest that PARC-mediated ubiquitination and degradation of Cyt c is a strategy engaged by both neurons and cancer cells to prevent apoptosis during conditions of mitochondrial stress. PMID- 25028718 TI - The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. AB - The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl( )-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote gamma-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism. PMID- 25028719 TI - Rapidly rendering cells phagocytic through a cell surface display technique and concurrent Rac activation. AB - Cell surfaces represent a platform through which extracellular signals that determine diverse cellular processes, including migration, division, adhesion, and phagocytosis, are transduced. Techniques to rapidly reconfigure the surface properties of living cells should thus offer the ability to harness these cellular functions. Although the molecular mechanism of phagocytosis is well characterized, the minimal molecular players that are sufficient to activate this elaborate process remain elusive. We developed and implemented a technique to present a molecule of interest at the cell surface in an inducible manner on a time scale of minutes. We simultaneously induced the cell surface display of the C2 domain of milk fat globule epidermal growth factor factor 8 (MFG-E8) and activated the intracellular small guanosine triphosphatase Rac, which stimulates actin polymerization at the cell periphery. The C2 domain binds to phosphatidylserine, a lipid exposed on the surface of apoptotic cells. By integrating the stimulation of these two processes, we converted HeLa cells into a phagocytic cell line that bound to and engulfed apoptotic human Jurkat cells. Inducing either the cell surface display of the C2 domain or activating Rac alone was not sufficient to stimulate phagocytosis, which suggests that attachment to the target cell and actin reorganization together constitute the minimal molecular events that are needed to induce phagocytosis. This cell surface display technique might be useful as part of a targeted, cell-based therapy in which unwanted cells with characteristic surface molecules could be rapidly consumed by engineered cells. PMID- 25028720 TI - Primary B-cell cardiac lymphoma presenting as a biatrial mass. PMID- 25028721 TI - Modeling time-dependent transcription effects of HER2 oncogene and discovery of a role for E2F2 in breast cancer cell-matrix adhesion. AB - MOTIVATION: Oncogenes are known drivers of cancer phenotypes and targets of molecular therapies; however, the complex and diverse signaling mechanisms regulated by oncogenes and potential routes to targeted therapy resistance remain to be fully understood. To this end, we present an approach to infer regulatory mechanisms downstream of the HER2 driver oncogene in SUM-225 metastatic breast cancer cells from dynamic gene expression patterns using a succession of analytical techniques, including a novel MP grammars method to mathematically model putative regulatory interactions among sets of clustered genes. RESULTS: Our method highlighted regulatory interactions previously identified in the cell line and a novel finding that the HER2 oncogene, as opposed to the proto oncogene, upregulates expression of the E2F2 transcription factor. By targeted gene knockdown we show the significance of this, demonstrating that cancer cell matrix adhesion and outgrowth were markedly inhibited when E2F2 levels were reduced. Thus, validating in this context that upregulation of E2F2 represents a key intermediate event in a HER2 oncogene-directed gene expression-based signaling circuit. This work demonstrates how predictive modeling of longitudinal gene expression data combined with multiple systems-level analyses can be used to accurately predict downstream signaling pathways. Here, our integrated method was applied to reveal insights as to how the HER2 oncogene drives a specific cancer cell phenotype, but it is adaptable to investigate other oncogenes and model systems. AVAILABILITY AND IMPLEMENTATION: Accessibility of various tools is listed in methods; the Log-Gain Stoichiometric Stepwise algorithm is accessible at http://www.cbmc.it/software/Software.php. PMID- 25028722 TI - ASP-G: an ASP-based method for finding attractors in genetic regulatory networks. AB - MOTIVATION: Boolean network models are suitable to simulate GRNs in the absence of detailed kinetic information. However, reducing the biological reality implies making assumptions on how genes interact (interaction rules) and how their state is updated during the simulation (update scheme). The exact choice of the assumptions largely determines the outcome of the simulations. In most cases, however, the biologically correct assumptions are unknown. An ideal simulation thus implies testing different rules and schemes to determine those that best capture an observed biological phenomenon. This is not trivial because most current methods to simulate Boolean network models of GRNs and to compute their attractors impose specific assumptions that cannot be easily altered, as they are built into the system. RESULTS: To allow for a more flexible simulation framework, we developed ASP-G. We show the correctness of ASP-G in simulating Boolean network models and obtaining attractors under different assumptions by successfully recapitulating the detection of attractors of previously published studies. We also provide an example of how performing simulation of network models under different settings help determine the assumptions under which a certain conclusion holds. The main added value of ASP-G is in its modularity and declarativity, making it more flexible and less error-prone than traditional approaches. The declarative nature of ASP-G comes at the expense of being slower than the more dedicated systems but still achieves a good efficiency with respect to computational time. AVAILABILITY AND IMPLEMENTATION: The source code of ASP-G is available at http://bioinformatics.intec.ugent.be/kmarchal/Supplementary_Information_Musthofa_ 014/asp-g.zip. PMID- 25028723 TI - Journaled string tree-a scalable data structure for analyzing thousands of similar genomes on your laptop. AB - MOTIVATION: Next-generation sequencing (NGS) has revolutionized biomedical research in the past decade and led to a continuous stream of developments in bioinformatics, addressing the need for fast and space-efficient solutions for analyzing NGS data. Often researchers need to analyze a set of genomic sequences that stem from closely related species or are indeed individuals of the same species. Hence, the analyzed sequences are similar. For analyses where local changes in the examined sequence induce only local changes in the results, it is obviously desirable to examine identical or similar regions not repeatedly. RESULTS: In this work, we provide a datatype that exploits data parallelism inherent in a set of similar sequences by analyzing shared regions only once. In real-world experiments, we show that algorithms that otherwise would scan each reference sequentially can be speeded up by a factor of 115. PMID- 25028724 TI - AffyPipe: an open-source pipeline for Affymetrix Axiom genotyping workflow. AB - The Affymetrix Axiom genotyping standard and 'best practice' workflow for Linux and Mac users consists of three stand-alone executable programs (Affymetrix Power Tools) and an R package (SNPolisher). Currently, SNP analysis has to be performed in a step-by-step procedure. Manual intervention and/or programming skills by the user is required at each intermediate point, as Affymetrix Power Tools programs do not produce input files for the program next-in-line. An additional problem is that the output format of genotypes is not compatible with most analysis software currently available. AffyPipe solves all the above problems, by automating both standard and 'best practice' workflows for any species genotyped with the Axiom technology. AffyPipe does not require programming skills and performs all the steps necessary to obtain a final genotype file. Furthermore, users can directly edit SNP probes and export genotypes in PLINK format. AVAILABILITY AND IMPLEMENTATION: https://github.com/nicolazzie/AffyPipe.git. PMID- 25028725 TI - Resolving complex tandem repeats with long reads. AB - MOTIVATION: Resolving tandemly repeated genomic sequences is a necessary step in improving our understanding of the human genome. Short tandem repeats (TRs), or microsatellites, are often used as molecular markers in genetics, and clinically, variation in microsatellites can lead to genetic disorders like Huntington's diseases. Accurately resolving repeats, and in particular TRs, remains a challenging task in genome alignment, assembly and variation calling. Though tools have been developed for detecting microsatellites in short-read sequencing data, these are limited in the size and types of events they can resolve. Single molecule sequencing technologies may potentially resolve a broader spectrum of TRs given their increased length, but require new approaches given their significantly higher raw error profiles. However, due to inherent error profiles of the single-molecule technologies, these reads presents a unique challenge in terms of accurately identifying and estimating the TRs. RESULTS: Here we present PacmonSTR, a reference-based probabilistic approach, to identify the TR region and estimate the number of these TR elements in long DNA reads. We present a multistep approach that requires as input, a reference region and the reference TR element. Initially, the TR region is identified from the long DNA reads via a 3-stage modified Smith-Waterman approach and then, expected number of TR elements is calculated using a pair-Hidden Markov Models-based method. Finally, TR-based genotype selection (or clustering: homozygous/heterozygous) is performed with Gaussian mixture models, using the Akaike information criteria, and coverage expectations. PMID- 25028726 TI - MToolBox: a highly automated pipeline for heteroplasmy annotation and prioritization analysis of human mitochondrial variants in high-throughput sequencing. AB - MOTIVATION: The increasing availability of mitochondria-targeted and off-target sequencing data in whole-exome and whole-genome sequencing studies (WXS and WGS) has risen the demand of effective pipelines to accurately measure heteroplasmy and to easily recognize the most functionally important mitochondrial variants among a huge number of candidates. To this purpose, we developed MToolBox, a highly automated pipeline to reconstruct and analyze human mitochondrial DNA from high-throughput sequencing data. RESULTS: MToolBox implements an effective computational strategy for mitochondrial genomes assembling and haplogroup assignment also including a prioritization analysis of detected variants. MToolBox provides a Variant Call Format file featuring, for the first time, allele-specific heteroplasmy and annotation files with prioritized variants. MToolBox was tested on simulated samples and applied on 1000 Genomes WXS datasets. AVAILABILITY AND IMPLEMENTATION: MToolBox package is available at https://sourceforge.net/projects/mtoolbox/. PMID- 25028727 TI - Gustaf: Detecting and correctly classifying SVs in the NGS twilight zone. AB - MOTIVATION: The landscape of structural variation (SV) including complex duplication and translocation patterns is far from resolved. SV detection tools usually exhibit low agreement, are often geared toward certain types or size ranges of variation and struggle to correctly classify the type and exact size of SVs. RESULTS: We present Gustaf (Generic mUlti-SpliT Alignment Finder), a sound generic multi-split SV detection tool that detects and classifies deletions, inversions, dispersed duplications and translocations of >= 30 bp. Our approach is based on a generic multi-split alignment strategy that can identify SV breakpoints with base pair resolution. We show that Gustaf correctly identifies SVs, especially in the range from 30 to 100 bp, which we call the next-generation sequencing (NGS) twilight zone of SVs, as well as larger SVs >500 bp. Gustaf performs better than similar tools in our benchmark and is furthermore able to correctly identify size and location of dispersed duplications and translocations, which otherwise might be wrongly classified, for example, as large deletions. PMID- 25028728 TI - Comparison of the web tools ARG-ANNOT and ResFinder for detection of resistance genes in bacteria. PMID- 25028729 TI - Reply to "Comparison of the web tools ARG-ANNOT and ResFinder for detection of resistance genes in bacteria". PMID- 25028730 TI - Risk for invasive fungal infections during acute myeloid leukemia induction therapy: a true association with echinocandins? PMID- 25028731 TI - Reply to "Risk for invasive fungal infections during acute myeloid leukemia induction therapy: a true association with echinocandins?". PMID- 25028736 TI - Reconstructive approach for patients with augmentation mammaplasty undergoing nipple-sparing mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) is a recent advance in the therapeutic and prophylactic management of breast cancer; however, the procedure is associated with increased reconstructive complications. Data on NSM after previous breast augmentation are limited. OBJECTIVES: The authors compared reconstructive complications after NSM between patients with previously augmented breasts and a larger cohort that had not undergone prior augmentation. An approach to NSM that involves 2-stage reconstruction in augmented patients is also described. METHODS: Medical records of NSMs performed at New York University Langone Medical Center from 2006 to 2013 were reviewed. Data points evaluated included patient characteristics, comorbidities, breast implant plane, and reconstructive complications. Fisher's exact and t tests were used for the comparisons. RESULTS: During the study period, NSMs were performed in 17 augmented breasts at this institution. After NSM, 15 of these breasts underwent implant-based reconstruction and 2 breasts underwent microvascular free flaps. Reconstructive complications included 1 hematoma managed nonoperatively (5.9%) and 1 partial necrosis of the nipple-areola complex (NAC) (5.9%). Compared with the larger nonaugmented cohort (n=332), patients with previously augmented breasts had fewer complications, and there were no statistically significant differences in the rates of mastectomy flap necrosis, partial NAC necrosis, complete NAC necrosis, hematoma, capsular contracture, explantation, implant displacement, seroma, or breast cellulitis. CONCLUSIONS: The results indicate that NSM reconstruction is associated with minimal complications in patients with previous augmentation mammaplasty. LEVEL OF EVIDENCE: 4. PMID- 25028737 TI - The lateral crural rein flap: a novel technique for management of tip rotation in primary rhinoplasty. AB - BACKGROUND: An important consideration in rhinoplasty is maintenance of the applied tip rotation. Different techniques have been proposed to accomplish this. Loss of rotation after surgery not only results in a derotated tip but also can create a supratip deformity. OBJECTIVES: As a supplement to dorsal reconstruction, the authors introduced and applied the lateral crural rein flap technique, whereby cartilage flaps are created from the cephalic portion of the lateral crura to control and stabilize tip rotation. METHODS: Eleven patients underwent primary open-approach rhinoplasty that included the lateral crural rein technique; the mean follow-up time was 18 months. Excess cephalic portions of the lateral crura were prepared as medial crura-based cartilaginous flaps and were incorporated into the nasal dorsum (similar to spreader grafts) and stabilized to achieve the desired tip rotation. RESULTS: The lateral crural rein flap technique provided stability to the nasal tip while minimizing derotation in the postoperative period. Long-term follow-up revealed maintenance of the nasal tip rotation and symmetric dorsal aesthetic lines. CONCLUSIONS: The lateral crural rein flap technique is effective for controlling nasal tip rotation while reducing lateral crural cephalic excess. Longevity of the applied tip rotation is reinforced by secure attachment of the lower nasal cartilage complex to the midvault structures. LEVEL OF EVIDENCE: 4. PMID- 25028738 TI - Long-term volumetric retention of autologous fat grafting processed with closed membrane filtration. AB - BACKGROUND: Some practitioners have criticized the unpredictable retention associated with autologous fat transfer. Potential causes of variations in predictability include intrinsic (patient-related) or extrinsic factors, such as harvesting, processing, and graft-delivery technique. OBJECTIVES: The authors sought to determine the long-term retention of autologous fat graft processed with a closed-membrane filtration system, to compare this retention with centrifuge-processed fat, and to analyze factors that affect graft retention. METHODS: This was a prospective analysis of 26 female patients (representing 52 hemi-midfaces) who underwent autologous fat transfer to the midface via the closed-membrane filtration system. The Vectra 3D camera and software were employed for all photography, which was then analyzed to compare immediate preoperative images with long-term follow-up images (obtained at least 10 months postprocedure). The authors compared the findings with data from their previous study of centrifuge-processed fat grafts (historical controls). RESULTS: Mean values were as follows: age, 55 years; follow-up period, 17 months; amount of autologous fat injected, 8.88 mL; absolute volume augmentation measured at the last postoperative visit, 3.71 mL; and retention, 41.2%. Results of Welch's t test, in which the membrane-filtration data were compared with the previous centrifuge data (31.8% long-term retention), showed a significant difference (P=.03). Retention in this study was significantly higher in patients younger than 55 years (53.0% vs 31% for older patients; P=.001) and lower in patients who underwent rhytidectomy (23.8% vs 47.6% for nonrhytidectomy patients; P<.001). CONCLUSIONS: Autologous fat processed by closed-membrane filtration had a significantly higher long-term retention rate than did centrifuged-processed fat injected by the same surgeons. LEVEL OF EVIDENCE: 3. PMID- 25028740 TI - Local anesthetic systemic toxicity. AB - Local anesthetic systemic toxicity (LAST) is a rare yet devastating complication from the administration of local anesthesia. The ability to recognize and treat LAST is critical for clinicians who administer these drugs. The authors reviewed the literature on the mechanism, treatment, and prevention of LAST, with the goal of proposing a practical method for its management. PMID- 25028741 TI - Thermal capsulorrhaphy: a modified technique for breast pocket revision. AB - BACKGROUND: Scant attention has been paid to breast capsule revision after augmentation mammaplasty. Dissatisfaction with traditional techniques prompted the senior authors to develop a thermal capsulorrhaphy (TC) technique to obliterate excess breast pocket space using ball cautery followed by barbed suture closure. OBJECTIVES: The authors propose a new periprosthetic technique for pocket closure, present a corresponding guide for surgical and postoperative management, and provide results of their retrospective review. METHODS: Medical records were reviewed for all patients who underwent TC after cosmetic augmentation mammaplasty during a 5-year period, for whom clinical photographs were available from at least 1 year postoperatively. Operating details and complications were documented. Outcomes were rated a success, partial success, or failure, based on analysis of the photographs. RESULTS: Of the 157 TC cases (41 unilateral, 58 bilateral) with a mean follow-up of 2 years, 141 (90%) outcomes were successful, 4 (2%) were partially successful, and 12 (8%) had failed. There were 16 complications: 10 over- or undercorrections and 1 episode each of hematoma, capsular contracture, slight deformity, nipple sensitivity, exposed suture knot, and suture abscess. CONCLUSIONS: The efficacy of TC derives from the symbiosis of stitches and heat: capsulorrhaphy reinforces apposition of the damaged walls, and cautery contracts and thickens the capsule, thus reducing dead space and improving suture purchase. Initially popularized in shoulder surgery, TC is even better suited for breast pocket closure due to superior visibility and maneuverability, more aggressive practices, and the lack of similar complications. Postoperative stabilization and guideline compliance are essential to successful revision. LEVEL OF EVIDENCE: 4. PMID- 25028742 TI - Geographic access to hospice care for children with cancer in Tennessee, 2009 to 2011. AB - The geographic interface between the need for and the supply of pediatric hospice may be critical in whether children with cancer access care. This study sought to describe the geographic distribution of pediatric hospice need and supply and identify areas lacking pediatric hospice care in Tennessee over a 3-year time period. Using ArcGIS, a series of maps were created. There was a consistent need for care among children with cancer across the state. Most urban areas were supplied by pediatric hospices, except the Knoxville area. Areas within the state were identified where the supply of pediatric hospice care declined, while the need for hospice care was unchanging. This study has important regulatory implications for clinicians practicing in certificate of need states such as Tennessee. PMID- 25028743 TI - Ketamine PCA for treatment of end-of-life neuropathic pain in pediatrics. AB - Control of neuropathic pain (NP) for children at end of life is challenging. Ketamine improves control of NP, but its use in children is not well described. We describe a retrospective case review of 14 children with terminal prognoses treated with ketamine patient-controlled analgesia (PCA) for management of opioid refractory NP at the end of life. Median ketamine dose was 0.06 mg/kg/h (range 0.014-0.308 mg/kg/h) with a 0.05 mg/kg (range 0.03-0.5mg/kg) demand dose available every 15 minutes (range 10-60 minutes). All patients noted subjective pain relief with ketamine, and 79% had no adverse effects. Benzodiazepines limited neuropsychiatric side effects. Ketamine treatment arrested dose escalation of opioids in 64% of patients, and 79% were discharged to home hospice. Ketamine PCA is an effective, well-tolerated therapy for opioid refractory NP in pediatric end-of-life care. PMID- 25028744 TI - New pharmacological therapies for vasomotor symptom management: focus on bazedoxifene/conjugated estrogens and paroxetine mesylate. AB - OBJECTIVE: To review 2 recently approved therapies for vasomotor symptoms (VMSs) of menopause. DATA SOURCES: PubMed searches (June 2003 to May 2014) were conducted using the keywords paroxetine vasomotor and bazedoxifene vasomotor. References from relevant articles were reviewed for pertinent citations that were not identified in the PubMed search. STUDY SELECTION AND DATA EXTRACTION: Phase 3 clinical trials of recently approved hormonal and nonhormonal therapies for the treatment of VMSs of menopause were selected. Studies that evaluated the use of paroxetine mesylate or bazedoxifene (BZA)/conjugated estrogens (CEs) for VMSs were included. DATA SYNTHESIS: Four studies for BZA/CEs were identified. One published report of low-dose paroxetine mesylate was identified that was a combined analysis of 2 phase 3 studies. Both agents significantly decrease the incidence of hot flushes compared with placebo and are approved for the treatment of moderate to severe VMSs associated with menopause. BZA/CEs is only approved for women with an intact uterus. In all circumstances, the use of BZA/CEs should be limited to the shortest duration possible. Paroxetine mesylate was not studied head-to-head against hormone therapy, but the magnitude of its effect on VMSs is less than expected with hormone therapy. CONCLUSIONS: BZA/CEs is an effective hormonal therapy for treating VMSs in women with an intact uterus. Paroxetine mesylate is the first nonhormonal therapy that the FDA has approved for VMSs, making both viable options for the treatment of VMSs of menopause. PMID- 25028745 TI - [MRT is nor suitable as the primary screening method after wrist injury and does not replace careful hand surgical exploration. Reply ]. PMID- 25028746 TI - Exploring young patients' perspectives on rehabilitation care: methods and challenges of organizing focus groups for children and adolescents. AB - BACKGROUND: In research on quality of care, the experiences of children and (pre)adolescents are usually assessed by asking their parents. However, these young patients may have preferences of their own, and their experiences do not necessarily concur with those of their parents. Therefore, our research aimed to give young patients an opportunity to speak up for themselves. METHODS: Focus group meetings and online focus groups were organized for two age groups (8-11 and 12-15 years) of young patients from two Dutch rehabilitation centres, with the use of a tailored interview technique. The feasibility and applicability of both types of focus groups were assessed. RESULTS: For both types of focus groups, recruitment proved a major problem. The focus group meetings with (pre)adolescents proved both feasible and applicable in obtaining information regarding the preferences and experiences towards rehabilitation care. Regarding children's meetings, there were mixed results. The setting suited most of them, but some were more anxious. In general, online focus groups were less successful than expected for both age groups. CONCLUSIONS: Possibilities for enhancing the recruitment rate should be considered, as the low participation rates limited generalizability of focus group results. The tailored design proved useful for obtaining relevant input from (pre)adolescents through meetings, but, especially for children, repeated meetings or other locations (e.g. at home) could be considered. This may make participants more at ease. For both age groups, the online focus groups proved far less useful, in terms of participation. PMID- 25028747 TI - Authors' reply. PMID- 25028748 TI - Crystal-storing histiocytosis with IgD kappa-associated plasma cell neoplasm. PMID- 25028749 TI - Cytospin preparation of AML in pleural fluid. PMID- 25028750 TI - Aspects of the Brazilian nutritional situation. PMID- 25028751 TI - Equity in access to healthcare among the urban elderly in China: does health insurance matter? AB - OBJECTIVE: The aim of this study was to examine if inequity in healthcare among the urban elderly in China has been improved through the implementation of Urban Resident Basic Medical Insurance (URBMI).METHODS AND DATA SOURCE: We used the data from a nationwide household health survey conducted between December 2011 and February 2012 to compare the needs, uses, and non-uses of health services of the 7618 urban Chinese elderly 60 years and older covered by two different health insurance schemes. Frequency and percentages were used to examine the data. RESULTS: Significant inequity in health service uses existed among different socioeconomic groups and the people covered by two different health insurance schemes. Compared with the elderly covered by Urban Employee Basic Medical Insurance, the elderly covered by URBMI had much lower rates of service use and higher non-use rates of health services. CONCLUSIONS: Universal health insurance coverage alone cannot mitigate the existing inequity in healthcare; the Chinese government must develop appropriate financial policies and measures to provide more financial support to URBMI in order to improve equitable and affordable access to healthcare. PMID- 25028752 TI - David James Purslove Barker: clinician, scientist and father of the 'fetal origins hypothesis'. PMID- 25028753 TI - Conceptions of 'community' among older adults living in high-density urban areas: an Australian case study. AB - AIM: The aim of this study was to explore the social networks of community and its connection to location for older people living in inner city high density (ICHD). METHOD: Using a case study approach employing qualitative (diaries, in depth interviews) and quantitative (global positioning systems and geographical information systems mapping) methods, this paper explores the everyday interaction and social networks and where they manifest spatially for a group of older ICHD Australians. RESULTS: Social networks in two community territories were found to be of particular importance to participants in terms of influencing feelings of well-being, support, social inclusion and cohesion. These two territories include the building where older people reside and the area immediately surrounding the building. CONCLUSION: This study highlights the importance of recognising the spatial aspect of community to better understand the social networks of community and their effects on well-being and social cohesion for ICHD older people. PMID- 25028754 TI - Yellow fever in Africa and South America, 2013. PMID- 25028755 TI - Monthly report on dracunculiasis cases, January-May 2014. PMID- 25028756 TI - Human cases of influenza at the human-animal interface, 2013. PMID- 25028757 TI - New compound could be an ideal candidate for visual restoration in patients with degenerative retinal disorders. PMID- 25028758 TI - Drug repurposing identifies therapeutic agents for gastrointestinal stromal tumors. PMID- 25028759 TI - Promising strategy developed to target drug-resistant cancer cells. PMID- 25028760 TI - Unified multiscale simulation software developed. PMID- 25028761 TI - Hypertension, diabetes, obesity and other ailments in contemporary Brazil. PMID- 25028762 TI - Complacency in asthma care is costing lives, UK experts warn. PMID- 25028763 TI - Sexual dysfunction in patients with lung disease. PMID- 25028764 TI - Antimicrobial resistance reaches crisis levels. PMID- 25028765 TI - COPD misdiagnosis linked to obesity. PMID- 25028766 TI - No FDA approval for over-the-counter use of montelukast. PMID- 25028767 TI - The future of intensive care. PMID- 25028768 TI - Asthma online: pros and cons of social media and networks. PMID- 25028769 TI - Electrochemically active nickel foams as support materials for nanoscopic platinum electrocatalysts. AB - Platinum is deposited on open-cell nickel foam in low loading amounts via chemical reduction of Pt cations (specifically, Pt(2+) or Pt(4+)) originating from aqueous Pt salt solutions. The resulting Pt-modified nickel foams (Pt/Ni foams) are characterized using complementary electrochemical and materials analysis techniques. These include electron microscopy to examine the morphology of the deposited material, cyclic voltammetry to evaluate the electrochemical surface area of the deposited Pt, and inductively coupled plasma optical emission spectrometry to determine the mass of deposited Pt on the Ni foam substrate. The effect of potential cycling in alkaline media on the electrochemical behavior of the material and the stability of Pt deposit is studied. In the second part of this paper, the Pt/Ni foams are applied as electrode materials for hydrogen evolution, hydrogen reduction, oxygen reduction, and oxygen evolution reactions in an aqueous alkaline electrolyte. The electrocatalytic activity of the electrodes toward these processes is evaluated using linear sweep voltammetry curves and Tafel plots. The results of these studies demonstrate that nickel foams are acceptable support materials for nanoscopic Pt electrocatalysts and that the resulting Pt/Ni foams are excellent electrocatalysts for the hydrogen evolution reaction. An unmodified Ni foam is shown to be a highly active electrode for the oxygen evolution reaction. PMID- 25028770 TI - Labile or stable: can homoleptic and heteroleptic PyrPHOS-copper complexes be processed from solution? AB - Luminescent Cu(I) complexes are interesting candidates as dopants in organic light-emitting diodes (OLEDs). However, open questions remain regarding the stability of such complexes in solution and therefore their suitability for solution processing. Since the emission behavior of Cu(I) emitters often drastically differs between bulk and thin film samples, it cannot be excluded that changes such as partial decomposition or formation of alternative emitting compounds upon processing are responsible. In this study, we present three particularly interesting candidates of the recently established copper-halide (diphenylphosphino)pyridine derivatives (PyrPHOS) family that do not show such changes. We compare single crystals, amorphous bulk samples, and neat thin films in order to verify whether the material remains stable upon processing. Solid state nuclear magnetic resonance (MAS (31)P NMR) was used to investigate the electronic environment of the phosphorus atoms, and X-ray absorption spectroscopy at the Cu K edge provides insight into the local electronic and geometrical environment of the copper(I) metal centers of the samples. Our results suggest that--unlike other copper(I) complexes--the copper-halide-PyrPHOS clusters are significantly more stable upon processing and retain their initial structure upon quick precipitation as well as thin film processing. PMID- 25028771 TI - A musclelike [2](2)rotaxane: synthesis, performance, and molecular dynamics simulations. AB - A novel bistable symmetric [2](2)rotaxane was prepared by a threading-followed-by stoppering strategy and characterized with (1)H, (13)C, and 2D ROESY NMR spectroscopy and HR-ESI spectrometry. The symmetric [2](2)rotaxane system consists of an anthracene-based bis(crown ether) as macrocycles, and each of the two dibenzo[24]crown-8 (DB24C8) rings is threaded by the pendant substituents of a symmetrically substituted central rotatable ferrocene subunit that possesses two distinguishable recognition sites for the DB24C8 ring: namely, a dibenzylammonium site and an N-methyltriazolium site. The uniform shuttling motion of the thread relative to the two DB24C8 rings in [2](2)rotaxane can be driven by external acid-base stimuli, which was evidenced by (1)H and 2D ROESY NMR spectroscopy. Furthermore, molecular dynamics simulations of the [2](2)rotaxane were carried out both in protonated (stretched) and in neutral (contracted) forms. The calculated percentage change in molecular length of the [2](2)rotaxane between the two end-capping bis(methoxyl)phenyl groups is about 48% in the two different states (in acetone), which is much larger than the percentage change (~27%) in human muscle. Moreover, in the two states, the C*-Cp Cp-C* dihedral angles are computed as -177 degrees in the stretched state and 112 degrees in the contracted state, indicating a correlation between the translational and rotational motions of the [2](2)rotaxane. PMID- 25028772 TI - Multimerization of solution-state proteins by tetrakis(4 sulfonatophenyl)porphyrin. AB - Surface binding and interactions of anionic porphyins bound to cationic proteins have been studied for nearly three decades and are relevant as models for protein surface molecular recognition and photoinitiated electron transfer. However, interpretation of data in nearly all reports explicitly or implicitly assumed interaction of porphyrin with monodisperse proteins in solutions. In this report, using small-angle X-ray scattering with solution phase samples, we demonstrate that horse heart cytochrome (cyt) c, triheme cytochrome c7 PpcA from Geobacter sulfurreducens, and hen egg lysozyme multimerize in the presence of zinc tetrakis(4-sulfonatophenyl)porphyrin (ZnTPPS). Multimerization of cyt c showed a pH dependence with a stronger apparent binding affinity under alkaline conditions and was weakened in the presence of a high salt concentration. Ferric-cyt c formed complexes larger than those formed by ferro-cyt c. Free base TPPS and FeTPPS facilitated formation of complexes larger than those of ZnTPPS. No increase in protein aggregation state for cationic proteins was observed in the presence of cationic porphyrins. All-atom molecular dynamics simulations of cyt c and PpcA with free base TPPS corroborated X-ray scattering results and revealed a mechanism by which the tetrasubstituted charged porphyrins serve as bridging ligands nucleating multimerization of the complementarily charged protein. The final aggregation products suggest that multimerization involves a combination of electrostatic and hydrophobic interactions. The results demonstrate an overlooked complexity in the design of multifunctional ligands for protein surface recognition. PMID- 25028773 TI - Reactions in elastomeric nanoreactors reveal the role of force on the kinetics of the Huisgen reaction on surfaces. AB - The force dependence of the copper-free Huisgen cycloaddition between an alkyne and a surface-bound azide was examined in elastomeric nanoreactors. These studies revealed that pressure and chain length are critical factors that determine the reaction rate. These experiments demonstrate the central role of pressure and surface structure on interfacial processes that are increasingly important in biology, materials science, and nanotechnology. PMID- 25028774 TI - Single bacteria identification by Raman spectroscopy. AB - We report on rapid identification of single bacteria using a low-cost, compact, Raman spectroscope. We demonstrate that a 60-s procedure is sufficient to acquire a comprehensive Raman spectrum in the range of 600 to 3300 cm-1. This time includes localization of small bacteria aggregates, alignment on a single individual, and spontaneous Raman scattering signal collection. Fast localization of small bacteria aggregates, typically composed of less than a dozen individuals, is achieved by lensfree imaging over a large field of view of 24 mm2. The lensfree image also allows precise alignment of a single bacteria with the probing beam without the need for a standard microscope. Raman scattered light from a 34-mW continuous laser at 532 nm was fed to a customized spectrometer (prototype Tornado Spectral Systems). Owing to the high light throughput of this spectrometer, integration times as low as 10 s were found acceptable. We have recorded a total of 1200 spectra over seven bacterial species. Using this database and an optimized preprocessing, classification rates of ~90% were obtained. The speed and sensitivity of our Raman spectrometer pave the way for high-throughput and nondestructive real-time bacteria identification assays. This compact and low-cost technology can benefit biomedical, clinical diagnostic, and environmental applications. PMID- 25028775 TI - Long-term effects of traffic particles on lung function decline in the elderly. AB - RATIONALE: Few studies have been performed on air pollution effects on lung function in the elderly, a vulnerable population with low reserve capacity, and even fewer have looked at changes in the rate of lung function decline. OBJECTIVES: We evaluated the effect of long-term exposure to black carbon on levels and rates of decline in lung function in the elderly. METHODS: FVC and FEV1 were measured one to six times during the period 1995-2011 in 858 men participating in the Normative Aging Study. Exposure to black carbon, a tracer of traffic emissions, was estimated by a spatiotemporal land use regression model. We investigated the effects of moving averages of black carbon of 1-5 years before the lung function measurement using linear mixed models. MEASUREMENTS AND MAIN RESULTS: A 0.5 MUg/m(3) increase in long-term exposure to black carbon was associated with an additional rate of decline in FVC and FEV1 of between 0.5% and 0.9% per year, respectively, depending on the averaging time. In addition, black carbon exposure before the baseline visit was associated with lower levels of both FVC and FEV1, with effect estimates increasing up to 6-7% with a 5-year average exposure. CONCLUSIONS: Our results support adverse effects of long-term exposure to traffic particles on lung function level and rate of decline in the elderly and suggest that functionally significant differences in health and risk of disability occur below the annual Environmental Protection Agency National Air Quality Standards. PMID- 25028777 TI - Checklist for percutaneous tracheostomy in critical care. PMID- 25028776 TI - Fluid therapy in patients with brain injury: what does physiology tell us? AB - The unique component of the cerebral circulation is the so called blood-brain barrier (BBB). The anatomical structures of the BBB consist of the cerebral vascular endothelial cells, the surrounding pericytes, the basal lamina and the perivascular astrocytes. These form the so-called neurovascular unit. Notably, the endothelial cells are interconnected by tight junctions; thus, any solute transport will be transcellular, as opposed to paracellular, in the peripheral circulation. The specific anatomy of the neurovascular unit allows the brain volume to be kept constant even in the context of marked changes in intravascular volume status. PMID- 25028778 TI - ADHD inattentive symptoms mediate the relationship between intelligence and academic performance in children aged 6-14. AB - OBJECTIVE: Fluid intelligence and the behavioral problems of attention deficit/hyperactivity disorder (ADHD) are related to academic performance, but how this association occurs is unclear. This study aimed to assess mediation and moderation models that test possible pathways of influence between these factors. METHODS: Sixty-two children with ADHD and 33 age-matched, typically developing students were evaluated with Raven's Colored Progressive Matrices and the spelling and arithmetic subtests of the Brazilian School Achievement Test. Dimensional ADHD symptomatology was reported by parents. RESULTS: Our findings suggest that fluid intelligence has a significant impact on academic tests through inattention. The inattentive dimension was the principal behavioral source of influence, also accounting for the association of hyperactive-impulsive manifestations with school achievement. This cognitive-to-behavioral influence path seems to be independent of diagnosis related group, and gender, but lower socioeconomic status might increase its strength. CONCLUSION: Fluid intelligence is a relevant factor in the influence of ADHD behavioral symptoms on academic performance, but its impact is indirect. Therefore, early identification of both fluid intelligence and inattentive symptoms is of the utmost importance to prevent impaired academic performance and future difficulties in functioning. PMID- 25028779 TI - Portuguese version of the PTSD Checklist-Military Version (PCL-M)--II: diagnostic utility. AB - OBJECTIVE: War veterans are at high risk of developing posttraumatic stress disorder (PTSD), and the development of brief self-report instruments that enable screening for PTSD in this population is crucial. The PTSD Checklist-Military Version (PCL-M) is widely used for this purpose. This study sought to explore the diagnostic utility of the Portuguese version of the PCL-M. METHODS: The participants were 86 Portuguese Colonial War veterans (42 with a PTSD diagnosis and 44 without PTSD). Participants completed a self-report instrument designed to collect sociodemographic data, the PCL-M, and the Clinician-Administered PTSD Scale (CAPS). RESULTS: The area under the receiver operator characteristic (ROC) curve showed excellent discriminant ability between subjects with and without PTSD (AUC = 0.94). To achieve a positive PTSD diagnosis, an optimal cutoff point of 49 for the PCL-M total score and cutoff points for each of its 17 items are recommended. CONCLUSIONS: This work is a relevant contribution for research and clinical practice in the vast population of Portuguese Colonial War veterans. Use of the PCL-M as a screening tool for PTSD symptoms will allow easier, resource aware targeting of subjects with a potential PTSD diagnosis, adding to the improvement of public health in Portugal. PMID- 25028780 TI - Factor structure of the Positive and Negative Syndrome Scale (PANSS) in Brazil: convergent validation of the Brazilian version. AB - OBJECTIVES: The Positive and Negative Syndrome Scale (PANSS) was developed to assess the symptoms of schizophrenia dimensionally. Although it is widely used in clinical trials in Brazil, it is not fully validated. The aim of this study is to assess the factor structure of the Brazilian PANSS and generate validation data for its current version. METHODS: A total of 292 patients diagnosed with schizophrenia were enrolled. RESULTS: Principal component analysis suggested a forced five-factor final model that accounted for 58.44% of the total variance, composed of negative, disorganization/cognition, excitement, positive, and depression/anxiety. CONCLUSION: The Brazilian PANSS has a similar factor structure and internal consistency compared to versions in several other languages. PMID- 25028781 TI - Radiogenomic analysis of breast cancer: luminal B molecular subtype is associated with enhancement dynamics at MR imaging. AB - PURPOSE: To investigate associations between breast cancer molecular subtype and semiautomatically extracted magnetic resonance (MR) imaging features. MATERIALS AND METHODS: Imaging and genomic data from the Cancer Genome Atlas and the Cancer Imaging Archive for 48 patients with breast cancer from four institutions in the United States were used in this institutional review board approval-exempt study. Computer vision algorithms were applied to extract 23 imaging features from lesions indicated by a breast radiologist on MR images. Morphologic, textural, and dynamic features were extracted. Molecular subtype was determined on the basis of genomic analysis. Associations between the imaging features and molecular subtype were evaluated by using logistic regression and likelihood ratio tests. The analysis controlled for the age of the patients, their menopausal status, and the orientation of the MR images (sagittal vs axial). RESULTS: There is an association (P = .0015) between the luminal B subtype and a dynamic contrast material-enhancement feature that quantifies the relationship between lesion enhancement and background parenchymal enhancement. Cancers with a higher ratio of lesion enhancement rate to background parenchymal enhancement rate are more likely to be luminal B subtype. CONCLUSION: The luminal B subtype of breast cancer is associated with MR imaging features that relate the enhancement dynamics of the tumor and the background parenchyma. PMID- 25028782 TI - Tracking eye gaze during interpretation of endoluminal three-dimensional CT colonography: visual perception of experienced and inexperienced readers. AB - PURPOSE: To identify and compare key stages of the visual process in experienced and inexperienced readers and to examine how these processes are used to search a moving three-dimensional ( 3D three-dimensional ) image and their relationship to false-negative errors. MATERIALS AND METHODS: Institutional review board research ethics approval was granted to use anonymized computed tomographic (CT) colonographic data from previous studies and to obtain eye-tracking data from volunteers. Sixty-five radiologists (27 experienced, 38 inexperienced) interpreted 23 endoluminal 3D three-dimensional CT colonographic videos. Eye movements were recorded by using eye tracking with a desk-mounted tracker. Readers indicated when they saw a polyp by clicking a computer mouse. Polyp location and boundary on each video frame were quantified and gaze data were related to the polyp boundary for each individual reader and case. Predefined metrics were quantified and used to describe and compare visual search patterns between experienced and inexperienced readers by using multilevel modeling. RESULTS: Time to first pursuit was significantly shorter in experienced readers (hazard ratio, 1.22 [95% confidence interval: 1.04, 1.44]; P = .017) but other metrics were not significantly different. Regardless of expertise, metrics such as assessment, identification period, and pursuit times were extended in videos where polyps were visible on screen for longer periods of time. In 97% (760 of 787) of observations, readers correctly pursued polyps. CONCLUSION: Experienced readers had shorter time to first eye pursuit, but many other characteristics of eye tracking were similar between experienced and inexperienced readers. Readers pursued polyps in 97% of observations, which indicated that errors during interpretation of 3D three-dimensional CT colonography in this study occurred in either the discovery or the recognition phase, but rarely in the scanning phase of radiologic image inspection. PMID- 25028783 TI - Radiologic-pathologic analysis of contrast-enhanced and diffusion-weighted MR imaging in patients with HCC after TACE: diagnostic accuracy of 3D quantitative image analysis. AB - PURPOSE: To evaluate the diagnostic performance of three-dimensional ( 3D three dimensional ) quantitative enhancement-based and diffusion-weighted volumetric magnetic resonance (MR) imaging assessment of hepatocellular carcinoma ( HCC hepatocellular carcinoma ) lesions in determining the extent of pathologic tumor necrosis after transarterial chemoembolization ( TACE transarterial chemoembolization ). MATERIALS AND METHODS: This institutional review board approved retrospective study included 17 patients with HCC hepatocellular carcinoma who underwent TACE transarterial chemoembolization before surgery. Semiautomatic 3D three-dimensional volumetric segmentation of target lesions was performed at the last MR examination before orthotopic liver transplantation or surgical resection. The amount of necrotic tumor tissue on contrast material enhanced arterial phase MR images and the amount of diffusion-restricted tumor tissue on apparent diffusion coefficient ( ADC apparent diffusion coefficient ) maps were expressed as a percentage of the total tumor volume. Visual assessment of the extent of tumor necrosis and tumor response according to European Association for the Study of the Liver ( EASL European Association for the Study of the Liver ) criteria was performed. Pathologic tumor necrosis was quantified by using slide-by-slide segmentation. Correlation analysis was performed to evaluate the predictive values of the radiologic techniques. RESULTS: At histopathologic examination, the mean percentage of tumor necrosis was 70% (range, 10%-100%). Both 3D three-dimensional quantitative techniques demonstrated a strong correlation with tumor necrosis at pathologic examination (R(2) = 0.9657 and R(2) = 0.9662 for quantitative EASL European Association for the Study of the Liver and quantitative ADC apparent diffusion coefficient , respectively) and a strong intermethod agreement (R(2) = 0.9585). Both methods showed a significantly lower discrepancy with pathologically measured necrosis (residual standard error [ RSE residual standard error ] = 6.38 and 6.33 for quantitative EASL European Association for the Study of the Liver and quantitative ADC apparent diffusion coefficient , respectively), when compared with non- 3D three-dimensional techniques ( RSE residual standard error = 12.18 for visual assessment). CONCLUSION: This radiologic-pathologic correlation study demonstrates the diagnostic accuracy of 3D three-dimensional quantitative MR imaging techniques in identifying pathologically measured tumor necrosis in HCC hepatocellular carcinoma lesions treated with TACE transarterial chemoembolization . PMID- 25028784 TI - Sex-based prognostic implications of nonobstructive coronary artery disease: results from the international multicenter CONFIRM study. AB - PURPOSE: To determine the clinical outcomes of women and men with nonobstructive coronary artery disease ( CAD coronary artery disease ) with coronary computed tomographic (CT) angiography data in patients who were similar in terms of CAD coronary artery disease risk factors, angina typicality, and CAD coronary artery disease extent and distribution. MATERIALS AND METHODS: Institutional review board approval was obtained for all participating sites, with either informed consent or waiver of informed consent. In a prospective international multicenter cohort study of 27 125 patients undergoing coronary CT angiography at 12 centers, 18 158 patients with no CAD coronary artery disease or nonobstructive (<50% stenosis) CAD coronary artery disease were examined. Men and women were propensity matched for age, CAD coronary artery disease risk factors, angina typicality, and CAD coronary artery disease extent and distribution, which resulted in a final cohort of 11 462 subjects. Nonobstructive CAD coronary artery disease presence and extent were related to incident major adverse cardiovascular events ( MACE major adverse cardiovascular events ), which were inclusive of death and myocardial infarction and were estimated by using multivariable Cox proportional hazards models. RESULTS: At a mean follow-up +/- standard deviation of 2.3 years +/- 1.1, MACE major adverse cardiovascular events occurred in 164 patients (0.6% annual event rate). After matching, women and men experienced identical annualized rates of myocardial infarction (0.2% vs 0.2%, P = .72), death (0.5% vs 0.5%, P = .98), and MACE major adverse cardiovascular events (0.6% vs 0.6%, P = .94). In multivariable analysis, nonobstructive CAD coronary artery disease was associated with similarly increased MACE major adverse cardiovascular events for both women (hazard ratio: 1.96 [95% confidence interval { CI confidence interval }: 1.17, 3.28], P = .01) and men (hazard ratio: 1.77 [95% CI confidence interval : 1.07, 2.93], P = .03). CONCLUSION: When matched for age, CAD coronary artery disease risk factors, angina typicality, and nonobstructive CAD coronary artery disease extent, women and men experience comparable rates of incident mortality and myocardial infarction. PMID- 25028786 TI - Complications of tuberculosis. AB - PURPOSE OF REVIEW: Diagnosis and management of tuberculosis (TB) remains challenging and complex because of the heterogeneity of disease presentations. Despite effective treatment, TB disease can lead to significant short-and long term health consequences. We review potential acute and chronic complications of TB disease and current management approaches. RECENT FINDINGS: Acute and subacute complications of TB disease are attributable to structural damage or vascular compromise caused by Mycobacterium tuberculosis, as well as metabolic abnormalities and host inflammatory responses. TB-related sepsis is a life threatening acute complication for which current diagnostic and management approaches are likely inadequate. Therapeutic intensification and usage of immunomodulators are areas of ongoing research. Paradoxical reaction or symptom worsening during TB treatment may benefit from corticosteroids. Despite successful cure of TB, chronic complications can arise from anatomic alterations at disease sites. Examples include mycetomas developing within residual TB cavities, impaired pulmonary function, or focal neurologic deficits from tuberculomas. SUMMARY: Effective management of TB requires attention to potential structural, metabolic, vascular, and infectious complications. In some instances, individualizing treatment regimens may be necessary. Imunosuppression and other host factors predispose to complications; others occur despite adequate treatment. Public health TB programs and health systems require additional resources to provide comprehensive TB and post-TB care. PMID- 25028787 TI - Anti-C1q in chronic hepatitis C virus genotype IV infection: association with autoimmune rheumatologic manifestations. AB - A growing body of evidence suggests that anti-complement-1q (anti-C1q) antibodies are elevated in a variety of autoimmune disease. Therefore, we investigated their prevalence and clinical significance in plasma of patients with hepatitis C virus (HCV) genotype IV in the presence and absence of autoimmune extra hepatic manifestations in comparison to normal healthy individuals. Plasma Anti-C1q Abs levels were assessed by an Enzyme Linked Immunosorbant Assay in 91 chronic HCV infected patients (51 with and 40 without autoimmune rheumatic manifestations) and 40 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. Positive Anti C1q antibodies were more frequent among HCV patients with extra-hepatic autoimmune involvement, than those without and healthy control subjects. No significant correlations were found between Anti-C1q levels with either the liver activity or the fibrosis scores. In HCV-patients with autoimmune involvements, plasma Anti-C1q levels were significantly higher in patients with positive cryoglobulin, and in those with lymphoma than in those without. These results were confirmed by multivariate analysis. Further large scale longitudinal studies are required to assess and clarify the significance and the pathogenic role of anti-C1q antibodies among HCV infected patients with positive cryoglobulinaemia and lymphoma. PMID- 25028788 TI - Pd-containing organopolyoxometalates derived from Dawson polyoxometalate [P2W15V3O62]9-: Lewis acidity and dual site catalysis. AB - Grafting of a palladium complex to the Dawson vanadotungstate polyanion [P2W15V3O62](9-) via an organic ligand generates a large family of pincer-type hybrid polyoxometalates. The palladium-POM derivatives have dual catalytic properties. Unlike their parent inorganic polyanions, they catalyze allylations while retaining their oxidant character, which leads to single-pot dual site catalysis. This opens a new route for multicatalytic reactions. PMID- 25028789 TI - The complete mitochondrial genome of the hybrid of Culter alburnus (?) * Ancherythroculter nigrocauda (?). AB - In this study, the complete mitochondrial genome sequence of the hybrid of Culter alburnus (?) * Ancherythroculter nigrocauda (?) was determined and analyzed for the first time. The total length of the mitogenome is 16,621 bp, with the base composition of 31.20% A, 24.78% T, 27.78% C, and 16.24% G. It contains the typical structure as that of most other vertebrates, including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 main non-coding regions (the origin of the light strand replication and the control region). The complete mitogenome of the hybrid of C. alburnus (?) * A. nigrocauda (?) provides an important data set for study in mitochondrial inheritance mechanism. PMID- 25028790 TI - The complete mitochondrial genome of the North Chinese Leopard (Panthera pardus japonensis). AB - The North Chinese Leopard (Panthera pardus japonensis) is an endemic subspecies of Panthera pardus to China, living in small and isolated populations with a severely fragmented distribution. Here we first sequenced and annotated its complete mitochondrial genome. The total length of the North Chinese Leopard is of 16,966 base pairs that consist of 2 rRNA gene, 22 tRNA genes, 13 protein coding genes, 1 OLR and 1 control region (CR). The structures of the genomes were highly similar to other Felidae. PMID- 25028791 TI - Single nucleotide polymorphisms in the mitochondrial displacement loop and age-at onset of epithelial ovarian cancer. AB - OBJECTIVE: The accumulation of the single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) has been reported in many types of cancers. And the association with the risk and prognosis of cancers also has been described extensively. In the present study, we investigated the association between the age-at onset and SNPs in the D-loop of mitochondria DNA (mtDNA) using a population-based series of primary epithelial ovarian cancer (EOC) patients. METHODS: The D-loop region of mtDNA samples from blood were obtained from 89 patients with primary EOC, who underwent surgery. The age-at-onset curves were calculated by Kaplan-Meier method and compared by the log-rank test. RESULTS: The SNP sites of nucleotide 248, 524 and 16,304 alleles were identified for their association with age-at-onset by the log-rank test. The age-at-onset of patients with the minor allele 248 G was lower than that of patients with 248 A. The same was seen for the rare allele 16,304 T genotype when compared with matched allele 16,304 C at the 16,304 site. But the age-at-onset of patients with the minor allele 524 C was higher than that of patients with frequent 524 deletions. CONCLUSION: Genetic polymorphisms in the D-loop are the predictive markers for age-at-onset in EOC patients. Accordingly, the analysis of genetic polymorphisms may help identify EOC patient subgroups at high risk of early onset. PMID- 25028792 TI - Relation between vitamin D status and body composition in collegiate athletes. AB - Excess body fat or obesity is known to increase risk of poor vitamin D status in nonathletes but it is not known if this is the case in athletes. Furthermore, the reason for this association is not understood, but is thought to be due to either sequestration of the fat-soluble vitamin within adipose tissue or the effect of volume dilution related to obese individuals' larger body size. Forty two US college athletes (24 men 18 women, 20.7 +/- 1.6 years, 85.0 +/- 28.7 kg, BMI = 25.7 +/- 6.1 kg/m2) provided blood samples during the fall and underwent measurement of body composition via dual energy X-ray absorptiometry. Serum samples were evaluated for 25-hydroxyvitamin D (25(OH)D) concentration to assess vitamin D status using Diasorin 25(OH)D radioiodine assay. Serum 25(OH)D concentration was negatively associated with height (r = -0.45), total body mass (r = -0.57), BMI (r = -0.57), body fat percentage (r = -0.45), fat mass (r = 0.60) and fat-free mass (r = -0.51) (p < .05). These associations did not change after controlling for sex. In a linear regression mixed model, fat mass (coefficient -0.47, p = .01), but not fat-free mass (coefficient -0.18, p = .32) significantly predicted vitamin D status and explained approximately 36% of the variation in serum 25(OH)D concentration. These results suggest that athletes with a large body size and/or excess adiposity may be at higher risk for vitamin D insufficiency and deficiency. In addition, the significant association between serum 25(OH)D concentration and fat mass in the mixed model, which remained after controlling for sex, is in support of vitamin D sequestration rather than volume dilution as an explanation for such association. PMID- 25028793 TI - Lipoapoptosis pathways in pancreatic beta-cells and the anti-apoptosis mechanisms of adiponectin. AB - Lipoapoptosis is the main form of pancreatic beta-cell death in diabetes. Adiponectin is an adipocyte-derived hormone, which has anti-apoptosis effect in numerous cells. The present study was designed to explore the role of the 'extrinsic' (death receptor-induced) and the 'intrinsic' (mitochondrial) pathways in pancreatic beta-cell lipoapoptosis and the anti-apoptosis effect of adiponectin on pancreatic beta-cells. Palmitate (0.4 mmol/l) or oleate (0.4 mmol/l) was used to induce the apoptosis of Min 6 cells for 24 h. Z-LETD-FMK or Z IEHD-FMK (40 MUM) was used to inhibit the activity of caspase-8 or -9. When adiponectin was used, Min 6 cultures were pretreated in the absence or presence of fAd (5 MUg/ml) for 2 h and then subjected to palmitate for 24 h. Apoptosis was evaluated using Annexin V-Cy3 kit. The expression levels of cleaved caspase-3, 8, -9, B-cell lymphoma 2 (BCL-2), and Bax were examined by Western blotting. Palmitate-induced pancreatic beta-cell apoptosis was accompanied by the activation of caspase-8, -9, and -3. Blockade of caspase-9 rather than caspase-8, showed an inhibitory effect on caspase-3 activation. Moreover, adiponectin treatment prevented palmitate-induced apoptosis by inhibition of caspase-9 activation, but not of caspase-8, and induced an upregulation of BCL-2 and a downregulation of Bax in protein level. Both extrinsic and intrinsic pathways are activated in pancreatic beta-cell lipoapoptosis, and the intrinsic apoptosis pathway is the major one. Adiponectin prevents pancreatic beta-cells from apoptosis by inhibition of intrinsic apoptosis pathway via regulation of the BCL2 family. Therefore, protection of intrinsic apoptosis pathway is a potential therapeutic strategy for diabetes. PMID- 25028794 TI - Cyclic AMP/PKA-promoted apoptosis: insights from studies of S49 lymphoma cells. AB - Increases in cyclic AMP (cAMP) are pro-apoptotic in numerous cell types, but the mechanisms of cAMP-promoted apoptosis are poorly defined. We have used murine S49 T-lymphoma cells as a model to provide insight into these mechanisms. Increases in cAMP in wild-type (WT) S49 cells were first noted to kill these cells in the 1970 s, but only in recent years, it was shown that this occurs by the intrinsic (mitochondria-dependent) apoptotic pathway. The apoptotic response does not occur in protein kinase A-null (kin-) clonal variants of WT S49 cells and thus is mediated by protein kinase A (PKA). A second S49 clonal variant, cAMP-Deathless (D-), has PKA activity but lacks cAMP-promoted apoptosis. Apoptosis in WT S49 cells occurs many hours after cAMP/PKA-promoted G1 cell cycle arrest and involves increased expression of Bim, a pro-apoptotic member of the Bcl-2 (B-cell lymphoma 2) family. This increase in Bim expression does not occur in kin- or D- S49 cells and knockdown of Bim blunts cAMP-mediated apoptosis in WT cells. Cytotoxic T lymphocyte antigen-2 also appears to contribute to cAMP/PKA-promoted apoptosis of S49 cells. Based on time-dependent differences in gene expression between WT, D- and kin- S49 cells following incubation with 8-(4-chlorophenylthio)-cAMP, additional genes and proteins are likely involved in this apoptosis. Studies with S49 cells should reveal further insight regarding the mechanisms of cAMP/PKA promoted cell death, including the identification of proteins that are targets to enhance (e. g., in cancer) or inhibit (e. g., cardiac failure) apoptosis in response to hormones, neurotransmitters, and drugs. PMID- 25028795 TI - In vitro antitumor activity of stellettin B, a triterpene from marine sponge Jaspis stellifera, on human glioblastoma cancer SF295 cells. AB - Stellettin B was isolated from marine sponge Jaspis stellifera. In vitro antitumor activities were investigated on 39 human cancer cell lines. Stellettin B exhibited highly potent inhibition against the growth of a human glioblastoma cell line SF295, with a GI50 of 0.01 MUM. In contrast, stellettin B showed very weak inhibitory activity on normal cell lines including HMEC, RPTEC, NHBE and PrEC, with GI50s higher than 10 MUM, suggesting its relatively selective cytotoxicity against human cancer cells compared to normal human cell lines. We then focused on the antitumor activity of this compound on SF295 cells. Flow cytometric analysis indicated that stellettin B induced apoptosis in SF295 cells in a concentration-dependent manner. Further study indicated that stellettin B increased the production of ROS, the activity of caspase 3/7, as well as the cleavage of PARP, each of which is known to be involved in apoptosis. To investigate the molecular mechanism for cell proliferation inhibition and apoptosis induction, effect on the phosphorylation of several signal proteins of PI3K/Akt and RAS/MAPK pathways was examined. Stellettin B inhibited the phosphorylation of Akt potently, with no activity on p-ERK and p-p38, suggesting that inhibition of PI3K/Akt pathway might be involved in the antiproliferative and apoptosis-inducing effect. However, homogenous time-resolved fluorescence (HTRF) assay indicated that stellettin B did not inhibit PI3K activity, suggesting that the direct target might be signal protein upstream of Akt pathway other than PI3K. PMID- 25028797 TI - A novel resorbable strontium-containing alpha-calcium sulfate hemihydrate bone substitute: a preparation and preliminary study. AB - Distraction osteogenesis after aggrieved bone segment resections is promising in the treatment of bone tumors and osteomyelitis. However, there is ambiguity with regard to the optimal choice of bone substitute, with biodegradability and excellent bone repair performance constituting key requirements. The purpose of this study was to develop a novel resorbable strontium-containing alpha-calcium sulfate hemihydrate (Sr-CaS) bone substitute to provide an alternative option for surgeons that better meets these requirements. The Sr-CaS was prepared using co precipitation and hydrothermal methods and analyzed using x-ray diffraction (XRD), Fourier transform infrared (FTIR) scanning and thermogravimetric differential scanning calorimeter (TG-DSC) patterns. Cytotoxicity by tetrazolium bromide (MTT), sub-acute toxicity and hemolysis tests were performed to assess the initial biocompatibility of the new bone substitute. Radiographic analysis, micro-CT measurements and histological observation were used to evaluate the bone repair ability in rat tibia bone defects. The XRD and FTIR patterns of Sr-CaS were both very similar to CaS and the product had comparable characteristics similar to alpha-CaS as demonstrated by TG-DSC. Cytotoxicity of the substitute was class 1 (no cytotoxicity) and hemolysis was 4.3% (no hemolysis). Sub-acute toxicity was not seen after a 14 day evaluation. The substitute was radio-opaque. The empty group exhibited the lowest levels of both bone mineral densities (BMD) and bone volume/total volume (BV/TV) of the defects when compared to all other groups. The two Sr-CaS groups resulted in significantly greater BMDs and BV/TV of the defect compared to the CaS only group. However, there was no significant difference between the 5% and 10% Sr-CaS groups. The Sr-CaS was resorbable with satisfactory biocompatibility. The doped strontium ions enhanced the bone repair performance of CaS in a rat model and the new substitute demonstrated promising results for clinical use. PMID- 25028796 TI - Fucoxanthin enhances the level of reduced glutathione via the Nrf2-mediated pathway in human keratinocytes. AB - Fucoxanthin, a natural carotenoid, is abundant in seaweed with antioxidant properties. This study investigated the role of fucoxanthin in the induction of antioxidant enzymes involved in the synthesis of reduced glutathione (GSH), synthesized by glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS), via Akt/nuclear factor-erythroid 2-related (Nrf2) pathway in human keratinocytes (HaCaT) and elucidated the underlying mechanism. Fucoxanthin treatment increased the mRNA and protein levels of GCLC and GSS in HaCaT cells. In addition, fucoxanthin treatment promoted the nuclear translocation and phosphorylation of Nrf2, a transcription factor for the genes encoding GCLC and GSS. Chromatin immune-precipitation and luciferase reporter gene assays revealed that fucoxanthin treatment increased the binding of Nrf2 to the antioxidant response element (ARE) sequence and transcriptional activity of Nrf2. Fucoxanthin treatment increased phosphorylation of Akt (active form), an up-regulator of Nrf2 and exposure to LY294002, a phosphoinositide 3-kinase (PI3K)/Akt inhibitor, suppressed the fucoxanthin-induced activation of Akt, Nrf2, resulting in decreased GCLC and GSS expression. In accordance with the effects on GCLC and GSS expression, fucoxanthin induced the level of GSH. In addition, fucoxanthin treatment recovered the level of GSH reduced by ultraviolet B irradiation. Taken together, these findings suggest that fucoxanthin treatment augments cellular antioxidant defense by inducing Nrf2-driven expression of enzymes involved in GSH synthesis via PI3K/Akt signaling. PMID- 25028798 TI - Chronic lack of sleep is associated with increased sports injuries in adolescent athletes. AB - BACKGROUND: Much attention has been given to the relationship between various training factors and athletic injuries, but no study has examined the impact of sleep deprivation on injury rates in young athletes. Information about sleep practices was gathered as part of a study designed to correlate various training practices with the risk of injury in adolescent athletes. METHODS: Informed consent for participation in an online survey of training practices and a review of injury records was obtained from 160 student athletes at a combined middle/high school (grades 7 to 12) and from their parents. Online surveys were completed by 112 adolescent athletes (70% completion rate), including 54 male and 58 female athletes with a mean age of 15 years (SD=1.5; range, 12 to 18 y). The students' responses were then correlated with data obtained from a retrospective review of injury records maintained by the school's athletic department. RESULTS: Multivariate analysis showed that hours of sleep per night and the grade in school were the best independent predictors of injury. Athletes who slept on average <8 hours per night were 1.7 times (95% confidence interval, 1.0-3.0; P=0.04) more likely to have had an injury compared with athletes who slept for >=8 hours. For each additional grade in school, the athletes were 1.4 times more likely to have had an injury (95% confidence interval, 1.2-1.6; P<0.001). CONCLUSION: Sleep deprivation and increasing grade in school appear to be associated with injuries in an adolescent athletic population. Encouraging young athletes to get optimal amounts of sleep may help protect them against athletic injuries. LEVEL OF EVIDENCE: Level III. PMID- 25028799 TI - Percutaneous screw fixation promotes healing of lateral condyle nonunion in children. AB - BACKGROUND: This retrospective study examined whether pediatric lateral condyle nonunions could be successfully managed by percutaneous screw fixation. We report the outcome of this minimally invasive technique avoiding open reduction and bone grafting associated with the risk of avascular necrosis (AVN), infection, and stiffness. METHODS: The hospital radiology database was searched between 1998 and 2008. This identified 16 consecutive patients aged 2 to 10 years, with lateral condyle nonunions treated with percutaneous screw fixation. We assessed clinical and radiographic outcomes from presentation to final follow-up. Potential risk factors for recalcitrant nonunion were identified. Categorical variables are presented as proportions and percentages. Continuous variables were assessed for normality with the d'Agostino-Pearson test. Normally distributed variables are presented as means with 1 SD. Non-normally distributed data are presented as medians with interquartile range. RESULTS: Outcome was defined as successful if radiologic and clinical union was achieved. Twelve patients (75%) united after surgery, at a mean of 16.2 weeks (+/-6.74). Four (25%) failed to unite. The failures presented with nonunion later (median of 225.5 wk from initial injury). This was significantly different (P=0.039) from presentation in the successful group (median time 15.7 wk).Median age at injury was 5.1 years (range, 3.2 to 7.2) in the successful and 2.8 years (range, 2.1 to 4.7) in the unsuccessful group (P=0.18). Overall, mean time from nonunion diagnosis to percutaneous surgery was 5.2 weeks (+/-4.11). Forty-four percent had implant removal once union was achieved and no cases of AVN were reported. CONCLUSIONS: We demonstrate this technique to be successful in nonunions addressed within 16 weeks from initial injury to diagnosis. Our 4 failures occurred in nonunions diagnosed >31 weeks from the injury (31, 68, 383, 427 wk). All had been managed nonoperatively as their primary treatment plan.Percutaneous fixation is feasible and safe. Patients not achieving union were diagnosed after a greater delay. There was a trend toward successfully treated patients being younger. There were no cases of AVN, infection, or elbow stiffness. LEVEL OF EVIDENCE: Level 4. PMID- 25028800 TI - Is there a role for the 5-degree rule in adolescent idiopathic scoliosis? AB - BACKGROUND: Nonstructural curves are defined in the Lenke classification system for adolescent idiopathic scoliosis as bending out to <25 degrees. A caveat in the original paper states, however, that if the difference in Cobb magnitude between the major and minor curves is <5 degrees, then the minor curve should be considered structural, regardless of its Cobb magnitude. It is unclear whether following this rule affects patient outcomes. METHODS: A multicenter retrospective study using a prospectively collected database was performed on surgical adolescent idiopathic scoliosis patients, with 2 years of minimum follow up. All the lumbar curves measured <25 degrees on bending x-ray. Curves (major and minor) that were within <5 degrees of each other were analyzed in 2 treatment subsets: nonselective fusion (NS) and selective thoracic fusion (STF1), and compared with similar selective fusion cases with false double major curves with a lumbar curve between 5 and 10 degrees less in magnitude than the thoracic curve magnitude (STF2). Preoperative and 2-year postoperative radiographic and SRS-22 parameters were compared. RESULTS: Of 58 patients, there were 14 NS, 11 STF1, and 33 STF2. NS had larger preoperative curves than STF1, but achieved better lumbar correction (58%) than STF1 (32%) or STF2 (41%) (P=0.004). STF1 tended to have more preoperative coronal imbalance than STF2 (-2.26 vs. -1.12 cm) (P=0.066) but were similar at 2 years. Preoperative thoracic rib prominence measures were similar for all groups, but NS had significantly worse rib prominence than STF1 (NS: 8.4 vs. STF1: 4.4, P=0.046) at 2 years. There were no differences among the 3 groups in SRS-22 scores preoperatively and at 2 years. CONCLUSIONS: Almost half of the cases with curves within <5 degrees of each other did not follow the 5 degree rule, suggesting that there is variability among surgeons in their definition of what is truly structural. Selective thoracic fusion cases behaved similarly regardless of whether or not the curves were within 5 degrees of each other. The results of our analysis of the 5-degree caveat challenge its utility as a criterion for defining structural curves. LEVEL OF EVIDENCE: Level II. PMID- 25028801 TI - Cervical and vaginal fluid soluble Toll-like receptor 2 in pregnancies complicated by preterm prelabor rupture of membranes. AB - OBJECTIVE: To determine the cervical and vaginal fluid soluble Toll-like receptor 2 (sTLR2) levels in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) and their correlation to microbial invasion of the amniotic cavity (MIAC) and/or histological chorioamnionitis (HCA). METHODS: Sixty-eight women with singleton pregnancies complicated by PPROM were included in this study. Cervical and vaginal fluid was collected at the time of admission, and levels of sTLR2 in the cervical and vaginal fluid were determined using enzyme linked immunosorbent assay. RESULT: Women with MIAC and both MIAC and HCA did not have different cervical and vaginal fluid sTLR2 levels compared to those without MIAC and without both MIAC and HCA. Women with HCA had higher cervical fluid sTLR2 levels in crude analysis (with HCA: median 11.6 pg/mL versus without HCA: median 5.5 pg/mL; p = 0.04) but not after adjustment for gestational age at sampling (p = 0.19). No difference in vaginal fluid sTLR2 levels between women with and without HCA was found. A positive correlation between cervical and vaginal fluid sTLR2 levels was identified (rho = 0.54; p < 0.0001). CONCLUSIONS: Cervical and vaginal fluid sTLR2 levels did not reflect the presence of MIAC and/or HCA. PMID- 25028802 TI - Sepsis guideline implementation: benefits, pitfalls and possible solutions. AB - Clinical practice guidelines are useful in improving quality of care and outcomes, reducing inappropriate variation in practice, promoting efficient use of resources, informing and empowering patients and informing public policy. However, difficulties arise when guidelines are poorly introduced into routine daily practice and, as a consequence, many patients do not receive the care intended or receive harmful or unnecessary care. PMID- 25028803 TI - Tethered protein display identifies a novel Kir3.2 (GIRK2) regulator from protein scaffold libraries. AB - Use of randomized peptide libraries to evolve molecules with new functions provides a means for developing novel regulators of protein activity. Despite the demonstrated power of such approaches for soluble targets, application of this strategy to membrane systems, such as ion channels, remains challenging. Here, we have combined libraries of a tethered protein scaffold with functional selection in yeast to develop a novel activator of the G-protein-coupled mammalian inwardly rectifying potassium channel Kir3.2 (GIRK2). We show that the novel regulator, denoted N5, increases Kir3.2 (GIRK2) basal activity by inhibiting clearance of the channel from the cellular surface rather than affecting the core biophysical properties of the channel. These studies establish the tethered protein display strategy as a means to create new channel modulators and highlight the power of approaches that couple randomized libraries with direct selections for functional effects. Our results further underscore the possibility for the development of modulators that influence channel function by altering cell surface expression densities rather than by direct action on channel biophysical parameters. The use of tethered library selection strategies coupled with functional selection bypasses the need for a purified target and is likely to be applicable to a range of membrane protein systems. PMID- 25028804 TI - Is pharmacological, H2S-induced 'suspended animation' feasible in the ICU? PMID- 25028805 TI - Pharmacokinetics of anidulafungin during albumin dialysis. PMID- 25028806 TI - Retrospective study of endoscopic treatment in children with primary vesicoureteral reflux and multivariate analysis of factors for failure. AB - OBJECTIVE: The aim of this study was to investigate endoscopic treatment in children with primary vesicoureteral reflux (VUR) and conduct a multivariate analysis of factors for failure. MATERIAL AND METHODS: Between August 2006 and January 2012, 216 children (32 boys and 184 girls) with primary VUR (grades I-IV) who underwent endoscopic treatment were analysed. Patients with grade V VUR were excluded. Hydrodistension tests and intraureteral injection techniques were performed, if applicable. Urinary ultrasound and voiding cystourethrography were studied 3-6 months after surgery. Univariate and multivariate logistic regression were used for statistical analyses. RESULTS: In total, 172 children (21 boys and 151 girls) were enrolled, and 280 ureters were treated (108 bilateral, 64 unilateral; three with grade I, 34 with grade II, 214 with grade III and 29 with grade IV VUR). The median (+/- SD) age was 7.8 +/- 3.1 years (boys 7 +/- 3.1 years, girls 7.9 +/- 3.1 years). The mean (+/- SD) follow-up was 24.4 +/- 4.1 months (boys 28.2 +/- 8.1 months, girls 21.4 +/- 4.1 months). Mean injected volume per ureter was 1.8 +/- 0.5 ml. A single injection resolved the reflux in 79.6% and a second injection resolved it in 90.4% of ureters. Eight children (4.6%) had postoperative febrile urinary tract infections (fUTIs). Postoperative fUTIs were significantly associated with failures in injection (p < 0.001). Renal scars were significantly associated with postoperative fUTI (p = 0.006). Haematuria occurred in three children (minor complication); a non-functional kidney was observed in one child (major complication) and a laparoscopic nephrectomy was performed. Fourteen children underwent ureteroneocystostomy owing to unsuccessful VUR treatment. CONCLUSIONS: Endoscopic injection of small diameter microsphere (80-120 MUm) non-animal dextranomer-hyaluronic acid copolymer seems to be an effective treatment for VUR. Only postoperative fUTI and the presence of a renal scar were correlated with failed endoscopic treatment of VUR. PMID- 25028807 TI - Performance of transrectal prostate biopsies in detecting tumours and implications for focal therapy. AB - OBJECTIVE: The aim of this study was to investigate the performance of transrectal biopsies in predicting pathological outcomes after radical prostatectomy (RP) and in estimating possible candidates for focal therapies. MATERIAL AND METHODS: The study was a retrospective analysis of 96 prostate cancer patients treated by robot-assisted laparoscopic RP at Helsinki University Central Hospital in 2009-2010. Data from diagnostic biopsies were compared with data from reassessment of RP slides. At reanalysis, an index tumour was chosen for all patients and was determined as being the most dedifferentiated tumour or the largest tumour with Gleason pattern 3 in case Gleason patterns 4 or 5 were absent. The performance of prostate biopsies in predicting cancer laterality, tumour size and tumour location was analysed. Statistical methods included Spearman's correlation, linear regression analysis and Pearson's chi-squared test. Suitability for focal therapies was assessed based on tumour morphology and laterality. RESULTS: The extent of cancer in biopsies correlated with tumour size in the apex and middle of the prostate [standard coefficients in linear regression for the apex 2.479-2.553, 95% confidence interval (CI) 1.952-3.056, p < 0.001-0.007; and for the middle 1.936-2.388, 95% CI 1.504-2.861, p < 0.001]. Prostate biopsies performed moderately in predicting tumour location in RP slides (positive predictive value 34.1-90.9%). Thirty-six patients (37.5%) would possibly have been candidates for focal therapy and thirty-nine (40.6%) patients for hemiablation. CONCLUSIONS: Contemporary transrectal prostate biopsies are a suboptimal tool for predicting pathological findings at RP. Approximately 40% of patients would possibly have been suitable candidates for focal or hemiablative therapies. PMID- 25028809 TI - Gold nanorods-based FRET assay for ultrasensitive detection of DNA methylation and DNA methyltransferase activity. AB - A fluorescence method for the detection of DNA methylation and the assay of methyltransferase activity is proposed using gold nanorods as a fluorescence quencher on the basis of fluorescence resonance energy transfer. It is demonstrated that this method is capable of detecting methyltransferase with a detection limit of 0.25 U mL(-1), which might make this method a good candidate for monitoring DNA methylation in the future. PMID- 25028810 TI - The small GTPase Rap1 promotes cell movement rather than stabilizes adhesion in epithelial cells responding to insulin-like growth factor I. AB - The Ras-related GTPase Rap1 promotes cell adhesion and migration. Although the significance of Rap1 contribution to cell migration is increasingly being recognized, little is known about the biochemical mechanisms driving this process. In the present study, we discovered a previously unidentified regulatory role of insulin-like growth factor type I (IGF-I) receptor (IGF-IR) in CRK Src homology 3 (SH3)-binding guanine-nucleotide-releasing protein (C3G)-Rap1-fascin actin axis promoting cell movement. We demonstrate that a burst of Rap1 activity, rather than presumed hyperactivation, is imperative for the onset of cell movement. We show that while autophosphorylated IGF-IR signals to C3G to activate Rap1, subsequent IGF-IR internalization promotes gradual inactivation of Rap1 by putative Rap1 GTPase-activating protein (GAP). Additionally, IGF-IR signalling recruits active Rap1 at sites of cell motile protrusions. C3G depletion prevents IGF-I-induced fascin accumulation at actin microspikes and blocks protrusions. In the absence of IGF-IR activity, the wild-type (WT) Rap1 and the constitutively active V12Rap1 mutant remain in cell-cell contacts. Forced inactivation of Rap1 signalling by overexpressing dominant negative N17Rap1, Rap1GAP or by silencing C3G has a detrimental effect on filamentous (F)-actin and cell adhesion irrespective of IGF-IR signalling. We conclude that the basal levels of Rap1 activity holds up cell adhesion, whereas sequential regulation of C3G and GAP by IGF-IR reverses the labile Rap1 function from supporting adhesion to promoting migration. PMID- 25028813 TI - Quantifying the Contributions of a Flexor Digitorum Brevis Muscle on Postural Stability. AB - Surprisingly little attention has been devoted to the role played by the intrinsic muscles of the human foot. The aim of this study was to quantify the capabilities of the flexor digitorum brevis (FDB) muscle to contribute to upright postural control. The approaches consisted of analysis of the effects of FDB contraction elicited by external electrical stimulation and quantification of the magnitude of FDB torque generation. The results showed the FDB can produce significant changes in static posture by itself as shown by changes in the center of pressure. Moreover, the FDB contribution to counterbalance the gravity's toppling force was estimated at around 14.5% of the total required active torque at the ankle to keep the subject from falling. A posteriori functional analysis during horizontal perturbations showed high and self-sustained activity of FDB. These results demonstrated that the FDB has a significant capability of contributing to postural control. PMID- 25028814 TI - Dietary glutamine supplementation partly reverses impaired macrophage function resulting from overload training in rats. AB - The aim of this study was to evaluate the effect of overload training on the function of peritoneal macrophages in rats, and to test the hypothesis that glutamine in vivo supplementation would partly reverse the eventual functional alterations induced by overload training in these cells. Forty male Wistar rats were randomly divided into 5 groups: control group (C), overload training group (E1), overload training and restore one week group (E2), glutamine supplementation group (EG1), and glutamine-supplementation and restore 1-week group (EG2). All rats, except those placed on sedentary control were subjected to 11 weeks of overload training protocol. Blood hemoglobin, serum testosterone, and corticosterone of rats were measured. Moreover, the functions (chemotaxis, phagocytosis, cytokines synthesis, reactive oxygen species generation) of peritoneal macrophages were determined. Data showed that blood hemoglobin, serum testosterone, corticosterone and body weight in the overload training group decreased significantly as compared with the control group. Meanwhile, the chemotaxis capacity (decreased by 31%, p = .003), the phagocytosis capacity (decreased by 27%, p = .005), the reactive oxygen species (ROS) generation (decreased by 35%, p = .003) and the cytokines response capability of macrophages were inhibited by overload training. However, the hindering of phagocytosis and the cytokines response capability of macrophages induced by overload training could be ameliorated and reversed respectively, by dietary glutamine supplementation. These results suggest that overload training impairs the function of peritoneal macrophages, which is essential for the microbicidal actions of macrophages. This may represent a novel mechanism of immunodepression induced by overload training. Nonetheless, dietary glutamine supplementation could partly reverse the impaired macrophage function resulting from overload training. PMID- 25028815 TI - Breast reconstruction with tissue expanders: implementation of a standardized best-practices protocol to reduce infection rates. AB - BACKGROUND: Periprosthetic infection remains a frustrating and costly complication of breast reconstruction with tissue expanders. Although some specific steps have been previously shown to reduce periprosthetic infections, no comprehensive protocol addressing all aspects of preoperative, intraoperative, and postoperative patient management has been evaluated in the literature. The authors' goal was to evaluate the effectiveness of their protocol at reducing periprosthetic infections. METHODS: A comprehensive, best-practices protocol was introduced and implemented in November of 2010. All patients undergoing breast reconstruction using tissue expanders at the authors' institution in the 5 years before the protocol, and in the 2 years after, were analyzed. RESULTS: Three hundred five patients underwent 456 tissue expander reconstructions in the 5 years before the protocol, and 198 patients underwent 313 reconstructions in the 2 years after. Significantly fewer patients developed periprosthetic infection after protocol (11.6 percent versus 18.4 percent; p=0.042), and the number of infected tissue expanders trended toward a decrease (9.3 percent versus 13.2 percent; p=0.097). On multivariate analysis, the protocol significantly reduced the odds of periprosthetic infection (OR, 0.45; p=0.022). Predictors of infection included obesity (OR, 2.01; p=0.045) and preoperative breast size larger than C cup (OR, 2.83; p=0.006). CONCLUSIONS: The authors' comprehensive, best-practices protocol allowed them to reduce the odds of tissue expander infections by 55 percent (OR, 0.45; p=0.022). The authors were able to identify several potential areas of improvement that may help them lower the rate of infection further in the future. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25028816 TI - Microvascular lifeboats: a stepwise approach to intraoperative venous congestion in DIEP flap breast reconstruction. AB - The deep inferior epigastric perforator (DIEP) flap is becoming a widely practiced method of autologous breast reconstruction. Although it has been shown to be a safe and reliable technique with acceptable morbidity, disadvantages include a comparatively higher incidence of venous congestion and total flap loss compared with autologous reconstruction with a pedicled or free transverse rectus abdominis myocutaneous flap. Venous congestion is reported in up to one-third of cases of breast reconstruction with a DIEP flap. If venous congestion is detected and addressed intraoperatively compared with postoperatively, outcomes are significantly improved. A wide variety of techniques have been introduced to augment venous drainage to treat congestion and prevent flap failure. Here, the authors offer a comprehensive review of techniques available to address intraoperative venous congestion in DIEP flaps for breast reconstruction. From this review, the authors propose a stepwise, algorithmic approach to diagnosing and treating this potentially devastating complication. PMID- 25028817 TI - Studies in fat grafting: Part II. Effects of injection mechanics on material properties of fat. AB - BACKGROUND: Although fat grafting can address many soft-tissue deficits, results remain inconsistent. In this study, the authors compared physical properties of fat following injection using an automated, low-shear device or the modified Coleman technique. METHODS: Lipoaspirate was obtained from nine patients and processed for injection using either a modified Coleman technique or an automated, low-shear device. Fat was passed through a 2-mm cannula and compared with minimally processed fat. A rheometer was used to measure the storage modulus and shear rate at which tissues began to lose their solid-like properties. Viscosity was also measured, and gross properties of treatment groups were evaluated qualitatively with a glass slide test. RESULTS: Fat injected through an automated, low-shear device closely matched physical properties of minimally processed fat. The storage modulus (G') of fat for the device group was greater than for the modified Coleman group, and the onset of breakdown was delayed. Similarly, viscosity measurement of fat from the automated device closely matched minimally processed fat and was greater than that of othe modified Coleman group. CONCLUSIONS: The physical properties of lipoaspirate processed using an automated, low-shear device with a 2-mm cannula preserved the intactness of fat more than the modified Coleman technique. The authors' rheologic data demonstrate less damage using an automated device compared with the modified Coleman technique and potentially support its use for improved fat graft integrity. PMID- 25028818 TI - Sterile inflammation after lymph node transfer improves lymphatic function and regeneration. AB - BACKGROUND: The aim of this study was to determine whether sterile inflammatory reactions can serve as a physiologic means of augmenting lymphangiogenesis in transplanted lymph nodes using a murine model. METHODS: The authors used their previously reported model of lymph node transfer to study the effect of sterile inflammation on lymphatic regeneration. Mice were divided into three groups: group 1 (controls) underwent lymphadenectomy followed by immediate lymph node transplantation without inflammation; group 2 (inflammation before transfer) underwent transplantation with lymph nodes harvested from donor animals in which a sterile inflammatory reaction was induced in the ipsilateral donor limb; and group 3 (inflammation after transfer) underwent transplantation with lymph nodes and then inflammation was induced in the ipsilateral limb. Lymphatic function, lymphangiogenesis, and lymph node histology were examined 28 days after transplantation and compared with those of normal lymph nodes. RESULTS: Animals that had sterile inflammation after transplantation (group 3) had significantly improved lymphatic function (>2-fold increase) on lympho scintigraphy, increased perinodal lymphangiogenesis, and functional lymphatics compared with the groups with no inflammation and inflammation before transplantation (p<0.01). Inflammation after transplantation was associated with a more normal lymph node architecture, expansion of B-cell zones, and decreased percentage of T cells compared with the other experimental groups. CONCLUSIONS: Sterile inflammation is a potent method of augmenting lymphatic function and lymphangiogenesis after lymph node transplantation and is associated with maintenance of lymph node architecture. Induction of inflammation after transplantation is the most effective method and promotes maintenance of normal lymph node B- and T-cell architecture. PMID- 25028819 TI - A modified V-Y chondromucosal composite flap for correction of secondary cleft nasal deformity: photogrammetric analysis of a case-control study. AB - BACKGROUND: Secondary cleft nasal deformity is a combination of the inherent cleft defects and the effects of operations to address the primary nasal deformity. The authors revisited a modified V-Y chondromucosal flap to restore symmetric nostril shape and balanced tip projection. METHODS: A retrospective case-control study of the senior author's (J.A.T.) experience with secondary cleft tip rhinoplasty using the V-Y chondromucosal flap was conducted. Preoperative and postoperative anteroposterior and worm's-eye photographs were compared by means of photogrammetric analysis. Results were compared with those of controls who had not undergone surgery. Interrater reliability was assessed using the Pearson coefficient. RESULTS: Seventeen cases and 24 controls were reviewed. Average age at repair was 9.3+/-3.6 years; average follow-up was 13 months. Interrater reliability was 0.98 overall. Photogrammetric analysis demonstrated postoperative increases in cleft-side columella length by 2.3 mm (p=0.0001) and nasal apex height by 1.3 mm (p=0.003); non-cleft-side measurements were statistically unchanged. Control measurements were similar across 1-year visit interval, and when compared with cases, patients undergoing tip rhinoplasty had significantly different cleft-side columella length postoperatively (increase of 2.31 mm versus 0.15 mm; p=0.0002) and nasal apex height (increase of 1.29 mm versus 0.17 mm; p=0.03). All other parameters remained comparable. No complications and no external nasal valve collapse were observed. CONCLUSIONS: In select patients, use of a V-Y chondromucosal flap increased cleft-side nasal tip projection and columellar height, improving overall nasal tip appearance. Although absolute width of the cleft alar base is unchanged, the cleft-side nostril is qualitatively more symmetric postoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25028820 TI - Evolution in minimal-incision palatoplasty: surgical technique and outcomes in 67 consecutive cases. AB - BACKGROUND: Conventional palatoplasty relies on extensive mucosal incisions and isolation of flaps on the palatine vessels to facilitate midline closure and velar reconstruction. This introduces substantial scarring, which has adverse effects on vascularity and growth. The authors have developed a minimally invasive palatoplasty technique that may have advantages over traditional techniques. The authors present their operative experience and outcomes when using the minimally invasive method paired with a novel cranial base maneuver for nasal mucosa closure. METHODS: Based on cadaveric dissections, the authors developed a modified minimal-incision approach that permits anatomical reconstruction from a midline approach. From 2003 to 2010, a retrospective review was performed on 67 consecutive minimal-incision palatoplasties. Cases requiring relaxing incision and/or conversion to other palatoplasty techniques were compared with minimal incision alone. RESULTS: Minimally invasive palatoplasty alone was able to be performed in 78 percent (n=52) of all cases. Fistula rates were 7.6 percent (n=4) in the minimally invasive palatoplasty group and 20 percent (n=3) in the relaxing/conversion group (p=0.04). Of patients requiring relaxing incisions/conversion, a higher percentage were syndromic (73 percent; p=0.01). Eighty-nine percent of all Veau class I defects were able to be successfully closed with the minimally invasive palatoplasty approach (p=0.01). CONCLUSIONS: Minimal-incision palatoplasty paired with a cranial base maneuver for nasal mucosa elevation results in adequate soft-tissue mobility and length to arrive at a tension-free closure. Fistula and velopharyngeal insufficiency rates are comparable to that of other techniques, and theoretical advantages of this technique will be borne out by longer term follow-up. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25028821 TI - Donor-recipient human leukocyte antigen matching practices in vascularized composite tissue allotransplantation: a survey of major transplantation centers. AB - BACKGROUND: Vascularized composite tissue allotransplant recipients are often highly sensitized to human leukocyte antigens because of multiple prior blood transfusions and other reconstructive operations. The use of peripheral blood obtained from dead donors for crossmatching may be insufficient because of life support measures taken for the donor before donation. No study has been published investigating human leukocyte antigen matching practices in this field. METHODS: A survey addressing human leukocyte antigen crossmatching methods was generated and sent to 22 vascularized composite tissue allotransplantation centers with active protocols worldwide. Results were compiled by center and compared using two-tailed t tests. RESULTS: Twenty of 22 centers (91 percent) responded to the survey. Peripheral blood was the most commonly reported donor sample for vascularized composite tissue allotransplant crossmatching [78 percent of centers (n=14)], with only 22 percent (n=4) using lymph nodes. However, 56 percent of the 18 centers (n=10) that had performed vascularized composite tissue allotransplantation reported that they harvested lymph nodes for crossmatching. Of responding individuals, 62.5 percent (10 of 16 individuals) felt that lymph nodes were the best donor sample for crossmatching. CONCLUSIONS: A slight majority of vascularized composite tissue allotransplant centers that have performed clinical transplants have used lymph nodes for human leukocyte antigen matching, and centers appear to be divided on the utility of lymph node harvest. The use of lymph nodes may offer a number of potential benefits. This study highlights the need for institutional review board-approved crossmatching protocols specific to vascularized composite tissue allotransplantation, and the need for global databases for sharing of vascularized composite tissue allotransplantation experiences. PMID- 25028822 TI - The first Smartphone application for microsurgery monitoring: SilpaRamanitor. AB - BACKGROUND: Postoperative monitoring of free flap tissue perfusion is vital. Devices available are expensive and complex to operate. Most surgeons rely on direct clinical observation. A monitoring system that is reliable, inexpensive, and easy to operate is needed. Using mobile phone technology, the authors developed and evaluated a new free flap monitoring system: SilpaRamanitor. METHODS: Software was developed for Android-operated mobile phones. Forty-two normal subjects were recruited to assess its effectiveness. Varying degrees of pressure were applied around the index finger to produce partial venous occlusion, partial arterial occlusion, complete venous occlusion, and complete arterial occlusion sequentially. Photographs of each subject's index and middle fingers were taken using the smartphone camera. To detect the abnormal perfusion presented on the index finger, the application was instructed to analyze photographs for color difference, with the unoccluded middle finger serving as the control. RESULTS: The sensitivity, specificity, accuracy, false-negative results, and false-positive results were 94, 98, 95, 6, and 1 percent, respectively. The accuracy of the application in grading occlusion severity was also evaluated. Thirty-nine cases (93 percent) were correctly identified as venous occlusion. The occlusion severity was correctly identified in 33 cases (85 percent). Likewise, for the 40 cases (95 percent) correctly identified as arterial occlusion, the method correctly categorized its severity in 33 cases (83 percent). CONCLUSIONS: The authors developed a new, accurate, and reliable diagnostic system for postoperative microsurgery monitoring using a smartphone application. SilpaRamanitor is inexpensive and easy to use, making it applicable in many microsurgical settings. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 25028823 TI - Predictive risk model of 30-day mortality in plastic and reconstructive surgery patients. AB - BACKGROUND: Death following surgical procedures, although uncommon, represents the most significant and costly postoperative complication. The authors delineate several key independently associated risk factors for 30-day mortality in a large nationwide plastic surgery population and generate a simple risk-assessment tool. METHODS: Patients who underwent a primary plastic surgery procedure (n=24,778) were identified from the 2005 to 2011 American College of Surgeons National Surgical Quality Improvement Program databases. Preoperative patient comorbidities and operative variables were analyzed to determine associations with mortality. Multivariate regression modeling and risk stratification were performed to generate a decision-support tool capable of assessing mortality risk. RESULTS: Seventy-eight patients (0.31 percent) experienced 30-day mortality. Age older than 65 years, inpatient surgery, hepatorenal disease, recent chemotherapy, and partial or dependent functional status were perioperative factors associated with 30-day mortality. A composite mortality risk score was used to stratify patients into groups of low (n=18,063) (30-day mortality, 0.06 percent), intermediate (n=1252) (30-day mortality, 0.96 percent), high (n=314) (30-day mortality, 5.10 percent), or extreme (n=126) (30-day mortality, 17.46 percent) risk. The scoring groups accurately separated risk (p<0.001) with a 291-fold variation between low- and extreme-risk patients (C statistic, 0.93). CONCLUSIONS: This study defines a 0.31 percent risk of perioperative 30-day mortality in a heterogeneous cohort of plastic surgery patients and identifies risk factors independently associated with 30-day mortality. These data can be used to tailor and improve informed consent, to optimize surgical decision-making, and to implement risk-reduction strategies in high-risk patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25028824 TI - Plastic and reconstructive surgery: a hybrid open-access medical journal. PMID- 25028825 TI - Reliability and reproducibility of landmarks on three-dimensional soft-tissue cephalometrics using different placement methods. AB - BACKGROUND: Affixing markers on the face in vivo with an optical surface imaging system and placing landmarks on a computed tomographic reconstructive facial model represent two helpful approaches prevailing in three-dimensional cephalometric analysis of facial aesthetics. In this study, the authors determine the suitability of these methods for soft-tissue evaluation along with the reproducibility and reliability of landmark placement. METHODS: Thirty-seven soft tissue landmarks were investigated in 35 normal healthy volunteers who underwent cephalometric analysis by direct and indirect placement methods. Two operators performed the analysis twice for each method at a 1-week interval. Landmark positions were measured on the three-dimensional coordinates, and data were standardized and converted into landmark placement errors for the estimation, by two-way random intraclass correlation coefficients. RESULTS: Using the direct method, 86.5 percent of the landmarks had a higher intraclass correlation coefficient than 0.75, and 67.6 percent were higher than 0.90. The authors found that 75.7 percent were higher than 0.75 and 43.2 percent were higher than 0.90 with the indirect method. Both methods showed good reliability in identifying midline-related structures, although the correlations of markers surrounding eyelashes and lips were better using the direct method. The direct method had a significantly smaller landmark placement error and better reproducibility than that identified indirectly (p<0.05). CONCLUSIONS: When evaluating well-defined contours and the natural texture of the face, the direct placement method shows better accuracy than the indirect method. The three-dimensional evaluation emphasizes the eye, lip, and some structures more laterally, therefore providing comprehensive analysis for clinical diagnosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 25028826 TI - Discussion: postmastectomy radiation therapy after immediate two-stage tissue expander/implant breast reconstruction: a university of british columbia perspective. PMID- 25028828 TI - Craniofacial syndromes. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Recognize the clinical presentations of commonly seen craniofacial syndromes. 2. Understand the most serious complications associated with each syndrome. 3. Formulate the best age-appropriate surgical plans. SUMMARY: Craniofacial syndromes fall into two major categories-those associated with craniosynostosis, and those associated with clefts. Each has a different set of potential complications requiring a unique approach for surgical management. Craniosynostosis is a congenital disorder in which one or more of the cranial sutures fuses prematurely. The most common syndromes associated with this condition include Crouzon, Apert, Pfeiffer, Muenke, and Saethre-Chotzen syndromes. Surgical management of these children requires a multidisciplinary approach and close involvement of the family. Operations must take into consideration the growing potential of the bony structures. Common syndromes associated with clefts include Pierre Robin, Treacher Collins, Nager, Binder, and Stickler syndromes. Many of these children have severe airway issues requiring immediate address before operative reconstruction. As with syndromes associated with craniosynostosis, the key to management is a multidisciplinary approach focused on the right timing. The purpose of this article is to review the clinical presentation, care, and treatment of these patients. PMID- 25028827 TI - Reconstruction of great toe soft-tissue defect with the retrograde-flow medial pedis island flap. AB - BACKGROUND: Several investigators have reported their clinical experience with medial pedis flaps for reconstruction of soft-tissue defects of the distal forefoot. However, they had only a few reports where this flap was used to repair soft-tissue defects of the great toe. Thus, reconstruction of soft-tissue defects of the great toe remains a challenge in reconstructive surgery. The authors describe the use of the medial pedis island flap to cover this region. METHODS: This study was divided into two parts: an anatomic study and clinical application. In the anatomic study, 48 cadaveric feet were injected with latex, and then the main vessels distributed at the medial aspect of the foot were observed. Clinically, retrograde-flow medial pedis island flaps were harvested to cover the soft-tissue defects of the great toe in eight cases. RESULTS: An anatomic study revealed that the arterial circle under the first metatarsophalangeal joint and the arterial network on the surface of the abductor hallucis were responsible for the blood supply of the medial region of the foot. The diameter of the pedicle was great, and the pedicle was longer than previously reported. In terms of clinical application, all flaps were successful, without any significant complications. CONCLUSIONS: Using the arterial circle under the first metatarsophalangeal joint, the medial pedis island flap has a reliable retrograde blood supply. This flap should be considered as a preferential way of reconstructing soft-tissue defects of the great toe. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 25028829 TI - Appropriate use of magnetic resonance imaging and ultrasound to detect early silicone gel breast implant rupture in postmastectomy reconstruction. AB - BACKGROUND: Implant rupture is one of the most important sequelae of breast reconstruction after mastectomy. The primary aim of this study was to compare magnetic resonance imaging and ultrasound evaluation with intraoperative findings and provide a reliable description of the occurrence of each radiological sign. METHODS: The authors prospectively recruited a consecutive series of 102 postmastectomy patients requiring implant change for aesthetic purposes. Magnetic resonance imaging and ultrasound evaluation results were compared with intraoperative findings. Sensitivity, specificity, positive predictive value, negative predictive value, and the overall accuracy of magnetic resonance imaging and ultrasound in detecting ruptured implants were calculated, along with their corresponding 95 percent confidence intervals. RESULTS: Magnetic resonance imaging performs better than ultrasound for diagnosis of breast implant rupture, with overall accuracies of 94 and 72 percent, respectively. The negative predictive value of ultrasound was 85 percent, meaning that in the case of negative ultrasound findings, magnetic resonance imaging may be avoided. Teardrop sign and water droplets are the most common findings on magnetic resonance imaging. CONCLUSIONS: Magnetic resonance imaging should be considered the method of choice for investigating silicone gel implant rupture in postmastectomy patients, and the standardization of magnetic resonance imaging criteria may improve magnetic resonance imaging accuracy. The authors therefore suggest a strategy of screening asymptomatic women with ultrasound every year and with magnetic resonance imaging every 5 years. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 25028830 TI - Lymphedema and obesity: is there a link? AB - Lymphedema is a chronic disorder that, in developed countries, occurs most commonly after lymph node dissection for cancer treatment. Although the pathophysiology of lymphedema is unknown, the disease is characterized histologically by fibrosis and abnormal adipose deposition. Clinical studies have provided evidence that obesity and postoperative weight gain are significant risk factors for the development of lymphedema. In fact, recent studies have shown that extreme obesity can result in markedly impaired lymphatic function and primary lymphedema. The aim of this Special Topic article is to review evidence linking obesity and lymphedema. In addition, the authors review recent studies that have analyzed the cellular mechanisms that may be responsible for this relationship, with a goal of highlighting areas of research that may have significant translational potential. PMID- 25028831 TI - Breast embryology and the double-bubble deformity. PMID- 25028832 TI - The incidence and management of secondary abdominoplasty and secondary abdominal contour surgery. PMID- 25028833 TI - Reply: the incidence and management of secondary abdominoplasty and secondary abdominal contour surgery. PMID- 25028834 TI - A novel murine model of hypertrophic scarring using subcutaneous infusion of bleomycin. PMID- 25028835 TI - Reply: a novel murine model of hypertrophic scarring using subcutaneous infusion of bleomycin. PMID- 25028836 TI - Le Fort III distraction using rotation advancement of the midface in patients with cleft lip and palate. PMID- 25028837 TI - Repair of bilateral incomplete cleft lip: techniques and outcomes. PMID- 25028838 TI - Assessing risk factors of respiratory complications following abdominal wall reconstruction. PMID- 25028839 TI - Reply: Assessing Risk Factors of Respiratory Complications following Abdominal Wall Reconstruction. PMID- 25028840 TI - Salvage of infected left ventricular assist device with antibiotic beads. PMID- 25028841 TI - Reply: salvage of infected left ventricular assist device with antibiotic beads. PMID- 25028842 TI - A comparison of vascularized cervical lymph node transfer with and without modified Charles' procedure for the treatment of lower limb lymphedema. PMID- 25028843 TI - Interpreting clinical differences in BREAST-Q scores: minimal important difference. PMID- 25028844 TI - A comparative study of postoperative patient-controlled analgesia use in latissimus dorsi and muscle-sparing latissimus dorsi flaps in breast reconstruction. PMID- 25028845 TI - A new approach for the treatment of unilateral coronal synostosis based on distraction osteogenesis. PMID- 25028846 TI - The value of innovation: face and hand transplantation programs at Brigham and Women's Hospital. PMID- 25028847 TI - Three-dimensional mock-up model for chondral framework in auricular reconstruction, built with a personal three-dimensional printer. PMID- 25028848 TI - Recycling the microanastomotic coupler. PMID- 25028849 TI - Chronic pain localized to the iliohypogastric nerve: treatment using an ultrasound-guided technique of hydrodissection for catheter placement as a guide for surgical iliohypogastric nerve resection. PMID- 25028850 TI - Postmastectomy radiation therapy after immediate two-stage tissue expander/implant breast reconstruction: a University of British Columbia perspective. AB - BACKGROUND: An increasing number of women who undergo immediate two-stage tissue expander/implant breast reconstruction will require postmastectomy radiation therapy. An important variable is the timing of radiotherapy relative to surgery. The authors report their experience treating a large consecutive series of patients who underwent postmastectomy radiation therapy to the tissue expander before exchange for a permanent implant. METHODS: Patients who had their tissue expander irradiated before implant exchange were identified. Complications, capsular contracture, revision surgery, and autologous salvage rates of irradiated patients were compared with a control group of nonirradiated patients. RESULTS: Immediate two-stage tissue expander/implant reconstruction was initiated in 604 patients, with 113 irradiated breasts meeting inclusion criteria. Three hundred thirty-nine nonirradiated breasts constituted the control group. There was a 4.2 increased odds of major complications in the irradiated group, after adjusting for plastic surgeon, age, body mass index, smoking, chemotherapy, and cancerous breast (OR, 4.2; p=0.001). The grade III and IV capsular contracture rate was significantly higher in the irradiated group compared with the control group (21.7 percent versus 10 percent; p<0.008). The revision rate in the control group was higher compared with the irradiated group (30.2 percent versus 20.9 percent; p<0.001). CONCLUSIONS: Postmastectomy irradiation to the tissue expander is associated with high complications; however, these patients have an acceptable capsular contracture rate that compares favorably with other implant-based radiotherapy algorithms. Revision rates were less than expected in irradiated breasts. This study suggests that immediate tissue expander/implant reconstruction is a reasonable surgical option in the setting of postmastectomy radiation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25028851 TI - Discussion: appropriate use of magnetic resonance imaging and ultrasound to detect early silicone gel breast implant rupture in postmastectomy reconstruction. PMID- 25028852 TI - Individualized Asian rhinoplasty: a systematic approach to facial balance. AB - BACKGROUND: Asian rhinoplasty, and rhinoplasty performed in other ethnic groups, remains a challenging operation for plastic surgeons. Precise clinical analysis and systematic planning preoperatively are widely accepted as the keys to success. Although a variety of analytical techniques have been published for other ethnic groups, a systematic approach for Asian rhinoplasty remains underrepresented in the current literature. METHODS: A systematic approach and a stepwise technique were developed concomitantly with concepts in facial balance and proper preoperative evaluation for Asian patients. A retrospective review of 110 cases in 4 years was performed to evaluate the effectiveness of this approach. RESULTS: Follow-up ranged from 6 to 48 months. Satisfactory results were achieved in 86 percent of cases. Typical cases were also reviewed. CONCLUSIONS: The systematic approach in Asian rhinoplasty presents a way to link appropriate analysis with specific techniques aimed at the subtleties of Asian rhinoplasty. This leads toward the individual's aesthetic goals. In the authors' experience, this approach allows for predictable and optimized results for this challenging procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25028853 TI - Discussion: individualized asian rhinoplasty: a systematic approach to facial balance. PMID- 25028854 TI - The impact of mastopexy on brassiere cup size. AB - BACKGROUND: Surgeon observation suggested that mastopexy alone resulted in decreased cup size. The purpose of this investigation was to assess change in cup size in women undergoing mastopexy alone. METHODS: A retrospective review of a single surgeon's experience from February of 2002 to May of 2011 was completed. Patients underwent mastopexy alone (specimen weight<150 g per side). Exclusion criteria were prior breast augmentation, implant removal at time of mastopexy, combination breast augmentation-mastopexy, and incomplete follow-up. Patients were surveyed by telephone regarding preoperative and postoperative cup size, changes in bra manufacturer, hormone status, and weight gain/loss, and data were analyzed. RESULTS: Sixty-one patients met inclusion criteria, and 20 completed the survey. Their average age was 46.6 years (range, 35 to 76 years) and average body mass index was 22.8 kg/m (range, 18.2 to 26.4 kg/m). Eighty percent (n=16) had grade II ptosis and 20 percent (n=4) had grade III ptosis preoperatively. Average specimen weight per breast was 57.8 g (range, 4 to 149 g). Patients reported an average decrease in cup size of 0.90 cup sizes (range, -3 to +2 cup sizes). Excluding one patient who reported an increase, an average decrease of 1.05 cup sizes (range, 0 to 3 cup sizes) was seen. No patients reported changing bra manufacturer. CONCLUSIONS: Mastopexy alone results in an average decrease in one brassiere cup size. This is important for preoperative counseling, because patients should recognize that their actual cup size is smaller than the brassiere they wear, which will be reflected postoperatively despite a relatively stable volume. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25028855 TI - Decreasing nasal tip projection in rhinoplasty. AB - BACKGROUND: Decreasing nasal tip projection is occasionally required in rhinoplasty and requires a working knowledge of nasal support and function. Equally important is an understanding of the evolution to a more conservative and incremental approach when decreasing nasal tip projection. Such a conservative approach reserves the most aggressive and precarious maneuvers to be used only when absolutely required. METHODS: The authors review the history and evolution of techniques regarding decrease in nasal tip projection. Anatomy of the nasal tip with focus on tip support structures is reviewed. Distinguishing between pseudo-overprojection and true overprojection of the nasal tip is discussed. Methods of diagnosing nasal tip projection are reviewed and a suggested surgical approach is presented. RESULTS: Reduction of nasal tip projection requires a thorough knowledge of relevant anatomy and tissue interplay. Although a variety of techniques and algorithms exist in addition to those recommended in this article, the goal should be an incremental approach with constant reassessment. Tip truncation is rarely if ever indicated and is often associated with eventual contour deformity. CONCLUSION: The described approach in this article has been proven reliable for the vast majority of patients undergoing rhinoplasty with the overprojected nose. PMID- 25028856 TI - The in vivo effect of esculetin ointment and esculetin-mixed Zyderm for Zyderm. AB - BACKGROUND: Injectable collagen is often used for treatment of wrinkles or scars in cosmetic surgery. However, it is degraded within a short period after subcutaneous injection. The authors aimed to achieve a long-lasting effect of the filler with a new collagenase inhibitor, esculetin (6,7-dihydroxy-2H-chromen-2 one). METHOD: Nude mice were divided into two study groups and a control group (35 mg cattle collagen): (1) those implanted with Zyderm 0.3 g subcutaneously into the dorsal region followed by daily topical application of 5% esculetin ointment (0.5 g/day) to the skin of the implanted area (the 5% esculetin ointment group), and (2) those implanted with a mixture of Zyderm 0.3 g and esculetin (1 to 4 mM) (the esculetin-mixed Zyderm groups). In each group, Zyderm was removed at different time points to measure the wet weight and hydroxyproline level. Furthermore, each removed Zyderm specimen was sectioned for histologic examination with Azan staining and immunostaining. RESULTS: In the esculetin ointment group and the 2 mM esculetin-mixed Zyderm group, the hydroxyproline levels at 30, 60, and 90 days were significantly higher than those in the control group, suggesting that esculetin suppresses the biodegradation of Zyderm. There was no significant difference in hydroxyproline level between the esculetin ointment group and the 2 mM esculetin-mixed Zyderm group; biodegradation occurred to a similar extent with either method of application. CONCLUSIONS: An atelocollagen implant is used as a safe and effective scaffold material for tissue regeneration. Future applications of the present study are expected. PMID- 25028857 TI - Osteoblastic differentiation of Wharton jelly biopsy specimens and their mesenchymal stromal cells after serum-free culture. AB - BACKGROUND: Cleft lip and cleft palate are increasingly being detected by prenatal ultrasound, which raises the opportunity of using the patient's own osteogenicity from umbilical cord mesenchymal cells for bony repair. The authors address the growth of the cells under a fully defined and regulated protocol. METHODS: Wharton jelly-derived mesenchymal stromal cells were isolated and expanded as a monolayer with defined serum-free medium. Osteoblastic differentiation was tested in the cells and in the entire Wharton jelly biopsy specimens. The serum-free-cultured cells were included in hydroxyapatite granule fibrin constructs and, without predifferentiation, subcutaneously implanted into immunoincompetent mice. RESULTS: Isolation and expansion of Wharton jelly-derived mesenchymal stromal cells were consistently successful under serum-free conditions, and the cells expressed standard mesenchymal stromal cell markers. The serum-free-cultivated cells produced a mineralized extracellular matrix under osteogenic differentiation, with a significant increase of osteoblastic lineage gene expression (Hox-A10 and Runx2) and an up-regulation of downstream osteogenic genes (OSX, OCN, ALPL, and BSP2). In vivo, they formed a dense matrix adjacent to the granules after 8 weeks, but no lamellar bone. serum-free-cultivated entire Wharton jelly biopsy specimens produced a mineralized extracellular matrix within the collagen matrix of the Wharton jelly. CONCLUSIONS: The osteogenic differentiation potential of Wharton jelly-derived mesenchymal stromal cells was maintained under serum-free isolation and expansion techniques. The cells without predifferentiation form a dense collagen matrix but not bone in vivo. Moreover, entire Wharton jelly biopsy specimens showed periosteal-like mineralization under osteogenic differentiation, which offers new options for autologous bone tissue engineering, including cleft palate surgery. PMID- 25028858 TI - Discussion: osteoblastic differentiation of wharton jelly biopsy specimens and their mesenchymal stromal cells after serum-free culture. PMID- 25028859 TI - Vascularization of the dorsal base of the second metacarpal bone: an anatomical study using C-arm cone beam computed tomography. AB - BACKGROUND: Vascularized bone grafts of the hand are a promising option for treatment of hand abnormalities. Therefore, the purpose of this study was to analyze the arterial anatomy of the dorsal aspect of the second metacarpal base to further investigate this possible donor site for bone grafts. METHODS: The authors examined 16 fresh frozen cadaveric hands by using a C-arm cone beam computed tomography scanner and depicted the three-dimensional course of the second dorsal metacarpal artery and measured the diameter, length, and arc of rotation of this nutritive vessel. In addition, the authors dissected six of the hands under a dissecting microscope and, after selective injection of gelatin dye solution, the authors analyzed the vessel entrances into the bones histologically. RESULTS: In all examined hands, the second dorsal metacarpal artery was a nutritive vessel to the dorsal base of the second metacarpal. The average diameter was 1.3+/-0.4 mm and the average length of the vascular pedicle was approximately 3.3+/-0.3 cm. In 14 of 16 cases, the arc of rotation was sufficient to reach the lunate without difficulty. Histologic analysis showed an intrinsic blood supply in the donor region with a vessel diameter of approximately 58 MUm. A clinical case with application in Kienbock disease is presented. CONCLUSION: Pedicled vascularized bone grafts from this area are suitable for clinical application to treat Kienbock disease if standard donor sites are unavailable. PMID- 25028860 TI - Craniectomy gap patency and neosuture formation following endoscopic suturectomy for unilateral coronal craniosynostosis. AB - BACKGROUND: The combination of endoscope-assisted suturectomy and postoperative helmet therapy has been advocated to treat unilateral coronal synostosis. However, surgical outcomes can vary. One possible explanation for this inconsistency is early closure of the craniectomy gap. The authors examined short term postoperative patency of the craniectomy gap and its relationship to phenotypic improvement. METHODS: A retrospective review was performed that included patients who (1) underwent endoscope-assisted suturectomy and postoperative helmet therapy for isolated unilateral coronal synostosis and (2) had preoperative and postoperative (>7 months) computed tomographic imaging. High resolution computed tomographic images were analyzed for craniectomy gap patency. RESULTS: Seventeen patients met the inclusion criteria. Mean age at operation was 2.5 months (range, 1.1 to 4.7 months). Mean duration of follow-up was 32.9 months (range, 10.6 to 64.9 months) and age at latest postsurgical computed tomography was 16.8 months (range, 7.5 to 40.9 months). Fifteen patients demonstrated "neosuture" formation and coronal patency on postoperative computed tomography. Three patients (17.6 percent) had complete formation of a normal-appearing coronal suture, whereas 12 patients (70.6 percent) had areas composed of both reformed suture and persistent craniectomy gap. These 15 patients demonstrated satisfactory phenotypic improvement and did not require subsequent procedures. The remaining two patients (11.8 percent) exhibited focal areas of refusion interspersed with areas of neosuture formation and persistent craniectomy gap. Both had poor phenotypic improvement; one underwent fronto-orbital advancement. CONCLUSION: Persistence of a craniectomy gap and neosuture formation are common early findings after endoscope-assisted suturectomy and postoperative helmet therapy and appear to correlate with better phenotypic improvement. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25028861 TI - Anatomy of the middle temporal vein: implications for skull-base and craniofacial reconstruction using free flaps. AB - BACKGROUND: Finding appropriate recipient veins for free flap reconstruction in the adjacent temporal region is sometimes difficult when performing skull base or craniofacial reconstruction because there is a limited number of recipient veins in the temporal region compared with the neck. The authors used cadaver dissection to evaluate the viability of the middle temporal vein as a recipient vein in the temporal region. METHODS: The authors examined the characteristics and landmarks of the middle temporal vein in 60 sides of 30 cadavers. Its existence, caliber size, distribution pattern, and landmarks for dissection were measured. RESULTS: The middle temporal vein was located beneath the superficial layer of the deep temporal fascia and joined the main trunk of the superficial temporal vein. The vein was identified in all specimens, and its mean caliber was 1.88 mm. It was classified into four representative distribution patterns. According to the distribution pattern, the middle temporal vein provided one recipient vein without exception, and only 13 percent of middle temporal veins could provide two recipient veins. According to landmarks, the middle temporal vein runs approximately along the line between 52 mm lateral from the bony lateral canthus and 12 mm medial from the external auditory canal. The mean distance between the middle temporal vein and the temporal branch of the facial nerve was 13 mm. CONCLUSIONS: The middle temporal vein can provide one recipient vein of adequate caliber in the temporal region. In addition, it can be easily localized, without damaging the facial nerve, by means of incision according to the landmarks described in this study. PMID- 25028862 TI - Stress: perspectives on its impact on cognition and pharmacological treatment. AB - Stress in life is unavoidable, affecting everyone on a daily basis. Psychological stress in mammals triggers a rapidly organized response for survival, but it may also cause a variety of behavioral disorders and damage cognitive function. Stress is associated with biases in cognitive processing; some of the most enduring memories are formed by traumatic events. Our understanding of how cognition is shaped by stress is still relatively primitive; however, evidence is rapidly accumulating that the 'mature' brain has a great capacity for plasticity and that there are numerous ways through which pharmacological therapeutics could rescue cognitive function and regain cognitive balance. In this review, we discuss recent advances in our understanding of the interplay between stress and cognitive processes and potential therapeutic approaches to stress-related behavioral and cognitive disorders. PMID- 25028863 TI - HDL-cholesterol is associated with systemic inflammation in cardiac syndrome X. AB - AIM: Microvascular inflammation is associated with cardiac syndrome X (CSX). High density lipoprotein cholesterol (HDL-C) reveals antiatherogenic features with stimulating endothelial NO production, inhibiting oxidative stress and vascular inflammation. We investigated relationship between HDL-C and inflammatory markers in CSX. METHODS: Hundred patients with CSX and control group of 80 subjects were evaluated. Hematologic indices, lipid levels and C-reactive protein (CRP) levels were studied in patients underwent coronary angiography. RESULTS: CRP levels were higher in CSX group than control group (4.59 +/- 3.82 mg/dL vs. 2.48 +/- 1.32 mg/dL, P<0.001). HDL-C was significantly lower in CSX group compared to control group (36.5 +/- 4.0 mg/dL vs. 47.5 +/- 12.7 mg/dL, P=0.008). White blood cell (WBC) count was higher in CSX group than in control group. Neutrophil-lymphocyte ratio (NLR) was found significantly increased in CSX group as compared to control group. On multivariate linear regression, lower HDL-C was found to be a significant predictor of higher NLR in patients with CSX independent from other clinical and biochemical variables. CONCLUSION: Lower HDL-C is associated with systemic inflammation in CSX. In patients with typical angina and normal epicardial coronaries,HDL-C and inflammatory markers should be investigated; one of the goals of treatment should be raising HDL-C. PMID- 25028864 TI - Contrast enhancement and elastography in endoscopic ultrasound: an overview of clinical applications in pancreatic diseases. AB - Endoscopic ultrasound is a very accurate imaging technique with a relevant clinical impact in the diagnosis and staging of various conditions such as pancreaticobiliary lesions, esophageal cancer, lung cancer, submucosal lesions and lymph nodes. Despite its increasing importance in everyday clinical routine, endoscopic ultrasound outcomes are still highly operator-dependent and tissue confirmation with fine needle aspiration is very often required for definitive differential diagnosis of tumors. Several techniques of image enhancement have been developed in recent years in the attempt to make the technique less operator dependent. Among them the most important appear to be contrast harmonic endoscopic ultrasound and endoscopic ultrasound-elastography. Contrast harmonic endoscopic ultrasound is performed with a dedicated harmonic which displays the fine vascular network of both normal and pathological tissues after injection of an ultrasound contrast agent. Endoscopic ultrasound-elastography displays with different colors the differences in hardness between tissues, thus estimating elasticity in soft normal tissues which appear red and hard neoplastic tissues which appear blue. While contrast harmonic-endoscopic ultrasound has been introduced into clinical practice, endoscopic ultrasound-elastography mainly represents an investigational tool. The purpose of this paper was to review the mechanism of action and the clinical outcomes of contrast harmonic-endoscopic ultrasound and endoscopic ultrasound-elastography in pancreatic diseases. Both techniques show promising applications in the study of pancreatic tumors including differential diagnosis and providing guidance to fine needle aspiration. PMID- 25028865 TI - Established EUS-guided therapeutic interventions. AB - Over the three last decades, endosonography ultrasound (EUS) has evolved from a diagnostic tool to an interventional modality through cumulative advances in experience, knowledge, equipment, and devices. EUS-guided therapeutic procedures appear feasible and safe when performed in highly-experienced centers. This review covers the technical aspects, indications, and results of the most commonly performed procedures. Celiac plexus neurolysis and collection drainages are now well-established techniques and considered to be first-line treatments. Biliary and pancreatic EUS-guided drainages are, conversely, more challenging, and there is currently insufficient clinical evidence documenting their superiority over established practice. Well-designed prospective trials are thus needed in order to accurately assess this modality's risks and long-term outcomes compared to radiological or surgical techniques. PMID- 25028866 TI - Performance of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) needles. How to handle specimens? PMID- 25028867 TI - Motor mutants bring wild-type motors to a halt stochastically. PMID- 25028868 TI - DNA, flexibly flexible. AB - Investigators have constructed dsDNA molecules with several different base modifications and have characterized their bending and twisting flexibilities using atomic force microscopy, DNA ring closure, and single-molecule force spectroscopy with optical tweezers. The three methods provide persistence length measurements that agree semiquantitatively, and they show that the persistence length is surprisingly similar for all of the modified DNAs. The circular dichroism spectra of modified DNAs differ substantially. Simple explanations based on base stacking strength, polymer charge, or groove occupancy by functional groups cannot explain the results, which will guide further high resolution theory and experiments. PMID- 25028869 TI - A critical pull to polarize the cell. PMID- 25028870 TI - New pipelines for novel allosteric GPCR modulators. PMID- 25028871 TI - Conformational mechanism for the stability of microtubule-kinetochore attachments. AB - Regulating the stability of microtubule (MT)-kinetochore attachments is fundamental to avoiding mitotic errors and ensuring proper chromosome segregation during cell division. Although biochemical factors involved in this process have been identified, their mechanics still need to be better understood. Here we introduce and simulate a mechanical model of MT-kinetochore interactions in which the stability of the attachment is ruled by the geometrical conformations of curling MT-protofilaments entangled in kinetochore fibrils. The model allows us to reproduce, with good accuracy, in vitro experimental measurements of the detachment times of yeast kinetochores from MTs under external pulling forces. Numerical simulations suggest that geometrical features of MT-protofilaments may play an important role in the switch between stable and unstable attachments. PMID- 25028872 TI - Contributions of cell growth and biochemical reactions to nongenetic variability of cells. AB - Cell-to-cell variability in the molecular composition of isogenic, steady-state growing cells arises spontaneously from the inherent stochasticity of intracellular biochemical reactions and cell growth. Here, we present a general decomposition of the total variance in the copy number per cell of a particular molecule. It quantifies the individual contributions made by processes associated with cell growth, biochemical reactions, and their control. We decompose the growth contribution further into variance contributions of random partitioning of molecules at cell division, mother-cell heterogeneity, and variation in cell cycle progression. The contribution made by biochemical reactions is expressed in variance generated by molecule synthesis, degradation, and their regulation. We use this theory to study the influence of different growth and reaction-related processes, such as DNA replication, variable molecule-partitioning probability, and synthesis bursts, on stochastic cell-to-cell variability. Using simulations, we characterize the impact of noise in the generation-time on cell-to-cell variability. This article offers a widely-applicable theory on the influence of biochemical reactions and cellular growth on the phenotypic variability of growing, isogenic cells. The theory aids the design and interpretation of experiments involving single-molecule counting or real-time imaging of fluorescent reporter constructs. PMID- 25028874 TI - Mechanical checkpoint for persistent cell polarization in adhesion-naive fibroblasts. AB - Cell polarization is a fundamental biological process implicated in nearly every aspect of multicellular development. The role of cell-extracellular matrix contacts in the establishment and the orientation of cell polarity have been extensively studied. However, the respective contributions of substrate mechanics and biochemistry remain unclear. Here we propose a believed novel single-cell approach to assess the minimal polarization trigger. Using nonadhered round fibroblast cells, we show that stiffness sensing through single localized integrin-mediated cues are necessary and sufficient to trigger and direct a shape polarization. In addition, the traction force developed by cells has to reach a minimal threshold of 56 +/- 1.6 pN for persistent polarization. The polarization kinetics increases with the stiffness of the cue. The polarized state is characterized by cortical actomyosin redistribution together with cell shape change. We develop a physical model supporting the idea that a local and persistent inhibition of actin polymerization and/or myosin activity is sufficient to trigger and sustain the polarized state. Finally, the cortical polarity propagates to an intracellular polarity, evidenced by the reorientation of the centrosome. Our results define the minimal adhesive requirements and quantify the mechanical checkpoint for persistent cell shape and organelle polarization, which are critical regulators of tissue and cell development. PMID- 25028873 TI - Vimentin enhances cell elastic behavior and protects against compressive stress. AB - Vimentin intermediate filament expression is a hallmark of epithelial-to mesenchymal transitions, and vimentin is involved in the maintenance of cell mechanical properties, cell motility, adhesion, and other signaling pathways. A common feature of vimentin-expressing cells is their routine exposure to mechanical stress. Intermediate filaments are unique among cytoskeletal polymers in resisting large deformations in vitro, yet vimentin's mechanical role in the cell is not clearly understood. We use atomic force microscopy to compare the viscoelastic properties of normal and vimentin-null (vim(-/-)) mouse embryo fibroblasts (mEFs) on substrates of different stiffnesses, spread to different areas, and subjected to different compression patterns. In minimally perturbed mEF, vimentin contributes little to the elastic modulus at any indentation depth in cells spread to average areas. On a hard substrate however, the elastic moduli of maximally spread mEFs are greater than those of vim(-/-)mEF. Comparison of the plastic deformation resulting from controlled compression of the cell cortex shows that vimentin's enhancement of elastic behavior increases with substrate stiffness. The elastic moduli of normal mEFs are more stable over time than those of vim(-/-)mEFs when cells are subject to ongoing oscillatory compression, particularly on a soft substrate. In contrast, increasing compressive strain over time shows a greater role for vimentin on a hard substrate. Under both conditions, vim(-/-)mEFs exhibit more variable responses, indicating a loss of regulation. Finally, normal mEFs are more contractile in three-dimensional collagen gels when seeded at low density, when cell-matrix contacts dominate, whereas contractility of vim(-/-)mEF is greater at higher densities when cell cell contacts are abundant. Addition of fibronectin to gel constructs equalizes the contractility of the two cell types. These results show that the Young's moduli of normal and vim(-/-)mEFs are substrate stiffness dependent even when the spread area is similar, and that vimentin protects against compressive stress and preserves mechanical integrity by enhancing cell elastic behavior. PMID- 25028876 TI - Quantitative analysis of the lamellarity of giant liposomes prepared by the inverted emulsion method. AB - The inverted emulsion method is used to prepare giant liposomes by pushing water in-oil droplets through the oil/water interface into an aqueous medium. Due to the high encapsulation efficiency of proteins under physiological conditions and the simplicity of the protocol, it has been widely used to prepare various cell models. However, the lamellarity of liposomes prepared by this method has not been evaluated quantitatively. Here, we prepared liposomes that were partially stained with a fluorescent dye, and analyzed their fluorescence intensity under an epifluorescence microscope. The fluorescence intensities of the membranes of individual liposomes were plotted against their diameter. The plots showed discrete distributions, which were classified into several groups. The group with the lowest fluorescence intensity was determined to be unilamellar by monitoring the exchangeability of the inner and the outer solutions of the liposomes in the presence of the pore-forming toxin alpha-hemolysin. Increasing the lipid concentration dissolved in oil increased the number of liposomes ~100 times. However, almost all the liposomes were unilamellar even at saturating lipid concentrations. We also investigated the effects of lipid composition and liposome content, such as highly concentrated actin filaments and Xenopus egg extracts, on the lamellarity of the liposomes. Remarkably, over 90% of the liposomes were unilamellar under all conditions examined. We conclude that the inverted emulsion method can be used to efficiently prepare giant unilamellar liposomes and is useful for designing cell models. PMID- 25028875 TI - High-throughput phenotyping of chlamydomonas swimming mutants based on nanoscale video analysis. AB - Studies on biflagellated algae Chlamydomonas reinhardtii mutants have resulted in significant contributions to our understanding of the functions of cilia/flagella components. However, visual inspection conducted under a microscope to screen and classify Chlamydomonas swimming requires considerable time, effort, and experience. In addition, it is likely that identification of mutants by this screening is biased toward individual cells with severe swimming defects, and mutants that swim slightly more slowly than wild-type cells may be missed by these screening methods. To systematically screen Chlamydomonas swimming mutants, we have here developed the cell-locating-with-nanoscale-accuracy (CLONA) method to identify the cell position to within 10-nm precision through the analysis of high-speed video images. Instead of analyzing the shape of the flagella, which is not always visible in images, we determine the position of Chlamydomonas cell bodies by determining the cross-correlation between a reference image and the image of the cell. From these positions, various parameters related to swimming, such as velocity and beat frequency, can be accurately estimated for each beat cycle. In the examination of wild-type and seven dynein arm mutants of Chlamydomonas, we found characteristic clustering on scatter plots of beat frequency versus swimming velocity. Using the CLONA method, we have screened 38 Chlamydomonas strains and detected believed-novel motility-deficient mutants that would be missed by visual screening. This CLONA method can automate the screening for mutants of Chlamydomonas and contribute to the elucidation of the functions of motility-associated proteins. PMID- 25028878 TI - Multimotor transport in a system of active and inactive kinesin-1 motors. AB - Long-range directional transport in cells is facilitated by microtubule-based motor proteins. One example is transport in a nerve cell, where small groups of motor proteins, such as kinesins and cytoplasmic dynein, work together to ensure the supply and clearance of cellular material along the axon. Defects in axonal transport have been linked to Alzheimer's and other neurodegenerative diseases. However, it is not known in detail how multimotor-based cargo transport is impaired if a fraction of the motors are defective. To mimic impaired multimotor transport in vitro, we performed gliding motility assays with varying fractions of active kinesin-1 motors and inactive kinesin-1 motor mutants. We found that impaired transport manifests in multiple motility regimes: 1), a fast-motility regime characterized by gliding at velocities close to the single-molecule velocity of the active motors; 2), a slow-motility regime characterized by gliding at close-to zero velocity or full stopping; and 3), a regime in which fast and slow motilities coexist. Notably, the transition from the fast to the slow regime occurred sharply at a threshold fraction of active motors. Based on single-motor parameters, we developed a stochastic model and a mean-field theoretical description that explain our experimental findings. Our results demonstrate that impaired multimotor transport mostly occurs in an either/or fashion: depending on the ratio of active to inactive motors, transport is either performed at close to full speed or is out of action. PMID- 25028877 TI - Self-assembly of polysaccharides gives rise to distinct mechanical signatures in marine gels. AB - Marine-gel biopolymers were recently visualized at the molecular level using atomic force microscopy (AFM) to reveal fine fibril-forming networks with low to high degrees of cross-linking. In this work, we use force spectroscopy to quantify the intra- and intermolecular forces within the marine-gel network. Combining force measurements, AFM imaging, and the known chemical composition of marine gels allows us to identify the microscopic origins of distinct mechanical responses. At the single-fibril level, we uncover force-extension curves that resemble those of individual polysaccharide fibrils. They exhibit entropic elasticity followed by extensions associated with chair-to-boat transitions specific to the type of polysaccharide at high forces. Surprisingly, a low degree of cross-linking leads to sawtooth patterns that we attribute to the unraveling of polysaccharide entanglements. At a high degree of cross-linking, we observe force plateaus that arise from unzipping, as well as unwinding, of helical bundles. Finally, the complex 3D network structure gives rise to force staircases of increasing height that correspond to the hierarchical peeling of fibrils away from the junction zones. In addition, we show that these diverse mechanical responses also arise in reconstituted polysaccharide gels, which highlights their dominant role in the mechanical architecture of marine gels. PMID- 25028879 TI - Characterization of nucleosome unwrapping within chromatin fibers using magnetic tweezers. AB - Nucleosomal arrays fold into chromatin fibers and the higher-order folding of chromatin plays a strong regulatory role in all processes involving DNA access, such as transcription and replication. A fundamental understanding of such regulation requires insight into the folding properties of the chromatin fiber in molecular detail. Despite this, the structure and the mechanics of chromatin fibers remain highly disputed. Single-molecule force spectroscopy experiments have the potential to provide such insight, but interpretation of the data has been hampered by the large variations in experimental force-extension traces. Here we explore the possibility that chromatin fibers are composed of both single turn and fully wrapped histone octamers. By characterizing the force-dependent behavior of in vitro reconstituted chromatin fibers and reanalyzing existing data, we show the unwrapping of the outer turn of nucleosomal DNA at 3 pN. We present a model composed of two freely-jointed chains, which reveals that nucleosomes within the chromatin fiber show identical force-extension behavior to mononucleosomes, indicating that nucleosome-nucleosome interactions are orders-of magnitude smaller than previously reported and therefore can be overcome by thermal fluctuations. We demonstrate that lowering the salt concentration externally increases the wrapping energy significantly, indicative of the electrostatic interaction between the wrapped DNA and the histone octamer surface. We propose that the weak interaction between nucleosomes could allow easy access to nucleosomal DNA, while DNA unwrapping from the histone core could provide a stable yet dynamic structure during DNA maintenance. PMID- 25028880 TI - Routes to DNA accessibility: alternative pathways for nucleosome unwinding. AB - The dynamic packaging of DNA into chromatin is a key determinant of eukaryotic gene regulation and epigenetic inheritance. Nucleosomes are the basic unit of chromatin, and therefore the accessible states of the nucleosome must be the starting point for mechanistic models regarding these essential processes. Although the existence of different unwound nucleosome states has been hypothesized, there have been few studies of these states. The consequences of multiple states are far reaching. These states will behave differently in all aspects, including their interactions with chromatin remodelers, histone variant exchange, and kinetic properties. Here, we demonstrate the existence of two distinct states of the unwound nucleosome, which are accessible at physiological forces and ionic strengths. Using optical tweezers, we measure the rates of unwinding and rewinding for these two states and show that the rewinding rates from each state are different. In addition, we show that the probability of unwinding into each state is dependent on the applied force and ionic strength. Our results demonstrate not only that multiple unwound states exist but that their accessibility can be differentially perturbed, suggesting possible roles for these states in gene regulation. For example, different histone variants or modifications may facilitate or suppress access to DNA by promoting unwinding into one state or the other. We anticipate that the two unwound states reported here will be the basis for future models of eukaryotic transcriptional control. PMID- 25028881 TI - Structure and dynamics of a compact state of a multidomain protein, the mercuric ion reductase. AB - The functional efficacy of colocalized, linked protein domains is dependent on linker flexibility and system compaction. However, the detailed characterization of these properties in aqueous solution presents an enduring challenge. Here, we employ a novel, to our knowledge, combination of complementary techniques, including small-angle neutron scattering, neutron spin-echo spectroscopy, and all atom molecular dynamics and coarse-grained simulation, to identify and characterize in detail the structure and dynamics of a compact form of mercuric ion reductase (MerA), an enzyme central to bacterial mercury resistance. MerA possesses metallochaperone-like N-terminal domains (NmerA) tethered to its catalytic core domain by linkers. The NmerA domains are found to interact principally through electrostatic interactions with the core, leashed by the linkers so as to subdiffuse on the surface over an area close to the core C terminal Hg(II)-binding cysteines. How this compact, dynamical arrangement may facilitate delivery of Hg(II) from NmerA to the core domain is discussed. PMID- 25028882 TI - Macromolecular crowding effects on two homologs of ribosomal protein s16: protein dependent structural changes and local interactions. AB - Proteins function in cellular environments that are crowded with biomolecules, and in this reduced available space, their biophysical properties may differ from those observed in dilute solutions in vitro. Here, we investigated the effects of a synthetic macromolecular crowding agent, dextran 20, on the folded states of hyperthermophilic (S16Thermo) and mesophilic (S16Meso) homologs of the ribosomal protein S16. As expected for an excluded-volume effect, the resistance of the mesophilic protein to heat-induced unfolding increased in the presence of dextran 20, and chemical denaturation experiments at different fixed temperatures showed the macromolecular crowding effect to be temperature-independent. Forster resonance energy transfer experiments show that intramolecular distances between an intrinsic Trp residue and BODIPY-labeled S16Meso depend on the level of the crowding agent. The BODIPY group was attached at three specific positions in S16Meso, allowing measurements of three intraprotein distances. All S16Meso variants exhibited a decrease in the average Trp-BODIPY distance at up to 100 mg/mL dextran 20, whereas the changes in distance became anisotropic (one distance increased, two distances decreased) at higher dextran concentrations. In contrast, the two S16Thermo mutants did not show any changes in Trp-BODIPY distances upon increase of dextran 20 concentrations. It should be noted that the fluorescence quantum yields and lifetimes of BODIPY attached to the two S16 homologs decreased gradually in the presence of dextran 20. To investigate the origin of this decrease, we studied the BODIPY quantum yield in three protein variants in the presence of a tyrosine-labeled dextran. The experiments revealed distinct tyrosine quenching behaviors of BODIPY in the three variants, suggesting a dynamic local interaction between dextran and one particular S16 variant. PMID- 25028883 TI - Investigating the structural impact of the glutamine repeat in huntingtin assembly. AB - Acquiring detailed structural information about the various aggregation states of the huntingtin-exon1 protein (Htt-exon1) is crucial not only for identifying the true nature of the neurotoxic species responsible for Huntington's disease (HD) but also for designing effective therapeutics. Using time-resolved small-angle neutron scattering (TR-SANS), we followed the conformational changes that occurred during fibrillization of the pathologic form of Htt-exon1 (NtQ42P10) and compared the results with those obtained for the wild-type (NtQ22P10). Our results show that the aggregation pathway of NtQ22P10 is very different from that of NtQ42P10, as the initial steps require a monomer to 7-mer transition stage. In contrast, the earliest species identified for NtQ42P10 are monomer and dimer. The divergent pathways ultimately result in NtQ22P10 fibrils that possess a packing arrangement consistent with the common amyloid sterical zipper model, whereas NtQ42P10 fibrils present a better fit to the Perutz beta-helix structural model. The structural details obtained by TR-SANS should help to delineate the key mechanisms that underpin Htt-exon1 aggregation leading to HD. PMID- 25028884 TI - Differences in allosteric communication pipelines in the inactive and active states of a GPCR. AB - G-protein-coupled receptors (GPCRs) are membrane proteins that allosterically transduce the signal of ligand binding in the extracellular (EC) domain to couple to proteins in the intracellular (IC) domain. However, the complete pathway of allosteric communication from the EC to the IC domain, including the role of individual amino acids in the pathway is not known. Using the correlation in torsion angle movements calculated from microseconds-long molecular-dynamics simulations, we elucidated the allosteric pathways in three different conformational states of beta2-adrenergic receptor (beta2AR): 1), the inverse agonist-bound inactive state; 2), the agonist-bound intermediate state; and (3), the agonist- and G-protein-bound fully active state. The inactive state is less dynamic compared with the intermediate and active states, showing dense clusters of allosteric pathways (allosteric pipelines) connecting the EC with the IC domain. The allosteric pipelines from the EC domain to the IC domain are weakened in the intermediate state, thus decoupling the EC domain from the IC domain and making the receptor more dynamic compared with the other states. Also, the orthosteric ligand-binding site becomes the initiator region for allosteric communication in the intermediate state. This finding agrees with the paradigm that the nature of the agonist governs the specific signaling state of the receptor. These results provide an understanding of the mechanism of allosteric communication in class A GPCRs. In addition, our analysis shows that mutations that affect the ligand efficacy, but not the binding affinity, are located in the allosteric pipelines. This clarifies the role of such mutations, which has hitherto been unexplained. PMID- 25028885 TI - Validating solution ensembles from molecular dynamics simulation by wide-angle X ray scattering data. AB - Wide-angle x-ray scattering (WAXS) experiments of biomolecules in solution have become increasingly popular because of technical advances in light sources and detectors. However, the structural interpretation of WAXS profiles is problematic, partly because accurate calculations of WAXS profiles from structural models have remained challenging. In this work, we present the calculation of WAXS profiles from explicit-solvent molecular dynamics (MD) simulations of five different proteins. Using only a single fitting parameter that accounts for experimental uncertainties because of the buffer subtraction and dark currents, we find excellent agreement to experimental profiles both at small and wide angles. Because explicit solvation eliminates free parameters associated with the solvation layer or the excluded solvent, which would require fitting to experimental data, we minimize the risk of overfitting. We further find that the influence from water models and protein force fields on calculated profiles are insignificant up to q~15nm(-1). Using a series of simulations that allow increasing flexibility of the proteins, we show that incorporating thermal fluctuations into the calculations significantly improves agreement with experimental data, demonstrating the importance of protein dynamics in the interpretation of WAXS profiles. In addition, free MD simulations up to one microsecond suggest that the calculated profiles are highly sensitive with respect to minor conformational rearrangements of proteins, such as an increased flexibility of a loop or an increase of the radius of gyration by < 1%. The present study suggests that quantitative comparison between MD simulations and experimental WAXS profiles emerges as an accurate tool to validate solution ensembles of biomolecules. PMID- 25028886 TI - Mechanical properties of base-modified DNA are not strictly determined by base stacking or electrostatic interactions. AB - This work probes the mystery of what balance of forces creates the extraordinary mechanical stiffness of DNA to bending and twisting. Here we explore the relationship between base stacking, functional group occupancy of the DNA minor and major grooves, and DNA mechanical properties. We study double-helical DNA molecules substituting either inosine for guanosine or 2,6-diaminopurine for adenine. These DNA variants, respectively, remove or add an amino group from the DNA minor groove, with corresponding changes in hydrogen-bonding and base stacking energy. Using the techniques of ligase-catalyzed cyclization kinetics, atomic force microscopy, and force spectroscopy with optical tweezers, we show that these DNA variants have bending persistence lengths within the range of values reported for sequence-dependent variation of the natural DNA bases. Comparison with seven additional DNA variants that modify the DNA major groove reveals that DNA bending stiffness is not correlated with base stacking energy or groove occupancy. Data from circular dichroism spectroscopy indicate that base analog substitution can alter DNA helical geometry, suggesting a complex relationship among base stacking, groove occupancy, helical structure, and DNA bend stiffness. PMID- 25028887 TI - The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion binding from atomistic molecular dynamics simulations. AB - The multidrug and toxic compound extrusion transporters extrude a wide variety of substrates out of both mammalian and bacterial cells via the electrochemical gradient of protons and cations across the membrane. The substrates transported by these proteins include toxic metabolites and antimicrobial drugs. These proteins contribute to multidrug resistance in both mammalian and bacterial cells and are therefore extremely important from a biomedical perspective. Although specific residues of the protein are known to be responsible for the extrusion of solutes, mechanistic details and indeed structures of all the conformational states remain elusive. Here, we report the first, to our knowledge, simulation study of the recently resolved x-ray structure of the multidrug and toxic compound extrusion transporter, NorM from Neisseria gonorrhoeae (NorM_NG). Multiple, atomistic simulations of the unbound and bound forms of NorM in a phospholipid lipid bilayer allow us to identify the nature of the drug protein/ion-protein interactions, and secondly determine how these interactions contribute to the conformational rearrangements of the protein. In particular, we identify the molecular rearrangements that occur to enable the Na(+) ion to enter the cation-binding cavity even in the presence of a bound drug molecule. These include side chain flipping of a key residue, GLU-261 from pointing toward the central cavity to pointing toward the cation binding side when bound to a Na(+) ion. Our simulations also provide support for cation binding in the drug-bound and apo states of NorM_NG. PMID- 25028888 TI - Explaining the non-newtonian character of aggregating monoclonal antibody solutions using small-angle neutron scattering. AB - A monoclonal antibody solution displays an increase in low shear rate viscosity upon aggregation after prolonged incubation at 40 degrees C. The morphology and interactions leading to the formation of the aggregates responsible for this non Newtonian character are resolved using small-angle neutron scattering. Our data show a weak repulsive barrier before proteins aggregate reversibly, unless a favorable contact with high binding energy occurs. Two types of aggregates were identified after incubation at 40 degrees C: oligomers with radius of gyration ~10 nm and fractal submicrometer particles formed by a slow reaction-limited aggregation process, consistent with monomers colliding many times before finding a favorable strong interaction site. Before incubation, these antibody solutions are Newtonian liquids with no increase in low shear rate viscosity and no upturn in scattering at low wavevector, whereas aggregated solutions under the same conditions have both of these features. These results demonstrate that fractal submicrometer particles are responsible for the increase in low shear rate viscosity and low wavevector upturn in scattered intensity of aggregated antibody solutions; both are removed from aggregated samples by filtering. PMID- 25028890 TI - Diffusion of MRI and CT contrast agents in articular cartilage under static compression. AB - Cartilage has a limited capacity for self-repair and focal damage can eventually lead to complete degradation of the tissue. Early diagnosis of degenerative changes in cartilage is therefore essential. Contrast agent-based computed tomography and magnetic resonance imaging provide promising tools for this purpose. However, the common assumption in clinical applications that contrast agents reach steady-state distributions within the tissue has been of questionable validity. Characterization of nonequilibrium diffusion of contrast agents rather than their equilibrium distributions may therefore be more effective for image-based cartilage assessment. Transport of contrast agent through the extracellular matrix of cartilage can be affected by tissue compression due to matrix structural and compositional changes including reduced pore size and fluid content. We therefore investigate the effects of static compression on diffusion of three common contrast agents: sodium iodide, sodium diatrizoate, and gadolinium diethylenetriamine-pentaacid (Gd-DTPA). Results showed that static compression was associated with significant decreases in diffusivities for sodium iodide and Gd-DTPA, with similar (but not significant) trends for sodium diatrizoate. Molecular mass of contrast agents affected diffusivities as the smallest one tested, sodium iodide, showed higher diffusivity than sodium diatrizoate and Gd-DTPA. Compression-associated cartilage matrix alterations such as glycosaminoglycan and fluid contents were found to correspond with variations in contrast agent diffusivities. Although decreased diffusivity was significantly correlated with increasing glycosaminoglycan content for sodium iodide and Gd-DTPA only, diffusivity significantly increased for all contrast agents by increasing fluid fraction. Because compounds based on iodine and gadolinium are commonly used for computed tomography and magnetic resonance imaging, present findings can be valuable for more accurate image-based assessment of variations in cartilage composition associated with focal injuries. PMID- 25028889 TI - Hierarchical cascades of instability govern the mechanics of coiled coils: helix unfolding precedes coil unzipping. AB - Coiled coils are a fundamental emergent motif in proteins found in structural biomaterials, consisting of alpha-helical secondary structures wrapped in a supercoil. A fundamental question regarding the thermal and mechanical stability of coiled coils in extreme environments is the sequence of events leading to the disassembly of individual oligomers from the universal coiled-coil motifs. To shed light on this phenomenon, here we report atomistic simulations of a trimeric coiled coil in an explicit water solvent and investigate the mechanisms underlying helix unfolding and coil unzipping in the assembly. We employ advanced sampling techniques involving steered molecular dynamics and metadynamics simulations to obtain the free-energy landscapes of single-strand unfolding and unzipping in a three-stranded assembly. Our comparative analysis of the free energy landscapes of instability pathways shows that coil unzipping is a sequential process involving multiple intermediates. At each intermediate state, one heptad repeat of the coiled coil first unfolds and then unzips due to the loss of contacts with the hydrophobic core. This observation suggests that helix unfolding facilitates the initiation of coiled-coil disassembly, which is confirmed by our 2D metadynamics simulations showing that unzipping of one strand requires less energy in the unfolded state compared with the folded state. Our results explain recent experimental findings and lay the groundwork for studying the hierarchical molecular mechanisms that underpin the thermomechanical stability/instability of coiled coils and similar protein assemblies. PMID- 25028891 TI - Network thermodynamic curation of human and yeast genome-scale metabolic models. AB - Genome-scale models are used for an ever-widening range of applications. Although there has been much focus on specifying the stoichiometric matrix, the predictive power of genome-scale models equally depends on reaction directions. Two-thirds of reactions in the two eukaryotic reconstructions Homo sapiens Recon 1 and Yeast 5 are specified as irreversible. However, these specifications are mainly based on biochemical textbooks or on their similarity to other organisms and are rarely underpinned by detailed thermodynamic analysis. In this study, a to our knowledge new workflow combining network-embedded thermodynamic and flux variability analysis was used to evaluate existing irreversibility constraints in Recon 1 and Yeast 5 and to identify new ones. A total of 27 and 16 new irreversible reactions were identified in Recon 1 and Yeast 5, respectively, whereas only four reactions were found with directions incorrectly specified against thermodynamics (three in Yeast 5 and one in Recon 1). The workflow further identified for both models several isolated internal loops that require further curation. The framework also highlighted the need for substrate channeling (in human) and ATP hydrolysis (in yeast) for the essential reaction catalyzed by phosphoribosylaminoimidazole carboxylase in purine metabolism. Finally, the framework highlighted differences in proline metabolism between yeast (cytosolic anabolism and mitochondrial catabolism) and humans (exclusively mitochondrial metabolism). We conclude that network-embedded thermodynamics facilitates the specification and validation of irreversibility constraints in compartmentalized metabolic models, at the same time providing further insight into network properties. PMID- 25028892 TI - A constitutive model for a maturing fibrin network. AB - Blood clot formation is crucial to maintain normal physiological conditions but at the same time involved in many diseases. The mechanical properties of the blood clot are important for its functioning but complicated due to the many processes involved. The main structural component of the blood clot is fibrin, a fibrous network that forms within the blood clot, thereby increasing its mechanical rigidity. A constitutive model for the maturing fibrin network is developed that captures the evolving mechanical properties. The model describes the fibrin network as a network of fibers that become thicker in time. Model parameters are related to the structural properties of the network, being the fiber length, bending stiffness, and mass-length ratio. Results are compared with rheometry experiments in which the network maturation is followed in time for various loading frequencies and fibrinogen concentrations. Three parameters are used to capture the mechanical behavior including the mass-length ratio. This parameter agrees with values determined using turbidimetry experiments and is subsequently used to derive the number of protofibrils and fiber radius. The strength of the model is that it describes the mechanical properties of the maturing fibrin network based on it structural quantities. At the same time the model is relatively simple, which makes it suitable for advanced numerical simulations of blood clot formation during flow in blood vessels. PMID- 25028893 TI - Collective cell movement promotes synchronization of coupled genetic oscillators. AB - Collective cell movement is a crucial component of embryonic development. Intercellular interactions regulate collective cell movement by allowing cells to transfer information. A key question is how collective cell movement itself influences information flow produced in tissues by intercellular interactions. Here, we study the effect of collective cell movement on the synchronization of locally coupled genetic oscillators. This study is motivated by the segmentation clock in zebrafish somitogenesis, where short-range correlated movement of cells has been observed. We describe the segmentation clock tissue by a Voronoi diagram, cell movement by the force balance of self-propelled and repulsive forces between cells, the dynamics of the direction of self-propelled motion, and the synchronization of genetic oscillators by locally coupled phase oscillators. We find that movement with a correlation length of about 2 ~ 3 cell diameters is optimal for the synchronization of coupled oscillators. Quantification of cell mixing reveals that this short-range correlation of cell movement allows cells to exchange neighbors most efficiently. Moreover, short-range correlated movement strongly destabilizes nonuniform spatial phase patterns, further promoting global synchronization. Our theoretical results suggest that collective cell movement may enhance the synchronization of the segmentation clock in zebrafish somitogenesis. More generally, collective cell movement may promote information flow in tissues by enhancing cell mixing and destabilizing spurious patterns. PMID- 25028894 TI - Diversity of magneto-aerotactic behaviors and oxygen sensing mechanisms in cultured magnetotactic bacteria. AB - Microorganisms living in gradient environments affect large-scale processes, including the cycling of elements such as carbon, nitrogen or sulfur, the rates and fate of primary production, and the generation of climatically active gases. Aerotaxis is a common adaptation in organisms living in the oxygen gradients of stratified environments. Magnetotactic bacteria are such gradient-inhabiting organisms that have a specific type of aerotaxis that allows them to compete at the oxic-anoxic interface. They biomineralize magnetosomes, intracellular membrane-coated magnetic nanoparticles, that comprise a permanent magnetic dipole that causes the cells to align along magnetic field lines. The magnetic alignment enables them to efficiently migrate toward an optimal oxygen concentration in microaerobic niches. This phenomenon is known as magneto-aerotaxis. Magneto aerotaxis has only been characterized in a limited number of available cultured strains. In this work, we characterize the magneto-aerotactic behavior of 12 magnetotactic bacteria with various morphologies, phylogenies, physiologies, and flagellar apparatus. We report six different magneto-aerotactic behaviors that can be described as a combination of three distinct mechanisms, including the reported (di-)polar, axial, and a previously undescribed mechanism we named unipolar. We implement a model suggesting that the three magneto-aerotactic mechanisms are related to distinct oxygen sensing mechanisms that regulate the direction of cells' motility in an oxygen gradient. PMID- 25028895 TI - Isolation of rare recombinants without using selectable markers for one-step seamless BAC mutagenesis. AB - Current methods to isolate rare (1:10,000-1:100,000) bacterial artificial chromosome (BAC) recombinants require selectable markers. For seamless BAC mutagenesis, selectable markers need to be removed after isolation of recombinants through counterselection. Here we illustrate founder principle driven enrichment (FPE), a simple method to rapidly isolate rare recombinants without using selectable markers, allowing one-step seamless BAC mutagenesis. As proof of principle, we isolated 1:100,000 seamless fluorescent protein-modified Nodal BACs and confirmed BAC functionality by generating fluorescent reporter mice. We also isolated small indel P1 phage-derived artificial chromosome (PAC) and BAC recombinants. Statistical analysis revealed that 1:100,000 recombinants can be isolated with <40 PCRs, and we developed a web-based calculator to optimize FPE. PMID- 25028897 TI - Impact of a major disaster on the mental health of a well-studied cohort. AB - IMPORTANCE: There has been growing research into the mental health consequences of major disasters. Few studies have controlled for prospectively assessed mental health. This article describes a natural experiment in which 57% of a well studied birth cohort was exposed to a major natural disaster (the Canterbury, New Zealand, earthquakes in 2010-2011), with the remainder living outside of the earthquake area. OBJECTIVE: To examine the relationships between the extent of earthquake exposure and mental health outcomes following the earthquakes-net of adjustment for potentially confounding factors related to personal circumstances, prior mental health, and childhood family background. DESIGN, SETTING, AND PARTICIPANTS: Data were gathered from the Christchurch Health and Development Study, a 35-year longitudinal study of a birth cohort of New Zealand children (635 males and 630 females). This general community sample included 952 participants with available data on earthquake exposure and mental health outcomes at age 35 years. EXPOSURES: A composite measure of exposure to the events during and subsequent to the 4 major (Richter Scale >6.0) Canterbury earthquakes during the years 2010-2011. MAIN OUTCOMES AND MEASURES: DSM-IV symptom criteria for major depression; posttraumatic stress disorder; anxiety disorder; suicidal ideation/attempt; nicotine dependence; alcohol abuse/dependence; and illicit drug abuse/dependence. Outcomes were measured approximately 20 to 24 months after the onset of exposure to the earthquakes and were assessed using DSM-IV diagnostic criteria and measures of subclinical symptoms. RESULTS: After covariate adjustment, cohort members with high levels of exposure to the earthquakes had rates of mental disorder that were 1.4 (95% CI, 1.1-1.7) times higher than those of cohort members not exposed. This increase was due to increases in the rates of major depression; posttraumatic stress disorder; other anxiety disorders; and nicotine dependence. Similar results were found using a measure of subclinical symptoms (incidence rate ratio, 1.4; 95% CI, 1.1 1.6). Estimates of attributable fraction suggested that exposure to the Canterbury earthquakes accounted for 10.8% to 13.3% of the overall rate of mental disorder in the cohort at age 35 years. CONCLUSIONS AND RELEVANCE: Following extensive control for prospectively measured confounding factors, exposure to the Canterbury earthquakes was associated with a small to moderate increase in the risk for common mental health problems. PMID- 25028896 TI - RNA motif discovery by SHAPE and mutational profiling (SHAPE-MaP). AB - Many biological processes are RNA-mediated, but higher-order structures for most RNAs are unknown, which makes it difficult to understand how RNA structure governs function. Here we describe selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) that makes possible de novo and large-scale identification of RNA functional motifs. Sites of 2'-hydroxyl acylation by SHAPE are encoded as noncomplementary nucleotides during cDNA synthesis, as measured by massively parallel sequencing. SHAPE-MaP-guided modeling identified greater than 90% of accepted base pairs in complex RNAs of known structure, and we used it to define a new model for the HIV-1 RNA genome. The HIV-1 model contains all known structured motifs and previously unknown elements, including experimentally validated pseudoknots. SHAPE-MaP yields accurate and high-resolution secondary-structure models, enables analysis of low abundance RNAs, disentangles sequence polymorphisms in single experiments and will ultimately democratize RNA-structure analysis. PMID- 25028898 TI - [Colorectal cancer screening ?Is it necessary?]. PMID- 25028899 TI - [Inherited colorectal cancer predisposition syndromes identified in the Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru;]. AB - BACKGROUND: Colorectal cancer (CRC) is the fourth most common cancer in the world and is classified according to their origin in sporadic CRC (~ 70%) and genetic CRC (~ 30%), this latter involves cases of familial aggregation and inherited sindromes that predispose to CRC. OBJECTIVE: To describe inherited CRC predisposition syndromes, polyposic and non-polyposic, identified in the Oncogenetics Unit at National Institute of Cancer Disease (INEN). MATERIAL AND METHODS: A descriptive observational record from the attentions of the Oncogenetics Unit at INEN during 2009 to 2013. We included patients with personal or familiar history of CRC and/or colonic polyposis who were referred for clinical assessment to the Oncogenetics Unitat INEN. RESULTS: 59.3 % were female, 40.7 % male, 69.8% under 50 years old, 60.5% had a single CRC, 23.2% had more than one CRC or CRC associated with other extracolonic neoplasia and 32.6% had a familiar history of cancer with autosomal dominant inheritance. According to the clinical genetic diagnosis, 93.1% of the included cases were inherited syndromes that predispose to CRC, with 33.8% of colonic polyposis syndromes, 23.3% of hereditary nonpolyposis CRC syndromes (HNPCC) and 36.0% of CCRHNP probable cases. CONCLUSIONS: Clinical genetic evaluation of patients with personal or familiar history of CRC and/or colonic polyposis can identify inherited colorectal cancer predisposition syndromes and provide an appropriategenetic counseling to patients and relatives at risk, establishing guidelines to follow-up and prevention strategies to prevent morbidity and mortality by cancer. PMID- 25028900 TI - [Surveillance cultures after high-level disinfection of flexible endoscopes in a general hospital]. AB - INTRODUCTION: Flexible endoscopes are instruments with a complex structure which are used in invasive gastroenterological procedures, therefore high-level disinfection (HLD) is recommended as an appropriate reprocessing method. However, most hospitals do not perform a quality control to assess the compliance and results of the disinfection process. OBJECTIVES: To evaluate the effectiveness of the flexible endoscopesa?TM decontamination after high-level disinfection by surveillance cultures and to assess the compliance with the reprocessing guidelines. MATERIAL AND METHODS: Descriptive study conducted in January 2013 in the Gastroenterological Unit of a tertiary hospital. 30 endoscopic procedures were randomly selected. Compliance with guidelines was evaluated and surveillance cultures for common bacteria were performed after the disinfection process. RESULTS: On the observational assessment, compliance with the guidelines was as follows: pre-cleaning 9 (30%), cleaning 5 (16.7%), rinse 3 (10%), first drying 30 (100%), disinfection 30 (100%), final rinse 0 (0%) and final drying 30 (100%), demonstrating that only 3 of 7 stages of the disinfection process were optimally performed. In the microbiological evaluation, 2 (6.7%) of the 30 procedures had a positive culture obtained from the surface of the endoscope. Furthermore, 1 (4.2%) of the 24 biopsy forcepsgave a positive culture. The organisms isolated were different Pseudomonas species. CONCLUSION: High-level disinfection procedures were not optimally performed, finding in 6.7% positive cultures of Pseudomonas species. PMID- 25028901 TI - [Assessment of the fulfillment of paracentesis in cirrotic patients admited in two services of internal medicine in hospitals of median complexity]. AB - The Spontaneous Bacterial Peritonitis (SBP) is a severe complication of cirrhosis. The prognosis depends on the time of initiation of therapy that is required for early diagnosis. OBJECTIVE: To evaluate the performance of diagnostic paracentesis (DP) in cirrhotic patients with ascites during hospitalization. MATERIALS AND METHODS: An observational, analytical, prospective, study conducted during October 2009 to June 2010. RESULTS: There were 92 income, average age was 60.3 years (SD 11.7), corresponding to 57.6% men, the most common etiology of CH was alcohol (48.9%). There were 40 PD (43.5%), of which 35% positive SBP. Of the DP, 47.5% were performed on admission and / or submission of warning signs. The average period of hospitalization was higher in those who underwent late DP. The MELD score both at admission and discharge was significantlyhigher in patients on admission punctured. CONCLUSION: DP was done in less than half of hospitalized cirrhotic, and its timely completion only 1 in 5 of revenues. The DP perform at the right time reduces hospital days. PMID- 25028902 TI - Risk factors associated with the development of hyperamylasemia and post-ERCP pancreatitis in the Cuban National Institute. AB - CONTEXT: Acute pancreatitis is the most common complication in ERCP, and some risk factors were associated with the development of hyperamylasemia and post ERCP pancreatitis. OBJECTIVES: identifying new factors associated with the development of hyperamylasemia or post-ERCP pancreatitis in patients attended at our center. MATERIAL AND METHODS: A (retrospective) cohort study was carried out in 170 patients on which a diagnostic-therapeutic ERCP was done due to biliopancreatic disease. 67 patients developed hyperamylasemia (39.4%) and 6 post ERCP pancreatitis (3.5%). The following diagnostic criteria were applied: Hyperamylasemia: increase in the serum amylase level above the normal value (90 I/U). Acute post-ERCP pancreatitis: clinical: continuous abdominal pain for over 24 hours and biochemical: elevation of amylase3 times above normal value (90 U/I). RESULTS: The number of cannulations more than 4 (19 patients), (p=0.006; RR= 3.00) was associated significantly with the development of hyperamylasemia and the placing of biliary stent (14 patients), (p=0.00; RR= 0.39) was a protective factor. The factors associated with the development of post-ERCP pancreatitis were related with the patient (peridiverticular location of the papilla (p=0.00; RR= 2.00) and the sphincter of Oddi dysfunction (p=0.000; RR=1.20). CONCLUSION: Technical factors were associated with the development of hyperamylasemia, however, the factors associated with the development of post ERCP pancreatitis in our universe of study were related mainly with the patient. PMID- 25028903 TI - [Rectal mucosal prolapse syndrome: study of cases. Hospital Daniel A Carrion, Lima, Peru, 2010-2013]. AB - OBJECTIVE: to describe the clinical, endoscopic, and histological characteristics of rectal mucosal prolapse syndrome, formerly known as Solitary rectal ulcer, in patients from a general hospital. MATERIAL AND METHODS: All patient diagnosed as rectal mucosal prolapse syndrome during 2010-2013 was selected; the medical history war reviewed and the histological slides were reevaluated by two pathologists. RESULTS: 17 cases of rectal mucosal prolapse syndrome were selected, the majority were males under 50 years, the most common clinical findings were rectal bleeding (82%) and constipation (65%), the endocopic findings were heterogeneous,: erythema (41%), ulcers (35%) and elevated lesions (29%). All cases presented fibromuscularhyperplasia in lamina propia and crypt distortion in the microscopic evaluation. CONCLUSION: In our study of rectal mucosal prolapse syndrome. The most common clinical findings were rectal bleeding and constipation. Erythematous mucosa was the most common endoscopic finding. PMID- 25028905 TI - [Brunners gland hiperplasia. Report of two cases]. AB - Brunner's gland hyperplasia is an infrequent benign injury located on the first or second portion of the duodenum. The disease spectrum includes diffuse nodular hyperplasia, circumscribed nodular hyperplasia, and Brunner's gland adenoma. We report two cases, one with an adenoma of Brunner's glands as a duodenal polyp and the other as a diffuse nodular hyperplasia of the duodenal bulb. PMID- 25028904 TI - Double pylorus in the era of proton pump inhibitors. AB - Double pylorus and gastroduodenal fistula are rare conditions and can be either congenital or acquired. We report a case of a 58-year-old man with epigastric pain and dyspepsia in which the upper gastrointestinal endoscopy revealed an acquired double pylorus, probably caused by a gastric ulcer. PMID- 25028906 TI - [Gastric Kaposi sarcoma in a patient with HIV]. AB - A 38 years old man with 48 hours of gastrointestinal bleeding was admitted to the hospital. The EGD revealed red-purple nodules in the gastric antrum. Histopathologically, there were spindle cells and capillary size vascular proliferation. These findings were consistent with Kaposi sarcoma of the stomach. Immediately after, the patient had a positive test for HIV. PMID- 25028907 TI - Metastasis of breast cancer to major duodenal papilla. AB - Metastasis is an infrequent cause of tumor involvement of the major duodenal papilla and of cholestasis. We report a case of obstructive jaundice due to a metastatic breast carcinoma to the major duodenal papilla, and assess curative and palliative treatment that interventional endoscopy can offer. PMID- 25028908 TI - [Introduction to the indirect meta-analyses]. AB - Meta-analyses are studies that aim to compile all available information, grouping them according to an specific theme and evaluating it through methodological quality tools. When there are two specific comparisons of treatments based on randomized clinical trials, standard meta-analyses are the best option, but there are scenarios in which there is no available literature for those direct comparisons. In these cases, an alternative method to consider is indirect comparison or indirect meta-analyses. The aim of this review is to understand the conceptual foundations, the need, applications and limitations of indirect comparisons for further understanding of network meta-analyses. PMID- 25028909 TI - Endoscopic ultrasound hemostasis techniques. AB - Since its development, endoscopic ultrasound (EUS) has evolved from a simple diagnostic technique to an important therapeutic tool for interventional endoscopy. EUS analysis provides real-time imaging of most major thoracic and abdominal vessels, and the possibility to use needle puncture with a curved linear array echoendoscope as a vascular intervention. In this review, we describe the endoscopic ultrasound approach to vascular therapy outside of the gastrointestinal wall. PMID- 25028910 TI - Recalcitrant papules and plaques on perianal area and buttocks. PMID- 25028911 TI - First-line antiretroviral therapy with nevirapine versus lopinavir-ritonavir based regimens in a resource-limited setting. AB - OBJECTIVE: To compare WHO first-line antiretroviral therapy (ART) with nonnucleoside reverse transcriptase inhibitors (NNRTI)-based regimen with a boosted protease inhibitor (bPI) regimen in a resource-limited setting regarding treatment outcome and emergence of drug resistance mutations (DRMs). METHODS: Treatment-naive adults were randomized to nevirapine (NVP) or ritonavir-boosted lopinavir (LPV/r) regimens each in combination with tenofovir (TDF)/emtricitabine (FTC) or zidovudine (ZDV)/lamivudine (3TC). Primary endpoint was the incidence of therapeutical (clinical and/or virologic) failure at week 48 with follow-up till week 96. RESULTS: Four hundred and twenty-five patients (120 men; 305 women) received at least one dose of the study drug. mITT analysis showed no difference in proportion of therapeutical failure between treatment arms [67/209 (32%) in NVP vs. 63/216 (29%) LPV/r at week 48 (P = 0.53); 88/209 (42%) in NVP vs. 83/216 (38%) in LPV/r at week 96 (P = 0.49)]. Per-protocol analysis demonstrated significantly more virologic failure with NVP than with LPV/r regimens [at week 48: 19/167 (11%) vs. 7/166 (4%), P = 0.014; at week 96: 27/158 (17%) vs. 13/159 (8%), P = 0.019)]. Drug resistance mutations to NNRTI were detected in 19 out of 22 (86.3%) and dual-class resistance to nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI in 15 out of 27 (68.2%) of NVP failing patients. K65R mutation was present in seven out of 14 patients failing NVP-TDF/FTC regimen. No major protease inhibitor-DRM was detected among LPV/r failing patients. Discontinuation for adverse events was similar between treatment groups. CONCLUSION: In resource-limited settings, first-line NNRTI-NRTI regimen as compared with bPI-based regimen provides similar outcome but is associated with a significantly higher number of virologic failure and resistance mutations in both classes that jeopardize future options for second-line therapy. PMID- 25028912 TI - HIV viral load levels and CD4+ cell counts of youth in 14 cities. AB - OBJECTIVES: To describe the HIV viral load and CD4 cell counts of youth (12-24 years) in 14 cities from March 2010 through November 2011. METHODS: Baseline HIV viral load and CD4 cell count data were electronically abstracted in a central location and in an anonymous manner through a random computer-generated coding system without any ability to link codes to individual cases. RESULTS: Among 1409 HIV reported cases, 852 participants had data on both viral load and CD4 cell counts. Of these youth, 34% had CD4 cell counts of 350 or less, 27% had cell counts from 351 to 500, and 39% had CD4 cell counts greater than 500. Youth whose transmission risk was male-to-male sexual contact had higher viral loads compared with youth whose transmission risk was perinatal or heterosexual contact. Greater than 30% of those who reported male-to-male sexual contact had viral loads greater than 50 000 copies, whereas less than 20% of heterosexual contact youth had viral loads greater than 50 000 copies. There were no differences noted in viral load by type of testing site. CONCLUSION: Most HIV-infected youth have CD4 cell counts and viral load levels associated with high rates of sexual transmission. Untreated, these youth may directly contribute to high rates of ongoing transmission. It is essential that any public health test and treat strategy place a strong emphasis on youth, particularly young MSM. PMID- 25028913 TI - Do ask, do tell: clinicians and the U.S. National AIDS strategy. PMID- 25028914 TI - A closer look at hepatitis C clearance in HIV controllers: a response. PMID- 25028915 TI - A closer look at hepatitis C clearance in HIV controllers. PMID- 25028916 TI - Biomarkers for sexual behaviour change: a role for nonpaternity studies? PMID- 25028917 TI - 3D graphene supported MoO2 for high performance binder-free lithium ion battery. AB - In this work, we report the synthesis of MoO2 nanoparticles grown on three dimensional graphene (3DG) via the reduction of alpha-MoO3 nanobelts through a facile chemical vapor deposition (CVD) approach under argon protection gas environment. In this synthesis approach, the presence of hydrophobic 3DG promoted the Volmer-Weber growth of MoO2 nanoparticles (30-60 nm). The as-prepared MoO2 3DG nanocomposite was directly used as a binder-free anode electrode for lithium ion batteries (LIBs) without additives and exhibited excellent electrochemical performance. It delivered high reversible capacities of 975.4 mA h g(-1) and 537.3 mA h g(-1) at the current densities of 50 and 1000 mA g(-1), respectively. Moreover, the electrode also showed an increased capacity from 763.7 mA h g(-1) to 986.9 mA h g(-1) after 150 discharge and charge cycles at a current density of 200 mA g(-1). The enhanced electrochemical performance of MoO2-3DG nanocomposite electrode may be attributed to the synergistic effects of MoO2 nanoparticles and 3DG layers. This facile CVD synthesis process presents a feasible route for large scale production of high performance, environmentally friendly electrode. In addition, this process also has the potential of being utilized in other materials for energy storage devices application. PMID- 25028925 TI - Differences in miRNA expression in early stage lung adenocarcinomas that did and did not relapse. AB - Relapse of adenocarcinoma, the most common non-small cell lung cancer (NSCLC), is a major clinical challenge to improving survival. To gain insight into the early molecular events that contribute to lung adenocarcinoma relapse, and taking into consideration potential cell type specificity, we used stringent criteria for sample selection. We measured miRNA expression only from flash frozen stage I lung adenocarcinomas, excluding other NSCLC subtypes. We compared miRNA expression in lung adenocarcinomas that relapsed within two years to those that did not relapse within three years after surgical resection prior to adjuvant therapy. The most significant differences in mRNA expression for recurrent tumors compared to non-recurrent tumors were decreases in miR-106b*, -187, -205, -449b, 774* and increases in miR-151-3p, let-7b, miR-215, -520b, and -512-3p. A unique comparison between adjacent normal lung tissue from relapse and non-relapse groups revealed dramatically different miRNA expression, suggesting dysregulation of miRNA in the environment around the tumor. To assess patient-to-patient variability, miRNA levels in the tumors were normalized to levels in matched adjacent normal lung tissue. This analysis revealed a different set of significantly altered miRNA in tumors that recurred compared to tumors that did not. Together our analyses elucidated miRNA not previously linked to lung adenocarcinoma that likely have important roles in its development and progression. Our results also highlight the differences in miRNA expression in normal lung tissue in adenocarcinomas that do and do not recur. Most notably, our data identified those miRNA that distinguish early stage tumors likely to relapse prior to treatment and miRNA that could be further studied for use as biomarkers for prognosis, patient monitoring, and/or treatment decisions. PMID- 25028927 TI - Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker. AB - BACKGROUND: Undifferentiated Pleomorphic Sarcoma (UPS) and high-grade Leiomyosarcoma (LMS) are soft tissue tumors with an aggressive clinical behavior, frequently developing local recurrence and distant metastases. Despite several gene expression studies involving soft tissue sarcomas, the potential to identify molecular markers has been limited, mostly due to small sample size, in-group heterogeneity and absence of detailed clinical data. MATERIALS AND METHODS: Gene expression profiling was performed for 22 LMS and 22 UPS obtained from untreated patients. To assess the relevance of the gene signature, a meta-analysis was performed using five published studies. Four genes (BAD, MYOCD, SRF and SRC) selected from the gene signature, meta-analysis and functional in silico analysis were further validated by quantitative PCR. In addition, protein-protein interaction analysis was applied to validate the data. SRC protein immunolabeling was assessed in 38 UPS and 52 LMS. RESULTS: We identified 587 differentially expressed genes between LMS and UPS, of which 193 corroborated with other studies. Cluster analysis of the data failed to discriminate LMS from UPS, although it did reveal a distinct molecular profile for retroperitoneal LMS, which was characterized by the over-expression of smooth muscle-specific genes. Significantly higher levels of expression for BAD, SRC, SRF, and MYOCD were confirmed in LMS when compared with UPS. SRC was the most value discriminator to distinguish both sarcomas and presented the highest number of interaction in the in silico protein-protein analysis. SRC protein labeling showed high specificity and a positive predictive value therefore making it a candidate for use as a diagnostic marker in LMS. CONCLUSIONS: Retroperitoneal LMS presented a unique gene signature. SRC is a putative diagnostic marker to differentiate LMS from UPS. PMID- 25028928 TI - Imine resveratrol analogues: molecular design, Nrf2 activation and SAR analysis. AB - Resveratrol is a natural phenol with protective effects against cancer and inflammation-related diseases. Its mechanism of action involves the activation of nuclear factor E2 p45-related factor 2 (Nrf2), which plays a key role in regulation of genes driven by antioxidant response element (ARE). Inspired by the effect of resveratrol, here we synthesized a series of imine resveratrol analogs (IRAs), evaluated their abilities to activate Nrf2 by using cell based ARE reporter assay. After the first-round screening, preliminary and quantitative structure-activity relationship (SAR) was analyzed, and the structural features determining Nrf2 activation ability were proposed. Two novel IRAs were designed and subsequently synthesized, namely 2-methoxyl-3,6-dihydroxyl-IRA and 2,3,6 trihydroxyl-IRA. They were proved to be the most potent Nrf2 activators among the IRAs. PMID- 25028929 TI - Dynamics of whale shark occurrence at their fringe oceanic habitat. AB - Studies have shown that the whale shark (Rhincodon typus), a vulnerable large filter feeder, seasonally aggregates at highly productive coastal sites and that individuals can perform large, trans-boundary migrations to reach these locations. Yet, the whereabouts of the whale shark when absent from these sites and the potential oceanographic and biological drivers involved in shaping their present and future habitat use, including that located at the fringes of their suitable oceanic habitat, are largely unknown. We analysed a 16-year (1998-2013) observer dataset from the pole-and-line tuna fishery across the Azores (mid-North Atlantic) and used GAM models to investigate the spatial and temporal patterns of whale shark occurrence in relation to oceanographic features. Across this period, the whale shark became a regular summer visitor to the archipelago after a sharp increase in sighting frequency seen in 2008. We found that SST helps predicting their occurrence in the region associated to the position of the seasonal 22 degrees C isotherm, showing that the Azores are at a thermal boundary for this species and providing an explanation for the post 2007 increase. Within the region, whale shark detections were also higher in areas of increased bathymetric slope and closer to the seamounts, coinciding with higher chl-a biomass, a behaviour most probably associated to increased feeding opportunities. They also showed a tendency to be clustered around the southernmost island of Santa Maria. This study shows that the region integrates the oceanic habitat of adult whale shark and suggests that an increase in its relative importance for the Atlantic population might be expected in face of climate change. PMID- 25028930 TI - Rebuilding biodiversity of Patagonian marine molluscs after the end-Cretaceous mass extinction. AB - We analysed field-collected quantitative data of benthic marine molluscs across the Cretaceous-Palaeogene boundary in Patagonia to identify patterns and processes of biodiversity reconstruction after the end-Cretaceous mass extinction. We contrast diversity dynamics from nearshore environments with those from offshore environments. In both settings, Early Palaeogene (Danian) assemblages are strongly dominated by surviving lineages, many of which changed their relative abundance from being rare before the extinction event to becoming the new dominant forms. Only a few of the species in the Danian assemblages were newly evolved. In offshore environments, however, two newly evolved Danian bivalve species attained ecological dominance by replacing two ecologically equivalent species that disappeared at the end of the Cretaceous. In both settings, the total number of Danian genera at a locality remained below the total number of late Cretaceous (Maastrichtian) genera at that locality. We suggest that biotic interactions, in particular incumbency effects, suppressed post-extinction diversity and prevented the compensation of diversity loss by originating and invading taxa. Contrary to the total number of genera at localities, diversity at the level of individual fossiliferous horizons before and after the boundary is indistinguishable in offshore environments. This indicates an evolutionary rapid rebound to pre-extinction values within less than ca 0.5 million years. In nearshore environments, by contrast, diversity of fossiliferous horizons was reduced in the Danian, and this lowered diversity lasted for the entire studied post-extinction interval. In this heterogeneous environment, low connectivity among populations may have retarded the recolonisation of nearshore habitats by survivors. PMID- 25028932 TI - Survey of academic field experiences (SAFE): trainees report harassment and assault. AB - Little is known about the climate of the scientific fieldwork setting as it relates to gendered experiences, sexual harassment, and sexual assault. We conducted an internet-based survey of field scientists (N = 666) to characterize these experiences. Codes of conduct and sexual harassment policies were not regularly encountered by respondents, while harassment and assault were commonly experienced by respondents during trainee career stages. Women trainees were the primary targets; their perpetrators were predominantly senior to them professionally within the research team. Male trainees were more often targeted by their peers at the research site. Few respondents were aware of mechanisms to report incidents; most who did report were unsatisfied with the outcome. These findings suggest that policies emphasizing safety, inclusivity, and collegiality have the potential to improve field experiences of a diversity of researchers, especially during early career stages. These include better awareness of mechanisms for direct and oblique reporting of harassment and assault and, the implementation of productive response mechanisms when such behaviors are reported. Principal investigators are particularly well positioned to influence workplace culture at their field sites. PMID- 25028931 TI - Isolation, characterization and potential role in beta cell-endothelium cross talk of extracellular vesicles released from human pancreatic islets. AB - The cross-talk between beta cells and endothelium plays a key role in islet physiopathology and in the revascularization process after islet transplantation. However, the molecular mechanisms involved in this cross-talk are not fully elucidated. Extracellular vesicles (EVs) are secreted membrane nanoparticles involved in inter-cellular communication through the transfer of proteins and nucleic acids. The aims of this study were: 1) isolation and characterization of EVs from human islets; 2) evaluation of the pro-angiogenic effect of islet derived EVs on human islet endothelial cells (IECs). EVs were isolated by ultracentrifugation from conditioned medium of human islets and characterized by nanotrack analysis (Nanosight), FACS, western blot, bioanalyzer, mRNA/microRNA RT PCR array. On IECs, we evaluated EV-induced insulin mRNA transfer, proliferation, resistance to apoptosis, in vitro angiogenesis, migration, gene and protein profiling. EVs sized 236+/-54 nm, expressed different surface molecules and islet specific proteins (insulin, C-peptide, GLP1R) and carried several mRNAs (VEGFa, eNOS) and microRNAs (miR-27b, miR-126, miR-130 and miR-296) involved in beta cell function, insulin secretion and angiogenesis. Purified EVs were internalized into IECs inducing insulin mRNA expression, protection from apoptosis and enhancement of angiogenesis. Human islets release biologically active EVs able to shuttle specific mRNAs and microRNAs (miRNAs) into target endothelial cells. These results suggest a putative role for islet-derived EVs in beta cell-endothelium cross-talk and in the neoangiogenesis process which is critical for engraftment of transplanted islets. PMID- 25028933 TI - Ecosystem scale declines in elk recruitment and population growth with wolf colonization: a before-after-control-impact approach. AB - The reintroduction of wolves (Canis lupus) to Yellowstone provided the unusual opportunity for a quasi-experimental test of the effects of wolf predation on their primary prey (elk--Cervus elaphus) in a system where top-down, bottom-up, and abiotic forces on prey population dynamics were closely and consistently monitored before and after reintroduction. Here, we examined data from 33 years for 12 elk population segments spread across southwestern Montana and northwestern Wyoming in a large scale before-after-control-impact analysis of the effects of wolves on elk recruitment and population dynamics. Recruitment, as measured by the midwinter juvenile?female ratio, was a strong determinant of elk dynamics, and declined by 35% in elk herds colonized by wolves as annual population growth shifted from increasing to decreasing. Negative effects of population density and winter severity on recruitment, long recognized as important for elk dynamics, were detected in uncolonized elk herds and in wolf colonized elk herds prior to wolf colonization, but not after wolf colonization. Growing season precipitation and harvest had no detectable effect on recruitment in either wolf treatment or colonization period, although harvest rates of juveniles?females declined by 37% in wolf-colonized herds. Even if it is assumed that mortality due to predation is completely additive, liberal estimates of wolf predation rates on juvenile elk could explain no more than 52% of the total decline in juvenile?female ratios in wolf-colonized herds, after accounting for the effects of other limiting factors. Collectively, these long-term, large-scale patterns align well with prior studies that have reported substantial decrease in elk numbers immediately after wolf recolonization, relatively weak additive effects of direct wolf predation on elk survival, and decreased reproduction and recruitment with exposure to predation risk from wolves. PMID- 25028934 TI - RGB plots as a tool for the simultaneous visualization of multiple data layers in a two dimensional space. AB - Visualization of multidimensional data helps in understanding complex systems and environments. We present here a red, green, blue (RGB) visualization method that can serve to display environmental properties. The saturation of each color is used to represent the concentration of a given property. The implementation of that figure is illustrated through visualization of three dissolved inorganic nutrient concentrations along a vertical transect of the Mediterranean, as well as through a vertical time series of three phytoplankton group cell numbers. The RGB figures show well known properties of the water column. In addition, they reveal some lesser-known properties, such as regions in shallow water in which the ratio of phosphorus and silica to nitrogen is high, and a deep eukariotic phytoplankton community. Visualization of such data is usually performed with three separate contour or surface plots, and occasionally two properties are presented as an overlay in a single figure. The RGB figure offers a better way to visualize the interactions among the three separate plots than is commonly available. PMID- 25028935 TI - Diesterified derivatives of 5-iodo-2'-deoxyuridine as cerebral tumor tracers. AB - With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2'-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3',5'-di-O-acetyl-2'-deoxyuridine (Ac2[125I]IUdR), 5 [125I]iodo-3',5'-di-O-pivaloyl-2'-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31-47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability. PMID- 25028936 TI - Embryogenesis and larval biology of the cold-water coral Lophelia pertusa. AB - Cold-water coral reefs form spectacular and highly diverse ecosystems in the deep sea but little is known about reproduction, and virtually nothing about the larval biology in these corals. This study is based on data from two locations of the North East Atlantic and documents the first observations of embryogenesis and larval development in Lophelia pertusa, the most common framework-building cold water scleractinian. Embryos developed in a more or less organized radial cleavage pattern from ~ 160 um large neutral or negatively buoyant eggs, to 120 270 um long ciliated planulae. Embryogenesis was slow with cleavage occurring at intervals of 6-8 hours up to the 64-cell stage. Genetically characterized larvae were sexually derived, with maternal and paternal alleles present. Larvae were active swimmers (0.5 mm s(-1)) initially residing in the upper part of the water column, with bottom probing behavior starting 3-5 weeks after fertilization. Nematocysts had developed by day 30, coinciding with peak bottom-probing behavior, and possibly an indication that larvae are fully competent to settle at this time. Planulae survived for eight weeks under laboratory conditions, and preliminary results indicate that these planulae are planktotrophic. The late onset of competency and larval longevity suggests a high dispersal potential. Understanding larval biology and behavior is of paramount importance for biophysical modeling of larval dispersal, which forms the basis for predictions of connectivity among populations. PMID- 25028938 TI - Dental calculus reveals unique insights into food items, cooking and plant processing in prehistoric central Sudan. AB - Accessing information on plant consumption before the adoption of agriculture is challenging. However, there is growing evidence for use of locally available wild plants from an increasing number of pre-agrarian sites, suggesting broad ecological knowledge. The extraction of chemical compounds and microfossils from dental calculus removed from ancient teeth offers an entirely new perspective on dietary reconstruction, as it provides empirical results on material that is already in the mouth. Here we present a suite of results from the multi-period Central Sudanese site of Al Khiday. We demonstrate the ingestion in both pre agricultural and agricultural periods of Cyperus rotundus tubers. This plant is a good source of carbohydrates and has many useful medicinal and aromatic qualities, though today it is considered to be the world's most costly weed. Its ability to inhibit Streptococcus mutans may have contributed to the unexpectedly low level of caries found in the agricultural population. Other evidence extracted from the dental calculus includes smoke inhalation, dry (roasting) and wet (heating in water) cooking, a second plant possibly from the Triticaceae tribe and plant fibres suggestive of raw material preparation through chewing. PMID- 25028939 TI - Research networks and their contribution to the quality of critical care. PMID- 25028937 TI - Reversion and T cell escape mutations compensate the fitness loss of a CD8+ T cell escape mutant in their cognate transmitted/founder virus. AB - Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrent reversion and other T cell escape mutations. Our findings indicate that the overall viral fitness is modulated by the complex interplay among T cell escape, compensatory and reversion mutations to maintain the balance between immune escape and viral replication capacity. PMID- 25028940 TI - Research networks and clinical trials in critical care in Brazil: current status and future perspectives. PMID- 25028941 TI - Sedation and memories in critical care. PMID- 25028942 TI - The use of hypothermia and outcome post cardiopulmonary resuscitation in 2014. PMID- 25028943 TI - Use of antipsychotics for the treatment of intensive care unit delirium. PMID- 25028945 TI - Sedation and memories of patients subjected to mechanical ventilation in an intensive care unit. AB - OBJECTIVE: To investigate the relationship between sedation and the memories reported by patients subjected to mechanical ventilation following discharge from the intensive care unit. METHODS: This prospective, observational, cohort study was conducted with individuals subjected to mechanical ventilation who remained in the intensive care unit for more than 24 hours. Clinical statistics and sedation records were extracted from the participants' clinical records; the data relative to the participants' memories were collected using a specific validated instrument. Assessment was performed three months after discharge from the intensive care unit. RESULTS: A total of 128 individuals were assessed, most of whom (84.4%) reported recollections from their stay in the intensive care unit as predominantly a combination of real and illusory events. The participants subjected to sedation (67.2%) at deep levels (Richmond Agitation-Sedation Scale [RASS] -4 and -5) for more than two days and those with psychomotor agitation (33.6%) exhibited greater susceptibility to occurrence of illusory memories (p>0.001). CONCLUSION: The probability of the occurrence of illusory memories was greater among the participants who were subjected to deep sedation. Sedation seems to be an additional factor that contributed to the occurrence of illusory memories in severely ill individuals subjected to mechanical ventilation. PMID- 25028946 TI - Inflammatory and perfusion markers as risk factors and predictors of critically ill patient readmission. AB - OBJECTIVE: To assess the performance of central venous oxygen saturation, lactate, base deficit, and C-reactive protein levels and SOFA and SWIFT scores on the day of discharge from the intensive care unit as predictors of patient readmission to the intensive care unit. METHODS: This prospective and observational study collected data from 1,360 patients who were admitted consecutively to a clinical-surgical intensive care unit from August 2011 to August 2012. The clinical characteristics and laboratory data of readmitted and non-readmitted patients after discharge from the intensive care unit were compared. Using a multivariate analysis, the risk factors independently associated with readmission were identified. RESULTS: The C-reactive protein, central venous oxygen saturation, base deficit, and lactate levels and the SWIFT and SOFA scores did not correlate with the readmission of critically ill patients. Increased age and contact isolation because of multidrug-resistant organisms were identified as risk factors that were independently associated with readmission in this study group. CONCLUSION: Inflammatory and perfusion parameters were not associated with patient readmission. Increased age and contact isolation because of multidrug-resistant organisms were identified as predictors of readmission to the intensive care unit. PMID- 25028947 TI - Ventilatory weaning practices in intensive care units in the city of Cali. AB - OBJECTIVE: Early weaning from mechanical ventilation is one of the primary goals in managing critically ill patients. There are various techniques and measurement parameters for such weaning. The objective of this study was to describe the practices of ventilatory weaning in adult intensive care units in the city of Cali. METHODS: A survey of 32 questions (some multiple choice) evaluating weaning practices was distributed to physiotherapists and respiratory therapists working in intensive care units, to be answered anonymously. RESULTS: The most common strategy for the parameter set was the combination of continuous positive airway pressure with pressure support (78%), with a large variability in pressure levels, the most common range being 6 to 8 cm H2O. The most common weaning parameters were as follows: tidal volume (92.6%), respiratory rate (93.3%) and oxygen saturation (90.4%). The most common waiting time for registration of the parameters was >15 minutes (40%). The measurements were preferably obtained from the ventilator display. CONCLUSION: The methods and measurement parameters of ventilatory weaning vary greatly. The most commonly used method was continuous positive airway pressure with more pressure support and the most commonly used weaning parameters were the measured tidal volume and respiratory rate. PMID- 25028944 TI - Brazilian recommendations of mechanical ventilation 2013. Part I. AB - Perspectives on invasive and noninvasive ventilatory support for critically ill patients are evolving, as much evidence indicates that ventilation may have positive effects on patient survival and the quality of the care provided in intensive care units in Brazil. For those reasons, the Brazilian Association of Intensive Care Medicine (Associacao de Medicina Intensiva Brasileira - AMIB) and the Brazilian Thoracic Society (Sociedade Brasileira de Pneumonia e Tisiologia - SBPT), represented by the Mechanical Ventilation Committee and the Commission of Intensive Therapy, respectively, decided to review the literature and draft recommendations for mechanical ventilation with the goal of creating a document for bedside guidance as to the best practices on mechanical ventilation available to their members. The document was based on the available evidence regarding 29 subtopics selected as the most relevant for the subject of interest. The project was developed in several stages, during which the selected topics were distributed among experts recommended by both societies with recent publications on the subject of interest and/or significant teaching and research activity in the field of mechanical ventilation in Brazil. The experts were divided into pairs that were charged with performing a thorough review of the international literature on each topic. All the experts met at the Forum on Mechanical Ventilation, which was held at the headquarters of AMIB in Sao Paulo on August 3 and 4, 2013, to collaboratively draft the final text corresponding to each sub topic, which was presented to, appraised, discussed and approved in a plenary session that included all 58 participants and aimed to create the final document. PMID- 25028948 TI - Fractional excretion of potassium in the course of acute kidney injury in critically ill patients: potential monitoring tool? AB - OBJECTIVE: To evaluate the behavior of fractional excretion of potassium in the course of acute kidney injury in critically ill patients. METHODS: As part of a larger study in which we have evaluated blood and urinary parameters in the course of acute kidney injury, 168 patients were included. Blood and urine samples were collected daily until the removal of the urinary catheter or the initiation of renal replacement therapy. We describe the evolution of fractional excretion of potassium based on whether acute kidney injury was diagnosed, its duration (transient or persistent) and its severity (creatinine-based Acute Kidney Injury Network - AKIN stage). The diagnostic performance of fractional excretion of potassium in predicting the duration of acute kidney injury and the need for renal replacement therapy on the day of acute kidney injury diagnosis was also evaluated. RESULTS: Fractional excretion of potassium was significantly higher in persistent acute kidney injury compared to transient acute kidney injury on the day of acute kidney injury diagnosis (24.8 vs. 13.8%, p<0.001). Both groups had the median fractional excretion of potassium increasing in the two days preceding the acute kidney injury diagnosis. Patients without acute kidney injury had stable low fractional excretion of potassium values. The fractional excretion of potassium was fairly accurate in predicting persistent acute kidney injury (area under the curve: 0.712; 95% confidence interval: 0.614 0.811; p<0.001) on the day of acute kidney injury diagnosis. The area under the curve was 0.663 (95% confidence interval: 0.523-0.803; p=0.03) for renal replacement therapy. The fractional excretion of potassium increased with maximum AKIN stage reached, in both transient and persistent acute kidney injury. CONCLUSION: Sequential fractional excretion of potassium assessment appears to be useful in critically ill patients at risk for acute kidney injury. PMID- 25028949 TI - Sepsis in intensive care unit patients with traumatic brain injury: factors associated with higher mortality. AB - OBJECTIVE: Patients with traumatic brain injury are particularly susceptible to sepsis, which may exacerbate the systemic inflammatory response and lead to organ dysfunction. The influence of clinical variables on the mortality of intensive care unit patients with traumatic brain injury and sepsis was investigated. METHODS: The present investigation was a retrospective study involving 175 patients with traumatic brain injury who were treated in a period of 1 year at a reference hospital for trauma and who had sepsis, severe sepsis, or septic shock. Demographic and clinical data were obtained, and the SOFA score was calculated at the time sepsis was found and after 72 hours. RESULTS: There was a predominance of young men with severe traumatic brain injury, multiple head injuries, sepsis with a pulmonary focus, prolonged hospital stay, and high mortality (37.7%). Circulatory and respiratory failure had a high incidence, but renal and coagulation failure were less frequent, and liver failure was not observed. After logistic regression, the presence of septic shock and respiratory failure 72 hours after the sepsis diagnosis was associated with higher mortality, with an odds ratio of 7.56 (95%CI=2.04-27.31, p=0.0024) and 6.62 (95%CI=1.93-22.78, p=0.0027), respectively. In addition, there was a higher mortality among patients who had no organ failure on D1 but who developed the condition after 72 hours of sepsis and in those patients who already had organ failure at the time sepsis was diagnosed and remained in this condition after 72 hours. CONCLUSION: Septic shock and progressive organ (particularly respiratory) dysfunction increases the mortality of patients with traumatic brain injury and sepsis. PMID- 25028950 TI - Adequacy of energy and protein balance of enteral nutrition in intensive care: what are the limiting factors? AB - OBJECTIVE: To determine the factors that influence the adequacy of enteral nutritional therapy in an intensive care unit. METHODS: This prospective observational study was conducted in an intensive care unit between 2010 and 2012. Patients >18 years of age underwent exclusive enteral nutritional therapy for >=72 hours. The energy and protein requirements were calculated according to the ICU protocols. The data regarding enteral nutrition, the causes of non compliance, and the biochemical test results were collected daily. RESULTS: Ninety-three patients admitted to the intensive care unit were evaluated. Among these patients, 82% underwent early enteral nutritional therapy, and 80% reached the nutritional goal in <36 hours. In addition, 81.6%+/-15.4% of the enteral nutrition volume was infused, with an adequacy of 82.2%+/-16.0% for calories, 82.2%+/-15.9% for proteins, and a mean energy balance of -289.9+/-277.1 kcal/day. A negative correlation of C-reactive protein with the volume infused and the energy and protein balance was observed. In contrast, a positive correlation was found between C-reactive protein and the time required to reach nutritional goals. Extubation was the main cause for interrupting the enteral nutritional therapy (29.9% of the interruption hours), and the patients >60 years of age exhibited a lower percentage of recovery of the oral route compared with the younger patients (p=0.014). CONCLUSION: Early enteral nutritional therapy and the adequacy for both energy and protein of the nutritional volume infused were in accordance with the established guidelines. Possible inadequacies of energy and protein balance appeared to be associated with an acute inflammatory response, which was characterized by elevated C-reactive protein levels. The main cause of interruption of the enteral nutritional therapy was the time spent in extubation. PMID- 25028951 TI - Comparative analysis between the alveolar recruitment maneuver and breath stacking technique in patients with acute lung injury. AB - OBJECTIVE: To compare the effectiveness of the alveolar recruitment maneuver and the breath stacking technique with respect to lung mechanics and gas exchange in patients with acute lung injury. METHODS: Thirty patients were distributed into two groups: Group 1 - breath stacking; and Group 2 - alveolar recruitment maneuver. After undergoing conventional physical therapy, all patients received both treatments with an interval of 1 day between them. In the first group, the breath stacking technique was used initially, and subsequently, the alveolar recruitment maneuver was applied. Group 2 patients were initially subjected to alveolar recruitment, followed by the breath stacking technique. Measurements of lung compliance and airway resistance were evaluated before and after the use of both techniques. Gas analyses were collected before and after the techniques were used to evaluate oxygenation and gas exchange. RESULTS: Both groups had a significant increase in static compliance after breath stacking (p=0.021) and alveolar recruitment (p=0.03), but with no significant differences between the groups (p=0.95). The dynamic compliance did not increase for the breath stacking (p=0.22) and alveolar recruitment (p=0.074) groups, with no significant difference between the groups (p=0.11). The airway resistance did not decrease for either groups, i.e., breath stacking (p=0.91) and alveolar recruitment (p=0.82), with no significant difference between the groups (p=0.39). The partial pressure of oxygen increased significantly after breath stacking (p=0.013) and alveolar recruitment (p=0.04), but there was no significant difference between the groups (p=0.073). The alveolar-arterial O2 difference decreased for both groups after the breath stacking (p=0.025) and alveolar recruitment (p=0.03) interventions, and there was no significant difference between the groups (p=0.81). CONCLUSION: Our data suggest that the breath stacking and alveolar recruitment techniques are effective in improving the lung mechanics and gas exchange in patients with acute lung injury. PMID- 25028952 TI - Influence of prone positioning on premature newborn infant stress assessed by means of salivary cortisol measurement: pilot study. AB - OBJECTIVE: This study sought to assess the influence of prone positioning on the stress of newborn premature infants through the measurement of the salivary cortisol concentration and the evaluation of physiological and behavioral responses before and after changes in body positioning. METHODS: Saliva samples were collected from newborn infants at two different times: the first (corresponding to the baseline) after a period of 40 minutes during which the infants were not subjected to any manipulation and were placed in the lateral or supine position, and the second 30 minutes after placement in the prone position. Variables including heart rate, respiratory rate, peripheral oxygen saturation, and the Brazelton sleep score were recorded before, during, and at the end of the period in the prone position. RESULTS: The sample comprised 16 newborn premature infants (56.3% male) with a gestational age between 26 and 36 weeks, postnatal age between 1 and 33 days, birth weight of 935 to 3,050g, and weight at the time of intervention of 870 to 2,890g. During the intervention, six participants breathed room air, while the remainder received oxygen therapy. The median salivary cortisol concentration was lower in the prone position compared to baseline (0.13 versus 0.20; p=0.003), as was the median Brazelton sleep score (p=0.02). The average respiratory rate was lower after the intervention (54.88+/ 7.15 versus 60+/-7.59; p=0.0004). The remainder of the investigated variables did not exhibit significant variation. CONCLUSION: Prone positioning significantly reduced the salivary cortisol level, respiratory rate, and Brazelton sleep score, suggesting a correlation between prone positioning and reduction of stress in preterm infants. PMID- 25028953 TI - Antiphospholipid antibodies in critically ill patients. AB - Antiphospholipid antibodies are responsible for a wide spectrum of clinical manifestations. Venous, arterial and microvascular thrombosis and severe catastrophic cases account for a large morbidly/mortality. Through the connection between the immune, inflammatory and hemostatic systems, it is possible that these antibodies may contribute to the development of organ dysfunction and are associated with poor short and long-term prognoses in critically ill patients. We performed a search of the PubMed/MedLine database for articles written during the period from January 2000 to February 2013 to evaluate the frequency of antiphospholipid antibodies in critically ill patients and their impact on the outcomes of these patients. Only eight original studies involving critically ill patients were found. However, the development of antiphospholipid antibodies in critically ill patients seems to be frequent, but more studies are necessary to clarify their pathogenic role and implications for clinical practice. PMID- 25028954 TI - [Strategies for prevention of acute kidney injury in cardiac surgery: an integrative review]. AB - Acute kidney injury is a common complication after cardiac surgery and is associated with increased morbidity and mortality and increased length of stay in the intensive care unit. Considering the high prevalence of acute kidney injury and its association with worsened prognosis, the development of strategies for renal protection in hospitals is essential to reduce the associated high morbidity and mortality, especially for patients at high risk of developing acute kidney injury, such as patients who undergo cardiac surgery. This integrative review sought to assess the evidence available in the literature regarding the most effective interventions for the prevention of acute kidney injury in patients undergoing cardiac surgery. To select the articles, we used the CINAHL and MedLine databases. The sample of this review consisted of 16 articles. After analyzing the articles included in the review, the results of the studies showed that only hydration with saline has noteworthy results in the prevention of acute kidney injury. The other strategies are controversial and require further research to prove their effectiveness. PMID- 25028955 TI - High-volume hemofiltration and prone ventilation in subarachnoid hemorrhage complicated by severe acute respiratory distress syndrome and refractory septic shock. AB - We report the successful treatment of two patients with aneurismal subarachnoid hemorrhage complicated by severe respiratory failure and refractory septic shock using simultaneous prone position ventilation and high-volume hemofiltration. These rescue therapies allowed the patients to overcome the critical situation without associated complications and with no detrimental effects on the intracranial and cerebral perfusion pressures. Prone position ventilation is now an accepted therapy for severe acute respiratory distress syndrome, and high volume hemofiltration is a non-conventional hemodynamic support that has several potential mechanisms for improving septic shock. In this manuscript, we briefly review these therapies and the related evidence. When other conventional treatments are insufficient for providing safe limits of oxygenation and perfusion as part of basic neuroprotective care in subarachnoid hemorrhage patients, these rescue therapies should be considered on a case-by-case basis by an experienced critical care team. PMID- 25028956 TI - Continuous ethanol production with a membrane bioreactor at high acetic Acid concentrations. AB - The release of inhibitory concentrations of acetic acid from lignocellulosic raw materials during hydrolysis is one of the main concerns for 2nd generation ethanol production. The undissociated form of acetic acid can enter the cell by diffusion through the plasma membrane and trigger several toxic effects, such as uncoupling and lowered intracellular pH. The effect of acetic acid on the ethanol production was investigated in continuous cultivations by adding medium containing 2.5 to 20.0 g.L-1 acetic acid at pH 5.0, at a dilution rate of 0.5 h 1. The cultivations were performed at both high (~25 g.L-1) and very high (100 200 g.L-1) yeast concentration by retaining the yeast cells inside the reactor by a cross-flow membrane in a membrane bioreactor. The yeast was able to steadily produce ethanol from 25 g.L-1 sucrose, at volumetric rates of 5-6 g.L-1.h-1 at acetic acid concentrations up to 15.0 g.L-1. However, the yeast continued to produce ethanol also at a concentration of 20 g.L-1 acetic acid but at a declining rate. The study thereby demonstrates the great potential of the membrane bioreactor for improving the robustness of the ethanol production based on lignocellulosic raw materials. PMID- 25028958 TI - High-protein, low-fat, short-term diet results in less stress and fatigue than moderate-protein moderate-fat diet during weight loss in male weightlifters: a pilot study. AB - PURPOSE: Athletes risk performance and muscle loss when dieting. Strategies to prevent losses are unclear. This study examined the effects of two diets on anthropometrics, strength, and stress in athletes. METHODS: This double-blind crossover pilot study began with 14 resistance-trained males (20-43 yr) and incurred one dropout. Participants followed carbohydrate-matched, high-protein low-fat (HPLF) or moderate-protein moderate-fat (MPMF) diets of 60% habitual calories for 2 weeks. Protein intakes were 2.8g/kg and 1.6g/kg and mean fat intakes were 15.4% and 36.5% of calories, respectively. Isometric midthigh pull (IMTP) and anthropometrics were measured at baseline and completion. The Daily Analysis of Life Demands of Athletes (DALDA) and Profile of Mood States (POMS) were completed daily. Outcomes were presented statistically as probability of clinical benefit, triviality, or harm with effect sizes (ES) and qualitative assessments. RESULTS: Differences of effect between diets on IMTP and anthropometrics were likely or almost certainly trivial, respectively. Worse than normal scores on DALDA part A, part B and the part A "diet" item were likely more harmful (ES 0.32, 0.4 and 0.65, respectively) during MPMF than HPLF. The POMS fatigue score was likely more harmful (ES 0.37) and the POMS total mood disturbance score (TMDS) was possibly more harmful (ES 0.29) during MPMF than HPLF. CONCLUSIONS: For the 2 weeks observed, strength and anthropometric differences were minimal while stress, fatigue, and diet-dissatisfaction were higher during MPMF. A HPLF diet during short-term weight loss may be more effective at mitigating mood disturbance, fatigue, diet dissatisfaction, and stress than a MPMF diet. PMID- 25028959 TI - Variation in broccoli cultivar phytochemical content under organic and conventional management systems: implications in breeding for nutrition. AB - Organic agriculture requires cultivars that can adapt to organic crop management systems without the use of synthetic pesticides as well as genotypes with improved nutritional value. The aim of this study encompassing 16 experiments was to compare 23 broccoli cultivars for the content of phytochemicals associated with health promotion grown under organic and conventional management in spring and fall plantings in two broccoli growing regions in the US (Oregon and Maine). The phytochemicals quantified included: glucosinolates (glucoraphanin, glucobrassicin, neoglucobrassin), tocopherols (delta-, gamma-, alpha-tocopherol) and carotenoids (lutein, zeaxanthin, beta-carotene). For glucoraphanin (17.5%) and lutein (13%), genotype was the major source of total variation; for glucobrassicin, region (36%) and the interaction of location and season (27.5%); and for neoglucobrassicin, both genotype (36.8%) and its interactions (34.4%) with season were important. For delta- and gamma-tocopherols, season played the largest role in the total variation followed by location and genotype; for total carotenoids, genotype (8.41-13.03%) was the largest source of variation and its interactions with location and season. Overall, phytochemicals were not significantly influenced by management system. We observed that the cultivars with the highest concentrations of glucoraphanin had the lowest for glucobrassicin and neoglucobrassicin. The genotypes with high concentrations of glucobrassicin and neoglucobrassicin were the same cultivars and were early maturing F1 hybrids. Cultivars highest in tocopherols and carotenoids were open pollinated or early maturing F1 hybrids. We identified distinct locations and seasons where phytochemical performance was higher for each compound. Correlations among horticulture traits and phytochemicals demonstrated that glucoraphanin was negatively correlated with the carotenoids and the carotenoids were correlated with one another. Little or no association between phytochemical concentration and date of cultivar release was observed, suggesting that modern breeding has not negatively influenced the level of tested compounds. We found no significant differences among cultivars from different seed companies. PMID- 25028960 TI - A proteomics sample preparation method for mature, recalcitrant leaves of perennial plants. AB - Sample preparation is key to the success of proteomics studies. In the present study, two sample preparation methods were tested for their suitability on the mature, recalcitrant leaves of six representative perennial plants (grape, plum, pear, peach, orange, and ramie). An improved sample preparation method was obtained: Tris and Triton X-100 were added together instead of CHAPS to the lysis buffer, and a 20% TCA-water solution and 100% precooled acetone were added after the protein extraction for the further purification of protein. This method effectively eliminates nonprotein impurities and obtains a clear two-dimensional gel electrophoresis array. The method facilitates the separation of high molecular-weight proteins and increases the resolution of low-abundance proteins. This method provides a widely applicable and economically feasible technology for the proteomic study of the mature, recalcitrant leaves of perennial plants. PMID- 25028961 TI - Work more, then feel more: the influence of effort on affective predictions. AB - Two studies examined how effort invested in a task shapes the affective predictions related to potential success in that task, and the mechanism underlying this relationship. In Study 1, PhD students awaiting an editorial decision about a submitted manuscript estimated the effort they had invested in preparing that manuscript for submission and how happy they would feel if it were accepted. Subjective estimates of effort were positively related to participants' anticipated happiness, an effect mediated by the higher perceived quality of one's work. In other words, the more effort one though having invested, the happier one expected to feel if it were accepted, because one expected a higher quality manuscript. We replicated this effect and its underlying mediation in Study 2, this time using an experimental manipulation of effort in the context of creating an advertising slogan. Study 2 further showed that participants mistakenly thought their extra efforts invested in the task had improved the quality of their work, while independent judges had found no objective differences in quality between the outcomes of the high- and low-effort groups. We discuss the implications of the relationship between effort and anticipated emotions and the conditions under which such relationship might be functional. PMID- 25028962 TI - Statistical Considerations When Assessing Short Latency Stretch Reflexes in the Human Soleus Muscle. AB - The aim was to investigate trial-by-trial response characteristics in the short latency stretch reflex (SSR). Fourteen dorsiflexion stretches were applied to the ankle joint with a pre-contracted soleus muscle on two days. The magnitude and variability of trial-by-trial responses of the SSR were assessed. The SSR was log normally distributed and variance heterogeneous between subjects. For some subjects, the magnitude and variance differed between days and stretches. As velocity increased, variance heterogeneity tended to decrease and response magnitude increased. The current study demonstrates the need to assess trial-by trial response characteristics and not averaged curves. Moreover, it provides an analysis of SSR characteristics accounting for log-normally distributed and variance heterogeneous trial-by-trial responses. PMID- 25028963 TI - Phase I/II clinical trial of encapsulated, cytochrome P450 expressing cells as local activators of cyclophosphamide to treat spontaneous canine tumours. AB - Based upon promising preclinical studies, a clinical trial was performed in which encapsulated cells overexpressing cytochrome P450 enzyme isoform 2B1 were implanted around malignant mammary tumours arising spontaneously in dogs. The dogs were then given cyclophosphamide, one of the standard chemotherapeutic agents used for the treatment of mammary tumours. The dogs were assessed for a number of clinical parameters as well as for reduction in tumour size. The treatment was well tolerated with no evidence of adverse reactions or side effects being associated with the administration of the encapsulated cells. Reductions in tumour size of more than 50% were observed for 6 out of the 11 tumours analysed while 5 tumours showing minor responses, i.e. stable disease. In contrast, the tumours that received cyclophosphamide alone showed only stable disease. Taken together, this data suggests that encapsulated cytochrome P450 expressing cells combined with chemotherapy may be useful in the local treatment of a number of dog mammary tumours and support the performance of further clinical studies to evaluate this new treatment. PMID- 25028964 TI - The polymorphism in the promoter of HSP70 gene is associated with heat tolerance of two congener endemic bay scallops (Argopecten irradians irradians and A. i. concentricus). AB - BACKGROUND: The heat shock protein 70 (HSP70) is one kind of molecular chaperones, which plays a key role in protein metabolism under normal and stress conditions. METHODOLOGY: In the present study, the mRNA expressions of HSP70 under normal physiological condition and after acute heat stress were investigated in gills of two bay scallop populations (Argopecten irradians irradians and A. i. concentricus). The heat resistant scallops A. i. concentricus showed significantly lower basal level and higher induction of HSP70 compared with that of the heat sensitive scallops A. i. irradians. The promoter sequence of HSP70 gene from bay scallop (AiHSP70) was cloned and the polymorphisms within this region were investigated to analyze their association with heat tolerance. Totally 11 single nucleotide polymorphisms (SNPs) were identified, and four of them (-967, -480, -408 and -83) were associated with heat tolerance after HWE analysis and association analysis. Based on the result of linkage disequilibrium analysis, the in vitro transcriptional activities of AiHSP70 promoters with different genotype were further determined, and the results showed that promoter from A. i. concentricus exhibited higher transcriptional activity than that from A. i. irradians (P<0.05). CONCLUSIONS: The results provided insights into the molecular mechanisms underlying the thermal adaptation of different congener endemic bay scallops, which suggested that the increased heat tolerance of A. i. concentricus (compared with A. i. irradians) was associated with the higher expression of AiHSP70. Meanwhile, the -967 GG, -480 AA, -408 TT and -83 AG genotypes could be potential markers for scallop selection breeding with higher heat tolerance. PMID- 25028965 TI - Exploring causality between TV viewing and weight change in young and middle-aged adults. The Cardiovascular Risk in Young Finns study. AB - BACKGROUND: Television viewing time (TV time) is associated with increased weight and obesity, but it is unclear whether this relation is causal. METHODS AND RESULTS: We evaluated changes in TV time, waist circumference (waist) and body mass index (BMI) in participants of the population-based Cardiovascular Risk in Young Finns study (761 women, 626 men aged 33-50 years in 2011). Waist and BMI were measured, and TV time was self-reported in 2001, 2007, and 2011. Changes in waist and BMI between 2001 and 2011 were studied a) for the whole group, b) in groups with constantly low (<= 1 h/d), moderate (1-3 h/d), or high (>= 3 h/d) TV time, and c) in groups with >= 1 hour in-/decrease in daily TV time between 2001 and 2011. BMIs in 1986 were also evaluated. We explored the causal relationship of TV time with waist and BMI by classical temporality criterion and recently introduced causal-discovery algorithms (pairwise causality measures). Both methods supported the hypothesis that TV time is causative to weight gain, and no evidence was found for reverse or bidirectional causality. Constantly low TV time was associated with less pronounced increase in waist and BMI, and waist and BMI increase was lower with decreased TV time (P<0.05). The increase in waist and BMI was at least 2-fold in the high TV time group compared to the low TV time group (P<0.05). Adjustment for age, sex, BMI/waist in 2001, physical activity, energy intake, or smoking did not change the results. CONCLUSIONS: In young and middle aged adults, constantly high TV time is temporally antecedent to BMI and waist increase. PMID- 25028966 TI - Associations between film preferences and risk factors for suicide: an online survey. AB - Several studies indicate that exposure to suicide in movies is linked to subsequent imitative suicidal behavior, so-called copycat suicides, but little is currently known about whether the link between exposure to suicidal movies and suicidality is reflected in individual film preferences. 943 individuals participated in an online survey. We assessed associations between preferred film genres as well as individual exposure to and rating of 50 pre-selected films (including 25 featuring a suicide) with suicidal ideation, hopelessness, depression, life satisfaction, and psychoticism. Multiple regression analyses showed that preferences for film noir movies and milieu dramas were associated with higher scores on suicidal ideation, depression and psychoticism, and low scores on life satisfaction. Furthermore, preferences for thrillers and horror movies as well as preferences for tragicomedies, tragedies and melodramas were associated with higher scores of some of the suicide risk factors. There was also a dose-response relationship between positive rating of suicide films and higher life satisfaction. Due to the cross-sectional design of the study causality cannot be assessed. Individual film genre preferences seem to reflect risk factors of suicide, with film genres focusing on sad contents being preferred by individuals with higher scores on suicide risk factors. However, suicide movies are more enjoyed by viewers with higher life satisfaction, which may reflect a better ability to cope with such content. PMID- 25028967 TI - Downregulation of Ras association domain family member 6 (RASSF6) underlies the treatment resistance of highly metastatic nasopharyngeal carcinoma cells. AB - Radiation and cisplatin-based chemotherapy are major treatments for nasopharyngeal carcinoma (NPC). However, a major impediment for further improving the cure rate is the development of treatment resistance with an undetermined molecular mechanism in metastatic NPC cells. Our established, highly metastatic NPC cells have been reported to be more resistant to cisplatin chemotherapy. In the present study, we found that Ras association domain family member 6 (RASSF6) was downregulated in highly metastatic cells but upregulated in low metastatic cells in comparison to their parental cell line. Ectopic-expression of RASSF6 enhanced the sensitivity of highly metastatic NPC cells to cisplatin or radiation by enhancing apoptosis. RASSF6 depletion conversely reduced treatment sensitivity by decreasing the apoptosis rate. Over-expression of RASSF6 in highly metastatic NPC cells could enhance the phosphorylation of JNK when exposed to cisplatin or radiation treatment, while knocking down RASSF6 in low metastatic NPC cells could reduce the level of phospho-JNK when exposed to the same treatments. The activation of JNK signaling by RASSF6 and its subsequent sensitivity to apoptosis in NPC cells could be inhibited by applying the JNK inhibitor SP600125. In conclusion, the downregulation of RASSF6 in highly metastatic NPC cells contributed to their treatment resistance, and over-expression of RASSF6 conferred treatment sensitivity to highly metastatic NPC cells by activating JNK signaling. RASSF6 could be a valuable molecular marker for identifying sensitive metastatic NPC tumors during cisplatin treatment or radiotherapy. PMID- 25028971 TI - Movement kinematics as an index of the level of motor skill: the case of Indian craftsmen stone knapping. AB - What are the differences between the movements of an expert exhibiting superior performance compared with those of a novice or even an experienced person? Adopting a functional approach to tool use, this study presents results from experimental field research on stone knapping from Indian craftsmen of different levels of skill. The results showed that the differences in the levels of motor skill appeared in movement variability rather than in particular kinematic content. The higher is the level of motor skill, the more kinematic solutions are used, the more stable are the functional and the more variable the nonfunctional joint loadings. This study strongly suggests that to really understand learning processes and motor expertise, naturalistic challenging activities that require years of practice need to be elicited. PMID- 25028969 TI - Methane production and methanogenic Archaea in the digestive tracts of millipedes (Diplopoda). AB - Methane production by intestinal methanogenic Archaea and their community structure were compared among phylogenetic lineages of millipedes. Tropical and temperate millipedes of 35 species and 17 families were investigated. Species that emitted methane were mostly in the juliform orders Julida, Spirobolida, and Spirostreptida. The irregular phylogenetic distribution of methane production correlated with the presence of the methanogen-specific mcrA gene. The study brings the first detailed survey of methanogens' diversity in the digestive tract of millipedes. Sequences related to Methanosarcinales, Methanobacteriales, Methanomicrobiales and some unclassified Archaea were detected using molecular profiling (DGGE). The differences in substrate preferences of the main lineages of methanogenic Archaea found in different millipede orders indicate that the composition of methanogen communities may reflect the differences in available substrates for methanogenesis or the presence of symbiotic protozoa in the digestive tract. We conclude that differences in methane production in the millipede gut reflect differences in the activity and proliferation of intestinal methanogens rather than an absolute inability of some millipede taxa to host methanogens. This inference was supported by the general presence of methanogenic activity in millipede faecal pellets and the presence of the 16S rRNA gene of methanogens in all tested taxa in the two main groups of millipedes, the Helminthophora and the Pentazonia. PMID- 25028968 TI - Small RNAs in the control of RpoS, CsgD, and biofilm architecture of Escherichia coli. AB - Amyloid curli fibers and cellulose are extracellular matrix components produced in the stationary phase top layer of E. coli macrocolonies, which confer physical protection, strong cohesion, elasticity, and wrinkled morphology to these biofilms. Curli and cellulose synthesis is controlled by a three-level transcription factor (TF) cascade with the RpoS sigma subunit of RNA polymerase at the top, the MerR-like TF MlrA, and the biofilm regulator CsgD, with two c-di GMP control modules acting as key switching devices. Additional signal input and fine-tuning is provided by an entire series of small RNAs-ArcZ, DsrA, RprA, McaS, OmrA/OmrB, GcvB, and RydC--that differentially control all three TF modules by direct mRNA interaction. This review not only summarizes the mechanisms of action of these sRNAs, but also addresses the question of how these sRNAs and the regulators they target contribute to building the intriguing three-dimensional microarchitecture and macromorphology of these biofilms. PMID- 25028970 TI - Content-based image retrieval using spatial layout information in brain tumor T1 weighted contrast-enhanced MR images. AB - This study aims to develop content-based image retrieval (CBIR) system for the retrieval of T1-weighted contrast-enhanced MR (CE-MR) images of brain tumors. When a tumor region is fed to the CBIR system as a query, the system attempts to retrieve tumors of the same pathological category. The bag-of-visual-words (BoVW) model with partition learning is incorporated into the system to extract informative features for representing the image contents. Furthermore, a distance metric learning algorithm called the Rank Error-based Metric Learning (REML) is proposed to reduce the semantic gap between low-level visual features and high level semantic concepts. The effectiveness of the proposed method is evaluated on a brain T1-weighted CE-MR dataset with three types of brain tumors (i.e., meningioma, glioma, and pituitary tumor). Using the BoVW model with partition learning, the mean average precision (mAP) of retrieval increases beyond 4.6% with the learned distance metrics compared with the spatial pyramid BoVW method. The distance metric learned by REML significantly outperforms three other existing distance metric learning methods in terms of mAP. The mAP of the CBIR system is as high as 91.8% using the proposed method, and the precision can reach 93.1% when the top 10 images are returned by the system. These preliminary results demonstrate that the proposed method is effective and feasible for the retrieval of brain tumors in T1-weighted CE-MR Images. PMID- 25028972 TI - Fluoroquinolone resistance mechanisms of Shigella flexneri isolated in Bangladesh. AB - OBJECTIVE: To investigate the prevalence and mechanisms of fluoroquinolone resistance in Shigella species isolated in Bangladesh and to compare with similar strains isolated in China. METHODS: A total of 3789 Shigella isolates collected from Clinical Microbiology Laboratory of icddr,b, during 2004-2010 were analyzed for antibiotic susceptibility. Analysis of plasmids, plasmid-mediated quinolone resistance genes, PFGE, and sequencing of genes of the quinolone-resistance determining regions (QRDR) were conducted in representative strains isolated in Bangladesh and compared with strains isolated in Zhengding, China. In addition, the role of efflux-pump was studied by using the efflux-pump inhibitor carbonyl cyanide-m-chlorophenylhydrazone (CCCP). RESULTS: Resistance to ciprofloxacin in Shigella species increased from 0% in 2004 to 44% in 2010 and S. flexneri was the predominant species. Of Shigella spp, ciprofloxacin resistant (CipR) strains were mostly found among S. flexneri (8.3%), followed by S. sonnei (1.5%). Within S. flexneri (n = 2181), 14.5% were resistance to ciprofloxacin of which serotype 2a was predominant (96%). MIC of ciprofloxacin, norfloxacin, and ofloxacin were 6-32 mg/L, 8-32 mg/L, and 8-24 mg/L, respectively in S. flexneri 2a isolates. Sequencing of QRDR genes of resistant isolates showed double mutations in gyrA gene (Ser83Leu, Asp87Asn/Gly) and single mutation in parC gene (Ser80Ile). A difference in amino acid substitution at position 87 was found between strains isolated in Bangladesh (Asp87Asn) and China (Asp87Gly) except for one. A novel mutation at position 211 (His->Tyr) in gyrA gene was detected only in the Bangladeshi strains. Susceptibility to ciprofloxacin was increased by the presence of CCCP indicating the involvement of energy dependent active efflux pumps. A single PFGE type was found in isolates from Bangladesh and China suggesting their genetic relatedness. CONCLUSIONS: Emergence of fluoroquinolone resistance in Shigella undermines a major challenge in current treatment strategies which needs to be followed up by using empirical therapeutic strategies. PMID- 25028974 TI - Preadoption adversity, MAOA, and behavioral adjustment in internationally adopted Chinese girls. AB - OBJECTIVES: We studied postinstitutionalized adopted Chinese girls to determine whether those with different variants of the MAOA gene promoter region (MAOA VNTR) differed in their internalizing and externalizing behavior problems and whether the MAOA genotype moderated the relation between preadoption adversity and current behavior problems. METHODS: MAOA genotyping was obtained for 94 girls (mean age: 9.2 years) and the number of 4-repeat (4R) alleles was determined (zero, one, or two). The adoptive mothers rated several indicators of preadoption adversity shortly after adoption (mean age at adoption 15.8 months) and completed the Child Behavior Checklist when the children were 8.1 years on average. RESULTS: No main effects were found for preadoption adversity. However, the MAOA genotype had a nominally significant effect (P<0.05) on internalizing problems. Regression analyses controlling for age, household income, authoritarian parenting, and family problems showed that among children with no physical signs of preadoption adversity, those carrying a greater number of 4R alleles scored significantly lower (P<0.01) on internalizing problems than those with fewer 4R alleles. Differences in internalizing scores related to the MAOA genotype were not observed for children who showed one or more physical signs of adversity at the time of adoption. A similar pattern was found for externalizing problems, although the results did not reach conventional levels of significance. CONCLUSION: Our results suggest that higher MAOA activity may be protective with respect to internalizing problems in internationally adopted Chinese girls, but that this protective effect decreases at higher levels of preadoption adversity. A similar pattern may exist for externalizing problems. PMID- 25028973 TI - Development of a lentivirus vector-based assay for non-destructive monitoring of cell fusion activity. AB - Cell-to-cell fusion can be quantified by endowing acceptor and donor cells with latent reporter genes/proteins and activators of these genes/proteins, respectively. One way to accomplish this goal is by using a bipartite lentivirus vector (LV)-based cell fusion assay system in which the cellular fusion partners are transduced with a flippase-activatable Photinus pyralis luciferase (PpLuc) expression unit (acceptor cells) or with a recombinant gene encoding FLPeNLS+, a nuclear-targeted and molecularly evolved version of flippase (donor cells). Fusion of both cell populations will lead to the FLPe-dependent generation of a functional PpLuc gene. PpLuc activity is typically measured in cell lysates, precluding consecutive analysis of one cell culture. Therefore, in this study the PpLuc-coding sequence was replaced by that of Gaussia princeps luciferase (GpLuc), a secretory protein allowing repeated analysis of the same cell culture. In myotubes the spread of FLPeNLS+ may be limited due to its nuclear localization signal (NLS) causing low signal outputs. To test this hypothesis, myoblasts were transduced with LVs encoding either FLPeNLS+ or an NLS-less version of FLPe (FLPeNLS-) and subsequently co-cultured in different ratios with myoblasts containing the FLPe-activatable GpLuc expression cassette. At different times after induction of cell-to-cell fusion the GpLuc activity in the culture medium was determined. FLPeNLS+ and FLPeNLS- both activated the latent GpLuc gene but when the percentage of FLPe-expressing myoblasts was limiting, FLPeNLS+ generally yielded slightly higher signals than FLPeNLS- while at low acceptor-to-donor cell ratios FLPeNLS- was usually superior. The ability of FLPeNLS+ to spread through myofibers and to induce reporter gene expression is thus not limited by its NLS. However, at high FLPe concentrations the presence of the NLS negatively affected reporter gene expression. In summary, a rapid and simple chemiluminescence assay for quantifying cell-to-cell fusion progression based on GpLuc has been developed. PMID- 25028975 TI - Contrast-enhanced FLAIR (fluid-attenuated inversion recovery) for evaluating mild traumatic brain injury. AB - PURPOSE: To evaluate whether adding a contrast-enhanced fluid-attenuated inversion recovery (FLAIR) sequence to routine magnetic resonance imaging (MRI) can detect additional abnormalities in the brains of symptomatic patients with mild traumatic brain injury. MATERIALS AND METHODS: Fifty-four patients with persistent symptoms following mild closed head injury were included in our retrospective study (M ? F = 32 ? 22, mean age: 59.8 +/- 16.4, age range: 26-84 years). All MRI examinations were obtained within 14 days after head trauma (mean: 3.2 +/- 4.1 days, range: 0.2-14 days). Two neuroradiologists recorded (1) the presence of traumatic brain lesions on MR images with and without contrast enhanced FLAIR images and (2) the pattern and location of meningeal enhancement depicted on contrast-enhanced FLAIR images. The number of additional traumatic brain lesions diagnosed with contrast-enhanced FLAIR was recorded. Correlations between meningeal enhancement and clinical findings were also evaluated. RESULTS: Traumatic brain lesions were detected on routine image sequences in 25 patients. Three additional cases of brain abnormality were detected with the contrast enhanced FLAIR images. Meningeal enhancement was identified on contrast-enhanced FLAIR images in 9 cases while the other routine image sequences showed no findings of traumatic brain injury. Overall, the additional contrast-enhanced FLAIR images revealed more extensive abnormalities than routine imaging in 37 cases (p<0.001). In multivariate logistic regression analysis, subdural hematoma and posttraumatic loss of consciousness showed a significant association with meningeal enhancement on contrast-enhanced FLAIR images, with odds ratios 13.068 (95% confidence interval 2.037 to 83.852), and 15.487 (95% confidence interval 2.545 to 94.228), respectively. CONCLUSION: Meningeal enhancement on contrast enhanced FLAIR images can help detect traumatic brain lesions as well as additional abnormalities not identified on routine unenhanced MRI. Therefore contrast-enhanced FLAIR MR imaging is recommended when a contrast MR study is indicated in a patient with a symptomatic prior closed mild head injury. PMID- 25028976 TI - Informing comprehensive HIV prevention: a situational analysis of the HIV prevention and care context, North West Province South Africa. AB - OBJECTIVE: Building a successful combination prevention program requires understanding the community's local epidemiological profile, the social community norms that shape vulnerability to HIV and access to care, and the available community resources. We carried out a situational analysis in order to shape a comprehensive HIV prevention program that address local barriers to care at multiple contextual levels in the North West Province of South Africa. METHOD: The situational analysis was conducted in two sub-districts in 2012 and guided by an adaptation of WHO's Strategic Approach, a predominantly qualitative method, including observation of service delivery points and in-depth interviews and focus groups with local leaders, providers, and community members, in order to recommend context-specific HIV prevention strategies. Analysis began during fieldwork with nightly discussions of findings and continued with coding original textual data from the fieldwork notebooks and a select number of recorded interviews. RESULTS: We conducted over 200 individual and group interviews and gleaned four principal social barriers to HIV prevention and care, including: HIV fatalism, traditional gender norms, HIV-related stigma, and challenges with communication around HIV, all of which fuel the HIV epidemic. At the different levels of response needed to stem the epidemic, we found evidence of national policies and programs that are mitigating the social risk factors but little community-based responses that address social risk factors to HIV. CONCLUSIONS: Understanding social and structural barriers to care helped shape our comprehensive HIV prevention program, which address the four 'themes' identified into each component of the program. Activities are underway to engage communities, offer community-based testing in high transmission areas, community stigma reduction, and a positive health, dignity and prevention program for stigma reduction and improve communication skills. The situational analysis process successfully shaped key programmatic decisions and cultivated a deeper collaboration with local stakeholders to support program implementation. PMID- 25028979 TI - Coronary calcium scoring and computed tomography angiography: current indications, future applications. AB - Cardiac computed tomography (CT) has evolved at a rapid pace over the last few years. The improved spatial and temporal resolution allows collection of valuable information about the coronary arteries and atherosclerosis not obtainable by other noninvasive modalities. Coronary artery calcium acquisition is more straightforward, and large datasets are available to help validate its use in risk stratification and prediction of future events. The data from CT angiography has excellent negative predictive value to rule out stenosis, with potential use in plaque characterization to predict plaque vulnerability and perfusion. In addition, a recent novel technique with fractional flow reserve CT (FFRCT) has been shown to predict ischemia-causing lesions noninvasively. The ability of FFRCT to reduce the need for invasive angiography has recently been studied for the third time in a multicenter study, which showed high concordance with the results of invasive fractional flow reserve. PMID- 25028978 TI - Microvascular endothelial dysfunction predicts the development of erectile dysfunction in men with coronary atherosclerosis without critical stenoses. AB - BACKGROUND: Erectile dysfunction (ED) is associated with an increased risk for cardiovascular disease, stroke, and all-cause mortality, independent of conventional cardiovascular risk factors. Coronary endothelial dysfunction is independently associated with ED in men with early coronary atherosclerosis. We aimed to investigate whether coronary microvascular dysfunction predicts development of ED in patients presenting with coronary atherosclerosis without critical stenoses. PATIENTS AND METHODS: Coronary microvascular function was evaluated in 130 men with coronary atherosclerosis without critical stenoses by administration of intracoronary acetylcholine at the time of diagnostic study. After a mean follow-up of 8.4 years, patients were assessed for the development of ED by administration of a questionnaire. RESULTS: In all, 68 (50%) men had microvascular endothelial dysfunction at baseline; 35 (51%) men with microvascular endothelial dysfunction developed ED on follow-up compared with 19 (31%) men without microvascular endothelial dysfunction. Men who developed ED had a lower coronary blood flow response (% [INCREMENT]CBF) compared with men who did not develop ED, with mean+/-SD of 25.4+/-71.3 versus 81.7+/-120 (P=0.003). In univariate analysis, microvascular endothelial dysfunction was a predictor for the development of ED, with relative risk of 2.4 (1.2-4.9) (P=0.016). In multivariate logistic regression adjusting for traditional cardiovascular risk factors (age, hypertension, hyperlipidemia, diabetes, vascular disease, and family history of coronary artery disease), only microvascular endothelial dysfunction (P=0.027) and age (P=0.044) remained significant predictors of development of ED. CONCLUSION: Coronary microvascular dysfunction is a predictor of the development of ED in men with coronary atherosclerosis without critical stenoses. This study underscores the systemic involvement of the endothelial function in vascular disease. PMID- 25028981 TI - A study into the extracted ion number for NASICON structured Na3V2(PO4)3 in sodium-ion batteries. AB - Excellent C-rate and cycling performance with a high specific capacity of 117.6 mA h g(-1) have been achieved on NASICON-structure Na3V2(PO4)3 sodium-ion batteries. Two different Na sites, namely Na(1) and Na(2), are reported in the open three-dimensional framework, of which the ions at the Na(2) sites should be mainly responsible for the electrochemical properties. It is vitally important and interesting to find that there are two kinds of possible ion occupation of Na ions in Na3V2(PO4)3 and the investigation of ion-extraction number is firstly explored by discussing ion occupations with the help of first-principles calculations. The ion occupation of 0.75 for all Na sites is suitable for the configuration of [Na3V2(PO4)3]2, and the two-step extraction process accompanied by structure reorganization can account for the theoretical capacity of Na3V2(PO4)3. PMID- 25028980 TI - Renal phosphate transporters. AB - PURPOSE OF REVIEW: Phosphate homeostasis is tightly controlled by the coordinated activity of bone, kidney, intestine, and parathyroid gland. The renal phosphate transporters have emerged as key regulators of both total body phosphate homeostasis and serum phosphate concentration. This review focuses on the latest updates in phosphate transport and transporters with an emphasis on renal phosphate transporters. RECENT FINDINGS: Structure function analysis of type II sodium phosphate cotransporters has revealed motifs with significant similarity to those seen in other sodium-coupled solute transporters, identifying key amino acid residues important for solute binding and transport. Previously unidentified regulators of these transporters have been found, although their physiologic significance and interaction with more traditional regulators have not been established. Type II and type III sodium phosphate cotransporters play critical roles in bone, choroid plexus, and vascular physiology and pathophysiology. SUMMARY: Increasing knowledge of structure function relationships for sodium phosphate cotransporters, as well as greater appreciation for the complexity of their regulation and role in renal and nonrenal tissue, brings the promise of newer, more specific treatments for disorders of phosphate homeostasis. VIDEO ABSTRACT: http://links.lww.com/CONH/A10. PMID- 25028982 TI - The effect of maximal physical exercise on relationships between the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) and transcriptional activity of CYP1A2 in young ice hockey players. AB - BACKGROUND: The maximal physical exercise influences on changes in GH, IGF-1 concentrations and activity of CYP1A2. The aim of this study was to answer the question whether the change of endogenous GH and IGF-1 influenced the expression of CYP1A2 and whether these changes correlate with others parameters of blood and test. METHODS: The twenty ice young hockey players were subjected to maximal exercise cycle test. The test duration was mean 21.0 +/- 2.4 min, and work done was mean 3261.3 +/- 558.3 J/kg. In blood samples collected before and after the exercise were evaluated: concentrations of GH and IGF-1 which were determined in the serum by IRMA method and the transcriptional activity of CYP1A2 in RNA isolated from whole blood by the QRT-PCR reaction. RESULTS: Before the exercise the median of GH was mean 0.31 +/- 0.23 MUU/mL and after the exercise increased to mean 21.6 +/- 16.6 MUU/mL (P<0.001). Mean of serum IGF-1 level before the exercise and immediately after test did not change. Statistically significant increase in value of Ct for CYP1A2 (P<0.001) was found. CONCLUSION: The results of the study showed that: an intense exercise of young ice hockey players led to a significant increase in GH concentration, which caused the Ct values of CYP1A2 increase, whereas IGF-1 did not change. GH and IGF-1 levels after the exercise depended on the work done and the relative levels of CYP1A2 expression correlated with the time and the amount of work done by the athletes. PMID- 25028983 TI - Impact of cool and warm water immersion on 50-m sprint performance and lactate recovery in swimmers. AB - AIM: The purpose of this study was to investigate the impact of recovery by cool or warm water immersion, between two 50-m sprints on performance determinants and lactate responses in simulated competition conditions. METHODS: Eight well trained sprint swimmers (21 +/- 2.4 years), after an initial warm-up and 15 minutes recovery with no immersion (NI), performed a maximal 50 m sprint. A second 50 m sprint followed after a second 15-minute recovery period with passive immersion in either warm (WI, 30 degrees C), or cool water (CI, 26.7 degrees C). In a crossover design, all subjects repeated the trial 48 hours later utilizing the alternate immersion temperature. During the 50-m sprints, time and stroke characteristics were recorded. Blood lactate and heart rates were measured before and after the trials. Strength and flexibility were recorded before and after immersions and ratings of perceived exertion were evaluated. RESULTS: There were no significant differences in time, event velocity, or stroke rate, between any of the trials. With WI, a significant reduction of handgrip strength was observed (P=0.029) with lower ratings of perceived exertion observed after the sprint. Higher resting lactate levels were recorded, prior to swimming, after both the 15-minute WI and CI water recoveries (P<0.01) as compared to NI. No correlation was observed between swim performance times and starting or peak lactate levels, with any type of recovery intervention (R2=0.047; slope NS from zero). CONCLUSION: Recovery by cool (26.7 degrees C) or warm (30 degrees C) water immersion does not affect velocity or stroke characteristics in a 50-m freestyle sprint, even when widely employed performance related determinants such as resting lactate levels and perceived exertion are not optimal. PMID- 25028984 TI - Simulated hypoxia does not further improve aerobic capacity during sprint interval training. AB - AIM: The aim of this study was to investigate the use of hypoxic sprint interval training (SIT) for the improvement of aerobic capacity. METHOD: Twenty-seven participants (mean+/-SD), age 21+/-1 yrs, body mass 72.4+/-9.7 kg and height 175+/-7 cm, completed an VO2peak Incremental Exercise Test and time to exhaustion (TTE) trial (80% VO2peak) pre and post SIT. Participants were randomly assigned to either, control (CONT), normoxic (NORM) or hypoxic (FiO2: 0.15) (HYP) conditions. SIT involved 30 s sprints interspersed with 4 min rest. The number of sprints progressed from four to seven over six sessions separated by 1-2 days rest. Two-way mixed design ANOVA was performed to determine changes between conditions. RESULTS: VO2peak improved (P<0.05) pre to post SIT in NORM (11.2+/ 10.8%) and HYP (10.9+/-6.2%), but not CONT (0.7+/-14.3%). TTE post SIT was significantly improved from pre SIT in NORM and HYP but not CONT (CONT=1+/-6, NORM=56+/-25, HYP=34+/-25%, P<0.05). Peak and recovery heart rate was lower in NORM (P<0.05) than HYP as SIT sessions progressed. SpO2 (%) was lower in HYP (86.1+/-4.3%) compared to NORM (97.1+/-0.7%), decreasing within all HYP sessions, and increasing with SIT. CONCLUSION: Hypoxic and normoxic SIT caused improvement in VO2peak and TTE compared to a control. Hypoxic SIT did not cause further improvements, indicating hypoxia based SIT offers no additional benefit for improvement of endurance performance. PMID- 25028985 TI - Short-term heart rate variability in asthmatic obese children: effect of exhaustive exercise and different humidity conditions. AB - AIM: Asthmatic obese children experience changes in functional capacity and autonomic control. Previous heart rate variability (HRV) studies were based on 24 hour recordings, little research has been conducted on the short-term HRV in asthmatic obese children, primarily during physical effort indifferent environmental humidity conditions. The aim of this study was to evaluate the effect of aerobic activity on short-term HRV in asthmatic obese children under two different environmental humidity conditions. METHODS: Ten obese boys with mild asthma as experimental group and 15 obese healthy boys with the same conditions were involved as a control group. Protocol included progressive and exhaustive aerobic activities on a calibrated ergometer pedal bicycle in two various environmental humidity 35+/-5% and 65+/-5%. HRV was measured by PADSY MEDSET Holter monitoring device during three phases; pre-test, mid-test and post test. Then, short-term HRV was assessed from calculation of the mean R-R interval measured on HRV at each phases. RESULTS: HRV significantly decreased at mid-test and post-test among asthmatic and health children. However, the aforesaid changes were significantly higher in the asthmatic than health children following. Moreover, decrease of short-term HRV was significantly greater in the 35+/-5% than 65+/-5% environmental humidity. CONCLUSION: Our findings suggest from the autonomic standpoint, asthmatic and non-asthmatic children respond differently to exhaustive exercise induced stress. Aerobic exercise at an environment with high humidity compared with the low humidity appears to have additional benefits on short-term HRV in that it enhances the parasympathetic and autonomic modulation of the heart in asthmatic obese children. PMID- 25028986 TI - Acute obturator internus muscle strain in a rugby player: a case report. AB - A 28-year-old male rugby player presented with severe onset of right hip pain when he fell awkward after a ruck during an international match. A rare case of an acute strain of the obturator internus muscle, a deep muscle of the hip joint, is reported, which resolved completely after a period of rest and intense active physical therapy. PMID- 25028987 TI - High-risk enteric pathogens associated with HIV infection and HIV exposure in Kenyan children with acute diarrhoea. AB - OBJECTIVE: HIV infection is an established risk for diarrhoeal severity, less is known about specific enteric pathogens associated with HIV status. We determined associations of selected enteric pathogens with HIV infection and HIV exposure among Kenyan children. DESIGN: A cross-sectional study among 6 months to 15 year olds presenting to two Western Kenya District hospitals with acute diarrhoea between 2011 and 2013. METHODS: Stool was tested using standard bacterial culture and microscopy for ova and parasites. HIV status was obtained from children and mothers. Enteric pathogen prevalence was compared between HIV-infected and HIV uninfected children and between HIV-exposed uninfected (HEU) and HIV-unexposed. Unadjusted and adjusted prevalence ratios for selected pathogens by HIV status were estimated using relative risk (RR) regression. Age, site, income, household crowding, water source/treatment, anthropometrics, cotrimoxazole use and breastfeeding history were accounted for in multivariable models. RESULTS: Among 1076 children, median age was 22 months (interquartile range: 11-42 months), 56 (5.2%) were HIV-infected and 105 (11.3%) of 926 HIV-uninfected children in whom maternal HIV status was obtained were HIV-exposed. The following organisms were most frequently isolated from stool: enteroaggregative Escherichia coli (13.3%), Giardia species (spp.) (11.1%), Campylobacter spp. (6.3%), enteropathogenic E. coli (EPEC) (6.1%) and Cryptosporidium spp. (3.7%). Accounting for age, HIV infection was associated with typical EPEC infection (prevalence ratio 3.70, P = 0.002) while HIV-exposure was associated with Cryptosporidium among HIV uninfected children (prevalence ratio 2.81, P = 0.005). CONCLUSION: EPEC and Cryptosporidium infections were more common in HIV-infected and HIV-exposed children, respectively. This could explain the increased mortality attributed to these pathogens in other studies. Interventions targeting EPEC and Cryptosporidium may reduce morbidity and mortality in high HIV-prevalence settings. PMID- 25028988 TI - Supply-and-demand discrepancy in academic pigmented lesion clinics: a case for a new health care delivery model. AB - IMPORTANCE: There is an increasing demand for a limited number of pigmented lesion clinic (PLC) visits at dermatology centers. OBJECTIVE: To determine the proportion of visits to PLCs that are more frequent ("additional screening") than the recommended ("standard") follow-up schedule and to determine if certain patient characteristics correlate with the demand for these visits. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical chart review of all PLC visits at an academic dermatology center from October 2010 to January 2012. A total of 609 patients associated with 1756 visits were identified. Of these, 25 patients associated with 26 visits were excluded owing to lack of melanoma diagnosis or risk factors, leaving 584 patients and 1730 visits. Diagnoses of these patients included in situ and invasive melanoma, dysplastic nevi, Spitz nevi, atypical nevus syndrome, family history of melanoma only, and other risk factors. The mean (SD) age was 48 (16) years, and 235 (40.2%) of the patients were male. MAIN OUTCOMES AND MEASURES: The proportion of additional screening visits compared with standard visits. Standard visits were defined as occurring at the following frequencies: annually for mildly dysplastic nevi, Spitz nevi, or solely family history of melanoma; biannually for the first year, then annually thereafter for moderately dysplastic nevi or atypical nevus syndrome; biannually for up to 3 years, then annually thereafter for severely dysplastic nevi or melanomas in situ; every 3 months for 2 years, biannually for the following 2 years, then annually thereafter for invasive melanoma. RESULTS: A total of 1400 visits (80.9%) were standard, 257 (14.9%) were for additional screening, and 73 (4.2%) were "problem focused." Thirty percent of patients had at least 1 additional screening visit. The distribution of diagnoses among standard vs additional screening visits differed significantly, with "family history only" and "other risk factors" taking up a larger percentage of standard visits (15.1%) than the percentage of additional screening visits (8.9%), and all other diagnoses being better represented among additional screening visits (P = .04). No particular patient characteristic described those who sought additional screening visits. CONCLUSIONS AND RELEVANCE: A substantial proportion of additional screening PLC visits exist and are desired by all patients with pigmented lesions. We propose alternative clinic models, such as diagnosis-specific, adjunctive fee-for additional-service, and teledermatology clinics to meet patient needs while creating resources to expand PLC visits. PMID- 25028989 TI - Comparing temporal aspects of visual, tactile, and microstimulation feedback for motor control. AB - OBJECTIVES: Current brain-computer interfaces (BCIs) rely on visual feedback, requiring sustained visual attention to use the device. Improvements to BCIs may stem from the development of an effective way to provide quick feedback independent of vision. Tactile stimuli, either delivered on the skin surface, or directly to the brain via microstimulation in somatosensory cortex, could serve that purpose. We examined the effectiveness of vibrotactile stimuli and microstimulation as a means of non-visual feedback by using a fundamental element of feedback: the ability to react to a stimulus while already in motion. APPROACH: Human and monkey subjects performed a center-out reach task which was, on occasion, interrupted with a stimulus cue that instructed a change in reach target. MAIN RESULTS: Subjects generally responded faster to tactile cues than to visual cues. However, when we delivered cues via microstimuation in a monkey, its response was slower on average than for both tactile and visual cues. SIGNIFICANCE: Tactile and microstimulation feedback can be used to rapidly adjust movements mid-flight. The relatively slow speed of microstimulation is surprising and warrants further investigation. Overall, these results highlight the importance of considering temporal aspects of feedback when designing alternative forms of feedback for BCIs. PMID- 25028990 TI - Microdevices for examining immunological responses of single cells to HIV. AB - More than 60 million people in the world have been diagnosed with HIV infections since the virus was recognized as the causative agent of AIDS in the 1980s. Even though more than half of the infected patients have died, effective disease treatment and prevention measures have not been established. ART (antiretroviral therapy) is the only proven HIV treatment that sustains the suppression of patient viraemia. Current routine approaches to treat HIV infections are targeted at developing vaccines that will induce humoral or cell memory immune responses. However, developing an effective vaccine has been challenging because the HIV mutates rapidly, which allows the virus to evade immune surveillances established against the previous strain. In addition, the virus is able to quickly establish a reservoir and treatment is difficult because of the general lack of knowledge about HIV immune response mechanisms. This review introduces common disease symptoms and the progression of HIV infection with a brief summary of the current treatment approaches. Different cellular immune responses against HIV are also discussed, with emphasis on a nanotechnology research that has focused on probing T-cell response to HIV infection. Furthermore, we discuss recent noteworthy nanotechnology updates on T-cell response screening that is focused on HIV infection. Finally, we review potential future treatment strategies based on the correlations between T-cell response and HIV infection. PMID- 25028991 TI - Order effects of combined strength and endurance training on testosterone, cortisol, growth hormone, and IGF-1 binding protein 3 in concurrently trained men. AB - Concurrent training (CT) has been widely used in fitness centers to simultaneously optimize cardiovascular and neuromuscular fitness, and induce a high-energy expenditure. Therefore, the aim of this study was to compare the acute effects of 2 different orders of CT on hormonal responses in concurrently trained men. Fourteen men (mean +/- SD: 24.7 +/- 5.1 years) were randomly divided into 2 groups: endurance training followed by strength (ES, n = 7) and strength training followed by endurance (SE, n = 7). Serum concentrations of testosterone, cortisol, growth hormone, and IGF-1 binding protein 3 (IGFBP-3) were measured before and after both training orders. A significant interaction between exercise order and time was only found in the IGFBP-3 levels (p = 0.022). The testosterone and IGFBP-3 concentrations significantly increased in the ES group after the exercise trainings (57.7 +/- 35.1%, p = 0.013 and 17.0 +/- 15.5%, p = 0.032, respectively) but did not change significantly in the SE group (15.5 +/- 36.6%, p = 0.527 and -4.2 +/- 13.9%, p = 0.421, respectively). Conversely, cortisol and growth hormone concentrations significantly increased in both ES (169.2 +/- 191.0%, p = 0.021 and 13,296.8 +/- 13,009.5%, p = 0.013, respectively) and SE (92.2 +/- 81.5%, p = 0.017 and 12,346.2 +/- 9714.1%, p = 0.001, respectively) groups compared with baseline values. No significant correlations were found between the changes in the hormonal concentrations. In conclusion, these results suggest that immediately postexercise testosterone and IGFPB-3 responses are significantly increased only after the ES order. Therefore, an ES training order should be prescribed if the main focus of the training intervention is to induce an acute postexercise anabolic environment. PMID- 25028992 TI - Effect of inspiratory muscle warm-up on submaximal rowing performance. AB - Performing inspiratory muscle warm-up might increase exercise performance. The aim of this study was to investigate the impact of inspiratory muscle warm-up to submaximal rowing performance and to find if there is an effect on lactic acid accumulation and breathing parameters. Ten competitive male rowers aged between 19 and 27 years (age, 23.1 +/- 3.8 years; height, 188.1 +/- 6.3 cm; body mass, 85.6 +/- 6.6 kg) were tested 3 times. During the first visit, maximal inspiratory pressure (MIP) assessment and the incremental rowing test were performed to measure maximal oxygen consumption and maximal aerobic power (Pamax). A submaximal intensity (90% Pamax) rowing test was performed twice with the standard rowing warm-up as test 1 and with the standard rowing warm-up and specific inspiratory muscle warm-up as test 2. During the 2 experimental tests, distance, duration, heart rate, breathing frequency, ventilation, peak oxygen consumption, and blood lactate concentration were measured. The only value that showed a significant difference between the test 1 and test 2 was breathing frequency (52.2 +/- 6.8 vs. 53.1 +/- 6.8, respectively). Heart rate and ventilation showed a tendency to decrease and increase, respectively, after the inspiratory muscle warm-up (p < 0.1). Despite some changes in respiratory parameters, the use of 40% MIP intensity warm-up is not suggested if the mean intensity of the competition is at submaximal level (at approximately 90% maximal oxygen consumption). In conclusion, the warm-up protocol of the respiratory muscles used in this study does not have a significant influence on submaximal endurance performance in highly trained male rowers. PMID- 25028993 TI - Can selected functional movement screen assessments be used to identify movement deficiencies that could affect multidirectional speed and jump performance? AB - The Functional Movement Screen (FMS) includes lower-body focused tests (deep squat [DS], hurdle step, in-line lunge) that could assist in identifying movement deficiencies affecting multidirectional sprinting and jumping, which are important qualities for team sports. However, the hypothesized relationship with athletic performance lacks supportive research. This study investigated relationships between the lower-body focused screens and overall FMS performance and multidirectional speed and jumping capabilities in team sport athletes. Twenty-two healthy men were assessed in the FMS, and multidirectional speed (0- to 5-m, 0- to 10-m, 0- to 20-m sprint intervals; 505 and between-leg turn differences, modified T-test and differences between initial movement to the left or right); and bilateral and unilateral multidirectional jumping (vertical [VJ], standing long [SLJ], and lateral jump) tests. Pearson's correlations (r) were used to calculate relationships between screening scores and performance tests (p <= 0.05). After the determination of any screens relating to athletic performance, subjects were stratified into groups (3 = high-performing group; 2 = intermediate-performing group; 1 = low-performing group) to investigate movement compensations. A 1-way analysis of variance (p <= 0.05) determined any between group differences. There were few significant correlations. The DS did moderately correlate with between-leg 505 difference (r = -0.423), and bilateral VJ (r = 0.428) and SLJ (r = -0.457). When stratified into groups according to DS score, high performers had a 13% greater SLJ when compared with intermediate performers, which was the only significant result. The FMS seems to have minimal capabilities for identifying movement deficiencies that could affect multidirectional speed and jumping in male team sport athletes. PMID- 25028994 TI - Inflammatory markers and adipocytokine responses to exercise training and detraining in men who are obese. AB - The purpose of this study was to compare the effects of nonlinear resistance training (NRT) and aerobic interval training (AIT), and detraining on selected inflammatory markers in men who are middle aged and obese. Subjects first were matched by aerobic capacity, age, and percentage body fat and then randomly assigned to NRT (n = 12), AIT (n = 10) and, control (CON, n = 11) groups. The experimental groups performed 3 weekly sessions for 12 weeks followed by a 4-week detraining period. Nonlinear resistance training consisted of 40-65 minutes of weight training with flexible periodization. Aerobic interval training consisted of running on a treadmill (4 * 4 minutes at 80-90% maximal heart rate, with 3 minute recovery intervals). Compared with CON, serum levels of interleukin 6 (IL 6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-alpha) did not significantly change after training, but adiponectin (ADPN) increased significantly only with AIT (5.09 +/- 2.29 vs. 4.36 +/- 0.84 MUg.ml). No significant changes in CRP and TNF-alpha occurred in both training groups after detraining, but ADPN (NRT: 3.6 +/- 1.2 and AIT: 3.4 +/- 1.7 vs. CON: 4.7 +/- 1.2 MUg.ml) and IL-6 (NRT: 5.8 +/- 3.3 and AIT: 5.5 +/- 2.9 vs. CON: 2.3 +/- 1.2 pg.ml) worsened significantly. Both the AIT and NRT were equally effective at reducing soluble intercellular cell adhesion molecule 1 (NRT: 187.2 +/- 117.5 and AIT: 215.2 +/- 142.4 vs. CON: 416.2 +/- 205.9 ng.ml) and insulin (NRT: 4.0 +/- 1.0 and AIT: 4.8 +/- 2.7 vs. CON: 7.4 +/- 3.0 MUU.ml) levels, but these variables returned to the pretraining levels after detraining. The practical applications are that both the AIT and NRT and detraining had similar effects on most inflammatory markers in men who are obese, but the AIT seems to have better anti inflammatory effects (as indicated by ADPN) compared with NRT. PMID- 25028995 TI - Overestimation of required recovery time during repeated sprint exercise with self-regulated recovery. AB - This study investigated the reliability and accuracy of self-regulated recovery time and performance during repeated sprinting. On 4 occasions, 14 men (24.5 +/- 5.0 years) completed 10 * 6 seconds cycle sprints against 7.5% body mass, self regulating (SR) recovery time to maintain performance. Subjects then repeated the test, but with a reduced recovery (RR) of 10% less recovery time. Across the first 4 trials, there were no between-trial differences in peak power output (PPO) or mean power output (MPO), recovery time, or fatigue index (p > 0.05). Random variation in recovery time was reduced across trials 3-4 (coefficient of variation [CV] = 7.5%, 95% confidence limits [CL] = 5.4-12.4%) compared with trials 1-2 (CV = 16.0, 95% CL = 11.4-27.0%) and 2-3 (CV = 10.1%, 95% CL = 7.2 16.7%) but was consistent across trials for PPO and MPO (between-trials CV, <=3.3%). There were no trial effects for any performance, physiological, or perceptual measures when comparing SR with RR (p > 0.05), although heart rate and perceptual measures increased with subsequent sprint efforts (p <= 0.05). After 2 familiarization trials, subjects can reliably self-regulate recovery time to maintain performance during repeated sprints. However, subjects overestimate the amount of recovery time required, as reducing this time by 10% had no effect on performance, perceptual, or physiological parameters. Self-regulated sprinting is potentially a reliable training tool, particularly for sprint training where maintenance of work is desired. However, overestimation of required recovery time means that performance improvements may not be achieved if the goal of training is improvement of repeated sprint performance with incomplete recovery. PMID- 25028996 TI - Physical qualities predict change-of-direction speed but not defensive agility in Australian rules football. AB - The purpose of this study was to determine the relationships between selected physical qualities, change-of-direction (COD) speed, and defensive agility performance in Australian Rules football players. Twenty-four male community level players were assessed on sprint acceleration (10-m time), maximum strength (3 repetition-maximum half squat), leg power (countermovement jump), reactive strength (drop jump), and a single COD speed test and a defensive agility test. Change-of-direction speed was correlated with reactive strength (r = -0.645, p = 0.001) and sprint acceleration (r = 0.510, p = 0.011). Multiple regression indicated that the combined physical qualities explained 56.7% of the variance associated with COD speed (adjusted R = 0.567, p <= 0.05). Participants were median split into faster and slower COD speed groups, and these were compared by independent t-tests. The faster group was significantly better (p <= 0.05) on the sprint acceleration and reactive strength tests (large effect size). The correlations between physical qualities and agility were trivial to small (r = 0.101 to 0.123, p > 0.05) and collectively explained only 14.2% of the variance associated with agility performance (adjusted R = -0.142, p > 0.05). When faster and slower agility groups were compared, there were trivial to moderate differences (p > 0.05) in all physical qualities. It was concluded that reactive strength and sprint acceleration are important for COD speed, but the physical qualities assessed are not associated with defensive agility performance. For agility tasks similar to those in this study, sprint and resistance training should not be emphasized, and training other factors, such as the development of sport-specific technique and cognitive skill, is recommended. PMID- 25028997 TI - Evaluation of a six-week whole-body vibration intervention on neuromuscular performance in older adults. AB - Research in the field of whole-body vibration (WBV) for the enhancement of neuromuscular performance is becoming increasingly popular. However, additional understanding of optimal WBV training protocols is still necessary to develop optimal and effective training and prevention concepts, especially for elderly people. The intention of this study was to evaluate a 6-week WBV intervention program based on optimal vibration loads adapted from the literature on lower limb strength parameters and performance, as well as on perceived exertion according to a subjective rating. A total of 21 older adults were allocated randomly into either a WBV training or control group (CO). Before and after the intervention period, jump height was measured during a countermovement jump. In addition, isolated isokinetic maximal knee extension and flexion strength, mean power, and work were recorded using a motor-driven dynamometer. Borg's scale for rating of perceived exertion was used to evaluate the intensity of WBV exercises within each training session. After the intervention period, jump height increased by 18.55% (p < 0.001) in the WBV group, whereas values of the CO remained unchanged. There were no statistically significant differences in isokinetic maximal strength, mean power, or work values in knee extension or flexion (all p > 0.05). Finally, the subjective perceived exertion of the WBV exercises and respective training parameters ranged between moderate rating levels of 7 and 13 of Borg's scale. Our data show that WBV is a feasible and safe training program for elderly people to increase multijoint strength performance of the lower limbs during a countermovement jump. This could help to determine the potential of WBV programs in training of the elderly to prevent age-related reduction of neuromuscular performance. PMID- 25028998 TI - Specific determination of maximal lactate steady state in soccer players. AB - The aim of this study was to establish the validity of the anaerobic threshold (AT) determined on the soccer-specific Hoff circuit (ATHoff) to predict the maximal lactate steady-state exercise intensity (MLSSHoff) with the ball. Sixteen soccer players (age: 16.0 +/- 0.5 years; body mass: 63.7 +/- 9.0 kg; and height: 169.4 +/- 5.3 cm) were submitted to 5 progressive efforts (7.0-11.0 km.h) with ball dribbling. Thereafter, 11 players were submitted to 3 efforts of 30 minutes at 100, 105, and 110% of ATHoff. The ATHoff corresponded to the speed relative to 3.5 mmol.L lactate concentration. The speed relative to 4.0 mmol.L was assumed to be ATHoff4.0, and the ATHoffBI was determined through bisegmented adjustment. For comparisons, Student's t-test, intraclass correlation coefficient (ICC), and Bland and Altman analyses were used. For reproducibility, ICC, typical error, and coefficient of variation were used. No significant difference was found between AT test and retest determined using different methods. A positive correlation was observed between ATHoff and ATHoff4.0. The MLSSHoff (10.6 +/- 1.3 km.h) was significantly different compared with ATHoff (10.2 +/- 1.2 km.h) and ATHoffBI (9.5 +/- 0.4 km.h) but did not show any difference from LAnHoff4.0 (10.7 +/- 1.4 km.h). The MLSSHoff presented high ICCs with ATHoff and ATHoff4.0 (ICC = 0.94; and ICC = 0.89; p <= 0.05, respectively), without significant correlation with ATHoffBI. The results suggest that AT determined on the Hoff circuit is reproducible and capable of predicting MLSS. The ATHoff4.0 was the method that presented a better approximation to MLSS. Therefore, it is possible to assess submaximal physiological variables through a specific circuit performed with the ball in young soccer players. PMID- 25028999 TI - Body composition and power performance improved after weight reduction in male athletes without hampering hormonal balance. AB - The aim of this study was to investigate the effects of a 4-week weight reduction period with high protein and reduced carbohydrate intake on body composition, explosive power, speed, serum hormones, and acid-base balance in male track and field jumpers and sprinters. Eight participants were assigned to a high weight reduction group (HWR; energy restriction 750 kcal.d) and 7 to a low weight reduction group (LWR; energy restriction 300 kcal.d). Energy and carbohydrate intake decreased significantly (p <= 0.05) only in HWR by 740 +/- 330 kcal.d and 130 +/- 29 g.d, respectively. Furthermore, total body mass and fat mass decreased (p <= 0.05) only in HWR by 2.2 +/- 1.0 kg and 1.7 +/- 1.6 kg, respectively. Fat free mass (FFM), serum testosterone, cortisol, and sex hormone-binding globulin did not change significantly. Ca ion and pH decreased (p <= 0.05) only in HWR (3.1 +/- 2.8% and 0.8 +/- 0.8%, respectively), whereas (Equation is included in full-text article.)declined (p <= 0.05) in both groups by 19.3 +/- 6.2% in HWR and by 13.1 +/- 8.5% in LWR. The countermovement jump and 20-m sprint time improved consistently (p <= 0.05) only in HWR, by 2.6 +/- 2.5 cm and 0.04 +/- 0.04 seconds, respectively. Finally, athletes with a fat percentage of 10% or more at the baseline were able to preserve FFM. In conclusion, altered acid-base balance but improved weight-bearing power performance was observed without negative consequences on serum hormones and FFM after a 4-week weight reduction of 0.5 kg.wk achieved by reduced carbohydrate but maintained high protein intake. PMID- 25029000 TI - Autonomic response to tactical pistol performance measured by heart rate variability. AB - This study evaluated changes in autonomic tone during a tactical pistol competition. At rest and during a match, heart rate variability (HRV) was examined in 28 healthy subjects. Heart rate variability time-domain variables (including interbeat interval [IBI]) and frequency-domain variables (low frequency [LF], high frequency [HF], total power [TP]) measured during shooting were subtracted from those measured during rest to produce Deltas. The shooting task involved several, rapid tactical maneuvers. Raw time to completion and inaccurate shots (points down [PDs]) were recorded and combined to form a match score where lower values indicated superior shooting performance. Mean (+/-SD) raw time was 135.9 +/- 34.1 seconds, PDs were 78 +/- 34, and match score was 175.3 +/- 39.8. Shooting decreased IBI (i.e., increased heart rate) and LF. DeltaLF, DeltaHF, and DeltaTP were independent of DeltaIBI. Raw time was significantly (p <= 0.05) correlated to shooting IBI (r = 0.404) and DeltaIBI (r = -0.426). Points down were significantly correlated to DeltaTP (r = 0.416) and DeltaLF (r = 0.376). Match score was significantly correlated to DeltaIBI (r = 0.458), DeltaHF (r = 0.467), DeltaLF (r = 0.377), and DeltaTP (r = 0.451). In conclusion, individuals with a greater decrease in IBI (and thus heart rate) performed better by accomplishing the match faster. Individuals with less change in stress-related HRV measures (LF, HF, and TP) performed better through improved accuracy. Thus, HRV-derived sympathetic response is significantly related to shooting performance and should be used to assess marksmanship effectiveness under duress. PMID- 25029001 TI - Effect of acute fatigue and training adaptation on countermovement jump performance in elite snowboard cross athletes. AB - Countermovement jump performance was examined in response to acute neuromuscular (NM) fatigue (study I) and chronic training (study II) in elite snowboard cross (SBX) athletes, through both typical (countermovement jump [CMJ]-TYP) and alternative (CMJ-ALT) CMJ variables. Seven (4 men and 3 women) elite (Olympic level) SBX athletes participated in study I, and 5 of the same athletes (2 men and 3 women) participated in study II. Countermovement jump variables relating to force, velocity, power, and time were measured during both eccentric and concentric jump phases, with CMJ-TYP variables reflecting CMJ output and CMJ-ALT variables reflecting CMJ mechanics. In study I, CMJ performance was assessed before and after a fatiguing lower-body exercise protocol, and in study II, CMJ performance was examined before and after a 19-week structured training block. Meaningful differences in CMJ performance were examined using the magnitude of change (effect sizes [ES]) for group and individual changes. Acute fatigue decreased peak force and eccentric function, while the duration of the jump increased. The structured training block increased peak force and eccentric function, while jump duration markedly decreased. In both study I and study II, the largest ES were associated with CMJ-ALT variables. The CMJ test seems a suitable monitoring tool in elite SBX athletes for the detection of both acute fatigue and training-adaptation. Compared with CMJ output, CMJ mechanics exhibits more marked and divergent changes after both acute NM fatigue and a structured training block. CMJ-ALT variables should therefore be incorporated into CMJ analysis. PMID- 25029002 TI - Time interval moderates the relationship between psyching-up and actual sprint performance. AB - This study attempted to test whether the strongest effect of psyching-up (PU) strategy on actual sprint performance can be observed when the strategy is used immediately (or almost) before performance compared with when there is a delay between PU and performance. To do so, 16 male sprinters (age, 20.6 +/- 1.3 years; body mass, 77.5 +/- 7.1 kg; height, 180.8 +/- 5.6 cm) were enrolled in a counterbalanced experimental design in which participants were randomly assigned to 10 sessions (2 [Experimental Condition: imagery vs. distraction] * 5 [Time Intervals: no interval, 1 minute, 2 minutes, 3 minutes, and 5 minutes]). Before performing the experimental tasks, participants rated: (a) the Hooper index, (b) their degree of self-confidence, and (c) after the completion of the experimental test; they rated their perceived effort. Findings showed that the imagery significantly improved sprint performance. Specifically, the imagery enhanced performance on the phase of acceleration (0-10 m) and on the overall sprint (0-30 m) when used immediately before performance and at 1- and 2-minute intervals but not for 3- and 5-minute intervals. These findings support the hypothesis that the potential effect of the PU strategy on performance vanishes over time. The pre experimental task Hooper and self-efficacy indexes did not change across the 10 experimental sessions, reinforcing the view that the observed performance changes were directly caused by the experimental manipulation and not through any altered status of the athletes (self-efficacy, fatigue/recovery, and stress). The potential mechanisms underlying such a process and practical applications are discussed. PMID- 25029003 TI - Quantification of training load, energy intake, and physiological adaptations during a rugby preseason: a case study from an elite European rugby union squad. AB - Rugby Union (RU) is a high-speed collision sport consisting of an intermittent activity profile. Given the extreme physical demands of the sport, significant emphasis is placed on players possessing high lean body mass while minimizing body fat. Anecdotally, the most significant changes in body composition are observed during the preseason; however, there are no objective data on the physiological demands and energy intake during this time. We therefore monitored 45 elite European RU players over the 10-week preseason period by assessing training load using Global Positioning System and session rate of perceived exertion (sRPE) while also assessing changes in anthropometry and physical performance. For forwards and backs, respectively, mean weekly distance covered was 9,774 m (1,404) and 11,585 m (1,810) with a total mean weekly sRPE of 3,398 (335) arbitrary units and 2,944 (410) arbitrary units. Mean daily energy intake was 14.8 MJ (1.9) and 13.3 MJ (1.9), carbohydrate (CHO) intake was 3.3 (0.7) and 4.14 (0.4) g.kg body mass, protein intake was 2.52 (0.3) and 2.59 (0.6) g.kg body mass, and fat intake was 1.0 (0.3) and 0.95 (0.3) g.kg body mass for forwards and backs, respectively. Markers of physical performance (1 repetition maximum strength, speed, and repeated sprint tests) and anthropometry (body fat and estimated lean mass) improved in all players. Interestingly, all players self selected a "low" CHO "high" protein diet. Based on physiological improvements the training load and energy intake seems appropriate, although further research is required to evaluate if such energy intakes would also be suitable for match day performance. PMID- 25029004 TI - A single electromyographic testing point is valid to monitor neuromuscular fatigue during continuous exercise. AB - Two different protocols for estimating the electromyographic fatigue threshold (EMGFT) have been proposed in the literature. These protocols are distinguished by the number of visits required to determine the EMGFT. The purpose of this study, therefore, was to statistically compare the estimated EMGFT from the single-visit incremental test and the multiple-visit constant workload tests for single-leg knee-extensor exercise. Seven healthy college-aged men [mean +/- SEM; age = 25.0 +/- 0.7 years] performed the incremental test and on separate occasions also performed 4 constant workload tests to voluntary exhaustion. The EMG amplitude was recorded from the rectus femoris muscle during all the testing sessions. For the single-visit test, the EMG amplitude vs. time relationship for each power output was examined using linear regression. For the multiple-visit tests, the EMG amplitude vs. time relationship was calculated for each constant power output. Thereafter, the power outputs were plotted as a function of the slope coefficient for the EMG amplitude vs. time relationships, and linear regression was performed. The EMGFT was defined as the intersection of the regression line with the y-intercept of the power output vs. slope coefficient plot. The results indicated that the estimated EMGFT from the single-visit test was significantly (p = 0.012) lower than the estimate from the multiple-visit tests. Because this test is performed during a single visit and concludes within 20 minutes, it may also have application in clinical rehabilitation settings and not merely for an athletic population. PMID- 25029005 TI - Acute effects of caffeine on strength and muscle activation of the elbow flexors. AB - The purpose of this study was to examine the effects of caffeine on strength and muscle activation of the elbow flexors. Thirteen recreationally active male volunteers (mean +/- SD, age: 21.38 +/- 1.26 years) came to the laboratory 4 times. Visit 1 served as a familiarization visit. During visits 2 through 4, subjects ingested a randomly assigned drink, with or without caffeine (0, 5, or 10 mg.kg of body mass), and performed 3 maximal isometric muscle actions of the elbow flexors 60 minutes after ingestion. Maximal strength and rate of torque development (RTD) were recorded. Electromyographic (EMG) and mechanomyographic (MMG) amplitude and frequency, and electromechanical delay (EMD), and phonomechanical delay (PMD) were measured from the biceps brachii. The results indicated that the ingestion of 0 (placebo), 5, or 10 mg.kg of body mass of caffeine did not significantly influence (p > 0.05) peak torque, RTD, normalized EMG amplitude or frequency, normalized MMG amplitude, or EMD and PMD. Normalized MMG frequency was significantly lower (p <= 0.05) following ingestion of 5 mg.kg of body mass of caffeine compared with the placebo trial. This was most likely an isolated finding because MMG frequency was the only variable to have a significant difference across all trials. The results suggested that ingestion of either 5 or 10 mg.kg of body mass of caffeine does not provide an ergogenic effect for the elbow flexors during isometric muscle actions. PMID- 25029006 TI - Dehydration and hyponatremia in professional rugby union players: a cohort study observing english premiership rugby union players during match play, field, and gym training in cool environmental conditions. AB - Fluid and sodium balance is important for performance and health; however, limited data in rugby union players exist. The purpose of the study was to evaluate body mass (BM) change (dehydration) and blood[Na] change during exercise. Data were collected from 10 premiership rugby union players, over a 4 week period. Observations included match play (23 subject observations), field (45 subject observations), and gym (33 subject observations) training sessions. Arrival urine samples were analyzed for osmolality, and samples during exercise were analyzed for [Na]. Body mass and blood[Na] were determined pre- and postexercise. Sweat[Na] was analyzed from sweat patches worn during exercise, and fluid intake was measured during exercise. Calculations of fluid and Na loss were made. Mean arrival urine osmolality was 423 +/- 157 mOsm.kg, suggesting players were adequately hydrated. After match play, field, and gym training, BM loss was 1.0 +/- 0.7, 0.3 +/- 0.6, and 0.1 +/- 0.6%, respectively. Fluid loss was significantly greater during match play (1.404 +/- 0.977 kg) than field (1.008 +/ 0.447 kg, p = 0.021) and gym training (0.639 +/- 0.536 kg, p < 0.001). Fluid intake was 0.955 +/- 0.562, 1.224 +/- 0.601, and 0.987 +/- 0.503 kg during match play, field, and gym training, respectively. On 43% of observations, players were hyponatremic when BM increased, 57% when BM was maintained, and 35% when there was a BM loss of 0.1-0.9%. Blood[Na] was the representative of normonatremia when BM loss was >1.0%. The findings demonstrate that rugby union players are adequately hydrated on arrival, fluid intake is excessive compared with fluid loss, and some players are at risk of developing hyponatremia. PMID- 25029007 TI - The power output and sprinting performance of young swimmers. AB - The aim of this article was to compare swimming power output between boys and girls and to model the relationship between swimming power output and sprinting performance in young swimmers. One hundred young swimmers (49 boys and 51 girls, aged between 11 and 13 years) underwent a test battery including anthropometrics (body mass, height, arm span [AS], and trunk transverse surface area), kinematic and efficiency (velocity, stroke frequency, stroke length, speed fluctuation, normalized speed fluctuation, stroke index, and Froude efficiency), hydrodynamics (active drag and active drag coefficient), and power output (power to overcome drag, power to transfer kinetic energy to water, and external power) assessments and sprinting performance (official 100 freestyle race). All variables but the trunk transverse surface area, stroke length normalize to AS, speed fluctuation, active drag coefficient, and Froude efficiency were significantly higher in boys than in girls with moderate-strong effects. Comparing both sexes but controlling the effect of the sprinting performance, most variables presented a no significant variation. There was a significant and strong relationship between power output and sprinting performance: y = 24.179x (R = 0.426; standard error of estimation = 0.485; p < 0.001). As a conclusion, boys presented better performances than girls because of their higher power output. There is a cubed relationship between power output and sprinting performance in young swimmers. PMID- 25029008 TI - Docosahexaenoic acid affects markers of inflammation and muscle damage after eccentric exercise. AB - The effect of docosahexaenoic acid (DHA) on inflammatory and muscle damage response to acute eccentric exercise and to the subsequent initiation of a resistance training program was studied in 41 untrained men. Subjects consumed either 2 g.d of either DHA or placebo (PL) for 28 days before a 17-day exercise phase (day 1 to day 17) that began with an eccentric exercise bout of the elbow flexors (day 1). For analysis, the exercise period was further divided into an acute response phase (day 1-4). Isometric muscle strength (STR), range of motion (ROM), and delayed onset muscle soreness (DOMS) were measured on days 1, 2, 3, 4, 7, 12, and 17. Fasted blood was measured for interleukin 6 (IL-6), interleukin 1 receptor antagonist, C-reactive protein (CRP), and creatine kinase (CK) on days 1, 2, and 4. Serum CK and CRP were also measured in blood collected on days 7, 12, and 17. In the acute phase, DHA significantly reduced the serum CK (12.5%) and the IL-6 response (32%) but did not affect STR or DOMS. Over the entire 17 day resistance exercise period, DOMS area under the curve was 183.2 +/- 96.2 for DHA and 203.2 +/- 120.9 for PL (p = 0.054) and the CK response was numerically lower for DHA (p = 0.093). Docosahexaenoic acid supplementation reduced some but not all indicators of muscle damage and inflammation in the 4 days after an acute eccentric exercise bout but did not significantly affect the response to initiation of resistance exercise. PMID- 25029009 TI - How does music aid 5 km of running? AB - This research investigated the effects of music and its time of application on a 5-km run. Fifteen well-trained male long-distance runners (24.87 +/- 2.47 years; 78.87 +/- 10.57 kg; 178 +/- 07 cm) participated in this study. Five randomized experimental conditions during a 5-km run on an official track were tested (PM: motivational songs, applied before 5 km of running; SM: slow motivational songs, applied during 5 km of running; FM: fast and motivational songs, applied during 5 km of running; CS: calm songs, applied after 5 km of running; CO: control condition). Psychophysiological assessments were performed before (functional near-infrared spectroscopy, heart rate variability [HRV], valence, and arousal), during (performance time, heart rate, and rate of perceived exertion [RPE]), and after (mood, RPE, and HRV) tests. The chosen songs were considered pleasurable and capable of activating. Furthermore, they activated the 3 assessed prefrontal cortex (PFC) areas (medial, right dorsolateral, and left dorsolateral) similarly, generating positive emotional consequences by autonomous system analysis. The first 800 m was accomplished faster for SM and FM compared with other conditions (p <= 0.05); moreover, there was a high probability of improving running performance when music was applied (SM: 89%; FM: 85%; PM: 39%). Finally, music was capable of accelerating vagal tonus after 5 km of running with CS (p <= 0.05). In conclusion, music was able to activate the PFC area, minimize perceptions, improve performance, and accelerate recovery during 5 km of running. PMID- 25029010 TI - Salivary hormone response to 12-week block-periodized training in naval special warfare operators. AB - Naval Special Warfare (NSW) Operators are expected to maintain a high degree of physical readiness requiring continual operational training. The physiological and psychological demands associated with operational training can result in physiological consequences evidenced by hormonal alterations justifying the need for periodized training to maintain or improve physical readiness. This study examined the pattern and time course of hormone changes during 12-week block periodized training program (BP) in NSW Operators undergoing routine training. Eighteen NSW Operators (31 +/- 6 years, 86.6 +/- 9.0 kg, 176.2 +/- 5.9 cm, 17.5 +/- 6.5% fat) participated in a 12-week BP during routine operational training. Salivary free testosterone (FT), dehydroepiandrosterone sulfate (DHEA-S), and cortisol (C) were obtained at 4 time points coincident with changes in intensity and volume. In the second block of training in which intensity and volume were increased, FT and C increased by 20.3 +/- 7.4 and 20.8 +/- 9.9%, respectively. Free testosterone and C returned to baseline values concomitant with the decrease in intensity and volume at the conclusion of the third block of training. No significant differences were observed in FT-to-C ratio over the course of training. DHEA-S increased 23.1 +/- 11.0% following block 1, with a further increase observed following block 2 (57.0 +/- 17.4%). Our data indicate training following BP produces a pattern and time course of hormone changes congruent with changes in intensity and volume suggesting BP as a potential training model for NSW Operators and other Special Forces Operators involved in operational training. PMID- 25029011 TI - Bioenergetical and Cardiac Adaptations of Pilots to a 24-Hour Team Kart Race. AB - This study aimed to evaluate energy expenditure (EE) and heart rate (HR) response in kart pilots to successive driving bouts during a 24-hour team race. Eight adult male pilots (22.8 +/- 4.1 years) participated to a team 24-hour speedway kart race in Le Mans (France). They alternatively piloted a 390 cm kart. Each relay was 45 minutes long and each pilot performed 4 relays. For each pilot, mean speeds were calculated from lap-to-lap duration recordings using a telemetric infrared timing device. Heart rate values were recorded continuously on 5-second intervals using a portable cardiometric device. Total energy expenditure (EET) and physical activity ratio (PAR) were determined by accelerometry. To pilot a kart during 45 minutes at a mean speed around 62 km.h induces a 300-kcal EET, corresponding to a 5.6-Mets PAR. This effort is responsive for a 73 b.min increase in HR, from 84.1 +/- 7.6 to 157.4 +/- 11.0 b.min (82% maximal heart rate intensity). However, during this relay period, HR values seemed independent to mean speed performance and bioenergetical values. Thus, in the context of the 24 hour team race, the variability in effort made during each relay and relay succession did not alter bioenergetical adaptation of pilots to kart driving. The high EE and HR values would be better explained by both emotional stress and environmental constraints such as speedway configuration and vibrations. The way how these factors specifically influence bioenergetical demand, and their relative importance, has to be specified to optimize training procedure and recommendations. PMID- 25029012 TI - Effectiveness of the modified progressive aerobic capacity endurance run test for assessing aerobic fitness in Hispanic children who are obese. AB - The purpose of this study was to evaluate the effectiveness of the progressive aerobic capacity endurance run (PACER) and a newly designed modified PACER (MPACER) for assessing aerobic fitness in Hispanic children who are obese. Thirty nine (aged 7-12 years) children who were considered obese (>= 95 th body mass index [BMI] percentile) and 16 children who were considered normal weight (<85th BMI percentile) participated in this study. Performance outcomes included test duration (in minutes) and exercise heart rate (HR) (first-stage and peak HR) for each test. Ninety-five percent confidence intervals and independent t-tests were used to assess differences in primary outcomes. Mean PACER test duration was 1.6 +/- 0.6 and 3.1 +/- 1.3 minutes for children who were obese and normal weight, respectively. Modified PACER duration was higher than 3 minutes for the obese (3.6 +/- 0.6 minutes) and normal weight (5.3 +/- 1.2 minutes) groups. Children first-stage HR, expressed as a percent of peak HR, was above the predicted anaerobic threshold during the PACER, but below the anaerobic threshold during the MPACER. Relative first-stage HR was not significantly different between groups for the PACER, but they were significantly different between groups for the MPACER. In conclusion, the MPACER was a better alternative than the PACER for assessing aerobic fitness in Hispanic children who were normal weight and obese. When validated, this modified field test could be used to assess aerobic fitness in Hispanic children, particularly those who are overweight or obese. Additionally, the study provides evidence in which physical educators, personal trainers, and others most apt to assess aerobic fitness in children who are obese, should modify tests originally designed for the population who are normal weight. PMID- 25029013 TI - Biomarkers of cardio-renal damage in chronic kidney disease: one size cannot fit all. AB - Biomarkers are useful tools for diagnosis and risk assessment of acute kidney injury and acute heart failure, particularly in ICU patients. Most biomarkers are produced or cleared by the kidney, so the presence of chronic kidney disease may affect their clinical reliability, particularly if the putative diagnosis of acute kidney injury or acute heart failure is based on a single measurement/single threshold approach. Better alternatives, such as establishing different diagnostic cutoff values per different chronic kidney disease strata or evaluating the diagnostic performance of a delta value (change from baseline levels) instead of a single threshold, should be carefully considered in critically ill patients with renal impairment and other co-morbidities. PMID- 25029014 TI - The impact of drug reimbursement policy on rates of testosterone replacement therapy among older men. AB - BACKGROUND: Despite a lack of data describing the long-term efficacy and safety of testosterone replacement therapy (TRT), prescribing of testosterone to older men has increased with the availability of topical formulations. The magnitude of this increase and the impact of formulary restrictions on testosterone prescribing are poorly characterized. METHODS: We conducted a time series analysis using the linked health administrative records of men aged 66 years or older in Ontario, Canada between January 1, 1997 and March 31, 2012. We used interventional autoregressive integrated moving average models to examine the impact of a restrictive drug reimbursement policy on testosterone prescribing and examined the demographic profile of men initiating testosterone in the final 2 years of the study period. RESULTS: A total of 28,477 men were dispensed testosterone over the study period. Overall testosterone prescribing declined 27.9% in the 6 months following the implementation of the restriction policy (9.5 to 6.9 men per 1000 eligible; p<0.01). However, the overall decrease was temporary and testosterone use exceeded pre-policy levels by the end of the study period (11.0 men per 1000 eligible), largely driven by prescriptions for topical testosterone (4.8 men per 1000 eligible). Only 6.3% of men who initiated testosterone had a documented diagnosis of hypogonadism, the main criteria for TRT reimbursement according to the new policy. CONCLUSION: Government-imposed restrictions did not influence long-term prescribing of testosterone to older men. By 2012, approximately 1 in every 90 men aged 66 or older was being treated with TRT, most with topical formulations. PMID- 25029015 TI - Association of symptoms following mild traumatic brain injury with posttraumatic stress disorder vs. postconcussion syndrome. AB - IMPORTANCE: A proportion of patients experience long-lasting symptoms following mild traumatic brain injury (MTBI). The postconcussion syndrome (PCS), included in the DSM-IV, has been proposed to describe this condition. Because these symptoms are subjective and common to other conditions, there is controversy whether PCS deserves to be identified as a diagnostic syndrome. OBJECTIVE: To assess whether persistent symptoms 3 months following head injury are specific to MTBI or whether they are better described as part of posttraumatic stress disorder (PTSD). DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study of injured patients recruited at the adult emergency department of the University Hospital of Bordeaux from December 4, 2007, to February 25, 2009. MAIN OUTCOMES AND MEASURES: At 3-month follow-up, we compared the prevalence and risk factors for PCS and PTSD. Multiple correspondence analyses were used to assess clustering of symptoms and their associations with the type of injury. RESULTS: We included 534 patients with head injury and 827 control patients with other nonhead injuries. Three months following the trauma, 21.2% of head-injured and 16.3% of nonhead-injured patients fulfilled the DSM-IV diagnosis of PCS; 8.8% of head-injured patients fulfilled the diagnostic criteria for PTSD compared with 2.2% of control patients. In multivariate analysis, MTBI was a predictor of PTSD (odds ratio, 4.47; 95% CI, 2.38-8.40) but not of PCS (odds ratio, 1.13; 95% CI, 0.82-1.55). Correspondence analysis suggested that symptoms considered part of PCS behave similarly to PTSD symptoms in the hyperarousal dimension. None of these 22 symptoms showed any pattern of clustering, and no clear proximity with head or nonhead injury status could be found. CONCLUSIONS AND RELEVANCE: Persistent subjective symptoms frequently reported 3 months after MTBI are not specific enough to be identified as a unique PCS and should be considered part of the hyperarousal dimension of PTSD. PMID- 25029016 TI - Activities of daily living in children with hemiparesis: influence of cognitive abilities and motor competence. AB - PURPOSE: The aim of the article is to investigate whether motor competence and cognitive abilities influence the quality of performance of activities of daily living (ADL) in children with hemiparesis. Patients and METHODS: A total of 20 children with hemiparesis (age, 6-12 years; 11 congenital, 9 acquired during childhood) were studied. Motor competence was assessed with the Assisting Hand Assessment, cognitive abilities with the German version of the Wechsler Intelligence Scale for Children IV, and the quality of ADL performance with the Assessment of Motor and Process Skills (AMPS). RESULTS: The motor skills scale of the AMPS correlated with motor competence, and the process skills scale of the AMPS correlated with cognitive abilities. CONCLUSION: The quality of ADL performance is influenced not only by motor competence but also by the cognitive abilities of a hemiparetic child. This suggests that, in addition to motor oriented training programs, an optimal therapy for hemiparetic children should also consider cognitive approaches. PMID- 25029017 TI - Copper-mediated hydroxylation of arenes and heteroarenes directed by a removable bidentate auxiliary. AB - A copper-mediated C-H hydroxylation of arenes and heteroarenes using our newly developed PIP directing group has been developed. This procedure is scalable and compatible with a wide range of functional groups and heteroarenes, providing an operationally simple protocol for the synthesis of o-hydroxybenzamides. The hydroxylation of nicotinamides gave 4-oxo-1,4-dihydropyridine-3-carboxamides selectively. Preliminary mechanistic studies implicate that a basic ligand enabled, irreversible, rate-determining CMD step is most likely involved in this process. PMID- 25029018 TI - The genotypic characterization of Cronobacter spp. isolated in China. AB - Cronobacter spp. (Enterobacter sakazakii) is an important pathogen contaminating powdered infant formula (PIF). To describe the genotypic diversity of Cronobacter isolated in China, we identified the isolates using fusA allele sequencing, and subtyped all of the isolates using pulsed-field gel electrophoresis (PFGE), multi locus sequence typing (MLST), and multiple-locus variable-number tandem-repeat analysis (MLVA). A total of 105 isolates were identified, which included C. sakazakii (58 isolates), C. malonaticus (30 isolates), C. dublinensis (11 isolates), C. turicensis (5 isolates), and C. muytjensii (1 isolate). These isolates were showed to have 85 PFGE-patterns, 71 sequence types (STs), and 55 MLVA-patterns. Comparisons among the three molecular subtyping methods revealed that the PFGE method was the most distinguishable tool in identifying clusters of Cronobacter spp. through DNA fingerprinting, and MLST method came second. However, ESTR-1, ESTR-2, ESTR-3, and ESTR-4 were not effective loci for subtyping Cronobacter spp. such that the MLVA method requires further improvement. PMID- 25029019 TI - Seasonal variation in female mate choice and operational sex ratio in wild populations of an annual fish, Austrolebias reicherti. AB - The intensity of mating competition and the potential benefits for female of mating with certain males can be influenced by several extrinsic factors, such that behavioral decisions can be highly context-dependent. Short-lived species with a single reproductive season are a unique model to study context-sensitive mating decisions. Through exhaustive sampling in the field and simultaneous choice tests in the laboratory, we evaluated operational sex ratio (OSR) and female mate choice at the beginning and end of the reproductive season in the annual killifish Austrolebias reicherti. We found seasonal change in both OSR and female mate choice. At the start of the reproductive season the OSR did not deviate from parity, and females preferred larger males. Later in the reproductive season, while the proportion of males in the ponds decreased, females became unselective with respect to male size. The particular biological cycle of annual killifish, where both life expectancy and mating opportunities decline sharply over a short timescale, could account for the seasonal change in female choice. Reduction in choosiness could arise from diminished reproductive prospects due to a decline in male availability. Moreover, as the end of the season approaches, any benefits of choosiness are presumably reduced: a female's fitness will be higher if she mates with any male than if she forgoes reproduction and dies. Future work will disentangle the mechanisms underlying seasonal changes in mating preferences, notably direct responses to demographic factors, environmental cues, or intrinsic changes during development. PMID- 25029020 TI - Ventilator-associated pneumonia in the ICU. PMID- 25029021 TI - Bacterial pathogenesis: Bartonella gets under the skin. PMID- 25029027 TI - Toward an asymmetric synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A. AB - A full account of our efforts toward an asymmetric synthesis of crisamicin A are presented. The key steps include a Hauser-Kraus annulation of a cyanophthalide with a chiral enone-lactone, a stereoselective cyclization-reduction to install the pyran unit, and a Suzuki homocoupling to forge the key biaryl bond. This work has culminated in the asymmetric synthesis of a dimer bearing the complete carbon skeleton of the dimeric pyranonaphthoquinone natural product crisamicin A. PMID- 25029026 TI - Millennium-scale crossdating and inter-annual climate sensitivities of standing California redwoods. AB - Extremely decay-resistant wood and fire-resistant bark allow California's redwoods to accumulate millennia of annual growth rings that can be useful in biological research. Whereas tree rings of Sequoiadendron giganteum (SEGI) helped formalize the study of dendrochronology and the principle of crossdating, those of Sequoia sempervirens (SESE) have proven much more difficult to decipher, greatly limiting dendroclimatic and other investigations of this species. We overcame these problems by climbing standing trees and coring trunks at multiple heights in 14 old-growth forest locations across California. Overall, we sampled 1,466 series with 483,712 annual rings from 120 trees and were able to crossdate 83% of SESE compared to 99% of SEGI rings. Standard and residual tree-ring chronologies spanning up to 1,685 years for SESE and 1,538 years for SEGI were created for each location to evaluate crossdating and to examine correlations between annual growth and climate. We used monthly values of temperature, precipitation, and drought severity as well as summer cloudiness to quantify potential drivers of inter-annual growth variation over century-long time series at each location. SESE chronologies exhibited a latitudinal gradient of climate sensitivities, contrasting cooler northern rainforests and warmer, drier southern forests. Radial growth increased with decreasing summer cloudiness in northern rainforests and a central SESE location. The strongest dendroclimatic relationship occurred in our southernmost SESE location, where radial growth correlated negatively with dry summer conditions and exhibited responses to historic fires. SEGI chronologies showed negative correlations with June temperature and positive correlations with previous October precipitation. More work is needed to understand quantitative relationships between SEGI radial growth and moisture availability, particularly snowmelt. Tree-ring chronologies developed here for both redwood species have numerous scientific applications, including determination of tree ages, accurate dating of fire-return intervals, archaeology, analyses of stable isotopes, long-term climate reconstructions, and quantifying rates of carbon sequestration. PMID- 25029025 TI - Adding new dimensions: towards an integrative understanding of HIV-1 spread. AB - In vitro studies in primary or immortalized cells continue to be used to elucidate the essential principles that govern the interactions between HIV-1 and isolated target cells. However, until recently, substantial technical barriers prevented this information from being efficiently translated to the more complex scenario of HIV-1 spread in the host in vivo, which has limited our understanding of the impact of host physiological parameters on the spread of HIV-1. In this Review, we discuss the recent development of imaging approaches to visualize HIV 1 spread and the adaptation of these approaches to organotypic ex vivo models and animal models. We focus on new concepts, including the mechanisms and in vivo relevance of cell-cell transmission for HIV-1 spread and the function of the HIV 1 pathogenesis factor Nef, which have emerged from the application of these integrative approaches in complex cell systems. PMID- 25029028 TI - Quantitative proteomic approach to understand metabolic adaptation in non-small cell lung cancer. AB - KRAS mutations in non-small cell lung cancer (NSCLC) are a predictor of resistance to EGFR-targeted therapies. Because approaches to target RAS signaling have been unsuccessful, targeting lung cancer metabolism might help to develop a new strategy that could overcome drug resistance in such cancer. In this study, we applied a large screening quantitative proteomic analysis to evidence key enzymes involved in metabolic adaptations in lung cancer. We carried out the proteomic analysis of two KRAS-mutated NSCLC cell lines (A549 and NCI-H460) and a non tumoral bronchial cell line (BEAS-2B) using an iTRAQ (isobaric tags for relative and absolute quantitation) approach combined with two-dimensional fractionation (OFFGEL/RP nanoLC) and MALDI-TOF/TOF mass spectrometry analysis. Protein targets identified by our iTRAQ approach were validated by Western blotting analysis. Among 1038 proteins identified and 834 proteins quantified, 49 and 82 proteins were respectively found differently expressed in A549 and NCI H460 cells compared to the BEAS-2B non tumoral cell line. Regarding the metabolic pathways, enzymes involved in glycolysis (GAPDH/PKM2/LDH-A/LDH-B) and pentose phosphate pathway (PPP) (G6PD/TKT/6PGD) were up-regulated. The up-regulation of enzyme expression in PPP is correlated to their enzyme activity and will be further investigated to confirm those enzymes as promising metabolic targets for the development of new therapeutic treatments or biomarker assay for NSCLC. PMID- 25029029 TI - Broadband antireflection and field emission properties of TiN-coated Si nanopillars. AB - Broadband antireflection and field emission characteristics of silicon nanopillars (Si-NPs) fabricated by self-masking dry etching in hydrogen containing plasma were systematically investigated. In particular, the effects of ultrathin (5-20 nm) titanium nitride (TiN) films deposited on Si-NPs by atomic layer deposition (ALD) on the optoelectronic properties were explored. The results showed that by coating the Si-NPs with a thin layer of TiN the antireflection capability of pristine Si-NPs can be significantly improved, especially in the wavelength range of 1000-1500 nm. The enhanced field emission characteristics of these TiN/Si-NP heterostructures suggest that, in addition to the reflectance suppression in the long wavelength range arising from the strong wavelength-dependent refractive index of TiN, the TiN-coating may have also significantly modified the effective work function at the TiN/Si interface as well. PMID- 25029030 TI - Variability is adaptability...also during weaning! AB - Heart rate variability in the frequency domain can now be obtained at the bedside in the ICU. Promising data suggest that it may help to characterize a patient response to a spontaneous breathing trial. Refinement of the analysis could even help to predict the outcome of extubation or at least help to detect early patients at risk of failure. It is possible that combining this type of analysis, the breathing pattern variability, and other objective indices could help clinicians in the decision-making process of weaning and extubation. PMID- 25029031 TI - Reduced oxygen uptake efficiency slope in patients with cardiac sarcoidosis. AB - BACKGROUND: The non-invasive diagnosis of cardiac sarcoidosis (CS) is difficult. Cardiovascular magnetic resonance (CMR) has become a very valuable diagnostic tool in patients with suspected CS, but usually a combination of different tests is used. Oxygen uptake efficiency slope (OUES) is a parameter of cardiopulmonary exercise testing (CPET), which is used as an indicator for cardiovascular impairment. We investigated the predictive value of OUES for the diagnosis of myocardial involvement in sarcoid patients. METHODS: Retrospectively 37 consecutive patients (44.9+/-13.8 years) with histologically confirmed sarcoidosis and clinical suspicion of heart involvement underwent noninvasive diagnostic testing including CMR. CS was diagnosed according to the guidelines from the Japanese Society of Sarcoidosis and other Granulomatous Disorders with additional consideration of CMR findings. Furthermore, CPET with calculation of predicted OUES according to equations by Hollenberg et al. was carried out. RESULTS: Patients with CS (11/37; 30%) had a worse cardiovascular response to exercise. OUES was significantly lower in CS-group compared to non-CS-group (59.3+/-19.1 vs 88.0+/-15.4%pred., p<0.0001). ROC curve method identified 70%pred. as the OUES cut-off point, which maximized sensitivity and specificity for detection of CS (96% sensitivity, 82% specificity, 89% overall accuracy). OUES <70%pred. was the single best predictor of CS (Odds ratio: 100.43, 95% CI: 1.99 to 5064, p<0.001) even in multivariate analyses. CONCLUSION: OUES assessed in CPET may be helpful in identifying patient with cardiac involvement of sarcoidosis. Patient selection for CMR may be assisted by CPET findings in patients with sarcoidosis. PMID- 25029032 TI - Two-dimensional nanocrystals of molecular Janus particles. AB - This paper describes a rational strategy to obtain self-assembled two-dimensional (2D) nanocrystals with definite and uniform thickness from a series of molecular Janus particles based on molecular nanoparticles (MNPs). MNPs are 3D framework with rigid shapes. Three different types of MNPs based on derivatives of polyhedral oligomeric silsesquioxane (POSS), [60]fullerene (C60), and Lindqvist type polyoxometalate (POM) are used as building blocks to construct these amphiphilic molecular Janus particles by covalently connecting hydrophobic crystalline BPOSS with a charged hydrophilic MNP. The formation of 2D nanocrystals with an exact thickness of double layers of molecules is driven by directional crystallization of the BPOSS MNP and controlled by various factors such as solvent polarity, number of counterions, and sizes of the MNPs. Strong solvating interactions of the ionic MNPs in polar solvents (e.g., acetonitrile and dimethylformamide) are crucial to provide repulsive interactions between the charged outlying ionic MNPs and suppress further aggregation along the layer normal direction. The number of counterions per molecule plays a major role in determining the self-assembled morphologies. Size matching of the hydrophobic and ionic MNPs is another critical factor in the formation of 2D nanocrystals. Self assembly of rationally designed molecular Janus particles provides a unique "bottom-up" strategy to engineer 2D nanostructures. PMID- 25029033 TI - Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. AB - Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg(2+)-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg(2+) free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg(2+)-free solution treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy. PMID- 25029035 TI - The use of automated bioacoustic recorders to replace human wildlife surveys: an example using nightjars. AB - To be able to monitor and protect endangered species, we need accurate information on their numbers and where they live. Survey methods using automated bioacoustic recorders offer significant promise, especially for species whose behaviour or ecology reduces their detectability during traditional surveys, such as the European nightjar. In this study we examined the utility of automated bioacoustic recorders and the associated classification software as a way to survey for wildlife, using the nightjar as an example. We compared traditional human surveys with results obtained from bioacoustic recorders. When we compared these two methods using the recordings made at the same time as the human surveys, we found that recorders were better at detecting nightjars. However, in practice fieldworkers are likely to deploy recorders for extended periods to make best use of them. Our comparison of this practical approach with human surveys revealed that recorders were significantly better at detecting nightjars than human surveyors: recorders detected nightjars during 19 of 22 survey periods, while surveyors detected nightjars on only six of these occasions. In addition, there was no correlation between the amount of vocalisation captured by the acoustic recorders and the abundance of nightjars as recorded by human surveyors. The data obtained from the recorders revealed that nightjars were most active just before dawn and just after dusk, and least active during the middle of the night. As a result, we found that recording at both dusk and dawn or only at dawn would give reasonably high levels of detection while significantly reducing recording time, preserving battery life. Our analyses suggest that automated bioacoustic recorders could increase the detection of other species, particularly those that are known to be difficult to detect using traditional survey methods. The accuracy of detection is especially important when the data are used to inform conservation. PMID- 25029034 TI - Synthesis and in vitro evaluation of BBB permeability, tumor cell uptake, and cytotoxicity of a series of carboranylporphyrin conjugates. AB - A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr D-Arg-Phe-beta-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50>400 MUM) and low phototoxicity (IC50>100 MUM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient. PMID- 25029036 TI - Elevated malondialdehyde levels in sepsis - something to 'stress' about? AB - Oxidative stress has been postulated as a mechanism of organ dysfunction - and thus a potential therapeutic target - in sepsis. Lorente and colleagues report increased serum levels of malondialdehyde, a biomarker of oxidative stress induced lipid peroxidation, in adults with severe sepsis, particularly in non survivors. While survivors exhibited a decrease in serum malondialdehyde over time, the elevation was sustained in non-survivors. These findings suggest that there is increased oxidative stress in sepsis and that membrane lipids in particular are targeted by free radical species. Further study is required to validate the utility of malondialdehyde as a prognostic biomarker in sepsis and to determine a role for antioxidant therapy. PMID- 25029037 TI - Organophosphonate biofunctionalization of diamond electrodes. AB - The modification of the diamond surface with organic molecules is a crucial aspect to be considered for any bioapplication of this material. There is great interest in broadening the range of linker molecules that can be covalently bound to the diamond surface. In the case of protein immobilization, the hydropathicity of the surface has a major influence on the protein conformation and, thus, on the functionality of proteins immobilized at surfaces. For electrochemical applications, particular attention has to be devoted to avoid that the charge transfer between the electrode and the redox center embedded in the protein is hindered by a thick insulating linker layer. This paper reports on the grafting of 6-phosphonohexanoic acid on OH-terminated diamond surfaces, serving as linkers to tether electroactive proteins onto diamond surfaces. X-ray photoelectron spectroscopy (XPS) confirms the formation of a stable layer on the surface. The charge transfer between electroactive molecules and the substrate is studied by electrochemical characterization of the redox activity of aminomethylferrocene and cytochrome c covalently bound to the substrate through this linker. Our work demonstrates that OH-terminated diamond functionalized with 6-phosphonohexanoic acid is a suitable platform to interface redox-proteins, which are fundamental building blocks for many bioelectronics applications. PMID- 25029039 TI - Investigating the role of solvent-solute interaction in crystal nucleation of salicylic acid from organic solvents. AB - In previous work, it has been shown that the crystal nucleation of salicylic acid (SA) in different solvents becomes increasingly more difficult in the order: chloroform, ethyl acetate acetonitrile, acetone, methanol, and acetic acid. In the present work, vibration spectroscopy, calorimetric measurements, and density functional theory (DFT) calculations are used to reveal the underlying molecular mechanisms. Raman and infrared spectra suggest that SA exists predominately as dimers in chloroform, but in the other five solvents there is no clear evidence of dimerization. In all solvents, the shift in the SA carbonyl peak reflecting the strength in the solvent-solute interaction is quite well correlated to the nucleation ranking. This shift is corroborated by DFT calculated energies of binding one solvent molecule to the carboxyl group of SA. An even better correlation of the influence of the solvent on the nucleation is provided by DFT calculated energy of binding the complete first solvation shell to the SA molecule. These solvation shell binding energies are corroborated by the enthalpy of solvent-solute interaction as estimated from experimentally determined enthalpy of solution and calculated enthalpy of cavity formation using the scaled particle theory. The different methods reveal a consistent picture and suggest that the stronger the solvent binds to the SA molecule in solution, the slower the nucleation becomes. PMID- 25029040 TI - Load-specific physical activity scores are related to tibia bone architecture. AB - Assessment of physical activity in clinical bone studies is essential. Two bone specific physical activity scoring methods, the Bone Loading History Questionnaire (BLHQ) and Bone-Specific Physical Activity Questionnaire (BPAQ), have shown correlations with bone density and geometry, but not architecture. The purpose of this study was to determine relationships between physical activity scoring methods and bone architecture in non-Hispanic white adolescent females (N = 24; 18-19 years of age). Bone loading scores (BLHQ [hip and spine] and past BPAQ) and energy expenditure (7-day physical activity recall) were determined from respective questionnaires. Estimates of trabecular and cortical bone architecture at the nondominant radius and tibia were assessed via magnetic resonance imaging. Total body and regional areal bone mineral density (aBMD), as well as total body fat mass and fat-free soft tissue (FFST) mass were assessed via dual energy X-ray absorptiometry. Pearson's correlations and partial correlations adjusting for height, total body fat mass, and FFST were performed. Hip BLHQ scores were correlated with midtibia cortical volume (r = .43; p = .03). Adjusted hip and spine BLHQ scores were correlated with all midtibia cortical measures (r = .50-0.58; p < .05) and distal radius apparent trabecular number (r = .46-0.53; p < .05). BPAQ scores were correlated with all midtibia cortical (r = .41-0.51; p < .05) and most aBMD (r = .47-0.53; p < .05) measures. Energy expenditure was inversely associated with femoral neck aBMD only after statistical adjustment (r = .49, p < .05). These data show that greater load specific physical activity scores, but not energy expenditure, are indicative of greater midtibia cortical bone quality, thus supporting the utility of these instruments in musculoskeletal research. PMID- 25029038 TI - A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. AB - RATIONALE: Alveolar liquid clearance is regulated by Na(+) uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na(+)-K(+)-ATPase in type II alveolar epithelial cells. Dysfunction of these Na(+) transporters during pulmonary inflammation can contribute to pulmonary edema. OBJECTIVES: In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na(+) uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY). METHODS: We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na(+) uptake stimulatory activity. MEASUREMENTS AND MAIN RESULTS: TIP peptide directly activates ENaC, but not the Na(+)-K(+)-ATPase, upon binding to the carboxy-terminal domain of the alpha subunit of the channel. In the presence of PLY, a mediator of pneumococcal induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-alpha protein expression, by means of blunting the protein kinase C-alpha pathway. Triple-mutant TNF knock-in mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-alpha subunit expression. CONCLUSIONS: These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation. PMID- 25029041 TI - Efficient ZnO-based visible-light-driven photocatalyst for antibacterial applications. AB - Herein, we report the development of a ZnO-based visible-light-driven photocatalyst by interfacial charge transfer process for the inactivation of pathogens under visible-light illumination. Surface modification by a cocatalyst on ZnO, prepared by flame spray pyrolysis process is carried out to induce the visible-light absorption in ZnO. Optical studies showed that surface modification of Cu(2+) induces the visible-light absorption in ZnO by interfacial charge transfer between ZnO and surface Cu(2+) ions upon light irradiation. The photocatalytic efficiency of pure and modified ZnO is evaluated for the inactivation of pathogens and the decomposition of methylene blue under visible light illumination. The antibacterial activity of Cu(2+)-ZnO is several orders higher than pure ZnO and commercial Degussa-P25 and comparable with Cu(2+)-TiO2. Cu(2+)-ZnO nanorods show better photocatalytic activity than Cu(2+)-ZnO nanosphere, which is attributed to high surface area to volume ratio of former than later. The holes generated in the valence band and the Cu(1+) species generated during the interfacial charge transfer process may attribute for the inactivation of bacteria, whereas the strong oxidation power of hole is responsible for the decomposition of methylene blue. Besides the advantage of Cu(2+)-modified ZnO for visible-light-assisted photocatalytic applications, the method (FSP) used for the synthesis of ZnO in the present study is attractive for commercial application because the process has potential for the production of large quantities (2-3 kg/h) of semiconductors. PMID- 25029042 TI - Temporal variation in fish mercury concentrations within lakes from the western Aleutian Archipelago, Alaska. AB - We assessed temporal variation in mercury (Hg) concentrations of threespine stickleback (Gasterosteus aculeatus) from Agattu Island, Aleutian Archipelago, Alaska. Total Hg concentrations in whole-bodied stickleback were measured at two week intervals from two sites in each of two lakes from June 1 to August 10, 2011 during the time period when lakes were ice-free. Across all sites and sampling events, stickleback Hg concentrations ranged from 0.37-1.07 ug/g dry weight (dw), with a mean (+/- SE) of 0.55 +/- 0.01 ug/g dw. Mean fish Hg concentrations declined by 9% during the study period, from 0.57 +/- 0.01 ug/g dw in early June to 0.52 +/- 0.01 ug/g dw in mid-August. Mean fish Hg concentrations were 6% higher in Loon Lake (0.56 +/- 0.01 ug/g dw) than in Lake 696 (0.53 +/- 0.01 ug/g dw), and 4% higher in males (0.56 +/- 0.01 ug/g dw) than in females (0.54 +/- 0.01 ug/g dw). Loon Lake was distinguished from Lake 696 by the presence of piscivorous waterbirds during the breeding season. Mercury concentrations in stickleback from Agattu Island were higher than would be expected for an area without known point sources of Hg pollution, and high enough to be of concern to the health of piscivorous wildlife. PMID- 25029043 TI - Contributions of nursing in elderly care. PMID- 25029044 TI - AIDS in adults 50 years of age and over: characteristics, trends and spatial distribution of the risk. AB - OBJECTIVE: to analyze the sociodemographic characteristics, epidemic trend and spatial distribution of the risk of AIDS in adults 50 years of age and over. METHOD: population-based, ecological study, that used secondary data from the Notifiable Disease Information System (Sinan/AIDS) of Paraiba state from the period January 2000 to December 2010. RESULTS: during the study period, 307 cases of AIDS were reported among people 50 years of age or over. There was a predominance of males (205/66, 8%), mixed race, and low education levels. The municipalities with populations above 100 thousand inhabitants reported 58.5% of the cases. There was a progressive increase in cases among women; an increasing trend in the incidence (positive linear correlation); and an advance in the geographical spread of the disease, with expansion to the coastal region and to the interior of the state, reaching municipalities with populations below 30 thousand inhabitants. In some locations the risk of disease was 100 times greater than the relative risk for the state. CONCLUSION: aging, with the feminization and interiorization of the epidemic in adults 50 years of age and over, confirms the need for the induction of affirmative policies targeted toward this age group. PMID- 25029045 TI - Mental health is the most important factor influencing quality of life in elderly left behind when families migrate out of rural China. AB - OBJECTIVES: to investigate the quality of life and the associated factors on left behind elderly in rural China. METHOD: the research was conducted cluster sampling to select 456 elderly left behind when family members migrated out of rural China to participate in a cross-sectional study by completing a general data questionnaire and Quality of Life questionnaire. RESULTS: 91.5% of the elderly requested psychological counseling and education. For the elderly, scores for mental health (39.56+/-13.73) were significantly lower compared with Chinese standard data (61.6+/-13.7) (P<0.001). Age, chronic disease type, gender, residence pattern and economic support from children were the main psychological factors influencing this population. CONCLUSION: mental health is the most important factor influencing quality of life of elderly left behind when family members migrated out of rural China. Our study suggested a need to widely establish a general practitioner team for psychological intervention for improving rural elderly people's Quality of Life level, especially in the psychological domain. PMID- 25029046 TI - Efficacy of Chinese auriculotherapy for stress in nursing staff: a randomized clinical trial. AB - OBJECTIVE: this randomized single blind clinical study aimed to evaluate the efficacy of auriculotherapy with and without a protocol for reducing stress levels among nursing staff. METHOD: a total of 175 nursing professionals with medium and high scores according to Vasconcelos' Stress Symptoms List were divided into 3 groups: Control (58), Group with protocol (58), Group with no protocol (59). They were assessed at the baseline, after 12 sessions, and at the follow-up (30 days). RESULTS: in the analysis of variance, statistically significant differences between the Control and Intervention groups were found in the two evaluations (p<0.05) with greater size of effect indices (Cohen) for the No protocol group. The Yang Liver 1 and 2, Kidney, Brain Stem and Shen Men were the points most used. CONCLUSION: individualized auriculotherapy, with no protocol, could expand the scope of the technique for stress reduction compared with auriculotherapy with a protocol. NCT: 01420835. PMID- 25029047 TI - Context of the beginning of tobacco use in different social groups. AB - OBJECTIVE: analyze contextual aspects of the beginning of tobacco use in different social groups, from everyday representations about the act of smoking. METHODS: five focus groups were conducted to promote discussion about the context of beginning of tobacco use, with groups of people who represented different patterns of social reproduction. The data analysis was based on the theory of social representations, which contextualizes how each group presents the tobacco consumption. RESULTS: the contexts of the beginning of tobacco use were diverse, according to patterns of social reproduction; there were common representations to all groups, but there were also unique representations of each social group. Tobacco is represented as indispensable for groups in unstable social reproduction situations, and as an instrument of pleasure and stress relief for those who can access other material assets. CONCLUSIONS: the study contributed to exposing the concepts on tobacco consumption that are socially disseminated, which can serve as an instrument to planning programs and health actions. PMID- 25029048 TI - Low back pain characterized by muscle resistance and occupational factors associated with nursing. AB - OBJECTIVE: to identify the occupational factors associated with low back pain using a surveillance tool and to characterize the low back pain by the resistance of the extensor muscles of the vertebral column among nursing professionals at an Intensive Care Unit. METHODS: Cross-sectional study. The workers answered a questionnaire about occupational factors and participated in a resistance test of the extensor muscles of the vertebral column. Associations were established through Student's T-test or Mann-Whitney's U-test and correlations using Pearson's test. RESULTS: Out of 48 participants, 32 (67%) suffered from low pain. For the resistance test, the subjects suffering from low back pain endured less time in comparison with asymptomatic subjects, but without significant differences (p=0.147). The duration of the pain episode showed a significant negative correlation (p=0.016) with the results of the resistance test though. The main factors identified as causes of low back pain were biomechanical and postural elements, conditions of the muscle structure and physical and organizational conditions. CONCLUSIONS: the main occupational factors associated with the low back pain were the posture and the characteristics of the physical and organizational conditions. In addition, the extensor muscles of the column showed a trend towards lesser resistance for workers in pain. This evidence is important when considering prevention and treatment strategies. PMID- 25029049 TI - Living with digestive stomas: strategies to cope with the new bodily reality. AB - OBJECTIVE: the objective in this study was to describe the strategies developed by digestive stoma patients to cope with their situation. METHOD: a qualitative and descriptive study was undertaken, involving 21 stoma patients living in the provinces of Malaga and Granada (Spain). The informants were selected in accordance with criteria of appropriateness and diversity, through intentional sampling. The data were collected by means of semistructured interviews. RESULTS: the content analysis revealed three categories around which the distinct strategies were developed: Self-care, Adaptation to the bodily change and Self help. CONCLUSION: the strategies developed are focusing on achieving the effective management of the stoma and are closely linked with the achievement of autonomy. Discovering the strategies applied is fundamental for the nursing professionals to offer high-quality care, centered on people and their process. PMID- 25029050 TI - Factors related to failure to attend the consultation to receive the results of the Pap smear test. AB - OBJECTIVE: to identify the factors related to the failure of women to attend the follow-up consultation to receive the results of the Pap smear test. METHOD: a cross-sectional study, carried out with 775 patients who underwent the Pap smear test in the Centro de Saude da Familia of Fortaleza, between September 2010 and February 2011. RESULTS: the majority of the women studied were young (<=35 years), had low levels of education (<=7 years of study), and commenced sexual activity early (<=20 years), with 17.0% of them failing to return to receive the test results. Statistically significant results for the failure to return were related to: young women (p=0.001); early onset of sexual activity (p=0.047); and inadequate knowledge about the Pap smear test (p=0.029). CONCLUSION: the fact that the women failed to return for the result is a problem for the control of cervical cancer, and must be addressed through educational strategies that reinforce the importance of the return for the early detection of this cancer. PMID- 25029051 TI - Experience of sexuality after breast cancer: a qualitative study with women in rehabilitation. AB - OBJECTIVE: to comprehend the psychosocial and cultural repercussions of breast cancer and its treatment on the sexuality of women. METHOD: this is a qualitative study grounded in the Sexual Scripts Theory with the participation of 23 women who were interviewed and participated in focus groups discussion. RESULTS: each category was related to a level of the sexual scripts. At the cultural scenario level a discourse on sexuality that includes definitions of sexual attractiveness and sexuality was highlighted. The interpersonal scripts level focused on the communication regarding sexuality established with the partner and with healthcare professionals category; and at the subjectivity scripts level the reports of improvement, deterioration and no change in the sexual life after cancer were analyzed. CONCLUSION: the experience of cancer involves cultural, relational, and subjective aspects that affect the sexual life, therefore, healthcare professionals should be aware of them to improve integral healthcare. PMID- 25029052 TI - Cochlear Implant: the complexity involved in the decision making process by the family. AB - OBJECTIVE: to understand the meanings the family attributes to the phases of the decision-making process on a cochlear implant for their child. METHOD: qualitative research, using Symbolic Interactionism and Grounded Theory as the theoretical and methodological frameworks, respectively. Data collection instrument: semistructured interview. Nine families participated in the study (32 participants). RESULTS: knowledge deficit, difficulties to contextualize benefits and risks and fear are some factors that make this process difficult. Experiences deriving from interactions with health professionals, other cochlear implant users and their relatives strengthen decision making in favor of the implant. CONCLUSION: deciding on whether or not to have the implant involves a complex process, in which the family needs to weigh gains and losses, experience feelings of accountability and guilt, besides overcoming the risk aversion. Hence, this demands cautious preparation and knowledge from the professionals involved in this intervention. PMID- 25029053 TI - The treatment of childhood cancer: unveiling the experience of parents. AB - OBJECTIVE: to understand the experiences of parents of children and adolescents with cancer undergoing treatment. METHOD: qualitative research, based on Heidegger's existential phenomenology, in which 13 parents of eight patients under 19 years of age, assisted by a charity association, were interviewed. RESULTS: three topics resulted from the analysis: "Experiencing the unpleasantness of the treatment"; "Fearing the possibility of a frightening situation" and "Experiencing the carelessness of another person". It was showed that during and after the treatment, the parents experience the fear of the unknown and the uncertainty of the future of their children, especially as they witness the death of other children; they also experience the indifference of professionals working in the local healthcare units and feel helpless and insecure. CONCLUSION: It is essential that the healthcare professionals, particularly the nurses, reflect about their care actions focused on the parents of children with cancer, recognizing their existential needs with the purpose of assisting them in their situation. PMID- 25029054 TI - The involvement of parents in the healthcare provided to hospitalzed children. AB - OBJECTIVE: to analyze the answers of parents and health care professionals concerning the involvement of parents in the care provided to hospitalized children. METHOD: exploratory study based on the conceptual framework of pediatric healthcare with qualitative data analysis. RESULTS: three dimensions of involvement were highlighted: daily care provided to children, opinions concerning the involvement of parents, and continuity of care with aspects related to the presence and participation of parents, benefits to the child and family, information needs, responsibility, right to healthcare, hospital infrastructure, care delivery, communication between the parents and health services, shared learning, and follow-up after discharge. CONCLUSION: the involvement of parents in the care provided to their children has many meanings for parents, nurses and doctors. Specific strategies need to be developed with and for parents in order to mobilize parental competencies and contribute to increasing their autonomy and decision-making concerning the care provided to children. PMID- 25029055 TI - Parental stress in mothers of children and adolescents with cerebral palsy. AB - OBJECTIVES: to evaluate parental stress of mothers of children and adolescents with cerebral palsy; to verify whether parental stress undergoes variations according to the level of motor compromise, the child's phase of life, and sociodemographic variables. METHOD: a cross-sectional, descriptive study, with 223 mothers of children and adolescents with cerebral palsy. RESULTS: 45.3% of the mothers presented high levels of stress; there were differences in stress between mothers of children with mild and severe motor impairment; mothers of older children were more stressed than mothers of younger children and of adolescents; paid work and leisure activities reduced the stress. CONCLUSION: mothers of children and adolescents with cerebral palsy, whose children present mild to severe motor impairment are vulnerable to parental stress. Paid work and leisure activities were the factors that contributed most to reducing the stress. PMID- 25029056 TI - How do primary health care professionals deal with pregnant women who are victims of domestic violence? AB - OBJECTIVES: to determine how Family Health Strategy professionals recognize and deal with domestic violence in pregnant women. METHOD: qualitative study based on the Theory of Praxis Intervention in Collective Health Nursing (TIPESC). Fourteen professionals at a Basic Health Unit in the east side of Sao Paulo/Brazil were interviewed. Empirical data were categorized and discussed in thematic groups. For data analysis was used the technique of Discourse Analysis. RESULTS: we identified low number of reported cases of domestic violence; lack of education and training of health care professionals; failure in the identification and intervention process due to bias on their personal problems, moral attitudes and prejudice against these women. In addition, the study showed that their labor process was based entirely on the biological aspects of the women and to overcome this, they need of proper rapport between health care professionals and pregnant women to deal with of domestic violence. CONCLUSION: professionals should develop skills to intervene in violence against pregnant women and also modify labor processes considering women in their totality and part of society. PMID- 25029057 TI - Quality of nursing care and satisfaction of patients attended at a teaching hospital. AB - OBJECTIVES: assess the quality of nursing care, the patients' satisfaction and the correlation between both. METHOD: cross-sectional study, involving 275 patients hospitalized at a teaching hospital in the Central-West of Brazil. The data were collected through the simultaneous application of three instruments. Next, they were included in an electronic database and analyzed in function of the positivity, median value and Spearman's correlation coefficients. RESULTS: among the nursing care assessed, only two were considered safe--hygiene and physical comfort; nutrition and hydration--while the remainder were classified as poor. Nevertheless, the patients were satisfied with the care received in the domains assessed: technical-professional, confidence and educational. This can be justified by the weak to moderate correlation that was observed among these variables. CONCLUSION: Despite the quality deficit, the patients' satisfaction level with the nursing care received was high. These results indicate that the institution needs to center its objectives on a continuing evaluation system of the care quality, aiming to attend to the patients' expectations. PMID- 25029059 TI - A behavior model for blood donors and marketing strategies to retain and attract them. AB - OBJECTIVE: analyze and propose a theoretical model that describes blood donor decisions to help staff working in blood banks (nurses and others) in their efforts to capture and retain donors. METHODS: analysis of several studies on the motivations to give blood in Spain over the last six years, as well as past literature on the topic, the authors' experiences in the last 25 years in over 15 Non Governmental Organizations with different levels of responsibilities, their experiences as blood donors and the informal interviews developed during those 25 years. RESULTS: a model is proposed with different internal and external factors that influence blood donation, as well as the different stages of the decision making process. CONCLUSION: the knowledge of the donation process permits the development of marketing strategies that help to increase donors and donations. PMID- 25029058 TI - Continuous use of intermittent bladder catheterization--can social support contribute? AB - OBJECTIVE: to investigate the factors affecting the adequate continuous use of intermittent catheterization and its relation with social support. METHOD: sectional, descriptive and correlational study involving 49 patients with neuropathic bladder caused by spinal cord injury. RESULTS: almost all (92%) participants continued the intermittent catheterization, but 46.9% made some changes in the technique. The complications (28.6% of the sample) were mainly infection and vesicolithiasis. There were high scores for social support in relation to people that were part of the patient's social support. CONCLUSION: All of them noticed great support from the family, but not from the society in general. The difficulties were related to the lack of equipment and inadequate infrastructure, leading to changes that increased urologic complications. PMID- 25029060 TI - Nursing care in tuberculosis patients at a Spanish sanatorium, 1943-1975. AB - OBJECTIVES: the objective in this study is to identify the profile of the nursing staff, the work conditions and to describe nursing care at a sanatorium located in Barcelona, Spain between 1943 and 1975. METHOD: historical study undertaken between 2008 and 2010, based on oral sources, five direct and one indirect testimonies, and the analysis of written documents. The data from the testimonies were collected through semistructured interviews. RESULTS: the nursing staff, mostly religious women, had scarce material and economic resources and no preventive measures to take care of the ill. The nurses undertook activities centered on the basic needs for physical and spiritual wellbeing. CONCLUSION: The study reveals how the nurses, despite working in hostile conditions, attempted to safeguard the wellbeing of the patients and accompany them during the death process. PMID- 25029061 TI - Risk factors for type 2 diabetes mellitus in college students: association with sociodemographic variables. AB - OBJECTIVE: identify the modifiable risk factors for type 2 diabetes mellitus in college students and associate these factors with their sociodemographic variables. METHOD: cross-sectional study, involving 702 college students from Fortaleza-CE, Brazil. Sociodemographic, anthropometric, physical exercise data and blood pressure and fasting plasma glucose levels were collected. RESULTS: the most prevalent risk factor was sedentariness, followed by overweight, central obesity, high fasting plasma glucose and arterial hypertension. A statistically significant association was found between overweight and sex (p=0.000), age (p=0.004) and marital status (p=0.012), as well as between central obesity and age (p=0.018) and marital status (p=0.007) and between high fasting plasma glucose and sex (p=0.033). CONCLUSION: distinct risk factors were present in the study population, particularly sedentariness and overweight. PMID- 25029062 TI - Knowledge about hypertension and factors associated with the non-adherence to drug therapy. AB - OBJECTIVES: to identify the degree of knowledge of people with hypertension concerning the disease and to verify the factors associated with the non adherence to anti-hypertensive drug therapy. METHOD: Cross sectional study, involving 422 people. Data collection took place at their homes, between December 2011 and March 2012, through interviews using the following instruments: Medication Adherence Questionnaire (MAQ-Q), Medication Regimen Complexity Index (MRCI) and a guide with questions related to sociodemographic profile, satisfaction with healthcare service and knowledge about the disease. RESULTS: 42.6% did not adhere to the drug therapy and 17.7% had poor knowledge about the disease. Factors associated with the non-adherence were: complex drug therapy, poor knowledge about the disease and dissatisfaction with the healthcare service. CONCLUSION: The findings reinforce that the complex drug therapy prescriptions, little knowledge about the disease and dissatisfaction with the healthcare service have influence on the process of non-adherence to anti-hypertensive drug therapy. PMID- 25029063 TI - Alignment of ICNP(r) 2.0 ontology and a proposed INCP(r) Brazilian ontology. AB - OBJECTIVE: to align the International Classification for Nursing Practice (ICNP(r)) Version 2.0 ontology and a proposed INCP(r) Brazilian Ontology. METHOD: document-based, exploratory and descriptive study, the empirical basis of which was provided by the ICNP(r) 2.0 Ontology and the INCP(r) Brazilian Ontology. The ontology alignment was performed using a computer tool with algorithms to identify correspondences between concepts, which were organized and analyzed according to their presence or absence, their names, and their sibling, parent, and child classes. RESULTS: there were 2,682 concepts present in the ICNP(r) 2.0 Ontology that were missing in the Brazilian Ontology; 717 concepts present in the Brazilian Ontology were missing in the ICNP(r) 2.0 Ontology; and there were 215 pairs of matching concepts. CONCLUSION: it is believed that the correspondences identified in this study might contribute to the interoperability between the representations of nursing practice elements in ICNP(r), thus allowing the standardization of nursing records based on this classification system. PMID- 25029064 TI - Theoretical assumptions of Maffesoli's sensitivity and problem-based learning in nursing education. AB - OBJECTIVE: understand the everyday and the imaginary of Nursing students in their knowledge socialization process through the Problem-Based Learning (PBL) strategy. METHOD: Action Research, involving 86 students from the second year of an undergraduate Nursing program in Spain. A Critical Incident Questionnaire and Group interview were used. Thematic/categorical analysis, triangulation of researchers, subjects and techniques. RESULTS: the students signal the need to have a view from within, reinforcing the criticism against the schematic dualism; PBL allows one to learn how to be with the other, with his mechanical and organic solidarity; the feeling together, with its emphasis on learning to work in group and wanting to be close to the person taking care. CONCLUSIONS: The great contradictions the protagonists of the process, that is, the students experience seem to express that group learning is not a form of gaining knowledge, as it makes them lose time to study. The daily, the execution time and the imaginary of how learning should be do not seem to have an intersection point in the use of Problem-Based Learning. The importance of focusing on the daily and the imaginary should be reinforced when we consider nursing education. PMID- 25029065 TI - The effectiveness of hydrocolloid dressings versus other dressings in the healing of pressure ulcers in adults and older adults: a systematic review and meta analysis. AB - OBJECTIVE: to evaluate the effectiveness of hydrocolloids in the healing of pressure ulcers in adult and older adult patients. METHOD: systematic review with meta-analysis, based on the recommendations of the Cochrane Handbook. The search was undertaken in the databases: Medical Literature Analysis and Retrieval System Online, Latin American and Caribbean Health Sciences Literature (LILACS), Cochrane Database, Cumulative Index to Nursing and Allied Health Literature, Web of Science and the Scientific Electronic Library Online. RESULTS: 646 primary studies were identified, 69 were evaluated and nine were selected, referring to the use of the hydrocolloid dressing in healing; of these, four studies allowed meta-analysis. There was no statistically significant difference between the hydrocolloid group and the foams group (p value=0.84; Odds Ratio 1.06, CI 95% 0.61-1.86). A slight superiority of the polyurethane dressings was observed in relation to the hydrocolloid dressings. CONCLUSION: the evidence is not sufficient to affirm whether the efficacy of hydrocolloid dressings is superior to that of other dressings. It is suggested that clinical randomized trials be undertaken so as to ascertain the efficacy of this intervention in the healing of pressure ulcers, in relation to other treatments. PMID- 25029067 TI - Effect of urea on phase transition of poly(N-isopropylacrylamide) investigated by differential scanning calorimetry. AB - The effect of urea on the phase transition of PNIPAM was studied using differential scanning calorimetry (DSC). For a certain urea concentration, the enthalpy change of phase transition of poly(N-isopropylacrylamide) (PNIPAM) aqueous solution increases with the number of DSC cycles, presumably due to the displacement of water molecules bound to the amide groups of PNIPAM by urea molecules at the temperature higher than the lower critical solution temperature (LCST) of PNIPAM and causes the decrease in the absolute value of the exothermic heat related to the dehydration of hydrophilic groups and interactions of hydrophilic residues to around 0. Moreover, the enthalpy change decreases with the urea concentration during the heating process of the first DSC cycle, indicating the replacement of water molecules around the apolar isopropyl groups by urea molecules at the temperature lower than LCST, and the endothermic heat caused by the dehydration of apolar groups decreases. Furthermore, the urea molecules which replace the water molecules at high temperature can be replaced again by water molecules at the temperature lower than LCST, but this process needs several days to complete. PMID- 25029069 TI - Relationship between voided volume and the urge to void among patients with lower urinary tract symptoms. AB - OBJECTIVE: The aim of this study was to explore the relationship between voided volume (VV) and urge to void among patients with lower urinary tract symptoms. MATERIAL AND METHODS: Consecutive adult patients (aged 23-90 years) were enrolled, and completed a 24 h bladder diary and the Urgency Perception Scale (UPS). Patients were categorized as urgency or non-urgency based on the Overactive Bladder Symptom Score. The relationship between UPS and VV (based on the bladder diary) was analyzed by Spearman's rho and proportional odds model. RESULTS: In total, 1265 micturitions were evaluated in 117 individuals (41 men, 76 women; 56 individuals in the urgency and 61 in the non-urgency group). The mean (+/- SD) VV and UPS were 192 +/- 127 ml and 2.4 +/- 1.2 ml in the urgency group and 173 +/- 124 ml and 1.7 +/- 1.1 ml in the non-urgency group, respectively. Spearman's rho (between UPS and VV) was 0.21 [95% confidence interval (CI) 0.13-029, p < 0.001] for the urgency group, 0.32 (95% CI 0.25-0.39, p < 0.001) for the non-urgency group, and 0.28 (95% CI 0.23-0.33, p < 0.001) for the total cohort. Urgency patients had higher UPS [odds ratio (OR) 3.1, 95% CI 2.5-3.8]. Overall, each additional 50 ml VV increased the odds of having a higher UPS with OR 1.2 (95% CI 1.2-1.3). The relationship between VV and UPS score was similar in both groups (p = 0.548 for interaction). CONCLUSION: Although urgency patients void with a higher UPS score, among both urgency and non-urgency patients there is only a weak correlation between VV and the urge to void. This suggests that there are factors other than VV that cause the urge to void. PMID- 25029070 TI - An erbium-based bifuctional heterogeneous catalyst: a cooperative route towards C C bond formation. AB - Heterogeneous bifuctional catalysts are multifunctional synthetic catalysts enabling efficient organic transformations by exploiting two opposite functionalities without mutual destruction. In this paper we report the first Er(III)-based metallorganic heterogeneous catalyst, synthesized by post calcination MW-assisted grafting and modification of the natural aminoacid L cysteine. The natural acid-base distance between sites was maintained to assure the cooperation. The applicability of this new bifunctional heterogeneous catalyst to C-C bond formation and the supposed mechanisms of action are discussed as well. PMID- 25029071 TI - QM/MM studies of contemporary and novel membrane raft fluorescent probes. AB - We have studied a number of contemporary and novel membrane probes, selected for their structural similarity to membrane raft components, in order to properly anchor themselves within a sphingolipid/cholesterol rich region. A QM/MM approach was adopted in order to understand the structural and electrostatic influences of fluorescence emission shifts of the probes in different lipid and solvation environments. The proposed modifications to the membrane probes have shown encouraging data relating not only to emission shifts within the membrane, but also their ability to anchor within a membrane raft domain and the stability to internalization within a membrane system. PMID- 25029072 TI - Jasmonic acid effect on the fatty acid and terpenoid indole alkaloid accumulation in cell suspension cultures of Catharanthus roseus. AB - The stress response after jasmonic acid (JA) treatment was studied in cell suspension cultures of Catharanthus roseus. The effect of JA on the primary and secondary metabolism was based on changes in profiles of fatty acids (FA) and terpenoid indole alkaloids (TIA). According to multivariate data analyses (MVDA), three major time events were observed and characterized according to the variations of specific FA and TIA: after 0-30 min of induction FA such as C18:1, C20:0, C22:0 and C24:0 were highly induced by JA; 90-360 min after treatment was characterized by variations of C14:0 and C15:0; and 1440 min after induction JA had the largest effect on both group of metabolites were C18:1, C18:2, C18:3, C16:0, C20:0, C22:0, C24:0, catharanthine, tabersonine-like 1, serpentine, tabersonine and ajmalicine-like had the most significant variations. These results unambiguously demonstrate the profound effect of JA particularly on the accumulation of its own precursor, C18:3 and the accumulation of TIA, which can be considered as late stress response events to JA since they occurred only after 1440 min. These observations show that the early events in the JA response do not involve the de novo biosynthesis of neither its own precursor nor TIA, but is due to an already present biochemical system. PMID- 25029073 TI - Bioassay-guided chemical study of the anti-inflammatory effect of Senna villosa (Miller) H.S. Irwin & Barneby (Leguminosae) in TPA-induced ear edema. AB - Senna villosa (Miller) is a plant that grows in Mexico. In traditional Mexican medicine, it is used topically to treat skin infections, pustules and eruptions and to heal wounds by scar formation. However, studies of its potential anti inflammatory effects have not been performed. The aim of the present study was to determine the anti-inflammatory effect of extracts from the leaves of Senna villosa and to perform a bioassay-guided chemical study of the extract with major activity in a model of ear edema induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). The results reveal that the chloroform extract from Senna villosa leaves has anti-inflammatory and anti-proliferative properties. Nine fractions were obtained from the bioassay-guided chemical study, including a white precipitate from fractions 2 and 3. Although none of the nine fractions presented anti inflammatory activity, the white precipitate exhibited pharmacological activity. It was chemically characterized using mass spectrometry and infrared and nuclear magnetic resonance spectroscopy, resulting in a mixture of three aliphatic esters, which were identified as the principal constituents: hexyl tetradecanoate (C20H40O2), heptyl tetradecanoate (C21H42O2) and octyl tetradecanoate (C22H44O2). This research provides, for the first time, evidence of the anti-inflammatory and anti-proliferative properties of compounds isolated from Senna villosa. PMID- 25029074 TI - The natural product citral can cause significant damage to the hyphal cell walls of Magnaporthe grisea. AB - In order to find a natural alternative to the synthetic fungicides currently used against the devastating rice blast fungus, Magnaporthe grisea, this study explored the antifungal potential of citral and its mechanism of action. It was found that citral not only inhibited hyphal growth of M. grisea, but also caused a series of marked hyphal morphological and structural alterations. Specifically, citral was tested for antifungal activity against M. grisea in vitro and was found to significantly inhibit colony development and mycelial growth with IC50 and IC90 values of 40.71 and 203.75 MUg/mL, respectively. Furthermore, citral reduced spore germination and germ tube length in a concentration-dependent manner. Following exposure to citral, the hyphal cell surface became wrinkled with folds and cell breakage that were observed under scanning electron microscopy (SEM). There was damage to hyphal cell walls and membrane structures, loss of villous-like material outside of the cell wall, thinning of the cell wall, and discontinuities formed in the cell membrane following treatment based on transmission electron microscopy (TEM). This increase in chitinase activity both supports the morphological changes seen in the hyphae, and also suggests a mechanism of action. In conclusion, citral has strong antifungal properties, and treatment with this compound is capable of causing significant damage to the hyphal cell walls of M. grisea. PMID- 25029076 TI - Poly(m-phenylenediamine)-based fluorescent nanoprobe for ultrasensitive detection of matrix metalloproteinase 2. AB - A novel fluorescence nanoprobe for the detection of matrix metalloproteinase 2 (MMP2) has been developed by engineering the fluorescein isothiocyanate-labeled peptide onto the surface of poly(m-phenylenediamine) (PMPD) nanoparticles through covalent linkage. The nanoprobe itself displays a low background signal due to the effective fluorescence quenching by electron-rich PMPD, but its reaction with MMP2 causes 11-fold fluorescence enhancement. Compared with similar fluorescence nanosystems for MMP2 assembled through physical adsorption, the as-prepared nanoprobe is significantly more stable and displays a strikingly higher signal-to background ratio, which leads to a high sensitivity for MMP2 assay, with a detection limit of 32 pM. Most notably, the nanoprobe has been successfully applied to determine MMP2 in human serum samples, demonstrating that the MMP2 level in serum from colorectal cancer (CRC) patients is 2 times higher than that from healthy people. Moreover, the nanoprobe has also been used to monitor MMP2 secreted by CRC cells that were grown under normoxic and hypoxic conditions, respectively, and the results show that the cells under hypoxic conditions produce higher level of MMP2 than those under normoxic conditions. Our method is simple and can offer a highly sensitive detection of MMP2 in relevant clinical samples. PMID- 25029077 TI - The relationship between bilingual exposure and morphosyntactic development. AB - PURPOSE: The study examined the effect of bilingual input on the grammatical development of bilingual children in comparison to monolingual peers. METHOD: Spontaneous language samples were collected in English and French from typically developing bilingual and monolingual pre-schoolers aged 3 years (n = 56) and 5 years (n = 83). Within each age group, children varied in bilingual exposure patterns but were matched on age, non-verbal cognition, maternal education and language status, speaking two majority languages. Measures included mean length of utterance (MLU) in words and morphemes, and accuracy and diversity of morphological use. RESULT: Grammatical development in each language was strongly influenced by amount of same-language experience. Children with equal exposure to both languages scored comparably to monolingual children in both languages, whereas children with unequal exposure evidenced similarly unequal performance across languages and scored significantly lower than monolinguals in their weaker language. Scoring significantly lower than monolinguals in both languages may, therefore, be a sign of language impairment. Each language followed a strongly language-specific sequence of acquisition and error patterns. Five-year-old children with low exposure to English displayed an optional infinitive pattern, a strong clinical marker for Primary Language Impairment in monolingual English speaking children. CONCLUSION: Descriptive normative data are presented that permit more accurate interpretation of bilingual assessment data. PMID- 25029078 TI - Influence of superstructure geometry on the mechanical behavior of zirconia implant abutments: a finite element analysis. AB - To predict the clinical performance of zirconia abutments, it is crucial to examine the mechanical behavior of different dental implant-abutment connection configurations. The international standard protocol for dynamic fatigue tests of dental implants (ISO 14801) allows comparing these configurations using standardized superstructure geometries. However, from a mechanical point of view, the geometry of clinical crowns causes modified boundary conditions. The purpose of this finite element (FE) study was to evaluate the influence of the superstructure geometry on the maximum stress values of zirconia abutments with a conical implant-abutment connection. Geometry models of the experimental setup described in ISO 14801 were generated using CAD software following the reconstruction of computerized tomography scans from all relevant components. These models served as a basis for an FE simulation. To reduce the numerical complexity of the FE model, the interaction between loading stamp and superstructure geometry was taken into account by defining the boundary conditions with regard to the frictional force. The results of the FE simulations performed on standardized superstructure geometry and anatomically shaped crowns showed a strong influence of the superstructure geometry and related surface orientations on the mechanical behavior of the underlying zirconia abutments. In conclusion, ISO testing of zirconia abutments should be accompanied by load bearing capacity testing under simulated clinical conditions to predict clinical performance. PMID- 25029079 TI - Analysis of emboli and blood flow in the ophthalmic artery to understand retinal artery occlusion. AB - Retinal artery occlusion (RAO) is a common ocular vascular occlusive disorder that may lead to partial or complete retinal ischemia with sudden visual deterioration and visual field defects. Although RAO has been investigated since 1859, the main mechanism is still not fully understood. While hypoperfusion of the ophthalmic artery (OA) due to severe stenosis of the internal carotid artery might lead to RAO, emboli are assumed to be the main reason. Intra-arterial thrombolysis is not a sufficient treatment for RAO, and current research is mainly focused on risk factors. In this study, a computational fluid dynamic model is presented to analyse flow conditions and clot behaviour at the junction of the internal carotid artery and OA based on a realistic geometry from a RAO patient. Clot diameters varied between 5 and 200 MUm, and the probability of clots reaching the OA or being washed into the brain was analysed. Results show sufficient blood flow and perfusion pressure at the end of OA. The probability that clots from the main blood flow will to be washed into the brain is 7.32 +/- 1.08%. A wall shear stress hotspot is observed at the curvature proximal to the internal carotid artery/OA junction. Clots released from this hotspot have a higher probability of causing RAO. The occurrence of such patient-specific pathophysiologies will have to be considered in the future. PMID- 25029080 TI - Red light as a 12-oxo-leukotriene B4 antagonist: an explanation for the efficacy of intensive red light in the therapy of peripheral inflammatory diseases. AB - To explain the successful treatment of various inflammatory diseases by using intensive red light, a non-linear theory is presented for the interaction of electric dipoles with light involving frequency doubling. It is applied to analyze the influence of light on organic molecules with permanent electric dipoles. The molecule 5-hydroxy-12-oxo-(5S,6Z,8E,10E,14Z)-6,8,10,14 eicosatetraenoic acid, 12-oxo-leukotriene B4 (12-Oxo-LTB4, an intermediate in the lipoxygenase-catalyzed path of arachidonic acid metabolism), is suspected to play a major role in the healing process, as, first, it plays a key role in the metabolism of leukotriene B4 (LTB4), which in many diseases acts as a source of inflammatory reactions; second, its dipole resonance is located at a wavelength of 316 nm, which can be excited by a 632 nm source through frequency doubling. From the structure of 12-Oxo-LTB4 and the knowledge of the partial charges of its 54 atoms, the equivalent values for dipole charges and dipole moment are derived. The power balance demonstrates that intensive red light with a power density of 0.4 W/cm2 transfers sufficient energy to 12-Oxo-LTB4 to render it biologically inactive. Hence, by generating a reactive high-energy leukotriene pathway intermediate, the law of mass action steers the chemical equilibrium to interrupt the inflammatory cascade. PMID- 25029082 TI - Effect of silymarin pretreatment on the bioavailability of domperidone in healthy human volunteers. AB - BACKGROUND: The aim of this study was to investigate the effect of silymarin pretreatment on domperidone oral bioavailability in humans. METHODS: The rats were pretreated with silymarin for 7 days. The transport of domperidone across the rat intestine (duodenum, jejunum, ileum, and colon) was studied by using in vitro everted and non-everted sac methods. Samples were collected at preset time points and replaced with buffer. The drug content in the samples was estimated. The first part of the study included oral administration of 10 mg domperidone tablet alone, and blood was sampled from the antecubital vein. The second part of the study was conducted after a washout period of 2 weeks. Five hundred milligrams of silymarin was administered twice daily for 6 days. On day 7, one tablet each of 10 mg domperidone and 500 mg silymarin were administered concomitantly. RESULTS: In the everted sac and non-everted sac study with silymarin pretreatment, domperidone transport increased from the duodenum, jejunum, ileum, and colon. The silymarin pretreatment increased the bioavailability of domperidone. There was a statistically significant difference in the pharmacokinetic parameters Cmax, T1/2, AUC0-infinity, and AUC0-24. CONCLUSIONS: The significant difference in absorption of domperidone on pretreatment with silymarin is due to the inhibition of P-glycoprotein and CYP3A. Silymarin, which inhibits CYP3A4, should be contraindicated for domperidone. PMID- 25029083 TI - Effects of cigarette smoking on circulating leukocytes and plasma cytokines in monozygotic twins. AB - BACKGROUND: Despite the well-documented role of cigarette smoke in the development of chronic obstructive pulmonary disease (COPD), lung cancer and cardiovascular disease, biomarkers for screening or monitoring disease progression and outcome remain elusive, particularly for COPD and lung cancer. Inflammatory cells and mediators are likely to be involved in the disease processes, but their importance is still poorly understood. The purpose of this study was to investigate early changes in immunological markers associated with smoking in healthy monozygotic twins without a detectable disease discordant for smoking, thereby minimising data variability due to genetic background. METHODS: Twenty-two monozygotic twin pairs, aged 31.5+/-6.3 years, entered the study. One of each twin pair was a smoker and the other a non-smoker. None of the subjects reported any diseases or clinically defined respiratory symptoms or airflow limitation. Each subject donated blood samples for determination of total leukocytes and subpopulations, lymphocyte subpopulation plus pro-inflammatory mediators (interleukin-8, tumour necrosis factor-alpha, soluble tumour necrosis factor-alpha receptors and C-reactive protein). RESULTS: We observed a significant increase in the number of circulating leukocytes and neutrophils in smokers compared to non-smokers. Smokers also had significantly higher numbers of B cells and CD4+ T cells, plus an increased CD4/CD8 ratio. The numbers of NK cells were statistically significant lower in smokers compared to non-smokers. CONCLUSIONS: While the prognostic significance of these changes is uncertain, results suggest that smoking is associated with immune changes, independent of genetic background and environmental conditions. PMID- 25029081 TI - Effect of depth on shear-wave elastography estimated in the internal and external cervical os during pregnancy. AB - AIM: To investigate the effect of depth on cervical shear-wave elastography. METHODS: Shear-wave elastography was applied to estimate the velocity of propagation of the acoustic force impulse (shear wave) in the cervix of 154 pregnant women at 11-36 weeks of gestation. Shear-wave speed (SWS) was evaluated in cross-sectional views of the internal and external cervical os in five regions of interest: anterior, posterior, lateral right, lateral left, and endocervix. Distance from the center of the ultrasound (US) transducer to the center of each region of interest was registered. RESULTS: In all regions, SWS decreased significantly with gestational age (P=0.006). In the internal os, SWS was similar among the anterior, posterior, and lateral regions and lower in the endocervix. In the external os, the endocervix and anterior regions showed similar SWS values, lower than those from the posterior and lateral regions. In the endocervix, these differences remained significant after adjustment for depth, gestational age, and cervical length. SWS estimations in all regions of the internal os were higher than those of the external os, suggesting denser tissue. CONCLUSION: Depth from the US probe to different regions in the cervix did not significantly affect the SWS estimations. PMID- 25029084 TI - Determination of reference limits: statistical concepts and tools for sample size calculation. AB - Reference limits are estimators for 'extreme' percentiles of the distribution of a quantitative diagnostic marker in the healthy population. In most cases, interest will be in the 90% or 95% reference intervals. The standard parametric method of determining reference limits consists of computing quantities of the form X+/-c.S. The proportion of covered values in the underlying population coincides with the specificity obtained when a measurement value falling outside the corresponding reference region is classified as diagnostically suspect. Nonparametrically, reference limits are estimated by means of so-called order statistics. In both approaches, the precision of the estimate depends on the sample size. We present computational procedures for calculating minimally required numbers of subjects to be enrolled in a reference study. The much more sophisticated concept of reference bands replacing statistical reference intervals in case of age-dependent diagnostic markers is also discussed. PMID- 25029085 TI - Laboratory medicine in the European Union. AB - The profession of laboratory medicine differs between countries within the European Union (EU) in many respects. The objective of professional organizations of the promotion of mutual recognition of specialists within the EU is closely related to the free movement of people. This policy translates to equivalence of standards and harmonization of the training curriculum. The aim of the present study is the description of the organization and practice of laboratory medicine within the countries that constitute the EU. A questionnaire covering many aspects of the profession was sent to delegates of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and Union Europeenne de Medecins Specialistes (UEMS) of the 28 EU countries. Results were sent to the delegates for confirmation. Many differences between countries were identified: predominantly medical or scientific professionals; a broad or limited professional field of interest; inclusion of patient treatment; formal or absent recognition; a regulated or absent formal training program; general or minor application of a quality system based on ISO Norms. The harmonization of the postgraduate training of both clinical chemists and of laboratory physicians has been a goal for many years. Differences in the organization of the laboratory professions still exist in the respective countries which all have a long historical development with their own rationality. It is an important challenge to harmonize our profession, and difficult choices will need to be made. Recent developments with respect to the directive on Recognition of Professional Qualifications call for new initiatives to harmonize laboratory medicine both across national borders, and across the borders of scientific and medical professions. PMID- 25029086 TI - Imputing genotypes using regularized generalized linear regression models. AB - As genomic sequencing technologies continue to advance, researchers are furthering their understanding of the relationships between genetic variants and expressed traits. However, missing data can significantly limit the power of a genetic study. Here, the use of a regularized generalized linear model, denoted by GLMNET, is proposed to impute missing genotypes. The method aims to address certain limitations of earlier regression approaches in regards to genotype imputation, particularly the specification of the number of neighboring SNPs to be included for imputing the missing genotype. The performance of GLMNET-based method is compared to the conventional multinomial regression method and two phase-based methods: fastPHASE and BEAGLE. Two simulation scenarios are evaluated: a sparse-missing model, and a small-panel expansion model. The sparse missing model simulates a scenario where SNPs were missing in a random fashion across the genome. In the small-panel expansion model, a set of individuals is only genotyped at a subset of the SNPs of the large panel. Each imputation method is tested in the context of two data-sets: Canadian Holstein cattle data and human HapMap CEU data. Results show that the proposed GLMNET method outperforms the other methods in the small panel expansion scenario and fastPHASE performs slightly better than the GLMNET method in the sparse-missing scenario. PMID- 25029087 TI - Spatiotemporal intracellular nitric oxide signaling captured using internalized, near-infrared fluorescent carbon nanotube nanosensors. AB - Fluorescent nanosensor probes have suffered from limited molecular recognition and a dearth of strategies for spatial-temporal operation in cell culture. In this work, we spatially imaged the dynamics of nitric oxide (NO) signaling, important in numerous pathologies and physiological functions, using intracellular near-infrared fluorescent single-walled carbon nanotubes. The observed spatial-temporal NO signaling gradients clarify and refine the existing paradigm of NO signaling based on averaged local concentrations. This work enables the study of transient intracellular phenomena associated with signaling and therapeutics. PMID- 25029088 TI - Synthesis of a "super bulky" guanidinate possessing an expandable coordination pocket. AB - Friedel-Crafts alkylation of 4-tert-butylaniline with 2 equiv of benzhydrol affords bulky 2,6-bis(diphenylmethyl)-4-tert-butylaniline (Ar*NH2) in good yield, which can be readily synthesized on a tens of grams scale. The reaction of 6 equiv of Ar*NH2 with triphosgene generates the symmetric urea (Ar*NH)2CO, which, upon dehydration with a P2O5/Al2O3 slurry in pyridine, produces the sterically encumbered carbodiimide (Ar*N)2C as an air-stable white solid. The treatment of (Ar*N)2C with LiN?C(t)Bu2 in tetrahydrofuran cleanly gives the monomeric lithium guanidinate Li[(Ar)*ketguan], free of coordinating solvent, in 85% yield. Protonation of Li[(Ar)*ketguan] with lutidinium chloride produces the guanidine (Ar)*ketguanH (MW = 1112.60 g/mol), which is easily derivatized to give the monomeric alkali metal complexes M[(Ar)*ketguan] (M = K, Cs) in 94% and 51% yield, respectively. The solid-state molecular structures of M[(Ar)*ketguan] (M = Li, K, Cs) show formally two-coordinate alkali metal cations encapsulated within a hydrophobic coordination pocket formed by the peripheral diphenylmethyl substituents of the guanidinate. Remarkably, percent buried volume analyses (% V(Bur)) of M[(Ar)*ketguan] [M = Li (94.8% V(Bur)), K (92.1% V(Bur)), Cs (81.7% V(Bur))] reveal a coordination cavity that adjusts to individually accommodate the variously sized metal ions despite the highly encumbering nature of the ligand. This demonstrates a flexible ligand framework that is able to stabilize low-coordinate metal centers within a "super bulky" coordination environment. PMID- 25029090 TI - Elite athletes refine their internal clocks. AB - Evaluating time properly is crucial for everyday activities from fundamental behaviors to refined coordinative movements such as in sport playing. Lately the concept of the existence of a unique internal clock for evaluating time in different scales has been challenged by recent neurophysiology studies. Here we provide evidence that individuals evaluate time durations below and above a second based on two different internal clocks for sub- and suprasecond time ranges: a faster clock for the subsecond range and a slower one for suprasecond time. Interestingly, the level of precision presented by these two clocks can be finely tuned through long-term sport training: Elite athletes, independently from their sport domains, generate better time estimates than nonathletes by showing higher accuracy and lower variability, particularly for subsecond time. We interpret this better time estimation in the short durations as being due to their extraordinary perceptual and motor ability in fast actions. PMID- 25029092 TI - Impact of strabismus surgery on health-related quality of life in adults. AB - PURPOSE OF REVIEW: Adult strabismus can cause many symptoms, which have generally been divided into functional complaints and social complaints. The validity of surgical correction has historically been based on the restoration of functional improvement. In the absence of this expectation, surgery was labeled cosmetic. Yet, many studies have revealed the immense impact of ocular misalignment on psychosocial variables. The purpose of this article is to review the potential functional and psychosocial benefits of strabismus surgery and to summarize the development and status of questionnaires to help quantify these benefits. RECENT FINDINGS: Functional benefits of strabismus surgery have been recently summarized with a meta-analysis. Several questionnaires have been evaluated to assess the functional and psychosocial factors in adult strabismus. Two strabismus-specific questionnaires, the Amblyopia and Strabismus Questionnaire and the Adult Strabismus-20, reveal improvements in adults following surgery. The appropriate patient population, impact of comorbidities on the scores, and the timing of the administration of the questionnaire postoperatively still need to be determined. SUMMARY: Future studies of the impact of strabismus surgery in adults will need to report not only objective motor results, but also the impact on health-related quality of life to encompass all the benefits of strabismus surgery. PMID- 25029089 TI - Structural and functional characterization of a cytochrome P450 2B4 F429H mutant with an axial thiolate-histidine hydrogen bond. AB - The structural basis of the regulation of microsomal cytochrome P450 (P450) activity was investigated by mutating the highly conserved heme binding motif residue, Phe429, on the proximal side of cytochrome P450 2B4 to a histidine. Spectroscopic, pre-steady-state and steady-state kinetic, thermodynamic, theoretical, and structural studies of the mutant demonstrate that formation of an H-bond between His429 and the unbonded electron pair of the Cys436 axial thiolate significantly alters the properties of the enzyme. The mutant lost >90% of its activity; its redox potential was increased by 87 mV, and the half-life of the oxyferrous mutant was increased ~37-fold. Single-crystal electronic absorption and resonance Raman spectroscopy demonstrated that the mutant was reduced by a small dose of X-ray photons. The structure revealed that the deltaN atom of His429 forms an H-bond with the axial Cys436 thiolate whereas the epsilonN atom forms an H-bond with the solvent and the side chain of Gln357. The amide of Gly438 forms the only other H-bond to the tetrahedral thiolate. Theoretical quantification of the histidine-thiolate interaction demonstrates a significant electron withdrawing effect on the heme iron. Comparisons of structures of class I-IV P450s demonstrate that either a phenylalanine or tryptophan is often found at the location corresponding to Phe429. Depending on the structure of the distal pocket heme, the residue at this location may or may not regulate the thermodynamic properties of the P450. Regardless, this residue appears to protect the thiolate from solvent, oxidation, protonations, and other deleterious reactions. PMID- 25029093 TI - Hereditary disorders affecting the lacrimal system. AB - PURPOSE OF REVIEW: Encountering a patient with lacrimal dysgenesis or agenesis is not an uncommon occurrence in an oculoplastic surgeon's practice. Eliciting a hereditary component in patients with lacrimal disorders is helpful in determining the underlying cause of the condition. The purpose of this review is to assist the clinician in understanding and categorizing those lacrimal disorders with a hereditary component. RECENT FINDINGS: Compared with genetic diseases which affect the eyelids, hereditary disorders that affect the lacrimal system are fewer in number. These disorders can be categorized into the following groups: fibroblast growth factor 10 associated disorders, tumor protein p63 associated disorders, disorders associated with the development of the branchial apparatus, and disorders associated with autonomic dysfunction. In addition, there are a number of reports of inherited disorders affecting the lacrimal system that have not been elucidated molecularly. SUMMARY: Inherited disorders that affect the lacrimal system are limited in number. Knowledge of these disorders by the oculoplastic surgeon may aid in the correct diagnosis, which in turn will allow appropriate treatment of these patients. PMID- 25029094 TI - The diagnosis and management of Cushing syndrome during pregnancy. PMID- 25029095 TI - Predictors of asymptomatic bacteriuria among pregnant women in a low-resource setting. AB - This study aims at identifying predictors of asymptomatic bacteriuria (AB) among pregnant women in a low-resource setting, with the intent of recommending a guideline for screening during antenatal care. A total of 266 healthy pregnant women were antenatally recruited after informed consent. They had routine antenatal investigations, a 1 h 50-g oral glucose tolerance test and quantitative urine culture and sensitivity. The data collected were analysed using statistical software package SPSS v. 17. Prevalence of AB was 23 (8.6%). Escherichia coli was the commonest isolate (6, 26.1%), closely followed by Staphylococcus aureus (5, 21.7%). AB was commoner among patients aged 25-34 years, of low parity and higher education. Blood group B- rhesus-positive significantly predicts the likelihood of developing AB in pregnancy (adjusted OR: 0.36; 95% CI: 0.14-0.96). We conclude that blood group B-rhesus-positive in association with other patients' characteristics, such as age 25-34 years, low parity and higher education could form guidelines for a screening algorithm in our environment. PMID- 25029096 TI - An unusual location of a vulvar leiomyoma. PMID- 25029097 TI - Surgical treatment for pelvic organ prolapse in elderly women. AB - The objective was to analyse the feasibility, safety and outcome of surgical treatment for pelvic organ prolapse in women >= 65 years of age. A single-centre retrospective, cohort study was performed through a medical records review and telephone interview. Women >= 65 years of age, who underwent a surgical operation for pelvic organ prolapse, were considered. Overall, 305 women were included. The following procedures (alone or in combination) were performed: 168 (52.1%) vaginal hysterectomy; 264 (81.9%) anterior colporrhaphy; 261 (81.0%) posterior colpoperineorrhaphy and 45 (13.8%) Manchester operation. There were two cases of bladder injury (0.6%) and two cases of vaginal haematoma (0.6%). Urinary retention and febrile morbidity were found in 33 (10.8%) and 35 (11.5%) of women, respectively. Clinical follow-up, median 10 months, showed that 178 of 200 (89.0%) women had anatomical success. Traditional reconstructive surgical operation for pelvic organ prolapse is a viable treatment option in elderly women. PMID- 25029099 TI - Supertoughened renewable PLA reactive multiphase blends system: phase morphology and performance. AB - Multiphase blends of poly(lactic acid) (PLA), ethylene-methyl acrylate-glycidyl methacrylate (EMA-GMA) terpolymer, and a series of renewable poly(ether-b-amide) elastomeric copolymer (PEBA) were fabricated through reactive melt blending in an effort to improve the toughness of the PLA. Supertoughened PLA blend showing impact strength of ~500 J/m with partial break impact behavior was achieved at an optimized blending ratio of 70 wt % PLA, 20 wt % EMA-GMA, and 10 wt % PEBA. Miscibility and thermal behavior of the binary blends PLA/PEBA and PLA/EMA-GMA, and the multiphase blends were also investigated through differential scanning calorimetric (DSC) and dynamic mechanical analysis (DMA). Phase morphology and fracture surface morphology of the blends were studied through scanning electron microscopy (SEM) and atomic force microscopy (AFM) to understand the strong corelation between the morphology and its significant effect on imparting tremendous improvement in toughness. A unique "multiple stacked structure" with partial encapsulation of EMA-GMA and PEBA minor phases was observed for the PLA/EMA-GMA/PEBA (70/20/10) revealing the importance of particular blend composition in enhancing the toughness. Toughening mechanism behind the supertoughened PLA blends have been established by studying the impact fractured surface morphology at different zones of fracture. Synergistic effect of good interfacial adhesion and interfacial cavitations followed by massive shear yielding of the matrix was believed to contribute to the enormous toughening effect observed in these multiphase blends. PMID- 25029098 TI - T-cell autophagy deficiency increases mortality and suppresses immune responses after sepsis. AB - BACKGROUND: Although the role of autophagy in sepsis has been characterized in several organs, its role in the adaptive immune system remains to be ascertained. This study aimed to investigate the role of autophagy in sepsis-induced T cell apoptosis and immunosuppression, using knockout mice with T cell specific deletion of autophagy essential gene Atg7. METHODS AND RESULTS: Sepsis was induced in a cecal ligation and puncture (CLP) model, with T-cell-specific Atg7 knockout mice compared to control mice. Autophagic vacuoles examined by electron microscopy were decreased in the spleen after CLP. Autophagy proteins LC3-II and ATG7, and autophagosomes and autolysosomes stained by Cyto-ID Green and acridine orange were decreased in CD4+ and CD8+ splenocytes at 18 h and 24 h after CLP. This decrease in autophagy was associated with increased apoptosis of CD4+ and CD8+ after CLP. Moreover, mice lacking Atg7 in T lymphocytes showed an increase in sepsis-induced mortality, T cell apoptosis and loss of CD4+ and CD8+ T cells, in comparison to control mice. This was accompanied by suppressed cytokine production of Th1/Th2/Th17 by CD4+ T cells, reduced phagocytosis in macrophages and decreased bacterial clearance in the spleen after sepsis. CONCLUSION: These results indicated that sepsis led to down-regulation of autophagy in T lymphocytes, which may result in enhanced apoptosis induction and decreased survival in sepsis. Autophagy may therefore play a protective role against sepsis induced T lymphocyte apoptosis and immunosuppression. PMID- 25029100 TI - An ecological method for the sampling of nonverbal signalling behaviours of young children with profound and multiple learning disabilities (PMLD). AB - BACKGROUND: Profound and multiple learning disabilities (PMLD) are a complex range of disabilities that affect the general health and well-being of the individual and their capacity to interact and learn. METHOD: We developed a new methodology to capture the non-symbolic signalling behaviours of children with PMLD within the context of a face-to-face interaction with a caregiver to provide analysis at a micro-level of descriptive detail incorporating the use of the ELAN digital video software. CONCLUSION: The signalling behaviours of participants in a natural, everyday interaction can be better understood with the use of this innovation in methodology, which is predicated on the ecology of communication. Recognition of the developmental ability of the participants is an integral factor within that ecology. The method presented establishes an advanced account of the modalities through which a child affected by PMLD is able to communicate. PMID- 25029101 TI - Further evaluation of latency-based brief functional analysis methods: An evaluation of treatment utility. AB - OBJECTIVE: Objectives were to evaluate latency-based brief functional analysis (BFA) model for identifying functions of aberrant behavior and treatments generated based on the results of the latency-based brief functional analysis. METHODS: We conducted latency-based BFA, including contingency reversals, and function-based treatment evaluations, including non-contingent reinforcement (NCR) and differential reinforcement of alternative behavior (DRA) with three individuals with autism using single subject design methodology. RESULTS: Socially-mediated functions (attention; tangible) were indicated for two participants and an automatic function was identified for one participant. The treatments generated based on results of the BFA were effective at reducing aberrant behavior for all participants. CONCLUSIONS: Results provide additional support that latency-based BFA model has utility in (a) the identification of functions of aberrant behavior and (b) the generation of function-based treatments. These results suggest clinicians who encounter setting and client specific constraints (e.g. time; severity of aberrant behavior) have additional flexibility in choosing assessment tools. PMID- 25029102 TI - Effect of community interventions on social-communicative abilities of preschoolers with autism spectrum disorder. AB - PURPOSE: To evaluate the effect that different intervention methods have on the social-communicative abilities of children with autism spectrum disorder (ASD) in community settings. METHODS: Intervention based on applied behaviour analysis was compared with a more specific intervention programme targeting imitation and joint attention (JA) and with treatment as usual in a sample of 85 children with ASD. Objective measures for imitation, JA, pretend play, language, autism severity and parent report measures were used to assess the effect of six months of intervention. RESULTS: Results revealed no differences between the intervention methods. There was, however, great individual variability in outcome within each treatment method. CONCLUSION: These results suggest that it is important to focus on "What works for whom" instead of trying to find a one-size fits-all-treatment for children with ASD. PMID- 25029103 TI - Selective decontamination: no oracle needed. PMID- 25029104 TI - The outcome of our modified double-flap technique for cochlear implantation: a case series of 342 consecutive patients. AB - OBJECTIVES: A lazy S-shaped postauricular incision with a modified double-flap technique has been used for cochlear implant surgery at our institution for the past 10 years. The postoperative surgical complications, morbidity, and outcome of this technique were evaluated. METHODS: A retrospective case review was conducted in a tertiary referral teaching center. A total of 342 patients with profound sensory hearing loss (173 female and 169 male subjects; age range, 11 months to 52 years) who underwent cochlear implantation using the double-flap postauricular transmastoid surgical approach during a 5-year period (2005 through 2009) with at least 5 years' follow-up were retrospectively evaluated. Postoperative wound complications were identified. Major complications included flap necrosis, wound infection requiring surgical intervention, and wound dehiscence with or without implant exposure. Swelling over the implant and superficial wound infections treated medically were considered minor complications. Other non-wound-related complications, surgical time, and number of electrodes inserted were also recorded. RESULTS: The surgical approach was accomplished in all the patients with four minor wound complications. The mean surgical time was 1.4 hours, and the mean time between surgery and the programming process was 2 weeks. CONCLUSION: This modified double-flap technique was easy to perform and appeared to reduce the incidence of wound complications in cochlear implant surgery. It allowed programming of the implant after a shorter period of time. PMID- 25029105 TI - Different assembly processes drive shifts in species and functional composition in experimental grasslands varying in sown diversity and community history. AB - BACKGROUND: The prevalence of different biotic processes (limiting similarity, weaker competitor exclusion) and historical contingency due to priority effects are in the focus of ongoing discussions about community assembly and non-random functional trait distributions. METHODOLOGY/PRINCIPAL FINDINGS: We experimentally manipulated assembly history in a grassland biodiversity experiment (Jena Experiment) by applying two factorially crossed split-plot treatments to all communities: (i) duration of weeding (never weeded since sowing or cessation of weeding after 3 or 6 years); (ii) seed addition (control vs. seed addition 4 years after sowing). Spontaneous colonization of new species in the control treatment without seed addition increased realized species richness and functional richness (FRic), indicating continuously denser packing of niches. Seed addition resulted in forced colonization and increased realized species richness, FRic, functional evenness (FEve) and functional divergence (FDiv), i.e. higher abundances of species with extreme trait values. Furthermore, the colonization of new species led to a decline in FEve through time, suggesting that weaker competitors were reduced in abundance or excluded. Communities with higher initial species richness or with longer time since cessation of weeding were more restricted in the entry of new species and showed smaller increases in FRic after seed addition than other communities. The two assembly-history treatments caused a divergence of species compositions within communities originally established with the same species. Communities originally established with different species converged in species richness and functional trait composition over time, but remained more distinct in species composition. CONCLUSIONS/SIGNIFICANCE: Contrasting biotic processes (limiting similarity, weaker competitor exclusion) increase functional convergence between communities initially established with different species. Historical contingency with regard to realized species compositions could not be eradicated by cessation of weeding or forced colonization and was still detectable 5 years after application of these treatments, providing evidence for the role of priority effects in community assembly. PMID- 25029106 TI - In vitro and in vivo studies on adlay-derived seed extracts: phenolic profiles, antioxidant activities, serum uric acid suppression, and xanthine oxidase inhibitory effects. AB - This study aimed to explore the potential of polished adlay, brown adlay, adlay bran, and adlay hull to prevent and treat hyperuricemia. Brown adlay extract effectively decreased the serum uric acid levels of oxonate-induced hyperuricemic rats. Free and bound phenolic extracts from these materials contained significant amounts of phenolics, with free phenolics dominated by chlorogenic acid and p coumaric acid while bound phenolics dominated by p-coumaric acid and ferulic acid. Free and bound phenolics of adlay bran exhibited significant xanthine oxidase inhibition activities, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities, oxygen radical absorbance capacities, and superoxide radical scavenging activities. Adlay bran phenolics could be effective xanthine oxidase inhibitors and radical scavengers. p-Coumaric acid is a xanthine oxidase inhibitor with strong superoxide radical scavenging activity. However, ferulic acid is a xanthine oxidase inhibitor with weak superoxide radical scavenging activity. Chlorogenic acid is a superoxide radical scavenger with weak xanthine oxidase inhibitory activity. PMID- 25029107 TI - Exposure to mission relevant doses of 1 GeV/Nucleon (56)Fe particles leads to impairment of attentional set-shifting performance in socially mature rats. AB - Previous ground-based experiments have shown that cranial irradiation with mission relevant (20 cGy) doses of 1 GeV/nucleon (56)Fe particles leads to a significant impairment in Attentional Set Shifting (ATSET) performance, a measure of executive function, in juvenile Wistar rats. However, the use of head only radiation exposure and the biological age of the rats used in that study may not be pertinent to determine the likelihood that ATSET will be impaired in Astronauts on deep space flights. In this study we have determined the impact that whole-body exposure to 10, 15 and 20 cGy of 1 GeV/nucleon (56)Fe particles had on the ability (at three months post exposure) of socially mature (retired breeder) Wistar rats to conduct the attentional set-shifting paradigm. The current study has established that whole-body exposures to 15 and 20 (but not 10) cGy of 1 GeV/nucleon (56)Fe particles results in the impairment of ATSET in both juvenile and socially mature rats. However, the exact nature of the impaired ATSET performance varied depending upon the age of the rats, whether whole-body versus cranial irradiation was used and the dose of 1 GeV/u (56)Fe received. Exposure of juvenile rats to 20 cGy of 1 GeV/nucleon (56)Fe particles led to a decreased ability to perform intra-dimensional shifting (IDS) irrespective of whether the rats received head only or whole-body exposures. Juvenile rats that received whole-body exposure also had a reduced ability to habituate to the assay and to complete intra-dimensional shifting reversal (IDR), whereas juvenile rats that received head only exposure had a reduced ability to complete compound discrimination reversal (CDR). Socially mature rats that received whole-body exposures to 10 cGy of 1 GeV/nucleon (56)Fe particles exhibited no obvious decline in set-shifting performance; however those exposed to 15 and 20 cGy had a reduced ability to perform simple discrimination (SD) and compound discrimination (CD). Exposure to 20 cGy of 1 GeV/nucleon (56)Fe particles also led to a decreased performance in IDR and to ~25% of rats failing to habituate to the task. Most of these rats started to dig for the food reward but rapidly (within 15 s) gave up digging, suggesting that they had developed appropriate procedural memories about food retrieval, but had an inability to maintain attention on the task. Our preliminary data suggests that whole-body exposure to 20 cGy of 1 GeV/nucleon (56)Fe particles reduced the cholinergic (but not the GABAergic) readily releasable pool (RRP) in nerve terminals of the basal forebrain from socially-mature rats. This perturbation of the cholinergic RRP could directly lead to the loss of CDR and IDR performance, and indirectly [through the metabolic changes in the medial prefrontal cortex (mPFC)] to the loss of SD and CD performance. These findings provide the first evidence that attentional set shifting performance in socially mature rats is impaired after whole-body exposure to mission relevant doses (15 and 20 cGy) of 1 GeV/nucleon (56)Fe particles, and importantly that a dose reduction down to 10 cGy prevents that impairment. The ability to conduct Discrimination tasks (SD and CD) and reversal learning (CDR) is reduced after exposure to 15 and 20 cGy of 1 GeV/nucleon (56)Fe particles, but at 20 cGy there is an additional decrement, ~ 25% of rats are unable to maintain attention to task. These behavioral decrements are associated with a reduction in the cholinergic RRP within basal forebrain, which has been shown to play a major role in regulating the activity of the PFC. PMID- 25029108 TI - Radiation biology in the context of changing patterns of radiotherapy. AB - The last decade has witnessed a revolution in the clinical application of high dose "ablative" radiation therapy. Initially this approach was limited to the treatment of brain tumors, but more recently we have seen its successful extension to tumors outside the brain, e.g., for small lung nodules. These advances have been driven largely by improvements in image-guided inverse treatment planning that allow the dose per fraction to the tumor to be increased over the conventional 2 Gy dose while keeping the late normal tissue complications at an acceptable level by dose limitation. Despite initial concerns about excessive late complications, as might be expected based on dose extrapolations using the linear-quadratic equation, these approaches have shown considerable clinical promise. Our knowledge of the biological consequences of high-doses of ionizing radiation in normal and cancerous tissues has lagged behind these clinical advances. Our intent here is to survey recent experimental findings from the perspective of better understanding the biological effects of high-dose therapy and whether they are truly different from conventional doses. We will also consider the implications of this knowledge for further refining and improving these approaches on the basis of underlying mechanisms. PMID- 25029109 TI - Evaluation of POSSUM for patients undergoing pancreatoduodenectomy. AB - BACKGROUND: The POSSUM score is a predictive scoring system for postoperative morbidity. Although numerous studies have validated its application in major abdominal surgery, few have exclusively considered pancreatic resections, which have unique complications that are costly and problematic. We examined whether POSSUM could accurately reflect the clinical outcomes in pancreatic resection. METHODS: A total of 694 consecutive resections of the pancreatic head were performed between 1993 and 2010 at the Department of General, Thoracic, and Vascular Surgery at the University Hospital Dresden. The POSSUM score calculated for each case was compared with the observed morbidity. Relevance and predictive performance of the score were assessed; in particular, because of the poor calibration of the POSSUM predictions on the Dresden data, a new score was created that was externally validated on patient cohorts from two different centers for pancreatic surgery. RESULTS: The goodness-of-fit analysis revealed that the POSSUM score was not well calibrated because the POSSUM-predicted morbidity rate was 58.9% on average whereas the observed morbidity rate was 43.4%. Discrepancies occurred particularly among the predicted high-risk patients, for whom the score actually overestimated the morbidity risk. Therefore, we adapted the score and complemented it with additional prognostic parameters. The new score was validated in a patient cohort from two other German centers and fitted better to the data. CONCLUSION: The new score, named PS-POSSUM (POSSUM in pancreatic surgery), fits the data better. However, the prediction ability remains rather poor. PS-POSSUM may still be helpful, as it draws attention to additional risk and protective factors in addition to those in the original POSSUM score. PMID- 25029112 TI - Prevalence of nodding syndrome--Uganda, 2012-2013. AB - Nodding syndrome (NS) is a seizure disorder of unknown etiology, predominately affecting children aged 3-18 years in three sub-Saharan countries (Uganda, South Sudan, and Tanzania), with the primary feature of episodic head nodding. These episodes are thought to be one manifestation of a syndrome that includes neurologic deterioration, cognitive impairment, and additional seizure types. NS investigations have focused on clinical features, progression, and etiology; however, none have provided a population-based prevalence assessment using a standardized case definition. In March 2013, CDC and the Ugandan Ministry of Health (MOH) conducted a single-stage cluster survey to perform the first systematic assessment of prevalence of NS in Uganda using a new consensus case definition, which was modified during the course of the investigation. Based on the modified definition, the estimated number of probable NS cases in children aged 5-18 years in three northern Uganda districts was 1,687 (95% confidence interval [CI] = 1,463-1,912), for a prevalence of 6.8 (CI = 5.9-7.7) probable NS cases per 1,000 children aged 5-18 years in the three districts. These findings can guide the MOH to understand and provide the health-care resources necessary to address NS in northern Uganda, and provide a basis for future studies of NS in Uganda and in other areas affected by NS. PMID- 25029111 TI - Pedestrian traffic deaths among residents, visitors, and homeless persons--Clark County, Nevada, 2008-2011. AB - Motor vehicle collisions and crashes are a leading cause of death among Nevada residents aged 5-34 years, representing 14% of all injury deaths in that age group in 2010. During 2008-2011, a total of 173 pedestrian deaths from motor vehicle collisions occurred in Nevada, accounting for 16% of motor vehicle deaths in the state. Approximately 75% (2 million persons) of Nevada residents live in Clark County, which includes the city of Las Vegas. To analyze pedestrian traffic deaths in Clark County among residents, visitors, and homeless persons, the Southern Nevada Health District used coroner's office data and death certificate data for the period 2008-2011. The results indicated that the average annual pedestrian traffic death rates from motor vehicle collisions during this period were 1.4 per 100,000 population for residents, 1.1 for visitors, and 30.7 for homeless persons. Among the three groups, time of day, location of motor vehicle collisions, and pedestrian blood alcohol concentration (BAC) differed. Effective interventions to increase roadway safety, such as lowering speed limits in areas with greater pedestrian traffic, targeting interventions during hours when alcohol-impaired walking is more likely, and modifying roadway designs to increase protection of pedestrians, might decrease pedestrian deaths among all three groups. PMID- 25029110 TI - Mammalian lysine histone demethylase KDM2A regulates E2F1-mediated gene transcription in breast cancer cells. AB - It is established that histone modifications like acetylation, methylation, phosphorylation and ubiquitination affect chromatin structure and modulate gene expression. Lysine methylation/demethylation on Histone H3 and H4 is known to affect transcription and is mediated by histone methyl transferases and histone demethylases. KDM2A/JHDM1A/FBXL11 is a JmjC-containing histone demethylase that targets mono- and dimethylated Lys36 residues of Histone H3; its function in breast cancer is not fully understood. Here we show that KDM2A is strongly expressed in myoepithelial cells (MEPC) in breast cancer tissues by immunohistochemistry. Ductal cells from ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) show positive staining for KDM2A, the expression decreases with disease progression to metastasis. Since breast MEPCs have tumor-suppressive and anti-angiogenic properties, we hypothesized that KDM2A could be contributing to some of these functions. Silencing KDM2A with small interfering RNAs demonstrated increased invasion and migration of breast cancer cells by suppressing a subset of matrix metalloproteinases (MMP-2, -9, -14 and 15), as seen by real-time PCR. HUVEC cells showed increased angiogenic tubule formation ability in the absence of KDM2A, with a concomitant increase in the expression of VEGF receptors, FLT-1 and KDR. KDM2A physically bound to both Rb and E2F1 in a cell cycle dependent manner and repressed E2F1 transcriptional activity. Chromatin immunoprecipitation (ChIP) assays revealed that KDM2A associates with E2F1-regulated proliferative promoters CDC25A and TS in early G phase and dissociates in S-phase. Further, KDM2A could also be detected on MMP9, 14 and 15 promoters, as well as promoters of FLT1 and KDR. KDM2A could suppress E2F1-mediated induction of these promoters in transient transfection experiments. These results suggest a regulatory role for KDM2A in breast cancer cell invasion and migration, through the regulation of E2F1 function. PMID- 25029113 TI - Update: vitamin B12 deficiency among Bhutanese refugees resettling in the United States, 2012. AB - In 2008, clinicians performing routine medical examinations in the United States reported high rates of hematologic and neurologic disorders caused by vitamin B12 deficiency in resettled Bhutanese refugees. To confirm this finding, CDC screened Bhutanese refugees' serum samples for vitamin B12 levels and found vitamin B12 deficiency in 64% (n = 99) of samples obtained before departure and 27% (n = 64) of samples obtained after arrival in the United States. In response, CDC recommended that arriving Bhutanese refugees receive oral vitamin B12 supplements and nutrition advice. In 2012, based on anecdotal reports of decreasing rates of vitamin B12 deficiency in this population, CDC worked with select domestic refugee health programs to determine if the recommendations had reduced the vitamin B12 deficiency rate among Bhutanese refugees. PMID- 25029114 TI - An unusual hernia. PMID- 25029116 TI - Strategies for interfacing inorganic nanocrystals with biological systems based on polymer-coating. AB - Interfacing inorganic nanoparticles and biological systems with the aim of developing novel imaging and sensing platforms has generated great interest and much activity. However, the effectiveness of this approach hinges on the ability of the surface ligands to promote water-dispersion of the nanoparticles with long term colloidal stability in buffer media. These surface ligands protect the nanostructures from the harsh biological environment, while allowing coupling to target molecules, which can be biological in nature (e.g., proteins and peptides) or exhibit specific photo-physical characteristics (e.g., a dye or a redox-active molecule). Amphiphilic block polymers have provided researchers with versatile molecular platforms with tunable size, composition and chemical properties. Hence, several groups have developed a wide range of polymers as ligands or micelle capsules to promote the transfer of a variety of inorganic nanomaterials to buffer media (including magnetic nanoparticles and semiconductor nanocrystals) and render them biocompatible. In this review, we first summarize the established synthetic routes to grow high quality nanocrystals of semiconductors, metals and metal oxides. We then provide a critical evaluation of the recent developments in the design, optimization and use of various amphiphilic copolymers to surface functionalize the above nanocrystals, along with the strategies used to conjugate them to target biomolecules. We finally conclude by providing a summary of the most promising applications of these polymer-coated inorganic platforms in sensor design, and imaging of cells and tissues. PMID- 25029117 TI - p40 is more specific than p63 for the distinction of atypical fibroxanthoma from other cutaneous spindle cell malignancies. AB - Poorly differentiated, cytologically malignant, spindle cell neoplasms of the skin may present a diagnostic challenge with important clinical consequences. In particular, the distinction between poorly differentiated cutaneous spindle cell squamous cell carcinoma (SpSCC) and atypical fibroxanthoma (AFX) remains controversial, but with important clinical implications: SpSCC exhibits an increased tendency for both local recurrence and metastasis compared with AFX. AFX is generally accepted as a diagnosis of exclusion based on negativity for a broad panel of immunohistochemical markers, including multiple cytokeratins, melanocytic markers, muscle markers, and vascular markers. As cytokeratins can also be occasionally lost in SpSCC, it would be of tremendous diagnostic value if there were additional specific markers to facilitate the distinction of lineage in this differential diagnostic context. Initial studies demonstrated p63 to be of utility in distinguishing AFX from SpSCC; however, p63 has proved to lack specificity, as it also exhibits variable reactivity in a subset of AFX. Recent studies have shown p40 immunohistochemistry to be a more specific marker than p63 for the designation of squamous differentiation in carcinomas involving other organ systems. In the current study, we define the utility of p40 immunohistochemistry among common cutaneous spindle cell malignancies, and, specifically, we compare the diagnostic accuracy of p40 and p63 in distinguishing AFX from SpSCC. We show that p40 and p63 exhibit comparable sensitivity, but p40 exhibits superior specificity in the distinction of AFX from SpSCC. PMID- 25029119 TI - Utility of immunohistochemical markers in irradiated breast tissue: an analysis of the role of myoepithelial markers, p53, and Ki-67. AB - Radiation therapy is an important adjunct to breast-conserving surgery, but the diagnosis of recurrent/de novo carcinoma in a background of radiation atypia can be difficult, especially on small biopsies. Immunostaining for myoepithelial cell proteins is often used to assess invasion in nonirradiated breast tissue, yet these stains have not been investigated specifically in irradiated breast. We studied 29 irradiated breast resection specimens, some with carcinoma in situ (CIS, n=13) and/or invasive carcinoma (n=13). Representative blocks were stained for the myoepithelial proteins p63, smooth muscle myosin heavy chain (SMM), calponin, CK5/6, the proliferative marker Ki-67, and the tumor-suppressor p53. Nonirradiated control tissue was also stained with Ki-67 and p53 (CIS, normal, contralateral). Areas of radiation atypia/atrophy and nearly all CIS in irradiated breast tissue had abundant myoepithelial cells as evidenced by SMM, calponin, and p63 stains, with focal staining attenuation or gaps with SMM and calponin and frequently absent CK5/6 staining. As predicted, myoepithelial cell staining was absent in invasive carcinoma. p63 staining revealed postradiation myoepithelial nuclear morphologic changes. p53 staining was increased, although weak, in irradiated non-neoplastic breast (12% irradiated; 4% nonirradiated); however, irradiated CIS had less p53 staining when compared with control CIS (3% irradiated; 38% nonirradiated). As expected, Ki-67 was increased in carcinoma as compared with non-neoplastic irradiated tissue. Thus, myoepithelial immunostaining is a useful diagnostic adjunct in irradiated breast, with caveats similar to nonirradiated breast. Ki-67 may be helpful in some postradiation specimens; however, p53 staining is not reliable in this setting. PMID- 25029118 TI - Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: invasive mucinous pattern and extracellular mucin are associated with KRAS mutation. AB - Multiple reports indicate that epidermal growth factor receptor (EGFR) mutations are associated with lepidic-pattern lung adenocarcinoma and that KRAS mutations are associated with invasive mucinous adenocarcinoma. We sought to investigate the association between EGFR and KRAS mutations and specific morphologic characteristics, such as predominant histologic subtype and mucinous features. Clinical data for 864 patients with resected lung adenocarcinoma that underwent molecular testing for EGFR and KRAS mutations were collected. Histologic subtyping was performed according to the IASLC/ATS/ERS lung adenocarcinoma classification, with attention given to signet-ring cell feature and extracellular mucin. EGFR mutations were detected using a polymerase chain reaction-based sizing assay, KRAS mutations were detected using Sanger sequencing, and ALK expression was detected using immunohistochemistry. Invasive mucinous adenocarcinoma was associated with KRAS mutation (P<0.001). Among invasive mucinous adenocarcinomas with KRAS mutation, a pure mucinous pattern was more common than a mixed mucinous/nonmucinous pattern (P=0.002). Invasive mucinous adenocarcinoma was associated with KRAS transition mutations (G->A) but not transversion mutations (G->T or G->C) compared with nonmucinous tumors (P=0.009). The lepidic-predominant group was associated with EGFR mutation compared with nonlepidic-predominant tumors (P=0.011). Extracellular mucin was associated with KRAS mutation (P<0.001), whereas signet-ring cell feature was not associated with EGFR or KRAS mutation (P=0.517). ALK expression was associated with signet-ring cell feature (P=0.001) but not with extracellular mucin (P=0.089). Our study shows that histologic patterns of mucin in lung adenocarcinoma-including invasive mucinous adenocarcinoma and extracellular mucin are associated with KRAS mutation. PMID- 25029120 TI - Isocitrate dehydrogenase-1 is mutated in inflammatory bowel disease-associated intestinal adenocarcinoma with low-grade tubuloglandular histology but not in sporadic intestinal adenocarcinoma. AB - The underlying molecular alterations in chronic idiopathic inflammatory bowel disease-associated intestinal adenocarcinoma remain largely unknown. Somatic IDH mutations are often seen in gliomas and myeloid leukemia but have also been recently reported in a subset of other neoplasms. We analyzed a series of intestinal adenocarcinomas with (n=23) and without (n=39) associated chronic idiopathic inflammatory bowel disease treated at our institution for IDH1 and IDH2 mutations and correlated the clinicopathologic findings with mutation status. Compared with intestinal adenocarcinomas not associated with inflammatory bowel disease, adenocarcinomas associated with inflammatory bowel disease more frequently demonstrated IDH mutations (13% vs. 0%, P=0.047). All IDH mutations were identified in IDH1 and resulted in substitution of arginine by cysteine at position 132 (p.R132C, c.394C>T). IDH1 mutations were frequently (66%) associated with concurrent KRAS mutations (p.G12D, c.35G>A). IDH1-mutated intestinal adenocarcinomas were seen in the setting of both Crohn disease and ulcerative colitis and were located in both the ileum and colon. Compared with IDH1-negative inflammatory bowel disease-associated adenocarcinoma, IDH1-positive adenocarcinomas more frequently demonstrated tubuloglandular histology (100% vs. 25%, P=0.032) and were more frequently associated with precursor lesions exhibiting serrated morphology (66% vs. 6%, P=0.034). IDH1 mutations were also identified in the precursor dysplastic lesions associated with IDH1-positive adenocarcinomas. In conclusion, we demonstrate that IDH1 mutations are occasionally identified in inflammatory bowel disease-associated intestinal adenocarcinoma but not in intestinal adenocarcinoma not associated with inflammatory bowel disease. In addition, IDH1-mutated intestinal adenocarcinoma is associated with a characteristic low-grade tubuloglandular histology and often harbors concurrent KRAS mutations. Identification of patients with IDH1-mutated intestinal adenocarcinoma may become clinically important as new therapies emerge that target tumors that harbor IDH mutations. PMID- 25029121 TI - Best practices recommendations in the application of immunohistochemistry in the bladder lesions: report from the International Society of Urologic Pathology consensus conference. AB - The bladder working group of the 2013 International Society of Urologic Pathology (ISUP) Conference on Best Practices Recommendation in the Application of Immunohistochemistry (IHC) in Urologic Pathology discussed 5 settings in which IHC is commonly used in clinical practice. With regard to markers for urothelial differentiation, the committee found that there is no ideal marker or established panel to confirm urothelial differentiation. On the basis of the differential diagnostic consideration, positivity for GATA3, CK20, p63, and either high molecular weight cytokeratin (HMWCK) or cytokeratin (CK)5/6 is of value in proving urothelial differentiation in the appropriate morphologic and clinical context. With regard to the role of IHC in the distinction of reactive atypia from urothelial carcinoma in situ, the committee recommended that morphology remains the gold standard in this differential diagnosis and that, at best, the IHC panel of CK20/p53/CD44(s) has potential utility but is variably used and has limitations. The immunostaining pattern must be interpreted with strict morphologic correlation, because overreliance on IHC may be misleading, particularly in the posttreatment setting. IHC has no role in the distinction of dysplasia versus carcinoma in situ and in the grading of papillary urothelial carcinoma. IHC may have a limited but distinct role in staging of bladder cancer. In a subset of cases, depending on the clinical and histologic context, broad spectrum cytokeratins (to identify early or obscured invasion) and desmin (distinction of muscle from desmoplasia and to highlight muscle contours for subclassification) may be helpful. Limited experience and conflicting data preclude smoothelin or vimentin to be recommended routinely for subclassifying muscle type at this time. In the workup of a spindled cell proliferation of the bladder and in limited specimens, we recommend an immunohistochemical panel of 6 markers including ALK1, SMA, desmin, cytokeratin (AE1/AE3), and p63 with either of HMWCK or CK5/6. Currently, there are no prognostic immunohistochemical or molecular studies that are recommended to be routinely performed on biopsy or resection specimens. PMID- 25029122 TI - Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. AB - The following are the International Society of Urological Pathology (ISUP) recommendations for the use of immunohistochemistry (IHC) in prostate specimens. Either high-molecular weight cytokeratin (34betaE12 or CK5/6 or others) or p63 or a combination of the 2 with AMACR either in a double or triple cocktail is recommended for the workup of small foci of atypical glands suspicious for adenocarcinoma of the prostate (PCa). ERG is optional as it is present in only 40% to 50% of prostate cancers and also positive in high-grade prostatic intraepithelial neoplasia. In the setting of obvious carcinoma or benign glands, there is no justification to do basal cell stains and AMACR. If there is a Gleason score of 3+4=7 or a higher-grade cancer on at least 1 part, the workup of other parts with an atypical focus suspicious for Gleason score 3+3=6 cancer is not recommended. In the setting of Gleason score 4+3 or 4+4=8 cancer on at least 1 part, the extent of high-grade cancer could affect clinical treatment such that workup of other atypical possible high-grade cancer foci is justified. In the setting of Gleason score 4+3 or higher-grade cancer on at least 1 part, given that intraductal carcinoma in the vast majority of cases is considered extension of high-grade cancer into prostatic ducts and acini, it is not recommended in the setting of definitive invasive high-grade cancer that workup of additional cribriform lesions be pursued. In the setting of Gleason score 3+3 on at least 1 part, the number of positive cores and/or their location could possibly affect subsequent therapy in terms of suitability for active surveillance or focal therapy, such that unless one knows with certainty that it would not affect therapy, it is justified to perform an IHC workup of additional atypical foci. In the differential diagnosis of high-grade PCa versus urothelial carcinoma (UC), the primary option is to use prostate-specific antigen (PSA) as a first test to identify PCa and GATA3 to identify UC. If GATA3 is not available, then HMWCK and p63 can be used. If the tumor is PSA positive with intense staining and HMWCK and p63 negative, the findings are diagnostic of PCa. If the tumor is equivocal/weak/negative for PSA and negative/focal for p63 and HMWCK, then one needs to perform staining for P501S, NKX3.1, and GATA3. Some experts also include PAP in this second round of staining. If the tumor is negative for PSA and diffusely strongly positive for p63 and HMWCK, the findings are diagnostic of UC. If the tumor is negative for PSA and moderately to strongly positive for GATA3, it is diagnostic of UC. Laboratories should be encouraged to use GATA3 for UC and add P501S and NKX3.1 as prostate markers in addition to PSA, p63, and HMWCK. If GATA3, p501S, and NKX3.1 are not available in equivocal cases, the case should be sent out for consultation to laboratories with these antibodies. The article also covers the use of IHC in: (1) high-grade PCa versus bladder adenocarcinoma; (2) prostatic small cell carcinoma versus high-grade PCa; (3) metastatic carcinoma of unknown primary: rule out PCa; (4) nonspecific granulomatous prostatitis/xanthoma versus high-grade PCa; (5) adult prostate sarcoma versus sarcomatoid PCa; (6) colorectal adenocarcinoma versus high-grade PCa; and (7) prognostic IHC markers. PMID- 25029123 TI - Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system. AB - Chronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT1R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1 9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by the AT2R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation. PMID- 25029124 TI - Evaluation of high-perimeter electrode designs for deep brain stimulation. AB - OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for movement disorders and a promising therapy for treating epilepsy and psychiatric disorders. Despite its clinical success, complications including infections and mis-programing following surgical replacement of the battery-powered implantable pulse generator adversely impact the safety profile of this therapy. We sought to decrease power consumption and extend battery life by modifying the electrode geometry to increase stimulation efficiency. The specific goal of this study was to determine whether electrode contact perimeter or area had a greater effect on increasing stimulation efficiency. APPROACH: Finite-element method (FEM) models of eight prototype electrode designs were used to calculate the electrode access resistance, and the FEM models were coupled with cable models of passing axons to quantify stimulation efficiency. We also measured in vitro the electrical properties of the prototype electrode designs and measured in vivo the stimulation efficiency following acute implantation in anesthetized cats. MAIN RESULTS: Area had a greater effect than perimeter on altering the electrode access resistance; electrode (access or dynamic) resistance alone did not predict stimulation efficiency because efficiency was dependent on the shape of the potential distribution in the tissue; and, quantitative assessment of stimulation efficiency required consideration of the effects of the electrode-tissue interface impedance. SIGNIFICANCE: These results advance understanding of the features of electrode geometry that are important for designing the next generation of efficient DBS electrodes. PMID- 25029125 TI - An international survey of aquaponics practitioners. AB - Aquaponics, a combination of fish farming and soilless plant farming, is growing in popularity and gaining attention as an important and potentially more sustainable method of food production. The aim of this study was to document and analyze the production methods, experiences, motivations, and demographics of aquaponics practitioners in the United States (US) and internationally. The survey was distributed online using a chain sampling method that relied on referrals from initial respondents, with 809 respondents meeting the inclusion criteria. The majority of respondents were from the US (80%), male (78%), and had at least a high school degree (91%). The mean age of respondents was 47+/-13 years old. Most respondents (52%) had three years or less of aquaponics experience. Respondents typically raised tilapia or ornamental fish and a variety of leafy green vegetables, herbs, and fruiting crops. Respondents were most often motivated to become involved in aquaponics to grow their own food, for environmental sustainability reasons, and for personal health reasons. Many respondents employed more than one method to raise crops, and used alternative or environmentally sustainable sources of energy, water, and fish feed. In general, our findings suggest that aquaponics is a dynamic and rapidly growing field with participants who are actively experimenting with and adopting new technologies. Additional research and outreach is needed to evaluate and communicate best practices within the field. This survey is the first large-scale effort to track aquaponics in the US and provides information that can better inform policy, research, and education efforts regarding aquaponics as it matures and possibly evolves into a mainstream form of agriculture. PMID- 25029126 TI - Multidrug resistance among Acinetobacter baumannii isolates from Iran: changes in antimicrobial susceptibility patterns and genotypic profile. AB - BACKGROUND AND AIM: Widespread multidrug-resistant Acinetobacter baumannii (MDR AB) strains have limited therapeutic options for treating intensive care unit (ICU) patients with MDR-AB infection in Iran. We aimed to evaluate MDR-AB diversity and antimicrobial susceptibility in Tehran (Iran) to address the need for feasible and effective control approaches against severe MDR-AB infections. METHODS: We used amplified fragment length polymorphism (AFLP) and minimum inhibitory concentration (MIC) determinations to compare genotypic diversity and susceptibility patterns of 100 MDR-AB isolates from ICU patients in two medical centers in Tehran (Iran), from 2006 to 2011. RESULTS: Within 5 years, drastic genotypic changes occurred among MDR-AB isolates, and resistance to antimicrobials increased 0-30%. In 2011, 6-100% of isolates were resistant to every agent tested. All isolates remained susceptible to either minocycline or tobramycin, however, MIC50 concentrations against these agents increased. Novel international clone (IC) variants (not IC I-III types) comprised 36% MDR-AB isolates in 2011. CONCLUSIONS: The MDR-AB population in Tehran is rapidly changing toward growing resistance to various antimicrobials, including colistin and tigecycline. Although increasing resistance to last-resort antimicrobials is alarming, simultaneous susceptibility of all MDR-AB isolates to some conventional antibiotics highlights the merits of investigating their synergistic activity against extended-spectrum and pandrug resistant A. baumannii. Integrating the novel Iranian MDR-AB IC variants into epidemiologic clonal and susceptibility profile databases can help global efforts toward the control of MDR-AB pandemic. PMID- 25029127 TI - The golden hour of antibiotic administration in severe sepsis: avoid a false start striving for gold*. PMID- 25029128 TI - The timing of renal replacement therapy initiation in acute kidney injury: is earlier truly better?*. PMID- 25029129 TI - Comorbidity or covert advantage? The obesity conundrum*. PMID- 25029130 TI - Raised intracranial pressure during CNS infection: what should we do about it?*. PMID- 25029131 TI - Further reduction in door-to-balloon times: diminishing marginal productivity in search of perfection?*. PMID- 25029132 TI - Daily goals: not just another piece of paper*. PMID- 25029133 TI - Lactate measurement after cardiac arrest: tissue hypoxia or adaptive response?*. PMID- 25029134 TI - Sepsis and pharmacogenomics: can the VAS(S)T majority of vasopressor treatment be individualized?*. PMID- 25029135 TI - Quality indicators: not everything that can be counted counts*. PMID- 25029136 TI - Antimicrobial utilization decision support in the critical care unit: is the glass half-empty or half-full?*. PMID- 25029137 TI - Ventilator-associated events (VAEs): VAE Victis? (Woe to the conquered?)*. PMID- 25029138 TI - Is alpha-stat or pH-stat the best strategy during hypothermia after cardiac arrest?*. PMID- 25029139 TI - Return on investment: just knowing the price is not enough!*. PMID- 25029140 TI - Weaning and the heart: from art to science*. PMID- 25029141 TI - Statins exposure and delirium risk: a winning association?*. PMID- 25029142 TI - Nature has no principle-inflammation following brain injury is neither good nor evil*. PMID- 25029143 TI - Prognostication following cardiac arrest: do we have our patients' safety in mind?*. PMID- 25029144 TI - Angiotensin-II: more than just another vasoconstrictor to treat septic shock induced hypotension?*. PMID- 25029145 TI - Cardiovascular variability as a measure of inflammation*. PMID- 25029146 TI - Tetracyclines in traumatic brain injury and sepsis: same, same, but different!*. PMID- 25029147 TI - Pharmacologic induction of heme oxygenase-1: it is time to take it seriously*. PMID- 25029148 TI - A plea for autopsy in the modern ICU. PMID- 25029149 TI - Timing of limitations in the ICU and sequential organ failure assessment scores. PMID- 25029150 TI - The authors reply. PMID- 25029151 TI - Is postoperative polymyxin B hemoperfusion for abdominal septic shock really ineffective? PMID- 25029152 TI - The authors reply. PMID- 25029153 TI - Systematic review of prone positioning: study selection and analysis. PMID- 25029154 TI - The authors reply. PMID- 25029155 TI - Multivessel percutaneous coronary intervention for patients with cardiogenic shock should be encouraged. PMID- 25029156 TI - Augmented renal clearance in critically ill: advantage or threat. PMID- 25029157 TI - The authors reply. PMID- 25029158 TI - Extracorporeal membrane oxygenation: is high volume better or worse for the patients? PMID- 25029159 TI - The author replies. PMID- 25029160 TI - Meta-analysis of nitric oxide in acute respiratory distress syndrome: dosage? PMID- 25029161 TI - The authors reply. PMID- 25029162 TI - Equating brain death with human death in medical practice: misconstruing scientific evidence as misconceptions. PMID- 25029163 TI - The authors reply. PMID- 25029164 TI - Fixed effects modelling for provider mortality outcomes: Analysis of the Australia and New Zealand Intensive Care Society (ANZICS) Adult Patient Data base. AB - BACKGROUND: Risk adjusted mortality for intensive care units (ICU) is usually estimated via logistic regression. Random effects (RE) or hierarchical models have been advocated to estimate provider risk-adjusted mortality on the basis that standard estimators increase false outlier classification. The utility of fixed effects (FE) estimators (separate ICU-specific intercepts) has not been fully explored. METHODS: Using a cohort from the Australian and New Zealand Intensive Care Society Adult Patient Database, 2009-2010, the model fit of different logistic estimators (FE, random-intercept and random-coefficient) was characterised: Bayesian Information Criterion (BIC; lower values better), receiver-operator characteristic curve area (AUC) and Hosmer-Lemeshow (H-L) statistic. ICU standardised hospital mortality ratios (SMR) and 95%CI were compared between models. ICU site performance (FE), relative to the grand observation-weighted mean (GO-WM) on odds ratio (OR), risk ratio (RR) and probability scales were assessed using model-based average marginal effects (AME). RESULTS: The data set consisted of 145355 patients in 128 ICUs, years 2009 (47.5%) & 2010 (52.5%), with mean(SD) age 60.9(18.8) years, 56% male and ICU and hospital mortalities of 7.0% and 10.9% respectively. The FE model had a BIC = 64058, AUC = 0.90 and an H-L statistic P-value = 0.22. The best-fitting random intercept model had a BIC = 64457, AUC = 0.90 and H-L statistic P-value = 0.32 and random-coefficient model, BIC = 64556, AUC = 0.90 and H-L statistic P-value = 0.28. Across ICUs and over years no outliers (SMR 95% CI excluding null-value = 1) were identified and no model difference in SMR spread or 95%CI span was demonstrated. Using AME (OR and RR scale), ICU site-specific estimates diverged from the GO-WM, and the effect spread decreased over calendar years. On the probability scale, a majority of ICUs demonstrated calendar year decrease, but in the for-profit sector, this trend was reversed. CONCLUSIONS: The FE estimator had model advantage compared with conventional RE models. Using AME, between and over year ICU site-effects were easily characterised. PMID- 25029165 TI - Cut points of muscle strength associated with metabolic syndrome in men. AB - INTRODUCTION: The loss of muscle strength with age increases the likelihood of chronic conditions, including metabolic syndrome (MetS). However, the minimal threshold of muscle strength at which the risk for MetS increases has never been established. OBJECTIVE: This study aimed to identify a threshold of muscle strength associated with MetS in men. METHODS: We created receiver operating curves for muscle strength and the risk of MetS from a cross-sectional sample of 5685 men age <50 yr and 1541 men age >=50 yr enrolled in the Aerobics Center Longitudinal Study. The primary outcome measure, the MetS, was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Upper and lower body muscle strength was treated as a composite measure of one repetition maximum tests on bench and leg press and scaled to body weight. Low muscle strength was defined as the lowest age-specific 20th percentile, whereas high muscle strength was defined as composite muscle strength above the 20th percentile. RESULTS: In men aged <50 yr, the odds of MetS were 2.20-fold (95% confidence interval = 1.89-2.54) higher in those with low muscle strength, independent of age, smoking, and alcohol intake. The strength of this association was similar for men age >=50 yr (odds ratio = 2.11, 95% confidence interval = 1.62-2.74). In men age < 50 yr, the composite strength threshold associated with MetS was 2.57 kg.kg body weight, whereas in men age >= 50 yr the threshold was 2.35 kg.kg body weight. CONCLUSION: This study is the first to identify a threshold of muscle strength associated with an increased likelihood of MetS in men. Measures of muscle strength may help identify men at risk of chronic disease. PMID- 25029166 TI - Sociodemographic moderators of relations of neighborhood safety to physical activity. AB - PURPOSE: This study aimed to investigate gender, race/ethnicity, education, and income as moderators of relations of perceived neighborhood crime, pedestrian, and traffic safety to physical activity. METHODS: Participants were from two samples: adults (N = 2199, age = 25-65 yr) and older adults (N = 718, age = 66+ yr) from high- and low-walkable neighborhoods in the Washington, DC, and Seattle, Washington, areas. Neighborhood safety and transportation and leisure walking were assessed via survey, and moderate to vigorous physical activity was assessed using accelerometers. Sociodemographic moderators were investigated using interaction terms and follow-up within-group tests from mixed-effects regression models. RESULTS: Overall direct effects of safety on physical activity were not found, with one exception. Seven interactions were found in each sample. Interactions were found for all physical activity outcomes, although total moderate to vigorous physical activity was involved in more interactions in adults than older adults. Half of the interactions revealed significant positive relations of pedestrian and traffic safety to physical activity in the more affluent/advantaged group (i.e., high education, high income, and non-Hispanic white) and null associations in the less affluent/advantaged group. Race/ethnicity was a moderator only in older adults. One-third of the interactions involved gender; half of these involved crime safety. Interactions involving crime safety showed nonsignificant positive trends in the more affluent/advantaged group and women and nonsignificant negative trends in the less affluent/advantaged group and men. CONCLUSIONS: Sociodemographic moderators of neighborhood safety explained some of the variation in adults' and older adults' physical activity. Patterns suggested positive associations between safety and physical activity in participants with more affluent/advantaged sociodemographic characteristics, although some patterns were inconsistent, particularly for gender. More refined conceptualizations and measures of safety are needed to understand if and how these constructs influence physical activity. PMID- 25029168 TI - Vienna revisited. PMID- 25029167 TI - The "bear" essentials: actualistic research on Ursus arctos arctos in the Spanish Pyrenees and its implications for paleontology and archaeology. AB - Neotaphonomic studies of large carnivores are used to create models in order to explain the formation of terrestrial vertebrate fossil faunas. The research reported here adds to the growing body of knowledge on the taphonomic consequences of large carnivore behavior in temperate habitats and has important implications for paleontology and archaeology. Using photo- and videotrap data, we were able to describe the consumption of 17 ungulate carcasses by wild brown bears (Ursus arctos arctos) ranging the Spanish Pyrenees. Further, we analyzed the taphonomic impact of these feeding bouts on the bones recovered from those carcasses. The general sequence of consumption that we charted starts with separation of a carcass's trunk; viscera are generally eaten first, followed by musculature of the humerus and femur. Long limb bones are not broken open for marrow extraction. Bears did not transport carcasses or carcass parts from points of feeding and did not disperse bones appreciably (if at all) from their anatomical positions. The general pattern of damage that resulted from bear feeding includes fracturing, peeling, crenulation, tooth pitting and scoring of axial and girdle elements and furrowing of the upper long limb bones. As predicted from observational data, the taphonomic consequences of bear feeding resemble those of other non-durophagus carnivores, such as felids, and are distinct from those of durophagus carnivores, such as hyenids. Our results have paleontological and archaeological relevance. Specifically, they may prove useful in building analogical models for interpreting the formation of fossil faunas for which bears are suspected bone accumulators and/or modifiers. More generally, our comparative statistical analyses draw precise quantitative distinctions between bone damage patterns imparted respectively by durophagus (modelled here primarily by spotted hyenas [Crocuta crocuta] and wolves [Canis lupus]) and non-durophagus (modelled here by brown bears and lions [Panthera leo]) carnivorans. PMID- 25029170 TI - Deaf children with cochlear implants do not appear to use sentence context to help recognize spoken words. AB - PURPOSE: The authors investigated the ability of deaf children with cochlear implants (CIs) to use sentence context to facilitate the perception of spoken words. METHOD: Deaf children with CIs (n = 24) and an age-matched group of children with normal hearing (n = 31) were presented with lexically controlled sentences and were asked to repeat each sentence in its entirety. Performance was analyzed at each of 3 word positions of each sentence (first, second, and third key word). RESULTS: Whereas the children with normal hearing showed robust effects of contextual facilitation-improved speech perception for the final words in a sentence-the deaf children with CIs on average showed no such facilitation. Regression analyses indicated that for the deaf children with CIs, Forward Digit Span scores significantly predicted accuracy scores for all 3 positions, whereas performance on the Stroop Color and Word Test, Children's Version (Golden, Freshwater, & Golden, 2003) predicted how much contextual facilitation was observed at the final word. CONCLUSIONS: The pattern of results suggests that some deaf children with CIs do not use sentence context to improve spoken word recognition. The inability to use sentence context may be due to possible interactions between language experience and cognitive factors that affect the ability to successfully integrate temporal-sequential information in spoken language. PMID- 25029171 TI - In vitro and in vivo activity of benzo[c]phenanthridines against Leishmania amazonensis. AB - Seven benzo[c]phenanthridines, synthetic or isolated from Zanthoxylum rhoifolium root bark, were evaluated against Leishmania amazonensis axenic amastigotes. Five of them were considered leishmanicidal, with IC50 values ranging from 0.03 to 0.54 uM, and were evaluated on intramacrophagic amastigotes of L. amazonensis. Chelerythrine displayed the best activity (IC50=0.5 uM), which was in the same range as the reference compound amphotericin B (IC50=0.4 uM). In vivo studies with chelerythrine, avicine, and fagaridine on a model of mice cutaneous leishmaniasis resulted in the identification of fagaridine as the most active compound. Fagaridine decreased the parasitic burden more than 50% at the 3rd and 6th weeks after the end of treatment. PMID- 25029172 TI - Uncommon chlorinated xanthone and other antibacterial compounds from the lichen Cladonia incrassata. AB - Bioassay-guided fractionation of an extract of the lichen Cladonia incrassata against Staphylococcus aureus led to a novel compound, 1,5-dihydroxy-2,4,6 trichloro-7-methylxanthone (1), along with six known compounds: (-)-usnic acid (2), didymic acid (3), condidymic acid (4), squamatic acid (5), thamnolic acid (6), and prasinic acid (7). Didymic, condidymic, and prasinic acids were isolated for the first time from C. incrassata. Didymic, condidymic, and (-)-usnic acids were active against S. aureus (a minimum inhibitory concentration of 7.5 ug/mL). PMID- 25029173 TI - Purification and characterization of a novel type i ribosome inactivating protein, pachyerosin, from Pachyrhizus erosus seeds, and preparation of its immunotoxin against human hepatoma cells. AB - Pachyrhizus erosus seeds have a high protein content and are used in China due to their cytotoxic effect. Here we report the biological and pharmacological activity of the protein extracts from P. erosus seeds. A novel ribosome inactivating protein, pachyerosin, from P. erosus seeds was successively purified to homogeneity using ammonium sulfate precipitation, DEAE-sepharose FF, and Sephacryl S-200. Pachyerosin showed to be a type I ribosome-inactivating protein with a molecular mass of 29 kDa and an isoelectric point of 9.19. It strongly inhibited protein synthesis of rabbit reticulocyte lysate with an IC50 of 0.37 ng/mL and showed N-glycosidase activity on rat liver ribosomes with an EC50 of 85.9 pM. The N-terminal 27 amino acids of pachyerosin revealed a 60.71% sequence identity with abrin A from the seeds of Abrus precatorius. With the aim of targeting the delivery of pachyerosin, immunotoxin was prepared by conjugating pachyerosin with anti-human AFP monoclonal antibodies SM0736. The immunotoxin pachyerosin-SM0736 efficiently inhibited the growth of the human hepatoma cell line HuH-7 with an IC50 of 0.050 +/- 0.004 nM, 2360 times lower than that of pachyerosin and 430 times lower than that of the immunotoxin against human gastric cancer cell line SGC7901. These results imply that pachyerosin may be used as a new promising anticancer agent. PMID- 25029174 TI - Cytotoxic and antimicrobial flavonoids from Cryptocarya concinna. AB - Five new flavonoids, cryptoconones A-E (1-5), along with six known compounds (6 11), were isolated from the stems of Cryptocarya concinna. The structures of these compounds were elucidated on the basis of spectroscopic data interpretation, and the absolute configurations were determined via circular dichroism spectra and X-ray crystal analysis. The cytotoxic and antimicrobial activities of these compounds were also evaluated. Compounds 9 and 10 exhibited moderate cytotoxic activities against HCT116, HT-29, SW480, and MDA-MB-231 cell lines with IC50 values ranging from 6.25 to 9.35 uM. Compounds 8 and 11 exhibited antimicrobial activity against Fusarium moniliforme and Botrytis cinerea, respectively, with the same minimum inhibitory concentration of 5 ug/mL. PMID- 25029175 TI - Depside alpha-glucosidase inhibitors from a culture of the mushroom Stereum hirsutum. AB - Nine new isoprenylated depsides, sterenins E-M (1-9), as well as five known compounds (10-14), were isolated from the solid culture of Stereum hirsutum. The structures of the new compounds were elucidated by spectroscopic methods. Their inhibitory activities against yeast alpha-glucosidase were evaluated in vitro. Compounds 1-4 and 7-14 showed inhibitory activities with IC50 values of 7.62, 3.06, 6.03, 22.70, 36.64, 13.09, 27.52, 25.10, 12.32, 3.31, 23.82, and 14.17 uM, respectively. Compounds 5 and 6 showed no inhibitory activities with IC50 values higher than 50 uM. Therefore, the culture of S. hirsutum and its secondary metabolites could have a potential usage for the development of hypoglycemic drugs. PMID- 25029176 TI - Triterpenoid saponins from the roots of Clematis argentilucida and their cytotoxic activity. AB - The reinvestigation of the n-BuOH extract of the roots of Clematis argentilucida led to the isolation of four new oleanane-type triterpenoid saponins, 1-4, four known saponins, 5-8, first isolated from the species, together with ten saponins, 9-18, reported in the preceding papers. The structures of saponins 1-8 were elucidated by extensive spectroscopic analysis and chemical evidences. The cytotoxicity of all the saponins were evaluated against human tumor HL-60, HepG 2, and SGC-7901 cell lines. The monodesmosidic saponins 4, 7, 8, and 14-18 exhibited cytotoxic activity against the three cell lines with IC50 values in the range of 0.87-19.48 uM. PMID- 25029177 TI - Four phragmalin orthoesters from the Chinese mangrove Xylocarpus granatum. AB - Four new 8,9,30-phragmalin orthoesters (1-4), along with six related known compounds, namely xyloccensins O-S (5-9) and V (10), were isolated and characterized from the twigs and leaves of the Chinese mangrove Xylocarpus granatum. The structures of the new compounds were determined on the basis of extensive spectroscopic analysis and by comparison with those of related known compounds in the literature. The absolute configuration of xyloccensin Q (7) was revised as its enantiomer by X-ray diffraction analysis employing graphite monochromated Cu Kalpha radiation (lambda=1.54178 A) with a Flack parameter of 0.04 and was further secured by a time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculation. Consequently, the absolute configurations of xyloccensins O (5), P (6), R (8), S (9), and V (10) were all corrected as their corresponding enantiomers, respectively. Xyloccensin S (9) exhibited inhibitory activity against protein tyrosine phosphatase 1B, a potential drug target for the treatment of type II diabetes and obesity, with an IC50 value of 8.72 ug/mL. PMID- 25029178 TI - Effects of a novel archaeal tetraether-based colipid on the in vivo gene transfer activity of two cationic amphiphiles. AB - Gene therapy for treating inherited diseases like cystic fibrosis might be achieved using multimodular nonviral lipid-based systems. To date, most optimizations have concerned cationic lipids rather than colipids. In this study, an original archaeal tetraether derivative was used as a colipid in combination with one or the other of two monocationic amphiphiles. The liposomes obtained, termed archaeosomes, were characterized regarding lipid self-assembling properties, macroscopic/microscopic structures, DNA condensation/neutralization/relaxation abilities, and colloidal stability in the presence of serum. In addition, gene transfer experiments were conducted in mice with lipid/DNA complexes being administered via systemic or local delivery routes. Altogether, the results showed that the tetraether colipid can provide complexes with different in vivo transfection abilities depending on the lipid combination, the lipid/colipid molar ratio, and the administration route. This original colipid appears thus as an innovative modular platform endowed with properties possibly beneficial for fine-tuning of in vivo lipofection and other biomedical applications. PMID- 25029179 TI - Intubation in the ICU: we could improve our practice. PMID- 25029182 TI - Failure to rescue. PMID- 25029183 TI - Failure to rescue. PMID- 25029184 TI - Failure to rescue--reply. PMID- 25029186 TI - Buckling of an elastic rod embedded on an elastomeric matrix: planar vs. non planar configurations. AB - We investigate the buckling of a slender rod embedded in a soft elastomeric matrix through a combination of experiments, numerics and theory. Depending on the control parameters, both planar wavy (2D) or non-planar coiled (3D) configurations are observed in the post-buckling regime. Our analytical and numerical results indicate that the rod buckles into 2D configurations when the compression forces associated to the two lowest critical modes are well separated. In contrast, 3D coiled configurations occur when the two buckling modes are triggered at onset, nearly simultaneously. We show that the separation between these two lowest critical forces can be controlled by tuning the ratio between the stiffness of the matrix and the bending stiffness of the rod, thereby allowing for specific buckling configurations to be target by design. PMID- 25029187 TI - Functionalization of amides via copper-catalyzed oxyalkylation of vinylarenes and decarboxylative alkenylation of sp3 C-H. AB - An efficient protocol was developed to prepare a series of derivatives from amides by copper-catalyzed oxyalkylation of vinylarenes and decarboxylative alkenylation of sp(3) C-H. This method is simple, practical, and inexpensive. PMID- 25029188 TI - Recognizing disguised faces: human and machine evaluation. AB - Face verification, though an easy task for humans, is a long-standing open research area. This is largely due to the challenging covariates, such as disguise and aging, which make it very hard to accurately verify the identity of a person. This paper investigates human and machine performance for recognizing/verifying disguised faces. Performance is also evaluated under familiarity and match/mismatch with the ethnicity of observers. The findings of this study are used to develop an automated algorithm to verify the faces presented under disguise variations. We use automatically localized feature descriptors which can identify disguised face patches and account for this information to achieve improved matching accuracy. The performance of the proposed algorithm is evaluated on the IIIT-Delhi Disguise database that contains images pertaining to 75 subjects with different kinds of disguise variations. The experiments suggest that the proposed algorithm can outperform a popular commercial system and evaluates them against humans in matching disguised face images. PMID- 25029189 TI - Repellency of the lotus leaf: contact angles, drop retention, and sliding angles. AB - Much of the modeling done on repellency and super hydrophobicity has focused on surfaces with rectilinear geometries, but their wetting behavior is simpler and can be quite different from that of repellent surfaces with curved features. In this study, we model the contact angles and sliding angles exhibited by the lotus leaf, accounting for the influence of curvature and pinning. Our estimates agree reasonably well with experimental observations. PMID- 25029190 TI - In situ TEM analysis of resistive switching in manganite based thin-film heterostructures. AB - The mechanism of the electric-pulse induced resistance change effect in Au/Pr0.65Ca0.35MnO3/SrTi0.99Nb0.01O3 thin-film samples is studied by means of in situ electrical stimulation inside a transmission electron microscope. A detailed equivalent-circuit model analysis of the measured current-voltage characteristics provides crucial information for the proper interpretation of the microscopy results. The electrical transport data of the electron-transparent samples used for the in situ investigations is verified by comparison to measurements of unpatterned thin-film samples. We find comprehensive evidence for electrochemical oxygen vacancy migration affecting the potential barrier of the pn junction between Pr0.65Ca0.35MnO3 and SrTi0.99Nb0.01O3 as well as the resistance of the manganite bulk. The high-resistance state formation in the Pr0.65Ca0.35MnO3 bulk is frequently accompanied by structural transformations, namely detwinning and superstructure formation, most likely as the result of the joint impact of dynamic charge inhomogenities by oxygen vacancy migration and injection of high carrier densities at the electrodes. PMID- 25029191 TI - Anthropogenic landscape in southeastern Amazonia: contemporary impacts of low intensity harvesting and dispersal of Brazil nuts by the Kayapo Indigenous people. AB - Brazil nut, the Bertholletia excelsa seed, is one of the most important non timber forest products in the Amazon Forest and the livelihoods of thousands of traditional Amazonian families depend on its commercialization. B. excelsa has been frequently cited as an indicator of anthropogenic forests and there is strong evidence that past human management has significantly contributed to its present distribution across the Amazon, suggesting that low levels of harvesting may play a positive role in B. excelsa recruitment. Here, we evaluate the effects of Brazil nut harvesting by the Kayapo Indigenous people of southeastern Amazonia on seedling recruitment in 20 B. excelsa groves subjected to different harvesting intensities, and investigated if management by harvesters influences patterns of B. excelsa distribution. The number of years of low-intensity Brazil nut harvesting by the Kayapo over the past two decades was positively related to B. excelsa seedling density in groves. One of the mechanisms behind the higher seedling density in harvested sites seems to be seed dispersal by harvesters along trails. The Kayapo also intentionally plant B. excelsa seeds and seedlings across their territories. Our results show not only that low-intensity Brazil nut harvesting by the Kayapo people does not reduce recruitment of seedlings, but that harvesting and/or associated activities conducted by traditional harvesters may benefit B. excelsa beyond grove borders. Our study supports the hypothesis that B. excelsa dispersal throughout the Amazon was, at least in part, influenced by indigenous groups, and strongly suggests that current human management contributes to the maintenance and formation of B. excelsa groves. We suggest that changes in Brazil nut management practices by traditional people to prevent harvesting impacts may be unnecessary and even counterproductive in many areas, and should be carefully evaluated before implementation. PMID- 25029192 TI - Four decades of forest persistence, clearance and logging on Borneo. AB - The native forests of Borneo have been impacted by selective logging, fire, and conversion to plantations at unprecedented scales since industrial-scale extractive industries began in the early 1970s. There is no island-wide documentation of forest clearance or logging since the 1970s. This creates an information gap for conservation planning, especially with regard to selectively logged forests that maintain high conservation potential. Analysing LANDSAT images, we estimate that 75.7% (558,060 km2) of Borneo's area (737,188 km2) was forested around 1973. Based upon a forest cover map for 2010 derived using ALOS PALSAR and visually reviewing LANDSAT images, we estimate that the 1973 forest area had declined by 168,493 km2 (30.2%) in 2010. The highest losses were recorded in Sabah and Kalimantan with 39.5% and 30.7% of their total forest area in 1973 becoming non-forest in 2010, and the lowest in Brunei and Sarawak (8.4%, and 23.1%). We estimate that the combined area planted in industrial oil palm and timber plantations in 2010 was 75,480 km2, representing 10% of Borneo. We mapped 271,819 km of primary logging roads that were created between 1973 and 2010. The greatest density of logging roads was found in Sarawak, at 0.89 km km-2, and the lowest density in Brunei, at 0.18 km km-2. Analyzing MODIS-based tree cover maps, we estimate that logging operated within 700 m of primary logging roads. Using this distance, we estimate that 266,257 km2 of 1973 forest cover has been logged. With 389,566 km2 (52.8%) of the island remaining forested, of which 209,649 km2 remains intact. There is still hope for biodiversity conservation in Borneo. Protecting logged forests from fire and conversion to plantations is an urgent priority for reducing rates of deforestation in Borneo. PMID- 25029193 TI - Linking perception, cognition, and action: psychophysical observations and neural network modelling. AB - It has been argued that perception, decision making, and movement planning are in reality tightly interwoven brain processes. However, how they are implemented in neural circuits is still a matter of debate. We tested human subjects in a temporal categorization task in which intervals had to be categorized as short or long. Subjects communicated their decision by moving a cursor into one of two possible targets, which appeared separated by different angles from trial to trial. Even though there was a 1 second-long delay between interval presentation and decision communication, categorization difficulty affected subjects' performance, reaction (RT) and movement time (MT). In addition, reaction and movement times were also influenced by the distance between the targets. This implies that not only perceptual, but also movement-related considerations were incorporated into the decision process. Therefore, we searched for a model that could use categorization difficulty and target separation to describe subjects' performance, RT, and MT. We developed a network consisting of two mutually inhibiting neural populations, each tuned to one of the possible categories and composed of an accumulation and a memory node. This network sequentially acquired interval information, maintained it in working memory and was then attracted to one of two possible states, corresponding to a categorical decision. It faithfully replicated subjects' RT and MT as a function of categorization difficulty and target distance; it also replicated performance as a function of categorization difficulty. Furthermore, this model was used to make new predictions about the effect of untested durations, target distances and delay durations. To our knowledge, this is the first biologically plausible model that has been proposed to account for decision making and communication by integrating both sensory and motor planning information. PMID- 25029194 TI - Transition state analysis of enantioselective Bronsted base catalysis by chiral cyclopropenimines. AB - Experimental (13)C kinetic isotope effects have been used to interrogate the rate limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst. The reaction is found to proceed via rate-limiting carbon-carbon bond formation. The origins of enantioselectivity and a key noncovalent CH...O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies. The resulting high-resolution experimental picture of the enantioselectivity-determining transition state is expected to guide new catalyst design and reaction development. PMID- 25029195 TI - A systematic study of the effects of relative configuration, protecting group, and enolate type on the diastereoselectivities of aldol reactions of a chiral ethyl ketone with 2-methylpropanal. AB - The diastereoselectivities of aldol reactions of 2-methylpropanal with various enolates of 5-O-methoxymethyl and 5-O-triethylsilyl derivatives of the four racemic diastereomers of 6-(2-ethyl-1,3-dioxolan-2-yl)-5-hydroxy-4-methylheptan-3 one are reported. Reactions of the (E)-enol dicyclohexylborinates, (Z)-enol 9-BBN borinates (i.e., 9-((Z)-enoxy)-9-borabicyclo[3.3.1]nonanes), Li (E)-enolates, Li (Z)-enolates, and Ti(IV) (Z)-enolates were examined. Boron and Li enolates were prepared by standard methods, but Ti(IV) enolates were obtained via transmetalation of the Li (Z)-enolates by reaction with TiCln(Oi-Pr)(4-n) (n = 0 2). Aldol relative topicity (simple diastereoselectivity) was strongly correlated to the enolate geometry: anti aldols from (E)-enolates and syn aldols from (Z) enolates. However, for each enolate type, the diastereoface selectivities varied widely (by factors of 5-400) with the relative configuration and nature of the C5 protecting group in the 8 starting ketones. Plausible transition state models are postulated to rationalize some of these observations. The relative configurations for the complete set of 16 diastereomeric 2-(2-ethyl-1,3-dioxolan-2-yl)-7-hydroxy 3-(methoxymethoxy)-4,6,8-trimethylnonan-5-one aldol adducts were confirmed by NMR analysis of 12 acetonide derivatives prepared from the corresponding 5,7-syn diols. Examination of the NMR data for the above set of aldol adducts revealed consistent trends that were exploited to assign the relative configurations of 13 diastereomeric 2-(2-ethyl-1,3-dioxolan-2-yl)-7-hydroxy-3-(triethylsilyloxy)-4,6,8 trimethylnonan-5-one aldol adducts. PMID- 25029197 TI - Surface morphology-dependent room-temperature LaFeO3 nanostructure thin films as selective NO2 gas sensor prepared by radio frequency magnetron sputtering. AB - In the present work, perovskite LaFeO3 thin films with unique morphology were obtained on silicon substrate using radio frequency magnetron sputtering technique. The effect of thickness and temperature on the morphological and structural properties of LaFeO3 films was systematically studied. The X-ray diffraction pattern explored the highly oriented orthorhombic perovskite phase of the prepared thin films along [121]. Electron micrograph images exposed the network and nanocube surface morphology of LaFeO3 thin films with average sizes of ~90 and 70 nm, respectively. The developed LaFeO3 thin films not only possess unique morphology, but also influence the gas-sensing performance toward NO2. Among the two morphologies, nanocubes exhibited high sensitivity, good selectivity, fast response-recovery time, and excellent repeatability for 1 ppm level of NO2 gas at room temperature. The response time for nanocubes was 24-11 s with a recovery duration of 35-15 s less than the network structure. The sensitivity toward NO2 detection was found to be in the range 29.60-157.89. The enhancement in gas-sensing properties is attributed to their porous structure, surface morphology, numerous surface active sites, and the oxygen vacancies. The gas-sensing measurements demonstrate that the LaFeO3 sensing material is an outstanding candidate for NO2 detection. PMID- 25029196 TI - Plasma membrane proteomics of human breast cancer cell lines identifies potential targets for breast cancer diagnosis and treatment. AB - The use of broad spectrum chemotherapeutic agents to treat breast cancer results in substantial and debilitating side effects, necessitating the development of targeted therapies to limit tumor proliferation and prevent metastasis. In recent years, the list of approved targeted therapies has expanded, and it includes both monoclonal antibodies and small molecule inhibitors that interfere with key proteins involved in the uncontrolled growth and migration of cancer cells. The targeting of plasma membrane proteins has been most successful to date, and this is reflected in the large representation of these proteins as targets of newer therapies. In view of these facts, experiments were designed to investigate the plasma membrane proteome of a variety of human breast cancer cell lines representing hormone-responsive, ErbB2 over-expressing and triple negative cell types, as well as a benign control. Plasma membranes were isolated by using an aqueous two-phase system, and the resulting proteins were subjected to mass spectrometry analysis. Overall, each of the cell lines expressed some unique proteins, and a number of proteins were expressed in multiple cell lines, but in patterns that did not always follow traditional clinical definitions of breast cancer type. From our data, it can be deduced that most cancer cells possess multiple strategies to promote uncontrolled growth, reflected in aberrant expression of tyrosine kinases, cellular adhesion molecules, and structural proteins. Our data set provides a very rich and complex picture of plasma membrane proteins present on breast cancer cells, and the sorting and categorizing of this data provides interesting insights into the biology, classification, and potential treatment of this prevalent and debilitating disease. PMID- 25029199 TI - Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer. AB - BACKGROUND: Since efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy in the treatment of patients with pretreated advanced non-small cell lung cancer (NSCLC) remain controversial, we performed a meta-analysis to compare them. METHODS: An internet search of several databases was performed, including PubMed, Embase, and the Cochrane database. Randomized trials that compared an EGFR-TKI with chemotherapy in the second-line setting were included. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 4 toxicities. The PFS, OS for the EGFR mutation-positive (EGFR M+) and EGFR mutation-negative (EGFR M-) subgroups were pooled. The pooled hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated on the STATA software. RESULTS: Our meta-analysis combined 3,825 patients from 10 randomized trials. Overall, EGFR-TKIs and second-line chemotherapy have equivalent efficacy in terms of PFS (HR, 1.03; 95%CI, 0.87 1.21; P = 0.73; I2 = 78.7%, Pheterogeneity<0.001), OS (HR, 1.00; 95%CI, 0.92 1.08; P = 0.90; I2 = 0.0%, Pheterogeneity = 0.88), and ORR (OR, 1.34; 95%CI, 0.86 2.08; P = 0.20; I2 = 73.1%, Pheterogeneity<0.001). However, subgroup analysis based on EGFR mutation status showed that second-line chemotherapy significantly improved PFS (HR, 1.35; 95%CI, 1.09-1.66; P = 0.01; I2 = 55.7%, Pheterogeneity = 0.046) for EGFR M- patients, whereas OS was equal (HR, 0.96; 95%CI, 0.77-1.19; P = 0.69; I2 = 0.0%, Pheterogeneity = 0.43); EGFR-TKIs significantly improved PFS (HR, 0.28; 95%CI, 0.15-0.53; P<0.001; I2 = 4.1%, Pheterogeneity = 0.35) for EGFR M+ patients, whereas OS was equal (HR, 0.86; 95%CI, 0.44-1.68; P = 0.65; I2 = 0.0%, Pheterogeneity = 0.77). Compared with chemotherapy, EGFR-TKIs led to more grade 3-4 rash, but less fatigue/asthenia disorder, leukopenia and thrombocytopenia. CONCLUSIONS: Our analysis suggests that chemotherapy in the second-line setting can prolong PFS in EGFR M- patients, whereas it has no impact on OS. EGFR-TKIs seem superior over chemotherapy as second-line therapy for EGFR M+ patients. Our findings support obtaining information on EGFR mutational status before initiation of second-line treatment. PMID- 25029200 TI - Lifestyle modification decreases arterial stiffness in overweight and obese men: dietary modification vs. exercise training. AB - Obesity and increased arterial stiffness are independent risk factors for cardiovascular disease. Arterial stiffness is increased in obese individuals than in age-matched nonobese individuals. We demonstrated that dietary modification and exercise training are effective in reducing arterial stiffness in obese persons. However, the differences in the effect on arterial stiffness between dietary modification and exercise training are unknown. The purpose of the current study was to compare the effect of dietary modification and aerobic exercise training on arterial stiffness and endothelial function in overweight and obese persons. Forty-five overweight and obese men (48 +/- 1 year) completed either a dietary modification (well-balanced nutrient, 1680 kcal/day) or an exercise-training program (walking, 40-60 min/day, 3 days/week) for 12 weeks. Before and after the intervention, all participants underwent anthropometric measurements. Arterial stiffness was measured based on carotid arterial compliance, brachial-ankle pulse wave velocity (baPWV), and endothelial function was determined by circulating level of endothelin-1 (ET-1) and nitric oxide metabolite (nitrites/nitrate as metabolite: NOx). Body mass and waist circumference significantly decreased after both intervention programs. Weight loss was greater after dietary modification than after exercise training (-10.1 +/- 0.6 kg vs. -3.6 +/- 0.5 kg, p < .01). Although arterial stiffness and the plasma levels of ET-1 and NOx were improved after dietary modification or exercise training, there were no differences in those improvements between the 2 types of interventions. Exercise training improves arterial function in obese men without as much weight loss as after dietary modification. PMID- 25029202 TI - Randomized controlled trial of calcitriol in severe sepsis. AB - RATIONALE: Vitamin D and its metabolites have potent immunomodulatory effects in vitro, including up-regulation of cathelicidin, a critical antimicrobial protein. OBJECTIVES: We investigated whether administration of 1,25-dihydroxyvitamin D (calcitriol) to critically ill patients with sepsis would have beneficial effects on markers of innate immunity, inflammation, and kidney injury. METHODS: We performed a double-blind, randomized, placebo-controlled, physiologic study among 67 critically ill patients with severe sepsis or septic shock. Patients were randomized to receive a single dose of calcitriol (2 MUg intravenously) versus placebo. The primary outcome was plasma cathelicidin protein levels assessed 24 hours after study drug administration. Secondary outcomes included leukocyte cathelicidin mRNA expression, plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-alpha, IL-1beta, and IL-2), and urinary kidney injury markers. MEASUREMENTS AND MAIN RESULTS: Patients randomized to calcitriol (n = 36) versus placebo (n = 31) had similar plasma cathelicidin protein levels at 24 hours (P = 0.16). Calcitriol-treated patients had higher cathelicidin (P = 0.04) and IL-10 (P = 0.03) mRNA expression than placebo-treated patients 24 hours after study drug administration. Plasma cytokine levels (IL-10, IL-6, tumor necrosis factor alpha, IL-1beta, and IL-2) and urinary kidney injury markers were similar in calcitriol- versus placebo-treated patients (P > 0.05 for all comparisons). Calcitriol had no effect on clinical outcomes nor were any adverse effects observed. CONCLUSIONS: Calcitriol administration did not increase plasma cathelicidin protein levels in critically ill patients with sepsis and had mixed effects on other immunomodulatory markers. Additional phase II trials investigating the dose and timing of calcitriol as a therapeutic agent in specific sepsis phenotypes may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 01689441). PMID- 25029204 TI - Asteatotic eczema in hypoesthetic skin: a case series. AB - IMPORTANCE: Asteatotic eczema (eczema craquele, xerotic eczema) occurs most frequently in areas of dehydrated skin, most often during the winter months when decreased humidity results in increased water loss from the stratum corneum. We present 5 cases in which asteatotic eczema was found outside of its normal distribution, within desensitized skin and scars. OBSERVATIONS: Five patients with a history of trauma and scar formation presented with erythematous, dry plaques with fine crackling involving hypoesthetic skin. Each of the 5 patients had classic asteatotic eczema skin findings, the only commonality being hypoesthesia. Borders of the hypoesthetic skin were identified using light touch and compared with the regions affected by asteatotic eczema. In all cases, the skin affected by asteatotic eczema was within the hypoesthetic areas. CONCLUSIONS AND RELEVANCE: Asteatotic eczema developing on skin with altered sensation is an underreported condition. Prompt recognition and treatment may lead to a more efficient patient encounter and alleviate unnecessary patient stress. PMID- 25029203 TI - Attenuation of typical sex differences in 800 adults with autism vs. 3,900 controls. AB - Sex differences have been reported in autistic traits and systemizing (male advantage), and empathizing (female advantage) among typically developing individuals. In individuals with autism, these cognitive-behavioural profiles correspond to predictions from the "extreme male brain" (EMB) theory of autism (extreme scores on autistic traits and systemizing, below average on empathizing). Sex differences within autism, however, have been under investigated. Here we show in 811 adults (454 females) with autism and 3,906 age matched typical control adults (2,562 females) who completed the Empathy Quotient (EQ), the Systemizing Quotient-Revised (SQ-R), and the Autism Spectrum Quotient (AQ), that typical females on average scored higher on the EQ, typical males scored higher on the SQ-R and AQ, and both males and females with autism showed a shift toward the extreme of the "male profile" on these measures and in the distribution of "brain types" (the discrepancy between standardized EQ and SQ-R scores). Further, normative sex differences are attenuated but not abolished in adults with autism. The findings provide strong support for the EMB theory of autism, and highlight differences between males and females with autism. PMID- 25029205 TI - Stimulation of innate immune cells by light-activated TLR7/8 agonists. AB - The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-kappaB production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population. PMID- 25029207 TI - All-color plasmonic nanolasers with ultralow thresholds: autotuning mechanism for single-mode lasing. AB - We report on the first demonstration of broadband tunable, single-mode plasmonic nanolasers (spasers) emitting in the full visible spectrum. These nanolasers are based on a single metal-oxide-semiconductor nanostructure platform comprising of InGaN/GaN semiconductor nanorods supported on an Al2O3-capped epitaxial Ag film. In particular, all-color lasing in subdiffraction plasmonic resonators is achieved via a novel mechanism based on a property of weak size dependence inherent in spasers. Moreover, we have successfully reduced the continuous-wave (CW) lasing thresholds to ultrasmall values for all three primary colors and have clearly demonstrated the possibility of "thresholdless" lasing for the blue plasmonic nanolaser. PMID- 25029208 TI - Long-range interaction between the Mn4CaO5 cluster and the non-heme iron center in photosystem II as revealed by FTIR spectroelectrochemistry. AB - It is known that inactivation of the Mn4CaO5 cluster, the catalytic center of water oxidation in photosystem II (PSII), induces a positive shift of the redox potential (Em) of the primary quinone electron acceptor QA by ~+150 mV, resulting in suppression of the electron transfer from QA to the secondary quinone acceptor QB. Although the relevance of this Em(QA(-)/QA) shift to the photoprotection of PSII has been debated, its molecular mechanism is still enigmatic from a structural viewpoint because QA is ~40 A from the Mn4CaO5 cluster. In this work, we have investigated the influence of Mn depletion on the Em of the non-heme iron, which is located between QA and QB, and its surrounding structure. Electrochemical measurements in combination with Fourier transform infrared (FTIR) spectroscopy revealed that Mn depletion shifts Em(Fe(2+)/Fe(3+)) by +18 mV, which is ~8 times smaller than the shift of Em(QA(-)/QA). Comparison of the Fe(2+)/Fe(3+) FTIR difference spectra between intact and Mn-depleted PSII samples showed that Mn depletion altered the pKa's of a His ligand to the non-heme iron, most probably the D1-His215 interacting QB, and a carboxylate group, possibly D1 Glu244, coupled with the non-heme iron. It was further shown that Mn depletion influences the C=N vibration of bromoxynil bound to the QB site, indicative of the modification of the QB binding site. On the basis of these results, we discuss the mechanism of a long-range interaction between the donor and acceptor sides of PSII. PMID- 25029209 TI - Probing the Hofmeister effect with ultrafast core-hole spectroscopy. AB - In the current work, X-ray emission spectra of aqueous solutions of different inorganic salts within the Hofmeister series are presented. The results reflect the direct interaction of the ions with the water molecules and therefore, reveal general properties of the salt-water interactions. Within the experimental precision a significant effect of the ions on the water structure has been observed but no ordering according to the structure maker/structure breaker concept could be mirrored in the results indicating that the Hofmeister effect-if existent-may be caused by more complex interactions. PMID- 25029210 TI - Metabolic fate of fructose ingested with and without glucose in a mixed meal. AB - Ingestion of pure fructose stimulates de novo lipogenesis and gluconeogenesis. This may however not be relevant to typical nutritional situations, where fructose is invariably ingested with glucose. We therefore assessed the metabolic fate of fructose incorporated in a mixed meal without or with glucose in eight healthy volunteers. Each participant was studied over six hours after the ingestion of liquid meals containing either 13C-labelled fructose, unlabeled glucose, lipids and protein (Fr + G) or 13C-labelled fructose, lipids and protein, but without glucose (Fr), or protein and lipids alone (ProLip). After Fr + G, plasma 13C-glucose production accounted for 19.0% +/- 1.5% and 13CO2 production for 32.2% +/- 1.3% of 13C-fructose carbons. After Fr, 13C-glucose production (26.5% +/- 1.4%) and 13CO2 production (36.6% +/- 1.9%) were higher (p < 0.05) than with Fr + G. 13C-lactate concentration and very low density lipoprotein VLDL 13C-palmitate concentrations increased to the same extent with Fr + G and Fr, while chylomicron 13C-palmitate tended to increase more with Fr + G. These data indicate that gluconeogenesis, lactic acid production and both intestinal and hepatic de novo lipogenesis contributed to the disposal of fructose carbons ingested together with a mixed meal. Co-ingestion of glucose decreased fructose oxidation and gluconeogenesis and tended to increase 13C pamitate concentration in gut-derived chylomicrons, but not in hepatic-borne VLDL triacylglycerol (TG). This trial was approved by clinicaltrial. gov. Identifier is NCT01792089. PMID- 25029211 TI - Dental care access among individuals with Down syndrome: a Malaysian scenario. AB - OBJECTIVE: The purpose of this cross-sectional study was to assess the legal representatives' perceptions on dental care access of individuals with Down syndrome (DS) compared to their non-DS siblings in Peninsular Malaysia. METHODS: This cross-sectional study was conducted throughout community-based rehabilitation centers (CBRC) and the Down Syndrome Organization. Legal representatives of individuals with DS within the criteria were given a structured and validated questionaire. RESULT: This study demonstrated that individuals with DS (76.9%) significantly utilized more health services than non DS siblings (23.1%). The service most regularly used was speech therapy followed by opthalmology and dental services. Twenty-five per cent of respondents reported difficulty in finding dental care services for their DS child and 46.9% admitted that healthcare for their DS child took more time. The majority of DS individuals received less complex dental treatment and none received any orthodontic treatment, despite their severe occlusal problems. CONCLUSION: A high proportion of parents appear to be able to access dental and medical care for their DS child. However, some parents perceived difficulty in finding oral healthcare. PMID- 25029212 TI - Technetium and rhenium pentacarbonyl complexes with C2 and C11 omega isocyanocarboxylic acid esters. AB - Technetium(I) and rhenium(I) pentacarbonyl complexes with ethyl 2-isocyanoacetate and methyl 11-isocyanoundecanoate, [M(CO)5(CNCH2COOEt)]ClO4 (M = Tc (1) and Re (2)) and [M(CO)5(CN(CH2)10COOMe)]ClO4 (M = Tc (3) and Re (4)), were prepared and characterized by IR, (1)H NMR, and (13)C{(1)H} NMR spectroscopy. The crystal structures of 1 and 2 were determined using single-crystal X-ray diffraction. The kinetics of thermal decarbonylation of technetium complexes 1 and 3 in ethylene glycol was studied by IR spectroscopy. The rate constants and activation parameters of this reaction were determined and compared with those for [Tc(CO)6](+). It was found that rhenium complexes 2 and 4 were stable with respect to thermal decarbonylation. Histidine challenge reaction of complexes 1 and 2 in phosphate buffer was examined by IR spectroscopy. In the presence of histidine, the rhenium pentacarbonyl isocyanide complex partially decomposes to form an unidentified yellow precipitate. Technetium analogue 1 is more stable under these conditions. PMID- 25029213 TI - Association between interleukin-4 gene -590 c/t, -33 c/t, and 70-base-pair polymorphisms and periodontitis susceptibility: a meta-analysis. AB - BACKGROUND: Several studies have investigated the association between interleukin (IL)-4 gene -590 C/T, -33 C/T, or 70-base pair (70-bp) polymorphisms and periodontitis susceptibility but with conflicting results. Hence, a meta-analysis was conducted to explore whether these polymorphisms are associated with periodontitis susceptibility. METHODS: A comprehensive literature search was conducted of PubMed, Embase, Scopus, ScienceDirect, and Web of Science up to April 5, 2014. After the eligible studies were identified, data were extracted and quality-assessed before performing the meta-analysis. RESULTS: The meta analysis included 23 eligible case-control studies from 11 articles involving 12 studies of the -590 C/T polymorphism (1,220 cases and 2,039 controls), five of the -33 C/T polymorphism (715 cases and 967 controls), and four of the 70-bp polymorphism (426 cases and 506 controls). The meta-analysis showed that none of these IL-4 gene polymorphisms were significantly associated with periodontitis susceptibility in all study participants. However, subgroup analysis showed that the IL-4 -590 T allele (odds ratio [OR] = 1.2, 95% confidence interval [CI] = 1.02 to 1.42, P = 0.03) and TT genotype (OR = 1.68, 95% CI = 1.05 to 2.67, P = 0.03) were associated with periodontitis in whites. CONCLUSIONS: Based on current evidence, the IL-4 -33 C/T and 70-bp polymorphisms were not associated with an increased risk of periodontitis. However, the IL-4 -590 T allele and TT genotype were associated with increased risk of periodontitis in whites. PMID- 25029214 TI - Trigonella foenum-graecum protection against deltamethrin-induced toxic effects on haematological, biochemical, and oxidative stress parameters in rats. AB - Trigonella foenum-graecum L. is enriched with many active ingredients. TFG oil was evaluated for its protective effect against deltamethrin toxicity in rats. Rats of the control group were administered saline. The 2nd group was administered deltamethrin (DLM) orally at a concentration of 15 mg/kg body mass. The 3rd and 4th groups were administered DLM at a concentration of 15 mg/kg body mass and were fed diets containing 2.5% and 5% TFG oil, respectively. DLM intoxication reduced red blood cell and platelet counts, hemoglobin concentration, and hematocrit value while it induced leucocytosis. Furthermore, it increased serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, triglycerides, cholesterol, uric acid, urea, and creatinine; increased hepatic, renal, and brain lipid peroxidation; decreased serum acetylcholine esterase level; and decreased hepatic, renal, and brain antioxidant markers' activities. However, TFG oil kept the studied hematological and biochemical parameters within normal ranges. In addition, it prevented lipid peroxidation and oxidative stress induced by DLM intoxication in a dose-dependent manner. Therefore, these results indicated that TFG oil inhibited the toxic effects of DLM on hematological and biochemical parameters as well as oxidative status by its free radical scavenging and potent antioxidant activities, and it appeared to be a promising protective agent against DLM-induced toxicity. PMID- 25029216 TI - The Effect of Footrest on Standing Postural Control. AB - The use of a footrest while performing activity in standing is frequently associated with improvement of a user's well-being however no information exists on the role of a footrest in improving postural stability. The aim of the study was to evaluate the effects of using a footrest in postural control. Twenty healthy young volunteers were tested using three experimental conditions: standing with two feet on the force platform and standing on the force platform when one foot was placed on a 15 cm footrest positioned in front or laterally. The mean and root mean square distance, range and velocity of the center of pressure (COP) were calculated in the anterior-posterior (AP) and medio-lateral (ML) directions using the force platform data. The COP displacements in AP and ML directions increased in conditions of standing with one foot placed on the footrest regardless of its location. Standing with eyes closed increased COP displacements further. The outcome of the study suggests the importance of using COP measures for evaluation of postural stability and provides additional information needed for optimization of working conditions involving standing with a footrest. PMID- 25029217 TI - Photoactive films of photosystem I on transparent reduced graphene oxide electrodes. AB - Photosystem I (PSI) is a photoactive electron-transport protein found in plants that participates in the process of photosynthesis. Because of PSI's abundance in nature and its efficiency with charge transfer and separation, there is a great interest in applying the protein in photoactive electrodes. Here, we developed a completely organic, transparent, conductive electrode using reduced graphene oxide (RGO) on which a multilayer of PSI could be deposited. The resulting photoactive electrode demonstrated current densities comparable to that of a gold electrode modified with a multilayer film of PSI and significantly higher than that of a graphene electrode modified with a monolayer film of PSI. The relatively large photocurrents produced by integrating PSI with RGO and using an opaque, organic mediator can be applied to the facile production of more economic solar energy conversion devices. PMID- 25029218 TI - The prevalence of abnormal preoperative neurological examination in Scheuermann kyphosis: correlation with X-ray, magnetic resonance imaging, and surgical outcome. AB - STUDY DESIGN: Retrospective. OBJECTIVE: The purpose of this study was to report the prevalence of abnormal neurological findings detected by physical examination in Scheuermann kyphosis and to correlate it to radiographs, magnetic resonance imaging (MRI) findings, and results of operative treatment. SUMMARY OF BACKGROUND DATA: There have been sporadic reports about abnormal neurological findings in patients with Scheuermann kyphosis. METHODS: Among 82 patients with Scheuermann kyphosis who underwent corrective surgery, 69 primary cases were selected. Patients' charts were reviewed retrospectively in terms of pre and postoperative neurological examinations. Sensory or motor change was defined as an abnormal neurological examination. Their duration, associated problems, and various parameters on preoperative radiographs and MRI examinations were also measured to search for any atypical findings associated with an abnormal neurological examination. RESULTS: There were 6 cases (9%) (group AbN), with an abnormal neurological examination ranging from severe myelopathy to a subtle change (e.g., sensory paresthesias on trunk). Five patients recovered to a normal neurological examination after corrective surgery. The remaining 1 patient with severe myelopathy also showed marked improvement and was ambulatory unassisted by 2-year follow-up. In patients with a normal neurological examination (group N, n = 63), only 1 patient had neurological sequelae because of anterior spinal artery syndrome after combined anterior-posterior correction. No preoperative radiographical parameters were significantly different between groups. Average age was 21.3 (AbN) and 18.6 (N) years (P = 0.55). Average preoperative T5-12 kyphosis was 69.0 degrees (AbN) and 72.5 degrees (N) (P = 0.61). Forty-two magnetic resonance images were obtained and all showed typical findings of Scheuermann kyphosis. Five patients in the AbN group (1 patient underwent computed tomography/myelography) and 37 patients in the N group underwent an MRI. CONCLUSION: The prevalence of abnormal neurological findings in Scheuermann kyphosis was 9%, emphasizing the importance of performing a detailed preoperative neurological examination. If congenital stenosis or a herniated thoracic disc is present, myelopathy can occur. No radiographical findings correlated with the abnormal preoperative neurological examinations. A normal MRI can exist in the face of an abnormal neurological examination, and conversely, a normal neurological examination can be seen with an abnormal MRI. Surgery was successful in alleviating abnormal neurological issues. LEVEL OF EVIDENCE: 4. PMID- 25029219 TI - Pathophysiological effects of lumbar instrumentation surgery on lumbosacral nerve roots in the vertebral foramen: measurement of local pressure of intervertebral foramen. AB - STUDY DESIGN: Measurement of local pressure of the intervertebral foramina. OBJECTIVE: To evaluate the pathophysiological effects of lumbar instrumentation surgery on lumbosacral nerve roots in the vertebral foramen. SUMMARY OF BACKGROUND DATA: The physiological states of lumbosacral nerve roots in the vertebral foramen remain controversial. METHODS: From 2000 to 2012, 11 of 710 patients with L4 degenerative spondylolisthesis failed to develop postoperative radiculopathy because of intraoperative pedicle screw malposition (L5: 10, L4: 1). We prospectively evaluated the local pressure at the L4-L5 and L5-LS vertebral foramina in 18 patients with L4 degenerative spondylolisthesis. All patients underwent L4-L5 posterolateral fusion (PLF) with L3-L4-L5 laminotomy. Intraoperatively, local pressure of the intervertebral foramen was measured using a catheter pressure transducer while changing the lumbar spine posture, and the measurement was performed before and after L4-L5 PLF. RESULTS: The local pressures at the L4-L5 vertebral foramen were 29.74 +/- 16.26 and 51.57 +/- 23.18 mm Hg (before fixation), and 39.13 +/- 17.69 and 41.71 +/- 17.94 mm Hg (after fixation) in the lumbar spine neutral and extension postures, respectively. The local pressure before fixation increased significantly during lumbar spine extension (P < 0.001), although the value after fixation was almost identical. The local pressures at the L5-LS vertebral foramen were 26.91 +/- 18.16 and 54.36 +/- 26.67 mm Hg (before fixation), and 24.82 +/- 17.1 and 58.46 +/- 32.78 mm Hg (after fixation) in the lumbar spine neutral and extension postures, respectively. The local pressure before and after fixation increased significantly during lumbar spine extension (P < 0.001), and the values after fixation were higher than those before fixation. CONCLUSION: The local pressure at the L4-L5 vertebral foramen did not change during lumbar extension after L4-L5 PLF, whereas the local pressure at the L5-LS vertebral foramen was significantly increased during lumbar extension after L4-L5 PLF. Our results suggested that the nerve roots caudal to the fixed segments may be exposed to higher external dynamic stresses after lumbar instrumentation surgery. LEVEL OF EVIDENCE: 4. PMID- 25029220 TI - Hospital readmission rates after surgical treatment of primary and metastatic tumors of the spine. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: This study aimed to identify the rates and causes of unplanned hospital readmission at 30 days and 1 year after surgical treatment of primary and metastatic spinal tumors. SUMMARY OF BACKGROUND DATA: Primary spine tumors and non-spine tumors metastatic to the spine can represent complex problems for surgical treatment, but surgical intervention can provide significant patients with significant improvements in quality of life. However, recent emphasis on decreasing the cost of health care has led to a focus on quality measures such as hospital readmission rates. METHODS: At a large referral spine center between 2005 and 2011, 197 patients with primary (n = 33) or metastatic (n = 164) tumors of the spine were enrolled. Hospital readmissions within 1 year were reviewed. Kaplan-Meier analysis was performed to estimate unplanned hospital readmission rates, and risk factors were evaluated using a Cox proportional hazards model. RESULTS: Unplanned hospital readmission rates were 6.1% and 16.8% at 30 days for primary and metastatic tumors (P = 0.126), respectively, and 27.5% and 37.8% at 1 year (P = 0.262). Metastatic tumors with aggressive biology (i.e., lung, osteosarcoma, stomach, bladder, esophagus, pancreas) caused higher rates of readmission than other types of metastatic tumors. One-third of readmissions were due to recurrent disease, whereas 23.3% were due to surgical complications and 43.3% due to medical complications. Numerous medical comorbidities increased the risk of unplanned hospital readmission. CONCLUSION: Unplanned hospital readmissions after surgical intervention for spine tumors are common, and patients with aggressive metastatic tumors are at increased risk. In addition, comorbid medical problems are important risk factors that increase the chance that a patient will require hospital readmission within 1 year. LEVEL OF EVIDENCE: 3. PMID- 25029221 TI - Defining hyoplasia of the atlas: a cadaveric study. AB - STUDY DESIGN: Cadaveric study. OBJECTIVE: To define congenital hypoplasia of the atlas. SUMMARY OF BACKGROUND DATA: Little has been written about hypoplasia of the atlas and it is usually described in the setting of other skeletal dysplasias or syndromes. METHODS: A total of 543 cervical spine specimens were randomly selected from the Hamann-Todd collection. Sagittal and coronal diameters of the atlas, axis, and C3 (when available), and the dens diameter were measured using digital calipers. Correction for modern size and radiographical magnification was performed. Hypoplasia of the atlas was defined as the lowest 2.5% of measurements. The correlation between inner sagittal diameters at C1 and C3 was calculated. RESULTS: The mean C1 inner sagittal diameter was 30.8 +/- 2.4 mm (range, 23.5-38.1 mm). We defined C1 hypoplasia as an inner sagittal diameter value representing the smallest 2.5% of subjects. Because the mean was 30.8 mm, hypoplasia was defined as a diameter of <=26.1 mm or less. Correcting for size and magnification of radiographs, hypoplasia is defined as an inner sagittal diameter of the atlas of 28.9 mm. Approximately 10% of cases had a dens that occupied more than 40% of the spinal canal at C1, thus not following Steel's Rule of Thirds. There was only a moderate correlation between the spinal canal diameter at C1 and at C3 (r = 0.483, N = 345; P < 0.001). CONCLUSION: With an inner sagittal diameter of 26 mm or less, one may describe the atlas as hypoplastic. Ten percent of the specimens had an odontoid process that occupied more than 40% of the spinal canal at C1. There was little correlation between the inner sagittal diameter at C1 and the diameter at C3. LEVEL OF EVIDENCE: N/A. PMID- 25029222 TI - Mother-child memory conversations and self-construal in Eastern Turkey, Western Turkey and the USA. AB - Eighty-seven mothers and their four-year-old children from Eastern Turkey (N = 32 pairs), Western Turkey (N = 30 pairs) and the USA (N = 25 pairs) participated in a study of mother-child memory talk as a reflection of mothers' self construal, in view of differences in the function of memory talk across cultures. Mother child pairs were audio-recorded while talking about shared past and anticipated future events. Mothers completed the Balanced Integration-Differentiation questionnaire measure of self-construal and were scored as high or low on individuation and relatedness orientations. Mothers' memory and future talk showed similar patterns of cultural differences: American mothers provided the most voluminous, descriptive and elaborative talk, while Eastern Turkish mothers showed the highest level of repetitiveness, and Western Turkish mothers' talk fell in between. Children's memory talk was similar across cultures. In all cultures, mothers who scored high on both individuation and relatedness (balanced self-construal subtype) engaged in more voluminous and contexted memory talk, and individuation was associated with more elaborative talk about future events. Results are discussed in light of literature on cultural differences in self construal and memory function. PMID- 25029223 TI - A critical evaluation of written discharge advice for people with mild traumatic brain injury: what should we be looking for? AB - OBJECTIVE: To formally evaluate the written discharge advice for people with mild traumatic brain injury (mTBI). METHODS: Eleven publications met the inclusion criteria: (1) intended for adults; (2) <=two A4 pages; (3) published in English; (4) freely accessible; and (5) currently used (or suitable for use) in Australian hospital emergency departments or similar settings. Two independent raters evaluated the content and style of each publication against established standards. The readability of the publication, the diagnostic term(s) contained in it and a modified Patient Literature Usefulness Index (mPLUI) were also evaluated. RESULTS: The mean content score was 19.18 +/- 8.53 (maximum = 31) and the mean style score was 6.8 +/- 1.34 (maximum = 8). The mean Flesch-Kincaid reading ease score was 66.42 +/- 4.3. The mean mPLUI score was 65.86 +/- 14.97 (maximum = 100). Higher scores on these metrics indicate more desirable properties. Over 80% of the publications used mixed diagnostic terminology. One publication scored optimally on two of the four metrics and highly on the others. DISCUSSION: The content, style, readability and usefulness of written mTBI discharge advice was highly variable. The provision of written information to patients with mTBI is advised, but this variability in materials highlights the need for evaluation before distribution. Areas are identified to guide the improvement of written mTBI discharge advice. PMID- 25029224 TI - Identifying longitudinal trajectories of emotional distress symptoms 5 years after traumatic brain injury. AB - PRIMARY OBJECTIVE: To evaluate longitudinal trajectories of emotional distress symptoms after traumatic brain injury (TBI). RESEARCH DESIGN: Longitudinal study. METHODS AND PROCEDURES: Patients with mild-to-severe TBI, 118 patients participated at 3 months, 109 attended at 1-year and 89 attended the 5-year follow-up. Emotional distress was measured with the Impact of Event Scale Revised. Patients were also assessed for coping style, anxiety, depression, substance abuse and trauma severity. MAIN OUTCOMES AND RESULTS: Based on growth mixture modelling, four trajectories of emotional distress symptoms were identified: 73.5% of patients were characterized by a pattern of resilience, 6.8% by a pattern of delayed distress, 14.6% by recovery and 5.1% by chronic distress. Relative to the resilience trajectory, avoidant-coping style and psychiatric problems were related to recovery and chronic trajectories. The delayed trajectory was similar to the resilience trajectory, except for elevated depressive and anxiety symptoms at 1- and 5-years. Demographics and injury related variables were not significantly associated with emotional distress trajectories. CONCLUSIONS: Resilience was the most common trajectory following TBI. Patients characterized by recovery and chronic trajectories required attention and long-term clinical monitoring of their symptoms. Future research would benefit from longitudinal studies to analyse emotional distress symptoms and the strength of resilience over time. PMID- 25029225 TI - Anionic surfactant micelle-mediated extraction coupled with dispersive magnetic microextraction for the determination of phthalate esters. AB - A novel and easy two-step microextraction technique combining anionic surfactant coacervation phase (CAP) extraction and dispersive microsolid-phase extraction (D MU-SPE) was developed for the high-performance liquid chromatography-ultraviolet detection to determination of phthalate esters (PEs) in water samples. The method started with the phase separation of sodium dodecylbenzenesulfonic acid (SDBSA) obtained by adding NaCl, whereas the target analytes were extracted in the CAP. The CAP was then retrieved using diatomaceous earth-supported magnetite nanoparticles. The effects of solution acidity, SDBSA, and electrolyte concentration, extraction time, magnetic material quantity, and elution solvent volume were discussed. Under optimal extraction conditions, the extraction recoveries ranged from 48.6 to 84.8%, and relative standard deviations ranged from 3.9 to 5.7% (n = 10). The detection limits ranged from 0.5 to 5.0 ng mL(-1) for the five PEs. The proposed method was used to determine the five PEs in the water samples and recoveries between 85.7 and 105.5%. PMID- 25029226 TI - Zinc deficiency and toxicity in pediatric practice. AB - PURPOSE OF REVIEW: Zinc is a commonly overlooked deficiency in developed countries, occurring in infants, children, and adolescents during critical growth periods. The purpose of this review is to present the evidence of zinc deficiencies and toxicities as well as treatment in pediatrics. RECENT FINDINGS: During the last decade, the significance of zinc deficiency in childhood growth, morbidity, and mortality has been recognized by a number of large-scale supplementation trials in underdeveloped countries. Recognition of the recent nationwide shortage of injectable zinc available for total parenteral nutrition supplementation over the last 2 years focused attention on the possibility of zinc deficiency in the United States. SUMMARY: Although primarily thought of as a problem reserved for underdeveloped countries, zinc deficiency has increasing pediatric prevalence in the USA. Zinc is an essential trace element in the body that is responsible for numerous structural, catalytic, and biochemical functions. Deficiencies can occur because of poor dietary intake, long-term parenteral nutrition without supplementation, and enteral causes such as malabsorption. Zinc deficiency is closely associated with stunting, respiratory infections, diarrhea, and dermatitis. Deficiency is hard to define solely by the serum levels. Clinicians should utilize a combination of serum zinc levels, presenting signs and symptoms, and nutritional intake via oral, enteral, and parenteral routes to accurately assess the deficiency risk and diagnosis. PMID- 25029227 TI - Imaging modalities in pediatric inflammatory bowel disease. AB - PURPOSE OF REVIEW: To review the various imaging modalities in the evaluation of pediatric inflammatory bowel disease (IBD) to determine disease location, clinical phenotype and the severity of disease in order to optimize treatment. RECENT FINDINGS: Assessment of the extent, location and severity of IBD routinely involves imaging of the gastrointestinal tract. Cross-sectional modalities such as magnetic resonance enterography (MRE) and computed tomography enterography visualize the lumen, transmural involvement, extraintestinal manifestations and may facilitate decision-making in disease management. MRE has evolved as the imaging modality of choice for many pediatric IBD indications because it does not involve exposure to ionizing radiation. SUMMARY: Advances in imaging modalities have revolutionized the assessment of children with IBD in recent years. Small bowel follow-through is no longer considered the imaging modality of choice in this setting. Cross-sectional enterography is now preferred because, among other advantages, it can potentially distinguish active inflammation from fibrosis, characterize stricturing and penetrating complications, and diagnose extraintestinal manifestations. Although MRE avoids ionizing radiation exposure, it remains costly. Cross-sectional imaging and endoscopy complement each other in the development of objective measures for the assessment of disease activity and monitoring of response to treatment. PMID- 25029228 TI - Employed adults with asthma who have frequent workplace exposures. AB - Abstract Objective: The recent increase in asthma prevalence is thought to be partially due to environmental changes such as changes in air pollution and occupational exposures. Nationally representative information on workplace exposures among US adults with asthma is limited. METHODS: We examined 2010 National Health Interview Survey data to determine the proportion of employed adults with asthma who had frequent workplace exposures. RESULTS: Among adults with current asthma, 19.6% frequently worked outdoors, 17.5% were frequently exposed to workplace secondhand smoke and 28.1% were frequently exposed to workplace vapors, gas, dust or fumes. Adults ever told by a health professional that asthma is probably work-related, when compared to adults who were not, had increased odds of frequent work outdoors [prevalence odds ratio (POR)=2.76], frequent workplace exposure to secondhand smoke (POR=3.08) and frequent workplace exposure to vapors, gas, dust or fumes (POR=3.56). CONCLUSIONS: To our knowledge, this is the first population-based study in USA that estimates the proportion of working adults with asthma that have frequent workplace exposures. Increasing the understanding of workplace exposures among adults with asthma will help enable prevention of asthma through workplace exposure reduction or avoidance. Future studies should further examine industries and occupations of individuals with asthma and frequent workplace exposures. PMID- 25029229 TI - Diet and diversification in the evolution of coral reef fishes. AB - The disparity in species richness among evolutionary lineages is one of the oldest and most intriguing issues in evolutionary biology. Although geographical factors have been traditionally thought to promote speciation, recent studies have underscored the importance of ecological interactions as one of the main drivers of diversification. Here, we test if differences in species richness of closely related lineages match predictions based on the concept of density dependent diversification. As radiation progresses, ecological niche-space would become increasingly saturated, resulting in fewer opportunities for speciation. To assess this hypothesis, we tested whether reef fish niche shifts toward usage of low-quality food resources (i.e. relatively low energy/protein per unit mass), such as algae, detritus, sponges and corals are accompanied by rapid net diversification. Using available molecular information, we reconstructed phylogenies of four major reef fish clades (Acanthuroidei, Chaetodontidae, Labridae and Pomacentridae) to estimate the timing of radiations of their subclades. We found that the evolution of species-rich clades was associated with a switch to low quality food in three of the four clades analyzed, which is consistent with a density-dependent model of diversification. We suggest that ecological opportunity may play an important role in understanding the diversification of reef-fish lineages. PMID- 25029230 TI - Resuscitation is better for combat casualty outcomes: now let's forcefully close the performance improvement loop on adverse outcomes. PMID- 25029231 TI - Malnutrition in patients with chronic GVHD. AB - Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD. PMID- 25029232 TI - Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP. AB - Adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis. Experience with allo-SCT for ATL appears encouraging but is limited to Japanese series. This retrospective analysis of the EBMT registry revealed 21 HTLV-I seropositive ATL including 7 acute and 12 lymphoma subtypes. Four patients received auto-SCT and rapidly died from ATL. Out of 17 allo-SCT (4 myeloablative, 13 reduced intensity), 6 are still alive (4 were in CR1 at SCT). Eleven patients died within 2 years, eight from relapse/progression and three from transplant toxicity. Six of seven informative patients who lived >12 months had chronic GVHD. Overall these results indicate that allo-SCT but not auto-SCT may salvage a subset of ATL patients, supporting the existence of graft vs ATL effect also in non-Japanese patients. PMID- 25029234 TI - Catastrophic ruptured Takotsubo cardiomyopathy. PMID- 25029233 TI - Report of disseminated Mycobacterium haemophilum infection after double cord blood allo-SCT. PMID- 25029235 TI - Molecular containers in complex chemical systems. AB - Over the last decade molecular containers have been increasingly studied within the context of complex chemical systems. Herein we discuss selected examples from the literature concerning three aspects of this field: complex host-guest behaviour, adaptive transformations of molecular containers and reactivity modulation within them. PMID- 25029236 TI - Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: a dose-finding study. AB - Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer. PMID- 25029237 TI - Evaluating mortality in an intensive care unit requires extended survival models. PMID- 25029239 TI - Computing proton dose to irregularly moving targets. AB - PURPOSE: While four-dimensional computed tomography (4DCT) and deformable registration can be used to assess the dose delivered to regularly moving targets, there are few methods available for irregularly moving targets. 4DCT captures an idealized waveform, but human respiration during treatment is characterized by gradual baseline shifts and other deviations from a periodic signal. This paper describes a method for computing the dose delivered to irregularly moving targets based on 1D or 3D waveforms captured at the time of delivery. METHODS: The procedure uses CT or 4DCT images for dose calculation, and 1D or 3D respiratory waveforms of the target position at time of delivery. Dose volumes are converted from their Cartesian geometry into a beam-specific radiological depth space, parameterized in 2D by the beam aperture, and longitudinally by the radiological depth. In this new frame of reference, the proton doses are translated according to the motion found in the 1D or 3D trajectory. These translated dose volumes are weighted and summed, then transformed back into Cartesian space, yielding an estimate of the dose that includes the effect of the measured breathing motion. The method was validated using a synthetic lung phantom and a single representative patient CT. Simulated 4DCT was generated for the phantom with 2 cm peak-to-peak motion. RESULTS: A passively-scattered proton treatment plan was generated using 6 mm and 5 mm smearing for the phantom and patient plans, respectively. The method was tested without motion, and with two simulated breathing signals: a 2 cm amplitude sinusoid, and a 2 cm amplitude sinusoid with 3 cm linear drift in the phantom. The tumor positions were equally weighted for the patient calculation. Motion corrected dose was computed based on the mid-ventilation CT image in the phantom and the peak exhale position in the patient. Gamma evaluation was 97.8% without motion, 95.7% for 2 cm sinusoidal motion, 95.7% with 3 cm drift in the phantom (2 mm, 2%), and 90.8% (3 mm, 3%)for the patient data. CONCLUSIONS: We have demonstrated a method for accurately reproducing proton dose to an irregularly moving target from a single CT image. We believe this algorithm could prove a useful tool to study the dosimetric impact of baseline shifts either before or during treatment. PMID- 25029238 TI - Individual distinctiveness in call types of wild western female gorillas. AB - Individually distinct vocalizations play an important role in animal communication, allowing call recipients to respond differentially based on caller identity. However, which of the many calls in a species' repertoire should have more acoustic variability and be more recognizable is less apparent. One proposed hypothesis is that calls used over long distances should be more distinct because visual cues are not available to identify the caller. An alternative hypothesis proposes that close calls should be more recognizable because of their importance in social interactions. To examine which hypothesis garners more support, the acoustic variation and individual distinctiveness of eight call types of six wild western gorilla (Gorilla gorilla) females were investigated. Acoustic recordings of gorilla calls were collected at the Mondika Research Center (Republic of Congo). Acoustic variability was high in all gorilla calls. Similar high inter individual variation and potential for identity coding (PIC) was found for all call types. Discriminant function analyses confirmed that all call types were individually distinct (although for call types with lowest sample size - hum, grumble and scream - this result cannot be generalized), suggesting that neither the distance at which communication occurs nor the call social function alone can explain the evolution of identity signaling in western gorilla communication. PMID- 25029240 TI - Attenuation of immune-mediated influenza pneumonia by targeting the inducible co stimulator (ICOS) molecule on T cells. AB - Inducible Co-stimulator (ICOS) plays a critical role in mediating T cell differentiation and function and is considered a key player in balancing T effector and T regulatory (Treg) cell responses. Here we show that activation of the ICOS signalling pathway during acute influenza A virus (IAV) infection by application of an agonistic ICOS antibody reduced the frequency of CD8+ T cells in the respiratory tract of IAV infected animals and delayed pathogen elimination. In line with this, immune-mediated influenza pneumonia was significantly ameliorated in mice that received ICOS agonist as indicated by significantly reduced alveolar infiltrations and bronchointerstitial pneumonia, while at the same time virus-related pathology remained unaffected. Importantly, ICOS agonist treatment resulted in expansion of CD4+Foxp3+ Tregs in IAV infected mice, which was associated with elevated levels of the immunosuppressive cytokine IL-10 in the alveolar space. Together, our findings suggest a prominent role of ICOS signaling during acute IAV infection by increasing the Treg/CD8+ T cell ratio with beneficial outcome on immune-mediated pneumonia and underline the suitability of ICOS as potential therapeutic target for immune intervention in those infectious conditions characterized by strong immunopathology rather than virus-mediated cytopathic effects. PMID- 25029241 TI - Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell autonomous mechanisms. AB - Wnt/beta-catenin (betacat) signaling is critical for adrenal homeostasis. To elucidate how Wnt/betacat signaling elicits homeostatic maintenance of the adrenal cortex, we characterized the identity of the adrenocortical Wnt responsive population. We find that Wnt-responsive cells consist of sonic hedgehog (Shh)-producing adrenocortical progenitors and differentiated, steroidogenic cells of the zona glomerulosa, but not the zona fasciculata and rarely cells that are actively proliferating. To determine potential direct inhibitory effects of betacat signaling on zona fasciculata-associated steroidogenesis, we used the mouse ATCL7 adrenocortical cell line that serves as a model system of glucocorticoid-producing fasciculata cells. Stimulation of betacat signaling caused decreased corticosterone release consistent with the observed reduced transcription of steroidogenic genes Cyp11a1, Cyp11b1, Star, and Mc2r. Decreased steroidogenic gene expression was correlated with diminished steroidogenic factor 1 (Sf1; Nr5a1) expression and occupancy on steroidogenic promoters. Additionally, betacat signaling suppressed the ability of Sf1 to transactivate steroidogenic promoters independent of changes in Sf1 expression level. To investigate Sf1-independent effects of betacat on steroidogenesis, we used Affymetrix gene expression profiling of Wnt-responsive cells in vivo and in vitro. One candidate gene identified, Ccdc80, encodes a secreted protein with unknown signaling mechanisms. We report that Ccdc80 is a novel betacat-regulated gene in adrenocortical cells. Treatment of adrenocortical cells with media containing secreted Ccdc80 partially phenocopies betacat-induced suppression of steroidogenesis, albeit through an Sf1-independent mechanism. This study reveals multiple mechanisms of betacat-mediated suppression of steroidogenesis and suggests that Wnt/betacat signaling may regulate adrenal homeostasis by inhibiting fasciculata differentiation and promoting the undifferentiated state of progenitor cells. PMID- 25029242 TI - Inhibition of BMP2-induced bone formation by the p65 subunit of NF-kappaB via an interaction with Smad4. AB - Bone morphogenic proteins (BMPs) stimulate bone formation in vivo and osteoblast differentiation in vitro via a Smad signaling pathway. Recent findings revealed that the activation of nuclear factor-kappaB (NF-kappaB) inhibits BMP-induced osteoblast differentiation. Here, we show that NF-kappaB inhibits BMP signaling by directly targeting the Smad pathway. A selective inhibitor of the classic NF kappaB pathway, BAY11-770682, enhanced BMP2-induced ectopic bone formation in vivo. In mouse embryonic fibroblasts (MEFs) prepared from mice deficient in p65, the main subunit of NF-kappaB, BMP2, induced osteoblastic differentiation via the Smad complex to a greater extent than that in wild-type MEFs. In p65(-/-) MEFs, the BMP2-activated Smad complex bound much more stably to the target element than that in wild-type MEFs without affecting the phosphorylation levels of Smad1/5/8. Overexpression of p65 inhibited BMP2 activity by decreasing the DNA binding of the Smad complex. The C-terminal region, including the TA2 domain, of p65 was essential for inhibiting the BMP-Smad pathway. The C-terminal TA2 domain of p65 associated with the MH1 domain of Smad4 but not Smad1. Taken together, our results suggest that p65 inhibits BMP signaling by blocking the DNA binding of the Smad complex via an interaction with Smad4. Our study also suggests that targeting the association between p65 and Smad4 may help to promote bone regeneration in the treatment of bone diseases. PMID- 25029243 TI - Inhibition of neogenin dampens hepatic ischemia-reperfusion injury. AB - OBJECTIVE: Liver ischemia and reperfusion injury is a common source of significant morbidity and mortality following liver transplantation, hemorrhagic shock, or major hepatic surgery. Based on studies showing a critical role for the neuronal guidance receptor neogenin (Neo1) outside the nervous system in mediating tissue adaption during acute inflammation, we hypothesized that Neo1 enhances hepatic ischemia and reperfusion injury. DESIGN: Animal study. SETTING: University-based experimental laboratory. SUBJECTS: Wid-type, neogenin deficient and chimeric mice. INTERVENTIONS: Neogenin expression was evaluated during inflammatory stimulation in vitro and during ischemia and reperfusion injury in vivo, intravital microscopy performed to study intravascular flow characteristics. The extent of liver injury was evaluated using histology, serum levels of lactate dehydrogenase, aspartate, and alanine aminotransferase. The functional role of Neo1 during liver IR was evaluated in mice with gene targeted repression of neogenin (Neo1-/-), bone marrow chimeric animals and controls. In addition, functional inhibition of neogenin was performed using antibody injection. MEASUREMENTS AND MAIN RESULTS: We observed an induction of Neo1 during inflammation in vitro and ischemia and reperfusion in vivo. Intravital microscopy demonstrated a decreased ability of Neo1 leukocytes to attach to endothelial vascular wall during inflammation. Subsequent studies in Neo1 mice showed attenuated serum levels of lactate dehydrogenase, aspartate, alanine, and proinflammatory cytokines during hepatic ischemia and reperfusion injury. This was associated with improved hepatic histology scores. Studies in chimeric animals demonstrated that the hematopoietic Neo1 expression to be crucial for the observed results. Treatment with an anti-Neo1 antibody resulted in a significant reduction of experimental hepatic ischemia and reperfusion injury, involving attenuated variable of lactate dehydrogenase, alanine, aspartate, and cytokine levels. CONCLUSIONS: These data provide a unique role for Neo1 in the development of hepatic ischemia and reperfusion injury and identified Neo1 as a potential target to prevent liver dysfunction in the future. PMID- 25029244 TI - HMGB1 as a drug target in staphylococcal pneumonia. AB - High mobility group box (HMGB)1 is a small DNA-binding protein. In the nucleus, HMGB1 plays a role in gene expression and DNA replication. When it is released or secreted into the extracellular milieu, HMGB1 functions as a pro-inflammatory cytokine-like mediator. Recently reported data support the view that treatment with a neutralizing anti-HMGB1 antibody ameliorated pulmonary damage in a murine model of pneumonia caused by a pathogenic strain of Staphylococcus aureus. These findings suggest that HMGB1 may be an important drug target as scientists, clinical investigators and pharmaceutical companies seek to develop better agents for the treatment of staphylococcal pneumonia. Unfortunately, however, encouraging results from murine models of human disease often fail to translate into positive findings in clinical trials. Thus, before moving from pre-clinical into clinical studies, it may be prudent to validate and extend the recent experimental findings by carrying out additional studies, using a large animal model of pneumonia. PMID- 25029245 TI - Optimal uniformity index selection and acquisition counts for daily gamma camera quality control. AB - INTRODUCTION: The purpose of this study was to investigate the optimized use of common uniformity indices [National Electrical Manufacturers' Association (NEMA) indices (differential and integral), Cox-Diffey and the coefficient of variation (CoV)]. METHODS: The indices were calculated for induced [localized two dimensional (2D) Gaussian and gradient] artefacts added to three image sets (5, 10 and 15 million counts), each containing 25 extrinsic images, using Matlab. The intensity of the induced artefacts was varied between a 1 and 10% drop in pixel counts. The induced artefacts simulated photomultiplier tube [10 cm full width at half maximum (FWHM)], smaller focused artefacts (2.5 cm FWHM) and gradients artefacts. RESULTS: For five million count acquisitions, the Cox-Diffey, CoV and NEMA integral indices detected the 6% 2D Gaussian artefacts [10 cm full-width at half-maximum (FWHM)], whereas the NEMA differential index performed relatively poorly. NEMA differential and integral indices performed equally well at detecting smaller 2D Guassian (2.5 cm FWHM) artefacts. The 10% artefact was the minimum artefact detected by both indices for five million count acquisitions. The Cox-Diffey and CoV indices did not detect any artefacts for five million acquired counts. The CoV index performed best at detecting gradient artefacts at five million acquired counts. CONCLUSION: This work provides evidence that daily quality control can be acquired with as few as five million counts while maintaining the same ability to detect both chronic and acute nonuniformities compared with higher count acquisitions. A combination of the NEMA integral and the CoV indices gives the optimal selection of uniformity indices for detecting a range of artefact forms and intensities. PMID- 25029246 TI - The dysfunctional host response to influenza A H7N9: a potential treatment option? AB - The newly emerging human pathogen influenza A H7N9 represents a potentially major threat to human health. The virus was first shown to be pathogenic in humans in 2013, and outbreaks continue to occur in China to the present time. The current incident mortality rate is disturbingly high despite the frequent use of antiviral therapy and intensive care management. If the virus gains the capacity for efficient person-to-person transmission, a global influenza pandemic could ensue with devastating consequences. In the absence of an effective vaccine, targeted regulation of the host immune response by immune modulators might be considered. Readily available, approved drugs with immune-modulating activities might prove to be a treatment option in combination with existing antiviral agents and supportive care. PMID- 25029247 TI - Face-viewing patterns in young children with autism spectrum disorders: speaking up for the role of language comprehension. AB - PURPOSE: The aim was to examine whether viewing patterns toward the mouth, eyes, and nonmouth-noneyes areas differed between young children with autism spectrum disorder (ASD) and typically developing (TD) children when viewing a person speaking. The role of language comprehension in such viewing patterns was also examined. METHOD: Eleven children with ASD (approximately 4.5 years old) and 29 TD toddlers (approximately 2.5 years old) participated. The groups were matched on language comprehension raw scores from the Reynell Developmental Language Scales III. All children viewed short films of a woman speaking while their eye movements were recorded with eye-tracking equipment. RESULTS: Children with ASD spent proportionally less time viewing the mouth and more time viewing the nonmouth-noneyes areas. Time viewing the eyes did not differ between groups. Increased mouth viewing was associated with lower language comprehension in the group with ASD. CONCLUSION: Variability in language comprehension is an important factor to monitor when interpreting face-viewing patterns in young children with ASD, particularly with regard to mouth viewing. The results may help explain divergent findings in this field of research. PMID- 25029248 TI - [Unhealthy lifestyle in patients of a psychosomatic outpatient and consultation liaison clinic]. AB - Patients with mental disorders have an increased risk for somatic diseases. Especially life style risk factors contribute to this increased risk. In order to identify targets for preventive measures, we aimed to determine the prevalence of an unhealthy lifestyle in a clinical sample and to analyze associations with severity of mental disorders and somatic complaints. We analyzed the medical records of n=1 919 outpatients, who were treated between 2009-2011 in the Department of Psychosomatic Medicine and Psychotherapy of the University Medical Center Mainz. 62.4% of the patients were physically inactive, 33.2% were smokers and 17.4% were obese. Lifestyle risk factors were associated with increased symptom burden and impairment. Smoking was strongly associated with more previous psychiatric or psychosomatic inpatient treatments. These results indicate an urgent need for targeting health behavior more rigorously in the treatment of patients with common mental disorders. PMID- 25029249 TI - [Gender differences in mental distress of patients with lung cancer and their partners]. AB - In a prospective uncontrolled observational study we investigated the influence of gender, resilience, and marital satisfaction on mental distress of patients suffering from lung cancer and their partners. Female patients and partners report-ed impaired physical and mental health as well as lower resilience and marital satisfaction than males. Mental distress was negatively associated with resilience and marital satisfaction, both, in patients and their partners. We found a partial mediation effect of resilience and marital satisfaction on the relationship between gender and mental distress. Taking these results into account, particularly female patients and partners should preferably receive psychooncological support. PMID- 25029250 TI - [Mental distress and wish for psychosomatic treatment of patients with pulmonary hypertension]. AB - BACKGROUND: The study investigated the level of mental distress in patients with pulmonary hypertension (PH) and assessed the use of and the wish for psychosomatic treatment. METHODS: A total sample of n=187 outpatients participated in the cross-sectional survey. The short form of the Patient Health Questionnaire (PHQ-D), the EuroQol (EQ-5D) and a questionnaire assessing the wish for psychosomatic treatment were applied. RESULTS: 50.6% of the patients exhibited depressive symptoms of varying degrees, 19.2% showed symptoms of major depression. 14.8% of the pa-tients reported panic attacks, and 7.1% demonstrated symptoms of a panic syndrome. Quality of life was low (EQ-5D VAS M=60). Experience with outpatient or inpatient psychotherapy was reported by 23.4% and 8.6% of the patients, respectively. 56.5% reported a wish for psychosomatic treatment. CONCLUSIONS: PH-Patients are more likely to suffer from mild or subthreshold depressive syndromes, but are very interested in psychosomatic treatment. The implementation of psychosomatic interventions into clinical practice would be desirable. PMID- 25029251 TI - [Stability of mental stress-induced hemodynamic and autonomic reaction despite successful treatment for psychosomatic disorder]. AB - Autonomic imbalance and exaggerated stress responses are associated with an increased risk of morbidity and mortality and have been associated with several psychosomatic disorders. Has in-patient psychotherapy any effect on autonomic regulation and mental stress reactivity? In 77 patients undergoing in-patient psychometric treatment psychometric examination and psychophysiological assessment of hemodynamic and autonomic parameters during rest and 2 mental stress tests was performed at the beginning and at the end of in-patient psychotherapy. Despite marked improvements in symptoms our short-term treatment for psychosomatic disorders did not affect autonomic and hemodynamic activation at rest or during stress testing. It remains to be investigated if increased physical activity and relaxation expected after improvement have beneficial physiological effects over longer time spans. PMID- 25029252 TI - [Development and correlation of work-related behavior and experience patterns, burnout and quality of life in medical students from their freshmanship to the first state examination]. AB - Symptoms of burnout are common among medical students. Although they usually start with a good health status, their condition deteriorates over the course of their studies. In our study ESTRELLAS we examined 530 medical students in the preclinical semesters with validated psychological questionnaires. The longer the students were studying, the more showed risky working habits. Cognitive and emotional burnout symptoms increased coincidentally in their intensity, whereas the mental quality of life continuously deteriorated. Medical students' cognitive and emotional burnout symptoms are constantly increasing from the beginning of their studies. Contemporaneously, the mental quality of life is deteriorating. This might be based on a drastic change towards risky working habits. We suggest to actively work against this process to keep our motivated students and prospective physicians productive and in good mental health. PMID- 25029253 TI - Generalize or personalize--do dogs transfer an acquired rule to novel situations and persons? AB - Recent studies have raised the question of whether dogs, like human infants, comprehend an established rule as generalizable, normative knowledge or rather as episodic information, existing only in the immediate situation. In the current study we tested whether dogs disobeyed a prohibition to take a treat (i) in the presence of the communicator of the ban, (ii) after a temporary absence of the communicator, and (iii) in the presence of a novel person. Dogs disobeyed the rule significantly more often when the communicator left the room for a moment or when they were faced with a new person, than when she stayed present in the room. These results indicate that dogs "forget" a rule as soon as the immediate human context becomes disrupted. PMID- 25029254 TI - Protective lung ventilation during general anesthesia: is there any evidence? PMID- 25029255 TI - Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta analysis. AB - OBJECTIVE: Compare the efficacy of ranibizumab, aflibercept, laser, and sham in the first-line treatment of diabetic macular edema (DME) to inform technology assessments such as those conducted by the UK National Institute for Health and Care Excellence (NICE). DATA SOURCES: MEDLINE, Embase, Cochrane Library, congress abstracts, ClinicalTrials.gov registry and Novartis data on file. INCLUSION CRITERIA: Studies reporting 6- or 12-month results of randomized controlled trials (RCTs) evaluating at least two of ranibizumab 0.5 mg pro re nata, aflibercept 2.0 mg bi-monthly, laser photocoagulation or sham. Study quality was assessed based on likelihood of bias in selection, attrition, detection and performance. OUTCOME MEASURE: Improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining >=10 letters on the Early Treatment Diabetic Retinopathy Study scale. The outcome was chosen following acceptance by NICE of a Markov model with 10-letter health states in the assessment of ranibizumab for DME. META-ANALYSIS: Bayesian network meta-analyses with fixed and random effects adjusted for differences in baseline BCVA or central retinal thickness. RESULTS: The analysis included 1,978 patients from eight RCTs. The random effects model adjusting for baseline BCVA was the best model based on total residual. The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept (odds ratio [OR] 1.59; 95% credible interval [CrI], 0.61-5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy with ORs of 5.50 (2.73-13.16) and 3.45 (1.62-6.84) respectively. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser. LIMITATIONS: Three of the eight RCTs included are not yet published. The models did not adjust for all potential effect modifiers. CONCLUSION: Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser. PMID- 25029256 TI - PHD and TFIIS-Like domains of the Bye1 transcription factor determine its multivalent genomic distribution. AB - The BYpass of Ess1 (Bye1) protein is a putative S. cerevisiae transcription factor homologous to the human cancer-associated PHF3/DIDO family of proteins. Bye1 contains a Plant Homeodomain (PHD) and a TFIIS-like domain. The Bye1 PHD finger interacts with tri-methylated lysine 4 of histone H3 (H3K4me3) while the TFIIS-like domain binds to RNA polymerase (Pol) II. Here, we investigated the contribution of these structural features to Bye1 recruitment to chromatin as well as its function in transcriptional regulation. Genome-wide analysis of Bye1 distribution revealed at least two distinct modes of association with actively transcribed genes: within the core of Pol II- and Pol III-transcribed genes concomitant with the presence of the TFIIS transcription factor and, additionally, with promoters of a subset of Pol II-transcribed genes. Specific loss of H3K4me3 abolishes Bye1 association to gene promoters, but doesn't affect its binding within gene bodies. Genetic interactions suggested an essential role of Bye1 in cell fitness under stress conditions compensating the absence of TFIIS. Furthermore, BYE1 deletion resulted in the attenuation of GAL genes expression upon galactose-mediated induction indicating its positive role in transcription regulation. Together, these findings point to a bimodal role of Bye1 in regulation of Pol II transcription. It is recruited via its PHD domain to H3K4 tri-methylated promoters at early steps of transcription. Once Pol II is engaged into elongation, Bye1 binds directly to the transcriptional machinery, modulating its progression along the gene. PMID- 25029257 TI - Tetrel-hydride interaction between XH3F (X = C, Si, Ge, Sn) and HM (M = Li, Na, BeH, MgH). AB - A tetrel-hydride interaction was predicted and characterized in the complexes of XH3F...HM (X = C, Si, Ge, Sn; M = Li, Na, BeH, MgH) at the MP2/aug-cc-pVTZ level, where XH3F and HM are treated as the Lewis acid and base, respectively. This new interaction was analyzed in terms of geometrical parameters, interaction energies, and spectroscopic characteristics of the complexes. The strength of the interaction is essentially related to the nature of X and M groups, with both the larger atomic number of X and the increased reactivity of M giving rise to a stronger tetrel-hydride interaction. The tetrel-hydride interaction exhibits similar substituent effects to that of dihydrogen bonds, where the electron donating CH3 and Li groups in the metal hydride strengthen the binding interactions. NBO analyses demonstrate that both BD(H-M) -> BD*(X-F) and BD(H-M) > BD*(X-H) orbital interactions play the stabilizing role in the formation of the complex XH3F...HM (X = C, Si, Ge, and Sn; M = Li, Na, BeH, and MgH). The major contribution to the total interaction energy is electrostatic energy for all of the complexes, even though the dispersion/polarization parts are nonnegligible for the weak/strong tetrel-hydride interaction, respectively. PMID- 25029258 TI - Carbon monoxide photoproduction: implications for photoreactivity of Arctic permafrost-derived soil dissolved organic matter. AB - Apparent quantum yields of carbon monoxide (CO) photoproduction (AQY(CO)) for permafrost-derived soil dissolved organic matter (SDOM) from the Yukon River Basin and Alaska coast were determined to examine the dependences of AQY(CO) on temperature, ionic strength, pH, and SDOM concentration. SDOM from different locations and soil depths all exhibited similar AQY(CO) spectra irrespective of soil age. AQY(CO) increased by 68% for a 20 degrees C warming, decreased by 25% from ionic strength 0 to 0.7 mol L(-1), and dropped by 25-38% from pH 4 to 8. These effects combined together could reduce AQY(CO) by up to 72% when SDOM transits from terrestrial environemnts to open-ocean conditions during summer in the Arctic. A Michaelis-Menten kinetics characterized the influence of SDOM dilution on AQY(CO) with a very low substrate half-saturation concentration. Generalized global-scale relationships between AQY(CO) and salinity and absorbance demostrate that the CO-based photoreactivity of ancient permaforst SDOM is comparable to that of modern riverine DOM and that the effects of the physicochemical variables revealed here alone could account for the seaward decline of AQY(CO) observed in diverse estuarine and coastal water bodies. PMID- 25029259 TI - Astragalus polysaccharides mediated preventive effects on bronchopulmonary dysplasia in rats. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a multifactor chronic lung disease that mainly affects premature infants. In this study, we investigate the preventive effects of Astragalus polysaccharides (APS) on BPD, and explore its potential molecular mechanisms. METHODS: Lung tissues of newborn Sprague-Dawley rats from the control group, the room air plus low-dose APS group, the room air plus high-dose APS group, the BPD model group, the low-dose APS group (20 mg/kg d), and the high-dose APS group (40 mg/kg d) were examined at the 4th, 10th, and 14th d of life. The pathomorphological change was evaluated by hematoxylin-eosin staining. The content levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by the assay kit. Moreover, the protein and/or mRNA expression levels of NF-kappaBp65, CD31, ICAM-1, and TNF-alpha were also detected by corresponding methods. RESULTS: APS decreased the inflammatory cells infiltrating compared with the BPD group. For the APS group, the activity of SOD was increased and the content of MDA was reduced compared with the BPD group at any time point. The protein and mRNA expression levels of NF-kappaBp65, ICAM-1, and TNF-alpha were all decreased, while the protein expression level of CD31 was increased in the APS-treated group, with the most significant difference of the high-dose group (P < 0.01) compared with the BPD group after birth on the 4th, 10th, and 14th d. CONCLUSION: APS can reduce airway remodeling and alveolar damage by its modulation of inflammatory mediators and antioxidation, suggesting some protective effects on BPD of neonatal rats. PMID- 25029260 TI - Pharmacokinetics and local safety profile of propranolol eye drops in rabbits. AB - BACKGROUND: Oral propranolol, a nonselective beta-blocker, is able to reduce the progression of retinopathy of prematurity in newborns, but it appeared unsafe. This study aimed to find, in rabbits, a propranolol eye drop concentration able to induce lower plasma but higher retinal concentrations than those obtained after oral administration. METHODS: Male New Zealand white rabbits were treated with oral propranolol (0.25 mg/kg/6 h) for 5 d, and propranolol concentrations were measured after 1, 2, 3, and 6 h in plasma, aqueous humor, vitreous humor, and retina. These concentrations were compared with those obtained after the administration of one drop of 25 MUl of propranolol 0.1% prepared in saline, applied every 6 h to both eyes for 5 d. A Draize eye test and histological analyses were performed to assess eye drop tolerability. RESULTS: The administration of eye drops produced retinal concentrations similar to, but plasma concentrations significantly lower than, those measured after oral administration. The local tolerability profile was excellent. CONCLUSION: Propranolol eye drops are able to ensure high retinal and low plasma concentrations of propranolol, and this finding opens the perspective of possible topical treatment with propranolol in newborns with retinopathy of prematurity. PMID- 25029261 TI - Hydrothermal synthesis of vanadium nitride and modulation of its catalytic performance for oxygen reduction reaction. AB - A creative hydrothermal synthesis method followed by calcination for vanadium nitride (VN) is reported. The oxygen reduction reaction (ORR) study of the catalyst shows that VN possesses a comparable catalytic performance to commercial Pt/C catalyst. The ORR catalytic activity study of vanadium nitride, vanadium carbonitride, and vanadium carbide reveals that tuning anions offers a promising route for the activity enhancement of the non-precious metal catalysts. PMID- 25029262 TI - Directed assembly of nanodiamond nitrogen-vacancy centers on a chemically modified patterned surface. AB - Nitrogen-vacancy (NV) centers in nanodiamond (ND) particles are an attractive material for photonic, quantum information, and biological sensing technologies due to their optical properties-bright single photon emission and long spin coherence time. To harness these features in practical devices, it is essential to realize efficient methods to assemble and pattern NDs at the micro-/nanoscale. In this work, we report the large scale patterned assembly of NDs on a Au surface by creating hydrophobic and hydrophilic regions using self-assembled monolayer (SAM). Hydrophobic regions are created using a methyl (-CH3) terminated SAM of octadecanethiol molecules. Evaporating a water droplet suspension of NDs on the SAM patterned surface assembles the NDs in the bare Au, hydrophilic regions. Using this procedure, we successfully produced a ND structures in the shape of dots, lines, and rectangles. Subsequent photoluminescence imaging of the patterned NDs confirmed the presence of optically active NV centers. Experimental evidence in conjunction with computational analysis indicates that the surface wettability of the SAM modified Au surface plays a dominant role in the assembly of NDs as compared to van der Waals and other substrate-ND interactions. PMID- 25029263 TI - Full range dielectric characteristics of calcium copper titanate thin films prepared by continuous composition-spread sputtering. AB - Perovskite CaCu3Ti4O12 has drawn a great deal of attention for various electronic applications due to its giant dielectric property as well as a strong stability in a wide range of temperature. In this paper, we use an off-axis continuous composition-spread (CCS) sputtering method to investigate the full range dielectric characteristics of calcium copper titanate thin films. The film compositions are continuously distributed by deposition from two targets of CaTiO3 and CuTiO3. A slightly Ca-deficient, Cu- and Ti-rich film, which has a 0.9:3.2:4.3 ratio for Ca:Cu:Ti, demonstrated the best performance by showing a dielectric constant of 781 at 100 kHz. On the other hand, all other films far away from the CaCu3Ti4O12 composition showed suppressed dielectric properties. Analyses by X-ray photon spectroscopy, micro-Raman microscopy, transmission electron microscopy, and Rutherford backscattering spectroscopy reveal that there are three possible origins for such superior performance at off stoichiometric thin films: (1) bulk doping by excessive Cu and Ti ions, (2) chemically modified grain boundary, and (3) the lowered electrode-sample interface resistance. Our result will provide a new insight into engineering the dielectric properties using off-stoichiometric synthesis. PMID- 25029264 TI - When more is better. AB - Nutrition support of critically ill patients with sepsis is one of the most debated issues among intensivists. The latest international sepsis guidelines recommend the prescription of a low volume of feeds through gastric or intestinal enteral nutrition (EN) for 7 days after admission to the ICU. The data to support such recommendations are scarce, and large trials are needed to clarify this issue. As reported in the previous issue of Critical Care, Elke and colleagues have revisited a database containing 13,630 ICU patients, of whom 2,270 met four inclusion criteria: sepsis or pneumonia, ICU stay of at least 3 days, mechanical ventilation within 48 hours after ICU admission, and exclusive EN. The goal of the authors was to assess the impact of various levels of energy and protein administration on mortality at 60 days after ICU admission and on the duration of mechanical ventilation. They found that standard levels of energy and protein recommended by international guidelines for patients in the ICU do also apply to patients with sepsis in the ICU. This is an important finding, which contradicts the current recommendations and beliefs for this subgroup of patients in the ICU and gives a strong rationale for launching a large prospective randomized trial. PMID- 25029265 TI - Methodology review: using dual-energy X-ray absorptiometry (DXA) for the assessment of body composition in athletes and active people. AB - Dual energy X-ray absorptiometry (DXA) is rapidly becoming more accessible and popular as a technique to monitor body composition, especially in athletic populations. Although studies in sedentary populations have investigated the validity of DXA assessment of body composition, few studies have examined the issues of reliability in athletic populations and most studies which involve DXA measurements of body composition provide little information on their scanning protocols. This review presents a summary of the sources of error and variability in the measurement of body composition by DXA, and develops a theoretical model of best practice to standardize the conduct and analysis of a DXA scan. Components of this protocol include standardization of subject presentation (subjects rested, overnight-fasted and in minimal clothing) and positioning on the scanning bed (centrally aligned in a standard position using custom-made positioning aids) as well as manipulation of the automatic segmentation of regional areas of the scan results. Body composition assessment implemented with such protocol ensures a high level of precision, while still being practical in an athletic setting. This ensures that any small changes in body composition are confidently detected and correctly interpreted. The reporting requirements for studies involving DXA scans of body composition include details of the DXA machine and software, subject presentation and positioning protocols, and analysis protocols. PMID- 25029267 TI - Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. AB - IMPORTANCE: The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are common in tuberous sclerosis complex (TSC) and are a frequent concern for patients. Recognition of these lesions is imperative for early diagnosis, given the treatment advances that may improve patient outcomes. OBJECTIVE: To detail recommendations for the diagnosis, surveillance, and management of skin and dental lesions in TSC. EVIDENCE REVIEW: The TSC Dermatology and Dentistry Subcommittee, 1 of 12 subcommittees, reviewed the relevant literature from 1997 to 2012. FINDINGS: A consensus on skin and dental issues was achieved within the Dermatology and Dentistry Subcommittee before recommendations were presented, discussed, and agreed on in a group meeting of all subcommittees from June 14 to 15, 2012. CONCLUSIONS AND RELEVANCE: Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor. PMID- 25029266 TI - Pathologic mechanical stress and endotoxin exposure increases lung endothelial microparticle shedding. AB - Acute lung injury (ALI) results from infectious challenges and from pathologic lung distention produced by excessive tidal volume delivered during mechanical ventilation (ventilator-induced lung injury [VILI]) and is characterized by extensive alveolar and vascular dysfunction. Identification of novel ALI therapies is hampered by the lack of effective ALI/VILI biomarkers. We explored endothelial cell (EC)-derived microparticles (EMPs) (0.1-1 MUm) as potentially important markers and potential mediators of lung vascular injury in preclinical models of ALI and VILI. We characterized EMPs (annexin V and CD31 immunoreactivity) produced from human lung ECs exposed to physiologic or pathologic mechanical stress (5 or 18% cyclic stretch [CS]) or to endotoxin (LPS). EC exposure to 18% CS or to LPS resulted in increased EMP shedding compared with static cells (~ 4-fold and ~ 2.5-fold increases, respectively). Proteomic analysis revealed unique 18% CS-derived (n = 10) and LPS-derived EMP proteins (n = 43). VILI-challenged mice (40 ml/kg, 4 h) exhibited increased plasma and bronchoalveolar lavage CD62E (E-selectin)-positive MPs compared with control mice. Finally, mice receiving intratracheal instillation of 18% CS derived EMPs displayed significant lung inflammation and injury. These findings indicate that ALI/VILI-producing stimuli induce significant shedding of distinct EMP populations that may serve as potential ALI biomarkers and contribute to the severity of lung injury. PMID- 25029269 TI - Pulsed direct flame deposition and thermal annealing of transparent amorphous indium zinc oxide films as active layers in field effect transistors. AB - Indium-zinc oxide (IZO) films were deposited via flame spray pyrolysis (FSP) by pulsewise shooting a Si/SiO2 substrate directly into the combustion area of the flame. Based on UV-vis measurements of thin-films deposited on glass substrates, the optimal deposition parameters with respect to low haze values and film thicknesses of around 100 nm were determined. Thermal annealing of the deposited films at temperatures between 300 and 700 degrees C was carried out and staggered bottom gate thin-film transistors (TFT) were fabricated. The thin films were investigated by scanning electron microscopy, atomic force microscopy, X-ray diffraction, Fourier transformed infrared spectroscopy, and room-temperature photoluminescence measurements. The outcome of these investigations lead to two major requirements in order to implement a working TFT: (i) organic residues from the deposition process need to be removed and (ii) the net free charge carrier concentration has to be minimized by controlling the trap states in the semiconductor. The optimal annealing temperature was 300 degrees C as both requirements are fulfilled best in this case. This leads to field effect transistors with a low hysteresis, a saturation mobility of MUSat = 0.1 cm(2)/(V s), a threshold voltage of Vth = -18.9 V, and an Ion/Ioff ratio on the order of 10(7). Depending on thermal treatment, the defect density changes significantly strongly influencing the transfer characteristics of the device. PMID- 25029268 TI - Quantitative molecular detection of putative periodontal pathogens in clinically healthy and periodontally diseased subjects. AB - Periodontitis is a multi-microbial oral infection with high prevalence among adults. Putative oral pathogens are commonly found in periodontally diseased individuals. However, these organisms can be also detected in the oral cavity of healthy subjects. This leads to the hypothesis, that alterations in the proportion of these organisms relative to the total amount of oral microorganisms, namely their abundance, rather than their simple presence might be important in the transition from health to disease. Therefore, we developed a quantitative molecular method to determine the abundance of various oral microorganisms and the portion of bacterial and archaeal nucleic acid relative to the total nucleic acid extracted from individual samples. We applied quantitative real-time PCRs targeting single-copy genes of periodontal bacteria and 16S-rRNA genes of Bacteria and Archaea. Testing tongue scrapings of 88 matched pairs of periodontally diseased and healthy subjects revealed a significantly higher abundance of P. gingivalis and a higher total bacterial abundance in diseased subjects. In fully adjusted models the risk of being periodontally diseased was significantly higher in subjects with high P. gingivalis and total bacterial abundance. Interestingly, we found that moderate abundances of A. actinomycetemcomitans were associated with reduced risk for periodontal disease compared to subjects with low abundances, whereas for high abundances, this protective effect leveled off. Moderate archaeal abundances were health associated compared to subjects with low abundances. In conclusion, our methodological approach unraveled associations of the oral flora with periodontal disease, which would have gone undetected if only qualitative data had been determined. PMID- 25029270 TI - Habitat fragmentation and species extirpation in freshwater ecosystems; causes of range decline of the Indus river dolphin (Platanista gangetica minor). AB - Habitat fragmentation of freshwater ecosystems is increasing rapidly, however the understanding of extinction debt and species decline in riverine habitat fragments lags behind that in other ecosystems. The mighty rivers that drain the Himalaya - the Ganges, Brahmaputra, Indus, Mekong and Yangtze - are amongst the world's most biodiverse freshwater ecosystems. Many hundreds of dams have been constructed, are under construction, or are planned on these rivers and large hydrological changes and losses of biodiversity have occurred and are expected to continue. This study examines the causes of range decline of the Indus dolphin, which inhabits one of the world's most modified rivers, to demonstrate how we may expect other vertebrate populations to respond as planned dams and water developments come into operation. The historical range of the Indus dolphin has been fragmented into 17 river sections by diversion dams; dolphin sighting and interview surveys show that river dolphins have been extirpated from ten river sections, they persist in 6, and are of unknown status in one section. Seven potential factors influencing the temporal and spatial pattern of decline were considered in three regression model sets. Low dry-season river discharge, due to water abstraction at irrigation barrages, was the principal factor that explained the dolphin's range decline, influencing 1) the spatial pattern of persistence, 2) the temporal pattern of subpopulation extirpation, and 3) the speed of extirpation after habitat fragmentation. Dolphins were more likely to persist in the core of the former range because water diversions are concentrated near the range periphery. Habitat fragmentation and degradation of the habitat were inextricably intertwined and in combination caused the catastrophic decline of the Indus dolphin. PMID- 25029271 TI - Stiffening-induced high pulsatility flow activates endothelial inflammation via a TLR2/NF-kappaB pathway. AB - Stiffening of large arteries is increasingly used as an independent predictor of risk and therapeutic outcome for small artery dysfunction in many diseases including pulmonary hypertension. The molecular mechanisms mediating downstream vascular cell responses to large artery stiffening remain unclear. We hypothesize that high pulsatility flow, induced by large artery stiffening, causes inflammatory responses in downstream pulmonary artery endothelial cells (PAECs) through toll-like receptor (TLR) pathways. To recapitulate the stiffening effect of large pulmonary arteries that occurs in pulmonary hypertension, ultrathin silicone tubes of variable mechanical stiffness were formulated and were placed in a flow circulatory system. These tubes modulated the simulated cardiac output into pulsatile flows with different pulsatility indices, 0.5 (normal) or 1.5 (high). PAECs placed downstream of the tubes were evaluated for their expression of proinflammatory molecules (ICAM-1, VCAM-1, E-selectin and MCP-1), TLR receptors and intracellular NF-kappaB following flow exposure. Results showed that compared to flow with normal pulsatility, high pulsatility flow induced proinflammatory responses in PAECs, enhanced TLR2 expression but not TLR4, and caused NF-kappaB activation. Pharmacologic (OxPAPC) and siRNA inhibition of TLR2 attenuated high pulsatility flow-induced pro-inflammatory responses and NF-kappaB activation in PAECs. We also observed that PAECs isolated from small pulmonary arteries of hypertensive animals exhibiting proximal vascular stiffening demonstrated a durable ex-vivo proinflammatory phenotype (increased TLR2, TLR4 and MCP-1 expression). Intralobar PAECs isolated from vessels of IPAH patients also showed increased TLR2. In conclusion, this study demonstrates for the first time that TLR2/NF-kappaB signaling mediates endothelial inflammation under high pulsatility flow caused by upstream stiffening, but the role of TLR4 in flow pulsatility-mediated endothelial mechanotransduction remains unclear. PMID- 25029272 TI - Pax6 regulates the expression of Dkk3 in murine and human cell lines, and altered responses to Wnt signaling are shown in FlpIn-3T3 cells stably expressing either the Pax6 or the Pax6(5a) isoform. AB - Pax6 is a transcription factor important for early embryo development. It is expressed in several cancer cell lines and tumors. In glioblastoma, PAX6 has been shown to function as a tumor suppressor. Dickkopf 3 (Dkk3) is well established as a tumor suppressor in several tumor types, but not much is known about the regulation of its expression. We have previously found that Pax6 and Pax6(5a) increase the expression of the Dkk3 gene in two stably transfected mouse fibroblast cell lines. In this study the molecular mechanism behind this regulation is looked at. Western blot and reverse transcriptase quantitative PCR (RT-qPCR) confirmed higher level of Dkk3 expression in both Pax6 and Pax6(5a) expressing cell lines compared to the control cell line. By the use of bioinformatics and electrophoretic mobility shift assay (EMSA) we have mapped a functional Pax6 binding site in the mouse Dkk3 promoter. The minimal Dkk3 promoter fragment required for transcriptional activation by Pax6 and Pax6(5a) was a 200 bp region just upstream of the transcriptional start site. Mutation of the evolutionary conserved binding site in this region abrogated transcriptional activation and binding of Pax6/Pax6(5a) to the mouse Dkk3 promoter. Since the identified Pax6 binding site in this promoter is conserved, RT-qPCR and Western blot were used to look for regulation of Dkk3/REIC expression in human cell lines. Six of eight cell lines tested showed changes in Dkk3/REIC expression after PAX6 siRNA knockdown. Interestingly, we observed that the Pax6/Pax6(5a) expressing mouse fibroblast cell lines were less responsive to canonical Wnt pathway stimulation than the control cell line when TOP/FOP activity and the levels of active beta-catenin and GSK3-beta Ser9 phosphorylation were measured after LiCl stimulation. PMID- 25029274 TI - Dosimetric measurements of (68)Ga-high affinity DOTATATE: twins in spirit - part III. AB - PURPOSE: 68Ga-labelled compounds are increasingly used for somatostatin-receptor scintigraphy because of their favourable biokinetic properties, a higher tumour to-background contrast and higher diagnostic accuracy compared to the gamma emitting tracer 111In-DTPA-octreotide. Recently, we have introduced the new tracer 68Ga-DOTA-3-iodo-Tyr3-Thr8-octreotide (68Ga-HA-DOTATATE). The present study demonstrates the biodistribution and radiation dosimetry of this tracer in humans. PATIENTS, METHODS: Seven men were enrolled in this analysis. Every patient underwent a 20 min dynamic PET scan after intravenous injection of about 114 +/- 9 MBq of 68Ga-HA-DOTATATE. This was followed by two whole-body scans at 30 min p. i. and 120 min p. i. Blood radioactivity concentration was determined non-invasively from a ROI drawn over the aorta. Urine was collected until the time of the last scan. Liver, spleen, kidneys and urinary bladder wall were included in the dosimetric estimation that was carried out with the software package OLINDA 1.0. RESULTS: Physiological 68Ga-HA-DOTATATE uptake was observed in the pituitary gland, thyroid, salivary glands, liver, spleen, kidneys, urinary bladder, adrenals and intestine. Organs with the highest absorbed dose were spleen (0.26 +/- 0.11 mSv/MBq), kidneys (0.14 +/- 0.03 mSv/MBq) and liver (0.12 +/- 0.02 mSv/MBq).The estimated effective dose was 0.024 +/- 0.001 mSv/MBq. CONCLUSION: Our study demonstrates biokinetics and radiation exposure of the 68Ga labelled tracer HA-DOTATATE to be comparable to other 68Ga-labelled SSR analogues in clinical use. PMID- 25029273 TI - Building up analgesia in humans via the endogenous MU-opioid system by combining placebo and active tDCS: a preliminary report. AB - Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous MU-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective MU-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous MU-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS. PMID- 25029275 TI - Rhodium-catalyzed highly enantioselective arylation of cyclic diketimines: efficient synthesis of chiral tetrasubstituted 1,2,5-thiadiazoline 1,1-dioxides. AB - A highly enantioselective rhodium-catalyzed arylation of cyclic diketimines with arylboronic acids was achieved under mild conditions by employing a simple, sulfinamide-based branched olefin ligand. This protocol provides an efficient access to valuable chiral tetrasubstituted 1,2,5-thiadiazoline 1,1-dioxides in high yields with excellent enantioselectivities of up to 99% ee. PMID- 25029276 TI - Communicating and dealing with uncertainty in general practice: the association with neuroticism. AB - BACKGROUND: Diagnostic reasoning in primary care setting where presented problems and patients are mostly unselected appears as a complex process. The aim was to develop a questionnaire to describe how general practitioners (GPs) deal with uncertainty to gain more insight into the decisional process. The association of personality traits with medical decision making was investigated additionally. METHODS: Raw items were identified by literature research and focus group. Items were improved by interviewing ten GPs with thinking-aloud-method. A personal case vignette related to a complex and uncertainty situation was introduced. The final questionnaire was administered to 228 GPs in Germany. Factorial validity was calculated with explorative and confirmatory factor analysis. The results of the Communicating and Dealing with Uncertainty (CoDU)-questionnaire were compared with the scales of the 'Physician Reaction to Uncertainty' (PRU) questionnaire and with the personality traits which were determined with the Big Five Inventory (BFI-K). RESULTS: The items could be assigned to four scales with varying internal consistency, namely 'communicating uncertainty' (Cronbach alpha 0.79), 'diagnostic action' (0.60), 'intuition' (0.39) and 'extended social anamnesis' (0.69). Neuroticism was positively associated with all PRU scales 'anxiety due to uncertainty' (Pearson correlation 0.487), 'concerns about bad outcomes' (0.488), 'reluctance to disclose uncertainty to patients' (0.287), 'reluctance to disclose mistakes to physicians' (0.212) and negatively associated with the CoDU scale 'communicating uncertainty' (-0.242) (p<0.01 for all). 'Extraversion' (0.146; p<0.05), 'agreeableness' (0.145, p<0.05), 'conscientiousness' (0.168, p<0.05) and 'openness to experience' (0.186, p<0.01) were significantly positively associated with 'communicating uncertainty'. 'Extraversion' (0.162), 'consciousness' (0.158) and 'openness to experience' (0.155) were associated with 'extended social anamnesis' (p<0.05). CONCLUSION: The questionnaire allowed describing the diagnostic decision making process of general practitioners in complex situations. Personality traits are associated with diagnostic reasoning and communication with patients, which might be important for medical education and quality improvement purposes. PMID- 25029277 TI - A new type of dual-Cys cyanobacteriochrome GAF domain found in cyanobacterium Acaryochloris marina, which has an unusual red/blue reversible photoconversion cycle. AB - Cyanobacteriochromes (CBCRs) form a large, spectrally diverse family of photoreceptors (linear tetrapyrrole covalently bound via a conserved cysteine) that perceive ultraviolet to red light. The underlying mechanisms are reasonably well understood with, in certain cases, reversible formation of an adduct between a second cysteine and the chromophore accounting, in part, for their spectral diversity. These CBCRs are denoted as dual-Cys CBCRs, and most such CBCRs had been shown to reversibly absorb blue and green light. Herein, we report the structural and mechanistic characterization of a new type of dual-Cys CBCR, AM1_1186, which exhibits reversible photoconversion between a red-absorbing dark state (lambdamax = 641 nm) and a blue-absorbing photoproduct (lambdamax = 416 nm). The wavelength separation of AM1_1186 photoconversion is the largest found to date for a CBCR. In addition to one well-conserved cysteine responsible for covalent incorporation of the chromophore into the apoprotein, AM1_1186 contains a second cysteine in a unique position of its photosensory domain, which would be more properly classified as a red/green CBCR according to its sequence. Carboxyamidomethylation and mutagenesis of the cysteines revealed that the second cysteine forms an adduct with the tetrapyrrole, the phycocyanobilin, that can be reversed under blue light. The proline immediately upstream of this cysteine appears to determine the rate at which the cysteinylation following photoexcitation of the dark state chromophore can occur. We propose a possible reaction scheme and color-tuning mechanism for AM1_1186 in terms of its structure and its place in a phylogenetic tree. PMID- 25029278 TI - Detecting the oligomeric state of Escherichia coli MutS from its geometric architecture observed by an atomic force microscope at a single molecular level. AB - Atomic force microscopy (AFM), which provides true 3D surface topography, can also be used to determine the geometric parameters of proteins quantitatively at a single molecular level. In this paper, two different kinds of Escherichia coli MutS (MutS) protein were observed using AFM, and the geometric parameters of the proteins such as height, perimeter, area, and volume were measured. On the basis of these measurements, the molecular weight, association constant, oligomeric state, and orientation of MutS proteins on a mica surface were deduced. The oligomerization mechanism of MutS was analyzed in detail, and the results show that two different kinds of interactions between MutS protein may be involved in oligomerization. Our results also show that AFM imaging is an accurate method for analyzing the geometric structures of a single protein quantitatively at a single molecule level. PMID- 25029280 TI - Implementation of a data packet generator using pattern matching for wearable ECG monitoring systems. AB - In this paper, a packet generator using a pattern matching algorithm for real time abnormal heartbeat detection is proposed. The packet generator creates a very small data packet which conveys sufficient crucial information for health condition analysis. The data packet envelopes real time ECG signals and transmits them to a smartphone via Bluetooth. An Android application was developed specifically to decode the packet and extract ECG information for health condition analysis. Several graphical presentations are displayed and shown on the smartphone. We evaluate the performance of abnormal heartbeat detection accuracy using the MIT/BIH Arrhythmia Database and real time experiments. The experimental result confirm our finding that abnormal heart beat detection is practically possible. We also performed data compression ratio and signal restoration performance evaluations to establish the usefulness of the proposed packet generator and the results were excellent. PMID- 25029281 TI - Inductive displacement sensors with a notch filter for an active magnetic bearing system. AB - Active magnetic bearing (AMB) systems support rotating shafts without any physical contact, using electromagnetic forces. Each radial AMB uses two pairs of electromagnets at opposite sides of the rotor. This allows the rotor to float in the air gap, and the machine to operate without frictional losses. In active magnetic suspension, displacement sensors are necessary to detect the radial and axial movement of the suspended object. In a high-speed rotating machine equipped with an AMB, the rotor bending modes may be limited to the operating range. The natural frequencies of the rotor can cause instability. Thus, notch filters are a useful circuit for stabilizing the system. In addition, commercial displacement sensors are sometimes not suitable for AMB design, and cannot filter the noise caused by the natural frequencies of rotor. Hence, implementing displacement sensors based on the AMB structure is necessary to eliminate noises caused by natural frequency disturbances. The displacement sensor must be highly sensitive in the desired working range, and also exhibit a low interference noise, high stability, and low cost. In this study, we used the differential inductive sensor head and lock-in amplifier for synchronous demodulation. In addition, an active low-pass filter and a notch filter were used to eliminate disturbances, which caused by natural frequencies. As a consequence, the inductive displacement sensor achieved satisfactory linearity, high sensitivity, and disturbance elimination. This sensor can be easily produced for AMB applications. A prototype of these displacement sensors was built and tested. PMID- 25029282 TI - Love-wave sensors combined with microfluidics for fast detection of biological warfare agents. AB - The following paper examines a time-efficient method for detecting biological warfare agents (BWAs). The method is based on a system of a Love-wave immunosensor combined with a microfluidic chip which detects BWA samples in a dynamic mode. In this way a continuous flow-through of the sample is created, promoting the reaction between antigen and antibody and allowing a fast detection of the BWAs. In order to prove this method, static and dynamic modes have been simulated and different concentrations of BWA simulants have been tested with two immunoreactions: phage M13 has been detected using the mouse monoclonal antibody anti-M13 (AM13), and the rabbit immunoglobulin (Rabbit IgG) has been detected using the polyclonal antibody goat anti-rabbit (GAR). Finally, different concentrations of each BWA simulants have been detected with a fast response time and a desirable level of discrimination among them has been achieved. PMID- 25029283 TI - Automated analysis of barley organs using 3D laser scanning: an approach for high throughput phenotyping. AB - Due to the rise of laser scanning the 3D geometry of plant architecture is easy to acquire. Nevertheless, an automated interpretation and, finally, the segmentation into functional groups are still difficult to achieve. Two barley plants were scanned in a time course, and the organs were separated by applying a histogram-based classification algorithm. The leaf organs were represented by meshing algorithms, while the stem organs were parameterized by a least-squares cylinder approximation. We introduced surface feature histograms with an accuracy of 96% for the separation of the barley organs, leaf and stem. This enables growth monitoring in a time course for barley plants. Its reliability was demonstrated by a comparison with manually fitted parameters with a correlation R(2) = 0:99 for the leaf area and R(2) = 0:98 for the cumulated stem height. A proof of concept has been given for its applicability for the detection of water stress in barley, where the extension growth of an irrigated and a non-irrigated plant has been monitored. PMID- 25029284 TI - Sensor distribution design of travel time tomography in explosion. AB - Optimal sensor distribution in explosion testing is important in saving test costs and improving experiment efficiency. Aiming at travel time tomography in an explosion, an optimizing method in sensor distribution is proposed to improve the inversion stability. The influence factors of inversion stability are analyzed and the evaluating function on optimizing sensor distribution is proposed. This paper presents a sub-region and multi-scale cell partition method, according to the characteristics of a shock wave in an explosion. An adaptive escaping particle swarm optimization algorithm is employed to achieve the optimal sensor distribution. The experimental results demonstrate that optimal sensor distribution has improved both indexes and inversion stability. PMID- 25029286 TI - Increasing the number of arcs improves head and neck volumetric modulated arc therapy plans. PMID- 25029287 TI - Copper(I) and copper(II) uranyl heterometallic hybrid materials. AB - Two copper-uranium heterometallic compounds, [(UO2)3Cu(II)O2(C6NO2)5] (1) and [(UO2)Cu(I)(C6NO2)3] (2), have been synthesized by the reaction of uranyl acetate with copper salts in the presence of isonicotinic acid. Both compounds have been characterized by single-crystal X-ray diffraction, IR, Raman, and UV-vis spectroscopy. In compound 1, interactions between copper and uranium centers occur and result in a three-dimensional pillar layered structure. Compound 1 is also the first example of a heterometallic uranyl organic framework with a trinuclear U3O18 building block. Compound 2 is the first uranyl organic framework that contains monovalent copper, which arises from the reaction of Cu(II) chloride and is assumed to be due to the oxidation of chloride at low pH. PMID- 25029285 TI - Prenatal alcohol exposure increases postnatal acceptability of nicotine odor and taste in adolescent rats. AB - Human studies indicate that alcohol exposure during gestation not only increases the chance for later alcohol abuse, but also nicotine dependence. The flavor attributes of both alcohol and nicotine can be important determinants of their initial acceptance and they both share the component chemosensory qualities of an aversive odor, bitter taste and oral irritation. There is a growing body of evidence demonstrating epigenetic chemosensory mechanisms through which fetal alcohol exposure increases adolescent alcohol acceptance, in part, by decreasing the aversion to alcohol's bitter and oral irritation qualities, as well as its odor. Given that alcohol and nicotine have noteworthy chemosensory qualities in common, we investigated whether fetal exposure to alcohol increased the acceptability of nicotine's odor and taste in adolescent rats. Study rats were alcohol-exposed during fetal development via the dams' liquid diet. Control animals received ad lib access to an iso-caloric, iso-nutritive diet throughout gestation. Odorant-induced innate behavioral responses to nicotine odor (Experiment 1) or orosensory-mediated responses to nicotine solutions (Experiment 2) were obtained, using whole-body plethysmography and brief access lick tests, respectively. Compared to controls, rats exposed to fetal alcohol showed an enhanced nicotine odor response that was paralleled by increased oral acceptability of nicotine. Given the common aversive component qualities imbued in the flavor profiles of both drugs, our findings demonstrate that like postnatal alcohol avidity, fetal alcohol exposure also influences nicotine acceptance, at a minimum, by decreasing the aversion of both its smell and taste. Moreover, they highlight potential chemosensory-based mechanism(s) by which fetal alcohol exposure increases the later initial risk for nicotine use, thereby contributing to the co-morbid expression with enhanced alcohol avidity. Where common chemosensory mechanisms are at play, our results suggest broader implications related to the consequence of fetal exposure with one substance of abuse and initial acceptability of others. PMID- 25029288 TI - Development of an experimental model of proliferative retinopathy by intravitreal injection of VEGF165. AB - PURPOSE: To develop an experimental model of proliferative retinopathy by intravitreal injection of vascular endothelial growth factor 165 (VEGF165) in pigmented rabbits. METHODS: A prospective, controlled, comparative intervention study. Six pigmented rabbits (Chinchilla breed) were subjected to intravitreal injection of VEGF165 in their right eye. The left eye was used as control and received an injection of balanced salt solution. In group 1, 3 rabbits received a 10-MUg injection, and in group 2, 3 rabbits received a 20-MUg injection. At baseline, all subjects were analyzed by anterior biomicroscopy, retinography, fluorescein angiography, and optical coherence tomography (OCT) fundus images. Biomicroscopy and all ancillary examinations were repeated at weeks 1, 2, and 5. In the fifth week after the injection, the rabbits were euthanized and the eyes were enucleated and subjected to histological evaluation. RESULTS: Seven days after the intravitreal VEGF165 injection, all rabbits developed intense neovascularization of the retina and anterior segment. Neovascularization of the posterior pole was similar in both groups, and the anterior segment was more florid in group 2. At weeks 1 and 2, neovascularization persisted with a minor decrease in conjunctival hyperemia in both groups. At week 5, there was a partial regression of neovascularization of the posterior pole, which was more prominent in group 1 than group 2, with persistent anterior neovascularization in both groups. OCT showed a statistically significant increase in retinal thickness, hyaloid detachment, and tractional retinal detachment. After the 5-week period, ocular histopathological evaluation showed an increase in retinal thickness, hyaloid detachment, and intense neovascularization in both groups, especially group 2. CONCLUSION: This pilot study of a neovascularization model using intravitreal injection of VEGF165 in pigmented rabbits showed that both doses of 10 and 20 MUg were successful and effective in inducing vascular growth in the retina and anterior segment and can therefore be used for evaluating drug efficacy in future studies. PMID- 25029289 TI - Prediction of rare single-nucleotide causative mutations for muscular diseases in pooled next-generation sequencing experiments. AB - Next-generation sequencing (NGS) is a new approach for biomedical research, useful for the diagnosis of genetic diseases in extremely heterogeneous conditions. In this work, we describe how data generated by high-throughput NGS experiments can be analyzed to find single nucleotide polymorphisms (SNPs) in DNA samples of patients affected by neuromuscular disorders. In particular, we consider untagged pooled NGS data, where DNA samples of different individuals are combined in a single experiment, still providing information with an uncertainty limited to only two patients. At the moment, only few publications address the problem of SNPs detection in pooled experiments, and existing tools are often inaccurate. We propose a computational procedure consisting of two parts. In the first, data are filtered by means of decision rules. The second phase is based on a supervised classification technique. In the present work, we compare different de facto standard supervised and unsupervised procedures to identify and classify variants potentially related to muscular diseases, and we discuss results in terms of statistical and biological validation. PMID- 25029290 TI - Gender-specific differences in outcome after trauma may be explained by differences in immunity. PMID- 25029291 TI - The relationships between muscle force steadiness and visual steadiness in young and old adults. AB - Since vision is used in studies of muscle force control, reduced muscle force control might be related to reduced visual ability. We investigated relationships between steadiness in eye movements and quadriceps muscle torque (a surrogate for force) during isometric contractions of constant and varying torques. Nineteen young adults with an average age of 20.7 years and 18 old adults with an average age of 71.6 years performed three vision tasks, three vision and torque tasks at 40% maximal voluntary contraction (MVC), and three vision and torque tasks at 54 nm. Age groups had identical torque steadiness (CV) in 40%-MVC and 54-nm conditions (p > .05). Old had similar vertical (p > .05) but decreased horizontal visual steadiness (SD) (p < .05) compared with young. Correlations between visual steadiness and muscle torque steadiness failed to show a significant relationship (p > .05). We were unable to identify a substantial relationship between muscle torque steadiness and eye movement, as a component of visual steadiness, and conclude that reduced visual steadiness does not contribute to reduced muscle torque steadiness. PMID- 25029292 TI - Au-Silica nanowire nanohybrid as a hyperthermia agent for photothermal therapy in the near-infrared region. AB - Nanomaterial-based photothermal therapy has shown great potential for efficient cancer treatment. Here, we report a new hyperthermia agent, Au-silica nanowire nanohybrid (Au-SiNW nanohybrid) with tunable optical properties, for photothermal therapy. The unique feature of the synthetic method is no need of surface modification of SiNWs for the direct deposition of Au seeds, which can avoid complicated synthetic procedures and improve the reproducibility. The Au-SiNW nanohybrid can generate significant amount of heat upon irradiation in the near infrared (NIR) region for inducing thermal cell death. Moreover, compared to reported hyperthermia nanomaterials, the new nanohybrid requires a much lower laser irradiation density of 0.3 W/cm(2) for destroying cancer cells. A549 lung cancer cells were used for in vitro photothermal study. The nanohybrid showed excellent in vitro biocompatibility by using a 96-nonradioactive-cell proliferation assay. Even at a high concentration of 0.500 mg/mL nanohybrid, over 80% cells were alive. In contrast, almost all the cells were killed when NIR irradiation was applied at a concentration of 0.100 mg/mL nanohybrid. The Au-SiNW nanohybrid may become a promising hyperthermia agent. PMID- 25029293 TI - High-throughput method for the quantification of lacosamide in serum using ultrafast SPE-MS/MS. AB - BACKGROUND: Lacosamide is an anticonvulsant drug approved for adjunctive therapy of partial-onset seizures in adults. Monitoring serum lacosamide concentrations may be useful in assessing compliance and optimizing therapy. The clinical need for faster turn-around-times and increased testing volumes has led to the desire to develop faster methods of analysis for higher throughput of samples. METHODS: Fifty microliters of calibration standards, quality controls, and patient samples were precipitated with methanol containing deuterated internal standard. The supernatant was then diluted with aqueous mobile phase and injected on an ultrafast solid-phase extraction-mass spectrometry with a cycle time of <10 seconds per sample. RESULTS: The analytic linear range for the assay was 0.5-50.0 mcg/mL with a limit of detection of 0.05 mcg/mL. The assay showed interassay and intraassay precision coefficient of variations <7%, with no significant carryover after a sample twice the upper limit of quantitation, and no interference from the top 24 prescribed drugs, other anticonvulsants, or common drugs of abuse. Analytical accuracy was determined by comparing 26 results (19 patients, 7 standards and quality control) with a reference laboratory using liquid chromatography-mass spectrometry in addition to 11 proficiency samples from the LGC Standards Proficiency Testing survey. The results were compared using a standard linear regression with the equation of the line being y = 1.093x - 0.166, with an r(2) = 0.99, and a y intercept 95% confidence interval that included zero. CONCLUSIONS: Herein, the authors present a method for the quantification of lacosamide in serum with ultrafast solid-phase extraction-mass spectrometry that uses 50 MUL of sample, is linear from 0.5 to 50 mcg/mL, has interassay and intraassay coefficient of variations of <7%, and has much faster sample cycle times with similar analytic results compared with traditional liquid chromatography-mass spectrometry. PMID- 25029295 TI - Socioemotional selectivity in older adults: Evidence from the subjective experience of angry memories. AB - Few studies have compared the phenomenological properties of younger and older adults' memories for emotional events. Some studies suggest that younger adults remember negative information more vividly than positive information whereas other studies suggest that positive emotion yields phenomenologically richer memories than negative emotion for both younger and older adults. One problem with previous studies is a tendency to treat emotion as a dichotomous variable. In contrast, emotional richness demands inclusion of assessments beyond just a positive and negative dimension (e.g., assessing specific emotions like anger, fear and happiness). The present study investigated different properties of autobiographical remembering as a function of discrete emotions and age. Thirty two younger and thirty-one older adults participated by recalling recent and remote memories associated with six emotional categories and completed the Memory Characteristics Questionnaire for each. Results demonstrated that older adults' angry memories received lower ratings on some phenomenological properties than other emotional memories whereas younger adults' angry memories did not show this same pattern. These results are discussed within the context of socioemotional selectivity theory. PMID- 25029296 TI - A planning target volume margin formula for hypofractionated intracranial stereotactic radiotherapy under cone beam CT image guidance with a six-degrees-of freedom robotic couch and a mouthpiece-assisted mask system: a preliminary study. AB - OBJECTIVE: A planning target volume (PTV) margin formula for hypofractionated intracranial stereotactic radiotherapy (SRT) has been proposed under cone beam CT (CBCT) image guidance with a six-degrees-of-freedom (6-DOF) robotic couch. METHODS: CBCT-based registration using a 6-DOF couch reportedly led to negligibly small systematic positioning errors, suggesting that each in-treatment positioning error during the treatment courses for the patients employing this combination was predominantly caused by a random gaussian process. Under this assumption, an anisotropic PTV margin for each axis was formulated based on a gaussian distribution model. 19 patients with intracranial lesions who underwent additional post-treatment CBCT were consecutively selected, to whom stereotactic hypofractionated radiotherapy was delivered by a linear accelerator equipped with a CBCT imager, a 6-DOF couch and a mouthpiece-assisted mask system. Time-averaged patient-positioning errors during treatment were estimated by comparing the post treatment CBCT with the reference planning CT images. RESULTS: It was suggested that each histogram of the in-treatment positioning error in each axis would approach each single gaussian distribution with a mean of zero. The calculated PTV margins in the x, y and z directions were 0.97, 1.30 and 0.88 mm, respectively. CONCLUSION: The empirical isotropic PTV margin of 2 mm used in our facility for intracranial SRT was consistent with the margin calculated by the proposed gaussian model. ADVANCES IN KNOWLEDGE: We have proposed a PTV margin formula for hypofractionated intracranial SRT under CBCT image guidance with a 6 DOF robotic couch. PMID- 25029297 TI - Inhibition of mammalian DNA polymerases and the suppression of inflammatory and allergic responses by tyrosol from used activated charcoal waste generated during sake production. AB - The components adsorbed onto activated charcoal following the fermentation process of the Japanese rice wine "sake" have been studied with the aim of identifying suitable applications for this industrial food waste product. The absorbed materials were effectively extracted from the charcoal, and inhibited the activity of several mammalian DNA polymerases (pols). Subsequent purification of the extract afforded tyrosol [4-(2-hydroxyethyl)phenol] as the active component, which selectively inhibited the activity of 11 mammalian pols with IC50 values in the range of 34.3-46.1 MUM. In contrast, this compound did not influence the activities of plant or prokaryotic pols or any of the other DNA metabolic enzymes tested. Tyrosol suppressed both anti-inflammatory and antiallergic effects in vivo, including 12-O-tetradecanoylphorbol-13-acetate induced inflammatory mouse ear edema, and immunoglobulin E-induced passive cutaneous anaphylactic reaction in mice. These results suggested that this byproduct formed during the sake-brewing process could be used as an anti inflammatory and/or antiallergic agent. PMID- 25029299 TI - Management of massive and submassive pulmonary embolism: focus on recent randomized trials. AB - PURPOSE OF REVIEW: Although early pulmonary revascularization is the treatment of choice for patients with high-risk (massive) pulmonary embolism, it remains controversial in patients with intermediate-risk (submassive) pulmonary embolism until recently. Recent published data on the management of high-risk and intermediate-risk pulmonary embolism patients will be the main focus of this review. RECENT FINDINGS: The PEITHO trial supports the rationale of risk stratification in normotensive patients with pulmonary embolism. Patients with right ventricular dilation on echocardiography and positive cardiac troponin test have a high intermediate risk of complication and death. Thrombolysis prevents hemodynamic collapse in these patients but with an increased risk of major bleeding particularly in older patients (>75 years). Reduced dose of thrombolysis and catheter-based reperfusion with or without fibrinolysis have shown promising results. SUMMARY: Thrombolysis is the treatment of choice for patients with high risk pulmonary embolism. Surgical embolectomy is recommended in case of absolute contra-indication to thrombolysis. In patients with acute right ventricular dysfunction on cardiac imaging and myocardial injury, thrombolysis should be considered if they are 75 years or less of age and are at low risk of bleeding. Full-dose thrombolysis may be excessively risky in patients over 75 years. In patients with either RV dilation or elevated cardiac biomarker, thrombolysis is not recommended. PMID- 25029301 TI - Southern specialty. PMID- 25029298 TI - Morbidity and mortality in sarcoidosis. AB - PURPOSE OF REVIEW: Chronic sarcoidosis is a complex disease with numerous comorbid conditions and can be fatal in some cases. Recognizing causes of morbidity and mortality is important to effectively select treatments, manage symptoms and improve outcomes. The purpose of this review is to examine emerging knowledge on morbidity and mortality in sarcoidosis. RECENT FINDINGS: Approximately 1-5% of patients with sarcoidosis die from complications of sarcoidosis. Recent population studies indicate that mortality may be increasing over the past decade. The reasons behind these trends are unclear, but could include increasing incidence, detection rates, severity of disease or age of the population. Morbidity of sarcoidosis is reflected by a trend of increased hospitalizations over recent years and increased use of healthcare resources. Morbidity can be caused by organ damage from granulomatous inflammation, treatment complications and psychosocial effects of the disease. Recent studies are focused on morbidity related to cardiopulmonary complications, bone health and ageing within the sarcoidosis population. Last, sarcoidosis is associated with autoimmune diseases, pulmonary embolism and malignancy; however, the underlying mechanisms linking diseases continue to be debated. SUMMARY: Morbidity in sarcoidosis is significant and multifactorial. Mortality is infrequent, but may be increasing over the years. PMID- 25029302 TI - What is your diagnosis? Porcelain gallbladder. PMID- 25029303 TI - What is your diagnosis? Pulmonary abscess. PMID- 25029304 TI - Diagnostic imaging in veterinary dental practice. Impaction of the right mandibular canine tooth. PMID- 25029305 TI - Animal behavior case of the month. Territorial aggression. PMID- 25029307 TI - Pathology in practice. Exfoliative cutaneous lupus erythematosus in a German Shorthaired Pointer. PMID- 25029308 TI - Use of trazodone to facilitate postsurgical confinement in dogs. AB - OBJECTIVE: To investigate the safety and efficacy of oral administration of the serotonin antagonist and reuptake inhibitor trazodone hydrochloride to facilitate confinement and calming after orthopedic surgery in dogs. DESIGN: Prospective open-label clinical trial. ANIMALS: 36 client-owned dogs that underwent orthopedic surgery. PROCEDURES: Starting the day after surgery, dogs were administered trazodone (approx 3.5 mg/kg [1.6 mg/lb], PO, q 12 h) with tramadol (4 to 6 mg/kg [1.8 to 2.7 mg/lb], PO, q 8 to 12 h) for pain management. After 3 days, administration of tramadol was discontinued, and the trazodone dosage was increased (approx 7 mg/kg [3.2 mg/lb], PO, q 12 h) and maintained for at least 4 weeks. If needed, trazodone dosage was increased (7 to 10 mg/kg [3.2 to 4.5 mg/lb], PO, q 8 h). Owners completed electronic surveys rating their dogs' confinement tolerance, calmness or hyperactivity level, and responses to specific provocative situations prior to surgery and 1, 2, 3, and 4 weeks after surgery and at the postsurgery evaluation (at 8 to 12 weeks). RESULTS: Most (32/36 [89%]) of owners reported that their dogs, when given trazodone during the 8 to 12 weeks following orthopedic surgery, improved moderately or extremely with regard to confinement tolerance and calmness. Trazodone was well tolerated, even in combination with NSAIDs, antimicrobials, and other medications; no dogs were withdrawn from the study because of adverse reactions. Owner-reported median onset of action of trazodone was 31 to 45 minutes, and median duration of action was >= 4 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that oral administration of trazodone was safe and efficacious and may be used to facilitate confinement and enhance behavioral calmness of dogs during the critical recovery period following orthopedic surgery. PMID- 25029309 TI - Sewing needle foreign body ingestion in dogs and cats: 65 cases (2000-2012). AB - OBJECTIVE: To characterize clinical signs, diagnostic test results, foreign body location, treatment, and outcome for dogs and cats with sewing needle foreign bodies. DESIGN: Retrospective case series. ANIMALS: 65 dogs and cats with sewing needle foreign bodies. PROCEDURES: Medical records of 27 dogs and 38 cats examined because of sewing needle foreign bodies from January 2000 to February 2012 were reviewed for signalment, medical history, physical examination findings, diagnostic test results, interval from witnessed exposure and radiographic imaging to definitive treatment, definitive treatment, sewing needle location, complications, and outcome. RESULTS: 7 (10.8%) animals had sewing needles in extragastrointestinal locations that were not causing clinical signs. The remaining 58 (89.2%) animals had known sewing needle exposure or acute clinical signs associated with ingestion. The esophageal and gastric regions were the most common location for a sewing needle (10/21 [47.6%] dogs; 19/37 [51.4%] cats), followed by the oropharynx (7/21 [33.3%] dogs; 11/37 [29.7%] cats) and small and large intestines (4/21 [19.0%] dogs; 7/37 [18.9%] cats). Gastrointestinal perforation was detected in 10 of 58 (17.2%) animals (5/21 [23.8%] dogs; 5/37 [13.5%] cats). Sewing needles in the esophagus and stomach were successfully removed endoscopically in 8 of 9 dogs and 18 of 19 cats. Survival rate was 98.1% (51/52) for animals receiving definitive treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Endoscopic removal of ingested sewing needles was highly successful and should be recommended to prevent gastrointestinal tract perforation and associated morbidity. Prognosis for dogs and cats receiving definitive treatment for sewing needle foreign body ingestion was excellent. PMID- 25029310 TI - Frequency of Corynebacterium pseudotuberculosis infection in horses across the United States during a 10-year period. AB - OBJECTIVE: To quantify the number of horses with Corynebacterium pseudotuberculosis infection identified in the United States from January 2003 through December 2012. DESIGN: Cross-sectional study. SAMPLE: State veterinary diagnostic laboratory records of 2,237 C pseudotuberculosis culture-positive samples from horses. PROCEDURES: 44 state veterinary diagnostic laboratories throughout the United States were invited by mail to participate in the study. Data requested included the number of C pseudotuberculosis culture-positive samples from horses identified per year, geographic location from which the C pseudotuberculosis culture-positive sample was submitted, month and year of sample submission, breed and age of horses, and category of clinical manifestation (ie, internal infection, external infection, or ulcerative lymphangitis). RESULTS: Of the 44 invited laboratories, 15 agreed to participate and provided data on affected horses from 23 states. The proportion of C pseudotuberculosis culture-positive samples submitted during 2011 through 2012 (1,213/2,237 [54%]) was significantly greater than that for the period from 2003 through 2010 (1,024/2,237 [46%]). Corynebacterium pseudotuberculosis was recovered from horses in states where the disease has not been previously recognized as endemic. Affected horses were identified year-round. The greatest proportion of C pseudotuberculosis culture-positive samples was identified during November, December, and January (789/2,237 [35%]). No significant association between the clinical form of disease and age or breed of horse was observed. CONCLUSIONS AND CLINICAL RELEVANCE: The occurrence of C pseudotuberculosis infection in horses increased during the 10-year period, and affected horses were identified throughout the United States. Further studies to determine changes in annual incidence and to identify potential changing climatic conditions or vector populations associated with disease transmission are warranted to help control the occurrence and spread of C pseudotuberculosis infection in horses. PMID- 25029311 TI - Diagnosis and management of Enterococcus spp infections during rehabilitation of cold-stunned Kemp's ridley turtles (Lepidochelys kempii): 50 cases (2006-2012). AB - OBJECTIVE: To evaluate clinical data for cold-stunned Kemp's ridley turtles (Lepidochelys kempii) with Enterococcus spp infections during rehabilitation. DESIGN: Retrospective case series. ANIMALS: 50 stranded cold-stunned Kemp's ridley turtles hospitalized between 2006 and 2012. PROCEDURES: Medical records for turtles from which Enterococcus spp were isolated were reviewed retrospectively, and clinical data, including morphometric data, body temperature at admission, physical examination findings, antimicrobial medication history, history of medications administered IV, environmental data, day of diagnosis, clinical signs at diagnosis, microbiological testing results, sources of positive culture results, hematologic and plasma biochemical data, cytologic and histopathologic results, radiographic findings, antimicrobial treatments, time to first negative culture result, treatment duration, results of subsequent cultures, and case outcome, were collated and analyzed. RESULTS: Enterococcus spp were isolated from bacteriologic cultures of blood, bone, joint, and respiratory tract samples and a skin lesion, with supporting evidence of infection provided by histopathologic, cytologic, and radiographic data. Positive culture results were associated with clinical problems such as lethargy, anorexia, and lameness. Most (34/43 [79%]) turtles for which an antemortem diagnosis was made survived with treatment and were released into the wild. CONCLUSIONS AND CLINICAL RELEVANCE: Cold-stunned Kemp's ridley turtles may be affected by serious Enterococcus spp infections during rehabilitation. Recognition and treatment of these infections are important for successful rehabilitation. PMID- 25029312 TI - Survey of electronic veterinary medical record adoption and use by independent small animal veterinary medical practices in Massachusetts. AB - OBJECTIVE: To estimate the proportion of independent small animal veterinary medical practices in Massachusetts that use electronic veterinary medical records (EVMRs), determine the purposes for which EVMRs are used, and identify perceived barriers to their use. DESIGN: Survey. SAMPLE: 100 veterinarians. PROCEDURES: 213 of 517 independent small animal veterinary practices operating in Massachusetts were randomly chosen for study recruitment. One veterinarian at each practice was invited by telephone to answer a hardcopy survey regarding practice demographics, medical records type (electronic, paper, or both), purposes of EVMR use, and perceived barriers to adoption. Surveys were mailed to the first 100 veterinarians who agreed to participate. Practices were categorized by record type and size (large [>= 5 veterinarians], medium [3 to 4 veterinarians], or small [1 to 2 veterinarians]). RESULTS: 84 surveys were returned; overall response was 84 of 213 (39.4%). The EVMRs were used alone or together with paper records in 66 of 82 (80.5%) practices. Large and medium-sized practices were significantly more likely to use EVMRs combined with paper records than were small practices. The EVMRs were most commonly used for ensuring billing, automating reminders, providing cost estimates, scheduling, recording medical and surgical information, and tracking patient health. Least common uses were identifying emerging infectious diseases, research, and insurance. Eleven veterinarians in paper record-only practices indicated reluctance to change, anticipated technological problems, time constraints, and cost were barriers to EVMR use. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated EVMRs were underutilized as a tool for tracking and improving population health and identifying emerging infectious diseases. Efforts to facilitate adoption of EVMRs for these purposes should be strengthened by the veterinary medical, human health, and public health professions. PMID- 25029313 TI - Rabies in rodents and lagomorphs in the United States, 1995-2010. AB - OBJECTIVE: To assess the epidemiology of rabies in rodents and lagomorphs and provide information that will enable public health officials to make recommendations regarding postexposure prophylaxis for humans after contact with these animals. DESIGN: Cross-sectional epidemiological analysis. SAMPLE: Rodents and lagomorphs submitted to state laboratories for rabies diagnosis from 1995 through 2010. PROCEDURES: Positive samples were identified by use of direct fluorescent antibody testing, typed by sequencing of viral genes, and quantified via titration in mice or cell culture. RESULTS: 737 rabid rodents and lagomorphs were reported from 1995 through 2010, which represented a 62.3% increase, compared with the number of rabid rodents and lagomorphs reported from 1979 through 1994. The most commonly reported rodents or lagomorphs were groundhogs (Marmota monax). All animals submitted to the CDC for additional viral characterization were positive for the raccoon rabies virus variant. Infectious virus or viral RNA was detected in salivary glands or oral cavity tissues in 11 of 13 rabid rodents. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in reported rabid rodents, compared with results of previous studies, appeared to be associated with spillover infections from the raccoon rabies epizootic during the first half of the study period. Analysis supported the assumption that rabies remained rare in rodents and lagomorphs. However, transmission of rabies virus via exposure to a rabid rodent or lagomorph may be possible. Given the rarity of rabies in these species, diagnostic testing and consideration of postexposure prophylaxis for humans with potential exposures should be considered on a case-by case basis. PMID- 25029314 TI - Are there repercussions associated with pregnancy-related attrition? PMID- 25029318 TI - Montagna symposium 2013-light and skin: how light sustains, damages, treats, images and modifies skin biology. PMID- 25029319 TI - The thinning top: why old people have less hair. AB - Changes in the hair cycle underlie age-related alopecia, but the causative mechanisms have remained unclear. Chen et al. point to an imbalance between stem cell-activating and -inhibitory signals as the key determinant of age-related regenerative decline. Further, they identify a secreted protein, follistatin, that may be able to shift the balance toward renewal. PMID- 25029320 TI - Toxic interaction between Th2 cytokines and Staphylococcus aureus in atopic dermatitis. AB - Patients with atopic dermatitis (AD) are commonly colonized/infected with Staphylococcus aureus, and this bacterium is known to worsen the dermatitis. In this issue, Brauweiler et al. demonstrate a newly discovered mechanism by which Th2 cytokines involved in AD augment the toxicity of the lytic staphylococcal protein alpha toxin. This review presents mechanisms by which Th2 cytokines may interact with S. aureus to the detriment of the dermatitis. PMID- 25029321 TI - A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis. AB - Atopic dermatitis (AD) is associated with the effects of T helper type 2 (Th2) and Th22 cytokines. Recent studies, however, have also implicated Th17 in acute AD. Functional studies of Th2 and Th22 cytokines revealed their roles in generating molecular changes during AD; IL-17A's role, however, has yet to be defined. The report by Nakajima et al. (this issue) begins to define that role by demonstrating IL-17A's ability to induce Th2 inflammation in acute disease. PMID- 25029322 TI - Oxidative stress and vitiligo: the Nrf2-ARE signaling connection. AB - Hypersensitivity of epidermal melanocytes to oxidative stress is known to contribute to vitiligo pathogenesis. Molecular mechanisms that connect melanocyte redox homeostasis to the complex disease phenotype are not fully understood. Jian et al. show that vitiligo melanocytes have impaired nuclear factor erythroid 2 related factor 2 (Nrf2)-antioxidant response element signaling and decreased activation of the antioxidant enzyme system. In patients with vitiligo, higher serum levels of IL-2 correlate with lower levels of hemeoxygenase-1, a product of the Nrf2 target gene. PMID- 25029323 TI - Nagashima-type palmoplantar keratosis: a common Asian type caused by SERPINB7 protease inhibitor deficiency. AB - Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive diffuse non-epidermolytic palmoplantar keratosis caused by mutations in SERPINB7, a member of the serine protease inhibitor superfamily. Genetic studies suggest that NPPK is the most common palmoplantar keratosis in Japan, and probably Asia, but one that is extremely rare in Western countries. In this issue, Yin et al. report a founder effect of a SERPINB7 mutation in Chinese populations. PMID- 25029324 TI - JID VisualDx Quiz: August 2014: pemphigus foliaceus. PMID- 25029325 TI - Use of induced pluripotent stem cells in dermatological research. PMID- 25029326 TI - Cells to surgery quiz: August 2014: reactive oxygen species mediate photoaging. PMID- 25029329 TI - The chemical induction of seizures in psychiatric therapy: were flurothyl (indoklon) and pentylenetetrazol (metrazol) abandoned prematurely? AB - BACKGROUND: Camphor-induced and pentylenetetrazol-induced brain seizures were first used to relieve psychiatric illnesses in 1934. Electrical inductions (electroconvulsive therapy, ECT) followed in 1938. These were easier and less expensive to administer and quickly became the main treatment method. In 1957, seizure induction with the inhalant anesthetic flurothyl was tested and found to be clinically effective.For many decades, complaints of memory loss have stigmatized and inhibited ECT use. Many variations of electricity in form, electrode placement, dosing, and stimulation method offered some relief, but complaints still limit its use. METHODS: The experience with chemical inductions of seizures was reviewed based on searches for reports of each agent in Medline and in the archival files of original studies by the early investigators. FINDINGS: Camphor injections were inefficient and were rapidly replaced by pentylenetetrazol. These were effective but difficult to administer. Flurothyl inhalation-induced seizures were as clinically effective as electrical inductions with lesser effects on memory functions. Flurothyl inductions were discarded because of the persistence of the ethereal aroma and the fears induced in the professional staff that they might seize. CONCLUSIONS: Persistent complaints of memory loss plague electricity induced seizures. Flurothyl induced seizures are clinically as effective without the memory effects associated with electricity. Reexamination of seizure inductions using flurothyl in modern anesthesia facilities is encouraged to relieve medication-resistant patients with mood disorders and catatonia. PMID- 25029330 TI - Patient-specific cortical electrodes for sulcal and gyral implantation. AB - PURPOSE: Noninvasive localization of certain brain functions may be mapped on a millimetre level. However, the interelectrode spacing of common clinical brain surface electrodes still remains around 10 mm. Here, we present details on development of electrodes for attaining higher quality electrocorticographic signals for use in functional brain mapping and brain-machine interface (BMI) technologies. METHODS: We used platinum-plate-electrodes of 1-mm diameter to produce sheet electrodes after the creation of individualized molds using a 3-D printer and a press system that sandwiched the electrodes between personalized silicone sheets. RESULTS: We created arrays to fit the surface curvature of the brain and inside the central sulcus, with interelectrode distances of 2.5 mm (a density of 16 times previous standard types). Rat experiments undertaken indicated no long term toxicity. We were also able to custom design, rapidly manufacture, safely implant, and confirm the efficacy of personalized electrodes, including the capability to attain meaningful high-gamma-band information in an amyotrophic lateral sclerosis patient. CONCLUSION: We developed cortical sheet electrodes with a high-spatial resolution, tailor-made to match an individual's brain. SIGNIFICANCE: This sheet electrode may contribute to the higher performance of BMI's. PMID- 25029332 TI - Choosing the correct metrics for glucose control. PMID- 25029333 TI - Development and validation of a modelling framework for simulating 2D-mammography and breast tomosynthesis images. AB - Planar 2D x-ray mammography is generally accepted as the preferred screening technique used for breast cancer detection. Recently, digital breast tomosynthesis (DBT) has been introduced to overcome some of the inherent limitations of conventional planar imaging, and future technological enhancements are expected to result in the introduction of further innovative modalities. However, it is crucial to understand the impact of any new imaging technology or methodology on cancer detection rates and patient recall. Any such assessment conventionally requires large scale clinical trials demanding significant investment in time and resources. The concept of virtual clinical trials and virtual performance assessment may offer a viable alternative to this approach. However, virtual approaches require a collection of specialized modelling tools which can be used to emulate the image acquisition process and simulate images of a quality indistinguishable from their real clinical counterparts. In this paper, we present two image simulation chains constructed using modelling tools that can be used for the evaluation of 2D-mammography and DBT systems. We validate both approaches by comparing simulated images with real images acquired using the system being simulated. A comparison of the contrast-to-noise ratios and image blurring for real and simulated images of test objects shows good agreement ( < 9% error). This suggests that our simulation approach is a promising alternative to conventional physical performance assessment followed by large scale clinical trials. PMID- 25029334 TI - Evaluating the stress response as a bioindicator of sub-lethal effects of crude oil exposure in wild house sparrows (Passer domesticus). AB - Petroleum can disrupt endocrine function in humans and wildlife, and interacts in particularly complex ways with the hypothalamus-pituitary-adrenal (HPA) axis, responsible for the release of the stress hormones corticosterone and cortisol (hereafter CORT). Ingested petroleum can act in an additive fashion with other stressors to cause increased mortality, but it is not clear exactly why--does petroleum disrupt feedback mechanisms, stress hormone production, or both? This laboratory study aimed to quantify the effects of ingested Gulf of Mexico crude oil on the physiological stress response of house sparrows (Passer domesticus). We examined baseline and stress-induced CORT, negative feedback, and adrenal sensitivity in house sparrows given a 1% oil or control diet (n = 12 in each group). We found that four weeks on a 1% oil diet did not alter baseline CORT titers or efficacy of negative feedback, but significantly reduced sparrows' ability to secrete CORT in response to a standardized stressor and adrenocorticotropin hormone injection, suggesting that oil damages the steroid synthesizing cells of the adrenal. In another group of animals on the same 1% oil (n = 9) or control diets (n = 8), we examined concentrations of eight different blood chemistry parameters, and CORT in feathers grown before and during the feeding experiments as other potential biomarkers of oil exposure. None of the blood chemistry parameters differed between birds on the oil and control diets after two or four weeks of feeding, nor did feather CORT differ between the two groups. Overall, this study suggests that the response of CORT to stressors, but not baseline HPA function, may be a particularly sensitive bioindicator of sub lethal chronic effects of crude oil exposure. PMID- 25029336 TI - STING-associated vasculopathy with onset in infancy--a new interferonopathy. PMID- 25029337 TI - Money, sex, and religion--the Supreme Court's ACA sequel. PMID- 25029335 TI - Activated STING in a vascular and pulmonary syndrome. AB - BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-beta, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.). PMID- 25029338 TI - Obesity and contraception. AB - Utilizing contraception is critical in preventing unintended pregnancies among obese women. However, clinicians and obese patients may be unclear about which contraceptive methods are optimal. This review discusses the literature on any weight gain associated with contraceptive use, contraceptive efficacy among obese women, and special considerations for contraceptive method selection for women after bariatric surgery. The review also covers new findings on oral emergency contraception and obesity. PMID- 25029339 TI - Acute and chronic tocolysis. AB - Preterm birth occurs in 12% of all births in the United States. Preterm labor precedes approximately half of these births. Tocolysis is used in the short term to prolong pregnancy long enough to administer corticosteroids and/or facilitate transfer to a tertiary care center. A number of agents have been used for this therapy, which will be discussed in the following chapter. PMID- 25029340 TI - Leukodepleted versus nonleukodepleted red blood cell transfusion in septic patients: a microcirculatory vision. AB - Storage time and residual leukocytes in red blood cell (RBC) units may be deleterious by increasing the accumulation of leukocyte-derived cytokines and by raising the adhesion of RBCs to endothelium. Leukodepleted RBC transfusion may reduce the incidence of infection and organ dysfunction. However, the influence of leukodepletion on microcirculation remains not well defined in ICU patients. In this context, an original study in a previous issue of Critical Care emphasizes the microcirculatory effects of transfusion of leukodepleted RBCs (post-storage leukoreduction) or nonleukodepleted RBCs in septic patients. This study suggests a positive rheological impact of leukodepleted RBCs in septic patients with an increase in sublingual microvascular flow and perfused vessel density. Given the variability in the microvascular response to RBC transfusion in individual patients, there is a need for monitoring the microcirculation to guide transfusion in patients with sepsis rather than deciding to transfuse RBCs according to an arbitrary hemoglobin level. Further studies to identify the microvascular response to RBC transfusion in ICU patients are warranted. PMID- 25029341 TI - Intramuscular Lipoma of Superior Rectus Muscle. AB - The authors describe a case of a 27-year-old man with progressive diplopia and proptosis in whom imaging studies revealed the presence of a mass in the superior rectus muscle. Biopsy showed an infiltrative tumor of mature adipocytes with striated muscle fibres, corresponding to an intramuscular lipoma. Although extraocular muscle lipomas are very rare, with only two cases reported, they must be considered in the differential diagnosis of an orbital mass. They may cause significant morbidity to the patient, thus requiring surgical removal. Complete excision is usually difficult because of their infiltrative nature to the surrounding muscular fibres and their tendency to recur. PMID- 25029342 TI - Pneumocystis pneumonia in HIV-infected and immunocompromised non-HIV infected patients: a retrospective study of two centers in China. AB - BACKGROUND: Pneumocystis pneumonia (PCP) is an emerging infectious disease in immunocompromised hosts. However, the clinical characteristics of these patients are poorly understood in mainland China. METHODS: We performed a retrospective study of PCP from 2008 to 2012. Information was collected regarding clinical manifestations, hospitalization, and outcome. A prognostic analysis was performed using a Cox regression model. RESULTS: 151 cases of PCP were included; 46 non-HIV and 105 HIV cases. All-cause mortality (15.2% vs. 12.4%, p = 0.64) and the results of time-to-event analysis (log-rank test, p = 0.62) were similar between non-HIV and HIV infected cases, respectively. From 2008 to 2012, time from admission to initial treatment in non-HIV infected PCP patients showed declining trend [median (range) 20 (9-44) vs. 12 (4-24) vs. 9 (2-23) vs. 7 (2-22) vs. 7 (1 14) days]. A similar trend was observed for all-cause mortality (33.3% vs. 20.0% vs.14.3% vs. 14.3% vs. 6.7%). Patients with four or more of the following clinical manifestations (cough, dyspnea, fever, chest pain, and weight loss) [adjusted HR (AHR) 29.06, 95% CI 2.13-396.36, P = 0.01] and admission to intensive care unit (ICU) [AHR 22.55, 95% CI 1.36-375.06, P = 0.03] were independently associated with all-cause mortality in non-HIV infected PCP patients. Variables associated with mortality in HIV infected PCP patients were admission to ICU (AHR 72.26, 95% CI 11.76-443.87, P<0.001) and albumin <= 30 g/L (AHR 9.93 95% CI 1.69-58.30, P = 0.01). CONCLUSIONS: Upon admission comprehensive clinical assessment including assessment of four or more clinical manifestations (cough, dyspnea, fever, chest pain, and weight loss) in non-HIV infected PCP patients and albumin <= 30 g/L in HIV infected patients might improve prognosis. PMID- 25029343 TI - Neuroinflammation and neurodegeneration in adult rat brain from binge ethanol exposure: abrogation by docosahexaenoic acid. AB - Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ~ 9 g/kg/d, achieving blood ethanol levels ~ 375 mg/dl; "Majchrowicz" model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA (p-cPLA2), secretory PLA2 GIIA (sPLA2) and PARP-1 in regions incurring extensive neurodegeneration in this model--hippocampus, entorhinal cortex, and olfactory bulb--but not in two regions typically lacking neurodamage, frontal cortex and cerebellum. Also, ethanol reduced hippocampal Ca+2-independent PLA2 GVIA (iPLA2) levels and increased brain "oxidative stress footprints" (4-hydroxynonenal-adducted proteins). For in vitro studies, organotypic cultures of rat hippocampal-entorhinocortical slices of adult age (~ 60 d) were ethanol-binged (100 mM or ~ 450 mg/dl) for 4 d, which augments AQP4 and causes neurodegeneration (Collins et al. 2013). Reproducing the in vivo results, cPLA2, p-cPLA2, sPLA2 and PARP-1 were significantly elevated while iPLA2 was decreased. Furthermore, supplementation with docosahexaenoic acid (DHA; 22:6n-3), known to quell AQP4 and neurodegeneration in ethanol-treated slices, blocked PARP-1 and PLA2 changes while counteracting endogenous DHA reduction and increases in oxidative stress footprints (3-nitrotyrosinated proteins). Notably, the PARP-1 inhibitor PJ-34 suppressed binge ethanol-dependent neurodegeneration, indicating PARP upstream involvement. The results with corresponding models support involvement of AQP4- and PLA2-associated neuroinflammatory pro-oxidative pathways in the neurodamage, with potential regulation by PARP-1 as well. Furthermore, DHA emerges as an effective inhibitor of these binge ethanol-dependent neuroinflammatory pathways as well as associated neurodegeneration in adult-age brain. PMID- 25029344 TI - Biomarkers and acute brain injuries: interest and limits. AB - For patients presenting with acute brain injury (such as traumatic brain injury, subarachnoid haemorrhage and stroke), the diagnosis and identification of intracerebral lesions and evaluation of the severity, prognosis and treatment efficacy can be challenging. The complexity and heterogeneity of lesions after brain injury are most probably responsible for this difficulty. Patients with apparently comparable brain lesions on imaging may have different neurological outcomes or responses to therapy. In recent years, plasmatic and cerebrospinal fluid biomarkers have emerged as possible tools to distinguish between the different pathophysiological processes. This review aims to summarise the plasmatic and cerebrospinal fluid biomarkers evaluated in subarachnoid haemorrhage, traumatic brain injury and stroke, and to clarify their related interests and limits for diagnosis and prognosis. For subarachnoid haemorrhage, particular interest has been focused on the biomarkers used to predict vasospasm and cerebral ischaemia. The efficacy of biomarkers in predicting the severity and outcome of traumatic brain injury has been stressed. The very early diagnostic performance of biomarkers and their ability to discriminate ischaemic from haemorrhagic stroke were studied. PMID- 25029345 TI - Suppression of tumor growth by Pleurotus ferulae ethanol extract through induction of cell apoptosis, and inhibition of cell proliferation and migration. AB - Cancer is the second leading cause of death worldwide. Edible medicinal mushrooms have been used in traditional medicine as regimes for cancer patients. Recently anti-cancer bioactive components from some mushrooms have been isolated and their anti-cancer effects have been tested. Pleurotus ferulae, a typical edible medicinal mushroom in Xinjiang China, has also been used to treat cancer patients in folk medicine. However, little studies have been reported on the anti-cancer components of Pleurotus ferulae. This study aims to extract bioactive components from Pleurotus ferulae and to investigate the anti-cancer effects of the extracts. We used ethanol to extract anti-cancer bioactive components enriched with terpenoids from Pleurotus ferulae. We tested the anti-tumour effects of ethanol extracts on the melanoma cell line B16F10, the human gastric cancer cell line BGC 823 and the immortalized human gastric epithelial mucosa cell line GES-1 in vitro and a murine melanoma model in vivo. Cell toxicity and cell proliferation were measured by MTT assays. Cell cycle progression, apoptosis, caspase 3 activity, mitochondrial membrane potential (MMP), migration and gene expression were studied in vitro. PFEC suppressed tumor cell growth, inhibited cell proliferation, arrested cells at G0/G1 phases and was not toxic to non cancer cells. PFEC also induced cell apoptosis and necrosis, increased caspase 3 activity, reduced the MMP, prevented cell invasion and changed the expression of genes associated with apoptosis and the cell cycle. PFEC delayed tumor formation and reduced tumor growth in vivo. In conclusion, ethanol extracted components from Pleurotus ferulae exert anti-cancer effects through direct suppression of tumor cell growth and invasion, demonstrating its therapeutic potential in cancer treatment. PMID- 25029346 TI - Soil biochemical responses to nitrogen addition in a bamboo forest. AB - Many vital ecosystem processes take place in the soils and are greatly affected by the increasing active nitrogen (N) deposition observed globally. Nitrogen deposition generally affects ecosystem processes through the changes in soil biochemical properties such as soil nutrient availability, microbial properties and enzyme activities. In order to evaluate the soil biochemical responses to elevated atmospheric N deposition in bamboo forest ecosystems, a two-year field N addition experiment in a hybrid bamboo (Bambusa pervariabilis * Dendrocalamopsis daii) plantation was conducted. Four levels of N treatment were applied: (1) control (CK, without N added), (2) low-nitrogen (LN, 50 kg N ha(-1) year(-1)), (3) medium-nitrogen (MN, 150 kg N ha(-1) year(-1)), and (4) high-nitrogen (HN, 300 kg N ha(-1) year(-1)). Results indicated that N addition significantly increased the concentrations of NH4(+), NO3(-), microbial biomass carbon, microbial biomass N, the rates of nitrification and denitrification; significantly decreased soil pH and the concentration of available phosphorus, and had no effect on the total organic carbon and total N concentration in the 0 20 cm soil depth. Nitrogen addition significantly stimulated activities of hydrolytic enzyme that acquiring N (urease) and phosphorus (acid phosphatase) and depressed the oxidative enzymes (phenol oxidase, peroxidase and catalase) activities. Results suggest that (1) this bamboo forest ecosystem is moving towards being limited by P or co-limited by P under elevated N deposition, (2) the expected progressive increases in N deposition may have a potential important effect on forest litter decomposition due to the interaction of inorganic N and oxidative enzyme activities, in such bamboo forests under high levels of ambient N deposition. PMID- 25029347 TI - Impact of osteopathic treatment on pain in adult patients with cystic fibrosis--a pilot randomized controlled study. AB - BACKGROUND: Pain is a common complication in patients with cystic fibrosis (CF) and is associated with shorter survival. We evaluated the impact of osteopathic manipulative treatment (OMT) on pain in adults with CF. METHODS: A pilot multicenter randomized controlled trial was conducted with three parallel arms: OMT (group A, 16 patients), sham OMT (sham treatment, group B, 8 patients) and no treatment (group C, 8 patients). Medical investigators and patients were double blind to treatment for groups A and B, who received OMT or sham OMT monthly for 6 months. Pain was rated as a composite of its intensity and duration over the previous month. The evolution of chest/back pain after 6 months was compared between group A and groups B+C combined (control group). The evolution of cervical pain, headache and quality of life (QOL) were similarly evaluated. RESULTS: There was no statistically significant difference between the treatment and control groups in the decrease of chest/back pain (difference = -2.20 IC95% [ 4.81; 0.42], p = 0.098); also, group A did not differ from group B. However, chest/back pain decreased more in groups A (p = 0.002) and B (p = 0.006) than in group C. Cervical pain, headache and QOL scores did not differ between the treatment and control groups. CONCLUSION: This pilot study demonstrated the feasibility of evaluating the efficacy of OMT to treat the pain of patients with CF. The lack of difference between the group treated with OMT and the control group may be due to the small number of patients included in this trial, which also precludes any definitive conclusion about the greater decrease of pain in patients receiving OMT or sham OMT than in those with no intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01293019. PMID- 25029348 TI - Assessing pragmatic language in autism spectrum disorder: the Yale in vivo Pragmatic Protocol. AB - PURPOSE: This study compared pragmatic language in youths (9-17 years) with autism spectrum disorder (ASD) and those with typical development (TD) on the Yale in vivo Pragmatic Protocol (YiPP), a semistructured, dynamic conversational assessment. METHOD: Participants (n = 118) were divided into groups based on age and diagnosis. Each completed the YiPP, which included 4 pragmatic domains (discourse management, communicative functions, conversational repair, presupposition). The participant's response to each probe was scored correct or incorrect; incorrect scores elicited cues from the examiner, and level of cue required for a correction was also scored. RESULTS: The YiPP showed high reliability and internal consistency, with moderate concurrent validity, sensitivity, and specificity. The group with ASD performed worse overall on YiPP probes compared to their TD counterparts on both error (d = 0.96) and cue (d = 0.91) scores. Item analyses revealed greater gaps between older students with ASD and their TD peers than between the 2 younger groups. CONCLUSIONS: These data suggest that a probe measure designed to assess pragmatic abilities in children with ASD within a conversational context has some validity for contributing to diagnostic classification and can identify specific areas of pragmatic vulnerabilities as part of a clinical assessment. PMID- 25029350 TI - [Radiology: Technology for people]. PMID- 25029349 TI - Rhinovirus infection induces interleukin-13 production from CD11b-positive, M2 polarized exudative macrophages. AB - Rhinovirus (RV) causes asthma exacerbations. Previously, we showed that adherent bronchoalveolar cells from allergen-treated mice produce IL-13 when stimulated with RV ex vivo, implicating cells of the monocyte/macrophage lineage in viral induced airway inflammation. In this study, we hypothesized that RV infection of allergen-treated mice results in IL-13 production by CD11b+ exudative macrophages in vivo. We sensitized and challenged BALB/c mice with ovalbumin (OVA), after which mice were inoculated with RV or sham HeLa cell lysate. After 1 day, lungs were harvested, and cell suspensions were analyzed by flow cytometry. We repeated this process in IL-13 reporter mice, CD11b-DTR mice in which diphtheria toxin selectively depletes CD11b+ cells, and chemokine receptor 2 (CCR2) null mice. We found that lungs of mice infected with RV alone showed increases in CD45+, CD68+, F4/80+, Ly6C+, and CD11b(high) cells, indicating an influx of inflammatory monocytes and exudative macrophages. The combination of OVA and RV had synergistic effects on the exudative macrophage number. However, CD11b+ cells from OVA-treated, RV-infected mice showed M2 polarization, including expression of CD206 and CD301 and production of IL-13. Similar results were obtained in IL 13 reporter mice. Diphtheria toxin depleted CD11b+, IL-13-producing cells in OVA treated, RV-infected, CD11b-DTR mice, decreasing airway inflammation and responsiveness. CD11b+, Ly6C+ cells were reduced in CCR2 knockout mice. We conclude that, in contrast to naive mice, RV infection of mice with allergic airways disease induces an influx of IL-13-producing CD11b+ exudative macrophages bearing M2 macrophage markers. This finding further implicates alternatively activated macrophages in RV-induced asthma exacerbations. PMID- 25029351 TI - Physical and energy requirements of competitive swimming events. AB - The aquatic sports competitions held during the summer Olympic Games include diving, open-water swimming, pool swimming, synchronized swimming, and water polo. Elite-level performance in each of these sports requires rigorous training and practice to develop the appropriate physiological, biomechanical, artistic, and strategic capabilities specific to each sport. Consequently, the daily training plans of these athletes are quite varied both between and within the sports. Common to all aquatic athletes, however, is that daily training and preparation consumes several hours and involves frequent periods of high intensity exertion. Nutritional support for this high-level training is a critical element of the preparation of these athletes to ensure the energy and nutrient demands of the training and competition are met. In this article, we introduce the fundamental physical requirements of these sports and specifically explore the energetics of human locomotion in water. Subsequent articles in this issue explore the specific nutritional requirements of each aquatic sport. We hope that such exploration will provide a foundation for future investigation of the roles of optimal nutrition in optimizing performance in the aquatic sports. PMID- 25029352 TI - Impairment of hepatocellular excretory function, sepsis and liver insufficiency after liver resection. PMID- 25029353 TI - Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability. AB - While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 +/- 8 vs. 61 +/- 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 * 10( 4), N = 12). These results suggest that serotonin is implicated in aspirin response variability. PMID- 25029354 TI - Immunomodulatory properties of carbon nanotubes are able to compensate immune function dysregulation caused by microgravity conditions. AB - Spaceflights lead to dysregulation of the immune cell functionality affecting the expression of activation markers and cytokine production. Short oxidized multi walled carbon nanotubes functionalized by 1,3-dipolar cycloaddition have been reported to activate immune cells. In this Communication we have performed surface marker assays and multiplex ELISA on primary monocytes and T cells under microgravity. We have discovered that carbon nanotubes, through their immunostimulatory properties, are able to fight spaceflight immune system dysregulations. PMID- 25029355 TI - Selective access to E- and Z-DeltaIle-containing peptides via a stereospecific E2 dehydration and an O -> N acyl transfer. AB - A concise synthesis of peptides that contain E- or Z-dehydroisoleucine (DeltaIle) residues is reported. The key reaction is an unusual anti dehydration of beta tert-hydroxy amino acid derivatives that is mediated by the Martin sulfurane. A subsequent tandem Staudinger reduction-O -> N acyl transfer process forges an amide bond to the DeltaIle residue with minimal E/Z alkene isomerization. Density functional calculations attribute the stereospecific dehydration to a highly asynchronous E2 anti process. PMID- 25029356 TI - Recycling potential of neodymium: the case of computer hard disk drives. AB - Neodymium, one of the more critically scarce rare earth metals, is often used in sustainable technologies. In this study, we investigate the potential contribution of neodymium recycling to reducing scarcity in supply, with a case study on computer hard disk drives (HDDs). We first review the literature on neodymium production and recycling potential. From this review, we find that recycling of computer HDDs is currently the most feasible pathway toward large scale recycling of neodymium, even though HDDs do not represent the largest application of neodymium. We then use a combination of dynamic modeling and empirical experiments to conclude that within the application of NdFeB magnets for HDDs, the potential for loop-closing is significant: up to 57% in 2017. However, compared to the total NdFeB production capacity, the recovery potential from HDDs is relatively small (in the 1-3% range). The distributed nature of neodymium poses a significant challenge for recycling of neodymium. PMID- 25029357 TI - Depletion of penicillin G residues in heavy sows after intramuscular injection. Part II: application of kidney inhibition swab tests. AB - Sows (n = 126; 228 +/- 30.1 kg) were administered daily IM doses of penicillin G procaine (33 000 IU/kg bw; 5* the label dose) for 3 consecutive days using three different administration patterns. Within treatment, six sows each were slaughtered on withdrawal day 5, 10, 15, 20, 25, 32, and 39. Tissues (injection site, kidney, liver, skeletal muscle) or body fluids (serum and urine) were screened for penicillin G using the KIS test, recently adopted by the USDA Food Safety and Inspection Service. The IM administration patterns had no discernible effect on penicillin G depletion. Residues were depleted more rapidly from liver and skeletal muscle and more slowly from kidney and urine. Kidney was the most sensitive and suitable tissue for detecting penicillin G residues on-site, with two positive results after a 39-day withdrawal period. Urine was the most suitable ante-mortem surrogate to predict the results of kidney tests. PMID- 25029358 TI - Synthesis of hierarchical iron hydrogen phosphate crystal as a robust peroxidase mimic for stable H2O2 detection. AB - To develop a green, cost-efficient and robust peroxidase mimic, micro/nano hierarchical morphology (for ease of separation and reuse), relative chemically stable composition (for ease of storage) and stable crystal structure (for long term stability) are highly desired. Herein, using phosphoric acid as a chelating ligand to control the release of iron ions, hierarchical iron(III) hydrogen phosphate hydrate crystals are successfully prepared by nanosheets formation and following self-assembling in a facile low-temperature hydrothermal process. They are first found to have peroxidase-like activity and showed higher affinity for H2O2 and lower affinity for 3,3',5,5'-tetramethylbenzidine compared with horseradish peroxidase. The affinity feature is used for quantitative detection of H2O2 and shows a wide linear detection range from 57.4 to 525.8 MUM (R(2) = 0.994) with a low detection limit of 1 MUM. Benefited from chemical stability of hierarchical iron(III) salt crystals, they own good reproducibility (relative standard deviation = 1.95% for 10 independent measurements), long-term stability (no activity loss after 10 cycles), and ease of recovery (by simple centrifugation). Because the method is easily accessible, iron hydrogen phosphate hierarchical crystals have great potential for practical use of H2O2 sensing and detection under harsh conditions. PMID- 25029359 TI - iSPIES--a novel approach to advanced endoscopic imaging. PMID- 25029360 TI - How surface potential determines the kinetics of the first hole transfer of photocatalytic water oxidation. AB - Interfacial hole transfer between n-SrTiO3 and OH(-) was investigated by surface sensitive transient optical spectroscopy of an in situ photoelectrochemical cell during water oxidation. The kinetics reveal a single rate constant with an exponential dependence on the surface hole potential, spanning time scales from 3 ns to 8 ps over a ~1 V increase. A voltage- and laser illumination-induced process moves the valence band edge at the n-type semiconductor/water interface to continuously change the surface hole potential. This single step of the water oxidation reaction is assigned to the first hole transfer h(+) + OH(-) -> OH(*). The kinetics quantify how much a change in the free energy difference driving this first hole transfer reduces the activation barrier. They are also used to extrapolate the kinetic rate due to the activation barrier when that free energy difference is zero, or the Nernstian potential. This is the first time transient spectroscopy has enabled the separation of the first hole transfer from the full four hole transfer cycle and a direct determination of these two quantities. The Nernstian potential for OH(-)/OH(*) is also suggested, in rough agreement with gas-phase studies. The observation of a distinct, much longer time scale upon picosecond hole transfer to OH(-) suggests that a dominant, more stable intermediate of the water oxidation reaction, possibly a surface bound oxo, may result. PMID- 25029361 TI - Antiproliferative action of aqueous extracts of Hymenaea stigonocarpa Mart. (Fabaceae) on the cell cycle of Allium cepa L. AB - In this study we evaluated the action of crude aqueous extracts obtained from rhytidome of Hymenaea stigonocarpa (jatoba-do-cerrado) on Allium cepa meristematic root cells in three concentrations: 0.082, 0.164, 0.328g/mL, at exposure times of 24 and 48 h. The slides were prepared by the crushing technique, and cells analyzed throughout the cell cycle, totaling 5000 for each control group and concentration. It was found that all three concentrations, including the lowest which is considered ideal for use, in all exposure times, had significant antiproliferative action on the cell cycle of this test system. For cells under division, we observed a high number of cells in prophase. Therefore, under the conditions studied H. stigonocarpa indicated to be cytotoxic. PMID- 25029362 TI - Distinct human and mouse membrane trafficking systems for sweet taste receptors T1r2 and T1r3. AB - The sweet taste receptors T1r2 and T1r3 are included in the T1r taste receptor family that belongs to class C of the G protein-coupled receptors. Heterodimerization of T1r2 and T1r3 is required for the perception of sweet substances, but little is known about the mechanisms underlying this heterodimerization, including membrane trafficking. We developed tagged mouse T1r2 and T1r3, and human T1R2 and T1R3 and evaluated membrane trafficking in human embryonic kidney 293 (HEK293) cells. We found that human T1R3 surface expression was only observed when human T1R3 was coexpressed with human T1R2, whereas mouse T1r3 was expressed without mouse T1r2 expression. A domain-swapped chimera and truncated human T1R3 mutant showed that the Venus flytrap module and cysteine-rich domain (CRD) of human T1R3 contain a region related to the inhibition of human T1R3 membrane trafficking and coordinated regulation of human T1R3 membrane trafficking. We also found that the Venus flytrap module of both human T1R2 and T1R3 are needed for membrane trafficking, suggesting that the coexpression of human T1R2 and T1R3 is required for this event. These results suggest that the Venus flytrap module and CRD receive taste substances and play roles in membrane trafficking of human T1R2 and T1R3. These features are different from those of mouse receptors, indicating that human T1R2 and T1R3 are likely to have a novel membrane trafficking system. PMID- 25029364 TI - Consentaneous agent-based and stochastic model of the financial markets. AB - We are looking for the agent-based treatment of the financial markets considering necessity to build bridges between microscopic, agent based, and macroscopic, phenomenological modeling. The acknowledgment that agent-based modeling framework, which may provide qualitative and quantitative understanding of the financial markets, is very ambiguous emphasizes the exceptional value of well defined analytically tractable agent systems. Herding as one of the behavior peculiarities considered in the behavioral finance is the main property of the agent interactions we deal with in this contribution. Looking for the consentaneous agent-based and macroscopic approach we combine two origins of the noise: exogenous one, related to the information flow, and endogenous one, arising form the complex stochastic dynamics of agents. As a result we propose a three state agent-based herding model of the financial markets. From this agent based model we derive a set of stochastic differential equations, which describes underlying macroscopic dynamics of agent population and log price in the financial markets. The obtained solution is then subjected to the exogenous noise, which shapes instantaneous return fluctuations. We test both Gaussian and q-Gaussian noise as a source of the short term fluctuations. The resulting model of the return in the financial markets with the same set of parameters reproduces empirical probability and spectral densities of absolute return observed in New York, Warsaw and NASDAQ OMX Vilnius Stock Exchanges. Our result confirms the prevalent idea in behavioral finance that herding interactions may be dominant over agent rationality and contribute towards bubble formation. PMID- 25029363 TI - Harmful effects of the azathioprine metabolite 6-mercaptopurine in vascular cells: induction of mineralization. AB - Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteo-chondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6 thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis. PMID- 25029365 TI - Dermatology and Dentistry Subcommittee of the 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference. PMID- 25029366 TI - Three-dimensional reconstructions come to life--interactive 3D PDF animations in functional morphology. AB - Digital surface mesh models based on segmented datasets have become an integral part of studies on animal anatomy and functional morphology; usually, they are published as static images, movies or as interactive PDF files. We demonstrate the use of animated 3D models embedded in PDF documents, which combine the advantages of both movie and interactivity, based on the example of preserved Trigonopterus weevils. The method is particularly suitable to simulate joints with largely deterministic movements due to precise form closure. We illustrate the function of an individual screw-and-nut type hip joint and proceed to the complex movements of the entire insect attaining a defence position. This posture is achieved by a specific cascade of movements: Head and legs interlock mutually and with specific features of thorax and the first abdominal ventrite, presumably to increase the mechanical stability of the beetle and to maintain the defence position with minimal muscle activity. The deterministic interaction of accurately fitting body parts follows a defined sequence, which resembles a piece of engineering. PMID- 25029367 TI - Nature of the charged headgroup determines the fusogenic potential and membrane properties of lithocholic acid phospholipids. AB - Phospholipids play a crucial role in many cellular processes ranging from selective membrane permeability, to membrane fission and fusion, to cellular signaling. Headgroups of phospholipids determine the membrane properties and fusogenicity of these lipids with target cell membranes. We studied the fusogenic and membrane properties of phospholipids possessing unnatural charged headgroups with model membranes using laurdan based membrane hydration studies, DPH based membrane fluidity, and differential scanning calorimetry. We unravel that fusogenicity, membrane hydration, and fluidity of membranes are strongly contingent on the nature of the phospholipid charged headgroup. Our studies unraveled that introduction of bulky headgroups like dimethylamino pyridine induces maximum membrane hydration and perturbations with high fusogenicity as compared to small headgroup based phospholipids. These phospholipids also have the capability of high retention in DPPC membranes. Hydration and fluidity of these phospholipid-doped DPPC membranes are contingent on the nature of the charged headgroup. This study would help in future design of phospholipid based nanomaterials for effective drug delivery. PMID- 25029369 TI - Genetic assessments and parentage analysis of captive Bolson tortoises (Gopherus flavomarginatus) inform their "rewilding" in New Mexico. AB - The Bolson tortoise (Gopherus flavomarginatus) is the first species of extirpated megafauna to be repatriated into the United States. In September 2006, 30 individuals were translocated from Arizona to New Mexico with the long-term objective of restoring wild populations via captive propagation. We evaluated mtDNA sequences and allelic diversity among 11 microsatellite loci from the captive population and archived samples collected from wild individuals in Durango, Mexico (n = 28). Both populations exhibited very low genetic diversity and the captive population captured roughly 97.5% of the total wild diversity, making it a promising founder population. Genetic screening of other captive animals (n = 26) potentially suitable for reintroduction uncovered multiple hybrid G. flavomarginatus*G. polyphemus, which were ineligible for repatriation; only three of these individuals were verified as purebred G. flavomarginatus. We used these genetic data to inform mate pairing, reduce the potential for inbreeding and to monitor the maintenance of genetic diversity in the captive population. After six years of successful propagation, we analyzed the parentage of 241 hatchlings to assess the maintenance of genetic diversity. Not all adults contributed equally to successive generations. Most yearly cohorts of hatchlings failed to capture the diversity of the parental population. However, overlapping generations of tortoises helped to alleviate genetic loss because the entire six year cohort of hatchlings contained the allelic diversity of the parental population. Polyandry and sperm storage occurred in the captives and future management strategies must consider such events. PMID- 25029368 TI - Sex specific incidence rates of type 2 diabetes and its risk factors over 9 years of follow-up: Tehran Lipid and Glucose Study. AB - OBJECTIVE: To investigate the population-based incidence of type 2 diabetes and its potential risk factors in a sex-split cohort of Iranian population. MATERIALS AND METHODS: A total of 8400 non-diabetic participants, aged >=20 years (3620 men and 4780 women) entered the study. Crude and age standardized incidence rates per 1000 person-years were calculated for whole population and each sex separately. Cox proportional hazard models were used to evaluate hazard ratios (HR) and 95% confidence intervals for all potential risk factors in both uni-variable and multivariable models. RESULTS: During a median follow-up of 9.5 years, 736 new cases of diabetes were identified, including 433 women and 303 men. The annual crude and age-standardized incidence rates (95% CI) of diabetes in the total population were 10.6 (9.92-11.4) and 9.94 (7.39-13.6) per 1000 person-years of follow-up and the corresponding sex specific rates were 10.2 (9.13-11.4) and 9.36 (5.84-14.92) in men and 11.0 (9.99-12.0) and 10.1 (7.24-13.9) in women, respectively. In the multivariable model, the risk for incident diabetes was significantly associated with fasting and 2 hour post challenge plasma glucose as well as family history of diabetes in both men and women. However, among women, only the contribution of wrist circumference to incident diabetes achieved statistical significance [HR: 1.16 (1.03-1.31)] with waist/height ratio being marginally significant [HR: 1.02 (0.99-1.04)]; while among men, only body mass index was a significant predictor [HR: 1.12 (1.02-1.22)]. Additionally, low education level conferred a higher risk for incident diabetes only among men [HR: 1.80 (1.23-2.36); P for interaction with sex = 0.003]. CONCLUSION: Overall, sex did not significantly modify the impact of risk factors associated with diabetes among Iranian adults; however, among modifiable risk factors, the independent role of lower education and general adiposity in men and central adiposity in women might require different preventive strategies. PMID- 25029370 TI - MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression. AB - Blood microRNA (miRNA) levels have been associated with and shown to participate in disease pathophysiology. However, the hematopoietic cell of origin of blood miRNAs and the individual blood cell miRNA profiles are poorly understood. We report the miRNA content of highly purified normal hematopoietic cells from the same individuals. Although T-cells, B-cells and granulocytes had the highest miRNA content per cell, erythrocytes contributed more cellular miRNA to the blood, followed by granulocytes and platelets. miRNA profiling revealed different patterns and different expression levels of miRNA specific for each lineage. miR 30c-5p was determined to be an appropriate reference normalizer for cross-cell qRT-PCR comparisons. miRNA profiling of 5 hematopoietic cell lines revealed differential expression of miR-125a-5p. We demonstrated endogenous levels of miR 125a-5p regulate reporter gene expression in Meg-01 and Jurkat cells by (1) constructs containing binding sites for miR-125a-5p or (2) over-expressing or inhibiting miR-125a-5p. This quantitative analysis of the miRNA profiles of peripheral blood cells identifies the circulating hematopoietic cellular miRNAs, supports the use of miRNA profiles for distinguishing different hematopoietic lineages and suggests that endogenously expressed miRNAs can be exploited to regulate transgene expression in a cell-specific manner. PMID- 25029371 TI - The middle X residue influences cotranslational N-glycosylation consensus site skipping. AB - Asparagine (N)-linked glycosylation is essential for efficient protein folding in the endoplasmic reticulum (ER) and anterograde trafficking through the secretory pathway. N-Glycans are attached to nascent polypeptides at consensus sites, N-X T/S (X ? P), by one of two enzymatic isoforms of the oligosaccharyltransferase (OST), STT3A or STT3B. Here, we examined the effect of the consensus site X and hydroxyl residue on the distributions of co- and post-translational N glycosylation of a type I transmembrane glycopeptide scaffold. Using rapid radioactive pulse-chase experiments to resolve co-translational (STT3A) and post translational (STT3B) events, we determined that NXS consensus sites containing large hydrophobic and negatively charged middle residues are frequently skipped by STT3A during protein translation. Post-translational modification of the cotranslationally skipped sites by STT3B was similarly hindered by the middle X residue, resulting in hypoglycosylation of NXS sites containing large hydrophobic and negatively charged side chains. In contrast, NXT consensus sites (barring NWT) were efficiently modified by the cotranslational machinery, reducing STT3B's role in modifying consensus sites skipped during protein translation. A strong correlation between cotranslational N-glycosylation efficiency and the rate of post-translational N-glycosylation was determined, showing that the OST STT3A and STT3B isoforms are similarly influenced by the hydroxyl and middle X consensus site residues. Substituting various middle X residues into an OST eubacterial homologous structure revealed that small and polar consensus site X residues fit well in the peptide binding site whereas large hydrophobic and negatively charged residues were harder to accommodate, indicating conserved enzymatic mechanisms for the mammalian OST isoforms. PMID- 25029374 TI - Tailored cyclodextrin pore blocker protects mammalian cells from clostridium difficile binary toxin CDT. AB - Some Clostridium difficile strains produce, in addition to toxins A and B, the binary toxin Clostridium difficile transferase (CDT), which ADP-ribosylates actin and may contribute to the hypervirulence of these strains. The separate binding and translocation component CDTb mediates transport of the enzyme component CDTa into mammalian target cells. CDTb binds to its receptor on the cell surface, CDTa assembles and CDTb/CDTa complexes are internalised. In acidic endosomes, CDTb mediates the delivery of CDTa into the cytosol, most likely by forming a translocation pore in endosomal membranes. We demonstrate that a seven-fold symmetrical positively charged beta-cyclodextrin derivative, per-6-S-(3 aminomethyl)benzylthio-beta-cyclodextrin, which was developed earlier as a potent inhibitor of the translocation pores of related binary toxins of Bacillus anthracis, Clostridium botulinum and Clostridium perfringens, protects cells from intoxication with CDT. The pore blocker did not interfere with the CDTa-catalyzed ADP-ribosylation of actin or toxin binding to Vero cells but inhibited the pH dependent membrane translocation of CDTa into the cytosol. In conclusion, the cationic beta-cyclodextrin could serve as the lead compound in a development of novel pharmacological strategies against the CDT-producing strains of C. difficile. PMID- 25029375 TI - The rational use of animal models in the evaluation of novel bone regenerative therapies. AB - Bone has a high potential for endogenous self-repair. However, due to population aging, human diseases with impaired bone regeneration are on the rise. Current strategies to facilitate bone healing include various biomolecules, cellular therapies, biomaterials and different combinations of these. Animal models for testing novel regenerative therapies remain the gold standard in pre-clinical phases of drug discovery and development. Despite improvements in animal experimentation, excessive poorly designed animal studies with inappropriate endpoints and inaccurate conclusions are being conducted. In this review, we discuss animal models, procedures, methods and technologies used in bone repair studies with the aim to assist investigators in planning and performing scientifically sound experiments that respect the wellbeing of animals. In the process of designing an animal study for bone repair investigators should consider: skeletal characteristics of the selected animal species; a suitable animal model that mimics the intended clinical indication; an appropriate assessment plan with validated methods, markers, timing, endpoints and scoring systems; relevant dosing and statistically pre-justified sample sizes and evaluation methods; synchronization of the study with regulatory requirements and additional evaluations specific to cell-based approaches. This article is part of a Special Issue entitled "Stem Cells and Bone". PMID- 25029376 TI - Mitochondrial activity during pre-maturational culture in in vitro-grown bovine oocytes is related to maturational and developmental competences. AB - The objective of this study was to investigate the dynamics of mitochondrial activity in in vitro-grown (IVG) bovine oocytes during pre-maturational culture (pre-IVM) and its relationship to their developmental competence upon being subjected to different pre-IVM durations. After 12-day IVG culture, oocytes were cultured for 0, 10 or 20h with 3-isobutyl-1-methylxanthine (IBMX) as pre-IVM. Mitochondrial activity in IVG oocytes after 10h pre-IVM was the highest among all the pre-IVM durations (P<0.05). In addition, cleavage (79.4%) and blastocyst rates (38.9%) of embryos derived from IVG oocytes with 10h pre-IVM were higher than those with 20h pre-IVM (63.0 and 25.8%, respectively; P<0.05) and similar to those of in vivo-grown oocytes (82.7 and 36.7%, respectively). To confirm the developmental ability of IVG oocytes with 10h pre-IVM beyond the blastocyst stage in vivo, embryo transfer was attempted. Transferred embryos developed to the elongated embryonic stage (63.6%, 7/11) in the recipient uterus at Day 16 of oestrus, and a male calf was delivered (50%, 1/2). In conclusion, it was indicated that the mitochondrial activity of bovine IVG oocytes peaked at 10h pre IVM and was closely correlated with the nuclear maturation and developmental competences of IVG oocytes. PMID- 25029377 TI - Efficacy and safety of transdermal fentanyl in the control of postoperative pain after photorefractive keratectomy. AB - PURPOSE: To evaluate the efficacy and safety of transdermal fentanyl (TDF) in the control of postoperative pain following photorefractive keratectomy (PRK). METHODS: One hundred ninety-nine consecutive PRK cases (398 eyes) were retrospectively reviewed. For postoperative pain control, 96 patients (63 females) were treated with tramadol 37.5 mg/acetaminophen 325 mg combination tablets (2 tablets bid), 103 patients (73 females) were treated with TDF (12 MUg/h). Postoperative pain intensity using the visual analog scale (VAS) during postoperative 3 days including the evening of the day of the operation and peak pain intensity, rated using the verbal descriptor scale (VDS) at postoperative 4 days, were compared between 2 groups. Overall adverse events in the 2 treatment groups were also compared. RESULTS: The differences in mean pain intensity scores were significant between the control group and the fentanyl group (P=0.001, Repeated-measures analysis of variance). The proportion of severe pain (VAS>54 mm) was significantly lower in the fentanyl group than the control group by morning of postoperative 2 days (P<0.007). The proportion of patients who rated their peak pain intensity as "intolerable pain" was significantly higher (P=0.001) in the control group (30/96, 31.3%) than the fentanyl group (13/103, 12.6%). Total number of patients who reported adverse events was significantly higher in the fentanyl group (P=0.013) than the control group. However, there were no irreversible or severe adverse events in both treatment groups and nausea was the most common (14/103, 13.6%) complaint reported in the fentanyl group. CONCLUSION: TDF was more effective in the control of postoperative pain after PRK than tramadol/acetaminophen and no irreversible or severe adverse effect was reported with 12 MUg/h concentration. TDF could be considered as alternative regimen of analgesic method after PRK. PMID- 25029378 TI - Artifact suppressed dictionary learning for low-dose CT image processing. AB - Low-dose computed tomography (LDCT) images are often severely degraded by amplified mottle noise and streak artifacts. These artifacts are often hard to suppress without introducing tissue blurring effects. In this paper, we propose to process LDCT images using a novel image-domain algorithm called "artifact suppressed dictionary learning (ASDL)." In this ASDL method, orientation and scale information on artifacts is exploited to train artifact atoms, which are then combined with tissue feature atoms to build three discriminative dictionaries. The streak artifacts are cancelled via a discriminative sparse representation operation based on these dictionaries. Then, a general dictionary learning processing is applied to further reduce the noise and residual artifacts. Qualitative and quantitative evaluations on a large set of abdominal and mediastinum CT images are carried out and the results show that the proposed method can be efficiently applied in most current CT systems. PMID- 25029379 TI - Prostate cancer grading: use of graph cut and spatial arrangement of nuclei. AB - Tissue image grading is one of the most important steps in prostate cancer diagnosis, where the pathologist relies on the gland structure to assign a Gleason grade to the tissue image. In this grading scheme, the discrimination between grade 3 and grade 4 is the most difficult, and receives the most attention from researchers. In this study, we propose a novel method (called nuclei-based method) that 1) utilizes graph theory techniques to segment glands and 2) computes a gland-score (based on the spatial arrangement of nuclei) to estimate how similar a segmented region is to a gland. Next, we create a fusion method by combining this nuclei-based method with the lumen-based method presented in our previous work to improve the performance of grade 3 versus grade 4 classification problem (the accuracy is now improved to 87.3% compared to 81.1% of the lumen-based method alone). To segment glands, we build a graph of nuclei and lumina in the image, and use the normalized cut method to partition the graph into different components, each corresponding to a gland. Unlike most state-of the-art lumen-based gland segmentation method, the nuclei-based method is able to segment glands without lumen or glands with multiple lumina. Moreover, another important contribution in this research is the development of a set of measures to exploit the difference in nuclei spatial arrangement between grade 3 images (where nuclei form closed chain structure on the gland boundary) and grade 4 image (where nuclei distribute more randomly in the gland). These measures are combined to generate a single gland-score value, which estimates how similar a segmented region (which is a set of nuclei and lumina) is to a gland. PMID- 25029380 TI - SVD compression for magnetic resonance fingerprinting in the time domain. AB - Magnetic resonance (MR) fingerprinting is a technique for acquiring and processing MR data that simultaneously provides quantitative maps of different tissue parameters through a pattern recognition algorithm. A predefined dictionary models the possible signal evolutions simulated using the Bloch equations with different combinations of various MR parameters and pattern recognition is completed by computing the inner product between the observed signal and each of the predicted signals within the dictionary. Though this matching algorithm has been shown to accurately predict the MR parameters of interest, one desires a more efficient method to obtain the quantitative images. We propose to compress the dictionary using the singular value decomposition, which will provide a low-rank approximation. By compressing the size of the dictionary in the time domain, we are able to speed up the pattern recognition algorithm, by a factor of between 3.4-4.8, without sacrificing the high signal-to noise ratio of the original scheme presented previously. PMID- 25029381 TI - Cobaloxime-based artificial hydrogenases. AB - Cobaloximes are popular H2 evolution molecular catalysts but have so far mainly been studied in nonaqueous conditions. We show here that they are also valuable for the design of artificial hydrogenases for application in neutral aqueous solutions and report on the preparation of two well-defined biohybrid species via the binding of two cobaloxime moieties, {Co(dmgH)2} and {Co(dmgBF2)2} (dmgH2 = dimethylglyoxime), to apo Sperm-whale myoglobin (SwMb). All spectroscopic data confirm that the cobaloxime moieties are inserted within the binding pocket of the SwMb protein and are coordinated to a histidine residue in the axial position of the cobalt complex, resulting in thermodynamically stable complexes. Quantum chemical/molecular mechanical docking calculations indicated a coordination preference for His93 over the other histidine residue (His64) present in the vicinity. Interestingly, the redox activity of the cobalt centers is retained in both biohybrids, which provides them with the catalytic activity for H2 evolution in near-neutral aqueous conditions. PMID- 25029382 TI - Another brick in the wall of needs for invasive ventilation? AB - Ventilator-induced lung injury and ventilator-induced diaphragmatic dysfunction are major complications in mechanically ventilated patients with acute respiratory failure. Invasive ventilation adds a further burden by increasing the risk of infections. An approach that protects both lung and diaphragm is pivotal. Mirabella and colleagues compared conventional controlled ventilation with a mode that combines several potentially lung-protective properties - non-invasively applied neurally adjusted ventilatory assist - in an animal experiment. This approach seemed to be as effective but potentially more lung-protective. Although the experimental setup and results cannot be translated directly to the clinical setting, they should motivate us to further study this innovative approach. PMID- 25029383 TI - Seriously ill patients as living unspecified kidney donors: rationale and justification. AB - BACKGROUND: Between 2000 and December 2013, 106 live donor nephrectomies from anonymous living-donors were performed at the Erasmus MC Rotterdam; five of the donors (5.4%) had a life-threatening disease. The aim of the present report is to give the rational and justification for this procedure. METHODS: All five donors underwent the national standard living-donor screening procedure. Additionally, motivation to donate and psychologic stability were assessed by a psychologist using in-depth interview techniques and a psychologic complaints questionnaire. Post-donor nephrectomy follow-up consisted of standard questionnaires and clinical check-ups. RESULTS: One patient had cerebral and caudal ependymomas, one had severe and progressive emphysema, two had Huntington's disease and one had a grade 2 oligodendroglioma. The psychologic screening revealed genuine motivation, adequate risk perception, and normal sense of reality. No contraindications for donation were found. The five donor nephrectomies made nine kidney transplantations possible. All donors were satisfied with the donation procedure. Three donors died during follow-up (0.6-4.9 years) as a result of their disease. CONCLUSION: In the absence of apparent additional health risks, medical, and psychologic contraindications, we consider it ethically justified to accept an offer from a cognitively competent patient with a life-threatening disease in view of their self-reported satisfaction during follow-up. Although based on a limited number of patients, we conclude that a stricter psychologic screening for seriously ill donors compared to healthy unspecified anonymous donors to unspecified patients is not necessary. PMID- 25029384 TI - Differential modulation of donor-specific antibodies after B-cell depleting therapies to cure chronic antibody mediated rejection. AB - BACKGROUND: Donor-specific antibodies (DSA) are considered as reliable biomarkers for antibody-mediated rejection (ABMR) diagnosis. However, it is unclear whether DSA monitoring is necessary and could predict graft outcome after antirejection treatment. METHODS: We analyzed 28 non-sensitized kidney transplant patients with ABMR associated with de novo anti-human leukocyte antigen (HLA) DSA. Donor specific antibody levels were measured by single antigen bead assays 12 months after antirejection therapy onset. Patients were placed in three groups according to their antirejection treatment: group I (n = 10), plasma exchange-Rituximab; group II (n = 8), Bortezomib; and group III (n = 10), optimization of maintenance immunosuppression. Half of the patients in group I demonstrated concomitant acute cellular rejection (ACR+). RESULTS: De novo DSA were mainly anti-DQ (60%). Anti class I and anti-DR DSA disappeared after treatment in group I and remained negative during follow-up, whereas anti-DQ DSA persisted without any modulation. In contrast, class I-II HLA-DSA mean fluorescence intensity remained unchanged in groups II and III.Graft loss was observed in 80% and 20% of patients from group I (ACR+) and group III, respectively. One year after the ABMR treatment, a 16 mL/min decline in estimated glomerular filtration rate was observed in patients from group I (ACR-) and group III. Group II showed better outcomes with a mean estimated glomerular filtration rate decline of 6.4 mL/min. CONCLUSION: Modulation of DSA at and after treatment of ABMR did not correlate with graft outcome over a 12-month period. PMID- 25029385 TI - Tumors with intrahepatic bile duct differentiation in cirrhosis: implications on outcomes after liver transplantation. AB - BACKGROUND: The role of liver transplantation (LT) in the management of cirrhotic patients with tumors exhibiting intrahepatic bile duct differentiation remains controversial. The objective of this study was to characterize the spectrum of these tumors and analyze post-LT outcomes. METHODS: Retrospective pathology database search of explant histology analysis of liver transplants between April 1993 and November 2013. RESULTS: Thirty-two patients were analyzed, 75% were men with a mean age of 60 years. Seven patients had nodules demonstrating intrahepatic cholangiocarcinoma (I-CCA), nine had I-CCA nodules occurring concomitantly with hepatocellular carcinoma (HCC), and 16 had mixed HCC-CCA nodules. The median number of tumors was 1 and size was 2.5 cm. Overall patient survival post-LT at 1 and 5 years was 71% and 57%, respectively. Patients within Milan criteria, especially with I-CCA features, showed a 5-year tumor recurrence rate (10%) and 5-year survival rate (78%) comparable with other patients having HCC within Milan criteria. CONCLUSION: This series showed that patients with CCA within Milan criteria may be able to achieve acceptable long-term post-LT survival. PMID- 25029386 TI - Sildenafil citrate in a donation after circulatory death experimental model of renal ischemia-reperfusion injury. AB - INTRODUCTION: Phosphodiesterase-5 inhibitors prevent the breakdown of cyclic guanosine 3',5'-monophosphate (cGMP) and therefore may be useful in reducing the detrimental effects of ischemia-reperfusion (I/R) injury. The aim of this study was to assess the effects of the phosphodiesterase-5 inhibitor sildenafil, on I/R injury in a porcine model of donation after circulatory death kidney transplantation. METHODS: Kidneys were subjected to 20 min warm ischemia followed by 2 or 18 hr of cold storage (n=6 kidneys per group). After preservation kidneys were reperfused on an ex vivo perfusion system for 3 hr with an oxygenated blood based solution. Kidneys were treated with 1.4 mg/kg sildenafil infused 10 min before and for 20 min after reperfusion (n=6 kidneys per group). Renal function and injury markers were measured throughout reperfusion. RESULTS: Prolonged cold ischemia (CI) significantly reduced levels of cGMP (2 hr 3.5 [1.5-5.7] vs. 18 hr 1.2 [0.3-2.8] pmol/mL; P=0.010). The administration of sildenafil significantly increased the levels (P=0.047, 0.064). Sildenafil improved the renal blood flow for the first 30 min in the 2-hr group (sildenafil, 81.8 [43.8-101.9] vs. control 40.2 [6.4-76.9] mL/min/100 g; P=0.026) and up to 60 min in the 18-hr group (sildenafil, 67.4 [38.0-87.0] vs. control 36.2 [30.5-50.0] mL/min/100 g; P=0.009) during reperfusion. Renal function was significantly impaired after 18-hr CI (P=0.0.26), and treatment with sildenafil did not improve renal function in the 2 hr (P=0.384) or 18-hr CI (P=0.099) groups. CONCLUSION: Sildenafil had a vasodilatory action and increased levels of cGMP but did not affect recovery of renal function or protect against I/R injury. PMID- 25029387 TI - Has the gap between pancreas and islet transplantation closed? AB - Both pancreas and islet transplantations are therapeutic options for complicated type 1 diabetes. Until recent years, outcomes of islet transplantation have been significantly inferior to those of whole pancreas. Islet transplantation is primarily performed alone in patients with severe hypoglycemia, and recent registry reports have suggested that results of islet transplantation alone in this indication may be about to match those of pancreas transplant alone in insulin independence. Figures of 50% insulin independence at 5 years for either procedure have been cited. In this article, we address the question whether islet transplantation has indeed bridged the gap with whole pancreas. Looking at the evidence to answer this question, we propose that although pancreas may still be more efficient in taking recipients off insulin than islets, there are in fact numerous "gaps" separating both procedures that must be taken into the equation. These "gaps" relate to organ utilization, organ allocation, indication for transplantation, and morbidity. In-depth analysis reveals that islet transplantation, in fact, has an edge on whole pancreas in some of these aspects. Accordingly, attempts should be made to bridge these gaps from both sides to achieve the same level of success with either procedure. More realistically, it is likely that some of these gaps will remain and that both procedures will coexist and complement each other, to ensure that beta cell replacement can be successfully implemented in the greatest possible number of patients with type 1 diabetes. PMID- 25029388 TI - What goes around comes around. PMID- 25029389 TI - Sexual activity and functioning in ovarian cancer survivors: an internet-based evaluation. AB - OBJECTIVES: Sexual dysfunction is a known complication of treatment for many cancers, but there have been relatively few studies investigating outcomes for ovarian cancer survivors. We have previously reported that women treated for ovarian cancer experience persistent psychological and physical problems. Sexual functioning was highlighted as a significant factor and we sought to investigate this further. METHODS: Women were invited to complete a questionnaire using both paper and online response formats. A validated tool, the Sexual Activity Questionnaire, was used to obtain information from women following a diagnosis of ovarian cancer. RESULTS: Across all responders (n = 102, mean age 51.3 years), 63% of women reported their ovarian cancer diagnosis had negatively changed their sex life. The most common reasons given for an absence of sexual activity were a lack of interest in sex, physical problems that prevented sex or no partner. Of the 46% of responders who stated they were sexually active, 77% reported pain or discomfort during intercourse and 87% described vaginal dryness. CONCLUSION: For the majority of women, treatment for ovarian cancer negatively impacts on their sex lives. Many of the symptoms described by participants are potentially reversible and clinicians should be open to raising the issue of sexual functioning with their patients. PMID- 25029390 TI - Secoiridoid type of antiallergic substances in olive waste materials of three Japanese varieties of Olea europaea. AB - 2-Hydroxy-3-ethylidene-5-(methoxycarbonyl)-3,4-dihydro-2H-pyran-4-acetic acid 2 (3,4-dihydroxyphenyl)ethyl ester (3,4-DHPEA-EA) is a kind of secoiridoid first found in three Japanese olive pomaces: Mission, Lucca, and Manzanillo. These varieties showed high activity of 3,4-DHPEA-EA as an antiallergic active substance with IC50 at 33.5 +/- 0.6 MUg/mL. Because 3,4-DHPEA-EA was the most abundant among the active substances in the pomaces and the activity of 3,4-DHPEA EA was greater than that of hydroxytyrosol and elenolic acid, 3,4-DHPEA-EA, which has the ester linkage of hydroxytyrosol and elenolic acid, should be essential for antiallergic activity. Although a trace amount (1.04 mg/kg) of luteolin in the pomace showed the highest antiallergic activity with IC50 at 0.752 +/- 0.1 MUg/mL, we concluded that the entire antiallergic effect derives from the abundance of 3,4-DHPEA-EA, especially in the green olive pomace of the Mission variety in October, which showed the highest level of 3,4-DHPEA-EA (5033 +/- 118 mg/kg). Therefore, the Mission variety had the most effective antiallergy property. PMID- 25029391 TI - Long-term prognosis of hearing loss in patients with unilateral Meniere's disease. AB - CONCLUSION: The finding of deteriorated hearing loss at the initial visit at middle to high frequencies is a factor of poor hearing prognosis in Meniere's disease. Early intervention with instructions for lifestyle changes may lead to good outcomes in hearing. OBJECTIVE: An attempt was made to examine long-term changes in hearing loss in unilateral Meniere's disease and factors associated with prognosis of hearing loss retrospectively. METHODS: Based on their last hearing level of the affected ear, 36 patients were subdivided into two groups: the poor prognosis of hearing (PPH) group and the good prognosis of hearing (GPH) group. RESULTS: In the PPH group, the hearing levels at the initial visit at middle and high frequencies were significantly worse than those in the GPH group. Moreover, the hearing loss progressed during the first 2 years of the disease, and stayed flat to approximately 50 dB at the later stage. Conversely, the hearing loss at the onset in the GPH group showed no further progression over the first 2 years, and remained constant to approximately 35 dB at the later stage. In addition, the mean intervals from the onset to the initial visit in the PPH group were significantly longer than those in the GPH group. PMID- 25029392 TI - Neuroimaging of central breathlessness mechanisms. AB - PURPOSE OF REVIEW: Breathlessness debilitates millions of people with cardiorespiratory conditions and cancer. Symptoms correlate poorly with the objective measures of disease (e.g. spirometry). Altered brain processing of respiratory sensations may contribute to this disparity. This article summarizes how functional neuroimaging works, focussing on functional MRI (FMRI) and magnetoencephalography, how neuroimaging has shed light on the central mechanisms of breathlessness and thus how it may help target new therapies. RECENT FINDINGS: Current understanding of central neural activity in breathlessness comes mainly from a small number of studies in healthy volunteers using models of induced acute breathlessness. Parallels with neuroimaging findings in pain and fear or anxiety have been used to interpret the neuroimaging studies of breathlessness to form hypotheses. Despite the lack of recent neuroimaging studies in breathlessness, there have been methodological advances in overcoming confounders with respiratory FMRI. In addition, developing interest in the distinction of emotional from the sensory aspects of breathlessness and the use of opioids for breathlessness has driven mechanistic understandings. SUMMARY: Neuroimaging of breathlessness remains in its infancy. However, advances in the understanding of central perception, combined with novel neuroimaging techniques, means that we are poised to increase our understanding of the brain processes of breathlessness and their modulation. PMID- 25029393 TI - Managing advanced penile cancer in 2014. AB - PURPOSE OF REVIEW: To highlight the recent treatment recommendations that are proposed to improve the outcomes of patients with advanced penile cancer. RECENT FINDINGS: Penile cancer is a rare disease that presents with many diagnostic and treatment specificities. Adequate treatment requires interdisciplinary discussions involving urologist oncologists, medical oncologists and radiation oncologists as well as many other health professionals. Localized disease can now be adequately treated with many different penile-sparing approaches associated with close surveillance. However, many patients present with high-risk features associated with an unfavorable outcome. Recent data and multiple interdisciplinary collaborative groups have fueled a more standardized approach to the treatment of these patients, leading to better survival outcomes and improved quality of life. This review will focus on the recognition of high-risk disease; the indications of lymph node dissections and minimally invasive surgical approaches; the role of neoadjuvant therapy in the setting of advanced lymph node involvement as well as the potential role of targeted therapy for the salvage treatment of metastatic disease. SUMMARY: Improved outcomes in advanced penile cancer requires an integrated approach, including better identification of high-risk disease, use of novel dynamic sentinel lymph node identification techniques and use of neo-adjuvant chemotherapy in selected patients with advanced lymph node involvement. Such cases should preferentially be managed by a dedicated interdisciplinary team. PMID- 25029394 TI - Spirituality and religiosity in supportive and palliative care. AB - PURPOSE OF REVIEW: To provide an updated overview about the role of spirituality and religiosity in the way patients with life-threatening illnesses cope, and the importance of providing a comprehensive spiritual assessment and spiritual care in an interdisciplinary team work setting, such as supportive and palliative care. RECENT FINDINGS: Spirituality is a lifelong developmental task, lasting until death. Spirituality and religion continue to play an important role across cultures globally. Spirituality is seen as a vital element connected to seeking meaning, purpose, and transcendence in life. Many individuals recognize their life-threatening illness as an opportunity for spiritual growth; therefore, these individuals who have access to spirituality through meaning, purpose, connections with others, or connections with a higher power will have the spiritual resources necessary to adjust to adverse circumstances. It is extremely important to pay attention to patients' and caregivers' cultural and spiritual identity and spiritual needs. SUMMARY: The interdisciplinary supportive and palliative care model of spiritual care proposes inclusion of the spiritual domain in the overall screening and history-taking process and spiritual care by all members of the team, including a full spiritual assessment by a professional chaplain. Research in this extremely important field needs to continue growing. PMID- 25029395 TI - Challenges in treating patients with advanced urologic cancers. PMID- 25029396 TI - Does electron capture dissociation (ECD) provide quantitative information on the chemical modification of lysine side chains in proteins? The glycation of ubiquitin. AB - Electron capture dissociation (ECD) as a method of quantitative and qualitative study of glycated ubiquitin was investigated. ECD has been successfully applied for sequencing of modified peptides and assigning glycated Lys residues. By using a hybrid Fourier transform mass spectrometry (FT-MS) system equipped for ECD, a series of multiply glycated ubiquitin ions was observed. Ions of the glycated ubiquitin with a defined number of glucose moieties attached to the protein were isolated by quadrupol and fragmented in the ICR cell by the ECD method. The fragmentation spectrum was dominated by c(n) and (z+1)n ions. The ECD technique was tested for the quantitative analysis of the modified ubiquitin and isomeric glycated peptides (fragments of bovine serum albumin (BSA)). Obtained results indicate that the ECD fragmentation cannot be applied for the quantitative determination of the relative reactivities of respective Lys residues in the ubiquitin. PMID- 25029397 TI - Ochratoxin A in dried vine fruits from Chinese markets. AB - A total of 56 dried vine fruits, including 31 sultanas and 25 currants, were selected from Chinese markets in 2012. All samples were analysed for Ochratoxin A (OTA) using solid-phase extraction and high-performance liquid chromatography (HPLC) with fluorescence detection. It turned out that 58.9% of the samples were positive and the OTA amount ranged from <0.07 to 12.83 MUg/kg, with a mean level of 0.99 MUg/kg. Only one sample exceeded the European Union (EU) maximum level of 10 MUg/kg. Meanwhile, it was shown that OTA contamination increased among north western, northern and southern China, which showed OTA means of 0.08, 0.99 and 2.01 MUg/kg, respectively. Moreover, in samples of products sold in sealed plastic bags, i.e. consumer-size packages (n = 19, mean = 0.30 MUg/kg) less OTA was detected when compared with sampled bulk packages (n = 37, mean = 1.67 MUg/kg). In addition, sultanas (mean = 0.92 MUg/kg) had less OTA contamination than currants (mean = 1.22 MUg/kg). PMID- 25029398 TI - Natural co-occurrence of aflatoxins and deoxynivalenol in poultry feed in Pakistan. AB - Two hundred and fifteen broiler poultry feed samples were analysed over the time period of one year for the co-occurrence of aflatoxins and deoxynivalenol (DON). These were determined by GC-MS and ELISA, respectively. LOD values for aflatoxins and DON were 0.5 and 5 ug/kg, respectively. From all investigated 215 poultry feed samples, aflatoxins and DON co-occurred in 100 samples (46%). DON was detected in 114 samples while 100 samples also were positive for aflatoxins. Mean concentrations of positive samples for aflatoxins and DON were 18 and 807 ug/kg, respectively. Twenty-one DON-positive and 42 aflatoxin positive samples were contaminated above the EU maximum legal limits of 1000 ug/kg and 20 ug/kg, respectively. The present study provided useful data on aflatoxin and DON contamination, which may be helpful for future strategies to control contamination and to formulate standards in poultry feeds. PMID- 25029399 TI - Simultaneous analysis of phthalates, adipate and polycyclic aromatic hydrocarbons in edible oils using isotope dilution-gas chromatography-mass spectrometry. AB - A method for simultaneous determination of 12 priority phthalates, adipate and polycyclic aromatic hydrocarbons (PAHs) in edible oils by isotope dilution-gas chromatography-mass spectrometry (ID-GC-MS) was developed for fast, accurate and trace analysis. The extraction and clean-up procedures were optimised, and using stable isotope-labelled internal standards for each analyte, relative standard deviations (RSDs) of 0.92-10.6% and spiked sample recoveries of 80.6-97.8% were obtained. Limits of detection for PAHs were in the range of 0.15-0.77 ug/kg and those for phthalates were in the range of 4.6-10.0 ug/kg. The calibration curves exhibited good linearities with regression coefficients of R(2) >= 0.99. Twelve edible oils were examined to evaluate the efficiency of this method. Among the 12 analytes, dibutyl phthalates (DBP), diethylhexyl phthalates (DEHP), diethylhexyl adipate (DEHA), benzo[a]anthracene (B[a]A), chrysene (Chry) and benzo[b]fluoranthene (B[b]F) were detected in the range of 1.17-806 ug/kg. PMID- 25029400 TI - Aflatoxin B1 in betel nuts (Areca catechu L.) imported to Pakistan from different regions of South Asia. AB - Aflatoxin B1 (AFB1) levels were evaluated in betel nuts (Areca catechu L.) being imported to Pakistan during 2010-2011. In total, 278 betel nut samples (India = 21, Indonesia = 51, Sri-Lanka = 34 and Thailand = 172) were received from the Department of Customs and were analysed by thin layer chromatography (TLC). All Indian origin betel nuts showed AFB1 contamination ranging from 11.7-262.0 ug kg( 1) with a mean of 92.5 ug kg(-1). Among Indonesian and Sri Lankan shipments, 80.4% and 73.5% betel nuts were contaminated with AFB1 ranging between 3.3-39.2 and 6.5-103.4 ug kg(-1) with a mean of 11.6 and 35.0 ug kg(-1), respectively. However, only 30.2% of Thailand origin samples showed AFB1 contamination ranging 3.3-77.0 ug kg(-1) with a mean of 6.6 ug kg(-1). The widespread occurrence of AFB1 increases the hazard associated with betel nuts. Thus, strict control is a pre-requisite for the production and import/export of psychoactive substances as betel nuts. PMID- 25029401 TI - Aflatoxin M1 in Tarhana chips. AB - Tarhana chips are a popular traditional fermented food consumed widely in the Kahramanmaras region of Turkey. Tarhana chips are different from many other types of fermented food in that they are produced in the form of tortilla chips. Cereal and yoghurt are the main ingredients in Tarhana chips. Aflatoxin M1 (AFM1) levels in dairy and dairy-based products are of concern for human health. To investigate AFM1 contamination, a total of 40 samples were collected from Kahramanmaras region and AFM1 levels were determined by competitive enzyme-linked immunosorbent assay (ELISA). Furthermore, physicochemical characteristics of Tarhana chips were investigated and compared with classic fried chips in terms of nutritional value. Based on data obtained from enzyme-linked immunosorbent assay, 21 (52.5%) out of 40 samples contained AFM1 in the range 0.5-36.6 ng/kg, so AFM1 levels of all samples were below the legal limit. PMID- 25029402 TI - Polychlorinated dibenzo-p-dioxins, dibenzofurans and dioxin-like polychlorinated biphenyls in food and feed in Latvia in 2009-2011. AB - During 2009-2011 a monitoring programme for 17 polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzofurans (PCDFs) and 12 dioxin-like polychlorinated biphenyls (DL-PCBs) was conducted in the Latvian food and feed market. Using ISO 17025-accredited analytical methodology, investigation of 121 food (milk, dairy products, meat, eggs, fish, fish products) and 66 feed samples (fish meal and oil, compound and mineral feed, vegetable and animal fats) was performed. Most samples showed contamination below the European Commission (EC) Regulation No. 1881/2006 and Commission Directive 2006/13/EC limits. Average total toxicological equivalent (total-TEQ(1998)) concentrations within the food sample groups, except fish and fish products, ranged between 0.41 and 15.1 pg total-TEQ(1998) g(-1) fat. Fish and fish products showed contamination levels from 0.18 to 46.0 pg total-TEQ(1998) g(-1) fresh weight (f.w.). Fifty-seven per cent of cod liver samples were non-compliant. The most contaminated feed samples were fish meal and fish oil. A comparison with WHO-TEF(2005) data is given. PMID- 25029403 TI - Aflatoxins and heavy metals in animal feed in Iran. AB - The occurrence of aflatoxin (aflatoxin B1, aflatoxin B2, aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2)) and heavy metal (Pb, Cd, As and Hg) contamination was determined in 40 industrially produced animal feed samples which were collected from the southwest of Iran. The results indicated that 75% of samples were contaminated by four aflatoxins and the level of AFB1 and sum of aflatoxins were higher than the permissible maximum levels in Iran (5 and 20 ug kg(-1), respectively) in all feed samples. A positive correlation was found between four types of aflatoxins in all the tested samples (p < 0.01) and the positive correlation between AFG1 and AFG2 was significant (r(2) = 0.708). All feed samples had lead concentrations lower than the maximum EU limit, while 5%, 17% and 42.5% of feed samples had As, Cd and Hg concentrations higher than the maximum limits, respectively. PMID- 25029404 TI - Aflatoxin M1 in raw and imported powdered milk sold in Khartoum state, Sudan. AB - The aim of this study is to determine the level of contamination of aflatoxin M1 (AFM1) in raw and imported powdered milk in Khartoum state, Sudan. Thirty-five samples of fresh cow milk were collected from different farms, based on the source of concentrated feed introduced to the dairy cows (locally vs. commercially produced) and the size of the farm (<= 50 vs. >50 cows/farm). Also 12 samples of powdered milk were obtained from repacking companies in Khartoum state. The samples were analysed by a fluorometer, using the Vicam method. AFM1 was detected in all raw and powdered milk samples. Almost 50% of the contaminated powdered milk samples and all the raw milk samples exceeded the European Union limit of 0.05 ug/kg whereas 33% of the contaminated powdered milk samples and 77% of the raw milk samples exceeded the limit of Codex regulations (0.5 ug/kg). The results revealed that the concentration of AFM1 is affected significantly (P < 0.05) by the source of concentrated feed (locally produced or purchased) but not by the farm size. It was concluded that the levels of AFM1 in the milk samples indicated that the feeds offered to the cows were contaminated with aflatoxin B1 to such a level that it might cause a serious health problem to the public. Therefore, there is a need to limit the exposure to aflatoxin by imposing regulatory limits, as well as further studies on large scale bases are needed to investigate the amount of AFM1 in milk and dairy products. PMID- 25029405 TI - Heavy metals in vegetables and respective soils irrigated by canal, municipal waste and tube well waters. AB - Heavy metal contamination in the food chain is of serious concern due to the potential risks involved. The results of this study revealed the presence of maximum concentration of heavy metals in the canal followed by sewerage and tube well water. Similarly, the vegetables and respective soils irrigated with canal water were found to have higher heavy metal contamination followed by sewerage- and tube-well-watered samples. However, the heavy metal content of vegetables under study was below the limits as set by FAO/WHO, except for lead in canal water-irrigated spinach (0.59 mg kg(-1)), radish pods (0.44 mg kg(-1)) and bitter gourd (0.33 mg kg(-1)). Estimated daily intakes of heavy metals by the consumption of selected vegetables were found to be well below the maximum limits. However, a complete estimation of daily intake requires the inclusion of other dietary and non-dietary exposure sources of heavy metals. PMID- 25029406 TI - Acrylamide in deep-fried snacks of India. AB - Acrylamide content in deep-fried snacks from 20 different production sites of South Indian province of Kerala (80 samples representing 4 important product categories) were determined using a modified high performance liquid chromatography (HPLC)-diode array detector (DAD) method. The limit of detection and the limit of quantification for this method were 1.04 and 3.17 MUg/kg, respectively. The mean recoveries of acrylamide obtained by using spiked samples ranged between 90% and 103%, which shows good extraction efficiency. Acrylamide concentrations in the four groups of snacks ranged from 82.0 to 4245.6 ug/kg for potato chips, 46.2-2431.4 ug/kg for jack chips, 24.8-1959.8 ug/kg for sweet plantain chips and 14.7-1690.5 ug/kg for plantain chips. These are the most widely consumed snacks in South India, and the results revealed reasonable levels of acrylamide in these foods, which indicated the general risk of consumer exposure. PMID- 25029407 TI - Minerals and metals in mushroom species in Anatolia. AB - Mineral and metal contents of 24 wild mushroom species collected from Anatolia were analysed by inductively coupled plasma optical emission spectrometry. Eight minerals (Na, Mg, Ca, Mn, Fe, Zn, P and K) and six metals (Cr, Ni, Ag, Co, Cu and Pb) were studied. The mineral content of mushroom samples ranged 77.1-1061.2 mg/kg for Na, 268.1-1927.9 mg/kg for Mg, 19.3-352.9 mg/kg for Ca, 1.23-75.36 mg/kg for Mn, 27.8-816.1 mg/kg for Fe, 1.61-122.13 mg/kg for Zn, 176.7-5726.4 mg/kg for P and 1133.3-9866.7 mg/kg for K. The metal content ranged 0.03-10.58 mg/kg for Cr, 0.24-48.65 mg/kg for Ni, 0.02-0.63 mg/kg for Ag, 0.02-5.13 mg/kg for Co, 1.10-9.04 mg/kg for Cu and 0.07-8.46 mg/kg for Pb. PMID- 25029408 TI - Mycoflora and deoxynivalenol in whole wheat grains (Triticum aestivum L.) from Southern Brazil. AB - The fungal species Fusarium graminearum is related to deoxynivalenol (DON) formation. The aim of this study was to evaluate mycoflora and DON occurrence in 53 whole wheat grain samples collected in Southern Brazil during the 2012 crop. Wheat grains showed adequate values of water activity ranging from 0.48 to 0.72, within the required limits of moisture content, ranging from 9.1% to 13.9%. In addition, low counts of fungal colonies, ranging from 10 to 8.2 * 10(2), were found. For Fusarium genera, there was predominance of Fusarium verticillioides (34%) and F graminearum (30.2%). For Aspergillus species, 37.7% of Aspergillus flavus was determined. Regarding the Penicillium species, Penicillium digitatum (49%) was the most found species. DON was detected in 47.2% (25 out of 53) of the samples analysed, with levels ranging from 243.7 to 2281.3 ug kg(-1) (mean: 641.9 ug kg(-1)). PMID- 25029409 TI - Asymmetric vesicle constructed by AB/CB diblock copolymer mixture and its behavior: a Monte Carlo study. AB - Asymmetric vesicles constructed from AB/CB diblock copolymer mixture in a selective solvent for A and C blocks are studied using Monte Carlo simulation. The effects of the mixed ratio of the two diblock copolymers, the solution pH, and the hydrophilic chain length on the distributions of hydrophilic blocks on the surfaces of asymmetric vesicles are studied systematically. The simulation results show that asymmetric vesicle, in which the inner and outer surfaces are constructed from different hydrophilic blocks, can be obtained from AB/CB diblock copolymer mixture. The formation of ABC or CBA three-layer asymmetric vesicle depends on the composition of the mixture, the chain length of hydrophilic block, and the solution pH. The hydrophilic block with the same charge (induced by the solution pH), or longer chain length, or lower content in the mixture is more likely to distribute on the outer surface of the vesicle. Moreover, the transition from ABC to CBA three-layer asymmetric vesicle in which blocks C are charged can occur by adjusting the composition of the mixture. On the other hand, the investigations of the interfacial energy density of asymmetric vesicles elucidate the distribution regularity of hydrophilic blocks. When the hydrophilic chain lengths are equal, the difference between the outer and inner interfacial energies is the main factor that determines the asymmetric vesicle structures; that is, the distributions of different hydrophilic blocks on asymmetric vesicles always tend to gain the largest difference between the outer and inner interfacial energies. However, when the hydrophilic chain lengths are different, the chain conformational entropy becomes the main driving force for determining the distribution of hydrophilic blocks on asymmetric vesicles. PMID- 25029410 TI - Optimization of long-range order in solvent vapor annealed poly(styrene)-block poly(lactide) thin films for nanolithography. AB - Detailed experiments designed to optimize and understand the solvent vapor annealing of cylinder-forming poly(styrene)-block-poly(lactide) thin films for nanolithographic applications are reported. By combining climate-controlled solvent vapor annealing (including in situ probes of solvent concentration) with comparative small-angle X-ray scattering studies of solvent-swollen bulk polymers of identical composition, it is concluded that a narrow window of optimal solvent concentration occurs just on the ordered side of the order-disorder transition. In this window, the lateral correlation length of the hexagonally close-packed ordering, the defect density, and the cylinder orientation are simultaneously optimized, resulting in single-crystal-like ordering over 10 MUm scales. The influences of polymer synthesis method, composition, molar mass, solvent vapor pressure, evaporation rate, and film thickness have all been assessed, confirming the generality of this behavior. Analogies to thermal annealing of elemental solids, in combination with an understanding of the effects of process parameters on annealing conditions, enable qualitative understanding of many of the key results and underscore the likely generality of the main conclusions. Pattern transfer via a Damascene-type approach verified the applicability for high fidelity nanolithography, yielding large-area metal nanodot arrays with center-to center spacing of 38 nm (diameter 19 nm). Finally, the predictive power of our findings was demonstrated by using small-angle X-ray scattering to predict optimal solvent annealing conditions for poly(styrene)-block-poly(lactide) films of low molar mass (18 kg mol(-1)). High-quality templates with cylinder center-to center spacing of only 18 nm (diameter of 10 nm) were obtained. These comprehensive results have clear and important implications for optimization of pattern transfer templates and significantly advance the understanding of self assembly in block copolymer thin films. PMID- 25029411 TI - Evaluating health care delivery reform initiatives in the face of "cost disease". AB - The authors analyzed historical claims data from 2007 to 2011 from the Vermont All-Payer Claims database for all individuals covered by commercial insurance and Medicaid to determine per capita inpatient expenditures, cost per discharge, and cost per inpatient day. The authors further evaluated the proportion of all health care expenditure allocated to mental health, maternity care, surgical services, and medical services. Although utilization of inpatient services declined during the study period, cost per discharge and cost per inpatient day increased in a compensatory manner. Although the utilization of inpatient services by the Medicaid population decreased by 8%, cost per discharge increased by 84%. Among the commercially insured, discharges per 1000 members were essentially unchanged during the study period and inpatient cost per discharge increased by a relatively modest 32%. The relative utilization of mental health, maternity care, surgical services, and medical services was unchanged during the study period. The significant increase in the cost of inpatient services increased the proportion of total expenditure on surgical services from 21% in 2007 to 33% in 2011. The authors conclude that although health care providers are increasingly being assessed on their ability to control health care costs while achieving better outcomes, there are many cost drivers that are outside of their control. Efforts to assess initiatives, such as patient-centered medical homes, should be focused on utilization trends and outcomes rather than cost or, at a minimum, reflect cost drivers that physicians and other providers cannot influence. PMID- 25029412 TI - Hemorrhagic intramedullary hemangioblastoma of the cervical spinal cord presenting with acute-onset quadriparesis: case report and review of the literature. AB - CONTEXT: Hemangioblastomas of the spinal cord are uncommon vascular tumors. Patients commonly present with subtle neurologic findings that are thought to represent growth of the lesion over time. Hemorrhage of an intramedullary hemangioblastoma presenting as acute neurologic deficit is an extremely rare occurrence. Although the cervical spine is the most common location for hemangioblastoma of the spinal cord, there have been no previously published cases in the literature of intramedullary hemorrhage from such a lesion. FINDINGS: A 22-year-old woman with a previously undiagnosed spinal cord hemangioblastoma presented with sudden-onset dense quadriparesis due to intramedullary hemorrhage in the cervical spinal cord. The patient did not have any clinical findings of von-Hippel Lindau disease. Laminoplasty from C5 to T2 and posterior midline myelotomy for resection of the intramedullary tumor with hematoma evacuation were completed without complication. CONCLUSION: Intramedullary hemangioblastoma of the spinal cord is uncommon, and hemorrhage from a cervical spinal cord lesion has not previously been reported. Symptoms from these usually indolent lesions are commonly associated with tumor growth, edema, or associated syrinx, whereas devastating acute neurologic deficit from hemorrhage is exceedingly rare. Microsurgical resection should be done in cases of symptomatic lesions and considered in isolated symptomatic lesions without the known diagnosis of von Hippel-Lindau disease. PMID- 25029413 TI - Processing large-diameter poly(L-lactic acid) microfiber mesh/mesenchymal stromal cell constructs via resin embedding: an efficient histologic method. AB - In this study, we performed a complete histologic analysis of constructs based on large diameter ( >100 MUm) poly-L-lactic acid (PLLA) microfibers obtained via dry wet spinning and rat Mesenchymal Stromal Cells (rMSCs) differentiated towards the osteogenic lineage, using acrylic resin embedding. In many synthetic polymer based microfiber meshes, ex post processability of fiber/cell constructs for histologic analysis may face deterring difficulties, leading to an incomplete investigation of the potential of these scaffolds. Indeed, while polymeric nanofiber (fiber diameter = tens of nanometers)/cell constructs can usually be embedded in common histologic media and easily sectioned, preserving the material structure and the antigenic reactivity, histologic analysis of large polymeric microfiber/cell constructs in the literature is really scant. This affects microfiber scaffolds based on FDA-approved and widely used polymers such as PLLA and its copolymers. Indeed, for such constructs, especially those with fiber diameter and fiber interspace much larger than cell size, standard histologic processing is usually inefficient due to inhomogeneous hardness and lack of cohesion between the synthetic and the biological phases under sectioning. In this study, the microfiber/MSC constructs were embedded in acrylic resin and the staining/reaction procedures were calibrated to demonstrate the possibility of successfully employing histologic methods in tissue engineering studies even in such difficult cases. We histologically investigated the main osteogenic markers and extracellular matrix molecules, such as alkaline phosphatase, osteopontin, osteocalcin, TGF-beta1, Runx2, Collagen type I and the presence of amorphous, fibrillar and mineralized matrix. Biochemical tests were employed to confirm our findings. This protocol permitted efficient sectioning of the treated constructs and good penetration of the histologic reagents, thus allowing distribution and expression of almost all the tested molecules to be revealed. Our results demonstrated that it is possible to perform histologic analyses of large-diameter PLLA-based microfiber scaffold/MSC constructs that face the failure of standard histologic procedures. PMID- 25029415 TI - The effect of long-term thyroid-stimulating hormone suppressive therapy on the cognitive function of elderly patients with differentiated thyroid carcinoma. AB - CONTEXT: Several studies have evidenced the association between subclinical hyperthyroidism and cognitive impairment in the elderly. However, the effect of long-term TSH suppressive therapy on the cognitive function in elderly patients with differentiated thyroid carcinoma (DTC) is still unclear. OBJECTIVE: Our aim was to investigate the effect of long-term TSH suppression on the cognitive function of elderly patients with DTC. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional case-control study including 50 DTC patients aged 65 years or older (mean age 70.9 +/- 5.0 y) who have received a TSH-suppressive therapy for at least 5 years and 90 control subjects matched for age, sex, education period, and depressive mood was conducted. Major Outcome Measure: Comprehensive cognitive domains were compared between the patient and control groups. The association between serum thyroid hormone concentration and cognitive function was investigated. RESULTS: The patient group had higher serum free T4 levels and suppressed TSH levels compared with the control group. Age, sex, education period, the Korean version of the Geriatric Depression Scale scores, and Cumulative Illness Rating Scale scores were not different between the 2 groups. All assessed neuropsychiatric tests were comparable in both groups. In the patient group, those with higher serum free T4 levels performed better on Mini Mental State Examination and Trail Making Test A. The association between serum free T4 and Trail Making Test A was maintained after adjusting for age, education period, the Korean version of the Geriatric Depression Scale, and Cumulative Illness Rating Scale. In the control group, serum free T4 and TSH levels were not associated with any of the assessed cognitive domains. CONCLUSION: Our results demonstrated the safety of long-term TSH suppression on the cognitive function in elderly DTC patients. Furthermore, the positive correlations between serum free T4 levels and some cognitive domains suggest the potential beneficial effects of exogenous levothyroxine on the cognitive function of patients who lack endogenous thyroid hormone. PMID- 25029414 TI - Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines. AB - CONTEXT: Thyroid growth is regulated by TSH and requires mammalian target of rapamycin (mTOR). Thyroid cancers frequently exhibit mutations in MAPK and/or phosphoinositol-3-kinase-related kinase effectors. OBJECTIVE: The objective of the study was to explore the contribution of RET/PTC, RAS, and BRAF to mTOR regulation and response to mTOR inhibitors. METHODS: PCCL3 cells conditionally expressing RET/PTC3, HRAS(G12V), or BRAF(V600E) and human thyroid cancer cells harboring mutations of these genes were used to test pathways controlling mTOR and its requirement for growth. RESULTS: TSH/cAMP-induced growth of PCCL3 cells requires mTOR, which is stimulated via protein kinase A in a MAPK kinase (MEK)- and AKT-independent manner. Expression of RET/PTC3, HRAS(G12V), or BRAF(V600E) in PCCL3 cells induces mTOR but does not entirely abrogate the cAMP-mediated control of its activity. Acute oncoprotein-induced mTOR activity is regulated by MEK and AKT, albeit to differing degrees. By contrast, mTOR was not activated by TSH/cAMP in human thyroid cancer cells. Tumor genotype did not predict the effects of rapamycin or the mTOR kinase inhibitor AZD8055 on growth, with the exception of a PTEN-null cell line. Selective blockade of MEK did not influence mTOR activity of BRAF or RAS mutant cells. Combined MEK and mTOR kinase inhibition was synergistic on growth of BRAF- and RAS-mutant thyroid cancer cells in vitro and in vivo. CONCLUSION: Thyroid cancer cells lose TSH/cAMP dependency of mTOR signaling and cell growth. mTOR activity is not decreased by the MEK or AKT inhibitors in the RAS or BRAF human thyroid cancer cell lines. This may account for the augmented effects of combining the mTOR inhibitors with selective antagonists of these oncogenic drivers. PMID- 25029417 TI - Circulating irisin and glucose-dependent insulinotropic peptide are associated with the development of polycystic ovary syndrome. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is characterized by oligo- or anovulation, polycystic ovary, and/or hyperandrogenism. In addition, many PCOS patients present with dyslipidemia, insulin resistance, and obesity. Due to the complexity of this disorder, the causes of PCOS remain to be identified. OBJECTIVES: Because many PCOS patients have a propensity to develop dyslipidemia, we hypothesized that the brown adipose-differentiation factor, irisin, and the glucose-dependent insulinotropic peptide (GIP) play a role in the development of PCOS. DESIGN AND SETTING: Serum hormone levels in 202 PCOS patients and 47 healthy women were investigated. PATIENTS OR OTHER PARTICIPANTS: Patients were stratified based on the presence/absence of metabolic syndrome risk factors, as defined by the National Cholesterol Education Program's Adult Treatment Panel III report (ATPIII [+] and ATPIII [-]), or body mass index (healthy-weight and overweight). MAIN OUTCOME MEASURES: We measured serum irisin, GIP, LH, anti Mullerian hormone (AMH), and androgens as well as metabolic indices including homeostasis model assessment-insulin resistance, Matsuda's sensitivity index, and quantitative insulin-sensitivity check index. RESULTS: PCOS patients exhibited hyperandrogenism, dyslipidemia, and hyperinsulinism, as well as elevated LH and AMH levels. In addition, fasting irisin level (P < .001) and glucose-induced GIP response (P = .013) in PCOS patients were significantly elevated as compared to those of control women. Remarkably, levels of fasting irisin and glucose-induced GIP response remained significantly elevated in ATP III [-] PCOS and healthy weight PCOS patients when compared to matched controls. Analysis of the effect size indicated that both fasting irisin and glucose-induced GIP response are significant risk factors for PCOS with odds ratios of 6.63 and 4.21, respectively. CONCLUSION: Although there is as yet no evidence for a causal link between irisin and/or GIP and PCOS, it is conceivable that irisin and GIP might contribute to the development of PCOS and may also represent novel PCOS biomarkers. PMID- 25029416 TI - Hormone changes in peripubertal girls. AB - CONTEXT: Studies of hormone changes in the peripubertal period note increases in adrenal hormones prior to increases in sex steroids. It is unclear how these processes are related to each other, except through this temporal relationship. OBJECTIVE: Examine relationships in adrenal and sex hormones in 252 peripubertal girls. SETTING AND DESIGN: Longitudinal observation study. School districts, at the Cincinnati site of the Breast Cancer and the Environment Research Centers, between 2004-2010. Participants were recruited between ages 6 and 7 years of age and were seen every 6 months. Main outcome measures included height, weight, maturation status, and fasting blood specimen. Serum was analyzed for selected hormones every six months, beginning 30 months prior to, and extending to 6 months after, breast development. Androstenedione, estradiol, estrone, and T were measured by high-performance liquid chromatography (HPLC) with tandem mass spectrometry. Dehydroepiandrosterone-sulfate (DHEA-S) and SHBG also were measured. RESULTS: DHEA-S concentrations increased 24 months before breast development; androstenedione and estrone between 12 to 18 months before breast development; whereas estradiol and T increased, and SHBG fell between 6 and 12 months before breast development. Girls with greater body mass index had lower estradiol concentrations at onset of breast development as well as 6 months after pubertal onset. CONCLUSIONS: Serum estrone and DHEA-S increased prior to estradiol concentrations, and the increase in estradiol occurred prior to breast development. Heavier peripubertal girls have lower estradiol levels at puberty, suggesting peripheral conversion of adrenal androgens to estrone. PMID- 25029418 TI - 11C-methionine PET/CT imaging of 99mTc-MIBI-SPECT/CT-negative patients with primary hyperparathyroidism and previous neck surgery. AB - CONTEXT: (99m)Tc-Methoxy-isobutyl-isonitrile (MIBI) scintigraphy is a standard preoperative localization imaging modality in patients with primary hyperparathyroidism (pHPT). Its accuracy in localizing a hyperactive parathyroid gland after previous cervical surgery is limited. Recently, (11)C-methionine has been introduced as a promising radiotracer for pHPT imaging. Yet, few data exist for this technique in patients with persisting or recurrent pHPT before reoperation. OBJECTIVES: We aimed to investigate the ability of (11)C-methionine positron emission tomography (PET)/computed tomography (CT) to localize a parathyroid disorder after cervical surgery and negative postsurgical (99m)Tc MIBI single-photon emission CT (SPECT)/CT. DESIGN, SETTING, AND PARTICIPANTS: Fifteen patients (6 males, 9 females; age range, 36-85 years) with pHPT and negative (99m)Tc-MIBI SPECT/CT who had undergone earlier neck surgery because of pHPT and/or thyroid disorder were recruited. Twelve of the 15 patients had thyroidectomy for goiter or differentiated thyroid carcinoma. Ten patients had previous parathyroid surgery for pHPT, and 2 patients had a history of parathyroid carcinoma. Thirteen of 15 patients showed elevated levels of intact PTH at the time of PET/CT imaging, whereas all patients had elevated serum calcium values. MAIN OUTCOME MEASUREMENTS: Pathological results of contrast enhanced (11)C-methionine PET/CT and surgical results were evaluated. RESULTS: In 6 of 15 patients (11)C-methionine PET/CT showed a hypermetabolic focus in the upper mediastinum in 2 patients, in the thoracic outlet in 1 patient, and in the cervical region in 3 patients. In 9 of the 15 patients, no hyperactive parathyroid gland could be visualized. Reoperation was performed in 5 of 6 patients without surgical complications. One patient refused surgery. In 2 of the 5 patients, a transsternal procedure was performed. Correlating with the (11)C methionine PET/CT results, a single parathyroid adenoma was found in 4 patients and parathyroid carcinoma metastasis in 1 patient. CONCLUSION: (11)C-Methionine PET/CT is a useful complementary imaging technique to localize parathyroid adenoma or carcinoma in (99m)Tc-MIBI SPECT/CT-negative patients. PMID- 25029419 TI - Extragestational betaHCG secretion due to an isolated lung epithelioid trophoblastic tumor: microsatellite genotyping of tumoral cells confirmed their placental origin and oriented specific chemotherapy. AB - CONTEXT: Persistent secretion of beta-human chorionic gonadotropin (betaHCG) in the absence of an ongoing or recent pregnancy and without persistent uterine gestational disease is a rare but challenging situation that requires locating the extrauterine secreting tumor and distinguishing between extragestational choriocarcinoma and gestational trophoblastic neoplasms. CASE PRESENTATION: An unexplained, persistent extragestational betaHCG secretion occurring in a 29-year old, nonsmoking woman with abnormal uterine bleeding 4 years after a normal pregnancy and without persistent gestational disease led to the discovery by whole-body computed tomography/positron emission tomography of an isolated pulmonary tumor. OBJECTIVE: Characterization of paternal alleles in tumoral cells in order to establish their fetal origin, which may be helpful for the diagnosis and treatment of such tumors. METHODS AND RESULTS: After the surgical procedure, clinical, histological, and immunocytochemical analysis ruled out primary or metastatic bronchopulmonary carcinoma or choriocarcinoma and supported the diagnosis of an isolated, primary, epithelioid trophoblastic tumor. Microsatellite genotyping of tumoral cells identifying paternal alleles confirmed their placental origin and their migration to the lungs, with likely secondary malignant transformation, and guided the choice of postsurgical chemotherapy needed to completely eradicate betaHCG secretion. CONCLUSION: Persistent extragestational secretion of betaHCG in a young nonsmoking woman with a precedent pregnancy and an isolated lung tumor suggests the diagnosis of epithelioid trophoblastic tumor, a very rare malignant tumor for which placental origin needs to be confirmed, especially when occurring several years after the patient's last pregnancy. Simple microsatellite genotyping of tumoral cells will allow this confirmation of diagnosis and help in personalizing chemotherapy. PMID- 25029420 TI - Persistent apparent pancreatic beta-cell defects in premenarchal PCOS relatives. AB - CONTEXT: Polycystic ovary syndrome confers an increased risk for type 2 diabetes in affected women as early as adolescence. First-degree relatives (FDRs) of affected women are at increased risk for associated reproductive and metabolic phenotypes. OBJECTIVE: We sought to prospectively assess insulin sensitivity and secretion and to measure reproductive hormone levels using sensitive techniques. DESIGN, SETTING, AND PARTICIPANTS: Twelve premenarchal FDR girls and 10 control girls of comparable age, Tanner stage, and body mass index were studied at an academic medical center. INTERVENTIONS: Frequently sampled intravenous glucose tolerance tests and oral glucose tolerance tests were performed. MAIN OUTCOME MEASURES: Reproductive hormone levels, lipid profiles, glucose tolerance, and frequently sampled iv glucose tolerance test parameters of insulin sensitivity and secretion were investigated. RESULTS: Disposition index (DI), insulin secretion corrected for insulin sensitivity, was decreased in FDR compared with control girls at baseline (P = .01), independent of dysglycemia. Decreases in DI persisted in FDR girls during the 2-year follow-up (P = .003). T levels were increased (P = .02) in FDR compared with control girls at baseline, but this difference did not persist because T levels increased in control girls. CONCLUSIONS: DI is decreased in peripubertal FDR girls, and this decrease persists as puberty progresses. These findings suggest that beta-cell dysfunction is an early defect in glucose homeostasis preceding decompensation in glucose tolerance in FDR girls. T levels were increased in FDR girls earlier than previously reported, but these changes did not persist, suggesting an earlier onset of pubertal increases in glandular androgen secretion in FDR girls. PMID- 25029421 TI - Increased plasma DPP4 activity is predictive of prediabetes and type 2 diabetes onset in Chinese over a four-year period: result from the China National Diabetes and Metabolic Disorders Study. AB - CONTEXT: The significance of associations between prediabetes, type 2 diabetes, and dipeptidyl peptidase-4 (DPP4) activity in a Chinese population is not clear. OBJECTIVE: The objective of the study was to determine whether DPP4 activity and active glucagon-like peptide-1 (GLP-1) were predictive of the onset of prediabetes and type 2 diabetes. DESIGN, SETTING, AND PATIENTS: This was a 4-year follow-up study conducted in Sichuan, China. A total of 474 Chinese women and men aged 18-70 years were studied. MAIN OUTCOME MEASURES: All subjects were divided into 3 groups (normal glucose tolerance, prediabetes, and type 2 diabetes) on the basis of their glucose metabolism status after 4 years. The DPP4 activity, active GLP-1, and glucagon were measured at baseline and 4 years later. RESULTS: The baseline DPP4 activity was significantly higher in subjects who had progressed to prediabetes or type 2 diabetes compared with subjects who remained normoglycemic (P < .01). In a multiple linear regression analysis, baseline DPP4 activity and active GLP-1 were independent predictors of an increase in insulin resistance over a 4-year period (P < .05). Cox proportional hazards models revealed that DPP4 activity independently predicted the risk of developing prediabetes [relative risk 2.77 (95% confidence interval 1.38-5.55), P < .01] and type 2 diabetes [5.10 (95% confidence interval 1.48-17.61), P < .05] after adjustment for confounding risk factors. CONCLUSIONS: DPP4 activity is an important predictor of the onset of insulin resistance, prediabetes, and type 2 diabetes in apparently healthy Chinese individuals. This finding may have important implications for understanding the etiology of diabetes. PMID- 25029422 TI - Novel genome-wide association study-based candidate loci for differentiated thyroid cancer risk. AB - CONTEXT: Genome-wide association studies (GWASs) on differentiated thyroid cancer (DTC) have identified robust associations with single nucleotide polymorphisms (SNPs) at 9q22.33 (FOXE1), 14q13.3 (NKX2-1), and 2q35 (DIRC3). Our recently published GWAS suggested additional susceptibility loci specific for the high incidence Italian population. OBJECTIVE: The purpose of this study was to identify novel Italian-specific DTC risk variants based on our GWAS and to test them further in low-incidence populations. DESIGN: We investigated 45 SNPs selected from our GWAS first in an Italian population. SNPs that showed suggestive evidence of association were investigated in the Polish and Spanish cohorts. RESULTS: The combined analysis of the GWAS and the Italian replication study (2260 case patients and 2218 control subjects) provided strong evidence of association with rs10136427 near BATF (odds ratio [OR] =1.40, P = 4.35 * 10(-7)) and rs7267944 near DHX35 (OR = 1.39, P = 2.13 * 10(-8)). A possible role in DTC susceptibility in the Italian populations was also found for rs13184587 (ARSB) (P = 8.54 * 10(-6)) and rs1220597 (SPATA13) (P = 3.25 * 10(-6)). Only the associations between rs10136427 and rs7267944 and DTC risk were replicated in the Polish and the Spanish populations with little evidence of population heterogeneity (GWAS and all replications combined, OR = 1.30, P = 9.30 * 10(-7) and OR = 1.32, P = 1.34 * 10(-8), respectively). In silico analyses provided new insights into the possible functional consequences of the SNPs that showed the strongest association with DTC. CONCLUSIONS: Our findings provide evidence for novel DTC susceptibility variants. Further studies are warranted to identify the specific genetic variants responsible for the observed associations and to functionally validate our in silico predictions. PMID- 25029423 TI - Long-acting progestin-only contraceptives enhance human endometrial stromal cell expressed neuronal pentraxin-1 and reactive oxygen species to promote endothelial cell apoptosis. AB - CONTEXT: Despite the absence of progesterone receptor protein in human endometrial endothelial cells (HEECs), endometria of women receiving long-acting progestin-only contraceptives (LAPCs) display reduced uterine blood flow, elevated reactive oxygen species generation, increased angiogenesis, and irregularly distributed, enlarged, fragile microvessels resulting in abnormal uterine bleeding. OBJECTIVE: We propose that paracrine factors from LAPC-treated human endometrial stromal cells (HESCs) impair HEEC functions by shifting the balance between HEEC viability and death in favor of the latter. DESIGN AND SETTING: Proliferation, apoptosis, and transcriptome analyses were performed in HEECs treated with conditioned medium supernatant (CMS) derived from HESCs treated with estradiol (E2) +/- medroxyprogesterone acetate or etonogestrel under normoxia or hypoxia. Mass spectrometry interrogated the CMS secretome while immunostaining for neuronal pentraxin-1 (NPTX1), cleaved caspase-3, and cytochrome c was performed in cultured HEECs and paired endometria from women using LAPCs. MAIN OUTCOME: HEEC apoptosis and its underlying mechanism. RESULTS: HESC CMS from E2 + medroxyprogesterone acetate or E2 + etonogestrel incubations under hypoxia induced HEEC apoptosis (P < .05), whereas mass spectrometry of the CMS revealed increased NPTX1 secretion (P < .05). Endothelial cleaved caspase-3 and stromal NPTX1 immunoreactivity were significantly higher in LAPC-treated endometria (P < .001). Transcriptomics revealed AKT signaling inhibition and mitochondrial dysfunction in HEECs incubated with HESC CMS. In vitro analyses proved that CMS decreased HEEC AKT phosphorylation (P < .05) and that recombinant NPTX1 (P < .05) or NPTX1 + H2O2 (P < .001) increase HEEC apoptosis and cytosolic cytochrome c levels. CONCLUSIONS: LAPC-enhanced NPTX1 secretion and reactive oxygen species generation in HESCs impair HEEC survival resulting in a loss in vascular integrity, demonstrating a novel paracrine mechanism to explain LAPC induced abnormal uterine bleeding. PMID- 25029424 TI - Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study. AB - CONTEXT: Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities. OBJECTIVE: The objective of the study was to suppress elevated PTH levels in XLH patients. DESIGN: This was a prospective, randomized, placebo-controlled, double blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later. SETTING: PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit. PATIENTS: Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less. INTERVENTION: The intervention for this study was the use of paricalcitol or placebo for 1 year. MAIN OUTCOME MEASURES: Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc methylenediphosphonate bone scans. RESULTS: PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject. CONCLUSIONS: Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use. PMID- 25029425 TI - The presentation of adrenarche is sexually dimorphic and modified by body adiposity. AB - CONTEXT: Adrenarche refers to the onset of increased production of adrenal androgens in childhood leading variably to clinical signs of androgen action. The prevalence and presentation of adrenarche in prepubertal girls and boys is not well known. OBJECTIVE: Our objective was to examine the prevalence and clinical presentation of adrenarche in a population sample of prepubertal children aged less than 9 years. DESIGN AND PARTICIPANTS: This cross-sectional study included prepubertal children (209 girls and 228 boys; median age 7.6 [range 6.8-8.9] years) taking part in The Physical Activity and Nutrition in Children (PANIC) Study. MAIN OUTCOME MEASURE: The prevalence of adrenarche was assessed. RESULTS: The prevalence of any clinical sign of androgen action was higher in girls than in boys (26.1% vs 10.0%; P < .001) and biochemical adrenarche without any clinical sign was less common in girls than in boys (8.1% vs 16.7%; P = .007). When premature adrenarche was defined by serum dehydroepiandrosterone sulfate concentration >=1 MUmol/L (>=37 MUg/dL) and any clinical sign before the age of 8 years in girls and 9 years in boys, its total prevalence was 8.6% in girls and 1.8% in boys. The risk of having any clinical sign increased with higher body fat percentage in boys and with higher serum dehydroepiandrosterone sulfate concentration in girls. CONCLUSIONS: Clinical signs of androgen action are more common, but biochemical adrenarche without any clinical sign is less common in prepubertal girls than boys. This sexual dimorphism of adrenarche might be explained by sex-dependent differences in peripheral androgen metabolism or action that are modified by body fat. PMID- 25029427 TI - Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis. AB - CONTEXT: Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. OBJECTIVE: The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons. DESIGN: The study was performed using human tissue analysis and cell culture. SETTING: The study was conducted at a university research institute. PATIENTS: Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18). MAIN OUTCOME MEASURES: mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens. RESULTS: TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P < .001, P < .01). TRPV1, SCN9A, and TAC1 were elevated in endometriosis lesions (P < .05). P2RX3 mRNA was increased in the peritoneum of women with CPP, with and without endometriosis (P < .05). Incubation of sensory neurons with 17beta-estradiol increased TRPV1 mRNA (P < .01). The estrogen receptor-beta-selective agonist 2,3 bis(4-hydroxy-phenyl)-propionitrile increased concentrations of TRPV1, P2RX3, SCN9A, and TAC1 mRNAs. CONCLUSIONS: Estrogen-dependent expression of TRPV1 in sensory neurons may explain why ovarian suppression can reduce endometriosis associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP. PMID- 25029428 TI - Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome. AB - While studies show that prolonged initial prednisone therapy reduces the frequency of relapses in nephrotic syndrome, they lack power and have risk of bias. In order to examine the effect of prolonged therapy on frequency of relapses, we conducted a blinded, 1:1 randomized, placebo-controlled trial in 5 academic hospitals in India on 181 patients, 1-12 years old, with a first episode of steroid-sensitive nephrotic syndrome. Following 12 weeks of standard therapy, in random order, 92 patients received tapering prednisolone while 89 received matching-placebo on alternate days for the next 12 weeks. On intention-to-treat analyses, primary outcome of number of relapses at 1 year was 1.26 in the 6-month group and 1.54 in the 3-month group (difference -0.28; 95% confidence interval (CI) -0.75, 0.19). Relative relapse rate for 6- vs. 3-month therapy, adjusted for gender, age, and time to initial remission, was 0.70 (95% CI 0.47-1.10). Similar proportions of patients had sustained remission, frequent relapses, and adverse effects due to steroids. Adjusted hazard ratios for first relapse and frequent relapses with prolonged therapy were 0.57 (95% CI, 0.36-1.07) and 1.01 (95% CI, 0.61-1.67), respectively. Thus, extending initial prednisolone treatment from 3 to 6 months does not influence the course of illness in children with nephrotic syndrome. These findings have implications for guiding the duration of therapy of nephrotic syndrome. PMID- 25029426 TI - Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans. AB - CONTEXT: Interruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear. OBJECTIVE: To test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans. DESIGN: We conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high sodium diet. SETTING: Academic clinical research center. PARTICIPANTS: Healthy, nondiabetic, normotensive volunteers. INTERVENTIONS: Infusion of exogenous aldosterone (0.7 MUg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5-7 days. MAIN OUTCOME MEASURES: Change in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle. RESULTS: A low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose stimulated insulin (-16.0 +/- 5.6%; P = .007) and C-peptide responses (-21.8 +/- 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (-1.0 +/- 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 +/- 4.8%; P = .72) or insulin sensitivity index (+2.0 +/- 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion. CONCLUSIONS: Low dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity. PMID- 25029429 TI - Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial. AB - Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60 ml/min per 1.73 m(2) and/or UACR over 30 mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mm Hg, eGFR 76.3 (77.1) ml/min per 1.73 m(2), and UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08 1.73) and log UACR estimated slope (beta) 0.33) and negatively associated with eGFR (beta -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82-1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000 mg/g. PMID- 25029430 TI - Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD. PMID- 25029431 TI - Does the metabolic syndrome impact left-ventricular mechanics? A two-dimensional speckle tracking study. AB - OBJECTIVE: To evaluate left-ventricular mechanics estimated by two-dimensional echocardiography (2DE) speckle tracking analyses in patients with the metabolic syndrome. METHODS: This cross-sectional study included 95 untreated patients with metabolic syndrome and 65 controls similar by sex and age. Metabolic syndrome was defined by the presence of at least three ATP-AHA-NHLB criteria. All the patients underwent adequate laboratory analyses and complete 2DE examination. RESULTS: 2DE global longitudinal and circumferential strain was significantly decreased in the metabolic syndrome group, whereas 2DE global radial strain was similar between the observed groups. The left-ventricular torsion was similar between the metabolic syndrome participants and the controls; whereas the left-ventricular untwisting rate was significantly increased in the metabolic syndrome group. The increasing number of the metabolic syndrome criteria induces progressive reduction of the left-ventricular longitudinal strain from the individuals with no metabolic syndrome risk factors to the individuals with five metabolic syndrome criteria. The same pattern was not noticed for left-ventricular circumferential and radial strain. The combination of increased blood pressure, abdominal obesity and increased fasting glucose level was associated with the higher level of left-ventricular mechanical impairment comparing with other clusters of the metabolic syndrome components. The multivariate analysis of the metabolic syndrome criteria showed that 24-h mean blood pressure, waist circumference and fasting glucose level were independently associated with 2DE global longitudinal and circumferential myocardial strain, and left-ventricular untwisting rate. The interaction between sex and metabolic syndrome significantly impacts the left-ventricular longitudinal strain and untwisting rate. CONCLUSION: Left-ventricular mechanics assessed by 2DE strain is significantly impaired in the metabolic syndrome patients. Among all metabolic syndrome components, blood pressure, waist circumference and fasting glucose level are the most responsible for damage of left-ventricular deformation. PMID- 25029432 TI - Changing patterns of in-hospital deaths following implementation of damage control resuscitation practices in US forward military treatment facilities. AB - IMPORTANCE: Analysis of combat deaths provides invaluable epidemiologic and quality-improvement data for trauma centers and is particularly important under rapidly evolving battlefield conditions. OBJECTIVE: To analyze the evolution of injury patterns, early care, and resuscitation among patients who subsequently died in the hospital, before and after implementation of damage control resuscitation (DCR) policies. DESIGN, SETTING, AND PARTICIPANTS: In a review of the Joint Theater Trauma Registry (2002-2011) of US forward combat hospitals, cohorts of patients with vital signs at presentation and subsequent in-hospital death were grouped into 2 time periods: pre-DCR (before 2006) and DCR (2006 2011). MAIN OUTCOMES AND MEASURES: Injury types and Injury Severity Scores (ISSs), timing and location of death, and initial (24-hour) and total volume of blood products and fluid administered. RESULTS: Of 57,179 soldiers admitted to a forward combat hospital, 2565 (4.5%) subsequently died in the hospital. The majority of patients (74%) were severely injured (ISS > 15), and 80% died within 24 hours of admission. Damage control resuscitation policies were widely implemented by 2006 and resulted in a decrease in mean 24-hour crystalloid infusion volume (6.1-3.2 L) and increased fresh frozen plasma use (3.2-10.1 U) (both P < .05) in this population. The mean packed red blood cells to fresh frozen plasma ratio changed from 2.6:1 during the pre-DCR period to 1.4:1 during the DCR period (P < .01). There was a significant increase in mean ISS between cohorts (pre-DCR ISS = 23 vs DCR ISS = 27; P < .05) and a marked shift in injury patterns favoring more severe head trauma in the DCR cohort. CONCLUSIONS AND RELEVANCE: There has been a significant shift in resuscitation practices in forward combat hospitals indicating widespread military adoption of DCR. Patients who died in a hospital during the DCR period were more likely to be severely injured and have a severe brain injury, consistent with a decrease in deaths among potentially salvageable patients. PMID- 25029433 TI - Fruits, vegetables and their polyphenols protect dietary lipids from oxidation during gastric digestion. AB - Previous studies indicate that the ingestion of oxidized vegetable oils leads to the incorporation of chemically reactive molecules issued from the decomposition of the initial lipid hydroperoxides into lipoproteins. The aim of the present study is to investigate the oxidation of dietary lipids in the gastric compartment and their inhibition by plant polyphenols provided either as fruit and vegetables (F&V) or an extract. Six minipigs received a standard Western diet containing primarily sunflower oil, ground beef meat, and starch. Polyphenols in different matrix forms were ingested either as cubed F&V or as the corresponding hydroacetonic extract. Sampling of the gastric digesta allowed the kinetic investigation of pH, heme and non-heme iron forms, total lipids, lipid-derived conjugated dienes (CD) and TBARS. F&V and the corresponding polyphenol extract delayed the gastric digestion process as shown for total lipid and heme iron contents. This study also demonstrated the occurrence of in vivo oxidation of dietary lipids in the presence of meat iron. Interestingly, F&V played a protective role by totally inhibiting the accumulation of CD while largely decreasing the formation of TBARS. The polyphenol extract similarly slowed down the TBARS formation although it had no effect on the CD accumulation. PMID- 25029434 TI - Calibration of the Al2O3:C optically stimulated luminescence (OSL) signal for linear energy transfer (LET) measurements in therapeutic proton beams. AB - Optically stimulated luminescence (OSL) detectors (OSLDs) have shown potential for measurements of linear energy transfer (LET) in proton therapy beams. However, the technique lacks the efficiency needed for clinical implementation, and a faster, simpler approach to LET measurements is desirable. The goal of this work was to demonstrate and evaluate the potential of calibrating Al2O3:C OSLDs for LET measurements using new methods. We exposed batches of OSLDs to unmodulated proton beams of varying LET and calibrated three parameters of the resulting OSL signals as functions of fluence-averaged LET (phi-LET) and dose averaged LET (D-LET). These three parameters included the OSL curve shape evaluated under continuous wave stimulation (CW-OSL), the OSL curve shape evaluated under pulsed stimulation (P-OSL), and the intensity ratio of the two main emission bands in the Al2O3:C OSL emission spectrum (ultraviolet [UV]/blue ratio). To test the calibration, we then irradiated new batches of OSLDs in modulated proton beams of varying LET, and used the OSL signal parameters to calculate phi-LET and D-LET under these new test conditions. Using the P-OSL curve shape, D-LET was measured within 5.7% of the expected value. We conclude that from a single 10 s readout (following initial calibration), both the absorbed dose and LET in proton therapy beams can be measured using OSLDs. This has potential future applications in the quality assurance of proton therapy treatment plans, particularly for those that may account for LET or relative biological effectiveness in their optimization. The methods demonstrated in this work may also be applicable to other particle therapy beams, including carbon ion beams. PMID- 25029435 TI - Chikungunya at the door--deja vu all over again? PMID- 25029436 TI - Intraoperative Assessment of Perfusion of the Gastric Graft and Correlation With Anastomotic Leaks After Esophagectomy. AB - OBJECTIVE: The aim of the study was to evaluate laser-assisted fluorescent-dye angiography (LAA) to assess perfusion in the gastric graft and to correlate perfusion with subsequent anastomotic leak. BACKGROUND: Anastomotic leaks are a major source of morbidity after esophagectomy with gastric pull-up (GPU). In large part, they occur as a consequence of poor perfusion in the gastric graft. METHODS: Real-time intraoperative perfusion was assessed using LAA before bringing the graft up through the mediastinum. When there was a transition from rapid and bright to slow and less robust perfusion, this site was marked with a suture. The location of the anastomosis relative to the suture was noted and the outcome of the anastomosis ascertained by retrospective record review. RESULTS: Intraoperative LAA was used to assess graft perfusion in 150 consecutive patients undergoing esophagectomy with planned GPU reconstruction. An esophagogastric anastomosis was performed in 144 patients. A leak was found in 24 patients (16.7%) and were significantly less likely when the anastomosis was placed in an area of good perfusion compared with when the anastomosis was placed in an area of less robust perfusion by LAA (2% vs 45%, P < 0.0001). By multivariate analysis perfusion at the site of the anastomosis was the only significant factor associated with a leak. CONCLUSIONS: Intraoperative real-time assessment of perfusion with LAA correlated with the likelihood of an anastomotic leak and confirmed the critical relationship between good perfusion and anastomotic healing. The use of LAA may contribute to reduced anastomotic morbidity. PMID- 25029437 TI - The role of biological sex in severely traumatized patients on outcomes: a matched-pair analysis. AB - OBJECTIVE: Analyze sex differences in TraumaRegister DGU (TR-DGU). BACKGROUND: Sex differences are considered to influence trauma outcomes. However, clinical study results are controversial. METHODS: Of 29,353 prospectively recorded cases of TR-DGU, we included primary trauma room admissions with Injury Severity Score of 9 or more into the analysis. Pairs (n = 3887) were formed from 1 male and 1 female according to age, mechanism, injury severity by Abbreviated Injury Scale (for head, thorax, abdomen, extremities), and occurrence of prehospital shock. Biochemical markers, treatment modalities, length of stay, and outcome (multiple organ failure, sepsis, mortality rates) were assessed. Statistical significance was accepted at P < 0.05. Odds ratios (ORs) are given with 95% confidence interval (CI). RESULTS: Females had less multiple organ failure [OR: 1.18 (95% CI, 1.05-1.33); P = 0.007], particularly in age group of 16 to 44 years; sepsis [OR: 1.45 (95% CI, 1.21-1.74); P < 0.001]), particularly at age more than 45 years; and mortality [OR: 1.14 (95% CI, 1.01-1.28); P = 0.037]. Prehospital chest tube insertions (214 vs 158) and surgical procedures before intensive care unit admission were more often performed in males (79.7% vs 76.4%). Females had lower mean hemoglobin levels [10.7 +/- 2.6 vs 11.9 +/- 2.8 (mg/dL)]. There were no sex differences in fluid resuscitation, shock index, coagulation, and base excess. CONCLUSIONS: Males are more susceptible to multiple organ failure, sepsis, and mortality after trauma. Differences were not exclusively related to reproductive age and thus cannot be attributed to sex hormones alone. Females aged 16 to 44 years seem to tolerate shock better. Higher susceptibility to sepsis might be explained by male immune function or increased systemic burden from higher rates of surgical interventions. PMID- 25029438 TI - Percutaneous dilatational tracheostomy: mostly safe, but do benefits outweigh risks? AB - Percutaneous dilatational tracheostomies have become one of the most frequently performed surgical procedures in the ICU, and are believed to offer a variety of advantages over open tracheostomies, including increased convenience. Recent publications have established that the risk of fatal complications related to the procedure is low. However, clinicians must still weigh these risks against expected but largely unproven benefits. More research is needed to establish the indications for the procedure, including the optimal patient selection and timing during a course of mechanical ventilation. Such studies should also seek to improve our ability to accurately identify which patients will require prolonged mechanical ventilation, and to quantify the potential benefits of tracheostomy compared with prolonged translaryngeal intubation. PMID- 25029439 TI - Dynamics of linker residues modulate the nucleic acid binding properties of the HIV-1 nucleocapsid protein zinc fingers. AB - The HIV-1 nucleocapsid protein (NC) is a small basic protein containing two zinc fingers (ZF) separated by a short linker. It is involved in several steps of the replication cycle and acts as a nucleic acid chaperone protein in facilitating nucleic acid strand transfers occurring during reverse transcription. Recent analysis of three-dimensional structures of NC-nucleic acids complexes established a new property: the unpaired guanines targeted by NC are more often inserted in the C-terminal zinc finger (ZF2) than in the N-terminal zinc finger (ZF1). Although previous NMR dynamic studies were performed with NC, the dynamic behavior of the linker residues connecting the two ZF domains remains unclear. This prompted us to investigate the dynamic behavior of the linker residues. Here, we collected 15N NMR relaxation data and used for the first time data at several fields to probe the protein dynamics. The analysis at two fields allows us to detect a slow motion occurring between the two domains around a hinge located in the linker at the G35 position. However, the amplitude of motion appears limited in our conditions. In addition, we showed that the neighboring linker residues R29, A30, P31, R32, K33 displayed restricted motion and numerous contacts with residues of ZF1. Our results are fully consistent with a model in which the ZF1-linker contacts prevent the ZF1 domain to interact with unpaired guanines, whereas the ZF2 domain is more accessible and competent to interact with unpaired guanines. In contrast, ZF1 with its large hydrophobic plateau is able to destabilize the double-stranded regions adjacent to the guanines bound by ZF2. The linker residues and the internal dynamics of NC regulate therefore the different functions of the two zinc fingers that are required for an optimal chaperone activity. PMID- 25029440 TI - The incidence of inflammatory bowel disease in Northern China: a prospective population-based study. AB - AIMS & BACKGROUNDS: Although inflammatory bowel diseases (IBD) are emerging and increasing in China, epidemiologic data are rarely available. This study was to investigate the epidemiological and clinical characteristics of IBD in Northern China. METHODS: This is a prospective, population-based study of incidence of IBD in Daqing, Heilongjiang province of Northern China from March 1, 2012 to February 28, 2013. All incident patients with IBD were clinically identified by IBD specialist group from five main General Hospitals covering the healthcare service for 1,343,364 residents in the urban areas of Daqing. IBD cases included in this study were followed-up for three months for diagnosis confirmation. RESULTS: A total of 27 new IBD cases including 25 cases of ulcerative colitis (UC) and 2 cases of Crohn's disease (CD) were identified. The population at risk was 1,343,364 person years. Age-adjusted incidence for total IBD, CD and UC were 1.77, 0.13, and 1.64 per 100,000 population, respectively. A male predominance was found in CD patients (male to female ratio was 2 ? 0). In contrast, no obvious gender predominance was found in UC patients (male to female ratio was 1 ? 1.1). CD patients were diagnosed at an average age of 39.5 years. The main disease phenotypes of UC were distal colitis with a 24% of proctitis and 56% of left-sided colitis. The mean diagnostic age of UC patients was 48.9 years. CONCLUSIONS: This is the first report on the incidence of IBD in the Northern Chinese population. A lower incidence of IBD, similar male predominance for CD, similar disease phenotype of UC, and lower disease activity was observed in Daqing compared to that in Southern China. PMID- 25029441 TI - Agro-environmental determinants of avian influenza circulation: a multisite study in Thailand, Vietnam and Madagascar. AB - Outbreaks of highly pathogenic avian influenza have occurred and have been studied in a variety of ecological systems. However, differences in the spatial resolution, geographical extent, units of analysis and risk factors examined in these studies prevent their quantitative comparison. This study aimed to develop a high-resolution, comparative study of a common set of agro-environmental determinants of avian influenza viruses (AIV) in domestic poultry in four different environments: (1) lower-Northern Thailand, where H5N1 circulated in 2004-2005, (2) the Red River Delta in Vietnam, where H5N1 is circulating widely, (3) the Vietnam highlands, where sporadic H5N1 outbreaks have occurred, and (4) the Lake Alaotra region in Madagascar, which features remarkable similarities with Asian agro-ecosystems and where low pathogenic avian influenza viruses have been found. We analyzed H5N1 outbreak data in Thailand in parallel with serological data collected on the H5 subtype in Vietnam and on low pathogenic AIV in Madagascar. Several agro-environmental covariates were examined: poultry densities, landscape dominated by rice cultivation, proximity to a water body or major road, and human population density. Relationships between covariates and AIV circulation were explored using spatial generalized linear models. We found that AIV prevalence was negatively associated with distance to the closest water body in the Red River Delta, Vietnam highlands and Madagascar. We also found a positive association between AIV and duck density in the Vietnam highlands and Thailand, and with rice landscapes in Thailand and Madagascar. Our findings confirm the important role of wetlands-rice-ducks ecosystems in the epidemiology of AI in diverse settings. Variables influencing circulation of the H5 subtype in Southeast Asia played a similar role for low pathogenic AIV in Madagascar, indicating that this area may be at risk if a highly virulent strain is introduced. PMID- 25029442 TI - Acidosis in the critically ill - balancing risks and benefits to optimize outcome. AB - Acidosis is associated with poor outcome in critical illness. However, acidosis - both hypercapnic and metabolic - has direct effects that can limit tissue injury induced by many causes. There is also a clear potential for off-target harm with acute exposure (for example, raised intracranial pressure, pulmonary hypertension), and with exposure for prolonged periods (for example, increased risk of infection) or at high doses. Ongoing comprehensive determination of molecular, cellular and physiologic impact across a range of representative pathologies will allow us to understand better the risks and benefits of hypercapnia and acidosis during critical illness. PMID- 25029444 TI - Apolipoprotein E polymorphism and colorectal neoplasm: results from a meta analysis. AB - To investigate the relationship of Apolipoprotein E (APOE) gene polymorphism to colorectal neoplasia (CRN), we performed a systematic review and meta-analysis. Eligible studies were identified through a systematic literature review from PubMed, EMBASE, and the Science Citation Index up to February 2014. A combined analysis was performed, followed by a subgroup analyses stratified by the study design. We used data collected from 8 prospective studies involving respectively a total of 9243 participants and 4310 CRN cases which including 438 patients with colorectal adenoma (CRA), and 3873 patients with colorectal carcinoma (CRC). The pooled data from this meta-analysis indicated there was no significant association between APOE polymorphism and CRN (epsilon2: P = 0.51, OR 1.04 95% CI 0.93 to 1.16; epsilon4: P = 0.72, OR 0.98 95% CI 0.90 to 1.07). Interestingly, subgroup analysis demonstrated there was a significant decreased risk for proximal CRN in patients with APOE epsilon4 (P = 0.0007, OR 0.52 95% CI 0.35 to 0.76). Data showed no significant association between APOE genotype and overall CRN. However, compared with those carry APOE epsilon3 alleles, persons with APOE epsilon4 genotype have significant decreased risk suffering from proximal CRN but not from distal CRN. PMID- 25029443 TI - Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. AB - Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, beta-catenin independent pathway and suppress a canonical Wnt/beta catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases. PMID- 25029445 TI - Mapping sleeping bees within their nest: spatial and temporal analysis of worker honey bee sleep. AB - Patterns of behavior within societies have long been visualized and interpreted using maps. Mapping the occurrence of sleep across individuals within a society could offer clues as to functional aspects of sleep. In spite of this, a detailed spatial analysis of sleep has never been conducted on an invertebrate society. We introduce the concept of mapping sleep across an insect society, and provide an empirical example, mapping sleep patterns within colonies of European honey bees (Apis mellifera L.). Honey bees face variables such as temperature and position of resources within their colony's nest that may impact their sleep. We mapped sleep behavior and temperature of worker bees and produced maps of their nest's comb contents as the colony grew and contents changed. By following marked bees, we discovered that individuals slept in many locations, but bees of different worker castes slept in different areas of the nest relative to position of the brood and surrounding temperature. Older worker bees generally slept outside cells, closer to the perimeter of the nest, in colder regions, and away from uncapped brood. Younger worker bees generally slept inside cells and closer to the center of the nest, and spent more time asleep than awake when surrounded by uncapped brood. The average surface temperature of sleeping foragers was lower than the surface temperature of their surroundings, offering a possible indicator of sleep for this caste. We propose mechanisms that could generate caste dependent sleep patterns and discuss functional significance of these patterns. PMID- 25029446 TI - A model of the effect of uncertainty on the C elegans L2/L2d decision. AB - At the end of the first larval stage, the C elegans larva chooses between two developmental pathways, an L2 committed to reproductive development and an L2d, which has the option of undergoing reproductive development or entering the dauer diapause. I develop a quantitative model of this choice using mathematical tools developed for pricing financial options. The model predicts that the optimal decision must take into account not only the expected potential for reproductive growth, but also the uncertainty in that expected potential. Because the L2d has more flexibility than the L2, it is favored in unpredictable environments. I estimate that the ability to take uncertainty into account may increase reproductive value by as much as 5%, and discuss possible experimental tests for this ability. PMID- 25029448 TI - Which drug should we use for stroke prevention in atrial fibrillation? AB - PURPOSE OF REVIEW: Oral anticoagulation (OAC) remains the mainstay for prevention of ischaemic stroke in atrial fibrillation. This article reviews the latest evidence and development of new oral anticoagulants for the prevention of ischaemic stroke, as well as bleeding risk assessment, mitigation and management. RECENT FINDINGS: Decision-making for stroke prevention has evolved towards the initial identification of 'low-risk' patients who do not need any antithrombotic therapy. Subsequent to this step, patients with at least 1 stroke risk factor can be offered effective stroke prevention, which is OAC. There is increased morbidity and mortality amongst warfarin users, if time in therapeutic range is poor. New oral anticoagulants (such as dabigatran, rivaroxaban, apixaban and edoxaban) offer relative efficacy, safety and convenience compared to warfarin, in relation to stroke prevention in atrial fibrillation. Bleeding risk can be assessed by HAS-BLED score, whereas the new SAMe-TT2R2 score can predict the patient's suitability for vitamin K antagonists. SUMMARY: The landscape for stroke prevention in atrial fibrillation has greatly changed. It is no longer a question of 'if we treat' but more of 'how to treat', as the presence of one or more stroke risk factors in atrial fibrillation confers a risk of fatal and devastating strokes. OAC use, whether as well controlled vitamin K antagonists or nonvitamin K antagonists oral anticoagulant, will reduce the burden of stroke in atrial fibrillation. PMID- 25029447 TI - Removal efficiency of radioactive cesium and iodine ions by a flow-type apparatus designed for electrochemically reduced water production. AB - The Fukushima Daiichi Nuclear Power Plant accident on March 11, 2011 attracted people's attention, with anxiety over possible radiation hazards. Immediate and long-term concerns are around protection from external and internal exposure by the liberated radionuclides. In particular, residents living in the affected regions are most concerned about ingesting contaminated foodstuffs, including drinking water. Efficient removal of radionuclides from rainwater and drinking water has been reported using several pot-type filtration devices. A currently used flow-type test apparatus is expected to simultaneously provide radionuclide elimination prior to ingestion and protection from internal exposure by accidental ingestion of radionuclides through the use of a micro-carbon carboxymethyl cartridge unit and an electrochemically reduced water production unit, respectively. However, the removability of radionuclides from contaminated tap water has not been tested to date. Thus, the current research was undertaken to assess the capability of the apparatus to remove radionuclides from artificially contaminated tap water. The results presented here demonstrate that the apparatus can reduce radioactivity levels to below the detection limit in applied tap water containing either 300 Bq/kg of 137Cs or 150 Bq/kg of 125I. The apparatus had a removal efficiency of over 90% for all concentration ranges of radio-cesium and -iodine tested. The results showing efficient radionuclide removability, together with previous studies on molecular hydrogen and platinum nanoparticles as reactive oxygen species scavengers, strongly suggest that the test apparatus has the potential to offer maximum safety against radionuclide contaminated foodstuffs, including drinking water. PMID- 25029449 TI - Myocardial injury after noncardiac surgery. AB - PURPOSE OF REVIEW: Recent investigations have substantially improved our understanding of myocardial injury after noncardiac surgery (MINS). RECENT FINDINGS: MINS is defined as a prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. MINS occurs in 8% of adults undergoing major noncardiac surgery and is diagnosed with an elevated postoperative troponin measurement. MINS is associated with significant morbidity, and approximately 10% of patients experiencing MINS will die within 30 days. There is a dose-graded response in mortality and time to death with increasing levels of postoperative troponin elevations. Most patients (>80%) suffering from MINS will not experience an ischemic symptom. Without troponin monitoring, the majority of MINS events would go undetected. To avoid missing these prognostically relevant events, guidelines now recommend perioperative troponin monitoring in high-risk patients having noncardiac surgery. In patients who suffer MINS, risk-adjusted observational data suggest that aspirin and a statin can reduce the risk of 30-day mortality. SUMMARY: Among adults, MINS is the most common cardiovascular complication that occurs after noncardiac surgery. Given that worldwide 200 million adult patients undergo major noncardiac surgery each year, at least 8 million of these patients will suffer MINS making this a substantial public health problem. PMID- 25029450 TI - Prevention and control of hypertension: developing a global agenda. AB - PURPOSE OF REVIEW: This review demonstrates the need for enhancing strategic approaches to the prevention and control of hypertension, a global health issue. RECENT FINDINGS: An epidemic of chronic noncommunicable diseases is threatening national healthcare systems' sustainability and the economy of many countries. Increased blood pressure is the leading risk for premature death and disability and accounts for approximately 10% of healthcare spending. Four of nine recent United Nations' targets for reducing chronic noncommunicable diseases relate directly or indirectly to hypertension. The expanded chronic care model provides a comprehensive framework for developing hypertension prevention and control strategies. The model addresses the roles of healthy public policy, healthy living environments, healthy communities, reorientation of health services delivery toward management of chronic illness, support for improving clinical decisions, enhanced skills of people to prevent and self-manage chronic disease, partnerships of stakeholders and information systems to track the impact of interventions and identify care 'gaps'. The authors advocate that hypertension organizations can lead aspects of hypertension strategy development and implementation. SUMMARY: Prevention and control of hypertension requires a strategic approach that could have a central role for hypertension experts and the hypertension community. PMID- 25029451 TI - Blood pressure reduction by reducing sodium intake in the population: one shoe fits all? AB - PURPOSE OF REVIEW: Current guidelines, based on extrapolations of observational studies or short-term relatively small clinical trials, recommend that daily sodium intake should be around 2 g/day or less. The assumption is that the relationship between sodium consumption and blood pressure (BP) levels is linear in all populations. Recent development suggests this may not be correct. We reviewed the literature on the association between sodium reduction and BP lowering, and preliminary data on 100,000 individuals from the Prospective Urban Rural Epidemiology study on sodium excretion and the association of sodium excretion with BP in general populations from 17 countries in five continents, with a focus on major subgroups. RECENT FINDINGS: Earlier observational studies have shown inconsistencies in their findings which were not addressed by the recommendations. The PURE results showed that associations between sodium intake and BP were not linear; proportionally, higher BP was found in individuals with higher sodium intake compared with those with lower sodium intake, in individuals with hypertension compared to those without hypertension, and in older individuals compared with younger individuals. SUMMARY: Recent data do not support the recommendation that all populations should reduce their sodium intake to one low level. PMID- 25029452 TI - Multidisciplinary approaches to the management of high blood pressure. AB - PURPOSE OF REVIEW: Studies on collaborative and multidisciplinary approaches to the management of hypertension published in the past 2 years are summarized. Expanding scopes of practice for nonphysician health professionals, a need to build capacity in the healthcare system, and a movement toward multidisciplinary care warrant an examination of the evidence in this area. RECENT FINDINGS: Multidisciplinary care for hypertension management, across the majority of studies identified, resulted in improved blood pressure (BP) outcomes and the timeliness of achieving treatment targets. Interventions involving therapeutic decision-making by nonphysician health professionals consistently resulted in significant BP improvements compared with usual care, whereas more passive approaches, such as education and lifestyle monitoring programs, were unable to significantly benefit participants' BP. SUMMARY: Our findings support recent efforts to integrate collaborative care approaches into chronic disease management, with the strongest evidence for pharmacist care. Expanding scopes of practice and clinical decision-making protocols for nurses, pharmacists, dietitians, and physiotherapists have the potential to further improve hypertension care. PMID- 25029453 TI - The many faces of hypertension in Canada. AB - PURPOSE OF REVIEW: To describe aspects of prevalence and incidence of hypertension in Canada. RECENT FINDINGS: Three databases have been used to determine prevalence and incidence of hypertension in Canada. Estimates of burden of hypertension varied by methods of data collection. The prevalence amongst adults was 23% based on administrative data in 2007 (which rely on physician diagnosis, but captures all adults, including those living in institutions or long-term care facilities), 18% based on self-report in the Canadian Community Health Survey in 2007 and 19% based on physical measurements in community dwelling adults in the Canadian Health Measures Survey in 2007-2009. In the absence of a large representative prospective cohort study, incidence in Canada can only be estimated using administrative data. SUMMARY: Representativeness and validity of these available national data are questionable for determining accurate prevalence and incidence of hypertension. The important selection criteria for these data limit their generalizability. Linkage of surveys, administrative data and electronic health records could provide rich data for determining a more accurate representation of hypertension in Canada. PMID- 25029454 TI - Should we expand the concept of coronary heart disease equivalents? AB - PURPOSE OF REVIEW: This narrative review discusses the associations between metabolic and inflammatory diseases, as well as radiotherapy and chemotherapy with coronary heart disease (CHD) and related risk factors, to support (or not) their potential role as CHD equivalents. RECENT FINDINGS: Although not regarded as CHD equivalents, several metabolic and inflammatory disorders are associated with an increased risk of CHD morbidity and/or mortality. These conditions include metabolic syndrome, impaired glucose metabolism, nonalcoholic fatty liver disease, obstructive sleep apnoea syndrome, erectile dysfunction, periodontitis, inflammatory bowel diseases, systemic vasculitis and HIV infection, as well as chemotherapy and radiotherapy. SUMMARY: More research should be carried out to identify which conditions can be added to the list of CHD equivalents. PMID- 25029456 TI - Heart rate variability analysis and weaning from mechanical ventilation: lessons from exercise physiology. PMID- 25029458 TI - Ordinal feature selection for iris and palmprint recognition. AB - Ordinal measures have been demonstrated as an effective feature representation model for iris and palmprint recognition. However, ordinal measures are a general concept of image analysis and numerous variants with different parameter settings, such as location, scale, orientation, and so on, can be derived to construct a huge feature space. This paper proposes a novel optimization formulation for ordinal feature selection with successful applications to both iris and palmprint recognition. The objective function of the proposed feature selection method has two parts, i.e., misclassification error of intra and interclass matching samples and weighted sparsity of ordinal feature descriptors. Therefore, the feature selection aims to achieve an accurate and sparse representation of ordinal measures. And, the optimization subjects to a number of linear inequality constraints, which require that all intra and interclass matching pairs are well separated with a large margin. Ordinal feature selection is formulated as a linear programming (LP) problem so that a solution can be efficiently obtained even on a large-scale feature pool and training database. Extensive experimental results demonstrate that the proposed LP formulation is advantageous over existing feature selection methods, such as mRMR, ReliefF, Boosting, and Lasso for biometric recognition, reporting state-of-the-art accuracy on CASIA and PolyU databases. PMID- 25029457 TI - Human quadrupeds, primate quadrupedalism, and Uner Tan Syndrome. AB - Since 2005, an extensive literature documents individuals from several families afflicted with "Uner Tan Syndrome (UTS)," a condition that in its most extreme form is characterized by cerebellar hypoplasia, loss of balance and coordination, impaired cognitive abilities, and habitual quadrupedal gait on hands and feet. Some researchers have interpreted habitual use of quadrupedalism by these individuals from an evolutionary perspective, suggesting that it represents an atavistic expression of our quadrupedal primate ancestry or "devolution." In support of this idea, individuals with "UTS" are said to use diagonal sequence quadrupedalism, a type of quadrupedal gait that distinguishes primates from most other mammals. Although the use of primate-like quadrupedal gait in humans would not be sufficient to support the conclusion of evolutionary "reversal," no quantitative gait analyses were presented to support this claim. Using standard gait analysis of 518 quadrupedal strides from video sequences of individuals with "UTS", we found that these humans almost exclusively used lateral sequence-not diagonal sequence-quadrupedal gaits. The quadrupedal gait of these individuals has therefore been erroneously described as primate-like, further weakening the "devolution" hypothesis. In fact, the quadrupedalism exhibited by individuals with UTS resembles that of healthy adult humans asked to walk quadrupedally in an experimental setting. We conclude that quadrupedalism in healthy adults or those with a physical disability can be explained using biomechanical principles rather than evolutionary assumptions. PMID- 25029459 TI - Accurate Iris Recognition at a Distance Using Stabilized Iris Encoding and Zernike Moments Phase Features. AB - Accurate iris recognition from the distantly acquired face or eye images requires development of effective strategies which can account for significant variations in the segmented iris image quality. Such variations can be highly correlated with the consistency of encoded iris features and the knowledge that such fragile bits can be exploited to improve matching accuracy. A non-linear approach to simultaneously account for both local consistency of iris bit and also the overall quality of the weight map is proposed. Our approach therefore more effectively penalizes the fragile bits while simultaneously rewarding more consistent bits. In order to achieve more stable characterization of local iris features, a Zernike moment-based phase encoding of iris features is proposed. Such Zernike moments-based phase features are computed from the partially overlapping regions to more effectively accommodate local pixel region variations in the normalized iris images. A joint strategy is adopted to simultaneously extract and combine both the global and localized iris features. The superiority of the proposed iris matching strategy is ascertained by providing comparison with several state-of-the-art iris matching algorithms on three publicly available databases: UBIRIS.v2, FRGC, CASIA.v4-distance. Our experimental results suggest that proposed strategy can achieve significant improvement in iris matching accuracy over those competing approaches in the literature, i.e., average improvement of 54.3%, 32.7% and 42.6% in equal error rates, respectively for UBIRIS.v2, FRGC, CASIA.v4-distance. PMID- 25029461 TI - Relationships between vocalization forms and functions in infancy: preliminary implications for early communicative assessment and intervention. AB - PURPOSE: This preliminary study explored relationships between form and function in prelinguistic vocalizations to increase our understanding of early communicative development and to provide potential clinical implications for early communicative assessment and intervention. METHOD: Twenty typically developing infants-5 infants in each of 4 age groups, from 3 to 20 months of age were included. Vocalizations from these infants had previously been categorized for their form (Nathani, Ertmer, & Stark, 2006) and function (Stark, Bernstein, & Demorest, 1993) characteristics. In the present study, cross-classification tabulations between form and function were conducted to examine relationships between vocalization types and their apparent uses. RESULTS: As anticipated, earlier developing forms were mostly associated with earlier developing functions, and later developing forms were mostly associated with later developing functions. However, there were some exceptions such that some forms were associated with a variety of functions, and vice versa. CONCLUSIONS: The results suggest that some forms are more tightly coupled to function than others in the prelinguistic and early linguistic period. Preliminary implications for developmental theory, future research, and clinical applications are discussed. Larger, longitudinal studies with typical and atypical populations and stricter methodological controls are needed to validate these findings. PMID- 25029460 TI - Toward statistical modeling of saccadic eye-movement and visual saliency. AB - In this paper, we present a unified statistical framework for modeling both saccadic eye movements and visual saliency. By analyzing the statistical properties of human eye fixations on natural images, we found that human attention is sparsely distributed and usually deployed to locations with abundant structural information. This observations inspired us to model saccadic behavior and visual saliency based on super-Gaussian component (SGC) analysis. Our model sequentially obtains SGC using projection pursuit, and generates eye movements by selecting the location with maximum SGC response. Besides human saccadic behavior simulation, we also demonstrated our superior effectiveness and robustness over state-of-the-arts by carrying out dense experiments on synthetic patterns and human eye fixation benchmarks. Multiple key issues in saliency modeling research, such as individual differences, the effects of scale and blur, are explored in this paper. Based on extensive qualitative and quantitative experimental results, we show promising potentials of statistical approaches for human behavior research. PMID- 25029462 TI - Semi-supervised morphosyntactic classification of Old Icelandic. AB - We present IceMorph, a semi-supervised morphosyntactic analyzer of Old Icelandic. In addition to machine-read corpora and dictionaries, it applies a small set of declension prototypes to map corpus words to dictionary entries. A web-based GUI allows expert users to modify and augment data through an online process. A machine learning module incorporates prototype data, edit-distance metrics, and expert feedback to continuously update part-of-speech and morphosyntactic classification. An advantage of the analyzer is its ability to achieve competitive classification accuracy with minimum training data. PMID- 25029463 TI - Diets rich in saturated and polyunsaturated fatty acids induce morphological alterations in the rat ventral prostate. AB - AIM: To evaluate the influence of dietary lipid quality on the body mass, carbohydrate metabolism and morphology of the rat ventral prostate. MATERIALS AND METHODS: Wistar rats were divided into four groups: SC (standard chow), HF-S (high-fat diet rich in saturated fatty acids), HF-P (high-fat diet rich in polyunsaturated fatty acids) and HF-SP (high-fat diet rich in saturated and polyunsaturated fatty acids). We analyzed body mass, fat mass deposits, plasma blood, insulin resistance and the ventral prostate structure. RESULTS: Groups that received high-fat diets were heavier and presented larger fat deposits than SC group. The HF-S and HF-SP groups had higher glucose, insulin and total cholesterol serum levels and insulin resistance compared with the SC. The acinar area, epithelium height and area density of the lumen were higher in the HF-SP than in the other groups. The epithelium area density and epithelial cell proliferation were greater in the HF-P and HF-SP than in the SC group. All of the groups that received high-fat diets had greater area density of the stroma, area density of smooth muscle cells and stromal cell proliferation compared with the SC group. CONCLUSION: Diets rich in saturated and/or polyunsaturated fatty acids induced overweight. Independently of insulin resistance, polyunsaturated fatty acids increased prostate stromal and epithelial cell proliferation. Saturated fatty acids influenced only stromal cellular proliferation. These structural and morphometric alterations may be considered risk factors for the development of adverse remodeling process in the rat ventral prostate. PMID- 25029464 TI - Preventing ischemic brain injury after sudden cardiac arrest using NO inhalation. PMID- 25029465 TI - Reliability of Intra-articular Rotational Axes at Standard Tibial Resection Level and Effect of Resecting Distally. AB - We determine the most reliable tibial intra-articular axis for rotational alignment of the tibial component at the standard resection level and at a distal resection level. The angles between the surgical transepicondylar axis and posterior condylar line, perpendicular to Akagi line, tibial anterior condylar line (ACL), and tibial maximum mediolateral line were measured at the standard resection level and 5 mm distal to the standard resection level. All axes exhibited relatively large standard deviations and ranges at the standard and distal resection level. t-test showed that there was a statistically significant difference (p < 0.05) for all the axes between the two resection levels, while only ACL showed a statistically significant difference (p = 0.047) with the equality of variance F-test. Akagi line exhibited good interobserver and intraobserver reliabilities but must be used with caution. Intra-articular axes are not reliable for tibial component alignment. PMID- 25029466 TI - MRI nanoprobes based on chemical exchange saturation transfer: Ln(III) chelates anchored on the surface of mesoporous silica nanoparticles. AB - The formation of ternary complexes between neutral Ln(III)-DO3A chelates anchored on MCM-41 mesoporous silica nanoparticles (MSNs) and silanol groups on the surface allows obtaining highly efficient chemical exchange saturation transfer (CEST) MRI nanoprobes. These new probes achieve excellent sensitivity in the MUM range (per Ln(III) ion), significantly greater than that of other paramagnetic CEST nanosystems such as dendrimers or micelles and three orders of magnitude higher than that of the corresponding molecular agents. PMID- 25029467 TI - Judging statistical models of individual decision making under risk using in- and out-of-sample criteria. AB - Despite the fact that conceptual models of individual decision making under risk are deterministic, attempts to econometrically estimate risk preferences require some assumption about the stochastic nature of choice. Unfortunately, the consequences of making different assumptions are, at present, unclear. In this paper, we compare three popular error specifications (Fechner, contextual utility, and Luce error) for three different preference functionals (expected utility, rank-dependent utility, and a mixture of those two) using in- and out-of sample selection criteria. We find drastically different inferences about structural risk preferences across the competing functionals and error specifications. Expected utility theory is least affected by the selection of the error specification. A mixture model combining the two conceptual models assuming contextual utility provides the best fit of the data both in- and out-of-sample. PMID- 25029469 TI - Mucinous nevus: report of a case and review of the literature. PMID- 25029468 TI - Time and frequency-dependent modulation of local field potential synchronization by deep brain stimulation. AB - High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS), is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP), the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson's disease (PD). We performed simultaneous multi-site local field potential (LFP) recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective), low-frequency (LF, 15 Hz; ineffective) and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR), ventroanterior thalamus (VA), primary motor cortex (M1), and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic effects of GPi DBS for conditions such as PD and dystonia. PMID- 25029470 TI - Mortality and embolic potential of cardiac tumors. AB - BACKGROUND: Cardiac tumors are rare, mostly benign with high embolic potential. OBJECTIVES: To correlate the histological type of cardiac masses with their embolic potential, implantation site and long term follow up in patients undergoing surgery. METHODS: Between January 1986 and December 2011, we retrospectively analyzed 185 consecutive patients who underwent excision of intracardiac mass (119 females, mean age 48+/-20 years). In 145 patients, the left atrium was the origin site. 72% were asymptomatic and prior embolization was often observed (19.8%). The diagnosis was established by echocardiography, magnetic resonance and histological examination. RESULTS: Most tumors were located in the left side of the heart. Myxoma was the most common (72.6%), followed by fibromas (6.9%), thrombi (6.4%) and sarcomas (6.4%). Ranging from 0.6cm to 15cm (mean 4.6 +/- 2.5cm) 37 (19.8%) patients had prior embolization, stroke 10.2%, coronary 4.8%, peripheral 4.3% 5.4% of hospital death, with a predominance of malignant tumors (40% p < 0.0001). The histological type was a predictor of mortality (rhabdomyomas and sarcomas p = 0.002) and embolic event (sarcoma, lipoma and fibroelastoma p = 0.006), but not recurrence. Tumor size, atrial fibrillation, cavity and valve impairment were not associated with the embolic event. During follow-up (mean 80+/-63 months), there were 2 deaths (1.1%) and two recurrences 1 and 11 years after the operation, to the same cavity. CONCLUSION: Most tumors were located in the left side of the heart. The histological type was predictor of death and preoperative embolic event, while the implantation site carries no relation with mortality or to embolic event. PMID- 25029471 TI - Prognostic value of TIMI score versus GRACE score in ST-segment elevation myocardial infarction. AB - BACKGROUND: The TIMI Score for ST-segment elevation myocardial infarction (STEMI) was created and validated specifically for this clinical scenario, while the GRACE score is generic to any type of acute coronary syndrome. OBJECTIVE: Between TIMI and GRACE scores, identify the one of better prognostic performance in patients with STEMI. METHODS: We included 152 individuals consecutively admitted for STEMI. The TIMI and GRACE scores were tested for their discriminatory ability (C-statistics) and calibration (Hosmer-Lemeshow) in relation to hospital death. RESULTS: The TIMI score showed equal distribution of patients in the ranges of low, intermediate and high risk (39 %, 27 % and 34 %, respectively), as opposed to the GRACE Score that showed predominant distribution at low risk (80 %, 13 % and 7%, respectively). Case-fatality was 11%. The C-statistics of the TIMI score was 0.87 (95%CI = 0.76 to 0.98), similar to GRACE (0.87, 95%CI = 0.75 to 0.99) - p = 0.71. The TIMI score showed satisfactory calibration represented by chi2 = 1.4 (p = 0.92), well above the calibration of the GRACE score, which showed chi2 = 14 (p = 0.08). This calibration is reflected in the expected incidence ranges for low, intermediate and high risk, according to the TIMI score (0 %, 4.9 % and 25 %, respectively), differently to GRACE (2.4%, 25% and 73%), which featured middle range incidence inappropriately. CONCLUSION: Although the scores show similar discriminatory capacity for hospital death, the TIMI score had better calibration than GRACE. These findings need to be validated populations of different risk profiles. PMID- 25029472 TI - Association of peripheral arterial and cardiovascular diseases in familial hypercholesterolemia. AB - BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by an elevation in the serum levels of total cholesterol and of low-density lipoproteins (LDL- c). Known to be closely related to the atherosclerotic process, FH can determine the development of early obstructive lesions in different arterial beds. In this context, FH has also been proposed to be a risk factor for peripheral arterial disease (PAD). OBJECTIVE: This observational cross-sectional study assessed the association of PAD with other manifestations of cardiovascular disease (CVD), such as coronary artery and cerebrovascular disease, in patients with heterozygous FH. METHODS: The diagnosis of PAD was established by ankle-brachial index (ABI) values <= 0.90. This study assessed 202 patients (35% of men) with heterozygous FH (90.6% with LDL receptor mutations), mean age of 51 +/- 14 years and total cholesterol levels of 342 +/- 86 mg /dL. RESULTS: The prevalences of PAD and previous CVD were 17% and 28.2 %, respectively. On multivariate analysis, an independent association between CVD and the diagnosis of PAD was observed (OR = 2.50; 95% CI: 1.004 - 6.230; p = 0.049). CONCLUSION: Systematic screening for PAD by use of ABI is feasible to assess patients with FH, and it might indicate an increased risk for CVD. However, further studies are required to determine the role of ABI as a tool to assess the cardiovascular risk of those patients. PMID- 25029473 TI - Spectral analysis related to bare-metal and drug-eluting coronary stent implantation. AB - BACKGROUND: The autonomic nervous system plays a central role in cardiovascular regulation; sympathetic activation occurs during myocardial ischemia. OBJECTIVE: To assess the spectral analysis of heart rate variability during stent implantation, comparing the types of stent. METHODS: This study assessed 61 patients (mean age, 64.0 years; 35 men) with ischemic heart disease and indication for stenting. Stent implantation was performed under Holter monitoring to record the spectral analysis of heart rate variability (Fourier transform), measuring the low-frequency (LF) and high-frequency (HF) components, and the LF/HF ratio before and during the procedure. RESULTS: Bare-metal stent was implanted in 34 patients, while the others received drug-eluting stents. The right coronary artery was approached in 21 patients, the left anterior descending, in 28, and the circumflex, in 9. As compared with the pre-stenting period, all patients showed an increase in LF and HF during stent implantation (658 versus 185 ms2, p = 0.00; 322 versus 121, p = 0.00, respectively), with no change in LF/HF. During stent implantation, LF was 864 ms2 in patients with bare metal stents, and 398 ms2 in those with drug-eluting stents (p = 0.00). The spectral analysis of heart rate variability showed no association with diabetes mellitus, family history, clinical presentation, beta-blockers, age, and vessel or its segment. CONCLUSIONS: Stent implantation resulted in concomitant sympathetic and vagal activations. Diabetes mellitus, use of beta-blockers, and the vessel approached showed no influence on the spectral analysis of heart rate variability. Sympathetic activation was lower during the implantation of drug eluting stents. PMID- 25029474 TI - Proposal intensity adequacy of expiratory effort and heart rate behavior during the valsalva maneuver in preadolescents. AB - BACKGROUND: When performing the Valsalva maneuver (VM), adults and preadolescents produce the same expiratory resistance values. OBJECTIVE: To analyze heart rate (HR) in preadolescents performing VM, and propose a new method for selecting expiratory resistance. METHOD: The maximal expiratory pressure (MEP) was measured in 45 sedentary children aged 9-12 years who subsequently performed VM for 20 s using an expiratory pressure of 60%, 70%, or 80% of MEP. HR was measured before, during, and after VM. These procedures were repeated 30 days later, and the data collected in the sessions (E1, E2) were analyzed and compared in periods before, during (0-10 and 10-20 s), and after VM using nonparametric tests. RESULTS: All 45 participants adequately performed VM in E1 and E2 at 60% of MEP. However, only 38 (84.4%) and 25 (55.5%) of the participants performed the maneuver at 70% and 80% of MEP, respectively. The HR delta measured during 0-10 s and 10-20 s significantly increased as the expiratory effort increased, indicating an effective cardiac autonomic response during VM. However, our findings suggest the VM should not be performed at these intensities. CONCLUSION: HR increased with all effort intensities tested during VM. However, 60% of MEP was the only level of expiratory resistance that all participants could use to perform VM. Therefore, 60% of MEP may be the optimal expiratory resistance that should be used in clinical practice. PMID- 25029476 TI - Entropy of Movement Outcome in Space-Time. AB - Information entropy of the joint spatial and temporal (space-time) probability of discrete movement outcome was investigated in two experiments as a function of different movement strategies (space-time, space, and time instructional emphases), task goals (point-aiming and target-aiming) and movement speed accuracy constraints. The variance of the movement spatial and temporal errors was reduced by instructional emphasis on the respective spatial or temporal dimension, but increased on the other dimension. The space-time entropy was lower in targetaiming task than the point aiming task but did not differ between instructional emphases. However, the joint probabilistic measure of spatial and temporal entropy showed that spatial error is traded for timing error in tasks with space-time criteria and that the pattern of movement error depends on the dimension of the measurement process. The unified entropy measure of movement outcome in space-time reveals a new relation for the speed-accuracy. PMID- 25029475 TI - A novel genomic signature with translational significance for human idiopathic pulmonary fibrosis. AB - The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat-human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-beta1-treated primary human lung fibroblasts and transforming growth factor-beta1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model-human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease. PMID- 25029477 TI - Errors in dual energy x-ray absorptiometry estimation of body composition induced by hypohydration. AB - Dual energy x-ray absorptiometry (DXA) is a popular tool to determine body composition (BC) in athletes, and is used for analysis of fat-free soft tissue mass (FFST) or fat mass (FM) gain/loss in response to exercise or nutritional interventions. The aim of the current study was to assess the effect of exercise heat stress induced hypohydration (HYP, >2% of body mass (BM) loss) vs. maintenance of euhydration (EUH) on DXA estimates of BC, sum of skinfolds (SF), and impedance (IMP) measurements in athletes. Competitive athletes (23 males and 15 females) recorded morning nude BM for 7 days before the first main trial. Measurements on the first trial day were conducted in a EUH condition, and again after exercise-heat stress induced HYP. On the second trial day, fluid and electrolyte losses were replaced during exercise using a sports drink. A reduction in total BM (1.6 +/- 0.4 kg; 2.3 +/- 0.4% HYP) and total FFST (1.3 +/- 0.4 kg), mainly from trunk (1.1 +/- 0.5 kg), was observed using DXA when participants were HYP, reflecting the sweat loss. Estimated fat percent increased (0.3 +/- 0.3%), however, total FM did not change (0.1 +/- 0.2 kg). SF and IMP declined with HYP (losses of 1.5 +/- 2.9% and 1.6 +/- 3% respectively) suggesting FM loss. When EUH was maintained there were no significant changes in BM, DXA estimates, or SF values pre to post exercise, but IMP still declined. We conclude that use of DXA for FFST assessment in athletes must ensure a EUH state, particularly when considering changes associated with nutritional or exercise interventions. PMID- 25029479 TI - Trion electroluminescence from semiconducting carbon nanotubes. AB - Near-infrared emission from semiconducting single-walled carbon nanotubes (SWNTs) usually results from radiative relaxation of excitons. By binding an additional electron or hole through chemical or electrochemical doping, charged three-body excitons, so-called trions, are created that emit light at lower energies. The energy difference is large enough to observe weak trion photoluminescence from doped SWNTs even at room temperature. Here, we demonstrate strong trion electroluminescence from electrolyte-gated, light-emitting SWNT transistors with three different polymer-sorted carbon nanotube species, namely, (6,5), (7,5) and (10,5). The red-shifted trion emission is equal to or even stronger than the exciton emission, which is attributed to the high charge carrier density in the transistor channel. The possibility of trions as a radiative relaxation pathway for triplets and dark excitons that are formed in large numbers by electron-hole recombination is discussed. The ratio of trion to exciton emission can be tuned by the applied voltages, enabling voltage-controlled near-infrared light sources with narrow line widths that are solution-processable and operate at low voltages (<3 V). PMID- 25029478 TI - Glutathione-coated luminescent gold nanoparticles: a surface ligand for minimizing serum protein adsorption. AB - Ultrasmall glutathione-coated luminescent gold nanoparticles (GS-AuNPs) are known for their high resistance to serum protein adsorption. Our studies show that these NPs can serve as surface ligands to significantly enhance the physiological stability and lower the serum protein adsorption of superparamagnetic iron oxide nanoparticles (SPIONs), in addition to rendering the NPs the luminescence property. After the incorporation of GS-AuNPs onto the surface of SPIONs to form the hybrid nanoparticles (HBNPs), these SPIONs' protein adsorption was about 10 fold lower than those of the pure glutathione-coated SPIONs suggesting that GS AuNPs are capable of providing a stealth effect against serum proteins. PMID- 25029480 TI - Sulfated glycosaminoglycans exploit the conformational plasticity of bone morphogenetic protein-2 (BMP-2) and alter the interaction profile with its receptor. AB - Sulfated glycosaminoglycans (GAGs) can direct cellular processes by interacting with proteins of the extracellular matrix (ECM). In this study we characterize the interaction profiles of chemically sulfated hyaluronan (HA) and chondroitin sulfate (CS) derivatives with bone morphogenetic protein-2 (BMP-2) and investigate their relevance for complex formation with the receptor BMPR-IA. These goals were addressed by surface plasmon resonance (SPR) and ELISA in combination with molecular modeling and dynamics simulation. We found not only the interaction of BMP-2 with GAGs to be dependent on the type and sulfation of GAGs but also BMP-2/GAG/BMPR-IA complex formation. The conformational plasticity of the BMP-2 N-termini plays a key role in the structural and thermodynamic characteristics of the BMP-2/GAG/BMPR-IA system. Hence we propose a model that provides direct insights into the importance of the structural and dynamical properties of the BMP-2/BMPR-IA system for its regulation by sulfated GAGs, in which structural asymmetry plays a key role. PMID- 25029481 TI - Imaging of N-linked glycans from formalin-fixed paraffin-embedded tissue sections using MALDI mass spectrometry. AB - Aberrant glycosylation is associated with most of the diseases. Direct imaging and profiling of N-glycans on tissue sections can reveal tissue-specific and/or disease-associated N-glycans, which not only could serve as molecular signatures for diagnosis but also shed light on the functional roles of these biomolecules. Mass spectrometry imaging (MSI) is a powerful tool that has been used to correlate peptides, proteins, lipids, and metabolites with their underlying histopathology in tissue sections. Here, we report an MSI technique for direct analysis of N-glycans from formalin-fixed paraffin-embedded (FFPE) tissues. This technique consists of sectioning FFPE tissues, deparaffinization, and rehydration of the sections, denaturing tissue proteins, releasing N-linked glycans from proteins by printing peptide-N-glycosidase F over the sections, spray-coating the tissue with matrix, and analyzing N-glycans by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Brain sections from a C57BL/6 mouse were imaged using this technique at a resolution of 100 MUm. Forty-two N glycans were analyzed from the mouse brain section. The mass spectrometry images were used to study the relative abundance of oligomannose, nonfucosylated, and fucosylated complex N-glycans in different brain areas including isocortex, hippocampal formation, and brainstem and specific glycans associated with different areas of the brain were identified. Furthermore, glioblastoma tumor xenografts in a NOD/SCID mouse were imaged. Several glycans with differential expression in tumor versus normal brain tissues were identified. The MSI technique allows for imaging of N-glycans directly from FFPE sections. This method can potentially identify tissue-specific and/or disease-associated glycans coexpressed with other molecular signatures or within certain histological structures. PMID- 25029482 TI - Ascorbic acid enhances oxidative stress tolerance and biological control efficacy of Pichia caribbica against postharvest blue mold decay of apples. AB - The effect of ascorbic acid (VC) on improving oxidative stress tolerance of Pichia caribbica and biocontrol efficacy against blue mold caused by Penicillium expansum on apples was investigated. P. caribbica showed susceptibility to the oxidative stress in vitro test, and 250 MUg/mL VC treatment improved its oxidative stress tolerance. The higher viability exhibited by VC-treated yeast was associated with a lower intracellular ROS level. The activities of antioxidant enzymes of P. caribbica were improved by VC treatment, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Additionally, VC-treated yeast exhibited greater biocontrol activity against P. expansum and faster growth when stored at 25 and 4 degrees C, respectively, compared to the performance of the non-VC-treated yeast. In response to the VC treatment under oxidative stress, several differentially expressed proteins were identified in P. caribbica, and most of the poteins were confirmed to be related to basic metabolism. Therefore, the application of ascorbic acid is a useful approach to improve oxidative stress tolerance of P. caribbica and its biocontrol efficacy on apples. PMID- 25029483 TI - Regio- and enantioselective Baeyer-Villiger oxidation: kinetic resolution of racemic 2-substituted cyclopentanones. AB - A kinetic resolution of racemic 2-substituted cyclopentanones via highly regio- and enantioselective Baeyer-Villiger oxidation has been successfully developed. The reaction could afford the normal 6-substituted delta-lactones in up to 98% ee and >19/1 regioselectivity. Meanwhile, the unreacted ketones were recovered in excellent ee values (up to 98%). It represents the best results of the kinetic resolution of racemic 2-substituted cyclopentanones via nonenzymic asymmetric BV oxidation. PMID- 25029484 TI - David. PMID- 25029485 TI - Molecular structure, infrared spectra, photochemistry, and thermal properties of 1-methylhydantoin. AB - The structural, vibrational, and photochemical study of 1-methylhydantoin (1-MH, C4H6N2O2) was undertaken by matrix isolation infrared spectroscopy (in argon matrix; 10 K), complemented by quantum chemical calculations performed at the DFT(B3LYP)/6-311++G(d,p) level of approximation. The theoretical calculations yielded the Cs symmetry structure, with planar heavy atom skeleton, as the minimum energy structure on the potential energy surface of the molecule. The electronic structure of this minimum energy structure of 1-MH was then studied in detail by means of the natural bond orbital (NBO) and atoms in molecules (AIM) approaches, allowing for the elucidation of specific characteristics of the molecule's sigma and pi electronic systems. The infrared spectrum of the matrix isolated 1-MH was fully assigned, also with the help of the theoretically predicted spectrum of the compound, and its UV-induced unimolecular photochemistry (lambda >= 230 nm) was investigated. The compound was found to fragment to CO, isocyanic acid, methylenimine, and N-methyl-methylenimine. Finally, a thermal behavior investigation on 1-MH samples was carried out using infrared spectroscopy (10 K until melting), differential scanning calorimetry and polarized light thermal microscopy. A new polymorph of 1-MH was identified. The IR spectra of the different observed phases were recorded and interpreted. PMID- 25029487 TI - Separating signal from noise: the challenge of identifying useful biomarkers in sepsis. AB - Sepsis diagnosis remains based largely on clinical presentation despite significant advances in the understanding of underlying pathophysiology and host pathogen interactions. The systematic review article by Zonneveld and colleagues in the previous issue of Critical Care describes another potential avenue of study for using biomarkers for sepsis diagnosis and prognostication. Soluble leukocyte adhesion molecules and their associated sheddase enzymes vary in detectable levels and activity in patients in relation to immunologic status, age, and systemic inflammation, including in the setting of sepsis. Unfortunately, studies of these molecules as diagnostic or prognostic aids (or both) in sepsis have thus far been disappointing. Zonneveld and colleagues propose two potential avenues to enhance the performance characteristics of soluble adhesion molecules and their sheddases in sepsis diagnosis and prognosis: (a) identifying age-adjusted normal values for soluble leukocyte adhesion molecules and their sheddases and (b) investigating simultaneous measurement of both soluble adhesion molecules and sheddases in integrated sepsis evaluation schema. This commentary discusses the proposed solutions of Zonneveld and colleagues in more detail and outlines additional considerations that should be addressed in order to develop robust and valid diagnostic and prognostic tools for clinicians managing patients with sepsis. PMID- 25029488 TI - Robust sensorimotor representation to physical interaction changes in humanoid motion learning. AB - This paper proposes a learning from demonstration system based on a motion feature, called phase transfer sequence. The system aims to synthesize the knowledge on humanoid whole body motions learned during teacher-supported interactions, and apply this knowledge during different physical interactions between a robot and its surroundings. The phase transfer sequence represents the temporal order of the changing points in multiple time sequences. It encodes the dynamical aspects of the sequences so as to absorb the gaps in timing and amplitude derived from interaction changes. The phase transfer sequence was evaluated in reinforcement learning of sitting-up and walking motions conducted by a real humanoid robot and compatible simulator. In both tasks, the robotic motions were less dependent on physical interactions when learned by the proposed feature than by conventional similarity measurements. Phase transfer sequence also enhanced the convergence speed of motion learning. Our proposed feature is original primarily because it absorbs the gaps caused by changes of the originally acquired physical interactions, thereby enhancing the learning speed in subsequent interactions. PMID- 25029486 TI - Pharmacological management of tetanus: an evidence-based review. AB - Tetanus is becoming rarer in both industrialized and developing nations due to an effective vaccination program. In 2010, the World Health Organization estimated there was a 93% reduction in newborns dying from tetanus worldwide, compared to the situation in the late 1980s. Due to its rarity, many diagnostic delays occur as physicians may not consider the diagnosis until the manifestations become overt. Without timely diagnosis and proper treatment, severe tetanus is fatal (mortality is also influenced by the comorbidities of the patient). The principles of treating tetanus are: reducing muscle spasms, rigidity and autonomic instability (with ventilatory support when necessary); neutralization of tetanus toxin with human antitetanus immunoglobulin or equine antitetanus sera; wound debridement; and administration of antibiotics to eradicate locally proliferating bacteria at the wound site. It is difficult to conduct trials on different treatment modalities in tetanus due to both logistical and ethical reasons. However, it is imperative that physicians are aware of the best evidence based treatment strategies currently available to improve the outcome of patients. This review concentrates on analyzing the current evidence on the pharmacological management of tetanus. PMID- 25029489 TI - Kernel association for classification and prediction: a survey. AB - Kernel association (KA) in statistical pattern recognition used for classification and prediction have recently emerged in a machine learning and signal processing context. This survey outlines the latest trends and innovations of a kernel framework for big data analysis. KA topics include offline learning, distributed database, online learning, and its prediction. The structural presentation and the comprehensive list of references are geared to provide a useful overview of this evolving field for both specialists and relevant scholars. PMID- 25029490 TI - Sparse multivariate gaussian mixture regression. AB - Fitting a multivariate Gaussian mixture to data represents an attractive, as well as challenging problem, in especial when sparsity in the solution is demanded. Achieving this objective requires the concurrent update of all parameters (weight, centers, and precisions) of all multivariate Gaussian functions during the learning process. Such is the focus of this paper, which presents a novel method founded on the minimization of the error of the generalized logarithmic utility function (GLUF). This choice, which allows us to move smoothly from the mean square error (MSE) criterion to the one based on the logarithmic error, yields an optimization problem that resembles a locally convex problem and can be solved with a quasi-Newton method. The GLUF framework also facilitates the comparative study between both extremes, concluding that the classical MSE optimization is not the most adequate for the task. The performance of the proposed novel technique is demonstrated on simulated as well as realistic scenarios. PMID- 25029491 TI - A comparison of self-reported leisure-time physical activity and measured moderate-to-vigorous physical activity in adolescents and adults. AB - BACKGROUND: Systematic reviews and results of Statistics Canada surveys have shown a discrepancy between self-reported and measured physical activity. This study compares these two methods and examines specific activities to explain the limitations of each method. DATA AND METHODS: Data are from cycle 1 (2007 to 2009) and cycle 2 (2009 to 2011) of the Canadian Health Measures Survey. The survey involved an interview in the respondent's home and a visit to a mobile examination centre (MEC) for physical measurements. In a questionnaire, respondents were asked about 21 leisure-time physical activities. They were requested to wear an Actical accelerometer for seven days after the MEC visit. The analysis pertains to respondents aged 12 to 79 who wore the accelerometer for 10 or more hours on at least four days (n = 7,158). RESULTS: Averages of self reported leisure-time physical activity and moderate-to-vigorous physical activity measured by accelerometer were within a couple of minutes of each other. However, at the individual level, the difference between estimates could exceed 37.5 minutes per day in one direction or the other, and around 40% of the population met physical activity thresholds according to one measurement method, but not according to the other. The disagreement is supported by weak observed correlations. INTERPRETATION: The lack of a systematic trend in the relationship between the two methods of measuring physical activity precludes the creation of correction factors or being confident in using one method instead of the other. Accelerometers and questionnaires measure different aspects of physical activity. PMID- 25029492 TI - Association between blood lead and blood pressure: Results from the Canadian Health Measures Survey (2007 to 2011). AB - BACKGROUND: Hypertension is the leading risk factor for cardiovascular disease, but its cause is not always known. Interest is increasing in the potential role of environmental chemicals, including lead. DATA AND METHODS: Data are from the first two cycles of the Canadian Health Measures Survey. Lead in whole blood (PbB), and systolic (SBP) and diastolic (DBP) blood pressure were measured and hypertension status was derived for 4,550 respondents aged 40 to 79. Linear regression estimated associations between PbB and SBP and DBP. Logistic regression estimated associations between PbB and hypertension. Adjusted least squares geometric means of PbB were estimated for hypertensive versus non hypertensive individuals. RESULTS: Compared with non-hypertensive individuals, those with hypertension had higher average PbB levels, were older, more likely to be male, and more likely to have other hypertension risk factors (diabetes, family history of high blood pressure). In adjusted regression models, a modest association emerged between PbB levels and SBP among 40- to 54-year-olds, and between PbB levels and DBP for the overall population. No association emerged between PbB levels and hypertension prevalence. INTERPRETATION: A modest association was observed between blood lead levels and blood pressure, but not with hypertension, in Canadian adults aged 40 to 79. PMID- 25029494 TI - Homocoupling defects in diketopyrrolopyrrole-based copolymers and their effect on photovoltaic performance. AB - We study the occurrence and effect of intrachain homocoupling defects in alternating push-pull semiconducting PDPPTPT polymers based on dithienyl diketopyrrolopyrrole (TDPPT) and phenylene (P) synthesized via a palladium catalyzed cross-coupling polymerization. Homocoupled TDPPT-TDPPT segments are readily identified by the presence of a low-energy shoulder in the UV/vis/NIR absorption spectrum. Remarkably, the signatures of these defects are found in many diketopyrrolopyrrole (DPP)-based copolymers reported in the literature. The defects cause a reduction of the band gap, a higher highest occupied molecular orbital (HOMO) level, a lower lowest unoccupied molecular orbital (LUMO) level, and a localization of these molecular orbitals. By synthesizing copolymers with a predefined defect concentration, we demonstrate that their presence reduces the short-circuit current and open-circuit voltage of solar cells based on blends of PDPPTPT with [70]PCBM. In virtually defect-free PDPPTPT, the power conversion efficiency is as high as 7.5%, compared to 4.5-5.6% for polymers containing 20% to 5% defects. PMID- 25029493 TI - Increased plasma cell-free DNA level during HTNV infection: correlation with disease severity and virus load. AB - Cell-free DNA (cf-DNA) in blood represents a promising DNA damage response triggered by virus infection or trauma, tumor, etc. Hantavirus primarily causes two diseases: haemorrhagic fever with renal syndrome (HFRS) and Hantavirus cardiopulmonary syndrome (HCPS), depending on different Hantavirus species. The aim of this study was to evaluate plasma cf-DNA levels in acute phase of HFRS, and to correlate plasma cf-DNA with disease severity and plasma Hanttan virus (HTNV) load. We observed the appearance of cf-DNA in 166 plasma samples from 76 HFRS patients: the plasma cf-DNA levels peaked at the hypotensive stage of HFRS, and then decreased gradually. Until the diuretic stage, there was no significant difference in plasma cf-DNA level between patients and the healthy control. Exclusively in the febrile/hypotensive stage, the plasma cf-DNA levels of severe/critical patients were higher than those of the mild/moderate group. Moreover, the plasma cf-DNA value in the early stage of HFRS was correlated with HTNV load and disease severity. In most of the patients, plasma cf-DNA displayed a low-molecular weight appearance, corresponding to the size of apoptotic DNA. In conclusion, the plasma cf-DNA levels were dynamically elevated during HFRS, and correlated with disease severity, which suggests that plasma cf-DNA may be a potential biomarker for the pathogenesis and prognosis of HFRS. PMID- 25029495 TI - Recess physical activity and perceived school environment among elementary school children. AB - Differences in recess physical activity (PA) according to perceived school environment among elementary school children were examined. Participants were 103 children from two schools in Japan. PA was measured using accelerometry for seven consecutive days. Time spent in sedentary or PA (light, moderate, or vigorous) during their morning recess (25 min) and lunch recess (15 min) was determined. The School Physical Activity Environment Scale (three factors: equipment, facility, and safety) was used to investigate perceived school environment. Environmental factor scores were assigned to low or high groups for each factor by median. An analysis of covariance, with grade as the covariate, was conducted separately by gender to examine differences in PA between two groups. During lunch recess, boys in the high-equipment group spent significantly more time in moderate PA (high: 1.5; low: 0.8 min) whereas girls in this group spent less time in light PA (9.3, 11.0). Boys in the high-facility group spent significantly less time in sedentary (2.3, 3.9) and more time in vigorous PA (2.4, 1.4) during lunch recess, and girls spent more time in moderate (2.1, 1.2) and vigorous PA (1.9, 1.3) during morning recess. Differences were observed in recess PA according to school environment perceptions. The present study may be useful for further intervention studies for the promotion of PA during recess. PMID- 25029496 TI - Emotional, restorative and vitalizing effects of forest and urban environments at four sites in Japan. AB - The present study investigated the well-being effects of short-term forest walking and viewing ("forest bathing"). The hypothesis in our study was that both environment (forest vs. urban) and activity (walking and viewing) would influence psychological outcomes. An additional aim was to enhance basic research using several psychological methods. We conducted the experiments using 45 respondents in four areas of Japan from August to September, 2011. The hypothesis in our study was supported, because significant interaction terms between the environment and activity were confirmed regarding the Profile of Mood States (POMS) indexes, Restorative Outcome Scale (ROS) and Subjective Vitality Scale (SVS). No statistical differences between the two experimental groups in any of the ten scales were found before the experiment. However, feelings of vigor and positive effects, as well as feelings of subjective recovery and vitality were stronger in the forest environment than in the urban environment. PMID- 25029497 TI - FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease. AB - Mutations in the F-box only protein 7 gene (FBXO7), the substrate-specifying subunit of SCF E3 ubiquitin ligase complex, cause Parkinson's disease (PD)-15 (PARK15). To identify new variants, we sequenced FBXO7 cDNA in 80 Taiwanese early onset PD patients (age at onset <= 50) and only two known variants, Y52C (c.155A>G) and M115I (c.345G>A), were found. To assess the association of Y52C and M115I with the risk of PD, we conducted a case-control study in a cohort of PD and ethnically matched controls. There was a nominal difference in the Y52C G allele frequency between PD and controls (p = 0.045). After combining data from China [1], significant difference in the Y52C G allele frequency between PD and controls (p = 0.012) and significant association of G allele with decreased PD risk (p = 0.017) can be demonstrated. Upon expressing EGFP-tagged Cys52 FBXO7 in cells, a significantly reduced rate of FBXO7 protein decay was observed when compared with cells expressing Tyr52 FBXO7. In silico modeling of Cys52 exhibited a more stable feature than Tyr52. In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced. Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination, which may be responsible for the reduced TRAF2 expression in Cys52 cells. After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. We therefore hypothesize that Cys52 variant of FBXO7 may contribute to reduced PD susceptibility in Chinese. PMID- 25029498 TI - Balancing energy budget in a central-place forager: which habitat to select in a heterogeneous environment? AB - Foraging animals are influenced by the distribution of food resources and predation risk that both vary in space and time. These constraints likely shape trade-offs involving time, energy, nutrition, and predator avoidance leading to a sequence of locations visited by individuals. According to the marginal-value theorem (MVT), a central-place forager must either increase load size or energy content when foraging farther from their central place. Although such a decision rule has the potential to shape movement and habitat selection patterns, few studies have addressed the mechanisms underlying habitat use at the landscape scale. Our objective was therefore to determine how Ring-billed gulls (Larus delawarensis) select their foraging habitats while nesting in a colony located in a heterogeneous landscape. Based on locations obtained by fine-scale GPS tracking, we used resource selection functions (RSFs) and residence time analyses to identify habitats selected by gulls for foraging during the incubation and brood rearing periods. We then combined this information to gull survey data, feeding rates, stomach contents, and calorimetric analyses to assess potential trade-offs. Throughout the breeding season, gulls selected landfills and transhipment sites that provided higher mean energy intake than agricultural lands or riparian habitats. They used landfills located farther from the colony where no deterrence program had been implemented but avoided those located closer where deterrence measures took place. On the other hand, gulls selected intensively cultured lands located relatively close to the colony during incubation. The number of gulls was then greater in fields covered by bare soil and peaked during soil preparation and seed sowing, which greatly increase food availability. Breeding Ring-billed gulls thus select habitats according to both their foraging profitability and distance from their nest while accounting for predation risk. This supports the predictions of the MVT for central-place foraging over large spatial scales. PMID- 25029499 TI - Identification of drug combinations containing imatinib for treatment of BCR-ABL+ leukemias. AB - The BCR-ABL translocation is found in chronic myeloid leukemia (CML) and in Ph+ acute lymphoblastic leukemia (ALL) patients. Although imatinib and its analogues have been used as front-line therapy to target this mutation and control the disease for over a decade, resistance to the therapy is still observed and most patients are not cured but need to continue the therapy indefinitely. It is therefore of great importance to find new therapies, possibly as drug combinations, which can overcome drug resistance. In this study, we identified eleven candidate anti-leukemic drugs that might be combined with imatinib, using three approaches: a kinase inhibitor library screen, a gene expression correlation analysis, and literature analysis. We then used an experimental search algorithm to efficiently explore the large space of possible drug and dose combinations and identified drug combinations that selectively kill a BCR-ABL+ leukemic cell line (K562) over a normal fibroblast cell line (IMR-90). Only six iterations of the algorithm were needed to identify very selective drug combinations. The efficacy of the top forty-nine combinations was further confirmed using Ph+ and Ph- ALL patient cells, including imatinib-resistant cells. Collectively, the drug combinations and methods we describe might be a first step towards more effective interventions for leukemia patients, especially those with the BCR-ABL translocation. PMID- 25029500 TI - A one-step, triplex, real-time RT-PCR assay for the simultaneous detection of enterovirus 71, coxsackie A16 and pan-enterovirus in a single tube. AB - The recent, ongoing epidemic of hand, foot, and mouth disease (HFMD), which is caused by enterovirus infection, has affected millions of children and resulted in thousands of deaths in China. Enterovirus 71 (EV71) and coxsackie A16 (CA16) are the two major distinct pathogens for HFMD. However, EV71 is more commonly associated with neurologic complications and even fatalities. Therefore, simultaneously detecting and differentiating EV71 and CA16 specifically from other enteroviruses for diagnosing HFMD is important. Here, we developed a one step, triplex, real-time RT-PCR assay for the simultaneous detection of EV71, CA16, and pan-enterovirus (EVs) in a single tube with an internal amplification control. The detection results for the serially diluted viruses indicate that the lower limit of detection for this assay is 0.001-0.04 TCID50/ml, 0.02 TCID50/ml, and 0.001 TCID50/ml for EVs, EV71, and CA16, respectively. After evaluating known HFMD virus stocks of 17 strains of 16 different serotypes, this assay showed a favorable detection spectrum and no obvious cross-reactivity. The results for 141 clinical throat swabs from HFMD-suspected patients demonstrated sensitivities of 98.4%, 98.7%, and 100% for EVs, EV71, and CA16, respectively, and 100% specificity for each virus. The application of this one-step, triplex, real-time RT-PCR assay in clinical units will contribute to HFMD surveillance and help to identify causative pathogen in patients with suspected HFMD. PMID- 25029501 TI - Pregnancy-related attrition in general surgery. AB - IMPORTANCE: Residency attrition rates remain a great challenge for general surgery training programs. Despite the increasing acceptance of pregnancy during training, 1 common perception is that women who become pregnant are at increased risk of leaving surgery programs. OBJECTIVE: To determine whether child rearing increases the risk of attrition from general surgery residency. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of all categorical general surgery residents in a single academic general surgery residency program over a 10-year period. All categorical general surgery residents matriculated from July 1, 1999, until July 1, 2009. MAIN OUTCOMES AND MEASURES: Voluntary attrition rate, involuntary attrition rate, and incidence of child rearing among residents. RESULTS: Eighty-five residents matched into categorical general surgery postgraduate year 1 spots from July 1, 1999, to July 1, 2009. Of the total residents, 49 (58%) were men while 36 (42%) were women. Attrition in the program was 18.8% (16 of 85). Seven (44%) of the residents who left the program were women; this was 19% of all female residents in the program. This was not significantly different from the proportion of men who left the program (P = .90). A higher percentage of women (57%) left after their intern year compared with men (22%). Furthermore, men had the highest rate of attrition during research (33%) while no women left during research years. Among the 85 residents, 9 women reported a total of 10 pregnancies and 16 men reported raising 21 children (1 woman and 1 man left the program). The proportion of child rearing was higher in those who did not leave the program but this did not reach significance (P = .10). Neither age (odds ratio, 1.0; 95% CI, 0.8-1.4), sex (odds ratio, 1.0; 95% CI, 0.2-3.6), nor incidence of child rearing during training (odds ratio, 1.0; 95% CI, 0.1-9.6) were associated with an increased risk of attrition. Residents with children born during training did not demonstrate fewer total case numbers (men, P = .40; women, P = .93) or board pass rates (men, P = .76; women, P = .50) compared with residents who did not have children during training. Women who had children during training were more likely to pursue fellowship (87.5%) than those who did not (66.7%)(P < .001). CONCLUSIONS AND RELEVANCE: The current study demonstrated there was no association between female sex and attrition at our institution. Child rearing did not appear to be a risk factor for attrition in either men or women. Furthermore, child rearing did not negatively impact the quality of training based on case numbers and board pass rates. Despite prevalent stereotypes, child rearing did not cause women or men to leave the program. PMID- 25029502 TI - Nitrogen sources, transport and processing in peri-urban floodplains. AB - Peri-urban floodplains are an important interface between developed land and the aquatic environment and may act as a source or sink for contaminants moving from urban areas towards surface water courses. With increasing pressure from urban development the functioning of floodplains is coming under greater scrutiny. A number of peri-urban sites have been found to be populated with legacy landfills which could potentially cause pollution of adjacent river bodies. Here, a peri urban floodplain adjoining the city of Oxford, UK, with the River Thames has been investigated over a period of three years through repeated sampling of groundwaters from existing and specially constructed piezometers. A nearby landfill has been found to have imprinted a strong signal on the groundwater with particularly high concentrations of ammonium and generally low concentrations of nitrate and dissolved oxygen. An intensive study of nitrogen dynamics through the use of N-species chemistry, nitrogen isotopes and dissolved nitrous oxide reveals that there is little or no denitrification in the majority of the main landfill plume, and neither is the ammonium significantly retarded by sorption to the aquifer sediments. A simple model has determined the flux of total nitrogen and ammonium from the landfill, through the floodplain and into the river. Over an 8 km reach of the river, which has a number of other legacy landfills, it is estimated that 27.5 tonnes of ammonium may be delivered to the river annually. Although this is a relatively small contribution to the total river nitrogen, it may represent up to 15% of the ammonium loading at the study site and over the length of the reach could increase in-stream concentrations by nearly 40%. Catchment management plans that encompass floodplains in the peri-urban environment need to take into account the likely risk to groundwater and surface water quality that these environments pose. PMID- 25029503 TI - Risk assessment of total and bioavailable potentially toxic elements (PTEs) in urban soils of Baghdad-Iraq. AB - The solubility of soil-associated potentially toxic elements (PTEs) in surrogate biological fluids provides valuable information about their potential health hazard. This work addresses the concentrations and bioaccessibility of nine PTEs (As, Co, Cr, Cu, Mn, Ni, Pb, V, and Zn) in thirty eight agricultural land and playground soils collected from a semi-arid urban area of Baghdad-Iraq. Two surrogate biological fluids (SBFs), macrophage vacuole (MS) and gastric (GS) solutions, were used to extract the metals to simulate the biological availability of the PTEs via inhalation and ingestion exposure routes. ICP/AES was used to quantify PTEs in both strong acid digests (for total concentration), and in the SBF extracts. Soil contamination factors showed that some sites exhibited elevated levels of As (36 +/- 10 mg/kg), however, these levels of As are not likely to have significant human health impacts whether the particulate arsenic is ingested or/and inhaled. Soil-geochemical variables (including: pH, EC, CO3(=), soil organic carbon (SOC)) and major elements (e.g. Al, Ca, and Fe) were used to interpret the lability of PTEs in the soils. Hazardous index (HI) based non-cancer risk of inhalation and ingestion of PTEs was estimated to be 2 fold higher for that based on total element concentrations compared with that for bioavailable fractions for both children and adults. A similar conclusion was reached for the estimated cancer risk (which was lower than the threshold level of concern for children and adults). A sensitivity analysis showed that there is a 97% chance for children and 90% for adults to have hazardous indices of the total PTEs >1 (the acceptable value); the corresponding metrics for the bioavailable fraction of the elements were 39% for children, and 3% for adults; these results were sensitive to the concentrations of "airborne" soil particles. PMID- 25029504 TI - Stereoisomeric profiling of drugs of abuse and pharmaceuticals in wastewaters of Valencia (Spain). AB - The enantiomeric and diastereomeric profiling of chiral pharmaceuticals (ephedrine, norephedrine, atenolol and venlafaxine) and illicit drugs (amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4 methylenedioxy-N-methylamphetamine (MDMA) and 3,4-methylenedioxy-N ethylamphetamine (MDEA)) was undertaken over a period of fourteen consecutive days in three wastewater treatment plants (WWTPs) in the city of Valencia, Spain. Degradation efficiency of WWTPs was found to be compound and enantiomer dependent. Selective enantiomer enrichment was observed for several target analytes. Amphetamine and MDMA were enriched with R(-)-enantiomers. 1S,2S(+) pseudoephedrine was found to be more readily degradable during activated sludge treatment than its diastereomer 1R,2S(-)-ephedrine. Atenolol underwent enrichment with either S(-)- or R(+)-enantiomer in different WWTPs. This unexpected enantiomeric variation in the stereoselective degradation of atenolol could be attributed to different processes utilized during activated sludge treatment. The application of (enantiomeric) profiling of wastewater revealed usage patterns of chiral drugs in the Valencia region. PMID- 25029505 TI - Potential bioactivity and association of 17beta-estradiol with the dissolved and colloidal fractions of manure and soil. AB - The dissolved (DF) and colloidal fractions (CF) of soil and manure play an important role in the environmental fate and transport of steroidal estrogens. The first objective of this study was to quantify the association of 17beta estradiol (E2) with the DF and CF isolated from (i) liquid swine manure (LSM), (ii) a soil:water mixture (soil), and (iii) a LSM:soil:water mixture (Soil+LSM). The appropriate CF and DF size fractions of the Soil, Soil+LSM, and LSM media were obtained by first filtering through a 0.45 MUm filter, which provided the combined DF and CF (DF/CF). The DF/CF from the three media was spiked with carbon 14 ([(14)C]) radiolabeled E2 ([(14)C]-E2), and then ultrafiltered to isolate the CF (<0.45 MUm and >1 kDa) from the DF (<1 kDa). The average recoveries of the [(14)C] associated with the DF were 67%-72%, 67%-79%, and 76%-78% for the Soil, Soil+LSM and LSM, respectively. For the CF that was retained on the 1 kDa filter, organic carbon and [(14)C]-E2 were dislodged with subsequent water rinses the Soil+LSM and LSM, but not the Soil. The second objective was to evaluate whether the E2 associated with the various fractions of the different media could still bind the estrogen receptor using an E2 receptor (17beta-ER) competitor assay, which allowed E2 equivalent concentrations to be determined. The estrogen receptor assay results indicated that E2 present in the DF of the Soil and Soil+LSM solutions could still bind the estrogen receptor. Results from this study indicated that E2 preferentially associated with the DF of soil and manure, which may enhance its dissolved advective transport in surface and subsurface water. Furthermore, this study indicated that E2 associated with DF solutions in the environment could potentially induce endocrine responses through its interactions with estrogen receptor. PMID- 25029506 TI - How many wolves (Canis lupus) fit into Germany? The role of assumptions in predictive rule-based habitat models for habitat generalists. AB - Due to legislative protection, many species, including large carnivores, are currently recolonizing Europe. To address the impending human-wildlife conflicts in advance, predictive habitat models can be used to determine potentially suitable habitat and areas likely to be recolonized. As field data are often limited, quantitative rule based models or the extrapolation of results from other studies are often the techniques of choice. Using the wolf (Canis lupus) in Germany as a model for habitat generalists, we developed a habitat model based on the location and extent of twelve existing wolf home ranges in Eastern Germany, current knowledge on wolf biology, different habitat modeling techniques and various input data to analyze ten different input parameter sets and address the following questions: (1) How do a priori assumptions and different input data or habitat modeling techniques affect the abundance and distribution of potentially suitable wolf habitat and the number of wolf packs in Germany? (2) In a synthesis across input parameter sets, what areas are predicted to be most suitable? (3) Are existing wolf pack home ranges in Eastern Germany consistent with current knowledge on wolf biology and habitat relationships? Our results indicate that depending on which assumptions on habitat relationships are applied in the model and which modeling techniques are chosen, the amount of potentially suitable habitat estimated varies greatly. Depending on a priori assumptions, Germany could accommodate between 154 and 1769 wolf packs. The locations of the existing wolf pack home ranges in Eastern Germany indicate that wolves are able to adapt to areas densely populated by humans, but are limited to areas with low road densities. Our analysis suggests that predictive habitat maps in general, should be interpreted with caution and illustrates the risk for habitat modelers to concentrate on only one selection of habitat factors or modeling technique. PMID- 25029508 TI - Making time for learning-oriented leadership in multidisciplinary hospital management groups. AB - BACKGROUND: Although the clinical requirements of health care delivery imply the need for interdisciplinary management teams to work together to promote frontline learning, such interdisciplinary, learning-oriented leadership is atypical. PURPOSE: We designed this study to identify behaviors enabling groups of diverse managers to perform as learning-oriented leadership teams on behalf of quality and safety. APPROACH: We randomly selected 12 of 24 intact groups of hospital managers from one hospital to participate in a Safety Leadership Team Training program. We collected primary data from March 2008 to February 2010 including pre and post-staff surveys, multiple interviews, observations, and archival data from management groups. We examined the level and trend in frontline perceptions of managers' learning-oriented leadership following the intervention and ability of management groups to achieve objectives on targeted improvement projects. Among the 12 intervention groups, we identified higher- and lower-performing intervention groups and behaviors that enabled higher performers to work together more successfully. FINDINGS: Management groups that achieved more of their performance goals and whose staff perceived more and greater improvement in their learning-oriented leadership after participation in Safety Leadership Team Training invested in structures that created learning capacity and conscientiously practiced prescribed learning-oriented management and problem solving behaviors. They made the time to do these things because they envisioned the benefits of learning, valued the opportunity to learn, and maintained an environment of mutual respect and psychological safety within their group. PRACTICE IMPLICATIONS: Learning in management groups requires vision of what learning can accomplish; will to explore, practice, and build learning capacity; and mutual respect that sustains a learning environment. PMID- 25029507 TI - Adherence to Internet-based and face-to-face cognitive behavioural therapy for depression: a meta-analysis. AB - BACKGROUND: Internet-based cognitive behavioural therapy (iCBT) is an effective and acceptable treatment for depression, especially when it includes guidance, but its treatment adherence has not yet been systematically studied. We conducted a meta-analysis, comparing the adherence to guided iCBT with the adherence to individual face-to-face CBT. METHODS: Studies were selected from a database of trials that investigate treatment for adult depression (see www.evidencebasedpsychotherapies.org), updated to January 2013. We identified 24 studies describing 26 treatment conditions (14 face-to-face CBT, 12 guided iCBT), by means of these inclusion criteria: targeting depressed adults, no comorbid somatic disorder or substance abuse, community recruitment, published in the year 2000 or later. The main outcome measure was the percentage of completed sessions. We also coded the percentage of treatment completers (separately coding for 100% or at least 80% of treatment completed). RESULTS: We did not find studies that compared guided iCBT and face-to-face CBT in a single trial that met our inclusion criteria. Face-to-face CBT treatments ranged from 12 to 28 sessions, guided iCBT interventions consisted of 5 to 9 sessions. Participants in face-to face CBT completed on average 83.9% of their treatment, which did not differ significantly from participants in guided iCBT (80.8%, P = .59). The percentage of completers (total intervention) was significantly higher in face-to-face CBT (84.7%) than in guided iCBT (65.1%, P < .001), as was the percentage of completers of 80% or more of the intervention (face-to-face CBT: 85.2%, guided iCBT: 67.5%, P = .003). Non-completers of face-to-face CBT completed on average 24.5% of their treatment, while non-completers of guided iCBT completed on average 42.1% of their treatment. CONCLUSION: We did not find studies that compared guided iCBT and face-to-face CBT in a single trial. Adherence to guided iCBT appears to be adequate and could be equal to adherence to face-to-face CBT. PMID- 25029509 TI - Leadership transitions in multisectoral health care alliances: Implications for member perceptions of participation value. AB - BACKGROUND: Collaborative forms of organizations such as multisectoral health care alliances play an increasingly prominent role in the U.S. health care system. A key feature of these organizations highlighted in previous research is leadership, yet little research has examined what happens when there is a change in leadership. PURPOSE: The aim of this study was to examine the relationship between leadership transitions in an alliance and member assessments of the benefits and costs of participation, indicators of the value that members derive from their involvement in the alliance. METHODOLOGY/APPROACH: The study used quantitative data collected from three rounds of surveys of alliance members participating in the Robert Wood Johnson Foundation's Aligning Forces for Quality Program. Qualitative interview data supplemented this analysis by providing examples of why leadership transitions may affect participation benefits and costs. FINDINGS: Quantitative analysis indicated that alliance members who experienced a change in leadership reported both higher and lower levels of participation benefits and costs, depending on the type of leadership change (i.e., alliance leader vs. programmatic leader). Qualitative analysis suggested that the scope of responsibilities of different types of leaders plays an important role in how members perceive changes. Likewise, interviews indicated that timing influences how disruptive a leadership transition is and whether it is perceived positively or negatively. PRACTICE IMPLICATIONS: Leadership transitions present both challenges and opportunities; whether the effects are felt positively or negatively depends on when a transition occurs and how it is handled by incoming leaders and remaining members. Furthermore, different types of members report higher levels of participation benefits and lower levels of participation costs, suggesting that efforts to maintain a sense of alliance value during times of transitions may be able to target certain types of individuals. PMID- 25029510 TI - Public hospitals in financial distress: Is privatization a strategic choice? AB - BACKGROUND: As safety net providers, public hospitals operate in more challenging environments than private hospitals. Such environments put public hospitals at greater risk of financial distress, which may result in privatization and deterioration of the safety net. PURPOSE: The purpose of this study was to investigate whether financial distress is associated with privatization among public hospitals. METHODOLOGY/APPROACH: We used panel data merged from the American Hospital Association Annual Survey, Medicare Cost Reports, Area Resource File, and Local Area Unemployment Statistics. Our study population consisted of all U.S. nonfederal acute care public hospitals in 1997 tracked through 2009, resulting in 6,426 hospital-year observations. The dependent variable "privatization" was defined as conversion from public status to either private not-for-profit or private for-profit status. The main independent variable, "financial distress," was based on the Altman Z-score methodology. Control variables included market and organizational factors. Two random-effects logistic regression models with state and year fixed-effects were constructed. The independent and control variables were lagged by 1 year and 2 years for Models 1 and 2, respectively. FINDINGS: Public hospitals in financial distress had greater odds of being privatized than public hospitals not in financial distress: (OR = 4.53, p < .001) for Model 1 and (OR = 3.05, p = .001) for Model 2. PRACTICE IMPLICATIONS: Privatization eases access to resources and may provide financial relief to government entities from the burden of continuously funding a hospital operating at a loss, which in turn may help keep the hospital open and preserve access to care for the community. Privatizing a financially distressed public hospital may be a better strategic alternative than closure. The Altman Z-score could be used as a managerial tool to monitor hospitals' financial condition and take corrective actions. PMID- 25029511 TI - Huddle up!: The adoption and use of structured team communication for VA medical home implementation. AB - BACKGROUND: Daily clinical team meetings (i.e., "huddles") may be helpful in implementing new roles and responsibilities for patient care because they provide a regular opportunity for member learning and feedback. PURPOSES: We examined how huddles were implemented in the context of the VA patient-centered medical home (PCMH) transformation, including assessing barriers and facilitators to regular huddling among small teams ("teamlets"). We assessed the extent to which teamlet members that huddled had higher self-efficacy for PCMH changes, reported better teamwork experiences, and perceived more supportive practice environments. METHODOLOGY/APPROACH: We used a convergent mixed-methods approach to analyze 79 teamlet member interviews from six VA primary care practices and 418 clinician and staff PCMH survey responses from the six interviewed practices and 13 additional practices in the same region. FINDINGS: Most members reported participating in teamlet huddles when asked in surveys (85%). A minority of interview participants, however, described routine huddling focused on previsit planning that included all members. When members reported routine teamlet huddling, activities included (a) previsit planning, (b) strategizing treatment plans for patients with special or complex needs, (c) addressing daily workflow and communication issues through collective problem solving, and (d) ensuring awareness of what team members do and what actions are happening on the teamlet and in the practice. Primary care providers (PCPs) were least likely to report routine huddling. PCP huddlers reported greater self-efficacy for implementing PCMH changes. All huddlers, irrespective of role, reported better teamwork and more supportive practice climates. The most common barriers to teamlet huddling were limited time and operational constraints. PRACTICE IMPLICATIONS: In order to improve the impact of huddles on patient care, practice leaders should clearly communicate the goals, requirements, and benefits of huddling and provide adequate time and resources to ensure that frontline teams use huddle time to improve patient care. PMID- 25029512 TI - The influence of organizational factors on patient safety: Examining successful handoffs in health care. AB - BACKGROUND: Although patient handoffs have been extensively studied, they continue to be problematic. Studies have shown poor handoffs are associated with increased costs, morbidity, and mortality. No prior research compared perceptions of management and clinical staff regarding handoffs. PURPOSE: Our aims were (a) to determine whether perceptions of organizational factors that can influence patient safety are positively associated with perceptions of successful patient handoffs, (b) to identify organizational factors that have the greatest influence on perceptions of successful handoffs, and (c) to determine whether associations between perceptions of these factors and successful handoffs differ for management and clinical staff. METHODOLOGY/APPROACH: A total of 515,637 respondents from 1,052 hospitals completed the Hospital Survey on Patient Safety Culture that assessed perceptions about organizational factors that influence patient safety. Using weighted least squares multiple regression, we tested seven organizational factors as predictors of successful handoffs. We fit three separate models using data collected from (a) all staff, (b) management only, and (c) clinical staff only. FINDINGS: We found that perceived teamwork across units was the most significant predictor of perceived successful handoffs. Perceptions of staffing and management support for safety were also significantly associated with perceived successful handoffs for both management and clinical staff. For management respondents, perceptions of organizational learning or continuous improvement had a significant positive association with perceived successful handoffs, whereas the association was negative for clinical staff. Perceived communication openness had a significant association only among clinical staff. PRACTICE IMPLICATIONS: Hospitals should prioritize teamwork across units and strive to improve communication across the organization in efforts to improve handoffs. In addition, hospitals should ensure sufficient staffing and management support for patient safety. Different perceptions between management and clinical staff with respect to the importance of organizational learning are noteworthy and merit additional study. PMID- 25029513 TI - Novel three-dimensional imaging volumetry in autosomal dominant polycystic kidney disease: comparison with 2D volumetry. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) volumetry is an important marker for evaluating the progression of disease. Three-dimensional (3D) volumetry is generally more timesaving than 2D volumetry, but its reliability and accuracy are uncertain. METHODS: Small and large phantoms simulating polycystic kidneys and 20 patients with ADPKD underwent magnetic resonance imaging (MRI) volumetry. We evaluated the total kidney volume (TKV) and total cyst volume (TCV) using a novel 3D volumetry program (XelisTM) and compared 3D volumetry data with the conventional 2D method (the reference volume values). After upload and threshold setting, the other organs surrounding the kidney were removed by picking and sculpting. The novel method involves drawing of the kidney or cyst and automatic measurement of kidney volume and cyst volume in 3D images. RESULTS: The 3D volume estimation of the small and large phantoms differed from the actual values by 6.9% and -8.2%, respectively, for TKV and by 2.1% and 1.4% for TCV. In ADPKD patients, the intra-reader reliability of 3D volumetry was 30 +/- 180 mL (1.3 +/- 10.3%) and 25 +/- 113 mL (1.2 +/- 9.4%), respectively, for TKV and TCV. Correlation between 3D volumetry and 2D volumetry of TKV and TCV resulted in a high correlation coefficient and a regression slope approaching 1.00 (r = 0.97 - 0.98). The mean of the volume percentage differences for 3D vs. 2D for TKV : TCV were -6.0 +/- 8.9% : 2.0 +/- 11.8% in large ADPKD and -16.1 +/- 10.4% : 13.2 +/- 21.9% in small ADPKD. CONCLUSION: Our study showed that 3D volumetry has reliability and accuracy compared with 2D volumetry in ADPKD. 3D volumetry is more accurate for TCV and large ADPKD. PMID- 25029515 TI - Preparation of highly anisotropic cobalt ferrite/silica microellipsoids using an external magnetic field. AB - Magnetic cobalt ferrite/silica microparticles having both an original morphology and an anisotropic nanostructure are synthesized through the use of an external magnetic field and nanoparticles characterized by a high magnetic anisotropy. The association of these two factors implies that the ESE (emulsion and solvent evaporation) sol-gel method employed here allows the preparation of silica microellipsoids containing magnetic nanoparticles aggregated in large chains. It is clearly shown that without this combination, microspheres characterized by an isotropic distribution of the magnetic nanoparticles are obtained. While the chaining of the cobalt ferrite nanoparticles inside the silica matrix is related to the increase of their magnetic dipolar interactions, the ellipsoidal shape of the microparticles may be explained by the elongation of the sol droplets in the direction of the external magnetic field during the synthesis. Because of their highly anisotropic structure, these microparticles exhibit permanent magnetic moments, which are responsible, at a larger scale, for the existence of strong magnetic dipolar interactions. Therefore, when they are dispersed in water, the microellipsoids self-assemble into large and irregular chains. These interactions can be reinforced by the use of external magnetic field, allowing the preparation of very large permanent chains. This research illustrates how nanostructured particles exhibiting complex architectures can be elaborated through simple, fast, and low-cost methods, such as the use of external fields in combination with soft chemistry. PMID- 25029514 TI - The risk of stable partnerships: associations between partnership characteristics and unprotected anal intercourse among men who have sex with men and transgender women recently diagnosed with HIV and/or STI in Lima, Peru. AB - BACKGROUND: Partnership type is an important factor associated with unprotected anal intercourse (UAI) and subsequent risk for HIV and sexually transmitted infections (STI). We examined the association of partnership type with UAI among men who have sex with men (MSM) and male-to-female transgender women (TGW) in Lima, Peru, recently diagnosed with HIV and/or STI. METHODS: We report data from a cross-sectional analysis of MSM and TGW recently diagnosed with HIV and/or STI in Lima, Peru between 2011 and 2012. We surveyed participants regarding UAI with up to their three most recent sexual partners according to partner type. Multivariable Generalized Estimate Equating (GEE) models with Poisson distribution were used to estimate prevalence ratios (PR) for UAI according to partner type. RESULTS: Among 339 MSM and TGW recently diagnosed with HIV and/or STI (mean age: 30.6 years, SD 9.0), 65.5% self-identified as homosexual/gay, 16.0% as bisexual, 15.2% as male-to-female transgender, and 3.3% as heterosexual. Participants provided information on 893 recent male or TGW partners with whom they had engaged in insertive or receptive anal intercourse: 28.9% stable partners, 56.4% non-stable/non-transactional partners (i.e. casual or anonymous), and 14.7% transactional partners (i.e. transactional sex client or sex worker). Unprotected anal intercourse was reported with 41.3% of all partners. In multivariable analysis, factors associated with UAI included partnership type (non-stable/non-transactional partner APR 0.73, [95% CI 0.59-0.91], transactional partner APR 0.53 [0.36-0.78], p<0.05) and the number of previous sexual encounters with the partner (>10 encounters APR 1.43 [1.06-1.92], p<0.05). CONCLUSION: UAI was more commonly reported for stable partners and in partnerships with >10 sexual encounters, suggesting UAI is more prevalent in partnerships with a greater degree of interpersonal commitment. Further research assessing partner-level factors and behavior is critical for improving HIV and/or STI prevention efforts among Peruvian MSM and TGW. PMID- 25029516 TI - Pitfalls in bromination reactions of zinc porphyrins: two-sided ring opening of the porphyrin macrocycle. AB - Reaction of [Zn(II)(TTP)] (1) (TTP = dianion of 5,10,15,20-meso-tetrakis(p tolyl)porphyrin) with 16 equiv of N-bromosuccinamide (NBS) in methanol at reflux led to the unexpected two-sidedd open-ring brominated product [Zn(II)(C26H20N2O2Br5)2] (2). Similar observations have been made with other meso substituted zinc porphyrins as well [Zn(II)(por)] {por = dianion of 5,10,15,20 meso-tetrakis(aryl)porphyrin; aryl = phenyl (TPP), p-(t)Bu-phenyl (TBPP), m-Cl phenyl (TClPP)}. The respective products [Zn(II)(C24H16N2O2Br5)2] (3), [Zn(II)(C32H32N2O2Br5)2] (4), and [Zn(II)(C24H14N2O2Cl2Br5)2] (5) have been isolated in good to moderate yields and characterized by elemental analysis and UV-vis, (1)H NMR, and mass spectrometry. Additional bromination reaction of 1 with 8 equiv of NBS in a chloroform/methanol mixture led (after the two-sided ring opening) to nonmetalated brominated bi(pyrrole) product, C36H34N2O4Br4 (6). The detailed structures of complexes 1, 2, 3, and 6, available in a single crystal form, have been confirmed by X-ray diffraction analysis. PMID- 25029517 TI - Should we breathe quiet or noisy? AB - External noise is introduced by computer-generated random levels of pressure assistance during noisy pressure support ventilation (PSV). In patients, noisy PSV was associated with higher tidal volume variability but not improved cardio pulmonary function compared with conventional PSV. The potential role of noisy PSV in the management of critically ill patients requiring ventilatory support has to be explored further. PMID- 25029518 TI - The effect of immunosuppressive therapy on renal cell apoptosis in native rat kidneys. AB - AIM: To analyse the impact of the most commonly used immunosuppressive drugs on the occurrence of apoptosis in the native kidneys of Wistar rats. METHOD: The study involved 36 rats. the animals being grouped according to the immunosuppressive regimen used (tacrolimus, mycophenolate mofetil, cyclosporine A, rapamycin and prednisone). The rats in all study groups were treated with a 3 drug protocol for 6 months. The medication dose was adjusted based on available literature data. No drugs were administered to the control group. The rats were then killed. Autopsies of all animals were performed and the kidneys were isolated for histopathology (HE + PAS). To assess cell apoptosis the TUNEL reaction was performed. Blood trough levels of immunosuppressive drugs as well as the parameters of peripheral blood were determined. RESULTS: 1. In rats treated with cyclosporine A distal nephron tubules were characterised by more pronounced apoptosis. 2. In tacrolimus-treated rats a lower intensity of apoptosis was found in the distal tubules. 3. In rapamycin-treated rats the apoptosis was inhibited both in the distal and proximal nephron tubules. 4. In MMF treated rats intense apoptosis was observed in the proximal nephron tubules. 5. There were no significant changes in renal histopathology (HE + PAS). CONCLUSIONS: The apoptosis in nephron tubules caused by immunosuppressive therapy is not accompanied by any histopathological changes (eg fibrosis, inflammation, tubular atrophy, vacuolation of the tubular cells) in light microscopy. PMID- 25029520 TI - Network-based modeling and intelligent data mining of social media for improving care. AB - Intelligently extracting knowledge from social media has recently attracted great interest from the Biomedical and Health Informatics community to simultaneously improve healthcare outcomes and reduce costs using consumer-generated opinion. We propose a two-step analysis framework that focuses on positive and negative sentiment, as well as the side effects of treatment, in users' forum posts, and identifies user communities (modules) and influential users for the purpose of ascertaining user opinion of cancer treatment. We used a self-organizing map to analyze word frequency data derived from users' forum posts. We then introduced a novel network-based approach for modeling users' forum interactions and employed a network partitioning method based on optimizing a stability quality measure. This allowed us to determine consumer opinion and identify influential users within the retrieved modules using information derived from both word-frequency data and network-based properties. Our approach can expand research into intelligently mining social media data for consumer opinion of various treatments to provide rapid, up-to-date information for the pharmaceutical industry, hospitals, and medical staff, on the effectiveness (or ineffectiveness) of future treatments. PMID- 25029519 TI - Empiric potassium supplementation and increased survival in users of loop diuretics. AB - BACKGROUND: The effectiveness of the clinical strategy of empiric potassium supplementation in reducing the frequency of adverse clinical outcomes in patients receiving loop diuretics is unknown. We sought to examine the association between empiric potassium supplementation and 1) all-cause death and 2) outpatient-originating sudden cardiac death (SD) and ventricular arrhythmia (VA) among new starters of loop diuretics, stratified on initial loop diuretic dose. METHODS: We conducted a one-to-one propensity score-matched cohort study using 1999-2007 US Medicaid claims from five states. Empiric potassium supplementation was defined as a potassium prescription on the day of or the day after the initial loop diuretic prescription. Death, the primary outcome, was ascertained from the Social Security Administration Death Master File; SD/VA, the secondary outcome, from incident, first-listed emergency department or principal inpatient SD/VA discharge diagnoses (positive predictive value = 85%). RESULTS: We identified 654,060 persons who met eligibility criteria and initiated therapy with a loop diuretic, 27% of whom received empiric potassium supplementation (N = 179,436) and 73% of whom did not (N = 474,624). The matched hazard ratio for empiric potassium supplementation was 0.93 (95% confidence interval, 0.89-0.98, p = 0.003) for all-cause death. Stratifying on initial furosemide dose, hazard ratios for empiric potassium supplementation with furosemide < 40 and >= 40 milligrams/day were 0.93 (0.86-1.00, p = 0.050) and 0.84 (0.79-0.89, p < 0.0001). The matched hazard ratio for empiric potassium supplementation was 1.02 (0.83 1.24, p = 0.879) for SD/VA. CONCLUSIONS: Empiric potassium supplementation upon initiation of a loop diuretic appears to be associated with improved survival, with a greater apparent benefit seen with higher diuretic dose. If confirmed, these findings support the use of empiric potassium supplementation upon initiation of a loop diuretic. PMID- 25029521 TI - A machine learning system to improve heart failure patient assistance. AB - In this paper, we present a clinical decision support system (CDSS) for the analysis of heart failure (HF) patients, providing various outputs such as an HF severity evaluation, HF-type prediction, as well as a management interface that compares the different patients' follow-ups. The whole system is composed of a part of intelligent core and of an HF special-purpose management tool also providing the function to act as interface for the artificial intelligence training and use. To implement the smart intelligent functions, we adopted a machine learning approach. In this paper, we compare the performance of a neural network (NN), a support vector machine, a system with fuzzy rules genetically produced, and a classification and regression tree and its direct evolution, which is the random forest, in analyzing our database. Best performances in both HF severity evaluation and HF-type prediction functions are obtained by using the random forest algorithm. The management tool allows the cardiologist to populate a "supervised database" suitable for machine learning during his or her regular outpatient consultations. The idea comes from the fact that in literature there are a few databases of this type, and they are not scalable to our case. PMID- 25029522 TI - Preventive maintenance prioritization index of medical equipment using quality function deployment. AB - Preventive maintenance is a core function of clinical engineering, and it is essential to guarantee the correct functioning of the equipment. The management and control of maintenance activities are equally important to perform maintenance. As the variety of medical equipment increases, accordingly the size of maintenance activities increases, the need for better management and control become essential. This paper aims to develop a new model for preventive maintenance priority of medical equipment using quality function deployment as a new concept in maintenance of medical equipment. We developed a three-domain framework model consisting of requirement, function, and concept. The requirement domain is the house of quality matrix. The second domain is the design matrix. Finally, the concept domain generates a prioritization index for preventive maintenance considering the weights of critical criteria. According to the final scores of those criteria, the prioritization action of medical equipment is carried out. Our model proposes five levels of priority for preventive maintenance. The model was tested on 200 pieces of medical equipment belonging to 17 different departments of two hospitals in Piedmont province, Italy. The dataset includes 70 different types of equipment. The results show a high correlation between risk-based criteria and the prioritization list. PMID- 25029523 TI - Computer-aided diagnosis software for hypertensive risk determination through fundus image processing. AB - The goal of the software proposed in this paper is to assist ophthalmologists in diagnosis and disease prevention, helping them to determine cardiovascular risk or other diseases where the vessels can be altered, as well as to monitor the pathology progression and response to different treatments. The performance of the tool has been evaluated by means of a double-blind study where its sensitivity, specificity, and reproducibility to discriminate between health fundus (without cardiovascular risk) and hypertensive patients has been calculated in contrast to an expert ophthalmologist opinion obtained through a visual inspection of the fundus image. An improvement of almost 20% has been achieved comparing the system results with the clinical visual classification. PMID- 25029524 TI - An ontology-based annotation of cardiac implantable electronic devices to detect therapy changes in a national registry. AB - The patient population benefitting from cardiac implantable electronic devices (CIEDs) is increasing. This study introduces a device annotation method that supports the consistent description of the functional attributes of cardiac devices and evaluates how this method can detect device changes from a CIED registry. We designed the Cardiac Device Ontology, an ontology of CIEDs and device functions. We annotated 146 cardiac devices with this ontology and used it to detect therapy changes with respect to atrioventricular pacing, cardiac resynchronization therapy, and defibrillation capability in a French national registry of patients with implants (STIDEFIX). We then analyzed a set of 6905 device replacements from the STIDEFIX registry. Ontology-based identification of therapy changes (upgraded, downgraded, or similar) was accurate (6905 cases) and performed better than straightforward analysis of the registry codes (F-measure 1.00 versus 0.75 to 0.97). This study demonstrates the feasibility and effectiveness of ontology-based functional annotation of devices in the cardiac domain. Such annotation allowed a better description and in-depth analysis of STIDEFIX. This method was useful for the automatic detection of therapy changes and may be reused for analyzing data from other device registries. PMID- 25029525 TI - Sediment and turbidity associated with offshore dredging increase coral disease prevalence on nearby reefs. AB - In recent decades, coral reef ecosystems have declined to the extent that reefs are now threatened globally. While many water quality parameters have been proposed to contribute to reef declines, little evidence exists conclusively linking specific water quality parameters with increased disease prevalence in situ. Here we report evidence from in situ coral health surveys confirming that chronic exposure to dredging-associated sediment plumes significantly increase the prevalence of white syndromes, a devastating group of globally important coral diseases. Coral health surveys were conducted along a dredging-associated sediment plume gradient to assess the relationship between sedimentation, turbidity and coral health. Reefs exposed to the highest number of days under the sediment plume (296 to 347 days) had two-fold higher levels of disease, largely driven by a 2.5-fold increase in white syndromes, and a six-fold increase in other signs of compromised coral health relative to reefs with little or no plume exposure (0 to 9 days). Multivariate modeling and ordination incorporating sediment exposure level, coral community composition and cover, predation and multiple thermal stress indices provided further confirmation that sediment plume exposure level was the main driver of elevated disease and other compromised coral health indicators. This study provides the first evidence linking dredging associated sedimentation and turbidity with elevated coral disease prevalence in situ. Our results may help to explain observed increases in global coral disease prevalence in recent decades and suggest that minimizing sedimentation and turbidity associated with coastal development will provide an important management tool for controlling coral disease epizootics. PMID- 25029526 TI - Potential therapeutic targets for oral cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70. AB - In India, oral cancer has consistently ranked among top three causes of cancer related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL 10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT 3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70. PMID- 25029528 TI - Scaling in transportation networks. AB - Subway systems span most large cities, and railway networks most countries in the world. These networks are fundamental in the development of countries and their cities, and it is therefore crucial to understand their formation and evolution. However, if the topological properties of these networks are fairly well understood, how they relate to population and socio-economical properties remains an open question. We propose here a general coarse-grained approach, based on a cost-benefit analysis that accounts for the scaling properties of the main quantities characterizing these systems (the number of stations, the total length, and the ridership) with the substrate's population, area and wealth. More precisely, we show that the length, number of stations and ridership of subways and rail networks can be estimated knowing the area, population and wealth of the underlying region. These predictions are in good agreement with data gathered for about 140 subway systems and more than 50 railway networks in the world. We also show that train networks and subway systems can be described within the same framework, but with a fundamental difference: while the interstation distance seems to be constant and determined by the typical walking distance for subways, the interstation distance for railways scales with the number of stations. PMID- 25029527 TI - Multi-tissue computational modeling analyzes pathophysiology of type 2 diabetes in MKR mice. AB - Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective. PMID- 25029529 TI - The capture and stabilization of curcumin using hydrophobically modified polyacrylate aggregates and hydrogels. AB - Hydrophobically modified polyacrylates are shown to suppress the degradation of the medicinal pigment curcumin under physiological conditions. In aqueous solution, the 3% octadecyl randomly substituted polyacrylate, PAAC18, forms micelle-like aggregates at a concentration of <1 wt % and a hydrogel at >1 wt %. Under both conditions, PAAC18 shows a remarkable ability to suppress the degradation of curcumin at pH 7.4 and 37 degrees C such that its degradation half-life is increased by 1600-2000-fold. The suppression of degradation is attributed to hydrophobic interactions between curcumin and the octadecyl substituents of PAAC18 within the micelle-like aggregates and the hydrogel, as indicated by 2D NOESY (1)H NMR spectroscopy. UV-visible absorption titration results are consistent with the interaction of curcumin with five octadecyl substituents on average, which appears to substantially exclude water and greatly decrease the curcumin degradation rate. Dynamic light scattering and zeta potential measurements show the average hydrodynamic diameters of the PAAC18 aggregates to be 0.86-1.15 MUm with a negative surface charge. In contrast to the octadecyl substitution, the 3% dodecyl randomly substituted polyacrylate, PAAC12, shows a negligible effect on slowing the degradation of curcumin, consistent with the dodecyl substituents being insufficiently long to capture curcumin in a adequately hydrophobic environment. These observations indicate the potential for PAAC18 to act as a model drug delivery system. PMID- 25029530 TI - The relationship between uric acid and erectile dysfunction in hypertensive subjects. AB - BACKGROUND: Endothelial dysfunction plays a major role in erectile dysfunction (ED). Uric acid (UA) is a marker of endothelial dysfunction. We hypothesized that increased UA levels may be associated with ED and aimed to investigate whether there is a relationship between, UA and ED in hypertensive patients. METHODS: A total of 200 hypertensive patients who have a normal treadmill exercise test were divided into two groups based on the Sexual Health Inventory for Men (SHIM) test (< 21 defined as ED n = 110, and >= 21 defined as normal erectile function n = 90). The differences between the ED and normal erectile function groups were compared and determinants of ED were analyzed. MAIN RESULTS: The prevalence of ED was found to be 55.0%. Office blood pressure level was comparable between groups. UA levels were significantly increased in the ED group (6.20 +/- 1.56 vs 5.44 +/- 1.32, p = 0.01). In a regression model, age [odds ratio (95% confidence interval): 1.08 (1.04-1.14), p = 0.001], smoking [odds ratio: 2.33 (1.04-5.20), p = 0.04] and UA [odds ratio: 1.76 (1.28-2.41), p = 0.04] were independent determinants of ED. An UA level of > 5.2 mg/dl had 76.2% sensitivity, 43.7% specificity, 62.9% positive and 59.4% negative predictive value for determining ED. CONCLUSION: UA is an independent determinant of ED irrespective of blood pressure control and questioning erectile function for hypertensive patients with increased UA levels may be recommended. PMID- 25029532 TI - Relevant influence of limestone crystallinity on CO2 capture in the Ca-looping technology at realistic calcination conditions. AB - We analyze the role of limestone crystallinity on its CO2 capture performance when subjected to carbonation/calcination cycles at conditions mimicking the Ca looping (CaL) technology for postcombustion CO2 capture. The behavior of raw and pretreated limestones (milled and thermally annealed) is investigated by means of thermogravimetric analysis (TGA) tests under realistic sorbent regeneration conditions, which necessarily involve high CO2 partial pressure in the calciner and quick heating rates. The pretreatments applied lead to contrasting effects on the solid crystal structure and, therefore, on its resistance to solid-state diffusion. Our results show that decarbonation at high CO2 partial pressure is notably promoted by decreasing solid crystallinity. CaO regeneration is fully achieved under high CO2 partial pressure at 900 degrees C in short residence times for the milled limestone whereas complete regeneration for raw limestone requires a minimum calcination temperature of about 950 degrees C. Such a reduction of the calcination temperature and the consequent mitigation of multicyclic capture capacity decay would serve to enhance the efficiency of the CaL technology. On the other hand, the results of our study suggest that the use of highly crystalline limestones would be detrimental since excessively high calcination temperatures should be required to attain full decarbonation at realistic conditions. PMID- 25029531 TI - Number and distribution of mouse retinal cone photoreceptors: differences between an albino (Swiss) and a pigmented (C57/BL6) strain. AB - We purpose here to analyze and compare the population and topography of cone photoreceptors in two mouse strains using automated routines, and to design a method of retinal sampling for their accurate manual quantification. In whole mounted retinas from pigmented C57/BL6 and albino Swiss mice, the longwave sensitive (L) and the shortwave-sensitive (S) opsins were immunodetected to analyze the population of each cone type. In another group of retinas both opsins were detected with the same fluorophore to quantify all cones. In a third set of retinas, L-opsin and Brn3a were immunodetected to determine whether L-opsin+cones and retinal ganglion cells (RGCs) have a parallel distribution. Cones and RGCs were automatically quantified and their topography illustrated with isodensity maps. Our results show that pigmented mice have a significantly higher number of total cones (all-cones) and of L-opsin+cones than albinos which, in turn, have a higher population of S-opsin+cones. In pigmented animals 40% of cones are dual (cones that express both opsins), 34% genuine-L (cones that only express the L opsin), and 26% genuine-S (cones that only express the S-opsin). In albinos, 23% of cones are genuine-S and the proportion of dual cones increases to 76% at the expense of genuine-L cones. In both strains, L-opsin+cones are denser in the central than peripheral retina, and all-cones density increases dorso-ventrally. In pigmented animals S-opsin+cones are scarce in the dorsal retina and very numerous in the ventral retina, being densest in its nasal aspect. In albinos, S opsin+cones are abundant in the dorsal retina, although their highest densities are also ventral. Based on the densities of each cone population, we propose a sampling method to manually quantify and infer their total population. In conclusion, these data provide the basis to study cone degeneration and its prevention in pathologic conditions. PMID- 25029533 TI - We should not abandon therapeutic cooling after cardiac arrest. PMID- 25029534 TI - Search for novel contrast materials in dual-energy x-ray breast imaging using theoretical modeling of contrast-to-noise ratio. AB - Contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging uses a low- and high energy x-ray spectral pair to eliminate soft-tissue signal variation and thereby increase the detectability of exogenous imaging agents. Currently, CEDE breast imaging is performed with iodinated contrast agents. These compounds are limited by several deficiencies, including rapid clearance and poor tumor targeting ability. The purpose of this work is to identify novel contrast materials whose contrast-to-noise ratio (CNR) is comparable or superior to that of iodine in the mammographic energy range. A monoenergetic DE subtraction framework was developed to calculate the DE signal intensity resulting from the logarithmic subtraction of the low- and high-energy signal intensities. A weighting factor is calculated to remove the dependence of the DE signal on the glandularity of the breast tissue. Using the DE signal intensity and weighting factor, the CNR for materials with atomic numbers (Z) ranging from 1 to 79 are computed for energy pairs between 10 and 50 keV. A group of materials with atomic numbers ranging from 42 to 63 were identified to exhibit the highest levels of CNR in the mammographic energy range. Several of these materials have been formulated as nanoparticles for various applications but none, apart from iodine, have been investigated as CEDE breast imaging agents. Within this group of materials, the necessary dose fraction to the LE image decreases as the atomic number increases. By reducing the dose to the LE image, the DE subtraction technique will not provide an anatomical image of sufficient quality to accompany the contrast information. Therefore, materials with Z from 42 to 52 provide nearly optimal values of CNR with energy pairs and dose fractions that provide good anatomical images. This work is intended to inspire further research into new materials for optimized CEDE breast functional imaging. PMID- 25029535 TI - Aligning practice redesign and interprofessional education to advance triple aim outcomes. PMID- 25029536 TI - Probability of observing a number of unfolding events while stretching polyproteins. AB - The mechanical stretching of single polyproteins is an emerging tool for the study of protein (un)folding, chemical catalysis and polymer physics at the single molecule level. The observed processes, i.e., unfolding or reduction events, are typically considered to be stochastic and by nature are susceptible to be censored by the finite duration of the experiment. A formal analytical and experimental description on the number of observed events under various conditions of practical interest is developed. Rules of thumb are provided to define an optimal experiment protocol duration. Finally, a methodology is described to accurately estimate the real number of stretched molecules based on the number of observed unfolding events. The model-free numerical analysis applied to experimental data confirms that poly-ubiquitin binds at a random position both to the substrate and to the pulling probe. PMID- 25029537 TI - SU-8 as a material for lab-on-a-chip-based mass spectrometry. AB - This short review focuses on the application of SU-8 for the microchip-based approach to the miniaturization of mass spectrometry. Chip-based mass spectrometry will make the technology commonplace and bring benefits such as lower costs and autonomy. The chip-based miniaturization of mass spectrometry necessitates the use of new materials which are compatible with top-down fabrication involving both planar and non-planar processes. In this context, SU-8 is a very versatile epoxy-based, negative tone resist which is sensitive to ultraviolet radiation, X-rays and electron beam exposure. It has a very wide thickness range, from nanometres to millimetres, enabling the formation of mechanically rigid, very high aspect ratio, vertical, narrow width structures required to form microfluidic slots and channels for laboratory-on-a-chip design. It is also relatively chemically resistant and biologically compatible in terms of the liquid solutions used for mass spectrometry. This review looks at the impact and potential of SU-8 on the different parts of chip-based mass spectrometry - pre-treatment, ionization processes, and ion sorting and detection. PMID- 25029538 TI - Improving relapse prevention after successful electroconvulsive therapy for patients with severe depression: completed audit cycle involving 102 full electroconvulsive therapy courses in West Sussex, United kingdom. AB - OBJECTIVES: The aim of this study was to determine whether current guidance or consensus regarding continuation pharmacotherapy after successful electroconvulsive therapy (ECT) was being followed by referring clinicians in West Sussex, United Kingdom. METHODS: A complete audit cycle examining psychotropic medication after successful ECT for patients with severe depression was performed. Clinical and ECT records (electronic and paper) were reviewed, and relapse rates in the 4 commonly prescribed psychotropic medication groups were compared. RESULTS: The pattern of relapse in the 4 groups was similar for both audits 1 and 2. Taking the 102 patients as a whole, the lowest relapse rates were recorded for patients taking a combination of an antidepressant and lithium (16% relapsed within 6 months of successful ECT). Patients taking a combination of antipsychotic and antidepressants fared the worst with 75% relapse rate. This was followed by those taking a combination of antidepressant and a mood stabilizer (other than lithium) (69%). Patients taking antidepressant(s) only were associated with a relapse rate of 60%. Audit 2 demonstrated that clinicians did not change their prescribing practices for their patients after successful ECT despite the efforts made in widely disseminating the results of audit 1. In particular, there was no increase in the use of lithium. CONCLUSIONS: Not all psychotropic medication prescribing for patients receiving ECT for depression followed available and current guidance or consensus. More needs to be done to understand the reasons for the reluctance to use lithium if relapse rates after ECT are to improve. PMID- 25029539 TI - Cloning and expression characteristics of the pig Stra8 gene. AB - Stra8 (Stimulated by Retinoic Acid 8) is considered a meiotic gatekeeper gene. Using reverse transcriptase PCR and rapid amplification of cDNA ends (RACE), the complete sequence of the pig Stra8 gene was cloned. Bioinformatics analyses of this sequence were performed. Using semi-quantitative methods, the expression characteristics of Stra8 in Testis, cauda epididymis, body epididymis, caput epididymis, seminal vesicles, prostate gland, Cowper's gland, heart, liver, spleen, lung, kidney, stomach, hypothalamus, pituitary gland, cerebrum, cerebellum, and hippocampus of adult Meishan boar and sow tissues were examined. The expression pattern in the testis of 2-, 30-, 60-, 90-, and 150-day old Meishan boars were analyzed using real-time PCR. We constructed a eukaryotic expression vector for the Stra8 gene and used it to transfect NIH-3T3 cells and third generation pig spermatogonial stem cells (SSCs) cultured in vitro. Testes weight and sperm count in the cauda epididymis were evaluated at various time points. The results showed that the length of the pig Stra8 gene cDNA was 1444 bp encoding 366 amino acids with one typical helix-loop-helix (HLH) domain. It is testes-specific expression. Expression was first detected in boar testis starting at day 2, and its expression significantly (p<0.05) increased with age and body weight. When NIH-3T3 cells and pig SSCs were transfected with the eukaryotic expression vector EGFP (enhanced green fluorescent protein)-N1-pStra8, it was expressed in the cytoplasm of NIH-3T3 cells. However, in SSCs, Stra8 was expressed predominantly in cytoplasm and few in nucleus. Our data suggest that perhaps Stra8 acts as a transcription factor to initiate meiosis in young boar. PMID- 25029540 TI - Stromal cell-derived factor 1 gene polymorphism is associated with susceptibility to adverse long-term allograft outcomes in non-diabetic kidney transplant recipients. AB - Although the genetic polymorphism of Stromal Cell-Derived Factor 1 (SDF-1) is associated with higher mortality of liver allograft recipients, the role of SDF-1 in the modulation of renal allograft outcomes is unclear. Between March 2000 and January 2008, we recruited 252 non-diabetic renal transplant recipients (RTRs). Baseline characteristics and blood chemistry were recorded. Genomic DNA extraction with polymerase chain reaction-restriction fragment length polymorphism was utilized to analyze the genetic polymorphisms of SDF-1 (rs1801157). The influence of SDF-1 on an adverse renal allograft outcome, defined as either a doubling of serum creatinine, graft failure, or patient death was evaluated. Sixteen patients with the SDF-1 AA/AG genotype and nine with the SDF-1 GG genotype reached an adverse outcome. According to Kaplan-Meier analysis, patients carrying the SDF-1 AA/AG genotype or A allele showed a significantly higher risk of reaching an adverse outcome than those carrying the SDF-1 GG genotype or G allele (p=0.041; p=0.0051, respectively; log rank test). Stepwise multivariate Cox proportional regression analysis revealed that patients carrying the SDF-1 AA/AG genotype and A allele had a 2.742-fold (95% CI. 1.106-6.799, p=0.03) and 2.306-fold (95% CI. 1.254-4.24, p=0.008) risk of experiencing an adverse outcome. The SDF-1 AA/AG genotype and A allele have a detrimental impact on the long-term outcome of RTRs. PMID- 25029541 TI - Baicalin ameliorates H2O2 induced cytotoxicity in HK-2 cells through the inhibition of ER stress and the activation of Nrf2 signaling. AB - Renal ischemia-reperfusion injury plays a key role in renal transplantation and greatly affects the outcome of allograft. Our previous study proved that Baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, protects kidney from ischemia-reperfusion injury. This study aimed to study the underlying mechanism in vitro. Human renal proximal tubular epithelial cell line HK-2 cells were stimulated by H2O2 with and without Baicalin pretreatment. The cell viability, apoptosis and oxidative stress level were measured. The expression of endoplasmic reticulum (ER) stress hallmarks, such as binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), were analyzed by western blot and real-time PCR. NF-E2-related factor 2 (Nrf2) expression was also measured. In the H2O2 group, cell viability decreased and cell apoptosis increased. Reactive Oxygen Species (ROS) and Glutathione/Oxidized Glutathione (GSH/GSSG) analysis revealed increased oxidative stress. ER stress and Nrf2 signaling also increased. Baicalin pretreatment ameliorated H2O2-induced cytotoxicity, reduced oxidative stress and ER stress and further activated the anti-oxidative Nrf2 signaling pathway. The inducer of ER stress and the inhibitor of Nrf2 abrogated the protective effects, while the inhibitor of ER stress and the inducer of Nrf2 did not improve the outcome. This study revealed that Baicalin pretreatment serves a protective role against H2O2-induced cytotoxicity in HK-2 cells, where the inhibition of ER stress and the activation of downstream Nrf2 signaling are involved. PMID- 25029542 TI - Applications of biosurfactants in the petroleum industry and the remediation of oil spills. AB - Petroleum hydrocarbons are important energy resources. However, petroleum is also a major pollutant of the environment. Contamination by oil and oil products has caused serious harm, and increasing attention has been paid to the development and implementation of innovative technologies for the removal of these contaminants. Biosurfactants have been extensively used in the remediation of water and soil, as well as in the main stages of the oil production chain, such as extraction, transportation, and storage. This diversity of applications is mainly due to advantages such as biodegradability, low toxicity and better functionality under extreme conditions in comparison to synthetic counterparts. Moreover, biosurfactants can be obtained with the use of agro-industrial waste as substrate, which helps reduce overall production costs. The present review describes the potential applications of biosurfactants in the oil industry and the remediation of environmental pollution caused by oil spills. PMID- 25029544 TI - The critical role of membrane cholesterol in salmonella-induced autophagy in intestinal epithelial cells. AB - It was previously observed that plasma membrane cholesterol plays a critical role in the Salmonella-induced phosphatidylinositol 3-kinase-dependent (PI3K) dependent anti-inflammatory response in intestinal epithelial cells (IECs). The PI3K/Akt pathway is associated with autophagy which has emerged as a critical mechanism of host defense against several intracellular bacterial pathogens. Plasma membrane contributes directly to the formation of early Atg16L1-positive autophagosome precursors. Therefore, this study aimed to investigate the role of plasma membrane cholesterol on the Salmonella-induced autophagy in IECs. By using methyl-beta-cyclodextrin (MBCD), it was demonstrated that disruption of membrane cholesterol by MBCD enhanced NOD2 and Atg16L1 proteins expression in membrane, and autophagic LC3II proteins expression and LC3 punctae in Salmonella-infected Caco-2 cells, which was counteracted by Atg16L1 siRNA. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) siRNA enhanced the Salmonella induced activation of Akt in Caco-2 cells. However, inhibitors of Akt or extracellular signal-regulated kinases (ERK) had no significant effect on Salmonella-induced autophagy Beclin 1 or LC3 proteins expression. In conclusion, our study suggests that cholesterol accumulation in the plasma membrane at the entry site of Salmonella results in the formation of Salmonella-containing vacuole (SCV) and decreased autophagy. Our results offer mechanistic insights on the critical role of membrane cholesterol in the pathogenesis of Salmonella infection in intestinal epithelial cells and the therapeutic potential of its antagonists. PMID- 25029543 TI - Cellular levels of 8-oxoguanine in either DNA or the nucleotide pool play pivotal roles in carcinogenesis and survival of cancer cells. AB - 8-Oxoguanine, a major oxidized base lesion formed by reactive oxygen species, causes G to T transversion mutations or leads to cell death in mammals if it accumulates in DNA. 8-Oxoguanine can originate as 8-oxo-dGTP, formed in the nucleotide pool, or by direct oxidation of the DNA guanine base. MTH1, also known as NUDT1, with 8-oxo-dGTP hydrolyzing activity, 8-oxoguanine DNA glycosylase (OGG1) an 8-oxoG DNA glycosylase, and MutY homolog (MUTYH) with adenine DNA glycosylase activity, minimize the accumulation of 8-oxoG in DNA; deficiencies in these enzymes increase spontaneous and induced tumorigenesis susceptibility. However, different tissue types have different tumorigenesis susceptibilities. These can be reversed by combined deficiencies in the defense systems, because cell death induced by accumulation of 8-oxoG in DNA is dependent on MUTYH, which can be suppressed by MTH1 and OGG1. In cancer cells encountering high oxidative stress levels, a high level of 8-oxo-dGTP accumulates in the nucleotide pool, and cells therefore express increased levels of MTH1 in order to eliminate 8-oxo dGTP. Suppression of MTH1 may be an efficient strategy for killing cancer cells; however, because MTH1 and OGG1 protect normal tissues from oxidative-stress induced cell death, it is important that MTH1 inhibition does not increase the risk of healthy tissue degeneration. PMID- 25029545 TI - Proteomic analyses reveal that Sky1 modulates apoptosis and mitophagy in Saccharomyces cerevisiae cells exposed to cisplatin. AB - Sky1 is the only member of the SR (Serine-Arginine) protein kinase family in Saccharomyces cerevisiae. When yeast cells are treated with the anti-cancer drug cisplatin, Sky1 kinase activity is necessary to produce the cytotoxic effect. In this study, proteome changes in response to this drug and/or SKY1 deletion have been evaluated in order to understand the role of Sky1 in the response of yeast cells to cisplatin. Results reveal differential expression of proteins previously related to the oxidative stress response, DNA damage, apoptosis and mitophagy. With these precedents, the role of Sky1 in apoptosis, necrosis and mitophagy has been evaluated by flow-cytometry, fluorescence microscopy, biosensors and fluorescence techniques. After cisplatin treatment, an apoptotic-like process diminishes in the ?sky1 strain in comparison to the wild-type. The treatment does not affect mitophagy in the wild-type strain, while an increase is observed in the ?sky1 strain. The increased resistance to cisplatin observed in the ?sky1 strain may be attributable to a decrease of apoptosis and an increase of mitophagy. PMID- 25029546 TI - A disease marker for aspirin-induced chronic urticaria. AB - There are currently no diagnostic methods in vitro for aspirin-induced chronic urticaria (AICU) except for the provocation test in vivo. To identify disease markers for AICU, we investigated the single nucleotide polymorphism (SNP) of the promoter loci of high-affinity IgE receptor (FcepsilonRIalpha) and CD203c expression level in Chinese patients with AICU. We studied two genotypic and allelic frequencies of rs2427827 (-344C/T) and rs2251746 (-66T/C) gene polymorphisms of FcepsilonRIalpha in 20 patients with AICU, 52 subjects with airway hypersensitivity without aspirin intolerance, and 50 controls in a Chinese population. The results showed that the frequencies of two SNPs (-344C>T, -66C>T) were similar to the normal controls. The allele frequency of -344CC was significantly higher in the patients with AICU compared to those with airway sensitivity (p=0.019). We also studied both histamine release and CD203c expression on KU812 cells to assess aspirin-induced basophil activation. We found that the activity of basophil activation of AICU was significantly higher in the patients with AICU compared to those with airway hypersensitivity without aspirin intolerance. The mean fluorescence intensity of the CD203c expression were 122.5+/-5.2 vs. 103.3+/-3.3 respectively, (p<0.05), and the percentages of histamine release were 31.3%+/-7.4% vs. -24.0%+/-17.5%, (p<0.05) respectively. Although the mean fluorescence intensity of CD203c expression and the percentage of histamine release were significantly up-regulated by aspirin, they were not affected by anti-IgE antibodies. These results suggest that a single SNP of FcepsilonRIalpha (-344C>T) is less likely to develop AICU and the basophil activation activity in the sera by measuring CD203c expression can be applicable to confirm the diagnosis of AICU. PMID- 25029547 TI - Texture classification and retrieval using shearlets and linear regression. AB - Statistical modeling of wavelet subbands has frequently been used for image recognition and retrieval. However, traditional wavelets are unsuitable for use with images containing distributed discontinuities, such as edges. Shearlets are a newly developed extension of wavelets that are better suited to image characterization. Here, we propose novel texture classification and retrieval methods that model adjacent shearlet subband dependences using linear regression. For texture classification, we use two energy features to represent each shearlet subband in order to overcome the limitation that subband coefficients are complex numbers. Linear regression is used to model the features of adjacent subbands; the regression residuals are then used to define the distance from a test texture to a texture class. Texture retrieval consists of two processes: the first is based on statistics in contourlet domains, while the second is performed using a pseudo-feedback mechanism based on linear regression modeling of shearlet subband dependences. Comprehensive validation experiments performed on five large texture datasets reveal that the proposed classification and retrieval methods outperform the current state-of-the-art. PMID- 25029548 TI - Learning local appearances with sparse representation for robust and fast visual tracking. AB - In this paper, we present a novel appearance model using sparse representation and online dictionary learning techniques for visual tracking. In our approach, the visual appearance is represented by sparse representation, and the online dictionary learning strategy is used to adapt the appearance variations during tracking. We unify the sparse representation and online dictionary learning by defining a sparsity consistency constraint that facilitates the generative and discriminative capabilities of the appearance model. An elastic-net constraint is enforced during the dictionary learning stage to capture the characteristics of the local appearances that are insensitive to partial occlusions. Hence, the target appearance is effectively recovered from the corruptions using the sparse coefficients with respect to the learned sparse bases containing local appearances. In the proposed method, the dictionary is undercomplete and can thus be efficiently implemented for tracking. Moreover, we employ a median absolute deviation based robust similarity metric to eliminate the outliers and evaluate the likelihood between the observations and the model. Finally, we integrate the proposed appearance model with the particle filter framework to form a robust visual tracking algorithm. Experiments on benchmark video sequences show that the proposed appearance model outperforms the other state-of-the-art approaches in tracking performance. PMID- 25029549 TI - Wireless capsule endoscopy of the small intestine: a review with future directions. AB - PURPOSE OF REVIEW: Here, we review the clinical applications of small bowel capsule endoscopy. Moreover, we provide an outlook on the exceptional future developments of small bowel capsule endoscopy. We discuss clinical algorithms for diagnosis of small bowel diseases. Multiple studies have shown the potential of capsule endoscopy for identification of the bleeding source located in the small bowel and the increased diagnostic yield over radiographic studies. Capsule endoscopy could detect villous atrophy and severe complications in patients with nonresponsive celiac disease. In addition, small bowel capsule endoscopy was proven as a valid tool to diagnose polyps and tumors and Crohn's disease. SUMMARY: Major current clinical indications of capsule endoscopy in the small bowel include evaluation of obscure gastrointestinal bleeding, diagnosis and surveillance of small bowel polyps and tumors, celiac disease and Crohn's disease. Recent developments have also passed the way for small bowel capsule endoscopy to become a therapeutic instrument. PMID- 25029550 TI - FAS-based cell depletion facilitates the selective isolation of mouse induced pluripotent stem cells. AB - Cellular reprogramming of somatic cells into induced pluripotent stem cells (iPSC) opens up new avenues for basic research and regenerative medicine. However, the low efficiency of the procedure remains a major limitation. To identify iPSC, many studies to date relied on the activation of pluripotency associated transcription factors. Such strategies are either retrospective or depend on genetically modified reporter cells. We aimed at identifying naturally occurring surface proteins in a systematic approach, focusing on antibody targeted markers to enable live-cell identification and selective isolation. We tested 170 antibodies for differential expression between mouse embryonic fibroblasts (MEF) and mouse pluripotent stem cells (PSC). Differentially expressed markers were evaluated for their ability to identify and isolate iPSC in reprogramming cultures. Epithelial cell adhesion molecule (EPCAM) and stage specific embryonic antigen 1 (SSEA1) were upregulated early during reprogramming and enabled enrichment of OCT4 expressing cells by magnetic cell sorting. Downregulation of somatic marker FAS was equally suitable to enrich OCT4 expressing cells, which has not been described so far. Furthermore, FAS downregulation correlated with viral transgene silencing. Finally, using the marker SSEA-1 we exemplified that magnetic separation enables the establishment of bona fide iPSC and propose strategies to enrich iPSC from a variety of human source tissues. PMID- 25029551 TI - The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2. AB - The number of Foxp3+ regulatory T cells (Treg cells) must be tightly controlled for efficient suppression of autoimmunity with no impairment of normal immune responses. Here we found that the adaptor TRAF3 was intrinsically required for restraining the lineage determination of thymic Treg cells. T cell-specific deficiency in TRAF3 resulted in a two- to threefold greater frequency of Treg cells, due to the more efficient transition of precursors of Treg cells into Foxp3+ Treg cells. TRAF3 dampened interleukin 2 (IL-2) signaling by facilitating recruitment of the tyrosine phosphatase TCPTP to the IL-2 receptor complex, which resulted in dephosphorylation of the signaling molecules Jak1 and Jak3 and negative regulation of signaling via Jak and the transcription factor STAT5. Our results identify a role for TRAF3 as an important negative regulator of signaling via the IL-2 receptor that affects the development of Treg cells. PMID- 25029552 TI - c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. AB - Although the transcription factor c-Myc is essential for the establishment of a metabolically active and proliferative state in T cells after priming, its expression is transient. It remains unknown how T cell activation is maintained after c-Myc expression is downregulated. Here we identified AP4 as the transcription factor that was induced by c-Myc and sustained activation of antigen-specific CD8+ T cells. Despite normal priming, AP4-deficient CD8+ T cells failed to continue transcription of a broad range of c-Myc-dependent targets. Mice lacking AP4 specifically in CD8+ T cells showed enhanced susceptibility to infection with West Nile virus. Genome-wide analysis suggested that many activation-induced genes encoding molecules involved in metabolism were shared targets of c-Myc and AP4. Thus, AP4 maintains c-Myc-initiated cellular activation programs in CD8+ T cells to control microbial infection. PMID- 25029554 TI - Facile access to functionalized spiro[indoline-3,2'-pyrrole]-2,5'-diones via post Ugi domino Buchwald-Hartwig/Michael reaction. AB - A novel access to spiro[indoline-3,2'-pyrrole]-2,5'-diones is presented via a palladium-catalyzed post-Ugi cascade cyclization approach involving a Buchwald Hartwig/Michael reaction sequence. The method allows the easy construction of a library of spirooxindoles in moderate to good yields starting from readily available precursors. In addition, alkynoic acids are replaced with alpha,beta unsaturated acids leading to variably substituted spirooxindoles. PMID- 25029553 TI - Monitoring lung aeration during respiratory support in preterm infants at birth. AB - BACKGROUND: If infants fail to initiate spontaneous breathing, resuscitation guidelines recommend respiratory support with positive pressure ventilation (PPV). The purpose of PPV is to establish functional residual capacity and deliver an adequate tidal volume (VT) to achieve gas exchange. OBJECTIVE: The aim of our pilot study was to measure changes in exhaled carbon dioxide (ECO2), VT, and rate of carbon dioxide elimination (VCO2) to assess lung aeration in preterm infants requiring respiratory support immediately after birth. METHOD: A prospective observational study was performed between March and July 2013. Infants born at <37 weeks gestational age who received continuous positive airway pressure (CPAP) or PPV immediately after birth had VT delivery and ECO2 continuously recorded using a sensor attached to the facemask. RESULTS: Fifty-one preterm infants (mean (SD) gestational age 29 (3) weeks and birth weight 1425 (592 g)) receiving respiratory support in the delivery room were included. Infants in the CPAP group (n = 31) had higher ECO2 values during the first 10 min after birth compared to infants receiving PPV (n = 20) (ranging between 18-30 vs. 13-18 mmHg, p<0.05, respectively). At 10 min no significant difference in ECO2 values was observed. VT was lower in the CPAP group compared to the PPV group over the first 10 min ranging between 5.2-6.6 vs. and 7.2-11.3 mL/kg (p<0.05), respectively. CONCLUSIONS: Immediately after birth, spontaneously breathing preterm infants supported via CPAP achieved better lung aeration compared to infants requiring PPV. PPV guided by VT and ECO2 potentially optimize lung aeration without excessive VT administered. PMID- 25029555 TI - Safety assessment of the biogenic amines in fermented soya beans and fermented bean curd. AB - To evaluate the safety of biogenic amines, high performance liquid chromatography (HPLC) was used to evaluate the levels of biogenic amines in fermented soya beans and fermented bean curd. In fermented soya beans, the total biogenic amines content was in a relatively safe range in many samples, although the concentration of histamine, tyramine, and beta-phenethylamine was high enough in some samples to cause a possible safety threat, and 8 of the 30 samples were deemed unsafe. In fermented bean curd, the total biogenic amines content was more than 900 mg/kg in 19 white sufu amples, a level that has been determined to pose a safety hazard; putrescine was the only one detected in all samples and also had the highest concentration, which made samples a safety hazard; the content of tryptamine, beta-phenethylamine, tyramine, and histamine had reached the level of threat to human health in some white and green sufu samples, and that may imply another potential safety risk; and 25 of the 33 samples were unsafe. In conclusion, the content of biogenic amines in all fermented soya bean products should be studied and appropriate limits determined to ensure the safety of eating these foods. PMID- 25029556 TI - (Gold core)@(ceria shell) nanostructures for plasmon-enhanced catalytic reactions under visible light. AB - Driving catalytic reactions with sunlight is an excellent example of sustainable chemistry. A prerequisite of solar-driven catalytic reactions is the development of photocatalysts with high solar-harvesting efficiencies and catalytic activities. Herein, we describe a general approach for uniformly coating ceria on monometallic and bimetallic nanocrystals through heterogeneous nucleation and growth. The method allows for control of the shape, size, and type of the metal core as well as the thickness of the ceria shell. The plasmon shifts of the Au@CeO2 nanostructures resulting from the switching between Ce(IV) and Ce(III) are observed. The selective oxidation of benzyl alcohol to benzaldehyde, one of the fundamental reactions for organic synthesis, performed under both broad-band and monochromatic light, demonstrates the visible-light-driven catalytic activity and reveals the synergistic effect on the enhanced catalysis of the Au@CeO2 nanostructures. PMID- 25029557 TI - Comparison of the effects of hydration with water or isotonic solution on the recovery of cardiac autonomic modulation. AB - Despite the importance of hydration during exercise, the impact of ingesting water or isotonic solution during and after exercise on the regulation of autonomic modulation is unclear. The study aimed to compare the effect of ingesting water or isotonic solution (Gatorade(r), Brazil) on cardiac autonomic modulation in young people after submaximal aerobic exercise. Thirty-one young men were subjected to a protocol consisting of 4 steps: 1) incremental test, 2) control protocol without hydration, 3) protocol with ingestion of water, and 4) protocol with ingestion of isotonic solution. The protocol consisted of 10 min of rest, 90 min of treadmill exercise at 60% VO2peak, and 60 min of recovery at rest. In the hydration protocols, hydration occurred during and after exercise, every 15 min beginning after the 15th minute of exercise, with the amount ingested proportional to body mass lost in the control protocol. Autonomic modulation was evaluated by heart rate variability. The hydration protocols promoted a more efficient recovery of autonomic modulation, and for the exercise performed, regardless of the hydration administered, the effect on autonomic modulation was similar. PMID- 25029558 TI - How do membranes initiate Alzheimer's Disease? Formation of toxic amyloid fibrils by the amyloid beta-protein on ganglioside clusters. AB - Alzheimer's disease (AD), a severe neurodegenerative disorder, causes more than half of dementia cases. According to the popular "Abeta hypothesis" to explain the mechanism of this disease, amyloid beta-peptides (Abeta) of 39-43 amino acid residues aggregate and deposit onto neurons, igniting the neurotoxic cascade of the disease. Therefore, researchers studying AD would like to elucidate the mechanisms by which essentially water-soluble but hydrophobic Abeta aggregates under pathological conditions. Most researchers have investigated the aggregation of Abeta in aqueous solution, and they concluded that the final aggregation product, the amyloid fibrils, were less toxic than the component peptide oligomers. They consequently shifted their interests to more toxic "soluble oligomers", structures that form as intermediates or off-pathway products during the aggregation process. Some researchers have also investigated artificial oligomers prepared under nonphysiological conditions. In contrast to these "in solution" studies, we have focused on "membrane-mediated" amyloidogenesis. In an earlier study, other researchers identified a specific form of Abeta that was bound to monosialoganglioside GM1, a sugar lipid, in brains of patients who exhibited the early pathological changes associated with AD. This Account summarizes 15 years of our research on this topic. We have found that Abeta specifically binds to GM1 that occurs in clusters, but not when it is uniformly distributed. Clustering is facilitated by cholesterol. Upon binding, Abeta changes its conformation from a random coil to an alpha-helix-rich structure. A CH-pi interaction between the aromatic side chains of Abeta and carbohydrate moieties appended to GM1 appears to be important for binding. In addition, as Abeta accumulates and reaches its first threshold concentration (Abeta/GM1 = ~0.013), aggregated beta-sheets of ~15 molecules appear and coexist with the helical form. However, this beta-structure is stable and does not form larger aggregates. When the disease progresses further and the Abeta/GM1 ratio exceeds ~0.044, the beta-structure converts to a second beta-structure that can seed aggregates. The seed recruits monomers from the aqueous phase to form toxic amyloid fibrils that have larger surface hydrophobicity and can contain antiparallel beta-sheets. In contrast, amyloid fibrils formed in aqueous solution are less toxic and have parallel beta-sheets. The less polar environments of GM1 clusters play an important role in the formation of these toxic fibrils. Membranes that contain GM1 clusters not only accelerate the aggregation of Abeta by locally concentrating Abeta molecules but also generate amyloid fibrils with unique structures and significant cytotoxicity. The inhibition of this aggregation cascade could be a promising strategy for the development of AD modulating therapies. PMID- 25029560 TI - Cutaneous hemophagocytosis after alemtuzumab injection in a patient with Sezary syndrome. PMID- 25029559 TI - Tailored interfacial rheology for gastric stable adsorption layers. AB - Human lipid digestion begins at the interface of oil and water by interfacial adsorption of lipases. Tailoring the available surface area for lipase activity can lead to specific lipid sensing in the body, thus, tailored satiety hormone release. In this study we present biopolymer layers at the MCT-oil/water interface with different stabilities under human gastric environment (37 degrees C, pH 2, pepsin). Physicochemical changes and enzymatic degradation of interfacial layers were monitored online by interfacial shear rheology. We show the weakening of beta-lactoglobulin (beta-lg) layers at body temperature and acidification and their hydrolysis by pepsin. If sufficient concentrations of nanocrystalline cellulose (NCC) are given to an existing beta-lg layer, this weakening is buffered and the proteolysis delayed. A synergistic, composite layer is formed by adding methylated NCC to the beta-lg layer. This layer thermogels at body temperature and resists hydrolysis by pepsin. Coexistence of these two emulsifiers at the air/water interface is evidenced by neutron reflectometry measurements, where morphological information are extracted. The utilized layers and their analysis provide knowledge of physicochemical changes during in vitro digestion of interfaces, which promote functional food formulations. PMID- 25029562 TI - Normal saline versus colloid solutions for induction of hypothermia: the effect of specific heat capacity on cooling. AB - The prevention of ischemic injury to preserve both end-organ function and improve neurological recovery by the implementation of therapeutic hypothermia has been well established in the literature. However, not only the means by which body temperature is cooled but also the rate by which target temperature is attained remains an area of continued interest and research. The induction of therapeutic hypothermia to begin the process of body temperature lowering through the infusion of a cold solution intravenously into the body may be one variable that influences not only rapidity of cooling but also subsequent clinical outcome. In a recent issue of Critical Care, Skulec and colleagues compared the induction of therapeutic hypothermia by cold normal saline versus cold colloid solution containing hydroxyethyl starch in a porcine animal model of cardiac arrest, assessing both the rate of temperature change and target temperature achieved, in addition to changes in intracranial pressure. PMID- 25029561 TI - Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis. AB - Activation of K-ras and inactivation of p16 are the most frequently identified genetic alterations in human pancreatic epithelial adenocarcinoma (PDAC). Mouse models engineered with mutant K-ras and deleted p16 recapitulate key pathological features of PDAC. However, a human cell culture transformation model that recapitulates the human pancreatic molecular carcinogenesis is lacking. In this study, we investigated the role of p16 in hTERT-immortalized human pancreatic epithelial nestin-expressing (HPNE) cells expressing mutant K-ras (K-rasG12V). We found that expression of p16 was induced by oncogenic K-ras in these HPNE cells and that silencing of this induced p16 expression resulted in tumorigenic transformation and development of metastatic PDAC in an orthotopic xenograft mouse model. Our results revealed that PI3K/Akt, ERK1/2 pathways and TGFalpha signaling were activated by K-ras and involved in the malignant transformation of human pancreatic cells. Also, p38/MAPK pathway was involved in p16 up-regulation. Thus, our findings establish an experimental cell-based model for dissecting signaling pathways in the development of human PDAC. This model provides an important tool for studying the molecular basis of PDAC development and gaining insight into signaling mechanisms and potential new therapeutic targets for altered oncogenic signaling pathways in PDAC. PMID- 25029563 TI - "Innovation" institutes in academic health centers: enhancing value through leadership, education, engagement, and scholarship. AB - In the next decade, the biggest change in medicine in the United States will be the organizational transformation of the delivery system. Organizations-including academic health centers-able to achieve better outcomes for less will be the financial winners as new payment models become more prevalent. For medical educators, the question is how to prepare the next generation of physicians for these changes. One solution is the development of new "innovation" or "value" institutes. Around the nation, many of these new institutes are focused on surmounting barriers to value-based care in academic health centers, educating faculty, house staff, and medical students in discussions of cost-conscious care. Innovation institutes can also lead discussions about how value-based care may impact education in environments where there may be less autonomy and more standardization. Quality metrics will play a larger role at academic health centers as metrics focus more on outcomes than processes. Optimizing outcomes will require that medical educators both learn and teach the principles of patient safety and quality improvement. Innovation institutes can also facilitate cross-institutional discussions to compare data on utilization and outcomes, and share best practices that maximize value. Another barrier to cost-conscious care is defensive medicine, which is highly engrained in U.S. medicine and culture. Innovation institutes may not be able to overcome all the barriers to making medical care more cost-conscious, but they can be critical in enabling academic health centers to optimize their teaching and research missions while remaining financially competitive. PMID- 25029564 TI - Describing treatment intensity in milieu teaching interventions for children with developmental disabilities: a review. AB - PURPOSE: This investigation aimed to apply the dosage framework proposed by Warren, Fey, and Yoder (2007) to variations of milieu language teaching intervention strategies to explore how each of the dosage parameters (i.e., dose, dose form, dose frequency, total duration, and cumulative intervention intensity) was reported in the located empirically based applications with learners between birth and 23 years of age. METHOD: A systematic search located existing studies that implemented a milieu teaching intervention for children with developmental disabilities. Dosage data were then extracted from 42 studies along with study characteristics and participant characteristics. RESULTS: Only 37.8% of empirical investigations provided a clear definition of treatment intensity and reported the full range of dosage parameters, thus making it difficult to compare the results across investigations. Of the investigations that reported on all dosage parameters, the majority were single-case design as opposed to group design studies. CONCLUSIONS: Given the limited reporting of dosage parameters in existing studies, there is a need for closer attention to reporting this information in early communication intervention protocols. Replication and customization of interventions for learners experiencing developmental disabilities will only be possible with additional empirical examination of dosage parameters. PMID- 25029566 TI - The percent change of strain and strain rate under dobutamine stress echocardiography predicts viability following myocardial infarction. AB - AIM: The aim of the present study was to explore the accuracy of the dobutamine induced percent change of myocardial deformation indices to detect viability following myocardial infarction. METHODS: We enrolled 60 consecutive patients presenting for myocardial viability assessment at least 4 weeks following ST segment-elevation myocardial infarction. Strain (S) and strain rate (SR) were individually measured for all myocardial segments, both at rest and during low dose dobutamine stress echocardiography. The percent change of S and SR from baseline to dobutamine-induced values (at a dose of 20 ug/kg/min) was calculated individually for each segment. Patients underwent myocardial viability assessment with resting 99mTc-sestamibi scintigraphy. Based on the results of scintigraphy, the percent change of S and SR was compared between viable and non-viable segments. RESULTS: For all segments, the percent change of both S and SR was significantly higher in viable as compared with non-viable segments (P<0.05 for all). Receiver-operating characteristics curve analysis identified the optimal cut-off value for the percent change of both S and SR that best discriminates viable from non-viable segments in the range of 20-25% with a sensitivity range from 95% to 100%, and a specificity range from 85% to 100%. CONCLUSION: In patients undergoing viability assessment following ST segment elevation myocardial infarction, the percent change of both S and SR (from baseline to dobutamine-induced values) was significantly higher in viable versus non-viable segments. A cut-off value of 20-25% of the percent change for both S and SR reliably identified viable from non-viable segments with a high sensitivity and specificity for both. PMID- 25029565 TI - Type II transmembrane serine protease gene variants associate with breast cancer. AB - Type II transmembrane serine proteases (TTSPs) are related to tumor growth, invasion, and metastasis in cancer. Genetic variants in these genes may alter their function, leading to cancer onset and progression, and affect patient outcome. Here, 464 breast cancer cases and 370 controls were genotyped for 82 single-nucleotide polymorphisms covering eight genes. Association of the genotypes was estimated against breast cancer risk, breast cancer-specific survival, and survival in different treatment groups, and clinicopathological variables. SNPs in TMPRSS3 (rs3814903 and rs11203200), TMPRSS7 (rs1844925), and HGF (rs5745752) associated significantly with breast cancer risk (Ptrend = 0.008 0.042). SNPs in TMPRSS1 (rs12151195 and rs12461158), TMPRSS2 (rs2276205), TMPRSS3 (rs3814903), and TMPRSS7 (rs2399403) associated with prognosis (P = 0.004-0.046). When estimating the combined effect of the variants, the risk of breast cancer was higher with 4-5 alleles present compared to 0-2 alleles (P = 0.0001; OR, 2.34; 95% CI, 1.39-3.94). Women with 6-8 survival-associating alleles had a 3.3 times higher risk of dying of breast cancer compared to women with 1-3 alleles (P = 0.001; HR, 3.30; 95% CI, 1.58-6.88). The results demonstrate the combined effect of variants in TTSPs and their related genes in breast cancer risk and patient outcome. Functional analysis of these variants will lead to further understanding of this gene family, which may improve individualized risk estimation and development of new strategies for treatment of breast cancer. PMID- 25029567 TI - The impact of a 600-mg loading dose of clopidogrel in diabetic and non-diabetic patients undergoing elective PCI. AB - BACKGROUND: High platelet reactivity (HPR) and suboptimal response to dual antiplatelet therapy (DAPT) may explain high recurrent rates of ischemic events in type 1 and 2 diabetes mellitus (DM) patients undergoing percutaneous coronary intervention (PCI). The aim of this study was to determine the effect of diabetes mellitus on clopidogrel activity in cardiac patients undergoing PCI. METHODS: This is an observational study. Patients were categorized according to DM status into diabetic group (N.=30) and non-diabetic group (N.=33). All patients received clopidogrel in a loading dose of 600 mg before PCI. Platelet function was assessed using light transmittance aggregometry (LTA) technique at baseline (before clopidogrel administration), 24 hour after clopidogrel loading dose administration and 7-10 days after PCI. All patients were followed up for at least one year after PCI for recurrence of acute cardiac events. RESULTS: There was no statistically significant difference between the two groups with respect to 10 um adenosine diphosphate (ADP)-induced platelet aggregation measured at baseline (P=0.64), 24 hours after PCI (P=0.874), and 7-10 days after PCI (0.643). Diabetics were not significantly different from non-diabetics in terms of post PCI acute stent thrombosis (P=0.945), sub-acute stent thrombosis (P=0.945), unstable angina (P=0.29) and cardiac death (P=0.64). There was a statistically significant difference between patients with and without post-PCI acute events regarding ADP aggregation measured 24 hours and 7-10 days after PCI. CONCLUSIONS: The use of a high loading dose of clopidogrel (600 mg) in patients undergoing elective PCI can overcome the significant increase in post-PCI platelet aggregation and rate of acute cardiac events induced by diabetes mellitus as co morbidity in those patients. PMID- 25029568 TI - Iatrogenic left main coronary dissection during primary sheathless transradial angioplasty: a rare but nasty complication. PMID- 25029569 TI - Cardiovascular risk associated with celecoxib or etoricoxib: a meta-analysis of randomized controlled trials which adopted comparison with placebo or naproxen. AB - AIM: The present meta-analysis attempted to assess whether an unfavourable cardiovascular risk profile could be identified in the case of two COX2 selective inhibitors (COXIBs), namely celecoxib and etoricoxib. Based on the data from the literature, our meta-analysis aimed to assess the probability of major cardiovascular events reported with the use of celecoxib or etoricoxib and compare this with the results seen in patients assigned to the placebo group. Furthermore, the risk of cardiovascular events found by using celecoxib or etoricoxib was also compared with that associated with the use of naproxen, a nonselective non-steroidal anti-inflammatory drug (NSAID) chosen as our reference drug. METHODS: The studies had to be randomized controlled trials with at least 4 week duration. Studies were included if they compared celecoxib or etoricoxib against placebo or naproxen. Moreover, the selected studies had to have determined the risk, odds or incidence of myocardial infarction, stroke or cardiovascular death. For the comparisons versus placebo, the endpoints of interest were "serious vascular events", "non-fatal myocardial infarction", "non fatal stroke" and "death from cardiovascular causes", whereas "myocardial infarction" and "stroke" were the endpoints of interest concerning the comparison versus naproxen. RESULTS: From the evaluation of 41 studies comparing celecoxib with placebo, we found a significantly higher incidence of serious vascular events in the celecoxib group compared to controls treated with placebo (rate ratio 1.598, 95% CI: 1.048 to 2.438; P=0.029). Furthermore, in patients allocated to treatment with celecoxib, we found an incidence rate of non-fatal acute myocardial infarction that was three times higher compared with the placebo group (rate ratio 3.074, 95% CI: 1.375-6.873, P=0.006). In contrast, we did not find any significant difference with regard to the incidence of nonfatal stroke and that of death from cardiovascular causes by comparing celecoxib and placebo. In addition, by examining cardiovascular outcomes that emerged from the 17 trials which compared etoricoxib with placebo, it was not possible to demonstrate statistically significant differences in incidence for each of the explored endpoints. With regard to the comparison of each coxib with the non-selective COX2 inhibitor naproxen, we did not find any significant difference for either the odds of myocardial infarction or that of stroke. CONCLUSION: On the basis of our meta-analysis, we can state that symptomatic benefits induced by the prolonged administration of celecoxib may be partially invalidated by a concomitant increase in vascular risk, particularly the increased risk of myocardial infarction found in celecoxib-treated patients, compared to controls taking placebo. In contrast, treatment with etoricoxib proved not to result in an increased risk of serious vascular events when compared with both the placebo and naproxen. Our meta-analysis also denotes that the alternative to COXIBs, represented by naproxen, does not show significant benefit in terms of reduced cardiovascular risk. Therefore, considering that the increase in incidence rate of cardiovascular events associated with treatment with celecoxib is small in absolute terms, it is reasonable to state that celecoxib is still a drug whose benefits outweigh the potential adverse effects on the cardiovascular system. PMID- 25029571 TI - Management of Pseudomonas aeruginosa pneumonia: one size does not fit all. AB - In view of the mortality associated with Pseudomonas aeruginosa (PSA) ventilator associated pneumonia (VAP) and the frequency of inadequate initial empiric therapy, recent findings underscore the need for a different management paradigm with effective anti-pseudomonal vaccines for prophylaxis of patients at risk. The association of virulence factors is a variable that splits PSA in two phenotypes, with the possibility of adjunctive immunomodulatory therapy for management of virulent strains. We comment on recent advances in and the state of the art of PSA-VAP management and discuss a new paradigm for tailored and optimal management. PMID- 25029572 TI - Performance of lead-free versus lead-based hunting ammunition in ballistic soap. AB - BACKGROUND: Lead-free hunting bullets are an alternative to lead-containing bullets which cause health risks for humans and endangered scavenging raptors through lead ingestion. However, doubts concerning the effectiveness of lead-free hunting bullets hinder the wide-spread acceptance in the hunting and wildlife management community. METHODS: We performed terminal ballistic experiments under standardized conditions with ballistic soap as surrogate for game animal tissue to characterize dimensionally stable, partially fragmenting, and deforming lead free bullets and one commonly used lead-containing bullet. The permanent cavities created in soap blocks are used as a measure for the potential wound damage. The soap blocks were imaged using computed tomography to assess the volume and shape of the cavity and the number of fragments. Shots were performed at different impact speeds, covering a realistic shooting range. Using 3D image segmentation, cavity volume, metal fragment count, deflection angle, and depth of maximum damage were determined. Shots were repeated to investigate the reproducibility of ballistic soap experiments. RESULTS: All bullets showed an increasing cavity volume with increasing deposited energy. The dimensionally stable and fragmenting lead-free bullets achieved a constant conversion ratio while the deforming copper and lead-containing bullets showed a ratio, which increases linearly with the total deposited energy. The lead-containing bullet created hundreds of fragments and significantly more fragments than the lead-free bullets. The deflection angle was significantly higher for the dimensionally stable bullet due to its tumbling behavior and was similarly low for the other bullets. The deforming bullets achieved higher reproducibility than the fragmenting and dimensionally stable bullets. CONCLUSION: The deforming lead-free bullet closely resembled the deforming lead-containing bullet in terms of energy conversion, deflection angle, cavity shape, and reproducibility, showing that similar terminal ballistic behavior can be achieved. Furthermore, the volumetric image processing allowed superior analysis compared to methods that involve cutting of the soap blocks. PMID- 25029570 TI - Structural DNA nanotechnology: state of the art and future perspective. AB - Over the past three decades DNA has emerged as an exceptional molecular building block for nanoconstruction due to its predictable conformation and programmable intra- and intermolecular Watson-Crick base-pairing interactions. A variety of convenient design rules and reliable assembly methods have been developed to engineer DNA nanostructures of increasing complexity. The ability to create designer DNA architectures with accurate spatial control has allowed researchers to explore novel applications in many directions, such as directed material assembly, structural biology, biocatalysis, DNA computing, nanorobotics, disease diagnosis, and drug delivery. This Perspective discusses the state of the art in the field of structural DNA nanotechnology and presents some of the challenges and opportunities that exist in DNA-based molecular design and programming. PMID- 25029573 TI - Stress ulceration: prevalence, pathology and association with adverse outcomes. PMID- 25029574 TI - Maternal postpartum complications according to delivery mode in twin pregnancies. AB - OBJECTIVE: We aimed to examine maternal postpartum complications of twin deliveries according to mode of delivery and investigate the associated risk factors. METHODS: This was a retrospective cohort review of twin pregnancies with delivery after 26 weeks at a tertiary teaching hospital (1993-2008). The rates of maternal postpartum complications were compared among vaginal, elective cesarean and emergency cesarean deliveries. Significant predictors of complications were investigated with stepwise regression analysis and relative risks were calculated. RESULTS: A total of 90 complications were observed in 56/817 (6.9%) deliveries: 7/131 (5.3%) vaginal, 10/251 (4.0%) elective cesarean and 39/435 (9.0%) emergency cesarean deliveries. Significant predictors included high-risk pregnancy, gestational age at birth and delivery mode. The occurrence of complications was significantly increased in emergency compared to elective cesarean deliveries (RR=2.34). CONCLUSIONS: Maternal postpartum complications in twin pregnancies are higher in emergency compared to elective cesarean deliveries and are also related to preexisting complications and earlier gestational age at delivery. PMID- 25029575 TI - Prevalence of scoliosis in Williams-Beuren syndrome patients treated at a regional reference center. AB - OBJECTIVE: This study assessed the prevalence of scoliosis and the patterns of scoliotic curves in patients with Williams-Beuren syndrome. Williams-Beuren syndrome is caused by a chromosome 7q11.23 deletion in a region containing 28 genes, with the gene encoding elastin situated approximately at the midpoint of the deletion. Mutation of the elastin gene leads to phenotypic changes in patients, including neurodevelopmental impairment of varying degrees, characteristic facies, cardiovascular abnormalities, hypercalcemia, urological dysfunctions, and bone and joint dysfunctions. METHODS: A total of 41 patients diagnosed with Williams-Beuren syndrome, who were followed up at the genetics ambulatory center of a large referral hospital, were included in the study. There were 25 male subjects. The patients were examined and submitted to radiographic investigation for Cobb angle calculation. RESULTS: It was observed that 14 patients had scoliosis; of these 14 patients, 10 were male. The pattern of deformity in younger patients was that of flexible and simple curves, although adults presented with double and triple curves. Statistical analysis showed no relationships between scoliosis and age or sex. CONCLUSION: This study revealed a prevalence of scoliosis in patients with Williams-Beuren syndrome of 34.1%; however, age and sex were not significantly associated with scoliosis or with the severity of the curves. PMID- 25029576 TI - Clinical profile of Parkinson's disease in the Gumei community of Minhang district, Shanghai. AB - OBJECTIVE: We examined the demographic and clinical profiles of Parkinson's disease in Shanghai, China, to assist in disease management and provide comparative data on Parkinson's disease prevalence, phenotype, and progression among different regions and ethnic groups. METHODS: A door-to-door survey and follow-up clinical examinations identified 180 community-dwelling Han-Chinese Parkinson's disease patients (104 males, 76 females). RESULTS: The average age at onset was 65.16 +/- 9.60 years. The most common initial symptom was tremor (112 patients, 62.22%), followed by rigidity (38, 21.11%), bradykinesia (28, 15.56%) and tremor plus rigidity (2, 1.11%). Tremor as the initial symptom usually began in a single limb (83.04% of patients). The average duration from onset to mild Parkinson's disease (Hoehn-Yahr phase 1-2) was 52.74 +/- 45.64 months. Progression from mild to moderate/severe Parkinson's disease (phase >= 3) was significantly slower (87.07 +/- 58.72 months; p<0.001), except for patients presenting initially with bradykinesia (53.83 +/- 24.49 months). Most patients (149/180, 82.78%) took levodopa with or without other drugs. The Hamilton Anxiety Scale revealed symptoms of clinical anxiety in 35 patients, and the Hamilton Depression Scale revealed depressive symptoms in 88 patients. The depressed or anxious subgroup (123 patients) demonstrated a significantly younger age at onset (55.54 +/- 7.68 years) compared with the overall mean (p<0.05). CONCLUSION: Unilateral limb tremor was the most common initial symptom, and motor function deteriorated slowly over ?4-9 years. Earlier-onset patients experience greater psychiatric dysfunction. PMID- 25029577 TI - Clinical and epidemiological characteristics of septic arthritis of the hip, 2006 to 2012, a seven-year review. AB - OBJECTIVE: To epidemiologically characterize the population treated at our orthopedic clinic with a diagnosis of septic arthritic of the hip between 2006 and 2012. METHODS: Fifteen patients diagnosed with septic arthritis of the hip between 2006 and 2012 were retrospectively evaluated. The patients' clinical and epidemiological characteristics were surveyed; a sensitivity profile relating to the microorganisms that caused the infections and the complications relating to the patients' treatment and evolution were identified. RESULTS: Septic arthritis was more common among males. Most diagnoses were made through positive synovial fluid cultures, after joint drainage was performed using the Smith-Petersen route. Among the comorbidities found, the most prevalent were systemic arterial hypertension, diabetes mellitus, and human immunodeficiency virus. The pathological joint conditions diagnosed prior to joint infection were osteoarthrosis and developmental dysplasia of the hip. The infectious agent most frequently isolated was Staphylococcus aureus. From the clinical and laboratory data investigated, 53.33% of the cases presented with fever, and all except one patient presented with increased measures in inflammation tests. Gram staining was positive in only 26.66% of the synovial fluid samples analyzed. Six patients presented with joint complications after treatment was administered. CONCLUSION: S. aureus is the most common pathogen in acute infections of the hip in our setting. Factors such as clinical comorbidities are associated with septic arthritis of the hip. Because of the relatively small number of patients, given that this is a condition of low prevalence, there was no statistically significant correlation in relation to worse prognosis for the disease. PMID- 25029578 TI - Audiological manifestations in HIV-positive adults. AB - OBJECTIVE: To characterize the findings of behavioral hearing assessment in HIV positive individuals who received and did not receive antiretroviral treatment. METHODS: This research was a cross-sectional study. The participants were 45 HIV positive individuals (18 not exposed and 27 exposed to antiretroviral treatment) and 30 control-group individuals. All subjects completed an audiological evaluation through pure-tone audiometry, speech audiometry, and high-frequency audiometry. RESULTS: The hearing thresholds obtained by pure-tone audiometry were different between groups. The group that had received antiretroviral treatment had higher thresholds for the frequencies ranging from 250 to 3000 Hz compared with the control group and the group not exposed to treatment. In the range of frequencies from 4000 through 8000 Hz, the HIV-positive groups presented with higher thresholds than did the control group. The hearing thresholds determined by high-frequency audiometry were different between groups, with higher thresholds in the HIV-positive groups. CONCLUSION: HIV-positive individuals presented poorer results in pure-tone and high-frequency audiometry, suggesting impairment of the peripheral auditory pathway. Individuals who received antiretroviral treatment presented poorer results on both tests compared with individuals not exposed to antiretroviral treatment. PMID- 25029579 TI - Nutritional parameters are associated with mortality in acute kidney injury. AB - OBJECTIVE: The objective of this study was to perform a nutritional assessment of acute kidney injury patients and to identify the relationship between nutritional markers and outcomes. METHOD: This was a prospective and observational study. Patients who were hospitalized at the Hospital of Botucatu School of Medicine were evaluated between January 2009 and December 2011. We evaluated a total of 133 patients with a clinical diagnosis of acute kidney injury and a clinical presentation suggestive of acute tubular necrosis. We explored the associations between clinical, laboratory and nutritional markers and in-hospital mortality. Multivariable logistic regression was used to adjust for confounding and selection bias. RESULTS: Non-survivor patients were older (67 +/- 14 vs. 59 +/- 16 years) and exhibited a higher prevalence of sepsis (57.1 vs. 21.4%) and higher Acute Tubular Necrosis-Individual Severity Scores (0.60 +/- 0.22 vs. 0.41 +/- 0.21) than did survivor patients. Based on the multivariable analysis, laboratorial parameters such as blood urea nitrogen and C-reactive protein were associated with a higher risk of death (OR: 1.013, p=0.0052; OR: 1.050, p=0.01, respectively), and nutritional parameters such as low calorie intake, higher levels of edema, lower resistance based on bioelectrical impedance analysis and a more negative nitrogen balance were significantly associated with a higher risk of death (OR: 0.950, p=0.01; OR: 1.138, p=0.03; OR: 0.995, p=0.03; OR: 0.934, p=0.04, respectively). CONCLUSIONS: In acute kidney injury patients, a nutritional assessment seems to identify nutritional markers that are associated with outcome. In this study, a low caloric intake, higher C-reactive protein levels, the presence of edema, a lower resistance measured during a bioelectrical impedance analysis and a lower nitrogen balance were significantly associated with risk of death in acute kidney injury patients. PMID- 25029580 TI - Correlation between intra-abdominal pressure and pulmonary volumes after superior and inferior abdominal surgery. AB - OBJECTIVE: Patients undergoing abdominal surgery are at risk for pulmonary complications. The principal cause of postoperative pulmonary complications is a significant reduction in pulmonary volumes (FEV1 and FVC) to approximately 65-70% of the predicted value. Another frequent occurrence after abdominal surgery is increased intra-abdominal pressure. The aim of this study was to correlate changes in pulmonary volumes with the values of intra-abdominal pressure after abdominal surgery, according to the surgical incision in the abdomen (superior or inferior). METHODS: We prospectively evaluated 60 patients who underwent elective open abdominal surgery with a surgical time greater than 240 minutes. Patients were evaluated before surgery and on the 3rd postoperative day. Spirometry was assessed by maximal respiratory maneuvers and flow-volume curves. Intra-abdominal pressure was measured in the postoperative period using the bladder technique. RESULTS: The mean age of the patients was 56 +/- 13 years, and 41.6% 25 were female; 50 patients (83.3%) had malignant disease. The patients were divided into two groups according to the surgical incision (superior or inferior). The lung volumes in the preoperative period showed no abnormalities. After surgery, there was a significant reduction in both FEV1 (1.6 +/- 0.6 L) and FVC (2.0 +/- 0.7 L) with maintenance of FEV1/FVC of 0.8 +/- 0.2 in both groups. The maximum intra abdominal pressure values were similar (p=0.59) for the two groups. There was no association between pulmonary volumes and intra-abdominal pressure measured in any of the groups analyzed. CONCLUSIONS: Our results show that superior and inferior abdominal surgery determines hypoventilation, unrelated to increased intra-abdominal pressure. Patients at high risk of pulmonary complications should receive respiratory care even if undergoing inferior abdominal surgery. PMID- 25029581 TI - Noise-induced tinnitus: auditory evoked potential in symptomatic and asymptomatic patients. AB - OBJECTIVES: We evaluated the central auditory pathways in workers with noise induced tinnitus with normal hearing thresholds, compared the auditory brainstem response results in groups with and without tinnitus and correlated the tinnitus location to the auditory brainstem response findings in individuals with a history of occupational noise exposure. METHOD: Sixty individuals participated in the study and the following procedures were performed: anamnesis, immittance measures, pure-tone air conduction thresholds at all frequencies between 0.25-8 kHz and auditory brainstem response. RESULTS: The mean auditory brainstem response latencies were lower in the Control group than in the Tinnitus group, but no significant differences between the groups were observed. Qualitative analysis showed more alterations in the lower brainstem in the Tinnitus group. The strongest relationship between tinnitus location and auditory brainstem response alterations was detected in individuals with bilateral tinnitus and bilateral auditory brainstem response alterations compared with patients with unilateral alterations. CONCLUSION: Our findings suggest the occurrence of a possible dysfunction in the central auditory nervous system (brainstem) in individuals with noise-induced tinnitus and a normal hearing threshold. PMID- 25029582 TI - The preventive effects of natural adjuvants, G2 and G2F on tracheal responsiveness and serum IL-4 and IFN-gamma (th1/th2 balance) in sensitized guinea pigs. AB - OBJECTIVE: The effects of natural adjuvants on lung inflammation and tracheal responsiveness were examined in sensitized guinea pigs. METHODS: The responses of guinea pig tracheal chains and the serum levels of interleukin-4 and interferon gamma were examined in control pigs and three other groups of guinea pigs: the sensitized group and two other sensitized groups treated with either adjuvant G2 or adjuvant G2F (n=7 for each group). Sensitization of the animals was achieved by injection and inhalation of ovalbumin. RESULTS: The results showed that sensitized animals had increased tracheal responsiveness and increased serum levels of interleukin-4 and interferon-gamma compared to controls (p<0.05 to p<0.001). Treatments with either G2 or G2F prevented the increase in tracheal responsiveness and serum interleukin-4 (p<0.01 to p<0.001). However, the serum levels of interferon-gamma and the interleukin-4-to-interferon-gamma ratio was increased in the treated groups (p<0.001 for all cases). CONCLUSIONS: These results indicate important preventive effects of two natural adjuvants, particularly G2, on the changes in tracheal responsiveness, serum cytokines and the interleukin-4-to-interferon-gamma ratio (T helper 1/T helper 2 balance) in sensitized guinea pigs. PMID- 25029583 TI - Crack/cocaine users show more family problems than other substance users. AB - OBJECTIVES: To evaluate family problems among crack/cocaine users compared with alcohol and other substance users. METHODS: A cross-sectional multi-center study selected 741 current adult substance users from outpatient and inpatient Brazilian specialized clinics. Subjects were evaluated with the sixth version of the Addiction Severity Index, and 293 crack users were compared with 126 cocaine snorters and 322 alcohol and other drug users. RESULTS: Cocaine users showed more family problems when compared with other drug users, with no significant difference between routes of administration. These problems included arguing (crack 66.5%, powder cocaine 63.3%, other drugs 50.3%, p=0.004), having trouble getting along with partners (61.5%* 64.6%* 48.7%, p=0.013), and the need for additional childcare services in order to attend treatment (13.3%*10.3%*5.1%, p=0.002). Additionally, the majority of crack/cocaine users had spent time with relatives in the last month (84.6%*86.5%*76.6%, p=0.011). CONCLUSIONS: Brazilian treatment programs should enhance family treatment strategies, and childcare services need to be included. PMID- 25029584 TI - Assessment of the mechanics of a tissue-engineered rat trachea in an image processing environment. AB - OBJECTIVES: Despite the recent success regarding the transplantation of tissue engineered airways, the mechanical properties of these grafts are not well understood. Mechanical assessment of a tissue-engineered airway graft before implantation may be used in the future as a predictor of function. The aim of this preliminary work was to develop a noninvasive image-processing environment for the assessment of airway mechanics. METHOD: Decellularized, recellularized and normal tracheas (groups DECEL, RECEL, and CONTROL, respectively) immersed in Krebs-Henseleit solution were ventilated by a small-animal ventilator connected to a Fleisch pneumotachograph and two pressure transducers (differential and gauge). A camera connected to a stereomicroscope captured images of the pulsation of the trachea before instillation of saline solution and after instillation of Krebs-Henseleit solution, followed by instillation with Krebs-Henseleit with methacholine 0.1 M (protocols A, K and KMCh, respectively). The data were post processed with computer software and statistical comparisons between groups and protocols were performed. RESULTS: There were statistically significant variations in the image measurements of the medial region of the trachea between the groups (two-way analysis of variance [ANOVA], p<0.01) and of the proximal region between the groups and protocols (two-way ANOVA, p<0.01). CONCLUSIONS: The technique developed in this study is an innovative method for performing a mechanical assessment of engineered tracheal grafts that will enable evaluation of the viscoelastic properties of neo-tracheas prior to transplantation. PMID- 25029585 TI - Invasive tests in pregnancy. PMID- 25029587 TI - Perception of Self-Motion and Regulation of Walking Speed in Young-Old Adults. AB - Whether a reduced perception of self-motion contributes to poor walking speed adaptations in older adults is unknown. In this study, speed discrimination thresholds (perceptual task) and walking speed adaptations (walking task) were compared between young (19-27 years) and young-old individuals (63-74 years), and the relationship between the performance on the two tasks was examined. Participants were evaluated while viewing a virtual corridor in a helmet-mounted display. Speed discrimination thresholds were determined using a staircase procedure. Walking speed modulation was assessed on a self-paced treadmill while exposed to different self-motion speeds ranging from 0.25 to 2 times the participants' comfortable speed. For each speed, participants were instructed to match the self-motion speed described by the moving corridor. On the walking task, participants displayed smaller walking speed errors at comfortable walking speeds compared with slower of faster speeds. The young-old adults presented larger speed discrimination thresholds (perceptual experiment) and larger walking speed errors (walking experiment) compared with young adults. Larger walking speed errors were associated with higher discrimination thresholds. The enhanced performance on the walking task at comfortable speed suggests that intersensory calibration processes are influenced by experience, hence optimized for frequently encountered conditions. The altered performance of the young-old adults on the perceptual and walking tasks, as well as the relationship observed between the two tasks, suggest that a poor perception of visual motion information may contribute to the poor walking speed adaptations that arise with aging. PMID- 25029586 TI - Who needs surgery for pediatric myelomeningocele? A retrospective study and literature review. AB - INTRODUCTION: Children with myelomeningocele (MMC) are usually subjected to multiple surgeries. However, the number and type of surgeries are not the same in every patient with MMC over time. This report summarizes the surgical interventions in a cohort of several ages. MATERIALS AND METHODS: Data on all of the patients with MMC, aged from 1 year and 10 months to 21 years and 11 months, were retrospectively reviewed at the Dona Estefania Hospital in Lisbon, Portugal. Data were collected by chart review and individual interviews. The factors analyzed were demographics, ambulatory status, neurological level of involvement, shunt status, Arnold-Chiari malformation type II, surgical history, and occurrence of fracture. The surgical interventions were categorized as neurosurgical, orthopedic, urinary, ulcer repair and others. RESULTS: A total of 84 alive were eligible and enrolled. The average age was 14 years and six months. A total of 59 patients received shunts (all but one ventriculoperitoneal). In the study group, the 84 patients required 663 surgeries. Neurosurgical interventions were the most frequent surgical procedure and predominated during the first 2 years of life. Surgical interventions related to shunts were the most common neurosurgical interventions. Orthopedic surgeries were more frequent in the age group 6-12 years. Urological surgeries were done mainly after 6 years of age. Surgical repair of pressure ulcers was more common after 12 years of age. CONCLUSIONS: Our study brings to light the complexity of this condition, with multiple surgeries among patients with MMC. PMID- 25029588 TI - Novel copper (II) alginate hydrogels and their potential for use as anti bacterial wound dressings. AB - The incorporation of a metal ion, with antimicrobial activity, into an alginate dressing is an attractive approach to minimize infection in a wound. In this work, copper (II) cross-linked alginate hydrogels were successfully prepared using a two-step cross-linking procedure. In the first step, solid alginate films were prepared using a solvent-casting method from soft gels of alginate solutions that had been lightly cross-linked using a copper (II) (Cu(2+)) sulfate solution. In the second step, the films were further cross-linked in a corresponding Cu(2+) sulfate solution using a dipping method to further improve their dimensional stability. Alginate solution (at 2%w/v) and Cu(2+) sulfate solution (at 2%w/v) in acetate buffer at a low pH provided soft films with excellent swelling behavior. An increase in either Cu(2+) ion concentration or cross-linking time led to hydrogels with more densely-cross-linked networks that limited water absorption. The hydrogels clearly showed antibacterial activity against Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis and Streptococcus pyogenes, which was proportional to the Cu(2+) ion concentration. Blood coagulation studies showed that the tested copper (II) cross-linked alginate hydrogels had a tendency to coagulate fibrin, and possibly had an effect on pro-thrombotic coagulation and platelet activation. Conclusively, the prepared films are likely candidates as antibacterial wound dressings. PMID- 25029590 TI - Tandem one-pot palladium-catalyzed coupling of hydrazones, haloindoles, and amines: synthesis of amino-N-vinylindoles and their effect on human colon carcinoma cells. AB - The synthesis of amino-substituted N-vinylazoles was achieved by a new palladium assisted tandem catalytic reaction involving N-tosylhydrazones, halo-substituted azoles, and amines. Accordingly, two Csp(2)-N bonds were formed through two mechanistically distinct reactions using a single Pd(II)/Pd(0) catalyst system in a one-pot fashion. This work paves the way for the design of biological relevant compounds in an amino-substituted N-vinylindole series. Among several polyoxygenated derivatives evaluated, compounds 5e and 5u were found to exhibit good antiproliferative activity. PMID- 25029591 TI - Collective dynamics of flowing colloids during pore clogging. AB - Based on direct numerical simulations of the coupled motion of particles and fluid, this study analyzes the collective hydrodynamic and colloidal effects of flowing microparticles during the formation of different 3D clogging patterns at a pore entrance. Simulations of flowing suspensions through a pore with various simulation conditions show that particle concentration and surface interactions play a major role in the occurrence of the bridging phenomenon (simultaneous adhesion of many particles). In the absence of DLVO repulsive forces, plugging is characterized by the temporal reduction of the bulk permeability when increasing the volume fraction of the flowing suspension up to 20%. Under these conditions, different structures of particle aggregates (from cluster to cake plug) are formed at the pore entrance yielding different evolution rates of hydrodynamic resistance to the flow. Taking into account DLVO repulsive forces in simulations for a particle concentration equal to 10%, we observe the transition from dendritic structures (for low repulsion) to dense aggregates (for high repulsion). At high DLVO repulsive forces, the scenario of pore clogging is controlled by the collective behavior of many interacting particles. It leads to the formation of a jamming phase (Wigner glass phase) with transient clusters of interacting particles at the pore entrance. The network of jammed particles collapses when the force chains among the particles are overcome by the flow stress. The build-up and the collapse of the jammed phase at the pore entrance induce temporal permeability fluctuations. According to the relative magnitude of particle-particle and particle-wall interactions, when the jammed phase is disorganized by the flow, the residual force in the network can accelerate particles and lead to particle adhesion at the wall inducing a pore blockage and a rapid reduction of the bulk permeability. PMID- 25029589 TI - Vaccination in HIV-infected adults. AB - Vaccines are critical components for protecting HIV-infected adults from an increasing number of preventable diseases. However, missed opportunities for vaccination among HIV-infected persons persist, likely due to concerns regarding the safety and efficacy of vaccines, as well as the changing nature of vaccine guidelines. In addition, the optimal timing of vaccination among HIV-infected adults in regards to HIV stage and receipt of antiretroviral therapy remain important questions. This article provides a review of the current recommendations regarding vaccines among HIV-infected adults and a comprehensive summary of the evidence-based literature of the benefits and risks of vaccines among this vulnerable population. PMID- 25029592 TI - Hematoma shape, hematoma size, Glasgow coma scale score and ICH score: which predicts the 30-day mortality better for intracerebral hematoma? AB - PURPOSE: To investigate the performance of hematoma shape, hematoma size, Glasgow coma scale (GCS) score, and intracerebral hematoma (ICH) score in predicting the 30-day mortality for ICH patients. To examine the influence of the estimation error of hematoma size on the prediction of 30-day mortality. MATERIALS AND METHODS: This retrospective study, approved by a local institutional review board with written informed consent waived, recruited 106 patients diagnosed as ICH by non-enhanced computed tomography study. The hemorrhagic shape, hematoma size measured by computer-assisted volumetric analysis (CAVA) and estimated by ABC/2 formula, ICH score and GCS score was examined. The predicting performance of 30 day mortality of the aforementioned variables was evaluated. Statistical analysis was performed using Kolmogorov-Smirnov tests, paired t test, nonparametric test, linear regression analysis, and binary logistic regression. The receiver operating characteristics curves were plotted and areas under curve (AUC) were calculated for 30-day mortality. A P value less than 0.05 was considered as statistically significant. RESULTS: The overall 30-day mortality rate was 15.1% of ICH patients. The hematoma shape, hematoma size, ICH score, and GCS score all significantly predict the 30-day mortality for ICH patients, with an AUC of 0.692 (P = 0.0018), 0.715 (P = 0.0008) (by ABC/2) to 0.738 (P = 0.0002) (by CAVA), 0.877 (P<0.0001) (by ABC/2) to 0.882 (P<0.0001) (by CAVA), and 0.912 (P<0.0001), respectively. CONCLUSION: Our study shows that hematoma shape, hematoma size, ICH scores and GCS score all significantly predict the 30-day mortality in an increasing order of AUC. The effect of overestimation of hematoma size by ABC/2 formula in predicting the 30-day mortality could be remedied by using ICH score. PMID- 25029593 TI - Comparison of linear measurements between CBCT orthogonally synthesized cephalograms and conventional cephalograms. AB - OBJECTIVES: The purposes of the study are to investigate the consistency of linear measurements between CBCT orthogonally synthesized cephalograms and conventional cephalograms and to evaluate the influence of different magnifications on these comparisons based on a simulation algorithm. METHODS: Conventional cephalograms and CBCT scans were taken on 12 dry skulls with spherical metal markers. Orthogonally synthesized cephalograms were created from CBCT data. Linear parameters on both cephalograms were measured via Photoshop CS v. 5.0 (Adobe((r)) Systems, San Jose, CA), named measurement group (MG). Bland Altman analysis was utilized to assess the agreement of two imaging modalities. Reproducibility was investigated using paired t-test. By a specific mathematical programme "cepha", corresponding linear parameters [mandibular corpus length (Go Me), mandibular ramus length (Co-Go), posterior facial height (Go-S)] on these two types of cephalograms were calculated, named simulation group (SG). Bland Altman analysis was used to assess the agreement between MG and SG. Simulated linear measurements with varying magnifications were generated based on "cepha" as well. Bland-Altman analysis was used to assess the agreement of simulated measurements between two modalities. RESULTS: Bland-Altman analysis suggested the agreement between measurements on conventional cephalograms and orthogonally synthesized cephalograms, with a mean bias of 0.47 mm. Comparison between MG and SG showed that the difference did not reach clinical significance. The consistency between simulated measurements of both modalities with four different magnifications was demonstrated. CONCLUSIONS: Normative data of conventional cephalograms could be used for CBCT orthogonally synthesized cephalograms during this transitional period. PMID- 25029595 TI - Cranial base manifestations of neurosarcoidosis: a review of 305 patients. AB - OBJECTIVE: Neurosarcoidosis is a rare granulomatous disease that can result in cranial neuropathy, chronic meningitis, and intracranial granuloma formation. Meningeal involvement may cause focal nodular enhancement that can simulate common cranial base tumors. The objective of the current study is to further define the clinical features of neurosarcoidosis in a large cohort of patients, focusing on characteristics relevant to the skull base surgeon. STUDY DESIGN: Retrospective series. SETTING: Two tertiary academic referral centers. PATIENTS: Consecutive patients diagnosed with neurosarcoidosis. INTERVENTION(S): Review of clinical presentation, physical examination, radiologic findings, biopsy results, and laboratory testing. MAIN OUTCOME MEASURES: Prevalence and distribution of cranial neuropathy, radiologic features of meningeal enhancement, and patterns of simulated tumors. RESULTS: A total of 305 patients met study criteria. The mean age at diagnosis was 47 years and 53% were female. The optic nerve was the most commonly involved cranial nerve, followed by the trigeminal and the facial nerve. Meningeal enhancement was present in 67% of cases with 17% demonstrating focal or multicentric nodular enhancement simulating tumor. The most common locations of inflammatory tumor development included the cavernous sinus, petrous temporal bone, and sphenoid wing; six patients had bilateral internal auditory canal lesions, several mimicking neurofibromatosis type II. CONCLUSION: Establishing the diagnosis of neurosarcoidosis remains challenging. Meningeal involvement and cranial neuropathy often mimic other more common conditions. Careful review of patient history and clinical imaging can reveal important clues toward the diagnosis of neurosarcoidosis. The clinician must maintain a high index of suspicion in patients with atypical presentation to avoid misdiagnosis and facilitate early medical treatment. PMID- 25029597 TI - Neuroendocrine tumors of unknown primary: is the primary site really not known? PMID- 25029596 TI - Treatment with echinocandins during continuous renal replacement therapy. AB - Echinocandins are indicated as first-line treatment for invasive candidiasis in moderate to severe illness. As sepsis is the main cause of acute kidney injury, the combination of echinocandin treatment and continuous renal replacement therapy (CRRT) is common. Optimizing antibiotic dosage in critically ill patients receiving CRRT is challenging. The pharmacokinetics of echinocandins have been studied under various clinical conditions; however, data for CRRT patients are scarce. Classically, drugs like echinocandins with high protein binding and predominantly non-renal elimination are not removed by CRRT, indicating that no dosage adjustment is required. However, recent studies report different proportions of echinocandins lost by filter adsorption. Nevertheless, the clinical significance of these findings remains unclear. PMID- 25029598 TI - 0.1 kilopascal difference for mechanophenotyping: soft matrix precisely regulates cellular architecture for invasion. AB - Current knowledge understands the mesenchymal cell invasion in a 3D matrix as a combined process of cell-to-matrix adhesion based cell migration and matrix remodeling. Excluding cell invasion stimulated by cytokines and chemokines, the basal cell invasion itself is a complicated process that can be regulated by matrix ligand type, density, geometry, and stiffness, etc. Understanding such a complicated biological process requires delicate dissections into simplified model studies by altering only one or two elements at a time. Past cell motility studies focusing on matrix stiffness have revealed that a stiffer matrix promotes 2D X-Y axis lateral cell motility. Here, we comment on two recent studies that report, instead of stiffer matrix, a softer matrix promotes matrix proteolysis and the formation of invadosome-like protrusions (ILPs) along the 3D Z axis. These studies also reveal that soft matrix precisely regulates such ILPs formation in the stiffness scale range of 0.1 kilopascal in normal cells. In contrast, malignant cells such as cancer cells can form ILPs in response to a much wider range of matrix stiffness. Further, different cancer cells respond to their own favorable range of matrix stiffness to spontaneously form ILPs. Thus, we hereby propose the idea of utilizing the matrix stiffness to precisely regulate ILP formation as a mechanophenotyping tool for cancer metastasis prediction and pathological diagnosis. PMID- 25029599 TI - Screening for neurocognitive impairment, depression, and anxiety in HIV-infected patients in Western Europe and Canada. AB - CRANIum, a cross-sectional epidemiology study in Western Europe and Canada, was conducted to describe and compare the prevalence of a positive screen for neurocognitive impairment (NCI), depressive symptoms, and anxiety in an HIV positive population either receiving combination antiretroviral therapy (cART) or who were naive to antiretroviral therapy (ART). HIV-positive patients >=18 years of age attending a routine medical follow-up visit and able to complete the designated screening tools were eligible for study inclusion. The Brief Neurocognitive Screen was used to assess NCI; depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale. The evaluable patient population (N = 2863) included 1766 men (61.7%) and 1096 (38.3%) women. A total of 1969 patients were cART-experienced (68.8%), and 894 were ART-naive (31.2%). A positive screen for NCI was found in 41.5% of patients (cART experienced, 42.5%; ART-naive, 39.4%; p = 0.12). A positive screen for depressive symptoms was found in 15.7% of patients (cART-experienced, 16.8%; ART-naive, 13.3%; p = 0.01), whereas 33.3% of patients screened positive for anxiety (cART experienced, 33.5%; ART-naive, 32.8%; p = 0.71). A greater percentage of women compared with men screened positive for NCI (51.78% vs. 35.1%; p < 0.0001) and depressive symptoms (17.9% vs. 14.3%; p = 0.01). These data suggest that neurocognitive and mood disorders remain highly prevalent in HIV-infected patients. Regular mental health screening in this population is warranted. PMID- 25029601 TI - Gene therapy briefs. PMID- 25029600 TI - Gene-modified cells for stem cell transplantation and cancer therapy. PMID- 25029602 TI - Phenotypic reversion of fair hair upon gene therapy of the phenylketonuria mice. PMID- 25029603 TI - Congratulations to the winners of the 12 Pioneer Awards for seminal work in gene and cell therapy. PMID- 25029604 TI - Stereoselective one-pot synthesis of beta-alkylsulfide enol esters. Base triggered rearrangement under mild conditions. AB - A stereoselective one-pot procedure was developed to prepare S-substituted (Z) enol esters through a base-triggered rearrangement. This transition metal-free multicomponent approach can be performed under an air atmosphere at room temperature, tolerates a wide set of chemical functionalities and generally affords high isolated yields. The (Z)-selectivity arises from the [1,4]-S- to O acyl migration. PMID- 25029605 TI - Severity of post-cardiac surgery acute kidney injury and long-term mortality: is chronic kidney disease the missing link? PMID- 25029606 TI - Improved electronic coupling in hybrid organic-inorganic nanocomposites employing thiol-functionalized P3HT and bismuth sulfide nanocrystals. AB - In this study, we employ a thiol-functionalized polymer (P3HT-SH) as a leverage to tailor the nanomorphology and electronic coupling in polymer-nanocrystal composites for hybrid solar cells. The presence of the thiol functional group allows for a highly crystalline semiconducting polymer film at low thiol content and allows for improved nanomorphologies in hybrid organic-inorganic systems when employing non-toxic bismuth sulfide nanocrystals. The exciton dissociation efficiency and carrier dynamics at this hybrid heterojunction are investigated through photoluminescence quenching and transient absorption spectroscopy measurements, revealing a larger degree of polaron formation when P3HT-SH is employed, suggesting an increased electronic interaction between the metal chalcogenide nanocrystals and the thiol-functionalized P3HT. The fabricated photovoltaic devices show 15% higher power conversion efficiencies as a result of the improved nanomorphology and better charge transfer mechanism together with the higher open circuit voltages arising from the deeper energy levels of P3HT SH. PMID- 25029607 TI - Regional economic activity and absenteeism: a new approach to estimating the indirect costs of employee productivity loss. AB - This paper presents a new approach to estimating the indirect costs of health related absenteeism. Productivity losses related to employee absenteeism have negative business implications for employers and these losses effectively deprive the business of an expected level of employee labor. The approach herein quantifies absenteeism cost using an output per labor hour-based method and extends employer-level results to the region. This new approach was applied to the employed population of 3 health insurance carriers. The economic cost of absenteeism was estimated to be $6.8 million, $0.8 million, and $0.7 million on average for the 3 employers; regional losses were roughly twice the magnitude of employer-specific losses. The new approach suggests that costs related to absenteeism for high output per labor hour industries exceed similar estimates derived from application of the human capital approach. The materially higher costs under the new approach emphasize the importance of accurately estimating productivity losses. PMID- 25029608 TI - Electrospun carbon nanofibers decorated with Ag-Pt bimetallic nanoparticles for selective detection of dopamine. AB - Electrospun nanoporous carbon nanofibers (pCNFs) decorated with Ag-Pt bimetallic nanoparticles have been successfully synthesized by combining template carbonization and seed-growth reduction approach. Porous-structured polyacrylonitrile (PAN) nanofibers (pPAN) were first prepared by electrospinning PAN/polyvinylpyrrolidone (PVP) blend solution, followed by subsequent water extraction and heat treatment to obtain pCNFs. Ag-Pt/pCNFs were then obtained by using pCNFs as support for bimetallic nanoparticle loading. Thus, the obtained Ag Pt/pCNFs were used to modify glassy carbon electrode (GCE) for selective detection of dopamine (DA) in the presence of uric acid (UA) and ascorbic acid (AA). This novel sensor exhibits fast amperometric response and high sensitivity toward DA with a wide linear concentration range of 10-500 MUM and a low detection limit of 0.11 MUM (S/N = 3), wherein the interference of UA and AA can be eliminated effectively. PMID- 25029609 TI - Copper-catalyzed three-component cyanotrifluoromethylation/azidotrifluoromethylation and carbocyclization of 1,6 enynes. AB - A novel three-component strategy for the cyanotrifluoromethylation/azidotrifluoromethylation and carbocyclization of 1,6 enynes is developed. The reaction proceeds smoothly under a moderate temperature by using a copper catalyst, which provides a rapid and concise access to addition carbocyclization products. Furthermore, the products obtained can be useful building blocks in discoveries of lead compounds and other biologically active CF3-containing heterocycles. PMID- 25029610 TI - On the uniqueness of the receding contact angle: effects of substrate roughness and humidity on evaporation of water drops. AB - Could a unique receding contact angle be indicated for describing the wetting properties of a real gas-liquid-solid system? Could a receding contact angle be defined if the triple line of a sessile drop is not moving at all during the whole measurement process? To what extent is the receding contact angle influenced by the intrinsic properties of the system or the measurement procedures? In order to answer these questions, a systematic investigation was conducted in this study on the effects of substrate roughness and relative humidity on the behavior of pure water drops spreading and evaporating on polycarbonate (PC) surfaces characterized by different morphologies. Dynamic, advancing, and receding contact angles were found to be strongly affected by substrate roughness. Specifically, a receding contact angle could not be measured at all for drops evaporating on the more rugged PC surfaces, since the drops were observed strongly pinning to the substrate almost until their complete disappearance. Substrate roughness and system relative humidity were also found responsible for drastic changes in the depinning time (from ~10 to ~60 min). Thus, for measurement observations not sufficiently long, no movement of the triple line could be noted, with, again, the failure to find a receding contact angle. Therefore, to keep using concepts such as the receding contact angle as meaningful specifications of a given gas-liquid-solid system, the imperative to carefully investigate and report the inner characteristics of the system (substrate roughness, topography, impurities, defects, chemical properties, etc.) is pointed out in this study. The necessity of establishing methodological standards (drop size, measurement method, system history, observation interval, relative humidity, etc.) is also suggested. PMID- 25029611 TI - All-carbon, neutral analogue of ExBox4+: A DFT study of polycyclic aromatic hydrocarbon binding. AB - To assess the role that electrostatic interactions play in the binding of polycyclic aromatic hydrocarbons within ExBox(4+) 1, we report omegaB97X-D/6 311G(d,p) computations of the binding of five small linear acenes with the hydrocarbon neutral analogue 5 in both the gas phase and acetonitrile solution. The terphenyl units of 5 are less bowed outward than are the ExBIPY units of 5, due to the lack of charge repulsion. This manifests in a much smaller ring strain energy in 5 than 1. The acenes bind to both 1 and 5 with increasing affinity as the size of the guest increases. The affinity of the PAHs to 1 is greater than the affinity to 5, though the difference in the binding enthapies to 1 and 5 is relatively small, ranging from 2.4 to 9.8 kcal mol(-1). Electrostatics account for only 10-20% of the total binding energy. PMID- 25029612 TI - Screening for methicillin-resistant Staphylococcus aureus ... all doors closed? AB - PURPOSE OF REVIEW: To describe the latest evidence for methicillin-resistant Staphylococcus aureus (MRSA) infection control strategies, with particular emphasis on active surveillance cultures with contact precautions and targeted decolonization, and their impact. RECENT FINDINGS: Several major trials published last year questioned the effectiveness of universal screening and contact precautions in controlling MRSA. These trials generally recommend universal decolonization as part of bundles to control MRSA, especially in ICUs, with some even concluding that universal decolonization should replace active screening and contact precautions. However, emerging resistance to agents used for decolonization, such as mupirocin and chlorhexidine, is a major concern. Several other studies confirmed a combination of hand hygiene enhancement, screening, contact precaution and targeted decolonization as a more viable MRSA infection control strategy for specific population groups. SUMMARY: Universal decolonization is an acceptable MRSA control strategy for intensive care units; however, close monitoring of chlorhexidine and mupirocin resistance is warranted. As a strategy, screening and contact precautions are suitable for hospital-wide MRSA control. Targeted decolonization is a proven measure for patients undergoing clean surgery. Enhancement of hand hygiene is a core measure regardless of the strategy. PMID- 25029614 TI - Small bowel adenocarcinomas complicating Crohn's disease are associated with dysplasia: a pathological and molecular study. AB - BACKGROUND: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. METHODS: Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, beta catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. RESULTS: All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for beta-catenin and p16. No PIK3CA mutations were observed. CONCLUSIONS: These results suggest that there is an inflammation dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer. PMID- 25029615 TI - A systematic review of measurement of endoscopic disease activity and mucosal healing in Crohn's disease: recommendations for clinical trial design. AB - BACKGROUND: Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials. METHODS: A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized. RESULTS: The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohn's Disease (SES-CD) are indices with the most extensively described operating properties. CONCLUSIONS: Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required. PMID- 25029616 TI - Systems biology approaches for inflammatory bowel disease: emphasis on gut microbial metabolism. AB - Although the prevalence of main idiopathic forms of inflammatory bowel disease (IBD) has risen considerably over the last decades, their clinical features do not allow accurate prediction of prognosis, likelihood of disease progression, or response to specific therapy. Through a better understanding of the molecular pathways involved in IBD and the promise of more targeted therapies, the personalized approach to the management of IBD shows potential. To achieve this, there remains a significant need to better understand the disease process at cellular and molecular levels for any given individual with IBD. The complexity of biological functional networks behind the etiology of IBD highlights the need for their comprehensive analysis. In this, omics technologies can generate a systemic view of IBD pathogenesis on which to base novel, multiple pathway integrated therapies. Omics sciences have just started to contribute here by generating gene, protein expression, metabolite data at global level and large scale, and more recently by offering new opportunities to explore gut functional ecology. In particular, there is much expectation regarding the putative role of the gut microbiome in IBD. No doubt it will provide additional insights and lead to the development of alternative, hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD. This review discusses perspectives of relevance to clinical translation with emphasis on gut microbial metabolic activities. PMID- 25029617 TI - 6-Mercaptopurine reduces macrophage activation and gut epithelium proliferation through inhibition of GTPase Rac1. AB - BACKGROUND: Inflammatory bowel disease is characterized by chronic intestinal inflammation. Azathioprine and its metabolite 6-mercaptopurine (6-MP) are effective immunosuppressive drugs that are widely used in patients with inflammatory bowel disease. However, established understanding of their immunosuppressive mechanism is limited. Azathioprine and 6-MP have been shown to affect small GTPase Rac1 in T cells and endothelial cells, whereas the effect on macrophages and gut epithelial cells is unknown. METHODS: Macrophages (RAW cells) and gut epithelial cells (Caco-2 cells) were activated by cytokines and the effect on Rac1 signaling was assessed in the presence or absence of 6-MP. RESULTS: Rac1 is activated in macrophages and epithelial cells, and treatment with 6-MP resulted in Rac1 inhibition. In macrophages, interferon-gamma induced downstream signaling through c-Jun-N-terminal Kinase (JNK) resulting in inducible nitric oxide synthase (iNOS) expression. iNOS expression was reduced by 6-MP in a Rac1-dependent manner. In epithelial cells, 6-MP efficiently inhibited tumor necrosis factor-alpha-induced expression of the chemokines CCL2 and interleukin 8, although only interleukin-8 expression was inhibited in a Rac1-dependent manner. In addition, activation of the transcription factor STAT3 was suppressed in a Rac1-dependent fashion by 6-MP, resulting in reduced proliferation of the epithelial cells due to diminished cyclin D1 expression. CONCLUSIONS: These data demonstrate that 6-MP affects macrophages and gut epithelial cells beneficially, in addition to T cells and endothelial cells. Furthermore, mechanistic insight is provided to support development of Rac1-specific inhibitors for clinical use in inflammatory bowel disease. PMID- 25029618 TI - Role in calcineurin inhibitors for inflammatory bowel disease in the biologics era: when and how to use. AB - Ulcerative colitis and Crohn's disease, which is the 2 major forms of inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. During the last 30 years, the therapy for patients with refractory inflammatory bowel diseases is still challenging despite the fact that morbidity and mortality rates have been obviously reduced. The conventional management with corticosteroids has been modified by the introduction of calcineurin inhibitors and biologics. In this review, we focus on role in calcineurin inhibitors for patients with inflammatory bowel disease in the currently clinical practice. PMID- 25029619 TI - Effect of a low-fat or low-carbohydrate weight-loss diet on markers of cardiovascular risk among premenopausal women: a randomized trial. AB - BACKGROUND: Low-fat and low-carbohydrate weight-loss diets can have a beneficial effect on longitudinal measures of blood pressure and blood lipids. We aimed to assess longitudinal changes in blood pressure and blood lipids in a population of premenopausal women. We hypothesized that results may differ by level of adherence to the respective diet protocol and baseline presence of hypertension or hyperlipidemia. METHODS: Overweight or obese premenopausal women were randomized to a low-fat (n=41) or low-carbohydrate (n=38) diet. As part of the 52 week Lifestyle Eating and Fitness (LEAF) intervention trial, we fit linear mixed models to determine whether a change in outcome differed by treatment arm. RESULTS: Within-group trends in blood pressure and blood lipids did not differ (p>0.30). Across study arms, there was a significant decrease in systolic blood pressure (SBP, 3 mm Hg, p=0.01) over time, but diastolic blood pressure (DBP) did not change significantly over the course of the study. Blood lipids (total cholesterol [TC], low-density lipoproteins [LDL], and high-density lipoproteins [HDL]) all exhibited nonlinear trends over time (p<0.01); each decreased initially but returned to levels comparable to baseline by study conclusion (p>0.20). We observed a decline in SBP among women who were hypertensive at baseline (p<0.01), but hypercholesterolemia at baseline did not affect trends in blood lipids (p>0.40). CONCLUSIONS: Our results support that dietary interventions may be efficacious for lowering blood pressure and blood lipids among overweight or obese premenopausal women. However, a decrease in SBP was the only favorable change that was sustained in this study population. These changes can be maintained over the course of a 1-year intervention, yet changes in blood lipids may be less sustainable. PMID- 25029620 TI - Size distribution of magnetic charge domains in thermally activated but out-of equilibrium artificial spin ice. AB - A crystal of emerging magnetic charges is expected in the phase diagram of the dipolar kagome spin ice. An observation of charge crystallites in thermally demagnetized artificial spin ice arrays has been recently reported by S. Zhang and coworkers and explained through the thermodynamics of the system as it approaches a charge-ordered state. Following a similar approach, we have generated a partial order of magnetic charges in an artificial kagome spin ice lattice made out of ferrimagnetic material having a Curie temperature of 475 K. A statistical study of the size of the charge domains reveals an unconventional sawtooth distribution. This distribution is in disagreement with the predictions of the thermodynamic model and is shown to be a signature of the kinetic process governing the remagnetization. PMID- 25029621 TI - The 'availability' bias: underappreciated but with major potential implications. AB - Many biases have been described that potentially introduce prejudice or a systemic error into a study that would favor one outcome versus another. One major source of bias has, so far, been underappreciated: the availability bias. When the study intervention is available to clinicians outside of the clinical trial, the trial could become biased to favor the control study arm. Clinicians may, consciously or unconsciously, use this intervention outside of the trial on patients whom they believe would benefit from the intervention, and enroll in the trial those patients for whom they do not feel strongly about the benefit of the intervention. The clinicians do not always share the equipoise of the study investigators. This could have major implications on the analysis of clinical trials, including the systematic reviews that originate from such trials. PMID- 25029622 TI - Chikungunya virus: a major emerging threat. PMID- 25029623 TI - Synergistic formation of carboxyl and methyl radicals in CO2 + methane mixed gas hydrates. AB - The formation mechanisms of gamma-ray-induced carboxyl (HOCO) and methyl radicals in CO2 + methane mixed gas hydrates, which are inclusion compounds of H2O, CO2, and methane, were investigated. The HOCO and methyl radicals were observed in CO2 + methane mixed gas hydrates by electron spin resonance (ESR) at 120 K after irradiation at 77 K. The amounts of the HOCO and methyl radicals induced in the mixed hydrates are much higher than those in pure CO2 and methane hydrates. Both radicals are synergistically formed in the mixed hydrates by efficient reactions between the guest molecules (CO2 and methane) and the active species (electron, proton, and hydroxyl radical) induced from H2O. PMID- 25029624 TI - Fever management in intensive care patients with infections. AB - With great interest we read the article by Dr Schoeneberg and colleagues regarding gender-specific differences with respect to outcome in patients with severe traumatic injury. The authors show that, apart from the acute phase after trauma, women have a more favorable trauma severity-adjusted outcome, with shorter ICU and hospital stay and lower sepsis rates. However, a possible mechanism of action behind this difference was not suggested. We hypothesize that, in view of the fact that morbidity and mortality in the post-acute phase after trauma are often caused by infectious complications, gender differences in immunity might explain the observed differences. PMID- 25029625 TI - The receptive-expressive gap in bilingual children with and without primary language impairment. AB - PURPOSE: In this study, the authors examined the magnitude of the discrepancy between standardized measures of receptive and expressive semantic knowledge, known as a receptive-expressive gap, for bilingual children with and without primary language impairment (PLI). METHOD: Spanish and English measures of semantic knowledge were administered to 37 Spanish-English bilingual 7- to 10 year old children with PLI and to 37 Spanish-English bilingual peers with typical development (TD). Parents and teachers completed questionnaires that yielded day by-day and hour-by-hour information regarding children's exposure to and use of Spanish and English. RESULTS: Children with PLI had significantly larger discrepancies between receptive and expressive semantics standard scores than their bilingual peers with TD. The receptive-expressive gap for children with PLI was predicted by current English experience, whereas the best predictor for children with TD was cumulative English experience. CONCLUSIONS: As a preliminary explanation, underspecified phonological representations due to bilingual children's divided language input as well as differences in their languages' phonological systems may result in a discrepancy between standardized measures of receptive and expressive semantic knowledge. This discrepancy is greater for bilingual children with PLI because of the additional difficulty these children have in processing phonetic information. Future research is required to understand these underlying processes. PMID- 25029627 TI - So you want to be a principal investigator? PMID- 25029628 TI - Protective effects of protocatechuic acid on retinal ganglion cells from oxidative damage induced by H2O2. AB - Oxidative stress-induced retinal ganglion cell (RGC) death is one of the important factors in ocular disease such as glaucoma. The aim of this study is to investigate whether protocatechuic acid (PCA), a monomeric phenolic acid with strong free radical scavenging effects, could protect RGC from oxidative stress induced by H2O2 and provide a potential therapy drug. The viability of RGC was determined by the MTT reduction and lactate dehydrogenase (LDH) assay. The possible protective mechanism was investigated via detecting apoptosis by Hoechst staining, Bcl-2 and Bax protein levels by ELISA, caspase-3 activation and membrane potential by immunofluorescence, and caspase-3 mRNA expression by polymerase chain reaction (PCR) method. The results showed that PCA was effective in reducing apoptotic death induced by oxidative stress, mainly through inhibiting depolarization of membrane and activation of caspase-3, down regulating of apoptosis-related protein Bax, and up-regulating Bcl-2. PMID- 25029629 TI - N-nitrosodimethylamine formation upon ozonation and identification of precursors source in a municipal wastewater treatment plant. AB - Ozone doses normalized to the dissolved organic carbon concentration were applied to the primary influent, primary effluent, and secondary effluent of a wastewater treatment plant producing water destined for potable reuse. Results showed the most N-Nitrosodimethylamine (NDMA) production from primary effluent, and the recycle streams entering the primary clarifiers were identified as the main source of NDMA precursors. The degradation of aminomethylated polyacrylamide (Mannich) polymer used for sludge treatment was a significant cause of precursor occurrence. A strong correlation between NDMA formation and ammonia concentration was found suggesting an important role of ammonia oxidation on NDMA production. During ozonation tests in DI water using dimethylamine (DMA) as model precursor, the NDMA yield significantly increased in the presence of ammonia and bromide due to the formation of hydroxylamine and brominated nitrogenous oxidants. In addition, NDMA formation during ozonation of dimethylformamide (DMF), the other model precursor used in this study, occurred only in the presence of ammonia, and it was attributable to the oxidation of DMF by hydroxyl radicals. Filtered wastewater samples (0.7 MUm) produced more NDMA than unfiltered samples, suggesting that ozone reacted with dissolved precursors and supporting the hypothesis of polymer degradation. Particularly, the total suspended solids content similarly affected NDMA formation and the UV absorbance decrease during ozonation due to the different ozone demand created in filtered and unfiltered samples. PMID- 25029630 TI - Amine functionalized nanodiamond promotes cellular adhesion, proliferation and neurite outgrowth. AB - In this study, we report the production of amine functionalized nanodiamond. The amine functionalized nanodiamond forms a conformal monolayer on a negatively charged surface produced via plasma polymerization of acrylic acid. Nanodiamond terminated surfaces were studied as substrates for neuronal cell culture. NG108 15 neuroblastoma-glioma hybrid cells were successfully cultured upon amine functionalized nanodiamond coated surfaces for between 1 and 7 d. Additionally, primary dorsal root ganglion (DRG) neurons and Schwann cells isolated from Wistar rats were also successfully cultured over a period of 21 d illustrating the potential of the coating for applications in the treatment of peripheral nerve injury. PMID- 25029631 TI - Improving population management through pharmacist-primary care integration: a pilot study. AB - Pharmacists have unique skills that may benefit primary care practices. The objective of this demonstration project was to determine the impact of integrating pharmacists into patient-centered medical homes, with a focus on population management. Pharmacists were partnered into 5 primary care practices in Vermont 1 day per week to provide direct patient care, population-based medication management, and prescriber education. The main measures included a description of drug therapy problems identified and cost avoidance models. The pharmacists identified 708 drug therapy problems through direct patient care (336/708; 47.5%), population-based strategies (276/708; 38.9%), and education (96/708; 13.6%). Common population-based strategies included adjusting doses and discontinuing unnecessary medications. Pharmacists' recommendations to correct drug therapy problems were accepted by prescribers 86% of the time, when data about acceptance were known. Of the 49 recommendations not accepted, 47/49 (96%) were population-based and 2/49 (4%) were related to direct patient care. The cost avoidance model suggests $2.11 in cost was avoided for every $1.00 spent on a pharmacist ($373,092/$176,690). There was clear value in integrating pharmacists into primary care teams. Their inclusion prevented adverse drug events, avoided costs, and improved patient outcomes. Primary care providers should consider pharmacists well suited to offer direct patient care, population-based management, and prescriber education to their practices. To be successful, pharmacists must have full permission to document findings in the primary care practices' electronic health records. Given that many pharmacist services do not involve billable activities, sustainability requires identifying alternative funding mechanisms that do not rely on a traditional fee-for-service approach. PMID- 25029632 TI - A modular approach for assembling aldehyde-tagged proteins on DNA scaffolds. AB - Expansion of antibody scaffold diversity has the potential to expand the neutralizing capacity of the immune system and to generate enhanced therapeutics and probes. Systematic exploration of scaffold diversity could be facilitated with a modular and chemical scaffold for assembling proteins, such as DNA. However, such efforts require simple, modular, and site-specific methods for coupling antibody fragments or bioactive proteins to nucleic acids. To address this need, we report a modular approach for conjugating synthetic oligonucleotides to proteins with aldehyde tags at either terminus or internal loops. The resulting conjugates are assembled onto DNA-based scaffolds with low nanometer spatial resolution and can bind to live cells. Thus, this modular and site-specific conjugation strategy provides a new tool for exploring the potential of expanded scaffold diversity in immunoglobulin-based probes and therapeutics. PMID- 25029633 TI - Korean, Japanese, and Chinese populations featured similar genes encoding drug metabolizing enzymes and transporters: a DMET Plus microarray assessment. AB - BACKGROUND: Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups. METHODS: The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used. RESULTS: On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA. CONCLUSION: Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination. PMID- 25029634 TI - Flexible and transparent polyimide films containing two-dimensional alumina nanosheets templated by graphene oxide for improved barrier property. AB - Unique two-dimensional alumina nanosheets (Alns) using graphene oxide (GO) as templates are fabricated and successfully incorporated with organo-soluble polyimide (PI) to obtain highly transparent PI nanocomposite films with improved moisture barrier property. The effects of filler types and contents on water vapor transmission rate (WVTR) and transparency of PI are systematically studied. The hydroxyl groups on GO react with aluminum isopropoxide via sol-gel process to obtain alumina coverd-GO (Al-GO), and then thermal decomposition is applied to obtain Alns. Alns are the most efficient fillers among others to restrict the diffusion of water vapor within PI matrix and simultaneously maintain the transparency of PI. XRD pattern, TEM, and AFM images confirm the sheet-like morphology of Alns with ultrahigh aspect ratio. With only 0.01 wt % of Alns, the PI nanocomposite film exhibits the most significant reduction of 95% in WVTR as compared to that of pure PI film. Most importantly, the resultant PI/Alns-0.01 film exhibits excellent optical transparency and high mechanical strength and great thermal stability. PMID- 25029635 TI - Glutamine supplementation to critically ill patients? PMID- 25029636 TI - HIV testing during the Canadian immigration medical examination: a national survey of designated medical practitioners. AB - HIV testing is mandatory for individuals wishing to immigrate to Canada. Since the Designated Medical Practitioners (DMPs) who perform these tests may have varying experience in HIV and time constraints in their clinical practices, there may be variability in the quality of pre- and posttest counseling provided. We surveyed DMPs regarding HIV testing, counseling, and immigration inadmissibility. A 16-item survey was mailed to all DMPs across Canada (N = 203). The survey inquired about DMP characteristics, knowledge of HIV, attitudes and practices regarding inadmissibility and counseling, and interest in continuing medical education. There were a total of 83 respondents (41%). Participants frequently rated their knowledge of HIV diagnostics, cultural competency, and HIV/AIDS service organizations as "fair" (40%, 43%, and 44%, respectively). About 25%, 46%, and 11% of the respondents agreed/strongly agreed with the statements "HIV infected individuals pose a danger to public health and safety," "HIV-positive immigrants cause excessive demand on the healthcare system," and "HIV seropositivity is a reasonable ground for denial into Canada," respectively. Language was cited as a barrier to counseling, which focused on transmission risks (46% discussed this as "always" or "often") more than coping and social support (37%). There was a high level of interest (47%) in continuing medical education in this area. There are areas for improvement regarding DMPs' knowledge, attitudes, and practices about HIV infection, counseling, and immigration criteria. Continuing medical education and support for DMPs to facilitate practice changes could benefit newcomers who test positive through the immigration process. PMID- 25029637 TI - Self-assembly of triangular amphiphiles into diverse nano/microstructures and release behavior of the hollow sphere. AB - Amphiphilic triangular derivatives containing imine bond have been designed and used as building blocks for the construction of soft colloidal materials. The acylhydrazone derivative was found to form various nano/microstructures in different solvents. The microspheres, flower-like, and hollow spheres were formed in the polar solvents, while organogels with microporous structures were formed in nonpolar solvents. However, the simple Schiff base amphiphile without amide group did not form any ordered structures in the tested solvents. Therefore, besides the pi-pi stacking between the aromatic core and the van der Waals interactions between the alkyl chains, the hydrogen bonding between the acylhydrazone moieties played an important role in promoting the formation of various organized structures. More interestingly, the hollow sphere structure which was formed in THF could be used to encapsulate and release the rhodamine B. It was found that rhodamine B was encapsulated within their interiors under neutral conditions and released in an acidic condition due to the breakage of the imine bond. PMID- 25029638 TI - Kimchi protects against azoxymethane/dextran sulfate sodium-induced colorectal carcinogenesis in mice. AB - The chemopreventive effects of different types and quantities of kimchi prepared with different subingredients, including commercial kimchi (CK), standardized kimchi (SK), cancer-preventive kimchi (CPK), and anticancer kimchi (ACK), on colorectal carcinogenesis in mice were evaluated. The development of colon cancer was induced in male BALB/c mice with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and subsequent treatment with 2% dextran sulfate sodium (DSS) in drinking water for 7 days for two cycles. After exposure to AOM and DSS, treatment with the methanolic extracts from different kimchis, particularly 1.89 g/kg of ACK, significantly increased colon length, decreased the ratio of colon weight/length, and resulted in the lowest number of tumors compared with the other kimchi-treated groups. Histological observation revealed that ACK was able to suppress AOM- and DSS-induced colonic mucosal damage and neoplasia. ACK also significantly decreased the mRNA levels of proinflammatory cytokines (TNF-alpha, IL-6, and IFN-gamma) as well as the mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase-2 (COX-2). In addition, the mRNA and protein expression of p53 and p21 was elevated in colon tissues from the ACK-treated mice compared with the other kimchi-treated groups. Our results suggest that kimchi exerted a suppressive effect on AOM- and DSS induced colorectal carcinogenesis in the BALB/c mice. The anticancer effects of ACK were particularly potent. Thus, it is possible that the health-promoting subingredients added to ACK might be used to prevent colon carcinogenesis in humans. PMID- 25029639 TI - Second hematologic malignancies in hairy cell leukemia: report of two patients with dynamic mutations in the BRAF gene. PMID- 25029640 TI - Allogeneic hematopoietic stem cell transplant for hematological malignancies from mismatched 9/10 human leukocyte antigen unrelated donors: comparison with transplants from 10/10 unrelated donors and human leukocyte antigen identical siblings. AB - We studied the outcome of 213 patients who received allo-HSCT for hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors. Engraftment was lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the sibling group (99%); 3 months CI of aGVHD >= 2 was 32% (23-41), 20% (15-26) and 27% (23-32) respectively; the one year CI of extensive cGVHD was 21% (13-30), 9% (5-13) and 17% (14-21) respectively. The median OS was 10 months (5-21), 18 months (11-NR) and 60 months (31-NR) respectively with 2 years probability of 19% (8-44), 43% (31-59) and 63% (54-74) respectively. TRM was significantly higher in the 9/10 HLA group with 1 year CI of 45% (35-55), compared to 33% (27-39) in the unrelated 10/10 HLA group and 12% (9-15) in the identical siblings group (p < 0.001). PMID- 25029641 TI - Fighting respiratory diseases: divided efforts lead to weakness. PMID- 25029642 TI - Translating patient-reported outcome measures: a multi-step process is essential. PMID- 25029643 TI - Leicester Cough Questionnaire: translation to Portuguese and cross-cultural adaptation for use in Brazil. AB - OBJECTIVE: To translate the Leicester Cough Questionnaire (LCQ) to Portuguese and adapt it for use in Brazil. METHODS: Cross-cultural adaptation of a quality of life questionnaire requires a translated version that is conceptually equivalent to the original version and culturally acceptable in the target country. The protocol used consisted of the translation of the LCQ to Portuguese by three Brazilian translators who were fluent in English and its back-translation to English by another translator who was a native speaker of English and fluent in Portuguese. The back-translated version was evaluated by one of the authors of the original questionnaire in order to verify its equivalence. Later in the process, a provisional Portuguese-language version was thoroughly reviewed by an expert committee. In 10 patients with chronic cough, cognitive debriefing was carried out in order to test the understandability, clarity, and acceptability of the translated questionnaire in the target population. On that basis, the final Portuguese-language version of the LCQ was produced and approved by the committee. RESULTS: Few items were questioned by the source author and revised by the committee of experts. During the cognitive debriefing phase, the Portuguese language version of the LCQ proved to be well accepted and understood by all of the respondents, which demonstrates the robustness of the process of translation and cross-cultural adaptation. CONCLUSIONS: The final version of the LCQ adapted for use in Brazil was found to be easy to understand and easily applied. PMID- 25029644 TI - Oxygen desaturation during the six-minute walk test in COPD patients. AB - OBJECTIVE: To evaluate the behavior of oxygen saturation curves throughout the six-minute walk test (6MWT) in patients with COPD. METHODS: We included 85 patients, all of whom underwent spirometry and were classified as having moderate COPD (modCOPD, n = 30) or severe COPD (sevCOPD, n = 55). All of the patients performed a 6MWT, in a 27-m corridor with continuous SpO2 and HR monitoring by telemetry. We studied the SpO2 curves in order to determine the time to a 4% decrease in SpO2, the time to the minimum SpO2 (Tmin), and the post-6MWT time to return to the initial SpO2, the last designated recovery time (RT). For each of those curves, we calculated the slope. RESULTS: The mean age in the modCOPD and sevCOPD groups was 66 +/- 10 years and 62 +/- 11 years, respectively. At baseline, SpO2 was > 94% in all of the patients; none received supplemental oxygen during the 6MWT; and none of the tests were interrupted. The six-minute walk distance did not differ significantly between the groups. The SpO2 values were lowest in the sevCOPD group. There was no difference between the groups regarding RT. In 71% and 63% of the sevCOPD and modCOPD group patients, respectively, a >= 4% decrease in SpO2 occurred within the first minute. We found that FEV1% correlated significantly with the DeltaSpO2 (r = -0.398; p < 0.001), Tmin (r = -0.449; p < 0.001), and minimum SpO2 (r = 0.356; p < 0.005). CONCLUSIONS: In the sevCOPD group, in comparison with the modCOPD group, SpO2 was lower and the Tmin was greater, suggesting a worse prognosis in the former. PMID- 25029645 TI - Hospitalized patients with COPD: analysis of prior treatment. AB - OBJECTIVE: Although COPD is a prevalent disease, it is undertreated, and there are no available data regarding previous treatment of COPD in Brazil. This study aimed to determine the appropriateness of maintenance treatment in COPD patients prior to their hospitalization and to identify variables associated with inappropriate treatment. METHODS: This was an observational, cross-sectional, analytical study involving 50 inpatients with COPD at two hospitals in the city of Florianopolis, Brazil. The patients completed a questionnaire on parameters related to the maintenance treatment of COPD. Non-pharmacological management and pharmacological treatment were assessed based on the recommendations made by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2011 and by the Brazilian National Ministry of Health in the chronic respiratory diseases section of its Caderno de Atencao Basica (CAB, Primary Care Guidebook). RESULTS: In most of the patients, the COPD was classified as being severe or very severe. Regarding non-pharmacological management, 33% of the patients were smokers, only 32% had been advised to receive the flu vaccine, 28% had received pneumococcal vaccine, and only 6.5% of the patients in the B, C, and D categories received pulmonary rehabilitation. Regarding GOLD and CAB recommendations, pharmacological treatment was inappropriate in 50% and 74% of the patients, respectively. Based on GOLD recommendations, 38% were undertreated. A low level of education, low income, not receiving oxygen therapy, and not receiving the flu vaccine were associated with inappropriate treatment. CONCLUSIONS: The application of various non-pharmacological management recommendations was unsatisfactory. Regarding the GOLD recommendations, the high rate of inappropriate maintenance treatment was mainly due to undertreatment. In Brazil, even in severe COPD cases, optimizing treatment to achieve greater benefits continues to be a challenge. PMID- 25029646 TI - Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs. AB - OBJECTIVE: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO) and total reactive antioxidant potential (TRAP), in rat lungs. METHODS: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.); acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days); and chronic control, comprising rats receiving normal drinking water. RESULTS: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. CONCLUSIONS: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels. PMID- 25029647 TI - Pulmonary function in advanced uncomplicated singleton and twin pregnancy. AB - OBJECTIVE: Pregnancy brings about significant changes in respiratory function, as evidenced by alterations in lung volumes and capacities, which are attributable to the mechanical impediment caused by the growing foetus. This study was undertaken in order to identify changes in respiratory function during normal pregnancy and to determine whether such changes are more pronounced in twin pregnancy than in singleton pregnancy. METHODS: Respiratory function was assessed in 50 women with twin pregnancies and in 50 women with singleton pregnancies (during the third trimester in both groups), as well as in 50 non-pregnant women. We measured the following pulmonary function test parameters: FVC; FEV1; PEF rate; FEV1/FVC ratio; FEF25-75%; and maximal voluntary ventilation. RESULTS: All respiratory parameters except the FEV1/FVC ratio were found to be lower in the pregnant women than in the non-pregnant women. We found no significant differences between women with twin pregnancies and those with singleton pregnancies, in terms of respiratory function. CONCLUSIONS: Despite its higher physiological demands, twin pregnancy does not appear to impair respiratory function to any greater degree than does singleton pregnancy. PMID- 25029648 TI - Reliability of a rapid hematology stain for sputum cytology. AB - OBJECTIVE: To determine the reliability of a rapid hematology stain for the cytological analysis of induced sputum samples. METHODS: This was a cross sectional study comparing the standard technique (May-Grunwald-Giemsa stain) with a rapid hematology stain (Diff-Quik). Of the 50 subjects included in the study, 21 had asthma, 19 had COPD, and 10 were healthy (controls). From the induced sputum samples collected, we prepared four slides: two were stained with May Grunwald-Giemsa, and two were stained with Diff-Quik. The slides were read independently by two trained researchers blinded to the identification of the slides. The reliability for cell counting using the two techniques was evaluated by determining the intraclass correlation coefficients (ICCs) for intraobserver and interobserver agreement. Agreement in the identification of neutrophilic and eosinophilic sputum between the observers and between the stains was evaluated with kappa statistics. RESULTS: In our comparison of the two staining techniques, the ICCs indicated almost perfect interobserver agreement for neutrophil, eosinophil, and macrophage counts (ICC: 0.98-1.00), as well as substantial agreement for lymphocyte counts (ICC: 0.76-0.83). Intraobserver agreement was almost perfect for neutrophil, eosinophil, and macrophage counts (ICC: 0.96 0.99), whereas it was moderate to substantial for lymphocyte counts (ICC = 0.65 and 0.75 for the two observers, respectively). Interobserver agreement for the identification of eosinophilic and neutrophilic sputum using the two techniques ranged from substantial to almost perfect (kappa range: 0.91-1.00). CONCLUSIONS: The use of Diff-Quik can be considered a reliable alternative for the processing of sputum samples. PMID- 25029649 TI - Indoor air quality and health in schools. AB - OBJECTIVE: To determine whether indoor air quality in schools is associated with the prevalence of allergic and respiratory diseases in children. METHODS: We evaluated 1,019 students at 51 elementary schools in the city of Coimbra, Portugal. We applied a questionnaire that included questions regarding the demographic, social, and behavioral characteristics of students, as well as the presence of smoking in the family. We also evaluated the indoor air quality in the schools. RESULTS: In the indoor air of the schools evaluated, we identified mean concentrations of carbon dioxide (CO2) above the maximum reference value, especially during the fall and winter. The CO2 concentration was sometimes as high as 1,942 ppm, implying a considerable health risk for the children. The most prevalent symptoms and respiratory diseases identified in the children were sneezing, rales, wheezing, rhinitis, and asthma. Other signs and symptoms, such as poor concentration, cough, headache, and irritation of mucous membranes, were identified. Lack of concentration was associated with CO2 concentrations above the maximum recommended level in indoor air (p = 0.002). There were no other significant associations. CONCLUSIONS: Most of the schools evaluated presented with reasonable air quality and thermal comfort. However, the concentrations of various pollutants, especially CO2, suggest the need for corrective interventions, such as reducing air pollutant sources and improving ventilation. There was a statistically significant association between lack of concentration in the children and exposure to high levels of CO2. The overall low level of pollution in the city of Coimbra might explain the lack of other significant associations. PMID- 25029650 TI - Association between serum selenium level and conversion of bacteriological tests during antituberculosis treatment. AB - OBJECTIVE: To determine whether serum selenium levels are associated with the conversion of bacteriological tests in patients diagnosed with active pulmonary tuberculosis after eight weeks of standard treatment. METHODS: We evaluated 35 healthy male controls and 35 male patients with pulmonary tuberculosis, the latter being evaluated at baseline, as well as at 30 and 60 days of antituberculosis treatment. For all participants, we measured anthropometric indices, as well as determining serum levels of albumin, C-reactive protein (CRP) and selenium. Because there are no reference values for the Brazilian population, we used the median of the serum selenium level of the controls as the cut-off point. At 30 and 60 days of antituberculosis treatment, we repeated the biochemical tests, as well as collecting sputum for smear microscopy and culture from the patients. RESULTS: The mean age of the patients was 38.4 +/- 11.4 years. Of the 35 patients, 25 (71%) described themselves as alcoholic; 20 (57.0%) were smokers; and 21 (60.0%) and 32 (91.4%) presented with muscle mass depletion as determined by measuring the triceps skinfold thickness and arm muscle area, respectively. Of 24 patients, 12 (39.2%) were classified as moderately or severely emaciated, and 15 (62.5%) had lost > 10% of their body weight by six months before diagnosis. At baseline, the tuberculosis group had lower serum selenium levels than did the control group. The conversion of bacteriological tests was associated with the CRP/albumin ratio and serum selenium levels 60 days after treatment initiation. CONCLUSIONS: Higher serum selenium levels after 60 days of treatment were associated with the conversion of bacteriological tests in pulmonary tuberculosis patients. PMID- 25029651 TI - Tuberculosis in hospitalized patients: clinical characteristics of patients receiving treatment within the first 24 h after admission. AB - OBJECTIVE: To evaluate clinical characteristics and outcomes in patients hospitalized for tuberculosis, comparing those in whom tuberculosis treatment was started within the first 24 h after admission with those who did not. METHODS: This was a retrospective cohort study involving new tuberculosis cases in patients aged >= 18 years who were hospitalized after seeking treatment in the emergency room. RESULTS: We included 305 hospitalized patients, of whom 67 (22.0%) received tuberculosis treatment within the first 24 h after admission ( <=24h group) and 238 (88.0%) did not (>24h group). Initiation of tuberculosis treatment within the first 24 h after admission was associated with being female (OR = 1.99; 95% CI: 1.06-3.74; p = 0.032) and with an AFB-positive spontaneous sputum smear (OR = 4.19; 95% CI: 1.94-9.00; p < 0.001). In the <=24h and >24h groups, respectively, the ICU admission rate was 22.4% and 15.5% (p = 0.258); mechanical ventilation was used in 22.4% and 13.9% (p = 0.133); in-hospital mortality was 22.4% and 14.7% (p = 0.189); and a cure was achieved in 44.8% and 52.5% (p = 0.326). CONCLUSIONS: Although tuberculosis treatment was initiated promptly in a considerable proportion of the inpatients evaluated, the rates of in-hospital mortality, ICU admission, and mechanical ventilation use remained high. Strategies for the control of tuberculosis in primary care should consider that patients who seek medical attention at hospitals arrive too late and with advanced disease. It is therefore necessary to implement active surveillance measures in the community for earlier diagnosis and treatment. PMID- 25029652 TI - Nicotine dependence and smoking habits in patients with head and neck cancer. AB - OBJECTIVE: To assess smoking habits and nicotine dependence (ND) in patients with head and neck cancer Methods: This study involved 71 smokers or former smokers with squamous cell carcinoma in the oral cavity, pharynx, or larynx who were treated at a university hospital in the city of Sao Paulo between January and May of 2010. We used the Fagerstrom Test for Nicotine Dependence to evaluate smoking habits and ND in the sample. Data regarding cancer treatment were collected from medical records. Depending on the variables studied, we used the chi-square test, Fisher's exact test, Student's t-test, or Spearman's correlation test. RESULTS: Of the 71 patients, 47 (66.2%) presented with high or very high ND, 40 (56.3%) smoked more than 20 cigarettes/day, and 32 (45.1%) smoked their first cigarette within 5 min of awakening. Advanced disease stage correlated significantly with the number of cigarettes smoked per day (p = 0.011) and with smoking history (p = 0.047). We found that ND did not correlate significantly with gender, disease stage, smoking cessation, or number of smoking cessation attempts, nor did the number of cigarettes smoked per day correlate with smoking cessation or gender. Treatment for smoking cessation was not routinely offered. CONCLUSIONS: In most of the patients studied, the level of ND was high or very high. The prevalence of heavy smoking for long periods was high in our sample. A diagnosis of cancer is a motivating factor for smoking cessation. However, intensive smoking cessation treatment is not routinely offered to smoking patients diagnosed with cancer. PMID- 25029653 TI - Performance of ICU ventilators during noninvasive ventilation with large leaks in a total face mask: a bench study. AB - OBJECTIVE: Discomfort and noncompliance with noninvasive ventilation (NIV) interfaces are obstacles to NIV success. Total face masks (TFMs) are considered to be a very comfortable NIV interface. However, due to their large internal volume and consequent increased CO2 rebreathing, their orifices allow proximal leaks to enhance CO2 elimination. The ventilators used in the ICU might not adequately compensate for such leakage. In this study, we attempted to determine whether ICU ventilators in NIV mode are suitable for use with a leaky TFM. METHODS: This was a bench study carried out in a university research laboratory. Eight ICU ventilators equipped with NIV mode and one NIV ventilator were connected to a TFM with major leaks. All were tested at two positive end expiratory pressure (PEEP) levels and three pressure support levels. The variables analyzed were ventilation trigger, cycling off, total leak, and pressurization. RESULTS: Of the eight ICU ventilators tested, four did not work (autotriggering or inappropriate turning off due to misdetection of disconnection); three worked with some problems (low PEEP or high cycling delay); and one worked properly. CONCLUSIONS: The majority of the ICU ventilators tested were not suitable for NIV with a leaky TFM. PMID- 25029654 TI - Combined pulmonary fibrosis and emphysema: an increasingly recognized condition. AB - Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized in the literature. Patients with CPFE are usually heavy smokers or former smokers with concomitant lower lobe fibrosis and upper lobe emphysema on chest HRCT scans. They commonly present with severe breathlessness and low DLCO, despite spirometry showing relatively preserved lung volumes. Moderate to severe pulmonary arterial hypertension is common in such patients, who are also at an increased risk of developing lung cancer. Unfortunately, there is currently no effective treatment for CPFE. In this review, we discuss the current knowledge of the pathogenesis, clinical characteristics, and prognostic factors of CPFE. Given that most of the published data on CPFE are based on retrospective analysis, more studies are needed in order to address the role of emphysema and its subtypes; the progression of fibrosis/emphysema and its correlation with inflammation; treatment options; and prognosis. PMID- 25029655 TI - Simultaneous interstitial pneumonitis and cardiomyopathy induced by venlafaxine. AB - Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used as an antidepressant. Interindividual variability and herb-drug interactions can lead to drug-induced toxicity. We report the case of a 35-year-old female patient diagnosed with synchronous pneumonitis and acute cardiomyopathy attributed to venlafaxine. The patient sought medical attention due to dyspnea and dry cough that started three months after initiating treatment with venlafaxine for depression. The patient was concomitantly taking Centella asiatica and Fucus vesiculosus as phytotherapeutic agents. Chest CT angiography and chest X-ray revealed parenchymal lung disease (diffuse micronodules and focal ground-glass opacities) and simultaneous dilated cardiomyopathy. Ecocardiography revealed a left ventricular ejection fraction (LVEF) of 21%. A thorough investigation was carried out, including BAL, imaging studies, autoimmune testing, right heart catheterization, and myocardial biopsy. After excluding other etiologies and applying the Naranjo Adverse Drug Reaction Probability Scale, a diagnosis of synchronous pneumonitis/cardiomyopathy associated with venlafaxine was assumed. The herbal supplements taken by the patient have a known potential to inhibit cytochrome P450 enzyme complex, which is responsible for the metabolization of venlafaxine. After venlafaxine discontinuation, there was rapid improvement, with regression of the radiological abnormalities and normalization of the LVEF. This was an important case of drug-induced cardiopulmonary toxicity. The circumstantial intake of inhibitors of the CYP2D6 isoenzyme and the presence of a CYP2D6 slow metabolism phenotype might have resulted in the toxic accumulation of venlafaxine and the subsequent clinical manifestations. Here, we also discuss why macrophage-dominant phospholipidosis was the most likely mechanism of toxicity in this case. PMID- 25029656 TI - Lung cancer and schwannoma--the pitfalls of positron emission tomography. PMID- 25029657 TI - Unilateral pulmonary agenesis. PMID- 25029658 TI - N-Bromoacetamide-mediated domino cyclization and elimination of homoallylic trichloroacetimidates: a novel approach toward the synthesis of 1-bromo-2-amino-3 butene derivatives. AB - A practical synthesis of 1-bromo-2-amino-3-butene derivatives from homoallylic trichloroacetimidates was reported. Simply heating the mixture of substrates and N-bromoacetamide in DMF at 90 degrees C would give the desired products in moderate to excellent yields. The reaction may proceed through a domino bromo cyclization and elimination pathway. The synthesis of 4,5-dihydrooxazoles from 1 bromo-2-amino-3-butene derivatives was also investigated. PMID- 25029660 TI - Hearing the shape of the Ising model with a programmable superconducting-flux annealer. AB - Two objects can be distinguished if they have different measurable properties. Thus, distinguishability depends on the Physics of the objects. In considering graphs, we revisit the Ising model as a framework to define physically meaningful spectral invariants. In this context, we introduce a family of refinements of the classical spectrum and consider the quantum partition function. We demonstrate that the energy spectrum of the quantum Ising Hamiltonian is a stronger invariant than the classical one without refinements. For the purpose of implementing the related physical systems, we perform experiments on a programmable annealer with superconducting flux technology. Departing from the paradigm of adiabatic computation, we take advantage of a noisy evolution of the device to generate statistics of low energy states. The graphs considered in the experiments have the same classical partition functions, but different quantum spectra. The data obtained from the annealer distinguish non-isomorphic graphs via information contained in the classical refinements of the functions but not via the differences in the quantum spectra. PMID- 25029659 TI - A Rehabilomics framework for personalized and translational rehabilitation research and care for individuals with disabilities: Perspectives and considerations for spinal cord injury. AB - Despite many people having similar clinical presentation, demographic factors, and clinical care, outcome can differ for those sustaining significant injury such as spinal cord injury (SCI) and traumatic brain injury (TBI). In addition to traditional demographic, social, and clinical factors, variability also may be attributable to innate (including genetic, transcriptomic proteomic, epigenetic) biological variation that individuals bring to recovery and their unique response to their care and environment. Technologies collectively called "-omics" enable simultaneous measurement of an enormous number of biomolecules that can capture many potential biological contributors to heterogeneity of injury/disease course and outcome. Due to the nature of injury and complex disease, and its associations with impairment, disability, and recovery, rehabilitation does not lend itself to a singular "protocolized" plan of therapy. Yet, by nature and by necessity, rehabilitation medicine operates as a functional model of "Personalized Care". Thus, the challenge for successful programs of translational rehabilitation care and research is to identify viable approaches to examine broad populations, with varied impairments and functional limitations, and to identify effective treatment responses that incorporate personalized protocols to optimize functional recovery. The Rehabilomics framework is a translational model that provides an "-omics" overlay to the scientific study of rehabilitation processes and multidimensional outcomes. Rehabilomics research provides novel opportunities to evaluate the neurobiology of complex injury or chronic disease and can be used to examine methods and treatments for person-centered care among populations with disabilities. Exemplars for application in SCI and other neurorehabilitation populations are discussed. PMID- 25029661 TI - A prospective observational study evaluating the ability of prelabor psychological tests to predict labor pain, epidural analgesic consumption, and maternal satisfaction. AB - BACKGROUND: Psychological characteristics may affect interpretation and expression of pain. In this study, we sought to determine whether validated psychological tests predict the labor pain experience. METHODS: Thirty-nine women with singleton term or post-term pregnancies undergoing induction of labor and successful vaginal delivery comprised the study population for this prospective observational study. Four validated psychological questionnaires (Anxiety Sensitivity Index [ASI], Fear of Pain [FPQIII], Pain Catastrophizing Scale [PCS]), and Eysenck Personality Questionnaire-Short Scale) and 3-scaled ratings of anxiety, confidence, and analgesic expectations were completed before onset of labor. Outcome measures included time to epidural analgesia request, pain at request for epidural analgesia, area under the pain * time curve (AUC), epidural local anesthetic use per hour, and maternal satisfaction with analgesia. The relationship between psychological predictors and clinical responses was assessed using bivariate correlations and regression modeling. RESULTS: Labor pain AUC (R = 0.45, P = 0.006), epidural local anesthetic use (R = 0.45, P = 0.019), and time to epidural analgesia request (R = 0.36, P = 0.015) were predicted with models incorporating some of the prelabor predictors. ASI, PCS, personality traits (lying, extroversion, psychoticism), and scaled ratings of anxiety, confidence, and analgesic expectations all contributed to the regression models of the outcomes. After proper model selection, neither FPQIII nor PCS was in the final multivariate linear regression model for labor pain AUC, although ASI was still included (P = 0.022). There was no significant correlation between ASI and self reported anxiety (r = 0.03, P = 0.91). CONCLUSIONS: Personality traits (psychoticism, extroversion, and lying), as well as scaled ratings of anxiety, confidence, and analgesia expectations, show some potential to predict labor pain, epidural local anesthetic use, and time to epidural analgesia request. Although ASI was included in the final model for labor pain AUC, and FPQ and PCS were not, further study is required to determine whether ASI is a better predictor than FPQ or PCS. PMID- 25029662 TI - Experience and net worth affects optimality in a motor decision task. AB - Previous research has shown in a motor decision task involving a target (yielding a reward) and overlapping penalty area (yielding a loss), people initially aim closer to the penalty area than optimal. This risky strategy may be adopted to increase target hits, thereby increasing net worth. The purpose of the current study was to determine whether the starting net worth level (either 5,000 or 0 points) affected the influence of task experience on endpoint selection. It was hypothesized the 5,000-point group should adopt a less risky strategy and aim further from the penalty area than those with 0 points. Net worth affected participants' initial endpoint where the 5,000-point group aimed further from the penalty circle, and closer to the optimal endpoint, than the 0-point group. The 0 point group adapted their endpoint over the course session to aim closer to the optimal endpoint whereas no such change was seen in the 5,000-point group. The results show that changing the participants' reference point through initial net worth can affect the optimality of participants' endpoint and how endpoints change with experience. PMID- 25029664 TI - Criticizing reporting standards fails to improve quality in animal research. PMID- 25029665 TI - Highly efficient one-dimensional ZnO nanowire-based dye-sensitized solar cell using a metal-free, D-pi-A-type, carbazole derivative with more than 5% power conversion. AB - Hydrothermally grown one-dimensional ZnO nanowire (1D ZnO NW) and a newly synthesized metal-free, D-pi-A type, carbazole dye (SK1) sensitizer-based photovoltaic device with a power conversion efficiency (PCE) of more than 5% have been demonstrated by employing the cobalt tris(2,2'-bipyridyl) redox shuttle. A short-circuit current density (Jsc) of ~12.0 mA/cm(2), an open-circuit voltage (Voc) of ~719 mV, and a fill factor (FF) of ~65% have been afforded by the 1D ZnO NW-based dye-sensitized solar cell (DSSC) incorporating [Co(bpy)3](3+/2+) complex as the one-electron redox mediator. In contrast, the identical DSSC with traditional I3(-)/I(-) electrolyte has shown a Jsc ~ 12.2 mA/cm(2), a Voc ~ 629 mV, and a FF ~ 62%, yielding a PCE of ~4.7%. The persuasive role of the inherent superior electron transport property of 1D ZnO NWs in enhancing the device efficiency is evidenced from the impoverished performance of the DSSCs with photoanodes fabricated using ZnO nanoparticles (NPs). The DSSCs having ZnO NP based photoanodes have achieved the PCEs of ~3.6% and ~3.2% using cobalt- and iodine-based redox electrolytes, respectively. The electronic interactions between the SK1 sensitizer and ZnO (NWs and NPs) to induce the photogenerated charge transfer from SK1 to the conduction band (CB) of ZnO are evidenced from the significant quenching of photoluminescence and exciton lifetime decay of SK1, when it is anchored onto the ZnO architectures. The energetics of the SK1 dye molecule are estimated by combining the spectroscopic and electrochemical techniques. The electronic distributions of SK1 dye molecule in its HOMO and LUMO energy levels are interpreted using density functional theory (DFT)-based calculations. The electron donor-pi linker-acceptor (D-pi-A) configuration of SK1 dye provides an intramolecular charge transfer within the molecule, prompting the electron migration from the carbazole donor to cyanoacrylic acceptor moiety via the oligo-phenylenevinylene linker group. The D-pi-A-mediated electron movement witnesses the favorable photoexcited electron transfer from the LUMO of SK1 dye to the CB of ZnO through the carboxyl anchoring group. PMID- 25029663 TI - Toward hypoxia-selective DNA-alkylating agents built by grafting nitrogen mustards onto the bioreductively activated, hypoxia-selective DNA-oxidizing agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). AB - Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4 benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells. PMID- 25029667 TI - Regioselective introduction of heteroatoms at the C-8 position of quinoline N oxides: remote C-H activation using N-oxide as a stepping stone. AB - Reported herein is the metal-catalyzed regioselective C-H functionalization of quinoline N-oxides at the 8-position: direct iodination and amidation were developed using rhodium and iridium catalytic systems, respectively. Mechanistic study of the amidation revealed that the unique regioselectivity is achieved through the smooth formation of N-oxide-chelated iridacycle and that an acid additive plays a key role in the rate-determining protodemetalation step. While this approach of remote C-H activation using N-oxide as a directing group could readily be applied to a wide range of heterocyclic substrates under mild conditions with high functional group tolerance, an efficient synthesis of zinquin ester (a fluorescent zinc indicator) was demonstrated. PMID- 25029666 TI - A functional anatomic defect of the cystic fibrosis airway. AB - RATIONALE: The mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown. OBJECTIVES: To establish mechanisms linking anion transport with the functional microanatomy, we evaluated normal and CF piglet trachea as well as adult swine trachea in the presence of selective anion inhibitors. METHODS: We investigated airway functional microanatomy using microoptical coherence tomography, a new imaging modality that concurrently quantifies multiple functional parameters of airway epithelium in a colocalized fashion. MEASUREMENTS AND MAIN RESULTS: Tracheal explants from wild-type swine demonstrated a direct link between periciliary liquid (PCL) hydration and mucociliary transport (MCT) rates, a relationship frequently invoked but never experimentally confirmed. However, in CF airways this relationship was completely disrupted, with greater PCL depths associated with slowest transport rates. This disrupted relationship was recapitulated by selectively inhibiting bicarbonate transport in vitro and ex vivo. CF mucus exhibited increased viscosity in situ due to the absence of bicarbonate transport, explaining defective MCT that occurs even in the presence of adequate PCL hydration. CONCLUSIONS: An inherent defect in CF airway surface liquid contributes to delayed MCT beyond that caused by airway dehydration alone and identifies a fundamental mechanism underlying the pathogenesis of CF lung disease in the absence of antecedent infection or inflammation. PMID- 25029668 TI - Predicting outcome from subacute unresponsive wakefulness syndrome or vegetative state. AB - Predicting recovery of consciousness in patients who survive their coma but evolve to a vegetative state (recently coined unresponsive wakefulness syndrome) remains a challenge. Most previous prognostic studies have focused on the acute coma phase. A novel outcome scale (combining behavioural, aetiology, electroencephalographic, sleep electroencephalographic and somatosensory evoked potential data) has been proposed for patients in subacute unresponsive wakefulness syndrome. The scale's clinical application awaits validation in a larger population. PMID- 25029669 TI - The short-term and long-term impact of a brief aging research training program for medical students. AB - Summer training in aging research for medical students is a strategy for improving the pipeline of medical students into research careers in aging and clinical care of older adults. Johns Hopkins University has been offering medical students a summer experience of mentored research, research training, and clinical shadowing since 1994. Long-term outcomes of this program have not been described. The authors surveyed all 191 participants who had been in the program from 1994-2010 (60% female and 27% underrepresented minorities) and received a 65.8% (N = 125) response rate. The authors also conducted Google and other online searches to supplement study findings. Thirty-seven percent of those who have completed training are now in academic medicine, and program participants have authored or coauthored 582 manuscripts. Among survey respondents, 95.1% reported that participation in the Medical Student Training in Aging Research program increased their sensitivity to the needs of older adults. This program may help to build commitment among medical students to choose careers in aging. PMID- 25029670 TI - Corroles that "click": modular synthesis of azido- and propargyl-functionalized metallocorrole complexes and convergent synthesis of a bis-corrole scaffold. AB - Bis-corroles have been prepared through a convergent synthesis using a copper catalyzed azide-alkyne cycloaddition. Synthesis of the final homo- and heterobimetallic complexes has been achieved in three to four steps from commercially available materials in good overall yield. Meso-substituted corroles functionalized with a single azido or propargyl group were used as key starting materials. (C6F5)2(p-O(CH2CCH)Ph)corroleH3 (1) and ((C6F5)2(m-CH2N3)Ph)corroleH3 (3) were metalated with copper or iron and attached by Huisgen azide-alkyne cycloaddition ("click" reaction) first to small substrates and then to each other, demonstrating a convergent synthesis of bimetallic bis-corrole molecules. PMID- 25029671 TI - Preliminary observations on MRI correlates of driving independence and performance in persons with heart failure. AB - PURPOSE/AIM: Heart failure patients often require assistance with activities of daily living, including driving. Recent work shows heart failure patients commit more errors on a simulated driving task relative to controls and cognitive dysfunction contributed to these errors. We sought to extend these findings by examining whether structural magnetic resonance imaging indices correlate with driving independence and performance in heart failure. MATERIALS AND METHODS: Forty-nine heart failure patients underwent brain magnetic resonance imaging and performed a battery assessing attention/executive function and memory. A self report instrument was used to assess independence in transportation. A subset of heart failure participants (N = 8) completed a validated driving simulator scenario. RESULTS: Among the larger sample (N = 49), reduced gray matter correlated with greater dependence in transportation and worse attention/executive function; in turn, worse attention/executive function predicted greater assistance with transportation (p < 0.05). Among the subset that completed the driving simulator (N = 8), reduced gray matter correlated with more stop signs missed and increased white matter hyperintensities correlated with greater collisions, centerline crossings and time out of lane (p < 0.05). Poorer attention/executive function was also associated with more time over the speed limit on the driving simulation (p < 0.05). Follow-up analyses showed the above effects were largely independent of age. CONCLUSIONS: Reduced structural brain integrity is associated with poorer reported and simulated driving in persons with heart failure. Larger prospective studies that employ on-road testing are needed to clarify brain changes and risk for unsafe driving in heart failure. PMID- 25029672 TI - Worker doses and potential health effects resulting from the accident at the Fukushima nuclear power plant in 2011. AB - PURPOSE: The reliability of exposure scenarios used in the World Health Organization's Health Risk Assessment (HRA) for Fukushima workers was examined. HRA risk estimates for cancer incidence in these workers were then reviewed. MATERIALS AND METHODS: The HRA constructed four exposure scenarios to estimate worker radiation doses; recent individual dosimetric data were used to assess their reliability. Risks of specified cancer types attributable to radiation exposure were estimated in the HRA by calculating Lifetime Attributable Risks (LAR) for each scenario, and comparisons of LAR are provided. RESULTS: The scenarios were confirmed as reliable for the purposes of the HRA. For the lowest dose scenario (Scenario 1: 69% of the workforce), the HRA found that any elevated cancer risk was insignificant. Significantly elevated cancer risks were, however, found for the three higher dose scenarios. CONCLUSIONS: For the highest dose scenario (Scenario 4: 13 workers), LAR values for thyroid cancer up to 3.5% were estimated, but a radiation-related increase in thyroid cancer incidence is unlikely to be observed because of the small number of workers. For the two intermediate dose scenarios, a small number of cancer cases may occur, but these are unlikely to be observed because the variability in baseline rates of cancer incidence is much larger than the predicted radiation-related incidence rates. PMID- 25029673 TI - Macrophages as key elements of Mixed-oxide [U-Pu(O2)] distribution and pulmonary damage after inhalation? AB - Abstract Purpose: To investigate the consequences of alveolar macrophage (AM) depletion on Mixed OXide fuel (MOX: U, Pu oxide) distribution and clearance, as well as lung damage following MOX inhalation. MATERIALS AND METHODS: Rats were exposed to MOX by nose only inhalation. AM were depleted with intratracheal administration of liposomal clodronate at 6 weeks. Lung changes, macrophage activation, as well as local and systemic actinide distribution were studied up to 3 months post-inhalation. RESULTS: Clodronate administration modified excretion/retention patterns of alpha activity. At 3 months post-inhalation lung retention was higher in clodronate-treated rats compared to Phosphate Buffered Saline (PBS)-treated rats, and AM-associated alpha activity was also increased. Retention in liver was higher in clodronate-treated rats and fecal and urinary excretions were lower. Three months after inhalation, rats exhibited lung fibrotic lesions and alveolitis, with no marked differences between the two groups. Foamy macrophages of M2 subtype [inducible Nitric Oxide Synthase (iNOS) negative but galectin-3 positive] were frequently observed, in correlation with the accumulation of MOX particles. AM from all MOX-exposed rats showed increased chemokine levels as compared to sham controls. CONCLUSION: Despite the transient reduced AM numbers in clodronate-treated animals no major differences on lung damage were observed as compared to non-treated rats after MOX inhalation. The higher lung activity retention in rats receiving clodronate seems to be part of a general inflammatory response and needs further investigation. PMID- 25029674 TI - The application of implementation science for pressure ulcer prevention best practices in an inpatient spinal cord injury rehabilitation program. AB - OBJECTIVES: To implement pressure ulcer (PU) prevention best practices in spinal cord injury (SCI) rehabilitation using implementation science frameworks. DESIGN: Quality improvement. SETTING: SCI Rehabilitation Center. PARTICIPANTS: Inpatients admitted January 2012 to July 2013. INTERVENTIONS: Implementation of two PU best practices were targeted: (1) completing a comprehensive PU risk assessment and individualized interprofessional PU prevention plan (PUPP); and (2) providing patient education for PU prevention; as part of the pan-Canadian SCI Knowledge Mobilization Network. At our center, the SCI Pressure Ulcer Scale replaced the Braden risk assessment scale and an interprofessional PUPP form was implemented. Comprehensive educational programing existed, so efforts focused on improving documentation. Implementation science frameworks provided structure for a systematic approach to best practice implementation (BPI): (1) site implementation team, (2) implementation drivers, (3) stages of implementation, and (4) improvement cycles. Strategies were developed to address key implementation drivers (staff competency, organizational supports, and leadership) through the four stages of implementation: exploration, installation, initial implementation, and full implementation. Improvement cycles were used to address BPI challenges. OUTCOME MEASURES: Implementation processes (e.g. staff training) and BPI outcomes (completion rates). RESULTS: Following BPI, risk assessment completion rates improved from 29 to 82%. The PUPP completion rate was 89%. PU education was documented for 45% of patients (vs. 21% pre implementation). CONCLUSION: Implementation science provided a framework and effective tools for successful pressure ulcer BPI in SCI rehabilitation. Ongoing improvement cycles will target timeliness of tool completion and documentation of patient education. PMID- 25029676 TI - Why space?: Harvesting the benefits of science in orbit. PMID- 25029675 TI - Effect of a carbohydrate-protein multi-ingredient supplement on intermittent sprint performance and muscle damage in recreational athletes. AB - Carbohydrate-protein-based multi-ingredient supplements have been proposed as an effective strategy for limiting the deleterious effects of exercise-induced muscle damage. This study compares the effects of a commercially available carbohydrate-protein supplement enriched with l-glutamine and l-carnitine-l tartrate to carbohydrate alone or placebo on sprint performance, muscle damage markers, and recovery from intermittent exercise. On 3 occasions, 10 recreationally trained males ingested a multi-ingredient, a carbohydrate supplement, or a placebo before, during, and immediately after a 90-min intermittent repeated sprint test. Fifteen-metre sprint times, creatine kinase, myoglobin, and interleukin-6 were assessed before (pre), immediately after (post), 1 h after (1h), and 24 h after (24h) exercise. Total sprint time measured during the intermittent protocol was not different between conditions. Fifteen metre sprint time was slower (p < 0.05) at post, 1h and 24h compared with pre without differences between conditions (p > 0.05). Creatine kinase at 24h was lower (p < 0.05) in the multi-ingredient (461.8 +/- 271.8 U.L) compared with both carbohydrate and placebo (606 +/- 314.5 U.L and 636 +/- 344.6 U.L, respectively). Myoglobin increased (p < 0.05) in all 3 conditions at post and 1h compared with pre, showing lower values at 1h (p < 0.05) for the carbohydrate and a trend (p = 0.060) for multi-ingredient compared with the placebo condition (211.4 +/- 127.2 ng.mL(-1) and 239.4 +/- 103.8 ng.mL(-1) vs. 484.6 +/- 200.0 ng.mL(-1), respectively). Interleukin-6 increased at both post and 1h compared with pre (p < 0.05) with no differences between conditions. In conclusion, ingesting a multi ingredient supplement before, during, and immediately after a 90-min intermittent sprint test resulted in no effects on performance and fatigue while the accumulation of some biomarkers of muscle damage could be attenuated. PMID- 25029677 TI - Space-age tech goes to the clinic: From better brain surgery to cleaner air and water, space tech comes to Earth. PMID- 25029678 TI - The view from space: Two astronauts provide an inside look at the rewards and challenges of space research. PMID- 25029679 TI - Crystal clear: The ability to crystallize proteins in space is accelerating drug development on Earth. PMID- 25029680 TI - The gravity of it all: From osteoporosis to immunosuppression, exploring disease in a microgravity environment holds promise for better treatments on Earth. PMID- 25029681 TI - Of mice and men: Rodent habitats in space have become essential to understanding human diseases on Earth. PMID- 25029682 TI - Houston, we have a problem: Math and science education lags in the United States, but CASIS is working to reverse the trend. PMID- 25029683 TI - The promise of nanopore technology: Nanopore DNA sequencing represents a fundamental change in the way that genomic information is read, with potentially big savings. PMID- 25029684 TI - Let there be light: A tutorial on optogenetics. PMID- 25029685 TI - Towards a more nuanced global mental health. AB - The World Health Organization has made concerted efforts to scale up mental health services in low- and middle-income countries through the Mental Health Gap Action Programme (mhGAP) initiative. However, an overreliance on scaling up services based on those used in high-income countries may risk causing more harm than good. PMID- 25029686 TI - Is the DSM-5 chapter on somatic symptom disorder any better than DSM-IV somatoform disorder? AB - DSM-5 is a modest improvement on DSM-IV, notably in abandoning the distinction between medically explained and unexplained symptoms, but problems remain. The chapter text is incoherent, contradicts the classification and will be clinically unhelpful. ICD-11 should attempt a more logical and consistent revision. PMID- 25029687 TI - Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies. AB - BACKGROUND: The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. AIMS: To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. METHOD: Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions. RESULTS: The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d = -0.32 (95% CI -0.68 to 0.03) for the thalamus, d = -0.23 (95% CI -0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI -0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus. CONCLUSIONS: There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis. PMID- 25029688 TI - Is depression one thing or many? PMID- 25029689 TI - CBT for psychosis: not a 'quasi-neuroleptic'. PMID- 25029690 TI - CBT for psychosis: not a 'quasi-neuroleptic'. PMID- 25029691 TI - Authors' reply. PMID- 25029692 TI - Stimulant treatment for ADHD. PMID- 25029693 TI - Authors' reply. PMID- 25029694 TI - Liaison services for older adults. PMID- 25029695 TI - Liaison services for older adults. PMID- 25029696 TI - Liaison services for older adults. PMID- 25029697 TI - Author's reply: To PMID 25029694. PMID- 25029698 TI - Assessing and staging bipolar disorder. PMID- 25029699 TI - Oxidative stress markers after a race in professional cyclists. AB - The aim was to determine the levels and activities of the oxidative stress markers in erythrocytes, plasma, and urine after a flat cyclist stage. Eight voluntary male professional trained-cyclists participated in the study. Exercise significantly increased erythrocyte, leukocyte, platelet, and reticulocyte counts. The exercise induced significant increases in the erythrocyte activities of catalase (19.8%) and glutathione reductase (19.2%), while glutathione peroxidase activity decreased significantly (29.3%). Erythrocyte GSSG concentration was significantly increased after exercise (21.4%), whereas GSH was significantly diminished (20.4%). Erythrocyte malondialdehyde levels evidenced a significant decrease 3 h after finishing the stage (44.3%). Plasma malondialdehyde, GSH and GSSG levels significantly decreased after 3 hr recovery (26.8%, 48.6%, and 31.1%, respectively). The exercise significantly increased the F2-isoprostane concentration in urine from 359 +/- 71 pg/mg creatinine to 686 +/- 139 pg/mg creatinine. In conclusion, a flat cycling stage induced changes in oxidative stress markers in erythrocytes, plasma, and urine of professional cyclists. Urine F2-isoprostane is a more useful biomarker for assessing the effects of acute exercise than the traditional malondialdehyde measurement. PMID- 25029700 TI - Assessment of physical demands and fluid balance in elite female handball players during a 6-day competitive tournament. AB - Little data exists on drinking behavior, sweat loss, and exercise intensity across a competitive handball tournament in elite female athletes. Heart rate (HR), fluid balance and sweat electrolyte content were assessed on 17 international players across a 6-day tournament involving 5 games and 2 training sessions played indoors (23 +/- 2 degrees C, 30 +/- 2% relative humidity). Active play (effective) mean HR was 155 +/- 14 bpm (80 +/- 7.5% HRmax) with the majority of time (64%) spent exercising at intensities >80% HRmax. Mean (SD) sweat rates during games were 1.02 +/- 0.07 L . h-1 and on 56% of occasions fluid intake matched or exceeded sweat loss. A significant relationship was observed between estimated sweat loss and fluid intake during exercise (r2 = .121, p = .001). Mean sweat sodium concentration was 38 +/- 10 mmol . L-1, with significant associations observed between player sweat rates and time spent exercising at intensities >90% HRmax (r2 = .181, p = .001). Fluid and electrolyte loss appear to be work rate dependent in elite female handball players, whom appear well capable of replacing fluids lost within a tournament environment. Due to large between-athlete variations, a targeted approach may be warranted for certain players only. PMID- 25029701 TI - Weight loss and psychological-related states in high-level judo athletes. AB - PURPOSE: This study aimed at comparing weight loss methods (WLM) performed near competition by elite judo athletes from different age and gender groups and relating WLM with the prevalence of eating disorders. METHODS: 144 athletes (66 females and 78 males) from the Spanish judo teams participated in this observational descriptive study grouped into cadets, juniors, and seniors. Data were collected during previous training meetings to international tournaments. The used tools are a basic data questionnaire, State-Trait Anxiety Inventory (STAI-T), Food Craving Questionnaire-Trait (FCQ-T), Restraint Scale (RS), and Eating Attitude Test (EAT- 40). Two-way ANOVAs and chi-square tests were used to compare groups. RESULTS: Seniors presented higher use of WLM, especially one week before competition compared with juniors. Judoists were more involved in their diets and reduced more weight as they were older. Females were more concerned about their diets, presented higher anxiety, scored higher in the emotion scale, and more eating disorders symptoms, although weight loss was lower. Anxiety and eating disorders symptoms differences were more common in juniors and cadets, respectively, with higher scores in females. CONCLUSIONS AND IMPLICATIONS: Seniors seem to develop more effective strategies to cope with weight loss. Cadet and junior females are more likely to suffer from the psychological-related states associated to weight loss. IMPLICATIONS: (1) Educational programs might help competitors and coaches to adopt and promote healthier weight loss processes, (2) special attention should be paid to female young judoists to detect eating disorders in its early stages, and (3) judo organizations should consider implementing new rules to sanction harmful weight loss practices. PMID- 25029702 TI - Dairy-based preexercise meal does not affect gut comfort or time-trial performance in female cyclists. AB - Some athletes avoid dairy in the meal consumed before exercise due to fears about gastrointestinal discomfort. Regular exclusion of dairy foods may unnecessarily reduce intake of high quality proteins and calcium with possible implications for body composition and bone health. This study compared the effects of meals that included (Dairy) or excluded (Control) dairy foods on gastric comfort and subsequent cycling performance. Well-trained female cyclists (n = 32; mean +/- SD; 24.3 +/- 4.1 y; VO(2peak) 57.1 +/- 4.9 ml/kg/min) completed two trials (randomized cross-over design) in which they consumed a meal (2 g/kg carbohydrate and 54 kJ/kg) 2 hr before a 90-min cycle session (80 min at 60% maximal aerobic power followed by a 10-min time trial; TT). The dairy meal contained 3 servings of dairy foods providing ~1350 mg calcium. Gut comfort and palatability were measured using questionnaires. Performance was measured as maximum mean power during the TT (MMP10(min)). There was no statistical or clinical evidence of an effect of meal type on MMP10(min) with a mean difference (Dairy - Control) of 4 W (95% CI [-2, 9]). There was no evidence of an association between pretrial gut comfort and meal type (p = .15) or between gut comfort delta scores and meal type postmeal (p = .31), preexercise (p = .17) or postexercise (p = .80). There was no statistical or clinical evidence of a difference in palatability between meal types. In summary, substantial amounts of dairy foods can be included in meals consumed before strenuous cycling without impairing either gut comfort or performance. PMID- 25029704 TI - The essentials to keep a man's heart healthy. Here is a checklist to lower your cardiac risk. A healthy weight and a physically active life will get you most of the way there. PMID- 25029703 TI - Effect of whey protein hydrolysate on performance and recovery of top-class orienteering runners. AB - This trial aimed to examine the effect of whey protein hydrolysate intake before and after exercise sessions on endurance performance and recovery in elite orienteers during a training camp. Eighteen elite orienteers participated in a randomized controlled intervention trial during a 1-week training camp (13 exercise sessions). Half of the runners (PRO-CHO) ingested a protein drink before (0.3 g kg(-1)) and a protein-carbohydrate drink after (0.3 g protein kg(-1) and 1 g carbohydrate kg(-1)) each exercise session. The others ingested energy and time matched carbohydrate drinks (CHO). A 4-km run-test with 20 control points was performed before and on the last day of the intervention. Blood and saliva were obtained in the mornings, before and after run-tests, and after the last training session. During the intervention, questionnaires were fulfilled regarding psychological sense of performance capacity and motivation. PRO-CHO and not CHO improved performance in the 4-km run-test (interaction p < .05). An increase in serum creatine kinase was observed during the week, which was greater in CHO than PRO-CHO (interaction p < .01). Lactate dehydrogenase (p < .001) and cortisol (p = .057) increased during the week, but the change did not differ between groups. Reduction in sense of performance capacity during the intervention was greater in CHO (p < .05) than PRO-CHO. In conclusion, ingestion of whey protein hydrolysate before and after each exercise session improves performance and reduces markers of muscle damage during a strenuous 1-week training camp. The results indicate that protein supplementation in conjunction with each exercise session facilitates the recovery from strenuous training in elite orienteers. PMID- 25029705 TI - On call. Ringing in the ears. Over the past few months, I have noticed a constant low-level ringing in my left ear. How can I make it stop? PMID- 25029706 TI - Dietary supplement safety. You've heard all the warnings about dietary supplements. Here are a few that men should use with caution or avoid. PMID- 25029708 TI - How to soothe a sore neck. The essentials are icing and heat, gentle therapeutic exercise, and good posture. PMID- 25029707 TI - Shingles vaccination pros and cons. Vaccination against the chicken pox virus prevents a painful rash common in older men, but it has limits. PMID- 25029709 TI - Which drug for erectile dysfunction? There are some potentially helpful differences between these medications, but price can limit your choices. PMID- 25029710 TI - Eat fruits and veggies for a long life. PMID- 25029711 TI - On call. The coconut craze. I have seen many products promoting the health benefits of coconut oil or coconut water. Is there any proof of those benefits? PMID- 25029712 TI - Blood pressure therapy fails test. PMID- 25029713 TI - Neck lump is common sign of throat cancer due to HPV virus. PMID- 25029714 TI - Matters of the heart: Sex and cardiovascular disease. Cardiovascular disease may change many aspects of your life, but sexual intimacy does not have to suffer as a result. PMID- 25029715 TI - Ask the doctor. Is it okay to eat leafy greens while taking warfarin? I was surprised to see spinach and kale recommended as "superfoods" for heart health in your March issue. I take Coumadin for atrial fibrillation and have been told to avoid green leafy vegetables. I had always enjoyed these foods in the past, so I'd be glad to know if it's okay to eat them. PMID- 25029716 TI - Ask the doctor. What is Prinzmetal's angina? A doctor recently told my wife that she might have Prinzmetal's angina. What is this condition, and how is it treated? PMID- 25029717 TI - Should you seek advanced cholesterol testing? Special tests measure different types of fat particles in the blood. But whether the results can improve your health remains uncertain. PMID- 25029718 TI - Heart failure caused by an infection. Most people with heart failure can trace it to long-standing cardiac risks. An unlucky few have a virus to blame. PMID- 25029719 TI - When high blood pressure affects the arteries to the lungs. New drugs help expand treatment options for pulmonary hypertension. PMID- 25029720 TI - A sugary diet may spell trouble for your heart. Don't let a sweet tooth derail your heart health. Avoid excess sugar from sodas and other sources. PMID- 25029721 TI - Measure blood pressure in both arms. A big gap between the two readings suggests a higher risk of cardiovascular disease. PMID- 25029722 TI - Beware of possible risks from cold and flu remedies. PMID- 25029723 TI - Married women less likely to succumb to heart disease. PMID- 25029724 TI - A new warning sign for heart failure: "Bendopnea". PMID- 25029725 TI - Easy exercises for healthy knees. Try these "anytime" exercises to help protect your mobility and independence. PMID- 25029726 TI - Ask the doctor. Is chelation therapy an effective way to stave off heart disease? I have heard that something called chelation therapy can help against heart disease. Can you tell me about that? PMID- 25029727 TI - 4 fast mood boosters. Exercising, meditating, socializing, and volunteering can lift you out of a funk. PMID- 25029728 TI - Quick fixes for aching elbows. Rest, heat, stretching, and bracing are effective ways to find relief right now. PMID- 25029729 TI - Restaurant meals: How to make them healthier. Dine without worry by watching portion sizes, ingredients, side dishes, and sauces. PMID- 25029730 TI - Best ways to battle irritable bowel syndrome. Get to know your triggers and ways to prevent flare-ups. PMID- 25029732 TI - Caregiver health needs more attention, says researchers. PMID- 25029731 TI - Are cholesterol-lowering statins for everyone? New guidelines are still controversial for older adults who don't appear to have heart disease. PMID- 25029733 TI - Are you getting all of your prescriptions filled? PMID- 25029734 TI - When dementia screenings are appropriate. PMID- 25029735 TI - New guidelines help doctors, patients recognize sarcopenia. Consensus is near regarding measurements of strength and muscle mass to diagnose this muscle condition. PMID- 25029736 TI - Progress in diagnosing and treating heart failure. New developments help keep patients out of hospital. PMID- 25029737 TI - Self-management is key to fibromyalgia treatment. Treating this common chronic pain disorder has baffled patients and physicians for years. PMID- 25029738 TI - New approach may help manage dementia-related behavior issues. A new technique known as DICE aims to assist caregivers, patients. PMID- 25029739 TI - Demystifying Meniere's disease. New research reveals some of the factors that can cause Meniere's disease, an affliction of the inner ear. PMID- 25029740 TI - I'm a woman in my mid-60s. What can I do to help prevent kidney stone formation? PMID- 25029741 TI - Can stress cause cognitive decline? I'm in a deadline-driven, pressure-cooker job, and I'm beginning to be nervous about the effects of stress on my wellbeing. PMID- 25029742 TI - I seem to have no energy lately, even though I drink energy drinks and eat protein bars at low points throughout the day. What can I do to get back my get up-and-go? PMID- 25029744 TI - Health tips. Everyday movements for better health. PMID- 25029743 TI - Aortic valve narrowing. Restricted blood flow may limit physical activity. PMID- 25029745 TI - Carbonation influences sweet taste perception. PMID- 25029746 TI - One-third of cat bites result in hospitalization. PMID- 25029747 TI - Atrial fibrillation choices. Picking an anti-clotting drug. PMID- 25029748 TI - Cancer-related symptoms. Finding relief. PMID- 25029749 TI - Shared decisions. A partnership with your doctor. PMID- 25029750 TI - My friend cooks with avocado oil. Does avocado oil provide the same health benefits as olive oil? PMID- 25029751 TI - I've been feeling really tired since my surgery a month ago. Should I check with my doctor? PMID- 25029752 TI - Highly functional foods. Eating your way to good health. PMID- 25029753 TI - Working on the Family 'Pharm'. PMID- 25029754 TI - Rise of the mumps. What's behind the new cases. PMID- 25029755 TI - E-cigarettes. No safe smoke. PMID- 25029756 TI - [Developments in tropical veterinary medicine at the Utrecht Faculty of Veterinary Medicine (1915-2013)]. AB - Education in livestock diseases in the tropics at the Faculty of Veterinary Medicine of Utrecht University started in 1915 at the Institute for Parasitic and Infectious Diseases. Subsequently, the Institute for Tropical and Protozoon Diseases was established in 1948 and here students and veterinarians were trained in tropical animal health. Research and training were mainly focused on African livestock diseases such as tick borne diseases and trypanosomosis. Training possibilities for students included an elective course ('Tropencursus'), membership of a debating club ('Tropische Kring'), and a traineeship in a project in a tropical country. From 1987 onwards training, education, research, and management of international collaborative projects in tropical animal health became the shared responsibility of the Department of Infectious Diseases and Immunology and the Office for International Cooperation. This article focuses on the last 50 years and highlights activities such as education, research, newsletters, networks, and project with African and Asian countries. PMID- 25029757 TI - The history of the veterinary profession and education in Indonesia. AB - The beginning of the veterinary profession in Indonesia dates back to the middle of the 19th century. During the Dutch colonization period a development program for large ruminants was started by the 'Nederlandsch-Indie' government. In 1907 this government established a veterinary laboratory, planned by Dr. J.K.F. de Does. The laboratory was then merged with a veterinary training course for Indonesian (bumiputera) 'veterinarians' named 'Cursus tot Opleiding van Inlandsche Veeartsen'. In 1910 the name of the training course was changed to 'Inlandsche Veeartsenschool', and in 1914 the school was named 'Nederlandsch Indische Veeartsenijschool' (NIVS). During the Japanese occupation (1942-1945) the veterinary school was named 'Bogor Semon Zui Gakko'. After the declaration of independence by Indonesia in August 1945, it became the High School of Veterinary Education. In 1946 the curriculum was extended from 4 to 5 years. Thereafter the school was closed and re-opened a few times due to the changing political circumstances. In 1947 the first Faculty of Veterinary Medicine ('Diergeneeskundige Faculteit') of the University of Indonesia was established in the former building of NIVS at Taman Kencana Campus in Bogor. Between 1948 and 1963, four more veterinary faculties were established in Indonesia: Gajah Mada, Syiahkuala, Airlangga and Udayana. The Indonesian Veterinary Medical Association (IVMA) was established on January 9, 1953. The membership now exceeds 20,000 veterinarians and the association has 15 special interest groups. Since 2008, five new faculties of veterinary medicine have been established, bringing the total to 10. PMID- 25029758 TI - [A legend of tropical veterinary medicine: Dick Zwart]. AB - An overview is given of the achievements of Professor Dr. D. Zwart (1930-2005). Following a brief introduction dealing with his background, his first eleven years of working in tropical countries are reviewed. Initially he was employed as a government veterinarian in Dutch New Guinea, followed by five years as a scientist at the agricultural faculty in Kumasi, Ghana, where he completed his PhD on liver cirrhosis in local pigs. He was seconded by the Department of Tropical Veterinary Medicine at Utrecht University to work as a virologist in Vom, Nigeria. Once back in The Netherlands, he was selected to take over the position of head of the Department due to the unexpected death of Professor S. G. Wilson. He stayed for 20 years at Utrecht University and was for another nine years department head at the Agricultural University of Wageningen. He was an influential man during this long period as department head, not only for his students, but also in the international field. Four aspects of the achievements by Dick are highlighted in detail: as a scientist, as an educator, as a stimulating figure, and as a visionary. PMID- 25029759 TI - On culture change. Every trust must shine a light on positive culture. PMID- 25029760 TI - Safe care is more complex than ratios. PMID- 25029761 TI - Involve the public more effectively. PMID- 25029762 TI - Technology. The big question. PMID- 25029763 TI - Technology: case studies. 'Patients really like it'. PMID- 25029764 TI - Patient safety. Just visiting. PMID- 25029765 TI - Technology. Image problem. PMID- 25029766 TI - Public health. Be prepared: what work in fight against flu. PMID- 25029767 TI - The passion of a people's leader. PMID- 25029768 TI - Harnessing the domino effect. PMID- 25029769 TI - Patient experience. Retail therapy for patient care. PMID- 25029771 TI - Teaching pharmacy in Malta 1676-1990s: Part I. PMID- 25029770 TI - Procurement. The gloves are off with new spending rules. PMID- 25029772 TI - Possible sources of therapeutic stone powder from north west Europe. PMID- 25029773 TI - Auxiliary Trades: added income for the pharmacy. PMID- 25029774 TI - The value of the Euganean thermalism in the treatment of human diseases: past, present and future health applications. From Michele Savonarola's De Balneis in Comitatu Paduano to innovative approaches. PMID- 25029775 TI - David Waldie (1813-89). PMID- 25029776 TI - Paracelsus experiments in a Persian book on compound remedies, Amal-e-Saleh (1766 A.D.). PMID- 25029777 TI - Hunger games. Cheerios has ditched GMOs. Does it matter? PMID- 25029778 TI - Lift squat repeat. Crossfit gyms' cultish painiacs love their max-out-and-do-it again training regimen. Their critics are getting a workout too. PMID- 25029779 TI - Delaying time to relapse in schizophrenia. The role of long-acting injectable antipsychotics. PMID- 25029780 TI - Managed care considerations. Optimal pharmacotherapy of schizophrenia. PMID- 25029781 TI - Small hospitals are still a vital NHS tool. PMID- 25029782 TI - Protect the public purse. PMID- 25029783 TI - Design. Changing rooms for the better. PMID- 25029784 TI - The wrong prescription for drug prices. PMID- 25029785 TI - Innovation and efficiency. Diagnostic services: the bigger picture. PMID- 25029786 TI - Primary care. Let the mavericks take a leap faith. PMID- 25029787 TI - Education. Breathe new life into old training. PMID- 25029788 TI - Health and wellbeing boards. Get over the language barrier. PMID- 25029789 TI - Man vs. microbe. We're losing the battle against bacteria. Can we win the war? PMID- 25029790 TI - The specialized generalist. PMID- 25029791 TI - Internal medicine incubator. An internal medicine interest group helps students explore career possibilities. PMID- 25029792 TI - A small-but-thriving specialty. Med-peds is an option for those who want to keep their options open. PMID- 25029793 TI - Reinventing the internist. Internal medicine programs change up the way they train physicians. PMID- 25029794 TI - On choosing primary care. Four graduating medical students share their stories. PMID- 25029795 TI - A closer view. The realities of practicing medicine in Tanzania. PMID- 25029796 TI - In between innings. A ballgame, an interview and an unforgettable patient. PMID- 25029797 TI - The art of compromise. PMID- 25029798 TI - Management of diabetes during Ramadan: practical guidelines. AB - Ramadan is a month-long period of heightened self-reflection about one's religion and one's relationships with others. During Ramadan, fasting during daylight hours is required. The fast is typically followed by a feast after dark. Although Muslims with certain medical conditions are allowed by Islamic law to abstain from fasting, many choose to fast during Ramadan for personal reasons. Diabetes is one of the most challenging conditions to manage during this time, and physicians and clinics with Muslim patients who have diabetes will need to be prepared if they are to support their patients who desire to fast. This article provides a general overview of Ramadan and offers practical guidance for managing adults and children with diabetes who are fasting during this important time in the Muslim calendar. PMID- 25029799 TI - The growth of palliative care. AB - Palliative care specialists focus on meeting the needs of patients with serious and/or life-threatening illnesses. These physicians have expertise in managing complex pain and nonpain symptoms, providing psychosocial and spiritual support to patients and their families, and communicating about complex topics and advance care planning. The American Board of Medical Specialties has allowed 10 of its member boards to co-sponsor certification in Hospice and Palliative Medicine. Thus, physicians from specialties ranging from pediatrics to surgery now practice hospice and palliative medicine. At the core of this field, however, are physicians who trained as internists and are boarded by the American Board of Internal Medicine. This article discusses the central principles of palliative care and explores its growth in two areas: oncology and critical care medicine. PMID- 25029800 TI - Positional effects on lung volumes and transpulmonary pressure during unilateral mechanical asymmetry. PMID- 25029801 TI - Miliary tuberculosis in a Somali refugee: a new normal? PMID- 25029802 TI - Exposed facial hair as a danger in home: supplemental oxygen use. PMID- 25029803 TI - An internist's dilemma: differentiating paraneoplastic from primary rheumatologic disease. PMID- 25029804 TI - Immunolocalization of ABC drug transporters in human placenta from normal and gestational diabetic pregnancies. AB - OBJECTIVES: ABC transporters, P-gp, MDR3, BCRP and MRP1, can bind both endo- and exogenous ligands. The latter include immunosuppressive, anticancer sedative, anticonvulsant, antiparasitic and cardiovascular drugs, as well as HIV protease inhibitors and antibiotics. Protein transporters are also involved in tissue distribution of orally administered medicines in combination therapy for gestational diabetes mellitus (GDM) and could be used during GDM treatment. The distribution depends on transporter specificity its expression and subcellular localization. THE AIM: The aim of the study was to compare P-gp, MDR3, BCRP and MRP1 localization in placental tissues from normal and GDM diabetic pregnancies. MATERIAL AND METHODS: Tissue samples were taken from 10 normal and 10 GDM placentas. Immunohistochemical reactions were performed with the use of adequate monoclonal antibodies. Avidin-biotin-peroxidase complex method was used for the visualization of antigen-antibody complexes. RESULTS: P-gp, MDR3 and BCRP were found in all parts of normal human placenta i.e. the amniotic epithelium, cytotrophoblast, syncytiotrophoblast and decidual cells. P-gp and BCRP, but not MDR3 and MRP1, were also localized on the endothelial cells of fetal blood vessels in the chorionic plate, as well as stem and tertiary villi. MRP1 expression was observed in the cytotrophoblast and the syncytiotrophoblast. Its expression was very low or undetectable in the amniotic epithelium and the majority of decidual cells. Immunohistochemical reactions within the syncytiotrophoblast showed apical (P-gp, BCRP), apical and basal (MRP1) or diffuse (MDR3) distribution. The main changes observed in GDM placentas included weaker MRP1 and MDR3 positive reactions in the syncytiotrophoblast, slightly lower expression of P-gp in the decidual and amniotic epithelial cells, and MDR3 in the amniotic epithelium. CONCLUSIONS: Our results indicate that GDM-related changes in the environment of placental cells do not substantially influence tissue and subcellular location of ABC transporters. Nevertheless, the expression of P-gp, MDR3 and MRP1 may be lower in comparison to normal placentas. Basal syncytiotrophoblast transporters, MRP1 and MDR3, seem to be more sensitive to the influence of GDM than apical proteins, what may result in altered biodisposition of endogenous substrates and drugs. PMID- 25029805 TI - [Indications for genetic amniocentesis investigated at the Department of Gynecology, Obstetrics, and Oncologic Gynecology, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz]. AB - INTRODUCTION: Genetic amniocentesis (GA) is the most common prenatal diagnostic test. One of the main indications for GA is maternal age of > or = 35 years. In many countries, the age indication has been replaced by an assessment of individual risk for chromosomal abnormalities, calculated on the basis of maternal age, pregnancy duration, as well as a combination of biochemical and ultrasound markers. OBJECTIVES: The aim of the study was to investigate indications for and results of GA performed between 2010-2012 at the Department of Gynecology Obstetrics, and Oncologic Gynecology Nicolaus Copernicus University Collegium Medicum, Bydgoszcz. MATERIALS AND METHODS: A total of 632 GA tests were performed at the Department of Gynecology Obstetrics, and Oncologic Gynecology Nicolaus Copernicus University Collegium Medicum, Bydgoszcz. Average maternal age was 34 (between 17 and 47 years), with patients < 35 constituting 47.9% (N = 303), and patients > or = 35 constituting 52.1% (N = 329) of the investigated group. Indications for GA as well as test results were analyzed in relation to maternal age. The result of earlier non-invasive tests were also analyzed. RESULTS: Abnormal ultrasound findings, combined with abnormal first-trimester screening results, were the most common indication (46.53%) for GA in patients < 35 years, whereas abnormal first-trimester screening results, combined with a history of obstetric complications, were the reason for GA in patients > or = 35 years. Mean time of GA was 16 gestational weeks in both groups. Abnormal karyotype was detected in 74 (11.7%) cases. 13 or any other abnormal karyotypes occurrence were observed in both age groups. GA-related complications (miscarriage/intrauterine fetal death) occurred in 9 (1.42%) cases. CONCLUSIONS: If performed properly GA between 15 and 20 weeks of pregnancy is a harmless procedure both, for the mother and the fetus, associated with an acceptable complication rate. Prenatal screening for the most common malformations and chromosomal aberrations should be offered to all pregnant women in Poland, regardless of their age. PMID- 25029806 TI - Umbilical cord blood NGAL concentration as an early marker of perinatal asphyxia in neonates. AB - INTRODUCTION: Recent reports have revealed increased concentration of neutrophil gelatinase-associated lipocalin (NGAL) in cardiovascular diseases and after episodes of hypoxia. We hypothesized that elevated plasma NGAL levels could be a result of vascular endothelial injury due to perinatal asphyxia. MATERIALS AND METHODS: Ninety-three newborns with a gestational age > or = 37 weeks, of which 32 newborns were asphyxiated (study group), and 61 were healthy children (control group), were enrolled in the study Serum NGAL, lactate and creatinine concentrations, acid-base balance, neutrophil and white blood cell count were measured in the umbilical cord blood. RESULTS: Asphyxiated newborns had a significantly lower pH value (7.0 vs. 7.3, p < 0.001), lower HCO3 (15.8 mmol/L vs. 23.2 mmol/L; p < 0.001) and higher lactate concentrations (7.5 mmol/L vs. 2.3 mmol/L; p < 0.001), as compared to controls. Neutrophil count (10.3 x 109/L vs. 6.5 x 109/L; p = 0.02) and NGAL concentration (122.5 ng/mL vs. 24.3 ng/ mL p < 0.001) were elevated in asphyxiated newborns as compared to healthy children. CONCLUSIONS: The measurement of NGAL in the umbilical blood can be a valuable biomarker of perinatal asphyxia in neonates. PMID- 25029807 TI - The significance of TNF-alpha gene polymorphisms in preterm delivery. AB - INTRODUCTION: Nowadays the strong genetic background of preterm delivery (PTD) in connection with immune answer has been indicated. The purpose of the study was the assessment of frequency of TNF-alpha -238G>A, -308G>A, -376G>A gene polymorphisms in the etiology of preterm delivery MATERIAL AND METHODS: The study group consisted of 150 women with PTD (22+0 - 36+6 gw.), the controls of 150 women who delivered at term (> 37 gw). PTD group was divided into subgroups: a/delivery between 22-28 gw, b/28-32 gw., and c/32-36+6 gw. Genetic analysis was performed by PCR/RLFP method. RESULTS: Overrepresentation of -238GA genotype (12.7 vs. 4.7%, p = 0.011) and -238A allele (7.7 vs. 2.3%, p = 0.002) in PTD group has been observed. In PTD 28-32 gw. subgroup, higher frequency of -238GA genotype (31.6 vs. 4.7%, p = 0.00095), and mutated -238A allele (21.1 vs. 2.3%, p = 0.00004) was noted. Moreover in PTD 28-32 gw. subgroup we have noted higher presence of heterozygous -376GA genotype (10.5 vs. 1.3%, p = 0.063) and mutated 376A allele (5.3 vs. 0.7%, p = 0.064). Analysis of TNF-alpha polymorphisms co occurrence showed statistically significant overrepresentation of genotypes containing mutated -238A allele in PTD group (-238GA/-308GG/-376GG: 8.0 vs. 2.7%, p = 0.035). Haplotype analysis revealed statistically significant difference between PTD and controls in the incidence of -376G/-308G/-238A haplotype containing mutated -238A allele (0.063067 vs. 0.016634, p = 0.030). CONCLUSION: The study indicated the strong association of mutated -238A allele of TNF-alpha gene with increased risk of PTD. Analysis of genotypes and alleles prevalence in PTD women divided according to gestational age suggests the possible role of mutated variants of -238G>A and -376G>A TNF-alpha polymorphisms in Polish women delivering between 28 and 32 gw. PMID- 25029808 TI - [Carcinoma of the cervical stump--multicenter study]. AB - OBJECTIVES: Cervix-sparing hysterectomy due to benign conditions remains controversial, especially when the presumed risk of cervical cancer in the retained cervical stump is concerned. On the other hand, supracervical hysterectomy is associated with shorter operative time, decreased blood loss and decreased intraoperative complications. Moreover, beneficial effects of retaining the cervix on the pelvic statics and female psychosexual functioning have been suggested, although not yet proven. THE AIM: The aim of the study was to determine the frequency and types of cervical cancers in the retained cervical stump after supracervical hysterectomy performed due to benign diseases of the uterine corpus in four academic settings. MATERIAL AND METHODS: Retrospective review of medical records of 903 women who underwent treatment due to cervical carcinoma in four departments participating in the study: Centre 1- 2nd Department of Gynecology, Medical University Lublin (years: 2001- 2011); Centre 2 Department of Gynecology and Gynecologic Oncology, Military Institute of Medicine, Warsaw (years: 2002-2012); Centre 3- Katedra i Kliniki Poloznictwa, Chorob Kobiecych i Ginekologii Onkologicznej II Wydzialu Lekarskiego WUM, Warsaw (years: 2008-2013) and Centre 4- Department of Gynecologic Oncology, Poznan University of Medical Sciences, (years: 2000-2012). The occurrence rate of cervical stump carcinoma was reported in relation to patient age, time elapsed between supracervical hysterectomy and diagnosis stump cancer and histological type of cancer. RESULTS: Only 3 cases of cervical stump carcinoma (0.33%) were identified among the 903 investigated women. In all these cases, cervical stump cancers were diagnosed several years after supracervical hysterectomy. In one case the only treatment was radiotherapy in one case only trachelectomy was performed, whereas in one case surgery followed by radiotherapy was used. CONCLUSIONS: It should be remembered that subtotal hysterectomy carries a risk, albeit relatively low, of developing stump cancer. Therefore, patients should be informed that after such operation further cervical cancer screening is mandatory. Moreover subtotal hysterectomy should not be offered in populations at risk of developing cancer of the uterine cervix. PMID- 25029809 TI - Synchronous tumors of the female genital tract: a 20-year experience in a single center. AB - OBJECTIVE: To evaluate the clinicopathological characteristics and the clinical outcome of synchronous malignant neoplasms of the female reproductive tract. MATERIAL AND METHODS: Patients who were operated and diagnosed with synchronous malignant tumor of the genital system (n = 25) at the Dokuz Eylul University Department of Obstetrics and Gynecology Gynecologic Oncology Unit between 1992 and 2012 were included into this study. Recurrent, metastatic and metachronously detected tumors were not included. Age at diagnosis, parity menopausal status, hormone use, presenting sign or symptoms and the clinical outcomes were evaluated. RESULTS: 20 of 25 patients had endometrial-ovarian cancer. The mean age at diagnosis was 53,6 years. The most common presenting symptom was abnormal uterine bleeding. The median follow-up duration for all patients was 69 months. Overall survival for all patients was 87 months and 81 months for patients with endometrial-ovarian cancer 5-year survival rate was 73% for all patients and 68% for patients with endometrial-ovarian cancer. CONCLUSIONS: Endometrial-ovarian cancer togetherness is the most common in synchronous gynecologic malignancies. They occur at a younger age and have more favorable prognosis than metastatic primary gynecologic tumors. PMID- 25029810 TI - Ovarian reserve assessment in women with different stages of pelvic endometriosis. AB - INTRODUCTION: Endometriosis is defined as the appearance of ectopic endometrial cells outside the uterine cavity. Ectopic cells demonstrate functional similarity to eutopic cells, but structural and molecular differences are significant and manifest themselves in gene expression of the metalloproteinase genes, integrin or the Bcl-2 gene. Pelvic pain remains to be the main symptom of the disease. Endometriosis may cause dysfunction of the reproductive system and lead to infertility. Pathogenesis of infertility in endometriosis is based on its influence on the hormonal, biochemical and immunological changes in the eutopic endometrium, as well as structural damages of the ovaries and the fallopian tubes. OBJECTIVES: The aim of the study was to assess the ovarian reserve in patients with endometriosis. MATERIAL AND METHODS: A total of 39 patients (aged 22-34 years) with different stages of endometrial changes were recruited for the study. The number of antral follicles was rated by vaginal ultrasonography and the level of FSH was measured between days 1-3 of the menstrual cycle. The stage of the disease was established after laparoscopy with the rASRM scale. RESULTS: No statistically significant correlation between the number of follicles (AFC), the level of FSH and the stage of endometriosis was found. CONCLUSIONS: Evaluation of the number of antral follicles and measurements of the FSH level do not allow to predict the ovarian reserve in women with endometriosis. PMID- 25029811 TI - [Decision-to-delivery interval (DDI) for emergency cesarean sections in Polish healthcare system]. AB - Cesarean section is one of most common obstetric procedures, with the incidence of 33.9-43.1% of all labors in Poland. If the indication for cesarean section is 'immediate threat to maternal or fetal life', then the procedure must be performed without delay. The fact that time elapsed between decision to operate and delivery (decision-to-delivery interval, DDI) affects fetal outcome has been widely discussed. Poland lacks recommendations for optimal DDI in emergency cesarean section but some foreign scientific associations, universally recognized as an authority recommend DDI not to exceed 30 minutes in such cases. Our review attempts to determine the most significant factors affecting DDI, which can be divided according to the competence and responsibility of people involved in the functioning of the obstetrics department. Obstetrician-depending factors include appropriate diagnosis of indications for cesarean section and proficiency during procedure (incision-to-delivery interval). Midwives are responsible for preparation of the patient and the operating theater as well as transport of the patient. Anesthesiologists deem patients eligible for anesthesia and are also responsible for efficiency of its administration. Furthermore, few additional factors which seem to be fundamentally important in achieving optimal DDI have been identified and they depend on hospital management decisions, namely sufficient number of qualified staff, regular training in emergency procedures, availability of operating theaters, as well as fast and safe transportation of patients between the admission room, obstetrics department and operating theaters. In conclusion, we wish to emphasize that optimal DDI depends on proper collaboration of numerous teams, what may be important when discussing personal responsibility in obstetric failures. PMID- 25029813 TI - [VEGF--targeted therapy for the treatment of cervical cancer --literature review]. AB - Cervical cancer is the third most common malignancy and the fourth leading cause of cancer-related death among women worldwide. Advances in the knowledge about molecular mechanisms of carcinogenesis have created opportunities for greater use of targeted therapies in contemporary oncology In view of the unsatisfactory results of advanced cervical cancer treatment and a well-documented role of the vascular endothelial growth factor (VEGF) family members in pathogenesis and progression of cervical cancer, the use of VEGF-targeted therapy in the treatment of cervical cancer offers interesting possibilities. The efficacy of bevacizumab, a monoclonal antibody neutralizing VEGF-A in the treatment of cervical cancer was first suggested in 2006 by a small retrospective analysis and confirmed in several Phase II clinical trials. Preliminary results of the randomized phase III studies presented at this year's ASCO (American Society of Clinical Oncology) conference shed new light on the role of VEGF-targeted therapy in the treatment of cervical cancer as they demonstrated that addition of bevacizumab to chemotherapy is associated with significantly improved overall survival in the group of patients with persistent, recurrent or metastatic cervical cancer. PMID- 25029812 TI - [Do we need a different approach to GBS screening?]. AB - Group B Streptococcus (GBS) infections remain an important cause of perinatal complications, despite advanced preventive measures. The most common clinical symptoms of early-onset disease, diagnosed in neonates up to 7 days of life, are sepsis and pneumonia. Late-onset disease is diagnosed in children between 7 and 89 days of life and presents also in forms of other infections. As a result of collaborative efforts of clinicians, researchers and many organizations, various recommendations for intrapartum prevention of perinatal GBS disease have been issued so far. Revised 2002 CDC guidelines for the prevention of early-onset GBS disease recommended universal culture-based screening of all pregnant women at 35 37 weeks of gestation to optimize the identification of those who should receive intrapartum antibiotic prophylaxis (IAP). They were customized by the Polish Gynecological Society and applied in Poland as well. As a result of preventive efforts worldwide, global incidence of GBS infections has declined dramatically over the past 15 years. About 10-30% of pregnant women are colonized with Group B Streptococcus. According to the literature, GBS culture at 35 to 37 weeks of gestation has about 95% negative predictive value for the absence of colonization at the time of labor. However, studies reporting early-onset GBS disease in newborns found that about 60 to 80% of all cases occurred in neonates with negative maternal screening during pregnancy. If the only available screening test is vagino-rectal swab during pregnancy about 7.5% of women with GBS colonization during labor are not administered IAP. It seems optimal to perform routine screening not during pregnancy but directly before the delivery- preferably at the time of regular uterine contractions or the rupture of membranes. As the screening test should be widely accessible and rapid, the usual microbiological culture is not a suitable option. Recently new biochemical and genetic methods have become available. Polymerase chain reaction (PCR) and optical immunoassay are candidates for rapid patient intrapartum GBS testing to determine whether women in labor are colonized with GBS. PCR tests have the sensitivity of over 90% with the specificity of 99%, which is about 13% higher than microbiological culture. According to the literature, IAP does not reduce the overall neonatal mortality mortality due to GBS infection, or due to other bacterial infections. The incidence of early-onset GBS infection was reduced with IAP in comparison to no intrapartum prophylaxis, but there was no difference in late-onset GBS disease occurrence. Besides GBS, IAP may influence maternal and neonatal infections caused by other pathogens. Moreover, it can also induce GBS and no-GBS pathogen resistance to antibiotics. It therefore seems necessary to replace the current type of GBS screening with GBS DNA PCR intrapartal test--a rapid, highly sensitive and specific method of carrier identification--in order to optimize IAP and, eventually to decrease the rate of early onset GBS disease in neonates. PMID- 25029814 TI - [Delayed delivery in a triplet pregnancy--a case report]. AB - In multiple pregnancy the following may be considered to delay the delivery: bed rest, antibiotics, tocolytics, steroids, and, possibly cervical cerclage. Analysis of uterine contraction intensity reevaluation of the chorion and the amnion, as well as monitoring of the mother and the fetus are also very important. Clinical and laboratory parameters ought to be carefully monitored to prevent intra-amniotic infection. We present a case of a delayed delivery in a trichorionic, triamniotic, triplet pregnancy after IVF. The first and the second fetuses were delivered spontaneously at 23 and 26 weeks of gestation, respectively. The third fetus was delivered by a cesarean section at 26 weeks of gestation. The delay between the first and the second/third fetuses was 18 days. Only the second child survived. At present, the psychomotor development of the infant is considered as normal. PMID- 25029815 TI - Thyroid dysfunction during severe ovarian hyperstimulation syndrome. A case report. AB - Thyroid disorders, both in women who wish to conceive and in gravidas, has become a topic of much interest to numerous researchers. Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening condition among women undergoing controlled ovarian hyperstimulation (COH). We present a case of thyroid dysfunction in severe OHSS in a patient diagnosed with subclinical hypothyroidism before COH. The dose of L-thyroxine (L-T4) was increased before the procedure in order to reach TSH levels below 2.5 mU/L, and from day 1 of the stimulation the dose of L-T4 was increased by 33%. The patient remained clinically and biochemically euthyroid until day 8 after the embriotransfer (ET). Then, the woman developed severe OHSS, with fluid in the pleural and peritoneal cavity and laboratory evidence of severe OHSS. Laboratory thyroid function tests revealed overt hypothyroidism. L-T4 dose was not increased due to serious clinical condition of the patient. Iodine supplementation was initiated instead. After the symptoms subsided, a period of clinical and laboratory euthyroid state was observed, followed by gestational hyperthyroidism. The L-T4 dose was reduced and iodine supplementation was temporarily ceased. The thyroid function stabilized, while maintaining the L-T4 and iodine supplementation, at 20 weeks of gestation. The patient gave birth by a caesarean section at 37 weeks of gestation and returned to the pre-pregnancy dose of L-T4. To the best of our knowledge, this has been the first report about a patient with thyroid dysfunction in severe OHSS in the Polish literature. On the basis of the presented case and a review of the literature on thyroid dysfunction in women undergoing COH and OHSS, we conclude that clinical signs and biochemical parameters need to be taken into consideration while making therapeutic decision in women with thyroid dysfunction in the course of OHSS. Also, further studies are necessary to elucidate the matter. PMID- 25029816 TI - [Actualisation of Polish Gyneacological Society standards of medical care in management of women with diabetes]. AB - Following changes in diagnostic criteria for gestational diabetes, made by IADPSG and WHO in 2013, the Experts' Panel decided on the update of the previous Polish Gynecological Society standards of medical care in management of women with diabetes published in 2011. Current Standards contain new criteria for the diagnosis of gestational diabetes as well as guidelines for prepregnancy care, treatment, antenatal and postpartum care in women with gestational diabetes mellitus. PMID- 25029817 TI - Transformations of geometrical objects in middle Egyptian mathematical texts. AB - This paper analyzes the algorithmic structure of geometrical problems in Egyptian papyri of the first half of the second millennium B.C. Processes of transformation of quantities from "false" values into actual values, and conversions from quantities expressed in the abstract system of numbers into metrological quantities, are known in Egyptian mathematics. Three further processes are identified in the present contribution: transformations of "false" dimensions of geometrical objects into true dimensions; transformations of geometrical objects into other geometrical objects; transformations of linear measures of monuments. These processes have relevant implications on the algorithmic structure of the problem texts, resulting in particular in the embedding of sub-algorithms and the creation of parallel structures. More in general, their wide employment in Egyptian mathematics has significant philosophic and cultural implications. PMID- 25029818 TI - [Galileo and centrifugal force]. AB - This work intends to focus on Galileo's study of what is now called "centrifugal force," within the framework of the Second Day of his Dialogo written in 1632, rather than on the previously published commentaries on the topic. Galileo proposes three geometrical demonstrations in order to prove that gravity will always overcome centrifugalforce, and that the potential rotation of the Earth, whatever its speed, cannot in any case project objects beyond it. Each of these demonstrations must consequently contain an error and it has seemed to us that the first one had not been understood up until now. Our analysis offers an opportunity to return to Galileo's geometrical representation of dynamical questions; actually, we get an insight into the sophistication of Galileo's practices more than into his mistakes. Our second point, concerning the historiography of the problem, shows an evolution from anachronic critics to more contextual considerations, in the course of the second half of the twentieth century. PMID- 25029819 TI - Four centuries later: how to close the Galileo case? AB - The "Galileo case" is still open: John Paul II's 1979 initiative to "recognize wrongs from whatever side they come" was carried out in an unsatisfactory manner. The task would have been easy had the Pontifical Study Commission created for that purpose concentrated on the 1616 decree alone and declared it not in line with the hermeneutical guidelines of the Council of Trent, in agreement with Galileo and not with Saint Robert Bellarmine. A possible avenue to closing the "Galileo case" on the part of the Church of Rome could, thus, be to change its current defensive attitude and declare itself no longer what it was in 1616, since another such "case" is, hopefully, no longer conceivable. PMID- 25029820 TI - [The production of optical glass in France and the experiences of Ruggiero Boscovich for the production of lead glass (Part One)]. AB - The experiences that in 1758 led John Dollond to create the first achromatic telescope highlighted the serious difficulties related to the production of lenses with a correction for chromatic aberration. These difficulties were due to the lack of suitable tools for measuring the refraction index and for verifying the curvatures of the lenses of such optical instruments. To this was added what was perhaps the greatest difficulty: i.e., that of acquiring the kinds of glass, the so-called "common" (crown) glass and "lead" (flint) glass, of which the lenses had to be made. If the theoretical works of Alexis Clairaut, of Samuel Klingenstierna, and of Ruggiero Boscovich furnished the theoretical basis for producing such lenses, and subsequently--after Boscovich's discovery of the role of the eyepieces--for creating also achromatic eyepieces, the greatest challenge from the practical point of view was that of the availability of the flint glass. In this first part of the article there is then a study of the numerous attempts and directions pursued by Clairaut and his valid collaborators--Antheaulme, George father and son, Charles Francois de l'Etang, and Claude Simeon Passemant- in order to find common glass and lead glass, and to produce the first achromatic lenses and binoculars in France. An analysis follows of the experiences conducted by Boscovich, first in Vienna, and then in Milan and Venice-Murano, addressed to the production of flint glass. PMID- 25029821 TI - [Anatomists, philosophers, "head hunters": Gall, Kant and the early days of phrenology]. AB - In 1798, the German physician and anatomist Franz Joseph Gall, after his transfer to Vienna, published a pioneer paper that gave rise to the Schadellehre (skull doctrine): a new discipline (today better known under the spurious name of phrenology) aimed at the study of the functional relations between mental faculties, cerebral areas, and skull bumps. During that same period (1796-1798), several Kantian texts began to circulate, in which--polemicizing with J.C. Lavater, and S.Th. Soemmerring--some anthropological and psychological issues, present also in Gall's paper (e.g., "the inner and outer side of man," "skull morphology," "the organ of the soul," etc.) were dealt with, but in an independent way. Kant will come to know of the Schadellehre only in the last years of his life, showing an unexpected interest in the subject. Proof of this may be found not only in the testimony of his Tischgenossen (table friends), but also in some posthumous notes (AA XV/2, AA XXI: 1802-1803), which are the object of a still controversial interpretation. In 1804, upon the death of the philosopher--on the background of the striking contemporaneous occurrence of the so-called "skull hunt" (Schadeljagd), raging at that time in the Austro-German area--also Kant's skull, like those of other prominent figures, became the object of a phrenological investigation, as Gall had for a long time been hoping. PMID- 25029822 TI - Raffaello Caverni and the Society for the Progress of the Sciences: an independent priest criticized by the lay scientists. AB - Raffaello Caverni (1837-1900), a Catholic priest, was a truly lay and anti establishment intellectual in his opinions both on Darwin and on Galileo. He opposed the mythicization of Galileo, as a rule common in Italy after the unification, even though he considered Galileo a great scientist. As a consequence the scientific community of that time, under the influence of Antonio Favaro, bitterly censured his work Storia del metodo sperimentale in Italia (History of the experimental method in Italy). In this way, Caverni's book was removed from the scientific debate in Italy for at least forty years. PMID- 25029823 TI - [Work, momentum and fatigue in the work of Daniel Bernoulli: toward the optimization of biological fact]. AB - The concept of mechanical work is inherited from the concepts of potentia absoluta and men's work, both implemented in the section IX of Daniel Bernoulli's Hydrodynamica in 1738. Nonetheless, Bernoulli did not confuse these two entities: he defined a link from gender to species between the former, which is general, and the latter, which is organic. In addition, Bernoulli clearly distinguished between vis viva and potentia absoluta (or work). Their reciprocal conversions are rarely mentioned explicitly in this book, except once, in the section X of his work, from vis viva to work, and subordinated to the mediation of a machine, in a driving forces substitution problem. His attitude evolved significantly in a text in 1753, in which work and vis viva were unambiguously connected, while the concept of potentia absoluta was reduced to that of human work, and the expression itself was abandoned. It was then accepted that work can be converted into vis viva, but the opposite is true in only one case, the intra-organic one. It is the concept of fatigue, seen as an expenditure of animal spirits themselves conceived of as little tensed springs releasing vis viva, that allowed the conversion, never quantified and listed simply as a model, from vis viva to work. Thus, work may have ultimately appeared as a transitional state between two kinds of vis viva, of which the first is non-quantifiable. At the same time, the natural elements were discredited from any hint of profitable production. Only men and animals were able to work in the strict sense of the word. Nature, left to itself, does not work, according to Bernoulli. In spite of his wish to bring together rational mechanics and practical mechanics, one perceived in the work of Bernoulli the subsistence of a rarely crossed disjunction between practical and theoretical fields. PMID- 25029824 TI - Joseph John Thomson's models of matter and radiation in the early 1890s. AB - In the late nineteenth century, Joseph John Thomson moved away from Maxwell's specific theoretical models of matter and energy, even though he continued to rely on the general framework of Maxwell's electromagnetic theory. In his 1893 book, he accomplished the conceptual drift towards a discrete model for matter, electricity, and fields. In Thomson's model, energy was linked to tubes of force, in particular to the aether contained in them and surrounding them: the energy was the kinetic energy of aether, of both a rotational and translational kind. Starting from Maxwell's electromagnetic fields, namely stresses propagating through a continuous solid medium, Thomson arrived at a representation of fields as a sea of discrete units carrying energy and momentum. He tried to transform Maxwell's theory into a unified picture in which atomic models of matter stood beside atomic models of fields. In 1904 his interpretation of X-rays was based on the integration between two complementary features of electromagnetic radiation, the continuity and the discreteness, and on some kind of fibrous aether. In recent secondary literature, the problematic conceptual link between J. J. Thomson's theory and contemporary theories on electromagnetic radiation has been underestimated. On the contrary, in the first half of the twentieth century, some physicists inquired into that link, and a widespread debate emerged, misunderstandings included. PMID- 25029825 TI - Philosophy and mathematics: interactions. AB - From Plato to the beginnings of the last century, mathematics provided philosophers with methods of exposition, procedures of demonstration, and instruments of analysis. The unprecedented development of mathematics on the one hand, and the mathematicians' appropriation of Logic from the philosophers on the other hand, have given rise to two problems with which the philosophers have to contend: (1) Is there still a place for the philosophy of mathematics? and (2) To what extent is a philosophy of mathematics still possible? This article offers some reflections on these questions, which have preoccupied a good many philosophers and continue to do so. PMID- 25029826 TI - [Extraordinary news of a curious apothecary. Monsters and wonders in the Florentine diary of Luca Landucci]. AB - This article offers a new reading of the well-known diary kept by the Florentine apothecary Luca Landucci between 1450 and 1516, examining its accounts of prodigies and other "monstrous" occurrences from a modern scientific point of view. Particular consideration is given to descriptions of a variety of birth defects observed in various Italian cities at the time, providing explanations for each case based on the latest medical theories. A detailed analysis is provided for a case of cranioschisis recorded in Volterra in 1474, a case of Opitz syndrome occurring in Venice in 1489, the birth of conjoined twins in Padua in the same year, conjoined triplets born to a 60-year-old woman in Venice, the well-publicized account of the 1512 Ravenna monster and, finally, the thoraco acephalus tetramelus adolescent that Landucci personally observed in Florence in 1513. PMID- 25029827 TI - [The enigma of the "punished suicide": an anatomical preparation of Lodovico Brunetti winner of the gold medal at the Universal Exhibition in Paris in 1867]. AB - This article reconstructs the figure of Lodovico Brunetti, the first Chair of Pathological Anatomy at the University of Padua, and Director of the homonymous Institute from 1869 to 1887. He was the inventor of a technique known as "tannization," for the conservation of animal tissue. In particular, we have reconstructed the episode related to a particularly choking anatomical preparation, created by Brunetti in 1863, called "The Punished Suicide." This composition, together with a series of 66 preparations, allowed him to win the "Gran prix" at the Universal Exposition of Paris in 1867. PMID- 25029828 TI - [Stories in history. Notes in the margins of a book on the history of Italian psychology]. AB - The first part of the article deals with a recent book on the history of Italian psychology, analyzing especially the historiographical choices made by the editors. This analysis then evolves into an original approach, which aims to place the particular 'history' analyzed within a broader context in which some specific historical reconstructions are taken as 'objects' of the historical discourse, giving rise to a comparison in various respects. In this perspective, the contribution is particularly concerned with the different periodization of the history of psychology in Italy. It also addresses the question, not merely nominalistic, of the adjectives (experimental, physiological) that at certain stages were thought indicated to accompany the noun 'psychology,' prior to being subsequently abandoned; and also the theme of applications, recalling the origins, highlighting the different meanings, and following the developments in the course of time. PMID- 25029829 TI - [Controversy of anterior knee pain after total knee arthroplasty]. PMID- 25029830 TI - [Case-control study on earlier medial tibial pain after total knee arthroplasty]. AB - OBJECTIVE: To compare the difference of anterior knee pain after total knee arthroplasty (TKA) between the ways using periosteal dissector and electric scalpel to release medial collateral ligament and pes anserinus. METHODS: From September 2009 to September 2012, 220 patients with unilateral osteoarthritis were treated with primary TKA in hospital 301. All the patients were randomly divided into periosteal dissector group (110 cases) or electric scalpel group (110 cases). In the periosteal dissector group, there were 47 males and 63 females,with an average age of (58.8 +/- 17.2) years old; the degree of genuavarus was (14.0 +/- 3.5) degrees; the weight was (65.6 +/- 12.8) kg; the body mass index (BMI) was (26.6 +/- 3.6) kg/m2. In the electric scalpel group,there were 49 males and 61 females,with an average age of (59.6 +/- 16.7) years old;the degree of genuavarus was (15.0 +/- 4.7) degrees; the weight was (66.4 +/- 13.4) kg; the BMI was (27.4 +/- 4.1) kg/m2. The mean follow-up period was 24.6 months. The AKS, VAS and HSS were used to evaluate clinical results. RESULTS: All incisions healed at the first stage;no deep vein thrombosis of lower limbs or pulmonary embolism occurred. Knee infection occurred in 3 cases (1 in the periosteal dissector group and 2 in the electric scalpel group), and the 3 patients received stage 2 total knee revision using antibiotic bone cement and TC3 prosthesis. No recurrence of infection occurred during follow-up. Among the 20 patients who had anterior knee pain, 16 patients were in the periosteal dissector group and 4 patients were in the electric scalpel group. The occurrence rate of anterior knee pain in the electric scalpel group was lower than that in the periosteal dissector group. The AKS knee score and HSS score after total knee arthroplasty in the electric scalpel group were all higher than those in the periosteal dissector group, and the VAS in electric scalpel group was lower than that of periosteal dossector group. CONCLUSION: Compared with using electric scalpel,using periosteal dissector used to release medial collateral ligament and pes anserinus may cause more anterior knee pain after total knee arthroplasty. PMID- 25029831 TI - [Comparison of therapeutic effects between patella replacement and patella osteotomy in total knee arthroplasty: a case-control study]. AB - OBJECTIVE: To compare therapeutic effects between patella replacement and patella osteotomy in total knee arthroplasty. METHODS: From April 2004 to April 2011, 52 patients (54 knees) were enrolled in the clinical trail of total knee arthroplasty, who received patella replacement (24 knees, including 13 males and 11 females,ranging in age from 53 to 78 years old or patella osteotomy (30 knees,including 16 males and 12 females,ranging in age from 55 to 79 years old. The average follow-up period was 56 months,ranging from 20 to 80 months. The American HSS Score for knee, the Feller score for patella, range of motion (ROM) for knee, patient satisfaction and complications related to the patella were used to evaluate therapeutic effects. RESULTS: In the patella replacement group,the preoperative and final follow-up HSS scores of patients were 38.4 +/- 8.2 and 91.2 +/- 8.6 respectively; Feller scores were 13.6 +/- 6.2 and 25.2 +/- 4.2; scores of anterior knee pain were 3.9 +/- 3.2 and 11.2 +/- 3.7; ROM were (78 +/- 26) degrees and(108 +/- 18) degrees. In the patella osteotomy group,the preoperative and final follow-up HSS scores of patients were 39.5 +/- 8.4 and 91.0 +/- 8.5 respectively;Feller scores were 13.4 +/- 6.5 and 25.6 +/- 4.0; scores of anterior knee pain were 3.7 +/- 3.1 and 11.3 +/- 3.6; ROM were (76 +/- 27) degrees and (110 +/- 19) degrees. In the patella replacement group,patient's satisfaction was 91%, and complication related to the patella was 16.7%; in the patella osteotomy group, patient's satisfaction was 89%, and complications related to the patella was 10.0%. There were no statistically significant differeneces in final follow-up HSS scores, Feller scores, scores of anterior knee pain and ROM between the two groups. However,there was no significant difference of patient's satisfaction between them. There was statistically significant differenece of patella-related complications between the two groups, and the complication rate in the patella replacement group was higher than that in the patella osteotomy group. CONCLUSION: Total knee arthroplasty with patella replacement or patella osteotomy dramatically relieves pain and improves the knee function. Patella-related complications are associated with its treatment methods, but post-operative anterior knee pain and patient's satisfaction are not related to treatment methods of the patella. PMID- 25029832 TI - [Case-control study on modified femoral prosthesis in reducing the incidence of patellar clunk syndrome after the initial posterior stabilized total knee arthroplasty]. AB - OBJECTIVE: To explore therapeutic effects of modified femoral prosthesis applied in the initial posterior stabilized total knee arthroplasty. METHODS: From April 1, 2012 to January 1, 2013, 156 patients with knee osteoarthritis underwent posterior stabilized total knee arthroplasty by the same director of orthopedic surgeon. Sixty-one patients were treated with modified femoral prosthesis, including 7 males and 54 females, with an average age of (68.34 +/- 5.41) years old; and 95 patients were treated with conventional designed femoral prosthesis, including 14 males and 81 females, with an average age of (69.92 +/- 5.11) years old. Indexes including age, body mass index, Insall-Salvati index, type of prosthesis, occurrence rate of patella click syndrome, postoperative line of force of lower extremity and postoperative function of the knee joint were observed and recorded. And American Knee Society (AKS) score was used to evaluate the clinical results. RESULTS: All the patients were followed up, and the duration ranged from 36 to 56 weeks, with a mean of 45.31 weeks. Among patients in the conventional designed femoral prosthesis group, 7 patients had patella click syndrome, but there was no patient having patellar click syndrome in the modified femoral prosthesis group. Postoperative knee activity of patients in the modified femoral prosthesis group was (110.98 +/- 10.32) degrees, which was better than (107.05 +/- 8.61) degrees in the conventional designed femoral prosthesis group. The AKS score in the modified femoral prosthesis group was 129.79 +/- 9.63 during 21 to 28 days after operation, which was higher than 126.85 +/- 7.79 in the conventional designed femoral prosthesis group. CONCLUSION: New designed femoral components are effective to reduce the occurrence rate of postoperative patellar click syndrome and obtain better early functional recovery from knee surgery. PMID- 25029833 TI - [Application of transcutaneous electrical nerve stimulation to multimodal analgesia after total knee arthroplasty]. AB - OBJECTIVE: To study the effects of transcutaneous electrical nerve stimulation on multimodal analgesia after total knee arthroplasty. METHODS: Sixty patients diagnosed as knee osteoarthritis and suffered unilateral total knee arthroplasty in the department of orthopedics, Zhejiang Traditional Chinese Medicine Hospital from March 2009 to May 2012 were randomly divided into control group and test group, 30 cases in each group. All the patients received celecoxib preoperatively, knee periarticular injection with the drug mixture intraoperatively, and celecoxib and morphine sulfate controlled-release tablets postoperatively. The patients in the test group were also treated with transcutaneous electrical nerve stimulation each day after operation. All the patients started doing functional exercises at 24 h after operation. Postoperative visual analogue scales(VAS), passive and active range of motion of knee joint,and complications were recorded. RESULTS: The VAS scores of test group during postoperative 24 h to 1 week were 3.39 +/- 0.69, 2.79 +/- 0.51, 2.16 +/- 0.52, and 1.07 +/- 0.57 separately,which were lower than 3.80 +/- 0.86, 3.22 +/- 0.58, 2.53 +/- 0.54 and 1.38 +/- 0.52 in the control group. The passive and active range of knee joint motion in the test group during postoperative 24 h to 2 weeks were (30.67 +/- 3.65) degrees, (39.17 +/- 3.96) degrees, (47.83 +/- 4.86) degrees, (93.67 +/- 7.30) degrees, (107.67 +/- 7.51) degrees and (29.83 +/- 5.33) degrees, (78.33 +/- 8.24) degrees, (95.17 +/- 5.94) degrees respectively,which were higher than (28.67 +/- 3.92) degrees, (36.83 +/- 4.25) degrees, (45.17 +/- 5.17) degrees, (89.83 +/- 7.25) degrees, (103.17 +/- 7.37) degrees and (24.17 +/- 10.26) degrees, (73.83 +/- 9.07) degrees, (91.33 +/- 7.42) degrees in the control group. In the test group, 19 patients had ring-shaped haemostasis impression to some extent in the skin of knee joint to different degree, and 5 patients had blister formation. CONCLUSION: It is meaningful to apply transcutaneous electrical nerve stimulation for treating multimodal analgesia after total knee arthroplasty,which can not only relieve patients' postoperative pain, and also promote the rehabilitation of knee function as far as possible. PMID- 25029834 TI - [Case-controll study on the synergistic effects of electroacupuncture on knee osteoarthritis after arthroscopic debridement]. AB - OBJECTIVE: To study the synergistic effects of electroacupuncture on the treatment of knee osteoarthritis after arthroscopic debridement. METHODS: From May 2008 to July 2010, 78 patients with knee osteoarthritis were randomly divided into two groups. There were 42 patients in the experimental group, including 16 males and 26 females, ranging in age from 41 to 63 years, with an average of (53.62 +/- 6.53) years; the disease course ranged from 8 to 24 months, with an average of (10.35 +/- 6.42) months. The patients were treated with arthroscopic debridement combined with electroacupuncture after operation. There were 36 patients in the control group, including 14 males and 22 females, ranging in age from 40 to 62 years, with an average of (54.34 +/- 7.67) years; the disease course ranged from 6 to 25 months, with an average of (11.94 +/- 5.13) months. Those patients were treated only with arthroscopic debridment. All the patients performed isometric quadriceps femoris contraction exercise and knee flexion and extension activities after operation. The visual analog scale(VAS) score and Lysholm knee score were used to evaluate the therapeutic effects. RESULTS: All the patients were followed up, and the duration ranged from 12 to 30 months, with an average of 15.6 months. At the final follow-up, VAS score was significantly decreased, and the Lysholm score, except for the item demanding for support, significantly increased, compared with those before surgery respectively in both groups. There was significant difference in VAS score between two groups after treatment. As to Lysholm score, there were significant differences in limp, pain, swelling, stair activity and squat, but there were no significant differences in items of interlocking and instability between two groups after treatment. CONCLUSION: Electroacupuncture can effectively improve the clinical symptoms and knee joint's motor function of knee joints in patients with knee osteoarthritis, as well as the synergistic effects on the treatment of knee osteoarthritis after arthroscopic debridement, leading to a much better long-term therapeutic effect with respect of improving the function of knee joint. This therapy, combined with traditional Chinese medicine and Western Medicine,is worth of clinical application in the treatment of knee osteoarthritis. PMID- 25029835 TI - [Case-control study on the treatment of patients with scapular muscle fasciitis by Pizhen]. AB - OBJECTIVE: To evaluate and analyze the mechanism of Pizhen for the treatment of patients with scapular muscle fasciitis. METHODS: One hundred and sixteen patients were divided into two groups according to random number table method, 58 cases in the treatment group and 58 cases in the control group. After treatment, 109 patients were followed up, and 7 patients lost follow-up (2 cases in the treatment group and 5 patients in the control group). In the treatment group, there were 15 males and 41 females, with a mean age of (28.02 +/- 4.85) years; the course of disease ranged from 0.25 to 3 years; and the patients were treated by Pizhen once a week,and 2 weeks were one treatment course. In the control group, there were 19 males and 34 females, with a mean age of (27.23 +/- 4.54) years old; the course of disease ranged from 0.25 to 1 year; and the patients were treated by acupuncture massage instrument, 20 minutes at a time,once a day for 2 weeks. Soft tissue displacement and banana area were tested by a soft tissue tension tester, pressure value was measured by pressure measuring instrument, and VAS was recorded by pain visual analog scale record. RESULTS: There were significant differences in tissue displacement, banana area, pressure value and VAS between two groups before and after treatment. The tissue displacement and pressure value in the treatment group were higher than those in the control group,while banana area and VAS were lower than those in the control group. In the treatment group, 30 patients healed, 13 patients got marked improvement, 12 good and 1 poor;while 16 patients healed, 19 patients got marked improvement,11 good and 7 poor in the control group. The therapeutic effects in the treatment group was better than that in the control group. CONCLUSION: Pizhen is an effective method to treat pain in patients with scapular muscle fasciitis by relaxing tendon of soft tissue around pain point of scapular and relaxing compress and stimulation of nerves. PMID- 25029836 TI - [Case-control study on therapeutic effects of ozone and triamcinolone acetonide on the treatment of meniscal injury]. AB - OBJECTIVE: To compare the clinical therapeutic effects between ozone and triamcinolone acetonide for the treatment of mild meniscal injury. METHODS: From January 2008 to December 2012, 119 patients with meniscal injury diagnosed as type I or II by MRI were divided into three groups. In the triamcinolone acetonide (A) group, there were 38 males and 2 females, with an average age of (25.34 +/- 6.34) years old, ranging from 18 to 48 years old; 36 patients had single knee injuries, 4 patients had double knee injuries and 44 knees with joint effusion. In the ozone (B) group,there were 37 males and 2 females, with an average age of (26.98 +/- 7.20) years old, ranging from 19 to 50 years old; 33 patients had single knee injuries, 6 patiens had double knees injuries and 40 knees with joint effusion. In the combination of ozone and triamcinolone acetonide (C) group, there were 37 males and 3 females,with an average age of (26.44 +/- 6.38) years old, ranging from 18 to 47 years old; 33 patients had single knee injuries, 7 patients had double knees injuries and 39 knees with joint effusion. The patients were treated with injection of 3 mg triamcinolone acetonide alone, 30 ml (30 microg/ml) ozone alone, or both two drugs respectively in knee joint cavity. All the treatment methods were carried out weekly and 4 times injections were required for a treatment course. Knee joint function was evaluated by Lysholm scale and knee joint effusion was examined by MRI before and after treatment. RESULTS: The scale of knee joint function was 35.68 +/- 4.15 and 65.55 +/- 7.66 in group A, 36.35 +/- 6.83 and 74.39 +/- 8.47 in group B, 36.62 +/ 6.03 and 95.47 +/- 4.78 in group C before and after treatment. Compared with that before treatment, the total scale of knee joint function improved after treatment in every group. The total scale of group C was better than that of the other groups after the treatment,but there was no significant difference between group A and group B. The effective rate of these drugson joint effusion was 68.18% in group A, 62.5% in group B and 87.18% in group C. The effect of co injection on joint effusion in group C was significantly better than that of triamcinolone acetonide or ozone alone, but the difference between group A and group B was not significant. CONCLUSION: Ozone and triamcinolone acetonide are effective in the treatment of mild meniscal injury, which can relieve symptoms and promote the recovery of joint function. Campared with the single injection, the combination of ozone and triamcinolone acetonide is better. PMID- 25029837 TI - [Case-control study on manipulation following arthroscopic capsular release for the treatment of frozen shoulder]. AB - OBJECTIVE: To compare therapeutic effects between the normal rehabilitation and combined with manipulative method after arthroscopic capsular release for the treatment of severe frozen shoulder, and to evaluate the application value of manipulationp. METHODS: From March 2007 to July 2010,arthroscopic capsular release was performed in 48 cases (48 shoulders, 23 left side, 25 right side). All the patients were divided into two groups: control group (11 males and 15 females) and manipulation group (9 males and 13 females). The patients in the control group were treated with conventional rehabilitation procedure, and the patients in the manipulation group were treated with additional manipulation procedure. From the 2nd day after operation, the manipulation was performed for 20 minutes every time, twice daily, and it continued for 10 days. All the cases were followed up and the scale of American Shoulder and Elbow Surgeons Standardized Assessment Form (ASES self-report section) and the range of motion (ROM) were recorded. RESULTS: The mean follow-up period was (12.54 +/- 5.78) months (ranging from 4 to 25 months). Both ASES scores and ROM in the manipulation group were better than those in the control group at the 1st month after operation, and the difference between the ASES scores and flexion of the shoulder were significant. However, there was no significan difference at the latest follow-up. CONCLUSION: Compared with the conventional rehabilitative procedure, manipulation following arthroscopic capsular release could promote the process of joint rehabilitation and help the patient back to normal life earlier, but there is no evidence of long term advantage. PMID- 25029839 TI - [Digital artery bilobed flap for the treatment of skin degloving injury of thumb]. AB - OBJECTIVE: To explore clinical effects of digital artery bilobed flap for the treatment of skin degloving injury of thumb. METHODS: From January 2007 to December 2012, 45 patients with skin degloving injury of thumb were treated with grafting of digital artery bilobed flap. There were 39 males and 6 females, ranging in age from 19 to 46 years, with an average of 32 years. The disease course ranged from 0.5 to 15 h. Eighteen patients suffered from defect of palmar skin above nail root and nail bed, 19 patients suffered from skin degloving injury of thumb phalangette, and 8 patients had whole skin degloving injury of thumb. The double lobe flaps were designed at the ulnar side of middle finger and the radial side of ring finger according to the defect of thumb skin. The arteria digitalis communis between the middle and ring fingers and its two branches of arteriae digitales propriae supplying the two fingers were used as a vessel pedicle. The flap with digitales proprii nervi was transposed and used to cover the exposed phalanx of thumb. Full thickness graft was used for the donor site. Observation of the appearance, texture, color and wear resistance of flap, appearance, color and depression of grafting area, skin feeling, and finger activities was conducted. RESULTS: All the flaps and grafts were alive. Forty three patients were followed up with an average duration of 25 months, and two patients lost follow-up. The color and texture of the flaps were similar to that of the contralateral thumb pulp. The average two point discrimination was 4.2 +/- 0.3 mm. The color of graft skin was slightly deeper than that of the surroundings skin. CONCLUSION: Digital artery bilobed flap graft is an effective and ideal operation, which is of low risk and high success rates for skin degloving injury of thumb. PMID- 25029838 TI - [Correlative analysis on metatarsalgia and the X-ray measurement indexes under weight-bearing and non-weight-bearing of hallux valgus]. AB - OBJECTIVE: To study changes in the radiographic appearance during weight-bearing and non-weigh-bearing in hallux valgus, and to analyse the correlation between the elasticity of plantar soft tissue of hallux valgus and the pain under the metatarsal head. METHODS: From May 2012 to October 2012, 240 feet of 120 patients with hallux valgus were enrolled in the study. The degrees of the pian under the metatarsal head of all the patients were observed. AP and lateral X-ray films of feet were taken on the condition of weight-bearing and non-weight-bearing. So the hallux valgus angle (HVA), the inter-metatarsal angle between the first and second metatarsals (IM1-2), the inter-metatarsal angle between the first and fifth metatarsals (IM1-5), top angle of the medial longitudinal arch (TAOTMLA),and anterior angle of the medial longitudinal arch (AAOTMLA) were measured on the X-ray films. The differences of HVA, IM1-2, IM1-5, TAOTMLA and AAOTMLA between two groups were compared, and the correlation between the changes of IM1-2, IM 1-5, TAOTMLA, AAOTMLA and the degree of the pain under the metatarsal head were analysed. RESULTS: One hundred and forty-eight feet had the pain under the metatarsal head. The IM1-2, IM1-5 and TAOTMLA increased on weight bearing position compared with those on non-weight-bearing position, but the HVA and AAOTMLA decreased on weight-bearing position compared with those on non weight-bearing position. There was a moderate relationship between the changes of IM 1-2,IM1-5 and the degree of the hallux valgus deformity, as well as the relationship between the different of IM1-5 and the degree of the pian under the metatarsal head. CONCLUSION: The degree of the collapse of the arch of foot with hallux valgus becomes serious with its deformity increasing. The pain under the metatarsal head of hallux valgus increases with the increased changes of IM 1 2,IM 1-5 and TAOTMLA. Analysis of the X-ray observation indexes of hallux valgus on weight-bearing position and non-weight-bearing position has important significance in evaluating the degree of the collapse of the arch of foot with hallux valgus,preventing and curing the the pain under the metatarsal head. PMID- 25029840 TI - [Case-control study on close manipulative reduction combined with minimally invasive percutaneous plate fixation for the treatment of proximal humeral fractures]. AB - OBJECTIVE: To compare the clinical effects of close manipulative reduction combined with minimally invasive percutaneous plate fixation(MIPPO) and conventional open reduction and internal fixation (ORIF) for the treatment of proximal humerus fractures. METHODS: From April 2008 to March 2013, among the 75 patients with fractures of proximal humerus, 26 patients were male and 49 patients were female, ranging in age from 22 to 80 years; 18 patients had injuries caused by traffic accident and 57 patients had injuries caused by falling down. According to Neer classification, there were 49 cases of two-part fractures and 26 cases of three-part fractures. All the patients were divided into two groups: MIPPO group and ORIF group. There were 12 males and 21 females in the MIPPO group,including 22 cases of Neer two parts and 11 cases of Neer three parts, who were treated with close manipulative reduction combined with MIPPO. While the other 42 patients were in the ORIF group,including 16 males and 26 females. Among those patients,27 cases belonged to Neer two parts and 15 cases of Neer three parts, who were treated with ORIF. Length of the incision, blood loss, operating time, early postoperative pain(recorded by VAS), neck-shaft angle of proximal humerus and postoperative function of shoulder(recorded by Constant Murley score, including pain, function, ROM and muscle length) were compared. RESULTS: The mean lengths of incision were (6.74 +/- 0.38) cm in MIPPO group and (16.82 +/- 1.74) cm in ORIF group;blood losses were (110.15 +/- 29.49) ml in MIPPO group and (326.19 +/- 59.71) ml in ORIF group; operation times were (48.60 +/- 10.18) min in MIPPO group and (68.84-16.22) min in ORIF group. VAS of patients in MIPPO group on the 1st and 3rd days postoperatively were lower than those of patients in the ORIF group. The postoperative radiographs verified good position of all screws and satisfactory reduction of bone fracture reduction in both groups. All the patients were followed up,and the durig ranged from 8 to 24 months (mean 14.2 months). In the MIPPO group, there was no humeral head necrosis and all patients gained bone union; while in the ORIF group, 3 patients sustained nonunion and received reoperation for bone grafting, and 2 patients sustained humeral head necrosis. The mean Constant-Murley scores of shoulder were 88.94 +/- 2.57 in the MIPPO group and 86.00 +/- 3.36 in the ORIF group. CONCLUSION: The close manipulative reduction combined with MIPPO is a better choice for fixation of proximal humerus fractures, compared with conventional plate. This method possesses such advantages as a shorter incision, less disturbance of the blood supply and stable fixation of the fracture, allowing early exercise so that the function of shoulder recovers rapidly. PMID- 25029841 TI - [Three-dimensional finite element analysis on mechanical behavior of the bone remodeling and bone integration between the bone-implant interface after hip replacement]. AB - OBJECTIVE: To discuss the primary stability of the fixed interface between the cementless prosthesis and femur, and its influence on bone ingrowth and secondary stability under the roughened surface and press fit of different prostheses by finite element analysis. METHODS: :A three-dimensional finite element module of total hip arthroplasty (THA) was developed with Mimics software. There was a collection of data when simulating hip arthroplasty. The frictional coefficient between the fixed interface was 0,0.15,0.40 and 1.00 representing the roughness of prosthesis surface. The press fit was 0, 0.01,0.05 and 0.10 mm according to the operation. The Vion Mises stress distribution and the contact pressure,friction stress and relative sliding displacement between the interface were analysed and compared when simulating the maneuver of climbing stairs. RESULTS: At a fixed press fit of 0.05 mm,the contact pressure between the interface was 230 , 231, 222 and 275 MN under four different frictional coefficient (0,0. 15,0.40 and 1.00) with little change; the relative sliding displacement was 0.529, 0.129, 0.107 and 0.087 mm with a consistent and obvious decline. As the fixed frictional coefficient was 0.40,the contact pressure between the interface were 56.0,67.7 ,60.4 and 49.6 MN under four different press fit (0, 0.01, 0.05 and 0.10 mm) with a reduction; the relative sliding displacement was 0.064,0.062,0.043 and 0.042 mm with an obvious decline, and there was a maximal friction stress when press fit of 0.01 mm. CONCLUSION: There is a dynamic process of the bone remodeling and bone integration between the interface after hip replacement, determining the long-term outcome. The interface clearance and the frictional coefficient are the key factors of the bone integration. PMID- 25029842 TI - [Anatomy study on the fixation technique of buttress plate in the posterior column of the acetabulum]. AB - OBJECTIVE: To solve the problem of screw penetrating the joint surface easily by determining the angle of inclination and the mean longth screw plated on the posterior column. METHODS: Ten specimens of adult male cadavers, aged 20 to 74 years old, averaged 54.5 years old, were collected. After removal of the bilateral femurs from the hip joints, and sawing through the sacral and pubic symphysis in the median sagittal plane, 20 semi pelvic specimens were used for this study when the osseous abnormalities were excluded. The specimens were air dried naturelly after the soft tissue attaching to the pelvis had been eliminated. The margin of superior acetabular and inferior acetabular were determined, and the serial cross-sections of the acetabular posterior column were made. The width of posterior column,the width of acetabulum,the width ratio of acetabulum to posterior column, the angle of inclination and the mean length of screw on all entry points were measured. Defined the level parallel to 1/2 section of superior acetabulum was cross-section B; 1/2 section of acetabulum was C; 1/2 section of inferior acettabulum was D. At the different levels, defined the entry point on the outer edge of posterior column of the acetabulum or the trailing edge of acetabulum was B0, C0 or D0; lateral 1/2 of posterior column of the acetabulum was B1, C1 or D1; 1/2 of posterior column of the acetabulum was B2, C2 or D2; medial 1/2 of posterior column of the acetabulum was B3, C3 or D3; the inner edge of posterior column of the acetabulum was B4,C4 or D4. RESULTS: On cross-section B, the angle of inclination and the mean length of screw at B0 was 41 degrees and 44.0 mm; at B1 was 66 degrees and 42.2 mm; at B2 was 91 degrees and 59.5 mm; at B3 was 107 degrees and 64.0 mm; the maximum angle and the mean length at point B4 was 123 degrees and 65.5 mm; the minimum angle and the mean length at point B4 was 109 degrees and 59.0 mm. On cross-section C,the angle and the mean length at point CO was 39 degrees and 39.0 mm; at C1 was 57 degrees and 36.0 mm; at C2 was 74 degrees and 36.0 mm;at C3 was 90 degrees and 36.0 mm; at C4 was 106 degrees and 76.0 mm. On cross-section D,the angle and the mean length at DO was 42 degrees and 35.5 mm; at D1 was 61 degrees and 33.0 mm; at D2 was 81 degrees and 32.0 mm; at D3 was 100 degrees and 31.0 mm; at D4 was 120 degrees and 74.0 mm. CONCLUSION: When using the fixation technique of acetabular posterior column plate, the angles of screw-posterior column are 40 degrees to 60 degrees, 60 degrees to 75 degrees, 75 degrees to 90 degrees and 90 degrees to the angle of parallel to the square area respectively on the region of outer 1/4,outer-middle 1/4,inner-middle 1/4 and inner 1/4 of the acetabulum region, and the screw length is 30 mm. PMID- 25029843 TI - [Effect of the anterior aspect of sacral nerve root tunnel on iliosacral screw placement on the standard lateral image of sacrum]. AB - OBJECTIVE: To introduce the location and course of S1, S2 sacral nerve root tunnel and to clarify the significance of the anterior aspect of sacral nerve root tunnel on placement of iliosacral screw on the standard lateral sacral view. METHODS: Firstly the data of 2.0 mm slice pelvic axial CT images were imported into Mimics 10.0, and the sacrum, innominate bones, and sacral nerve root tunnels were reconstructed into 3D views respectively, which were rotated to the standard lateral sacral views, pelvic outlet and inlet views. Then the location and course of the S1, S2 sacral nerve root tunnel on each view were observed. RESULTS: The sacral nerve root tunnel started from the cranial end and anterior aspect of the vertebral canal of the same segment and ended up to the anterior sacral foramen with a direction from cranial-posterior-medial to caudal-anterior-lateral. The tunnel had a lower density than the iliac cortex and greater sciatic notch on the pelvic X-rays,especially on the standard sacral lateral view, on which it showed up as a disrupted are line and required more careful recognition. CONCLUSION: It can prevent the iliosacral screw from penetrating the sacral nerve root tunnel and vertebral canal when recognizing the anterior aspect of sacral nerve root tunnel and choosing it as the caudal-posterior boundary of the "safe zone" on the standard lateral sacral view. PMID- 25029844 TI - [Over-articular external fixator combined with limited internal fixation for the treatment of high-energy Pilon fractures]. AB - OBJECTIVE: To study clinical effects of the over-articular external fixator combined with limited internal fixation for the treatment of Pilon fractures caused by high energy. METHODS: From September 2003 to April 2011, 36 patients with Pilon fractures caused by high energy were treated with the over-articular external fixator combined with limited internal fixator. There were 25 males and 11 females, ranging in age from 16 to 72 years old,with an average of 38 years old. The diagnoses of all patients were determined by conventional X-ray examination or three-dimensional spiral CT examination. The AOFAS scoring criteria was used to evaluate the therapeutic effects. The patients with comminuted fractures were treated with screw or Kirschner wire fixation without uncovering periost so as to enhance stability between fracture end and bone blocks,followed by the fixation with over-articular external fixators. RESULTS: All the patients were followed up, and the duration ranged from 4 to 27 months, with an average of 13 months. Thirty-two patients got wound healing at the first stage. And the bone union duration ranged from 2 to 6 months, with a mean of 3 months. According to the AOFAS ankle-hindfoot subjective scoring standard, 13 patients got an excellent result, 20 good and 3 fair, with an score of 88.2 +/- 3.6. Twelve patients had infections at pinhole, 5 patients had pinhole pain. One patient had the fixator broken induced by over loading, who was cured after treatment. There were no complications such as nerve or vascular injuries, or osteomyelitis. CONCLUSION: The over-articular external fixation combined with limited internal fixation for the treatment of Pilon fractures caused by high energy is an ideal method, which has such advantages as reliable fixation, simple operation, coincidence with principles of biomechanical fixation, and benefit for fracture healing. PMID- 25029845 TI - [Case-control study on the modified ilioinguinal incision of anterior approach for the treatment of pelvic and acetabular fractures]. AB - OBJECTIVE: To study modified ilioinguinal approach through the retrospective analysis on the surgical treatment of 63 patients with pelvic and acetabular fractures through anterior approach. METHODS: From January 2006 to January 2013, 63 patients with pelvic and acetabular fractures were treated with the ilioinguinal anterior approach, including 45 males and 18 females, ranging in age from 12 to 68 years old, with an average of (37.71 +/- 13.41) years old. All the patients were divided into two groups: standard ilioinguinal anterior approach group (group A) and modified ilioinguinal anterior approach group(group B). In group A, there were 26 males and 11 females, with an average age of (38.49 +/- 13.64) years old. In group B, there were 19 males and 7 females, with an average age of (36.62 +/- 13.29) years old. Intraoperative and postoperative indicators in group A and B were observed and compared, including operation incision exposure time (from skin incision to complete the ilioinguinal in front of three "windows"), the blood loss, incision close time and treatment effect of Majeed function score. RESULTS: Compared to group A, the incision exposure time of patients in group B was shorter, the blood loss (bleeding during exposure process) was less, and the close incision time was shorter, but the treatment effect of Majeed function score had no significant differences between two groups. All the patients were followed up, and the during ranged from 3 to 36 months, with an average of (18.6 +/- 9.2) months. According to Matta standard assessment reduction of pelvic and acetabular fracture, there were 28 patients got an excellent result, 8 good, and 1 fair in the group A; and 20 patients got an excellent result, 5 good, and 1 fair in the group B. According to Majeed function score for hip function, 20 patients got a satisfactory result, 12 good,4 fair and 1 poor in group A, and the mean score was 82.51 +/- 9.72; and 13 patients got an satisfactory result, 10 good, 3 fair and 0 poor in group B, and the mean score was 80.54 +/- 10.79. CONCLUSION: The modified approach has several advantages as follows: providing a good surgical exposure; preventing from the injury of femoral nerve, femoral artery and vein under the inguinal ligament; not needing to open the inguinal canal, which can avoid the occurrence of inguinal hernia, reduce operation prodedures and shorten operation time. PMID- 25029846 TI - [Minimally invasive treatment for distal radial fracture and dislocation of type IV based on Fernandez classification]. AB - OBJECTIVE: To investigate the effects of external fixation combined with minimally invasive internal fixation for the treatment of distal radial fracture and dislocation of type IV based on Fernandez classification. METHODS: From January 2007 to October 2012,19 patients with the distal radius fracture and dislocation of type IV according to Fernandez classification were reviewed. There were 14 males and 5 females,ranging in age from 22 to 42 years old,with an average of 36.5 years old. All the patients were treated with minimally invasive reduction, and external fixation with finite internal fixation. The K-wire was used to fix radiolunate articular surface for correcting the instability of dorsal and volar intercalated segment. The radiolunate angle, scapholunate angle, and the length of the radial shorting were measured by the standard X-ray. Gartland and Werley evaluation system was used to evaluate recovery of function. RESULTS: No complications such as injury of blood vessels and radial nerves and pin track infections occurred. After operation, the radiolunate angle, scapholunate angle and the length of the radial shorting time were (9.5 +/- 3.3) degrees, (51.3 +/- 11.2) degrees and (11.2 +/- 1.8) mm by the standard X-ray. On the 3rd month after operation, GW score was 3.02 +/- 3.05. There was no re displacement and subluxation occurred during the follow-up period. Good functional recovery were improved wrist function significantly. CONCLUSION: External fixation combined with minimally invasive internal fixation can treat distal radial fracture and dislocation of type IV based on Fernandez classification. Wrist joint stability depends on the structure of the bone and ligament around wrist joint. Emphasis on the diagnosis and treatment of carpal instability, and postoperative functional rehabilitation can improve wrist function. PMID- 25029847 TI - [Percutaneous screw fixation for the treatment of pelvic fractures under C-arm fluoroscopy]. AB - OBJECTIVE: To investigate the applications of percutaneous screw fixation for the treatment of pelvic fractures and its related surgical considerations. METHODS: From June 2010 to June 2012,19 patients with pelvic fractures were treated with percutaneous hollow screws. There were 13 males and 6 females, with an average age of 41 years (ranged from 22 to 58 years). Fractures were caused by traffic accidents in 11 cases, by falling down from high place in 8 cases. Based on the Tile classification, there were 15 cases of Tile C type and 4 case of Tile B type. The indexes such as screw inserting time, intraoperative blood loss, complications, functional recovery and reduction conditions were observed. Fixation methods included sacroiliac screws, cannulated screw fixation of the pubic ramus and cannulated screw fixation of the pubic symphysis separation. RESULTS: Anatomical reduction achieved in 7 cases, satisfactory reduction 11 cases, and unsatisfactory reduction 1 case. Union time of fracture union ranged from 8 to 12 weeks (mean 10 weeks). Wound infection,ununion of fracture and nerve injuries were not found. According to the Majeed standards, 12 patients obtained an excellent results, 6 good and 1 fair. CONCLUSION: Percutaneous screw fixation for the treatment of pelvic fractures under fluoroscopy has several advantages such as less trauma, less blood loss, fewer rates of complications, reliable fixation and no blood transfusion, which can reconstruct the stability of the pelvic ring, but it needs adequate preoperative preparation and high requirements for the surgeon. PMID- 25029848 TI - [Severe infection of low limb open wound after surgery: a case report]. PMID- 25029849 TI - [Progress on prevention for anterior knee pain after primary total knee arthroplasty]. AB - Total knee arthroplasty (TKA) identified as an effective treatment for ultimate knee joint disease can effectively relieve pain, correct deformity, improve knee function and enhance the quality of life of patients. Patient satisfaction has been increasingly considered as an important factor in evaluating the success of primary TKA. Anterior knee pain that usually appears in the region of the anterior knee is a recognized complaint for primary TKA and has a strong impact on the improvement of knee function and patient satisfaction of primary TKA. Accordingly, the relief of anterior knee pain has become one of the primary goals of primary TKA. At present, soft tissue lesions around the patellar caused by patellar maltracking and the elevation of internal pressure in subchondral bone because of the high contact stress of patellofemoral joint are both considered as the mechanism of anterior knee pain. For the past few years,on increasing number of studies have focused on the prevention of anterior knee pain following primary TKA. However, none of the past treatment such as patellar resurfacing, patellar denervation without patellar resurfacing or a mobile-bearing prosthesis has a good and affirmative effect on it. The prevention and treatment of anterior knee pain following primary TKA still is a difficult solved problem. To address this problem, we need further researches about the cause of anterior knee pain, knee joint prosthesis and biomechanics of patellofemoral joint, as well as lots of randomized controlled trials. PMID- 25029850 TI - [Risks and benefits: new concepts of treatment of late-onset hypogonadism]. AB - Late-onset hypogonadism (LOH) is a clinical and bio-chemical syndrome associated with advancing age in males and seriously affects the quality of life of some of the patients. A classical therapeutic option for LOH is testosterone supplementary treatment (TST). Its effectiveness has been verified, whereas its long-term safety remains to be further evaluated. With deeper insights into LOH, many new therapeutic strategies have been proposed, which include the treatments with gonadotropins, testosterone precursors (such as dehydroepiandrosterone [DHEA]), non-aromatizable androgens (such as dihydrotestosterone [DHT]), antiestrogens (such as aromatase inhibitors and estrogen receptor antagonists), and Chinese medicine. Meanwhile, studies on the transplantation of Leydig stem cells, selective androgen receptor modulators (SARMs), and selective estrogen receptor beta (ERbeta) agonists have shed new light on the treatment of LOH. PMID- 25029851 TI - [Changes of mechanical pain threshold in rats with experimental autoimmune prostatitis]. AB - OBJECTIVE: To observe the changes of the mechanical pain threshold in the rat model of autoimmune prostatitis, explore the mechanism of autoimmune prostatitis pain and offer some animal experimental evidence for the drug therapy of the condition. METHODS: Twenty male Wistar rats weighing 180 - 220 g were divided into a model and a control group. The autoimmune prostatitis model was established by subcutaneous injection of an extract of male rat prostate glands (RPG) at 60 mg/ml in Freund's complete adjuvant (FCA) and pertussis-diphtheria tetanus vaccine at 0 and 30 days, respectively. Mechanical tactile hyperalgesia was measured once a week using Von Frey Filaments from the beginning of the study. At 8 weeks after modeling, the rats were sacrificed and the prostate tissues harvested for observation of histomorphological changes by HE staining. RESULTS: HE staining revealed different degrees of benign prostatitis in the model rats. Compared with the controls, the mechanical pain threshold in the model rats was significantly decreased with the increased time of modeling, from (65.52 +/- 6.27) g at 0 week to (23.67 +/- 4.09) g at 8 weeks (P < 0.01). Statistically significant differences were found in the variation trend at different time points between the two groups (P < 0.01). CONCLUSION: Autoimmune prostatitis models were successfully established in rats and hyperalgesia was induced after modeling. PMID- 25029852 TI - [MiR-124 suppresses the proliferation of human prostate cancer PC3 cells by targeting PKM2]. AB - OBJECTIVE: To explore the mechanism of miR-124 inhibiting the proliferative activity of prostate cancer PC3 cells. METHODS: Luciferase reporter gene assay was used to examine the specific binding ability of miR-124 to PKM2 mRNA 3'-UTR. After miR-124 was transfected mimic to PC3 cells, the expression levels of PKM2 mRNA and protein were detected by real-time fluorescence quantitative PCR (qRT PCR) and Western blot, respectively. The effects of miR-124 mimic and PKM2 siRNA on the proliferative activity of the PC3 cells were determined by MTT assay. RESULTS: The expressions of PKM2 mRNA and protein were upregulated (5.12 +/- 0.35) times and (4.05 +/- 0.20) times respectively in the PC3 cells as compared with those in the RWPE-1 cells (P < 0.05). Luciferase reporter gene assay demonstrated that miR-124 targeted PKM2 3'-UTR. At 24 hours after transfection with miR-124 mimic, the PKM2 protein expression in the PC3 cells was downregulated (0.16 +/- 0.04) times (P < 0.05), while the PKM2 mRNA level was not changed significantly (P > 0.05), as compared with the control group. MTT assay showed that both miRNA-124 mimic and PKM2 siRNA could inhibit the proliferation of the PC3 cells, but the former exhibited a greater inhibitory effect than the latter. After transfection with miR-124 mimic and PKM2 siRNA, the cell growth rates were (66.20 +/- 5.10)% vs (82.10 +/- 6.35)% at 24 hours (P < 0.05) and (49.34 +/- 2.37)% vs (70.10 +/- 5.80)% at 48 hours (P < 0.05). CONCLUSION: miR 124 can suppress the proliferation of PC3 cells by regulating the PKM2 gene. PMID- 25029853 TI - [Microbubbles targeted to P-selectin for evaluating testicular ischemia reperfusion injury in rabbits]. AB - OBJECTIVE: To explore the feasibility of evaluating complete ischemia-reperfusion injury (IRI) of the testis by contrast-enhanced ultrasonography with microbubbles (MB) targeted to P-selectin (MBp) in rabbits. METHODS: We randomly divided 30 healthy adult rabbits into five groups of equal number (control, 0.5 h IRI, 1 h IRI, 2 h IRI, and 4 h IRI), prepared phospholipid MB and MBp, and performed contrast-enhanced ultrasonography of the bilateral testes with MB or MBp at an interval of 20 min at different times after IRI. When MB or MBp disappeared completely in the healthy testis at 4 to 5 min after intravenous injection, we recorded the power of the first frame (F-P) in the IRI testes followed by immunohistochemical staining of the testis tissue. RESULTS: CEU with MBp achieved a significantly higher F-P than that with MB in all the IRI groups (P < 0.05), which was (8.34 +/- 1.20) versus (1.87 +/- 0.25) 10(-5) AU at 2 hours, but there was no significant difference between MB and MBp in the control rabbits (0 AU, P > 0.05). Immunohistochemistry showed a significantly time-dependent increase in the expression of P-selectin in the vascular endothelial cells of the IRI testes, but not in those of the control. CONCLUSION: Contrast-enhanced ultrasonography with MBp can be used to evaluate the inflammatory reaction of testicular ischemia reperfusion injury. PMID- 25029854 TI - [Anatomical variability of the left spermatic vein and establishment of the experimental left varicocele model in adolescent rats]. AB - OBJECTIVE: To identify the anatomical variability of the left spermatic vein (LSV) and determine its effect on the induction of experimental left varicocele (ELV) in adolescent rats. METHODS: We equally randomized 30 adolescent male SD rats to groups A (LSV collaterals fully ligated and the left renal vein constricted), B (only the left renal vein constricted), and C (sham operation), observed the courses of the LSVs and measured their diameters. At 30 days after operation, we analyzed the changes in the left kidneys and the diameters of the LSVs. RESULTS: Irregular collaterals were observed in 90% of the LSVs and no abnormal changes were found in the left kidneys after surgery. The postoperative LSV diameter was remarkably increased in group A as compared with the baseline ([1.47 +/- 0.15 ] vs [0.16 +/- 0.08] mm, P < 0.01), but showed no significant difference in group B ([0.31 +/- 0.49] vs [0.15 +/- 0.07] mm, P > 0.05) and C ([0.17 +/- 0.07] vs [0.16 +/- 0.06] mm, P > 0.05), and it was significantly longer in A than in B (P < 0.01). The success rate of ELV induction was 100% in group A and 10% in group B, but no varicocele was observed in group C. CONCLUSION: Correct identification of the anatomical course of the LSV and ligation of its irregular collaterals are essential for the establishment of a stable and consistent ELV model. PMID- 25029855 TI - [Oral-appliance for erectile dysfunction induced by obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To evaluate the effect of the oral-appliance in the treatment of ED induced by obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: This study included 40 cases of OSAHS-induced ED. Based on the apnea-hyponea index (AHI) and lowest SaO2, we divided the patients into groups A (AHI < or = 30/h and lowest SaO2 > or = 80%) and B (AHI > 30/h and lowest SaO2 < 80%), and treated them with the oral-appliance for 3 months, followed by evaluation of the therapeutic effect using polysomnography, IIEF-5 questionnaire and Sexual Encounter Profile (SEP) diaries. RESULTS: Thirty-seven of the patients accomplished the treatment, 16 in group A and 21 in group B. Compared with the baseline, the AHI was significantly decreased in both groups A (21.4 +/- 7.3 vs 14.2 +/- 6.6, P < 0.05) and B (51.4 +/- 9.5 vs 29.7 +/- 8.1, P < 0.05) after treatment, the IIEF-5 scores increased, even more remarkably in B than in A (3.36 +/- 2.48 vs 1.12 +/- 1.27, P < 0.05). The positive rates of SEP2 and SEP3 were markedly lower in A than in B (37.5% vs 76.2% and 25.0% vs 61.9%, P < 0.05). CONCLUSION: The oral-appliance can improve the erectile function of OSAHS-induced ED patients, particularly for those with severe OSAHS. PMID- 25029856 TI - [Basic features of the ISUP prostate carcinoma Gleason grading system: a preliminary analysis]. AB - OBJECTIVE: To explore the basic features of the prostate carcinoma Gleason grading system of the International Society of Urological Pathology (ISUP). METHODS: We analyzed the means and proportions of the Gleason score (GS), primary grade (PG), secondary grade (SG) and third grade (TG) of 667 cases of prostate carcinoma. RESULTS: The means of GS, PG, SG and TG were 7.06 +/- 1.10, 3.53 +/- 0.66, 3.53 +/- 0.72 and 4.30 +/- 0.96, respectively. The cases with GS 5, 6, 7, 8, 9 and 10 accounted for 0.4% (3/677), 37.2% (252/677), 34.4% (233/677), 13.7% (93/677), 12.0% (81/677) and 2.2% (15/677), respectively; those with GS < or = 6 and > or = 7 constituted 37.7% (255/677) and 62.3% (422/677); those with GS3 + 3, 4 + 3 and 3 + 4 made up 37.2% (252/677), 19.2% (130/677) and 15.2% (103/677); and the TG cases held 10.3% (70/677), including 30.0% (21/70) of grade 3, 10% (7/70) of grade 4 and 60.0% (42/70) of grade 5. CONCLUSION: Our study showed a high proportion of GS, a low proportion of GS < or = 6, and a high proportion of GS > or = 7 in the ISUP prostate carcinoma Gleason grading system. TG of GS needs to be further understood. PMID- 25029857 TI - [Association of 8-hydroxyguanine glycosidase OGG1 Ser326Cys polymorphism with male infertility]. AB - OBJECTIVE: To explore the association of 8-hydroxyguanine glycosidase OGG1 Ser326Cys polymorphism with semen quality and the risk of male infertility. METHODS: This case-control study included 620 idiopathic infertile patients and 385 normal fertile controls. We determined their genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and analyzed their semen quality by computer-aided semen analysis (CASA). RESULTS: The individuals with OGG1 326 Cys/Cys showed significantly lower sperm motility and concentration ([52.1 +/- 26.7]% and (3.75 +/- 0.91) x 10(6)/ml, ln transformed value) than the Ser/Ser carriers ([59.0 +/- 21.8] % and (4.12 +/- 0.88) x 10(6)/ml, ln transformed value) (P < 0.05). The risk of male infertility increased 69% in the OGG1 326Cys allele carriers as compared with the Ser carriers (OR = 1.69, 95% CI: 1.24 -2.31). CONCLUSION: OGG1 326 Ser/Cys polymorphism might contribute to the risk of male infertility in the southern Chinese population. PMID- 25029858 TI - [Influence factors on the cryosurvival rate of post-thaw spermatozoa from sperm donors]. AB - OBJECTIVE: To investigate the influence of seasons, blood types and semen parameters on the cryosurvival rate of frozen-thawed spermatozoa from sperm donors. METHODS: We retrospectively analyzed the influence of seasons, blood types, abstinence period, semen volume, sperm morphology, and pre-freeze sperm motility and concentration on the cryosurvival rate of frozen-thawed sperm in 4 088 semen samples from Shaanxi Human Sperm Bank. RESULTS: The cryosurvival rate of the post-thaw sperm was correlated negatively with the progressive motility of the pre-freeze sperm (r = -0.262, P < 0.01), but positively with pre-freeze sperm concentration (r = 0.247, P < 0.01), and it was significantly higher in the 6-day abstinence group ([70.2 +/- 5.4]%) than in the other abstinence groups (P < 0.01), so was it in the normal sperm morphology rate > 20% group ([71.4 +/- 5.1]%) than in the others (P < 0.01). The survival rate of the post-thaw sperm was not correlated with seasons, blood types, and semen volume (P > 0.05). CONCLUSION: Sperm motility, concentration and morphology and the abstinence period of sperm donors may be valuable predictors of the cryosurvival rate of post-thaw sperm, but no correlation was found between the survival rate and seasons, blood types and semen volume. PMID- 25029859 TI - [Transurethral enucleation plus pneumo-cystostomy rotary cut for large benign prostatic hyperplasia]. AB - OBJECTIVE: To investigate the feasibility, effectiveness and practicability of transurethral enucleation plus pneumocystostomy rotary cut (TUE + PCRC) for large benign prostatic hyperplasia (BPH). METHODS: We performed TUE + PCRC for 26 BPH patients aged 62 - 85 years with the prostate volume of 80 - 165 ml. We conducted transurethral enucleation of the hyperplastic prostate glands and pushed them into the bladder, followed by bladder puncture for pneumo-cystostomy rotary cut. RESULTS: All the surgical procedures were successfully accomplished, with the mean surgical time of 41 (32 - 54) minutes and intraoperative blood loss < 60 ml in all the cases. Twenty-three of the patients were followed up for 2 - 8 months, which revealed no stricture of the urethra or any other severe complications. Compared with the preoperative baseline, significant improvement was achieved in the IPSS (6.5 +/- 2.2 vs 26.2 +/- 2.4), QOL (1.4 +/- 0.9 vs 4.6 +/- 1.2) and Qmax ([5.8 +/- 1.0 ] vs [19.6 +/- 2.8] ml/s) of the patients after surgery (P < 0.01). CONCLUSION: TUE + PCRC, with its advantages of short operation time and less severe complications, is a safe and effective approach to the management of large BPH. PMID- 25029860 TI - [Spermatic vein ligation and intra-vaginal ejaculation latency]. AB - OBJECTIVE: To investigate the intra-vaginal ejaculation latency time (IELT) of varicocele patients, the influence of spermatic vein ligation on IELT, and the relationship of Visual Analogue Score (VAS) with IELT. METHODS: We selected 112 males who had regular sexual life after spermatic vein ligation and conducted follow-up visits for 6 months. According to preoperative IELT, we divided the patients into an IELT < or = 2 min group and an IELT > 2 min group, and compared their IELT, VAS and Chinese Index of Sexual Function for Premature Ejaculation-5 (CIPE-5) scores before and 6 months after operation. RESULTS: Follow-up was accomplished in 81 of the patients, 18 in the IELT < or = 2 min group and 63 in the IELT >2 min group. Compared with the baseline, IELT was significantly prolonged postoperatively in both the IELT < or = 2 min group ([1.26 +/- 0.37] vs [4.53 +/- 1.69] min, P < 0.01) and the IELT >2 min group ([5.14 +/- 2.03] vs [7.69 +/- 4.51] min, P < 0.05); the postoperative CIPE-5 scores were remarkably improved in the former (11.27 +/- 3.52 vs 15.64 +/- 2.37, P < 0.05) but insignificantly in the latter group (20.42 +/- 4.65 vs 21.83 +/- 5.49, P > 0.05); the postoperative grades of the CIPE-5 scores showed significant differences in both groups (chi2 = 6.353, P = 0.042 and chi2 = 3.910, P = 0.048); the postoperative VAS was markedly increased (3.18 +/- 0.92 vs 1.56 +/- 0.83 and 3.24 +/- 0.95 vs 1.74 +/- 0.79, P < 0.05), with significant differences in the grades of VAS in both groups (chi2 = 4.433, P = 0.035 and chi2 = 10.088, P = 0.001). The variation of VAS was negatively correlated with that of IELT in both groups (r = 0.572, P < 0.01 and r = -0.465, P < 0.05). CONCLUSION: Varicocele may be one of the causes of premature ejaculation, and some of the varicocele patients with IELT < or = 2 min may benefit from spermatic vein ligation. Improved VAS is negatively correlated with prolonged IELT. The relationship between varicocele and premature ejaculation deserves further studies. PMID- 25029861 TI - [Transurethral seminal vesiculoscopy combined with finasteride for recurrent hematospermia]. AB - OBJECTIVE: To evaluate the clinical effectiveness of transurethral seminal vesiculoscopy (TUSV) combined with finasteride in the treatment of recurrent hemospermia. METHODS: This study included 32 patients with recurrent hematospermia, with the disease course of 3 months to 4 years. After administration of finasteride at 5 mg/d for 2 weeks, the patients underwent TUSV for both exploration of the causes and treatment, followed by medication with finasteride at the same dose for another 2 weeks. Postoperative follow-up was conducted for observation of the outcomes and complications. RESULTS: TUSV was successfully accomplished in all the 32 cases, which revealed 16 cases of seminal vesiculitis, 10 seminal calculi, 1 seminal vesicle cyst, 2 seminal vesicle polyps, and 3 seminal vesicle abscess. The operative time was 20 to 51 (31.0 +/- 5.2) minutes. Postoperative complications included 1 case of acute epididymitis and 3 cases of breast discomfort within the first 4 weeks. No incontinence, urethral stricture, rectal injury, retrograde ejaculation, and sexual dysfunction occurred postoperatively. All the patients but 1 were followed up for 6 months to 2 years. Twenty-nine of the cases were cured, and 2 experienced recurrence. CONCLUSION: Transurethral seminal vesiculoscopy combined with finasteride is safe and effective for the treatment of recurrent hemospermia. PMID- 25029862 TI - [Shenfu injection induces the apoptosis of prostate cancer PC-3 cells]. AB - OBJECTIVE: To study the effect of Shenfu Injection (SF) on the apoptosis of prostate cancer PC-3 cells and its possible mechanism. METHODS: We divided prostate cancer PC-3 cells into a blank control group and three experimental groups, the latter treated with SF at 50, 100, and 200 microl/ml, respectively, for 24, 48, and 72 hours. Then we determined the proliferation of the cells by MTT assay, measured their apoptosis by Annexin V/PI flow cytometry, and detected the expression of P53 mRNA by RT-qPCR. RESULTS: Compared with the blank control group, the survival rates of the prostate cancer PC-3 cells in the 50, 100, and 200 microl/ml SF groups were (93.76 +/- 2.63)%, (81.21 +/- 1.80)% and (18.01 +/- 3.84)% at 24 hours, (94.67 +/-1.11)%, (78.33 +/- 2.89)% and (10.34 +/- 1.44)% at48 hours, and (91.30 +/- 0.47)%, (36.67 +/- 1.56)% and (1.33 +/- 0.32)% at 72 hours, all significantly increased in a dose- and time-dependent manner (P < 0.05). The expression of p53 mRNA was also markedly increased in all the three experimental groups at 48 hours (P < 0. 05). CONCLUSION: SF can inhibit the proliferation and induce the apoptosis of PC-3 cells, which may due to its upregulation of the p53 mRNA expression. PMID- 25029863 TI - [Recurrent implantation failure: gamete and embryo factors]. AB - Despite the immense achievement in the field of IVF in recent years, many patients still suffer from recurrent implantation failure. Therefore, much attention has been drawn to its etiology and treatment. Chromosomal abnormality, sperm DNA damage, zona hardening, and inappropriate culture conditions are important factors that lead to recurrent implantation failure. Results of studies suggest that preimplantation genetic screening does not improve the rate of implantation or live birth. Comparative genomic hybridization array and single nucleotide polymorphism array could offer a more comprehensive screening of chromosomes. Assisted hatching may help to solve the problem of zona hardening in some situations. Co-culture and blastocyst transfer could be conducive to the improvement of the rates of implantation and pregnancy. Cytoplasmic transfer may give a solution to ooplasmic composition anomalies. PMID- 25029864 TI - [Melatonin regulates ovarian function: an update]. AB - Melatonin (N-acetyl-5-methoxytryptamine, MT) is a hormone synthesized and secreted by the pineal gland. Recent studies show that melatonin plays an essential role in the pathogenesis of many reproductive processes. High concentration melatonin exists in human preovulatory follicular fluid and melatonin receptors are present in ovarian granulosa cells, which indicates the direct effects of melatonin on ovarian function. Reactive oxygen species are involved in a number of reproductive events, including folliculogenesis, follicular atresia, ovulation, oocyte maturation, and corpus luteum formation. Melatonin and its metabolites, as powerful antioxidants and free radical scavengers, can potentially inhibit premature ovarian failure. Literature published in recent years shows the essential roles of melatonin in improving human ovarian function and oocyte quality as well as in the management of infertility. Researches on the action mechanisms of melatonin may provide a theoretical basis for the prevention and treatment of some clinical diseases. PMID- 25029865 TI - [Spinal gastrin-releasing peptide system mediates sexual function of males: advances in studies]. AB - A collection of neurons in the upper lumbar spinal cord (lumbar segments 3 and 4) of male rats project to the lower lumbar spinal cord (lumbar segments 5 and 6) and release a gastrin-releasing peptide (GRP) to the somatic and autonomic regions, which are known to regulate male sexual reflexes. The GRP plays some special functions when bound to the specific GRP receptor (GRPR). The spinal GRP system is regulated by androgens. Accumulating evidence shows that GRP plays an important role in rat penile erection and ejaculation, and pharmacological stimulation of GRPRs with a specific agonist can restore penile reflexes and ejaculation in castrated male rats. Therefore, the GRP system appears to be a potential therapeutic target for the treatment of erectile dysfunction or ejaculatory dysfunction. The present paper briefly reviews the recent studies on the role of the spinal GRP system in regulating the sexual function of males. PMID- 25029866 TI - [Pathogeneses of erectile dysfunction after rectal cancer treatment]. AB - Rectal cancer is a common malignancy in the alimentary tract with an increasing incidence, the current treatments of which include surgery, radiotherapy, chemotherapy, and integrated comprehensive options. Sexual dysfunction, especially erectile dysfunction (ED), is one of the commonest complications in men after rectal cancer treatment and is generally attributed to the damage to the pelvic autonomic nerves. However, recent studies show that ED after rectal cancer treatment is a complex pathophysiological process associated with neurogenic, vasculogenic, and psychological factors. This article reviews the pathogeneses of ED after rectal cancer treatment in order to provide some theoretical evidence for its prevention and treatment. PMID- 25029867 TI - Meta-analysis of drug-eluting versus bare metal stents in patients with indications for oral anticoagulation undergoing coronary stenting. AB - BACKGROUND: Current expert consensus recommends the use of bare metal stent (BMS) for patients with an indication for oral anticoagulation (OAC) undergoing coronary stenting. The use of drug-eluting stents (DES) should be limited. However, there is a lack of evidence to support these recommendations. We performed a meta-analysis to compare the efficacy and safety of DES to BMS in these patients. METHODS: We searched PubMed, Embase, the Cochrane library, and relevant journals. Studies comparing the efficacy and safety of DES to BMS in patients with an indication for OAC undergoing coronary stenting were included. End points included major adverse cardiac events (MACE), death, bleeding complications, and stroke. The outcome assessments were measured by hazard ratio (HR) and its 95% confidence interval. RESULTS: We yielded 453 studies by primary searching. According to the inclusion criteria, four studies enrolling 1,522 patients were finally included. A pooled estimate of HR for MACE, all-cause mortality, myocardial infarction, and bleeding complications showed no significant differences between patients treated with DES and BMS. The risk of target vessel revascularization (TVR) was significantly decreased in the DES implanted patients in comparison with patients with a BMS implantation. CONCLUSION: For patients with an indication for OAC undergoing coronary stenting, DES might a DES can be as safely used as a BMS, and is superior in reducing the risk of TVR. PMID- 25029868 TI - Reperfusion strategy for patients with renal dysfunction presenting with STEMI: which is better in the North African context? AB - BACKGROUND: Patients with renal insufficiency experience worse prognosis after STEMI. The current guidelines do not clearly draw specific strategies for patients with renal dysfunction (RD). AIM: The aim of this study is to compare primary PCI (PPCI) and thrombolysis results as well as in-hospital mortality after successful reperfusion between the RD patients (RD+) and patients with normal renal function (RD-). METHODS: We retrospectively reviewed data for 1,388 patients admitted for STEMI between January 1995 and October 2011. Two groups were identified: PPCI (315 patients) and thrombolysis (379 patients). Ninety patients (13%) had RD defined by creatinine levels at admission > 130 micromol/l, they were equally treated by PPCI and thrombolysis. RESULTS: In the PPCI group, despite a similar pre-procedural TIMI flow (P = 0.82),TIMI III restoring was significantly lower in the RD+ group (78.6% vs. 91.8%, P = 0.013). Suboptimal result was also higher in the RD+ group (13.6% vs. 2.7%, P < 0.001), but ST regression after TIMI III achievement was similar in the 2 groups (P = 0.43), probably reflecting no microvascular damage. In the thrombolysis group, successful reperfusion was also significantly lower when RD exists (58% vs. 74%, P = 0.03). After successful reperfusion, RD+ patients experienced higher in hospital mortality in the PPCI group (29% vs. 4.3%; P < 0.001), whereas mortality was similar in the thrombolysis group (3% vs. 0%, P = 0.42). CONCLUSION: RD reduces either PPCI or thrombolysis success, with no proven microvascular damage after PPCI. In-hospital prognosis, however, is worse in the RD group only after successful PPCI, but not after successful streptokinase thrombolysis. PMID- 25029869 TI - Frequency of angina and quality of life in outpatients with stable coronary artery disease in Turkey: insights from the PULSE study. AB - OBJECTIVE: Cardiologists' approach to angina in outpatients with stable coronary artery disease (CAD) is unclear. Therefore, we analysed data from the national multicentre, observational PULSE study to evaluate the frequency of angina, clinical variables affecting angina frequency and the impact of frequent angina on quality of life (QoL) in outpatients with stable CAD managed by cardiologists in secondary and tertiary health-care centres in Turkey. METHODS AND RESULTS: Adult outpatients with stable CAD in sinus rhythm were included. Data were collected at a single study visit from 83 centres. Patients were divided into five categories according to angina attack frequency. QoL was measured by the MacNew heart disease health-related QoL Questionnaire. The mean (standard deviation; SD) age of all patients (n = 2661) was 61.2 (10.2) years. Of 2,661 patients, 48.7% had no anginal attacks while 16.5% had minimal, 14.5% occasional, 12.2% regular and 8.1% frequent attacks. Angina attack frequency correlated positively with female sex, heart rate, the severity of angina. Emotional, physical, social, and global scores of QoL tended to decrease across angina attack frequency categories. Short- and long-acting nitrates, ivabradine were significantly more preferred in patients with higher frequency of angina attacks rather than beta blockers and calcium channel blockers. CONCLUSIONS: Insufficient angina control in outpatients with stable CAD requires reassessment of medical approach since it has a negative impact on QoL. The social and economic consequences of this burden should be sought on a national basis. PMID- 25029870 TI - Novel hybrid management for aortic dissection with crevasse in the vicinity of critical branching: report of 53 cases. AB - Open surgery for aortic dissection with crevasse in the vicinity of critical branching (CVCB-AD) is frequently associated with several complications and a high mortality rate. We report the management of 53 patients with CVCB-AD who underwent a novel hybrid procedure including both open surgery and endovascular stenting. During the follow-up period no paraplegia, stroke, renal failure, or bleeding was observed, and no elective or emergency surgical conversion was required, suggesting that this hybrid procedure is a feasible, safe, and effective strategy for the treatment of CVCB-AD. PMID- 25029871 TI - Percutaneous mitral valve repair in high-risk patients: initial experience with the Mitraclip system in Belgium. AB - AIMS: Treatment with percutaneous edge-to-edge mitral valve repair (Mitraclip) has recently been recommended as an alternative to conventional mitral valve repair for high surgical risk patients with symptomatic severe mitral regurgitation (MR). In this study, we report the first use of Mitraclip therapy in Belgium. METHODS AND RESULTS: This prospective registry includes 41 consecutive patients treated with the Mitraclip in two Belgian centres from October 2010 to June 2013. Acute procedural success, in-hospital safety end points and clinical status were analysed on an intention-to-treat basis up to one year after the procedure. In addition, determinants of major adverse cardiac events (MACE, death, surgical mitral valve intervention, and rehospitalization for heart failure) were analysed. Acute procedural success (successful clip placement and reduction of colour Doppler flow MR to < or = 2) was obtained in 32 patients (78%) and 18 of these patients received two clips. The primary safety end point was reached in 36 pts (88%): one patient died due to intracranial bleeding, there were three urgent surgical interventions and one severe access site bleeding. The MACE rate after one year was 41% (17 patients). There were 11 deaths (27%), six surgical interventions (15%) and 10 rehospitalizations for heart failure (24%). Additional subgroup analysis revealed that the one-year MACE rate was particularly high in patients with left ventricular ejection fraction (LVEF) < 25%: 62% vs. 36% in patients with LVEF > or = 5% (P = 0.05). At one year, MR < or = 2+ and NYHA class < or = 2 was present in 83% of the surviving patients CONCLUSION: In high-risk patients with functional MR, treatment with the Mitraclip-device is a feasible and safe option resulting in improvement of MR severity and clinical symptoms. However, as MACE is high in some subgroups (e.g. LVEF < 25%), careful patient selection is crucial to ensure the maximum benefit from this new technique. PMID- 25029872 TI - Prevalence and outcome of diastolic dysfunction in liver transplantation recipients. AB - OBJECTIVE: Cirrhotic cardiomyopathy (CCMP) denotes a chronic cardiac dysfunction in cirrhotic patients. It is characterized by systolic (SD) and diastolic dysfunction (DD), and electromechanical abnormalities, in the absence of other cardiac diseases. Liver transplantation (LTx) has a favourable effect on CCMP, but CCMP is in itself a risk factor. Aims of the study were (1) to estimate the prevalence of DD among LTx candidates, (2) to compare outcome between patients with and without DD, and (3) to determine if tricuspid regurgitation (TR) is a predictor of post-transplantation outcome. METHODS: 173 LTx recipients were retrospectively evaluated. Diagnostic criteria for SD and DD were a resting ejection fraction < 55% and an E/A ratio < 1 or a deceleration time > 200 msec on echocardiography, respectively, according to the criteria proposed during the World Congress of Gastroenterology in Montreal, 2005. The difference in outcome between patients with and without DD was evaluated in terms of mortality and cardiovascular complications post-transplantation. RESULTS: SD and DD were diagnosed in 3 (2%) and 74 (43%) patients, respectively. Patients with DD had significantly older age (P < 0.0001). Regarding outcome, no statistically significant difference could be documented. Moderate/severe TR is, in contrast to no or mild TR, associated with worse posttransplantation outcome (P = 0.01 short term, P = 0.02 long-term). CONCLUSION: In this study population, a prevalence of SD and DD of 2% and 43%, respectively, was registered. Outcome does not seem to be strongly affected by the presence of DD. Tricuspid regurgitation severity on echocardiography is predictive of survival. PMID- 25029873 TI - Comparing echocardiographic assessment of systolic function with catheterization data in patients with single right ventricles. AB - PURPOSE: Echocardiographic evaluation of systolic function in patients with single right ventricles (SRV) is important but remains challenging. Minimal data exist correlating echocardiographic indices with catheterization data in this population. The goal of this study was to evaluate which echocardiographic measurement correlated best with dP/dt (max) obtained by cardiac catheterization in SRV patients. METHODS: Patients with SRV physiology who underwent simultaneous echocardiography and cardiac catheterization were evaluated. Echocardiographic data included fractional area change % (FAC), displacement, TDI s'wave, myocardial performance index (MPI), global systolic strain, and global SR s wave. Maximum positive rate of ventricular pressure change measured as dP/dt (max) was obtained from the cardiac catheterization report. Correlations of echocardiographic and catheterization variables were examined using the Pearson correlation. RESULTS: Twenty-seven SRV patients were studied. Median age at the time of the catheterization was 11.4 months (range 0 - 132 months). dP/dt (max) values ranged from 337-1860 mmHg/s with a median of 994 mmHg/s. Mean FAC was 27.15 +/- 7.13%, displacement was 7.35 +/- 2.88 mm, TDI s' was 4.98 +/- 1.93 cm/sec, MPI was 0.41 +/- 0.17, global strain was-14.85 +/- 4.32%, and global SR s wave was -1.03 +/- 0.34 sec(-1). There were no significant correlations between dP/dt (max) and any of the echocardiographic measurements of systolic function in SRV patients. CONCLUSION: In patients with SRV physiology, catheterization derived dP/dt (max) did not correlate with echocardiographic measurements of systolic function. Larger studies are needed to determine which non-invasive parameter best describes systolic function in patients with SRV. PMID- 25029874 TI - Occurrence of poor sleep quality in atrial fibrillation patients according to the EHRA score. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia that affects the quality of life by causing deleterious health consequences, and impairing sleep quality. The severity of AF symptoms may range from very mild to the very intense which can be assessed by the European Heart Rhythm Association (EHRA) score. The aim of the study was to assess the prevalence of poor sleep quality in AF patients, in relation to the symptom severity based on the EHRA score. METHODS: 177 consecutive patients, hospitalized between 2011 and 2013 with non valvular AF and no history of myocardial infarction, stroke or decompensation of heart failure within the last 6 months, were enrolled into the study. Sleep quality was assessed by the Pittsburg Sleep Quality Index (PSQI) in all patients at admission. Medical history and data concerning AF symptoms and severity by the EHRA score were gathered by a qualified physician. RESULTS: Poor sleep quality was present in 49.7% of patients. Patients with poor sleep quality were more often females (66.6% vs. 35.8%; P = 0.007), were older (57.9 +/- 10.1 vs. 53.9 +/ 10.0 years; P = 0.005), and had higher systolic blood pressures (134.4 +/- 16.4 vs. 129.8 +/- 17.8 mmHg; P = 0.03). Poor sleep quality was present in 33.3% of the EHRA I group, 43.9% of the EHRA II group, 58.1% of the EHRA III group, and 61.5% of the EHRA IV group (p value for trend 0.01). CONCLUSIONS: Poor sleep quality is highly prevalent in AF patients, affecting approximately half of them. It is related to the severity of symptoms, and prevalence rises with every degree of the EHRA score. PMID- 25029876 TI - Cardiac rhabdomyoma mimicking haemodynamics of hypoplastic left heart syndrome. AB - Cardiac rhabdomyomas are rare and often regress spontaneously. However, the management of rhabdomyoma with severe inflow and outflow obstructions is a challenge. An infant with a massive left ventricular rhabdomyoma mimicking the haemodynamics of hypoplastic left heart syndrome is reported. Surgery could not be contemplated because the mitral valve leaflets and chordae were imbedded in the tumour mass. The arterial duct (AD) was kept open to perfuse the systemic circulation and palliations with pulmonary artery branch banding and AD stenting were planned. However; while waiting for spontaneous regression of the tumour, the child died of circulatory collapse when 4 weeks old. PMID- 25029875 TI - Biofeedback on heart rate variability in cardiac rehabilitation: practical feasibility and psycho-physiological effects. AB - OBJECTIVE: Biofeedback is a self-regulation therapy by which the patient learns how to optimize the functioning of his autonomic nervous system. It has been applied to patients with various cardiovascular disorders. The purpose of this study was to investigate the practical feasibility and the psychophysiological effects of biofeedback applied to heart rate variability (HRV biofeedback) in order to increase cardiac coherence in coronary artery disease (CAD) patients participating in a cardiac rehabilitation programme. METHODS AND RESULTS: In this randomised and controlled study, 31 CAD patients were randomly assigned to an experimental or to a control group. The experimental group participated in a programme of 10 sessions of cardiac coherence biofeedback training, in addition to the rehabilitation programme. The control group participated in the usual cardiac rehabilitation programme only. Physiological variables (systolic and diastolic blood pressure, SDNN) and psychosocial variables (anxiety, depression, type D personality) were measured at the start and at the end of the programme in both groups. Statistical comparisons assessed the inter and intra group differences. The small sample size precludes any firm conclusions concerning the effect of cardiac coherence biofeedback on physiological or psychological variables. However, we observed a significant increase of the percentage of cardiac coherence, in relation with an increased SDNN index. CONCLUSIONS: Our study demonstrated the practical feasibility of cardiac coherence biofeedback training in CAD patients. Further research is desirable to investigate the potential benefit of cardiac coherence biofeedback as an adjunct to stress management in cardiac rehabilitation. PMID- 25029877 TI - Resection of giant mediastinal liposarcoma. PMID- 25029878 TI - Pneumopericardium after permanent pacemaker implantation. PMID- 25029879 TI - A rare consequence of malignant hypertension. PMID- 25029880 TI - A calcified left ventricular mass. AB - Mitral annular calcification is a degenerative process. It is mostly asymptomatic. As the calcification becomes more extensive it might be mistaken for an intracardiac tumour. Mitral annular calcification predicts cardiovascular events, cardiovascular death and overall death. It is predictive of a doubling of the stroke risk. Extensive mitral annular calcification may undergo liquefaction. Surgery is seldom needed. PMID- 25029882 TI - A patient with progressive dyspnoea and a new heart murmur. AB - A 74-year-old man was referred to the outpatient clinic of the cardiology department with progressive dyspnoea and a new heart murmur. Physical examination of the chest wall showed a hard immobile and painless sternal swelling at the level of the angulus of Ludovici. There was an increase of the velocities across the pulmonary valve (continuous Doppler) on echocardiography as a result of the RVOT and pulmonary trunk stenosis. Computed tomography (CT) of the chest revealed a mass in the anterior mediastinum which had grown through the sternum into the skin, as well as an external compression of the ascending aorta, the truncus pulmonalis and the pericardium. Anatomo-pathological examination revealed a non small-cell lung carcinoma. PET CT showed another nodule with FDG uptake in the right kidney, suspected for metastasis, and an uptake in a right paratracheal lymph node. The tumour was staged as a cT4cN2M1b. Palliative radiochemotherapy was started. The patient had a good clinical and radiographic response, but relapsed a few months later. PMID- 25029881 TI - Congenital anomalous coronary sinus ostium. AB - Congenital anomalous coronary sinus ostium is extremely rare. We describe a case of congenital left atrial coronary sinus ostium in a patient scheduled for ablation for atrial fibrillation. The anomalous coronary sinus ostium was found when contrast was injected during the ablation procedure and was confirmed by cardiac computed tomography. PMID- 25029883 TI - Large bronchogenic cyst compressing the left atrium. AB - Bronchogenic cysts are listed among the less common mediastinal tumours and either remain unnoticed and are randomly found or they are manifested with respiratory or thoracic symptoms such as chest pain, dyspnoea, haemoptysis and recurrent thoracic infections. More severe symptoms (e.g. sepsis, compression) are rare. We present a case of a male patient with progressive dyspnoea on exertion attributed to a large bronchogenic cyst. PMID- 25029885 TI - An irregular approach of right atrial lead placement in a patient with persistent left superior vena cava and concomitant agenesis of the right-sided superior vena cava. AB - Persistent left superior vena cava (PLSVC) is the most common venous anomaly of the thorax. It could lead to catheter malplacement and even vascular injuries. We describe an unusual way to deliver a right atrial (RA) endocardial pacing lead in a 61-year-old female with a PLSVC concomitant agenesis of the right-sided SVC. After failed attempts with the standard procedure, we placed the RA lead tip in the PLSVC near the right auricle. The pacemaker worked well after one and 17 months of follow-up. We conclude that when placement of the RA lead fails, the PLSVC near the right auricle could be a next choice in the RA lead placement in patients with PLSVC concomitant agenesis of the right-sided SVC. PMID- 25029884 TI - Interrupted aortic arch with retrograde subclavian perfusion. AB - Type B interrupted aortic arch results in the left subclavian artery being perfused by a patent ductus arteriosus and antegrade flow is usually seen in the left subclavian artery. We describe a case of retrograde perfusion of the left subclavian artery through the circle of Willis in the presence of interrupted aortic arch type B and a restrictive patent ductus arteriosus. This is similar to subclavian steal syndrome when the perfusion pressure from the cerebral circuit is greater than that from the left subclavian artery. Early recognition of this phenomenon may alter management by indicating restriction at ductal level. This case highlights the need for a comprehensive review of both ventricular systolic function and ductal haemodynamics when retrograde flow is seen in the subclavian artery. PMID- 25029886 TI - Left lateral free wall pathway ablation complicated by plaque rupture and acute occlusion of the left anterior descending coronary artery. AB - Radiofrequency (RF) ablation of accessory bypass tracts associated with the Wolff Parkinson-White (WPW) syndrome has become the treatment of choice for many arrhythmias. Complications are unusual and acute coronary artery occlusion is very rare. We here present a 38-year-old male patient with an acute occlusion of proximal left anterior descending (LAD) coronary artery after RF ablation of a left free wall accessory pathway. An interesting feature is the site of the coronary artery occlusion which is remote from the RF application site. The occlusion was successfully treated with the placement of an intracoronary stent. PMID- 25029887 TI - Diaphragm fibrillation--an incidental finding detected by transoesophageal echocardiography. AB - We present a case of diaphragmatic fibrillation (with a frequency of 600/min) in a patient at the early post-operative stages. In view of the decreased oxygen saturation and confusion, the patient was sedated and mechanically ventilated. His declining physical condition was partially associated with diaphragmatic fibrillation superimposed on heart failure and lung disease. The transthoracic echocardiography was technically difficult. Consequently, transoesophageal echocardiography was undertaken. This is the first case report presenting diaphragmatic fibrillation as an incidental finding on transoesophageal echocardiography. PMID- 25029888 TI - Almanac 2013: heart failure. PMID- 25029889 TI - Pedal errors among younger and older individuals during different pedal operating conditions. AB - OBJECTIVE: The objective of this study was to investigate the characteristics of pedal errors by younger and older drivers that relate to sudden unintended acceleration (SUA) accidents. BACKGROUND: SUA during an accident is a serious issue that causes numerous critical injuries and deaths every year. Previous studies have indicated that the major factor in these accidents is pedal error; however, the characteristics that relate to SUA accidents in older drivers remain unclear. METHOD: Twenty younger drivers (YDs; 23.1 +/- 0.22 years) and 20 older drivers (ODs; 68.9 +/- 1.16 years) used either one or both feet to participate in six tasks that involved pressing accelerator or brake pedals in response to various visual stimuli. RESULTS: Both the reaction times (RTs) and the pedal error rates of theYD and OD groups significantly increased with the difficulty of the task. Other than the simple reaction condition, we found that the pedal error rates were significantly higher for the OD group than for the YD group; the OD group also demonstrated longer RTs. Moreover, the rates of accelerator error were consistently two or three times higher than the rates of brake error in both theYD and OD groups. CONCLUSION: For the older population, the use of the left foot to operate the brake pedal and the right foot to operate the accelerator could decrease the accelerator error rate and may reduce the rate of SUA-related accidents that are caused by pedal error. PMID- 25029890 TI - Failure to detect critical auditory alerts in the cockpit: evidence for inattentional deafness. AB - OBJECTIVE: The aim of this study was to test whether inattentional deafness to critical alarms would be observed in a simulated cockpit. BACKGROUND: The inability of pilots to detect unexpected changes in their auditory environment (e.g., alarms) is a major safety problem in aeronautics. In aviation, the lack of response to alarms is usually not attributed to attentional limitations, but rather to pilots choosing to ignore such warnings due to decision biases, hearing issues, or conscious risk taking. METHOD: Twenty-eight general aviation pilots performed two landings in a flight simulator. In one scenario an auditory alert was triggered alone, whereas in the other the auditory alert occurred while the pilots dealt with a critical windshear. RESULTS: In the windshear scenario, II pilots (39.3%) did not report or react appropriately to the alarm whereas all the pilots perceived the auditory warning in the no-windshear scenario. Also, of those pilots who were first exposed to the no-windshear scenario and detected the alarm, only three suffered from inattentional deafness in the subsequent windshear scenario. CONCLUSION: These findings establish inattentional deafness as a cognitive phenomenon that is critical for air safety. Pre-exposure to a critical event triggering an auditory alarm can enhance alarm detection when a similar event is encountered subsequently. APPLICATION: Case-based learning is a solution to mitigate auditory alarm misperception. PMID- 25029891 TI - Effects of mental fatigue on the development of physical fatigue: a neuroergonomic approach. AB - OBJECTIVE: The present study used a neuroergonomic approach to examine the interaction of mental and physical fatigue by assessing prefrontal cortex activation during submaximal fatiguing handgrip exercises. BACKGROUND: Mental fatigue is known to influence muscle function and motor performance, but its contribution to the development of voluntary physical fatigue is not well understood. METHOD: A total of 12 participants performed separate physical (control) and physical and mental fatigue (concurrent) conditions at 30% of their maximal handgrip strength until exhaustion. Functional near infrared spectroscopy was employed to measure prefrontal cortex activation, whereas electromyography and joint steadiness were used simultaneously to quantify muscular effort. RESULTS: Compared to the control condition, blood oxygenation in the bilateral prefrontal cortex was significantly lower during submaximal fatiguing contractions associated with mental fatigue at exhaustion, despite comparable muscular responses. CONCLUSION: The findings suggest that interference in the prefrontal cortex may influence motor output during tasks that require both physical and cognitive processing. APPLICATION: A neuroergonomic approach involving simultaneous monitoring of brain and body functions can provide critical information on fatigue development that may be overlooked during traditional fatigue assessments. PMID- 25029892 TI - Factors influencing power hand tool fastening accuracy and reaction forces. AB - OBJECTIVE: A laboratory study investigated the relationship between power hand tool and task-related factors affecting threaded fastener torque accuracy and associated handle reaction force. BACKGROUND: We previously developed a biodynamic model to predict handle reaction forces. We hypothesized that torque accuracy was related to the same factors that affect operator capacity to react against impulsive tool forces, as predicted by the model. METHOD: The independent variables included tool (pistol grip on a vertical surface, right angle on a horizontal surface), fastener torque rate (hard, soft), horizontal distance (30 cm and 60 cm), and vertical distance (80 cm, 110 cm, and 140 cm). Ten participants (five male and five female) fastened 12 similar bolts for each experimental condition. RESULTS: Average torque error (audited - target torque) was affected by fastener torque rate and operator position. Torque error decreased 33% for soft torque rates, whereas handle forces greatly increased (170%). Torque error also decreased for the far horizontal distance 7% to 14%, when vertical distance was in the middle or high, but handle force decreased slightly 3% to 5%. CONCLUSION: The evidence suggests that although both tool and task factors affect fastening accuracy, they each influence handle reaction forces differently. We conclude that these differences are attributed to different parameters each factor influences affecting the dynamics of threaded faster tool operation. Fastener torque rate affects the tool dynamics, whereas posture affects the spring-mass-damping biodynamic properties of the human operator. APPLICATION: The prediction of handle reaction force using an operator biodynamic model may be useful for codifying complex and unobvious relationships between tool and task factors for minimizing torque error while controlling handle force. PMID- 25029893 TI - A physical workload index to evaluate a safe resident handling program for nursing home personnel. AB - OBJECTIVE: The aim of this study was to obtain a comprehensive analysis of the physical workload of clinical staff in long-term care facilities, before and after a safe resident handling program (SRHP). BACKGROUND: Ergonomic exposures of health care workers include manual handling of patients and many non-neutral postures. A comprehensive assessment requires the integration of loads from these varied exposures into a single metric. METHOD: The Postures, Activities, Tools, and Handling observational protocol, customized for health care, was used for direct observations of ergonomic exposures in clinical jobs at 12 nursing homes before the SRHP and 3, 12, 24, and 36 months afterward. Average compressive forces on the spine were estimated for observed combinations of body postures and manual handling and then weighted by frequencies of observed time for the combination. These values were summed to obtain a biomechanical index for nursing assistants and nurses across observation periods. RESULTS: The physical workload index (PWI) was much higher for nursing assistants than for nurses and decreased more after 3 years (-24% versus -2.5%). Specifically during resident handling, the PWI for nursing assistants decreased by 41% of baseline value. CONCLUSION: Spinal loading was higher for nursing assistants than for nurses in long-term care centers. Both job groups experienced reductions in physical loading from the SRHP, especially the nursing assistants and especially while resident handling. APPLICATION: The PWI facilitates a comprehensive investigation of physical loading from both manual handling and non-neutral postures. It can be used in any work setting to identify high-risk tasks and determine whether reductions in one exposure are offset by increases in another. PMID- 25029894 TI - Biomechanical and performance implications of weapon design: comparison of bullpup and conventional configurations. AB - OBJECTIVE: Shooter accuracy and stability were monitored while firing two bullpup and two conventional configuration rifles of the same caliber in order to determine if one style of weapon results in superior performance. BACKGROUND: Considerable debate exists among police and military professionals regarding the differences between conventional configuration weapons, where the magazine and action are located ahead of the trigger, and bullpup configuration, where they are located behind the trigger (closer to the user). To date, no published research has attempted to evaluate this question from a physical ergonomics standpoint, and the knowledge that one style might improve stability or result in superior performance is of interest to countless military, law enforcement, and industry experts. METHOD: A live-fire evaluation of both weapon styles was performed using a total of 48 participants. Shooting accuracy and fluctuations in biomechanical stability (center of pressure) were monitored while subjects used the weapons to perform standard drills. RESULTS: The bullpup weapon designs were found to provide a significant advantage in accuracy and shooter stability, while subjects showed considerable preference toward the conventional weapons. CONCLUSION: Although many mechanical and maintenance issues must be considered before committing to a bullpup or conventional weapon system, it is clear in terms of basic human stability that the bullpup is the more advantageous configuration. APPLICATION: Results can be used by competitive shooter, military, law enforcement, and industry experts while outfitting personnel with a weapon system that leads to superior performance. PMID- 25029895 TI - Memory and metacognition in dangerous situations: investigating cognitive impairment from gas narcosis in undersea divers. AB - OBJECTIVE: The current study tested whether undersea divers are able to accurately judge their level of memory impairment from inert gas narcosis. BACKGROUND: Inert gas narcosis causes a number of cognitive impairments, including a decrement in memory ability. Undersea divers may be unable to accurately judge their level of impairment, affecting safety and work performance. METHOD: In two underwater field experiments, performance decrements on tests of memory at 33 to 42 m were compared with self-ratings of impairment and resolution. The effect of depth (shallow [I-II m] vs. deep [33-42 m]) was measured on free-recall (Experiment I; n = 41) and cued-recall (Experiment 2; n = 39) performance, a visual-analogue self-assessment rating of narcotic impairment, and the accuracy of judgements-of-learning JOLs). RESULTS: Both free- and cued recall were significantly reduced in deep, compared to shallow, conditions. This decrement was accompanied by an increase in self-assessed impairment. In contrast, resolution (based on JOLs) remained unaffected by depth. The dissociation of memory accuracy and resolution, coupled with a shift in a self assessment of impairment, indicated that divers were able to accurately judge their decrease in memory performance at depth. CONCLUSION: These findings suggest that impaired self-assessment and resolution may not actually be a symptom of narcosis in the depth range of 33 to 42 m underwater and that the divers in this study were better equipped to manage narcosis than prior literature suggested. The results are discussed in relation to implications for diver safety and work performance. PMID- 25029896 TI - Situation awareness recovery. AB - OBJECTIVE: We describe a novel concept, situation awareness recovery (SAR), and we identify perceptual and cognitive processes that characterize SAR. BACKGROUND: Situation awareness (SA) is typically described in terms of perceiving relevant elements of the environment, comprehending how those elements are integrated into a meaningful whole, and projecting that meaning into the future. Yet SA fluctuates during the time course of a task making it important to understand the process by which SA is recovered after it is degraded. METHOD: We investigated SAR using different types of interruptions to degrade SA. In Experiment I, participants watched short videos of an operator performing a supervisory control task, and then the participants were either interrupted or not interrupted, after which SA was assessed using a questionnaire. In Experiment 2, participants performed a supervisory control task in which they guided vehicles to their respective targets and either experienced an interruption, during which they performed a visual search task in a different panel, or were not interrupted. RESULTS: The SAR processes we identified included shorter fixation durations, increased number of objects scanned, longer resumption lags, and a greater likelihood of refixating on objects that were previously looked at. CONCLUSIONS: We interpret these findings in terms of the memory-for-goals model, which suggests that SAR consists of increased scanning in order to compensate for decay, and previously viewed cues act as associative primes that reactivate memory traces of goals and plans. PMID- 25029897 TI - Choice in multitasking: how delays in the primary task turn a rational into an irrational multitasker. AB - OBJECTIVE: The objective was to establish the nature of choice in cognitive multitasking. BACKGROUND: Laboratory studies of multitasking suggest people are rational in their switch choices regarding multitasking, whereas observational studies suggest they are not. Threaded cognition theory predicts that switching is opportunistic and depends on availability of cognitive resources. METHOD: A total of 21 participants answered e-mails by looking up information (similar to customer service employees) while being interrupted by chat messages. They were free to choose when to switch to the chat message. We analyzed the switching behavior and the time they needed to complete the primary mail task. RESULTS: When participants are faced with a delay in the e-mail task, they switch more often to the chat task at high-workload points. Choosing to switch to the secondary task instead of waiting makes them slower. It also makes them forget the information in the e-mail task half of the time, which slows them down even more. CONCLUSION: When many cognitive resources are available, the probability of switching from one task to another is high. This does not necessarily lead to optimal switching behavior. APPLICATION: Potential applications of this research include the minimization of delays in task design and the inability or discouragement of switching in high-workload moments. PMID- 25029898 TI - Catastrophe models for cognitive workload and fatigue in a vigilance dual task. AB - OBJECTIVE: This study investigated two cusp catastrophe models for cognitive workload and fatigue for a vigilance dual task, the role of emotional intelligence and frustration in the performance dynamics, and the dynamics for individuals and teams of two participants. BACKGROUND: The effects of workload, fatigue, practice, and time on a specific task can be separated with the two models and an appropriate experimental design. Group dynamics add further complications to the understanding of workload and fatigue effects for teams. METHOD: In this experiment, 141 undergraduates responded to target stimuli that appeared on a simulated security camera display at three rates of speed while completing a jigsaw puzzle. Participants worked alone or in pairs and completed additional measurements prior to or after the main tasks. RESULTS: The workload cusp verified the expected effects of speed and frustration on change in performance. The fatigue cusp showed that positive and negative changes in performance were greater if more work on the secondary task was completed and whether the participants who started with the fast vigilance condition demonstrated less fatigue. CONCLUSION: The results supported the efficacy of the cusp models and suggested, furthermore, that training modules that varied speed of presentation could buffer the effects of fatigue. APPLICATION: The cusp models can be used to analyze virtually any cognitively demanding task set. The particular results generalize to vigilance tasks, although a wider range of conditions within vigilance tasks needs to be investigated further. PMID- 25029899 TI - The effect of keyboard key spacing on typing speed, error, usability, and biomechanics, Part 2: Vertical spacing. AB - OBJECTIVE: The objective was to evaluate the effects of vertical key spacing on a conventional computer keyboard on typing speed, percentage error, usability, forearm muscle activity, and wrist posture for both females with small fingers and males with large fingers. BACKGROUND: Part I evaluated primarily horizontal key spacing and found that for male typists with large fingers, productivity and usability were similar for spacings of 17, 18, and 19 mm but were reduced for spacings of 16 mm. Few other key spacing studies are available, and the international standards that specify the spacing between keys on a keyboard have been mainly guided by design convention. METHOD: Experienced female typists (n = 26) with small fingers (middle finger length < or = 7.71 cm or finger breadth of < or = 1.93 cm) and male typists (n = 26) with large fingers (middle finger length > or = 8.37 cm or finger breadth of > or = 2.24 cm) typed on five keyboards that differed primarily in vertical key spacing (17 x 18, 17 x 17, 17 x 16, 17 x 15.5, and 18 x 16 mm) while typing speed, error, fatigue, preference, forearm muscle activity, and wrist posture were recorded. RESULTS: Productivity and usability ratings were significantly worse for the keyboard with 15.5 mm vertical spacing compared to the other keyboards for both groups.There were few significant differences on usability ratings between the other keyboards. Reducing vertical key spacing,from 18 to 17 to 16 mm, had no significant effect on productivity or usability. CONCLUSIONS: The findings support the design of keyboards with vertical key spacings of 16, 17, or 18 mm. APPLICATIONS: These findings may influence keyboard design and standards. PMID- 25029900 TI - Interactive effects of the COMT gene and training on individual differences in supervisory control of unmanned vehicles. AB - OBJECTIVE: We examined whether a gene known to influence dopamine availability in the prefrontal cortex is associated with individual differences in learning a supervisory control task. BACKGROUND: Methods are needed for selection and training of human operators who can effectively supervise multiple unmanned vehicles (UVs). Compared to the valine (Val) allele, the methionine (Met) allele of the COMT gene has been linked to superior executive function, but it is not known whether it is associated with training-related effects in multi-UV supervisory control performance. METHOD: Ninety-nine healthy adults were genotyped for the COMT Val158Met single nucleotide polymorphism (rs4680) and divided into Met/Met, Val/Met, and Val/Val groups. Participants supervised six UVs in an air defense mission requiring them to attack incoming enemy aircraft and protect a no-fly zone from intruders in conditions of low and high task load (numbers of enemy aircraft). Training effects were examined across four blocks of trials in each task load condition. RESULTS: Compared to the Val/Met and Val/Val groups, Met/Met individuals exhibited a greater increase in enemy targets destroyed and greater reduction in enemy red zone incursions across training blocks. CONCLUSION: Individuals with the COMT Met/Met genotype can acquire skill in executive function tasks, such as multi-UV supervisory control, to a higher level and/or faster than other genotype groups. APPLICATION: Potential applications of this research include the development of individualized training methods for operators of multi-UV systems and selecting personnel for complex supervisory control tasks. PMID- 25029901 TI - Auditory azimuthal localization performance in water as a function of prior exposure. AB - OBJECTIVE: We report two psychoacoustical experiments that assessed the relationship between auditory azimuthal localization performance in water and duration of prior exposure to the milieu. BACKGROUND: The adaptability of spatial hearing abilities has been demonstrated in air for both active and passive exposures to altered localization cues. Adaptability occurred faster and was more complete for elevation perception than for azimuth perception. In water, spatial hearing is believed to solely rely on smaller than normal cues-to-azimuth: interaural time differences. This should produce a medial bias in localization judgments toward the center of the horizontal plane, unless the listeners have adapted to the environment. METHOD: Azimuthal localization performance was measured in seawater for eight azimuthal directions of a low-frequency (< 500 Hz) auditory target. Seventeen participants performed a forced-choice task in Experiment 1. Twenty-eight other participants performed a pointing task in Experiment 2. RESULTS: In both experiments we observed poor front/back discrimination but accurate left/right discrimination, regardless of prior exposure. A medial bias was found in azimuth perception, whose size decreased as the exposure duration of the participant increased. CONCLUSION: The study resembles earlier results showing that passive exposure to altered azimuth cues elicits the adaptability of internal audio-spatial maps, that is, the behavioral plasticity of spatial hearing abilities. APPLICATION: Studies of the adaptability of the auditory system to altered spatial information may yield practical implications for scuba divers, hearing-impaired listeners with reduced sensitivity to spatial cues, and various normal-hearing users of virtual auditory displays. PMID- 25029902 TI - The feasibility and accuracy of using a remote method to assess computer workstations. AB - OBJECTIVE: The objective was to test the accuracy of using remote methods (tele ergonomics) to identify potential mismatches between workers and their computer workstations. BACKGROUND: Remote access to ergonomic assessments and interventions using two-way interactive communications, tele-ergonomics, increases the ability to deliver computer ergonomic services. However, this mode of delivery must first be tested for accuracy. METHOD: In this single group study, the computer workstations of 30 participants who reported mild to moderate discomfort were remotely assessed using photographs taken by a research assistant and the self-report Computer Workstation Checklist (CWC) completed by the study participant. Mismatches identified remotely by an ergonomics expert were compared to results obtained from an onsite computer workstation visit completed by the same expert. RESULTS: We accurately identified 92% of mismatches. The method was more sensitive (0.97) than specific (0.88), indicating that experts using the remote method were likely to overidentify mismatches. CONCLUSION: These results suggest that an expert using the self-reported CWC combined with workstation photographs can accurately identify mismatches between workers and their computer workstations. APPLICATION: Remote assessment is a promising method to improve access to computer workstation ergonomic assessments. PMID- 25029903 TI - The critical tracking task: a potentially useful method to assess driver distraction? AB - OBJECTIVE: We report on four experiments that investigated the critical tracking task's (CTT) potential as a tool to measure distraction. BACKGROUND: Assessment of the potential of new in-vehicle information systems to be distracting has become an important issue. An easy-to-use method, which might be a candidate to assess this distraction, is the CTT. The CTT requires an operator to stabilize a bar, which is displayed on a computer screen, such that it does not depart from a predefined target position. As the CTT reflects various basic aspects of the operational level of the driving task, we used it as a simple surrogate for driving to assess the CTT's capabilities. METHOD: We employed secondary tasks of varying demand, artificial tasks as well as tasks representative of secondary tasks while driving, and asked participants to perform them together with the CTT in parallel. CTT performance, secondary task performance, and subjective ratings of load were recorded and analyzed. RESULTS: Overall, the CTT was able to differentiate between different levels of demand elicited by the secondary tasks. The results obtained corresponded with our a priori assumptions about the respective secondary tasks' potential to distract. CONCLUSION: It appears that the CTT can be used to assess in-vehicle information systems with regard to their potential to distract drivers. Additional experiments are necessary to further clarify the relationship between driving and CTT performance. APPLICATION: The CTT can provide a cost-effective solution as part of a battery of tests for early testing of new in-vehicle devices. PMID- 25029905 TI - The mouse intranasal challenge model for potency testing of whole-cell pertussis vaccines. AB - INTRODUCTION: A mouse intracerebral challenge model is used for potency testing of whole-cell pertussis (wP) vaccines. We investigated the use of a mouse nasopharyngeal challenge model, which better reflects the clinical features of pertussis disease, to differentiate between efficacy of wP vaccines. METHODS: Efficacy of three wP vaccines (Quinvaxem((r)), Easyfive((r)) and Pentavac((r))) was tested in the nasopharyngeal challenge model. Mice were vaccinated at 4 and 7 weeks and challenged with Bordetella pertussis at 9 weeks. Vaccine efficacy was determined based on CFU in the lungs 5 days after challenge. RESULTS: The mouse nasopharyngeal challenge model has the capacity to differentiate between the efficacy of whole cell pertussis vaccines. CONCLUSION: The mouse nasopharyngeal challenge model could be considered as a potency and release assay for wP vaccines. Whether this model directly correlates with clinical vaccine efficacy requires further investigations. Whether this model directly correlates with clinical vaccine efficacy requires further investigations. The mouse nasopharyngeal challenge model could be considered as a potency and release assay for wP vaccines. PMID- 25029904 TI - The hypusine-containing translation factor eIF5A. AB - In addition to the small and large ribosomal subunits, aminoacyl-tRNAs, and an mRNA, cellular protein synthesis is dependent on translation factors. The eukaryotic translation initiation factor 5A (eIF5A) and its bacterial ortholog elongation factor P (EF-P) were initially characterized based on their ability to stimulate methionyl-puromycin (Met-Pmn) synthesis, a model assay for protein synthesis; however, the function of these factors in cellular protein synthesis has been difficult to resolve. Interestingly, a conserved lysine residue in eIF5A is post-translationally modified to hypusine and the corresponding lysine residue in EF-P from at least some bacteria is modified by the addition of a beta-lysine moiety. In this review, we provide a summary of recent data that have identified a novel role for the translation factor eIF5A and its hypusine modification in the elongation phase of protein synthesis and more specifically in stimulating the production of proteins containing runs of consecutive proline residues. PMID- 25029906 TI - Prognostic impact of TAZ and beta-catenin expression in adenocarcinoma of the esophagogastric junction. AB - BACKGROUND: TAZ is a downstream agent of Hippo signal pathway. beta-catenin is a cell adhesion molecule associated with the invasion and metastasis of carcinomas as well as a critical component of Wnt pathway. TAZ and beta-catenin have long been thought to play a vital role in tumour development and progression. This study aimed to detect expression of TAZ and beta-catenin in adenocarcinoma of the esophagogastric junction (AEG) and explore their clinicopathological significance. METHODS: The expression of TAZ and beta-catenin were detected by immunohistochemistry of 135 AEG samples, and analyzed with complete clinicopathological features. Overall survival rates were also calculated using the Kaplan-Meier method. Cox proportional hazard model was performed to assess the prognostic values. 37 normal mucosa and 41 dysplasia samples of esophagogastric junction (EGJ) were studied comparably. RESULTS: TAZ protein showed a strictly nuclear staining pattern in AEG and dysplasia with IHC. Expression of TAZ was higher in dysplasia and AEG compared with normal mucosa (P < 0.001, 0.008). The positive expression rate of nuclear beta-catenin was significantly higher in carcinoma and dysplasia than that in normal mucosa (P < 0.001, =0.046). Abnormal expression rate of membranous beta-catenin in AEG was significantly higher than that in normal mucosa tissues and dysplasia (P = 0.001, 0.002). In AEG, over expression of TAZ was directly correlated with abnormal nuclear beta-catenin expression (r = 0.298, P < 0.001) and membranous beta catenin (r = 0.202, P = 0.019). Patients with abnormal TAZ or beta-catenin expression of AEG exhibited a shorter overall survival (OS) and lower overall survival rate than those with normal TAZ or beta-catenin expression (P < 0.05). In addition, patients with abnormal expression of both TAZ and beta-catenin exhibited worst overall survival. In multivariate survival analysis, abnormal expression of TAZ, TAZ & beta-catenin (nuclear and membranous) and tumour differentiation were found to be independent prognostic factors related to OS of AEG patients. CONCLUSIONS: Over expression of TAZ was associated with abnormal expression of beta-catenin, which is correlated with poor prognosis of patients with AEG. Abnormal expression of TAZ and TAZ & beta-catenin (nuclear and membranous) are independent prognostic factors, so targeting TAZ and beta-catenin could prove to be a promising therapeutic strategy for the treatment of AEG. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2558852841276335. PMID- 25029907 TI - Access and utilisation of maternity care for disabled women who experience domestic abuse: a systematic review. AB - BACKGROUND: Although disabled women are significantly more likely to experience domestic abuse during pregnancy than non-disabled women, very little is known about how maternity care access and utilisation is affected by the co-existence of disability and domestic abuse. This systematic review of the literature explored how domestic abuse impacts upon disabled women's access to maternity services. METHODS: Eleven articles were identified through a search of six electronic databases and data were analysed to identify: the factors that facilitate or compromise access to care; the consequences of inadequate care for pregnant women's health and wellbeing; and the effectiveness of existing strategies for improvement. RESULTS: Findings indicate that a mental health diagnosis, poor relationships with health professionals and environmental barriers can compromise women's utilisation of maternity services. Domestic abuse can both compromise, and catalyse, access to services and social support is a positive factor when accessing care. Delayed and inadequate care has adverse effects on women's physical and psychological health, however further research is required to fully explore the nature and extent of these consequences. Only one study identified strategies currently being used to improve access to services for disabled women experiencing abuse. CONCLUSIONS: Based upon the barriers and facilitators identified within the review, we suggest that future strategies for improvement should focus on: understanding women's reasons for accessing care; fostering positive relationships; being women-centred; promoting environmental accessibility; and improving the strength of the evidence base. PMID- 25029908 TI - Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. AB - OBJECTIVES: The randomized phase 3 PRIMA trial established that 2 years of rituximab maintenance therapy after attaining disease response to immunochemotherapy as first-line treatment of follicular lymphoma, reduced the risk of disease progression, compared with observation, without adversely affecting patient-reported quality of life (QoL). We now report additional analyses of symptom burden and toxicity. METHODS: Symptom burden was measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items. The proportion of patients with worsening, no change, or improvement in symptoms from maintenance baseline was compared between rituximab maintenance and observation groups with Pearson chi(2) tests. Improvement in symptoms after 1 and 2 years of maintenance was further analyzed using generalized mixed models. The adverse event (AE) rate was calculated from the toxicity checklist at each visit to explore the frequency and timing of the toxicity AE in each treatment arm. The study protocol was approved by local ethics committees and is registered at ClinicalTrials.gov under NCT00140582. RESULTS: Being tired, needing to rest, feeling weak, and trouble sleeping were the most frequently reported symptoms at the end of immunochemotherapy. By the end of maintenance, notable improvement was seen for fatigue symptoms, trouble sleeping, shortness of breath, lack of appetite, and nausea, with no significant difference in QoL symptoms between the rituximab maintenance and observation groups. The rate of AEs was low, and hematologic toxicity induced during chemotherapy treatment improved in both rituximab maintenance and observation groups. DISCUSSION: These results indicated that rituximab maintenance did not negatively impact disease- or treatment-related symptoms. PMID- 25029909 TI - Breast cancer screening among homeless women of New York City shelter-based clinics. AB - BACKGROUND: Millions of Americans experience homelessness annually. Data on breast cancer screening among homeless women is extremely limited. METHODS: We performed a retrospective study evaluating 100 female patients 50 to 74 years old with at least three visits to two major New York City shelter-based clinics between 2010 and 2012 to evaluate and compare rates and predictors of mammograms in homeless and low-income domicile patients. RESULTS: Of those we included, 44% were homeless with majority Black and Hispanic. Mean age was 59.28 (+/-5.84) years. The majority were insured, with 44% smokers and 87% with chronic illnesses. Rates of mammogram within past 2 years were 59% in homeless and 57.1% in low-income domicile patients; 53% did not know the results of their mammogram. Homeless and domicile patients received equal provider counseling. Homeless women were more likely to be uninsured (p < .01). Domicile patients were more likely to have a chronic illness (p < .01). A history of mental illness or substance abuse was not different between the two groups. In logistic regression, provider counseling predicted mammogram (odds ratio, 31.69; 95% CI, 3.76-266.8); race, insurance status, housing status, and history of mental illness or substance abuse did not. CONCLUSION: The overall low rate of mammogram in this population compared with the national average is alarming. We suggest trained patient navigators to address social barriers and tailored patient education and counseling at any clinical encounter to address misconceptions, along with broader structural approaches to address homelessness. PMID- 25029910 TI - Targeting of viral interleukin-10 with an antibody fragment specific to damaged arthritic cartilage improves its therapeutic potency. AB - INTRODUCTION: We previously demonstrated that a single-chain fragment variable (scFv) specific to collagen type II (CII) posttranslationally modified by reactive oxygen species (ROS) can be used to target anti-inflammatory therapeutics specifically to inflamed arthritic joints. The objective of the present study was to demonstrate the superior efficacy of anti-inflammatory cytokines when targeted to inflamed arthritic joints by the anti-ROS modified CII (anti-ROS-CII) scFv in a mouse model of arthritis. METHODS: Viral interleukin-10 (vIL-10) was fused to anti-ROS-CII scFv (1-11E) with a matrix-metalloproteinase (MMP) cleavable linker to create 1-11E/vIL-10 fusion. Binding of 1-11E/vIL-10 to ROS-CII was determined by enzyme-linked immunosorbent assay (ELISA), Western blotting, and immune-staining of arthritic cartilage, whereas vIL-10 bioactivity was evaluated in vitro by using an MC-9 cell-proliferation assay. Specific in vivo localization and therapeutic efficacy of 1-11E/vIL-10 was tested in the mouse model of antigen-induced arthritis. RESULTS: 1-11E/vIL-10 bound specifically to ROS-CII and to damaged arthritic cartilage. Interestingly, the in vitro vIL-10 activity in the fusion protein was observed only after cleavage with MMP-1. When systemically administered to arthritic mice, 1-11E/vIL-10 localized specifically to the arthritic knee, with peak accumulation observed after 3 days. Moreover, 1-11E/vIL-10 reduced inflammation significantly quicker than vIL-10 fused to the control anti-hen egg lysozyme scFv (C7/vIL10). CONCLUSIONS: Targeted delivery of anti-inflammatory cytokines potentiates their anti-arthritic action in a mouse model of arthritis. Our results further support the hypothesis that targeting biotherapeutics to arthritic joints may be extended to include anti inflammatory cytokines that lack efficacy when administered systemically. PMID- 25029911 TI - Egr-1 regulates the transcription of NGX6 gene through a Sp1/Egr-1 overlapping site in the promoter. AB - BACKGROUND: As a novel candidate metastasis suppressor gene, Nasopharyngeal carcinoma-associated gene 6 (NGX6) is involved in cellular growth, cell cycle progression and tumor angiogenesis. Previous studies have shown that NGX6 gene is down-regulated in colorectal cancer (CRC). However, little is known about its transcriptional regulation. RESULTS: We defined the minimal promoter of NGX6 gene in a 186-bp region (from-86 to +100) through mutation construct methods and luciferase assays. Results from Electrophoretic mobility shift assays (EMSA) and Chromatin immunoprecipitation (ChIP) revealed that Early growth response gene 1 (Egr-1) binds to the Sp1/Egr-1 overlapping site of NGX6 minimal promoter. Overexpression of Egr-1 increased the promoter activity and mRNA level of NGX6 gene; while knock-down of endogenous Egr-1 decreased mRNA expression of NGX6 gene. CONCLUSION: These results demonstrate that Egr-1 regulates NGX6 gene transcription through an overlapping Sp1/Egr-1 binding site as a positive regulator of NGX6 gene. PMID- 25029913 TI - Necrolytic migratory erythema as the first manifestation of pancreatic neuroendocrine tumor. AB - Necrolytic migratory erythma (NME) is an obligatory paraneoplastic syndrome. Here we describe a woman admitted to the dermatology ward with NME which was later found to be associated with glucagonoma, a slow-growing, rare pancreatic neuroendocrine tumor. Even more rarely, the tumor was located in the pancreas head, while most of such lesions are located in the distal pancreas. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. After surgical removal of the tumor, the patient's cutaneous and systemic features resolved. It is therefore imperative that clinicians recognize NME early in order to make an accurate diagnosis and to provide treatment for this rare tumor. PMID- 25029912 TI - Screening and genetic characterization of thermo-tolerant Synechocystis sp. PCC6803 strains created by adaptive evolution. AB - BACKGROUND: Temperature tolerance is an important aspect for commercial scale outdoor cultivation of microalgae and cyanobacteria. While various genes are known to be related to Synechocystis sp. PCC6803's heat shock response, there is very limited published data concerning the specific genes involved in long term thermal tolerance. We have previously used random mutagenesis and adaptive evolution to generate a mixture of strains of Synechocystis sp. PCC6803 with significantly increased thermal tolerance. The genetic modifications leading to the phenotypes of the newly generated strains are the focus of this work. RESULTS: We used a custom screening platform, based on 96-deepwell microplate culturing in an in house designed cultivation chamber integrated in a liquid handling robot for screening and selection; in addition we also used a more conventional system. The increased thermal tolerances of the isolated monoclonal strains were validated in larger bioreactors and their whole genomes sequenced. Comparison of the sequence information to the parental wild type identified various mutations responsible for the enhanced phenotypes. Among the affected genes identified are clpC, pnp, pyk2, sigF, nlpD, pyrR, pilJ and cya1. CONCLUSIONS: The applied methods (random mutagenesis, in vivo selection, screening, validation, whole genome sequencing) were successfully applied to identify various mutations, some of which are very unlikely to have been identified by other approaches. Several of the identified mutations are found in various strains and (due to their distribution) are likely to have occurred independently. This, coupled with the relatively low number of affected genes underscores the significance of these specific mutations to convey thermal tolerance in Synechocystis. PMID- 25029914 TI - Pressure pain sensitivity changes after use of shock-absorbing insoles among young soccer players training on artificial turf: a randomized controlled trial. AB - STUDY DESIGN: Prospective, randomized, controlled single-blind intervention trial. OBJECTIVES: Shock-absorbing insoles (SAIs), compared with usual insoles, were hypothesized to result in larger increases in pressure pain threshold (PPT) after 3 weeks of use. BACKGROUND: Shock-absorbing insoles can decrease self reported pain among young soccer players training on artificial turf. However, nothing is known about the underlying changes in pain sensitivity assessed by PPT. Methods Seventy-five players were included from the youth teams of under 15, under 17, and under 19 years of age, playing for the Aalborg Boldspilklub (AaB) professional sports club. After a randomization stratified by team and age, players were divided into 2 groups, one that received SAIs and a control group that used their usual insoles. Assessments were made in both groups after 3 weeks of training on artificial turf (baseline) and 3 weeks later (follow-up). The primary outcome was change in PPTs from baseline to follow-up, with PPTs measured over 13 locations on the plantar surface of the foot, leg, and low back of the nonpreferred kicking leg. RESULTS: A significantly larger increase was found in PPTs from baseline to follow-up for the SAI group compared with the control group (mean difference, 62 kPa; 95% confidence interval [CI]: 40, 85 kPa). The PPTs increased significantly more among the SAI group compared with the control group (P<.05) for the abductor digiti minimi (mean difference, 82 kPa; 95% CI: 6, 157 kPa), tibialis anterior (mean difference, 125 kPa; 95% CI: 20, 230 kPa), medial gastrocnemius (mean difference, 83 kPa; 95% CI: -6, 171 kPa), and erector spinae (mean difference, 86 kPa; 95% CI: -17, 188 kPa). CONCLUSION: The use of SAIs resulted in increased PPTs after 3 weeks of training on artificial turf compared with controls, suggesting a protective role of SAIs in pressure sensitivity and pain perception. PMID- 25029915 TI - Evaluative measurement properties of the patient-specific functional scale for primary shoulder complaints in physical therapy practice. AB - STUDY DESIGN: Clinical measurement, longitudinal. OBJECTIVES: To assess the test retest reliability, construct validity, and responsiveness of the Patient Specific Functional Scale (PSFS) in patients with a primary shoulder complaint. BACKGROUND: Health measurement outcomes have become increasingly important for evaluating treatment. Patient-specific questionnaires are useful tools for determining treatment goals and evaluating treatment in individual patients. These questionnaires have not yet been validated in patients with nonspecific shoulder pain. METHODS: Patients completed the PSFS, the numeric pain rating scale, and the Shoulder Pain and Disability Index at baseline, and after 1 week and 4 to 6 weeks. Test-retest reliability was determined using intraclass correlation coefficients. To assess convergent validity, change scores of the PSFS were correlated with the numeric pain rating scale and Shoulder Pain and Disability Index change scores. Responsiveness was assessed by calculating the area under the curve, the minimal clinically important change, and minimal detectable change, using the global rating of change as an external criterion. RESULTS: Fifty patients (37 men; mean age, 47.7 years) participated in the study. Reliability was high (intraclass correlation coefficient = 0.87; 95% confidence interval [CI]: 0.72, 0.94). The correlations between the change scores of the PSFS and those of the Shoulder Pain and Disability Index and numeric pain rating scale were 0.45 (95% CI: 0.17, 0.80) and 0.55 (95% CI: 0.29, 0.73), respectively. The area under the curve for the PSFS was 0.67 (95% CI: 0.51, 0.83). The minimal detectable change and minimal clinically important change were 0.97 and 1.29 points, respectively. CONCLUSION: These results suggest that the PSFS is a reliable, valid, and responsive instrument that can be used as an evaluative instrument in patients with a primary shoulder complaint. PMID- 25029916 TI - Sonographic measures of the gluteus medius, gluteus minimus, and vastus medialis muscles. AB - STUDY DESIGN: Intrarater, repeated-measures, within-session reliability study. OBJECTIVE: To describe a standardized method and preliminary reliability estimates for sonographic measures of resting and contracted gluteus medius (GMd), gluteus minimus (GMn), and resting vastus medialis (VM) muscles. BACKGROUND: Sonography has been used to assess the morphology of a diversity of muscles in relation to a variety of musculoskeletal dysfunctions. Although the GMd, GMn, and VM muscles are associated with dysfunctions such as patellofemoral pain and osteoarthritis, there is a paucity of information regarding protocols for sonographic measurements of these muscles. METHODS: A standardized method was developed and used to gather sonographic measures of resting and contracted (sidelying hip abduction task) GMd and GMn thickness and resting VM cross sectional area during 1 measurement session in 29 female soccer players 14 to 17 years of age. RESULTS: Intrarater reliability values for ultrasound imaging measurements of resting, contracted, and change during contraction (intraclass correlation coefficient model 3,3 [ICC3,3]) of the GMd were 0.98 (95% confidence interval [CI]: 0.97, 0.99), 0.98 (95% CI: 0.96, 0.99), and 0.84 (95% CI: 0.71, 0.92), respectively, and of the GMn were 0.98 (95% CI: 0.97, 0.99), 0.94 (95% CI: 0.88, 0.97), and 0.53 (95% CI: 0.21, 0.76), respectively. Reliability (ICC3,3) for resting VM cross-sectional area was 0.99 (95% CI: 0.99, 0.99). Standard error of measurement for GMd, GMn, and VM varied between 0.5 and 1.6 mm, 0.3 and 1.4 mm, and 0.4 cm2, respectively, and 95% minimal detectable change ranged from 0.8 to 4.5 mm for the gluteals and 0.4 to 0.5 cm2 for the VM. CONCLUSION: Reliable sonographic measurements of the lateral hip and knee musculature at rest and during contraction are feasible. Further investigation is required to establish the generalizability and reproducibility of the protocols presented in this report. PMID- 25029917 TI - Blood pressure and heart rate response to posteriorly directed pressure applied to the cervical spine in young, pain-free individuals: a randomized, repeated measures, double-blind, placebo-controlled study. AB - STUDY DESIGN: Randomized clinical trial. Objectives To compare the blood pressure (BP) and heart rate (HR) response of healthy volunteers to posteriorly directed (anterior-to-posterior [AP]) pressure applied to the cervical spine versus placebo. BACKGROUND: Manual therapists employ cervical spine AP mobilizations for various cervical-shoulder pain conditions. However, there is a paucity of literature describing the procedure, cardiovascular response, and safety profile. METHODS: Thirty-nine (25 female) healthy participants (mean +/- SD age, 24.7 +/- 1.9 years) were randomly assigned to 1 of 2 groups. Group 1 received a placebo, consisting of light touch applied to the right C6 costal process. Group 2 received AP pressure at the same location. Blood pressure and HR were measured prior to, during, and after the application of AP pressure. One-way analysis of variance and paired-difference statistics were used for data analysis. RESULTS: There was no statistically significant difference between groups for mean systolic BP, mean diastolic BP, and mean HR (P >.05) for all time points. Within group comparisons indicated statistically significant differences between baseline and post-AP pressure HR (-2.8 bpm; 95% confidence interval: -4.6, -1.1) and between baseline and post-AP pressure systolic BP (-2.4 mmHg; 95% confidence interval: -3.7, -1.0) in the AP group, and between baseline and postplacebo systolic BP (-2.6 mmHg; 95% confidence interval: -4.2, -1.0) in the placebo group. No participants reported any adverse reactions or side effects within 24 hours of testing. CONCLUSION: AP pressure caused a statistically significant physiologic response that resulted in a minor drop in HR (without causing asystole or vasodepression) after the procedure, whereas this cardiovascular change did not occur for those in the placebo group. Within both groups, there was a small but statistically significant reduction in systolic BP following the procedure. PMID- 25029918 TI - Myofascial treatment for patients with acetabular labral tears: a single-subject research design study. AB - STUDY DESIGN: Single-subject research design using 4 consecutive patients. OBJECTIVE: To assess whether treatment using soft tissue therapy (ART or Active Release Technique), stretching, and strengthening of the hip abductors, hip external rotators, and tensor fascia latae muscles reduces pain and improves self reported hip function in patients with acetabular labral tears who also have posterolateral hip pain of suspected myofascial origin. BACKGROUND: Acetabular labral tears cause pain in some but not all patients. Pain commonly presents anteriorly but may also present posteriorly and laterally. The standard of care is arthroscopic repair, which helps many but not all patients. It is possible that these patients may present with extra-articular contributions to their pain, such as myofascial pain, making their clinical presentation more complex. No previous study has assessed soft tissue therapy as a treatment option for this subset of patients. METHODS: This A-B-A design used repeated measures of the Hip Outcome Score and visual analog scale for pain. Four patients were treated for 6 to 8 weeks, using a combination of soft tissue therapy, stretching, and strengthening for the hip abductors, external rotators, and tensor fascia latae. Data were assessed visually, statistically, and by comparing mean differences before and after intervention. RESULTS: All 4 patients experienced both statistically significant and clinically meaningful improvement in posterolateral hip pain and hip-related function. Three patients also experienced reduction in anteromedial hip pain. CONCLUSION: Myofascial hip pain may contribute to hip related symptoms and disability in patients with acetabular labral tears and posterolateral hip pain. These patients may benefit from soft tissue therapy combined with stretching and strengthening exercises targeting the hip abductors, tensor fascia latae, and hip external rotator muscles. Level of Evidence Therapy, level 4. PMID- 25029921 TI - Korean Americans' beliefs about colorectal cancer screening. AB - PURPOSE: The purpose of this study was to assess Korean Americans' (KAs) health and cultural beliefs about colorectal cancer (CRC) and their CRC screening utilization in order to understand how health and cultural beliefs play a role in CRC screening utilization and why KAs have a low rate of CRC screening. METHODS: Face-to-face, individual interviews with 26 Korean immigrants aged 50 and older were conducted in Korean. A semi-structured interview guide with open-ended questions was used to explore participants' health and cultural beliefs about CRC and CRC screening. Recorded audio interviews were transcribed verbatim in Korean and coded using thematic analysis. RESULTS: The themes that emerged from analyzing the individual interview data were: (a) valuing their families before themselves; (b) seeing a doctor only if they have symptoms; (c) believing that they would not get CRC; (d) balancing the will to stay healthy and fatalism; and (e) refusing health information. CONCLUSION: Results show the critical need for in-depth understanding of unique health and cultural beliefs about CRC screening in KAs. These beliefs could be useful for future intervention strategies to change health and cultural beliefs in order to increase CRC screening participation in KAs. PMID- 25029920 TI - Mutants in the lipopolysaccharide of Brucella ovis are attenuated and protect against B. ovis infection in mice. AB - Brucella spp. are Gram-negative bacteria that behave as facultative intracellular parasites of a variety of mammals. This genus includes smooth (S) and rough (R) species that carry S and R lipopolysaccharides (LPS), respectively. S-LPS is a virulence factor, and mutants affected in the S-LPS O-polysaccharide (R mutants), core oligosaccharide or both show attenuation. However, B. ovis is naturally R and is virulent in sheep. We studied the role of B. ovis LPS in virulence by mutating the orthologues of wadA, wadB and wadC, three genes known to encode LPS core glycosyltransferases in S brucellae. When mapped with antibodies to outer membrane proteins (Omps) and R-LPS, wadB and wadC mutants displayed defects in LPS structure and outer membrane topology but inactivation of wadA had little or no effect. Consistent with these observations, the wadB and wadC but not the wadA mutants were attenuated in mice. When tested as vaccines, the wadB and wadC mutants protected mice against B. ovis challenge. The results demonstrate that the LPS core is a structure essential for survival in vivo not only of S brucellae but also of a naturally R Brucella pathogenic species, and they confirm our previous hypothesis that the Brucella LPS core is a target for vaccine development. Since vaccine B. melitensis Rev 1 is S and thus interferes in serological testing for S brucellae, wadB mutant represents a candidate vaccine to be evaluated against B. ovis infection of sheep suitable for areas free of B. melitensis. PMID- 25029922 TI - Clinical outcomes and quality of life of home health care patients. AB - PURPOSE: This study aimed to evaluate the quality of life (QOL) in home health care patients according to change in health status outcomes between the start of care and discharge or 60 days, whichever came first. METHODS: This is a prospective descriptive study. The convenience sample consisted of 100 home health care patients, who started receiving home health care services from a home health care agency in the United States. The World Health Organization Quality of Life Scale-Brief (WHOQOL-BREF) was used for measuring QOL; activities of daily living (ADLs) and instrumental ADLs were collected from the Outcome and Assessment Information Set data via Centers for Medicare and Medicaid Services required home health agencies. Descriptive statistics, paired t tests, and multiple linear regressions were used for data analysis. RESULTS: ADLs and instrumental ADLs of participants significantly improved between start of care and discharge or 60 days. Overall QOL, general health, and three of four QOL domains (physical, psychological, and environmental, but not social domain) were significantly improved at discharge or 60 days. CONCLUSION: Home health care nurses should maintain and improve the functional ability of patients, as this could improve the QOL of these patients. PMID- 25029923 TI - Psychometric properties of the Korean short form-36 health survey version 2 for assessing the general population. AB - PURPOSE: To evaluate the psychometric properties of the Korean short form-36 health survey version 2 for assessing the general population and to provide normative data on the general population. METHODS: Six hundred members of the general Korean population were recruited using a multistage quota sampling method. Data quality was evaluated in terms of the completeness of the data and the response consistency index. Each psychometric property was evaluated using descriptive statistics, item internal consistency, item discriminant validity, known-group validity, internal consistency reliability, and exploratory factor analysis. RESULTS: The rate of missing data was low, and the rate of consistent responses was similar to conventional criteria. Item internal consistency was acceptable across all scales, whilst item discriminant validity was satisfactory for five of the eight scales. Social functioning was the least acceptable in terms of not only item discriminant validity but also item consistency reliability (Cronbach's alpha = .64). Test-retest Pearson correlation coefficients ranged from .54 to .80. In known group comparison, male sex, age <60 years, high educational status, and the absence of any comorbidities were associated with higher scores than their counterparts. Item factor analysis yields the presence of six factors, accounting for 68.8% of the variance. CONCLUSION: The findings of this study generally support the use of the Korean short form-36 version 2 for evaluating the general population, although caution is recommended when interpreting the vitality, social functioning, and mental health scales. Further research is needed in Korea. PMID- 25029924 TI - Factors affecting diabetic screening behavior of Korean adults: a multilevel analysis. AB - PURPOSE: We investigated the role of individual and community level factors on diabetes screening test behavior. METHODS: We used individual-level data from 170,193 adults aged 30 years or older who were not diagnosed with diabetes and participated in the 2009 community health survey. Community-level data includes 253 communities and were collected from various national statistics. Multilevel logistic regression analysis was conducted. RESULTS: The rate of diabetes screening within the year prior to this study was 53.2%. Community variance of Model I, Model II and Model III was 0.236, 0.252 and 0.238, respectively. The proportional change in variance of Model II and Model III was -6.8% and -1.2%. The odds ratio for participation of diabetic screening of areas with bottom financial independence compared to areas with top was 0.84 (95% confidence interval, 0.74-0.96); the odds ratio of areas with top internist compared to areas with bottom was 1.15 (95% confidence interval, 1.01-1.31). CONCLUSION: This study identified a contextual effect influencing the participation of Korean adults in diabetes screening. It is necessary to develop specific policies that consider not only individual factors, but also community factors relating to individual behaviors to increase the likelihood of diabetes screening. PMID- 25029925 TI - Effects of a workplace multiple cardiovascular disease risks reduction program. AB - PURPOSE: Interventions targeting multiple risk behaviors have the potential to offer greater health benefits on public health. The purpose of this study was to evaluate the effects of a Workplace Multiple Cardiovascular Disease Risks Reduction Program (WMCVDRRP) on male participants at high risk for cardiovascular disease. METHODS: One group pretest-posttest design was applied in this study. No control group was assigned as this study was the first one in Taiwan conducted to promote participants' health using WMCVDRRP and thus with the nature of a pilot study. The program design was based on the collaboration between the health clinic at the corporation and a nursing school targeting six health behaviors. Of the 465 individuals who participated, data from 283 participants were included in the analysis. The change in any of six health behaviors and eight physical indicators were tested as the effect of the WMCVDRRP. RESULTS: Nearly 40% of the participants improved their regular exercise, diet control, stress management, and medication adherence. Although the improvement in drinking behaviors did not show statistical significance, 21% of the participants changed in alcohol consumption and 21% quit smoking. Eight physical indicators including systolic and diastolic blood pressure, total cholesterol, triglyceride, body mass index, waist-hip ratio, body fat, and muscle weight improved significantly. CONCLUSION: Dual collaboration between the industry and nursing schools could establish a cost-effective program to improve health behaviors and health status of participants. PMID- 25029926 TI - Lived experiences of nursing home residents in Korea. AB - PURPOSE: The goal of the study was to understand the experiences of life among nursing home residents. METHODS: Qualitative study was conducted using Colaizzi's phenomenological method. The participants were 11 people aged 76-96 years in two nursing homes in Korea. RESULTS: Nine themes were identified: giving up on one self, growing apart from familiar relationships, perceiving the monotony of daily life as suffering, feeling anxious about one's future upon observing other residents, being dissatisfied with the lack of consideration for individualized care, developing interpersonal skills for communal life, missing the daily routines of their past lives, feeling optimistic about living in a nursing home, and having a strategy for the remainder of life in the nursing home. CONCLUSION: The results of this study confirmed the positive and negative emotions that elderly people typically experience while in nursing homes. Nurses should educate the families of nursing home residents, so that the family can better respect elderly people's opinions and provide them with adequate support. Furthermore, nurses must not only provide reliable support, resources and serve as advocates, but they must also pay more attention to the environment of the nursing home to make it feel like home to the elderly residents. PMID- 25029927 TI - Emotional labour of caring for hematopoietic stem cell transplantation patients: Iranian nurses' experiences. AB - PURPOSE: The purpose of this study was to describe the emotional labour experienced by nurses who care for hematopoietic stem cell transplantation (HSCT) patients in Iran. METHODS: Eighteen nurses participated in semi-structured interviews. The interviews were analyzed using qualitative content analysis methods. RESULTS: Three main categories described the emotional labour involved, namely, emotional intimacy, feeling overwhelmed with the sadness and suffering, and changing self. Nurses had compassion for their patients, contributing to a close nurse-patient relationship. The nurses' emotional labour resulted in their feeling overwhelmed with sadness and suffering. Five subcategories described this emotional toll: (a) witnessing suffering, (b) struggling mentally, (c) hurting emotionally, (d) feeling drained of energy, and (e) escaping grief. Dealing with death and dying on an ongoing basis promoted the nurses' changing self. CONCLUSION: Iranian nurses who care for HSCT patients experience a range of positive and negative emotions. Establishing appropriate support systems for nurses might help mediate the negative aspects of emotional labour. thereby improving nursing work life and ultimately the quality of patient care. PMID- 25029928 TI - Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Recent observational studies have suggested that use of statins reduces mortality in patients suffering from chronic obstructive pulmonary disease. However, no meta-analysis has reported the pooled hazard ratio of statins to all-cause mortality. METHODS: We searched for eligible articles using five databases. We included randomized controlled trials and cohort studies written in English using original data reporting the hazard ratio of statins to all-cause, cardiovascular-related, cancer-related, or respiratory-related mortality. A fixed model with the confidence interval method was used. Publication bias was evaluated by funnel plot and Begg's test, and was corrected using Duval's trim and fill method. Sensitivity analyses were also conducted. RESULTS: We included 10 out of 128 articles. The pooled hazard ratio of statins to all-cause mortality involving 16269 patients was 0.81 (95% CI: 0.75-0.86, P < 0.001) with moderate heterogeneity (I2 = 52%, P = 0.032). The sensitivity analysis and funnel plot suggested the existence of publication bias. After three possibly unpublished cohorts were imputed, the pooled hazard ratio of 0.83 (95% CI: 0.78-0.88, P < 0.001) still suggested a favorable prognosis in statin-treated patients. The pooled hazard ratio of statins to cardiovascular-related, cancer related, and respiratory-related mortality were 0.52 (95% CI: 0.27-1.01, P = 0.052), 0.57 (95% CI: 0.32-1.01, P = 0.056), and 0.55 (95% CI: 0.43-0.78, P < 0.001), respectively, although these results were not conclusive as we could not find a sufficient number of original studies dealing with those forms of mortality. CONCLUSIONS: The use of statins for patients suffering from chronic obstructive pulmonary disease may reduce all-cause mortality. This conclusion should be re-evaluated by a registered large-scale randomized controlled trial. PMID- 25029929 TI - Nuclear medicine procedures in the diagnosis of NET: a historical perspective. AB - Novel diagnostic tools and therapies have emerged as a result of the continuous endeavors relating to neuroendocrine tumors (NETs). Nuclear medicine plays a pivotal role in the imaging and treatment of NETs. Somatostatin receptor analogues and metaiodobenzylguanidine remain front-line single-photon emission computed tomography (SPECT) radiotracers in the imaging of NET; their utility has been augmented by the increasing availability of SPECT/CT. Positron emission tomography has been growing rapidly in the imaging of NETs, paralleled by great efforts toward the development of new tracers. Hybrid imaging will play an important role in the future of NETs. PMID- 25029930 TI - Single-photon emission computed tomography tracers in the diagnostics of neuroendocrine tumors. AB - Different imaging strategies have been developed targeting the peculiar features of neuroendocrine tumors (NETs). Metabolic characteristics and receptor expression on the tumor surface have been studied, and expertise and knowledge are increasing as a result of the implementation of fusion imaging and the development of more detailed positron emission tomography tracers. Scintigraphic study of NETs is the most diffused and convenient technique for evaluating patients suspected to have NETs. PMID- 25029931 TI - 18F-fluorodihydroxyphenylalanine in the diagnosis of neuroendocrine tumors. AB - (18)F-fluorodihydroxyphenylalanine (FDOPA) is a powerful tool for the diagnosis and detection of neuroendocrine tumors when planning and monitoring surgical and oncologic therapies. Pheochromocytomas, paragangliomas, and medullary thyroid cancers especially are amenable to FDOPA imaging because of the high specific uptake of this amino acid analogue and excellent tumor-to-background contrast on PET/computed tomography. PMID- 25029932 TI - 68Ga-DOTA-peptides in the diagnosis of NET. AB - (68)Ga-DOTA-peptides are increasingly used for the detection of neuroendocrine tumors (NET) in clinical trials in Europe. They have been proved accurate for the detection of NET lesions (at primary and metastatic sites) and no adverse effects were recorded. Moreover, providing data on somatostatin receptors expression on NET cells, (68)Ga-DOTA-peptides PET/CT is becoming a fundamental procedure to be performed before starting therapy and to guide treatment with either hot or cold somatostatin analogues. The easy and economic synthesis process is another advantage that is supporting its clinical use even in centers without an on-site cyclotron. PMID- 25029933 TI - Role of 18F-fluorodeoxyglucose PET in the study of neuroendocrine tumors. AB - The most widely used PET radiopharmaceutical in daily clinical practice is (18)F fluorodeoxyglucose (FDG). The evaluation of glycolytic metabolism by (18)F-FDG is potentially useful in identifying high-risk patients with aggressive neuroendocrine disease associated with a poor outcome. Although the use of new somatostatin analogues labeled with 68-Gallium for PET has significantly increased the sensitivity of NET imaging compared with single photon emission computed tomography and (18)F-FDG-PET, (18)F-FDG may retain an important role in managing patients with NETs owing to its high prognostic value and its higher sensitivity in delineating disease extent, especially in aggressive and high grade tumors. PMID- 25029934 TI - Other PET tracers for neuroendocrine tumors. AB - In this article the applicability of (124)I-MIBG and (11)C-5-HTP PET for the detection of abdominal gastro-enteropancreatic neuroendocrine tumors is discussed. (124)I-MIBG is a positron-emitting variant of (123)I-MIBG and therefore suited for PET imaging. Due to the better intrinsic characteristics of PET, (124)I-MIBG PET has a higher spatial resolution than (123)I-MIBG and may therefore lead to better lesion detection in patients with neuroblastoma and pheochromocytoma. Research is ongoing to develop (18)F-labeled analogues and to assess its place in staging patients with gastro-enteropancreatic neuroendocrine tumors when compared with (18)F-FDOPA and (68)Ga-somatostatin PET analogues. PMID- 25029935 TI - Preclinical studies of SPECT and PET tracers for NET. AB - Radiolabeled somatostatin analogues are routinely used for the detection of neuroendocrine tumors (NETs), exploiting the expression of somatostatin-receptor subtypes on the cell membrane. Because of the heterogeneity of the origin of these tumors, the performance of radiolabeled somatostatin analogues in certain types of NETs is limited due to the low incidence or low levels of receptor expression. In this review, the most recent developments and in vitro and in vivo characterization of these radiolabeled peptide analogues are discussed. PMID- 25029936 TI - Yttrium-based therapy for neuroendocrine tumors. AB - Peptide receptor radionuclide therapy with (90)Y-peptides is generally well tolerated. Acute side effects are usually mild; some are related to the coadministration of amino acids and others to the radiopeptide itself. Chronic and permanent effects on target organs, particularly kidneys and bone marrow, are generally mild if necessary precautions are taken. The potential risk to kidney and red marrow limits the amount of radioactivity that may be administered. However, when tumor masses are irradiated with adequate doses, volume reduction may be observed. (90)Y-octreotide has been the most used radiopeptide in the first 8 to 10 years of experience. PMID- 25029937 TI - Patient selection for personalized peptide receptor radionuclide therapy using Ga 68 somatostatin receptor PET/CT. AB - Neuroendocrine tumors are malignant solid tumors originating from neuroendocrine cells dispersed throughout the body. Differentiated neuroendocrine tumors overexpress somatostatin receptors (SSTRs), which enable the diagnosis using radiolabeled somatostatin analogues. Internalization and retention within the tumor cell are important for peptide receptor radionuclide therapy using the same peptide. The use of the same DOTA-peptide for SSTR PET/CT using (68)Ga and for peptide receptor radionuclide therapy using therapeutic radionuclides like (177)Lu and (90)Y offers a unique theranostic advantage. PMID- 25029938 TI - Theranostics with Ga-68 somatostatin receptor PET/CT: monitoring response to peptide receptor radionuclide therapy. AB - Peptide receptor radionuclide therapy involves selective targeting of neuroendocrine tumors through the somatostatin receptors, the aim being to increase radiation dose to the tumors and spare the normal tissue. The advantage of this internal radiation therapy is the ability to selectively target multiple metastases throughout the body. Early and accurate assessment of therapy response helps not only to identify the poor responders but also to personalize the treatment regimes with the aim of achieving maximum treatment benefit. This is the basis of theranostics. PMID- 25029939 TI - Relevance of PET for pretherapeutic prediction of doses in peptide receptor radionuclide therapy. AB - Personalized dosimetry in radionuclide therapy has gained much attention in recent years. This attention has also an impact on peptide receptor radionuclide therapy (PRRT). This article reviews the PET-based imaging techniques that can be used for pretherapeutic prediction of doses in PRRT. More specifically the usage of (86)Y, (90)Y, (68)Ga, and (44)Sc are discussed: their characteristics for PET acquisition, the available peptides for labeling, the specifics of the imaging protocols, and the experiences gained from phantom and clinical studies. These techniques are evaluated with regard to their usefulness for dosimetry predictions in PRRT, and future perspectives are discussed. PMID- 25029944 TI - Geographical and sociodemographic risk factors for allergic diseases in korean children. AB - PURPOSE: (a) To examine geographical distribution of childhood allergic diseases in Korea and (b) to identify geographical and sociodemographic risk factors for allergic diseases. METHODS: Data on doctor-diagnosed asthma during lifetime and allergic rhinitis and atopic dermatitis during the past 12 months of 8,631 children (<= 18 years) were obtained from the Third Korea National Health and Nutrition Examination Survey, along with information on housing type and presence of an indoor smoker. The SaTScan program identified geographical case clusters of allergic diseases, and multiple logistic regression determined risk factors, including geographical case clusters, for each allergic disease. RESULTS: Prevalence of asthma, allergic rhinitis, and atopic dermatitis was 3.2%, 13.2%, and 15.5%, respectively. Older children (10-18 years) were more likely to have allergic rhinitis whereas younger children were more likely to have atopic dermatitis. It is noteworthy that children living in areas of geographical risk for asthma and atopic dermatitis were more likely to develop the respective allergic disease than children living in other areas (odds ratio [OR] = 3.47 for asthma, and OR = 9.74 for atopic dermatitis). CONCLUSIONS: This study indicates that the areas in which children live may influence the development of certain allergic diseases. Implications include the need to assess geographical location of children with allergic diseases and to develop community-based preventive programs for children with allergic diseases. PMID- 25029945 TI - Influences of Allocating HIV/AIDS Specialized Nurses on Clinical Outcomes in Japan. AB - PURPOSE: This retrospective cohort study was conducted to demonstrate how allocation of nurses specialized in HIV care influences clinical outcomes of antiretroviral therapy (ART) for people living with HIV (PLWH). METHODS: The medical records of 116 PLWH who started ART between January 2002 and December 2004 were analyzed. Occurrence of viral suppression and viral relapse after suppression achievement and their time from baseline were observed as clinical outcomes related to ART. Clinical outcomes were obtained from medical records between January 2002 and December 2006. PLWH were classified into two groups according to allocation (n = 95, nurse allocated group) or nonallocation (n =21, nurse nonallocated group) of nurses specialized in HIV. RESULTS: Survival analysis showed that HIV viral load was suppressed more rapidly and continuously in nurse allocated group than nonallocated group (p < .0001). Viral relapse after suppression achievement occurred easily in nurse nonallocated group than allocated group (p = .003). CONCLUSIONS: The present findings demonstrated that the role of specialized nurses is critically important from the viewpoint of clinical outcome. PMID- 25029946 TI - Music Therapy on Anxiety, Stress and Maternal-fetal Attachment in Pregnant Women During Transvaginal Ultrasound. AB - PURPOSE: The purpose of this study was to examine the effects of music therapy on anxiety, stress and maternal-fetal attachment in pregnant women during a transvaginal ultrasound. METHODS: This study was a nonequivalent control group nonsynchronized design. Pregnant women (n =232) were assigned to experimental (n= 117) and control (n =116) groups respectively. The data were collected from August 2 to 27, 2010. The experimental group received general prenatal care and single 30-minute session of music therapy, while the control group received only general prenatal care. Anxiety, stress, and maternal-fetal attachment was assessed using three self-report measures by State scale of the State-Trait Anxiety Inventory (1976), Pregnant women's stress scale of Ahn (1984) and Cranley's (1981) maternal-fetal attachment scale. RESULTS: The music therapy group showed statistically significant decrease in anxiety compared to control group but no significant difference was identified in stress and maternal-fetal attachment. CONCLUSIONS: The finding provides evidence for use of nursing intervention in prenatal care unit to reduce pregnant women's anxiety. Further research is necessary to test the benefits of music therapy with different frequency and duration. PMID- 25029947 TI - A comparative study on the validity of fall risk assessment scales in korean hospitals. AB - PURPOSE: The purpose of this study was to compare the validity of three fall risk assessment scales including the Morse Fall Scale (MFS), the Bobath Memorial Hospital Fall Risk Assessment Scale (BMFRAS), and the Johns Hopkins Hospital Fall Risk Assessment Tool (JHFRAT). METHODS: This study was a prospective validation cohort study in five acute care hospitals in Seoul and Gyeonggi-Do, Korea. In total, 356 patients over the age of 18 years admitted from December 2009 to February 2010 participated. The three fall risk assessment scales listed above were tested for sensitivity, specificity, positive predictive and negative predictive values. A receiver-operating characteristic (ROC) curve was generated to show sensitivities and specificities for predicting falls based on different threshold scores for considering patients at high risk. RESULTS: Based on the mean scores of each scale for falls, the MFS at a cut-off score of 50 had a sensitivity of 78.9%, specificity of 55.8%, positive predictive value of 30.8%, and negative predictive value of 91.4%, which were the highest values among the three fall assessment scales. Areas under the curve of the ROC curves were .761 for the MFS, .715 for the BMFRAS, and .708 for the JHFRAT. CONCLUSIONS: Accordingly, of the three fall risk assessment scales, the highest predictive validity for identifying patients at high risk for falls was achieved by the MFS. PMID- 25029948 TI - What influences malaysian nurses to participate in continuing professional education activities? AB - PURPOSE: A cross sectional descriptive study, which involved government hospitals and health clinics from Peninsular Malaysia sought to identify the continuing professional education (CPE) needs and their readiness for E-learning. This paper focuses on the first phase of that study that aimed to determine the factors that influence nurses' participation in CPE. METHODS: Multistage cluster sampling was used to recruit 1,000 nurses randomly from 12 hospitals and 24 health clinics from four states in Peninsular Malaysia who agreed to be involved. The respondent rate was 792 (79.2%), of which 562 (80%) had participated in CPE in the last 12 months. RESULTS: Findings suggested that updating knowledge and providing quality care are the most important factors that motivate participation in CPE, with respective means of 4.34 and 4.39. All the mean scores for educational opportunity were less than 3.0. Chi-square tests were used to test the association of demographic data and CPE participation. All demographical data were significantly associated with CPE participation, except marital status. CONCLUSIONS: Implementation of mandatory CPE is considered an important measure to increase nurse's participation in CPE. However, effective planning that takes into consideration the learning needs of nurses is recommended. PMID- 25029949 TI - Factors Affecting the Self-directed Learning of Students at Clinical Practice Course for Advanced Practice Nurse. AB - PURPOSE: The current study aimed to examine the casual relationships among belongingness during clinical practice, stress, satisfaction with clinical practice, and self-esteem, which are factors affecting the self-directed learning that results from the clinical practice of advanced practice nurse (APN) students. METHODS: Data were collected between April 5 and May 19, 2010, from 202 students in 11 APN training institutions located in and outside of Seoul, who were selected using convenience sampling. For hypothesis testing, the collected data were analyzed using AMOS 8.0. RESULTS: Analysis of the path coefficients in this study showed that 37% of the variation in self-directed learning could be explained by variations in the model. Self-esteem and belongingness during clinical practice directly affected the self-directed learning of APN students, and belongingness also had an indirect effect via self-esteem. However, stress and satisfaction with clinical practice had no significant mediating effect on self-directed learning. At the same time, belongingness during clinical practice was found to be a good predictive factor to explain stress and satisfaction with clinical practice. CONCLUSIONS: This study demonstrated the hierarchical relationship among belongingness, self-esteem, and self-directed learning based on the conceptual framework developed by Levett-Jones and Lathlean, thus proving the usefulness of this framework for application in the field. Therefore, this study found that there are needs of high self-esteem and belongingness in order to improve self-directed learning for APN students in clinical practice. PMID- 25029950 TI - Chest physiotherapy on the respiratory mechanics and elimination of sputum in paralyzed and mechanically ventilated patients with acute lung injury: a pilot study. AB - PURPOSE: Chest physiotherapy (CPT) is commonly used for mechanically ventilated patients, but little is known about its physiological effects, particularly in patients with acute lung injury (ALI). The aim of the study was to determine the benefits and risks of delivering multimodal respiratory physiotherapy to mechanically ventilated patients with ALI receiving paralytic agents. METHODS: A repeated measure-experimental design using a counterbalancing method was employed. Fifteen patients received CPT (vibration, percussion, or palm-cup percussion) in addition to the routine CPT in a randomized order. Another 15 patients, contraindicated for the percussion technique, received routine CPT including manual hyperinflation and position change, and were observed as a comparative group. The effects of CPT were evaluated by measuring the volume of aspirated secretions and the dynamic lung compliance (Cd) over time. For the adverse effects, peripheral oxygen saturation (SpO2) was recorded. Cd and SpO2 were recorded at the baseline period, immediately after the physiotherapy treatment, and at 10, 20, 30 and 60 minutes posttreatment. RESULTS: The volume of collected secretions did not differ significantly when compared between the groups (p = .838). Cd increased significantly over time in the manual percussion (p = .042) and palm-cup percussion (p = .046) group, where Cd in the latter remained elevated twice longer than in the former. None of the CPT techniques exerted major detrimental effects on SpO2. CONCLUSIONS: We found that the palm cup percussion technique was the most effective in increasing Cd without any accompanying detrimental effects on SpO2. However, additional CPT did not affect the volume of aspirated secretions. PMID- 25029952 TI - Cell detachment and label-free cell sorting using modulated surface acoustic waves (SAWs) in droplet-based microfluidics. AB - We present a droplet-based surface acoustic wave (SAW) system designed to viably detach biological cells from a surface and sort cell types based on differences in adhesion strength (adhesion contrast) without the need to label cells with molecular markers. The system uses modulated SAW to generate pulsatile flows in the droplets and efficiently detach the cells, thereby minimizing the SAW excitation power and exposure time. As a proof of principle, the system shows efficient sorting of HEK 293 from A7r5 cells based on adhesion contrast. Results are obtained in minutes with sorting purity and efficiency reaching 97% and 95%, respectively. PMID- 25029951 TI - Interventions for adult Eustachian tube dysfunction: a systematic review. AB - BACKGROUND: Eustachian tube dysfunction (ETD) is the inability of the Eustachian tube (ET) to adequately perform at least one of its functions: to protect the middle ear from sources of disease, to ventilate the middle ear, and to help drain secretions away from the middle ear. There are a number of treatment options for ETD, but there is little consensus about management. OBJECTIVES: To determine the clinical effectiveness of interventions for adult ETD and to identify gaps in the evidence to inform future research. DATA SOURCES: Twelve databases were searched up to October 2012 for published and unpublished studies in English (e.g. MEDLINE from 1946, EMBASE from 1974, Biosis Previews from 1969 and Cumulative Index to Nursing and Allied Health Literature from inception). References of included studies, relevant systematic reviews and regulatory agency websites were checked. REVIEW METHODS: A systematic review was undertaken. Controlled studies evaluating prespecified treatments for adult patients diagnosed with ETD were eligible. Uncontrolled studies with at least 10 participants were included for interventions where no controlled studies were found. Outcomes included change in symptoms severity/frequency (primary outcome), quality of life, middle ear function, hearing, clearance of middle ear effusion, early ventilation tube extrusion, additional treatment, adverse events and complications. All aspects of the review process were performed using methods to reduce reviewer error and bias. Owing to heterogeneous data, a quantitative synthesis could not be performed, and results were reported in a narrative synthesis. RESULTS: Nineteen studies were included: three randomised controlled trials (RCTs) and two non-RCTs evaluating pharmacological interventions or mechanical devices for middle ear pressure equalisation; and 13 case series and one retrospective controlled before-and-after study evaluating surgical interventions. None was conducted in the UK. All studies were small (11 to 108 participants). Most non-surgical studies reported including mixed populations of adults and children. All except two studies were at high risk of bias, and subject to multiple limitations. Based on a single RCT, nasal steroids showed no improvement in symptoms or middle ear function for patients with otitis media with effusion and/or negative middle ear pressure. Very short-term improvements in middle ear function were observed in patients receiving directly applied topical decongestants or a combination of antihistamine and ephedrine. Single trials found two pressure equalisation devices were each associated with significant short-term improvements in symptoms, middle ear function and/or hearing. Eustachian tuboplasty (seven case series) and balloon dilatation (three case series) were associated with improved outcomes. Positive results were also reported for myringotomy (two case series), directly applied topical steroids (one case series) and laser point coagulation (one controlled before-and-after study). High rates of co-interventions were documented. Minor complications of surgery and pharmacological treatments but no serious adverse effects were reported. LIMITATIONS: The evidence was limited in quantity and overall was of poor quality. No data were identified on several interventions despite extensive searches. CONCLUSIONS: It is not possible to draw conclusions regarding the effectiveness of any of the interventions for the treatment of adults with an ETD diagnosis, and there is insufficient evidence to recommend a trial of any particular intervention. Further research is needed to address lack of consensus on several issues, including the definition of ETD in adults, its relation to broader middle ear ventilation problems and clear diagnostic criteria. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003035. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25029953 TI - Effect of six-month lifestyle intervention on adiponectin, resistin and soluble tumor necrosis factor-alpha receptors in obese adolescents. AB - The aim of this study was to evaluate the effect of a six-month lifestyle intervention on adiponectin, resistin, and two soluble forms of tumor necrosis factor-alpha receptor (sTNFR) in obese adolescents. A total of 54 obese adolescents aged 10 to 16 years completed the program. Twenty-four adolescents with normal weight at baseline were used as a control group. Our results demonstrated that obese adolescents had abnormal lipid profile, homeostasis model assessment (HOMA) index, adiponectin level (5.6 +/- 2.7 vs. 7.6 +/- 2.9 MUg/mL, p = 0.005) as well as resistin level (31.0 +/- 9.0 vs. 24.3 +/- 8.5 ng/mL, p = 0.003), whereas levels of both sTNFRs were similar to those in normal weight subjects. After the six-month lifestyle intervention, obese adolescents had a slight but significant drop in standard deviation score-body mass index (SDS BMI), a significant decrease in waist circumference, total cholesterol, triglycerides, HOMA index, as well as resistin, and a significant increase in adiponectin and high-density lipoprotein-cholesterol. In adolescents without decreased SDS-BMI, no change was observed in adipokines. Changes in adiponectin correlated negatively with changes in waist circumference (r = -0.275, p = 0.044). Changes in resistin correlated positively with changes in triglycerides (r = 0.302, p = 0.027). The study demonstrated the increase of resistin and the decrease of adiponectin in obese adolescents. Lifestyle intervention improved adipokine abnormalities in obese subjects. PMID- 25029954 TI - Changes in serum thyroglobulin antibody levels as a dynamic prognostic factor for early-phase recurrence of thyroglobulin antibody-positive papillary thyroid carcinoma after total thyroidectomy. AB - We demonstrated previously that dynamic prognostic markers such as the thyroglobulin (Tg)-doubling time in thyroglobulin antibody (TgAb)-negative papillary thyroid carcinoma (PTC) and changes in pre- and postoperative TgAb levels in TgAb-positive PTC patients more keenly reflect patients' prognosis than conventional static prognostic factors. Here we investigated periodic changes in TgAb levels in 513 TgAb-positive PTC patients who underwent total thyroidectomy. The TgAb levels at 1 year after surgery decreased to <50% of the preoperative values in 407 (79%) patients, and the remaining 106 (21%) patients showed no decrease in TgAb. In 426 patients, TgAb was also measured more than 1 year after surgery. Compared with their TgAb levels 1 year after surgery, 59 patients (14%) showed an increase in TgAb levels of >20% during the follow-up. The postoperative Tg levels at 1 year after surgery remained positive in 44 (9%) patients despite their TgAb positivity. To date (median follow-up period 35 months), 12 of the 426 patients (3%) showed PTC recurrence, and 11 of these patients showed either or both a TgAb elevation later than 1 year after surgery and postoperative Tg positivity. Although further studies with longer follow-ups are necessary, we can conclude that changes in postoperative TgAb levels may be usable as a surrogate tumor marker for TgAb-positive PTC patients after total thyroidectomy. PMID- 25029955 TI - Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study. AB - The aim of this study was to evaluate the dose-dependent effect of dulaglutide, a glucagon-like peptide-1 receptor agonist, on glycaemic control in Japanese patients with type 2 diabetes mellitus who were treated with diet/exercise or oral antidiabetic drug monotherapy. In this randomised, double-blind, placebo controlled, parallel-group, 12-week study, patients received once weekly subcutaneous dulaglutide doses of 0.25, 0.5, or 0.75 mg (DU 0.25, DU 0.5, and DU 0.75, respectively) or placebo (n=36, 37, 35, and 37, respectively). The primary measure was change from baseline in glycated haemoglobin (HbA1c; %) at 12 weeks. Continuous variables were analysed using a mixed-effects model for repeated measures. Significant dose-dependent reductions in HbA1c were observed (least squares mean difference versus placebo [95% confidence interval]): DU 0.25=-0.72% (-0.95, -0.48), DU 0.5=-0.97% (-1.20, -0.73), and DU 0.75=-1.17% (-1.41, -0.93); p<0.001. Significant improvements in plasma glucose (PG), both fasting and average 7-point self-monitored blood glucose, were also observed with dulaglutide versus placebo (p<0.001). Dulaglutide was well-tolerated. Gastrointestinal adverse events (AEs) were more common in dulaglutide-treated patients, with nausea the most frequent (8 [5.5%]). Few dulaglutide-treated patients discontinued due to AEs (4 [3.7%]), and no serious AEs related to study medication occurred. Three patients (DU 0.5=1 and DU 0.75=2) reported asymptomatic hypoglycaemia (PG <=70 mg/dL). The observed dose-dependent reduction in HbA1c and acceptable safety profile support further clinical development of dulaglutide for treatment of type 2 diabetes mellitus in Japan. PMID- 25029956 TI - Reduction in circulating ghrelin concentration after maturation does not affect food intake. AB - Ghrelin has a potent orexigenic effect and induces adiposity when administered exogenously. Since plasma ghrelin levels rise before meals, ghrelin was thought to play a crucial role in the regulation of appetite. In contrast, mice deficient in the production of ghrelin or the corresponding receptor, GHS-R, do not eat less, throwing the role of ghrelin in the regulation of energy homeostasis into question. Since these mice lack ghrelin or GHS-R from the time of conception, the possibility that compensatory mechanisms may have arisen during development cannot be ruled out. In this study, we used a transgenic mouse model that expresses human diphtheria toxin (DT) receptor cDNA under the control of the ghrelin promoter (GPDTR-Tg mice). As previously reported, an injection of DT into this mouse model ablates ghrelin-secreting cells in the stomach but not in the hypothalamus, resulting in a reduction in circulating ghrelin levels. We used this model system to evaluate the physiological roles of circulating ghrelin in the regulation of food intake. Meal patterns, diurnal and nocturnal meal sizes, and cumulative food intake of DT-treated GPDTR-Tg mice were not affected, although circulating ghrelin levels markedly decreased even after fasting. These mice also displayed normal responses to starvation; however, the use of fat increased and slower weight gain when maintained on a high fat diet was observed. Together, these data suggest that circulating ghrelin does not play a crucial role in feeding behavior, but rather is involved in maintaining body weight. PMID- 25029957 TI - Family caregivers of older people in nursing homes. AB - PURPOSE: This paper aims to review literature related to the experiences of family caregivers after institutionalization of their older relatives. METHODS: Thirty-one research-based articles were reviewed for information on the following six dimensions: caregivers' involvement in care; the effects of institutionalization on mental health of caregivers; predictors of caregivers' mental health; caregivers' feelings; caregivers' difficulties and needs; and interventions for caregivers. RESULTS: Family caregivers continued their caregiver roles after institutionalization. There was a significant decrease in the caregivers' burden after institutionalization. Depression in caregivers, however, was not significantly reduced. The predictors of caregivers' mental health included characteristics of care recipients, caregivers, and institutions as well as interactions. After institutionalization, caregivers experienced positive feelings, negative feelings, and mixed feelings. Caregivers encountered many difficulties related to care recipients' decreasing cognitive functions, care recipients' behavioral problems, and institutional problems. Interventions improved caregivers' outcomes, care recipients' outcomes, staff members' outcomes, and the communication/relationships among the three groups. CONCLUSION: This review expands existing knowledge and provides valuable information. Nurses and researchers need to conduct more research related to family caregivers' difficulties and needs. Future studies should develop more effective interventions and test the effects of interventions on family caregivers as well as care recipients and staff members. PMID- 25029958 TI - Levinas' ethics of caring: implications and limits in nursing. AB - Nursing scholars consider caring a key concept in understanding what is involved in nursing and believe that it is a major issue in nursing ethics. In this paper, the moral characteristics required for nursing care are described and these characteristics are discussed on the basis of taking responsibility for the Other, as described in Levinas' ethics. First of all, the altruistic aspect of care in terms of Levinas' ethics is examined. That is, a nurse should meet the needs of a person who is suffering, respond to them morally, and take responsibility. Levinas puts an emphasis on passive sensibilities that lead a nurse to respond to the needs of someone who is suffering, and also on the moral responsibility that encourages a nurse to empathize with others. However, his ethics cannot explain clearly how a nurse, as a moral subject with autonomy, forms a caring relationship with others. PMID- 25029959 TI - Fear of falling in older adults: comprehensive review. AB - Fear of falling has been reported in a high percentage of community-dwelling elderly who both do and don't have a history of falling. The aims of this review are to: (a) elucidate the definition of fear of falling; (b) clarify measurements of fear of falling based on its definition; and (c) describe the risk factors for fear of falling. Despite the importance of the percentage and the consequences of fear of falling, its definition is still vague and warrants clarification. Based on a literature review, major fear of falling measurements involve the evaluation of fear of falling and use of a fall efficacy scale. Using a correct definition of fear of falling, nurses working close with older adults need to identify the different definitions of fear of falling and fall efficacy scale. In addition, nurses who work closely with older adults should encourage them to increase or maintain modifiable factors by maximizing their basic health status and enhancing their physical activity to decrease fear of falling. PMID- 25029960 TI - Family Experiences in End-of-Life Care: A Literature Review. AB - PURPOSE: The purpose of this study was to summarize and analyze families' experiences of end-of-life care by conducting a systematic review of peer reviewed journals both in Korea and abroad. BACKGROUND: Families play an increasingly important role in care and medical treatment, acting as caregivers or decision makers rather than just being passive observers. It is necessary to understand the experiences of family members in order to provide appropriate care for them. METHODS: A systematic search of the literature was performed using the Cumulative Index for Nursing and Allied Health Literature (CINAHL) and the Korea Education & Research Information Service (KERIS) for the period of January 1990 through to December 2006. A total of 35 studies met the inclusion criteria. RESULTS: Seventeen studies used a quantitative design, while 18 studies used qualitative methods. Quantitative studies reported that the family's quality of life was relatively low when the patient was in need of high medical/nursing services. The perceived burden levels were moderately high, and depression levels were high among family caregivers. Various concepts emerged from the 18 qualitative studies, including psychological issues, physical problems, burdens, needs and interpersonal relationships. CONCLUSION: This study found that most previous research findings were focused on negative and neutral experiences. A few studies identified positive experiences. Based on the study results, we suggest that nurses need to be more aware of the experiences of patients' families and their potential needs. PMID- 25029961 TI - The effects of tai chi exercise on elders with osteoarthritis: a longitudinal study. AB - PURPOSE: Tai Chi exercise has been proven to be beneficial among elders with osteoarthritis (OA). The long-term effects of this exercise remain unclear. The purpose of this study was to evaluate the effects of the Tai Chi exercise for Arthritis (TCEA) program on the physical status and quality of life of OA elders. METHODS: This was a time series study with one group design. Subjects diagnosed with OA of the lower extremities, aged 60 years or over, were recruited from an outpatient clinic at a community teaching hospital. Thirteen participants joined a TCEA exercise class three times per week for 2 years. Physical status including body mass index (BMI), lean body mass, hand grasp strength, flexibility, and equilibrium were measured four times-at baseline, 3 months, 1 year, and 2 years of the TCEA exercise class. Quality of life was also measured at these time points. RESULTS: Lean body mass was significantly decreased within the study period (p < .05). Participants experienced significant improvements in physical functioning, role limitations, and social functioning on the dimensions of quality of life (SF-36) (p < .05). CONCLUSION: Elderly people with OA should be encouraged to exercise using Tai Chi for maintaining physical function and improving quality of life. PMID- 25029962 TI - Evaluation of the bioaccumulation of heavy metals in white shrimp (Litopenaeus vannamei) along the Persian Gulf coast. AB - The concentrations of heavy metals in Persian Gulf are low, but petrochemical and refinery activities have caused an increase in heavy metal wastes, especially in coastal regions. The present study was done to determine the bioaccumulation of heavy metals in the muscle of white shrimp (Litopenaeus vannamei) using flame atomic absorption spectrophotometry. The experiment was conducted in four important coastal regions of the Persian Gulf: Bushehr, Deylam, Mahshahr, and Abadan. Amounts of seven heavy metals such as Copper (Cu), Iron (Fe), Lead (Pb), Zinc (Zn), Nickel (Ni), Cadmium (Cd), and Cobalt (Co), were measured as ug/g heavy metal in dry weight in the muscle of white shrimp from the afore-mentioned regions during 2011. This study revealed information that the primary risk for human health and the marine life chain was lead in the muscles of white shrimp in Mahshahr, where intense petrochemical and refinery activities are conducted. Concentrations of other heavy metals were lower than world standards. PMID- 25029963 TI - Historical trends of atmospheric black carbon on Sanjiang Plain as reconstructed from a 150-year peat record. AB - Black carbon (BC), one of the major components of atmosphere aerosol, could be the second dominant driver of climate change. We reconstructed historical trend of BC fluxes in Sanjiang Plain (Northeast China) through peat record to better understand its long-term trend and relationship of this atmosphere aerosol with intensity of human activities. The BC fluxes in peatland were higher than other sedimentary archives. Although global biomass burning decreased in last 150 years, regional large scale reclaiming caused BC fluxes of the Sanjiang Plain increased dramatically between 1950s' and 1980s', most likely resulting from using fire to clearing dense pastures and forests for reclaiming. The BC fluxes have increased since 1900s with increasing of the population and the area of farmland; the increase trend has been more clearly since 1980s. Based on Generalized additive models (GAM), the proportional influence of regional anthropogenic impacts have increased and became dominant factors on BC deposition. PMID- 25029964 TI - Reduction of false-positive recalls using a computerized mammographic image feature analysis scheme. AB - The high false-positive recall rate is one of the major dilemmas that significantly reduce the efficacy of screening mammography, which harms a large fraction of women and increases healthcare cost. This study aims to investigate the feasibility of helping reduce false-positive recalls by developing a new computer-aided diagnosis (CAD) scheme based on the analysis of global mammographic texture and density features computed from four-view images. Our database includes full-field digital mammography (FFDM) images acquired from 1052 recalled women (669 positive for cancer and 383 benign). Each case has four images: two craniocaudal (CC) and two mediolateral oblique (MLO) views. Our CAD scheme first computed global texture features related to the mammographic density distribution on the segmented breast regions of four images. Second, the computed features were given to two artificial neural network (ANN) classifiers that were separately trained and tested in a ten-fold cross-validation scheme on CC and MLO view images, respectively. Finally, two ANN classification scores were combined using a new adaptive scoring fusion method that automatically determined the optimal weights to assign to both views. CAD performance was tested using the area under a receiver operating characteristic curve (AUC). The AUC = 0.793 +/- 0.026 was obtained for this four-view CAD scheme, which was significantly higher at the 5% significance level than the AUCs achieved when using only CC (p = 0.025) or MLO (p = 0.0004) view images, respectively. This study demonstrates that a quantitative assessment of global mammographic image texture and density features could provide useful and/or supplementary information to classify between malignant and benign cases among the recalled cases, which may eventually help reduce the false-positive recall rate in screening mammography. PMID- 25029966 TI - Fluorescent probes for hydrogen sulfide detection and bioimaging. AB - In comparison with other biological detection technologies, fluorescence bioimaging technology has become a powerful supporting tool for intracellular detection, and can provide attractive facilities for investigating physiological and pathological processes of interest with high spatial and temporal resolution, less invasiveness, and a rapid response. Due to the versatile roles of hydrogen sulfide (H2S) in cellular signal transduction and intracellular redox status regulation, fluorescent probes for the detection of this third signalling gasotransmitter have rapidly increased in number in recent years. These probes can offer powerful means to investigate the physiological actions of H2S in its native environments without disturbing its endogenous distribution. In this feature article, we address the synthesis and design strategies for the development of fluorescent probes for H2S based on the reaction type between H2S and the probes. Moreover, we also highlight fluorescent probes for other reactive sulfur species, such as sulfane sulfurs and SO2 derivatives. PMID- 25029965 TI - Is experimentally induced pain associated with socioeconomic status? Do poor people hurt more? AB - BACKGROUND: The association of pain and socioeconomic status is widely reported, yet much less clearly understood. The aim of this study was to investigate the association of experimentally induced pain threshold and tolerance with socioeconomic status. MATERIAL/METHODS: The study sample consisted of 319 adult subjects from the population of the island of Vis, Croatia, which was previously shown to have a high level of social homogeneity. A manual dolorimeter was used to measure mechanical pressure pain threshold (least stimulus intensity) and pain tolerance (maximum tolerance stimulus intensity) on both hands. Pain tolerance interval was defined as the difference between pain tolerance and threshold. Years of schooling and material status were used as socioeconomic estimates. RESULTS: Both of the socioeconomic estimates were significantly correlated with pain threshold, tolerance, and tolerance interval (P<0.001). The mixed modeling analysis, controlled for the effects of age, gender, and 4 psychological variables, indicated that education was not a significant predictor in any of the 3 models. However, lower material status was significantly associated with lower pain tolerance (P=0.038) and narrower pain tolerance interval (P=0.032), but not with pain threshold (P=0.506). The overall percentages of explained variance were lower in the tolerance interval model (20.2%) than in pain tolerance (23.1%) and threshold (33.1%), suggesting the increasing share of other confounding variables in pain tolerance and even more so in tolerance interval model. CONCLUSIONS: These results suggest a significant association between experimentally induced pain tolerance and tolerance interval with material status, suggesting that poor people indeed do hurt more. PMID- 25029967 TI - Effects on electrochemical performances for host material caused by structure change of modifying material. AB - High ionic conductive lithium niobium oxides were selected as the modifying material to investigate the effects on the electrochemical performances for host material LiNi1/3Co1/3Mn1/3O2 caused by the structure change of the modifying material at various calcination temperatures and modifying amounts. X-ray diffraction (XRD) studies revealed that the structure of the modifying material was single LiNbO3 phase after being calcined at 500 degrees C and changed to LiNbO3-Li3NbO4 mixture phases at 600 and 700 degrees C, and further changed to single Li3NbO4 phase at 800 degrees C. Electrochemical tests displayed that both LiNbO3 and Li3NbO4 phases of modifying material could contribute to the improvement of the cycle performances for the host material, but the improvement degree of Li3NbO4 phase was more evident. The cycle performances and high rate performances of the modified host material (calcined at 700 degrees C) electrodes were improved with the right modifying amount. PMID- 25029968 TI - Excitonic quasiparticles in a spin-orbit Mott insulator. AB - In condensed matter systems, out of a large number of interacting degrees of freedom emerge weakly coupled quasiparticles (QPs), in terms of which most physical properties are described. The lack of identification of such QPs is a major barrier for understanding myriad exotic properties of correlated electrons, such as unconventional superconductivity and non-Fermi liquid behaviours. Here we report the observation of a composite particle in a quasi-two-dimensional spin 1/2 antiferromagnet Sr2IrO4--an exciton dressed with magnons--that propagates with the canonical characteristics of a QP: a finite QP residue and a lifetime longer than the hopping time scale. The dynamics of this charge-neutral excitation mirrors the fundamental process of the analogous one-hole propagation in the background of spins-1/2, and reveals the same intrinsic dynamics that is obscured for a single, charged-hole doped into two-dimensional cuprates. PMID- 25029970 TI - Using value-of-information methods when the disease is rare and the treatment is expensive--the example of hemophilia A. AB - BACKGROUND: Hemophilia A is a rare, sex-linked genetic disorder treated with intravenous administration of factor VIII (FVIII) to prevent bleeding; however, approaches vary across and within countries. Value-of-information (VOI) methods identify situations in which the cost-benefit evidence is sufficient to adopt one treatment strategy over another; when the evidence is insufficient, VOI methods provide the optimal sample size for additional research. OBJECTIVE: The objective of the study was to use VOI methods in a cost-benefit decision context to evaluate the current evidence in support of using (1) alternate day prophylaxis (AP), (2) tailored prophylaxis (TP) or (3) on-demand treatment (OD) with FVIII to prevent arthropathy in children with severe hemophilia A. METHODS: To apply VOI methods, several parameters such as incidence, time horizon for the decision, costs, and threshold values to avoid MRI-detected joint damage or arthropathy were defined. Two baseline threshold values of willingness to pay for avoiding arthropathy--$200,000 and $400,000--were selected for comparing the treatment strategies. RESULTS: For threshold values < $200,000, OD had a higher expected net benefit than either prophylaxis strategy, and the evidence was sufficient for its adoption. For threshold values > $400,000 prophylaxis strategies had higher expected net benefit; however, a new trial with 38 patients per arm was needed to compare AP and TP, yielding an expected net gain of over $17 million. In sensitivity analyses, the results were robust to assumptions regarding discount rate, trial fixed and variable costs, enrollment fraction, and the time horizon. CONCLUSIONS: In rare diseases, evidence is often scarce and insufficient for decision making. In considering the funding of new research and patient reimbursement in rare diseases, VOI methodology may provide more relevant determinations of the value and costs of additional research, compared to standard frequentist methods. PMID- 25029971 TI - Important role of translational science in rare disease innovation, discovery, and drug development. AB - Rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science. Most rare diseases are genetic disorders or atypical manifestations of infectious, immunologic, or oncologic diseases; they all provide opportunities to study extremes of human pathology and provide insight into both normal and aberrant physiology. Recently, drug development has become increasingly focused on classifying diseases largely on genetic grounds; this has allowed the identification of molecularly defined targets and the development of targeted therapies. Clinical trials are now focusing on progressively smaller subgroups within both common and rare disease populations, often based on genetic tests or biomarkers. Drug developers, researchers, and regulatory agencies face a variety of challenges throughout the life cycle of drug research and development for rare diseases. These include the small numbers of patients available for study, lack of knowledge of the disease's natural history, incomplete understanding of the basic mechanisms causing the disorder, and variability in disease severity, expression, and course. Traditional approaches to rare disease clinical research have not kept pace with advances in basic science, and increased attention to translational science is needed to address these challenges, especially diagnostic testing, registries, and novel trial designs. PMID- 25029972 TI - Orphan therapies: making best use of postmarket data. AB - BACKGROUND: Postmarket surveillance of the comparative safety and efficacy of orphan therapeutics is challenging, particularly when multiple therapeutics are licensed for the same orphan indication. To make best use of product-specific registry data collected to fulfill regulatory requirements, we propose the creation of a distributed electronic health data network among registries. Such a network could support sequential statistical analyses designed to detect early warnings of excess risks. We use a simulated example to explore the circumstances under which a distributed network may prove advantageous. METHODS: We perform sample size calculations for sequential and non-sequential statistical studies aimed at comparing the incidence of hepatotoxicity following initiation of two newly licensed therapies for homozygous familial hypercholesterolemia. We calculate the sample size savings ratio, or the proportion of sample size saved if one conducted a sequential study as compared to a non-sequential study. Then, using models to describe the adoption and utilization of these therapies, we simulate when these sample sizes are attainable in calendar years. We then calculate the analytic calendar time savings ratio, analogous to the sample size savings ratio. We repeat these analyses for numerous scenarios. KEY RESULTS: Sequential analyses detect effect sizes earlier or at the same time as non sequential analyses. The most substantial potential savings occur when the market share is more imbalanced (i.e., 90% for therapy A) and the effect size is closest to the null hypothesis. However, due to low exposure prevalence, these savings are difficult to realize within the 30-year time frame of this simulation for scenarios in which the outcome of interest occurs at or more frequently than one event/100 person-years. CONCLUSIONS: We illustrate a process to assess whether sequential statistical analyses of registry data performed via distributed networks may prove a worthwhile infrastructure investment for pharmacovigilance. PMID- 25029973 TI - Application of a policy framework for the public funding of drugs for rare diseases. AB - BACKGROUND: In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs. OBJECTIVE: To report the initial experience of applying a novel evaluation framework to funding applications for drugs for rare diseases. METHODS: Retrospective observational cohort study. MEASURES: Clinical effectiveness, costs, funding recommendations, funding approval. KEY RESULTS: Between March 2008 and February 2013, eight drugs were evaluated using the DRDWG framework. The estimated average annual drug cost per patient ranged from 28,000 to 1,200,000 Canadian dollars (CAD). For five drugs, full evaluations were completed, specific funding recommendations were made by the DRDWG, and funding was approved after risk-sharing agreements with the manufacturers were negotiated. For two drugs, the disease indications were determined to be ineligible for consideration. For one drug, there was insufficient natural history data for the disease to provide a basis for recommendation. For the five drugs fully evaluated, 32 patients met the predefined eligibility criteria for funding, and five were denied based on predefined exclusion criteria. CONCLUSIONS: The framework improved transparency and consistency for evaluation and public funding of drugs for rare diseases in Ontario. The evaluation process will continue to be iteratively refined as feedback on actual versus expected clinical and economic outcomes is incorporated. PMID- 25029974 TI - Patient-reported outcomes in clinical trials of rare diseases. AB - The science of measuring patient-reported outcomes (PROs) has advanced substantially in recent decades, allowing evaluation of how patients feel and function in clinical research. Assessment of the patient experience in populations with rare diseases can be successfully achieved using PRO measures when careful planning and rigorous methods are employed. A number of challenges exist when designing and implementing PRO analyses in rare disease contexts, including heterogeneity of outcomes, availability of suitable measures, recruitment, and selection of appropriate data collection methods. Strategies to address these exist and have been employed in past clinical research, particularly in pediatric populations. PRO assessments in rare disease clinical trials have been particularly successful through partnerships between investigators, PRO methodologists, and patient organizations. The overall goal of PRO measurement is to understand the patient experience and it provides an essential part of evaluating the impact of disease and treatment. PMID- 25029975 TI - Longitudinal changes in health-related quality of life for chronic diseases: an example in hemophilia A. AB - BACKGROUND: Patients with well-managed rare chronic diseases such as hemophilia maintain a stable health state and health-related quality of life (HrQoL) that may be affected by acute events. Longitudinal HrQoL assessments analyzed using multivariate multilevel (MVML) modelling can determine the impact of such events on individuals (within-person effect) and identify factors influencing within population differences (between-person effect). OBJECTIVES: To demonstrate the application of MVML modelling in a longitudinal study of HrQoL in hemophilia A. METHODS/DESIGN/PARTICIPANTS: Using data on 136 adults and 125 children from a two year observational cohort study of burden of illness in US hemophilia A patients, MVML modelling determined the effect of time-invariant (sociodemographic and clinical characteristics) and time-varying factors (bleeding frequency, emergency room visits, and missed work/school days) on within-person and between-person HrQoL changes. HrQoL was assessed using the SF-12 health survey (adults) and PedsQL inventory (children) at baseline, then every 6 months. RESULTS: In children, within-person (p < 0.0001) and between-person (p < 0.0001) psychosocial functioning was reduced by each additional bleed and missed day (within-person: p = 0.0089; between-person: p = 0.0060). Within-person physical functioning was reduced by each additional bleed (p < 0.0001), emergency room (ER) visit (p = 0.0284), and missed day (p = 0.0473). Between-persons, additional missed days (p < 0.0001) significantly decreased physical functioning. In adults, each additional missed day reduced SF-12 Health Survey mental (p = 0.0025) and physical (p = 0.0093) component summary scores. Each additional bleed also decreased physical component summary (PCS) significantly (p = 0.0093). CONCLUSIONS: This study demonstrated the applicability of MVML modelling in identifying time-invariant and time-varying factors influencing HrQoL in a rare chronic disease population. Small but significant within-person and between person changes in HrQoL with each additional acute event experienced were identified, which if frequent, could have a large cumulative impact. The results suggest that MVML modelling may be applied to future studies of longitudinal change in HrQoL in other rare chronic disease populations. PMID- 25029976 TI - The Rare Diseases Clinical Research Network's organization and approach to observational research and health outcomes research. AB - Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2 months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases. PMID- 25029977 TI - Highly effective cystic fibrosis clinical research teams: critical success factors. AB - BACKGROUND: Bringing new therapies to patients with rare diseases depends in part on optimizing clinical trial conduct through efficient study start-up processes and rapid enrollment. Suboptimal execution of clinical trials in academic medical centers not only results in high cost to institutions and sponsors, but also delays the availability of new therapies. Addressing the factors that contribute to poor outcomes requires novel, systematic approaches tailored to the institution and disease under study. OBJECTIVE: To use clinical trial performance metrics data analysis to select high-performing cystic fibrosis (CF) clinical research teams and then identify factors contributing to their success. DESIGN: Mixed-methods research, including semi-structured qualitative interviews of high performing research teams. PARTICIPANTS: CF research teams at nine clinical centers from the CF Foundation Therapeutics Development Network. APPROACH: Survey of site characteristics, direct observation of team meetings and facilities, and semi-structured interviews with clinical research team members and institutional program managers and leaders in clinical research. KEY RESULTS: Critical success factors noted at all nine high-performing centers were: 1) strong leadership, 2) established and effective communication within the research team and with the clinical care team, and 3) adequate staff. Other frequent characteristics included a mature culture of research, customer service orientation in interactions with study participants, shared efficient processes, continuous process improvement activities, and a businesslike approach to clinical research. CONCLUSIONS: Clinical research metrics allowed identification of high-performing clinical research teams. Site visits identified several critical factors leading to highly successful teams that may help other clinical research teams improve clinical trial performance. PMID- 25029978 TI - RD-Connect: an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research. AB - Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical phenotype, genomic data, biomaterial availability, and research/trial data sets. Such data must be linked at both an individual patient and whole-cohort level to enable researchers to gain a complete view of their disease and patient population of interest. Data access and authorization procedures are required to allow researchers in multiple institutions to securely compare results and gain new insights. Funded by the European Union's Seventh Framework Programme under the International Rare Diseases Research Consortium (IRDiRC), RD-Connect is a global infrastructure project initiated in November 2012 that links genomic data with registries, biobanks, and clinical bioinformatics tools to produce a central research resource for rare diseases. PMID- 25029979 TI - Quantifying a rare disease in administrative data: the example of calciphylaxis. AB - BACKGROUND: Calciphylaxis, a rare disease seen in chronic dialysis patients, is associated with significant morbidity and mortality. As is the case with other rare diseases, the precise epidemiology of calciphylaxis remains unknown. Absence of a unique International Classification of Diseases (ICD) code impedes its identification in large administrative databases such as the United States Renal Data System (USRDS) and hinders patient-oriented research. This study was designed to develop an algorithm to accurately identify cases of calciphylaxis and to examine its incidence and mortality. DESIGN, PARTICIPANTS, AND MAIN MEASURES: Along with many other diagnoses, calciphylaxis is included in ICD-9 code 275.49, Other Disorders of Calcium Metabolism. Since calciphylaxis is the only disorder listed under this code that requires a skin biopsy for diagnosis, we theorized that simultaneous application of code 275.49 and skin biopsy procedure codes would accurately identify calciphylaxis cases. This novel algorithm was developed using the Partners Research Patient Data Registry (RPDR) (n = 11,451 chronic hemodialysis patients over study period January 2002 to December 2011) using natural language processing and review of medical and pathology records (the gold-standard strategy). We then applied this algorithm to the USRDS to investigate calciphylaxis incidence and mortality. KEY RESULTS: Comparison of our novel research strategy against the gold standard yielded: sensitivity 89.2%, specificity 99.9%, positive likelihood ratio 3,382.3, negative likelihood ratio 0.11, and area under the curve 0.96. Application of the algorithm to the USRDS identified 649 incident calciphylaxis cases over the study period. Although calciphylaxis is rare, its incidence has been increasing, with a major inflection point during 2006-2007, which corresponded with specific addition of calciphylaxis under code 275.49 in October 2006. Calciphylaxis incidence continued to rise even after limiting the study period to 2007 onwards (from 3.7 to 5.7 per 10,000 chronic hemodialysis patients; r = 0.91, p = 0.02). Mortality rates among calciphylaxis patients were noted to be 2.5-3 times higher than average mortality rates for chronic hemodialysis patients. CONCLUSIONS: By developing and successfully applying a novel algorithm, we observed a significant increase in calciphylaxis incidence. Because calciphylaxis is associated with extremely high mortality, our study provides valuable information for future patient-oriented calciphylaxis research, and also serves as a template for investigating other rare diseases. PMID- 25029980 TI - Utilization of health care services and satisfaction with care in adults affected by disorders of sex development (DSD). AB - BACKGROUND: Disorders of sex development (DSD) are a heterogeneous group of rare genetic disorders of sex determination or differentiation. Evidence-based guidelines concerning gender assignment and surgical and hormonal treatment are limited for many DSD entities, and health care is highly fragmented across various sub-specialties and settings. A lack of informed consent, secrecy about the condition, shame, and impaired sexual and psychosocial functioning may affect satisfaction with care. OBJECTIVES: The main goal of this study was to describe satisfaction with care in individuals with DSD and to identify factors associated with low satisfaction with care. METHODS/MAIN MEASURES: Using both biological (chromosomes) and social categories (sex of rearing), we classified participants according to the nomenclature of the European Society for Pediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society (ESPE/LWPES) consensus statement. We used standardized measures to assess satisfaction with care (CSQ 8), health-related quality of life (SF-36), psychological symptoms (BSI), and gender identity (FGI), in addition to self-constructed questionnaires probing experiences with health care and access to self-help groups. PARTICIPANTS: A total of 110 adults were recruited between January 2005 and December 2007 in four study centers in Germany, Austria, and German-speaking Switzerland. RESULTS: Reports of half the participants scored below the cut-off indicating low quality of care. Women with XX DSD conditions and virilization (i.e., congenital adrenal hyperplasia) reported the highest scores for satisfaction with care, and women with XY DSD conditions and complete lack of androgen effects reported the lowest scores. Satisfaction with care was positively associated with indicators of psychological well-being. CONCLUSIONS: Satisfaction with care is lowest among participants with the rarest conditions, highlighting the lack of evidence-based recommendations and the lack of coordination of care. Associations of satisfaction and well-being indicate the need to ensure access to mental health services. PMID- 25029981 TI - Introduction to a supplement on innovative approaches to studying health outcomes in rare diseases. PMID- 25029982 TI - Preface to the AHRQ supplement. PMID- 25029983 TI - A lesson in participatory research for a rare mutation of cystic fibrosis. PMID- 25029984 TI - Use of state administrative data sources to study adolescents and young adults with rare conditions. AB - BACKGROUND: Effective care of young people with rare conditions requires ongoing coordinated medical treatment as well as educational and social support services. However, information on treatment is often lacking due to limited data. South Carolina has a repository of comprehensive health and human service data with which individuals may be tracked across the data systems of multiple state agencies and organizations. OBJECTIVE: To develop a method for studying health care of young persons with rare conditions using this repository. METHODS: We identified individuals aged 15 to 24 years diagnosed during 2000-2010 with Fragile X syndrome (FXS), spina bifida (SB), or muscular dystrophy (MD) using a series of algorithms. ICD-9-CM codes were used to initially identify the cohort from medical billing data. Demographics, medical care, employment, education, and socioeconomic status data were then extracted from linked administrative sources. RESULTS: We identified 1,040 individuals with these rare conditions: 125 with FXS, 695 with SB, and 220 with MD. The vast majority of the cases (95%) were identified in the Medicaid database. Half of the cohort was male, with a higher percentage in the FXS and MD groups. Sixty-two percent of the cohort was enrolled in the last year of high school. Over half of the cohort received support services from the state's disability and special-needs agency; 16% received food assistance. Thirty-eight percent were employed at some point during the study period. Forty-nine individuals with SB and 56 with MD died during the study period. CONCLUSIONS: We used a linked statewide data system to study rare conditions. Strengths include the diversity of information, rigorous identification strategies, and access to longitudinal data. Despite limitations inherent to administrative data, we found that linked state data systems are valuable resources for investigating important public health questions on rare conditions. PMID- 25029986 TI - Magnetic and pairing properties of a two-orbital model for the pnictide superconductors: a quantum Monte Carlo study. AB - Using the constrained-path Monte Carlo method, a two-orbital model for the pnictide superconductors is studied at half filling and in both the electron- and hole-doped cases. At half filling, a stable (pi, 0)/(0, pi) magnetic order is explicitly observed and the system tends to be in an orthomagnetic order rather than the striped antiferromagnetic order on increasing the Coulomb repulsion U. In the electron-doped case, the (pi, 0)/(0, pi) magnetic order is enhanced upon doping and suppressed eventually and a s(+/-) pairing state dominates all the possible nearest-neighbour-bond pairings. Whereas in the hole-doped case, the magnetic order is straightforwardly suppressed and two nearly degenerate A(1g) and B(1g) intraband pairings become the dominant ones. PMID- 25029985 TI - Enhancement of the cytotoxic activity of cytokine-induced killer cells transfected with IL3PE38KDEL gene against acute myeloid leukemia cells. AB - Cytokine-induced killer (CIK) cells, one of the feasible and effective methods of adoptive immunotherapy, have shown anti-leukemia activity in vivo and in vitro. But the strategy exhibits limited cytotoxic activity in clinical studies. In this study, CIK cells were transfected with an interleukin-3/Pseudomonas exotoxin gene (IL3PE38KDEL). RT-PCR and ELISA were used to verify the expression of IL3PE38KDEL in the transfected CIK cells. These cells released 1,186.7 +/- 149.6 pg IL3PE38KDEL/10(4) cells over 48 h into the medium and the culture supernatant selectively killed IL3 receptor(IL3R)-positive HL60 cells, but not IL3R-negative K562 cells. Moreover, IL3PE38KDEL transfection did not influence phenotypes and cytokine production of CIK cells. Co-cultured with leukemia cells, IL3PE38KDEL transfected CIK cells showed enhanced cytotoxicity against IL3R-positive HL60 cells at all effector-to-target (E:T) ratios, but exerted a basal anti-leukemia activity against IL3R-negative K562 cells. Our findings demonstrate that IL3PE38KDEL gene transfection may be a novel strategy for improving anti-leukemia activity of CIK cells. PMID- 25029987 TI - Evaluation of respiratory function monitoring at the resuscitation of prematurely born infants. AB - Our aim was to determine whether neonatal trainees found respiratory function monitoring (RFM) helpful during the resuscitation of prematurely born infants, what decisions they made on the basis of RFM and whether those decisions were evidence based. Fifty one trainees completed an electronic questionnaire. Eighty three percent found the tidal volume display useful, 59 % altered the inflation pressure based on the tidal volume: 52 % considered 5 ml/kg adequate; 33 % 4 ml/kg; 13 % 6 ml/kg; and 2 % 7 ml/kg, despite no evidence on which to decide was the optimum tidal volume. If there was no detectable expired carbon dioxide (CO2), 30 trainees said they would reintubate, yet the absence of expired CO2 can indicate inadequate vasodilation of the pulmonary circulation rather than inappropriate placement of the endotracheal tube. If there was no chest wall expansion, but expired CO2, a third of junior trainees would reintubate which is inappropriate. If the oxygen saturation (SaO2) was <85 % at 1 min, no senior trainee, but 50 % of junior trainees would increase the inspired oxygen. The majority of healthy babies have an SaO2 > 85 % by 1 min. CONCLUSIONS: The usefulness of respiratory function monitoring for trainees during neonatal resuscitation is often not evidence based. PMID- 25029988 TI - Fracture of a HTR-PMI cranioplastic implant after severe TBI. AB - A 13-year-old girl with a large left fronto-parietal hard-tissue replacement patient-matched implant (HTR(r)-PMI) cranioplasty-since she suffered from a traumatic brain injury (TBI) 6 years ago-had a new severe TBI that detached and fractured the implant as well as caused a left subdural hematoma and a large frontal contusion. The hematoma and contusion were removed and the implant was substituted by a provisional titanium mesh. To the best of our knowledge, this is the first case reported about an HTR(r)-PMI fracture. It is theorized that the bone ingrowth into the macroporous implants, like those of hydroxyapatite, gives strength and resistance to the implant. But in the case we describe, no macroscopic bone ingrowth was detected 6 years after implantation and the traumatic force that impacted over the cranioplasty exceeded its properties. PMID- 25029990 TI - Clinical significance of GAB2, a scaffolding/docking protein acting downstream of EGFR in human colorectal cancer. AB - PURPOSE: Recent studies indicated that the scaffolding adaptor protein GAB2 (GRB2 associated binding protein 2) plays a critical role in the proliferation and migration of various cancers. This study aimed to determine the role of aberrant GAB2 expression in human colorectal cancer (CRC). METHODS: Quantitative real-time reverse transcription polymerase chain reaction was used to evaluate GAB2 mRNA expression in 152 CRC tissues samples to determine the clinicopathological significance of GAB2 expression. We also performed in vitro proliferation assays using siGAB2-transfected CRC cells. RESULTS: GAB2 expression in tumor colorectal tissues was significantly higher than in normal colorectal tissues (p = 0.0212). High GAB2 expression levels were associated with malignant clinicopathologic potential factors, including lymphatic invasion (p = 0.0003), venous invasion (p = 0.0170), and liver metastasis (p = 0.0144). The survival rate of patients with high GAB2 expression levels was significantly lower than that of patients with low GAB2 expression (p = 0.0074). Multivariate analysis indicated that GAB2 expression was a factor affecting lymph node metastasis. Cell proliferation was significantly suppressed by siGAB2 expression in CRC cells in vitro. CONCLUSIONS: GAB2 expression was associated with lymph node metastasis and may play a role in the growth and metastasis of CRC. These results suggest that GAB2 is a potential therapeutic target in CRC. PMID- 25029991 TI - Genetic testing today. AB - BACKGROUND: The commercial introduction of next-generation sequencing has made it possible to test for mutations in all known or suspected breast cancer predisposition genes in one panel, at one time, for about the same cost as a BRCA gene test. Clinicians are increasingly presented with the challenge of advising patients with mutations in rare breast cancer predisposition genes. METHODS: Literature review and personal experience with panel tests. RESULTS: Panel tests are more likely to identify a variant of uncertain clinical significance than a deleterious mutation. In addition, not all of the genes included in panel tests are unequivocally linked to increased breast cancer risk, and for most genes the penetrance is highly variable, making it difficult to translate a specific mutation into an absolute breast cancer risk. The three-generation cancer family history should be used to select truly high-risk families for panel testing, and then referred to again when the results are received in order to guide risk management decisions. Knowing a breast cancer patient's mutation status can influence decisions about local-regional and systemic therapy, but turnaround times for many tests are still too long to incorporate them into the initial evaluation of a new breast cancer. CONCLUSION: The commercialization of next generation sequencing has the potential to greatly enhance the identification and management of individuals with an inherited predisposition to breast cancer. A period of uncertainty is anticipated before the full potential of this new technology is realized. PMID- 25029992 TI - Assembly, characterization, and electrochemical properties of immobilized metal bipyridyl complexes on silicon(111) surfaces. AB - Silicon(111) surfaces have been functionalized with mixed monolayers consisting of submonolayer coverages of immobilized 4-vinyl-2,2'-bipyridyl (1, vbpy) moieties, with the remaining atop sites of the silicon surface passivated by methyl groups. As the immobilized bipyridyl ligands bind transition metal ions, metal complexes can be assembled on the silicon surface. X-ray photoelectron spectroscopy (XPS) demonstrates that bipyridyl complexes of [Cp*Rh], [Cp*Ir], and [Ru(acac)2] were formed on the surface (Cp* is pentamethylcyclopentadienyl, acac is acetylacetonate). For the surface prepared with Ir, X-ray absorption spectroscopy at the Ir LIII edge showed an edge energy as well as post-edge features that were essentially identical with those observed on a powder sample of [Cp*Ir(bpy)Cl]Cl (bpy is 2,2'-bipyridyl). Charge-carrier lifetime measurements confirmed that the silicon surfaces retain their highly favorable photoelectronic properties upon assembly of the metal complexes. Electrochemical data for surfaces prepared on highly doped, n-type Si(111) electrodes showed that the assembled molecular complexes were redox active. However the stability of the molecular complexes on the surfaces was limited to several cycles of voltammetry. PMID- 25029993 TI - Postnatal development of lung T lymphocytes in a porcine model. AB - PURPOSE: Despite the high prevalence of respiratory diseases in the world and the extensive information available on the mucosal immune system, research on the development of the lung immune system in humans is limited by technical and ethical considerations; therefore, we studied the postnatal development of T lymphocytes in lung lobes in a porcine model. METHODS: Using less than 36-hour old (NB), 1-week-weaned (5-week-old -AW-), 3-month-old (3M), and 4-year-old (4YR) healthy, nonvaccinated, specific pathogen free (SPF) Vietnamese miniature pigs, we studied the CD3+, CD4+, CD8+, TCR1 (gamma-delta T cells), and CD25+ (IL-2R alpha) cell subpopulations in lung lobes parenchyma, bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMC), and cervical lymph nodes (LN) by flow cytometry. RESULTS: No differences among lung lobes were detected in any of the cell subpopulations tested. A low proportion of T cell subsets was detected in NB and 4YR groups in lung and BAL. Besides, the AW and 3M groups showed important changes in T cell subpopulations. CONCLUSIONS: These results suggest that in healthy animals the lung lobes behave as a homogeneous immune organ. T cells were detected in very low percentages at birth and in adult life, which may explain the high susceptibility to respiratory infections both early and later in life. Postweaning antigenic challenges and endocrine and sexual maturity at 3M had important effects on the development of the mucosal immune system. It was also evident that changes at mucosal sites were poorly correlated with PBMC and LN. PMID- 25029994 TI - Effect of fenofibrate on retinal neurodegeneration in an experimental model of type 2 diabetes. AB - There is now consistent evidence from two major clinical trials (the Fenofibrate Intervention and Event Lowering in Diabetes and the Action to Control Cardiovascular Risk in Diabetes Eye) that fenofibrate arrests the progression of diabetic retinopathy in type 2 diabetic patients. However, the underlying mechanisms of this beneficial effect remain to be elucidated. The aim of the study was to evaluate the potential effect of fenofibric acid (FA), the active metabolite of fenofibrate, in preventing retinal neurodegeneration in an experimental mouse model of type 2 diabetes. For this purpose, we evaluated a total of 24 diabetic mice (db/db) aged 8 weeks that were randomly assigned to daily oral treatment (by gavage) with FA (100 mg/kg/day) (n = 12) or vehicle (n = 12) for 1 week. Ten non-diabetic mice (db/+) were used as control group. Retinal neurodegeneration was evaluated by measuring glial activation (immunofluorescence and Western blot) and apoptosis. Glutamate/aspartate transporter (GLAST) was assessed by immunofluorescence. Functional abnormalities were assessed by electroretinography (ERG). We observed that diabetic mice presented significantly higher glial activation and apoptosis in ganglion cell layer (GCL) than in age matched non-diabetic mice. Treatment with FA resulted in a significant decrease in both glial activation and the rate of apoptosis in GCL in comparison with diabetic mice treated with vehicle. In addition, FA prevented GLAST downregulation induced by diabetes. Furthermore, a significant improvement of ERG parameters (oscillatory potential amplitudes and b-wave implicit time) was observed. We conclude that FA prevents retinal neurodegeneration induced by diabetes. Our results suggest that neuroprotection is one of the underlying mechanisms by which fenofibrate exerts its beneficial actions in diabetic retinopathy. PMID- 25029995 TI - The role of the extended MNS in emotional and nonemotional judgments of human song. AB - In the present study, we examined the involvement of the extended mirror neuron system (MNS)-specifically, areas that have a strong functional connection to the core system itself-during emotional and nonemotional judgments about human song. We presented participants with audiovisual recordings of sung melodic intervals (two-tone sequences) and manipulated emotion and pitch judgments while keeping the stimuli identical. Mu event-related desynchronization (ERD) was measured as an index of MNS activity, and a source localization procedure was performed on the data to isolate the brain sources contributing to this ERD. We found that emotional judgments of human song led to greater amounts of ERD than did pitch distance judgments (nonemotional), as well as control judgments related to the singer's hair, or pitch distance judgments about a synthetic tone sequence. Our findings support and expand recent research suggesting that the extended MNS is involved to a greater extent during emotional than during nonemotional perception of human action. PMID- 25029996 TI - Real time PCR in childhood tuberculosis: a valuable diagnostic tool. AB - The present study was conducted to detect and quantitate Mycobacterium tuberculosis from various body fluid specimens of cases of tuberculosis by real time PCR technique and compare results with conventional PCR technique and culture. One hundred fifteen children (<18 y) with tuberculosis (diagnosed as per IAP guidelines) and 32 disease matched controls from the Department of Pediatrics, S.N. Medical College, Agra, were included in the study. Different body fluids (CSF, gastric aspirate, pleural fluid, ascitic fluid and lymph node aspirate) were subjected to culture, conventional PCR targeting insertion sequence 1S6110 and Real time PCR targeting 16srRNA of Mycobacterium tuberculosis. Real time PCR showed significantly better results than culture in all body fluids (p < 0.05). It was superior to conventional PCR in CSF (p < 0.05) but showed comparable results in gastric aspirate, pleural fluid, ascitic fluid and lymph node aspirate (p > 0.05). Hence, real time PCR is a promising diagnostic tool for childhood tuberculosis, particularly tubercular meningitis. PMID- 25029997 TI - Self-propelled droplets for extracting rare-earth metal ions. AB - We have developed self-propelled droplets having the abilities to detect a chemical gradient, to move toward a higher concentration of a specific metal ion (particularly the dysprosium ion), and to extract it. Such abilities rely on the high surface activity of di(2-ethylhexyl) phosphoric acid (DEHPA) in response to pH and the affinity of DEHPA for the dysprosium ion. We used two external stimuli as chemical signals to control droplet motion: a pH signal to induce motility and metal ions to induce directional sensing. The oil droplets loaded with DEHPA spontaneously move around beyond the threshold of pH even in a homogeneous pH field. In the presence of a gel block containing metal ions, the droplets show directional sensing and their motility is biased toward higher concentrations. The metal ions investigated can be arranged in decreasing order of directional sensing as Dy(3+)? Nd(3+) > Y(3+) > Gd(3+). Furthermore, the analysis of components by using an atomic absorption spectrophotometer reveals that the metal ions can be extracted from the environmental media to the interiors of the droplets. This system may offer alternative self-propelled nano/microscale machines to bubble thrust engines powered by asymmetrical catalysts. PMID- 25029998 TI - Study of in vitro degradation of brushite cements scaffolds. AB - An interest path to fabricate supports for tissue engineering is to foam calcium phosphate cement's pastes leading to an increase on material's total porosity and interconnectivity which facilitates cells' adhesion, proliferation and differentiation. The aim of this work is to develop scaffolds of brushite cement and to evaluate its in vitro degradation rate. Macroporosity was obtained by foaming the liquid phase with different non-ionic surfactants (Tween 80 and Lutensol ON-110). The foam stability was achieved by adding chitosan. The scaffolds were immersed in Ringers((r)) solution during 7, 14, 21 and 28 days and samples' microstructure, weight loss, mechanical resistance and apparent porosity were evaluated. Both scaffolds presented interconnected macropores with sizes ranging from 100 to 360 um and total porosities higher than 60%. These properties could facilitate cell infiltration, bone growth and vascularization. The scaffolds obtained in this work should be considered as promising materials for application in bone tissue engineering. PMID- 25029999 TI - Hybrid nanostructured Ag/ZnO decorated powder cellulose fillers for medical plastics with enhanced surface antibacterial activity. AB - Hybrid inorganic-organic fillers based on nanostructured silver/zinc oxide decorations on micro-cellulose carrier particles were prepared by stepwise microwave assisted hydrothermal synthesis using soluble salts as precursors of silver and zinc oxide. Hexamethylenetetramine was used as precipitating agent for zinc oxide and reducing agent for silver. The inorganics covered all available surfaces of the cellulose particles with a morphology resembling a coral reef. Prepared particulate fillers were compounded to medical grade poly(vinyl chloride) matrix. Scanning electron microscopy and powder X-ray diffractometry were used to investigate the morphology and crystalline phase structure of fillers. The scanning electron microscopy was used for morphological study of composites. With respect to prospective application, the composites were tested on electrical and antibacterial properties. A small effect of water absorption in polymer composites on their dielectric properties was observed but no adverse effect of water exposure on prepared materials was manifested. Electrical conductivity of fillers and composites was measured and no influence of water soaking of composites was found at all. The surface antibacterial activity of prepared composites was evaluated according to the standard ISO 22196. Excellent performance against Escherichia coli and very high against Staphylococcus aureus was achieved. PMID- 25030001 TI - Size control of noble metal clusters and metallic heterostructures through the reduction kinetics of metal precursors. AB - Eight precious metal salts/complexes were reduced in propylene glycol at temperatures ranging between 110 and 170 degrees C. We found that the reduction temperature and the size of precipitated metallic nanoparticles formed were significantly affected by the structure and reactivity of the metal precursors. The choice of noble metal precursor offers flexibility for designing, fabricating and controlling the size of metallic heterostructures with tunable properties. PMID- 25030000 TI - Repopulation of decellularized whole organ scaffold using stem cells: an emerging technology for the development of neo-organ. AB - Demand of donor organs for transplantation in treatment of organ failure is increasing. Hence there is a need to develop new strategies for the alternative sources of organ development. Attempts are being made to use xenogenic organs by genetic manipulation but the organ rejection against human always has been a major challenge for the survival of the graft. Advancement in the genetic bioengineering and combination of different allied sciences for the development of humanized organ system, the therapeutic influence of stem cell fraction on the reconstitution of organ architecture and their regenerative abilities in different tissues and organs provides a better approach to solve the problem of organ shortage. However, the available strategies for generating the organ/tissue scaffolds limit its application due to the absence of complete three-dimensional (3D) organ architecture, mechanical strength, long-term cell survival, and vascularization. Repopulation of whole decellularized organ scaffolds using stem cells has added a new dimension for creating new bioengineered organs. In recent years, several studies have demonstrated the potential application of decellularization and recellularization approach for the development of functional bio-artificial organs. With the help of established procedures for conditioning, extensive stem cells and organ engineering experiments/transplants for the development of humanized organs will allow its preclinical evaluation for organ regeneration before translation to the clinic. This review focuses on the major aspects of organ scaffold generation and repopulation of different types of whole decellularized organ scaffolds using stem cells for the functional benefit and their confines. PMID- 25030002 TI - [Both sides of the river: the importance of north-south conversation about neglected tropical diseases]. PMID- 25030004 TI - Regional anesthesia for pectoralis major tendon repair. PMID- 25030003 TI - Complete remission achieved by steroid pulse therapy following rituximab treatment in a case with autoimmune haemorrhaphilia due to anti-factor XIII antibodies. PMID- 25030005 TI - [Chronic kidney disease and sudden death]. AB - Cardiovascular disease represents the major cause of death in chronic kidney disease patients accounting for about 43% of all mortality causes among hemodialysis patients. Sudden cardiac death (SCD) is one of the most frequent and dangerous clinical syndrome occurring in end stage renal disease (ESRD) patients. Hemodialysis patients present a great number of non traditional risk factors for cardiovascular disease such as left ventricular hypertrophy, coronary artery disease, rapid electrolyte shifts, QT dispersion, sympathetic hyperactivity and hyperphosphatemia. The aim of the following review is to summarize epidemiological aspects and pathophysiological pathways of SCD in CKD patients, defining prevention and treatment guidelines. PMID- 25030006 TI - [Epidemiology of chronic kidney disease in a population: residents in the territory of Umbria "Gubbio - Gualdese"]. AB - The incidence of chronic kidney disease (CKD) has clearly increased in recent years. It is likely to be correlated with the aging population and with the growing association with vascular diseases. In Italy, there are different registers of dialysis and transplantation, providing an excellent means of monitoring patients in substitution treatment. On the contrary, few material is in our possession regarding CKD patients on conservative therapy. Therefore it lacks a necessary mean to implement mechanisms of prevention and programming for a disease that increasingly shows significant social - health consequences. PMID- 25030007 TI - [Heparin-induced trombocytopenia: pathogenesis, clinical manifestations and management in hemodialysis]. AB - Heparin has remained the most commonly used anticoagulant in hemodialysis patients (HD). Its use is usually safe but, in some cases, important adverse effects can occur. Heparin-induced thrombocytopenia (HIT) is an immuno-mediated condition due to the formation of PF4/heparin/IgG complex leading to the activation of platelets and coagulative cascade. The consequent prothrombotic hypercoagulable state may cause venous or arterial thrombosis, skin gangrene and acute platelet activation syndrome. Clinical and laboratory findings may be suggestive for HIT, but formal diagnosis requires the demonstration of the presence of circulating antibodies. Clinical management is complex including the withdrawal of any form of heparin and the administration of anticoagulants. In addition, since anticoagulation is routinely required to prevent clotting of the dialysis lines and membranes, in HD patients presenting HIT it is mandatory to establish heparin-free anticoagulation strategies. Thus, the use of citrate, direct thrombin inhibitors or eparinods have been proposed as alternative anticoagulation approaches in HIT. Here, we review the most important pathogenic factors and clinical features of HIT occurring in HD patients. PMID- 25030008 TI - [Chest ultrasound in nephrology]. AB - The pulmonary study represents a constant appointment for Nephroplogist who frequently asks for a chest-xray in the nephrologic patient, especially in dialysis therapy. The chest x-ray and the Computed Tomography are normally used in pulmonary study, but they are not always rapidly executable and not practicable in the ambulatory and in dialysis room. The ultrasonography has recently been proposed for the study of the lung because it can be carried out rapidly in every nephro-dialytic room, also in frequent follow-up and it doesn't need particular equipment and probes. In this paper we present the fundamental notions of the management of a correct pulmonary ultrasonographic examination and some of the most common pathological pictures (pleural effusion, interstitial and alveolar syndrome, pneumothorax, etc). PMID- 25030009 TI - [Prune-Belly Syndrome: a case report]. AB - Prune-Belly Syndrome (PBS) is a rare congenital syndrome characterized by the absence of abdominal muscles, anomalies in the urinary tract, megaureter, cryptorchidism or testicular agenesis, hypertension and worsening chronic kidney disease (CKD). The incidence is estimated between 1 out of 35,000 and 1 out of 50,000 born alive, and it affects males in prevalence (97%). In the present study we describe the case of a 38 year old male patient (followed since May 2011) affected by PBS, CKD, one functional kidney at the scintigraphy, pediatric testicular implants, bladder surgery and correction of pectus excavatum. At the beginning of the observation, renal function was deteriorated, with a creatinine 3.3 mg/dl, GFR calculated at MDRD 23 ml/min, proteinuria in nephrotic range (4 g/day), high blood pressure, anemia and hyperparathyroidism. In the following examinations renal function framework worsened, despite the adoption of a low protein diet. Due to the functional trend, the patient was prescribed hemodialysis as substitute treatment. In January 2013 a first attempt of artero venous fistula (AVF) did not succeed, while a new AVF in March 2013 resulted effective. In July hemodialysis was started. In the future, we expect to insert the patient in the Kidney Transplant List (since surgical feasibility has already been positively evaluated). Our case is quite peculiar due to the late beginning of substitute treatment. Further, SPB represents a challenge that, in the absence of a prompt and effective treatment, inevitably it leads to terminal uremia; nevertheless, given a proper treatment, a transplant with good chances of success can be envisaged. PMID- 25030010 TI - [Renal denervation in ADPKD: an exceptional case]. AB - Sympathetic overactivity plays a crucial role in the genesis and aggravation of arterial hypertension in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Renal denervation has been shown to be effective and safe in reducing blood pressure (BP) in patients with treatment-resistant hypertension, even with chronic kidney disease (CKD). However, there are no cases in hypertensive patients with ADPKD. We report the exceptional case of a woman with stage 4 CKD secondary to ADPKD and uncontrolled treatment-resistant hypertension. Because of the ineffectiveness of all pharmacological and surgical therapeutic strategies, including the uninephrectomy, renal denervation by radiofrequency ablation of the renal artery was performed. The patient decreased the requirement of antihypertensive medication and the BP showed a remarkable reduction, that resulted stable 12 months after the procedure. PMID- 25030011 TI - [The Canadian Society of Nephrology 2014 clinical practice guideline for timing the initiation of chronic dialysis: a paradigm shift and the return of the clinical nephrologist]. AB - The recent guideline of the Canadian Society of Nephrology for timing the initiation of chronic dialysis may be seen as a "paradigm shift", meaning, according to the Kuhns theory, the development of a different viewpoint. The guideline is based on a careful review of the literature, with primary emphasis on patient survival and quality of life. Hence, the Authors choose qualitative keywords (intention -to-defer, in place of the intention-to-start-early), but also a qualitative process for deciding the start of dialysis, by providing an intentionally concise list of signs and symptoms not reducible to numbers, such as the presence of uremic symptoms. The recent guideline of the Canadian Society of Nephrology, regarding the timing of the initiation of chronic dialysis, may be seen as a "paradigm shift", that means, according to Kuhns theory, the development of a different viewpoint. The guideline is based on a careful review of the literature, with primary emphasis on patient survival and quality of life. Hence, the Authors choose not only qualitative keywords (intention -to-defer, in place of intention-to-start-early), but also a qualitative process for deciding the start of dialysis, by providing an intentionally concise list of signs and symptoms not reducible to numbers, such as the presence of uremic symptoms. The clinical Nephrologist emerges victorious; the decision to initiate dialysis is in his-her hands; it is not a team-work, or a numeric algorhythm: its a clinical choice. The clinical judgment is the only guide above 6 mL/min of eGFR. Below this limit, dialysis has to be started; however, the Authors state that the optimal management of patients with an eGFR of 6 mL/min per 1.73 m2 or less, it is based on limited data. Hence, numbers are back to haunt us; nevertheless, we should take the best of this paradigm shift: the decision is again in our hands, the clinic is our weapon, the responsibility is not reducible to pretty formulae. If we cannot hide behind a computer screen, we have good reasons to exist, and we are alive. PMID- 25030012 TI - [The centrality of the nurse in the prevention of the infections in Hemodialysis]. AB - Hemodialysis is an essential life-saving treatment. At the same time, due to the singularity of invasive actions undertaken for its implementation, as well as for the particular impairment of the immune system in patients undergoing hemodialysis, it appears clearly to be a dangerous source of infection. As evidenced by an extensive national and international literature, the nurse is a key figure in the prevention of such infections. Among the nursing interventions aimed at preventing the emergence and spread of infections in hemodialysis, there is the adoption of standard precautions. The most important is the washing hands, followed by the use of D.P.I., the management of the hemodialyzers rooms and other medical devices, the management of vascular access, and finally the educational and psychological support provided to the patient. The combination of these precautionary measures is critical to the achievement of the preventive objectives that each nurse in hemodialysis should pursue. PMID- 25030013 TI - [The Italian Places of Nicholas Green 20 years after his assassination]. AB - Twenty years ago, Nicholas Green, a 7- year-old American boy was shot, while on vacation, on the Autostrada (motorway) Salerno to Reggio Calabria in Italy. His organs, with the consent of his parents, Reg and Maggie, were removed and 7 persons had their lives changed. In Italy in these last 20 years, organ donation has increased powerfully from 6.2 to 18.2 per million population with a peak at 20 in 2006. Reg and Maggie Green, after Nicholas death, started campaigning for organ donation by making full use of the media. Italian justice was efficient and the criminals were imprisoned quickly. With popular enthusiasm, a total of 103 places were dedicated to Nicholas (schools, halls, squares, streets, parks, gardens, private collections), a proof of great appreciation. Teaching organ donation to children, nurses and medical students is a powerful tool to convey the message of organ donation. To prevent opposition to organ removal when brain death occurs as Professor Francesco Casavola says signing for organ donation should be a family decision and laws for organ donation should be updated frequently in order to meet the progress of modernity. PMID- 25030014 TI - [An unusual case of acute kidney insufficiency]. AB - Acute aortic dissection (AAD) is a life-threatening condition with high morbidity and mortality, that involves renal arteries in at least 5-10% so leading to renal ischemia and insufficiency. AAD presenting with anuria and the necessity of renal replacement therapy occurs rarely. Here we describe a case of a hypertensive and obese patient presenting with anuria and acute kidney injury, who underwent to hemodialysis and later was diagnosed with aortic dissection. Through this case, we underline the importance of considering AAD as an important differential in patients with a long history of uncontrolled hypertension presenting with anuria. PMID- 25030015 TI - [The hepatorenal syndrome - a review]. AB - The Hepato Renal Syndrome (HRS) remains a diagnostic and therapeutic conundrum. Controversies persist in the definition, understanding of pathophysiological mechanisms, diagnosis, and therapy of renal dysfunction complicating End Stage Liver Disease (ESLD).While ESLD is complicated by dysfunction in multiple organs, renal disease holds particular bearing on long term outcomes. Liver transplantation is the therapy of choice for ESLD-and co existing renal dysfunction makes it more difficult and challenging. Given that a bare minimum of patients with ESLD will ultimately receive a liver transplant, especially in the developing world, renal dysfunction may ultimately portend untimely death in a many of these patients. It is also critical to recognize the fact that HRS is not the sole cause of renal failure in ESLD. Hence, early recognition and therapy may prolong life even in those who will not receive a transplant for multitude of reasons. Renal Replacement Therapy (RRT) is also a challenge in this patient population, leading to issues with hemodynamics, vascular access and anticoagulation. We take a look at recent literature and advances in the understanding of the pathophysiology of this particularly difficult condition, and its diagnosis and management. PMID- 25030016 TI - [Anti-phospholipase A2 receptor (anti-PLA2R) antibodies and idiopathic membranous nephropathy: which role in diagnosis and prognosis of this disease?]. AB - The discovery of the M-type phospholipase A2 receptor (PLA2R) as a major antigen in idiopathic membranous nephropathy (iMN) was a breakthrough in understanding the pathogenesis of this disease, establishing iMN as an autoimmune disease. Subsequent studies confirmed that detection of circulating antibodies against PLA2R was positive in approximately 70% of incident iMN patients. We discuss several studies that have suggested the potential role of measuring PLA2R antibodies for clinical practice. Recently, it has been shown that the presence of PLA2R antibodies supported a diagnosis of iMN, changes in antibody levels were related to clinical disease activity, disappearance of antibodies preceded and predicted subsequent decrease of proteinuria and high titers of antibodies were associated with a low likelihood spontaneous remission. PMID- 25030017 TI - [Administrative databases of the Local Health Unit: possible use for clinical governance of chronic kidney disease]. AB - Nowadays a large amount of medical data are available, although they are not always homogeneous, they arise from different backgrounds and are used for different purposes. The aggregation of these data could give huge boost to the epidemiology and, in particular, to nephrology. In many parts of Italy there is the aim to reorganize the hospital health care, as well as the territorial setting. In this framework, the role of nephrology is evaluated without data to support the ongoing decisions, therefore the linkage among the data stored in the administrative and clinical databases of the Local Health Unit could contribute to the planning of nephrological (but not only) activities, in order to ensure the best cost-effectiveness possible for each different reality. PMID- 25030018 TI - [Vascular calcification in chronic kidney disease]. AB - Cardiovascular risk is higher in patients with chronic kidney disease (CKD) or with End-Stage Renal Disease (ESRD) than general population because in addition to the traditional cardiovascular (CV ) risk factors, CKD patients also have others non-traditional CV risk factors linked to CKD. Among these factors, presence and progression of coronary calcifications (CAC) are considered very important in CKD or ESRD patients in recent years. A number of noninvasive imaging methods are available to detect the presence, extent and progression of CAC. In this review, we discuss the importance of CAC as non-traditional CV risk factors in CKD patients and the noninvasive methods most frequently used to assess CAC. PMID- 25030019 TI - A Case of mild idiopathic adulthood ductopenia and brief review of literature. AB - Mild idiopathic adulthood ductopenia (IAD) is a rare cholestatic disease of unknown cause and characterized by interlobular bile duct loss in less than 50% of the portal tracts. We describe the case of a middLe-aged male who presented with persistent elevation of transaminases and alkaline phosphatase. He had a normal biliary tree on endoscopic retrograde cholangiopathy and negative anti mitochondrial antibody. His liver biopsy specimen showed chronic biliary disease, duct loss in 4 out of 15 portal tracts and prominent cholestasis. Based on the work-up, he likely had mild IAD. Liver transplantation would be necessary if his disease becomes progressive. PMID- 25030020 TI - GNAQ mutation in a patient with metastatic mucosal melanoma. AB - BACKGROUND: Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. CASE PRESENTATION: A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. CONCLUSION: Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma. PMID- 25030021 TI - Noninvasive detection of a balanced fetal translocation from maternal plasma. AB - BACKGROUND: Massively parallel sequencing of circulating cell free (ccf) DNA from maternal plasma has been demonstrated to be a powerful method for the detection of fetal copy number variations (CNVs). Although the detection of CNVs has been described by multiple independent groups, genomic aberrations resulting in copy number-neutral events including balanced translocations have proven to be more challenging to detect noninvasively from ccf DNA. METHODS: Data modeling was initially performed to evaluate multiple methods, ultimately leveraging the short length of ccf DNA and paired-end sequencing to construct read-specific mapping characteristics. After testing in a model system, we evaluated the methods on ccf DNA isolated from the plasma of a donor known to be carrying a fetus with a balanced translocation [t(8;11)]. Sequencing was performed with Illumina sequencing technology. RESULTS: Our methodology identified the known translocation (P = 1.21 * 10(-8)) and discounted the likelihood of others, enabling the base specific identification of the rearrangement positions. In total, 402 unique sequencing reads spanned the putative breakpoints, of which 76 contained the structural rearrangement. In addition, 38 of the chimeric reads were mapped to each of the resulting derivative chromosomes, supporting the presence of a reciprocal translocation. Finally, we identified a 6-bp deletion present within der(8) that was absent from the der(11) reciprocal rearrangement. CONCLUSIONS: We have developed an algorithm to detect balanced rearrangements and applied our methodology to demonstrate the first proof-of-principle study on the noninvasive detection of a fetal-specific balanced translocation by sequencing ccf DNA from maternal plasma. PMID- 25030022 TI - Metaplastic carcinoma of the breast: an immunohistochemical study. AB - BACKGROUND: Metaplastic breast carcinoma is a rare entity of breast cancer expressing epithelial and/or mesenchymal tissue within the same tumor. The aim of this study is to evaluate the clinicopathological features of metaplastic breast carcinoma and to confirm the triple negative, basal-like and/or luminal phenotype of this type of tumor by using immunohistochemical staining. METHODS: Seven cases of MBC were evaluated for clinico-pathological features including follow up data. Cases were studied immunohistochemically by CK-Pan, Vimentin, ER, PR, HER2, basal markers (CK5/6, p63, EGFR, SMA and S-100), luminal cytokeratins (CK8, CK18 and CK19), markers for syncytial cells (beta-HCG and PLAP), as well as prognostic markers (p53, ki-67 and calretinin). RESULTS: The mean age of the patients was 36 years. Three cases showed choriocarcinomatous features. All of our cases were negative for ER, PR and HER2. Six out of the 7 cases showed basal-like differentiation by demonstrating positivity with at least one of the basal/myoepithelial markers. Also 6 out of the 7 cases expressed luminal type cytokeratins (CK8, CK18 and/or CK19). P53 was positive in 3 cases, ki-67 was strongly expressed in only one case, while calretinin was expressed in 6 cases. CONCLUSION: Metaplastic breast carcinoma presents in our population at a younger age group than other international studies. All cases are categorized immunohistochemically under the triple negative group of breast cancer and 86% of them exhibited basal-like and luminal phenotype. Majority of cases developed local recurrence and distant metastasis in a relatively short period of time. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1101289295115804. PMID- 25030023 TI - Clinician-trialist rounds: 24. Modernizing your introductory graduate course in clinical trials. Part 1: Commonsense meets evidence. PMID- 25030024 TI - Thermogravimetric characteristics and kinetics of scrap tyre and Juglans regia shell co-pyrolysis. AB - The degradation kinetics of Juglans regia shell, scrap tyre and their blends were investigated using a thermogravimetric analysis method. Experiments were performed under dynamic conditions and a nitrogen atmosphere in the range 293 to 973 K at different heating rates. During pyrolysis of J. regia shell three mass loss zones were specified as removal of water, decomposition of hemicelluloses and cellulose, and decomposition of lignin. The degradation curves of scrap tyre showed merely one stage which was due to decomposition of styrene butadiene rubber. The kinetic parameters were calculated using both Arrhenius and Coats Redfern methods. By adopting the Arrhenius method, the average value of activation energies of J. regia shell, scrap tyre and their 1 : 1 blends were found to be 69.22, 71.48 and 47.03 kJ mol(-1), respectively. Additionally, by using the Coats-Redfern method, the average value of activation energies of J. regia shell, scrap tyre and their 1 : 1 blend were determined as 99.85, 78.72 and 63.81 kJ mol(-1), respectively. The addition of J. regia shell to scrap tyre caused a reduction in the activation energies. The difference of weight loss was measured to examine interactions between raw materials. The maximum difference between experimental and theoretical mass loss was 5% at about 648 K with a heating rate of 20 K min(-1). These results indicated a significant synergistic effect was available during co-pyrolysis of J. regia shell and scrap tyre in the high temperature region. PMID- 25030025 TI - Is intra-abdominal hypertension a missing factor that drives multiple organ dysfunction syndrome? AB - In a recent issue of Critical Care, Cheng and colleagues conducted a rabbit model study that demonstrated that intra-abdominal hypertension (IAH) may damage both gut anatomy and function. With only 6 hours of IAH at 25 mmHg, these authors observed an 80% reduction in mucosal blood flow, an exponential increase in mucosal permeability, and erosion and necrosis of the jejunal villi. Such dramatic findings should remind all caring for the critically ill that IAH may severely damage the normal gut barrier functions and thus may be reasonably expected to facilitate bacterial and mediator translocation. The potential contribution of IAH as a confounding factor in the efficacy of selective decontamination of the digestive tract should be considered. PMID- 25030026 TI - Genome-wide analysis reveals divergent patterns of gene expression during zygotic and somatic embryo maturation of Theobroma cacao L., the chocolate tree. AB - BACKGROUND: Theobroma cacao L. is a tropical fruit tree, the seeds of which are used to create chocolate. In vitro somatic embryogenesis (SE) of cacao is a propagation system useful for rapid mass-multiplication to accelerate breeding programs and to provide plants directly to farmers. Two major limitations of cacao SE remain: the efficiency of embryo production is highly genotype dependent and the lack of full cotyledon development results in low embryo to plant conversion rates. With the goal to better understand SE development and to improve the efficiency of SE conversion we examined gene expression differences between zygotic and somatic embryos using a whole genome microarray. RESULTS: The expression of 28,752 genes was determined at 4 developmental time points during zygotic embryogenesis (ZE) and 2 time points during cacao somatic embryogenesis (SE). Within the ZE time course, 10,288 differentially expressed genes were enriched for functions related to responses to abiotic and biotic stimulus, metabolic and cellular processes. A comparison ZE and SE expression profiles identified 10,175 differentially expressed genes. Many TF genes, putatively involved in ethylene metabolism and response, were more strongly expressed in SEs as compared to ZEs. Expression levels of genes involved in fatty acid metabolism, flavonoid biosynthesis and seed storage protein genes were also differentially expressed in the two types of embryos. CONCLUSIONS: Large numbers of genes were differentially regulated during various stages of both ZE and SE development in cacao. The relatively higher expression of ethylene and flavonoid related genes during SE suggests that the developing tissues may be experiencing high levels of stress during SE maturation caused by the in vitro environment. The expression of genes involved in the synthesis of auxin, polyunsaturated fatty acids and secondary metabolites was higher in SEs relative to ZEs despite lack of lipid and metabolite accumulation. These differences in gene transcript levels associated with critical processes during seed development are consistent with the fact that somatic embryos do not fully develop the large storage cotyledons found in zygotic embryos. These results provide insight towards design of improved protocols for cacao somatic embryogenesis. PMID- 25030027 TI - Short-term periodic consumption of multiprobiotic from childhood improves insulin sensitivity, prevents development of non-alcoholic fatty liver disease and adiposity in adult rats with glutamate-induced obesity. AB - BACKGROUND: Today the impairment of metabolism and obesity are being extensively investigated due to the significant increase of the prevalence of these diseases. There is scientific evidence that probiotics are beneficial for human health. Thus, the aim of the study was to investigate the effect of multiprobiotic "Symbiter acidophilic concentrated" on obesity parameters in the rats under experimental obesity. METHODS: The study was carried out on 60 newborn Wistar rats, divided into 3 groups, 20 animals in each (females - n = 10, males - n = 10): intact rats, monosodium glutamate (MSG-) and MSG + probiotic group. Rats of intact group were administered with saline (8 MUl/g, subcutaneously (s.c.)). Newborns rats of MSG-group and MSG + probiotic group were injected with a solution of MSG (4.0 mg/g) s.c. at 2nd - 10th postnatal days. The MSG + probiotic group was treated with 140 mg/kg (1.4 * 10(10) CFU/kg) of multiprobiotic "Symbiter". MSG-group was treated with 2.5 ml/kg of water (per os) respectively. Administration was started at the age of 4 weeks just after wean and continued for 3 month intermittently alternating two-week course of introduction with two week course of break. RESULTS: Neonatal treatment with MSG caused a stunted growth in both MSG-groups, which manifested with significantly smaller naso-anal length compared to adult intact rats. There was no significant difference in weight between intact and MSG-groups on 120th day. The adiponectin level in the serum of rats with MSG-induced obesity decreased by 2.43 times (p = 0.001) in males and 1.75 (p = 0.020) in females. Concentration of leptin in adipose tissue were significantly higher by 45.9% (p = 0.019) and 61.2% (p = 0.009) respectively in males and females compared to intact rats. Our study has indicated that daily oral administration of multiprobiotic to neonatal MSG-treated rats by 2-week courses led to significant reduce of total body and VAT weight with subsequent improvement in insulin sensitivity and prevention of non-alcoholic fatty liver (NAFLD) development. CONCLUSIONS: These results have shown that periodic treatment with multiprobiotic prevents the MSG-induced obesity and NAFLD development. PMID- 25030028 TI - Endoscopic submucosal dissection of esophageal granular cell tumor. AB - BACKGROUND: Esophageal granular cell tumor (GCT) is a rare benign tumor with malignant potential. With wide application of endoscopic techniques, the esophageal GCT discovery rate and treatment strategy has changed. This study was to preliminarily evaluate outcomes of endoscopic diagnosis and treatment for esophageal GCT. METHODS: Fourteen patients (eight men, six women; median age, 48.5 years) with esophageal GCT diagnosed and treated by esophageal endoscopy. Esophagoscopy, endoscopic ultrasound (EUS), and endoscopic submucosal dissection (ESD) techniques were employed in diagnosis and resection. RESULTS: Esophageal GCTs are tumors which arise from the submucosal layer, and vary in color but with a yellowish color on endoscopy being most common. On EUS, features were homogenous (ten cases) or mildly heterogeneous (four cases) hypoechoic solid pattern originating from the muscularis mucosa (six cases) or submucosal layer (eight cases) of the esophageal wall. Tumors ranged from 4 to 26 mm (mean 12.1 mm). ESD was performed in all patients without complication. Clinical diagnosis was confirmed by pathology and immunohistochemical examination (positive for S 100 and vimentin). The en bloc resection rate was 92.9% (13/14) pathologically. Operation time was 25 to 60 minutes, mean 38.2 +/- 10.1 minutes. No recurrence was observed during a mean follow-up of 16.6 +/- 12.7 (range, 4 to 40) months. CONCLUSIONS: Esophagoscopy and EUS increased the esophageal GCT discovery rate, and its features were summarized. Minimally invasive ESD is feasible and safe for excisional biopsy, providing pathological diagnosis and treatment. PMID- 25030029 TI - Mutation and expression analysis in medulloblastoma yields prognostic variants and a putative mechanism of disease for i17q tumors. AB - Current consensus identifies four molecular subtypes of medulloblastoma (MB): WNT, sonic hedgehog (SHH), and groups "3/C" and "4/D". Group 4 is not well characterized, but harbors the most frequently observed chromosomal abnormality in MB, i17q, whose presence may confer a worse outcome. Recent publications have identified mutations in chromatin remodeling genes that may be overrepresented in this group, suggesting a biological role for these genes in i17q. This work seeks to explore the pathology that underlies i17q in MB. Specifically, we examine the prognostic significance of the previously-identified gene mutations in an independent set of MBs as well as to examine biological relevance of these genes and related pathways by gene expression profiling. The previously-implicated p53 signaling pathway is also examined as a putative driver of i17q tumor oncogenesis. The data show gene mutations associated with i17q tumors in previous studies (KMD6A, ZMYM3, MLL3 and GPS2) were correlated with significantly worse outcomes despite not being specific to i17q in this set. Expression of these genes did not appear to underlie the biology of the molecular variants. TP53 expression was significantly reduced in i17q/group 4 tumors; this could not be accounted for by dosage effects alone. Expression of regulators and mediators of p53 signaling were significantly altered in i17q tumors. Our findings support that chromatin remodeling gene mutations are associated with significantly worse outcomes in MB but cannot explain outcomes or pathogenesis of i17q tumors. However, expression analyses of the p53 signaling pathway shows alterations in i17q tumors that cannot be explained by dosage effects and is strongly suggestive of an oncogenic role. PMID- 25030030 TI - Shift work and diabetes mellitus: a meta-analysis of observational studies. AB - BACKGROUND: Observational studies suggest that shift work may be associated with diabetes mellitus (DM). However, the results are inconsistent. No systematic reviews have applied quantitative techniques to compute summary risk estimates. OBJECTIVES: To conduct a meta-analysis of observational studies assessing the association between shift work and the risk of DM. METHODS: Relevant studies were identified by a search of PubMed, Embase, Web of Science and ProQuest Dissertation and Theses databases to April 2014. We also reviewed reference lists from retrieved articles. We included observational studies that reported OR with 95% CIs for the association between shift work and the risk of DM. Two authors independently extracted data and assessed the study quality. RESULTS: Twelve studies with 28 independent reports involving 226 652 participants and 14 595 patients with DM were included. A pooled adjusted OR for the association between ever exposure to shift work and DM risk was 1.09 (95% CI 1.05 to 1.12; p=0.014; I(2)=40.9%). Subgroup analyses suggested a stronger association between shift work and DM for men (OR=1.37, 95% CI 1.20 to 1.56) than for women (OR=1.09, 95% CI 1.04 to 1.14) (p for interaction=0.01). All shift work schedules with the exception of mixed shifts and evening shifts were associated with a statistically higher risk of DM than normal daytime schedules, and the difference among those shift work schedules was significant (p for interaction=0.04). CONCLUSIONS: Shift work is associated with an increased risk of DM. The increase was significantly higher among men and the rotating shift group, which warrants further studies. PMID- 25030031 TI - In silico single strand melting curve: a new approach to identify nucleic acid polymorphisms in Totiviridae. AB - BACKGROUND: The PCR technique and its variations have been increasingly used in the clinical laboratory and recent advances in this field generated new higher resolution techniques based on nucleic acid denaturation dynamics. The principle of these new molecular tools is based on the comparison of melting profiles, after denaturation of a DNA double strand. Until now, the secondary structure of single-stranded nucleic acids has not been exploited to develop identification systems based on PCR. To test the potential of single-strand RNA denaturation as a new alternative to detect specific nucleic acid variations, sequences from viruses of the Totiviridae family were compared using a new in silico melting curve approach. This family comprises double-stranded RNA virus, with a genome constituted by two ORFs, ORF1 and ORF2, which encodes the capsid/RNA binding proteins and an RNA-dependent RNA polymerase (RdRp), respectively. RESULTS: A phylogenetic tree based on RdRp amino acid sequences was constructed, and eight monophyletic groups were defined. Alignments of RdRp RNA sequences from each group were screened to identify RNA regions with conserved secondary structure. One region in the second half of ORF2 was identified and individually modeled using the RNAfold tool. Afterwards, each DNA or RNA sequence was denatured in silico using the softwares MELTSIM and RNAheat that generate melting curves considering the denaturation of a double stranded DNA and single stranded RNA, respectively. The same groups identified in the RdRp phylogenetic tree were retrieved by a clustering analysis of the melting curves data obtained from RNAheat. Moreover, the same approach was used to successfully discriminate different variants of Trichomonas vaginalis virus, which was not possible by the visual comparison of the double stranded melting curves generated by MELTSIM. CONCLUSION: In silico analysis indicate that ssRNA melting curves are more informative than dsDNA melting curves. Furthermore, conserved RNA structures may be determined from analysis of individuals that are phylogenetically related, and these regions may be used to support the reconstitution of their phylogenetic groups. These findings are a robust basis for the development of in vitro systems to ssRNA melting curves detection. PMID- 25030032 TI - Automated clinical trial eligibility prescreening: increasing the efficiency of patient identification for clinical trials in the emergency department. AB - OBJECTIVES: (1) To develop an automated eligibility screening (ES) approach for clinical trials in an urban tertiary care pediatric emergency department (ED); (2) to assess the effectiveness of natural language processing (NLP), information extraction (IE), and machine learning (ML) techniques on real-world clinical data and trials. DATA AND METHODS: We collected eligibility criteria for 13 randomly selected, disease-specific clinical trials actively enrolling patients between January 1, 2010 and August 31, 2012. In parallel, we retrospectively selected data fields including demographics, laboratory data, and clinical notes from the electronic health record (EHR) to represent profiles of all 202795 patients visiting the ED during the same period. Leveraging NLP, IE, and ML technologies, the automated ES algorithms identified patients whose profiles matched the trial criteria to reduce the pool of candidates for staff screening. The performance was validated on both a physician-generated gold standard of trial-patient matches and a reference standard of historical trial-patient enrollment decisions, where workload, mean average precision (MAP), and recall were assessed. RESULTS: Compared with the case without automation, the workload with automated ES was reduced by 92% on the gold standard set, with a MAP of 62.9%. The automated ES achieved a 450% increase in trial screening efficiency. The findings on the gold standard set were confirmed by large-scale evaluation on the reference set of trial-patient matches. DISCUSSION AND CONCLUSION: By exploiting the text of trial criteria and the content of EHRs, we demonstrated that NLP-, IE , and ML-based automated ES could successfully identify patients for clinical trials. PMID- 25030033 TI - Health information technology interventions enhance care completion, engagement in HIV care and treatment, and viral suppression among HIV-infected patients in publicly funded settings. AB - BACKGROUND: The National HIV/AIDS Strategy (NHAS) emphasizes the use of technology to facilitate coordination of comprehensive care for people with HIV. We examined the effect of six health information technology (HIT) interventions in a Ryan White-funded Special Projects of National Significance (SPNS) on care completion services, engagement in HIV care, and viral suppression. METHODS: Interventions included use of surveillance data to identify out-of-care individuals, extending access to electronic health records to support service providers, use of electronic laboratory ordering and prescribing, and development of a patient portal. Data from a sample of electronic patient records from each site were analyzed to assess changes in utilization of comprehensive care (prevention screening, support service utilization), engagement in primary HIV medical care (receipt of services and use of antiretroviral therapy), and viral suppression. We used weighted generalized estimating equations to estimate outcomes while accounting for the unequal contribution of data and differences in the distribution of patient characteristics across sites and over time. RESULTS: We observed statistically significant changes in the desired direction in comprehensive care utilization and engagement in primary care outcomes targeted by each site. Five of six sites experienced statistically significant increases in viral suppression. DISCUSSION: These results provide additional support for the use of HIT as a valuable tool for achieving the NHAS goal of providing comprehensive care for all people living with HIV. HIT has the potential to increase utilization of services, improve health outcomes for people with HIV, and reduce community viral load and subsequent transmission of HIV. PMID- 25030035 TI - Preventing thalassemia in Lebanon: successes and challenges in a developing country. AB - Thalassemia continues to be a major health burden. The chronicity of the disease and the high cost of life-long treatment make prevention strategies crucial in the management of this disease. In this article, we revisit different successful prevention strategies, and underline the Lebanese model. The Chronic Care Center (CCC), Beirut, is the only specialized center in Lebanon for the treatment and prevention of thalassemia. The current number of patients registered up to August 2013 was 724, representing cases from all over Lebanon. In 1994, the center launched a national prevention program following the World Health Organization (WHO) recommendations. The major activities of the program include awareness campaigns, screening for thalassemia carriers in the general population and high risk groups, registry of new cases and follow-up on the mandatory premarital law (established at the same time). Screening programs showed a carrier rate of around 2.3% in the general population, and 4.0-41.0% in high risk groups. The major pitfall in the law is that only persons with a mean corpuscular volume (MCV) of >70.0 fL are asked to perform further hemoglobin (Hb) testing. A significant decrease in the number of new cases of thalassemia patients in Lebanon reflects the efforts deployed in the prevention of the disease. However, some limitations are faced in reaching a complete eradication of the disease, mainly due to the fact that abortion is illegal and due to pitfalls and incorrect implementation of the premarital law. PMID- 25030034 TI - Epigallocatechin-3-gallate and tetracycline differently affect ataxin-3 fibrillogenesis and reduce toxicity in spinocerebellar ataxia type 3 model. AB - The polyglutamine (polyQ)-containing protein ataxin-3 (AT3) triggers the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) when its polyQ tract is expanded beyond a critical length. This results in protein aggregation and generation of toxic oligomers and fibrils. Currently, no effective treatment is available for such and other polyQ diseases. Therefore, plenty of investigations are being carried on to assess the mechanism of action and the therapeutic potential of anti-amyloid agents. The polyphenol compound epigallocatechin-3-gallate (EGCG) and tetracycline have been shown to exert some effect in preventing fibrillogenesis of amyloidogenic proteins. Here, we have incubated an expanded AT3 variant with either compound to assess their effects on the aggregation pattern. The process was monitored by atomic force microscopy and Fourier transform infrared spectroscopy. Whereas in the absence of any treatment, AT3 gives rise to amyloid beta-rich fibrils, whose hallmark is the typical glutamine side-chain hydrogen bonding, when incubated in the presence of EGCG it generated soluble, SDS-resistant aggregates, much poorer in beta-sheets and devoid of any ordered side-chain hydrogen bonding. These are off-pathway species that persist until the latest incubation time and are virtually absent in the control sample. In contrast, tetracycline did not produce major alterations in the structural features of the aggregated species compared with the control, but substantially increased their solubility. Both compounds significantly reduced toxicity, as shown by the MTT assay in COS-7 cell line and in a transgenic Caenorhabditis elegans strain expressing in the nervous system an AT3 expanded variant in fusion with GFP. PMID- 25030036 TI - Prevalence of targetable oncogenic mutations and genomic alterations in Epstein Barr virus-associated diffuse large B-cell lymphoma of the elderly. AB - Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma (DLBCL) of the elderly constitutes a provisional clinicopathological entity in the current World Health Organization (WHO) classification and its genomic features remain sparsely characterized. We investigated a cohort of 26 cases of untreated de novo EBV positive DLBCL of the elderly by high-resolution array-based comparative genomic profiling and fluorescence in situ hybridization (FISH). Moreover, we screened for activating mutations affecting nuclear factor (NF)-kappaB pathway signaling and chromatin remodeling (EZH2, CD79B, CARD11 and MYD88) due to their impact of gene expression signatures and postulated upcoming therapeutic targetability. We identified an overlap between genomic aberrations previously described to be exclusive features of plasmablastic lymphoma (PL), post-transplant lymphoproliferative disorder (PTLD) and DLBCL, respectively, indicating a close cytogenetic relationship between these entities. Few mutations affecting CD79B and CARD11 and no MYD88 mutations were detectable, hinting at EBV-mediated activation of NF-kappaB as an alternative to pathologically enforced B-cell receptor signaling in this rare entity. PMID- 25030037 TI - A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes. PMID- 25030038 TI - Inflammatory and immune-related conditions associated with Waldenstrom macroglobulinemia: a single center experience. PMID- 25030040 TI - Methicillin-resistant Staphylococcus aureus pneumonia in adults. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become one of the leading etiologies of nosocomial pneumonia as a result of an increase in staphylococcal infections caused by methicillin-resistant strains paired with extended ventilatory support of critically, and often, chronically ill patients. The prevalence of community-acquired MRSA pneumonia, which historically affects younger patients and is often preceded by an influenza-like illness, is also increasing. A high index of suspicion and early initiation of appropriate antibiotics are key factors for the successful treatment of this disease. Even with early diagnosis and appropriate treatment, MRSA pneumonia still carries an unacceptably high mortality rate. This article will review historical differences between hospital-acquired and community-acquired MRSA pneumonia, as well as, clinical features of, diagnosis and treatment of MRSA pneumonia. PMID- 25030039 TI - Skeletal, neuromuscular and fitness impairments among children with newly diagnosed acute lymphoblastic leukemia. AB - This study describes skeletal, neuromuscular and fitness impairments among 109 children (median age 10 [range 4-18] years, 65.1% male, 63.3% white) with acute lymphoblastic leukemia (ALL). Outcomes were measured 7-10 days after diagnosis and compared to age- and sex-specific expected values. Associations between function and health-related quality of life (HRQL) were evaluated with logistic regression. Children with ALL had sub-optimal bone mineral density (BMD) Z score/height (mean +/- standard error: - 0.53 +/- 0.16 vs. 0.00 +/- 0.14, p < 0.01), body mass index percentile (57.6 +/- 3.15 vs. 50.0 +/- 3.27%, p = 0.02), quadriceps strength (201.9 +/- 8.3 vs. 236.1 +/- 5.4 N, p < 0.01), 6 min walk distance (385.0 +/- 13.1 vs. 628.2 +/- 7.1 m, p < 0.001) and Bruininks-Oseretsky Test of Motor Proficiency scores (23 +/- 2.5 vs. 50 +/- 3.4%, p < 0.01). Quadriceps weakness was associated with a 20.9-fold (95% confidence interval 2.5 173.3) increase in poor physical HRQL. Children with newly diagnosed ALL have weakness and poor endurance and may benefit from early rehabilitation that includes strengthening and aerobic conditioning. PMID- 25030041 TI - Application of human FcRn transgenic mice as a pharmacokinetic screening tool of monoclonal antibody. AB - 1. For drug discovery, useful screening tools are essential to select superior candidates. Here, we evaluated the applicability of transgenic mice expressing human neonatal Fc receptor (FcRn) (hFcRn Tgm) as a pharmacokinetic screening tool of therapeutic monoclonal antibodies (mAbs) and Fc-fusion proteins that overcomes the species difference in FcRn binding. 2. Marketed 11 mAbs and 2 Fc-fusion proteins were intravenously administered to hFcRn Tgm and WT mice. The half-lives in hFcRn Tgm and WT mice were compared with those in human obtained from literature. The linear half-lives in human and monkey were also calculated by nonlinear pharmacokinetic analysis. For comparison, correlations of half-lives between monkey and human were also evaluated. 3. The half-lives of mAbs and Fc fusion proteins after intravenous administration ranged from 1.1 to 13.2 days in hFcRn Tgm and from 1.2 to 30.3 days in WT mice. The half-lives in human correlated more closely with those in hFcRn Tgm than in WT mice and monkey. 4. Our results suggest that hFcRn Tgm are a valuable and useful tool for pharmacokinetic screening of mAbs and Fc-fusion proteins in the preclinical stage. Furthermore, we believe that hFcRn Tgm are broadly applicable to preclinical pharmacokinetic screening of mAbs-based therapeutics. PMID- 25030042 TI - Does delivery of a training program for healthcare professionals increase access to pulmonary rehabilitation and improve outcomes for people with chronic lung disease in rural and remote Australia? AB - OBJECTIVE: Access to pulmonary rehabilitation (PR), an effective management strategy for people with chronic respiratory disease, is often limited particularly in rural and remote regions. Difficulties with establishment and maintenance of PR have been reported. Reasons may include a lack of adequately trained staff. There have been no published reports evaluating the impact of training programs on PR provision. The aim of this project was to evaluate the impact of an interactive training and support program for healthcare professionals (the Breathe Easy, Walk Easy (BEWE) program) on the delivery of PR in rural and remote regions. METHODS: The study was a quasi-experimental before after design. Data were collected regarding the provision of PR services before and after delivery of the BEWE program and patient outcomes before and after PR. RESULTS: The BEWE program was delivered in one rural and one remote region. Neither region had active PR before the BEWE program delivery. At 12-month follow up, three locally-run PR programs had been established. Audit and patient outcomes indicated that the PR programs established broadly met Australian practice recommendations and were being delivered effectively. In both regions PR was established with strong healthcare organisational support but without significant external funding, relying instead on the diversion of internal funding and/or in-kind support. CONCLUSIONS: The BEWE program enabled the successful establishment of PR and improved patient outcomes in rural and remote regions. However, given the funding models used, the sustainability of these programs in the long term is unknown. Further research into the factors contributing to the ability of rural and remote sites to provide ongoing delivery of PR is required. PMID- 25030043 TI - Emerging issues in the evolution of animal nuptial gifts. AB - Uniquely positioned at the intersection of sexual selection, nutritional ecology and life-history theory, nuptial gifts are widespread and diverse. Despite extensive empirical study, we still have only a rudimentary understanding of gift evolution because we lack a unified conceptual framework for considering these traits. In this opinion piece, we tackle several issues that we believe have substantively hindered progress in this area. Here, we: (i) present a comprehensive definition and classification scheme for nuptial gifts (including those transferred by simultaneous hermaphrodites), (ii) outline evolutionary predictions for different gift types, and (iii) highlight some research directions to help facilitate progress in this field. PMID- 25030044 TI - Maternal food quantity affects offspring feeding rate in Daphnia magna. AB - Maternal effects have wide-ranging effects on life-history traits. Here, using the crustacean Daphnia magna, we document a new effect: maternal food quantity affects offspring feeding rate, with low quantities of food triggering mothers to produce slow-feeding offspring. Such a change in the rate of resource acquisition has broad implications for population growth or dynamics and for interactions with, for instance, predators and parasites. This maternal effect can also explain the previously puzzling situation that the offspring of well-fed mothers, despite being smaller, grow and reproduce better than the offspring of food starved mothers. As an additional source of variation in resource acquisition, this maternal effect may also influence relationships between life-history traits, i.e. trade-offs, and thus constraints on adaptation. Maternal nutrition has long-lasting effects on health and particularly diet-related traits in humans; finding an effect of maternal nutrition on offspring feeding rate in Daphnia highlights the utility of this organism as a powerful experimental model for exploring the relationship between maternal diet and offspring fitness. PMID- 25030045 TI - Indirect evidence for elastic energy playing a role in limb recovery during toad hopping. AB - Elastic energy is critical for amplifying muscle power during the propulsive phase of anuran jumping. In this study, we use toads (Bufo marinus) to address whether elastic recoil is also involved after take-off to help flex the limbs before landing. The potential for such spring-like behaviour stems from the unusually flexed configuration of a toad's hindlimbs in a relaxed state. Manual extension of the knee beyond approximately 90 degrees leads to the rapid development of passive tension in the limb as underlying elastic tissues become stretched. We hypothesized that during take-off, the knee regularly extends beyond this, allowing passive recoil to help drive limb flexion in mid-air. To test this, we used high-speed video and electromyography to record hindlimb kinematics and electrical activity in a hindlimb extensor (semimembranosus) and flexor (iliofibularis). We predicted that hops in which the knees extended further during take-off would require less knee flexor recruitment during recovery. Knees extended beyond 90 degrees in over 80% of hops, and longer hops involved greater degrees of knee extension during take-off and more intense semimembranosus activity. However, knee flexion velocities during recovery were maintained despite a significant decrease in iliofibularis intensity in longer hops, results consistent with elastic recoil playing a role. PMID- 25030046 TI - Tuning of near-infrared luminescence of SrTiO3:Ni2+ thin films grown on piezoelectric PMN-PT via strain engineering. AB - We report the tunable near-infrared luminescence of Ni(2+) doped SrTiO3 (STO:Ni) thin film grown on piezoelectric Pb(Mg(1/3)Nb(2/3))(0.7)Ti(0.3)O3 (PMN-PT) substrate via strain engineering differing from conventional chemical approach. Through controlling the thickness of STO:Ni film, the luminescent properties of the films including emission wavelength and bandwidth, as well as lifetime can be effectively tuned. The observed phenomena can be explained by the variation in the crystal field around Ni(2+) ions caused by strain due to the lattice mismatch. Moreover, the modulation of strain can be controlled under an external electric field via converse piezoelectric effect of PMN-PT used in this work. Consequently, controllable emission of the STO:Ni thin film is demonstrated in a reversible and real-time way, arising from the biaxial strain produced by piezoelectric PMN-PT. Physical mechanism behind the observation is discussed. This work will open a door for not only investigating the luminescent properties of the phosphors via piezoelectric platform, but also potentially developing novel planar light sources. PMID- 25030047 TI - Cytokines secreted by bone marrow stromal cells protect c-KIT mutant AML cells from c-KIT inhibitor-induced apoptosis. PMID- 25030049 TI - An overweight or obese status in childhood predicts subclinical atherosclerosis and prehypertension/hypertension in young adults. AB - AIM: The aim of this study, the YOung TAiwanese Cohort (YOTA) Study, was to investigate the relationship between a childhood overweight/obese status and young adult preclinical atherosclerosis, including assessments of the carotid intima-media thickness (CIMT) and prehypertension or hypertension. METHODS: From among children who participated in the 1992-2000 mass urine screening program in Taiwan, we recruited 303 subjects with an elevated blood pressure (EBP) and 486 subjects with a normal BP in childhood during the period of 2006-2008. These 789 young adults received health check-ups for cardiovascular health, including examinations of blood and urine parameters, anthropometrics, BP and the CIMT, a subclinical cardiovascular risk index. Data analyses were used to evaluate the associated risks in both childhood and young adulthood. RESULTS: The school students with a childhood overweight/obese status had a higher risk of prehypertension or hypertension, with a relative risk of 3.20 (1.40-7.33) for being overweight and 6.51 (3.36-12.63) for being obese in young adulthood at an average age of 21. A childhood overweight/obese status also predicted a higher risk of having a thicker CIMT, with a relative risk of 2.82 (1.26-6.28) and 4.17 (2.21-7.85) for being overweight and obese in adulthood, respectively, after a mean follow-up of 8.5 years. The body mass index exhibited a consistent trend from childhood to adulthood, with an adjusted R square of 0.551. The participants who were not overweight/obese in childhood also demonstrated a higher risk of prehypertension or hypertension if they became overweight or obese in adulthood. CONCLUSIONS: This study highlights the importance of preventing and treating an overweight or obese status in childhood for the primary prevention of cardiovascular disease in adulthood. PMID- 25030050 TI - Utility of the triglyceride level for predicting incident diabetes mellitus according to the fasting status and body mass index category: the Ibaraki Prefectural Health Study. AB - AIM: The levels of lipids, especially triglycerides (TG), and obesity are associated with diabetes mellitus (DM). Although typically measured in fasting individuals, non-fasting lipid measurements play an important role in predicting future DM. This study compared the predictive efficacy of lipid variables according to the fasting status and body mass index (BMI) category. METHODS: Data were collected for 39,196 nondiabetic men and 87,980 nondiabetic women 40-79years of age who underwent health checkups in Ibaraki-Prefecture, Japan in 1993 and were followed through 2007. The hazard ratios (HRs) for DM in relation to sex, the fasting status and BMI were estimated using a Cox proportional hazards model. RESULTS: A total of 8,867 participants, 4,012 men and 4,855 women, developed DM during a mean follow-up of 5.5 years. TG was found to be an independent predictor of incident DM in both fasting and non-fasting men and non-fasting women. The multivariable-adjusted HR for DM according to the TG quartile (Q) 4 vs. Q1 was 1.18 (95% confidence interval (CI): 1.05, 1.34) in the non-fasting men with a normal BMI (18.5-24.9). This trend was also observed in the non-fasting women with a normal BMI. That is, the multivariable-adjusted HRs for DM for TG Q2, Q3 and Q4 compared with Q1 were 1.07 (95% CI: 0.94, 1.23), 1.17 (95%CI: 1.03, 1.34) and 1.48 (95%CI: 1.30, 1.69), respectively. CONCLUSIONS: The fasting and non fasting TG levels in men and non-fasting TG levels in women are predictive of future DM among those with a normal BMI. Clinicians must pay attention to those individuals at high risk for DM. PMID- 25030051 TI - Binding of fullerenes and nanotubes to MscL. AB - Multi-drug resistance is becoming an increasing problem in the treatment of bacterial infections and diseases. The mechanosensitive channel of large conductance (MscL) is highly conserved among prokaryotes. Evidence suggests that a pharmacological agent that can affect the gating of, or block the current through, MscL has significant potential as a new class of antimicrobial compound capable of targeting a range of pathogenic bacteria with minimal side-effects to infected patients. Using molecular dynamics we examine the binding of fullerenes and nanotubes to MscL and demonstrate that both are stable within the MscL pore. We predict that fullerenes will attenuate the flow of ions through MscL by reducing the pore volume available to water and ions, but nanotubes will prevent pore closure resulting in a permanently open pore. Moreover, we confirm experimentally that it is possible to attenuate the flow of ions through MscL using a C60-gamma cyclodextrin complex. PMID- 25030053 TI - The ID93 tuberculosis vaccine candidate does not induce sensitivity to purified protein derivative. AB - The tuberculin skin test (TST) is a simple and inexpensive test to determine whether individuals have been exposed to Mycobacterium tuberculosis. This test is not always reliable, however, in people previously immunized with BCG and/or who have been exposed to environmental mycobacterial species due to a reaction to purified protein derivative (PPD) used in the skin test. An issue with BCG, therefore, is that the resulting sensitization to PPD in some individuals compromises the diagnostic use of the skin test. The ability to induce protective immune responses without sensitizing to the tuberculin skin test will be important properties of next-generation tuberculosis (TB) vaccine candidates. We show here that guinea pigs immunized with the candidate TB vaccine ID93/GLA-SE, currently in clinical trials, do not react to intradermal PPD administration. In contrast, positive DTH responses to both ID93 and components thereof were induced in ID93/GLA-SE-immunized animals, indicating robust but specific cellular responses were present in the immunized animals. Noninterference with the TST is an important factor for consideration in the development of a vaccine against M. tuberculosis. PMID- 25030052 TI - Topical resiquimod protects against visceral infection with Leishmania infantum chagasi in mice. AB - New prevention and treatment strategies are needed for visceral leishmaniasis, particularly ones that can be deployed simply and inexpensively in areas where leishmaniasis is endemic. Synthetic molecules that activate Toll-like receptor 7 and 8 (TLR7/8) pathways have previously been demonstrated to enhance protection against cutaneous leishmaniasis. We initially sought to determine whether the TLR7/8-activating molecule resiquimod might serve as an effective vaccine adjuvant targeting visceral leishmaniasis caused by infection with Leishmania infantum chagasi. Resiquimod was topically applied to the skin of mice either prior to or after systemic infection with L. infantum chagasi, and parasite burdens were assessed. Surprisingly, topical resiquimod application alone, in the absence of vaccination, conferred robust resistance to mice against future intravenous challenge with virulent L. infantum chagasi. This protection against L. infantum chagasi infection persisted as long as 8 weeks after the final topical resiquimod treatment. In addition, in mice with existing infections, therapeutic treatment with topical resiquimod led to significantly lower visceral parasite loads. Resiquimod increased trafficking of leukocytes, including B cells, CD4(+) and CD8(+) T cells, dendritic cells, macrophages, and granulocytes, in livers and spleens, which are the key target organs of visceralizing infection. We conclude that topical resiquimod leads to systemic immune modulation and confers durable protection against visceralizing L. infantum chagasi infection, in both prophylactic and therapeutic settings. These studies support continued studies of TLR-modulating agents to determine mechanisms of protection and also provide a rationale for translational development of a critically needed, novel class of topical, preventative, and therapeutic agents for these lethal infections. PMID- 25030054 TI - Commercially available complement component-depleted sera are unexpectedly codepleted of ficolin-2. AB - The ficolins are a family of innate pattern recognition molecules that are known to bind acetylated compounds and activate complement through the association of mannose binding lectin (MBL)/ficolin-associated serine proteases (MASPs). Their importance has more recently become appreciated, as they have been shown to play a role in a variety of disease processes from infection to autoimmunity. While studying ficolin-2-mediated complement deposition on Streptococcus pneumoniae, we found that sera depleted of C1q or other complement components were also codepleted of ficolin-2 but not ficolin-1, ficolin-3, or MBL. MBL present in C1q depleted sera was able to mediate complement deposition on Saccharomyces cerevisiae, suggesting the presence of MASPs. We found that complement was activated on pneumococci in C1q-depleted serum only after opsonization with exogenous recombinant ficolin-2 (rFicolin-2). Also, no complement deposition was observed in C1q-depleted serum when pneumococci were opsonized with rFicolin-2 mutated at its lysine-57 residue, where MASPs are known to associate. Thus, these depleted sera are a unique tool to study ficolin-2-mediated complement pathways; however, one should be aware that ficolin-2 is absent from complement component depleted sera. PMID- 25030055 TI - Glycosylated and nonglycosylated complement control protein of the lister strain of vaccinia virus. AB - The vaccinia virus complement control protein (VCP) is a secreted viral protein that binds the C3b and C4b complement components and inhibits the classic and alternative complement pathways. Previously, we reported that an attenuated smallpox vaccine, LC16m8, which was derived from the Lister strain of vaccinia virus (VV-Lister), expressed a glycosylated form of VCP, whereas published sequence data at that time indicated that the VV-Lister VCP has no motif for N linked glycosylation. We were interested in determining whether the glycosylation of VCP impairs its biological activity, possibly contributing to the attenuation of LC16m8, and the likely origin of the glycosylated VCP. Expression analysis indicated that VV-Lister contains substrains expressing glycosylated VCP and substrains expressing nonglycosylated VCP. Other strains of smallpox vaccine, as well as laboratory strains of vaccinia virus, all expressed nonglycosylated VCP. Individual Lister virus clones expressing either the glycosylated VCP or the nonglycosylated species were isolated, and partially purified VCP from the isolates were found to be functional equivalents in binding human C3b and C4b complement proteins and inhibiting hemolysis and in immunogenicity. Recombinant vaccinia viruses expressing FLAG-tagged glycosylated VCP (FLAG-VCPg) and nonglycosylated VCP (FLAG-VCP) were constructed based on the Western Reserve strain. Purified FLAG-VCP and FLAG-VCPg bind human C3b and C4b and blocked complement-mediated hemolysis. Our data suggest that glycosylation did not affect the biological activity of VCP and thus may not have contributed to the attenuation of LC16m8. In addition, the LC16m8 virus likely originated from a substrain of VV-Lister that expresses glycosylated VCP. PMID- 25030056 TI - Evolutionary conservation of cold-induced antisense RNAs of FLOWERING LOCUS C in Arabidopsis thaliana perennial relatives. AB - Antisense RNA (asRNA) COOLAIR is expressed at A. thaliana FLOWERING LOCUS C (FLC) in response to winter temperatures. Its contribution to cold-induced silencing of FLC was proposed but its functional and evolutionary significance remain unclear. Here we identify a highly conserved block containing the COOLAIR first exon and core promoter at the 3' end of several FLC orthologues. Furthermore, asRNAs related to COOLAIR are expressed at FLC loci in the perennials A. alpina and A. lyrata, although some splicing variants differ from A. thaliana. Study of the A. alpina orthologue, PERPETUAL FLOWERING 1 (PEP1), demonstrates that AaCOOLAIR is induced each winter of the perennial life cycle. Introduction of PEP1 into A. thaliana reveals that AaCOOLAIR cis-elements confer cold-inducibility in this heterologous species while the difference between PEP1 and FLC mRNA patterns depends on both cis-elements and species-specific trans-acting factors. Thus, expression of COOLAIR is highly conserved, supporting its importance in FLC regulation. PMID- 25030057 TI - Protease inhibitors and adverse birth outcomes: is progesterone the missing piece to the puzzle? PMID- 25030058 TI - HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction. AB - BACKGROUND: Protease inhibitor (PI)-based combination antiretroviral therapy (cART) is administered during pregnancy to prevent perinatal human immunodeficiency virus (HIV) transmission. However, PI use has been associated with adverse birth outcomes, including preterm delivery and small-for-gestational age (SGA) births. The mechanisms underlying these outcomes are unknown. We hypothesized that PIs contribute to these adverse events by altering progesterone levels. METHODS: PI effects on trophoblast progesterone production were assessed in vitro. A mouse pregnancy model was used to assess the impact of PI-based cART on pregnancy outcomes and progesterone levels in vivo. Progesterone levels were assessed in plasma specimens from 27 HIV-infected and 17 HIV-uninfected pregnant women. RESULTS: PIs (ritonavir, lopinavir, and atazanavir) but not nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors reduced trophoblast progesterone production in vitro. In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight. Progesterone supplementation resulted in a significant improvement in fetal weight. We observed lower progesterone levels and smaller infants in HIV-infected women receiving PI-based cART, compared with the control group. In HIV-infected women, progesterone levels correlated significantly with birth weight percentile. CONCLUSIONS: Our data suggest that PI use in pregnancy may lead to lower progesterone levels that could contribute to adverse birth outcomes. PMID- 25030059 TI - In memoriam: Morton N. Swartz. PMID- 25030060 TI - The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. AB - BACKGROUND: Administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (SARIs) of viral etiology. We conducted a systematic review and exploratory meta-analysis to assess the overall evidence. METHODS: Healthcare databases and sources of grey literature were searched in July 2013. All records were screened against the protocol eligibility criteria, using a 3 stage process. Data extraction and risk of bias assessments were undertaken. RESULTS: We identified 32 studies of SARS coronavirus infection and severe influenza. Narrative analyses revealed consistent evidence for a reduction in mortality, especially when convalescent plasma is administered early after symptom onset. Exploratory post hoc meta-analysis showed a statistically significant reduction in the pooled odds of mortality following treatment, compared with placebo or no therapy (odds ratio, 0.25; 95% confidence interval, .14-.45; I(2) = 0%). Studies were commonly of low or very low quality, lacked control groups, and at moderate or high risk of bias. Sources of clinical and methodological heterogeneity were identified. CONCLUSIONS: Convalescent plasma may reduce mortality and appears safe. This therapy should be studied within the context of a well-designed clinical trial or other formal evaluation, including for treatment of Middle East respiratory syndrome coronavirus CoV infection. PMID- 25030061 TI - An earlier uterine environment favors the in vivo development of fresh pig morulae and blastocysts transferred by a nonsurgical deep-uterine method. AB - This study aimed to evaluate the effect of recipient-donor estrous cycle synchrony on recipient reproductive performance after nonsurgical deep-uterine (NsDU) embryo transfer (ET). The transfers (N=132) were conducted in recipients sows that started estrus 24 h before (-24 h; N=9) or 0 h (synchronous; N=31), 24 h (+24 h; N=74) or 48 h (+48 h; N=18) after the donors. A total of 30 day 5 morulae or day 6 blastocysts (day 0=onset of estrus) were transferred per recipient. The highest farrowing rates (FRs) were achieved when estrus appeared in recipients 24 h later than that in the donors (81.1%), regardless of the embryonic stage used for the transfers. The FR notably decreased (P<0.05) when recipients were -24 h asynchronous (0%), synchronous (61.3%) or +48 h asynchronous (50%) relative to the donors. No differences in litter size (LS) and piglet birth weights were observed among the synchronous and +24 h or +48 h asynchronous groups. While a +24 h asynchronous recipient was suitable for transfers performed with either morulae (FR, 74.3%; LS, 9.2 +/- 0.6 piglets) or blastocysts (FR, 84.6%; LS, 9.8 +/- 0.6 piglets), a + 48 h asynchronous recipient was adequate for blastocysts (FR, 87.5%; LS, 10.4 +/- 0.7 piglets) but not for morulae (FR, 30.0%; LS, 7.3 +/- 2.3 piglets). In conclusion, this study confirms the effectiveness of the NsDU-ET technology and shows that porcine embryos tolerate better a less advanced uterine environment if they are nonsurgically transferred deep into the uterine horn. PMID- 25030062 TI - Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models. AB - Acute graft-versus-host disease (GVHD) is induced by alloreactivity of donor T cells toward host antigens presented on antigen-presenting cells (APCs). Apoptotic cells are capable of inducing tolerance by altering APC maturation. Apoptosis can be induced by extracorporeal photopheresis (ECP). We demonstrate that the use of ECP as a prophylaxis prior to conditioning significantly improves survival (P < .0001) after bone marrow transplantation (BMT) by inhibiting the initiation phase of acute GVHD in a murine BMT model. ECP-treated autologous splenocytes resulted in immune tolerance in the host, including reduced dendritic cell activation with decreased nuclear factor-kappaB engagement, increased regulatory T-cell (Treg) numbers with enhanced expression of cytolytic T lymphocyte-associated antigen 4, potentiating their suppressive function. The protective effect required host production of interleukin-10 and host Tregs. Conventional T cells that entered this tolerant environment experienced reduced proliferation, as well as a reduction of tissue homing and expression of activation markers. The induction of this tolerant state by ECP was obviated by cotreatment with lipopolysaccharide, suggesting that the inflammatory state of the recipient prior to treatment would play a role in potential clinical translation. The use of prophylactic ECP may provide an alternative and safe method for immunosuppression in the bone marrow transplant setting. PMID- 25030063 TI - Human CD68 promoter GFP transgenic mice allow analysis of monocyte to macrophage differentiation in vivo. AB - The recruitment of monocytes and their differentiation into macrophages at sites of inflammation are key events in determining the outcome of the inflammatory response and initiating the return to tissue homeostasis. To study monocyte trafficking and macrophage differentiation in vivo, we have generated a novel transgenic reporter mouse expressing a green fluorescent protein (GFP) under the control of the human CD68 promoter. CD68-GFP mice express high levels of GFP in both monocyte and embryo-derived tissue resident macrophages in adult animals. The human CD68 promoter drives GFP expression in all CD115(+) monocytes of adult blood, spleen, and bone marrow; we took advantage of this to directly compare the trafficking of bone marrow-derived CD68-GFP monocytes to that of CX3CR1(GFP) monocytes in vivo using a sterile zymosan peritonitis model. Unlike CX3CR1(GFP) monocytes, which downregulate GFP expression on differentiation into macrophages in this model, CD68-GFP monocytes retain high-level GFP expression for 72 hours after differentiation into macrophages, allowing continued cell tracking during resolution of inflammation. In summary, this novel CD68-GFP transgenic reporter mouse line represents a powerful resource for analyzing monocyte mobilization and monocyte trafficking as well as studying the fate of recruited monocytes in models of acute and chronic inflammation. PMID- 25030065 TI - Frustration of ferroelectricity in epitaxial film of relaxor ferroelectric PbSc1/2Nb1/2O3. AB - Relaxor-to-ferroelectric transformations induced by varying electric fields and temperatures are studied experimentally in acube-on-cubetype epitaxial PbSc(1/2)Nb(1/2)O3 film grown on La(1/2)Sr(1/2)CoO3/MgO(001). Dielectric response, quasi-static and dynamic polarization, and dynamic current-voltage characteristics evidence the absence of spontaneous relaxor-to-ferroelectric transition. The electricfield-induced transformation from a glass-like relaxor state to a new dynamic polar state is detected at low temperatures below 100 K only. The frustration of ferroelectricity is discussed in relation to orientational anisotropy of the dipolar system in the epitaxial (001) film. PMID- 25030064 TI - COX-1-derived thromboxane A2 plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse. AB - Cyclooxygenases (COXs) and their prostanoid products play important roles in a diverse range of physiological processes, including in the immune system. Here, we provide evidence that COX-1 is an essential regulator in early stages of B cell development. COX-1-deficient mice displayed systematic reduction in total B cells, which was attributed to the arrest of early B-cell development from pro-B to pre-B stage. We further demonstrated that this defect was mediated through downregulation of the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling and its target genes, including Pax5, in COX-1(-/-) mice. Mechanistic studies revealed that COX-1-derived thromboxane A2 (TxA2) could regulate JAK3/STAT5 signaling through the cyclic adenosine monophosphate-protein kinase A pathway, via binding with its receptor thromboxane A2 receptor (TP). Administration of the TP agonist could rescue the defective B cell development and JAK/STAT5 signaling activity in COX-1-deficient mice. Moreover, administration of low-dose aspirin caused a significant reduction in total B cells in peripheral blood of healthy human volunteers, coincidentally with reduced TxA2 production and downregulation of JAK/STAT5 signaling. Taken together, our results demonstrate that COX-1-derived TxA2 plays a critical role in the stage transition of early B-cell development through regulation of JAK/STAT5 signaling and indicate a potential immune-suppressive effect of low dose aspirin in humans. PMID- 25030066 TI - Meta-analysis of postoperative efficacy in patients receiving chemoradiotherapy followed by surgery for resectable esophageal carcinoma. AB - BACKGROUND: Many studies have demonstrated that chemoradiotherapy followed by surgery (CRTS) prolongs the 5-year survival rate of resectable esophageal carcinoma patients. However, the effect of CRTS on postoperative complications, local recurrence and distant metastasis remains controversial. We performed a systematic review of the literature and conducted a meta-analysis to assess the postoperative efficacy of CRTS compared with surgery alone (SA). METHODS: Pubmed, Web of Science and the Cochrane library Databases were used to identify published studies between 2000 and 2013 that directly compared CRTS with SA. The pooled relative risk (RR) and its corresponding 95% confidence interval (95% CI) constituted the principal measure of treatment effects. Heterogeneity was assessed by the chi2 and I2 statistic. RESULTS: The final analysis included 1930 resectable esophageal carcinoma cases from 13 randomized controlled trials (RCTs). Compared with SA, CRTS was associated with significantly decreased postoperative mortality, local recurrence and distant metastasis rates, with RR (95% CI) = 0.64 (0.49-0.84), 0.53 (0.39-0.73), 0.82 (0.68-0.98); p = 0.001, <0.00001, =0.03, respectively. However, there was no significant difference in postoperative complication incidence between the two groups (RR, 1.09; 95% CI, 0.96-1.24; p = 0.18). CONCLUSIONS: CRTS significantly decreased postoperative mortality, local recurrence and distant metastasis rates compared to SA. Additionally, there were no increased postoperative complications for patients with resectable esophageal carcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1531519216130950. PMID- 25030067 TI - Syntheses of sterically shielded stable carbenes of the 1,2,4-triazole series and their corresponding palladium complexes: efficient catalysts for chloroarene hydrodechlorination. AB - The new sterically shielded 1,3,4-trisubstituted 1,2,4-triazol-5-ylidenes 8b-d were synthesized by a three step method starting from 2-phenyl-1,3,4-oxadiazole. The syntheses of palladium complexes 9a-d and 10a-d (including the sterically shielded derivatives 9c,d and 10a-d) were carried out via the reactions of the stable carbenes 8a-d with palladium halogenide salts in THF or toluene solution. Complexes 9c,d and 10a-d were found to be excellent catalysts for the reductive dechlorination (hydrodechlorination) of p-dichlorobenzene. The structures of 8c, 9a,b, and 10a were determined by single-crystal X-ray diffraction. PMID- 25030068 TI - [Empathy and moral judgements in the elderly population]. AB - INTRODUCTION: Social cognition refers to mental processes that operate in situations of social interaction and facilitate adjustment and functioning in such scenarios. AIM: To study the empathic response in two groups of older people and their relationship to emotional intelligence and moral judgment. SUBJECTS AND METHODS: We enrolled 60 subjects divided into two groups of 30 subjects each completed a battery of tests: TMMS-24, DEX, IRI and moral dilemmas. RESULTS. In the dimension of the IRI perspective taking older group scored significantly less than the middle age group (U = 279; p < 0.05). In all other variables, no statistically significant differences were found. CONCLUSIONS: The results show the absence of a generalized deficit in social cognition in the elderly sample evaluated. However, differences were observed based on age on empathy and executive performance: over time a progressive impairment in theory of mind and a decline in the general empathic capacity occur. With regard to emotional intelligence, the elderly evaluated show a correct perception and understanding of their emotions even report a poorer ability to manage and regulate their emotions. PMID- 25030069 TI - [Stroke in children. Experience in an emergency service]. AB - AIMS: To describe the characteristics of cerebrovascular disease (CVD) in patients treated in a paediatric emergency department and to detect clinical differences, depending on whether the condition was ischaemic or haemorrhagic. PATIENTS AND METHODS: An analytical, observation-based, retrospective study was conducted in the paediatric emergency department of a tertiary care hospital. The sample included patients aged between 1 month and 18 years who were treated in the service over a period of 10 years (January 2001 to December 2011) with a final diagnosis of CVD. Haemorrhages due to traumatic injury or secondary to tumours, thrombosis of the venous sinuses and patients who were not treated in the service were all excluded. RESULTS: The final sample consisted of 61 patients, 39 (63.9%) of whom were males, with a mean age of 4.6 years (range: 1.3 months-17.5 years). Of them, 26 (42.6%) presented ischaemic CVD and 35 (57.4%) had haemorrhagic CVD. Headache (n = 20; 57.1%; p = 0.008) and vomiting (n = 25; 71.4%; p = 0.001) are more frequent in haemorrhagic CVD, and hemiparesis (n = 17; 65.4%; p < 0.001) and facial palsy (n = 7; 26.9%; p = 0.001) in ischaemic CVD. The main causes of haemorrhagic CVD are arteriovenous malformations (n = 17; 38.6%) and the ischaemic ones are triggered by arteriopathies (n = 6; 42.3%). On discharge from hospital, 27 (44.3%) presented different degrees of disability and 6 (9.8%) died. CONCLUSIONS: CVD is a rare entity, although it presents a high morbidity and mortality rate. Haemorrhagic CVD is seen to predominate slightly and it is observed how haemorrhagic CVD presents more often with signs of intracranial hypertension, while the ischaemic form tends to have more neurological focus. PMID- 25030070 TI - [Detection of the PMP22 gene duplication in peripheral neuropathy patients: a study in Mexican population]. AB - INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is a neuropathy that affects sensory and motor nerves. The most common CMT subtype is CMT1A due to a PMP22 duplication of a 1.5 Mb fragment on the 17p11.2-p12. The development of a specific molecular technique that detects the PMP22 duplication is necessary for the diagnosis of CMT1A. AIM: To establish a routinary test for detection of the PMP22 gene duplication in Mexican population and to estimate the CMT1A frequency in patients clinically diagnosed as CMT. PATIENTS AND METHODS: A cohort of 157 individuals clinically diagnosed as CMT were analyzed. The detection of the PMP22 gene duplication was performed using the comparative 2-DeltaDeltaCT qPCR method. RESULTS: The comparative 2-DeltaDeltaCT method was sensitive and reliable for the detection of the PMP22 duplication. In order to validate the testing, data was compared with FISH results. Duplication of PMP22 was detected in 79 patients (50.3%). Although CMT1A frequency is different among populations, in Mexican patients it was similar with other populations such as United States, Australia, Finland, Sweden and Spain. CONCLUSIONS: The qPCR technique is an accurate and inexpensive method for the diagnosis of CMT1A. This method can be routinely used in Mexico where CMT1A represents ? 50% of CMT cases. Molecular diagnosis of CMT1A is essential for the genetic counseling and treatment of patients. PMID- 25030071 TI - [Endovascular treatment of critical basilar stenosis with a Solitaire(r) stent device: a first experience in our centre]. AB - INTRODUCTION: Although intracranial arteriosclerosis is an important cause of stroke, the therapeutic attitude has still not been clearly established. Hence, the SAMMPRIS study compared intensive medical treatment with angioplasty and stent placement, with outcomes favouring the pharmacological treatment. These results could be partly due to the device used (Wingspan(r) stent). CASE REPORT: A 71-year-old male with a severe stenosis of the basilar artery, who suffered repeated episodes of transient neurological focus despite being treated with antiplatelet therapy and statins. Given the circumstances, the decision was made to perform a therapeutic arteriography with angioplasty and placement of a Solitaire(r) stent in order to optimise results, a residual stenosis of 40% being achieved. Subsequent progress was favourable and the control tests carried out showed a minimum progression. CONCLUSIONS: As far as we know, this is the first case of critical stenosis of the basilar artery being treated by placement of a Solitaire(r) stent to be reported in the literature. PMID- 25030072 TI - Central effects of fingolimod. AB - INTRODUCTION: Fingolimod, a sphingosine-1-phosphate receptor modulator, was the first oral therapy approved for relapsing-remitting multiple sclerosis, and shows a novel mechanism of action. Upon binding to S1P1 receptors in lymphocytes, the selective retention of naive and central memory T cells in secondary lymphoid tissues is promoted, preventing their egress to the central nervous system (CNS). In addition, fingolimod readily crosses the blood brain barrier, and several reports suggest a direct neuroprotective effect in the CNS. AIM: To review the available data on the central effects of fingolimod. DEVELOPMENT: Imbalances between damage and repair processes are a reflection of chronic demyelination, axonal degeneration and gliosis, and seem to contribute to multiple sclerosis associated disability. Given fingolimod readily crosses the blood brain barrier, it can exert its action directly on S1P receptors present in CNS cells. Fingolimod occupies S1P receptors in oligodendrocytes, oligodendrocyte precursor cells, astrocytes, microglial cells and neurons, promoting remyelination, neuroprotection, and endogenous regeneration processes. Efficacy results from clinical trials are consistent with a mechanism of action that includes direct effects in CNS cells. CONCLUSIONS: Current evidence suggests that the efficacy of fingolimod in the treatment of Multiple Sclerosis is due to its dual action as an immunomodulatory molecule and as a direct modulator of S1PRs in the CNS. In fact, recent reports propose that fingolimod has neuroprotective effects in several models, and open new avenues of potential therapeutic applications, such as Alzheimer's disease, cerebral malaria, neuroblastoma and neuroprotection in cranial irradiation. PMID- 25030074 TI - [Ischaemic stroke as the presenting symptom of essential thrombocythaemia]. PMID- 25030075 TI - [Importance of molecular genetics in refractory epilepsy in infants with a normal phenotype]. PMID- 25030076 TI - [Oliver Sacks and literary neurology]. PMID- 25030077 TI - Effect of temperature on the anthocyanin extraction and color evolution during controlled dehydration of Tempranillo grapes. AB - In this paper, the influence of temperature during the controlled dehydration of Tempranillo red grapes has been studied. Two experiments at fixed temperatures of 30 and 40 degrees C, and a third experiment alternating temperatures of 40 and 15 degrees C every 12 h were carried out. The must from grapes dried at 40 degrees C presented the reddest color, and the highest anthocyanin concentration and antioxidant activity. A possible hypothesis could be that the high temperature induced a continuous water evaporation from the grapes, preventing the oxygen entry. At the same time, the dehydration resulted in broken skins, which facilitated the transfer of colored compounds to the pulp, increasing the red color of the musts. However, when the temperature dropped, oxygen could penetrate through the skin and the browning reactions started. As a result, the must obtained from gra pes dehydrated by alternating high and low temperatures presented the least anthocyanin content and the least red color. PMID- 25030078 TI - Enhanced photocatalytic performance at a Au/N-TiO2 hollow nanowire array by a combination of light scattering and reduced recombination. AB - We demonstrate one-step gold nanoparticle (AuNP) coating and the surface nitridation of TiO2 nanowires (TiO2-NWs) to amplify visible-light photon reflection. The surface nitridation of TiO2-NW arrays maximizes the anchoring of AuNPs, and the subsequent reduction of the band gap energy from 3.26 eV to 2.69 eV affords visible-light activity. The finite-difference time-domain (FDTD) simulation method clearly exhibits the enhancement in the strengths of localized electric fields between AuNPs and the nanowires, which significantly improves the photocatalytic (PC) performance. Both nitridation and AuNP decoration of TiO2-NWs result in beneficial effects of high (e(-)/h(+)) pair separation through healing of the oxygen vacancies. The combined effect of harvesting visible-light photons and reducing recombination in Au/N-doped TiO2-NWs promotes the photocatalytic activity towards degradation of methyl orange to an unprecedented level, ~4 fold (1.1 * 10(-2) min) more than does TiO2-NWs (2.9 * 10(-3) min(-1)). The proposed AuNP decoration of nitridated TiO2-NW surfaces can be applied to a wide range of n-type metal oxides for photoanodes in photocatalytic applications. PMID- 25030079 TI - Structurally modified natural sesquiterpene lactones constitute effective and less toxic schistosomicidal compounds. AB - Sesquiterpene lactones are known to be active, but are also known to present high cytotoxicity. In the present work an evaluation of how slight structural alterations affect the cytotoxicity and the schistosomicidal activity of sesquiterpene lactones was undertaken. More specifically, we assessed the activity of budlein-A, a furanoheliangolide sesquiterpene lactone, and four of its derivatives. The structural modifications of budlein-A, presented in this work, diminished the cytotoxicity and changed the antiparasitary behavior of the molecule. They also provided data for a better understanding of the sesquiterpene lactone cytotoxicity. The establishment of the structures of three synthesized sesquiterpene lactones on the basis of NMR and HRESIMS data is also presented here. Complete and detailed (1)H and (13)C 1D and 2D NMR data, with measurements of all J values and all multiplicities clarified, are presented for five sesquiterpene lactones for the first time. PMID- 25030080 TI - The influence of encoding manipulations on the dynamics of free recall. AB - In three experiments, the influence of various encoding manipulations on the dynamics of free recall were investigated. In Experiment 1, increasing study time increased the number of items recalled with no change in recall latency. In Experiment 2, a levels-of-processing manipulation increased the number of items recalled with no change in recall latency. Finally, in Experiment 3, massed presentations of items increased the number of items recalled with no change in recall latency; however, spaced presentations of items increased both the number of items recalled and recall latency. These results suggest that some encoding manipulations serve to increase the absolute strength of items, whereas other encoding manipulations create copies of target items. In both cases, the number of items recalled is increased, but differences arise in recall latency. These results point to the importance of examining both the number of items recalled and recall latency as means of better understanding encoding and retrieval processes that lead to successful remembering. PMID- 25030081 TI - What does visual suffix interference tell us about spatial location in working memory? AB - A visual object can be conceived of as comprising a number of features bound together by their joint spatial location. We investigate the question of whether the spatial location is automatically bound to the features or whether the two are separable, using a previously developed paradigm whereby memory is disrupted by a visual suffix. Participants were shown a sample array of four colored shapes, followed by a postcue indicating the target for recall. On randomly intermixed trials, a to-be-ignored suffix array consisting of two different colored shapes was presented between the sample and the postcue. In a random half of suffix trials, one of the suffix items overlaid the location of the target. If location was automatically encoded, one might expect the colocation of target and suffix to differentially impair performance. We carried out three experiments, cuing for recall by spatial location (Experiment 1), color or shape (Experiment 2), or both randomly intermixed (Experiment 3). All three studies showed clear suffix effects, but the colocation of target and suffix was differentially disruptive only when a spatial cue was used. The results suggest that purely visual shape-color binding can be retained and accessed without requiring information about spatial location, even when task demands encourage the encoding of location, consistent with the idea of an abstract and flexible visual working memory system. PMID- 25030082 TI - Synthesis and kinetic resolution of N-Boc-2-arylpiperidines. AB - The chiral base n-BuLi/(-)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39-48% and ers up to 97 : 3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities. PMID- 25030083 TI - Understanding the variability of properties in Antheraea pernyi silk fibres. AB - Variability is a common feature of natural silk fibres, caused by a range of natural processing conditions. Better understanding of variability will not only be favourable for explaining the enviable mechanical properties of animal silks but will provide valuable information for the design of advanced artificial and biomimetic silk-like materials. In this work, we have investigated the origin of variability in forcibly reeled Antheraea pernyi silks from different individuals using dynamic mechanical thermal analysis (DMTA) combined with the effect of polar solvent penetration. Quasi-static tensile curves in different media have been tested to show the considerable variability of tensile properties between samples from different silkworms. The DMTA profiles (as a function of temperature or humidity) through the glass transition region of different silks as well as dynamic mechanical properties after high temperature and water annealing are analysed in detail to identify the origin of silk variability in terms of molecular structures and interactions, which indicate that different hydrogen bonded structures exist in the amorphous regions and they are notably different for silks from different individuals. Solubility parameter effects of solvents are quantitatively correlated with the different glass transitions values. Furthermore, the overall ordered fraction is shown to be a key parameter to quantify the variability in the different silk fibres, which is consistent with DMTA and FTIR observations. PMID- 25030084 TI - A copper-responsive gene cluster is required for copper homeostasis and contributes to oxidative resistance in Deinococcus radiodurans R1. AB - Excess copper is toxic to organisms, and therefore, copper homeostasis is important for the limitation of its cellular levels. However, copper homeostasis has not been studied to date in the bacteria Deinococcus radiodurans R1, which exhibits extreme resistance to various environmental stresses. We have identified a copper-responsive gene cluster that encodes CopA, which is a copper transporting P1-type ATPase, CopZ, which is a copper metallochaperone, and CsoR, which is a copper-sensing repressor. Copper induces the transcription of genes in this cluster. Mutants lacking copA exhibited reduced copper resistance and the overaccumulation of copper compared with the wild-type strain. Additionally, both in the absence and presence of copper, the copZ mutation increased the expression of copA and led to the accumulation of lower levels of copper compared with the wild type. The bioinformatic analysis showed that CsoR in D. radiodurans R1 shares high sequence similarity and identity with the CsoR of Mycobacterium tuberculosis and Bacillus subtilis. We also demonstrated through DNase I footprinting and electrophoretic mobility shift assays that CsoR binds to the promoter of the cluster and that copper ions eliminate this interaction. This implies that CsoR is the repressor of this cluster and that CopA, CopZ and CsoR participate in the regulation of copper homeostasis. Our data also indicate that after treatment with H2O2 and cumene hydroperoxide, the viability of the copA mutants was significantly reduced. This suggests that copper homeostasis plays an important role in oxidative resistance in D. radiodurans R1. PMID- 25030085 TI - Comparing classification methods for diffuse reflectance spectra to improve tissue specific laser surgery. AB - BACKGROUND: In the field of oral and maxillofacial surgery, newly developed laser scalpels have multiple advantages over traditional metal scalpels. However, they lack haptic feedback. This is dangerous near e.g. nerve tissue, which has to be preserved during surgery. One solution to this problem is to train an algorithm that analyzes the reflected light spectra during surgery and can classify these spectra into different tissue types, in order to ultimately send a warning or temporarily switch off the laser when critical tissue is about to be ablated. Various machine learning algorithms are available for this task, but a detailed analysis is needed to assess the most appropriate algorithm. METHODS: In this study, a small data set is used to simulate many larger data sets according to a multivariate Gaussian distribution. Various machine learning algorithms are then trained and evaluated on these data sets. The algorithms' performance is subsequently evaluated and compared by averaged confusion matrices and ultimately by boxplots of misclassification rates. The results are validated on the smaller, experimental data set. RESULTS: Most classifiers have a median misclassification rate below 0.25 in the simulated data. The most notable performance was observed for the Penalized Discriminant Analysis, with a misclassifiaction rate of 0.00 in the simulated data, and an average misclassification rate of 0.02 in a 10-fold cross validation on the original data. CONCLUSION: The results suggest a Penalized Discriminant Analysis is the most promising approach, most probably because it considers the functional, correlated nature of the reflectance spectra.The results of this study improve the accuracy of real-time tissue discrimination and are an essential step towards improving the safety of oral laser surgery. PMID- 25030086 TI - Restoring TRAIL mediated signaling in ovarian cancer cells. AB - Ovarian cancer has emerged as a multifaceted and genomically complex disease. Genetic/epigenetic mutations, suppression of tumor suppressors, overexpression of oncogenes, rewiring of intracellular signaling cascades and loss of apoptosis are some of the deeply studied mechanisms. In vitro and in vivo studies have highlighted different molecular mechanisms that regulate tumor necrosis factor related apoptosis-inducing ligand (TRAIL) mediated apoptosis in ovarian cancer. In this review, we bring to limelight, expansion in understanding systematical characterization of ovarian cancer cells has led to the rapid development of new drugs and treatments to target negative regulators of TRAIL mediated signaling pathway. Wide ranging synthetic and natural agents have been shown to stimulate mRNA and protein expression of death receptors. This review is compartmentalized into programmed cell death protein 4, platelet-derived growth factor signaling and miRNA control of TRAIL mediated signaling to ovarian cancer. Mapatumumab and PRO95780 have been tested for efficacy against ovarian cancer. Use of high throughput screening assays will aid in dissecting the heterogeneity of this disease and increasing a long-term survival which might be achieved by translating rapidly accumulating information obtained from molecular and cellular studies to clinic researches. PMID- 25030087 TI - Predicting visceral obesity based on facial characteristics. AB - BACKGROUND: Visceral obesity is associated with facial characteristics and chronic disease, but no studies on the best predictor of visceral obesity based on facial characteristics have been reported. The aims of the present study were to investigate the association of visceral obesity with facial characteristics, to determine the best predictor of normal waist and visceral obesity among these characteristics, and to compare the predictive power of individual and combined characteristics. METHODS: Cross-sectional data were obtained from 11347 adult Korean men and women ranging from 18 to 80 years old. We examined 15 facial characteristics to identify the strongest predictor of normal and viscerally obese subjects and assessed the predictive power of the combined characteristics. RESULTS: FD_94_194 (the distance between both inferior ear lobes) was the best indicator of the normal and viscerally obese subjects in the following groups: Men-18-50 (p <= 0.0001, OR = 4.610, AUC = 0.821), Men-50-80 (p <= 0.0001, OR = 2.624, AUC = 0.735), and Women-18-50 (p <= 0.0001, OR = 2.979, AUC = 0.76). In contrast, FD_43_143 (mandibular width) was the strongest predictor in Women-50-80 (p <= 0.0001, OR = 2.099, AUC = 0.679). In a comparison of the combined characteristics, the area under the receiver operating characteristic curve (AUC) and the kappa values of the 4 groups ranged from 0.826 to 0.702 and from 0.483 to 0.279, respectively. The model for Men-18-50 showed the strongest predictive values and the model for Women-51-80 had the lowest predictive value for both the individual and combined characteristics. CONCLUSIONS: In both men and women, the predictive power of the young and middle-age groups was better than that of the elderly groups for predicting normal waist and viscerally obese subjects for both the individual and combined characteristics. The predictive power appeared to increase slightly with the combined characteristics. PMID- 25030088 TI - KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma. AB - PURPOSE: Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC). METHODS: In silico, meta-analysis showed that XPO1 is overexpressed in HCC. Six HCC cell lines were treated with KPT-330, and cell proliferation and expression of cell growth regulators were examined by cell proliferation assays and Western blot analysis, respectively. The in vivo anti-cancer activity of KPT 330 was examined in a HCC xenograft murine model. RESULTS: KPT-330 reduced the viability of HCC cell lines in vitro and this anti-proliferative effect was associated with cell cycle arrest and induction of apoptosis. The expression of the pro-apoptotic protein PUMA was markedly up-regulated by KPT-330. In addition, SINE treatment increased the expression of the tumor suppressor proteins p53 and p27, while it reduced the expression of HCC promoting proteins, c-Myc and c-Met. XPO1 levels itself were also down-regulated following KPT-330 treatment. Finally, a HCC xenograft murine model showed that treatment of mice with oral KPT-330 significantly inhibited tumor growth with little evidence of toxicity. CONCLUSION: Our results suggest that SINE compounds, such as KPT-330, are promising novel drugs for the targeted therapy of HCC. PMID- 25030089 TI - A multicenter phase II study of G17DT immunogen plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan. AB - BACKGROUND: The G17DT is a novel human immunogen that raises antibodies to the growth factor gastrin 17 (G17). The purpose of this study was to determine the safety and efficacy of G17DT in combination with irinotecan in patients refractory to irinotecan, and to correlate efficacy with anti-G17 immune response. METHODS: Patients received G17DT immunogen as a single intramuscular injection of 500 MUg at weeks 1, 5, 9, and 26. Irinotecan was administered as an intravenous infusion of 125 mg/m(2) over 90 min starting at week 5. Each cycle of treatment consisted of irinotecan administered once weekly for 4 weeks, followed by a 2-week rest period. RESULTS: Of 161 patients who received G17DT, the best overall tumor response in the intent-to-treat population was complete response 0 (0 %), partial response 3 (3 %), stable disease 32 (32 %), and progressive disease 64 (65 %). Median survival was 217 days. About 94 (62 %) subjects evaluable for antibody titers were anti-G17 responders. Survival was significantly longer for anti-G17 responders compared with non-responders (9.0 vs. 5.6 months; P < 0.001). Toxicity was consistent with irinotecan (diarrhea, nausea, anemia, vomiting, fatigue, constipation, anorexia, and neutropenia) except for injection site reactions (pain 42 %, induration 13 %, edema 11 %, erythema 10 %, and three abscesses) attributed to G17DT in 52 % of the patients. CONCLUSION: Treatment with G17DT in combination with irinotecan results in an acceptable anti-G17 immune response, which correlated with promising survival activity in patients refractory to irinotecan-based chemotherapy. PMID- 25030090 TI - Immune derangement occurs in patients with H7N9 avian influenza. AB - INTRODUCTION: Currently, little is known about the immunological characteristics of patients with avian influenza A (H7N9) virus infection. METHODS: The numbers and percentages of peripheral blood immune cells were measured in 27 patients with laboratory-confirmed H7N9 virus infection and 30 healthy controls (HCs). The functional phenotypes of T cells and monocytes, as well as serum cytokine levels, were analyzed by flow cytometry. RESULTS: There were 19 patients (70.4%) with acute respiratory distress syndrome, 13 (48.1%) with secondary respiratory infection, 20 (74%) with systemic inflammatory response syndrome (SIRS; defined as having at least two concurrent SIRS components), 18 (66.7%) with lymphocytopenia and 11 (40.7%) with reduced numbers of monocytes. In comparison with levels in the HCs, the levels of serum interleukin 6 (IL-6), IL-8 and IL-10 and the percentages of CD38+ or Tim-3+ T cells were significantly increased. However, the percentages of human leukocyte antigen-DR + and Tim-3+ monocytes were significantly decreased in patients compared with HCs. CONCLUSIONS: Patients with avian H7N9 virus infection display profound SIRS concomitantly with an anti inflammatory response, which may be associated with the rapid progression of and high mortality associated with this novel viral disease. PMID- 25030091 TI - Laparoscopic adjustable gastric banding outcomes in patients with gastroesophageal reflux disease or hiatal hernia. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) and hiatal hernia (HH) are classically considered contraindications to bariatric restrictive procedures. Despite the high number of studies that have been published, the relationship between laparoscopic adjustable gastric banding (LAGB) and GERD/HH is still not clear. METHODS: We have retrospectively analyzed the outcomes of LAGB in patients operated in 2010 with HH and/or GERD. The gastroesophageal reflux was diagnosed if the patients had heartburn and regurgitation more than once a week, and hiatal hernia was assessed by esophagogastroduodenoscopy and/or upper GI radiogram with swallow. Data on heartburn, assumption of antacid medication, weight loss, and rate of complications in both patients with and without GERD or HH were collected. RESULTS: One hundred and twenty patients that underwent LAGB at our department were enrolled in our study; 40 had symptoms of GERD and 25 had hiatal hernia preoperatively. There was no difference of percentage excess weight loss (%EWL) at 12 months (45.4 +/- 20.4 vs 4.6 +/- 19.5 kg/m(2)) and 36 months follow up (49.4 +/- 16.5 vs 48.6 +/- 18.9 kg/m(2)) between asymptomatic patients and patients with HH or GERD symptoms. The number of patients with preoperative heartburn (40 to 10) and/or assumption of antacid drugs (38 to 7) significantly decreased after LAGB CONCLUSIONS: LAGB is an effective and safe surgical treatment for morbidly obesity in patients with GERD or HH, since it induces both a significant weight loss and an improvement of reflux symptoms. PMID- 25030092 TI - Qualitative investigation of targets for and barriers to interventions to prevent psychosis relapse. AB - BACKGROUND: Early signs based relapse prevention interventions for psychosis show promise. In order to examine how they might be improved we sought to better understand the early relapse process, service users' abilities to identify early signs, and any potential facilitators and barriers to early signs interventions. METHODS: Data from in-depth interviews with a convenience sample of service users with psychosis varying in gender, age, duration of mental health problems, and time since last relapse were analysed using a thematic approach. Interview transcripts were coded inductively and relationships between emerging themes were examined by the research team to provide a thorough synthesis of the data. RESULTS: Three central themes emerged from the analysis: 1) recognising risk factors (how risk factors were identified and linked to relapse, and reactions to such risk factors); 2) identifying early signs (issues related to both recognising and recalling signs of relapse); 3) reacting to deterioration (participants' thoughts and feelings in response to early signs, including help seeking and its challenges). CONCLUSIONS: There was considerable variation in the attention participants had paid to pre-relapse signs, the ease with which they were able to recall them, and their reactions to them. For many, there were substantial barriers to help seeking from services. A family or friend confidant was an important means of assistance, although the supportive presence of significant others was not always available. Based on these results, a number of recommendations about facilitating service users' recognition of early signs and targeting potential accelerants of relapse are made. PMID- 25030093 TI - Combination treatment with oncolytic Vaccinia virus and cyclophosphamide results in synergistic antitumor effects in human lung adenocarcinoma bearing mice. AB - BACKGROUND: The capacity of the recombinant Vaccinia virus GLV-1h68 as a single agent to efficiently treat different human or canine cancers has been shown in several preclinical studies. Currently, its human safety and efficacy are investigated in phase I/II clinical trials. In this study we set out to evaluate the oncolytic activity of GLV-1h68 in the human lung adenocarcinoma cell line PC14PE6-RFP in cell cultures and analyzed the antitumor potency of a combined treatment strategy consisting of GLV-1h68 and cyclophosphamide (CPA) in a mouse model of PC14PE6-RFP lung adenocarcinoma. METHODS: PC14PE6-RFP cells were treated in cell culture with GLV-1h68. Viral replication and cell survival were determined by plaque assays and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays, respectively. Subcutaneously implanted PC14PE6-RFP xenografts were treated by systemic injection of GLV-1h68, CPA or a combination of both. Tumor growth and viral biodistribution were monitored and immune-related antigen profiling of tumor lysates was performed. RESULTS: GLV 1h68 efficiently infected, replicated in and lysed human PC14PE6-RFP cells in cell cultures. PC14PE6-RFP tumors were efficiently colonized by GLV-1h68 leading to much delayed tumor growth in PC14PE6-RFP tumor-bearing nude mice. Combination treatment with GLV-1h68 and CPA significantly improved the antitumor efficacy of GLV-1h68 and led to an increased viral distribution within the tumors. Pro inflammatory cytokines and chemokines were distinctly elevated in tumors of GLV 1h68-treated mice. Factors expressed by endothelial cells or present in the blood were decreased after combination treatment. A complete loss in the hemorrhagic phenotype of the PC14PE6-RFP tumors and a decrease in the number of blood vessels after combination treatment could be observed. CONCLUSIONS: CPA and GLV-1h68 have synergistic antitumor effects on PC14PE6-RFP xenografts. We strongly suppose that in the PC14PE6-RFP model the enhanced tumor growth inhibition achieved by combining GLV-1h68 with CPA is due to an effect on the vasculature rather than an immunosuppressive action of CPA. These results provide evidence to support further preclinical studies of combining GLV-1h68 and CPA in other highly angiogenic tumor models. Moreover, data presented here demonstrate that CPA can be combined successfully with GLV-1h68 based oncolytic virus therapy and therefore might be promising as combination therapy in human clinical trials. PMID- 25030094 TI - Renal bone metaplasia: an incidental negligible finding or a disease to treat? AB - Renal bone metaplasia (RBM) is a uncommon condition and is often an incidental finding. The pathogenesis of this phenomenon is not clearly understood. The radiological signs described are not always present and the diagnosis is challenging. In the literature, there is no any conclusion about the optimal management of this condition due to the absence of some conclusions regarding its etiology. In our opinion, no treatment should be applied to prevent its possible evolution into urolithiasis. Surgical removal of the RBM is an overtreatment for a phenomenon not understood and potentially insignificant. We report our experience with a watchful waiting approach in a case of incidental diagnosis of RBM. After 3 years, the patient is asymptomatic, with no evidence of malignancies evolution, new renal stones or growth of the residual RBM. PMID- 25030095 TI - What should be the ideal time interval between repeated extracorporeal shock wave lithotripsy sessions for renal stone treatment? PMID- 25030096 TI - Cannabis poisoning in children. PMID- 25030097 TI - Comment on Adamzik et al.: An increased alveolar CD4 + CD25 + Foxp3 + T regulatory cell ratio in acute respiratory distress syndrome is associated with increased 30-day mortality. PMID- 25030098 TI - Induction and enhancement of platelet aggregation in vitro and in vivo by model polystyrene nanoparticles. AB - Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream or during proposed medical applications. Studies with model polystyrene latex nanoparticles (PLNPs) have shown that NPs are able to induce platelet aggregation in vitro suggesting a poorly defined potential mechanism of increased cardiovascular risk upon NP exposure. We aimed to provide insight into the mechanisms by which NPs may increase cardiovascular risk by determining the impact of a range of concentrations of PLNPs on platelet activation in vitro and in vivo and identifying the signaling events driving NP-induced aggregation. Model PLNPs of varying nano-size (50 and 100 nm) and surface chemistry [unmodified (uPLNP), amine-modified (aPLNP) and carboxyl-modified (cPLNP)] were therefore examined using in vitro platelet aggregometry and an established mouse model of platelet thromboembolism. Most PLNPs tested induced GPIIb/IIIa-mediated platelet aggregation with potencies that varied with both surface chemistry and nano-size. Aggregation was associated with signaling events, such as granule secretion and release of secondary agonists, indicative of conventional agonist mediated aggregation. Platelet aggregation was associated with the physical interaction of PLNPs with the platelet membrane or internalization. 50 nm aPLNPs acted through a distinct mechanism involving the physical bridging of adjacent non-activated platelets leading to enhanced agonist-induced aggregation in vitro and in vivo. Our study suggests that should they translocate the pulmonary epithelium, or be introduced into the blood, NPs may increase the risk of platelet-driven events by inducing or enhancing platelet aggregation via mechanisms that are determined by their distinct combination of nano-size and surface chemistry. PMID- 25030099 TI - Thirteen-week study of toxicity of fiber-like multi-walled carbon nanotubes with whole-body inhalation exposure in rats. AB - Cancer development due to fiber-like straight type of multi-walled carbon nanotubes (MWCNTs) has raised concerns for human safety because of its shape similar to asbestos. To set concentrations of MWCNT for a rat carcinogenicity study, we conducted a 13-week whole body inhalation study. F344 male and female rats, 6-week-old at the commencement of the study, were exposed by whole-body inhalation to MWCNT at concentrations of 0, 0.2, 1 and 5 mg/m(3) with a generation and exposure system utilizing the cyclone sieve method. Measured concentrations in the exposure chambers were 0.20 +/- 0.02, 1.01 +/- 0.11 and 5.02 +/- 0.25 mg/m(3) for 13 weeks. The MMAD (GSD) of MWCNT were 1.4-1.6 MUm (2.3 3.0), and mean width and length were 94.1-98.0 nm and 5.53-6.19 MUm, respectively, for each target concentration. Lung weights were increased 1.2-fold with 1 mg/m(3) and 1.3-fold with 5 mg/m(3) in both sexes compared to the controls. In the bronchoalveolar lavage fluid (BALF) analyses, inflammatory parameters were increased concentration-dependently in both sexes from 0.2 mg/m(3). Granulomatous changes in the lung were induced at 1 and 5 mg/m(3) in females and even at 0.2 mg/m(3) in males. Focal fibrosis of the alveolar wall was observed in both sexes at 1 mg/m(3) or higher. Inflammatory infiltration in the visceral pleural and subpleural areas was induced only at 5 mg/m(3). In conclusion, we determined 0.2 mg/m(3) as the low-observed-adverse-effect level (LOAEL) for respiratory tract toxicity in the present inhalation exposure study of rats. PMID- 25030100 TI - A novel system improves preservation of osteochondral allografts. AB - BACKGROUND: Osteochondral allografting is an option for successful treatment of large articular cartilage defects. Use of osteochondral allografting is limited by graft availability, often because of loss of chondrocyte viability during storage. QUESTIONS/PURPOSES: The purpose of this study was to compare osteochondral allografts implanted in canine knees after 28 days or 60 days of storage for (1) initial (1 week) safety and feasibility; (2) integrity and positioning with time (12 weeks and 6 months); and (3) gross, cell viability, histologic, biochemical, and biomechanical characteristics at an endpoint of 6 months. METHODS: With Institutional Animal Care and Use Committee approval, adult dogs (n=16) were implanted with 8-mm cylindrical osteochondral allografts in the lateral and medial femoral condyles of one knee. Osteochondral allografts preserved for 28 or 60 days using either the current tissue bank standard-of-care (SOC) or a novel system (The Missouri Osteochondral Allograft Preservation System, or MOPS) were used, creating four treatment groups: SOC 28-day, MOPS 28 day, SOC 60-day, and MOPS 60-day. Bacteriologic analysis of tissue culture and media were performed. Dogs were assessed by radiographs and arthroscopy at interim times and by gross, cell viability, histology, biochemistry, and biomechanical testing at the 6-month endpoint. RESULTS: With the numbers available, there was no difference in infection frequency during storage (5% for SOC and 3% for MOPS; p=0.5). No infected graft was implanted and no infections occurred in vivo. MOPS grafts had greater chondrocyte viability at Day 60 (90% versus 53%; p=0.002). For 60-day storage, MOPS grafts were as good as or better than SOC grafts with respect to all outcome measures assessed 6 months after implantation. CONCLUSIONS: Donor chondrocyte viability is important for osteochondral allograft success. MOPS allows preservation of chondrocyte viability for up to 60 days at sufficient levels to result in successful outcomes in a canine model of large femoral condylar articular defects. CLINICAL RELEVANCE: These findings provide a promising development in osteochondral allograft technology that can benefit the quantity of grafts available for use and the quality of grafts being implanted. PMID- 25030102 TI - Case studies. PMID- 25030101 TI - Benefit of cup medialization in total hip arthroplasty is associated with femoral anatomy. AB - BACKGROUND: Medialization of the cup with a respective increase in femoral offset has been proposed in THA to increase abductor moment arms. Insofar as there are potential disadvantages to cup medialization, it is important to ascertain whether the purported biomechanical benefits of cup medialization are large enough to warrant the downsides; to date, studies regarding this question have disagreed. QUESTIONS/PURPOSES: The purpose of this study was to quantify the effect of cup medialization with a compensatory increase in femoral offset compared with anatomic reconstruction for patients undergoing THA. We tested the hypothesis that there is a (linear) correlation between preoperative anatomic parameters and muscle moment arm increase caused by cup medialization. METHODS: Fifteen patients undergoing THA were selected, covering a typical range of preoperative femoral offsets. For each patient, a finite element model was built based on a preoperative CT scan. The model included the pelvis, femur, gluteus minimus, medius, and maximus. Two reconstructions were compared: (1) anatomic position of the acetabular center of rotation, and (2) cup medialization compensated by an increase in the femoral offset. Passive abduction-adduction and flexion-extension were simulated in the range of normal gait. Muscle moment arms were evaluated and correlated to preoperative femoral offset, acetabular offset, height of the greater trochanter (relative to femoral center of rotation), and femoral antetorsion angle. RESULTS: The increase of muscle moment arms caused by cup medialization varied among patients. Muscle moment arms increase by 10% to 85% of the amount of cup medialization for abduction-adduction and from -35% (decrease) to 50% for flexion-extension. The change in moment arm was inversely correlated (R(2) = 0.588, p = 0.001) to femoral antetorsion (anteversion), such that patients with less femoral antetorsion gained more in terms of hip muscle moments. No linear correlation was observed between changes in moment arm and other preoperative parameters in this series. CONCLUSIONS: The benefit of cup medialization is variable and depends on the individual anatomy. CLINICAL RELEVANCE: Cup medialization with compensatory increase of the femoral offset may be particularly effective in patients with less femoral antetorsion. However, cup medialization must be balanced against its tradeoffs, including the additional loss of medial acetabular bone stock, and eventual proprioceptive implications of the nonanatomic center of rotation and perhaps joint reaction forces. Clinical studies should better determine the relevance of small changes of moment arms on function and joint reaction forces. PMID- 25030103 TI - Developing a transcultural academic-community partnership to arrest obesity. AB - Innovative and empirically tested strategies are needed to define and understand obesity prevention and reduction in a transcultural society. This manuscript describes the development of Science & Community, a partnership developed over a 3-year period with the end goal of implementing a community-based participatory research (CBPR) trial to reduce and prevent obesity. Outreach strategies focused on promoting the project via existing and new channels and identifying and contacting potential partners using established strategies. Science & Community developed and fostered partnerships by hosting a series of interactive meetings, including three Opportunity Receptions, four Community Open Forum Symposia, and quarterly Community Advisory Board (CAB) meetings. Opportunity Reception (N = 62) and Symposia attendees (N = 103) represented the diversity of the community, and participants reported high satisfaction with content and programming. From these events, the CAB was formed and was comprised of 13 community representatives. From these meetings, a Partnership representing 34 organizations and 614 individuals emerged that has helped to guide the development of future proposals and strategies to reduce obesity in Houston/Harris County. PMID- 25030104 TI - Physical activity attitudes, beliefs, and practices among adults 50 and older: baseline community assessment. AB - This study aligned with the National Blueprint, a coalition of national organizations to identify the principal barriers to physical activity participation in older adults and to outline strategies for increasing physical activity levels. A community coalition took the initiative to conduct a baseline assessment of health attitudes, perceptions, and behaviors among community adults in order to understand the immediate needs of the adult community. Adults 50 and older (N = 309) completed surveys of health and physical activity (PA) behaviors. Individuals reported below average physical activity levels. Motives and barriers to PA differed by gender and race/ethnicity. Age and health perceptions significantly predicted PA levels. Findings support previous research with this age group, thus discussion of the utility of multi-level approaches (e.g., social ecological model) to health betterment in communities is forwarded. Providing multi-level resources (personal, social, environmental, policy) can increase opportunities for adoption and maintenance of health behaviors. PMID- 25030105 TI - Case-management of malaria in children attending an outpatient clinic in southwest Nigeria. AB - This study examined the case-management of malaria in 135 febrile children attending an outpatient clinic in southwest Nigeria. Specifically, we examined the degree of concordance between physician's diagnosis of malaria, maternal perceptions of child febrile illness, and the results of malaria rapid diagnostic tests. The results indicate poor concordance in the diagnosis of malaria by physicians and the results of malaria RDTs (kappa = 0.030, p-value = 0.269) as well as between mother's perception of malaria in their children and malaria RDTs (kappa = 0.071, p-value = 0.369). While physicians can correctly identify children that have malaria according to the RDT test (Sensitivity = 95.23%), they were poor identifiers of children who do not have malaria (Specificity = 13.15). On the other hand, while mothers are poor identifiers of children that have malaria according to the malaria RDT test (Sensitivity = 38.1%), they are better at identifying children who do not have malaria (Specificity = 71.1%). The findings demonstrate the importance of exploring the contextual factors that influence case management of child malaria in outpatient clinics. PMID- 25030106 TI - HIV/AIDS stigma and persons living with HIV/AIDS in rural Ghana. AB - This qualitative study investigated community and family members' perceptions and attitudes toward persons living with HIV/AIDS (PLWHAs) in rural Ghana and how PLWHAs viewed themselves. The purpose was to provide insights into the nature and extent of HIV/AIDS-related stigma for program and policy interventions. Interviews and focus group discussions examined the stigma. Seventy-four participants 18 years and above (60 community members, 10 PLWHAs, 2 family members of PLWHAs, and 2 HIV/AIDS counselors) participated. Results showed that PLWHAs experienced various forms of negative perceptions, were stigmatized by community and family members, and held strong negative views of HIV/AIDS, which negatively affected the way they lived. To reduce HIV/AIDS related stigma in rural areas, HIV/AIDS education programs that call for strong community and family member support for PLWHAs are essential. PMID- 25030107 TI - Characterizing active transportation behavior among college students using the theory of planned behavior. AB - Physical inactivity poses concern for health risks among all groups in the United States. Active transportation (AT) (e.g., bicycling) is one way of being physically active and may be helpful in promoting physical activity. This study characterized active transportation behavior among college students using the Theory of Planned Behavior. This study sought to describe predictors, including Theory of Planned Behavior (TPB) constructs, of AT behavior among college students at a large Midwest university. Students were recruited through the university registrar's office and e-mailed an electronic survey. Differences among AT users were determined using t-tests, and predictors of AT were identified using regression analysis. Significant differences between AT users for all TPB constructs were observed. Regression analysis using only TPB constructs accounted for 11.58% explained variation in AT use. Other variables added to the model resulted in 44.44% explained variation in AT use. The final model included subjective norms, age, perceived behavioral control, and transportation type and destination. The results of this research are insightful in explaining AT behavior. Perceived norms and the level of control students had regarding their method of transportation were important contributions to AT use. These results may be applied to promoting physical activity in community health. PMID- 25030109 TI - World Bank Group: inadequate response to killings, land grabs: human rights watch. PMID- 25030110 TI - NMR resonance assignments of the archaeal ribosomal protein L7Ae in the apo form and bound to a 25 nt RNA. AB - The archaeal protein L7Ae forms part of a protein complex in the ribosome that specifically recognizes and binds to kink-turn RNA. In this complex, L7Ae directly interacts with the oligonucleotide and creates a functional arrangement for site-specific 2'-O-methylation. We report the solution NMR backbone assignment of Methanocaldococcus jannaschii L7Ae (117 residues, 12.7 kDa) in the ligand-free state and when bound to a 25 nucleotide C/D box kink-turn mimic RNA. PMID- 25030111 TI - Sequence-specific backbone (1)H, (13)C, and (15)N resonance assignments of human ribonuclease 4. AB - Human ribonuclease 4 (RNase 4) is the most evolutionarily conserved member of the 8 canonical human pancreatic-like RNases, showing more than 90% identity with bovine and porcine homologues. The enzyme displays ribonucleolytic activity with a strong preference for uracil-containing RNA substrates, a feature only shared with human eosinophil derived-neurotoxin (EDN, or RNase 2) and eosinophil cationic protein (ECP, or RNase 3). It is also the shortest member of the human family, with a significantly truncated C-terminal tail. Its unique active-site pocket and high degree of conservation among vertebrates suggest that the enzyme plays a crucial biological function. Here, we report on the (1)H, (13)C and (15)N backbone resonance assignments of RNase 4, providing means to characterize its molecular function at the atomic level by NMR. PMID- 25030112 TI - DBSecSys: a database of Burkholderia mallei secretion systems. AB - BACKGROUND: Bacterial pathogenicity represents a major public health concern worldwide. Secretion systems are a key component of bacterial pathogenicity, as they provide the means for bacterial proteins to penetrate host-cell membranes and insert themselves directly into the host cells' cytosol. Burkholderia mallei is a Gram-negative bacterium that uses multiple secretion systems during its host infection life cycle. To date, the identities of secretion system proteins for B. mallei are not well known, and their pathogenic mechanisms of action and host factors are largely uncharacterized. DESCRIPTION: We present the Database of Burkholderia malleiSecretion Systems (DBSecSys), a compilation of manually curated and computationally predicted bacterial secretion system proteins and their host factors. Currently, DBSecSys contains comprehensive experimentally and computationally derived information about B. mallei strain ATCC 23344. The database includes 143 B. mallei proteins associated with five secretion systems, their 1,635 human and murine interacting targets, and the corresponding 2,400 host-B. mallei interactions. The database also includes information about 10 pathogenic mechanisms of action for B. mallei secretion system proteins inferred from the available literature. Additionally, DBSecSys provides details about 42 virulence attenuation experiments for 27 B. mallei secretion system proteins. Users interact with DBSecSys through a Web interface that allows for data browsing, querying, visualizing, and downloading. CONCLUSIONS: DBSecSys provides a comprehensive, systematically organized resource of experimental and computational data associated with B. mallei secretion systems. It provides the unique ability to study secretion systems not only through characterization of their corresponding pathogen proteins, but also through characterization of their host-interacting partners.The database is available at https://applications.bhsai.org/dbsecsys. PMID- 25030113 TI - Dietary mercury exposure causes decreased escape takeoff flight performance and increased molt rate in European starlings (Sturnus vulgaris). AB - Mercury is a widespread and persistent environmental contaminant that occurs in aquatic and terrestrial habitats. Recently, songbirds that forage from primarily terrestrial sources have shown evidence of bioaccumulation of mercury, but little research has assessed the effects of mercury on their health and fitness. There are many indications that mercury negatively affects neurological functioning, bioenergetics, and behavior through a variety of mechanisms and in a wide array of avian taxa. Effective flight is crucial to avian fitness and feather molt is an energetically expensive life history trait. Therefore, we investigated whether mercury exposure influenced flight performance and molt in a common songbird, the European starling (Sturnus vulgaris). Specifically, we dosed the diet of captive starlings with methylmercury cysteine at 0.0, 0.75, or 1.5 MUg/g wet weight and recorded changes in flight performance after 1 year of dietary mercury exposure. We also recorded the annual molt of wing feathers. We found that individuals dosed with mercury exhibited decreased escape takeoff flight performance compared with controls and blood mercury was also correlated with an increased rate of molt, which can reduce flight performance and thermoregulatory ability. This study reveals two novel endpoints, flight performance and molt, that may be affected by dietary mercury exposure. These findings suggest a potential impact on wild songbirds exposed to mercury levels comparable to the high dosage levels in the present study. Any decrease in flight efficiency could reduce fitness due to a direct impact on survival during predation events or by decreased efficiency in other critical activities (such as foraging or migration) that require efficient flight. PMID- 25030114 TI - Inhaled dry powder formulations for treating tuberculosis. AB - Tuberculosis is the second leading cause of death from infectious diseases. Although antitubercular drugs have been traditionally administered orally, there is a growing interest in delivering drugs via the pulmonary route using nebulisers or dry powder inhalers. Drugs in dry powder inhalers (DPI) are stable and DPI are user-friendly compared to nebulisation which is time consuming, inconvenient and inefficient and requires special equipment. For tuberculosis treatment, drugs should target alveolar macrophages that harbour microorganisms and/or maintain high drug concentration at the infection site in the lung. Drug particles include micro-particles or nanoparticles. Powders can be engineered by micronisation, crystallisation, spray drying, freeze drying and particle coating approaches. The formulation may contain single or combination drugs. This paper will provide an update on current status of TB, its pathogenesis, current treatment strategies, shortcomings of current oral or parenteral delivery strategies, pulmonary delivery devices, advantages of pulmonary delivery of powder formulations, formulation approaches and pharmacokinetic studies of pulmonary delivery of powders for inhalation. PMID- 25030115 TI - Impact of solidification on the performance of lipid-based colloidal carriers: oil-based versus self-emulsifying systems. AB - The study aims to develop and optimise lipid-based colloidal carriers (LBCC) for enhancing solubilisation and reducing fed/fasted variation for the poorly water soluble danazol (DAN). Oil-based and self-microemulsifying delivery systems (SMEDDS) were developed, and the effect of solidification was investigated. Liquid SMEDDS (L-SMEDDS, Capmul MCM:Tween 80:Transcutol HP 1:2:1, w/w) and emulsion (Capmul MCM:soya lecithin 100:0.6, w/w) were developed. Solid-state formulations were prepared via (i) physical adsorption of L-SMEDDS (P-SMEDDS) or (ii) spray drying of emulsion (silica-lipid hybrid, SLH) and L-SMEDDS (spray dried SMEDDS, S-SMEDDS) using Aerosil 380 silica nanoparticles as the solid carrier. In vitro lipid digestion and drug solubilisation under simulated intestinal conditions in both fasted and fed states were investigated. Solubilisation of unformulated DAN under both fasted and fed conditions was low, and a large fed/fasted variation was observed, i.e. 6.6-fold difference. All LBCC formulations provided enhanced drug solubilisation and significantly reduced the fed/fasted variation. For self-emulsifying LBCC, the fasted state drug solubilisation was ranked as L-SMEDDS > PSMEDDS > S-SMEDDS, suggesting that solidification reduced the capability of SMEDDS in presenting DAN to the aqueous phase. However, in the case of oil-based LBCC, improved drug solubility was observed with the solid form SLH under both fasted and fed state in comparison to that of the equivalent liquid form. Overall, the SLH, which provided the highest drug solubilisation in the fasted state (i.e. 10-fold higher than the pure DAN) and the smallest fed/fasted variation, was considered an optimised solid LBCC to enhance the solubilisation of DAN and reduce the fed/fasted variation. PMID- 25030116 TI - Cucullanus egyptae sp. nov. (Nematoda, Cucullanidae) infecting the European eel Anguilla anguilla in Egypt. Morphological and molecular phylogenetic studies. AB - A total of 80 specimens of the European eel Anguilla anguilla were collected during the period from February 2013 to March 2014 at the coast of the Gulf of Suez (Red Sea, Egypt). A new species of parasitic nematodes was recovered and described as Cucullanus egyptae. It was found in the eel's intestine with a prevalence of 68.7%. The morphology of the recovered parasite was studied by light and scanning electron microscopy. The adult worms had a wide cephalic extremity with a slit-like oral aperture being surrounded by a cuticular ring and delimited internally by a row of small teeth in addition to four sub-median cephalic papillae and one pair of lateral amphids. Body measurements showed that the male worms were smaller than females measuring 7.5-8.9 mm (8.3 +/- 0.2) in length and 1.6-1.9 mm (1.8 +/- 0.1) in width. Females measured 12.9-13.5 mm (13.1 +/- 0.2) in length and 2.9-3.2 mm (3.1 +/- 0.1) in width. The posterior end of the males is provided with ten pairs of caudal papillae and two long spicules which are slightly sclerotized, equal in size measuring 0.59-0.65 mm (0.62 +/- 0.01) in length. Comparing the present worms with other species of the genus Cucullanus, several similarities were observed. However, peculiar new characteristics such as the precloacal sucker (especially the spicula length), the arrangement and the distribution of the post-cloacal papillae, and the position of the excretory pore make it reasonable to describe a new species. The sequence data of the small subunit (SSU) ribosomal DNA (rDNA) obtained from the present nematode supported its taxonomic position within the genus Cucullanus. The new species is closely related to the first clade of Spirurina and even more closely related to Cucullanus dodsworthi as a sister taxon with a high percentage of identity. The sequence of the recorded SSU rDNA of this parasite is deposited in the GenBank with the accession no. KF681520. It is proposed to name the new species C. egyptae as the first representative of Cucullanidae in Egypt with a new host record. PMID- 25030118 TI - Helminth community structure in the Argentinean bufonid Melanophryniscus klappenbachi: importance of habitat use and season. AB - The goal of this study was to evaluate the relative influence of terrestrial habits, season, and host body size on the species richness and abundance of helminth parasites in the toad Melanophryniscus klappenbachi, for which a greater abundance of nematode parasites was expected. A total of 90 toads were collected in the Chaco Province, Argentina. The helminth community found in infected toads included 17 taxa and was dominated particularly by larval parasites. Contrary to our expectations, nematode species showed lower values of infection parameters. Infected toads harbored a maximum of seven species, and the mean helminth richness was 3.16 +/- 1.66 species per infected toads. Season played a significant effect on determining the species richness and abundance of the parasite infracommunity. Similarly, the prevalence of infection of several helminth species (8/47%) varied greatly over time. Host body size was the main factor in determining the infrapopulation structure of helminth parasites. Species richness was significantly and negatively correlated with host body size. Strong associations were observed mainly between larvae of some species. The transmission strategies of parasites suggest that this bufonid acquires infections through direct contact with larval parasites from aquatic and terrestrial habitats and by ingestion of infective larvae. The characteristic of the host tegument, such as the presence of alkaloids, could significantly contribute to the low occurrence of infection by skin-penetrating nematodes. Results also showed that diets and mobility of the host and the local microhabitat conditions play an important role in parasitic infections of toads. PMID- 25030117 TI - Larvicidal and pupicidal activities of ecbolin A and ecbolin B isolated from Ecbolium viride (Forssk.) Alston against Culex quinquefasciatus Say (Diptera: Culicidae). AB - The mosquitocidal activity of different fractions and isolated compounds from the ethyl acetate extract of Ecbolium viride root was assessed on larvae and pupae of Culex quinquefasciatus Say (Diptera: Culicidae). The larvae and pupae were exposed to concentrations of 6.125, 12.5, 25 and 50 ppm for fractions and 1, 2.5, 5 and 10 ppm for compound. Among the 12 fractions screened, fraction 6 from the ethyl acetate extract of E. viride was recorded to have the highest larvicidal and pupicidal activities against C. quinquefasciatus. The lethal concentration (LC50 and LC90) values of fraction 6 were 4.26 and 9.0 ppm against C. quinquefasciatus larvae and 6.55 and 12.19 ppm against C. quinquefasciatus pupae, respectively, in 24 h. Fraction 7 was recorded to have moderate activity with LC50 and LC90 values of 11.25 and 25.02 ppm against C. quinquefasciatus larvae and 13.33 and 31.15 ppm against C. quinquefasciatus pupae, respectively, in 24 h. Ecbolin A and ecbolin B were identified from fractions 7 and 6, respectively. The structure of the isolated compounds was identified on the basis of spectral data ((1)H NMR and (13)C NMR) and compared with literature spectral data. Further, the isolated compound, ecbolin B, from fraction 6 was recorded to have strong larvicidal and pupicidal activities than ecbolin A. The LC50 and LC90 values of ecbolin B on C. quinquefasciatus larvae were 1.36 and 2.76 ppm, and on pupae, these were 1.54 and 3.51 ppm, respectively. The present results suggest that ecbolin B could be used as a mosquitocidal agent against C. quinquefasciatus. PMID- 25030119 TI - New insights into the reaction of Schistosoma mansoni cercaria to the human complement system. AB - Schistosomes are parasitic worms that have a complex life cycle. The larval stage cercaria, infectious to mammals, is described as highly susceptible to the complement system, largely due to the glycocalyx that covers the cercarial membrane. In an attempt to have a more complete understanding of cercaria reaction to the complement system, three different approaches were used. Live cercariae exposed to normal human serum (NHS) as source of complement factors were assessed for (i) membrane attack complex (MAC) deposition on the parasite surface, (ii) cercaria survival rate by Hoechst staining of parasite DNA, and (iii) transformation into schistosomula by detection of the glucose transporter protein 4 (SGTP4), a marker for new tegument formation. We found that 82-95% of cercariae directly exposed to NHS for 18 h were viable and retained their ability to shed the glycocalyx, suggesting minimal tegument damage. In contrast, inhibition of glycocalyx shedding using eserine caused significant MAC binding and parasite death. Culturing complement-exposed cercariae to measure long-term survival showed that more parasites died over time, reaching a survival rate of 18-31% by day 6 in culture. The reason for this slow death is unknown, but the surviving parasites were able to form a new tegument as shown by detection of SGTP4 on the parasite surface. Furthermore, we found that complement activation significantly damaged the acetabular gland ducts and lysed secretory vesicles released by transforming cercariae. These findings should contribute for future in vivo studies of the effects of the complement system in skin migrating cercariae. PMID- 25030121 TI - Relationship between sexual compulsivity and sexual risk behaviors among Chinese sexually active males. AB - Compulsivity is defined as "an insistent, repetitive, intrusive, and unwanted urge to perform specific acts often in ritualized or routinized fashions." Sexual compulsivity has been shown to be associated with some high risk sexual behaviors related to HIV and sexually transmitted infection (STI). In some Western countries, the 10-item Sexual Compulsivity Scale (SCS) has been developed to assess people's sexual compulsivity but no Chinese version has been validated. This study validated the Chinese version of the SCS and investigated its associations with specific sexual behaviors. In 2008, a random telephone survey was conducted in the sexually active male general population in Hong Kong, interviewing 1,048 participants. The Chinese version of the SCS was found to be internally consistent (Cronbach's alpha = 0.88 for the overall scale), with a mean total score of 20.7 (SD = 4.7). An exploratory factor analysis procedure extracted two factors that were named Controllability and Functional Consequences. Higher SCS scores were associated with multiple female sexual partnerships in the last 6 months, having had sex with either non-regular partner(s) or female sex worker(s) in the last 6 months, having contracted STI in the last 6 months, and inconsistent condom use with either non-regular partner(s) or female sex worker(s) in the last 6 months. The scale can be used to assess sexual compulsivity among sexually active Chinese men in Hong Kong. It can potentially be used in other Chinese communities. Further confirmatory studies are warranted. PMID- 25030120 TI - Using a two-step method to measure transgender identity in Latin America/the Caribbean, Portugal, and Spain. AB - Few comparative data are available internationally to examine health differences by transgender identity. A barrier to monitoring the health and well-being of transgender people is the lack of inclusion of measures to assess natal sex/gender identity status in surveys. Data were from a cross-sectional anonymous online survey of members (n > 36,000) of a sexual networking website targeting men who have sex with men in Spanish- and Portuguese-speaking countries/territories in Latin America/the Caribbean, Portugal, and Spain. Natal sex/gender identity status was assessed using a two-step method (Step 1: assigned birth sex, Step 2: current gender identity). Male-to-female (MTF) and female-to male (FTM) participants were compared to non-transgender males in age-adjusted regression models on socioeconomic status (SES) (education, income, sex work), masculine gender conformity, psychological health and well-being (lifetime suicidality, past-week depressive distress, positive self-worth, general self rated health, gender related stressors), and sexual health (HIV-infection, past year STIs, past-3 month unprotected anal or vaginal sex). The two-step method identified 190 transgender participants (0.54%; 158 MTF, 32 FTM). Of the 12 health-related variables, six showed significant differences between the three groups: SES, masculine gender conformity, lifetime suicidality, depressive distress, positive self-worth, and past-year genital herpes. A two-step approach is recommended for health surveillance efforts to assess natal sex/gender identity status. Cognitive testing to formally validate assigned birth sex and current gender identity survey items in Spanish and Portuguese is encouraged. PMID- 25030122 TI - A failure to demonstrate changes in sexual interest in pedophilic men: comment on Muller et Al. (2014). PMID- 25030124 TI - Tetramethylpyrazine alleviated cytokine synthesis and dopamine deficit and improved motor dysfunction in the mice model of Parkinson's disease. AB - It was previously reported that cytokines and neurotoxins released from activated inflammatory cells induced the loss of projecting dopaminergic neurons in the substantia nigra, which triggered the pathogenesis of PD. The present study investigated the effect of treatment with tetramethylpyrazine (TMP) on the central cytokine synthesis, striatal dopamine content and glutamatergic transmission, and behavioral performance in the rotarod task in mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with TMP significantly improved the behavioral performance in the rotarod task in mice injected with MPTP. It also decreased the upregulation of cytokines (tumor necrosis factor-alpha and interleukin-1beta) in the substantia nigra and striatum in these modeled mice. Furthermore, treatment with TMP significantly improved the dopamine deficits and attenuated the upregulation of striatal basal glutamatergic strength in the striatum of mice injected with MPTP. These results indicated that TMP might serve as a novel approach for the treatment of patients with PD. PMID- 25030125 TI - Reasons for low thrombolysis rate in a Norwegian ischemic stroke population. AB - Only a minor proportion of patients with acute ischemic stroke receive treatment with intravenous thrombolysis. The purpose of this study was to explore reasons for not giving thrombolysis and to determine if there was a correlation between prehospital and in-hospital delay in a Norwegian ischemic stroke population. Patients with acute ischemic stroke were included during a 1-year period. Time intervals for prehospital and in-hospital delay, reasons for not treating with thrombolytic therapy in patients admitted within the time window and reasons for late arrival were recorded. In all, 290 patients were included, and 7.6 % were treated with intravenous thrombolysis. The most frequent reasons for not treating eligible patients were: minor symptoms (22.8 %), clinical improvement (17.5 %) and uncertainty about the diagnosis (12.3 %). Patients' reasons for delayed admission were: not attributing their symptoms to stroke (25.4 %), a wait-and-see attitude (25.4 %), and choosing to wait for the GP's office to open (14.3 %). Prehospital delay was strongly correlated to in-hospital delay (p < 0.001). In conclusion, a large percentage of patients with AIS are not treated with thrombolysis because of mild or rapidly improving symptoms, and because patients arrive too late to the hospital. Absolute and relative contraindications account for a minor proportion of reasons for excluding patients. PMID- 25030123 TI - Lentivirus-mediated delivery of sonic hedgehog into the striatum stimulates neuroregeneration in a rat model of Parkinson disease. AB - Parkinson disease (PD) is a progressive neurodegenerative disorder in which the nigrostriatal pathway, consisting of dopaminergic neuronal projections from the substantia nigra to the striatum, degenerates. Viral transduction is currently the most promising in vivo strategy for delivery of therapeutic proteins into the brain for treatment of PD. Sonic hedgehog (Shh) is necessary for cell proliferation, differentiation and neuroprotection in the central nervous system. In this study, we investigated the effects of overexpressed N-terminal product of SHH (SHH-N) in a PD model rat. A lentiviral vector containing SHH-N was stereotactically injected into the striatum 24 h after a striatal 6-OHDA lesion. We found that overexpressed SHH-N attenuated behavioral deficits and reduced the loss of dopamine neurons in the substantia nigra and the loss of dopamine fibers in the striatum. In addition, fluoro-ruby-labeled nigrostriatal projections were also repaired. Together, our results demonstrate the feasibility and efficacy of using the strategy of lentivirus-mediated Shh-N delivery to delay nigrostriatal pathway degeneration. This strategy holds the potential for therapeutic application in the treatment of PD. PMID- 25030126 TI - Quantitative assessment of the association between fibroblast growth factor 20 rs1721100 C/G polymorphism and the risk of sporadic Parkinson's diseases: a meta analysis. AB - Fibroblast growth factor 20 (FGF20) is a neurotrophic factor which enhances the survival of rat midbrain dopamine neurons. Genetic variation in FGF20 may influence the risk of occurrence and development in Parkinson's diseases (PD). Many studies have evaluated the association between FGF20 rs1721100 C/G polymorphism and the risk of sporadic PD; however, published data are still controversial. The aim of the present meta-analysis was to evaluate the association of FGF20 rs1721100 C/G polymorphism with susceptibility of PD. The summary odds ratio (OR) with its 95 % confidence interval (CI) was calculated to estimate the association. Five case-control studies with a total of 3,463 sporadic PD cases and 4,606 controls were finally included into this meta analysis. Neither the basic allele frequencies nor the genotypic distributions of rs1721100 C/G within FGF20 were different between two groups when all studies were pooled into the meta-analysis. Subgroup analysis by ethnicity showed FGF20 rs1721100 C/G polymorphism was significantly associated with increased risk in the heterozygote comparison model (CG versus GG: OR = 0.83, 95 % CI, 0.72-0.95, P = 0.009) in Asians but not in Caucasians. Overall, this meta-analysis suggests that FGF20 rs1721100 C/G polymorphism is associated with sporadic PD in Asians. PMID- 25030127 TI - Midterm outcomes of endovascular repair for abdominal aortic aneurysms with the on-label use compared with the off-label use of an endoprosthesis. AB - PURPOSE: Endovascular repair of an abdominal aortic aneurysm (EVAR) is sometimes not performed in accordance with the instructions for use (IFU) of the endoprosthesis ("off-label use"). We investigated whether the off-label use of the endograft affected the outcomes of EVAR. METHODS: Demographic, anatomical, intraoperative and follow-up data on 100 patients in whom the endograft was used on-label in EVAR were compared retrospectively with the corresponding data of 50 patients with off-label endograft use. RESULTS: The endograft IFU were most often not followed in patients with challenging aortic neck anatomy or iliac access or fixation, steep neck angulation or bilateral hypogastric artery embolization. Compared with patients in whom the device was used on-label, patients with off label use had significantly higher rates of intraoperative type I or III endoleaks and proximal aortic cuff placement or other adjunctive procedures. However, there were no midterm differences between the two groups in the rates of type 1b or II endoleaks, sac enlargement, device-limb occlusion or patient survival. CONCLUSIONS: Most midterm outcomes of EVAR in which the endografts were used off-label were similar to those associated with on-label use of the devices. Off-label use of EVAR endoprostheses is feasible, but requires the use of special techniques in patients with challenging anatomical features. PMID- 25030129 TI - Within reach. PMID- 25030130 TI - Struggle for independence. PMID- 25030128 TI - The safety of primary repair or anastomosis in high-risk trauma patients. AB - PURPOSE: There is currently not enough data regarding the management of bowel injury and the results of primary repair or resection and anastomosis in high risk trauma patients. We aimed to determine whether there were any short-term (30 days) postoperative complications relevant to the primary reconstruction of such bowel injuries. METHOD: In a retrospective study, all trauma patients who underwent a definite laparotomy after penetrating or blunt injury in our institution during the last decade were identified. The study group consisted of those who underwent primary repair or resection and anastomosis of the small or large bowel or both. Patients who died within 72 h of admission, who had only serosal injuries or who received resection and diversion, were excluded. RESULTS: Seventeen of the trauma patients who were treated at our institution during the study period had bowel injuries. Thirteen fit our criteria. All of them had at least one risk factor, and 61.5% of them had at least three risk factors for anastomotic or suture line disruption. Overall, 35 repairs and anastomoses took place. Only one patient developed clinical anastomotic leakage, resulting in a fistula, which did not require re-operation. CONCLUSION: Our study contributes to the controversial issue of post-traumatic bowel reconstruction in high-risk trauma patients, and suggests that primary reconstruction is feasible and can provide a good outcome. PMID- 25030131 TI - Food for thought. PMID- 25030132 TI - Misjudgements will drive social trials underground. PMID- 25030144 TI - Quantum-hub finalists picked. PMID- 25030145 TI - Landslide risks rise up agenda. PMID- 25030146 TI - Scripps merger fiasco highlights US funding woes. PMID- 25030148 TI - Charity begins at CERN. PMID- 25030149 TI - Physics: Wave of the future. PMID- 25030150 TI - Weight-loss surgery: A gut-wrenching question. PMID- 25030151 TI - Infectious disease: Polio eradication hinges on child health in Pakistan. PMID- 25030154 TI - Policy matters: Editorials should heed social scientists. PMID- 25030152 TI - Psychological treatments: A call for mental-health science. PMID- 25030155 TI - Careers: Virtual mobility can drive equality. PMID- 25030156 TI - European research: Brain project leaders need an open mind. PMID- 25030157 TI - Teaching: China is closing its rural education gap. PMID- 25030158 TI - High-pressure physics: Piling on the pressure. PMID- 25030159 TI - Ecology: Pesticides linked to bird declines. PMID- 25030160 TI - Astrophysics: Survival of the largest. PMID- 25030161 TI - Neurobiology: Keeping a lid on it. PMID- 25030162 TI - Cancer: Sugar-coated cell signalling. PMID- 25030163 TI - Materials science: A superelastic organic crystal. PMID- 25030164 TI - Stem cells: Reprogramming finds its niche. PMID- 25030166 TI - A deep crust-mantle boundary in the asteroid 4 Vesta. AB - The asteroid 4 Vesta was recently found to have two large impact craters near its south pole, exposing subsurface material. Modelling suggested that surface material in the northern hemisphere of Vesta came from a depth of about 20 kilometres, whereas the exposed southern material comes from a depth of 60 to 100 kilometres. Large amounts of olivine from the mantle were not seen, suggesting that the outer 100 kilometres or so is mainly igneous crust. Here we analyse the data on Vesta and conclude that the crust-mantle boundary (or Moho) is deeper than 80 kilometres. PMID- 25030167 TI - Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. AB - Generating engraftable human haematopoietic cells from autologous tissues is a potential route to new therapies for blood diseases. However, directed differentiation of pluripotent stem cells yields haematopoietic cells that engraft poorly. Here, we have devised a method to phenocopy the vascular-niche microenvironment of haemogenic cells, thereby enabling reprogramming of human endothelial cells into engraftable haematopoietic cells without transition through a pluripotent intermediate. Highly purified non-haemogenic human umbilical vein endothelial cells or adult dermal microvascular endothelial cells were transduced with the transcription factors FOSB, GFI1, RUNX1 and SPI1 (hereafter referred to as FGRS), and then propagated on serum-free instructive vascular niche monolayers to induce outgrowth of haematopoietic colonies containing cells with functional and immunophenotypic features of multipotent progenitor cells (MPPs). These endothelial cells that have been reprogrammed into human MPPs (rEC-hMPPs) acquire colony-forming-cell potential and durably engraft into immune-deficient mice after primary and secondary transplantation, producing long-term rEC-hMPP-derived myeloid (granulocytic/monocytic, erythroid, megakaryocytic) and lymphoid (natural killer and B cell) progenies. Conditional expression of FGRS transgenes, combined with vascular induction, activates endogenous FGRS genes, endowing rEC-hMPPs with a transcriptional and functional profile similar to that of self-renewing MPPs. Our approach underscores the role of inductive cues from the vascular niche in coordinating and sustaining haematopoietic specification and may prove useful for engineering autologous haematopoietic grafts to treat inherited and acquired blood disorders. PMID- 25030169 TI - Rapid formation of large dust grains in the luminous supernova 2010jl. AB - The origin of dust in galaxies is still a mystery. The majority of the refractory elements are produced in supernova explosions, but it is unclear how and where dust grains condense and grow, and how they avoid destruction in the harsh environments of star-forming galaxies. The recent detection of 0.1 to 0.5 solar masses of dust in nearby supernova remnants suggests in situ dust formation, while other observations reveal very little dust in supernovae in the first few years after explosion. Observations of the spectral evolution of the bright SN 2010jl have been interpreted as pre-existing dust, dust formation or no dust at all. Here we report the rapid (40 to 240 days) formation of dust in its dense circumstellar medium. The wavelength-dependent extinction of this dust reveals the presence of very large (exceeding one micrometre) grains, which resist destruction. At later times (500 to 900 days), the near-infrared thermal emission shows an accelerated growth in dust mass, marking the transition of the dust source from the circumstellar medium to the ejecta. This provides the link between the early and late dust mass evolution in supernovae with dense circumstellar media. PMID- 25030168 TI - The cancer glycocalyx mechanically primes integrin-mediated growth and survival. AB - Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function. PMID- 25030170 TI - Ramp compression of diamond to five terapascals. AB - The recent discovery of more than a thousand planets outside our Solar System, together with the significant push to achieve inertially confined fusion in the laboratory, has prompted a renewed interest in how dense matter behaves at millions to billions of atmospheres of pressure. The theoretical description of such electron-degenerate matter has matured since the early quantum statistical model of Thomas and Fermi, and now suggests that new complexities can emerge at pressures where core electrons (not only valence electrons) influence the structure and bonding of matter. Recent developments in shock-free dynamic (ramp) compression now allow laboratory access to this dense matter regime. Here we describe ramp-compression measurements for diamond, achieving 3.7-fold compression at a peak pressure of 5 terapascals (equivalent to 50 million atmospheres). These equation-of-state data can now be compared to first principles density functional calculations and theories long used to describe matter present in the interiors of giant planets, in stars, and in inertial confinement fusion experiments. Our data also provide new constraints on mass radius relationships for carbon-rich planets. PMID- 25030171 TI - A low-cost non-toxic post-growth activation step for CdTe solar cells. AB - Cadmium telluride, CdTe, is now firmly established as the basis for the market leading thin-film solar-cell technology. With laboratory efficiencies approaching 20 per cent, the research and development targets for CdTe are to reduce the cost of power generation further to less than half a US dollar per watt (ref. 2) and to minimize the environmental impact. A central part of the manufacturing process involves doping the polycrystalline thin-film CdTe with CdCl2. This acts to form the photovoltaic junction at the CdTe/CdS interface and to passivate the grain boundaries, making it essential in achieving high device efficiencies. However, although such doping has been almost ubiquitous since the development of this processing route over 25 years ago, CdCl2 has two severe disadvantages; it is both expensive (about 30 cents per gram) and a water-soluble source of toxic cadmium ions, presenting a risk to both operators and the environment during manufacture. Here we demonstrate that solar cells prepared using MgCl2, which is non-toxic and costs less than a cent per gram, have efficiencies (around 13%) identical to those of a CdCl2-processed control group. They have similar hole densities in the active layer (9 * 10(14) cm(-3)) and comparable impurity profiles for Cl and O, these elements being important p-type dopants for CdTe thin films. Contrary to expectation, CdCl2-processed and MgCl2-processed solar cells contain similar concentrations of Mg; this is because of Mg out-diffusion from the soda-lime glass substrates and is not disadvantageous to device performance. However, treatment with other low-cost chlorides such as NaCl, KCl and MnCl2 leads to the introduction of electrically active impurities that do compromise device performance. Our results demonstrate that CdCl2 may simply be replaced directly with MgCl2 in the existing fabrication process, thus both minimizing the environmental risk and reducing the cost of CdTe solar-cell production. PMID- 25030172 TI - Pathway from subducting slab to surface for melt and fluids beneath Mount Rainier. AB - Convergent margin volcanism originates with partial melting, primarily of the upper mantle, into which the subducting slab descends. Melting of this material can occur in one of two ways. The flow induced in the mantle by the slab can result in upwelling and melting through adiabatic decompression. Alternatively, fluids released from the descending slab through dehydration reactions can migrate into the hot mantle wedge, inducing melting by lowering the solidus temperature. The two mechanisms are not mutually exclusive. In either case, the buoyant melts make their way towards the surface to reside in the crust or to be extruded as lava. Here we use magnetotelluric data collected across the central state of Washington, USA, to image the complete pathway for the fluid-melt phase. By incorporating constraints from a collocated seismic study into the magnetotelluric inversion process, we obtain superior constraints on the fluids and melt in a subduction setting. Specifically, we are able to identify and connect fluid release at or near the top of the slab, migration of fluids into the overlying mantle wedge, melting in the wedge, and transport of the melt/fluid phase to a reservoir in the crust beneath Mt Rainier. PMID- 25030173 TI - Declines in insectivorous birds are associated with high neonicotinoid concentrations. AB - Recent studies have shown that neonicotinoid insecticides have adverse effects on non-target invertebrate species. Invertebrates constitute a substantial part of the diet of many bird species during the breeding season and are indispensable for raising offspring. We investigated the hypothesis that the most widely used neonicotinoid insecticide, imidacloprid, has a negative impact on insectivorous bird populations. Here we show that, in the Netherlands, local population trends were significantly more negative in areas with higher surface-water concentrations of imidacloprid. At imidacloprid concentrations of more than 20 nanograms per litre, bird populations tended to decline by 3.5 per cent on average annually. Additional analyses revealed that this spatial pattern of decline appeared only after the introduction of imidacloprid to the Netherlands, in the mid-1990s. We further show that the recent negative relationship remains after correcting for spatial differences in land-use changes that are known to affect bird populations in farmland. Our results suggest that the impact of neonicotinoids on the natural environment is even more substantial than has recently been reported and is reminiscent of the effects of persistent insecticides in the past. Future legislation should take into account the potential cascading effects of neonicotinoids on ecosystems. PMID- 25030176 TI - Retraction: Generation of cell polarity in plants links endocytosis, auxin distribution and cell fate decisions. PMID- 25030174 TI - ABCB5 is a limbal stem cell gene required for corneal development and repair. AB - Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63alpha-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency. PMID- 25030175 TI - WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis. AB - The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases. PMID- 25030180 TI - Cost analysis of non-invasive fractional flow reserve derived from coronary computed tomographic angiography in Japan. AB - Percutaneous coronary intervention (PCI) based on fractional flow reserve (FFRcath) measurement during invasive coronary angiography (CAG) results in improved patient outcome and reduced healthcare costs. FFR can now be computed non-invasively from standard coronary CT angiography (cCTA) scans (FFRCT). The purpose of this study is to determine the potential impact of non-invasive FFRCT on costs and clinical outcomes of patients with suspected coronary artery disease in Japan. Clinical data from 254 patients in the HeartFlowNXT trial, costs of goods and services in Japan, and clinical outcome data from the literature were used to estimate the costs and outcomes of 4 clinical pathways: (1) CAG-visual guided PCI, (2) CAG-FFRcath guided PCI, (3) cCTA followed by CAG-visual guided PCI, (4) cCTA-FFRCT guided PCI. The CAG-visual strategy demonstrated the highest projected cost ($10,360) and highest projected 1-year death/myocardial infarction rate (2.4 %). An assumed price for FFRCT of US $2,000 produced equivalent clinical outcomes (death/MI rate: 1.9 %) and healthcare costs ($7,222) for the cCTA-FFRCT strategy and the CAG-FFRcath guided PCI strategy. Use of the cCTA FFRCT strategy to select patients for PCI would result in 32 % lower costs and 19 % fewer cardiac events at 1 year compared to the most commonly used CAG-visual strategy. Use of cCTA-FFRCT to select patients for CAG and PCI may reduce costs and improve clinical outcome in patients with suspected coronary artery disease in Japan. PMID- 25030181 TI - Role of glucagon-like peptide-1 analogue versus amylin as an adjuvant therapy in type 1 diabetes in a closed loop setting with ePID algorithm. AB - Postprandial hyperglycemia due to paradoxical hyperglucagonemia is a major challenge of diabetes treatment despite the use of the artificial pancreas. We postulated that adjunctive therapy with pramlintide or exenatide would attenuate hyperglycemia in the postprandial phase through glucagon suppression, thereby optimizing the functioning of the closed-loop (CL) system. Subjects with type 1 diabetes (T1DM) on insulin pump therapy were recruited to participate in a 27 hour hospitalized admission on 3 occasions (2-4 weeks apart) and placed on the insulin delivery via CL system in random order to receive (1) insulin alone (control), (2) exenatide 2.5 ug + insulin, (3) pramlintide 30 ug + insulin. Medications were given prior to lunch and dinner, which was a standardized meal of 60 grams of carbohydrates. Insulin delivery was as per the ePID algorithm via the Medtronic CL system and continuous subcutaneous glucose monitoring via Medtronic Sof-sensors. Ten subjects age 23 +/- 1 years with a HbA1c of 7.29 +/- 0.3% (56 +/- 1 mmol/mol) and duration of T1DM 10.6 +/- 2.0 years participated in the 3-part study. Exenatide was found to be significantly better in attenuating postprandial hyperglycemia as compared to insulin monotherapy (P < .03) and pramlintide (P > .05). Glucagon suppression was statistically significant with exenatide (P < .03) as compared to pramlintide. Insulin requirements were lower with adjunctive therapy, but statistically insignificant. Insulin monotherapy results in postprandial hyperglycemia in T1DM in the CL setting and adjunctive therapy with exenatide reduces postprandial hyperglycemia effectively and should be considered as adjunctive therapy in T1DM. PMID- 25030183 TI - Does vitamin D protect against respiratory viral infections? AB - The active form of vitamin D has effects on both innate and adaptive immune responses that may influence the outcome in many infectious diseases. Observational studies conclusively show that a low vitamin D status is associated with an increased occurrence of respiratory viral infections, which globally represent significant health and financial burdens. However, no consistent protective effects are evident in prospective clinical trials carried out to date where vitamin D was provided as a dietary supplement, except possibly in cases where the starting vitamin D status of the individual was considered deficient. Thus far, vitamin D has not been found to enhance the immune response to vaccines. The design of future prospective clinical trials assessing a role for vitamin D in respiratory viral infections requires very careful planning to avoid the uncertainties associated with the data available currently. PMID- 25030182 TI - An update on complex I assembly: the assembly of players. AB - Defects in Complex I assembly is one of the emerging underlying causes of severe mitochondrial disorders. The assembly of Complex I has been difficult to understand due to its large size, dual genetic control and the number of proteins involved. Mutations in Complex I subunits as well as assembly factors have been reported to hinder its assembly and give rise to a range of mitochondria disorders. In this review, we summarize the recent progress made in understanding the Complex I assembly pathway. In particularly, we focus on the known as well as novel assembly factors and their role in assembly of Complex I and human disease. PMID- 25030184 TI - Tetanus toxoids loaded glucomannosylated chitosan based nanohoming vaccine adjuvant with improved oral stability and immunostimulatory response. AB - PURPOSE: The present report embarks on rational designing of stable and functionalized chitosan nanoparticles for oral mucosal immunization. METHODS: Stable glucomannosylated sCh-GM-NPs were prepared by tandem cross linking method followed by lyophilization. The in vitro stability of antigen and formulation, cellular uptake and immunostimulatory response were assessed by suitable experimental protocol. RESULTS: Stability testing ensured the chemical and conformation permanency of encapsulated TT as well as robustness of sCh-GM-NPs in simulated biological media. The antigen release from sCh-GM-NPs followed initial burst followed by controlled Weibull's type of release profile. The higher intracellular uptake of sCh-GM-NPs in Raw 264.7 and Caco-2 was concentration and time dependent which mainly attributed to Clathrin and receptor mediated endocytosis via mannose and glucose receptor. The in vivo evaluation in animals revealed that sCh-GM-NPs posed significantly (p < 0.001) higher humoral, mucosal and cellular immune response than other counterparts. More importantly, commercial TT vaccine administered through oral or intramuscular route was unable to elicit all type of immune response. CONCLUSION: The sCh-GM-NPs could be considered as promising vaccine adjuvant for oral tetanus immunization. Additionally, this technology expected to benefit the design and development of stable peroral formulation for administration of protein, peptides and variety of other antigens. PMID- 25030185 TI - Oxidative stress protection by exogenous delivery of rhHsp70 chaperone to the retinal pigment epithelium (RPE), a possible therapeutic strategy against RPE degeneration. AB - PURPOSE: To measure the cytoprotective effects of rhHsp70 against oxidative stress and study its cellular uptake, intracellular and intraocular distribution in the retinal pigment epithelium. METHODS: Human retinal pigment epithelial cells (ARPE-19) were pre-treated with rhHsp70 for 24 h, 48 h, and 72 h before being exposed to 1.25 mM hydrogen peroxide. Non-treated cells served as control. We analysed interleukin 6 secretion, cell viability, and cytolysis. Uptake and intracellular distribution of fluorescently labelled rhHsp70 were investigated with flow cytometry and confocal microscopy, respectively. Ocular distribution of radioactively labelled rhHsp70 was followed ex vivo in porcine eyes by micro SPECT/CT. RESULTS: After exposure to hydrogen peroxide, IL-6 secretion decreased by 35-39% when ARPE-19 cells were pre-treated with rhHsp70. Cell viability increased by 17-32%, and cell lysis, measured by the release of lactate dehydrogenase, decreased by 6-43%. ARPE-19 cells endocytosed rhHsp70 added to the culture medium and the protein was localized in late endosomes and lysosomes. Following intravitreal injection into isolated porcine eyes, we found 20% rhHsp70 in the RPE. CONCLUSIONS: Recombinant hHsp70 protein offers protection against oxidative stress. RPE cells take up the exogenously delivered rhHsp70 and localize it in late endosomes and lysosomes. This work provides the basis for a therapeutic strategy to target aggregate-associated neurodegeneration in AMD. PMID- 25030186 TI - Semi-interpenetrating network (sIPN) co-electrospun gelatin/insulin fiber formulation for transbuccal insulin delivery. AB - PURPOSE: This work was aimed at developing a semi-interpenetrating network (sIPN) co-electrospun gelatin/insulin fiber scaffold (GIF) formulation for transbuccal insulin delivery. METHODS: Gelatin was electrospun into fibers and converted into an sIPN following eosin Y-initiated polymerization of polyethylene glycol diacrylate (PEG-DA). The cytocompatibility, degradation rate and mechanical properties were examined in the resulting sIPNs with various ratios of PEG-DA to eosin Y to find a suitable formulation for transbuccal drug delivery. Insulin was co-electrospun with gelatin into fibers and converted into an sIPN-GIF using this suitable formulation. The in vitro release kinetics of insulin was evaluated using ELISA. The bioactivity of released insulin was analyzed in 3T3-L1 preadipocytes using Western blotting and Oil Red O staining. The transbuccal permeability of released insulin was determined using an in vitro porcine oral mucosa model. RESULTS: The sIPN-GF formulation of GF cross-linked by PEG-DA (1% w/v) with eosin Y (5% v/v) possessed no cytotoxic effect, a moderate degradation rate with degradation half-life of 49 min, and a significant enhancement in mechanical properties. This formulation was used to fabricate sIPN-GIF. Insulin release was extended up to 4 h by sIPN-GIF. The released insulin successfully triggered intracellular AKT phosphorylation and induced adipocyte differentiation in 3T3-L1 preadipocytes. The transbuccal permeability of released insulin was determined on the order of 10(-7) cm/s. CONCLUSIONS: Insulin can be fabricated into an sIPN-GIF formulation following co-electrospinning and cross-linking without losing bioactivity. It proved the potential of this new formulation for transbuccal insulin delivery. PMID- 25030187 TI - Age estimation in northern Chinese children by measurement of open apices in tooth roots. AB - The aim of this study was to assess the accuracy of Cameriere's methods on dental age estimation in the northern Chinese population. A sample of orthopantomographs of 785 healthy children (397 girls and 388 boys) aged between 5 and 15 years was collected. The seven left permanent mandibular teeth were evaluated with Cameriere's method. The sample was split into a training set to develop a Chinese specific prediction formula and a test set to validate this novel developed formula. Following the training dataset study, the variables gender (g), x 3 (canine teeth), x 4 (first premolar), x 7 (second molar), N 0, and the first order interaction between s and N 0 contributed significantly to the fit, yielding the following linear regression formula: Age = 10.202 + 0.826 g - 4.068x 3 - 1.536x 4 - 1.959x 7 + 0.536 N 0 - 0.219 s [Symbol: see text] N 0, where g is a variable, 1 for boys and 0 for girls. The equation explained 91.2 % (R (2) = 0.912) of the total deviance. By analyzing the test dataset, the accuracy of the European formula and Chinese formula was determined by the difference between the estimated dental age (DA) and chronological age (CA). The European formula verified on the collected Chinese children underestimated chronological age with a mean difference of around -0.23 year, while the Chinese formula underestimated the chronological age with a mean difference of -0.04 year. Significant differences in mean differences in years (DA - CA) and absolute difference (AD) between the Chinese-specific prediction formula and Cameriere's European formula were observed. In conclusion, a Chinese-specific prediction formula based on a large Chinese reference sample could ameliorate the age prediction accuracy in the age group of children. PMID- 25030188 TI - Can post-mortem CT reliably distinguish between drowning and non-drowning asphyxiation? AB - PURPOSE: The aim of this study is to evaluate whether previously reported post mortem CT findings in drowning can reliably distinguish drowning from asphyxiation by any other manner. MATERIALS AND METHODS: Cases (n = 14) were corpses with cause of death determined as drowning by concordant autopsy findings and physical and circumstantial evidence. Controls (n = 11) were corpses in which the cause of death was defined as asphyxiation by any other manner than submersion in a liquid. Images were evaluated for the presence of fluid in paranasal sinuses, mastoid air cells and lower airways, frothy foam in the upper airways, ground-glass opacity of the lung parenchyma, the height of the right hemi-diaphragm, the interpulmonary distance at the level of the aortic valve, the mean density of intracardiac blood, and gastric and esophageal contents. Descriptive statistics, Fisher's exact test, and Student's t test were used when appropriate. RESULTS: Only the height of the right hemi-diaphragm differed significantly (p = 0.045) between cases (mean 5.4) and controls (mean 4.3). Other findings were not significantly different between both groups. CONCLUSION: Our results indicate that it is not possible to reliably distinguish drowning from non-drowning asphyxiation on CT, because many findings in drowning were also present in non-drowning asphyxiation. CT indicators for drowning as the cause of death should therefore be defined with great caution, keeping in mind that they are not specific to only a single cause of death. PMID- 25030189 TI - Observation of vertebral artery damage using angioscopy in autopsy cases. AB - The vertebral arteries are important blood vessels that supply the cerebral circulation in conjunction with the internal carotid arteries. In cases of subarachnoid hemorrhage, it is necessary to examine the vertebral arteries as potential sources of bleeding due to blunt trauma (head and neck) or of cerebral embolism that originated on the surface of the damaged intima as a result of hyperflexion or hyperextension. However, a considerable part of the vertebral arterial surface is surrounded by bone, resulting in challenges during examination in a routine autopsy. In this study, angioscopy was used to inspect the vertebral artery intima for damage in cases of neck injury, head injury, or neck strangulation. Intimal damage was detected in 34 out of the total 75 cases. Of the 28 cases with cervical discopathy or fracture, 61% had intimal damage. In addition, postmortem application of computed tomography angiography was performed to identify the injured vessel in a case with traumatic subarachnoid hemorrhage, and a perforated hole was detected using angioscopy, which did not introduce autopsy-related artifacts. Therefore, angioscopy may be a useful and nondestructive method to identify intimal damage in the vertebral arteries during an autopsy. PMID- 25030190 TI - Application of Locked Nucleic Acid (LNA) oligonucleotide-PCR clamping technique to selectively PCR amplify the SSU rRNA genes of bacteria in investigating the plant-associated community structures. AB - The simultaneous extraction of plant organelle (mitochondria and plastid) genes during the DNA extraction step is a major limitation in investigating the community structures of bacteria associated with plants because organelle SSU rRNA genes are easily amplified by PCR using primer sets that are specific to bacteria. To inhibit the amplification of organelle genes, the locked nucleic acid (LNA) oligonucleotide-PCR clamping technique was applied to selectively amplify bacterial SSU rRNA genes by PCR. LNA oligonucleotides, the sequences of which were complementary to mitochondria and plastid genes, were designed by overlapping a few bases with the annealing position of the bacterial primer and converting DNA bases into LNA bases specific to mitochondria and plastids at the shifted region from the 3' end of the primer-binding position. PCR with LNA oligonucleotides selectively amplified the bacterial genes while inhibited that of organelle genes. Denaturing gradient gel electrophoresis (DGGE) analysis revealed that conventional amplification without LNA oligonucleotides predominantly generated DGGE bands from mitochondria and plastid genes with few bacterial bands. In contrast, additional bacterial bands were detected in DGGE patterns, the amplicons of which were prepared using LNA oligonucleotides. These results indicated that the detection of bacterial genes had been screened by the excessive amplification of the organelle genes. Sequencing of the bands newly detected by using LNA oligonucleotides revealed that their similarity to the known isolated bacteria was low, suggesting the potential to detect novel bacteria. Thus, application of the LNA oligonucleotide-PCR clamping technique was considered effective for the selective amplification of bacterial genes from extracted DNA containing plant organelle genes. PMID- 25030191 TI - Attitudes towards disclosure and relationship to donor offspring among a national cohort of identity-release oocyte and sperm donors. AB - STUDY QUESTION: What are oocyte donors and sperm donors' attitudes towards disclosure and relationship to donor offspring? SUMMARY ANSWER: Oocyte and sperm donors in an identity-release donor programme support disclosure to donor offspring and have overall positive or neutral attitudes towards future contact with offspring. WHAT IS KNOWN ALREADY: There is a global trend towards open identity gamete donation with an increasing number of countries introducing legislation allowing only identifiable donors. While women and men who enrol in identity-release donor programmes accept that they may be contacted by donor offspring, there is limited knowledge of their attitudes towards disclosure to donor offspring and how they perceive their relationship to potential donor offspring. STUDY DESIGN, SIZE AND DURATION: The present study is part of the 'Swedish study on gamete donation', a prospective cohort study including donors at all fertility clinics performing donation treatment in Sweden. During a 3-year period (2005-2008), donors were recruited consecutively and a total of 157 oocyte donors and 113 sperm donors (who did not donate to a specific 'known' couple) were included prior to donation. Participants in the present study include 125 female (80%) and 80 male donors (71%) that completed two follow-up assessments. PARTICIPANTS/MATERIALS, SETTINGS AND METHODS: Participants completed two postal questionnaires 2 months after donation and 14 months after donation. Attitudes towards disclosure to donor offspring were assessed with an established instrument. Perceptions of involvement with donor offspring and need for counselling was assessed with study-specific instruments. Statistical analyses were performed with non-parametric tests. MAIN RESULTS AND THE ROLE OF CHANCE: A majority of oocyte and sperm donors supported disclosure to donor offspring (71 91%) and had positive or neutral attitudes towards future contact with offspring (80-87%). Sperm donors reported a higher level of involvement with potential donor offspring compared with oocyte donors (P = 0.005). Few donors reported a need for more counselling regarding the consequences of their donation. LIMITATIONS, REASONS FOR CAUTION: While the multicentre study design strengthens external validity, attrition induced a risk of selection bias. In addition, the use of study-specific instruments that have not been psychometrically tested is a limitation. WIDER IMPLICATIONS OF THE FINDINGS: The positive attitudes towards disclosure to offspring of female and male identity-release donors are in line with previous reports of anonymous and known donors. While our results on donors' general positive or neutral attitudes towards future contact with potential donor offspring are reassuring, a subset of donors with negative attitudes towards such contact warrants concern and suggests a need for counselling on long-term consequences of donating gametes. STUDY FUNDING: The 'Swedish study on gamete donation' was funded by the Swedish Research Council, the Swedish Council for Health, Working Life and Welfare, and the Regional Research Council in Uppsala Orebro. There are no conflicts of interest to declare. PMID- 25030194 TI - Thalassemias and hemoglobinopathies in Turkey. AB - Thalassemias and hemoglobinopathies are a serious health problem in Turkey. There is a 70-year history of thalassemia in Turkey. The first patient with beta thalassemia major (beta-TM) was reported in 1941. The first clinical and hematological studies were published by Aksoy in 1958. The overall incidence of beta-thalassemia (beta-thal) was reported by Cavdar and Arcasoy to be 2.1% in 1971. Important steps such as written regulations, education and prevention campaigns, have been taken to prevent thalassemia in Turkey by the Ministry of Health (MOH), the Turkish National Hemoglobinopathy Council (TNHC) and the Thalassemia Federation of Turkey (TFT) since 2000. A national hemoglobinopathy prevention program was started in provinces with a high prevalence by the MOH in 2003. While the percentage of premarital screening test was 30.0% of all couples in 2003, it reached 86.0% in 2013. While the number of newborn with thalassemias and hemoglobinopathies was 272 in 2002, it had dropped to 25 in 2010. There has been a 90.0% reduction of affected births in the last 10 years. PMID- 25030195 TI - GP payment system and support services are to be privatised. PMID- 25030197 TI - Nine-dimensional quantum dynamics study of the H2 + NH2 -> H + NH3 reaction: a rigorous test of the sudden vector projection model. AB - Reaction dynamics and mode specificity in the H2 + NH2 -> H + NH3 reaction are investigated in full dimensionality on a recent ab initio based global potential energy surface. Integral cross sections from several low-lying vibrational states of both reagents have been calculated under the centrifugal sudden or J-shifting approximations, using an initial state selected time-dependent wave packet method. This nine-dimensional system provides an ideal proving ground to test our recently proposed Sudden Vector Projection (SVP) model. Our results indicate that vibrational excitation of H2 enhances the reactivity. On the other hand, excitation of either the symmetric or antisymmetric stretching mode of NH2 inhibits the reaction, while excitation of its bending mode has a negligible effect. Furthermore, all vibrational modes are less effective than translational energy in promoting the reaction. These mode-specific features are rationalized with the SVP model. PMID- 25030198 TI - Inhaled corticosteroids in children with persistent asthma: effects on growth. AB - BACKGROUND: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. OBJECTIVES: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. MAIN RESULTS: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI 0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi2 = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 MUg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 MUg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to 0.50) in adult height compared with those treated with placebo. AUTHORS' CONCLUSIONS: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma. PMID- 25030199 TI - Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. AB - BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 MUg) versus low to medium (200 MUg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma. PMID- 25030200 TI - Lipases in wheat breadmaking: analysis and functional effects of lipid reaction products. AB - The baking activity of two different lipases was evaluated by a microbaking test on a 10 g flour basis, and the altered lipid composition of lipase-treated wheat lipids was quantitated. To identify and quantitate the various lipid classes, pure glycolipids and phospholipids were isolated from a wheat flour lipid extract by a silica gel batch procedure and silica gel column chromatography. These reference compounds were used to establish a high-performance liquid chromatographic method with evaporative light scattering detection, which was able to separate all of the wheat lipid classes and lipase reaction products. Wheat lipids, dough lipids, and dough lipids after lipase addition were quantitated using cholesterol as an internal standard. Especially digalactosyl diglycerides (-0.9 mmol/kg flour), monogalactosyl diglycerides (-0.4 mmol/kg), and N-acyl-phosphatidyl ethanolamine (-0.3 mmol/kg) were hydrolyzed, and a concomitant formation of digalactosyl monoglycerides (+0.6 mmol/kg), monogalactosyl monoglycerides (+0.6 mmol/kg), and N-acyl-lysophosphatidyl ethanolamine (+0.5 mmol/kg) was found. The lipase-induced changes of the lipid fraction caused increases in bread volume of 56-58%, depending on the type and concentration of the added lipase. The current results confirm the important relationship between the lipid fraction composition and the baking performance of flour. PMID- 25030201 TI - Association between interleukin-6 gene polymorphisms and rheumatoid arthritis in Chinese Han population: a case-control study and a meta-analysis. AB - The aim of this study was to investigate the possible association in the interleukin-6 (IL-6) gene with Rheumatoid arthritis (RA) in Chinese Han population from Shandong Province. Target regions of IL-6 gene were amplified by polymerase chain reaction (PCR) and genotyped. A logistic regression analysis was performed to detect potential associations in our case-control sample, the odd ratio(OR) and 95% confidence intervals(CIs) were calculated. Furthermore, we systematically tracked all the published studies in the field and performed a meta-analysis for the single nucleotide polymorphisms (SNPs) under study. 256 RA patients and 331 healthy controls were recruited into the case-control study. We found allele frequencies of rs1800795, rs1800797 and rs1474347 in RA patients differ from control subjects (P = 0.016, 0.024, 0.020, respectively). Significant difference was observed in haplotype frequencies of GCCGCT between RA patients and controls (P = 0.0001, OR = 4.066, 95%CI = 1.891 ~ 8.746), while GGCGCT frequencies was found lower in RA than controls (P = 0.006, OR = 0.669, 95%CI = 0.501 ~ 0.894). The results of the meta-analysis showed association polymorphism within the IL-6 promoter with RA. These findings suggest that rare IL-6 gene polymorphisms may associate with RA susceptibility in Han Chinese populations; however further studies are needed to assess the validity of the association of IL-6 with RA. PMID- 25030202 TI - Origin and structure of dynamic cooperative networks. AB - Societies are built on social interactions among individuals. Cooperation represents the simplest form of a social interaction: one individual provides a benefit to another one at a cost to itself. Social networks represent a dynamical abstraction of social interactions in a society. The behaviour of an individual towards others and of others towards the individual shape the individual's neighbourhood and hence the local structure of the social network. Here we propose a simple theoretical framework to model dynamic social networks by focussing on each individual's actions instead of interactions between individuals. This eliminates the traditional dichotomy between the strategy of individuals and the structure of the population and easily complements empirical studies. As a consequence, altruists, egoists and fair types are naturally determined by the local social structures, while globally egalitarian networks or stratified structures arise. Cooperative interactions drive the emergence and shape the structure of social networks. PMID- 25030204 TI - Efficacy of modified constraint-induced movement therapy in acute stroke. AB - BACKGROUND: Modified constraint induced movement therapy (m-CIMT) discourages the use of the unaffected extremity and encourages the active use of the hemiplegic arm in order to restore the motor function. AIM: The aim was to assess the efficacy of m-CIMT on functional recovery of upper extremity (UE) in acute stroke patients, as compared to conventional rehabilitation therapy. DESIGN: This is a prospective comparative study. SETTING: This study included sixty patients with acute stroke recruited from neurology department. METHODS: This study included sixty acute stroke patients. Inclusion criteria were: patients within two weeks from the onset of stroke, persistent hemiparesis leading to impaired upper extremity function, evidence of preserved cognitive function, and a minimum of 10 degrees of active finger extension and 20 degrees of active wrist extension. Exclusion criteria were: intra-cerebral hemorrhage, previous stroke on the same side, presence of neglect or a degree of aphasia impeding understanding of instructions, and conditions that limit the use of the upper limb before the stroke. Patients were assessed by Fugl-Meyer motor assessment (FMA), action research arm test (ARAT) and motor evoked potentials (MEPs), recorded from the abductor pollicis brevis (APB) of the affected hand. The clinical and neurophysiological tests were performed pre and postrehabilitation. The patients were divided into two groups: Conventional rehabilitation program group (CRP) included 30 patients who were given a conventional rehabilitation program for two weeks. CIMT group included 30 patients who were subjected to modified CIMT for two consecutive weeks. Total treatment time was the same in both groups. RESULTS: CRP group showed a non-significant improvement in FMA and ARAT. CIMT group showed a significant improvement in clinical scores on all tests (P<0.05). When comparing both groups using FMA and ARAT tests pre- and post- therapy, a significant difference (P<0.05) was found between both groups with CIMT group showing greater improvement. When comparing MEPs in CRP group, pre and postrehabilitation, a non-significant improvement was found for resting motor threshold (RMT), central motor conduction time (CMCT) and amplitude of MEPs. In contrast, each of the MEP parameters exhibited a significant improvement in CIMT group (P<0.05). CONCLUSION: In contrast to conventional rehabilitation therapy, modified CIMT revealed a significant functional and MEP improvement in acute stroke patients indicating that m-CIMT might be a more efficient treatment strategy. CLINICAL REHABILITATION IMPACT: It is advised to use modified constraint movement therapy in rehabilitation of cerebrovascular stroke during acute stage. PMID- 25030203 TI - Hepatic inflammation scores correlate with common carotid intima-media thickness in rats with NAFLD induced by a high-fat diet. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), an emerging public health problem, may be a highly atherogenic condition. But the relationship between fatty liver diseases and carotid atherosclerosis in small-animal is incompletely understood. The purpose of the present study was to evaluate carotid intima-media thickness (IMT) in NAFLD rats using high-frequency ultrasonic diagnostic equipment, and to ascertain if the degree of hepatic pathological changes was associated with carotid IMT. RESULTS: Liver injury was induced by a high-fat diet for 8, 12 and 16 weeks, separately, in fifty four SD rats (27 treated, 27 controls). Liver echogenicity and IMT of the carotid and aorta were evaluated and compared to histological findings of them. In comparison with the rats in the control group, fatty liver disease in rats was characterized by homogeneous and diffusely increased echogenicity (bright liver), an increased anteroposterior diameter of the liver and serum biochemical changes. Hepatic histological analyses demonstrated indications of simple steatosis in rats induced by an 8 week high-fat diet, and a high-fat diet for 12 weeks and 16 weeks could induce steatohepatitis (NASH) in rats. The 12- and 16-week groups had a significantly higher inflammation scores than those of the control groups. IMT values for the carotid and aorta were remarkably increased in the NASH groups compared with the control groups (P < 0.05). The end-diastolic velocity and systolic peak velocity of the carotid and aorta in the NASH groups were significantly smaller than those in the control group. A significant correlation between the IMT of the carotid with hepatic inflammation score (r2 = 0.598, P = 0.001) and the systolic peak velocity of the carotid (r2 = -0.342, P = 0.041) were shown in NAFLD rats. CONCLUSION: We demonstrated that ultrasound imaging in the diagnosis of fatty liver disease and early atherosclerosis in rats is feasible and efficient, and that carotid IMT increased significantly in NASH rats but not in simple steatotic rats. A significant correlation between the IMT of the carotid artery with hepatic inflammation score were shown in NAFLD rats. This method for non-invasive diagnosis is especially relevant in the research of the pathogenesis and therapy of NAFLD and atherosclerosis using rodent models. PMID- 25030206 TI - Does ambiguity aversion influence the framing effect during decision making? AB - Decision-makers present a systematic tendency to avoid ambiguous options for which the level of risk is unknown. This ambiguity aversion is one of the most striking decision-making biases. Given that human choices strongly depend on the options' presentation, the purpose of the present study was to examine whether ambiguity aversion influences the framing effect during decision making. We designed a new financial decision-making task involving the manipulation of both frame and uncertainty levels. Thirty-seven participants had to choose between a sure option and a gamble depicting either clear or ambiguous probabilities. The results revealed a clear preference for the sure option in the ambiguity condition regardless of frame. However, participants presented a framing effect in both the risk and ambiguity conditions. Indeed, the framing effect was bidirectional in the risk condition and unidirectional in the ambiguity condition given that it did not involve preference reversal but only a more extreme choice tendency. PMID- 25030207 TI - Reassembly of S-layer proteins. AB - Crystalline bacterial cell surface layers (S-layers) represent the outermost cell envelope component in a broad range of bacteria and archaea. They are monomolecular arrays composed of a single protein or glycoprotein species and represent the simplest biological membranes developed during evolution. They are highly porous protein mesh works with unit cell sizes in the range of 3 to 30 nm, and pore sizes of 2 to 8 nm. S-layers are usually 5 to 20 nm thick (in archaea, up to 70 nm). S-layer proteins are one of the most abundant biopolymers on earth. One of their key features, and the focus of this review, is the intrinsic capability of isolated native and recombinant S-layer proteins to form self assembled mono- or double layers in suspension, at solid supports, the air-water interface, planar lipid films, liposomes, nanocapsules, and nanoparticles. The reassembly is entropy-driven and a fascinating example of matrix assembly following a multistage, non-classical pathway in which the process of S-layer protein folding is directly linked with assembly into extended clusters. Moreover, basic research on the structure, synthesis, genetics, assembly, and function of S-layer proteins laid the foundation for their application in novel approaches in biotechnology, biomimetics, synthetic biology, and nanotechnology. PMID- 25030208 TI - Channeling the SmI2 reactions to the radical path: radicals resisting reduction by SmI2. AB - Studies on the reaction of 4-(2,2-diphenylvinyl)pyridine with SmI2 revealed that the intermediate radical strongly resists further reduction to the corresponding anion. The resistance of the radical to accepting another electron is traced to its stabilization by the nitrogen lone pair. The literature suggests that oxygen may also play a role similar to that of nitrogen in directing the course of the reaction toward radical rather than to anionic chemistry. PMID- 25030209 TI - Exfoliation of layered double hydroxides for enhanced oxygen evolution catalysis. AB - The oxygen evolution reaction is a key reaction in water splitting. The common approach in the development of oxygen evolution catalysts is to search for catalytic materials with new and optimized chemical compositions and structures. Here we report an orthogonal approach to improve the activity of catalysts without alternating their compositions or structures. Specifically, liquid phase exfoliation is applied to enhance the oxygen evolution activity of layered double hydroxides. The exfoliated single-layer nanosheets exhibit significantly higher oxygen evolution activity than the corresponding bulk layered double hydroxides in alkaline conditions. The nanosheets from nickel iron and nickel cobalt layered double hydroxides outperform a commercial iridium dioxide catalyst in both activity and stability. The exfoliation creates more active sites and improves the electronic conductivity. This work demonstrates the promising catalytic activity of single-layered double hydroxides for the oxygen evolution reaction. PMID- 25030210 TI - An acridinium-based sensor as a fluorescent photoinduced electron transfer probe for proton detection modulated by anionic micelles. AB - A water-soluble fluorescent pH sensor of 9-amino-10-methylacridinium chromophore with the 2-(diethylamine)ethyl chain as a receptor shows an "off-on" response going from basic to acidic solution. Photoinduced electron transfer has been directly demonstrated to be the quenching mechanism by the observation of the long-lived acridinyl radical. The interaction of the protonated sensor with anionic micelles causes a significant increase in the detection sensitivity of pH. PMID- 25030211 TI - Synthesis and characterisation of first row transition metal complexes of functionalized 1,2,4-benzothiadiazines. AB - Reaction of the novel ligand 3-(2'-pyridyl)-benzo-1,2,4-thiadiazine (L) with the transition metal chloride salts MCl2.xH2O (M(II) = Mn, Fe, Co, Cu and Zn) in a 2 : 1 mole ratio afforded the mononuclear octahedral (high spin) complexes L2MCl2 (1a-1e respectively) in which L binds in a chelate fashion via N(2) and the pyridyl N atoms. In the case of CuCl2 the intermediate 1 : 1 four-coordinate complex LCuCl2 (2) was also isolated which adopts a polymeric structure with pseudo-square planar molecules linked via long Cu...S contacts (d(Cu...S) = 2.938(1) A) in the apical position. In the presence of non-interacting ions, 3 : 1 complexes are isolated, exemplified by the reaction of L with Fe(CF3SO3)2 in a 3 : 1 ratio which affords the low spin complex [L3Fe][CF3SO3]2 (3). Reaction of L with VCl3 in a 2 : 1 mole ratio under aerobic conditions afforded the vanadyl complex [L2V(=O)Cl][Cl] (4). PMID- 25030212 TI - Stripe systems with competing interactions on quasi-one dimensional periodic substrates. AB - We numerically examine the two-dimensional ordering of a stripe forming system of particles with competing long-range repulsion and short-range attraction in the presence of a quasi-one-dimensional corrugated substrate. As a function of increasing substrate strength or period we show that a remarkable variety of distinct orderings can be realized, including modulated stripes, prolate clump phases, two dimensional ordered kink structures, crystalline void phases, and smectic phases. Additionally in some cases the stripes align perpendicular to the substrate troughs. Our results suggest that a new route to self assembly for systems with competing interactions can be achieved through the addition of a simple periodic modulated substrate. PMID- 25030213 TI - Individualized prostate-specific antigen threshold values to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy in elderly men. AB - OBJECTIVE: To individualize prostate-specific antigen threshold values to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy in elderly men. METHODS: A total of 406 men aged over 70 years old with prostate-specific antigen levels between 4.0 and 20.0 ng/ml, normal digital rectal examination results and diagnosed by transrectal needle biopsy were retrospectively analyzed. The patients were divided into a no/favorable-risk cancer group or an unfavorable risk cancer group based on their Gleason score and the number of positive cores. Prostate-specific antigen levels, percent free prostate-specific antigen level, prostate transition zone volume and the number of previous biopsies were used to discriminate between the two groups. The optimal individualized prostate-specific antigen threshold values based on the other variables that gave a sensitivity of 95% for the detection of unfavorable-risk cancer were calculated using a boosting method for maximizing the area under the receiver operating characteristic curve. RESULTS: A total of 66 men had favorable-risk cancer, and 139 had unfavorable risk cancer. The area under the receiver operating characteristic curve of the combination model determined by the boosting method for maximizing the area under the receiver operating characteristic curve was 0.852. The sensitivity and specificity of the threshold values for the detection of unfavorable-risk cancer were 95 and 36%, respectively. By using the threshold values, 100 (25%) of the subjects with no/favorable-risk cancer could have avoided undergoing biopsies, with a <5% risk of missing the detection of unfavorable-risk cancer. CONCLUSIONS: These individualized prostate-specific antigen threshold values may be useful for determining an indication of prostate biopsy for elderly men to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy. PMID- 25030214 TI - Observational study of axilla treatment for breast cancer patients with 1-3 positive micrometastases or macrometastases in sentinel lymph nodes. AB - Sentinel node biopsy is a standard procedure in clinically node-negative breast cancer patients. It has eliminated unnecessary axillary lymph node dissection in more than half of the early breast cancers. However, one of the unresolved issues in sentinel node biopsy is how to manage axilla surgery for sentinel node positive patients and clinically node-negative patients. To evaluate the outcome of no axillary lymph node dissection in sentinel node-positive breast cancer, a prospective cohort study registering early breast cancer patients with positive sentinel nodes has been conducted (UMIN 000011782). Patients with 1-3 positive micrometastases or macrometastases in sentinel lymph nodes are eligible for the study. The primary endpoint is the recurrence rate of regional lymph nodes in patients treated with sentinel node biopsy. Patients treated with sentinel node biopsy followed by axillary lymph node dissection are also registered simultaneously to compare the prognosis. The propensity score matching is used to make the distributions of baseline risk factors comparable. PMID- 25030215 TI - Acupuncture for smoking cessation: where now? PMID- 25030216 TI - Nesting doctoral students in collaborative North-South partnerships for health systems research. AB - BACKGROUND: The European Union (EU) supports North-South Partnerships and collaborative research projects through its Framework Programmes and Horizon 2020. There is limited research on how such projects can be harnessed to provide a structured platform for doctoral level studies as a way of strengthening health system research capacity in sub-Saharan Africa (SSA). OBJECTIVE: The aim of this study was to explore the challenges of, and facilitating factors for, 'nesting' doctoral students in North-South collaborative research projects. The term nesting refers to the embedding of the processes of recruiting, supervising, and coordinating doctoral students in the overall research plan and processes. DESIGN: This cross-sectional qualitative study was undertaken by the EU-funded QUALMAT Project. A questionnaire was implemented with doctoral students, supervisors, and country principal investigators (PIs), and content analysis was undertaken. RESULTS: Completed questionnaires were received from nine doctoral students, six supervisors, and three country PIs (86% responses rate). The doctoral students from SSA described high expectations about the input they would receive (administrative support, equipment, training, supervision). This contrasted with the expectations of the supervisors for proactivity and self management on the part of the students. The rationale for candidate selection, and understandings of the purpose of the doctoral students in the project were areas of considerable divergence. There were some challenges associated with the use of the country PIs as co-supervisors. Doctoral student progress was at times impeded by delays in the release of funding instalments from the EU. The paper provides a checklist of essential requirements and a set of recommendations for effective nesting of doctoral students in joint North-South projects. CONCLUSION: There are considerable challenges to the effective nesting of doctoral students within major collaborative research projects. However, ways can be found to overcome them. The nesting process ultimately helped the institutions involved in this example to take better advantage of the opportunities that collaborative projects offer to foster North-South partnerships as a contribution to the strengthening of local research capacity. PMID- 25030217 TI - Parallel p-n junctions across nanowires by one-step ex situ doping. AB - The bottom-up synthesis of nanoscale building blocks is a versatile approach for the formation of a vast array of materials with controlled structures and compositions. This approach is one of the main driving forces for the immense progress in materials science and nanotechnology witnessed over the past few decades. Despite the overwhelming advances in the bottom-up synthesis of nanoscale building blocks and the fine control of accessible compositions and structures, certain aspects are still lacking. In particular, the transformation of symmetric nanostructures to asymmetric nanostructures by highly controlled processes while preserving the modified structural orientation still poses a significant challenge. We present a one-step ex situ doping process for the transformation of undoped silicon nanowires (i-Si NWs) to p-type/n-type (p-n) parallel p-n junction configuration across NWs. The vertical p-n junctions were measured by scanning tunneling microscopy (STM) in concert with scanning tunneling spectroscopy (STS), termed STM/S, to obtain the spatial electronic properties of the junction formed across the NWs. Additionally, the parallel p-n junction configuration was characterized by off-axis electron holography in a transmission electron microscope to provide an independent verification of junction formation. The doping process was simulated to elucidate the doping mechanisms involved in the one-step p-i-n junction formation. PMID- 25030218 TI - Simultaneous SERS detection and imaging of two biomarkers on the cancer cell surface by self-assembly of branched DNA-gold nanoaggregates. AB - A surface-enhanced Raman scattering (SERS) method has been proposed for simultaneous detection and imaging of two biomarkers on the surface of a single human breast cancer cell (MCF-7) by self-assembly of branched DNA-gold nanoaggregates. PMID- 25030219 TI - MR and CT imaging of pulmonary valved conduits in children and adolescents: normal appearance and complications. AB - BACKGROUND: The Contegra(r) is a conduit made from the bovine jugular vein and then interposed between the right ventricle and the pulmonary artery. It is used for cardiac malformations in the reconstruction of right ventricular outflow tract. OBJECTIVE: To describe both normal and pathological appearances of the Contegra(r) in radiological imaging, to describe imaging of complications and to define the role of CT and MRI in postoperative follow-up. MATERIALS AND METHODS: Forty-three examinations of 24 patients (17 boys and 7 girls; mean age: 10.8 years old) with Contegra(r) conduits were reviewed. Anatomical description and measurements of the conduits were performed. Pathological items examined included stenosis, dilatation, plicature or twist, thrombus or vegetations, calcifications and valvular regurgitation. Findings were correlated to the echographic gradient through the conduit when available. RESULTS: CT and MR work-up showed Contegra(r) stenosis (n = 12), dilatation (n = 9) and plicature or twist (n = 7). CT displayed thrombus or vegetations in the Contegra(r) in three clinically infected patients. Calcifications of the conduit were present at CT in 12 patients and valvular regurgitation in three patients. The comparison between CT and/or MR results showed a good correlation between the echographic gradient and the presence of stenosis in the Contegra(r). CONCLUSION: CT and MR bring additional information about permeability and postoperative anatomy especially when echocardiography is inconclusive. Both techniques depict the normal appearance of the conduit, and allow comparison and precise evaluation of changes in the postoperative follow-up. PMID- 25030220 TI - Exposure of the French paediatric population to ionising radiation from diagnostic medical procedures in 2010. AB - BACKGROUND: Medical examination is the main source of artificial radiation exposure. Because children present an increased sensitivity to ionising radiation, radiology practices at a national level in paediatrics should be monitored. OBJECTIVE: This study describes the ionising radiation exposure from diagnostic medical examinations of the French paediatric population in 2010. MATERIALS AND METHODS: Data on frequency of examinations were provided by the French National Health Insurance through a representative sample including 107,627 children ages 0-15 years. Effective doses for each type of procedure were obtained from the published French literature. Median and mean effective doses were calculated for the studied population. RESULTS: About a third of the children were exposed to at least one examination using ionising radiation in 2010. Conventional radiology, dental exams, CT scans and nuclear medicine and interventional radiology represent respectively 55.3%, 42.3%, 2.1% and 0.3% of the procedures. Children 10-15 years old and babies from birth to 1 year are the most exposed populations, with respectively 1,098 and 734 examinations per 1,000 children per year. Before 1 year of age, chest and pelvis radiographs are the most common imaging tests, 54% and 32%, respectively. Only 1% of the studied population is exposed to CT scan, with 62% of these children exposed to a head and-neck procedure. The annual median and mean effective doses were respectively 0.03 mSv and 0.7 mSv for the exposed children. CONCLUSION: This study gives updated reference data on French paediatric exposure to medical ionising radiation that can be used for public health or epidemiological purposes. Paediatric diagnostic use appears much lower than that of the whole French population as estimated in a previous study. PMID- 25030221 TI - Half-dose abdominal CT with sinogram-affirmed iterative reconstruction technique in children - comparison with full-dose CT with filtered back projection. AB - BACKGROUND: Iterative reconstruction can be helpful to reduce radiation dose while maintaining image quality. However, this technique has not been fully evaluated in children during abdominal CT. OBJECTIVE: To compare objective and subjective image quality between half-dose images reconstructed with iterative reconstruction at iteration strength levels 1 to 5 (half-S1 to half-S5 studies) and full-dose images reconstructed with filtered back projection (full studies) in pediatric abdominal CT. MATERIALS AND METHODS: Twenty-one children (M:F = 13:8; mean age 8.2 +/- 5.7 years) underwent dual-source abdominal CT (mean effective dose 4.8 +/- 2.1 mSv). The objective image quality was evaluated as noise. Subjective image quality analysis was performed comparing each half study to the full study for noise, sharpness, artifact and diagnostic acceptability. RESULTS: Both objective and subjective image noise decreased with increasing iteration strength. Half-S4 and -S5 studies showed objective image noise similar to or lower than that of full studies. The half-S2 and -S3 studies produced the greatest sharpness and the half-S5 studies were the worst from a blocky appearance. Full and half studies did not differ in artifacts. Half-S3 studies showed the best diagnostic acceptability. CONCLUSION: Half-S4 and -S5 studies objectively and half-S3 studies subjectively showed comparable image quality to full studies in pediatric abdominal CT. PMID- 25030223 TI - Comparisons of serum vitamin D levels, status, and determinants in populations with and without chronic kidney disease not requiring renal dialysis: a 24-hour urine collection population-based study. AB - OBJECTIVE: Vitamin D deficiency is frequent in the general population and might be even more prevalent among populations with kidney failure. We compared serum vitamin D levels, vitamin D insufficiency/deficiency status, and vitamin D level determinants in populations without chronic kidney disease (CKD) and with CKD not requiring renal dialysis. DESIGN AND METHODS: This was a cross-sectional, multicenter, population-based study conducted from 2010 to 2011. Participants were from 10 centers that represent the geographical and cultural diversity of the Swiss adult population (>=15 years old). INTERVENTION: CKD was defined using estimated glomerular filtration rate and 24-hour albuminuria. Serum vitamin D was measured by liquid chromatography-tandem mass spectrometry. Statistical procedures adapted for survey data were used. MAIN OUTCOME MEASURE: We compared 25-hydroxy-vitamin D (25(OH)D) levels and the prevalence of vitamin D insufficiency/deficiency (serum 25(OH)D < 30 ng/mL) in participants with and without CKD. We tested the interaction of CKD status with 6 a priori defined attributes (age, sex, body mass index, walking activity, serum albumin-corrected calcium, and altitude) on serum vitamin D level or insufficiency/deficiency status taking into account potential confounders. RESULTS: Overall, 11.8% (135 of 1,145) participants had CKD. The 25(OH)D adjusted means (95% confidence interval [CI]) were 23.1 (22.6-23.7) and 23.5 (21.7-25.3) ng/mL in participants without and with CKD, respectively (P = .70). Vitamin D insufficiency or deficiency was frequent among participants without and with CKD (75.3% [95% CI 69.3-81.5] and 69.1 [95% CI 53.9-86.1], P = .054). CKD status did not interact with major determinants of vitamin D, including age, sex, BMI, walking minutes, serum albumin-corrected calcium, or altitude for its effect on vitamin D status or levels. CONCLUSION: Vitamin D concentration and insufficiency/deficiency status are similar in people with or without CKD not requiring renal dialysis. PMID- 25030224 TI - Suture anchor repair of proximal rectus femoris avulsions in elite football players. AB - PURPOSE: To report the results of suture anchor repair of proximal rectus femoris avulsions in elite football players. METHODS: Four professional football players (first-team regulars of European first division football clubs) underwent suture anchor repair of complete proximal rectus femoris avulsions with significant tendon retraction. The following parameters were analysed: demographic data, mechanism of injury, type of injury, classification according to the Munich consensus statement, time between injury and surgery, time between surgery and full participation in training and availability for match and/or competition selection (return to play/RTP), and time between surgery and the comeback to the first official league match (return to competition/RTC). Radiographic evaluation was performed by magnetic resonance imaging (MRI) obtained pre-operatively and at 6 and 12 weeks post-operatively. All players were followed for at least 24 months after return to play to exclude recurrence. RESULTS: Mean age at surgery was 30 +/- 2 years. All injuries occurred while kicking a ball, with the dominant leg affected in all patients. The injury was considered acute in three cases and chronic in one case. According to the Munich classification, all injures were type 4. Mean time to surgery was 60 +/- 88 days (range, 8-191), mean time to RTP was 111 +/- 15 days (range, 100-134), and mean time to RTC was 140 +/- 23 days (range, 114-166). Follow-up MRIs demonstrated anatomically reinserted tendons with decreasing signal intensity over time in all cases. After a mean follow-up of 35 +/- 6 months, all players were still competing at the same level as before the injury without re-injury. CONCLUSION: Suture anchor repair of proximal rectus femoris avulsions allows unrestricted return to play in professional elite football players. Return to play can be expected at approximately 16 weeks post operatively. PMID- 25030225 TI - Ectopic expression of CaRLK1 enhances hypoxia tolerance with increasing alanine production in Nicotiana spp. AB - In a previous report, the pepper receptor-like kinase 1 (CaRLK1) gene was shown to be responsible for negatively regulating plant cell death caused by pathogens via accumulation of superoxide anions. Here, we examined whether this gene also plays a role in regulating cell death under abiotic stress. The total concentrations of free amino acids in CaRLK1-overexpressed cells (RLKox) increased by twofold compared with those of the wild-type Nicotiana tabacum BY-2 cells. Additionally, alanine and pyruvate concentrations increased by approximately threefold. These accumulations were associated with both the expression levels of the isocitrate lyase (ICL) and malate synthase genes and their specific activities, which were preferentially up-regulated in the RLKox cells. The expression levels of ethylene biosynthetic genes (ACC synthase and ACC oxidase) were suppressed, but those of both the metallothionein and lesion simulating disease 1 genes increased in the RLKox cells during submergence induced hypoxia. The specific activity of catalase, which is involved in protecting ICL from reactive oxygen species, was also induced threefold in the RLKox cells. The primary roots of the transgenic plants that were exposed to hypoxic conditions grew at similar rates to those in normal conditions. We propose that CaRLK1 maintains a persistent hypoxia-resistant phenotype. PMID- 25030227 TI - Causal model structure analysis of emotional unrest in first time mothers faced with persistent infant crying 6-7 weeks postpartum. AB - First time mothers faced with a continuously crying infant, who do not know how to stop their child from crying, are at risk of developing anxiety and other types of Emotional Unrest. Because continuous Emotional Unrest may lead to an emotional crisis, it is important for healthcare providers to understand causal factors associated with Emotional Unrest among first time mothers faced with a persistently crying infant 6-7 weeks postpartum. METHODS: A cross-sectional survey was carried out on a study population of 217 first time mothers with infants aged 6-7 weeks. A self-administered questionnaire was used to measure Emotional Unrest, Neigh- borhood Social Organization, Effective Parenting Support, Understanding of Crying and the Effect of Infor- mation Available on Crying, Current Parenting Environment and Characteristics of the Mother and Child. Potential causal factors for Emotional Unrest were explored using structural equation modeling. RESULTS: One hundred and thirty two (60.8%) of the mothers experienced persistent crying in the period 6-7 weeks after the birth of their child and 108 (49.7%) mothers experienced Emotional Unrest. Factor analysis revealed five important constructs to be causal factors of Emotional Unrest: Effective Parenting Support, Effective Assistance with Regard to Crying, Confused by Information, Neighborhood Social Organi- zation and Feelings of Fatigue and Anxiety. Structural equation modeling indicated that Effective Parenting Support, Effective Assistance with Regard to Crying, Confused by Information and Neighborhood Social Organization affect Feelings of Fatigue and Anxiety, which then leads to Emotional Unrest. CONCLUSION: This study demonstrated that it will be necessary in future for health-care workers to pro- vide early intervention, such as accurate information about crying as well as concrete and appropriate response measures for dealing with crying. Furthermore, in motherhood/parenting classes and the dis- charge guidance conducted at birthing centers, it will be necessary to provide guidance on what kind of effective support and local area resources are available to parents following the birth of their child. [Asian Nursing Research 2009;3(1):1-14]. PMID- 25030226 TI - Dominance of Methanosarcinales phylotypes and depth-wise distribution of methanogenic community in fresh water sediments of Sitka stream from Czech Republic. AB - The variation in the diversity of methanogens in sediment depths from Sitka stream was studied by constructing a 16S rRNA gene library using methanogen specific primers and a denaturing gradient gel electrophoresis (DGGE)-based approach. A total of nine different phylotypes from the 16S rRNA library were obtained, and all of them were clustered within the order Methanosarcinales. These nine phylotypes likely represent nine new species and at least 5-6 new genera. Similarly, DGGE analysis revealed an increase in the diversity of methanogens with an increase in sediment depth. These results suggest that Methanosarcinales phylotypes might be the dominant methanogens in the sediment from Sitka stream, and the diversity of methanogens increases as the depth increases. Results of the present study will help in making effective strategies to monitor the dominant methanogen phylotypes and methane emissions in the environment. PMID- 25030228 TI - Mediating effects of self-efficacy in the transtheoretical model among adolescent male smokers in Korea. AB - PURPOSE: This study examined the moderating and mediating effects of self efficacy on the relationships between predictor variables (decisional balance and processes of change) and the outcome variable (stages of change) using the Transtheoretical Model. DESIGN: Cross-sectional data were collected from 147 current and former smokers at three vocational technical high schools in Korean metropolitan areas. METHODS: The survey instruments included decisional balance, self-efficacy, processes of change (behavioral and experiential), and stages of change. Regression analyses were used to identify the mediating effects of self efficacy. RESULTS: Self-efficacy mediated the relationships of decisional balance and behavioral processes with stages of change, but not that of experiential processes with stages of change. CONCLUSIONS: The study results will provide valuable information regarding how each predictor variable is connected and path through adoption of smoking cessation behavior. By understanding mechanisms of behavior change, health professionals could develop effective smoking cessation interventions with consideration of roles of self-efficacy in the smoking cessation behavior change. [Asian Nursing Research2009;3(1):15-23]. PMID- 25030229 TI - Evaluation of a home-based hospice and palliative care program in a community health center in Korea. AB - PURPOSE: To evaluate the effects of a home-based palliative care program, delivered by a community health center in Korea, in terms of quality of life and health care utilization. METHODS: A cross-sectional comparative study was utilized. Data were collected from 30 terminally ill cancer patients who had received palliative care from the community health center and 46 terminally ill cancer patients not receiving palliative care from the center. The measurements used in the study were a Revised Korean version of Quality of Life at the End of Life survey, self-reports on days of hospital admission and the frequency of outpatient care and ER visits during the past 6 months. RESULTS: The palliative care group had a higher quality of life only in a physical aspect. The palliative care group had a lower frequency of outpatient visits and ER visits in the last 6 months than the nonpalliative group, but no significant statistical differences were found. CONCLUSIONS: A home-based palliative service program delivered by the community health center appears to be an appropriate care model for managing physical symptoms. Reinforcing services for psychosocial and spiritual counseling and encouraging affiliation with free-standing inpatient healthcare providers are warranted. [Asian Nursing Research 2009;3(1):24-30]. PMID- 25030230 TI - BMI and Breast Cancer in Korean Women: A Meta-Analysis. AB - INTRODUCTION: The number of breast cancer women has increased dramatically in Korea. The cause is perceived to stem from adaptation to a westernized life style which increases body mass index (BMI). However, there are no meta-analysis data available that could help in understanding the relationship between Korean females' BMI and breast cancer occurrence. METHOD: All the published articles that investigated the relationship of Korean women's BMI with breast cancer prevalence between 1950 and 2007 were included in this study, based on a screen of the comput- erized databases that search for these articles (MEDLINE, RISS4U and KMBase). The commercial software Comprehensive Meta Analysis was used for the analysis. RESULTS: The high BMI score group presented a higher prevalence of breast cancer on both a fixed-effects model [odds ratio (OR) = 1.282; 95% confidence interval (CI) = 1.209, 1.361] and a random-effects model (OR = 1.388; 95% CI = 1.129, 1.706). In addition, a high BMI score on pre- and postmenopausal groups was found to have a significantly higher prevalence of breast cancer on both a fixed-effects model (OR = 1.467; 95% CI = 1.268, 1.698, OR = 1.614; 95% CI = 1.360, 1.917, pre- and postmenopausal, respectively) and a random-effects model (OR = 1.387; 95% CI = 1.134, 1.696, OR = 1.681; 95% CI = 1.149, 2.461, pre- and postmenopausal, respectively). CONCLUSION: This meta-analysis of Korean women showed that a high BMI was related to a higher inci- dence rate of breast cancer. This study used a subgroup analysis of pre- and postmenopausal groups; the high BMI subset in both the pre- and postmenopausal groups was shown to have a higher incidence rate of breast cancer. [Asian Nursing Research 2009;3(1):31-40]. PMID- 25030231 TI - Touch-Screen Computerized Quality-of-Life Assessment for Patients with Cancer. AB - PURPOSE: To evaluate a computerized self-reported, touch-screen version of the cancer-specific quality-of- life (cC-QOL) questionnaire against the traditional paper-and-pencil version (the pC-QOL) for equivalence, time for completion, user preference and ease of use. METHODS: One hundred and five patients were recruited from a cancer center of a university hospital in South Korea. A randomized crossover design was used, with patients randomly assigned into two groups. Group A patients completed the cC-QOL first while waiting to see a physician, and completed the pC-QOL version of the questionnaire after seeing the physician. Group B patients completed these questionnaires in the reverse order. Subjects were asked about user preference and ease of use. Time taken to complete both versions was measured. RESULTS: Weighted kappa coefficients of items showed very good to moderate agreement. The time required to complete the cC-QOL did not differ statistically from the pC-QOL. The same proportion of patients preferred both versions. Most patients (94.8%) reported that the cC-QOL was "easy" or "very easy" to complete. CONCLUSION: The cC-QOL is the computerized equivalent of the pC-QOL, which is used to assess the health-related quality of life (HRQOL) of cancer patients. The cC-QOL can be helpful to oncology nurses and physicians for assessing, collecting, and evaluating their patients' HRQOL scores in busy clinical practices. [Asian Nursing Research 2009;3(1):41-48]. PMID- 25030232 TI - [Gender medicine. Sex- and gender-specific aspects of clinical medicine]. AB - Gender medicine studies sex- and gender-based differences in the development and prevention of diseases, the awareness and presentation of symptoms, and the effectiveness of therapy. Gender medicine is part of personalized medicine, considering differences in biological and psychosocial factors individually. There are differences in genes, chromosomes, hormones, and metabolism as well as differences in culture, environment, and society. Lifelong interactions between physical and psychosocial factors will influence the health and ill-health of men and women in different ways. Epigenetic modifications provide evidence of the impact of environment and lifestyle during vulnerable phases on biological processes, effecting future generations. Maternal lifestyle and environmental factors during pregnancy can impact the health of offspring in later life already in utero in a sex-specific way. Pain, stress, and coping styles differ between men and women. Women experience more dramatic physical changes during their lifetime, which are associated with specific burdens and psychosocial alterations. Women with multiple roles and responsibilities suffering from stress develop depression more frequently. However, men are often not diagnosed and treated appropriately in cases of depression or osteoporosis, diseases that are typically considered "female." There are prominent differences between men and women in medicine regarding the immune system, inflammation, and noncommunicable diseases such as obesity, type 2 diabetes, hypertension, and cardiovascular disease. Women experience more often autoimmune diseases and suffer more frequently from (chronic) pain, neurodegenerative changes, and functional disabilities. Men have shorter life expectancy but relatively more healthy years of life, which is in greater part ascribed to psychosocial determinants. State-of the-art clinical medicine comprises individual risk factors based on sex- and gender-sensitive health programs in order to improve the health-related quality of life for men and women. PMID- 25030233 TI - [Sex and gender differences in pharmacotherapy]. AB - Many drugs have act differently in women and men. Biological differences between women and men lead to sex differences in pharmacokinetics, i.e., in drug absorption, distribution in tissues, metabolism by liver enzymes, and excretion via the kidney and intestine. In addition there are sex differences in pharmacodynamics, leading to a different efficacy of drugs in women and men. The biological differences between women and men may be caused by sex-specific gene expression, by sex-specific epigenetic modifications, and finally by the effect of sex hormones. In addition, gender plays a role in drug efficacy as a sociocultural dimension that may lead to differences between women and men. Frequently drugs are only tested on animals of one sex and thereby optimized for one sex. This is based on the notion that sex differences are not important for clinical drug effects. Furthermore, to date, sex and gender differences have been underestimated in clinical studies, and phase III studies were not prospectively designed to assess sex differences in drug effects. In addition, women and men use drugs differently with respect to compliance, adherence, and self-medication with over-the-counter drugs. Further, it is known that male and female physicians treat women and men as patients differently. In conclusion, drug therapy is not yet optimized for both genders. However, there is increasing awareness that differences between women and men should be respected in order to provide optimal drugs in optimal doses for both genders. PMID- 25030234 TI - Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease. AB - BACKGROUND: Neks, mammalian orthologs of the fungal protein kinase never-in mitosis A, have been implicated in the pathogenesis of polycystic kidney disease. Among them, Nek1 is the primary protein inactivated in kat2J mouse models of PKD. RESULT: We report the expression pattern of Nek1 and characterize the renal cysts that develop in kat2J mice. Nek1 is detectable in all murine tissues but its expression in wild type and kat2J heterozygous kidneys decrease as the kidneys mature, especially in tubular epithelial cells. In the embryonic kidney, Nek1 expression is most prominent in cells that will become podocytes and proximal tubules. Kidney development in kat2J homozygous mice is aberrant early, before the appearance of gross cysts: developing cortical zones are thin, populated by immature glomeruli, and characterized by excessive apoptosis of several cell types. Cysts in kat2J homozygous mice form postnatally in Bowman's space as well as different tubular subtypes. Late in life, kat2J heterozygous mice form renal cysts and the cells lining these cysts lack staining for Nek1. The primary cilia of cells lining cysts in kat2J homozygous mice are morphologically diverse: in some cells they are unusually long and in others there are multiple cilia of varying lengths. CONCLUSION: Our studies indicate that Nek1 deficiency leads to disordered kidney maturation, and cysts throughout the nephron. PMID- 25030235 TI - High-frequency electric welding: a novel method for improved immediate chorioretinal adhesion in vitreoretinal surgery. AB - PURPOSE: To evaluate high-frequency electric welding (HFEW) as a novel technique for retinopexy with improved immediate chorioretinal adhesion METHODS: In a prospective, randomized, experimental study, we examined 104 eyes of 52 rabbits randomly assigned to either standard 810 nm endolaser retinopexy, alternating current 14-16 V or 18-20 V HFEW retinopexy. A full-thickness fragment of eye wall tissue containing the retinopexy was isolated 1 h, 3 days, 1 week, or 1 month respectively after the intervention, and fixed to an analytical electronic scale. A nylon suture passed through the retina was elevated by a biomechanical force elongation tester. The reduction in weight at the time of retinopexy rupture was registered as a measure for retinopexy adhesion strength. RESULTS: One hour post exposure, adhesive strengths were significantly higher in both HFEW groups than in controls (212 +/- 26.6 mg and 122 +/- 16 mg vs 104 +/- 10 mg; p = 0.0001 and p = 0.024 respectively) while laser retinopexy did not significantly change adhesive strength (114 +/- 14.0 mg, p = 0.149). Subsequent adhesive strengths were significantly increased for all retinopexy techniques: 3 days post-op 14-16 V HFEW 224 +/- 30.0 mg (p = 0.001), 18-20 V HFEW 128 +/- 15.6 (p = 0.001), laser 131 +/- 12.7 mg (p = 0.0007); at 1 week 14-16 HFEW 235 +/- 24.7 mg, 18-20 V HFEW 213 +/- 22.4 mg, laser 188 +/- 18.7 mg (all p <= 0.001); 1 month post-op 14-16 V HFEW 275 +/- 32.0 mg, 18-20 V HFEW 283 +/- 31.0 mg, laser 276 +/- 21.7 mg, rspectively (all p <= 0.0001). CONCLUSION: HFEW represents a novel technique for retinopexy during vitreoretinal surgery. It allows firm chorioretinal adhesion immediately after exposure. In non-vitrectomized eyes, using 14-16 V is particularly effective. PMID- 25030236 TI - Inner and outer central retinal findings after surgery for rhegmatogenous retinal detachment using different spectral-domain optical coherence tomography devices. AB - PURPOSE: The aim of the study was to analyse macular changes after rhegmatogenous retinal detachment (RRD) repair using spectral-domain optical coherence tomography (SD-OCT). METHODS: Forty eyes with macula-on and 27 eyes with macula off RRD underwent scleral buckling or vitrectomy and were postoperatively imaged using 2 SD-OCT devices (Cirrus(r) HD-OCT, RTVue-100(r)). Measurement of total and inner macular thickness consisting of ganglion cell layer + inner plexiform layer (GCL-IPL) using Cirrus or retinal nerve fibre layer + ganglion cell layer + inner plexiform layer (RNFL-GCL-IPL) using RTVue was performed. Results of inner macular thickness were compared with image results of 40 healthy controls. Qualitative analysis of inner and outer retinal layers was additionally assessed. RESULTS: Measurement of overall retinal thickness within the 9 ETDRS sectors was highly correlated between both OCTs (Pearson's r, range 0.88-0.99; p < 0.001). Correlation of RNFL-GCL-IPL complex between OCTs was excellent in both surgery groups (Pearson's r, range 0.73-0.88; p < 0.001) and normal controls (Pearson's r, range 0.79-0.90; p < 0.001). The RNFL-GCL-IPL complex was thicker in both surgery groups compared to normal controls using Cirrus. Outer retinal findings of macula-off patients were seen in four eyes (14.8 %). Visual acuity (VA) significantly improved in both groups independent of preoperative VA or duration of symptoms. CONCLUSION: Agreement between both OCTs was excellent for overall and inner retinal thickness, although RTVue measured a thicker RNFL-GCL-IPL complex. Thinning of inner retinal layers as a potential cause of poor VA was rarely detected, possibly due to tractional changes at the vitreomacular interface. VA improved even in patients with macula-involving RRD. PMID- 25030237 TI - Evaluation of plasma vascular endothelial growth factor levels after intravitreal injection of ranibizumab and aflibercept for exudative age-related macular degeneration. AB - BACKGROUND: To evaluate the plasma vascular endothelial growth factor (VEGF) levels after one intravitreal injection of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). METHODS: Twenty-four Japanese with exudative AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation were included. Fourteen patients received an intravitreal injection of aflibercept, and ten patients received an intravitreal injection of ranibizumab. Plasma VEGF levels were evaluated within 7 days before the intravitreal injections and 1 day, 1 week, and 1 month after the intravitreal injection. RESULTS: In the ranibizumab group, the mean plasma VEGF levels were 245.7 +/- 233.4 pg/ml before the injection, 246.6 +/- 304.8 pg/ml after 1 day, 217.8 +/- 212.9 pg/ml after 1 week, and 260.0 +/- 290.1 pg/ml after 1 month. The plasma VEGF levels did not decrease significantly in patients in the ranibizumab group at any time point. In the aflibercept group, the mean plasma VEGF levels were 280.0 +/- 170.3 pg/ml before the intravitreal injection and 8.2 +/- 12.9 pg/ml after 1 day, 9.1 +/- 9.1 pg/ml after 1 week, and 41.9 +/- 41.4 pg/ml after 1 month (p < 0.0001, vs before injection). CONCLUSION: Intravitreally injected aflibercept reduced plasma VEGF over at least 1 month. In contrast, intravitreal injection of ranibizumab did not cause a significant reduction in the plasma VEGF levels. PMID- 25030238 TI - Can we trust intraocular pressure measurements in eyes with intracameral air? AB - PURPOSE: To evaluate the effect of intracameral air on intraocular pressure (IOP) measurements using Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) in an in-vitro porcine eye model. METHODS: IOP was measured on thirteen freshly enucleated eyes at three reference pressures: 20, 30, and 40 mmHg. Six measurements/method were performed in a standardized order with GAT and ART respectively. Air was injected intracamerally in the same manner as during Descemet's stripping endothelial keratoplasty (DSEK) and Descemet's membrane endothelial keratoplasty (DMEK), and the measurements were repeated. RESULTS: Measured IOP increased significantly for both tonometry methods after air injection: 0.7 +/- 2.1 mmHg for GAT and 10.6 +/- 4.9 mmHg for ART. This difference was significant at each reference pressure for ART but not for GAT. CONCLUSIONS: Although slightly affected, this study suggests that we can trust GAT IOP-measurements in eyes with intracameral air, such as after DSEK/DMEK operations. Ultrasound-based methods such as ART should not be used. PMID- 25030239 TI - Measurement of retinal function with flash-electroretinography in Chinese patients with hyperlipidemia. AB - BACKGROUND: We used flash electroretinography (F-ERG) to determine if retinal function was impaired in patients with hyperlipidemia, including visual acuity and fundus morphological changes, and to identify predictors of impaired retinal function in hyperlipidemia patients. METHODS: This was a prospective case-control study (Shanghai, China; February 2011 to January 2012) in 696 hyperlipidemia patients and 136 healthy controls. Exclusion criteria included best-corrected visual acuity <0.6, previous intraocular surgery, and chronic comorbidities. Each participant underwent a comprehensive series of ophthalmologic examinations, and standard F-ERG examination. Data were analyzed using t-tests and multivariate analysis. RESULTS: Six hundred and twenty-six hyperlipidemia patients (57.69 +/- 14.01 years; 59.58% female) and 120 healthy controls (55.13 +/- 14.03 years; 60% female) were included in the final analysis. After adjustment for age and gender using multivariate covariance analysis, F-ERG result revealed significantly lower response amplitudes in the hyperlipidemia group (P < 0.05), and longer implicit times (P < 0.05) than the control group. F-ERG parameters were significantly different between the two groups. Stepwise multiple linear regression analysis showed that serum LDL levels (P < 0.001), BMI (P < 0.001), duration of hyperlipidemia (P < 0.001), and serum HDL levels (P = 0.03) were negatively correlated with SigmaOps. CONCLUSION: The present study suggests that the retinal function of hyperlipidemia patients was significantly lower than in healthy controls, even before the occurrence of pathological changes in the fundus. PMID- 25030240 TI - The effect of cataract surgery on blue-yellow and standard-pattern visual-evoked potentials. AB - PURPOSE: Blue-yellow visual-evoked potentials (BY-VEPs) may be used for diagnostics of functional ganglion cell damage in glaucoma and other ocular diseases. In this study we investigated the impact of lenticular opacities on BY- and standard pattern reversal VEPs by examining patients before and after cataract surgery. METHODS: Eighteen patients with moderate cataract were included in a prospective study. Transient on/off isoluminant blue-yellow 2 degrees checks were used for short-wavelength stimulation (BY-VEP), transient large 1 degrees (M1) and small 0.25 degrees (M2) black-white checks for standard pattern reversal VEPs. VEPs were acquired before (24 +/- 30 days) and after cataract surgery (14 +/- 16 days). The contralateral eye was used as a control. RESULTS: Amplitude and latency of M1 and M2 peaks did not change significantly from before to after surgery. The amplitude of the BY-VEPs did not change significantly after cataract surgery (pre-surgery, -7.42 +/- 3.43 MUV, post surgery, -7.93 +/- 3.65 MUV, p = 0.42), yet the latency of the main negative peak showed a significant decrease (pre-surgery, 143.9 +/- 12.9 ms, post-surgery, 133.2 +/- 7.7 ms, p = 0.0006). The BCVA improvement was significant from before to after cataract surgery (pre-surgery, 0.344 +/- 0.125 LogMAR, post-surgery, 0.224 +/- 0.179 LogMAR, p = 0.013) yet not correlated to the absolute decrease in latency of the BY-VEP after surgery (r = 0.309, p = 0.22). No significant changes were found in the contralateral eye. CONCLUSIONS: The BY-VEP is sensitive to lenticular opacities of the human lens, presumably due to the increased short wavelength absorption in the aging eye. This fact should be considered when applying BY-VEPs for diagnostics. PMID- 25030242 TI - Expression of SGTA correlates with neuronal apoptosis and reactive gliosis after spinal cord injury. AB - Small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) is a novel TPR-containing protein involved in various biological processes. However, the expression and roles of SGTA in the central nervous system remain unknown. We have produced an acute spinal cord injury (SCI) model in adult rats and found that SGTA protein levels first significantly increase, reach a peak at day 3 and then gradually return to normal level at day 14 after SCI. These changes are striking in neurons, astrocytes and microglia. Additionally, colocalization of SGTA/active caspase-3 has been detected in neurons and colocalization of SGTA/proliferating cell nuclear antigen has been detected in astrocytes and microglial. In vitro, SGTA depletion by short interfering RNA inhibits astrocyte proliferation and decreases cyclinA and cyclinD1 protein levels. SGTA knockdown also reduces neuronal apoptosis. We speculate that SGTA is involved in biochemical and physiological responses after SCI. PMID- 25030241 TI - Risk factors, microbial profiles and prognosis of microbial keratitis-associated endophthalmitis in high-risk eyes. AB - BACKGROUND: Microbial keratitis (MK) is a sight-threatening emergency. Delayed diagnosis and treatment may exacerbate the condition and infection may spread to the posterior segment with resultant endophthalmitis. We describe the presentation, management, visual outcomes and microbial profiles of MK-associated endophthalmitis presenting to a tertiary referral centre. METHODS: Prospective collection of data on all patients presenting with presumed MK-associated endophthalmitis from 1997 to 2007, to the Royal Victorian Eye and Ear Hospital. Outcome measures included: visual acuity, microbial profiles, and management strategy. RESULTS: Thirty-seven cases of MK-associated endophthalmitis were identified over the study period, with a mean age of 73 years and 19 were male. Presenting acuities ranged from Snellen 2/60 to no perception of light (NPL). Thrity-four (91.9%) patients had a prior history of ocular disease. Identifiable non-ocular risk factors were present in 31 (83.8%), including steroid use, dementia, nursing home care or relative systemic immunosuppression. A culture positivity rate of 83.8% was recorded. The most common organisms identified included: Streptococcal species in 12 (32.4%), Pseudomonas aeruginosa in 11 (29.7%), and Staphylococcus aureus in eight (21.6%). Final acuities ranged from 6/36 to NPL. Sixteen (43.2%) eyes were eviscerated/enucleated as primary treatment. Overall, 23 (62.2%) patients required evisceration/enucleation, of which nine (39.1%) were due to Pseudomonas aeruginosa and seven (30.4%) to Streptococcal species (Streptococcal pneumonia). CONCLUSIONS: MK-associated endophthalmitis is a serious ocular condition occurring more frequently in elderly populations, and those with long standing severe pre-existing ocular disease. Visual outcomes are poor, often requiring evisceration/enucleation. PMID- 25030244 TI - Consumption of unsafe food in the adjacent area of Hazaribag tannery campus and Buriganga River embankments of Bangladesh: heavy metal contamination. AB - The concentrations of Cr, Cd, Pb, Hg, and As in water, poultry meat, fish, vegetables, and rice plants obtained from the area adjacent to the Hazaribag tannery campus, Dhaka, Bangladesh, were estimated and compared with permissible levels established by the WHO and FAO and levels reported previously by other authors. The metal contents were in the following order according to the concentration in contaminated irrigation water: Cr > Pb > As > Hg > Cd. Mean concentrations of Cr, Pb, Hg, and As in irrigated water were above the permissible levels, whereas the results were below the permissible levels for Cd. The metal concentrations in poultry meat, fish, rice, and vegetables were in the following orders: Pb > Cr > Cd > Hg > As, Pb > Cr > Cd > As > Hg, Pb > As, and Cr > Pb > Cd > As > Hg, respectively. The mean concentrations of metals in poultry meat, fish, rice, and vegetables were much higher than the permissible levels. The trends of weekly intake of heavy metals (WIMs) from poultry meat, fish, rice, and vegetables were as follows: Pb > Cr > Cd > Hg > As, Pb > Cr > Cd > As > Hg, Pb > As, and Cr > Pb > Cd > As > Hg, respectively. WIMs for all the metals were lower than the provisional maximum weekly intake recommended by WHO/FAO and USNAS. PMID- 25030246 TI - Long-term care nurses' communication difficulties with people living with dementia in Taiwan. AB - PURPOSE: Impairments in word finding, language skills and memory in dementia patients increase the obstacles for health professionals to provide effective care. Although some research on communication with dementia patients has been done, no research that pre-assessed nurses' difficulties in communicating with dementia patients has been identified. This study aims to explore nurses' difficulties in communicating with patients who have dementia. METHODS: This was a qualitative research using the phenomenological approach. Data were collected through in-depth interviews. Fifteen nurses with at least 6 months of dementia care experience participated in this study. Each interview was audio-taped and transcribed within 48 hours after each interview. Participants were asked to respond to the question, "Please describe the difficulties in communicating with patients who have dementia." RESULTS: Through content analysis, two themes, each with two subthemes emerged: Different language, including repetitive responses and lack of language consensus; blocked messages, including difficulty in accessing emotions and in understanding needs. Ineffective language refers to a lack of agreement dialect between the nurse and the patient while blocked messages refer to the inability of nurses to understand the true underlying meaning of messages the patients send out through verbal or nonverbal behaviors or expression. CONCLUSION: The results can serve as reference for planning dementia communication education for school curriculum to enhance student nurses' communication abilities and for junior nurses working in long-term or acute care settings to increase nurses' patient-centered communication abilities with the ultimate goal of improving quality of care for patients with dementia. PMID- 25030245 TI - Physiologically achievable doses of resveratrol enhance 3T3-L1 adipocyte differentiation. AB - PURPOSE: Resveratrol is a natural polyphenolic stilbene widely found in grapes, berries, and other plants. Caloric restriction-like effects of resveratrol have been associated with suppressive and apoptotic effects on adipocyte differentiation in vitro when used at high doses (>= 20 uM), which may not be achievable in vivo. The aim of this study was to investigate the effects of resveratrol at physiologically achievable low doses (1 and 10 MUM) on 3T3-L1 adipocyte differentiation. METHODS: 3T3-L1 preadipocytes were differentiated into adipocytes using a modified adipogenic cocktail in the presence or absence of resveratrol. Differentiation was determined by lipid accumulation and mRNA expression of marker genes. Activation of glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor gamma (PPARgamma) was determined by transcription factor-mediated reporter assays and mRNA expression of target genes. Protein samples were collected for the study of AMPK activation. RESULTS: Resveratrol at physiologically achievable doses (1 and 10 uM) significantly enhanced 3T3-L1 adipocyte differentiation although the effect was less pronounced compared with that achieved under optimal differentiation cocktail in vitro. Resveratrol (1-50 uM) dose dependently activated or synergized with the synthetic ligand or adipogenic treatment to activate GR and PPARgamma. However, resveratrol induced cell death when used at doses above 10 uM in differentiating cells. CONCLUSIONS: Our results report for the first time that resveratrol at physiologically achievable doses (1 and 10 uM) enhances 3T3-L1 adipocyte differentiation, which supports the emerging paradigm that enhanced adipocyte differentiation may be associated with caloric restriction-like metabolic effects for resveratrol. PMID- 25030247 TI - Cultural adaptation and the psychometric properties of the Korean version of the symptom management beliefs questionnaire. AB - PURPOSE: Assessment of aging-stereotyped and erroneous beliefs in managing symptoms is an essential task to enhance self-care and health outcomes of the older population. The purpose of this study was to examine the psychometric properties of the Korean version of the Symptom Management Beliefs Questionnaire (K-SMBQ) to measure ageist beliefs in managing symptoms of older people. METHODS: A convenience sample of 211 community-dwelling older women was used. The 12-item K-SMBQ was finalized after translation, synthesis, back-translation, content validity, and pilot testing. The psychometric properties of the K-SMBQ scale were examined by exploratory and confirmatory factor analyses, convergent validity, hypothesized relationship testing, and known-groups method, as well as internal consistency and test-retest reliability. RESULTS: Three factors (i.e., Aging Stereotypes, Pessimistic Expectations, and Good Patient's Attitudes) were extracted by exploratory factor analysis and the good fit of the three-factor structure was demonstrated by confirmatory factor analysis. Construct validity was supported by significant correlations with conceptually and theoretically relevant concepts as well as by distinguishable features between three older age groups. The internal consistency was supported by Cronbach's alpha coefficient, item-total scale correlations, and inter-item correlations; thus, adequate test retest reliability was demonstrated. CONCLUSION: This study verified the psychometric properties of the K-SMBQ and provided evidence on the cultural relevance for the concept of ageist beliefs regarding symptom management in older Korean people. The development of nursing interventions to promote self-care of older people should be based on the consideration of negatively stereotyped and erroneous beliefs about health in old age. PMID- 25030248 TI - Structural equation modeling on life-world integration in people with severe burns. AB - PURPOSE: The aim of this study was to construct and test a structural equation modeling on life-world integration in people with severe burns. METHODS: A survey design was used. Data were collected in 2008 from 376 people who had experienced severe burns using questionnaires. The data were analyzed using structural equation modeling. RESULTS: The fitness parameters of the modified model (chi(2)/df = 3.15, goodness of fit: .91, normal fit index: .93, Tucker Lewis Index: .93, root mean square error of approximation: .07, root mean square residual: .04, and comparative fit index: .95) indicated its suitability as the research model. Physical function directly influenced burn factor, and family support indirectly influenced life-world integration. CONCLUSION: Physical function should be directly improved to adjust to life-world integration. A comprehensive integration approach is also necessary to help people with severe burns successfully return to society. PMID- 25030249 TI - Posture management program based on theory of planned behavior for adolescents with mild idiopathic scoliosis. AB - PURPOSE: The purpose of this study was to evaluate the effects of a devised posture management program based on the Theory of Planned Behavior in adolescents with mild idiopathic scoliosis. METHODS: A quasi-experimental study was conducted. It involved a nonequivalent comparison group design with pretest and posttest. Forty-four female adolescents with mild idiopathic scoliosis participated; data from 35 participants (20 for the test group, 15 for the control group) were used for the final analyses. The devised posture management program ran for 6 weeks. Posture management behavioral determinants (attitude, subjective norms, perceived behavioral control, and behavioral intention) as cognitive outcomes and muscular strength and flexibility as physical outcomes were measured three times: at baseline, week 6 and week 8. Cobb's angle as another physical outcome was measured twice: at baseline and week 8. Descriptive analysis, repeated measures analysis of variance and t test were used for data analyses. RESULTS: Attitude, perceived control, and behavioral intention were consistently enhanced by the posture management program. The intervention increased flexibility and muscular strength and decreased Cobb's angle, which reduced spinal curvature. Frequency of posture management exercise showed a gradual increase in the test group. CONCLUSION: The results indicate that the posture management program is effective in maintaining posture management behavior in adolescents with mild idiopathic scoliosis for both cognitive and physical outcomes. The posture management program should be helpful in expanding the role of school nurses in improving the health status of adolescents with mild idiopathic scoliosis. PMID- 25030250 TI - Application of revised nursing work index to hospital nurses of South Korea. AB - PURPOSE: Based on the Revised Nursing Work Index (NWI-R), this research aimed to develop a Korean Hospital General Inpatient Unit-Nursing Work Index (KGU-NWI). This study also aimed to compare the common points and differences between the subfactors of the KGU-NWI and the subfactors from previous studies. METHODS: Based on opinions from 3,151 nurses in Korean hospital general inpatient unit, this research used 57 items of NWI-R and the principal axis factor analysis for deriving subfactors. We evaluated the convergent validity through factor analysis and the content validity of KGU-NWI in terms of the association between nurses' job outcome and the subfactors derived. RESULTS: Six subfactors and 26 items for KGU-NWI were derived from NWI-R. Among them, 'physician-nurse relationship', 'adequate nurse staffing' and 'organizational support and management of hospital' were the same with results from previous studies. In addition, two subfactors, 'participation of decision-making processes' and 'education for improving quality of care', which were similar with results from previous Korean studies, were newly added by using Korean hospital cases. In contrast to previous Korean studies, a unique subfactor this study found was 'nursing processes'. This research confirmed that the six subfactors were highly correlated with job satisfaction, intention to leave, and quality of health care, which represented a nurse's job outcome. CONCLUSION: KGU-NWI including six subfactors and 26 items is an applicable instrument to investigate nurse work environment in Korean hospital general inpatient unit. PMID- 25030251 TI - Factors influencing post-traumatic stress in Korean forensic science investigators. AB - PURPOSE: The aim of this study was to understand factors that influence post traumatic stress (PTS) in Korean forensic science investigators. METHODS: A total of 111 forensic science investigators were recruited in Korea. PTS was measured using the tool modified by Choi (2001) from the original developed by Foa, Riggs, Dancu, and Rothbaum (1993) based on DSM-IV. Factors influencing PTS included demographic and job-related characteristics, emotional intelligence, and death anxiety. RESULTS: PTS scores were positively correlated with personality type, fatigue from work, and death anxiety. PTS scores were negatively correlated with length of career as a forensic science investigator and emotional intelligence. The factors that had the greatest influence on PTS were death anxiety, years spent as a forensic science investigator, personality type, emotional intelligence, fatigue, and homicide experience. The explanatory power of these six factors was 44.0%. CONCLUSION: Therefore, it is necessary to regularly evaluate the mental health of those who are vulnerable to PTS. Based on these results, various interventions could be implemented for promoting overall health of the forensic science investigators. PMID- 25030252 TI - Validity and reliability of Korean version of health empowerment scale (K-HES) for older adults. AB - PURPOSE: The purpose of this study was to assess the validity and reliability of the Korean version of the Health Empowerment Scale (K-HES). METHODS: This was a methodological study, which included translation, pilot study, main study and expert verification. The K-HES was translated and modified based on the Diabetes Empowerment Scale-Short Form. Where diabetes was mentioned in the original tool, the K-HES expanded the items to cover all kinds of health conditions that affected health empowerment. Expert-verification, pilot-test and main study were conducted among 175 Korean elderly. RESULTS: The K-HES had an acceptable internal consistency with a Cronbach's alpha of .80. Construct validity was tested using item analysis and convergent validity. Item analysis demonstrated that all of the corrected item to total correlation coefficients possessed good internal consistency (alpha > .60) except for item 1 (.32) and item 6 (.19). Convergent validity was supported by significant correlations between the total scores of the K-HES and the Exercise Self-Efficacy Scale (Pearson's coefficient = .60). Content validity was supported by scale content validity index of .96 and item content validity index ranging from .96 to 1.0. CONCLUSION: The K-HES had acceptable validity and reliability. The brevity and ease of administration of the K-HES makes it a suitable tool for evaluating empowerment-based education programs targeted towards older populations. PMID- 25030253 TI - Systematic review of exercise effects on health outcomes in women with breast cancer. AB - PURPOSE: Exercise is commonly recommended to women after breast cancer surgery, yet it is difficult for patients and health professionals to adopt safe and beneficial types and modes of exercise. Thus studies on exercise interventions targeting women with breast cancer treatment were systematically reviewed. METHODS: The review process and quality assessment of the studies followed the guideline of the National Evidence-based Healthcare Collaborating Agency. Relevant studies were obtained from electronic databases, and two trained reviewers independently analyzed the studies. Of the 902 articles sorted, 11 were selected. Then, quality assessment for each study was carried out with the Scottish Intercollegiate Guideline Network (SIGN) checklist. RESULTS: Seven different types of exercise interventions were identified from 3 quasi experimental and 8 randomized controlled trial studies. The interventions varied in duration from several days to 13 weeks, and tended to show significant effects on psychological outcomes and upper body functions within a short-term period and were effective in alleviating lymphedema at a longer 1-year point. Supervised, professional intervention had significant effects on health indicators and a higher adherence rate. CONCLUSION: Well-designed exercises are effective and beneficial for improving women's physical, physiological, and psychological health outcomes after breast cancer treatment as well as to facilitate changes in exercise behaviors. The feasibility of applying intervention protocols, efficiency of interventions, and strengths of exercise protocols should be further examined. PMID- 25030254 TI - Erratum to review of the psychometric evidence of the perceived stress scale [asian nursing research 6 (2012) 121-127]. PMID- 25030256 TI - Development of an instrument to measure patient perception of the quality of nursing care and related hospital services at the national hospital of sri lanka. AB - PURPOSE: This study aimed to develop and validate an instrument to measure patient perception of quality of nursing care and related hospital services in a tertiary care setting. METHODS: We compiled an instrument with 72 items that patients may perceive as quality of nursing care and related hospital services, following an extensive literature search, discussions with patients and care pro I viders and a brainstorming session with an expert panel. A cross-sectional study was conducted at the National Hospital of Sri Lanka. A sample (n = 120) of patients stayed in general surgical or medical units responded to the interviewer administered instrument upon discharge. Item analysis and principal component factor analysis were performed to assess validity, and internal consistency was calculated to measure reliability. RESULTS: Of the 72 items, 18 had greater than 20% of responses as 'not relevant'. A further 11 items were eliminated since item total correlations were less than .2. Factor analysis was performed on remaining 43 items which resulted in 36 items classifying into eight factors accounting for 71% of the variation. Factor loadings in the final solution after Varimax rotation were interpersonal aspects (.68-.85), efficiency (.62-.79), competency (.66-.68), comfort (.60-.84), physical environment (.65-.82), cleanliness (.81 .85), personalized information (.76-.83), and general instructions (.61-.78). The instrument had high Internal consistency (Cronbach's alpha = .91). CONCLUSION: We developed a comprehensive, reliable and valid, 36-item instrument that may be used to measure patient perception of quality of nursing care in tertiary care settings. PMID- 25030255 TI - Inborn errors of pyrimidine metabolism: clinical update and therapy. AB - Inborn errors involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into their fundamental physiological roles as vital constituents of nucleic acids as well as substrates of lipid and carbohydrate metabolism and in oxidative phosphorylation. Genetic aberrations of pyrimidine pathways lead to diverse clinical manifestations including neurological, immunological, haematological, renal impairments, adverse reactions to analogue therapy and association with malignancies. Maintenance of cellular nucleotides depends on the three aspects of metabolism of pyrimidines: de novo synthesis, catabolism and recycling of these metabolites. Of the ten recognised disorders of pyrimidine metabolism treatment is currently restricted to only two disorders: hereditary orotic aciduria (oral uridine therapy) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; allogeneic hematopoetic stem cell transplant and enzyme replacement). The ubiquitous role that pyrimidine metabolism plays in human life highlights the importance of improving diagnostic evaluation in suggestive clinical settings, which will contribute to the elucidation of new defects, future development of novel drugs and therapeutic strategies. Limited awareness of the expanding phenotypic spectrum, with relatively recent descriptions of newer disorders, compounded by considerable genetic heterogeneity has often contributed to the delays in the diagnosis of this group of disorders. The lack of an easily recognisable, easily measurable end product, akin to uric acid in purine metabolism, has contributed to the under recognition of these disorders.This review describes the currently known inborn errors of pyrimidine metabolism, their variable phenotypic presentations, established diagnostic methodology and recognised treatment options. PMID- 25030257 TI - Relationship between bullying and health problems in primary school children. AB - PURPOSE: The aim of this study is to analyze the relationship between bullying and exposure to bullying and the health problems in the primary school children. METHODS: This study was conducted on 92 parents and 92 students who were sixth grade students in two primary schools in Izmir. The data were collected using the Peer Bullying Scale Adolescent Form and the Identification of Health Problems Form. The data were analyzed through chi(2) analysis and odds ratios with a 95% confidence interval. RESULTS: About forty-nine percent of the students (48.9%) was male, 51.1% of them was female and the average age was 11.6 +/- 0.53 years. It was found that students who had high scores for being exposed to bullying were significantly more likely to experience headache, feeling bad, crying restlessness, nervousness, sleeping problems, dizziness; whereas students who had high bullying scores were significantly more likely to experience only poor appetite. CONCLUSIONS: Students exposed to bullying have more health problems than the bullying students. It is recommended that programs designed to prevent the negative effects of bullying be developed. PMID- 25030258 TI - Factors influencing breast symptoms in breastfeeding women after cesarean section delivery. AB - PURPOSE: The purposes of this study were to explore postpartum stress and breast symptoms in postpar-tum breastfeeding of parturient mothers as well as to identify the factors influencing the breast symptoms in breastfeeding women after cesarean section delivery. METHODS: A cross-sectional survey was conducted. A total of 162 breastfeeding women after cesarean section delivery were recruited from five hospitals in Taiwan. Structured questionnaires were used to collect data. RESULTS: The five highest postpartum stress comes from the flabby flesh of maternal belly, the baby getting sick suddenly, interrupted sleep, insufficient breast milk, and discomfort due to breast engorgement. The most two common breast symptoms in breastfeeding encountered by subjects in this study were breast engorgement and breast hardening, whereas the least common one was nipple bloody discharge. Cesarean section women with early suckling on the operating table had more breast symptoms in postpartum breastfeeding; and the higher the postpartum stress of them, the more the breast symptoms. CONCLUSIONS: Breastfeeding in a comfortable condition is a key factor of precipitating breast milk secretion, so early suckling on the operating table may result in discomfort and stress of the woman and interfere with the secretion or production of breast milk. Additionally, it is a crucial factor of the success in breastfeeding that the nursing personnel can provide women help in maintaining breast milk production and secretion, taking care of a baby, and reminding women's families (especially their husbands) of giving their assistance, encouragement and praises to relieve women's postpartum stress. PMID- 25030259 TI - Evaluation of handwashing behaviors and analysis of hand flora of intensive care unit nurses. AB - PURPOSE: The aim of this study was to evaluate the handwashing behaviors of intensive care nurses based on personal statements, and to identify the microorganisms represented in the hand flora preshift and postshift. METHODS: This prospective study was performed with 60 intensive care nurses between January and December 2008, at a training and research hospital at a university in Turkey. Samples were taken from the hands of the nurses for bacteriological culture, using the bag-broth method, at the beginning and end of the shift. The samples were cultured aerobically and the colonies that grew were counted and identified. The nurses completed a self-report questionnaire, and their answers were evaluated. RESULTS: The frequency of handwashing by participants during each shift was 32.8+/-13.9. Overall, 65% of the nurses preferred alcohol-based antiseptic solutions for handwashing, 95% used paper towels to dry their hands, and 98.3-100% of the nurses washed their hands after performing care procedures. The Escherichia coli and coagulase negative Staphylococcus species were found to be at significantly higher levels in the postshift hand culture samples when compared to the preshift hand culture sample values. Enterobacter cloacae was the only species found in the postshift hand culture samples of the nurses. CONCLUSIONS: The number of colonies of the microorganisms in the hand flora of the nurses increased postshift. The handwashing behavior of intensive care nurses must be improved as they nurse critical patients. PMID- 25030260 TI - Maternal identity development education on maternity role attainment and my baby perception of primiparas. AB - PURPOSE: There are no interventional study results directed at maternal identity development education, including all stages of maternity role attainment, for expectant mothers with healthy babies. This research was conducted to assess the effect of maternal identity development education on the maternity role attainment and my baby perception of primigravidas. METHODS: The research was carried out by using pretest-posttest quasi-experimental model with control group. A total of 120 mothers and their babies participated in this study. In the collection of the data, Personal Information Form, Semantic Differentation Scale Myself as Mother and My Baby and the Pharis Self-Confidence Scale were used. RESULTS: It was detected that the training of identification development given for the mothers increased score averages taken from the scales of Myself as Mother, My Baby and the Pharis Self-Confidence Scale; this increase was statistically significant. There was a significant positive correlation between the Pharis Self-Confidence Scale post-test score averages and scales of Myself as Mother and My Baby. CONCLUSIONS: Nurses should offer maternal identity development education, support the baby perception process in the early postnatal stages, and help develop the self-confidence of the mother in order for mothers to develop successful motherhood behaviors. Maternal identity development education should be routinely offered to all expectant mothers by specialized nurses, not just to primigravidas. There is a requirement for similar studies to be conducted on broader populations related to the subject. PMID- 25030261 TI - Adherence to Physical Activity Among Older Adults Using a Geographic Information System: Korean National Health and Nutrition Examinations Survey IV. AB - PURPOSE: The purpose of this study was to examine the adherence to physical activity (PA) among older adults in Korea using data from the Fourth Korean National Health and Nutrition Examination Survey (KNHANESIV), and to illustrate geographic variations in PA using Geographic Information Systems (GIS). METHODS: A secondary analysis of the KNHANES IV data from 2007 to 2008 was used for this study. Participants of the study included 2,241 older adults over the age of 65. Estimates on adherence to PA were obtained for vigorous, moderate, walking, strengthening, and stretching activities. All estimates were weighted to represent Korean population. The association between participants' characteristics and PA was analyzed using Wald chi-square test. Maps depicting regional variations in PA were created using GIS software. RESULTS: Adherence to PA among Korean older adults who met national recommendations during the period of year 2007-2008 was about 9% in vigorous activity, 10% in moderate activity, and 48% in walking. The most common type of PA was walking. A higher level of PA was associated with male gender, younger age, high level of income and education, and living with family. CONCLUSION: The majority of older adults did not meet the national PA recommendations, suggesting that consistent surveillance and intervention for PA in the geriatric population are needed in the future. Maps generated using GIS visually showed regional differences in PA among the study participants. PMID- 25030262 TI - Exploring wisdom in the korean elderly: a q methodology study. AB - PURPOSE: The purpose of this study is to analyze the subjectivity of wisdom in the Korean elderly. METHODS: Q-methodology was used. The 33 selected Q-statements from each of the 41 participants were classified into a shape of normal distribution using a 9-point scale. The collected data were analyzed using the Analysis Software for (Technique. RESULTS: Four types of wisdom for research participants of Korean elderly were identified. Type I is experience-oriented action type; Type II is emotion-oriented sympathy type; Type III is human relationship-oriented consideration type; and Type IV is problem solution oriented insight type. CONCLUSION: The results of this study indicate that different approaches to health and nursing care for elders can be recommended based on the four types studied. PMID- 25030263 TI - Perceived cognitive function and related factors in korean women with breast cancer. AB - PURPOSE: The aim of this study was to explore perceived cognitive function and its related factors in breast cancer patients that had received or were receiving adjuvant chemotherapy after surgery. METHODS: A cross-sectional and correlational design was used in this study. A total of 118 women who had undergone or were undergoing adjuvant chemotherapy after breast cancer surgery recruited from a convenience sample from a university hospital in Korea were included in the study. The attentional function index was used to measure perceived cognitive function while the linear analogue self-assessment scale was used to measure mood disturbance. Hierarchical multiple regression analyses were done to determine possible predictors of perceived cognitive function in patients with breast cancer. RESULTS: Perceived cognitive function and mood disturbance had a mean score of 66.22 (SD= 13.43) and 159.78 (SD = 81.40), respectively. Mood disturbance was a statistically significant predictor of cognitive function in patients with breast cancer. CONCLUSIONS: Breast cancer patients with mood disturbance may experience decrements in perceived cognitive function. Nurses should be aware of mood changes and its influence on perceived cognitive function in breast cancer patients. PMID- 25030264 TI - Sleep architecture and cognitive changes in olanzapine-treated patients with depression: a double blind randomized placebo controlled trial. AB - BACKGROUND: Disturbance in sleep quality is a symptom of Major Depressive Disorder (MDD) and Bipolar Disorder (BD) and thus improving quality of sleep is an important aspect of successful treatment. Here, a prospective, double-blind, randomized, placebo-controlled study examined the effect of olanzapine (an atypical antipsychotic) augmentation therapy on sleep architecture, specifically slow wave sleep (SWS), in the treatment of depression. The effect of olanzapine augmentation therapy on other features of sleep (e.g., sleep continuity) and depression (e.g., illness severity and cognitive function) were also determined. METHODS: Patients currently experiencing a major depressive episode and who were on a stable medication were included. Sleep architecture was measured by overnight ambulatory polysomnography. Illness severity was determined using the Montgomery-Asberg Depression Rating Scale (MADRS). Cognitive function was examined using Cambridge Neuropsychological Test Automated Battery (CANTAB): Spatial Working Memory (SWM), Spatial Span (SSP), and Reaction Time (RTI) tasks. Polysomnographs, clinical measures and cognitive tests were administered at baseline, after 2-4 days of treatment and after 28-31 days of treatment. Twenty five patients participated in the study (N = 10, N = 15 for placebo and olanzapine treated groups respectively). RESULTS: The primary objective of the study was to assess the objective (polysomnographic) changes in sleep quality, defined as changes in SWS, following olanzapine treatment for depression. Latency to but not duration of SWS was found to significantly differ between olanzapine- and placebo-treated participants (Hedge's g: 0.97, 0.13 respectively). A significant improvement in olanzapine-treated participants over placebo-treated participants was observed in secondary outcome measures, including sleep efficiency, total sleep time, and sleep latency. Secondary objectives assessed the subjective changes in sleep quality parameters and correlated them with measures of illness severity and changes in cognition. MADRS scores were significantly improved in olanzapine-treated participants over time but not more than placebo treatment. There was no significant difference between olanzapine- and placebo-treated participants in SWM, SSP or RTI tasks. CONCLUSIONS: Olanzapine augmentation treatment generally did not improve SWS but did improve sleep continuity and depression. Olanzapine may be one of few medications that improve sleep continuity, thus directly targeting symptoms of depression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00520507. PMID- 25030265 TI - Self-antigen expression in the peripheral immune system: roles in self-tolerance and type 1 diabetes pathogenesis. AB - Type 1 diabetes (T1D) may result from a breakdown in peripheral tolerance that is partially controlled by the ectopic expression of peripheral tissue antigens (PTAs) in lymph nodes. Various subsets of lymph node stromal cells and certain hematopoietic cells play a role in maintaining T cell tolerance. These specialized cells have been shown to endogenously transcribe, process, and present a range of PTAs to naive T cells and mediate the clonal deletion or inactivation of autoreactive cells. During the progression of T1D, inflammation leads to reduced PTA expression in the pancreatic lymph nodes and the production of novel islet antigens that T cells are not tolerized against. These events allow for the escape and activation of autoreactive T cells and may contribute to the pathogenesis of T1D. In this review, we discuss recent findings in this area and propose possible therapies that may help reestablish self-tolerance during T1D. PMID- 25030266 TI - Developing personal attributes of professionalism during clinical rotations: views of final year bachelor of clinical medical practice students. AB - BACKGROUND: Medical professionalism as a set of behaviours that transcends personal values, beliefs and attitudes to incorporate ethical and moral principles is considered a covenant between society and the practice of medicine. The Bachelor of Clinical Medical Practice (BCMP) a three year professional degree was launched at the University of the Witwatersrand in January 2009 in response to a documented shortage of doctors especially in the rural areas of South Africa. The BCMP programme is unique in its offering as it requires a teaching approach that meets the needs of an integrated curriculum, providing for an accelerated transition from the classroom to the patient's bedside. METHODS: Following five week attachments in designated District Education Campuses, 25 final year BCMP students were required to reflect individually on the covenant that exists between society and the practice of medicine based on their daily interactions with health care workers and patients for three of the five rotations in a one page document. A retrospective, descriptive case study employed qualitative methods to group emerging themes from 71 portfolios. Ethical clearance was obtained from the Human Research Ethics Committee at the University of the Witwatersrand. RESULTS: As an outcome of an ethical analysis, the majority of BCMP students reflected on the determinants of accountable and responsible practice (N=54). The commitment to the Oath became significant with a personalised reference to patients 'as my patients'. Students acknowledged professional health care workers (HCWs) who demonstrated commitment to core values of good practice as they recognised the value of constantly reflecting as a skill (n=51). As the students reflected on feeling like 'guinea pigs' (n=25) migrating through periods of uncertainity to become 'teachable learners', they made ethical judgements that demonstrated the development of their moral integrity. A few students felt vulnerable in instances where they were pressured into 'pushing the line'. CONCLUSIONS: Through their portfolio narratives, BCMP students showed a willingness to shape their evolving journeys of moral growth and personal development. This study has highlighted as an ongoing challenge the need to identify a process by which professionalism is sustained by HCWs to benefit health sciences students. PMID- 25030267 TI - Flow-related intracranial aneurysms associated with unfused arterial twigs relevant to different vascular anomalies: embryologic and hemodynamic considerations. AB - OBJECT: Cerebrovascular anomalies resulting from the persistence of unfused embryonic twig-like vessels are associated with intracranial aneurysms. All records of patients with ruptured intracranial aneurysms who were treated at our institution were retrospectively reviewed for the presence of aneurysm associated, unfused, twig-like vessels in the middle cerebral artery (MCA). Such vessels were recorded as twig-like MCA (T-MCA) or twig-like networks of an anomalous collateral artery (T-NACA). Additionally, we sought to characterize vulnerable intracranial aneurysms associated with those vascular anomalies. METHODS: A total of 442 ruptured aneurysms were treated from June 2006 to November 2013; of these, 4 ruptured aneurysms exhibited the presence of ipsilateral, unfused, twig-like vessels. Computed tomography (CT) scans, three dimensional CT angiography, and digital subtraction angiography (DSA) were performed immediately after the initial ictus. Data analysis included age, sex, Hunt and Hess grade (HHG), Fisher grade (FG), medical risk factors, angiographic architecture, operative methods and findings, radiologic outcomes, and Glasgow outcome scale (GOS). The average follow-up period was 26 months. RESULTS: Patient ages ranged from 26 to 49 years with a mean age of 41; there were two females and two males. All four patients showed FG IV, and three patients had unfavorable HHG (IV in 2 and V in one) at admission. An M1 segmental occlusion and an adjacent small aneurysmal pouch were detected with three-dimensional CT angiography in three patients. Hypertension was recorded in all patients. The initial DSA revealed T-MCA in one patient and T-NACA in three patients. Six aneurysms in all, including two unruptured aneurysms, were found; three ruptured aneurysms existed inside of the twigs. All but one patient required diverse treatment modalities, and four of the five aneurysms were completely occluded after treatment. The remaining aneurysm, treated only with gluing, disappeared during follow-up. In two of the three patients with T-NACA, atresia of the M1 segment was confirmed intraoperatively. The GOS during follow-up was recorded as favorable (good recovery) in two patients and unfavorable (severe disability and permanent vegetative state) in two patients. CONCLUSIONS: These unique vascular anomalies, T-MCA and T-NACA, which are caused by heterogeneous maldevelopment of the primitive cerebral vessels, are not benign because of their frequent association with flow-related aneurysms, which are vulnerable to rupture. Microsurgical or endovascular treatments for this type of flow-related aneurysm associated with twigs are mandatory to prevent fatal rebleeding, and more attention has to be given when physicians encounter steno-occlusive MCA lesions in patients with subarachnoid hemorrhage to detect any vulnerable aneurysms associated with twig like vessels. PMID- 25030268 TI - Intrafistula pressure measurement in traumatic carotid cavernous fistulas--key to increasing safety and effectiveness of endovascular coiling. AB - BACKGROUND: Very few diseases demostrate the tremendous variation and capricious results common with the clinical ensemble of carotid cavernous fistulas (CCFs). The treatment modality for CCFs has changed from surgical to endovascular therapy. Many options exist in endovascular therapy ranging from balloons to coils and liquid embolization agents like Onyx. This study was undertaken to assess the role of recording intra-fistula pressure (IFP) during endovascular coiling of CCFs in order to help us better understand the angiodynamics of the fistula and to make coiling safer and effective. METHODS: IFP measurement was done in 15 cases of traumatic CCF undergoing endovascular coiling. Patients were prospectively analyzed by pre- and post- procedural clinical profile, degree of recovery and time until fistula occlusion. Univariate analysis was used to find the correlation between the reduction in IFP, the degree of fistula obliteration and time until occlusion. RESULTS: Of the 15 patients who underwent endovascular coiling 13 had total occlusion of the fistula, 1 patient had subtotal occlusion and 1 patient had no occlusion of the fistula. There was 100 % internal carotid artery (ICA) patency. Univariate analysis showed a strong correlation between the degree of reduction in IFP and time required for fistula occlusion (p < 0.001). Patients with a significant drop in IFP were also preceived as having a higher chance of fistula occlusion after waiting 30 min. CONCLUSION: To our knowledge this is the largest series in published literature focused on using only detachable coils as the first line embolizing agent in treatment of traumatic CCFs. We conclude that IFP monitoring will play an important role in making treatment of CCFs safer and more effective. The aim of coiling the fistula is not to tightly pack the fistula as during treatment of aneurysms; rather it is to reduce flow across the fistula leading to thrombosis thus reducing the requirement of coils. PMID- 25030269 TI - Assessing deaf awareness training: knowledge and attitudes of recent genetic counseling graduates. AB - Research suggests that when healthcare providers lack cultural competence, minority groups, including the Deaf community, are adversely affected. Although most genetic counseling programs incorporate cultural competency training into their curricula, the extent and impact of Deaf awareness training is unknown. The purpose of this study is to assess Deaf awareness training of recent graduates and its impact on knowledge of deafness and Deaf culture, and attitudes toward deaf people. Genetic counselors who graduated within the past 5 years were invited to participate in an anonymous, online survey. Of the 135 respondents, 26 % reported no Deaf awareness training and 51 % reported limited training (1-2 h) conducted primarily by program instructors. Nearly one-third felt their Deaf awareness training was insufficient. Respondents lacked knowledge regarding effects of cochlear implants on residual hearing, communication between deaf children and hearing parents, and working with sign language interpreters. However, scores on knowledge of deafness and Deaf culture items and scores on attitudes toward deaf people scale did not differ significantly between respondents who had Deaf awareness training and those who did not. These findings suggest that genetic counseling students may not receive adequate Deaf awareness training. Future efforts should focus on increasing Deaf awareness in genetic counseling students, and investigating whether this change improves genetic counseling experiences for Deaf individuals. PMID- 25030270 TI - Development of antibiotic treatment algorithms based on local ecology and respiratory surveillance cultures to restrict the use of broad-spectrum antimicrobial drugs in the treatment of hospital-acquired pneumonia in the intensive care unit: a retrospective analysis. AB - INTRODUCTION: Timely administration of appropriate antibiotic therapy has been shown to improve outcome in hospital-acquired pneumonia (HAP). Empirical treatment guidelines tailored to local ecology have been advocated in antibiotic stewardship programs. We compared a local ecology based algorithm (LEBA) to a surveillance culture based algorithm (SCBA) in terms of appropriate coverage and spectrum of antimicrobial activity. METHODS: We retrospectively assessed 2 hypothetical empirical antibiotic treatment algorithms for HAP on an existing high-quality prospectively collected database in a mixed 36-bed tertiary intensive care unit (ICU). Data on consecutive episodes of microbiologically confirmed HAP were collected over a period of 40 months and divided in a derivation (1 July 2009 to 31 October 2010) and validation (1 November 2010 until 31 October 2012) cohort. On the derivation cohort we constructed a LEBA, based on overall observed bacterial resistance patterns, and a SCBA, which targeted therapy to surveillance culture (SC) in the individual patient. Therapy was directed against pathogens found in respiratory SC collected two to five days before HAP, and in the absence of these, presence or absence of multi-drug resistant (MDR) pathogens in other SC dictated broad-spectrum, respectively narrow spectrum antibiotic therapy. Subsequently, LEBA and SCBA were retrospectively reviewed and compared with actually prescribed antibiotics in the validation cohort. RESULTS: The first 100 HAP episodes made up the derivation cohort and the subsequent 113 HAP episodes the validation cohort. Appropriate antibiotic coverage rates by applying LEBA and SCBA were 88.5% and 87.6%, respectively, and did not differ significantly with respect to appropriateness of the actually prescribed initial therapy (84.1%). SCBA proposed more narrow spectrum therapy as compared to LEBA and the actually prescribed antimicrobials (P <0.001). SCBA recommended significantly less combination therapy and carbapenems compared to LEBA (P <0.001). SCBA targeted antibiotics to recent respiratory SC in 38.1% (43 out of 113 episodes) of HAP; in these cases adequacy was 93% (40 out of 43). CONCLUSION: Rates of appropriate antimicrobial coverage were identical in LEBA and SCBA. However, in this setting of moderate MDR prevalence, the use of SCBA would result in a significant reduction of the use of broad-spectrum drugs and may be a preferential strategy when implementing antibiotic stewardship programs. PMID- 25030271 TI - Training obstetrics and gynecology residents to be effective communicators in the era of the 80-hour workweek: a pilot study. AB - BACKGROUND: To ensure optimal patient care, physicians must establish effective patient-physician relationships and thoughtfully incorporate their patients' perspectives into their counseling. Historically, these skills are acquired with increasing clinical experience. However, given increasing work-hour restrictions, OB/GYN residents have fewer opportunities to develop these skills. Therefore, the objective of this study was to determine if an interactive learning method is an effective tool by which to teach OB/GYN residents how to communicate with complicated patients. METHODS: An experiential simulation model was developed to teach OB/GYN residents effective communication skills for dealing with patients experiencing a pregnancy-related complication. A simulated patient interaction was designed for first-year residents. Specific scenarios were constructed based on challenging clinical scenarios identified by second-year residents. Non judgmental communication, culture competency awareness and reflective listening were key skills that were taught as part of the clinical scenarios. Both acceptability and utility of the exercise with the first-years was assessed by a follow-up survey. RESULTS: Seven first-year residents participated in the education session consisting of four physician-patient interactions with specific learning objectives for each. These first-year residents all indicated that they would employ the skills practiced during the intervention into their future practice of medicine, and that their comfort level in caring for complex obstetric patients had increased. Moreover, all first-year residents endorsed that this educational strategy was potentially applicable to other aspects of their training. CONCLUSIONS: Simulated patient exercises can be utilized in multiple arenas to teach OB/GYN residents communication skills, while simultaneously addressing their clinical knowledge deficits. Early implementation of such a curriculum in an OB/GYN residency will lay the foundation for the development of empathetic and culturally competent physicians. PMID- 25030272 TI - A 3.8-V earth-abundant sodium battery electrode. AB - Rechargeable lithium batteries have ushered the wireless revolution over last two decades and are now matured to enable green automobiles. However, the growing concern on scarcity and large-scale applications of lithium resources have steered effort to realize sustainable sodium-ion batteries, Na and Fe being abundant and low-cost charge carrier and redox centre, respectively. However, their performance is limited owing to low operating voltage and sluggish kinetics. Here we report a hitherto-unknown material with entirely new composition and structure with the first alluaudite-type sulphate framework, Na2Fe2(SO4)3, registering the highest-ever Fe(3+)/Fe(2+) redox potential at 3.8 V (versus Na, and hence 4.1 V versus Li) along with fast rate kinetics. Rare-metal free Na-ion rechargeable battery system compatible with the present Li-ion battery is now in realistic scope without sacrificing high energy density and high power, and paves way for discovery of new earth-abundant sustainable cathodes for large-scale batteries. PMID- 25030273 TI - Persistence, clearance and reinfection regarding six high risk human papillomavirus types in Colombian women: a follow-up study. AB - BACKGROUND: The design of new healthcare schemes which involve using molecular HPV screening means that both persistence and clearance data regarding the most prevalent types of HR-HPV occurring in cities in Colombia must be ascertained. METHODS: This study involved 219 HPV positive women in all of whom 6 types of HR HPV had been molecularly identified and quantified; they were followed-up for 2 years. The Kaplan-Meier survival function was used for calculating the time taken for the clearance of each type of HPV. The role of a group of independent variables concerning the time taken until clearance was evaluated using a Cox proportional-hazards regression model or parametric (log-logistic) methods when necessary. Regarding viral load, the Wilcoxon rank-sum test was used for measuring the difference of medians for viral load for each type, according to the state of infection (cleared or persistent). The Kruskal-Wallis test was used for evaluating the change in the women's colposcopy findings at the start of follow-up and at the end of it (whether due to clearance or the end of the follow up period). RESULTS: It was found that HPV-18 and HPV-31 types had the lowest probability of becoming cleared (1.76 and 2.75 per 100 patients/month rate, respectively). Women from Colombian cities other than Bogota had a greater probability of being cleared if they had HPV-16 (HR 2.58: 1.51-4.4 95% CI) or HPV 58 (1.79 time ratio: 1.33-2.39 95% CI) infection. Regarding viral load, HPV-45 infected women having 1 * 106 to 9.99 * 109 viral copies had better clearance compared to those having greater viral loads (1.61 time ratio: 1.01-2.57 95% CI). Lower HPV-31 viral load values were associated with this type's persistence and changes in colposcopy findings for HPV-16 gave the worst prognosis in women having low absolute load values. CONCLUSIONS: HPV infection clearance in this study was related to factors such as infection type, viral load and the characteristics of the cities from which the women came. Low viral load values would indicate viral persistence and a worse prognosis regarding a change in colposcopy findings. PMID- 25030274 TI - Features of S-nitrosylation based on statistical analysis and molecular dynamics simulation: cysteine acidity, surrounding basicity, steric hindrance and local flexibility. AB - S-Nitrosylation is involved in protein functional regulation and cellular signal transduction. Although intensive efforts have been made, the molecular mechanisms of S-nitrosylation have not yet been fully understood. In this work, we carried out a survey on 213 protein structures with S-nitrosylated cysteine sites and molecular dynamic simulations of hemoglobin as a case study. It was observed that the S-nitrosylated cysteines showed a lower pKa, a higher population of basic residues, a lower population of big-volume residues in the neighborhood, and relatively higher flexibility. The case study of hemoglobin showed that, compared to that in the T-state, Cysbeta93 in the R-state hemoglobin possessed the above structural features, in agreement with the previous report that the R-state was more reactive in S-nitrosylation. Moreover, basic residues moved closer to the Cysbeta93 in the dep-R-state hemoglobin, while big-volume residues approached the Cysbeta93 in the dep-T-state. Using the four characteristics, i.e. cysteine acidity, surrounding basicity, steric hindrance, and local flexibility, a 3 dimensional model of S-nitrosylation was constructed to explain 61.9% of the S nitrosylated and 58.1% of the non-S-nitrosylated cysteines. Our study suggests that cysteine deprotonation is a prerequisite for protein S-nitrosylation, and these characteristics might be useful in identifying specificity of protein S nitrosylation. PMID- 25030275 TI - Updates in biological therapies for knee injuries: bone. AB - Bone is a unique tissue because of its mechanical properties, ability for self repair, and enrollment in different metabolic processes such as calcium homeostasis and hematopoietic cell production. Bone barely tolerates deformation and tends to fail when overloaded. Fracture healing is a complex process that in particular cases is impaired. Osteoprogenitor cells proliferation, growth factors, and a sound tridimensional scaffold at fracture site are key elements for new bone formation and deposition. Mechanical stability and ample vascularity are also of great importance on providing a proper environment for bone healing. From mesenchymal stem cells delivery to custom-made synthetic scaffolds, many are the biological attempts to enhance bone healing. Impaired fracture healing represents a real burden to contemporary society. Sound basic science knowledge has contributed to newer approaches aimed to accelerate and improve the quality of bone healing. PMID- 25030277 TI - Standardization and quantification in FDG-PET/CT imaging for staging and restaging of malignant disease. AB - There is a growing interest in using quantification in FDG-PET/CT in oncology, especially for evaluating response to therapy. Complex full quantitative procedures with blood sampling and dynamic scanning have been clinically replaced by the use of standardized uptake value measurements that provide an index of regional tracer uptake normalized to the administered dose of FDG. Some approaches have been proposed for assessing quantitative metabolic response, such as EORTC and PERCIST criteria in solid tumors. When using standardized uptake value in clinical routine and multicenter trials, standardization of protocols and quality control procedures of instrumentation is required. PMID- 25030278 TI - Head and neck: normal variations and benign findings in FDG positron emission tomography/computed tomography imaging. AB - Positron emission tomography (PET)/computed tomography with FDG of the head and neck region is mainly used for the diagnosis of head and neck cancer, for staging, treatment evaluation, relapse, and planning of surgery and radio therapy. This article is a practical guide of imaging techniques, including a detailed protocol for FDG PET in head and neck imaging, physiologic findings, and pitfalls in selected case stories. PMID- 25030279 TI - Thorax: normal and benign pathologic patterns in FDG-PET/CT imaging. AB - This article describes the normal patterns of thoracic (18)F-fluorodeoxyglucose (FDG) biodistribution, and expands on the role of FDG-PET/computed tomography (CT) for the evaluation of patients suffering from a spectrum of benign pathologic conditions that affect the chest. The discussion addresses the applications of FDG-PET/CT imaging in a wide variety of chest-related disorders. Familiarity with the normal thoracic biodistribution of FDG, coupled with knowledge of the potential nonmalignant causes of increased FDG uptake in the chest, is essential to minimize the incidence of incorrect interpretation of FDG PET images in daily clinical practice. PMID- 25030280 TI - Abdomen: normal variations and benign conditions resulting in uptake on FDG PET/CT. AB - The increasing use of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in oncology has led to: improved sensitivity and specificity in detecting localized and metastatic disease, increased ability to target biopsies to the site of most aggressive disease, and development of a noninvasive biomarker to assess prognosis and effects of therapy. However, for correct interpretation of FDG-PET/CT studies, an understanding of both normal and abnormal imaging appearances commonly encountered in oncology patients is important. This article discusses commonly seen normal variations and benign findings on FDG-PET/CT of the abdomen. PMID- 25030281 TI - Pelvis: normal variants and benign findings in FDG-PET/CT imaging. AB - With the widespread use of whole-body fluorodeoxyglucose (FDG)-PET/computed tomography as a diagnostic tool in patients with cancer, incidental findings are of increasing importance. This is particularly true within the pelvis, where several benign findings might present with increased FDG uptake. In addition, physiologic excretion of radiotracer by way of the urinary tract can complicate image analysis. This article reviews potential incidental benign findings in the pelvis that one should be aware of when interpreting FDG-PET/computed tomography scans. PMID- 25030282 TI - Normal variations and benign findings in pediatric 18F-FDG-PET/CT. AB - (18)F-FDG PET and PET/CT have a wide variety of indications in children and young adults. Oncologic indications are the most common, but others include neurology, sports medicine, cardiology, and infection imaging. Accurate interpretation of pediatric (18)F-FDG PET and PET/CT requires a technically adequate study and knowledgeable interpretation of the images. A successful pediatric (18)F-FDG PET requires age-appropriate patient preparation and consideration of patient age and developmental stage. Accurate interpretation of the study requires familiarity with normal patterns of physiologic (18)F-FDG uptake in children at all stages of development. PMID- 25030283 TI - Differential background clearance of fluorodeoxyglucose activity in normal tissues and its clinical significance. AB - The clearance of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) activity in normal tissues varies significantly with extended distribution time. Although most tissues have lower standardized uptake value (SUV) on 2-hour/3-hour delayed images, others may have stable or higher FDG activity with longer distribution times. The continuously decreased SUV on delayed imaging in some tissues, especially in the liver, indicates that longer distribution time will decrease background activity, increase lesion-to-background ratio, and thus improve imaging quality, whereas the continuously increased SUV from 1 to 3 hours in the heart suggest that longer distribution time will improve detection of viable myocardium in a viability study. PMID- 25030284 TI - Postradiation changes in tissues: evaluation by imaging studies with emphasis on fluorodeoxyglucose-PET/computed tomography and correlation with histopathologic findings. AB - Efforts have been made to minimize the damage to adjacent normal tissues during radiotherapy, primarily by shifting from the use of conventional radiotherapy to more advanced techniques. Reviewing the overall pattern on combined anatomic and functional imaging can enhance diagnostic accuracy. Several radiotracers can be used; [(18)F]fluorodeoxyglucose is the most common. Familiarity with the type and timing of previous radiation therapy, the spectrum of imaging findings after radiation injury, and the appropriate use of the different radiotracers can be crucial. This article summarizes postradiation histologic findings and multimodality imaging findings, with emphasis on PET/computed tomography. PMID- 25030285 TI - Fluorodeoxyglucose positron emission tomography/magnetic resonance imaging: current status, future aspects. AB - Simultaneous positron emission tomography (PET)/magnetic resonance (MR) imaging is a promising novel technology for oncology diagnosis and staging and neurologic and cardiac applications. Our institution's current research protocol results in a total imaging time of approximately 45 to 70 minutes with simultaneous PET/MR imaging, making this a feasible total body imaging protocol. Further development of MR-based attenuation correction will improve PET quantification. Quantitatively accurate multiparametric PET/MR data sets will likely improve diagnosis of disease and help guide and monitor the therapies for individualized patient care. PMID- 25030290 TI - FDG PET/CT: normal variations and benign findings--translation to PET/MRI. PMID- 25030294 TI - Effect of double-step steam explosion pretreatment in bioethanol production from softwood. AB - The study investigated the production of bioethanol from softwood, in particular pine wood chip. The steam explosion pretreatment was largely investigated, evaluating also the potential use of a double-step process to increase ethanol production through the use of both solid and liquid fraction after the pretreatment. The pretreatment tests were carried out at different conditions, determining the composition of solid and liquid fraction and steam explosion efficiency. The enzymatic hydrolysis was carried out with Ctec2 enzyme while the fermentation was carried out using Saccharomyces Cerevisiae yeast "red ethanol". It was found that the best experimental result was obtained for a single-step pretreated sample (10.6 g of ethanol/100 g of initial biomass dry basis) for a 4.53 severity. The best double-step overall performance was equal to 8.89 g ethanol/100 g of initial biomass dry basis for a 4.27 severity. The enzymatic hydrolysis strongly depended on the severity of the pretreatment while the fermentation efficiency was mainly influenced by the concentration of the inhibitors. The ethanol enhancing potential of a double-step steam explosion could slightly increase the ethanol production compared to single-step potential. PMID- 25030291 TI - Evaluation of the sensitivity of IgG and IgM ELISA in detecting Schistosoma mansoni infections in a low endemicity setting. AB - Schistosomiasis is a major public health concern, with 200 million people infected worldwide. In Brazil, this disease has been reported in 19 states, and its prevalence in the city of Barra Mansa in Rio de Janeiro State is 1 %. The parasitological diagnostic methods currently available in these areas lack sensitivity; however, enzyme-linked immunosorbent assays (ELISAs) have been employed successfully for the diagnosis of schistosomiasis by using antibodies against antigens of Schistosoma mansoni adult worms and eggs, and for the detection of circulating antigens. The objective of this study was to determine systematically the prevalence of S. mansoni infection in the peripheral areas of Barra Mansa. A cross-sectional study was conducted from April to December 2011 by using probabilistic sampling that collected 610 fecal samples and 612 serum samples. ELISA-IgG with total extracts and ELISA-IgM with trichloroacetic acid soluble fractions were employed to detect antibodies against S. mansoni and were compared with the Kato-Katz and Hoffman parasitological techniques. Among the individuals studied, anti-S. mansoni antibodies were detected in 11.16 % (n = 71) by ELISA-IgG and in 20.75 % (n = 132) by ELISA-IgM, while the parasitological techniques showed 0.82 % (n = 5) positivity. The agreement between the two ELISA tests was 85.38 % (n = 543), and 8.65 % (n = 55) of the serum samples showed positive results in both tests. The higher positivity of the ELISA-IgM test corroborates the results of previous reports and indicates that the test may be a useful tool in epidemiological studies, particularly in areas of low endemicity for S. mansoni. PMID- 25030295 TI - Restoration of accelerator facilities damaged by Great East Japan Earthquake at Cyclotron and Radioisotope Center, Tohoku University. AB - The Cyclotron and Radioisotope Center (CYRIC) of Tohoku University is a joint-use institution for education and research in a wide variety of fields ranging from physics to medicine. Accelerator facilities at the CYRIC provide opportunities for implementing a broad research program, including medical research using positron emission tomography (PET), with accelerated ions and radioisotopes. At the Great East Japan Earthquake on March 11, 2011, no human injuries occurred and a smooth evacuation was made in the CYRIC, thanks to the anti-earthquake measures such as the renovation of the cyclotron building in 2009 mainly to provide seismic strengthening, fixation of shelves to prevent the falling of objects, and securement of the width of the evacuation route. The preparation of an emergency response manual was also helpful. However, the accelerator facilities were damaged because of strong shaking that continued for a few minutes. For example, two columns on which a 930 cyclotron was placed were damaged, and thereby the 930 cyclotron was inclined. All the elements of beam transport lines were deviated from the beam axis. Some peripheral devices in a HM12 cyclotron were broken. Two shielding doors fell from the carriage onto the floor and blocked the entrances to the rooms. The repair work on the accelerator facilities was started at the end of July 2011. During the repair work, the joint use of the accelerator facilities was suspended. After the repair work was completed, the joint use was re-started at October 2012, one and a half years after the earthquake. PMID- 25030296 TI - Interaction of tryptophan and related compounds with oxygen- and carbon-centered radicals. AB - Effects of tryptophan, 5-hydroxytryptophan, serotonin, and melatonin on final product formation during radiolysis of deaerated and oxygen-saturated ethanol and aqueous 1M ethanol solutions were studied. The named amino acids were found to be capable of adding alpha-hydroxyethyl radicals, thereby suppressing recombination reactions of these species. Unlike melatonin, tryptophan, 5-hydroxytryptophan, and serotonin were able to reduce oxygen-centered radicals being formed on radiation-chemical oxidation of ethanol in the presence of oxygen via electron transfer from the amine nitrogen lone pair. PMID- 25030298 TI - Everyday-like memory and its cognitive correlates in healthy older adults and in young patients with traumatic brain injury: a pilot study based on virtual reality. AB - PURPOSE STATE: A pilot-study with a comparison approach between aging and traumatic brain injury (TBI) is proposed to investigate everyday object memory patterns using a virtual HOMES test. METHODS: Sixteen young controls, 15 older adults and 15 TBI patients underwent the HOMES test and traditional tests. RESULTS: Older adults and TBI patients exhibited similar HOMES performances: poor recall, a greater recognition benefit, high false recognitions, but intact clustering and proactive interference effects. The age-related differences for HOMES measures were mainly mediated by executive functioning, while the HOMES performances in the TBI group were correlated with memory measures. CONCLUSION: The differential cognitive mediating effects for a similar everyday-like memory pattern are discussed by highlighting the need for more cautious interpretations of cognitive mechanisms behind similar behavioral patterns in different populations especially in clinical and rehabilitation settings. PMID- 25030297 TI - Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons. AB - Recent studies have demonstrated that human tau can be secreted by neurons and non-neuronal cells, an event linked to the propagation of tau pathology in the brain. In the present study, we confirmed that under physiological conditions, one tau-positive band was detected in the culture medium with an anti-tau antibody recognizing total tau and the Tau-1 antibody directed against unphosphorylated tau. We then examined whether tau secretion was modified upon insults. Tau secretion was increased by starvation [Earle's Balanced Salt Solution (EBSS)], inhibition of lysosomal function (leupeptin) and when both of these conditions were superimposed, this combined treatment having the most important effects on tau secretion. Interestingly, the pattern of tau secretion was distinct from that of control neurons when neurons were treated either with EBSS alone or EBSS + leupeptin. In these conditions, three tau-positive bands were detected in the culture medium. Two of these three bands were immunoreactive to Tau-1 antibody revealing that at least two tau species were released upon these treatments. Collectively, our results indicate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain. PMID- 25030299 TI - Preoperative tissue Doppler imaging-derived atrial conduction time can predict postoperative atrial fibrillation in patients undergoing aortic valve replacement for aortic valve stenosis. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and may result in stroke or heart failure and poor prognosis. This study aimed to evaluate a novel index of total atrial conduction time derived from the P-wave onset (lead II) to the peak A' wave on tissue Doppler imaging (PA-TDI duration). The PA-TDI duration was compared with previously reported predictors of POAF, and the optimal cutoff value of PA-DTI was calculated in patients undergoing aortic valve replacement (AVR) for AV stenosis (AS). METHODS AND RESULTS: We enrolled 63 patients undergoing isolated AVR. They underwent transthoracic echocardiography with TDI preoperatively and were monitored postoperatively with continuous electrocardiographic telemetry for 7 days. The hospital stay was significantly longer in the 41 patients with POAF than in the 22 without POAF (33.8+/-19.7 vs. 24.1+/-8.1 days, P=0.03). Multivariate analysis revealed that PA-TDI duration (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.02-1.13; P=0.0072) and age (OR, 1.14; CI, 1.03-1.28; P=0.016) were significant independent predictors of POAF. Receiver-operating characteristic curve analysis showed the optimal cutoff values of PA-TDI duration and age were 147.3 ms and 74 years, respectively. CONCLUSIONS: The PA-TDI duration was an independent predictor of POAF after AVR for AS. Patients with PA TDI duration >147 ms should be considered high risk and treated appropriately to improve outcomes. PMID- 25030300 TI - Appropriate duration of driving restrictions after inappropriate therapy from implantable cardiac shock devices-interim analysis of the Nippon Storm Study. AB - BACKGROUND: Little is known regarding the appropriate duration for driving restrictions after inappropriate implantable cardiac shock device (ICSD) therapy. METHODS AND RESULTS: We evaluated the Nippon Storm Study data, and found that inappropriate ICSD therapy occurred in 114 (7.6%) patients during a median follow up of 464 days. Among those patients, 25 experienced further inappropriate ICSD therapy during a subsequent median follow-up of 380 days. Time-dependent recurrence of inappropriate ICSD therapy occurred in 19 (76%) patients within 180 days. CONCLUSIONS: The interval for driving restrictions after inappropriate ICSD therapy can be reduced. PMID- 25030301 TI - Intracellular delivery of tumor antigenic peptides in biodegradable-polymer adjuvant for enhancing cancer immunotherapy. AB - Tumor antigenic peptides therapeutics is a promising field for cancer immunotherapy; advantages include convenient synthesis and modification of antigenic peptides, as well as little toxicity associated with its administration. Vaccination of the peptides derived from tumor-associated antigen (TAA) was specifically designed for T cells in the context of MHC molecules. In the past decades, tumor antigenic peptides have been examined in clinic but numbered success has been obtained because of the stability of peptide and delivery approaches, consequently leading to an inefficient antigen presentation and low response rates in cancer patients. Thus, the appropriate and efficient peptide vaccine carrier systems still continue to be a major obstacle. However, both sipuleucel-T vaccine and anti-CTLA-4 antibody have been approved by FDA for the treatment of metastatic prostate cancer and melanoma, respectively. PLGA has been recently used as the adjuvant to elicit enhanced immune responses while delivering tumor antigenic peptides. Intracellular delivery of the peptides derived from TAA into DCs would prolong antigen presentation of APC to T cells. This article aims to describe a new delivery method regarding tumor antigenic peptides and rationales of DCs-based vaccination. PMID- 25030302 TI - Strategies for improved modeling of GPCR-drug complexes: blind predictions of serotonin receptors bound to ergotamine. AB - The recent increase in the number of atomic-resolution structures of G protein coupled receptors (GPCRs) has contributed to a deeper understanding of ligand binding to several important drug targets. However, reliable modeling of GPCR ligand complexes for the vast majority of receptors with unknown structure remains to be one of the most challenging goals for computer-aided drug design. The GPCR Dock 2013 assessment, in which researchers were challenged to predict the crystallographic structures of serotonin 5-HT(1B) and 5-HT(2B) receptors bound to ergotamine, provided an excellent opportunity to benchmark the current state of this field. Our contributions to GPCR Dock 2013 accurately predicted the binding mode of ergotamine with RMSDs below 1.8 A for both receptors, which included the best submissions for the 5-HT(1B) complex. Our models also had the most accurate description of the binding sites and receptor-ligand contacts. These results were obtained using a ligand-guided homology modeling approach, which combines extensive molecular docking screening with incorporation of information from multiple crystal structures and experimentally derived restraints. In this work, we retrospectively analyzed thousands of structures that were generated during the assessment to evaluate our modeling strategies. Major contributors to accuracy were found to be improved modeling of extracellular loop two in combination with the use of molecular docking to optimize the binding site for ligand recognition. Our results suggest that modeling of GPCR-drug complexes has reached a level of accuracy at which structure-based drug design could be applied to a large number of pharmaceutically relevant targets. PMID- 25030303 TI - Fully printable transparent monolithic solid-state dye-sensitized solar cell with mesoscopic indium tin oxide counter electrode. AB - We present a new transparent monolithic mesoscopic solid-state dye-sensitized solar cell based on trilamellar films of mesoscopic TiO2 nanocrystalline photoanode, a ZrO2 insulating layer and an indium tin oxide counter electrode (ITO-CE), which were screen-printed layer by layer on a single substrate. When the thickness of the ITO-CE was optimized to 2.1 MUm, this very simple and fully printable solid-state DSSC with D102 dye and spiro-OMeTAD hole transport materials presents efficiencies of 1.73% when irradiated from the front side and 1.06% when irradiated from the rear side under a standard simulated sunlight condition (AM 1.5 Global, 100 mW cm(-2)). Higher parameters could be expected with a better transparent mesoscopic counter electrode and hole conductor for the printable monolithic mesoscopic solid-state DSSC. PMID- 25030304 TI - Mirror-symmetric magneto-optical Kerr rotation using visible light in [(GeTe)2(Sb2Te3)1]n topological superlattices. AB - Interfacial phase change memory (iPCM), that has a structure of a superlattice made of alternating atomically thin GeTe and Sb2Te3 layers, has recently attracted attention not only due to its superior performance compared to the alloy of the same average composition in terms of energy consumption but also due to its strong response to an external magnetic field (giant magnetoresistance) that has been speculated to arise from switching between topological insulator (RESET) and normal insulator (SET) phases. Here we report magneto-optical Kerr rotation loops in the visible range, that have mirror symmetric resonances with respect to the magnetic field polarity at temperatures above 380 K when the material is in the SET phase that has Kramers-pairs in spin-split bands. We further found that this threshold temperature may be controlled if the sample was cooled in a magnetic field. The observed results open new possibilities for use of iPCM beyond phase-change memory applications. PMID- 25030305 TI - Liver and kidney concentrations of strontium, barium, cadmium, copper, zinc, manganese, chromium, antimony, selenium and lead in cats. AB - BACKGROUND: In order to provide new knowledge on the storage of strontium (Sr), barium (Ba), cadmium (Cd), copper (Cu), zinc (Zn), manganese (Mn), chromium (Cr), antimony (Sb), selenium (Se) and lead (Pb) in the feline organism, we measured the concentrations of these elements in the liver, renal cortex and renal medulla, evaluating also the impact of age, sex or the occurrence of a chronic kidney disease (CKD). The element concentrations in the tissues of 47 cats (22 male; 25 female; aged between 2 months and 18 years) were measured using inductively coupled plasma mass spectrometry. RESULTS: Cu, Zn and Mn were the highest in the liver, followed by the renal cortex and the renal medulla. The Cd concentrations were lower in the renal medulla compared to the renal cortex and the liver, and Sr was higher in the renal medulla compared to the liver. The Se concentrations in the cortex of the kidneys were higher than in the medulla of the kidneys and in the liver. Higher Cd concentrations were measured in the renal cortex of female cats, while no further gender-related differences were observed. Except for Cr, Sb and Se, age-dependencies were detected for the storage of all elements. The occurrence of a CKD also affected the storage of the elements, with lower concentrations of Ba (renal medulla), Zn (renal cortex; renal medulla) and Mn (liver; renal medulla), but higher Cd concentrations (liver; renal cortex) in diseased cats. CONCLUSIONS: In conclusion, the present results provide new information on the accumulation of specific elements in the feline liver and kidneys, demonstrating a dependency on age and an impaired kidney function, but not on the sex of the animals. PMID- 25030306 TI - Experience with percardiac interventions for multiple congenital heart diseases in children. AB - OBJECTIVES: To report our experience with percardiac interventions for multiple congenital heart diseases in children. METHODS: From April 2010 to December 2013, a total of 64 patients (33 males and 31 females), aged 4.38 +/- 2.97 years, with multiple congenital heart diseases underwent attempted percardiac interventional procedures. The cohort included 34 ventricular septal defects (VSDs) with atrial septal defect (ASD), 9 VSDs with patent foramen ovale (PFO), 17 VSDs with patent ductus arteriosus (PDA), 2 VSDs with pulmonary stenosis (PS) and 2 VSDs with ASD and PDA. A mini-incision in the inferior sternum was made, and percardiac device closure and balloon valvuloplasty were performed for VSD, ASD, PDA and PS. RESULTS: Fifty-nine patients (92%) were successfully occluded, and 5 (8%) were converted to open-heart surgery after the failure of occlusion. A total of 111 devices were implanted in the patients (average of 1.88 devices/patient). No severe complications occurred. Incomplete right bundle branch block (IRBBB) occurred in 5 patients (8%) after the operation. Atrioventricular valve regurgitation decreased in 4 patients (6%), but new trivial regurgitation was detected in another patient (2%). A trivial residual shunt without murmur was found in 1 patient (2%), and the residual shunt was closed in the 3-month follow up. Pericardial effusion occurred in 1 patient (2%). CONCLUSIONS: Treating the patients who have multiple congenital heart diseases with a percardiac intervention is feasible, and the results should be satisfactory. However, more experience and long-term follow-up are mandatory to assess the safety and effectiveness of these procedures as alternatives to conventional therapy. PMID- 25030307 TI - Uncovering adaptive evolution in the human lineage. AB - BACKGROUND: The recent increase in human polymorphism data, together with the availability of genome sequences from several primate species, provides an unprecedented opportunity to investigate how natural selection has shaped human evolution. RESULTS: We compared human branch-specific substitutions with variation data in the current human population to measure the impact of adaptive evolution on human protein coding genes. The use of single nucleotide polymorphisms (SNPs) with high derived allele frequencies (DAFs) minimized the influence of segregating slightly deleterious mutations and improved the estimation of the number of adaptive sites. Using DAF >= 60% we showed that the proportion of adaptive substitutions is 0.2% in the complete gene set. However, the percentage rose to 40% when we focused on genes that are specifically accelerated in the human branch with respect to the chimpanzee branch, or on genes that show signatures of adaptive selection at the codon level by the maximum likelihood based branch-site test. In general, neural genes are enriched in positive selection signatures. Genes with multiple lines of evidence of positive selection include taxilin beta, which is involved in motor nerve regeneration and syntabulin, and is required for the formation of new presynaptic boutons. CONCLUSIONS: We combined several methods to detect adaptive evolution in human coding sequences at a genome-wide level. The use of variation data, in addition to sequence divergence information, uncovered previously undetected positive selection signatures in neural genes. PMID- 25030308 TI - Differential effect of liver cirrhosis on the pregnane X receptor-mediated induction of CYP3A1 and 3A2 in the rat. AB - Conflicting results have been obtained by clinical studies investigating the effect of liver cirrhosis on enzyme induction. Because ethical concerns do not give consent for methodologically rigorous studies in humans, we addressed this question by examining the effect of the prototypical inducer dexamethasone (DEX) on the pregnane X receptor (PXR)-mediated induction of CYP3A1 and 3A2 in a validated animal model of liver cirrhosis obtained by exposure of rats to carbon tetrachloride. For this purpose, we assessed mRNA levels, protein expressions, and enzymatic activities of both CYP3A enzymes, as well as mRNA and protein expressions of PXR in rat populations rigorously stratified according to the severity of liver insufficiency. Constitutive mRNA and protein expressions of CYP3A1 and CYP3A2 and their basal enzyme activities were not affected by liver dysfunction. DEX treatment markedly increased steady-state mRNA level, protein content, and enzymatic activity of CYP3A1 in healthy and cirrhotic rats, irrespective of the degree of liver dysfunction. On the contrary, the inducing effect of DEX on gene and protein expressions and enzyme activity of CYP3A2 was preserved in moderate liver insufficiency, whereas it was greatly curtailed when liver insufficiency became severe. mRNA and protein expressions of PXR were neither reduced by liver dysfunction nor increased by DEX treatment. These results indicate that even the inducibility of cytochrome P450 isoforms under the transcriptional control of the same nuclear receptor may be differentially affected by cirrhosis and may partly explain why conflicting results were obtained by human studies. PMID- 25030309 TI - Intensive care unit-acquired blood stream infections: a 5-year retrospective analysis of a single tertiary care hospital in Korea. AB - PURPOSE: Bloodstream infections (BSIs) are serious complications with high mortality and morbidity in patients with critical illness. This study was conducted to analyze the clinical and microbiological characteristics as well as outcomes in patients with intensive care unit (ICU)-acquired BSIs. METHODS: Data from 1,545 patients admitted to the ICU were retrospectively collected from January 2005 to December 2010. ICU-acquired BSI was defined as a positive blood culture for a clinically significant bacterial or fungal pathogen obtained >72 h after admission to the ICU. Data on clinical and demographic characteristics, comorbid illness, causes of infections, causative pathogens, and clinical outcomes were analyzed. RESULTS: Among the 1,545 ICU patients analyzed, 129 ICU acquired BSIs occurred in 124 patients. Catheter-related BSIs (CR-BSIs) and ventilator-associated pneumonia (VAP) were the most common causes (29.4 and 20.9%, respectively). The most common isolates were Staphylococcus aureus in 35 (25.7%) and Candida species in 32 (24.8%) cases. Ninety-eight patients died (overall hospital mortality rate, 75.9%). ICU-acquired BSI-related mortality occurred in 23 (63.8%) and 7 (19.4%) of the VAP and CR-BSIs cases, respectively. The most commonly isolated microorganisms from these fatalities were S. aureus (12, 25.7%) and Acinetobacter species (12, 25.7%). In 99 ICU-acquired BSI cases, patients did not receive adequate empirical antimicrobial treatment at the onset of BSIs, whereas the patients in 30 cases did. CONCLUSION: ICU-acquired BSIs may be associated with high mortality in patients with critical illness. Meticulous infection control and adequate treatment may reduce ICU-acquired BSI-related mortality. PMID- 25030310 TI - Nanostructured molybdenum oxide-based antibacterial paint: effective growth inhibition of various pathogenic bacteria. AB - The prevention of bacterial infections in the health care environment is paramount to providing better treatment. Covering a susceptible environment with an antimicrobial coating is a successful way to avoid bacterial growth. Research on the preparation of durable antimicrobial coatings is promising for both fundamental surface care and clinical care applications. Herein, we report a facile, efficient, and scalable preparation of MoO3 paint using a cost-effective ball-milling approach. The MoO3 nanoplates (synthesized by thermal decomposition of ammonium heptamolybdate) are used as a pigment and antibacterial activity moiety in alkyd resin binders and other suitable eco-friendly additives in the preparation of paint. Surface morphology, chemical states, bonding nature, and intermolecular interaction between the MoO3 and the alkyd resin were studied using Raman and x-ray photoelectron spectroscopic analysis. The antibacterial properties of a prepared MoO3 nanoplate against various bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae) was determined using the microdilution method. Bacterial strains exposed to an MoO3 paint coated surface exhibit a significant loss of viability in a time-dependent manner. Fundamental modes of antibacterial activities ascribed from a biocompatible and durable MoO3 nanostructure incorporated into an alkyd resin complex are discussed. The obtained experimental findings suggest the potential utility of prepared MoO3-based paint coating for the prevention of health care associated infections. PMID- 25030311 TI - [Retinopathy of prematurity. Part I]. AB - Retinopathy of prematurity (ROP) is a disease that affects immature vasculature in the eyes of premature babies that potentially leads to blindness. Authors describe incidence, risk factors, pathophysiology and international classification of retinopathy of prematurity (ICROP). Key words: retinopathy of prematurity, incidence, pathophysiology, international classification. PMID- 25030312 TI - [Retinopathy of prematurity - therapy. Part 2]. AB - Retinopathy of prematurity (ROP) is a disease that affects immature vasculature in the eyes of premature babies that potentially leads to blindness. Authors describe revised indications for the treatment of ROP, standard treatment - peripheral retinal ablation by laser photocoagulation and the cryotherapy using off label treatment-intravitreal anti-VEGF injection. Key words: retinopathy of prematurity, indications, laser photocoagulation, cryotherapy, intravitreal anti VEGF therapy. PMID- 25030313 TI - [Long term results of phakic 6 refractive implantation for myopia correction]. AB - OBJECTIVE: To evaluate the safety and the long term results of anterior chamber phakic lens, Phakic 6 Refractive, for myopia correction. METHODS: In this retrospective study we reviewed the charts of 35 myopic patients (62 eyes) who had implantation of anterior chamber phakic lenses (Phakic 6 Refractive, Ophthalmic Innovations International, California, USA) for correction of myopia. The mean age of patients was 26 years (18 to 45 years). The mean spherical refraction was -9.9 (-4 to -18 D). The best corrected distant visual acuity (BCDVA) was 0.92 (1.2 to 0.3) before surgery. The mean follow-up was 8 years (4 to 10). The mean endothelial cell count was 2481 cells/mm2 and the mean pachymetry was 540 MUm before surgery. In those patients who needed a second surgical intervention (explantation or lens reposition) the last follow-up visit is the visit before the lens explantation or reposition. The same surgeon (P. R.) performed all surgeries and used the same technique in each surgery. RESULTS: On the final follow up visit the BCDVA was in the mean 1.02 (1.5 to 0.5). The spherical refraction was in the mean - 0.53 D (-3.0 to +1.0). We noticed a 16% decrease in the mean number of corneal endothelial cells, and no change in the pachymetry values. We had to explant the lenses in 7 eyes (12 %) because of the decreased endothelial cells count. 2 eyes (3.0 %, 1 patient) had to receive treatment for glaucoma, 4 eyes (6.5 %) had to have the artificial lens repositioned, 1 patient had to have photocoagulation therapy for a retinal tear. 93 % of the study eyes had stable refraction during the study period. There was a 10 % increase in the average BCDVA, and there was a 95 % improvement of the original refractive error. CONCLUSIONS: In selected cases, the implantation of Phakic 6 Refractive anterior chamber lens is a viable option despite it is currently largely abandoned. Key words: Phakic 6 Refractive implantation, myopia correction. PMID- 25030314 TI - [Screening retinopathy of prematurity (ROP)]. AB - Retinopathy of prematurity (ROP) is abnormal blood vessel development in the retina of the eye in a premature infant that potentially leads to blindness. The guidelines present the timing of initial examination and subsequent reexamination intervals for screening and treating ROP. Key words: retinopathy of prematurity, screening, timing of the examination. PMID- 25030315 TI - [Eye manifestation of extrarenal malignant rhabdoid tumour]. AB - Extrarenal malignant rhabdoid tumour (EMRT) is very rare and aggresive childhood neoplasm with a rapid progression. The prognosis is still very poor with 80 % mortality rate. We report a case of a newborn baby with extrarenal malignant rhabdoid tumour of an upper eyelid. An EMRT was diagnosed based on the histological examination. This case report highlights the clinical presentation, radiological features and difficulty in diagnosis. The purpose is to underline the importance of its inclusion in the differential diagnosis of any aggresive lesion in a child. Key words: malignant rhabdoid tumour, childhood, diagnostic process. PMID- 25030316 TI - [Extraocular muscle involvement in patients with thyroid-associated orbitopathy]. AB - AIM: To determine the frequency of extraocular rectus muscle involvement in patients with thyroid-associated orbitopathy (TAO). MATERIALS AND METHODS: A total of 154 orbits of 77 adult patients (53 women and 24 men) with TAO aged from 18 to 81 years (median 49 years) were investigated. Only patients with clear signs of TAO and confirmed thyroid disease who had been referred to the Department of Ophthalmology of the Olomouc University Hospital from May 2007 to December 2012 were included. All patients underwent general ophthalmic examination and ultrasonographic and MRI examinations of the orbit. The largest short and long cross-sectional diameter for every rectus muscle was measured on MRI scans. Spearman correlation analysis was used to determine the correlations between the diameters of rectus muscles and exophthalmos values obtained. RESULTS: A positive moderate correlation (r = 0.514) was shown between the sum of short parameters of all rectus muscles and exophthalmos values. When compared with the normative values and taking gender into account, enlargement of the medial rectus muscle (RM) was found in 55.2 %, of the lateral rectus muscle (RL) in 33.8 %, the inferior rectus muscle (RI) in 57.1 %, and of the superior muscle group (RS) in 59.1 %. In the cases of single-muscle enlargement, the most frequently affected muscle was the RS (48.8 %), followed by the RI (31.7 %) and RM (19.5 %). No case of single-muscle enlargement of the RL was observed. In the cases of two-muscle enlargement, the RS was involved in 64.3 %, the RI and RM in 60.7 %, and the RL in 14.3 %. In the cases of three-muscle enlargement, the most frequently affected muscle was the RM (93.1 %), followed by the RI (86.2 %), RS (69%), and RL (51.7 %). CONCLUSION: Our study found that, in cases with single muscle enlargement in patients with TAO, the vertical rectus muscles were most likely involved. On the other hand, in cases with multiple-muscle enlargement, the muscle most likely involved was the medial rectus muscle. In addition, the superior muscle group was noted to be affected more frequently than reported in the world literature. Key words: thyroid-associated orbitopathy, extraocular muscles, magnetic resonance imaging. PMID- 25030317 TI - [Acute posterior multifocal placoid pigment epitheliopathy - case report]. AB - Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) affects individuals between 20 to 30 years of age and ocular manifestations are often preceded by flu-like illness. Symptoms of the disease include acute vision decrease associated with central and paracentral scotoma. Impairment of vision is usually bilateral, but may be asymmetric. We report the case of a man at the age of twenty-one, who was treated for APMPPE. Due to the involvement of the macula, low visual acuity and related immunogenetic predisposition (HLA-B27 positivity) was recommended corticosteroid therapy with a good therapeutic effect. Key words: acute posterior multifocal placoid pigment epitheliopathy (APMPPE), white dot syndromes, macular edema. PMID- 25030318 TI - A series of 3D metal organic frameworks based on [24-MC-6] metallacrown clusters: structure, magnetic and luminescence properties. AB - Four isostructural metal organic frameworks (MOFs), namely [Co6(HipO)6].6H2O (1), [Mn6(HipO)6].6H2O (2), [Cd6(HipO)6].6H2O (3) and [Zn6(HipO)6].7H2O (4) (H3ipO = 2 hydroxyisophthalic acid), were synthesized and structurally characterized. They have a 3D (4,6)-connected framework based on [24-MC-6] metallacrown clusters ([24 MC-6]-based MOFs). The arrangements of the 24-MC-6 metallacrown SBUs show a regular change indicated by the orientation of their symmetry axes, resulting in a special dense packing mode different from other [24-MC-6]-based MOFs. The analysis of SQUID measurements reveal that compound 1 displays the dominant antiferromagnetic exchanges in 300-10 K between the adjacent Co(II) ions and a ferromagnetic-like behavior at lower temperatures, whereas compound 2 shows an antiferromagnetic interaction between the adjacent Mn(II) ions. Compound 1 exhibits a magnetocaloric effect (MCE) with the resulting entropy change ( DeltaS(m)) of 15.20 J kg(-1) K(-1) for DeltaH = 50 kG at 6 K, which is the highest value among the cobalt-based MOFs with MCE reported so far. The luminescence properties of compounds 3 and 4 were studied, both of them exhibit photoluminescence in the solid state at room temperature which can be ascribed to intraligand pi->pi* transitions. PMID- 25030319 TI - Novel peptides that inhibit heparanase activation of the coagulation system. AB - Heparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator - tissue factor (TF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11-14 amino acids, inhibited heparanase procoagulant activity but did not affect TF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency. PMID- 25030320 TI - Susceptibility of sheep, human, and pig erythrocytes to haemolysis by the antimicrobial peptide Modelin 5. AB - Modelin-5-CONH2, a synthetic antimicrobial peptide, was used to gain an insight into species-selective haemolytic activity. The peptide displayed limited haemolytic activity against sheep (12%), human (2%), and pig (2%) erythrocytes. Our results show that Modelin-5-CONH2 had a disordered structure in the presence of vesicles formed from sheep, human, and pig erythrocyte lipid extract (<26% helical) yet folded to form helices in the presence of a phosphatidylcholine (PC) membrane interface (e.g. >42% in the presence of 1,2-dimyristoyl-sn-glycero-3 phosphocholine). Monolayer studies showed a strong correlation between anionic lipid content and monolayer insertion and lysis inducing surface pressure changes of 9.17 mN m(-1) for 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine compared with PC monolayers, which induced pressure changes of ca. 3 mN m(-1). The presence of cholesterol in the membrane is shown to increase the packing density as the PC:sphingomyelin (SM) ratio increases so preventing the peptide from forming a stable association with the membrane. The data suggests that the key driver for membrane interaction for Modelin-5-CONH2 is the anionic lipid attraction. However, the key factors in the species-specific haemolysis level for this peptide are the differing packing densities which are influenced by the SM:PC:cholesterol ratio. PMID- 25030321 TI - Detailed observation of space-charge dynamics using ultracold ion bunches. AB - Control of Coulomb expansion in charged particle beams is of critical importance for applications including electron and ion microscopy, injectors for particle accelerators and in ultrafast electron diffraction, where space-charge effects constrain the temporal and spatial imaging resolution. The development of techniques to reverse space-charge-driven expansion, or to observe shock waves and other striking phenomena, have been limited by the masking effect of thermal diffusion. Here we show that ultracold ion bunches extracted from laser-cooled atoms can be used to observe the effects of self-interactions with unprecedented detail. We generate arrays of small closely spaced ion bunches that interact to form complex and surprising patterns. We also show that nanosecond cold ion bunches provide data for analogous ultrafast electron systems, where the dynamics occur on timescales too short for detailed observation. In a surprising twist, slow atoms may underpin progress in high-energy and ultrafast physics. PMID- 25030322 TI - Highly sensitive real-time assay of inorganic pyrophosphatase activity based on the fluorescent gold nanoclusters. AB - On the basis of the competition assay approach and fluorescent 11 mercaptoundecanoic acid-capped AuNCs (AuNCs@11-MUA) with unique optical properties, a convenient, reliable and highly sensitive real-time assay of pyrophosphatase (PPase) activity is established and developed for the first time. Pyrophosphate (PPi) could recover the Cu(2+)-quenched AuNCs@11-MUA fluorescence selectively owing to the higher binding affinity between PPi and Cu(2+) than that between 11-MUA and Cu(2+). Whereas PPase could catalyze the hydrolysis of PPi, thus released Cu(2+), leading to fluorescence requenching of the AuNCs@11-MUA. In the assay, a good linearity between the fluorescence response and PPase activity within a range from 1 to 20 mU is found, with a detection limit of less than 1 mU, which is better than other PPase assays using PPi as the substrate. Additionally, we demonstrate that our AuNCs@11-MUA-based fluorescent assay can be applied to assay the PPase activity in real biological samples such as the cell lysate. This strategy paves a new avenue for exploring the sensing applications of fluorescence AuNCs and improving the development of competition assay approach. PMID- 25030323 TI - Ab initio molecular dynamics simulations of water and an excess proton in water confined in carbon nanotubes. AB - Ab initio molecular dynamics simulations were performed to investigate the effects of nanoscale confinement on the structural and dynamical properties of water and slightly acidic water. Single-walled carbon nanotubes (CNTs) of two different diameters (11.0 and 13.3 A) were used as confinement vessels, and the inner walls of the CNT were either left bare or fluorinated to explore the influence of the confined environment on the determined properties. The water molecules in the fluorinated nanotubes were found to preferentially localize near the CNT surface and exhibit highly ordered structures while those in the bare CNTs were more randomly distributed. Additionally, weak interactions that resembled hydrogen bonds between the water molecules and the fluorine atoms were observed which occurred at a greater frequency in the smaller diameter CNT indicating an influence of the confinement dimensions on these interactions. This was further pronounced when an excess proton was added where, on average, approximately half of the water molecules in the smaller tube were involved in these interactions. This also led to a structured hydrogen bond network with regular defect sites that hindered proton transfer along the channel axis. Addition of the proton in the larger fluorinated CNT, however, disrupted the structural ordering and proton transfer down the nanotube axis near the surface of the CNT wall readily occurred. Proton transfer through the channel was also observed in the smaller nonfluorinated system, however, the proton was located closer to the center of the CNT, while in the larger nonfluorinated CNT proton transfer exhibited less directional preference indicating an impact of the scale of confinement and nature of the surface on proton transfer. PMID- 25030324 TI - Prevalence and predictors of low bone density and fragility fractures in women with systemic lupus erythematosus in a Mediterranean region. AB - Studies have found an increase in bone loss and fracture in individuals with systemic lupus erythematosus (SLE) compared with general population. The aim of this study was to describe the prevalence of osteopenia, osteoporosis, and fragility fractures and to find potential predictors of bone loss in our cohort of SLE patients. We performed a cross-sectional study and collected 67 bone density measurements (BMD) of our SLE patients. We also collected sociodemographic data, 25-OH-vitamin D levels, serological markers, activity index, SLE cumulative damage index, and pharmacologic treatment. Sixty-seven consecutive BMD from SLE patients were assessed. Osteopenia was found in 28-46% of SLE patients. Osteoporosis ranged from 3 to 6%[corrected]. The only statistically significant correlation we found was between weight and height with total hip and femoral neck BMD (p < 0.05). The most frequent BMD-affected site was at the femoral neck, showing osteopenia in 40.3% [corrected] of SLE patients. Osteoporosis was found in up to 6% [corrected] of SLE patients. We found no predictors of bone loss in relation to the disease activity or its treatment. Fragility fractures were seen in 4.4% of SLE patients. All patients with fragility fractures showed osteopenia at BMD. There is a high prevalence of bone loss in SLE patients, since up to 40% [corrected] of SLE patients showed low BMD. Total hip and femoral neck osteopenia were the most frequent findings correlated with low BMI. We found a lower prevalence of fragility fractures compared with other series. PMID- 25030325 TI - Third-line treatment for overactive bladder: should mirabegron be tried before intravesical botulinum toxin A therapy? AB - INTRODUCTION AND HYPOTHESIS: Mirabegron is a new beta 3 agonist for the treatment of overactive bladder (OAB). Although there are extensive data from randomised controlled trials, there is little real world evidence about its effectiveness and side effects. We conducted a prospective cohort study to evaluate the effectiveness of mirabegron as third-line treatment in patients with refractory OAB who did not benefit from antimuscarinic therapy and bladder drill. METHODS: The study was a prospective consecutive cohort of 67 women treated with mirabegron 50 mg. All the patients had symptoms of urgency with or without urgency incontinence and had failed to improve with bladder drill and at least one antimuscarinic medication. The outcomes were assessed after 6 weeks using the International Consultation of Incontinence Modular Questionnaire Short Form (ICIQ SF), Patient Global Impression of Improvement (PGI-I) scale and Kings Health Questionnaire (KHQ). RESULTS: The mean number of previous antimuscarinics was 2.81 (range 1-6). Forty out of 67 patients (60 %) described an improvement in their OAB. Responders demonstrated a significant improvement in 5 out of 10 domains of the KHQ. Similarly, the ICI-Q score improved from a mean of 12.7 (+/ 5.3) to 9.2 (+/-5.3; p <= 0.008). Seven women (10 %) stopped mirabegron because of side effects. CONCLUSIONS: This post-marketing surveillance study confirms that mirabegron improves clinical and quality of life outcomes in patients with OAB. The rate of side effects was low. This study supports mirabegron use as a third-line treatment for overactive bladder. PMID- 25030326 TI - Robotic Burch colposuspension: a surgical case and instructional video. AB - INTRODUCTION AND HYPOTHESIS: The Burch colposuspension is a well-studied and proven surgical treatment for stress urinary incontinence without intrinsic sphincter deficiency. The advent of the minimally invasive mid-urethral sling has given rise to diminished surgical experience in performing the Burch. Recent anti mesh media and FDA notifications have caused patients to demand mesh-free surgery, resulting in an opportunity for the resurgence of the Burch procedure. The objective of this video is to demonstrate surgical technique and instruction for a robotic Burch colposuspension as well as recommendations for successful completion of the procedure. Additionally, the video reviews and illustrates pertinent surgical anatomy regardless of approach. METHODS: The patient is a 53 year-old woman who presented with symptoms of vaginal pressure, urinary incontinence, and constipation. She had symptoms and urodynamics consistent with mixed urinary incontinence without intrinsic sphincter deficiency and had been treated with antimuscarinics for overactive bladder. On examination she was found to have stage II prolapse. She desired surgical management of both her prolapse and stress incontinence. CONCLUSION: Robotic Burch colposuspension can be completed in a safe and effective manner and should be considered as an option for patients in whom an anti-incontinence procedure is indicated and who are already undergoing robotic surgery. PMID- 25030327 TI - Contasure-Needleless(r) single incision sling compared with transobturator TVT O(r) for the treatment of stress urinary incontinence: long-term results. AB - INTRODUCTION AND HYPOTHESIS: This study compared transobturator tension-free vaginal tape (TVT-O(r)) and Contasure-Needleless (C-NDL(r)) at long-term follow up . METHODS: Non-inferiority, prospective, single-centre , quasi-randomised trial started in September 2006 and finished in April 2011 to compare C-NDL(r) with transobturator vaginal tape (TVT-O(r)) mesh in the treatment of stress urinary incontinence (SUI) . Epidemiological information, intraoperative and postoperative complications, subjective estimates of blood loss and pain levels were recorded. We also analysed the postoperative stress test, the subjective impression of improvement using the Sandvik Severity Index and the quality of life during follow-up using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) . RESULTS: Two hundred and fifty-seven women with primary SUI were scheduled to receive TVT-O(r) or C-NDL(r) and were followed up at least 3 years after the procedure . One hundred and eleven women in the C NDL(r) group (84.7%) had a negative stress test, compared with 54 women (88.9%) in the TVT-O(r) group (p = 0.0065 for the non-inferiority test). The postoperative Sandvik Severity Index was 0 or better than the preoperative score in 90.7% of patients in the C-NDL(r) group and 95.4% of patients in the TVT-O(r) group (p = 0.0022). The complication rate was similar in both groups. There were significant differences (p = 0.02) in postoperative pain within the TVT-O(r) group. The degree of satisfaction was not statistically significant between the two groups. CONCLUSIONS: The outcomes for the C-NDL(r) group were similar to those of the TVT-O(r) group, adding the concept of "single incision tape" to the tension-free sling option. PMID- 25030328 TI - Epilepsy in newborns with tuberous sclerosis complex. AB - BACKGROUND: Epilepsy affects up to 90% of TSC patients and majority of them have seizure at the age of 3-5 months, after a period of latent epileptogenesis, but some develop epilepsy earlier. AIMS: The aim of this work was to identify incidence, clinical characteristics, and risk factors for neonatal onset of epilepsy in a large cohort of TSC patients. METHODS: A retrospective review of medical data of 421 TSC patients was performed. Patients who developed epilepsy within first 4 weeks of life were included in the study. Clinical and treatment data, EEG, MRI, and genetic analyses were assessed. RESULTS: Epilepsy was present in 366 (86.9%) patients. Twenty-one (5.7%) developed epilepsy as newborns. Mean follow-up was 44.86 (6-170) months. Six patients were seizure free and 15 had drug-resistant seizures at the end of follow-up. Mental retardation was found in 81% of patients. In 11 (52.4%) patients brain MRI revealed large malformations of cerebral cortex, meeting the criteria for focal cortical dysplasia (FCD). FCD was revealed in both TSC1 and TSC2 mutation cases. Other risk factors for neonatal epilepsy included: perinatal complications and congenital SEGAs. Presence of FCD was associated with more severe epilepsy and worse neuropsychological outcome. Epilepsy surgery resulted in improvement in seizure control. CONCLUSIONS: Neonatal onset of epilepsy in TSC is frequently associated with large malformations of cerebral cortex. Patients with FCD are at high risk of severe drug-resistant epilepsy and poor neuropsychological outcome. Early epilepsy surgery may be beneficial and should be considered in such cases. PMID- 25030329 TI - Headache types, related morbidity, and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross sectional study. AB - BACKGROUND: Increased headache prevalence was recently reported in survivors of childhood ALL. Headache sub types, related morbidity, and effect on quality of life has not been reported thus far. OBJECTIVE: To study headache prevalence and type, related disability, and quality of life in a cohort of childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: Childhood ALL survivors in at least 1-year of remission and 5 years from diagnosis completed questionnaires and were evaluated by a neurologist. Disability was evaluated with Pediatric Migraine Disability Assessment scale and the Short Form-36 Health Survey assessed quality of life. RESULTS: Thirty nine of 72 (54%) females and 37 of 90 (41%) males reported headaches. Median time from ALL diagnosis to first headache was 5.2 years and median age at headache onset was 10.1 years in 76 participants with headache. Migraine headaches were diagnosed in 51 (31%) and episodic tension-type headaches in 49 (30%); migraine and tension-type headaches co-existed in 24 (15%) and 18 (11%) participants had chronic daily headaches. Fatigue was associated with migraine headache while hypertension and female gender associated with tension type headache. Headache-related disability was mild in 22 (29%), moderate in 7 (9%), and severe in 5 (7%) survivors, and was absent in the remaining 42 (55%) survivors with headache. Both migraine and tension type headaches associated with reduced mental component scores, while headache related disability associated with a reduced physical component scores. CONCLUSIONS: Headaches are common in ALL survivors but only a minority has significant disability or impairment of quality of life. PMID- 25030330 TI - Calcific embolization with infective endocarditis involving the posterior mitral leaflet in a patient with underlying hypertrophic obstructive cardiomyopathy. AB - We report a case of infective endocarditis (IE) involving the posterior mitral leaflet (PML) with calcific embolization in a patient with hypertrophic obstructive cardiomyopathy (HOCM). Amongst HOCM patients with IE, the anterior mitral leaflet and basal septal myocardium are almost always involved due to the endocardial damage caused by recurrent outflow obstruction and valvular regurgitation. The management of our patient was complicated by moderate mitral stenosis, repeated calcific embolic strokes, dynamic left ventricular outflow track obstruction, and respiratory failure due to flash pulmonary edema. To our knowledge, this is the first reported case of PML involvement in HOCM presenting in this manner. PMID- 25030331 TI - Right atrial thrombosis associated with hemodialysis catheter: first description of recurrence in a poorly understood problem. AB - Catheter-related right atrial thrombosis (CRAT) is an underreported and potentially life-threatening complication of central venous catheter in hemodialysis patients. The accurate incidence is unknown, with reported rates ranging from 2 to 12.8% [1] in series, up to 29% [2] in a postmortem prospective study, and high mortality rates (18%) [1]. The optimal treatment for CRAT is controversial and nonsystematized, including anticoagulation, thrombolysis, and surgical thrombectomy. We report two cases of CRAT in dialysis patients, who underwent surgical thrombectomy. One case required reintervention because of recurrence, a first reported case in hemodialysis population. PMID- 25030332 TI - Measuring anxiety in children: a methodological review of the literature. AB - This paper provides a comprehensive methodological review of the literature concerning anxiety measurement in children. Initially, a conceptual basis for anxiety measures is introduced, followed by specific approaches to measuring childhood anxiety based on 14 original articles. In particular, a variety of strategies that have been used in previous research are discussed in detail with theoretical underpinnings. Common approaches to measure anxiety such as self reported instruments, observational ratings, and behavioral checklists are reviewed one by one with a critical look at the strengths and weaknesses of each of these approaches. While multiple measures of anxiety are available to assess the level of anxiety in children, selection of measurement approach should be an iterative process based on rigorous evaluation of evidence of reliability and cross-validation of the tool across different age groups of children. PMID- 25030333 TI - Loneliness, depression and health status of the institutionalized elderly in Korea and Japan. AB - PURPOSE: The purpose of the study was to describe loneliness, depression, and health status in Korean and Japanese institutionalized elderly and explore differences between the countries. Also this study determined predictors of depression in each group. METHODS: Elderly subjects, aged 65-98 (n = 184), were recruited from private nursing homes in Korea and Japan. Subjects were interviewed on health status, loneliness, and depression. RESULTS: Korean subjects had higher loneliness scores than Japanese. More Korean elderly had depressive symptoms than Japanese elderly. The mean GDS score of Korean elderly was 8.07 and that of Japanese elderly was 5.21. Korean elderly had less physical function, and perceived their general health to be poor. Loneliness and perception of general health were significant predictors of depression in Korean and Japanese subjects. CONCLUSION: It is necessary to assess the levels of loneliness and depression of institutionalized Korean elderly and pursue an intervention to reduce these problems. PMID- 25030334 TI - Mammography use and its demographic correlates among women in South Korea. AB - OBJECTIVE: This study aimed to investigate the mammography rate and its demographic correlates among Korean women in order to provide basic understanding of factors related to the performance of mammography as a method of breast cancer screening. METHODS: A descriptive secondary analysis was conducted using a national data set from the Korean National Health and Nutrition Examination Survey (KNHNES III) in South Korea. A total number of 2,602 women over 40 years of age were chosen for the analysis. Main research variables included the use of mammography, monthly income, residential area, age, marriage, education, insurance, smoking habits, drinking habits, job type, current health status, and other cancer screening results. RESULTS: Only 30.59% of women adhered to the national guidelines. Monthly income, age, education, insurance, and smoking habits had statistically significant effects on breast cancer screening performance. CONCLUSIONS: The demographic correlates of the performance of mammography highlight the fact that not all Korean women, at this stage, are in a socioeconomic or societal position to undergo biannual mammography screening. IMPLICATIONS FOR NURSING: Targeted and tailored nursing intervention should be implemented in middle- and senior-aged women who lack the ability to access medical resources in South Korea. This will make it possible for marginalized women to utilize cancer screening tests and in turn promote their health. PMID- 25030335 TI - Mentorship in the Japanese nursing education community. AB - OBJECTIVES: The purpose of this study was to investigate the characteristics of mentorship in the Japanese nursing education community. METHODS: The participants of this study were sophomore and graduate students and faculty members from a nursing school at a Japanese university. The study was described to each of the subjects and potential participants had the choice to participate in the study. This descriptive study utilized a self-administered questionnaire that included questions about years of nursing experience, educational level, their relationship with mentors, characteristics of mentors, and mentoring behaviors. Fifty-eight of 115 sophomores (Group 1), all 28 graduate students (Group 2), and 17 of 21 faculty members completed the questionnaire (Group 3). Chi-square and Kruskal-Wallis tests were used to investigate if differences existed among the groups. Data were collected from 2001 to 2002. RESULTS: The mentors' characteristics which were 1) supportive, 2) provide vision, and 3) objective/clear-thinker were similar for the three groups. Group 1 and Group 2 received a significantly higher percentage of support for personal problems and offered more quotable quotes from their mentors compared with Group 3. Group 2 received the greatest amount of mentoring support from their mentors among the three groups. CONCLUSIONS: Findings from the study suggest that the characteristics of mentors in the Japanese nursing education community may be described as supportive, visionary, and objective/clear-thinkers. The combination of situation and position appears to influence the participants' identification of characteristics of their mentors, the type of behaviors they look for in a mentor, and if they view themselves as a mentor. PMID- 25030336 TI - Depression and PTSD in Pashtun Women in Kandahar, Afghanistan. AB - OBJECTIVES: The objectives were (a) to establish prevalence of depression and post-traumatic stress disorder (PTSD) in Afghanistan and, (b) to investigate sociodemographic and quality of life variables, which predict depression and PTSD. METHODS: Translated versions of the Beck Depression Inventory, Impact of Event Scale-Revised, and Quality of Life Inventory were administered to 125 Pashtun women in Kandahar, and statistically analyzed. RESULTS: Approximately half of the participants showed moderate to severe levels of depression, and more than half of the participants exhibited symptoms of PTSD. Education and income showed significant associations with PTSD symptoms or depression. The way one spends time, general health status, and general feeling towards life predicted low levels of depression and PTSD. CONCLUSIONS: The high prevalence of depression and PTSD indicate the continuing need for mental health intervention. While education has been found to be a protective factor for mental health in previous studies, the relationship between education and mental health appear to be more complex among Afghan women. Quality of life variables could be further investigated and incorporated into mental health interventions for Afghan women. PMID- 25030337 TI - Efficient utilization of cassava pulp for succinate production by metabolically engineered Escherichia coli KJ122. AB - A metabolically engineered Escherichia coli KJ122 was efficiently utilized for succinate production from cassava pulp during batch separate hydrolysis and fermentation (SHF) under simple anaerobic conditions. Succinate concentration of 41.46 +/- 0.05 g/L with yield and productivity of 82.33 +/- 0.14 g/100 g dry pulp and 0.84 +/- 0.02 g/L/h was obtained. In batch simultaneous saccharification and fermentation (SSF), hydrolysis of 12 % (w/v) cassava pulp with an enzyme loading of 2 % AMG + 3 % Cel (v/w) at pH 6.5 was optimized at 39 degrees C. Succinate concentration of 80.86 +/- 0.49 g/L with a yield of 70.34 +/- 0.37 g/100 g dry pulp and a productivity of 0.84 +/- 0.01 g/L/h was attained using E. coli KJ122. Fed-batch SSF significantly enhanced succinate concentration to 98.63 +/- 0.12 g/L at yield and productivity of 71.64 +/- 0.97 g/100 g dry pulp and 1.03 +/- 0.01 g/L/h. This result indicated an efficient and economical succinate production from cassava pulp using SHF and SSF by the use of E. coli KJ122. PMID- 25030338 TI - Improving the catalytic potential and substrate tolerance of Gibberella intermedia nitrilase by whole-cell immobilization. AB - Comparative studies of immobilized and free cells of Gibberella intermedia CA3-1 in bioconversion of 3-cyanopyridine to nicotinic acid were performed. Entrapping method was chosen based on the advantages in enzymatic activity recovery, mechanical strength and preparation procedure. Four entrapment matrices were investigated and sodium alginate was screened to be the most suitable material. Maximal nitrilase activity of alginate immobilized cells was obtained under conditions of 2 % alginate, 0.6 % CaCl2, 0.4 g cell/g alginate, 1.8 mm bead size. The immobilized cells showed excellent substrate tolerance even when the 3 cyanopyridine concentration was 700 mM. The half-lives of immobilized cells at 30, 40 and 50 degrees C were 315, 117.5 and 10.9 h, respectively, correspondingly 1.4, 1.6 and 1.7-fold compared with that of the free cells. Efficient reusability of immobilized cells up to 28 batches was achieved and 205.7 g/(g dcw) nicotinic acid was obtained with 80.55 % enzyme activity preserved. PMID- 25030339 TI - Health 2.0: Relational Resources for the Development of Quality in Healthcare. AB - Traditional approaches in healthcare have been challenged giving way to broader forms of users' participation in treatment. In this article we present the Health 2.0 movement as an example of relational and participatory practices in healthcare. Health 2.0 is an approach in which participation is the major aim, aspiring to reshape the system into more collaborative and less hierarchical relationships. We offer two illustrations in order to discuss how Health 2.0 is related and can contribute to a positive uptake of patient's knowledge, which implies challenging healthcare practices exclusively focused on scientific expertise. In contrast, the illustrations we discuss focus on relations and cultural practices, searching for responsive and context-sensitive interventions, entertaining multiple views and allowing space for creativity. Finally we introduce two relational resources to contribute with the development and sustainability of Health 2.0 practices: Relational being and edge of fluidity. Those are resources aiming to engage professionals in a type of conversation with their clients, which is different from the hierarchical, linear and fact-oriented approach. This conversation aims at creating a space where the voices of all involved are welcomed, raising different opinions and points of view, bringing up new light and possibilities to the problem being investigated. These resources may be useful for those who are interested in improving quality in healthcare by investing in collaboration, contextual sensitivity and relational engagement. PMID- 25030340 TI - Weight Gain and its Correlates among Breast Cancer Survivors. AB - PURPOSE: Weight gain after diagnosis of breast cancer is a profound issue that may negatively impact cancer prognosis. However, most existing research on weight change has been conducted in Western countries. In addition, several factors related to weight gain have been reported; however, the evidence is inconsistent. The purpose of this study was to examine weight gain and its correlates among Korean breast cancer survivors. METHODS: A total of 132 female breast cancer survivors were recruited from one university hospital in South Korea. Participants completed anthropometric measurements (i.e., body weight, height) and a self-reported questionnaire, including the International Physical Activity Questionnaire Short Form and Mini Dietary Assessment. RESULTS: The mean weight change was -0.09 kg (SD = 4.28). Only 27 women (19.7%) gained more than 5% of their weight at diagnosis, 59.1% maintained weight, and 21.2% lost weight. In multivariate logistic regression analysis, significant correlates of weight gain were younger age, obesity at diagnosis, duration of more than 36 months since diagnosis, and low diet quality. CONCLUSION: Younger women, women who were obese at diagnosis, women with more than 36 months since diagnosis, or women who showed lower diet quality should be considered at high-risk for weight gain. Findings from our study suggest that optimal weight management strategies should be developed using ethnically- or culturally-appropriate approaches. PMID- 25030341 TI - Effect of the Group Music Therapy on Brain Wave, Behavior, and Cognitive Function among Patients with Chronic Schizophrenia. AB - PURPOSE: The purpose of the study was to examine the effect of group music therapy on brain waves, behavior, and cognitive function among patients with chronic schizophrenia. METHODS: A quasi-experimental pretest-posttest design was used with nonequivalent control group. The potential participants were recruited from inpatients in a psychiatric facility in a metropolitan city, assigned either to the experimental group (n = 28) or to the control group (n = 27) according to their wards to avoid treatment contamination. The experimental group participated in the group music therapy for 13 sessions over 7 weeks while continuing their standard treatment. The control group only received a standard treatment provided in the hospitals. The outcome measures include brain wave by electroencephalography, behavior by Nurses' Observation Scale for Inpatient Evaluation, and cognitive function by Mini-Mental State Examination. RESULTS: After participating in 13 sessions of the group music therapy, alpha waves measured from eight different sites were consistently present for the experimental group (p = .006-.045) than the control group, revealing that the participants in the music therapy may have experienced more joyful emotions throughout the sessions. The experimental group also showed improved cognitive function (F = 13.46, p = .001) and positive behavior (social competence, social interest & personal neatness) while their negative behaviors was significantly less than those of the control group (F = 24.04, p < .001). CONCLUSION: The group music therapy used in this study was an effective intervention for improving emotional relaxation, cognitive processing abilities along with positive behavioral changes in patients with chronic schizophrenia. Our results can be useful for establishing intervention strategies toward psychiatric rehabilitation for those who suffer from chronic mental illnesses. PMID- 25030342 TI - Experiences with nausea and vomiting during pregnancy in Turkish women based on roy adaptation model: a content analysis. AB - PURPOSE: This qualitative study aimed to explore how Turkish women experience nausea and vomiting in pregnancy based on the Roy Adaptation Model. METHODS: To collect data, in-depth interviews were undertaken with 35 pregnant women who had nausea and vomiting. The sample of the study included pregnant women who were in their first 12 weeks of gestation, did not have medical problems and had nausea, retching and/or vomiting for at least the last 3 days. Data were collected in semi-structured interview form based on the Roy Adaptation Model and with a background data sheet. Data were analyzed using direct content analysis. RESULTS: Data were classified into four adaptive modes according to the Roy Adaptation Model. The behaviors in the physiological mode were nausea, vomiting, fatigue, changes in sleep patterns, inadequate nutrition, inguinal pain, burning sensation and irritation in the throat, ketosis, and urinary incontinence. The behaviors in the self-concept mode were feeling weak, crying, inadequate self-care, changes in sexual intercourse, and social isolation. The behaviors in the role function mode were being unable to fulfill the responsibilities at home and work. The behaviors in the interdependence mode were dissatisfaction with relationships. CONCLUSION: The study findings help nursing staff detect the stimuli and the behaviors of pregnant women with nausea and vomiting. Further research may evaluate the impact of a counseling program prepared under the guidance of a nursing model on nausea and vomiting in pregnancy. PMID- 25030343 TI - Integrative smoking cessation stage model for chinese students studying in Korea. AB - PURPOSE: The present study aimed at developing an integrative stage model of smoking cessation behavior by combining highly predictable constructs extracted from previously verified health behavior models. The fitness of the hypothetical model was also tested. METHODS: The study participants were 214 Chinese students studying in Korea, presenting high smoking rates. Perceived severity, benefit, barrier, self-efficacy, and social support were measured using the modified Attitudes-Social Influences-Self Efficacy Questionnaire. Demographic and smoking related characteristics were also evaluated. RESULTS: Results showed that the hypothetical model provides a good fit. Significant psychosocial predictors of smoking cessation stage were perceived benefit (p = .050), barrier (p = .003), and social support (p = .003). Among demographic and smoking-related characteristics, gender (p = .030), duration of smoking (p = .010), and previous smoking cessation experience (p = .020) were found to influence smoking cessation stage. In addition, gender, age, number of cigarettes smoked, previous smoking cessation experience, smoking-related symptoms, and smoking cessation education needs were found to influence psychosocial constructs significantly. CONCLUSION: The significant psychosocial predictors and demographic and smoking-related characteristics defined in the present study appear to be potent and promising predictors of smoking cessation behavior stages for a cohort of Chinese students studying in Korea. PMID- 25030344 TI - Body mass index and weight loss in overweight and obese korean women: the mediating role of body weight perception. AB - PURPOSE: This study were to assess the relationships among BMI, body weight perception, and efforts to lose weight in a public sample of Korean women who are overweight and obese and to examine the mediating role of body weight perception on the relationship between BMI and weight loss efforts. METHODS: This cross sectional study used data from the 2008 Korea National Health and Nutrition Examination Survey. The sample was 1,739 Korean women 20 years old or older with body mass index (BMI) >= 23 kg/m(2). Bivariate relationships among variables of interests were assessed. Three separate regressions were used to test the mediating role of body weight perception on the relationship between BMI and weight loss efforts. RESULTS: BMI and body weight perception were significant correlates of weight loss efforts. BMI was significantly associated with weight perception, but a large proportion of women underestimated their weight. Weight perception partially mediated the relationship between BMI and weight loss efforts in Korean women. CONCLUSION: In light of the high prevalence of overweight or obesity and the many health consequences associated with obesity, Korean women should be aware of a healthy body weight and try to achieve that weight. Nursing interventions should consider body weight perception to effectively motivate overweight and obese Korean women to lose weight, as necessary. PMID- 25030345 TI - Nursing students' experiences with facilitator in problem-based learning class. AB - PURPOSE: Problem-based learning (PBL) is now extensively utilized within contemporary nursing education. This study was done to explore the nursing students' experiences with facilitators in PBL classes as they transitioned from the first package to the fourth package during the entire sophomore year. METHODS: Twelve nursing students who had taken the course were interviewed after PBL classes. Data were analyzed using dimensional and comparative analysis based on Strauss and Corbin's grounded theory. RESULTS: Findings were organized into phases of participants' experiences with facilitators during PBL classes. They faced interpersonal relationship challenges with facilitators as they moved through the three phases of the continuum: feeling uneasy, overcoming the uneasiness, and valuing the help of the facilitator. In the beginning, uneasiness resulted from proximity to the facilitator. However, seven strategies were derived to respond to the uneasiness during the continuum: (a) searching for information about the facilitator, (b) making efforts to build a positive impression with the facilitator, (c) wanting facilitation, (d) weighing own experiences with facilitator against others' experiences, (e) following facilitator's guidance, (f) reflecting on facilitation experience, and (g) retaining facilitator's remarks. CONCLUSION: Participants overcame the uneasiness and accepted the facilitator as an advisor. These results are significant in providing optimal facilitation for students in PBL classes because they are based on the PBL participants' perspectives of facilitation. Further studies related to facilitators' experiences in the PBL are recommended. PMID- 25030346 TI - Relationships of Factors Affecting Self-care Compliance in Acute Coronary Syndrome Patients Following Percutaneous Coronary Intervention. AB - PURPOSE: This study was conducted to identify direct and indirect factors influencing self-care compliance in patients with first acute coronary syndrome through examining the relationship among multidimensional factors. METHODS: Outpatients who made hospital visits to receive a follow-up care at more than 6 months after percutaneous coronary intervention were recruited at a national university hospital in Korea. Data of 430 participants were collected through self-administered questionnaires and analyzed using AMOS version 7.0. The fitness of the hypothetical model and the degree of significance of direct and indirect paths were analyzed. RESULTS: Three paths were found to have a significant effect on self-care compliance in the modified model. Social support indirectly influenced self-care compliance through enhancing self-efficacy, reducing anxiety and increasing perceived benefit. In addition, social support and body function indirectly influenced self-care compliance through reducing depression which affected self-efficacy. Self-efficacy was the most influential factor and played an important role as a mediating variable. CONCLUSION: Results of this study suggest that nurses' counselling and education as a form of social support should be encouraged to enhance self-efficacy and self-care compliance among outpatients during follow-up care after percutaneous coronary intervention. PMID- 25030347 TI - Validity and reliability of the Turkish version of the thirst distress scale in patients on hemodialysis. AB - PURPOSE: Thirst has been reported as an important source of distress for patients on hemodialysis. However, there is no instrument available that assesses thirst distress of Turkish patients on hemodialysis. Therefore, the aim of this study was to examine the psychometric properties of the Turkish version of the Thirst Distress Scale (TDS-T) for patients on hemodialysis. METHODS: This study was conducted methodologically. A convenience sample of 142 Turkish patients on hemodialysis participated in this study. Data were collected by using a questionnaire, the TDS-T and a visual analogue scale for thirst intensity. The analysis of data included descriptive statistics, the one-sample Kolmogorov Smirnov test, Kruskal-Wallis test, Mann-Whitney U test, correlation coefficients and psychometric tests. RESULTS: The TDS-T demonstrated acceptable internal consistency (Cronbach's alpha coefficient = .81), good test-retest reliability (intraclass correlation coefficient = .88), and correlations with interdialytic weight gain values and thirst intensity scores (measured by visual analogue scale) indicating concurrent and convergent validity, respectively. Construct validity was supported by known-group comparisons. The results revealed a one component structure of the instrument. CONCLUSIONS: The psychometric properties of the TDS-T were consistent with those reported in the original study. The TDS-T was found to be a valid and reliable tool for evaluating thirst distress in patients on hemodialysis. PMID- 25030348 TI - Polyphyletic origin of Brassica juncea with B. rapa and B. nigra (Brassicaceae) participating as cytoplasm donor parents in independent hybridization events. AB - * Premise of the study: Brassica juncea is a major source of edible oil in the Indian subcontinent and northern China. It is also used as a root and leaf vegetable in China and as a condiment in Europe and America. There is a long standing view that B. juncea originated from multiple hybridization events between B. rapa and B. nigra and that hybridizations were always unidirectional with B. rapa as the cytoplasmic donor. These conclusions were, however, centered primarily on nuclear markers.* Methods: Two hundred forty-six accessions of B. juncea, B. rapa, and B. nigra were genotyped using chloroplast and nuclear simple sequence repeat (SSR) markers.* Key results: A structure analysis assigned B. juncea germplasm (122) into three major groups based on plasmotype variation. The bulk of Indian B. juncea genotypes were grouped along with Chinese and Australian accessions. This plasmotype was absent in sampled accessions of B. rapa (97), B. nigra (27), and other wild crucifers (10). The second group of B. juncea included East European genotypes and four accessions from India. It showed unambiguous homology with the predominant B. nigra plasmotype. The neighbor joining tree produced seven subgroups, arranged into two broad lineages. The first lineage included Indian, Australian, and Chinese B. juncea genotypes; it was associated with wild species belonging to the "rapa" lineage. Nuclear SSR marker-based analyses were largely supportive of results from chloroplast SSR analyses.* Conclusions: Based on these results, we provide the first report that B. juncea originated several times with both B. rapa and B. nigra as cytoplasmic donors in separate hybridization events. PMID- 25030349 TI - Variation in susceptibility to wind along the trunk of an isolated Larix kaempferi (Pinaceae) tree. AB - * Premise of the study: The force of the wind is a significant hazard to the survival of trees and can affect tree morphology. However, the actual distribution of the stress that wind causes to a tree trunk is not well understood in spite of its expected importance to tree morphology. The uniform stress hypothesis (i.e., tree trunks take a form that equalizes the distribution of stress along the outer surface of the stem) has been tested indirectly as a model, placing high importance on the mechanical safety of a trunk, and rejected theoretically. But stress on a tree's trunk has not yet been measured directly.* Methods: Actual strains at the surface of the trunk of an isolated Larix kaempferi tree due to wind loads were measured at seven heights on the trunk for 1 yr.* Key results: During the measurement period, wind-induced stress was higher in the upper portions of the trunk than in the lower portions, regardless of wind speed, and the difference increased as wind speed increased. The deflection of the trunk recorded at each position was also larger in the upper portions than in the lower portions.* Conclusions: The results indicate that the upper portions of the trunk of an isolated Larix kaempferi tree are more susceptible to wind than are the lower portions. These results do not support the uniform stress hypothesis and suggest that another limitation (either mechanical or nonmechanical) acts on the morphology of the tree. PMID- 25030350 TI - The structure and development of incompletely closed carpels in an apocarpous species, Sagittaria trifolia (Alismataceae). AB - * Premise of the study: Carpel closure is commonly considered as a key innovation in angiosperms; however, some families continue to exhibit a variety of forms of incomplete carpel closure. The carpel of Sagittaria species contains an unusual structure. In this study, we confirm the closure type of the carpel of Sagittaria trifolia and discuss its development and evolution.* Methods: Scanning electron microscopy and light microscopy of semithin sections were used to observe the development and the mature structure of the carpel. Pollen tube growth in the carpel and seed germination in the achene was also studied.* Key results: During late carpel development, the middle parts of the carpel margins underwent postgenital fusion. However, at maturity the lowest and uppermost parts of the carpel margins remained open. The mature carpel was incompletely closed and contained a secretion-filled canal, which extended from the stigma to the opening at the carpel base. At that site, pollen tubes could either grow to the ovule or exit the carpel and grow to other carpels. The basal opening also served as an exit point for the seedling to emerge.* Conclusions: Incomplete carpel closure by S. trifolia differs from the closure types recorded in previous studies because two entrances link the ovary in the carpel to the outside environment. This type of carpel closure occurs as a result of the lack of fusion of the carpel margins at the base of the carpel and could improve the seed set and seedling germination of S. trifolia. PMID- 25030351 TI - Population genetics of the endemic and endangered Vriesea minarum (Bromeliaceae) in the Iron Quadrangle, Espinhaco Range, Brazil. AB - * Premise of the study: Knowledge about genetic variability in plant populations is one of the main branches of conservation genetics, linking genetic data to conservation strategies. Vriesea minarum is a bromeliad endemic to the Iron Quadrangle region (southeastern Brazil), occurring on mountaintop rock outcrops. It is listed as endangered due to habitat loss, particularly from iron ore mining. Thus, determining the structure and genetic diversity of V. minarum populations could help develop strategies to conserve the species.* Methods: We studied the genetic structure of 12 populations of V. minarum using 10 microsatellite loci transferred from other species of Bromeliaceae. Statistical analyses to compare and describe the genetic diversity of each population were performed, and genetic structure within and among populations, isolation by distance, and Bayesian structure were also analyzed.* Key results: Our results show high inbreeding (GIS = 0.376) and low population structure (FST = 0.088), possibly related to high gene flow due to great pollinator efficiency and/or efficient seed dispersal, thus leading to high connectivity among populations of these fragmented rock outcrops. Two clusters were observed, corresponding to the basins of rivers Sao Francisco and Doce.* Conclusions: Gene flow among populations is high but, given the rate of habitat loss to mining, most populations are vulnerable and will become increasingly isolated if no action is taken to preserve them. Thus, conservation of this species depends on in situ and ex situ actions, such as controlling overexploitation and creating a germoplasm bank. PMID- 25030353 TI - [In memoriam Prof. em. Dr. med. Ernst Kern]. PMID- 25030352 TI - [Minimally invasive pancreatic tumor surgery : oncological safety and surgical feasibility]. AB - INTRODUCTION AND PURPOSE: Despite being technically challenging, minimally invasive pancreatic surgery is increasingly being used to treat pancreatic diseases. Therefore, the evaluation of its oncological safety and its advantages arebecoming increasingly more important. This review focuses on these questions based on the currently available literature. MATERIAL AND METHODS: The technically less demanding laparoscopic distal pancreatectomy has been evaluated in numerous meta-analyses. Minimally invasive pancreaticoduodenectomy has only been reported from a few centers worldwide. RESULTS AND CONCLUSION: Minimally invasive pancreatic surgery, in particular laparoscopic distal pancreatectomy, is increasingly being used to treat pancreatic tumors. The advantages of laparoscopy, such as less intraoperative blood loss, reduced postoperative pain and a shorter length of stay have all been demonstrated in large trials. However, a sufficient oncological treatment was only assessed via indirect surrogate parameters, such as the number of lymph nodes obtained and R0 resection rates; therefore, larger prospective trials are needed to prove adequate oncological treatment. To date, minimally invasive techniques should only be employed in trials on treatment of pancreatic malignancies. PMID- 25030354 TI - Socioeconomic position and incidence of ischemic stroke in Denmark 2003-2012. A nationwide hospital-based study. AB - BACKGROUND: A greater burden of stroke risk factors in general is associated with a higher risk for stroke among people of lower than those of higher socioeconomic position. The relative impact of individual stroke risk factors is still unclear. METHODS AND RESULTS: We studied the relations between socioeconomic position, measured as household income and length of education, and all hospital admissions for a first ischemic stroke among 54 048 people over the age of 40 years in Denmark in 2003-2012 in comparison with the general Danish population (23.5 million person-years). We also studied the cardiovascular risk factor profile associated with socioeconomic position in stroke patients. Relative risks for stroke were estimated in log-linear Poisson regression models. The risk for hospitalization for a first ischemic stroke was almost doubled for people in the lowest income group, and the risk of those of working age (<65 years) was increased by 36% among people with the shortest education. Diabetes, obesity, smoking, and high alcohol consumption in particular and, to a lesser extent, previous myocardial infarction or intermittent arterial claudication were significantly overrepresented among stroke patients with lower socioeconomic position. Atrial fibrillation and hypertension were not. CONCLUSIONS: In Denmark, there is a strong relation between low socioeconomic position and risk for hospitalization for stroke. Lifestyle, as indicated by smoking, obesity, and alcohol consumption, and diabetes appears to increase the risk for stroke in people with lower socioeconomic position. PMID- 25030355 TI - PID15, a novel 6 kDa secreted peptide, mediates Naja naja venom phospholipase A2 induced apoptosis in isolated human peripheral lymphocytes. AB - BACKGROUND: Snake venoms are a complex mixture of active principles mainly peptides and proteins also including amino acids, nucleotides, free lipids, carbohydrates and metallic elements bound to proteins that interfere in several biological systems. In this study, we aimed to understand the mode of action of the apoptosis inducing ability of Naja naja venom phospholipase A2 (NV-PLA2) using isolated human peripheral lymphocytes. RESULTS: Human peripheral lymphocytes when incubated with Naja naja venom phospholipase A2 (NV-PLA2) induced up to 68% DNA fragmentation. The dialysed conditioned media obtained by incubating lymphocytes with NV-PLA2 at 15th min induced 44% DNA fragmentation, referred to as cmlp-active. Cmlp-active showed 20.5% increased protein concentration than the corresponding control condition media cmlp-c-15. Test for creatine kinase activity in cmlp-active proved negative and negligible amount of lactate dehydrogenase did not show significant DNA fragmentation. Fractionation of cmlp-active on Sephadex G-25 showed two peaks, major peak induced 38% DNA fragmentation, which was further rechromatographed on Sephadex G-25. The single peak obtained was named PID15 (Phospholipase A2Induced DNA fragmentation factor secreted at 15th min). Q-Tof MS/MS analysis of PID-15 showed it is a 6 kDa peptide. PID15 sequence analysis gave 40 amino acids in the following order, msilpcknvs iwvikdtaas dkevvlgsdr aikflylatg. The homology search for the sequence revealed it to be an Apoptosis Inducing Factor (AIF). CONCLUSION: Results indicate that the secretion of PID15 is dependent on concentration of NV-PLA2 treatment, incubation time and also on temperature and the probable membrane origin of PID15 and not of cytosolic origin with apoptosis inducing ability. PMID- 25030356 TI - Correlative video-light-electron microscopy: development, impact and perspectives. AB - Green fluorescent protein (GFP)-based video microscopy can provide profound insight into biological processes by generating information on the 'history,' or dynamics, of the cellular structures involved in such processes in live cells. A crucial limitation of this approach, however, is that many such structures may not be resolved by light microscopy. Like more recent super-resolution techniques, correlative video-light-electron microscopy (CLEM) was developed to overcome this limitation. CLEM integrates GFP-based video microscopy and electron microscopy through a series of ancillary techniques, such as proper fixation, hybrid labeling and retracing, and so provides sufficient resolution as well as, crucially, cellular 'context' to the fluorescent dynamic structures of interest. CLEM 'multiplies' the power of video microscopy and is having an important impact in several areas cell and developmental biology. Here, we discuss potential, limitations and perspectives of correlative approaches aimed at integrating the unique insight generated by video microscopy with information from other forms of imaging. PMID- 25030357 TI - Discontinuation of anti-hypertensive drugs increases 11-year cardiovascular mortality risk in community-dwelling elderly (the Bambui Cohort Study of Ageing). AB - BACKGROUND: Hypertension remains a major public health problem whose management is hampered by poor persistence with pharmacological therapy. The aim of this study was to evaluate the association between discontinuing antihypertensive drugs (AHDs) and the risk of cardiovascular mortality in the elderly. METHODS: A population-based prospective cohort study of all of the >= 60-year-old residents in Bambui city (Brazil) enrolled 1606 subjects (92.2%), of whom 1494 (93.0%) were included in this study. The use of AHDs was ascertained annually in a real clinical context, and time-varying AHD exposure was categorised as non-use, current use or stopped. The predicted cardiovascular mortality rates were estimated using interval Poisson models for ungrouped person-time data, taking into account current levels of systolic blood pressure (BP). RESULTS: The overall adjusted cardiovascular mortality risk ratio of AHD stoppers vs current users was 3.12 (95% CI: 2.35-4.15). There was a significant interaction with BP levels: the association between discontinuing AHDs and the risk of cardiovascular mortality was stronger at higher systolic BP levels. The estimates of the risk of cardiovascular mortality over the follow-up period were similar in AHD users and non-users, for whom AHDs were never prescribed. CONCLUSION: Discontinuing AHDs increases the risk of cardiovascular mortality in the elderly. Misconceptions about symptoms or drug-related adverse effects could underlie a subject's decision to discontinue AHDs. Greater attention should be paid to the choice of AHDs and informative action. PMID- 25030358 TI - Inhibition of breast cancer metastasis with microRNA-302a by downregulation of CXCR4 expression. AB - Metastasis remains a main cause of mortality from breast cancer and an unresolved issue. The purpose of this study is to investigate the role of miR-302a in the development of breast cancer metastasis mediated by CXCR4, a critical regulator of metastasis, and to identify miR-302a as an effective therapeutic agent for therapy and prevention of breast cancer metastasis. Our studies show that miR 302a expression levels were downregulated in metastatic breast cancer cells and tumor tissues. Additionally, the expression levels of miR-302a were inversely correlated with CXCR4 levels. More promisingly, miR-302a inhibited the invasion and metastasis of breast cancer cells in vitro and in vivo and reduced the expression of CXCR4. Our findings demonstrated that the repression of miR-302a levels contributes to breast cancer metastasis and restoration of miR-302a baseline expression inhibits the invasion and metastasis of breast cancer cells. These data suggest that miR-302a mimics are potential therapeutic agents for breast cancer metastasis. PMID- 25030359 TI - Living with diabetes - development of learning patterns over a 3-year period. AB - BACKGROUND: Learning involves acquiring new knowledge and skills, and changing our ways of thinking, acting, and feeling. Learning in relation to living with diabetes is a lifelong process where there is limited knowledge of how it is experienced and established over time. It was considered important to explore how learning was developed over time for persons living with diabetes. AIM: The aim of the study was to identify patterns in learning when living with diabetes, from recently being diagnosed, and over a 3-year period. MATERIALS AND METHODS: A longitudinal qualitative descriptive design was used. Thirteen participants, with both type I and type II diabetes, were interviewed at three different occasions during a 3-year period. Qualitative content analysis was used in different steps in order to distinguish patterns. FINDINGS: Five main patterns of learning were identified. Two of the patterns (I and II) were characterized by gradually becoming comfortable living with diabetes, whereas for one pattern (IV) living with diabetes became gradually more difficult. For pattern V living with diabetes was making only a limited impact on life, whereas for Pattern III there was a constant management of obstacles related to illness. The different patterns in the present study showed common and different ways of learning and using different learning strategies at different timespans. CONCLUSION: The present study showed that duration of illness is not of importance for how far a person has come in his own learning process. A person-centered care is needed to meet the different and changing needs of persons living with diabetes in relation to learning to live with a lifelong illness. PMID- 25030362 TI - Safety aspects of incobotulinumtoxinA high-dose therapy. AB - Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective non-interventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (Xeomin((r))) high-dose therapy (HD group, n = 100, single dose >=400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose <=200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 +/- 13.8 years, 46 dystonia, 54 spasticity) were treated with Xeomin((r)) 570.1 +/- 158.9 (min 400, max 1,200) MU during 10.2 +/- 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 +/- 19.1 MU, in spasticity patients 35 and 114.9 +/- 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibody-induced therapy failure. Xeomin((r)) can be used safely in doses >=400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies-carefully designed and rigorously monitored-are necessary to explore the threshold dose for clinically detectable systemic toxicity. PMID- 25030363 TI - Health Beliefs Concerning Breast Self-examination of Nurses in Turkey. AB - PURPOSE: The purpose of the study was to evaluate the health beliefs regarding breast self-examination (BSE) and their relationship with age, educational status and history of breast cancer in the family among nurses working in a university hospital. METHODS: A cross-sectional design was used, with a convenience sample of 381 nurses at a military university hospital in Ankara in Turkey. Data were collected by using a personal data form and the Champion's Health Belief Model Scale. Descriptive statistics, logistic regression, Mann-Whitney U test and Kruskal Wallis Test were conducted. RESULTS: The proportion of nurses reported doing BSE regularly is 47.2%. Controlling variables such as age, body mass index, the age at first birth, breast cancer in the family history and educational background, we found that the subscales of the health belief model, BSE benefit (OR = 0.782), self-efficacy (OR = 0.919), and risk perception (OR = 0.114) have statistically significant effects on the risk of not making BSE. CONCLUSION: It is important to be aware of the health beliefs of nurses regarding BSE so that their own health can be protected and improved. Beneficial attitudes and behaviors of nurses regarding BSE will enable them to provide more effective services to women regarding breast cancer. Understanding the nurses' health beliefs, attitude and behavior that are influential to make BSE will guide nursing practices towards early diagnosis of breast cancer at the societal level. PMID- 25030361 TI - Towards neuroimmunotherapy for cancer: the neurotransmitters glutamate, dopamine and GnRH-II augment substantially the ability of T cells of few head and neck cancer patients to perform spontaneous migration, chemotactic migration and migration towards the autologous tumor, and also elevate markedly the expression of CD3zeta and CD3epsilon TCR-associated chains. AB - In previous studies we found that several Neurotransmitters and Neuropeptides among them: Glutamate, Dopamine, Gonadotropin-releasing-hormone (GnRH) I and II, Somatostatin, CGRP and Neuropeptide Y, can each by itself, at low physiological concentration (~10 nM) bind its receptors in human T cells and trigger several key T cell functions. These findings showed that the nervous system, via Neurotransmitters and Neuropeptides, can 'talk' directly to the immune system, and stimulate what we coined 'Nerve-Driven Immunity': immune responses dictated by the nervous system. In various human cancers, the immune system of the patients, and their T cells in particular, are not functioning well enough against the cancer due to several reasons, among them the suppressive effects on the immune system induced by: (1) the cancer itself, (2) the chemotherapy and radiotherapy, (3) the ongoing/chronic stress, anxiety, depression and pain felt by the cancer patients. In Head and Neck Cancer (HNC), 5-year survival rate remains below 50%, primarily because of local recurrences or second primary tumors. Two-thirds of HNC patients are diagnosed at advanced clinical stage and have significantly poorer prognosis. Most HNC patients have multiple severe immunological defects especially in their T cells. A major defect in T cells of patients with HNC or other types of cancer is low CD3zeta expression that correlates with poor prognosis, decreased proliferation, apoptotic profile, abnormal cytokine secretion and poor abilities of destructing cancer cells. T cells of cancer patients are often also unable to migrate properly towards the tumor. In this study we asked if Glutamate, Dopamine or GnRH-II can augment the spontaneous migration, chemotactic migration and towards autologous HNC migration, and also increase CD3zeta and CD3epsilon expression, of peripheral T cells purified from the blood of five HNC patients. These HNC patients had either primary tumor or recurrence, and have been already treated by surgery and/or radiotherapy and/or chemotherapy without satisfactory outcomes. We found that Glutamate, Dopamine and GnRH-II, each by itself, at 10 nM, and during 30 min incubation only with the peripheral T cells of the HNC patients increased substantially their: (1) spontaneous migration (up to 4.4 fold increase), (2) chemotactic migration towards the key chemokine SDF-1 (up to 2.3 fold increase), (3) migration towards the autologous HNC tumor removed surgically ~48 h earlier in a pre-planned operation (up to 3.5 fold increase). Each of the Neurotransmitters even 'allowed' the T cells of one HNC patient to overcome completely the suppressive anti-migration effect of his autologous tumor, (4) cell surface CD3zeta expression (up to 4.3 fold increase), (5) cell surface CD3epsilon expression (up to 1.9 fold increase). If the absolutely essential larger scale subsequent studies would validate our present findings, Glutamate, Dopamine and GnRH-II could be used for a completely novel indication: adoptive T cell immunotherapy for some patients with HNC and maybe also other types of cancer. We coin here a novel term-'Neuroimmunotherapy' for this new form of T cell immunotherapy, based on the direct activation of the patient's own T cells by Neurotransmitters. Such 'Neuroimmunotherapy' could be reduced to practice by rather simple, painless and repeated/periodical removal of peripheral T cells from the cancer patients, activating them ex vivo for 30 min by either Glutamate, Dopamine or GnRH-II, and infusing them back to the patients by intravenous and/or intratumoral injection. The 'rejuvenated' Neurotransmitter-treated T cells are expected to have significantly improved abilities to reach and eradicate the cancer, and also combat infectious organisms that cancer patients often suffer from. Since the T cells are autologous, since the Neurotransmitters are physiological molecules, and since the ex vivo 'parking period' is very short, such Neuroimmunotherapy is expected to be very safe. PMID- 25030364 TI - Breast cancer screening practice and health-promoting behavior among chinese women. AB - PURPOSE: This study examined breast cancer screening practice and health promoting behaviors and the predicting factors of breast cancer screening practice in Chinese women. METHODS: A correlational research design was used to recruit a convenience sample of 770 women living in four cities (Beijing, Shanghai, Guangzhou, and Xi'an) in China. Participants completed self-report questionnaire consisting of general characteristics, breast cancer screening, health promoting behaviors, perceived benefits and perceived barriers. RESULTS: The participants were mostly 36-55 years old (51.3%), married (86.8%), premenopause (77.7%), had children (83.4%), and breastfed (73%). About 60% of Chinese women participated in some type of breast cancer screening practices, among them only 60 (7.8%) women used mammography, ultrasonogram and breast self examination. The main reason for doing breast cancer screening was "feeling necessary for the screening". About 36% of the participants reported they did not perform any of screening practices, because they "don't feel it necessary". The women who had breast cancer screening regularly reported better health promoting behavior and perceived benefits and less perceived barriers than those who did not (F=10.45, p<.001). Logistic regression showed that model 1 (age, higher education, being employed) and model 2 (perceived benefits and health behaviors) were the significant predicting factors (p<.05), explaining 10-13.8% of variance in breast cancer screening practice. CONCLUSION: On the basis of these results, public education about importance of breast cancer screening and health promoting behavior should be strongly advocated by health professionals and mass media in China. PMID- 25030365 TI - Factors related to risk of cardiovascular disease among older korean chinese with hypertension. AB - PURPOSE: The purpose of this study was to assess the prevalence of cardiovascular disease (CVD) risk factors among older Korean Chinese with hypertension-one of the most underserved and understudied ethnic minority groups in China. In addition, factors underlying the risk of CVD were examined. METHODS: A total of 334 participants were recruited at the Community Health Service Center in Yanji, China. Data regarding socioeconomic, health-related, psychosocial, and other CVD risk factors were collected between June and October 2009. In this cross sectional study, factors related to the risk of CVD were assessed by multivariate logistic regression; the Framingham Risk Score was used to measure the risk of CVD. RESULTS: The prevalence of dyslipidemia, diabetes, and current smoking were 75.4%, 6.6%, and 23.1% respectively. Participants who lived alone were twice as likely to have a high risk of CVD (10-year risk of CVD >=15%; odds ratio [OR], 2.00; 95% confidence interval [CI], 1.13-3.54). Those with a higher education level and greater knowledge about hypertension were at 57% and 62% reduced risk for CVD (OR, 0.43; 95% CI, 0.21-0.92 and OR, 0.38; 95% CI, 0.15-0.95, respectively). CONCLUSION: Future intervention should include strategies to addressing social isolation and also focus on older Korean Chinese with low education. Knowledge enhancement program is warranted for the prevention of CVD in this population. PMID- 25030366 TI - Experience and perception of sexual harassment during the clinical practice of korean nursing students. AB - PURPOSE: The purpose of this study was to identify the experience and perception of sexual harassment during the clinical practice of Korean nursing students. METHODS: The descriptive study was conducted using a self-report questionnaire from December 2009 to January 2010. Participants were 542 nursing students recruited from 12 nursing colleges in Korea, who had finished 1,000 hours of clinical practice which is the minimum requirement for graduation. Data were analyzed by descriptive statistics. RESULTS: Ninety-seven participants (17.9%) reported that they experienced sexual harassment during clinical practice and 36 participants (6.7%) answered whether it was a sexual harassment or not. When sexual harassment was asked by the specific 18 items in the sexual harassment checklist, 52.0% (n = 282) of participants reported that they experienced at least 1 item among 18 items of sexual harassment. Sexual harassments were frequently made by the persons in their 40s (41.2%), men (97.9%) and patients (96.9%) and in the psychiatric wards (67.0%). Many respondents recognized that sexual harassment during clinical practice was caused by abnormal sexual desire of a pervert (34.5%) or men's sexual impulse (26.2%). Also, sexual harassment was perceived as a serious problem (19.4%) and education was necessary for prevention (88.3%). CONCLUSION: Education program is needed to prevent sexual harassment and enhance the gender sensitivity of nursing students, who are in the high-risk group of sexual harassment during clinical practice. This will in turn contribute to a safe educational environment for clinical practice. PMID- 25030367 TI - Adaptation of questionnaire measuring working conditions and health problems among Iranian nursing personnel. AB - PURPOSE: To adapt a questionnaire in the Persian language measuring working conditions and health problems among nursing personnel. A further aim was to test the validity and reliability of the questionnaire. METHODS: The adapted questionnaire was based on three well-established questionnaires. Physical working conditions items were from Nurse Early Exit Study. Psychosocial working conditions scales were included from Copenhagen Psychosocial Questionnaire which contains two scales on general and mental health as well. The Nordic Musculoskeletal Questionnaire was the origin of the musculoskeletal disorders questions. During the culture adaptation process, an expert panel method was used. To achieve equivalence between the sources and target version, some changes were made by the expert panel. Then the questionnaire was examined in the field for face validity and construct validity (n = 92) among Iranian nursing personnel from two hospitals. Construct validity was assessed using a priori hypothesized correlations of the outcomes with exposures. Finally the adaptation process was completed by reliability assessment using Cronbach's alpha and Intra-class Correlation Coefficient (ICC). RESULTS: The construct validity result was the correlation of the health outcome with the work-related exposure (physical rs = .71 and psychosocial rs = .66). In the reliability assessment, Cronbach's alpha and ICC were .60 and .70 respectively. CONCLUSION: The findings show that the adapted questionnaire has an acceptable conceptual structure and provides reliable information from the nursing profession. Consequently, the questionnaire is applicable to work situation studies among nurses and other health care workers. PMID- 25030368 TI - Psychometric evaluation of hill-bone medication adherence subscale. AB - PURPOSE: Medication adherence is an essential part of the management and control of high blood pressure (HBP). Although the Hill-Bone Medication Adherence (HBMA) scale is one of the most frequently used instruments for measuring HBP medication adherence, the psychometric properties of the scale have never been tested among Korean Americans, a population that experiences a disproportionately high prevalence of HBP. Therefore, the objective of this study is to validate a Korean version of the HBMA subscale (HBMA-K). METHOD: We used two, independent samples of Korean Americans (KAs) (combined n = 525) who participated in community-based intervention trials for HBP control. To develop the HBMA-K, the original scale was translated into Korean and then back translated into English. Reliability was assessed by calculating the Cronbach's alpha. Exploratory factor analysis (EFA) was done to assess construct validity. We also calculated the Pearson's correlation coefficients between the scale and theoretically driven variables such as blood pressure, knowledge, and HBP belief to test concurrent validity. RESULTS: The EFA revealed a one-factor solution with eight items, explaining 35.4% of the variance. Cronbach's alpha was .80. The 8-item HBMA-K scale was significantly associated with systolic blood pressure (BP) (r = .18, p < .01), diastolic BP (r = .24, p < .01), HBP knowledge (r = -.13, p < .01), and HBP belief score (r = -.18, p < .05). CONCLUSIONS: The 8-item HBMA-K scale is a valid and reliable instrument for measuring medication adherence among KAs with HBP. It can be easily administered at community and clinical settings to screen hypertensive patients with low medication adherence. PMID- 25030369 TI - Prevalence and risk factors of adolescents smoking: difference between korean and korean-chinese. AB - PURPOSE: The purpose of this study was to compare smoking prevalence and risk factors of smoking between Korean and Korean-Chinese middle school students. METHODS: Data was collected from seventh and eighth grade students from 12 schools in Korea and 6 schools in China. Descriptive statistics, Chi-square test, and t test were performed. RESULTS: For data analysis 10,002 usable surveys were utilized. The smoking prevalence was higher in Korean-Chinese students than in Korean students. Risk factors, such as father smoking, friends smoking, gender, grade, academic achievement, alcohol use, and family income were associated with current smoking, and the differences in the two samples were significant. Korean Chinese students were more likely than Korean students to have friends who smoked and a father who smoked. Smokers had a significantly higher rate of friends smoking, father smoking, and alcohol use. Korean-Chinese male students smoking prevalence was more than three times higher than Korean students. Korean students could sense a more anti-tobacco atmosphere in their environment. Korean-Chinese students were more likely than Korean students to perceive that it was easy to buy cigarettes and to smoke cigarettes in a public computer room. CONCLUSION: These results highlight the differences of smoking prevalence and risk factors between Korean-Chinese students and Korean students. The findings may help health educators and researchers to better understand adolescent smoking and risk factors cross culturally and aid in the development of more effective education programs, which could lead to preventing tobacco use among these populations. PMID- 25030370 TI - Factors influencing breast symptoms in breastfeeding women after cesarean section delivery [asian nursing research 5 (2011) 88-98]. PMID- 25030371 TI - G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis. AB - The role of 17beta-estradiol (E2) in breast cancer development and tumor growth has traditionally been attributed exclusively to the activation of estrogen receptor-alpha (ERalpha). Although targeted inhibition of ERalpha is a successful approach for patients with ERalpha(+) breast cancer, many patients fail to respond or become resistant to anti-estrogen therapy. The discovery of the G protein-coupled estrogen receptor (GPER) suggested an additional mechanism through which E2 could exert its effects in breast cancer. Studies have demonstrated clinical correlations between GPER expression in human breast tumor specimens and increased tumor size, distant metastasis, and recurrence, as well as established a proliferative role for GPER in vitro; however, direct in vivo evidence has been lacking. To this end, a GPER-null mutation [GPER knockout (KO)] was introduced, through interbreeding, into a widely used transgenic mouse model of mammary tumorigenesis [MMTV-PyMT (PyMT)]. Early tumor development, assessed by the extent of hyperplasia and proliferation, was not different between GPER wild type/PyMT (WT/PyMT) and those mice harboring the GPER-null mutation (KO/PyMT). However, by 12 to 13 weeks of age, tumors from KO/PyMT mice were smaller with decreased proliferation compared with those from WT/PyMT mice. Furthermore, tumors from the KO/PyMT mice were of histologically lower grade compared with tumors from their WT counterparts, suggesting less aggressive tumors in the KO/PyMT mice. Finally, KO/PyMT mice displayed dramatically fewer lung metastases compared with WT/PyMT mice. Combined, these data provide the first in vivo evidence that GPER plays a critical role in breast tumor growth and distant metastasis. IMPLICATIONS: This is the first description of a role for the novel estrogen receptor GPER in breast tumorigenesis and metastasis, demonstrating that it represents a new target in breast cancer diagnosis, prognosis, and therapy. PMID- 25030372 TI - Hypoxia provokes base excision repair changes and a repair-deficient, mutator phenotype in colorectal cancer cells. AB - Regions of acute and chronic hypoxia exist within solid tumors and can lead to increased rates of mutagenesis and/or altered DNA damage and repair protein expression. Base excision repair (BER) is responsible for resolving small, non helix-distorting lesions from the genome that potentially cause mutations by mispairing or promoting DNA breaks during replication. Germline and somatic mutations in BER genes, such as MutY Homolog (MUTYH/MYH) and DNA-directed polymerase (POLB), are associated with increased risk of colorectal cancer. However, very little is known about the expression and function of BER proteins under hypoxic stress. Using conditions of chronic hypoxia, decreased expression of BER proteins was observed because of a mechanism involving suppressed BER protein synthesis in multiple colorectal cancer cell lines. Functional BER was impaired as determined by MYH- and 8-oxoguanine (OGG1)-specific glycosylase assays. A formamidopyrimidine-DNA glycosylase (Fpg) Comet assay revealed elevated residual DNA base damage in hypoxic cells 24 hours after H2O2 treatment as compared with normoxic controls. Similarly, high-performance liquid chromatography analysis demonstrated that 8-oxo-2'-deoxyguanosine lesions were elevated in hypoxic cells 3 and 24 hours after potassium bromate (KBrO3) treatment when compared with aerobic cells. Correspondingly, decreased clonogenic survival was observed following exposure to the DNA base damaging agents H2O2 and MMS, but not to the microtubule interfering agent paclitaxel. Thus, a persistent downregulation of BER components by the microenvironment modifies and facilitates a mutator phenotype, driving genetic instability and cancer progression. IMPLICATIONS: Aberrant BER is a contributing factor for the observed genetic instability in hypoxic tumor cells. PMID- 25030374 TI - The lncRNA PCAT29 inhibits oncogenic phenotypes in prostate cancer. AB - Long noncoding RNAs (lncRNA) have recently been associated with the development and progression of a variety of human cancers. However, to date, the interplay between known oncogenic or tumor-suppressive events and lncRNAs has not been well described. Here, the novel lncRNA, prostate cancer-associated transcript 29 (PCAT29), is characterized along with its relationship to the androgen receptor. PCAT29 is suppressed by DHT and upregulated upon castration therapy in a prostate cancer xenograft model. PCAT29 knockdown significantly increased proliferation and migration of prostate cancer cells, whereas PCAT29 overexpression conferred the opposite effect and suppressed growth and metastases of prostate tumors in chick chorioallantoic membrane assays. Finally, in prostate cancer patient specimens, low PCAT29 expression correlated with poor prognostic outcomes. Taken together, these data expose PCAT29 as an androgen-regulated tumor suppressor in prostate cancer. IMPLICATIONS: This study identifies PCAT29 as the first androgen receptor-repressed lncRNA that functions as a tumor suppressor and that its loss may identify a subset of patients at higher risk for disease recurrence. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/07/31/1541-7786.MCR-14 0257/F1.large.jpg. PMID- 25030375 TI - Nationwide survey to evaluate the decision-making process in euthanasia requests in Belgium: do specifically trained 2nd physicians improve quality of consultation? AB - BACKGROUND: Following the 2002 enactment of the Belgian law on euthanasia, which requires the consultation of an independent second physician before proceeding with euthanasia, the Life End Information Forum (LEIF) was founded which provides specifically trained physicians who can act as mandatory consultants in euthanasia requests. This study assesses quality of consultations in Flanders and Brussels and compares these between LEIF and non-LEIF consultants. METHODS: A questionnaire was sent in 2009 to a random sample of 3,006 physicians in Belgium from specialties likely involved in the care of dying patients. Several questions about the last euthanasia request of one of their patients were asked. As LEIF serves the Flemish speaking community (i.e. region of Flanders and the bilingual Brussels Capital Region) and no similar counterpart is present in Wallonia, analyses were limited to Flemish speaking physicians in Flanders and Brussels. RESULTS: Response was 34%. Of the 244 physicians who indicated having received a euthanasia request seventy percent consulted a second physician in their last request; in 30% this was with a LEIF physician. Compared to non-LEIF physicians, LEIF physicians were more often not a colleague (69% vs 42%) and not a co attending physician (89% vs 66%). They tended to more often discuss the request with the attending physician (100% vs 95%) and with the family (76% vs 69%), and also more frequently helped the attending physician with performing euthanasia (44% vs 24%). No significant differences were found in the extent to which they talked to the patient (96% vs 93%) and examined the patient file (94% vs 97%). CONCLUSION: In cases of explicit euthanasia requests in Belgium, the consultation procedure of another physician by the attending physician is not optimal and can be improved. Training and putting at disposal consultants through forums such as LEIF seems able to improve this situation. Adding stipulations in the law about the necessary competencies and tasks of consulting physicians may additionally incite improvement. Irrespective of whether euthanasia is a legal practice within a country, similar services may prove useful to also improve quality of consultations in various other difficult end-of-life decision-making situations. PMID- 25030373 TI - GPER-targeted, 99mTc-labeled, nonsteroidal ligands demonstrate selective tumor imaging and in vivo estrogen binding. AB - Our understanding of estrogen (17beta-estradiol, E2) receptor biology has evolved in recent years with the discovery and characterization of a 7-transmembrane spanning G protein-coupled estrogen receptor (GPER/GPR30) and the development of GPER-selective functional chemical probes. GPER is highly expressed in certain breast, endometrial, and ovarian cancers, establishing the importance of noninvasive methods to evaluate GPER expression in vivo. Here, we developed (99m)Tc-labeled GPER ligands to demonstrate the in vivo status of GPER as an estrogen receptor (ER) and for GPER visualization in whole animals. A series of (99m)Tc(I)-labeled nonsteroidal tetrahydro-3H-cyclopenta[c]quinolone derivatives was synthesized utilizing pyridin-2-yl hydrazine and picolylamine chelates. Radioligand receptor binding studies revealed binding affinities in the 10 to 30 nmol/L range. Cell signaling assays previously demonstrated that derivatives retaining a ketone functionality displayed agonist properties, whereas those lacking such a hydrogen bond acceptor were antagonists. In vivo biodistribution and imaging studies performed on mice bearing human endometrial and breast cancer cell xenografts yielded significant tumor uptake (0.4-1.1%ID/g). Blocking studies revealed specific uptake in multiple organs (adrenals, uterus, and mammary tissue), as well as tumor uptake with similar levels of competition by E2 and G 1, a GPER-selective agonist. In conclusion, we synthesized and evaluated a series of first-generation (99m)Tc-labeled GPER-specific radioligands, demonstrating GPER as an estrogen-binding receptor for the first time in vivo using competitive binding principles, and establishing the utility of such ligands as tumor imaging agents. These results warrant further investigation into the role of GPER in estrogen-mediated carcinogenesis and as a target for diagnostic/therapeutic/image guided drug delivery. IMPLICATIONS: These studies provide a molecular basis to evaluate GPER expression and function as an ER through in vivo imaging. PMID- 25030376 TI - A new device for continuous assessment of gut perfusion: proof of concept on a porcine model of septic shock. AB - INTRODUCTION: We evaluate an innovative device consisting of an enteral feeding tube equipped with a photoplethysmography (PPG) sensor in contact with the duodenal mucosa. This study aims to determine if the PPG signal, composed of a continuous (PDC) and a pulsatile part (PAC), is a reliable method to assess gut perfusion in a porcine model of septic shock. METHOD: Fourteen piglets were anesthetized and mechanically ventilated. They were randomly assigned to two groups: the nonseptic (NS) group received an infusion of Ringer's lactate solution (RL) alone, the septic (S) group received in addition a suspension of live Pseudomonas aeruginosa. Heart rate (HR), pulse oximetry (SpO2), mean arterial pressure (MAP), cardiac index (CI) and serum lactates were recorded and gut microcirculation (GM) was monitored with a laser Doppler probe applied on the duodenal serosa. PDC and PAC were given by the PPG probe inserted in the duodenum. Data was collected every 15 minutes (t0, t15...) during 150 minutes (t150). After administration of the bacteria suspension (t0), resuscitation maneuvers were performed following a defined algorithm. GM PAC, and PDC were expressed as variation from baseline (GMvar, PACvar, PDCvar). Analysis of variance (ANOVA) with repeated measures was performed to compare hemodynamic variables, with Bonferroni correction as post hoc analysis on t0, t60 and t150. RESULTS: One piglet was withdrawn from analysis due to a defective probe. S group (six piglets) received resuscitation therapy while NS group (seven piglets) did not. A significant group effect was found for the all parameters except HR. Post hoc analysis found a significant decrease for GM and PAC at t60. The correlation between PAC, PDC and microcirculatory parameters were as follows: rPACvar-GMvar = 0.496, P <0.001, rPDCvar-GMvar = 0.244; P = 0.002. In the septic group, correlations were as follows: rPAC-lactate = -0.772, P <0.001; rPDC-lactate = 0.681, P <0.01). At the onset of shock, a decrease of PAC, PDC and GM occurred before the alteration of MAP. CONCLUSIONS: PAC and PDC decreased at the onset of shock and were correlated with GM and lactate. These results confirm that PPG signal reliably reflects the early perfusion alteration of the gut. Further studies should assess the clinical use of this device. PMID- 25030378 TI - The Icarus Project: a counter narrative for psychic diversity. AB - Over the past 12 years, I've had the good fortune of collaborating with others to create a project which challenges and complicates the dominant biopsychiatric model of mental illness. The Icarus Project, founded in 2002, not only critiqued the terms and practices central to the biopsychiatric model, it also inspired a new language and a new community for people struggling with mental health issues in the 21st century. The Icarus Project believes that humans are meaning makers, that meaning is created through developing intrapersonal and interpersonal narratives, and that these narratives are important sites of creativity, struggle, and growth. The Icarus counter narrative and the community it fostered has been invaluable for people around the world dealing with psychic diversity- particularly for people alienated by mainstream approaches. But, despite the numbers of people who have been inspired by this approach, the historical background of the Icarus Project is hard to find. It exists primarily in oral history, newspaper articles, unpublished or self-published Icarus documents, and in internet discussion forums. As the co-founder of the Icarus Project, I use this article to make my understanding of that history and its key documents more widely available. PMID- 25030377 TI - Population genetics of Leishmania (Leishmania) major DNA isolated from cutaneous leishmaniasis patients in Pakistan based on multilocus microsatellite typing. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a major and fast increasing public health problem, both among the local Pakistani populations and the Afghan refugees in camps. Leishmania (Leishmania) major is one of the etiological agents responsible for CL in Pakistan. Genetic variability and population structure have been investigated for 66 DNA samples of L. (L.) major isolated from skin biopsy of CL patients. METHODS: Multilocus microsatellite typing (MLMT), employing 10 independent genetic markers specific to L. (L.) major, was used to investigate the genetic polymorphisms and population structures of Pakistani L. (L.) major DNA isolated from CL human cases. Their microsatellite profiles were compared to those of 130 previously typed strains of L. (L.) major from various geographical localities. RESULTS: All the markers were polymorphic and fifty-one MLMT profiles were recognized among the 66 L. (L.) major DNA samples. The data displayed significant microsatellite polymorphisms with rare allelic heterozygosities. A Bayesian model-based approach and phylogenetic analysis inferred two L. (L.) major populations in Pakistan. Thirty-four samples belonged to one population and the remaining 32 L. (L.) major samples grouped together into another population. The two Pakistani L. (L.) major populations formed separate clusters, which differ genetically from the populations of L. (L.) major from Central Asia, Iran, Middle East and Africa. CONCLUSIONS: The considerable genetic variability of L. (L.) major might be related to the existence of different species of sand fly and/or rodent reservoir host in Sindh province, Pakistan. A comprehensive study of the epidemiology of CL including the situation or spreading of reservoirs and sand fly vectors in these foci is, therefore, warranted. PMID- 25030379 TI - Copy number variants (CNVs) analysis in a deeply phenotyped cohort of individuals with intellectual disability (ID). AB - BACKGROUND: DNA copy number variants (CNVs) are found in 15% of subjects with ID but their association with phenotypic abnormalities has been predominantly studied in smaller cohorts of subjects with detailed yet non-systematically categorized phenotypes, or larger cohorts (thousands of cases) with smaller number of generalized phenotypes. METHODS: We evaluated the association of de novo, familial and common CNVs detected in 78 ID subjects with phenotypic abnormalities classified using the Winter-Baraitser Dysmorphology Database (WBDD) (formerly the London Dysmorphology Database). Terminology for 34 primary (coarse) and 169 secondary (fine) phenotype features were used to categorize the abnormal phenotypes and determine the prevalence of each phenotype in patients grouped by the type of CNV they had. RESULTS: In our cohort more than 50% of cases had abnormalities in primary categories related to head (cranium, forehead, ears, eye globes, eye associated structures, nose) as well as hands and feet. The median number of primary and secondary abnormalities was 12 and 18 per subject, respectively, indicating that the cohort consisted of subjects with a high number of phenotypic abnormalities (median De Vries score for the cohort was 5). The prevalence of each phenotypic abnormality was comparable in patients with de novo or familial CNVs in comparison to those with only common CNVs, although a trend for increased frequency of cranial and forehead abnormalities was noted in subjects with rare de novo and familial CNVs. Two clusters of subjects were identified based on the prevalence of each fine phenotypic feature, with an average of 28.3 and 13.5 abnormal phenotypes/subject in the two clusters respectively (P < 0.05). CONCLUSIONS: Our study is a rare example of using standardized, deep morphologic phenotype clustering with phenotype/CNV correlation in a cohort of subjects with ID. The composition of the cohort inevitably influences the phenotype/genotype association, and our studies show that the influence of the de novo CNVs on the phenotype is less obvious in cohorts consisting of subjects with a high number of phenotypic abnormalities. The outcome of phenotype/genotype analysis also depends on the choice of phenotypes assessed and standardized phenotyping is required to minimize variability. PMID- 25030380 TI - Grain rotation mediated by grain boundary dislocations in nanocrystalline platinum. AB - Grain rotation is a well-known phenomenon during high (homologous) temperature deformation and recrystallization of polycrystalline materials. In recent years, grain rotation has also been proposed as a plasticity mechanism at low temperatures (for example, room temperature for metals), especially for nanocrystalline grains with diameter d less than ~15 nm. Here, in tensile-loaded Pt thin films under a high-resolution transmission electron microscope, we show that the plasticity mechanism transitions from cross-grain dislocation glide in larger grains (d>6 nm) to a mode of coordinated rotation of multiple grains for grains with d<6 nm. The mechanism underlying the grain rotation is dislocation climb at the grain boundary, rather than grain boundary sliding or diffusional creep. Our atomic-scale images demonstrate directly that the evolution of the misorientation angle between neighbouring grains can be quantitatively accounted for by the change of the Frank-Bilby dislocation content in the grain boundary. PMID- 25030381 TI - Nanoparticles for photothermal therapies. AB - The current status of the use of nanoparticles for photothermal treatments is reviewed in detail. The different families of heating nanoparticles are described paying special attention to the physical mechanisms at the root of the light-to heat conversion processes. The heating efficiencies and spectral working ranges are listed and compared. The most important results obtained in both in vivo and in vitro nanoparticle assisted photothermal treatments are summarized. The advantages and disadvantages of the different heating nanoparticles are discussed. PMID- 25030383 TI - Continuous versus bolus intragastric tube feeding for preterm and low birth weight infants with gastro-oesophageal reflux disease. AB - BACKGROUND: Gastro-oesophageal reflux disease is a particularly common condition in preterm and low birth weight infants. These infants are also more likely to have excessive regurgitation, as they do not have a fully developed antireflux mechanism. Preterm and low birth weight infants who are unable to suck oral feeds are required to be fed via an intragastric tube for varying lengths of time. Intragastric tube feeding can be delivered by the intermittent bolus or continuous feeding method. Use of continuous or intermittent bolus intragastric feeding may have a positive or negative effect on the incidence or severity of gastro-oesophageal reflux disease. OBJECTIVES: To determine whether continuous or intermittent bolus intragastric tube feeding reduces the number of episodes and the duration of gastro-oesophageal reflux disease (GORD) in preterm and low birth weight infants.We intended to perform subgroup analyses for gestational age; birth weight; age in days from birth at full enteral feeding via intragastric tube (breast vs bottle); frequency of intermittent bolus feed; and type of medication for treatment of GORD (only if medication prescribed and given similarly to both intervention groups). SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Group as described in The Cochrane Library (www.thecochranelibrary.com) to search for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 9), MEDLINE (1966 to September 2013), EMBASE (1980 to September 2013) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to September 2013). We also searched previous reviews, including cross-references, abstracts and conference and symposia proceedings of the Perinatal Society of Australia and New Zealand and the Pediatric Academic Societies (American Pediatric Society/Society for Pediatric Research and European Society for Paediatric Research) from 1990 to 2012. SELECTION CRITERIA: Published and unpublished RCTs and quasi-RCTs were eligible for inclusion in this review, as were cluster-randomised and cross-over randomised trials that compared the effects of continuous versus intermittent bolus intragastric tube feeding on gastro-oesophageal reflux disease in preterm and low birth weight infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and quality. MAIN RESULTS: We found no trials that met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: We did not identify any randomised trials that evaluated the effects of continuous versus intermittent bolus intragastric tube feeding on gastro-oesophageal reflux disease in preterm and low birth weight infants. Well-designed and adequately powered trials are needed. PMID- 25030382 TI - C-terminal amino acids are essential for human heat shock protein 70 dimerization. AB - The human inducible heat shock protein 70 (hHsp70), which is involved in several major pathologies, including neurodegenerative disorders and cancer, is a key molecular chaperone and contributes to the proper protein folding and maintenance of a large number of protein structures. Despite its role in disease, the current structural knowledge of hHsp70 is almost exclusively based on its Escherichia coli homolog, DnaK, even though these two proteins only share ~50 % amino acid identity. For the first time, we describe a complete heterologous production and purification strategy that allowed us to obtain a large amount of soluble, full length, and non-tagged hHsp70. The protein displayed both an ATPase and a refolding activity when combined to the human Hsp40. Multi-angle light scattering and bio-layer interferometry analyses demonstrated the ability of hHsp70 to homodimerize. The role of the C-terminal part of hHsp70 was identified and confirmed by a study of a truncated version of hHsp70 that could neither dimerize nor present refolding activity. PMID- 25030384 TI - Fast, high-throughput measurement of collective behaviour in a bacterial population. AB - Swimming bacteria explore their environment by performing a random walk, which is biased in response to, for example, chemical stimuli, resulting in a collective drift of bacterial populations towards 'a better life'. This phenomenon, called chemotaxis, is one of the best known forms of collective behaviour in bacteria, crucial for bacterial survival and virulence. Both single-cell and macroscopic assays have investigated bacterial behaviours. However, theories that relate the two scales have previously been difficult to test directly. We present an image analysis method, inspired by light scattering, which measures the average collective motion of thousands of bacteria simultaneously. Using this method, a time-varying collective drift as small as 50 nm s(-1) can be measured. The method, validated using simulations, was applied to chemotactic Escherichia coli bacteria in linear gradients of the attractant alpha-methylaspartate. This enabled us to test a coarse-grained minimal model of chemotaxis. Our results clearly map the onset of receptor methylation, and the transition from linear to logarithmic sensing in the bacterial response to an external chemoeffector. Our method is broadly applicable to problems involving the measurement of collective drift with high time resolution, such as cell migration and fluid flows measurements, and enables fast screening of tactic behaviours. PMID- 25030385 TI - High coverage fluid-phase floating lipid bilayers supported by omega-thiolipid self-assembled monolayers. AB - Large area lipid bilayers, on solid surfaces, are useful in physical studies of biological membranes. It is advantageous to minimize the interactions of these bilayers with the substrate and this can be achieved via the formation of a floating supported bilayer (FSB) upon either a surface bound phospholipid bilayer or monolayer. The FSB's independence is enabled by the continuous water layer (greater than 15 A) that remains between the two. However, previous FSBs have had limited stability and low density. Here, we demonstrate by surface plasmon resonance and neutron reflectivity, the formation of a complete self-assembled monolayer (SAM) on gold surfaces by a synthetic phosphatidylcholine bearing a thiol group at the end of one fatty acyl chain. Furthermore, a very dense FSB (more than 96%) of saturated phosphatidylcholine can be formed on this SAM by sequential Langmuir-Blodgett and Langmuir-Schaefer procedures. Neutron reflectivity used both isotopic and magnetic contrast to enhance the accuracy of the data fits. This system offers the means to study transmembrane proteins, membrane potential effects (using the gold as an electrode) and even model bacterial outer membranes. Using unsaturated phosphatidylcholines, which have previously failed to form stable FSBs, we achieved a coverage of 73%. PMID- 25030386 TI - Composition and substrate-dependent strength of the silken attachment discs in spiders. AB - Araneomorph spiders have evolved different silks with dissimilar material properties, serving different purposes. The two-compound pyriform secretion is used to glue silk threads to substrates or to other threads. It is applied in distinct patterns, called attachment discs. Although ubiquitously found in spider silk applications and hypothesized to be strong and versatile at low material consumption, the performance of attachment discs on different substrates remains unknown. Here, we analyse the detachment forces and fracture mechanics of the attachment discs spun by five different species on three different substrates, by pulling on the upstream part of the attached thread. Results show that although the adhesion of the pyriform glue is heavily affected by the substrate, even on Teflon it is frequently strong enough to hold the spider's weight. As plant surfaces are often difficult to wet, they are hypothesized to be the major driving force for evolution of the pyriform secretion. PMID- 25030387 TI - Ants work harder during consensus decision-making in small groups. AB - Individuals derive many benefits from being social, one of which is improved accuracy of decision-making, the so-called 'wisdom of the crowds' effect. This advantage arises because larger groups can pool information from more individuals. At present, limited empirical data indicate that larger groups outperform smaller ones during consensus decision-making in human and non-human animals. Inaccurate decisions can lead to significant costs, and we might therefore expect individuals in small groups to employ mechanisms to compensate for the lack of numbers. Small groups may be able to maintain decision accuracy if individuals are better informed than those in larger groups and/or by increasing the proportion of the group involved in collective decision-making relative to larger groups. In this study, we use interactive computer vision software to investigate individual contributions to consensus decision-making during house-hunting in different sized groups of the ant Myrmecina nipponica. We show that individuals in small colonies invest greater effort in the consensus decision process than those in large colonies and should be better informed as a result. This may act to ameliorate the limitations of group size, but could leave smaller groups more susceptible to additional stresses. PMID- 25030388 TI - What makes an accurate and reliable subject-specific finite element model? A case study of an elephant femur. PMID- 25030389 TI - Standardization and quantification in PET/CT imaging: tracers beyond FDG. AB - Standardization of FDG PET-CT is becoming a reality, at least in centers that perform clinical trials. Non-FDG radiopharmaceuticals used with PET/CT are far from standard in clinical trials and in clinical use. This article only gives an example of different protocols and indications related to the availability of different radiopharmaceuticals. This scenario will be probably the reality in the near future in many centers throughout the world. Starting from the FDG experience, it will be easy to implement standards for acquisition and interpretation of PET/CT studies with other radiopharmaceuticals. PMID- 25030390 TI - Brain: positron emission tomography tracers beyond [18F]fluorodeoxyglucose. AB - Several PET radiopharmaceuticals beyond FDG have been used to study the physiology and pathophysiology in neurosciences. This article provides a broad overview of some of the commonly studied radiopharmaceuticals for PET imaging in selected neurologic conditions, particularly attempting to study their clinical relevance. Future studies on the use of advanced PET imaging in delineating neural pathophysiology, drug development, and altering patient management and outcomes across the disciplines of neurosciences are needed. PMID- 25030391 TI - 18F-fluoride PET/computed tomography imaging. AB - In view of the increasing number of cyclotrons and PET/CT systems, 18F-fluoride PET/CT imaging should be considered for the assessment of bone abnormality in clinical practice, not only in patients with cancer but also in benign scenarios. Accumulated data on the use of 18F-fluoride indicate that this modality is highly sensitive for the detection of skeletal lesions, allowing assessment of pathophysiologic processes in normal and abnormal bone. PMID- 25030392 TI - 18F-fluoride PET and PET/CT in children and young adults. AB - 18F-fluoride PET/CT has been used for a wide variety of indications in children and young adults. Nearly all pediatric 18F-fluoride PET/CTs are performed to evaluate benign conditions. The most common indication is the evaluation of back pain in a wide variety of circumstances, including patients with sports injuries, scoliosis, trauma, and back pain after surgery. The high image quality of 18F fluoride PET/CT can make it particularly useful for evaluating benign skeletal lesions such as osteoid osteoma and Langerhans cell histiocytosis. Quantitative assessment of bone turnover with 18F-fluoride PET/CT may make it useful for assessing the skeleton in patients with metabolic bone diseases, eating disorders, and avascular necrosis. There is little pediatric experience using 18F fluoride PET/CT for evaluation of skeletal or soft tissue disease in childhood cancers. PMID- 25030393 TI - Fluorocholine PET/computed tomography: physiologic uptake, benign findings, and pitfalls. AB - Choline PET has a role in the diagnosis of malignancies. Knowledge of normal biodistribution plays a vital role in disease characterization and in differentiating normal variants from disease processes. CT and MR scans provide complementary information, and choline-positive sites should be correlated clinically to exclude inflammatory disorders. PMID- 25030394 TI - 18F-DOPA PET/computed tomography imaging. AB - 18F-DOPA is a radiopharmaceutical with interesting clinical applications and promising performances in the evaluation of the integrity of dopaminergic pathways, brain tumors, NETs (especially MTCs, paragangliomas, and pheochromocytomas), and congenital hyperinsulinism. 18F-DOPA traces a very specific metabolic pathway and has a very precise biodistribution pattern. As for any radiopharmaceutical, the knowledge of the normal distribution of 18F-DOPA, its physiologic variants, and its possible pitfalls is essential for the correct interpretation of PET scans. Moreover, it is important to be aware of the potential false-positive and false-negative episodes that can occur in the various clinical settings. PMID- 25030395 TI - The use of gallium-68 labeled somatostatin receptors in PET/CT imaging. AB - 68Ga-DOTA-SSTRTs PET/CT has become the most promising noninvasive procedure to study well-differentiated NET. Although the excellent diagnostic accuracy of the procedure is well known, its use is limited to specialized centers in Europe as parts of clinical trials. Literature reports confirm the superiority of 68Ga-DOTA SSTRTs PET/CT for the assessment of well-differentiated NET over morphologic imaging procedures, SRS, and even PET/CT using metabolic radiotracers. 68Ga-DOTA SSTRTs provide good visualization of NET lesions at both the primary and the metastatic sites (node, bone, liver, and unusual localizations). The advantages of their use over metabolic tracers (18F-DOPA, 18F-FDG) are not only limited to a better overall detection rate but also to the fact that they also provide data on SSTR expression on target lesions, resulting a fundamental procedure before starting therapy with either hot or cold somatostatin analogues. Moreover, they can be used also in centers without an on-site cyclotron. To interpret 68Ga-DOTA SSTRTs images correctly, it is crucial to understand the tracer's biodistribution as well as the conditions that may alter tracer uptake. Considering that SSTR are expressed on activated lymphocytes, all areas of inflammation show 68Ga-DOTA SSTRTs uptake. Areas of increased uptake in frequent sites of inflammation (eg, thyroid, mediastinal nodes, inguinal nodes, and nodes adjacent to areas of recent surgery/trauma) should be interpreted with care. A detailed clinical history with particular attention to concomitant disorders (eg, sarcoidosis, chronic gastritis, chronic thryoiditis) and recent invasive procedures or trauma may often help image interpretation. The presence of uptake in the head of the pancreas should always be carefully evaluated because it may often be benign. Otherwise, because the pancreas is also a frequent site of NET onset, particular attention should be devoted to the evaluation of the uptake pattern (diffuse more likely to be benign) and to the comparison with other imaging techniques. PMID- 25030396 TI - Proliferation imaging with 18F-fluorothymidine PET/computed tomography: physiologic uptake, variants, and pitfalls. AB - For noninvasive in vivo imaging of proliferation, 18F-FLT PET/CT remains a promising tool, owing to its correlation with proliferation indexes in many tumor entities. Future clinical applications will focus on monitoring response to cancer therapy, whereas tumor detection will be limited to organs with high physiologic 18F-FDG uptake. Use and interpretation of 18F-FLT requires knowledge of the physiologic tracer distribution and how it will be affected by anticancer treatment. Further studies are needed to determine the optimal timing of 18F-FLT PET/CT imaging in the course of cancer therapies or at the conclusion of therapy. PMID- 25030397 TI - 11C-acetate PET/CT imaging: physiologic uptake, variants, and pitfalls. AB - (11)C-acetate PET is used in the assessment of various cardiologic and oncologic diseases. This article describes the physiologic uptake of (11)C-acetate and presents the common benign findings in different anatomic parts of the body. Salivary glands, tonsils, thyroid, meningeal tuberculoma, meningiomas, and macroadenomas of pituitary gland are sites of mild to moderate tracer uptake in the head and neck region. Parenchymal diseases of the lung and reactive and/or inflammatory mediastinal lymphadenopathies cause benign (11)C-acetate uptake in the thorax. Liver, spleen, pancreas, and rectum show an increased uptake. Urinary tract and prostate gland show faint tracer uptake. PMID- 25030398 TI - PET/MRI radiotracer beyond 18F-FDG. AB - The recent development and introduction of new hybrid imaging devices combining positron emission tomography (PET) technology with magnetic resonance imaging (MRI) opens up new perspectives in clinical molecular imaging. Combining MRI and fluorine-18 choline PET would theoretically produce valuable clinical data in a single imaging session, which can be used for staging, prognosis, and assessment of treatment response. Fluorine-18-sodium fluoride (18F-NaF) is a highly sensitive PET tracer used as a marker of osteoblastic abnormalities. PET imaging with (68)Ga-DOTATATE or DOTATOC has demonstrated promising results for locating metastatic lesions, occasionally with superior sensitivity than whole-body MRI. l DOPA PET adds data regarding l-DOPA metabolism, which may increase the specificity and sensibility of the study itself. Fluoromisonidazole is known to be not only a useful tracer for determining hypoxic cells but also an efficient hypoxic radiosensitizer. PMID- 25030403 TI - PET tracers beyond FDG: normal variations and benign findings. PMID- 25030404 TI - Effect of methylene blue-mediated photodynamic therapy for treatment of basal cell carcinoma. AB - Photodynamic therapy (PDT) is regarded as a treatment option for basal cell carcinoma (BCC). The aim of this study is to investigate the efficacy of methylene blue (MB)-based PDT in patients suffering from nodular or ulcerative BCCs. This study is a prospective clinical trial with a 6-months follow-up. The study setting is at the Dermatology Clinic at NILES, Cairo University, Egypt. Seventeen patients complaining of nodular BCC (nBCC) and three patients complaining of ulcerative BCC (uBCC) were taken as samples. Methylene blue, the photosensitizer, was prepared in two different formulas: liposomal-loaded MB (LMB) was prepared and formulated in hydrogel (MB 0.2%) to be used topically alone for treating BCCs <2 cm in diameter or to be combined with intralesional injection (ILI) of free MB 2% aqueous solution for treating BCCs >=2 cm in diameter. A session was performed every 2 weeks until complete response (CR) of the lesion or for a maximum of six sessions. Clinical assessments of clinical improvement, dermatological photography, monthly follow-up visits for 6 months, and skin biopsy after 3 months of follow-up to confirm the response, recurrence, or both in cases in which the clinical evaluation was ambiguous. Seventeen patients of the 20 completed the study, 11 patients achieved CR with very good cosmetic outcome, photosensitizer tolerance, and minimal reported side effects. MB is a cheap promising alternative photosensitizer for PDT of nBCC. PMID- 25030405 TI - Association between single nucleotide polymorphisms of asporin (ASPN) and BMP5 with the risk of knee osteoarthritis in a Chinese Han population. AB - The aim of this study was to investigate associations between single nucleotide polymorphisms rs13301537 in asporin (ASPN) and rs373444 in the bone morphogenetic protein 5 (BMP5) gene with knee osteoarthritis (OA) susceptibility in a Chinese Han population. ASPN rs13301537 and BMP5 rs373444 polymorphisms were genotyped in patients with knee OA and age- and sex-matched OA-free controls from a Chinese Han population. A total of 510 patients with knee OA and 520 controls were enrolled in the study. CT and CC genotypes of rs13301537, and variant C, were associated with a significantly increased risk of knee OA. On stratification analysis, the association between the risk of OA and rs13301537 CT heterozygotes compared with TT homozygotes was stronger in females and those aged >65 years. In contrast, the CT and CC genotypes of rs373444 in BMP5 were not significantly associated with the risk of knee OA, even after further stratification analysis according to age or sex. Our results showed that ASPN rs13301537 T to C change and variant C genotype may contribute to knee OA risk in a Chinese Han population. PMID- 25030406 TI - Effect of obtusifolin administration on retinal capillary cell death and the development of retinopathy in diabetic rats. AB - Oxidative stress is increased in the retina in diabetes, and it is considered to play an important role in the development of retinopathy. Findings indicate that obtusifolin has antioxidant properties. The purpose of this study was to examine the effect of obtusifolin on retinal capillary cell apoptosis and the development of pathology in diabetes. Retina was used from streptozotocin-induced diabetic rats receiving diets supplemented with or without obtusifolin (100, 200, and 400 mg/kg) for 11 months of diabetes. Capillary cell apoptosis (by terminal transferase-mediated dUTP nick-end labeling) and formation of acellular capillaries were investigated in the trypsin-digested retinal microvessels. The effect of obtusifolin administration on retinal 8-hydroxy-2'deoxyguanosine (8 OHdG) and nitrotyrosine levels was determined by enzyme-linked immunosorbent assay. Obtusifolin administration for the entire duration of diabetes inhibited capillary cell apoptosis and the number of acellular capillaries in the retina, despite similar severity of hyperglycemia in the four diabetic groups (with and without obtusifolin). Retinal 8-OHdG and nitrotyrosine levels were significantly increased, respectively, in diabetes, and obtusifolin administration inhibited these increases. Our results demonstrate that the long-term administration of obtusifolin has beneficial effects on the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine in the retina. Obtusifolin represents an achievable adjunct therapy to help prevent vision loss in diabetic patients. PMID- 25030407 TI - Voltage-gated potassium+ channel expression in coronary artery smooth muscle cells of SHR and WKY. AB - This study aims to compare the expression of genes and the molecular characteristic of voltage-gated K(+) channels, which make great effort in maintaining and controlling smooth muscle contraction, cellular membrane potential, and intracellular calcium ion currents in artery smooth muscle cells of SHR and WKY. Expression of potassium ions family in coronary artery was detected through reverse transcription polymerase chain reaction quantitatively. Significant levels of voltage-gated K(+) channels alpha1.2, alpha1.5, and beta1.1 expression were all proved to be significantly higher in smooth muscles of SHR than WKY. Whole-cell voltage-gated K(+) channel currents were larger in SHR artery smooth muscles than the ones of WKY. Moreover, the voltage dependence of voltage-gated potassium channel activation was more negative in artery smooth muscle of SHR than that of WKY, while voltage dependence of availability was not different. The above diversity of voltage-gated potassium channel detected in gene expression and electrical character in coronary artery smooth muscle of SHR than that of WKY might be an underling mechanism associated with the membrane potential depolarization in artery smooth muscle of SHR. PMID- 25030408 TI - IL-8 promote carcinogenesis of primary epithelial cells from familial adenomatous polyposis. AB - Accumulated evidences supported IL-8 play an important role during colorectal carcinogenesis. However, few direct-related evidences are available. In this paper, we found that high level of IL-8 was constitutively present both in familial adenomatous polyposis (FAP) tissue and carcinoma tissue. Using primary epithelial cells from FAP samples, we study IL-8 effect on their growth, migration, and colonies formation. The results showed that IL-8 stimulated cells proliferation, migration, and colonies formation. Furthermore, High level of CEA, CK20, and EGFR was detected after exposure to IL-8 in primary epithelial cells. In conclusion, our findings showed that IL-8 promotes the adenoma-carcinoma transition in primary epithelial cells from FAP. Targeting IL-8 at adenoma stage may prevent or reduce carcinogenesis. PMID- 25030409 TI - Serum gamma-glutamyltransferase is associated with impaired fasting glucose in Chinese adults: the Cardiometabolic Risk in Chinese (CRC) study. AB - Recently, several studies found raised serum gamma-glutamyltransferase (GGT), and traditional marker of liver damage was associated with the risk of type 2 diabetes. The purpose of this study was to investigate the relationship between GGT and impaired fasting glucose (IFG), and evaluate the modification effects of age, BMI, prehypertension, and lipids in a large sample of Chinese adults. The study samples are from a community-based health examination survey in China. The sample for our analysis included 7,309 participants. IFG was defined as FBG from 6.1 to 7.0 mmol/L. Serum GGT, lipids, blood pressure, and glucose were measured. The odds ratios (ORs, 95 % CI) of IFG across increasing quintiles of GGT were 1.00, 0.91 (0.49-1.72), 1.27 (0.68-2.38), 2.31 (1.29-4.15), and 2.42 (1.32-4.42) (P for trend < 0.0001), adjusting for age, sex, BMI, blood pressure, glucose, and lipids. We found significant interactions between age, BMI, and GGT on IFG risk. When the joint effects were examined, we found an additional effect of triglycerides (TG) and GGT levels on IFG. Our data indicate that serum GGT concentration was associated with the risk of IFG, and the association was modified by TG level. PMID- 25030410 TI - Therapeutical effects and mechanism of salubrinal combined with ulinastatin on treating paraquat poisoning. AB - To explore therapeutic effects and underlying mechanism of Salubrinal combined with Ulinastatin (UTI) on acute Paraquat (PQ) poisoning. Four hundred rats were randomly allocated into UTI group, SAL group, SAL + UTI and control group according to random number table with 100 rats in each group. Acute PQ poisoning models were established, and all rats received UTI, Salubrinal, SAL + UTI and normal saline injection, respectively. Afterward, we analyzed the change of lung tissue and explored the mechanism. Acute PQ poisoning caused significantly damage in rat lung tissue structure, and UTI could effectively repair lung tissue damage. Salubrinal suppressed hemorrhage and fibrosis, but promoted inflammatory infiltration. In contrast, UTI + Salubrinal suppressed hemorrhage, fibrosis and inflammatory infiltration, but could not improve lung tissue damage. Expression of LC3 and Bcl-2 showed statistically significant difference among different groups (p < 0.05). LC3 and Bcl-2 levels in UTI group were much higher than in the other groups, and LC3 and Bcl-2 levels in UTI + SAL group was second higher. LC expression in SAL group was lower than in UTI group and UTI + SAL group with Bcl 2 in control group significantly lower than in the other groups (p < 0.05). Expression of Caspase-3 and Bcl-2/Bax in lung tissue in different groups had statistically significant difference (p < 0.05). Caspase-3 in UTI group was lower than in the other groups; however, Bcl-2/Bax in UTI group was higher than in the other groups (p < 0.05). Acute PQ poisoning can cause endoplasmic reticulum stress-autophagy in rat, and UTI can increase Bcl-2 expression, decrease Caspase 3, which can inhibit progress of lung injury by suppressing apoptosis and exert good therapeutic effects. Although salubrinal has marked effects on protecting lung tissue, it can increase Bcl-2 expression, which is not beneficial to lung tissue protection. The underlying mechanism still needs further exploration. PMID- 25030411 TI - Rural residents who are hospitalized in rural and urban hospitals: United States, 2010. AB - In 2010, 17% of the U.S. population lived in rural (nonmetropolitan) areas. Many rural areas are medically underserved due to physician (especially specialist) shortages. Rural hospitals often are small, with a low volume of services, and have difficulty remaining financially viable under the regular hospital prospective payment system. Special Medicare hospital payment categories have been established so that rural residents have access to hospital care without traveling to urban areas. The share of rural residents' hospitalizations that take place in urban (metropolitan) compared with rural hospitals has been of interest for a number of years. Those who go to urban hospitals have been described as "bypassing" rural hospitals. This data brief compares characteristics of rural residents who stay in rural areas with those who travel to urban areas for their inpatient care. PMID- 25030412 TI - Burnout, anxiety, depression, and social skills in medical residents. AB - The medical residency is recognized as a risk period for the development of burnout and mental health problems, such as anxiety and depression, which have impact on the physician and clientele alike. There is a need for studies that address conditions of risk and protection for the development of such problems. This study aimed to verify the rates of burnout, anxiety, and depression presented by resident physicians, as well as the associations of these problems with social skills, as potential protective factors. The hypothesis was defined that the problems (burnout, anxiety, and depression) would be negatively associated with social skills. A total of 305 medical residents, of both genders, of different specialties, from clinical and surgical areas of a Brazilian university hospital were evaluated using the following standardized self-report instruments: Burnout Syndrome Inventory, Social Skills Inventory, and the Patient Health Questionnaire-4. High rates of burnout and mental health problems were verified and social skills were negatively associated with burnout dimensions such as emotional exhaustion, emotional detachment, and dehumanization, but positively associated with personal accomplishment. Furthermore, residents with indicators of problems presented significantly lower social skills means than those of residents without indicators of burnout, anxiety, or depression. More studies are needed, which include other types of instruments in addition to self report ones and evaluate not only social skills but also social competence in the professional practice. These should adopt intervention and longitudinal designs that allow the continuity or overcoming of the problems to be verified. Since social skills can be learned, the results of the study highlight the importance of developing the interpersonal skills of the professionals during the training of resident physicians in order to improve their practice. PMID- 25030413 TI - Generation of marker-free transgenic plants concurrently resistant to a DNA geminivirus and a RNA tospovirus. AB - Global threats of ssDNA geminivirus and ss(-)RNA tospovirus on crops necessitate the development of transgenic resistance. Here, we constructed a two-T DNA vector carrying a hairpin of the intergenic region (IGR) of Ageratum yellow vein virus (AYVV), residing in an intron inserted in an untranslatable nucleocapsid protein (NP) fragment of Melon yellow spot virus (MYSV). Transgenic tobacco lines highly resistant to AYVV and MYSV were generated. Accumulation of 24-nt siRNA, higher methylation levels on the IGR promoters of the transgene, and suppression of IGR promoter activity of invading AYVV indicate that AYVV resistance is mediated by transcriptional gene silencing. Lack of NP transcript and accumulation of corresponding siRNAs indicate that MYSV resistance is mediated through post transcriptional gene silencing. Marker-free progenies with concurrent resistance to both AYVV and MYSV, stably inherited as dominant nuclear traits, were obtained. Hence, we provide a novel way for concurrent control of noxious DNA and RNA viruses with less biosafety concerns. PMID- 25030415 TI - Inhibitory effects of calf thymus DNA on metabolism activity of CYP450 enzyme in human liver microsomes. AB - The present study investigated the effect of calf thymus DNA (ctDNA) on human hepatic cytochrome P450s (CYP450s) in vitro. Specific substrate probes for each isoform, CYP1A2, 2C9, 2C19, 2D6 and 3A4, were incubated using pooled human liver microsomes with or without ctDNA, and liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) method was developed for the analysis of probe metabolites. Enzyme kinetics parameters Ki and IC50 values were estimated to determine the types and strength of inhibition. ctDNA could specifically inhibit the metabolism of CYP2C9 probe substrates, with the IC50 = 0.9955 ug/ml, while it was not able to inhibit CYP1A2, CYP2C19, CYP2D6 or CYP3A4 (IC50 > 100 ug/ml). The results showed that ctDNA was a potent inhibitor of CYP2C9 enzyme, and has the metabolic interaction potential with the model drugs which are metabolism substrates of CYP2C9. The inhibition mechanism study suggested ctDNA may inhibit CYP2C9 by decreasing the activity of CYP450 reductase. These findings indicated that when the medical agents catalyzed mainly by CYP2C9 were co-administered in vivo with adsorptive material in vitro, the potential inhibitory effect of ctDNA on enzyme activity and the following metabolism character changes of the former should be highly focused on. PMID- 25030414 TI - Coniothyren: a new phenoxyphenyl ether from the endophytic fungus, Coniothyrium sp. AB - Phytochemical investigation of the endophytic fungus Coniothyrium sp. resulted in the isolation of a new phenoxyphenyl ether, named coniothyren (1), and two known compounds, coniol (2) and (+)-epoxydon (3). The structure of the new compound was elucidated by detailed spectroscopic analysis, namely, (1)H NMR, (13)C NMR, COSY, HMQC, HMBC, and HR-EI-MS. Preliminary studies demonstrated that (+)-epoxydon (3) displayed good antibacterial and antialgal activities toward Bacillus megaterium and Chlorella fusca, respectively. PMID- 25030416 TI - Partnering for success through community-based participatory research in Indian country. PMID- 25030417 TI - Lactobacillus paracasei CBA L74 interferes with gliadin peptides entrance in Caco 2 cells. AB - Several recent reports describe a role of probiotics as a therapeutic approach for celiac disease (CD). Two undigested A-gliadin peptides, P31-43 and P57-68, are central to CD pathogenesis, inducing an innate and an adaptive immune response, respectively. They enter enterocytes and localize to vesicular compartment to induce their toxic/immunogenics effects. In this article, we tested the effect of probiotic Lactobacillus paracasei (LP) CBA L74 (International Depository Accession Number LMG P-24778), its supernatant and LP fermented cereals on gliadin peptides, P31-43 and P57-68, entrance in Caco-2 cells. Both LP CBA L74 and its supernatant inhibit P31-43 (intensity of fluorescence; FI: 75%) and P57-68 (FI: 50%) entrance in Caco2 cells, indicating that this biological effect is due to some product included in LP CBA L74 supernatant. This effect was present also after fermentation of cereals. This study describes a novel effect of probiotics in the prevention of undigested gliadin peptides toxic effects. PMID- 25030418 TI - Long-term outcomes of transcatheter closure of ruptured sinus valsalva aneurysms using patent ductus arteriosus occluders. AB - BACKGROUND: Transcatheter closure (TCC) of ruptured sinus of Valsalva aneurysm (RSVA) is an alternative strategy to surgery, but there is a lack of long-term outcome data. METHODS AND RESULTS: From 2004 to 2012, 17 patients (8 males, 9 females) were treated with patent ductus arteriosus (PDA) occluders by antegrade venous approach and were followed for 18-102 months. Of the 17 patients, transthoracic echocardiography revealed rupture of the right coronary sinus into the right ventricle in 9 and into the right atrium in 4, and noncoronary sinus rupture into the right ventricle in 3 and into the right atrium in 1. Most (10/17) were in New York Heart Association (NYHA) functional class III or IV. Aortography showed that the size of the defect was 7.71+/-2.84 mm (4-15 mm). TCC was attempted using PDA occluders 2-5 mm larger than the aortic end of the defects. The device sizes ranged from 8/6 to 18/16 mm (median, 10/8 mm). The procedure was successful in 16 (94.1%), and all of them had complete occlusion at discharge. On a median follow-up of 42 months, 14 patients were in NYHA class I and 2 were in class II, and there was no residual shunt, device embolization, infective endocarditis, or aortic regurgitation. CONCLUSIONS: TCC of RSVA is a safe and effective alternative to surgery with favorable long-term follow-up results. PMID- 25030419 TI - Transcatheter intervention for complex ascending aortic pseudoaneurysm after cardiac surgery. AB - BACKGROUND: Ascending aortic pseudoaneurysm (PsA) is an uncommon but surgically challenging problem with high morbidity and mortality. Herein we describe the efficacy and safety of the different approaches to transcatheter intervention for repair of ascending PsA and assess the selection of occluder devices using real time 3-dimensional (RT 3D) color Doppler transesophageal echocardiography (TEE).METHODS AND RESULTS: Three patients with complex ascending PsA after cardiac or aortic root surgery were treated with transcatheter intervention due to high risk for redo surgery. Perioperative RT 3D-TEE combined with fluoroscopy was used for monitoring. All ascending PsA were successfully occluded with different devices using the transcatheter technique either with the transapical, transarterial approach, or transvenous combined with hybrid process depending on lesion anatomy. CONCLUSIONS: Treatment of complex ascending PsA with transcatheter or combined hybrid intervention with cautious planning based on patient presentation and well-coordinated teamwork was successful. RT 3D color Doppler TEE provided precise information for the selection of appropriate occluder device, and also facilitated the procedure by guiding the catheter through difficult anatomy. PMID- 25030420 TI - Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice. AB - Hepatic Macs, consisting of resident KCs and infiltrating monocytes/IMs, are thought to play an important role in the pathogenesis of ALD. Previous work has focused on KCs or studied hepatic Macs as one cell population. The aim of the current study is to distinguish IMs from KCs and to compare their phenotypes and functions. We show here that a 4-week ethanol feeding of C57BL/6J mice causes recruitment of IMs into the liver. KCs and IMs can be distinguished based on their differential expression of F4/80 and CD11b. IMs can be divided further into two subsets based on their differential expression of Ly6C. KCs and two subsets of IMs were separately purified by FACS. The phagocytosis abilities and the expression profiles of genes related to various functions were compared among different populations of hepatic Macs. Ly6C(low) IMs exhibit an anti-inflammatory and tissue-protective phenotype; in contrast, Ly6C(hi) IMs exhibit a proinflammatory, tissue-damaging phenotype. The ratio of Ly6C(hi)/Ly6C(low) increases when mice chronically fed ethanol were binged, which significantly enhanced liver injury. Moreover, upon phagocytosis of apoptotic hepatocytes, Ly6C(hi) IMs switch to Ly6C(low) IMs. Taken together, chronic ethanol feeding induces the recruitment of two subsets of hepatic IMs, which play different or even opposite roles in regulating liver inflammation and repair. These findings may not only increase our understanding of the complex functions of Macs in the pathogenesis of ALD but also help us to identify novel therapeutic targets for the treatment of this disease. PMID- 25030421 TI - Aberrant host defense against Leishmania major in the absence of SLPI. AB - SLPI, a potent epithelial and myeloid-derived serine protease inhibitor with antimicrobial and anti-inflammatory functions, is induced by the intracellular parasite Leishmania major, and increased SLPI expression is evident within lesions that follow L. major infection. In contrast to self-resolving infection in C57Bl/6 WT mice, Slpi(-/-) mice launch a strong Th1 response to L. major, yet fail to control infection and develop destructive, nonhealing lesions with systemic spread of parasites. Because SLPI is both produced by murine macrophages and antagonizes their function, we examined the contribution of macrophage polarization to the defective host response in the absence of SLPI. Slpi(-/-) and Slpi(+/+) macrophages were first primed with either IFNgamma or IL-4 to generate classically activated M1 or alternatively activated M2 macrophages. After infection with L. major, Slpi(-/-) M1 macrophages expressed elevated iNOS RNA, whereas arginase was more highly expressed in WT than Slpi(-/-) M2 macrophages. After in vivo infection, we found that both IFNgamma and iNOS were persistently overexpressed in chronic lesions in Slpi(-/-) mice, but surprisingly, IL-4 and arginase concomitantly remained elevated. Moreover, overexpression of the negative regulators SOCS1 and IL-27 provided insight into the failure of IFNgamma to clear L. major from the dermal lesions. Notably, adenoviral delivery of SLPI to L. major-infected Slpi(-/-) mice significantly limited the progression of infection. These studies suggest that convergence of M1 and M2 macrophage responses may influence the outcome of innate host defense against intracellular parasites and that SLPI is critical for coordinating resistance to chronic leishmaniasis. PMID- 25030422 TI - The TGF-beta-inducible miR-23a cluster attenuates IFN-gamma levels and antigen specific cytotoxicity in human CD8+ T cells. AB - Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN-gamma and inhibition of degranulation by TGF-beta are well established, we wondered whether TGF-beta could also induce immune-regulatory miRNAs in human CD8(+) T cells. We used miRNA microarrays and high-throughput sequencing in combination with qRT-PCR and found that TGF-beta promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF-beta up-regulated expression of the cluster in CD8(+) T cells from wild-type mice, but not in cells from mice with tissue-specific expression of a dominant-negative TGF-beta type II receptor. Reporter gene assays including site mutations confirmed that miR-23a specifically targets the 3'UTR of CD107a/LAMP1 mRNA, whereas the further miRNAs expressed in this cluster-namely, miR-27a and 24-target the 3'UTR of IFN-gamma mRNA. Upon modulation of the miR-23a cluster by the respective miRNA antagomirs and mimics, we observed significant changes in IFN-gamma expression, but only slight effects on CD107a/LAMP1 expression. Still, overexpression of the cluster attenuated the cytotoxic activity of antigen specific CD8(+) T cells. These functional data thus reveal that the miR-23a cluster not only is induced by TGF-beta, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF-beta signaling. PMID- 25030423 TI - Structural distortions in molecular-based quantum cellular automata: a minimal model based study. AB - Molecular-based quantum cellular automata (m-QCA), as an extension of quantum-dot QCAs, offer a novel alternative in which binary information can be encoded in the molecular charge configuration of a cell and propagated via nearest-neighbor Coulombic cell-cell interactions. Appropriate functionality of m-QCAs involves a complex relationship between quantum mechanical effects, such as electron transfer processes within the molecular building blocks, and electrostatic interactions between cells. The influence of structural distortions of single m QCA are addressed in this paper within a minimal model using an diabatic-to adiabatic transformation. We show that even small changes of the classical square geometry between driver and target cells, such as those induced by distance variations or shape distortions, can make cells respond to interactions in a far less symmetric fashion, modifying and potentially impairing the expected computational behavior of the m-QCA. PMID- 25030424 TI - Parallel photonic quantum computation assisted by quantum dots in one-side optical microcavities. AB - Universal quantum logic gates are important elements for a quantum computer. In contrast to previous constructions on one degree of freedom (DOF) of quantum systems, we investigate the possibility of parallel quantum computations dependent on two DOFs of photon systems. We construct deterministic hyper controlled-not (hyper-CNOT) gates operating on the spatial-mode and the polarization DOFs of two-photon or one-photon systems by exploring the giant optical circular birefringence induced by quantum-dot spins in one-sided optical microcavities. These hyper-CNOT gates show that the quantum states of two DOFs can be viewed as independent qubits without requiring auxiliary DOFs in theory. This result can reduce the quantum resources by half for quantum applications with large qubit systems, such as the quantum Shor algorithm. PMID- 25030425 TI - Experimental infection of duck origin virulent Newcastle disease virus strain in ducks. AB - BACKGROUND: Newcastle disease (ND) caused by virulent Newcastle disease virus (NDV) is an acute, highly contagious and fatal viral disease affecting most species of birds. Ducks are generally considered to be natural reservoirs or carriers of NDV while being resistant to NDV strains, even those most virulent for chickens; however, natural ND cases in ducks have been gradually increasing in recent years. In the present study, ducks of different breeds and ages were experimentally infected with duck origin virulent NDV strain duck/Jiangsu/JSD0812/2008 (JSD0812) by various routes to investigate the pathogenicity of NDV in ducks. RESULTS: Six breeds (mallard, Gaoyou, Shaoxing, Jinding, Shanma, and Pekin ducks) were infected intramuscularly (IM) with JSD0812 strain at the dose of 5 * 108 ELD50. Susceptibility to NDV infection among breeds varied, per morbidity and mortality. Mallard ducks were the most susceptible, and Pekin ducks the most resistant. Fifteen-, 30-, 45-, 60-, and 110-day-old Gaoyou ducks were infected with JSD0812 strain at the dose of 5 * 108 ELD50 either IM or intranasally (IN) and intraocularly (IO), and their disease development, viral shedding, and virus tissue distribution were determined. The susceptibility of ducks to NDV infection decreased with age. Most deaths occurred in 15- and 30-day old ducklings infected IM. Ducks infected IN and IO sometimes exhibited clinical signs, but seldom died. Clinical signs were primarily neurologic. Infected ducks could excrete infectious virus from the pharynx and/or cloaca for a short period, which varied with bird age or inoculation route; the longest period was about 7 days. The rate of virus isolation in tissues from infected ducks was generally low, even in those from dead birds, and it appeared to be unrelated to bird age and infection route. CONCLUSIONS: The results confirmed that some of the naturally occurring NDV virulent strains can cause the disease in ducks, and that ducks play an important role in the epidemiology of ND. The prevention of NDV spread in ducks should receive more attention and research in terms of preventing the occurrence and prevalence of ND. PMID- 25030426 TI - HelicoBase: a Helicobacter genomic resource and analysis platform. AB - BACKGROUND: Helicobacter is a genus of Gram-negative bacteria, possessing a characteristic helical shape that has been associated with a wide spectrum of human diseases. Although much research has been done on Helicobacter and many genomes have been sequenced, currently there is no specialized Helicobacter genomic resource and analysis platform to facilitate analysis of these genomes. With the increasing number of Helicobacter genomes being sequenced, comparative genomic analysis on members of this species will provide further insights on their taxonomy, phylogeny, pathogenicity and other information that may contribute to better management of diseases caused by Helicobacter pathogens. DESCRIPTION: To facilitate the ongoing research on Helicobacter, a specialized central repository and analysis platform for the Helicobacter research community is needed to host the fast-growing amount of genomic data and facilitate the analysis of these data, particularly comparative analysis. Here we present HelicoBase, a user-friendly Helicobacter resource platform with diverse functionality for the analysis of Helicobacter genomic data for the Helicobacter research communities. HelicoBase hosts a total of 13 species and 166 genome sequences of Helicobacter spp. Genome annotations such as gene/protein sequences, protein function and sub-cellular localisation are also included. Our web implementation supports diverse query types and seamless searching of annotations using an AJAX-based real-time searching system. JBrowse is also incorporated to allow rapid and seamless browsing of Helicobacter genomes and annotations. Advanced bioinformatics analysis tools consisting of standard BLAST for similarity search, VFDB BLAST for sequence similarity search against the Virulence Factor Database (VFDB), Pairwise Genome Comparison (PGC) tool for comparative genomic analysis, and a newly designed Pathogenomics Profiling Tool (PathoProT) for comparative pathogenomic analysis are also included to facilitate the analysis of Helicobacter genomic data. CONCLUSIONS: HelicoBase offers access to a range of genomic resources as well as tools for the analysis of Helicobacter genome data. HelicoBase can be accessed at http://helicobacter.um.edu.my. PMID- 25030427 TI - Mapping genetic variants in the CFH gene for association with leprosy in Han Chinese. AB - Complement factor H (CFH) is an essential regulator in the homeostasis of the complement system that plays multiple roles in leprosy. We previously reported a preliminary association of CFH with leprosy, but potentially causal variants remain to be identified. In this study, we performed a fine-mapping association analysis in 1110 individuals (527 leprosy patients and 583 controls) followed by bioinformatic analyses. We identified no association of typical missense CFH variants with leprosy and factor H-binding protein was not detected in Mycobacterium leprae. However, robust associations (PBonferroni<0.003) of several CFH intronic tag single-nucleotide polymorphisms with leprosy were observed. Expression quantitative trait locus analysis showed that these leprosy-protective alleles were associated with higher CFH level and lower CFHR3 (complement factor H-related 3) level. Our results indicated that CFH variants may contribute to leprosy pathogenesis through altering CFH expression, leading to regulation of complement activity rather than mediating immune evasion by bacteria binding. PMID- 25030428 TI - Annotation of functional variation within non-MHC MS susceptibility loci through bioinformatics analysis. AB - There is a strong and complex genetic component to multiple sclerosis (MS). In addition to variation in the major histocompatibility complex (MHC) region on chromosome 6p21.3, 110 non-MHC susceptibility variants have been identified in Northern Europeans, thus far. The majority of the MS-associated genes are immune related; however, similar to most other complex genetic diseases, the causal variants and biological processes underlying pathogenesis remain largely unknown. We created a comprehensive catalog of putative functional variants that reside within linkage disequilibrium regions of the MS-associated genic variants to guide future studies. Bioinformatics analyses were also conducted using publicly available resources to identify plausible pathological processes relevant to MS and functional hypotheses for established MS-associated variants. PMID- 25030429 TI - Emerging role of epigenetics in systemic sclerosis pathogenesis. AB - Systemic sclerosis is a connective tissue disease of unknown aetiology characterised by autoimmunity, inflammation, vascular abnormalities and ultimately fibrosis. Although great advances have been made in determining the molecular mechanisms of disease pathogenesis over the last decade, aided by new genetic screens, no current specific disease-modifying treatment is yet available. Epigenetics is defined as heritable changes that are not due to changes in DNA sequence, and there is at present intense research effort to understand the basic mechanisms of epigenetic regulation and how these impact diseases. Epigenetic modifications and dysregulation are associated now with autoimmune disease, inflammatory disease and cancer. In rheumatic diseases all three epigenetic processes are associated with various diseases including rheumatoid arthritis and systemic sclerosis. In systemic sclerosis much focus has been on microRNAs; however, other modifications including DNA methylation are emerging to have a key role. This review examines the role of epigenetics in systemic sclerosis and appraises the contribution of each modification and suggests that modulators of epigenetic changes may be a novel therapeutic option. PMID- 25030430 TI - Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. AB - The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 * 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region. PMID- 25030432 TI - Plasmonic-photonic crystal coupled nanolaser. AB - We propose and demonstrate a hybrid photonic-plasmonic nanolaser that combines the light harvesting features of a dielectric photonic crystal cavity with the extraordinary confining properties of an optical nano-antenna. For this purpose, we developed a novel fabrication method based on multi-step electron-beam lithography. We show that it enables the robust and reproducible production of hybrid structures, using a fully top-down approach to accurately position the antenna. Coherent coupling of the photonic and plasmonic modes is highlighted and opens up a broad range of new hybrid nanophotonic devices. PMID- 25030431 TI - Glutamate receptor antagonists in the management of migraine. AB - Migraine is a neurovascular disorder that is associated with severe headache and neurologic symptoms. The pathogenesis of migraine is believed to involve trigeminovascular system activation with the primary dysfunction located in brainstem. Glutamate, the major excitatory neurotransmitter in the central nervous system, and its receptors have since long been suggested in migraine pathophysiology. Different preclinical studies have confirmed their potential role in migraine. Moreover, several glutamate receptor modulators have been studied in clinical studies, some with promising results. In this review, we will give an overview of what is known about the role of glutamate in the pathogenesis of migraine, which will be followed by an overview of available efficacy, safety and tolerability data for glutamate receptor inhibitors in clinical development for the treatment of migraine. PMID- 25030433 TI - Diffuse large B-cell lymphoma: the history, current view and new perspectives. AB - The basic principles of lymphoma classification(s) in general have been widely evolving in a course of decades of years wiht the use of contemporary resources and recent cutting edges in hematooncology on a clinical, morphological and molecular level bring new possibilities not only in improvements of diagnostic and prognostic algorithms and also bear new opportunities in so called targeted and tailored strategies of lymphoma therapy. The pathogenesis and biologic behavior of lymphoproliferations and even lymphomas should be studied in a context of lymphocytic and (neoplastic) lymphoid stage and chronologic development. In a current more complex insight into lymphoproliferations we would like to describe huge heterogeneity of diffuse large B-cell lymphoma in relationship to mandatory WHO classification since 2008 and the next development of knowledge in this field with potential new influence on an advancement of both classification and therapy. PMID- 25030434 TI - SKLB-287, a novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model. AB - Colorectal cancer (CRC) is the third common cancer and most of the chemotherapies of CRC currently used often suffer limited efficacy and large side effects. Targeted small-molecule by anti-tumor drugs are thought a promising strategy for improving the efficacy and reducing the side effects. In this investigation, we report a novel multikinase inhibitor, termed SKLB-287, which was discovered by us recently. SKLB-287 could efficiently inhibit the activation of endothelial growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2). It displayed very good anti-proliferative activity against LoVo CRC cells and considerable antiangiogenic potency in transgenic zebrafish embryos. Oral administration of SKLB-287 resulted in dose-dependent suppression of tumor growth in LoVo xenograft mouse model. Immunohistochemistry was adopted to examine the in vivo anti-tumor mechanism of action of SKLB-287. PMID- 25030435 TI - RNA interference-mediated knockdown of brain-derived neurotrophic factor (BDNF) promotes cell cycle arrest and apoptosis in B-cell lymphoma cells. AB - Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily that has been reported to be involved in a number of neurological and psychological situations. Recently, high expression level of BDNF is observed in diverse human malignancies, delineating a role of BDNF in tumorigenesis. Nevertheless, its effect on B-cell lymphoma remains unclear. In this study, RNA interference technology mediated by short hairpin RNA (shRNA) was performed to inhibit endogenous BDNF expression in B-cell lymphoma cells. Results showed that knockdown of BDNF reduced cell growth and proliferation of Raji and Ramos cells. Furthermore, down-regulation of BDNF induced a cell cycle arrest at G0/G1 phase in Raji cells, and consequently led to cell apoptosis in vitro. Meanwhile, down regulation of Bcl-2 and up-regulation of Bax, activated caspase-3 and caspase-9 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in Raji cells when endogenous BDNF was inhibited. Besides, we also found that suppression of BDNF in Raji cells increased their sensitivity to chemotherapeutic drug, 5-Fluorouracil (5-FU). Our research provides a promising therapeutic strategy for human B-cell lymphoma by targeting BDNF. PMID- 25030436 TI - Far upstream element-binding protein 1(FUBP1) expression differs between human colorectal cancer and non-cancerous tissue. AB - Presented study aimed to detect the expression of far upstream element-binding protein 1 (FUBP1) in clinical samples of colorectal carcinoma (CRC) and explore the correlations of their expression with the clinicopathological characteristics of CRC.The streptavidin-perosidase (SP) method of immunohistochemistry was used to detect the expression of FUBP1 in 34 cases of colorectal cancer and their surrounding surrounding normal tissue, 30 cases of adenoma tissue. Using fluorescent quantitative reverse transcription polymerase chain reaction (qPCR), the expression of FUBP1 mRNA was measured in colorectal cancer and its surrounding normal tissue from 32 patients. FUBP1 protein expression level was detected by the Western blot method in 32 pairs of colorectal cancer tissue and surrounding normal tissue, and 30 cases of adenoma tissue.The positive rate of FUBP1 was detected through histochemistry in colorectal carcinomas (82.3%) which was higher than that in colorectal adenomas (46.7%) and surrounding normal tissues (20.5%). The relative amount of FUBP1 mRNA by qPCR method in colorectal carcinoma tissues (0.2703+/-0.1118) was higher than that of surrounding normal tissues (0.1898+/-0.0635; P<0.05). The Western blot showed that FUBP1 was mainly expressed in colorectal carcinoma tissues (0.6499+/-0.1473),which barely expressed in adenoma tissues (0.3756+/-0.1377; P<0.05) and surrounding normal tissues (0.1675+/-0.0613; P < 0.05).FUBP1 expression differs among colorectal tissues, which is overexpressed in colorectal carcinoma tissue. Further studies are needed to explore the role of FUBP1 in the pathogenesis of colorectal carcinoma. PMID- 25030437 TI - Fusion of human bone hemopoietic stem cell with esophageal carcinoma cells didn't generate esophageal cancer stem cell. AB - Prior studies showed that cell fusion between bone marrow-derived cell (BMDC) and somatic cell might be the origin of cancer stem cell. Our previous study suggested that cell fusion of human bone marrow-derived mesenchymal stem cell (MSC) with esophageal cancer cell did not generate cancer stem cells. But up to now, the origin of cancer stem cell is still ambiguous. In this study, we carried out the cell fusion experiment between hemopoietic stem cells (HSCs) and human esophageal cancer cells, and found that cell fusion slowed the growth speed of esophageal cancer cells and decreased the clone formation ability and tumorigenicity in NOD/SCID mice. In addition, cell fusion did not increase the ratio of side population (SP) cells and the resistance to chemotherapeutic drugs. Collectively, our data indicated that cell fusion between HSCs and esophageal cancer cells has a therapeutic effect rather than generate cells with characteristics of esophageal cancer stem cells. PMID- 25030438 TI - The decreased expression of protease-activated receptor 4 in esophageal squamous carcinoma. AB - Protease-activated receptors (PARs) are a unique family of G-protein coupled receptors. PAR4, a member of PARs family, was reported to be related to the development of cancers. Whether PAR4 plays a role in the progress of esophageal squamous cancer is unknown. In this study, differential expression of PAR4 in esophageal squamous cancer was measured by real-time PCR (n = 28), western blot and tissue microarrays (n = 78). The results showed that PAR4 expression was remarkably decreased in esophageal squamous cancer tissues compared with the matched noncancerous tissues, especially in low differentiation and positive distant metastasis carcinoma tissues. Furthermore, the methylation level of PAR4 promoter in esophageal cancer cells and normal epithelial cells was determined. Human esophageal cancer cells TE-1 displayed significant hypermethylation of 19 CpG sites, but pronounced hypomethylation of the sites in esophageal epithelial cells HEEpiC. The results suggested that down-regulation expression of PAR4 occurs frequently in esophageal squamous cancers, and the loss of PAR4 expression may partly result from hypermethylation of the PAR4 promoter. That PAR4 expression difference in tumor progression possibly makes PAR4 become a molecular mark of tumor diagnosis. PMID- 25030439 TI - Effect of 9-cis retinoic acid and all-trans retinoic acid in combination with verapamil on P-glycoprotein expression in L1210 cells. AB - The development of the most common multidrug resistance (MDR) phenotype is associated with a massive overexpression of P-glycoprotein (P-gp) in neoplastic cells. In the current study, we used three L1210 cell variants: S cells - parental drug-sensitive cells; R cells - drug-resistant cells with P-gp overexpression due to selection with vincristine; T cells - drug-resistant cells with P-gp overexpression due to stable transfection with the pHaMDRwt plasmid, which encodes human full-length P-gp. Several authors have described the induction of P-gp expression/activity in malignant cell lines after treatment with all-trans retinoic acid (AtRA; ligand of retinoic acid nuclear receptors, RARs). An isomer of AtRA also exists, 9-cis retinoic acid, which is a ligand of both RARs and nuclear retinoid X receptors (RXRs). In a previous work, we described that the combined treatment of R cells with verapamil and AtRA induces the downregulation of P-gp expression/activity. In the current study, we studied the expression of RARs and RXRs in S, R and T cells and the effects of treatment with AtRA, 9cRA and verapamil on P-gp expression, cellular localization and efflux activity in R and T cells. We found that the overexpression of P-gp in L1210 cells is associated with several changes in the specific transcription of both subgroups of nuclear receptors, RARs and RXRs. We also demonstrated that treatment with AtRA, 9cRA and verapamil induces alterations in P-gp expression in R and T cells. Particularly, combined treatment of R cells with verapamil and AtRA induced downregulation of P-gp content/activity. In contrast, similar treatment of T cells induced slight increase of P-gp content without any changes in efflux activity of this protein. These findings indicate that active crosstalk between the RAR and RXR regulatory pathways and P-gp-mediated MDR could take place. PMID- 25030440 TI - Expression of serine and glycine-related enzymes in phyllodes tumor. AB - Expression patterns of proteins involved in serine and glycine metabolism, and correlations of these patterns with clinicopathologic factors in phyllodes tumor were investigated. Tissue microarrays were prepared from 203 phyllodes tumors (PT) and stained with antibodies specific for glycine decarboxylase (GLDC), phosphoserine aminotransferase 1 (PSAT1), phosphoserine phosphatase (PSPH), phosphoglycerate dehydrogenase (PHGDH), and serine hydroxymethyltransferase 1 (SHMT1). These immunohistochemical results and clinicopathologic parameters were analyzed for correlation. Numbers of benign, borderline, and malignant tumors were 155, 32, and 16, respectively. Stromal expression of PHGDH, PSAT1, PSPH, SHMT1, and GLDC increased with increasing tumor grade, and epithelial expression of SHMT1 also increased with increasing tumor grade (p<0.001, and p=0.005, respectively). On univariate analysis, positive stainings for stromal PHGDH (p<0.001), stromal PSAT1 (p<0.001), stromal PSPH (p=0.003), epithelial SHMT1 (p=0.001), stromal SHMT1 (p=0.022), and stromal GLDC (p<0.001) were each associated with shorter disease-free survival. Stromal GLDC was associated with shorter overall survival (p<0.001). In conclusion, expression of proteins related to serine and glycine metabolism increased with increasing histologic grade in stromal components of phyllodes tumor. KEYWORDS: glycine, tumor grade, metabolism, phyllodes tumor, serine. PMID- 25030441 TI - Serum high mobility group box protein 1 as a clinical marker for ovarian cancer. AB - The aim of the study was to evaluate the clinical value of serum high mobility group box chromosomal protein 1 (HMGB1) in ovarian cancer and analyze the correlation between HMGB1 and ovarian cancer clinicopathologic outcomes.A total of 105 patients with diagnosed epithelial ovarian cancer, 46 patients with ovarian benign disease and 33 healthy volunteers were enrolled from January 2011 through January 2013. Serum HMGB1 levels were analyzed by enzyme-linked immunosorbent assay.The mean value of serum HMGB1 levels in ovarian cancer patients (78.18+/-54.87ng/ml) was significantly higher than those in benign patients (33.98+/-9.97ng/ml) and healthy control (26.71+/-7.99ng/ml, p < 0.0001), respectively. The serum HMGB1 levels were 40.33+/-6.50ng/ml, 61.16+/-20.15ng/ml, 81.81+/-51.15ng/ml and 119.48+/-84.28ng/ml in patients with TNM stage I, II, III, and IV, respectively (p < 0.0001). There were 81 of the 105 ovarian cancer patients obtained complete remission, the serum HMGB1 levels before treatment(71.99+/-42.49ng/ml) were much higher than that at remission stage(42.10+/-15.48ng/ml) (p < 0.0001). During our investigating period, 28 ovarian cancer patients underwent recurrence, the serum HMGB1 levels were 75.54+/ 39.50ng/ml in these recurrent ovarian cancer patients compared to 42.04+/ 10.68ng/ml in non-recurrent ovarian cancer (p < 0.0001). None of the remission or recurrent patients came from benign ovarian tumor group.Our study suggests that HMGB1 may be a useful clinical marker for evaluating progression and predicting prognosis of ovarian carcinoma. Targeting HMGB1 production or release might have potential approaches for ovarian carcinoma treatment. PMID- 25030443 TI - A myeloablative conditioning regimen with fludarabine demonstrates good results in UCBT for 30 pediatric patients with hematologic malignancies, especially acute lymphoblastic leukemia. AB - We retrospectively analyzed the safety and efficacy of a myeloablative conditioning regimen with fludarabine (FLU) in unrelated cord blood transplantation (UCBT) of 30 pediatric patients with hematologic malignancies. The conditioning regimen consisted of FLU, busulfan (BU) and cyclophosphamide (CY). All of the patients received Cyclosporine (CSA) and mycophenolate mofetil (MMF) as graft versus host disease (GVHD) prophylaxis. We achieved high engraftment rates (96.7%) and rapid hematopoietic reconstitution. Acute GVHD occurred in 12 cases of the 29 engraftment patients (41.4%), and 6 cases (20.7%) were of grade III-IV. Chronic GVHD only occurred in 1 of 28 evaluable patients (3.6%). Twenty-three patients (76.7%) became infected, and 3 cases (10.0%) died of severe infections. Cytomegalovirus (CMV) reactivation occurred in 70.0% of the patients, but no CMV diseases were observed, nor did any patients die of CMV infection. The cumulative incidence of relapse (6.7%) was significantly reduced, and none of the acute lymphoblastic leukemia (ALL) patients relapsed. The 3-year overall survival (OS) and event-free survival (EFS) rates were 73.3% and 70.0%, respectively. The 3-year OS and EFS of the ALL patients was 75.0%. This conditioning regimen demonstrates good results and security in UCBT, especially in acute lymphoblastic leukemia. PMID- 25030442 TI - Prognostic relevance of angiopoietin-2, fibroblast growth factor-2 and endoglin mRNA expressions in chronic lymphocytic leukemia. AB - Elevated levels of circulating angiogenic cytokines and increased expression of genes encoding angiogenic factors have been reported in recent years in patients with chronic lymphocytic leukemia (CLL) but data regarding prognostic and predictive significance are still limited. Therefore, in the present study based upon our prior pilot results, we measured mRNA expressions of angiopoietin-2 (Ang 2), fibroblast growth factor-2 (FGF-2) and endoglin (CD105) by reverse transcription quantitative PCR in purified CD19+ cells from 70 untreated CLL patients (median age, 63 years; males, 64%; Rai III/IV stages, 29 %; unmutated IgVH genes, 60 %) and evaluated their possible association with established prognostic factors and clinical course of the disease. Higher expression of Ang-2 was significantly associated with unmutated IgVH genes (n = 55, p = 0.003). Higher CD105 expression was significantly associated with unmutated IgVH genes (n = 55, p < 0.001), high CD38 expression (n = 66, p = 0.022), high ZAP-70 expression (n = 66, p = 0.010), Rai stage I-IV (n = 70, p < 0.001), progressive clinical course of CLL (n = 70, p = 0.001) and shorter time to treatment (n = 70; p < 0.001). Expression of FGF-2 was not significantly associated with any of the prognostic markers. These results indicate that elevated expression of Ang-2 and in particular CD105 by CLL cells is associated with unfavorable prognostic features and clinical outcome; thus, both cytokines appear to play an important role in biology and progression of CLL and warrant further investigation. PMID- 25030444 TI - Surgical management of breast cancer liver metastases. AB - We analyzed the treatment results in patients who underwent hepatic resection for breast cancer liver metastases(BCLM).Between 1/2003 and 12/2012, 15 patients underwent hepatic resection for BCLM. All primary breast tumors were diagnosed as invasive breast cancer. Synchronous BCLM ocurred in 2 patients and 13 patients presented with metachronous BCLM. Median age of patients at the time of BCLM diagnosis was 51 years(range from 31 to 73 years). All resections were considered as R0. From among 15 resections we performed 10 major hepatic resections according to Couinaud classification(>=3 segments) and the rest were minor ones. There was no postoperative mortality within 60 days . All postoperative complications were managed conservatively. Median hospital stay was 10,5 days, ranging from 7-14 days.Standard therapy for patients with BCLM remains systemic chemo- and hormonal therapy. Hepatic resection as a part of multimodal treatment in tertiary HPB centers can offer in a selected group of patients a safe option for improved survival. Keywords: breast cancer, liver metastases, hepatic resection. PMID- 25030446 TI - Predictive energy landscapes for folding alpha-helical transmembrane proteins. AB - We explore the hypothesis that the folding landscapes of membrane proteins are funneled once the proteins' topology within the membrane is established. We extend a protein folding model, the associative memory, water-mediated, structure, and energy model (AWSEM) by adding an implicit membrane potential and reoptimizing the force field to account for the differing nature of the interactions that stabilize proteins within lipid membranes, yielding a model that we call AWSEM-membrane. Once the protein topology is set in the membrane, hydrophobic attractions play a lesser role in finding the native structure, whereas polar-polar attractions are more important than for globular proteins. We examine both the quality of predictions made with AWSEM-membrane when accurate knowledge of the topology and secondary structure is available and the quality of predictions made without such knowledge, instead using bioinformatically inferred topology and secondary structure based on sequence alone. When no major errors are made by the bioinformatic methods used to assign the topology of the transmembrane helices, these two types of structure predictions yield roughly equivalent quality structures. Although the predictive energy landscape is transferable and not structure based, within the correct topological sector we find the landscape is indeed very funneled: Thermodynamic landscape analysis indicates that both the total potential energy and the contact energy decrease as native contacts are formed. Nevertheless the near symmetry of different helical packings with respect to native contact formation can result in multiple packings with nearly equal thermodynamic occupancy, especially at temperatures just below collapse. PMID- 25030447 TI - Molecular extraction in single live cells by sneaking in and out magnetic nanomaterials. AB - Extraction of intracellular molecules is crucial to the study of cellular signal pathways. Disruption of the cellular membrane remains the established method to release intracellular contents, which inevitably terminates the time course of biological processes. Also, conventional laboratory extractions mostly use bulky materials that ignore the heterogeneity of each cell. In this work, we developed magnetized carbon nanotubes that can be sneaked into and out of cell bodies under a magnetic force. Using a testing model with overexpression of GFP, the nanotubes successfully transported the intracellular GFP out at the single-cell level. The confined nanoscale invasiveness did not change cell viability or proliferation. This study presents the proof of concept of a previously unidentified real-time and single-cell approach to investigate cellular biology, signal messengers, and therapeutic effects with nanomaterials. PMID- 25030449 TI - Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter. AB - ATP binding cassette (ABC) transporters mediate vital transport processes in every living cell. ATP hydrolysis, which fuels transport, displays positive cooperativity in numerous ABC transporters. In particular, heterodimeric ABC exporters exhibit pronounced allosteric coupling between a catalytically impaired degenerate site, where nucleotides bind tightly, and a consensus site, at which ATP is hydrolyzed in every transport cycle. Whereas the functional phenomenon of cooperativity is well described, its structural basis remains poorly understood. Here, we present the apo structure of the heterodimeric ABC exporter TM287/288 and compare it to the previously solved structure with adenosine 5'-(beta,gamma imido)triphosphate (AMP-PNP) bound at the degenerate site. In contrast to other ABC exporter structures, the nucleotide binding domains (NBDs) of TM287/288 remain in molecular contact even in the absence of nucleotides, and the arrangement of the transmembrane domains (TMDs) is not influenced by AMP-PNP binding, a notion confirmed by double electron-electron resonance (DEER) measurements. Nucleotide binding at the degenerate site results in structural rearrangements, which are transmitted to the consensus site via two D-loops located at the NBD interface. These loops owe their name from a highly conserved aspartate and are directly connected to the catalytically important Walker B motif. The D-loop at the degenerate site ties the NBDs together even in the absence of nucleotides and substitution of its aspartate by alanine is well tolerated. By contrast, the D-loop of the consensus site is flexible and the aspartate to alanine mutation and conformational restriction by cross-linking strongly reduces ATP hydrolysis and substrate transport. PMID- 25030448 TI - TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I. AB - The US11 gene product of human cytomegalovirus promotes viral immune evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US11 initiates dislocation of newly translocated MHC I from the ER to the cytosol for proteasome-mediated degradation. Despite the critical role for ubiquitin in this degradation pathway, the responsible E3 ligase is unknown. In a forward genetic screen for host ERAD components hijacked by US11 in near-haploid KBM7 cells, we identified TMEM129, an uncharacterized polytopic membrane protein. TMEM129 is essential and rate-limiting for US11-mediated MHC-I degradation and acts as a novel ER resident E3 ubiquitin ligase. TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. Together with its E2 conjugase Ube2J2, TMEM129 is responsible for the ubiquitination, dislocation, and subsequent degradation of US11-associated MHC-I. US11 engages two degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for "free" US11 degradation. Our data show that TMEM129 is a novel ERAD E3 ligase and the central component of a novel mammalian ERAD complex. PMID- 25030450 TI - Enhanced receptor-clathrin interactions induced by N-glycan-mediated membrane micropatterning. AB - Glycan-protein interactions are emerging as important modulators of membrane protein organization and dynamics, regulating multiple cellular functions. In particular, it has been postulated that glycan-mediated interactions regulate surface residence time of glycoproteins and endocytosis. How this precisely occurs is poorly understood. Here we applied single-molecule-based approaches to directly visualize the impact of glycan-based interactions on the spatiotemporal organization and interaction with clathrin of the glycosylated pathogen recognition receptor dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). We find that cell surface glycan-mediated interactions do not influence the nanoscale lateral organization of DC-SIGN but restrict the mobility of the receptor to distinct micrometer-size membrane regions. Remarkably, these regions are enriched in clathrin, thereby increasing the probability of DC-SIGN-clathrin interactions beyond random encountering. N glycan removal or neutralization leads to larger membrane exploration and reduced interaction with clathrin, compromising clathrin-dependent internalization of virus-like particles by DC-SIGN. Therefore, our data reveal that cell surface glycan-mediated interactions add another organization layer to the cell membrane at the microscale and establish a novel mechanism of extracellular membrane organization based on the compartments of the membrane that a receptor is able to explore. Our work underscores the important and complex role of surface glycans regulating cell membrane organization and interaction with downstream partners. PMID- 25030451 TI - Convenient access to readily soluble symmetrical dialkyl-substituted alpha oligofurans. AB - An expedient approach to the synthesis of well soluble symmetrical dialkyl substituted alpha-oligofurans containing up to 8 pi-conjugated furan heterocycles is reported. An ultimate symmetry and high solubility of these alpha-oligofurans were guaranteed using the 3,3'-diheptyl-2,2'-bifuran core and its symmetrical elongation through Suzuki-Miyaura or Stille cross-couplings. 3,3'-Diheptyl-2,2' bifuran was prepared from 2,2'-bifuran-3,3'-dicarbaldehyde by the Wittig olefination and subsequent Pd/C-catalyzed transfer hydrogenation. The most appropriate access to 2,2'-bifuran-3,3'-dicarbaldehyde was achieved through a regioselective lithiation of 3-furanaldehyde acetal followed by CuCl2-induced homocoupling and deprotection. Single crystal X-ray analysis of 2,2'-bifuran-3,3' dicarbaldehyde revealed anti-arrangement of the furan rings in planar molecules and an unexpected tight herringbone-type packing in crystals. PMID- 25030452 TI - Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices. AB - Haemorrhagic episodes in patients carrying circulatory assist devices represent a severe life-threatening clinical complication. These bleeding episodes may originate from a reduced functionality of von Willebrand factor (VWF), a multimeric protein pertinent to the formation of a haemostatic plug. It has been reported that the reduced functionality is due to increased proteolytic degradation by the enzyme ADAMTS13, a phenomenon that is facilitated by device induced increases in shear stress to which VWF is exposed. Here, we have tested a series of VWF-derived protein fragments and monoclonal murine anti-VWF antibodies for their capacity to reduce shear stress-dependent degradation of VWF. Via direct binding experiments, we identified an anti-VWF antibody that partially blocked VWF-ADAMTS13 interactions (46 +/- 14%). Epitope mapping experiments revealed that the antibody, designated mAb508, is directed against the distal portion of the VWF D4-domain (residues 2134-2301) and recognises a synthetic peptide encompassing residues 2158-2169. Consistent with its partial inhibition of VWF-ADAMTS13 interactions in binding assays, mAb508 reduced ADAMTS13-mediated VWF degradation in a vortex-based degradation assay by 48 +/- 10%. In a HeartMateII-based whole blood-perfusion system, mAb508 was able to reduce degradation of high-molecular-weight (HMW)-VWF-multimers dose-dependently, with a maximal inhibition (83 +/- 8%) being reached at concentrations of 10 MUg/ml or higher. In conclusion, we report that partial inhibition of VWF-ADAMTS13 interactions using an anti-VWF antibody can prevent excessive degradation of HMW VWF multimers. This strategy may be used for the development of therapeutic options to treat bleeding episodes due to shear stress-dependent VWF degradation, for instance in patients carrying circulatory assist devices. PMID- 25030453 TI - Sulfonic acid-functionalized silica-coated magnetic nanoparticles as an efficient reusable catalyst for the synthesis of 1-substituted 1H-tetrazoles under solvent free conditions. AB - Regarding green chemistry goals, silica-coated magnetite nanoparticles open up a new avenue to introduce a very useful and efficient system for facilitating catalyst recovery in different organic reactions. Therefore, in this paper the preparation of sulfonic acid-functionalized silica-coated magnetic nanoparticles with core-shell structure (Fe3O4@silica sulfonic acid) is presented by using Fe3O4 spheres as the core and silica sulfonic acid nanoparticles as the shell. The catalyst was characterized by infrared spectroscopy, scanning electron microscopy, X-ray diffraction analysis, dynamic light scattering, thermogravimetric analysis and vibrating sample magnetometry. Nanocatalyst can be recovered using an external magnet and reused for subsequent reactions 6 times without noticeable deterioration in catalytic activity. PMID- 25030454 TI - Engineering Escherichia coli for odd straight medium chain free fatty acid production. AB - Microbial biosynthesis of free fatty acids (FFAs) can be achieved by introducing an acyl-acyl carrier protein thioesterase gene into Escherichia coli. The engineered E. coli usually produced even chain FFAs. In this study, propionyl-CoA synthetase (prpE) from Salmonella enterica was overexpressed in two efficient even chain FFAs producers, ML103 (pXZM12) carrying the acyl-ACP thioesterase gene from Umbellularia californica and ML103 (pXZ18) carrying the acyl-ACP thioesterase gene from Ricinus communis combined with supplement of extracellular propionate. With these metabolically engineered E. coli, the odd straight chain FFAs, undecanoic acid (C11:0), tridecanoic acid (C13:0), and pentadecanoic acid (C15:0) were produced from glucose and propionate. The highest total odd straight chain FFAs produced by ML103 (pXZM12, pBAD-prpE) reached 276 mg/l with a ratio of 23.43 % of the total FFAs. In ML103 (pXZ18, pBAD-prpE), the highest total odd straight chain FFAs accumulated to 297 mg/l, and the ratio reached 17.68 % of the total FFAs. Due to the different substrate specificity of the acyl-ACP thioesterases, the major odd straight chain FFA components of ML103 (pXZM12, pBAD prpE) were undecanoic acid and tridecanoic acid, while the ML103 (pXZ18, pBAD prpE) preferred pentadecanoic acid. PMID- 25030455 TI - Biogenic magnetic nanoparticles from Burkholderia sp. YN01 exhibiting intrinsic peroxidase-like activity and their applications. AB - A novel bacterial strain containing biogenic magnetic nanoparticles (BMNPs) was isolated from the sediments of Songhua River in Harbin, China, and was identified as Burkholderia sp. YN01. Extracted BMNPs from YN01 were characterized as pure face-centered cubic Fe3O4 with an average size of 80 nm through transmission electron microscope (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The hysteresis parameters of the BMNP samples such as Bc and Bcr and ratios Mrs/Ms were deduced as 35.6 mT, 43.2 mT, and 0.47, respectively, indicating that the BMNPs exhibit a ferromagnetic behavior. This is the first report concerning on biogenic Fe3O4 NPs produced in Burkholderia genus. Significantly, the BMNPs were proved to possess intrinsic peroxidase-like activity that could catalyze the oxidation of peroxidase substrate 3,3',5,5' tetramethylbenzidine (TMB) in the presence of H2O2. Kinetic analysis indicates that the catalytic behavior is in accord with typical Michaelis-Menten kinetics and follows ping-pong mechanism. The catalytic constants (K cat) were 6.5 * 10(4) s(-1) and 0.78 * 10(4) s(-1) with H2O2 and TMB as substrate, respectively, which was higher than that of horseradish peroxidase (HRP). Electron spin resonance (ESR) spectroscopy experiments showed that the BMNPs could catalyze H2O2 to produce hydroxyl radicals. The origin of peroxidase-like activity is also associated with their ability to transfer electron between electrode and H2O2 according to an electrochemical study. As a novel peroxidase mimetic, the BMNPs were employed to offer a simple, sensitive, and selective colorimetric method for H2O2 and glucose determination, and the BMNPs could efficiently catalyze the degradation of phenol and Congo red dye. PMID- 25030456 TI - Ammonia- and methane-oxidizing microorganisms in high-altitude wetland sediments and adjacent agricultural soils. AB - Ammonia oxidation is known to be carried out by ammonia-oxidizing bacteria (AOB) and archaea (AOA), while methanotrophs (methane-oxidizing bacteria (MOB)) play an important role in mitigating methane emissions from the environment. However, the difference of AOA, AOB, and MOB distribution in wetland sediment and adjacent upland soil remains unclear. The present study investigated the abundances and community structures of AOA, AOB, and MOB in sediments of a high-altitude freshwater wetland in Yunnan Province (China) and adjacent agricultural soils. Variations of AOA, AOB, and MOB community sizes and structures were found in water lily-vegetated and Acorus calamus-vegetated sediments and agricultural soils (unflooded rice soil, cabbage soil, and garlic soil and flooded rice soil). AOB community size was higher than AOA in agricultural soils and lily-vegetated sediment, but lower in A. calamus-vegetated sediment. MOB showed a much higher abundance than AOA and AOB. Flooded rice soil had the largest AOA, AOB, and MOB community sizes. Principal coordinate analyses and Jackknife Environment Clusters analyses suggested that unflooded and flooded rice soils had relatively similar AOA, AOB, and MOB structures. Cabbage soil and A. calamus-vegetated sediment had relatively similar AOA and AOB structures, but their MOB structures showed a large difference. Nitrososphaera-like microorganisms were the predominant AOA species in garlic soil but were present with a low abundance in unflooded rice soil and cabbage soil. Nitrosospira-like AOB were dominant in wetland sediments and agricultural soils. Type I MOB Methylocaldum and type II MOB Methylocystis were dominant in wetland sediments and agricultural soils. Moreover, Pearson's correlation analysis indicated that AOA Shannon diversity was positively correlated with the ratio of organic carbon to nitrogen (p < 0.05). This work could provide some new insights toward ammonia and methane oxidation in soil and wetland sediment ecosystems. PMID- 25030458 TI - Asymmetric criticality of binary ionic solutions containing 1-butyl-3 methylimidazolium tetrafluoroborate and alcohol. AB - The liquid-liquid coexistence curves for binary solutions {1-butyl-3 methylimidazolium tetrafluoroborate ([C4mim][BF4]) + 1-propanol} and {1-butyl-3 methylimidazolium tetrafluoroborate ([C4mim][BF4]) + 2-propanol} have been precisely measured. The values of the critical exponents beta obtained from the liquid-liquid equilibrium data in the critical region confirmed the 3D-Ising universality. The isobaric heat capacities per unit volume were measured for {[C4mim][BF4] + 1-propanol (or 2-propanol, 1,3-propanediol, 1,4-butanediol)} in both critical and non-critical regions. The experimental results indicate a major solvophobic contribution to the criticality for the studied ionic solutions. The complete scaling theory was applied to well represent the asymmetric behavior of the diameter of the coexistence curves with the consideration of the heat capacity contribution. It was found that the contribution of the heat capacity related term in the ionic solution decreased with the increase of the permittivity of alcohol and was more important in the description of the asymmetry of the coexistence curve of the ionic solutions than that of the molecular solutions. PMID- 25030457 TI - Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? AB - Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of 'cholinergic tone'. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations. PMID- 25030459 TI - Hepatobiliary magnetic resonance imaging in patients with liver disease: correlation of liver enhancement with biochemical liver function tests. AB - OBJECTIVES: To evaluate hepatobiliary magnetic resonance imaging (MRI) using Gd EOB-DTPA in relation to various liver function tests in patients with liver disorders. METHODS: Fifty-one patients with liver disease underwent Gd-EOB-DTPA enhanced liver MRI. Based on region-of-interest (ROI) analysis, liver signal intensity was calculated using the spleen as reference tissue. Liver-spleen contrast ratio (LSCR) and relative liver enhancement (RLE) were calculated. Serum levels of total bilirubin, gamma glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), serum albumin level (AL), prothrombin time (PT), creatinine (CR) as well as international normalised ratio (INR) and model for end-stage liver disease (MELD) score were tested for correlation with LSCR and RLE. RESULTS: Pre-contrast LSCR values correlated with total bilirubin (r = 0.39; p = 0.005), GGT (r = -0.37; p = 0.009), AST (r = -0.38; p = 0.013), ALT (r = -0.29; p = 0.046), PT (r = 0.52; p < 0.001), GLDH (r = -0.55; p = 0.044), INR (r = -0.42; p = 0.003), and MELD Score (r = -0.53; p < 0.001). After administration of Gd-EOB-DTPA bilirubin (r = -0.45; p = 0.001), GGT (r = -0.40; p = 0.004), PT (r = 0.54; p < 0.001), AST (r = -0.46; p = 0.002), ALT (r = -0.31; p = 0.030), INR (r = -0.45; p = 0.001) and MELD Score (r = -0.56; p < 0.001) significantly correlated with LSCR. RLE correlated with bilirubin (r = -0.40; p = 0.004), AST (r = -0.38; p = 0.013), PT (r = 0.42; p = 0.003), GGT (r = -0.33; p = 0.020), INR (r = -0.36; p = 0.011) and MELD Score (r = -0.43; p = 0.003). CONCLUSIONS: Liver-spleen contrast ratio and relative liver enhancement using Gd EOB-DTPA correlate with a number of routinely used biochemical liver function tests, suggesting that hepatobiliary MRI may serve as a valuable biomarker for liver function. The strongest correlation with liver enhancement was found for the MELD Score. KEY POINTS: * Relative enhancement (RLE) of Gd-EOB-DTPA is related to biochemical liver function tests. * Correlation of RLE with bilirubin, ALT, AST, GGT, INR and MELD Score is reverse. * The correlation of relative liver enhancement with prothrombin time is positive. * AST, ALT, GLDH, prothrombin time, INR and MELD Score correlate with pre-contrast liver-spleen contrast ratio. * Such biomarkers may help to evaluate liver function. PMID- 25030460 TI - Prognosis of small hepatocellular nodules detected only at the hepatobiliary phase of Gd-EOB-DTPA-enhanced MR imaging as hypointensity in cirrhosis or chronic hepatitis. AB - PURPOSE: To evaluate the prognosis of "strict" high-risk nodules (small hepatocellular nodules detected only in the hepatobiliary phase of initial Gd-EOB DTPA-enhanced MR examination) in patients with cirrhosis or chronic hepatitis. METHODS AND MATERIALS: The study included thirty-three patients with 60 "strict" high-risk nodules showing hypointensity at the hepatobiliary phase that was undetectable at the vascular phase and other conventional sequences of initial Gd EOB-DTPA-enhanced MR imaging. These nodules were observed on follow-up MR examinations until hypervascularity was detected. The potential predictive factors for hypervascular transformation were compared between two groups (group A showing hypervascular transformation, group B not showing hypervascularization). RESULTS: Ten (16.7 %) of 60 "strict" high-risk nodules showed hypervascular transformation during follow-up periods (group A). The growth rates of the nodules in group A (6.3 +/- 4.5 mm/year) were significantly higher than those in group B (3.4 +/- 7.2 mm/year) (p = 0.003). Additionally, the median observation period in group A (177.5 +/- 189.5 day) was significantly shorter than in group B (419 +/- 372.2 day) (p = 0.045). The other predictive factors were not significantly correlated with hypervascularization. CONCLUSIONS: Subsets of "strict" high-risk nodules showed hypervascular transformation during follow-up periods in association with increased growth rates, indicating that nodule growth rate is an important predictive factor for hypervascularization. KEY POINTS: * "Strict" high-risk nodules are defined as hepatocellular nodules detected only in the hepatobiliary-phase. * Subsets of "strict" high-risk nodules showed hypervascular transformation during follow-up periods. * Increased growth rate is an important predictive factor for hypervascular transformation. * Management of patients with "strict" high-risk nodules becomes more appropriate. PMID- 25030461 TI - CT-based abdominal aortic calcification score as a surrogate marker for predicting the presence of asymptomatic coronary artery disease. AB - OBJECTIVES: To assess the value of a CT-based abdominal aortic calcification (AAC) score as a surrogate marker for the presence of asymptomatic coronary artery disease (CAD). METHODS: The AAC scores of 373 patients without cardiac symptoms who underwent both screening coronary CT angiography and abdominal CT within one year were calculated according to the Agatston method. Logistic regression was used to derive two multivariate models from traditional cardiovascular risk factors, with and without AAC scores, to predict the presence of CAD. The AAC score and the two multivariate models were compared by calculating the area under the receiver operating characteristic curve (AUC) and the net reclassification improvement (NRI). RESULTS: The AAC score alone showed a marginally higher AUC (0.823 vs. 0.767, P = 0.061) and significantly better risk classification (NRI = 0.158, P = 0.048) than the multivariate model without AAC. The multivariate model using traditional factors and AAC did not show a significantly higher AUC (0.832 vs. 0.823, P = 0.616) or NRI (0.073, P = 0.13) than the AAC score alone. The optimal cutoff value of the AAC score for predicting CAD was 1025.8 (sensitivity, 79.5 %; specificity, 75.9 %). CONCLUSIONS: AAC scores may serve as a surrogate marker for the presence or absence of asymptomatic CAD. KEY POINTS: * Severe vascular calcification indicates a high probability of coronary artery disease. * Vascular calcification in the abdominal aorta can be quantified by computed tomography. * Abdominal CT could lead to early detection of asymptomatic coronary artery disease. PMID- 25030462 TI - Single-portal-phase low-tube-voltage dual-energy CT for short-term follow-up of acute pancreatitis: evaluation of CT severity index, interobserver agreement and radiation dose. AB - OBJECTIVES: To intra-individually compare single-portal-phase low-tube-voltage (100-kVp) computed tomography (CT) with 120-kVp images for short-term follow-up assessment of CT severity index (CTSI) of acute pancreatitis, interobserver agreement and radiation dose. METHODS: We retrospectively analysed 66 patients with acute pancreatitis who underwent initial dual-contrast-phase CT (unenhanced, arterial, portal phase) at admission and short-term (mean interval 11.4 days) follow-up dual-contrast-phase dual-energy CT. The 100-kVp and linearly blended images representing 120-kVp acquisition follow-up CT images were independently evaluated by three radiologists using a modified CTSI assessing pancreatic inflammation, necrosis and extrapancreatic complications. Scores were compared with paired t test and interobserver agreement was evaluated using intraclass correlation coefficients (ICC). RESULTS: Mean CTSI scores on unenhanced, portal- and dual-contrast-phase images were 4.9, 6.1 and 6.2 (120 kVp) and 5.0, 6.0 and 6.1 (100 kVp), respectively. Contrast-enhanced series showed a higher CTSI compared to unenhanced images (P < 0.05) but no significant differences between single- and dual-contrast-phase series (P > 0.7). CTSI scores were comparable for 100-kVp and 120-kVp images (P > 0.05). Interobserver agreement was substantial for all evaluated series and subcategories (ICC 0.67-0.93). DLP of single-portal phase 100-kVp images was reduced by 41 % compared to 120-kVp images (363.8 versus 615.9 mGy cm). CONCLUSIONS: Low-tube-voltage single-phase 100-kVp CT provides sufficient information for follow-up evaluation of acute pancreatitis and significantly reduces radiation exposure. KEY POINTS: * Single-portal-phase CT provides sufficient evaluation for follow-up of acute pancreatitis. * Follow-up CT does not benefit from unenhanced or arterial-phase acquisition. * CT severity index scores are equal for dual-contrast-phase 100-/120-kVp acquisition (P > 0.05). * 100-kVp single-portal-phase follow-up CT of acute pancreatitis significantly reduces radiation exposure. PMID- 25030463 TI - Associative transcriptomics study dissects the genetic architecture of seed glucosinolate content in Brassica napus. AB - Breeding new varieties with low seed glucosinolate (GS) concentrations has long been a prime target in Brassica napus. In this study, a novel association mapping methodology termed 'associative transcriptomics' (AT) was applied to a panel of 101 B. napus lines to define genetic regions and also candidate genes controlling total seed GS contents. Over 100,000 informative single-nucleotide polymorphisms (SNPs) and gene expression markers (GEMs) were developed for AT analysis, which led to the identification of 10 SNP and 7 GEM association peaks. Within these peaks, 26 genes were inferred to be involved in GS biosynthesis. A weighted gene co-expression network analysis provided additional 40 candidate genes. The transcript abundance in leaves of two candidate genes, BnaA.GTR2a located on chromosome A2 and BnaC.HAG3b on C9, was correlated with seed GS content, explaining 18.8 and 16.8% of phenotypic variation, respectively. Resequencing of genomic regions revealed six new SNPs in BnaA.GTR2a and four insertions or deletions in BnaC.HAG3b. These deletion polymorphisms were then successfully converted into polymerase chain reaction-based diagnostic markers that can, due to high linkage disequilibrium observed in these regions of the genome, be used for marker-assisted breeding for low seed GS lines. PMID- 25030464 TI - Performance of the Santa Ines breed raised on pasture in semiarid tropical regions and factors that explain trait variation. AB - This study aimed to evaluate sex, the number of lambs per birth, and the family effects on production traits in the Santa Ines breed of sheep by estimating the least square means and coefficient of variance for those traits. A total of 484 lambs were evaluated for the following traits: weight at birth, at weaning, and at 240 days of age; weight gain during the pre-weaning and post-weaning periods; height, width, and length of different body regions; and rib eye area and fat thickness between the 12th and 13th ribs. We observed coefficients of variation higher than 10 % for several traits. Generally, males were larger than females (P < 0.05), while lambs from single and double births were larger than lambs from triple births (P < 0.05). Family effect was significant (P < 0.05) for most traits and explained the highest percentage of residual variance. The results showed good development of Santa Ines sheep, especially during the pre-weaning period but no in post-weaning. Our study also showed that there is an effect of sex, birth type, and family, which must be included in any statistical model for the estimation of least square means and residual variance in ANOVA. PMID- 25030465 TI - Association between cattle herd Mycobacterium avium subsp. paratuberculosis (MAP) infection and infection of a hare population. AB - Paratuberculosis has long been considered a disease of domestic and wild ruminants only. The known host range of Mycobacterium avium subsp. paratuberculosis (MAP) was recently extended to include non-ruminant wildlife species believed to be exposed to spillover of MAP from infected domestic cattle herds. The aim of the present study was to assess the association between cattle herd MAP infection pressure level and the infection level of a hare population in two dairy farms of southern Chile. Fifty hares from a herd A and 42 hares from herd B were captured and sampled for MAP culture. The results showed a statistically significant association between the cattle herds' infection prevalence and the hare infection prevalence. PMID- 25030466 TI - Leukaemia and lymphoma: why has survival improved? PMID- 25030468 TI - Patterns of antecedents of catastrophic reactions in nursing home residents with dementia in the United States. AB - PURPOSE: The purpose of this study was to describe the patterns of antecedents of catastrophic reactions (CRs) in nursing home residents with dementia in the United States. METHODS: A total of 229 catastrophic reaction events were the sample for this study. Ten antecedent variables were selected and analyzed using cluster analysis to address the patterns of antecedents of CRs in dementia. Data were obtained from field observation and a structured recording form over a 6 week period covering all 7 days of the week and all three shifts (i.e., 21 shifts in total) in two nursing homes in the United States. RESULTS: This study showed that there were two distinct patterns of antecedent conditions at the time of, or immediately prior to, CRs in dementia: (a) a cluster of antecedents that consists of components of the physical environment including public location, olfactory stimulation, use of media, sundowning hours, and being in a dementia unit ("Stimulation in Early Evening"); and (b) a cluster of antecedents that is composed of mixed components of the physical and social environment including olfactory stimulation, activities of daily living (ADL)-related care activities, demands of tasks, and being in a dementia unit ("Stress due to Care, Tasks, and Odors"). CONCLUSION: The findings suggest that elders who are exposed to overstimulation in sundowning hours or experience stress from care activities and task performance beyond their baseline competency are likely to be at risk of presenting with CRs. Health care providers need to be aware that a CR is a multi factorial phenomenon in which multiple contextual antecedents are involved and that creation of a therapeutic physical and social milieu is an important nursing goal in preventing the occurrence of CRs in nursing home residents with dementia. [Asian Nursing Research 2009;3(3):99-110]. PMID- 25030469 TI - Is reflective practice a useful task for student nurses? AB - BACKGROUND: Reflective practices have been advocated as a method to bridge the gap between nursing theory and practice, and as a tool to develop knowledge embedded in practice. AIM: The aim of this study was to examine the perceptions of student nurses towards reflective practice in their clinical practice. METHODS: A cross sectional descriptive survey was carried out to examine the perception of a cohort of 108 final year, pre-registration Diploma of Nursing students towards reflective practice. A structured questionnaire was used to collect the quantitative data. The questionnaire consisted of two parts; part A: perception of students towards reflective practice; and part B: issues reflected by students. Data collected were analyzed using descriptive statistics. All (n = 98) students completed the questionnaire. RESULTS: The mean score of perception to reflective practice was 4.07. Students found reflective practice useful to them with a mean score of 3.82, despite the perceived barrier to good reflective practice with a mean of 3.60. The perception on the appropriateness of reflective practice as a tool to assess was 3.47. The validity of reflective practice as an assessment tool for practical examinations was not conclusive, as the mean score was only 3.47. CONCLUSION: The results indicated that even though some students were skeptical with reflective practice, they found it useful. The College of Nursing should review the content of reflective practice and prepare nurse educators for their role in teaching this subject more effectively. [Asian Nursing Research 2009; 3(3):111-120]. PMID- 25030467 TI - Survival for haematological malignancies in Europe between 1997 and 2008 by region and age: results of EUROCARE-5, a population-based study. AB - BACKGROUND: More effective treatments have become available for haematological malignancies from the early 2000s, but few large-scale population-based studies have investigated their effect on survival. Using EUROCARE data, and HAEMACARE morphological groupings, we aimed to estimate time trends in population-based survival for 11 lymphoid and myeloid malignancies in 20 European countries, by region and age. METHODS: In this retrospective observational study, we included patients (aged 15 years and older) diagnosed with haematological malignancies, diagnosed up to Dec 31, 2007, and followed up to Dec 31, 2008. We used data from the 30 cancer registries (across 20 countries) that provided continuous incidence and good quality data from 1992 to 2007. We used a hybrid approach to estimate age-standardised and age-specific 5-year relative survival, for each malignancy, overall and for five regions (UK, and northern, central, southern, and eastern Europe), and four 3-year periods (1997-99, 2000-02, 2003-05, 2006-08). For each malignancy, we also estimated the relative excess risk of death during the 5 years after diagnosis, by period, age, and region. FINDINGS: We analysed 560 444 cases. From 1997-99 to 2006-08 survival increased for most malignancies: the largest increases were for diffuse large B-cell lymphoma (42.0% [95% CI 40.7 43.4] to 55.4% [54.6-56.2], p<0.0001), follicular lymphoma (58.9% [57.3-60.6] to 74.3% [72.9-75.5], p<0.0001), chronic myeloid leukaemia (32.3% [30.6-33.9] to 54.4% [52.5-56.2], p<0.0001), and acute promyelocytic leukaemia (50.1% [43.7 56.2] to 61.9% [57.0-66.4], p=0.0038, estimate not age-standardised). Other survival increases were seen for Hodgkin's lymphoma (75.1% [74.1-76.0] to 79.3% [78.4-80.1], p<0.0001), chronic lymphocytic leukaemia/small lymphocytic lymphoma (66.1% [65.1-67.1] to 69.0% [68.1-69.8], p<0.0001), multiple myeloma/plasmacytoma (29.8% [29.0-30.6] to 39.6% [38.8-40.3], p<0.0001), precursor lymphoblastic leukaemia/lymphoma (29.8% [27.7-32.0] to 41.1% [39.0-43.1], p<0.0001), acute myeloid leukaemia (excluding acute promyelocytic leukaemia, 12.6% [11.9-13.3] to 14.8% [14.2-15.4], p<0.0001), and other myeloproliferative neoplasms (excluding chronic myeloid leukaemia, 70.3% [68.7-71.8] to 74.9% [73.8-75.9], p<0.0001). Survival increased slightly in southern Europe, more in the UK, and conspicuously in northern, central, and eastern Europe. However, eastern European survival was lower than that for other regions. Survival decreased with advancing age, and increased with time only slightly in patients aged 75 years or older, although a 10% increase in survival occurred in elderly patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic myeloid leukaemia. INTERPRETATION: These trends are encouraging. Widespread use of new and more effective treatment probably explains much of the increased survival. However, the persistent differences in survival across Europe suggest variations in the quality of care and availability of the new treatments. High-resolution studies that collect data about stage at diagnosis and treatments for representative samples of cases could provide further evidence of treatment effectiveness and explain geographic variations in survival. FUNDING: Compagnia di San Paolo, Fondazione Cariplo, European Commission, and Italian Ministry of Health. PMID- 25030470 TI - Prevalence and predictors of geriatric depression in community-dwelling elderly. AB - PURPOSE: This study aimed to examine the relationship between depressive mood and physical and socio-environmental variables of community-dwelling elderly. METHODS: This study was designed as a cross-sectional descriptive survey. The setting was two elderly welfare centers and two public health centers in Korea. The subjects were recruited by public announcement and participated after giving their written informed consent. A total of 295 participants were included in the final analysis. The Korean version of the short form of Geriatric Depression Scale (SGDS-K), Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) of activities of daily living (ADL) and a socio-demographic questionnaire were administered to participants. Hand-grip strength was measured with a hand dynamometer. RESULTS: The prevalence of depression among the subjects was 63%. Of the elderly, 21% had severe depressive symptoms. The mean depression score was 6.21 (SD = 3.83) and it was higher in women than in men. In the regression analysis, perceived health status alone had an accountability of 17.3% to depression. When TMIG-IC was added, this increased to 22.6%. Additionally, when hand-grip strength and social activities were input, it increased to 25.2%. Therefore, perceived health status was a significant and powerful factor explaining depression among the Korean elderly. CONCLUSION: In this research, perceived health status was the most powerful predictor of elderly depression. TMIG-IC, hand-grip strength and social activities also predicted Korean elderly depression. These factors should be considered when the program is developed for elderly people with depression. [Asian Nursing Research 2009;3(3):121-129]. PMID- 25030471 TI - Using ACHIS to Analyze Nursing Health Promotion Interventions for Vulnerable Populations in a Community Nursing Center: A Pilot Study. AB - OBJECTIVES: The purpose of the study was to describe the health promotion interventions of nurses serving a low-income urban population in an academic community nursing center (CNC) in Wisconsin. METHODS: The Omaha System (OS) was used to code client problems and nursing interventions for 9,839 visits at the CNC. A dataset created by the Automated Community Health Information System (ACHIS), a computerized clinical information system, was used. A pilot testing was performed with the ACHIS data repository. Each intervention was linked to a nursing diagnosis coded with modifiers as either actual or potential problems or health promotion issues. The Lundeen's Comprehensive Community-based Primary Health Care Model (CCPHCM) which emphasizes primary prevention and health promotion activities served as the conceptual framework for this study. RESULTS: A total of 58,747 modifiers were documented for 58,747 nursing diagnoses where a total of 9,836 nursing interventions were provided to 9,839 community center visits at the CNC. Although a majority of the nursing diagnoses (61.8%) were coded as actual problems as might be expected for this vulnerable population, 38% of the client problems were documented as potential problems (20.6%) and health promotion issues (17.7%.) Health Teaching, Guidance and Counseling (38.9%) and Case Management (25.8%) were the most frequently coded interventions. CONCLUSION: This research adds to the understanding of the importance of nurses' interventions toward health promotion with the vulnerable population. This preliminary analysis suggests that the ACHIS provide a clinical information system for collecting, storing, processing, retrieving, and managing clinical data in a data repository. [Asian Nursing Research 2009;3(3):130-138]. PMID- 25030472 TI - Self-care, Self-efficacy, and Glycemic Control of Koreans With Diabetes Mellitus. AB - PURPOSE: The purpose of this study was to examine the differences in diabetes related characteristics, self-care, self-efficacy, and glycemic control of Koreans with diabetes mellitus according to the types of health care providers in Korea. METHOD: A total of 175 patients with Type II Diabetes were included in the analysis. Using SPSS WIN 10.0 program, chi(2)-test and t-tests were performed to answer the research questions. RESULTS: Forty-five percent of the participants received specialist care by endocrinologists at secondary or tertiary hospitals and 55% had general physician's care at public health centers. Participants who were cared for by specialists had higher educational levels and better annual household incomes than those that were cared by generalists. Participants receiving specialist care were more likely to have insulin therapy, exercised more regularly, and smoked less than those receiving generalist care. Participants within the specialist groups performed self-care better, reported better self-efficacy in diabetic management, and displayed better glycemic control (blood-glucose levels and HbA1c) than those in generalist group. CONCLUSION: The study represents the possibilities in healthcare disparities within Korea. Further study is warranted to explore the specific aspects of service disparities and possible methods of intervention to reduce the variations in health care service. [Asian Nursing Research 2009;3(3):139-146]. PMID- 25030473 TI - Long-term outcomes of radiologic recurrence after paraesophageal hernia repair with mesh. AB - INTRODUCTION: Paraesophageal hernia (PEH) repair has a high radiologic recurrence rate, even with the use of biologic mesh as a prosthetic buttress to reinforce the primary crural repair. This review was done to evaluate outcomes after PEH repair with mesh. METHODS: A retrospective analysis was done of all patients who underwent PEH repair with mesh at our institution between December 2004 and March 2013. Patients were reviewed for evidence of recurrence on upper gastrointestinal studies (UGI). Time-specific, mesh-specific, and size-specific recurrence was analyzed as well as pre- and postoperative symptom scores. RESULTS: A total of 209 patients underwent PEH repair with mesh. Mean follow-up was 25 months (range 0-101). In all cases, an absorbable mesh was used (159 Alloderm, 35 BioA, 15 Strattice). One hundred and fifty-six (75 %) were 5 cm or larger. Of the patients, 166 (79 %) had UGIs available to review for radiologic recurrence. Total recurrence was 21 % (n = 35). No mesh erosions were seen. Recurrence rates increased over time from 16 % (n = 23) at 1 year up to 39 % after 5-year follow up (n = 11). Recurrence rates were higher for large hernias (23 vs. 16 %). The median size of the recurrence was 4 cm (range 2-7 cm). Overall, patients showed significant improvement in their symptom scores. At long-term follow-up, heartburn had 70.6 % reduction (p < 0.05) and regurgitation had 76.5 % reduction (p < 0.05). There was no significant difference in postoperative symptom scores between patients with or without radiologic recurrence. CONCLUSIONS: In this study, PEH repair with mesh was safe and effective at controlling symptoms over the long term. Radiologic recurrence rate increased over time and was highest in patients with hernias >5 cm. Therefore, in our experience, PEH repair with mesh is a safe therapy and though radiologic recurrence does increase with time, symptom resolution is maintained. PMID- 25030474 TI - Simultaneous development of laparoscopy and robotics provides acceptable perioperative outcomes and shows robotics to have a faster learning curve and to be overall faster in rectal cancer surgery: analysis of novice MIS surgeon learning curves. AB - BACKGROUND: Laparoscopy offers some evidence of benefit compared to open rectal surgery. Robotic rectal surgery is evolving into an accepted approach. The objective was to analyze and compare laparoscopic and robotic rectal surgery learning curves with respect to operative times and perioperative outcomes for a novice minimally invasive colorectal surgeon. METHODS: One hundred and six laparoscopic and 92 robotic LAR rectal surgery cases were analyzed. All surgeries were performed by a surgeon who was primarily trained in open rectal surgery. Patient characteristics and perioperative outcomes were analyzed. Operative time and CUSUM plots were used for evaluating the learning curve for laparoscopic versus robotic LAR. RESULTS: Laparoscopic versus robotic LAR outcomes feature initial group operative times of 308 (291-325) min versus 397 (373-420) min and last group times of 220 (212-229) min versus 204 (196-211) min-reversed in favor of robotics; major complications of 4.7 versus 6.5 % (NS), resection margin involvement of 2.8 versus 4.4 % (NS), conversion rate of 3.8 versus 1.1 (NS), lymph node harvest of 16.3 versus 17.2 (NS), and estimated blood loss of 231 versus 201 cc (NS). Due to faster learning curves for extracorporeal phase and total mesorectal excision phase, the robotic surgery was observed to be faster than laparoscopic surgery after the initial 41 cases. CUSUM plots demonstrate acceptable perioperative surgical outcomes from the beginning of the study. CONCLUSIONS: Initial robotic operative times improved with practice rapidly and eventually became faster than those for laparoscopy. Developing both laparoscopic and robotic skills simultaneously can provide acceptable perioperative outcomes in rectal surgery. It might be suggested that in the current milieu of clashing interests between evolving technology and economic constrains, there might be advantages in embracing both approaches. PMID- 25030475 TI - The effect of divided attention on novices and experts in laparoscopic task performance. AB - BACKGROUND: Attention is important for the skilful execution of surgery. The surgeon's attention during surgery is divided between surgery and outside distractions. The effect of this divided attention has not been well studied previously. We aimed to compare the effect of dividing attention of novices and experts on a laparoscopic task performance. METHODS: Following ethical approval, 25 novices and 9 expert surgeons performed a standardised peg transfer task in a laboratory setup under three randomly assigned conditions: silent as control condition and two standardised auditory distracting tasks requiring response (easy and difficult) as study conditions. Human reliability assessment was used for surgical task analysis. Primary outcome measures were correct auditory responses, task time, number of surgical errors and instrument movements. Secondary outcome measures included error rate, error probability and hand specific differences. Non-parametric statistics were used for data analysis. RESULTS: 21109 movements and 9036 total errors were analysed. Novices had increased mean task completion time (seconds) (171 +/- 44SD vs. 149 +/- 34, p < 0.05), number of total movements (227 +/- 27 vs. 213 +/- 26, p < 0.05) and number of errors (127 +/- 51 vs. 96 +/- 28, p < 0.05) during difficult study conditions compared to control. The correct responses to auditory stimuli were less frequent in experts (68 %) compared to novices (80 %). There was a positive correlation between error rate and error probability in novices (r (2) = 0.533, p < 0.05) but not in experts (r (2) = 0.346, p > 0.05). CONCLUSION: Divided attention conditions in theatre environment require careful consideration during surgical training as the junior surgeons are less able to focus their attention during these conditions. PMID- 25030476 TI - Percutaneous endoscopic caecostomy for severe constipation in adults: feasibility, durability, functional and quality of life results at 1 year follow up. AB - BACKGROUND: The percutaneous endoscopic ceacostomy (PEC) for antegrade colonic enemas (ACE) has recently been proposed as a less invasive alternative to the Malone procedure in chronic constipated patients. Although the feasibility and safety of this innovative approach has been demonstrated, its functional results remain unknown. The aim of this study was to evaluate constipation symptoms and quality of life 1 year after the PEC placement. METHOD: From Oct 2007 to Apr 2011, 21 severely constipated patients who required ACE were prospectively included. They underwent endoscopic placement of Chait caecostomy catheter (Cook Medical). Patients completed standardized questionnaires to assess constipation (KESS) and quality of life (GIQLI) scores pre PEC placement and at 1 year. Adverse events and caecostomy use data were also documented. RESULTS: The caecostomy catheter was successfully placed in 19 patients. Complications were all minor, including chronic wound pain (n = 9), serous leakage (n = 7), superficial wound infection (n = 2) and accidental catheter removal (n = 2). Chronic wound pain led to definitive catheter removal in 5 (26 %) patients. One patient died from unrelated cause before the end of the follow-up. At 1 year, 11 (61 %) of the alive patients still performed ACE. During the period of ACE administration, 14 (74 %) patients suspended use of laxatives and retrograde irrigations. Constipation and quality of life scores were available in 15 patients. Median KESS score improved from 25 (12-39) before PEC to 17 (6-34) 1 year after PEC (p < 0.05). Median GIQLI score increased from 69 (25-108) to 95 (48-119) (p < 0.05). CONCLUSION: PEC placement achieves satisfying functional and quality of life results, and allows approximately 3/4 of patients to suspend laxatives and retrograde enemas. Nevertheless, 1/4 of the patients ask for the PEC removal because of chronic wound pain. In order to improve long-term durability of the device, a better prevention of pain is required. PMID- 25030477 TI - The patterns of reflux can affect regression of non-dysplastic and low-grade dysplastic Barrett's esophagus after medical and surgical treatment: a prospective case-control study. AB - BACKGROUND: To date, therapeutic guidelines and pattern of reflux for patients with no-dysplasia (ND) or low-grade dysplasia (LGD) Barrett's esophagus (BE) remain unclear. We aimed to analyze pattern of reflux and regression of ND- or LGD-BE after medical and surgical treatment. METHODS: We studied a cohort of ND- and LGD-BE patients who underwent laparoscopic total fundoplication and a cohort of ND- and LGD-BE patients managed medically. Patients were matched for age, sex, and disease duration. After 1 year of follow-up at least, all patients underwent upper endoscopy with esophageal biopsies to evaluate any histological changes, as well as manometry and impedance-pH-metry to re-assess reflux patterns. RESULTS: Thirty-seven patients (20 LGD, 17 ND) undergoing laparoscopic fundoplication were enrolled and compared with 25 patients (13 LGD, 12 ND) managed with proton pump inhibitors (PPI). Laparoscopic fundoplication resulted in a better control of both acidic and weakly acidic reflux (P < 0.001) and was associated with a higher probability of reversion for LGD (P < 0.01). Esophageal motility did not differ between surgically and medically treated patients. CONCLUSIONS: In patients with ND- or LGD-BE, laparoscopic fundoplication seems to warrant a better control of all kinds of refluxate and it is associated with a higher likelihood of reversion of both LGD- and ND-BE, compared with PPI therapy. PMID- 25030478 TI - Potential advantages of robotic radical gastrectomy for gastric adenocarcinoma in comparison with conventional laparoscopic approach: a single institutional retrospective comparative cohort study. AB - BACKGROUND: We have previously reported that laparoscopic approach improved short term postoperative courses even for advanced gastric adenocarcinoma, but not morbidity, in comparison with open approach. The objective of this study was to determine the impact of the use of the surgical robot, da Vinci Surgical System, in minimally invasive radical gastrectomy on short-term outcomes. METHODS: A single institutional retrospective cohort study was performed (UMIN000011749). Five hundred twenty-six patients who underwent radical gastrectomy were enrolled. Eighty-eight patients who agreed to uninsured use of the surgical robot underwent robotic gastrectomy, whereas the remaining 438 patients who wished for laparoscopic (lap) approach with health insurance coverage underwent conventional laparoscopic gastrectomy. RESULTS: In the robotic group, morbidity (robotic vs lap 2.3 vs 11.4 %, p = 0.009) and hospital stay following surgery (robotic vs lap 14 [2-31] vs 15 [8-136] days, p = 0.021) were significantly improved, even though operative time (p = 0.003) and estimated blood loss (p = 0.026) were slightly greater. In particular, local (robotic vs lap 1.1 vs 9.8 %, p = 0.007) rather than systemic (robotic vs lap 1.1 vs 2.5 %, p = 0.376) complication rates were attenuated using the surgical robot. Multivariate analyses revealed that non-use of the surgical robot (OR 6.174 [1.454-26.224], p = 0.014), total gastrectomy (OR 4.670 [2.503-8.713], p < 0.001), and D2 lymphadenectomy (OR 2.095 [1.124-3.903], p = 0.020) were the significant independent risk factors determining postoperative complications. CONCLUSIONS: The use of the surgical robot might reduce surgery-related complications, leading to further improvement in short term postoperative courses following minimally invasive radical gastrectomy. PMID- 25030479 TI - Anderson-Fabry cardiomyopathy: prevalence, pathophysiology, diagnosis and treatment. AB - Anderson-Fabry disease (AFD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide in tissues due to a deficiency in the enzyme alpha-galactosidase A (alpha-Gal A). Anderson-Fabry cardiomyopathy is characterized by structural, valvular, vascular and conduction abnormalities, and is now the most common cause of mortality in patients with AFD. Large-scale metabolic and genetic screening studies have revealed AFD to be prevalent in populations of diverse ethnic origins, and the variant form of AFD represents an unrecognized health burden. Anderson-Fabry disease is an X-linked disorder, and genetic testing is critical for the diagnosis of AFD in women. Echocardiography with strain imaging and cardiac magnetic resonance imaging using late enhancement and T1 mapping are important imaging tools. The current therapy for AFD is enzyme replacement therapy (ERT), which can reverse or prevent AFD progression, while gene therapy and the use of molecular chaperones represent promising novel therapies for AFD. Anderson-Fabry cardiomyopathy is an important and potentially reversible cause of heart failure that involves LVH, increased susceptibility to arrhythmias and valvular regurgitation. Genetic testing and cardiac MRI are important diagnostic tools, and AFD cardiomyopathy is treatable if ERT is introduced early. PMID- 25030481 TI - Correlations among ultrasonographic and microscopic characteristics of prepubescent ram lamb testes. AB - The onset of spermatogenesis during prepubertal development is accompanied by dynamic changes in testicular microstructure. Computer-assisted analysis of scrotal ultrasonograms may allow us to track these changes in a noninvasive manner; however, the echotextural characteristics of different histomorphological variables remain unclear. Hence the objective of this study was to compare echotextural and microscopic attributes of the testis over the first wave of spermatogenesis in prepubescent ram lambs. Bi-weekly ultrasound examinations and weekly testicular biopsies were carried out in 22 ram lambs from 9.5-10 weeks of age or the attainment of 15 cm(3) in testicular volume, respectively, to the first detection of elongated spermatids (ESt). Testicular echogenicity was highly variable with age; however, after the alignment of data to the first detection of ESt, there was an initial increase followed by a decline, corresponding to the mitotic and postmitotic phases of spermatogenesis in prepubescent ram lambs. Testicular echotextural attributes (mean numerical pixel values and pixel heterogeneity) correlated with seminiferous tubule (ST) diameter, the number of degenerating cells/ST cross-section (XS), and the number of ubiquitin C-terminal hydrolase L-1 (a marker for prespermatogonia and undifferentiated spermatogonia) staining cells/ST XS during the mitotic and postmitotic phases. Additionally, in the postmitotic phase, significant correlations were recorded between the quantitative echotextural characteristics and ST cell density, nuclear:ST area and percentages of STs with different spermatogenic cells as the most mature germ cell type present. These results indicate that ram testes exhibit distinctive echotextural characteristics during the mitotic and postmitotic phases of germ cell differentiation. It is concluded that scrotal ultrasonography in conjunction with computerized image analysis holds potential as a noninvasive alternative to testicular biopsy in monitoring the reproductive status throughout different stages of testicular development. PMID- 25030480 TI - Tissue-engineered microenvironment systems for modeling human vasculature. AB - The high attrition rate of drug candidates late in the development process has led to an increasing demand for test assays that predict clinical outcome better than conventional 2D cell culture systems and animal models. Government agencies, the military, and the pharmaceutical industry have started initiatives for the development of novel in-vitro systems that recapitulate functional units of human tissues and organs. There is growing evidence that 3D cell arrangement, co culture of different cell types, and physico-chemical cues lead to improved predictive power. A key element of all tissue microenvironments is the vasculature. Beyond transporting blood the microvasculature assumes important organ-specific functions. It is also involved in pathologic conditions, such as inflammation, tumor growth, metastasis, and degenerative diseases. To provide a tool for modeling this important feature of human tissue microenvironments, we developed a microfluidic chip for creating tissue-engineered microenvironment systems (TEMS) composed of tubular cell structures. Our chip design encompasses a small chamber that is filled with an extracellular matrix (ECM) surrounding one or more tubular channels. Endothelial cells (ECs) seeded into the channels adhere to the ECM walls and grow into perfusable tubular tissue structures that are fluidically connected to upstream and downstream fluid channels in the chip. Using these chips we created models of angiogenesis, the blood-brain barrier (BBB), and tumor-cell extravasation. Our angiogenesis model recapitulates true angiogenesis, in which sprouting occurs from a "parent" vessel in response to a gradient of growth factors. Our BBB model is composed of a microvessel generated from brain-specific ECs within an ECM populated with astrocytes and pericytes. Our tumor-cell extravasation model can be utilized to visualize and measure tumor cell migration through vessel walls into the surrounding matrix. The described technology can be used to create TEMS that recapitulate structural, functional, and physico-chemical elements of vascularized human tissue microenvironments in vitro. PMID- 25030482 TI - Ozone therapy ameliorates paraquat-induced lung injury in rats. AB - Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-beta1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (P<0.05, PQ vs. PQ+OT). Total antioxidant capacity in PQ+OT group was significantly higher than PQ group (P < 0.05, PQ+OT vs. PQ). These findings suggest that outcome in PQ induced lung injury may be improved by using OT as an adjuvant therapy. PMID- 25030484 TI - An application of embryonic skin cells to repair diabetic skin wound: a wound reparation trail. AB - Cell therapy has shown its power to promote diabetic chronic wound healing. However, problems of scar formation and loss of appendages have not yet been solved. Our study aims to explore the potential of using embryonic skin cells (ESkCs) to repair diabetic wounds. Circular wound was created on the back of the diabetic mice, and ESkCs stained with CM-DIL were transplanted into the wound. Wound area was recorded at the day 4, 7, 11, and 14 after transplantation. The tissue samples were obtained at week 1, 2, and 3, and the tissue sections were stained by transforming growth factor beta1 (TGF-beta1), TGF-beta3, vascular endothelial growth factor (VEGF), and CD31. The new skin formed on the wound of the diabetic mice with ESkC treatment at week 1 but not on the wounds of the non treatment group. The histological scores of diabetic group with ESkC treatment were significantly better than the non-treatment group (P < 0.05). The fluorescence examination of CM-DIL and CD31 staining indicated that the ESkCs participated in the tissue regeneration, hair follicles formation, and angiogenesis. The expression of TGF-beta1 and VEGF in ESkC-treated groups was noticeable in week 1 but disappeared in week 2. TGF-beta3 was not expressed at week 1 but expressed markedly around hair follicles in week 2 in ESkC-treated groups. Our study demonstrated that ESkCs are capable of developing new skin with appendage restoration to repair the diabetic wounds. PMID- 25030483 TI - Dietary salt restriction in hyperthyroid rats. Differential influence on left and right ventricular mass. AB - This study assessed the impact of salt restriction on cardiac morphology and biochemistry and its effects on hemodynamic and renal variables in experimental hyperthyroidism. Four groups of male Wistar rats were used: control, hyperthyroid, and the same groups under low salt intake. Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 4 weeks. Morphologic, metabolic, plasma, cardiac, and renal variables were also measured. Low salt intake decreased BP in T(4)-treated rats but not in controls. Low salt intake reduced relative left ventricular mass but increased absolute right ventricular weight and right ventricular weight/BW ratio in both control and hyperthyroid groups. Low salt intake increased Na(+)/H(+) exchanger-1 (NHE-1) protein abundance in both ventricles in normal rats but not in hyperthyroid rats, independently of its effect on ventricular mass. Mammalian target of rapamycin (mTOR) protein abundance was not related to left or right ventricular mass in hyperthyroid or controls rats under normal or low salt conditions. Proteinuria was increased in hyperthyroid rats and attenuated by low salt intake. In this study, low salt intake produced an increase in right ventricular mass in normal and hyperthyroid rats. Changes in the left or right ventricular mass of control and hyperthyroid rats under low salt intake were not explained by the NHE-1 or mTOR protein abundance values observed. In hyperthyroid rats, low salt intake also slightly reduced BP and decreased HR, proteinuria, and water and sodium balances. PMID- 25030485 TI - Selective blockade of the OGF-OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing. AB - Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10(-6) M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF-OGFr regulatory axis. PMID- 25030486 TI - Predictors for successful smoking cessation in Korean adults. AB - PURPOSE: A better understanding of the factors contributing to smoking cessation would be of substantial benefit to public health. The purpose of this study was to identify significant predictors of successful smoking cessation in the Korean population. METHODS: We compared 1,181 successful quitters with 940 current smokers who made a recent attempt to quit but failed in the past 12 months using the fourth Korea National Health and Nutrition Examination Survey. We examined the relationship of sociodemographic, behavioral and environmental characteristics, comorbid conditions, and quitting methods to successful smoking cessation. RESULTS: Older age, female, being married, having higher education, having a lower level of stress, having smoked 20 or more cigarettes per day, and one's own will for quitting have been identified as significant determinants of successful cessation. Frequency of alcohol consumption and trying numerous quitting methods was inversely related to stopping smoking. CONCLUSION: This study suggests that cessation programs need to take a holistic approach and should consider these factors in setting up. PMID- 25030487 TI - Health behaviors and risk factors associated with chronic kidney disease in Korean patients with diabetes: the Fourth Korean National Health and Nutritional Examination Survey. AB - PURPOSE: The purpose of this study was to identify health behavior and risk factors for chronic kidney disease (CKD) in Korean patients with diabetes. METHODS: This study was a secondary analysis of the Fourth Korean National Health and Nutritional Examination Survey (2007-2009). Of the 24,871 participants, 1,239 aged over 19 years with diagnosis of diabetes were included. Stratified and cluster variables in the analysis-plan file for a weighted, complex sample were analyzed. CKD was confirmed by the estimated glomerular filtration rate level of 15.0-59.9 mL/min/1.732 m(2). Odds ratios between the variables and CKD were calculated using logistic regression analysis with adjustment for gender, age, educational background, income, and duration of diagnosis. RESULTS: The results showed that 14.7% of participants with diabetes were accompanied with CKD. The risk of developing CKD in those who made efforts to take proper nutrition but failed was 1.76 times higher than those taking nutrition properly. In those who used to smoke compared to their nonsmoking counterparts, the risk was 2.06 times higher; in those who did not do vigorous exercise compared to those who did, the risk was 2.12 times higher; in those with hypertension than those without, the risk was 2.4 times higher; and in those with anemia compared to those without, the risk was 2.32 times higher. Only 19% of the participants received health education for diabetes, which did not affect the incidence of CKD. CONCLUSION: Since renal functions are affected by lifestyle factors, it is critical for healthcare professionals to provide diabetic patients with health education focused on changing their behavior so that it is conducive to health. It is also necessary to consider that diabetes education should be made more available and provided more effectively to these patients. PMID- 25030488 TI - Problems of clinical nurse performance appraisal system: a qualitative study. AB - PURPOSE: The purpose of this study is to explore problems of clinical nurse performance appraisal system. METHODS: This study employed a descriptive qualitative approach. The participants were purposively selected from clinical nurses working across all of the hospital units in a large metropolitan teaching hospital in Tehran, Iran in 2012. Data were collected using five focus group interviews, which were audio taped. The number of participants in each group ranged from 7 to 10. The semi-structured interviews were guided by a set of nondirective questions, and continued until the data reached saturation. Data were analyzed using framework analysis. RESULTS: Four major themes regarding the problems of clinical nurse performance appraisal system emerged from the analysis of textual data. These themes were contextual problems, problems related to performance appraisal structure, problems related to performance appraisal process and those related to performance appraisal results. CONCLUSION: The findings of this study reveal that the nurse performance appraisal system confronts with various problems. Some of these problems are related to organizational context while the others concerned structure, process and results of the performance appraisal system. In order to achieve high quality of patient care as the final goal of performance appraisal, changing and revision of this system is necessary. PMID- 25030489 TI - Efficacy of distraction methods on procedural pain and anxiety by applying distraction cards and kaleidoscope in children. AB - PURPOSE: This study aims to investigate two different distraction methods, distraction cards and kaleidoscope, on pain and anxiety relief of children during phlebotomy. METHODS: This study is a prospective, randomized and controlled trial. The sample consisted of 7-11 year-old children who required blood tests. Children were randomized into three groups: the distraction cards group, the kaleidoscope group, and the control group. Data were obtained by interviewing the children with their parents and the observer before and after the procedure. The pain levels of the children were assessed by the parent and observer reports as well as self report using the Wong Baker FACES Pain Rating Scale. The anxiety levels of children were assessed by parent and observer reports using Children Fear Scale. RESULTS: One hundred and eighty-eight children (mean age, 8.8 +/- 1.5 years) were included. The pain levels of children showed significant differences among the groups (p = .005). Both the distraction card group (2.41 +/- 2.49) and the kaleidoscope group (3.10 +/- 2.16) had lower pain levels than the control group did (4.44 +/- 3.64). The distraction card group had the lowest pain levels (2.41 +/- 2.49) among all groups. The procedural anxiety levels of children were significantly different among the groups (p = <.001). Both the distraction card group (1.10 +/- 1.20) and the kaleidoscope group (1.61 +/- 1.12) had lower anxiety levels than the control group did (2.41 +/- 1.30). The distraction card group had the lowest anxiety levels (p = <.001). CONCLUSION: The distraction cards were the most effective method for pain and anxiety relief of children during phlebotomy. Also the distraction method with kaleidoscope was an effective method for pain and anxiety relief during phlebotomy in children. PMID- 25030490 TI - Taiwanese parents' experience of making a "do not resuscitate" decision for their child in pediatric intensive care unit. AB - PURPOSE: The purpose of this project was to explore the parental experience of making a "do not resuscitate" (DNR) decision for their child who is or was cared for in a pediatric intensive care unit in Taiwan. METHODS: A descriptive qualitative study was conducted following parental signing of a standard hospital DNR form on behalf of their critically ill child. Sixteen Taiwanese parents of 11 children aged 1 month to 18 years were interviewed. Interviews were recorded, transcribed, analyzed and sorted into themes by the sole interviewer plus other researchers. RESULTS: Three major themes were identified: (a) "convincing points to sign", (b) "feelings immediately after signing", and (c) "post-signing relief or regret". Feelings following signing the DNR form were mixed and included "frustration", "guilt", and "conflicting hope". Parents adjusted their attitudes to thoughts such as "I have done my best," and "the child's life is beyond my control." Some parents whose child had died before the time of the interview expressed among other things "regret not having enough time to be with and talk to my child". CONCLUSION: Open family visiting hours plus staff sensitivity and communication skills training are needed. To help parents with this difficult signing process, nurses and other professionals in the pediatric intensive care unit need education on initiating the conversation, guiding the parents in expressing their fears, and providing continuing support to parents and children throughout the child's end of life process. PMID- 25030491 TI - Relationship between quality of life and nurse-led bedside symptom evaluations in patients with chemotherapy-induced peripheral neuropathy. AB - PURPOSE: This cross-sectional study aimed at determining the relationship between patient-reported quality of life (QOL) and nurse-led bedside evaluations of chemotherapy-induced peripheral neuropathy symptoms. METHODS: One hundred ninety five patients treated at the oncology clinic at our institution were assessed using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity and nurse-led bedside examinations. The relationship between self reported QOL and bedside examinations was evaluated using Spearman rank correlations. RESULTS: Scores of upper and lower extremity muscle strength based on the bedside examinations showed a weak negative correlation with the emotional well-being subscale of Functional Assessment of Cancer Therapy-General. Further, weak negative relationships were present between QOL and the following nurse reported parameters: vibration perception in the hand, upper extremity muscle strength, touch and vibration perception in the feet, and tendon reflexes. CONCLUSION: Collectively, our results indicate that nurse-led bedside evaluation is a noninvasive and useful method for detecting neurotoxicity and evaluating the patient's QOL both during and after treatment. PMID- 25030493 TI - Effect of a mind-body therapeutic program for infertile women repeating in vitro fertilization treatment on uncertainty, anxiety, and implantation rate. AB - PURPOSE: The study aimed to develop a mind-body therapeutic program and evaluate its effects on mitigating uncertainty, anxiety, and implantation rate of second trial in vitro fertilization (IVF) women. METHODS: This study employed a nonequivalent control group nonsynchronized design. The conceptual framework and program content were developed from a preliminary survey of eight infertile women and the extensive review of the literature. Program focuses on three uncertainty induced anxieties in infertile women: cognitive, emotional, and biological responses. To evaluate the effect of the intervention, the infertile women with unknown cause preparing for a second IVF treatment were sampled at convenience (26 experimental and 24 control). RESULTS: The experimental group in the study showed greater decrease in uncertainty and anxiety in premeasurements and postmeasurements than the control group did. However, no statistically significant differences in the implantation rate between groups were observed. CONCLUSION: This study is meaningful as the first intervention program for alleviating uncertainty and anxiety provided during the IVF treatment process. The positive effects of the mind-body therapeutic program in alleviating both uncertainty and anxiety have direct meaning for clinical applications. PMID- 25030492 TI - Path analysis of empowerment and work effectiveness among staff nurses. AB - PURPOSE: The purpose of this study was to test a predictive model that could predict and explain work effectiveness among staff nurses at local hospitals. METHODS: Between April 1 and May 15, 2009, 340 nurses were recruited from two hospitals (one in Ulsan and one in Yangsan). Data were collected via self administered questionnaires and analyzed using structural equation modeling. RESULTS: A modified model was retained, as the final path model showed a very good fit with the data. Job characteristics and compensation justice were found to have direct and positive effects on empowerment. Job characteristics, transformational leadership, and empowerment were found to directly and positively affect work effectiveness. In addition, job characteristics were found to have a greater effect on empowerment and work effectiveness than other factors do. CONCLUSION: This structural equation model was used to test the relationships between these factors and work effectiveness. Empowerment mediated the relationship between job characteristics, transformational leadership, and work effectiveness. Findings from this study can be used to design the strategies for increasing work effectiveness in Korean nurses. PMID- 25030494 TI - Development of a standardized job description for healthcare managers of metabolic syndrome management programs in Korean community health centers. AB - PURPOSE: This study aimed to develop a job description for healthcare managers of metabolic syndrome management programs using task analysis. METHODS: Exploratory research was performed by using the Developing a Curriculum method, the Intervention Wheel model, and focus group discussions. Subsequently, we conducted a survey of 215 healthcare workers from 25 community health centers to verify that the job description we created was accurate. RESULTS: We defined the role of healthcare managers. Next, we elucidated the tasks of healthcare managers and performed needs analysis to examine the frequency, importance, and difficulty of each of their duties. Finally, we verified that our job description was accurate. Based on the 8 duties, 30 tasks, and 44 task elements assigned to healthcare managers, we found that the healthcare managers functioned both as team coordinators responsible for providing multidisciplinary health services and nurse specialists providing health promotion services. In terms of importance and difficulty of tasks performed by the healthcare managers, which were measured using a determinant coefficient, the highest-ranked task was planning social marketing (15.4), while the lowest-ranked task was managing human resources (9.9). CONCLUSION: A job description for healthcare managers may provide basic data essential for the development of a job training program for healthcare managers working in community health promotion programs. PMID- 25030495 TI - Validation of the Korean version of the 39-Item Parkinson's Disease Questionnaire (PDQ-39). AB - PURPOSE: To evaluate the reliability and validity of the Korean version of the 39 item Parkinson's disease questionnaire (PDQ-39). METHODS: Cross-cultural adaptation was performed according to the international guidelines: forward and backward translation, focus group meeting, and a field test. With Korean consensus translation produced, validation was assessed by evaluating reliability and validity. Ninety-three outpatients with Parkinson's disease (PD) and 89 healthy aged controls were recruited. Internal consistency reliability was assessed by Cronbach's alpha. Validity was assessed by Spearman correlation analysis, t test, factor analysis, and analysis of variance with Duncan's multiple range tests. RESULTS: In the PD group, mean age was 65.13 +/- 9.84 years, and mean duration of PD was 42.41 +/- 37.01 months. Ceiling and floor effects ranged 1.1%-2.2% and 1.1%-15.1%, respectively. Cronbach's alpha of eight dimensions ranged from .70 to .97. All dimensions were correlated with each other, except for the stigma dimension. PD patients had significantly lower quality of life than healthy aged controls did, except for the bodily discomfort dimension. Eight dimensions of Korean PDQ-39 loaded on one factor. PD patients with a Modified Hoehn and Yarh Staging score of 4 had the worst quality of life. The relationships among the eight dimensions of Koran PDQ-39 and the Modified Hoehn and Yarh Staging is fair to good, except for the stigma and social support dimension. CONCLUSION: The Korean PDQ-39 was proved to be reliable and valid. Our results suggest that Korean PDQ-39 could be used in clinical research to assess and evaluate the disease process and its impacts on health-related quality of life in Korean PD patients. PMID- 25030496 TI - Preliminary development of humanistic care indicators for residents in nursing homes: a Delphi technique. AB - PURPOSE: The overwhelming majority of residents among nursing homes are the elderly in Taiwan. Previous studies have shown the dissatisfaction with care from the viewpoints of nursing home residents. For improving the care quality of nursing homes, the study aims to develop humanistic care indicators (HCIs). METHODS: The Delphi technique was used to develop the HCIs through the consensus of 23 experts. Through three rounds of questionnaires, the expert panel reached a consensus. RESULTS: Forty-four HCIs for nursing home were identified and grouped into eight elements: friendly environment, holistic care, empathy, individualization, autonomy, decision-making participation, appropriate use of tools, and serious assessment of customer opinion. CONCLUSION: This study compiled related literature and conducted a Delphi survey to transform humanistic care from an abstract concept into concrete indicators for evaluation. These findings could serve as a guideline for the care providers in nursing homes. Further studies are needed to test the practicability of HCIs and evaluate the outcomes of applying HCIs in nursing homes. PMID- 25030497 TI - A Web-based health promotion program for patients with metabolic syndrome. AB - PURPOSE: The population of metabolic syndrome is increasing in Korea. The prevalence is related to lifestyle, such as lack of physical activity and irregular diet. Most patients with metabolic syndrome know that lifestyle intervention is important to managing the condition. However, they do not always follow the intervention for various reasons, including lack of knowledge on how to change their lifestyle and lack of accessibility to that knowledge. The purpose of this study was to test the web-based health promotion program we developed. METHODS: Fifty-six adult workers from eight areas of business were recruited. They all had a confirmed metabolic syndrome diagnosis after being registered at a university hospital for annual health checkups. Twenty-nine workers were assigned to the experimental group, and the others were assigned to the control group. The web-based program was applied to the experimental group as an intervention for 8 weeks. Waist circumference, fasting blood glucose, triglyceride, high-density lipoprotein cholesterol, and blood pressure were measured before and after the program. Data were analyzed using chi-square test, Fisher's exact test, and t test. RESULTS: There were statistically significant differences between the two groups in waist circumference and high-density lipoprotein cholesterol (t = -4.43, p < .001; t = 2.22, p = .031, respectively). Of the 29 participants, 13 (44.83%) in the intervention group had less than two indices for metabolic syndrome. CONCLUSIONS: This study suggests that a web-based program is useful for patients with metabolic syndrome to improve physiologic parameters related to metabolic syndrome. The web-based program may be easily applicable to community as well as clinical setting. PMID- 25030498 TI - [Therapy of chronic inflammatory bowel diseases. Standards, controversies and perspectives]. AB - Crohn's disease and ulcerative colitis are the most common forms of chronic inflammatory bowel disease. The therapeutic algorithm is complex and individualized especially in complicated courses of the disease. This article gives a comprehensive overview on the typical courses of disease and the standard therapy of both diseases. Furthermore, ongoing controversies will be highlighted including early immunosuppression and immunomodulation as well as new therapeutic goals, such as mucosal healing. Finally, a perspective on future therapeutic options is given focusing especially on vedolizumab, the new antibody against the bowel-specific alpha4beta7-integrin. PMID- 25030499 TI - Development and reliability of a scale of physical-activity related informal social control for parents of Chinese pre-schoolers. AB - BACKGROUND: Parents' perceived informal social control, defined as the informal ways residents intervene to create a safe and orderly neighbourhood environment, may influence young children's physical activity (PA) in the neighbourhood. This study aimed to develop and test the reliability of a scale of PA-related informal social control relevant to Chinese parents/caregivers of pre-schoolers (children aged 3 to 5 years) living in Hong Kong. METHODS: Nominal Group Technique (NGT), a structured, multi-step brainstorming technique, was conducted with two groups of caregivers (mainly parents; n = 11) of Hong Kong pre-schoolers in June 2011. Items collected in the NGT sessions and those generated by a panel of experts were used to compile a list of items (n = 22) for a preliminary version of a questionnaire of informal social control. The newly-developed scale was tested with 20 Chinese-speaking parents/caregivers using cognitive interviews (August 2011). The modified scale, including all 22 original items of which a few were slightly reworded, was subsequently administered on two occasions, a week apart, to 61 Chinese parents/caregivers of Hong Kong pre-schoolers in early 2012. The test-retest reliability and internal consistency of the items and scale were examined using intraclass correlation coefficients (ICC), paired t-tests, relative percentages of shifts in responses to items, and Cronbach's alpha coefficient. RESULTS: Thirteen items generated by parents/caregivers and nine items generated by the panel of experts (total 22 items) were included in a first working version of the scale and classified into three subscales: "Personal involvement and general informal supervision", "Civic engagement for the creation of a better neighbourhood environment" and "Educating and assisting neighbourhood children". Twenty out of 22 items showed moderate to excellent test-test reliability (ICC range: 0.40-0.81). All three subscales of informal social control showed acceptable levels of internal consistency (Cronbach's alpha >0.70). CONCLUSIONS: A reliable scale examining PA-related informal social control relevant to Chinese parents/caregivers of pre-schoolers living in Hong Kong was developed. Further studies should examine the factorial validity of the scale, its associations with Chinese children's PA and its appropriateness for other populations of parents of young children. PMID- 25030500 TI - Surgical treatment of extrahepatic recurrence of hepatocellular carcinoma. AB - PURPOSE: The purpose of this study was to clarify the clinicopathological features of extrahepatic hepatocellular carcinoma (HCC) recurrence after hepatectomy in order to schedule optimal treatment strategies for better long term outcomes. METHODS: A cohort of 206 patients who had undergone curative hepatectomy for HCC was analysed; 133 patients had developed relapse. Among them, 101 patients had intrahepatic recurrence only (IHR), and 32 patients had extrahepatic recurrence (EHR). Clinicopathological and survival data were compared between the two groups. RESULTS: The overall survival rate after hepatectomy was better in the IHR than in the EHR group (p<0.0001). The recurrence-free interval after hepatectomy was significantly shorter in the EHR than in the IHR group (258 vs. 487 days, p<0.0043). Patients in the EHR group were more likely to have a high PIVKA II, a large tumour, and microscopic portal vein invasion when compared with patients in the IHR group. Microscopic portal vein invasion was the most important independent risk factor for EHR after hepatectomy (p=0.0295). Patients with more than two risk factors for EHR showed poor prognosis in comparison with patients without any risk factors (p<0.001). In the EHR group, patients who underwent repeated resection had significantly better survival than patients receiving only the best supportive care (539 vs. 133 days, p=0.0098). Furthermore, among EHR patients with concomitant IHR, patients with controllable IHR had significantly better survival than those with uncontrollable IHR (524 vs. 147 days, p=0.0131). CONCLUSIONS: EHR of HCC was associated with early recurrence, and risk factors for the occurrence of EHR included the presence of high PIVKA II, large tumours, and microscopic portal vein invasion. Resection of recurrent tumour and local control of concomitant IHR may improve the prognosis of EHR patients. PMID- 25030501 TI - 'My health is not a job': a qualitative exploration of personal health management and imperatives of the 'new public health'. AB - BACKGROUND: There is an increasing push in Western healthcare for people to 'manage' their health, a key aspect of what has been called the 'new public health'. It has been argued that this 'personal health management' - informal work done to monitor, inform, or influence one's health - may be a burden, with potential to contribute to poor health outcomes. However, there is little research actually examining perceptions of personal health management and the 'burden' of these activities, particularly for generally healthy individuals. METHODS: We conducted exploratory qualitative interviews with 30 generally healthy men and women about their perceptions and experiences of personal health management. Questions focused on health behaviours (e.g., information seeking), as well as feelings about these behaviours and perceptions of the time dedicated to health. Audio-recorded interviews were transcribed and analyzed qualitatively using NVivo 10. Where appropriate, quantitative codes were applied and descriptive statistics are reported alongside qualitative findings. RESULTS: Participants were generally satisfied with the amount of time spent on their health and few perceived personal health management as a burden. Many participants took issue with the concept of 'work' being associated with health and stressed the importance of taking personal responsibility for health. CONCLUSIONS: Our findings suggest that generally healthy people have internalised the notion of the 'new public health' and accepted the imperative of personal health responsibility. On the one hand, this bodes well for healthy individuals; their positive attitude may lead to better health outcomes, and the manageable amount of time spent suggests personal health management is unlikely to cause negative health consequences associated with stress. On the other hand, our findings may indicate that other factors, such as social determinants of health, are ignored in health promotion efforts and that those who cannot manage their own health may fall further behind. Future research should continue to explore the time people spend 'working' for their health, and how they perceive and respond to 'new public health' imperatives. PMID- 25030503 TI - Maternal consumption of coffee and tea during pregnancy and risk of childhood brain tumors: results from an Australian case-control study. AB - PURPOSE: The causes of childhood brain tumors (CBT) are largely unknown, but gestational diet may influence this risk. The aim of this analysis was to investigate whether maternal coffee or tea consumption during pregnancy was associated with the risk of CBT. METHODS: The Australian Study of the Causes of Childhood Brain Tumours was a population-based, Australian case-control study conducted between 2005 and 2010. Case children were recruited from 10 pediatric oncology centers and control children by nationwide random-digit dialing, frequency matched to cases on the basis of age, sex and state of residence. Coffee and tea intake were assessed using a food frequency questionnaire. RESULTS: Data on coffee and tea consumption during pregnancy were available from 293 case mothers and 726 control mothers. Odds ratios (ORs) and confidence intervals (CIs) were calculated using multivariable unconditional logistic regression. There was little evidence of an association between gestational consumption of any coffee (OR 1.23, 95% CI 0.92, 1.64) or tea (OR 1.00, 95% CI 0.74, 1.36) and CBT risk. Among children aged under 5 years, the OR for any coffee consumption during pregnancy was 1.76 (95% CI 1.09, 2.84) and for >=2 cups per day during pregnancy was 2.52 (95% CI 1.26, 5.04). There was little evidence that associations with coffee or tea intake differed by parental smoking status. CONCLUSIONS: These results suggest a positive association between coffee intake >=2 cups per day and risk of CBT in younger children, although some estimates are imprecise. There was no association between maternal tea drinking and risk of CBT. PMID- 25030502 TI - Using structural and diffusion magnetic resonance imaging to differentiate the dementias. AB - Dementia is one of the major causes of personal, societal and financial dependence in older people and in today's ageing society there is a pressing need for early and accurate markers of cognitive decline. There are several subtypes of dementia but the four most common are Alzheimer's disease, Lewy body dementia, vascular dementia and frontotemporal dementia. These disorders can only be diagnosed at autopsy, and ante-mortem assessments of "probable dementia (e.g. of Alzheimer type)" are traditionally driven by clinical symptoms of cognitive or behavioural deficits. However, owing to the overlapping nature of symptoms and age of onset, a significant proportion of dementia cases remain incorrectly diagnosed. Misdiagnosis can have an extensive impact, both at the level of the individual, who may not be offered the appropriate treatment, and on a wider scale, by influencing the entry of patients into relevant clinical trials. Magnetic resonance imaging (MRI) may help to improve diagnosis by providing non invasive and detailed disease-specific markers of cognitive decline. MRI-derived measurements of grey and white matter structural integrity are potential surrogate markers of disease progression, and may also provide valuable diagnostic information. This review summarises the latest evidence on the use of structural and diffusion MRI in differentiating between the four major dementia subtypes. PMID- 25030504 TI - Innate immune cells express IL-17A/F in acute generalized exanthematous pustulosis and generalized pustular psoriasis. AB - Acute generalized exanthematous pustulosis (AGEP) and generalized pustular psoriasis (GPP) are rare pustular skin disorders with systemic involvement. IL 17A/F is a proinflammatory cytokine involved in various neutrophilic inflammatory disorders. Here we show that IL-17A/F is highly expressed by innate immune cells such as neutrophils and mast cells in both AGEP and GPP. PMID- 25030505 TI - Tackling the sports-related concussion crisis. PMID- 25030506 TI - Capitalising on modifiable risk factors for Alzheimer's disease. PMID- 25030507 TI - The Glasgow Coma Scale: time for critical reappraisal? PMID- 25030508 TI - Urate and neuroprotection trials. PMID- 25030509 TI - Urate and neuroprotection trials--authors' reply. PMID- 25030510 TI - Does neurology need a faster FDA? PMID- 25030511 TI - David Gutmann: making science work for patients. PMID- 25030512 TI - Measures and outcomes. PMID- 25030513 TI - Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. AB - BACKGROUND: Recent estimates suggesting that over half of Alzheimer's disease burden worldwide might be attributed to potentially modifiable risk factors do not take into account risk-factor non-independence. We aimed to provide specific estimates of preventive potential by accounting for the association between risk factors. METHODS: Using relative risks from existing meta-analyses, we estimated the population-attributable risk (PAR) of Alzheimer's disease worldwide and in the USA, Europe, and the UK for seven potentially modifiable risk factors that have consistent evidence of an association with the disease (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment). The combined PAR associated with the risk factors was calculated using data from the Health Survey for England 2006 to estimate and adjust for the association between risk factors. The potential of risk factor reduction was assessed by examining the combined effect of relative reductions of 10% and 20% per decade for each of the seven risk factors on projections for Alzheimer's disease cases to 2050. FINDINGS: Worldwide, the highest estimated PAR was for low educational attainment (19.1%, 95% CI 12.3-25.6). The highest estimated PAR was for physical inactivity in the USA (21.0%, 95% CI 5.8-36.6), Europe (20.3%, 5.6-35.6), and the UK (21.8%, 6.1-37.7). Assuming independence, the combined worldwide PAR for the seven risk factors was 49.4% (95% CI 25.7 68.4), which equates to 16.8 million attributable cases (95% CI 8.7-23.2 million) of 33.9 million cases. However, after adjustment for the association between the risk factors, the estimate reduced to 28.2% (95% CI 14.2-41.5), which equates to 9.6 million attributable cases (95% CI 4.8-14.1 million) of 33.9 million cases. Combined PAR estimates were about 30% for the USA, Europe, and the UK. Assuming a causal relation and intervention at the correct age for prevention, relative reductions of 10% per decade in the prevalence of each of the seven risk factors could reduce the prevalence of Alzheimer's disease in 2050 by 8.3% worldwide. INTERPRETATION: After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression. FUNDING: National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough. PMID- 25030514 TI - Stroke and cerebrovascular diseases in patients with chronic kidney disease. AB - Chronic kidney disease, defined as a reduced glomerular filtration rate or increased urinary albumin excretion, is recognised as a rapidly growing global health burden, and increasing evidence suggests that it contributes to the risk and severity of cerebrovascular diseases. In particular, chronic kidney disease is an established risk factor for stroke and is also strongly associated with subclinical cerebrovascular abnormalities and cognitive impairment, partly because it shares several traditional and non-traditional risk factors, and sometimes uraemia-related and dialysis-related factors, with cerebrovascular diseases. The effect of chronic kidney disease on incident stroke differs among regions and races and is greater in Asian than in non-Asian people. Chronic kidney disease seems to be predictive of severe neurological deficits and poor vital and functional outcomes after both ischaemic and haemorrhagic strokes, which is partly due to the limitations of pharmacotherapies, including limited use and effects of novel oral anticoagulants, other antithrombotic treatments, and reperfusion treatment for hyperacute ischaemic stroke. In view of the strong two-way association between stroke and kidney disease, the pathophysiological interactions between the brain and kidney should be the subject of intensive study. PMID- 25030515 TI - Neurofibromatosis type 1: a multidisciplinary approach to care. AB - Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to different medical and surgical specialists and, therefore, the association of clinical symptoms with neurofibromatosis type 1 might not be appreciated. Thus, for prompt diagnosis and to provide optimum care for patients with neurofibromatosis type 1, clinicians must be aware of the diverse clinical features of this disorder. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient. As our understanding of this disorder deepens through basic laboratory and clinical investigations, swift implementation of new effective treatments becomes feasible. PMID- 25030516 TI - The Glasgow Coma Scale at 40 years: standing the test of time. AB - Since 1974, the Glasgow Coma Scale has provided a practical method for bedside assessment of impairment of conscious level, the clinical hallmark of acute brain injury. The scale was designed to be easy to use in clinical practice in general and specialist units and to replace previous ill-defined and inconsistent methods. 40 years later, the Glasgow Coma Scale has become an integral part of clinical practice and research worldwide. Findings using the scale have shown strong associations with those obtained by use of other early indices of severity and outcome. However, predictive statements should only be made in combination with other variables in a multivariate model. Individual patients are best described by the three components of the coma scale; whereas the derived total coma score should be used to characterise groups. Adherence to this principle and enhancement of the reliable practical use of the scale through continuing education of health professionals, standardisation across different settings, and consensus on methods to address confounders will maintain its role in clinical practice and research in the future. PMID- 25030517 TI - Isolation and characterisation of the trichocysts of the dinophyte Prorocentrum micans. AB - Trichocyst-enriched fractions were isolated from the marine dinophyte Prorocentrum micans. Transmission electron microscopy revealed that most of the trichocysts were discharged and had elongated to long filaments. Some trichocysts were still condensed. Fragments of discharged trichocysts measured up to 20 MUm in length and 260 nm in width, those still condensed measured up to 1 MUm in width and 16 MUm in length. A distinct banding pattern with a transversal periodicity of approximately 16-18 nm and a periodic longitudinal striation of 3 4 nm could be measured along the trichocyst filaments. At higher magnifications, a fragile, alveolated, net-like organisation became obvious which resembled the one shown for the trichocysts of ciliates. When trichocyst-enriched fractions were treated with sodium dodecyl sulfate and centrifuged subsequently, no trichocysts were registered any longer in the sodium dodecyl sulfate-insoluble fraction by electron microscopy. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of trichocyst-enriched fractions and of the SDS-soluble fractions revealed a protein banding pattern which was dominated by polypeptides of 50-30, 12.5, and approximately 8.5 kDa. The polypeptide banding pattern deviated significantly from those registered for ejectisomes of cryptophytes and of the prasinophyte Pyramimonas grossii, for the Reb polypeptides which constitute the R bodies of Caedibacter taeniospiralis, and also from the banding pattern of trichocysts of Paramecium. An antiserum directed against trichocysts of Paramecium did not cross-react with the polypeptides present in the trichocyst enriched fraction of Prorocentrum micans. PMID- 25030518 TI - Deinococcus phoenicis sp. nov., an extreme ionizing-radiation-resistant bacterium isolated from the Phoenix Lander assembly facility. AB - A bacterial strain, designated 1P10ME(T), which was resistant to extreme doses of ionizing radiation, pale-pink, non-motile, and a tetrad-forming coccoid was isolated from a cleanroom at the Kennedy Space Center, where the Phoenix spacecraft was assembled. Strain 1P10ME(T) showed optimum growth at 30 degrees C, with a pH range for growth of 6.5-9.0 and was highly sensitive to sodium chloride, growing only in medium with no added NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 1P10ME(T) represents a novel member of the genus Deinococcus, with low sequence similarities (<93.5%) to recognized species of the genus Deinococcus. The predominant cellular fatty acid was C15:1omega6c. This novel strain exhibits extreme resistance to gamma radiation (D10 >8 kGy) and UV (D10 >1000 Jm(-2)). The results of our polyphasic taxonomic analyses suggest that strain 1P10ME(T) represents a novel species of the genus Deinococcus, for which the name Deinococcus phoenicis sp. nov. is proposed. The type strain is 1P10ME(T) ( = NRRL B-59546(T) = DSM 27173(T)). PMID- 25030519 TI - Streptomyces zagrosensis sp. nov., isolated from soil. AB - The taxonomic position of a novel actinomycete isolated from soil in Fars Province (Iran) was determined using a polyphasic approach. Phenotypic characterization and 16S rRNA gene sequence analysis of the isolate matched those described for members of the genus Streptomyces. On ISP2 medium, strain HM 1154(T) produced a dark cream, branched substrate mycelium and Retinaculiaperti aerial hyphae that in some images also appeared spiral and that developed into greyish-white spore chains with a smooth surface. The isolate showed optimal growth at 28 degrees C and pH 6-9 with 0-4% (w/v) NaCl. Whole-cell hydrolysates contained ll-diaminopimelic acid as diagnostic diamino acid, ribose and glucose. The main phospholipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, three unknown phospholipids and an unknown aminophospholipid; MK-9(H4) and MK-9(H2) were the predominant menaquinones. The major cellular fatty acids were the branched saturated iso-C16:0 and anteiso C15:0. Strain HM 1154(T) exhibited the highest 16S rRNA gene sequence similarities to Streptomyces coerulescens DSM 40146(T) (99.4%), Streptomyces varsoviensis DSM 40346(T) (99.3%), Streptomyces youssoufiensis DSM 41920(T) (99.2%), Streptomyces abikoensis DSM 40831(T) (99.2%), Streptomyces rimosus subsp. rimosus DSM 40260(T) (99.1%), Streptomyces luteireticuli DSM 40509(T) (99.1%), Streptomyces thioluteus DSM 40027(T) (99.1%), Streptomyces blastmyceticus DSM 40029(T) (99.0%) and Streptomyces hiroshimensis DSM 40037(T) (99.0%). DNA-DNA hybridization studies showed relatedness values of 11.0-35.8% with the closest related species. Based on these results, strain HM 1154(T) is considered to represent a novel species within the genus Streptomyces, for which the name Streptomyces zagrosensis sp. nov. is proposed. The type strain is HM 1154(T) ( = DSM 42018(T) = UTMC 1154(T) = CECT 8305(T)). PMID- 25030520 TI - A survey of violence against staff working in the emergency department in ankara, Turkey. AB - PURPOSE: Workplace violence in the emergency department is a significant problem world wide. The aims of this study were to identify the proportion of staff subjected to the types of violence, its sources, factors affecting violence experiences, reporting the incidence and the emotions of the victims after violence. METHODS: This descriptive study was conducted between March and August 2009 in the the emergency department of six hospitals in Ankara, Turkey. Data were collected from 270 staff working in various emergency settings. The instrument was a 36-item questionnaire on types of violence, its sources, feelings, and ways to cope with violent behaviors. Descriptive statistics and chi square tests were used for data analysis. RESULTS: The results showed 85.2% of participants had been subjected to at least one kind of violence: 41.1% to physical assault, 79.6% to verbal abuse, 55.5% to verbal threats and 15.9% to sexual harassment. Patients' companions (90.9%) were identified as the primary perpetrators of violence. The rates of violence types were highest towards security officers and housekeepers. The most common reactions to violence were sadness and anger. "Did nothing and keeping silent" was the coping method used most commonly by the staff. Participants exposed to physical assaults and verbal threat did not report the incidence of violence to managers were at 43.3% and 65.3% respectively. CONCLUSION: Based on results of the study, it is suggested that every hospital institute reliable reporting procedures that staff members feel comfortable using, and also provide a comprehensive program of support services for staff that has been assaulted. PMID- 25030521 TI - Relationship Between Health-related Behavioral and Psychological Factors and Cardiovascular and Cerebrovascular Diseases Comorbidity Among Korean Adults With Diabetes. AB - PURPOSE: This study aims to explore the relationships between health-related behavioral and psychological factors and cardiovascular and cerebrovascular diseases (CCVD) comorbidities among Korean adults with diabetes mellitus (DM). METHODS: Data included in the Fourth Korean National Health and Nutrition Examination Survey were used. This study compared three groups: those diagnosed with DM only, DM and hypertension, DM, hypertension and CCVD using multinomial logistic regression analyses and the classification and regression tree (CART) model. RESULTS: Weight control (OR = 4.01) and depression (OR = 2.37) are related with increased odds of having hypertension and CCVD comorbidity in those with DM. The CART model suggested that the high prevalence risk groups for hypertension or CCVD comorbidities were diabetic adults aged between 51 and 69 with a body mass index of 25 and above and those aged 70 and above. CONCLUSION: For effective control of CCVD comorbidities among diabetic Korean adults, psychological support for depression and weight control need to be prioritized when managing DM. Weight control intervention needs to be reinforced for DM patients aged between 51 and 69 and that even if BMI is below 25, the occurrence of comorbidities needs to be carefully monitored for DM patients aged 70 or older. PMID- 25030522 TI - Predictive validity of the postpartum depression predictors inventory-revised. AB - PURPOSE: This study aimed to investigate the predictive validity of three versions of the Postpartum Depression Predictors Inventory-Revised (PDPI-R) in Korea. METHODS: A descriptive cross-sectional design with a self-administered questionnaire, including 43 items of the PDPI-R, using the Edinburgh Postpartum Depression Scale as the gold standard was used. Data were collected from 316 women within 6 weeks after childbirth in Busan, Korea, from August to November 2010. RESULTS: The postpartum depression and postpartum depressive symptom (PDS) rate was 22.5%. The area under the curve of the receiver operating characteristic curve was .882 for the prenatal version of the PDPI-R and .927 for the full version. The sensitivity and specificity were 87.3% and 85.1%, respectively, at a cutoff point of 9.5 for the full version, and 91.5% and 66.1%, respectively, at a cutoff point of 5.5 for the prenatal version. The Hosmer-Lemeshow goodness-of-fit statistics was 3.554 (p=.829) for the prenatal version and 8.305 (p=.404) for the full version; this showed a good degree of correspondence between the estimated and observed probabilities of PDS. By age, education, and socioeconomic groups, the discrimination and calibration were generally good for both the prenatal and full versions. CONCLUSION: The PDPI-R showed good predictive validity among women in Korea. It is recommended that the prenatal version of the PDPI-R be used to predict PDS for pregnant women and the full version of the PDPI-R be used for women during the postpartum period. PMID- 25030523 TI - Construct equivalence and latent means analysis of health behaviors between male and female middle school students. AB - PURPOSE: The purpose of this study was to investigate the construct equivalence of the five general factors (subjective health, eating habits, physical activities, sedentary lifestyle, and sleeping behaviors) and to compare the latent means between male and female middle school students in Incheon, Korea. METHODS: The 2008 Korean Youth Risk Behavior Survey data was used for analysis. Multigroup confirmatory factor analysis was performed to test whether the scale has configural, metric, and scalar invariance across gender. RESULTS: Configural invariance, metric invariance, and factor invariance were satisfied for latent means analysis (LMA) between genders. Male and female students were significantly different in LMA of all factors. Male students reported better subjective health, consumed more fast food and carbonated drinks, participated in more physical activities, showed less sedentary behavior, and enjoyed better quality of sleep than female students. CONCLUSION: Health providers should consider gender differences when they develop and deliver health promotion programs aimed at adolescents. PMID- 25030524 TI - Hypoglycemia Fear and Self-efficacy of Turkish Patients Receiving Insulin Therapy. AB - PURPOSE: The purpose of this study was to determine hypoglycemia fear and self efficacy levels of patients receiving insulin and the factors affecting these levels. METHOD: In total, 345 diabetic patients who met the inclusion criteria participated in this descriptive, correlational study. Patients were invited to participate in the study during their regular visits to the diabetes outpatient clinic of Istanbul University, Istanbul Medicine Faculty. Data were collected using a patient-information form as well as the Hypoglycemia Fear Survey and Confidence in Diabetes Self-care Scale. RESULTS: It was found that patients who had type 1 diabetes, received intensive insulin therapy and experienced more frequent and severe hypoglycemia had more hypoglycemia worry and fear. It was also determined that patients who had type 1 diabetes and received intensive insulin therapy had higher self-efficacy levels than patients who had type 2 diabetes and received conventional therapy. CONCLUSION: The effects of experiences of frequent and severe hypoglycemia in patients with diabetes emphasize the need for programs that support diabetes-specific self-efficacy and also guide and teach hypoglycemia prevention. PMID- 25030525 TI - The Quality of Life in Patients With Behcet's Disease. AB - PURPOSE: This study aims to evaluate the quality of life (QoL) in patients with Behcet's disease. METHODS: This study is a cross-sectional descriptive study. The sample of the study consists of 94 volunteer patients, who were diagnosed with Behcet's disease at least 3 months before the study, were literate, and never diagnosed with a psychiatric illness. Short Form-36 QoL Scale and personal information form were used to collect data. The mean, percentage distribution of the sample were calculated; one-way analysis of variance, student t test, Mann Whitney U, Kruskal Wallis, Shapiro-Wilk tests were used to evaluate the data. RESULTS: It was found that QoL scores in patients with Behcet's disease were low and wasaffected by gender, age, work status, education status as well as complaints of oral and genital ulcerations, arthritis, skin lesions and bodily pain. Patients who were suffering from bodily pain, sleeplessness and fatigue were found to score lower in the QoL scale. Moreover, patients who states that their social relationships are affected by the disease had significantly lower QoL scores. CONCLUSION: The need for evaluating the patients holistically and of the planning of their care were highlighted. PMID- 25030526 TI - A cross-sectional study describing factors associated with utilisation of GP services by a cohort of people who inject drugs. AB - BACKGROUND: People who inject drugs (PWID) use healthcare services, including primary care, at a disproportionately high rate. We investigated key correlates of general practitioner (GP) related service utilisation within a cohort of PWID. METHODS: Using baseline data from a cohort of 645 community-recruited PWID based in Melbourne, Victoria, we conducted a secondary analysis of associations between past month use of GP services unrelated to opioid substitution therapy (OST) and socio-demographic and drug use characteristics and self-reported health using multivariate logistic regression. RESULTS: Just under one-third (29%) of PWID had accessed GP services in the month prior to being surveyed. Participants who reported living with children (adjusted odds ratio, AOR 1.97, 95% CI 1.04 - 3.73) or having had contact with a social worker in the past month (AOR 1.92, 95% CI 1.24 - 2.98) were more likely to have seen a GP in the past month. Participants who were injecting daily or more frequently (AOR 0.50, 95% CI 0.30 - 0.83) or had a weekly income of less than $400 (AOR 0.59, 95% CI 0.38 - 0.91) were less likely to report having seen a GP in the past month. CONCLUSIONS: Our sample frequently attended GP services for health needs unrelated to OST. Findings highlight both the characteristics of PWID accessing GP services and also those potentially missing out on primary care and preventive services. PMID- 25030527 TI - Climatic effects on mosquito abundance in Mediterranean wetlands. AB - BACKGROUND: The impact of climate change on vector-borne diseases is highly controversial. One of the principal points of debate is whether or not climate influences mosquito abundance, a key factor in disease transmission. METHODS: To test this hypothesis, we analysed ten years of data (2003-2012) from biweekly surveys to assess inter-annual and seasonal relationships between the abundance of seven mosquito species known to be pathogen vectors (West Nile virus, Usutu virus, dirofilariasis and Plasmodium sp.) and several climatic variables in two wetlands in SW Spain. RESULTS: Within-season abundance patterns were related to climatic variables (i.e. temperature, rainfall, tide heights, relative humidity and photoperiod) that varied according to the mosquito species in question. Rainfall during winter months was positively related to Culex pipiens and Ochlerotatus detritus annual abundances. Annual maximum temperatures were non linearly related to annual Cx. pipiens abundance, while annual mean temperatures were positively related to annual Ochlerotatus caspius abundance. Finally, we modelled shifts in mosquito abundances using the A2 and B2 temperature and rainfall climate change scenarios for the period 2011-2100. While Oc. caspius, an important anthropophilic species, may increase in abundance, no changes are expected for Cx. pipiens or the salt-marsh mosquito Oc. detritus. CONCLUSIONS: Our results highlight that the effects of climate are species-specific, place specific and non-linear and that linear approaches will therefore overestimate the effect of climate change on mosquito abundances at high temperatures. Climate warming does not necessarily lead to an increase in mosquito abundance in natural Mediterranean wetlands and will affect, above all, species such as Oc. caspius whose numbers are not closely linked to rainfall and are influenced, rather, by local tidal patterns and temperatures. The final impact of changes in vector abundance on disease frequency will depend on the direct and indirect effects of climate and other parameters related to pathogen amplification and spillover on humans and other vertebrates. PMID- 25030529 TI - Engineering chiral porous metal-organic frameworks for enantioselective adsorption and separation. AB - The separation of racemic molecules is of substantial significance not only for basic science but also for technical applications, such as fine chemicals and drug development. Here we report two isostructural chiral metal-organic frameworks decorated with chiral dihydroxy or -methoxy auxiliares from enantiopure tetracarboxylate-bridging ligands of 1,1'-biphenol and a manganese carboxylate chain. The framework bearing dihydroxy groups functions as a solid state host capable of adsorbing and separating mixtures of a range of chiral aromatic and aliphatic amines, with high enantioselectivity. The host material can be readily recycled and reused without any apparent loss of performance. The utility of the present adsorption separation is demonstrated in the large-scale resolution of racemic 1-phenylethylamine. Control experiments and molecular simulations suggest that the chiral recognition and separation are attributed to the different orientations and specific binding energies of the enantiomers in the microenvironment of the framework. PMID- 25030528 TI - Association between genetic polymorphisms of cytochrome P450 2C19 and the risk of cerebral ischemic stroke in Chinese. AB - BACKGROUND: Cytochrome P450 (CYP) 2C19 is a very important drug metabolizing enzyme. Although the single nucleotide polymorphisms (SNPs) of CYP2C19 G681A and G636A have been suggested that they may increase the incidence of cardiovascular events, the relationship between SNPs in CYP2C19 and cerebral ischemic stroke (CIS) are unclear. The aim of this study was to investigate the correlation between the distribution of G681A and G636A polymorphisms in CYP2C19 gene and the risk of CIS in Chinese. METHODS: The peripheral blood DNA was extracted from 299 patients with CIS and 295 healthy controls. The genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism. The sampled sequencing was applied to verify the correctness of genotyping results. Both the genotype and allele distributions were compared in patients with CIS and healthy controls. RESULTS: The frequencies of CYP2C19 681AA (11.7% vs. 2.7%; P = 0.000), 636AA (4.0% vs. 0.7%; P = 0.007), 636AG (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (30.9% vs. 20.8%; P = 0.000) and 636A (13.0% vs. 5.8%; P = 0.000) allele in the CIS group are significantly higher than those in the controls. The frequencies of CYP2C19 681AA (16.7% vs. 8.6%; P = 0.036), CYP2C19 636AA (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (36.4% vs. 27.6%; P = 0.023) and CYP2C19 636A (17.5% vs.10.3%; P = 0.010) allele in the recurrent stroke group are significantly higher than those in the first onset group. Multivariate logistic regression analysis of risk factors for cerebral ischemic stroke and recurrent stroke respectively suggests that the CYP2C19 681AA genotype may be an independent risk factor for CIS (OR = 6.179, 95% CI: 2.285 ~ 16.708; P = 0.000) and recurrent stroke (OR = 2.305, 95% CI: 1.121 ~ 4.743; P = 0.023). CONCLUSIONS: The AA genotype and A allele of CYP2C19 G681A may be related to the occurrence and recurrence of cerebral ischemic stroke. PMID- 25030530 TI - The addition of whey protein to a carbohydrate-electrolyte drink does not influence post-exercise rehydration. AB - The addition of whey protein to a carbohydrate-electrolyte drink has been shown to enhance post-exercise rehydration when a volume below that recommended for full fluid balance restoration is provided. We investigated if this held true when volumes sufficient to restore fluid balance were consumed and if differences might be explained by changes in plasma albumin content. Sixteen participants lost ~1.9% of their pre-exercise body mass by cycling in the heat and rehydrated with 150% of body mass lost with either a 60 g . L(-1) carbohydrate drink (CHO) or a 60 g . L(-1) carbohydrate, 20 g . L(-1) whey protein isolate drink (CHO-P). Urine and blood samples were collected pre-exercise, post-exercise, post rehydration and every hour for 4 h post-rehydration. There was no difference between trials for total urine production (CHO 1057 +/- 319 mL; CHO-P 970 +/- 334 mL; P = 0.209), drink retention (CHO 51 +/- 12%; CHO-P 55 +/- 15%; P = 0.195) or net fluid balance (CHO -393 +/- 272 mL; CHO-P -307 +/- 331 mL; P = 0.284). Plasma albumin content relative to pre-exercise was increased from 2 to 4 h during CHO-P only. These results demonstrate that the addition of whey protein isolate to a carbohydrate-electrolyte drink neither enhances nor inhibits rehydration. Therefore, where post-exercise protein ingestion might benefit recovery, this can be consumed without effecting rehydration. PMID- 25030531 TI - Solving the nanostructure problem: exemplified on metallic alloy nanoparticles. AB - With current technology moving rapidly toward smaller scales nanometer-size materials, hereafter called nanometer-size particles (NPs), are being produced in increasing numbers and explored for various useful applications ranging from photonics and catalysis to detoxification of wastewater and cancer therapy. Nature also is a prolific producer of useful NPs. Evidence can be found in ores on the ocean floor, minerals and soils on land and in the human body that, when water is excluded, is mostly made of proteins that are 6-10 nm in size and globular in shape. Precise knowledge of the 3D atomic-scale structure, that is how atoms are arranged in space, is a crucial prerequisite for understanding and so gaining more control over the properties of any material, including NPs. In the case of bulk materials such knowledge is fairly easy to obtain by Bragg diffraction experiments. Determining the 3D atomic-scale structure of NPs is, however, still problematic spelling trouble for science and technology at the nanoscale. Here we explore this so-called "nanostructure problem" from a practical point of view arguing that it can be solved when its technical, that is the inapplicability of Bragg diffraction to NPs, and fundamental, that is the incompatibility of traditional crystallography with NPs, aspects are both addressed properly. As evidence we present a successful and broadly applicable, 6 step approach to determining the 3D atomic-scale structure of NPs based on a suitable combination of a few experimental and computational techniques. This approach is exemplified on 5 nm sized Pd(x)Ni(100-x) particles (x = 26, 56 and 88) explored for catalytic applications. Furthermore, we show how once an NP atomic structure is determined precisely, a strategy for improving NP structure dependent properties of particular interest to science and technology can be designed rationally and not subjectively as frequently done now. PMID- 25030532 TI - Measuring Patient Safety in the Emergency Department: The Spanish Experience. PMID- 25030533 TI - Perioperative Surgical Outcomes 100 (PSO 100). PMID- 25030536 TI - President's Remarks. PMID- 25030535 TI - Relation of high-density lipoprotein cholesterol:apolipoprotein a-I ratio to progression of coronary atherosclerosis in statin-treated patients. AB - High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels are inversely associated with adverse cardiovascular outcomes. Associations between these HDL-C-related measurements and coronary plaque progression have not been studied. We performed a retrospective analysis of 2,566 statin-treated patients with angiographic coronary artery disease who underwent serial evaluation of atheroma burden with intravascular ultrasound. Relations between achieved levels of HDL-related measurements with clinical characteristics and changes in plaque burden were determined. A strong correlation between HDL-C and apoA-I (r = 0.80, p <0.001) was observed. HDL-C, apoA-I, and the HDL-C:apoA-I ratio demonstrated negative correlations with the change in percent atheroma volume and total atheroma volume (all p <=0.001). Increasing levels of achieved HDL-C:apoA-I (p = 0.04), but not HDL-C (p = 0.18) or apoA-I (p = 0.67), were associated with less progression of percent atheroma volume. Similar results were seen for change in total atheroma volume, with less progression seen with increased HDL-C:apoA-I (p = 0.002) but not with increases in HDL-C (p = 0.09) or apoA-I (p = 0.19). In conclusion, increasing levels of HDL-C:apoA-I associated with less progression of coronary atherosclerosis. This suggests that interventions increasing the cholesterol content of HDL particles may be of cardiovascular benefit. PMID- 25030537 TI - Make a difference with asian nursing research. PMID- 25030538 TI - Congratulatory note. PMID- 25030539 TI - The past and future of nursing research. AB - The past three decades have witnessed a remarkable growth in nursing science development. In both Korea and the United States, nurse scientists are poised to address important issues related to the prevention and management of significant health care problems. The need for greater nursing science development in the areas of self management, genetics, geriatrics, health promotion across the lifespan, technology, and mental health are briefly highlighted. Future research efforts will be enhanced by interdisciplinary collaboration and the creation of international nursing research centers. At the same time, we need to remain cognizant of the importance of mentoring future nurse scientists. PMID- 25030540 TI - Interpersonal caring: a theory for improved self-esteem in patients with long term serious mental illness - I. AB - This article describes a process of theory development in nursing care. The Interpersonal Caring theory empirically arose from a problematic nursing situation of caring for patients with long-term serious mental illness, to guide practical applications of interpersonal caring behaviors. The authors describe the phases of theory development with patient statements that illustrate how to conceptualize the phenomenon, and present theoretical and statistical analyses that validate the 10 domains of interpersonal caring: noticing, participating, sharing, active listening, companioning, complimenting, comforting, hoping, forgiving, and accepting. PMID- 25030541 TI - A proposed theoretical framework addressing the effects of informal caregivers on health-related outcomes of elderly recipients in home health care. AB - PURPOSE: The purpose of this review is to develop a theoretical framework addressing the effects of informal caregivers on health-related outcomes of elderly recipients in home health care. METHODS: The investigator a) reviewed theories and literature related to informal caregiving and health-related outcomes of elderly recipients, b) critiqued the strengths and limitations of these theories and literature for research in this area, and c) developed a new conceptual framework by deductively applying these theories and literature to the effects of informal caregivers on health-related outcomes of elderly recipients in home health care. RESULTS: Social network theories, social support theories, and the literature on informal caregiving are useful in understanding how informal caregivers affect the outcomes of elderly recipients in home health care. This review synthesizes these theories and literature into a new theoretical framework in order to fully address the effects of informal caregivers on health-related outcomes of elderly recipients in home health care. CONCLUSION: The proposed theoretical framework suggests that health-related outcomes of elderly recipients are the result of interactions among types of informal caregivers, the nature of the caregiving relationship, caregiving as a function of such relationships, and the internal processes of the care recipient. PMID- 25030542 TI - Effects of nutrition education and exercise programs on perceived dietary behaviors, food intake and serum lipid profiles in elderly korean women living in residential homes. AB - PURPOSE: Strong predictors for the risk of cardiovascular disease in older adults include levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, which can be modified by dietary behavioral changes and regular physical exercise. The purpose of this study was to evaluate changes in perceived dietary behaviors, food intake, and serum lipid profiles after providing a nutrition education and exercise program to elderly women living in residential homes. METHODS: The nutrition education classes and supervised Korean dance exercise classes (four times per week) were provided for 10 weeks to 64 elderly women from residential homes in Korea. Subjects were interviewed to assess perceived dietary behaviors, food intake by 24-hour recall, and fasting blood samples were obtained before and after the program and at a 3 month follow-up. RESULTS: Initially, the intakes of vitamin A, vitamin C, riboflavin and calcium of our subjects were insufficient. After the program, the actual food intake and perceived dietary behaviors were significantly improved, but had declined back to baseline levels by the 3-month follow-up. The index of nutritional quality and serum lipid profiles were significantly improved after the program, and they remained significant at the 3-month follow-up. CONCLUSION: The nutrition education and exercise program for institutionalized elderly women was effective in leading to positive changes shortly after the program, but the effects only partially remained at the 3-month follow-up. A health promotion program designed for an elderly population should consider strategies of motivating them to initiate a healthy lifestyle and subsequently maintain improvements in dietary behavior-related health in the long term. PMID- 25030543 TI - Difference in needs for physical activity among healthy women, women with physical limitations and korean immigrant women. AB - PURPOSE: The purpose of this study was to explore the difference in needs for physical activity among healthy women, women with physical limitations, and Korean immigrant women in the U.S., and a significant association between needs for physical activity and other sociodemographic and contextual variables. METHODS: Healthy Korean women (n = 53), women with physical limitations (n = 51), and Korean immigrant women in the U.S. (n = 54) were recruited using a convenience sampling method. The settings included cultural centers in Seoul, S University Hospital in Seoul, Korea, and Korean ethnic churches in California. Data on sociodemographic characteristics and needs for physical activity were collected using questionnaires. Group difference in needs for physical activity and difference in needs for physical activity according to sociodemographic and contextual variables were determined. RESULTS: There were significant differences in 11 needs for physical activity among the three groups (p < .05). The needs for physical activity were significantly different (p < .05) according to the categories of needs; affiliation, accomplishment and autonomy needs among the three groups. The needs for physical activity were significantly different (p < .05) according to sociodemographic and contextual variables. CONCLUSION: Three groups of women had different needs for physical activity, and their needs for physical activity were influenced by multiple factors reflecting their daily lives in immigration transition and health/illness transition. PMID- 25030544 TI - Health behavioral patterns associated with psychologic distress among middle-aged korean women. AB - PURPOSE: Middle aged women are exposed to high levels of psychologic distress due to various factors including health problems of family members, their own declining health, negative outlook towards menopause, loss of significant supportive relationships, and uncertainties regarding the future. The purpose of this study was to identify the factors associated with psychologic distress of middle-aged Korean women in the Seoul metropolitan area. METHODS: The data were collected from 277 community-dwelling women between the ages of 40 and 60 years without any known severe illnesses from May 6, 2004 to May 31, 2004. The researcher or two research assistants visited the participants in person, handed out copies of the questionnaire after receiving study permission, and answered if they had any questions. RESULTS: Hierarchical multiple regression analysis found that women with low scores of health promoting behaviors for self-actualization, nutrition, and interpersonal relation reported high levels of psychologic distress. In addition, women with low scores of marital satisfaction reported high psychologic distress. CONCLUSION: The study found cultural characteristics of middle-aged Korean women in psychologic distress. Health care providers should consider marital satisfaction, self-actualization, nutrition, and interpersonal relations, in particular, among Korean middle-aged women. PMID- 25030545 TI - Thinking in clinical nursing practice: a study of critical care nurses' thinking applying the think-aloud, protocol analysis method. AB - PURPOSE: The purpose of the paper is to discover the patterns and processes of decision-making in clinical nursing practice. METHODS: A set of think-aloud data from five critical care nurses during 40 to 50 minutes of caregiving in intensive care units were obtained and analyzed by applying the procedures recommended by Ericsson and Simon for protocol analysis. RESULTS: Four thinking processes before acting were identified to constitute various sorts of thoughts in which the nurses were engaged during patient care: reviewing, validation, consideration, rationalization, and action. In addition, three patterns of sequential streaming of thinking (short, intermediate, long) were identified to reveal various ways the nurses dealt with clinical situations involving nursing tasks and responsibilities. CONCLUSION: This study specifies the initial categories of thoughts for each of the processes and various patterns with which these processes are sequentially combined, providing insights into the ways nurses think about problems and address their concerns. The findings suggest that the thinking in clinical practice involves more than focused decision-making and reasoning, and needs to be examined from a broader perspective. PMID- 25030546 TI - 4-step 4-h carboplatin desensitization protocol for patients with gynecological malignancies showing platinum hypersensitivity: a retrospective study. AB - BACKGROUND: Platinum agents are essential for treating gynecological malignancies, particularly ovarian cancer. However, multiple carboplatin doses may cause hypersensitivity reactions (HSRs). Carboplatin desensitization prevents life-threatening HSRs and promotes the successful completion of planned chemotherapy. METHODS: Since January 2010, carboplatin desensitization was performed at our institution. Solutions with 1/1000, 1/100, and 1/10 dilutions of carboplatin and an undiluted solution were prepared in 250 mL of 5% glucose. Each solution was administered as a 1-h intravenous infusion (4-step 4-h protocol). This retrospective analysis was approved by the institutional review board. RESULTS: From January 2010 to December 2013, 20 patients with gynecological malignancies (median age 62 years, range 43-74 years) received desensitization treatment. The International Federation of Gynecology and Obstetrics stages at presentation were I, II, III, and IV in 1, 1, 15, 13 patients, respectively. During first-line and second-line treatments, 3 and 17 patients, respectively, experienced carboplatin-induced HSRs. The median carboplatin cycle number was 11 (range 2-16). In the first desensitization cycle, 17 (85%) patients completed treatment without adverse events, 2 experienced Grade 1 HSRs but completed treatment, and 1 experienced Grade 3 HSR and discontinued treatment. The first desensitization cycle completion rate was 95%. Of 83 desensitization cycles administered, 79 (95.2%) were completed. No treatment-related deaths occurred. CONCLUSIONS: Most patients completed the planned chemotherapy. Our protocol could be conducted safely with shorter duration and simpler procedures than previous protocols. Carboplatin desensitization seems beneficial for patients with a history of carboplatin-induced HSRs; however, the risk of HSR recurrence still remains. Desensitization should therefore be performed only by well-trained staff. PMID- 25030547 TI - Evaluation of postoperative chemotherapy in patients with uterine carcinosarcoma: a retrospective survey of the Tohoku Gynecologic Cancer Unit. AB - BACKGROUND: The aim of this study was to evaluate prognostic factors including efficacy of postoperative chemotherapy in Japanese patients with uterine carcinosarcoma. METHODS: We conducted a retrospective survey of seven medical facilities in the Tohoku Gynecologic Cancer Unit. RESULTS: A total of 45 patients who had undergone hysterectomy and bilateral salpingo-oophorectomy were enrolled. No significant difference was observed in overall survival according to patient age (<= 50 years vs >50 years) or retroperitoneal lymphadenectomy (performed vs. not performed). However, the International Federation of Gynecology and Obstetrics stage (stage I/II vs stage III/IV) and postoperative chemotherapy (provided vs not provided) were significant prognostic factors in both univariate and multivariate analyses for the 25-month median follow-up period. CONCLUSIONS: Our results revealed that postoperative chemotherapy should be considered for all uterine carcinosarcoma stages in Japanese patients. PMID- 25030548 TI - Effect of early life stress on pancreatic isolated islets' insulin secretion in young adult male rats subjected to chronic stress. AB - Early stressful experiences may predispose organisms to certain disorders, including those of metabolic defects. This study aimed to explore the effects of early life stress on pancreatic insulin secretion and glucose transporter 2 (GLUT2) protein levels in stressed young adult male rats. Foot shock stress was induced in early life (at 2 weeks of age) and/or in young adulthood (at 8-10 weeks of age) for five consecutive days. Blood samples were taken before and after stress exposure in young adult rats. At the end of the experiment, glucose tolerance, isolated islets' insulin secretion, and pancreatic amounts of GLUT2 protein were measured. Our results show that early life stress has no effect on basal plasma corticosterone levels and adrenal weight, either alone or combined with young adulthood stress, but that early life + young adulthood stress could prevent weight gain, and cause an increase in basal plasma glucose and insulin. The homeostasis model assessment of insulin resistance index did not increase, when the rats were subjected to early life stress alone, but increased when combined with young adulthood stress. Moreover, glucose tolerance was impaired by the combination of early life + young adult stress. There was a decrease in islet's insulin secretion in rats subjected to early life stress in response to 5.6 mM glucose concentration, but an increase with a concentration of 16.7 mM glucose. However, in rats subjected to early life + young adulthood stress, islet's insulin secretion increased in response to both the levels of glucose concentrations. GLUT2 protein levels decreased in response to early life stress and early life + young adulthood stress, but there was a greater decrease in the early life stress group. In conclusion, perhaps early life stress sensitizes the body to stressors later in life, making it more susceptible to metabolic syndrome only when the two are in combination. PMID- 25030549 TI - The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing's disease. AB - Prolactin may reduce false-negative results in diagnosing Cushing's disease (CD) during inferior petrosal sinus sampling (IPSS). Prolactin normalization could improve the accuracy of IPSS in predicting adenoma lateralization in CD. However, none of the previous studies had involved the use of desmopressin during IPSS. Our objective was to examine the utility of prolactin measurement during IPSS with desmopressin stimulation. We conducted a retrospective analysis of 40 patients (including 31 females) with ACTH-dependent Cushing's syndrome who underwent IPSS between 2010 and 2013. Thirty-eight CD patients were partitioned into true positive (n = 35) and false negative (n = 3). The proportion of improper IPSS venous sampling defined by corresponding IPS:P (inferior petrosal sinus to peripheral) prolactin ratio <1.8 was significantly different between two groups (P = 0.004). Applying a prolactin-normalized ACTH IPS:P ratio >0.8 cutoff could increase the sensitivity of IPSS to 38/38 (100 %). Among the 31 patients with histopathologically proven adenoma localization, correct prediction of adenoma lateralization was obtained in 14/31 (45 %) patients by a peak intersinus ACTH gradient of >=1.4 in baseline and was not improved by desmopressin stimulation. Left-right intersinus gradients of unilateral prolactin-adjusted ACTH IPS:P ratios could increase the correct prediction of adenoma lateralization to 20/31 (65 %) in baseline and 24/31 (77 %) (P = 0.006) after desmopressin stimulation, respectively. Prolactin is helpful to adjust negative results of IPSS with desmopressin stimulation. It may improve the accuracy in predicting adenoma lateralization in CD as well. PMID- 25030550 TI - Activity and safety of sunitinib in patients with advanced radioactive iodine refractory differentiated thyroid carcinoma in clinical practice. AB - Our aim was to evaluate the effectiveness of off-label use of sunitinib in patients with advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) therapy. We performed a retrospective analysis of patients treated in the setting of clinical practice in a University General Hospital. Eleven consecutive patients (5 women, 6 men, mean age 63.0 +/- 12.9 year) with advanced papillary (n = 7) or follicular (n = 4) thyroid carcinoma not suitable for curative surgery or RAI therapy were studied. Two patients were treated with one line of tyrosine kinase inhibitors before sunitinib therapy. All patients had evidence of objective progressive disease (PD). We analysed the objective response rate (ORR) and changes in thyroglobulin levels during therapy. Complete response was achieved in 1 patient (9 %) and partial response (PR) in 2 patients (18 %). Five patients (45 %) had stable disease (SD). Therefore, ORR was 27 % and disease control rate was 72 %. We found that the decrement in thyroglobulin concentrations was significantly higher in patients with radiological disease control than in patients with PD. Most frequent grade 1 and 2 adverse events were fatigue, mucositis, hand-and-foot syndrome, hyporexia, rash, hypertension, and edema. In routine clinical practice, sunitinib appears to be effective and feasible in patients with advanced RAI-refractory DTC. Most patients achieved SD or PR, despite having PD at the start of treatment, and safety profile was consistent with that reported in previous clinical trials. PMID- 25030551 TI - Annual bone loss and success rates of dental implants based on radiographic measurements. AB - OBJECTIVES: Bone loss around dental implants is generally measured by monitoring changes in marginal bone level using radiographs. After the first year of implantation, an implant should have <0.2 mm annual loss of marginal bone level to satisfy the criteria of success. However, the process of measuring marginal bone level on radiographs has a precision of 0.2 mm (or more) owing to variations in exposure geometry, exposure time and observer perception. Therefore, the value of the annual loss may vary considerably, especially when short intervals are considered. This study investigates how the success rate of dental implants depends on the way annual bone loss is calculated. METHODS: Panoramic radiographs of 82 implant patients with an average follow-up of 10.4 years were analysed. Marginal bone levels near the implants were indicated by one observer. The annual loss of marginal bone level was determined according to four different calculation methods. RESULTS: The methods yielded success rates of 9%, 45%, 81% and 89%. CONCLUSIONS: The success rate of dental implants measured on radiographs greatly depends on the details of the calculation method. Without rigorous standardization, annual bone loss and implant success rate are not well defined. PMID- 25030552 TI - alpha-Glucosidase and lipoxygenase inhibitory derivatives of cryptosporioptide from the endophytic fungus Cryptosporiopsis sp. AB - Two new cryptosporioptide-derived polyketides cryptosporioptides A (2) and B (3) were isolated from the extract of endophytic fungus Cryptosporiopsis sp. associated with the shrub, Viburnum tinus. The structures of the isolates were determined through spectral analysis including 1D NMR ((1)H, (13)C) and 2D NMR (HSQC, HMBC, COSY) techniques, HR-FAB-MS and by comparison with the reported data of cryptosporioptide (1). The relative stereochemistry was assigned with the help of NOESY analysis, the molecular model, and comparison of the optical rotation values with the reference compound 1. PMID- 25030554 TI - J wave monitoring and drug efficacy in Brugada syndrome. PMID- 25030553 TI - Inactivation of TRPM7 kinase activity does not impair its channel function in mice. AB - Transient receptor potential (TRP) family channels are involved in sensory pathways and respond to various environmental stimuli. Among the members of this family, TRPM7 is a unique fusion of an ion channel and a C-terminus kinase domain that is highly expressed in immune cells. TRPM7 serves as a key molecule governing cellular Mg(2+) homeostasis in mammals since its channel pore is permeable to Mg(2+) ions and can act as a Mg(2+) influx pathway. However, mechanistic links between its kinase activity and channel function have remained uncertain. In this study, we generated kinase inactive knock-in mutant mice by mutagenesis of a key lysine residue involved in Mg(2+)-ATP binding. These mutant mice were normal in development and general locomotor activity. In peritoneal macrophages isolated from adult animals the basal activity of TRPM7 channels prior to cytoplasmic Mg(2+) depletion was significantly potentiated, while maximal current densities measured after Mg(2+) depletion were unchanged in the absence of detectable kinase function. Serum total Ca(2+) and Mg(2+) levels were not significantly altered in kinase-inactive mutant mice. Our findings suggest that abolishing TRPM7 kinase activity does not impair its channel activity and kinase activity is not essential for regulation of mammalian Mg(2+) homeostasis. PMID- 25030555 TI - Association between gene polymorphisms of connective tissue growth factor and the progression of chronic liver disease associated with hepatitis C. AB - OBJECTIVE: Fibrogenic cytokines, such as transforming growth factor-beta 1 play a central role in the progression of liver fibrosis. Recently, functional gene polymorphisms in these cytokines have been identified, and some reports have validated the presence of associations between these polymorphisms and disease progression. Connective tissue growth factor (CTGF) is a stimulating factor for fibroblast proliferation and matrix production. This study aimed to examine the relationship between CTGF gene polymorphisms and the progression of hepatitis C virus (HCV)-related chronic liver disease, as well as the incidence and prognosis of hepatocellular carcinoma (HCC). METHODS: A review was conducted among 235 HCV patients (117 patients with chronic hepatitis (CH) and 118 patients with liver cirrhosis (LC)). The CTGF gene polymorphism (rs6918698; -945 G/C) was identified according to the chimeric cycling probe method. The rate of liver fibrosis progression was measured using two liver fibrosis prediction formulas, the Forns index and the FibroIndex. All HCC patients were followed regularly every month. RESULTS: The frequency of the -945 C allele was higher among the LC patients than the CH patients. Regarding the rate of liver fibrosis progression over five years, C homozygotes tended to exhibit a faster rate than G carriers, although the difference was not significant. Among the LC patients, the C homozygotes demonstrated lower prothrombin times, higher rates of indocyanine green retention and higher Child-Pugh scores than the G carriers. There were no significant tendencies in the genotype distribution, irrespective of the status of HCC. However, the prognosis of HCC was poorer for the C homozygotes than for the G carriers. CONCLUSION: A CTGF -945 C homozygote status is a significant risk factor for the progression of HCV-related chronic liver disease, including HCC. PMID- 25030556 TI - Branched-chain amino acid granules improve the non-protein respiratory quotient after radiofrequency ablation. AB - OBJECTIVE: The supplementation of oral branched-chain amino acid (BCAA) granules is known to improve energy metabolism in cirrhotic patients, but not those with hepatocellular carcinoma (HCC). We aimed to clarify whether BCAA granules improve energy metabolism in HCC patients after radiofrequency ablation (RFA). METHODS: We performed a prospective cohort study (UMIN000004624) involving 40 HCC patients who underwent RFA at Kobe University Hospital. Indirect calorimetry and urinary/blood biochemical examinations were performed before and seven days after RFA. Blood biochemical examinations were also conducted three months after RFA. The patients treated with and without BCAA supplementation were compared, and univariate factors were statistically examined. RESULTS: The non-protein respiratory quotient (npRQ) and albumin levels before RFA were significantly lower in the BCAA group than in the control group (p=0.024 and 0.005). The npRQ ratio (seven days after/before RFA) was significantly higher in the BCAA group than in the control group (p=0.019). In addition, the albumin ratio (three months after/before RFA) was significantly higher in the BCAA group than in the control group (p=0.018). CONCLUSION: Supplementation with BCAA granules improves energy metabolism in addition to the liver function after RFA. Improvements in the liver function may result in consistently adequate treatment for HCC recurrence after RFA. PMID- 25030557 TI - Relationship between aortic stiffness and the left ventricular function in patients with prediabetes. AB - OBJECTIVE: Several studies have shown that arterial stiffness and ventricular dysfunction are increased in individuals with type 2 diabetes. Aortic stiffness (AS) reflects the mechanical tension and elasticity of the aorta, and increased aortic stiffness is a risk factor for cardiovascular disease. The aim of this study was to evaluate the degree of aortic stiffness and its relationship with the left ventricular (LV) function in patients with prediabetes and healthy control subjects. METHODS: The study groups were composed of 50 patients with prediabetes and 47 healthy adults with similar demographic characteristics. The LV systolic and diastolic functions were assessed using standard two dimensional (2D) echocardiography, M-mode echocardiography, pulsed-wave (PW) echocardiography and tissue Doppler echocardiography. The degree of aortic strain and distensibility were calculated based on the aortic diameters measured on M-mode echocardiography at a level 3 cm above the aortic valve and the blood pressure values obtained on sphygmomanometry. RESULTS: There were significant differences between the prediabetic and control groups in the degree of aortic strain (4.7 +/ 2.8% vs. 14.9 +/- 4.5%; respectively, p<0.001) and distensibility (2.0 +/- 1.5 vs. 6.8 +/- 2.3; 10(-3) cm(2) dyn(-1), respectively, p<0.001). In addition, significant differences were observed between the patient and control groups in the parameters of the LV systolic and diastolic functions. The left atrial diameter was significantly larger in the prediabetics than in the controls (35.9 +/- 3.9 vs. 33.7 +/- 4.2; respectively, p=0.027). CONCLUSION: AS is increased in patients with prediabetes. In addition, there is a significant relationship between the degree of aortic stiffness and the LV function in this patient population. Therefore, the aortic elasticity parameters calculated on 2D echocardiography are useful for predicting early cardiovascular risks in prediabetics. PMID- 25030558 TI - Clinical manifestation of hypercalcemia caused by adrenal insufficiency in hemodialysis patients: a case-series study. AB - OBJECTIVE: The goal of this study was to clarify the clinical manifestation of hypercalcemia due to hypoadrenalism in hemodialysis (HD) patients. METHODS: We retrospectively analyzed the clinical characteristics of five HD patients who had presented with hypercalcemia due to adrenal insufficiency (age: 69 +/- 7 [58-75] years old, time on HD: 13 +/- 11 [2-32] years). We conducted corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) stimulation tests. We also examined serum bone turnover markers before and after glucocorticoid replacement. RESULTS: All patients had critical illnesses at the onset of hypercalcemia. They had at least one symptom, such as eosinophilia, hypoglycemia, or fever. The prevalence of hypercalcemia due to adrenal insufficiency was 1.3% in maintenance HD patients on admission. The causes of adrenal insufficiency were isolated ACTH deficiency, pituitary apoplexy, pituitary atrophy, glucocorticoid withdrawal syndrome, and unilateral adrenalectomy. Serum calcium (Ca) levels corrected by serum albumin were maximally increased to 12.9 to 14.3 mg/dL in four anuric HD patients and mildly elevated to 10.4 mg/dL in a patient with residual diuresis. Their basal serum cortisol levels ranged from <1.0 to 15.4 MUg/dL. Single CRH injections failed to increase serum cortisol in any of the patients. Glucocorticoid replacement acutely normalized serum Ca and decreased levels of carboxy-terminal telopeptide of type I collagen, a marker of bone resorption. CONCLUSION: Adrenal insufficiency could therefore be an occult cause of hypercalcemia in anuric HD patients who are critically ill. PMID- 25030559 TI - Status of diabetes treatment in Japanese adults: an analysis of the 2009 Japan Society of Ningen Dock database. AB - OBJECTIVE: The Japan Diabetes Society (JDS) has recommended target levels of glycemic control based on guidelines for the management of diabetes mellitus (DM). The Japan Society of Ningen Dock created a database of subjects receiving annual health examinations nationwide. Using this database, we evaluated the efficacy of current treatment for patients with DM based on the JDS recommendations. METHODS: This multicenter, retrospective study was conducted using data obtained from 21 institutions across Japan. In order to assess the level of glycemic control in the Japanese population, we analyzed previously obtained measurements of HbA1c in 7,180 patients 20 to 79 years of age (mean age: 57.9 +/- 8.7 years, 6,007 men and 1,173 women) taking DM medications. RESULTS: According to the JDS guidelines, 44.7% of the patients fell into the good glycemic control group, with an HbA1c level of <7.0% while 22.4% were classified into the poor glycemic control group, with an HbA1c level of >= 8.0%. The control of other arteriosclerosis risk factors deteriorated as the glycemic control deteriorated. Lifestyle factors were strongly found to be associated with glycemic control in the patients receiving DM treatment. CONCLUSION: Aggressive lifestyle modification is needed to improve glycemic control in patients with DM. PMID- 25030560 TI - Clinical utility of procalcitonin as a marker of sepsis: a potential predictor of causative pathogens. AB - OBJECTIVE: Sepsis is one of the leading causes of mortality in critically ill patients, and providing a timely diagnosis and early intervention is necessary for successful treatment. Procalcitonin (PCT) may be a better marker of sepsis than conventional inflammatory markers. The aim of this study was to evaluate the clinical utility of the PCT level as a marker of sepsis. METHODS: Forty-five patients with sepsis, 24 patients with pneumonia who did not meet the SIRS criteria (PN) and 56 controls were enrolled in this study. The levels of PCT and other serum markers were measured, and their utility as markers of sepsis was assessed. RESULTS: The serum PCT levels exhibited statistically significant differences between the three groups (p<0.0001). The PCT levels in the sepsis group (29.3 +/- 85.3 ng/mL) were significantly higher (p<0.001) than those observed in the PN group (0.34 +/- 8.6 ng/mL) and the control group (0.74 +/- 2.1 ng/mL), according to a post hoc analysis. There were no differences in the white blood cell (WBC) counts or C-reactive protein (CRP) levels between the three groups. Fourteen of the 45 patients with sepsis had positive microbiological blood cultures (Gram-positive cocci [GPC] in seven patients, Gram-negative rods [GNR] in six patients, other types of bacteria in one patient). The 13 patients with GNR or GPC were categorized into the GNR group or GPC group according to the identified pathogens. The serum PCT levels were significantly higher in the GNR group (149.8 +/- 199.7 ng/mL) than in the GPC group (19.1 +/- 41.8 ng/mL) (p<0.05), although there were no differences in the WBC counts or CRP levels between these groups. When the cut-off value for the PCT level was set at 16.9 ng/mL, the sensitivity and specificity for the detection of GNR infection were 85.7% and 83.3%, respectively. CONCLUSION: The PCT level is a potentially useful marker of the type of causative pathogen in patients with sepsis whose measurement may facilitate the selection of appropriate empiric antibiotic treatment. PMID- 25030561 TI - Supportive management resolved a colonic intramural hematoma in an anticoagulant user. AB - Intramural hematomas of the colon are rare. Intramural hematomas of the gastrointestinal tract often result from blunt trauma, although they may also occur spontaneously in patients taking anticoagulants or those with blood dyscrasia. Affected patients present with abdominal pain and lower gastrointestinal bleeding, as well as occasional signs of intestinal obstruction. The diagnosis is made using colonoscopy and abdominal CT. Resection of the involved bowel segment is accepted as the standard therapy; however, experience with conservative treatment has also been reported. We herein report the case of a 62-year-old woman taking warfarin who was diagnosed with a colonic intramural hematoma and completely recovered with conservative management. PMID- 25030562 TI - Acute appendicitis with intestinal malrotation: the usefulness of coronal computed tomography. AB - We herein present a rare case of acute appendicitis with intestinal malrotation. Coronal images of contrast-enhanced computed tomography (CT) revealed the small intestine on the right side and the large intestine on the left side, thus indicating intestinal malrotation (non-rotation type). In addition, an enhanced, tubular, fluid-filled structure was detected attached to the cecum, which was located superior to the urinary bladder, suggesting acute appendicitis. The present study shows that coronal CT images provide important information for the diagnosis and treatment of acute appendicitis in patients with intestinal malrotation. PMID- 25030563 TI - Recombinant tissue-type plasminogen activator (rt-PA) therapy in an acute stroke patient taking dabigatran etexilate: a case report and literature review. AB - Whether recombinant tissue-type plasminogen activator (rt-PA) therapy can be administered in acute stroke patients treated with dabigatran remains controversial. We administered rt-PA (0.6 mg/kg) in an acute stroke patient treated with dabigatran (110 mg bid) whose activated partial thromboplastin time (APTT) was 37.1 seconds 113 minutes after onset, 10 hours after the last dose of dabigatran. His symptoms improved from the National Institute of Health Stroke Scale score of 10 to 1 after treatment without hemorrhagic complications. The administration of rt-PA therapy is feasible in acute stroke patients on dabigatran when taking into account the APTT and time from the last dose. PMID- 25030564 TI - Successful ablation of atrioventricular nodal reentrant tachycardia in a patient with coexistent congenitally corrected transposition of the great vessels and situs inversus. AB - Congenitally corrected transposition of the great vessels (CTGV) is a rare congenital cardiac and great vessel abnormality. The anomalous inversion of the ventricles and great vessels makes performing catheter ablation difficult. We herein report a successful case of atrioventricular node reentrant tachycardia ablation in a patient with coexistent CTGV and situs inversus. PMID- 25030565 TI - Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy? AB - We herein describe two patients with Brugada syndrome in whom J-waves were successfully modified by drugs. Case 1 was a 54-year-old man who presented with repeated ventricular fibrillations (VF) and J-point elevation in the right precordial and lateral leads. After administration of cilostazol (200 mg/d), J waves disappeared and coved-type ST-segment elevation changed to a saddleback type for 25 months. Case 2 was a 31-year-old man who presented with a VF storm and J-point elevation in the lateral leads. After administration of quinidine (300 mg/d), J-waves and coved-type ST-segment elevation disappeared for 20 months. J-wave disappearance and coved-type ST-segment elevation were followed by VF suppression, probably due to transient outward potassium current (Ito) suppression. PMID- 25030566 TI - Two-dimensional speckle tracking imaging as a novel strategy for accurately identifying the accessory pathway. AB - A 14-year-old patient was diagnosed with hypertrophic cardiomyopathy associated with Wolff-Parkinson-White syndrome. The two-dimensional speckle tracking strain method showed normal left ventricular local contraction, but the peak systolic longitudinal strain of the right ventricular (RV) anterior wall was earlier than that of the septal wall. As expected, the location of the accessory pathway was at the RV anterior wall. The patient's RV local contraction was normalized by successful radiofrequency application. PMID- 25030567 TI - Therapeutic dose of acetaminophen as a possible risk factor for acute kidney injury: learning from two healthy young adult cases. AB - Acetaminophen overdose can lead to severe liver and kidney failure; however, the risk of therapeutic doses in healthy individuals causing acute kidney injury (AKI) is less clear. We herein describe the cases of two young adults with renal biopsy-proven acute tubular necrosis under a therapeutic dose of acetaminophen. The first patient exhibited mild reversible renal insufficiency, whereas, in the second case, the patient demonstrated a slightly increased serum creatinine level and enlarged kidneys and the administration of contrast media and antibiotics may have worsened the renal dysfunction, leading to the need for temporal hemodialysis. Physicians should be aware of the risk of acetaminophen causing AKI and avoid administering other nephrotoxic agents in such cases. PMID- 25030568 TI - Benign myoepithelioma in the intrathoracic trachea. AB - A 67-year-old woman who was followed as a patient with bronchial asthma for 1.5 years visited our hospital with progressive dyspnea. Although the chest radiography findings were normal, a chest computed tomography scan revealed a mass obliterating the intrathoracic tracheal lumen. The patient's symptoms disappeared immediately after tumor excision, and no recurrence was observed during a 1.5-year follow-up period. Microscopically, the tumor was composed of densely packed polygonal-, oval- and spindle-shaped cells that were positive for pan-cytokeratin, alpha-smooth muscle actin and p63. These pathological findings confirmed the diagnosis of benign myoepithelioma. Chest physicians should recognize that benign myoepithelioma can develop in the trachea, although it is very rare. PMID- 25030569 TI - Amyopathic dermatomyositis complicated with eosinophilic pneumonia. AB - A 67-year-old woman was admitted to our hospital due to dyspnea on exertion with lung abnormal shadows. A transbronchial lung biopsy specimen demonstrated eosinophilic pneumonia (EP). The patient also exhibited heliotrope eyelids without muscle weakness, which led to a diagnosis of amyopathic dermatomyositis (ADM). As we were unable to find any other causes of EP, we diagnosed her as having EP associated with ADM. Dermatomyositis (DM) has been reported to be associated with various interstitial lung diseases; however, only one case of EP associated with DM has been reported. We herein report the first case of EP complicated with ADM. PMID- 25030570 TI - IgG4-related pleuritis with chylothorax. AB - Presently, 6 cases of IgG4-related pleuritis have been reported. We encountered a patient who developed chylothorax due to IgG4-related disease. To our knowledge, such patients have not been reported. This patient developed right-sided chylothorax and left-sided non-chylothorax lymphocyte-predominant pleuritis. Elevated serum and pleural IgG4 concentrations and histopathological analysis of pleural biopsy confirmed the diagnosis of IgG4-related pleuritis. Left-sided pleuritis improved with corticosteroid therapy, but right-sided chylothorax persists. IgG4-related disease can be one cause of chylothorax. PMID- 25030571 TI - Pleural solitary fibrous tumor complicated with autoimmune hemolytic anemia. AB - We herein report a 74-year-old woman who presented with autoimmune hemolytic anemia (AIHA) associated with pleural solitary fibrous tumor (SFT). Her AIHA was initially treated with 1 mg/kg daily of oral prednisolone (PSL) for 2 months, which had a limited effect. However, after surgical tumor resection, the patient showed remarkable improvement of AIHA with normalizations of serum lactate dehydrogenase and bilirubin levels, and we were able to rapidly reduce the PSL dosage. This is the first description of a case of AIHA caused by SFT. PMID- 25030572 TI - Right hand predominant constructional apraxia due to right hemisphere infarction without corpus callosum lesions. AB - A 74-year-old right-handed woman without cognitive impairment suddenly developed nonfluent aphasia. Brain MRI showed acute infarction in the right frontal lobe and insula without involvement of the corpus callosum. A neurological examination demonstrated not only transcortical motor aphasia, but also ideomotor apraxia and right hand predominant constructional apraxia (CA). To date, right hand predominant CA has only been reported in patients with corpus callosum lesions. The right hand predominant CA observed in our patient may be associated with the failure to transfer information on the spatial structure from the right hemisphere to the motor cortex of the left hemisphere. PMID- 25030573 TI - Recurrent unilateral headache associated with SAPHO syndrome. AB - A 57-year-old woman was admitted with recurrent episodes of right frontal headache. Head magnetic resonance imaging (MRI) revealed extensive thickening and enhancement of the right frontal dura, muscle and fascia, as well as abnormal signal intensity and enhancement of bone marrow at the lesions. Synovitis-acne pustulosis-hyperostosis osteomyelitis (SAPHO) syndrome was diagnosed based on the patient's 8-year history of treatment of palmoplantar pustulosis and abnormal accumulations in the right temporal, sternum, and left medial clavicula on bone scintigraphy. SAPHO syndrome may be associated with skull lesions, which can contribute to the onset of repeated headache or dural thickening, thus these symptoms should be recognized as manifestations of this syndrome. PMID- 25030575 TI - Occam's Razor or Hickam's dictum: a paraneoplastic or coincidental occurrence of lung cancer and Guillain-Barre syndrome. AB - A 67-year-old man was admitted due to weakness, coughing, shortness of breath and fever. He had decreased breath sounds in the left lung and muscle weakness in the lower and upper extremities. Chest imaging showed a mass in the left lung, and a biopsy revealed small cell lung cancer. The nerve conduction velocity was decreased, and anti-GM1 IgG antibodies were positive. The patient showed a temporary neurologic recovery following the administration of cancer chemotherapy, although he eventually died of progression of lung cancer. As a result of the almost simultaneous symptomatic development of lung cancer and Guillain-Barre syndrome, this case may be considered to involve a paraneoplastic neurologic syndrome. PMID- 25030574 TI - Partial deficiency of emerin caused by a splice site mutation in EMD. AB - Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the EMD gene on the X chromosome, which codes for emerin, an inner nuclear membrane protein. Monoclonal antibodies against the N-terminus of emerin protein are used to screen for emerin deficiency in clinical practice. However, these tests may not accurately reflect the disease in some cases. We herein describe the identification of a splice site mutation in the EMD gene in a Japanese patient who suffered from complete atrioventricular conduction block, mild muscle weakness and joint contracture, and a persistently elevated serum creatine kinase level. We used multiple antibodies to confirm the presence of a novel truncating mutation in emerin without the transmembrane region and C-terminus in the skeletal muscle. PMID- 25030576 TI - Fatal pulmonary co-infection with pneumocystis and cytomegalovirus in a patient with acquired immunodeficiency syndrome. AB - A 33-year-old homosexual Japanese man who admitted to having sex with men presented with a two-week history of dyspnea and fever. Chest imaging showed diffuse pulmonary frosted-glass-like shadows. A blood test revealed positive HIV antibodies with a CD4 cell count of 66/MUL. Bronchoalveolar lavage identified pneumocystis. Although the patient exhibited a transient response to anti pneumocystis treatment and mega-dose steroid pulse therapy, he eventually died from respiratory failure. An autopsy suggested massive cytomegalovirus and pneumocystis pneumonitis. The pulmonary co-infection with cytomegalovirus may have been worsened by the use of mega-dose steroids, and such therapy should be avoided in patients with a high HIV viral load and low CD4 count. PMID- 25030577 TI - Hepatocellular carcinoma-induced hemobilia. PMID- 25030578 TI - Acute respiratory distress syndrome in diabetic ketoacidosis. PMID- 25030579 TI - Spontaneous multiple tendon rupture in a hemodialysis patient. PMID- 25030580 TI - Hemophagocytic syndrome with febrile neutropenia after chemotherapy. PMID- 25030581 TI - Gallium-67 scintigraphy findings in a patient with early Takayasu's arteritis. PMID- 25030582 TI - Benign pneumatosis intestinalis. PMID- 25030583 TI - Polyarteritis nodosa mimicking giant cell (temporal) arteritis. PMID- 25030584 TI - [New strategies in the proteomic research on tumor stem cells]. PMID- 25030585 TI - [Effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma]. AB - OBJECTIVE: The study intended to investigate the effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma. METHODS: RT-PCR and Western blot were used to test the expression of mTOR and Beclin1 mRNA and protein in ovarian cancer SKOV3 cells after saquinavir induction. MTT assay was used to analyze the influence of saquinavir on cisplatin sensitivity in SKOV3 cells. RESULTS: The IC50 of SKOV3 cells was (5.490 +/- 1.148) ug/ml. After induced by Saquinavair 10 umol/L and 20 umol/L, the IC50 of SKOV3 cells was increased to (11.199 +/- 0.984) ug/ml and (14.906 +/- 2.015) ug/ml, respectively. It suggested that the sensitivity of ovarian cancer cells to cisplatin was decreased significantly (P = 0.001). The expression of mTOR and Beclin1 mRNA and protein was significantly different among the five groups: the (Saquinavair+DDP) group of, Saquinavair group, LY294002 group, DDP group and control group (P < 0.001) . The expressions of mTOR and Beclin1 mRNA were highest in the (Saquinavair+DDP) group, 0.684 +/- 0.072 and 0.647 +/- 0.047, respectively; Secondly, the Saquinavair group, 0.577 +/- 0.016 and 0.565 +/- 0.037, respectively. The expressions of mTOR and Beclin1 proteins were also highest in the (Saquinavair+DDP) group, 0.624 +/- 0.058 and 0.924 +/- 0.033, respectively, followed by the Saquinavair group, 0.544 +/- 0.019 and 0.712 +/- 0.024. 3-MA inhibited the autophagy and restored cisplatin sensitivity in the SKOV3 cells after Saquinavir induced ER stress (P < 0.001). CONCLUSIONS: Saquinavir can effectively induce endoplasmic reticulum stress in SKOV3 cells. Endoplasmic reticulum stress can decrease the sensitivity to cisplatin in SKOV3 cells. The mechanism of the decrease of sensitivity to cisplatin in SKOV3 cells may be that ERS regulates cell autophagy through the mTOR and Beclin1 pathways. ERS of tumor cells and autophagy may become a new target to improve the therapeutic effect of chemotherapy and to reverse the drug resistance in tumor treatment. PMID- 25030586 TI - [Gene-targeted radiation therapy mediated by radiation-sensitive promoter in lung adenocarcinoma and the feasibility of micro-PET/CT in evaluation of therapeutic effectiveness in small animals]. AB - OBJECTIVE: To explore the combined anti-tumor effect of radiation therapy and gene-targeted suppression of tumor neovasculature in lung adenocarcinoma in vivo, and to explore the feasibility of micro-PET/CT in dynamic evaluation of treatment effectiveness. METHODS: Thirty 5-6-week old male BALB/c nude mice were used in this study. The mouse models of xenotransplanted human lung adenocarcinoma were divided into 5 groups at random, six mice in each group: the control group, radiation treatment alone group and three groups of recombinant baculovirus plus radiation treatment (intratumoral injection, tail vein injection, and intramuscular injection). The tumor volume was measured every 2 days. Growth delay time (GD) and growth inhibition rate was calculated. FDG metabolism was evaluated by micro-PET-CT before and after treatment. The expressions of VEGF, CD31 and Ki-67 were detected by immunohistochemistry (IHC). RESULTS: The tumor growth delay was >12 days, and the tumor inhibition rate was >45% in the recombinant baculovirus combined with radiotherapy groups, significantly higher than that of the radiotherapy alone group (P < 0.05). Immunohistochemical analysis showed that the expressions of VEGF, CD31 and Ki-67 were significantly lower than that in other groups (P < 0.05). The micro-PET-CT assessment showed that the FDG-metabolism in the recombinant baculovirus combined with radiotherapy groups was significantly reduced (P < 0.05), and the SUVmax (FDG metabolism) of transplanted tumors after treatment was also markedly decreased in comparison with that of the control group. The tumor volume after treatment was significantly correlated with SUVmax in the recombinant baculovirus intratumoral injection + radiotherapy group(r = 0.976), recombinant baculovirus intravenous injection + radiotherapy group (r = 0.954), recombinant baculovirus intramuscular injection + radiotherapy group (r = 0.929), and radiotherapy alone group (r = 0.871, P < 0.05). CONCLUSIONS: The recombinant baculovirus containing Egr1 promoter and K5 gene combined with radiotherapy enhances the suppressing effect on the growth of lung adenocarcinoma in the tumor-bearing nude mice. The inducibility of Egr1 promoter by radiation allows the targeting and controllability of treatment. Micro-PET-CT results have a good correlation with the treatment effectiveness. Therefore, it can be used in real-time evaluation of tumor metabolic function in vivo. PMID- 25030587 TI - [Mechanism of SPARC-enhanced chemosensitivity of pancreatic cancer cells to gemcitabine]. AB - OBJECTIVE: The aim of this study was to explore the effect of SPARC on the anti cancer effect of gemcitabine and underlying mechanism in pancreatic cancer. METHODS: After treating with gemcitabine, the proliferation rate of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells was detected by MTT assay. The cell cycle distribution and cell apoptosis in each group were examined by flow cytometry, and the capability of clone formation was tested by adhesion-dependent clone formation assay. The apoptosis-related proteins were analyzed by Western blot. RESULTS: The growth of pancreatic cancer cells was inhibited by gemcitabine in a time-dependent and dose-dependent manner. Its IC50 at 24, 48, and 72-h was (40.1 +/- 2.5) umol/L, (15.0 +/- 0.5) umol/L and (6.6 +/- 0.1) umol/L, respectively. The overexpression of SPARC increased the inhibitory effect of gemcitabine on growth of pancreatic cancer MIA PaCa2/SPARC69 cells, presenting a dose- and time- dependent manner. Its IC50 at 24, 48, 72 h was (24.3 +/- 1.5) umol/L, (7.7 +/- 0.3) umol/L and (4.8 +/- 0.2) umol/L, respectively. The clone formation assay showed that before gemcitabine treatment, the clone numbers of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were (2350 +/- 125), (2130 +/- 120) and (1567 +/- 11), respectively. After gemcitabine treatment, the clone numbers of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were ( 1674 +/- 79) , (1587 +/- 94) and (557 +/- 61), respectively. The overexpression of SPARC enhanced the chemosensitivity of MIA PaCa2 cells to gemcitabine chemotherapy. After treating with 10 umol/L gemcitabine for 48 h, the ratio of G0/G1 cells in MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were (56.0 +/- 5.5)%, (55.0 +/- 4.5)% and (68.0 +/- 7.0)%, respectively. The cells arrested at G0/G1 phase were significantly increased in the MIA PaCa2/SPARC69 cells. The apoptosis rates of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were (22.4 +/- 2.5)%, (19.9 +/ 2.0)% and (37.7 +/- 3.9)%, respectively, indicating that overexpression of SPARC enhanced the gemcitabine-induced apoptosis in MIA PaCa2 cells. The Western blot analysis showed that, compared with MIA PaCa2 and MIA PaCa2/V cells, the expression of caspase-2, -8, -9 and cleaved PARP protein was significantly increased, while the expression of Bcl-2 was not changed significantly in the MIA PaCa2/SPARC69 cells. CONCLUSION: SPARC can enhance the chemosensitivity of pancreatic cancer cells to gemcitabine via regulating the expression of apoptosis related proteins. PMID- 25030588 TI - [Relationship between promoter methylation of Syk and Runx3 genes and postoperative recurrence and metastasis in gastric carcinoma]. AB - OBJECTIVE: To investigate the relationship between aberrant methylation of Syk and Runx3 genes and recurrence and metastasis after resection of gastric cancer. METHODS: Applying methylation-specific polymerase chain reaction technique, promoter methylation of Syk and Runx3 genes in the tumor tissues and adjacent normal tissues of gastric cancer patients were detected to investigate the relationship between methylation status of the promoter region of Syk and Runx3 genes and postoperative recurrence and metastasis. RESULTS: In the 70 cases of gastric cancer, the frequencies of promoter methylation of Syk and Runx3 genes were 45.7% (32/70) and 55.7% (39/70) in gastric cancer, and 0 (0/70) and 7.1% (5/70), respectively, in the adjacent normal tissues. The rates of promoter methylation of Syk and Runx3 genes in the gastric cancers were significantly higher than that in the adjacent normal tissues (P < 0.001 for all). The promoter methylation of Syk and Runx3 genes was significantly correlated with the degree of tumor differentiation, depth of invasion, lymph node metastasis and pathological staging (P < 0.05 for all). The frequency of postoperative recurrence and metastasis in 32 patients with Syk promoter methylation was 65.6% (21/32) and that in 38 cases with Syk promoter unmethylation was 18.4% (7/38), showing a significant difference between the two subgroups (chi(2) = 16.13, P < 0.001). The rate of postoperative recurrence and metastasis in 39 patients with Runx3 promoter methylation was 61.5% (24/39) and that in 31 patients with Runx3 promoter unmethylation was 12.9% (4/31, P < 0.001). CONCLUSIONS: The methylation of Syk and Runx3 promoters plays an important role in postoperative recurrence and metastasis of gastric cancer. Combined detection of promoter methylation of Syk and Runx3 genes is helpful for early diagnosis and evaluation of prognosis of gastric cancer. PMID- 25030589 TI - [Detection and significance of epidermal growth factor receptor mutation in esophageal, esophagogastric junction and gastric cancers]. AB - OBJECTIVE: Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have been reported to be effective in the treatment of esophageal and esophagogastric junction cancers. The aim of this study was to detect the frequency of EGFR mutation and expression in Chinese patients with esophageal, esophagogastric junction and gastric cancers, and to clarify the value of EGFR mutation and expression in predicting the efficacy of TKI in the treatment of these tumors. METHODS: In this study, 180 tumor samples with histologically confirmed esophageal cancer (39 cases), cancer of the esophagogastric junction (92 cases) and gastric cancer (49 cases) were collected. Twenty-nine different EGFR mutations in exons 18-21 were assessed by real-time PCR-optimized oligonucleotide probe method. EGFR protein expression was evaluated by immunohistochemistry (IHC) in 89 tumor samples. RESULTS: The mutation analysis for EGFR (exons 18-21) showed no mutations in any of the hotspots of the gene in the 180 tumor samples analyzed. EGFR expression was negative in 12 tumor samples, 1+ in 31 tumor samples, 2+ in 24 tumor samples, and 3+ in 22 tumor samples. EGFR expression was 2+ or 3+ in 12 (92.3%) of the 13 esophageal squamous cell carcinomas, 29 (47.5%) of the 61 esophagogastric junction cancers, and 5 (33.3%) of the 15 gastric adenocarcinomas. CONCLUSIONS: Our results indicate that EGFR mutation in exons 18-21 is absent in the examined samples of esophageal, esophagogastric junction and gastric cancers. More studies are warranted to explore the predictive biological markers for the therapeutic response to EGFR TKI. PMID- 25030590 TI - [Expression and clinical significance of plasma small RNA in patients with pancreatic cancer]. AB - OBJECTIVE: The aim of this study was to identify six miRNAs expressed in plasma of patients with pancreatic cancer (PCa) and analyze their value as a diagnostic index of pancreatic cancer. METHODS: Plasma total RNAs were extracted from 30 PCa patients and 26 normal controls, and the abundance of six microRNAs was measured using real-time PCR. The possibility to combine them with CA19-9 as diagnostic biomarkers was analyzed. RESULTS: The expression level of miR-21, miR-210, miR 155, miR-20a, miR-25 and miR-196a in plasma of patients with pancreatic cancer were 1.65*10(6), 5.98*10(4), 2.83*10(3), 3.47*10(6), 2.76*10(6), and 1.03*10(3) (copies/ul), while the normal controls were 4.08*10(5), 2.54*10(4), 8.55*10(2), 1.79*10(6), 9.32*10(5), and 4.67*10(2) (copies/ul), respectively, with a significant difference between the two groups (P < 0.05). The areas under the ROC curve of miR-21, miR-210, miR-155, miR-20a, miR-25 and miR-196a were 0.893, 0.810, 0.820, 0.766, 0.816 and 0.729, respectively. MiR-21 had the highest diagnostic value when it was used as diagnostic marker alone. The combination of miR-155 and miR-25 was more effective to distinguish PCa from normal than to be used alone, and the area under the ROC curve was 0.913 (95%CI 0.838-0.988) .When CA199 associated with miR -210 and miR-25, respectively, the areas under the ROC curves were 0.96 (95%CI was 0-1.0) and 0.942 (95% CI was 0.876-1.0), which were higher than CA199 alone (0.862, 95%CI was 0.748-0.975). There was a high improvement in diagnostic sensitivity and accuracy when miR-210 and miR-25 were combined with CA19-9, respectively. CONCLUSIONS: Plasma miR-21, miR-155, miR-25, miR-210 have diagnostic value for pancreatic cancer, and deserve further study. PMID- 25030591 TI - [Comparative analysis of the correlation between HRCT image features and histopathologic characteristics of cyst-like lung adenocarcinoma]. AB - OBJECTIVE: To evaluate the high resolution CT (HRCT) features of cyst-like lung adenocarcinoma, explore the correlation between HRCT image features and histopathological characteristics, and observe the pathological basis of air containing space. METHODS: HRCT and histopathologic findings of cyst-like lung adenocarcinoma in 86 patients were investigated retrospectively. The image features of both tumor and air-containing space were analyzed. All surgically resected specimens were reviewed. The pathological analysis included histologic subtype, differentiation degree, and the pathological basis of air-containing space formation. The correlation between HRCT image features and histopathologic grades was analyzed. RESULTS: On HRCT, intratumoral necrosis was detected in 17 cases (19.8%), air-containing space with septa in 40 cases (46.5%), wall nodule in the air-containing space in 16 cases (18.6%), mixed thick and thin walls of air-containing space in 49 cases (57.0%). Air-containing space and its wall were observed in 63 cases on histological specimens, among which destruction of the alveolar wall by tumor cells might be the pathological basis of air-containing space in 42 (66.7%) cases. Differences of tumor attenuation (P = 0.030), intratumoral necrosis (P = 0.003) and proportion of thin-wall in air-containing space (P = 0.014) among different histopathologic grades were significant. The proportion of thin-wall in air-containing space was negatively correlated with histological grade (r = 0.267, P = 0.015). Differences of tumor contour (P = 0.002), tumor attenuation (P = 0.006), intratumoral necrosis (P < 0.001), septa in air-containing space (P = 0.016) and proportion of thin-wall in the air containing space (P = 0.005) among different differentiation degrees were significant. The proportion of thin-wall in air-containing space was positively correlated with differentiation degree (r = 0.266, P = 0.013). CONCLUSIONS: On HRCT, cyst-like lung adenocarcinoma may manifest as an air-containing space with septa and mixed thin and thick walls, whereas wall nodule of air-containing space and intratumoral necrosis are not common. There is a certain correlation of HRCT manifestation with pathological subtype grading and tumor differentiation. Analysis of HRCT image features is helpful in prediction of the histopathologic grading and histological differentiation degree of the tumors. Destruction of the alveolar structure by tumor cells may be the main pathological basis of air containing space formation in cyst-liked lung adenocarcinoma. PMID- 25030592 TI - [OLC1 protein levels in plasma of patients with non-small cell lung cancer and its clinical application]. AB - OBJECTIVE: The aim of this study was to detect the plasma concentration of OLC1 (overexpressed in lung cancer 1) protein as a potential cancer biomarker, and evaluating its clinical application value in the diagnosis of non-small cell lung cancer (NSCLC). METHODS: We prepared OLC1 antibody with OLC1 full length protein, in 5-6-week old Bal B/c mice. Each mouse was immunized four times at a dose of 15 30 ug antigen protein, and the interval between two consecutive immunizations was two weeks. Antibody screening was made by ELISA and Western blot, and a double antibody sandwich ELISA kit was developed. We used this established ELISA kit to detect the plasma concentration of OLC1 protein in 281 NSCLC patients and 92 gender- and age-matched healthy controls. Area under the receiver operating characteristic curve (AUC) was used to evaluate the detection efficacy of OLC1. RESULTS: We obtained 11 OLC1 monoclonal antibodies and successfully established the ELISA kit to detect the plasma concentration of OLC1 with a detection range from 1.95 ng/ml to 62.50 ng/ml. OLC1 concentration in the case group (124.69 ng/ml) was significantly higher than that in the control group (67.07 ng/ml, P < 0.001). In the scenario of distinguishing NSCLC from control group, AUC result was 0.69. When the cut-off was set at 67.72 ng/ml, the sensitivity and specificity was 84.4% and 51.1%, respectively. In term of distinguishing early lung cancer (IA) from normal controls, the AUC, sensitivity and specificity were 0.68, 77.8% and 54.4%, respectively. CONCLUSION: The plasma concentration of OLC1 protein is significantly elevated in NSCLC patients. OLC1 may be as a potential cancer biomarker applied in clinical diagnosis. PMID- 25030593 TI - [Treatment patterns and affecting factors in breast cancer patients over 65-years of age]. AB - OBJECTIVE: To explore different therapies and affecting factors in breast cancer patients >= 65 years old. METHODS: To retrospectively analyze the clinical characteristics, treatments, comorbidity and survival rate of 126 female breast cancer patients over 65 years old who underwent surgical operation in our hospital from January 2009 to December 2010. To compare and analyze the differences in the treatment patterns, and find out the affecting factors. RESULTS: One hundred and twenty-six cases were included in this retrospective study, and they were divided into two groups according to age: 65-74 years old group (71 cases) and >74 years group (55 cases). Most patients in the two groups received modified radical mastectomy (84.5% and 89.1%); 73.2% and 54.5% of patients received adjuvant chemotherapy in the two groups, respectively. 67.6% and 61.8% of the patients had adjuvant endocrine therapy respectively. 19.7% and 7.3% of the patients received radiotherapy, respectively. Chemotherapy in elderly breast cancer patients was correlated with age, pathological types, progesterone receptor (PR) status and comorbidity. Radiotherapy in elderly breast cancer patients was related to age, surgical patterns, TNM stage and lymph node status. Multivariate analysis showed that age, pathological types, PR expression and comorbidity were independent factors affecting choice of chemotherapy in elderly breast cancer patients (P < 0.05 for all). Age and surgical patterns were independent factors affecting choice of radiotherapy (P < 0.05 for all). The 3 year disease-free survival (DFS) rate and overall survival (OS) rate in these patients were 91.3% and 92.0%, respectively. Furthermore, endocrine therapy was related to 3-year DFS rate (P = 0.038) and age was correlated with 3-year OS rate (P = 0.037) in these elderly patients. CONCLUSIONS: Breast cancer in the elderly patients receive similar surgery and endocrine therapy, but the elderly patients are less likely to have chemotherapy and radiotherapy, due to age, PR expression, pathological types, surgical patterns and comorbidity. Only age contributes to the lower 3-year overall survival rate in >74-year old patients. PMID- 25030594 TI - [Efficacy and safety of trastuzumab plus different chemotherapy regimens in treatment of the patients with HER-2-positive advanced breast cancer]. AB - OBJECTIVE: To evaluate the efficacy and safety of trastuzumab plus different chemotherapy regimens in treatment of patients with HER-2-positive advanced breast cancer. METHODS: 132 patients with advanced HER-2-positive breast cancer were treated with trastuzumab plus different regimens. The clinical characteristics, efficacy and toxicity of the 132 patients were retrospectively analyzed. RESULTS: Five patients had complete response (CR), 61 patients had partial response (PR), 39 patients had stable disease (SD), and 27 patients had progressive disease (PD). The objective response rate was 50.0% and the disease control rate was 79.5%. The median progression-free survival was 9.3 months. The median overall survival time was 46.2 months. The 1-, 2-, 5- year survival rates were 98.3%, 81.9% and 40.2%, respectively. Trastuzumab combined with chemotherapy is superior to trastuzumab monotherapy (51.2% vs. 33.3%). The number of metastatic sites, efficacy, different previous treatment lines were independent prognostic factors of PFS (P = 0.002, P < 0.0001 and P < 0.0001, respectively). Visceral metastases, pathological grade, and PFS were independent prognostic factors of OS (P = 0.041, P = 0.001, P = 0.025, P < 0.001, P < 0.0001 and P < 0.0001, respectively). Regarding the toxicities, one case discontinued treatment due to the decrease of left ventricular ejection fraction to 47%, two cases had heartbeat tachycardia, 6 cases had palpitation, 17 cases had a fever during first input trastuzumab. No other serious cardiac toxicity was observed. The most common toxicities were chemotherapy-related hematological and non-hematological toxicities. CONCLUSIONS: Trastuzumab combined with chemotherapy is superior to trastuzumab monotherapy. Patients may get benefits for early use of trastuzumab. Trastuzumab plus chemotherapy is effective and well tolerated in patients with advanced HER-2 positive breast cancer. No heart failure occurred in this series of patients, and cardiac safety seems better than that in Caucasians because of younger age at the onset in Chinese advanced breast cancer patients. PMID- 25030595 TI - [Value of (18)F-FDG PET in preoperative TACE of hepatocellular carcinoma]. AB - OBJECTIVE: To evaluate the prognostic significance of (18)F-FDG PET-CT SUVmax value in 85 patients with hepatocellular carcinoma (HCC) before transarterial chemoembolization (TACE). METHODS: A retrospective analysis was conducted on 85 patients with HCC before TACE to evaluate the prognostic significance of SUVmax of (18)F-FDG PET-CT. The survival rates were calculated using Kaplan-Meier method. Log-rank method was used for univariate analysis, and Cox regression model was used for multivariate analysis. RESULTS: The patients were divided into two groups before TACE: The high metabolic group (63 patients, with SUVmax value 7.71 +/- 2.78) and low metabolic group (22 patients, with SUVmax value 3.89 +/- 0.80). The SUVmax levels were statistically different (P < 0.001). The 1-, 2- and 3-year survival rates of the 63 patients of high metabolic group were 66.6%, 26.9% and 12.6%, respectively. The 1-, 2- and 3-year survival rates of the 22 patients of low metabolic group were 81.8%, 72.7% and 63.6%, respectively. The median survival time of the high metabolic group was 16.0 months and that of the low metabolic group was 48.0 months (P = 0.001). Univariate analysis indicated that SUVmax value of the intrahepatic primary tumor, hepatic cirrhosis, Child Pugh score, ECOG score, intrahepatic tumor size, number of tumors(solitary or multiple), portal vein tumor thrombus, BCLC stage, and serum AFP level were significantly correlated with prognosis of the patients (P < 0.05 for all). Multivariate analysis indicated that SUVmax value, tumor size >8 cm, number of tumors (solitary or multiple) and AFP level were independent prognostic factors (P < 0.05 for all). CONCLUSION: The SUVmax value of the primary intrahepatic tumor can be used as an important prognostic factor to predict the effect of TACE in patients with hepatocellular carcinoma. PMID- 25030596 TI - [Lymph node metastasis and prognostic analysis of 354 cases of T1 breast cancer]. AB - OBJECTIVE: To analyze the characteristics of lymph node metastasis and prognosis in patients with T1 breast cancer. METHODS: The clinicopathological data of 354 patients with T1 breast cancer after standard treatment from March 2007 to September 2011 were collected to analyze the relationship between the clinical characteristics of T1 breast cancer, lymph node metastasis and prognostic features. RESULTS: In the 354 patients with T1 breast cancer, 105 patients (29.7%) had lymph node metastasis, among them 73 cases (69.5%) had 1-3 lymph node metastasis, and 32 cases (30.5%) had more than 4 lymph node metastasis. The lymph node metastasis rate was 8.3% in T1a patients, 39.7% in T1b patients, and 30.4% in T1c cases (P = 0.005). Pairwise comparison showed that the difference of lymph node metastasis rate between T1a, T1b and T1c patients was statistically significant (P = 0.001 and P = 0.006, respectively). The difference of lymph node metastasis rates in T1b and T1c patients was statistically insignificant (P = 0.171). In the 354 patients of T1 breast cancer, 92 patients had vascular tumor thrombi and their lymph node metastasis rate was 71.7%, while the lymph node metastasis rate in 262 patients without vascular tumor thrombus was 14.9% (P < 0.001). The median follow-up was 49 months (range 27-81 months). 12 patients developed recurrence, and 3 patients died, one of them died of cerebrovascular accident. The 4-year disease-free survival for all patients was 96.6%, and the 4 year overall survival rate was 99.2%. CONCLUSIONS: There is a correlation between vascular tumor thrombus, tumor size and lymph node metastasis rate. The lymph node metastasis rate is lower in T1a patients and relatively higher in T1b/c patients. Compared with patients without vascular tumor thrombus, the T1 breast cancer patients with vascular tumor thrombi have a higher lymph node metastasis rate. Generally speaking, there is a still good prognosis in patients with T1 breast cancer. PMID- 25030597 TI - [Clinical analysis of 11 cases of thymic squamous cell carcinoma]. PMID- 25030598 TI - [Feasibility analysis of endostatin combined with chemotherapy in the treatment of metastatic angiosarcoma]. PMID- 25030599 TI - [Evaluation of screening performance of HPV DNA test on specimens from different sites of the female genital tract]. AB - OBJECTIVE: To evaluate the diagnostic performance of different specimens for detecting CIN2(+), and to find the solution of the problem that why the performance of self-collected specimen is worse than cervical specimen collected by physician. METHODS: The cervix, lower 1/3 vagina, upper 1/3 vagina and self collected specimens from each of the 806 women who took part in this multi-center screening program from May 2006 to April 2007 were tested by hybrid capture 2 (HC2) technique. The diagnostic performance of HC2 on the four specimens for detecting CIN2(+) lesions was calculated. Linear array was performed on the four specimens from 489 out of the 806 women and the diagnostic performance of linear array on the four specimens for detecting CIN2(+) lesions was also calculated. Z test was used to compare the area under ROC and McNemar or chi(2) test was used to compare the sensitivity and specificity of different specimens. RESULTS: The area under ROC of the cervix, 1/3 upper vagina, 1/3 lower vagina and self collected samples testing by HC2 for detecting CIN2(+) lesions were 0.902, 0.793, 0.769 and 0.773, respectively (P < 0.001). Using 1 RUL/CO as the cut-point of HC2, the sensitivity of the cervix, upper vagina, lower vagina and self-collected samples were 98.0%, 91.8%, 83.7% and 81.6%. Compared with the cervical specimen, the sensitivity of self-collected specimen for detecting CIN2(+) lesions was significantly lower (P = 0.008). Lowering the cutoff value for HC2 test could improve the sensitivity of self-collected specimen, but it significantly compromised the specificity. The sensitivity of self-collected specimen tested by linear array for detecting CIN2(+) lesions was 95.7% and it was not significantly different compared with the sensitivity of cervical specimen (97.9%) tested by HC2. CONCLUSIONS: The performance of self-collected specimen tested by HC2 for detecting CIN2(+) lesions is lower than that of physician-collected cervical specimen, and lowering the cutoff value can't improve its diagnostic performance. Using linear array as the HPV DNA test can significantly improve the screening diagnostic performance of self-collected specimens. PMID- 25030600 TI - [Understanding of and thoughts on surgical treatment of breast cancer]. PMID- 25030601 TI - Strong influence of dietary intake and physical activity on body fatness in elderly Japanese men: age-associated loss of polygenic resistance against obesity. AB - Genome-wide association studies identified single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) in middle-aged populations; however, it is unclear whether these SNPs are associated with body fatness in elderly people. We examined the association between genetic risk score (GRS) from BMI-associated SNPs and body fatness in elderly Japanese men. We also examined the contribution of GRS, dietary macronutrient intake, and physical activity to body fatness by different age groups. GRS was calculated from 10 BMI-associated SNPs in 84 middle aged (30-64 years) and 97 elderly (65-79 years) Japanese men; subjects were divided into low, middle, and high GRS groups. Dietary macronutrient intake was assessed using a questionnaire, and physical activity was evaluated using both a questionnaire and an accelerometer. The middle-aged individuals with a high GRS had greater BMI; waist circumference; and total abdominal fat, visceral fat, and subcutaneous fat areas than the middle-aged individuals with low GRS, whereas the indicators were not different between the GRS groups in elderly individuals. Multiple linear regression analysis showed that GRS was the strongest predictor of BMI, total abdominal fat, and visceral fat in the middle-aged group, whereas fat, alcohol, and protein intakes or vigorous-intensity physical activity were more strongly associated with these indicators than was GRS in the elderly group. These results suggest that GRS from BMI-associated SNPs is not predictive of body fatness in elderly Japanese men. The stronger contribution of dietary macronutrient intake and physical activity to body fatness may attenuate the genetic predisposition in elderly men. PMID- 25030602 TI - Visible, safe and certain endotracheal intubation using endoscope system and inhalation anesthesia for rats. AB - Anesthesia strongly influences laboratory animals, and it can also greatly affect the experimental data. Rats rank only second to mice in the number used in research fields, such as organ transplantation, regenerative medicine and imaging. Therefore, appropriate and effective anesthesia, including the protocol of the endotracheal intubation and inhalation anesthesia, is crucial. Hence, we evaluated these methods in this study. Twelve Wistar rats were intraperitoneally injected with M/M/B: 0.3/4/5, comprising of medetomidine, midazolam and butorphanol at a dose of 0.3 mg/kg + 4.0 mg/kg + 5.0 mg/kg body weight/rat, respectively. An endotracheal tube was then intubated into the trachea. After intubation, the rats were connected to the inhalation anesthesia circuit using isoflurane, and vital signs were measured until 30 min after connection. All intubations were successfully finished within 1 min, and the values of the vital signs were normal and stable. In addition, histopathological observation of the trachea and lungs showed no trauma. These results suggest that this visible endotracheal intubation method is simple, reliable, safe and favorable with regard to the rats' welfare. PMID- 25030603 TI - Molecular genetic diversity of the Gyeongju Donggyeong dog in Korea. AB - The present study was conducted to analyze the genetic characteristics of the Donggyeong dog and establish parentage conservation systems for it by using 10 microsatellite markers recommended by the International Society for Animal Genetics (ISAG). A total of 369 dogs from 12 dog breeds including the Donggyeong dog were genotyped using 10 microsatellite loci. The number of alleles per locus varied from 5 to 10 with a mean value of 7.6 in the Donggyeong dog. The observed heterozygosity and expected heterozygosity ranged from 0.4706 to 0.9020 (mean 0.7657) and from 0.4303 to 0.8394 (mean 0.7266), respectively. The total exclusion probability of 10 microsatellite loci was 0.99955. Of the 10 microsatellite markers, the AHT121, AHTh260 and CXX279 markers had relatively high PIC values (>=0.7). This study found that there were specific alleles, 116 allele at AHT121 in the Donggyeong dog when compared with other dog breeds. Also, the results showed two (Korean native dogs and the foreign dog breeds) distinct clusters. The closest distance (0.1184) was observed between the Donggyeong dog and Jindo dog, and the longest distance (0.3435) was observed between the Donggyeong dog and Bulgae. The Korean native dog breeds have comparatively near genetic distances between each other. PMID- 25030604 TI - Synergetic effect of dual cocatalysts in photocatalytic H2 production on Pd IrOx/TiO2: a new insight into dual cocatalyst location. AB - Introducing appropriate dual cocatalysts is one of the most efficient strategies to improve the photocatalytic activity. Herein, we investigated the promotion effect of dual cocatalysts on TiO2 for hydrogen production. Compared with the Pd/TiO2 and Ir/TiO2 with the individual cocatalyst, TiO2 coloaded with Pd and Ir species exhibited an obviously enhanced H2 production activity and reduced CO/H2 ratio. XPS and IR spectra of CO adsorption analysis indicated that the dual cocatalysts on TiO2 were actually composed of Pd(0) and partially oxidized IrOx, which acted as the reduction and oxidation cocatalysts, respectively. Interestingly, EDX elemental mappings of Pd and Ir indicated that the two elements on TiO2 were inclined to depositing together. The synergetic effect of reduction and oxidation cocatalysts with their intimate contact is proposed to contribute to the high H2 production activity, which is different from the common view that the reduction and oxidation sites should be spatially separated to avoid the charge recombination. PMID- 25030605 TI - Comparison of clinical outcomes and safety of catheter ablation for atrial fibrillation supported by data from CT scan or three-dimensional rotational angiogram of left atrium and pulmonary veins. AB - BACKGROUND: Catheter ablation in the left atrium has become a common therapeutic strategy in the management of atrial fibrillation (AF). The high degree of success and safety profile of this procedure is dependent on precise knowledge of the true anatomy in the chamber. This information is imported mostly from cardiac computed tomography. A novel method for imaging the left atrial anatomy is three dimensional rotational angiography (3DRA). METHODS: The aim of our study was to the compare clinical outcome and safety of catheter ablation for atrial fibrillation guided by 3DRA vs. conventional CT scan. One hundred and twenty-five patients referred for AF catheter ablation at St. Anne's University Hospital Brno were included in the retrospective analysis of clinical outcome within the first year after the procedure. RESULTS: There was a close correlation in overall procedural parameters between the groups. The frequency of recurrent episodes of AF (24% in CT-guided group vs. 27% in 3DRA-guided group, P=0.721) as well as the onset of atypical atrial flutter after the procedure (10% vs. 8%, respectively, P=0.731) were similar in both groups. No difference in the number of patients necessitating repeat ablation (5% vs. 5%, P=0.984) was found. Procedural complications of ablations guided by 3DRA were comparable with those guided by CT (2% vs. 3%, respectively, P=0.568). CONCLUSION: 3DRA has proven to be a safe and simple method for imaging the left atrium and guiding catheter ablation for AF. This approach is anticipated to become a new standard in 3D reconstruction of the left atrium. PMID- 25030606 TI - Eosinophil count is related with coronary thrombus in non ST-elevated acute coronary syndrome. AB - BACKGROUND: White blood cells are reported as important not only in plaque vulnerability but also in thrombus formation and thrombus growth in acute coronary syndromes. Eosinophils contain granules that promote thrombus formation and thrombus growth in some heart diseases. In this study we aimed to investigate the relation of eosinophil count with coronary thrombus formation in patients with non ST-elevated acute coronary syndrome (NST-ACS). METHOD: A total of 251 consecutive patients were hospitalized in our hospital with a diagnosis of NST ACS. Venous blood is collected for measurement of hematologic indices in all patients undergoing the coronary angiography. Coronary angiographies were performed in our clinic using the standard Judkins technique and angiographic assessment of the presence of thrombus was made. RESULTS: During coronary angiography, coronary thrombus was not detected in 82 patients (Group 1). In the coronary angiography of 169 patients, coronary thrombus was detected at various grades (Group 2). While the neutrophil count (6.84+/-1.94 vs. 5.53+/-1.37; P<0.001) and eosinophil count (0.257+/-0.125 vs. 0.163+/-0.114; P<0.005) was significnatly increased in the group with coronary thrombus, the lymphocyte count (1.87+/-0.66 vs. 2.00+/-0.70; P<0.001) was significantly decreased in the group with coronary thrombus as compared to the patient group without coronary thrombus. In the correlation analyzes; presence of coronary thrombus is correlated with total cholesterol, LDL-C, total CK, CK-MB, troponin, total number of diseased coronary, platelet count, neutrophil count, lymphocyte count and eosinophil count. On multivariate linear regression analysis, total leukocyte count, neutrophil count, lymphocyte count, eosinophil count, troponin and total cholesterol was found to be independent predictor of coronary thrombus in patients with NST-ACS. CONCLUSION: Beside the increased neutrophil count, increased eosinophil count in CBC should alert the clinician about coronary thrombus development in patients with NST-ACS in order to make early medical interventions at acute phase of the disease. PMID- 25030607 TI - Deciphering next-generation pharmacogenomics: an information technology perspective. AB - In the post-genomic era, the rapid evolution of high-throughput genotyping technologies and the increased pace of production of genetic research data are continually prompting the development of appropriate informatics tools, systems and databases as we attempt to cope with the flood of incoming genetic information. Alongside new technologies that serve to enhance data connectivity, emerging information systems should contribute to the creation of a powerful knowledge environment for genotype-to-phenotype information in the context of translational medicine. In the area of pharmacogenomics and personalized medicine, it has become evident that database applications providing important information on the occurrence and consequences of gene variants involved in pharmacokinetics, pharmacodynamics, drug efficacy and drug toxicity will become an integral tool for researchers and medical practitioners alike. At the same time, two fundamental issues are inextricably linked to current developments, namely data sharing and data protection. Here, we discuss high-throughput and next-generation sequencing technology and its impact on pharmacogenomics research. In addition, we present advances and challenges in the field of pharmacogenomics information systems which have in turn triggered the development of an integrated electronic 'pharmacogenomics assistant'. The system is designed to provide personalized drug recommendations based on linked genotype-to phenotype pharmacogenomics data, as well as to support biomedical researchers in the identification of pharmacogenomics-related gene variants. The provisioned services are tuned in the framework of a single-access pharmacogenomics portal. PMID- 25030608 TI - Whole-genome sequence analysis reveals differences in population management and selection of European low-input pig breeds. AB - BACKGROUND: A major concern in conservation genetics is to maintain the genetic diversity of populations. Genetic variation in livestock species is threatened by the progressive marginalisation of local breeds in benefit of high-output pigs worldwide. We used high-density SNP and re-sequencing data to assess genetic diversity of local pig breeds from Europe. In addition, we re-sequenced pigs from commercial breeds to identify potential candidate mutations responsible for phenotypic divergence among these groups of breeds. RESULTS: Our results point out some local breeds with low genetic diversity, whose genome shows a high proportion of regions of homozygosis (>50%) and that harbour a large number of potentially damaging mutations. We also observed a high correlation between genetic diversity estimates using high-density SNP data and Next Generation Sequencing data (r = 0.96 at individual level). The study of non-synonymous SNPs that were fixed in commercial breeds and also in any local breed, but with different allele, revealed 99 non-synonymous SNPs affecting 65 genes. Candidate mutations that may underlie differences in the adaptation to the environment were exemplified by the genes AZGP1 and TAS2R40. We also observed that highly productive breeds may have lost advantageous genotypes within genes involve in immune response--e.g. IL12RB2 and STAB1-, probably as a result of strong artificial in the intensive production systems in pig. CONCLUSIONS: The high correlation between genetic diversity computed with the 60K SNP and whole genome re-sequence data indicates that the Porcine 60K SNP Beadchip provides reliable estimates of genomic diversity in European pig populations despite the expected bias. Moreover, this analysis gave insights for strategies to the genetic characterization of local breeds. The comparison between re-sequenced local pigs and re-sequenced commercial pigs made it possible to report candidate mutations to be responsible for phenotypic divergence among those groups of breeds. This study highlights the importance of low input breeds as a valuable genetic reservoir for the pig production industry. However, the high levels of ROHs, inbreeding and potentially damaging mutations emphasize the importance of the genetic characterization of local breeds to preserve their genomic variability. PMID- 25030610 TI - AdLTR2EF1alpha-FGF2-mediated prevention of fractionated irradiation-induced salivary hypofunction in swine. AB - Patients frequently experience a loss of salivary function following irradiation (IR) for the treatment of an oral cavity and oropharyngeal cancer. Herein, we tested if transfer of fibroblast growth factor-2 (FGF2) cDNA could limit salivary dysfunction after fractionated IR (7.5 or 9 Gy for 5 consecutive days to one parotid gland) in the miniature pig (minipig). Parotid salivary flow rates steadily decreased by 16 weeks post-IR, whereas blood flow in the targeted parotid gland began to decrease ~3 days after beginning IR. By 2 weeks, post-IR salivary blood flow was reduced by 50%, at which point it remained stable for the remainder of the study. The single preadministration of a hybrid serotype 5 adenoviral vector encoding FGF2 (AdLTR2EF1a-FGF2) resulted in the protection of parotid microvascular endothelial cells from IR damage and significantly limited the decline of parotid salivary flow. Our results suggest that a local treatment directed at protecting salivary gland endothelial cells may be beneficial for patients undergoing IR for oral cavity and oropharyngeal cancer. PMID- 25030612 TI - The role of academic psychiatry in leading health policy reform. AB - The authors discuss the current state of mental health care reform and the opportunity for academic psychiatry to emerge in a leadership role in the organization and delivery of mental health care. PMID- 25030609 TI - Overexpression of superoxide dismutase 3 gene blocks high-fat diet-induced obesity, fatty liver and insulin resistance. AB - Oxidative stress has an important role in the development of obesity and obesity associated metabolic disorders. As an endogenous antioxidant enzyme, superoxide dismutase 3 (SOD3) has the potential to affect diet-induced obesity and obesity associated complications. In the current work, we overexpressed SOD3 in C57BL/6 mice fed a high-fat diet (HFD) to study its effect on HFD-induced obesity, fatty liver and insulin resistance. We demonstrated that the Sod3 gene transfer blocked HFD-induced obesity, fatty liver and insulin resistance. Real-time PCR analysis of adipose and liver tissues revealed that overexpression of the Sod3 gene suppressed expression of pro-inflammatory genes in adipose tissue including F4/80, Tnfalpha, Cd11c, Mcp1 and Il6, and increased expression of anti inflammatory genes such as adiponectin. In the liver, high levels of SOD3 activity in animals enhanced expression of the genes responsible for energy expenditure including Cpt1alpha, Cpt1beta, Pgc1alpha, Pgc1beta and Ucp2. These results suggest that overexpression of the Sod3 gene through gene transfer is an effective approach in preventing diet-induced obesity and obesity-associated complications. PMID- 25030611 TI - A dystrophic muscle broadens the contribution and activation of immune cells reacting to rAAV gene transfer. AB - Recombinant adeno-associated viral vectors (rAAVs) are used for therapeutic gene transfer in skeletal muscle, but it is unclear if immune reactivity to gene transfer and persistence of transgene are affected by pathologic conditions such as muscular dystrophy. Thus, we compared dystrophic mice devoid of alpha sarcoglycan with healthy mice to characterize immune cell activation and cellular populations contributing to the loss of gene-modified myofibers. Following rAAV2/1 delivery of an immunogenic alpha-sarcoglycan reporter transgene in the muscle, both strains developed strong CD4 and CD8 T-cell-mediated immune responses in lymphoid organs associated with muscle CD3+ T and CD11b+ mononuclear cell infiltrates. Selective cell subset depletion models revealed that CD4+ T cells were essential for transgene rejection in both healthy and pathologic mice, but macrophages and CD8+ T cells additionally contributed as effector cells of transgene rejection only in dystrophic mice. Vectors restricting transgene expression in antigen-presenting cells showed that endogenous presentation of transgene products was the sole mechanism responsible for T-cell priming in normal mice, whereas additional and protracted antigenic presentation occurred in dystrophic animals, leading to secondary CD4+ T-cell activation and failure to maintain transgene expression. Therefore, the dystrophic environment diversifies cellular immune response mechanisms induced by gene transfer, with a negative outcome. PMID- 25030613 TI - Ubiquitous element approach to plasmonic enhanced photocatalytic water splitting: the case of Ti@TiO2 core-shell nanostructure. AB - We demonstrate a new approach to plasmonic enhanced photocatalytic water splitting by developing a novel core-shell Ti@TiO2 brush nanostructure where an elongated Ti nanorod forms a plasmonic core that concentrates light inside of a nanotubular anodic TiO2 shell. Following the ubiquitous element approach aimed at providing an enhanced device functionality without the usage of noble or rare earth elements, we utilized only inexpensive Ti to create a complex Ti@TiO2 nanostructure with an enhanced UV and Vis photocatalytic activity that emerges from the interplay between the surface plasmon resonance in the Ti core, Vis light absorption in the Ti-rich oxide layer at the Ti/TiO2 interface and UV light absorption in the nanotubular TiO2 shell. PMID- 25030614 TI - Factors associated with cord blood vitamin D concentration in Saskatchewan newborns. AB - This prospective study investigated associations between cord blood vitamin D, risk factors for low vitamin D, and pregnancy and neonatal outcomes. The study included 65 maternal-fetal dyads delivering between December and February in Saskatoon, Saskatchewan. Eighty-five percent of mothers reported taking daily prenatal vitamin D but 70% of their newborns had insufficient or deficient cord blood vitamin D, suggesting that usual prenatal supplementation may be inadequate to achieve sufficient cord blood vitamin D in most newborns. PMID- 25030615 TI - Synthesis and evaluation of antineurotoxicity properties of an amyloid-beta peptide targeting ligand containing a triamino acid. AB - Peptide-like compounds containing an arginine have been shown to bind and stabilize the central helix of the Alzheimer's disease related amyloid-beta peptide (Abeta) in an alpha-helical conformation, thereby delaying its aggregation into cytotoxic species. Here we study a novel Abeta targeting ligand AEDabDab containing the triamino acid, N(gamma)-(2-aminoethyl)-2,4 diaminobutanoic (AEDab) acid. The new AEDab triamino acid carries an extra positive charge in the side chain and is designed to be incorporated into a ligand AEDabDab where the AEDab replaces an arginine moiety in a previously developed ligand Pep1b. This is done in order to increase the Abeta-ligand interaction, and molecular dynamics (MD) simulation of the stability of the Abeta central helix in the presence of the AEDabDab ligand shows further stabilization of the helical conformation of Abeta compared to the previously reported Pep1b as well as compared to the AEOrnDab ligand containing an N(delta)-(2-aminoethyl)-2,5 diaminopentanoic acid unit which has an additional methylene group. To evaluate the effect of the AEDabDab ligand on the Abeta neurotoxicity the AEDab triamino acid building block is synthesized by reductive alkylation of N-protected glycinal with alpha-amino-protected diaminobutanoic acid, and the Abeta targeting ligand AEDabDab is prepared by solid-phase synthesis starting with attachment of glutarate to the Wang support. Replacement of the arginine residue by the AEDab triamino acid resulted in an improved capability of the ligand to prevent the Abeta1-42 induced reduction of gamma (gamma) oscillations in hippocampal slice preparation. PMID- 25030616 TI - A magnetically isolated cuprate spin-ladder system: synthesis, structures, and magnetic properties. AB - We synthesized and characterized two magnetically isolated spin ladders, Cu2(CO3)(ClO4)2(NH3)6 (1) and Cu2(CO3)(ClO4)2(H2O)(NH3)5 (2), which are the first examples of carbonate bridging molecular spin ladders. Compounds 1 and 2 form a ladder configuration by stacking a structural unit composed of two Cu(2+) ions and one CO3(2-), where the Cu-O-Cu interactions form the rungs and legs of each ladder and the counter anions (ClO4(-)) occupy the space between the ladders and ensure their magnetic isolation. A S = 1/2 magnetically isolated spin-ladder model with a ladder-rung magnetic interaction J1/k(B) = 364 K (where J is defined as positive for antiferromagnetic interactions) and a ladder-leg magnetic interaction J2/k(B) = 27.4 K accurately predicts the temperature dependence of the molar magnetic susceptibility for 1. The ladder configuration of 2 is similar to that of 1 except that the CO3(2-) is alternately skewed in different directions in the stacked structural unit. Interestingly, this minor structural variation in 2 results in its remarkably different magnetic behavior; the magnetic susceptibility curve of 2 is accurately described by an alternating chain model with J3/k(B) = 7.26 K and J4/k(B) = 4.42 K. PMID- 25030617 TI - Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis induced arteriovenous fistula failure in chronic kidney disease. AB - High shear stress that develops in the arteriovenous fistula of chronic kidney diseases (CKD) may increase H2O2 and thromboxane A2 (TXA2) release, thereby exacerbating endothelial dysfunction, thrombosis, and neointimal hyperplasia. We investigated whether glucagon-like peptide-1 receptor agonist/exendin-4, a potentially cardiovascular protective agent, could improve TXA2-induced arteriovenous fistula injury in CKD. TXA2 administration to H2O2-exposed human umbilical vein endothelial cells increased apoptosis, senescence, and detachment; these phenotypes were associated with the downregulation of phosphorylated endothelial nitric oxide synthase/heme oxygenase-1 (eNOS/HO-1) signalling. Exendin-4 reduced H2O2/TXA2-induced endothelial injury via inhibition of apoptosis-related mechanisms and restoration of phosphorylated eNOS/HO-1 signalling. Male Wistar rats subjected to right common carotid artery-external jugular vein anastomosis were treated with exendin-4 via cervical implant osmotic pumps for 16-42 days. High shear stress induced by the arteriovenous fistula significantly increased venous haemodynamics, blood and tissue H2O2 and TXB2 levels, macrophage/monocyte infiltration, fibrosis, proliferation, and adhesion molecule-1 expression. Apoptosis was also increased due to NADPH oxidase gp91 activation and mitochondrial Bax translocation in the proximal end of the jugular vein of CKD rats. Exendin-4-treatment of rats with CKD led to the restoration of normal endothelial morphology and correction of arteriovenous fistula function. Exendin-4 treatment or thromboxane synthase gene deletion in CKD mice markedly reduced ADP-stimulated platelet adhesion to venous endothelium, and prevented venous occlusion in FeCl3-injured vessels by upregulation of HO-1. Together, these data reveal that the use of glucagon-like peptide-1 receptor agonists is an effective strategy for treatment of CKD-induced arteriovenous fistula failure. PMID- 25030618 TI - Comparison of the prognostic values of 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT in patients with well-differentiated neuroendocrine tumor. AB - PURPOSE: To determine the prognostic value of (68)Ga-DOTANOC PET/CT in patients with well-differentiated neuroendocrine tumor (NET), and to compare the prognostic value with that of (18)F-FDG PET/CT and other conventional clinicopathological prognostic factors. METHODS: Data from 37 consecutive patients (age 46.6 +/- 13.5 years, 51% men) with well-differentiated NET who underwent (68)Ga-DOTANOC PET/CT and (18)F-FDG PET/CT were analyzed. All patients underwent a baseline visit with laboratory and radiological examinations. Clinical and imaging follow-up was performed in all patients. Progression-free survival (PFS) was measured from the date of the first PET/CT scan to the first documentation of progression of disease. RESULTS: (68)Ga-DOTANOC PET/CT was positive in 37 of the 37 patients and (18)F-FDG PET/CT was positive in 21. During follow-up 10 patients (27%) showed progression of disease and 27 (73%) showed no progression (24 stable disease, 3 partial response). The median follow-up was 25 months (range 2 - 52 months). Among the variables evaluated none was significantly different between the progressive disease and nonprogressive disease groups, with only SUVmax on (68)Ga-DOTANOC PET/CT being borderline significant (P = 0.073). In the univariate analysis for PFS outcome, SUVmax on (68)Ga-DOTANOC PET/CT (HR 0.122, 95% CI 0.019 - 0.779; P = 0.026) and histopathological tumor grade (HR 4.238, 95% CI 1.058 - 16.976; P = 0.041) were found to be associated with PFS. Other factors including age, sex, primary site, Ki-67 index, TNM stage, (18)F-FDG PET/CT status (positive/negative), SUVmax on (18)F-FDG PET/CT and type of treatment were not significant. In multivariable analysis, only SUVmax on (68)Ga-DOTANOC PET/CT was found to be an independent positive predictor of PFS (HR 0.122, 95% CI 0.019 - 0.779; P = 0.026). CONCLUSION: SUVmax measured on (68)Ga-DOTANOC PET/CT is an independent, positive prognostic factor in patients with well-differentiated NET and is superior to SUVmax on (18)F-FDG PET/CT and conventional clinicopathological factors for predicting PFS. PMID- 25030619 TI - The number of 131I therapy courses needed to achieve complete remission is an indicator of prognosis in patients with differentiated thyroid carcinoma. AB - PURPOSE: To assess the risk of differentiated thyroid cancer (DTC) recurrence, DTC-related mortality and life expectancy in relation to the number of courses of (131)I therapy (RIT) and cumulative (131)I activities required to achieve complete remission (CR). METHODS: The study was a database review of 1,229 patients with DTC, 333 without and 896 with CR (negative TSH-stimulated thyroglobulin and negative (131)I diagnostic whole-body scintigraphy) after one or more courses of RIT. RESULTS: The median follow-up was 9.0 years (range 0.1 - 31.8 years) after CR. Recurrence rates at 5 years, 10 years and the end of follow up were 1.0 +/- 0.3%, 4.0 +/- 0.7 % and 6.2 +/- 1.1 %, and DTC-related mortality was 0.1 +/- 0.1%, 0.5 +/- 0.3% and 3.4 +/- 1.1%, respectively. Recurrence rates also increased with an increasing number of RIT courses required (p = 0.001). DTC related mortality increased from four RIT courses. In patients with CR after one RIT course, there were no differences in recurrence or DTC-related mortality rates between low-risk and high-risk patients. In patients requiring two RIT courses these rates remain elevated in high-risk patients. Recurrence and DTC related mortality rates were only significantly elevated in those requiring a cumulative activity over 22.2 GBq (600 mCi) from multiple RIT courses for CR. Regardless of the number of RIT courses or activity needed, life expectancy was not significantly lowered. CONCLUSION: If more than one RIT course is needed to achieve CR, higher recurrence and DTC-related mortality rates are observed, especially in high-risk patients. Patients requiring >22.2 GBq (131)I for CR should be followed in the same way as patients in whom CR is never reached as long-term mortality rates are similar. PMID- 25030620 TI - Synthesis of adhesive peptides similar to those found in blue mussel (Mytilus edulis) using papain and tyrosinase. AB - The blue mussel (Mytilus edulis) foot protein 5 (Mefp-5) is an adhesive protein that is mainly composed of glycine, l-lysine, and 3,4-dihydroxy-l-phenylalanine (DOPA). Thousands of adhesive pads have been analyzed in previous studies, whereby it has been found that adhesion is largely achieved by the redox chemistry of DOPA, and that l-lysine (approximately 20 mol %) affects the formation of molecular networks. While DOPA and lysine are essential for biomimetic adhesive design, the synthesis of copolymers containing DOPA is limited, in terms of yield, by the multiple reaction steps required. Here, we synthesized adhesive peptides containing DOPA and l-lysine via two enzymatic reactions, namely, chemoenzymatic synthesis of copolypeptides of l-tyrosine and l lysine by Papaya peptidase I (papain), as well as the enzymatic conversion from l tyrosine to DOPA by tyrosinase. The synthesis was characterized in terms of yield, degree of polymerization, and composition of the polypeptide. In addition, the conversion of tyrosine to DOPA by tyrosinase was evaluated quantitatively by nuclear magnetic resonance and amino acid analysis. The adhesive properties of the resulting peptides, consisting of DOPA, l-lysine, and l-tyrosine, were evaluated at various pH levels with different protonation/deprotonation states. Our results show that deprotonated DOPA is required for adhesive function, and the deprotonated primary amine group of lysine induces molecular networks by varying the elastic moduli of the adhesives. In this study, we demonstrate the benefit of combining multiple enzymatic reactions, including chemoenzymatic polymerization, in obtaining new types of peptide-based materials. PMID- 25030622 TI - Enhanced photoluminescence and photoactivity of plasmon sensitized nSiNWs/TiO2 heterostructures. AB - A light sensitive wide band gap radial heterojunction between TiO2 and nSiNWs sensitized by gold nanoparticles is reported. The surface plasmon of AuNPs influences the optical and photocurrent properties of the heterojunction considerably. Improvement in the band gap emission of TiO2 has been found at the expense of defect radiation. Excitation of AuNPs deposited on nSiNWs/TiO2 by light irradiation shows a wavelength-dependent photocurrent due to the increased photoactivity of the heterojunction. PMID- 25030621 TI - Exploring patients' views of primary care consultations with contrasting interventions for acute cough: a six-country European qualitative study. AB - BACKGROUND: In a pan-European randomised controlled trial (GRACE INTRO) of two interventions, (i) a point-of-care C-reactive protein test and/or (ii) training in communication skills and use of an interactive patient booklet, both interventions resulted in large reductions in antibiotic prescribing for acute cough. AIMS: This process evaluation explored patients' views of primary care consultations using the two interventions in six European countries. METHODS: Sixty-two interviews were conducted with patients who had participated in the GRACE INTRO trial. Interviews were transcribed verbatim and translated into English where necessary. Analysis used techniques from thematic and framework analysis. RESULTS: Most patients were satisfied with their consultation despite many not receiving an antibiotic. Patients appeared to accept the use of both intervention approaches. A minority, but particularly in the trial arm with both interventions, reported that they would wait longer before consulting for cough in future. CONCLUSIONS: Patients perceived that both interventions supported the general practitioner's (GP's) prescribing decisions by helping them understand when an antibiotic was, and was not, needed. Patients consulting with acute cough had largely positive views about the GP's enhanced communication skills, which included understanding their concerns, and the use of a near-patient test as an additional investigation. PMID- 25030623 TI - Cellular and molecular effects of beta radiation from I-131 on human tumor cells: a comparison with gamma radiation. AB - To study the comparative effects of beta radiation emitted from Na(131)I with equivalent dose of (60)Co gamma- radiation across a range of tumor types and underlying mechanism of cytotoxicity. Different tumor cell lines of various tissue origin viz. Raji, U937, A431 and MCF-7 were irradiated with beta radiation emitted from Na(131)I and equivalent dose of (60)Co gamma- radiation (0.4 Gy). Cellular toxicity and apoptosis study were carried out in four cell lines and the effects were compared. Gene expression studies of P21, RAD51 and BAX genes were analyzed by q-PCR after beta- and gamma-irradiation. Cell viability (trypan blue assay) and apoptosis (DNA fragmentation and cleavage of PARP assays) studies for both types of radiation showed that among the four cell lines, A431 is most radio resistant while MCF-7 and U937 are moderately radiation resistant and Raji cells showed maximum radiosensitivity. However, irradiation of cells with beta radiation from I-131 resulted in enhanced toxicity and apoptosis in tumor cells compared to equivalent dose of gamma- rays. Gene expression studies in Raji cells showed difference in magnitude and kinetics of RAD51 and P21 expression after beta- and gamma-irradiation. Our results showed higher efficacy of beta radiation in induction of tumor cell cytotoxicity and apoptosis compared to an equivalent dose of gamma-radiation, which may be associated with differential DNA damage and subsequent repair kinetics in tumor cells after these radiations. PMID- 25030624 TI - Diversity and antibacterial activities of culturable fungi associated with coral Porites pukoensis. AB - The diversity of coral associated fungi is not enough understood, especially for scleractinian corals. Members of Porites are common and dominant species of scleractinian corals. To date, the fungal communities associated with coral Porites pukoensis have been not reported. In this paper, the diversity and activity of coral associated fungi in P. pukoensis were explored, 23 fungal strains were isolated, belonging to 10 genera and Aspergillus sp. (30.4 %) was predominant fungal genera. The sequence of isolate C1-23 in GenBank was only 90 % similarity to the most closely related sequences. It is concluded that rich fungal symbionts are attached to P. pukoensis, the rate of isolates with antibacterial activity was up to 30 %, particularly some isolates showed stronger bioactivities to gram-negative bacteria. It is included that the diversity of coral associated fungi in P. pukoensis is abundant and its activity is obviously. So the activities of fungi in P. pukoensis were deserved for further study. PMID- 25030626 TI - Management of continuing education of nurse midwives by chief nurses in community hospitals in southern Thailand. AB - PURPOSE: To explore the levels of continuing education management in hospitals according to their size, and to investigate problems in the management of continuing education of nurse midwives by chief nurses in community hospitals. METHODS: The target population was 128 chief nurses, 103 of whom (80.47%) returned the questionnaires. Data were collected using a questionnaire that had been tested for its content validity by three experts (content validity index was .80 and the Cronbach's alpha was .83). Descriptive statistics and ANOVA were used to investigate if differences existed among groups. RESULTS: The mean score of the level of continuing education management in nurse midwives for the chief nurses was low. The levels of education management for chief nurses according to hospital size (10-bed, 30-bed, and 60-bed hospitals) were not significantly different (p > .05). The problems for chief nurses in the management of continuing education in nurse midwives in the community hospitals were: lack of manpower (70%); financial problems (45%); lack of lecturers in advanced nurse midwifery (38%); insufficient number of courses in advanced nurse midwifery (29%); length of time for study leave taken for training (21%); and safety problems in the unrest areas in the southern provinces (21%). CONCLUSION: The levels of continuing education management by chief nurses in all the community hospitals were low, primarily due to a lack of manpower and budgetary constraints. Therefore, the Nursing Council of Thailand should provide training and funds to support advanced nurse midwifery education programs in all parts of the country. PMID- 25030627 TI - Influences of Psychological Well-being, Quality of Caregiver-patient Relationship, and Family Support on the Health of Family Caregivers for Cancer Patients in Taiwan. AB - PURPOSE: The purpose of this study was to examine the influences of psychological well-being, quality of caregiver-patient relationship, and family support on the health of family caregivers for cancer patients in a Taiwanese hospital. METHODS: A cross-sectional, correlational design was used. A sample of 91 family caregivers of hospitalized cancer patients completed the Caregiver Reaction Assessment and Psychological Well-Being Scale. Pearson's product moment correlation and regression analyses were used to examine the data. RESULTS: The psychological well-being and the quality of the caregiver-patient relationship of family caregivers were found to be significantly positively correlated with caregivers' health. The lack of family support was found to be significantly negatively correlated with caregivers' health. Psychological well-being, quality of caregiver-patient relationship, and family support accounted for 59% of the variance in caregivers' health. CONCLUSION: The findings suggest that nurses, while providing care in the hospital and upon discharge need to be aware of the psychological well-being, quality of caregiver-patient relationship, and family support of a family caregiver, as these factors all have an impact on a family caregiver' health. PMID- 25030628 TI - Defining Reported Errors on Web-based Reporting System Using ICPS From Nine Units in a Korean University Hospital. AB - PURPOSE: The aim of the present study was to delineate and evaluate the feasibility of a web-based error reporting system using the International Classification of Patient Safety (ICPS) in a Korean university hospital. METHOD: Seventy-five staff nurses were encouraged to complete error reports on the website during an 8-week period from December, 2008 to February, 2009. To solve the research question, chi(2) test, t test and descriptive statistics were used. RESULTS: Of the 75 enrolled participants, 36% (n = 27) completed at least one web based report during the 8-week period. There were no significant mean differences in demographics and job-related characteristics between the two groups (compliance group vs. non-compliance group). Error reports were distinguished between those observed that involved others (77%) and those that involved themselves (23%). The majority of incident types involved medications (60.9%), in particular their administration (77.6% of the medication errors). About 90% of events caused "no harm and no change in monitoring" or "no harm, but monitoring initiated or increased". About 45% percent of errors increased in required resource allocation for patients (13.1/10,000 patient-days) and 33.9% of errors augmented to a "formal complaint" (9.8/10,000 patient-days). CONCLUSION: The web based error reporting system using ICPS proved to be an easy, feasible system for hospitals in Korea. This system will be helpful for inducing general agreement upon errors within clinical nursing practice and bring more attention to any errors made or near misses. Also, it will be able to ameliorate the punitive culture for errors and transform error reporting into a habit for healthcare providers. PMID- 25030625 TI - Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma. AB - Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma. PMID- 25030629 TI - Korean nurses' experience of preparing for and taking the national council licensure examination for registered nurses. AB - PURPOSE: This study explores the Korean nurses' experience of preparing for and taking the National Council Licensure Examination for Registered Nurses (NCLEX RN) in order to provide a deeper understanding of their experiences. METHOD: The study utilizes the qualitative research method, Colaizzi's phenomenological methodology. Twenty-six Korean nurses were interviewed using semi-structured research questions and their interviews were analyzed. RESULTS: Seven clusters of themes emerged: (a) motivation; (b) flow in studying, (c) expansion of nursing knowledge for nursing practice; (d) reflections of nursing practice and attitude toward themselves; (e) time management struggles; (f) increased self-confidence and self-esteem; (g) setting a new life direction and new challenges. In general, our analyses demonstrated that the nurses' experiences of preparing for and taking the NCLEX-RN showed positive impacts on the nurses, psychologically, intellectually and interpersonally. CONCLUSION: The results suggest that developing NCLEX-RN preparation programs is needed to promote global capabilities for nurses and nursing students. Further studies on the effect of exposure to the NCLEX-RN exam while nursing school for nurses is recommended. PMID- 25030630 TI - Familiarity, preference, and utilization of ethnic items among asian americans. AB - PURPOSE: The purpose was to determine whether Asian Americans are still seeking familiar and preferred ethnic items and whether they are using them in daily life after they have immigrated to the United States. METHODS: A descriptive exploratory study design was used. A convenience sample of 224 Asian Americans was recruited from the states of Michigan and Ohio. RESULTS: It was found that (a) participants were significantly different in mean age, duration of stay in country of origin and the United States, and proficiency in English; (b) the familiarity, preference and utilization of overall ethnic items were statistically different by ethnic group; (c) overall, familiar feeling with ethnic items had the highest mean score for all ethnic items, and ethnic food was the most familiar, preferred and used item in daily life; (d) Asian Americans who sought more ethnic items had greater proficiency in English and more preference, use and familiarity with ethnic items; and (e) daily use of ethnic items was the best predictor of familiarity, followed by preference, and fluency in English. CONCLUSION: Asian Americans have different backgrounds in terms of customs, food preferences, beliefs, lifestyles, and languages. Despite being in different age groups, having different lengths of stay in the United States, and different countries of origin, a common trait among Asian Americans was that they were consciously seeking ethnic items regardless of ethnic group. Healthcare professionals should consider providing culturally relevant care to Asian Americans to promote their overall health. Future study should focus on exploring the relationship between familiarity, preference, and attitude in health behavior among Asian Americans. PMID- 25030631 TI - Avoid surgery as first line treatment for non-specific low back pain. PMID- 25030632 TI - Low back pain in primary care. PMID- 25030634 TI - Maureen Baker: The invisible woman. PMID- 25030635 TI - The BMJ's editor wins publishing industry award. PMID- 25030633 TI - Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications. AB - OBJECTIVE: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN: Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING: Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS: Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials. PMID- 25030637 TI - All emergency departments should include GP staff, say experts. PMID- 25030638 TI - Mental health patients pose high suicide risk in first two weeks after discharge, inquiry finds. PMID- 25030639 TI - HIV negative men who have sex with men should consider taking daily antiretroviral, says WHO. PMID- 25030640 TI - An integrative model of workplace self-protective behavior for Korean nurses. AB - PURPOSE: This study was conducted to develop and test a hypothetical stage model of workplace self-protective behaviors with respect to blood transmitted infections and musculoskeletal injuries for Korean nurses. METHODS: A nonexperimental, cross-sectional study design was adopted. The study participants were 320 nurses at two Korean university hospitals. Perceived sensitivity, severity, barriers, benefits, self-efficacy, social support, and safety climate were assessed. RESULTS: Overall, fit indicators showed a good fit for the hypothetical model of self-protective behaviors against blood transmitted infections and musculoskeletal injuries. The significant factors of self protective behaviors against blood transmitted infections were perceived barriers and social support. The significant factors of self-protective behaviors against musculoskeletal injuries were perceived benefits, barriers, and self-efficacy. CONCLUSION: Our findings suggest that the significant psychosocial constructs of stages of self-protective behavior are dependent on health problem type. Accordingly, we advise that characteristics of behavior and types of disease and health problem should be given priority when developing intervention programs for particular self-protective health behaviors. PMID- 25030641 TI - Helping teachers conduct sex education in secondary schools in Thailand: overcoming culturally sensitive barriers to sex education. AB - PURPOSE: The purpose of this quasi experimental study was to evaluate the effects of Culturally Sensitive Sex Education Skill Development, a teacher-led sex education program in secondary schools in Thailand. METHODS: Two public secondary schools in the suburban areas of Bangkok were randomly selected. One was designated as the experimental school and the other as the comparison school. Ninety grade seven and eight teachers, 45 from each school, were selected to participate in the study. Self efficacy theory and culturally appropriate basis were applied to develop the program which included 4 weeks of intervention and 2 weeks of follow up. Primary outcomes were attitudes toward sex education, perceived self efficacy, and sex education skills. Statistical analysis included independent and paired t test, and repeated one-way analysis of variance. RESULTS: At the end of the intervention and during the follow-up period, the intervention group had significantly higher mean scores of attitudes toward sex education, perceived self efficacy, and sex education skills than their scores before (p < .001), and than those of the comparison group (p < .001). CONCLUSION: The results showed that Culturally Sensitive Sex Education Skill Development could enhance attitudes and sex education self efficacy to promote the implementation of sex education among teachers. PMID- 25030642 TI - Does pain mediate or moderate the effect of cognitive impairment on aggression in nursing home residents with dementia? AB - PURPOSE: The purpose of this study was to investigate if pain mediates or moderates the relationship between cognitive impairment and aggressive behaviors in nursing home residents with dementia based on the Need-driven Dementia compromised Behavior model. METHODS: This was a secondary analysis of the Minimum Data Set assessment data on long-term care from the state of Florida during calendar year 2009. The data used in this study was the first comprehensive assessment data from residents with dementia (N = 56,577) in Medicare-certified or Medicaid-certified nursing homes. Path analysis using a series of hierarchical regression analyses and two-way analysis of variance was used to evaluate the mediating and moderating effect of pain on the relationship between the level of cognitive impairment and aggression. RESULTS: Results indicated that pain did not mediate the relationship between cognition and aggressive behaviors, but there was evidence of a significant moderating effect of pain only for residents with severe cognitive impairment. Only among the residents with severe cognitive impairment, those with pain had significantly more frequent aggressive behaviors than those without pain. CONCLUSION: A change in the frequency of aggressive behaviors in severely cognitively impaired residents should signal the possibility that the person is experiencing pain. Accurate but simple pain assessment in this population including these behavioral changes should be developed further, and pain should be well controlled to reduce these problematic behaviors. PMID- 25030643 TI - Effect of infant health problem, mother's depression and marital relationship on infant abuse in Korea: mediating pathway of marital relationship. AB - PURPOSE: The purpose of this study is to test a model linking infant health problem, mother's depression and marital relationship to infant abuse. METHODS: This study employed a cross-sectional survey design. Data were collected from 2009 Data of Index Studies for Korean Children and Adolescents Development. Survey data from 1,060 infants and their mothers (including infant health status and infant physical illness scale, depression scale, marital relationship scale, and child abuse scale) were used to test the model. The model was tested using path analysis techniques within structural equation modeling. RESULTS: The model fit indices suggested that the original hypothesized model adequately fit the data (chi(2) = .33, df = 5, p = .84, Tucker-Lewis Index = 1.04, Comparative Fit Index = 1.00, Root Mean Square Error of Approximation = .00). Infant health problem and mother's depression had a negative direct effect on marital relationship, which in turn had a direct negative effect on infant abuse. Infant health problems directly affected infant abuse and also influenced infant abuse indirectly through the marital relationship. Mother's depression had significant direct effects on infant abuse and also influenced infant abuse indirectly through the marital relationship. CONCLUSION: The findings from this study demonstrate the fundamental importance of infant health as linked to the mother's mental health, and marital relationship and increasing the quality of marital relationship may be the key to infant abuse prevention. PMID- 25030644 TI - Concept analysis of empowerment in old people with chronic diseases using a hybrid model. AB - PURPOSE: The purpose of this study was to clarify the meaning and the nature of empowerment concept in some Iranian old people suffering from chronic diseases. METHODS: Concept analysis was undertaken according to the hybrid model, which consists of three phases: an initial theoretical phase, a fieldwork phase and a final analytical phase. After an extensive review of the literature in order to describe the characteristics and definition of the concept, a fieldwork phase followed in order to empirically elucidate the empowerment concept in the Iranian old people with chronic diseases. In the third phase, attributes of empowerment were extracted from the first and second phases. Purposive sampling was done for 13 participants consisted of 7 old people with chronic diseases, 3 family caregivers of elderly adult with chronic disease and 3 health care providers with experience of care with elderly patients with chronic disease. RESULTS: The review of literature in theoretical phase determined the attributes of the concept, including "active participation", "informed change", "knowledge to problem solve", "self-care responsibility", "presence of client competency", and "control of health or life". Fieldwork phase determined attributes such as "awareness promotion", "sense of control", "the development of personal abilities", "autonomy", and "coping". In the final analytical phase, the critical attributes of old people with chronic diseases were investigated. They included "social participation", "informed change", "awareness promotion to problem solve", "presence of client competency", and "control of health or life", "autonomy", "coping" and "the development of personal abilities". CONCLUSION: The concept analysis of empowerment showed some of the required conditions for the empowerment of older people with chronic diseases in nursing care, which have not been mentioned in the literature. PMID- 25030645 TI - An integrative review of infection control research in Korean nursing journals. AB - PURPOSE: This study was performed to analyze the characteristics and trends of published research papers related to infection control in Korean nursing journals. METHODS: A total of 177 studies published between 1970 and 2011 were reviewed using analysis criteria. Subject articles were selected through KoreaMed and journal database searches on the website of subject academic societies using key words related to healthcare-associated infections. RESULTS: Most reports were quantitative studies and the majority of them were descriptive studies. The most common subjects of research were infection control measures for pathogens, followed by disinfection and sterilization, and hand hygiene. Among them, the most descriptive studies were conducted on the knowledge, attitude, and performance of infection control. Theoretical framework, criteria for sample size and ethical consideration were rarely presented in quantitative studies. CONCLUSIONS: To enhance the quality of infection control studies and establish infection control studies as a nursing knowledge body, meta-analyses and systematic literature reviews as well as quantitative studies are needed. Moreover, studies employing behavioral science to identify factors influencing the level of knowledge and practice and to change infection control behaviors are also warranted. PMID- 25030646 TI - Effect of evidence-based postoperative pain guidelines via web for patients undergoing abdominal surgery in South Korea. AB - PURPOSE: The purpose of this study was to develop evidence-based guidelines on postoperative pain management via the web and to examine the effects in terms of pain level of patients undergoing abdominal surgery and nurses' knowledge of postoperative pain management. METHODS: First, evidence-based pain guidelines were developed via the web in a tertiary hospital. Second, a special educational program on evidence-based pain guidelines for nurses was developed after validation of content by experts. Third, diverse strategies were adopted in order to facilitate incorporation of evidence-based pain guidelines in practice. Fourth, nurses in the study units were educated on evidence-based guidelines using the developed educational program for 3 weeks before their implementation of evidence-based pain guidelines to patients. Patients were assigned to the control group (from July 29 to August 20, 2011) and the experimental group (from September 24 to October 25, 2011) according to interrupted time interval. The data were analyzed using chi-square test, analysis of variance test with Scheffe's test as a post hoc and repeated measure of analysis of variance. RESULTS: Patients in the experimental group showed a significantly lower level of pain. Nurses' knowledge of management of postoperative pain showed a significant increase after installation of evidence-based guidelines. CONCLUSION: Evidence based pain guidelines were effective in reducing the pain level of patients as well as improving nurses' knowledge of pain management. PMID- 25030647 TI - Predictive factors associated with death of elderly in nursing homes. AB - PURPOSE: An increasing elderly population reflects a great need for readily accessible, clinically useful methods to identify mortality-related factors in nursing home residents. The purpose of this study was to identify factors associated with the deaths of nursing home residents. METHODS: Data was collected from a Minimal Data Set of 195 elderly nursing home residents, followed by analysis of demographic factors, disease and nursing condition factors, Activities of Daily Living (ADL), cognitive function, behavioral patterns, and dysfunctional status. RESULTS: Major factors associated with death among nursing home residents were identified as dyspnea (odds ratio [OR] = 4.88), problematic behaviors (OR = 3.95), and ADL (OR = 3.61). These variables accounted for 31.1% of the variance in death. CONCLUSION: Dyspnea, problematic behaviors, and ADL data were identified as the key factors associated with death among nursing home residents. Future plans for the prediction of death among nursing home residents can be made by nursing staff, factoring in these identified variables, to ensure more comfortable conditions and more responsive care. PMID- 25030648 TI - Health behaviors and related demographic factors among Korean adolescents. AB - PURPOSE: The purposes of this study were to explore health behaviors, examine health behaviors in relation to demographic factors, and investigate the relationships between health risk behaviors (e.g., tobacco use, alcohol consumption, and sexual experience) among Korean adolescents. METHODS: The study used a cross-sectional descriptive relational design and a population-based data collection of 1,716 middle and high school Korean adolescents. The 72-item Korean Adolescent Health Behavior Scale was used for data collection, while descriptive statistics, t test and chi-square test were used in the data analyses. RESULTS: Females were doing better on weight control, hygiene, safety, and computer use than were males. Males were doing better on physical activity. Adolescents living in cities were more likely to be addicted to computer but were consuming alcohol and using tobacco less than adolescents in rural areas were. In addition, religion, grade level, and living area also made the adolescents' health behavior significantly different. CONCLUSION: As the result suggested, gender, religion, grade level, and region need to be considered when designing health promotion interventions among Korean adolescents. PMID- 25030649 TI - Probing concept of critical thinking in nursing education in Iran: a concept analysis. AB - PURPOSE: Given the wide disagreement over the definition of critical thinking in different disciplines, defining and standardizing the concept according to the discipline of nursing is essential. Moreover, there is limited scientific evidence regarding critical thinking in the context of nursing in Iran. The aim of this study was to analyze and clarify the concept of critical thinking in nursing education in Iran. METHODS: We employed the hybrid model to define the concept of critical thinking. The hybrid model has three interconnected phases- the theoretical phase, the fieldwork phase, and the final analytic phase. In the theoretical phase, we searched the online scientific databases (such as Elsevier, Wiley, CINAHL, Proquest, Ovid, and Springer as well as Iranian databases such as SID, Magiran, and Iranmedex). In the fieldwork phase, a purposive sample of 17 nursing faculties, PhD students, clinical instructors, and clinical nurses was recruited. Participants were interviewed by using an interview guide. In the analytical phase we compared the data from the theoretical and the fieldwork phases. RESULTS: The concept of critical thinking had many different antecedents, attributes, and consequences. Antecedents, attributes, and consequences of critical thinking concept identified in the theoretical phase were in some ways different and in some way similar to antecedents, attributes, and consequences identified in the fieldwork phase. Finally critical thinking in nursing education in Iran was clarified. CONCLUSION: Critical thinking is a logical, situational, purposive, and outcome-oriented thinking process. It is an acquired and evolving ability which develops individually. Such thinking process could lead to the professional accountability, personal development, God's consent, conscience appeasement, and personality development. PMID- 25030651 TI - Sustaining clinician penetration, attitudes and knowledge in cognitive-behavioral therapy for youth anxiety. AB - BACKGROUND: Questions remain regarding the sustainment of evidence-based practices following implementation. The present study examined the sustainment of community clinicians' implementation (i.e., penetration) of cognitive-behavioral therapy, attitudes toward evidence-based practices, and knowledge of cognitive behavioral therapy for youth anxiety two years following training and consultation in cognitive-behavioral therapy for youth anxiety. METHODS: Of the original 115 participants, 50 individuals (43%) participated in the two-year follow-up. A t- test examined sustainment in penetration over time. Hierarchical linear modeling examined sustainment in knowledge and attitudes over time. Time spent in consultation sessions was examined as a potential moderator of the change in knowledge and attitudes. RESULTS: Findings indicated sustained self reported penetration of cognitive-behavioral therapy for anxious youth, with low fidelity to some key CBT components (i.e., exposure tasks). Follow-up knowledge was higher than at baseline but lower than it had been immediately following the consultation phase of the study. Belief in the utility of evidence-based practices was sustained. Willingness to implement an evidence-based practice if required to do so, appeal of evidence-based practices, and openness toward evidence-based practices were not sustained. Participation in consultation positively moderated changes in knowledge and some attitudes. CONCLUSIONS: Sustainment varied depending on the outcome examined. Generally, greater participation in consultation predicted greater sustainment. Implications for future training include higher dosages of consultation. PMID- 25030650 TI - Molecular and cellular basis of scleroderma. AB - Systemic sclerosis (scleroderma) is a chronic inflammatory disease that leads to fibrosis of the skin and involved internal organs. No efficient therapy is currently available. This review summarizes recent progress made in basic as well as clinical science and concludes with a concept that therapy targeting fibrosis in scleroderma needs to take into account the global microenvironment in the skin with its diverse cellular players interacting with a complex extracellular matrix environment and matrix-associated growth factors. PMID- 25030652 TI - VuDREB2A, a novel DREB2-type transcription factor in the drought-tolerant legume cowpea, mediates DRE-dependent expression of stress-responsive genes and confers enhanced drought resistance in transgenic Arabidopsis. AB - MAIN CONCLUSION: VuDREB2A exists in cowpea as a canonical DREB2-type transcription factor, having the ability to bind dehydration-responsive elements in vitro and confer enhanced drought resistance in transgenic Arabidopsis. Cowpea (Vigna unguiculata L. Walp) is an important cultivated legume that can survive better in arid conditions than other crops. But the molecular mechanisms involved in the drought tolerance of this species remain elusive with very few reported candidate genes. The Dehydration-Responsive Element-Binding Protein2 (DREB2) group of transcription factors plays key roles in plant responses to drought. However, no DREB2 ortholog has been reported from cowpea so far. In this study, we isolated and characterized a gene from cowpea, namely VuDREB2A, encoding a protein of 377 amino acids exhibiting features of reported DREB2-type proteins. In cowpea, VuDREB2A transcript accumulation was highly induced by desiccation, heat and salt, but slightly by exogenous abscisic acid (ABA) treatment. We also isolated the VuDREB2A promoter and predicted stress-responsive cis-elements in it using Arabidopsis microarray data. The E. coli-expressed VuDREB2A protein showed binding to synthetic oligonucleotides with Dehydration-Responsive Elements (DREs) from Arabidopsis, in electrophoretic mobility shift assays. Heterologous expression of VuDREB2A in Arabidopsis significantly improved plant survival under drought. In addition, overexpression of a truncated version of VuDREB2A, after removal of a putative negative regulatory domain (between amino acids 132-182) led to a dwarf phenotype in the transgenic plants. Microarray and quantitative PCR analyses of VuDREB2A overexpressing Arabidopsis revealed up-regulation of stress-responsive genes having DRE overrepresented in their promoters. In summary, our results indicate that VuDREB2A conserves the basic functionality and mode of regulation of DREB2A in Arabidopsis and could be a potent candidate gene for the genetic improvement of drought resistance in cowpea. PMID- 25030654 TI - Immunotherapeutic agents in non-small-cell lung cancer finally coming to the front lines. AB - Non-small-cell lung cancer usually carries a dismal prognosis. Novel treatment approaches are clearly warranted. Immunotherapy has emerged as a promising area of research developing agents that manipulate the immune system to induce antitumor responses while avoiding major toxicity. New vaccines and checkpoint inhibitors are currently undergoing investigation in phase II and phase III clinical trials. In advanced non-small-cell lung cancer (NSCLC), belagenpumatucel L, an allogeneic cell vaccine directed against transforming growth factor beta in the tumor microenvironment, knocks down the immune suppression caused by the tumor and has demonstrated a dose- and time-dependent efficacy in some subgroups of patients. L-BLP25 and TG4010 are both antigenic vaccines that target mucin 1, whose encoding proto-oncogene is commonly mutated in solid tumors. The L-BLP25 vaccine achieved a significant improvement in overall survival in the subgroup of patients with stage IIIB NSCLC treated with chemoradiotherapy. TG4010 vaccination resulted in better progression-free survival when added to cisplatin-gemcitabine chemotherapy. These results are being addressed in the currently ongoing phase III TIME trial. In the adjuvant setting, MAGE-A3, an antigen-based vaccine, showed promising results in melanoma-associated antigen A3 positive lung cancer patients who underwent resection in the phase II study; however, no improvement in progression-free survival was observed in the phase III MAGRIT study. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti EGF antibody production and prevents EGF from binding to its receptor. It has improved overall survival in patients with advanced NSCLC who achieve seroconversion. Ipilimumab, an immune checkpoint inhibitor that targets cytotoxic T-lymphocyte antigen 4, demonstrated improved progression-free survival in advanced NSCLC patients who received the drug after chemotherapy in a phased regimen. Finally, anti-programmed death receptor 1 agents have achieved durable response rates in phase I studies. This review gives an overview of the current data and the most promissory immunotherapeutic agents for NSCLC. PMID- 25030653 TI - Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? AB - Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-beta-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical loading, or to unloading, leading correspondingly to bone formation or resorption. This review shows a key role of the osteocyte-produced sclerostin as a major mediator of the molecular mechanisms involved in the process of adaptive bone remodeling. PMID- 25030655 TI - Prospects and pitfalls of personalizing therapies for sarcomas: from children, adolescents, and young adults to the elderly. AB - Sarcomas are a heterogeneous class of tumors that affect all ages, from children, adolescents, and young adults to the elderly. Within this panoply of tumor subtypes lies the opportunity to bring to bear a vision of personalized medicine in which the fast-paced evolution from the "one gene, one test, one drug" approach to a comprehensive "panomic," multiplex, multianalyte method coupled with advances in bioinformatics platforms can unravel the biology of this disease. The increasingly enlarging repertoire of novel agents provides innumerable prospects in precision medicine. Personalized therapy covers the entire spectrum of cancer care, from risk factor assessment through prevention, risk reduction, therapy, follow-up after therapy, and survivorship care. Challenges remain in implementing the science of precision medicine in the clinic, including providing comprehensive multidisciplinary care and overcoming regulatory and economic hurdles, which must be facilitated within the collaborative framework of academia, industry, federal regulators, and third party payers. PMID- 25030656 TI - Long-term smoking increases the need for acute care among asthma patients: a case control study. AB - BACKGROUND: To examine risk factors for asthma patients' emergency room (ER) visits in a well organized asthma care setting. METHODS: A random sample of 344 asthma patients from a Pulmonary Clinic of a University Hospital were followed through medical records from 1995 to 2006. All the ER visits due to dyspnea, respiratory infections, chest pain, and discomfort were evaluated. RESULTS: The mean age of the study population was 56 years (SD 13 years), 72% being women. 117 (34%) of the patients had had at least one ER visit during the follow-up (mean 0.5 emergency visits per patient year, range 0-7). Asthma exacerbation, lower and upper respiratory infections accounted for the 71% of the ER visits and 77% of the hospitalizations. The patients with ER visits were older, had suffered longer from asthma and more frequently from chronic sinusitis, were more often ex- or current smokers, and had lower lung function parameters compared to the patients without emergency visits. Previous (HR 1.9, CI 1.3-3.1) and current smoking (HR 3.6, CI 1.6-8.2), poor self-reported health related quality of life (HRQoL) (HR 2.5, CI 1.5-4), and poor lung function (FEV1<65%, HR 2.2, CI 1.3-3.7) remained independent risk factors for ER visits after adjustment for age and gender. CONCLUSIONS: Asthma patients who are or have been long-term smokers are more likely to require ER care compared to never smokers. PMID- 25030657 TI - Oxidative stress in pregnancy and fertility pathologies. AB - Oxidative stress designates the state of imbalance between reactive oxygen species (ROS) production and antioxidant levels. In a healthy placenta, there is an increase in ROS production, due to formation of new tissues and inherent metabolism, but this is balanced by higher levels of antioxidants. However, this balance is lost in some situations, with a consequent increase in oxidative stress levels. Oxidative stress has been implicated in several placental disorders and pregnancy pathologies. The present review intends to summarize what is known about the relationship between oxidative stress and well-known pregnancy disorders. PMID- 25030658 TI - Unusual case of OHVIRA syndrome with a single uterus, unrecognized before labor and followed by an intrapartal rupture of obstructed hemivagina. AB - PURPOSE: The acronym for obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) was created to describe patients with an obstructed hemivagina and ipsilateral renal anomaly and enables inclusion of other uterine anomalies except uterus didelphys. The main goal of this article is to present a rare case of OHVIRA syndrome with intrapartal rupture of obstructed hemivagina. METHODS: We present an unusual case of OHVIRA syndrome with single uterus, uterine septum (previously resected by hysteroscopy) and renal agenesis, unrecognized before labor and followed by an intrapartal rupture of obstructed hemivagina. RESULTS AND CONCLUSION: Various symptoms, included in OHVIRA acronym, are a result of different morphologic variants included in this syndrome. Most likely, in our case, the absence of communication between the cervical canal/patent vagina and the obstructed hemivagina prevented formation of mucocolpos or hematocolpos. This rare clinical variant made our MRI diagnosis of obstructed hemivagina, as well of the entire OHVIRA syndrome, ineffective. We did not find OHVIRA cases in the literature with a single septate uterus and single cervix, associated with obstructed hemivagina diagnosed during and after labor and presented with intrapartal rupture of hemivagina. Because of lack of guidelines, the final decision about management of the labor in such rare cases of OHVIRA syndrome is difficult. PMID- 25030659 TI - Herpes simplex virus type 2 and the risk of cervical cancer: a meta-analysis of observational studies. AB - OBJECTIVES: To assess whether herpes simplex virus type 2 (HSV-2) infection has an effect on the risk of cervical cancer. METHODS: A systematic literature search of PubMed, Embase, Web of Science, and Scopus from their inception through July 2013 was conducted and reference lists of retrieved articles were reviewed. Information on the characteristics of the included studies, risk estimates, and control for possible confounding factors was extracted independently by two investigators. A random effects model was used to calculate the pooled risk estimates. MAIN RESULTS: Sixteen articles with 20 studies (14 case control and 6 longitudinal) involving 3,337 patients with cervical cancer were included. Compared with individuals who did not experience HSV-2 infection, the pooled ORs of cervical cancer for individuals with HSV-2 infection were 1.37 (95 % CI 1.12 1.69) for traditional case-control studies and 1.04 (95 % CI 0.82-1.31) for prospective or retrospective nested case-control studies. CONCLUSIONS: Given that a longitudinal study gives a higher level of evidence than a traditional case control study, the existing observational epidemiological evidence do not support a harmful effect of HSV-2 infection on cervical cancer. PMID- 25030660 TI - Is transdermal menopausal hormone therapy (MHT) associated with an increased cardiovascular risk? PMID- 25030661 TI - Gastric endometriosis associated with transverse colon endometriosis: a case report of a very rare event. AB - Gastric endometriosis is a very rare event. It enters in the differential diagnosis of cyclical or chronic epigastric pain, especially in the context of endometriotic patients. The diagnosis of a gastric submucosal mass requires further investigations to rule out the presence of malignancy or associated adenocarcinoma. Because of it can be associated with transverse colon endometriosis and/or diaphragmatic endometriosis, careful examination of the upper abdomen at laparoscopy should be emphasized. We report here a very rare case of gastric endometriosis associated with transverse colon endometriosis. PMID- 25030664 TI - A concise synthesis of benzimidazoles via the microwave-assisted one-pot batch reaction of amino acids up to a 10-g scale. AB - An efficient method for the synthesis of aminomethyl benzimidazoles is developed by using a one-pot batch reaction between amino acids and o-phenylenediamines. This reaction proceeds smoothly in an unmodified household microwave oven, even though scale-up is to 10 g. A desirable method for the quick synthesis of benzimidazoles, which are used as a kind of important intermediates in drug synthesis, is provided by the scale-up utilization of amino acid resource. PMID- 25030662 TI - Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids. AB - Liver X receptors (Lxrs) are master regulators of cholesterol catabolism, driving the elimination of cholesterol from the periphery to the lumen of the intestine. Development of pharmacological agents to activate Lxrs has been hindered by synthetic Lxr agonists' induction of hepatic lipogenesis and hypertriglyceridemia. Elucidating the function of Lxrs in regulating enterocyte lipid handling might identify novel aspects of lipid metabolism that are pharmacologically amenable. We took a genetic approach centered on the single Lxr gene nr1h3 in zebrafish to study the role of Lxr in enterocyte lipid metabolism. Loss of nr1h3 function causes anticipated gene regulatory changes and cholesterol intolerance, collectively reflecting high evolutionary conservation of zebrafish Lxra function. Intestinal nr1h3 activation delays transport of absorbed neutral lipids, with accumulation of neutral lipids in enterocyte cytoplasmic droplets. This delay in transport of ingested neutral lipids protects animals from hypercholesterolemia and hepatic steatosis induced by a high-fat diet. On a gene regulatory level, Lxra induces expression of acsl3a, which encodes acyl-CoA synthetase long-chain family member 3a, a lipid droplet-anchored protein that directs fatty acyl chains into lipids. Forced overexpression of acls3a in enterocytes delays, in part, the appearance of neutral lipids in the vasculature of zebrafish larvae. Activation of Lxr in the intestine cell-autonomously regulates the rate of delivery of absorbed lipids by inducting a temporary lipid intestinal droplet storage depot. PMID- 25030665 TI - [Not Available]. PMID- 25030663 TI - Intestine-specific MTP and global ACAT2 deficiency lowers acute cholesterol absorption with chylomicrons and HDLs. AB - Intestinal cholesterol absorption involves the chylomicron and HDL pathways and is dependent on microsomal triglyceride transfer protein (MTP) and ABCA1, respectively. Chylomicrons transport free and esterified cholesterol, whereas HDLs transport free cholesterol. ACAT2 esterifies cholesterol for secretion with chylomicrons. We hypothesized that free cholesterol accumulated during ACAT2 deficiency may be secreted with HDLs when chylomicron assembly is blocked. To test this, we studied cholesterol absorption in mice deficient in intestinal MTP, global ACAT2, and both intestinal MTP and global ACAT2. Intestinal MTP ablation significantly increased intestinal triglyceride and cholesterol levels and reduced their transport with chylomicrons. In contrast, global ACAT2 deficiency had no effect on triglyceride absorption but significantly reduced cholesterol absorption with chylomicrons and increased cellular free cholesterol. Their combined deficiency reduced cholesterol secretion with both chylomicrons and HDLs. Thus, contrary to our hypothesis, free cholesterol accumulated in the absence of MTP and ACAT2 is unavailable for secretion with HDLs. Global ACAT2 deficiency causes mild hypertriglyceridemia and reduces hepatosteatosis in mice fed high cholesterol diets by increasing hepatic lipoprotein production by unknown mechanisms. We show that this phenotype is preserved in the absence of intestinal MTP in global ACAT2-deficient mice fed a Western diet. Further, we observed increases in hepatic MTP activity in these mice. Thus, ACAT2 deficiency might increase MTP expression to avoid hepatosteatosis in cholesterol-fed animals. Therefore, ACAT2 inhibition might avert hepatosteatosis associated with high cholesterol diets by increasing hepatic MTP expression and lipoprotein production. PMID- 25030666 TI - [Not Available]. PMID- 25030668 TI - [Not Available]. PMID- 25030667 TI - [Not Available]. PMID- 25030669 TI - [Not Available]. PMID- 25030670 TI - [Not Available]. PMID- 25030671 TI - [Not Available]. PMID- 25030672 TI - [Not Available]. PMID- 25030673 TI - [Not Available]. PMID- 25030674 TI - [Not Available]. PMID- 25030675 TI - [Not Available]. PMID- 25030676 TI - [Not Available]. PMID- 25030677 TI - [Not Available]. PMID- 25030678 TI - [Not Available]. PMID- 25030679 TI - [Not Available]. PMID- 25030680 TI - [Not Available]. PMID- 25030681 TI - [Not Available]. PMID- 25030682 TI - [Not Available]. PMID- 25030683 TI - The effect of metformin on mortality following cancer among patients with diabetes. AB - Diabetes may be a risk factor for cancer and is associated with worse cancer outcomes. Metformin may reduce cancer risk; however, its effect on mortality following cancer remains less clear. EMBASE and Medline were searched through February 10, 2014, for studies reporting an adjusted risk estimate for the effect of metformin therapy on mortality following cancer among diabetic patients. Random-effects models were used to obtain summary HR for the association between metformin and all-cause and cancer-specific mortality. Twenty-one observational studies were meta-analyzed in the primary analysis. Metformin was associated with a reduction in all-cause mortality [HR, 0.73; 95% confidence intervals (CI), 0.64 0.83] and cancer-specific mortality (HR, 0.74; 95% CI, 0.62-0.88). Subgroup analyses by cancer site showed a significant reduction in mortality for colon cancer (four studies, HR, 0.65; 95% CI, 0.56-0.76) but not for breast and prostate cancers. Observational studies indicate that metformin exposure at cancer diagnosis may be associated with a reduction in mortality. However, these findings need to be interpreted with caution as methodologic limitations of individual studies may have introduced biases in these findings. Our results emphasize the need for well-designed studies to further understand the relationship between metformin and survival following cancer. PMID- 25030684 TI - Cardiovascular Risk Factors and 10-year Risk for Coronary Heart Disease in Korean Women. AB - PURPOSE: The purpose of this study is to describe the prevalence of cardiovascular risk factors and to estimate the 10-year risk for coronary heart disease (CHD) in a nationally representative sample of Korean women. METHODS: This is a secondary data analysis using the data set from the 2008 Korea National Health and Nutrition Examination Survey IV. The sample was 2,998 Korean women (weighted n = 14,420,987) aged 20-79 years without cardiovascular disease or diabetes. Prevalence of cardiovascular risk factors was calculated using sampling weights and presented in percentages. Ten-year risk for CHD was estimated with the Framingham Risk Score, and the proportions for three levels of 10-year risk were presented. RESULTS: About 18% of the sample had hypertension, 7.5% are current smoker, 30.0% had total cholesterol >= 200 mg/dL, 25.7% had low-density lipoprotein cholesterol >= 130 mg/dL, and 47.3% had high-density lipoprotein cholesterol < 50 mg/dL. About 46% of Korean women were overweight or obese, and 33.3% were sedentary. About 75% of women had one or more major risk factors. In this study sample, 98.5% had a 10-year risk for CHD of < 10%, 1.4% had a risk of 10-20%, and 0.1% had a risk of > 20%. CONCLUSION: Modifiable cardiovascular risk factors are highly prevalent in Korean women, and the combination of risk factors is common. Development and implementation of multifaceted nursing interventions are required to confront the current epidemic rise of CHD in Korean women. PMID- 25030685 TI - Reliability and Validity of the Turkish Version of Children's Somatization Inventory. AB - PURPOSE: The purpose of this study was to examine the psychometric properties of the Children's Somatization Inventory (CSI) in Turkish schoolchildren and adolescents. METHODS: The CSI was translated using translation and back translation. The participants were 813 schoolchildren, adolescents and their parents (n=453). Content and construct validity were assessed to test the validity of the CSI-24. Internal consistency reliability, interrater reliability (child-parent agreement) and test-retest reliability were assessed to test the reliability of the CSI-24. RESULTS: Psychometric analyses of the Turkish version of the CSI-24 indicate high reliability and good content and construct validity. CONCLUSION: The Turkish version of the CSI-24 is a useful instrument for measuring self-reported somatic complaints in Turkish schoolchildren and adolescents between the ages of 9 and 15. PMID- 25030686 TI - Prevalence of High Blood Pressure and its Relationship with Body Weight Factors among Inpatients with Schizophrenia in Taiwan. AB - PURPOSE: The objective of this study was to document the prevalence of high blood pressure (BP) and to explore its relationship with weight among inpatients with schizophrenia. Additionally, other possible risk factors impacting BP levels in relation to patients' demographic characteristics and use of atypical antipsychotic drugs and medications to reduce blood pressure were analyzed. METHODS: Using medical records, demographic data, and results of physical examination, this cross-sectional study investigated the prevalence of hypertension and high BP and its association with body weight among 1,030 inpatients with schizophrenia in a large psychiatric facility in Taiwan. RESULTS: The prevalence of high BP and hypertension were found to be higher among inpatients with schizophrenia in Taiwan in comparison with those of the general population in line with the latest evidence. Hypertension was significantly associated with body mass index; meanwhile, other risk factors, including age, gender, length of hospital stay, time since initial schizophrenia diagnosis, medications used to reduce blood pressure, and atypical antipsychotics, were identified. However, body mass index was the most effective predictor of blood pressure in the study. CONCLUSION: The findings of this research shed light on the importance of developing effective weight and blood pressure monitoring and management programs for inpatients with schizophrenia. There is also a need for clinical nurses to employ multiple behavioral intervention strategies to minimize risks of high BP in patients with schizophrenia. We recommend that clinical nurses carefully monitor and control BP among inpatients with schizophrenia. PMID- 25030687 TI - Informal caregiving patterns in Korea and European countries: a cross-national comparison. AB - PURPOSE: This ecological study examined demographic and institutional differences in informal caregiving. We conducted a cross-national study about the characteristics of informal caregivers in 12 European countries and Korea. METHODS: Data were collected from individuals aged 50 years and older participating in the 2004/2005 Survey of Health, Ageing and Retirement in Europe and the 2006 Korean Longitudinal Study of Ageing. We examined the associations between informal caregiving and macrolevel characteristics (gross domestic product, total fertility rates, labor force participation rates, level of women's empowerment, long-term care resources). RESULTS: Korea and some southern European countries, notably Spain and Italy, had high percentages of women, homemakers, coresidents, and spouses in informal caregiving roles. In contrast, Northern European countries such as Denmark and Sweden had high proportions of employed informal caregivers. Lower female labor force participation was associated with higher proportions of women caregivers. A higher proportion of women caregivers in the population were also associated with a lower national gross domestic product per capita. CONCLUSION: Our findings suggest that several contextual and institutional variables are associated with the proportion of women participating in caregiving. PMID- 25030688 TI - Traditional Chinese Pregnancy Restrictions, Health-Related Quality of Life and Perceived Stress among Pregnant Women in Macao, China. AB - PURPOSE: The objectives of this study were to identify the prevalence and rationales of traditional Chinese pregnancy restrictions and to investigate the relationship between pregnancy restriction, health-related quality of life, and perceived stress level at a two-stage design. METHODS: Stage I consisted of exploring the traditional Chinese pregnancy restrictions and their underlying beliefs based on extensive literature review followed by in-depth interviews with 30 pregnant women. Stage II investigated the relationship between pregnancy restrictions, health-related quality of life, and perceived stress among 1,151 women. Self-developed traditional Chinese pregnancy restrictions lists were measured on adherence towards the traditional Chinese pregnancy restriction. Perceived stress and health-related quality of life were measured by the Perceived Stress Scale and the Short Form-12 (SF-12) Health Survey, respectively. RESULTS: The majority of the women adhered to traditional Chinese pregnancy restrictions in order to protect the unborn child from danger and to avoid the problems associated pregnancy and birth, such as miscarriage, stillbirth, death of the mother, and imperfections in the newborn. Pregnant women who adhered to behavioral restrictions were more likely to associate with poor physical component of health-related quality of life. However, there was no significant difference between pregnancy restrictions and Perceived Stress Scale scores. CONCLUSION: The findings provided cultural rationales of pregnancy restrictions within a Macao context that may assist health professionals to better understand women from different cultures. It is essential in the development of culturally appropriate healthcare to support women in making a healthy transition to motherhood. PMID- 25030689 TI - The Effects of Baby Massage on Attachment between Mother and their Infants. AB - PURPOSE: This study was conducted to examine the effect of baby massage on attachment between mothers and their newborns. METHODS: This study was carried out from June 2008 to February 2010 in a quasi-experimental design (57 in the experimental group, 60 in the control group). Between the dates of the study, all healthy primipara mothers and their healthy babies were included. Data were collected regarding their demographic characteristics and by using the Maternal Attachment Inventory (MAI). All mothers were assessed on the first and the last days of the 38-day study period. In the experimental group, the babies received a 15-minute massage therapy session everyday during the 38 days. RESULTS: There was no significant difference found in the pretest mean value baseline of the MAI score in both groups. The posttest mean values of the MAI of the experimental group mothers (90.87 +/- 10.76) were significantly higher than those of control group (85.10 +/- 15.50). There was a significant difference between groups (p < .05). CONCLUSION: The results of the study have shown that baby massage is effective in increasing the mother-infant attachment. PMID- 25030690 TI - A Comparative Study on Physical Function Test between Faller Group and Nonfaller Group among Community-Dwelling Elderly. AB - PURPOSE: This study aimed to identify the physical function test differences between the faller group and the nonfaller group in a sample of the community dwelling elderly. METHODS: This study used a nonexperimental two-group comparative study design. The participants were 356 people aged 65 years and over living in an urban area. From May to December 2010, data were collected through personal interviews using questionnaires and measurements of muscle strength, physical endurance, flexibility, motor agility and dynamic balance, and static balance. The collected data were analyzed by descriptive statistics, Chi square analysis, and t test. RESULTS: Upper muscle strength was significantly weaker in the faller group (p<.05). Lower muscle strength was significantly weaker in the faller group; both hip flexion (p=.004), knee extension (Right: p=.004; Left: p=.031), left ankle plantar flexion (p=.045), and left ankle inversion (p=.036). Tandem standing with eyes opened and closed was significantly shorter, indicating decreased static balance in the faller group. CONCLUSION: Nurses should make efforts to implement exercise programs focused on physical fitness enhancement for community-dwelling elderly adults for fall prevention. PMID- 25030691 TI - Trends in clinical features, postoperative outcomes, and long-term survival for gastric cancer: a Western experience with 1,278 patients over 30 years. AB - BACKGROUND: The aim of the present study was to identify temporal trends in long term survival and postoperative outcomes and to analyze prognostic factors influencing the prognosis of patients with gastric cancer (GC) treated in a 30 year interval in a tertiary referral Western institution. METHODS: Between January 1980 and December 2010, 1,278 patients who were diagnosed with GC at the Digestive Surgery Department, Catholic University of Rome, Italy, were identified. Among them, 936 patients underwent surgical resection and were included in the analysis. RESULTS: Over time there was a significant improvement in postoperative outcomes. Morbidity and mortality rates decreased to 19.4% and 1.6%, respectively, in the last decade. By contrast, the multivisceral resection rate steadily increased from 12.7% to 29.6%. The overall five-year survival rate steadily increased over time, reaching 51% in the last decade, and 64.5% for R0 resections. Multivariate analysis showed a higher probability of overall survival for early stages (I and II), extended lymphadenectomy, and R0 resections. CONCLUSIONS: Over three decades there was a significant improvement in perioperative and postoperative care and a steady increase in overall survival. PMID- 25030692 TI - Wnt some lose some: transcriptional governance of stem cells by Wnt/beta-catenin signaling. AB - In mammals, Wnt/beta-catenin signaling features prominently in stem cells and cancers, but how and for what purposes have been matters of much debate. In this review, we summarize our current knowledge of Wnt/beta-catenin signaling and its downstream transcriptional regulators in normal and malignant stem cells. We centered this review largely on three types of stem cells--embryonic stem cells, hair follicle stem cells, and intestinal epithelial stem cells--in which the roles of Wnt/beta-catenin have been extensively studied. Using these models, we unravel how many controversial issues surrounding Wnt signaling have been resolved by dissecting the diversity of its downstream circuitry and effectors, often leading to opposite outcomes of Wnt/beta-catenin-mediated regulation and differences rooted in stage- and context-dependent effects. PMID- 25030693 TI - Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling. AB - Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span. PMID- 25030694 TI - Two waves of de novo methylation during mouse germ cell development. AB - During development, mammalian germ cells reprogram their epigenomes via a genome wide erasure and de novo rewriting of DNA methylation marks. We know little of how methylation patterns are specifically determined. The piRNA pathway is thought to target the bulk of retrotransposon methylation. Here we show that most retrotransposon sequences are modified by default de novo methylation. However, potentially active retrotransposon copies evade this initial wave, likely mimicking features of protein-coding genes. These elements remain transcriptionally active and become targets of piRNA-mediated methylation. Thus, we posit that these two waves play essential roles in resetting germ cell epigenomes at each generation. PMID- 25030695 TI - Healing for destruction: tRNA intron degradation in yeast is a two-step cytoplasmic process catalyzed by tRNA ligase Rlg1 and 5'-to-3' exonuclease Xrn1. AB - In eukaryotes and archaea, tRNA splicing generates free intron molecules. Although ~ 600,000 introns are produced per generation in yeast, they are barely detectable in cells, indicating efficient turnover of introns. Through a genome wide search for genes involved in tRNA biology in yeast, we uncovered the mechanism for intron turnover. This process requires healing of the 5' termini of linear introns by the tRNA ligase Rlg1 and destruction by the cytoplasmic tRNA quality control 5'-to-3' exonuclease Xrn1, which has specificity for RNAs with 5' monophosphate. PMID- 25030696 TI - The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages. AB - RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program. PMID- 25030697 TI - Lineage of origin in rhabdomyosarcoma informs pharmacological response. AB - Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1. PMID- 25030698 TI - Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions. AB - Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development. PMID- 25030699 TI - A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. AB - A key function of the cellular DNA damage response is to facilitate the bypass of replication fork-stalling DNA lesions. Template switch reactions allow such a bypass and involve the formation of DNA joint molecules (JMs) between sister chromatids. These JMs need to be resolved before cell division; however, the regulation of this process is only poorly understood. Here, we identify a regulatory mechanism in yeast that critically controls JM resolution by the Mus81 Mms4 endonuclease. Central to this regulation is a conserved complex comprising the scaffold proteins Dpb11 and Slx4 that is under stringent control. Cell cycle dependent phosphorylation of Slx4 by Cdk1 promotes the Dpb11-Slx4 interaction, while in mitosis, phosphorylation of Mms4 by Polo-like kinase Cdc5 promotes the additional association of Mus81-Mms4 with the complex, thereby promoting JM resolution. Finally, the DNA damage checkpoint counteracts Mus81-Mms4 binding to the Dpb11-Slx4 complex. Thus, Dpb11-Slx4 integrates several cellular inputs and participates in the temporal program for activation of the JM-resolving nuclease Mus81. PMID- 25030700 TI - MicL, a new sigmaE-dependent sRNA, combats envelope stress by repressing synthesis of Lpp, the major outer membrane lipoprotein. AB - In enteric bacteria, the transcription factor sigma(E) maintains membrane homeostasis by inducing synthesis of proteins involved in membrane repair and two small regulatory RNAs (sRNAs) that down-regulate synthesis of abundant membrane porins. Here, we describe the discovery of a third sigma(E)-dependent sRNA, MicL (mRNA-interfering complementary RNA regulator of Lpp), transcribed from a promoter located within the coding sequence of the cutC gene. MicL is synthesized as a 308-nucleotide (nt) primary transcript that is processed to an 80-nt form. Both forms possess features typical of Hfq-binding sRNAs but surprisingly target only a single mRNA, which encodes the outer membrane lipoprotein Lpp, the most abundant protein of the cell. We show that the copper sensitivity phenotype previously ascribed to inactivation of the cutC gene is actually derived from the loss of MicL and elevated Lpp levels. This observation raises the possibility that other phenotypes currently attributed to protein defects are due to deficiencies in unappreciated regulatory RNAs. We also report that sigma(E) activity is sensitive to Lpp abundance and that MicL and Lpp comprise a new sigma(E) regulatory loop that opposes membrane stress. Together MicA, RybB, and MicL allow sigma(E) to repress the synthesis of all abundant outer membrane proteins in response to stress. PMID- 25030701 TI - Fetal sex and race modify the predictors of fetal growth. AB - The objective of this study is unknown if fetal sex and race modify the impact of maternal pre-pregnancy body mass index (BMI), and smoking on fetal growth. The authors studied markers of fetal growth in singleton offspring of 8,801 primiparous, normotensive women, enrolled in the Collaborative Perinatal Project. The authors tested for departures from additivity between sex/race and each predictor. The head-to-chest circumference ratio (HCC) decreased more, while birthweight and ponderal index (PI) increased more for each 1 kg/m(2) increase in pre-pregnancy BMI among term females versus males (P = 0.07, P < 0.01 and P = 0.08, interaction respectively). For term offspring of White compared with Black women, smoking independent of "dose" was associated with larger reductions in growth (165 g vs. 68 g reduction in birthweight, P < 0.01, interaction), greater reduction in fetal placental ratio (P < 0.01, interaction), PI (P < 0.01, interaction), and greater increase in HCC (P = 0.02), respectively. The association of BMI and smoking with fetal size appeared to be reversed in term versus preterm infants. Our study provides evidence that the associations of pre pregnancy BMI and smoking are not constant across sex and race. This finding may be relevant to sex and race differences in neonatal and long term health outcomes. PMID- 25030702 TI - A root-cause analysis of maternal deaths in Botswana: towards developing a culture of patient safety and quality improvement. AB - BACKGROUND: In 2007, 95% of women in Botswana delivered in health facilities with 73% attending at least 4 antenatal care visits. HIV-prevalence in pregnant women was 28.7%. The maternal mortality ratio in 2010 was 163 deaths per 100,000 live births versus the government target of 130 for that year, indicating that the Millennium Development Goal 5 was unlikely to be met. A root-cause analysis was carried out with the aim of determining the underlying causes of maternal deaths reported in 2010, to categorise contributory factors and to prioritise appropriate interventions based on the identified causes, to prevent further deaths. METHODS: Case-notes for maternal deaths were reviewed by a panel of five clinicians, initially independently then discussed together to achieve consensus on assigning contributory factors, cause of death and whether each death was avoidable or not at presentation to hospital. Factors contributing to maternal deaths were categorised into organisational/management, personnel, technology/equipment/supplies, environment and barriers to accessing healthcare. RESULTS: Fifty-six case notes were available for review from 82 deaths notified in 2010, with 0-4 contributory factors in 19 deaths, 5-9 in 27 deaths and 9-14 in nine. The cause of death in one case was not ascertainable since the notes were incomplete. The high number of contributory factors demonstrates poor quality of care even where deaths were not avoidable: 14/23 (61%) of direct deaths were considered avoidable compared to 12/32 (38%) indirect deaths. Highest ranking categories were: failure to recognise seriousness of patients' condition (71% of cases); lack of knowledge (67%); failure to follow recommended practice (53%); lack of or failure to implement policies, protocols and guidelines (44%); and poor organisational arrangements (35%). Half the deaths had some barrier to accessing health services. CONCLUSIONS: Root-cause analysis demonstrates the interactions between patients, health professionals and health system in generating adverse outcomes for patients. The lessons provided indicate where training of undergraduate and postgraduate medical, midwifery and nursing students need to be intensified, with emphasis on evidence-based practice and adherence to protocols. Action plans and interventions aimed at changing the circumstances that led to maternal deaths can be implemented and re-evaluated. PMID- 25030703 TI - One-stage extra-anatomical total thoracic aortic repair. PMID- 25030705 TI - Effect of bed height and use of hands on trunk angular velocity during the sit-to stand transfer. AB - The ability to rise from a chair or bed is critical to an individual's quality of life because it determines functional independence. This study was to investigate the effect of bed height and use of hands on trunk angular velocity and trunk angles during the sit-to-stand (STS) performance. Twenty-four older persons (median age 74 years) were equipped with a body-fixed gyroscopic sensor and stood up from a bed adjusted to different heights, with and without the use of hands at each height. Peak angular velocity and trunk range of motion decreased with increasing bed height (all p <= 0.038) and were lower using hands during STS transfer indicating less effort. In conclusion, gyroscopic sensor data of the STS transfer of older persons show differences as an effect of bed height and use of hands. These results provide the rationale for recommending a relatively high bed height for most of the older persons. PRACTITIONER SUMMARY: To minimise the effort during sit-to-stand transfer performance from bed, it is necessary to understand the effect of bed height and use of hands. It is concluded that a relatively high bed height and the use of hands is helpful for most of the older persons during sit-to-stand transfer. PMID- 25030706 TI - Shape-defined nanodimers by tailored heterometallic epitaxy. AB - The systematic construction of heterogeneous nanoparticles composed of two distinct metal domains (Au and Pt) and exhibiting a broad range of morphologically defined shapes is reported. It is demonstrated that careful Au overgrowth on Pt nanocrystal seeds with shapes mainly corresponding to cubeoctahedra, octahedra and octapods can lead to heterometallic systems whose intrinsic structures result from specific epitaxial relationships such as {111} + {111}, {200} + {200} and {220} + {220}. Comprehensive analysis shows also that nanoparticles grown from octahedral seeds can be seen as comprising of four Au tetrahedral subunits and one Pt octahedral unit in a cyclic arrangement that is similar to the corresponding one in decahedral gold nanoparticles. However, in the present case, the multi-component system is characterized by a broken five fold rotational symmetry about the [011] axis. This set of bimetallic dimers could provide new platforms for fuel cell catalysts and plasmonic devices. PMID- 25030704 TI - Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. AB - Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure. PMID- 25030707 TI - The practice of in vitro fertilization according to the published literature. PMID- 25030708 TI - Comparison of dust release from epoxy and paint nanocomposites and conventional products during sanding and sawing. AB - The release of dust generated during sanding or sawing of nanocomposites was compared with conventional products without nanomaterials. Epoxy-based polymers with and without carbon nanotubes, and paints with different amounts of nano sized titanium dioxide, were machined in a closed aerosol chamber. The temporal evolution of the aerosol concentration and size distribution were measured simultaneously. The morphology of collected dust by scanning electron microscopy was different depending on the type of nanocomposites: particles from carbon nanotubes (CNTs) nanocomposites had protrusions on their surfaces and aggregates and agglomerates are attached to the paint matrix in particles emitted from alkyd paints. We observed no significant differences in the particle size distributions when comparing sanding dust from nanofiller containing products with dust from conventional products. Neither did we observe release of free nanomaterials. Instead, the nanomaterials were enclosed or partly enclosed in the matrix. A source strength term Si (cm(-3) s(-1)) that describes particle emission rates from continuous sources was introduced. Comparison between the Si parameters derived from sanding different materials allows identification of potential effects of addition of engineered nanoparticles to a composite. PMID- 25030709 TI - Spontaneous subdural fluid collection following aneurysmal subarachnoid hemorrhage: subdural hygroma or external hydrocephalus? AB - BACKGROUND: Subdural fluid collections (hygromas and effusions) in adults are usually seen following head trauma or overdrainage of cerebrospinal fluid (CSF) after CSF diversion procedures. We report an unusual case of subdural fluid collection that developed spontaneously 5 days after an aneurysmal subarachnoid hemorrhage (SAH). This patient neither had permanent CSF diversion procedure nor history of significant head trauma during her clinical course. METHODS: This study is a Case report of the patient suffering from an SAH. RESULTS: A 71-year old woman suffered an SAH from a ruptured right-sided posterior communicating artery aneurysm. Computed tomography (CT) demonstrated diffuse SAH and signs of early hydrocephalus that did not require treatment. The aneurysm was treated with endovascular coil occlusion without any complications. Throughout her hospital course, she remained alert without neurological deficits. A large subdural fluid collection was discovered incidentally during a routine CT scan of the brain 5 days after the SAH. The patient remained asymptomatic; therefore, the collection was treated conservatively. It resolved spontaneously at five days after the initial diagnosis. CONCLUSION: Subdural fluid collections following SAH can occur as a result of head trauma, external hydrocephalus, or as a treatment complication of CSF shunting and craniotomies. It is critical to differentiate simple hygromas from external hydrocephalus since their response to CSF diversion is entirely different. PMID- 25030710 TI - Electroencephalography in survivors of cardiac arrest: comparing pre- and post therapeutic hypothermia eras. AB - Electroencephalography in the setting of hypothermia and anoxia has been studied in humans since the 1950s. Specific patterns after cardiac arrest have been associated with prognosis since the 1960s, with several prognostic rating scales developed in the second half of the twentieth century. In 2002, two pivotal clinical trials were published, demonstrating improved neurologic outcomes in patients treated with therapeutic hypothermia (TH) after cardiac arrest of shockable rhythms. In the following years, TH became the standard of care in these patients. During the same time period, the use of continuous EEG monitoring in critically ill patients increased, which led to the recognition of subclinical seizures occurring in patients after cardiac arrest. As a result of these changes, greater amounts of EEG data are being collected, and the significance of specific patterns is being re-explored. We review the current role of EEG for the identification of seizures and the estimation of prognosis after cardiac resuscitation. PMID- 25030711 TI - The functional exercise capacity and its correlates in obese treatment-seeking people with binge eating disorder: an exploratory study. AB - PURPOSE: The primary aim was to compare the functional exercise capacity between obese treatment-seeking people with and without binge eating disorder (BED) and non-obese controls. The secondary aim was to identify clinical variables including eating and physical activity behaviour, physical complaints, psychopathology and physical self-perception variables in obese people with BED that could explain the variability in functional exercise capacity. METHODS: Forty people with BED were compared with 20 age-, gender- and body mass index (BMI)-matched obese persons without BED and 40 age and gender matched non-obese volunteers. A 6-minute walk test (6MWT), the Baecke physical activity questionnaire, the Symptom Checklist-90, the Physical Self-Perception Profile and the Eating Disorder Inventory were administered. Physical complaints before and after the 6MWT were also documented. RESULTS: The distance achieved on the 6MWT was significantly lower in obese participants with BED (512.1 +/- 75.8 m versus 682.7 +/- 98.4, p < 0.05) compared to non-obese controls. No significant differences were found between obese participants with and without BED. Participants with BED reported significantly (p < 0.05) more musculoskeletal pain and fatigue after the walk test than obese and non-obese controls. A forward stepwise regression analysis demonstrated that sports participation and perceived physical strength explained 41.7% of the variance on the 6MWT in obese participants with BED. CONCLUSION: Physical activity participation, physical self perception and perceived physical discomfort during walking should be considered when developing rehabilitation programs for obese people with BED. IMPLICATIONS FOR REHABILITATION: Rehabilitation programmes in people with binge eating disorder should incorporate a functional exercise capacity assessment. Clinicians involved in the rehabilitation of people with binge eating disorder should consider depression and lower self-esteem as potential barriers. Clinicians should take into account the frequently observed physical discomfort when developing rehabilitation programmes for people with binge eating disorder. PMID- 25030712 TI - Volatile constituents of Stachys palaestina L. (Palestine woundwort) growing in Lebanon. AB - The hydrodistillation of the aerial parts of Stachys palaestina L. collected in Lebanon in the Kadisha Valley, yielded 0.1% (w/w) of essential oil. GC and GC-MS analyses enabled the identification of 87 compounds representing 90.8% of the total oil. Hexadecanoic acid (10%), hexahydrofarnesyl acetone (6.9%), eugenol (4.3%) and (E)-caryophyllene (4.3%) were the main components. On the whole, the oil was constituted mainly of sesquiterpenes (37.7%), among which sesquiterpene hydrocarbons (20.7%) slightly prevailed over oxygenated sesquiterpenes (17.0%). This is the first report on the chemical composition of S. palaestina essential oil. PMID- 25030713 TI - IR Li2Ga2GeS6 nanocrystallized GeS2-Ga2S3-Li2S electroconductive chalcogenide glass with good nonlinearity. AB - GeS(2)-Ga(2)S(3)-Li(2)S electroconductive glasses were prepared by the conventional melt-quenching method through carefully controlling the heating rate. Comparing with the reference of glass-forming region, our investigated GeS(2)-Ga(2)S(3)-Li(2)S system was extended to the cation ratio of 0-20% Li with around 40% Ga. GeS(2)-Ga(2)S(3)-Li(2)S glass-ceramics containing IR Li2Ga2GeS6 nonlinear nanocrystals were obtained by the more carefully controlled heating rate. Its optical nonlinearity was investigated by the Maker fringe measurements, the maximum second harmonic intensity was observed to be 0.35 of the reference Z cut quartz. IR Li(2)Ga(2)GeS(6) nonlinear crystals were directly obtained at the composition of 40GeS(2)-30GaS(1.5)-30LiS(0.5). PMID- 25030714 TI - Oral rabeprazole administration on a procedure day suppresses bleeding after endoscopic submucosal dissection for gastric neoplasms. AB - AIM: The efficacy of pre-procedure oral proton pump inhibitor (PPI) administration for gastric endoscopic submucosal dissection (ESD) is unclear. This study evaluated oral PPI administration effectiveness on the day of ESD to prevent post-ESD bleeding. METHODS: This study examined 55 patients who underwent ESD for gastric neoplasm. Group A comprised 31 patients who took rabeprazole sodium (RPZ) 20 mg/day beginning 7-8 hr before ESD. Group B comprised 24 who took RPZ 20 mg/day beginning three days before ESD. Gastric pH (G-pH) was measured at one month before ESD (pre-ESD pH), immediately before ESD (ESD pH), and seven days after ESD (post-ESD pH). The post-ESD bleeding rate and changes in G-pH were recorded. RESULTS: No significant difference in post-ESD bleeding rates was found (Group A 3.2%, Group B 0%). ESD pH and post-ESD pH were significantly higher than pre-ESD pH in both groups (P<0.001). The ESD pH for Group A was higher than 6 (6.5+/-1.1), providing hemostasis for intragastric bleeding. CONCLUSIONS: Oral RPZ administration on the day of gastric ESD can suppress post-ESD bleeding equivalently to administration three days before ESD. PMID- 25030715 TI - Psychological distress after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident: results of a mental health and lifestyle survey through the Fukushima Health Management Survey in FY2011 and FY2012. AB - BACKGROUND: On 11 March 2011, the Great East Japan Earthquake followed by a gigantic tsunami hit the Pacific coast of Northeast Japan (Tohoku) and damaged Tokyo Electric Power Company's Fukushima Daiichi Nuclear Power Plant, causing a radiation hazard in the entire Fukushima Prefecture. The radiation dose exposed either externally and internally in Fukushima residents have been evaluated to be low so far and it is hardly believed that they may have any direct radiation risk on physical condition. The purpose of this report is, therefore, to describe results of a mental health and lifestyle survey intended to facilitate adequate care for residents who are at a higher risk of developing mental health problems after the complicated accident. PARTICIPANTS AND METHODS: The target population of this survey is the residents of evacuation zones including Hirono Town, Naraha Town, Tomioka Town, Kawauchi Village, Okuma Town, Futaba Town, Namie Town, Katsurao Village, Minamisoma City, Tamura City, Yamakiya district of Kawamata Town, and Iitate Village. The targeted population was 210,189 in fiscal year 2011 (FY2011) and 211,615 in fiscal year 2012 (FY2012). Questionnaires have been mailed since January 2012, and subsequently, January 2013, 10 and 22 months after the disaster. Among of them, children 63.4%, adults 40.7% for FY2011, and children 41.0%, adults 29.7% for FY2012 responded to the questionnaires mailed. RESULTS: Sociodemographic data showed that many evacuee households were separated after the disaster and had to move several times. K6 was used in this survey to estimate general mental health. The proportion (14.6% in FY2011 and 11.9% inFY2012) of adults who scored above the K6 cut-off (>=13) for general mental health was higher than usual, indicating severe mental health problems among evacuees. The proportion (21.6% in FY2011 and 18.3% inFY2012) of adults who scored above the cut-off (>=44) of PTSD checklist (PCL), reflecting traumatic symptoms, was almost equal to that of the workers after the 9.11 World Trade Center attacks. These results also indicate the presence of severe traumatic problems among evacuees. The proportions of children (4-6 years old) and children of primary school age (6-12 years old) who scored above the cut-off (>=16) of Strengths and Difficulties Questionnaire (SDQ) reflecting the mental health status in children, 24.4% and 22.0% in the survey of FY2011, were double the usual state respectively, whereas 16.6% in children of 4-6 years old and 15.8% in children of 6-12 years old in FY2012 were 1.5 times. These findings also disclosed the presence of severe mental difficulties in children, with relative improvement year by year. CONCLUSION: As revealed by the present mental health survey, the earthquake and tsunami followed by the nuclear accident caused psychological distress among residents in Fukushima prefecture. Continuous survey and mental care programs are required. PMID- 25030717 TI - Pregnant and birth survey after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident In Fukushima Prefecture. PMID- 25030716 TI - An overview of internal dose estimation using whole-body counters in Fukushima Prefecture. AB - A large amount of radioactive cesium was released by the Fukushima Daiichi Nuclear Power Plant accident following the Great East Japan Earthquake. Due to the increasing concerns about internal exposure, more than 50 whole-body counters (WBCs) have been installed at various locations in Fukushima Prefecture. A study on around 10,000 subjects in the early stage after the accident revealed that very few received a committed effective dose of more than 0.3 mSv for subjects (age >13 years old). Another study on WBC results for one hospital showed that the ratio of cesium-positive was 1.0% among all the subjects. Assuming a constant daily intake, the detection limit of 300 Bq/body for a typical WBC corresponds to an effective dose of 21 MUSv/y even for a subject of age up to 10. It was also seen out that the subjects with a significant amount of body cesium are likely to regularly eat wild products, which they harvested or caught themselves without testing for radioactive cesium. These study findings suggested that the internal exposure for most of the residents was controlled at a very low level. Future tasks regarding WBC measurements are how to personally explain the WBC results to each subject and how to disclose the statistically processed WBC data to the general public. PMID- 25030718 TI - Isolation and autoxidation profile of fish myoglobin from hoki (Macruronus magellanicus). AB - Myoglobin is known to be present exclusively in cardiac and red skeletal muscles, but not in white skeletal muscles. Thus, to date, only a few studies on myoglobin from fish species with white flesh have been reported. For comparative examination, we directly isolated myoglobin from cardiac muscle of hoki (Macruronus magellanicus), one of the most important commercial fish species with white muscle. The ferrous myoglobin was separated from its ferric met-form by anion exchange column chromatography. The absorption spectra of hoki myoglobin were similar to those of bigeye tuna skeletal myoglobin, in both oxy- and met forms. However, hoki oxymyoglobin was found to be susceptible to autoxidation in 0.1 M buffer (pH 7.2) at 25 degrees C, with its rate being more than 3 times higher than that of bigeye tuna oxymyoglobin. PMID- 25030719 TI - Pregnancy and birth survey after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident in Fukushima prefecture. AB - BACKGROUND: On 11 March 2011, the Great East Japan Earthquake followed by a powerful tsunami hit the Pacific Coast of Northeast Japan and damaged Tokyo Electric Power Company's Fukushima Daiichi Nuclear Power Plant, causing a radiation hazard in Fukushima Prefecture. The objective of this report is to describe some results of a questionnaire-based pregnancy and birth survey conducted by the Radiation Medical Science Center for the Fukushima Health Management Survey. MATERIALS AND METHODS: Questionnaires were sent to women who received maternal and child health handbooks from municipal officers in Fukushima Prefecture between 1 August 2010 and 31 July 2011, with the aim of reaching those who were pregnant at the time of the disaster. Mailing began 18 January 2012. Data were analyzed separately for six geographic areas in Fukushima Prefecture. RESULTS: The total number of women meeting survey criteria was 15,972. The number of responses received to date is 9,298 (58.2%). Data from 8602 respondents were analyzed after excluding 634 invalid responses and 5 induced and 57 spontaneous abortions (less than 22 gestational weeks). The incidences of stillbirth (over 22 completed gestational weeks), preterm birth, low birth weight and congenital anomalies were 0.25%, 4.4%, 8.7% and 2.72%, respectively. These incidences are similar to recent averages elsewhere in Japan. CONCLUSION: Considering the pregnancy and birth survey data in aggregate, our disaster seemed to provoke no significant adverse outcomes over the whole of Fukushima prefecture. But post disaster prenatal care and support intended for patients' safety and security should be coupled with ongoing surveillance and rigorous data analysis. PMID- 25030720 TI - Prediction of recurrence for non-small cell lung cancer by combined analysis of molecular markers and 18F 2-fluoro-2-deoxy-D-glucose positron emission tomography. AB - PURPOSE: Numerous biomarkers have been reported to reflect prognosis in patients with non-small cell lung cancer, but most of them remain controversial in terms of the clinical benefits. The aim of this study is to establish a novel procedure in combined analyses of molecular markers and biomedical image for precise prediction for patient prognosis of non-small cell lung cancer. EXPERIMENTAL DESIGN: Molecular markers related to cell cycle and proliferation and (18)F 2 fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) were retrospectively analyzed for their utility as prognostic parameters in 54 patients with non-small cell lung cancer. Expression of ten representative molecular markers (Glut-1, proliferating cell nuclear antigen, Ki-67, cyclin B1, cyclin D1, cyclin E, E2F-1, p21, p27, and p53) were immunohistochemically analyzed using tissue microarray. The maximum standardized uptake value (SUVmax) on FDG-PET was analyzed as a semiquantitative value of FDG uptake of the primary tumor. RESULTS: Several molecular markers were significantly correlated with some of clinicopathological parameters, whereas none of each marker were correlated with recurrence or survival. Hierarchical clustering analysis in combination of immunohistochemical analysis of molecular expressions and SUVmax divided them into three subgroups significantly different in two-year recurrent-free survival (Cluster A, 56.3%; B, 100%; C 93.8%). These clustering subgroups were also significantly correlated with disease recurrence (p=0.0282). CONCLUSIONS: Hierarchical clustering analysis, based on molecular markers and FDG accumulation, could be an efficient tool for prediction of recurrence and survival in patients with non-small cell lung cancer. PMID- 25030721 TI - Successful endovascular treatment of chronic total occlusion of superficial femoral artery using retrograde approach from deep femoral artery. AB - An 82 years-old man with intermittent claudication was admitted to our hospital. Computed tomography angiography showed his right superficial femoral artery (SFA) was chronic total occlusion (CTO), and we performed endovascular treatment (EVT). We advanced a guide-wire by contralateral transfemoral approach, but guide-wires could not penetrate the occluded SFA lesion antegradely. Thus, we tried to approach the CTO lesion retrogradely. A guide-wire passed through the collateral channel from deep femoral artery (DFA) to distal SFA. With a reverse-controlled antegrade and retrograde subintimal tracking (CART) technique, we were able to pass the CTO lesion. Finally two SMART stents were implanted. We experienced a case in which retrograde approach via collateral channel from DFA was effective to CTO of SFA. PMID- 25030722 TI - Therapeutic efficacy of pregabalin in patients with leg symptoms due to lumbar spinal stenosis. AB - The purpose of this study was to evaluate the therapeutic efficacy of pregabalin in patients with leg symptoms due to lumbar spinal stenosis. Study subjects were classified into two groups according to their pharmacotherapy: the pregabalin group, treated with nonsteroidal anti-inflammatory drug and pregabalin combination therapy, and the control group, treated with nonsteroidal anti inflammatory drug monotherapy. The two groups were compared in terms of the duration of pain after the onset of leg symptoms and the type of neurogenic intermittent claudication, whether radicular-, caudal-, or mixed-type. Numerical rating scale and Roland-Morris Disability Questionnaire scores were evaluated before and 3 months after treatment. After 3 months of treatment, there were significant differences in the numerical rating scale for radicular- and mixed types, but not for caudal-type, between the two groups in the subjects with leg symptoms for greater than 3 months. There were significant differences between the two groups in Roland-Morris Disability Questionnaire scores for mixed-type, but not for radicular- and caudal-types, in the subjects with leg symptoms for less than 3 months and for radicular- and mixed-types, but not for caudal-type, in the subjects with leg symptoms for greater than 3 months. Nonsteroidal anti inflammatory drug and pregabalin combination therapy may be more effective than nonsteroidal anti-inflammatory drug monotherapy for the relief of leg symptoms due to lumbar spinal stenosis, preventing aggravation of subjective symptoms and improving quality of life for patients with radicular- and mixed-types in subjects with leg symptoms for greater than 3 months, although it may be necessary to consider alternative therapy for patients with caudal-type. PMID- 25030723 TI - Current techniques to improve outcomes for early return of urinary continence following robot-assisted radical prostatectomy. AB - Although open retropubic radical prostatectomy has been the most commonly used surgical technique for patients with localized prostate cancer for decades, robot assisted radical prostatectomy (RARP) has recently become an alternative option and widely used in Japan as well as around the world. RARP has been shown to have higher postoperative continent rates than retropubic and laparoscopic radical prostatectomy; however, urinary incontinence has remained one of the most significant causes for concern among patients who seek surgical treatment for prostate cancer, even after the introduction of RARP. The literature has shown that certain technical modifications to improve urinary continence are advocated as potential aids to reduce the risk of urinary incontinence after RARP. These modifications might be divided into 3 categories to realize the improvement of early return of urinary continence after RARP: 1) preservation, 2) reconstruction, and 3) reinforcement of the anatomic structures in the pelvis, which will make a new supporting system after radical prostatectomy. In this review, we discuss the intraoperative techniques to improve outcomes for early return of urinary continence following RARP, and provide a critical summary of current knowledge on its outcome in the literature. PMID- 25030724 TI - Radioactive substances in tap water. AB - A 9.0 magnitude (M) earthquake with an epicenter off the Sanriku coast occurred at 14: 46 on March 11, 2011. TEPCO Fukushima Daiichi Nuclear Power Plant (F-1 NPP) was struck by the earthquake and its resulting tsunami. Consequently a critical nuclear disaster developed, as a large quantity of radioactive materials was released due to a hydrogen blast. On March 16(th), 2011, radioiodine and radioactive cesium were detected at levels of 177 Bq/kg and 58 Bq/kg, respectively, in tap water in Fukushima city (about 62km northwest of TEPCO F-1 NPP). On March 20th, radioiodine was detected in tap water at a level of 965 Bq/kg, which is over the value-index of restrictions on food and drink intake (radioiodine 300 Bq/kg (infant intake 100 Bq/kg)) designated by the Nuclear Safety Commission. Therefore, intake restriction measures were taken regarding drinking water. After that, although the all intake restrictions were lifted, in order to confirm the safety of tap water, an inspection system was established to monitor all tap water in the prefecture. This system has confirmed that there has been no detection of radioiodine or radioactive cesium in tap water in the prefecture since May 5(th), 2011. Furthermore, radioactive strontium ((89) Sr, (90)Sr) and plutonium ((238)Pu, (239)Pu+(240)Pu) in tap water and the raw water supply were measured. As a result, (89) Sr, (238)Pu, (239)Pu+(240)Pu were undetectable and although (90)Sr was detected, its committed effective dose of 0.00017 mSv was much lower than the yearly 0.1 mSv of the World Health Organization guidelines for drinking water quality. In addition, the results did not show any deviations from past inspection results. PMID- 25030725 TI - Focal bacterial nephritis without pyuria in a boy presenting with high urinary beta2-MG and NAG levels. AB - Acute focal bacterial nephritis (AFBN) is a localized bacterial infection of the kidney presenting as an inflammatory mass without frank abscess formation. We report a case of acute focal bacterial nephritis without pyuria in a five-month old boy presenting with high urinary beta2-microglobulin (beta2-MG) and N-Acetyl beta-(D)-Glucosaminidase (NAG) levels. The infant initially presented with high grade fever, and plain computed tomography (CT) showed a nearly isodense mass, and contrast-enhanced abdominal CT showed a wedge-shaped hypodense lesion. Enterococcus was detected in the subsequent urine culture. A diagnosis of AFBN was made on the basis of his high inflammatory reaction, contrast-enhanced abdominal CT findings and high urinary beta2-MG and NAG levels. He was treated with Ceftriaxone and subsequent improvement in inflammatory reaction and contrast enhanced CT findings were observed. Voiding cystourethrogram (VCUG) showed a grade V right VUR. This case suggests that urinary beta2-MG and NAG levels may be useful additional markers for the diagnosis of AFBN without pyuria. PMID- 25030726 TI - [Analysis of the effect of risk factors at gestational diabetes mellitus]. AB - OBJECTIVE: To assesment the effect of risk factors at gestational diabetes mellitus (GDM). METHODS: We collected 427 pregnant women who had done 75 g oral glucose tolerance test (OGTT) between September 1(st), 2012 and April 19(th), 2013 in Peking University First Hospital, including 74 pregnant women diagnosed as GDM (GDM group) and 353 pregnant women undiagnosed (non-GDM group). Then we conducted a multiple logistic regression to analyze the clinical datas collected from two groups, which included age, pre-pregnancy body weight and body mass index (BMI), body weight during 11-12 weeks pregnancy, body weight during 23-24 weeks pregnancy; and fasting plasma glucose (FPG), triglyceride (TG) , total cholesterol (TCH) , high density lipoprotein (HDL) , low density lipoprotein (LDL), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) during early pregnancy; and family history of diabetes mellitus. RESULTS: (1) There were significant difference in age, pre-pregnancy BMI, and FPG, TG, FINS, HOMA-IR during early pregnancy, and family history of diabetes mellitus between two groups (P < 0.05). (2) The risk factors of GDM that have statistical significance included FPG during early pregnancy (OR:4.03, 95%CI:1.62 10.02), family history of diabetes mellitus (OR:3.15, 95%CI:1.66-5.99), TG during early pregnancy (OR:2.13, 95%CI:1.17-3.87),BMI before pregnancy (OR:1.36, 95%CI:1.08-1.70), age >= 35 years (OR:1.15, 95%CI:1.05-1.26), early pregnancy weight gain (OR:1.20, 95%CI:1.06-1.35), mid pregnancy weight gain (OR:1.28, 95%CI:1.12-1.47), FINS during early pregnancy (OR:1.09, 95%CI:1.01-1.17). CONCLUSIONS: FPG, TG and FINS during early pregnancy, BMI before pregnancy, early and mid pregnancy weight gain, family history of diabetes mellitus and age >= 35 years are the indepadent risk factors for GDM. We should pay more attention to FPG and TG during early pregnancy, and put weight management into practise since early pregnancy and try to control pregnancy weight gain within reasonable limits. PMID- 25030727 TI - [Effects, safety and cost-benefit analysis of Down syndrome screening in first trimester]. AB - OBJECTIVE: To investigate the effects, safety and cost-benefit analysis of Down syndrome screening in first trimester. METHODS: From January 2009 to December 2012, 43 729 pregnant women undergoing 3 methods of Down syndrome traditional screening strategies in Shenzhen Maternity and Child Healthcare Hospital were studied retrospectively, including in 17 502 cases in pregnancy associated plasma protein A (PAPP-A) and free beta-hCG measured biochemistry screening, 14 080 cases in nuchal translucency (NT) screening and 12 147 cases in combined screening, meanwhile, 7 389 cases on non-invasive fetal trisomy test (NIFTY) were performed in Huada Gene Research Institute(BGI). The effects and safety of four screening strategies were assessed throughout a decision tree. The economical characters of each screening strategy were compared by cost-effectiveness analysis as well as cost-benefit analysis. RESULTS: (1) The effects of four strategies are: NIFTY > combined screening > NT screening > biochemistry screening. (2) The safety of four strategies are: NIFTY > combined screening > NT screening > biochemistry screening. (3) Cost-effectiveness analysis and cost benefit analysis:the biochemistry screening has lowest cost-effectiveness ratio (CER) and highest cost-benefit ratio (CBR), which performed a better economical efficiency. The incremental CER of three traditional screening strategies are all less than the economical burden of Down syndrome.NIFTY has highest CER and negative net present value (NPV), NPV would be positive and CBR would be more than 1 if the price of NIFTY reduce to 1 434 Yuan. CONCLUSIONS: Combined screening possess best screening efficiency, while biochemistry screening was demonstrated more economical in traditional screening.NIFTY is the future of Down syndrome screening. PMID- 25030728 TI - [Clinical study on 67 cases with uterine rupture]. AB - OBJECTIVE: To investigate the incidence, etiology, diagnosis, treatment and outcome of uterus rupture. METHODS: From January 1999 to May 2013, clinical data of 67 cases with uterine rupture in Woman's Hospital, School of Medicine, Zhejiang University were studied retrospectively. RESULTS: A total of 67 cases of uterine rupture with 21(+2)-39(+2) gestational weeks out of 128 599 deliveries were recorded giving an incidence of uterine rupture was 0.052 1% (67/128 599) . Cesarean scar rupture were found in 59 cases (88%, 59/67) and noncesarean scar rupture were found in 8 cases (12%, 8/67). The causes of uterine rupture include 60 cases of scar uterus (59 cesarean scar cases and 1 myomyectomy scar case), 2 cases of assisted delivery operation trauma, 2 cases of malformed uterus, 3 cases of unknown causes (all with artificial abortion history).Non obstructive dystocia and improper oxytocin use were found to be related with uterine rupture.Fifty-two cases of cesarean scar spontaneous incomplete rupture were found and repaired during repeated cesarean delivery without maternal and fetal complications. The remaining 15 cases need emergency rescue operation for fetal distress or dead fetus, severe acute abdomen, prepartum or postpartum vaginal bleeding even maternal hypovolemia; 6/15 uterine rupture cases were diagnosed with the history, clinical symptoms and signs, 3/15 cases with ultrasonic found dead fetus in the peritoneal cavity before exploratory laparotomy and 6 cases were diagnosed just during laparotomy.Hysterectomy was done in 10/15 cases and uterine repair in 5/15 cases; there was no maternal death and 12 perinatal fetal death (5 cases of mid late pregnancy termination for deformed fetus) of the 15 uterine rupture cases.One case with hysterectomy was complicated with stress pancreatitis and dysfunction of liver and kidney and discharged 20 days after operation, the remaining 14 cases were discharged 5-7 days postpartum.One case with repaired malformed uterus got pregnancy 4 years later and delivered a 2 000 g healthy baby by cesarean section at gestational age of 33(+4) weeks. CONCLUSION: Uterine scar caused by caesarean section or other operations became the leading cause of uterine rupture, assisted delivery operations, history of intrauterine manipulation and uterine malformations were the predisposing risk factors of uterine rupture. PMID- 25030729 TI - [Anatomical characteristics of the pelvic floor muscles in young nulliparous women based on three-dimensional MRI]. AB - OBJECTIVE: To analyse anatomical characteristics of the pelvic floor in young nulliparous volunteers based on three-dimensional MRI. METHODS: Thin-slice MRI was performed in 25 young nulliparous volunteers in Southern Medical University, MRI were imported into Mimics 10.01 for 3D reconstruction.Using 3D models we measured follow indicators: the levator ani muscle volume (LVOL) , levator plate angle (LPA), levator hiatus width (LH-W)and length (LH-L), distance between symphysis and levator sling muscle (LSG). RESULTS: (1) 25 cases of pelvic three dimensional models was successfully constructed, including the pelvis, pelvic organs and the pelvic floor muscles (including the ischial coccyx muscle, levator ani muscle and its various components, perineal muscles), the models could be able to clearly reflect the level of the pelvic floor muscles; (2) 25 cases of levator ani muscle measurement results:LVOL: (34 +/- 6) cm(3), LPA: (43 +/- 4) degrees , LH-W: (33 +/- 4) mm, LH-L: (54 +/- 5) mm, left LSG: (18.8 +/- 2.5) mm, right LSG: (18.3 +/- 2.5) mm. CONCLUSIONS: It is an effective way to use the computer to reconstruct the 3D model of female pelvic floor muscles using MRI data set. The quantitative analysis of levator ani muscle three-dimensional model can be assessed pelvic floor function, which is of great value in clinical practice.It is helpful to understand the pelvic floor disorders pathogenesis, clinical diagnosis, treatment options and treatment evaluation to provide reference standards. PMID- 25030730 TI - [Evaluation of postoperative bladder function and prognosis after modified nerve sparing radical hysterectomy]. AB - OBJECTIVE: To compare the nerve plane sparing radical hysterectomy (NPSRH) with conventional radical hysterectomy (CRH) in terms of postoperative bladder function and prognosis. METHODS: One hundred and two patients with International Federation of Gynecology and Obstetrics (FIGO) stage Ib1-IIa2 cervical cancer were treated by open NPSRH (study group) from January 2008 to March 2013. During the same time periods, two hundred and four patients who underwent open CRH were randomly selected as the control group. Age, pathological type and FIGO stage were matched. RESULTS: The median operation time in NPSRH group and CRH group were 268.8 and 242.4 minutes, respectively (P < 0.01). The median hospital stay were 14.6 and 17.2 days (P < 0.01). The median volume of blood loss in the two groups were respectively 394 and 450 ml (P > 0.05). The blood transfusion rate was respectively 46.1% (47/102) and 41.7% (85/204; P > 0.05). The rate of postoperative complications were not significantly difference [14.7% (15/102) vs 11.8% (24/204), P > 0.05]. The median duration of catheterization was 9.1 and 15.2 days between two groups (P < 0.01). Eighty-five patients in NPSRH group and one hundred and sixty-seven patients in CRH group completed the telephone interview about the long-term bladder function. The incidence of long-term urinary frequency [14.1% (12/85) vs 33.5% (56/167)], urinary incontinence [36.5% (31/85) vs 54.5% (91/167) ], urinary retention [23.5% (20/85) vs 38.9% (65/167) ] and straining to void [10.6% (9/85) vs 40.7% (68/167)], there were significantly lower in NPSRH group than those in CRH group ( all P < 0.05). The rate of recurrence was 10.8% (11/102) in NPSRH group and 12.2% (25/204) in CRH group (P = 0.707). Three-year recurrence-free survival (RFS) estimate was 88.5% in NPSRH group and 91.1% in CRH group (P = 0.746). Three-year overall survival (OS) estimate was 93.7% in NPSRH group and 96.3% in CRH group (P = 0.701). The univariate analysis shown that pathological type, lymph node metastases, and lymph-vascular space invasion (LVSI) presented the trend for a worst 3-year RFS and OS (P < 0.05) . The multivariate analyses shown that both pathological type and lymph node metastases were associated with a worst 3-year RFS (P < 0.05) . Lymph node metastases was a significant independent predictor of 3-year OS (P = 0.001) . NPSRH was not a significant independent predictor by Cox regression model analyses. CONCLUSION: NPSRH contributes to bladder function recovery without compromising survival. PMID- 25030731 TI - [Outcomes and prognostic factors of advanced squamous cervical cancer after concurrent chemoradiotherapy]. AB - OBJECTIVE: To evaluate the outcomes and the prognostic factors for advanced squamous cervical cancer after concurrent chemoradiotherapy (CCRT). METHODS: Totally 172 patients with International Federation of Gynecology and Obstetrics stage IIb-IV who were treated in Cancer Hospital, Chinese Academy of Medical Sciences between January 2007 and December 2008 were retrospectively analyzed. Patients were received external radiotherapy, high-dose rate brachytherapy and cisplatin-based chemotherapy concurrently. RESULTS: The median follow-up period was 54.5 months. The 2-year and 5-year overall survival (OS) were separately 81.5% and 68.8%. The 2-year and 5-year progress-free survival (PFS) were separately 69.2% and 63.1%. Using univariate analysis followed with multivariate analysis, the results showed that these clinicopathological factors including stage (III and above versus IIb; P = 0.021, HR = 1.95; P = 0.020, HR = 1.86), maximum diameter of local tumor size (>4 versus <= 4 cm; P = 0.009, HR = 2.55; P = 0.033, HR = 1.94), squamous cell carcinoma antigen (SCC) level before treatment (>3 versus <= 3 ug/L; P = 0.010, HR = 2.47; P = 0.013, HR = 2.09) and retroperitoneal lymph node status on imaging (para-aortic lymph node positive versus negative, P = 0.009, HR = 3.00, P = 0.010, HR = 2.74; pelvic lymph node positive only versus negative, P = 0.044, HR = 1.98, P = 0.033, HR = 1.92) had the significant effect on OS and PFS. Patients with no above adverse prognostic factor were assigned to Group A (n = 18), those with one factor were assigned to Group B (n = 43), and those with no less than two factors were assigned to Group C (n = 111). Among three groups, the 2-year OS were separately 94.1%, 97.7% and 73.1%, the 5-year OS were separately 81.4%, 90.1% and 58.6%, the 2-year PFS were separately 88.2%, 90.4% and 57.9%, the 5-year PFS were 82.4%, 87.9% and 50.0%. The results showed that group C was significant difference from Group A or B in OS and PFS (all P < 0.05), while Group A had no significant difference from Group B in OS and PFS (P > 0.05). CONCLUSIONS: Stage III or above, maximum diameter of local tumor size >4 cm, SCC level >3 ug/L before treatment and positive retroperitoneal lymph nodes on imaging are four independent adverse factors for prognosis of squamous cervical cancer of advanced stage after CCRT. The treatment of patients with no less than two adverse factors should be considered to be improved. PMID- 25030732 TI - [Efficacy and safety of a combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 ug in a 24+4-day regimen in China]. AB - OBJECTIVE: To assess the efficacy, bleeding pattern, cycle control and safety of a combined oral contraceptive (YAZ) containing drospirenone 3 mg and ethinylestradiol 20 ug in a 24+4-day regimen in China. METHODS: This is a multi center, open, one-label study. Healthy females aged 18-45 years received YAZ for 13 cycles. Following-ups were scheduled during the treatment phase on Day 12-19 of Cycle 1, 4, 7 and 10 and 10-17 days after completing the study. The efficacy variables were the number of unintended pregnancies, bleeding pattern and cycle control. The safety variables were adverse events (AE), lab examinations, physical and gynecological examinations, vital signs and body weights and questionnaires. RESULTS: Four pregnancies occurred among 675 women for 603.78 women-years, resulting in a Pearl index (PI) of 0.7 and adjusted PI of 0.6. The cumulative 1-year pregnancy rate was 0.66%. The mean number of bleeding/spotting days was (26.3 +/- 12.4) days in reference period 1 and (15.4 +/- 5.5) days in reference period 4. 94.2% (582/618)- 96.8% (538/558) subjects experienced scheduled bleeding. The mean duration of scheduled bleeding decreased from (5.9 +/- 3.2) to (5.0 +/- 1.6) days. The percentage of women with intermenstrual bleeding decreased from 14.5% (90/621) at Cycle 1 to 2.3% (13/558) at Cycle 12. The common AE relating treatment include nausea (3.4%, 23/675), breast tenderness (1.2%, 8/675), dizzy (1.2%), vagina bleeding (1.2%). No serious AE relating treatment occurred. 85.6% (542/633) subjects were satisfied or very satisfied with the study treatment. CONCLUSION: YAZ is highly effective, acceptable and safe for Chinese women. PMID- 25030733 TI - [Effects of PPARgamma gene expression on cell migration, invasion, and proliferation in endometrial cancer cells]. AB - OBJECTIVE: To observe the effects of differentially expressed peroxisome proliferator-activated receptor gamma (PPARgamma) on cell migration, invasion and proliferation of endometrial cancer cells. METHODS: Two endometrial cancer cell lines ECC-1 (ER positive) and KLE (ER negative) cells were used in this study. To up or down regulate PPARgamma expression, the transient transfection by using PPARgamma expression vector (PPARgamma expression vector group) and PPARgamma small interference RNA (PPARgamma siRNA group) were done. The negative control groups were cells transfected by nonsence sequence siRNA (siRNA nonsence sequence group) or empty vector (empty vector group). At the same time, cells only added with liposome were used as blank control group. Then, quantitative real time (RT) -PCR and western blot were used to detect PPARgamma expression both in mRNA and protein levels. To assess the expression levels of Wnt signaling pathway, western blot was performed to analysis protein levels of beta-catenin and C-myc. The effects on cell migration, invasion and proliferation using in vitro transwell migration, invasion assays and cell counting kit-8 (CCK-8) assay were further be examined. RESULTS: After transfection for 48 hours, quantitative RT-PCR and western blot showed that PPARgamma mRNA(5.18 +/- 0.99, 4.54 +/- 0.89) and protein (1.45 +/- 0.12, 1.30 +/- 0.13) expression levels significantly increased and the protein levels of beta-catenin (0.44 +/- 0.06, 0.46 +/- 0.04) and C-myc (0.42 +/- 0.08, 0.30 +/- 0.11) decreased in PPARgamma expression vector group, while in PPARgamma siRNA group, PPARgamma mRNA(0.48 +/- 0.08, 0.53 +/- 0.11) and protein (0.41 +/- 0.04, 0.49 +/- 0.05) expression levels decreased and the protein levels of beta-catenin (1.18 +/- 0.12, 0.89 +/- 0.07) and C-myc (0.91 +/- 0.08, 0.77 +/- 0.12) increased significantly compared with control groups (all P < 0.05) . In vitro migration and invasion assay indicated that the migratory and invasive cell numbers of PPARgamma expression vector group (ECC-1:129 +/- 9, 63 +/- 12; KLE:119 +/- 9, 68 +/- 16) were significantly decreased, while the migratory and invasive cell numbers of were PPARgamma siRNA group (ECC-1:201 +/- 14, 142 +/- 9; KLE:170 +/- 11, 138 +/- 7) increased significantly compared with those in control groups (all P < 0.05). CCK-8 assay showed that A values (0.66 +/- 0.14, 0.78 +/- 0.06) in PPARgamma expression vector group were lower than those in control groups, and in PPARgamma siRNA group, A values (1.42 +/- 0.16, 1.23 +/- 0.04) were higher than those in control groups, and there were statistically significant difference among them (all P < 0.05). CONCLUSION: Up-regulated PPARgamma gene expression could inhibit endometrial cancer cell migration, invasion and proliferation abilities, and down-regulated PPARgamma gene expression could promote endometrial cancer cell migration, invasion and proliferation abilities. PMID- 25030734 TI - Renin inhibition improves the survival of mesenchymal stromal cells in a mouse model of myocardial infarction. AB - The aim of this study was to determine if renin inhibition is able to improve the survival of transplanted stem cells in a mouse model of myocardial infarction. Myocardial infarction was induced in FVB/NJ inbred mice (n = 23). Bone marrow derived mouse mesenchymal stromal cells (mMSCs, 3 * 10(5)) expressing the reporter gene firefly luciferase were delivered intramyocardially (n = 12) and monitored non-invasively by bioluminescence imaging. A group of these mice (n = 6) received aliskiren (15 mg/kg/day) via an osmotic pump implanted subcutaneously. The survival of mMSCs was significantly increased in those animals that received aliskiren leading to a significant improvement in systolic function after myocardial infarction. Histological analysis revealed a significant reduction in inflammation and collagen deposition in those mice that received aliskiren compared to controls. Renin inhibition of the ischemic myocardium is able to modulate the microenvironment improving the survival and efficacy of transplanted mMSCs in a mouse model of myocardial infarction. PMID- 25030735 TI - Overexpression of RFC3 is correlated with ovarian tumor development and poor prognosis. AB - Replication factor C3 (RFC3) is an oncogene that can potentially predict prognosis in a variety of human cancers. RFC3 expression in ovarian carcinoma has not yet been determined. In this study, we evaluated the messenger RNA (mRNA) and protein expression levels of RFC3 in normal ovarian and ovarian carcinoma tissues using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blots (WB). Results showed that higher RFC3 mRNA and protein levels were detected in ovarian carcinoma tissues by RT-PCR and WB. High RFC3 expression was defined as positive staining in >70 % of each tumor cell. High RFC3 expression was detected in 28.1, 17.6, 11.1, and 5.0 % of invasive carcinomas, borderline tumors, cystadenomas, and in normal ovary cells, respectively. Overexpression of RFC3 was associated with later pN status (p = 0.001), pM status (p = 0.001), and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.012) in ovarian carcinomas. Univariate survival analyses showed that RFC3 overexpression was also associated with shortened patient survival (mean 7.7 months in tumors with RFC3 overexpression vs 92.9 months in tumors with normal RFC3 levels; p < 0.001). In multivariate analyses, RFC3 protein levels were a significant prognostic factor for ovarian carcinoma (p < 0.001). In conclusion, our findings suggest that RFC3 protein is an important and independent biomarker with prognostic implications for patients with ovarian carcinoma. PMID- 25030737 TI - Editor's Note. PMID- 25030738 TI - Home-Delivered Meals and Nutrition Status Among Older Adults. AB - The trend among older adults in the United States is to "age in place" instead of opting for institutionalization. To maintain older adults with chronic conditions in their homes and to improve health after hospitalization, comprehensive social, health, and nutrition services are essential. Quality of dietary intake is crucial and yet often underestimated. Calorie needs decrease with age while nutrient needs remain the same, even increasing for some nutrients. This poses difficulties for individuals with functional disabilities who are unable to shop and cook due to physical or mental limitations or on a limited budget. The Older American Act home-delivered meal (HDM) program offers at least 1 healthy meal per day, 5 or more days per week, and targets individuals homebound due to illness, disability, or social isolation and those with greatest economic or social need. This review summarizes the available literature on the relationship between HDM and health outcomes. The HDM program is difficult to evaluate because of the multifactorial effect on health status. However, national surveys and smaller studies show that it is well targeted, efficient, and well liked; provides quality food to needy individuals; and helps individuals remain living independently. Studies show that HDMs improve dietary intake, with greater health benefits when more meals reach the neediest individuals. HDMs also decrease institutionalization of older adults and resulting healthcare expenditures. However, funding has not kept up with increased demand for this program. More studies with improved designs may provide more information supporting the program's impact on nutrition status and decreased health expenditures. PMID- 25030736 TI - Upregulation of the long noncoding RNA HOTAIR predicts recurrence in stage Ta/T1 bladder cancer. AB - Stage Ta/T1 urothelial carcinoma of the bladder (Ta/T1 BC) has a marked tendency to recurrence. Long noncoding RNA HOTAIR has been reported to be expressed in some human cancers such as breast cancer, and it may be positively correlated with patient's prognosis. The aim of our study was to evaluate the prognostic value of HOTAIR in Ta/T1 BC. HOTAIR expression in Ta/T1 BC tissues and adjacent normal tissues was collected from 110 patients and measured by real-time quantitative PCR. The relationships between HOTAIR and the clinical pathological characteristics of Ta/T1 BC patients were analyzed. Immunohistochemistry was done to detect the protein of Wnt inhibitory factor 1 (WIF-1) as well. Ninety out of 110 specimens were detected in HOTAIR high expression. Histological grade and expression levels of HOTAIR were positively correlated with the recurrence rate. HOTAIR expression (hazard ratio 4.712; 95 % CI 2.894-8.714; P < 0.001) was an independent predictor of recurrence rate in multivariate Cox regression analysis. HOTAIR expression is correlated with patients' poor prognosis. A significant inverse correlation between HOTAIR and WIF-1 expression was demonstrated in Ta/T1 BC tissues. The expression levels of HOTAIR are an independent prognostic factor of recurrence in Ta/T1 BC patients. PMID- 25030739 TI - The Canadian Critical Care Nutrition Guidelines in 2013: Importance of Nasojejunal Enteral Feeding Tube Design in Improving Rates of Small Bowel Enteral Feeding in Patients With High Gastric Residual Volumes. PMID- 25030740 TI - Response to "The Canadian Critical Care Nutrition Guidelines in 2013: Importance of Nasojejunal Enteral Feeding Tube Design in Improving Rates of Small Bowel Enteral Feeding in Patients With High Gastric Residual Volumes" PMID- 25030741 TI - Termination of aconitine-induced atrial fibrillation by the KACh-channel blocker tertiapin: underlying electrophysiological mechanism. AB - The acetylcholine receptor-operated K(+) (KACh) channel may be a novel target for atrial-specific antiarrhythmic therapy. Recently it has been demonstrated that tertiapin, a selective blocker of KACh channel, suppressed aconitine-induced atrial fibrillation (AF) in dogs. However, the precise mechanism by which the KACh-channel blocker inhibits the aconitine-induced AF remains unknown. This study was undertaken to determine the role of KACh channel in aconitine-induced AF in guinea pigs. Tertiapin terminated the aconitine-induced AF in anesthetized guinea pigs. The results of an in vitro electrophysiological experiment using atrial cells and atrial preparations suggest that aconitine might activate KACh channels in atrial cells, probably by intracellular Na(+) accumulation, and inhibition of KACh channels by tertiapin might suppress AF by producing conduction block, probably due to further decrease in the resting membrane potential. Since it has been reported that constitutively active KACh channels can be observed in atrial cells of patients with chronic AF, aconitine-induced AF may be used as an experimental model for evaluation of drug effect on chronic AF. PMID- 25030742 TI - Key components of store-operated Ca2+ entry in non-excitable cells. AB - Store-operated Ca(2+) entry (SOCE) is a ubiquitous Ca(2+) entry pathway in non excitable cells. It is activated by the depletion of Ca(2+) from intracellular Ca(2+) stores, notably the endoplasmic reticulum (ER). In the past 9 years, it has been established that two key proteins, stromal interacting molecule 1 (STIM1) and Orai1, play critical roles in SOCE. STIM1 is a single-pass transmembrane protein located predominantly in the ER that serves as a Ca(2+) sensor within the ER, while Orai1 is a tetraspanning plasma membrane (PM) protein that functions as the pore-forming subunit of store-operated Ca(2+) channels. A decrease in the ER Ca(2+) concentration induces translocation of STIM1 into puncta close to the PM. STIM1 oligomers directly interact with Orai1 channels and activates them. This review summarizes the molecular basis of the interaction between STIM1 and Orai1 in SOCE. Further, we describe current findings on additional regulatory proteins, such as Ca(2+) release-activated Ca(2+) regulator 2A and septin, novel roles of STIM1, and modulation of SOCE by protein phosphorylation. PMID- 25030743 TI - Significance of vascular dipeptidyl peptidase-4 inhibition on vascular protection in Zucker diabetic fatty rats. AB - To clarify the role of dipeptidyl peptidase-4 (DPP-4) inhibition in vascular tissues, we compared the effects of the poorly tissue-penetrative DPP-4 inhibitor sitagliptin to the highly tissue-penetrative DPP-4 inhibitor linagliptin in Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats were orally treated with placebo, sitagliptin (10 mg/kg), or linagliptin (3 mg/kg) for 4 weeks. Sitagliptin and linagliptin produced equivalent decreases in blood glucose concentrations and increased plasma insulin concentrations during oral glucose tolerance tests after the first and the last treatments. In isolated arteries, acetylcholine-induced vascular relaxation was significantly augmented by sitagliptin and linagliptin, with significantly stronger relaxation observed with linagliptin compared to sitagliptin. Vascular DPP-4 activity was attenuated by these drugs, with linagliptin producing significant greater attenuation than sitagliptin. Vascular malondialdehide levels were significantly lower with linagliptin compared to sitagliptin. Significantly greater attenuation of vascular gene expressions of p22(phox) and monocyte chemoattractant protein-1 by linagliptin, compared with sitagliptin, was also observed. In conclusion, the superior vascular protection by linagliptin compared with sitagliptin was unrelated to the regulation of circulating glucose and insulin levels, and the stronger vascular DPP-4 inhibition by linagliptin may contribute to the mechanism of vascular protection. PMID- 25030744 TI - Protein tyrosine phosphorylation in the ischemic brain. AB - Cerebral ischemia, a pathological condition in which brain tissue experiences a shortage of cerebral blood flow, is associated with cerebrovascular disease, brain trauma, epilepsy, and cardiac arrest. A reduction in blood flow leaves the brain tissue unsupplied with oxygen and glucose, thus leading to cell death in the ischemic core as well as subsequent peripheral injury in the penumbra. Neurons in the penumbra, where reperfusion occurs, are functionally inactive but still viable. Many biochemical changes, which may lead to neuronal cell death, thereby induce dysfunction of the central nervous system. However, the mechanisms responsible for ischemic stroke-induced cell damage remain to be determined. Protein phosphorylation has been implicated in the regulation of diverse cellular responses in the brain. Initially, tyrosine phosphorylation was considered to be involved in the regulation of cell growth and development. In addition, a variety of synaptic and cellular functions mediated by tyrosine phosphorylation in the brain were found to be associated with relatively high levels of protein tyrosine kinase activity. However, the involvement of this protein tyrosine kinase activity in ischemic cell death is still not fully understood. This review summarizes recent advances dealing with the possible implications of protein tyrosine phosphorylation in the ischemic brain. PMID- 25030745 TI - Nurses' job satisfaction and patient falls. AB - PURPOSE: The growing concern about the low job satisfaction among nurses and the achievement of positive patient outcomes are critical healthcare issues. The purpose of this descriptive correlational study was to determine the relationship between nurses' job satisfaction and patient fall rate on adult medical and surgical units. METHODS: Secondary data from a nurses' job satisfaction survey at a large not-for-profit acute care hospital on the East coast was used. The National Database of Nursing Quality Indicators-Adapted Index of Work Satisfaction (NDNQI-AIWS) was used to measure nurses' job satisfaction. The sample included 161 nurses from 12 adult acute medical and surgical units. The study used retrospective data collected by the Department of Nursing on patient fall rate. Pearson's correlation coefficient was used to determine the relationship between nurse job satisfaction and patient fall rate. In addition, exploratory descriptive analysis was conducted by type of unit (i.e., medical or surgical). RESULTS AND CONCLUSION: No significant relationship was found between overall nurses' job satisfaction and patient fall rate. MD-RN interactions (r = .65) and decision-making (r = .57) were the job satisfaction subscales that showed a significant positive correlation with patient fall rate (p < .05). Recommendations for future research are provided. PMID- 25030746 TI - The process of change in the sexual attitudes of sexual offenders in Korea. AB - PURPOSE: This study aimed to explore the process of change in the sexual views and attitudes of sexual offenders, in light of their experiences. METHODS: Data were collected from six sexual offenders who were accused of sexual offenses. All collected data by in-depth and direct observation were analyzed by Corbin and Strauss' Ground theory methodology. RESULTS: Participants were sexually aroused as a result of their distorted knowledge of sex. They were stimulated by easy access to sex and surrendered to it. Their intervening conditions were legal regulation, voice of conscience and social support. Participants were responding to the problem through strategies. These strategies were: reflecting self, distracting one's attention, and building a stable relationship with a woman. They resulted in stigma of being a sexual offender, alteration in sexual views, confidence and futility. The core variable revealing the essence of the sexual offenders' experiences was reconstructing sound sex values. CONCLUSION: The results of the study can provide school nurses and sex educators with useful knowledge grounded in actual sexual offense cases, not only to refine the interventions for sexual offenders but also to prevent future sexual offenses. PMID- 25030747 TI - The effect of a comprehensive lifestyle modification program on glycemic control and body composition in patients with type 2 diabetes. AB - PURPOSE: This paper describes the effects of a comprehensive lifestyle modification program (CLMP) on glycemic control and body composition in patients with type 2 diabetes. METHODS: This study was performed from October 2003 to April 2005, and used an experimental design with random assignment. The experimental group (n = 25) received CLMP for 4 months and follow-up sessions for 9 months. CLMP included nurse-led education on exercise and diet, and counseling on stress management and self-monitoring of their diabetic health. The control group (n = 23) received a 1-hour educational session on diabetic diet at the beginning of the study. Glucose level and body composition were measured in both groups a total of five times: at baseline (pre-intervention) and at 0, 3, 6 and 9 months post intervention. RESULTS: Repeated-measures ANOVA showed that there were statistically significant differences in fasting blood sugar and HbA1c levels between the two groups (both p < .05). Both groups demonstrated statistically significant changes in body composition over time, but there was no significant difference in the pattern of change between the two groups. CONCLUSION: CLMP is a useful program, and its multiple approaches by nurses as the leaders and coordinators appear to have positive and synergistic roles in improving and maintaining stable glucose level and body composition in patients with type 2 diabetes. PMID- 25030748 TI - Parenting stress in mothers of children with congenital heart disease. AB - PURPOSE: The main purposes of this study were to examine the relationships among uncertainty, social support and parenting stress in mothers of children with congenital heart disease (CHD) and to identify the factors related to parenting stress. METHODS: This was a survey study using a questionnaire. Fifty-one mothers of children with CHD were recruited at the pediatric cardiac outpatient clinic at one university-affiliated hospital in Seoul between July 14th and September 25th, 2006. Abidin's Parenting Stress Index-Short Form, Mishel's Parents' Perception Uncertainty in Illness Scale, and Brandt and Weinert's Personal Resource Questionnaire were used to collect data. RESULTS: The results of bivariate analysis showed that parenting stress was significantly related to social support, ambiguity, lack of clarity, and lack of information, but was not related to unpredictability, one of the subconcepts of uncertainty. Multiple regression analysis showed that parenting stress was significantly related to social support and Internet information. CONCLUSION: Mothers who reported they had more social support and less uncertainty showed lower parenting stress. Also, the Internet could be an effective method to obtain information and to share child-rearing experiences with other mothers of children with CHD. PMID- 25030749 TI - Comfort and quality of life of cancer patients. AB - PURPOSE: This study aimed to quantify the comfort level and quality of life (QoL) of cancer patients, to identify the variables associated with comfort level and QoL, and to identify the relationship between comfort level and QoL. METHODS: This was a cross-sectional descriptive study. The participants comprised 100 cancer patients, of which 98 were analyzed. Participants completed a self reporting questionnaire that included the Hospice Comfort Questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-C30 at outpatient clinics, inpatient units, at home, and a day-care chemotherapy unit. RESULTS: The mean age of the participants was 53.36 years, and 56.1% of them were female. The mean +/- standard deviation score for total comfort was 61.50 +/- 12.02, with the sociocultural comfort score being the highest (71.05 +/- 16.01), followed by physical comfort (60.30 +/- 16.71), psychospiritual comfort (57.65 +/- 16.81), and environmental comfort (56.32 +/- 16.86). There were significant subgroup differences in educational attainment, the site where they completed the questionnaire, and perceived disease status and prognosis. The QoL score for global health status was 46.34 +/- 20.76, and comfort was significantly correlated with all dimensions of QoL (r = -.549 - .581). CONCLUSION: This study showed lower comfort level in psychospiritual and environmental comfort than physical and sociocultural comfort in cancer patients. Improvement in environment and psychospiritual support is suggested as strategies to enhance the comfort of cancer patients. PMID- 25030750 TI - Predictors of Women's Postpartum Health Status in the First 3 Months After Childbirth. AB - PURPOSE: The purpose of this study was to examine the significant predictors of postpartum health indicated by physical health, mental health, and role performance during the first 3 months postpartum. METHODS: This study used a correlational survey design. The study subjects were 152 mothers at 6 weeks postpartum (T1) and 131 mothers at 3 months postpartum (T2). At 6 weeks and 3 months postpartum, subjects completed a packet of instruments-measuring physical and mental health, role performance, sense of mastery, social support, and infant temperament. RESULTS: Findings indicated that lower family income, more difficult infant temperament, and lower sense of mastery were consistently significant predictors of poorer health outcomes during the postpartum period. Having preterm infants and caring for them was related to higher levels of maternal fatigue in the morning at 6 weeks. Employment did not influence postpartum health. CONCLUSION: The findings suggest that mother and infant's individual factors and environmental context may continue to negatively affect the mother's health outcomes during the postpartum period. PMID- 25030751 TI - Efficacy and safety of fluoroscopic manipulation using the alpha-replacer for peritoneal catheter malposition. AB - BACKGROUND: Catheter malposition is one of the reasons for outflow failure in peritoneal dialysis (PD) patients. Fluoroscopic manipulation is a non-surgical treatment option for catheter malposition. We retrospectively analyzed the efficacy and safety of fluoroscopic manipulation using an alpha-replacer guidewire. METHODS: The alpha-replacer (JMS Co. Ltd., Tokyo, Japan) is a guidewire for the treatment of catheter malposition. We used the alpha-replacer in 23 PD cases at our hospital from January 2008 to December 2012. We evaluated body mass index, time interval between catheter placement and malposition, and interval between catheter exteriorization and malposition. Primary failure was defined as malposition at the time of catheter exteriorization, and secondary failure as malposition after functional PD therapy (correct position at time of exteriorization). RESULTS: Successful catheter replacement rate using the alpha replacer was 60.8 % (14 of 23 cases). This was similar to the rates in previous reports. Successful replacement was mostly observed in those with a long interval between catheter placement and malposition (p = 0.048), between catheter placement and exteriorization (p = 0.047) and with secondary failure (p = 0.030). In multivariate analysis, secondary failure cases had a higher rate of successful replacement than primary failure cases (odds ratio [OR] 7.33, p = 0.038). Serious complications, such as abdominal trauma or peritonitis, were not observed. CONCLUSION: Fluoroscopic manipulation using an alpha-replacer may be safe and effective for the management of peritoneal catheter malposition, particularly in patients who were under functional PD therapy until catheter malposition. PMID- 25030752 TI - Increasing incidence of testicular cancer in the United States and Europe between 1992 and 2009. AB - PURPOSE: Increasing in incidence, testicular cancer is the most commonly diagnosed cancer in young men in the USA and in Europe. We sought to determine contemporary trends in testicular cancer incidence in the USA and Europe. METHODS: Testicular cancer incidence data covering the USA and Europe were extracted from the SEER-13 (SEER*Stat 8.0.1) and the EUREG databases, respectively. Trends were determined using JoinPoint 3.5.3. RESULTS: Testicular germ cell tumor (TGCT) incidence among US males >15 years increased from 1992 (5.7/100,000) to 2009 (6.8/100,000) with a significant annual percentage change (APC: 1.1%, p < 0.001). Seminomas were 29% of all TGCTs in 15-26 year-olds, increasing to 78% in those 40+ years of age. TGCT rates were highest in White men (1992: 7.5/100,000; 2009: 8.6/100,000) followed by Hispanic men (1992: 4.0/100,000; 2009: 6.3/100,000) and lowest among Asian (1992: 2.0/100,000; 2009: 2.8/100,000) and Black men (1992: 0.7/100,000; 2009: 1.7/100,000). Significantly increasing incidence rates were observed in White men (APC: 1.2%, p < 0.001) and most prominently in Hispanic men, especially from 2002 to 2009 (APC: 5.6%, p < 0.01). Incidence of testicular cancer increased in 15 of 19 (79%) European countries analyzed (p < 0.05). Denmark (13.4/100,000 man-years), Switzerland (12.7/100,000 man-years), and Norway (12.7/100,000 man-years) exhibited the highest age-standardized rates, while Spain had the greatest APC (APC = 5.5, 95% CI 3.9-7.0%, p < 0.001). CONCLUSIONS: Between 1992 and 2009, testicular cancer incidence in the USA and Europe continued to increase, most notably in US Hispanic, Northern European, Spanish, and younger and older populations. PMID- 25030753 TI - Successful diagnosis of tuberculous lymphadenitis by loop-mediated isothermal amplification of cutaneous samples from an ulcerated surface lesion: a case report. AB - INTRODUCTION: Tuberculous lymphadenitis is the most frequent form of extrapulmonary tuberculous. Although nucleic acid amplification assays such as polymerase chain reaction have recently become mainstream techniques for diagnosing tuberculous lymphadenitis, they are still not routinely performed in developing countries because of their high costs and complicated procedures. CASE PRESENTATION: We describe a case of tuberculous lymphadenitis in a 79-year-old Japanese man who had been on continuous hemodialysis for end-stage renal disease. We employed loop-mediated isothermal amplification and the procedure for ultrarapid extraction to develop a fast and easy-to-perform procedure for diagnosing tuberculous lymphadenitis. CONCLUSIONS: The commercially available loop-mediated isothermal amplification assay kit and a rapid purification procedure enabled us to identify and amplify a Mycobacterium tuberculosis specific gene within just 1.5 hours. PMID- 25030754 TI - Carotid atherosclerosis progression: the importance of systolic blood pressure. PMID- 25030756 TI - High-contrast electroswitching of emission and coloration based on single molecular fluoran derivatives. AB - Multifunctional electroswitching of both emission and coloration was demonstrated by using fluoran derivatives in an electrolytic solution. Further, in order to investigate changes in the photophysical properties induced by electrical stimuli, we measured cyclic voltammogram, absorption spetra, emission spectra, and molecular orbital calculation. The mechanism for this electroswitching was attributed to the reversible electrochemically induced closing and opening of the lactone ring in the fluoran molecule. All neutral fluoran molecules were colorless and did not exhibit any fluorescence, while the oxidized (lactone ring opened form) molecule was yellow and displayed a green fluorescence as a consequence of the extended, planar, conjugated system. Furthermore, this fluoran molecule achieved reversible electroswitchable emission and coloration with high on/off contrast. PMID- 25030755 TI - Mating system shifts and transposable element evolution in the plant genus Capsella. AB - BACKGROUND: Despite having predominately deleterious fitness effects, transposable elements (TEs) are major constituents of eukaryote genomes in general and of plant genomes in particular. Although the proportion of the genome made up of TEs varies at least four-fold across plants, the relative importance of the evolutionary forces shaping variation in TE abundance and distributions across taxa remains unclear. Under several theoretical models, mating system plays an important role in governing the evolutionary dynamics of TEs. Here, we use the recently sequenced Capsella rubella reference genome and short-read whole genome sequencing of multiple individuals to quantify abundance, genome distributions, and population frequencies of TEs in three recently diverged species of differing mating system, two self-compatible species (C. rubella and C. orientalis) and their self-incompatible outcrossing relative, C. grandiflora. RESULTS: We detect different dynamics of TE evolution in our two self-compatible species; C. rubella shows a small increase in transposon copy number, while C. orientalis shows a substantial decrease relative to C. grandiflora. The direction of this change in copy number is genome wide and consistent across transposon classes. For insertions near genes, however, we detect the highest abundances in C. grandiflora. Finally, we also find differences in the population frequency distributions across the three species. CONCLUSION: Overall, our results suggest that the evolution of selfing may have different effects on TE evolution on a short and on a long timescale. Moreover, cross-species comparisons of transposon abundance are sensitive to reference genome bias, and efforts to control for this bias are key when making comparisons across species. PMID- 25030757 TI - Sperm proteases and extracellular ubiquitin-proteasome system involved in fertilization of ascidians and sea urchins. AB - Ascidians (primitive chordates) are hermaphroditic animals that release spermatozoa and eggs almost simultaneously, but some species, including Halocynthia roretzi, show strict self-sterility. In H. roretzi, a 70-kDa vitelline coat (VC) protein consisting of 12 EGF-like repeats, named HrVC70, appears to be a promising candidate for the self/nonself-recognition (or allorecognition) system during gamete interaction. After spermatozoon recognizes the VC as nonself, sperm 700-kDa extracellular ubiquitin-conjugating enzyme complex appears to ubiquitinate Lys234 of HrVC70, and the ubiquitinated HrVC70 is degraded by the sperm 26S proteasome that is located on the sperm head surface. This novel ubiquitin-proteasome system enables spermatozoa to penetrate through the VC. Sperm trypsin-like proteases, acrosin and spermosin, also participate in fertilization, probably as sperm-side 'movable' binding proteins to the VC. PMID- 25030758 TI - ISGylation: a conserved pathway in mammalian pregnancy. AB - Successful pregnancy includes remodeling and differentiation of the endometrium in response to sex steroid hormones, development of maternal immunotolerance to the implanting embryo, and modification of the local uterine environment by the embryo to suit its own needs. The major signal released by the ruminant conceptus during establishment of pregnancy is interferon-tau (IFNT) that stimulates the expression of many genes in the endometrium and ovary. One of these genes is called interferon stimulated gene 15 (ISG15), which encodes a ubiquitin homolog with a C-terminal Gly that becomes covalently attached to Lys residues on targeted proteins through an ATP-dependent multi-step enzymatic reaction called ISGylation. The conceptus-derived induction of endometrial ISGs also occurs in mouse and human deciduas and placenta, in response to pregnancy presumably through action of cytokines such as interleukins and type I IFN. Described herein is evidence to support the concept that ISGylation is a maternal response to the developing conceptus, implantation and placentation that is conserved across mammalian pregnancy. Although the precise role for ISG15 remains elusive during pregnancy, it is clear that up-regulation in response to pregnancy may impart a pre-emptive defense to infection or other environmental insults, and protection of the conceptus against inflammatory insults across species. PMID- 25030760 TI - Posttranslationally modified tubulins and other cytoskeletal proteins: their role in gametogenesis, oocyte maturation, fertilization and Pre-implantation embryo development. AB - The cytoskeleton, mainly consisting of microtubules, intermediate filaments and microfilaments, along with cytoskeleton associated and interconnecting proteins as well as the centrosome, plays enormously important roles in all stages of embryogenesis and undergoes significant changes to accommodate a diversity of cellular functions during gametogenesis, oocyte maturation, fertilization and pre implantation embryo development. The varied functions of the cytoskeleton can be accomplished on many different levels, among which are a diversity of different posttranslational modifications (PTMs), chemical modifications that regulate activity, localization and interactions with other cellular molecules. PTMs of the cytoskeleton, including phosphorylation, glycosylation, ubiquitination, detyrosination/tyrosination, (poly)glutamylation and (poly)glycylation, acetylation, sumoylation, and palmitoylation, will be addressed in this chapter. Focus will be on (1) Microtubules, microtubule organizing centers (centrosomes), intermediate filaments, microfilaments and their PTMs; (2) Cytoskeletal functions and cytoskeletal PTMs during gametogenesis and oocyte maturation; and (3) Cytoskeletal functions and cytoskeletal PTMs during fertilization and pre implantation embryo development. PMID- 25030761 TI - Deubiquitinating enzymes in oocyte maturation, fertilization and preimplantation embryo development. AB - Post-translational modifications of cellular proteins by ubiquitin and ubiquitin like protein modifiers are important regulatory events involved in diverse aspects of gamete and embryo physiology including oocyte maturation, fertilization and development of embryos to term. Deubiquitinating enzymes (DUBs) regulate proteolysis by reversing ubiquitination, which targets proteins to the 26S proteasome. The ubiquitin C-terminal hydrolases (UCHs) comprise are DUBs that play a role in the removal of multi-ubiquitin chains. We review here the roles of UCHs in oocytes maturation, fertilization and development in mouse, bovine, porcine and rhesus monkeys. Oocyte UCHs contributes to fertilization and embryogenesis by regulating the physiology of the oocyte and blastomere cortex as well as oocyte spindle. Lack of UCHs in embryos reduces fertilization, while mutant embryos fail to undergo compaction and blastocyst formation. In addition to advancing our understanding of reproductive process, research on the role of deubiquitinating enzymes will allow us to better understand and treat human infertility, and to optimize reproductive performance in agriculturally important livestock species. PMID- 25030759 TI - SRC-family tyrosine kinases in oogenesis, oocyte maturation and fertilization: an evolutionary perspective. AB - The oocyte is a highly specialized cell poised to respond to fertilization with a unique set of actions needed to recognize and incorporate a single sperm, complete meiosis, reprogram maternal and paternal genomes and assemble them into a unique zygotic genome, and finally initiate the mitotic cell cycle. Oocytes accomplish this diverse series of events through an array of signal transduction pathway components that include a characteristic collection of protein tyrosine kinases. The src-family protein kinases (SFKs) figure importantly in this signaling array and oocytes characteristically express certain SFKs at high levels to provide for the unique actions that the oocyte must perform. The SFKs typically exhibit a distinct pattern of subcellular localization in oocytes and perform critical functions in different subcellular compartments at different steps during oocyte maturation and fertilization. While many aspects of SFK signaling are conserved among oocytes from different species, significant differences exist in the extent to which src-family-mediated pathways are used by oocytes from species that fertilize externally vs those which are fertilized internally. The observation that several oocyte functions which require SFK signaling appear to represent common points of failure during assisted reproductive techniques in humans, highlights the importance of these signaling pathways for human reproductive health. PMID- 25030762 TI - Posttranslational modifications of zona pellucida proteins. AB - The zona pellucida (ZP), which surrounds the mammalian oocyte, functions in various aspects of fertilization. The ZP consists of three or four glycoproteins, which are derived from transmembrane proteins that lack the ability to self assemble. Following posttranslational processing at specific sites, ectodomains of ZP precursor proteins are released from the membrane and begin to form a matrix. Glycosylational modification is thought to be involved in species selective sperm recognition by ZP proteins. However, in mice, the supramolecular structure of the zona matrix is also important in sperm recognition. One ZP protein, ZP2, is processed at a specific site upon fertilization by ovastacin, which is released from cortical granules inside the oocyte. This phenomenon is involved in the block to polyspermy. The proteolysis of ubiquitinated ZP proteins by a sperm-associated proteasome is involved in penetration of the zona matrix by sperm, at least in the pigs. Thus, the posttranslational modification of ZP proteins is closely tied to ZP formation and the regulation of sperm-oocyte interactions. PMID- 25030763 TI - Role of aberrant protein modification, assembly, and localization in cloned embryo phenotypes. AB - Aberrant post-translational modifications of proteins contribute markedly to the abnormal characteristics of cloned embryos. This review summarizes aberrant aspects of protein modifications and protein interactions, taking an inside outside view to the cell. These aberrant aspects affect a range of processes including the control of chromatin structure, expression of pluripotency genes, propagation of epigenetic inheritance, protein trafficking, localization and signaling, cytoskeletal structure, mitosis, and correct localization of membrane proteins. By observing these aberrant features of cloned embryos, how they arise, and their impacts on development, it is possible to gain insight into normal development and identify novel strategies for enhancing cloning outcomes. PMID- 25030764 TI - Role of posttranslational protein modifications in epididymal sperm maturation and extracellular quality control. AB - The epididymal lumen is a complex microenvironment in which spermatozoa acquire motility and fertility. Spermatozoa are synthetically inactive and therefore the maturation process requires their interaction with proteins that are synthesized and secreted in a highly regionalized manner by the epididymal epithelium. In addition to the integration of epididymal secretory proteins, posttranslational modifications of existing sperm proteins are important for sperm maturation and acquisition of fertilizing potential. Phosphorylation, glycosylation, and processing are several of the posttranslational modifications that sperm proteins undergo during epididymal transit resulting in changes in protein function and localization ultimately leading to mature spermatozoa. In addition to these well characterized modifications, protein aggregation and cross-linking also occur within the epididymal lumen and may represent unique mechanisms for controlling protein function including that for maturation as well as for extracellular quality control. PMID- 25030765 TI - Ubiquitin-proteasome system in spermatogenesis. AB - Spermatogenesis represents a complex succession of cell division and differentiation events resulting in the continuous formation of spermatozoa. Such a complex program requires precise expression of enzymes and structural proteins which is effected not only by regulation of gene transcription and translation, but also by targeted protein degradation. In this chapter, we review current knowledge about the role of the ubiquitin-proteasome system in spermatogenesis, describing both proteolytic and non-proteolytic functions of ubiquitination. Ubiquitination plays essential roles in the establishment of both spermatogonial stem cells and differentiating spermatogonia from gonocytes. It also plays critical roles in several key processes during meiosis such as genetic recombination and sex chromosome silencing. Finally, in spermiogenesis, we summarize current knowledge of the role of the ubiquitin-proteasome system in nucleosome removal and establishment of key structures in the mature spermatid. Many mechanisms remain to be precisely defined, but present knowledge indicates that research in this area has significant potential to translate into benefits that will address problems in both human and animal reproduction. PMID- 25030766 TI - Role of posttranslational modifications in C. elegans and ascaris spermatogenesis and sperm function. AB - Generally, spermatogenesis and sperm function involve widespread posttranslational modification of regulatory proteins in many different species. Nematode spermatogenesis has been studied in detail, mostly by genetic/molecular genetic techniques in the free-living Caenorhabditis elegans and by biochemistry/cell biology in the pig parasite Ascaris suum. Like other nematodes, both of these species produce sperm that use a form of amoeboid motility termed crawling, and many aspects of spermatogenesis are likely to be similar in both species. Consequently, work in these two nematode species has been largely complementary. Work in C. elegans has identified a number of spermatogenesis defective genes and, so far, 12 encode enzymes that are implicated as catalysts of posttranslational protein modification. Crawling motility involves extension of a single pseudopod and this process is powered by a unique cytoskeleton composed of Major Sperm Protein (MSP) and accessory proteins, instead of the more widely observed actin. In Ascaris, pseudopod extension and crawling motility can be reconstituted in vitro, and biochemical studies have begun to reveal how posttranslational protein modifications, including phosphorylation, dephosphorylation and proteolysis, participate in these processes. PMID- 25030767 TI - High throughput first-principles calculations of bixbyite oxides for TCO applications. AB - We present a high-throughput computing scheme based on density functional theory (DFT) to generate a class of oxides and screen them with the aim of identifying those that might be electronically appropriate for transparent conducting oxide (TCO) applications. The screening criteria used are a minimum band gap to ensure sufficient transparency, a band edge alignment consistent with easy n- or p-type dopability, and a minimum thermodynamic phase stability to be experimentally synthesizable. Following this scheme we screened 23 binary and 1518 ternary bixbyite oxides in order to identify promising candidates, which can then be a subject of an in-depth study. The results for the known TCOs are in good agreement with the reported data in the literature. We suggest a list of several new potential TCOs, including both n- and p-type compounds. PMID- 25030768 TI - Size-dependent elastic moduli and vibrational properties of fivefold twinned copper nanowires. AB - Based on atomistic simulations, the elastic moduli and vibration behaviors of fivefold twinned copper nanowires are investigated in this paper. Simulation results show that the elastic (i.e., Young's and shear) moduli exhibit size dependence due to the surface effect. The effective Young's modulus is found to decrease slightly whereas the effective shear modulus increases slightly with the increase in the wire radius. Both moduli tend to approach certain values at a larger radius and can be suitably described by core-shell composite structure models. Furthermore, we show by comparing simulation results and continuum predictions that, provided the effective Young's and shear moduli are used, classic elastic theory can be applied to describe the small-amplitude vibration of fivefold twinned copper nanowires. Moreover, for the transverse vibration, the Timoshenko beam model is more suitable because shear deformation becomes apparent. PMID- 25030769 TI - Dietary enrichment with alpha-linolenic acid during pregnancy attenuates insulin resistance in adult offspring in mice. AB - OBJECTIVE: Our objective was to test the contribution of dietary enrichment in essential or saturated fatty acids, in normocaloric diets, on the lipid accumulation and insulin resistance in the adult offspring in a C57Bl6/J mice model. METHODS: Pregnant mothers were fed normocaloric diets containing 6% fat enriched in essential fatty acids (EFA): alpha-linolenic (ALA-18:3, n-3), linoleic (LA-18:2, n-6), or saturated fatty acids (SFA). After a washing-out period with regular diet, the offspring received a high-fat diet before euthanization. RESULTS: Adult mice fed maternal ALA showed lower body weight gain and lower liver fat accumulation, lower HOMA index and lower stearoyl-CoA desaturase (SCD1) activity than those fed maternal SFA. CONCLUSION: The results observed using this novel model suggest that ALA in maternal diet may have the potential to inhibit insulin resistance in adult offspring. PMID- 25030770 TI - Comparison of the substrate selectivity and biochemical properties of human and bacterial gamma-butyrobetaine hydroxylase. AB - 2-Oxoglutarate and iron dependent oxygenases have potential for the stereoselective hydroxylation of amino acids and related compounds. The biochemical and kinetic properties of recombinant gamma-butyrobetaine hydroxylase from human and Pseudomonas sp. AK1 were compared. The results reveal differences between the two BBOXs, including in their stimulation by ascorbate. Despite their closely related sequences, the two enzymes also display different substrate selectivities, including for the production of (di)hydroxylated betaines, implying use of engineered BBOXs for biocatalytic purposes may be productive. PMID- 25030771 TI - The value of direct radionuclide cystography in the detection of vesicoureteral reflux in children with normal voiding cystourethrography. AB - BACKGROUND: Vesicoureteral reflux (VUR) is one of the most important risk factors for urinary tract infection (UTI). Diagnosis and treatment of VUR is important to prevent irreversible complications, such as renal scarring and chronic renal failure. This study was conducted to assess the value of direct radionuclide cystography (DRNC) in the detection of VUR in children with UTI and a normal voiding cystourethrography (VCUG). METHODS: DRNC was performed in 35 children with a normal VCUG after an episode of febrile UTI who had hydronephrosis or hydroureter, abnormal acute dimercaptosuccinic acid (DMSA) scan results and/or febrile UTI recurrence. This study was conducted in the nephrology department of Mofid Children's Hospital, Tehran (Iran). RESULTS: The results were statistically analyzed. Among the 70 ureters studied, 33 (49.1 %) were observed to have VUR. Of these, 17 (51.5 %) had mild, 14 (42.4 %) moderate, and 2 (6.1 %) severe reflux. A significant relationship was observed between DRNC results and DMSA renal scan findings (P < 0.05). CONCLUSIONS: Based on our results, we suggest that DRNC may reveal VUR despite a normal VCUG in children with hydronephrosis, abnormal acute DMSA, and/or recurrent febrile UTI. PMID- 25030772 TI - Vitamin C exerts beneficial hepatoprotection against Concanavalin A-induced immunological hepatic injury in mice through inhibition of NF-kappaB signal pathway. AB - The present study was designed to investigate the potential benefits of vitamin C (VC) in treating immunological liver injury induced by Concanavalin A (Con A, 20 mg kg(-1)) in mice. Interestingly, VC administration significantly reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total-bilirubin (T-bilirubin) in Con A-lesioned mice, while serum concentrations of albumin and total-protein (T-protein) were increased. Moreover, inflammatory cytokine profiles, such as interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-6 (IL-6) and interleukin-8 (IL-8), were decreased in liver tissue by VC administration. Morphological examination showed that Con A-induced liver damage was effectively mitigated. As shown in RT-PCR assay, VC administration resulted in down-regulated mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). In addition, VC contributed towards the reduction of intrahepatic tumor necrosis factor alpha (TNF-alpha) and the receptor (TNF-R) protein levels, as well as decreasing IKKbeta, p-IkappaBalpha, p50 and NF-kappaB expressions; furthermore, VC blocked intranuclear DNA-binding NF-kappaB locus. Our findings show that VC effectively attenuates Con A-mediated immunotoxicity in liver tissue, through an underlying mechanism which relates to dampening of the intrahepatic NF-kappaB signal pathway, thereby reducing cytotoxicity within hepatocytes. PMID- 25030773 TI - Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. AB - Acute coronary syndrome (ACS) is a medical emergency. Patients who survive the initial event remain at risk of recurrent cardiovascular events. In most cases, ACS is triggered by thrombosis after rupture of an atherosclerotic plaque. Key to thrombus formation at this site is the generation of thrombin, which not only converts fibrinogen to fibrin but also serves as a potent platelet agonist and induces platelet aggregation at the site of vascular injury. Although dual antiplatelet therapy is more effective for the prevention of recurrent events than aspirin alone after ACS, there remains an approximately 10 % risk of recurrent ischaemic events at one year. Recent studies have evaluated whether the addition of an anticoagulant to antiplatelet therapy reduces the risk of recurrent ischaemia after an ACS event. Rivaroxaban, an oral factor Xa inhibitor, attenuates thrombin generation. When used in conjunction with dual antiplatelet therapy in patients with stabilised ACS, rivaroxaban 2.5 mg twice daily significantly reduced the risk of the composite endpoint of cardiovascular death, myocardial infarction and stroke compared with placebo. Although it increased the risk of bleeding, rivaroxaban was associated with a reduction in mortality; a finding that supports the use of a dual-pathway approach that combines anticoagulant and antiplatelet therapy. This review explores the pathophysiology of ACS to provide perspective on the results of recent clinical trials with novel oral anticoagulants for ACS and to identify their potential role in this setting. PMID- 25030774 TI - A piezoelectric-based immunosensor for high density lipoprotein particle measurement. AB - A piezoelectric-based immunosensor was developed for high density lipoprotein particle (HDL-P) measurement. Monoclonal anti-human apolipoprotein A1 antibody was used as a specific binding molecule for the major apolipoprotein of HDL-P. This sensing element was fabricated by immobilizing the anti-human apolipoprotein A1 on a 12 MHz AT-cut quartz crystal via a 3-mercaptopropionic acid (MPA) self assembled monolayer. The frequency shift from the mass change of the antigen antibody binding refers to the amount of HDL-P. The optimal antibody immobilization was performed to achieve the maximum potential of the antibody. The appropriate quantity and immobilization time of the antibody were 0.1 mg ml( 1) and 90 minutes, respectively. The immobilized antibody in the HDL-P immunosensor accomplished perfect binding with HDL-P within 60 minutes. The dose response curve for HDL-P showed a linear response from 0.21 to 2.50 mg protein per ml equivalent to 0.40 * 10(10) to 3.65 * 10(10) particles per MUl without significant interference from other lipoproteins. The intra- and inter-assay imprecision (CV) were 7.8 and 18.5%, respectively. The analytical accuracy of this measurement was 96.29-96.31%. The HDL-P concentration obtained from the sensor revealed a 2.05 mg protein per ml with 0.26 mg protein per ml of expanded uncertainty at the 95% confidence level. This immunosensor gave an assay result which correlated with the homogeneous enzymatic colorimetric assay (R(2) = 0.902). PMID- 25030775 TI - Motion Planning Under Uncertainty In Highly Deformable Environments. AB - Many tasks in robot-assisted surgery, food handling, manufacturing, and other applications require planning and controlling the motions of manipulators or other devices that must interact with highly deformable objects. We present a unified approach for motion planning under uncertainty in deformable environments that maximizes probability of success by accounting for uncertainty in deformation models, noisy sensing, and unpredictable actuation. Unlike prior planners that assume deterministic deformations or treat deformations as a type of small perturbation, our method explicitly considers the uncertainty in large, time-dependent deformations. Our method requires a simulator of deformable objects but places no significant restrictions on the simulator used. We use a sampling-based motion planner in conjunction with the simulator to generate a set of candidate plans based on expected deformations. Our method then uses the simulator and optimal control to numerically estimate time-dependent state distributions based on uncertain parameters (e.g. deformable material properties or actuation errors). We then select the plan with the highest estimated probability of successfully avoiding obstacles and reaching the goal region. Using FEM-based simulation of deformable tissues, we demonstrate the ability of our method to generate high quality plans in two medical-inspired scenarios: (1) guiding bevel-tip steerable needles through slices of deformable tissue around obstacles for minimally invasive biopsies and drug-delivery, and (2) manipulating planar tissues to align interior points at desired coordinates for precision treatment. PMID- 25030776 TI - Pancreatic adenocarcinoma: MRI conspicuity and pathologic correlations. AB - PURPOSE: To identify the MRI sequences producing the greatest pancreatic adenocarcinoma conspicuity and to assess correlations linking MRI signal intensity and apparent diffusion coefficient to histopathological findings. METHODS: We retrospectively included 22 patients with pancreatic adenocarcinoma who underwent MRI (1.5 or 3 T) before surgical resection. Fat-suppressed (FS) T1- and T2-weighted sequences; 3D FS dynamic T1-weighted gadolinium-enhanced gradient echo (GRE) imaging at the arterial, portal, and delayed phases; and diffusion weighted imaging (DWI) with b values of 600-800 s/mm(2) were reviewed. On each sequence, we assessed tumor conspicuity both qualitatively (3-point scale) and quantitatively (tumor-to-proximal and -distal pancreas contrast ratios), and we performed paired Wilcoxon tests to compare these data across sequences. We evaluated correlations between histopathological characteristics and MRI features. RESULTS: 21/22 (95%) tumors were hypointense by 3D FS T1 GRE arterial phase imaging, which produced the greatest tumor conspicuity (p <= 0.02). By DWI, 5/20 (25%) of tumors were isointense. The correlation between size by histology and MRI was strongest with DWI. A progressive enhancement pattern was associated with extensive and dense fibrous stroma (p <= 0.03). CONCLUSIONS: 3D FS T1 GRE arterial phase imaging produces greater pancreatic adenocarcinoma conspicuity compared to DWI but underestimates tumor size. DWI provides the best size evaluation but fails to delineate the tumor in one-fourth of cases. PMID- 25030777 TI - Patient-reported outcomes in primary care patients with COPD: psychometric properties and usefulness of the Clinical COPD Questionnaire (CCQ). A cross sectional study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common disease with considerable consequences for patients' daily lives. The Clinical COPD Questionnaire (CCQ) was designed to measure these consequences in daily practice. Although the CCQ is widely used, its original structure has never been tested. AIMS: This study examines the psychometric properties of the CCQ with regard to its latent structure in a sample of primary care patients with COPD. METHODS: Two cross-sectional studies were conducted; in study 1 (N=243) exploratory analyses, including exploratory factor analysis (EFA) and Mokken scale analysis, were performed to explore the latent structure of the CCQ. In study 2 (N=244), confirmatory factor analysis (CFA) was conducted to evaluate the model fit of the structure found in study 1. RESULTS: Both EFA and Mokken scale analysis revealed a structure of two dimensions ('general impact' alpha=0.91 and 'cough' alpha=0.84). This structure, however, was not confirmed in study 2, nor was the original structure. However, subsequently removing items that violated the assumption of a normal response distribution did result in an excellent model fit with two dimensions measuring 'dyspnoea' and 'cough' (CFA: comparative fit index (CFI) 0.98; normed fit index (NFI) 0.97; root mean squared error of approximation (RMSEA) 0.08 (0.04)). CONCLUSIONS: In primary care, factor analyses on the CCQ revealed a two-component structure measuring 'general impact', and 'cough'. A shortened and more specific version of the CCQ could be regarded as a useful instrument to screen for exacerbations by measuring dyspnoea, coughing and producing phlegm. PMID- 25030778 TI - Catalytic oxidation of CO with N2O on isolated copper cluster anions. AB - A catalytic redox reaction involving N2O and CO on size-selected copper cluster anions, Cun(-), was investigated in the gas phase using a guided ion-beam tandem mass spectrometer. When Cun(-) is exposed to a mixture of N2O and CO, CunO(-) is produced via the decomposition of N2O. Increase of the CO partial pressure results in the reproduction of Cun(-) and decrease of CunO(-) through the oxidation of CO. The present results demonstrate that a full catalytic cycle for the reaction, N2O + CO -> N2 + CO2, takes place on copper cluster anions. Furthermore, in the investigations of the elementary reactions of Cun(-) + N2O and CunO(-) + CO, we found that the catalytic oxidation of CO with N2O on Cun(-) proceeds most efficiently at n = 7 in the size range of n = 5-16. PMID- 25030779 TI - Comparison of the effects of slowly and rapidly absorbed carbohydrates on postprandial glucose metabolism in type 2 diabetes mellitus patients: a randomized trial. AB - BACKGROUND: Isomaltulose attenuates postprandial glucose and insulin concentrations compared with sucrose in patients with type 2 diabetes mellitus (T2DM). However, the mechanism by which isomaltulose limits postprandial hyperglycemia has not been clarified. OBJECTIVE: The objective was therefore to assess the effects of bolus administration of isomaltulose on glucose metabolism compared with sucrose in T2DM. DESIGN: In a randomized, double-blind, crossover design, 11 participants with T2DM initially underwent a 3-h euglycemic hyperinsulinemic (0.8 mU . kg(-1) . min(-1)) clamp that was subsequently combined with 1 g/kg body wt of an oral (13)C-enriched isomaltulose or sucrose load. Hormonal responses and glucose kinetics were analyzed during a 4-h postprandial period. RESULTS: Compared with sucrose, absorption of isomaltulose was prolonged by ~50 min (P = 0.004). Mean plasma concentrations of insulin, C-peptide, glucagon, and glucose-dependent insulinotropic peptide were ~10-23% lower (P < 0.05). In contrast, glucagon-like peptide 1 (GLP-1) was ~64% higher (P < 0.001) after isomaltulose ingestion, which results in an increased insulin-to-glucagon ratio (P < 0.001) compared with sucrose. The cumulative amount of systemic glucose appearance was ~35% lower after isomaltulose than after sucrose (P = 0.003) because of the reduction in orally derived and endogenously produced glucose and a higher first-pass splanchnic glucose uptake (SGU). Insulin action was enhanced after isomaltulose compared with sucrose (P = 0.013). CONCLUSIONS: Ingestion of slowly absorbed isomaltulose attenuates postprandial hyperglycemia by reducing oral glucose appearance, inhibiting endogenous glucose production (EGP), and increasing SGU compared with ingestion of rapidly absorbed sucrose in patients with T2DM. In addition, GLP-1 secretion contributes to a beneficial shift in the insulin-to-glucagon ratio, suppression of EGP, and enhancement of SGU after isomaltulose consumption. This trial was registered at clinicaltrials.gov as NCT01070238. PMID- 25030780 TI - Differences in survival associated with processed and with nonprocessed red meat consumption. AB - BACKGROUND: High red meat consumption is associated with an increased mortality risk. This association is partly explained by the negative effect of processed meat consumption, which is widely established. The role of nonprocessed meat is unclear. OBJECTIVE: The objective was to examine the combined association of processed and nonprocessed meat consumption with survival in a Swedish large prospective cohort. DESIGN: In a population-based cohort of 74,645 Swedish men (40,089) and women (34,556), red meat consumption was assessed through a self administered questionnaire. We estimated differences in survival [15th percentile differences (PDs), differences in the time by which the first 15% of the cohort died] according to levels of total red meat and combined levels of processed and nonprocessed red meat consumption. RESULTS: During 15 y of follow-up (January 1998 to December 2012), we documented 16,683 deaths (6948 women; 9735 men). Compared with no consumption, consumption of red meat >100 g/d was progressively associated with shorter survival--up to 2 y for participants consuming an average of 300 g/d (15th PD: -21 mo; 95% CI: -31, -10). Compared with no consumption, high consumption of processed red meat (100 g/d) was associated with shorter survival (15th PD: -9 mo; 95% CI: -16, -2). High and moderate intakes of nonprocessed red meat were associated with shorter survival only when accompanied by a high intake of processed red meat. CONCLUSIONS: We found that high total red meat consumption was associated with progressively shorter survival, largely because of the consumption of processed red meat. Consumption of nonprocessed red meat alone was not associated with shorter survival. PMID- 25030781 TI - Accuracy of prediction equations for serum osmolarity in frail older people with and without diabetes. AB - BACKGROUND: Serum osmolality is an accurate indicator of hydration status in older adults. Glucose, urea, and electrolyte concentrations are used to calculate serum osmolarity, which is an indirect estimate of serum osmolality, but which serum osmolarity equations best predict serum osmolality in the elderly is unclear. OBJECTIVE: We assessed the agreement of measured serum osmolality with calculated serum osmolarity equations in older people. DESIGN: Serum osmolality was measured by using freezing point depression in a cross-sectional study. Plasma glucose, urea, and electrolytes were analyzed and entered into 38 serum osmolarity-prediction equations. The Bland-Altman method was used to evaluate the agreement and differential bias between measured osmolality and calculated osmolarity. The sensitivity and specificity of the most-promising equations were examined against serum osmolality (reference standard). RESULTS: A total of 186 people living in UK residential care took part in the Dehydration Recognition In our Elders study (66% women; mean +/- SD age: 85.8 +/- 7.9 y; with a range of cognitive and physical impairments) and were included in analyses. Forty-six percent of participants had impending or current dehydration (serum osmolality >=295 mmol/kg). Participants with diabetes (n = 33; 18%) had higher glucose (P < 0.001) and serum osmolality (P < 0.01). Of 38 predictive equations used to calculate osmolarity, 4 equations showed reasonable agreement with measured osmolality. One [calculated osmolarity = 1.86 * (Na+ + K+) + 1.15 * glucose + urea +14; all in mmol/L] was characterized by narrower limits of agreement and the capacity to predict serum osmolality within 2% in >80% of participants, regardless of diabetes or hydration status. The equation's sensitivity (79%) and specificity (89%) for impending dehydration (>=295 mmol/kg) and current dehydration (>300 mmol/kg) (69% and 93%, respectively) were reasonable. CONCLUSIONS: The assessment of a panel of equations for the prediction of serum osmolarity led to identification of one formula with a greater diagnostic performance. This equation may be used to predict hydration status in frail older people (as a first-stage screening) or to estimate hydration status in population studies. This trial was registered at the Research Register for Social Care (http://www.researchregister.org.uk) as 122273. PMID- 25030783 TI - Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. AB - BACKGROUND: Sugar-sweetened soda consumption is consistently associated with an increased risk of several chronic inflammatory diseases such as type 2 diabetes and cardiovascular diseases. Whether it plays a role in the development of rheumatoid arthritis (RA), a common autoimmune inflammatory disease, remains unclear. OBJECTIVE: The aim was to evaluate the association between sugar sweetened soda consumption and risk of RA in US women. DESIGN: We prospectively followed 79,570 women from the Nurses' Health Study (NHS; 1980-2008) and 107,330 women from the NHS II (1991-2009). Information on sugar-sweetened soda consumption (including regular cola, caffeine-free cola, and other sugar sweetened carbonated soda) was obtained from a validated food-frequency questionnaire at baseline and approximately every 4 y during follow-up. Incident RA cases were validated by medical record review. Time-varying Cox proportional hazards regression models were used to calculate HRs after adjustment for confounders. Results from both cohorts were pooled by an inverse-variance weighted, fixed-effects model. RESULTS: During 3,381,268 person-years of follow up, 857 incident cases of RA were documented in the 2 cohorts. In the multivariable pooled analyses, we found that women who consumed >=1 serving of sugar-sweetened soda/d had a 63% (HR: 1.63; 95% CI: 1.15, 2.30; P-trend = 0.004) increased risk of developing seropositive RA compared with those who consumed no sugar-sweetened soda or who consumed <1 serving/mo. When we restricted analyses to those with later RA onset (after age 55 y) in the NHS, the association appeared to be stronger (HR: 2.64; 95% CI: 1.56, 4.46; P-trend < 0.0001). No significant association was found for sugar-sweetened soda and seronegative RA. Diet soda consumption was not significantly associated with risk of RA in the 2 cohorts. CONCLUSION: Regular consumption of sugar-sweetened soda, but not diet soda, is associated with increased risk of seropositive RA in women, independent of other dietary and lifestyle factors. PMID- 25030782 TI - Moderate amounts of fructose- or glucose-sweetened beverages do not differentially alter metabolic health in male and female adolescents. AB - BACKGROUND: Adolescents consume more sugar-sweetened beverages than do individuals in any other age group, but it is unknown how the type of sugar sweetened beverage affects metabolic health in this population. OBJECTIVE: The objective was to compare the metabolic health effects of short-term (2-wk) consumption of high-fructose (HF) and high-glucose (HG)-sweetened beverages in adolescents (15-20 y of age). DESIGN: In a counterbalanced, single-blind fashion, 40 male and female adolescents completed two 2-wk trials that included 1) an HF trial in which they consumed 710 mL of a sugar-sweetened beverage/d (equivalent to 50 g fructose/d and 15 g glucose/d) for 2 wk and 2) an HG trial in which they consumed 710 mL of a sugar-sweetened beverage/d (equivalent to 50 g glucose/d and 15 g fructose/d) for 2 wk in addition to their normal ad libitum diet. In addition, the participants maintained similar physical activity levels during each trial. The day after each trial, insulin sensitivity and resistance [assessed via Quantitative Insulin Sensitivity Check Index (QUICKI) and homeostatic model assessment of insulin resistance (HOMA-IR) index] and fasting and postprandial glucose, lactate, lipid, cholesterol, insulin, C-peptide, insulin secretion, and clearance responses to HF or HG mixed meals were assessed. RESULTS: Body weight, QUICKI (whole-body insulin sensitivity), HOMA-IR (hepatic insulin resistance), and fasting lipids, cholesterol, glucose, lactate, and insulin secretion or clearance were not different between trials. Fasting HDL- and HDL3-cholesterol concentrations were ~10-31% greater (P < 0.05) in female adolescents than in male adolescents. Postprandial triacylglycerol, HDL cholesterol, HDL3-cholesterol, and glucose concentrations were not different between HF and HG trials. The lactate incremental area under the curve was ~3.7 fold greater during the HF trial (P < 0.05), whereas insulin secretion was 19% greater during the HG trial (P < 0.05). CONCLUSIONS: Moderate amounts of HF- or HG-sweetened beverages for 2 wk did not have differential effects on fasting or postprandial cholesterol, triacylglycerol, glucose, or hepatic insulin clearance in weight-stable, physically active adolescents. PMID- 25030784 TI - Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Heart failure (HF) is a major source of morbidity and mortality, particularly among the elderly. Magnesium, phosphorus, and calcium are micronutrients traditionally viewed in relation to bone health or chronic kidney disease. However, they also may be associated with risk of cardiovascular disease through a broad range of physiologic roles. OBJECTIVE: With the use of data from the Atherosclerosis Risk in Communities (ARIC) cohort, we tested the hypotheses that the incidence of HF is greater among individuals with low serum magnesium and those with high serum phosphorus and calcium. DESIGN: A total of 14,709 African Americans (27%) and whites from the ARIC cohort [aged 45-64 y at baseline (1987-1989)] were observed through 2009. Proportional hazards regression was used to explore associations between biomarkers and incident HF. Serum calcium was corrected for serum albumin. Models were adjusted for demographics, behaviors, and physiologic characteristics. RESULTS: A total of 2250 incident HF events accrued over a median follow-up of 20.6 y. Participants in the lowest (<=1.4 mEq/L) compared with the highest (>=1.8 mEq/L) category of magnesium were at greater HF risk (HR: 1.71; 95% CI: 1.46, 1.99). For phosphorus, there appeared to be a threshold whereby only those in the highest quintile were at greater HF risk [HR(Q5 vs Q1): 1.34; 95% CI: 1.16, 1.54]. Higher concentrations of calcium were also associated with greater risk of HF [HR(Q5 vs Q1): 1.24; 95% CI: 1.07, 1.43]. Results were not modified by race, sex, or kidney function and were similar when incident coronary heart disease was included as a time-varying covariate. CONCLUSIONS: Low serum magnesium and high serum phosphorus and calcium were independently associated with greater risk of incident HF in this population based cohort. Whether these biomarkers will be useful candidates for HF risk prediction or targets for prevention remains to be seen. PMID- 25030785 TI - Consumption of added sugars among US children and adults by food purchase location and food source. AB - BACKGROUND: The proposed changes to the Nutrition Facts Label by the US Food and Drug Administration will include information on added sugars for the first time. OBJECTIVE: The objective was to evaluate the sources of added sugars in the diets of a representative sample of US children and adults by food purchase location and food source (eg, food group). DESIGN: This cross-sectional study among 31,035 children, adolescents, and adults aged >=6 y from the 2003-2004, 2005-2006, 2007 2008, and 2009-2010 NHANES used data from a 24-h dietary recall to evaluate consumption of added sugars. Food locations of origin were identified as stores (supermarket or grocery store), quick-service restaurants/pizza (QSRs), full service restaurants (FSRs), schools, and others (eg, vending machines or gifts). Added sugars consumption by food purchase location was evaluated by age, family income-to-poverty ratio, and race-ethnicity. Food group sources of added sugars were identified by using the National Cancer Institute food categories. RESULTS: Added sugars accounted for ~14.1% of total dietary energy. Between 65% and 76% of added sugars came from stores, 6% and 12% from QSRs, and 4% and 6% from FSRs, depending on age. Older adults (aged >=51 y) obtained a significantly greater proportion of added sugars from stores than did younger adults. Lower-income adults obtained a significantly greater proportion of added sugars from stores than did higher-income adults. Intake of added sugars did not vary by family income among children/adolescents. Soda and energy and sports drinks were the largest food group sources of added sugars (34.4%), followed by grain desserts (12.7%), fruit drinks (8.0%), candy (6.7%), and dairy desserts (5.6%). CONCLUSIONS: Most added sugars came from foods obtained from stores. The proposed changes to the Nutrition Facts Label should capture the bulk of added sugars in the US food supply, which suggests that the recommended changes have the potential to reduce added sugars consumption. PMID- 25030787 TI - Reduction of Fusarium rot and maintenance of fruit quality in melon using eco friendly hot water treatment. AB - Significant losses in harvested fruit can be directly attributable to decay fungi and quality deterioration. Hot water treatment (HWT) has been demonstrated to be an effective and economic environment-friendly approach for managing postharvest decay and maintaining fruit quality. In this study, the effects of HWT (45 degrees C for 10, 15, 20, and 25 min) on in vitro growth of Fusarium oxysporum, in vivo Fusarium rot, and natural decay of melon were investigated. HWT inhibited spore germination and germ tube elongation of F. oxysporum. Protein impairment and ATP consumption triggered by HWT contributed to the inhibitory effect. Results of in vivo studies showed that HWT effectively controlled Fusarium rot and natural decay of melon. Correspondingly, HWT induced a significant increase in content of total phenolic compounds and lignin of melon. These findings indicate that the effects of HWT on Fusarium rot may be associated with the direct fungal inhibition and the elicitation of defense responses in fruit. Importantly, HWT used in this study had beneficial effects on fruit quality as well. HWT may represent an effective non-chemical approach for management of postharvest Fusarium rot. PMID- 25030786 TI - Risk for estrogen-dependent diseases in relation to phthalate exposure and polymorphisms of CYP17A1 and estrogen receptor genes. AB - Evidence has shown that polymorphisms of various genes known to be involved in estrogen biosynthesis and function are associated with estrogen-dependent diseases (EDDs). These genes include CYP17A1, estrogen receptor 1 (ESR1), and 2 (ESR2). Phthalates are considered estrogenic endocrine disruptors, and recent research has suggested that they may act as a risk factor for EDDs. However, extremely few studies have assessed the effects of gene-environment interaction on these diseases. We recruited 44 patients with endometriosis or adenomyosis, 36 patients with leiomyoma, and 69 healthy controls from a medical center in Taiwan between 2005 and 2007. Urine samples were collected and analyzed for seven phthalate metabolites using liquid chromatography tandem mass spectrometry. Peripheral lymphocytes were used for DNA extraction to determine the genotype of CYP17A1, ESR1, and ESR2. Compared to controls, patients with leiomyoma had significantly higher levels of total urinary mono-ethylhexyl phthalate (SigmaMEHP) (52.1 vs. 29.6 MUg/g creatinine, p = 0.040), mono-n-butyl phthalate (MnBP) (75.4 vs. 51.3 MUg/g creatinine, p = 0.019), and monoethyl phthalate (MEP) (103.7 vs. 59.3 MUg/g creatinine, p = 0.031). In contrast, patients with endometriosis or adenomyosis showed a marginally increased level of urinary MEHP only. Subjects who were homozygous for both the ESR1 C allele (rs2234693) and CYP17A1 C allele (rs743572) showed a significantly increased risk for leiomyoma (OR = 19.8; 95 % CI, 1.70; 231.5; p = 0.017) relative to subjects with other genotypes of ESR1 and CYP17A1. These results were obtained after adjusting for age, cigarette smoking, MEHP level, GSTM1 genotype and other covariates. Our results suggested that both CYP17A1 and ESR1 polymorphisms may modulate the effects of phthalate exposure on the development of leiomyoma. PMID- 25030788 TI - Development and validation of a scale for the end of life caregiving appraisal. AB - PURPOSE: End-of-life caregiving experiences can be complex. Family members experience physical and mental suffering as they anticipate their impending loss. Healthcare providers should be able to provide good quality of end-of-life (EOL) care and support for primary EOL caregivers. Studies have highlighted the role of healthcare providers providing information in the EOL situation to caregivers of chronic disease patients. This has resulted in the development of the End-of-life Caregiving Experience Appraisal Scale (EOLCAS) presented in this paper. The purposes of this study were to develop a scale that can evaluate the experiences of EOL caregivers, and to test the reliability and validity of this scale. METHODS: The scale domains were derived from systematic review of 35 relevant studies. We then examined its content validity with nurse scholars and clinicians using content validity index. To examine construct validity, a total of 175 caregivers from tertiary hospital setting in Korea participated in this study from December 2007 to May 2008. For the construct validity, factor analysis was utilized. RESULTS: The scale was composed of 32 items with four subscales: two negative appraisals (physical suffering and burden), one positive appraisal (maturation), and one neutral appraisal (social support pursuit). In this sample, the Cronbach's alpha for the entire scale was .84 indicating adequate reliability. However, Cronbach's alpha of subscales was varied. CONCLUSION: Nurses and other healthcare professionals could use the EOLCAS to assess the experiences of EOL caregivers to understand their experience in the EOL and enhance their quality of life although psychometrics of EOLCAS shows limited findings. PMID- 25030789 TI - Predictors of hearing protection behavior among power plant workers. AB - PURPOSE: This study aimed to identify factors affecting the use of the hearing protection devices (HPDs) among workers exposed to noise using the Pender Health Promotion Model. METHODS: The 222 subjects came from thermal power plants with similar noise levels, which are between 80 dB and 90 dB in South Korea. Data were collected with self-administered questionnaires designed to measure concepts from the Health Promotion Model. RESULTS: Mean percent times of using the HPDs at their most recent job site were 50.9%, and 20.3% had never the HPDs. The predictors of HPD use were social modeling (OR = 1.380), perceived benefits (OR = 1.150), and working at noisy worksites (OR = 4.925) when the outcome was based on the "non-use" versus "used at least once". However, the predictors of HPD use were social modeling (OR = 1.795) and perceived benefits (OR = 1.139) based on the "less than half-of-the-time-use" versus "more than half-of-the-time-use". CONCLUSION: Social modeling and perceived benefits of using the HPDs are important for workers to keep minimal or certain level of using the HPDs. PMID- 25030790 TI - Identification of Hypertension Management-related Errors in a Personal Digital Assistant-based Clinical Log for Nurses in Advanced Practice Nurse Training. AB - PURPOSE: The purposes of this study were to develop a taxonomy for detection of errors related to hypertension management and to apply the taxonomy to retrospectively analyze the documentation of nurses in Advanced Practice Nurse (APN) training. METHOD: We developed the Hypertension Diagnosis and Management Error Taxonomy and applied it in a sample of adult patient encounters (N = 15,862) that were documented in a personal digital assistant-based clinical log by registered nurses in APN training. We used Standard Query Language queries to retrieve hypertension-related data from the central database. The data were summarized using descriptive statistics. RESULT: Blood pressure was documented in 77.5% (n = 12,297) of encounters; 21% had high blood pressure values. Missed diagnosis, incomplete diagnosis and misdiagnosis rates were 63.7%, 6.8% and 7.5% respectively. In terms of treatment, the omission rates were 17.9% for essential medications and 69.9% for essential patient teaching. Contraindicated anti hypertensive medications were documented in 12% of encounters with co-occurring diagnoses of hypertension and asthma. CONCLUSION: The Hypertension Diagnosis and Management Error Taxonomy was useful for identifying errors based on documentation in a clinical log. The results provide an initial understanding of the nature of errors associated with hypertension diagnosis and management of nurses in APN training. The information gained from this study can contribute to educational interventions that promote APN competencies in identification and management of hypertension as well as overall patient safety and informatics competencies. PMID- 25030791 TI - Appraisals, burnout and outcomes in informal caregiving. AB - OBJECTIVES: This study draws from the resource depletion and conservation theories to develop a process model of informal caregiving. The model includes the burnout as a key mediator of the relationship between benefit/threat appraisals and critical outcomes including perceived physical health, depression and life satisfaction. METHODS: A self-report questionnaire was utilized to collect relevant data from 137 informal caregivers of older adults. The proposed model and hypotheses were evaluated with the Structural Equation Modeling method using the software EQS. RESULTS: The relatively high reported levels of emotional exhaustion and reduced personal accomplishment established the relevance of the burnout construct for informal caregivers. In addition, the test of the proposed model provides support for the hypothesis that burnout is an important mediator in the appraisal process model of informal caregiving. However, while burnout effectively mediates the influence of threat appraisals, its role in mediating the effect of benefit appraisals is mixed. CONCLUSION: The proposed model and results highlight the significance and potential for utilizing a process approach for understanding the link between appraisals and outcomes for informal caregivers. More importantly, the proposed model suggests that attention must be paid toward burnout tendencies to reveal fruitful intervention directions for researchers and practitioners to enhance the positive outcomes of informal caregivers, and maintain their psychological and physical well-being. PMID- 25030792 TI - Correlates of health behaviors in patients with coronary artery disease. AB - PURPOSE: To investigate the effect of cardiac knowledge and cardiac self-efficacy on health behaviors after controlling for influences from associating factors of health behaviors in patients with coronary artery diseases (CADs). METHODS: A descriptive correlational and cross-sectional design was used. Subjects with CADs were recruited from outpatient clinics of three academic medical centers. The cardiac knowledge, cardiac self-efficacy, and health behaviors were measured by Coronary Heart Disease Awareness and Knowledge Questionnaire, Cardiac Self Efficacy Scale, and Health-Promoting Lifestyle Profile II respectively. The data collected were statistically analyzed by descriptive statistics, t test, Kruskal Wallis test, analysis of variance, Pearson's correlation analysis, and the hierarchical multiple regression analysis. RESULTS: A total of 157 subjects were recruited for this study. The mean age of subjects was 59.38 +/- 10.04 years, and three-fourths (75.2%) were male. Subjects showed relatively low cardiac knowledge, moderately high cardiac self-efficacy, and moderate level of health behaviors. The overall model significantly explained 48% of variance in health behaviors (F = 14.52, p < .001). Among predictors, age, education, smoking status, experience of receiving patient education, and cardiac self-efficacy significantly affected health behaviors, and cardiac self-efficacy had the greatest effect on health behaviors (beta= .39). However, cardiac knowledge had no statistically significant influence on health behaviors after controlling for the other factors. CONCLUSION: The findings suggested that cardiac self-efficacy was shown to be the most influencing factor on health behaviors but cardiac knowledge had no influence on health behaviors. The nursing interventions tailored on the patient characteristics should be developed in order to improve the health behaviors of patients with CADs. PMID- 25030793 TI - Parental perfectionism and overcontrol: examining mechanisms in the development of child anxiety. AB - It has been theorized that perfectionistic parents will engage in behaviors characterized by overcontrol, which then increase child anxiety. Previous research has yet to test this theory within a single study. The current study investigated the proposed theory in a single model, examining the mediational roles of parent perfectionism and overcontrol in the association between parent and child anxiety. Participants were 77 parent-child dyads, with 46 parents and 40 children diagnosed with an anxiety disorder. Children were between 3 and 12 years old (57.1% female, 76.6% Caucasian, 22.1% African American). Path analysis indicated that the overall model fit the data well. Analyses showed that parental overcontrol mediated the relation between parental perfectionism and child anxiety and parental perfectionism mediated the relation between parental anxiety and parental overcontrol. Further, parental perfectionism and overcontrol sequentially mediated the parent to child anxiety relation. However, when parental perfectionism was accounted for in the model, parental overcontrol did not mediate the relation between parent and child anxiety. The findings suggest that parent perfectionism and overcontrol, together, may represent a specific pathway of risk for the development of anxiety disorders in children. The implications of these findings are reviewed in the context of previous theory on parental perfectionism, overcontrol, and the development of child anxiety. The clinical importance of the findings and future directions are also discussed. PMID- 25030794 TI - Adjustment as process and outcome: Measuring adjustment to HIV in Uganda. AB - 'Adjustment' in health refers to both processes and outcomes. Its measurement and conceptualisation in African cultures is limited. In total, 263 people living with HIV and receiving anti-retroviral therapy in clinics in Uganda completed a translated Mental Adjustment to HIV Scale, depression items from the Hopkins checklist and demographic questions. Factor analysis revealed four Mental Adjustment to HIV factors of active coping, cognitive-social adjustment, hopelessness and denial/avoidance. Correlations with depression supported the Mental Adjustment to HIV's validity and the importance of active adjustment, while the role of cognitive adjustment was unclear. Factors were process or outcome focussed, suggesting a need for theory-based measures in general. PMID- 25030795 TI - Why practice yoga? Practitioners' motivations for adopting and maintaining yoga practice. AB - We examined motives for adopting and maintaining yoga practice in a national survey of yoga practitioners (360 yoga students, 156 yoga teachers). Both students and teachers adopted yoga practice primarily for exercise and stress relief, but reported many other reasons, including flexibility, getting into shape, and depression/anxiety relief. Over 62 percent of students and 85 percent of teachers reported having changed their primary reason for practicing or discovering other reasons; for both, the top changed primary reason was spirituality. Findings suggest that most initiate yoga practice for exercise and stress relief, but for many, spirituality becomes their primary reason for maintaining practice. PMID- 25030796 TI - Self-esteem mediates the effect of the parent-adolescent relationship on depression. AB - There is a trend of rapid growth in both the level and occurrence of depression when people reach adolescence. The present study aimed to investigate the impact of the parent-adolescent relationship on depression in adolescents, and mainly focused on the confirmation of the mediator role of self-esteem. A total of 364 senior middle school students accomplished the Parent-Adolescent Relationship Scale, Rosenberg Self-Esteem Scale, and Zung Self-Rating Depression Scale. The results suggested that both parent-adolescent relationship and self-esteem were significantly correlated with depression. Structural equation modeling indicated that self-esteem partially mediated the relationship between parent-adolescent relationship and depression. PMID- 25030797 TI - Predicting post-traumatic stress and health anxiety following a venous thrombotic embolism. AB - This research identified psychosocial factors associated with post-traumatic stress and health anxiety following a venous thrombotic embolism. In all, 158 participants, largely registered with a venous thrombotic embolism information website (Lifeblood: The Thrombosis Charity), completed an online survey. Post traumatic symptom scores were linked to health threat, and not moderated by perceived control over risk for further venous thrombotic embolism. Health anxiety was associated with continuing symptoms and a negative emotional response to the venous thrombotic embolism. There is a need to intervene to reduce both short- and long-term distress in this population, ideally using a stepped-care model. PMID- 25030801 TI - The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study. AB - RATIONALE: Posttraumatic stress disorder (PTSD) and alcoholism are frequently comorbid, suggesting the possibility of overlapping neural substrates. The neurokinin 1 (NK1) receptor for substance P (SP) has been implicated in both stress- and alcohol-related behaviors. The NK1 antagonist aprepitant, clinically available as a treatment for chemotherapy-induced nausea, offers a tool to probe a potential role of the SP/NK1 system in comorbid PTSD and alcoholism. OBJECTIVES: The aim of this study is to evaluate the efficacy of aprepitant for treatment of comorbid PTSD and alcoholism. METHODS: Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to an inpatient unit at the NIH Clinical Center and randomized to double-blind aprepitant (125 mg/day; based on PET studies reporting >90 % central receptor occupancy at this dose) or placebo. After reaching steady state, subjects were assessed for PTSD symptom severity, behavioral and neuroendocrine responses to stress and alcohol cues, and functional magnetic resonance imaging (fMRI) responses to stimuli with positive or negative emotional valence. RESULTS: Aprepitant treatment had no effect on PTSD symptoms or subjective or physiological responses to stress or alcohol cues. However, aprepitant robustly potentiated ventromedial prefrontal cortex (mPFC) fMRI responses to aversive visual stimuli. CONCLUSIONS: Despite the lack of effect on PTSD symptoms and responses to stress/alcohol cues, NK1 antagonism activated the ventral mPFC, an area considered hypoactive in PTSD, during exposure to aversive stimuli. Because this brain area is critically important for extinction of fear memories and in alcohol craving and relapse, our finding suggests that NK1 antagonism might be a useful pharmacological treatment to enhance extinction-based cue-exposure therapies. PMID- 25030802 TI - Effects of quetiapine treatment on cocaine self-administration and behavioral indices of sleep in adult rhesus monkeys. AB - RATIONALE: Clinical literature suggests a link between substance abuse and sleep disturbances. Quetiapine, an atypical antipsychotic, has shown efficacy in treating sleep disturbances, with clinical studies showing promise for quetiapine as a treatment for cocaine abuse. OBJECTIVE: The goal of this study was to examine the effects of quetiapine on cocaine self-administration and behavioral indices of sleep in monkeys. METHODS: Seven adult male rhesus monkeys, fitted with Actical(r) activity monitors, were trained to respond under a choice paradigm of food (1.0-g pellets) and cocaine (0.003-0.3 mg/kg per injection) presentation. First, monkeys received acute pretreatment (45 min) with quetiapine (25-75 mg, p.o.) prior to choice sessions; three cocaine doses were studied in combination with quetiapine. Next, the effect of chronic (14-16 days) quetiapine treatment (25-250 mg, p.o., BID) was examined in combination with the lowest preferred cocaine dose (>=80 % cocaine choice). Behavioral indices of sleep, based on activity measures obtained during lights-out, were recorded throughout the study. RESULTS: Acute quetiapine decreased cocaine choice in four of the seven monkeys. Chronic quetiapine treatment resulted in initial decreases in cocaine choice, but tolerance developed to these effects. Acute doses of quetiapine did not improve sleep efficiency the following night nor did chronic quetiapine. The first night after discontinuing quetiapine treatment resulted in significant decreases in sleep efficiency and increases in nighttime activity. CONCLUSIONS: These findings do not offer support for the use of quetiapine as a monotherapy for treatment of cocaine abuse nor as an adjunct therapy to treat sleep disturbances associated with stimulant abuse. PMID- 25030804 TI - Activity levels and participation in physical activities by Korean patients following total knee arthroplasty. AB - BACKGROUND: The objectives of this study were to describe changes in physical activity profiles of Korean patients after TKA and to determine whether the postoperative physical activity level is influenced by patient socio-demographic factors and postoperative functional outcomes. We also sought to determine whether regular postoperative physical activity is associated with greater patient satisfaction after TKA. METHODS: This observational study included 369 patients. Physical activity profiles before and after TKA were evaluated using a questionnaire that contained the UCLA activity scale and types of sports activities. The associations of socio-demographic features and postoperative functional outcomes with the physical activity levels were assessed using subgroup comparisons and partial correlation analyses. In addition, the effects of regular physical activity on patient satisfaction with replaced knees were evaluated using subgroup comparisons. RESULTS: Walking, swimming and bicycling were the three most common sports activities both before and after TKA. After TKA, the mean activity level remained similar (UCLA score = 4.5 before TKA vs. 4.8 after TKA); however, the frequency of moderate activity levels (UCLA scale, 4 6) and moderate types of physical activities increased. Patients with higher postoperative function scores reported higher postoperative activity levels, but socio-demographic factors were not associated with activity level. Regular physical activity was associated with greater patient satisfaction. CONCLUSIONS: This study provides valuable information about realistic expectations for physical activity after TKA. Regular participation in physical activity should be encouraged to improve patient satisfaction. PMID- 25030803 TI - Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. AB - RATIONALE: Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. OBJECTIVE: The objective of this study is to conduct a randomized controlled trial of adjunctive pregnenolone in schizophrenia. METHODS: Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment-Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized. RESULTS: No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n = 56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n = 55), p = 0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p < 0.001). Serum pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s = 0.497, p < 0.042, n = 17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. CONCLUSIONS: Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia. PMID- 25030805 TI - High school dropouts in emerging adulthood: substance use, mental health problems, and crime. AB - This study examined the distribution of substance use, mental health, and criminal behavior among dropouts derived from a nationally representative sample of 18-25 year old (N = 19,312) emerging adults in the United States. Using public use data from the 2010 National Survey on Drug Use and Health, this study employed multiple logistic regression with adjustments for complex survey sampling and compared high school dropouts with graduates with respect to substance use, mental health, and criminal behavior. After controlling for the effects of age, gender, race/ethnicity, family income, receipt of government assistance, employment status, and metropolitan population density, dropouts were more likely to meet criteria for nicotine dependence and report daily cigarette use, and more likely to report having attempted suicide in the previous year, been arrested for larceny, assault, drug possession or drug sales relative to their high school graduate counterparts. The findings of this study provide important insights and an initial epidemiologic portrait of mental health, substance use, and criminal behaviors of dropouts during emerging adulthood. PMID- 25030806 TI - Describing the potential crossreactome between mumps virus and spermatogenesis associated proteins. AB - This study documents that mumps virus shares several peptide sequences with human proteins that, when altered, may be involved in oligospermia/azoospermia, sterility and testicular atrophy. Examples are sperm flagellar protein 2 and spermatogenesis and centriole-associated protein 1. The data invite to further investigate crossreactivity as a potential mechanism linking anti-mumps immune responses, alterations of spermatogenesis-associated antigens and male fertility disorders. PMID- 25030807 TI - Predictors of mental health-related acute service utilisation and treatment costs in the 12 months following an acute psychiatric admission. AB - OBJECTIVE: A key step in informing mental health resource allocation is to identify the predictors of service utilisation and costs. This project aims to identify the predictors of mental health-related acute service utilisation and treatment costs in the year following an acute public psychiatric hospital admission. METHOD: A dataset containing administrative and routinely measured outcome data for 1 year before and after an acute psychiatric admission for 1757 public mental health patients was analysed. Multivariate regression models were developed to identify patient- and treatment-related predictors of four measures of service utilisation or cost: (a) duration of index admission; and, in the year after discharge from the index admission (b) acute psychiatric inpatient bed days; (c) emergency department (ED) presentations; and (d) total acute mental health service costs. Split-sample cross-validation was used. RESULTS: A diagnosis of psychosis, problems with living conditions and prior acute psychiatric inpatient bed-days predicted a longer duration of index admission, while prior ED presentations and self-harm predicted a shorter duration. A greater number of acute psychiatric inpatient bed-days in the year post-discharge were predicted by psychosis diagnosis, problems with living conditions and prior acute psychiatric inpatient admissions. The number of future ED presentations was predicted by past ED presentations. For total acute care costs, diagnosis of psychosis was the strongest predictor. Illness acuity and prior acute psychiatric inpatient admission also predicted higher costs, while self-harm predicted lower costs. DISCUSSION: The development of effective models for predicting acute mental health treatment costs using existing administrative data is an essential step towards a workable activity-based funding model for mental health. Future studies would benefit from the inclusion of a wider range of variables, including ethnicity, clinical complexity, cognition, mental health legal status, electroconvulsive therapy, problems with activities of daily living and community contacts. PMID- 25030808 TI - The prescription. PMID- 25030809 TI - Mechanical and physical properties of recombinant spider silk films using organic and aqueous solvents. AB - Spider silk has exceptional mechanical and biocompatibility properties. The goal of this study was optimization of the mechanical properties of synthetic spider silk thin films made from synthetic forms of MaSp1 and MaSp2, which compose the dragline silk of Nephila clavipes. We increased the mechanical stress of MaSp1 and 2 films solubilized in both HFIP and water by adding glutaraldehyde and then stretching them in an alcohol based stretch bath. This resulted in stresses as high as 206 MPa and elongations up to 35%, which is 4* higher than the as-poured controls. Films were analyzed using NMR, XRD, and Raman, which showed that the secondary structure after solubilization and film formation in as-poured films is mainly a helical conformation. After the post-pour stretch in a methanol/water bath, the MaSp proteins in both the HFIP and water-based films formed aligned beta-sheets similar to those in spider silk fibers. PMID- 25030810 TI - Exploring the relationship between bone density and severity of distal radius fragility fracture in women. AB - BACKGROUND: Bone mineral density (BMD) has been shown to be a consistent and independent risk factor for distal radius fracture. Inconsistent data have been reported on the association between BMD and severity of distal radius fracture. Our primary aim was to explore if there is an association between cortical BMD at the hand and the severity of fragility distal radius fracture. METHODS: Consecutively recruited females aged >= 50 years with fragility fracture at the distal radius (n = 110) from a county hospital were included. Cortical hand BMD was assessed by the digital X-ray radiogrammetry (DXR) method. X-rays of the fracture were scored by experienced orthopedic surgeons for fracture severity according to the Muller AO classification of long bones and radiographic parameters such as ulnar variance and dorsal angle. RESULTS: A weak association between lower DXR BMD and increased ulnar variance and dorsal angle was found but not with the AO scoring system for fracture type. A history of glucocorticoid (GC) use but not DXR-BMD was found to be significantly associated with the presence of having an intra- or extra-articular fracture. CONCLUSION: Our data indicate that bone material properties which are impaired by GC use are more important for fracture severity than BMD. PMID- 25030811 TI - Near-exact enthalpy-entropy compensation governs the thermal unfolding of protonation states of oxidized cytochrome c. AB - This paper reports the first quantitative analysis of the thermal transitions of all protonation states of oxidized horse heart cytochrome c at low anion concentration. Changes of secondary and tertiary structure were probed by ultraviolet (UV) as well as visible circular dichroism and absorption spectroscopy, respectively. The temperature dependence of spectra were recorded at pH values assignable to a set of different protonation states which encompass the canonical Theorell-Akesson states and the recently discovered III* state. Our experimental data suggest a two-step process of thermal unfolding for all protonation states. The respective thermodynamic parameters were obtained from a global analysis of the temperature dependence of corresponding visible circular dichroism (CD) and absorption spectra. The results of this analysis revealed a statistically significant enthalpy-entropy compensation with different apparent compensation temperatures for the two consecutive thermal transitions (319 and 357 K). This reflects the narrow distribution of the respective folding temperatures. UVCD spectra suggest that even the thermal transitions of protonation states occupied at acidic and alkaline pH cause only a very modest unfolding of the protein's helical structure. Our data indicate the protonation induced unfolding at room temperatures predominantly affects the Omega-loops of the protein. The two thermal transitions involve changes of two foldons, i.e. the unfolding of two short beta-strand segments (associated with the yellow foldon) followed by the unfolding of the 60' helix (green foldon) that connects the two Omega-loops of the protein. Apparently, intra-backbone hydrogen bonding is strong enough to mostly protect the terminal N- and C-helices from unfolding even at rather extreme conditions. PMID- 25030812 TI - Contextual control over selective attention: evidence from a two-target method. AB - Selective attention is generally studied with conflict tasks, using response time as the dependent measure. Here, we study the impact of selective attention to a first target, T1, presented simultaneously with a distractor, on the accuracy of subsequent encoding of a second target item, T2. This procedure produces an "attentional blink" (AB) effect much like that reported in other studies, and allowed us to study the influence of context on cognitive control with a novel method. In particular, we examined whether preparation to attend selectively to T1 had an impact on the selective encoding of T1 that would translate to report of T2. Preparation to attend selectively was manipulated by varying whether difficult selective attention T1 trials were presented in the context of other difficult selective attention T1 trials. The results revealed strong context effects of this nature, with smaller AB effects when difficult selective attention T1 trials were embedded in a context with many, rather than few, other difficult selective attention T1 trials. Further, the results suggest that both the trial-to-trial local context and the block-wide global context modulate performance in this task. PMID- 25030813 TI - Second-order motor planning in children: insights from a cup-manipulation-task. AB - The present study examined the development of anticipatory motor planning in an object manipulation task that has been used to successfully demonstrate motor planning in non-human primates (Weiss et al. in Psychol Sci 18:1063-1068, 2007). Seventy-five participants from four different age groups participated in a cup manipulation task. One group was preschool children (average age of 5.1 years), two groups were primary school children (7.7 and 9.8 years old respectively) and the final group was comprised of adults. The experimental task entailed reaching for a plastic cup that was vertically suspended in an apparatus in either upright or inverted orientation, removing the cup by its stem and then retrieving a small toy from the inside of the cup. When the cup was inverted in the apparatus, evidence for anticipatory motor planning could be achieved by initially gripping the stem using an inverted (thumb-down) grip posture. We found that when the cup was in upright orientation, all participants reached for the cup using an upright grip (i.e., thumb-up posture). However, when the cup was inverted in the apparatus, only adults consistently used an inverted grasping posture, though the percentage of inverted grips among participants did increase with age. These results suggest a protracted development for anticipatory motor planning abilities in children. Surprisingly, the performance of adults on this task more closely resembles the performance of several nonhuman primate species as opposed to children even at approximately 10 years of age. We discuss how morphological constraints on flexibility may help account for these findings. PMID- 25030815 TI - [Not Available]. PMID- 25030814 TI - Attentional capture by completely task-irrelevant faces. AB - The present study investigated whether faces capture attention regardless of attentional set. The presentation of a face as a distractor during a visual search has been shown to impair performance relative to when the face was absent, implying that faces automatically attract attention. If attentional control is contingent on the observer's current goal, faces should not capture attention when they are irrelevant to the observer's attentional set. Previous studies demonstrating face-induced attentional capture used faces that were relevant to the task. Thus, a task in which faces were completely irrelevant to the observer's set was created. Participants identified a target letter among heterogeneously colored non-targets while ignoring a peripheral facial image that appeared as a brief distractor. No face-specific capture was observed when the target-distractor stimulus onset asynchrony (SOA) was long (Experiment 1). When the SOA was shortened, attentional capture by irrelevant faces was observed (Experiment 2). Experiment 3 extended this finding to all conditions, regardless of the attractiveness of faces. No such capture effect was found in Experiment 4 with inverted-face distractors. These results indicate that completely task irrelevant faces break through top-down attentional set given a brief distractor target SOA. PMID- 25030816 TI - [Not Available]. PMID- 25030817 TI - [Not Available]. PMID- 25030818 TI - [Not Available]. PMID- 25030819 TI - [Not Available]. PMID- 25030820 TI - [Not Available]. PMID- 25030822 TI - [Not Available]. PMID- 25030821 TI - [Not Available]. PMID- 25030823 TI - [Not Available]. PMID- 25030825 TI - [Not Available]. PMID- 25030824 TI - [Not Available]. PMID- 25030826 TI - [Not Available]. PMID- 25030827 TI - Suboptimal attainment of cardiovascular disease prevention guideline goals in korean women. AB - PURPOSE: The purposes of this study were to estimate the distribution of three levels of risk for developing coronary heart disease (CHD; low, moderate, and high risk) and to evaluate the attainment of cardiovascular disease prevention guideline goals by the American Heart Association in a nationally representative sample of Korean women. METHODS: This is a secondary data analysis study using the data set from the 2008 Korea National Health and Nutrition Examination Survey IV. The sample was 3,301 Korean women (representing 15,600,514 women) older than 20 years without cardiovascular disease. Distribution of CHD risk and level of goal attainment were calculated using sampling weights and presented in percentages. RESULTS: Among Korean women without established cardiovascular disease, 7.9% were at high risk for CHD, 20.5% were at moderate risk, and 71.6% were at low risk. The proportion of Korean women who did not meet their goals was substantial, and most women at high risk remained unmanaged for their high blood lipids. CONCLUSION: Korean women at risk for developing CHD need to be managed as soon as possible to attain the guideline goals and to lower their risk for future CHD. Aggressive risk reduction efforts are urgently needed to reduce the public burden of CHD in Korean women. PMID- 25030828 TI - Patients' perceptions and expectations of family participation in the informed consent process of elective surgery in taiwan. AB - PURPOSE: This study investigated patients' perceptions and expectations of their families' participation in the informed consent process of elective surgery. METHODS: This is a survey study. Anonymous questionnaires that were mailed to potential participants included a demographic data sheet and a scale, measuring patients' perceptions of themselves and their families' participation level in the informed consent process. A convenience sample of patients who had undergone surgery and had been discharged within 4 months from a medical center in southern Taiwan (n = 1,737) were recruited. RESULTS: One hundred and forty-five recipients replied, gaining a response rate of 10.0%, and 120 provided complete data. The mean age of the participants was 56.0 years (range 20-85, SD = 14.98), and more than half were female (54.2%). Twenty-one participants (17.5%) perceived having less family participation than their own participation in the surgery informed consent process, and 40% expected more family participation in the process. The mean scores of the self-rated participation level was significantly higher than that of the families (p < .001). Patients' expectations of family participation were significantly higher than their perceptions of family participation (p < .001). Eleven patients (9.2%) reported having more family participation than they expected. Participants received the most information about the disease during the informed consent process and the least information about alternatives to surgery. Age, gender, number of previous surgeries and admissions influenced the study participants' perceived level of participation in the informed consent process. CONCLUSION: This preliminary study demonstrates that patients' perceptions and expectations for family participation in the surgical informed consent process vary. Healthcare providers should be aware of patients' expectation to appropriately invite their family into the informed consent process. PMID- 25030829 TI - Sodium Bicarbonate Solution versus Chlorhexidine Mouthwash in Oral Care of Acute Leukemia Patients Undergoing Induction Chemotherapy: A Randomized Controlled Trial. AB - PURPOSE: The objective of this study was to compare the effectiveness of sodium bicarbonate (SB) solution with chlorhexidine (CHX) mouthwash in oral care of acute leukemia patients under induction chemotherapy. METHODS: Forty-eight patients were randomly selected and assigned to an SB solution group or CHX-based product group according to acute myelogenous leukemia or acute lymphoblastic leukemia. Patients were asked to rinse their mouth four times a day from the day before chemotherapy started until discharge. The World Health Organization mucositis grade, patient-reported Oral Mucositis Daily Questionnaire, and clinical signs associated with infection were assessed on a daily basis. The oral microbial count was assessed on a weekly basis from the 1st day of chemotherapy started to the 28th day or to the day of discharge from the hospital. RESULTS: Of all the patients in the SB group, 25.0% developed ulcerative oral mucositis, whereas 62.5% in the CHX group did. The onset of oral mucositis was later in the SB group than the CHX group. The oral bacterial colonization in the SB group was significantly higher than that in the CHX group, but clinical signs associated with infection did not differ in both groups. CONCLUSION: As a result of this study, it was found that oral care by SB solution for acute leukemia patients undergoing chemotherapy was an effective intervention to improve oral health. PMID- 25030830 TI - Programmatic and teaching initiatives for ethnically diverse nursing students: a literature review. AB - PURPOSE: The purpose of this study was to examine the evidence of programmatic and teaching initiatives implemented by nursing faculty to enhance the academic success rates of ethnically diverse students (EDS). METHODS: A search of the literature in the Cumulative Index to Nursing and Allied Health Literature and MEDLINE databases, wherein primary sources about programmatic and teaching initiative to promote academic success among EDS, was conducted. Using specific the Cumulative Index to Nursing and Allied Health Literature subject headings and Medical Subject Headings, 230 articles were retrieved from both databases. A total of 22 peer-reviewed articles published between 2000 and 2011 were included in the literature review. RESULTS: We found that evidence on the predominant programmatic and teaching initiatives for EDS academic success was inconclusive. The most common programmatic and teaching initiatives implemented by nursing faculty were peer mentoring, faculty-student mentoring, social networking, academic support, and financial support. CONCLUSION: Although positive student outcomes were reported about programmatic and teaching initiatives for EDS, the evidence remained inconclusive. Recommendations for policy and future research in this area of nursing education research were provided. PMID- 25030831 TI - Correlates of social engagement in nursing home residents with dementia. AB - PURPOSE: The social needs of nursing home (NH) residents with dementia are often ignored even though they are capable of expressing their emotions and responding in social interactions. Insufficient social engagement in this population is known to be associated with low quality of life as well as many negative health outcomes, such as mortality, agitation, and functional decline. The purpose of this study was to identify the correlates of social engagement in NH residents with dementia. METHODS: The study used a descriptive, correlational design. A total of 153 older adults with dementia in 17 Iowa NHs participated in this study. Minimum Data Set for NH version 2.0 served as an outcome measure to evaluate social engagement, cognitive and physical functions, depression, and behavioral symptoms. Demographic data were obtained from the participants' medical records. RESULTS: The findings indicated that no significant relationship was found between demographic characteristics and social engagement. There were significant and negative correlations between the degree of social engagement and the levels of cognitive impairment, activities of daily living impairment, depression, and vision. Among these correlates, depression was the most potent predictor of engagement. CONCLUSION: The study provided information about the correlates of social engagement in NH residents with dementia. Future research needs to be conducted to develop nursing interventions to involve these individuals in social activities tailored to functional levels, and depression in more diverse geographic regions. PMID- 25030832 TI - Significance of attending to instrument planning and validation stages in nursing discipline. PMID- 25030833 TI - Paraganglioma of the pancreas: a potentially functional and malignant tumor. AB - Paragangliomas are neoplasms that arise from extra-adrenal chromaffin cells. Pancreatic paragangliomas are rare, and few are malignant. To the best of our knowledge, no cases of functional pancreatic paragangliomas have been reported in the literature to date. We present two cases of pancreatic paragangliomas with pathological confirmation. In the case 1, clinical testing and pathological analysis revealed functional and malignant characteristics of the tumor, which carried a poor prognosis. In case 2, functional paraganglioma was suspected. The clinical presentations and outcomes of these two patients are summarized, and the relevant literature is reviewed. Because of the small number of cases reported previously, few characteristics of these tumors are known. The best methods of predicting the malignant and functional potential of these tumors remain unknown. We propose careful preoperative treatment and close postoperative follow-up of paraganglioma patients because of the functional and malignant potential of these tumors. PMID- 25030834 TI - Diagnostic value of circulating microRNAs for hepatocellular carcinoma. AB - Much evidence indicates that microRNAs could play potential roles as diagnostic and prognostic biomarkers of human cancers, including hepatocellular carcinoma (HCC). The present meta-analysis aimed to systematically evaluate the diagnostic accuracy of circulating microRNAs for HCC. Eligible studies were identified through multiple search strategies and assessed for relevance and quality. Results from different studies were pooled using random-effects models. The quality of each study was scored with the revised quality assessment of diagnostic accuracy studies tool. The summary receiver operator characteristic (SROC) curve and other measures were used to assess the overall performance of microRNA-based assays. Evidence of heterogeneity was evaluated using the I (2) test. Meta-regressions were conducted to analyze potential sources of heterogeneity. Deeks' test was used to test for potential publication bias. Thirty studies from 13 publications, including 1,314 patients with HCC and 1,407 controls, comprised healthy individuals and patients with hepatitis B/C or cirrhosis, were included in this meta-analysis. For diagnostic meta-analysis, the overall pooled results were as follows: sensitivity was 0.80 (95 % CI 0.74-0.84), specificity was 0.81 (95 % CI 0.74-0.87), positive likelihood ratio was 4.2 (95 % CI 3.0-6.0), negative likelihood ratio was 0.25 (95 % CI 0.19-0.38) and diagnostic odds ratio was 17 (95 % CI 10-29). The area under the SROC curve was 0.86 (95 % CI 0.84-0.90). Subgroup analyses suggested that multiple microRNAs had much better accuracy than single microRNA. Our findings suggest that circulating microRNAs show significant potential as diagnostic markers of HCC, particularly when using multiple microRNAs. However the results of this meta-analysis justify larger, more rigorous studies to confirm our conclusions. PMID- 25030835 TI - Differential responses of three sweetpotato metallothionein genes to abiotic stress and heavy metals. AB - Metallothioneins (MTs) are cysteine-rich, low molecular weight, metal-binding proteins that are widely distributed in living organisms. Plants produce metal chelating proteins such as MTs to overcome the toxic effects of heavy metals. We cloned three MT genes from sweetpotato leaves [Ipomoea batatas (L.) Lam.]. The three IbMT genes were classified according to their cysteine residue alignment into type 1 (IbMT1), type 2 (IbMT2), and type 3 (IbMT3). IbMT1 was the most abundantly transcribed MT. It was predominantly expressed in leaves, roots, and callus. IbMT2 transcript was detected only in stems and fibrous roots, whereas IbMT3 was strongly expressed in leaves and stems. The IbMT expression profiles were investigated in plants exposed to heavy metals and abiotic stresses. The levels of IbMT1 expression were strongly elevated in response to Cd and Fe, and moderately higher in response to Cu. The IbMT3 expression pattern in response to heavy metals was similar to that of IbMT1. Exposure to abiotic stresses such as methyl viologen (MV; paraquat), NaCl, polyethylene glycol (PEG), and H2O2 up regulated IbMT expression; IbMT1 responded strongly to MV and NaCl, whereas IbMT3 was induced by low temperature and PEG. Transgenic Escherichia coli overexpressing IbMT1 protein exhibited results suggest that IbMT could be a useful tool for engineering plants with enhanced tolerance to environmental stresses and heavy metals. PMID- 25030836 TI - Sociocultural influences on newborn health in the first 6 weeks of life: qualitative study in a fishing village in Karachi, Pakistan. AB - BACKGROUND: Given regional variability and minimal improvement in infant mortality rates in Pakistan, this study aimed to explicate sociocultural influences impacting mothers' efforts to maintain or improve newborn health. METHODS: We used a qualitative phenomenological approach. A total of 10 mothers and 8 fathers from a fishing village in Karachi, Pakistan were purposefully sampled and interviewed individually. A focus group was undertaken with four grandmothers (primary decision makers). Transcripts were independently reviewed using interpretive thematic analysis. RESULTS: A multigenerational approach was used in infant care, but mothers did not have a voice in decision-making. Parents connected breast milk to infant health, and crying was used as cue to initiate feeding. Participants perceived that newborns required early supplementation, given poor milk supply and to improve health. There were tensions between traditional (i.e., home) remedies and current medical practices. Equal importance was given to sons and daughters. CONCLUSION: Findings suggest that social and cultural influences within families and the community must be considered in developing interventions to improve newborn health. Introducing non-breast milk substances into newborn diets may reduce the duration of exclusive or partial breastfeeding and increase risks to infant health. PMID- 25030838 TI - The influence of cooling forearm/hand and gender on estimation of handgrip strength. AB - Handgrip strength is essential in manual operations and activities of daily life, but the influence of forearm/hand skin temperature on estimation of handgrip strength is not well documented. Therefore, the present study intended to investigate the effect of local cooling of the forearm/hand on estimation of handgrip strength at various target force levels (TFLs, in percentage of MVC) for both genders. A cold pressor test was used to lower and maintain the hand skin temperature at 14 degrees C for comparison with the uncooled condition. A total of 10 male and 10 female participants were recruited. The results indicated that females had greater absolute estimation deviations. In addition, both genders had greater absolute deviations in the middle range of TFLs. Cooling caused an underestimation of grip strength. Furthermore, a power function is recommended for establishing the relationship between actual and estimated handgrip force. Statement of relevance: Manipulation with grip strength is essential in daily life and the workplace, so it is important to understand the influence of lowering the forearm/hand skin temperature on grip-strength estimation. Females and the middle range of TFL had greater deviations. Cooling the forearm/hand tended to cause underestimation, and a power function is recommended for establishing the relationship between actual and estimated handgrip force. Practitioner Summary: It is important to understand the effect of lowering the forearm/hand skin temperature on grip-strength estimation. A cold pressor was used to cool the hand. The cooling caused underestimation, and a power function is recommended for establishing the relationship between actual and estimated handgrip force. STATEMENT OF RELEVANCE: Manipulation with grip strength is essential in daily life and the workplace, so it is important to understand the influence of lowering the forearm/hand skin temperature on grip-strength estimation. Females and the middle range of TFL had greater deviations. Cooling the forearm/hand tended to cause underestimation, and a power function is recommended for establishing the relationship between actual and estimated handgrip force. PRACTITIONER SUMMARY: It is important to understand the effect of lowering the forearm/hand skin temperature on grip-strength estimation. A cold pressor was used to cool the hand. The cooling caused underestimation, and a power function is recommended for establishing the relationship between actual and estimated handgrip force PMID- 25030837 TI - Super-resolution imaging and tracking of protein-protein interactions in sub diffraction cellular space. AB - Imaging the location and dynamics of individual interacting protein pairs is essential but often difficult because of the fluorescent background from other paired and non-paired molecules, particularly in the sub-diffraction cellular space. Here we develop a new method combining bimolecular fluorescence complementation and photoactivated localization microscopy for super-resolution imaging and single-molecule tracking of specific protein-protein interactions. The method is used to study the interaction of two abundant proteins, MreB and EF Tu, in Escherichia coli cells. The super-resolution imaging shows interesting distribution and domain sizes of interacting MreB-EF-Tu pairs as a subpopulation of total EF-Tu. The single-molecule tracking of MreB, EF-Tu and MreB-EF-Tu pairs reveals intriguing localization-dependent heterogonous dynamics and provides valuable insights to understanding the roles of MreB-EF-Tu interactions. PMID- 25030839 TI - Tuning the electrical property via defect engineering of single layer MoS2 by oxygen plasma. AB - We have demonstrated that the electrical property of single-layer molybdenum disulfide (MoS2) can be significantly tuned from the semiconducting to the insulating regime via controlled exposure to oxygen plasma. The mobility, on current and resistance of single-layer MoS2 devices were varied by up to four orders of magnitude by controlling the plasma exposure time. Raman spectroscopy, X-ray photoelectron spectroscopy and density functional theory studies suggest that the significant variation of electronic properties is caused by the creation of insulating MoO3-rich disordered domains in the MoS2 sheet upon oxygen plasma exposure, leading to an exponential variation of resistance and mobility as a function of plasma exposure time. The resistance variation calculated using an effective medium model is in excellent agreement with the measurements. The simple approach described here can be used for the fabrication of tunable two dimensional nanodevices based on MoS2 and other transition metal dichalcogenides. PMID- 25030841 TI - A new era in medical therapy for retinal degenerative disease? PMID- 25030840 TI - Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial. AB - BACKGROUND: Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients. METHODS: In our open-label, prospective, phase 1b trial, we enrolled patients (aged >=6 years) with Leber congenital amaurosis and RPE65 or LRAT mutations at McGill University's Montreal Children's Hospital. Patients received 7 days of oral QLT091001 (10-40 mg/m(2) per day). We assessed patients at baseline and days 7, 9, 14, and 30, and then 2 months and every 2 months thereafter for up to 2.2 years for safety outcomes and visual function endpoints including Goldmann visual fields (GVF), visual acuity, and functional MRI assessment. We regarded patients as having an improvement in vision if we noted at least a 20% improvement in retinal area on GVF compared with baseline or a visual acuity improvement of five or more letters compared with baseline in two consecutive study visits (or any improvement from no vision at baseline). This study is registered with ClinicalTrials.gov, number NCT01014052. FINDINGS: Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6-38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28-683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2-30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients). INTERPRETATION: Non-invasive oral QLT091001 therapy is well tolerated, and can rapidly improve visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations. FUNDING: QLT, Foundation Fighting Blindness Canada, CIHR, FRSQ, Reseau Vision. PMID- 25030842 TI - Intrathecal siRNA against GPNMB attenuates nociception in a rat model of neuropathic pain. AB - Neuropathic pain is characterized by hyperalgesia, allodynia, and spontaneous pain. Recent studies have shown that glycoprotein nonmetastatic melanoma B (GPNMB) plays a pivotal role in neuronal survival and neuroprotection. However, the role of GPNMB in neuropathic pain remains unknown. The aim of the present study was to assess the role of GPNMB in neuropathic pain. In cultured spinal cord neurons, we used two small interfering RNAs (siRNAs) targeting the complementary DNA (cDNA) sequence of rat GPNMB that had potent inhibitory effects on GPNMB, and siRNA1-GPNMB was selected for further in vivo study as it had the higher inhibitory effect. After sciatic nerve injury in rats, the endogenous level of GPNMB was increased in a time-dependent manner in the spinal cord. Furthermore, the intrathecal injection of siRNA1-GPNMB inhibited the expression of GPNMB and pro-inflammatory factors (TNF-alpha, IL-1beta, and IL-6) and alleviated mechanical allodynia and thermal hyperalgesia in the chronic constriction injury (CCI) model of rats. Taken together, our findings suggest that siRNA against GPNMB can alleviate the chronic neuropathic pain caused by CCI, and this effect may be mediated by attenuated expression of TNF-alpha, IL 1beta, and IL-6 in the spinal cord of CCI rats. Therefore, inhibition of GPNMB may provide a novel strategy for the treatment of neuropathic pain. PMID- 25030843 TI - Diagnosis and monitoring of postoperative recurrence in Crohn's disease. AB - Despite advances in medical management, many patients with Crohn's disease (CD) require intestinal surgery throughout their lives. Surgery is not a cure, and postoperative recurrence is common in patients with CD. Ileocolonoscopy has been considered to be the gold standard in the diagnosis and monitoring of postoperative recurrence. However, the optimal monitoring strategy for postoperative recurrence has yet to be established. Capsule endoscopy and cross sectional imaging techniques, including ultrasonography, computed tomography and MRI, have been used in the postoperative setting, and their usefulness in the monitoring of disease activity has been evaluated in recent clinical trials. The value of fecal markers, such as calprotectin and lactoferrin, has been also assessed in several studies. This review was to identify optimized methods for the diagnosis and monitoring of postoperative recurrence in CD. PMID- 25030844 TI - Anti-Mullerian hormone as a possible predictor of fecundability in subfertile women over 38 years: a retrospective cohort study. AB - Anti-Mullerian hormone (AMH) is a relatively novel method for examining the ovarian reserve that reflects female reproductive function. In the era in which the number of women delaying attempts to conceive has increased, a good predictor for long-term fecundability has been explored. We performed the retrospective cohort study to investigate whether initial serum AMH levels are useful for predicting long-term fertility during infertility treatments. We recruited 149 women in the retrospective cohort, and 52 women were gravid during the follow-up period. According to the multiple logistic analyses, only age was found to have a significant correlation with pregnancy success in all women. In women >=38 years, significantly higher serum AMH levels were detected in the pregnant group (median = 2.83 ng/mL, range = 1.11-6.29 ng/mL) than the non-pregnant group (median = 1.22 ng/mL, range = 0-9.46 ng/mL; p = 0.015). None of the women with serum AMH levels <0.7 ng/mL were pregnant during treatment. AMH may be used to identify poor pregnancy prospects in women who are above 38 years. PMID- 25030845 TI - Increased levels of oxidative and carbonyl stress markers in normal ovarian cortex surrounding endometriotic cysts. AB - Many evidence support the view that endometriotic cyst may exert detrimental effect on the surrounding ovarian microenvironment so representing a risk to functionality of adjacent follicles. Patients with benign ovarian cyst (endometriotic, follicular and dermoid cysts) subjected to laparoscopic cystectomy were enrolled in the present retrospective study in order to analyze whether endometriotic tissue could negatively affect the surrounding normal ovarian cortex more severely than other ovarian cysts. To this end we carried out immunohistochemistry analysis and comparative determination of the transcription factor FOXO3A, oxidized DNA adduct 8-OHdG (8-hydroxy-2'-deoxyguanosine) and damaged proteins known as AGEs (Advanced Glycation End products) as markers of ovarian stress response and molecular damage. Our results show that all the markers analyzed were present in normal ovarian tissue surrounding benign cysts. We observed higher levels of FOXO3A (15.90 +/- 0.28), 8-OHdG (13.33 +/- 2.07) and AGEs (12.58 +/- 4.34) staining in normal ovarian cortex surrounding endometriotic cysts in comparison with follicular cysts (9.04 +/- 0.29, 2.67 +/- 2.67, 11.31 +/ 2.95, respectively) and dermoid cysts (2.02 +/- 0.18, 4.33 +/- 2.58 and 10.56 +/ 4.03, respectively). These results provide evidence that ovarian endometrioma is responsible for more severe alterations to cellular biomolecules than follicular and dermoid cysts. PMID- 25030846 TI - CdS sensitized 3D hierarchical TiO2/ZnO heterostructure for efficient solar energy conversion. AB - For conventional dye or quantum dot sensitized solar cells, which are fabricated using mesoporous films, the inefficient electron transport due to defects such as grain boundaries and surface traps is a major drawback. To simultaneously increase the carrier transport efficiency as well as the surface area, optimal assembling of hierarchical nanostructures is an attractive approach. Here, a three dimensional (3D) hierarchical heterostructure, consisting of CdS sensitized one dimensional (1D) ZnO nanorods deposited on two dimensional (2D) TiO2 (001) nanosheet, is prepared via a solution-process method. Such heterstructure exhibits significantly enhanced photoelectric and photocatalytic H2 evolution performance compared with CdS sensitized 1D ZnO nanorods/1D TiO2 nanorods photoanode, as a result of the more efficient light harvesting over the entire visible light spectrum and the effective electron transport through a highly connected 3D network. PMID- 25030847 TI - CCL5/RANTES is important for inducing osteogenesis of human mesenchymal stem cells and is regulated by dexamethasone. AB - In this study, we examine the effect of chemokine (C-C motif) ligand 5 (CCL5)/Regulated on Activation Normal T cell Expressed and Secreted (RANTES), a pro-inflammatory cytokine on osteogenic differentiation of human mesenchymal stem cells (hMSCs). We found CCL5 expression was increased during osteogenic differentiation of hMSCs and CCL5 expression is dependent on the presence of dexamethasone. Knocking down endogenous CCL5 expression blocked osteogenesis, as revealed by decreasing alkaline phosphatase (ALP) activity and a reduction in the expression levels of ALP, bone sialoprotein (BSP), and osteopontin (OPN). Of note, the overexpression of CCL5 was sufficient to increase ALP expression and activity. Moreover, the down-regulation of chemokine (C-C motif) receptor 1 (CCR1), one of the CCL5 receptors, significantly decreased the osteogenesis of hMSCs. Interestingly, the down-regulation of CCR1, but not CCL5, was sufficient to affect the cell numbers during the process of osteogenesis. Our findings reveal that both CCL5 and CCR1 are required for osteogenesis of human MSCs, CCL5 is sufficient for the osteogenesis, and provide a novel link between dexamethasone and CCL5 in human osteogenesis. PMID- 25030848 TI - Serum levels of soluble carbonic anhydrase IX are decreased in patients with diffuse cutaneous systemic sclerosis compared to those with limited cutaneous systemic sclerosis. AB - Hypoxia may play an important role in the pathogenesis of systemic sclerosis (SSc). Carbonic anhydrase IX (CA IX) is one of the hypoxia markers and its extracellular domain can be released into the serum. However, the clinical significance of serum CA IX levels in SSc is still unknown. The aim of this study is to evaluate the possibility that serum CA IX levels can be a specific disease marker of SSc. Serum samples were obtained from SSc patients and healthy controls. Patients diagnosed as scleroderma spectrum disorder (SSD), who did not fulfill the ACR criteria of SSc but were thought that they might develop SSc in the future, were also included in this study. Serum CA IX levels were measured with specific enzyme-linked immunosorbent assays. SSD patients had significantly lower CA IX levels than diffuse cutaneous SSc (dcSSc), limited cuntaneous SSc (lcSSc) and healthy control groups. Also, we found a significant decrease in the values in dcSSc patients compared to those of lcSSc patients. Serum levels of CA IX may be useful for the differentiation of lcSSc from SSD. Decreased serum CA IX levels in spite of the presence of hypoxia in SSc may indicate an impaired response to hypoxia, which leads to the persistent hypoxic condition. Our results suggest that the abnormal response to hypoxia may already exist in SSD patients, and may be involved in its pathogenesis. PMID- 25030849 TI - Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro. AB - It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D KYN as the substrate. DAO inhibitors 3-methylpyrazole-5-carboxylic acid and 4H thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 +/- 0.47 MUM and 4.70 +/- 0.17 MUM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy. PMID- 25030850 TI - Comparison of mechanisms underlying changes in glucose utilization in fasted rats anesthetized with propofol or sevoflurane: Hyperinsulinemia is exaggerated by propofol with concomitant insulin resistance induced by an acute lipid load. AB - The effects of anesthesia with sevoflurane and with propofol on glucose utilization in rats were investigated. Sevoflurane significantly impairs glucose utilization whereas propofol does not. Both insulin secretion and sensitivity affect glucose utilization. Propofol is hydrophobic, and anesthesia with this agent is always accompanied by an acute lipid load, which can exaggerate insulin resistance. The role of the acute lipid load in the effects of anesthesia with sevoflurane and propofol on glucose utilization in fasted rats was investigated. Rats were allocated to groups anesthetized with sevoflurane and infused with physiological saline (group S) or 10% w/v lipid (group SL), or those anesthetized with propofol (group P). Intravenous glucose tolerance tests and insulin tolerance tests were then performed to measure glucose utilization, and blood glucose, plasma insulin, and plasma TNF-alpha levels were measured. In the intravenous glucose tolerance test, groups SL and P showed significantly higher plasma insulin levels than group S, and group P showed significantly higher plasma insulin levels than group SL. In the insulin tolerance test, groups SL and P showed insulin resistance compared to group S, but no significant difference was observed between groups SL and P. In summary, propofol anesthesia enhances insulin secretion and concomitantly exaggerates insulin resistance, compared with sevoflurane anesthesia. Propofol appears to be the main cause of hyperinsulinemia, and the acute lipid load exaggerates insulin resistance. PMID- 25030851 TI - Relationship between T-SPOT.TB responses and numbers of circulating CD4+ T-cells in HIV infected patients with active tuberculosis. AB - This study sought to evaluate the performance of the T-SPOT.TB assay for the diagnosis of active tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients. One hundred confirmed HIV-infected patients with active TB and known T-SPOT.TB and CD4+ T-cell counts were enrolled in this clinical retrospective study. We found that patients with lower CD4+ T-cell counts (11-50 cells/MUL) had the lowest T-SPOT.TB positive rates (50%), and patients with higher CD4+ T-cell counts (50-100 cells/MUL) had the highest T-SPOT.TB positive rates (75%). However, there were no significant differences between the T-SPOT.TB positive rates of patients with different CD4+ T-cell counts (< 10, 11-50, 51-100 and > 100 cells/MUL) (chi(2) = 3.7747, p = 0.287). The patients with positive TB culture results had significantly higher T-SPOT.TB positive rates (78.9%) than patients that were culture-negative (44.3%) (chi(2) = 12.8303, p < 0.001). Other variables, including gender, age, TB disease classification, HIV RNA level, and highly reactive antiretroviral therapy (HAART), had no significant effects on T SPOT.TB positive rates. The number of spot-forming cells (SFCs) reactive with ESAT-6, CFP-10 and ESAT-6/CFP-10-specific T cells detected by T-SPOT.TB were positively is strongly related to the degree of immunodeficiency, while the T SPOT.TB positive rates are less dependent on the level of CD4+ T-cell depletion in HIV infection and active TB. PMID- 25030852 TI - Repeated doses of intravenous tranexamic acid are effective and safe at reducing perioperative blood loss in total knee arthroplasty. AB - Fibrin sealant (FS) and tranexamic acid (TXA) have been used in total knee arthroplasty (TKA) to minimize perioperative blood loss. The efficacy of FS has been debated, and few studies have looked into the effects of FS and TXA on perioperative coagulability. The current study retrospectively reviewed 100 cases of unilateral primary TKA. Twenty-five cases served as blank controls, FS was used without TXA in 23, TXA was used without FS in 20, and both FS and TXA (FS + TXA) were used in 32. FS was sprayed before wound closure whereas 1 g of TXA was intravenously administered before incision and 1 g was administered 15 min before tourniquet release. Hematocrit and hemoglobin levels and thromboelastography (TEG) parameters were assessed pre-operatively and on day 1, 4, and 9 post operatively. Blood transfusions were noted and the incidence of symptomatic DVT/PE was determined. Hematocrit and hemoglobin levels were significantly higher in the TXA and FS + TXA groups compared to the control and FS groups on day 1, 4, and 9 post-operatively. Hematocrit and hemoglobin levels in the control group were similar to those in the FS group and hematocrit and hemoglobin levels in the TXA group were similar to those in the FS + TXA group. TEG parameters (R, K, alpha, MA, and CI) remained within normal ranges. Mean CI was less than +3 in all four groups, suggesting that hypercoagulation was not promoted. One patient in the FS group received an allogeneic transfusion. Incidence of symptomatic DVT/PE was not noted. Intravenous TXA significantly reduced perioperative blood loss in patients undergoing a TKA but FS did not. Administration of FS in addition to TXA was not superior to TXA alone. FS and/or TXA did not increase the risk of hypercoagulation according to TEG parameters. Intravenous administration of 1 g of TXA pre-operatively and administration of 1 g before tourniquet release is an effective and safe method of reducing blood loss in TKA. PMID- 25030853 TI - Effects of lifestyle factors on urinary oxidative stress and serum antioxidant markers in pregnant Japanese women: A cohort study. AB - Oxidative stress plays a major pathological role in pregnancy-related complications. Although oxidative stress is induced by exogenous toxins in association with a poor lifestyle in normal subjects, there is little information on the factors altering oxidative stress and antioxidant levels during pregnancy. The purpose of this study was to determine the relationship between lifestyle factors and oxidative stress/antioxidant levels during each trimester and 1-month postpartum. This prospective cohort study followed 54 healthy women through pregnancy; first, second, and third trimester and 1-month postpartum. Participants were administered a questionnaire on characteristics and lifestyle factors. Morning blood and urine samples were obtained to measure urinary biopyrrins and serum coenzyme Q10 (CoQ10) levels. The levels of urinary biopyrrins and serum CoQ10 increased significantly throughout pregnancy, with peak values registered during the third trimester. Higher biopyrrin levels were significantly associated with non-consumption of morning meal during the first trimester, smoking during the third trimester and 1-month postpartum, alcohol consumption during the third trimester, high food-based polyunsaturated fatty acid intake during the third trimester, and poor mental health scores during the first and third trimesters. Higher CoQ10 levels were significantly associated with no smoking during pregnancy and at 1-month postpartum, and with a high frequency of exercise during the third trimester and 1-month postpartum. Thus, pregnancy represents a state of oxidative stress, which can be counterbalanced by increased levels of antioxidants, such as CoQ10. We speculate that certain lifestyle choices such as avoiding smoking can reduce oxidative stress and increase antioxidant levels during pregnancy. PMID- 25030854 TI - Primary hepatic mucosa-associated lymphoid tissue lymphoma and hemangioma with chronic hepatitis B virus infection as an underlying condition. AB - Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma has a low incidence and is a rare subtype of hepatic malignant lymphoma. Described here is a rare case of primary hepatic MALT lymphoma and hepatic hemangioma with chronic HBV infection as an underlying condition. Possible treatment modalities, which should be selected in accordance with tumor size, tumor location, tumor number, and underlying liver disease, are discussed in conjunction with a review of the literature. In addition, the potential use of hepatic resection, radio frequency ablation (RFA), or radiotherapy followed by chemotherapy via the R-CHOP regimen is also discussed. PMID- 25030855 TI - Why are some HIV/AIDS patients reluctant to receive antiviral therapy as soon as possible in China? AB - In more than 20 years of medical practice, a surprising phenomenon has often occurred: some patients with acquired immunodeficiency syndrome (AIDS) decide not to go to the hospital and they do not let others know that they are suffering from the disease unless they believe that they are dieing. Zhang Shan (a pseudonym) is one such patient with human immunodeficiency virus (HIV)/AIDS who was reluctant to receive antiviral therapy as soon as possible, and this paper shares Zhang's story as he related it. Clearly, there are numerous views as to why patients in China behave as Zhang did. Presented here are several reasons, including society, history, morality and ideology, family, and education. Although all of these reasons do play a role, the patient's mindset and behavior is the most significant reason for a patient's reluctance to seek treatment or disclose his/her status. If the individual patient's mindset and behavior are not dealt with effectively, then HIV/AIDS can continue to spread and threaten additional lives and even the fabric of society. This paper analyzes the reasons why patients are hesitant to receive antiviral therapy, but this paper also suggests steps healthcare personnel can take to encourage patients to seek treatment. Such steps can save the lives of current patients with HIV/AIDS. In addition, sound public health measures and a rational approach to treatment are important to helping potential patients with HIV/AIDS. PMID- 25030856 TI - Synthesis and anticancer effects of some novel 2-(4-phenoxyphenyl)-1H benzimidazole derivatives on K562 cell line. AB - A series of novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives was synthesized and tested in vitro on human chronic myelogenous leukemia (CML) cell line K562. Benzimidazoles containing 5-amidino (10), 5-N-isopropylamidino (11), 5 bromo (13), and 5,6-dimethyl (14) derivatives exhibited remarkable cytotoxic activity. The quantitative analysis of apoptosis by flow-cytometry demonstrated that the percentages of early and late apoptotic K562 cells treated with these compounds were significantly higher than cells without treatment. We also investigated the effects of these compounds on the expression of apoptosis related genes BAX, BCL-2, BAD and BIM. Treatment of K562 cells wih compounds 10 14 significantly increased the expression levels of the proapoptotic genes BAX, BAD and BIM, whereas compound 20 increased BAX and BAD. PMID- 25030857 TI - Propofol treatment modulates neurite extension regulated by immunologically challenged rat primary astrocytes: a possible role of PAI-1. AB - Propofol, a widely used anesthetic, regulates neurological processes including neurotoxicity, neuroprotection, glial activation, synaptic plasticity and neuronal maturation. Tissue plasminogen activator/tissue plasminogen activator inhibitor-1 (tPA/PAI-1) in CNS acts as a neuromodulator regulating synaptic plasticity, neurite outgrowth, seizure spreading and cell survival. Here, we investigated the effects of propofol on tPA/PAI-1 system using cultured neurons and astrocytes and their role in the regulation of neurite extension. Cultured rat primary astrocytes were treated with propofol (1-10 uM) and LPS (10 ng/ml). The expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and RT-PCR. Alternatively, culture supernatants were added to cultured rat primary neuron to investigate the effects on neurite extension. Propofol alone did not affect tPA activity in rat primary cortical neuron. Similarly, propofol alone changed neither tPA nor PAI-1 activity in rat primary astrocytes. In immunologically challenged situation using LPS, propofol synergistically increased expression of PAI-1 in rat primary astrocytes without affecting tPA expression in a manner dependent on MAPKs activation. Increased expression of PAI 1 reduced tPA activity in LPS plus propofol-treated rat primary astrocytes. Consistent with the critical role of tPA activity in the regulation of neurite extension (Cho et al. 2013), the diminished tPA activity in astrocyte culture supernatants resulted in decreased neurite extension when administered to cultured rat primary cortical neuron. The results from the present study suggest that propofol, especially in immunologically-challenged situation, dysregulates tPA/PAI-1 system in brain. Whether the dysregulated tPA/PAI-1 activity adversely affects neural differentiation as well as regeneration of neuron in vivo should be empirically determined in the future. PMID- 25030858 TI - [Emphasis on diagnosis of thyroid carcinoma]. PMID- 25030859 TI - [Morphologic changes and pathologic significance of expansile invasion of breast tumors]. PMID- 25030860 TI - [Clinicopathologic features of parathyroid carcinoma: a study of 11 cases with review of literature]. AB - OBJECTIVE: To study the clinicopathologic characteristics of parathyroid carcinoma (PTC). METHODS: Eleven cases of PTC encountered during the period from 1994 to 2012 were enrolled into the study. Forty cases of parathyroid adenoma (PA) were also retrieved for comparison. The clinical manifestations, laboratory results and pathologic features were analyzed, with literature review. RESULTS: The main clinical manifestations of PTC included neck mass (11/11), hypercalcemia (11/11) and hyperparathyroidism (11/11). Most patients also had osteoporosis (10/11). In contrast, PA often manifested as hypercalcemia (40/40) and hyperparathyroidism (40/40). Histologic examination of PTC showed that the tumor cells contained clear to eosinophilic cytoplasm and separated by dense bands of fibrosis. The tumor mass was surrounded by thick fibrous capsule. Foci of capsular invasion and vascular permeation were identified at the tumor periphery in all cases. Cellular atypia was not conspicuous but mitotic figures and coagulative necrosis were easily identified. On the other hand, PA were composed of tumor cells with clear to eosinophilic cytoplasm, forming glands, trabeculae or nests. Most of them (35/40) had intact fibrous capsule. Mitotic figures were rarely encountered and tumor necrosis was absent. Immunohistochemical study showed that the tumor cells in PTC were positive for CK19 (11/11), chromogranin A (9/11), synaptophysin (7/11) and parathyroid hormone (11/11). They were negative for thyroglobulin, TTF-1 and calcitonin. The Ki-67 index was less than 10% (range = 2% to 9%). In contrast, the tumor cells in PA were positive (40/40) for CK19, chromogranin A, synaptophysin and parathyroid hormone. They were negative for thyroglobulin, TTF-1 and calcitonin. The Ki-67 index was less than 3%. Follow up data were available in 9 cases of PTC (duration of follow up = 11 months to 224 months) and 7 of the patients were still alive. Follow up of all PA cases showed no evidence of recurrence. CONCLUSIONS: PTC is a rare malignant endocrine tumor presenting as neck mass. Histologic features suggestive of malignant behavior include presence of coagulative tumor necrosis and capsular/vascular invasion. It needs to be distinguished from other entities such as parathyroid adenoma, papillary thyroid carcinoma and medullary thyroid carcinoma. PMID- 25030861 TI - [Dysplastic nodule of liver versus early hepatocellular carcinoma: a clinicopathologic and prognostic study]. AB - OBJECTIVE: To study the clinical features, pathologic findings and prognosis of patients with dysplastic nodules of liver (DN) and early hepatocellular carcinomas (eHCC). METHODS: One hundred and forty-five archival cases previously diagnosed as DN or eHCC or well-differentiated HCC during the period from 2000 to 2009 were retrieved and reevaluated with the new diagnostic criteria by two experienced pathologists, according to International Consensus Group for Hepatocellular Neoplasia (ICGHN) 2008. Immunohistochemical study (EnVision method) for CD34, HSP70, glutamine synthetase, glypican 3 and Ki-67 was carried out. The original diagnosis and diagnosis after review were compared and correlated with the survival data of the patients, with statistical analysis. RESULTS: With the new criteria, 16 cases were diagnosed as low-grade DN, 50 cases as high-grade DN, 72 cases as DN with microinvasion, 7 cases as advanced HCC. Slide review showed no diagnostic discrepancy in 112 cases (77.2%). Amongst the 33 (22.8%) underdiagnosed cases, there were 7 cases of advanced HCC initially diagnosed as DN or DN with microinvasion and 26 cases of eHCC initially diagnosed as high-grade DN. Kaplan-Meier analysis showed that the diagnosis of high-grade DN or early HCC carried no statistically significant difference in overall survival (P = 0.778, 0.677) or disease-free survival (P = 0.949, 0.700) in all patients and in patients with no history of HCC. The co-existence of advanced HCC in patients with DN or eHCC significantly correlated with overall survival (P = 0.004) but not with disease-free survival (P = 0.079). CONCLUSIONS: The new diagnostic criteria by ICGHN 2008 are useful in delineating high-grade DN and eHCC. The overall survival and disease-free survival of patients with eHCC or high-grade DN undergoing hepatectomy show no statistically significant difference. Patients with DN or eHCC have better prognosis than patients with advanced HCC, though there is still a high risk of tumor recurrence. PMID- 25030862 TI - [Grey zone lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: clinicopathologic characterization of 16 cases showing different patterns]. AB - OBJECTIVE: To profile the clinicopathologic features of a series of grey zone lymphoma (GZL) cases with hybrid features of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (CHL), with a purpose to gain an in-depth understanding of the borderline B-cell neoplasm. METHODS: The clinical, morphologic and immunophenotyical characteristics of 16 cases were retrospectively analyzed. RESULTS: The patients were mostly male adults, with a male to female ratio of 1.7: 1.0 and a mean age of 40.2 years. Eight patients presented with peripheral nodal lesions and five cases with mediastinal involvement. Histologically and immunophenotypically, the 16 cases were classified into three sub-categories. In 4 cases, the morphologic features resembled CHL more closely, but the neoplastic cells showed uniform and intense positive staining of CD20 (pattern 1). Although the initial impression of the other 8 cases was that of DLBCL, the expression levels of CD20 and PAX5 were variable, and CD30 or CD15 was positive (pattern 2). A characteristic feature of pattern 3, observed in the remaining 4 cases, demonstrated a broad spectrum of morphology with hybrid features of both CHL and DLBCL. The neoplastic cells in pattern 3 were positive for CD20, CD30 and CD15. EBV-LMP1 was detected in 6 of the 11 tested cases. Clinically, most patients with GZL seemed insensitive to immuno-chemotherapy of the R-CHOP regimen. CONCLUSIONS: The diagnostic criteria for GZL with features intermediate between DLBCL and CHL is proposed by the three histologic patterns commonly seen in these lesions. Cases presented with peripheral lesions might differ from those with mediastinal presentation pathologically. At current time, there is no effective treatment for these borderline B-cell lymphomas and the prognosis is poor. PMID- 25030863 TI - [Expression profiling of metastasis-related microRNAs in early esophageal squamous cell carcinoma]. AB - OBJECTIVE: To study the difference of microRNA (miRNA) expression between two groups of early stage (pT1N0) esophageal squamous cell carcinoma (ESCC) patients who had different outcome and the prognostic significance of different miRNA in metastatic of early ESCC, and to identify useful prognostic markers in the selection of appropriate treatment for early ESCC patients. METHODS: TaqMan human miRNA arrays and bioinformatics were used to detect and analyze the expression profiles of miRNAs in the two groups, and RT-PCR was used to verify the differences in miRNA expression. RESULTS: The miRNA arrays revealed a total of 41 markedly changed miRNAs in the survival group compared with the death group. Bioinformatics analysis, prediction and significant function analyses of targeted genes and pathway analysis identified that miR-27a, miR-143 and miR-886-5p levels were increased or decreased by seven-folds or more. The enriched target genes were GRB2, SOS1, MAPK1, EGFR, CBL, SPRY2, RPS6KA5, IGF1R, NGFR, MAPK14 and CREB1. These genes were significantly related to the following signaling pathways, i.e.Sprouty regulation of tyrosine kinase signals pathway, Erk1/Erk2 Mapk signaling pathway and transcription factor CREB and its extracellular signals. CONCLUSIONS: miR-27a, miR-886-5p, and miR-143 may be potential prognostic markers of metastasis for early ESCC. The detection of these miRNAs plays a directive role for the treatment options of early ESCC. The regulation of targeted genes and mechanism remain to be further studied. PMID- 25030864 TI - [Expression of neuronal marker protein gene product 9.5 and its clinicopathologic significance in breast cancer]. AB - OBJECTIVE: To detect the expression of pan-neuronal marker protein gene product (PGP)9.5 and its clinicopathologic significance in breast cancer. METHODS: The expression of PGP9.5 was examined by immunohistochemistry EnVision method in 196 cases during 2007 to 2011, including 20 normal tissues, 14 cases of fibroadenoma, 18 cases of ductal carcinoma in situ (DCIS) and 144 cases of invasive ductal carcinoma (IDC) of the breast. The relationship between PGP9.5 expression and clinicopathologic characteristics of IDC was assessed. RESULTS: PGP9.5 expression was localized in the stroma of all normal breast tissues, but there was no expression observed in all fibroadenomas and DCIS. Overall, the expression rate of PGP9.5 in IDC was 61.8% (89/144). PGP9.5 expression increased from grade 1 tumors (29.4%, 10/34) to grade 2-3 tumors (71.8%, 79/110; P = 0.000). In addition, patients with less than 3 years disease-free survival tended to show higher PGP9.5 expression (64.8%, 35/54), compared to patients with equal to and/or more than 3 years disease-free survival (46.7%, 42/90; P = 0.035). However, there was no correlation between PGP9.5 expression and tumor size, tumor stage, lymph metastasis, hormone receptor expression. CONCLUSION: PGP9.5 expression is correlated with tumor grade and prognosis in IDC of the breast. PMID- 25030865 TI - [Recurrent Mullerian adenofibroma of uterus: a clinicopathologic study of 7 cases]. AB - OBJECTIVE: To study the clinicopathologic features and differential diagnosis of recurrent Mullerian adenofibroma (MAF) of the uterus. METHODS: Clinicopathologic information of 7 cases of recurrent MAF of uterus was retrieved from January 1992 to April 2006 and compared with 12 cases of MAF without recurrence and 14 cases of low-grade Mullerian adenosarcoma (MAS). EnVision immunohistochemistry of estrogen receptor (ER), progesterone receptor (PR), smooth muscle actin (SMA), CD10, Ki-67 and p53 were performed in all cases. RESULTS: All cases of recurrent MAF of the uterus were polypoid, lobulated, and broad based mass arising from the corpus or cervix. Microscopically, the tumor consisted of benign epithelial and mesenchymal components with low mitotic activity ( <= 1/10 HPF). The clinical and pathologic features of 3 recurrent tumors were similar to their primary tumors, while 4 cases of recurrent tumor presented with focally higher cellularity and mitotic activity, meeting the diagnostic criteria of adenosarcoma. The stromal expression patterns of ER, PR, SMA and p53 in recurrent MAF were similar to those of clinically benign MAF and low-grade MAS. Negative or focally positive stromal cell expression of CD10 was seen infrequently in recurrent MAF (1/7) and clinically benign MAF (1/12). In contrast, a moderate to strong CD10 staining was frequently seen in MAS (9/14, P < 0.05). The difference of Ki-67-labeling index between MAF and MAS did not reach a statistical significance (P > 0.05). Ki-67 labeling index increased in areas of periglandular stromal cuffing as compared with interglandular areas in all MAS cases, but it was not observed in either recurrent MAF or clinically benign MAF cases. CONCLUSIONS: Recurrent MAF may be associated with aggressive behavior. It is difficult to distinguish MAF from low grade MAS. CD10 and Ki-67 staining pattern in stromal cells may be helpful for the differential diagnosis. PMID- 25030866 TI - [Clinicopathological significance of gastric mucosal infection with coccoid Helicobacter pylori]. AB - OBJECTIVE: To study the detection method of coccoid helicobacter pylori (HP) and to investigate the significance of pure coccoid HP infection of gastric mucous membrane. METHODS: A total of 171 gastric biopsy specimens were reviewed by HE stain, and the presence, density and tissue distribution of HP were investigated by sliver stain and immunohistochemistry(S-P method). RESULTS: The rates of mucosal erosion and active inflammation with the presence of pure coccoid HP infection were 36.0% (9/25) and 44.0% (11/25), respectively, both higher than those without HP infection (13.5%, 10/74; 24.3%, 18/74), while lower than those infected with spiral HP (72.1%, 49/68; 79.4%, 54/68). The quantity of interstitial lymphocyte and inflammation severity were also higher than those without HP infection, while lower than those with spiral HP infection. CONCLUSIONS: Pure coccoid HP causes human gastritis, similar to that of spiral HP infection but at a lesser degree. Further studies are important to confirm its clinical significance. PMID- 25030867 TI - [Establishment of a two-layer cell spheroid model and its applications in colorectal tumor cell-fibroblast interactions with effect on Cx43 expression]. AB - OBJECTIVE: To imitate tumor microenvironment in vivo through construction of two layer cell spheroid as a three-dimensional tumor model, and to validate its application in the study of Cx43 expression in colorectal cancer cell-fibroblast interactions and colorectal cancer progression. METHODS: The two-layer cell spheroid was constructed from SW620 colorectal cancer cells and HELF fibroblasts. The expression of Cx43 in the spheroid was detected by immunocytochemistry. The expression of Cx43 in cultured SW620 cells with or without co-cultured fibroblasts was detected by immunocytochemistry and immunofluorescence. The expression of Cx43 in colorectal cancer tissue was detected by immunohistochemistry. RESULTS: The spheroid showed well-defined cellular morphology and clear boundary between two cell lines.Significant expression of Cx43 was found along the boundary.SW620 cells had no expression of Cx43 when cultured alone, while the expression of Cx43 was induced upon co-culturing with fibroblasts.In the colorectal cancer tissue, expression of Cx43 was minimal in the centre of tumor in contrast to an upregulated expression at invasive front. CONCLUSIONS: The two-layer cell spheroid is an observable and sensitive model for cell-cell interaction for studies of tumor microenvironment.It can simulate colorectal cancer cell-fibroblast interactions through up-regulation of Cx43 expression. PMID- 25030868 TI - [Pathologic diagnosis of malignant rhabdoid tumor of skin]. PMID- 25030869 TI - [Bronchial metastasis of thyroid follicular carcinoma: report of a case]. PMID- 25030870 TI - [Gastric mucosa-associated lymphoid tissue lymphoma with Schistosoma japonica infection: report of a case]. PMID- 25030871 TI - [Mesonephric hyperplasia in uterine cervix: report of two cases]. PMID- 25030872 TI - [Correlation between histological characteristics, molecular expression and clinical outcome of papillary thyroid carcinoma]. PMID- 25030873 TI - [Recommendations for pathologic evaluation of gastric endoscopic submucosal dissection specimens]. PMID- 25030874 TI - [Problems in pathologic diagnosis of thyroid follicular cell carcinoma]. PMID- 25030875 TI - [Research progress of Twist in breast cancer]. PMID- 25030877 TI - Antibiotic prophylaxis in VUR: should we or shouldn't we? PMID- 25030876 TI - [Factors affecting expression of differentiation-related gene NDRG1]. PMID- 25030878 TI - Obstetric outcome of twin gestations in a tertiary hospital South-western Nigeria. AB - BACKGROUND: Twin pregnancy is considered a high risk pregnancy due to associated adverse obstetric outcomes. The objective was to determine the prevalence, complications and the obstetric outcomes of twin deliveries in EKSUTH. MATERIAL AND METHODS: A retrospective analysis of twin gestations managed at the Ekiti State University Teaching Hospital, Ado-Ekiti between January 2009 and December 2012 was done. RESULTS: The prevalence of twin deliveries was 1 in 23 deliveries (4.3%). Increasing age and parity and Yoruba ethnicity were associated with higher twinning rate. The mean gestational age at delivery was 36.6 +/- 2.9 weeks and the mean birth weight was 2.47 +/- 0.49 kg with first twins having higher birth weight. Spontaneous vaginal delivery was the most common mode of delivery accounting for 52.6% and 49.3% in twin 1 and twin 2, respectively, and majority (39.5%) of the twins were in cephalic-cephalic presentation. The most common indication for caesarean delivery was breech presentation in the first twin. Preterm labour was the commonest maternal complications occurring in 25.7% of cases. The perinatal mortality rate was 105 per 1000 deliveries and this was significantly associated with unbooked patients, p = 0.001. There were no maternal deaths. CONCLUSION: Preterm labour remains the commonest complication with associated high perinatal mortality. PMID- 25030879 TI - Novel and effective balanced intravenous-inhalant anaesthetic protocol in swine by using unrestricted drugs. AB - Nowadays, because of increasing employment of swine for experimental studies and medical training, it is hopeful to investigate novel and effective anaesthetic protocols for preserving the animal welfare in medical investigation and concurrently improving the quality of research. Therefore, the aim of this study was to investigate a novel and effective anaesthetic protocol in swine undergoing major surgery, by translating know-how of combined anaesthesia from human protocols. Seven landrace swine were anaesthetized for three hours by a combined trial anaesthetic protocol (sedation: medetomidine, acepromazine, atropine and tramadol; induction: propofol, medetomidine and acepromazine; anaesthesia: isofluorane, propofol, medetomidine and acepromazine) and both clinical and haemodynamic parameters were compared with those of five swine anaesthetized with a control protocol (sedation: diazepam, ketamine and atropina; induction: diazepam and ketamine; anaesthesia: isofluorane). Both cardiac frequency (CF) and mean blood pressure (MBP) were significantly (P<0.05) more stable in trial protocol (CF: 78.3 +/- 4.6-81.1 +/- 5, MBP: 63.9 +/- 10.7-96.4 +/- 13.0) compared to control protocol (CF: 93.7 +/- 5.5-102.5 +/- 8.5, MBP: 71.0 +/- 6.6-108.7 +/- 7.2). The body temperature remained stable in trial protocol ( degrees C: 36.9 +/ 0.7-37.2 +/- 0.3) compared to control anaesthesia ( degrees C: 36.4 +/- 0.3-37.3 +/- 0.2, P<0.05). Haematosis improved undergoing combined anaesthesia (+2%, P<0.05) whereas did not change in control animals. There were no differences in respiratory rate between trial and control protocols. This study demonstrates that the proposed balanced intravenous-inhalant protocol permits to carry out a very effective, stable and safe anaesthesia in swine undergoing deep anaesthesia. PMID- 25030880 TI - Role of articular disc in condylar regeneration of the mandible. AB - The articular disc in the temporomandibular joint plays an important role in mandibular growth. Functional appliances induce regeneration of the condyle even after condylectomy. The aim of this study was to examine the role of the articular disc in regeneration of the condyle after unilateral condylectomy with use of a functional appliance in growing rats. Fifty growing rats were subjected to unilateral condylectomy and then half of them underwent discectomy. The functional appliance was applied to half of the rats in each group to induce regeneration of the condyle. Four and eight weeks later, morphometric and histologic analyses of the mandible were performed. Regeneration of the condyle was demonstrated in the two condylectomy groups. In the condylectomy+appliance group, the shape and cartilage of the condyle were equivalent to a normal condyle. However, regeneration of the condyle was not observed in the two discectomy groups even with the use of the functional appliance. The articular disc appears to be crucial in the regeneration of a damaged condyle, suggesting that defects or damage to the articular disc may influence mandibular growth and regeneration or repair of the condyle. PMID- 25030882 TI - Working together: health promoting schools and school nurses. AB - The health of children and adolescents pose multiple challenges for health professionals in these times of rapid socioeconomic, political, cultural, epidemiological and health system changes. The health promoting schools approach and accompanying national models, regional and global initiatives, provide a mechanism for integrating health promotion and core nursing functions into schools and communities, while preventing premature morbidity and mortality from chronic and debilitating conditions. Nurses, in collaboration with educators, other health professionals, students, parents, councils and community members, are core and instrumental means to generate and support change in school settings, aimed at creating environments supportive to health. PMID- 25030881 TI - Fenitrothion alters sperm characteristics in rats: ameliorating effects of palm oil tocotrienol-rich fraction. AB - Exposure to organophosphate insecticides such as fenitrothion (FNT) in agriculture and public health has been reported to affect sperm quality. Antioxidants may have a potential to reduce spermatotoxic effects induced by organophosphate. The present study was carried out to evaluate the effects of palm oil tocotrienol-rich fraction (TRF) in reducing the detrimental effects occurring in spermatozoa of FNT-treated rats. Adult male Sprague-Dawley rats were divided into four equal groups: a control group and groups of rats treated orally with palm oil TRF (200 mg/kg), FNT (20 mg/kg) and palm oil TRF (200 mg/kg) combined with FNT (20 mg/kg). The sperm characteristics, DNA damage, superoxide dismutase (SOD) activity, and levels of reduced glutathione (GSH), malondialdehyde (MDA), and protein carbonyl (PC) were evaluated. Supplementation with TRF attenuated the detrimental effects of FNT by significantly increasing the sperm counts, motility, and viability and decreased the abnormal sperm morphology. The SOD activity and GSH level were significantly increased, whereas the MDA and PC levels were significantly decreased in the TRF+FNT group compared with the rats receiving FNT alone. TRF significantly decreased the DNA damage in the sperm of FNT-treated rats. A significant correlation between abnormal sperm morphology and DNA damage was found in all groups. TRF showed the potential to reduce the detrimental effects occurring in spermatozoa of FNT-treated rats. PMID- 25030883 TI - Quality evaluation of randomized controlled trials on complementary and alternative medicine. AB - PURPOSE: This study aims to describe the research characteristics and analyze the methodological quality of randomized clinical trials on complementary and alternative medicine (CAM). METHODS: A total of 76 studies using randomized controlled trials (RCTs) on CAM (16 by Koreans, 60 by internationals) published in the 6 years from 2000 to 2005 were reviewed systematically and analyzed with assessment criteria developed by the researchers on the basis of Jadad guidelines. RESULTS: Most of the studies were carried out in the area of medicine, nursing and CAM. More than 80% of the study subjects were patients. CAM modalities for independent variables were mainly on energy medicine, mind-body medicine and manipulative and body-based practices, while dependent variables were mostly physiological and psychological indexes. Most of the studies utilized randomization (93.4%) and identified the dropout rate (90.8%), whereas allocation concealment (49.3%) and double-blinding (18.9%) were specified in a small number of studies. The overall quality of RCTs based on the assessment criteria of this study was satisfactory. However, the quality score of the Korean studies (2.87) was lower than that of the international studies (3.37). CONCLUSION: The methodological objectivity of CAM studies has been improving in spite of controversy over the scientific bases of CAM. More Korean studies with rigorous experimental design are needed to build up the evidence-based practice of CAM. PMID- 25030884 TI - Differences in knowledge of hepatitis B among korean immigrants in two cities in the rocky mountain region. AB - PURPOSE: To assess knowledge and attitude toward hepatitis B virus (HBV) infection among Korean immigrants in two cities in the Rocky Mountain region and to determine whether sociodemographic and cultural factors are related to the level of HBV knowledge. METHODS: Community-based participatory study was conducted in five Korean churches in the Rocky Mountain region to develop baseline data on HBV infection and vaccination behavior. All documents, including announcements, brochures, consent forms, and questionnaires were in Korean and English, and trained Korean interviewers collected the surveys by reviewing the questionnaires with participants at the churches. RESULTS: Knowledge of HBV infection was low and city of residence did not have a statistically significant impact on HBV infection knowledge. In the total sample, 62% identified transmission by sharing utensils and 21% believed that HBV was hereditary, while only 21% thought that HBV was spread through sexual contact. The majority of participants (61%) rated their English level as "minimum". Knowledge of HBV infection was found to be associated with both demographic and acculturation factors (p < .05). CONCLUSION: This study found not only a low level of knowledge of HBV infection but also misunderstanding of the risks of HBV infection. Knowledge of HBV infection was significantly associated with education and acculturation; therefore, culturally sensitive and group-tailored public health education for Korean and other Asian American Pacific Islanders should be developed to clarify misconceptions and misunderstandings about HBV infection. PMID- 25030885 TI - Informational needs of korean women with breast cancer: cross-cultural adaptation of the toronto informational needs questionnaire of breast cancer. AB - PURPOSE: The purpose of this study was to adopt an instrument suitable for assessing the informational needs of Korean women with breast cancer. METHODS: This was a cross-cultural adaptation into Korean and quantitative validation of the 52-item Toronto Informational Needs Questionnaire of Breast Cancer (TINQ-BC). In the validation phase, we assessed the psychometric properties of the instrument in a cross-sectional survey of 164 Korean women with breast cancer participating in self-support groups. RESULTS: Construct and content validity of the instrument was established. Internal consistency using Cronbach's alpha was .97. Using confirmatory factor analysis, factor loadings ranging from .54 to .87 were obtained and considered satisfactory. All 52 items of the TINQ-BC were found to be effective at measuring the informational needs of Korean women with breast cancer. According to the adapted scale, the Korean Informational Needs Questionnaire of Breast Cancer, the informational needs of Korean women with breast cancer were high, with a mean total score of 203.61 (standard deviation, 34.43; range, 109-255). CONCLUSION: The TINQ-BC, developed and tested in Canada, was adapted and successfully utilized in this study in Korea, indicating that it has the potential to assess the informational needs of women with breast cancer on an international basis. Health care professionals must be aware of the domains of information that these women perceive to be important so that educational interventions can be effectively planned and executed. PMID- 25030886 TI - Interpersonal Caring Theory: An Empirical Test of Its Effectiveness Utilizing Growth Curve Analysis - II. AB - PURPOSE: To test the impact of interpersonal caring theory empirically on six major psychosocial functioning outcomes of persons with serious mental illness. METHODS: This was a quasi-experimental pre- and post-test design with data collection from a total of 266 patients with long-term serious mental illness, who were diagnosed with schizophrenia spectrum disorder and followed at 6-month intervals over a 24-month period in three groups: a community psychiatric service group, a community service with interpersonal caring intervention group, and a control group. Three hypotheses between the intensity, specificity, and longitudinality of services were tested using growth curve analysis. RESULTS: Hierarchical linear modeling supported associations of hypotheses between the intensity, specificity, and longitudinality of services and improved patient outcomes. CONCLUSION: This study suggests that the intensity, specificity, and longitudinality of interpersonal caring interventions in community psychiatric service programs deserve attention in order to improve and maintain patient functional outcomes. PMID- 25030887 TI - Parental Perception of Neonates, Parental Stress and Education for NICU Parents. AB - PURPOSE: The purpose of this study was to conduct a comparative analysis between the perception of parents with premature infants in the NICU and parents with full-term newborns, and in the process to evaluate the effects of NICU educational support on parents with regard to their perception of neonate and parental stress. METHODS: A mixed quantitative design was employed to compare parental perception of neonates using the Neonatal Perception Index (NPI) between the parents of 26 full-term infants (full-term group) and the parents of 22 premature infants in the NICU (NICU group), and also to evaluate the effect of NICU educational support on NPI and parental stress using the Parental Stress Scale (PSS) between the mothers and fathers in the NICU group. RESULTS: NICU mothers showed the lowest NPI score among full-term and NICU parents. However, no difference in direction of NPI scores was observed between parents in either the full-term or NICU group. NICU education improved NPI and decreased PSS in fathers but not in mothers. CONCLUSION: Environmental modifications of the nursery setting, particularly its remote location to the NICU, could improve mothers' perception of full-term neonates. NICU mothers, as the principal care- givers, may suffer from culturally-grounded, psychoemotional disturbances after giving birth to a sick infant, which may not be applicable to fathers. The quality of family-centered care in the NICU environment, parental role alteration, and the condition of infants need to be improved to decrease parental stress in the NICU. Fathers may have significant potential in caring for mothers and sick infants during the transition to parenthood. Education for NICU parents should be done for both mothers and fathers in the acute postpartum period. PMID- 25030888 TI - C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency. AB - Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage-fusion-bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin B1 induced substitutions of guanines in a GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling "chromoanasynthesis," a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease. PMID- 25030889 TI - Probing the effect of promoters on noise in gene expression using thousands of designed sequences. AB - Genetically identical cells exhibit large variability (noise) in gene expression, with important consequences for cellular function. Although the amount of noise decreases with and is thus partly determined by the mean expression level, the extent to which different promoter sequences can deviate away from this trend is not fully known. Here, we present a high-throughput method for measuring promoter driven noise for thousands of designed synthetic promoters in parallel. We use it to investigate how promoters encode different noise levels and find that the noise levels of promoters with similar mean expression levels can vary more than one order of magnitude, with nucleosome-disfavoring sequences resulting in lower noise and more transcription factor binding sites resulting in higher noise. We propose a kinetic model of gene expression that takes into account the nonspecific DNA binding and one-dimensional sliding along the DNA, which occurs when transcription factors search for their target sites. We show that this assumption can improve the prediction of the mean-independent component of expression noise for our designed promoter sequences, suggesting that a transcription factor target search may affect gene expression noise. Consistent with our findings in designed promoters, we find that binding-site multiplicity in native promoters is associated with higher expression noise. Overall, our results demonstrate that small changes in promoter DNA sequence can tune noise levels in a manner that is predictable and partly decoupled from effects on the mean expression levels. These insights may assist in designing promoters with desired noise levels. PMID- 25030890 TI - Mouse models of altered gonadotrophin action: insight into male reproductive disorders. AB - The advent of technologies to genetically manipulate the mouse genome has revolutionised research approaches, providing a unique platform to study the causality of reproductive disorders in vivo. With the relative ease of generating genetically modified (GM) mouse models, the last two decades have yielded multiple loss-of-function and gain-of-function mutation mouse models to explore the role of gonadotrophins and their receptors in reproductive pathologies. This work has provided key insights into the molecular mechanisms underlying reproductive disorders with altered gonadotrophin action, revealing the fundamental roles of these pituitary hormones and their receptors in the hypothalamic-pituitary-gonadal axis. This review will describe GM mouse models of gonadotrophins and their receptors with enhanced or diminished actions, specifically focusing on the male. We will discuss the mechanistic insights gained from these models into male reproductive disorders, and the relationship and understanding provided into male human reproductive disorders originating from altered gonadotrophin action. PMID- 25030891 TI - Identification and characterization of an oocyte factor required for sperm decondensation in pig. AB - Mammalian oocytes possess factors to support fertilization and embryonic development, but knowledge on these oocyte-specific factors is limited. In the current study, we demonstrated that porcine oocytes with the first polar body collected at 33 h of in vitro maturation sustain IVF with higher sperm decondensation and pronuclear formation rates and support in vitro development with higher cleavage and blastocyst rates, compared with those collected at 42 h (P<0.05). Proteomic analysis performed to clarify the mechanisms underlying the differences in developmental competence between oocytes collected at 33 and 42 h led to the identification of 18 differentially expressed proteins, among which protein disulfide isomerase associated 3 (PDIA3) was selected for further study. Inhibition of maternal PDIA3 via antibody injection disrupted sperm decondensation; conversely, overexpression of PDIA3 in oocytes improved sperm decondensation. In addition, sperm decondensation failure in PDIA3 antibody injected oocytes was rescued by dithiothreitol, a commonly used disulfide bond reducer. Our results collectively report that maternal PDIA3 plays a crucial role in sperm decondensation by reducing protamine disulfide bonds in porcine oocytes, supporting its utility as a potential tool for oocyte selection in assisted reproduction techniques. PMID- 25030892 TI - Characterization of human spermatogonial stem cell markers in fetal, pediatric, and adult testicular tissues. AB - Autologous spermatogonial stem cell (SSC) transplantation is a potential therapeutic modality for patients with azoospermia following cancer treatment. For this promise to be realized, definitive membrane markers of prepubertal and adult human SSCs must be characterized in order to permit SSC isolation and subsequent expansion. This study further characterizes the markers of male gonocytes, prespermatogonia, and SSCs in humans. Human fetal, prepubertal, and adult testicular tissues were analyzed by confocal microscopy, fluorescence activated cell sorting, and qRT-PCR for the expression of unique germ cell membrane markers. During male fetal development, THY1 and KIT (C-Kit) are transient markers of gonocytes but not in prespermatogonia and post-natal SSCs. Although KIT expression is detected in gonocytes, THY1 expression is also detected in the somatic component of the fetal testes in addition to gonocytes. In the third trimester of gestation, THY1 expression shifts exclusively to the somatic cells of the testes where it continues to be detected only in the somatic cells postnatally. In contrast, SSEA4 expression was only detected in the gonocytes, prespermatogonia, SSCs, and Sertoli cells of the fetal and prepubertal testes. After puberty, SSEA4 expression can only be detected in primitive spermatogonia. Thus, although THY1 and KIT are transient markers of gonocytes, SSEA4 is the only common membrane marker of gonocytes, prespermatogonia, and SSCs from fetal through adult human development. This finding is essential for the isolation of prepubertal and adult SSCs, which may someday permit fertility preservation and reversal of azoospermia following cancer treatment. PMID- 25030893 TI - Effects of WT1 down-regulation on oocyte maturation and preimplantation embryo development in pigs. AB - The Wilms' tumour 1 (WT1) gene originally identified as a tumour suppressor associated with WTs encodes a zinc finger-containing transcription factor that is expressed in multiple tissues and is an important regulator of cellular and organ growth, proliferation, development, migration and survival. However, there is a deficiency of data regarding the expression and function of WT1 during oocyte maturation and preimplantation embryonic development. Herein, we sought to define the expression characteristics and functions of WT1 during oocyte maturation and preimplantation embryonic development in pigs. We show that WT1 is expressed in porcine oocytes and at all preimplantation stages in embryos generated by ICSI. We then evaluated the effects of down-regulating WT1 expression at germinal vesicle and early ICSI stages using a recombinant plasmid (pGLV3-WT1-shRNA). Down regulation of WT1 did not affect oocyte maturation but significantly decreased preimplantation embryonic development and increased apoptosis in blastocysts. These results indicate that WT1 plays important roles in the development of porcine preimplantation embryos. PMID- 25030894 TI - Outcrossing rates and organelle inheritance estimated from two natural populations of the Japanese endemic conifer Sciadopitys verticillata. AB - The Japanese endemic conifer Sciadopitys verticillata is one of the most phylogenetically isolated species of all plants. Occurring in small and scattered populations, the species is currently classified as Near Threatened by the International Union for Conservation of Nature and Natural Resources (IUCN) and as Vulnerable in three prefectures of Japan. This study investigated two major factors that should impact the genetic structure of the species at both the nuclear and organelle DNA level, the mating system and the inheritance of both the chloroplast and mitochondrial genomes. The mating system is crucial to determining the degree of outcrossing of plant species and thus should have a key role in shaping the species' population level genetic diversity and gene flow between populations but as yet has not been studied in S. verticillata. Nine mother trees and their seedling progeny from two natural populations were genotyped using genetic markers from three plant genomes (eight nuclear microsatellites and DNA sequence for the chloroplast and mitochondria). Using a maximum likelihood method implemented in the software MLTR, the study found an outcrossing rate in the seedling stage of 0.49 and 0.79 for Aburazaka and Mount Shirotori populations, respectively, and an average of 0.66 at the species level. These outcrossing rates were low for conifers and therefore may have potential deleterious implications for the conservation of the species. The test of organelle inheritance supported paternal transmission of both the chloroplast and mitochondria consistent with previous microscopic evidence. PMID- 25030895 TI - Satellite-DNA diversification and the evolution of major lineages in Cardueae (Carduoideae Asteraceae). AB - In a previous work, we characterized the HinfI satellite DNA family in the subtribe Centaureinae (Cardueae) demonstrating that a "library" of eight HinfI subfamilies would exist in the common ancestor of all Centaureinae, which were differentially amplified in different lineages. Now, we extend our study by analyzing a total of 219 additional repeats from fifteen species belonging to Carlininae, Echinopsinae and Carduinae, and comparing them to those of Centaureinae. Most HinfI sequences belonged to the subfamily II, although a few sequences of other subfamilies were detected in some species. Additionally, a new subfamily characteristic of several Carduinae species was discovered. Although phylogenetic trees grouped sequences by subfamily affinity instead of species provenance, when comparing repeats of the same subfamily, the degree of divergence between any pair of sequences was related to the evolutionary distance between the species compared in most cases. Exceptions were in comparisons between sequences of some Centaureinae species, and between sequences of some Carduinae species and those of Centaureinae. Our results demonstrate that: (1) At least nine HinfI subfamilies would exist in the common ancestor of Cardueae, each one differentially amplified in different lineages; (2) After differential spreading, sequences of each subfamily evolved concertedly through molecular drive, resulting in the gradual divergence of repeats between different species; (3) The rate to which concerted evolution occurred was different between lineages according to the evolutionary history of each one. PMID- 25030896 TI - [Comparison of the OSDI and SPEED questionnaires for the evaluation of dry eye disease in clinical routine]. AB - BACKGROUND: For the diagnosis of dry eye, taking an accurate medical history of the patient is critical. For this purpose the ocular surface disease index (OSDI) can be regarded as the established standard questionnaire but the standard patient evaluation of eye dryness (SPEED) questionnaire has recently been developed. The advantages of the SPEED questionnaire are the lower number of questions and easier interpretability. MATERIAL AND METHODS: In a retrospective analysis of 153 patients of our special clinic for dry eyes we performed a comparison of the SPEED with the established OSDI questionnaire regarding the evaluation of the severity of dry eye. In addition, we analyzed possible correlations with various objective parameters for classification of dry eye syndrome. RESULTS: There was a highly significant correlation between OSDI and SPEED values with a correlation coefficient of 0.47 (p < 0.001). In addition, significant correlations between OSDI values and the tear meniscus height (r = - 0.1374, p = 0.0226), Schirmer values (r = - 0.26, p < 0.0001) and lid margins parallel conjunctival folds (r = 0.1261, p = 0.034) were observed. The SPEED values showed a significant correlation with age (r = - 0.2106, p = 0.0107) and lipid layer thickness (r = - 0.159, p = 0.0081). DISCUSSION: The OSDI and SPEED questionnaires are both suitable for detecting the symptoms of dry eye; however the results of the questionnaires cannot be used interchangeably. While the SPEED levels seemed to correlate more with the parameters of evaporative dry eye, the OSDI values were more correlated with parameters of aqueous tear-deficient dry eye. However, a distinction between evaporative and aqueous tear-deficient dry eye is not possible based only on the results of the questionnaires. PMID- 25030897 TI - [Bilateral vascularized disciform corneal scar of herpetic origin in a child]. AB - BACKGROUND: Bilateral keratitis is rare and can have various causes. For a good outcome after treatment, the correct diagnosis is decisive. CASE REPORT: A 15 year-old boy presented to our clinic with recurrent keratoconjunctivitis and progressive loss of vision in both eyes since 6 years. The best corrected visual acuity was 0.1 in the right eye and 1/12 in the left eye. Slit-lamp examination verified keratitis disciformis with strongly vascularized corneal stromal scars without conjunctival follicles on both sides. Based on the clinical diagnosis, antiviral treatment was initiated. Best corrected visual acuity 8 weeks later increased to 0.4 in the right eye and 0.8 in the left eye and the corneal edema decreased in both eyes. Due to noncompliance the patient returned with a perforated corneal ulcer of the left eye, where an a chaud penetrating keratoplasty had to be performed. RESULTS: Herpes simplex virus is one of the most common causes of keratitis and has different manifestations. In the treatment of keratitis disciformis the use of topical steroids is mandatory as there is an active immunological process. The use of systemic and local antiviral treatment is necessary at the same time in order to avoid reactivation of viral replication. Bilateral keratitis is relatively frequent in children. CONCLUSION: Herpetic keratitis is now well treatable if the various manifestations of the disease are recognized early and an appropriate therapy is adjusted accordingly. PMID- 25030898 TI - Combined central and peripheral stimulation for treatment of chronic tinnitus: a randomized pilot study. AB - BACKGROUND: Tinnitus is a common untreatable condition that originates from central maladaptive plasticity initiated by peripheral injury. Repetitive transcranial magnetic stimulation (rTMS), direct cochlear low-level laser therapy (LLLT), and acupuncture were tried for tinnitus treatment, but the results of these methods were clinically unsatisfactory. OBJECTIVE: This study aimed to test the combined effect of the 3 methods targeting both peripheral and central auditory areas as a new therapeutic strategy for tinnitus. METHODS: For this, 30 patients were randomized to 3 equal groups receiving 3 different interventions: inhibitory rTMS to the left auditory cortex, LLLT (which includes a combination of direct cochlear LLLT and laser acupuncture) to the affected ear(s), and finally, a combination of rTMS and LLLT. The Tinnitus Handicap Inventory (THI) and Visual Analogue Scale (VAS) were assessed before, immediately after, and at 2 weeks and 4 weeks after 10 consecutive every-other-day sessions for each intervention type. RESULTS: We found that combined stimulation was effective in tinnitus treatment. This effect remained for 4 weeks after the end of the treatment. However, each of rTMS and LLLT alone had no significant effect. Repeated-measures ANOVA showed a significant effect of Time and Time * Intervention interaction for THI and VAS scores. The post hoc t test for different time points per intervention revealed a significant difference between baseline and all postintervention measurements of both THI and VAS for the combination intervention. CONCLUSION: Combined central rTMS and peripheral LLLT is more beneficial as a new method for management of tinnitus rather than these two used separately. PMID- 25030899 TI - Embryonic stem cell-specific microRNAs contribute to pluripotency by inhibiting regulators of multiple differentiation pathways. AB - The findings that microRNAs (miRNAs) are essential for early development in many species and that embryonic miRNAs can reprogram somatic cells into induced pluripotent stem cells suggest that these miRNAs act directly on transcriptional and chromatin regulators of pluripotency. To elucidate the transcription regulatory networks immediately downstream of embryonic miRNAs, we extended the motif activity response analysis approach that infers the regulatory impact of both transcription factors (TFs) and miRNAs from genome-wide expression states. Applying this approach to multiple experimental data sets generated from mouse embryonic stem cells (ESCs) that did or did not express miRNAs of the ESC specific miR-290-295 cluster, we identified multiple TFs that are direct miRNA targets, some of which are known to be active during cell differentiation. Our results provide new insights into the transcription regulatory network downstream of ESC-specific miRNAs, indicating that these miRNAs act on cell cycle and chromatin regulators at several levels and downregulate TFs that are involved in the innate immune response. PMID- 25030900 TI - G-quadruplexes within prion mRNA: the missing link in prion disease? AB - Cellular ribonucleic acid (RNA) plays a crucial role in the initial conversion of cellular prion protein PrP(C) to infectious PrP(Sc) or scrapie. The nature of this RNA remains elusive. Previously, RNA aptamers against PrP(C) have been isolated and found to form G-quadruplexes (G4s). PrP(C) binding to G4 RNAs destabilizes its structure and is thought to trigger its conversion to PrP(Sc). Here it is shown that PrP messenger RNA (mRNA) itself contains several G4 motifs, located in the octarepeat region. Investigation of the RNA structure in one of these repeats by circular dichroism, nuclear magnetic resonance and ultraviolet melting studies shows evidence of G4 formation. In vitro translation of full length PrP mRNA, naturally harboring five consecutive G4 motifs, was specifically affected by G4-binding ligands, lending support to G4 formation in PrP mRNA. A possible role of PrP binding to its own mRNA and the role of anti-prion drugs, many of which are G4-binding ligands, in prion disease are discussed. PMID- 25030901 TI - In vitro selection of DNA-cleaving deoxyribozyme with site-specific thymidine excision activity. AB - Single-nucleotide polymorphisms, either inherited or due to spontaneous DNA damage, are associated with numerous diseases. Developing tools for site-specific nucleotide modification may one day provide a way to alter disease polymorphisms. Here, we describe the in vitro selection and characterization of a new deoxyribozyme called F-8, which catalyzes nucleotide excision specifically at thymidine. Cleavage by F-8 generates 3'- and 5'-phosphate ends recognized by DNA modifying enzymes, which repair the targeted deoxyribonucleotide while maintaining the integrity of the rest of the sequence. These results illustrate the potential of DNAzymes as tools for DNA manipulation. PMID- 25030902 TI - Identification and genetic analysis of cancer cells with PCR-activated cell sorting. AB - Cell sorting is a central tool in life science research for analyzing cellular heterogeneity or enriching rare cells out of large populations. Although methods like FACS and FISH-FC can characterize and isolate cells from heterogeneous populations, they are limited by their reliance on antibodies, or the requirement to chemically fix cells. We introduce a new cell sorting technology that robustly sorts based on sequence-specific analysis of cellular nucleic acids. Our approach, PCR-activated cell sorting (PACS), uses TaqMan PCR to detect nucleic acids within single cells and trigger their sorting. With this method, we identified and sorted prostate cancer cells from a heterogeneous population by performing >132 000 simultaneous single-cell TaqMan RT-PCR reactions targeting vimentin mRNA. Following vimentin-positive droplet sorting and downstream analysis of recovered nucleic acids, we found that cancer-specific genomes and transcripts were significantly enriched. Additionally, we demonstrate that PACS can be used to sort and enrich cells via TaqMan PCR reactions targeting single copy genomic DNA. PACS provides a general new technical capability that expands the application space of cell sorting by enabling sorting based on cellular information not amenable to existing approaches. PMID- 25030903 TI - Engineering modular and tunable genetic amplifiers for scaling transcriptional signals in cascaded gene networks. AB - Synthetic biology aims to control and reprogram signal processing pathways within living cells so as to realize repurposed, beneficial applications. Here we report the design and construction of a set of modular and gain-tunable genetic amplifiers in Escherichia coli capable of amplifying a transcriptional signal with wide tunable-gain control in cascaded gene networks. The devices are engineered using orthogonal genetic components (hrpRS, hrpV and PhrpL) from the hrp (hypersensitive response and pathogenicity) gene regulatory network in Pseudomonas syringae. The amplifiers can linearly scale up to 21-fold the transcriptional input with a large output dynamic range, yet not introducing significant time delay or significant noise during signal amplification. The set of genetic amplifiers achieves different gains and input dynamic ranges by varying the expression levels of the underlying ligand-free activator proteins in the device. As their electronic counterparts, these engineered transcriptional amplifiers can act as fundamental building blocks in the design of biological systems by predictably and dynamically modulating transcriptional signal flows to implement advanced intra- and extra-cellular control functions. PMID- 25030904 TI - SigFuge: single gene clustering of RNA-seq reveals differential isoform usage among cancer samples. AB - High-throughput sequencing technologies, including RNA-seq, have made it possible to move beyond gene expression analysis to study transcriptional events including alternative splicing and gene fusions. Furthermore, recent studies in cancer have suggested the importance of identifying transcriptionally altered loci as biomarkers for improved prognosis and therapy. While many statistical methods have been proposed for identifying novel transcriptional events with RNA-seq, nearly all rely on contrasting known classes of samples, such as tumor and normal. Few tools exist for the unsupervised discovery of such events without class labels. In this paper, we present SigFuge for identifying genomic loci exhibiting differential transcription patterns across many RNA-seq samples. SigFuge combines clustering with hypothesis testing to identify genes exhibiting alternative splicing, or differences in isoform expression. We apply SigFuge to RNA-seq cohorts of 177 lung and 279 head and neck squamous cell carcinoma samples from the Cancer Genome Atlas, and identify several cases of differential isoform usage including CDKN2A, a tumor suppressor gene known to be inactivated in a majority of lung squamous cell tumors. By not restricting attention to known sample stratifications, SigFuge offers a novel approach to unsupervised screening of genetic loci across RNA-seq cohorts. SigFuge is available as an R package through Bioconductor. PMID- 25030905 TI - DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal. AB - We previously identified the heterogeneous ribonucleoprotein SAF-A/hnRNP U as a substrate for DNA-PK, a protein kinase involved in DNA damage response (DDR). Using laser micro-irradiation in human cells, we report here that SAF-A exhibits a two-phase dynamics at sites of DNA damage, with a rapid and transient recruitment followed by a prolonged exclusion. SAF-A recruitment corresponds to its binding to Poly(ADP-ribose) while its exclusion is dependent on the activity of ATM, ATR and DNA-PK and reflects the dissociation from chromatin of SAF-A associated with ongoing transcription. Having established that SAF-A RNA-binding domain recapitulates SAF-A dynamics, we show that this domain is part of a complex comprising several mRNA biogenesis proteins of which at least two, FUS/TLS and TAFII68/TAF15, exhibit similar biphasic dynamics at sites of damage. Using an original reporter for live imaging of DNA:RNA hybrids (R-loops), we show a transient transcription-dependent accumulation of R-loops at sites of DNA damage that is prolonged upon inhibition of RNA biogenesis factors exclusion. We propose that a new component of the DDR is an active anti-R-loop mechanism operating at damaged transcribed sites which includes the exclusion of mRNA biogenesis factors such as SAF-A, FUS and TAF15. PMID- 25030906 TI - Inferring population structure and relationship using minimal independent evolutionary markers in Y-chromosome: a hybrid approach of recursive feature selection for hierarchical clustering. AB - Inundation of evolutionary markers expedited in Human Genome Project and 1000 Genome Consortium has necessitated pruning of redundant and dependent variables. Various computational tools based on machine-learning and data-mining methods like feature selection/extraction have been proposed to escape the curse of dimensionality in large datasets. Incidentally, evolutionary studies, primarily based on sequentially evolved variations have remained un-facilitated by such advances till date. Here, we present a novel approach of recursive feature selection for hierarchical clustering of Y-chromosomal SNPs/haplogroups to select a minimal set of independent markers, sufficient to infer population structure as precisely as deduced by a larger number of evolutionary markers. To validate the applicability of our approach, we optimally designed MALDI-TOF mass spectrometry based multiplex to accommodate independent Y-chromosomal markers in a single multiplex and genotyped two geographically distinct Indian populations. An analysis of 105 world-wide populations reflected that 15 independent variations/markers were optimal in defining population structure parameters, such as FST, molecular variance and correlation-based relationship. A subsequent addition of randomly selected markers had a negligible effect (close to zero, i.e. 1 * 10(-3)) on these parameters. The study proves efficient in tracing complex population structures and deriving relationships among world-wide populations in a cost-effective and expedient manner. PMID- 25030907 TI - Physiological state co-regulates thousands of mammalian mRNA splicing events at tandem splice sites and alternative exons. AB - Thousands of tandem alternative splice sites (TASS) give rise to mRNA insertion/deletion variants with small size differences. Recent work has concentrated on the question of biological relevance in general, and the physiological regulation of TASS in particular. We have quantitatively studied 11 representative TASS cases in comparison to one mutually exclusive exon case and two cassette exons (CEs) using a panel of human and mouse tissues, as well as cultured cell lines. Tissues show small but significant differences in TASS isoform ratios, with a variance 4- to 20-fold lower than seen for CEs. Remarkably, in cultured cells, all studied alternative splicing (AS) cases showed a cell-density-dependent shift of isoform ratios with similar time series profiles. A respective genome-wide co-regulation of TASS splicing was shown by next-generation mRNA sequencing data. Moreover, data from human and mouse organs indicate that this co-regulation of TASS occurs in vivo, with brain showing the strongest difference to other organs. Together, the results indicate a physiological AS regulation mechanism that functions almost independently from the splice site context and sequence. PMID- 25030908 TI - Antagonistic control of a dual-input mammalian gene switch by food additives. AB - Synthetic biology has significantly advanced the design of mammalian trigger inducible transgene-control devices that are able to programme complex cellular behaviour. Fruit-based benzoate derivatives licensed as food additives, such as flavours (e.g. vanillate) and preservatives (e.g. benzoate), are a particularly attractive class of trigger compounds for orthogonal mammalian transgene control devices because of their innocuousness, physiological compatibility and simple oral administration. Capitalizing on the genetic componentry of the soil bacterium Comamonas testosteroni, which has evolved to catabolize a variety of aromatic compounds, we have designed different mammalian gene expression systems that could be induced and repressed by the food additives benzoate and vanillate. When implanting designer cells engineered for gene switch-driven expression of the human placental secreted alkaline phosphatase (SEAP) into mice, blood SEAP levels of treated animals directly correlated with a benzoate-enriched drinking programme. Additionally, the benzoate-/vanillate-responsive device was compatible with other transgene control systems and could be assembled into higher-order control networks providing expression dynamics reminiscent of a lap-timing stopwatch. Designer gene switches using licensed food additives as trigger compounds to achieve antagonistic dual-input expression profiles and provide novel control topologies and regulation dynamics may advance future gene- and cell-based therapies. PMID- 25030909 TI - The direction and severity of penile curvature does not have an impact on concomitant vasculogenic erectile dysfunction in patients with Peyronie's disease. AB - Although the association between Peyronie's disease (PD) and erectile dysfunction (ED) is well established, limited data are available correlating penile curvature and penile hemodynamic parameters. We sought to examine this association in a cohort of PD men undergoing penile duplex Doppler ultrasound (PDDU). PD patients were retrospectively evaluated to correlate the extent and direction of penile curvature with measured vascular parameters. Demographic variables, disease characteristics and PDDU parameters were tabulated and statistically compared based on extent (<= 45 degrees and >45 degrees ) and direction (dorsal, ventral, lateral, ventrolateral, dorsolateral) of curvature. A total of 220 PD patients (mean age of 55.0 +/- 9.2 years) underwent PDDU at one institution from January 2008 to December 2010. Overall, 69.5% of patients were found to have vasculogenic ED (arterial insufficiency (AI): 10%; veno-occlusive dysfunction (VOD): 43.2%; AI + VOD: 16.4%). Mean curvature was similar among all PDDU groups (AI: 41.7 +/- 5.2 degrees ; VOD: 41.3 +/- 2.5 degrees ; AI+VOD: 37 +/- 4.1 degrees ; no-ED: 37.3 +/ 3 degrees ; P > 0.85). No significant differences were noted in the presence or type of ED among various directions of curvature (P = 0.34) or when curvatures were stratified by <= 45 degrees and >45 degrees . The direction and extent of penile curvature are not associated with altered rates of vasculogenic ED on PDDU in PD patients. PMID- 25030910 TI - High temperature sensitivity is intrinsic to voltage-gated potassium channels. AB - Temperature-sensitive transient receptor potential (TRP) ion channels are members of the large tetrameric cation channels superfamily but are considered to be uniquely sensitive to heat, which has been presumed to be due to the existence of an unidentified temperature-sensing domain. Here we report that the homologous voltage-gated potassium (Kv) channels also exhibit high temperature sensitivity comparable to that of TRPV1, which is detectable under specific conditions when the voltage sensor is functionally decoupled from the activation gate through either intrinsic mechanisms or mutations. Interestingly, mutations could tune Shaker channel to be either heat-activated or heat-deactivated. Therefore, high temperature sensitivity is intrinsic to both TRP and Kv channels. Our findings suggest important physiological roles of heat-induced variation in Kv channel activities. Mechanistically our findings indicate that temperature-sensing TRP channels may not contain a specialized heat-sensor domain; instead, non obligatory allosteric gating permits the intrinsic heat sensitivity to drive channel activation, allowing temperature-sensitive TRP channels to function as polymodal nociceptors. PMID- 25030911 TI - Large-scale filament formation inhibits the activity of CTP synthetase. AB - CTP Synthetase (CtpS) is a universally conserved and essential metabolic enzyme. While many enzymes form small oligomers, CtpS forms large-scale filamentous structures of unknown function in prokaryotes and eukaryotes. By simultaneously monitoring CtpS polymerization and enzymatic activity, we show that polymerization inhibits activity, and CtpS's product, CTP, induces assembly. To understand how assembly inhibits activity, we used electron microscopy to define the structure of CtpS polymers. This structure suggests that polymerization sterically hinders a conformational change necessary for CtpS activity. Structure guided mutagenesis and mathematical modeling further indicate that coupling activity to polymerization promotes cooperative catalytic regulation. This previously uncharacterized regulatory mechanism is important for cellular function since a mutant that disrupts CtpS polymerization disrupts E. coli growth and metabolic regulation without reducing CTP levels. We propose that regulation by large-scale polymerization enables ultrasensitive control of enzymatic activity while storing an enzyme subpopulation in a conformationally restricted form that is readily activatable. PMID- 25030913 TI - The UF Family of hybrid phantoms of the pregnant female for computational radiation dosimetry. AB - Efforts to assess in utero radiation doses and related quantities to the developing fetus should account for the presence of the surrounding maternal tissues. Maternal tissues can provide varying levels of protection to the fetus by shielding externally-emitted radiation or, alternatively, can become sources of internally-emitted radiation following the biokinetic uptake of medically administered radiopharmaceuticals or radionuclides located in the surrounding environment--as in the case of the European Union's SOLO project (Epidemiological Studies of Exposed Southern Urals Populations). The University of Florida had previously addressed limitations in available computational phantom representation of the developing fetus by constructing a series of hybrid computational fetal phantoms at eight different ages and three weight percentiles. Using CT image sets of pregnant patients contoured using 3D DOCTOR(TM), the eight 50th percentile fetal phantoms from that study were systematically combined in Rhinoceros(TM) with the UF adult non-pregnant female to yield a series of reference pregnant female phantoms at fetal ages 8, 10, 15, 20, 25, 30, 35 and 38 weeks post-conception. Deformable, non-uniform rational B spline surfaces were utilized to alter contoured maternal anatomy in order to (1) accurately position and orient each fetus and surrounding maternal tissues and (2) match target masses of maternal soft tissue organs to reference data reported in the literature. PMID- 25030912 TI - Gene expression profiling of candidate virulence factors in the laminated root rot pathogen Phellinus sulphurascens. AB - BACKGROUND: Phellinus sulphurascens is a fungal pathogen that causes laminar root rot in conifers, one of the most damaging root diseases in western North America. Despite its importance as a forest pathogen, this fungus is still poorly studied at the genomic level. An understanding of the molecular events involved in establishment of the disease should help to develop new methods for control of this disease. RESULTS: We generated over 4600 expressed sequence tags from two cDNA libraries constructed using either mycelia grown on cellophane sheets and exposed to Douglas-fir roots or tissues from P. sulphurascens-infected Douglas fir roots. A total of 890 unique genes were identified from the two libraries, and functional classification of 636 of these genes was possible using the Functional Catalogue (FunCat) annotation scheme. cDNAs were identified that encoded 79 potential virulence factors, including numerous genes implicated in virulence in a variety of phytopathogenic fungi. Many of these putative virulence factors were also among 82 genes identified as encoding putatively secreted proteins. The expression patterns of 86 selected fungal genes over 7 days of infection of Douglas-fir were examined using real-time PCR, and those significantly up-regulated included rhamnogalacturonan acetylesterase, 1,4 benzoquinone reductase, a cyclophilin, a glucoamylase, 3 hydrophobins, a lipase, a serine carboxypeptidase, a putative Ran-binding protein, and two unknown putatively secreted proteins called 1 J04 and 2 J12. Significantly down-regulated genes included a manganese-superoxide dismutase, two metalloproteases, and an unknown putatively secreted protein called Ps0058. CONCLUSIONS: This first collection of Phellinus sulphurascens EST sequences and its annotation provide an important resource for future research aimed at understanding key virulence factors of this forest pathogen. We examined the expression patterns of numerous fungal genes with potential roles in virulence, and found a collection of functionally diverse genes that are significantly up- or down-regulated during infection of Douglas-fir seedling roots by P. sulphurascens. PMID- 25030914 TI - Genome-wide mapping of RNA Pol-II promoter usage in mouse tissues by ChIP-seq. AB - Chromatin immunoprecipitation (ChIP), using antibody against RNA Pol-II, followed by massive parallel sequencing (ChIP-seq) are invaluable techniques for genome wide identification of alternative promoters and their patterns of use in different tissues, cell types, and/or developmental stages. However, the identification of promoters cannot be performed solely based on the presence of Pol-II enrichment on a genomic location because of its enrichment throughout the transcribed genomic region and lack of highly specific antibodies that can distinguish promoter-bound Pol-II from elongating Pol-II. In order to overcome this limitation, we developed a combined Pol-II ChIP-seq and bioinformatics promoter prediction approach to identify promoter regions and their activity in different mouse tissues. Here, we describe the integrative approach to identify alternative promoters in the mouse genome. PMID- 25030915 TI - Using native chromatin immunoprecipitation to interrogate histone variant protein deposition in embryonic stem cells. AB - Chromatin immunoprecipitation combined with massive parallel sequencing (ChIP Seq) is a powerful epigenetics technique for interrogating the genome-wide localization of histone modifications, histone variants, and other chromatin associating factors. In brief, chromatin pellets are fractionated from the nuclei, and then fragmented by enzymatic digestion or sonication. Chromatin regions associated with proteins of interest are enriched by immunoprecipitation with specific antibodies. After the immunoprecipitation, DNA fragments are extracted, amplified during sequencing library construction, and sequenced by high-throughput sequencing. Here, we describe the native chromatin immunoprecipitation of a rare histone variant, H2A.X, followed by high-throughput sequencing, in mouse embryonic stem cells. PMID- 25030916 TI - Reduced representation bisulfite sequencing to identify global alteration of DNA methylation. AB - Reduced representation bisulfite sequencing is a cost-effective high-throughput sequencing-based method to obtain DNA methylation status at a single-nucleotide level. DNA methylation status is determined by utilizing DNA methylation-specific restriction enzymes to selectively amplify for genomic regions that are rich in methylated DNA. Although the method is genome-wide, DNA methyl sequencing does not require the sequencing of the whole genome, hence the name "reduced representation." However, a large majority of CpG islands are covered by reduced representation bisulfite sequencing allowing for the acquisition of comprehensive information of the methylation landscape in diseases like cancer. Data generated by this approach is typically reproducible and often covers between 65 and 75 % of the whole genome. PMID- 25030917 TI - A high-throughput microRNA expression profiling system. AB - As small noncoding RNAs, microRNAs (miRNAs) regulate diverse biological functions, including physiological and pathological processes. The expression and deregulation of miRNA levels contain rich information with diagnostic and prognostic relevance and can reflect pharmacological responses. The increasing interest in miRNA-related research demands global miRNA expression profiling on large numbers of samples. We describe here a robust protocol that supports high throughput sample labeling and detection on hundreds of samples simultaneously. This method employs 96-well-based miRNA capturing from total RNA samples and on site biochemical reactions, coupled with bead-based detection in 96-well format for hundreds of miRNAs per sample. With low-cost, high-throughput, high detection specificity, and flexibility to profile both small and large numbers of samples, this protocol can be adapted in a wide range of laboratory settings. PMID- 25030918 TI - Using pooled miR30-shRNA library for cancer lethal and synthetic lethal screens. AB - Pooled shRNA library is a powerful, rapid, and cost-effective technology to carry out functional genomic screens in mammalian cells. This approach has been applied extensively to identify genetic dependencies in cancer cells that might be exploited for therapeutic purposes. In this chapter we provide a detailed protocol for using the Hannon-Elledge miR30-based library to conduct dropout screens in cancer cell lines. This protocol is readily adaptable to other pooled shRNA libraries and should facilitate the functional annotation of the human genome. PMID- 25030919 TI - A diphtheria toxin negative selection in RNA interference screening. AB - RNA interference (RNAi) screening is a powerful technique for understanding the molecular biology of cancer and searching drug targets. Genes and their upstream activators that are essential for the survival of cancer cells often dictate cancer formation/progression. Hence, they are preferable therapeutic targets. Identifying these genes using RNAi is, however, problematic because knocking them down leads to cell death. Here we describe a diphtheria toxin (DT) negative selection method to circumvent the problem of cell death in RNAi screening. DT fails to kill mouse cells due to the lack of functional DT receptor (DTR). Thus, we first prepare a construct encoding a human functional DTR driven by the promoter of mouse Atf5, a gene essential for the survival of malignant glioma. Then a DT-sensitive mouse malignant glioma cell line is established by over expressing this DTR. Finally, an RNAi screen is performed in this cell line and genes that activate Atf5 expression are identified. The negative selection approach described here allows RNAi screening to be used for identifying genes controlling cell survival in cancers or perhaps other human diseases with potential in therapeutic intervention. PMID- 25030920 TI - Cancer metabolism: cross talk between signaling and O-GlcNAcylation. AB - Cancer cells exhibit a unique metabolic shift to aerobic glycolysis that has been exploited diagnostically and therapeutically in the clinic. Oncogenes and tumor suppressors alter signaling pathways that lead to alterations of glycolytic flux. Stemming from glycolysis, the hexosamine biosynthetic pathway leads to elevated posttranslational addition of O-linked-beta-N-acetylglucosamine (O-GlcNAc) on a diverse population of nuclear and cytosolic proteins, many of which regulate signaling pathways. This unit outlines techniques used to detect metabolic alterations in cancer cells, regulation by signaling pathways, and cellular O GlcNAcylation. PMID- 25030921 TI - Targeted genome modification via triple helix formation. AB - Triplex-forming oligonucleotides (TFOs) are capable of coordinating genome modification in a targeted, site-specific manner, causing mutagenesis or even coordinating homologous recombination events. Here, we describe the use of TFOs such as peptide nucleic acids for targeted genome modification. We discuss this method and its applications and describe protocols for TFO design, delivery, and evaluation of activity in vitro and in vivo. PMID- 25030922 TI - Synthesis of stabilized alpha-helical peptides. AB - Stabilized alpha-helical (SAH) peptides are valuable laboratory tools to explore important protein-protein interactions. Whereas most peptides lose their secondary structure when isolated from the host protein, stapled peptides incorporate an all-hydrocarbon "staple" that reinforces their natural alpha helical structure. Thus, stapled peptides retain their functional ability to bind their native protein targets and serve multiple experimental uses. First, they are useful for structural studies such as NMR or crystal structures that map and better define binding sites. Second, they can be used to identify small molecules that specifically target that interaction site. Third, stapled peptides can be used to test the importance of specific amino acid residues or posttranslational modifications to the binding. Fourth, they can serve as structurally competent bait to identify novel binding partners to specific alpha-helical motifs. In addition to markedly improved alpha-helicity, stapled peptides also display resistance to protease cleavage and enhanced cell permeability. Most importantly, they are useful for intracellular experiments that explore the functional consequences of blocking particular protein interactions. Because of their remarkable stability, stapled peptides can be applied to whole-animal, in vivo studies. Here we describe a protocol for the synthesis of a peptide that incorporates an all-hydrocarbon "staple" employing a ring-closing olefin metathesis reaction. With proper optimization, stapled peptides can be a fundamental, accurate laboratory tool in the modern chemical biologist's armory. PMID- 25030923 TI - Arginine-grafted biodegradable polymer: a versatile transfection reagent for both DNA and siRNA. AB - Effective delivery of DNA or siRNA into primary cells demands an efficient delivery system. However, the significant differences in physical and molecular characteristics of the two molecules generally necessitate distinct delivery systems or considerable differences in carrier formulation protocols for effective transfection. Arginine-grafted bioreducible poly (disulfide amine) (ABP) is a redox-sensitive, bioreducible, positively charged polymer which complexes with siRNA and DNA via charge interactions to form nanoplexes. ABP effectively mediates cytoplasmic delivery of both DNA and siRNA into multiple cell types, including primary cells like myoblast, human umbilical vein endothelial cells (HUVECs), and primary rat aorta vascular smooth muscle cells (SMCs) eliciting functional activity. In this chapter, we provide the detailed protocols for the synthesis of ABP as well as transfection of both siRNA and DNA using ABP. PMID- 25030924 TI - Using LacO arrays to monitor DNA double-strand break dynamics in live Schizosaccharomyces pombe cells. AB - LacO arrays, when combined with LacI-GFP, have been a valuable tool for studying nuclear architecture and chromatin dynamics. Here, we outline an experimental approach to employ the LacO/LacI-GFP system in S. pombe to assess DNA double strand break (DSB) dynamics and the contribution of chromatin state to DSB repair. Previously, integration of long, highly repetitive LacO arrays in S. pombe has been a challenge. To address this problem, we have developed a novel approach, based on the principles used for homologous recombination-based genome engineering in higher eukaryotes, to integrate long, repetitive LacO arrays with targeting efficiencies as high as 70 %. Combining this facile LacO/LacI-GFP system with a site-specific, inducible DSB provides a means to monitor DSB dynamics at engineered sites within the genome. PMID- 25030925 TI - Zebrafish as a platform to study tumor progression. AB - The zebrafish has emerged as a powerful model system to study human diseases, including a variety of neoplasms. Principal components that have contributed to the rise in use of this vertebrate model system are its high fecundity, ease of genetic manipulation, and low cost of maintenance. Vital imaging of the zebrafish is possible from the transparent embryonic stage through adulthood, the latter enabled by a number of mutant lines that ablate pigmentation. As a result, high resolution analyses of tumor progression can be accomplished in vivo. Straightforward transgenesis of zebrafish has been employed to develop numerous tumor models that recapitulate many aspects of human neoplastic disease, both in terms of pathologic and molecular conservation. The small size of zebrafish embryos has enabled screens for novel chemotherapeutic agents. Its facile genetics have been exploited in studies that extend beyond modeling cancer to investigations that define new cancer genes and mechanisms of cancer progression. Together, these attributes have established the zebrafish as a robust and versatile model system for investigating cancer. In this chapter we describe methods that are used to study a gene's impact on melanoma progression. We detail methods for making transgenic animals and screening for tumor onset as well as methods to investigate tumor invasion and propagation. PMID- 25030926 TI - Clonal screens to find modifiers of partially penetrant phenotypes in C. elegans. AB - Unbiased genetic screens are an excellent way to discover novel genes involved in specific biological processes in vivo. Modifier screens, whether to suppress or enhance a phenotype, are a powerful way to find proteins that modulate biological processes responsible for specific phenotypes. However, modification of phenotypes that are only partially penetrant, which is often the case, are often extremely difficult to screen this way in a traditional F2 or non-clonal genetic screen. Here we describe an F3 or clonal screen in the nematode Caenorhabditis elegans to search for genes that modify partially penetrant phenotypes. Specifically we describe a screen to search for modifiers of genes that cause defects in migration of a specific developmentally regulated cell, the distal tip cell. PMID- 25030927 TI - Serum profiling using protein microarrays to identify disease related antigens. AB - Disease related antigens are of great importance in the clinic. They are used as markers to screen patients for various forms of cancer, to monitor response to therapy, or to serve as therapeutic targets (Chapman et al., Ann Oncol 18(5):868 873, 2007; Soussi et al., Cancer Res 60:1777-1788, 2000; Anderson and LaBaer, J Proteome Res 4:1123-1133, 2005; Levenson, Biochim Biophy Acta 1770:847-856, 2007). In cancer endogenous levels of protein expression may be disrupted or proteins may be expressed in an aberrant fashion resulting in an immune response that bypasses self tolerance (Soussi et al., Cancer Res 60:1777-1788, 2000; Disis et al., J Clin Oncol 15(11):3363-3367, 1997; Molina et al., Breast Cancer Res Treat 51:109-119, 1998). Protein microarrays, which represent a large fraction of the human proteome, have been used to identify antigens in multiple diseases including cancer (Anderson and LaBaer, J Proteome Res 4:1123-1133, 2005; Disis et al., J Clin Oncol 15(11):3363-3367, 1997; Hudson et al., Proc Natl Acad Sci U S A 104(44):17494-17499, 2007; Beyer et al., J Neuroimmunol 242:26-32, 2012). Typically, arrays are probed with immunoglobulin (Ig) samples from patients as well as healthy controls, then compared to determine which antigens (Ag's) are more reactive within the patient group (Hudson et al., Proc Natl Acad Sci U S A 104(44):17494-17499). PMID- 25030928 TI - Interrogation of in vivo protein-protein interactions using transgenic mouse models and stable isotope labeling. AB - Methods in mass spectrometry have evolved in recent years, facilitating proteomic analyses that were previously beyond the limits of the technology. Transgenic mouse models, coupled with mass spectrometry proteomics, have served as valuable platform for elucidating the in vivo function of individual genes and proteins. Here we discuss the methods we have recently employed to characterize protein protein interactions and posttranslational modifications in tagged knock-in mouse models. These methods can be broadly applied to other systems for various applications in both basic and translational science. PMID- 25030929 TI - New biophysical methods to study the membrane activity of Bcl-2 proteins. AB - The proteins of Bcl-2 family are key regulators of apoptosis. Many Bcl-2 proteins have the unique ability to switch between two possible conformations, soluble in the cytosol or associated to cellular membranes. Importantly, their membrane inserted form is the main responsible for their apoptotic function. Unfortunately, there are only a limited number of methods available to study the membrane activity of these proteins. Here, we present a methodology to study protein binding to membranes and membrane permeabilization at the single vesicle level. It is based on purified proteins and giant unilamellar vesicles and involves directly visualization of the process with a confocal microscope. This approach allows for the characterization of the membrane activity of the Bcl-2 proteins (or of any other pore-forming molecule) with unprecedented detail. PMID- 25030930 TI - Purification of recombinant 2XMBP tagged human proteins from human cells. AB - The ability to purify an intact, functional protein or protein complex is an essential step in biochemical characterization studies. Challenges in purification arise when proteins are of low abundance or are unstable resulting in low yields or poor in vitro activity. In this protocol we describe a method to purify active, recombinant human proteins fused to a tandem MBP tag after expression in human 293T cells. PMID- 25030931 TI - Computational analysis in cancer exome sequencing. AB - Exome sequencing in cancer is a powerful tool for identifying mutational events across the coding region of human genes. Here, we describe computational methods that use exome sequencing reads from cancer samples to identify somatic single nucleotide variants (SNVs), copy number alterations, and short insertions and deletions (InDels). We further describe analytical methods to generate lists of driver genes with more mutational events than expected by chance. PMID- 25030932 TI - Matrix factorization methods for integrative cancer genomics. AB - With the rapid development of high-throughput sequencing technologies, many groups are generating multi-platform genomic profiles (e.g., DNA methylation and gene expression) for their biological samples. This activity has generated a huge number of so-called "multidimensional genomic datasets," providing unique opportunities and challenges to study coordination among different regulatory levels and discover underlying combinatorial patterns of cellular systems. We summarize a matrix factorization framework to address the challenge of integrating multiple genomic datasets, as well as a semi-supervised variant of the method that can incorporate prior knowledge. The basic idea is to project the different kinds of genomic data onto a common coordinate system, wherein genetic variables that are strongly correlated in a subset of samples form a multidimensional module. In the context of cancer biology, such modules reveal perturbed pathways and clinically distinct patient subgroups that would have been overlooked with only a single type of data. In summary, the matrix factorization framework can uncover associations between distinct layers of cellular activity and explain their biological implications in multidimensional data. PMID- 25030933 TI - Computational methods for DNA copy-number analysis of tumors. AB - Study of DNA copy-number variation is a key part of cancer genomics. With the help of a comprehensive multistep computational procedure described here, copy number profiles of tumor tissues or individual tumor cells may be generated and interpreted, starting with data acquired by next-generation sequencing. Several of the methods presented are specifically designed to handle cancer-related copy number profiles. These include accounting for variation of ploidy and distilling somatic copy number alterations from the inherited background. PMID- 25030935 TI - Cavitation: a blessing in disguise? New method to establish vulnerability curves and assess hydraulic capacitance of woody tissues. AB - The hydraulic performance of woody species during drought is currently of high interest in the context of climate change. It is known that woody species have the capacity to mitigate water shortage by using internally stored water. Elastic shrinkage of living cells and also water release during cavitation contribute to the so-called 'hydraulic capacitance' (C) of the plant, which adds water to the transpiration stream and buffers fluctuations in water potential. Although sap conducting conduits may ultimately serve as a water pool, cavitation will hamper the conduction of sap. Both hydraulic conductivity and C are thus inextricably linked and the interaction between both should be studied to better understand hydraulic functioning of woody species during drought. However, measurements of C are scarce and no distinction is usually made between C from elastic storage and C supplied by cavitation. In this paper, we propose a new method to assess both the decrease in hydraulic conductivity and the change in C during bench dehydration of a whole-branch segment using continuous measurements of acoustic emissions, radial diameter shrinkage and gravimetrical water loss. With this method we could establish proper vulnerability curves for grapevine (Vitis vinifera L. 'Johanniter') and quantify C during dehydration. Our results showed that loss in hydraulic conductivity during the cavitation phase was accompanied by 22-92% gain in hydraulic capacitance; therefore, a certain degree of cavitation may be tolerated in grapevine during periods of drought stress. PMID- 25030934 TI - On the causes of rising gross ecosystem productivity in a regenerating clearcut environment: leaf area vs. species composition. AB - Clearcutting a forest ecosystem can result in a drastic reduction of stand productivity. Despite the severity of this disturbance type, past studies have found that the productivity of young regenerating stands can quickly rebound, approaching that of mature undisturbed stands within a few years. One of the obvious reasons is increased leaf area (LA) with each year of recovery. However, a less obvious reason may be the variability in species composition and distribution during the natural regeneration process. The purpose of this study was to investigate to what extent the increase in gross ecosystem productivity (GEP), observed during the first 4 years of recovery in a naturally regenerating clearcut stand, was due to (i) an overall expansion of leaf area and (ii) an increase in the canopy's photosynthetic capacity stemming from either species compositional shifts or drift in physiological traits within species. We found that the multi-year rise in GEP following harvest was clearly attributed to the expansion of LA rather than a change in vegetation composition. Sizeable changes in the relative abundance of species were masked by remarkably similar leaf physiological attributes for a range of vegetation types present in this early successional environment. Comparison of upscaled leaf-chamber estimates with eddy covariance-based estimates of light-response curves revealed a broad consistency in both maximum photosynthetic capacity and quantum yield efficiency. The approaches presented here illustrate how chamber- and ecosystem-scale measurements of gas exchange can be blended with species-level LA data to draw conclusive inferences about changes in ecosystem processes over time in a highly dynamic environment. PMID- 25030936 TI - Role of hydraulic and chemical signals in leaves, stems and roots in the stomatal behaviour of olive trees under water stress and recovery conditions. AB - The control of plant transpiration by stomata under water stress and recovery conditions is of paramount importance for plant performance and survival. Although both chemical and hydraulic signals emitted within a plant are considered to play a major role in controlling stomatal dynamics, they have rarely been assessed together. The aims of this study were to evaluate (i) the dynamics of chemical and hydraulic signals at leaf, stem and root level, and (ii) their effect on the regulation of stomatal conductance (gs) during water stress and recovery. Measurements of gs, water potential, abscisic acid (ABA) content and loss of hydraulic functioning at leaf, stem and root level were conducted during a water stress and recovery period imposed on 1-year-old olive plants (Olea europaea L.). Results showed a strong hydraulic segmentation in olive plants, with higher hydraulic functioning losses in roots and leaves than in stems. The dynamics of hydraulic conductance of roots and leaves observed as water stress developed could explain both a protection of the hydraulic functionality of larger organs of the plant (i.e., branches, etc.) and a role in the down-regulation of gs. On the other hand, ABA also increased, showing a similar pattern to gs dynamics, and thus its effect on gs in response to water stress cannot be ruled out. However, neither hydraulic nor non-hydraulic factors were able to explain the delay in the full recovery of gs after soil water availability was restored. PMID- 25030937 TI - Elevated levels of D-dimers increase the risk of ischaemic and haemorrhagic stroke. Findings from the EPICOR Study. AB - Elevated D-dimer levels are reportedly associated with coronary artery disease. It was the study objective to investigate the association of baseline D-dimer levels with strokes that occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Using a nested case-cohort design, a centre- stratified sample of 832 subjects (66 % women, age 35-71) was selected as subcohort and compared with 289 strokes in a mean follow-up of nine years. D dimers were measured by an automated latex-enhanced immunoassay (HemosIL-IL). The multivariable hazard ratios were estimated by a Cox regression model using Prentice method. Individuals with elevated D-dimer levels had significantly higher risk of incident stroke. It was evident from the second quartile (D-dimers > 100 ng/ml) and persisted almost unchanged for higher D-dimers (hazard ratio [HR] 2.10, 95 % confidence interval [CI]: 1.28-3.47; 2.42, 95 %CI: 1.44-4.09 and 2.10, 95 %CI: 1.27-3.48 for the second, third or fourth quartile compared with the lowest quartile, respectively). The association was independent of several confounders, including triglycerides and C-reactive protein. No differences were observed in men and women (P for interaction=0.46), in hypertensive or non hypertensive subjects (P for interaction=0.88) or in subjects with low (< 1 mg/l) or elevated (>= 1 mg/l) C-reactive protein (P for interaction=0.35). After stratification for stroke type, the hazard ratio for every standard deviation increase was statistically significant both for ischaemic (1.21; 95 %CI: 1.01 to 1.45) and haemorrhagic (1.24; 95 %CI: 1.00 to 1.65) strokes. In conclusion, our data provide clear evidence that elevated levels of D-dimers are potential risk factors not only for ischaemic but also for haemorrhagic strokes. PMID- 25030938 TI - Developing a palliative care service model for Muslim Middle Eastern countries. AB - PURPOSE: Palliative Care (PC) was first introduced to Muslim Middle Eastern (MME) countries in 1992, but growth of PC has been slow and access to PC is still limited in the region. While most PC models have been developed in Western countries, MME societies have different cultural and religious values that are not incorporated in Western models. We conducted a qualitative study to look at these differences, in order to inform a culturally acceptable model of PC that meets the needs of MME patients and their families. METHODS: We conducted semi structured interviews of PC physicians and nurses with experience in both Western and MME countries. Participants were identified by snowball sampling. Interviews were transcribed and analyzed using a modified grounded-theory approach. RESULTS: We achieved conceptual saturation after 13 interviews. Participants identified four differences between PC practice in Western and MME countries including: cultural differences, legal and policy differences, stances on PC philosophy, and the availability of resources and support for PC. Participants identified five barriers to advancing PC in the MME: shortage of resources, unclear laws and policies, healthcare system barriers, unfamiliarity with the role and benefits of PC, and cultural barriers. Respondents suggested many facilitators at the institutional, regional, and societal levels. CONCLUSIONS: We identified a number of important differences in PC practice, as well as common barriers and facilitators for developing PC services in MME countries. This information can help clinicians who are developing PC services in a MME country. PMID- 25030939 TI - Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism. AB - Pramlintide (Symlin(r)), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity. PMID- 25030940 TI - Comparative effectiveness research of chronic hepatitis B and C cohort study (CHeCS): improving data collection and cohort identification. AB - BACKGROUND AND AIMS: The Chronic Hepatitis Cohort Study (CHeCS) is a longitudinal observational study of risks and benefits of treatments and care in patients with chronic hepatitis B (HBV) and C (HCV) infection from four US health systems. We hypothesized that comparative effectiveness methods-including a centralized data management system and an adaptive approach for cohort selection-would improve cohort selection while controlling data quality and reducing the cost. METHODS: Cohort selection and data collection were performed primarily via the electronic health record (EHR); cases were confirmed via chart abstraction. Two parallel sources fed data to a centralized data management system: direct EHR data collection with common data elements, and chart abstraction via electronic data capture. An adaptive Classification and Regression Tree (CART) identified a set of electronic variables to improve case ascertainment accuracy. RESULTS: Over 16 million patient records were collected on 23 case report forms in 2006-2008. The vast majority of data (99.2%) were collected electronically from EHR; only 0.8% was collected via chart abstraction. Initial electronic criteria identified 12,144 chronic hepatitis patients; 10,098 were confirmed via chart abstraction with positive predictive values (PPV) 79 and 83% for HBV and HCV, respectively. CART-optimized models significantly increased PPV to 88 for HBV and 95% for HCV. CONCLUSIONS: CHeCS is a comparative effectiveness research project that leverages electronic centralized data collection and adaptive cohort identification approaches to enhance study efficiency. The adaptive CART model significantly improved the positive predictive value of cohort identification methods. PMID- 25030941 TI - Ethnic disparities in gastric cancer incidence and survival in the USA: an updated analysis of 1992-2009 SEER data. AB - BACKGROUND: Gastric cancer (GC) is the second-leading cause of cancer-related deaths worldwide, with overall 5-year survival less than 20%. However, limited data exist investigating ethnic disparities in stage-specific GC incidence and survival in the USA. AIM: To evaluate ethnicity-specific differences in GC incidence and survival in the USA. METHODS: Using data from the surveillance, epidemiology, and end results 1992-2009 population-based cancer registry, we evaluated ethnic disparities in GC incidence stratified by year of diagnosis, cancer stage at presentation, and geographical distribution of disease. Ethnic disparities in survival were evaluated using Kaplan-Meier and multivariate Cox proportional hazards models. RESULTS: Among men and women combined and among all cancer stages, Asians had the highest incidence of GC, more than double that among Whites (15.6 vs. 7.4 per 100,000/year, p < 0.005). In addition, Asians had the highest survival of all race groups (3-year survival: 26.6%, p < 0.001). Compared with Whites, Blacks (12.8 vs. 7.4 per 100,000/year, p < 0.005) and Hispanics (12.9 vs. 7.4 per 100,000/year, p < 0.005) also had significantly higher incidence of GC. Multivariate Cox models (adjusted for age, year of diagnosis, sex, race/ethnicity, stage of disease, and treatment received) demonstrated significantly higher survival in Asians compared with Whites (HR 0.82, 95% CI 0.80-0.85, p < 0.04). CONCLUSIONS: Racial/ethnic disparities in GC incidence and survival exist in the USA Asians have the highest incidence of GC and the highest overall survival. Outlining high-risk groups may inform potential screening practices and physician awareness for GC. PMID- 25030942 TI - Risk factors for serrated polyps of the colorectum. AB - Serrated pathway polyps are a relatively new area of interest in the field of colorectal cancer screening and prevention. Akin to conventional adenomas, some serrated polyps (SPs) have the potential to develop into malignant serrated neoplasms, yet little is known regarding risk factors for these lesions. Early epidemiological studies of hyperplastic polyps were performed without knowledge of the serrated pathway and likely included a mixture of SPs. More recently, studies have specifically evaluated premalignant SPs, such as the sessile serrated adenoma (SSA) or surrogates for these polyps such as large or proximally located SPs. SPs share some risk factors with conventional adenomas and have been associated with tobacco use, obesity, and age. Nonsteroidal anti-inflammatory drug (NSAID) use, fiber, folic acid, and calcium have been associated with reduced risk of SPs. Studies focused on SSAs specifically have reported associations with age, female sex, smoking, obesity, diabetes, and possibly diets high in fat, carbohydrates, and calories. Higher education has also been associated with risk of SSAs, while an inverse association between NSAID use and SSAs has been reported. Risk factors for traditional serrated adenomas are largely unknown. Studies are largely limited by varying inclusion criteria, as well as differences in pathological classification schemes. Further epidemiological studies of SPs are needed to aid in risk stratification and screening, and etiological research. PMID- 25030943 TI - Effect of diclofenac on the levels of lipoxin A4 and Resolvin D1 and E1 in the post-ERCP pancreatitis. AB - OBJECTIVES: Acute pancreatitis is one of the most common complications of endoscopic retrograde cholangiopancreatography (ERCP). Numerous studies have shown that administered nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the incidence of acute pancreatitis after ERCP. Little is known, however, about the mechanism of NSAIDs in preventing pancreatitis (PEP). METHODS: In this study, we assigned patients to receive a single dose of intramuscular diclofenac 75 mg immediately after ERCP (diclofenac group) or without (control group). The primary outcome measure was the occurrence of PEP. The serum amylase levels were measured before ERCP and at 3 and 24 h post-procedure in all patients. The Lipoxin A4 (LXA4), Resolvin D1 (Rvd1), and Resolvin E1 (RvE1) levels were measured before ERCP, and 3 and 24 h after the procedure in 30 patients from the diclofenac group and 30 patients from the control group. RESULTS: A total of 120 patients were enrolled and completed the follow-up. The overall incidence of PEP was 13.3% (16/120). It occurred in four of 60 patients (6.67%) in the diclofenac group and in 12 of 60 patients (20.00%) in the control group (p = 0.032). The LxA4, RvD1, and RvE1 levels in the diclofenac group at 3 h after ERCP were significantly increased compared with before ERCP (p < 0.05). Compared with the control group, the LxA4, RvD1, and RvE1 levels in the diclofenac group at 3 and 24 h after ERCP were significantly increased (p < 0.05). CONCLUSIONS: Intramuscular diclofenac after ERCP can reduce the incidence of PEP. This may be related to the fact that diclofenac can increase the levels of LxA4, RvD1, and RvE1. PMID- 25030944 TI - Which patients have greatest need for elvitegravir/cobicistat/ emtricitabine/tenofovirDF-based therapy? AB - Elvitegravir/cobicistat/emtricitabine/tenofovirDF (EVG/COBI/FTC/TDF) is the new single-tablet, fixed-dose formulation containing an integrase strand transfer inhibitor recently approved as antiretroviral treatment. In this paper we analysed its use and advantages in naive and experienced HIV-infected patients and we focused on special populations in which EVG/COBI/FTC/TDF could be a suitable option. Furthermore the manuscript reports the recent patent of EVG which may have an influence on the management of HIV-infected patients in the next future. PMID- 25030945 TI - Melanotic neuroectodermal tumor of infancy: a wolf in sheep's clothing. AB - INTRODUCTION: The melanotic neuroectodermal tumor of infancy (MNTI) is an exceptionally rare neoplasm. Despite their potential for local invasion, MNTI are considered benign neoplasms. Sporadic cases have been reported of MNTI acting in a malignant fashion; however, the majority of these tumors were of extragnathic origin. METHODS: A 2-month-old male presented with a rapidly expanding maxillary mass. The patient underwent excisional biopsy of the mass and a diagnosis of MNTI was returned. Tumor recurrence was appreciated postoperatively. Neoadjuvant chemotherapy was initiated to render it more amenable to surgical resection. Chemotherapy was suspended prematurely and the patient returned to the operating room for hemimaxillectomy. The postchemotherapy surgical pathology report demonstrated a unique mixed chemotherapy response. DISCUSSION: This report highlights the aggressive nature of gnathic MNTI, the importance of early diagnosis and definitive intervention, and the mixed clinical and histologic response of the lesion to neoadjuvant chemotherapy. PMID- 25030946 TI - Validity and reliability of Seattle angina questionnaire Japanese version in patients with coronary artery disease. AB - PURPOSE: The aim of this study was to evaluate the validity and reliability of the Seattle Angina Questionnaire, Japanese version (SAQ-J) as a disease-specific health outcome scale in patients with coronary artery disease. METHODS: Patients with coronary artery disease were recruited from a university hospital in Tokyo. The patients completed self-administered questionnaires, and medical information was obtained from the subjects' medical records. Face validity, concurrent validity evaluated using Short Form 36 (SF-36), known group differences, internal consistency, and test-retest reliability were statistically analyzed. RESULTS: A total of 354 patients gave informed consent, and 331 of them responded (93.5%). The concurrent validity was mostly supported by the pattern of association between SAQ-J and SF-36. The patients without chest symptoms showed significantly higher SAQ-J scores than did the patients with chest symptoms in 4 domains. Cronbach's alpha ranged from .51 to .96, meaning that internal consistency was confirmed to a certain extent. The intraclass correlation coefficient of most domains was higher than the recommended value of 0.70. The weighted kappa ranged from .24 to .57, and it was greater than .4 for 14 of the 19 items. CONCLUSIONS: The SAQ-J could be a valid and reliable disease-specific scale in some part for measuring health outcomes in patients with coronary artery disease, and requires cautious use. PMID- 25030947 TI - Factors related to performance of health practices among asian adolescents in the United States. AB - PURPOSE: This study examined factors related to positive health practices (PHP) among Asian adolescents. More specifically, it tested theoretical relationships postulated between PHP and social support, optimism, self-esteem, loneliness, and acculturation in this population. METHOD: A correlational research design was used and a convenience sample of 151 Asian adolescents was obtained. Participants completed a demographic sheet and six study instruments. RESULTS: Significant positive relationships were found between reported performance of PHP and social support, optimism, self-esteem, and acculturation. A significant inverse relationship was found between loneliness and PHP. CONCLUSIONS: Study findings extend existing knowledge and contribute to a more comprehensive knowledge base regarding health practices among Asian adolescents. Having this knowledge base provides practitioners with a better understanding of the factors related to health practices in Asian adolescents and assists them in developing culturally sensitive interventions aimed at promoting PHP in this population. PMID- 25030948 TI - Child rearing experiences of foreign wives married to korean husbands. AB - PURPOSE: This study was conducted to explore the child rearing experience and associated issues of foreign women married to Korean men. METHODS: Eleven foreign women married to Korean men were selected by a purposive and snowball sampling method. Data were collected during the period from May to August, 2007 by a semi structured interview guide. Transcribed interview data were analyzed using Giorgi's step of phenomenological analysis. RESULTS: The findings revealed six major themes and relevant subthemes: (a) having motherhood, (b) struggling with obstacles, (c) getting lost, (d) finding ways, (e) harvesting; and (f) looking into the future. CONCLUSIONS: The participants were experiencing multiple acculturative stressors which negatively affected their capacity for rearing children. However, when they had appropriate support, they were able to achieve many successes. Moreover, they were self-directed and making their best efforts to realize their dreams. This study contributed to the limited knowledge on immigrant women's child rearing experiences. It supported the need for comprehensive community programs that meet a variety of needs for this population and the need for public education. PMID- 25030949 TI - Effectiveness of an education program to reduce negative attitudes toward persons with mental illness using online media. AB - PURPOSE: The purpose of this study was to develop an educational program to reduce negative attitudes toward persons with mental illness (PMIs) using online media and to test its effectiveness. METHODS: A nonequivalent control group with a pre-posttest was employed in this study. A total of 143 lay people were enrolled. The study variables were knowledge and attitudes about mental illness, and social distance. The four domains of attitudes were authoritarianism, benevolence, social restrictiveness and community mental health ideology. RESULTS: Phase 1: In an attempt to develop an educational program, the researcher conducted interviews with lay people and families of PMIs, and reviewed the pertinent literature. Three mental health professionals were consulted after developing the program. The program consisted of eight sessions. Phase 2: Community mental health ideology differed significantly between groups after the experiment. Knowledge tended to increase in the experimental group, while social restrictiveness showed a tendency to decrease. However, the changes were not significant in either case. Authoritarianism, benevolence, and social distance were not significantly different between groups. There was a significant difference in the pattern of change over time for both groups regarding authoritarianism, benevolence, and social restrictiveness. CONCLUSIONS: The program developed here was partially effective at changing negative attitudes. The online video program can be used by community mental health nurses to enhance general knowledge and help reduce stigma. PMID- 25030950 TI - Adequacy of nutritional support and reasons for underfeeding in neurosurgical intensive care unit patients. AB - PURPOSE: The purpose of the study was to identify the adequacy of enteral feeding, and the reason and prevalence of under-nutrition, and to determine the relationships between caloric intake and resulting nutritional parameters among neurosurgical intensive care unit (ICU) patients. METHODS: The participants for this descriptive study were 47 neurosurgical ICU patients who had enteral feeding initiated after ICU admission. Data were collected from the initial day of enteral feeding for 7 days. Data related to enteral feeding, feeding interruptions or delay, prealbumin, and transferrin were collected. RESULTS: The mean age of the participants was 56.62 years. Twenty-six patients did not receive their feeding formula more than once during 7 days, and 11 had interruptions more than 6 times. The mean number of feeding interruptions was 3.23 (SD = 4.47). On the average, only 76.44% of the estimated energy requirement was provided by enteral feeding to the patients. The frequency of underfeeding was 52.17% with respect to enteral feeding. The most frequent reason for the feeding interruption was observation before and after intubation and extubation, which was unavoidable. The next most common reason was gastrointestinal bleeding, mostly due to old clots or trace, followed by residual volume less than 100 mL. Changes in prealbumin and transferrin levels for 7 days between the underfed and adequately fed groups were not statistically significant. CONCLUSION: The management of enteral feeding by nurses was overprotective because of the unpredictable nature of ICU patients in terms of their underlying disease process. The management of feeding intolerance needs to be evidence-based and nurses must consistently follow the protocol that has been supported as a useful measure. PMID- 25030951 TI - Evaluation of intrafraction motion of the organs at risk in image-based brachytherapy of cervical cancer. AB - PURPOSE/INTRODUCTION: To assess the variation in the doses received by the organs at risk (OARs) that can occur during treatment planning of cervical cancer by image-based brachytherapy. METHODS AND MATERIALS: After intracavitary application, two sets of images-CT and MRI-were obtained. The two sets of images were fused together with respect to the applicator. Contouring was done separately on CT and MR images. Dose received by the OARs on CT images with respect to the plans made on the MR images was estimated and compared with those on the MR images. RESULTS: Although there was always a difference between the dose received by the OARs based on the CT and MRI contours, it was not significant for the bladder and rectum; 2 cc doses differed by 0.49 Gy (+/-0.44) p = 0.28 for the bladder and 0.30 Gy (+/-0.29) p = 0.16 for the rectum. The 1 cc and 0.1 cc differences were also not significant. However for the sigmoid colon, there was significant intrafraction variation in the 2 cc doses 0.61 (+/-0.6) p = 0.001, 1 cc doses 0.73 (+/-0.67) Gy p = 0.00, and 0.1 cc dose 0.97 (+/-0.93) Gy p = 0.009. CONCLUSIONS: The variation in the doses to the OARs must be considered while weighing target coverage against overdose to the OARs. Although not significant for the bladder and rectum, it was significant for the sigmoid colon. Estimated doses to OARs on the planning system may not be the same dose delivered at the time of treatment. PMID- 25030952 TI - Cancer: pathological nuclear reprogramming? AB - The ability of stem cells to self-renew and generate different lineages during development and organogenesis is a fundamental, tightly controlled, and generally unidirectional process, whereas the 'immortality' of cancer cells could be regarded as pathological self-renewal. The molecular mechanisms that underpin the generation of induced pluripotent stem cells are remarkably similar to those that are deregulated in cancer - so much so that aberrant reprogramming is tumorigenic. The similarities also suggest that mutations in genes implicated in DNA methylation dynamics might represent a hallmark of cancers with a stem cell origin, and they highlight an alternative view of cancer that may be of clinical benefit. PMID- 25030954 TI - Recovery of normal esophageal function in a kitten with diffuse megaesophagus and an occult lower esophageal stricture. AB - An 8-week-old male domestic shorthair was presented to the Internal Medicine Service at North Carolina State University for regurgitation. Radiographic diagnosis of generalized esophageal dilation and failure of esophageal peristalsis were compatible with diagnosis of congenital megaesophagus. Endoscopic examination of the esophagus revealed a fibrous stricture just orad to the lower esophageal sphincter. Conservative management to increase the body condition and size of the kitten consisted of feeding through a gastrostomy tube, during which time the esophagus regained normal peristaltic function, the stricture orifice widened in size and successful balloon dilatation of the stricture was performed. Esophageal endoscopy should be considered to rule out a stricture near the lower esophageal sphincter in kittens with radiographic findings suggestive of congenital megaesophagus. Management of such kittens by means of gastrostomy tube feeding may be associated with a return of normal esophageal motility and widening of the esophageal stricture, and facilitate subsequent success of interventional dilation of the esophageal stricture. PMID- 25030955 TI - Factors affecting urine specific gravity in apparently healthy cats presenting to first opinion practice for routine evaluation. AB - Evidence suggests that apparently healthy cats presenting for routine evaluation should have a randomly sampled urine specific gravity (USG) >1.035. A USG <1.035 might reflect inappropriate concentrating ability warranting further investigation. We measured the USG of 1040 apparently healthy cats presenting to first opinion practice in an observational study, using either in-clinic refractometers or measurements provided by reference laboratories, and examined factors that might affect USG. In-clinic refractometers were calibrated using distilled water (specific gravity = 1.000). The USG was >1.030 in 91% of cats and >1.035 in 88% of cats; 121 adult cats (?6 months old) and five young cats (<6 months old) had USGs of <1.035. Of these 126 cats, a pathological cause was identified in 27 adult cats - of these, 26 were >9 years old - but no young cats. No cause was identified in 43 adult cats, and further investigation was not pursued in 51 adult cats. Factors that affected USG included age, diet type, sex, fasting status, drinking avidity, refractometer type, and the interaction between sex and diet - increasing dietary moisture content lowered USG only in female cats. Most factors minimally affected USG. The odds of having a USG <1.035 without apparent pathology included age and dietary moisture content. Drinking avidity decreased with increasing dietary moisture content. Our results show that most apparently healthy cats presenting to first-opinion practice should have a USG >1.035. Dietary management strategies to lower USG might be less effective than anticipated, and warrant monitoring of USG to determine efficacy. Older cats with USG <1.035 are more likely to have pathological causes identified, although clinicians are more likely to examine these cats for possible pathology. A lack of stringent refractometer calibration could have caused some errors in estimates of USG by some observers, but would be unlikely to alter markedly the findings. PMID- 25030956 TI - [Interdisciplinary treatment of osteosarcomas: Part II]. PMID- 25030953 TI - Inside and out: the activities of senescence in cancer. AB - The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy. PMID- 25030957 TI - [Pathological fractures due to malignant bone tumors]. AB - BACKGROUND: Malignant bone tumors should be treated within interdisciplinary treatment concepts. The prognosis of pathological fractures is on the whole relatively poor because the fracture is indicative of a large and highly aggressive tumor and the hematoma associated with the fracture could possibly result in spreading of the tumor into the surrounding soft tissues. OBJECTIVES: This article summarizes the current interdisciplinary treatment concepts under special consideration of pathological fractures in primary bone tumors. METHODS: A selective literature search was carried out taking own experience into consideration. RESULTS: Due to the multimodal therapy approach for osteosarcoma and Ewing's sarcoma, the 5-year survival rate could be increased to 60-70 %. CONCLUSION: The therapeutic treatment should always be carried out within the framework of an interdisciplinary, oncological bone expert team, especially in cases of pathological fractures of malignant bone tumors. PMID- 25030958 TI - [Resection margins in bone tumors: what is adequate?]. AB - BACKGROUND: In multimodal therapy concepts for bone sarcomas, tumor resection is a deciding factor. Modern imaging techniques have made preoperative resection planning much easier and precisely allow tumor boundaries to be defined. OBJECTIVES: There is recent data clearly showing that compartmental resections have no significant advantages compared to wide resections in terms of local recurrence or overall survival. But it remains unclear, how "wide" a "wide resection" should be done. MATERIALS AND METHODS: A literature review of the last 15 years, discussion of review articles and multidisciplinary expert opinions as published in major multinational studies. RESULTS: Intralesional resection (R1) is feasible in highly differentiated (G1) chondrosarcoma (atypical cartilaginous tumor) of the extremity. In both osteosarcoma and Ewing's sarcoma, R0 resection is mandatory. If these fails, there is evidence that in selected cases of osteosarcoma, adjuvant radiotherapy is justified if a second resection is not possible. Expecting contaminated (R1) margins in patients with Ewing's sarcoma (e.g., in critical locations such as the pelvis), radiotherapy only is better than hoping for the "cure" of insufficient resections margins with a combination of both methods. With regard to the necessary safety distances for a R0 resection, recommendations from the literature are heterogeneous. In addition to the distance measurement, the quality of the anatomic resection margins (e.g., fascia) is of great importance. A distinct recommendation of at least x millimeters or centimeters cannot be given based on the currently available data. CONCLUSION: The aim of the resection of a bone sarcoma should be a wide margin with the exception of chondrosarcoma (G1). Ultraradical resections which sacrifice vital structures in order to extend an already wide (R0) resection margin showed no significant benefits. In patients with osteosarcoma, adjuvant radiotherapy should be considered if resection or re-resection is not in sound tissue (R1). Patients with Ewing's sarcoma should not undergo resection if a contaminated margin is expected. In patients with chondrosarcoma, the available data as for example from pelvic tumors are contradictory and do not allow a clear recommendation. PMID- 25030959 TI - [Bone defect reconstruction in bone sarcoma surgery: tumour endoprosthesis versus biological reconstruction]. AB - BACKGROUND: Primary bone sarcomas typically arise in the long bones and the pelvis of children and adolescence but may also occur in adults. Meta/diaphysial tumour involvement resulting in the necessity of a joint replacement is more common than diaphysial tumour sites. AIM: In the treatment of these tumours, both endoprosthetic replacement and biological reconstruction techniques are used. Each technique has method-specific advantages and disadvantages. RESULTS: To choose the appropriate surgical method, a multitude of influencing parameters need to be considered. The age at treatment (soft tissue situation/estimated growth/biological potential of the bone), therapeutic concept (palliative vs. curative), the tumour site (upper/lower extremity), tumour expansion (diaphysis/metaphysis) and oncological treatment concept (chemotherapy/radiotherapy) are key factors significantly influencing the surgical technique in terms of functional outcome and longevity of the reconstruction. CONCLUSION: Surgical treatment of bone sarcoma requires broad based experience of the oncological surgeon. Knowledge of the different surgical technics and reconstruction methods is decisive to offer the individual patient the best oncological and functional outcome. PMID- 25030960 TI - [Management of complications in megaprostheses]. AB - BACKGROUND: Megaprostheses are frequently used after segmental resection of bone sarcomas, bone metastases, and in large osseous defects in revision arthroplasty. OBJECTIVES: The incidence of the most common complications associated the use of megaprostheses are reported. The management of complications including therapeutic recommendations are described. MATERIALS AND METHODS: The current knowledge and our own experience of complication management with the use of megaprostheses are presented. RESULTS: Prospective, randomized studies or meta analyses on this topic are lacking. An analysis of the literature shows that beside the occurrence of a local recurrence, periprosthetic infection remains the most serious complication. Two-stage revision remains the gold standard, but a single-stage exchange of the prosthesis without removing the stems might be possible in selected cases. Infection is associated with a higher risk of secondary amputation. In contrast, mechanical failures (e.g., wear of the bushings in knee replacements and aseptic loosening of the stems) can be treated more easily. Dislocation of a proximal femur replacement can mostly be prevented by using bi- or tripolar cups. CONCLUSIONS: Complications with the use of megaprostheses can be successfully treated by revision surgery in most cases. PMID- 25030961 TI - [Acute extremity compartment syndrome: current concepts in diagnostics and therapy]. AB - Acute compartment syndrome of the upper and lower limbs is observed following trauma, reperfusion or as an intraoperative complication caused by positioning. The pathophysiology of the disorder has been extensively described and is well known as a loss of perfusion due to rising compartmental pressures. It is a serious and potentially limb- and life-threatening complication. Early diagnosis is made primarily based on clinical findings. Early and focused therapy is crucial to prevent the devastating complications of this acute condition. However, diagnosis can be difficult, particularly in unconscious patients. Thus, in uncertain cases, pressure measurements are essential. Dermato-fasciotomy is the routine method to decompress the compartmental space. This review article examines the clinical findings, diagnostic techniques, and management options for the patient with musculoskeletal injuries. PMID- 25030962 TI - Systemically available bone morphogenetic protein two and seven affect bone metabolism. AB - PURPOSE: Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones. METHODS: Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies. RESULTS: TPTx resulted in bone loss, which was restored by systemic administration of 10-70 MUg/kg of BMP-2 and 10-250 MUg/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts. CONCLUSIONS: Surprisingly, both BMP 2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss. PMID- 25030963 TI - Outcome of Birmingham hip resurfacing at ten years: role of routine whole blood metal ion measurements in screening for pseudotumours. AB - PURPOSE: Emerging concern has arisen because of recent papers reporting a high prevalence of pseudotumours (PTs), even in patients with surface arthroplasties with a good clinical track record. The aim of our study was to establish the ten year survivorship of Birmingham hip resurfacing (BHR), to investigate whole blood (WB) metal ion levels and prevalence of adverse reactions to metal debris (ARMeD) and to determine the association of blood metal ion levels and symptoms with ARMeD in patients operated on with BHR at our institution. METHODS: Between May 2001 and May 2004, 261 consecutive BHRs were implanted in 219 patients. All living, nonrevised patients underwent a systematic screening programme consisting of clinical examination, WB cobalt and chromium measurements and targeted cross sectional imaging. RESULTS: The ten year survival for the entire cohort was 91% (89-93%), with any revision as the endpoint. Prevalence of ARMeD was 6.9% in male and 8.8% in female patients. Symptomatic patients with elevated metal ion levels evinced highest prevalence (63%) of PTs compared with asymptomatic patients with elevated metal ion levels (42%) and symptomatic patients with nonelevated metal ions (11%). CONCLUSIONS: Contradicting the current international guidelines, our results suggest that it seems beneficial to combine routine metal ion measurement with clinical assessment, even in patients with well-functioning BHRs. Further follow-up will reveal whether new PTs will develop in these patients and BHR survivorship in the longer term. PMID- 25030964 TI - Simulated microgravity affects chondrogenesis and hypertrophy of human mesenchymal stem cells. AB - PURPOSE: During in vitro chondrogenesis of human mesenchymal stem cells (hMSCs) hypertrophy is an inadvertent event associated with cell differentiation toward the osteogenic lineage. Up to now, there is no stringent experimental control mechanism to prevent hypertrophy of MSCs. Microgravity is known to have an impact on osteogenesis. In this study, the influence of simulated microgravity (SMG) on both chondrogenesis and hypertrophy of hMSCs was evaluated. METHODS: A bioreactor using a rotating wall vessel was constructed to simulate microgravity. Pellet cultures formed from hMSCs (P5) were supplemented with human transforming growth factor-beta3 (TGF-beta3). The hMSC pellet cultures treated with TGF-beta3 were either kept in SMG or in a control system. After three weeks of culture, the chondrogenic differentiation status and level of hypertrophy were examined by safranin-O staining, immunohistochemistry and quantitative real-time PCR. RESULTS: SMG reduced the staining for safranin-O and collagen type II. The expression of collagen type X alpha1 chain (COL10A1) and collagen type II alpha1 chain (COL2A1) were both significantly reduced. There was a higher decrease in COL2A1 than in COL10A1 expression, resulting in a low COL2A1/COL10A1 ratio. CONCLUSIONS: SMG reduced hypertrophy of hMSCs during chondrogenic differentiation. However, the expression of COL2A1 was likewise reduced. Even more, the COL2A1/COL10A1 ratio decreased under SMG conditions. We therefore assume that SMG has a significant impact on the chondrogenic differentiation of hMSCs. However, due to the high COL2A1 suppression under SMG, this culture system does not yet seem to be suitable for a potential application in cartilage repair. PMID- 25030965 TI - Cementless bilateral synchronous total hip arthroplasty in ankylosing spondylitis with hip ankylosis. AB - PURPOSE: This study was a retrospective analysis of early and mid-term clinical effects and perioperative management of cementless bilateral synchronous total hip arthroplasty (THA) in patients with ankylosing spondylitis (AS) with bilateral hip ankylosis. METHODS: Fifteen AS patients (30 hips) with bilateral hip ankylosis were managed with cementless bilateral synchronous THA. Surgical outcome was evaluated using the visual analogue scale (VAS), the range of motion and the Harris score. RESULTS: The mean follow-up period was 29.3 months. At the last follow-up visit, the VAS score decreased from 7.53 +/- 0.99 before the operation to 2.40 +/- 0.91. The Harris score increased from 24.8 +/- 7.42 before the operation to 83.8 +/- 4.61. The total range of motion increased from 78.73 +/ 14.53 before the operation to 209.73 +/- 16.19 after the operation. After the operation, there was one case of early hip dislocation, one case of femoral nerve stretch injury and one case of superficial incision infection. There were no cases of deep venous thrombosis. X-ray examinations did not show prosthetic loosening or displacement. CONCLUSION: AS patients with bilateral hip ankylosis can be treated with cementless bilateral synchronous THA, which could greatly improve hip joint function without significant complications. The clinical effects proved to be satisfactory. PMID- 25030966 TI - Reaction time in ankle movements: a diffusion model analysis. AB - Reaction time (RT) is one of the most commonly used measures of neurological function and dysfunction. Despite the extensive studies on it, no study has ever examined the RT in the ankle. Twenty-two subjects were recruited to perform simple, 2- and 4-choice RT tasks by visually guiding a cursor inside a rectangular target with their ankle. RT did not change with spatial accuracy constraints imposed by different target widths in the direction of the movement. RT increased as a linear function of potential target stimuli, as would be predicted by Hick-Hyman law. Although the slopes of the regressions were similar, the intercept in dorsal-plantar (DP) direction was significantly smaller than the intercept in inversion-eversion (IE) direction. To explain this difference, we used a hierarchical Bayesian estimation of the Ratcliff's (Psychol Rev 85:59, 1978) diffusion model parameters and divided processing time into cognitive components. The model gave a good account of RTs, their distribution and accuracy values, and hence provided a testimony that the non-decision processing time (overlap of posterior distributions between DP and IE < 0.045), the boundary separation (overlap of the posterior distributions < 0.1) and the evidence accumulation rate (overlap of the posterior distributions < 0.01) components of the RT accounted for the intercept difference between DP and IE. The model also proposed that there was no systematic change in non-decision processing time or drift rate when spatial accuracy constraints were altered. The results were in agreement with the memory drum hypothesis and could be further justified neurophysiologically by the larger innervation of the muscles controlling DP movements. This study might contribute to assessing deficits in sensorimotor control of the ankle and enlighten a possible target for correction in the framework of our on-going effort to develop robotic therapeutic interventions to the ankle of children with cerebral palsy. PMID- 25030967 TI - Restricted and repetitive behaviors in individuals with a history of ASDs who have achieved optimal outcomes. AB - Studies of autism spectrum disorders (ASDs) suggest that restricted and repetitive behaviors (RRBs) are particularly difficult to remediate. We examined present and past RRBs in 34 individuals who achieved optimal outcomes (OOs; lost their ASD diagnosis), 45 high-functioning individuals with ASD (HFA) and 34 typically developing (TD) peers. The OO group exhibited minimal residual RRBs at the time of the study. All OO participants were reported to have at least one RRB in early childhood and almost 90 % met the RRB cutoff for ASD in early childhood, but RRBs were not more present in the OO than the TD group at the time of the study. History of RRBs in the HFA and OO groups differed only in oversensitivity to noise and insistence on sameness. Reports of current behavior indicated that RRB's had almost totally disappeared in the OO group. Thus, although RRB's were present in the OO group in childhood, they resolved along with social and communication deficits. PMID- 25030968 TI - The role of interventional radiology in the treatment of biliary strictures after paediatric liver transplantation. AB - PURPOSE: The aim of this study is to evaluate the safety and efficacy of percutaneous treatment of biliary strictures after paediatric liver transplantation. MATERIALS AND METHODS: In the period between October 1999 and October 2010, a total of 92 transplants in 86 children were performed at our Liver Transplant Centre. Eighteen patients had anastomotic biliary strictures (in four cases associated with intrahepatic bile duct stenosis). Percutaneous treatment (transhepatic biliary drainage and conventional/cutting balloon dilatation) was proposed as a first approach in 13/18 patients. Strict radiation protection precautions were taken in accordance with the ALARA (as low as reasonably achievable) principle. Mean follow-up time was 2,364 days. RESULTS: Surgical correction was required in 3/13 patients; in 8/13 cases, there was complete disappearance of clinical symptoms without bile duct dilatation; in one case, an asymptomatic persistent bile duct dilatation was detected while in the other case, the liver is currently in cirrhotic degeneration (69 % clinical success including the asymptomatic patient with biliary dilatation). Two of the five patients who were initially treated with surgery required percutaneous revision (clinical success of 100 %). There were two cases of long-term restenosis and two cases of transient haemobilia. CONCLUSIONS: Percutaneous procedures are safe and effective therapeutic options for the treatment of biliary strictures after paediatric liver transplantation. PMID- 25030970 TI - Correlated mass spectrometry imaging and confocal Raman microscopy for studies of three-dimensional cell culture sections. AB - A novel method of correlated imaging, combining confocal Raman microscopy (CRM) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) was developed in order to investigate the structural and chemical diversity inherent in three-dimensional (3D) cell cultures. These 3D spheroidal cell cultures are high throughput in vitro model systems that recapitulate some of the chemical and physiological gradients characteristic of tissues. As a result, they are ideal for testing new imaging approaches due to the native diversity of cellular phenotypes found within a single culture. Individually, confocal Raman microscopy (CRM) and mass spectrometry imaging (MSI) produce different kinds of chemical information. CRM imaging reveals differences in cellular integrity and protein secretion across a typical near-equatorial transverse slice, while MSI shows localization of small molecules to discrete regions of the spheroid section. Correlating information obtained from these disparate imaging methods begins with an external fiducial mask, added to the spheroidal samples to orient image acquisition on the two orthogonal platforms. Rather than combine the images directly, principal component analysis is used to reveal the most chemically informative elements, which are then combined using digital image correlation. Using this approach, relationships between the principal components of each method are visualized so that they may be compared on commensurate spatial length scales. PMID- 25030969 TI - Cardiac MR perfusion imaging: where we are. AB - To date, several clinical and multicentre studies have demonstrated the accuracy of perfusion cardiac magnetic resonance to detect ischaemia in comparison with quantitative coronary angiography, other noninvasive diagnostic techniques (single photon emission computed tomography; positron-emission tomography), and invasive haemodynamic measurements (fractional flow reserve). Moreover, the favourable safety profile and increasing availability contribute to make perfusion cardiac magnetic resonance one of the modalities of choice for the detection of myocardial ischaemia. Recently, the first evidence of the prognostic value of perfusion cardiac magnetic resonance results has also become available. This review summarises the technical and interpretation key points of perfusion cardiac magnetic resonance scan, the clinical indications, the most recent available literature about its diagnostic performance and prognostic value, and how perfusion cardiac magnetic resonance compares with other noninvasive techniques. PMID- 25030971 TI - Suicide risk in primary care: identification and management in older adults. AB - The National Strategy for Suicide Prevention (2012) has set a goal to reduce suicides by 20% within 5 years. Suicide rates are higher in older adults compared to most other age groups, and the majority of suicide completers have visited their primary care physician in the year before suicide. Primary care is an ideal setting to identify suicide risk and initiate mental health care. We review risk factors for late-life suicide; methods to assess for different levels of suicidality; and recent research developments regarding both effective assessment and management of suicide risk among older primary care patients. We highlight that broader scale screening of suicide risk may be considered in light of findings that suicidality can occur even in the absence of major risk factors like depression. We also highlight collaborative care models targeting suicide risk, and recent innovative interventions that aim to prevent the development of suicidal ideation and suicidal behavior. PMID- 25030973 TI - Newly graduated nurses' job satisfaction: comparison with allied hospital professionals, social workers, and elementary school teachers. AB - PURPOSE: The purposes of this study are to examine differences in job satisfaction among professional groups including nurses, allied hospital professionals, social workers, and elementary school teachers, and to identify specific characteristics of job satisfaction of nurses. METHODS: The study design was a cross-sectional exploratory study using secondary data analysis with the 2009 Graduates Occupational Mobility Survey. The sample was female new graduates. The differences in job satisfaction among professional groups were analyzed using logistic regression (satisfied vs. not satisfied). RESULTS: Overall, 41.5% of nurses, 50.1% of allied hospital professionals, 58.2% of social workers, and 89% of elementary school teachers were satisfied with their job. Nurses were significantly less satisfied than the other professionals in 5 of the 11 job characteristics and had the lowest odds ratio (OR) when compared with elementary school teachers: work content (OR = 0.197, 95% CI [0.128, 0.304]), physical work environment (OR = 0.353, 95% CI [0.236, 0.529]), working hours (OR = 0.054, 95% CI [0.033, 0.088]), personal growth (OR = 0.242, 95% CI [0.160, 0.366]), and autonomy (OR = 0.188, 95% CI [0.123, 0.288]). Work content, physical work environment, interpersonal relationship, advancement system, and autonomy were significantly associated with the overall job satisfaction of nurses. CONCLUSION: Relatively dissatisfying job characteristics in nursing work environment that were significant predictors for nurses' job satisfaction should be improved. Newly graduated nurses are at risk for job dissatisfaction. This can result in high turnover rates and can exacerbate the nursing shortage. Efforts to improve the work environment are needed. PMID- 25030974 TI - Exploring experiences of psychiatric nursing simulations using standardized patients for undergraduate students. AB - PURPOSE: This study was conducted to explore and understand the experiences of nursing students related to psychiatric simulation using standardized patients and to identify the value of such simulations in relation to the psychiatric clinical practicum. METHODS: This study was designed using qualitative research. Eleven undergraduate students were individually interviewed regarding their experiences with psychiatric nursing simulation. A thematic content analysis was conducted to derive themes from subthemes, which were derived from contents of the interview. RESULTS: Four themes were derived from nine subthemes by means of thematic analysis of nursing students' experiences regarding psychiatric nursing simulation with standardized patients compared to clinical psychiatric nursing practicum. The topics studied included gaining practice without fear, gaining confidence in clinical practicum, being embarrassed by the gap and being in need of further simulation. CONCLUSION: Exploration of student responses comparing simulation and clinical practicum enhances integration of dichotomous experiences that bridge the theory-practice gap, which magnifies the benefits of the simulation. PMID- 25030972 TI - Insomnia as a transdiagnostic process in psychiatric disorders. AB - Insomnia is a major public health concern, and is highly comorbid with a broad range of psychiatric disorders. Although insomnia has historically been considered a symptom of other disorders, this perspective has shifted. Epidemiological and experimental studies suggest that insomnia is related to the onset and course of several psychiatric disorders. Furthermore, several randomized controlled trials show that cognitive behavioral therapy for insomnia delivered to individuals who meet diagnostic criteria for insomnia and another psychiatric disorder improves the insomnia as well as the symptoms of the comorbid psychiatric disorder. Taken together, these results encompassing a range of methodologies have provided encouraging evidence and point toward insomnia as a transdiagnostic process in psychiatric disorders. PMID- 25030975 TI - Association between knowledge and attitude about aging and life satisfaction among older koreans. AB - PURPOSE: The purpose of this study was to measure knowledge and attitude about aging and life satisfaction among older Korean adults and to examine the influence of attitude and knowledge about aging on these adults' life satisfaction. METHODS: A cross-sectional and correlational design was used. A total of 405 older adults were surveyed using a written questionnaire at six elderly welfare centers in a metropolitan city in South Korea in mid April 2011. The data were analyzed using descriptive statistics, Pearson's correlation analysis, and multiple regression. RESULTS: The score of knowledge on aging was below the medium level. Attitude about aging was neutral, and life satisfaction was at the medium level. Variables such as female sex, age, economic status, monthly allowance, living with a spouse, self-rated overall health, knowledge and attitude about aging accounted for 33.8% of the total variance in predicting life satisfaction of the older adults. Older age and lower economic status reduced life satisfaction. Being female, having a monthly income of 300,000 Korea Republic Won or more, living with a spouse, and better knowledge and attitude about aging were associated with enhanced life satisfaction. CONCLUSION: The effect of knowledge and attitude about aging on life satisfaction is significant. Economic status, living with a spouse and self-rated overall health status are also predictive factors in life satisfaction. Consequently, nursing interventions for education and psychological support to increase knowledge about aging and induce a positive attitude towards it should be developed to improve older adults' life satisfaction. PMID- 25030976 TI - Time trends of allergic rhinitis and effects of residence on allergic rhinitis in Korea from 1998 through 2007-2009. AB - PURPOSE: Longitudinal changes in the prevalence of self-reported physician diagnosed allergic rhinitis (AR) in Korea and the association between the prevalence of AR and type of residence area among Korean males and females in 1998, 2001, 2005 and 2007-2009 were evaluated. METHODS: Age-standardized prevalence was calculated using the Korea National Health and Nutrition Examination Survey (KNHANES) I-IV. Stratified factors of sex, age, and socioeconomic status were adjusted to compare the prevalence of AR in relation to residential area by multiple logistic analysis. RESULTS: The prevalence of AR increased by tenfolds from 1.2 % in 1998 to 12.0 % in 2007-2009. The trends for prevalence of AR were also statistically significant (p < .05). The age standardized prevalence of AR among urban females was higher (13.9%) than that in rural females (11.5%). After adjustment for survey years, age, socioeconomic levels and asthma, the odds of AR were higher in urban than rural residents, except for males in 1998. CONCLUSION: The prevalence of AR in Korea has increased over the past decade, and living in an urban area may be a susceptible factor. For prevention and management of AR, further evaluations of contributing factors and mechanisms underlying differences in AR are needed. PMID- 25030977 TI - Traditional and religious death practices in Western Turkey. AB - PURPOSE: To investigate death-related traditional and religious practices in Narlidere, a district of Izmir province in Turkey. METHODS: A descriptive design was used (n = 181). The interview form was composed of 28 open-ended questions. The data were collected through face-to-face interviews by the researchers. Descriptive statistics and chi-square significance test were conducted. RESULTS: Of all the participants, 36.5% described death as the end of life. Praying took place first among the religious practices following death. A total of 42.0% said that relatives and friends who joined the burial ceremony shovel some soil into the pit over the corpse in order to express that they would not claim any rights from the deceased person thereafter, and 55.2% stated that they visited the deceased person's home to give social support to his or her relatives. CONCLUSION: We recommended that nurses and physicians be closely acquainted with the prevailing traditions and religious beliefs in the communities where they served. PMID- 25030978 TI - Factors related to korean nurses' willingness to report suspected elder abuse. AB - PURPOSE: This study aimed to describe Korean nurses' willingness to report suspected elder abuse and examine its related factors. METHODS: A descriptive correlational design was used. A convenience sample of 365 nurses from a hospital completed our questionnaires. Stepwise logistic regression analysis was performed to examine predictors of willingness to report. RESULTS: Sixty-eight nurses (18.6%) were not willing to report suspected elder abuse. In the stepwise logistic regression analysis, fewer years in clinical work, a higher level of knowledge on elder abuse law, and the perception of more severe abuse were found to be significant predictors of willingness to report elder abuse. CONCLUSION: As the Welfare of the Aged Act included a clause on mandated reporters, nurses' role in intervening in elder abuse cases has become more critical. In order to increase nurses' reporting, education on elder abuse should be provided to all nurses, and support programs should be designed for nurses to effectively involve them in reporting elder abuse. PMID- 25030979 TI - Horse-related trauma in children and adults during a two year period. AB - INTRODUCTION: Horse riding, with almost 200,000 participants, is the eighth most popular sport in Sweden. Severe injuries can occur with horse riding accidents which is well documented. This study was undertaken to investigate if injuries associated with horse riding are common, which type of injuries occur, what mechanisms are involved and to estimate the costs to the society. MATERIAL AND METHODS: All patients attending the emergency department at Linkoping University Hospital, during the years 2003-2004, due to horse related trauma were prospectively recorded. The patients were divided into two groups according to age, 147 children and 141 adults. The medical records were retrospectively scrutinized. RESULTS: The most common mechanism of injury was falling from the horse. Most commonly, minor sprains and soft tissue injuries were seen, but also minor head injuries and fractures, mainly located in the upper limb. In total 26 adults and 37 children were admitted. Of these 63 patients 19 were considered having a serious injury. In total, four patients needed treatment in intensive care units. The total cost in each group was 200,000 Euro/year. CONCLUSION: Horse riding is a sport with well known risks. Our results corresponds to the literature, however we have not observed the same incidence of serious injuries. In contrast we find these to be fairly uncommon. The injuries are mainly minor, with a small risk of long term morbidity. Over time regulations and safety equipment seem to have decreased the number of serious accidents. PMID- 25030980 TI - Respirometric Profiling of Muscle Mitochondria and Blood Cells Are Associated With Differences in Gait Speed Among Community-Dwelling Older Adults. AB - BACKGROUND: Gait speed provides an integrated measure of physical ability that is predictive of morbidity, disability, and mortality in older adults. Energy demands associated with walking suggest that mitochondrial bioenergetics may play a role in gait speed. Here, we examined the relationship between gait speed and skeletal muscle mitochondrial bioenergetics, and further evaluated whether blood based bioenergetic profiling might have similar associations with gait speed. METHODS: Participants in this study were comprised of two subsets (n = 17 per subset) and were overweight/obese (body mass index, 30.9 +/- 2.37), well functioning, community-dwelling older adults (69.1 +/- 3.69 years) without major comorbidity. Gait speeds were calculated from a fast-paced 400 m walk test. Respiratory control ratios were measured from mitochondria isolated from leg skeletal muscle biopsies from one subset. Maximal respiration and spare respiratory capacity were measured from peripheral blood mononuclear cells from the other subset. RESULTS: Individual differences in gait speed correlated directly with respiratory control ratio of mitochondria isolated from skeletal muscle (r = .536, p = .027) and with both maximal respiration and spare respiratory capacity of peripheral blood mononuclear cells (r = .585 and p = .014; r = .609 and p = .009, respectively). CONCLUSIONS: The bioenergetic profile of mitochondria isolated from skeletal muscle is associated with gait speed in older adults. Blood-based bioenergetic profiling is also associated with gait speed and may provide an alternative measure of mitochondrial function. PMID- 25030981 TI - Sex-biased immunity is driven by relative differences in reproductive investment. AB - Sex differences in immunity are often observed, with males generally having a weaker immune system than females. However, recent data in a sex-role-reversed species in which females compete to mate with males suggest that sexually competitive females have a weaker immune response. These findings support the hypothesis that sexual dimorphism in immunity has evolved in response to sex specific fitness returns of investment in traits such as parental investment and longevity, but the scarcity of data in sex-reversed species prevents us from drawing general conclusions. Using an insect species in which males make a large but variable parental investment in their offspring, we use two indicators of immunocompetence to test the hypothesis that sex-biased immunity is determined by differences in parental investment. We found that when the value of paternal investment was experimentally increased, male immune investment became relatively greater than that of females. Thus, in this system, in which the direction of sexual competition is plastic, the direction of sex-biased immunity is also plastic and appears to track relative parental investment. PMID- 25030983 TI - The link between behavioural type and natal dispersal propensity reveals a dispersal syndrome in a large herbivore. AB - When individuals disperse, they modify the physical and social composition of their reproductive environment, potentially impacting their fitness. The choice an individual makes between dispersal and philopatry is thus critical, hence a better understanding of the mechanisms involved in the decision to leave the natal area is crucial. We explored how combinations of behavioural (exploration, mobility, activity and stress response) and morphological (body mass) traits measured prior to dispersal were linked to the subsequent dispersal decision in 77 roe deer Capreolus capreolus fawns. Using an unusually detailed multi-trait approach, we identified two independent behavioural continuums related to dispersal. First, a continuum of energetic expenditure contrasted individuals of low mobility, low variability in head activity and low body temperature with those that displayed opposite traits. Second, a continuum of neophobia contrasted individuals that explored more prior to dispersal and were more tolerant of capture with those that displayed opposite traits. While accounting for possible confounding effects of condition-dependence (body mass), we showed that future dispersers were less neophobic and had higher energetic budgets than future philopatric individuals, providing strong support for a dispersal syndrome in this species. PMID- 25030984 TI - Stochastically driven adult-recruit associations of tree species on Barro Colorado Island. AB - The spatial placement of recruits around adult conspecifics represents the accumulated outcome of several pattern-forming processes and mechanisms such as primary and secondary seed dispersal, habitat associations or Janzen-Connell effects. Studying the adult-recruit relationship should therefore allow the derivation of specific hypotheses on the processes shaping population and community dynamics. We analysed adult-recruit associations for 65 tree species taken from six censuses of the 50 ha neotropical forest plot on Barro Colorado Island (BCI), Panama. We used point pattern analysis to test, at a range of neighbourhood scales, for spatial independence between recruits and adults, to assess the strength and type of departure from independence, and its relationship with species properties. Positive associations expected to prevail due to dispersal limitation occurred only in 16% of all cases; instead a majority of species showed spatial independence (~73%). Independence described the placement of recruits around conspecific adults in good approximation, although we found weak and noisy signals of species properties related to seed dispersal. We hypothesize that spatial mechanisms with strong stochastic components such as animal seed dispersal overpower the pattern-forming effects of dispersal limitation, density dependence and habitat association, or that some of the pattern-forming processes cancel out each other. PMID- 25030985 TI - Dispersal distance is influenced by parental and grand-parental density. AB - Non-genetic transmission of information across generations, so-called parental effects, can have significant impacts on offspring morphology, physiology, behaviour and life-history traits. In previous experimental work using the two spotted spider mite Tetranychus urticae Koch, we demonstrated that dispersal distances increase with local density and levels of genetic relatedness. We here show that manipulation of parental and grand-parental density has a significant effect on offspring dispersal distance, of the same order of magnitude as manipulation of offspring density. We demonstrate that offspring exposed to the same density disperse further if they were born to parents exposed to higher density compared with parents exposed to low density. Offspring dispersal distance also increases when grand-parents were exposed to higher density, except for offspring exposed to low densities, which disperse at shorter distances whatever the grand-parental density. We also show that offspring from mothers exposed to higher densities were overall larger, which suggests that parents in high densities invest more in individual offspring, enabling them to disperse further. We propose that our findings should be included in models investigating the spread rate of invasive species or when predicting the success of conservation measures of species attempting to track changing climates. PMID- 25030986 TI - Predator-induced flow disturbances alert prey, from the onset of an attack. AB - Many prey species, from soil arthropods to fish, perceive the approach of predators, allowing them to escape just in time. Thus, prey capture is as important to predators as prey finding. We extend an existing framework for understanding the conjoint trajectories of predator and prey after encounters, by estimating the ratio of predator attack and prey danger perception distances, and apply it to wolf spiders attacking wood crickets. Disturbances to air flow upstream from running spiders, which are sensed by crickets, were assessed by computational fluid dynamics with the finite-elements method for a much simplified spider model: body size, speed and ground effect were all required to obtain a faithful representation of the aerodynamic signature of the spider, with the legs making only a minor contribution. The relationship between attack speed and the maximal distance at which the cricket can perceive the danger is parabolic; it splits the space defined by these two variables into regions differing in their values for this ratio. For this biological interaction, the ratio is no greater than one, implying immediate perception of the danger, from the onset of attack. Particular attention should be paid to the ecomechanical aspects of interactions with such small ratio, because of the high degree of bidirectional coupling of the behaviour of the two protagonists. This conclusion applies to several other predator-prey systems with sensory ecologies based on flow sensing, in air and water. PMID- 25030987 TI - A proprioceptive neuromechanical theory of crawling. AB - The locomotion of many soft-bodied animals is driven by the propagation of rhythmic waves of contraction and extension along the body. These waves are classically attributed to globally synchronized periodic patterns in the nervous system embodied in a central pattern generator (CPG). However, in many primitive organisms such as earthworms and insect larvae, the evidence for a CPG is weak, or even non-existent. We propose a neuromechanical model for rhythmically coordinated crawling that obviates the need for a CPG, by locally coupling the local neuro-muscular dynamics in the body to the mechanics of the body as it interacts frictionally with the substrate. We analyse our model using a combination of analytical and numerical methods to determine the parameter regimes where coordinated crawling is possible and compare our results with experimental data. Our theory naturally suggests mechanisms for how these movements might arise in developing organisms and how they are maintained in adults, and also suggests a robust design principle for engineered motility in soft systems. PMID- 25030989 TI - Red fluorescence increases with depth in reef fishes, supporting a visual function, not UV protection. AB - Why do some marine fishes exhibit striking patterns of natural red fluorescence? In this study, we contrast two non-exclusive hypotheses: (i) that UV absorption by fluorescent pigments offers significant photoprotection in shallow water, where UV irradiance is strongest; and (ii) that red fluorescence enhances visual contrast at depths below -10 m, where most light in the 'red' 600-700 nm range has been absorbed. Whereas the photoprotection hypothesis predicts fluorescence to be stronger near the surface and weaker in deeper water, the visual contrast hypothesis predicts the opposite. We used fluorometry to measure red fluorescence brightness in vivo in individuals belonging to eight common small reef fish species with conspicuously red fluorescent eyes. Fluorescence was significantly brighter in specimens from the -20 m sites than in those from -5 m sites in six out of eight species. No difference was found in the remaining two. Our results support the visual contrast hypothesis. We discuss the possible roles fluorescence may play in fish visual ecology and highlight the possibility that fluorescent light emission from the eyes in particular may be used to detect cryptic prey. PMID- 25030988 TI - A texture-processing model of the 'visual sense of number'. AB - It has been suggested that numerosity is an elementary quality of perception, similar to colour. If so (and despite considerable investigation), its mechanism remains unknown. Here, we show that observers require on average a massive difference of approximately 40% to detect a change in the number of objects that vary irrelevantly in blur, contrast and spatial separation, and that some naive observers require even more than this. We suggest that relative numerosity is a type of texture discrimination and that a simple model computing the contrast energy at fine spatial scales in the image can perform at least as well as human observers. Like some human observers, this mechanism finds it harder to discriminate relative numerosity in two patterns with different degrees of blur, but it still outpaces the human. We propose energy discrimination as a benchmark model against which more complex models and new data can be tested. PMID- 25030982 TI - The evolution of peafowl and other taxa with ocelli (eyespots): a phylogenomic approach. AB - The most striking feature of peafowl (Pavo) is the males' elaborate train, which exhibits ocelli (ornamental eyespots) that are under sexual selection. Two additional genera within the Phasianidae (Polyplectron and Argusianus) exhibit ocelli, but the appearance and location of these ornamental eyespots exhibit substantial variation among these genera, raising the question of whether ocelli are homologous. Within Polyplectron, ocelli are ancestral, suggesting ocelli may have evolved even earlier, prior to the divergence among genera. However, it remains unclear whether Pavo, Polyplectron and Argusianus form a monophyletic clade in which ocelli evolved once. We estimated the phylogeny of the ocellated species using sequences from 1966 ultraconserved elements (UCEs) and three mitochondrial regions. The three ocellated genera did form a strongly supported clade, but each ocellated genus was sister to at least one genus without ocelli. Indeed, Polyplectron and Galloperdix, a genus not previously suggested to be related to any ocellated taxon, were sister genera. The close relationship between taxa with and without ocelli suggests multiple gains or losses. Independent gains, possibly reflecting a pre-existing bias for eye-like structures among females and/or the existence of a simple mutational pathway for the origin of ocelli, appears to be the most likely explanation. PMID- 25030990 TI - Functional connectivity architecture of the human brain: not all the same. AB - Imaging studies suggest that individual differences in cognition and behavior might relate to differences in brain connectivity, particularly in the higher order association regions. Understanding the extent to which two brains can differ is crucial in clinical and basic neuroscience research. Here we highlight two major sources of variance that contribute to intersubject variability in connectivity measurements but are often mixed: the spatial distribution variability and the connection strength variability. We then offer a hypothesis about how the cortical surface expansion during human evolution may have led to remarkable intersubject variability in brain connectivity. We propose that a series of changes in connectivity architecture occurred in response to the pressure for processing efficiency in the enlarged brain. These changes not only distinguish us from our evolutionary ancestors, but also enable each individual to develop more uniquely. This hypothesis may gain support from the significant spatial correlations among evolutionary cortical expansion, the density of long range connections, hemispheric functional specialization, and intersubject variability in connectivity. PMID- 25030991 TI - Determination of rutin in rat plasma by ultra performance liquid chromatography tandem mass spectrometry and application to pharmacokinetic study. AB - A sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS-MS) method for the determination of rutin in rat plasma was developed and validated. After addition of tolbutamide as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation. The chromatographic separation was performed on an Acquity UPLC BEH C18 column (2.1 * 50 mm, 1.7 MUm particle size), using acetonitrile-0.1% formic acid as the mobile phase with gradient elution, delivered at a flow-rate of 0.4 mL/min. Mass spectrometric analysis was performed using a XEVO TQD mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions of m/z 610.91->302.98 and m/z 271.2->155.1 were used to quantify for rutin and tolbutamide, respectively. This assay method has been fully validated in terms of specificity, linearity, recovery and matrix effect, accuracy, precision and stability. Calibration curves were linear in the concentration ranges of 25-2000 ng/mL for rutin. Only 3 min was needed for an analytical run. This developed method was successfully used for determination of rutin in rat plasma for pharmacokinetic study. PMID- 25030992 TI - Development and validation of a quick, easy, cheap, effective, rugged and safe method for the determination of imidacloprid and its metabolites in soil. AB - A simplified quick, easy, cheap, effective, rugged and safe method was standardized and validated for the estimation of residues of imidacloprid and its metabolites from different types of soil comprising sandy loam, loamy sand and clay loam soil. The samples were extracted with acetonitrile, clean up by treatment with primary secondary amine sorbent and graphitized carbon. High performance liquid chromatography (HPLC) is a technique to separate and quantitate residues of polar, nonvolatile and thermolabile chemical compounds, using high-pressure pumps, short and narrow columns packed with microparticulate phases and a detector. The residues were estimated using HPLC equipped with a photodiode array detector system, C18 column. Acetonitrile and water (30 : 70) were used as an isocratic mobile phase at 0.3 mL/min. Imidacloprid and its metabolites presented distinct peaks at retention factors of 4.93 min (6 chloronicotinic acid), 7.91 min (nitroguanidine), 9.12 min (olefin), 11.32 min (nitrosimine), 13.82 min (urea), 15.45 min (5-hydroxy) and 22.47 min (imidacloprid). Consistent recoveries above 80% for imidacloprid and its metabolites were observed when samples were spiked at 0.01, 0.05 and 0.10 mg/kg levels. The limit of quantification of the method was 0.01 mg/kg. The analytical method was validated in terms of parameters including selectivity, linearity, precision and accuracy of the detection system. PMID- 25030993 TI - Serum 25-hydroxyvitamin D levels correlate with EGFR mutational status in pulmonary adenocarcinoma. AB - There have been several epidemiological studies of the association between 25 hydroxyvitamin D (25(OH)D) level and lung cancer risk. We explored the potential association between serum 25(OH)D levels and mutations in epidermal growth factor receptor (EGFR) in patients with pulmonary adenocarcinoma. We analyzed clinical data from 135 patients whose serum 25(OH)D levels were measured and EGFR mutational status was tested at the time of diagnosis. The relationship between 25(OH)D and clinical factors such as EGFR mutational status and sex was examined. The median serum 25(OH)D level in patients with pulmonary adenocarcinoma was 16.8 ng/ml (range: 3.0-84.3 ng/ml). The level of 25(OH)D was lower in female patients than in male patients (P=0.03). Interestingly, 25(OH)D levels of patients with EGFR-mutated tumors were low compared with those with wild-type tumors (median 18.2 vs 14.7 ng/ml, P=0.011). After a dose-response relationship between EGFR mutations and 25(OH)D levels (as a continuous variable) was observed (OR=0.96, P=0.036), we categorized 25(OH)D levels as low (<=16.8 ng/ml) and high (>16.8 ng/ml). Multivariate analysis revealed the association between low 25(OH)D levels and a high incidence of EGFR mutations (adjusted OR=2.42, 95% CI: 1.11-5.26, P=0.026). The results from this study indicate that low 25(OH)D levels are associated with EGFR mutations in pulmonary adenocarcinoma. PMID- 25030994 TI - [Outcome of root canal treatments reconsidered]. PMID- 25030995 TI - [NiTi rotary instrumentation: concerns and strategies]. PMID- 25030996 TI - [Vital pulp therapy and bioactive pulp capping medicament: treatment perspective and research]. PMID- 25030997 TI - [Guidelines for root canal treatment]. PMID- 25030998 TI - [Guidelines for direct adhesive composite dental restoration]. PMID- 25030999 TI - [Comparison of the shaping ability of reciprocating instruments in simulated S shaped canals]. AB - OBJECTIVE: To evaluate the shaping ability of Reciproc, WaveOne,Mtwo and ProTaper instruments in simulated S-shaped root canals. METHODS: A total of 40 simulated S shaped resin blocks were divided randomly into four groups, each group was prepared with Reciproc (group A), WaveOne (group B), Mtwo (group C) and ProTaper (group D), respectively. The preparation time and reduction of working length after preparation were measured. Pre- and postoperative images were obtained by a scanner and superimposed using Photoshop. Changes of coronal curve and apical curve curvature, as well as material removal from the inner and outer canal wall at 10 points beginning 1 mm from the end point of the canal, were measured using ImageJ. Centering ability was determined, accordingly. The data were analyzed using the one-way ANOVA and Student-Newman-Keuls. RESULTS: The preparation time of group A and group B were (42.1 +/- 2.7) and (41.5 +/- 3.2) s respectively, significantly less than that of group C and group D [(62.7 +/- 2.8), (62.8 +/- 5.2) s] (P < 0.05).Reductions of working length after preparation were not significantly different among the four groups (P > 0.05). Coronal curve curvature changes of group A, group B and group D were (4.69 +/- 0.63) degrees , (4.15 +/- 0.89) degrees and (4.13 +/- 0.59) degrees respectively, significantly less than that of group C[(5.26 +/- 0.70) degrees ], P < 0.05. Apical curve curvature changes were not significantly different among the four groups (P > 0.05). At the 2 mm point, the centering ability of group A[ (-0.242 +/- 0.042) mm], group B[( 0.191 +/- 0.077) mm], and group D[(-0.272 +/- 0.046) mm] was better than group C[(-0.343 +/- 0.057 mm] significantly (P < 0.05). At the 3 mm and 4 mm point, the centering ability of group A and group B was better than group C and group D significantly (P < 0.05). Whilst at the 5 mm point, the centering ability of group D was better than group A and group B (P < 0.05). CONCLUSIONS: Reciproc and WaveOne could complete preparation faster and could maintain the original S shaped canal curvature better than Mtwo and ProTaper, especially in the apical part. PMID- 25031000 TI - [Expression profiles and bioinformatic analysis of miRNA in human dental pulp cells during endothelial differentiation]. AB - OBJECTIVE: To investigate the differential expression profile and bioinformatic analysis of microRNA (miRNA) in human dental pulp cells (DPC) during endothelial differentiation. METHODS: DPC were cultured in endothelial induction medium (50 ug/L vascular endothelial growth factor, 10 ug/L basic fibroblast growth factor and 2% fetal calf serum) for 7 days. Meanwhile non-induced DPC were used as control.Quantitative real-time PCR (qRT-PCR) was applied to detect vascular endothelial marker genes [CD31, von Willebrand factor (vWF) and vascular endothelial-cadherin (VE-cadherin)] and in vitro tube formation on matrigel was used to analyze the angiogenic ability of differentiated cells. And then miRNA expression profiles of DPC were examined using miRNA microarray and then the differentially expressed miRNA were validated by qRT-PCR. Furthermore, bioinformatic analysis was employed to predict the target genes of miRNA and to analyze the possible biological functions and signaling pathways that were involved in DPC after induction. RESULTS: The relative mRNA level of CD31, vWF and VE-cadherin in the control group were (3.48 +/- 0.22) *10(-4), (3.13 +/- 0.31) *10(-4) and (39.60 +/- 2.36) *10(-4), and (19.57 +/- 2.20) *10(-4), (48.13 +/- 0.54) *10(-4) and (228.00 +/- 8.89) *10(-4) in the induced group. The expressions of CD31, vWF and VE-cadherin were increased significantly in endothelial induced DPC compared to the control group (P < 0.05). For in vitro tube formation assay, tubular structures were formed on the matrigel by differentiated DPC. A total of 47 miRNA were differentially expressed, in which 15 miRNA were up-regulated and 32 miRNAs down-regulated in differentiated DPC compared with the control. Of these, 4 miRNA were confirmed by qRT-PCR. The target genes of differential miRNA were predicted to associate with several biological functions, such as the regulation of transcription, cell motion, blood vessel morphogenesis, angiogenesis and cytoskeletal protein, and signaling pathways including the mitogen-activated protein kinase (MAPK) and the Wnt signaling pathway. CONCLUSIONS: The differential miRNA expression identified in this study may be involved in governing DPC endothelial differentiation, thus contributing to the future research on regulatory mechanisms in dental pulp angiogenesis. PMID- 25031001 TI - [Maxillary sinus related dental diagnosis and treatment: report of three cases]. PMID- 25031002 TI - [Management of apical 1/3 separated instrument: a case report]. PMID- 25031003 TI - [Surgical repair of root crack: a case report]. PMID- 25031004 TI - [Summary of the Fourth China-National Conference of Cariology and Endodontics]. PMID- 25031005 TI - [Orthodontic treatment of adult skeletal crossbite with mandibular deviation]. AB - OBJECTIVE: To investigate the effects of orthodontic treatment of skeletal crossbite adults with mandibular deviation. METHODS: Eighteen skeletal Class III adult patients with borderline skeletal crossbite and mandibular deviation were selected (5 males, 13 females). The mean age was 25 years. All cases were treated with straight-wire appliance in upper arch and occlusal plate in the lower arch.Elastics were applied to correct mandibular deviation. Cephalometric analysis was carried out before and after treatment. Paired t-test was performed. RESULTS: After treatment, the anterior crossbite was corrected and Class I molar and canine relationships were achieved. The inclination of upper incisors was increased significantly. CONCLUSIONS: Straight-wire appliance combined with occlusal plate was effective on correcting adult patients with mild, moderate skeletal crossbite and mandibular deviation. PMID- 25031006 TI - [Effect of light centrifugal force on the asporin gene expression in human periodontal ligament cells]. AB - OBJECTIVE: To observe the expression of asporin, bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) in cultured human periodontal ligament cells in vitro under relative centrifugal force. METHODS: Human periodontal ligament cell was cultured in vitro and applied 30 *g centrifugal force for 0, 1, 2, 6, 10 hours. The expression of asporin, BMP-2 and ALP was observed with real time-PCR. RESULTS: All the cells showed normal figuration. The expression of asporin, BMP-2, ALP in no force loading group did not have any statistical significance change (P > 0.05). In 1 hour force loading group, the expressions of asporin and BMP-2 were 0.50 +/- 0.05 and 0.40 +/- 0.13. In 2 hour force loading group, the expressions of asporin and BMP-2 were 0.42 +/- 0.09 and 0.58 +/- 0.19, which decreased significantly from no force loading group (P < 0.05). The expression of asporin and BMP-2 increased significantly in 6 hour force loading group than in 1 and 2 hour force loading groups (P < 0.05). Then the expression of asporin decreased to no force loading group level (P > 0.05) and the expression of BMP-2 decreased rapidly lower than no force loading group level (P < 0.05). During the 10 hour interval of stress loading, the expression of asporin and BMP-2 showed a positive correlation (r = 0.995, P < 0.05). CONCLUSIONS: The expression of asporin in human periodontal ligament cell was stable. Short and light centrifugal force could up-regulate the expression of asporin rapidly, and suppress the abnormal BMP-2 expression back to baseline level. PMID- 25031007 TI - [Signal transducer and activator of transcription-3 inhibitor WP1066 affects human tongue squamous cell carcinoma proliferation and apoptosis in vitro and in vivo]. AB - OBJECTIVE: To investigate the antitumour molecular mechanisms of WP1066 (STAT-3 inhibitor ) to human tongue squamous cell carcinoma in vitro and in vivo. METHODS: WP1066 was used to inhibit the p-STAT-3 expression in Tscca human tongue squamous cell carcinoma cell line .Real-time PCR was used to detect the microRNA 21 expression after treatment with DMSO and WP1066. Methyl thiazolyl tatrozolium (MTT) assay was employed to determine cell survival. Flow cytometry (FCM) was used to measure apoptosis. The expression level of STAT-3/p-STAT-3, programmed cell death protein 4 (PDCD-4), antigen 67 (Ki-67), B cell lymphoma 2 (Bcl-2) and cleaved cysteinyl aspartate specific proteinase-3 (CCASP-3) was examined by Western blotting. Luciferase reporter gene assay was conducted to verify the regulation of STAT-3 to microRNA-21. Tscca xenograft tumor model was established in BALB/c nude mice and the tumors were divided into control, DMSO and WP1066 treated groups. The tumor tissues were measured by immunohistochemistry stain and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay. RESULTS: STAT-3/p-STAT-3 protein was suppressed after treatment with WP1066 (STAT 3:F = 15.336, P = 0.004, p-STAT-3: F = 52.837, P = 0.000). MicroRNA-21 relative expression level was down-regulated (F = 8.197, P = 0.019). Cell survival rate was significantly reduced after treatment with WP1066 than control groups (F = 94.388, P = 0.000). Early apoptosis rate increased after treatment with WP1066 (F = 217.080, P = 0.000) . PDCD-4 and cleaved cysteinyl aspartate specific proteinase-3 (CCASP-3) protein expression was increased after treatment with WP1066 (PDCD-4:F = 8.771, P = 0.017; CCASP-3: F = 26.611, P = 0.001) .Ki-67 and Bcl-2 protein was down regulated (Ki-67:F = 5.854, P = 0.039; Bcl-2:F = 125.502, P = 0.000). Luciferase reporter gene assay proved that STAT-3 combined with specific promoter region of microRNA-21.In vivo, the tumor volume after treatment with WP1066 was significantly smaller than control groups by the end of observation (F = 15.390, P = 0.000) .Immunological histological chemistry indicated that PDCD-4 and CCASP-3 protein expression was up-regulated simultaneously while Ki-67 and Bcl-2 protein of tumor tissue was down-regulated after treatment with WP1066 than control groups. TUNEL assay suggested that apoptosis index rose after treatment with WP1066 than control groups (F = 133.368, P = 0.000) . CONCLUSIONS: WP1066 affected Tscca cancer cell proliferation and apoptosis via inhibiting STAT-3/microRNA-21.WP1066 provided new direction and possibility to human tongue squamous cell carcinoma therapy. PMID- 25031008 TI - [Vascularized free tissue transfer: technical key points and complications]. PMID- 25031009 TI - [Mandibular reconstruction with vascularized bone flap: choice of flaps, technique of bone graft and dental implant]. PMID- 25031010 TI - The hemagglutinin: a determinant of pathogenicity. AB - The hemagglutinin (HA) is a prime determinant of the pathogenicity of influenza A viruses. It initiates infection by binding to cell surface receptors and by inducing membrane fusion. The fusion capacity of HA depends on cleavage activation by host proteases, and it has long been known that highly pathogenic avian influenza viruses displaying a multibasic cleavage site differ in protease sensitivity from low pathogenic avian and mammalian influenza viruses with a monobasic cleavage site. Evidence is increasing that there are also variations in proteolytic activation among the viruses with a monobasic cleavage site, and several proteases have been identified recently that activate these viruses in a natural setting. Differences in protease sensitivity of HA and in tissue specificity of the enzymes are important determinants for virus tropism in the respiratory tract and for systemic spread of infection. Protease inhibitors that interfere with cleavage activation have the potential to be used for antiviral therapy and attenuated viruses have been generated by mutation of the cleavage site that can be used for the development of inactivated and live vaccines. It has long been known that human and avian influenza viruses differ in their specificity for sialic acid-containing cell receptors, and it is now clear that human tissues contain also receptors for avian viruses. Differences in receptor binding specificity of seasonal and zoonotic viruses and differential expression of receptors for these viruses in the human respiratory tract account, at least partially, for the severity of disease. Receptor binding and fusion activation are modulated by HA glycosylation, and interaction of the glycans of HA with cellular lectins also affects virus infectivity. Interestingly, some of the mechanisms underlying pathogenicity are determinants of host range and transmissibility, as well. PMID- 25031011 TI - Au nanoparticles in carbon nanotubes with high photocatalytic activity for hydrocarbon selective oxidation. AB - High-efficiency and high-selectivity catalytic oxidation of alkanes under mild conditions with air is a major aim of current catalytic chemistry and chemical production. Despite extensive development efforts on new catalysts for cyclohexane oxidation, current commercial processes still suffer from low conversion, poor selectivity, and excessive production of waste. Here, we present the design and synthesis of gold nanoparticle/carbon nanotube (CNT) composites for high-efficiency and high-selectivity photocatalyst systems for the green oxidation of cyclohexane. Remarkably, Au nanoparticles confined in carbon nanotubes (Au-in-CNTs) are photocatalytically active for the oxidation of cyclohexane with 14.64% conversion of cyclohexane and a high selectivity of 86.88% of cyclohexanol using air and visible light at room temperature. Given its diversity and versatility of structural and composition design, gold nanoparticle/CNT composites may provide a powerful pathway for the development of high-performance catalysts and production processes for green chemical industry. PMID- 25031012 TI - MGMT promoter methylation and correlation with protein expression in primary central nervous system lymphoma. AB - The O (6)-methylguanine-DNA-methyltransferase (MGMT) gene encodes for a DNA repairing enzyme of which silencing by promoter methylation is involved in brain tumorigenesis. MGMT promoter methylation represents a favorable prognostic factor and has been associated with a better response to alkylating agents in glioma and systemic lymphoma. Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal malignant lymphoma. The current standard of care, based on high-dose methotrexate chemotherapy, has improved prognosis but outcome remains poor for a majority of patients. Therapeutic progress in this field is conditioned by limited biological and molecular knowledge about the disease. Temozolomide has recently emerged as an alternative option for PCNSL treatment. We aimed to analyze the MGMT gene methylation status in a series of 24 PCNSLs, to investigate the relationship between methylation status of the gene and immunohistochemical expression of MGMT protein and to evaluate the possible prognostic significance of these biomarkers. Our results confirm that methylation of the MGMT gene and loss of MGMT protein are frequent events in these lymphomas (54 % of our cases) and suggest that they are gender and age related. MGMT methylation showed high correlation with loss of protein expression (concordance correlation coefficient = -0.49; Fisher exact test: p < 0.01), different from what has been observed in other brain tumors. In the subgroup of ten patients who received high dose chemotherapy, the presence of methylated MGMT promoter (n = 4), seems to be associated with a prolonged overall survival (>60 months in three of four patients). The prognostic significance of these molecular markers in PCNSL needs to be further studied in groups of patients treated in a homogeneous way. PMID- 25031013 TI - The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma. AB - Ewing sarcoma (ES) is a high-grade malignant neoplasm primarily affecting children and young adults. The diagnosis of ES is often difficult because of its broad differential diagnosis comprising a diverse group of small round cell tumors (SRCTs). Although the identification of tumor type-specific fusion genes by molecular testing is the gold standard for the diagnosis of ES, such approaches are not always available in a routine pathology practice. Thus, a reliable immunohistochemical marker is required. A recent study using a limited number of tumor samples has shown that NKX2.2, a putative transcriptional target of EWSR1-FLI1, is a useful marker for the diagnosis of ES. In the present study, the immunohistochemical expression of NKX2.2 was evaluated on 46 genetically confirmed ES and 85 non-ES SRCTs, together with comparative assessment of CD99 and other molecular targets of EWSR1-FLI1, including NR0B1, E2F3, and EZH2. NKX2.2 was expressed in 37 (80 %) of the ES samples with a mostly diffuse and strong staining pattern, and 14 (16 %) of the non-ES SRCTs, including olfactory neuroblastomas, extraskeletal myxoid chondrosarcoma, mesenchymal chondrosarcoma, small cell carcinomas, and Merkel cell carcinoma, also expressed this marker. The sensitivity and specificity of the NKX2.2 expression in this cohort were 80 and 84 %, respectively. The specificity when combined with CD99 was 98 %, with exceptional expression of both markers in only two non-ES SRCTs, including one case each of mesenchymal chondrosarcoma and small cell carcinoma. NR0B1, E2F3, and EZH2 were less sensitive for specific markers for ES when applied singly or in any combination. In conclusion, the study reinforces that NKX2.2 is a useful immunohistochemical marker for ES, and that the combination of CD99 and NKX2.2 is a powerful diagnostic tool that can differentiate ES from other SRCTs. PMID- 25031014 TI - Cutaneous carcinosarcoma: further insights into its mutational landscape through massive parallel genome sequencing. AB - Cutaneous carcinosarcoma (CCS) is an extraordinarily rare neoplasm with a biphasic morphological pattern exhibiting both epithelial and sarcomatoid components. Although its histogenesis and biological aspects remain poorly understood, previous studies have postulated that this tumor may arise from single cancer stem cells which subsequently differentiate into distinct tumor lineages. In this study, we explored a wide array of mutational hot spot regions, through high-depth next-generation sequencing of 47 cancer-associated genes in order to assess the mutational landscape of these tumors and investigate whether the epithelial and mesenchymal components shared the same genetic signatures. Results from this study confirm that despite their striking phenotypic differences, both elements of this infrequent tumor indeed share a common clonal origin. Additionally, CCS appears to embrace a heterogeneous spectrum with specific underlying molecular signatures correlating with the defining epithelial morphotype, with those carcinosarcomas exhibiting a squamous cell carcinoma epithelial component exhibiting diverse point mutations and deletions in the TP53 gene, and those with a basal cell carcinoma morphotype revealing a more complex mutational landscape involving several genes. Also, the fact that our findings involve several targetable gene pathways suggests that the underlying molecular events driving the pathogenesis of CCS may represent future potential targets for personalized therapies. PMID- 25031015 TI - Clinicopathological characteristics of anaplastic carcinoma of the pancreas with rhabdoid features. AB - Undifferentiated (anaplastic) carcinoma with rhabdoid features is a rare and aggressive subtype of pancreatic carcinoma. Here, we report the clinical, histological, and immunohistochemical phenotypes in six autopsy cases of anaplastic carcinoma with rhabdoid features. The patients ranged between 44 and 76 years of age (median, 61 years) and consisted of four males and two females. All patients except one case died within 3 months of diagnosis, as these tumors were found at an advanced stage and were chemoresistant. At autopsy, tumor masses measuring 4-22 cm in maximum diameter were mainly located in the pancreatic body and tail. Microscopically, all cases showed anaplastic carcinoma with rhabdoid features that were discohesive with round to polygonal eosinophilic cytoplasm with occasional inclusions, and that had vesicular nuclei, and prominent nucleoli. Immunohistochemistry showed that the rhabdoid cells, particularly the inclusions, were strongly positive for pan-cytokeratin (AE1/AE3) and vimentin. Meanwhile, downregulation or aberrant cytoplasmic localization with focal aggregation of E-cadherin, beta-catenin, and EMA were frequently observed in the rhabdoid cells. Moreover, the intracytoplasmic inclusions were labeled with selective autophagy-related molecules including p62/SQSTM1, ubiquitin, and kelch like ECH-associated protein 1 (KEAP1). In addition, nuclear factor erythroid 2 related factor 2 (NRF2) and overexpression of its target molecule multidrug resistance-associated protein 1 (MRP1) were commonly observed in the rhabdoid cells. Therefore, these results suggest that p62-mediated aggregation of ubiquitinated intermediate filaments and membranous proteins is an important phenomenon in the rhabdoid phenotype. Indeed, the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1, leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features. PMID- 25031016 TI - Salt and nephrolithiasis. AB - Dietary sodium chloride intake is nowadays globally known as one of the major threats for cardiovascular health. However, there is also important evidence that it may influence idiopathic calcium nephrolithiasis onset and recurrence. Higher salt intake has been associated with hypercalciuria and hypocitraturia, which are major risk factors for calcium stone formation. Dietary salt restriction can be an effective means for secondary prevention of nephrolithiasis as well. Thus in this paper, we review the complex relationship between salt and nephrolithiasis, pointing out the difference between dietary sodium and salt intake and the best methods to assess them, highlighting the main findings of epidemiologic, laboratory and intervention studies and focusing on open issues such as the role of dietary salt in secondary causes of nephrolithiasis. PMID- 25031017 TI - Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor alpha-mediated transforming growth factor-beta1/Smad signaling pathway. AB - BACKGROUND: After insult to the kidney, a renal fibrotic process is initiated with sustained inflammation, fibroblast activation and accumulation of extracellular matrix (ECM). Tamoxifen has been used as an anti-estrogen for the prevention and treatment of breast cancer. In this study, we investigated the protective effects of tamoxifen on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis and its molecular mechanism. METHODS: Renal fibrosis was induced by UUO in 7-week-old C57BL/6 mice. Tamoxifen (50 mg/kg) was given by oral gavage for 5 days before induction of renal fibrosis. Tamoxifen treatment was continued for 14 days after UUO operation. Histologic changes were examined by periodic acid-Schiff stain and Masson's trichrome stain. Expression of alpha-smooth muscle actin, vimentin, type I collagen, fibronectin and cell adhesion molecules were evaluated by immunohistochemistry and western blot analysis. We also evaluated the effect of tamoxifen on estrogen receptor (ER) alpha-mediated transforming growth factor (TGF)-beta1/Smad signaling pathway in vitro. RESULTS: Renal tubular injury and fibrosis were increased after UUO. Tamoxifen treatment significantly decreased UUO-induced renal tubular injury and fibrosis. Renal fibroblast activation, ECM deposition and inflammation were significantly increased after ureteral ligation. However, tamoxifen treatment significantly decreased UUO-induced renal fibroblast activation, ECM deposition and inflammation by suppression of TGF-beta1/Smad signaling pathway in vivo. Tamoxifen decreased TGF-beta1-induced fibroblast proliferation and cell migration by modulating ERalpha-mediated TGF-beta1/Smad signaling pathway in vitro. CONCLUSION: These findings indicate that tamoxifen has a beneficial effect on UUO induced tubulointerstitial fibrosis by suppression of renal fibroblast activation via modulation of ERalpha-mediated renal TGF-beta1/Smad signaling pathway. PMID- 25031018 TI - Of mice and men: modeling cardiovascular complexity in diabetes. Focus on "Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart". PMID- 25031019 TI - Investigating pulmonary arterial hypertension from "stem" to stern. Focus on "Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension". PMID- 25031020 TI - Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages. AB - Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe(-/-) mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3(+/+) bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3(-/-)Apoe(-/-) animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages. PMID- 25031021 TI - Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy. AB - Partial bladder outlet obstruction (pBOO)-induced remodeling of bladder detrusor smooth muscle (DSM) is associated with the modulation of cell signals regulating contraction. We analyzed the DSM from obstructed murine urinary bladders for the temporal regulation of RhoA GTPase and Rho-activated kinase (ROCK), which are linked to Ca(2+) sensitization. In addition, the effects of equibiaxial cell stretch, a condition thought to be associated with pBOO-induced bladder wall smooth muscle hypertrophy and voiding frequency, on the expression of RhoA, ROCK, and C-kinase-activated protein phosphatase I inhibitor (CPI-17) were investigated. DSM from 1-, 3-, 7-, and 14-day obstructed male mice bladders and benign prostatic hyperplasia (BPH)-induced obstructed human bladders revealed overexpression of RhoA and ROCK-beta at the mRNA and protein levels compared with control. Primary human bladder myocytes seeded onto type I collagen-coated elastic silicone membranes were subjected to cyclic equibiaxial stretch, mimicking the cellular mechanical stretch in the bladder in vivo, and analyzed for the expression of RhoA, ROCK-beta, and CPI-17. Stretch caused a significant increase of RhoA, ROCKbeta, and CPI-17 expression. The stretch-induced increase in CPI-17 expression occurs at the transcriptional level and is associated with CPI-17 promoter binding by GATA-6 and NF-kappaB, the transcription factors responsible for CPI-17 gene transcription. Cell stretch caused by bladder overdistension in pBOO is the likely mechanism for initiating overexpression of the signaling proteins regulating DSM tone. PMID- 25031022 TI - Uroguanylin inhibits H-ATPase activity and surface expression in renal distal tubules by a PKG-dependent pathway. AB - Cumulative evidence suggests that guanylin peptides play an important role on electrolyte homeostasis. We have previously reported that uroguanylin (UGN) inhibits bicarbonate reabsorption in a renal distal tubule. In the present study, we tested the hypothesis that the bicarbonaturic effect of UGN is at least in part attributable to inhibition of H(+)-ATPase-mediated hydrogen secretion in the distal nephron. By in vivo stationary microperfusion experiments, we were able to show that UGN inhibits H(+)-ATPase activity by a PKG-dependent pathway because KT5823 (PKG inhibitor) abolished the UGN effect on distal bicarbonate reabsorption and H89 (PKA inhibitor) was unable to prevent it. The in vivo results were confirmed by the in vitro experiments, where we used fluorescence microscopy to measure intracellular pH (pHi) recovery after an acid pulse with NH4Cl. By this technique, we observed that UGN and 8 bromoguanosine-cGMP (8Br cGMP) inhibited H(+)-ATPase-dependent pHi recovery and that the UGN inhibitory effect was abolished in the presence of the PKG inhibitor. In addition, by using RT-PCR technique, we verified that Madin-Darby canine kidney (MDCK)-C11 cells express guanylate cyclase-C. Besides, UGN stimulated an increase of both cGMP content and PKG activity but was unable to increase the production of cellular cAMP content and PKA activity. Furthermore, we found that UGN reduced cell surface abundance of H+-ATPase B1 subunit in MDCK-C11 and that this effect was abolished by the PKG inhibitor. Taken together, our data suggest that UGN inhibits H(+)-ATPase activity and surface expression in renal distal cells by a cGMP/PKG-dependent pathway. PMID- 25031023 TI - Interferon stimulated gene 15 has an anti-apoptotic effect on MIN6 cells. AB - Type 1 diabetes, one of two major forms of diabetes, results from the complete destruction of pancreatic beta cells. Viral infection has been suggested to be a trigger of beta cell destruction, the pathogenesis of type 1 diabetes. The aim of this study was to clarify the role of the protein encoded by intherferon stimulated gene (ISG) 15, an antiviral effector, in the development of this clinical entity. We used the mouse beta cell line MIN6 to investigate the role of ISG15 and paid special attention to apoptosis. Although not detected in native MIN6 cells, free ISG15 and ISG15 conjugated proteins were both present in dose dependently increased amounts following stimulation with interferon alpha. As assessed both by caspase 3/7 activity and an annexin V assay, the percentage of apoptotic MIN6 cells (after exposure to the inflammatory cytokines of interleukin 1beta plus interferon gamma or tumor necrosis factor alpha) was decreased by pretreatment with adenovirus-expressing ISG15 and increased by expressing a short hairpin RNA directed against ISG15. In conclusion, ISG15 has an anti-apoptotic effect on MIN6 cells. Thus, promoting ISG15 expression in the pancreatic beta cells could be a potential therapeutic approach for patients with type 1 diabetes. PMID- 25031024 TI - Clinical utilisation of a rapid low-pass whole genome sequencing technique for the diagnosis of aneuploidy in human embryos prior to implantation. AB - BACKGROUND: The majority of human embryos created using in vitro fertilisation (IVF) techniques are aneuploid. Comprehensive chromosome screening methods, applicable to single cells biopsied from preimplantation embryos, allow reliable identification and transfer of euploid embryos. Recently, randomised trials using such methods have indicated that aneuploidy screening improves IVF success rates. However, the high cost of testing has restricted the availability of this potentially beneficial strategy. This study aimed to harness next-generation sequencing (NGS) technology, with the intention of lowering the costs of preimplantation aneuploidy screening. METHODS: Embryo biopsy, whole genome amplification and semiconductor sequencing. RESULTS: A rapid (<15 h) NGS protocol was developed, with consumable cost only two-thirds that of the most widely used method for embryo aneuploidy detection. Validation involved blinded analysis of 54 cells from cell lines or biopsies from human embryos. Sensitivity and specificity were 100%. The method was applied clinically, assisting in the selection of euploid embryos in two IVF cycles, producing healthy children in both cases. The NGS approach was also able to reveal specified mutations in the nuclear or mitochondrial genomes in parallel with chromosome assessment. Interestingly, elevated mitochondrial DNA content was associated with aneuploidy (p<0.05), a finding suggestive of a link between mitochondria and chromosomal malsegregation. CONCLUSIONS: This study demonstrates that NGS provides highly accurate, low-cost diagnosis of aneuploidy in cells from human preimplantation embryos and is rapid enough to allow testing without embryo cryopreservation. The method described also has the potential to shed light on other aspects of embryo genetics of relevance to health and viability. PMID- 25031025 TI - Horror films and psychiatry. AB - OBJECTIVES: Horror films have been popular for generations. The purpose of this article is to illustrate psychiatric conditions, themes and practice seen in horror films. CONCLUSIONS: Horror films often either include psychiatrists as characters or depict (Hollywood's dangerous version of) serious mental illness. Demonic possession, zombies, and 'slasher' killers are described, as well as the horror genre's characterizations of psychiatrists. PMID- 25031026 TI - An ergonomics action research demonstration: integrating human factors into assembly design processes. AB - In action research (AR), the researcher participates 'in' the actions in an organisation, while simultaneously reflecting 'on' the actions to promote learning for both the organisation and the researchers. This paper demonstrates a longitudinal AR collaboration with an electronics manufacturing firm where the goal was to improve the organisation's ability to integrate human factors (HF) proactively into their design processes. During the three-year collaboration, all meetings, workshops, interviews and reflections were digitally recorded and qualitatively analysed to inform new 'actions'. By the end of the collaboration, HF tools with targets and sign-off by the HF specialist were integrated into several stages of the design process, and engineers were held accountable for meeting the HF targets. We conclude that the AR approach combined with targeting multiple initiatives at different stages of the design process helped the organisation find ways to integrate HF into their processes in a sustainable way. PRACTITIONER SUMMARY: Researchers acted as a catalyst to help integrate HF into the engineering design process in a sustainable way. This paper demonstrates how an AR approach can help achieve HF integration, the benefits of using a reflective stance and one method for reporting an AR study. PMID- 25031027 TI - Genetic engineering combined with random mutagenesis to enhance G418 production in Micromonospora echinospora. AB - G418, produced by fermentation of Micromonospora echinospora, is an aminoglycoside antibiotic commonly used in genetic selection and maintenance of eukaryotic cells. Besides G418, M. echinospora produces many G418 analogs. As a result, the G418 product always contains impurities such as gentamicin C1, C1a, C2, C2a, gentamicin A and gentamicin X2. These impurities are less potent but more toxic than G418, but the purification of G418 is difficult because it has similar properties to its impurities. G418 is an intermediate in the gentamicin biosynthesis pathway. From G418 the pathway proceeds via successive dehydrogenation and aminotransferation at the C-6' position to generate the gentamicin C complex, but genes responsible for these steps are still obscure. Through disruption of gacJ, which is deduced to encode a C-6' dehydrogenase, the biosynthetic impurities gentamicin C1, C1a, C2 and C2a were all removed, and G418 became the main product of the gacJ disruption strain. These results demonstrated that gacJ is in charge of conversion of the 6'-OH of G418 into 6'-NH2. Disruption of gacJ not only eliminates the impurities seen in the original strain but also improves G418 titers by 15-fold. G418 production was further improved by 26.6 % through traditional random mutagenesis. Through the use of combined traditional and recombinant genetic techniques, we produced a strain from which most impurities were removed and G418 production was improved by 19 fold. PMID- 25031028 TI - Modulated SmA(b) phases formed by anchor shaped liquid crystalline molecules. AB - Bent-core molecules with a linear alkyl chain in the bay position (anchor shaped molecules) form new liquid crystalline phases combining periodicities with different coherence lengths in distinct directions; in these LC phases the molecules are organized on average orthogonal in modulated layers (ribbons or patches) with restricted rotation around the long axis, thus representing modulated SmA(b) phases. PMID- 25031029 TI - Maternal reported indicators and causes of insufficient milk supply. AB - BACKGROUND: Although the breastfeeding initiation rate is high in China, exclusivity is low. Not having enough breast milk has been frequently reported as a reason for supplementing and weaning. OBJECTIVE: The objective was to explore maternal perception of indicators and causes of self-reported insufficient milk supply (IMS) among a sample of southwestern Chinese mothers. METHODS: This was a cross-sectional study, conducted in a hospital in Chengdu, China. RESULTS: The majority of mothers were of Han ethnicity and primiparous. Most initiated breastfeeding (n = 325, 95.3%). Among mothers who had weaned by the time of questionnaire completion, more than half (n = 52) reported IMS as a reason, and 53.8% of these mothers reported this occurring during the first 2 days postpartum. Mothers often identified IMS by using less sensitive indicators of adequate intake such as receiving a hungry look from the infant after nursing (34.6%) and not feeling the presence of milk (28.8%). More sensitive indicators of adequate intake, such as the number of wet/soiled diapers, were not reported. More than a third of mothers (39.2%) could not express a reason for the occurrence of IMS. Among those who identified reasons, nearly one-fourth of mothers attributed IMS, at least partially, to dietary factors such as poor appetite (23.5%). CONCLUSION: Self-reported IMS appears to be a common barrier to breastfeeding continuation among this sample of Chinese mothers. Culturally appropriate intervention, designed to inform mothers how to correctly identify and address IMS, might be an effective strategy to support optimal infant-feeding behaviors in China. PMID- 25031030 TI - WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors. AB - Kidney organogenesis requires the tight control of proliferation, differentiation and apoptosis of renal progenitor cells. How the balance between these cellular decisions is achieved remains elusive. The Wilms' tumour suppressor Wt1 is required for progenitor survival, but the molecular cause for renal agenesis in mutants is poorly understood. Here we demonstrate that lack of Wt1 abolishes fibroblast growth factor (FGF) and induces BMP/pSMAD signalling within the metanephric mesenchyme. Addition of recombinant FGFs or inhibition of pSMAD signalling rescues progenitor cell apoptosis induced by the loss of Wt1. We further show that recombinant BMP4, but not BMP7, induces an apoptotic response within the early kidney that can be suppressed by simultaneous addition of FGFs. These data reveal a hitherto unknown sensitivity of early renal progenitors to pSMAD signalling, establishes FGF and pSMAD signalling as antagonistic forces in early kidney development and places WT1 as a key regulator of pro-survival FGF signalling pathway genes. PMID- 25031031 TI - Stable nuclear transformation of Pandorina morum. AB - BACKGROUND: Volvocine green algae like Pandorina morum represent one of the most recent inventions of multicellularity diverged from their unicellular relatives. The 8-16 celled P. morum alga and its close multicellular relatives constitute a model lineage for research into cellular differentiation, morphogenesis and epithelial folding, sexual reproduction and evolution of multicellularity. Pandorina is the largest and most complex organism in the volvocine lineage that still exhibits isogamous sexual reproduction. So far, molecular-biological investigations in P. morum were constricted due to the absence of methods for transformation of this species, which is a prerequisite for introduction of reporter genes and (modified) genes of interest. RESULTS: Stable nuclear transformation of P. morum was achieved using chimeric constructs with a selectable marker, a reporter gene, promoters and upstream and downstream flanking sequences from heterologous sources. DNA was introduced into the cells by particle bombardment with plasmid-coated gold particles. The aminoglycoside 3' phosphotransferase VIII (aphVIII) gene of Streptomyces rimosus under control of an artificial, heterologous promoter was used as the selectable marker. The artificial promoter contained a tandem arrangement of the promoter of both the heat shock protein 70A (hsp70A) and the ribulose-1,5-bisphosphat-carboxylase/ oxygenase S3 (rbcS3) gene of Volvox carteri. Due to the expression of aphVIII, transformants gained up to 333-fold higher resistance to paromomycin in comparison to the parent wild-type strain.The heterologous luciferase (gluc) gene of Gaussia princeps, which was previously genetically engineered to match the nuclear codon usage of Chlamydomonas reinhardtii, was used as a co-transformed, unselectable reporter gene. The expression of the co-bombarded gluc gene in transformants and the induction of gluc by heat shock were demonstrated through bioluminescence assays. CONCLUSION: Stable nuclear transformation of P. morum using the particle bombardment technique is now feasible. Functional expression of heterologous genes is achieved using heterologous flanking sequences from Volvox carteri and Chlamydomonas reinhardtii. The aphVIII gene of the actinobacterium S. rimosus can be used as a selectable marker for transformation experiments in the green alga P. morum. The gluc gene of the marine copepod G. princeps, expressed under control of heterologous promoter elements, represents a suitable reporter gene for monitoring gene expression or for other applications in P. morum. PMID- 25031032 TI - Localizing seizure-susceptible brain regions associated with low-grade gliomas using voxel-based lesion-symptom mapping. AB - BACKGROUND: Patients afflicted with low-grade glioma (LGG) frequently suffer from seizures. The mechanisms of seizure initiation in these patients remain poorly understood. Tumor location has been correlated with seizure initiation. However, these correlative studies relied on dichotomized data analysis based on arbitrary lobe assignments. As a result, the lesion-symptom correlation may be incorrectly interpreted. Here, we present the first study that used a voxel-wise quantitative lesion analysis to investigate the spatial correlation between tumor location and seizure susceptibility. METHODS: We collected the medical records and magnetic resonance images of 410 LGG patients. The dataset was divided into a discovery set and a validation set. A voxel-based lesion-symptom correlative analysis was performed to determine whether tumor location was associated with seizure risk and could be related to the specific type of seizure. RESULTS: For all seizure types, increased seizure risks were identified for LGGs that involved the left premotor area. The LGGs that involved the posterior portion of the left inferior and middle frontal gyrus were associated with increased risk of simple partial seizures. LGGs that involved the right temporal-insular region were associated with an increased risk of complex partial seizures. LGGs that involved the left premotor area were more likely to be associated with seizures that generalize. These correlations were consistently observed in both the discovery and the validation datasets. CONCLUSIONS: Our quantitative neuroimaging analyses support the concept that the anatomic location of an LGG is a contributing factor in tumor-related seizure. PMID- 25031033 TI - Localization of prestin and expression in the early period after radiation in mice. AB - This study aimed to examine expression and microstructural distribution of prestin in outer hair cells, and the effect of dose and time of radiation on prestin expression in the BALB/c mouse. We also investigated the molecular biological characteristics of prestin and possible mechanisms of sensorineural hearing loss caused by radiation. Seventy 4-week-old mice were randomly divided into four groups, including one control group and three experimental groups. Each experimental group was randomly divided into two groups, which were killed to collect specimens of the cochlea on the 3rd and 7th days after exposure to different doses of 8, 12, and 16 Gy radiation. These cochleas were embedded in paraffin, and then cut into sections. The sections were immunostained with anti prestin antibodies. The distribution of prestin was observed under optical microscopy and the density of prestin-positive expression was quantitatively calculated by Image-Pro Plus. Prestin had high expression in the lateral membrane and low expression in the cytoplasm of outer hair cells above the nucleus. The density of prestin protein expression of the basal turn was not significantly different after exposure to the different doses of radiation compared with the control group, but up-regulation occurred after radiation in the apex turn. We conclude that prestin protein is mainly expressed in the lateral membrane above the nucleus. Prestin protein may be responsible for the mechanism of injury to the inner ear caused by radiation. PMID- 25031034 TI - Cervical compression due to benign thyroid disorders is not associated with increased postoperative morbidity. AB - Compressive symptoms due to malignant thyroid disorders and retrosternal goiter have been shown to be associated with increased perioperative morbidity. However, little is known about the risk associated with the surgical management of patients presenting with cervical compressive symptoms secondary to benign thyroid disorders. A retrospective review of data of patients undergoing thyroid surgery in a tertiary referral center was performed. The outcomes of patients with compressive symptoms due to benign thyroid disorders were compared to those of patients without compressive symptoms. 886 patients operated upon between 2005 and 2012 were included for analysis. 284 cases with compressive symptoms (study group) were compared to 602 cases without compressive symptoms (control group). There was no difference in the duration of surgery among both groups (123 vs. 126 min, p = 0.75). There was no significant difference among both groups with regard to postoperative hypocalcemia (1.4 vs. 1.1 %), rate of recurrent laryngeal nerve palsy (6.3 vs. 7.2 %) and postoperative bleeding (2.1 vs. 3.1 %). Compressive symptoms resolved in a significant number of patients following surgery. There was no significant difference in postoperative outcome between patients with and without compressive symptoms. Therefore, cervical compression due to benign thyroid disorders is not associated with increased perioperative morbidity. PMID- 25031036 TI - Radon and radium concentration in water from North-West of Romania and the estimated doses. AB - In the present study, the measurements of radon were carried out using the LUK-VR system based on radon gas measurements with Lucas cells. The radium concentration in water was determined, with the same device, immediately after was established the radon equilibrium with radium. The results presented here are from a survey carried out in the N-W region of Transylvania (Romania) in which were investigated the radon concentrations in natural (spring, well and surface) and drinking (tap) waters. The results showed radon concentrations within the range of 0.4-187.3 Bq l(-1) with an average value of 15.9 Bq l(-1) whereas radium concentration varied between 0.05 and 0.825 Bq l(-1) with an average value of 0.087 Bq l(-1) for all types of water covered within this survey. The corresponding annual effective ingestion dose due to radon and radium from water was determined from drinking water used by the population inhabiting the area. PMID- 25031035 TI - Diverse definitions of prolonged labour and its consequences with sometimes subsequent inappropriate treatment. AB - BACKGROUND: Prolonged labour very often causes suffering from difficulties that may have lifelong implications. This study aimed to explore the prevalence and treatment of prolonged labour and to compare birth outcome and women's experiences of prolonged and normal labour. METHOD: Women with spontaneous onset of labour, living in a Swedish county, were recruited two months after birth, to a cross-sectional study. Women (n = 829) completed a questionnaire that investigated socio-demographic and obstetric background, birth outcome and women's feelings and experiences of birth. The prevalence of prolonged labour, as defined by a documented ICD-code and inspection of partogram was calculated. Four groups were identified; women with prolonged labour as identified by documented ICD-codes or by partogram inspection but no ICD-code; women with normal labour augmented with oxytocin or not. RESULTS: Every fifth woman experienced a prolonged labour. The prevalence with the documented ICD-code was (13%) and without ICD-code but positive partogram was (8%). Seven percent of women with prolonged labour were not treated with oxytocin. Approximately one in three women (28%) received oxytocin augmentation despite having no evidence of prolonged labour. The length of labour differed between the four groups of women, from 7 to 23 hours.Women with a prolonged labour had a negative birth experience more often (13%) than did women who had a normal labour (3%) (P <0.00). The factors that contributed most strongly to a negative birth experience in women with prolonged labour were emergency Caesarean section (OR 9.0, 95% CI 1.2-3.0) and to strongly agree with the following statement 'My birth experience made me decide not to have any more children' (OR 41.3, 95% CI 4.9-349.6). The factors that contributed most strongly to a negative birth experience in women with normal labour were less agreement with the statement 'It was exiting to give birth' (OR 0.13, 95% CI 0.34-0.5). CONCLUSIONS: There is need for increased clinical skill in identification and classification of prolonged labour, in order to improve care for all women and their experiences of birthing processes regardless whether they experience a prolonged labour or not. PMID- 25031037 TI - Oxygen removal from water versus arterial oxygen delivery: calibrating the Fick equation in Pacific salmon. AB - While it is well known that O2 is directly removed from the water by skin and gill tissues of fish, the mismatch between O2 removal from water (O2 uptake; [Formula: see text]) and the O2 delivered to tissues by the primary circulation (O2 consumption; [Formula: see text]) has never been measured directly. Using data from four recent studies that simultaneously measured [Formula: see text] and [Formula: see text] in 2-5 kg Pacific salmon, our analysis revealed that sockeye salmon can remove an additional 12-48 % more O2 from the water than the primary circulation delivers to the systemic tissues. This percentage did not change significantly during swimming activity, a result that contradicts an earlier prediction that the difference should decrease when [Formula: see text] increases during exercise. In resting Chinook salmon, a similar percentage difference in simultaneously measured [Formula: see text] and [Formula: see text] was observed, yet the difference tended to disappear during acute heat stress to a near lethal temperature. These results emphasize that caution should be exercised when using the Fick equation to estimate cardiac output because the overestimate of cardiac output that results from using the Fick equation in Pacific salmon is not small, may not be fixed and may exist in other teleosts. PMID- 25031039 TI - Laparoscopic management of a delayed traumatic diaphragmatic rupture complicated by bowel strangulation. AB - Traumatic rupture of the diaphragm (TDR) presents diagnostic difficulty, with basic radiological investigations discovering less than half of all cases. As a consequence, complications of diaphragmatic rupture may present long after the initial injury has occurred-the time delay obscuring diagnosis. Once discovered repair is necessary with previous reports advocating open repair. Here, we report a case of traumatic diaphragmatic rupture causing small bowel obstruction 20 years after initial injury. The patient, a young woman, underwent successful laparoscopic assisted diaphragmatic repair with small bowel resection. TDR is an unusual but important differential diagnosis of an acute abdomen. A high index of suspicion is required to avoid delayed diagnosis and increased mortality. PMID- 25031038 TI - Sugar flux through the flight muscles of hovering vertebrate nectarivores: a review. AB - In most vertebrates, uptake and oxidation of circulating sugars by locomotor muscles rises with increasing exercise intensity. However, uptake rate by muscle plateaus at moderate aerobic exercise intensities and intracellular fuels dominate at oxygen consumption rates of 50% of maximum or more. Further, uptake and oxidation of circulating fructose by muscle is negligible. In contrast, hummingbirds and nectar bats are capable of fueling expensive hovering flight exclusively, or nearly completely, with dietary sugar. In addition, hummingbirds and nectar bats appear capable of fueling hovering flight completely with fructose. Three crucial steps are believed to be rate limiting to muscle uptake of circulating glucose or fructose in vertebrates: (1) delivery to muscle; (2) transport into muscle through glucose transporter proteins (GLUTs); and (3) phosphorylation of glucose by hexokinase (HK) within the muscle. In this review, we summarize what is known about the functional upregulation of exogenous sugar flux at each of these steps in hummingbirds and nectar bats. High cardiac output, capillary density, and blood sugar levels in hummingbirds and bats enhance sugar delivery to muscles (step 1). Hummingbird and nectar bat flight muscle fibers have relatively small cross-sectional areas and thus relatively high surface areas across which transport can occur (step 2). Maximum HK activities in each species are enough for carbohydrate flux through glycolysis to satisfy 100 % of hovering oxidative demand (step 3). However, qualitative patterns of GLUT expression in the muscle (step 2) raise more questions than they answer regarding sugar transport in hummingbirds and suggest major differences in the regulation of sugar flux compared to nectar bats. Behavioral and physiological similarities among hummingbirds, nectar bats, and other vertebrates suggest enhanced capacities for exogenous fuel use during exercise may be more wide spread than previously appreciated. Further, how the capacity for uptake and phosphorylation of circulating fructose is enhanced remains a tantalizing unknown. PMID- 25031040 TI - A case of CD68 negative histiocytic sarcoma of axilla masquerading as metastatic breast cancer. AB - Histiocytic sarcoma is a malignant proliferation of cells showing morphological and immunophenotypic features of mature tissue histiocytes. Most of the cases in the literature have reported CD68 positivity. We report a case of histiocytic sarcoma whose presentation mimicked a metastatic breast cancer. A 40-year-female patient presented with a 13 * 11 cm left axillary mass in close proximity to the left breast. Tru-cut biopsy from the lesion suggested the diagnosis of a lymphoid neoplasm. Complete excision of the axillary mass was done. On simple microscopy, numerous mature small lymphocytes were seen dispersed in the follicles. Immunohistochemistry revealed CD31- and CD163-positive cells, which stained negative for CD68, CD1a, cytokeratin and S100; thus, confirming the diagnosis of histiocytic sarcoma. PMID- 25031041 TI - Perspectives on a combined test of multi serum biomarkers in China: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. AB - China has 50% of the worldwide hepatocellular carcinoma (HCC) cases, and the HBV related cases accounts for approximately 85%. Over the past few decades, although a series of standardized management methods for HCC has been implemented in China, most HCC patient in China still suffered from advanced-stage disease, in consequence, reducing the opportunity of curable treatment that can be offered to achieve long-term disease-free survival for HCC patient. Accordingly, strategies including screening and diagnose HCC at an earlier stage are urgently needed in China. In this study, the current status, challenges, and prospects of early detection of HCC in China have been analyzed. The result indicated the need for using multi serum biomarkers for early HCC detection. During the past ten years, the research on the clinical usefulness of novel serum biomarkers of des-gamma carboxy-prothrombin (DCP), Dickkopf-1 (DKK1) and Midkine (MDK) in early HCC detection for Chinese patients found that the novel serum biomarker can complete the measurement of alpha-fetoprotein (AFP) in the diagnosis process of HCC, particularly for the patient with negative AFP with/or at an early stage. More large-scale, multi-center studies are expected to be performed in China to provide further evidence, and using novel and reliable serum biomarkers to complement AFP as a new trend is expected to be extensively used in clinical practice to facilitate early detection for those patients with HCC in China. PMID- 25031042 TI - Synthesis and biological evaluation of novel indoline-2,3-dione derivatives as antitumor agents. AB - A new series of 1,5-disubstituted indolin-2,3-diones was synthesized and their inhibition of the growth of a human acute promyelocytic leukemia (HL-60) cell line was evaluated. These compounds had promising inhibition of HL-60 cell growth in vitro. Results indicated that compounds with a benzyl substituent at the N-1 position on the indolin-2,3-dione ring had more potent antiproliferative activity than those with a (4-fluorobenzyl) amino-2-oxoethyl substituent at the N-1 position. Among the compounds synthesized, compound 8l inhibited half of cell growth at a concentration of 0.07 MUM and compound 8p did so at a concentration of 0.14 MUM. These compounds may serve as lead compounds for further optimization in order to develop novel anticancer agents. PMID- 25031043 TI - Synthesis and crystal structure of 6-fluoro-3-hydroxypyrazine-2-carboxamide. AB - As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA viruses in vitro and in vivo. A four-step synthesis of the compound is described in this article, amidation, nitrification, reduction and fluorination with an overall yield of about 8%. In addition, we reported the crystal structure of the title compound. The molecule is almost planar and the intramolecular O-H(***)O hydrogen bond makes a 6-member ring. In the crystal, molecules are packing governed by both hydrogen bonds and stacking interactions. PMID- 25031044 TI - Effectiveness of Chinese prescription Kangen-karyu for dyslipi-demia, using 3T3 L1 adipocytes and type 2 diabetic mice. AB - The Chinese prescription Kangen-karyu, comprised of six crude drugs, has received much attention due to its numerous biological activities. The present study was conducted to examine whether Kangen-karyu has an ameliorative effect on dyslipidemia. The effect of Kangen-karyu was evaluated using 3T3-L1 adipocytes, and also db/db mice as an experimental model for diabetic dyslipidemia. Kangen karyu significantly inhibited adipocyte differentiation and lipid accumulation. Kangen-karyu also down-regulated the mRNA levels of peroxisome proliferator activated receptor (PPAR)gamma, sterol regulatory element-binding protein (SREBP) 1c, and fatty acid synthase, and the protein levels of aP2 and PPARgamma, which indicates that Kangen-karyu inhibited adipogenesis during adipocyte differentiation, and may have potential anti-dyslipidemia effects. In addition, the administration of Kangen-karyu reduced hyperlipidemia in db/db type 2 diabetic mice through a decline in the serum levels of lipids, and an improvement of lipoprotein profiles. The enhanced hepatic triglyceride level of the db/db mice was significantly reduced by Kangen-karyu administration through the down regulation of SREBP-1 and lipogenic enzymes in the liver. These findings indicate that Kangen-karyu exerts anti-dyslipidemia effects in adipocytes and type 2 diabetic db/db mice. PMID- 25031045 TI - Management of inappropriate sinus tachycardia with ivabradine in a renal transplant recipient. AB - Inappropriate sinus tachycardia (IST) is a syndrome characterized by unexplained tachycardia (heart rate > 100 beats /min) and related symptoms at rest. We describe a case of a 35 year old male with end stage renal disease who developed IST after renal transplant in the surgical intensive care unit. Management of IST is usually nonspecific and includes bradycardic agents, radiofrequency ablation or surgical ablation of the sinus node. This patient was well managed with ivabradine (If pacemaker current inhibitor) after failure and intolerance of beta adrenergic blockers. PMID- 25031046 TI - Can gamma-glutamyl transferase levels contribute to a better prognosis for patients with hepatocellular carcinoma? AB - Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Hepatic resection has long been considered a main treatment option for HCC, but the high rate of recurrence after hepatic resection remains a problem that impacts the prognosis and survival of patients with HCC. Thus, clarifying the factors for survival and risk factors for tumor recurrence after hepatic resection is crucial. Imaging studies are currently emphasized before selecting a treatment and predicting the prognosis for patients with HCC. Recently, laboratory testing of des-gamma-carboxyprothrombin (DCP), alpha-fetoprotein (AFP), indocyanine green 15 min after administration (ICG-R15), and gamma-glutamyl transpeptidase (gamma GTP) has garnered attention as a way to select treatment and predict the prognosis of patients with HCC. gamma-GTP in particular has critical clinical significance as an indicator of prognosis. This indicator helps to predict prognosis and it helps with the selection of further treatment, as was revealed by studies based on different subgroups of patients published in the past 5 years. The reason for the association between gamma-GTP and early recurrence and poor survival is being investigated. Preoperative laboratory results (DCP, AFP, ICG-R15, and gamma-GTP) may warrant attention and need to be fully evaluated before selecting a treatment and predicting prognosis in order to improve the prognosis for patients with HCC. PMID- 25031047 TI - Social disorder and diagnostic order: the US Mental Hygiene Movement, the Midtown Manhattan study and the development of psychiatric epidemiology in the 20th century. AB - Recent scholarship regarding psychiatric epidemiology has focused on shifting notions of mental disorders. In psychiatric epidemiology in the last decades of the 20th century and the first decade of the 21st century, mental disorders have been perceived and treated largely as discrete categories denoting an individual's mental functioning as either pathological or normal. In the USA, this grew partly out of evolving modern epidemiological work responding to the State's commitment to measure the national social and economic burdens of psychiatric disorders and subsequently to determine the need for mental health services and to survey these needs over time. Notably absent in these decades have been environmentally oriented approaches to cultivating normal, healthy mental states, approaches initially present after World War II. We focus here on a set of community studies conducted in the 1950s, particularly the Midtown Manhattan study, which grew out of a holistic conception of mental health that depended on social context and had a strong historical affiliation with: the Mental Hygiene Movement and the philosophy of its founder, Adolf Meyer; the epidemiological formation of field studies and population surveys beginning early in the 20th century, often with a health policy agenda; the recognition of increasing chronic disease in the USA; and the radical change in orientation within psychiatry around World War II. We place the Midtown Manhattan study in historical context--a complex narrative of social institutions, professional formation and scientific norms in psychiatry and epidemiology, and social welfare theory that begins during the Progressive era (1890-1920) in the USA. PMID- 25031048 TI - The World Health Organization and the contested beginnings of psychiatric epidemiology as an international discipline: one rope, many strands. AB - This paper focuses on the relatively late emergence of psychiatric epidemiology as an international discipline, through local-global exchanges during the first 15 years of the World Health Organization (WHO). Building an epidemiological canon within WHO's Mental Health Programme faced numerous obstacles. First, an idealist notion of mental health inherent in WHO's own definition of health contributed to tensions around the object of psychiatric epidemiology. Second, the transfer of methods from medical epidemiology to research on mental disorders required mobilizing conceptual justifications, including a 'contagion argument'. Third, epidemiological research at WHO was stymied by other public health needs, resource scarcity and cultural barriers. This history partly recapitulates the development of psychiatric epidemiology in North America and Europe, but is also shaped by concerns in the developing world, translated through first-world 'experts'. Resolving the tensions arising from these obstacles allowed WHO to establish its international schizophrenia research, which in turn provided proof of concept for psychiatric epidemiology in the place of scepticism within and without psychiatry. PMID- 25031049 TI - Five years of implementation of guidelines in hematology and transfusion medicine in Brazil. PMID- 25031050 TI - Shed some (sun)light on vitamin D deficiency. PMID- 25031051 TI - Comments on: frequency of alleles and haplotypes of the human leukocyte antigen system in Bauru, Sao Paulo. PMID- 25031052 TI - Spirituality, religiousness and health: implications for the field of hematology. PMID- 25031053 TI - Utility of the p53 mutant protein in patients with low-risk myelodysplastic syndrome. PMID- 25031054 TI - Scientific comment on tumor suppressor p53 protein expression: prognostic significance in patients with low-risk myelodysplastic syndrome. PMID- 25031055 TI - Comment on: Homocysteine and vitamin B12 status and iron deficiency anemia in female university students from Gaza, Palestine. PMID- 25031056 TI - Normal lymphocyte immunophenotype in an elderly population. AB - OBJECTIVE: The aim of this work was to evaluate the lymphocyte immunophenotype in an elderly population. METHODS: This study enrolled 35 over 60-year-old volunteers and a control group composed of 35 young adults. The study included elderly without diseases that might affect the functioning of the immune system. These individuals were consulted by doctors and after a physical examination, laboratory tests were performed using a Beckman Coulter((r)) flow cytometer. The GraphPad Prism computer program was employed for statistical analysis with the level of significance being set for p-values <0.05. RESULTS: There is a statistically significant reduction in the number of lymphocytes (CD8(+), CD2(+) and CD3(+) cells) in the elderly compared to young adults. These low rates are explained by changes attributed to aging and may be partly responsible for the reduction in the cellular immune response, lower proliferative activity and the low cytotoxicity of lymphocytes. CONCLUSION: These parameters showed greater impairment of adaptive immunity in the elderly population and can therefore explain the greater fragility of the aged body to developing diseases. PMID- 25031057 TI - Association between religiousness and blood donation among Brazilian postgraduate students from health-related areas. AB - OBJECTIVE: The aim of this study was to examine the association between religiousness and blood donation among postgraduate students. METHODS: The Portuguese-language version of the Duke University Religion Index was administered to a sample of 226 Brazilian students with ages ranging from 22 to 55 years. All study participants had completed undergraduate courses in health related areas. RESULTS: In the present study, 23.5% of the students were regular donors. Organizational religiousness was found to be associated with attitudes related to blood donation. This study also shows evidence that regular blood donors have a higher intrinsic religiousness than subjects who donate only once and do not return. CONCLUSION: This study shows that the attitudes concerning blood donation may have some association with religiosity. PMID- 25031058 TI - Risk factors associated with the occurrence of adverse events in plateletpheresis donation. AB - OBJECTIVE: To recognize the profile of platelet donors and the profile of the plateletpheresis session as well as to investigate the main adverse events of platelet donation using plateletpheresis and associated risk factors. METHODS: This retrospective, cross-sectional and analytical study was performed with a quantitative approach by analyzing 316 donation files from February 2010 to December 2011. The IBM SPSS Statistics program was used for data processing and analysis. The chi-square test was used to verify whether there was an association between factors related to the procedure and the donor, and the adverse events that occurred. RESULTS: The mean age of platelet donors was 40 years old (standard deviation=8.9), with the prevalent age group being between 40 and 49 years old; the prevalent blood type was O positive (53.8%), the mean duration of the procedure was 73min and the mean amount of anticoagulant used was 360mL. The association between procedure duration and the volume of anticoagulant was inverse and statistically significant; the longer the procedure and the greater the volume of anticoagulant used, the less adverse reactions occurred. CONCLUSION: The low incidence of adverse events indicates that the procedure is well tolerated by donors. Obtaining data regarding the incidence of adverse events is a way of promoting a dynamic review of medical and nursing teams to improve the safety and comfort of the donor. PMID- 25031059 TI - Tumor suppressor p53 protein expression: prognostic significance in patients with low-risk myelodysplastic syndrome. AB - BACKGROUND: At the time of diagnosis, more than 50% of patients with myelodysplastic syndrome have a normal karyotype and are classified as having a favorable prognosis. However, these patients often show very variable clinical outcomes. Furthermore, current diagnostic tools lack the ability to look at genetic factors beyond karyotyping in order to determine the cause of this variability. OBJECTIVE: To evaluate the impact of p53 protein expression at diagnosis in patients with low-risk myelodysplastic syndrome. METHODS: This study enrolled 38 patients diagnosed with low-risk myelodysplastic syndrome. Clinical data were collected by reviewing medical records, and immunohistochemical p53 staining was performed on bone marrow biopsies. RESULTS: Of the 38 participants, 13 (34.21%) showed p53 expression in their bone marrow. At diagnosis, this group of patients also presented clinical features characteristic of a poor prognosis more often than patients who did not express p53. Furthermore, patients expressing p53 had a shorter median survival time compared to those without p53 expression. CONCLUSION: This study shows that the expression of p53 at diagnosis is a useful indicator of distinct clinical characteristics and laboratory profiles found in low-risk myelodysplastic syndrome patients. These data indicate that the immunohistochemical analysis of p53 may be a prognostic tool for myelodysplastic syndrome and should be used as an auxiliary test to help determine the best therapeutic choice. PMID- 25031060 TI - Genetic evaluation of mesenchymal stem cells by G-banded karyotyping in a Cell Technology Center. AB - OBJECTIVE: To present the initial results of first three years of implementation of a genetic evaluation test for bone marrow-derived mesenchymal stem cells in a Cell Technology Center. METHODS: A retrospective study was carried out of 21 candidates for cell therapy. After the isolation of bone marrow mononuclear cells by density gradient, mesenchymal stem cells were cultivated and expanded at least until the second passage. Cytogenetic analyses were performed before and after cell expansion (62 samples) using G-banded karyotyping. RESULTS: All the samples analyzed, before and after cell expansion, had normal karyotypes, showing no clonal chromosomal changes. Signs of chromosomal instability were observed in 11 out of 21 patients (52%). From a total of 910 analyzed metaphases, five chromatid gaps, six chromatid breaks and 14 tetraploid cells were detected giving as total of 25 metaphases with chromosome damage (2.75%). CONCLUSION: The absence of clonal chromosomal aberrations in our results for G-banded karyotyping shows the maintenance of chromosomal stability of bone marrow-derived mesenchymal stem cells until the second passage; however, signs of chromosomal instability such as chromatid gaps, chromosome breaks and tetraploidy indicate that the long-term cultivation of these cells can provide an intermediate step for tumorigenesis. PMID- 25031061 TI - Homocysteine and vitamin B12 status and iron deficiency anemia in female university students from Gaza Strip, Palestine. AB - OBJECTIVE: Nutritional deficiencies are very significant to the overall health of humans at all ages and for both genders, yet in infants, children and women of childbearing age these deficiencies can seriously affect growth and development. The present work is aimed to assess homocysteine and vitamin B12 status in females with iron deficiency anemia from the Gaza Strip. METHODS: Venous blood samples were randomly collected from 240 female university students (18-22 years old) and parameters of the complete blood count, serum ferritin, homocysteine and vitamin B12 were measured. Statistical analysis included the t-test and analysis of variance (ANOVA) using the IBM SPSS software (version 18). Statistical significance was set for p-values <0.05. RESULTS: The results revealed that 20.4% of the students have iron deficiency anemia. The mean serum vitamin B12 level in females with iron deficiency anemia (212.9+/-62.8pg/mL) was significantly lower than in normal controls (286.9+/-57.1pg/mL) and subjects with microcytic anemia and normal ferritin (256.7+/-71.1pg/mL). Significantly higher serum homocysteine levels were reported in the iron deficiency anemia group (27.0+/-4.6MUmol/L) compared to normal controls (15.5+/-2.9MUmol/L) and in subjects with microcytic anemia and normal ferritin (18.1+/-2.7MUmol/L). Statistically significant negative correlations were reported for serum homocysteine with serum ferritin, vitamin B12, hemoglobin, and hematocrit levels. CONCLUSION: Important associations were found between serum homocysteine and markers of iron deficiency. Monitoring homocysteine levels might be essential to understand the development of different clinical conditions including anemia. It seems necessary to conduct prospective trials to determine whether treating anemia ameliorates homocysteine levels. PMID- 25031062 TI - Murine leukemia virus-derived retroviral vector has differential integration patterns in human cell lines used to produce recombinant factor VIII. AB - OBJECTIVE: Nowadays recombinant factor VIII is produced in murine cells including in Chinese hamster ovary (CHO) and baby hamster kidney cells (BHK). Previous studies, using the murine leukemia virus-derived retroviral vector pMFG-FVIII P140K, modified two recombinant human cell lines, HepG2 and Hek293 to produce recombinant factor VIII. In order to characterize these cells, the present study aimed to analyze the integration pattern of retroviral vector pMFG-FVIII-P140K. METHODS: This study used ligation-mediated polymerase chain reaction to locate the site of viral vector integration by sequencing polymerase chain reaction products. The sequences were compared to genomic databases to characterize respective clones. RESULTS: The retroviral vector presented different and non random profiles of integration between cells lines. A preference of integration for chromosomes 19, 17 and 11 was observed for HepG2FVIIIdB/P140K and chromosome 9 for Hek293FVIIIdB/P140K. In genomic regions such as CpG islands and transcription factor binding sites, there was no difference in the integration profiles for both cell lines. Integration in intronic regions of encoding protein genes (RefSeq genes) was also observed in both cell lines. Twenty percent of integrations occurred at fragile sites in the genome of the HepG2 cell line and 17% in Hek293. CONCLUSION: The results suggest that the cell type can affect the profile of chromosomal integration of the retroviral vector used; these differences may interfere in the level of expression of recombinant proteins. PMID- 25031063 TI - Are the review criteria for automated complete blood counts of the International Society of Laboratory Hematology suitable for all hematology laboratories? AB - OBJECTIVE: to verify whether the review criteria for automated blood counts suggested by the International Consensus Group for Hematology Review of the International Society for Laboratory Hematology are suitable for the Hematology Laboratory of Hospital de Clinicas, Universidade Federal do Parana. METHODS: initially, the review criteria of the International Society for Laboratory Hematology were adapted due to limitations in the Institution's electronic hospital records and interfacing systems. The adapted review criteria were tested using 1977 samples. After this first assessment, an additional 180 inpatient samples were analyzed to evaluate the screening criteria of the review criteria in conjunction with positive smear findings established by the institution. The performance of the review criteria was verified by determining false positive, false negative, true positive and true negative rates, sensitivity, specificity, positive predictive value, negative predictive value, microscopic review rate and efficiency. RESULTS: initial analysis showed false negatives=6.73%, false positives=23.27%, microscopic review rate=46.03% and efficiency=70.0%. An evaluation of the screening criteria adapted from the review criteria together with the positive smear findings of the institution showed false negatives=15.5%, false positives=10.5%, microscopic review rate=37.3% and efficiency=73.8%. In both situations the safety limit (false negative <5%) recommended by the review criteria was exceeded. CONCLUSIONS: the review criteria adapted from the International Society for Laboratory Hematology are neither suitable nor safe for use in the hematology laboratory of the Hospital de Clinicas. This implies a need to develop and validate institution-specific review criteria in order to decrease false negative results to an acceptable and safe rate for patients. PMID- 25031064 TI - Systemic mastocytosis - a diagnostic challenge. AB - Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. It is a rare hematologic disorder in all its forms. The exact incidence is unknown; it affects patients of any age and males and females equally. Its molecular pathogenesis is incompletely understood. The clinical features of mastocytosis result from both chronic and episodic mast cell mediator release, signs and symptoms arising from diffuse or focal tissue infiltration, and, occasionally, the presence of an associated non-mast cell clonal hematologic disease. The histopathologic analysis is essential for definitive diagnosis but there is no curative treatment. The authors report a clinical case of a 72-year-old woman with no history of allergies, with bicytopenia, weight loss, and diffuse axial osteolytic lesions. This is a rare clinical case of aggressive systemic mastocytosis for which palliative treatment can improve survival and quality of life. A brief review of the literature about this pathology is also included. PMID- 25031065 TI - De novo alpha 2 hemoglobin gene (HBA2) mutation in a child with hemoglobin M Iwate and symptomatic methemoglobinemia since birth. AB - Cyanosis in an apparently healthy newborn baby may be caused by hemoglobin variants associated with the formation of methemoglobin, collectively known as M hemoglobins. They should not be confused with genetic alterations in methemoglobin reductase enzyme systems of red cells since treatment and prognosis are completely different. A newborn male child was noted to be significantly cyanotic at birth and is the basis for this report. Hemoglobin isoelectric focusing, acid and alkaline gel electrophoresis, and HBA/HBB gene sequencing were performed for the child, both parents and a sister. The newborn child was treated with methylene blue in an intensive care unit fearing that he had a defective reductase system and exposure to oxidant drugs or toxins. Newborn hemoglobin screening with high performance liquid chromatography was abnormal on the 10th and 45th days but no conclusive diagnosis was reached. Cyanosis persisted up to four years of age with no other symptoms. Hemoglobin M Iwate [alpha2 87(F8) His>Tyr, HBA2:c.262C>T] was detected. It was not present in the child's presumed mother, father, sister, and brother. The analysis of 15 short tandem repeats in the trio demonstrated a de novo mutation occurrence (p-value<1*10(-8)). The family was reassured that no further action was necessary and genetic counseling was provided. Methemoglobins should be considered for differential diagnosis of cyanosis in newborns even if no familial cases are detected. Except for cosmetic consequences, the clinical course of patients with hemoglobin M Iwate is unremarkable. PMID- 25031066 TI - Thrombohemostatic disorders in the new emerging H7N9 influenza. PMID- 25031067 TI - Extracting a respiratory signal from raw dynamic PET data that contain tracer kinetics. AB - Data driven gating (DDG) methods provide an alternative to hardware based respiratory gating for PET imaging. Several existing DDG approaches obtain a respiratory signal by observing the change in PET-counts within specific regions of acquired PET data. Currently, these methods do not allow for tracer kinetics which can interfere with the respiratory signal and introduce error. In this work, we produced a DDG method for dynamic PET studies that exhibit tracer kinetics. Our method is based on an existing approach that uses frequency-domain analysis to locate regions within raw PET data that are subject to respiratory motion. In the new approach, an optimised non-stationary short-time Fourier transform was used to create a time-varying 4D map of motion affected regions. Additional processing was required to ensure that the relationship between the sign of the respiratory signal and the physical direction of movement remained consistent for each temporal segment of the 4D map. The change in PET-counts within the 4D map during the PET acquisition was then used to generate a respiratory curve. Using 26 min dynamic cardiac NH3 PET acquisitions which included a hardware derived respiratory measurement, we show that tracer kinetics can severely degrade the respiratory signal generated by the original DDG method. In some cases, the transition of tracer from the liver to the lungs caused the respiratory signal to invert. The new approach successfully compensated for tracer kinetics and improved the correlation between the data-driven and hardware based signals. On average, good correlation was maintained throughout the PET acquisitions. PMID- 25031068 TI - Evidence-based estimation of insulin resistance. AB - Insulin resistance is a complex phenotype. Surrogate markers based on peripheral glucose and insulin (and in some cases NEFA) concentrations can provide, at best, moderate approximations to direct physiological measurements (Pearson r values 0.6-0.7). Where the focus is solely on insulin resistance, the evidence reviewed in the paper by Otten et al in this issue (DOI: 10.1007/s00125-014-3285-x ) suggests that surrogate markers based on fasting samples alone are as valid as those that require multiple samples and an oral glucose load. This provides an evidence base for simplifying the design of some clinical studies. PMID- 25031069 TI - Fermentable fibres condition colon microbiota and promote diabetogenesis in NOD mice. AB - AIMS/HYPOTHESIS: Gut microbiota (GM) and diet both appear to be important in the pathogenesis of type 1 diabetes. Fermentable fibres (FFs), of which there is an ample supply in natural, diabetes-promoting diets, are used by GM as a source of energy. Our aim was to determine whether FFs modify GM and diabetes incidence in the NOD mouse. METHODS: Female NOD mice were weaned to a semisynthetic diet and the effects of FF supplementation on diabetes incidence and insulitis were evaluated. Real-time quantitative PCR was employed to determine the effects imposed to gene transcripts in the colon and lymph nodes. Changes to GM were analysed by next-generation sequencing. RESULTS: NOD mice fed semisynthetic diets free from FFs were largely protected from diabetes while semisynthetic diets supplemented with the FFs pectin and xylan (PX) resulted in higher diabetes incidence. Semisynthetic diet free from FFs altered GM composition significantly; addition of PX changed the composition of the GM towards that found in natural diet-fed mice and increased production of FF-derived short-chain fatty acid metabolites in the colon. The highly diabetogenic natural diet was associated with expression of proinflammatory and stress-related genes in the colon, while the semisynthetic diet free from FFs promoted Il4, Il22, Tgfbeta and Foxp3 transcripts in the colon and/or pancreatic lymph node. PX in the same diet counteracted these effects and promoted stress-related IL-18 activation in gut epithelial cells. 16S RNA sequencing revealed each diet to give rise to its particular GM composition, with different Firmicutes to Bacteroidetes ratios, and enrichment of mucin-degrading Ruminococcaceae following diabetes-protective FF free diet. CONCLUSIONS/INTERPRETATION: FFs condition microbiota, affect colon homeostasis and are important components of natural, diabetes-promoting diets in NOD mice. PMID- 25031070 TI - Common GI Drug Interactions in the Elderly. AB - OPINION STATEMENT: The careful review of drug-drug interactions is vital to the safe prescribing of medications for chronic medical conditions. The elderly population suffers from multiple medical problems, and polypharmacy leads to further morbidity in this vulnerable group of patients. We discuss gastrointestinal conditions such as GERD, peptic ulcer disease, gastroparesis, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, chronic liver disease and the commonly used medications in these conditions. Treatment options must be individualized and tailored to accommodate the underlying pharmacokinetics and known drug-drug interactions. The indication for the use of a therapeutic agent in the elderly and the duration of use must be frequently readdressed to help prevent polypharmacy and adverse drug reactions. Medications should be started at a low dose with careful titration to achieve a clinical response to prevent toxicity. The aim of this article is to increase awareness of important drug-drug interactions of commonly prescribed gastrointestinal medications in the elderly. PMID- 25031071 TI - Aberrant expression of nuclear KPNA2 is correlated with early recurrence and poor prognosis in patients with small hepatocellular carcinoma after hepatectomy. AB - Karyopherin alpha2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. Emerging evidence suggests that KPNA2 plays a crucial role in oncogenesis and early recurrence. In the present study, we evaluated the expression pattern of KPNA2 in 221 hepatocellular carcinoma (HCC) specimens and matching adjacent, non-tumorous tissues (NT) by immunohistochemical assays. We found that nuclear KPNA2 expression was significantly upregulated (30.3 %, 67/221) in HCC tissues; however, no nuclear expression of KPNA2 in NT tissues was observed. A correlation analysis demonstrated that nuclear KPNA2 expression was positively associated with serum AFP level, tumor differentiation, vascular invasion, BCLC stage and early recurrence (all p < 0.05). Nuclear KPNA2 expression was associated with a poor prognosis in HCC patients. Univariate and multivariate analyses demonstrated that KPNA2 was an independent prognostic factor for both overall survival (p < 0.001) and time to recurrence (p < 0.001) in HCC patients. Furthermore, in a validation cohort, nuclear expression of KPNA2 was observed in 16 of 47 (34.0 %) small hepatocellular carcinoma patients. Importantly, the risk of recurrence associated with nuclear KPNA2 expression (9/16, 56.2 %) was significantly higher than the risk associated with an absence of nuclear KPNA2 expression (6/31, 19.3 %; p = 0.01). Our results demonstrate that nuclear KPNA2 expression is a poor prognostic biomarker for HCC, especially for early-stage HCC. PMID- 25031072 TI - Robot-assisted nephroureterectomy for upper tract urothelial carcinoma: the Taiwan Robot Urological Surgery Team (TRUST) experience. AB - BACKGROUND: To report Taiwan's experience in robot-assisted laparoscopic nephroureterectomy (RANU) for upper tract urothelial carcinoma (UTUC). METHODS: Twenty patients with a diagnosis of renal pelvic or ureteral urothelial carcinoma underwent RANU at three medical centers. We performed RANU by re-docking the robot after the nephrectomy with or without repositioning for excision of the distal ureter and bladder cuff. RESULTS: From November 2010 to July 2013, a total of 20 patients with a mean age of 70.1 +/- 9.9 years (range 43 to 92 years) and mean body mass index (BMI) of 22.9 +/-3.8 kg/m2 underwent RANU for renal pelvic or ureteral urothelial carcinoma. Mean operative time was 251.6 +/- 126.7 minutes (range 110 to 540 minutes), estimated blood loss was 50.0 +/- 42.9 mL (range 10 to 200 mL), and mean length of hospital stay was 6.7 +/- 2.4 days (range 4 to 12 days). Pathology data revealed 19 high and one low-grade urothelial carcinoma and staged Ta for three, T1 for five, T2 for five and T3 for seven. With a mean follow-up of 14.7 months (range 2 to 34 months), three intravesical recurrences developed in the bladder, and four of them also developed metastatic disease. CONCLUSIONS: The TRUST early experience showed that RANU is a safe and feasible minimally invasive procedure for UTUC. PMID- 25031073 TI - Psychotropic medication in geriatric psychiatric patients: use and unreported use in relation to serum concentrations. AB - PURPOSE: The aim of this observational study was to describe the type, number, and serum concentration levels of psychotropic drugs in elderly patients, on admission to a geriatric psychiatric inpatient unit. We further wanted to investigate the use and unreported use of psychotropic drugs by analyzing for a broad spectrum of drugs in the serum samples. METHODS: A total of 236 patients were included. Drug use, patient characteristics, and diagnoses were recorded, and serum analysis was performed for a total of 56 psychotropic drugs in 233 of the patients. RESULTS: Nine out of ten patients (88%) used one or more psychotropic drugs on admission to hospital; the mean use was 2.8 (95% confidence interval (CI) 2.6-2.9) drugs. In 25 patients (11%), drugs reported used were not detected in serum. Unreported use of drugs (serum analysis revealing one or more drugs not reported) was found in 100 patients (43%). This was more common in younger patients. Psychotropic polypharmacy (use of three or more psychotropic drugs) was found in 109 patients (47%). Patients with a main diagnosis of affective disorder used the most psychotropic drugs. CONCLUSIONS: Psychotropic drugs are commonly used among geriatric psychiatric patients on admission to hospital. Psychotropic polypharmacy is a major concern among these patients. There was considerable unreported use of drugs within this population, and a low threshold for a broader serum analysis for psychotropic drugs appears indicated. PMID- 25031074 TI - Ocular and systemic pharmacokinetics of lidocaine hydrochloride ophthalmic gel in rabbits after topical ocular administration. AB - Lidocaine hydrochloride ophthalmic gel is a novel ophthalmic preparation for topical ocular anesthesia. The study is aimed at evaluating the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. Thirty-six rabbits were randomly placed in 12 groups (3 rabbits per group). The rabbits were quickly killed according to their groups at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose and then the ocular tissue and plasma samples were collected. All the samples were analyzed by a validated LC-MS/MS method. The test result showed that the maximum concentration (C max) of lidocaine in different ocular tissues and plasma were all achieved within 20 min after drug administration, and the data of C max were (2,987 +/- 1814) MUg/g, (44.67 +/- 12.91) MUg/g, (26.26 +/- 7.19) MUg/g, (11,046 +/- 2,734) ng/mL, and (160.3 +/- 61.0) ng/mL for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The data of the elimination half-life in these tissues were 1.5, 3.2, 3.5, 1.9, and 1.7 h for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The intraocular lidocaine levels were significantly higher than that in plasma, and the elimination half-life of lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. The high intraocular penetration, low systemic exposure, and long duration in the ocular tissues suggested lidocaine hydrochloride 3.5 % ophthalmic gel as an effective local anesthetic for ocular anesthesia during ophthalmic procedures. PMID- 25031075 TI - ChemStable: a web server for rule-embedded naive Bayesian learning approach to predict compound stability. AB - Predicting compound chemical stability is important because unstable compounds can lead to either false positive or to false negative conclusions in bioassays. Experimental data (COMDECOM) measured from DMSO/H2O solutions stored at 50 degrees C for 105 days were used to predicted stability by applying rule-embedded naive Bayesian learning, based upon atom center fragment (ACF) features. To build the naive Bayesian classifier, we derived ACF features from 9,746 compounds in the COMDECOM dataset. By recursively applying naive Bayesian learning from the data set, each ACF is assigned with an expected stable probability (p(s)) and an unstable probability (p(uns)). 13,340 ACFs, together with their p(s) and p(uns) data, were stored in a knowledge base for use by the Bayesian classifier. For a given compound, its ACFs were derived from its structure connection table with the same protocol used to drive ACFs from the training data. Then, the Bayesian classifier assigned p(s) and p(uns) values to the compound ACFs by a structural pattern recognition algorithm, which was implemented in-house. Compound instability is calculated, with Bayes' theorem, based upon the p(s) and p(uns) values of the compound ACFs. We were able to achieve performance with an AUC value of 84% and a tenfold cross validation accuracy of 76.5%. To reduce false negatives, a rule-based approach has been embedded in the classifier. The rule based module allows the program to improve its predictivity by expanding its compound instability knowledge base, thus further reducing the possibility of false negatives. To our knowledge, this is the first in silico prediction service for the prediction of the stabilities of organic compounds. PMID- 25031076 TI - Molecular insight into gamma-gamma tubulin lateral interactions within the gamma tubulin ring complex (gamma-TuRC). AB - gamma-Tubulin is essential for the nucleation and organization of mitotic microtubules in dividing cells. It is localized at the microtubule organizing centers and mitotic spindle fibres. The most well accepted hypothesis for the initiation of microtubule polymerization is that alpha/beta-tubulin dimers add onto a gamma-tubulin ring complex (gammaTuRC), in which adjacent gamma-tubulin subunits bind to the underlying non-tubulin components of the gammaTuRC. This template thus determines the resulting microtubule lattice. In this study we use molecular modelling and molecular dynamics simulations, combined with computational MM-PBSA/MM-GBSA methods, to determine the extent of the lateral atomic interaction between two adjacent gamma-tubulins within the gammaTuRC. To do this we simulated a gamma-gamma homodimer for 10 ns and calculated the ensemble average of binding free energies of -107.76 kcal/mol by the MM-PBSA method and of -87.12 kcal/mol by the MM-GBSA method. These highly favourable binding free energy values imply robust lateral interactions between adjacent gamma-tubulin subunits in addition to their end-interactions longitudinally with other proteins of gammaTuRC. Although the functional reconstitution of gamma-TuRC subunits and their stepwise in vitro assembly from purified components is not yet feasible, we nevertheless wanted to recognize hotspot amino acids responsible for key gamma-gamma interactions. Our free energy decomposition data from converting a compendium of amino acid residues identified an array of hotspot amino acids. A subset of such mutants can be expressed in vivo in living yeast. Because gammaTuRC is important for the growth of yeast, we could test whether this subset of the hotspot mutations support growth of yeast. Consistent with our model, gamma-tubulin mutants that fall into our identified hotspot do not support yeast growth. PMID- 25031077 TI - Substituent effects in 1-nitro-4-substituted bicyclo[2.2.2]octane derivatives: inductive or field effects? AB - Interactions between the NO2 group and 13 different substituents (BF2, BH2, CF3, CH3, CHO, CN, F, NH2, NMe2, NO2, NO, OH, OMe) were investigated computationally for bicyclo[2.2.2]octane (BCO) and benzene substituted at 1,4 and 1,3 positions in the ring. Three methods were employed to estimate the character and strength of the substituent effect: substituent effect stabilization energy (SESE), sigma/pi electron donor acceptor index (sEDA/pEDA) and substituent active region (cSAR) parameter. For the first time the sEDA/pEDA parameters were calculated not for the ring but for the NO2 group. All calculations were performed at the B3LYP/6-31G(d,p) level of theory. For 1,4 derivatives, a direct comparison of slopes of linear regressions between BCO and benzene reveals a much better transmission of the substituent effect in the latter. The ratio of slopes (benzene over BCO) is always larger than 4. It follows that the resonance effects, which are absent in the BCO, dominate in this case. For 1,3 derivatives, because of much lower correlation coefficients, estimated standard deviations (ESD) were used to calculate the ratio instead of the slopes. For these systems the ratio is much closer to the unity, which indicates that only the sigma/through space effects are present and they are of similar magnitude in benzene and BCO. It follows from natural population analysis (NPA) charges that the substituent effect in the studied systems is due mainly to through-space interactions. PMID- 25031078 TI - Spin-orbit splitting for inner-shell 2p states. AB - A strategy to calculate spin-orbit splitting for inner-shell transitions at an ab initio level is presented. The initial wave function is calculated for a spinless Hamiltonian at a multiconfigurational level, with just a few configurations, followed by multireference configuration interaction in order to establish a set of singlet and triplet states at 2p excitation edge. Then, the full Breit-Pauli Hamiltonian is formed and diagonalized on this state basis. The spin-orbit splitting is determined by a graphical procedure depending on the intensity of the transition from ground state. The specific states studied are those originating from 2p transitions in argon, HCl, H2S, and PH3. PMID- 25031079 TI - Study of interaction of human serum albumin with curcumin by NMR and docking. AB - Curcumin has been reported to be therapeutically active but has poor bioavailability, half life, and high rate of metabolic detoxifcation. Most of the hydrophobic and acidic drugs get transported through human serum albumin (HSA). Binding of drugs to serum protein increases their half-life. The present study is focused to analyze interaction of curcumin with HSA by NMR and docking studies. In order to investigate the binding affinity of curcumin with HSA, NMR based diffusion techniques and docking study have been carried out. We report that curcumin has shown comparable binding affinity value vis-a-vis standard, the accessible surface area (ASA) of human serum albumin (uncomplexed) and its docked complex with curcumin at both binding sites was calculated and found to be close to that of warfarin and diazepam respectively. Conclusion drawn from our study demonstrates that curcumin interacts with HSA strongly thereby its poor half life is due to high rate of its metabolic detoxification as reported in literature. PMID- 25031080 TI - Tunable electronic properties of ultra-thin boron-carbon-nitrogen heteronanotubes for various compositions. AB - A first-principles calculation was carried out to investigate the stability and electronic properties of ultra-thin Cx(BN)y heteronanotubes which were composed by joining pure CNT and BNNT segments with different composition and configurations. We found that the stability of Cx(BN)y heteronanotubes is increased with the increasing number of B and N atoms. In addition, all armchair (3,3) Cx|(BN)y heteronanotubes were found to be semiconductors with tunable energy gaps between 0.45 to 1.62 eV. Whereas zigzag (5,0) Cx|(BN)y heteronanotubes can be metal (y<=4) or semiconductor (y>4), and it is different from the relatively big zigzag Cx|(BN)y heteronanotubes which are always conductors. It indicates that the energy gap of (5,0) Cx|(BN)y heteronanotubes can be tuned by modifying the value of y. Further, zigzag (5,0) and armchair (3,3) C-BN heteronanotubes were found to be metal and semiconductor, respectively; but zigzag and armchair C-BN heteronanotubes with relatively big diameter are always semiconductor and conductor, respectively. Therefore, the electronic properties of ultra-thin Cx(BN)y heteronanotubes are abnormal when comparing with the relatively big ones. Highlights* The stability of Cx(BN)y heteronanotubes is increased with the increasing value of y.* Zigzag (5,0) Cx|(BN)y heteronanotubes can change from metal (y<=4) to semiconductor (y>4) when the value of y increases from 1 to 7.* The band gaps of armchair (3,3) Cx|(BN)y heteronanotubes increase from 0.45 to 1.62 eV when the value of y increases from 1 to 7.* The electronic properties (energy gap) of Cx(BN)y heteronanotubes are tunable and different in comparison with the relatively big ones. PMID- 25031081 TI - Theoretical study of adsorption of nitrogen-containing environmental contaminants on kaolinite surfaces. AB - The adsorption of nitrogen-containing compounds (NCCs) including 2,4,6 trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), 2,4-dinitroanisole (DNAN), and 3 nitro-1,2,4-triazol-5-one (NTO) on kaolinite surfaces was investigated. The M06 2X and M06-2X-D3 density functionals were applied with the cluster approximation. Several different positions of NCCs relative to the adsorption sites of kaolinite were examined, including NCCs in perpendicular and parallel orientation toward both surface models of kaolinite. The binding between the target molecules and kaolinite surfaces was analyzed and bond energies were calculated applying the atoms in molecules (AIM) method. All NCCs were found to prefer a parallel orientation toward both kaolinite surfaces, and were bound more strongly to the octahedral than to the tetrahedral site. TNT exhibited the strongest interaction with the octahedral surface and DNAN with the tetrahedral surface of kaolinite. Hydrogen bonding was shown to be the dominant non-covalent interaction for NCCs interacting with the octahedral surface of kaolinite with a small stabilizing effect of dispersion interactions. In the case of adsorption on the tetrahedral surface, kaolonite-NCC binding was shown to be governed by the balance between hydrogen bonds and dispersion forces. The presence of water as a solvent leads to a significant decrease in the adsorption strength for all studied NCCs interacting with both kaolinite surfaces. PMID- 25031082 TI - Main chemical species and molecular structure of deep eutectic solvent studied by experiments with DFT calculation: a case of choline chloride and magnesium chloride hexahydrate. AB - The infrared spectrum of deep eutectic solvent of choline chloride and magnesium chloride hexahydrate was measured by the FTIR spectroscopy and analyzed with the aid of DFT calculations. The main chemical species and molecular structure in deep eutectic solvent of [MgClm(H2O)6-m]2-m and [ChxCly]x+y complexes were mainly identified and the active ion of magnesium complex during the electrochemical process was obtained. The mechanism of the electrochemical process of deep eutectic solvent of choline chloride and magnesium chloride hexahydrate was well explained by combination theoretical calculations and experimental. Besides, based on our results we proposed a new system for the dehydration study of magnesium chloride hexahydrate. PMID- 25031083 TI - Role of pH in structural changes for Pin1 protein: an insight from molecular dynamics study. AB - Pin1 protein is closely associated with the pathogenesis of cancers and Alzheimer's disease (AD). Previously, we have shown the acid-induced denaturation of Pin1 was determined by means of fluorescence emission, synchronous fluorescence etc., indicating an intermediate state around chromophores in Pin1 at about 4.0. Molecular dynamics simulations for the wild type Pin1 and its mutants were performed to explore the role of pH in the conformation changes of Pin1 protein. Our present study shows that one protein domain (PPIase domain) is more sensitive than the other one (WW domain) in Pin1 protein, and also our study shows that the integrality of the two conserve tryptophan in one domain (WW) is important in response to low pH. We arrive at the last result with the analysis of the protein root mean square distance and the analysis of the radius of gyration. The analysis of protein solvent accessible surface area values have proven our previous experiment result that there is an intermediate state around tryptophan residues at about pH 4.0. Moreover, acidic states of the protein can break the alpha-helixes in Pin1, especially the alpha-helix alpha3 close to active sites; as a result, Pin1 loses most of its activity at low pH. The results help us to understand the role of pH in Pin1, provide us insights into the conformation change at the atomic-level and emphasize the important role of decreased pH in the pathogenesis of some Pin1-related diseases, and support the therapeutic approach for the related Pin1 diseases by targeting acidosis and modifying the intracellular pH gradients. PMID- 25031084 TI - Conserved structure and domain organization among bacterial Slc26 transporters. AB - The Slc26 proteins are a ubiquitous superfamily of anion transporters conserved from bacteria to humans, among which four have been identified as human disease genes. Our functional knowledge of this protein family has increased but limited structural information is available. These proteins contain a transmembrane (TM) domain and a C-terminal cytoplasmic sulfate transporter and anti-sigma factor (STAS) domain. In a fundamental step towards understanding the structure/function relationships within the family we have used small-angle neutron scattering (SANS) on two distantly related bacterial homologues to show that there is a common, dimeric and structural architecture among Slc26A transporters. Pulsed electron-electron double resonance (PELDOR) spectroscopy supports the dimeric SANS-derived model. Using chimaeric/truncated proteins we have determined the domain organization: the STAS domains project away from the TM core and are essential for protein stability. We use the SANS-generated envelopes to assess a homology model of the TM core. PMID- 25031085 TI - In vitro antifungal susceptibility of Malassezia pachydermatis strains isolated from dogs with chronic and acute otitis externa. AB - Malassezia pachydermatis is a yeast that is frequently involved as a secondary/perpetuating factor in canine otitis externa. Topical therapies with different antifungal agents, mainly azole compounds, are generally successful in controlling the yeast overgrowth, but treatment failure and rapid recurrences are common. This study compared the in vitro antifungal susceptibility of M. pachydermatis isolates obtained from chronic and acute cases of otitis externa. The aim was to assess the possible onset of resistance mechanisms in isolates involved in long-lasting episodes with poor response to treatment. We evaluated the in vitro susceptibility to miconazole (MCZ) and clotrimazole (CTZ) of 42 isolates of M. pachydermatis obtained from dogs with chronic (group A, n = 25) and acute otitis (group B, n = 17), using a modified CLSI M27-A3 microdilution method. All isolates were inhibited by the antifungal agents employed, but Malassezia isolates from group A were significantly associated with higher minimum inhibitory concentration (MIC) values for both agents (Median MIC values: MCZ group A 2 ug/ml, group B 1 ug/ml; CTZ group A 8 ug/ml, group B 4 ug/ml). These findings prove that these isolates had a reduced in vitro susceptibility to the antifungal agents tested. However, it is unlikely that this could have any influence on the outcome of a topical treatment. Indeed, marketed products include concentrations of the tested agents that largely exceed even the highest MICs found in this study (in most cases at least 1,000 * the MIC, or greater). In conclusion, this study suggests that isolates of M. pachydermatis involved in chronic cases of canine external otitis and exposed to repeated antifungal treatments are unlikely to develop mechanisms of resistance of clinical relevance. PMID- 25031086 TI - Common variants in PCSK1 influence blood pressure and body mass index. AB - Proprotein convertase subtilisin/kexin-type 1 (PCSK1) activates precursors pro opiomelanocortin (POMC), proinsulin and prorenin. We investigated if common variants in the PCSK1 gene influence blood pressure and risk of hypertension. Additionally, we investigated the risk of obesity and type 2 diabetes (T2D). In the Rotterdam Study (RS1), a prospective, population-based cohort (n=5974), four single-nucleotide polymorphisms (rs10515237, rs6232, rs436321 and rs3792747) in PCSK1 were studied. Linear and Cox regression models served to analyze associations between variants and end points. Replication was performed in the Rotterdam Study Plus1 (RSPlus1, n=1895). Rs436321 was significantly associated with systolic and diastolic blood pressure and risk of hypertension (odds ratio (OR): 1.1-1.3; P<0.05 in both populations). Rs6232 was associated with body mass index (BMI) (P=0.007 and P=0.04 in RS1 and RSPlus1, respectively). In RSPlus1, heterozygotes for rs6232 had 1.5 times higher risk of obesity (OR: 1.46; 95% confidence interval: 1.04-2.03; P=0.03). We did not find significant associations of PCSK1 with fasting insulin levels and T2D. We found an association of genetic variation in the PCSK1 gene with blood pressure and hypertension. Furthermore, we replicated the association of PCSK1 with BMI and obesity. No relationship was found between PCSK1 variants and fasting insulin levels and T2D. Our findings suggest that genetic variation in PCSK1 may contribute to, at least, some of these interrelated disorders. PMID- 25031088 TI - Depressed transition temperature of W(x)V(1-x)O2: mechanistic insights from the X ray absorption fine structure (XAFS) spectroscopy. AB - The mechanism for the decreasing critical temperature (T(C)) of the metal insulator transition (MIT) in vanadium dioxide (VO2) by tungsten (W) doping is a matter of debate. Here, to clarify the correlation between W doping and T(C), the electronic and geometrical structures around W and V atoms in W(x)V(1-x)O2 samples are systematically investigated by X-ray absorption fine structure (XAFS) spectroscopy. The evidence of electron doping of W(6+) ions in VO2 is obtained from the reduction of V(4+) to V(3+) ions. This kind of electron doping has been considered to favor the MIT process. Moreover, from the XAFS results, the local rutile structure around W dopants is identified even at low doping, and acts as the structure-guided domain to facilitate the MIT in VO2. Considering the electronic band structures of W(x)V(1-x)O2 samples, the internal stresses induced by W(6+) doping yield the detwisting of the nearby monoclinic VO2 lattice. This lattice detwisting will drive the downward shift of the pi* electron band and a smaller separation between antibonding and bonding d? orbitals in the band structure of VO2, which induces the decreased band gaps of W(x)V(1-x)O2 samples. As a consequence, the potential energy barrier for phase transition is lowered and the reduced T(C) is observed. PMID- 25031087 TI - Coherent longitudinal acoustic phonon approaching THz frequency in multilayer Molybdenum Disulphide. AB - Coherent longitudinal acoustic phonon is generated and detected in multilayer Molybdenum Disulphide (MoS2) with number of layers ranging from 10 to over 1300 by femtosecond laser pulse. For thin MoS2, the excited phonon frequency exhibits a standing wave nature and shows linear dependence on the sample thickness. The frequency varies from 40 GHz to 0.2 THz (10 layers), which promises possible application in THz frequency mechanical resonators. This linear thickness dependence gradually disappears in thicker samples above about 150 layers, and the oscillation period shows linear dependence on the probe wavelength. From both the oscillation period of the coherent phonon and the delay time of acoustic echo, we can deduce a consistent sound velocity of 7.11*10(3) m/s in MoS2. The generation mechanisms of the coherent acoustic phonon are also discussed through pump power dependent measurement. PMID- 25031089 TI - Complement depletion with humanised cobra venom factor: efficacy in preclinical models of vascular diseases. AB - The complement system is an intrinsic part of the immune system and has important functions in both innate and adaptive immunity. On the other hand, inadvertent or misdirected complement activation is also involved in the pathogenesis of many diseases, contributing solely or significantly to tissue injury and disease development. Multiple approaches to develop pharmacological agents to inhibit complement are currently being pursued. We have developed a conceptually different approach of not inhibiting but depleting complement, based on the complement-depleting activities of cobra venom factor (CVF), a non-toxic cobra venom component with structural and functional homology to complement component C3. We developed a humanised version of CVF by creating human complement component C3 derivatives with complement-depleting activities of CVF (humanised CVF) as a promising therapeutic agent for diseases with complement pathogenesis. Here we review the beneficial therapeutic effect of humanised CVF in several murine models of vascular diseases such as reperfusion injury. PMID- 25031090 TI - Whole-body vibration improves cognitive functions of an adult with ADHD. AB - Adult attention deficit hyperactivity disorder (ADHD) is associated with a variety of cognitive impairments, which were shown to affect academic achievement and quality of life. Current treatment strategies, such as stimulant drug treatment, were demonstrated to effectively improve cognitive functions of patients with ADHD. However, most treatment strategies are associated with a number of disadvantages in a considerable proportion of patients, such as unsatisfactory effects, adverse clinical side effects or high financial costs. In order to address limitations of current treatment strategies, whole-body vibration (WBV) might represent a novel approach to treat cognitive dysfunctions of patients with ADHD. WBV refers to the exposure of the whole body of an individual to vibration and was found to affect physiology and cognition. In the present study, WBV was applied on 10 consecutive days to an adult diagnosed with ADHD. Neuropsychological assessments were performed repeatedly at three different times, i.e., the day before the start of the treatment, on the day following completion of treatment and 14 days after the treatment have been completed (follow-up). An improved neuropsychological test performance following WBV treatment points to the high clinical value of WBV in treating patients with neuropsychological impairments such as ADHD. PMID- 25031092 TI - Psychometric properties of the child feeding scale in Turkish mothers. AB - PURPOSE: The objective of this study was to adopt the Child Feeding Scale (CFS) to the Turkish language and culture and to assess the validity and the reliability of the Turkish version of the scale. METHODS: The research was methodological study design. A convenience sample of 158 mothers at a primary health care center completed a structured questionnaire including the CFS for mothers in 2008. RESULTS: In the assessment of construct validity, seven factors were identified; they related to Perceived Responsibility, Perceived Parent Weight, Perceived Child Weight, Concern About Child Weight, Pressure to Eat, Restriction, and Monitoring. The seven factors explained 57.6% of the total variance. The overall internal reliability coefficient of this scale was .75. CONCLUSIONS: The present study provides evidence of the CFS's validity and reliability. The scale has potential applications for use in research. The CFS can be used to assess aspects of child-feeding perceptions, attitudes, and practices and their relationships to children's developing food acceptance patterns, the control of food intake and obesity. PMID- 25031093 TI - Knowledge, behaviors and prevalence of reproductive tract infections: a descriptive study on rural women in hunchun, china. AB - PURPOSE: The aim of the study was to assess the prevalence, knowledge and behavior about reproductive tract infections (RTIs) among rural Chinese women in Hunchun, China. METHODS: The study employed a cross-sectional research design with a convenience sample of 190 participants who had received microfinancing. Data were collected by trained research staff, utilizing face to face interviews and physical examinations. RESULTS: About 1 in 5 participants (20.3%) had had more than 5 pregnancies and 26.7% had had 3 or more abortions. More than half (57.3%) of study participants had an RTI at the time of examination, and 92.3% reported having had at least one RTI symptom. Nearly half (49.6%) of the women who exhibited RTI symptoms reported no utilization of any healthcare services. Age, number of pregnancies, RTI knowledge, and behavior were found to be significant correlates in the sample. CONCLUSIONS: The prevalence of RTI among low-income rural Chinese women were extremely high, indicating the urgent need for effective and culturally sensitive health education, particularly targeted to the poor rural population. PMID- 25031094 TI - Nursing staff stress from caregiving and attitudes toward family members of nursing home residents with dementia in Korea. AB - PURPOSE: The purpose of this study was to examine nursing staff stress with their caregiving roles and attitudes toward family members of nursing home residents in Korea. METHODS: The sample consisted of 267 nursing staff members from 10 long term care facilities. Participants completed the Caregiver Stress Inventory and the Attitudes About Family Checklist. RESULTS: The mean score on the total Caregiver Stress Inventory was 4.34 for nurses and 4.53 for nursing assistants (t = -1.42, p = .161). Nursing assistants reported higher stress levels than nurses from caring for the residents with aggressive behaviors (t = -2.28, p = .040). In contrast, nurses reported higher stress levels regarding resources deficiency (t = 2.18, p = .045). The mean score on the data from the Attitudes About Family Checklist was 4.45 for nurses and 3.56 for nursing assistants (t = 2.52, p = .025), indicating that nursing assistants reported more negative attitudes toward family members of residents with dementia. CONCLUSIONS: The findings in this study showed a need for systematic educational programs for staff to enhance their dementia care knowledge, alleviate their stress, and finally change positively their attitudes toward family. As the number of dementia patients in long-term care facilities increases, it will be important for staff members to develop individually satisfying and mutually acceptable caregiving roles. PMID- 25031095 TI - Comparison of Catheter-associated Urinary Tract Infection Rates by Perineal Care Agents in Intensive Care Units. AB - PURPOSE: This study compared the catheter-associated urinary tract infection (CAUTI) rates resulting from the use of four perineal care agents (soap-and water, skin cleansing foam, 10% povidone-iodine, and normal saline) among patients in intensive care units (ICUs). METHODS: This four-group experimental study was done with 97 adult patients who had urinary catheters over 2 days in three ICUs between April and July 2008. The patients received one of the four types of perineal care. Data collected included the incidence of CAUTI at baseline (prior to perineal care) and 1 week, 2 weeks, and 4 weeks after beginning perineal care. Patients were divided into UTI and non-UTI groups based on the Centers for Disease Control and Prevention/National Healthcare Safety Network UTI definition to calculate incidence rates. The hazard ratio (HR) and 95% confidence intervals were calculated by Cox's proportional hazard analysis. RESULTS: The cumulative incidence of CAUTIs per 100 urinary catheter days were 3.18 episodes during 1 week with urinary catheter, 3.31 during 2 weeks, and 3.04 during 4 weeks. No statistically significant difference in hazard ratios of CAUTIs for each perineal care agent was evident with reference to soap-and-water at 1 week, 2 weeks, and 4 weeks after beginning perineal care after controlling for age, use of antibiotics, fecal incontinence, consciousness level, fever, and diabetes. CONCLUSIONS: The type of perineal care does not influence the incidence of CAUTIs. Further confirmatory studies with a larger patient population should be conducted, as well as determining perineal agent preference. PMID- 25031096 TI - Prediction model for demands of the health meteorological information using a decision tree method. AB - PURPOSE: Climate change affects human health and calls for health meteorological services. The purpose of this study is to find the significant predictors for the demands of the health meteorological information. METHODS: This study used a descriptive design through structured self-report questionnaires. Data from 956 participants who were at least 18 years old and living in Busan, Korea, were collected from June 1 to July 31, 2009. The data was analyzed using a decision tree method, one of the data mining techniques by SAS 9.1 and Enterprise Miner 4.3 program. RESULTS: Two hundred and ninety participants (30.3%) demanded the information, and 505 of them (52.8%) perceived the necessity of health meteorological information. From the decision tree method, the predictors related to the demands of the health meteorological information were determined as "the perception of the necessity of health meteorological information," "the coping to the weather warnings" and "the importance of the weather forecasting in daily life." In Particular, the significant different variables in the perception of the necessity of health meteorological information were "female," "aged over 40" and "environmental diseases." Thus, the model derived in this study is considered for explaining and predicting the demands of health meteorological information. CONCLUSIONS: It can be effectively used as a reference model for future studies and is a suggested direction in health meteorological information service and policy development. We suggest health forecasting as a nursing service and a primary health care network for healthier and more comfortable life. PMID- 25031097 TI - Tribute to James L. Skinner. PMID- 25031098 TI - Autobiography of James L. Skinner. PMID- 25031101 TI - Temperature-dependent dynamic response to flash heating of molecular monolayers on metal surfaces: vibrational energy exchange. AB - An ultrafast nonlinear coherent laser spectroscopy termed vibrational sum frequency generation (SFG) was used to monitor vibrational transitions of a self assembled monolayer (SAM) of 4-nitrobenzenethiolate (NBT) on Au after Au flash heating. Ultrafast thermoreflectance measurements showed the surface temperature jumps DeltaT were in the 35-250 K range. The NBT symmetric and antisymmetric nitro stretches nusNO2 and nuasNO2 and a phenyl ring stretch nuCC were probed. Flash heating caused these transitions to lose intensity, shift, and broaden. The time dependences all had overshoot-decay-plateau structures. In the long-lived plateau, the SAM was in thermal equilibrium with the hot Au surface. The SFG plateau intensity losses of nusNO2 and nuCC, two vibrations with parallel transition moments, were identical, indicating that the SFG intensity loss was caused by thermally induced SAM orientational disorder. The T-jump-induced frequency shifts of nusNO2 and nuasNO2 were identical and opposite in sign. The rise times of the shifts were identical and equal to the ~3.5 ps time constant for the rise of Au surface temperature, which indicates that both shifts were caused by anharmonic coupling to the same lower-energy vibration. The temperature dependence of the nusNO2 shift and width indicated that this vibration was the ~480 cm(-1) nitro bend. The nusNO2 temperature dependence was interpreted using a vibrational energy exchange mechanism between the nitro stretch and bend. PMID- 25031102 TI - Quantum-confined single photon emission at room temperature from SiC tetrapods. AB - Controlled engineering of isolated solid state quantum systems is one of the most prominent goals in modern nanotechnology. In this letter we demonstrate a previously unknown quantum system namely silicon carbide tetrapods. The tetrapods have a cubic polytype core (3C) and hexagonal polytype legs (4H)--a geometry that creates spontaneous polarization within a single tetrapod. Modeling of the tetrapod structures predicts that a bound exciton should exist at the 3C-4H interface. The simulations are confirmed by the observation of fully polarized and narrowband single photon emission from the tetrapods at room temperature. The single photon emission provides important insights into understanding the quantum confinement effects in non-spherical nanostructures. Our results pave the way to a new class of crystal phase nanomaterials that exhibit single photon emission at room temperature and therefore are suitable for sensing, quantum information and nanophotonics. PMID- 25031103 TI - Employment status and intimate partner violence among Mexican women. AB - Exploring risk factors and profiles of intimate partner violence in other countries provides information about whether existing theories of this phenomenon hold consistent in different cultural settings. This study will present results of a regression analysis involving domestic violence among Mexican women (n = 83,159). Significant predictors of domestic violence among Mexican women included age, number of children in the household, income, education, self-esteem, family history of abuse, and controlling behavior of the husband. Women's employment status was not a significant predictor when all variables were included in the model; however, when controlling behavior of the husband was withdrawn from the model, women's employment status was a significant predictor of domestic violence toward women. Results from this research indicate that spousal controlling behavior may serve as a mediator of the predictive relationship between women's employment status and domestic violence among Mexican women. Findings provide support for continued exploration of the factors that mediate experiences of domestic violence among women worldwide. PMID- 25031106 TI - Meaning in life: translating nursing concepts to research. AB - It is proposed that individuals who find meaning in their lives experience a higher level of health and wellness. In this paper, research focused on life meaning is described. This program of research includes studies of life meaning from the individual person and/or patient perspective and studies of the meaningfulness of nurses' professional work life. Translations of the theoretical concepts into research and professional nursing interventions are described. PMID- 25031105 TI - Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness. AB - PURPOSE: Intervertebral discs exhibit time-dependent deformation (creep), which could influence the relation between applied stress and intradiscal pressure. This study investigates the effect of prolonged dynamic loading on intradiscal pressure, disc height and compressive stiffness, and examines their mutual relationships. METHODS: Fifteen caprine lumbar discs with 5 mm of vertebral bone on either side were compressed by 1 Hz sinusoidal load for 4.5 h. After preload, 'High' (130 +/- 20 N) or 'Low' (50 +/- 10 N) loads were alternated every half hour. Continuous intradiscal pressure measurement was performed with a pressure transducer needle. RESULTS: Each disc showed a linear relationship between axial compression and intradiscal pressure (R (2) > 0.91). The intercept of linear regression analysis declined over time, but the gradient remained constant. Disc height changes were correlated to intradiscal pressure changes (R (2) > 0.98): both decreased during High loading, and increased during Low loading. In contrast, compressive stiffness increased during High loading, and was inversely related to intradiscal pressure and disc height. CONCLUSIONS: Intradiscal pressure is influenced by recent loading due to fluid flow. The correlations found in this study suggest that intradiscal pressure is important for disc height and axial compliance. These findings are relevant for mechanobiology studies, nucleus replacements, finite element models, and ex vivo organ culture systems. PMID- 25031104 TI - Genetic variation in the G72 gene is associated with increased frontotemporal fiber tract integrity. AB - G72 (syn. DAOA, D-amino acid oxidase activator) is a susceptibility gene for both schizophrenia and bipolar disorder. Diffusion tensor imaging studies hint at changes in fiber tract integrity in both disorders. We aimed to investigate whether a G72 susceptibility haplotype causes changes in fiber tract integrity in young healthy subjects. We compared fractional anisotropy in 47 subjects that were either homozygous for the M23/M24 risk haplotype (n = 20) or homozygous for M23(rs3918342)/M24(rs1421292) wild type (n = 27) using diffusion tensor imaging with 3 T. Tract-based spatial statistics, a method especially developed for diffusion data analysis, was used to delineate the major fiber tracts. We found clusters of increased FA values in homozygous risk haplotype carriers in the right periinsular region and in the right inferior parietal lobe (IPL). We did not find clusters indicating decreased FA values. The insula and the IPL have been implicated in both schizophrenia and bipolar pathophysiology. Increased FA values might reflect changes in dendritic morphology as previously described by in vitro studies. These findings further corroborate the hypothesis that a shared gene pool between schizophrenia and bipolar disorder might lead to neuroanatomic changes that confer an unspecific vulnerability for both disorders. PMID- 25031107 TI - Heart rate variability as a measure of disease state in irritable bowel syndrome. AB - Heart rate variability (HRV) is a noninvasive measure of sympathovagal balance in the autonomic nervous system (ANS). This review will: (a) consider HRV measurement in irritable bowel syndrome (IBS); (b) discuss the applicability of HRV measurement in IBS by addressing strengths and limitations; and (c) propose future directions in this field of gastrointestinal research and clinical practice. As a strength, analyzing HRV components is a useful method and appears most suitable for detection of changes in ANS sympathovagal balance in both stress and non-stress conditions with good validity and reliability. Also, it is an appropriate measure for ANS in studies with large populations, in both laboratory and clinical settings, and for longitudinal studies because of its noninvasive assets. With regard to limitations of measuring HRV, these are poor standardization, additional human editing, not considering medication or other confounding factors, inconsistent results in gastrointestinal vagal tone study, and different time periods. PMID- 25031108 TI - Common factor analysis versus principal component analysis: choice for symptom cluster research. AB - PURPOSE: The purpose of this paper is to examine differences between two factor analytical methods and their relevance for symptom cluster research: common factor analysis (CFA) versus principal component analysis (PCA). METHODS: Literature was critically reviewed to elucidate the differences between CFA and PCA. A secondary analysis (N = 84) was utilized to show the actual result differences from the two methods. RESULTS: CFA analyzes only the reliable common variance of data, while PCA analyzes all the variance of data. An underlying hypothetical process or construct is involved in CFA but not in PCA. PCA tends to increase factor loadings especially in a study with a small number of variables and/or low estimated communality. Thus, PCA is not appropriate for examining the structure of data. CONCLUSION: If the study purpose is to explain correlations among variables and to examine the structure of the data (this is usual for most cases in symptom cluster research), CFA provides a more accurate result. If the purpose of a study is to summarize data with a smaller number of variables, PCA is the choice. PCA can also be used as an initial step in CFA because it provides information regarding the maximum number and nature of factors. In using factor analysis for symptom cluster research, several issues need to be considered, including subjectivity of solution, sample size, symptom selection, and level of measure. PMID- 25031109 TI - Multidisciplinary practice experience of nursing faculty and their collaborators for primary health care in Korea. AB - PURPOSE: This study aimed to describe the range of participation of nursing faculty members and their collaborators in multidisciplinary primary health care in Korea and to analyze facilitators, benefits, barriers, and learned lessons. METHODS: An exploratory descriptive research design was utilized. A total of 13 nursing faculty members and 13 multidisciplinary collaborators were interviewed face to face using a brief questionnaire and semi-structured interview guide. Descriptive statistics, comparative analysis, and content analysis were used for data analysis. RESULTS: About 43% of the nursing faculty had multidisciplinary primary health care experience. Facilitators included a government-funded research/demonstration project, personal belief and expertise in primary health care, and well-delineated role boundaries. Benefits included improved quality of life, more convenient community life, meeting multifaceted needs of community residents, and enhanced research activities. Barriers were lack of teamwork; territoriality and self-protective behaviors; lack of insight into primary health care among stakeholders; nurses undervaluing their work; and the rigid bureaucratic system of public health centers. Learned lessons were the importance of teamwork and its synergistic benefits, the importance of conducting clinically relevant research, having the government's support in the improvement of public health, developing health policies through multidisciplinary primary health care (M-D PHC) work, and respecting each other's territory and expertise. CONCLUSION: Teamwork should be included in all health professions' curricula, and nursing clinical practicums should include primary health care in all specialty areas. More faculties should engage in multidisciplinary primary health care. The benefits of a multidisciplinary approach to primary health care outweigh the difficulties experienced by multidisciplinary team members. The findings of this study may be useful for future multidisciplinary primary health care work worldwide. PMID- 25031110 TI - Effects of an off-site walking program on fibrinogen and exercise energy expenditure in women. AB - PURPOSE: Increased fibrinogen levels may trigger cardiac events in patients with atherosclerosis. Early control of fibrinogen levels before the progression of atherosclerosis that occurs with aging and menopause may benefit women, but the effects of exercise on fibrinogen levels as a preventive value have not been examined in early to middle adulthood women with lack of regular exercise. The present study aims to identify the effect of an off-site walking-based exercise program on fibrinogen levels in such women. METHODS: A prospective, 12-week, randomized and controlled study was used. Fifty-two women aged 32 to 57 years who did not exercise regularly or exercised with a weak intensity level were randomly assigned to either an intervention group (IG, n = 26) or a control group (CG, n = 26) for a 12-week study. Exercise energy expenditure (EEE) was measured using a microelectronic device. Fibrinogen levels were assessed using the clotting time method before and after the exercise program. RESULTS: The mean change from baseline EEE was 1.17 +/- 0.98 kcal/kg/day in IG subjects (n = 24) and 0.46 +/- 0.68 kcal/kg/day in CG subjects (n = 25), a 30% difference between groups (p = .01). The mean change in fibrinogen levels was -8.0 +/- 34.5 mg/dl (3% decrease) in IG subjects (n = 24) and -3.6 +/- 40.0 mg/dl (1% decrease) in CG subjects (n = 25). No significant difference in fibrinogen levels was seen between groups (F = 1.179, p = .279). CONCLUSION: EEE increased significantly, but fibrinogen levels did not decrease significantly. The effects of a 12-week off-site walking program on fibrinogen levels were inconclusive. As implications for nursing practice, our findings have suggested fibrinogen levels are not a novel cardiovascular risk factor any more, and provide important information on safe exercise to minimize adverse effects from fibrinogen arising from exercise intensity, especially in women with advanced atherosclerosis when nurses increase exercise intensity levels. Further studies with larger sample sizes in women to confirm the effect of exercise on reducing fibrinogen levels are necessary. PMID- 25031111 TI - Demands of immigration among Indian nurses who immigrated to the United States. AB - PURPOSE: To describe the demands of immigration of Indian nurses who immigrated to the United States, and to compare the demands of immigration of Indian nurses who immigrated less than 3 years ago to those who immigrated 3 or more years ago. METHODS: A comparative descriptive design was used to examine the Demands of Immigration (DI) total and subscale scores of Indian nurses (n = 105) who immigrated to the United States between 1985 and 2005, who were categorized into two groups: those who immigrated less than 3 years ago (n = 44) and those who immigrated 3 or more years ago (n = 61). The DI total score and subscale scores (loss, novelty, occupation, discrimination, language and not feeling at home) are reported. Study findings are related to previous research on immigration of women and nurses. Recommendations for future research are included. RESULTS: There was a significant difference between groups in total DI scores and language and novelty subscale scores. CONCLUSION: Additional research in these areas could help to assess the demands of immigration of Indian nurses and immigrant nurses from other countries. PMID- 25031112 TI - Developing a rehabilitation model of breast cancer patients through literature review and hospital rehabilitation programs. AB - PURPOSE: This study aimed to develop a rehabilitation model of breast cancer patients through review of literature and available online hospital rehabilitation programs. METHODS: Electronic searches of the literature related to rehabilitation programs of breast cancer patients in Cumulative Index to Nursing & Allied Health Literature, PubMed Clinical Queries, and Academic Search were carried out. In addition, hospital websites were reviewed for their rehabilitation programs, which in turn were reviewed and analyzed regarding their contents. RESULTS: The four dimensions, 12 categories, and concepts related to rehabilitation of breast cancer patients were uncovered. The four dimensions were concerns and problems, types of rehabilitation, activities, and quality of life. The 12 categories consisted of 2 categories in concerns and problems, 4 categories in types of rehabilitation, 4 categories in activities, and 2 categories in quality of life. A rehabilitation model for breast cancer patients was constructed that was grounded in the four dimensions, 12 categories, and concepts. CONCLUSION: Rehabilitation of breast cancer patients deserves special attention to achieve optimal quality of life. Health care professionals need to be educated about rehabilitation as an effective intervention. PMID- 25031113 TI - Review of the psychometric evidence of the perceived stress scale. AB - PURPOSE: The purpose of this study was to review articles related to the psychometric properties of the Perceived Stress Scale (PSS). METHODS: Systematic literature searches of computerized databases were performed to identify articles on psychometric evaluation of the PSS. RESULTS: The search finally identified 19 articles. Internal consistency reliability, factorial validity, and hypothesis validity of the PSS were well reported. However, the test-retest reliability and criterion validity were relatively rarely evaluated. In general, the psychometric properties of the 10-item PSS were found to be superior to those of the 14-item PSS, while those of the 4-item scale fared the worst. The psychometric properties of the PSS have been evaluated empirically mostly using populations of college students or workers. CONCLUSION: Overall, the PSS is an easy-to-use questionnaire with established acceptable psychometric properties. However, future studies should evaluate these psychometric properties in greater depth, and validate the scale using diverse populations. PMID- 25031114 TI - Effective intervention strategies to improve health outcomes for cardiovascular disease patients with low health literacy skills: a systematic review. AB - PURPOSE: Systematic studies on the relationship between health literacy and health outcomes demonstrate that as health literacy declines, patients engage in fewer preventive health and self-care behaviors and have worse disease-related knowledge. The purpose of this study was to identify effective intervention strategies to improve health outcomes in patients with cardiovascular disease and low literacy skills. METHODS: This study employs the following criteria recommended by Khan Kunz, Keijnen, and Antes (2003) for systematic review: framing question, identifying relevant literature, assessing quality of the literature, summarizing the evidence, and interpreting the finding. A total of 235 articles were reviewed by the research team, and 9 articles met inclusion criteria. Although nine studies were reviewed for their health outcomes, only six studies, which had a positive quality grade evaluation were used to recommend effective intervention strategies. RESULTS: Interventions were categorized into three groups: tailored counseling, self-monitoring, and periodic reminder. The main strategies used to improve health outcomes of low literacy patients included tailored counseling, improved provider-patient interactions, organizing information by patient preference, self-care algorithms, and self-directed learning. Specific strategies included written materials tailored to appropriate reading levels, materials using plain language, emphasizing key points with large font size, and using visual items such as icons or color codes. CONCLUSION: With evidence-driven strategies, health care professionals can use tailored interventions to provide better health education and counseling that meets patient needs and improves health outcomes. PMID- 25031115 TI - Reliability and validity of the korean version of belongingness scale-clinical placement experience. AB - PURPOSE: The purpose of this cross-sectional survey was to determine the reliability and validity of the Korean version of the Belongingness Scale Clinical Placement Experience (BS-CPE). METHODS: The study conducted a cross sectional survey which used a self-report questionnaire. A convenient sampling method was utilized, and data on 335 students was gathered. We verified construct validity by performing confirmatory factor analysis. RESULTS: The overall Cronbach's alpha score was .90 (range: .71-.84). BS-CPE was correlated with self respect (r = .47, p < .001) and self-directed learning (r = .50, p < .001). The original BS-CPE was modified based on the validity test. CONCLUSION: This modified Korean version of the BS-CPE is applicable for use with university undergraduates to measure belongingness in clinical practice. PMID- 25031116 TI - Nursing Home Placement: The Process of Decision Making and Adaptation among Adult Children Caregivers of Demented Parents in Korea. AB - PURPOSE: The goal of this study was to explore and describe the process of nursing home placement decision making and adaptation among adult children caregivers of demented parents in Korea and to generate a substantive theory grounded in their experiences. METHODS: The participants were 16 adult children caregivers who had placed their demented elders into nursing homes. Data were collected by in-depth unstructured interviews with individual participants. Data were analyzed by Strauss and Corbin's Grounded Theory methodology. RESULTS: Analysis revealed that the core category of the process of nursing home placement decision making and adaptation among adult children caregivers was accepting the inevitable and reorienting to changes. It consisted of four phases: realizing a dead end, seeking a way out, accepting the inevitable decision, and reorienting to changes. Participants were driven to the corner of making the inevitable decision by the overwhelming care situation and confronted by various challenges in dealing with the decision. But they managed to accept the inevitableness of the decision and further learned to reorient themselves to the changed care situation utilizing various action/interaction strategies. CONCLUSION: The findings of the study provide the basic information for developing proactive strategies to support family caregivers better in the difficult period of nursing home placement. PMID- 25031117 TI - Relationships between Body Mass Index and Social Support, Physical Activity, and Eating Habits in African American University Students. AB - PURPOSE: We aimed to examine the relationships between obesity and the level of social support for healthy behaviors, amount of physical activity (PA), and dietary habits in African Americans. METHODS: The subjects were 412 university students who visited a health promotion center at North Carolina A&T State University, Greensboro, NC, USA between September 1, 2009 and April 30, 2010. We administered a social support survey, the National Institutes of Health Fruit, Vegetable, and Fat Screener, the Paffenbarger PA Questionnaire, and measures of body mass index, waist circumference (WC), and blood pressure. Data were analyzed using a one-way analysis of variance and logistic regression analyses. RESULTS: Results showed that men in the overweight group had WC and systolic blood pressure (SBP) measurements associated with increased risk of cardiovascular disease (CVD) and below average PA; those in the obese group had WC, SBP, and diastolic blood pressure (DBP) measurements associated with CVD risk and below average PA. Women in the overweight group had WC and SBP measurements associated with CVD risk, and those in the obesity group had WC, SBP, and DBP measurements associated with CVD risk and below average PA. Logistic regression analysis showed that increasing PA by 1,000 kcal/week decreased the prevalence of obesity by 9.3% in men and 9.0% in women. CONCLUSION: Thus, low PA was a significant risk factor for obesity among African Americans. However, the level of social support and consumption of fruits, vegetables, and fat were not found to be significant risk factors in this study. PMID- 25031118 TI - Changes in depressive symptoms in spouses of post myocardial infarction patients. AB - PURPOSE: To identify parsimonious models for changes in depression in spouses of post myocardial infarction (MI) patients over 2 years based on the biopsychosocial model. METHODS: A total of 442 community living patients who had experienced an MI and their spouses were included for analysis. Patients and spouses completed psychosocial assessments at baseline, 1 year, and 2 years after enrollment in the Patients' and Families' Psychological Response to Home Automated External Defibrillator Trial. Linear mixed models were used for testing hypotheses. RESULTS: A total of 15.2% (baseline), 11.5% (1-year follow up), and 8.1% (2-year follow up) of spouses were depressed. Spouse biological factors did not influence changes in depression. Among all spouses, two groups of spouses showed increased depression over time: spouses with lower baseline depression scores (p < .001), and spouses of patients who had higher baseline depression scores (p = .001). Among psychologically distressed (anxious or depressed) spouses, three groups of spouses showed increased depression over time: spouses who had lower baseline depression scores (p < .001), spouses who had more social support at baseline (p = .023), and spouses of patients who had higher baseline depression scores (p < .001). CONCLUSION: Spouse and patient baseline depression significantly predicted changes in depression for all spouses and psychologically distressed spouses. Among psychologically distressed spouses, higher baseline social support predicted higher depression scores over time. This study is an important step in understanding longitudinal changes in the psychological status of spouses of MI patients for evaluating the need for interventions. It is crucial that patient couples' psychosocial factors are continuously assessed. PMID- 25031119 TI - Creating and validating educational material for patients undergoing orthognathic surgery. AB - PURPOSE: To create and validate educational material for patients undergoing orthognathic surgery. METHODS: The design included five phases: (a) a review of the literature regarding surgical complications; (b) gathering information on the needs of patients through blogs and virtual communities; (c) evaluating patient perceptions of the post-operative period through a focus group; (d) obtaining information through specialists using the Delphi technique and validation by judges; and (e) validation by patients in terms of understanding the exhibited material. RESULTS: The first three phases of the study and the first round of the Delphi technique assisted in generating the perioperative patient booklet. The following rounds of the Delphi technique introduced modifications to improve the material, with the judges agreeing on the final material to be validated by patients. CONCLUSION: Creating a booklet involves more than simply writing summarized ideas on a paper and handing it to the patient. One must understand the population, involve the relevant professionals, and obtain high-quality graphic aids for this type of educational material. PMID- 25031120 TI - Nursing staff views of barriers to physical restraint reduction in nursing homes. AB - PURPOSE: There are few studies globally regarding the barriers to restraint reduction. The purpose of this study was to describe the views of nursing staff (both nurses and geriatric care assistants) regarding the barriers to reducing physical restraint use in Korean nursing homes. METHODS: Forty registered nurse and geriatric care assistant informants participated in the first round of interviews and 16 of them participated in second confirmatory interviews. All interviews were conducted on site, one-on-one and face-to-face, using semi structured interview protocols. Qualitative descriptive method was used and qualitative content analysis was employed. RESULTS: Six themes were identified: (a) being too busy, (b) lack of resources, (c) beliefs and concerns, (d) lack of education, (e) differences and inconsistencies, and (f) relationship issues. CONCLUSION: The findings of this study provide a valuable basis for developing restraint reduction education programs. Korean national leaders and nursing homes should develop and employ practice guidelines regarding restraints, support nursing staff to follow the guidelines, provide more practical and professional education, employ alternative equipment, use a multidisciplinary team approach, and engage volunteers in care support as well as employ more nursing staff to achieve restraint-free care. PMID- 25031121 TI - Experiences living with fatigue in Iranian veterans chemically injured by sulfur mustard gas: a phenomenological study. AB - PURPOSE: Fatigue affects the quality of life. Evidence shows that the phenomenon of fatigue is experienced differently depending on the type of disease and its consequences. The aim of the study was to explicate the meanings of the experience of living with fatigue in chemically injured veterans. METHODS: The hermeneutic phenomenology approach was used in this study, with an emphasis on Van Mennen's viewpoint and approach. According to Van Mennen, six overlapping dynamic activities are recommended to conduct a phenomenological study. During unstructured interviews, the participants were asked to describe their daily living experiences with fatigue. The participants were individuals who were chemically injured due to exposure to mustard gas. After examining every statement in the interview text, extractions of the meaning units, clustering, and themes were performed. RESULTS: The data explication was based on the third to sixth stages of Van Mennen's approach. The experience living with fatigue was classified into four essential themes: fatigue as a chronic condition, as an unstable and affected situation, as a physical condition of the entire individual, and as a mental condition of the entire individual. CONCLUSION: Due to unique social interactions and pathogenicity, victims of mustard gas experience fatigue differently than patients with other chronic diseases. PMID- 25031122 TI - Distinguishing highly-related outbreak-associated Clostridium botulinum type A(B) strains. AB - BACKGROUND: In the United States, most Clostridium botulinum type A strains isolated during laboratory investigations of human botulism demonstrate the presence of an expressed type A botulinum neurotoxin (BoNT/A) gene and an unexpressed BoNT/B gene. These strains are designated type A(B). The most common pulsed-field gel electrophoresis (PFGE) pattern in the C. botulinum PulseNet database is composed of A(B) strains. The purpose of this study was to evaluate the ability of genome sequencing and multi-loci variable number of tandem repeat analysis (MLVA) to differentiate such strains. RESULTS: The genome sequences of type A(B) strains evaluated in this study are closely related and cluster together compared to other available C. botulinum Group I genomes. In silico multilocus sequence typing (MLST) analysis (7-loci) was unable to differentiate any of the type A(B) strains isolated from seven different outbreak investigations evaluated in this study. A 15-locus MLVA scheme demonstrated an improved ability to differentiate these strains, however, repeat unit variation among the strains was restricted to only two loci. Reference-free single nucleotide polymorphism (SNP) analysis demonstrated the ability to differentiate strains from all of the outbreaks examined and a non-outbreak associated strain. CONCLUSIONS: This study confirms that type A(B) strains that share the same PFGE pattern also share closely-related genome sequences. The lack of a complete type A(B) strain representative genome sequence hinders the ability to assemble genomes by reference mapping and analysis of SNPs at pre-identified sites. However, compared to other methods evaluated in this study, a reference-free SNP analysis demonstrated optimal subtyping utility for type A(B) strains using de novo assembled genome sequences. PMID- 25031123 TI - The use of animal models in behavioural neuroscience research. AB - Animal models are used in experiments in the behavioural neurosciences that aim to contribute to the prevention and treatment of cognitive and affective disorders in human beings, such as anxiety and depression. Ironically, those animals that are likely to be the best models for psychopathology are also likely to be considered the ones that are most morally problematic to use, if it seems probable that (and if indeed they are initially selected as models because) they have experiences that are similar to human experiences that we have strong reasons to avoid causing, and indeed aim to alleviate (such as pain, anxiety or sadness). In this paper, against the background of contemporary discussions in animal ethics and the philosophy of animal minds, we discuss the views that it is morally permissible to use animals in these kinds of experiments, and that it is better to use less cognitively complex animals (such as zebrafish) than more complex animals (such as dogs). First, we criticise some justifications for the claim that human beings and more complex animals have higher moral status. We argue that contemporary approaches that attribute equal moral status to all beings that are capable of conscious strivings strivings (e.g. avoiding pain and anxiety; aiming to eat and play) are based on more plausible assumptions. Second, we argue that it is problematic to assume that less cognitively complex animals have a lesser sensory and emotional experience than more complex beings across the board. In specific cases, there might be good reasons to assume that more complex beings would be harmed more by a specific physical or environmental intervention, but it might also be that they sometimes are harmed less because of a better ability to cope. Determining whether a specific experiment is justified is therefore a complex issue. Our aim in this chapter is to stimulate further reflection on these common assumptions behind the use of animal models for psychopathologies. In order to be able to draw more definite conclusions, more research will have to be done on the influence of cognitive complexity on the experience of (human and non-human) animals. PMID- 25031124 TI - Redefining the proximal ulna anatomy. AB - PURPOSE: Complex fractures of the olecranon have always been a difficult condition for treatment. Successful reconstruction depends on restoration of the anatomic contributors to stability. The purpose of this study was to define the proximal ulna anatomy in detail with respect to fracture fixation and arthroscopy. METHODS: In 50 normal adult ulnae (26 left, 24 right); posterior olecranon height (POH), olecranon width (OW), trochlear notch width (TW), the distances between the olecranon and the trochlear notch on radial and ulnar sides (RTH, UTH), and proximal ulnar angulations were measured with a ruler and a digital goniometer. RESULTS: The average POH was 24.6 mm, OW was 23.1 mm, TW was 22.3 mm, RTH was 16.2 mm, and UTH was 15.8 mm. The mean value for proximal ulna torsion angle (PUTA) was found 11.1 degrees . The mean varus angulation was 9.3 degrees . The average articular angle was 27.7 degrees and proximal ulnar dorsal angulation (PUDA) was 8 degrees . CONCLUSIONS: The unique bony architecture of the proximal ulna presents particular difficulties for the implants used in fracture fixation and arthroplasty of the elbow. Knowing the detailed anatomy of the variations of proximal ulna will guide the surgeon to obtain a more reliable length of the olecranon and to offer a safe place for Kirschner wire replacement concerning humero-ulnar joint functionality. In this study, PUTA was also defined. The angle determines the rotation of the proximal ulna and it has a great importance for the movements of the joint. The measured angulations will help the surgeon to design the proper prosthesis for the maintenance of the functions of the elbow joint. PMID- 25031125 TI - Extrarenal calyces: a rare renal congenital anomaly. AB - The congenital anomalies of urogenital system are not uncommon. The anomalies of renal collecting system form a complex subset of urogenital anomalies. Among these, extrarenal calyces are one of the infrequently found anomalies of the renal collecting system. Extrarenal calyces may be detected incidentally or when thoroughly investigated for its associated complications. We report two cases of extrarenal calyces characterized by the presence of major calyces and renal pelvis outside the renal parenchyma. The awareness of this anomaly can help in making the definitive preoperative diagnosis and prevent injury to pelvicalyceal system during surgery. PMID- 25031127 TI - Tuberculosis control in India: why are we failing? AB - In spite of being the pioneer-leader of research into epidemiology and prevention of tuberculosis among low-income countries, India has the highest population based burden of tuberculosis among all nations. Children with latent tuberculosis are the pool from which adult pulmonary tuberculosis emerges many years later. In the absence of primary prevention of infection by BCG, sociologic/behavioral interventions must be applied to reduce air-borne transmission. In addition to maximizing passive surveillance of adult disease, pediatric tuberculosis must also be brought under surveillance. Those with latent tuberculosis must be detected and treated to remove them from the pool. Epidemiologically, the realistic monitoring method of tuberculosis control trajectory is documenting progressive reduction of the short incubation period pediatric disease through surveillance, and not the reduction of long incubation period adult pulmonary tuberculosis. Application of scientific tools for the detection and management of pediatric tuberculosis infection - latent and active - holds the key to effective tuberculosis control. PMID- 25031128 TI - Energy drinks: potions of illusion. AB - Energy drinks are widely consumed by adolescents as these claim to improve performance, endurance and alertness. Recent reports have shown that there are no real health benefits of these drinks. On the contrary, certain adverse effects due to energy drinks have come to the forefront, casting a big question-mark on their safety and utility. This review discusses the present status of energy drinks, their active ingredients and their safety. We conclude that energy drinks, despite having some short pleasant effects, can be harmful for the body and are best avoided. PMID- 25031129 TI - Improving diagnosis of epilepsy in India--how difficult is it? PMID- 25031130 TI - Diagnostic questionnaire and its validation. Biostatistician's perspective. PMID- 25031132 TI - Prevalence of overweight and obesity among school children and adolescents in Chennai. AB - OBJECTIVE: To determine the prevalence of overweight and obesity among children and adolescents in Chennai, India, using national and international age- and sex- specific body mass index (BMI) cut-off points. METHODS: The Obesity Reduction and Awareness and Screening of Non communicable diseases through Group Education in Children and Adolescents (ORANGE) project is a cross-sectional study carried out on 18,955 children (age 6-11 years) and adolescents (age 12-17 years) across 51 schools (31 private and 20 government) of Chennai. Overweight and obesity was classified by the International Obesity Task Force (IOTF 2000) and Khadilkars criteria (2012), and Hypertension by the IDF criteria (in children >=10 years and adolescents). RESULTS: The prevalence of overweight/obesity was significantly higher in private compared to government schools both by the IOTF criteria [private schools: 21.4%, government schools: 3.6%, (OR: 7.4, 95% CI:6.3-8.6; P<0.001) and by Khadilkar criteria (private school: 26.4%, government schools: 4.6% OR: 6.9, 95% CI:6.2-7.8; P<0.001). Overweight/obesity was higher among girls (IOTF: 18%, Khadilkar: 21.3%) compared to boys (IOTF: 16.2%, Khadilkar: 20.7%) and higher among adolescents (IOTF: 18.1%, Khadilkar: 21.2%) compared to children (IOTF: 15.5%, Khadilkar: 20.7%). Prevalence of hypertension was 20.4% among obese/overweight and 5.2% among non-obese (OR 4.7, 95%CI: 4.2-5.3, P<0.001). CONCLUSIONS: The prevalence of overweight and obesity is high among private schools in Chennai, and hypertension is also common. PMID- 25031131 TI - INCLEN Diagnostic Tool for Epilepsy (INDT-EPI) for primary care physicians: development and validation. AB - OBJECTIVE: To evaluate the diagnostic accuracy of a new diagnostic instrument for epilepsy - INCLEN Diagnostic Tool for Epilepsy (INDT-EPI) - with evaluation by expert pediatric neurologists. STUDY DESIGN: Evaluation of diagnostic test. SETTING: Tertiary care pediatric referral centers in India. METHODS: Children aged 2-9 years, enrolled by systematic random sampling at pediatric neurology out patient clinics of three tertiary care centers were independently evaluated in a blinded manner by primary care physicians trained to administer the test, and by teams of two pediatric neurologists. OUTCOMES: A 13-item questionnaire administered by trained primary care physicians (candidate test) and comprehensive subject evaluation by pediatric neurologists (gold standard). RESULTS: There were 240 children with epilepsy and 274 without epilepsy. The candidate test for epilepsy had sensitivity and specificity of 85.8% and 95.3%; positive and negative predictive values of 94.0% and 88.5%; and positive and negative likelihood ratios of 18.25 and 0.15, respectively. CONCLUSIONS: The INDT EPI has high validity to identify children with epilepsy when used by primary care physicians. PMID- 25031133 TI - Comparative short term efficacy and tolerability of methylphenidate and atomoxetine in attention deficit hyperactivity disorder. AB - OBJECTIVE: To compare the short term efficacy and tolerability of methylphenidate and atomoxetine in children with Attention deficit hyperactivity disorder (ADHD). DESIGN: Open label randomized parallel group clinical trial. SETTING: Child Guidance Clinic of a tertiary care hospital of Northern India from October 2010 to June 2012. PARTICIPANTS: 69 patients (age 6-14 y) with a diagnosis of ADHD receiving methylphenidate or atomoxetine. INTERVENTION: Methylphenidate (0.2-1 mg/kg/d) or atomoxetine (0.5-1.2 mg/kg/d) for eight weeks. MAIN OUTCOME MEASURES: Treatment response (>25% change in baseline Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS); Vanderbilt ADHD Diagnostic Teacher Rating Scale (VADTRS); Clinical Global Impression Severity Scale (CGI-S) at eight weeks and adverse effects. RESULTS: Treatment response was observed in 90.7% patients from methylphenidate group and 86.2% patients of atomoxetine group at an average dose of 0.45 mg/kg/d and 0.61 mg/kg/d, respectively. The patients showed comparable improvement on VADPRS (P=0.500), VADTRS (P=0.264) and CGI-S (P=0.997). Weight loss was significantly higher in methylphenidate group (-0.57+/-0.78 kg; P=0.001), and heart rate increase was observed at higher rate in atomoxetine group (7+/- 9 bpm; P=0.021). CONCLUSIONS: Methylphenidate and atomoxetine are efficacious in Indian children with ADHD at lesser doses than previously used. Their efficacy and tolerability are comparable. TRIAL REGISTRATION NO.: CTRI/2011/08/001981. PMID- 25031134 TI - Body fat indices for identifying risk of hypertension in Indian children. AB - BACKGROUND: High adiposity is major risk factor for hypertension. Various anthropometric indices are used to assess excess fatness. OBJECTIVES: (1) To examine relationship of body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR), triceps skin fold thickness (TSFT) and wrist measurements with blood pressure in children and adolescents 2) to suggest age- and gender specific cutoffs for these indices in Indian children. METHODS: Cross-sectional school-based study on a random sample of 6380 children (6-18 yr old, 3501 boys) from five major cities in India. Height, weight, waist and wrist circumference, TSFT, and blood pressure were recorded. Children with systolic blood pressure (BP) and/or Diastolic BP >95th percentile were classified as hypertensive. RESULTS: Prevalence of overweight and obesity was 23.5% and 9.7%, respectively. Hypertension was observed in 5.6%. Multiple logistic regression (adjustments: age, gender) indicated double risk of hypertension for overweight and 7 times higher odds for obese than normal-weight children. Children with TSFT >95th centile for US children showed three times risk and with TSFT from 85th to 95th double risk of hypertension. Higher WC and WHtR exhibited 1.5 times risk and larger Wrist 1.3 times higher risk of hypertension (P<0.001). Receiver operating curve (ROC) analysis provided age-gender specific cut offs for the five indices to detect the risk of high BP. Area under ROC curves (AUC) for five indices were similar and greater in older age groups indicating equal sensitivity and specificity. Conclusion: Using age- and gender-specific cutoffs for BMI, TSFT, WC or WHtR may offer putative markers for early detection of hypertension. CONCLUSION: Using age- and gender-specific cutoffs for BMI, TSFT, WC or WHtR may offer putative markers for early detection of hypertension. PMID- 25031135 TI - Proficiency of residents and fellows in performing neonatal intubation. AB - OBJECTIVE: To determine success rate and time taken for intubation by pediatric residents/fellows. METHODS: Prospective observational study among neonates requiring endotracheal intubation. RESULTS: 212 attempts and 118 successful intubations were recorded in 153 videos. An average of 1.93 attempts per successful intubation was observed. Success rate at first attempt and mean time taken by first year, second year, third year residents and fellows were 26% and 51.9; 79% and 39.8; 69% and 40.1; and 67% and 31.5 seconds, respectively. Complications were noted in 77 (36%) attempts. 44 (21%) intubations were performed within 30 seconds. Increase in complications was noted with increase in attempt time beyond 40 seconds. CONCLUSIONS: Skill improved from first year to second year. Most intubations exceeded 30 second time limit. There is a need to improve training methodology to ensure intubation time by health personnel does not exceed the expected time limit. PMID- 25031136 TI - Lactate clearance as a marker of mortality in pediatric intensive care unit. AB - OBJECTIVE: To correlate lactate clearance with Pediatric Intensive Care Unit (PICU) mortality. METHODS: 45 (mean age 40.15 mo, 60% males) consecutive admissions in the PICU were enrolled between May 2012 to June 2013. Lactate clearance (Lactate level at admission - level 6 hr later x 100 / lactate level at admission) in first 6 hours of hospitalization was correlated to in-hospital mortality and PRISM score. RESULTS: Twelve out of 45 patients died. 90% died among those with delayed/poor clearance (clearance <30%) compared to 8.5% in those with good clearance (clearance >30%) (P<0.001). Lactate clearance <30% predicted mortality with sensitivity of 75%, specificity of 97%, positive predictive value of 90%, and negative predictive value of 91.42%. Predictability was comparable to PRISM score >30. CONCLUSION: Lactate clearance at six hours correlates with mortality in the PICU. PMID- 25031137 TI - Iodine deficiency status amongst school children in Pauri, Uttarakhand. AB - OBJECTIVE: To assess the iodine deficiency status amongst school age children in district Pauri, Uttarakhand. METHODS: 2067 children (age of 6-12 years) were included. Clinical examination of thyroid gland of each child was conducted. On the-spot urine and salt samples were collected from children. RESULTS: Total Goitre Rate was found to be 16.8% and median Urinary Iodine Concentration level was 115 ug/L. Only 40.4% of salt samples had e 15 ppm of iodine. CONCLUSION: There is a mild degree of iodine deficiency in school age children in district Pauri. There is a need of strengthening the National Iodine Deficiency Disorder Control Program. PMID- 25031141 TI - Small bowel volvulus with a jejunal trichobezoar. AB - BACKGROUND: Small bowel volvulus caused by a jejunal trichobezoar is an extremely rare and life-threatening emergency in children. CASE CHARACTERISTICS: An 8-year old girl with abdominal pain and persistent bilious vomiting. OBSERVATION: The abdominal computed tomography scan showed a solitary intraluminal mass and a whirl sign, suggesting the small bowel volvulus. Emergency laparoscopic exploration revealed the rotated segment of small bowel loops by a jejunal trichobezoar. OUTCOME: Satisfactory recovery after surgery. MESSAGE: Trichobezoars should be considered in the differential diagnosis of abdominal pain and projectile vomiting in children. PMID- 25031142 TI - Communicating hydrocephalus in systemic lupus erythematosus. AB - BACKGROUND: Central nervous system involvement is common in systemic lupus erythematosus but hydrocephalus, especially in children, is rare. CASE CHARACTERISTICS: 6-year-old girl with systemic lupus erythematosus with nephritis, on treatment for four months prior to the presentation with features of raised intracranial pressure. OBSERVATION: Computed tomography revealed communicating hydrocephalus without any evidence of granulomatous lesion, infarction or thrombosis, with no features of lupus flare. Ventriculoperitoneal shunting provided symptomatic relief after failed medical management. MESSAGE: Hydrocephalus may be seen in systemic lupus erythematosus without tuberculosis or major vessel vasculitis. PMID- 25031143 TI - ATP-binding cassette transporter A3 (ABCA3) mutation in a late preterm with respiratory distress syndrome. AB - BACKGROUND: Surfactant protein abnormalities are rare causes of respiratory distress syndrome. CASE CHARACTERISTICS: A late preterm (36 wks) who presented with respiratory distress syndrome. OBSERVATION: He was found to be a homozygous for a G to T transversion at the first base in intron 24, of ABCA3 gene which is necessary for lamellar body formation and surfactant production. OUTCOME: He died of severe respiratory failure even after multiple doses of surfactants and ventilation. MESSAGE: Surfactant deficiency with ABCA3 gene mutation needs to be suspected in late preterms who present with respiratory distress syndrome. PMID- 25031144 TI - How are we pediatricians different? PMID- 25031145 TI - Intravenous immunoglobulin in children with acute myocarditis and/or early dilated cardiomyopathy. AB - We retrospectively studied medical records of all children with acute myocarditis and/or early DCM admitted to the Pediatric Critical Care Unit of our hospital between January 2010 and December 2012 were reviewed. 28 patients were included in the study, of which 12 were treated with IVIG (1 g/kg per day) for two days. The patients who received IVIG therapy had a higher left ventricular ejection fraction and a reduced left ventricular end diastolic diameter six months after treatment, as compared to children who had not received IVIG (P<0.001 and P=0.002, respectively). PMID- 25031146 TI - Standard treatment guidelines for pediatrics under Clinical Establishment Act 2010. PMID- 25031147 TI - Benign infantile seizures with mild gastroenteritis. PMID- 25031148 TI - Management of patent ductus arteriosus. PMID- 25031149 TI - Management of children with severe acute malnutrition. PMID- 25031150 TI - Artemesinin-based combination therapy in malaria non-endemic areas. PMID- 25031151 TI - Benign neonatal hemangiomatosis. PMID- 25031152 TI - Linear non-epidermolytic verrucous epidermal nevus. PMID- 25031153 TI - Oxidation-induced loss of the ability of HDL to counteract the inhibitory effect of oxidized LDL on vasorelaxation. AB - Several current diseases are associated with an increase in the oxidation of HDL, which is likely to impair their functionality. Our aim was to identify whether oxidation could change the protective effect of HDL against the deleterious effect on vasoreactivity induced by oxidative stress. HDL from healthy subjects were oxidized in vitro by Cu(2+), and the ability of oxidized HDL to counteract the inhibitory effect of oxidized LDL on acetylcholine-induced vasodilation was tested on isolated rabbit aorta rings. Oxidation of HDL was evidenced by the increase in the 7-oxysterols/cholesterol ratio (3.20 +/- 1.12 vs 0.02 +/- 0.01 % in native HDL, p < 0.05). Oxidized LDL inhibited endothelium-dependent vasodilation (E max = 50.2 +/- 5.0 vs 92.5 +/- 1.7 % for incubation in Kreb's buffer, p < 0.05) and native HDL counteracted this inhibition (E max = 72.4 +/- 4.8 vs 50.2 +/- 5.0 % p < 0.05). At the opposite, oxidized HDL had no effect on oxidized LDL-induced inhibition on endothelium-dependent vasorelaxation (E max = 53.7 +/- 4.8 vs 50.2 +/- 5.0 %, NS). HDL oxidation is associated with a decreased ability of HDL to remove 7-oxysterols from oxidized LDL. In conclusion, these results show that oxidation of HDL induces the loss of their protective effect against endothelial dysfunction, which could promote atherosclerosis in diseases associated with increased oxidative stress. PMID- 25031155 TI - Iridium(I) hydroxides in catalysis: rearrangement of allylic alcohols to ketones. AB - The iridium(I) hydroxide complex [Ir(OH)(COD)(I(i)Pr)] has been shown to be a competent catalyst for the rearrangement of allylic alcohols to ketones. Reactions proceed in short reaction times (1-1.5 h) with microwave heating, in the absence of additives. PMID- 25031154 TI - Simultaneous occlusion of left anterior descending and left circumflex arteries by very late stent thrombosis: vascular response to drug-eluting stents assessed by intravascular ultrasound. AB - Very late stent thrombosis (VLST) is a catastrophic complication after implantation of a drug-eluting stent (DES). It has been reported that VLST is associated with pathological changes, which often include late acquired incomplete stent apposition (LAISA) with thrombus formation. In addition, the vascular response to the stent (evaginations, neointimal growth, and thrombosis) and the incidence of LAISA are reported to vary among the different types of DES. We experienced a patient with cardiogenic shock induced by simultaneous VLST of both the left anterior descending artery (LAD) and the left circumflex artery (LCX) at 3 years after implantation of two sirolimus-eluting stents. Intravascular ultrasound (IVUS) showed LAISA of both arteries. A paclitaxel eluting stent, which had been implanted in the right coronary artery 3 years earlier, did not show such a finding. IVUS revealed "different vascular reactions" to "different types of DES" in this patient. PMID- 25031156 TI - Catalytic defluorination of perfluorinated aromatics under oxidative conditions using N-bridged diiron phthalocyanine. AB - Carbon-fluorine bonds are the strongest single bonds in organic chemistry, making activation and cleavage usually associated with organometallic and reductive approaches particularly difficult. We describe here an efficient defluorination of poly- and perfluorinated aromatics under oxidative conditions catalyzed by the MU-nitrido diiron phthalocyanine complex [(Pc)Fe(III)(MU-N)Fe(IV)(Pc)] under mild conditions (hydrogen peroxide as the oxidant, near-ambient temperatures). The reaction proceeds via the formation of a high-valent diiron phthalocyanine radical cation complex with fluoride axial ligands, [(Pc)(F)Fe(IV)(MU N)Fe(IV)(F)(Pc(+*))], which was isolated and characterized by UV-vis, EPR, (19)F NMR, Fe K-edge EXAFS, XANES, and Kbeta X-ray emission spectroscopy, ESI-MS, and electrochemical techniques. A wide range of per- and polyfluorinated aromatics (21 examples), including C6F6, C6F5CF3, C6F5CN, and C6F5NO2, were defluorinated with high conversions and high turnover numbers. [(Pc)Fe(III)(MU-N)Fe(IV)(Pc)] immobilized on a carbon support showed increased catalytic activity in heterogeneous defluorination in water, providing up to 4825 C-F cleavages per catalyst molecule. The MU-nitrido diiron structure is essential for the oxidative defluorination. Intramolecular competitive reactions using C6F3Cl3 and C6F3H3 probes indicated preferential transformation of C-F bonds with respect to C-Cl and C-H bonds. On the basis of the available data, mechanistic issues of this unusual reactivity are discussed and a tentative mechanism of defluorination under oxidative conditions is proposed. PMID- 25031157 TI - Sorting drops and cells with acoustics: acoustic microfluidic fluorescence activated cell sorter. AB - We describe a versatile microfluidic fluorescence-activated cell sorter that uses acoustic actuation to sort cells or drops at ultra-high rates. Our acoustic sorter combines the advantages of traditional fluorescence-activated cell (FACS) and droplet sorting (FADS) and is applicable for a multitude of objects. We sort aqueous droplets, at rates as high as several kHz, into two or even more outlet channels. We can also sort cells directly from the medium without prior encapsulation into drops; we demonstrate this by sorting fluorescently labeled mouse melanoma cells in a single phase fluid. Our acoustic microfluidic FACS is compatible with standard cell sorting cytometers, yet, at the same time, enables a rich variety of more sophisticated applications. PMID- 25031158 TI - Is there justification for universal leukoreduction? PMID- 25031159 TI - Genetic evaluation of mesenchymal stem cells. PMID- 25031160 TI - Comment on: Transfusion practices in a neonatal intensive care unit in a Brazilian town. PMID- 25031161 TI - National neonatal screening program for hemoglobinopathies: how far have we advanced? PMID- 25031162 TI - Transfusion practices in a neonatal intensive care unit in a city in Brazil. AB - OBJECTIVE: Newborn infants are the most heavily transfused population inside intensive care units. The hemoglobin level used to indicate the need of transfusions is not well established. The aim of this study was to evaluate transfusional practices in newborns in the neonatal intensive care units of one specific city. METHODS: Red blood cell transfusion practices of all transfused newborns in all five of the neonatal intensive care units of the city were analyzed. Data are reported as descriptive statistics, including numbers and percentages and means and standard deviation. Univariate analysis, followed by stepwise logistic regression was performed in respect to transfusional data and outcomes. RESULTS: A total of 949 patients were admitted to the intensive care units during the 12-month study period with 20.9% receiving at least one transfusion, most (62.4%) of whom received more than one transfusion. The mean number of transfusions per infant was 2.7+/-2.16; in the liberal transfusion group the mean number was 1.59+/-1.63 and in the restrictive group it was 1.08+/ 1.51. The mean hemoglobin and hematocrit levels were 9.0g/dL (+/-1.4g/dL) and 27.4% (+/-4.3%), respectively. The most common indications for blood transfusions were sepsis and prematurity. CONCLUSION: This study shows that the characteristics and the transfusion practices for newborns admitted in the neonatal intensive care units of Juiz de Fora are similar to recent pubications. There was no significant reduction in the number of transfusions per child in the restrictive group compared to the liberal group. Restrictive transfusions are an independent risk factor for peri-intraventricular hemorrhages and death. PMID- 25031163 TI - Follow-up of children with hemoglobinopathies diagnosed by the Brazilian Neonatal Screening Program in the State of Pernambuco. AB - OBJECTIVE: To determine the geographical distribution of hemoglobinopathies in the State of Pernambuco, to characterize the children with these diseases and to describe factors associated with their follow-up at the referral center during the period from 2003 to 2010. METHODS: A retrospective, cross-sectional, descriptive study was carried out of 275 medical records from a total of 302 children with hemoglobinopathies diagnosed by the National Neonatal Screening Program in the State of Pernambuco in the study period. Microsoft Excel was used for data processing and analysis. The chi-square and the Fisher test were used for statistical analysis. The level of significance was set at 5%. Terra View software was used to analyze the geographical distribution of hemoglobinopathies in the State. RESULTS: A total of 8.9% of the cases of hemoglobinopathies detected in the period were not followed up at the referral center. For the mothers of children with diseases, this was their second or third or more pregnancy in 64.2% and 30.2%, respectively. Regarding the influence of region of residence and regular medical appointments, the study demonstrated that children from the Zona da Mata, Sertao and Vale do Sao Francisco regions did not attend 45.2%, 50% and 55.6% of their appointments in the outpatient department, respectively. CONCLUSIONS: This study shows that a significant number of children do not begin consultations in the outpatient clinic and even those who started treatment early and who have the most severe form of the disease, usually miss medical appointments. PMID- 25031164 TI - Clinical complications in pregnant women with sickle cell disease: prospective study of factors predicting maternal death or near miss. AB - OBJECTIVE: To evaluate complications in pregnant women with sickle cell disease, especially those leading to maternal death or near miss (severe obstetric complications). METHODS: A prospective cohort of 104 pregnant women registered in the Blood Center of Belo Horizonte (Hemominas Foundation) was followed up at high risk prenatal units. They belonged to Group I (51 hemoglobin SS and three hemoglobin S/beta(0)-thalassemia) or Group II (49 hemoglobin SC and one hemoglobin S/beta(+)-thalassemia). Both groups had similar median ages. Predictive factors for 'near miss' or maternal death with p-value<=0.25 in the univariate analysis were included in a multivariate logistic model (significance set for p-value<=0.05). RESULTS: Group I had more frequent episodes of vaso occlusive crises, more transfusions in the antepartum and postpartum, and higher percentage of preterm deliveries than Group II. Infections and painful crises during the postpartum period were similar in both the groups. The mortality rate was 4.8%: three deaths in Group I and two in Group II. One-third of the women in both the groups experienced near miss. The most frequent event was pneumonia/acute chest syndrome. Alpha-thalassemia co-inheritance and beta-gene haplotypes were not associated with near miss or maternal death. In multivariate analysis predictors of near miss or death were parity above one and baseline red blood cell macrocytosis. In Group I, baseline hypoxemia (saturation<94%) was also predictive of near miss or death. CONCLUSION: One-third of pregnant women had near miss and 4.8% died. Both hemoglobin SS and SC pregnant women shared the same risk of death or of severe complications, especially pulmonary events. PMID- 25031165 TI - Analysis of the feasibility of early hospital discharge after autologous hematopoietic stem cell transplantation and the implications to nursing care. AB - INTRODUCTION: Autologous hematopoietic stem cell transplantation is a conduct used to treat some hematologic diseases and to consolidate the treatment of others. In the field of nursing, the few published scientific studies on nursing care and early hospital discharge of transplant patients are deficient. Knowledge about the diseases treated using hematopoietic stem cell transplantation, providing guidance to patients and caregivers and patient monitoring are important nursing activities in this process. Guidance may contribute to long term goals through patients' short-term needs. AIM: To analyze the results of early hospital discharge on the treatment of patients submitted to autologous transplantation and the influence of nursing care on this conduct. METHODS: A retrospective, quantitative, descriptive and transversal study was conducted. The hospital records of 112 consecutive patients submitted to autologous transplantation in the period from January to December 2009 were revisited. Of these, 12 patients, who remained in hospital for more than ten days after transplantation, were excluded from the study. RESULTS: The medical records of 100 patients with a median age of 48.5 years (19-69 years) were analyzed. All patients were mobilized and hematopoietic stem cells were collected by leukapheresis. The most common conditioning regimes were BU12Mel100 and BEAM 400. Toxicity during conditioning was easily managed in the outpatient clinic. Gastrointestinal toxicity, mostly Grades I and II, was seen in 69% of the patients, 62% of patients had diarrhea, 61% of the patients had nausea and vomiting and 58% had Grade I and II mucositis. Ten patients required hospitalization due to the conditioning regimen. Febrile neutropenia was seen in 58% of patients. Two patients died before Day +60 due to infections, one with aplasia. The median times to granulocyte and platelet engraftment were 12 days and 15 days, respectively, with median red blood cell and platelet transfusions until discharge of three and four units, respectively. Twenty-three patients required rehospitalization before being discharged from the outpatient clinic. CONCLUSION: The median time to granulocyte engraftment was 12 days and during the aplasia phase few patients were hospitalized or suffered infections. The toxicity of the conditioning was the leading cause of rehospitalization. The nursing staff participated by providing guidance to patients and during the mobilization, transplant and outpatient follow-up phases, thus helping to successfully manage toxicity. PMID- 25031166 TI - Transfusion-transmitted malaria in endemic zone: epidemiological profile of blood donors at the Fundacao HEMOAM and use of rapid diagnostic tests for malaria screening in Manaus. AB - OBJECTIVE: With 99% of the cases in Brazil, malaria is endemic in the Amazon region. Transfusion-transmitted malaria, an important risk in endemic areas, has been reported. The aim of this study was to describe the epidemiological profile of blood donor candidates at the Fundacao de Hematologia e Hemoterapia do Amazonas and evaluate the efficacy of rapid diagnostic tests used for malaria screening of blood donors within endemic regions. METHODS: Between May 2008 and May 2009, 407 blood donor candidates were selected and grouped based on the Malaria Annual Parasite Index of the geographic area in which they originated: Group 1 (eligible donors - n=265) originated from areas of low to medium risk of exposure to malaria and Group 2 (ineligible donors - n=142) originated from high risk areas. All samples were concurrently screened using two immunochromatic antigen-based rapid tests and by the thick smear test. RESULTS: All samples were negative by all three methods. The demographic profile indicated that the majority of participants were male, ages ranged from 18 to 39 years and less than half the candidates had only elementary schooling. Two issues need to be addressed: one is the ineligibility of donors and its impact on blood donor centers as, in this study, 22.7% of the donors were considered ineligible. The other is the limited sensitivity of the parasitological tests used, allowing a risk of false-negative results. CONCLUSION: New methods are needed to ensure transfusion safety without rejecting potential donors, which would ensure safe transfusion without harming the blood supply. PMID- 25031167 TI - Concentrations of blood folate in Brazilian studies prior to and after fortification of wheat and cornmeal (maize flour) with folic acid: a review. AB - BACKGROUND: In July 2004, the Brazilian Ministry of Health through the National Health Surveillance Agency made the fortification of wheat flour and cornmeal (maize flour) with iron and folic acid mandatory, with the intention of reducing the rate of diseases such as neural tube defects. OBJECTIVE: The aim of the study was to investigate the impact of the folic acid fortified wheat flour and cornmeal on serum and red blood cell folate levels and on the reduction of neural tube defects in different Brazilian studies. METHODS: In order to compare folate concentrations in the Brazilian population prior to and following the implementation of mandatory fortification of wheat and cornmeal, studies that involved blood draws between January 1997 and May 2004 (pre-fortification period), and from June 2004 to the present (post-fortification period) were chosen. The data search included PubMed and Scopus databases as well as the Brazilian Digital Library of Theses and Dissertations. The following keywords were employed for the query: folate, folic acid, fortification, Brazil, healthy population, the elderly, children and pregnant women. RESULTS: A total of 47 Brazilian studies were selected; 26 from the pre-fortification period and 22 after the fortification implementation. The studies were classified according to the cohort investigated (pregnant women, children, adolescents, adults and the elderly). After the implementation of flour fortification with folic acid in Brazil, serum folate concentrations increased in healthy populations (57% in children and adolescents and 174% in adults), and the incidence of neural tube defects dropped. CONCLUSION: Folic acid fortification of wheat flour and cornmeal increased the blood folate concentrations and reduced the incidence of neural tube defects. PMID- 25031168 TI - Transmission of lupus anticoagulant by allogeneic stem cell transplantation. AB - Passive transmission of autoimmune diseases by allogeneic stem cell transplantation is rare and is ascribed to passive transfer of memory B-cells from donor to recipient. We hereby report a case of transmission of an asymptomatic lupus anticoagulant from a sibling donor to a recipient of transplantation for secondary acute myeloid leukemia. On pre-harvest evaluation, the sibling donor with no history of bleeding or thrombosis was found to have a lupus anticoagulant. After engraftment, the recipient was found to have a new prolonged activated partial thromboplastin time and was subsequently shown to have a lupus anticoagulant on Day +73 after stem cell transplantation. The recipient remained well with no evidence of bleeding, thrombosis, or graft-versus host disease and was on a stable dose of tacrolimus at the time the lupus anticoagulant was detected. There was no other identifiable trigger for the appearance of a lupus anticoagulant. PMID- 25031169 TI - Pathologic rupture of the spleen in a patient with acute myelogenous leukemia and leukostasis. AB - Rupture of the spleen can be classified as spontaneous, traumatic, or pathologic. Pathologic rupture has been reported in infectious diseases such as infectious mononucleosis, and hematologic malignancies such as acute and chronic leukemias. Splenomegaly is considered the most relevant factor that predisposes to splenic rupture. A 66-year-old man with acute myeloid leukemia evolved from an unclassified myeloproliferative neoplasm, complaining of fatigue and mild upper left abdominal pain. He was pale and presented fever and tachypnea. Laboratory analyses showed hemoglobin 8.3g/dL, white blood cell count 278*10(9)/L, platelet count 367*10(9)/L, activated partial thromboplastin time (aPTT) ratio 2.10, and international normalized ratio (INR) 1.60. A blood smear showed 62% of myeloblasts. The immunophenotype of the blasts was positive for CD117, HLA-DR, CD13, CD56, CD64, CD11c and CD14. Lactate dehydrogenase was 2384U/L and creatinine 2.4mg/dL (normal range: 0.7-1.6mg/dL). Two sessions of leukapheresis were performed. At the end of the second session, the patient presented hemodynamic instability that culminated in circulatory shock and death. The post mortem examination revealed infiltration of the vessels of the lungs, heart, and liver, and massive infiltration of the spleen by leukemic blasts. Blood volume in the peritoneal cavity was 500mL. Acute leukemia is a rare cause of splenic rupture. Male gender, old age and splenomegaly are factors associated with this condition. As the patient had leukostasis, we hypothesize that this, associated with other factors such as lung and heart leukemic infiltration, had a role in inducing splenic rupture. Finally, we do not believe that leukapheresis in itself contributed to splenic rupture, as it is essentially atraumatic. PMID- 25031170 TI - T-cell/myeloid mixed-phenotype acute leukemia with monocytic differentiation and isolated 17p deletion. AB - Mixed phenotype acute leukemia is a rare subtype of leukemia that probably arises from a hematopoietic pluripotent stem cell. The co-expression of two of myeloid, B- or T-lymphoid antigens is the hallmark of this disease. Herein, the case of a 28-year-old female patient is reported who presented with hemoglobin of 5.8g/dL, white blood cell count of 138*10(9)/L and platelet count of 12*10(9)/L. The differential count of peripheral blood revealed 96% of blasts. Moreover, the patient presented with lymphadenopathy, splenomegaly and bone marrow infiltration by monocytoid blasts characterized as 7% positivity by Sudan Black cytochemical staining. Immunophenotyping revealed the involvement of blasts of both T- and monocytic lineages. The cytogenetic analysis showed an isolated 17p deletion. Thus, the diagnosis of T-cell/myeloid mixed phenotype acute leukemia was made with two particular rare features, that is, the monocytic differentiation and the 17p deletion as unique cytogenetic abnormalities. The possibility of concomitant expressions of T-cell and monocytic differentiation antigens in the same blast population is hard to explain using the classical model of hematopoiesis. However, recent studies have suggested that myeloid potential persists even when the lineage branches segregate toward B- and T-cells. The role of an isolated 17p deletion in the pathogenesis of this condition is unclear. At present, the patient is in complete remission after an allogeneic stem cell transplantation procedure. PMID- 25031171 TI - Bleomycin-induced flagellate dermatitis. AB - A 29-year-old woman with stage IVB Hodgkin's lymphoma was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine. Two weeks after the first cycle was completed, she developed pruritic, linear erythematous lesions in a flagellate-like pattern on the trunk, neck and arms. After oral prednisone therapy and cessation of bleomycin, the lesions started to recede. PMID- 25031172 TI - Mycobacterium leprae in bone marrow. PMID- 25031173 TI - Correcting an unintentional injustice: a comment on the doctorate thesis 'Transfusion' by Jose Carvalho Tolentino presented in 1878. PMID- 25031174 TI - Perspectives on the production of pluripotent cells from hematopoietic cells. PMID- 25031175 TI - Erratum on "Risk factors associated with the occurrence of adverse events in plateletpheresis donation" [Rev Bras Hematol Hemoter. 2014;36(3):191-5]. PMID- 25031177 TI - Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD). AB - Down syndrome (DS) is caused by the triplication of human chromosome 21 (HSA21) and is the most common genetic cause of intellectual disability, with individuals having deficits in cognitive function including hippocampal learning and memory and neurodegeneration of cholinergic basal forebrain neurons, a pathological hallmark of Alzheimer's disease (AD). To date, the molecular underpinnings driving this pathology have not been elucidated. The Ts65Dn mouse is a segmental trisomy model of DS and like DS/AD pathology, displays age-related cognitive dysfunction and basal forebrain cholinergic neuron (BFCN) degeneration. To determine molecular and cellular changes important for elucidating mechanisms of neurodegeneration in DS/AD pathology, expression profiling studies were performed. Molecular fingerprinting of homogeneous populations of Cornu Ammonis 1 (CA1) pyramidal neurons was performed via laser capture microdissection followed by Terminal Continuation RNA amplification combined with custom-designed microarray analysis and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting. Significant alterations were observed within CA1 pyramidal neurons of aged Ts65Dn mice compared to normal disomic (2N) littermates, notably in excitatory and inhibitory neurotransmission receptor families and neurotrophins, including brain-derived neurotrophic factor as well as several cognate neurotrophin receptors. Examining gene and protein expression levels after the onset of BFCN degeneration elucidated transcriptional and translational changes in neurons within a vulnerable circuit that may cause the AD-like pathology seen in DS as these individuals age, and provide rational targets for therapeutic interventions. PMID- 25031179 TI - Aneurysm permeability following coil embolization: packing density and coil distribution. AB - BACKGROUND: Rates of durable aneurysm occlusion following coil embolization vary widely, and a better understanding of coil mass mechanics is desired. The goal of this study is to evaluate the impact of packing density and coil uniformity on aneurysm permeability. METHODS: Aneurysm models were coiled using either Guglielmi detachable coils or Target coils. The permeability was assessed by taking the ratio of microspheres passing through the coil mass to those in the working fluid. Aneurysms containing coil masses were sectioned for image analysis to determine surface area fraction and coil uniformity. RESULTS: All aneurysms were coiled to a packing density of at least 27%. Packing density, surface area fraction of the dome and neck, and uniformity of the dome were significantly correlated (p<0.05). Hence, multivariate principal components-based partial least squares regression models were used to predict permeability. Similar loading vectors were obtained for packing and uniformity measures. Coil mass permeability was modeled better with the inclusion of packing and uniformity measures of the dome (r(2)=0.73) than with packing density alone (r(2)=0.45). The analysis indicates the importance of including a uniformity measure for coil distribution in the dome along with packing measures. CONCLUSIONS: A densely packed aneurysm with a high degree of coil mass uniformity will reduce permeability. PMID- 25031178 TI - Evidence for Alzheimer's disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. AB - Alzheimer's disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity. PMID- 25031180 TI - Do candidate genes mediating conspecific sperm precedence affect sperm competitive ability within species? A test case in Drosophila. AB - When females mate to multiple males, the last male to mate fathers the majority of progeny. When males of different species inseminate a female, the sperm of the male conspecific to the female is favored in fertilization in a process known as conspecific sperm precedence (CSP). A large number of studies in Drosophila have assayed the genetic basis of sperm competition, with a main focus on D. melanogaster and accessory gland protein genes. Only a few studies have attempted to disentangle the genetic basis of CSP between related species of Drosophila. Although there is no a priori reason to believe that genes influencing intraspecific sperm competitive ability might also mediate conspecific sperm precedence, no study has addressed the question. Here, we test a group of candidate CSP genes between D. simulans and D. mauritiana for their effect on sperm competition in D. melanogaster. The use of P-element insertion lines identified CG14891 gene disruption as the only one causing a significant decrease in second male paternity success relative to wild-type and ebony tester males. The gene disruption affected both sperm displacement and the sperm fertilizing ability. Out of five genes tested using RNA interference, only gene knockdown of CG6864(Mst89B) [corrected] significantly reduced the male's ability to father progeny when second to mate. Our results suggest that CG14891 and CG6468 might have been co-opted from an intraspecies gene function (i.e., sperm competition) into an interspecies avoidance phenotype (i.e., CSP). Alternatively, the dual role of these genes could be a consequence of their pleiotropic roles. PMID- 25031181 TI - Fast and cost-effective genetic mapping in apple using next-generation sequencing. AB - Next-generation DNA sequencing (NGS) produces vast amounts of DNA sequence data, but it is not specifically designed to generate data suitable for genetic mapping. Recently developed DNA library preparation methods for NGS have helped solve this problem, however, by combining the use of reduced representation libraries with DNA sample barcoding to generate genome-wide genotype data from a common set of genetic markers across a large number of samples. Here we use such a method, called genotyping-by-sequencing (GBS), to produce a data set for genetic mapping in an F1 population of apples (Malus * domestica) segregating for skin color. We show that GBS produces a relatively large, but extremely sparse, genotype matrix: over 270,000 SNPs were discovered but most SNPs have too much missing data across samples to be useful for genetic mapping. After filtering for genotype quality and missing data, only 6% of the 85 million DNA sequence reads contributed to useful genotype calls. Despite this limitation, using existing software and a set of simple heuristics, we generated a final genotype matrix containing 3967 SNPs from 89 DNA samples from a single lane of Illumina HiSeq and used it to create a saturated genetic linkage map and to identify a known QTL underlying apple skin color. We therefore demonstrate that GBS is a cost effective method for generating genome-wide SNP data suitable for genetic mapping in a highly diverse and heterozygous agricultural species. We anticipate future improvements to the GBS analysis pipeline presented here that will enhance the utility of next-generation DNA sequence data for the purposes of genetic mapping across diverse species. PMID- 25031182 TI - Striatal hemihypoplasia: an early embryonic variant of cerebral hemiatrophy. AB - We present a case of hemihypoplasia of the striatum with ipsilateral cerebral hemispheric atrophy. The head of the caudate nucleus and putamen were hypoplastic, and gray matter cell bridges between them located in the anterior limb of the internal capsule were sparse. Cerebral atrophy was accompanied by ipsilateral mesial temporal sclerosis without thalamic atrophy. The anterior limb of the internal capsule showed no signal abnormalities or volume loss. These imaging findings and the hyperintensity at the fundus striati suggest an early embryonic insult of lateral striatal elevation. PMID- 25031183 TI - Reliable identification of cross-linked products in protein interaction studies by 13C-labeled p-benzoylphenylalanine. AB - We describe the use of the (13)C-labeled artificial amino acid p-benzoyl-L phenylalanine (Bpa) to improve the reliability of cross-linked product identification. Our strategy is exemplified for two protein-peptide complexes. These studies indicate that in many cases the identification of a cross-link without additional stable isotope labeling would result in an ambiguous assignment of cross-linked products. The use of a (13)C-labeled photoreactive amino acid is considered to be preferred over the use of deuterated cross-linkers as retention time shifts in reversed phase chromatography can be ruled out. The observation of characteristic fragment ions additionally increases the reliability of cross-linked product assignment. Bpa possesses a broad reactivity towards different amino acids and the derived distance information allows mapping of spatially close amino acids and thus provides more solid structural information of proteins and protein complexes compared to the longer deuterated amine-reactive cross-linkers, which are commonly used for protein 3D-structure analysis and protein-protein interaction studies. PMID- 25031185 TI - Ion-pair formation in aqueous strontium chloride and strontium hydroxide solutions under hydrothermal conditions by AC conductivity measurements. AB - Frequency-dependent electrical conductivities of solutions of aqueous strontium hydroxide and strontium chloride have been measured from T = 295 K to T = 625 K at p = 20 MPa, over a very wide range of ionic strength (3 * 10(-5) to 0.2 mol kg(-1)), using a high-precision flow AC conductivity instrument. Experimental values for the concentration-dependent equivalent conductivity, Lambda, of the two electrolytes were fitted with the Turq-Blum-Bernard-Kunz ("TBBK") ionic conductivity model, to determine ionic association constants, K(A,m). The TBBK fits yielded statistically significant formation constants for the species SrOH(+) and SrCl(+) at all temperatures, and for Sr(OH)2(0) and SrCl2(0) at temperatures above 446 K. The first and second stepwise association constants for the ion pairs followed the order K(A1)(SrOH(+)) > K(A1)(SrCl(+)) > K(A2)[Sr(OH)2(0)] > K(A2)[SrCl2(0)], consistent with long-range solvent polarization effects associated with the lower static dielectric constant and high compressibility of water at elevated temperatures. The stepwise association constants to form SrCl(+) agree with previously reported values for CaCl(+) to within the combined experimental error at high temperatures and, at temperatures below ~375 K, the values of log10 KA1 for strontium are lower than those for calcium by up to ~0.3-0.4 units. The association constants for the species SrOH(+) and Sr(OH)2(0) are the first accurate values to be reported for hydroxide ion pairs with any divalent cation under these conditions. PMID- 25031184 TI - Anatomical specificity of O6-methylguanine DNA methyltransferase protein expression in glioblastomas. AB - O6-methylguanine DNA methyltransferase (MGMT) is one of the important tumor related biomarkers and is considered to be a prognostic factor for glioblastoma. This study aimed to investigate the anatomical location of tumor-related MGMT protein expression in histologically confirmed de novo glioblastoma multiforme (GBM). Preoperative magnetic resonance images were retrospectively examined from GBM patients. Tumor tissues were manually segmented based on the structural image of each patient and subsequently registered to a standard brain atlas. Superimposition of the tumor tissues was carried out in patients with and without epigenetic changes. We used voxel-based lesion symptom mapping (VLSM) to identify the specific brain regions that were associated with level of MGMT protein expression. The tumors with low expression of MGMT protein and those with high expression of MGMT protein showed not significant differences in tumor size on T2 imaging. The VLSM analysis demonstrated that tumors with low expression of MGMT protein were more likely to occur in the right temporal-parietal lobe, while tumors with high expression of MGMT protein occurred more often in the left frontal lobe. Based upon VLSM data, our results suggest that the epigenetic changes, which occur during tumorigenesis, may have anatomical specificity. The identified correlation between molecular biomarkers and anatomical distribution underscores the current understanding of the biological characteristics of glioblastoma. PMID- 25031186 TI - Can changes in psychosocial factors and residency explain the decrease in physical activity during the transition from high school to college or university? AB - BACKGROUND: When students make the transition from high school to college or university, their physical activity (PA) levels decrease strongly. Consequently, it is of crucial importance to identify the determinants of this decline in PA. PURPOSE: The study aims were to (1) examine changes in psychosocial factors in students during the transition from high school to college/university, (2) examine if changes in psychosocial factors and residency can predict changes in PA, and (3) investigate the moderating effects of residency on the relationship between changes in psychosocial factors and changes in PA. METHOD: Between March 2008 and October 2010, 291 Flemish students participated in a longitudinal study, with baseline measurements during the final year of high school and follow-up measurements at the start of second year of college/university. At both time points, participants completed a questionnaire assessing demographics, active transportation, leisure-time sports, psychosocial variables, and residency. Repeated measures MANOVA analyses and multiple moderated hierarchic regression analyses were conducted. RESULTS: Modeling, self-efficacy, competition-related benefits, and health-related, external and social barriers decreased, while health-related benefits and time-related barriers increased from baseline to follow-up. Decreases in modeling and time-related barriers were associated with a decrease in active transportation (adjusted R(2) = 3.2%); residency, decreases in self-efficacy, competition-related benefits, and increases in health- and time related barriers predicted a decrease in leisure-time sports (adjusted R(2) = 29.3%). Residency only moderated two associations between psychosocial factors and changes in PA. CONCLUSION: Residency and changes in psychosocial factors were mainly important to explain the decrease in leisure-time sports. Other factors such as distance to college/university are likely more important to explain the decrease in active transportation; these are worth exploring in future studies. Because few interactions were found, similar interventions, focusing on self efficacy, time management, and increasing perceived benefits may be effective to increase leisure-time sports in all students. PMID- 25031187 TI - The changeability and predictive value of dysfunctional cognitions in cognitive behavior therapy for chronic tinnitus. AB - BACKGROUND: Multidimensional tinnitus models describe dysfunctional cognitions as a complicating factor in the process of tinnitus habituation. However, this concept has rarely been investigated in previous research. PURPOSE: The present study investigated the effects of two cognitive-behavioral treatments on dysfunctional tinnitus-related cognitions in patients with chronic tinnitus. Furthermore, dysfunctional cognitions were examined as possible predictors of the therapeutic effect on tinnitus distress. METHOD: A total of 128 patients with chronic tinnitus were randomly assigned to either an Internet-delivered guided self-help treatment (Internet-based cognitive-behavioral therapy, ICBT), a conventional face-to-face group therapy (cognitive-behavioral group therapy, GCBT), or an active control group in the form of a web-based discussion forum (DF). To assess tinnitus-related dysfunctional thoughts, the Tinnitus Cognitions Scale (T-Cog) was used at pre- and post-assessment, as well as at the 6- and 12 month follow-up. RESULTS: Multivariate ANOVAs with post hoc tests revealed significant and comparable reductions of dysfunctional tinnitus-related cognitions for both treatments (GCBT and ICBT), which remained stable over a 6- and 12-month period. Negative correlations were found between the catastrophic subscale of the T-Cog and therapy outcome for ICBT, but not for GCBT. This means a higher degree of catastrophic thinking at baseline was associated with lower benefit from ICBT directly after the treatment. Hierarchical regression analysis confirmed catastrophizing as a predictor of poorer therapy outcome regarding emotional tinnitus distress in ICBT. No associations were detected in the follow up assessments. CONCLUSION: Both forms of CBT are successful in reducing dysfunctional tinnitus-related cognitions. Catastrophizing significantly predicted a less favorable outcome regarding emotional tinnitus distress in ICBT. Clinical implications of these results are described. Dysfunctional cognitions could be targeted more intensively in therapy and in future research on tinnitus. PMID- 25031188 TI - A randomised controlled trial for the evaluation of risk for type 2 diabetes in hypertensive patients receiving thiazide diuretics: Diuretics In the Management of Essential hypertension (DIME) study. AB - OBJECTIVES: Thiazide diuretics are one of the first choice antihypertensives but not optimally utilised because of concerns regarding their adverse effects on glucose metabolism. The Diuretics In the Management of Essential hypertension (DIME) study was designed, for the first time, to assess the risk for type 2 diabetes mellitus in patients with essential hypertension during antihypertensive treatment with low-dose thiazide diuretics compared to those not treated with diuretics. DESIGN: Multicentre, unblinded, pragmatic, randomised, controlled trial with blinded assessment of end points and intention-to-treat analysis that was started in 2004 and finished in 2012. SETTING: Hypertension clinics at 106 sites in Japan, including general practitioners' offices and teaching hospitals. PARTICIPANTS: Non-diabetic patients with essential hypertension. INTERVENTIONS: Antihypertensive treatment with low-dose thiazide diuretics at 12.5 mg/day of hydrochlorothiazide or equivalent (Diuretics group) or that without thiazide diuretics (No-diuretics group). MAIN OUTCOME: The primary outcome was new onset of type 2 diabetes diagnosed according to WHO criteria and the criteria of Japanese Society of Diabetes. RESULTS: 1130 patients were allocated to Diuretics (n=544) or No-diuretics group (n=586). Complete end point information was collected for 1049 participants after a median follow-up of 4.4 years. Diabetes developed in 25 (4.6%) participants in the Diuretics group, as compared with 29 (4.9%) in the No-diuretics group (HR 0.93; 95% CI 0.55 to 1.58; p=0.800). CONCLUSIONS: Antihypertensive treatment with thiazide diuretics at low doses may not be associated with an increased risk for new onset of type 2 diabetes. This result might suggest safety of use of low doses of thiazide diuretics. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00131846. PMID- 25031189 TI - Comparison of two anterior fusion methods in two-level cervical spondylosis myelopathy: a meta-analysis. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of anterior cervical corpectomy and fusion (ACCF) and anterior cervical discectomy and fusion (ACDF) for treating two-adjacent-level cervical spondylosis myelopathy (CSM). DESIGN: A meta-analysis of the two anterior fusion methods was conducted. The electronic databases of PubMed, the Cochrane Central Register of Controlled Trials, ScienceDirect, CNKI, WANFANG DATA and CQVIP were searched. Quality assessment of the included studies was evaluated using the Cochrane Risk of Bias Tool and the Methodological Index for Non-Randomised Studies criteria. Pooled risk ratios of dichotomous outcomes and standardised mean differences (SMDs) of continuous outcomes were generated. Using the chi(2) and I(2) tests, the statistical heterogeneity was assessed. Subgroup and sensitivity analyses were also performed. PARTICIPANTS: Nine eligible trials with a total of 631 patients and a male-to-female ratio of 1.38:1 were included in this meta-analysis. INCLUSION CRITERIA: Randomised controlled trials (RCTs) and non-randomised controlled trials that adopted ACCF and ACDF to treat two-adjacent-level CSM were included. RESULTS: No significant differences were identified between the two groups regarding hospital stay, the Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) scores for neck and arm pain, total cervical range of motion (ROM), fusion ROM, fusion rate, adjacent-level ossification and complications, while ACDF had significantly less bleeding (SMD=1.14, 95% CI (0.74 to 1.53)); a shorter operation time (SMD=1.13, 95% CI (0.82 to 1.45)); greater cervical lordosis, total cervical (SMD=-2.95, 95% CI (-4.79 to -1.12)) and fused segment (SMD=-2.24, 95% CI (-3.31 to -1.17)); higher segmental height (SMD=-0.68, 95% CI (-1.03 to -0.34)) and less graft subsidence (SMD=0.40, 95% CI (0.06 to 0.75)) compared to ACCF. CONCLUSIONS: The results suggested that ACDF has more advantages compared to ACCF. However, additional high-quality RCTs and a longer follow-up duration are needed. PMID- 25031190 TI - Increased homocysteine levels in valproate-treated patients with epilepsy: a meta analysis. AB - OBJECTIVE: To determine whether valproate (VPA) monotherapy influences homocysteine metabolism in patients with epilepsy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched all articles in English through PubMed, Web of Science and EMBASE published up to August 2013 concerning the homocysteine levels in VPA monotherapeutic patients with epilepsy. PARTICIPANTS: VPA-treated patients with epilepsy (n=266) and matched healthy controls (n=489). OUTCOME MEASURES: Heterogeneity between studies was assessed using I(2) statistics. Pooled standardised mean difference (SMD) and 95% CIs were calculated using a random effect model. RESULTS: A total of eight eligible studies were enrolled in our meta-analysis. We compared the plasma levels of homocysteine in VPA-treated patients with epilepsy and healthy controls. There was significant heterogeneity in the estimates according to the I(2) test (I(2)=65.6%, p=0.005). Plasma homocysteine levels in VPA-treated patients with epilepsy were significantly higher than in healthy controls under a random effect model. (SMD, 0.62; 95% CI 0.32 to 0.92). Further subgroup analyses suggested that no significant differences were present when grouped by ethnicity and age, but the risk of heterogeneity in the West Asian group (I(2)=47.4%, p=0.107) was diminished when compared with that of the overall group (I(2)=65.6%, p=0.005). CONCLUSIONS: Our meta-analysis indicates that VPA monotherapy is associated with the increase in plasma homocysteine levels in patients with epilepsy. Whether this association is influenced by ethnicity needs further research. PMID- 25031191 TI - Stem cell transplantation of matched sibling donors compared with immunosuppressive therapy for acquired severe aplastic anaemia: a Cochrane systematic review. AB - OBJECTIVES: Acquired severe aplastic anaemia is a rare and potentially fatal disease. The aim of this Cochrane review was to evaluate the effectiveness and adverse events of first-line allogeneic haematopoietic stem cell transplantation of human leucocyte antigen (HLA)-matched sibling donors compared with first-line immunosuppressive therapy. SETTING: Specialised stem cell transplantations units in primary care hospitals. PARTICIPANTS: We included 302 participants with newly diagnosed acquired severe aplastic anaemia. The age ranged from early childhood to young adulthood. We excluded studies on participants with secondary aplastic anaemia. INTERVENTIONS: We included allogeneic haematopoietic stem cell transplantation as the test intervention harvested from any source of matched sibling donor and serving as a first-line therapy. We included immunosuppressive therapy as comparator with either antithymocyte/antilymphocyte globulin or ciclosporin or a combination of the two. PRIMARY AND SECONDARY OUTCOME MEASURES PLANNED AND FINALLY MEASURED: The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, graft-versus host disease, no response to immunosuppressive therapy, relapse after initial successful treatment, secondary clonal disease or malignancies, health-related quality of life and performance scores. RESULTS: We identified three prospective non-randomised controlled trials with a study design that was consistent with the principle of 'Mendelian randomisation' in allocating patients to treatment groups. All studies had a high risk of bias due to the study design and were conducted more than 15 years. The pooled HR for overall mortality for the donor group versus the no donor group was 0.95 (95% CI 0.43 to 2.12, p=0.90). CONCLUSIONS: There are insufficient and biased data that do not allow any firm conclusions to be made about the comparative effectiveness of first-line allogeneic haematopoietic stem cell transplantation of HLA-matched sibling donors and first-line immunosuppressive therapy of patients with acquired severe aplastic anaemia. PMID- 25031192 TI - Estimating smoking prevalence in general practice using data from the Quality and Outcomes Framework (QOF). AB - OBJECTIVES: To determine to what extent underlying data published as part of Quality and Outcomes Framework (QOF) can be used to estimate smoking prevalence within practice populations and local areas and to explore the usefulness of these estimates. DESIGN: Cross-sectional, observational study of QOF smoking data. Smoking prevalence in general practice populations and among patients with chronic conditions was estimated by simple manipulation of QOF indicator data. Agreement between estimates from the integrated household survey (IHS) and aggregated QOF-based estimates was calculated. The impact of including smoking estimates in negative binomial regression models of counts of premature coronary heart disease (CHD) deaths was assessed. SETTING: Primary care in the East Midlands. PARTICIPANTS: All general practices in the area of study were eligible for inclusion (230). 14 practices were excluded due to incomplete QOF data for the period of study (2006/2007-2012/2013). One practice was excluded as it served a restricted practice list. MEASUREMENTS: Estimates of smoking prevalence in general practice populations and among patients with chronic conditions. RESULTS: Median smoking prevalence in the practice populations for 2012/2013 was 19.2% (range 5.8-43.0%). There was good agreement (mean difference: 0.39%; 95% limits of agreement (-3.77, 4.55)) between IHS estimates for local authority districts and aggregated QOF register estimates. Smoking prevalence estimates in those with chronic conditions were lower than for the general population (mean difference 3.05%), but strongly correlated (Rp=0.74, p<0.0001). An important positive association between premature CHD mortality and smoking prevalence was shown when smoking prevalence was added to other population and service characteristics. CONCLUSIONS: Published QOF data allow useful estimation of smoking prevalence within practice populations and in those with chronic conditions; the latter estimates may sometimes be useful in place of the former. It may also provide useful estimates of smoking prevalence in local areas by aggregating practice based data. PMID- 25031193 TI - Association of socioeconomic status measured by education, and cardiovascular health: a population-based cross-sectional study. AB - OBJECTIVE: Cardiovascular health (CVH) is a relatively new concept defined by the American Heart Association (AHA). The aim of the present study was to assess whether the indices of CVH were discriminators of socioeconomic status (SES) in the adult population of the Republic of Srpska (RS). DESIGN: Population-based cross-sectional study. SETTING: RS, Bosnia and Herzegovina. PARTICIPANTS: The study involved 4165 adults aged >=18 years (mean age 50.2; 54% women) who participated in the National Health Survey performed from September to November 2010 in the RS. STUDY VARIABLES: Participant's education was a proxy for SES. Potential discriminators of SES were indices of CVH presented according to AHA as: ideal health behaviours index (non-smoking, body mass index <25 kg/m(2), physical activity at goal level and healthy diet); ideal health factors index (untreated total cholesterol <200 mg/dL, untreated blood pressure <120/<80 mm Hg, untreated fasting glucose <100 mg/dL and non-smoking); and ideal CVH status (defined as all seven ideal health metrics present) versus intermediate and poor CVH status. RESULTS: Participants with high educational levels had a significantly greater number of ideal CVH metrics, and ideal health factor metrics compared with those with low or medium educational level (OR 0.88 95% CI 0.77 to 0.99 and OR 0.88 95% CI 0.80 to 0.96; OR 0.81 95% CI 0.69 to 0.96 and OR 0.77 95% CI 0.68 to 0.87; respectively). The number of ideal behaviour metrics was not a discriminator of educational groups. Concerning the categories of CVH status the poor CVH was a discriminator for low and medium education compared with those with high education (OR 1.93 95% CI 1.24 to 3.01 and OR 1.54 95% CI 1.08 to 2.19, respectively). CONCLUSIONS: Our findings emphasise the large potential for preventing cardiovascular disease, showing a low proportion with a favourable CVH profile, especially among low-educated people. It is necessary to consider prevention strategies aimed at improving CVH in RS, targeting primarily low educational groups. PMID- 25031195 TI - Prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study. AB - INTRODUCTION: The prevalence of urate crystals in residual tissue samples from coronary arteries, aortic valves and prostate glands was assessed. METHODS: Alcohol-fixed coronary arteries from 55 explanted hearts, alcohol-fixed aortic valves collected from 75 valve replacement surgeries and 40 frozen, unfixed prostate specimens resected during cancer surgery were examined for birefringent crystals with polarising microscopy. RESULTS: In the 55 explanted hearts, 6 (10.9%) contained a coronary artery with birefringent crystals. One of the 75 aortic valves (1.4%) contained negatively and positively birefringent crystals. Nineteen of the 40 (47.5%) prostates contained birefringent crystals. CONCLUSIONS: We found that a remarkable percentage of coronary arteries and prostate specimens contained birefringent crystals. Crystal presence is an obvious prerequisite for possible crystal induced-inflammation in these tissues, just as similar crystals elicit a gouty inflammatory cascade in synovial joints. Further studies are necessary to determine whether urate crystals may play this role in these tissues and, if so, to establish whether urate-lowering therapy may be beneficial in prostatitis and coronary disease. PMID- 25031194 TI - The effect of a behaviour change intervention on the diets and physical activity levels of women attending Sure Start Children's Centres: results from a complex public health intervention. AB - OBJECTIVES: The UK government's response to the obesity epidemic calls for action in communities to improve people's health behaviour. This study evaluated the effects of a community intervention on dietary quality and levels of physical activity of women from disadvantaged backgrounds. DESIGN: Non-randomised controlled evaluation of a complex public health intervention. PARTICIPANTS: 527 women attending Sure Start Children's Centres (SSCC) in Southampton (intervention) and 495 women attending SSCCs in Gosport and Havant (control). INTERVENTION: Training SSCC staff in behaviour change skills that would empower women to change their health behaviours. OUTCOMES: Main outcomes dietary quality and physical activity. Intermediate outcomes self-efficacy and sense of control. RESULTS: 1-year post-training, intervention staff used skills to support behaviour change significantly more than control staff. There were statistically significant reductions of 0.1 SD in the dietary quality of all women between baseline and follow-up and reductions in self-efficacy and sense of control. The decline in self-efficacy and control was significantly smaller in women in the intervention group than in women in the control group (adjusted differences in self-efficacy and control, respectively, 0.26 (95% CI 0.001 to 0.50) and 0.35 (0.05 to 0.65)). A lower decline in control was associated with higher levels of exposure in women in the intervention group. There was a statistically significant improvement in physical activity in the intervention group, with 22.9% of women reporting the highest level of physical activity compared with 12.4% at baseline, and a smaller improvement in the control group. The difference in change in physical activity level between the groups was not statistically significant (adjusted difference 1.02 (0.74 to 1.41)). CONCLUSIONS: While the intervention did not improve women's diets and physical activity levels, it had a protective effect on intermediate factors-control and self-efficacy-suggesting that a more prolonged exposure to the intervention might improve health behaviour. Further evaluation in a more controlled setting is justified. PMID- 25031196 TI - Is there a causal link between knee loading and knee osteoarthritis progression? A systematic review and meta-analysis of cohort studies and randomised trials. AB - OBJECTIVE: We performed a systematic review, meta-analysis and assessed the evidence supporting a causal link between knee joint loading during walking and structural knee osteoarthritis (OA) progression. DESIGN: Systematic review, meta analysis and application of Bradford Hill's considerations on causation. DATA SOURCES: We searched MEDLINE, Scopus, AMED, CINAHL and SportsDiscus for prospective cohort studies and randomised controlled trials (RCTs) from 1950 through October 2013. STUDY ELIGIBILITY CRITERIA: We selected cohort studies and RCTs in which estimates of knee joint loading during walking were used to predict structural knee OA progression assessed by X-ray or MRI. DATA ANALYSES: Meta analysis was performed to estimate the combined OR for structural disease progression with higher baseline loading. The likelihood of a causal link between knee joint loading and OA progression was assessed from cohort studies using the Bradford Hill guidelines to derive a 0-4 causation score based on four criteria and examined for confirmation in RCTs. RESULTS: Of the 1078 potentially eligible articles, 5 prospective cohort studies were included. The studies included a total of 452 patients relating joint loading to disease progression over 12-72 months. There were very serious limitations associated with the methodological quality of the included studies. The combined OR for disease progression was 1.90 (95% CI 0.85 to 4.25; I(2)=77%) for each one-unit increment in baseline knee loading. The combined causation score was 0, indicating no causal association between knee loading and knee OA progression. No RCTs were found to confirm or refute the findings from the cohort studies. CONCLUSIONS: There is very limited and low-quality evidence to support for a causal link between knee joint loading during walking and structural progression of knee OA. TRIAL REGISTRATION NUMBER: CRD42012003253. PMID- 25031199 TI - Comparison of the hospice systems in the United States, Japan and taiwan. AB - PURPOSE: The aim of hospice care is to provide the best possible quality of life both for people approaching the end of life and for their families and carers. The Korean government has been implementing a pilot project for hospital hospice services and trying to develop the national hospice system. To assist in the development of the Korean hospice system, the Korean government supported the present study comparing the hospice systems of three countries, United States, Japan, and Taiwan, which currently have a developed hospice system. METHODS: Data from three countries were collected in the following ways: reviewing hospice related literature, searching government documents on the Internet, collecting government hospice data, surveying six hospice institutions in each country, and conducting an international workshop. RESULTS: The hospice system was evaluated by comparing hospice management systems and hospice cost systems. The comparison of the hospice management system included five items of hospice infra structures and four items of hospice services. The hospice cost system included four items: funding source, hospital hospice cost, day care hospice cost, and home hospice cost. CONCLUSIONS: Based on the comparison of three countries, the most interesting thing was that home hospice care accounted for more than 90% of all hospice services in the United States and Taiwan. The results of this study will aid the countries that are in the process of developing a hospice system including Korea, which has been implementing a pilot project only for hospital hospice services. PMID- 25031198 TI - Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study): a randomised controlled study protocol. AB - INTRODUCTION: Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves beta-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA), liraglutide, is currently used for treatment of T2DM but its potential effect on cardiac function has not been investigated in detail. We hypothesised that liraglutide added to metformin backbone therapy in patients with CAD and newly diagnosed T2DM will improve beta-cell function and left ventricular systolic function during dobutamine stress. METHODS AND ANALYSES: 40 patients with CAD and newly diagnosed T2DM will receive the intervention liraglutide+metformin and placebo+metformin in this investigator-initiated, double blind, randomised, placebo-controlled, cross over 12 plus 12 weeks intervention study with a 2-week washout period. The primary cardiovascular end point is changes in left ventricular ejection fraction during stress echocardiography. The primary endocrine end point is beta-cell function evaluated during a frequently sampled intravenous glucose tolerance test. Secondary end points include heart rate variability, diurnal blood pressure, glucagon suppression and inflammatory response (urine, blood and adipose tissue). ETHICS AND DISSEMINATION: This study is approved by the Danish Medicines Agency, the Danish Dataprotection Agency and the Regional Committee on Biomedical Research Ethics of the Capital Region of Denmark. The trial will be carried out under the guidance from the GCP unit at Copenhagen University Hospital of Bispebjerg and in accordance with the ICH-GCP guidelines and the Helsinki Declaration. TRIAL REGISTRATIONS NUMBER: Clinicaltrials.gov ID: NCT01595789, EudraCT: 2011-005405-78. PMID- 25031200 TI - Relationship between survivors' perceived health status following acute coronary syndrome and depression symptoms during early recovery phase. AB - PURPOSE: To examine and describe perceived health status and depression symptoms among Acute Coronary Syndrome (ACS) survivors, and to examine their relationship during survivors' recovery phase. METHODS: A prospective design was used to test changeability of the key variables over a 1-month period for a cohort group of 82 post ACS patients, prior to their hospital discharge (Time 1) and at 4 weeks post discharge (Time 2). The revised version of Short Form-12 Health Survey and Beck Depression Inventory were used to measure the perceived health status and depression symptoms. The data were collected between 2003 and 2004. RESULTS: Perceived health status including mental health and physical health significantly improved over the 4-week period (t = -2.58, p <.05). Perceived health status during the hospitalization and length of hospital stay were significant predictors of depression symptoms during the early recovery phase. CONCLUSIONS: Patients' own perceptions about their health status need to be closely evaluated during the hospitalization in order to reduce the occurrences of later depression symptoms. Consequently, reducing depression symptoms and improving perceived health status should be addressed both in acute and chronic phases of ACS. PMID- 25031201 TI - Perspectives of korean patients, families, physicians and nurses on advance directives. AB - PURPOSE: The purpose of this study was to explore the perspectives of lung cancer patients, their families, physicians and nurses on advance directives. METHODS: The study employed a comparative descriptive design. A total of 124 participants from six general hospitals in Seoul and metropolitan area participated in this study from January 1, 2009 to November 15, 2009. Face-to-face interviews were conducted using a structured questionnaire. RESULTS: The majority of participants were not aware of advance directives. Most participants desired the establishment of a reliable legal system and a specific legal protocol for the design and application of advance directives. The perspectives of patients, their families, physicians and nurses differed regarding end-of-life care decisions. The least preferred treatment by patients with lung cancer was intensive care, followed by cardiopulmonary resuscitation, tracheotomy and artificial ventilation, and radiotherapy. CONCLUSIONS: There were many differences in the perspectives of patients, families, physicians and nurses on advance directives. End-of-life care decisions should take the wishes of patients into account, and that such decisions should therefore be made before the patients lose the capacity to make them. To make well-informed decisions regarding future care, patients and families must be fully educated about advance directives and expected outcomes. PMID- 25031202 TI - Psychometric evaluation of the korean version of the adapted illness intrusiveness rating scale. AB - PURPOSE: To examine the psychometric properties of the Korean version of the adapted Illness Intrusive-ness Rating Scale (a-IIRS). The a-IIRS is a modified version of the original IIRS that measures illness-disruptions to daily life in patients with diverse diagnoses. While the psychometric properties of the original IIRS have been validated, no study has been conducted to validate the Korean version of a-IIRS. METHODS: After translation and back-translation processes, the Korean version of a-IIRS was developed. A pilot test was conducted with 10 patients with chronic diseases. A convenience sample of 380 patients with diabetes, hypertension, and/or arthritis was used. Exploratory and confirmatory factor analyses, known-group technique, hypothesized relationships, internal consistency, and item analysis were tested. RESULTS: Three factors were extracted from principal components analysis with varimax rotation: Relationships and Personal Development, Instrumental Life, and Intimacy. Confirmatory factor analysis corroborated the good fit of the three-factor model. Illness intrusiveness was significantly different among the study subjects categorized into three groups according to different health status: poor, fair and good. The instrument was positively correlated with the scales of fatigue and depression. The tool demonstrated high internal consistency with adequate item-total correlations. CONCLUSIONS: The findings are consistent with previous study results on IIRS and support the reliability and validity of the Korean version of a-IIRS. The instrument is culturally relevant for Korean patients with chronic diseases. Health care professionals need to consider illness intrusiveness when caring for patients with chronic diseases and promote their quality of life. PMID- 25031203 TI - Health promotion and related factors among korean goose mothers. AB - PURPOSE: The purpose of this study was to further understand the health promotion behaviors of Korean goose mothers in the North America area. Health promotion behaviors measured in this study were self-actualization, health responsibility, physical activity, nutrition, interpersonal relations, and stress management. METHODS: The study is part of a larger study which used surveys (N=140) and in person interviews (n=18). In this study, analysis of survey results is presented. Advertisements and snowballing technique were used to recruit study participants. Pearson's correlation was used to explore the relationships between health promotion and social support, acculturation attitudes, and perceived family health. Multiple regressions were used to examine the predictors of health promotion behaviors. RESULTS: Women in the study were most frequently engaging in self-actualization and least in physical activity. Physical activity did not correlate with any of the study variables. When multiple regressions were performed, the model for each health promotion behavior was found to be statistically significant except for that of physical activity. Overall, study variables worked differently across models. Social support predicted self actualization, health responsibility, interpersonal relations, and stress management. None of the acculturation attitudes predicted health promotion behaviors. The subdimensions of perceived family health predicted health promotion behaviors except physical activity. CONCLUSIONS: The findings of this study contributed to the body of knowledge of health promotion among international migrant populations by identifying the differential effects of social support, acculturation attitudes, and perceived family health for six areas of health promotion. PMID- 25031204 TI - An investigation into breastfeeding characteristics of mothers attending childbirth education classes. AB - PURPOSE: This paper is a report of a study of the effects of breastfeeding education on the breastfeeding success and breastfeeding characteristics of mothers in a Turkish context. METHODS: The research was designed as quasi experimental. The sample consisted of 93 mothers who participated in (n = 46) and did not participate in childbirth education classes (n= 47). The date was collected between 2005 and 2007. The childbirth education class comprised 16 hours in total. Two hours of this class involved breastfeeding education. The course was carried out with the principles of adult education principles. Data on mothers' breastfeeding were collected in the sixth week postpartum. RESULTS: The majority of the mothers (63.4%) were university graduates. No difference was found between breastfeeding frequency in the control and experimental groups and starting supplemental food. It was found that 80.4% of the women in the experimental group breastfed in line with the techniques. This rate was found to be 48.9% in the control group. It was documented that the first breastfeeding times were earlier in the experimental group, their babies slept longer after being fed, their perceived spouse support was higher, and had even higher perceived breastfeeding success. CONCLUSIONS: On the basis of the study results it could be argued that attending childbirth preparation class with the husband has a positive effect over breastfeeding. Childbirth education classes will greatly contribute to the health of the society by affecting breastfeeding positively. PMID- 25031205 TI - Evidence-based Nursing Practice for Health Promotion in Adults With Hypertension: A Literature Review. AB - PURPOSE: This paper is a report of the results of a literature review conducted with the goal of identifying the nursing process components: assessment, diagnoses, interventions and outcomes related to health promotion in adults with hypertension in primary settings. METHODS: A search of MEDLINE, CINAHL, and PantherCat Online Catalogue of UWM database, PsycInfo, Cochrane Database, and Social Services Abstracts was conducted to retrieve literature published from 1988 to 2006. RESULTS: A total of 115 articles were reviewed. Overall, 70 relevant studies were selected on health promotion in adults with hypertension in primary settings. A total of 39 nursing process components (nursing diagnoses outcomes and interventions) related to health promotion with adults with high blood pressure were identified in primary healthcare settings. CONCLUSIONS: Research-based evidence material provides an evidence-based nursing practice guideline with specific nursing process components on the topic. The evidence based nursing practice guideline developed from this referential study for promoting health of adults with hypertension should be reflected in nursing practice in primary healthcare settings. For a future study, focus groups and key informant interview are recommended with nurses who actually provide nursing services in primary healthcare settings to clients who are diagnosed with high blood pressure. PMID- 25031206 TI - Results of total knee arthroplasty with NexGen LPS-Flex for osteoarthritis in the valgus knee: a study of 26 patients followed for a minimum of 2 years. AB - The present study aimed to examine the results of total knee arthroplasty (TKA) with the NexGen Legacy posterior-stabilized (LPS)-Flex system for osteoarthritis in the valgus knee. Between 2003 and 2011, 27 valgus knees in 26 patients who underwent TKA with the NexGen LPS-Flex implant were clinically and radiologically evaluated after a minimum follow-up of 2 years. The original diagnosis was osteoarthritis. Knee Society Knee Score (KSKS), Knee Society Function Score (KSFS), maximum flexion angle, maximum extension angle, and radiological femorotibial angle (FTA) were evaluated pre- and postoperatively. The mean KSKS improved from 42.6 before surgery to 82.2 by the final follow-up (p < 0.01), and the mean KSFS improved from 41.1 to 80.9 (p < 0.01). The mean maximum flexion angle changed from 109.1 degrees to 117.3 degrees (no statistical significance) and the maximum extension angle improved from -9.7 degrees to -3.6 degrees (p < 0.05) postoperatively. The postoperative radiological FTA was 172.4 degrees , which was closer to a neutral angle (174 degrees ) than the preoperative FTA (166.4 degrees ) (p < 0.01). None of the patients had undergone revision surgery by the final follow-up. As a conclusion, TKA with the NexGen LPS-Flex implant for osteoarthritis in the valgus knee resulted in satisfactory improvement regarding objective outcomes, although a longer term follow-up with a greater number of cases is necessary to verify these results. PMID- 25031207 TI - An experimental novel study: hyperbaric oxygen treatment on reduction of epidural fibrosis via down-regulation of collagen deposition, IL-6, and TGF-beta1. AB - OBJECTIVE: To investigate the effect of hyperbaric oxygen treatment (HBO) on prevention of epidural fibrosis in laminectomy rats. METHODS: A controlled, double-blinded study was performed in sixty healthy adult Wistar rats, mean weight 250 g. L1-L2 levels laminectomy were performed. Randomly, all rats were divided into three groups, with 20 in each group: (1) short-term HBO treatment group; (2) long-term HBO treatment (LHBO) group; and (3) Sham group (laminectomy without treatment). Four weeks post-operation, all rats were killed. The Rydell classification, hydroxyproline content, vimentin cells density, capillary density, and inflammatory factors expression were evaluated. RESULTS: The histological evaluation showed less epidural scar adhesions in LHBO group than other two groups. The hydroxyproline content, Rydell score, vimentin cells density, capillary density, and inflammatory factors expression all suggested better results in LHBO group than other two groups. CONCLUSION: It was concluded that HBO treatment might be beneficial in inhibiting collagen deposition and inflammatory activity and prevent epidural scar adhesion in laminectomy rat and, therefore, shows potential for clinical use. PMID- 25031208 TI - A simple one-step method to prepare fluorescent carbon dots and their potential application in non-invasive glioma imaging. AB - Fluorescent carbon dots (CD) possess impressive potential in bioimaging because of their low photobleaching, absence of optical blinking and good biocompatibility. However, their relatively short excitation/emission wavelengths restrict their application in in vivo imaging. In the present study, a kind of CD was prepared by a simple heat treatment method using glycine as the only precursor. The diameter of CD was lower than 5 nm, and the highest emission wavelength was 500 nm. However, at 600 nm, there was still a relatively strong fluorescent emission, suggesting CD could be used for in vivo imaging. Additionally, several experiments demonstrated that CD possessed good serum stability and low cytotoxicity. In vitro, CD could be taken up into C6 glioma cells in a time- and concentration-dependent manner, with both endosomes and mitochondria involved. In vivo, CD could be used for non-invasive glioma imaging because of its high accumulation in the glioma site of the brain, which was demonstrated by both in vivo imaging and ex vivo tissue imaging. Furthermore, the fluorescent distribution in tissue slices also showed CD distributed in glioma with high intensity, while with a low intensity in normal brain tissue. In conclusion, CD were prepared using a simple method with relatively long excitation and emission wavelengths and could be used for non-invasive glioma imaging. PMID- 25031209 TI - Effects of nordic walking on body composition, muscle strength, and lipid profile in elderly women. AB - PURPOSE: The purpose of this study was to investigate the effects of Nordic walking on body composition, muscle strength, and lipid profile in elderly women. METHOD: Sixty-seven women were assigned to the Nordic walking group (n = 21), the normal walking group (n = 21), and the control group (n = 25). Nordic walking and normal walking were performed three times a week for 12 weeks. Body weight, body mass index, total body water, skeletal muscle mass, percent body fat, grip strength, sit to stand, arm curl, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured before and after the program. A Chi-square test, one way analysis of variance, paired t test and repeated-measure two-factor analysis were used with the SAS program for data analysis. RESULTS: There was a significant difference in the weight (F=8.07, p<.001), grip strength (F=10.30, p<.001), sit to stand (F=16.84, p<.001), arm curl (F=41.16, p<.001), and total cholesterol (F=5.14, p=.009) measurements between the groups. In addition, arm curl was significantly increased in the Nordic walking group compared to the normal walking group and the control group. CONCLUSION: The results indicate that Nordic walking was more effective than normal walking in improving upper extremity strength. PMID- 25031210 TI - Evaluation of the clinical usefulness of critical patient severity classification system and glasgow coma scale for neurological patients in intensive care units. AB - PURPOSE: The purpose of this study was to evaluate the clinical usefulness of the Critical Patient Severity Classification System (CPSCS) and Glasgow Coma Scale (GCS) for critically ill neurological patients and to determine the applicability of CPSCS and GCS in predicting their mortality. METHODS: Data were collected from the medical records of 187 neurological patients who were admitted to the intensive care unit of C university hospital. The data were analyzed through chi square test, t test, Mann-Whitney, Kruskal-Wallis, goodness-of-fit test, and receiver operating characteristic curve. RESULTS: In accordance with patients' general and clinical characteristics, patient mortality turned out to be significantly different depending on intensive care unit stay, endotracheal intubation, central venous catheter, and severity by CPSCS. Hosmer-Lemeshow goodness-of-fit tests were applied to CPSCS and GCS. The results of the discrimination test using the receiver operating characteristic curve were CPSCS0, .743, GCS0 .583, CPSCS24, .734, GCS24 .612, CPSCS48, .591, GCS48 .646, CPSCS72, .622, and GCS72 .623. Logistic regression analysis showed that each point on the CPSCS score signifies a 1.034 higher likelihood of dying. CONCLUSION: Applied to neurologically ill patients, early CPSCS scores can be regarded as a useful tool. PMID- 25031211 TI - An exploratory study of parents' perceived educational needs for parenting a child with learning disabilities. AB - PURPOSE: This exploratory, qualitative study was conducted to explore Chinese couples' perceived educational needs for parenting a child with specific learning difficulties (SLD). METHODS: We recruited a purposive sample of 25 couples who were caring for a child with SLD at home from one regional child mental health center in Hong Kong. Data were collected from individual couples via audio-taped, semi-structured interviews between April and June 2011. Each interview lasted for about an hour. We analyzed the interview data using qualitative content analysis, as suggested by Graneheim and Lundman (2004). RESULTS: Four identified categories of parents' perceived educational needs were information needs for caregiving, a variety of health concerns with themselves and their child, inadequate psychosocial support, and perceived stigma attached to help-seeking. These results reveal challenges and information for mental health professionals in providing effective educational and psychosocial support and culture-specific health care for these families and their children with learning disabilities. CONCLUSION: Our findings indicate a few important educational needs of parents in caring for a child with SLD that might be underestimated by mental health professionals and teachers, such as psychological support and information needs. To facilitate effective parenting, holistic and individualized needs assessment and education should be provided to address each parent's biopsychosocial and cultural needs in relation to caregiving. PMID- 25031212 TI - Factors Affecting the Perception of Importance and Practice of Patient Safety Management among Hospital Employees in Korea. AB - PURPOSE: The study was undertaken to identify factors affecting perception of the importance and practice of patient safety management (PSM) among hospital employees in Korea. METHODS: This study was conducted using a descriptive design and a self-report questionnaire. Two hundred and eighty employees were recruited from three hospitals using a convenience sampling method. Measures were perception of the importance, practice, and characteristics of PSM. Data were analyzed using descriptive statistics including t test, one-way analysis of variance, Pearson's correlation analysis, and multiple regression. RESULTS: Factors affecting perception of the importance of PSM were whether hospital employees were in contact with patients while on duty, weekly working hours, education on PSM, and perceived adequacy of PSM system construction. Factors affecting the practice of PSM were perceived adequacy of work load, perceived adequacy of PSM system construction and perception of its importance. CONCLUSION: The findings of this study indicate a need for developing strategies to improve perception of the importance and practice of PSM among all hospital employees, and provide a reference for future experimental studies. PMID- 25031213 TI - Understanding of Technical Terms and Contents of Informed Consent Forms for Sedative Gastrointestinal Endoscopy Procedures. AB - PURPOSE: This was a cross-sectional study designed to evaluate the subjective understanding of technical terms and contents of the informed consent forms given to patients about to undergo conscious sedative upper gastrointestinal endoscopy. METHODS: A group of conveniently selected 180 patients, who were undergoing sedative endoscopy were recruited in the endoscopy procedure room in a tertiary hospital from June to July 2011. Data were collected with a structured questionnaire. RESULTS: The average number of terms exposed was 8.12 out of 10 items, the average number of terms understood well by the patients was 5.53 out of 10 items, and the average number of right answers was 3.30 out of 5 items, and the percent of correct answers ranged from 26.1% to 90.0%. The exposure to terms differed by gender, education, and previous exposure to sedative endoscopy procedures. The number of "understanding of the terms well" responses differed according to age and previous exposure to sedative endoscopy procedures, and the correct answer rate was differed by education. CONCLUSION: The understanding of the terms and knowledge about the procedures were disappointing. Therefore, sufficient explanations should be provided to the patients. While the informed consent was taken by doctors, the level of understanding should be monitored by nurses. In particular, subjects who did not have any previous experience with endoscopy procedures showed relatively lower level of understanding. We recommend that medical terms should be replaced with more common and nontechnical words in consent forms. PMID- 25031214 TI - Changing the care process: a new concept in Iranian rural health care. AB - PURPOSE: Health care delivery systems in rural areas face numerous challenges in meeting the community's needs. There is a lack of adequate attention for this problem. This study aims to explore the challenges of the health care process in rural Iran according to health care providers' experiences. METHODS: This was a qualitative study that used the content analysis method. We selected a total of 21 health care providers based on purposive sampling. Data collection consisted of semi-structured individual interviews that were analyzed by qualitative content analysis. RESULTS: Data analysis led to the formation of one main category, the challenges of process of health care in rural society. Within this main category, we created the following subcategories: change in characteristics of the rural society, increase in complexity of the health care process, decrease in workforce efficiency, and decrease in propensity of people's care. CONCLUSION: The findings of this study indicate that the process of health care in Iranian rural society is changing rapidly with community health workers encountering new challenges. There is diminished efficiency in responding to the changing care process in Iran's rural society. Considering this change in process of care, therefore, the health care system should respond to these new challenges by establishing new health care models. PMID- 25031215 TI - [Iron deficiency: risk factor of frailty in elderly?]. PMID- 25031216 TI - [Iron metabolism: pathophysiology and biomarkers in elderly population]. AB - Iron deficiency is frequent in elderly population and is responsable for numerous clinical situations. Because of the frequent association of inflammatory diseases, chronic diseases associated with iron loss, diagnosis of iron deficiency is often difficult in elderly population. For the last ten years, new biomarkers of iron physiology lead to better understand physiology and pathophysiology of iron metabolism particularly in iron deficiency. This overview aims to show modifications of iron metabolism with ageing, pathophysiological mecanisms associated with iron deficiency and give a stratification of the use of biomarkers as diagnostic tools differentiating absolute deficiency or functional deficeincy. PMID- 25031217 TI - [Iron deficiency in elderly people: clinical presentation and management]. AB - Iron deficiency (absolute or functional) is commonly observed (frequently without associated anemia) in up to one third of old people. Iron deficiency is the most cause of anemia in adults. Many non hematological consequences of iron deficiency are described like: cardiac failure, mood or cognitive disorders, chronic fatigue or restless leg syndrome. Iron deficiency can be orally or with intravenous iron replacement treates if necessary. Long term compliance of patients orally treated for iron deficiency is poor mainly because of fair tolerability of drugs. New regimen of intravenous iron replacement are now available when orally iron administration can not be achieved. In functional iron deficiency iron intravenous replacement seems especially relevant. However further controlled studies are necessary to assess their clinical benefits. PMID- 25031219 TI - Behavioral and cellular consequences of high-electrode count Utah Arrays chronically implanted in rat sciatic nerve. AB - OBJECTIVE: Before peripheral nerve electrodes can be used for the restoration of sensory and motor functions in patients with neurological disorders, the behavioral and histological consequences of these devices must be investigated. These indices of biocompatibility can be defined in terms of desired functional outcomes; for example, a device may be considered for use as a therapeutic intervention if the implanted subject retains functional neurons post implantation even in the presence of a foreign body response. The consequences of an indwelling device may remain localized to cellular responses at the device tissue interface, such as fibrotic encapsulation of the device, or they may affect the animal more globally, such as impacting behavioral or sensorimotor functions. The objective of this study was to investigate the overall consequences of implantation of high-electrode count intrafascicular peripheral nerve arrays, High Density Utah Slanted Electrode Arrays (HD-USEAs; 25 electrodes mm(-2)). APPROACH: HD-USEAs were implanted in rat sciatic nerves for one and two month periods. We monitored wheel running, noxious sensory paw withdrawal reflexes, footprints, nerve morphology and macrophage presence at the tissue device interface. In addition, we used a novel approach to contain the arrays in actively behaving animals that consisted of an organic nerve wrap. A total of 500 electrodes were implanted across all ten animals. MAIN RESULTS: The results demonstrated that chronic implantation (?8 weeks) of HD-USEAs into peripheral nerves can evoke behavioral deficits that recover over time. Morphology of the nerve distal to the implantation site showed variable signs of nerve fiber degeneration and regeneration. Cytology adjacent to the device-tissue interface also showed a variable response, with some electrodes having many macrophages surrounding the electrodes, while other electrodes had few or no macrophages present. This variability was also seen along the length of the electrodes. Axons remained within the proximity of the electrode tips at the distances required for theoretically effective stimulation and recording (?100 MUm). SIGNIFICANCE: We conclude from these studies that HD-USEAs do not cause overall global effects on the animals, at least up to the two-month period investigated here. These results demonstrate for the first time that the consequences of high-electrode count intrafascicular arrays compare with other peripheral nerve electrodes currently available for clinical or investigational neuromodulation. PMID- 25031218 TI - [Care of elderly subject with iron deficiency anaemia: evaluation of geriatric practice]. AB - The anemia with iron deficiency is frequent in the elder subjects. Few studies have reported the practice of the geriatric medicine about anemia. METHODS: A national survey asked geriatric medical practitioners of hospital geriatric ward from June till September, 2013. Questionnaires were sent, filled over the phone. On 568 sent questionnaires, 312 (55%) were filled. The frequency of the anemia is considered of 46 +/- 21%. The definition of the anemia in an elderly person is on average 10.7 +/- 0.8 g/dL, taking into account the situation of the patient. The wanted biological examinations are the haemoglobin and the ferritinaemia, but many people suggest measuring also folates and vitamin B12 given strong prevalence of comorbidity. Prevalence of iron deficiency anemia estimated between 20 and 80% because of high prevalence of mixed cause which modified the answer. The major causes were reported as of digestive, gynecological and post-operative origins. The treatment is proposed from 9 g/dL. The oral iron and the transfusions are the most quoted. The possibility of injectable iron is reported only by 17%, of the geriatricians. CONCLUSION: The answers of the geriatricians show strong coherences in the management of the iron deficiency anemia. Guidelines should be adapted for elderly people for exercice capacity, mainly on high frequency of mixed cases. PMID- 25031220 TI - Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 positive allosteric modulator. AB - Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fear-conditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5 mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multi-electrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit. PMID- 25031221 TI - Mediodorsal and visual thalamic connectivity differ in schizophrenia and bipolar disorder with and without psychosis history. AB - Empirical and theoretical studies implicate thalamocortical circuits in schizophrenia, supported by emerging resting-state functional connectivity studies (rs-fcMRI). Similar but attenuated alterations were found in bipolar disorder (BD). However, it remains unknown if segregated loops within thalamocortical systems show distinct rs-fcMRI alterations in schizophrenia. For instance, the mediodorsal (MD) nucleus, known to project to prefrontal networks, may be differently altered than the lateral geniculate nucleus (LGN), known to project to the occipital cortex. Also, it remains unknown if these circuits show different patterns of alterations in BD as a function of psychosis history, which may be associated with a more severe clinical course. We addressed these questions in 90 patients with chronic schizophrenia and 73 remitted BD patients (33 with psychosis history) matched to 146 healthy comparison subjects. We hypothesized that the MD vs LGN would show dissociations across diagnostic groups. We found that MD and LGN show more qualitative similarities than differences in their patterns of dysconnectivity in schizophrenia. In BD, patterns qualitatively diverged between thalamic nuclei although these effects were modest statistically. BD with psychosis history was associated with more severe dysconnectivity, particularly for the MD nucleus. Also, the MD nucleus showed connectivity reductions with the cerebellum in schizophrenia but not in BD. Results suggest dissociations for thalamic nuclei across diagnoses, albeit carefully controlling for medication is warranted in future studies. Collectively, these findings have implications for designing more precise neuroimaging-driven biomarkers that can identify common and divergent large-scale network perturbations across psychiatric diagnoses with shared symptoms. PMID- 25031222 TI - How cannabis causes paranoia: using the intravenous administration of ?9 tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia. AB - Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-?(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences. PMID- 25031223 TI - Impaired working memory capacity is not caused by failures of selective attention in schizophrenia. AB - The cognitive impairments associated with schizophrenia have long been known to involve deficits in working memory (WM) capacity. To date, however, the causes of WM capacity deficits remain unknown. The present study examined selective attention impairments as a putative contributor to observed capacity deficits in this population. To test this hypothesis, we used an experimental paradigm that assesses the role of selective attention in WM encoding and has been shown to involve the prefrontal cortex and the basal ganglia. In experiment 1, participants were required to remember the locations of 3 or 5 target items (red circles). In another condition, 3-target items were accompanied by 2 distractor items (yellow circles), which participants were instructed to ignore. People with schizophrenia (PSZ) exhibited significant impairment in memory for the locations of target items, consistent with reduced WM capacity, but PSZ and healthy control subjects did not differ in their ability to filter the distractors. This pattern was replicated in experiment 2 for distractors that were more salient. Taken together, these results demonstrate that reduced WM capacity in PSZ is not attributable to a failure of filtering irrelevant distractors. PMID- 25031225 TI - Acoustic interactions between inversion symmetric and asymmetric two-level systems. AB - Amorphous solids, as well as many disordered lattices, display remarkable universality in their low temperature acoustic properties. This universality is attributed to the attenuation of phonons by tunneling two-level systems (TLSs), facilitated by the interaction of the TLSs with the phonon field. TLS-phonon interaction also mediates effective TLS-TLS interactions, which dictates the existence of a glassy phase and its low energy properties. Here we consider KBr:CN, the archetypal disordered lattice showing universality. We calculate numerically, using conjugate gradients method, the effective TLS-TLS interactions for inversion symmetric (CN flips) and asymmetric (CN rotations) TLSs, in the absence and presence of disorder, in two and three dimensions. The observed dependence of the magnitude and spatial power law of the interaction on TLS symmetry, and its change with disorder, characterizes TLS-TLS interactions in disordered lattices in both extreme and moderate dilutions. Our results are in good agreement with the two-TLS model, recently introduced to explain long standing questions regarding the quantitative universality of phonon attenuation and the energy scale of ~ 1-3 K below which universality is observed. PMID- 25031224 TI - A microRNA gene signature for identification of lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide, compounded by late diagnosis. MicroRNAs (miRNA) are recently discovered short, noncoding genes that play essential roles in tissue differentiation during normal development and tumorigenesis. miRNA profiles across all histologic grades can provide a reliable and standardized method for the identification of lung cancer. METHODS: A microRNA lung cancer dataset was analyzed. Differentially expressed microRNAs were obtained post-normalization of data using t-test (p < 0.01). The data for differentially expressed microRNAs were processed using K-nearest neighbors classification method to obtain unique miRNAs expression patterns. The predicted mRNA targets were identified using TargetScan and the molecular functions associated with the predicted targets were retrieved from the Gene Ontology Consortium and represented using GO IDs in a directed acyclic graph. RESULTS: The results indicate that lung cancer samples can be classified using a small panel of 19 unique microRNAs (8 down-regulated and 11 up-regulated) with over 85% classification accuracy. Furthermore, using classical enrichment analysis, this study identified 66 molecular function groups which are potentially the functional signaling pathways altered by these differentially expressed microRNAs. CONCLUSIONS: We identified a microRNA gene signature representative of functioning as a diagnostic biomarker for lung cancer. These findings can potentially form the basis for the development of a standardized diagnostic assay that can be used for early diagnosis of lung cancer equally well from resection specimens and cytology samples. PMID- 25031226 TI - Importance of defining loss of response before therapeutic drug monitoring. PMID- 25031227 TI - Caffeine promotes glutamate and histamine release in the posterior hypothalamus. AB - Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 min. GABA levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 min. Immunostaining showed a significantly elevated number of c-Fos-labeled histamine neurons in caffeine-treated rats compared with saline-treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness. PMID- 25031228 TI - Sleep efficiency and nocturnal hemodynamic dipping in young, normotensive adults. AB - Blunted dipping of nocturnal systolic arterial pressure (SAP) and heart rate (HR) are independent risk factors for hypertension and all-cause mortality. While several epidemiological studies report a significant association between short sleep duration and hypertension, associations between sleep efficiency and the nocturnal drop of SAP remain controversial. Moreover, relations between sleep efficiency and HR diurnal patterns have been overlooked. We hypothesized that low sleep efficiency (<85%) would be associated with blunted nocturnal SAP and HR dipping. Twenty-two normotensive subjects (13 men, 9 women; age: 18-28 yr) wore an actigraphy watch for 7 days and nights, and an ambulatory blood pressure monitor for 24 h on a nonactigraph night. There were no differences in age, sex, body mass index, mean sleep time, number of awakenings, or 24-h blood pressure between the low (n = 12) and high (n = 10) sleep efficiency groups. However, the low sleep efficiency subjects demonstrated a blunted dip of nocturnal SAP (10 +/- 1% vs. 14 +/- 1%, P = 0.04) and HR (12 +/- 3% vs. 21 +/- 3%, P = 0.03) compared with the high sleep efficiency group. The low sleep efficiency group also demonstrated a higher mean nocturnal HR (63 +/- 2 vs. 55 +/- 2 beats/min; P = 0.02). These findings support growing evidence that sleep efficiency, independent of total sleep time, may be an important cardiovascular risk factor. PMID- 25031229 TI - Brain somatostatin receptor 2 mediates the dipsogenic effect of central somatostatin and cortistatin in rats: role in drinking behavior. AB - Intracerebroventricular injection of stable somatostatin (SST) agonists stimulates food and water intake in rats. We investigated the receptor subtype(s) involved in the dipsogenic effect of intracerebroventricular injection of SST agonists, mechanisms of action, and role. In nonfasted and non-water-deprived male rats with chronic intracerebroventricular cannula, intake of water without food or food without water was monitored separately to avoid any interactions compared with intracerebroventricular vehicle. SST-14 and cortistatin (CST-14) (1 MUg/rat icv) increased water intake by 3.1- and 2.7-fold, respectively, while both peptides did not alter food intake at 1 h postinjection in the light phase. By contrast, the stable pan-somatostatin agonist ODT8-SST (1 MUg/rat icv) increased both water and food intake by 4.9- and 3.7-fold, respectively. S-346 011, a selective receptor 2 (sst2) agonist (1 MUg/rat icv) induced water ingestion, while sst1 or sst4 agonist, injected under the same conditions, did not. The sst2 antagonist S-406-028 (1 MUg/rat icv) prevented the 1-h water intake induced by intracerebroventricular ODT8-SST and CST-14. Losartan (100 MUg/rat icv), an angiotensin receptor 1 (AT1) antagonist, completely blocked the water consumption induced by intracerebroventricular ODT8-SST, whereas intracerebroventricular injection of S-406-028 did not modify the intracerebroventricular ANG II-induced dipsogenic response. The sst2 antagonist reduced by 40% the increase of the 3-h water intake in the early dark phase. These data indicate that SST-14 and CST-14 interact with sst2 to exert a potent dipsogenic effect, which is mediated downstream by angiotensin-AT1 signaling. These data also indicate that sst2 activation by brain SST-14 and/or CST-14 may play an important role in the regulation of drinking behavior. PMID- 25031231 TI - Water and electrolyte homeostasis brings balance to physiology. AB - The American Physiological Society officially recognized the area of research in Water and Electrolyte Homeostasis (WEH) over 30 years ago when the Section of WEH was established. This minireview illuminates the importance of WEH research to the physiology community. By the narrowest definition, WEH research studies the regulation of body fluids; however, this research area is much broader and more relevant today than when this subdiscipline was first recognized because of the translational and systemic "point of view" of WEH research. This minireview highlights how WEH research serves as a balanced force between the full range of other more traditional organ-based physiological and pathophysiological concepts. The breadth of research in which WEH investigators engage is on full display with the publication of minireviews from the annual Data Diuresis session at Experimental Biology. PMID- 25031230 TI - Tissue oxygen saturation during hyperthermic progressive central hypovolemia. AB - During normothermia, a reduction in near-infrared spectroscopy (NIRS)-derived tissue oxygen saturation (So2) is an indicator of central hypovolemia. Hyperthermia increases skin blood flow and reduces tolerance to central hypovolemia, both of which may alter the interpretation of tissue So2 during central hypovolemia. This study tested the hypothesis that maximal reductions in tissue So2 would be similar throughout normothermic and hyperthermic central hypovolemia to presyncope. Ten healthy males (means +/- SD; 32 +/- 5 yr) underwent central hypovolemia via progressive lower-body negative pressure (LBNP) to presyncope during normothermia (skin temperature ~34 degrees C) and hyperthermia (+1.2 +/- 0.1 degrees C increase in internal temperature via a water perfused suit, skin temperature ~39 degrees C). NIRS-derived forearm (flexor digitorum profundus) tissue So2 was measured throughout and analyzed as the absolute change from pre-LBNP. Hyperthermia reduced (P < 0.001) LBNP tolerance by 49 +/- 33% (from 16.7 +/- 7.9 to 7.2 +/- 3.9 min). Pre-LBNP, tissue So2 was similar (P = 0.654) between normothermia (74 +/- 5%) and hyperthermia (73 +/- 7%). Tissue So2 decreased (P < 0.001) throughout LBNP, but the reduction from pre LBNP to presyncope was greater during normothermia (-10 +/- 6%) than during hyperthermia (-6 +/- 5%; P = 0.041). Contrary to our hypothesis, these findings indicate that hyperthermia is associated with a smaller maximal reduction in tissue So2 during central hypovolemia to presyncope. PMID- 25031232 TI - Dual implantable electronic device therapy. PMID- 25031233 TI - Therapeutic moderate hypothermia: a novel modality for management of electrical storm due to ventricular fibrillation. PMID- 25031234 TI - Predictors of hospitalization for heart failure and of all-cause mortality after atrioventricular nodal ablation and right ventricular pacing for atrial fibrillation. AB - AIMS: Atrioventricular junction ablation (AVJA) is a highly effective treatment in patients with therapy refractory atrial fibrillation (AF) but renders the patient pacemaker dependent. We aimed to analyse the long-term incidence of hospitalization for heart failure (HF) and all-cause mortality in patients who underwent AVJA because of AF and to determine predictors for HF and mortality. METHODS AND RESULTS: We retrospectively enrolled 162 consecutive patients, mean age 67 +/- 9 years, 48% women, who underwent AVJA because of symptomatic AF refractory to pharmacological treatment (n = 117) or unsuccessful repeated pulmonary vein isolation (n = 45). Hospitalization for HF occurred in 32 (20%) patients and 35 (22%) patients died, representing a cumulative incidence for hospitalization for HF and mortality over the first 2 years after AVJA of 9.1 and 5.2%, respectively. Hospitalization for HF occurred to the same extent in patients who failed pharmacological treatment as in patients with repeated pulmonary vein isolation (PVI), although the mortality was slightly higher in the former group. QRS prolongation >=120 ms and left atrial diameter were independent predictors of hospitalization for HF, while hypertension and previous HF were independent predictors of death. CONCLUSION: The long-term hospitalization rate for HF and all-cause mortality was low, which implies that long-term ventricular pacing was not harmful in this patient population, including patients with unsuccessful repeated PVI. PMID- 25031235 TI - A comparison between radial strain evaluation by speckle-tracking echocardiography and cardiac magnetic resonance imaging, for assessment of suitable segments for left ventricular lead placement in cardiac resynchronization therapy. AB - AIMS: A cut-off of 9.8% maximum speckle-tracking radial strain in the segment with the latest mechanical delay has been proposed as predictive for selecting the best left ventricular lead placement for positive response on cardiac resynchronization therapy (CRT). However, pacing transmural scar should be avoided, and the purpose of this study was to evaluate the ability of echocardiographic radial strain to predict the presence of scar in the left ventricle segments. METHODS AND RESULTS: A total of 404 left ventricular segments were analysed, from 34 patients eligible for CRT. Pre-operative cardiac magnetic resonance (CMR) and echocardiography were performed, and maximal strain values from echocardiography speckle tracking were compared with CMR data. Hypokinesia and strain values showed a strong correlation (P < 0.001). Even though segments with CMR-verified scar had lower strain values than segments without scar (14.8 +/- 7 vs. 16.0 +/- 10), the predictive value of the proposed 9.8% cut-off was low (sensitivity 33% and specificity 72%). Scar burden was higher in ischaemic patients (13.5 vs. 5.3% P = 0.0001). Relative difference in strain values (target segment strain compared with the average strain value of the adjacent segments) was higher if there was transmural scar in the target segment as compared with a hypokinetic but viable target segment (87 vs. 38% difference, P = 0.03). CONCLUSION: Speckle tracking radial strain should ideally be complemented by CMR for accurate assessment of viability, especially for patients with ischaemic aetiology of heart failure where transmural scar is more common. Comparison of strain values with the adjacent segments may be helpful for assessing viability. PMID- 25031236 TI - Failed anti-tachycardia pacing can be used to differentiate atrial arrhythmias from ventricular tachycardia in implantable cardioverter-defibrillators. AB - BACKGROUND: Atrial fibrillation/tachycardia (AF/AT) may result in inappropriate therapies in implantable cardioverter-defibrillators (ICDs). The post-pacing interval (PPI) and tachycardia cycle length difference (PPI - TCL) has been previously demonstrated to indicate the proximity of the pacing site to a tachycardia origin. AIMS: We postulated that the PPI and PPI - TCL would be greater in AT/AF vs. ventricular tachycardia (VT) after episodes of failed anti tachycardia pacing (ATP). METHODS AND RESULTS: This was a single-centre, retrospective study evaluating consecutive patients implanted with dual (DR)/biventricular (BIV) ICDs. Stored electrograms were used to determine whether the ATP captured the arrhythmia and the arrhythmia did not present with primary or secondary termination. Measurements were done using manual calipers. A total of 155 patients were included. There were 79 BIV and 76 DR devices. In total, 39 episodes were identified in 20 patients over a 23-month follow-up period. A total of 76 sequences of ATP (burst/ramp) were delivered, 28 (37%) of them inappropriate. Fifty-one events (18 AT/AF and 33 VT) were compared. The mean PPI was 693 +/- 96 vs. 512 +/- 88 ms (P < 0.01) and the mean PPI - TCL was 330 +/- 97 vs. 179 +/- 103 ms (P < 0.01) for AT/AF and VT, respectively. Cut-offs of 615 ms for the PPI [area under curve (AUC) 0.93; 95% confidence interval (CI): 0.84 1.00; P < 0.01] and 260 ms for PPI - TCL (AUC 0.86; 95% CI: 0.74-0.98; P < 0.01) were identified. CONCLUSION: The PPI and PPI - TCL after failed ATP differs significantly between AF/AT and VT and are therefore useful indices to discriminate between supraventricular tachycardia and VT in ICDs. PMID- 25031237 TI - Visually guided laser ablation: a single-centre long-term experience. AB - AIMS: Durable isolation of the pulmonary veins (PVs) remains the cornerstone of treatment for paroxysmal atrial fibrillation (PAF) and is also used in the treatment of some patients with persistent atrial fibrillation. Visually guided laser ablation (VGLA) has been proven to be safe and effective as a treatment for atrial fibrillation (AF). It has shown high levels of durable PV isolation (PVI), even in the hands of less experienced users. This paper presents the long-term clinical outcomes of all patients treated with VGLA over the course of 4 years in the world's most experienced centre: from early product feasibility work treating only PAF patients to our work using the commercially available product, when we also treated persistent AF patients. METHODS AND RESULTS: One hundred and ninety four patients (63 females, mean age 61 years) with either a history of drug refractory PAF (time since initial diagnosis: 60.73 months) or persistent AF (time since initial diagnosis: 62.75 months) were treated in our laboratory with VGLA between 7 January 2009 and 17 May 2013. Follow-up of all patients was consistent with our standard clinical practice with a 7-day Holter being performed at the first clinical visit between 4 and 6 months and, for most patients, again at 12 months post-procedure. Twelve lead electrocardiograms were performed at all clinical visits. Recurrence of AF is defined as any documented AF episode >30 s. Acute procedural results show that 692 veins were acutely isolated with a mean procedure and fluoroscopy time of 226 and 20.4 min, respectively. One hundred and seventy (158 PAF and 12 persistent AF) patients reached 1 year of follow-up, 130 (82.3%) patients remained free of AF in the PAF group, and 9 (75%) in the persistent group. Eighty-seven PAF patients have now reached 24 months follow-up and 66 (75.9%) remain free of AF. Fifty-four PAF patients have reached 36 months follow-up with 41 (75.9%) remaining free of AF. Thirty-two PAF patients have reached 48 months follow-up and 24 (75%) remain free of AF. The peri-procedural complications we encountered were phrenic nerve injury in four patients (2.06%), tamponade or pericardial effusion in one patient (0.51%), stroke or transient ischaemic attack in one patient (0.514%), and vascular injury in six patients (3.09%). We experienced no cases of PV stenosis or atrio-oesophageal fistula. CONCLUSION: Our single-centre experience using VGLA over 4 years shows that it can be used safely and effectively in normal clinical practice and gives high levels of acute PVI accompanied by good clinical outcomes, even after long-term follow-up. PMID- 25031239 TI - DFT + U investigation of charged point defects and clusters in UO2. AB - We present a physically justified formalism for the calculation of point defects and cluster formation energies in UO2. The accessible ranges of chemical potentials of the two components U and O are calculated using the U-O experimental phase diagram and a constraint on the formation energies of vacancies. We then apply this formalism to the DFT + U investigation of the point defects and cluster defects in this material (including charged ones). The most stable charge states obtained for these defects near stoichiometry are consistent with a strongly ionic system. Calculations predict similarly low formation energies for V(U)(4)(-) and I(O)(2)(-) in hyperstoichiometric UO2. In stoichiometric UO2, V(O)(2)(+) and I(o)(@)(-) have the same formation energy in the middle of the gap and in hypostoichiometric UO2, V[Formula: see text] is the most stable defect. PMID- 25031238 TI - Encoding of sequence boundaries in the subthalamic nucleus of patients with Parkinson's disease. AB - Sequential behaviour is widespread not only in humans but also in animals, ranging in different degrees of complexity from locomotion to birdsong or music performance. The capacity to learn new motor sequences relies on the integrity of basal ganglia-cortical loops. In Parkinson's disease the execution of habitual action sequences as well as the acquisition of novel sequences is impaired partly due to a deficiency in being able to generate internal cues to trigger movement sequences. In addition, patients suffering from Parkinson's disease have difficulty initiating or terminating a self-paced sequence of actions. Direct recordings from the basal ganglia in these patients show an increased level of beta (14-30 Hz) band oscillatory activity associated with impairment in movement initiation. In this framework, the current study aims to evaluate in patients with Parkinson's disease the neuronal activity in the subthalamic nucleus related to the encoding of sequence boundaries during the explicit learning of sensorimotor sequences. We recorded local field potential activity from the subthalamic nucleus of 12 patients who underwent deep brain stimulation for the treatment of advanced Parkinson's disease, while the patients in their usual medicated state practiced sequences of finger movements on a digital piano with corresponding auditory feedback. Our results demonstrate that variability in performance during an early phase of sequence acquisition correlates across patients with changes in the pattern of subthalamic beta-band oscillations; specifically, an anticipatory suppression of beta-band activity at sequence boundaries is linked to better performance. By contrast, a more compromised performance is related to attenuation of beta-band activity before within sequence elements. Moreover, multivariate pattern classification analysis reveals that differential information about boundaries and within-sequence elements can be decoded at least 100 ms before the keystroke from the amplitude of oscillations of subthalamic nucleus activity across different frequency bands, not just from the beta-band. Additional analysis was performed to assess the strength of how much the putative signal encoding class of ordinal position (boundaries, within-sequence elements) is reflected in each frequency band. This analysis demonstrates that suppression of power in the beta-band contains the most class-related information, whereas enhancement of gamma band (31-100 Hz) activity is the second main contributor to the encoding. Our findings support the hypothesis that subthalamic nucleus-mediated gating of salient boundary elements during sequence encoding may be a prerequisite for the adequate acquisition of action sequences and the transition to habitual behaviour. PMID- 25031240 TI - Predictors of perceived barriers to mammography in korean women. AB - PURPOSE: The purpose of the study was to investigate the effects of cancer fatalism, breast cancer fear, and health motivation on perceived barriers to mammography in Korean women living in the community. METHODS: The sample for this study was a convenience sample of 138 Korean women. Data were collected through a questionnaire that included Cancer Fatalism, the Breast Cancer Fear Scale, Health Motivation, and the Revised Barriers Scale for Mammography. The data were analyzed by multiple regression using SPSS version 11.0. RESULTS: The level of cancer fatalism was low with a mean of 1.07. The levels of fear of breast cancer, health motivation and barriers to mammography were moderate with means of 27.10, 26.44 and 25.80, respectively. Age (F = 3.22, p = .02) was significantly related to mammography barriers but breast-related characteristics were not significantly associated with any mammography barriers. Health motivation (b =-.34, p = .00) and breast cancer fear (b = .22, p = .00) were predictive variables of perceived barriers to mammography. The model explained 19% of the variance in mammography barriers scores (F = 9.98, p = .00). CONCLUSION: Nurses who work with Korean women for breast cancer screening need to assess these predictive factors, including health motivation and breast cancer fear. Further extensive research will be needed to demonstrate the relationship between breast cancer fatalism and perceived barriers to mammography. PMID- 25031241 TI - An Exploration of Hmong Women's Perspectives on Cancer. AB - PURPOSE: The purpose of this study was to explore the perspectives of Hmong women on cancer, using focus groups as the research method. METHODS: Two focus group interviews were conducted and the narrative data were analyzed using thematic content analysis. RESULTS: Themes that emerged from the focus group discussions included "fatalistic and 'black and white' thinking", "valuing rumors rather than scientific information", "strong adherence to traditional medicine", "male leaders controlling health care decisions", "embarrassment discussing women's bodies", and "preferred strategies in addressing cancer". CONCLUSION: Many Hmong people in the United States believe that both traditional and Western health care practices are effective, but when health professionals do not address differences in language, communication, and beliefs about health, trust between the provider and client may erode. The findings of this study provide new insight into the importance of cultural accommodation to improve early cancer detection in the Hmong community. PMID- 25031242 TI - Testing a theoretical model predicting uncertainty and depression in patients undergoing renal replacement therapy in Korea. AB - PURPOSE: The purpose of this study was to test hypothesized relationships among experiences of uncertainty, depression, and social support in a sample of subjects undergoing renal replacement therapy in Korea. METHODS: Path analysis was used in the sample to examine the relationships among depression and experiences of uncertainty, direct social support, indirect social support, and demographic variables. The size of the sample was 104 patients. Patients received either hemodialysis at one of three clinics or continuous ambulatory peritoneal dialysis. RESULTS: One hundred and four subjects participated in the study. It was found that 6.2% of variance in uncertainty was predicted by direct social support (beta =- .267), and 46.2% of variance in depression was predicted by three variables: direct social support (beta =- .517), economic status (beta = .299), and number of admissions (beta = .275). Unlike the theoretical model, experiences of uncertainty could not predict depression. CONCLUSION: The effectiveness of social support in relieving experiences of uncertainty and consequently depression was shown in this study. Moreover, depression in this population could be predicted by direct social support, economic status, and frequency of admission. The study was needed to investigate the relationship between depression and experiences of uncertainty with time covariates, as well as to find the factors that influence depression in patients with chronic renal failure. PMID- 25031243 TI - Probing the issue of informed consent in health care in Korea-concept analysis and guideline development. AB - PURPOSE: The purpose of the study was to identify how informed consent is conceptualized by patients, family members, physicians, and nurses in Korea, and to develop guidelines for clinical practice in Korea. METHODS: This study employed the hybrid model to define the concept of informed consent through theoretical and fieldwork phases. For the theoretical phase, attributes of informed consent were identified through a review of the literature, and in-depth interviews were conducted for the fieldwork phase to develop attributes from the data and to verify the attributes identified from the literature review. Purposive sampling was done for 48 participants (12 patients, 12 family members, 12 physicians, 12 nurses), who were interviewed from selected units (orthopedics, cardiothoracic surgery, obstetrics/gynecology) from two university hospitals in Seoul and Kwangju, Korea. Attributes and processing issues of informed consent were extracted from both phases. RESULTS: Core attributes of informed consent include the patient's self-directed decision-making, fulfillment of legal responsibility, focusing on forging a trusting relationship, assuming active responsibility for explanations (physicians) and granting consent (patient), factors related to sufficient explanation, and the role of family. Findings were integrated into a set of guidelines for patients and family and health care professionals. CONCLUSION: The guidelines developed in the present study offer empirical parameters for an effective process of obtaining informed consent in Korea by seeking to decrease the gap in perceptions of informed consent among patients, family members, physicians, and nurses. The importance of advocating patients and developing a trusting relationship between health care providers and patients is especially noteworthy. PMID- 25031244 TI - Predicting factors of physical activity in adolescents: a systematic review. AB - PURPOSE: The main goal of this systematic review is to summarize and identify the current literature that addresses factors associated with adolescents' physical activity. METHODS: A systematic review of the literature was undertaken using a reference period between 1998 and 2008, based primarily on the PubMed/CINAHL/PsycINFO/ProQuest databases. A total of 35 articles were considered appropriate for this review. RESULTS: This systematic review found some evidence of associations between physical activity and the following variables: age, sex, parental education level, socioeconomic status, self-efficacy, perceived benefits, perceived barriers, perceived behavior control, parental support, parent modeling, peer support, past physical activity, depressive symptoms, smoking, alcohol consumption, and environmental determinants. CONCLUSION: Some variables have been studied too few times to deduce any conclusion, so more research is needed to test variables. Variables that did not have consistent results also need further testing. PMID- 25031245 TI - Effects of Logo-autobiography Program on Meaning in Life and Mental Health in the Wives of Alcoholics. AB - PURPOSE: This study aimed to identify the effectiveness of a newly developed group therapy, called the logo-autobiography program, in improving meaning in life and mental health in the wives of alcoholics. METHODS: The program was developed in four steps: literature review, pilot program development, pilot study and detailed program structuring. The pilot program was developed by combining a modified guided autobiography program with logotherapy. A non randomized controlled trial was conducted with a pre- and post-test design. The instruments chosen for the study were the Purpose in Life (PIL) test and the Symptom Checklist-90-Revision (SCL-90-R) to measure the meaning in life and mental health. Data were collected between November 2006 and March 2007 from 19 subjects in the experimental group and 21 subjects in the control group, who were all wives of alcoholics from four South Korean cities. RESULTS: The score for meaning in life was significantly higher in the experimental group than in the control group (p = .047). Also, the scores for somatization (p = .001), interpersonal sensitivity (p = .008), depression (p = .003), hostility (p = .002) and global severity index (p = .001) were significantly lower in the experimental group than in the control group. CONCLUSION: This study indicated that the logo autobiography program enhanced both meaning in life and mental health in alcoholics' wives, which suggests that the program would be very beneficial to this population. Furthermore, it might be suitable for improving mental health in families and communities that suffer from psychological trauma and meaninglessness. PMID- 25031246 TI - Registered nurses are delaying retirement, a shift that has contributed to recent growth in the nurse workforce. AB - The size of the registered nurse (RN) workforce has surpassed forecasts from a decade ago, growing to 2.7 million in 2012 instead of peaking at 2.2 million. Much of the difference is the result of a surge in new nursing graduates. However, the size of the RN workforce is particularly sensitive to changes in retirement age, given the large number of baby-boomer RNs now in the workforce. We found that in the period 1969-90, for a given number of RNs working at age fifty, 47 percent were still working at age sixty-two and 9 percent were working at age sixty-nine. In contrast, in the period 1991-2012 the proportions were 74 percent at age sixty-two and 24 percent at age sixty-nine. This trend, which largely predates the recent recession, extended nursing careers by 2.5 years after age fifty and increased the 2012 RN workforce by 136,000 people. Because many RNs tend to shift out of hospital settings as they age, employers seeking RNs for nonhospital roles may welcome (and seek to capitalize on) the growing numbers of experienced RNs potentially able to fill these positions. PMID- 25031248 TI - Nutrient profiles of korean-americans, non-Hispanic whites and blacks with and without hypertension in the United States. AB - PURPOSE: We compared the nutrient profiles of hypertensive Korean-Americans, non Hispanic Whites and Blacks with those of normotensive Korean-Americans, Whites, and Blacks. METHODS: This study was a cross-sectional comparative design of nutrient profiles among three ethnic groups. Korean-Americans were interviewed at Korean-American health clinics and churches in Chicago and data were collected by the 24-hour dietary recall method. Age- and sex-matched data of non-Hispanic Whites and Blacks were selected from the Third National Health and Nutrition Examination Survey for comparison. Descriptive statistics, one way ANOVA with post hoc test, and the propensity score matching method within each hypertensive and normotensive group were used for data analysis. Subjects included 102 subjects with hypertension (Korean-Americans, n = 37; Whites, n = 37; Blacks, n = 28), and 149 subjects without hypertension (Korean-Americans, n = 55; Whites, n = 55; Blacks, n = 39) for final statistical analyses. RESULTS: Significant differences in nutrient profiles among the three groups were as follows. In both hypertensive and normotensive groups, Korean-Americans consumed less energy from fat and saturated fatty acids and more energy from carbohydrates than did Whites and Blacks. All three ethnic groups exceeded the dietary reference intakes of sodium, but did not meet those of calcium and potassium. CONCLUSION: The findings suggest that protein may be needed to replace excessive carbohydrate intake in Korean-Americans and to replace fat intake in Whites and Blacks. Health professionals need to emphasize the importance of increasing calcium and potassium intake and decreasing sodium intake in their nutrition education for these ethnic groups to help prevent and control hypertension. PMID- 25031247 TI - Managing alcohol problems in general practice in Europe: results from the European ODHIN survey of general practitioners. AB - AIMS: To document the attitudes of general practitioners (GPs) from eight European countries to alcohol and alcohol problems and how these attitudes are associated with self-reported activity in managing patients with alcohol and alcohol problems. METHODS: A total of 2345 GPs were surveyed. The questionnaire included questions on the GP's demographics, reported education and training on alcohol, attitudes towards managing alcohol problems and self-reported estimates of numbers of patients managed for alcohol and alcohol problems during the previous year. RESULTS: The estimated mean number of patients managed for alcohol and alcohol problems during the previous year ranged from 5 to 21 across the eight countries. GPs who reported higher levels of education for alcohol problems and GPs who felt more secure in managing patients with such problems reported managing a higher number of patients. GPs who reported that doctors tended to have a disease model of alcohol problems and those who felt that drinking was a personal rather than a medical responsibility reported managing a lower number of patients. CONCLUSION: The extent of alcohol education and GPs' attitudes towards alcohol were associated with the reported number of patients managed. Thus, it is worth exploring the extent to which improved education, using pharmacotherapy in primary health care and a shift to personalized health care in which individual patients are facilitated to undertake their own assessment and management (individual responsibility) might increase the number of heavy drinkers who receive feedback on their drinking and support to reduce their drinking. PMID- 25031249 TI - The effects of a weight loss program focusing on maternal education on childhood obesity. AB - PURPOSE: Childhood obesity is a matter of great concern because of its negative health and social consequences. We examined the effect of a weight control program focusing on maternal education on childhood obesity, given that the incidence of obesity is greatly affected by parents. METHODS: A two-group pre test/post-test design was used. Participants consisted of 65 obese children and their mothers. The children were fourth- to sixth-grade elementary students who did not currently receive any therapy for weight loss. The children and their mothers were randomly assigned to either an experimental (n = 32) or a control group (n = 33). The 8-week intervention for mothers included one-time group education, three-time phone counseling, and four-time fliers regarding obesity management. Four outcomes (self-control, obesity index, abdominal circumference, and body fat percentage) were measured before and after the intervention. Chi squared test or t test was used to test homogeneity between the two groups. Analysis of covariance was used to test the intervention effects. RESULTS: After the intervention was completed, the level of self-control was significantly heightened and obesity levels in the other three outcomes were greatly lowered in the experimental group when compared with the control group. CONCLUSION: Due to strong maternal effects on children's weight control, mothers' active participation must be encouraged in order to resolve childhood obesity. PMID- 25031250 TI - Assessment of salivary human herpesvirus-6 and immunoglobulin a levels in nurses working shifts. AB - PURPOSE: The purpose of the present study was to assess whether salivary human herpesvirus (HHV)-6 acted as a new sensitive stress marker, providing a reliable indicator of stress among shift work nurses. Salivary HHV-6, immunoglobulin (Ig) A and mood states were compared among nurses who worked day shifts only and nurses who worked different numbers of night shifts. METHODS: Participants included 56 female nurses working in Japanese general hospitals. The 56 subjects were categorized into three groups: Group A (n = 7), which consisted of nurses who only worked day shifts; group B (n = 29), which consisted of nurses working shifts with L8 night shifts per month; and group C (n = 20), which consisted of nurses working shifts with (3) 9 night shifts per month. Mood was assessed using the Profile of Mood States Short Form Japanese version (POMS-SFJ). Salivary biomarker levels and mood were compared among the three groups. RESULTS: Although the salivary HHV-6 level was significantly higher in group C than in group A (p < .05), salivary IgA and mood levels were not significantly different among the three groups. CONCLUSION: Salivary HHV-6 level may be a more sensitive stress marker than salivary IgA or mood for assessing chronic fatigue in nurses working shifts. Improvement to shift assignments using assessment by salivary HHV-6 is required. PMID- 25031251 TI - Assessing self-efficacy in infant care: a comparison of two scales. AB - PURPOSE: The Self-efficacy in Infant Care Scale (SICS) was developed with acceptable psychometric properties to assess the degree of Thai mothers' belief in their ability to perform designated infant care tasks. The purpose of this study was to identify whether the SICS, with a 6-point rating scale, can be used as an alternative to a rating scale with 0-100 confidence continuum scale. METHODS: Eligible subjects included 42 mothers with 6 or 9 years of education who took their infants to the well-baby clinic for immunizations at Samutsakorn Hospital. Each mother first completed the original scale and then the 6-point SICS rating scale. Afterwards, the mothers were asked to indicate which of the questionnaires was easier to administer. RESULTS: Using Cronbach's alpha, the reliability of both scales was .95. Correlations between the same items of both response formats of the SICS revealed that only 11 pairs of items demonstrated high magnitudes of correlation. Correlations between the same subscales and between the total scales of both response formats were high but less than .95. Slightly over half of all mothers (57%) preferred the 6-point rating scale. Interestingly, 59% of the group with 6 years of education preferred the original scale, compared with only 25% of the group with 9 years of education. CONCLUSION: The findings suggest that correlations between SICS and two different response formats do not reach the criteria for use as alternatives to each other. However, further research is needed, with particular emphasis on the investigation of construct validity and comparisons between the two scales. PMID- 25031252 TI - Methodological issues and challenges in data collection and analysis of qualitative meta-synthesis. AB - Qualitative meta-synthesis is an emerging method for synthesis of findings of qualitative studies. Based on a qualitative meta-synthesis study on the lived experiences of immigrant Asian nurses working in Western countries (Xu, 2007), this paper discusses several methodological issues and challenges encountered during the data collection and analysis processes and strategies used to resolve them. These issues and challenges include, but are not limited to: adequacy of qualifying studies and inclusion criteria; availability and accessibility of qualified studies; publication bias; quality versus quantity of primary studies; studies containing both quantitative and qualitative data; studies based on identical samples; separation of relevant data for analysis; and validity of synthesis findings. The strategies used (or desired) to resolve these issues and challenges were illustrated with exemplars from the published meta-synthesis study. This paper argues and concludes that: (a) the quality of qualified available studies is more essential for a qualitative meta-synthesis study and the quality versus quantity issue must be dealt with in context and perspective; (b) creativity and flexibility consistent with the principles and spirit of qualitative inquiry is required in resolving these issues; and (c) working within multiple constraints, the meta-synthesist frequently has to settle with less than ideal solutions during the research process in the real world. PMID- 25031253 TI - Workplace violence and abuse against nurses in hospitals in iran. AB - PURPOSE: The rising rate of violence and abuse in health care centers has become a major problem for nurses. The purpose of this cross-sectional study was to explore the prevalence of assaults during nurses' careers in the Islamic Republic of Iran. METHODS: Self-report questionnaires were filled out by 1,317 nurses. RESULTS: Verbal abuse was experienced by 87.4% of the population during a 6-month period, and physical violence by 27.6% during the same period of time. No physical harm was reported in 66.4% of cases. Only 35.9% cases of verbal abuse and 49.9% cases of physical violence were actually reported. The majority of cases reported that abuse was followed by either inaction or by actions which failed to satisfy the victim. According to the findings, men were exposed to more abuse than women, and the risk of experiencing abuse was higher in nurses with more job experience or who worked more hours. Also, nurses who are responsible for first aid were subjected to more abuse than those in other positions. CONCLUSION: The findings showed a noticeable trend of a rising number of assaults against nurses. The findings of this study may help hospital staff and nurses to avoid, reduce and control violence and abuse. PMID- 25031254 TI - Individual differences in intrinsic brain connectivity predict decision strategy. AB - When humans are provided with ample time to make a decision, individual differences in strategy emerge. Using an adaptation of a well-studied decision making paradigm, motion direction discrimination, we probed the neural basis of individual differences in strategy. We tested whether strategies emerged from moment-to-moment reconfiguration of functional brain networks involved in decision making with task-evoked functional MRI (fMRI) and whether intrinsic properties of functional brain networks, measured at rest with functional connectivity MRI (fcMRI), were associated with strategy use. We found that human participants reliably selected one of two strategies across 2 days of task performance, either continuously accumulating evidence or waiting for task difficulty to decrease. Individual differences in decision strategy were predicted both by the degree of task-evoked activation of decision-related brain regions and by the strength of pretask correlated spontaneous brain activity. These results suggest that spontaneous brain activity constrains strategy selection on perceptual decisions. PMID- 25031255 TI - Balance-corrective responses to unexpected perturbations at the arms during treadmill walking. AB - The arms have been shown to be involved in the regulation of balance during walking. The use of a walking aid enhances balance by increasing the base of support and reducing the load on the legs by partly transferring it to the arms. However, when actively engaged during a balance task, perturbations to the arms can destabilize balance. Previous studies have investigated postural adjustments associated with focal arm movements during standing and walking. However, balance corrective reactions to unexpected perturbations to the arms during walking have not been well studied. In the present study, subjects walked on a treadmill while grasping a pair of handles when sudden perturbations were delivered by displacing the handles in the forward or backward direction. Instructing subjects to oppose the displacement of the handles resulted in strong responses in the arms that were accompanied by activation of muscles in the legs, comparable to those observed in other balance disturbance studies. Conversely, when subjects were instructed to allow the handles to move when displaced, no responses were observed in the arms. However, similar responses were observed in the legs whether subjects opposed the displacement of the handles or not when perturbations were applied at heel strike. The results from this study show that balance reactions can be elicited in the legs in response to perturbations applied at the arms, and that the expression of these responses is affected by the task engaged in by the arms. PMID- 25031256 TI - Receptive field properties of bipolar cell axon terminals in direction-selective sublaminas of the mouse retina. AB - Retinal bipolar cells (BCs) transmit visual signals in parallel channels from the outer to the inner retina, where they provide glutamatergic inputs to specific networks of amacrine and ganglion cells. Intricate network computation at BC axon terminals has been proposed as a mechanism for complex network computation, such as direction selectivity, but direct knowledge of the receptive field property and the synaptic connectivity of the axon terminals of various BC types is required in order to understand the role of axonal computation by BCs. The present study tested the essential assumptions of the presynaptic model of direction selectivity at axon terminals of three functionally distinct BC types that ramify in the direction-selective strata of the mouse retina. Results from two-photon Ca(2+) imaging, optogenetic stimulation, and dual patch-clamp recording demonstrated that 1) CB5 cells do not receive fast GABAergic synaptic feedback from starburst amacrine cells (SACs); 2) light-evoked and spontaneous Ca(2+) responses are well coordinated among various local regions of CB5 axon terminals; 3) CB5 axon terminals are not directionally selective; 4) CB5 cells consist of two novel functional subtypes with distinct receptive field structures; 5) CB7 cells provide direct excitatory synaptic inputs to, but receive no direct GABAergic synaptic feedback from, SACs; and 6) CB7 axon terminals are not directionally selective, either. These findings help to simplify models of direction selectivity by ruling out complex computation at BC terminals. They also show that CB5 comprises two functional subclasses of BCs. PMID- 25031257 TI - Modulation of phase durations, phase variations, and temporal coordination of the four limbs during quadrupedal split-belt locomotion in intact adult cats. AB - Stepping along curvilinear paths produces speed differences between the inner and outer limb(s). This can be reproduced experimentally by independently controlling left and right speeds with split-belt locomotion. Here we provide additional details on the pattern of the four limbs during quadrupedal split-belt locomotion in intact cats. Six cats performed tied-belt locomotion (same speed bilaterally) and split-belt locomotion where one side (constant side) stepped at constant treadmill speed while the other side (varying side) stepped at several speeds. Cycle, stance, and swing durations changed in parallel in homolateral limbs with shorter and longer stance and swing durations on the fast side, respectively, compared with the slow side. Phase variations were quantified in all four limbs by measuring the slopes of the regressions between stance and cycle durations (rSTA) and between swing and cycle durations (rSW). For a given limb, rSTA and rSW were not significantly different from one another on the constant side whereas on the varying side rSTA increased relative to tied-belt locomotion while rSW became more negative. Phase variations were similar for homolateral limbs. Increasing left-right speed differences produced a large increase in homolateral double support on the slow side, while triple-support periods decreased. Increasing left-right speed differences altered homologous coupling, homolateral coupling on the fast side, and coupling between the fast hindlimb and slow forelimb. Results indicate that homolateral limbs share similar control strategies, only certain features of the interlimb pattern adjust, and spinal locomotor networks of the left and right sides are organized symmetrically. PMID- 25031258 TI - Contribution of PKC to the maintenance of 5-HT-induced short-term facilitation at sensorimotor synapses of Aplysia. AB - Aplysia sensorimotor synapses provide a useful model system for analyzing molecular processes that contribute to heterosynaptic plasticity. For example, previous studies demonstrated that multiple kinase cascades contribute to serotonin (5-HT)-induced short-term synaptic facilitation (STF), including protein kinase A (PKA) and protein kinase C (PKC). Moreover, the contribution of each kinase is believed to depend on the state of the synapse (e.g., depressed or nondepressed) and the time after application of 5-HT. Here, a previously unappreciated role for PKC-dependent processes was revealed to underlie the maintenance of STF at relatively nondepressed synapses. This PKC dependence was revealed when the synapse was stimulated repeatedly after application of 5-HT. The contributions of the PKA and PKC pathways were examined by blocking adenylyl cyclase-coupled 5-HT receptors with methiothepin and by blocking PKC with chelerythrine. STF was assessed 20 s after 5-HT application. The effects of PKC were consistent with enhanced mobilization of transmitter, as assessed by application of hypertonic sucrose solutions to measure the readily releasable pool of vesicles and recovery of the readily releasable pool after depletion. A computational model of transmitter release demonstrated that a PKC-dependent mobilization process was sufficient to explain the maintenance of STF at nondepressed synapses and the facilitation of depressed synapses. PMID- 25031259 TI - Honeybee Kenyon cells are regulated by a tonic GABA receptor conductance. AB - The higher cognitive functions of insects are dependent on their mushroom bodies (MBs), which are particularly large in social insects such as honeybees. MB Kenyon cells (KCs) receive multisensory input and are involved in associative learning and memory. In addition to receiving sensory input via excitatory nicotinic synapses, KCs receive inhibitory GABAergic input from MB feedback neurons. Cultured honeybee KCs exhibit ionotropic GABA receptor currents, but the properties of GABA-mediated inhibition in intact MBs are currently unknown. Here, using whole cell recordings from KCs in acutely isolated honeybee brain, we show that KCs exhibit a tonic current that is inhibited by picrotoxin but not by bicuculline. Bath application of GABA (5 MUM) and taurine (1 mM) activate a tonic current in KCs, but l-glutamate (0.1-0.5 mM) has no effect. The tonic current is strongly potentiated by the allosteric GABAA receptor modulator pentobarbital and is reduced by inhibition of Ca(2+) channels with Cd(2+) or nifedipine. Noise analysis of the GABA-evoked current gives a single-channel conductance value for the underlying receptors of 27 +/- 3 pS, similar to that of resistant to dieldrin (RDL) receptors. The amount of injected current required to evoke action potential firing in KCs is significantly lower in the presence of picrotoxin. KCs recorded in an intact honeybee head preparation similarly exhibit a tonic GABA receptor conductance that reduces neuronal excitability, a property that is likely to contribute to the sparse coding of sensory information in insect MBs. PMID- 25031261 TI - Local anaesthetic use in cancer surgery and disease recurrence: role of voltage gated sodium channels? PMID- 25031260 TI - Maintenance of relational information in working memory leads to suppression of the sensory cortex. AB - Working memory (WM) for sensory-based information about individual objects and their locations appears to involve interactions between lateral prefrontal and sensory cortexes. The mechanisms and representations for maintenance of more abstract, nonsensory information in WM are unknown, particularly whether such actively maintained information can become independent of the sensory information from which it was derived. Previous studies of WM for individual visual items found increased electroencephalogram (EEG) alpha (8-13 Hz) power over posterior electrode sites, which appears to correspond to the suppression of cortical areas that represent irrelevant sensory information. Here, we recorded EEG while participants performed a visual WM task that involved maintaining either concrete spatial coordinates or abstract relational information. Maintenance of relational information resulted in higher alpha power in posterior electrodes. Furthermore, lateralization of alpha power due to a covert shift of attention to one visual hemifield was marginally weaker during storage of relational information than during storage of concrete information. These results suggest that abstract relational information is maintained in WM differently from concrete, sensory representations and that during maintenance of abstract information, posterior sensory regions become task irrelevant and are thus suppressed. PMID- 25031262 TI - Bone cement implantation syndrome in cemented hemiarthroplasty for femoral neck fracture: incidence, risk factors, and effect on outcome. AB - BACKGROUND: Bone cement implantation syndrome (BCIS) is characterized by hypoxia, hypotension, and loss of consciousness occurring around the time of bone cementation. Using a recently proposed severity classification of BCIS, we estimated the incidence of and risk factors for BCIS and its impact on mortality in cemented hemiarthroplasty for femoral neck fractures. METHODS: In this retrospective study, 1016 patients undergoing cemented hemiarthroplasty were included. Medical history and medication were obtained from medical records. Anaesthesia charts for all patients were reviewed for mean arterial pressure, arterial oxygen saturation, and heart rate before, during, and after cementation. Each patient was classified as having no BCIS (grade 0) or BCIS grade 1, 2, or 3, depending on the degree of hypotension, arterial desaturation, or loss of consciousness around cementation. RESULTS: The incidence of BCIS grade 1, 2, and 3 were 21%, 5.1%, and 1.7%, respectively. Early mortality in BCIS grade 1 (9.3%) did not differ significantly from BCIS grade 0 (5.2%), while early mortality in BCIS grade 2 (35%) and grade 3 (88%) were significantly higher when compared with grades 0 and 1. Early mortality was also higher in BCIS grade 3 when compared with grade 2. Independent predictors for severe BCIS were: ASA grade III-IV, chronic obstructive pulmonary disease, and medication with diuretics or warfarin. Severe BCIS was associated with 16-fold increase in mortality. CONCLUSIONS: BCIS is a commonly occurring phenomenon in cemented hemiarthroplasty and severe BCIS has a huge impact on early and late mortality. PMID- 25031263 TI - Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications. AB - OBJECTIVE: Epilepsy is associated with increased risk for sudden cardiac death (SCD). We aimed to establish, in a community based study, whether this association is mediated by epilepsy per se, use of antiepileptic medications (AEMs), or both. METHODS: We studied SCD cases and age/sex matched controls in a case-control study in a large scale general practitioners' research database (n=478 661 patients). SCD risk for symptomatic epilepsy (seizure <2 years before SCD), stable epilepsy (no seizure <2 years before SCD), and use of AEMs (any indication) was determined. RESULTS: We identified 926 SCD cases and 9832 controls. Fourteen cases had epilepsy. Epilepsy was associated with an increased SCD risk (cases 1.5%, controls 0.5%; adjusted OR 2.8, 95% CI 1.4 to 5.3). SCD risk was increased for symptomatic epilepsy (cases 0.9%, controls 0.1%; adjusted OR 5.8, 95% CI 2.1 to 15.6), but not with stable epilepsy (cases 0.6%, controls 0.4%; adjusted OR 1.6, 95% CI 0.7 to 4.1). AEM use was found in 23 cases and was associated with an increased SCD risk (cases 2.5%, controls 0.8%; adjusted OR overall 2.6, 95% CI 1.5 to 4.3) among symptomatic epilepsy cases (cases 0.9%, controls 0.1%; adjusted OR 6.4, 95% CI 2.4 to 17.4) and non-epilepsy cases (cases 1.0%, controls 0.4%; adjusted OR 2.3, 95% CI 1.01 to 5.2). Increased SCD risk was associated with sodium channel blocking AEMs (cases 1.6%, controls 0.4%; adjusted OR 2.8, 95% CI 1.1 to 7.2), but not with non-sodium channel blocking AEMs. Carbamazepine and gabapentin were associated with increased SCD risk (carbamazepine: cases 1.1%, controls 0.3%; adjusted OR 3.2, 95% CI 1.1 to 9.2; gabapentin: cases 0.3%, controls 0.1%; adjusted OR 5.7, 95% CI 1.2 to 27.9). CONCLUSIONS: Epilepsy and AEM use are both associated with increased SCD risk in the general population. Poor seizure control contributes to increased SCD risk in epilepsy, while sodium channel blockade contributes to SCD susceptibility in AEM users. PMID- 25031264 TI - Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease. AB - OBJECTIVE: To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry. METHODS: We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured alpha-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing. RESULTS: Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of alpha-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause. CONCLUSIONS: We describe a novel familial Gb3 associated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified. PMID- 25031265 TI - Right ventricular stroke work in children with pulmonary arterial hypertension: a promising approach. PMID- 25031266 TI - More health for the money--toward a more rigorous implementation science. PMID- 25031267 TI - Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. AB - Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery, preeclampsia is the leading cause of iatrogenic preterm birth. We show that preeclampsia shares pathophysiologic features with recognized protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic dye Congo red), affinity for conformational state-dependent antibodies, and dysregulation of prototype proteolytic enzymes involved in amyloid precursor protein (APP) processing. Assessment of global protein misfolding load in pregnancy based on urine congophilia (Congo red dot test) carries diagnostic and prognostic potential for preeclampsia. We used conformational state-dependent antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with preeclampsia severity. In the first attempt to characterize the preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of ceruloplasmin, immunoglobulin free light chains, SERPINA1, albumin, interferon inducible protein 6-16, and Alzheimer's beta-amyloid. The human placenta abundantly expresses APP along with prototype APP-processing enzymes, of which the alpha-secretase ADAM10, the beta-secretases BACE1 and BACE2, and the gamma secretase presenilin-1 were all up-regulated in preeclampsia. The presence of beta-amyloid aggregates in placentas of women with preeclampsia and fetal growth restriction further supports the notion that this condition should join the growing list of protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for preeclampsia. PMID- 25031268 TI - Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. AB - In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (<= 500 ms) of radiation delivered at ultrahigh dose rate (>= 40 Gy/s, FLASH) or to conventional dose-rate irradiation (<= 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-beta (transforming growth factor beta) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-alpha (tumor necrosis factor alpha) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue. PMID- 25031269 TI - Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. AB - Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18 transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model. PMID- 25031270 TI - An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life threatening, cutaneous adverse drug reactions that are accompanied by keratinocyte cell death. Dead keratinocytes from SJS/TEN lesions exhibited necrosis, by morphological criteria. Supernatant from peripheral blood mononuclear cells (PBMCs) that had been exposed to the causative drug from patients with SJS/TEN induced the death of SJS/TEN keratinocytes, whereas supernatant from PBMCs of patients with ordinary drug skin reactions (ODSRs) exposed to the same drug did not. Keratinocytes from ODSR patients or from healthy controls were unaffected by supernatant from SJS/TEN or ODSR PBMCs. Mass spectrometric analysis identified annexin A1 as a key mediator of keratinocyte death; depletion of annexin A1 by a specific antibody diminished supernatant cytotoxicity. The necroptosis-mediating complex of RIP1 and RIP3 was indispensable for SJS/TEN supernatant-induced keratinocyte death, and SJS/TEN keratinocytes expressed abundant formyl peptide receptor 1 (FPR1), the receptor for annexin A1, whereas control keratinocytes did not. Inhibition of necroptosis completely prevented SJS/TEN-like responses in a mouse model of SJS/TEN. Our results demonstrate that a necroptosis pathway, likely mediated by annexin 1 acting through the FPR1 receptor, contributes to SJS/TEN. PMID- 25031272 TI - Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma. AB - Recently, we found upregulation of fibroblast growth factor receptor 4 (FGFR4) in a subset of hepatocellular carcinoma (HCC). Here, we provide mechanistic insight into the role of FGFR4-mediated signalling for the aggressive behaviour of HCC cells. To overexpress FGFR4, hepatoma/hepatocarcinoma cells were transfected with a construct coding for FGFR4. For downmodulation of endogenous FGFR4, we used small interfering RNA or adenoviral infection with dominant-negative FGFR4 constructs being either kinase dead (kdFGFR4) or coding for the autoinhibitory soluble domain (solFGFR4). FGFR4 overexpression in non-tumourigenic hepatocarcinoma cells significantly reduced cell-matrix adhesion, enabled cells to grow anchorage-independently in soft agar, to disintegrate the lymph-/blood endothelial barrier for intra-/extravasation of tumour cells and to form tumours in SCID mice. Transcriptome analysis revealed altered expression of genes involved in cell-matrix interactions. Conversely, in highly tumourigenic cell lines, kdFGFR4 or solFGFR4 lowered the proportion of cells in S phase of the cell cycle, enhanced the G0/G1 and G2/M-phase proportions, reduced anchorage independent growth in vitro and attenuated disintegration of the lymph-/blood endothelium and tumour formation in vivo. These findings were confirmed by altered expression profiles of genes being important for late stages of cell division. Deregulated FGFR4 expression appears to be one of the key drivers of the malignant phenotype of HCC cells. Accordingly, blockade of FGFR4-mediated signalling by soluble dominant-negative constructs, like solFGFR4, may be a feasible and promising therapeutic approach to antagonize aggressive behaviour of hepatoma/hepatocarcinoma cells. PMID- 25031273 TI - Treatment trends, risk of lymph node metastasis, and outcomes for localized esophageal cancer. AB - BACKGROUND: Endoscopic resection is increasingly used to treat localized, early stage esophageal cancer. We sought to assess its adoption, characterize the risks of nodal metastases, and define differences in procedural mortality and 5-year survival between endoscopic and surgical resection in the United States. METHODS: From the National Cancer Data Base, patients with T1a and T1b lesions were identified. Treatment patterns were characterized, and hierarchical regression methods were used to define predictors and evaluate outcomes. All statistical tests were two-sided. RESULTS: Five thousand three hundred ninety patients were identified and underwent endoscopic (26.5%) or surgical resection (73.5%). Endoscopic resection increased from 19.0% to 53.0% for T1a lesions (P < .001) and from 6.6% to 20.9% for T1b cancers (P < .001). The strongest predictors of endoscopic resection were depth of invasion (T1a vs T1b: odds ratio [OR] = 4.45; 95% confidence interval [CI] = 3.76 to 5.27) and patient age of 75 years or older (vs age less than 55 years: OR = 4.86; 95% CI = 3.60 to 6.57). Among patients undergoing surgery, lymph node metastasis was 5.0% for T1a and 16.6% for T1b lesions. Predictors of nodal metastases included tumor size greater than 2 cm (vs. <2 cm) and intermediate-/high-grade lesions (vs low grade). For example, 0.5% of patients with low-grade T1a lesions less than 2 cm had lymph node involvement. The risk of 30-day mortality was less after endoscopic resection (hazard ratio [HR] = 0.33; 95% CI = 0.19 to 0.58) but greater for conditional 5 year survival (HR = 1.63; 95% CI = 1.07 to 2.47). CONCLUSIONS: Endoscopic resection has become the most common treatment of T1a esophageal cancer and has increased for T1b cancers. It remains important to balance the risk of nodal metastases and procedural risk when counseling patients regarding their treatment options. PMID- 25031275 TI - Nodes or no nodes? The lymph node metastasis risk of T1 esophageal cancer revisited. PMID- 25031274 TI - Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. AB - BACKGROUND: Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitizing properties of erlotinib and its direct effect on brain metastases and systemic activity. METHODS: Eighty NSCLC patients with KPS of 70 and greater and multiple brain metastases were randomly assigned to placebo (n = 40) or erlotinib (100mg, n = 40) given concurrently with WBRT (20 Gy in 5 fractions). Following WBRT, patients continued with placebo or erlotinib (150 mg) until disease progression. The primary end point was neurological progression-free survival (nPFS); hazard ratios (HRs) were calculated using Cox regression. All P values were two-sided. RESULTS: Fifteen patients (37.5%) from each arm were alive and without neurological progression 2 months after WBRT. Median nPFS was 1.6 months in both arms; nPFS HR 0.95 (95% CI = 0.59 to 1.54; P = .84). Median overall survival (OS) was 2.9 and 3.4 months in the placebo and erlotinib arms; HR 0.95 (95% CI = 0.58 to 1.55; P = .83). The frequency of epidermal growth factor receptor (EGFR) mutations was low with only 1 of 35 (2.9%) patients with available samples had activating EGFR-mutations. Grade 3/4 adverse event rates were similar between the two groups (70.0% in each arm), except for rash 20.0% (erlotinib) vs 5.0% (placebo), and fatigue 17.5% vs 35.0%. No statistically significant quality of life differences were found. CONCLUSIONS: Our study showed no advantage in nPFS or OS for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC and multiple brain metastases compared to placebo. Future studies should focus on the role of erlotinib with or without WBRT in patients with EGFR mutations. PMID- 25031276 TI - Exposure to indoor tanning without burning and melanoma risk by sunburn history. AB - Indoor tanning is carcinogenic to humans. Individuals report that they tan indoors before planning to be in the sun to prevent sunburns, but whether skin cancer is subsequently reduced is unknown. Using a population-based case-control study, we calculated the association between melanoma and indoor tanning after excluding exposed participants reporting indoor tanning-related burns, stratified by their number of lifetime sunburns (0, 1-2, 3-5, >5). Confounding was addressed using propensity score analysis methods. All statistical tests were two-sided. We observed increased risk of melanoma across all sunburn categories for participants who had tanned indoors without burning compared with those who never tanned indoors, including those who reported zero lifetime sunburns (odds ratio = 3.87; 95% confidence interval = 1.68 to 8.91; P = .002). These data provide evidence that indoor tanning is a risk factor for melanoma even among persons who reported never experiencing burns from indoor tanning or outdoor sun exposure. PMID- 25031271 TI - Cell and tissue engineering for liver disease. AB - Despite the tremendous hurdles presented by the complexity of the liver's structure and function, advances in liver physiology, stem cell biology and reprogramming, and the engineering of tissues and devices are accelerating the development of cell-based therapies for treating liver disease and liver failure. This State of the Art Review discusses both the near- and long-term prospects for such cell-based therapies and the unique challenges for clinical translation. PMID- 25031277 TI - The usefulness of a diagnostic method combining high-resolution CT findings and serum markers for cytomegalovirus pneumonia and pneumocystis pneumonia in non AIDS patients. AB - BACKGROUND: The combination of high-resolution computed tomography (HRCT) findings and serum markers would be of great value in diagnosing cytomegalovirus pneumonia (CMVP) and pneumocystis pneumonia (PCP) considering low invasiveness. PURPOSE: To compare the HRCT findings of CMVP and PCP and to evaluate the differences in HRCT findings between patients diagnosed based on pathologic evidence and serum markers. MATERIAL AND METHODS: Two radiologists retrospectively evaluated the HRCT findings of 21 patients with CMVP and 70 patients with PCP. Eight patients with CMVP and 32 patients with PCP were diagnosed based on pathologic evidence ("Path" group), while 13 patients with CMVP and 38 patients with PCP were diagnosed based on serum markers (CMV antigenemia, beta-D-glucan) ("Serum-Marker" group). A total of 19 CT morphological criteria were evaluated, and the significance of the differences between the two diseases and between the "Path" and "Serum-Marker" groups with respect to each disease was calculated. RESULTS: The presence of small nodules, the tree-in-bud pattern, and the halo sign was found more frequently in the CMVP group. Extensive ground-glass attenuation (GGA), a mosaic pattern, and a diffuse distribution were observed more frequently in the PCP group. There were significant differences between the "Path" and "Serum-Marker" groups in average extent of consolidation and distribution of consolidation in PCP, and the distribution of GGA in CMVP, respectively. CONCLUSION: The combined use of HRCT findings and serum markers is useful for the diagnosis of CMVP and PCP in non AIDS patients. The typical HRCT findings for the differential diagnosis included extensive GGA with mosaic pattern in PCP and nodules, nodules with or without the tree-in-bud pattern, and the halo sign in CMVP. PMID- 25031278 TI - JPEN Journal Club 6. Meta-analysis. PMID- 25031279 TI - A novel ischemic stroke risk locus at 12q24.12 using a genome-wide association study approach. PMID- 25031280 TI - Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia. AB - OBJECTIVE: In this study, we aimed to investigate the effect of hypoglycemia on cardiovascular outcomes in a sample of patients with chronic kidney disease (CKD). METHODS: Information about study participants was extracted from the National Health Insurance Research Database of Taiwan for the years 1998 through 2008. We conducted this retrospective cohort study of patients with CKD, with and without hypoglycemia, to evaluate the risk of overall mortality and cardiovascular complications including stroke, coronary heart disease, and congestive heart failure in both groups. RESULTS: This study included 46,135 patients with CKD, of whom 2,117 (4.59%) were hospitalized and had hypoglycemia. Results of multivariate Cox proportional hazard regression analyses indicated that stroke (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.29-2.03), coronary heart disease (HR = 1.25, 95% CI = 1.00-1.57), congestive heart failure (HR = 1.49, 95% CI = 1.13-1.98), and death (HR = 2.53, 95% CI = 1.99-3.21) were associated with hypoglycemia in patients with CKD. Recurrent episodes of hypoglycemia were associated with a higher risk of death (HR = 33.0, 95% CI = 22.3-48.8 for >2 episodes, p for trend <0.0001), and a similar trend was observed for other multiple cardiovascular events. We observed an increased risk of stroke and overall mortality in patients with hypoglycemia compared to those without hypoglycemia, regardless of whether the patient had diabetes. CONCLUSIONS: CKD was associated with a higher risk of stroke and mortality in patients with hypoglycemia. Recurrent hypoglycemia considerably increased the risk of stroke and overall mortality in patients with CKD regardless of whether they had diabetes. These results suggest that hypoglycemia has a crucial role in stroke and death in patients with CKD. PMID- 25031281 TI - Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers. AB - OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and could not thus far be correlated with disease presence or severity. METHODS: To investigate the link between clinical signs of FSHD and DNA methylation, we explored 95 cases (37 FSHD1, 29 asymptomatic individuals carrying a shortened D4Z4 array, 9 patients with FSHD2, and 20 controls) by implementing 2 approaches: methylated DNA immunoprecipitation and sodium bisulfite sequencing. RESULTS: Both methods revealed statistically significant differences between asymptomatic carriers or controls and individuals with clinical FSHD, especially in the proximal region of the repeat. Absence of clinical expression in asymptomatic carriers is associated with a level of methylation similar to controls. CONCLUSIONS: We provide a proof of concept that the targeted approaches that we describe could be applied systematically to patient samples in routine diagnosis and suggest that local hypomethylation within D4Z4 might serve as a modifier for clinical expression of FSHD phenotype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD. PMID- 25031282 TI - White matter correlates of cognitive dysfunction after mild traumatic brain injury. AB - OBJECTIVE: To relate neurophysiologic changes after mild/moderate traumatic brain injury to cognitive deficit in a longitudinal diffusion tensor imaging investigation. METHODS: Fifty-three patients were scanned an average of 6 days postinjury (range = 1-14 days). Twenty-three patients were rescanned 1 year later. Thirty-three matched control subjects were recruited. At the time of scanning, participants completed cognitive testing. Tract-Based Spatial Statistics was used to conduct voxel-wise analysis on diffusion changes and to explore regressions between diffusion metrics and cognitive performance. RESULTS: Acutely, increased axial diffusivity drove a fractional anisotropy (FA) increase, while decreased radial diffusivity drove a negative regression between FA and Verbal Letter Fluency across widespread white matter regions, but particularly in the ascending fibers of the corpus callosum. Raised FA is hypothesized to be caused by astrogliosis and compaction of axonal neurofilament, which would also affect cognitive functioning. Chronically, FA was decreased, suggesting myelin sheath disintegration, but still regressed negatively with Verbal Letter Fluency in the anterior forceps. CONCLUSIONS: Acute mild/moderate traumatic brain injury is characterized by increased tissue FA, which represents a clear neurobiological link between cognitive dysfunction and white matter injury after mild/moderate injury. PMID- 25031283 TI - Epileptic kinetopsia localizes to superior parietal lobule and intraparietal sulcus. PMID- 25031284 TI - Homocysteine, small-vessel disease, and atherosclerosis: an MRI study of 825 stroke patients. AB - OBJECTIVE: We evaluated the relationship between hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and small-vessel disease (SVD) and atherosclerotic large-vessel disease (LVD) in stroke patients. METHODS: A total of 825 noncardioembolic ischemic stroke patients whose plasma concentrations of total homocysteine were measured and whose MTHFR C677T polymorphism status was identified were included in this retrospective study. MRI of the brain and magnetic resonance angiography of the intracranial and extracranial cerebral arteries had been performed. SVD and LVD were assessed by the Scheltens scale (the SVD score) and by the number of atherosclerotic steno occlusive arteries (the LVD score), respectively. RESULTS: The TT genotype of the MTHFR C677T polymorphism was associated with hyperhomocysteinemia (p < 0.001), but not with SVD (p = 0.182) or LVD (p = 0.988) scores. Multiple logistic regression analysis showed that hyperhomocysteinemia was associated with SVD (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.01-1.07; p = 0.005) and LVD (OR 1.02; 95% CI 1.00-1.05; p = 0.041) scores. Hyperhomocysteinemia was related to the LVD score of extracranial arteries (p = 0.008), but not to the LVD score of intracranial arteries (p = 0.730). In multiple logistic regression analysis, however, hyperhomocysteinemia was not related to the LVD score of extracranial arteries (p = 0.255). CONCLUSIONS: Hyperhomocysteinemia was associated with SVD of the brain and LVD of cerebral arteries. The MTHFR C677T polymorphism was not related to SVD and LVD, although the TT genotype was an important determinant of hyperhomocysteinemia. PMID- 25031285 TI - Epigenetic hypomethylation in FSHD: it's not what you inherit, it's whether it shows. PMID- 25031286 TI - Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease. AB - OBJECTIVE: To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls. BACKGROUND: Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD. Subjects with ADAD are generally free of significant vascular disease and offer the opportunity to measure CBF early in the pathologic process before significant symptom onset when unique markers might be identified. METHODS: Fourteen MCs (presenilin-1 and amyloid beta precursor protein) (Clinical Dementia Rating [CDR] 0 = 9, CDR 0.5 = 4, CDR 1 = 1) and 50 controls underwent 3-tesla pulsed arterial spin-labeled MRI. SPM8 was used to test the effect of MC status at the voxel level on CBF before and after controlling for age and CDR. RESULTS: MCs had decreased perfusion in the caudate and inferior striatum bilaterally even after controlling for age and CDR. In MCs, separate areas of decreased CBF were associated with increasing cerebral amyloid and to decreased performance of attention and executive function. CONCLUSIONS: Early CBF changes were identified in asymptomatic and mildly symptomatic subjects with ADAD, particularly in the anterior striatum. Furthermore, amyloid deposition was associated with decreased CBF in a number of regions including anterior and posterior cortical areas. Both amyloid and decreased CBF were associated with declines primarily in executive cognitive function. PMID- 25031287 TI - Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. AB - OBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 * 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695). CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage. PMID- 25031288 TI - Motoric cognitive risk syndrome: multicountry prevalence and dementia risk. AB - OBJECTIVES: Our objective is to report prevalence of motoric cognitive risk syndrome (MCR), a newly described predementia syndrome characterized by slow gait and cognitive complaints, in multiple countries, and its association with dementia risk. METHODS: Pooled MCR prevalence analysis of individual data from 26,802 adults without dementia and disability aged 60 years and older from 22 cohorts from 17 countries. We also examined risk of incident cognitive impairment (Mini-Mental State Examination decline >=4 points) and dementia associated with MCR in 4,812 individuals without dementia with baseline Mini-Mental State Examination scores >=25 from 4 prospective cohort studies using Cox models adjusted for potential confounders. RESULTS: At baseline, 2,808 of the 26,802 participants met MCR criteria. Pooled MCR prevalence was 9.7% (95% confidence interval [CI] 8.2%-11.2%). MCR prevalence was higher with older age but there were no sex differences. MCR predicted risk of developing incident cognitive impairment in the pooled sample (adjusted hazard ratio [aHR] 2.0, 95% CI 1.7 2.4); aHRs were 1.5 to 2.7 in the individual cohorts. MCR also predicted dementia in the pooled sample (aHR 1.9, 95% CI 1.5-2.3). The results persisted even after excluding participants with possible cognitive impairment, accounting for early dementia, and diagnostic overlap with other predementia syndromes. CONCLUSION: MCR is common in older adults, and is a strong and early risk factor for cognitive decline. This clinical approach can be easily applied to identify high risk seniors in a wide variety of settings. PMID- 25031290 TI - Editorial commentary: The shifting sands of gonococcal antimicrobial resistance. PMID- 25031291 TI - Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus colonization in HIV infection: a meta-analysis. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals who are colonized with methicillin-resistant Staphylococcus aureus (MRSA) have increased risk for MRSA infection. We conducted a meta-analysis of published studies to estimate the prevalence of MRSA colonization in this population. METHODS: We performed a systematic literature review and meta-analysis. The PubMed and Embase databases were searched and studies reporting prevalence of MRSA colonization among HIV-infected individuals were included. RESULTS: Among 7940 citations, 32 studies reporting data on 6558 HIV-infected individuals were considered eligible for our meta-analysis. We found that 6.9% (95% confidence interval [CI], 4.8-9.3) of individuals with HIV infection are MRSA carriers, with the corresponding figure across North American studies being 8.8% (95% CI, 6.0-12.2). History of hospitalization during the previous 12 months was associated with a 3.1 times higher risk of MRSA colonization (risk ratio [RR], 3.11 [95% CI, 1.62-5.98]). Previous or current incarceration was also associated with a higher risk for carriage (RR, 1.77 [95% CI, 1.26-2.48]). Current antiretroviral therapy or use of trimethoprim-sulfamethoxazole did not impact the risk of MRSA carriage (RR, 1.02 [95% CI, .64-1.63] and 1.45 [95% CI, .69-3.03], respectively). Extranasal screening increased the detection of MRSA colonization by at least 31.6% (95% CI, 15.8-50.0). The added yield from groin screening was 19.3% (95% CI, 11.5-28.5), from perirectal screening 18.5% (95% CI, 7.4-33.2), and from throat cultures 17.5% (95% CI, 12.0-24). CONCLUSIONS: Individuals with HIV infection constitute a highly vulnerable population for MRSA colonization, and prior exposure to hospital or incarceration are significant factors. Nasal screening alone will underestimate the rate of colonization by at least one-third. PMID- 25031289 TI - The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. AB - BACKGROUND: Ceftriaxone is the foundation of currently recommended gonorrhea treatment. There is an urgent need for backup treatment options for patients with cephalosporin allergy or infections due to suspected cephalosporin-resistant Neisseria gonorrhoeae. We evaluated the efficacy and tolerability of 2 combinations of existing noncephalosporin antimicrobials for treatment of patients with urogenital gonorrhea. METHODS: We conducted a randomized, multisite, open-label, noncomparative trial in 5 outpatient sexually transmitted disease clinic sites in Alabama, California, Maryland, and Pennsylvania. Patients aged 15-60 years diagnosed with uncomplicated urogenital gonorrhea were randomly assigned to either gentamicin 240 mg intramuscularly plus azithromycin 2 g orally, or gemifloxacin 320 mg orally plus azithromycin 2 g orally. The primary outcome was microbiological cure of urogenital infections (negative follow-up culture) at 10-17 days after treatment among 401 participants in the per protocol population. RESULTS: Microbiological cure was achieved by 100% (lower 1-sided exact 95% confidence interval [CI] bound, 98.5%) of 202 evaluable participants receiving gentamicin/azithromycin, and 99.5% (lower 1-sided exact 95% CI bound, 97.6%) of 199 evaluable participants receiving gemifloxacin/azithromycin. Gentamicin/azithromycin cured 10 of 10 pharyngeal infections and 1 of 1 rectal infection; gemifloxacin/azithromycin cured 15 of 15 pharyngeal and 5 of 5 rectal infections. Gastrointestinal adverse events were common in both arms. CONCLUSIONS: Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed. Clinical Trials Registration. NCT00926796. PMID- 25031293 TI - Eplerenone reduces arterial thrombosis in diabetic rats. AB - INTRODUCTION: Clinical studies demonstrated the benefits of eplerenone (EPL) in reduction of cardiovascular events in diabetic patients. Since acute myocardial infarction (AMI) and stroke are related to acute intravascular thrombosis, we postulate that the beneficial effects of EPL may result from its antithrombotic action. MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic rats were treated with EPL (100 mg/kg/day) for 10 days. Thrombosis in the carotid artery was stimulated electrically. RESULTS: Thrombosis development was enhanced in STZ induced diabetic rats as compared to normoglycaemic controls. EPL caused prolongation of the time to artery occlusion, reduction in the incidence of occlusion and decrease in thrombus weight. Changes in the thrombi structure and the inhibition of hypertrophy of the tunica media in the artery wall were also observed. EPL caused reduction in tissue factor, plasminogen activator inhibitor type 1 and interleukin-1beta plasma levels. CONCLUSIONS: Our study demonstrated the antithrombotic effect of EPL manifested by a decrease in the dynamics of thrombus formation and changes in its structure. The changes in thrombosis process were accompanied by antihaemostatic, profibrinolytic and anti inflammatory effects. The aldosterone blockade with EPL seems to be an additional pharmacological strategy for the prevention and treatment of thrombotic disorders in diabetes. PMID- 25031294 TI - A polymorphism in AGT and AGTR1 gene is associated with lead-related high blood pressure. AB - We investigated the association of polymorphisms in two renin-angiotensin system related genes, expressed as angiotensinogen (AGT) and angiotensin II type 1 receptor (AGTR1), with blood lead levels and lead-related blood pressure in lead exposed male workers in Korea. A cross-sectional study involving 808 lead-exposed male workers in Korea was conducted using a restriction fragment length polymorphism-based strategy to differentiate the various genotypes of polymorphisms in the AGT and AGTR1 genes. The association of clinical characteristics with genotypes as modifiers was estimated after adjustment for age, smoking status, drinking status, body mass index and job duration of each subject. Genotype and allele frequencies of the M235T polymorphism in AGT were associated with lead-related high blood pressure status. Moreover, blood lead levels were associated with allele frequencies of the AGT M235T polymorphism. These results suggested that the M/M genotype and M allele of AGT are risk factors for lead-related high blood pressure. PMID- 25031296 TI - Protective effects of aliskiren and valsartan in mice with diabetic nephropathy. AB - AIM: We investigated whether aliskiren, a direct renin inhibitor, provided protection in a model of diabetic nephropathy in mice and compared its protective effects to valsartan, an angiotensin II type 1 receptor blocker. MATERIALS AND METHODS: Hyperglycemia was induced with streptozotocin (STZ, 40 mg/kg/day * 5 days) injection in DBA/2J mice fed on a high fat diet. Mice were treated with either aliskiren (25 mg/kg/day) or valsartan (8 mg/kg/day) for 6 weeks. RESULTS: Aliskiren and/or valsartan treatment significantly attenuated albuminuria, urinary nephrin excretion and glomerulosclerosis. Aliskiren and/or valsartan prevented reduction of podocin and WT1 protein abundance in diabetic mice. Aliskiren and/or valsartan significantly prevented increased expression of profibrotic growth factors (TGFbeta, CTGF and PAI-1), proinflammatory cytokines (MCP-1, TNFalpha and IL-1beta), endoplasmic reticulum (ER) stress markers (CHOP and XBP-1) and lipid accumulation in the kidney of diabetic animals. Aliskiren showed similar efficacy compared to valsartan therapy and dual treatment in some aspects has synergistic protective effects. CONCLUSION: Our study indicates that aliskiren and/or valsartan protects against diabetic kidney disease through multiple mechanisms, including decreasing podocyte injury, activation of profibrotic growth factors and proinflammatory cytokines, ER stress and accumulation of lipids. PMID- 25031297 TI - The D allele of angiotensin-converting enzyme gene is associated with greater hemodynamic response to resistance exercises. AB - HYPOTHESIS/INTRODUCTION: The association of ACE I/D polymorphism and hemodynamic response to exercise have been limited to primarily aerobic exercises. We hypothesized that D allele carriers would show greater hemodynamic response to resistance exercise, as has been observed with aerobic. This study aimed to investigate the association of ACE I/D polymorphism and hemodynamic (blood pressure (BP), heart rate (HR) and rate-pressure product (RPP)) response to resistance exercise in young healthy subjects. MATERIALS AND METHODS: ACE I/D polymorphisms were studied by PCR analysis from 75 healthy men. Subjects completed a resistance exercise session of three sets of 10 knee extension repetitions with loads of 50, 75 and 100% of 10RM and two-minute rest intervals. Hemodynamic measures were recorded before and immediately after each set. Analysis of variance was used to identify significant differences among ACE genotypes. RESULTS: ACE I/D polymorphism is associated with hemodynamic response to resistance exercise, as healthy subjects with ACE D allele were prone to higher responses. In addition, this phenotypic difference seems to be a load dependent trend. CONCLUSION: ACE DD carriers exhibit greater heart work during resistance exercise. Future studies should focus on the influence of resistance training period with different workloads on the hemodynamic response in healthy individuals with different ACE genotypes. PMID- 25031295 TI - The value of losartan suppression test in the confirmatory diagnosis of primary aldosteronism in patients over 50 years old. AB - OBJECTIVE: The diagnosis of primary aldosteronism (PA) among the older-aged population has posed a crucial challenge. Among patients over 50 years old, this trial assessed comparability of the performance of two PA diagnostic tests: losartan and captopril suppression tests. METHODS: A post-hoc subgroup analysis from a prospective cohort was conducted by the TAIPAI (Taiwan Primary Aldosteronism Investigation) group between July 2003 and July 2006. Of the 160 patients in the cohort, 60 patients over 50 years old received captopril and losartan tests to confirm PA. RESULTS: Among the 60 patients over 50 years old, 31 patients had PA confirmed by standardized protocol. The area under the receiver-operating characteristic (ROC) curve for post-captopril aldosterone was significantly less than that for post-losartan plasma aldosterone concentration (PAC) (0.87 vs 0.94, p=0.02). Using the aldosterone-renin ratio (ARR)>35 with PAC>10 ng/dl, the specificity was 82.76% vs 93.1% and the sensitivity was 77.42% vs 87.10% for the captopril and losartan tests, respectively. The equivalence between the two tests were confirmed by the exact McNemar's test (p=1.0). CONCLUSION: The losartan test showed comparable accuracy to confirm PA. Verification of this "elderly-friendly" confirmatory test will be the first step to prepare a specific diagnostic model of PA for the older-aged population. PMID- 25031298 TI - Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury. AB - BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis. METHODS: The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment. RESULTS: Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-beta1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, 0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, 0.773, -0.769, -0.841, -0.794, -0.826; each p < 0.05), but positively correlated with ACE2, SOD, and GSH (PHB1: r = 0.796, 0.879, 0.824; PHB2: r = 0.785, 0.914, 0.849; each p < 0.05). ACE1 was positively correlated with angiotensin I, angiotensin II, TGF-beta1, Col-IV, FN, ROS, and MDA, and negatively correlated with ACE2, SOD, and GSH (each p < 0.05). ACE2 was negatively correlated with ACE1, angiotensin I, angiotensin II, TGF-beta1, Col-IV, FN, ROS, and MDA, and positively correlated with SOD and GSH (each p < 0.05). CONCLUSION: The results suggest that ATRA acts as a positive regulator of PHB1, PHB2 and ACE2, and as a negative regulator of ACE1, angiotensin I, and angiotensin II in a RTEC model system under hypoxia/reoxygenation conditions. PMID- 25031299 TI - The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts. AB - INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR 132/212 family as novel regulators of cardiovascular function including regulation of cardiac hypertrophy, heart failure and blood pressure possibly through AT1R signalling. However, the miR-132/212 targets in the heart remain unknown. MATERIALS AND METHODS: To understand the role of these miRNAs in cardiac signalling networks, we undertook comprehensive in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. RESULTS: MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors, signalling molecules and transcription factors. Subsequent comprehensive in silico analysis identified 24 target genes, of which 22 genes were qPCR validated. We identified seven genes involved in AngII signalling pathways. CONCLUSION: We here report novel insight of an extensive network of molecular pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function. PMID- 25031301 TI - Sleep deprivation and false memories. AB - Many studies have investigated factors that affect susceptibility to false memories. However, few have investigated the role of sleep deprivation in the formation of false memories, despite overwhelming evidence that sleep deprivation impairs cognitive function. We examined the relationship between self-reported sleep duration and false memories and the effect of 24 hr of total sleep deprivation on susceptibility to false memories. We found that under certain conditions, sleep deprivation can increase the risk of developing false memories. Specifically, sleep deprivation increased false memories in a misinformation task when participants were sleep deprived during event encoding, but did not have a significant effect when the deprivation occurred after event encoding. These experiments are the first to investigate the effect of sleep deprivation on susceptibility to false memories, which can have dire consequences. PMID- 25031302 TI - Love is in the gaze: an eye-tracking study of love and sexual desire. AB - Reading other people's eyes is a valuable skill during interpersonal interaction. Although a number of studies have investigated visual patterns in relation to the perceiver's interest, intentions, and goals, little is known about eye gaze when it comes to differentiating intentions to love from intentions to lust (sexual desire). To address this question, we conducted two experiments: one testing whether the visual pattern related to the perception of love differs from that related to lust and one testing whether the visual pattern related to the expression of love differs from that related to lust. Our results show that a person's eye gaze shifts as a function of his or her goal (love vs. lust) when looking at a visual stimulus. Such identification of distinct visual patterns for love and lust could have theoretical and clinical importance in couples therapy when these two phenomena are difficult to disentangle from one another on the basis of patients' self-reports. PMID- 25031303 TI - Bioinformatics multivariate analysis determined a set of phase-specific biomarker candidates in a novel mouse model for viral myocarditis. AB - BACKGROUND: Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler's murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains. METHODS AND RESULTS: Using this novel model for viral myocarditis induced with Theiler's murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler's murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity-related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity-related genes, such as Cd3g and H2-Aa; and cardiac remodeling-related genes, such as Mmp12 and Gpnmb. CONCLUSIONS: Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers. PMID- 25031305 TI - Multiplicity of child maltreatment and biopsychosocial outcomes in young adulthood: the moderating role of resiliency characteristics among female survivors. AB - This study examined the moderating role of resiliency characteristics in the relationship between multiplicity of child maltreatment and biopsychosocial outcomes (i.e., psychological, physical, and interpersonal distress) in young adulthood. Participants included 765 college women who completed surveys. Structural equation modeling showed that resiliency characteristics moderated the relationship between multiplicity of child maltreatment and psychological distress; at high levels of resiliency characteristics, there was a nonsignificant relationship between multiplicity of child maltreatment and psychological distress. There was no evidence of moderation for physical or interpersonal distress. However, for both interpersonal and physical distress, the main effects of multiplicity of child maltreatment were positively related to each form of distress, and the main effect of resiliency characteristics was negatively related to each form of distress. These findings underscore the importance of promoting resiliency characteristics among survivors of multiplicity of child maltreatment to promote optimal functioning. PMID- 25031306 TI - Sixteenth biannual report of the Cochrane Haematological Malignancies Group: focus on Non-Hodgkin's lymphoma. AB - This sixteenth biannual report of the Cochrane Haematological Malignancies Group highlights recently published randomized controlled trials (RCTs) in the field of hemato-oncology, with special focus on non-Hodgkin's lymphoma. The report covers the publication period June 2012 to July 2013. Trials are selected regarding their methodology and implication for clinical practice. Studies were identified by electronic search of MEDLINE using a broad search filter that covers all topics in hemato-oncology combined with a highly sensitive search filter for randomized trials (Cochrane Handbook for Systematic Reviews of Interventions). Four RCTs are presented in detail, followed by two further RCTs of high importance in a short version. The report is finalized with an overview of new and updated Cochrane Reviews. PMID- 25031304 TI - Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. AB - BACKGROUND: Heterozygous mutations in sarcomere genes in hypertrophic cardiomyopathy (HCM) are proposed to exert their effect through gain of function for missense mutations or loss of function for truncating mutations. However, allelic expression from individual mutations has not been sufficiently characterized to support this exclusive distinction in human HCM. METHODS AND RESULTS: Sarcomere transcript and protein levels were analyzed in septal myectomy and transplant specimens from 46 genotyped HCM patients with or without sarcomere gene mutations and 10 control hearts. For truncating mutations in MYBPC3, the average ratio of mutant:wild-type transcripts was ~1:5, in contrast to ~1:1 for all sarcomere missense mutations, confirming that nonsense transcripts are uniquely unstable. However, total MYBPC3 mRNA was significantly increased by 9 fold in HCM samples with MYBPC3 mutations compared with control hearts and with HCM samples without sarcomere gene mutations. Full-length MYBPC3 protein content was not different between MYBPC3 mutant HCM and control samples, and no truncated proteins were detected. By absolute quantification of abundance with multiple reaction monitoring, stoichiometric ratios of mutant sarcomere proteins relative to wild type were strikingly variable in a mutation-specific manner, with the fraction of mutant protein ranging from 30% to 84%. CONCLUSIONS: These results challenge the concept that haploinsufficiency is a unifying mechanism for HCM caused by MYBPC3 truncating mutations. The range of allelic imbalance for several missense sarcomere mutations suggests that certain mutant proteins may be more or less stable or incorporate more or less efficiently into the sarcomere than wild type proteins. These mutation-specific properties may distinctly influence disease phenotypes. PMID- 25031307 TI - Evolution of breast cancer screening in the Medicare population: clinical and economic implications. AB - BACKGROUND: Newer approaches to mammography, including digital image acquisition and computer-aided detection (CAD), and adjunct imaging (e.g., magnetic resonance imaging [MRI]) have diffused into clinical practice. The impact of these technologies on screening-related cost and outcomes remains undefined, particularly among older women. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we constructed two cohorts of women without a history of breast cancer and followed each cohort for 2 years. We compared the use and cost of screening mammography including digital mammography and CAD, adjunct procedures including breast ultrasound, MRI, and biopsy between the period of 2001 and 2002 and the period of 2008 and 2009 using chi(2) and t test. We also assessed the change in breast cancer stage and incidence rates using chi(2) and Poisson regression. All statistical tests were two-sided. RESULTS: There were 137150 women (mean age = 76.0 years) in the early cohort (2001-2002) and 133097 women (mean age = 77.3 years) in the later cohort (2008 2009). The use of digital image acquisition for screening mammography increased from 2.0% in 2001 and 2002 to 29.8% in 2008 and 2009 (P < .001). CAD use increased from 3.2% to 33.1% (P < .001). Average screening-related cost per capita increased from $76 to $112 (P < .001), with annual national fee-for service Medicare spending increasing from $666 million to $962 million. There was no statistically significant change in detection rates of early-stage tumors (2.45 vs 2.57 per 1000 person-years; P = .41). CONCLUSIONS: Although breast cancer screening-related costs increased substantially from 2001 through 2009 among Medicare beneficiaries, a clinically significant change in stage at diagnosis was not observed. PMID- 25031308 TI - Survival outcomes after contralateral prophylactic mastectomy: a decision analysis. AB - BACKGROUND: Contralateral prophylactic mastectomy (CPM) rates have substantially increased in recent years and may reflect an exaggerated perceived benefit from the procedure. The objective of this study was to evaluate the magnitude of the survival benefit of CPM for women with unilateral breast cancer. METHODS: We developed a Markov model to simulate survival outcomes after CPM and no CPM among women with stage I or II breast cancer without a BRCA mutation. Probabilities for developing contralateral breast cancer (CBC), dying from CBC, dying from primary breast cancer, and age-specific mortality rates were estimated from published studies. We estimated life expectancy (LE) gain, 20-year overall survival, and disease-free survival with each intervention strategy among cohorts of women defined by age, estrogen receptor (ER) status, and stage of cancer. RESULTS: Predicted LE gain from CPM ranged from 0.13 to 0.59 years for women with stage I breast cancer and 0.08 to 0.29 years for those with stage II breast cancer. Absolute 20-year survival differences ranged from 0.56% to 0.94% for women with stage I breast cancer and 0.36% to 0.61% for women with stage II breast cancer. CPM was more beneficial among younger women, stage I, and ER-negative breast cancer. Sensitivity analyses yielded a maximum 20-year survival difference with CPM of only 1.45%. CONCLUSIONS: The absolute 20-year survival benefit from CPM was less than 1% among all age, ER status, and cancer stage groups. Estimates of LE gains and survival differences derived from decision models may provide more realistic expectations of CPM. PMID- 25031309 TI - How big is big enough? Thinking about contralateral prophylactic mastectomy. PMID- 25031310 TI - Higher mammography screening costs without appreciable clinical benefit: the case of digital mammography. PMID- 25031312 TI - How do smokers use a smoking cessation text messaging intervention? AB - INTRODUCTION: Mobile-phone-based text (SMS) messaging is an effective method for delivering smoking cessation assistance; however, little is known about optimal program use. This paper reports on the use of 2 forms of interaction (reporting changes in quit status and emergency help) among users of QuitTxt, an interactive, automated text messaging advice program. We examined preferences for messaging intensity, duration of use, and their associations with short-term cessation outcome or perceived helpfulness. METHODS: QuitTxt was offered during participation in a previously reported randomized controlled trial and was activated by 924 smokers or recent quitters, of whom 862 used it to a criterion level. Outcome data (quit attempts, 7-day point prevalence abstinence, and perceived helpfulness) were collected 1 month after first use. RESULTS: Most (68.9%) accepted the default of 4-8 messages per day, and median use duration was 27 days. Half (49.1%) appeared to miss reporting at least 1 status change, with relapses less likely to be reported than quit progression. Emergency help was used by 27.0% of those eligible for it; emergency help was used more frequently among those with recent quit experience and lower nicotine dependence. Use of emergency help was unrelated to short-term cessation outcome. CONCLUSIONS: The most notable finding is the variability in use. Some users complied fully with the requirement to report status changes, while even among those who did not, many found QuitTxt to be very helpful, suggesting that perfect congruence between message content and quit status is not essential. The use of emergency help functionality was relatively rare but was appreciated. PMID- 25031311 TI - Depressive symptoms are associated with obesity in adults with heart failure: An analysis of gender differences. AB - BACKGROUND: Depression is a predictor and consequence of obesity in the general population. Up to 50% of patients with heart failure exhibit elevated depressive symptoms or depressive disorders; however, research on the depression-obesity relationship in heart failure populations is limited, especially in regard to gender differences. AIMS: To conduct total-sample and gender-stratified analyses to determine whether depressive symptoms are associated with body mass index (BMI) in a sample of patients with heart failure. METHOD: Participants were 348 (39% female, 26% non-White) patients with heart failure (aged 68.7+/-9.7 years) recruited from urban medical centers. Depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9). Height and weight were used to compute BMI (kg/m(2)). Regressions were performed for total sample and both genders. Regressions for BMI were run with demographic, medical, and psychological covariates in Step 1 and the PHQ-9 in Step 2. RESULTS: Regression results (total sample) revealed that the PHQ-9 was associated with BMI after adjusting for covariates (beta=.22, p=.004). For males, the relationship between PHQ-9 and BMI remained (beta=.23, p=.024) and was driven by those with severe obesity (BMI >= 40 kg/m(2)). A trend between PHQ-9 and BMI was detected among females (beta=.19, p=.091). CONCLUSION: BMI is related to depressive symptoms in adults with heart failure even after adjusting for demographic and medical covariates. Depressive symptoms were associated with BMI in males, whereas a trend was detected among females. These findings could ultimately be used to improve heart failure outcomes for depressed, obese individuals with heart failure. PMID- 25031313 TI - Probing the smoking-suicide association: do smoking policy interventions affect suicide risk? AB - INTRODUCTION: Smokers exhibit elevated risk for suicide, but it is unknown whether smoking interventions reduce suicide risk. We examined whether state level policy interventions-increases in cigarette excise taxes and strengthening of smoke-free air laws-corresponded to a reduction in suicide risk during the 1990s and the early 2000s. We also examined whether the magnitude of such reductions correlated with individuals' predicted probability of smoking, which would be expected if the associations stemmed from changes in smoking behavior. METHODS: We paired individual-level data on suicide deaths from the U.S. Multiple Cause of Death files, years 1990-2004, with living population data from the same period. These were linked with state data on cigarette excise taxes and smoke free air policies. Utilizing a quasiexperimental analytical approach, we estimated the association between changes in policy and suicide risk. To examine whether associations correlated with individuals' probability of smoking, we used external survey data to derive a predicted probability of smoking function from demographic variables, which was then used to stratify the population by predicted smoking prevalence. RESULTS: Cigarette excise taxes, smoke-free air policies, and an index combining the two policies all exhibited protective associations with suicide. The associations were strongest in segments of the population where predicted smoking prevalence was the highest and weaker in segments of the population where predicted smoking prevalence was the lowest, suggesting that the protective associations were related to changes in smoking behavior. CONCLUSION: These results provide support for the proposition that population interventions for smoking could reduce risk for suicide. PMID- 25031314 TI - Tobacco education in U.S. respiratory care programs. AB - INTRODUCTION: Exposure to tobacco smoke impacts the onset or exacerbation of most respiratory disorders, and respiratory therapists are well positioned to identify tobacco use and provide cessation assistance. The purpose of this study was to characterize the level of tobacco cessation education provided to students in U.S. respiratory care training programs. METHODS: A national survey of 387 respiratory care programs assessed the extent to which tobacco is addressed in required coursework, methods of instruction, perceived importance, and adequacy of current levels of tobacco education in curricula and perceived barriers to enhancing the tobacco-related education. RESULTS: A total of 244 surveys (63.0% response) revealed a median of 165 min (IQR, 88-283) of tobacco education throughout the degree program. Pathophysiology of tobacco-related disease (median, 45 min) is the most extensively covered content area followed by aids for cessation (median, 20 min), assisting patients with quitting (median, 15 min), and nicotine pharmacology and principles of addiction (median, 15 min). More than 40% of respondents believed that latter 3 content areas are inadequately covered in the curriculum. Key barriers to enhancing tobacco training are lack of available curriculum time, lack of faculty expertise, and lack of access to comprehensive evidence-based resources. Nearly three-fourths of the respondents expressed interest in participating in a nationwide effort to enhance tobacco cessation training. CONCLUSIONS: Similar to other disciplines, enhanced tobacco cessation education is needed in respiratory care programs to equip graduates with the knowledge and the skills necessary to treat tobacco use and dependence. PMID- 25031315 TI - Safety of varenicline tartrate and counseling versus counseling alone for smoking cessation: a randomized controlled trial for inpatients (STOP study). AB - INTRODUCTION: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting. METHODS: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline counseling alone (n = 196). RESULTS: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8+/-2.89 and 53.7+/-2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. CONCLUSIONS: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting. PMID- 25031316 TI - Endometrial CXCL13 expression is cycle regulated in humans and aberrantly expressed in humans and Rhesus macaques with endometriosis. AB - C-X-C ligand 13 (CXCL13), a regulator of mucosal immunity, is secreted by human endometrial epithelium and may be involved in embryo implantation. However, cyclic expression of human endometrial CXCL13 in health and disease is not well studied. This study examines cycle stage-specific endometrial CXCL13 expression in normal humans when compared to those with biopsy-confirmed, stage 1 to 4 endometriosis using real-time reverse transcriptase, real-time polymerase chain reaction and immunohistochemistry. Eutopic endometrial CXCL13 expression was also compared between normal, control Rhesus macaques, and macaques with advanced endometriosis. In healthy women, CXLC13 messenger RNA expression was minimal in the proliferative phase and maximal in the secretory phase. However, in the presence of endometriosis, proliferative-phase endometrial expression markedly increased in both humans and rhesus subjects (P < .05). The cross-species and cross-stage concordance suggests a pathophysiologic role for CXCL13 in endometriosis and its use as a biomarker for disease. PMID- 25031317 TI - Tissue-engineered endometrial model for the study of cell-cell interactions. AB - Endometrial stromal and epithelial cell cross talk is known to influence many of the dynamic changes that occur during the menstrual cycle. We modified our previous model and embedded telomerase-immortalized human endometrial stromal cells and Ishikawa adenocarcinoma epithelial cells in a collagen-Matrigel hydrogel to create a tissue-engineered model of the endometrium. Comparisons of single and cocultured cells examined communication between endometrial stromal and epithelial cells, which were cultured with 0 or 10 nmol/L 17beta estradiol; conditioned medium was used to look at the production of paracrine factors. Using this model, we were able to identify the changes in interleukin 6 (IL-6) and active matrix metalloproteinase 2, which appear to be due to paracrine signaling and differences in transforming growth factor beta1 (TGF-beta1) that do not appear to be due to paracrine signaling. Moreover, IL-6, TGF-beta1, and DNA content were also affected by the presence of estradiol in many of the tissues. These results indicate that paracrine and endocrine signaling are involved in human endometrial responses and support the use of coculture models to further investigate cell-cell and cell-matrix interactions. PMID- 25031318 TI - Adenine nucleotide translocase 4 is expressed within embryonic ovaries and dispensable during oogenesis. AB - Adenine nucleotide translocase (Ant) facilitates the exchange of adenosine triphosphate across the mitochondrial inner membrane and plays a critical role for bioenergetics in eukaryotes. Mice have 3 Ant paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5), and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. We previously identified that Ant4 was expressed exclusively in testicular germ cells in adult mice and essential for spermatogenesis and subsequently male fertility. Further investigation into the process of spermatogenesis revealed that Ant4 was particularly highly expressed during meiotic prophase I and indispensable for normal progression of leptotene spermatocytes to the stages thereafter. In contrast, the expression and roles of Ant4 in female germ cells have not previously been elucidated. Here, we demonstrate that the Ant4 gene is expressed during embryonic ovarian development during which meiotic prophase I occurs. We confirmed embryonic ovary-specific Ant4 expression using a bacterial artificial chromosome transgene. In contrast to male, however, Ant4 null female mice were fertile although the litter size was slightly decreased. They showed apparently normal ovarian development which was morphologically indistinguishable from the control animals. These data indicate that Ant4 is a meiosis-specific gene expressed during both male and female gametogenesis however indispensable only during spermatogenesis and not oogenesis. The differential effects of Ant4 depletion within the processes of male and female gametogenesis may be explained by meiosis-specific inactivation of the X-linked Ant2 gene in male, a somatic paralog of the Ant4 gene. PMID- 25031319 TI - Epidermoid cyst of the soft palate in a 2-year-old: a case report and review of literature of pediatric soft palate lesions. PMID- 25031320 TI - Autism in the emergency department. AB - BACKGROUND: This is a retrospective chart review of autistic patients presenting to the emergency department (ED) in a tertiary care pediatric center during the year 2011. RESULTS: There were 160 ED visits by 130 patients, 25% of visits were repeated, and 20% were admitted to the hospital. There were 126 (79%) male and 34 (21%) female patients mean age of 12 years, 79% had comorbid health conditions. Forty percent were CTAS 2 (Canadian Triage Acuity Score) acuity, 42% of visits were CTAS 3 acuity, and 7% rated their pain as "severe." Visits were for behavior (10%), neurological concern (13%), 3% dental related, and the remainder were for gastrointestinal infections and other complaints. Average length of stay was 6 hours 21 minutes, with 2-hour wait to start assessment with physician. CONCLUSIONS: Autism is a prevalent diagnosis and patients with autism are accessing the ED. We hope to use these demographic findings to better serve these patients and their families. PMID- 25031321 TI - GPR107, a G-protein-coupled receptor essential for intoxication by Pseudomonas aeruginosa exotoxin A, localizes to the Golgi and is cleaved by furin. AB - A number of toxins, including exotoxin A (PE) of Pseudomonas aeruginosa, kill cells by inhibiting protein synthesis. PE kills by ADP-ribosylation of the translation elongation factor 2, but many of the host factors required for entry, membrane translocation, and intracellular transport remain to be elucidated. A genome-wide genetic screen in human KBM7 cells was performed to uncover host factors used by PE, several of which were confirmed by CRISPR/Cas9-gene editing in a different cell type. Several proteins not previously implicated in the PE intoxication pathway were identified, including GPR107, an orphan G-protein coupled receptor. GPR107 localizes to the trans-Golgi network and is essential for retrograde transport. It is cleaved by the endoprotease furin, and a disulfide bond connects the two cleaved fragments. Compromising this association affects the function of GPR107. The N-terminal region of GPR107 is critical for its biological function. GPR107 might be one of the long-sought receptors that associates with G-proteins to regulate intracellular vesicular transport. PMID- 25031322 TI - Assembly mechanism of Trypanosoma brucei BILBO1, a multidomain cytoskeletal protein. AB - Trypanosoma brucei BILBO1 (TbBILBO1) is an essential component of the flagellar pocket collar of trypanosomes. We recently reported the high resolution structure of the N-terminal domain of TbBILBO1. Here, we provide further structural dissections of its other three constituent domains: EF-hand, coiled coil, and leucine zipper. We found that the EF-hand changes its conformation upon calcium binding, the central coiled coil forms an antiparallel dimer, and the C-terminal leucine zipper appears to contain targeting information. Furthermore, interdimer interactions between adjacent leucine zippers allow TbBILBO1 to form extended filaments in vitro. These filaments were additionally found to condense into fibers through lateral interactions. Based on these experimental data, we propose a mechanism for TbBILBO1 assembly at the flagellar pocket collar. PMID- 25031323 TI - Dynamin1 is a novel target for IRSp53 protein and works with mammalian enabled (Mena) protein and Eps8 to regulate filopodial dynamics. AB - Filopodia are dynamic actin-based structures that play roles in processes such as cell migration, wound healing, and axonal guidance. Cdc42 induces filopodial formation through IRSp53, an Inverse-Bin-Amphiphysins-Rvs (I-BAR) domain protein. Previous work from a number of laboratories has shown that IRSp53 generates filopodia by coupling membrane protrusion with actin dynamics through its Src homology 3 domain binding partners. Here, we show that dynamin1 (Dyn1), the large guanosine triphosphatase, is an interacting partner of IRSp53 through pulldown and Forster resonance energy transfer analysis, and we explore its role in filopodial formation. In neuroblastoma cells, Dyn1 localizes to filopodia, associated tip complexes, and the leading edge just behind the anti-capping protein mammalian enabled (Mena). Dyn1 knockdown reduces filopodial formation, which can be rescued by overexpressing wild-type Dyn1 but not the GTPase mutant Dyn1-K44A and the loss-of-function actin binding domain mutant Dyn1-K/E. Interestingly, dynasore, an inhibitor of Dyn GTPase, also reduced filopodial number and increased their lifetime. Using rapid time-lapse total internal reflection fluorescence microscopy, we show that Dyn1 and Mena localize to filopodia only during initiation and assembly. Dyn1 actin binding domain mutant inhibits filopodial formation, suggesting a role in actin elongation. In contrast, Eps8, an actin capping protein, is seen most strongly at filopodial tips during disassembly. Taken together, the results suggest IRSp53 partners with Dyn1, Mena, and Eps8 to regulate filopodial dynamics. PMID- 25031324 TI - Expanding the proteome of an RNA virus by phosphorylation of an intrinsically disordered viral protein. AB - The human proteome contains myriad intrinsically disordered proteins. Within intrinsically disordered proteins, polyproline-II motifs are often located near sites of phosphorylation. We have used an unconventional experimental paradigm to discover that phosphorylation by protein kinase A (PKA) occurs in the intrinsically disordered domain of hepatitis C virus non-structural protein 5A (NS5A) on Thr-2332 near one of its polyproline-II motifs. Phosphorylation shifts the conformational ensemble of the NS5A intrinsically disordered domain to a state that permits detection of the polyproline motif by using (15)N-, (13)C based multidimensional NMR spectroscopy. PKA-dependent proline resonances were lost in the presence of the Src homology 3 domain of c-Src, consistent with formation of a complex. Changing Thr-2332 to alanine in hepatitis C virus genotype 1b reduced the steady-state level of RNA by 10-fold; this change was lethal for genotype 2a. The lethal phenotype could be rescued by changing Thr 2332 to glutamic acid, a phosphomimetic substitution. Immunofluorescence and transmission electron microscopy showed that the inability to produce Thr(P)-2332 NS5A caused loss of integrity of the virus-induced membranous web/replication organelle. An even more extreme phenotype was observed in the presence of small molecule inhibitors of PKA. We conclude that the PKA-phosphorylated form of NS5A exhibits unique structure and function relative to the unphosphorylated protein. We suggest that post-translational modification of viral proteins containing intrinsic disorder may be a general mechanism to expand the viral proteome without a corresponding expansion of the genome. PMID- 25031325 TI - Janus-faced role of Kruppel-like factor 2-dependent regulation of microRNAs in endothelial proliferation. PMID- 25031326 TI - New targets for atherothrombosis. PMID- 25031328 TI - A higher proportion of iron-rich leafy vegetables in a typical Burkinabe maize meal does not increase the amount of iron absorbed in young women. AB - Food-to-food fortification can be a promising approach to improve the low dietary iron intake and bioavailability from monotonous diets based on a small number of staple plant foods. In Burkina Faso, the common diet consists of a thick, cereal based paste consumed with sauces composed of mainly green leaves, such as amaranth and jute leaves. Increasing the quantity of leaves in the sauces substantially increases their iron concentration. To evaluate whether increasing the quantity of leaves in sauces would provide additional bioavailable iron, an iron absorption study in 18 young women was conducted in Zurich, Switzerland. Burkinabe composite test meals consisting of the maize paste to accompanied by an iron-improved amaranth sauce, an iron-improved jute sauce, or a traditional amaranth sauce were provided as multiple meals twice a day for 2 consecutive days. Iron absorption was measured as erythrocyte incorporation of stable iron isotopes. Mean fractional iron absorption from maize paste consumed with an iron improved amaranth sauce (4.9%) did not differ from the same meal consumed with an iron-improved jute sauce (4.9%; P = 0.9), resulting in a similar quantity of total iron absorbed (679 vs. 578 MUg; P = 0.3). Mean fractional iron absorption from maize paste accompanied by a traditional amaranth sauce (7.4%) was significantly higher than that from the other 2 meal types (P < 0.05), but the quantity of total iron absorbed was similar (591 MUg; P = 0.4 and 0.7, respectively). A food-to-food fortification approach based on an increase in leafy vegetables does not provide additional bioavailable iron, presumably due to the high phenolic compound concentration of the leaves tested. Alternative measures, such as adding iron absorption enhancers to the sauces, need to be investigated to improve iron nutrition from Burkinabe maize meals. PMID- 25031329 TI - Arm span and ulnar length are reliable and accurate estimates of recumbent length and height in a multiethnic population of infants and children under 6 years of age. AB - Surrogate measures are needed when recumbent length or height is unobtainable or unreliable. Arm span has been used as a surrogate but is not feasible in children with shoulder or arm contractures. Ulnar length is not usually impaired by joint deformities, yet its utility as a surrogate has not been adequately studied. In this cross-sectional study, we aimed to examine the accuracy and reliability of ulnar length measured by different tools as a surrogate measure of recumbent length and height. Anthropometrics [recumbent length, height, arm span, and ulnar length by caliper (ULC), ruler (ULR), and grid (ULG)] were measured in 1479 healthy infants and children aged <6 y across 8 study centers in the United States. Multivariate mixed-effects linear regression models for recumbent length and height were developed by using ulnar length and arm span as surrogate measures. The agreement between the measured length or height and the predicted values by ULC, ULR, ULG, and arm span were examined by Bland-Altman plots. All 3 measures of ulnar length and arm span were highly correlated with length and height. The degree of precision of prediction equations for length by ULC, ULR, and ULG (R(2) = 0.95, 0.95, and 0.92, respectively) was comparable with that by arm span (R(2) = 0.97) using age, sex, and ethnicity as covariates; however, height prediction by ULC (R(2) = 0.87), ULR (R(2) = 0.85), and ULG (R(2) = 0.88) was less comparable with arm span (R(2) = 0.94). Our study demonstrates that arm span and ULC, ULR, or ULG can serve as accurate and reliable surrogate measures of recumbent length and height in healthy children; however, ULC, ULR, and ULG tend to slightly overestimate length and height in young infants and children. Further testing of ulnar length as a surrogate is warranted in physically impaired or nonambulatory children. PMID- 25031330 TI - Maternal urinary iodine concentration up to 1.0 mg/L is positively associated with birth weight, length, and head circumference of male offspring. AB - Adequate iodine status in early life is crucial for neurodevelopment. However, little is known about the effects of maternal iodine status during pregnancy on fetal growth. The present study investigated the potential impact of maternal iodine status during pregnancy on offspring birth size. This large prospective cohort study was nested in a Bangladeshi population-based randomized supplementation trial in pregnant women [MINIMat (Maternal and Infant Nutrition Interventions in Matlab)]. Urine samples obtained at 8 wk of gestation from 1617 women were analyzed for iodine and other elements, such as arsenic and cadmium, using inductively coupled plasma mass spectrometry. Anthropometric measurements at birth included weight, length, and head and chest circumference. Maternal urinary iodine concentrations (UICs) ranged from 0.020 to 10 mg/L, with a median of 0.30 mg/L. Below ~1.0 mg/L, UIC was significantly positively associated with birth weight and length. Birth weight and length increased by 9.3 g (95% CI: 2.9, 16) and 0.042 cm (95% CI: 0.0066, 0.076), respectively, for each 0.1-mg/L increase in maternal UIC. No associations were observed between UIC and head or chest circumference. When we stratified the analyses by newborn sex, the positive associations between maternal UIC (<1 mg/L) and measurements of size at birth were restricted to boys, with no evidence in girls. Among boys, the mean weight, length, and head circumference increased by 70 g (P = 0.019), 0.41 cm (P = 0.013), and 0.28 cm (P = 0.031) for every 0.5-mg/L increase in maternal UIC. Maternal iodine status was positively associated with weight, length, and head circumference in boys up to ~1 mg/L, which is well above the recommended maximum concentration of 0.5 mg/L. The associations leveled off at UIC >= 1 mg/L. Our findings support previous conclusions that the advantages of correcting potential iodine deficiency outweigh the risks of excess exposure. PMID- 25031331 TI - Carob pod insoluble fiber exerts anti-atherosclerotic effects in rabbits through sirtuin-1 and peroxisome proliferator-activated receptor-gamma coactivator 1alpha. AB - The aim of this study was to evaluate the potential effects of an insoluble dietary fiber from carob pod (IFC) (1 g ? kg(-1) ? d(-1) in the diet) on alterations associated with atherosclerosis in rabbits with dyslipidemia. Male New Zealand rabbits (n = 30) were fed the following diets for 8 wk: 1) a control diet (SF412; Panlab) as a control group representing normal conditions; 2) a control supplemented with 0.5% cholesterol + 14% coconut oil (DL) (SF302; Panlab) for 8 wk as a dyslipidemic group; and 3) a control containing 0.5% cholesterol + 14% coconut oil plus IFC (1 g ? kg(-1) ? d(-1)) (DL+IFC) for 8 wk. IFC was administered in a pellet mixed with the DL diet. The DL-fed group developed mixed dyslipidemia and atherosclerotic lesions, which were associated with endothelial dysfunction, inflammation, and fibrosis. Furthermore, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) protein expression in the aorta were reduced to 77% and 63% of the control group, respectively (P < 0.05), in these rabbits. Administration of IFC to DL-fed rabbits reduced the size of the aortic lesion significantly (DL, 15.2% and DL+IFC, 2.6%) and normalized acetylcholine-induced relaxation (maximal response: control, 89.3%; DL, 61.6%; DL+IFC, 87.1%; P < 0.05) and endothelial nitric oxide synthase expression (DL, 52% and DL+IFC, 104% of the control group). IFC administration to DL-fed rabbits also reduced cluster of differentiation 36 (DL, 148% and DL+IFC, 104% of the control group; P < 0.05), plasminogen activator inhibitor-1 (DL, 141% and DL+IFC, 107% of the control group), tumor necrosis factor-alpha (DL, 166% and DL+IFC, 120% of the control group), vascular cell adhesion molecule-1 (DL, 153% and DL+IFC, 110% of the control group), transforming growth factor-beta (DL, 173% and DL+IFC, 99% of the control group), and collagen I (DL, 157% and DL+IFC, 112% of the control group) in the aorta. These effects were accompanied by an enhancement of SIRT1 and PGC-1alpha (160% and 121% of the control group, respectively; P < 0.05) vascular expression. In summary, we demonstrated for the first time, to our knowledge, that administration of IFC reduces the development of atherosclerosis in rabbits. This effect seems to be related to an improvement in endothelial function and a reduction of inflammation and fibrosis, most probably as a consequence of the reduction of serum concentrations of cholesterol and triglycerides. Increased expression of aortic SIRT1 and PGC-1alpha could play an important role in the observed effects of IFC in rabbits with dyslipidemia. PMID- 25031332 TI - Green tea, black tea, and oolong tea polyphenols reduce visceral fat and inflammation in mice fed high-fat, high-sucrose obesogenic diets. AB - Green tea (GT) and caffeine in combination were shown to increase energy expenditure and fat oxidation, but less is known about the effects of black tea (BT) and oolong tea (OT). This study investigated whether decaffeinated polyphenol extracts from GT, BT, and OT decrease body fat and inflammation in male C57BL/6J mice fed high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose)] diets. Mice were fed either an HF/HS diet with 0.25% of polyphenol from GT, OT, or BT or a low-fat/high-sucrose [LF/HS (10.6% energy from fat, 25% energy from sucrose)] diet for 20 wk. Monomeric tea polyphenols were found in the liver and adipose tissue of mice fed the HF/HS diet with GT polyphenols (GTPs) and OT polyphenols (OTPs) but not BT polyphenols (BTPs). Treatment with GTPs, OTPs, BTPs, and an LF/HS diet led to significantly lower body weight, total visceral fat volume by MRI, and liver lipid weight compared with mice in the HF/HS control group. Only GTPs reduced food intake significantly by ~10%. GTP, BTP, and LF/HS-diet treatments significantly reduced serum monocyte chemotactic protein-1 (MCP-1) compared with HF/HS controls. In mesenteric fat, monocyte chemotactic protein-1 (Mcp1) gene expression was significantly decreased by treatment with GTPs, BTPs, OTPs, and an LF/HS diet and in liver tissue by GTP and BTP treatments. Mcp1 gene expression in epididymal fat was significantly decreased by the BTP and LF/HS diet interventions. In epididymal fat, consistent with an anti-inflammatory effect, adiponectin gene expression was significantly increased by GTPs and OTPs. Angiogenesis during adipose tissue expansion is anti inflammatory by maintaining adipocyte perfusion. We observed significantly increased gene expression of vascular endothelial growth factor A by GTPs and vascular endothelial growth factor receptor 2 by BTPs and the LF/HS diet and a decrease in pigment epithelium-derived factor gene expression by OTPs and BTPs. In summary, all 3 tea polyphenol extracts induced weight loss and anti inflammatory and angiogenic effects, although the tissue content of polyphenols differed significantly. PMID- 25031333 TI - Amino acid substitutions in PB1 of avian influenza viruses influence pathogenicity and transmissibility in chickens. AB - Amino acid substitutions were introduced into avian influenza virus PB1 in order to characterize the interaction between polymerase activity and pathogenicity. Previously, we used recombinant viruses containing the hemagglutinin (HA) and neuraminidase (NA) genes from the highly pathogenic avian influenza virus (HPAIV) H5N1 strain and other internal genes from two low-pathogenicity avian influenza viruses isolated from chicken and wild-bird hosts (LP and WB, respectively) to demonstrate that the pathogenicity of highly pathogenic avian influenza viruses (HPAIVs) of subtype H5N1 in chickens is regulated by the PB1 gene (Y. Uchida et al., J. Virol. 86:2686-2695, 2012, doi:http://dx.doi.org/10.1128/JVI.06374-11). In the present study, we introduced a C38Y substitution into WB PB1 and demonstrated that this substitution increased both polymerase activity in DF-1 cells in vitro and the pathogenicity of the recombinant viruses in chickens. The V14A substitution in LP PB1 reduced polymerase activity but did not affect pathogenicity in chickens. Interestingly, the V14A substitution reduced viral shedding and transmissibility. These studies demonstrate that increased polymerase activity correlates directly with enhanced pathogenicity, while decreased polymerase activity does not always correlate with pathogenicity and requires further analysis. IMPORTANCE: We identified 2 novel amino acid substitutions in the avian influenza virus PB1 gene that affect the characteristics of highly pathogenic avian influenza viruses (HPAIVs) of the H5N1 subtype, such as viral replication and polymerase activity in vitro and pathogenicity and transmissibly in chickens. An amino acid substitution at residue 38 in PB1 directly affected pathogenicity in chickens and was associated with changes in polymerase activity in vitro. A substitution at residue 14 reduced polymerase activity in vitro, while its effects on pathogenicity and transmissibility depended on the constellation of internal genes. PMID- 25031335 TI - A substitution in the transmembrane region of the glycoprotein leads to an unstable attenuation of Machupo virus. AB - Machupo virus (MACV) is the etiologic agent of Bolivian hemorrhagic fever (BHF). Utilizing a reverse-genetics system recently developed, we report the rescue of a rationally modified recombinant MACV containing a single mutation in the transmembrane region of the glycoprotein. Following challenge of susceptible mice, we identified a significant reduction in virulence in the novel virus. We also identified an instability leading to reversion of the single mutation to a wild-type genotype. PMID- 25031334 TI - Herpes simplex virus gE/gI extracellular domains promote axonal transport and spread from neurons to epithelial cells. AB - Following reactivation from latency, there are two distinct steps in the spread of herpes simplex virus (HSV) from infected neurons to epithelial cells: (i) anterograde axonal transport of virus particles from neuron bodies to axon tips and (ii) exocytosis and spread of extracellular virions across cell junctions into adjacent epithelial cells. The HSV heterodimeric glycoprotein gE/gI is important for anterograde axonal transport, and gE/gI cytoplasmic domains play important roles in sorting of virus particles into axons. However, the roles of the large (~400-residue) gE/gI extracellular (ET) domains in both axonal transport and neuron-to-epithelial cell spread have not been characterized. Two gE mutants, gE-277 and gE-348, contain small insertions in the gE ET domain, fold normally, form gE/gI heterodimers, and are incorporated into virions. Both gE-277 and gE-348 did not function in anterograde axonal transport; there were markedly reduced numbers of viral capsids and glycoproteins compared with wild-type HSV. The defects in axonal transport were manifest in neuronal cell bodies, involving missorting of HSV capsids before entry into proximal axons. Although there were diminished numbers of mutant gE-348 capsids and glycoproteins in distal axons, there was efficient spread to adjacent epithelial cells, similar to wild-type HSV. In contrast, virus particles produced by HSV gE-277 spread poorly to epithelial cells, despite numbers of virus particles similar to those for HSV gE 348. These results genetically separate the two steps in HSV spread from neurons to epithelial cells and demonstrate that the gE/gI ET domains function in both processes. IMPORTANCE: An essential phase of the life cycle of herpes simplex virus (HSV) and other alphaherpesviruses is the capacity to reactivate from latency and then spread from infected neurons to epithelial tissues. This spread involves at least two steps: (i) anterograde transport to axon tips followed by (ii) exocytosis and extracellular spread from axons to epithelial cells. HSV gE/gI is a glycoprotein that facilitates this virus spread, although by poorly understood mechanisms. Here, we show that the extracellular (ET) domains of gE/gI promote the sorting of viral structural proteins into proximal axons to begin axonal transport. However, the gE/gI ET domains also participate in the extracellular spread from axon tips across cell junctions to epithelial cells. Understanding the molecular mechanisms involved in gE/gI-mediated sorting of virus particles into axons and extracellular spread to adjacent cells is fundamentally important for identifying novel targets to reduce alphaherpesvirus disease. PMID- 25031336 TI - Histone deacetylase 6 inhibits influenza A virus release by downregulating the trafficking of viral components to the plasma membrane via its substrate, acetylated microtubules. AB - Mammalian cells produce many proteins, such as IFITM3, ISG15, MxA, and viperin, that inhibit influenza A virus (IAV) infection. Here, we show that a new class of host protein, histone deacetylase 6 (HDAC6), inhibits IAV infection. We found that HDAC6-overexpressing cells release about 3-fold less IAV progeny, whereas HDAC6-depleted cells release about 6-fold more IAV progeny. The deacetylase activity of HDAC6 played a role in its anti-IAV function as tubacin, a specific small-molecule inhibitor of HDAC6, increased the release of IAV progeny in a dose dependent manner. Further, as visualized by electron microscopy, tubacin-treated cells showed an increase in IAV budding at the plasma membrane, the site of IAV assembly. Tubacin is a domain-specific inhibitor and binds to one of the two HDAC6 catalytic domains possessing tubulin deacetylase activity. This indicated the potential involvement of acetylated microtubules in the trafficking of viral components to the plasma membrane. Indeed, as quantified by flow cytometry, there was about a 2.0- to 2.5-fold increase and about a 2.0-fold decrease in the amount of viral envelope protein hemagglutinin present on the plasma membrane of tubacin treated/HDAC6-depleted and HDAC6-overexpressing cells, respectively. In addition, the viral ribonucleoprotein complex was colocalized with acetylated microtubule filaments, and viral nucleoprotein coimmunoprecipitated with acetylated tubulin. Together, our findings indicate that HDAC6 is an anti-IAV host factor and exerts its anti-IAV function by negatively regulating the trafficking of viral components to the host cell plasma membrane via its substrate, acetylated microtubules. IMPORTANCE: Host cells produce many proteins that have the natural ability to restrict influenza virus infection. Here, we discovered that another host protein, histone deacetylase 6 (HDAC6), inhibits influenza virus infection. We demonstrate that HDAC6 exerts its anti-influenza virus function by negatively regulating the trafficking of viral components to the site of influenza virus assembly via its substrate, acetylated microtubules. HDAC6 is a multisubstrate enzyme and regulates multiple cellular pathways, including the ones leading to various cancers, neurodegenerative diseases, and inflammatory disorders. Therefore, several drugs targeting HDAC6 are under clinical development for the treatment of a wide range of diseases. Influenza virus continues to be a major global public health problem due to regular emergence of drug-resistant and novel influenza virus strains in humans. As an alternative antiviral strategy, HDAC6 modulators could be employed to stimulate the anti-influenza virus potential of endogenous HDAC6 to inhibit influenza virus infection. PMID- 25031337 TI - P2X-selective purinergic antagonists are strong inhibitors of HIV-1 fusion during both cell-to-cell and cell-free infection. AB - Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4+ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cell-to-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to cell transfer of HIV-1. During both cell-free and cell-to-cell CD4+ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4+ T lymphocytes by both cell-free and cell-to-cell transmission. IMPORTANCE: This study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a stepwise determination of when these compounds inhibit HIV-1 infection. These data provide a rationale for the development of novel antiretroviral therapies that have a dual role in both direct antiviral activity and the reduction of HIV-associated inflammation. Purinergic antagonists are shown here to have equivalent efficacy in inhibiting HIV infection via cell-free and cell-to-cell infection, and it is shown that purinergic receptors could provide an attractive therapeutic anti-HIV target that might avoid resistance by targeting a host signaling pathway that potently regulates HIV infection. The high-throughput screen of HIV-1 fusion inhibitors further defines P2X-selective compounds among the purinergic compounds as being the most potent HIV entry inhibitors. Clinical studies on these drugs for other inflammatory indications suggest that they are safe, and thus, if developed for use as anti-HIV agents, they could reduce both HIV replication and HIV-related inflammation. PMID- 25031338 TI - Inhibition of antiviral innate immunity by birnavirus VP3 protein via blockage of viral double-stranded RNA binding to the host cytoplasmic RNA detector MDA5. AB - Chicken MDA5 (chMDA5), the sole known pattern recognition receptor for cytoplasmic viral RNA in chickens, initiates type I interferon (IFN) production. Infectious bursal disease virus (IBDV) evades host innate immunity, but the mechanism is unclear. We report here that IBDV inhibited antiviral innate immunity via the chMDA5-dependent signaling pathway. IBDV infection did not induce efficient type I interferon (IFN) production but antagonized the antiviral activity of beta interferon (IFN-beta) in DF-1 cells pretreated with IFN alpha/beta. Dual-luciferase assays and inducible expression systems demonstrated that IBDV protein VP3 significantly inhibited IFN-beta expression stimulated by naked IBDV genomic double-stranded RNA (dsRNA). The VP3 protein competed strongly with chMDA5 to bind IBDV genomic dsRNA in vitro and in vivo, and VP3 from other birnaviruses also bound dsRNA. Site-directed mutagenesis confirmed that deletion of the VP3 dsRNA binding domain restored IFN-beta expression. Our data demonstrate that VP3 inhibits antiviral innate immunity by blocking binding of viral genomic dsRNA to MDA5. IMPORTANCE: MDA5, a known pattern recognition receptor and cytoplasmic viral RNA sensor, plays a critical role in host antiviral innate immunity. Many pathogens escape or inhibit the host antiviral immune response, but the mechanisms involved are unclear for most pathogens. We report here that birnaviruses inhibit host antiviral innate immunity via the MDA5 dependent signaling pathway. The antiviral innate immune system involving IFN beta did not function effectively during birnavirus infection, and the viral protein VP3 significantly inhibited IFN-beta expression stimulated by naked viral genomic dsRNA. We also show that VP3 blocks MDA5 binding to viral genomic dsRNA in vitro and in vivo. Our data reveal that birnavirus-encoded viral protein VP3 is an inhibitor of the antiviral innate immune response and inhibits the antiviral innate immune response via the MDA5-dependent signaling pathway. PMID- 25031339 TI - Epstein-Barr virus EBNA1 protein regulates viral latency through effects on let-7 microRNA and dicer. AB - The EBNA1 protein of Epstein-Barr virus (EBV) plays multiple roles in EBV latent infection, including altering cellular pathways relevant for cancer. Here we used microRNA (miRNA) cloning coupled with high-throughput sequencing to identify the effects of EBNA1 on cellular miRNAs in two nasopharyngeal carcinoma cell lines. EBNA1 affected a small percentage of cellular miRNAs in both cell lines, in particular, upregulating multiple let-7 family miRNAs, including let-7a. The effects of EBNA1 on let-7a were verified by demonstrating that EBNA1 silencing in multiple EBV-positive carcinomas downregulated let-7a. Accordingly, the let-7a target, Dicer, was found to be partially downregulated by EBNA1 expression (at the mRNA and protein levels) and upregulated by EBNA1 silencing in EBV-positive cells. Reporter assays based on the Dicer 3' untranslated region with and without let-7a target sites indicated that the effects of EBNA1 on Dicer were mediated by let-7a. EBNA1 was also found to induce the expression of let-7a primary RNAs in a manner dependent on the EBNA1 transcriptional activation region, suggesting that EBNA1 induces let-7a by transactivating the expression of its primary transcripts. Consistent with previous reports that Dicer promotes EBV reactivation, we found that a let-7a mimic inhibited EBV reactivation to the lytic cycle, while a let-7 sponge increased reactivation. The results provide a mechanism by which EBNA1 could promote EBV latency by inducing let-7 miRNAs. IMPORTANCE: The EBNA1 protein of Epstein-Barr virus (EBV) contributes in multiple ways to the latent mode of EBV infection that leads to lifelong infection. In this study, we identify a mechanism by which EBNA1 helps to maintain EBV infection in a latent state. This involves induction of a family of microRNAs (let-7 miRNAs) that in turn decreases the level of the cellular protein Dicer. We demonstrate that let-7 miRNAs inhibit the reactivation of latent EBV, providing an explanation for our previous observation that EBNA1 promotes latency. In addition, since decreased levels of Dicer have been associated with metastatic potential, EBNA1 may increase metastases by downregulating Dicer. PMID- 25031340 TI - Prolidase is required for early trafficking events during influenza A virus entry. AB - Influenza A virus (IAV) entry is a multistep process that requires the interaction of the virus with numerous host factors. In this study, we demonstrate that prolidase (PEPD) is a cellular factor required by IAV for successful entry into target cells. PEPD was selected as a candidate during an entry screen performed on nonvalidated primary hits from previously published genome-wide small interfering RNA (siRNA) screens. siRNA-mediated depletion of PEPD resulted in the decreased growth of IAV during mono- and multicycle growth. This growth defect was independent of cell type or virus strain. Furthermore, IAV restriction was apparent as early as 3 h postinfection, and experiments in the absence of protein biosynthesis revealed that the nuclear import of viral ribonucleoprotein complexes (vRNPs) was already blocked in the absence of PEPD. These results led us to investigate which step during entry was affected. Receptor expression, IAV attachment, or IAV internalization was not dependent on the presence of PEPD. However, when looking at the distribution of incoming IAV particles in PEPD-knockdown cells, we found a localization pattern that differed from that in control cells: IAV mostly localized to the cell periphery, and consequently, viral particles displayed reduced colocalization with early and late endosome markers and fusion between viral and endosomal membranes was strongly reduced. Finally, experiments using a competitive inhibitor of PEPD catalytic activity suggested that the enzymatic function of the dipeptidase is required for its proviral effect on IAV entry. In sum, this study establishes PEPD as a novel entry factor required for early endosomal trafficking of IAV. IMPORTANCE: Influenza A virus (IAV) continues to be a constant threat to public health. As IAV relies on its host cell for replication, the identification of host factors required by the virus is of importance. First, such studies often reveal novel functions of cellular factors and can extend our knowledge of cellular processes. Second, we can further our understanding of processes that are required for the entry of IAV into target cells. Third, the identification of host factors that contribute to IAV entry will increase the number of potential targets for the development of novel antiviral drugs that are of urgent need. Our study identifies prolidase (PEPD) to be a novel entry factor required by IAV for correct routing within the endosomal compartment following virus internalization. Thereby, we link PEPD, which has been shown to play a role during collagen recycling and growth factor signaling, to early events of viral infection. PMID- 25031341 TI - Expression of porcine fusion protein IRF7/3(5D) efficiently controls foot-and mouth disease virus replication. AB - Several studies have demonstrated that the delivery of type I, II, or III interferons (IFNs) by inoculation of a replication-defective human adenovirus 5 (Ad5) vector expressing IFNs can effectively control foot-and-mouth disease (FMD) in cattle and swine during experimental infections. However, relatively high doses are required to achieve protection. In this study, we identified the functional properties of a porcine fusion protein, poIRF7/3(5D), as a biotherapeutic and enhancer of IFN activity against FMD virus (FMDV). We showed that poIRF7/3(5D) is a potent inducer of type I IFNs, including alpha IFN (IFN alpha), IFN-beta, and IFN-omega but not type III IFN (interleukin-28B), without inducing cytotoxicity. Expression of poIRF7/3(5D) significantly and steadily reduced FMDV titers by up to 6 log10 units in swine and bovine cell lines. Treatment with an IFN receptor inhibitor (B18R) combined with an anti-IFN-alpha antibody neutralized the antiviral activity in the supernatants of cells transduced with an Ad5 vector expressing poIRF7/3(5D) [Ad5-poIRF7/3(5D)]. However, several transcripts with known antiviral function, including type I IFNs, were still highly upregulated (range of increase, 8-fold to over 500-fold) by poIRF7/3(5D) in the presence of B18R. Furthermore, the sera of mice treated with Ad5-poIRF7/3(5D) showed antiviral activity that was associated with the induction of high levels of IFN-alpha and resulted in complete protection against FMDV challenge at 6, 24, or 48 h posttreatment. This study highlights for the first time the antiviral potential of Ad5-poIRF7/3(5D) in vitro and in vivo against FMDV. IMPORTANCE: FMD remains one of the most devastating diseases that affect livestock worldwide. Effective vaccine formulations are available but are serotype specific and require approximately 7 days before they are able to elicit protective immunity. We have shown that vector-delivered IFN is an option to protect animals against many FMDV serotypes as soon as 24 h and for about 4 days postadministration. Here we demonstrate that delivery of a constitutively active transcription factor that induces the production of endogenous IFNs and potentially other antiviral genes is a viable strategy to protect against FMD. PMID- 25031342 TI - Adeno-associated virus type 2 wild-type and vector-mediated genomic integration profiles of human diploid fibroblasts analyzed by third-generation PacBio DNA sequencing. AB - Genome-wide analysis of adeno-associated virus (AAV) type 2 integration in HeLa cells has shown that wild-type AAV integrates at numerous genomic sites, including AAVS1 on chromosome 19q13.42. Multiple GAGY/C repeats, resembling consensus AAV Rep-binding sites are preferred, whereas rep-deficient AAV vectors (rAAV) regularly show a random integration profile. This study is the first study to analyze wild-type AAV integration in diploid human fibroblasts. Applying high throughput third-generation PacBio-based DNA sequencing, integration profiles of wild-type AAV and rAAV are compared side by side. Bioinformatic analysis reveals that both wild-type AAV and rAAV prefer open chromatin regions. Although genomic features of AAV integration largely reproduce previous findings, the pattern of integration hot spots differs from that described in HeLa cells before. DNase-Seq data for human fibroblasts and for HeLa cells reveal variant chromatin accessibility at preferred AAV integration hot spots that correlates with variant hot spot preferences. DNase-Seq patterns of these sites in human tissues, including liver, muscle, heart, brain, skin, and embryonic stem cells further underline variant chromatin accessibility. In summary, AAV integration is dependent on cell-type-specific, variant chromatin accessibility leading to random integration profiles for rAAV, whereas wild-type AAV integration sites cluster near GAGY/C repeats. IMPORTANCE: Adeno-associated virus type 2 (AAV) is assumed to establish latency by chromosomal integration of its DNA. This is the first genome-wide analysis of wild-type AAV2 integration in diploid human cells and the first to compare wild-type to recombinant AAV vector integration side by side under identical experimental conditions. Major determinants of wild-type AAV integration represent open chromatin regions with accessible consensus AAV Rep binding sites. The variant chromatin accessibility of different human tissues or cell types will have impact on vector targeting to be considered during gene therapy. PMID- 25031343 TI - Phosphorylation of hepatitis C virus RNA polymerases ser29 and ser42 by protein kinase C-related kinase 2 regulates viral RNA replication. AB - Hepatitis C virus (HCV) nonstructural protein 5B (NS5B), an RNA-dependent RNA polymerase (RdRp), is the key enzyme for HCV RNA replication. We previously showed that HCV RdRp is phosphorylated by protein kinase C-related kinase 2 (PRK2). In the present study, we used biochemical and reverse-genetics approaches to demonstrate that HCV NS5B phosphorylation is crucial for viral RNA replication in cell culture. Two-dimensional phosphoamino acid analysis revealed that PRK2 phosphorylates NS5B exclusively at its serine residues in vitro and in vivo. Using in vitro kinase assays and mass spectrometry, we identified two phosphorylation sites, Ser29 and Ser42, in the Delta1 finger loop region that interacts with the thumb subdomain of NS5B. Colony-forming assays using drug selectable HCV subgenomic RNA replicons revealed that preventing phosphorylation by Ala substitution at either Ser29 or Ser42 impairs HCV RNA replication. Furthermore, reverse-genetics studies using HCV infectious clones encoding phosphorylation-defective NS5B confirmed the crucial role of these PRK2 phosphorylation sites in viral RNA replication. Molecular-modeling studies predicted that the phosphorylation of NS5B stabilizes the interactions between its Delta1 loop and thumb subdomain, which are required for the formation of the closed conformation of NS5B known to be important for de novo RNA synthesis. Collectively, our results provide evidence that HCV NS5B phosphorylation has a positive regulatory role in HCV RNA replication. IMPORTANCE: While the role of RNA-dependent RNA polymerases (RdRps) in viral RNA replication is clear, little is known about their functional regulation by phosphorylation. In this study, we addressed several important questions about the function and structure of phosphorylated hepatitis C virus (HCV) nonstructural protein 5B (NS5B). Reverse genetics studies with HCV replicons encoding phosphorylation-defective NS5B mutants and analysis of their RdRp activities revealed previously unidentified NS5B protein features related to HCV replication and NS5B phosphorylation. These attributes most likely reflect potential structural changes induced by phosphorylation in the Delta1 finger loop region of NS5B with two identified phosphate acceptor sites, Ser29 and Ser42, which may transiently affect the closed conformation of NS5B. Elucidating the effects of dynamic changes in NS5B phosphorylation status during viral replication and their impacts on RNA synthesis will improve our understanding of the molecular mechanisms of NS5B phosphorylation-mediated regulation of HCV replication. PMID- 25031344 TI - Annexin V incorporated into influenza virus particles inhibits gamma interferon signaling and promotes viral replication. AB - During the budding process, influenza A viruses (IAVs) incorporate multiple host cell membrane proteins. However, for most of them, their significance in viral morphogenesis and infectivity remains unknown. We demonstrate here that the expression of annexin V (A5) is upregulated at the cell surface upon IAV infection and that a substantial proportion of the protein is present in lipid rafts, the site of virus budding. Western blotting and immunogold analysis of highly purified IAV particles showed the presence of A5 in the virion. Significantly, gamma interferon (IFN-gamma)-induced Stat phosphorylation and IFN gamma-induced 10-kDa protein (IP-10) production in macrophage-derived THP-1 cells was inhibited by purified IAV particles. Disruption of the IFN-gamma signaling pathway was A5 dependent since downregulation of its expression or its blockage reversed the inhibition and resulted in decreased viral replication in vitro. The functional significance of these results was also observed in vivo. Thus, IAVs can subvert the IFN-gamma antiviral immune response by incorporating A5 into their envelope during the budding process. IMPORTANCE: Many enveloped viruses, including influenza A viruses, bud from the plasma membrane of their host cells and incorporate cellular surface proteins into viral particles. However, for the vast majority of these proteins, only the observation of their incorporation has been reported. We demonstrate here that the host protein annexin V is specifically incorporated into influenza virus particles during the budding process. Importantly, we showed that packaged annexin V counteracted the antiviral activity of gamma interferon in vitro and in vivo. Thus, these results showed that annexin V incorporated in the viral envelope of influenza viruses allow viral escape from immune surveillance. Understanding the role of host incorporated protein into virions may reveal how enveloped RNA viruses hijack the host cell machinery for their own purposes. PMID- 25031345 TI - In vivo reactivation of latent herpes simplex virus 1 in mice can occur in the brain before occurring in the trigeminal ganglion. AB - Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ. IMPORTANCE: Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain. PMID- 25031346 TI - Up to four distinct polypeptides are produced from the gamma34.5 open reading frame of herpes simplex virus 2. AB - The herpes simplex virus 1 (HSV-1) ICP34.5 protein strongly influences neurovirulence and regulates several cellular antiviral responses. Despite the clinical importance of HSV-2, relatively little is known about its ICP34.5 ortholog. We found that HSV-2 produces up to four distinct forms of ICP34.5 in infected cells: a full-length protein, one shorter form sharing the N terminus, and two shorter forms sharing the C terminus. These forms appeared with similar kinetics and accumulated in cells over much of the replication cycle. We confirmed that the N-terminal form is translated from the primary unspliced transcript to a stop codon within the intron unique to HSV-2 gamma34.5. We found that the N-terminal form was produced in a variety of cell types and by 9 of 10 clinical isolates. ICP27 influenced but was not required for expression of the N terminal form. Western blotting and reverse transcription-PCR indicated the C terminal forms did not contain the N terminus and were not products of alternative splicing or internal transcript initiation. Expression plasmids encoding methionine at amino acids 56 and 70 generated products that comigrated in SDS-PAGE with the C1 and C2 forms, respectively, and mutation of these sites abolished C1 and C2. Using a recombinant HSV-2 encoding hemagglutinin (HA)-tagged ICP34.5, we demonstrated that the C-terminal forms were also produced during infection of many human and mouse cell types but were not detectable in mouse primary neurons. The protein diversity generated from the HSV-2 gamma34.5 open reading frame implies additional layers of cellular regulation through potential independent activities associated with the various forms of ICP34.5. IMPORTANCE: The herpes simplex virus 1 (HSV-1) protein ICP34.5, encoded by the gamma34.5 gene, interferes with several host defense mechanisms by binding cellular proteins that would otherwise stimulate the cell's autophagic, translational arrest, and type I interferon responses to virus infection. ICP34.5 also plays a crucial role in determining the severity of nervous system infections with HSV-1 and HSV-2. The HSV-2 gamma34.5 gene contains an intron not present in HSV-1 gamma34.5. A shorter N-terminal form of HSV-2 ICP34.5 can be translated from the unspliced gamma34.5 mRNA. Here, we show that two additional forms consisting of the C-terminal portion of ICP34.5 are generated in infected cells. Production of these N- and C-terminal forms is highly conserved among HSV-2 strains, including many clinical isolates, and they are broadly expressed in several cell types, but not mouse primary neurons. Multiple ICP34.5 polypeptides add additional complexity to potential functional interactions influencing HSV-2 neurovirulence. PMID- 25031347 TI - Seed sequence-matched controls reveal limitations of small interfering RNA knockdown in functional and structural studies of hepatitis C virus NS5A-MOBKL1B interaction. AB - Hepatitis C virus (HCV) is a widespread human pathogen causing liver cirrhosis and cancer. Similar to the case for other viruses, HCV depends on host and viral factors to complete its life cycle. We used proteomic and yeast two-hybrid approaches to elucidate host factors involved in HCV nonstructural protein NS5A function and found that MOBKL1B interacts with NS5A. Initial experiments with small interfering RNA (siRNA) knockdown suggesting a role in HCV replication led us to examine the interaction using biochemical and structural approaches. As revealed by a cocrystal structure of a core MOBKL1B-NS5A peptide complex at 1.95 A, NS5A binds to a hydrophobic patch on the MOBKL1B surface. Biosensor binding assays identified a highly conserved, 18-amino-acid binding site in domain II of NS5A, which encompasses residues implicated in cyclophilin A (CypA)-dependent HCV RNA replication. However, a CypA-independent HCV variant had reduced replication in MOBKL1B knockdown cells, even though its NS5A does not interact with MOBKL1B. These discordant results prompted more extensive studies of MOBKL1B gene knockdowns, which included additional siRNAs and specifically matched seed sequence siRNA controls. We found that reduced virus replication after treating cells with MOBKL1B siRNA was actually due to off-target inhibition, which indicated that the initial finding of virus replication dependence on the MOBKL1B NS5A interaction was incorrect. Ultimately, using several approaches, we found no relationship of the MOBKL1B-NS5A interaction to virus replication. These findings collectively serve as a reminder to investigators and scientific reviewers of the pervasive impact of siRNA off-target effects on interpretation of biological data. IMPORTANCE: Our study illustrates an underappreciated shortcoming of siRNA gene knockdown technology. We initially identified a cellular protein, MOBKL1B, as a binding partner with the NS5A protein of hepatitis C virus (HCV). MOBKL1B siRNA, but not irrelevant RNA, treatment was associated with both reduced virus replication and the absence of MOBKL1B. Believing that HCV replication depended on the MOBKL1B-NS5A interaction, we carried out structural and biochemical analyses. Unexpectedly, an HCV variant lacking the MOBKL1B-NS5A interaction could not replicate after cells were treated with MOBKL1B siRNA. By repeating the MOBKL1B siRNA knockdowns and including seed sequence-matched siRNA instead of irrelevant siRNA as a control, we found that the MOBKL1B siRNAs utilized had off target inhibitory effects on virus replication. Collectively, our results suggest that stricter controls must be utilized in all RNA interference (RNAi)-mediated gene knockdown experiments to ensure sound conclusions and a reliable scientific knowledge database. PMID- 25031348 TI - Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile virus infection. AB - Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2mu/mu) in several Irf5-/- mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5-/-*Dock2wt/wt mice (here called Irf5-/- mice) and independently generated CMV-Cre Irf5fl/fl mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5-/- and CMV-Cre Irf5fl/fl mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5-/- mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5-/- mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. IMPORTANCE: Although the roles of IRF3 and IRF7 in orchestrating innate and adaptive immunity after viral infection are established, the function of the related transcription factor IRF5 remains less certain. Prior studies in Irf5-/- mice reported conflicting results as to the contribution of IRF5 in regulating type I interferon and adaptive immune responses. The lack of clarity may stem from a recently discovered homozygous loss-of-function mutation of the immunoregulatory gene Dock2 in several colonies of Irf5-/- mice. Here, using a mouse model with a deficiency in IRF5 and wild-type Dock2 alleles, we investigated how IRF5 modulates West Nile virus (WNV) pathogenesis and host immune responses. Our in vivo studies indicate that IRF5 has a key role in shaping the early proinflammatory cytokine response in the draining lymph node, which impacts immunity and control of WNV infection. PMID- 25031349 TI - Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an African bat. AB - The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes lethal respiratory infections mainly on the Arabian Peninsula. The evolutionary origins of MERS-CoV are unknown. We determined the full genome sequence of a CoV directly from fecal material obtained from a South African Neoromicia capensis bat (NeoCoV). NeoCoV shared essential details of genome architecture with MERS CoV. Eighty-five percent of the NeoCoV genome was identical to MERS-CoV at the nucleotide level. Based on taxonomic criteria, NeoCoV and MERS-CoV belonged to one viral species. The presence of a genetically divergent S1 subunit within the NeoCoV spike gene indicated that intraspike recombination events may have been involved in the emergence of MERS-CoV. NeoCoV constitutes a sister taxon of MERS CoV, placing the MERS-CoV root between a recently described virus from African camels and all other viruses. This suggests a higher level of viral diversity in camels than in humans. Together with serologic evidence for widespread MERS-CoV infection in camelids sampled up to 20 years ago in Africa and the Arabian Peninsula, the genetic data indicate that camels act as sources of virus for humans rather than vice versa. The majority of camels on the Arabian Peninsula is imported from the Greater Horn of Africa, where several Neoromicia species occur. The acquisition of MERS-CoV by camels from bats might have taken place in sub Saharan Africa. Camelids may represent mixing vessels for MERS-CoV and other mammalian CoVs. IMPORTANCE: It is unclear how, when, and where the highly pathogenic MERS-CoV emerged. We characterized the full genome of an African bat virus closely related to MERS-CoV and show that human, camel, and bat viruses belong to the same viral species. The bat virus roots the phylogenetic tree of MERS-CoV, providing evidence for an evolution of MERS-CoV in camels that preceded that in humans. The revised tree suggests that humans are infected by camels rather than vice versa. Although MERS-CoV cases occur mainly on the Arabian Peninsula, the data from this study together with serologic and molecular investigations of African camels indicate that the initial host switch from bats may have taken place in Africa. The emergence of MERS-CoV likely involved exchanges of genetic elements between different viral ancestors. These exchanges may have taken place either in bat ancestors or in camels acting as mixing vessels for viruses from different hosts. PMID- 25031350 TI - Dynamic regulation of host restriction factor expression over the course of HIV-1 infection in vivo. AB - In this study, we investigated the expression levels of host restriction factors in six untreated HIV-1-positive patients over the course of infection. We found that the host restriction factor gene expression profile consistently increased over time and was significantly associated with CD4+ T cell activation and viral load. Our data are among the first to demonstrate the dynamic nature of host restriction factors in vivo over time. PMID- 25031351 TI - A viral protein mediates superinfection exclusion at the whole-organism level but is not required for exclusion at the cellular level. AB - Superinfection exclusion (SIE), the ability of an established virus infection to interfere with a secondary infection by the same or a closely related virus, has been described for different viruses, including important pathogens of humans, animals, and plants. Citrus tristeza virus (CTV), a positive-sense RNA virus, represents a valuable model system for studying SIE due to the existence of several phylogenetically distinct strains. Furthermore, CTV allows SIE to be examined at the whole-organism level. Previously, we demonstrated that SIE by CTV is a virus-controlled function that requires the viral protein p33. In this study, we show that p33 mediates SIE at the whole-organism level, while it is not required for exclusion at the cellular level. Primary infection of a host with a fluorescent protein-tagged CTV variant lacking p33 did not interfere with the establishment of a secondary infection by the same virus labeled with a different fluorescent protein. However, cellular coinfection by both viruses was rare. The obtained observations, along with estimates of the cellular multiplicity of infection (MOI) and MOI model selection, suggested that low levels of cellular coinfection appear to be best explained by exclusion at the cellular level. Based on these results, we propose that SIE by CTV is operated at two levels--the cellular and the whole-organism levels--by two distinct mechanisms that could function independently. This novel aspect of viral SIE highlights the intriguing complexity of this phenomenon, further understanding of which may open up new avenues to manage virus diseases. IMPORTANCE: Many viruses exhibit superinfection exclusion (SIE), the ability of an established virus infection to interfere with a secondary infection by related viruses. SIE plays an important role in the pathogenesis and evolution of virus populations. The observations described here suggest that SIE could be controlled independently at different levels of the host: the whole-organism level or the level of individual cells. The p33 protein of citrus tristeza virus (CTV), an RNA virus, was shown to mediate SIE at the whole-organism level, while it appeared not to be required for exclusion at the cellular level. SIE by CTV is, therefore, highly complex and appears to use mechanisms different from those proposed for other viruses. A better understanding of this phenomenon may lead to the development of new strategies for controlling viral diseases in human populations and agroecosystems. PMID- 25031352 TI - Structural insights into the human metapneumovirus glycoprotein ectodomain. AB - Human metapneumovirus is a major cause of respiratory tract infections worldwide. Previous reports have shown that the viral attachment glycoprotein (G) modulates innate and adaptive immune responses, leading to incomplete immunity and promoting reinfection. Using bioinformatics analyses, static light scattering, and small-angle X-ray scattering, we show that the extracellular region of G behaves as a heavily glycosylated, intrinsically disordered polymer. We discuss potential implications of these findings for the modulation of immune responses by G. PMID- 25031353 TI - Novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo. AB - Neurotropic alphaviruses, including western, eastern, and Venezuelan equine encephalitis viruses, cause serious and potentially fatal central nervous system infections in humans for which no currently approved therapies exist. We previously identified a series of thieno[3,2-b]pyrrole derivatives as novel inhibitors of neurotropic alphavirus replication, using a cell-based phenotypic assay (W. Peng et al., J. Infect. Dis. 199:950-957, 2009, doi:http://dx.doi.org/10.1086/597275), and subsequently developed second- and third-generation indole-2-carboxamide derivatives with improved potency, solubility, and metabolic stability (J. A. Sindac et al., J. Med. Chem. 55:3535 3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; J. A. Sindac et al., J. Med. Chem. 56:9222-9241, 2013, http://dx.doi.org/10.1021/jm401330r). In this report, we describe the antiviral activity of the most promising third-generation lead compound, CCG205432, and closely related analogs CCG206381 and CCG209023. These compounds have half-maximal inhibitory concentrations of ~1 MUM and selectivity indices of >100 in cell-based assays using western equine encephalitis virus replicons. Furthermore, CCG205432 retains similar potency against fully infectious virus in cultured human neuronal cells. These compounds show broad inhibitory activity against a range of RNA viruses in culture, including members of the Togaviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Although their exact molecular target remains unknown, mechanism-of-action studies reveal that these novel indole-based compounds target a host factor that modulates cap-dependent translation. Finally, we demonstrate that both CCG205432 and CCG209023 dampen clinical disease severity and enhance survival of mice given a lethal western equine encephalitis virus challenge. These studies demonstrate that indole-2-carboxamide compounds are viable candidates for continued preclinical development as inhibitors of neurotropic alphaviruses and, potentially, of other RNA viruses. IMPORTANCE There are currently no approved drugs to treat infections with alphaviruses. We previously identified a novel series of compounds with activity against these potentially devastating pathogens (J. A. Sindac et al., J. Med. Chem. 55:3535-3545, 2012, doi:http://dx.doi.org/10.1021/jm300214e; W. Peng et al., J. Infect. Dis. 199:950 957, 2009, doi:http://dx.doi.org/10.1086/597275; J. A. Sindac et al., J. Med. Chem. 56:9222-9241, 2013, http://dx.doi.org/10.1021/jm401330r). We have now produced third-generation compounds with enhanced potency, and this manuscript provides detailed information on the antiviral activity of these advanced generation compounds, including activity in an animal model. The results of this study represent a notable achievement in the continued development of this novel class of antiviral inhibitors. PMID- 25031354 TI - Potent neutralization of vaccinia virus by divergent murine antibodies targeting a common site of vulnerability in L1 protein. AB - Vaccinia virus (VACV) L1 is an important target for viral neutralization and has been included in multicomponent DNA or protein vaccines against orthopoxviruses. To further understand the protective mechanism of the anti-L1 antibodies, we generated five murine anti-L1 monoclonal antibodies (MAbs), which clustered into 3 distinct epitope groups. While two groups of anti-L1 failed to neutralize, one group of 3 MAbs potently neutralized VACV in an isotype- and complement independent manner. This is in contrast to neutralizing antibodies against major VACV envelope proteins, such as H3, D8, or A27, which failed to completely neutralize VACV unless the antibodies are of complement-fixing isotypes and complement is present. Compared to nonneutralizing anti-L1 MAbs, the neutralization antibodies bound to the recombinant L1 protein with a significantly higher affinity and also could bind to virions. By using a variety of techniques, including the isolation of neutralization escape mutants, hydrogen/deuterium exchange mass spectrometry, and X-ray crystallography, the epitope of the neutralizing antibodies was mapped to a conformational epitope with Asp35 as the key residue. This epitope is similar to the epitope of 7D11, a previously described potent VACV neutralizing antibody. The epitope was recognized mainly by CDR1 and CDR2 of the heavy chain, which are highly conserved among antibodies recognizing the epitope. These antibodies, however, had divergent light-chain and heavy-chain CDR3 sequences. Our study demonstrates that the conformational L1 epitope with Asp35 is a common site of vulnerability for potent neutralization by a divergent group of antibodies. IMPORTANCE: Vaccinia virus, the live vaccine for smallpox, is one of the most successful vaccines in human history, but it presents a level of risk that has become unacceptable for the current population. Studying the immune protection mechanism of smallpox vaccine is important for understanding the basic principle of successful vaccines and the development of next-generation, safer vaccines for highly pathogenic orthopoxviruses. We studied antibody targets in smallpox vaccine by developing potent neutralizing antibodies against vaccinia virus and comprehensively characterizing their epitopes. We found a site in vaccinia virus L1 protein as the target of a group of highly potent murine neutralizing antibodies. The analysis of antibody-antigen complex structure and the sequences of the antibody genes shed light on how these potent neutralizing antibodies are elicited from immunized mice. PMID- 25031355 TI - A virulent bioluminescent and fluorescent dual-reporter Marek's disease virus unveils an alternative spreading pathway in addition to cell-to-cell contact. AB - Marek's disease virus (MDV) is a growing threat for the poultry industry. Unfortunately, despite successful vaccination against the disease, MDV remains in circulation within vaccinated flocks, leading to the selection of increasingly virulent pathotypes. Detailed knowledge of the virus biology and the host-virus interaction is required to improve the vaccine efficiency. In the present study, I engineered an original, dual-reporter MDV to track and quantify virus replication in vitro and in vivo. PMID- 25031357 TI - Activation of 5' adenosine monophosphate-activated protein kinase blocks cumulus cell expansion through inhibition of protein synthesis during in vitro maturation in Swine. AB - The serine/threonine kinase 5' adenosine monophosphate-activated protein kinase (AMPK), a heterotrimeric protein known as a metabolic switch, is involved in oocyte nuclear maturation in mice, cattle, and swine. The present study analyzed AMPK activation in cumulus cell expansion during in vitro maturation (IVM) of porcine cumulus-oocyte complexes (COC). 5-Aminoimidazole-4-carboxamide-1-beta-d ribofuranoside (AICAR) is a well-known activator of AMPK. It inhibited oocyte meiotic resumption in COC. Moreover, cumulus cell expansion did not occur in the presence of AICAR, demonstrating its marked impact on cumulus cells. Activation of AMPK was supported by AICAR-mediated phosphorylation of alpha AMPK subunits. Furthermore, the presence of AICAR increased glucose uptake, a classical response to activation of this metabolic switch in response to depleted cellular energy levels. Neither nuclear maturation nor cumulus expansion was reversed by glucosamine, an alternative substrate in hyaluronic acid synthesis, through the hexosamine biosynthetic pathway, which ruled out possible depletion of substrates. Both increased gap junction communication and phosphodiesterase activity in COC are dependent on protein synthesis during the initial hours of IVM; however, both were inhibited in the presence of AICAR, which supports the finding that activation of AMPK by AICAR mediated inhibition of protein synthesis. Moreover, this protein synthesis inhibition was equivalent to that of the well-known protein synthesis inhibitor cycloheximide, as observed on cumulus expansion and protein concentration. Finally, the phosphorylation level of selected kinases was investigated. The pattern of raptor phosphorylation is supportive of activation of AMPK-mediated inhibition of protein synthesis. In conclusion, AICAR-mediated AMPK activation in porcine COC inhibited cumulus cell expansion and protein synthesis. These results bring new considerations to the importance of this kinase in ovarian physiology and to the development of new oocyte culture medium. PMID- 25031356 TI - High-risk human papillomavirus E6 protein promotes reprogramming of Fanconi anemia patient cells through repression of p53 but does not allow for sustained growth of induced pluripotent stem cells. AB - DNA repair plays a crucial role in embryonic and somatic stem cell biology and cell reprogramming. The Fanconi anemia (FA) pathway, which promotes error-free repair of DNA double-strand breaks, is required for somatic cell reprogramming to induced pluripotent stem cells (iPSC). Thus, cells from Fanconi anemia patients, which lack this critical pathway, fail to be reprogrammed to iPSC under standard conditions unless the defective FA gene is complemented. In this study, we utilized the oncogenes of high-risk human papillomavirus 16 (HPV16) to overcome the resistance of FA patient cells to reprogramming. We found that E6, but not E7, recovers FA iPSC colony formation and, furthermore, that p53 inhibition is necessary and sufficient for this activity. The iPSC colonies resulting from each of these approaches stained positive for alkaline phosphatase, NANOG, and Tra-1 60, indicating that they were fully reprogrammed into pluripotent cells. However, FA iPSC were incapable of outgrowth into stable iPSC lines regardless of p53 suppression, whereas their FA-complemented counterparts grew efficiently. Thus, we conclude that the FA pathway is required for the growth of iPSC beyond reprogramming and that p53-independent mechanisms are involved. IMPORTANCE: A novel approach is described whereby HPV oncogenes are used as tools to uncover DNA repair-related molecular mechanisms affecting somatic cell reprogramming. The findings indicate that p53-dependent mechanisms block FA cells from reprogramming but also uncover a previously unrecognized defect in FA iPSC proliferation independent of p53. PMID- 25031358 TI - The LIF-mediated molecular signature regulating murine embryo implantation. AB - The establishment of a receptive uterus is the prime requirement for embryo implantation. In mice, the E2-induced cytokine leukemia inhibitory factor (LIF) is essential in switching the uterine luminal epithelium (LE) from a nonreceptive to a receptive state. Here we define the LIF-mediated switch using array analysis and informatics to identify LIF-induced changes in gene expression and annotated signaling pathways specific to the LE. We compare gene expression profiles at 0, 1, 3, and 6 h, following LIF treatment. During the first hour, the JAK-STAT signaling pathway is activated and the expression of 54 genes declines, primarily affecting LE cytoskeletal and chromatin organization as well as a transient reduction in the progesterone, TGFbetaR1, and ACVR1 receptors. Simultaneously 256 genes increase expression, of which 42 are transcription factors, including Sox, Kfl, Hes, Hey, and Hox families. Within 3 h, the expression of 3987 genes belonging to more than 25 biological process pathways was altered. We confirmed the mRNA and protein distribution of key genes from 10 pathways, including the Igf-1, Vegf, Toll-like receptors, actin cytoskeleton, ephrin, integrins, TGFbeta, Wnt, and Notch pathways. These data identify novel LIF-activated pathways in the LE and define the molecular basis between the refractory and receptive uterine phases. More broadly, these findings highlight the staggering capacity of a single cytokine to induce a dynamic and complex network of changes in a simple epithelium essential to mammalian reproduction and provide a basis for identifying new routes to regulating female reproduction. PMID- 25031359 TI - Disruption of rat testis development following combined in utero exposure to the phytoestrogen genistein and antiandrogenic plasticizer di-(2-ethylhexyl) phthalate. AB - Fetal exposure to environmental endocrine disruptors (EDs) is thought to contribute to reported idiopathic increases in adult male reproductive abnormalities. Although humans are exposed to myriad EDs from conception to adulthood, few studies have evaluated the effects of combined EDs on male reproduction. In the present study, we demonstrate that simultaneous gestational exposure to the phytoestrogen genistein and the antiandrogenic plasticizer di-(2 ethyhexyl) phthalate (DEHP) induces long-term alterations in testis development and function. Pregnant Sprague Dawley rats were gavaged from Gestational Day 14 to birth with corn oil, genistein, DEHP, or their mixture at 10 mg/kg/day, a dose selected from previous dose-response studies using single chemicals for its lack of long-term testicular effects. Hormonal and testicular end points were examined in adult male offspring. Serum testosterone levels were unchanged. However, significant increases were observed in testis weight and in the expression of mast cell markers in testes from adult rats exposed gestationally to combined compounds. The ED mixture also altered the mRNA expression of Sertoli cell makers Wt1 and Amh and germ cell markers cKit and Sox17, measured by quantitative real time PCR (qPCR), suggesting long-term disruption in testis function and spermatogenesis. Alterations in germ cell markers might reflect direct effects on fetal gonocytes or indirect effects via primary targeting of somatic cells, as suggested by differentially regulated Leydig cell associated genes (Hsd3b, Anxa1, Foxa3, and Pdgfra), determined by gene expression array, qPCR, and protein analyses. The two chemicals, when given in combination, induced long-term reproductive toxicity at doses not previously reported to produce any conspicuous long-term effects. Our study therefore highlights a need for a more comprehensive evaluation of the effects of ED mixtures. PMID- 25031360 TI - Evidence supporting a functional requirement of SMAD4 for bovine preimplantation embryonic development: a potential link to embryotrophic actions of follistatin. AB - Transforming growth factor beta (TGFbeta) superfamily signaling controls various aspects of female fertility. However, the functional roles of the TGFbeta superfamily cognate signal transduction pathway components (e.g., SMAD2/3, SMAD4, SMAD1/5/8) in early embryonic development are not completely understood. We have previously demonstrated pronounced embryotrophic actions of the TGFbeta superfamily member-binding protein, follistatin, on oocyte competence in cattle. Given that SMAD4 is a common SMAD required for both SMAD2/3- and SMAD1/5/8 signaling pathways, the objectives of the present studies were to determine the temporal expression and functional role of SMAD4 in bovine early embryogenesis and whether embryotrophic actions of follistatin are SMAD4 dependent. SMAD4 mRNA is increased in bovine oocytes during meiotic maturation, is maximal in 2-cell stage embryos, remains elevated through the 8-cell stage, and is decreased and remains low through the blastocyst stage. Ablation of SMAD4 via small interfering RNA microinjection of zygotes reduced proportions of embryos cleaving early and development to the 8- to 16-cell and blastocyst stages. Stimulatory effects of follistatin on early cleavage, but not on development to 8- to 16-cell and blastocyst stages, were observed in SMAD4-depleted embryos. Therefore, results suggest SMAD4 is obligatory for early embryonic development in cattle, and embryotrophic actions of follistatin on development to 8- to 16-cell and blastocyst stages are SMAD4 dependent. PMID- 25031361 TI - Neurotensin enhances sperm capacitation and acrosome reaction in mice. AB - Neurotensin (NT) has multiple functions, ranging from acting as a neurotransmitter to regulating intestinal movement. However, its function in reproductive physiology is unknown. Here, we confirmed the expression and localization of NT receptors (NTR1) in mouse epididymal spermatozoa and investigated the effect of NT on sperm function. Sperm protein tyrosine phosphorylation, one of the indices of sperm capacitation, was facilitated dose dependently by NT administration. In addition, the acrosome reaction was promoted in capacitated spermatozoa, and addition of a selective antagonist of NTR1 and NTR2 blocked the induction. Furthermore, intracellular calcium mobilization by NT addition was observed. This showed that NT was an accelerator of sperm function via its functional receptors. The presence of NT was confirmed by immunohistochemistry and its localization was observed in epithelia of the uterus and oviduct isthmus and ampulla, which correspond to the fertilization route of spermatozoa. The NT mRNA level in ovulated cumulus cell was remarkably increased by treatment with human chorionic gonadotropin (hCG). Using an in vitro maturation model, we analyzed the effects of FSH, epidermal growth factor (EGF), estradiol, and progesterone in NT production in cumulus cells. We found that FSH and EGF upregulated NT release and mRNA expression. Both FSH- and EGF-induced upregulation were inhibited by U0126, an MAPK kinase inhibitor, indicating that FSH and EGF regulate NT expression via a MAPK-dependent pathway. This evidence suggests that NT can act as a promoter of sperm capacitation and the acrosome reaction in the female reproductive tract. PMID- 25031362 TI - A safety awareness program for women with diverse disabilities: a randomized controlled trial. AB - Women with diverse disabilities (N = 213), recruited through 10 centers for independent living (CILs), were randomly assigned to either a personal safety awareness program or usual care. The 8-week program, led by CIL staff, was designed to increase safety awareness, abuse and safety knowledge, safety skills, safety self-efficacy, social support, and safety promoting behaviors. All participants completed pre-, post-, and 6-month follow-up questionnaires. Results revealed that participation in a brief safety awareness program may improve safety protective factors among women with disabilities who vary widely in their experience with abuse. The program holds promise for enhancing safety among women with disabilities. PMID- 25031363 TI - Feminism, status inconsistency, and women's intimate partner victimization in heterosexual relationships. AB - This study used a random community sample of 303 women in romantic relationships to investigate the role of educational and employment status inconsistency and patriarchal family ideology as risk factors for intimate partner violence (IPV) victimization, while considering demographic factors and relationship context variables. Sequential multivariate logistic regression models demonstrated a decrease in the odds of IPV victimization for Hispanic women and women who were older as compared with their counterparts. In addition, increased relationship distress, family-of-origin violence, and employment status inconsistency significantly increased the odds of IPV. Clinical intervention strategies and future research directions are discussed. PMID- 25031364 TI - Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance. AB - Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear conditioning, there is a high level of variability across reports, especially regarding responses to the conditioned stimulus (CS). Here, we compare C57BL/6 and DBA/2 mice using delay fear conditioning, trace fear conditioning, and a nonassociative condition. Our data highlight both the significant strain differences apparent in these fear conditioning paradigms and the significant differences in conditioning type within each strain. We then compare our data to an extensive literature review of delay and trace fear conditioning in these two strains. Finally, we apply a number of commonly used baseline normalization approaches to compare how they alter the reported differences. Our findings highlight three major sources of variability in the fear conditioning literature: CS duration, number of CS presentations, and data normalization to baseline measures. PMID- 25031365 TI - Prefrontal consolidation supports the attainment of fear memory accuracy. AB - The neural mechanisms underlying the attainment of fear memory accuracy for appropriate discriminative responses to aversive and nonaversive stimuli are unclear. Considerable evidence indicates that coactivator of transcription and histone acetyltransferase cAMP response element binding protein (CREB) binding protein (CBP) is critically required for normal neural function. CBP hypofunction leads to severe psychopathological symptoms in human and cognitive abnormalities in genetic mutant mice with severity dependent on the neural locus and developmental time of the gene inactivation. Here, we showed that an acute hypofunction of CBP in the medial prefrontal cortex (mPFC) results in a disruption of fear memory accuracy in mice. In addition, interruption of CREB function in the mPFC also leads to a deficit in auditory discrimination of fearful stimuli. While mice with deficient CBP/CREB signaling in the mPFC maintain normal responses to aversive stimuli, they exhibit abnormal responses to similar but nonrelevant stimuli when compared to control animals. These data indicate that improvement of fear memory accuracy involves mPFC-dependent suppression of fear responses to nonrelevant stimuli. Evidence from a context discriminatory task and a newly developed task that depends on the ability to distinguish discrete auditory cues indicated that CBP-dependent neural signaling within the mPFC circuitry is an important component of the mechanism for disambiguating the meaning of fear signals with two opposing values: aversive and nonaversive. PMID- 25031366 TI - Modulation of olfactory bulb network activity by serotonin: synchronous inhibition of mitral cells mediated by spatially localized GABAergic microcircuits. AB - Although inhibition has often been proposed as a central mechanism for coordinating activity in the olfactory system, relatively little is known about how activation of different inhibitory local circuit pathways can generate coincident inhibition of principal cells. We used serotonin (5-HT) as a pharmacological tool to induce spiking in ensembles of mitral cells (MCs), a primary output neuron in the olfactory bulb, and recorded intracellularly from pairs of MCs to directly assay coincident inhibitory input. We find that 5-HT disynaptically depolarized granule cells (GCs) only slightly but robustly increased the frequency of inhibitory postsynaptic inhibitory currents in MCs. Serotonin also triggered more coincident IPSCs in pairs of nearby MCs than expected by chance, including in MCs with truncated apical dendrites that lack glomerular synapses. That serotonin-triggered coincident inhibition in the absence of elevated GC somatic firing rates suggested that synchronized MC inhibition arose from glutamate receptor-mediated depolarization of GC dendrites or other (non-GC) interneurons outside the glomerular layer. Tetanic stimulation of GCL afferents to GCs triggered robust GC spiking, coincident inhibition in pairs of MCs, and recruited large-amplitude IPSCs in MCs. Enhancing neurotransmission through NMDARs by lowering the external Mg2+ concentration also increased inhibitory tone onto MCs but failed to promote synchronized inhibition. These results demonstrate that coincident MC inhibition can occur through multiple circuit pathways and suggests that the functional coordination between different GABAergic synapses in individual GCs can be dynamically regulated. PMID- 25031367 TI - British athletics muscle injury classification: a new grading system. AB - The commonly used muscle injury grading systems based on three grades of injury, representing minor, moderate and complete injuries to the muscle, are lacking in diagnostic accuracy and provide limited prognostic information to the clinician. In recent years, there have been a number of proposals for alternative grading systems. While there is recent evidence regarding the prognostic features of muscle injuries, this evidence has not often been incorporated into the grading proposals. The British Athletics Muscle Injury Classification proposes a new system, based on the available evidence, which should provide a sound diagnostic base for therapeutic decision-making and prognostication. Injuries are graded 0-4 based on MRI features, with Grades 1-4 including an additional suffix 'a', 'b' or 'c' if the injury is 'myofascial', 'musculo-tendinous' or 'intratendinous'. Retrospective and prospective studies in elite track and field athletes are underway to validate the classification for use in hamstring muscle injury management. It is intended that this grading system can provide a suitable diagnostic framework for enhanced clinical decision-making in the management of muscle injuries and assist with future research to inform the development of improved prevention and management strategies. PMID- 25031369 TI - Perfusion MRI in Early Stage of Legg-Calve-Perthes Disease to Predict Lateral Pillar Involvement: A Preliminary Study. AB - BACKGROUND: Current radiographic classifications for Legg-Calve-Perthes disease cannot be applied at the early stages of the disease. The purpose of this study was to quantify the perfusion of the femoral epiphysis in the early stages of Legg-Calve-Perthes disease with use of perfusion magnetic resonance imaging (MRI) and to determine if the extent of epiphyseal perfusion can predict the lateral pillar involvement at the mid-fragmentation stage. METHODS: Twenty-nine patients had gadolinium-enhanced perfusion MRI at the initial stage or early fragmentation stage of Legg-Calve-Perthes disease and were followed prospectively. The percent perfusion of the whole epiphysis and its lateral third was measured by four independent observers using image analysis software. The radiographs obtained at the mid-fragmentation stage were used for the lateral pillar classification. Intraclass correlation coefficient (ICC) and logistic regression analyses were performed. RESULTS: The mean age (and standard deviation) at diagnosis was 7.7 +/ 1.7 years (range, 5.3 to 11.3 years). The mean interval between the MRI and the time of maximum fragmentation was 8.2 +/- 5.5 months. The interobserver ICC for the percent perfusion of the lateral third of the epiphysis was 0.90 (95% confidence interval [CI]: 0.83 to 0.95). The mean percent perfusion of the lateral third of the epiphysis was 92% +/- 2%, 68% +/- 18%, and 46% +/- 12% for the hips in which the lateral pillar was later classified as A, B, and C, respectively (p = 0.001). When the perfusion level was >=90% in the lateral third of the epiphysis, the odds ratio of the lateral pillar being later classified as group A, as opposed to B or C, was 72.0 (CI: 3.5 to 1476). With a perfusion level of <=55% in the lateral third of the epiphysis, the odds ratio of the lateral pillar being later classified as group C, as opposed to A or B, was 33.3 (CI: 2.8 to 392). Similar results were obtained for the whole epiphysis. CONCLUSIONS: Perfusion MRI measurements of the total epiphysis and its lateral third obtained at the early stages of Legg-Calve-Perthes disease were predictive of lateral pillar involvement at the mid-fragmentation stage of the disease. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031370 TI - Preoperative Radiographic and CT Findings Predicting Syndesmotic Injuries in Supination-External Rotation-Type Ankle Fractures. AB - BACKGROUND: The Lauge-Hansen classification system does not provide sufficient data related to syndesmotic injuries in supination-external rotation (SER)-type ankle fractures. The aim of the present study was to investigate factors helpful for the preoperative detection of syndesmotic injuries in SER-type ankle fractures using radiographs and computed tomography (CT). METHODS: A cohort of 191 consecutive patients (104 male and eighty-seven female patients with a mean age [and standard deviation] of 50.7 +/- 16.4 years) with SER-type ankle fractures who had undergone operative treatment were included. Preoperative ankle radiographs and CT imaging scans were made for all patients, and clinical data, including age, sex, and mechanism of injury (high or low-energy trauma), were collected. Patients were divided into two groups: the stable syndesmotic group and the unstable syndesmotic group, with a positive intraoperative lateral stress test leading to syndesmotic screw fixation. Fracture height, fracture length, medial joint space, extent of fracture, and bone attenuation were measured on radiographs and CT images and were compared between the groups. Binary logistic regression analysis was performed to identify the factors that significantly contributed to unstable syndesmotic injuries. Receiver operating characteristic curves were calculated, and cutoff values were suggested to predict unstable syndesmotic injuries on preoperative imaging measurements. RESULTS: Of the 191 patents with a SER-type ankle fracture, thirty-eight (19.9%) had a concurrent unstable syndesmotic injury. Age, sex, mechanism of injury, fracture height, medial joint space, and bone attenuation were significantly different between the two groups. In the binary logistic analysis, fracture height, medial joint space, and bone attenuation were found to be significant factors contributing to unstable syndesmotic injuries. The cutoff values for predicting unstable syndesmotic injuries were a fracture height of >3 mm and a medial joint space of >4.9 mm on CT scans, and a fracture height of >7 mm and medial joint space of >4.5 mm on radiographs. CONCLUSIONS: Fracture height, medial joint space, and bone attenuation were useful factors for the preoperative detection of unstable syndesmotic injuries in SER-type ankle fractures. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031371 TI - Outcomes and Costs of Reverse Shoulder Arthroplasty in the Morbidly Obese: A Case Control Study. AB - BACKGROUND: The rising number of morbidly obese patients has important consequences for the health-care system. We investigated the effect of morbid obesity on outcomes, complications, discharge disposition, and costs in patients undergoing reverse shoulder arthroplasty. METHODS: Our joint registry was searched for all patients who had undergone primary reverse shoulder arthroplasty for a reason other than fracture from 2003 to 2010 and had a minimum of twenty four months of follow-up. Twenty-one patients with a body mass index (BMI) of >=40 kg/m2 were identified (follow-up, 45 +/- 16 months; sex, seventeen female and four male; age, 69 +/- 7 years) and were compared with sixty-three matched control patients with a BMI of <30 kg/m2 (follow-up, 48 +/- 20 months; sex, fifty female and thirteen male; age, 71 +/- 6 years) after an a priori sample size calculation. Outcome instrument data were obtained preoperatively and postoperatively. The Charlson-Deyo comorbidity index (CDI) score, total comorbidities, operative time, blood loss, duration of hospital stay, discharge disposition, costs, and complications were recorded. RESULTS: Compared with nonobese patients, morbidly obese patients had similar improvements in functional outcomes (e.g., American Shoulder and Elbow Surgeons score, 32 to 69 compared with 40 to 78) and in shoulder motion (e.g., forward flexion, 61 degrees to 140 degrees compared with 74 degrees to 153 degrees ); all improvements were significant (p < 0.05). Morbidly obese patients had a similar rate of scapular notching (odds ratio [OR] = 0.58, p = 0.63), more total comorbidities excluding obesity (six compared with four, p = 0.001), a higher CDI (2 compared with 1, p = 0.025), and a higher rate of obstructive sleep apnea (OR = 27.7, p = 0.0001). Their operative time was thirteen minutes longer (p = 0.014) and their blood loss was 40 mL greater (p = 0.008). Morbidly obese patients had a similar duration of stay (3.1 compared with 2.6 days, p = 0.823) and hospital readmission rate (OR = 16.3, p = 0.08) but a sixfold higher rate of discharge to rehabilitation facilities rather than to home (OR = 8, p < 0.0001). Hospital costs were higher by $2974 (p = 0.009). The rates of major complications (n = 4 compared with 8, p = 0.479) and of minor complications (n = 3 compared with 14, p = 0.440) were similar. No intraoperative complications or mechanical device failures were noted in either group. CONCLUSIONS: Reverse shoulder arthroplasty appears to be as safe and effective in morbidly obese patients, although it has an increased cost and patients have a lower rate of discharge to home and greater care needs after discharge. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031368 TI - Osteoarthritis Classification Scales: Interobserver Reliability and Arthroscopic Correlation. AB - BACKGROUND: Osteoarthritis of the knee is commonly diagnosed and monitored with radiography. However, the reliability of radiographic classification systems for osteoarthritis and the correlation of these classifications with the actual degree of confirmed degeneration of the articular cartilage of the tibiofemoral joint have not been adequately studied. METHODS: As the Multicenter ACL (anterior cruciate ligament) Revision Study (MARS) Group, we conducted a multicenter, prospective longitudinal cohort study of patients undergoing revision surgery after anterior cruciate ligament reconstruction. We followed 632 patients who underwent radiographic evaluation of the knee (an anteroposterior weight-bearing radiograph, a posteroanterior weight-bearing radiograph made with the knee in 45 degrees of flexion [Rosenberg radiograph], or both) and arthroscopic evaluation of the articular surfaces. Three blinded examiners independently graded radiographic findings according to six commonly used systems-the Kellgren Lawrence, International Knee Documentation Committee, Fairbank, Brandt et al., Ahlback, and Jager-Wirth classifications. Interobserver reliability was assessed with use of the intraclass correlation coefficient. The association between radiographic classification and arthroscopic findings of tibiofemoral chondral disease was assessed with use of the Spearman correlation coefficient. RESULTS: Overall, 45 degrees posteroanterior flexion weight-bearing radiographs had higher interobserver reliability (intraclass correlation coefficient = 0.63; 95% confidence interval, 0.61 to 0.65) compared with anteroposterior radiographs (intraclass correlation coefficient = 0.55; 95% confidence interval, 0.53 to 0.56). Similarly, the 45 degrees posteroanterior flexion weight-bearing radiographs had higher correlation with arthroscopic findings of chondral disease (Spearman rho = 0.36; 95% confidence interval, 0.32 to 0.39) compared with anteroposterior radiographs (Spearman rho = 0.29; 95% confidence interval, 0.26 to 0.32). With respect to standards for the magnitude of the reliability coefficient and correlation coefficient (Spearman rho), the International Knee Documentation Committee classification demonstrated the best combination of good interobserver reliability and medium correlation with arthroscopic findings. CONCLUSIONS: The overall estimates with the six radiographic classification systems demonstrated moderate (anteroposterior radiographs) to good (45 degrees posteroanterior flexion weight-bearing radiographs) interobserver reliability and medium correlation with arthroscopic findings. The International Knee Documentation Committee classification assessed with use of 45 degrees posteroanterior flexion weight-bearing radiographs had the most favorable combination of reliability and correlation. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031372 TI - Hand Function in Adults with Radial Longitudinal Deficiency. AB - BACKGROUND: Functional impairment in individuals with radial longitudinal deficiency can be influenced by several factors, including a short and bowed forearm, radial deviation of the wrist, a non-functional or absent thumb, limited finger motion, and impaired grip strength, but their relationship with activity and participation in adults with radial deficiency is not known. METHODS: Twenty individuals, eighteen to sixty years of age, who had Bayne type-II to V radial longitudinal deficiency, were examined in the context of the International Classification of Functioning, Disability and Health. Body function and structure were evaluated by measures of range of motion, grip strength, key pinch, sensibility, and radiographic parameters. Activity was evaluated by the Box and Block Test and the Sollerman test, and participation was evaluated by QuickDASH (the short form of the Disabilities of Arm, Shoulder and Hand outcome measure) and by the Medical Outcomes Study 12-Item Short Form Health Survey. Statistical correlations among assessments of body function and structure, activity, and participation were examined. RESULTS: The mean total active motion of the wrist (43 degrees ) and mean total active motion of the digits (377 degrees ) were less than the norms. The mean radial deviation of the wrist was 31 degrees . The mean grip strength (4.0 kg), key pinch (1.4 kg), and scores for the Box and Block Test (55 blocks per minute) and the Sollerman test on hand function (56 points) were considerably lower than the norms. The mean scores were 18 points for QuickDASH, 51 points for Short Form-12 physical component summary, and 53 points for Short Form-12 mental component summary. Significant relationships were found between the Box and Block Test and grip strength (p = 0.012), key pinch (p < 0.001), and total active motion of digits (p < 0.001); between the Sollerman test and the total active motion of elbow (p < 0.001) and the total active motion of digits (p < 0.001); between the QuickDASH and forearm length (p < 0.001), the total active motion of elbow (p = 0.001), and the total active motion of digits (p < 0.001); between the Short Form-12 physical component summary and grip strength (p = 0.016), forearm length (p < 0.001), total active elbow motion (p < 0.001), and total active digit motion (p < 0.001); and between the Short-Form-12 mental component summary and radial deviation of the wrist (p = 0.019). No significant correlations were found between the radiographic measurement of the radial deviation of the wrist (total forearm angle) and the Box and Block Test (p = 0.244), the Sollerman test (p = 0.775), QuickDASH (p = 0.156), Short Form-12 physical component summary (p = 0.107), or Short Form-12 mental component summary (p = 0.129). CONCLUSIONS: In individuals with radial longitudinal deficiency, grip strength, key pinch, forearm length, and elbow and digital motion seem to be more important for the individual's activity and participation than the radial angulation of the wrist. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031373 TI - Trends in the Incidence and In-Hospital Outcomes of Elective Major Orthopaedic Surgery in Patients Eighty Years of Age and Older in the United States from 2000 to 2009. AB - BACKGROUND: Although life expectancy continues to increase worldwide and advances occur in surgical techniques and medical treatment, the chronological age limit for patients to undergo elective major orthopaedic procedures remains a controversial subject. The purpose of this study was to examine the trends in the incidence and in-hospital outcomes of elective major orthopaedic surgery in patients eighty years of age and older in the United States as a whole. METHODS: ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) codes were used to identify patients at least eighty years of age in the Nationwide Inpatient Sample who underwent spinal fusion, total hip arthroplasty, or total knee arthroplasty from 2000 to 2009. Demographic data regarding the patient and health-care system were retrieved and analyzed. RESULTS: From 2000 to 2009, there were increasing trends in the age-adjusted incidence of spinal fusion, total hip arthroplasty, and total knee arthroplasty in patients at least eighty years of age (rate per 100,000 per year, 40 to 102 for spinal fusion, 181 to 257 for total hip arthroplasty, and 300 to 477 for total knee arthroplasty; p <= 0.001 for each). The overall in-hospital complication rate remained stable over time for spinal fusion and total knee arthroplasty and increased for total hip arthroplasty (9.0% to 10.3%, p = 0.008). The in-hospital mortality rate decreased over time (1.1% to 0.6% for spinal fusion, 0.5% to 0.3% for total hip arthroplasty, and 0.3% to 0.2% for total knee arthroplasty; p < 0.05 for each). The overall in-hospital complication and mortality rates of patients at least eighty years of age were significantly higher than those of patients sixty-five to seventy-nine years of age (p < 0.001 for both). CONCLUSIONS: During the previous decade, the rates of elective major orthopaedic surgical procedures in patients at least eighty years of age increased in the U.S. The in-hospital mortality rates decreased, whereas the overall in-hospital complication rates remained stable or increased. The overall event rates were low, and these elective procedures could be offered to very elderly patients. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031374 TI - A Comparison of the Accuracy of Three Intraoperative Techniques for Measuring Rotational Correction in Varus Derotational Osteotomies of the Femur. AB - BACKGROUND: Based on the complexity of proximal femoral geometry, osteotomies in the coronal plane may change femoral version, while osteotomies in the plane of the femoral neck should not. Theoretically, this relationship can lead to a systematic error when measuring rotational correction in the proximal part of the femur. METHODS: We developed a mathematical model to predict the error with three different techniques for rotational measurement: (1) a pin along the axis of the femoral neck and a lateral pin across the femoral condyles, (2) a proximal lateral pin perpendicular to the femur and a lateral pin across the femoral condyles, and (3) two anterior pins representing a score mark on the proximal part of the femur. Varus derotational osteotomies were performed on twenty-four Sawbone femora, and femoral anteversion and the angles between each set of pins were measured. RESULTS: Our mathematical model predicted no error with the neck pin technique regardless of the type of osteotomy performed. With the lateral pin technique, there was no predicted error with the neck plane osteotomy but a large error with the coronal plane osteotomy. The score-mark technique had a small amount of error with the neck plane osteotomy and a large error with the coronal plane osteotomy. Our Sawbones model measurements correlated well with the mathematical model, with intraclass correlation coefficients of 0.96, 0.89, and 0.91 for the neck-pin, lateral pin, and score-mark techniques, respectively. CONCLUSIONS: This study describes and validates a model for predicting the error of three different techniques for measuring femoral rotation. It demonstrates that inadvertent systematic error can occur with lateral pin and score-mark techniques, particularly when the osteotomy is out of plane with the femoral neck. CLINICAL RELEVANCE: Although the mathematics of this study are complex, the conclusions are clinically straightforward: rotational error is minimized by performing an osteotomy in the plane of the femoral neck or by using a pin in the femoral neck to judge rotation. If neither of these techniques is employed, then systematic error can be introduced and can be substantial. PMID- 25031375 TI - Factors Affecting Readmission Rates Following Primary Total Hip Arthroplasty. AB - BACKGROUND: Readmissions following total hip arthroplasty are a focus given the forthcoming financial penalties that hospitals in the United States may incur starting in 2015. The purpose of this study was to identify both preoperative comorbidities and postoperative conditions that increase the risk of readmission following total hip arthroplasty. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program data for 2011, a study population was identified using the Current Procedural Terminology code for primary total hip arthroplasty (27130). The sample was stratified into readmitted and non readmitted cohorts. Demographic variables, preoperative comorbidities, laboratory values, operative characteristics, and surgical outcomes were compared between the groups using univariate and multivariate logistic regression models. RESULTS: Of the 9441 patients, there were 345 readmissions (3.65%) within the first thirty days following surgery. Comorbidities that increased the risk for readmission were diabetes (p < 0.001), chronic obstructive pulmonary disease (p < 0.001), bleeding disorders (p < 0.001), preoperative blood transfusion (p = 0.035), corticosteroid use (p < 0.001), dyspnea (p = 0.001), previous cardiac surgery (p = 0.002), and hypertension (p < 0.001). A multivariate regression model was used to control for potential confounders. Having a body mass index of >=40 kg/m2 (odds ratio, 1.941 [95% confidence interval, 1.019 to 3.696]; p = 0.044) and using corticosteroids preoperatively (odds ratio, 2.928 [95% confidence interval, 1.731 to 4.953]; p < 0.001) were independently associated with a higher likelihood of readmission, and a high preoperative serum albumin (odds ratio, 0.688 [95% confidence interval, 0.477 to 0.992]; p = 0.045) was independently associated with a lower risk for readmission. Postoperative surgical site infection, pulmonary embolism, deep venous thrombosis, and sepsis (p < 0.001) were also independent risk factors for readmission. CONCLUSIONS: The risk of readmission following total hip arthroplasty increases with growing preoperative comorbidity burden, and is specifically increased in patients with a body mass index of >=40 kg/m2, a history of corticosteroid use, and low preoperative serum albumin and in patients with postoperative surgical site infection, a thromboembolic event, and sepsis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031376 TI - The Talar Body Prosthesis: Results at Ten to Thirty-six Years of Follow-up. AB - BACKGROUND: Satisfactory results of implantation of the talar body prosthesis were reported in 1997, although some complications associated with the initial design were noted. The present study evaluated outcomes of treatment with a modified talar body prosthesis. METHODS: Of the thirty-six talar body prostheses implanted with use of a transmalleolar surgical approach from 1974 to 2011, thirty-three were available for follow-up at ten to thirty-six years or had failed prior to that time. The indication for implantation had been osteonecrosis in twenty-three patients, a comminuted talar fracture in eight, and a talar body tumor in two. RESULTS: Twenty-eight of the thirty-three prostheses were still in place at the time of final follow-up and five had failed prior to five years. The duration of follow-up was ten to twenty years in eight patients, twenty to thirty years in eleven, and thirty to thirty-six years in nine. The AOFAS (American Orthopaedic Foot & Ankle Society) ankle-hindfoot score did not differ significantly among these three groups. Patients over sixty-five years of age with underlying disease that impeded walking ability had lower AOFAS scores. Early prosthesis failure occurred as a result of size mismatch in two patients, tumor recurrence in one, infection in one, and osteonecrosis of the talar head and neck in one. These failures, which occurred at eight to fifty-seven months, were treated with tibiotalar arthrodesis in three patients, prosthesis revision in one, and below-the-knee amputation in one. CONCLUSIONS: Although early prosthesis failure may occur, survival of the talar body prosthesis can provide satisfactory ankle and foot function. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031377 TI - The American Academy of Orthopaedic Surgeons Appropriate Use Criteria on the Non Arthroplasty Treatment of Osteoarthritis of the Knee. PMID- 25031379 TI - A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis. AB - BACKGROUND: Congenital tibial dysplasia is a severe pediatric condition that classically results in a persistent pseudarthrosis. A majority of these cases are associated with neurofibromatosis type I (NF1), a genetic disorder in which inactivation of the NF1 gene leads to overactivity of the Ras-MEK-MAPK (mitogen activated protein kinase) signaling pathway. We therefore hypothesized that pharmaceutical inhibition of MEK-MAPK may be a beneficial therapeutic strategy. METHODS: In vitro methods were used to demonstrate a role for the MEK inhibitor PD0325901 in promoting osteogenic differentiation in Nf1-/- calvarial osteoblasts. Local applications of rhBMP-2 and/or PD0325901 were then tested in a mouse model of NF1 tibial pseudarthrosis featuring localized double inactivation of the Nf1 gene in a fracture. Mice received no treatment, PD0325901 (10 mg/kg/day from two days before fracture to ten days after fracture), rhBMP-2 (10 MUg), or a combination of rhBMP-2 and PD0325901. RESULTS: Animals treated with the delivery vehicle alone, PD0325901, rhBMP-2, or the PD0325901 + rhBMP-2 combination showed union rates of 0%, 8%, 69% (p < 0.01), or 80% (p < 0.01), respectively, at twenty-one days after fracture. Mice treated with the rhBMP-2 + PD0325901 combination displayed a callus volume sixfold greater than the vehicle controls and twofold greater than the group receiving rhBMP-2 alone. Although MEK inhibition combined with rhBMP-2 led to increases in bone formation and union, the proportion of fibrous tissue in the callus was not significantly reduced. CONCLUSIONS: The data suggest that MEK inhibition can promote bone formation in combination with rhBMP-2 in the context of an NF1 pseudarthrosis. However, PD0325901 did not promote substantive bone anabolism in the absence of an exogenous anabolic stimulus and did not suppress fibrosis. CLINICAL RELEVANCE: This study examines a signaling pathway-based approach to treating poor bone healing in a model of NF1 pseudarthrosis. PMID- 25031380 TI - Use of Continuous Passive Motion in the Postoperative Treatment of Intra Articular Knee Fractures. AB - BACKGROUND: The use of continuous passive motion in the postoperative treatment of intra-articular fractures around the knee is increasing. The purpose of this study was to determine the effects of a continuous passive motion device on knee range of motion after operative treatment of intra-articular fractures around the knee. METHODS: Forty patients with intra-articular fractures of either the proximal part of the tibia or the distal end of the femur were prospectively randomized to the use of continuous passive motion or standardized physical therapy in the immediate postoperative period for forty-eight hours. The primary outcome was knee range of motion. Secondary outcome measures included pain scores, Lower Limb Outcomes Questionnaire scores, and Short Musculoskeletal Function Assessment scores. Evaluations were conducted at forty-eight hours, two weeks, six weeks, three months, and six months postoperatively. RESULTS: There was no significant difference in knee extension between the groups at any time point measured. Knee flexion was significantly greater at forty-eight hours in the group managed with the continuous passive motion device than in the group managed without the continuous passive motion device (p < 0.005). However, there was no significant difference in knee flexion at any other time point. There was no significant difference in knee pain at forty-eight hours between groups. Six (30%) of twenty patients were unable to tolerate the use of the continuous passive motion device. There were no significant differences in overall complications. CONCLUSIONS: The results of this study suggest that the use of continuous passive motion in the immediate postoperative period following the treatment of intra-articular fractures offers no benefit with regard to knee motion at six months and is not tolerated by all patients. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031381 TI - Arthroscopic-Assisted Latissimus Dorsi Transfer for the Management of Irreparable Rotator Cuff Tears: Short-Term Results. AB - BACKGROUND: Irreparable rotator cuff tears associated with shoulder functional impairment represent a challenge, especially in young and active patients. Latissimus dorsi muscle-tendon transfer is performed to replace the irreversibly lost contractile elements in patients with irreparable tears of the posterosuperior aspect of the rotator cuff. METHODS: From 2008 to 2010, we enrolled twenty-seven patients (mean age, sixty years; range, forty-six to sixty seven years) with irreparable, full-thickness rotator cuff tears involving at least two tendons who underwent arthroscopic-assisted latissimus dorsi muscle tendon transfer. Outcome measures included the Constant and Murley score, shoulder range of motion in external rotation, and muscle strength in forward elevation. The mean duration of follow-up was twenty-seven months (range, twenty four to thirty-six months). RESULTS: There was a significant improvement (p < 0.05) in the mean Constant and Murley score, pain score, muscle strength in forward elevation, and range of motion in external rotation at the time of the last follow-up. There was no significant correlation between the mean preoperative range of motion, pain, and strength and the mean postoperative Constant and Murley score. There was no significant osteoarthritis progression and proximal migration of the humeral head after surgery in the time period studied. CONCLUSIONS: Arthroscopic-assisted latissimus dorsi muscle-tendon transfer at short-term follow-up is an effective alternative to open surgery for the management of painful irreparable posterosuperior rotator cuff tears refractory to conservative management. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031382 TI - Anatomic Determinants of Sacral Dysmorphism and Implications for Safe Iliosacral Screw Placement. AB - BACKGROUND: Upper sacral segment dysplasia increases the risk of cortical perforation during iliosacral screw insertion. Dysmorphic sacra have narrow and angled upper osseous corridors. However, there is no validated definition of this anatomic variation. We hypothesized that pelves could be quantitatively grouped by anatomic measurements. METHODS: One hundred and four computed tomography (CT) scans and virtual outlet views of uninjured pelves were analyzed for the presence of the five qualitative characteristics of upper sacral segment dysplasia. CT scans were reformatted to measure the cross-sectional area, angulation, and length of the osseous corridor. Principal components analysis was used to identify multivariable explanations of anatomic variability, and discriminant analysis was used to assess how well such combinations can classify dysmorphic pelves. RESULTS: The prevalences of the five radiographic qualitative characteristics of upper sacral segment dysplasia, as determined by two reviewers, ranged from 28% to 53% in the cohort. The rates of agreement between the two reviewers ranged from 70% to 81%, and kappa coefficients ranged from 0.26 to 0.59. Cluster analysis revealed three pelvic phenotypes based on the maximal length of the osseous corridor in the upper two sacral segments. Forty-one percent of the pelves fell into the dysmorphic cluster. The five radiographic qualitative characteristics of dysmorphism were significantly more frequent (p < 0.007) in this cluster. A combination of upper sacral coronal and axial angulation effectively explained the variance in the data, and an inverse linear relationship between these angles and a long upper sacral segment corridor was identified. A sacral dysmorphism score was derived with the equation: (first sacral coronal angle) + 2(first sacral axial angle). An increase in the sacral dysmorphism score correlated with a lower likelihood of a safe transsacral first sacral corridor. No subjects with a sacral dysmorphism score >70 had a safe transsacral first sacral corridor. CONCLUSIONS: Sacral dysmorphism was found in 41% of the pelves. The major determinants of sacral dysmorphism are upper sacral segment coronal and axial angulation. The sacral dysmorphism score quantifies dysmorphism and can be used in preoperative planning of iliosacral screw placement. PMID- 25031383 TI - Comparative Survivorship of Different Tibial Designs in Primary Total Knee Arthroplasty. AB - BACKGROUND: Few registry-based studies in the United States have compared the survivorship of different knee implant designs in total knee arthroplasty. The purpose of this study was to compare differences in survivorship of commonly used tibial implant designs in primary total knee arthroplasty. METHODS: A total of 16,584 primary total knee arthroplasties in 11,992 patients were performed at a single institution from 1985 to 2005. Patients were prospectively followed at regular intervals to ascertain details of subsequent revisions. Overall revision rates and revisions for aseptic loosening, wear, and osteolysis were compared across twenty-two tibial implant designs using Cox proportional hazards regression models adjusting for age, sex, calendar year, and body mass index. RESULTS: In comparison with metal-backed modular implants, all-polyethylene tibial components had a significantly lower risk of revision (hazard ratio, 0.3; 95% confidence intervals: 0.2, 0.5 [p < 0.0001]). The risk reduction with all polyethylene tibial components was not affected by age, sex, or body mass index. With metal-backed modular tibial designs, cruciate-retaining knees performed better than the posterior-stabilized knees (p = 0.002), but this finding was limited to one specific metal-backed modular tibial component, the Press Fit Condylar design. With all-polyethylene tibial components, there was no survivorship difference between cruciate-retaining and posterior-stabilized designs. CONCLUSIONS: All-polyethylene tibial components were associated with better outcomes than metal-backed modular components. Cruciate-retaining and posterior-stabilized designs performed equally well, except with the Press Fit Condylar design. Obese patients may have superior results with all-polyethylene and posterior-stabilized components. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25031384 TI - Scapular Winging: A Great Masquerader of Shoulder Disorders: AAOS Exhibit Selection. AB - BACKGROUND: The incidence of scapular winging is unclear, but it may be more common than previously thought. It can be difficult to diagnose because the presenting complaint and physical examination may direct the practitioner toward more common shoulder and neck conditions. Ongoing scapular dysfunction may result in inappropriate or failed surgery. Our goals were to (1) describe the common misdiagnoses (instability, labral abnormality, impingement, and cervical spine disease), the clinical scenarios and examination findings leading to diagnostic difficulty, the definitive treatment options available, and the clinical outcomes and complications; and (2) review the important aspects of the patient history, physical examination of the scapula, and associated studies necessary to make the correct diagnosis of scapular winging. METHODS: We reviewed the literature relative to, and our own experience with, the treatment of scapular winging and identified a series of patients with this condition who were initially misdiagnosed with other shoulder or spine abnormalities. In our literature search, only nine clinical studies reported on a series of patients with scapular winging that was initially misdiagnosed or had a delay in diagnosis (n = 53 patients). We examined these cases for presenting or preexisting diagnoses and for surgical procedures that had been performed before the diagnosis of scapular winging. RESULTS: For patients ultimately diagnosed with scapular winging, initial presentations and diagnoses included rotator cuff disorders (20%), glenohumeral instability (8%), peripheral nerve disorders (6%), cervical spine disease (6%), acromioclavicular disorders (6%), thoracic outlet syndrome (4%), and unknown or unspecified (41%). The most common surgical procedures performed before definitive scapular winging treatment were rotator cuff (22%), instability (22%), nerve (14%), acromioclavicular (12%), cervical spine (5%), and thoracic outlet (4%) procedures. CONCLUSIONS: Clinically, scapular winging often mimics more common shoulder abnormalities and can result in unnecessary or unsuccessful surgical procedures. Diagnosis can be readily achieved with simple physical examination and specific provocative maneuvers in conjunction with electromyography and nerve conduction studies. Prompt diagnosis and recognition can avoid substantial shoulder dysfunction. PMID- 25031385 TI - A Survey of Expert Opinion Regarding Rotator Cuff Repair. AB - Many patients with rotator cuff tears have questions for their surgeons regarding the surgical procedure, perioperative management, restrictions, therapy, and ability to work after a rotator cuff repair. The purpose of our study was to determine common clinical practices among experts regarding rotator cuff repair and to assist them in counseling patients. We surveyed 372 members of the American Shoulder and Elbow Surgeons (ASES) and the Association of Clinical Elbow and Shoulder Surgeons (ACESS); 111 members (29.8%) completed all or part of the survey, and 92.8% of the respondents answered every question. A consensus response (>50% agreement) was achieved on 49% (24 of 49) of the questions. Variability in responses likely reflects the fact that clinical practices have evolved over time based on clinical experience. PMID- 25031386 TI - Radiograph to Reality: Pathways to Objectivity in the Grading of the Degenerative Joint: Commentary on an article by the MARS Group: "Osteoarthritis Classification Scales: Interobserver Reliability and Arthroscopic Correlation". PMID- 25031387 TI - Do We Need Another Gold Standard to Assess Acute Legg-Calve-Perthes Disease? Commentary on an article by Harry K.W. Kim, MD, MS, et al.: "Perfusion MRI in Early Stage of Legg-Calve-Perthes Disease to Predict Lateral Pillar Involvement. A Preliminary Study". PMID- 25031388 TI - Putting It All Together: Commentary on an article by Young Choi, MD, et al.: "Preoperative Radiographic and CT Findings Predicting Syndesmotic Injuries in Supination-External Rotation-Type Ankle Fractures". PMID- 25031389 TI - Gene of the month: Interleukin 6 (IL-6). AB - The Interleukin 6 (IL-6) gene encodes the classic proinflammatory cytokine IL-6. It is also known as interferon-beta2 (IFN-beta2), B cell stimulatory factor-2 and hybridoma/plasmacytoma growth factor. IL-6 is a multifunctional cytokine with a central role in many physiological inflammatory and immunological processes. Due to its major role in initiation as well as resolving inflammation, deregulation of IL-6 is a mainstay of chronic inflammatory and autoimmune diseases. Additionally, IL-6 has been shown to be implicated in pathogenesis of many human malignancies. Thus, a better understanding of IL-6 and its role in various pathological conditions could enable the development of strategies to use it as a therapeutic target. This short review focuses on the structure, regulation and biological activities of IL-6. In addition we discuss the role of IL-6 in diseases with inflammatory background and cancer and also the therapeutic applications of anti-IL-6 agents. PMID- 25031390 TI - New insights into the role of respiratory inputs in hippocampal oscillations. PMID- 25031391 TI - Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIgamma. AB - Emerging evidence has shown that miRNA-mediated gene expression modulation contributes to chronic pain, but its functional regulatory mechanism remains unknown. Here, we found that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly reduced miRNA-219 (miR-219) expression in mice spinal neurons. Furthermore, the expression of spinal CaMKIIgamma, an experimentally validated target of miR-219, was increased in CFA mice. Overexpression of spinal miR-219 prevented and reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization induced by CFA. Concurrently, increased expression of spinal CaMKIIgamma was reversed by miR-219 overexpression. Downregulation of spinal miR-219 in naive mice induced pain responsive behaviors and increased p-NMDAR1 expression, which could be inhibited by knockdown of CaMKIIgamma. Bisulfite sequencing showed that CFA induced the hypermethylation of CpG islands in the miR-219 promoter. Treatment with demethylation agent 5'-aza-2'-deoxycytidine markedly attenuated pain behavior and spinal neuronal sensitization, which was accompanied with the increase of spinal miR-219 and decrease of CaMKIIgamma expression. Together, we conclude that methylation-mediated epigenetic modification of spinal miR-219 expression regulates chronic inflammatory pain by targeting CaMKIIgamma. PMID- 25031392 TI - Phasic dopamine neuron activity elicits unique mesofrontal plasticity in adolescence. AB - The mesofrontal dopaminergic circuit, which connects the midbrain motivation center to the cortical executive center, is engaged in control of motivated behaviors. In addition, deficiencies in this circuit are associated with adolescent-onset psychiatric disorders in humans. Developmental studies suggest that the mesofrontal circuit exhibits a protracted maturation through adolescence. However, whether the structure and function of this circuit are modifiable by activity in dopaminergic neurons during adolescence remains unknown. Using optogenetic stimulation and in vivo two-photon imaging in adolescent mice, we found that phasic, but not tonic, dopamine neuron activity induces the formation of mesofrontal axonal boutons. In contrast, in adult mice, the effect of phasic activity diminishes. Furthermore, our results showed that dopaminergic and glutamatergic transmission regulate this axonal plasticity in adolescence and inhibition of dopamine D2-type receptors restores this plasticity in adulthood. Finally, we found that phasic activation of dopamine neurons also induces greater changes in mesofrontal circuit activity and psychomotor response in adolescent mice than in adult mice. Together, our findings demonstrate that the structure and function of the mesofrontal circuit are modifiable by phasic activity in dopaminergic neurons during adolescence and suggest that the greater plasticity in adolescence may facilitate activity-dependent strengthening of dopaminergic input and improvement in behavioral control. PMID- 25031393 TI - Estimates of projection overlap and zones of convergence within frontal-striatal circuits. AB - Frontal-striatal circuits underlie important decision processes, and pathology in these circuits is implicated in many psychiatric disorders. Studies have shown a topographic organization of cortical projections into the striatum. However, work has also shown that there is considerable overlap in the striatal projection zones of nearby cortical regions. To characterize this in detail, we quantified the complete striatal projection zones from 34 cortical injection locations in rhesus monkeys. We first fit a statistical model that showed that the projection zone of a cortical injection site could be predicted with considerable accuracy using a cross-validated model estimated on only the other injection sites. We then examined the fraction of overlap in striatal projection zones as a function of distance between cortical injection sites, and found that there was a highly regular relationship. Specifically, nearby cortical locations had as much as 80% overlap, and the amount of overlap decayed exponentially as a function of distance between the cortical injection sites. Finally, we found that some portions of the striatum received inputs from all the prefrontal regions, making these striatal zones candidates as information-processing hubs. Thus, the striatum is a site of convergence that allows integration of information spread across diverse prefrontal cortical areas. PMID- 25031394 TI - Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Abeta accumulation. AB - Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-beta (Abeta) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Abeta accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. PMID- 25031395 TI - Beyond classical inheritance: the influence of maternal genotype upon child's brain morphology and behavior. AB - Genetic variance has been associated with variations in brain morphology, cognition, behavior, and disease risk. One well studied example of how common genetic variance is associated with brain morphology is the serotonin transporter gene polymorphism within the promoter region (5-HTTLPR). Because serotonin is a key neurotrophic factor during brain development, genetically determined variations in serotonin activity during maturation, in particular during early prenatal development, may underlie the observed association. However, the intrauterine microenvironment is not only determined by the child's, but also the mother's genotype. Therefore, we hypothesized that maternal 5-HTTLPR genotype influences the child's brain development beyond direct inheritance. To test this hypothesis, we investigated 76 children who were all heterozygous for the 5 HTTLPR (sl) and who had mothers who were either homozygous for the long (ll) or the short allele (ss). Using MRI, we assessed brain morphology as a function of maternal genotype. Gray matter density of the somatosensory cortex was found to be greater in children of ss mothers compared with children of ll mothers. Behavioral assessment showed that fine motor task performance was altered in children of ll mothers and the degree of this behavioral effect correlated with somatosensory cortex density across individuals. Our findings provide initial evidence that maternal genotype can affect the child's phenotype beyond effects of classical inheritance. Our observation appears to be explained by intrauterine environmental differences or by differences in maternal behavior. PMID- 25031396 TI - The ion transport peptide is a new functional clock neuropeptide in the fruit fly Drosophila melanogaster. AB - The clock network of Drosophila melanogaster expresses various neuropeptides, but a function in clock-mediated behavioral control was so far only found for the neuropeptide pigment dispersing factor (PDF). Here, we propose a role in the control of behavioral rhythms for the ion transport peptide (ITP), which is expressed in the fifth small ventral lateral neuron, one dorsal lateral neuron, and in only a few nonclock cells in the brain. Immunocytochemical analyses revealed that ITP, like PDF, is most probably released in a rhythmic manner at projection terminals in the dorsal protocerebrum. This rhythm continues under constant dark conditions, indicating that ITP release is clock controlled. ITP expression is reduced in the hypomorph mutant Clk(AR), suggesting that ITP expression is regulated by CLOCK. Using a genetically encoded RNAi construct, we knocked down ITP in the two clock cells and found that these flies show reduced evening activity and increased nocturnal activity. Overexpression of ITP with two independent timeless-GAL4 lines completely disrupted behavioral rhythms, but only slightly dampened PER cycling in important pacemaker neurons, suggesting a role for ITP in clock output pathways rather than in the communication within the clock network. Simultaneous knockdown (KD) of ITP and PDF made the flies hyperactive and almost completely arrhythmic under constant conditions. Under light-dark conditions, the double-KD combined the behavioral characteristics of the single-KD flies. In addition, it reduced the flies' sleep. We conclude that ITP and PDF are the clock's main output signals that cooperate in controlling the flies' activity rhythms. PMID- 25031397 TI - Natural whisker-guided behavior by head-fixed mice in tactile virtual reality. AB - During many natural behaviors the relevant sensory stimuli and motor outputs are difficult to quantify. Furthermore, the high dimensionality of the space of possible stimuli and movements compounds the problem of experimental control. Head fixation facilitates stimulus control and movement tracking, and can be combined with techniques for recording and manipulating neural activity. However, head-fixed mouse behaviors are typically trained through extensive instrumental conditioning. Here we present a whisker-based, tactile virtual reality system for head-fixed mice running on a spherical treadmill. Head-fixed mice displayed natural movements, including running and rhythmic whisking at 16 Hz. Whisking was centered on a set point that changed in concert with running so that more protracted whisking was correlated with faster running. During turning, whiskers moved in an asymmetric manner, with more retracted whisker positions in the turn direction and protracted whisker movements on the other side. Under some conditions, whisker movements were phase-coupled to strides. We simulated a virtual reality tactile corridor, consisting of two moveable walls controlled in a closed-loop by running speed and direction. Mice used their whiskers to track the walls of the winding corridor without training. Whisker curvature changes, which cause forces in the sensory follicles at the base of the whiskers, were tightly coupled to distance from the walls. Our behavioral system allows for precise control of sensorimotor variables during natural tactile navigation. PMID- 25031398 TI - Cortical neurodynamics of inhibitory control. AB - The ability to inhibit prepotent responses is critical for successful goal directed behaviors. To investigate the neural basis of inhibitory control, we conducted a magnetoencephalography study where human participants performed the antisaccade task. Results indicated that neural oscillations in the prefrontal cortex (PFC) showed significant task modulations in preparation to suppress saccades. Before successfully inhibiting a saccade, beta-band power (18-38 Hz) in the lateral PFC and alpha-band power (10-18 Hz) in the frontal eye field (FEF) increased. Trial-by-trial prestimulus FEF alpha-band power predicted successful saccadic inhibition. Further, inhibitory control enhanced cross-frequency amplitude coupling between PFC beta-band (18-38 Hz) activity and FEF alpha-band activity, and the coupling appeared to be initiated by the PFC. Our results suggest a generalized mechanism for top-down inhibitory control: prefrontal beta band activity initiates alpha-band activity for functional inhibition of the effector and/or sensory system. PMID- 25031399 TI - Conserved single residue in the BK potassium channel required for activation by alcohol and intoxication in C. elegans. AB - Alcohol directly modulates the BK potassium channel to alter behaviors in species ranging from invertebrates to humans. In the nematode Caenorhabditis elegans, mutations that eliminate the BK channel, SLO-1, convey dramatic resistance to intoxication by ethanol. We hypothesized that certain conserved amino acids are critical for ethanol modulation, but not for basal channel function. To identify such residues, we screened C. elegans strains with different missense mutations in the SLO-1 channel. A strain with the SLO-1 missense mutation T381I in the RCK1 domain was highly resistant to intoxication. This mutation did not interfere with other BK channel-dependent behaviors, suggesting that the mutant channel retained normal in vivo function. Knock-in of wild-type versions of the worm or human BK channel rescued intoxication and other BK channel-dependent behaviors in a slo-1 null mutant background. In contrast, knock-in of the worm T381I or equivalent human T352I mutant BK channel selectively rescued BK channel-dependent behaviors while conveying resistance to intoxication. Single-channel patch-clamp recordings confirmed that the human BK channel engineered with the T352I missense mutation was insensitive to activation by ethanol, but otherwise had normal conductance, potassium selectivity, and only subtle differences in voltage dependence. Together, our behavioral and electrophysiological results demonstrate that the T352I mutation selectively disrupts ethanol modulation of the BK channel. The T352I mutation may alter a binding site for ethanol and/or interfere with ethanol induced conformational changes that are critical for behavioral responses to ethanol. PMID- 25031400 TI - CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory. AB - cAMP-responsive element binding protein (CREB) phosphorylation and signaling plays an important role in long-term memory formation, but other posttranslational modifications of CREB are less known. Here, we found that CREB1Delta, the short isoform of CREB, could be sumoylated by the small ubiquitin like modifier (SUMO) E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys271 and Lys290 and PIAS1 SUMOylation of CREB1Delta increased the expression level of CREB1Delta. CREB1Delta could also be sumoylated by other PIAS family proteins, but not by the E3 ligases RanBP2 and Pc2 or by the E2 ligase Ubc9. Furthermore, water maze training increased the level of endogenous CREB SUMOylation in rat CA1 neurons determined by in vitro SUMOylation assay, but this effect was not observed in other brain areas. Moreover, transduction of Lenti CREBWT to rat CA1 area facilitated, whereas transduction of Lenti-CREB double sumo-mutant (CREBK271RK290R) impaired, spatial learning and memory performance. Transduction of Lenti-CREBWT-SUMO1 fusion vector to rat CA1 area showed a more significant effect in enhancing spatial learning and memory and CREB SUMOylation. Lenti-CREBWT transduction increased, whereas Lenti-CREBK271RK290R transduction decreased, CREB DNA binding to the brain-derived neurotrophic factor (bdnf) promoter and decreased bdnf mRNA expression. Knock-down of PIAS1 expression in CA1 area by PIAS1 siRNA transfection impaired spatial learning and memory and decreased endogenous CREB SUMOylation. In addition, CREB SUMOylation was CREB phosphorylation dependent and lasted longer. Therefore, CREB phosphorylation may be responsible for signal transduction during the early phase of long-term memory formation, whereas CREB SUMOylation sustains long-term memory. PMID- 25031401 TI - N-cadherin promotes recruitment and migration of neural progenitor cells from the SVZ neural stem cell niche into demyelinated lesions. AB - Discrete cellular microenvironments regulate stem cell pools and their development, as well as function in maintaining tissue homeostasis. Although the signaling elements modulating neural progenitor cells (NPCs) of the adult subventricular zone (SVZ) niche are fairly well understood, the pathways activated following injury and the resulting outcomes, are less clear. In the present study, we used mouse models of demyelination and proteomics analysis to identify molecular cues present in the adult SVZ niche during injury, and analyzed their role on NPCs in the context of promoting myelin repair. Proteomic analysis of SVZ tissue from mice with experimental demyelination identified several proteins that are known to play roles in NPC proliferation, adhesion, and migration. Among the proteins found to be upregulated were members of the N cadherin signaling pathway. During the onset of demyelination in the subcortical white matter (SCWM), activation of epidermal growth factor receptor (EGFR) signaling in SVZ NPCs stimulates the interaction between N-cadherin and ADAM10. Upon cleavage and activation of N-cadherin signaling by ADAM10, NPCs undergo cytoskeletal rearrangement and polarization, leading to enhanced migration out of the SVZ into demyelinated lesions of the SCWM. Genetically disrupting either EGFR signaling or ADAM10 inhibits this pathway, preventing N-cadherin regulated NPC polarization and migration. Additionally, in vivo experiments using N-cadherin gain- and loss-of-function approaches demonstrated that N-cadherin enhances the recruitment of SVZ NPCs into demyelinated lesions. Our data revealed that EGFR dependent N-cadherin signaling physically initiated by ADAM10 cleavage is the response of the SVZ niche to promote repair of the injured brain. PMID- 25031403 TI - Prolonged adenosine A1 receptor activation in hypoxia and pial vessel disruption focal cortical ischemia facilitates clathrin-mediated AMPA receptor endocytosis and long-lasting synaptic inhibition in rat hippocampal CA3-CA1 synapses: differential regulation of GluA2 and GluA1 subunits by p38 MAPK and JNK. AB - Activation of presynaptic adenosine A1 receptors (A1Rs) causes substantial synaptic depression during hypoxia/cerebral ischemia, but postsynaptic actions of A1Rs are less clear. We found that A1Rs and GluA2-containing AMPA receptors (AMPARs) form stable protein complexes from hippocampal brain homogenates and cultured hippocampal neurons from Sprague Dawley rats. In contrast, adenosine A2A receptors (A2ARs) did not coprecipitate or colocalize with GluA2-containing AMPARs. Prolonged stimulation of A1Rs with the agonist N(6)-cyclopentyladenosine (CPA) caused adenosine-induced persistent synaptic depression (APSD) in hippocampal brain slices, and APSD levels were blunted by inhibiting clathrin mediated endocytosis of GluA2 subunits with the Tat-GluA2-3Y peptide. Using biotinylation and membrane fractionation assays, prolonged CPA incubation showed significant depletion of GluA2/GluA1 surface expression from hippocampal brain slices and cultured neurons. Tat-GluA2-3Y peptide or dynamin inhibitor Dynasore prevented CPA-induced GluA2/GluA1 internalization. Confocal imaging analysis confirmed that functional A1Rs, but not A2ARs, are required for clathrin-mediated AMPAR endocytosis in hippocampal neurons. Pharmacological inhibitors or shRNA knockdown of p38 MAPK and JNK prevented A1R-mediated internalization of GluA2 but not GluA1 subunits. Tat-GluA2-3Y peptide or A1R antagonist 8-cyclopentyl-1,3 dipropylxanthine also prevented hypoxia-mediated GluA2/GluA1 internalization. Finally, in a pial vessel disruption cortical stroke model, a unilateral cortical lesion compared with sham surgery reduced hippocampal GluA2, GluA1, and A1R surface expression and also caused synaptic depression in hippocampal slices that was consistent with AMPAR downregulation and decreased probability of transmitter release. Together, these results indicate a previously unknown mechanism for A1R induced persistent synaptic depression involving clathrin-mediated GluA2 and GluA1 internalization that leads to hippocampal neurodegeneration after hypoxia/cerebral ischemia. PMID- 25031402 TI - Enhancing astrocytic lysosome biogenesis facilitates Abeta clearance and attenuates amyloid plaque pathogenesis. AB - In sporadic Alzheimer's disease (AD), impaired Abeta removal contributes to elevated extracellular Abeta levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood-brain barrier, and cellular uptake facilitate physiologic Abeta clearance. Astrocytes can take up and degrade Abeta, but it remains unclear whether this function is insufficient in AD or can be enhanced to accelerate Abeta removal. Additionally, age-related dysfunction of lysosomes, the major degradative organelles wherein Abeta localizes after uptake, has been implicated in amyloid plaque pathogenesis. We tested the hypothesis that enhancing lysosomal function in astrocytes with transcription factor EB (TFEB), a master regulator of lysosome biogenesis, would promote Abeta uptake and catabolism and attenuate plaque pathogenesis. Exogenous TFEB localized to the nucleus with transcriptional induction of lysosomal biogenesis and function in vitro. This resulted in significantly accelerated uptake of exogenously applied Abeta42, with increased localization to and degradation within lysosomes in C17.2 cells and primary astrocytes, indicating that TFEB is sufficient to coordinately enhance uptake, trafficking, and degradation of Abeta. Stereotactic injection of adeno-associated viral particles carrying TFEB driven by a glial fibrillary acidic protein promoter was used to achieve astrocyte-specific expression in the hippocampus of APP/PS1 transgenic mice. Exogenous TFEB localized to astrocyte nuclei and enhanced lysosome function, resulting in reduced Abeta levels and shortened half-life in the brain interstitial fluid and reduced amyloid plaque load in the hippocampus compared with control virus-injected mice. Therefore, activation of TFEB in astrocytes is an effective strategy to restore adequate Abeta removal and counter amyloid plaque pathogenesis in AD. PMID- 25031404 TI - A hybrid electrical/chemical circuit in the spinal cord generates a transient embryonic motor behavior. AB - Spontaneous network activity is a highly stereotyped early feature of developing circuits throughout the nervous system, including in the spinal cord. Spinal locomotor circuits produce a series of behaviors during development before locomotion that reflect the continual integration of spinal neurons into a functional network, but how the circuitry is reconfigured is not understood. The first behavior of the zebrafish embryo (spontaneous coiling) is mediated by an electrical circuit that subsequently generates mature locomotion (swimming) as chemical neurotransmission develops. We describe here a new spontaneous behavior, double coiling, that consists of two alternating contractions of the tail in rapid succession. Double coiling was glutamate-dependent and required descending hindbrain excitation, similar to but preceding swimming, making it a discrete intermediary developmental behavior. At the cellular level, motoneurons had a distinctive glutamate-dependent activity pattern that correlated with double coiling. Two glutamatergic interneurons, CoPAs and CiDs, had different activity profiles during this novel behavior. CoPA neurons failed to show changes in activity patterns during the period in which double coiling appears, whereas CiD neurons developed a glutamate-dependent activity pattern that correlated with double coiling and they innervated motoneurons at that time. Additionally, double coils were modified after pharmacological reduction of glycinergic neurotransmission such that embryos produced three or more rapidly alternating coils. We propose that double coiling behavior represents an important transition of the motor network from an electrically coupled spinal cord circuit that produces simple periodic coils to a spinal network driven by descending chemical neurotransmission, which generates more complex behaviors. PMID- 25031405 TI - Layer 6 corticothalamic neurons activate a cortical output layer, layer 5a. AB - Layer 6 corticothalamic neurons are thought to modulate incoming sensory information via their intracortical axons targeting the major thalamorecipient layer of the neocortex, layer 4, and via their long-range feedback projections to primary sensory thalamic nuclei. However, anatomical reconstructions of individual layer 6 corticothalamic (L6 CT) neurons include examples with axonal processes ramifying within layer 5, and the relative input of the overall population of L6 CT neurons to layers 4 and 5 is not well understood. We compared the synaptic impact of L6 CT cells on neurons in layers 4 and 5. We found that the axons of L6 CT neurons densely ramified within layer 5a in both visual and somatosensory cortices of the mouse. Optogenetic activation of corticothalamic neurons generated large EPSPs in pyramidal neurons in layer 5a. In contrast, excitatory neurons in layer 4 exhibited weak excitation or disynaptic inhibition. Fast-spiking parvalbumin-positive cells in both layer 5a and layer 4 were also strongly activated by L6 CT neurons. The overall effect of L6 CT activation was to suppress layer 4 while eliciting action potentials in layer 5a pyramidal neurons. Together, our data indicate that L6 CT neurons strongly activate an output layer of the cortex. PMID- 25031406 TI - Hypoactivation of CRF receptors, predominantly type 2, in the medial-posterior BNST is vital for adequate maternal behavior in lactating rats. AB - Maternal behavior ensures the proper development of the offspring. In lactating mammals, maternal behavior is impaired by stress, the physiological consequence of central corticotropin-releasing factor receptor (CRF-R) activation. However, which CRF-R subtype in which specific brain area(s) mediates this effect is unknown. Here we confirmed that an intracerebroventricularly injected nonselective CRF-R antagonist enhances, whereas an agonist impairs, maternal care. The agonist also prolonged the stress-induced decrease in nursing, reduced maternal aggression and increased anxiety-related behavior. Focusing on the bed nucleus of the stria terminalis (BNST), CRF-R1 and CRF-R2 mRNA expression did not differ in virgin versus lactating rats. However, CRF-R2 mRNA was more abundant in the posterior than in the medial BNST. Pharmacological manipulations within the medial-posterior BNST showed that both CRF-R1 and CRF-R2 agonists reduced arched back nursing (ABN) rapidly and after a delay, respectively. After stress, both antagonists prevented the stress-induced decrease in nursing, with the CRF-R2 antagonist actually increasing ABN. During the maternal defense test, maternal aggression was abolished by the CRF-R2, but not the CRF-R1, agonist. Anxiety related behavior was increased by the CRF-R1 agonist and reduced by both antagonists. Both antagonists were also effective in virgin females but not in males, revealing a sexual dimorphism in the regulation of anxiety within the medial-posterior BNST. In conclusion, the detrimental effects of increased CRF-R activation on maternal behavior are mediated via CRF-R2 and, to a lesser extent, via CRF-R1 in the medial-posterior BNST in lactating rats. Moreover, both CRF-R1 and CRF-R2 regulate anxiety in females independently of their reproductive status. PMID- 25031407 TI - Long-term plasticity in the regulation of olfactory bulb activity by centrifugal fibers from piriform cortex. AB - Olfactory bulb granule cells are activated synaptically via two main pathways. Mitral/tufted (M/T) cells form dendrodendritic synapses on granule cells that can be activated by antidromic stimulation of the lateral olfactory tract (LOT). Centrifugal fibers originating from the association fiber (AF) system in piriform cortex (PC) make axodendritic synapses on granule cells within the granule cell layer (GCL) that can be activated by orthodromic stimulation of AF axons in the PC. We explored functional plasticity in the AF pathway by recording extracellularly from individual M/T cells and presumed granule cells in male Long Evans rats under urethane anesthesia while testing their response to LOT and AF stimulation. Presumed granule cells driven synaptically by LOT stimulation (type L cells) were concentrated in the superficial half of the GCL and were activated at short latencies, whereas those driven synaptically by AF stimulation (type A cells) were concentrated in the deep half of the GCL and were activated at longer latencies. Type A cells were readily detected only in animals in which the AF input to the GCL had been previously potentiated by repeated high-frequency stimulation. An additional bout of high-frequency stimulation administered under urethane caused an immediate increase in the number of action potentials evoked in type A cells by AF test stimulation and a concomitant increase in inhibition of M/T cells. These results underscore the importance of the role played in olfactory processing by PC regulation of OB activity and document the long lasting potentiation of that regulation by repeated high-frequency AF activation. PMID- 25031408 TI - Unmasking of spiral ganglion neuron firing dynamics by membrane potential and neurotrophin-3. AB - Type I spiral ganglion neurons have a unique role relative to other sensory afferents because, as a single population, they must convey the richness, complexity, and precision of auditory information as they shape signals transmitted to the brain. To understand better the sophistication of spiral ganglion response properties, we compared somatic whole-cell current-clamp recordings from basal and apical neurons obtained during the first 2 postnatal weeks from CBA/CaJ mice. We found that during this developmental time period neuron response properties changed from uniformly excitable to differentially plastic. Low-frequency, apical and high-frequency basal neurons at postnatal day 1 (P1)-P3 were predominantly slowly accommodating (SA), firing at low thresholds with little alteration in accommodation response mode induced by changes in resting membrane potential (RMP) or added neurotrophin-3 (NT-3). In contrast, P10 P14 apical and basal neurons were predominately rapidly accommodating (RA), had higher firing thresholds, and responded to elevation of RMP and added NT-3 by transitioning to the SA category without affecting the instantaneous firing rate. Therefore, older neurons appeared to be uniformly less excitable under baseline conditions yet displayed a previously unrecognized capacity to change response modes dynamically within a remarkably stable accommodation framework. Because the soma is interposed in the signal conduction pathway, these specializations can potentially lead to shaping and filtering of the transmitted signal. These results suggest that spiral ganglion neurons possess electrophysiological mechanisms that enable them to adapt their response properties to the characteristics of incoming stimuli and thus have the capacity to encode a wide spectrum of auditory information. PMID- 25031410 TI - Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs. AB - The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated Na(+) channels, which are thought to underlie the inhibition of pathological high frequency firing. However, some GABAergic inhibitory neurons are capable of firing at very high rates, suggesting that these anticonvulsants should cause impaired GABAergic inhibition. We have, therefore, studied the effects of anticonvulsant drugs acting via use-dependent block of voltage-gated Na(+) channels on GABAergic inhibitory micronetworks in the rodent hippocampus. We find that firing of pyramidal neurons is reliably inhibited in a use-dependent manner by the prototypical Na(+) channel blocker carbamazepine. In contrast, a combination of intrinsic and synaptic properties renders synaptically driven firing of interneurons essentially insensitive to this anticonvulsant. In addition, a combination of voltage imaging and electrophysiological experiments reveal that GABAergic feedforward and feedback inhibition is unaffected by carbamazepine and additional commonly used Na(+) channel-acting anticonvulsants, both in control and epileptic animals. Moreover, inhibition in control and epileptic rats recruited by in vivo activity patterns was similarly unaffected. These results suggest that sparing of inhibition is an important principle underlying the powerful reduction of CNS excitability exerted by anticonvulsant drugs. PMID- 25031409 TI - ER-mitochondrial calcium flow underlies vulnerability of mechanosensory hair cells to damage. AB - Mechanosensory hair cells are vulnerable to environmental insult, resulting in hearing and balance disorders. We demonstrate that directional compartmental flow of intracellular Ca(2+) underlies death in zebrafish lateral line hair cells after exposure to aminoglycoside antibiotics, a well characterized hair cell toxin. Ca(2+) is mobilized from the ER and transferred to mitochondria via IP3 channels with little cytoplasmic leakage. Pharmacological agents that shunt ER derived Ca(2+) directly to cytoplasm mitigate toxicity, indicating that high cytoplasmic Ca(2+) levels alone are not cytotoxic. Inhibition of the mitochondrial transition pore sensitizes hair cells to the toxic effects of aminoglycosides, contrasting with current models of excitotoxicity. Hair cells display efficient ER-mitochondrial Ca(2+) flow, suggesting that tight coupling of these organelles drives mitochondrial activity under physiological conditions at the cost of increased susceptibility to toxins. PMID- 25031411 TI - Neural structures mediating expression and extinction of platform-mediated avoidance. AB - Individuals use both passive and active defensive responses to environmental threats. Much is known about the neural circuits of passive defensive responses (e.g., freezing), but less is known about the substrates of active defensive responses (e.g., avoidance). We developed an active avoidance task in which rats learn to avoid a tone-signaled footshock by stepping onto a nearby platform. An advantage of this task is that freezing, which can interfere with avoidance, is reduced, thereby facilitating comparison of the effects of manipulations on avoidance versus freezing. After 10 d of avoidance training, rats were infused with muscimol to pharmacologically inactivate the prelimbic cortex (PL), infralimbic cortex (IL), ventral striatum (VS), or basolateral amygdala (BLA). Inactivating PL, VS, or BLA all impaired avoidance expression, but these areas differed with respect to freezing. Inactivating BLA decreased freezing consistent with loss of the tone-shock association, whereas inactivation of VS increased freezing consistent with loss of avoidance memory. Inactivation of PL had no effect on freezing. Inactivation of IL did not impair avoidance expression but did impair avoidance extinction. Our findings suggest that active avoidance is mediated by prefrontal-striatal circuits, which may be overactive in individuals suffering from trauma-related disorders. PMID- 25031412 TI - Long-term potentiation in hilar circuitry modulates gating by the dentate gyrus. AB - The dentate gyrus serves as a gateway to the hippocampus, filtering and processing sensory inputs as an animal explores its environment. The hilus occupies a strategic position within the dentate gyrus from which it can play a pivotal role in these functions. Inputs from dentate granule cells converge on the hilus, and excitatory hilar mossy cells redistribute these signals back to granule cells to transform a pattern of cortical input into a new pattern of output to the hippocampal CA3 region. Using voltage-sensitive dye to image electrical activity in rat hippocampal slices, we explored how long-term potentiation (LTP) of different excitatory synapses modifies the flow of information. Theta burst stimulation of the perforant path potentiated responses throughout the molecular layer, but left responses in the CA3 region unchanged. By contrast, theta burst stimulation of the granule cell layer potentiated responses throughout the molecular layer, as well as in the CA3 region. Theta burst stimulation of the granule cell layer potentiated CA3 responses not only to granule cell layer stimulation but also to perforant path stimulation. Potentiation of responses in the CA3 region reflected NMDA receptor-dependent LTP of upstream synapses between granule cells and mossy cells, with no detectable contribution from NMDA receptor-independent LTP of local CA3 mossy fiber synapses. Potentiation of transmission to the CA3 region required LTP in both granule cell->mossy cell and mossy cell->granule cell synapses. This bidirectional plasticity enables hilar circuitry to regulate the flow of information through the dentate gyrus and on to the hippocampus. PMID- 25031413 TI - Frontal white matter tracts sustaining speech production in primary progressive aphasia. AB - In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insular-striatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this "speech production network" is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brain-behavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior-dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases. PMID- 25031414 TI - Progressive disorganization of paranodal junctions and compact myelin due to loss of DCC expression by oligodendrocytes. AB - Paranodal axoglial junctions are critical for maintaining the segregation of axonal domains along myelinated axons; however, the proteins required to organize and maintain this structure are not fully understood. Netrin-1 and its receptor Deleted in Colorectal Cancer (DCC) are proteins enriched at paranodes that are expressed by neurons and oligodendrocytes. To identify the specific function of DCC expressed by oligodendrocytes in vivo, we selectively eliminated DCC from mature myelinating oligodendrocytes using an inducible cre regulated by the proteolipid protein promoter. We demonstrate that DCC deletion results in progressive disruption of the organization of axonal domains, myelin ultrastructure, and myelin protein composition. Conditional DCC knock-out mice develop balance and coordination deficits and exhibit decreased conduction velocity. We conclude that DCC expression by oligodendrocytes is required for the maintenance and stability of myelin in vivo, which is essential for proper signal conduction in the CNS. PMID- 25031415 TI - A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats. AB - Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1beta in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management. PMID- 25031417 TI - A new pathway mediating social effects on the endocrine system: female presence acting via norepinephrine release stimulates gonadotropin-inhibitory hormone in the paraventricular nucleus and suppresses luteinizing hormone in quail. AB - Rapid effects of social interactions on transient changes in hormonal levels are known in a wide variety of vertebrate taxa, ranging from fish to humans. Although these responses are mediated by the brain, neurochemical pathways that translate social signals into reproductive physiological changes are unclear. In this study, we analyzed how a female presence modifies synthesis and/or release of various neurochemicals, such as monoamines and neuropeptides, in the brain and downstream reproductive hormones in sexually active male Japanese quail. By viewing a female bird, sexually active males rapidly increased norepinephrine (NE) release in the paraventricular nucleus (PVN) of the hypothalamus, in which gonadotropin-inhibitory hormone (GnIH) neuronal cell bodies exist, increased GnIH precursor mRNA expression in the PVN, and decreased luteinizing hormone (LH) concentration in the plasma. GnIH is a hypothalamic neuropeptide that inhibits gonadotropin secretion from the pituitary. It was further shown that GnIH can rapidly suppress LH release after intravenous administration in this study. Centrally administered NE decreased plasma LH concentration in vivo. It was also shown that NE stimulated the release of GnIH from diencephalic tissue blocks in vitro. Fluorescence double-label immunohistochemistry indicated that GnIH neurons received noradrenergic innervations, and immunohistochemistry combined with in situ hybridization have further shown that GnIH neurons expressed alpha2A adrenergic receptor mRNA. These results indicate that a female presence increases NE release in the PVN and stimulates GnIH release, resulting in the suppression of LH release in sexually active male quail. PMID- 25031416 TI - Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula. AB - Neuronal nAChRs in the medial habenula (MHb) to the interpeduncular nucleus (IPN) pathway are key mediators of nicotine's aversive properties. In this paper, we report new details regarding nAChR anatomical localization and function in MHb and IPN. A new group of knock-in mice were created that each expresses a single nAChR subunit fused to GFP, allowing high-resolution mapping. We find that alpha3 and beta4 nAChR subunit levels are strong throughout the ventral MHb (MHbV). In contrast, alpha6, beta2, beta3, and alpha4 subunits are selectively found in some, but not all, areas of MHbV. All subunits were found in both ChAT-positive and ChAT-negative cells in MHbV. Next, we examined functional properties of neurons in the lateral and central part of MHbV (MHbVL and MHbVC) using brain slice patch-clamp recordings. MHbVL neurons were more excitable than MHbVC neurons, and they also responded more strongly to puffs of nicotine. In addition, we studied firing responses of MHbVL and MHbVC neurons in response to bath applied nicotine. Cells in MHbVL, but not those in MHbVC, increased their firing substantially in response to 1 MUm nicotine. Additionally, MHbVL neurons from mice that underwent withdrawal from chronic nicotine were less responsive to nicotine application compared with mice withdrawn from chronic saline. Last, we characterized rostral and dorsomedial IPN neurons that receive input from MHbVL axons. Together, our data provide new details regarding neurophysiology and nAChR localization and function in cells within the MHbV. PMID- 25031418 TI - Emergence of feature-specific connectivity in cortical microcircuits in the absence of visual experience. AB - In primary visual cortex (V1), connectivity between layer 2/3 (L2/3) excitatory neurons undergoes extensive reorganization after the onset of visual experience whereby neurons with similar feature selectivity form functional microcircuits (Ko et al., 2011, 2013). It remains unknown whether visual experience is required for the developmental refinement of intracortical circuitry or whether this maturation is guided intrinsically. Here, we correlated the connectivity between V1 L2/3 neurons assayed by simultaneous whole-cell recordings in vitro to their response properties measured by two-photon calcium imaging in vivo in dark-reared mice. We found that neurons with similar responses to oriented gratings or natural movies became preferentially connected in the absence of visual experience. However, the relationship between connectivity and similarity of visual responses to natural movies was not as strong in dark-reared as in normally reared mice. Moreover, dark rearing prevented the normally occurring loss of connections between visually nonresponsive neurons after eye opening (Ko et al., 2013). Therefore, our data suggest that the absence of visual input does not prevent the emergence of functionally specific recurrent connectivity in cortical circuits; however, visual experience is required for complete microcircuit maturation. PMID- 25031420 TI - Is preventive suicide a rational response to a presymptomatic diagnosis of dementia? PMID- 25031419 TI - Sounds activate visual cortex and improve visual discrimination. AB - A recent study in humans (McDonald et al., 2013) found that peripheral, task irrelevant sounds activated contralateral visual cortex automatically as revealed by an auditory-evoked contralateral occipital positivity (ACOP) recorded from the scalp. The present study investigated the functional significance of this cross modal activation of visual cortex, in particular whether the sound-evoked ACOP is predictive of improved perceptual processing of a subsequent visual target. A trial-by-trial analysis showed that the ACOP amplitude was markedly larger preceding correct than incorrect pattern discriminations of visual targets that were colocalized with the preceding sound. Dipole modeling of the scalp topography of the ACOP localized its neural generators to the ventrolateral extrastriate visual cortex. These results provide direct evidence that the cross modal activation of contralateral visual cortex by a spatially nonpredictive but salient sound facilitates the discriminative processing of a subsequent visual target event at the location of the sound. Recordings of event-related potentials to the targets support the hypothesis that the ACOP is a neural consequence of the automatic orienting of visual attention to the location of the sound. PMID- 25031421 TI - Psychiatric taxonomy: at the crossroads of science and ethics. PMID- 25031422 TI - Teaching medical humanities in the digital world: affordances of technology enhanced learning. AB - Medical humanities courses are typically taught in face-to-face teaching environments, but now medical humanities educators, alongside educators from other disciplines, are facing shifts in higher education towards online (and sometimes open) courses. For the medical humanities educator, there is limited guidance regarding how technology-enhanced learning design can support the learning outcomes associated with medical humanities. This article aims to provide useful direction for such educators on how digital technologies can be used through learner-focused pedagogies. Specific examples are provided as to how the affordances of Web 2.0 and other tools can be realised in innovative ways to help achieve skills development within the medical humanities. The guidance, alongside the practical suggestions for implementation, can provide important conceptual background for medical humanities educators who wish to embrace technology-enhanced learning, and reconceptualise or redesign medical humanities for an online or blended teaching environment. PMID- 25031424 TI - Differential expression of metallothioneins in response to heavy metals and their involvement in metal tolerance in the symbiotic basidiomycete Laccaria bicolor. AB - Cysteine-rich peptides such as metallothioneins (MTs) are involved in metal homeostasis and detoxification in many eukaryotes. We report the characterization and expression of two MT genes, LbMT1 and LbMT2 from the ectomycorrhizal fungus Laccaria bicolor under metal stress conditions. LbMT1 and LbMT2 differ with respect to the length of the encoded peptides (58 versus 37 aa, respectively) and also by their expression patterns in response to metals. The expression levels of both LbMT1 and LbMT2 increased as a function of increased external Cu concentration, the expression levels for LbMT2 were always significantly higher compared with those of LbMT1. Only LbMT1, but not LbMT2, responded to Cd supply in the range of 25-100 uM while Zn did not affect the transcription of either LbMT1 or LbMT2. Both genes also responded to oxidative stress, but to a lesser extent compared to their responses to either Cu or Cd stress. Heterologous complementation assays in metal-sensitive yeast mutants indicated that both LbMT1 and LbMT2 encode peptides capable of conferring higher tolerance to both Cu and Cd. The present study identified LbMTs as potential determinants of the response of this mycorrhizal fungus to Cu and Cd stress. PMID- 25031423 TI - Strong mutator phenotype drives faster adaptation from growth on glucose to growth on acetate in Salmonella. AB - The metabolic adaptation of strong mutator strains was studied to better understand the link between the strong mutator phenotype and virulence. Analysis of the growth curves of isogenic strains of Salmonella, which were previously grown in M63 glucose media, revealed that the exponential phase of growth was reached earlier in an M63 acetate medium with strong mutator strains (mutated in mutS or in mutL) than with normomutator strains (P<0.05). Complemented strains confirmed the direct role of the strong mutator phenotype in this faster metabolic adaptation to the assimilation of acetate. In a mixed cell population, proliferation of strong mutators over normomutators was observed when the carbon source was switched from glucose to acetate. These results add to the sparse body of knowledge about strong mutators and highlight the selective advantage conferred by the strong mutator phenotype to adapt to a switch of carbon source in the environment. This work may provide clinically useful information given that there is a high prevalence of strong mutators among pathogenic strains of Salmonella and that acetate is the principal short chain fatty acid of the human terminal ileum and colon where Salmonella infection is localized. PMID- 25031425 TI - Transcriptional regulation of the l-lactate permease gene lutP by the LutR repressor of Bacillus subtilis RO-NN-1. AB - The Bacillus subtilis lutABC operon encodes three iron-sulfur-containing proteins required for l-lactate utilization and involved in biofilm formation. The transcriptional regulator LutR of the GntR family negatively controls lutABC expression. The lutP gene, which is situated immediately upstream of lutR, encodes an l-lactate permease. Here, we show that lutP expression can be strongly induced by l-lactate and is subject to partial catabolite repression by glucose. Disruption of the lutR gene led to a strong derepression of lutP and no further induction by l-lactate, suggesting that the LutR repressor can also negatively control lutP expression. Electrophoretic mobility shift assay revealed a LutR binding site located downstream of the promoter of lutA or lutP and containing a consensus inverted repeat sequence 5'-TCATC-N1-GATGA-3'. Reporter gene analysis showed that deletion of each LutR-binding site caused a strong derepression of lutA or lutP. These results indicated that these two LutR-binding sites can function as operators in vivo. Moreover, deletion analysis identified a DNA segment upstream of the lutP promoter to be important for lutP expression. In contrast to the truncated LutR of laboratory strains 168 and PY79, the full length LutR of the undomesticated strain RO-NN-1, and probably many other B. subtilis strains, can directly and negatively regulate lutP transcription. The absence or presence of the N-terminal 21 aa of the full-length LutR, which encompass a small part of the predicted winged helix-turn-helix DNA-binding motif, may probably alter the DNA-binding specificity or affinity of LutR. PMID- 25031426 TI - Hierarchical management of carbon sources is regulated similarly by the CbrA/B systems in Pseudomonas aeruginosa and Pseudomonas putida. AB - The CbrA/B system in pseudomonads is involved in the utilization of carbon sources and carbon catabolite repression (CCR) through the activation of the small RNAs crcZ in Pseudomonas aeruginosa, and crcZ and crcY in Pseudomonas putida. Interestingly, previous works reported that the CbrA/B system activity in P. aeruginosa PAO1 and P. putida KT2442 responded differently to the presence of different carbon sources, thus raising the question of the exact nature of the signal(s) detected by CbrA. Here, we demonstrated that the CbrA/B/CrcZ(Y) signal transduction pathway is similarly activated in the two Pseudomonas species. We show that the CbrA sensor kinase is fully interchangeable between the two species and, moreover, responds similarly to the presence of different carbon sources. In addition, a metabolomics analysis supported the hypothesis that CCR responds to the internal energy status of the cell, as the internal carbon/nitrogen ratio seems to determine CCR and non-CCR conditions. The strong difference found in the 2-oxoglutarate/glutamine ratio between CCR and non-CCR conditions points to the close relationship between carbon and nitrogen availability, or the relationship between the CbrA/B and NtrB/C systems, suggesting that both regulatory systems sense the same sort or interrelated signal. PMID- 25031427 TI - Quality of life, disability scores, and distress index in fungal rhinosinusitis. AB - Our goal was to determine quality of life (QOL), disability, and distress in the day-to-day lives of patients suffering from fungal rhinosinusitis (FRS) based on a prospective questionnaire. The study included 125 patients suffering from FRS, excluding those with acute fulminant FRS and any other comorbid illness. The data were compared with data for 50 age- and sex-matched controls who did not have any other chronic illness and obtained outpatient services from the Department of Otolaryngology and Head and Neck Surgery of our institute. Analysis showed that patients with FRS had worse QOL, with an average score of 87.34 compared with 94.15 for the control group. QOL score further decreased to 85.31 for patients with extensive disease that included intracranial or intraorbital extension and to 71.1 in those with recurrent disease. Patients showed significant disability and had decreased work efficiency in disability parameters. Distress among these patients was also greater and further increased in those with extensive disease or recurrence. We conclude that patients with FRS have worse QOL, more disability, and more distress compared with age- and sex-matched controls. This issue needs to be addressed while treating cases of FRS. PMID- 25031428 TI - Proinflammatory cytokine-induced tight junction remodeling through dynamic self assembly of claudins. AB - Tight junctions (TJs) are dynamic, multiprotein intercellular adhesive contacts that provide a vital barrier function in epithelial tissues. TJs are remodeled during physiological development and pathological mucosal inflammation, and differential expression of the claudin family of TJ proteins determines epithelial barrier properties. However, the molecular mechanisms involved in TJ remodeling are incompletely understood. Using acGFP-claudin 4 as a biosensor of TJ remodeling, we observed increased claudin 4 fluorescence recovery after photobleaching (FRAP) dynamics in response to inflammatory cytokines. Interferon gamma and tumor necrosis factor alpha increased the proportion of mobile claudin 4 in the TJ. Up-regulation of claudin 4 protein rescued these mobility defects and cytokine-induced barrier compromise. Furthermore, claudins 2 and 4 have reciprocal effects on epithelial barrier function, exhibit differential FRAP dynamics, and compete for residency within the TJ. These findings establish a model of TJs as self-assembling systems that undergo remodeling in response to proinflammatory cytokines through a mechanism of heterotypic claudin-binding incompatibility. PMID- 25031429 TI - Drosophila pericentrin requires interaction with calmodulin for its function at centrosomes and neuronal basal bodies but not at sperm basal bodies. AB - Pericentrin is a critical centrosomal protein required for organizing pericentriolar material (PCM) in mitosis. Mutations in pericentrin cause the human genetic disorder Majewski/microcephalic osteodysplastic primordial dwarfism type II, making a detailed understanding of its regulation extremely important. Germaine to pericentrin's function in organizing PCM is its ability to localize to the centrosome through the conserved C-terminal PACT domain. Here we use Drosophila pericentrin-like-protein (PLP) to understand how the PACT domain is regulated. We show that the interaction of PLP with calmodulin (CaM) at two highly conserved CaM-binding sites in the PACT domain controls the proper targeting of PLP to the centrosome. Disrupting the PLP-CaM interaction with single point mutations renders PLP inefficient in localizing to centrioles in cultured S2 cells and Drosophila neuroblasts. Although levels of PCM are unaffected, it is highly disorganized. We also demonstrate that basal body formation in the male testes and the production of functional sperm does not rely on the PLP-CaM interaction, whereas production of functional mechanosensory neurons does. PMID- 25031430 TI - SERCaMP: a carboxy-terminal protein modification that enables monitoring of ER calcium homeostasis. AB - Endoplasmic reticulum (ER) calcium homeostasis is disrupted in diverse pathologies, including neurodegeneration, cardiovascular diseases, and diabetes. Temporally defining calcium dysregulation during disease progression, however, has been challenging. Here we describe secreted ER calcium-monitoring proteins (SERCaMPs), which allow for longitudinal monitoring of ER calcium homeostasis. We identified a carboxy-terminal modification that is sufficient to confer release of a protein specifically in response to ER calcium depletion. A Gaussia luciferase (GLuc)-based SERCaMP provides a simple and sensitive method to monitor ER calcium homeostasis in vitro or in vivo by analyzing culture medium or blood. GLuc-SERCaMPs revealed ER calcium depletion in rat primary neurons exposed to various ER stressors. In vivo, ER calcium disruption in rat liver was monitored over several days by repeated sampling of blood. Our results suggest that SERCaMPs will have broad applications for the long-term monitoring of ER calcium homeostasis and the development of therapeutic approaches to counteract ER calcium dysregulation. PMID- 25031432 TI - Cordon Bleu serves as a platform at the basal region of microvilli, where it regulates microvillar length through its WH2 domains. AB - Cordon Bleu (Cobl) is a WH2-containing protein believed to act as an actin nucleator. We show that it has a very specific localization in epithelial cells at the basal region of microvilli, a localization unlikely to be involved in actin nucleation. The protein is localized by a central region between the N terminal COBL domain and the three C-terminal WH2 domains. Ectopic expression of Cobl shortens apical microvilli, and this requires functional WH2 domains. Proteomic studies reveal that the COBL domain binds several BAR-containing proteins, including SNX9, PACSIN 2/syndapin 2, and ASAP1. ASAP1 is recruited to the base of microvilli by binding the COBL domain through its SH3. We propose that Cobl is localized to the basal region of microvilli both to participate in length regulation and to recruit BAR proteins that associate with the curved membrane found at the microvillar base. PMID- 25031431 TI - Regulation of spindle pole body assembly and cytokinesis by the centrin-binding protein Sfi1 in fission yeast. AB - Centrosomes play critical roles in the cell division cycle and ciliogenesis. Sfi1 is a centrin-binding protein conserved from yeast to humans. Budding yeast Sfi1 is essential for the initiation of spindle pole body (SPB; yeast centrosome) duplication. However, the recruitment and partitioning of Sfi1 to centrosomal structures have never been fully investigated in any organism, and the presumed importance of the conserved tryptophans in the internal repeats of Sfi1 remains untested. Here we report that in fission yeast, instead of doubling abruptly at the initiation of SPB duplication and remaining at a constant level thereafter, Sfi1 is gradually recruited to SPBs throughout the cell cycle. Like an sfi1Delta mutant, a Trp-to-Arg mutant (sfi1-M46) forms monopolar spindles and exhibits mitosis and cytokinesis defects. Sfi1-M46 protein associates preferentially with one of the two daughter SPBs during mitosis, resulting in a failure of new SPB assembly in the SPB receiving insufficient Sfi1. Although all five conserved tryptophans tested are involved in Sfi1 partitioning, the importance of the individual repeats in Sfi1 differs. In summary, our results reveal a link between the conserved tryptophans and Sfi1 partitioning and suggest a revision of the model for SPB assembly. PMID- 25031433 TI - Clinical significance of low-positive histoplasma urine antigen results. AB - Histoplasma urine antigen (UAg) detection is an important biomarker for histoplasmosis. The clinical significance of low-positive (<0.6 ng/ml) UAg results was evaluated in 25 patients without evidence of prior Histoplasma infection. UAg results from 12/25 (48%) patients were considered falsely positive, suggesting that low-positive UAg values should be interpreted cautiously. PMID- 25031434 TI - Fast and accurate identification of dermatophytes by matrix-assisted laser desorption ionization-time of flight mass spectrometry: validation in the clinical laboratory. AB - The performance of a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) workflow using an extensive reference database for dermatophyte identification was evaluated on 176 clinical strains. Using a direct-deposit procedure after 3 incubation days yielded 40% correct identification. Both increasing incubation time and using an extraction procedure resulted in 100% correct identification. PMID- 25031435 TI - Evaluation of performance and acceptability of two rapid oral fluid tests for HIV detection in Mozambique. AB - Simplified HIV testing based on oral fluid (OF) may allow the expansion of HIV infection counseling and testing (CT) while reducing the risk due to exposure to needles and blood collection. This study evaluated the performance and acceptability of two OF tests (the OraQuick Advance Rapid HIV-1/2 and the Chembio DPP HIV-1/2) from May to September 2009 in two CT sites in Maputo City, Mozambique, compared with results for the national testing algorithm. OF testing was conducted in parallel with whole blood-based testing according to the national HIV algorithm. Blood samples were collected as dried blood spot (DBS) specimens from all participants for quality assurance. HIV infection results were delivered according to the national algorithm. According to the national HIV algorithm, 512 (30.5%) samples were reactive, 1,151 (68.7%) were nonreactive, and 13 (0.8%) were discordant. All discordant cases were retested with an enzyme immunoassay followed by Western blotting, and five (38.5%) were confirmed as HIV positive. The OraQuick OF test showed 518 (30.9%) reactive samples and 1,158 (69.1%) nonreactive samples, with a sensitivity and specificity of 99.8% and 99.8%, respectively. The Chembio DPP OF test showed 519 (31.0%) reactive samples and 1,157 (69.0%) nonreactive samples with a sensitivity and specificity of 100% and 99.8%, respectively. The participants perceived blood testing (49.9%) to be more accurate than OF testing (46.8%). The OF tests showed high performance for the diagnosis of HIV infection when examined individually and in an algorithm, compared with results according to the national testing algorithm. PMID- 25031436 TI - Sequential asymptomatic enterovirus infections in a patient with major histocompatibility complex class II primary immunodeficiency. AB - Patients with primary immunodeficiencies are usually susceptible to enterovirus infections and have higher risks to develop severe clinical forms. We report a unique description of a boy with major histocompatibility complex class II (MHC II) deficiency infected by 9 different enterovirus serotypes during a 2-year period, with very mild clinical symptoms, probably due to the immunoglobulin therapy he was receiving. PMID- 25031437 TI - Neonatal infection with Neisseria meningitidis: analysis of a 97-year period plus case study. AB - Neisseria meningitidis is one of the major causes of meningitis in children and adolescents, but it is rarely found during the neonatal period. Here, we describe a neonate with meningococcal sepsis who was admitted to the hospital on postnatal day 10, and we discuss the clinical features of neonatal infection with N. meningitidis in relation to the literature (analysis of a 97-year period). PMID- 25031438 TI - Unusual detection of an Acinetobacter class D carbapenemase gene, blaOXA-23, in a clinical Escherichia coli isolate. PMID- 25031439 TI - Molecular epidemiology of the pertussis epidemic in Washington State in 2012. AB - Although pertussis disease is vaccine preventable, Washington State experienced a substantial rise in pertussis incidence beginning in 2011. By June 2012, the reported cases reached 2,520 (37.5 cases per 100,000 residents), a 1,300% increase compared with the same period in 2011. We assessed the molecular epidemiology of this statewide epidemic using 240 isolates collected from case patients reported from 19 of 39 Washington counties during 2012 to 2013. The typing methods included pulsed-field gel electrophoresis (PFGE), multilocus variable number tandem repeat analysis (MLVA), multilocus sequence typing (MLST), and pertactin gene (prn) mutational analysis. Using the scheme PFGE-MLVA-MLST-prn mutations-Prn deficiency, the 240 isolates comprised 65 distinct typing profiles. Thirty-one PFGE types were found, with the most common types, CDC013 (n = 51), CDC237 (n = 44), and CDC002 (n = 42), accounting for 57% of them. Eleven MLVA types were observed, mainly comprising type 27 (n = 183, 76%). Seven MLST types were identified, with the majority of the isolates typing as prn2-ptxP3-ptxA1 fim3-1 (n = 157, 65%). Four different prn mutations accounted for the 76% of isolates exhibiting pertactin deficiency. PFGE provided the highest discriminatory power (D = 0.87) and was found to be a more powerful typing method than MLVA and MLST combined (D = 0.67). This study provides evidence for the continued predominance of MLVA 27 and prn2-ptxP3-ptxA1 alleles, along with the reemergence of the fim3-1 allele. Our results indicate that the Bordetella pertussis population causing this epidemic was diverse, with a few molecular types predominating. The PFGE, MLVA, and MLST profiles were consistent with the predominate types circulating in the United States and other countries. For prn, several mutations were present in multiple molecular types. PMID- 25031440 TI - Use of the BacT/alert system for rapid detection of microbial contamination in a pilot study using pancreatic islet cell products. AB - At the Islet Isolation Laboratory of the Scottish National Blood Transfusion Service, manual sterility testing data show that contamination rates are 57.7% for pancreas transport fluid, 4.3% for postpurification islet samples, and 0% for pretransplant islet samples. This pilot study presents the BacT/Alert System as an alternative to manual testing to provide more rapid and sensitive sterility results for islet cell products. PMID- 25031441 TI - Performance of two resin-containing blood culture media in detection of bloodstream infections and in direct matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) broth assays for isolate identification: clinical comparison of the BacT/Alert Plus and Bactec Plus systems. AB - We compared the clinical performances of the BacT/Alert Plus (bioMerieux) and Bactec Plus (Becton Dickinson) aerobic and anaerobic blood culture (BC) media with adsorbent polymeric beads. Patients >= 16 years old with suspected bloodstream infections (BSIs) were enrolled in intensive care units and infectious disease wards. A single 40-ml blood sample was collected from each and used to inoculate (10 ml/bottle) one set of BacT/Alert Plus cultures and one set of Bactec Plus cultures, each set consisting of one aerobic and one anaerobic bottle. Cultures were incubated <= 5 days in the BacT/Alert 3D and Bactec FX instruments, respectively. A total of 128 unique BSI episodes were identified based on the recovery of clinically significant growth in 212 aerobic cultures (106 BacT/Alert and 106 Bactec) and 151 anaerobic cultures (82 BacT/Alert and 69 Bactec). The BacT/Alert aerobic medium had higher recovery rates for Gram positive cocci (P = 0.024), whereas the Bactec aerobic medium was superior for recovery of Gram-negative bacilli (P = 0.006). BacT/Alert anaerobic medium recovery rates exceeded those of the Bactec anaerobic medium for total organisms (P = 0.003), Gram-positive cocci (P = 0.013), and Escherichia coli (P = 0.030). In terms of capacity for diagnosing the 128 septic episodes, the BacT/Alert and Bactec sets were comparable, although the former sets diagnosed more BSIs caused by Gram-positive cocci (P = 0.008). They also allowed earlier identification of coagulase-negative staphylococcal growth (mean, 2.8 h; P = 0.003) and growth in samples from patients not on antimicrobial therapy that yielded positive results (mean, 1.3 h; P < 0.001). Similarly high percentages of microorganisms in BacT/Alert and Bactec cultures (93.8% and 93.3%, respectively) were identified by direct matrix-assisted laser desorption ionization-time of flight mass spectrometry assay of BC broths. The BacT/Alert Plus media line appears to be a reliable, timesaving tool for routine detection of BSIs in the population we studied, although further studies are needed to evaluate their performance in other settings. PMID- 25031442 TI - Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates. AB - An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes. PMID- 25031443 TI - Evaluation of a commercially developed semiautomated PCR-surface-enhanced raman scattering assay for diagnosis of invasive fungal disease. AB - Nonculture-based tests are gaining popularity in the diagnosis of invasive fungal disease (IFD), but PCR is excluded from disease-defining criteria because of limited standardization and a lack of commercial assays. Commercial PCR assays may have a standardized methodology while providing quality assurance. The detection of PCR products by a surface-enhanced Raman scattering (SERS) assay potentially provides superior analytical sensitivity and multiplexing capacity compared to that of real-time PCR. Using this approach, the RenDx Fungiplex assay was developed to detect Candida and Aspergillus. Analytical and clinical evaluations of the assay were undertaken using extraction methods according to European Aspergillus PCR Initiative (EAPCRI) recommendations. A total of 195 previously extracted samples (133 plasma, 49 serum, and 13 whole blood) from 112 patients (29 with proven/probable IFD) were tested. The 95% limit of detection of Candida and Aspergillus was 200 copies per reaction, with an overall reproducibility of 92.1% for detecting 20 input copies per PCR, and 89.8% for the nucleic acid extraction-PCR-SERS process for detecting fungal burdens of <20 genome equivalents per sample. A clinical evaluation showed that assay positivity significantly correlated with IFD (P < 0.0001). The sensitivity of the assay was 82.8% and was similar for both Candida (80.0%) and Aspergillus (85.7%). The specificity was 87.5% and was increased (97.5%) by using a multiple (>= 2 samples) PCR-positive threshold. In summary, the RenDx Fungiplex assay is a PCR SERS assay for diagnosing IFD and demonstrates promising clinical performance on a variety of samples. This was a retrospective clinical evaluation, and performance is likely to be enhanced through a prospective analysis of clinical validity and by determining clinical utility. PMID- 25031444 TI - SAMBA HIV semiquantitative test, a new point-of-care viral-load-monitoring assay for resource-limited settings. AB - Routine viral-load (VL) testing of HIV-infected individuals on antiretroviral therapy (ART) is used to monitor treatment efficacy. However, due to logistical challenges, implementation of VL has been difficult in resource-limited settings. The aim of this study was to evaluate the performance of the SAMBA semi-Q (simple amplification-based assay semiquantitative test for HIV-1) in London, Malawi, and Uganda. The SAMBA semi-Q can distinguish between patients with VLs above and below 1,000 copies/ml. The SAMBA semi-Q was validated with diluted clinical samples and blinded plasma samples collected from HIV-1-positive individuals. SAMBA semi-Q results were compared with results from the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 test, v2.0. Testing of 96 2- to 10-fold dilutions of four samples containing HIV-1 subtype C as well as 488 samples from patients in the United Kingdom, Malawi, and Uganda yielded an overall accuracy for the SAMBA semi-Q of 99% (95% confidence interval [CI], 93.8 to 99.9%) and 96.9% (95% CI 94.9 to 98.3%), respectively, compared to to the Roche test. Analysis of VL data from patients in Malawi and Uganda showed that the SAMBA cutoff of 1,000 copies/ml appropriately distinguished treated from untreated individuals. Furthermore, analysis of the viral loads of 232 patients on ART in Malawi and Uganda revealed similar patterns for virological control, defined as either <1,000 copies/ml (SAMBA cutoff) or <5,000 copies/ml (WHO 2010 criterion; WHO, Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach, 2010). This study suggests that the SAMBA semi-Q has adequate concurrency with the gold standard measurements for viral load. This test can allow VL monitoring of patients on ART at the point of care in resource-limited settings. PMID- 25031445 TI - Evaluation of FilmArray and Verigene systems for rapid identification of positive blood cultures. AB - The Verigene tests for Gram-positive and Gram-negative organisms in blood culture and the FilmArray blood culture identification panel were assessed for their ability to identify pathogens from positive blood cultures. Both platforms correctly identified bacteria in 92% of monomicrobial cultures analyzed, with times to identification that were significantly shorter than those for identification from subcultures. PMID- 25031446 TI - The Bristol stool scale and its relationship to Clostridium difficile infection. AB - The Bristol stool form scale classifies the relative density of stool samples. In a prospective cohort study, we investigated the associations between stool density, C. difficile assay positivity, hospital-onset C. difficile infection, complications, and severity of C. difficile. We describe associations between the Bristol score, assay positivity, and clinical C. difficile infection. PMID- 25031447 TI - First isolate of KPC-2-producing Klebsiella pneumonaie sequence type 23 from the Americas. AB - KPC-2-producing Klebsiella pneumoniae isolates mainly correspond to clonal complex 258 (CC258); however, we describe KPC-2-producing K. pneumoniae isolates belonging to invasive sequence type 23 (ST23). KPC-2 has scarcely been reported to occur in ST23, and this report describes the first isolation of this pathogen in the Americas. Acquisition of resistant markers in virulent clones could mark an evolutionary step toward the establishment of these clones as major nosocomial pathogens. PMID- 25031448 TI - Antimicrobial susceptibilities of group B streptococcus isolates from prenatal screening samples. PMID- 25031450 TI - The unknown citizen: epidemiological challenges in child mental health. AB - Growing concern about the global burden of child mental health disorders has generated an increased interest in population-level efforts to improve child mental health. This in turn has led to a shift in emphasis away from treatment of established disorders and towards prevention and promotion. Prevention efforts are able to draw on a substantial epidemiological literature describing the prevalence and determinants of child mental health disorders. However, there is a striking lack of clearly conceptualised and measurable positive outcomes for child mental health, which may result in missed opportunities to identify optimal policy and intervention strategies. In this paper, we propose an epidemiological approach to child mental health which is in keeping with public health principles and with the WHO definition of health, and which is grounded in current thinking about child development. Constructs such as competence offer the opportunity to develop rigorous outcome measures for epidemiological research, while broader ideas about 'the good life' and 'the good society' derived from philosophical thinking can enable us to shape policy initiatives based on normative ideas of optimal child mental health that extend beyond individuals and undoubtedly beyond the traditional boundaries of the health sector. PMID- 25031449 TI - Bacteriophage-based latex agglutination test for rapid identification of Staphylococcus aureus. AB - Rapid diagnosis is essential for the management of Staphylococcus aureus infections. A host recognition protein from S. aureus bacteriophage phiSLT was recombinantly produced and used to coat streptavidin latex beads to develop a latex agglutination test (LAT). The diagnostic accuracy of this bacteriophage based test was compared with that of a conventional LAT, Pastorex Staph-Plus, by investigating a clinical collection of 86 S. aureus isolates and 128 coagulase negative staphylococci (CoNS) from deep tissue infections. All of the clinical S. aureus isolates were correctly identified by the bacteriophage-based test. While most of the CoNS were correctly identified as non-S. aureus isolates, 7.9% of the CoNS caused agglutination. Thus, the sensitivity of the bacteriophage-based LAT for identification of S. aureus among clinical isolates was 100%, its specificity was 92.1%, its positive predictive value (PPV) was 89.6%, and its negative predictive value (NPV) was 100%. The sensitivity, specificity, PPV, and NPV of the Pastorex LAT for the identification of S. aureus were 100%, 99.2%, 98.9%, and 100%, respectively. Among the additionally tested 35 S. aureus and 91 non-S. aureus staphylococcal reference and type strains, 1 isolate was false negative by each system; 13 and 8 isolates were false positive by the bacteriophage-based and Pastorex LATs, respectively. The ability of the phiSLT protein to detect S. aureus was dependent on the presence of wall teichoic acid (WTA) and corresponded to the production of ribitol phosphate WTA, which is found in most S. aureus clones but only a small minority of CoNS. Bacteriophage-based LAT identification is a promising strategy for rapid pathogen identification. Finding more specific bacteriophage proteins would increase the specificity of this novel diagnostic approach. PMID- 25031451 TI - The recent economic recession and self-rated health in Estonia, Lithuania and Finland: a comparative cross-sectional study in 2004-2010. AB - BACKGROUND: The late-2000s financial crisis had a severe impact on the national economies on a global scale. In Europe, the Baltic countries were among those most affected with more than a 20% decrease in per capita gross domestic product in 2008-2009. In this study, we explored the effects of economic recession on self-rated health in Estonia and Lithuania using Finland, a neighbouring Nordic welfare state, as a point of reference. METHODS: Nationally representative cross sectional data for Estonia (n=10 966), Lithuania (n=7249) and Finland (n=11 602) for 2004-2010 were analysed for changes in age-standardised prevalence rates of less-than-good self-rated health and changes in health inequalities using logistic regression analysis. RESULTS: The prevalence of less-than-good self rated health increased slightly (albeit not statistically significantly) in all countries during 2008-2010. This was in sharp contrast to the statistically significant decline in the prevalence of less-than-good health in 2004-2008 in Estonia and Lithuania. Health disparities were larger in Estonia and Lithuania when compared to Finland, but decreased in 2008-2010 (in men only). In Finland, both the prevalence of less-than-good health and health disparities remained fairly stable throughout the period. CONCLUSIONS: Despite the rapid economic downturn, the short-term health effects in Estonia and Lithuania did not differ from those in Finland, although the recession years marked the end of the previous positive trend in self-rated health. The reduction in health disparities during the recession indicates that different socioeconomic groups were affected disproportionately; however, the reasons for this require further research. PMID- 25031452 TI - Psychosocial and behavioural factors in the explanation of socioeconomic inequalities in adolescent health: a multilevel analysis in 28 European and North American countries. AB - BACKGROUND: The relative contribution of different pathways leading to health inequalities in adolescence was rarely investigated, especially in a cross national perspective. The aim of the study is to analyse the contribution of psychosocial and behavioural factors in the explanation of inequalities in adolescent self-rated health (SRH) by family wealth in 28 countries. METHODS: This study was based on the international WHO 'Health Behaviour in School-aged Children' (HBSC) study carried out in 2005/2006. The total sample included 117 460 adolescents aged 11-15 in 28 European and North American countries. Socioeconomic position was measured using the Family Affluence Scale (FAS). Multilevel logistic regression models were conducted to analyse the direct (independent) and indirect contribution of psychosocial and behavioural factors on SRH. RESULTS: Across all countries, adolescents from low affluent families had a higher risk of reporting fair/poor SRH (OR1.76, CI 1.69 to 1.84). Separate adjustments for psychosocial and behavioural factors reduced the OR of students with low family affluence by 39% (psychosocial) and 22% (behavioural). Together, both approaches explained about 50-60% of inequalities by family affluence in adolescent SRH. Separate analyses showed that relationship to father and academic achievement (psychosocial factors) as well as physical activity and consumption of fruits/vegetables (behavioural factors) were the most important factors in explaining inequalities in SRH. CONCLUSIONS: More than half of the inequalities by family affluence in adolescent SRH were explained by an unequal distribution of psychosocial and behavioural factors. Combining both approaches showed that the contribution of psychosocial factors was higher due to their direct (independent) and indirect impact through behavioural factors. PMID- 25031453 TI - Wealth, income, and health before and after retirement. AB - BACKGROUND: It was supposed that associations of wealth and health might be higher after retirement than in the economically active periods of life, but no comparisons were available. Most studies on wealth were based on net worth, a measure combining several elements of wealth into an index. We examined associations between different elements of wealth and health by comparing retired women and men with economically active ones. METHOD: Data were drawn from the German Socio-Economic Panel, a nationwide longitudinal survey project. Two waves (2002 and 2007) included indicators of wealth in addition to household income and education. Wealth was not depicted by an index. Instead, debts, property of life insurances, home ownership and assets were considered separately with their associations with self-rated health. Two data sets were used to examine whether the results were occasional, or whether they can be replicated. RESULTS: Associations of income and education emerged in respondents in their active periods of life. In most cases indicators of wealth were associated with subjective health. In retired respondents home ownership was the only indicator yielding consistent associations with health, but their sizes turned out as rather moderate. CONCLUSIONS: Contrary to expectation, the associations of wealth and health were inconsistent in the retired study population. These results were obtained in a country with national pension schemes, and it has to be examined whether the findings can be generalised to other countries. The inconsistent findings of indicators of wealth are calling the utility of net worth into question. PMID- 25031454 TI - Revisiting the positive aspects of negative work. PMID- 25031455 TI - The metabolic cost of human running: is swinging the arms worth it? AB - Although the mechanical function is quite clear, there is no consensus regarding the metabolic benefit of arm swing during human running. We compared the metabolic cost of running using normal arm swing with the metabolic cost of running while restricting the arms in three different ways: (1) holding the hands with the arms behind the back in a relaxed position (BACK), (2) holding the arms across the chest (CHEST) and (3) holding the hands on top of the head (HEAD). We hypothesized that running without arm swing would demand a greater metabolic cost than running with arm swing. Indeed, when compared with running using normal arm swing, we found that net metabolic power demand was 3, 9 and 13% greater for the BACK, CHEST and HEAD conditions, respectively (all P<0.05). We also found that when running without arm swing, subjects significantly increased the peak-to-peak amplitudes of both shoulder and pelvis rotation about the vertical axis, most likely a compensatory strategy to counterbalance the rotational angular momentum of the swinging legs. In conclusion, our findings support our general hypothesis that swinging the arms reduces the metabolic cost of human running. Our findings also demonstrate that arm swing minimizes torso rotation. We infer that actively swinging the arms provides both metabolic and biomechanical benefits during human running. PMID- 25031456 TI - A systems-level approach to understanding transcriptional regulation by p53 during mammalian hibernation. AB - Presumably to conserve energy, many mammals enter into hibernation during the winter. Homeostatic processes such as transcription and translation are virtually arrested. To further elucidate transcriptional regulation during hibernation, we studied the transcription factor p53. Here, we demonstrate that changes in liver mRNA and protein concentrations of known regulators of p53 are consistent with activation. p53 mRNA and protein concentrations are unrelated. Importantly, p53 protein concentration is increased ~2-fold during the interbout arousal that punctuates bouts of torpor. As a result, both the interbout arousal and the torpid state are characterized by high levels of nuclear-localized p53. Chromatin immunoprecipitation assays indicate that p53 binds DNA during the winter. Furthermore, p53 recruits RNA polymerase II, as indicated by nuclear run-on data. However, and consistent with previous data indicating an arrest of transcriptional elongation during torpor, p53 'activity' does not result in expected changes in target gene transcripts. These data demonstrate the importance of using a systems level-approach in understanding a complex phenotype such as mammalian hibernation. Relying on interpretations of data that are based on steady-state regulation in other systems may be misleading in the context of non-steady-state conditions such as torpor. PMID- 25031457 TI - Directional vibration sensing in the termite Macrotermes natalensis. AB - Although several behavioural studies demonstrate the ability of insects to localise the source of vibrations, it is still unclear how insects are able to perceive directional information from vibratory signals on solid substrates, because time-of-arrival and amplitude difference between receptory structures are thought to be too small to be processed by insect nervous systems. The termite Macrotermes natalensis communicates using vibrational drumming signals transmitted along subterranean galleries. When soldiers are attacked by predators, they tend to drum with their heads against the substrate and create a pulsed vibration. Workers respond by a fast retreat into the nest. Soldiers in the vicinity start to drum themselves, leading to an amplification and propagation of the signal. Here we show that M. natalensis makes use of a directional vibration sensing in the context of colony defence. In the field, soldiers are recruited towards the source of the signal. In arena experiments on natural nest material, soldiers are able to localise the source of vibration. Using two movable platforms allowing us to vibrate the legs of the left and right sides of the body with a time delay, we show that the difference in time-of arrival is the directional cue used for orientation. Delays as short as 0.2 ms are sufficient to be detected. Soldiers show a significant positive tropotaxis to the platform stimulated earlier, demonstrating for the first time perception of time-of-arrival delays and vibrotropotaxis on solid substrates in insects. PMID- 25031458 TI - Attachment to challenging substrates--fouling, roughness and limits of adhesion in the northern clingfish (Gobiesox maeandricus). AB - Northern clingfish use a ventral suction disc to stick to rough substrates in the intertidal zone. Bacteria, algae and invertebrates grow on these surfaces (fouling) and change the surface properties of the primary substrate, and therefore the attachment conditions for benthic organisms. In this study, we investigate the influence of fouling and surface roughness on the adhesive strength of northern clingfish, Gobiesox maeandricus. We measured clingfish tenacity on unfouled and fouled substrates over four surface roughnesses. We exposed surfaces for 6 weeks in the Pacific Ocean, until they were covered with periphyton. Clingfish tenacity is equivalent on both fouled and unfouled smooth substrates; however, tenacity on fouled rough surfaces is less compared with tenacity on unfouled ones. We hypothesize that parts of biofilm may act as a lubricant and decrease friction of the disc margin, thereby making disc margins slip inwards and fail at lower tenacities. Nevertheless, even on fouled surfaces the adhesive forces are approximately 150 times the body weight of the fish. To identify the upper threshold of surface roughness the fish can cling to, we tested seven unfouled substrates of increasing surface roughness. The threshold roughness at which northern clingfish failed increased with specimen size. We hypothesize that because of the elastic properties of the disc margin, a larger disc can adapt to larger surface irregularities. The largest specimens (length 10 12 cm) were able to cling to surfaces with 2-4 mm grain size. The fish can attach to surfaces with roughness between 2 and 9% of the suction disc width. PMID- 25031459 TI - Regulation of intestinal IgA responses by dietary palmitic acid and its metabolism. AB - Enhancement of intestinal IgA responses is a primary strategy in the development of oral vaccine. Dietary fatty acids are known to regulate host immune responses. In this study, we show that dietary palmitic acid (PA) and its metabolites enhance intestinal IgA responses. Intestinal IgA production was increased in mice maintained on a PA-enriched diet. These mice also showed increased intestinal IgA responses against orally immunized Ag, without any effect on serum Ab responses. We found that PA directly stimulates plasma cells to produce Ab. In addition, mice receiving a PA-enriched diet had increased numbers of IgA-producing plasma cells in the large intestine; this effect was abolished when serine palmitoyltransferase was inhibited. These findings suggest that dietary PA regulates intestinal IgA responses and has the potential to be a diet-derived mucosal adjuvant. PMID- 25031460 TI - Therapy of peritoneally disseminated colon cancer by TAP-deficient embryonic stem cell-derived macrophages in allogeneic recipients. AB - We established a method to generate a large quantity of myeloid lineage cells from mouse embryonic stem (ES) cells, termed ES cell-derived proliferating myeloid cell lines (ES-ML). ES-ML continuously proliferated in the presence of M CSF and GM-CSF. ES-ML genetically modified to express an anti-HER2 (neu) mAb single-chain V region fragment reduced the number of cocultured mouse Colon-26 cancer cells expressing HER2. Stimulation of ES-ML with IFN-gamma plus LPS or TNF resulted in almost complete killing of the Colon-26 cells by the ES-ML, and the cytotoxicity was mediated, in part, by NO produced by ES-ML. When ES-ML were injected into mice with i.p. established Colon-26 tumors, they efficiently infiltrated the tumor tissues. Injection of ES-ML with rIFN-gamma and LPS inhibited cancer progression in the mouse peritoneal cavity. Coinjection of TNF transfected or untransfected ES-ML with rIFN-gamma inhibited cancer growth and resulted in prolonged survival of the treated mice. In this experiment, transporter associated with Ag processing (TAP)1-deficient ES-ML exhibited therapeutic activity in MHC-mismatched allogeneic recipient mice. Despite the proliferative capacity of ES-ML, malignancy never developed from the transferred ES-ML in the recipient mice. In summary, TAP-deficient ES-ML with anticancer properties exhibited a therapeutic effect in allogeneic recipients, suggesting the possible use of TAP-deficient human-induced pluripotent stem cell-derived proliferating myeloid cell lines in cancer therapy. PMID- 25031462 TI - Paleoparasitological studies on mummies of the Joseon Dynasty, Korea. AB - Paleoparasitology is the application of conventional or molecular investigative techniques to archeological samples in order to reveal parasitic infection patterns among past populations. Although pioneering studies already have reported key paleoparasitological findings around the world, the same sorts of studies had not, until very recently, been conducted in sufficient numbers in Korea. Mummified remains of individuals dating to the Korean Joseon Dynasty actually have proved very meaningful to concerned researchers, owing particularly to their superb preservation status, which makes them ideal subjects for paleoparasitological studies. Over the past several years, our study series on Korean mummies has yielded very pertinent data on parasitic infection patterns prevailing among certain Joseon Dynasty populations. In this short review, we summarized the findings and achievements of our recent paleoparasitological examinations of Joseon mummies and discussed about the prospects for future research in this vein. PMID- 25031461 TI - CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120. AB - The innate immune system has been implicated in several neurodegenerative diseases, including HIV-1-associated dementia. In this study, we show that genetic ablation of CCR5 prevents microglial activation and neuronal damage in a transgenic model of HIV-associated brain injury induced by a CXCR4-using viral envelope gp120. The CCR5 knockout (KO) also rescues spatial learning and memory in gp120-transgenic mice. However, the CCR5KO does not abrogate astrocytosis, indicating it can occur independently from neuronal injury and behavioral impairment. To characterize further the neuroprotective effect of CCR5 deficiency we performed a genome-wide gene expression analysis of brains from HIVgp120tg mice expressing or lacking CCR5 and nontransgenic controls. A comparison with a human brain microarray study reveals that brains of HIVgp120tg mice and HIV patients with neurocognitive impairment share numerous differentially regulated genes. Furthermore, brains of CCR5 wild-type and CCR5KO gp120tg mice express markers of an innate immune response. One of the most significantly upregulated factors is the acute phase protein lipocalin-2 (LCN2). Using cerebrocortical cell cultures, we find that LCN2 is neurotoxic in a CCR5-dependent fashion, whereas inhibition of CCR5 alone is not sufficient to abrogate neurotoxicity of a CXCR4 using gp120. However, the combination of pharmacologic CCR5 blockade and LCN2 protects neurons from toxicity of a CXCR4-using gp120, thus recapitulating the finding in CCR5-deficient gp120tg mouse brain. Our study provides evidence for an indirect pathologic role of CCR5 and a novel protective effect of LCN2 in combination with inhibition of CCR5 in HIV-associated brain injury. PMID- 25031463 TI - Lethal effects of Helianthemum lippii (L.) on Acanthamoeba castellanii cysts in vitro. AB - Acanthamoeba spp. commonly cause Acanthamoeba keratitis which is typically associated with the wear of contact lenses. Therefore, finding an economic, efficient, and safe therapy of natural origin is of outmost importance. This study examined the in vitro lethal potential of ethyl acetate and methanol extracts of Helianthemum lippii (L.) (sun roses) against Acanthamoeba castellanii cysts isolated from patients with amoebic keratitis. Both extracts proved to be potent as regard to their lethal effects on A. castellanii cysts with comparable results to chlorhexidine. The ethyl acetate was more promising with cumulative lethality. It showed a highly significant lethal percentage along the duration of treatment. The analysis of the more potent ethyl acetate extract revealed the presence of 2.96 mg/100 g of total phenolics, 0.289 mg/100 ml of total flavonoids and 37 mg/100 mg of total tannins which highlighted their phytomedicinal role. PMID- 25031464 TI - A novel recombinant BCG vaccine encoding eimeria tenella rhomboid and chicken IL 2 induces protective immunity against coccidiosis. AB - A novel recombinant Bacille Calmette-Guerin (rBCG) vaccine co-expressed Eimeria tenella rhomboid and cytokine chicken IL-2 (chIL-2) was constructed, and its efficacy against E. tenella challenge was observed. The rhomboid gene of E. tenella and chIL-2 gene were subcloned into integrative expression vector pMV361, producing vaccines rBCG pMV361-rho and pMV361-rho-IL2. Animal experiment via intranasal and subcutaneous route in chickens was carried out to evaluate the immune efficacy of the vaccines. The results indicated that these rBCG vaccines could obviously alleviate cacal lesions and oocyst output. Intranasal immunization with pMV361-rho and pMV361-rho-IL2 elicited better protective immunity against E. tenella than subcutaneous immunization. Splenocytes from chickens immunized with either rBCG pMV361-rho and pMV361-rho-IL2 had increased CD4(+) and CD8(+) cell production. Our data indicate recombinant BCG is able to impart partial protection against E. tenella challenge and co-expression of cytokine with antigen was an effective strategy to improve vaccine immunity. PMID- 25031465 TI - Genotyping of Toxoplasma gondii from Rats (Rattus rattus) in Riyadh, Saudi Arabia. AB - Toxoplasma 3 main clonal lineages are designated as type I, II, and III; however, atypical and mixed genotypes were also reported. This study was conducted for detection of Toxoplasma gondii genotypes in rats (Rattus rattus) in Riyadh region, Saudi Arabia. PCR test on T. gondii B1 gene was conducted on ELISA IgM positive samples for confirmation of the infection. However, genetic analysis of the SAG2 locus was performed to determine T. gondii genotypes using PCR-RFLP technique. PCR test on T. gondii B1gene showed that 22 (81.5%) out of the 27 ELISA IgM positive samples have T. gondii DNA. Genotypic analysis shows that, of the total 22 PCR positive samples, only 13 (59.1%) were of type II, 7 (31.8%) were of type III, and 2 (9.1%) were of an unknown genotype. It is obvious that the prevalence of both type II and III is high in rats. No reports have been available on T. gondii genotypes among rats in Riyadh region, and only little is known about its seroprevalence in rats. Future studies on T. gondii genotypes in rats using multi-locus markers is needed in Riyadh region, Saudi Arabia for better understanding of T. gondii pathogenesis and treatment in humans and animals. PMID- 25031466 TI - DNA extraction from protozoan oocysts/cysts in feces for diagnostic PCR. AB - PCR detection of intestinal protozoa is often restrained by a poor DNA recovery or by inhibitors present in feces. The need for an extraction protocol that can overcome these obstacles is therefore clear. QIAamp(r) DNA Stool Mini Kit (Qiagen) was evaluated for its ability to recover DNA from oocysts/cysts directly from feces. Twenty-five Giardia-positive, 15 Cryptosporidium-positive, 15 Entamoeba histolytica-positive, and 45 protozoa-free samples were processed as control by microscopy and immunoassay tests. DNA extracts were amplified using 3 sets of published primers. Following the manufacturer's protocol, the kit showed sensitivity and specificity of 100% towards Giardia and Entamoeba. However, for Cryptosporidium, the sensitivity and specificity were 60% (9/15) and 100%, respectively. A series of optimization experiments involving various steps of the kit's protocol were conducted using Cryptosporidium-positive samples. The best DNA recoveries were gained by raising the lysis temperature to the boiling point for 10 min and the incubation time of the InhibitEX tablet to 5 min. Also, using a pre-cooled ethanol for nucleic acid precipitation and small elution volume (50 100 ul) were valuable. The sensitivity of the amended protocol to Cryptosporidium was raised to 100%. Cryptosporidium DNA was successfully amplified by either the first or the second primer set. When applied on parasite-free feces spiked with variable oocysts/cysts counts, ~ 2 oocysts/cysts were theoretically enough for detection by PCR. To conclude, the Qiagen kit with the amended protocol was proved to be suitable for protozoan DNA extraction directly from feces and support PCR diagnosis. PMID- 25031467 TI - Increased intestinal epithelial cell turnover and intestinal motility in Gymnophalloides seoi-infected C57BL/6 mice. AB - The changing patterns of goblet cell hyperplasia, intestinal epithelial cell turnover, and intestinal motility were studied in ICR and C57BL/6 mice infected with Gymnophalloides seoi (Digenea: Gymnophallidae). Whereas ICR mice retained G. seoi worms until day 7 post-infection (PI), C57BL/6 mice showed a rapid worm expulsion within day 3 PI. Immunosuppression with Depo-Medrol significantly delayed the worm expulsion in C57BL/6 mice. Goblet cell counts were increased in both strains of mice, peaking at day 1 PI in C57BL/6 mice and slowly increasing until day 7 PI in ICR mice. In C57BL/6 mice infected with G. seoi, newly proliferating intestinal epithelial cells were remarkably increased in the crypt, and the increase was the highest at day 1 PI. However, in ICR mice, newly proliferating intestinal epithelial cells increased slowly from day 1 to day 7 PI. Intestinal motility was increased in G. seoi-infected mice, and its chronological pattern was highly correlated with the worm load in both strains of mice. Meanwhile, immunosuppression of C57BL/6 mice abrogated the goblet cell proliferation, reduced the epithelial cell proliferation, and suppressed the intestinal motility. Goblet cell hyperplasia, increased intestinal epithelial cell turnover, and increased intestinal motility should be important mucosal defense mechanisms in G. seoi-infected C57BL/6 mice. PMID- 25031468 TI - Ticks collected from wild and domestic animals and natural habitats in the Republic of Korea. AB - Ticks were collected from 35 animals from 5 provinces and 3 metropolitan cities during 2012. Ticks also were collected by tick drag from 4 sites in Gyeonggi-do (2) and Jeollabuk-do (2) Provinces. A total of 612 ticks belonging to 6 species and 3 genera were collected from mammals and a bird (n=573) and by tick drag (n=39). Haemaphyalis longicornis (n=434) was the most commonly collected tick, followed by H. flava (158), Ixodes nipponensis (11), Amblyomma testudinarium (7), H. japonica (1), and H. formosensis (1). H. longicornis and H. flava were collected from all animal hosts examined. For animal hosts (n>1), the highest Tick Index (TI) was observed for domestic dogs (29.6), followed by Siberian roe deer (17.4), water deer (14.4), and raccoon dogs (1.3). A total of 402 H. longicornis (adults 86, 21.4%; nymphs 160, 39.8%; larvae 156, 38.9%) were collected from wild and domestic animals. A total of 158 H. flava (n=158) were collected from wild and domestic animals and 1 ring-necked pheasant, with a higher proportion of adults (103, 65.2%), while nymphs and larvae only accounted for 12.7% (20) and 22.2% (35), respectively. Only 7 A. testudinarium were collected from the wild boar (6 adults) and Eurasian badger (1 nymph), while only 5 I. nipponensis were collected from the water deer (4 adults) and a raccoon dog (1 adult). One adult female H. formosensis was first collected from vegetation by tick drag from Mara Island, Seogwipo-si, Jeju-do Province. PMID- 25031469 TI - A case of Echinostoma cinetorchis (Trematoda: Echinostomatidae) infection diagnosed by colonoscopy. AB - Human cases of echinostomiasis have been sporadically diagnosed by extracting worms in the endoscopy in Korea and Japan. Most of these were caused by Echinostoma hortense infection. However, in the present study, we detected 2 live worms of Echinostoma cinetorchis in the ascending colon of a Korean man (68-year old) admitted to the Gyeongsang National University Hospital with complaint of intermittent right lower quadrant abdominal pain for 5 days. Under colonoscopy, 1 worm was found attached on the edematous and hyperemic mucosal surface of the proximal ascending colon and the other was detected on the mid-ascending colon. Both worms were removed from the mucosal surface with a grasping forceps, and morphologically identified as E. cinetorchis by the characteristic head crown with total 37 collar spines including 5 end-group ones on both sides, disappearance of testes, and eggs of 108*60 um with abopercular wrinkles. The infection source of this case seems to be the raw frogs eaten 2 months ago. This is the first case of endoscopy-diagnosed E. cinetorchis infection in Korea. PMID- 25031470 TI - Four human cases of Acanthotrema felis (Digenea: Heterophyidae) infection in Korea. AB - Acanthotrema felis is an intestinal trematode of cats originally reported from the Republic of Korea. Only 1 human case infected with a single adult worm has been previously recorded. In the present study, we report 4 human cases infected with a total of 10 worms recovered after anthelmintic treatment and purging. All 4 patients reside in coastal areas of Jeollanam-do, Korea, and have consumed brackish water fish including the gobies, Acanthogobius flavimanus. The worms averaged 0.47 mm in length and 0.27 mm in width, and had 3 sclerites on the ventrogenital sac; 1 was short and thumb-like, another was long and blunt-ended, and the 3rd was long and broad-tipped. They were identified as A. felis Sohn, Han, & Chai, 2003. Surveys on coastal areas to detect further human cases infected with A. felis are required. PMID- 25031471 TI - Primary renal hydatid cyst: mis-interpretation as a renal malignancy. AB - Primary renal echinococcosis, a rare disease involving the kidney, accounts for 2 3% of human echinococcosis. A 64-year-old female patient from Uzbekistan presented with complaints of left flank pain. A CT scan revealed a cystic mass in the upper to midpole of the left kidney. We regarded this lesion as a renal malignancy and hand-assisted laparoscopic radical nephrectomy was performed to remove the renal mass. The mass consisted of a large unilocular cyst and multiple smaller cysts without any grossly visible renal tissue. The final pathologic diagnosis was a renal hydatid cyst. For patients from endemic areas, hydatid cyst should be included in the differential diagnosis. Here, we present a case of renal hydatid cyst in a female patient who relocated from Uzbekistan to Korea. PMID- 25031472 TI - Genotyping of Giardia duodenalis isolates from dogs in Guangdong, China based on multi-locus sequence. AB - This study aimed to identify the assemblages (or subassemblages) of Giardia duodenalis by using normal or nested PCR based on 4 genetic loci: glutamate dehydrogenase (gdh), triose phosphate isomerase (tpi), beta-giardin (bg), and small subunit ribosomal DNA (18S rRNA) genes. For this work, a total of 216 dogs' fecal samples were collected in Guangdong, China. The phylogenetic trees were constructed with MEGA5.2 by using the neighbor-joining method. Results showed that 9.7% (21/216) samples were found to be positive; moreover, 10 samples were single infection (7 isolates assemblage A, 2 isolates assemblage C, and 1 isolate assemblage D) and 11 samples were mixed infections where assemblage A was predominant, which was potentially zoonotic. These findings showed that most of the dogs in Guangdong were infected or mixed-infected with assemblage A, and multi-locus sequence typing could be the best selection for the genotype analysis of dog-derived Giardia isolates. PMID- 25031473 TI - Development of loop-mediated isothermal amplification targeting 18s ribosomal DNA for rapid detection of Azumiobodo hoyamushi (Kinetoplastea). AB - Ascidian soft tunic syndrome (AsSTS) caused by Azumiobodo hoyamushi (A. hoyamushi) is a serious aquaculture problem that results in mass mortality of ascidians. Accordingly, the early and accurate detection of A. hoyamushi would contribute substantially to disease management and prevention of transmission. Recently, the loop-mediated isothermal amplification (LAMP) method was adopted for clinical diagnosis of a range of infectious diseases. Here, the authors describe a rapid and efficient LAMP-based method targeting the 18S rDNA gene for detection of A. hoyamushi using ascidian DNA for the diagnosis of AsSTS. A. hoyamushi LAMP assay amplified the DNA of 0.01 parasites per reaction and detected A. hoyamushi in 10 ng of ascidian DNA. To validate A. hoyamushi 18S rDNA LAMP assays, AsSTS-suspected and non-diseased ascidians were examined by microscopy, PCR, and by using the LAMP assay. When PCR was used as a gold standard, the LAMP assay showed good agreement in terms of sensitivity, positive predictive value (PPV), and negative predictive value (NPV). In the present study, a LAMP assay based on directly heat-treated samples was found to be as efficient as DNA extraction using a commercial kit for detecting A. hoyamushi. Taken together, this study shows the devised A. hoyamushi LAMP assay could be used to diagnose AsSTS in a straightforward, sensitive, and specific manner, that it could be used for forecasting, surveillance, and quarantine of AsSTS. PMID- 25031474 TI - In vitro trypanocidal activity of macela (Achyrocline satureioides) extracts against Trypanosoma evansi. AB - The aim of this study was to verify the trypanocidal effectiveness of aqueous, methanolic, and ethanolic extracts of Achyrocline satureioides against Trypanosoma evansi in vitro. A. satureioides extracts, known as macela, were used on trypomastigotes at different concentrations (1, 5, 10, 50, 100, 500, and 1,000 ug/ml) and exposure times (0, 1, 3, 6, and 9 hr). A dose-dependent effect was observed when the 3 extracts were tested. The concentrations of 1, 5, and 10 ug/ml were not able to kill trypomastigotes until 3 hr after exposure, and the highest concentrations (500 and 1,000 ug/ml) were able to kill all trypomastigotes after 1 hr. When the time of exposure was increased up to 9 hr, the concentrations at 50 and 100 ug/ml were 100% effective to 3 extracts. The chemical analysis of the extracts revealed the presence of flavonoids, a trypanocidal compound already described. Based on the results, we can conclude that the A. satureioides extracts exhibit trypanocidal effects. PMID- 25031475 TI - Effects of different sizes of glass beads on the release of sporocysts from Eimeria tenella oocysts. AB - The oocyst wall is severed by means of mechanical injury or chemical agents. This study reports the percentage of in vitro sporocyst release following mechanical shaking in the presence of varying sizes of glass beads. Glass beads measured 0.5, 1, and 3 mm in diameter and were shaken with the oocysts for different times ranging from 5 sec to 5 min. Approximately 80% of sporocysts were released with 5 min of shaking in the presence of 3 mm glass beads, as well as 30 sec with 0.5 mm beads and 1 mm glass beads. The release of sporocysts of E. tenella was most efficient using 1 mm glass beads and treatment times of 30 sec to 1 min. Therefore, the use of 1 mm glass beads with 30 sec to 1 min of agitation is recommended in order to maximize sporocyst release and recovery and to improve the yield of viable sporozoites for use in biochemical, tissue culture, and immunological applications of coccidia. PMID- 25031476 TI - Seroprevalence of Encephalitozoon cuniculi in pet rabbits in Korea. AB - Encephalitozoon cuniculi is a microsporidian parasite commonly found in rabbits that can infect humans, causing encephalitozoonosis. The prevalence of encephalitozoonosis is not well documented, even when many clinics suspect pet rabbits as being highly infected. This study investigated the seropositivity of E. cuniculi using ELISA. The examination of 186 rabbits using ELISA showed that 22.6% (42/186) were seropositive against E. cuniculi. In analysis with healthy status, all 42 seropositive sera were collected from clinically normal rabbits. Moreover, the gender and age of pet rabbits did not have anysignificant effect on E. cuniculi infection. To the best of our knowledge, this is the first report to describe the seroprevalence of E. cuniculi in pet rabbits and suggests that pet rabbits could act as an important reservoir of encephalitozoonosis for both pet animals and humans in Korea. PMID- 25031477 TI - Phylogenetic relationships of 3 Korean Neodiplostomum species (Digenea: Neodiplostomidae) based on partial CO1 gene. AB - The phylogenetic relationships of the 3 Neodiplostomum spp. (Digenea: Neodiplostomidae) occurring in Korea (N. seoulense, N. leei, and N. boryongense) were analyzed using the partial mitochondrial cytochrome c oxidase subunit 1 (CO1) gene. The adult flukes were recovered from Sprague-Dawley rats (N. seoulense) and newborn chicks (N. leei and N. boryongense) experimentally infected with the neodiplostomula from the grass snake, Rhabdophis tigrinus tigrinus. The genomic DNA was amplified using specific primers, and the sequence of CO1 was obtained. According to the results, the pairwise similarity was 96.1% between N. boryongense and N. seoulense, but was 95.0% between N. boryongense and N. leei and 94.2% between N. leei and N. seoulense. The results demonstrated a closer phylogenetic relationship between N. seoulense and N. boryongense. This high relationship of N. seoulense and N. boryongense may be related to their similar morphologic features including the limited distribution of vitellaria and the presence of a genital cone. N. leei is distinct on the other hand with an extensive distribution of vitellaria and the absence of a genital cone. PMID- 25031478 TI - Prevalence of hydatid cysts in livestock animals in Xinjiang, China. AB - Hydatid worms, hosted by humans and animals, impose serious human health risk and cause significant livestock production loss. To better understand the disease infection status in Xinjiang, China, we investigated the disease epidemics in 4 livestock animals, i.e., cattle, sheep (both sheep and goat), camels, and horses, slaughtered at the abattoirs in Urumqi, Yining, Tacheng, and Altay areas. The results showed that the animals were infected at different rates, in the order of sheep (9.8%), cattle (8.4%), camels (6.8%), and horses (4.3%). The infection rates were found to be different between the abattoirs in various regions even for the same animals. For sheep, the rates increased significantly as the animals grew older. It was 1.9% before 1 year of age and increased to 8.2% in the age of 1-2 years, and further increased to 12.3% when the animals were 3-4 years old, and reached 17.2% when they were 5-6 year old. Sheep older than 6 years had an infection rate of 19.5%. This study demonstrates that the 4 livestock animals in the pastoral areas in Xinjiang were infected by the parasites to various extend. This study is the first systematic investigation of the hydatid worms in various livestock animals in Xinjiang, China, which provides epidemiological information about the infection of hydatid worms in livestock, and is valuable in developing strategies for prevention and control of the hydatid disease. PMID- 25031479 TI - Parasitic diseases as the cause of death of prisoners of war during the Korean War (1950-1953). AB - To determine the cause of death of prisoners of war during the Korean War (1950 1953), death certificates or medical records were analyzed. Out of 7,614 deaths, 5,013 (65.8%) were due to infectious diseases. Although dysentery and tuberculosis were the most common infectious diseases, parasitic diseases had caused 14 deaths: paragonimiasis in 5, malaria in 3, amoebiasis in 2, intestinal parasitosis in 2, ascariasis in 1, and schistosomiasis in 1. These results showed that paragonimiasis, malaria, and amoebiasis were the most fatal parasitic diseases during the early 1950s in the Korean Peninsula. Since schistosomiasis is not endemic to Korea, it is likely that the infected private soldier moved from China or Japan to Korea. PMID- 25031481 TI - Parents' rules about underage drinking: a qualitative study of why parents let teens drink. AB - Results from a qualitative study with parents about underage drinking are presented. Semistructured interviews (n = 44) were conducted with parents of teens to investigate whether and why parents permit underage drinking. Parents had three primary reasons for allowing underage drinking: deliberate, spontaneous, and harm reduction. Deliberate reasons included passing on knowledge about drinking responsibly and appreciating alcohol. Parents also spontaneously decided to let their teen drink. Some of these spontaneous situations involved feeling pressure from other adults to let their teen drink. Another reason was a desire to reduce potential harm. Parents feared that forbidding underage drinking would harm their relationship with their teen and potentially lead to drunk driving. Prevention efforts aimed at parents should take into account parents' motivations to let teens drink. PMID- 25031482 TI - Differentiation of Calcium Carbonate Polymorphs by Surface Analysis Techniques - An XPS and TOF-SIMS study. AB - Calcium carbonate has evoked interest owing to its use as a biomaterial, and for its potential in biomineralization. Three polymorphs of calcium carbonate, i.e. calcite, aragonite, and vaterite were synthesized. Three conventional bulk analysis techniques, Fourier transform infrared (FTIR), X-ray diffraction (XRD), and SEM, were used to confirm the crystal phase of each polymorphic calcium carbonate. Two surface analysis techniques, X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectroscopy (TOF-SIMS), were used to differentiate the surfaces of these three polymorphs of calcium carbonate. XPS results clearly demonstrate that the surfaces of these three polymorphs are different as seen in the Ca(2p) and O(1s) core-level spectra. The different atomic arrangement in the crystal lattice, which provides for a different chemical environment, can explain this surface difference. Principal component analysis (PCA) was used to analyze the TOF-SIMS data. Three polymorphs of calcium carbonate cluster into three different groups by PCA scores. This suggests that surface analysis techniques are as powerful as conventional bulk analysis to discriminate calcium carbonate polymorphs. PMID- 25031483 TI - The effects of whole body vibration on mobility and balance in Parkinson disease: a systematic review. AB - Whole body vibration (WBV) is a contemporary treatment modality that holds promise as an exercise training method in health-compromised individuals. A growing number of studies on individuals with Parkinson Disease are examining whether WBV improves balance and functional mobility. However, interpreting WBV studies is challenging since there is variability in the manner in which WBV intervention is conducted. The primary goal of this systematic review was to investigate the effect of WBV on improving mobility and balance as measured by a battery of clinical tests, in patients with Parkinson disease. Studies based on WBV parameters were characterized and a systematic search of peer-reviewed literature in five major databases was conducted. Randomized-controlled trials investigating the effects of WBV in patients with a Parkinson diagnosis and no cognitive impairment were included. A total of six publications met the inclusion criteria. Overall, studies demonstrated mixed results in favor of WBV for improving balance or mobility. The majority of studies seem to suggest a favorable benefit following WBV for mobility and balance, but not when compared to other active intervention or placebo. There was variability in the manner in which WBV intervention was applied. Variations among the six studies included: duration of intervention and rest, follow-up period, type of control groups, frequency of vibration, number of treatment sessions and sex distribution of subjects. Future research is needed to investigate the effects of different types of equipment and treatment dosage in individuals with Parkinson disease. PMID- 25031484 TI - The use of aloe vera extract as a novel storage media for the avulsed tooth. AB - BACKGROUND: Tooth avulsion is one of the most severe dental traumas which most often occur in children. When immediate replantation is not possible, storage in a proper media may lead to a prolonged survival rate. Aloe Vera is a cactus like plant with green, tapered leaves that are filled with a transparent viscous gel. This medicinal plant has significant anti-inflammatory, antioxidant, antibacterial and antifungal effects. The purpose of this study was to assess the effectiveness of different concentrations of Aloe Vera extract compared to DMEM (cell culture medium) and egg white. METHODS: The periodontal ligament (PDL) cells were cultured and certain number of cells were treated with Aloe Vera extract (in four different concentrations), egg white and culture media for 1, 3, 6, and 9 hours. Cell viability was determined by using the (3-[4, 5 dimethylthiazolyl-2]-2, 5-diphenyltetrazolium bromide) assay. Moreover, One-way ANOVA and post hoc (LSD) test were used for analyzing the study groups. RESULTS: The results indicate that culture media and Aloe Vera extract (10, 30, and 50% concentration) were statistically similar and significantly preserved more PDL cells compared to other experimental storage media. CONCLUSION: Aloe Vera 10, 30, and 50% may be recommended as a suitable storage media for avulsed teeth. PMID- 25031485 TI - Bone marrow and karyotype findings of patients with pancytopenia in southern iran. AB - BACKGROUND: Pancytopenia is a manifestation of a wide range of disorders. The main prognostic factor for predicting outcome and response to treatment is based on the underlying cause. To detect the root cause of this problem, depending on other accompanied signs or symptoms, the need for bone marrow examination and other advanced work ups is different at least at the practical level. This study focuses on the karyotype abnormality and to demonstrate the ability of this complimentary study in diagnosis and prognosis of such patients. METHODS: In this cross sectional study, bone marrow aspiration samples of all patients with Pancytopenia underwent cytogenetic investigation on bone marrow aspiration. Gathered data were analyzed by SPSS software. RESULTS: Among the 100 eligible patients, 67% revealed hypercellular, 19% had hypocellular and 13% had normocellular marrow. Most common causes of pancytopenia were myelodysplastic syndrome (MDS) (33%), MDS vs. megaloblastic anemia (23%) and acute leukemia (18%). Thirty one patients had karyotype abnormality in which majority (13 patients) were diagnosed as MDS followed by 11 patients with acute leukemia. CONCLUSION: Beside bone marrow examination, there is a need for more supplementary studies like karyotyping to detect the exact cause of pancytopenia. It is concluded that cytogenetic study on bone marrow aspiration can be a complementary test in diagnosis of pancytopenic patients. However, there are also cases where diagnosis even with implementing bone marrow examination and cytogenetic analysis is not possible. Such patients require more clinical follow up and investigation. PMID- 25031486 TI - Treatment results and prognostic indicators in thymic epithelial tumors: a clinicopathological analysis of 45 patients. AB - BACKGROUND: Thymomas are rare epithelial tumors arising from thymus gland. This study aims at investigating the clinical presentation, prognostic factors and treatment outcome of forty five patients with thymoma and thymic carcinoma. METHODS: Forty-five patients being histologically diagnosed with thymoma or thymic carcinoma that were treated and followed-up at a tertiary academic hospital during January 1987 and December 2008 were selected for the present study. Twelve patients were solely treated with surgery, 14 with surgery followed by adjuvant radiotherapy, 12 with sequential combined treatment of surgery, radiotherapy and/or chemotherapy and 7 with non-surgical approach including radiotherapy and/or chemotherapy. Tumors were classified based on the new World Health Organization (WHO) histological classification. RESULTS: There were 18 women and 27 men with a median age of 43 years. Twelve patients (26.7%) had stage I, 7 (17.8%) had stage II, 23 (51%) had stage III and 2 (4.5%) had stage IV disease. Tumors types were categorized as type A (n=4), type AB (n=10), type B1 (n=9), type B2 (n=10), type B3 (n=5) and type C (n=7). In univariate analysis for overall survival, disease stage (P=0.001), tumor size (P=0.017) and the extent of surgical resection (P<0.001) were prognostic factors. Regarding the multivariate analysis, only the extent of the surgical resection (P<0.001) was the independent prognostic factor and non-surgical treatment had a negative influence on the survival. The 5-year and 10-year overall survival rates were 70.8% and 62.9%, respectively. CONCLUSION: Complete surgical resection is the most important prognostic factor in patients with thymic epithelial tumors. PMID- 25031487 TI - IL-23/IL-27 Ratio in Peripheral Blood of Patients with Breast Cancer. AB - BACKGROUND: Interleukin (IL)-23 and IL-27 are two IL-12-related cytokines which their function may dramatically influence the inflammatory response to tumor development. IL-12 and IL-27 seem to have antagonistic roles with IL-23 in tumor site. In this study, IL-23 and IL-27 mRNA expressions were analyzed in peripheral blood of patients with breast cancer and healthy volunteers using quantitative real-time PCR. METHODS: Peripheral blood samples were collected from 50 women with breast cancer and 50 healthy ones. The total RNA was extracted from peripheral blood after lysis with ammonium chloride and TRizol reagent and the cDNA was synthesized. The expression of IL-23 and IL-27 gene transcripts was determined with real-time polymerase chain reaction (qRT-PCR) using Syber Green PCR Master Mix. RESULTS: It is found that IL-23 and IL-27 transcripts had significantly higher expression in peripheral blood of patients compared with the healthy controls. The ratio of IL-23 transcript expression to IL-27 was 3.4 fold lower in the studied patients compared with the normal individuals. CONCLUSION: It is concluded that the over expression of IL-23 and IL-27 gene transcript in peripheral blood of breast cancer patients may be an immune response against tumor development and the inflammatory response plays a critical role in tumor development via up regulating the corresponding cytokines. However, the IL-23/IL 27 ratio may play an important role in cytokine-based immunotherapy against cancer. Further research should be carried out to assess these cytokines in a larger sample size. . PMID- 25031488 TI - Combination Therapy with Losartan and alpha-Tocopherol in Acute Ureteral Obstruction-Induced Renal Excretory Dysfunction and Acidification Defect. AB - BACKGROUND: Previous study by the authors showed that a-tocopherol prevents oxidative stress but would not improve depressed excretory variables in post obstructed kidney (POK) after release of 24-h unilateral ureteral obstruction (UUO). This study is a supplementary investigation on the effects of a-tocopherol combined with an antagonist of angiotensin-II type-1 (AT1) receptor on renal dysfunction following release of acute UUO. METHODS: The left ureter was ligated in different groups of male Sprague-Dawley rats that received normal saline, losartan or losartan/a-tocopherol (n=6 in each group). After releasing 24-h UUO, urine of each kidney was separately collected under paraffin during 1-3 h of post release period and then both kidneys were removed for measuring malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP). RESULTS: Losartan-treatment decreased MDA and increased FRAP, creatinine-clearance and sodium-reabsorption in POK, while co-treatment with losartan and a-tocopherol not only augmented improvement in these variables but also elevated potassium-excretion, free-water reabsorption and urine-osmolality. However, UUO-induced fall in urinary pCO2 and rise in pH and bicarbonate-excretion of POK were ameliorated equally with losartan and losartan/a-tocopherol. CONCLUSION: Activation of AT1-receptor contributes to the development of renal distal acidification defect induced by acute ureteral obstruction. The co-treatment with losartan and a-tocopherol showed that their effects on preventing oxidative stress along with ameliorating glomerular filtration and tubular fluid-delivery in POK could lead to improvement in tubular transport of sodium and potassium as well as urine-concentrating ability at the early post-release period. PMID- 25031489 TI - Genetic Polymorphisms of CCL22 and CCR4 in Patients with Lung Cancer. AB - BACKGROUND: An association between lung cancer and chemokines has been advocated in the recent years. This study aims at investigating the association between lung cancer and 16C/A single nucleotide polymorphism (SNP) (rs. 4359426) in C-C motif chemokine 22 (CCL22) as well as C1014T SNP (rs. 2228428) in C-C chemokine receptor type 4 (CCR4), which serves as the receptor for CCL22. METHODS: Genotyping was performed in 148 lung cancer patients and 148 normal controls using Polymerase Chain Reaction-Restriction-Fragment Length Polymorphism (PCR RFLP). The data were verified by direct automated sequencing. RESULTS: Frequencies of CC, CA and AA genotypes of 16C/A SNP in CCL22 gene were 112 (75.7%), 33 (22.3%) and 3 (2.0%) in patients, and 119 (80.4%), 24 (16.2%) and 5 (3.4%) in controls respectively. No significant differences were observed in genotype frequencies at this position between cases and controls (P=0.34). Moreover, there was no significant association between CCL22 polymorphism and types of lung cancer in patients. The distribution of CC, CT and TT genotypes of C1014T SNP in CCR4 gene, was 76 (51.4%), 60 (40.5%) and 12 (8.1%) in patients, and 80 (54.1%), 49 (33.1%) and 19 (12.8%) in controls respectively. No statistically significant differences were observed in genotypes frequencies of CCR4 gene between patients and controls (P=0.24). The genotype inherited by patients observed not to be associated with the type of lung cancer (P>0.05). CONCLUSION: RESULTS reveal that CCL22 gene polymorphism at position 16C/A and CCR4 gene polymorphism at position C1014T, appear not to be associated with susceptibility to lung cancer. PMID- 25031490 TI - Evaluation of GABA Receptors of Ventral Tegmental Area in Cardiovascular Responses in Rat. AB - BACKGROUND: The ventral tegmental area (VTA) is well known for its role in cardiovascular control. It is demonstrated that about 20-30% of the VTA neurons are GABAergic though their role in cardiovascular control is not yet understood. This study is carried out to find the effects of GABA A and GABA B receptors on cardiovascular response of the VTA. METHODS: Experiments were performed on urethane anesthetized male Wistar rats. Drugs were microinjected unilaterally into the VTA. The average changes in mean arterial pressure (MAP) and heart rate (HR) were compared between the case and the control groups using t test and with the pre-injection values using paired t test. RESULTS: Microinjection of muscimol, a GABAA agonist (500, 1500 and 2500 pmol/100nl) into the VTA had no significant effect on MAP and HR compared with the saline group and pre-injection values. Injection of bicuculline methiodide (BMI, 100 and 200 pmol/100 nl), a GABAA antagonist, caused a significant increase in the MAP (11.1+/-1.95mmHg, P<0.5) and a decrease in HR (-32.07+/-10.2, P<0.01). Microinjection of baclofen a GABAB receptor agonist (500 or 1000 pmole/100 nl) and phaclofen a GABAB receptor antagonist (500 or 1000 pmole/100 nl) had no significant effects on MAP and HR. CONCLUSION: For the first time it was demonstrated that GABA system of the VTA inhibits the cardiovascular system through the activation of GABAA but not the GABAB receptors. PMID- 25031491 TI - The role of serum level of interleukin-6 in severity of pulmonary complications of sulfur mustard injuries. AB - Diverse studies suggest that interleukin-6 (IL6), as a member of cytokines family, has a major role in inflammatory processes of airways and lungs. In this study, an attempt was made to determine the serum level of IL6 in sulfur mustard (SM) injured patients and its comparison with controls. The measured IL6 mean level in patients with chemical injuries (0.76+/-0.3 ng/ml) was significantly higher than the control group's mean level (0.34+/-0.12 ng/ml). Furthermore, patients with moderate to severe symptoms had a serum level of (0.95+/-0.92 ng/ml) which was significantly higher than mild (0.47+/-0.54) and control (0.34+/ 0.12) groups. The outcome of this research program demonstrates that an increase in serum level of IL6 can have a role in pulmonary complications of SM, similar to other well defined pulmonary diseases. However, further studies are required to clarify the role and mechanism of IL6 in such patients. PMID- 25031492 TI - Stereological estimation of granule cell number and purkinje cell volume in the cerebellum of noise-exposed young rat. AB - In spite of the existing reports on behavioural and biochemical changes related to the cerebellum due to noise stress, not much is known about the effect of noise stress on the neuronal changes in the cerebellum. The present study aims at investigating the effects from one week noise exposure on granule cell number and Purkinje cell volume within the neonate rat cerebellum. 15-day-old male Wistar rats were randomly divided into noise exposed (NE) and control groups (n=8 in each group). NE rats exposed to loud noise (100 dB/30 min/3 times per day) during the third postnatal week. One cerebellar half was selected at random for estimating the volume of the cerebellar layers and neuronal quantifications and the other was used for estimating individual somal volume of Purkinje cells. Cavalieri's principle, physical disector and nucleator methods were employed respectively for unbiased estimation of the volumes of the cerebellar layers, the numerical density of neurons and the individual volume of Purkinje cells. Results of this study show that noise stress significantly decreases the volume of granule layer together with decreased numerical density and total number of granule cells in the cerebellum. Furthermore, a decrease in somal volume of Purkinje cells was found in NE rats. These results, for the first time, demonstrate an effect of noise stress on the granule cell number and individual volume of Purkinje cells in rat cerebellum. PMID- 25031493 TI - Marfan syndrome in an Iranian family: a case series. AB - Marfan syndrome (MFS) is a genetic disorder which is inherited by autosomal dominant traits. In MFS, lens displacement and cardiovascular involvement are important causes of morbidity and mortality in the clinical course of the disease. In this case study, the ocular involvement in a family with severe penetration of MFS is reported. Twelve members of a family (father, two daughters, three sons, and six grandchildren) had MFS. Lens ectopia was the most common ophthalmic involvement among the family (100%). Other ocular involvements were as follows; Hypoplastic iris or ciliary's muscle hypoplasia (50%), on gated eyeball (42%), flat cornea (30%), glaucoma and cataract (25%), retinal detachment (16%). Three members of the family underwent eye surgery including lens extraction, glaucoma surgery and retinal surgery. PMID- 25031494 TI - Pulmonary Embolism with Abdominal Pain and ST Elevation: A Case Report. AB - Pulmonary embolism is considered as a great masquerader due to its frequent nonspecific signs and symptoms. Typically pulmonary embolism is under-diagnosed or over-diagnosed. In this study a patient with pulmonary embolism is reported in which the patient exhibited two unusual manifestations namely; right upper quadrant abdominal pain and ST-T elevation in anterior precordial leads. Due to the fact that the patient did not display typical pulmonary embolism symptoms and its major risk factors, extensive workup to discern the cause was carried out. The examination included abdominal sonography, kidney ureter and bladder Computed Tomography scan (CT-scan) and coronary angiography. Eventually after a six-day delay, pulmonary embolism was diagnosed by spiral chest CT scan. This case and several other similar reports underlines the fact that while various other common causes may exist for right upper abdominal pain, one should always consider pulmonary embolism as a possible cause especially when backed up with ECG finding. PMID- 25031495 TI - Causes of Mortality during the First Five Years of Life, Yazd City, Iran (2005 2008). PMID- 25031496 TI - Anticoagulant therapy in pediatrics. AB - Thromboembolic episodes are disorders encountered in both children and adults, but relatively more common in adults. However, the occurrence of venous thromboembolism and use of anticoagulants in pediatrics are increasing. Unfractionated Heparin (UH) is used as a treatment and prevention of thrombosis in adults and critically ill children. Heparin utilization in pediatric is limited by many factors and the most important ones are Heparin Induced Thrombocytopenia (HIT) and anaphylaxis. However, Low Molecular Weight Heparin (LMWH) appears to be an effective and safe alternative treatment. Hence, it is preferred over than UH due to favorable pharmacokinetic and side effect profile. Direct Thrombin Inhibitors (DTI) is a promising class over the other anticoagulants since it offers potential advantages. The aim of this review is to discuss the differences between adult and pediatric thromboembolism and to review the current anticoagulants in terms of pharmacological action, doses, drug reactions, pharmacokinetics, interactions, and parameters. This review also highlights the differences between old and new anticoagulant therapy in pediatrics. PMID- 25031497 TI - Knowledge and use of dietary supplements by students of College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria. AB - RATIONALE: Nutritional supplements are preparations intended to supplement the diet and provide nutrients. They include vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet. Many health professionals including dietitians, physicians and pharmacists are supplement users. OBJECTIVES: The objectives of the present study were to determine knowledge and use of dietary supplements among students of College of Medicine, University of Lagos who are potential health professionals. METHODOLOGY: A self-administered questionnaire with a mix of open and close ended questions was employed to collect data in this study. It was distributed to 300 students that were in their final year in various departments of the college. FINDINGS: Response rate was 89%. About 86% of the students have used dietary supplement before while half of them (50%) have used it in the past 12 months. The common types of dietary supplements used in the past 12 months are the vitamins. The reasons for use by the students were good health, poor diet, to boost immunity, weight gain and doctor's prescription. Most of the students were occasional and once in a while users. CONCLUSIONS: Majority of the students were aware of dietary supplement use and most of them were occasional users. PMID- 25031498 TI - Prescribing pattern of interns in a primary health center in India. AB - BACKGROUND: Prescription is the written order of the physician which is conveyed to the patient. Rational prescription writing is a skill which should be mastered at the earliest. Internship is the period where undergraduate medical education can be consolidated through continued learning under the direct supervision of teachers. The attitude of interns toward rational drug use is of utmost importance. The present study aimed to explore the prescribing pattern of interns in a primary health center in India. MATERIALS AND METHODS: A cross-sectional study was conducted for a period of 2 months (June 1 2010-July 30 2010) in a primary health center attached to a medical college in India. The main outcome measure was to assess rationality of prescribing pattern of interns was measured as per World Health Organization enlisted prescribing indicators. Data analysis was done by using descriptive and inferential statistical methods: Frequencies, percentage, and mean standard deviation. RESULTS: A total of 1968 drugs were prescribed in 760 prescriptions analyzed with an average of 2.58 drugs per prescription. Analgesic was the most commonly prescribed drug (25.78%) followed by antibiotics (22.1%), drugs used for gastrointestinal symptom (15.78%), multivitamins (11.84%), anti-malarials (8.35%), antihistaminics (6.25%), and hematinics (5.36%). Regarding prescribing indicators, in 435 prescriptions (22.4%), antibiotics were advised. A total of 688 (34.97%) drugs were prescribed by generic name, while the percentage of drugs prescribed from essential drug list of India was 58.47%. Injectables were prescribed in 89 prescriptions (4.49%). CONCLUSION: The present study shows that irrational prescribing practices are common among interns of the institute. The art of rational prescribing should be taught to them by medical teachers who are adequately trained in rational drug use. PMID- 25031499 TI - A study of potential adverse drug-drug interactions among prescribed drugs in medicine outpatient department of a tertiary care teaching hospital. AB - OBJECTIVE: To evaluate prevalence, types, and severity of potential adverse drug drug interaction in medicine out-patient department. MATERIALS AND METHODS: A single-point, prospective, and observational study was carried out in medicine OPD. Study began after obtaining approval Institutional Ethics Committee. Data were collected and potential drug-drug interactions (pDDIs) were identified using medscape drug interaction checker and were analyzed. RESULT: A total of 350 prescriptions with mean age 52.45 +/- 14.49 years were collected over a period of 5 months. A total of 2066 pDDIs were recorded with mean of 5.90 +/- 6.0. The prevalence of pDDI was 83.42%. Aspirin was most frequently prescribed drug in 185 (10.15%) out of total of 1821 drugs It was also the most frequent drug implicated in pDDI i.e. in 48.16%. The most common pDDI identified was metoprolol with aspirin in 126 (6.09%). Mechanism of interactions was pharmacokinetic in 553 (26.76%), pharmacodynamic in 1424 (68.92%) and 89 (4.30%) having an unknown mechanism. Out of all interactions, 76 (3.67%) were serious, 1516 (73.37%) significant, and 474 (22.94%) were minor interaction. Age of the patients (r = 0.327, P = 0.0001) and number of drugs prescribed (r = 0.714, P = 0.0001) are significantly correlated with drug interactions. CONCLUSION: Aspirin being the most common drug interacting. The use of electronic decision support tools, continuing education and vigilance on the part of prescribers toward drug selection may decrease the problem of pDDIs. PMID- 25031500 TI - A clinical study on drug-related problems associated with intravenous drug administration. AB - BACKGROUND: Infusion therapy through intravenous (IV) access is a therapeutic option used in the treatment of many hospitalized patients. IV therapy is complex, potentially dangerous and error prone. The objectives were to ascertain the drug-related problems (DRPs) involved in IV medication administration and further to develop strategies to reduce and prevent the occurrence of DRPs during IV administration. MATERIALS AND METHODS: A prospective observational study was carried out for a period of 4 months. Patients receiving more than two medications through IV route were included and studied. RESULTS: Of 110 patients, 76 (69.09%) were male and the rest were female. Nearly, half of the patients (46.3%, n = 51) were reported with DRPs. Of the 80 DRPs (72.72%) documented, 61 problems (55.4%) were seen in patients given IV medications through peripheral line. Among the DRPs majority seen were incompatibilities (40.9%, n = 45), followed by complications developed (12.7%, n = 14), errors in rate of administration (10.9%), and dilution errors (8%). To study the association of DRPs among gender, statistical analysis was performed and significant association was seen between DRPs and gender (P = 0.03). CONCLUSION: Among the reported DRPs, simultaneous IV administration of two incompatible drugs was the main predicament faced. PMID- 25031501 TI - Fixed drug eruptions caused by cross-reactive quinolones. AB - Fixed drug eruptions (FDE) are the common dermatological adverse drug reaction accounts for 16-21% of all cutaneous drug reactions in India. Drugs most frequently implicated in FDE are antimicrobials, anticonvulsants, and nonsteroidal antiinflammatory drugs. Here, we report a rare case of bullous FDE due to ciprofloxacin followed by ofloxacin administration. PMID- 25031502 TI - Why angiotensin converting enzyme inhibitors and angiotensin II receptor blockers are not prescribed in the management of hypertension among hemodialysis patients in India. PMID- 25031503 TI - Design Considerations for CMOS-Integrated Hall-Effect Magnetic Bead Detectors for Biosensor Applications. AB - We describe a design methodology for on-chip magnetic bead label detectors based on Hall-effect sensors. Signal errors caused by the label-binding process and other factors that limit the minimum detection area are quantified and adjusted to meet typical assay accuracy standards. The methodology is demonstrated by designing an 8192 element Hall sensor array, implemented in a commercial 0.18 MUm CMOS process with single-mask postprocessing. The array can quantify a 1% surface coverage of 2.8 MUm beads in 30 seconds with a coefficient of variation of 7.4%. This combination of accuracy and speed makes this technology a suitable detection platform for biological assays based on magnetic bead labels. PMID- 25031504 TI - Matrix metalloproteinases, atherosclerosis, proteinuria and kidney disease: Linkage-based approaches. AB - Matrix metalloproteinases (MMPs) are important enzymes of extracellular matrix (ECM) degradation for creating the cellular environments required during development and morphogenesis. MMPs, collectively called matrixins, regulate also the biological activity of non matrix substrates such as cytokines, chemokines, receptors, growth factors and cell adhesion molecules. Enzymatic activity is regulated at multiple levels. Endogenous specific inhibitors of metalloproteinases (TIMPs) participate in controlling the local activities of MMPs in tissues. The pathological effects of MMPs and TIMPs are involved in cardiovascular disease (CVD) processes, including atherosclerosis and in a number of renal pathophysiologic alterations, both acute and chronic, linking them to acute kidney injury, glomerulosclerosis and tubulointerstitial fibrosis. This review presents an overview of the place of MMPs in atherosclerosis, proteinuria and kidney disease as a subject of considerable interest, given the differentiated and ambiguous role of MMPs in the progression of these diseases. PMID- 25031505 TI - Clinicopathological features, diagnosis and treatment of clear cell sarcoma/melanoma of soft parts. AB - BACKGROUND: Clear cell sarcoma of tendons and aponeuroses is a rare, high grade malignant soft tissue tumor resembling melanoma and soft tissue sarcomas. Clinical and Imaging Presentation: The median age at presentation is 27 years and the most common location are the foot and the ankle. MR imaging typically shows a benign looking, well defined, homogenous mass; on T1-weighted MR images, it is usually homogeneous and isointense or slight hyperintense to muscle, whereas on T2-weighted MR images, it is usually more heterogeneous with variable signal intensity. Pathology: Microscopically, the clear cell appearance is due to the accumulation of glycogen. The cells show no or minimal pleomorphism, and paucity of mitotic figures that is in concordance with the slow-growing behavior of the tumor. Scattered multinucleated giant cells are commonly present; areas of necrosis and melanin pigment may be identified. The reciprocal translocation t(12;22)(q13;q12) is observed in more than 90% of clear cell sarcoma cases. In addition, polysomy of chromosome 8 has been observed as a secondary abnormality in many cases of clear cell sarcoma. The differential diagnosis of clear cell sarcoma should include melanoma, epithelioid malignant peripheral nerve sheath tumor, melanotic schwannoma, paraganglioma-like dermal melanocytic tumor, perivascular epithelioid cell neoplasms (PEComas), cellular blue naevus, synovial sarcoma (monophasic type), alveolar soft part sarcoma, paraganglioma, epithelioid sarcoma and carcinomas. Treatment and Prognosis: The treatment of choice for clear cell sarcoma is wide surgical resection. If complete excision is achieved, adjuvant treatments are not unnecessary. Chemotherapy is predominantly employed in patients with metastatic disease. The 5 to 20 year survival of the patients with clear cell sarcoma range from 67% to 10%. The rates of local recurrence ranges up to 84%, late metastases up to 63%, and metastases at presentation up to 30%. PMID- 25031506 TI - Reliability of balance evaluation in children with cerebral palsy. AB - The evaluation of balance in children with cerebral palsy (CP) is an extremely difficult and complex procedure. The purpose of the present study was the evaluation of three balance tests: Berg Balance Scale (BBS), time up and go (TUG) and Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) and their reliability in children with CP. The control of the reliability of the tests was based on the successive application to twenty children with CP within a short period in order to substantiate their ability to give the same results in a stable sample. No difference was found according to scores between the measures but important statistical differences were found of the scores of the children in all tests. The tests BBS, TUG and BOTMP are considered to be reliable and valid tests, able to objectively define the quantitative mutation of the balance of the child in test with CP. PMID- 25031507 TI - Anemia is independently associated with NT-proBNP levels in asymptomatic predialysis patients with chronic kidney disease. AB - BACKGROUND: Although anemia and renal dysfunction are related to increased natriuretic peptides levels in heart failure patients, less is known about this relationship in asymptomatic predialysis patients with chronic kidney disease (CKD). The aim of this study was to investigate relationship between hemoglobin (Hb) concentration, N-terminal proBNP (NT-proBNP) levels and echocardiographic findings in these patients. METHODS: The study included 61 patients with CKD stage IV-V (34 male, mean age 62.6 +/- 13.6 years) and 22 age- and sex -matched healthy persons as control group. All participants underwent clinical, laboratory and echocardiographic examination, including Tissue Doppler Imaging and colour M mode Doppler. RESULTS: Patients with CKD had lower Hb levels (p<0.001), and higher levels of NT-proBNP (p<0.001) than healthy controls. Patients were divided into two groups according to their mean Hb levels: group A, Hb<10.3 g/dL and group B, Hb>=10.3 g/dL. Patients from group A was significantly older (p<0.001), left ventricular mass index was significantly higher (LVMI, p<0.001), LV diastolic function was worse (septal and lateral E'/A' ratio: p<0.05 and p<0.01, respectively), and the level NT-proBNP was higher (p<0.001) compared to patients from group B. The natural logarithm of NT-proBNP (lnNT-proBNP) showed highly significant correlation with Hb (p<0.001) and significant correlation with estimated glomerular filtration rate (p=0.035) in CKD patients. Multiple regression analysis revealed Hb levels (p<0.01), cholesterol (p<0.001), LV ejection fraction (p<0.001) and septal E/E' ratio (p<0.01) as the independent variables predicting as much as 54% variability of lnNTpro-BNP. CONCLUSIONS: The increased NT-proBNP levels in asymptomatic patients with advanced CKD were independently associated with echocardiographic parameters of LV function, but anemia may represent one of the important confounder of the relationship between NT-proBNP and cardiovascular abnormalities. PMID- 25031508 TI - Laryngeal cancer: epidemiological data from Nuorthern Greece and review of the literature. AB - BACKGROUND: Cancer of the larynx accounts for 1% to 2.5% of all human neoplasms and is the most common malignancy of the Head and Neck region. The purpose of this study is to analyze epidemiological data of patients with laryngeal cancer and to point out the geographical variations. METHODS: This is the first systematic recording of the laryngeal cancer epidemiological data in Northern Greece. During the period 1992-2010 1,638 patients were diagnosed with and treated for malignant head and neck tumors. One thousand one hundred and four cases (67.4%) were malignant laryngeal tumors, 98.4% of which (1,088 cases) were squamous cell carcinomas (SCC). Only 16 patients (1.5%) presented with other types of malignancies. RESULTS: The average age of the SCC patients was 62.1 years. Only 35 patients were women (3.2%). More than 60% of the patients were farmers or labor workers, 86.9%, were smokers, 43.2% were consuming alcohol on a daily basis and 36.1% had a positive family history of malignancy. Concerning tumor location, 60.2% were glottic cancers. T staging revealed that 1.2% of the cases were carcinomas in situ, 28% T1 tumors, 19% T2, 32 % T3, and 20% T4. Tumor grading showed that 43% of the cases were G1, 42.1% were G2, and 11.8% were G3. CONCLUSIONS: The pathogenesis of laryngeal carcinoma is the result of the combined action of endogenous and environmental factors. The recording and analysis of the epidemiology of the disease is important for its better study and understanding. PMID- 25031509 TI - Prevalence and antimicrobial susceptibility of Ureaplasma urealyticum in asymptomatic women in Northern Greece. AB - AIM: This study attends to determine the prevalence and the antimicrobial susceptibility of Ureaplasma urealyticum in asymptomatic women in Northern Greece. MATERIALS-METHODS: A total of 347 cervical smears were divided into 5 groups according to age. Samples were cultured, Ureaplasma urealyticum isolation was confirmed by the detection of the urease gene and the antimicrobial susceptibility of the isolates to 9 commercially available antibiotics was determined. RESULTS: Fifty-six (16.13%) samples were found positive. Women >60 years old were rarely infected. Only 9 (16.07%) isolates were susceptible to all antimicrobials tested. Thirteen isolates were resistant and 34 intermediately resistant to ciprofloxacin, two resistant and 29 intermediately resistant to ofloxacin, three intermediately resistant to macrolides, while all were susceptible to tetracyclines. CONCLUSIONS: In Northern Greece, 16.13% of asymptomatic women seem to be carriers of Ureaplasma urealyticum mostly in reproductive ages. Almost no resistance to macrolides and tetracyclines has been noticed, while most of the isolates present resistance or moderate sensitivity to quinolones. PMID- 25031510 TI - Prevalence of Crimean-Congo hemorrhagic fever virus antibodies in Greek residents in the area where the AP92 strain was isolated. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a viral disease with fatality rate up to 30%. Up to date, only one CCHF case has been reported in Greece, while a distinct virus strain (AP92) had been isolated in 1975 from ticks in Imathia prefecture, northern Greece. The aim of the present study was to estimate the CCHF virus (CCHFV) seroprevalence among humans residing in the prefecture of Imathia, and the neighboring prefecture of Pella, and to investigate the risk factors associated with the seropositivity. MATERIAL AND METHODS: A total of 277 persons randomly selected from the general population were tested for the presence of CCHFV IgG antibodies. Additional 51 persons belonging in groups with risk for acquisition of CCHFV infection (19 slaughterhouse workers and 32 hunters) were also tested. All participants filled in a questionnaire related to demographics and probable risk factors (e.g. occupation, former tick bite, animal contact). RESULTS: Six of the 277 (2.2%) persons were found to carry CCHFV IgG antibodies: 3 in Imathia and 3 in Pella prefecture, resulting in seroprevalence of 1.7% and 2.9%, respectively. History of tick bite, residence in a hilly territory and increased age were significantly associated with CCHFV seropositivity. None of the slaughterers was found IgG positive, while CCHFV IgG antibodies were detected in a 67-year old hunter who reported agricultural activities and a former tick bite. CONCLUSIONS: A relatively low seroprevalence is observed in the area where the AP92 strain has been isolated, with tick bite being significantly associated with CCHFV seropositivity. Further studies in ticks in the area will show whether are they infected by the AP92 strain or other more pathogenic CCHFV strains and at which rate. PMID- 25031511 TI - The synergistic antinociceptive interactions of morphine and dexmedetomidine in rats with nerve-ligation injury. AB - BACKGROUND: Peripheral nerve injury may result in chronic neuropathic pain, which is characterized by spontaneous pain, hyperalgesia, and allodynia. Intrathecal administration of opioids and alpha2-adrenoceptor agonists produces spinal analgesia by activation of opioidergic and noradrenergic systems. In our study, we have compared the synergistic antiallodynic interaction and side-effects of intrathecal morphine and dexmedetomidine in a rat model of neuropathic pain. METHODS: Male Wistar rats, weighing 380-440 g, were treated with tight ligation of left L5-6 spinal nerves and a chronic catheter was implanted intrathecally. Morphine and dexmedetomidine were administered intrathecally to obtain the dose response curves and the 50 % effective doses (ED50) for each drug and fractional analysis of the ED50 of each drug administered concurrently was performed to examine the interaction. Mechanical allodynia was measured by using application of von Frey filaments to the hindpaw. RESULTS: Intrathecal administration of morphine and dexmedetomidine alone and in combination resulted in a dose dependent antiallodynic effect, and the combination produced a synergistic effect state magnitude. Moreover, the incidence of side-effects was higher when morphine or dexmedetomidine were administered in high doses alone and extremely low when these two drugs were used in combination. These results are suggestive of a synergistic effect at lower doses of both drugs. CONCLUSIONS: These findings may provide a rationale for combining such drugs for the improvement of human postoperative or neuropathic pain treatment in the future. PMID- 25031512 TI - Surgical management of iatrogenic femoral artery pseudoaneurysms: A 10-year experience. AB - BACKGROUND: Vascular complications of cardiac catheterization have increased in line with increasing number of percutaneous interventions. Open repair is the standard method of treatment for true and false aneurysms of femoral artery. We report results of patients operated due to femoral artery pseudoaneurysm after cardiac catheterization. METHODS: Data from 12,261 patients who underwent percutaneous intervention for cardiac catheterization between January 2003 and January 2013 were evaluated. Diagnosis of pseudoaneurysm was established mainly by doppler ultrasonography in patients with complaints of pain and hematoma at the intervention site. Pseudoaneurysms less than 2 cm in diameter were treated non-operatively and were followed up by regular ultrasonographic examination at the outpatient clinic. Pseudoaneurysms with a diameter of 2 cm or more underwent primary repair. All patients were followed up for one year. RESULTS: We detected 55 (0.44%) patients with femoral artery pseudoaneurysm and 42 of them were operated. The mean age was 60.7 +/- 6.3 years. Thirty nine (94.5%) patients underwent elective surgery, three (5.5%) patients were operated on under emergency conditions. Operation was performed under local anesthesia in 32 patients, under local anesthesia and sedation in eight patients, and under general anesthesia in three patients. Location of the pseudoaneurysm was the superficial femoral artery in 29 (69%), the common femoral artery in nine (21.4%), and the deep femoral artery in four (9.6%) patients. No limb loss occurred, no patient died and no recurrence was detected during the follow up. CONCLUSIONS: Performing vascular reconstruction before the rupture of pseudoaneurysm is important in terms of morbidity and mortality. We concluded that surgical repair in pseudoaneurysms larger than 20 mm is safe and essential. PMID- 25031513 TI - Prevalence of microalbuminuria and risk factor analysis in type 2 diabetes patients in Albania: the need for accurate and early diagnosis of diabetic nephropathy. AB - BACKGROUND: Microalbuminuria is often the first sign of renal dysfunction in diabetes. This study aimed to investigate the prevalence of microalbuminuria in Albanian type 2 diabetes patients and its association with other cardiovascular risk factors. METHODS: Three hundred and twenty-one patients with type 2 diabetes attending, diabetes centers in Albania were enrolled in this cross-sectional, multicenter study. The subjects, aged 40-70 years, had no known proteinuria or other kidney disease. Pregnant women and patients with acute infections were excluded. Data including waist circumference, duration of diabetes and history of hypertension were obtained by questionnaire. Blood samples were drawn after 12 h overnight fasting to measure glycosylated hemoglobin (HbA1c), serum cholesterol, triglyceride and creatinine. Microalbuminuria was assessed using dipstick kits in early morning urine samples. RESULTS: The prevalence of normoalbuminuria was 56.3%, microalbuminuria 40.8% and macroalbuminuria 2.8%. Systolic and diastolic blood pressure (p<0.01), HbA1c (p<0.01) and fasting plasma glucose (p<0.001) were significantly higher in microalbuminuric than in normoalbuminuric subjects. Independent risk factors for microalbuminuria were duration of diabetes (OR: 2.785, 95% CI: 1.156-3.759), systolic blood pressure (OR: 2.88, 95% CI: 1.85 6.85) and waist circumference (OR: 2.15, 95% CI: 1.01-5.45) in males and poor glycemic control (OR: 4.51, 95% CI: 1.45-13.98), duration of diabetes (OR: 2.568, 95% CI: 1.702-3.778) and waist circumference (OR: 4.87, 95% CI: 1.80-13.11) in females. CONCLUSIONS: The high proportion of type 2 diabetes patients with microalbuminuria raises implications for health policy in Albania. Screening programs and optimized control of modifiable risk factors are needed to reduce the risk of diabetic nephropathy. PMID- 25031514 TI - Assessing personality traits by questionnaire: psychometric properties of the Greek version of the Zuckerman-Kuhlman personality questionnaire and correlations with psychopathology and hostility. AB - BACKGROUND: The Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) was developed in an attempt to define the basic factors of personality or temperament. We aimed to assess the factor structure and the psychometric properties of its Greek version and to explore its relation to psychopathological symptoms and hostility features. METHODS: ZKPQ was translated into Greek using back-translation and was administered to 1,462 participants (475 healthy participants, 619 medical patients, 177 psychiatric patients and 191 opiate addicts). Confirmatory and exploratory factor analyses were performed. Symptoms Distress Check-List (SCL 90R) and Hostility and Direction of Hostility Questionnaire (HDHQ) were administered to test criterion validity. RESULTS: Five factors were identified, largely corresponding to the original version's respective factors. Retest reliabilities were acceptable (rli's: 0.79-0.89) and internal consistency was adequate for Neuroticism-Anxiety (0.87), Impulsive Sensation Seeking (0.80), Aggression-Hostility (0.77) and Activity (0.72), and lower for Sociability (0.64). Most components were able to discriminate psychiatric patients and opiate addicts from healthy participants. Opiate addicts exhibited higher rates on Impulsive Sensation Seeking compared to healthy participants. Neuroticism-Anxiety (p<0.001) and Impulsive Sensation Seeking (p<0.001) were significantly associated with psychological distress and Aggression-Hostility was the most powerful correlate of Total Hostility (p<0.001), and Neuroticism-Anxiety was the stronger correlate of introverted hostility (p<0.001), further supporting the instrument's concurrent validity. CONCLUSIONS: Present findings support the applicability of the Greek version of ZKPQ within the Greek population. Future studies could improve its psychometric properties by finding new items, especially for the Sociability scale. PMID- 25031515 TI - Effect of ropivacaine infiltration on muscle regeneration: a morphometric analysis. AB - BACKGROUND/AIM: Local anaesthetic myotoxicity is a well described phenomenon resulting in reversible muscle damage. Considering that in previous studies microscopic images were evaluated without quantification of morphologic characteristics, the aim of the present study was evaluate muscle regeneration after local anaesthetic infiltration. MATERIALS AND METHODS: Wistar rats underwent injection of the left tibialis anterior muscle with ropivacaine (0.75%, group HC or 0.375%, group LC), while the contralateral muscle was injected with saline (group SL). Six weeks later, the muscles were dissected, stained using acid ATPase and examined under light microscope coupled with a computer imaging system for morphometric analysis. Sections were evaluated regarding the content of different muscle fibre types (type I, IIa and IIb), fibre cross-section area and perimeter. RESULTS: Groups were comparable regarding the ratio of different muscle fibre types. Regenerated type I fibres of both HC and LC groups had significant greater mean cross-sectional area and perimeter, compared to SL fibres. No signs of necrosis or inflammation were observed. Type IIa and IIb fibres didn't show significant differences. CONCLUSIONS: Regenerated muscles, following local anaesthetic application, showed long-term morphological differences, which could lead to impaired function. Further studies are needed, in order to clarify the underlying cellular mechanisms and the subsequent possible functional impairment. PMID- 25031516 TI - Detection of OqxAB efflux pumps, OmpK35 and OmpK36 porins in extended-spectrum beta-lactamase-producing Klebsiella pneumoniae isolates from Iran. AB - BACKGROUND & AIM: The aim of this study was the detection of OqxAB efflux pumps, OmpK35 and OmpK36 porins among extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae isolates from Iran. MATERIALS AND METHODS: This study was conducted with 83 K. pneumoniae isolates from two hospitals in Tehran, Iran. Antibiotic susceptibility tests were performed by Kirby-Bauer disc diffusion and Broth Microdilution methods according to CLSI guidelines. The OqxAB , blaTEM, blaSHV and blaCTX-M genes were detected by PCR and sequencing methods.The outer membrane porins OmpK35 and OmpK36 were analyzed by SDS-PAGE, PCR and sequencing methods. RESULTS: Among the 83 K. pneumoniae strains, 48 (57.5%) were ESBL positive. The existence of blaTEM, blaSHV and blaCTX-M was detected in 24 (50%), 30 (62.5%) and 28 (58.33%) ESBL-producing isolates respectively. The prevalence of both oqxA and oqxB detected in K. pneumoniae was high: 50 (60.2%) and 50 (60.2%), respectively. OmpK35 was detected in 30 (62.5%) while OmpK36 was found in 35 (72.91%) out of 48 ESBL-producing isolates. In this study, fosfomycin and tigecycline were more active than other antibiotics. CONCLUSIONS: The prevalence of beta-lactamase-producing K. pneumoniae detected in this study is of great concern and highlights the need of infection control measures including antibacterial management and prompt identification of beta-lactamase-producing isolates. PMID- 25031517 TI - Prevalence of thrombophilia in asymptomatic individuals with a family history of thrombosis. AB - OBJECTIVE: The present study investigates the prevalence of thrombophilia in individuals with first or/and second degree family history of thromboembolism. MATERIAL-METHODS: The study group consisted of 68 individuals with a first or second degree family history of venous or arterial thromboembolism, but without a personal history of thrombosis. The activity of ATIII, PC, PS, FVIII, FChiIotaIota and total homocysteine was measured on the ACL Advance coagulation analyzer. In addition, hemi-quantitative determination of CRP was performed to exclude an acute phase reaction. The existence of V-Leiden mutation was investigated by the modified pre-dilution method (1:5) with V-DEF. Prothrombin G20210A mutation was detected by the use of an in house PCR protocol. Family history was termed as follows: positive (thrombosis was reported in one parent and his/her family members) (group Alpha) or strongly positive (thrombosis was reported in both parents and their family members (group Beta). RESULTS: Data analysis revealed decreased activity of ATIII:1.47%, PC:1.47%, and FXII:5.9%, increased activity of FVIII (without inflammation):11.8%, V-Leiden:13%, elevated Hcy:14.7%, and G20210A mutation:2.9%. Group A consisted of 55 individuals (74.5%), whereas group B of 16 (23.5%). The total percentage of thrombophilia was 48.5%, while the percentage within group A was 44.2% and within group B 62.5%. CONCLUSION: The high prevalence of thrombophilia, reinforce the importance of an extensive laboratory thrombophilia screening when a family history of thromboembolism has been recorded, especially when it concerns both parents and/or their family members and even more when one or more acquired thrombophilic factors coexist. PMID- 25031518 TI - Glutathion-S-Transferase P1 polymorphisms association with broncopulmonary dysplasia in preterm infants. AB - BACKGROUND: Oxidative stress, characterized by the excretion of pre-oxidative and anti-oxidative proteases, has a key role in the pathogenesis of bronchopulmonary dysplasia (BPD). One of the many host anti-oxidant enzymes is glutathione-S transferase P1 (GSTP1), with three polymorphic alleles having been identified: homozygous ile, heterozygous ile/val and homozygous val isomorph. The aim of this study was to examine the genetic predisposition to BPD in the GSTP1 polymorphisms. METHODS: A prospective case-control study was carried out in the 2nd Neonatal Intensive Care Unit of Aristotle University in Thessaloniki, Greece during 2008. The genetic polymorphisms of GSTP1 in 28 preterms <32 weeks gestational age (GA) with BPD compared to 74 controls (33 preterms without BPD and 41 healthy terms) were examined. RESULTS: The homozygous ile isomorph was predominant in all groups (preterms with BPD: 82%, preterms without BPD: 70%, healthy terms: 78%), followed by the heterozygous ile/val (14%, 18% and 20% respectively) and the homozygous val isomorph (4%, 12% and 2% respectively). The homozygous ile isomorph was also identified in the majority of preterms with mild (80%), moderate (100%) and severe (73%) BPD. The GSTP1 genetic distribution did not differ between the groups and GSTP1 polymorphisms were not associated with the severity of BPD. CONCLUSIONS: This study could not confirm an association between GSTP1 polymorphisms and the development of BPD or the severity of the disease. PMID- 25031519 TI - Brugada-like ECG pattern due to giant mediastinal lipoma. AB - A case of a 33-year-old female who presented with mild dyspnea and palpitations is presented. Diagnostic investigation was consistent with a giant intrathoracic mass filling the right thoracic cavity and an abnormal electrocardiogram (Brugada like pattern). The patient underwent surgical removal of the mass (benign lipoma) with a normal postoperative ECG pattern. PMID- 25031520 TI - Horizontal gaze palsy and scoliosis: a case report and review of the literature. AB - BACKGROUND: The syndrome of horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare human disease and while its association with scoliosis was first reported in 1974, thirty years later the responsible genetic mutations are being elucidated. This progress was due to the reporting of single interesting cases. CASE DESCRIPTION: We present the case of a 27 year-old male patient who was admitted for elective scoliosis correction surgery and who represented after an uncomplicated discharge with headache and vomiting; because of a gaze palsy he underwent brain imaging that confirmed a brainstem abnormality, consistent with the syndrome of horizontal gaze palsy with progressive scoliosis (HGPPS), a rare autosomal recessive human disease. CONCLUSION: This rare syndrome is a good example of how single case reports can lead to advances in laboratory research and genetic characterisation of diseases, together with implications for neurodevelopment. Vigilance in the neurological examination in an otherwise 'non neurological' scoliosis will help identify potential such cases, whilst further genetic/molecular analysis may shed further light into neuro-embryological development and patterning. PMID- 25031521 TI - Emphysematous pyelonephritis: a case report. AB - BACKGROUND/AIM: Emphysematous pyelonephritis (EP) is an acute necrotic infection of the kidney which is characterized by the presence of gas. Uncontrolled diabetes mellitus and obstruction of the urinary tract are the main predisposing factors and Escherichia Coli is the most frequent causative pathogen. CASE REPORT: We herein report a case of a patient with undiagnosed diabetes mellitus who was admitted to the emergency department with symptoms of pyelonephritis. Imaging revealed the gas in the renal parenchyma establishing the diagnosis and the patient was treated successfully with antibiotics. CONCLUSION: EP is a medical emergency and once diagnosed, attention must be paid to the selection of treatment to avoid high mortality rates. PMID- 25031522 TI - Non traumatic liver herniation due to persistent cough mimicking a pulmonary mass. AB - BACKGROUND: Non traumatic liver herniation through a diaphragmatic defect is rare. CASE REPORT: A 44 year old woman presented with lower lobe opacity at the right lung. Chest Computed tomography (CT) demonstrated a round tumor adjacent to the right diaphragm. Percutaneous needle biopsy revealed liver tissue. A small liver herniation through a diaphragmatic defect was detected in saggital and coronal CT views but no traumatic rupture of the diaphragm or endometriosis were documented. CONCLUSIONS: The patient suffered from gastroesophageal reflux disease and increased transdiaphragmatic pressure from paroxysmal cough due to aspirations may have provoked the diaphragmatic rupture. PMID- 25031523 TI - Obstructive jaundice resulted from hydatid cyst of pancreatic head. AB - BACKGROUND/AIM: Compression of the common bile duct by a hydatid cyst located at the head of the pancreas is one of the quite rare causes of obstructive jaundice in childhood. CASE REPORT: We report a 9-year-old child with obstructive jaundice caused by compression of the intrapancreatic portion of the bile duct by a hydatid cyst located at the pancreatic head. Furthermore, we considered that this is a reportable case in aspect of childhood development. The patient was treated successfully by surgical procedure and albendazole chemoprophylaxis. The postoperative course was uneventful. CONCLUSION: In endemic areas, hydatid cysts should be considered among the differential diagnosis in cystic lesions of any organ including the pancreas. PMID- 25031524 TI - Primary rectal malignant melanoma-case report. AB - INTRODUCTION: Primary malignant melanoma that arises from the true anatomic rectal mucosa is extremely rare. CASE REPORT: An endoscopic investigation of a 79 year-old woman with long history of tenesmus and rectal bleeding revealed posterior fleshy mass 4.5 cm from the anal verge. Biopsies demonstrated malignant melanoma. She underwent abdominoperineal resection and is doing well one year after the operation. CONCLUSION: Owing to its rarity and histologic variability, misdiagnosis as lymphoma, carcinoma or sarcoma is common. PMID- 25031525 TI - Insulin edema in a girl with newly diagnosed diabetes mellitus type I. PMID- 25031526 TI - Venous pulsatile tinnitus due to pseudotumor cerebri syndrome in a young morbid obese female. PMID- 25031527 TI - A study of the causes of bilateral optic disc swelling in Japanese patients. AB - PURPOSE: To investigate the etiology of bilateral disc swelling in Japanese. METHODS: Using Kitasato University's Department of Neuro-Ophthalmology medical records and fundus photographs of the period December 1977 through November 2010, we retrospectively identified 121 outpatients who had been initially confirmed with bilateral disc swelling. RESULTS: The most common cause of the bilateral disc swelling was increased intracranial pressure (ICP) (59%); followed by pseudopapillitis (16%); uveitis (8%); hypertensive retinopathy (5%); bilateral optic neuritis, acute disseminated encephalomyelitis (ADEM) and optic disc drusen (all at 2% each); and leukemia (1%). Unknown etiology accounted for 6% of the cases. CONCLUSION: Although increased ICP is the most common etiology for bilateral disc swelling, it can also be triggered by a variety of other causes. Pseudopapillitis is the most important progenitor of bilateral disc swelling in Japanese. PMID- 25031528 TI - The relationship between sex and symmetry in thyroid eye disease. AB - PURPOSE: To examine the relationships between sex and symmetry in the context of disease activity, severity, and thyroid status in thyroid eye disease. METHODS: Retrospective chart review of 31 men and 31 women with untreated thyroid eye disease. Subjective complaints, smoking status, thyroid status, and objective findings pertinent to the clinical activity score (CAS) and "NO SPECS" classification were recorded. Overall disease asymmetry was defined as having simultaneous asymmetry of both more than one symptom and more than one external finding. Asymmetry was compared across sex and thyroid status. CAS and NO SPECS severity were compared across sex, symmetry, and thyroid status. RESULTS: Asymmetric appearance was reported by 58% of men and 19% of women. Asymmetric proptosis (>2 mm difference) was seen in 45% of men and 23% of women (P=0.036). Overall asymmetry was seen in 55% of men and 19% of women (P=0.017). Thyroid status and sex had a combined effect on symmetry, as 15 of 16 hyperthyroid females (94%) demonstrated symmetric disease. Average NO SPECS severity was 3.5 (standard deviation [SD] 1.4) in men and 3.3 (SD 1.1) in women (P=0.51), and was 3.8 (SD 1.4) in asymmetric patients versus 3.2 (SD 1.3) in symmetric patients (P=0.08). The CAS was higher in asymmetric than symmetric patients (1.84 versus 0.97; P=0.012). CONCLUSION: Men demonstrated more asymmetric disease (proptosis and overall asymmetry) than women, while hyperthyroid females demonstrated more symmetry than euthyroid and hypothyroid males and females. NO SPECS severity score was unaffected by sex, thyroid status, or symmetry. Asymmetric patients demonstrated higher clinical activity scores. PMID- 25031529 TI - Twelve-week, prospective, open-label, randomized trial on the effects of an anticholinergic agent or antidiuretic agent as add-on therapy to an alpha-blocker for lower urinary tract symptoms. AB - PURPOSE: The effects of an anticholinergic or antidiuretic agent as add-on therapy to an alpha-blocker for lower urinary tract symptoms (LUTS) according to a voiding diary in 3 days are unknown. We prospectively investigated the efficacy of an anticholinergic or antidiuretic agent as add-on therapy for nocturia in men previously treated with an alpha-blocker for LUTS. SUBJECTS AND METHODS: Patients were randomly subdivided into two groups. All patients had a 4-week washout. Group A had alpha-blocker for 4 weeks, then an alpha-blocker plus an anticholinergic agent for 4 weeks, and, finally, 4 weeks of an alpha-blocker plus an antidiuretic agent. Group B had an alpha-blocker for 4 weeks, then an alpha blocker plus an antidiuretic agent for 4 weeks, and, finally, 4 weeks of an alpha blocker plus an anticholinergic agent. In both groups, patients were subdivided into nocturnal polyuria, decreased nocturnal bladder capacity (NBC), or nocturia by both causes subgroups. A 3-day voiding diary, total International Prostate Symptom Score (IPSS), IPSS sub-scores, Overactive Bladder Symptom Score, uroflowmetry, and post-void residual urine volume, were assessed at baseline, and at 4, 8, and 12 weeks. RESULTS: A total of 405 patients completed the study. During treatment, the changes from baseline in total IPSS and IPSS sub-scores were significantly decreased at 4 weeks and were maintained for 12 weeks. In the nocturnal polyuria subgroup of Groups A and B, the number of episodes of nocturia in 3 days, nocturnal urine volume, and nocturnal index were significantly decreased using an alpha-blocker plus an antidiuretic agent. In the decreased NBC subgroup of Groups A and B, IPSS storage sub-score, Overactive Bladder Symptom Score, number of episodes of nocturia in 3 days, number of episodes of urgency in 3 days, and NBC index were all significantly decreased using an alpha-blocker plus an anticholinergic agent. CONCLUSION: An anticholinergic agent or antidiuretic agent as an add-on therapy in men previously treated with an alpha blocker improves nocturia including LUTS. PMID- 25031530 TI - The merits and problems of Neuropsychiatric Inventory as an assessment tool in people with dementia and other neurological disorders. AB - OBJECTIVE: The Neuropsychiatric Inventory (NPI) is one of the most commonly used assessment scales for assessing symptoms in people with dementia and other neurological disorders. This paper analyzes its conceptual framework, measurement mode, psychometric properties, and merits and problems. METHOD: All articles discussing the psychometric properties and factor structure of the NPI were searched for in Medline via Ovid. The abstracts of these papers were read to determine their relevance to the purpose of this paper. If deemed appropriate, a full paper was then obtained and read. RESULTS: The NPI has reasonably good content validity and internal consistency, and good test-retest and interrater reliability. There is limited information about its sensitivity, specificity, positive and negative predictive values, and, in particular, responsiveness. Merits of the NPI include being comprehensive, avoiding symptom overlap, ease of use, and flexibility. It has problems in scoring (no multiples of 5, 7, and 11) and, therefore, analysis using parametric tests may not be appropriate. The use of individual subscales also warrants further investigation. CONCLUSION: In terms of its content and concurrent validity, intra- and interrater reliability, test retest reliability, and internal consistency, the NPI can be considered as valid and reliable, and can be used across different ethnic groups. The tool is most likely unable to deliver as good a performance in terms of discriminating between different disorders. More studies are required to further evaluate its psychometric properties, particularly in the areas of factor structure and responsiveness. The clinical utility of the NPI also needs to be further explored. PMID- 25031531 TI - Associations between apolipoprotein E genotypes and serum levels of glucose, cholesterol, and triglycerides in a cognitively normal aging Han Chinese population. AB - PURPOSE: To determine the associations between apolipoprotein E (APOE) genotypes and serum levels of glucose, total cholesterol, and triglycerides in a cognitively normal aging Han Chinese population. METHODS: There were 1,003 cognitively normal aging subjects included in this study. APOE genotypes were analyzed and biochemical parameters were tested. All the subjects were divided into three groups according to APOE genotypes: (1) E2/2 or E2/3 (APOE E2); (2) E3/3 (APOE E3); and (3) E2/4, E3/4, or E4/4 (APOE E4). Correlations of serum levels of glucose, total cholesterol, and triglycerides with APOE genotypes were assessed. RESULTS: E2, E3, and E4 allele frequencies were found to be 6.2%, 82.1%, and 11.7%, respectively. Serum levels of total cholesterol were higher in the APOE E4 group (P<0.05). A higher level of total cholesterol was associated with the E4 allele (adjusted odds ratio 1.689, 95% confidence interval 1.223 2.334, P<0.01). However, no association was found between APOE status and serum levels of glucose (adjusted odds ratio 0.981, 95% confidence interval 0.720 1.336, P=0.903) or total triglycerides (adjusted odds ratio 1.042, 95% confidence interval 0.759-1.429, P=0.800). CONCLUSION: A higher serum level of total cholesterol was significantly correlated with APOE E4 status in a cognitively normal, nondiabetic aging population. However, there was no correlation between APOE genotypes and serum levels of glucose or total triglycerides. PMID- 25031532 TI - Age, physical inactivity, obesity, health conditions, and health-related quality of life among patients receiving conservative management for musculoskeletal disorders. AB - BACKGROUND: Musculoskeletal conditions and insufficient physical activity have substantial personal and economic costs among contemporary aging societies. This study examined the age distribution, comorbid health conditions, body mass index (BMI), self-reported physical activity levels, and health-related quality of life of patients accessing ambulatory hospital clinics for musculoskeletal disorders. The study also investigated whether comorbidity, BMI, and self-reported physical activity were associated with patients' health-related quality of life after adjusting for age as a potential confounder. METHODS: A cross-sectional survey was undertaken in three ambulatory hospital clinics for musculoskeletal disorders. Participants (n=224) reported their reason for referral, age, comorbid health conditions, BMI, physical activity levels (Active Australia Survey), and health-related quality of life (EQ-5D). Descriptive statistics and linear modeling were used to examine the associations between age, comorbidity, BMI, intensity and duration of physical activity, and health-related quality of life. RESULTS: The majority of patients (n=115, 51.3%) reported two or more comorbidities. In addition to other musculoskeletal conditions, common comorbidities included depression (n=41, 18.3%), hypertension (n=40, 17.9%), and diabetes (n=39, 17.4%). Approximately one-half of participants (n=110, 49.1%) self-reported insufficient physical activity to meet minimum recommended guidelines and 150 (67.0%) were overweight (n=56, 23.2%), obese (n=64, 28.6%), severely obese (n=16, 7.1%), or very severely obese (n=14, 6.3%), with a higher proportion of older patients affected. A generalized linear model indicated that, after adjusting for age, self-reported physical activity was positively associated (z=4.22, P<0.001), and comorbidities were negatively associated (z= 2.67, P<0.01) with patients' health-related quality of life. CONCLUSION: Older patients were more frequently affected by undesirable clinical attributes of comorbidity, obesity, and physical inactivity. However, findings from this investigation are compelling for the care of patients of all ages. Potential integration of physical activity behavior change or other effective lifestyle interventions into models of care for patients with musculoskeletal disorders is worthy of further investigation. PMID- 25031533 TI - Adjunctive treatment with oral AKL1, a botanical nutraceutical, in chronic obstructive pulmonary disease. AB - PURPOSE: The objective of this pilot trial was to evaluate the safety and efficacy of AKL1, a patented botanical formulation containing extracts of Picrorhiza kurroa, Ginkgo biloba, and Zingiber officinale, as add-on therapy for patients with chronic obstructive pulmonary disease (COPD) and chronic cough. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial enrolled male and female patients >18 years old with COPD and Leicester Cough Questionnaire (LCQ) score of <18. The 10-week study period comprised a 2-week single-blind placebo run-in period followed by add-on treatment with AKL1 or placebo twice daily for 8 weeks. The primary study endpoint was the change from week 0 to week 8 in cough-related health status, as assessed by the LCQ. RESULTS: Of 33 patients enrolled, 20 were randomized to AKL1 and 13 to placebo. Patients included 19 (58%) men and 14 (42%) women of mean (standard deviation [SD]) age of 67 (9.4) years; 15 (45%) patients were smokers and 16 (49%) were ex-smokers. The mean (SD) change from baseline in LCQ score at 8 weeks was 2.3 (4.9) in the AKL1 group and 0.6 (3.7) in the placebo group, with mean difference in change of 1.8 (95% confidence interval: -1.5 to 5.1; P=0.28). The St George's Respiratory Questionnaire score improved substantially in the AKL1 treatment group by a mean (SD) of -7.7 (11.7) versus worsening in the placebo group (+1.5 [9.3]), with mean difference in change of -9.2 (95% confidence interval: -19.0 to 0.6; P=0.064). There were no significant differences between treatment groups in change from baseline to week 8 in other patient-reported measures, lung function, or the 6 minute walk distance. CONCLUSION: Further study is needed with a larger patient population and over a longer duration to better assess the effects of add-on therapy with AKL1 in COPD. PMID- 25031534 TI - Abdominal closure reinforcement by using polypropylene mesh functionalized with poly-epsilon-caprolactone nanofibers and growth factors for prevention of incisional hernia formation. AB - Incisional hernia affects up to 20% of patients after abdominal surgery. Unlike other types of hernia, its prognosis is poor, and patients suffer from recurrence within 10 years of the operation. Currently used hernia-repair meshes do not guarantee success, but only extend the recurrence-free period by about 5 years. Most of them are nonresorbable, and these implants can lead to many complications that are in some cases life-threatening. Electrospun nanofibers of various polymers have been used as tissue scaffolds and have been explored extensively in the last decade, due to their low cost and good biocompatibility. Their architecture mimics the natural extracellular matrix. We tested a biodegradable polyester poly-epsilon-caprolactone in the form of nanofibers as a scaffold for fascia healing in an abdominal closure-reinforcement model for prevention of incisional hernia formation. Both in vitro tests and an experiment on a rabbit model showed promising results. PMID- 25031535 TI - Manganese ferrite-based nanoparticles induce ex vivo, but not in vivo, cardiovascular effects. AB - Magnetic nanoparticles (MNPs) have been used for various biomedical applications. Importantly, manganese ferrite-based nanoparticles have useful magnetic resonance imaging characteristics and potential for hyperthermia treatment, but their effects in the cardiovascular system are poorly reported. Thus, the objectives of this study were to determine the cardiovascular effects of three different types of manganese ferrite-based magnetic nanoparticles: citrate-coated (CiMNPs); tripolyphosphate-coated (PhMNPs); and bare magnetic nanoparticles (BaMNPs). The samples were characterized by vibrating sample magnetometer, X-ray diffraction, dynamic light scattering, and transmission electron microscopy. The direct effects of the MNPs on cardiac contractility were evaluated in isolated perfused rat hearts. The CiMNPs, but not PhMNPs and BaMNPs, induced a transient decrease in the left ventricular end-systolic pressure. The PhMNPs and BaMNPs, but not CiMNPs, induced an increase in left ventricular end-diastolic pressure, which resulted in a decrease in a left ventricular end developed pressure. Indeed, PhMNPs and BaMNPs also caused a decrease in the maximal rate of left ventricular pressure rise (+dP/dt) and maximal rate of left ventricular pressure decline ( dP/dt). The three MNPs studied induced an increase in the perfusion pressure of isolated hearts. BaMNPs, but not PhMNPs or CiMNPs, induced a slight vasorelaxant effect in the isolated aortic rings. None of the MNPs were able to change heart rate or arterial blood pressure in conscious rats. In summary, although the MNPs were able to induce effects ex vivo, no significant changes were observed in vivo. Thus, given the proper dosages, these MNPs should be considered for possible therapeutic applications. PMID- 25031536 TI - Eye movement analysis and cognitive processing: detecting indicators of conversion to Alzheimer's disease. AB - A great amount of research has been developed around the early cognitive impairments that best predict the onset of Alzheimer's disease (AD). Given that mild cognitive impairment (MCI) is no longer considered to be an intermediate state between normal aging and AD, new paths have been traced to acquire further knowledge about this condition and its subtypes, and to determine which of them have a higher risk of conversion to AD. It is now known that other deficits besides episodic and semantic memory impairments may be present in the early stages of AD, such as visuospatial and executive function deficits. Furthermore, recent investigations have proven that the hippocampus and the medial temporal lobe structures are not only involved in memory functioning, but also in visual processes. These early changes in memory, visual, and executive processes may also be detected with the study of eye movement patterns in pathological conditions like MCI and AD. In the present review, we attempt to explore the existing literature concerning these patterns of oculomotor changes and how these changes are related to the early signs of AD. In particular, we argue that deficits in visual short-term memory, specifically in iconic memory, attention processes, and inhibitory control, may be found through the analysis of eye movement patterns, and we discuss how they might help to predict the progression from MCI to AD. We add that the study of eye movement patterns in these conditions, in combination with neuroimaging techniques and appropriate neuropsychological tasks based on rigorous concepts derived from cognitive psychology, may highlight the early presence of cognitive impairments in the course of the disease. PMID- 25031537 TI - Does participation in a weight control program also improve clinical and functional outcomes for Chinese patients with schizophrenia treated with olanzapine? AB - OBJECTIVES: This study examined whether participation in a weight control program (WCP) by patients with schizophrenia treated with olanzapine was also associated with improvements in clinical and functional outcomes. METHODS: A post-hoc analysis was conducted using data from the Chinese subgroup (n=330) of a multi country, 6-month, prospective, observational study of outpatients with schizophrenia who initiated or switched to oral olanzapine. At study entry and monthly visits, participants were assessed with the Clinical Global Impression of Severity, and measures of patient insight, social activities, and work impairment. The primary comparison was between the 153 patients who participated in a WCP at study entry (n=93) or during the study (n=60) and the 177 patients who did not participate in a weight control program (non-WCP). Mixed Models for Repeated Measures with baseline covariates were used to compare outcomes over time. Kaplan-Meier survival analysis was used to assess time to response. RESULTS: Participants had a mean age of 29.0 years and 29.3 years, and 51.0% and 57.6% were female for WCP and non-WCP groups, respectively. Average initiated daily dose for olanzapine was 9.5+/-5.4 mg. WCP participants gained less weight than non-participants (3.9 kg vs 4.9 kg, P=0.03) and showed statistically significant better clinical and functional outcomes: greater improvement in illness severity (-2.8 vs -2.1, P<0.001), higher treatment response rates (94.1% vs 80.9%, P<0.001), shorter time to response (P<0.001), and greater improvement in patients' insight (P<0.001). Patients who enrolled in a WCP during the study had greater initial weight gain than those who enrolled at baseline (P<0.05), but similar total weight gain. CONCLUSION: Participation in a WCP may not only lower the risk of clinically significant weight gain in olanzapine-treated patients, but may also be associated with additional clinical and functional benefits. PMID- 25031538 TI - Drug assessment by a Pharmacy and Therapeutics committee: from drug selection criteria to use in clinical practice. AB - BACKGROUND: In Spain, hospital medicines are assessed and selected by local Pharmacy and Therapeutics committees (PTCs). Of all the drugs assessed, cancer drugs are particularly important because of their budgetary impact and the sometimes arguable added value with respect to existing alternatives. This study analyzed the PTC drug selection process and the main objective was to evaluate the degree of compliance of prescriptions for oncology drugs with their criteria for use. METHODS: This was a retrospective observational study (May 2007 to April 2010) of PTC-assessed drugs. The variables measured to describe the committee's activity were number of drugs assessed per year and number of drugs included in any of these settings: without restrictions, with criteria for use, and not included in formulary. These drugs were also analyzed by therapeutic group. To assess the degree of compliance of prescriptions, a score was calculated to determine whether prescriptions for bevacizumab, cetuximab, trastuzumab, and bortezomib were issued in accordance with PTC drug use criteria. RESULTS: The PTC received requests for inclusion of 40 drugs, of which 32 were included in the hospital formulary (80.0%). Criteria for use were established for 28 (87.5%) of the drugs included. In total, 293 patients were treated with the four cancer drugs in eight different therapeutic indications. The average prescription compliance scores were as follows: bevacizumab, 83% for metastatic colorectal cancer, 100% for metastatic breast cancer, and 82.3% for non-small-cell lung cancer; cetuximab, 62.0% for colorectal cancer and 50% for head and neck cancer; trastuzumab, 95.1% for early breast cancer and 82.4% for metastatic breast cancer; and bortezomib, 63.7% for multiple myeloma. CONCLUSION: The degree of compliance with criteria for use of cancer drugs was reasonably high. PTC functions need to be changed so that they can carry out more innovative tasks, such as monitoring conditions for drug use. PMID- 25031539 TI - Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review. AB - Ovarian cancer is the most common cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease; although chemotherapeutic advances have improved progression-free survival, conventional treatments offer limited results in terms of long-term responses and survival. Research has recently focused on targeted therapies, which represent a new, promising therapeutic approach, aimed to maximize tumor kill and minimize toxicity. Besides antiangiogenetic agents and poly (ADP-ribose) polymerase inhibitors, the folate, with its membrane-bound receptor, is currently one of the most investigated alternatives. In particular, folate receptor (FR) has been shown to be frequently overexpressed on the surface of almost all epithelial ovarian cancers, making this receptor an excellent tumor-associated antigen. There are two basic strategies to targeting FRs with therapeutic intent: the first is based on anti-FR antibody (ie, farletuzumab) and the second is based on folate-chemotherapy conjugates (ie, vintafolide/etarfolatide). Both strategies have been investigated in Phase III clinical trials. The aim of this review is to analyze the research regarding the activity of these promising anti-FR agents in patients affected by ovarian cancer, including anti-FR antibodies and folate chemotherapy conjugates. PMID- 25031540 TI - Randomized double-blind trial of prophylactic topical Evozac((r)) Calming Skin Spray for gefitinib-associated acne-like eruption. AB - BACKGROUND: "Gefitinib" is a first-generation epidermal growth factor receptor tyrosine-kinase inhibitor. More than half of patients receiving gefitinib develop acne-like eruption. Evozac((r)) Calming Skin Spray (Evaux Laboratoires, Evaux-les Bains, France) is made of Evaux thermal spring water and commonly used for the treatment of dermatological toxicities caused by anti-epidermal growth factor receptor therapy. The aim of the study reported here was to test the effect of Evozac Calming Skin Spray on the prevention of rash in patients receiving gefitinib. METHODS: Non-small-cell lung cancer patients preparing to initiate gefitinib therapy were randomly assigned to apply Evozac Calming Skin Spray or physiological saline to the face three times a day. The treatment was started on the same day as initiation of gefitinib therapy and continued for 4 weeks. RESULTS: A total of 51 patients in the Evozac Calming Skin Spray group and 50 patients in the physiological saline group completed the study per the protocol. The number of facial lesions peaked at the end of 3 weeks in both groups. There were significantly fewer lesions in the Evozac Calming Skin Spray group than in the physiological saline group at the end of 1 week (0.25 versus [vs] 1.10, P=0.031) and 3 weeks (6.67 vs 12.26, P=0.022). Patients from the Evozac Calming Skin Spray group also developed fewer facial lesions at the end of 2 weeks and 4 weeks, however, the difference was not statistically significant. At the end of 4 weeks, fewer patients from the Evozac Calming Skin Spray group developed rash of grade 2 or greater severity (17.6% vs 36.0%, P=0.037), or experienced rash associated symptoms (13.7% vs 34.0%, P=0.017). CONCLUSION: Prophylactic treatment with Evozac Calming Skin Spray appears to decrease the number of facial lesions at the peak of the rash, reduce the incidence of grade 2 or more severe rash and relieve rash-associated symptoms. PMID- 25031541 TI - Anaphylaxis avoidance and management: educating patients and their caregivers. AB - Anaphylaxis is an increasingly prevalent problem in westernized countries. Therefore, it is of utmost importance that the increasing numbers of patients at risk for anaphylaxis receive proper education on the etiology and risk factors as well as appropriate treatment of anaphylaxis with epinephrine. The physician's role is crucial in order to educate the patients and care takers on effective measures to prevent anaphylaxis and empower them to take charge of early recognition and proper management of an anaphylactic reaction to prevent poor outcomes. This review summarizes the clinical presentation, triggers, avoidance, and management of anaphylaxis. PMID- 25031542 TI - Considerations for payers in managing hormone receptor-positive advanced breast cancer. AB - Breast cancer (BC) is the second most common cause of death in women. In 2010, the direct cost associated with BC care in the US was $16.5 billion, the highest among all cancers. By the year 2020, at the current rates of incidence and survival, the cost is projected to increase to approximately $20 billion. Although endocrine therapies to manage hormone receptor-positive (HR+) BC are highly effective, endocrine resistance results in disease progression. Increased understanding of endocrine resistance and the mechanisms of disease progression has led to development and subsequent approval of novel targeted treatments, resulting in the expansion of the therapeutic armamentarium to combat HR+ BC. Clear guidelines based on the safety and efficacy of treatment options exist; however, the optimal sequence of therapy is unknown, and providers, payers, and other key players in the health care system are tasked with identifying cost effective and evidence-based treatment strategies that will improve patient outcomes and, in time, help curb the staggering increase in cost associated with BC care. Safety and efficacy are key considerations, but there is also a need to consider the impact of a given therapy on patient quality of life, treatment adherence, and productivity. To minimize cost associated with overall management, cost-effectiveness, and financial burden that the therapy can impose on patients, caregivers and managed care plans are also important considerations. To help evaluate and identify the optimal choice of therapy for patients with HR+ advanced BC, the available data on endocrine therapies and novel agents are discussed, specifically with respect to the safety, efficacy, financial impact on patients and the managed care plan, impact on quality of life and productivity of patients, and improvement in patient medication adherence. PMID- 25031543 TI - Novel diagnostic approaches and biological therapeutics for intrinsic asthma. AB - Intrinsic asthma has been considered as a specific disease entity for a long time, although many controversies have emerged in relation to this concept. Of note, not finding specific allergen sensitization in an asthmatic patient neither excludes an allergic component nor the essential role that immunoglobulin E may play in asthma. The diagnostic approach should be similar in any patient suspected to have asthma. The atopic status is one among many other questions. Omalizumab, the only monoclonal anti-immunoglobulin E antibody commercialized for asthma, should be tried in patients with uncontrolled severe asthma independent of their atopic status. PMID- 25031544 TI - Clinical profile, management, and outcome in patients with out of hospital cardiac arrest: insights from a 20-year registry. AB - BACKGROUND: There is limited information regarding the clinical characteristics and outcome of out of hospital cardiac arrest (OHCA) in Middle Eastern patients. The aim of this study was to evaluate clinical characteristics, treatment, and outcomes in patients admitted following OHCA at a single center in the Middle East over a 20-year period. METHODS: The data used for this hospital-based study were collected for patients hospitalized with OHCA in Doha, Qatar, between 1991 and 2010. Baseline clinical characteristics, in-hospital treatment, and outcomes were studied in comparison with the rest of the admissions. RESULTS: A total of 41,453 consecutive patients were admitted during the study period, of whom 987 (2.4%) had a diagnosis of OHCA. Their average age was 57+/-15 years, and 72.7% were males, 56.5% were Arabs, and 30.9% were South Asians. When compared with the rest of the admissions taken as a reference, patients with OHCA were more likely to have diabetes mellitus (42.8% versus 39.1%, respectively, P=0.02), prior myocardial infarction (21.8% versus 19.2%, P=0.04), and chronic renal failure (7.4% versus 3.9%, P=0.001), but were less likely to have dyslipidemia (16.9% versus 25.4%, P=0.001). Further, 52.6% of patients had preceding symptoms, the most common of which was chest pain (27.2%) followed by dyspnea (24.8%). An initially shockable rhythm (ventricular fibrillation or ventricular tachycardia) was present in 25.1% of OHCA patients, with ST segment elevation myocardial infarction documented in 30.0%. Severely reduced left ventricular systolic function (ejection fraction <=35%) was present in 53.2% of OHCA patients; 42.9% had cardiogenic shock requiring use of inotropes at presentation. An intra-aortic balloon pump was inserted in 3.6% of cases. Antiarrhythmic medications were used in 27.4% and thrombolytic therapy in 13.9%, and 10.8% underwent a percutaneous coronary procedure (coronary angiography +/- percutaneous coronary intervention). The in-hospital mortality rate was 59.8%. CONCLUSION: OHCA was associated with higher incidences of diabetes, prior myocardial infarction, and chronic kidney disease as compared with the remaining admissions. Approximately half of the patients had no preceding symptoms. In-hospital mortality was high (59.8%), but similar to the internationally published data. PMID- 25031545 TI - Cognitive processing styles of children and adolescents with headache and back pain: a longitudinal epidemiological study. AB - BACKGROUND: Previous research has shown positive relationships between dysfunctional cognitive styles and different aspects of pain (eg, pain frequency). One goal of our longitudinal study was to investigate potential risk factors for the incidence of headache (HA) and back pain (BP). METHODS: In the first wave (2003), questionnaires were sent to 6,400 children between the ages of 9 and 14 years. Those who answered in wave 1 were contacted again every year (four survey waves in total: 2003-2006). The data presented are based on the children's self-reports in the second wave (2004) and third wave (2005). Potential risk factors (dysfunctional stress coping, pain catastrophizing, anxiety sensitivity, and somatosensory amplification) were collected in wave 2. Binary logistic regression analyses - for boys and girls - were performed to assess the predictive value of the risk factors for HA and BP in wave 3. RESULTS: In the comprehensive model, none of the examined variables predicted the incidence of HA. Anxiety sensitivity increased the risk that boys would report BP after 1 year by 50% and dysfunctional stress coping increased the risk by 40%. For girls, somatosensory amplification increased the risk of the incidence of BP 1 year later by 80%, whereas pain catastrophizing reduced the risk by 50%. CONCLUSION: In this incidence sample, the amount of variance explained by the psychological variables investigated was very small. Integrating this result with existing findings from cross-sectional studies suggests that dysfunctional cognitive processing styles may develop more as a consequence or a concomitant feature of BP or HA, but play a less important role in its initial development. PMID- 25031546 TI - Methodological issues in the design of a rheumatoid arthritis activity score and its cut-offs. AB - Activity of rheumatoid arthritis (RA) can be evaluated using several scoring scales based on clinical features. The most widely used one is the Disease Activity Score involving 28 joint counts (DAS28) for which cut-offs were proposed to help physicians classify patients. However, inaccurate scoring can lead to inappropriate medical decisions. In this article some methodological issues in the design of such a score and its cut-offs are highlighted in order to further propose a strategy to overcome them. As long as the issues reviewed in this article are not addressed, results of studies based on standard disease activity scores such as DAS28 should be considered with caution. PMID- 25031547 TI - Pulse oximetry: fundamentals and technology update. AB - Oxygen saturation in the arterial blood (SaO2) provides information on the adequacy of respiratory function. SaO2 can be assessed noninvasively by pulse oximetry, which is based on photoplethysmographic pulses in two wavelengths, generally in the red and infrared regions. The calibration of the measured photoplethysmographic signals is performed empirically for each type of commercial pulse-oximeter sensor, utilizing in vitro measurement of SaO2 in extracted arterial blood by means of co-oximetry. Due to the discrepancy between the measurement of SaO2 by pulse oximetry and the invasive technique, the former is denoted as SpO2. Manufacturers of pulse oximeters generally claim an accuracy of 2%, evaluated by the standard deviation (SD) of the differences between SpO2 and SaO2, measured simultaneously in healthy subjects. However, an SD of 2% reflects an expected error of 4% (two SDs) or more in 5% of the examinations, which is in accordance with an error of 3%-4%, reported in clinical studies. This level of accuracy is sufficient for the detection of a significant decline in respiratory function in patients, and pulse oximetry has been accepted as a reliable technique for that purpose. The accuracy of SpO2 measurement is insufficient in several situations, such as critically ill patients receiving supplemental oxygen, and can be hazardous if it leads to elevated values of oxygen partial pressure in blood. In particular, preterm newborns are vulnerable to retinopathy of prematurity induced by high oxygen concentration in the blood. The low accuracy of SpO2 measurement in critically ill patients and newborns can be attributed to the empirical calibration process, which is performed on healthy volunteers. Other limitations of pulse oximetry include the presence of dyshemoglobins, which has been addressed by multiwavelength pulse oximetry, as well as low perfusion and motion artifacts that are partially rectified by sophisticated algorithms and also by reflection pulse oximetry. PMID- 25031548 TI - Catridecacog: a breakthrough in the treatment of congenital factor XIII A-subunit deficiency? AB - Circulating factor XIII (FXIII) consists of two active (A) and two carrier (B) subunits in tetrameric form. Congenital FXIII deficiency is a rare autosomal recessive trait that mostly results from an FXIII A-subunit deficiency. Classic coagulation assays, such as prothrombin time or activated partial thromboplastin time, are not sensitive to FXIII; therefore, specific FXIII assays are necessary to detect the deficiency. The clinical picture of congenital FXIII deficiency comprises abortions, umbilical cord bleeding, increased surgical bleeding, intracerebral hemorrhage (which can, unfortunately, be the very first sign of severe FXIII deficiency), menorrhagia, and wound-healing disorders. Given the risk of intracranial hemorrhage, continued prophylaxis is to be recommended in severe deficiency, even in the actual absence of bleeding symptoms. Functional FXIII half-life decreases in consumptive processes (eg, surgery), explaining why increased dosing is needed in such situations. A recombinant FXIII (rFXIII) subunit-A molecule, which is expressed in Saccharomyces cerevisiae, has been evaluated for replacement therapy in congenital FXIII deficiency. The bleeding frequency under continued rFXIII prophylaxis during a year-long treatment period was significantly lower compared to on-demand treatment. Importantly, no severe spontaneous bleedings occurred, and bleeding requiring additional intervention only occurred after relevant trauma. Treatment with rFXIII proved to be safe: antibodies against rFXIII detected in four patients were not considered clinically relevant. No allergic reactions were observed. These data show that rFXIII can be used safely and effectively for continued prophylaxis in congenital FXIII deficiency; it is conceivable that this also holds true for treatment of acute bleeding, but clinical proof of this is pending. PMID- 25031549 TI - Undivided attention improves postoperative anesthesia handover recall. AB - BACKGROUND: For years, undivided attention during the presurgical "timeout" has been utilized as a precaution to ensure patient safety. The information relayed during the timeout is presented in a confirmatory nature rather than a delegation of new information. However, it is a standard of practice in which all members of the operating theater provide their full and undivided attention. Standards of patient care should be contiguous throughout the preoperative, perioperative, and postoperative stages of surgery. In this manner, it is expected that the same undivided attention afforded during the timeout should be maintained when transferring the patient to the postanesthesia care unit. METHODS: In this study, information was collected regarding handover of information during the transfer status postsurgical procedures. Data were collected via observing interactions between the anesthesiologist and the nurse during verbal patient transfers. RESULTS: This study demonstrated that the presence of undivided attention during the handover of a surgical patient in the postanesthesia care unit has a direct correlation with improved recall of the information discussed during handover. CONCLUSION: Focus is on the quantity of information that can be recalled by the transferring nurse, and whether or not undivided attention affects the outcome. Analysis focuses on suggestions to better improve patient safety and recovery when being transferred in an anesthetic setting. The practice of patient handover should be standardized to better improve the safety and quality of medical care. PMID- 25031551 TI - Serum TFF3 may be a pharamcodynamic marker of responses to chemotherapy in gastrointestinal cancers. AB - BACKGROUND: As a secreted protein, serum trefoil factor 3 (TFF3) has been reported to be a biomarker of several malignancies. We further investigated whether TFF3 can be applied as a biomarker for and predictor of responses to chemotherapy in gastrointestinal cancer. METHODS: Serum and urine samples were collected from 90 patients with gastric cancer, 128 patients with colorectal cancer and 91 healthy individuals. Serum and urine TFF3 levels were measured using an ELISA. RESULTS: Serum and urine TFF3 levels were significantly higher in the patients with gastric and colorectal cancer compared with the healthy individuals (P < 0.05). Higher serum levels of TFF3 were significantly correlated with distant metastasis and an advanced stage in the two types of cancer (P < 0.05). Age and the number of lymph node metastases were significantly correlated with serum TFF3 levels in colorectal cancer, and decreased serum TFF3 levels were significantly correlated with responses to chemotherapy in both the gastric and the colorectal cancer partial response (PR) groups. A combination of serum and urine data did not significantly improve the detection of either cancer, although urine levels have shown a significant negative relationship with the glomerular filtration rate (GFR). CONCLUSIONS: Our data indicate that TFF3 may be an effective biomarker of tumor stage and the presence of distant metastasis, and may be a pharmacodynamic marker of response to chemotherapy in gastrointestinal cancer. PMID- 25031552 TI - Welcoming systematic reviews to the Journal of the Medical Library Association. PMID- 25031553 TI - Current findings from research on structured abstracts: an update. PMID- 25031554 TI - Linda J. Walton Medical Library Association President, 2014-2015. PMID- 25031555 TI - International health sciences library perspectives. PMID- 25031550 TI - Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy. AB - Estrogen and estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Compromised signaling vis-a-vis the estrogen receptor is believed to be a major contributing factor in the malignancy of breast cells. Targeting the ER signaling pathway has been a focal point in the development of breast cancer therapy. Although approximately 75 % of breast cancer patients are classified as luminal type (ER(+)), which predicts for response to endocrine-based therapy; however, innate or acquired resistance to endocrine-based drugs remains a serious challenge. The complexity of regulation for estrogen signaling coupled with the crosstalk of other oncogenic signaling pathways is a reason for endocrine therapy resistance. Alternative strategies that target novel molecular mechanisms are necessary to overcome this current and urgent gap in therapy. A thorough analysis of estrogen signaling regulation is critical. In this review article, we will summarize current insights into the regulation of estrogen signaling as related to breast carcinogenesis and breast cancer therapy. PMID- 25031556 TI - A survey study of evidence-based medicine training in US and Canadian medical schools. AB - PURPOSE: The authors conducted a survey examining (1) the current state of evidence-based medicine (EBM) curricula in US and Canadian medical schools and corresponding learning objectives, (2) medical educators' and librarians' participation in EBM training, and (3) barriers to EBM training. METHODS: A survey instrument with thirty-four closed and open-ended questions was sent to curricular deans at US and Canadian medical schools. The survey sought information on enrollment and class size; EBM learning objectives, curricular activities, and assessment approaches by year of training; EBM faculty; EBM tools; barriers to implementing EBM curricula and possible ways to overcome them; and innovative approaches to EBM education. Both qualitative and quantitative methods were used for data analysis. Measurable learning objectives were categorized using Bloom's taxonomy. RESULTS: One hundred fifteen medical schools (77.2%) responded. Over half (53%) of the 900 reported learning objectives were measurable. Knowledge application was the predominant category from Bloom's categories. Most schools integrated EBM into other curricular activities; activities and formal assessment decreased significantly with advanced training. EBM faculty consisted primarily of clinicians, followed by basic scientists and librarians. Various EBM tools were used, with PubMed and the Cochrane database most frequently cited. Lack of time in curricula was rated the most significant barrier. National agreement on required EBM competencies was an extremely helpful factor. Few schools shared innovative approaches. CONCLUSIONS: Schools need help in overcoming barriers related to EBM curriculum development, implementation, and assessment. IMPLICATIONS: Findings can provide a starting point for discussion to develop a standardized competency framework. PMID- 25031557 TI - Information-seeking behavior and the use of online resources: a snapshot of current health sciences faculty. AB - OBJECTIVE: The research assesses the information-seeking behaviors of health sciences faculty, including their use of online databases, journals, and social media. METHODOLOGY: A survey was designed and distributed via email to 754 health sciences faculty at a large urban research university with 6 health sciences colleges. RESULTS: Twenty-six percent (198) of faculty responded. MEDLINE was the primary database utilized, with 78.5% respondents indicating they use the database at least once a week. Compared to MEDLINE, Google was utilized more often on a daily basis. Other databases showed much lower usage. CONCLUSIONS: Low use of online databases other than MEDLINE, link-out tools to online journals, and online social media and collaboration tools demonstrates a need for meaningful promotion of online resources and informatics literacy instruction for faculty. IMPLICATIONS: Library resources are plentiful and perhaps somewhat overwhelming. Librarians need to help faculty discover and utilize the resources and tools that libraries have to offer. PMID- 25031558 TI - Searching ClinicalTrials.gov and the International Clinical Trials Registry Platform to inform systematic reviews: what are the optimal search approaches? AB - BACKGROUND: Since 2005, International Committee of Medical Journal Editors (ICMJE) member journals have required that clinical trials be registered in publicly available trials registers before they are considered for publication. OBJECTIVES: The research explores whether it is adequate, when searching to inform systematic reviews, to search for relevant clinical trials using only public trials registers and to identify the optimal search approaches in trials registers. METHODS: A search was conducted in ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) for research studies that had been included in eight systematic reviews. Four search approaches (highly sensitive, sensitive, precise, and highly precise) were performed using the basic and advanced interfaces in both resources. RESULTS: On average, 84% of studies were not listed in either resource. The largest number of included studies was retrieved in ClinicalTrials.gov and ICTRP when a sensitive search approach was used in the basic interface. The use of the advanced interface maintained or improved sensitivity in 16 of 19 strategies for Clinicaltrials.gov and 8 of 18 for ICTRP. No single search approach was sensitive enough to identify all studies included in the 6 reviews. CONCLUSIONS: Trials registers cannot yet be relied upon as the sole means to locate trials for systematic reviews. Trials registers lag behind the major bibliographic databases in terms of their search interfaces. IMPLICATIONS: For systematic reviews, trials registers and major bibliographic databases should be searched. Trials registers should be searched using sensitive approaches, and both the registers consulted in this study should be searched. PMID- 25031559 TI - How are medical students trained to locate biomedical information to practice evidence-based medicine? A review of the 2007-2012 literature. AB - OBJECTIVES: This study describes how information retrieval skills are taught in evidence-based medicine (EBM) at the undergraduate medical education (UGME) level. METHODS: The authors systematically searched MEDLINE, Scopus, Educational Resource Information Center, Web of Science, and Evidence-Based Medicine Reviews for English-language articles published between 2007 and 2012 describing information retrieval training to support EBM. Data on learning environment, frequency of training, learner characteristics, resources and information skills taught, teaching modalities, and instructor roles were compiled and analyzed. RESULTS: Twelve studies were identified for analysis. Studies were set in the United States (9), Australia (1), the Czech Republic (1), and Iran (1). Most trainings (7) featured multiple sessions with trainings offered to preclinical students (5) and clinical students (6). A single study described a longitudinal training experience. A variety of information resources were introduced, including PubMed, DynaMed, UpToDate, and AccessMedicine. The majority of the interventions (10) were classified as interactive teaching sessions in classroom settings. Librarians played major and collaborative roles with physicians in teaching and designing training. Unfortunately, few studies provided details of information skills activities or evaluations, making them difficult to evaluate and replicate. CONCLUSIONS: This study reviewed the literature and characterized how EBM search skills are taught in UGME. Details are provided on learning environment, frequency of training, level of learners, resources and skills trained, and instructor roles. IMPLICATIONS: The results suggest a number of steps that librarians can take to improve information skills training including using a longitudinal approach, integrating consumer health resources, and developing robust assessments. PMID- 25031560 TI - Breaking inertia: increasing access to journals during a period of declining budgets: a case study. AB - Beginning in January 2012, a 1-year pilot pay-per-view (PPV) service was implemented. Twenty-four journal subscriptions were canceled to fund the service, and through the PPV service, the library was able to offer patrons access to over 700 previously unavailable biomedical journals. At the end of the pilot period, the total PPV cost for each journal accessed was compared to the subscription cost to determine if PPV was an effective use of library money. While remaining essentially budget neutral, the number of full-text articles accessed increased over 400%. PPV can be a cost-effective method for expanding access to journals. PMID- 25031561 TI - Taking library instruction into the online environment: one health sciences library's experience. AB - In 2012, an academic health sciences library serving a large research university and medical center introduced synchronous online training for a diverse group of users, including clinicians, researchers, faculty, and distance students. Participants in these "Express Training" classes completed two surveys to assess their experiences. Survey results indicated classes were well received but revealed some areas for improvement. Included are issues that should be considered when implementing online library instruction to meet the diverse needs of academic health sciences library users. Given the popularity of online training among on-campus and distance users, it will be continued and expanded. PMID- 25031562 TI - The persistence of clinical questions across shifts on an intensive care unit: an observational pilot study. AB - How do clinical questions emerge and move toward resolution in the intensive care setting over the course of 24 hours? In a 20-bed surgical intensive care unit in a large, tertiary-care teaching hospital, informationists shadowed clinicians for 2 48-hour periods to record questions, noting when they were asked and whether they were answered. Thirty-eight percent of 112 recorded questions remained unanswered. Some unanswered questions persisted across shifts, and clinicians' information-seeking behaviors changed over time. Clinical information services can be improved and integrated more fully into clinical workflows based on a fuller understanding of the life cycle of clinical inquiry. PMID- 25031563 TI - Library workers' personal beliefs about childhood vaccination and vaccination information provision. AB - This is a report on the impact of library workers' personal beliefs on provision of vaccination information. Nine public librarians were interviewed about a hypothetical scenario involving a patron who is concerned about possible vaccination-autism connections. The analysis employed thematic coding. Results suggested that while most participants supported childhood vaccination, tension between their personal views and neutrality impacted their ability to conduct the interaction. The neutrality stance, though consonant with professional guidelines, curtails librarians' ability to provide accurate health information. Outreach and communication between public and health sciences libraries can help librarians provide resources to address health controversies. PMID- 25031564 TI - Evidence-based practice instruction by faculty members and librarians in North American optometry and ophthalmology programs. AB - North American optometry and ophthalmology faculty members and vision science librarians were surveyed online (14% response rate) about teaching evidence-based practice (EBP). Similar to studies of other health care programs, all five EBP steps (Ask, Acquire, Appraise, Apply, Assess) were taught to varying degrees. Optometry and ophthalmology EBP educators may want to place further emphasis on (1) the Apply and Assess steps, (2) faculty- and student-generated questions and self-assessment in clinical settings, (3) online teaching strategies, (4) programmatic integration of EBP learning objectives, and (5) collaboration between faculty members and librarians. PMID- 25031565 TI - Academic health sciences librarians' contributions to institutional animal care and use committees. AB - The study gathered data about librarians' membership in institutional animal care and use committees (IACUCs) and their professional activities supporting animal researchers. Libraries affiliated with medical schools that were members of the Association of American Medical Colleges were surveyed. A survey was distributed via library directors' email discussion lists and direct email messages. Sixty surveys were completed: 35 (58%) reported that librarians performed database searches for researchers, and 22 (37%) reported that a librarian currently serves on the IACUC. The survey suggests that academic health sciences librarians provide valuable, yet underutilized, services to support animal research investigators. PMID- 25031566 TI - Editor's Introduction to This Issue. PMID- 25031567 TI - New lung cancer panel for high-throughput targeted resequencing. AB - We present a new next-generation sequencing-based method to identify somatic mutations of lung cancer. It is a comprehensive mutation profiling protocol to detect somatic mutations in 30 genes found frequently in lung adenocarcinoma. The total length of the target regions is 107 kb, and a capture assay was designed to cover 99% of it. This method exhibited about 97% mean coverage at 30* sequencing depth and 42% average specificity when sequencing of more than 3.25 Gb was carried out for the normal sample. We discovered 513 variations from targeted exome sequencing of lung cancer cells, which is 3.9-fold higher than in the normal sample. The variations in cancer cells included previously reported somatic mutations in the COSMIC database, such as variations in TP53, KRAS, and STK11 of sample H-23 and in EGFR of sample H-1650, especially with more than 1,000* coverage. Among the somatic mutations, up to 91% of single nucleotide polymorphisms from the two cancer samples were validated by DNA microarray-based genotyping. Our results demonstrated the feasibility of high-throughput mutation profiling with lung adenocarcinoma samples, and the profiling method can be used as a robust and effective protocol for somatic variant screening. PMID- 25031568 TI - Association Analysis of TEC Polymorphisms with Aspirin-Exacerbated Respiratory Disease in a Korean Population. AB - The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signaling transmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses, such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbated respiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects, which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed to examine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed that TEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for the fall rate of forced expiratory volume in 1 second (FEV1) by aspirin provocation, two variations (rs7664091 and rs12500534) and one haplotype (TEC_BL2_ht4) showed nominal associations with FEV1 decline (p = 0.03-0.04). However, the association signals were not retained after performing corrections for multiple testing. Despite TEC playing an important role in immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis. PMID- 25031569 TI - Elucidating Molecular Interactions of Natural Inhibitors with HPV-16 E6 Oncoprotein through Docking Analysis. AB - Human papillomavirus (HPV) infection is the leading cause of cancer mortality among women worldwide. The life-threatening infection caused by HPV demands the need for designing anticancerous drugs. In the recent years, different compounds from natural origins, such as carrageenan, curcumin, epigallocatechin gallate, indole-3-carbinol, jaceosidin, and withaferin, have been used as a hopeful source of anticancer therapy. These compounds have been shown to suppress HPV infection by different researchers. In the present study, we explored these natural inhibitors against E6 oncoprotein of high-risk HPV-16, which is known to inactivate the p53 tumor suppressor protein. A robust homology model of HPV-16 E6 was built to anticipate the interaction mechanism of E6 oncoprotein with natural inhibitory molecules using a structure-based drug designing approach. Docking analysis showed the interaction of these natural compounds with the p53-binding site of E6 protein residues 113-122 (CQKPLCPEEK) and helped the restoration of p53 functioning. Docking analysis, besides helping in silico validation of natural compounds, also helps understand molecular mechanisms of protein-ligand interactions. PMID- 25031570 TI - Examining the Gm18 and m(1)G Modification Positions in tRNA Sequences. AB - The tRNA structure contains conserved modifications that are responsible for its stability and are involved in the initiation and accuracy of the translation process. tRNA modification enzymes are prevalent in bacteria, archaea, and eukaryotes. tRNA Gm18 methyltransferase (TrmH) and tRNA m(1)G37 methyltransferase (TrmD) are prevalent and essential enzymes in bacterial populations. TrmH involves itself in methylation process at the 2'-OH group of ribose at the 18th position of guanosine (G) in tRNAs. TrmD methylates the G residue next to the anticodon in selected tRNA subsets. Initially, m(1)G37 modification was reported to take place on three conserved tRNA subsets (tRNA(Arg), tRNA(Leu), tRNA(Pro)); later on, few archaea and eukaryotes organisms revealed that other tRNAs also have the m(1)G37 modification. The present study reveals Gm18, m(1)G37 modification, and positions of m(1)G that take place next to the anticodon in tRNA sequences. We selected extremophile organisms and attempted to retrieve the m(1)G and Gm18 modification bases in tRNA sequences. Results showed that the Gm18 modification G residue occurs in all tRNA subsets except three tRNAs (tRNA(Met), tRNA(Pro), tRNA(Val)). Whereas the m(1)G37 modification base G is formed only on tRNA(Arg), tRNA(Leu), tRNA(Pro), and tRNA(His), the rest of the tRNAs contain adenine (A) next to the anticodon. Thus, we hypothesize that Gm18 modification and m(1)G modification occur irrespective of a G residue in tRNAs. PMID- 25031571 TI - SFannotation: A Simple and Fast Protein Function Annotation System. AB - Owing to the generation of vast amounts of sequencing data by using cost effective, high-throughput sequencing technologies with improved computational approaches, many putative proteins have been discovered after assembly and structural annotation. Putative proteins are typically annotated using a functional annotation system that uses extant databases, but the expansive size of these databases often causes a bottleneck for rapid functional annotation. We developed SFannotation, a simple and fast functional annotation system that rapidly annotates putative proteins against four extant databases, Swiss-Prot, TIGRFAMs, Pfam, and the non-redundant sequence database, by using a best-hit approach with BLASTP and HMMSEARCH. PMID- 25031572 TI - NADH dehydrogenase subunit-2 237 Leu/Met polymorphism modifies effects of cigarette smoking on risk of elevated levels of serum liver enzyme in male Japanese health check-up examinees: a cross-sectional study. AB - BACKGROUND: NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism reportedly influences the effects of cigarette smoking on respiratory function, risk of dyslipidemia, serum non-high-density lipoprotein cholesterol levels, hematological parameters and intraocular pressure. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of cigarette smoking on serum liver enzyme levels in male Japanese health check-up examinees. METHODS: A total of 421 male subjects (mean age +/- SD, 54.1 +/- 7.7 years) were selected from among individuals visiting the hospital for regular medical check-ups. After ND2-237 Leu/Met genotyping, a cross sectional study assessing the combined effects of ND2-237 Leu/Met polymorphism and cigarette smoking on serum aspartate aminotransferase levels, serum alanine aminotransferase (ALT) levels and serum gamma-glutamyltransferase (GGT) levels was then conducted. RESULTS: No statistically significant differences in serum liver enzyme levels among the three smoking status groups (never- or ex-smokers, 1-20 cigarettes smoked per day and >20 cigarettes smoked per day) by ND2-237 Leu/Met genotype were observed. However, for men with ND2-237Met, cigarette smoking significantly increased the risk of elevated levels of serum ALT (>30 U/L) or serum GGT (>=60 U/L or >51 U/L) (P for trend = 0.031, P for trend = 0.007 and P for trend = 0.004, respectively). After adjustment for age, body mass index, alcohol consumption, coffee consumption, antihypertensive treatment and antidiabetic treatment, a significant association between cigarette smoking and risk of elevated levels of serum ALT (>30 U/L) or serum GGT (>=60 U/L or >51 U/L) was also observed (P for trend = 0.032, P for trend = 0.019 and P for trend = 0.009, respectively). Surprisingly, for men with ND2-237Leu, cigarette smoking significantly decreased the risk of elevated levels of serum ALT (>30 U/L or >=25 U/L) (P for trend = 0.026 and P for trend = 0.003, respectively). CONCLUSIONS: Cigarette smoking appears to increase the risk of elevated levels of serum ALT or serum GGT in ND2-237Met genotypic men, but to decrease the risk of elevated levels of serum ALT in ND2-237Leu genotypic men. PMID- 25031573 TI - Comparison of reactive oxygen species in neat and washed semen of infertile men. AB - BACKGROUND: Male are involved in near 50% of cases of infertility and reactive oxygen species (ROS) playing an important role in decreasing fertility potential. Accurate measurement of ROS seems to be important in evaluation of infertile male patients. OBJECTIVE: To compare ROS measurement in neat and washed semen samples of infertile men and define the best method for evaluation of ROS in these patients. MATERIALS AND METHODS: We measured the level of ROS in semen samples of thirty five non-azoospermic men with infertility. The semen samples were divided into two parts and the semen parameters and ROS levels in neat and washed samples were evaluated. We also evaluated the presence of pyospermia using peroxidase test. RESULTS: The differences regarding sperm count and quick motility were significant in neat and washed semen samples. The mean ROS level was significantly higher in neat samples compared with washed spermatozoa (7.50 RLU vs. 1.20 RLU respectively). Difference in ROS levels was more significant in patients with pyospermia compared to whom with no pyospermia (378.67 RLU vs. 9.48 RLU respectively). CONCLUSION: Our study confirmed that neat or unprocessed samples are better index of normal oxidative status of semen samples. Because we do not artificially add or remove factors that may play an important role in oxidative equilibrium status. PMID- 25031574 TI - Saccharin consumption increases sperm DNA fragmentation and apoptosis in mice. AB - BACKGROUND: Saccharin is an artificial non-caloric sweetener that used to sweeten products such as drinks, candies, medicines, and toothpaste, but our bodies cannot metabolize it. Sodium saccharin is considered as an important factor in tumor promotion in male rats but not in humans. OBJECTIVE: The objective of this study was to investigate the effect of saccharin consumption on sperm parameters and apoptosis in adult mice. MATERIALS AND METHODS: Totally 14 adult male mice were divided into 2 groups. Group 1 served as control fed on basal diet and group 2 or experimental animals received distilled water containing saccharin (0.2% w/v) for 35 days. After that, the left cauda epididymis of each mouse was cut and placed in Ham's F10. Swimmed-out spermatozoa were used to analyze count, motility, morphology (Pap-staining) and viability (eosin-Y staining). Sperm DNA integrity, as an indicator of apoptosis, was assessed by SCD (sperm chromatin dispersion) and terminal deoxynucleotidyl transferase (TUNEL) assay. RESULTS: Following saccharin consumption, we had a reduction in sperm motility with respect to control animals (p=0.000). In addition, the sperm count diminished (17.70+/-1.11 in controls vs. 12.80+/-2.79 in case group, p=0.003) and the rate of sperm normal morphology decreased from 77.00+/-6.40 in control animals into 63.85+/-6.81 in saccharin-treated mice (p=0.001). Also, we saw a statistically significant increase in rates of sperm DNA damage and apoptosis in experimental group when compared to control one (p=0.001, p=0.002 respectively). CONCLUSION: Saccharin consumption may have negative effects on sperm parameters, and increases the rate of sperm DNA fragmentation and apoptosis in mice. PMID- 25031575 TI - Expression of Glycogen synthase kinase 3-beta (GSK3-beta) gene in azoospermic men. AB - BACKGROUND: The Wnt/beta- The Wnt/beta-catenin signaling pathway is involved in many developmental processes in both fetal and adult life; its abnormalities can lead to disorders including several types of cancers and malfunction of specific cells and tissues in both animals and humans. Its role in reproductive processes has been proven. OBJECTIVE: This study was designed to evaluate the expression of the key regulator of this signaling pathway GSK3-beta and its presumed role in azoospermia. MATERIALS AND METHODS: WNT3a protein concentration and GSK3-beta gene expression levels were measured and compared between two groups of infertile men. The test groups consisted of 10 patients with obstructive and 10 non obstructive azoospermia. The control group was selected among healthy men after vasectomies that were willing to conceive a child using a testicular biopsy technique. Samples were obtained by testicular biopsy and screened for the most common mutations (84, 86 and 255) in the SRY region before analyzing. GSK3-beta gene expression was assessed quantitatively by real time-PCR. RESULTS: The WNT3a protein concentration had no significant difference between the two test groups and controls. Expression of GSK3-beta was down-regulated in non-obstructive azoospermia (3.10+/-0.19) compared with normal (7.12+/-0.39) and obstructive azoospermia (6.32+/-0.42) groups (p=0.001). CONCLUSION: Down-regulation of GSK 3beta may cause to non-obstructive azoospermia. Regulation and modification of GSK-3beta gene expression by drugs could be used as a therapeutic solution. PMID- 25031576 TI - Assessemnt of nasal bone in first trimester screening for chromosomal abnormalities in Khuzestan. AB - BACKGROUND: Fetal nasal bone assessment is a non-invasive procedure that helps provide even greater assurance to patients undergoing their first trimester risk assessment for aneuploidies. Absence or presence of this factor is different in some races. OBJECTIVE: The study was aimed to evaluate nasal bone in the first trimester of pregnancy in the indigenous population of Khuzestan Province, and to monitor its value in the diagnosis of chromosomal abnormalities. MATERIALS AND METHODS: This study was conducted on 2314 pregnant women between 17-43 years old who referred for first trimester screening for chromosomal abnormalities. Gestational age was between 11-13w + 6 days. Nuchal translucency (NT), fetal heart rate (FHR), crown rump length (CRL), and maternal age and maternal blood serum factors (Free HCG) and pregnancy-associated plasma protein-A (PAPP-A) and nasal bone were assessed. Finally the risk of trisomies was calculated. The statistical tests are based on the relationship between chromosomal abnormality and the presence or absence of the nasal bone. RESULTS: In 114 cases we could not examine the nasal bone. Also, in 20 cases missed abortion happened without knowing the karyotype. 2173 cases were delivered normal baby, and in seven cases chromosomal abnormalities were diagnosed. Nasal bone was absent in all three cases with trisomy 21 and six of 2173 cases with normal phenotype (0.3%). With use of the Fisher exact test (p=0.0001), a significant correlation was found between the absence of the nasal bone and the risk of chromosomal abnormality. CONCLUSION: Inclusion of the nasal bone in first-trimester combined screening for aneuploidies achieves greater detection rate especially in Down syndrome. PMID- 25031577 TI - Molecular and serologic diagnostic approaches; the prevalence of herpes simplex in idiopathic men infertile. AB - BACKGROUND: Human pathogens that can cause infertility may also affect sperm count and quality. Viral infections can be considered as direct and/or indirect cause of male factor infertility. OBJECTIVE: Our goal was to investigate the prevalence of herpes simplex virus in the semen of infertile men attending the Avicenna Infertility Clinic, and to compare it with the herpes virus serology results. MATERIALS AND METHODS: This cross sectional study was conducted during 2009-2010. Infertile men participating without any clinical signs of infection with herpes simplex virus, and no obvious cause for their infertility were included. Semen and blood samples were used for Polymerase Chain Reaction (PCR) and serologic testing for these people. Two samples were collected: one ml semen sample to verify the existence of genital herpes simplex virus in infertile men, and blood samples of 217 individuals tested for antibodies to herpes simplex virus. Data were analyzed by SPSS 16. RESULTS: According to the PCR results of semen samples the prevalence of herpes simplex in semen was 12% and serologic test showed 3.2% prevalence within blood. Nine to 10% of IgM negative were PCR positive and only 2-3% of IgM positive were PCR positive. Between herpes serologic studies with positive controls and negative controls by using both tests, there was a significant positive relationship (r=0.718 and p<0.001). The relationship between semen PCR test results and serological survey of herpes patients with a negative control in both Pearson and Spearman tests was positive and significant (r=0.229 and p=0.001). Correlation between the PCR results of semen samples with two positive control subjects and a positive IgM test was statistically confirmed (r=0.235 and p<0.001). CONCLUSION: We recommend that if there is suspicion to herpes simplex as a microorganism that theoretically could impact semen parameters and cause infertility it is prudent to use PCR technique on semen sample rather than ELISA on serum. PMID- 25031578 TI - Effects of acrylamide on sperm parameters, chromatin quality, and the level of blood testosterone in mice. AB - BACKGROUND: Acrylamide (AA) is an important industrial chemical primarily. AA is also found in carbohydrate-rich foods that are prepared at high temperatures, such as French fries and potato chips. It is demonstrated that AA is a carcinogen and reproductive toxin and has ability to induce sperm damage. OBJECTIVE: The aim of this study was to observe the effects of AA on sperm parameters and evaluation of sperm chromatin quality and testosterone hormone in mice. MATERIALS AND METHODS: Totally, 16 adult male mice were divided into two groups. Mice of group A fed on basal diet; group B received basal diet and AA (10 mg/kg, water solution) for 35 days. The right cauda epididymis was incised and then placed in Ham's F10 culture media at 37(o)C for 15 min. Released spermatozoa were used to analyze count, motility, morphology and viability. To determine the sperm DNA integrity and chromatin condensation, the cytochemical techniques including Aniline blue, Acridine orange and Chromomycin A3 staining were used. RESULTS: AA treated mice had poor parameters in comparison with control animals. In sperm chromatin assessments, except TB (p=0.16), significant differences were found in all of the tests between two groups. It was also seen a significant decrease in concentration of blood testosterone in AA-treated animals when compared to controls (p<0.001). CONCLUSION: According to our results, AA can affect sperm parameters as well as sperm chromatin condensation and DNA integrity in mice. These abnormalities may be related to the reduction in blood testosterone. PMID- 25031579 TI - Effect of saffron on rat sperm chromatin integrity. AB - BACKGROUND: Currently, relation between reactive oxygen species (ROS) ROS concentration and semen quality was indicated. Saffron has traditionally been not only considered as a food additive but also as a medicinal herb, which has a good antioxidant properties. OBJECTIVE: The aim of this study was to evaluate the protection potency of saffron and vitamin E on sperm chromatin integrity. MATERIALS AND METHODS: Thirty adult male Wistar rats divided equally into saffron (100 mg/kg), vitamin E (100 mg/kg) and control (0.5cc distilled water /day) groups. After 60 days, cauda epididymis dissected and sperm cells were used for analysis of sperm chromatin packaging by chromomycin A3 (CMA3) staining, and sperm chromatin susceptibility to acid denaturation by acridine orange (AO) staining. RESULTS: The mean percentage of CMA3 positive sperm was significantly decreased in saffron and vitamin E groups relative to control group (p<0.001). Moreover, the AO staining results showed that the mean percentage of sperm with DNA damage was significantly decreased in saffron and vitamin E groups as compared with control group (p<0.001). CONCLUSION: Our results purposed that saffron can protect sperm against DNA damage and chromatin anomalies. PMID- 25031580 TI - A newborn with ambiguous genitalia and a complex X;Y rearrangement. AB - BACKGROUND: In most mammals, sex is determined at the beginning of gestation by the constitution of the sex chromosomes, XY in males and XX in females. CASE: Here we report an interesting case characterized by ambiguous genitalia and ovotestis in a newborn carrying an apparently female karyotype (46 XX). Array Comparative Genomic Hybridization (Array-CGH) revealed an unbalanced rearrangement resulting in the deletion of the distal Xp and the duplication of the proximal Xp contiguous region with presence of the Y chromosome from Ypter to Yq11. Fluorescent in situ hybridization (FISH) showed that this portion of the Y was translocated to the tip of the abnormal X and that the duplicated portion of chromosome X was inverted. Altogether, the abnormal chromosome was a dicentric one with the centromere of the Y chromosome apparently inactivated. CONCLUSION: The presence within the translocated Y chromosome of the SRY gene explains the devolopment of testes although it is not clear the reason for the genitalia ambiguity. PMID- 25031581 TI - Association of heteromorphism of chromosome 9 and recurrent abortion (ultrasound diagnosed blighted ovum): A case report. AB - BACKGROUND: Chromosomal disorders are the most common cause of first trimester spontaneous abortion. Among the human chromosomes, chromosome no.9 was the most common structural chromosomal variant and it is not thought to be of any functional importance, which often considers as a normal variation in structural polymorphisms, nevertheless there are some studies which claim that there is an association between heteromorphism of chromosome no.9 and some pregnancy complication. CASE: To postulate any correlation between chromosome no. 9 heteromorphism and recurrent abortion, chromosomal analysis was performed on the basis of G-banding technique at high resolution for a couple with the history of 4 ultrasound diagnosed blighted ovum and Chromosome constitution appeared with chromosome no.9 heteromorphism in all 30 metaphases screened for both partners (9p11-q13). CONCLUSION: Observation of reproductive failure in couples with heteromorohic pattern of chromosome no.9 suggests that, although the heteromorphism of chromosome no.9 is not a rare condition which often consider as a normal variation with no evidence of any phenotypic effect of patient, nevertheless it seems as if the location of heteromorphic region maybe interfere with meiotic events like the phenomenon of crossing over or miotic segregation of fertilized egg that eventually lead to the development of fertilized eggs with chromosomal abnormalities leading to the possibility of anemberyonic pregnancy, therefore chromosomal analysis for detecting of chromosome no.9 heteromorphism for couples with the history of ultrasound diagnosed blighted ovum will be strongly suggested. PMID- 25031582 TI - Tuboplasty as a reversal macrosurgery for tubal ligation, is pregnancy possible? A case series. AB - BACKGROUND: Reversal of tubal ligation is requested by some women for various reasons. The present study aims to determine the rate of pregnancy after tubal ligation reversal. CASE: In these case series, we reported fifteen women who requested tuboplasty after tubal ligation. In these cases reversal of tubal ligation was done in 15 women. Pregnancy occurred in 4 women (26.6%). Two term pregnancy and 2 abortions were determined. CONCLUSION: The success rate of pregnancy after macro surgical reversal of tubal ligation is good and can be considered before in vitro fertilization. The type of tubal ligation and the procedure used will determine the best procedure for reversal and have a major impact on chance of success for reversal surgery. PMID- 25031583 TI - Protective effects of celery (Apium Graveolens) on testis and cauda epididymal spermatozoa in rat. PMID- 25031584 TI - Effect of ketotifen premedication on adverse reactions during peanut oral immunotherapy. AB - BACKGROUND: Oral immunotherapy (OIT) has shown promise in inducing desensitization for food allergy. However, there are safety concerns regarding the frequency and severity of adverse events during food OIT. OBJECTIVE: To evaluate the effect of Ketotifen premedication on adverse reactions during peanut OIT. METHODS: A randomized single blind placebo controlled pilot study was performed. Peanut OIT was performed using a previously published protocol. Ketotifen was up-titrated to 2 mg twice daily over two weeks (week -2 to 0), followed by a peanut OIT initial escalation day (day 1). Ketotifen was administered from week 0-4 of peanut OIT; reactions to peanut OIT doses were recorded by clinic staff and subject diary. RESULTS: Six subjects (median age 10 years, peanut IgE >100kUA/L) were enrolled, 4 randomized to Ketotifen, 2 to placebo. The most common side effect of Ketotifen was fatigue (9% during up titration). The rate of reaction per peanut OIT dose was lower for subjects on ketotifen (K) compared to placebo (P) during initial escalation on day 1 (K: 22% (8/36) vs. P: 67% (12/18)); week 0-4 build-up doses (K: 75% (3/4) vs. P: 100% (2/2)); and week 0-4 home doses (K: 50% (54/108) vs. P: 82% (27/33)). The rate of gastrointestinal symptoms per peanut OIT dose was also lower for subjects on ketotifen during initial escalation on day 1 (K: 17% (6/36) vs. P: 61% (11/18)); week 0-4 build-up doses (K: 75% (3/4) vs P: 100% (2/2)); and week 0-4 home doses (K: 46% (50/108) vs. P: 82% (27/33)). CONCLUSIONS: Ketotifen premedication is well tolerated and reduces the rate of gastrointestinal symptoms during peanut OIT. These findings require confirmation in a larger study of Ketotifen premedication used throughout peanut OIT. TRIAL REGISTRATION: CLINICAL TRIALS NUMBER: NCT0162515. PMID- 25031585 TI - Interleukin 18 gene promoter polymorphisms and susceptibility to chronic hepatitis B infection: a review study. AB - CONTEXT: The variation in clinical outcome of hepatitis B virus (HBV) infection is determined by virological, immunological and host genetic factors. Genes encoding cytokines are one of the candidates among host genetic factors. Polymorphisms in gene promoter can lead to different levels of cytokine expression and unique immune response. Being involved in the inflammatory cytokine network, interleukin-18 (IL-18) plays an important role in pathogenesis of HBV infection. The aim of this review is considering available literature on the association between IL-18 gene promoter single nucleotide polymorphisms (-137 C/G and -607 A/C) and susceptibility to chronic HBV infection. EVIDENCE ACQUISITION: Published literature from PubMed, EMBASE, and other databases were retrieved. All studies investigating the association of IL-18 gene promoter SNPs, -137 C/G and -607 A/C, with susceptibility to chronic HBV infection were included. RESULTS: Findings showed that the genotype -607A/A is associated with the susceptibility to chronic hepatitis B. Furthermore, allele C at position -137 is suggested to play a protective role against development of chronic HBV infection. CONCLUSIONS: Host genetic factors play an important role in determining the outcome of HBV infection. It is suggested that IL-18 genotype 607 A/A is associated with susceptibility to chronic hepatitis B. Furthermore, the carriage of allele C at position -137 may play a protective role in the development of chronic HBV infection. PMID- 25031586 TI - Anesthesia for patients with liver disease. AB - CONTEXT: Liver plays an important role in metabolism and physiological homeostasis in the body. This organ is unique in its structure and physiology. So it is necessary for an anesthesiologist to be familiar with various hepatic pathophysiologic conditions and consequences of liver dysfunction. EVIDENCE ACQUISITION: WE SEARCHED MEDLINE (PUB MED, OVID, MD CONSULT), SCOPUS AND THE COCHRANE DATABASE FOR THE FOLLOWING KEYWORDS: liver disease, anesthesia and liver disease, regional anesthesia in liver disease, epidural anesthesia in liver disease and spinal anesthesia in liver disease, for the period of 1966 to 2013. RESULTS: Although different anesthetic regimens are available in modern anesthesia world, but anesthetizing the patients with liver disease is still really tough. Spinal or epidural anesthetic effects on hepatic blood flow and function is not clearly investigated, considering both the anesthetic drug induced changes and outcomes. Regional anesthesia might be used in patients with advanced liver disease. In these cases lower drug dosages are used, considering the fact that locally administered drugs have less systemic effects. In case of general anesthesia it seems that using inhalation agents (Isoflurane, Desflurane or Sevoflurane), alone or in combination with small doses of fentanyl can be considered as a reasonable regimen. When administering drugs, anesthetist must realize and consider the substantially changed pharmacokinetics of some other anesthetic drugs. CONCLUSIONS: Despite the fact that anesthesia in chronic liver disease is a scary and pretty challenging condition for every anesthesiologist, this hazard could be diminished by meticulous attention on optimizing the patient's condition preoperatively and choosing appropriate anesthetic regimen and drugs in this setting. Although there are paucity of statistics and investigations in this specific group of patients but these little data show that with careful monitoring and considering the above mentioned rules a safe anesthesia could be achievable in these patients. PMID- 25031588 TI - Hepatitis C virus; its implication for endodontists. AB - Over 170 million patients worldwide are chronically infected with Hepatitis C virus (HCV); making it a globally important infection. Dentists constantly handle sharp instruments infected with biological fluids and are therefore considered at high-risk of contracting HCV infection. Needle-stick injuries seem to be the most common route of exposure to blood-borne pathogens in dental practice. Moreover, endodontist's constant use of sharp instruments such as endodontic files with limited operative vision in a small working field (i.e. root canal system) increases their risk of exposure to infection. The aim of this study was to review the epidemiology of HCV infection in dental healthcare staff and the tests required for its diagnosis. We also look at the protocols for dental treatment in infected individuals and screening and dental examination tailored for HCV patients. PMID- 25031587 TI - A review of antibacterial agents in endodontic treatment. AB - Microorganisms play a major role in initiation and perpetuation of pulpal and periapical diseases. Therefore, elimination of the microorganisms present in the root canal system is the fundamental objective of endodontic treatment. The use of mechanical debridement, chemical irrigation or other antimicrobial protocols and intra-canal medicaments are critical to attain this goal. The aim of this article was to review the antimicrobial agents and their properties in endodontics. PMID- 25031589 TI - Canal transportation and centering ability of twisted file and reciproc: a cone beam computed tomography assessment. AB - INTRODUCTION: The purpose of this in vitro study was to compare the canal transportation and centering ability of Twisted File (TF) to that of Reciproc system. METHODS AND MATERIALS: Forty noncalcified roots with mature apices, minimum length of 19 mm and an apical curvature of 15-30 degrees (according to Schneider's method), from freshly extracted mandibular and maxillary teeth, were selected for this study. Samples were randomly divided into two groups (n=20) and canal preparation with either TF or Reciproc was performed according to manufacturers' instruction. Pre- and post-instrumentation cone-beam computed tomography (CBCT) images were captured and the extent of canal transportation and centering ability of the files were calculated, using the NNT Viewer software and Photoshop CS5, at levels of 3, 4, and 5 mm from the apex. The Mann-Whitney U test was used to analyze the statistical significance between the two groups. RESULTS: One fracture occurred in the TF group. TF produced more transportation than Reciproc in both mesiodistal and buccolingual directions; however, the difference between the two systems were not statistically significant except for the TF group at 5-mm distance from the working length, where the difference was significant (P>0.05). CONCLUSION: Both file systems were able keep the original curvature of the canal and thus can be considered safe for clinical application. PMID- 25031590 TI - Cone-Beam Computed Tomography Comparison of Canal Transportation after Preparation with BioRaCe and Mtwo Rotary Instruments and Hand K-Flexofiles. AB - INTRODUCTION: The aim of this in vitro study was to evaluate the transportation of mesiobuccal canals of mandibular first molars prepared with either BioRaCe or Mtwo rotary instruments or hand K-Flexofile, by means of cone-beam computed tomography (CBCT). METHODS AND MATERIALS: Forty-five mandibular molars were selected and randomly divided into three groups (n=15). Mesiobuccal roots of these teeth were prepared by BioRaCe, Mtwo, or hand K-Flexofile. Transportation was measured by pre- and post-operative CBCT images. Two-way ANOVA analysis was applied to detect any differences between the groups followed by the post hoc Tukey's tests. The level of significance was set at 0.05. RESULTS: The non parametric Friedman test was used to compare the behavior of each file at 3-, 6- and 9-mm levels. There were no significant differences between different levels in Mtwo group (P=0.15); however, the differences in K-Flexofile and BioRaCe groups were significant (P>0.05). The post hoc Tukey's test revealed significant differences between BioRaCe and K-Flexofile and also between Mtwo and K Flexofile, both in the 3-mm depths (P<0.05). CONCLUSION: Under the limitations of the present study, BioRaCe and Mtwo rotary instruments are considered suitable for canal preparation to greater apical sizes provided that the recommended sequences are observed. PMID- 25031591 TI - The long-term effect of calcium hydroxide, calcium-enriched mixture cement and mineral trioxide aggregate on dentin strength. AB - INTRODUCTION: Many of highly-alkaline dental materials have some adverse effects on physical properties of dentin. As basic substances, mineral trioxide aggregate (MTA), calcium hydroxide (CH) and the new endodontic material, calcium-enriched mixture (CEM) cement, may adversely affect dentin. The purpose of this in vitro study was to evaluate the effect of long-term application of CEM cement, MTA and CH on flexural strength of bovine dentin. MATERIALS AND METHODS: Three hundred and twenty bovine dentin samples were divided into 4 groups, which were either exposed to CEM cement, CH, MTA or normal saline (control group). Samples of each group were divided into 4 subgroups which were tested by means of Instron Universal Testing Machine for periods of 7, 30, 180 and 365 days after exposure to the test materials. The required force for sample breakage was recorded. The data were analyzed by the two-way ANOVA and Tukey tests. RESULTS: The mean value of forces to break the samples in CEM cement and CH groups was significantly lower than the control group after 1 month (P<0.05). After 180 days, the samples of CEM cement group retrieved their strength but in MTA and CH groups the time interval weakened the samples. After one year of exposure to CH and MTA, flexural strength of the dentin reduced to 72% and 38.7%, respectively (P<0.05). Yet the flexural strength of samples in CEM cement group did not change significantly compared to control group. CONCLUSION: Following 365 days of application of experimental materials to bovine dentin, the CEM cement showed an interesting result and the samples in this group reached their initial strength during the first week of the study but the other materials caused a reduction in dentin strength at the end of the study. PMID- 25031592 TI - Cone-beam computed tomography evaluation of maxillary first and second molars in Iranian population: a morphological study. AB - INTRODUCTION: The aim of this in vitro study was to identify the root and canal morphology of maxillary first and second molars in Iranian population by taking and analyzing cone-beam computed tomography (CBCT) scans. METHODS AND MATERIALS: Extracted maxillary first (n=125) and second (n=125) molars were collected from native Iranians and scanned by using a CBCT scanner. The number of roots and configuration of root canal system were classified according to Vertucci's classification. RESULTS: Two (1.6%) maxillary first and two (1.6%) maxillary second molars had four roots. Prevalence of root fusion was 2.4% and 8.8% in maxillary first and second molars, respectively. The most common canal morphology in the mesiobuccal roots of three-rooted first and second molars was type I (46.4% and 80.8%, respectively), followed by type VI (17.6%) in first molars. The predominant morphology of distobuccal and palatal roots in first and second molars was type I. Additional canal types were also identified. CONCLUSION: Profound knowledge of anatomic variations is necessary prior to cleaning and obturation of the root canal system. The most common discovered root morphology was three separate roots in both tooth types. The greatest variation in canal anatomy was discovered in the MB canals of both the first and second molars. PMID- 25031593 TI - Antimicrobial effects of four intracanal medicaments on enterococcus faecalis: an in vitro study. AB - INTRODUCTION: The aim of this in vitro study was to evaluate the antimicrobial activity of four intracanal medicaments on Enterococcus Faecalis (E. Faecalis). METHODS AND MATERIALS: Fifty extracted single-rooted human teeth were prepared with standard method. After contaminating the canals with E. Faecalis, the samples were divided into one control and four experimental groups (n=10). The teeth in each group were treated with one of the experimental medicaments, including calcium hydroxide (CH), 2% chlorhexidine gel (CHX), triple antibiotic paste (TAP) and nanosilver (NS). In control group, canals were filled with a neutral gel. Microbial samples were obtained from the roots after 7 days and optical density of the cultures was determined after 24 h of incubation. Optical density values were analyzed with one-way analysis of variance and Tukey's post hoc tests. RESULTS: CHX gel and TAP were significantly more effective against E. Faecalis than CH, which was also significantly more efficient than NS and normal saline. In the paper cone samples, CHX gel was more effective than TAP; however, samples obtained with sizes 2 and 4 Gate Glidden drills, indicated that TAP was much more efficient than CHX. Normal saline and NS had similar effects on E. Faecalis. CONCLUSION: NS gel was not efficient enough against E. Faecalis; however, TAP and CHX gel showed better antibacterial efficacy than CH and can be used as an alternative intracanal medicaments in root canal therapies. PMID- 25031594 TI - The Efficacy of FlexMaster's IntroFile, PreRaCe and Gates Glidden Drills in Straight-Line Access: A CBCT Assessment. AB - INTRODUCTION: An overlooked but important part of successful root canal treatment is a straight-line access (SLA). The purpose of this in vitro study was to compare the efficacy of IntroFile and PreRaCe rotary instruments with Gates Glidden (GG) drills in gaining SLA by cone-beam computed tomography (CBCT). METHODS AND MATERIALS: A total of forty five extracted mandibular first molars were selected and mounted in dental like arches. Subsequently, they were randomly classified into three groups (n=15). After preparation of a standard access cavity, orifices of the mesiobuccal canal was reached and a #10 file was inserted to explore the canals until the file tip was visible at the apex. Then, preoperative CBCT images were taken. SLA was gained in three groups; group 1, FlexMaster's IntroFile (FM); group 2, PreRaCe (RC) and group 3, GG. Again, the first binding file at the working length (WL) was placed in the canal and postoperative CBCT images in similar positions were taken. The pre/post operative morphology of the canal was evaluated for changes. Data was analyzed using the one-way ANOVA and post-hoc Bonferroni analysis. RESULTS: The average amount of reduction in coronal canal curvature in FM, RC and GG groups was 2.43+/-1.79, 3.17+/-2.05 and 8.7+/-3.45, respectively. This descending trend was statistically significant. The difference between pre/post SLA changes in FM and RC groups was significant compared to GG group, while there were no significant differences between RC and FM. CONCLUSION: GG drills produced extraordinary results in reducing coronal curvature of the canal and achieving SLA. They are also more effective than nickel-titanium (NiTi) rotary instruments in canals with coronal curvature. PMID- 25031595 TI - Comparative Evaluation of Physical Surface Changes and Incidence of Separation in Rotary Nickel-Titanium Instruments: An in Vitro SEM Study. AB - INTRODUCTION: The aim of the present study was to comparatively evaluate the physical surface changes and incidence of separation in rotary nickel-titanium (NiTi) instruments using scanning electron microscope (SEM). METHODS AND MATERIALS: A total number of 210 freshly extracted human maxillary and mandibular first molars were selected and distributed between three groups. Three different systems of rotary NiTi instruments, namely ProFile (PF), RaCe (RC) and Twisted File (TF), were used to prepare the canals using crown-down technique. All instruments were evaluated by means of SEM with 500* and 1500* magnifications, at four different stages; before use, after preparation of 7 and 14 canals and after instrument separation. Photomicrographs were also taken. The data was analyzed using the Kruskal-Wallis test and the level of significance was set at 0.001. It was found that H (HAT matrix) was 15.316 with 2 degrees of freedom. Moreover the various groups were compared using the Student-Newman-Keuls test with P<0.05 and it was found that all groups were significantly different. RESULTS: RC showed the maximum wear of the surface followed by TF (P<0.05). PF showed the minimum wear except for its tip. There was no correlation between electropolishing and file fracture. Insignificant difference was observed in the mean number of canals shaped by PF and TF before their separation. CONCLUSION: Clinically, TF performance was superior, followed by PF then RC. RC fracture rate was the greatest after preparing the least number of canals. PMID- 25031596 TI - Smear Layer Removal in the Apical Third of Root Canals by Two Chelating Agents and Laser: A Comparative in vitro Study. AB - INTRODUCTION: Smear layer (SL) is produced as a result of mechanical instrumentation of the canal(s). Despite the controversies regarding its removal, the evidence-based trend has shifted towards removing and eliminating the SL. Different methods have been used to remove the SL and the aim of this in vitro study was to evaluate the ability of 17% ethylenediaminetetraacetic acid (EDTA), 18% etidronate and Er: YAG on effective removal of the SL. METHODS AND MATERIALS: Fifty straight single-rooted teeth were divided into three experimental groups (n=15) and one control group of five. The canals were instrumented with HERO 642 rotary files up to 30/0.06. In group 1, canals were irradiated with Er: YAG laser; in groups 2 and 3, canals were irrigated with 17% EDTA and 18% etidronate, respectively. In group 4 (control) distilled water was used for canal irrigation. The amount of remaining SL was quantified according to Hulsmann's method with scanning electron microscopy (SEM). Data was analyzed by the Kruskal-Wallis and Mann-Whitney U tests (P<0.05). RESULTS: The results showed statistically significant differences in terms of SL removal among the groups (P<0.05). The amount of removed SL by EDTA was significantly greater followed by Er: YAG laser and 18% etidronate. CONCLUSION: Within the limitations of this study, EDTA was more effective in removing SL compared to Er: YAG and etidronate. PMID- 25031597 TI - The Influence of Composite Thickness with or without Fibers on Fracture Resistance of Direct Restorations in Endodontically Treated Teeth. AB - INTRODUCTION: This in vitro study evaluated the influence of composite thickness (with or without fiber reinforcement) on fracture resistance of direct restorations in endodontically treated teeth. METHODS AND MATERIALS: Fifty-six intact human premolars were chosen and randomly divided into four groups (n=14). After preparation of a mesio-occluso-distal (MOD) cavities and cusp reduction, the teeth were endodontically treated. Subsequently, the samples were restored with composite resin using the following protocols: group 1; composite onlay with cusp coverage of 1.5 mm, group 2; composite onlay with cusp coverage of 2.5 mm, group 3; composite onlay (including resin-impregnated fiber) with cusp coverage of 1.5 mm and group 4; composite onlay (including resin-impregnated fiber) with cusp coverage of 2.5 mm. The fracture resistance of teeth in all test groups was calculated by subjecting them to a progressively increasing compressive axial force in the universal testing machine with the cross-head speed of 1 mm/min to the point of fracture. The data were analyzed using the Kruskal-Wallis test. RESULTS: The mean fracture strengths and obtained standard error were 1263.85+/ 74.03 N, 1330.26+/-128.01 N, 1344.92+/-64.40 N and 1312.54+/-75.63 N for groups 1 to 4, respectively. Statistical analysis revealed no significant difference between groups. CONCLUSION: Cusp coverage of 1.5 and 2.5 mm in MOD access cavities with or without insertion of resin impregnated fiber had similar fracture rates in the endodontically treated teeth. PMID- 25031598 TI - Effect of Mineral Trioxide Aggregate, Calcium-Enriched Mixture Cement and Mineral Trioxide Aggregate with Disodium Hydrogen Phosphate on BMP-2 Production. AB - INTRODUCTION: One of the hypotheses regarding the calcification induction by mineral trioxide aggregate (MTA) is the involvement of transforming growth factor Beta (TGF-beta) super family. Calcium-enriched mixture (CEM) cement is one of the endodontic biomaterials with clinical applications similar to MTA. The aim of the present in vitro study was to compare the induction of bone morphogenic protein-2 (BMP-2) by a combination of disodium hydrogen phosphate (DSHP) and tooth colored ProRoot MTA (WMTA), to that of CEM cement and WMTA. METHODS AND MATERIALS: Human gingival fibroblasts (HGFs) were obtained from the attached gingiva of human premolars. HGFs were cultured in Dulbecco's Modified Eagle's medium, supplemented with 10% fetal calf serum, penicillin, and streptomycin. Cells in groups 1, 2 and 3 were exposed to WMTA, CEM and WMTA+DSHP discs, respectively. The fourth group served as the control. After 72 h of exposure, HGF viability was determined by Mosmann's tetrazolium toxicity (MTT) assay. BMP-2 levels in cell-free culture media were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using the one-way ANOVA, followed by the post hoc Games Howell test for BMP-2 and post hoc Tukey's test for the results of MTT assay. RESULTS: Cellular viability was significantly higher in group 3 compared to the other groups (P<0.05); however, CEM and WMTA did not exhibit significant differences (P=0.08). The control group exhibited significantly higher cellular viability in comparison to the other groups of the study (P<0.05). The highest and lowest protein production rates were observed in the WMTA (3167+/-274.46 pg/mL) and WMTA+DSHP (1796+/-839.49 pg/mL) groups, respectively. There were no significant differences between the control, WMTA and CEM groups (P>0.05). CONCLUSION: WMTA and CEM did not exhibit any significant differences in terms of inducing BMP-2 production; however, incorporation of DSHP into WMTA resulted in a decrease in the induction of this protein. PMID- 25031599 TI - Repair of a strip perforation with calcium-enriched mixture cement: a case report. AB - The present report reviews the diagnostic and treatment challenges of a mandibular molar with previous root canal treatment and signs of a procedural mishap, i.e. furcal radiolucency and localized swelling of the gingival margin in which a sinus tract was present. By tracing the sinus tract, it became evident that the lesion originated from the furcation area, not the root apices. This case was treated by cleaning/filling the coronal half of the canals and leaving the rest of obturating material untouched. The strip perforation zone in the mesial root was sealed off with calcium-enriched mixture cement. One week after treatment, the patient's symptoms had faded away and one year later, the lesion completely healed with bone replacement. PMID- 25031600 TI - Presence of two distal and one mesial root canals in mandibular second molars: report of four cases. AB - Most mandibular second molars have one and two canals in distal and mesial roots, respectively. This report represents four cases of mandibular second molars with a single mesial and two distal root canals with two different canal configurations. After access cavity preparation, two teeth had one distal and two mesial orifices, whereas in the two other teeth one mesial and two distal orifices were found. In the teeth with two mesial canal orifices, the distal root canal and one of root canals with a mesial orifice joined together in the apical part of the root, whereas in the two other teeth with one mesial and two distal canal orifices, three separate canals each with a different apical foramen were detected. Dental practitioners should be aware that despite higher prevalence of one distal and two mesial root canals, the mandibular second molars may also have one mesial and two distal root canals. PMID- 25031601 TI - Management of Complicated Crown Fracture with Miniature Pulpotomy: A case report. AB - Crown fractures account for the majority of dental traumas. If handled properly, prognosis of the pulp following a traumatic crown fracture can be favorable. The present case report focuses on the treatment of a traumatized mature permanent incisor with exposed pulp that was treated with the novel technique of miniature pulpotomy using calcium-enriched mixture (CEM) cement. One-year follow-up revealed that the tooth was responsive to vitality tests and radiographic assessment showed the presence of a thick dentinal bridge beneath the CEM layer. PMID- 25031603 TI - Effect of Nourishing "Yin"-Removing "Fire" Chinese Herbal Mixture on Hypothalamic NKB/NK3R Expression in Female Precocious Rats. AB - Aim. The present study aims to investigate the effects of nourishing "Yin" removing "Fire" Chinese herb mixture on the hypothalamic NKB/NK3R expression in female precocious model rats. Materials and Methods. Female Sprague-Dawley rats were randomly divided into four groups: normal (N), central precocious puberty (CPP) model (M), CPP fed with Chinese herbal mixture (CHM), and CPP fed with normal saline (MS). Rats on postnatal day 5 were given a single subcutaneous injection of 300 MUg to establish CPP model rats. Rats of CHM and MS groups were continuously administered with nourishing "Yin"-removing "Fire" Chinese herb mixture or saline since postnatal day 15. The expressions of hypothalamic NKB/NK3R were detected by means of real-time PCR, western blot, and immunofluorescence histochemistry. Results. The day of vaginal opening and establishment of two regular estrous cycles were delayed in the CHM group compared with M and MS groups. The expression of hypothalamic NKB/NK3R mRNA and protein in the arcuate nucleus (ARC) and medial preoptic (MPO) area were decreased significantly in the CHM group compared with the M and MS groups on the day of onset-puberty. Conclusions. These results indicate that the NKB/NK3R signaling pathway might be involved in the effect of herbal mixture treatment on CPP. PMID- 25031602 TI - Traditional chinese medicine shuang shen ning xin attenuates myocardial ischemia/reperfusion injury by preserving of mitochondrial function. AB - To investigate the potential cardioprotective effects of Shuang Shen Ning Xin on myocardial ischemia/reperfusion injury. Wistar rats were treated with trimetazidine (10 mg/kg/day, ig), Shuang Shen Ning Xin (22.5, 45 mg/kg/day, ig), or saline for 5 consecutive days. Myocardial ischemia/reperfusion injury was induced by ligation of the left anterior descending coronary artery for 40 min and reperfusion for 120 min on the last day of administration. It is found that Shuang Shen Ning Xin pretreatment markedly decreased infarct size and serum LDH levels, and this observed protection was associated with reduced myocardial oxidative stress and cardiomyocyte apoptosis after myocardial ischemia/reperfusion injury. In addition, further studies on mitochondrial function showed that rats treated with Shuang Shen Ning Xin displayed decreased mitochondrial swelling and cytosolic cytochrome c levels, which were accompanied by a preservation of complex I activities and inhibition of mitochondrial permeability transition. In conclusion, the mitochondrial protective effect of Shuang Shen Ning Xin could be a new mechanism, by which Shuang Shen Ning Xin attenuates myocardial ischemia/reperfusion injury. PMID- 25031605 TI - Bioactives and traditional herbal medicine for the treatment of cardiovascular/cerebrovascular diseases. PMID- 25031604 TI - Cognitive-Enhancing Effect of Steamed and Fermented Codonopsis lanceolata: A Behavioral and Biochemical Study. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment. Codonopsis lanceolata (C. lanceolata) has been employed clinically for lung inflammatory diseases such as asthma, tonsillitis, and pharyngitis. The present study was undertaken to evaluate the effect of fermented C. lanceolata (300, 500, and 800 mg/kg) on learning and memory impairment induced by scopolamine by using the Morris water maze and passive avoidance tests. To elucidate possible mechanism of cognitive-enhancing activity, we measured acetylcholinesterase (AchE) activity, brain-derived neurotrophic factor (BDNF), and cyclic AMP response element-binding protein (CREB) expression in the brain of mice. Administration of fermented C. lanceolata (800 mg/kg) led to reduced scopolamine-induced memory impairment in the Morris water maze and passive avoidance tests. Accordingly, the administration of fermented C. lanceolata inhibited AchE activity. Interestingly, the level of CREB phosphorylation and BDNF expression in hippocampal tissue of scopolamine-treated mice was significantly increased by the administration of fermented C. lanceolata. These results indicate that fermented C. lanceolata can ameliorate scopolamine-induced memory deficits in mouse and may be an alternative agent for the treatment of AD. PMID- 25031606 TI - In Vivo Hypocholesterolemic Effect of MARDI Fermented Red Yeast Rice Water Extract in High Cholesterol Diet Fed Mice. AB - Fermented red yeast rice has been traditionally consumed as medication in Asian cuisine. This study aimed to determine the in vivo hypocholesterolemic and antioxidant effects of fermented red yeast rice water extract produced using Malaysian Agricultural Research and Development Institute (MARDI) Monascus purpureus strains in mice fed with high cholesterol diet. Absence of monacolin-k, lower level of gamma-aminobutyric acid (GABA), higher content of total amino acids, and antioxidant activities were detected in MARDI fermented red yeast rice water extract (MFRYR). In vivo MFRYR treatment on hypercholesterolemic mice recorded similar lipid lowering effect as commercial red yeast rice extract (CRYR) as it helps to reduce the elevated serum liver enzyme and increased the antioxidant levels in liver. This effect was also associated with the upregulation of apolipoproteins-E and inhibition of Von Willebrand factor expression. In summary, MFRYR enriched in antioxidant and amino acid without monacolin-k showed similar hypocholesterolemic effect as CRYR that was rich in monacolin-k and GABA. PMID- 25031607 TI - Nerve growth factor in diabetic retinopathy: beyond neurons. AB - Diabetic retinopathy (DR), a major ocular complication of diabetes, is a leading cause of blindness in US working age adults with limited treatments. Neurotrophins (NTs), a family of proteins essential for growth, differentiation and survival of retinal neurons, have emerged as potential players in the pathogenesis of DR. NTs can signal through their corresponding tropomyosin kinase related receptor to mediate cell survival or through the p75 neurotrophin receptor with the co-receptor, sortilin, to mediate cell death. This review focuses on the role of NGF, the first discovered NT, in the development of DR. Impaired processing of proNGF has been found in ocular fluids from diabetic patients as well as experimental models. Evidence from literature and our studies support the notion that NTs appear to play multiple potential roles in DR, hence, understanding their contribution to DR may lead to promising therapeutic approaches for this devastating disease. PMID- 25031608 TI - In favour of the definition "adolescents with idiopathic scoliosis": juvenile and adolescent idiopathic scoliosis braced after ten years of age, do not show different end results. SOSORT award winner 2014. AB - BACKGROUND: The most important factor discriminating juvenile (JIS) from adolescent idiopathic scoliosis (AIS) is the risk of deformity progression. Brace treatment can change natural history, even when risk of progression is high. The aim of this study was to compare the end of growth results of JIS subjects, treated after 10 years of age, with final results of AIS. METHODS: DESIGN: prospective observational controlled cohort study nested in a prospective database. SETTING: outpatient tertiary referral clinic specialized in conservative treatment of spinal deformities. INCLUSION CRITERIA: idiopathic scoliosis; European Risser 0-2; 25 degrees to 45 degrees Cobb; start treatment age: 10 years or more, never treated before. EXCLUSION CRITERIA: secondary scoliosis, neurological etiology, prior treatment for scoliosis (brace or surgery). Groups: 27 patients met the inclusion criteria for the AJIS, (Juvenile Idiopathic Scoliosis treated in adolescence), demonstrated by an x-ray before 10 year of age, and treatment start after 10 years of age. AIS group included 45 adolescents with a diagnostic x-ray made after the threshold of age 10 years. Results at the end of growth were analysed; the threshold of 5 Cobb degree to define worsened, improved and stabilized curves was considered. STATISTICS: Mean and SD were used for descriptive statistics of clinical and radiographic changes. Relative Risk of failure (RR), Chi-square and T-test of all data was calculated to find differences among the two groups. 95% Confidence Interval (CI) , and of radiographic changes have been calculated. RESULTS: We did not find any Cobb angle significant differences among groups at baseline and at the end of treatment. The only difference was in the number of patients progressed above 45 degrees, found in the JIS group. The RR of progression of AJIS was, 1.35 (IC95% 0.57-3.17) versus AIS, and it wasn't statistically significant in the AJIS group, in respect to AIS group (p = 0.5338). CONCLUSION: There are no significant differences in the final results of AIS and JIS, treated with total respect of the SRS and SOSORT criteria, in adolescence. Brace efficacy can neutralize the risk of progression. PMID- 25031609 TI - Ensuring Access to HIV Prevention Services in South African HIV Vaccine Trials: Correspondence Between Guidelines and Practices. AB - Researchers and sponsors are required to assist HIV prevention trial participants to remain HIV-uninfected by ensuring access to prevention services. Ethics guidelines require that these HIV risk-reduction services be state of the art. This and related ethics recommendations have been intensely debated. This descriptive study aimed to identify actual HIV prevention practices for two HIV vaccine trials at five South African sites, to explore whether actual practices meet guideline recommendations and to discuss implications for practices and ethics guidelines. Practices were examined through a review of site documents and interviews with site staff and network representatives, as well as community advisory board and research ethics committee representatives. A thematic analysis of HIV prevention practices, perspectives and perceived challenges was undertaken. Findings indicated that there was a high degree of correspondence between actual practices in South African HIV vaccine trials and guideline recommendations. Key challenges for implementing prevention services were identified as partnerships, provider-promotion of services and participant uptake of services. Practices deviated most from guidelines with regard to the description of prevention plans in informed consent forms. Recommendations are made for both practices and ethics guidelines. PMID- 25031610 TI - Influence of surrounding tissues on biomechanics of aortic wall. AB - The present study investigates effects of surrounding tissues and non-uniform wall thickness on the biomechanics of the thoracic aorta. We construct two idealised computational models exemplifying the importance of surrounding tissues and non-uniform wall thickness, namely the uniform-thickness model and the histology image-based model. While the former neglects a connective tissue layer surrounding the aorta, the latter takes it into account with non-uniform wall thickness. Using plane strain finite element analysis, stress distributions in the aortic media between the two models are compared. The histology image-based model substantially enhances the uniformity of stress throughout the aortic media. Furthermore, the altered mechanical properties of surrounding tissues change the stress distribution. These results suggest that surrounding tissues and non-uniform wall thickness should be included in biomechanical analysis to better understand regional adaptation of the aortic wall during normal physiological conditions or pathological conditions such as aortic aneurysms and dissections. PMID- 25031612 TI - Genomic medicine in Africa: promise, problems and prospects. PMID- 25031613 TI - International ethics harmonization and the global alliance for genomics and health. PMID- 25031611 TI - Targeted Chromatin Capture (T2C): a novel high resolution high throughput method to detect genomic interactions and regulatory elements. AB - BACKGROUND: Significant efforts have recently been put into the investigation of the spatial organization and the chromatin-interaction networks of genomes. Chromosome conformation capture (3C) technology and its derivatives are important tools used in this effort. However, many of these have limitations, such as being limited to one viewpoint, expensive with moderate to low resolution, and/or requiring a large sequencing effort. Techniques like Hi-C provide a genome-wide analysis. However, it requires massive sequencing effort with considerable costs. Here we describe a new technique termed Targeted Chromatin Capture (T2C), to interrogate large selected regions of the genome. T2C provides an unbiased view of the spatial organization of selected loci at superior resolution (single restriction fragment resolution, from 2 to 6 kbp) at much lower costs than Hi-C due to the lower sequencing effort. RESULTS: We applied T2C on well-known model regions, the mouse beta-globin locus and the human H19/IGF2 locus. In both cases we identified all known chromatin interactions. Furthermore, we compared the human H19/IGF2 locus data obtained from different chromatin conformation capturing methods with T2C data. We observed the same compartmentalization of the locus, but at a much higher resolution (single restriction fragments vs. the common 40 kbp bins) and higher coverage. Moreover, we compared the beta-globin locus in two different biological samples (mouse primary erythroid cells and mouse fetal brain), where it is either actively transcribed or not, to identify possible transcriptional dependent interactions. We identified the known interactions in the beta-globin locus and the same topological domains in both mouse primary erythroid cells and in mouse fetal brain with the latter having fewer interactions probably due to the inactivity of the locus. Furthermore, we show that interactions due to the important chromatin proteins, Ldb1 and Ctcf, in both tissues can be analyzed easily to reveal their role on transcriptional interactions and genome folding. CONCLUSIONS: T2C is an efficient, easy, and affordable with high (restriction fragment) resolution tool to address both genome compartmentalization and chromatin-interaction networks for specific genomic regions at high resolution for both clinical and non-clinical research. PMID- 25031614 TI - Response to 'pervasive sequence patents cover the entire human genome'. AB - A response to Pervasive sequence patents cover the entire human genome by J Rosenfeld and C Mason. Genome Med 2013, 5:27. See related Correspondence by Rosenfeld and Mason, http://genomemedicine.com/content/5/3/27 and related letter by Rosenfeld and Mason, http://genomemedicine.com/content/6/2/15. PMID- 25031615 TI - Enabling multiscale modeling in systems medicine. PMID- 25031616 TI - The translation of cancer genomics: time for a revolution in clinical cancer care. AB - The introduction of next-generation sequencing technologies has dramatically impacted the life sciences, perhaps most profoundly in the area of cancer genomics. Clinical applications of next-generation sequencing and associated methods are emerging from ongoing large-scale discovery projects that have catalogued hundreds of genes as having a role in cancer susceptibility, onset and progression. For example, discovery cancer genomics has confirmed that many of the same genes are altered by mutation, copy number gain or loss, or structural variation across multiple tumor types, resulting in a gain or loss of function that likely contributes to cancer development in these tissues. Beyond these frequently mutated genes, we now know there is a 'long tail' of less frequently mutated, but probably important, genes that play roles in cancer onset or progression. Here, I discuss some of the remaining barriers to clinical translation, and look forward to new applications of these technologies in cancer care. PMID- 25031617 TI - Correcting for cell-type composition bias in epigenome-wide association studies. AB - Recent epigenome-wide association studies have indicated a potential role for epigenetic variation in the etiology of complex human diseases. However, one major challenge is to distinguish true epigenetic variation from changes caused by differences in cellular composition between the disease and non-disease state, a problem that is particularly relevant when analyzing whole blood. For studies with large numbers of samples, it can be expensive and very time consuming to perform cell sorting, and it is often not clear which is the correct cell type to profile. Two recently published papers have attempted to address this confounding issue using bioinformatics. PMID- 25031619 TI - Personalised medicine in the UK: challenges of implementation and impact on healthcare system. PMID- 25031618 TI - Mutation signatures of carcinogen exposure: genome-wide detection and new opportunities for cancer prevention. AB - Exposure to environmental mutagens is an important cause of human cancer, and measures to reduce mutagenic and carcinogenic exposures have been highly successful at controlling cancer. Until recently, it has been possible to connect the chemical characteristics of mutagens to actual mutations observed in human tumors only indirectly. Now, next-generation sequencing technology enables us to observe in detail the DNA-sequence-level effects of well-known mutagens, such as ultraviolet radiation and tobacco smoke, as well as endogenous mutagenic processes, such as those involving activated DNA cytidine deaminases (APOBECs). We can also observe the effects of less well-known but potent mutagens, including those recently found to be present in some herbal remedies. Crucially, we can now tease apart the superimposed effects of several mutational exposures and processes and determine which ones occurred during the development of individual tumors. Here, we review advances in detecting these mutation signatures and discuss the implications for surveillance and prevention of cancer. The number of sequenced tumors from diverse cancer types and multiple geographic regions is growing explosively, and the genomes of these tumors will bear the signatures of even more diverse mutagenic exposures. Thus, we envision development of wide ranging compendia of mutation signatures from tumors and a concerted effort to experimentally elucidate the signatures of a large number of mutagens. This information will be used to link signatures observed in tumors to the exposures responsible for them, which will offer unprecedented opportunities for prevention. PMID- 25031620 TI - Optimizing the treatment of BRAF mutant melanoma. AB - Selective inhibitors of the kinases BRAF and MEK for the treatment of patients with otherwise refractory BRAF mutant melanoma have demonstrated impressive efficacy, and combination treatment with these agents may prove to be even more effective. However, these drugs are not curative, mainly because of the relatively rapid development of drug resistance. Furthermore, they can produce undesired, and even unanticipated, side effects, including the emergence of neoplastic lesions harboring activating RAS mutations. Two recent reports reveal new considerations for the optimal approach to targeting this key oncogenic pathway in melanoma, highlighting the importance of combination treatment and therapeutic scheduling. PMID- 25031621 TI - Fourth-generation sequencing in the cell and the clinic. AB - Nearly 40 years ago, DNA was sequenced for the first time. Since then, DNA sequencing has undergone continuous development, passing through three generations of sequencing technology. We are now entering the beginning of a new phase of genomic analysis in which massively parallel sequencing is performed directly in the cell. Two methods have recently been described for in situ RNA sequencing, one targeted and one untargeted, that rely on ligation chemistry. This fourth generation of sequencing technology opens up prospects for transcriptomic analysis, biomarker validation, diagnosis and patient stratification for cancer treatment. PMID- 25031622 TI - DNA methylation in cancer: three decades of discovery. AB - Andrew Feinberg shares his views on the field of cancer epigenetics, from its beginnings to the most exciting recent findings. PMID- 25031623 TI - Synergy and competition between cancer genome sequencing and epigenome mapping projects. AB - EDITORIAL SUMMARY: Large-scale projects in the fields of cancer genomics and epigenomics have different aims, cultures and outcomes. The author argues that by working together a complete picture of cancer biology could be painted, and he advocates the creation of an International Cancer Epigenome Consortium. PMID- 25031624 TI - Why epistasis is important for tackling complex human disease genetics. AB - EDITORIAL SUMMARY: Epistasis has been dismissed by some as having little role in the genetic architecture of complex human disease. The authors argue that this view is the result of a misconception and explain why exploring epistasis is likely to be crucial to understanding and predicting complex disease. PMID- 25031625 TI - Colorectal cancer screening: will non-invasive procedures triumph? AB - In the US, colorectal cancer is the fourth most common cancer and the second most deadly. Screening is recommended, not only to reduce mortality, but to prevent cancer by detecting precancerous polyps. Many screening methods are available now, and newer methods based on molecular markers show promise for the future. PMID- 25031626 TI - Educating physicians in the era of genomic medicine. AB - Michael F Murray, MD, of Geisinger Health System in Pennsylvania discusses how to meet the need for better training for physicians in genomics as it moves further into the clinic. PMID- 25031627 TI - Intersection of suicidality and substance abuse among young Asian-American women: implications for developing interventions in young adulthood. AB - PURPOSE: The purpose of this paper is to provide a review of the current literature uncovering specific factors associated with self-harm and suicidality among young Asian American women, as well as to present the Fractured Identity Model as a framework for understanding these factors. This paper offers concrete suggestions for the development of culturally competent interventions to target suicidality, substance abuse, and mental illness among young Asian American women. DESIGN/METHODOLOGY/APPROACH: Empirical studies and theory-based papers featured in peer-reviewed journals between 1990 and 2014 were identified through scholarly databases, such as PubMed, MEDLINE, PsycINFO, JSTOR, and Google Scholar. FINDINGS: We identified several factors associated with suicidality among young Asian American women: (1) family dynamics, or having lived in a household where parents practice "disempowering parenting styles," (2) substance use/abuse, and (3) untreated mental illness(es), which are exacerbated by the stigma and shame attached to seeking out mental health services. The Fractured Identity Model by Hahm et al. (2014) is presented as a possible pathway from disempowering parenting to suicidal and self-harm behaviors among this population, with substance abuse playing a significant mediating role. Research limitations/implications - Our review focused on Asian American women, substance use among Asian Americans, and mental health among Asian Americans. Literature that focused on Asians living in Asia or elsewhere outside of the USA was excluded from this review; the review was limited to research conducted in the USA and written in the English language. PRACTICAL IMPLICATIONS: The complex interplay among Asian American culture, family dynamics, gender roles/expectations, and mental health justifies the development of a suicide and substance abuse intervention that is tailored to the culture- and gender-specific needs of Asian Pacific Islander young women. It is imperative for professionals in the fields of public health, mental health, medicine, and substance abuse to proactively combat the "model minority" myth and to design and implement interventions targeting family dynamics, coping with immigration/acculturative stresses, mental illnesses, suicidal behaviors, and substance abuse among Asian American populations across the developmental lifespan. ORIGINALITY/VALUE: This paper provides specific suggestions for interventions to adequately respond to the mental health needs of young Asian-American women. These include addressing the cultural stigma and shame of seeking help, underlying family origin issues, and excessive alcohol and drug use as unsafe coping, as well as incorporating empowerment-based and mind-body components to foster an intervention targeting suicidality among Asian-American women in early adulthood. PMID- 25031628 TI - Acanthosis nigricans in type 2 diabetes: prevalence, correlates and potential as a simple clinical screening tool - a cross-sectional study in the Caribbean. AB - BACKGROUND: This study aimed to evaluate the role of acanthosis nigricans (AN) as a marker of Type 2 Diabetes Mellitus (T2DM) by studying its prevalence and relationship with age, ethnicity, anthropometry and other risk factors for T2DM in the Trinidadian population. METHODS: 311 successive adult patients with T2DM were recruited at diabetic clinics and inpatient wards across Trinidad. The presence, severity and texture of AN at the neck were assessed. Demographic, clinical and anthropometric characteristics were also measured, and logistic regression was used to model their relationship with presence of AN. RESULTS: The mean (SD) age was 58.1 years (12.6). 55.6% were female. 61.1% were East Indian, 24.4% African and 14.5% mixed ethnicity. The mean (SD) BMI was 27.3 kg/m(2) (6.0) and the mean (SD) waist circumference was 96.7 cm (14.2). Prevalence of AN was 52.7% (95% CI 47.2, 58.3). THERE WAS A GREATER ODDS OF AN AMONG DIABETIC PATIENTS WHO WERE: younger (p < 0.001); female (OR 1.67; 95% CI 1.06, 2.62); or East Indian rather than African (0.45; 0.26, 0.77) or mixed (0.43; 0.22, 0.84) descendents. There was a greater age-, sex- and ethnicity-adjusted odds of AN among those: overweight (3.98; 2.10, 7.55) or obese (8.31; 3.84, 18.00) versus normal BMI; centrally obese (4.72; 2.65, 8.43); with history of hypertension (2.19; 1.27, 3.79) or history of hypercholesterolemia (1.72; 1.02, 2.90), but there was no evidence of this demographic-adjusted association (p > 0.4) between AN and history of previous MI or CVA, family history of T2DM, T2DM treatment regimen, duration of T2DM or random blood glucose. On further multivariable analysis, only age, sex, ethnicity, BMI and waist circumference were independently associated with AN (p < 0.05) and the effect of BMI varied with ethnicity. CONCLUSIONS: There was a high prevalence of AN both overall and across age, sex and ethnic groups of diabetic patients. AN exhibited much potential as a valuable addition to T2DM risk assessment in the Trinidadian and similar settings. PMID- 25031629 TI - Circulating biomarkers that predict incident dementia. AB - Dementia is currently diagnosed based on clinical symptoms and signs, but significant brain damage has already occurred by the time a clinical diagnosis of dementia is made, and it is increasingly recognized that this may be too late for any effective intervention. It would therefore be of great public health and preventive value to define a variety of biomarkers that could permit early detection of persons at a higher risk for developing dementia, and specifically dementia due to Alzheimer's disease. Nevertheless, for the purpose of large-scale screening, circulating biomarkers are more appropriate because they are less invasive than lumbar puncture, less costly than brain amyloid imaging and can be easily assessed repeatedly in a primary care clinic setting. In this brief review we will review a number of candidate molecules implicated as possible predictors of dementia risk. These candidates include markers of vascular injury, metabolic and inflammatory states, amyloid and tau pathway markers, measures of neural degeneration and repair efforts, and other molecules that might contribute to anatomical and functional changes characteristic of dementia and Alzheimer's disease. PMID- 25031630 TI - Neuroimaging in repetitive brain trauma. AB - Sports-related concussions are one of the major causes of mild traumatic brain injury. Although most patients recover completely within days to weeks, those who experience repetitive brain trauma (RBT) may be at risk for developing a condition known as chronic traumatic encephalopathy (CTE). While this condition is most commonly observed in athletes who experience repetitive concussive and/or subconcussive blows to the head, such as boxers, football players, or hockey players, CTE may also affect soldiers on active duty. Currently, the only means by which to diagnose CTE is by the presence of phosphorylated tau aggregations post-mortem. Non-invasive neuroimaging, however, may allow early diagnosis as well as improve our understanding of the underlying pathophysiology of RBT. The purpose of this article is to review advanced neuroimaging methods used to investigate RBT, including diffusion tensor imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging, susceptibility weighted imaging, and positron emission tomography. While there is a considerable literature using these methods in brain injury in general, the focus of this review is on RBT and those subject populations currently known to be susceptible to RBT, namely athletes and soldiers. Further, while direct detection of CTE in vivo has not yet been achieved, all of the methods described in this review provide insight into RBT and will likely lead to a better characterization (diagnosis), in vivo, of CTE than measures of self-report. PMID- 25031631 TI - Protein recycling pathways in neurodegenerative diseases. AB - Many progressive neurodegenerative diseases, including Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal lobe dementia, are associated with the formation of insoluble intracellular proteinaceous inclusions. It is therefore imperative to understand the factors that regulate normal, as well as abnormal, protein recycling in neurons. Dysfunction of the ubiquitin-proteasome or autophagy pathways might contribute to the pathology of various neurodegenerative diseases. Induction of these pathways may offer a rational therapeutic strategy for a number of these diseases. PMID- 25031632 TI - Interpreting Alzheimer's disease clinical trials in light of the effects on amyloid-beta. AB - The failure of several potential Alzheimer's disease therapeutics in mid- to late stage clinical development has provoked significant discussion regarding the validity of the amyloid hypothesis. In this review, we propose a minimum criterion of 25% for amyloid-beta (Abeta) lowering to achieve clinically meaningful slowing of disease progression. This criterion is based on genetic, risk factor, clinical and preclinical studies. We then compare this minimum criterion with the degree of Abeta lowering produced by the potential therapies that have failed in clinical trials. If the proposed minimum Abeta lowering criterion is used, then the amyloid hypothesis has yet to be adequately tested in the clinic. Therefore, we believe that the amyloid hypothesis remains valid and remains to be confirmed or refuted in future clinical trials. PMID- 25031633 TI - Perspectives on future Alzheimer therapies: amyloid-beta protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. AB - The symptomatic drugs currently on the market for Alzheimer's disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy: vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatment effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-amyloid-beta (anti-Abeta) vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-up study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis that Abeta immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclonal antibody targeting fibrillar Abeta, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly and Company) was developed to target soluble, monomeric Abeta. In two phase 3 studies, Solanezumab did not meet primary endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing of cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation of soluble Abeta protofibrils, an Abeta species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclonal antibody, mAb158, was developed to target Abeta protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity for protofibrils as compared with monomers of Abeta, thus targeting the toxic species of the peptide. A humanized version of mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisai without the safety concerns seen in previous phase 1 and 2a trials. Experiences from the field indicate the importance of initiating treatment early in the course of the disease and of enriching the trial population by improving the diagnostic accuracy. BAN2401 is a promising candidate for Abeta immunotherapy in early AD. Other encouraging efforts in immunotherapy as well as in the small-molecule field offer hope for new innovative therapies for AD in the future. PMID- 25031634 TI - Neuroimaging characteristics of dementia with Lewy bodies. AB - This review summarises the findings and applications from neuroimaging studies in dementia with Lewy bodies (DLB), highlighting key differences between DLB and other subtypes of dementia. We also discuss the increasingly important role of imaging biomarkers in differential diagnosis and outline promising areas for future research in DLB. DLB shares common clinical, neuropsychological and pathological features with Parkinson's disease dementia and other dementia subtypes, such as Alzheimer's disease. Despite the development of consensus diagnostic criteria, the sensitivity for differential diagnosis of DLB in clinical practice remains low and many DLB patients will be misdiagnosed. The importance of developing accurate imaging markers in dementia is highlighted by the potential for treatments targeting specific molecular abnormalities as well as the responsiveness to cholinesterase inhibitors and marked neuroleptic sensitivity of DLB. We review various brain imaging techniques that have been applied to investigate DLB, including the characteristic nigrostriatal degeneration in DLB using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers. Dopamine transporter loss has proven to reliably differentiate DLB from other dementias and has been incorporated into the revised clinical diagnostic criteria for DLB. To date, this remains the 'gold standard' for diagnostic imaging of DLB. Regional cerebral blood flow, 18 F-fluorodeoxygluclose-PET and SPECT have also identified marked deficits in the occipital regions with relative sparing of the medial temporal lobe when compared to Alzheimer's disease. In addition, structural, diffusion, and functional magnetic resonance imaging techniques have shown alterations in structure, white matter integrity, and functional activity in DLB. We argue that the multimodal identification of DLB-specific biomarkers has the potential to improve ante-mortem diagnosis and contribute to our understanding of the pathological background of DLB and its progression. PMID- 25031635 TI - Lewy body dementia: the impact on patients and caregivers. AB - Lewy body dementia (LBD) is the second most common neurodegenerative dementia in older adults, yet there remains a delay in diagnosis that limits healthcare providers' ability to maximize therapeutic outcomes and enhance patient and caregiver quality of life. The impact of LBD on patients includes limiting the potential exposure to medications that may cause adverse outcomes, and addressing how the disease manifestations, such as autonomic features and behavior, affect quality of life. LBD impact on caregivers has been discussed to a greater degree in the literature, and there is clear evidence of caregiver burden and grief associated with disease manifestations. Other common caregiving concerns, such as access to care, prevention of hospitalization, managing behavior, and reviewing prognosis and nursing home placement, are important to comprehensively address the needs of patients with LBD and their caregivers. PMID- 25031636 TI - Roadblocks for integration of novel biomarker concepts into clinical routine: the peptoid approach. AB - In the field of Alzheimer's disease, the development of novel biomarker assays is critically needed to improve the early diagnosis of the disease, to estimate the risk of developing the disease, to predict the rate of cognitive decline, and to monitor the response or effectiveness of a therapy. The molecular mechanisms of the disease are becoming more evident. This basic knowledge has yet to be translated into novel biomarker tools with a clinical value for general use by the community. There is therefore high interest in evaluating new technological approaches beside the classical immunoassay approach. The present paper discusses the hypothesis that there might be an adaptive immune response, unique to Alzheimer's disease, which can be visualized by the presence in body fluids of antibodies against specific analytes. Current technologies to identify such antibodies are reviewed. In addition, the major challenges to transfer discovery results of the novel antibody-based biomarker assays to a clinically relevant test will be discussed. PMID- 25031637 TI - Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease? AB - Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Abeta) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Abeta senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Abeta plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Abeta deposition in pathological aging. PMID- 25031638 TI - Truncated and modified amyloid-beta species. AB - Alzheimer's disease pathology is closely connected to the processing of the amyloid precursor protein (APP) resulting in the formation of a variety of amyloid-beta (Abeta) peptides. They are found as insoluble aggregates in senile plaques, the histopathological hallmark of the disease. These peptides are also found in soluble, mostly monomeric and dimeric, forms in the interstitial and cerebrospinal fluid. Due to the combination of several enzymatic activities during APP processing, Abeta peptides exist in multiple isoforms possessing different N-termini and C-termini. These peptides include, to a certain extent, part of the juxtamembrane and transmembrane domain of APP. Besides differences in size, post-translational modifications of Abeta - including oxidation, phosphorylation, nitration, racemization, isomerization, pyroglutamylation, and glycosylation - generate a plethora of peptides with different physiological and pathological properties that may modulate disease progression. PMID- 25031639 TI - Acetylation: a new key to unlock tau's role in neurodegeneration. AB - The identification of tau protein as a major constituent of neurofibrillary tangles spurred considerable effort devoted to identifying and validating pathways through which therapeutics may alleviate tau burden in Alzheimer's disease and related tauopathies, including chronic traumatic encephalopathy associated with sport- and military-related injuries. Most tau-based therapeutic strategies have previously focused on modulating tau phosphorylation, given that tau species present within neurofibrillary tangles are hyperphosphorylated on a number of different residues. However, the recent discovery that tau is modified by acetylation necessitates additional research to provide greater mechanistic insight into the spectrum of physiological consequences of tau acetylation, which may hold promise as a novel therapeutic target. In this review, we discuss recent findings evaluating tau acetylation in the context of previously accepted notions regarding tau biology and pathophysiology. We also examine the evidence demonstrating the neuroprotective and beneficial consequences of inhibiting histone deacetylase (HDAC)6, a tau deacetylase, including its effect on microtubule stabilization. We also discuss the rationale for pharmacologically modulating HDAC6 in tau-based pathologies as a novel therapeutic strategy. PMID- 25031640 TI - PERK: a novel therapeutic target for neurodegenerative diseases? AB - Identification of therapeutic targets based on novel mechanistic studies is urgently needed for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and prion disease. Multiple lines of evidence have emerged to suggest that inhibition of the stress-induced endoplasmic reticulum kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase) is a potential therapeutic strategy for these diseases. A recently published study demonstrated that oral treatment with a newly characterized PERK inhibitor was able to rescue disease phenotypes displayed in prion disease model mice. Here, we discuss the background and rationale for targeting PERK as a viable therapeutic approach as well as implications of these findings for other neurodegenerative diseases. The promise and caveats of applying this strategy for disease therapy also are discussed. PMID- 25031644 TI - Medicines shortages in Australia-the reality. PMID- 25031645 TI - Carcinoid Klatskin tumour: A rare cause of obstructive jaundice. AB - Carcinoid tumours of the extrahepatic biliary ducts represent an extremely rare cause of bile duct obstruction. We report a case of obstructive jaundice secondary to carcinoid tumour arising at the hilar confluence. Resection of the primary tumour was done and the patient is doing well on follow-up. This case demonstrated that surgery offers the only potential cure for biliary carcinoid and aggressive surgical therapy should be the preferred treatment in cases of potentially resectable biliary tumours. PMID- 25031641 TI - Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3beta pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3beta pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD. PMID- 25031646 TI - Isolated hepatic tuberculosis: An uncommon presentation of a common culprit. AB - Hepatic tuberculosis (HTB) is commonly encountered in patients with widespread miliary disease. Isolated affection of the liver is extremely rare. We present a case of a young woman who presented with a subacute afebrile hepatic failure. Investigations including a liver biopsy proved that the presentation was due to granulomatous hepatitis secondary to mycobacterial infection of the liver. It is important that tuberculosis (TB) be kept in mind especially in endemic areas even in atypical clinical scenarios by clinicians, radiologists, and pathologists. Use of anti-tuberculous drugs in such cases is usually successful and must be instituted early. PMID- 25031647 TI - Validation of the Thai QOL-AD version in Alzheimer's patients and caregivers. AB - BACKGROUND: Quality of life (QOL) plays an important role in determining the improvement of patient care in Alzheimer's disease (AD). The simple and easily used Thai instrument for measuring QOL is still limited. AIMS: This study aimed to translate the Quality of Life-Alzheimer's Disease (QOL-AD) scale original version into a Thai version and test its psychometric properties. METHOD: A Thai version of QOL-AD was translated following the sequential method. The validation was tested in 136 pairs of patients and their caregivers. Mild to moderate Alzheimer's patients were recruited from outpatient clinics at Chiang Mai Neurological Hospital and Chiang Mai Psychiatry Hospital from April to September 2012. Internal consistency, factor analysis, and construct validity were evaluated. RESULTS: Internal consistency of Thai QOL-AD version was good for both patients (0.82) and caregivers (0.82). The results of factor analysis indicated three factors (physical and psychological well-being, social well-being, and close interpersonal relationships) in the patient group, while four factors were found (social well-being, functional ability, psychological well-being, and physical well-being) in the caregiver group. The scaling success in the patient group was around 80-83 per cent for convergent validity, and 70-83 per cent for discriminant validity. The caregiver group showed higher scaling success in convergent validity except for the psychological well-being domain. The scaling success of discriminant validity was around 44-83 per cent for caregivers. CONCLUSION: The findings of the study demonstrate a good reliability of a Thai QOL-AD version for both patient and caregiver groups. Validity, especially in the caregiver group, might need to be re-examined. PMID- 25031648 TI - An unusual right popliteal vein aneurysm in an adult cadaver: A case report. AB - The incidence of venous aneurysm is less than arterial aneurysms. Most are incidental findings with no major clinical significance. However, popliteal vein aneurysms (PVA) may be potentially life threatening, as they can be a source of pulmonary embolism and potentially even death. We report a case of right PVA in a 67-year-old male cadaver. Information from this case study may contribute to an improved understanding of these phenomena, including early detection of these or similar thromboembolic events. PMID- 25031649 TI - Adipogenesis: it is not just lipid that comprises adipose tissue. AB - Adipogenesis is the initial component of forming cells (adipocytes) capable of assimilating lipid. Lipid metabolism is a metabolic process whereby lipid is stored for use when energy is required. Both processes involve cellular and molecular components. The gene regulations of each are different and (yet) confusingly, markers for both are used interchangeably. The focus of this paper is to provide elementary information regarding both processes and to introduce this issue of Journal of Genomics, whereby important aspects of adipogenesis and lipid metabolism involving gene expression are provided. PMID- 25031650 TI - Cellular and molecular implications of mature adipocyte dedifferentiation. AB - There is a voluminous amount of scientific literature dealing with the involvement of adipocytes in molecular regulation of carcass composition, obesity, metabolic syndrome, or diabetes. To form adipocytes (process termed adipogenesis) nearly all scientific papers refer to the use of preadipocytes, adipofibroblasts, stromal vascular cells or adipogenic cell lines, and their differentiation to form lipid-assimilating cells containing storage triacylglyceride. However, mature adipocytes, themselves, possess ability to undergo dedifferentiation, form proliferative-competent progeny cells (the exact plasticity is unknown) and reinitiate formation of cells capable of lipid metabolism and storage. The progeny cells would make a viable (and alternative) cell system for the evaluation of cell ability to reestablish lipid assimilation, ability to differentially express genes (as compared to other adipogenic cells), and to form other types of cells (multi-lineage potential). Understanding the dedifferentiation process itself and/or dedifferentiated fat cells could contribute to our knowledge of normal growth processes, or to disease function. Indeed, the ability of progeny cells to form other cell types could turn-out to be important for processes of tissue reconstruction/engineering and may have implications in clinical, biochemical or molecular processes. PMID- 25031651 TI - Topics in transcriptional control of lipid metabolism: from transcription factors to gene-promoter polymorphisms. AB - The central dogma of biology (DNA>>RNA>>Protein) has remained as an extremely useful scaffold to guide the study of molecular regulation of cellular metabolism. Molecular regulation of cellular metabolism has been pursued from an individual enzyme to a global assessment of protein function at the genomic (DNA), transcriptomic (RNA) and translation (Protein) levels. Details of a key role by inhibitory small RNAs and post-translational processing of cellular proteins on a whole cell/global basis are now just emerging. Below we emphasize the role of transcription factors (TF) in regulation of adipogenesis and lipogenesis. Additionally we have also focused on emerging additional TF that may also have hitherto unrecognized roles in adipogenesis and lipogenesis as compared to our present understanding. It is generally recognized that SNPs in structural genes can affect the final structure/function of a given protein. The implications of SNPs located in the non-transcribed promoter region on transcription have not been examined as extensively at this time. Here we have also summarized some emerging results on promoter SNPs for lipid metabolism and related cellular processes. PMID- 25031652 TI - Adipogenic transcriptome profiling using high throughput technologies. AB - The recent technological innovations in the area of functional genomics, gene expression/transcriptomic profiling can provide new insights to understand the molecular basis of adipogenesis. The focus of this review is to highlight the recent advances in our understanding of the complex interplay of gene expression events and the regulatory mechanisms of adipogenesis in mouse cell lines, humans and farm animals. All these studies have employed the availability of constantly evolving high throughput 'omics' technologies including microarrays, RNA-Seq, chromatin immunoprecipitation, next generation sequencing, RNAi, miRNA profiling and quantitative PCR arrays. PMID- 25031654 TI - Cell supermarket: adipose tissue as a source of stem cells. AB - Adipose tissue is derived from numerous sources, and in recent years this tissue has been shown to provide numerous cells from what seemingly was a population of homogeneous adipocytes. Considering the types of cells that adipose tissue derived cells may form, these cells may be useful in a variety of clinical and scientific applications. The focus of this paper is to reflect on this area of research and to provide a list of potential (future) research areas. PMID- 25031653 TI - Developmental programming of fetal skeletal muscle and adipose tissue development. AB - All important developmental milestones are accomplished during the fetal stage, and nutrient fluctuation during this stage produces lasting effects on offspring health, so called fetal programming or developmental programming. The fetal stage is critical for skeletal muscle development, as well as adipose and connective tissue development. Maternal under-nutrition at this stage affects the proliferation of myogenic precursor cells and reduces the number of muscle fibers formed. Maternal over-nutrition results in impaired myogenesis and elevated adipogenesis. Because myocytes, adipocytes and fibrocytes are all derived from mesenchymal stem cells, molecular events which regulate the commitment of stem cells to different lineages directly impact fetal muscle and adipose tissue development. Recent studies indicate that microRNA is intensively involved in myogenic and adipogenic differentiation from mesenchymal stem cells, and epigenetic changes such as DNA methylation are expected to alter cell lineage commitment during fetal muscle and adipose tissue development. PMID- 25031655 TI - Obesity gene atlas in mammals. AB - Obesity in humans has increased at an alarming rate over the past two decades and has become one of the leading public health problems worldwide. Studies have revealed a large number of genes/markers that are associated with obesity and/or obesity-related phenotypes, indicating an urgent need to develop a central database for helping the community understand the genetic complexity of obesity. In the present study, we collected a total of 1,736 obesity associated loci and created a freely available obesity database, including 1,515 protein-coding genes and 221 microRNAs (miRNAs) collected from four mammalian species: human, cattle, rat, and mouse. These loci were integrated as orthologs on comparative genomic views in human, cattle, and mouse. The database and genomic views are freely available online at: http://www.integratomics-time.com/fat_deposition. Bioinformatics analyses of the collected data revealed some potential novel obesity related molecular markers which represent focal points for testing more targeted hypotheses and designing experiments for further studies. We believe that this centralized database on obesity and adipogenesis will facilitate development of comparative systems biology approaches to address this important health issue in human and their potential applications in animals. PMID- 25031656 TI - Stromal Vascular Cells and Adipogenesis: Cells within Adipose Depots Regulate Adipogenesis. AB - A collection of investigations indicate the importance of adipose tissue stromal/stem cells to vasculogenesis and angiogenesis during adipogenesis. Early in development the stromal-vascular (S-V) elements control and dictate the extent of adipogenesis. For instance, the vasculature and connective tissue collagen matrix develops before overt adipocyte differentiation. Definitive studies of human adipose tissue stem cells (ADSC) provided an understanding of stem cell identity and function. In this regard, a novel vascular stem cell theory proposes that ADSC are a mixed population of vascular stem cells (VSC) with differential potential proportional to the angiogenic potential of the vasculature. The differential potential of VSC can range considerably in a continuous fashion and can include vascular smooth cells, endothelial cells (EC) and adipocytes. These observations are consistent with fetal adipose tissue studies that show location dependent angiogenic potential ranging from more to less in regards to a predominant presence of EC and developing arterioles before overt adipogenesis. PMID- 25031657 TI - A novel dataset for identifying sex-biased genes in Drosophila. AB - Phenotypic differences between males and females of sexually dimorphic species are caused in large part by differences in gene expression between the sexes, most of which occurs in the gonads. To accurately identify genes differentially expressed between males and females in Drosophila, we sequenced the testis and ovary transcriptomes of D. yakuba, D. pseudoobscura, and D. ananassae and used them to identify sex-biased genes in the latter two species. We highlight the increased sensitivity and improved power of sex-biased gene detection methods when using our testis/ovary data versus male and female whole body transcriptome data. We thus provide a resource specifically designed to accurately identify and characterize sex-biased genes across Drosophila. This dataset is available through NCBI GEO accession GSE52058. PMID- 25031658 TI - The sex chromosomes of frogs: variability and tolerance offer clues to genome evolution and function. AB - Frog sex chromosomes offer an ideal system for advancing our understanding of genome evolution and function because of the variety of sex determination systems in the group, the diversity of sex chromosome maturation states, the ease of experimental manipulation during early development. After briefly reviewing sex chromosome biology generally, we focus on what is known about frog sex determination, sex chromosome evolution, and recent, genomics-facilitated advances in the field. In closing we highlight gaps in our current knowledge of frog sex chromosomes, and suggest priorities for future research that can advance broad knowledge of gene dose and sex chromosome evolution. PMID- 25031660 TI - Enly: Improving Draft Genomes through Reads Recycling. AB - The reconstruction of the complete genome sequence of an organism is an important point for comparative, functional and evolutionary genomics. Nevertheless, overcoming the problems encountered while completing the sequence of an entire genome can still be demanding in terms of time and resources. We have developed Enly, a simple tool based on the iterative mapping of sequence reads at contig edges, capable to extend the genomic contigs deriving from high-throughput sequencing, especially those deriving by Newbler-like assemblies. Testing it on a set of de novo draft genomes led to the closure of up to 20% of the gaps originally present. Enly is cross-platform and most of the steps of its pipeline are parallelizable, making easy and fast to improve a draft genome resulting from a de novo assembly. PMID- 25031659 TI - Chromosome imbalance as a driver of sex disparity in disease. AB - It has long been recognized that men and women exhibit different risks for diverse disorders ranging from metabolic to autoimmune diseases. However, the underlying causes of these disparities remain obscure. Analysis of patients with chromosomal abnormalities, including Turner syndrome (45X) and Klinefelter syndrome (47XXY), has highlighted the importance of X-linked gene dosage as a contributing factor for disease susceptibility. Escape from X-inactivation and X linked imprinting can result in transcriptional differences between normal men and women as well as in patients with sex chromosome abnormalities. Animal models support a role for X-linked gene dosage in disease with O-linked N acetylglucosamine transferase (OGT) emerging as a prime candidate for a pleiotropic effector. OGT encodes a highly regulated nutrient-sensing epigenetic modifier with established links to immunity, metabolism and development. PMID- 25031661 TI - Liposome Bupivacaine for Postsurgical Analgesia in Adult Patients Undergoing Laparoscopic Colectomy: Results from Prospective Phase IV Sequential Cohort Studies Assessing Health Economic Outcomes. AB - BACKGROUND: Opioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms. METHODS: We analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs. RESULTS: Eighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were $11,234 and $13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine. CONCLUSIONS: Compared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy. PMID- 25031662 TI - Losartan Inhibits Nuclear Factor-kappaB Activation Induced by Small, Dense LDL Cholesterol Particles in Human Umbilical Vein Endothelial Cells. AB - OBJECTIVE: We aimed to investigate how losartan exerts protective effects on human umbilical vein endothelial cell injury induced by small, dense, LDL (sLDL) cholesterol particles. METHODS: sLDL cholesterol was isolated by a 2-steps method and the nuclear translocation and activation of nuclear factor-kappaB (NF-kappaB) in endothelial cells was observed by confocal microscopy and electrophoretic mobility shift assays. RESULTS: Losartan greatly inhibited the nuclear translocation of NF-kappaB induced by sLDL cholesterol in a dose-dependent manner. CONCLUSIONS: sLDL cholesterol may be involved in endothelial dysfunction possibly through NF-kappaB activation; losartan protects against sLDL cholesterol inducing endothelial cell injury by inhibiting NF-kappaB activation, suggesting that losartan may play a role in the prevention and treatment of cardiovascular disease. PMID- 25031663 TI - Therapeutic effects of thymoquinone in a model of neuropathic pain. AB - BACKGROUND: The goal of our study was to determine the therapeutic effects of thymoquinone in a dose-dependent manner in a model of neuropathic pain following an experimentally applied spinal cord injury (SCI). METHODS: Fifty female adult Wistar albino rats weighing between 220 and 260 g were included in the study and were divided into 5 groups as follows: Group S (sham), Group C (control), Group T100 (100 mg/kg thymoquinone), Group T200 (200 mg/kg thymoquinone), and Group T400 (400 mg/kg thymoquinone). To begin the experiment, SCI was applied to all groups (with the exception of the sham group) following a mechanical and heat cold test. Two weeks later, the mechanical and heat-cold tests were repeated, and a single normal saline dose was given to the sham and control groups, whereas 3 varying doses of thymoquinone were given to the other groups. The mechanical and heat-cold tests were repeated at 30, 60, 120, and 180 minutes after receiving thymoquinone. Finally, the animals were put to death via the removal of intracardiac blood. The levels of nitric oxide, total oxidant status, total antioxidant status, paraoxonase, malondialdehyde, tumor necrosis factor-alpha, and interleukin-1beta were determined in all of the blood samples. RESULTS: The withdrawal threshold and withdrawal latency values recorded from the mechanical and heat-cold allodynia measurements for all 3 thymoquinone groups were higher than that of the control group at all time points (ie, 30, 60, 120, and 180 minutes). There were no differences in these results between the 3 thymoquinone groups. The paraoxonase and total antioxidant status serum levels of all 3 thymoquinone groups were higher than those of the control group, whereas total oxidant status, nitric oxide, malondialdehyde, interleuken-1beta, and tumor necrosis factor-alpha levels were lower in the 3 thymoquinone groups than in the control group. CONCLUSIONS: Thymoquinone is beneficial for decreasing experimental neuropathic pain following SCI. However, increasing the dose does not change the effect. PMID- 25031664 TI - Effect of administration route on the pharmacokinetics of cobalamin in elderly patients: a randomized controlled trial. AB - BACKGROUND: The gold standard for cobalamin deficiency treatment is administration of cobalamin by intramuscular injection. The injection is painful and inconvenient, particularly for elderly persons. Cobalamin might also be administered intranasally. Previous studies do not provide insight into the pharmacokinetics of intranasal cobalamin administration in comparison with cobalamin injection. AIM: To quantify the pharmacokinetics of intranasally and intramuscularly administered cobalamin to determine if intranasal administration might be an alternative for intramuscular administration. METHODS: Ten inpatients and outpatients of a geriatrics unit were recruited and randomly assigned to receive a single dose of 1000 MUg cobalamin administered either by intranasal spray or intramuscular injection (5 per group). Inclusion criteria were written informed consent, age >65 years, and a cobalamin serum concentration <200 pmol/L. Total cobalamin serum concentrations were determined 10 times within 48 hours after administration. The differences in Cmax, Tmax, and AUC0-48 h per administration route were statistically compared using ANOVA. RESULTS: The average Cmax was 1 nmol/L after intranasal and 38.5 nmol/L after intramuscular administration. The average Tmax for intranasal and intramuscular administration was 42 minutes versus 342 minutes, respectively, and the AUC0-48 h was 1.3 umol/L/min versus 45.4 umol/L/min, respectively. These values also differed significantly (P<0.05). The estimated bioavailability of the intranasal administration was 2%. CONCLUSIONS: The pharmacokinetics of intranasal and intramuscular cobalamin administration in elderly, cobalamin-deficient patients differ significantly. However, the estimated 2% bioavailability of cobalamin after intranasal administration makes intranasal cobalamin administration a potentially interesting administration route for elderly patients. Netherlands Trial Registry identifier: NTR 3005. PMID- 25031665 TI - Recovery time of platelet function after aspirin withdrawal. AB - INTRODUCTION: Inappropriate antiplatelet therapy discontinuation increases the risk of thrombotic complications and bleeding after dental procedures. To determine the platelet reactivity recovery time after aspirin withdrawal in vivo, our study was conducted in patients with low-risk cardiovascular disease who can stop aspirin administration following the guidelines stipulated by the American College of Chest Physicians. The time it takes for platelet activity to normalize and the diagnostic accuracy of testing methods were assessed for a residual antiplatelet activity with multiple electrode aggregometry. Our study included patients with clinically indicated hypertension preparing for a dental extraction procedure. MATERIALS AND METHODS: A total of 212 patients not taking aspirin (control group) and 248 patients with hypertension receiving long-time aspirin treatment at a 100-mg daily dose were prospectively included in the study, which involved stopping aspirin intake before dental extraction. The residual platelet activity and dental bleeding in patients who stopped aspirin intake were analyzed and compared with those of the control group. In addition, platelet reactivity recovery time and bleeding risk in patients who stopped taking aspirin every 24 hours for 0 to 5 days (0-143 hours) before dental extraction was also assessed. RESULTS: Platelet reactivity normalized 96 hours after aspirin withdrawal. The cut-off value of 49 arbitrary units in the arachidonic acid platelet aggregation test excluded the effect of aspirin with 91% sensitivity and 66% specificity. AUC showed 0.86 (P < 0.001) diagnostic accuracy. The immediate bleeding complications in all treatment groups were similar to those seen in the control group and were successfully managed with local hemostatic measures. CONCLUSIONS: The antiplatelet effects of aspirin disappeared 96 hours after aspirin withdrawal in our study, and dental extractions may be safely performed in this period when appropriate local hemostatic measures are taken. Based on these results, a shorter aspirin intake cessation period may be allowable in complex dental procedures and surgery for which a longer aspirin intake cessation period (7-10 days) is recommended based on the American College of Chest Physicians guidelines. PMID- 25031666 TI - Primary central nervous system amelanotic melanoma in a Hispanic male: Case report. AB - BACKGROUND: Primary melanotic neoplasms of the central nervous system (CNS) are uncommon; amelanotic melanomas in this region are extremely rare. Very few cases of amelanotic variation of primary melanoma in the CNS were reported on. General guidelines or recommendations to establish this diagnosis do not exist. CASE REPORT: A sixty-year-old male Hispanic patient presented with a 7-day history of numbness and dizziness. Initial laboratory work-up and physical examination were inconclusive. Cerebral radiological imaging showed a left frontal lesion. Further work-up after clinical deterioration revealed an increase in the lesion size consistent with hemorrhage and changes in T1WI. Biopsy and immunochemistry demonstrated the presence of amelanotic melanoma in the CNS without evidence of another primary lesion. CONCLUSIONS: Primary amelanotic melanoma of the CNS represents a challenge, clinically and diagnostically. Magnetic resonance imaging can be helpful in early stages. Final diagnosis is established with immunohistochemical testing. Physicians should be aware of the existence of this rare manifestation and difficulties faced while building this diagnosis. PMID- 25031667 TI - Calculating the home advantage in soccer leagues. AB - A recent article published in the Journal of Human Kinetics (Saavedra et al., 2013) was based on a flawed methodology when calculating the home advantage values in soccer leagues. This led to incorrect calculations, false conclusions and some misleading results about home advantage in 52 soccer leagues of UEFA countries over a 10 year period. The aim of this letter was to explain these flaws and to make sure future research would not be influenced by the subsequent results and conclusions that had been presented. PMID- 25031668 TI - Sleep-related offline learning in a complex arm movement sequence. AB - Sleep is known to elicit off-line improvements of newly learned procedural skills, a phenomenon attributed to enhancement consolidation of an internal skill representation. In the motor domain, enhancement consolidation has been reported almost exclusively for sequential-finger-tapping skills. The aim of the present study was to extend the notion of sleep-related enhancement consolidation to tasks closer to everyday motor skills. This was achieved by employing a sequence of unrestrained reaching-movements with the non-dominant arm. Fifteen reaching movements had to be executed as fast as possible, following a spatial pattern in the horizontal plane. Terminating each movement, a peg had to be fitted into a hole on an electronic pegboard. Two experimental groups received initial training, one in the evening, the other one in the morning. Subsequently, performance in both groups was retested twelve, and again 24 hrs later. Thus, during retention each individual experienced a night of sleep, either followed or preceded by a wake interval. Performance error remained low throughout training and retests. Yet mean total execution time, indicative of task execution-speed, significantly decreased for all individuals throughout initial training (no group differences), and significantly decreased again in either group following nocturnal sleep, but not following wake. This finding does not appear to result merely from additional practice afforded at the time of retests, because only after a night of sleep individuals of both experimental groups also revealed performance improvement beyond that estimated from their initial training performance. PMID- 25031669 TI - Effects of body mass index and full body kinematics on tennis serve speed. AB - Effective training to improve serve speed is important for competitive tennis players. The purposes of this study were to investigate the effects of anthropometric factors and whole body kinematics of elite players on ball speed and to propose possible training strategies for improving the quality of tennis serves. Body and racket kinematics of tennis serves of 12 male elite Hong Kong players were investigated. The tennis serve was divided into four phases: I) Back Swing Phase, II) Lead-Leg-Drive Phase, III) Forward-Swing Phase, and IV) Follow Through Phase. It was shown that racket-side knee range of motion during phases II and III (r=0.705; p<0.05), racket-side knee peak extension velocity during phase II (r=0.751; p<0.01), racket-side hip peak extension velocity during phase II (r=0.657; p<0.05), racket-side shoulder range of motion in the coronal plane during phase III (r=0.616; p<0.05), racket-side elbow peak extension velocity during phase III (r=0.708; p<0.01) and body mass index (r=0.577; p<0.05) were significantly correlated with ball speed. Body mass index and the identified kinematic parameters that were significantly correlated with ball speed could be used as training guidelines for coaches and players to improve serve speed. Players should pay particular attention in training to increasing the extension velocity and range of motion of the identified joints. PMID- 25031670 TI - Biomechanical evaluation of the phases of the triple jump take-off in a top female athlete. AB - The triple jump is one of two track and field events in which the athlete aims to maximize the horizontal distance jumped. This jump is comprised of 3 take-off phases (hop, step, and jump), each playing an important role, as they require the jumper to tolerate extremely high forces of impact and to maintain a high level of horizontal velocity. The purpose of the study was to investigate the biomechanical characteristics of the 3 take-off phases in the triple jump in a top female athlete. The 3 take-off phases of the top national female triple jumper were videotaped and analyzed using 2D motion analysis. Three cameras (DSR SR 68) were placed on the lateral sides of the 3 take-off points, to record the motions of the 3 take-off phases. Results indicated that maximum loss of the horizontal velocity was in the hop phase (1.13 m/s), while the maximum braking time was in the jump phase (0.05 sec). The maximum pushing time was in the jump phase (0.10 s), while the pushing time was equal in the hop and step phases (0.05 s). In conclusion, the success of the triple jump is the result of the physical and technical qualities of the jumper. The excessive loss in horizontal velocity during the 3 take-off phases is the main factor limiting the performance of the top female athlete. PMID- 25031671 TI - Effect of three technical arms swings on the elevation of the center of mass during a standing back somersault. AB - Arms swing during standing back somersaults relates to three different "gymnastics schools", each is considered "optimal" by its adepts. In the three cases, technical performance, elevation and safety differ. Therefore, the aim of this study was to compare the mechanical variables of three different arms swing techniques in the performance of a standing back tucked somersault. Five high level male gymnasts (age: 23.17+/-1.61 yrs; body height: 1.65+/-0.05 m; body mass: 56.80+/-7.66 kg) randomly performed standing somersaults under three conditions, each following a different arms' swing technical angle (270 degrees , 180 degrees and 90 degrees ). A force plate synchronized with a three dimensional movement analysis system was used to collect kinetic and kinematic data. Significant differences were observed between somersaults' performance. The back somersault performed with 270 degrees arms swing showed the best vertical displacement (up to 13.73%), while the back somersaults performed with 180 degrees arms swing showed a decrease in power (up to 22.20%). The back somersault with 90 degrees arms swing showed the highest force (up to 19.46%). Considering that the higher elevation of the centre of mass during the flight phase would allow best performance and lower the risk of falls, this study demonstrated that optimal arms' swing technique prior to back tucked somersault was 270 degrees . PMID- 25031672 TI - Ground reaction forces and throwing performance in elite and novice players in two types of handball shot. AB - The purpose of this study was to examine the differences in the ground reaction force (GRF) patterns between elite and novice players during two types of handball shots, as well as the relationships between throwing performance and the GRF variables. Ball velocity and throwing accuracy were measured during jump shots and 3-step shots performed by 15 elite and 15 novice players. The GRF pattern was recorded for the vertical and the anterior-posterior GRF components (Kistler forceplate type-9281, 750Hz). One-way ANOVA was used for the group differences and the Pearson coefficient for the correlation between throwing performance and GRF variables (SPSS 21.0, p <= 0.05). The elite players performed better in both types of shot. Both groups developed consistent and similar GRF patterns, except for the novices' inconsistent Fz pattern in the 3-step shot. The GRF variables differed significantly between groups in the 3-step shot (p <= 0.05). Significant correlations were found only for ball velocity and predominantly for the novice players during the 3-step shot (p <= 0.05). The results possibly highlight a shortage in the novice ability to effectively reduce their forward momentum so as to provide a stable base of support for the momentum transfer up the kinetic chain, a situation that may predispose athletes to injury. PMID- 25031673 TI - Effect of Fatigue Upon Performance and Electromyographic Activity in 6-RM Bench Press. AB - The aim of this study was to examine the effect of fatigue during one set of 6-RM bench pressing upon the muscle patterning and performance. Fourteen resistance trained males (age 22.5+/-2.0 years, stature 1.82+/-0.07 m, body mass 82.0+/-7.8 kg) conducted a 6-RM bench press protocol. Barbell kinematics and EMG activity of pectoralis major, deltoid anterior, biceps brachii, triceps brachii, rectus abdominis, oblique external and erector spinae were measured in each repetition during the 6-RM bench press. Total lifting time increased and the velocity in the ascending movement decreased (p<=0.001). However, the kinematics in the descending phase deferred: the time decreased and velocity increased during the 6 RM (p<=0.001). Generally, muscles increased their EMG amplitude during the six repetitions in the ascending movement, while only three of the seven measured muscles showed an increase over the six repetitions in the descending part in 6 RM bench pressing. It was concluded that the bench pressing performance decreased (lower barbell velocities and longer lifting times) with increasing fatigue in the 6-RM execution. Furthermore EMG increased in the prime movers and the trunk stabilizers (abdominal and spine), while the antagonist muscle (biceps) activity was not affected by fatigue during the lifting phase in a single set of 6-RM bench pressing. PMID- 25031674 TI - Ground Reaction Force and Valgus Knee Loading during Landing after a Block in Female Volleyball Players. AB - A non-contact anterior cruciate ligament (ACL) injury is both a serious and very common problem in volleyball. The aim of the study was to determine the association between stick, step-back, and run-back landings after a block and select risk factors of ACL injuries for female professional volleyball players. The research sample involved fourteen female professional volleyball players. Two force plates were used to determine ground reaction forces. Eight infrared cameras were employed to collect the kinematic data. The one-factor repeated measures analysis of variance, where the landing type was the factor, was used for comparing the valgus moment and ground reaction force on the right lower limb. ANOVA showed that the type of landing has a main effect on the valgus moment on the right lower limb (F) = 5.96, p = 0.019df = 1.18, partial eta(2) = 0.239 and SP = 0.693). Furthermore, it did not show a main effect on the vertical reaction force on the right lower limb ((F)=2.77, p=0.090, df=1.55, partial eta(2)= 0.128 and SP=0.448). The highest valgus moment occurred during the run back landing. This moment, however, did not have any effect within the first 100 ms after initial contact with the ground, but rather upon the subsequent motion carried out when stepping back off the net. A comparison between a run-back landing and a step-back landing showed relevant higher values of vertical ground reaction forces during the run-back landing. PMID- 25031675 TI - Effect of choline supplementation on rapid weight loss and biochemical variables among female taekwondo and judo athletes. AB - Taekwondo and judo competitions are divided into weight categories. Many athletes reduce their body mass a few days before competition in order to obtain a competitive advantage over lighter opponents. To achieve fast body mass reduction, athletes use a number of nutritional strategies, including choline supplementation. The goal of this study was to identify the effects of choline supplementation on body mass reduction and leptin levels among female taekwondo and judo athletes. Twenty-two female athletes (15 taekwondo and 7 judo athletes) were selected from different weight categories and divided into two groups, according to weight. The players in the experimental group took choline tablets for one week before a competition. The results revealed significant differences between pre- and post-competition measurements of leptin, free plasma choline, urine choline and urine malondialdehyde levels; body mass was also reduced in the post-competition measurements. In conclusion, choline supplementation could rapidly reduce body mass without any side effects on biochemical levels or static strength. PMID- 25031676 TI - Measurement of cardiorespiratory fitness in children from two commonly used field tests after accounting for body fatness and maturity. AB - Body fat and maturation both influence cardiorespiratory fitness, however few studies have taken these variables into account when using field tests to predict children's fitness levels. The purpose of this study was to determine the relationship between two field tests of cardiorespiratory fitness (20 m Maximal Multistage Shuttle Run [20-MST], 550 m distance run [550-m]) and direct measurement of VO2max after adjustment for body fatness and maturity levels. Fifty-three participants (25 boys, 28 girls, age 10.6 +/- 1.2 y, mean +/- SD) had their body fat levels estimated using bioelectrical impedance (16.6% +/- 6.0% and 20.0% +/- 5.8% for boys and girls, respectively). Participants performed in random order, the 20-MST and 550-m run followed by a progressive treadmill test to exhaustion during which gas exchange measures were taken. Pearson correlation coefficient analysis revealed that the participants' performance in the 20-MST and 550-m run were highly correlated to VO2max obtained during the treadmill test to exhaustion (r = 0.70 and 0.59 for 20-MST and 550-m run, respectively). Adjusting for body fatness and maturity levels in a multivariate regression analysis increased the associations between the field tests and VO2max (r = 0.73 for 20-MST and 0.65 for 550-m). We may conclude that both the 20-MST and the 550 m distance run are valid field tests of cardiorespiratory fitness in New Zealand 8-13 year old children and incorporating body fatness and maturity levels explains an additional 5-7% of the variance. PMID- 25031677 TI - Norms for an isometric muscle endurance test. AB - Musculoskeletal performance assessment is critical in the analysis of physical training programs in order to prioritize goals for decreasing injury risk and focusing performance goals. Abdominal endurance as part of this analysis is often assessed with techniques that have validity that has been debated in literature. The purpose of this study was to develop normative sex- and athlete-specific percentiles for a trunk stabilization and muscular endurance by using a prone forearm plank test in college-aged students. A second purpose of this study was to investigate the effect of habitual physical activity and the reason for test termination. There were 471 participants (means +/- SE; males: n = 194, age 20.4 +/- 0.2 years, body height 179.4 +/- 0.5 cm, body mass 81.1 +/- 1.2 kg; females: n = 277, age 20.2 +/- 0.2 years, body height 165.7 +/- 0.4 cm, body mass 63.9 +/- 0.7 kg) who performed this test to volitional or technique failure. Males produced significantly higher test durations than females (means +/- SD; 124 +/- 72 seconds vs. 83 +/- 63 seconds) and athletes produced significantly longer test durations than non-athletes (123 +/- 69 s vs. 83 +/- 63 s) but no interaction effects were seen in the variables of sex and athletic status. The activity level was found to have a threshold of influence (>3 times/week) on abdominal endurance that is dose-specific where greater than 5 times/week showed the greatest influence. The fatigue of the abdominals was the termination reason producing the lowest test duration and there was no sex effect on reason for test termination. These normative percentiles for abdominal endurance suggest that the abdominal plank test can now be used as an alternative to other abdominal assessments in college students, but further investigation is warranted prior to confirmation and generalization to other populations. PMID- 25031678 TI - Adrenergic response to maximum exercise of trained road cyclists. AB - The aim of this study was to evaluate adrenergic responses in the peripheral blood of trained road cyclists at rest, at maximal intensity of incremental bicycle exercise test, and during 15 minutes of recovery, as well as the relationship between them. Competitive male road cyclists, in the pre-competitive phase of a season, mean age 21.7 +/- 6.4 years, and BMI 20.7 +/- 0.8 kg.m(-2), performed an incremental test on a bicycle ergometer with unloaded cycling for 5 min, then increased the load to 40 W every 3 min, up to maximal exercise intensity. The plasma catecholamine concentrations (epinephrine, norepinephrine) and oxygen uptake were estimated. The expression of 132 genes related to the adrenergic system in leukocytes was measured. A statistically significant increase in plasma epinephrine concentration (p < 0.01) was observed in response to exercise. The mean of maximal oxygen uptake was 65.7 +/- 5.5 ml.kg(-1).min( 1). The RGS2 gene expression was highest regardless of the test phase for all athletes. The effort had a statistically significant influence on ADRB2 and RAB2A expression. In addition, the RAB2A, ADM and HSPB1 expression level increased during recovery. We can conclude that plasma epinephrine concentration and genes related to the adrenergic system such as ADM, ADRB2, CCL3, GPRASP1, HSPB1, RAB2A, RGS2 and ROCK1 seem to have an influence on the response to high-intensity exercise in trained cyclists. PMID- 25031679 TI - Physical determinants of interval sprint times in youth soccer players. AB - Relationships between sprinting speed, body mass, and vertical jump kinetics were assessed in 243 male soccer athletes ranging from 10-19 years. Participants ran a maximal 36.6 meter sprint; times at 9.1 (10 y) and 36.6 m (40 y) were determined using an electronic timing system. Body mass was measured by means of an electronic scale and body composition using a 3-site skinfold measurement completed by a skilled technician. Countermovement vertical jumps were performed on a force platform - from this test peak force was measured and peak power and vertical jump height were calculated. It was determined that age (r=-0.59; p<0.01), body mass (r=-0.52; p<0.01), lean mass (r=-0.61; p<0.01), vertical jump height (r=-0.67; p<0.01), peak power (r=-0.64; p<0.01), and peak force (r=-0.56; p<0.01) were correlated with time at 9.1 meters. Time-to-complete a 36.6 meter sprint was correlated with age (r=-0.71; p<0.01), body mass (r=-0.67; p<0.01), lean mass (r=-0.76; p<0.01), vertical jump height (r=-0.75; p<0.01), peak power (r=-0.78; p<0.01), and peak force (r=-0.69; p<0.01). These data indicate that soccer coaches desiring to improve speed in their athletes should devote substantive time to fitness programs that increase lean body mass and vertical force as well as power generating capabilities of their athletes. Additionally, vertical jump testing, with or without a force platform, may be a useful tool to screen soccer athletes for speed potential. PMID- 25031680 TI - Short-term performance effects of three different low-volume strength-training programmes in college male soccer players. AB - This study aimed to analyse the short-term performance effects of three in-season low-volume strength-training programmes in college male soccer players. Fifty seven male college soccer players (age: 20.3+/-1.6 years) were randomly assigned to a resistance-training group (n=12), plyometric training group (n=12), complex training group (n=12), or a control group (n=21). In the mid-season, players underwent a 9-week strength-training programme, with two 20 min training sessions per week. Short-term effects on strength, sprint, agility, and vertical jump abilities were measured. All training groups increased 1-RM squat (range, 17.2 24.2%), plantar flexion (29.1-39.6%), and knee extension (0.5-22.2%) strength compared with the control group (p<0.05). The resistance-training group increased concentric peak torque of the knee extensor muscles by 9.9-13.7%, and changes were greater compared with the control group (p<0.05). The complex training group presented major increments (11.7%) in eccentric peak torque of the knee flexor muscles on the non-dominant limb compared with the control group and plyometric training group (p<0.05). All training groups improved 20-m sprint performance by 4.6-6.2% (p<0.001) compared with the control group. No differences were observed in 5-m sprint and agility performances (p>0.05). Overall, the results suggest that in-season low-volume strength training is adequate for developing strength and speed in soccer players. PMID- 25031681 TI - Chronic effects of different resistance training exercise orders on flexibility in elite judo athletes. AB - The aim of this study was to examine the effects of twelve weeks of resistance training with different exercise orders (upper limbs and lower limbs vs. lower limbs and upper limbs) on flexibility levels in elite judo athletes. Thirty-nine male athletes were randomly divided into 3 groups as follows: G1 (n = 13), G2 (n = 13), and CG (n = 13). The flexibility was assessed on 8 joint movements: shoulder flexion and shoulder extension, shoulder abduction and shoulder adduction, trunk flexion and trunk extension, and hip flexion and hip extension. Two-way repeated measures ANOVAs (time [pre-experimental vs. post-experimental] * group [G1 vs. G2 vs. CG]) were used to compare the differences between pre- and post-test situations and the differences among groups. The results from the within-group (pre vs. post) comparisons demonstrated significant increases (p < 0.05) in the range of motion of 3.93 and 5.96% for G1 and G2 training groups, respectively, in all joints. No significant changes (p > 0.05) were observed for the CG. The results from the between-group comparisons demonstrated no significant differences (p > 0.05) in the range of motion between G1post vs. G2post (1.15%). Although both exercise orders (from upper to lower limbs and from lower to upper limbs) increased flexibility, no significant variations were observed between the different exercise orders. Nevertheless, these findings demonstrate that flexibility gains could be obtained with a resistance training program, and thus, more time can be devoted to sports-specific judo training. PMID- 25031682 TI - Relationship Between Repeated Sprint Performance and both Aerobic and Anaerobic Fitness. AB - The aims of this study were firstly, to examine the relationship between repeated sprint performance indices and anaerobic speed reserve (AnSR), aerobic fitness and anaerobic power and secondly, to identify the best predictors of sprinting ability among these parameters. Twenty nine subjects (age: 22.5 +/- 1.6 years, body height: 1.8 +/- 0.1 m, body mass: 68.8 +/- 8.5 kg, body mass index (BMI): 22.2 +/- 2.1 kg*m-2, fat mass: 11.3 +/- 2.9 %) participated in this study. All participants performed a 30 m sprint test (T30) from which we calculated the maximal anaerobic speed (MAnS), vertical and horizontal jumps, 20m multi-stage shuttle run test (MSRT) and repeated sprint test (10 * 15 m shuttle run). AnSR was calculated as the difference between MAnS and the maximal speed reached in the MSRT. Blood lactate sampling was performed 3 min after the RSA protocol. There was no significant correlation between repeated sprint indices (total time (TT); peak time (PT), fatigue index (FI)) and both estimated VO2max and vertical jump performance). TT and PT were significantly correlated with T30 (r=0.63, p=0.001 and r=0.62, p=0.001; respectively), horizontal jump performance (r = 0.47, p = 0.001 and r = -0.49, p = 0.006; respectively) and AnSR (r=-0.68, p= 0.001 and r=-0.70, p=0.001, respectively). Significant correlations were found between blood lactate concentration and TT, PT, and AnSR (r=-0.44, p=0.017; r= 0.43, p=0.018 and r=0.44, p=0.016; respectively). Stepwise multiple regression analyses demonstrated that AnSR was the only significant predictor of the TT and PT, explaining 47% and 50% of the shared variance, respectively. Our findings are of particular interest for coaches and fitness trainers in order to predict repeated sprint performance by using AnSR that can easily identify the respective upper performance limits supported by aerobic and anaerobic power of a player involved in multi-sprint team sports. PMID- 25031683 TI - Profile, correlation and structure of speed in youth elite soccer players. AB - Speed, power and agility are important components of fitness and determine the level of success and performance in soccer. The aim of this study was to identify speed variables and to determine their mutual correlation and structure in youth elite soccer players. The research group consisted of players from the Czech U16 national team (n = 22, age = 15.6 +/- 0.4 years). Speed variables were assessed using the following tests: a) linear speed: 5 m sprint (S5), 10 m sprint (S10) and 20 m flying sprint (F20); b) the agility: agility test 505 with turning on the dominant (A505D) and non-dominant legs (A505N) and the K-test (K) and c) ball velocity after an instep kick with the dominant (IKD) and non-dominant (IKN) legs. Significant dependence was found for S5 compared with S10, F20 vs. A505N, K vs. A505N (p < 0.01) and S10 vs. F20 (p < 0.05). The factor analysis revealed three components of the latent variable - speed. The first component consisted of linear sprint (S10, S20) and also partially consisted of maximum speed (F20). The second component was primarily composed of agility (A505D, A505N, K) and also included maximum speed (F20). The third independent component represented ball velocity after an instep kick (IKD, IKN). The speed variables in youth elite players exhibited significant heterogeneity from the perspective of performance, as determined by the monitored tests. The structure of the speed predisposition indicated that there were three components of speed. The results of our studies support the notion that each component of speed must be considered independently when designing training programmes. PMID- 25031684 TI - The effect of active recovery on power performance during the bench press exercise. AB - The objective of this study was to verify the effect of active and passive recovery on blood lactate concentration and power performance. Twelve male subjects were submitted to a maximal strength test in the the bench press, a maximal aerobic test in the bench step, and to four sets of bench press exercise performed as fast and as long as possible, using 80% of maximal strength when active or passive recovery was performed. The maximum number of repetitions, mean and peak power in eccentric and concentric phases were computed and blood lactate concentration was measured. Comparisons for the variables were made using a two way variance analysis (recovery type and set numer) with repeated measures in the second factor. When significant differences were detected (p < 0.05), a Tukey post-hoc test was used. There was a main effect of set number on maximum number of repetitions (p < 0.05) (1 > 2, 3, and 4; 2 > 3 and 4; 3 > 4). Mean and peak power in both eccentric and concentric phases also differed across sets (1 > 2, 3, and 4; 2 > 4). There was also a main effect for the recovery type, with lower values (p < 0.05) observed for the active recovery compared to the passive one. It can be concluded that active recovery resulted in lower lactate concentration, but did not improve power performance in the bench press exercise. PMID- 25031685 TI - Swimming Stroke Mechanical Efficiency and Physiological Responses of 100-m Backstroke with and without the use of paddles. AB - The use of swimming aids during training contributes to greater swimming efficiency by the improvement of the swimming specific power of the athlete. The purpose of this study was to compare the swimming stroke technical characteristics and the physiological responses of swimming 100-m backstroke, with and without the use of paddles at maximum and sub-maximum intensities at the same swimming speed. Eight swimmers competing at the national level participated in this study. The measurements took place at 4 different sessions. At every session, each participant swam individually one 100-m backstroke swimming trial with or without paddles at the same speed and two levels of intensity (100% and 85% of maximum speed). The results revealed lower stroke length, greater stroke number and gliding length without the use of swimming paddles at both intensities. Blood lactate concentration (10.03+/-2.96 vs. 5.85+/-2.23 mmol/l) and Rating of Perceived Exertion (17.43+/-2.07 vs. 12+/-2.82) were greater without the use of swimming paddles only at 100% of maximum speed. Thus, swimming backstroke with paddles compared to unaided swimming, at a similar speed, showed a greater efficiency at maximal but not at sub-maximal intensity. PMID- 25031686 TI - Somatotype of top-level serbian rhythmic gymnasts. AB - Body size and build influence performance in many sports, especially in those belonging to the group of female aesthetic sports (rhythmic gymnastics, artistic gymnastics, and figure skating). These sports pose high specific demands upon the functional, energy, motor and psychological capacities of athletes, but also upon the size, body build and composition of the performers, particularly of the top level female athletes. The study of the top athletes (rhythmic gymnasts, in this case) may provide valuable information on the morphological requirements for achieving success in this sport. Therefore, the main objective of this research was to analyze the somatotype of 40 Serbian top-level rhythmic gymnasts, aged 13.04+/-2.79, and to form the five age group categories. The anthropometric variables included body height, body mass, the selected diameters, girths and skinfolds, and the Heath-Carter anthropometric somatotype. All of the anthropometric data were collected according to International Biological Programme, and then processed in the Somatotype 1.2. The applied analysis of variance indicated an increase in endomorphic component with age. The obtained results show that the balanced ectomorph is a dominant somatotype, being similar for all of the athletes that took part in the research (3.54-3.24-4.5). These results are in line with the ones obtained in previous studies. PMID- 25031687 TI - Relationship between performance characteristics and the selection process in youth soccer players. AB - The purpose of this study was to establish the anthropometric and physical profiles of elite young soccer players according to their playing position, and to determine their relevance for the selection process. One hundred and fifty-six young male soccer players participated in the study. Players were classified into the following groups: Goalkeepers (n=16), Central Defenders (n=26), External Defenders (n=29), Central Midfielders (n=34), External Midfielders (n=28), and Forwards (n=23). Anthropometric variables of participants (body height, body mass, body mass index, 6 skinfolds, 4 diameters, and 3 perimeters) were measured. Participants performed the Yo-Yo test, sprint tests (30 m flat sprint and Balsom agility test) and 2 jump tests (countermovement jump and the Abalakov test). At the end of the season, the technical staff of the club selected some of the players to continue playing on the same team and the rest were not selected. The results show that heavier and taller outfield players performed better in vertical jumps and sprint tests, whereas leaner outfield players performed better in the Yo-Yo test. Fat percentage of selected players was lower than that of the non-selected ones. The rest of the body components were similar in the selected and non-selected players within each playing position. Moreover, the selected players performed slightly better than the non-selected players in the physical test, but these differences were not statistically significant. PMID- 25031688 TI - Importance of muscle power variables in repeated and single sprint performance in soccer players. AB - This study examined the relationship between lower body power and repeated as well as single sprint performance in soccer players. The performance of nineteen male soccer players was examined. The first testing session included the countermovement jump (CMJL) and the progressive full squat (FSL), both with external loads. Power in the CMJL and FSL was measured with each load that was lifted. The second session included a protocol of 40-m repeated sprints with a long recovery period (2 min). The number of sprints executed until there was a 3% decrease in performance for the best 40-m sprint time was recorded as a repeated sprint index (RSI). The RSI was moderately associated with power output relative to body mass in the CMJL and FSL (r = 0.53/0.54, p <= 0.05). The most and least powerful players (determined by FSL) showed significant differences in the RSI (9.1 +/- 4.2 vs. 6.5 +/- 1.6) and 10 m sprint time (p +/- 0.01). Repeated and single sprints are associated with relatively lower body power in soccer players. PMID- 25031689 TI - Inter-individual Variability in Soccer Players of Different Age Groups Playing Different Positions. AB - THE PURPOSE OF THIS STUDY WAS TWOFOLD: (a) to profile physical characteristics and motor abilities of three age groups of soccer players - under 14 years, 14 17, and over 17, playing different positions - goalkeepers, defenders, midfielders, and forwards; and (b) to examine the inter-individual variability among the players in each age group in all physical and physiological measurements performed in the study. In addition, anthropometric, power, strength, and flexibility tests were administered. Findings showed large inter individual variability in all three age groups and in all playing positions. Differences between playing positions were found only in the 14-17 group (body mass) and in the over-17 group (body height, body mass, fat-free mass, and mean power in the Wingate Anaerobic Test). Due to the observed large inter-individual variability, it was concluded that the findings obtained in the physical and physiological tests should be interpreted with caution when attempting to differentiate between successful and unsuccessful soccer players, as well as when trying to predict future success in soccer. PMID- 25031690 TI - Relationship Between Break-Time Physical Activity, Age, and Sex in a Rural Primary Schools, Wales, UK. AB - The aim of this study was to examine the physical activity during the break-times of primary school children in rural areas, and its relationship with age and sex. 380 children (192 boys and 188 girls; age=9.5+/-1.1 years) participated in the study. Break-time physical activity in the morning and lunch breaks was measured by accelerometry. An ANOVA was used to determine differences by sex in each age group, together with the respective confidence intervals and effect sizes. The results showed that 8-year-olds performed more physical exercise than 11-year olds during the two breaks (p=0.005). For the boys, the 8-year-olds did more physical activity than the 10-year-olds, while, for the girls, those aged 8 and 9 years did more PA than girls aged 11 years (p<0.001). The only difference between boys and girls was for the 10-year-olds (p=0.043), with the boys doing more physical activity. Teachers might find it useful to take these findings into account to design physical activity programmes aimed at increasing the playground physical activity of older children. PMID- 25031691 TI - The elements of executive attention in top soccer referees and assistant referees. AB - The aim of the present study was to compare executive attention of top soccer referees and assistant referees at different levels of professional attainment. The sample consisted of 53 subjects (FIFA and national level) - 30 referees and 23 assistant referees. Executive attention of assistant referees was significantly better than the referees' (p<0.01). Furthermore, extraclass and international referees demonstrated better executive attention than the first league referees (p<0.01). The research results have proved that referees' executive attention differs depending on their function and professional level, as well as indicated that the quality of abilities may influence the number and correctness of decisions made during a game. This elementary cognitive process may be strongly shaped by individual's experience and age. This finding may be instrumental in screening referees and developing criteria for recruiting future referees. PMID- 25031692 TI - Can Achievement Goals be Primed in Competitive Tasks? AB - This study examined whether achievement goal priming effects would be observed within an overtly competitive setting. Male soccer players (N = 66) volunteered to participate in a soccer penalty-kick taking competition during which they took 20 penalty-kicks on 2 occasions. Following a pretest, participants were allocated to 1 of 5 priming conditions. Immediately prior to the posttest, participants in the priming conditions were asked to complete what was presented as an ostensibly unrelated task that took the form of either a computer task (subliminal priming) or wordsearch task (supraliminal priming). Results revealed that priming had no significant influence on performance. PMID- 25031693 TI - Solitary fibrous tumor of the kidney with focus on clinical and pathobiological aspects. AB - Renal solitary fibrous tumor (SFT) is a rare, and a large scale study on this topic is lacking to date. In this article, we summarize the previously reported cases. The symptoms and signs resemble those of renal cell carcinoma, including hematuria, flank/abdominal/lumbar pain and palpable abdominal mass. Grossly, the tumor demonstrates a well-circumscribed solid mass. Microscopically, the tumor consists of fusiform or ovoid spindle cells and a various amounts of collagen bundles with patternless, storiform, or fascicular arrangements with an occasional hemangiopericytomatous pattern. Immunohistochemically, CD34, CD99 and bcl-2 are often detected. Ultrastructurally, tumor cells contain irregular nuclei, prominent Golgi apparatus, branching rough endoplasmic reticulum, variable numbers of mitochondria. Surgical resection is considered to be the gold standard therapy. Most of renal SFT are benign, but cases of approximately 10 to 15% behave in an aggressive fashion. All patients need to be on long-term follow up because clinical behavior is rather unpredictable. As the molecular genetic study of renal SFTs is lacking, a large scale study will be desirable in the future. PMID- 25031694 TI - Indoleamine 2,3-dioxygenase-1 (IDO1) in human endometrial stromal cells induces macrophage tolerance through interleukin-33 in the progression of endometriosis. AB - In the peritoneal fluid, macrophages and their secretory cytokines are essential for endometriosis, but the factors that favor their involvement in the endometriosis-associated inflammatory response are still elusive. Given the anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) and its potentially important roles in immune modulation, we aimed to determine the effects of IDO1 in ESCs on macrophages and the mechanism of those effects. Normal ESCs and ectopic ESCs transfected with the SD11-IDO1 shRNA (short hairpin RNA) or vector-only plasmid SD11 were subsequently co cultured with peripheral blood (PB)-derived monocytes (PBMC)-driven macrophages directly and indirectly. Cytokine production was determined by analyzing the supernatant of the co-culture unit by enzyme-linked immunosorbent assay (ELISA). The phenotypes and the phagocytic ability of the macrophages were determined by flow cytometry. Compared to normal ESCs, the PBMC-driven macrophages co-cultured with ectopic ESCs displayed lower phagocytic ability. Additionally, macrophages co-cultured with ectopic ESCs exhibited higher levels of CD163 and CD209 and lower levels of HLA-DR and CD11c. Moreover, both the intracellular expression and extracellular secretion of interleukin-10 (IL-10) and transforming growth factor beta1 (TGF-beta1) were significantly increased, while that of IL-12p70 was decreased in macrophages after being co-cultured with ectopic ESCs. However, there was no significant difference in macrophage phagocytic ability, immunophenotype or cytokine secretion between the direct and indirect co-culture units. Reversely, SD11-IDO1 shRNA transfection of ectopic ESCs could abrogate the decreased phagocytic ability and alternative activation of macrophages in ectopic ESC-macrophage co-culture unit, suggesting that higher IDO1 in ectopic ESCs was indispensable for the induction of macrophage tolerance. Furthermore, the decrease in phagocytic macrophages and alternatively activated macrophages induced by IDO1 in ectopic ESCs was reversed by the addition of an IL-33 inhibitor, that is, soluble ST2 (sST2). Therefore, through the activation of IL 33, the increased expression of IDO1 in ectopic ESCs contributed to the truncated phagocytic ability of macrophages in endometriosis. PMID- 25031695 TI - Decreased expression of a novel lncRNA CADM1-AS1 is associated with poor prognosis in patients with clear cell renal cell carcinomas. AB - The clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinomas. Rapidly accumulating studies show that the long non-coding RNAs (lncRNAs) may play essential roles in cancers. In this study, we investigated the expression pattern of a novel lncRNA CADM1-AS1 in ccRCC by quantitative real time PCR. The results showed that CADM1-AS1 expression was down-regulated in tumor tissues in 64 patients with ccRCC compared with adjacent non-tumor tissues. Furthermore, the expression of CADM1-AS1 was positively correlated with the expression of mRNA CADM1 in ccRCC specimens (R = 0.611, P <0.0001). Decreased CADM1-AS1 expression was correlated with the progression of AJCC stage (P = 0.039) and worse survival of ccRCC patients (P <0.05). Also, multivariate analysis identified low CADM1-AS1 expression as an independent prognostic factor for ccRCC (P <0.001, HR = 0.211, 95% CI = 0.088-0.504). In addition, we used small interfering RNA (siRNA) to evaluate the biological function of CADM1-AS1 in vitro. The results showed that CADM1-AS1 expression was positively associated with CADM1 mRNA expression in 786-O cells and ACHN cells. Functional experiments demonstrated markedly enhanced ability of growth and migration, and reduced apoptotic rate in CADM1-AS1 knocking down in 786-O cells. Conversely, overexpression of CADM1-AS1 showed a significant decrease in growth and migration, along with an increase in apoptotic rate in ACHN cells. In conclusion, our data demonstrated CADM1-AS1 is a new tumor suppressor in ccRCC which regulates cell proliferation, apoptosis and migration via the expression pattern of "CADM1-AS1/CADM1 mRNA gene pairs". CADM1-AS1 may be a potential biomarker and therapeutic target in patients with ccRCC. PMID- 25031696 TI - Characterization of karyopherins in androgen receptor intracellular trafficking in the yeast model. AB - BACKGROUND: Mechanisms regulating androgen receptor (AR) subcellular localization represent an essential component of AR signaling. Karyopherins are a family of nucleocytoplasmic trafficking factors. In this paper, we used the yeast model to study the effects of karyopherins on the subcellular localization of the AR. METHODS: Yeast mutants deficient in different nuclear transport factors were transformed with various AR based, GFP tagged constructs and their localization was monitored using microscopy. RESULTS: We showed that yeast can mediate androgen-induced AR nuclear localization and that in addition to the import factor, Importinalpha/beta, this process required the import karyopherin Sxm1. We also showed that a previously identified nuclear export sequence (NES(AR)) in the ligand binding domain of AR does not appear to rely on karyopherins for cytoplasmic localization. CONCLUSIONS: These results suggest that while AR nuclear import relies on karyopherin activity, AR nuclear export and/or cytoplasmic localization may require other undefined mechanisms. PMID- 25031697 TI - Effect of Nrf2 on rat ovarian tissues against atrazine-induced anti-oxidative response. AB - The environmental persistence and bioaccumulation of herbicide atrazine may pose a significant threat to human health. In this experiment, Wistar rats were treated by 5, 25 and 125 mg.kg(-1) atrazine respectively for 28 days, and the oxidative stress responses as well as the activations of Nrf2 signaling pathway in ovarian tissues induced by atrazine were observed. The results showed that after be treated by atrazine, the proportion of atretic follicles in the rat ovary were increased, the contents of NO and MDA in the tissue homogenates were increased, the over-expressed Nrf2 transferred into the nuclei and played an antioxidant role by up-regulated the expression of II phase detoxifying enzymes such as HO1 and NQO1 and the expression of antioxidant enzymes such as CAT, SOD and GSH-PX. PMID- 25031698 TI - Comparative analysis of arterial spin labeling and dynamic susceptibility contrast perfusion imaging for quantitative perfusion measurements of brain tumors. AB - We comparatively analyzed the difference between three-dimensional arterial spin labeling (3D-ASL) and the conventional dynamic susceptibility contrast (DSC) perfusion imaging in the setting of assessing brain tumor perfusion in 28 patients with proved brain tumors. All patients were scheduled with standard MRI, 3D-ASL and DSC scannings on a GE DISCOVERY MR 750 system. Maximal relative tumor perfusion was obtained based on the region of interest (ROI) method. A close correlation between 3D-ASL and DSC perfusion imaging was noted as manifested by the absence of significant differences between ASL nTBF and DSC nTBF when normalized to M (mirror region) and GM (contralateral gray matter). However, ASL nTBF was found to be highly correlated with DSC nTBF and DSC nTBV when normalized to M, GM and WM (contralateral normal white matter). Together, our data support that 3D-ASL possesses the potential to be a noninvasive alternate for DSC-MRI in assessing brain tumor perfusion in the setting of treatment prognosis and metastasis, particularly for those patients with renal failure and patients required for collection of follow up information. PMID- 25031699 TI - Gnathic osteosarcomas, experience of four institutions from Turkey. AB - Osteosarcoma is the most frequent primary gnathic sarcoma. Neither the etiology nor the variables effecting the prognosis are fully known due mostly to the rarity of gnathic osteosarcomas. To date a considerable number of clinicopathologic features have been suggested in the evaluation of gnathic osteosarcomas. Still there is a need to experience on several aspects of management. The aim of this study is to report a series of 33 cases of osteosarcoma involving either mandible or maxilla. The clinical, radiological and histopathological features of our cases have usually been non-specific and the most frequent provisional diagnosis were "benign fibroosseous lesion, abnormal mass, giant cell granuloma and benign bone tumor". This non-specific presentation of osteosarcomas of the jaws is compatible with those reported previously. A combined clinical, radiological and pathological study is essential in arriving at the correct diagnosis. PMID- 25031700 TI - Brain edema and protein expression of c-Fos and c-Jun in the brain after diffused brain injury. AB - OBJECTIVE: To investigate brain edema and protein expression of c-Fos and c-Jun in brain after diffuse brain injury, and to investigate the pathological change after brain injury, which may provide evidence for the clinical treatment of diffused brain injury. METHODS: Marmarou method was used to establish the diffuse brain injury in rats. RESULTS: After diffused brain injury, brain water content increased at 1 h, reached the peak at 1 d and remained at a high level at 7 d when compared with control group. One day after injury, diffuse subarachnoid hemorrhage was observed in the brain. HE staining showed vascular swelling and bleeding at the cortex and corpus callosum at 1 d. beta-APP expression was found at the brainstem, hippocampus, thalamus, corpus callosum and periventricular regions. Pathological examination of ultrathin sections showed evidence edema and fracture of axons at 3 d after brain injury. The brain injury caused severe cerebral ischemia. The c-Fos and c-Jun expression increased at 1 h. The c-Fos expression peaked at 3 h (P < 0.05), then reduced, reached a maximal level again at 3 d (P < 0.05), and reduced significantly at 7 d but remained at a higher level when compared with control group (P < 0.05). The number of c-Jun positive cells peaked at 6 h (P < 0.05), then reduced, reached a maximal level again at 3 d and reduced markedly but still remained at a higher level when compared with control group (P < 0.05). CONCLUSION: After diffuse brain injury, brain water content and c-Fos/c-Jun expression change over time. PMID- 25031701 TI - Curcumin induces apoptosis in breast cancer cells and inhibits tumor growth in vitro and in vivo. AB - Curcumin has shown therapeutic and/or adjuvant therapeutic effects on the treatment of some patients with breast cancer. However, its mechanisms of action are largely unknown. This study was designed to investigate its antitumor effect and underlying mechanisms in human breast cancer MDA-MB-231 and MCF-7 cells. The MTT assay was used to evaluate cell viability, and flow cytometry, acridine orange staining and transmission electron microscopy were used to detect apoptosis for cultured cells. The protein expression in cells was evaluated by western blot analysis. Breast tumors were established by subcutaneous injection of MDA-MB-231 cells in nude BALB/c mice, and curcumin was administered to the mice. The size of tumors was monitored and the weight of tumors was examined. The exposure of breast cancer cells to curcumin resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner. We also found that the expression of Bcl-2 protein decreased and the expression of Bax protein increased which lead to an increase of the Bax/Bcl-2 ratio. In mice bearing MDA-MB-231 xenograft tumors, administration of curcumin showed a significant decrease of tumor volumes and tumor weight compared with the control. Our results showed that curcumin exhibited antitumor effects in breast cancer cells with an induction of apoptosis. PMID- 25031702 TI - Astrocytic expression of cannabinoid type 1 receptor in rat and human sclerotic hippocampi. AB - Cannabinoid type 1 receptor (CB1R), which is traditionally located on axon terminals, plays an important role in the pathology of epilepsy and neurodegenerative diseases by modulating synaptic transmission. Using the pilocarpine model of chronic spontaneous recurrent seizures, which mimics the main features of mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) in humans, we examined the expression of CB1R in hippocampal astrocytes of epileptic rats. Furthermore, we also examined the expression of astrocytic CB1R in the resected hippocampi from patients with medically refractory mesial TLE. Using immunofluorescent double labeling, we found increased expression of astrocytic CB1R in hippocampi of epileptic rats, whereas expression of astrocytic CB1R was not detectable in hippocampi of saline treated animals. Furthermore, CB1R was also found in some astrocytes in sclerotic hippocampi in a subset of patients with intractable mesial TLE. Detection with immune electron microscopy showed that the expression of CB1R was increased in astrocytes of epileptic rats and modest levels of CB1R were also found on the astrocytic membrane of sclerotic hippocampi. These results suggest that increased expression of astrocytic CB1R in sclerotic hippocampi might be involved in the cellular basis of the effects of cannabinoids on epilepsy. PMID- 25031703 TI - A novel long non-coding RNA FOXCUT and mRNA FOXC1 pair promote progression and predict poor prognosis in esophageal squamous cell carcinoma. AB - Accumulating evidences demonstrated that many long non-coding RNAs (lncRNAs) can cooperate with the adjacent coding genes, forming into "lncRNA-mRNA gene pairs" in multiple biological cellular processes. Here, we showed that a novel long non coding RNA FOXCUT (FOXC1 promoter upstream transcript) and its neighboring gene FOXC1 played a similar important role in the oncogenesis and progression of esophageal squamous cell carcinoma (ESCC). In this study, the expression of FOXCUT/FOXC1 was measured in 82 ESCC tissues and adjacent noncancerous tissues by real-time quantitative PCR (qPCR). The prognostic significance of the lncRNA-mRNA gene pair was evaluated using Kaplan-Meier survival analysis and log-rank test. Cell biological experiments were performed in ESCC cell lines to explore their functions in tumor progression. Notably elevated FOXCUT and FOXC1 expression levels were observed in cancerous tissues compared to adjacent noncancerous tissues (86.6% and 84.1%, respectively; P < 0.01), showing strong correlations with poor differentiation, advanced lymph node classification and metastasis (P < 0.05). Moreover, patients with upregulated FOXCUT or FOXC1 experienced a significantly worse prognosis than those with downregulated FOXCUT or FOXC1 (P < 0.001 and P = 0.014, respectively). In addition, the expression of FOXCUT was positively correlated with expression of FOXC1 in ESCC specimens. And the expression of FOXC1 was also decreased as the FOXCUT expression was silenced by siRNA. Assays in vitro demonstrated that knockdown of either FOXCUT or FOXC1 remarkably inhibited cell proliferation, colony formation, migration, invasion in ESCC cells. In conclusion, FOXCUT may be functionally involved in the tumor progression and survival of ESCC patients, at least in part, by modulating FOXC1. FOXCUT and FOXC1 may function as a lncRNA-mRNA gene pair, which may represent a potential prognostic biomarker and therapeutic target for ESCC patients. PMID- 25031705 TI - PDGFR-beta (+) perivascular cells from infantile hemangioma display the features of mesenchymal stem cells and show stronger adipogenic potential in vitro and in vivo. AB - Infantile hemangioma, a common benign tumor of infancy, grows quickly in the first year of life, and then regresses slowly to fibrofatty tissue in childhood. The accumulation of fibrofatty tissue in hemangioma involution indicates adipogenesis during this period. Perivascular cells (PCs) from multiple organs display multi-lineage differentiation, including adipogenesis. So we supposed that PCs in hemangioma may contribute to the adipogenesis in the involution. In this study, PDGFR-beta (+) PCs was isolated from hemangioma tissue (hemangioma derived perivascular cells, Hem-PCs) by fluorescence-activated cell sorter. In vitro, Hem-PCs showed fibroblast-like morphology. Immunofluorescence staining and flow cytometry showed Hem-PCs expressed MSCs markers CD105, CD90, CD29 and vimentin, pericyte markers alpha-SMA and PDGFR-beta, stem cell marker CD133, and the adipogenic transcription factor PPAR-gamma, but not hematopoietic/endothelial markers CD45, CD34, CD31, and flt-1. In vitro inductions confirmed multi-lineage differentiation of Hem-PCs, especially strong adipogenic potential. Then a murine model was established to observe in vivo differentiation of Hem-PCs by subcutaneous injection of cells/Matrigel compound into nude mice. The results showed Hem-PCs differentiated into adipocytes in vivo. To the best of our knowledge, this is the first study reporting the isolation of multipotential PDGFR-beta (+) PCs from hemangioma, and observing their adipogenic differentiation in vivo. PCs may be the cellular basis of adipogenesis in hemangioma involution, and may be the target cells of adipogenic induction to promote hemangioma involution. PMID- 25031704 TI - A fiber-modified adenovirus co-expressing HSV-TK and Coli.NTR enhances antitumor activities in breast cancer cells. AB - Breast cancers especially in late and metastatic stages remain refractory to treatment despite advances in surgical techniques and chemotherapy. Suicide gene therapy based on adenoviral technology will be promising strategies for such advanced diseases. We previously showed that co-expression of herpes simplex virus thymidine kinase (HSV-TK) and Escherichia coli nitroreductase (Coli.NTR) by an hTERT-driven adenovirus vector resulted in additive anti-tumor effects in breast cancer cells in vitro and in vivo. As many tumor tissue and cancer cells express low level of coxsackie-adenovirus receptor (CAR), which is the functional receptor for the fiber protein of human adenovirus serotype 5 (Ad5), novel Ad5 vectors containing genetically modifi ed fiber are attractive vehicles for achieving targeted gene transfer and improving suicide gene expression in these cancer cells. In the present study, we first built a simplified Ad5 vector platform for fiber modification and quick detection for gene transfer. Then a fiber-modified adenovirus vector containing an RGD motif in the HI loop of the fiber knob was constructed. After recombined with HSV-TK and Coli.NTR gene, this fiber-modified Ad5 vector (Ad-RGD-hT-TK/NTR) was compared with that of our previously constructed Ad5 vector (Ad-hT-TK/NTR) for its therapeutic effects in human breast cancer cell lines. The anti-tumor activity of Ad-RGD-hT-TK/NTR was significantly enhanced compared with Ad-hT-TK/NTR both in vitro and in vivo. This new vector platform provided a robust and simplified approach for capsid modification, and the fiber-modified Ad5 with double suicide genes under the control of hTERT promoter would be a useful gene therapy strategy for breast cancer. PMID- 25031706 TI - Establishment and characterization of a new highly metastatic human osteosarcoma cell line derived from Saos2. AB - Osteosarcoma is the most common primary malignancy of bone in adolescents and young adults. There is a shortage of tumorigenic and highly metastatic human osteosarcoma cell lines that can be used for metastasis study. Here we establish and characterize a highly metastatic human osteosarcoma cell line that is derived from Saos2 cell line based on bioluminescence. The occasional pulmonary metastatic cells developed from Saos2 were isolated, harvested, characterized and named Saos2-l. The parental Saos2 and Saos2-l cells were further characterized both in vitro and in vivo. Results showed that Saos2-l cells demonstrated increased cell adhesion, migration and invasion compared to the parental Saos2 cells. Conversely, Saos2-l cells grew at a slightly slower rate than that of the parental cells. When injected into nude mice, Saos2-l cells had a greater increase in developing pulmonary metastases compared to the parental Saos2 cells. Further transcriptional profiling analysis revealed that some gene expression were up-regulated or down-regulated in the highly metastatic Saos2-l cells, indicating possible influencing factors of metastasis. Thus, we have established and characterized a highly metastatic human osteosarcoma cell line that should serve as a valuable tool for future investigations on the pathogenesis, metastasis and potential treatments of human osteosarcoma. PMID- 25031707 TI - Androgen deprivation therapy induces androgen receptor-dependent upregulation of Egr1 in prostate cancers. AB - Early growth response gene-1 (Egr1) has a crucial function in the development and progression of prostate cancer. However, whether Egr1 contributes to the transition of advanced androgen-independent prostate cancer (AIPC) from androgen dependent prostate cancer (ADPC) remains largely unknown. To the best of our knowledge, through immunohistochemical staining methods, we were the first to identify that Egr1 is more highly expressed in AIPC clinical specimens than in androgen-dependent prostate cancer (ADPC). An in vitro study with quantitative RT PCR and Western blot demonstrated that Egr1 also has a higher expression in androgen-independent PC3 cells than in the androgen-dependent LNCaP cells. Egr1 expression in LNCaP cells was significantly upregulated during the androgen deprivation treatment (ADT) and was re-downregulated through the addition of dihydrotestosterone. Although no variation in PC3 cells was identified, Egr1 responded to dihydrotestosterone and flutamide in the androgen receptor (AR) transfected PC3 cells. Further investigation with Egr1 agonist and specific siRNA targeting Egr1 revealed that Egr1 upregulation or downregulation was accompanied by a change in inhibitors of differentiation and DNA binding-1 (Id1) in the same direction in both LNCaP and PC3 cells. The variation is shown to be negatively regulated by androgen through AR during ADT. Our data suggested that upregulated Egr1 might partially contribute to the emergence of AIPC after prolonged ADT. This study also elucidated the potential mechanism underlying Id1 participation in the progression of prostate cancer. Understanding the key molecular events in the transition from ADPC to AIPC may provide new therapeutic intervention strategies for patients with AIPC. PMID- 25031708 TI - Adiponectin exerts antiproliferative effect on human placenta via modulation of the JNK/c-Jun pathway. AB - To determine the effects of adiponectin on human placenta during gestational diabetes mellitus (GDM) and on high glucose (HG)-induced BeWo cell proliferation. We examined the expression levels of adiponectin in control and GDM placenta using quantitative real-time PCR, Western blot, and immunohistochemistry (IHC). Cell proliferation and viability were assessed using a colorimetric assay (cell counting kit-8), PCNA immunocytochemical staining, and Western blot analysis of cyclin D1. Transfection of siRNA against c-jun was performed using Lipofectamine 2000. Cell cycle analysis was performed using propidium iodide staining and flow cytometry. Results show a decreased expression of adiponectin and an increased degree of trophoblast cell proliferation in GDM placenta compared to the normal placenta. Similarly, HG can promote BeWo cell proliferation that is associated with adiponectin down-regulation. This proliferation could be depressed by addition of exogenous adiponectin, i.e. adiponectin exerts antiproliferative effects on HG-induced trophoblast cells. Adiponectin suppresses the HG-induced BeWo cell proliferation by inhibiting the activation of JNK/c-jun. In conclusion, adiponectin inhibits HG-induced proliferation of BeWo cells through down regulation of JNK/c-jun phosphorylation. PMID- 25031709 TI - Sub-chronic lead and cadmium co-induce apoptosis protein expression in liver and kidney of rats. AB - The combined subchronic effects of exposure to lead acetate and cadmium chloride on apoptosis protein expression were detected in the liver and kidney of rats to investigate the hazards of environmentally relevant, low-dose exposure to these compounds. The TUNEL assay showed that there were increased numbers of apoptotic cells. Immunohistochemical tests showed increased numbers of positive cells under Bax and caspase-3 protein detection and decreased Bcl-2 protein. Furthermore, mitochondrial injury and increased numbers of apoptotic cells with condensed nuclei were observed by TEM. These results suggested that low-dose exposure to Pb and Cd can cause significant hepatic and renal apoptosis and finally impair their function. Hepatic and renal apoptosis induced by low-dose exposure is associated with mitochondrial injury and changes in levels of apoptogenic proteins, such as Bcl-2, Bax, and caspase-3. PMID- 25031710 TI - TGF-beta1/Smad signaling, MMP-14, and MSC markers in arterial injury: discovery of the molecular basis of restenosis. AB - Transforming growth factor (TGF)-beta1 has been suggested to be involved in the recruitment of mesenchymal stem cells (MSCs) following arterial injury, but the role of downstream signaling and the contribution of the recruited MSCs are still unknown. The release of latent TGF-beta1 from latent TGF-binding protein (LTBP) by matrix metallopeptidase-14 (MMP-14) proteolysis was demonstrated, which contributed to neointima formation, but the relationship between MMP-14 and activated TGF-beta1 in the process of restenosis has yet to be explored. In this study, we observed the change in expression and distribution of TGF-beta1/Smad signaling pathway proteins, MMP-14, and MSC markers in the process of neointima formation using a rat model for balloon-induced carotid artery injury. We found that the increase in downstream Smad signaling was consistent with the elevation of TGF-beta1 levels and MSCs accumulated at the lumen side of neointima. Furthermore, the activation of MMP-14 in the injured artery was preceded by the increase in TGF-beta1 levels. Herein, we conclude that MMP-14 induces an elevation in the levels of TGF-beta1/Smad signaling proteins in injured arteries, and that MSCs are recruited by TGF-beta1/Smad signaling and MMP-14, possibly differentiating into vascular smooth muscle cell (VSMC)-like cells and VSMC via modulation of TGF-beta1/Smads signaling and MMP-14. PMID- 25031711 TI - High-level expression of HOXB13 is closely associated with tumor angiogenesis and poor prognosis of hepatocellular carcinoma. AB - Homeobox B13 (HOXB13) is generally considered as a crucial regulator of terminal cellular differentiation. More recently, the absent or aberrant expression of HOXB13 has been increasingly implicated in cancer development and metastasis. However, the expression of HOXB13 in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis and prognosis still remain unclear. The aim of the study was to evaluate the expression of HOXB13 in patients with HCC and explore the relationship of HOXB13 expression with clinicopathologic factors, tumor angiogenesis and prognosis. Immunohistochemistry was performed to determine the expression of HOXB13 in HCC and corresponding paracarcinomatous tissues from 72 patients. Vascular endothelial growth factor (VEGF) and CD31 were only examined in tissues of HCC patients mentioned above. The results showed that HOXB13 expression was significantly (P <0.001) higher in HCC (69.4%) than that in surrounding non-tumor tissues (26.4%), positively correlated with tumor VEGF (P <0.001) and microvessel density (MVD) (P = 0.013). Besides, it was associated with tumor capsula (P <0.001), vascular invasion (P <0.001), Edmondson grade (P <0.001), AFP (P = 0.007) and TNM stage (P <0.001). Univariate analysis showed poorer overall survival (OS) rate and disease free survival (DFS) rate in patients expressing higher levels of HOXB13. HOXB13 was also found to be an independent poor prognostic factor of OS and DFS in multivariate analysis. Taken together, our results suggest that increased HOXB13 expression is associated with tumor angiogenesis and progression in HCC and may function as a promising biomarker for unfavorable prognosis of HCC. PMID- 25031712 TI - MAGE-A3 is highly expressed in a cancer stem cell-like side population of bladder cancer cells. AB - Cancer stem cells (CSCs), which have the abilities of tumor-initiating, self renewal and differentiation, are thought to cause post-therapeutic recurrence and the progression of cancer. However, CSCs are commonly resistant to current cancer therapies including chemotherapy and radiotherapy. In this study, we isolated cancer stem celllike side population (SP) cells from human bladder cancer cell line SW780 by a flow cytometry-based SP technique. SP cells were only about 3.6% of SW780 cells and showed higher expression of ATP-binding cassette sub-family G member 2 (ABCG2) and CD133. In vitro assay of tumor sphere growth as well as in vivo assay of xenograft transplantation confirmed the higher tumorigenicity of isolated SP cells. These data indicated that SP cells were enriched with CSCs of bladder cancer. Furthermore, we determined the expression of melanoma antigen family A, 3 (MAGEA3), one of the most studied cancer testis (CT) antigens, in these SP and main population (MP) cells derived from SW780 cells. SW780 SP cells representing CSCs of bladder cancer showed an up-regulated expression of MAGE-A3 and a positive coexpression of MAGE-A3 and CD133, indicating that MAGE-A3 was a novel CT antigen preferentially expressed in the CSCs of bladder cancer. In summary, our findings confirmed the existence of cancer stem cell-like SP cells in bladder cancer cells, and further indicated that MAGE-A3 is a novel CSC antigen and therefore may serve as an immunotherapeutic target for CSCs of bladder cancer. PMID- 25031713 TI - Oncogenic roles of carbonic anhydrase IX in human nasopharyngeal carcinoma. AB - Carbonic anhydrase IX (CA IX), a hypoxia-inducible protein in tumors, has been shown to be valuable for the prognosis of nasopharyngeal carcinoma (NPC). However, the function and mechanism of CA IX has been not explored in NPC. Here, we found that CA IX was detected at higher levels in NPC cells and tissues than their corresponding partners. Furthermore, the cell growth, migration and invasion in vitro were altered with shRNA or overexpression of CA IX in NPC cells. More importantly, the metastatic ability of NPC cells stably expressing CA IX was significantly enhanced using the hepatic metastasis model of nude mice in vivo. Finally, the mTOR pathway was indicated to be involved in such effects of CA IX on NPC. This is the first evidence that CA IX may promote the NPC metastasis to potentially be a therapeutic target for NPC, and that the inhibitory molecules of CA IX and/or the mTOR pathway alone or combination with both may be worth to have a clinical trial for the patients with NPC. PMID- 25031714 TI - Stability of preclinical models of aggressive renal cell carcinomas. AB - Renal-cell carcinomas (RCC) are often resistant to conventional cytotoxic agents. Xenograft models are used for in vivo preclinical studies and drug development. The validity of these studies is highly dependent on the phenotypic and genotypic stability of the models. Here we assessed the stability of six aggressive human RCC xenografted in nude/NMRI mice. We compared the initial samples (P0), first (P1) and fifth (P5) passages for the following criteria: histopathology, immunohistochemistry for CK7, CD10, vimentin and p53, DNA allelic profiles using 10 microsatellites and CGH-array. Next we evaluated the response to sunitinib in primary RCC and corresponding xenografted RCC. We observed a good overall stability between primary RCC and corresponding xenografted RCC at P1 and P5 regarding histopathology and immunohistochemistry except for cytokeratin 7 (one case) and p53 (one case) expression. Out of 44 groups with fully available microsatellite data (at P0, P1 and P5), 66% (29 groups) showed no difference from P0 to P5 while 34% (15 groups) showed new or lost alleles. Using CGH-array, overall genomic alterations at P5 were not different from those of initial RCC. The xenografted RCC had identical response to sunitinib therapy compared to the initial human RCC from which they derive. These xenograft models of aggressive human RCC are clinically relevant, showing a good histological and molecular stability and are suitable for studies of basic biology and response to therapy. PMID- 25031715 TI - Alternative splicing in the variable domain of CaMKIIbeta affects the level of F actin association in developing neurons. AB - The Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) beta has an essential function in dendritic spines via binding to and reorganization of the actin cytoskeleton during plasticity events not shared by CaMKIIalpha isoform. CaMKIIbeta and CaMKIIalpha isoforms have remarkable structural differences within the variable region. Three exons (E1, E3, and E4) are present in CaMKIIbeta but not in CaMKIIalpha gene. Four splice variants of CaMKIIbeta isoforms (CaMKIIbeta, beta', betae and beta'e) were discovered in embryonic and adult brains. Exons E1 (lacked in betae and beta'e) and E4 (lacked in beta' and beta'e) are subject to differential alternative splicing. We hypothesized that the sequences encoded by exons E1, E3, and/or E4 are involved in CaMKIIbeta-specific bundling to the F actin cytoskeleton. We tested the colocalization and association of these CaMKIIbeta variants within an F-actin-rich structure (microspike) in CaMKIIalpha free embryonic day 18 (E-18) rat cortical neurons. Our results showed that CaMKIIbeta and CaMKIIbeta' containing exon E1 displayed an association with F actin, while CaMKIIbetae and CaMKIIbeta'e lacking E1 did not. Moreover, CaMKIIbeta' lacking exon E4 but having E1 showed decreased actin bindingcapacity compared to WT CaMKIIbeta. This suggested E1 is required for the association between CaMKIIbeta and F-actin, while E4 assists CaMKIIbeta to associate with F actin better. Thus, alternative splicing of CaMKIIbeta variants in developing neurons may serve as a developmental switch for actin cytoskeleton-associated isoforms and therefore correlated with dendritic arborization and synapse formation during LTP. PMID- 25031716 TI - Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma. AB - PURPOSE: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC. METHODS AND RESULTS: In this study, we examined ALDH1A1 expression by immunohistochemistry including 406 cases of primary CRC with corresponding adjacent mucosa, with confirmation of real-time PCR and Western blotting. We found that the expression patterns of ALDH1A1 were heterogeneous in the CRC and corresponding adjacent tissues. We defined the ratio of ALDH1A1 level in adjacent mucosa to that in tumor tissues as RA/C and found that the capabilities of tumor invasion and metastasis in the tumors with RA/C < 1 were significantly higher than those with RA/C >= 1. Follow-up data showed the worse prognoses in the CRC patients with RA/C < 1. For understanding the underlying mechanism, the localization of beta-catenin was detected in the CRC tissues with different patterns of ALDH1A1 expression from 221 patients and beta-catenin was found preferentially expressed in cell nuclei of the tumors with RA/C < 1 and ALDH1A1(high) expression of HT29 cell line, indicating that nuclear translocation of beta-catenin might contribute to the increased potentials of invasion and metastasis. CONCLUSION: Our results indicate that RA/C is a novel biomarker to reflect the distinct expression patterns of ALDH1A1 for predicting metastasis and prognosis of CRC. PMID- 25031717 TI - Central circuits regulating the sympathetic outflow to lumbar muscles in spinally transected mice by retrograde transsynaptic transport. AB - Despite considerable interest in the mechanisms that control the hyperalgesia associated with muscle inflammation, the CNS descending pathways that coordinate autonomic circuits regulating lumbar muscles are not adequately understood. Here we used both pseudorabies virus (PRV)-614 retrograde transsynaptic tracing and spinally transected method in 33 C57BL/6J mice to map the polysynaptic pathways between lumbar muscle and CNS. Tissues were processed for dual-label immunocytochemical detection between PRV-614 and tryptophan hydroxylase (TPH) or tyrosine hydroxylase (TH)-expressing neurons in CNS. In intact mice, PRV-614 was transported to the intermediolateral column (IML) and ventral horn (VH) of spinal cord, with subsequent transport to many brain regions, including the medullary raphe nuclei, rostral ventrolateral medulla (RVLM), A5 cell group regions (A5), locus coeruleus (LC), the medullary and pontine reticular formation nucleus (MRN and PRN), paraventricular nucleus of the hypothalamus (PVN), and other central sites. However, PRV-614 in spinally transected mice produced retrograde infection of IML, with subsequent transport to main brain regions that have been shown to contribute to regulating sympathetic circuits, including RVLM, Lateral paragigantocellular reticular nucleus (LPGi), A5, LC, and PVN, whereas PRV-614 labeling in VH and MRN was eliminated in almost every case. In above five brain regions, dual-labeling immunocytochemistry showed coexpression of PRV-614/TPH and PRV-614/TH immunoreactive (IR) neurons involved in these regulatory circuits. Our results reveal a hierarchical organization of central autonomic circuits controlling the lumbar muscles, thus providing neuroanatomical substrates for the central catecholaminergic and serotonergic system to regulate the lumbar muscles. PMID- 25031718 TI - HOXA9 regulates angiogenesis in human hypertrophic scars: induction of VEGF secretion by epidermal stem cells. AB - Hypertrophic scars are fibroproliferative disorders of excessive wound healing after skin injury. Vascular endothelial growth factor (VEGF)-induced angiogenesis plays a major role in fibrogenesis and hypertrophic scar formation. Over recent years, there has been a major interest in homeobox gene regulation of VEGF-VEGFR mediated angiogenesis in dermal tissue. In the current study, we investigated the role of homeobox genes in the epidermis, for their role in angiogenesis, with a focus on epidermal-mesenchymal interactions. As epidermal stem cells (ESCs) have a central role in epidermal homeostasis, we tested the hypothesis that these cells play a key role in the pathogenesis of hypertrophic scars through the HOXA9 VEGF/VEGFR signaling pathways. We found significant differences in the expression of homeobox A9 in hyperplastic scar tissue during different phases of development. These differences coincided with similar regulations in VEGF expression and with the distribution of ESCs. HOXA9 is expressed in cultured human ESCs in vitro. Antisense suppression of HOXA9 expression was found to suppress VEGF levels in ESCs. Together these findings indicate that homeobox A9 regulates the expression of VEGF in ESCs. PMID- 25031719 TI - IMP3 expression is associated with epithelial-mesenchymal transition in breast cancer. AB - IMP3 plays an important role in tumor invasion and metastasis, to which epithelial to mesenchymal transition (EMT) also contributes. The purpose of this study was to investigate whether IMP3 can regulate invasion and metastasis through EMT in breast cancers. The protein expression levels of IMP3 and EMT markers were analyzed by immunohistochemistry in 180 paraffin-embedded human breast tissue samples. There was an inverse correlation of IMP3 with E-cadherin protein expression (P = 0.042). IMP3 expression directly correlated with both Slug (P = 0.004) and vimentin (P < 0.001). Changes in E-cadherin, vimentin, and Slug mRNA and protein levels were examined by quantitative real-time reverse polymerase chain reaction (qRT-PCR) and western blotting. Overexpression of IMP3 reduced the expression of E-cadherin and upregulated Slug and vimentin in transfected cells. In contrast, knocking down IMP3 had the opposite expression of the three proteins. Ribo-immunoprecipitation qPCR revealed that IMP3 binds Slug mRNA directly. In a transwell assay, overexpression of Slug rescued the cell migration and invasion caused by silencing IMP3 in MDA-MB-231 cells. On the other hand, knockdown of Slug in T47D-IMP3 cells could also have the opposite change. Our results strengthen the association of IMP3 with the regulation of EMT. Slug is a functional target of IMP3. IMP3 could therefore promote invasion and migration through the EMT in breast cancer cells. PMID- 25031720 TI - Overexpression of sineoculis homeobox homolog 1 predicts poor prognosis of hepatocellular carcinoma. AB - High expression levels of the human sineoculis homeobox homolog 1 (SIX1) gene have been correlated with numerous human malignancies. The SIX1 protein is involved in chromatin reconstruction and gene transcription, and plays an important role in cell apoptosis. This study explores the role of SIX1 in tumor progression and in the prognostic evaluation of hepatocellular carcinoma (HCC). Real-time PCR, Western blotting analysis, immunofluorescence (IF) staining, and immunohistochemistry (IHC) were performed to examine SIX1 expression in HCC cell line/tissues compared with adjacent non-tumor and normal liver tissues. Statistical analysis was applied to evaluate the correlation between SIX1 overexpression and the clinicopathological features of HCC. Survival rates were calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was analyzed using the Cox proportional hazard models. The SIX1 protein was detected in 80.9% of HCCs, which was significantly higher than that in either adjacent non tumor liver or normal liver tissues (P < 0.01). SIX1 overexpression was positively correlated with tumor size, pTNM stage and venous infiltration. Moreover, the 5-year survival rate of patients with high expression of SIX1 was significantly lower than that of patients with low SIX1 expression. Multivariate analysis suggested that pTNM stage and SIX1 protein expression were independent risk factors for survival in HCC. In conclusion, SIX1 plays an important role in the progression of HCC. High level expression of SIX1 is an independent poor prognostic factor of HCC. PMID- 25031721 TI - Effects of vitamin D on renal fibrosis in diabetic nephropathy model rats. AB - This study is to investigate the effects of vitamin D on renal fibrosis in rat diabetic nephropathy models, as well as the changes and interactions in the expressions of renal fibrogenesis- and inflammation-related genes. Rat diabetic nephropathy models were established by high-fat diets, which were subjected to TGF-beta1 manipulation, as well as vitamin D treatment. H&E staining, Masson staining, and TEM detection were performed to assess the effects of vitamin D treatment and/or TGF-beta1 manipulation on pathological changes in the renal tissues in these rat diabetic nephropathy models. Immunohistology and real-time PCR were used to evaluate the expressions of TGF-beta1, MCP-1, CTGF, and VDR. Histological staining and TEM detection showed that, in both TGF-beta1 over expressed and interfered groups, vitamin D administration alleviated the renal fibrosis, compared with the vehicle treatment. Similar results were observed with the immunohistological staining. Real-time PCR analysis indicated that, when TGF beta1 was over-expressed in diabetic nephropathy, the expressions of MCP-1 and CTGF were also up-regulated, which would be decreased by the treatment of vitamin D. On the other hand, when TGF-beta1 was interfered in DN, the expressions of MCP 1 and CTGF were relatively down-regulated, which would be further lowered by vitamin D administration. The mRNA expression of VDR was elevated by vitamin D treatment in these diabetic nephropathy models. Active vitamin D3 and lentivirus mediated TGF-beta1 interference could effectively reduce the renal fibrosis and protect the renal function in diabetic nephropathy rat models, which makes a promising therapeutic strategy for the disease. PMID- 25031722 TI - ZNF217 is associated with poor prognosis and enhances proliferation and metastasis in ovarian cancer. AB - ZNF217 is an alternatively spliced Kruppel-like transcription factor that has recently been implicated to play a role in human carcinogenesis. Here, we used immunohistochemistry (IHC) to show that ZNF217 protein is overexpressed in nearly 60% of ovarian tumor samples. The disease-free survival time was shorter in patients with positive ZNF217 expression than in ZNF217-negative patients (P=0.042). Fluorescence in situ hybridization (FISH) analysis showed ZNF217 genomic amplification in the poorly differentiated tumors, suggesting that ZNF217 is associated with the progression of ovarian cancer. Invasion was enhanced in HO 8910 cells stably transfected with constructs carrying full-length ZNF217 relative to cells transfected with the empty vector. To confirm our findings in vivo, we performed a tumorigenicity assay in nude mice inoculated with the HO 8910 overexpressing ZNF217 cells. As expected, tumors grown in the ZNF217 group were more invasive and prone to metastasis than those formed control groups. Based on these clinical and laboratory observations, we conclude that ZNF217 may contribute to ovarian cancer invasion and metastasis, and associated with worse clinical outcomes. PMID- 25031723 TI - Immunolocalization of MMP-2 and MMP-9 in human rheumatoid synovium. AB - Matrix metalloproteinase (MMP)-2 and MMP-9, two important members of the matrix metalloproteinase family, have been shown critical contributions in intra-tumor angiogenesis and invasion of tumor progression, and they might also play important roles in the angiogenesis as well as the pannus formation of rheumatoid arthritis (RA). In the present study, we used the immunohistochemistry, the immunofluorescence staining and the con-focal scanning methods to characterize the immunolocalization of MMP-2 and MMP-9 in RA synovium tissues. Our results showed that both MMP-2 and MMP-9 immunostaining could be found in synoviocytes and vascular endothelial cells. Moreover, our con-focal scanning also showed that MMP-2 could be found in infiltrating CD14(+) monocytes and CD68(+) macrophages, and MMP-9 could be found in infiltrating CD68(+) macrophages in RA synovium tissues, while weak or negative staining of these two MMPs could be found in infiltrating CD20(+)B cells and CD3(+)T cells in RA synovium. Thus, our finding suggests that both MMP-2 and MMP-9 expressed by synoviocytes as well as certain infiltrating immune cells role importantly in the angiogenesis in RA progression. PMID- 25031724 TI - Bmi-1 regulates epithelial-to-mesenchymal transition to promote migration and invasion of breast cancer cells. AB - Breast cancer is a highly invasive and metastatic disease. Recent studies report that breast cancer cells that have undergo epithelial-to-mesenchymal transition (EMT) obtain malignant characteristic, however, the molecular mechanism underlying this transition are poorly understood. Here, we found that over expression associated with the process of breast cancer and that high B-cell specific moloney murine leukemia virus insertion site 1 (Bmi-1) levels predict shorter survival of breast cancer patients. We demonstrate that Bmi-1 regulates EMT and the migration of breast cancer cells. RNA interference-mediated knockdown Bmi-1 expression restored E-cadherin expression and cell-cell junction formation in breast cancer cells, suppressing cell migration and invasion. In contrast, the over-expression of Bmi-1 decreased the expression of the epithelial mark (E cadherin) but increased the mesenchymal makers (N-cadherin and vimentin) in breast cancer cells. PMID- 25031725 TI - LncRNA TSLC1-AS1 is a novel tumor suppressor in glioma. AB - Growing evidence demonstrates that long non coding RNAs (lncRNAs) play an important role in cancer origination and progression. A novel lncRNA, TSLC1-AS1, is the antisense transcript of tumor suppressor TSLC1. The expression profile and function of TSLC1-AS1 in glioma were investigated using Real-Time Quantitative PCR and siRNA knockdown. The data showed that TSLC1-AS1 expression was down regulated in tumor tissues compared with that in adjacent normal tissues, and negatively associated with the WHO criteria of the tumors. Overexpression of TSLC1-AS1 resulted in up-regulation of TSLC1 and significant inhibition of cell proliferation, migration and invasion in U87 cells, while knockdown of TSLC1-AS1 in SNB-19 cells showed the opposite effect. The expression of TSLC1-AS1 was also positively correlated with other tumor suppressors NF1, VHL, PIK3R1 and negatively correlated with the oncogene BRAF. The results suggested that TSLC1 AS1 was a tumor suppressor of glioma and a mediator of TSLC1 expression. LncRNA TSLC1-AS1 may serve as a potential biomarker and therapeutic target for glioma. PMID- 25031726 TI - Lenalidomide after stem-cell transplantation for multiple myeloma: a meta analysis of randomized controlled trials. AB - The efficacy and safety of lenalidomide maintenance therapy after ASCT in patients with MM has been in question. In order to address the issue, we conducted a meta-analysis of two randomized double-blind placebo-controlled studies encompassing 1074 patients treated with lenalidomide or placebo maintenance therapy after ASCT. The predominant clinical outcomes of interest were overall survival (OS), progression-free survival (PFS), and adverse events. There was a marked benefit in PFS with lenalidomide (Odds Ratio [OR] = 2.5, 95% confidence interval [CI] = 1.93 to 3.24). There was statistically non-significant tendency toward benefit in OS with lenalidomide (OR = 1.21, 95% CI = 0.65 to 2.24). For adverse events, more patients in lenalidomide treatment arm experienced neutropenia (OR = 4.88, 95% CI = 3.67 to 6.50), infection (OR = 2.82, 95% CI = 1.67 to 4.73), hematologic cancers (OR = 3.31, 95% CI = 1.30 to 8.41), and solid tumors (OR = 2.24, 95% CI = 1.01 to 4.98). No significant differences were seen with deep vein thrombosis (OR = 2.15, 95% CI = 0.92 to 5.06), peripheral neuropathy (OR = 1.50, 95% CI = 0.53 to 4.25), thrombocytopenia (OR = 1.05, 95% CI = 0.12 to 9.54), and anemia (OR = 1.36, 95% CI = 0.02 to 83.86). Based on these results, we conclude that lenalidomide maintenance therapy for patients with MM after ASCT was effective in the improvement of PFS. However, treatment-related adverse events must be close monitored. Although there was a trend for increased OS with lenalidomide, there was no statistically significant difference in OS between lenalidomide maintenance therapy arm and placebo maintenance therapy arm. Therefore, longer follow-up and additional high quality RCTs were needed to evaluate the effects of lenalidomide maintenance on OS. PMID- 25031727 TI - Hypoxia-inducible factor 1 alpha contributes to pulmonary vascular dysfunction in lung ischemia-reperfusion injury. AB - The revascularization therapy of pulmonary embolism is associated with ischemia reperfusion (IR) injury. However, the effect of IR injury on pulmonary arterial endothelial function has not been elucidated. Male Sprague-Dawley rats were divided into a control, an IR and an IR plus hypoxia-inducible factor 1 alpha (HIF-1alpha) stabilizer DMOG group. We found that the acetylcholine (ACh)-induced relaxation was dramatically reduced in pulmonary arteries from IR-injured rats compared with controls (P < 0.01). Interestingly, pre-treatment with the DMOG significantly improved ACh-stimulated pulmonary arterial dilatation (P < 0.01). The protein expression of HIF-1alpha in pulmonary artery was significantly down regulated by IR injury (P < 0.01). Moreover, DMOG remarkably reversed IR-induced down-regulation of HIF-1alpha (P < 0.01). There was no difference in ACh stimulated relaxation of endothelium-denuded or L-NMMA-treated pulmonary arteries among the three groups. The bioavailability of nitric oxide (NO) and the phosphorylation level of inducible NO synthase (iNOS) in pulmonary artery were significantly decreased by IR injury (both P < 0.01), which were reversed by DMOG (P < 0.05 or P < 0.01). In addition, the levels of superoxide in pulmonary artery were not affected by the IR injury as well as IR injury plus administration with DMOG. The present study demonstrated that HIF-1alpha contributes to pulmonary vascular dysfunction in lung IR injury. PMID- 25031728 TI - The role of pleomorphic adenoma gene-like 2 in gastrointestinal cancer development, progression, and prognosis. AB - Numerous previous studies have revealed that pleomorphic adenoma gene-like 2 (PLAGL2) is a transcription factor that is active in cancer progression. The aim of this study was to investigate the role of PLAGL2 in the development, progression and prognosis of gastrointestinal cancer. Immunohistochemical analysis revealed that PLAGL2 was expressed in gastrointestinal tumors and adjacent normal tissues. The expression of PLAGL2 was significantly higher in 225 colorectal cancer tissues than in 66 adjacent non-tumor tissues (P = 0.037). However, expression was not significantly different between 286 gastric tumors and 57 adjacent non-tumor tissues (P = 0.352). Moreover, the PLAGL2 expression level significantly correlated with the depth of tumor invasion in colorectal cancer (P = 0.030). However, the PLAGL2 expression level significantly correlated with tumor size in gastric cancer (P = 0.046). Furthermore, we performed survival analyses and found that neither higher nor lower PLAGL2 expression was a prognostic factor in gastrointestinal cancer. Our findings indicate that PALGL2 serves as a tumor oncoprotein in the development and progression of colorectal cancer. However, the role of this protein in the development, progression and prognosis of gastric cancer is uncertain. Further investigation into the molecular mechanisms of PLAGL2 activity in gastrointestinal cancer is warranted. PMID- 25031729 TI - Maternal protein restriction alters VEGF signaling and decreases pulmonary alveolar in fetal rats. AB - Epidemiological studies have demonstrated that intrauterine growth restriction (IUGR) increases the risk for respiratory morbidity from infancy, throughout childhood and into adulthood. Chronic restriction of nutrients causes abnormalities in the airways and lungs of offspring, but whether IUGR adversely impacts fetal pulmonary vascular development and underlying mechanisms remain under investigation. In this study, we investigated the effects of protein malnutrition in utero on pulmonary alveolarization and vascular growth of the fetal lung and placentae. Pregnant rats were feed with an isocaloric low-protein diet (8% protein) until delivery. Placenta and fetal lungs were harvested on 20th day of gestation (term 21 days of gestation). Lung index (lung weight as a percentage of body weight), total DNA and protein, radial alveolar count, arteriolar wall thickness, lung maturity and angiogenic factor VEGF were assessed. The lung was hypoplastic in IUGR fetus, evidenced by reduction in lung weight, DNA and protein content. Protein restriction in utero led to higher glycogen levels, but reduced number of alveoli as confirmed by the measurement of radial alveolar counts. IUGR fetus had significantly reduced VEGF, Flk-1 levels in lung but no changes in Flt-1 mRNA. Furthermore, IUGR was associated with increased lung miR-126-3p levels, which modulated the expression of angiogenic factor. In contrast, with regard to the placenta, IUGR fetus presented with decreased expression of VEGF, with no changes in VEGF receptors and expression regulating miRNAs. This work suggested that VEGF signaling defect plays an important role in the defective lung development, which may explain the increased incidence of respiratory infections in IUGR patients. PMID- 25031730 TI - Clinicopathological characterization of so-called "cholangiocarcinoma with intraductal papillary growth" with respect to "intraductal papillary neoplasm of bile duct (IPNB)". AB - Cholangiocarcinoma (CC) of the biliary tract occasionally presents a predominant intraductal papillary growth in the bile ducts, called as biliary tract carcinoma (BTC) of papillary growth (PG) and intrahepatic CC (ICC) of intraductal growth (IG) type. Recently, intraductal papillary neoplasm of bile duct (IPNB) has been proposed as a pre-invasive biliary neoplasm. This study was performed to characterize pathologically BTC of PG type and ICC of IG type with respect to IPNB. It was found that 126 of such 154 CCs (81.8%) fulfilled the criteria of IPNB, while the remaining 28 cases showed different histologies, such as tubular adenocarcinoma and carcinosarcoma. These IPNBs occurred in old aged patients with a male predominance, and the left lobe was rather frequently affected in the liver. A majority of these cases were high grade IPNB (43 cases) and invasive IPNB (77 cases), while low grade IPNB was rare (6 cases). Pancreatobiliary type was predominant (48 cases) followed by gastric (30 cases), intestinal (29 cases) and oncocytic (19 cases) types. Mucus hypersecretion was found in 45 cases, and this was frequent in IPNB at the intrahepatic large bile duct and hilar bile ducts but rare at the extrahepatic bile ducts. Interestingly, 36 cases of high grade and invasive IPNBs contained foci of moderately differentiated adenocacinoma within the intraductal papillary tumor. In conclusion, a majority of ICC of IG type and BTC of PG type could be regarded as a IPNB lineage, and clinically detectable IPNBs were already a malignant papillary lesion. PMID- 25031731 TI - Loss of expression of MHC class I-related chain A (MICA) is a frequent event and predicts poor survival in patients with hepatocellular carcinoma. AB - Natural killer (NK) cells are important effector cells for the first line of defense against tumor. Distant MHC class I homolog MICA has been identified as human ligand for NK cell activating receptor NKG2D. Engagement of MICA triggers NK cells and augments antigen-specific CTL anti-tumor immunity. However, the expression level of MICA and its clinical significance in hepatocellular carcinoma remains to be elucidated. In the present study, a hospital-based study cohort of 143 HCC patients was involved. MICA expression levels were determined by immunohistochemical staining. The association of MICA expression with tumor clinicopathologic features, disease-free survival, and overall survival of HCC patients were analyzed. Significantly decreased expression of MICA was detected in tumor specimens. MICA expression was significantly associated with AFP level (P < 0.001) and tumor node metastasis stage (P = 0.003). Patients with reduced level of MICA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of MICA. However, in multivariate analysis, MICA expression level was found not to be an independent prognostic factor for both disease-free survival and overall survival of HCC patients. Our findings suggest that decreased MICA expression may play an important role in HCC tumor evasion of host immunity, which warrants further investigation in future studies. PMID- 25031732 TI - Overexpression of GRB2 is correlated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. AB - The adapter protein growth factor receptor-bound 2 (GRB2) is essential for various basic cellular functions by mediating the regulation of receptor tyrosine kinase (RTK) signaling, however, little is known about GRB2 expression in esophageal squamous cell carcinoma (ESCC). We sought to characterize GRB2 expression and its relationship with clinicopathological parameters and prognostic significance in ESCC patients. Here, it was presented that GRB2 was overexpressed in cytoplasm in 58.1% (100/172) of ESCC cases by immunohistochemistry. Survival analysis demonstrated overexpression of GRB2 protein was significantly related to poor prognosis of ESCC patients (P = 0.021). Furthermore, overexpression of GRB2 was significantly associated with the lymph node metastases. In addition, subgroup analysis according to lymph node metastasis revealed a shorter disease-free survival (DFS) in the ESCC patients with GRB2 overexpression than the patients with GRB2 low-expression (Means for DFS months: 33.8 versus 52.1). Finally, the significant difference between overexpression of GRB2 and poor survival rates exhibited in univariate analysis (P = 0.022) and multivariate Cox analysis (close to significance, P = 0.065), demonstrated that GRB2 was an independent factor in prognosis of ESCC patients. In conclusion, GRB2 expression status could be as a positive biomarker of ESCC progression and lymph node metastasis. PMID- 25031734 TI - Zinc-finger protein X-linked is a novel predictor of prognosis in patients with colorectal cancer. AB - Zinc-finger protein X-linked (ZFX) has been demonstrated to play an important role in the development of human malignancies. However, its prognostic significance in cancer patients remains unclear and less is known about its role in colorectal cancer (CRC). In this study, we found that the expression of ZFX in CRC tissues was significantly higher than that in corresponding normal tissues by quantitative real-time polymerase chain reaction and Western blot. Using immunohistochemistry, we explored the associations between protein expression of ZFX and clinicopathological parameters in 120 CRC cases. The results showed that ZFX expression was significantly associated with tumor differentiation (P = 0.022), tumor size (P = 0.037), tumor invasion (P = 0.027), lymph node metastasis (P = 0.042), distant metastasis (P = 0.011), and Dukes' classification (P = 0.028). Moreover, according to Kaplan-Meier model, patients with high expression of ZFX had a significantly poorer prognosis compared to those with low expression of ZFX. Multivariate analysis suggested that high expression of ZFX was an independent prognostic factor for CRC patients. In conclusion, our findings for the first time demonstrated that ZFX expression may be associated with the progress of CRC and suggested that ZFX has the potential value to be an effective prognostic predictor for CRC patients. PMID- 25031733 TI - STAT3 serine 727 phosphorylation influences clinical outcome in glioblastoma. AB - Besides STAT3 tyrosine 705 phosphorylation (pTyr705-STAT3), phosphorylation of STAT3 at serine 727 (pSer727-STAT3) is shown to contribute to tumorigenesis and be closely related with resistance to radiotherapy and chemotherapy in glioma, but there is currently no study regarding its relevance to prognosis in glioblastoma (GBM). Here, the expression of phosphorylated STAT3 was detected in tumor specimens from 88 patients with newly diagnosed GBM by immunohistochemistry, the Kaplan-Meier survival curve and COX proportional hazards regression model were applied to estimate its influences on progression free survival (PFS) and overall survival (OS). Immunohistochemical assay showed elevated expression of pSer727-STAT3 in GBM compared with normal brain tissue. Univariate analysis indicated significant correlations of high percentage of pSer727-STAT3 positive tumor cells with shorter PFS (P = 0.006) and OS (P = 0.002). In multivariate analysis, high pSer727-STAT3 expression was demonstrated as an independent unfavorable prognostic indicator for PFS (HR 1.830, P = 0.022) and OS (HR 1.797, P = 0.040). And patients with high expression of both pTyr705 STAT3 and pSer727-STAT3 had a poorer prognosis compared with the remainder (P < 0.005). In conclusion, the high proportion of pSer727-STAT3 positive neoplastic cells in GBM is an independent unfavorable prognostic factor, and increased expression of both pTyr705-STAT3 and pSer727-STAT3 is predictive of poorer clinical outcome, thereby adding to the growing evidence that STAT3 inhibition may be a potential therapeutic strategy in glioblastoma. PMID- 25031735 TI - High expression of Twist is associated with tumor aggressiveness and poor prognosis in patients with renal cell carcinoma. AB - AIMS: Twist has been reported to play crucial roles for malignant aggressiveness; however, detailed pathological significance of Twist in renal cell carcinoma (RCC) is not fully understood. The present study was to clarify clinical significance and molecular functions of Twist in patients with RCC. METHODS: Twist expression was examined by immunohistochemical techniques in 156 formalin fixed specimens. Cell proliferation, angiogenesis, and apoptosis were measured as the percentage of Ki-67-positive cells (proliferation index, PI), CD31-stained vessels (microvessel density, MVD), and TUNEL-positive cells (apoptotic index, AI). In addition, semi-quantification of matrix metalloproteinase (MMP)-2 was performed. Macrophages were identified with anti-CD68 antibody, and the tumor associated macrophage (TAM) density was calculated as CD68-positive cells per high-power field. RESULTS: Twist expression was positively associated with grade, pT stage, and metastasis (p<0.001). We also noticed that its expression was considerably higher in cancer cells of sarcomatoid RCC and in those at the edge of the tumors. Twist expression was positively correlated with PI, MVD, MMP2 expression, and TAM density (P<0.001), but not with AI, and MMP-2 expression and TAM density were independently correlate by multi-variate analyses. Kaplan-Meir survival curves showed high Twist expression was a worse predictor for cause specific survival (P<0.001). CONCLUSIONS: Twist plays important roles in tumor growth, progression, and survival in patients with RCC patients. Such pathological mechanisms are significantly associated with increased cancer cell proliferation, angiogenesis, MMP2 expression, and macrophage recruitment. These findings are important information for discussion of treatment and observation strategies in these patients. PMID- 25031736 TI - Langerhans cell histiocytosis in Chinese adults: absence of BRAF mutations and increased FOXP3(+) regulatory T cells. AB - Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of abnormal Langerhans cells. Previous studies mainly focused on children with LCH. However, there is limited information on the clinical and pathological aspects of LCH in adults. Therefore, this study aimed to investigate the clinical and pathological aspects of LCH in Chinese adults. The results showed that the average age of 18 LCH patients was 35.22 +/- 16.57 years old. The ratio of male to female was 3.5:1.14 patients (77.8%) had single-system involvement and 4 patients (22.2%) had multi-system diseases. The skin (38.9%) and lungs (44.4%) were the mainly affected organs. No BRAF mutations were detected in the lesions of 18 cases. The number of FOXP3(+) Tregs was significantly increased in LCH. In conclusion, clinical features of LCH in adults are distinct from those in children. Adult LCH has a relatively good prognosis and presents as a benign disease. Immune regulation plays an important role in the pathogenesis of adult LCH. PMID- 25031738 TI - Maternal serum lead levels and risk of preeclampsia in pregnant women: a cohort study in a maternity hospital, Riyadh, Saudi Arabia. AB - Preeclampsia is one of the major cause of maternal morbidity and mortality. Despite numerous studies, the etiology of preeclampsia has not yet been fully elucidated. There has been confliction in results on the role of maternal lead in preeclampsia. Keeping in view with the scarcity of data on role of lead in preeclamptic women of Saudi Arabia and the disparity in earlier findings, the present study was carried out to determine the levels of maternal serum lead in patients with preeclampsia in comparison to normal pregnancy. The study consisted of 120 pregnant women divided into three groups of 40 each, control, HR group and PET group. The serum levels of lead were estimated by Inductively coupled plasma optical emission spectrometry. We found that the mean value of serum lead was 18.23 +/- 2.34, 20.08 +/- 2.15 and 27.18 +/- 2.13 ug/dl in control, high risk group and preeclamptic group respectively. The levels of Pb were found to decrease significantly (P < 0.05) in preeclamptic group compared to control. However, there was no significant change in levels of Pb when HR group was compared to Control and preeclamptic group. In the present study, we observed that serum levels of lead were positively correlated with systolic and diastolic blood pressure and were statistically significant (P < 0.05). However, negative correlation was observed between Pb and BMI ruling out the association of BMI with preeclampsia. It is thus concluded that preeclampsia is associated with significant increase in maternal lead and these increasing levels of serum lead pose a significant risk in pregnant women to preeclampsia. PMID- 25031737 TI - High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. AB - OBJECTIVE: This study sought to investigate the role of the long noncoding RNA MALAT1 in the prognosis of stage II/III colorectal cancer (CRC) patients. METHODS: The expression of MALAT1 was evaluated in cancer tissues from 146 stage II/III CRC patients undergoing radical resection and 23 paired normal colonic mucosa samples using quantitative real-time reverse transcriptase PCR. Differences in the expression of MALAT1 between 23 CRC and paired normal colonic mucosa samples were analysed with the Wilcoxon test. Relationships between the expression level of MALAT1, patient clinicopathological parameters and disease free survival (DFS) and overall survival (OS) were analysed using the univariate Kaplan-Meier method and the multivariate COX regression model. RESULTS: The MALAT1 levels in cancerous tissues were 2.26 times higher than those measured in noncancerous tissues, and this difference was statistically significant (P = 0.0004). Based on their expression level of MALAT1, the patients were divided into a high MALAT1 expression group (n = 73) and a low expression group (n = 73). Patients with tumours harbouring higher expression of MALAT1 showed a significantly worse prognosis with a hazard ratio (HR) of 2.863 (95% CI, 1.659 to 4.943; P < 0.001) for DFS and 3.968 (95% CI, 1.665 to 9.456; P = 0.002) for OS. Furthermore, patients with perineural invasion demonstrated significantly worse DFS (HR = 3.459, 95% CI 2.008 to 5.957; P < 0.001) and OS (HR = 3.750, 95% CI 1.743 to 8.069; P = 0.001) than those without perineural invasion. Multivariate analyses indicated that MALAT1 expression and perineural invasion were two independent prognostic risk factors for patients with CRC. CONCLUSION: The expression of MALAT1 is upregulated in CRC tissues, and a higher expression level of MALAT1 might serve as a negative prognostic marker in stage II/III CRC patients. PMID- 25031739 TI - Expression of Wnt-5a and beta-catenin in primary hepatocellular carcinoma. AB - It has been reported that changes in Wnt5a expression are closely related to hepatocellular carcinoma (HCC) development, while decreased or abnormal beta catenin expression may promote the invasion and metastasis of tumor cells. In this study, the roles and clinical significance of Wnt-5a and beta-catenin expression were analyzed in primary HCC. Real-time PCR (RT-PCR) analysis of Wnt 5a mRNA expression was performed in 26 fresh HCC samples and the corresponding para-carcinoma tissues. Wnt-5a and beta-catenin protein expression was detected by immunohistochemical staining of paraffin-embedded tissues of 85 cases of HCC and corresponding para-carcinoma tissues and 15 cases of hepatic cirrhosis. Results showed that Wnt-5a mRNA levels were significantly higher in HCC tissue than in the para-carcinoma tissue (0.102 +/- 0.159 and 0.020 +/- 0.022, respectively; P < 0.05), while Wnt-5a protein was absent or low in HCC. Wnt-5a expression was detected in significantly fewer HCC tissue samples than in the para-carcinoma and hepatic cirrhosis tissue samples (21.2% (18/85), 81.26% (69/85) and 86.7% (13/15), respectively; P < 0.01). Abnormal localization of beta catenin protein shown by intracytoplasmic or intranuclear staining was observed in 72.94% (62/85) of HCC samples. These observations indicate that the role of Wnt-5a in HCC is mediated at the protein level rather than the transcriptional level. Furthermore, the abnormal localization of beta-catenin observed in HCC tissues may be associated with gene mutation leading to the generation of truncated beta-catenin proteins, which in turn, may represent an initiating or contributing factor in the development of HCC. PMID- 25031740 TI - Homozygous inv(11)(q21q23) and MLL gene rearrangement in two patients with myeloid neoplasms. AB - Rearrangements of the MLL gene located at chromosome 11q23 are common chromosomal abnormalities associated with acute leukemias. In vast majority of cases with MLL gene rearrangements, only one chromosome 11 or a single MLL allele got involved. We report two very unusual cases of myeloid neoplasms with homozygous inv(11)(q21q23) and biallelic MLL rearrangement. Both patients, a 12-year old boy and a 29-year old woman, presented initially with T lymphoblastic leukemia/lymphoma (T-ALL), achieved complete remission with intensive chemotherapy, then recurred as acute myeloid leukemia in one patient and therapy related myelodysplastic syndromes in the other patient, 24 and 15 months after initial T-ALL diagnosis, respectively. In both cases, biallelic MLL gene rearrangements were confirmed by fluorescence in situ hybridization. Mastermind like 2 gene was identified as MLL partner gene in one case. To our knowledge, homozygous inv(11)(q21q23) with two MLL genes rearrangement are extremely rare; it is likely a result of acquired uniparental disomy. PMID- 25031741 TI - Predictors of recurrence in breast cancer subtypes with negative lymph node in a Chinese population. AB - To establish a series of objective parameters to predict the risk of relapse from axillary lymph node-negative (ANN) breast cancer, and evaluate the patterns of recurrence according to molecular subtypes, we collected information on 2126 consecutive breast cancer patients operated between 2002 and 2006. In this case control study, 212 patients experiencing recurrence or breast cancer related death were defined as 'poor group'. Another 212 patients were selected from the remaining cases with stratified sampling method to comprise the 'good group'. Significant differences were found in vascular invasion, grade and molecular subtype between the two groups. Expression of ER and PR in the 'poor group' was lower (P < 0.05). However, positive rates of Ki67, p53 and VEGF in the 'poor group' were higher (P < 0.05). Multivariate analysis revealed that molecular subtype, expression of VEGF, tumor grade, and vascular invasion were closely correlated with bad outcome. Analysis of the 'poor group' demonstrated that 'HER2 positive' and 'triple negative' subtypes more commonly suffered from distant metastases and death. No metastasis was found in patients with pure invasive papillary carcinoma, invasive cribriform carcinoma or adenoid cystic carcinoma, whereas the diagnoses of invasive micropapillary carcinoma, invasive apocrine carcinoma, invasive papillary carcinoma mixed with invasive ductal carcinoma, or metaplastic carcinoma were correlated with distant metastasis and death. In conclusion, molecular subtype and expression of VEGF are useful markers for predicting prognosis of ANN breast cancer patients. 'Luminal A-like' subtype has better outcome than others. Moreover, molecular subtypes have different recurrence patterns. PMID- 25031742 TI - High expression of GPER1, EGFR and CXCR1 is associated with lymph node metastasis in papillary thyroid carcinoma. AB - Clinical and epidemiological studies have shown that estrogen may be involved in the development and progression of papillary thyroid carcinoma (PTC). G protein coupled estrogen receptor 1 (GPER1) is a novel seven-transmembrane estrogen receptor that functions alongside traditional nuclear estrogen receptors (ERs) to regulate the cellular responses to estrogen. The purpose of this study was to examine GPER1, EGFR and CXCR1 expression in PTC and to assess the association of their expression with clinicopathological indicators. GPER1, EGFR and CXCR1 protein expression in 129 PTCs, 61 nodular hyperplasia and 118 normal thyroid tissue specimens were analyzed using immunohistochemistry. The protein expression levels of these three molecules were up-regulated in PTCs. High protein expression of GPER1, EGFR and CXCR1 was significantly correlated with lymph node metastasis (LNM) (P <= 0.001). Furthermore, GPER1, EGFR and CXCR1 protein expression were correlated with one another. Concomitant high expression of these molecules had stronger correlation with LNM than did each alone (P = 0.002 for GPER1/EGFR, P = 0.013 for GPER1/CXCR1, P = 0.018 for EGFR/CXCR1 and P < 0.001 for GPER1/EGFR/CXCR1). Additionally, GPER1, EGFR and CXCR1 mRNA expression was assessed in 30 PTCs, 10 nodular hyperplasia and 10 normal thyroid tissue specimens using real-time RT-PCR. GPER1, EGFR and CXCR1 mRNA expression levels were up-regulated in PTCs, and high mRNA expression of GPER1, EGFR and CXCR1 was significantly correlated with LNM (P < 0.001 for all these three molecules). These results demonstrated that the evaluation of GPER1, EGFR and CXCR1 expression in PTC may be useful in predicting the risk of LNM. PMID- 25031743 TI - Yes-associated protein (YAP) is differentially expressed in tumor and stroma according to the molecular subtype of breast cancer. AB - In this study, we aimed to clarify the expression profiles of Yes-associated protein (YAP) and phosphorylated YAP (pYAP) protein and to verify the clinical implication of the expression of YAP protein in human breast cancer. We selected 678 cases of formalin-fixed paraffin-embedded (FFPE) breast cancer tissue to construct tissue microarray (TMA) blocks. We performed immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth receptor-2 (HER-2) and Ki-67 and fluorescent in situ hybridization (FISH) assay for HER-2 on the TMA sections and divided breast cancers into molecular subtypes: luminal A, luminal B, HER-2, triple negative breast cancer (TNBC). Then, we examined YAP and pYAP expression status using immunohistochemical analysis according to the molecular subtypes of breast cancer. We found that HER 2 type breast cancer demonstrated elevated expression level in tumoral cytoplasmic YAP (P = 0.011) and pYAP (P = 0.049). Expressions of stromal YAP (P = 0.002) and pYAP (P < 0.001) were higher in luminal B and HER-2 type breast cancer but lower in TNBC. In univariate analysis, nuclear YAP expression of tumor cells was associated with shorter overall survival (OS) (P = 0.024). Cytoplasmic YAP expression of HER-2 type breast cancer cells negatively affected disease-free survival (DFS) (P = 0.034). In conclusion, we concluded that there was a significant difference in YAP and pYAP expression status according to molecular subtypes and tumoral and cellular components of breast cancers. Finally, we found that nuclear and cytoplasmic YAP expression could be a prognostic marker for breast cancer patients. PMID- 25031744 TI - Concurrent CD44s and STAT3 expression in human clear cell renal cellular carcinoma and its impact on survival. AB - Although CD44 was overexpressed and considered as a useful prognostic marker in renal cell carcinoma, the prognostic role of CD44s in clear cell renal cell carcinoma (ccRCC) remains controversial. Moreover, the correlation and prognostic significance of CD44s and its downstream signaling target pSTAT3 are unclear in ccRCC. In this study, 75 pairs of carcinoma and paired adjacent non-tumor renal tissue samples were collected from patients with localized ccRCC who underwent a nephrectomy. The expression levels of CD44s and pSTAT3 were analyzed using immunohistochemistry. Correlations between CD44s/pSTAT3 expression and clinical and pathological characteristics were determined using x(2) test, Kaplan-Meier analysis and Cox's proportional hazards model. We found that CD44s is highly expressed in 46.67% of tumor tissues, and its high expression was significantly associated with high tumor grade (P < 0.001), large tumor size (P = 0.009) and advanced T stage (P = 0.004). A strong correlation exists between high expression of CD44s and pSTAT3 (r = 0.4013, P = 0.0004). The joint over expression of CD44s and pSTAT3 was present in 42.66% of tumor specimens and had an additive negative impact on overall survival. Patients with CD44s(high)pSTAT3(high) expression had significantly poor survival as compared to patients with CD44s(low)pSTAT3(low) tumor expression (P = 0.024), though the concurrent overexpression of CD44s and pSTAT3 was not an independent prognostic factor for overall survival. Our data indicate that expression of both CD44s and pSTAT3 in ccRCC is associated with advanced tumor stage and patient survival. The conclusions from this study may improve the prediction of ccRCC prognosis information when CD44s and pSTAT3 expression are evaluated together with classical clinicopathological parameters. PMID- 25031745 TI - Concurrent alterations of RAGE, RECK, and MMP9 protein expression are relevant to Epstein-Barr virus infection, metastasis, and survival in nasopharyngeal carcinoma. AB - This study aimed to concurrently investigate the expressions of receptor for advanced glycation end products (RAGE), reversion inducing cysteine-rich protein with Kazal motifs (RECK) and matrix metalloproteinase 9 (MMP9) in nasopharyngeal carcinoma (NPC) and their correlations with clinicopathological properties. Using immunohistochemistry, we found that RECK expression was downregulated in NPC tissues compared with chronic nasopharyngitis (CNT) tissues, while RAGE and MMP9 expressions were upregulated. We further found that RECK expression level was inversely correlated with MMP9 expression level in NPC, whereas RAGE expression level was positively correlated with MMP9 expression level. Moreover, aberrant expressions of these proteins had a positive correlation with the titers of EBVCA IgA, lymphatic metastasis, recurrence and survival. Together, these findings suggest that dysregulations of RECK and RAGE expressions may be collectively involved in tumor progression of NPC by regulating MMP9 expression and that they may be a good prognostic predictors for NPC. PMID- 25031746 TI - Expression of APC protein during tongue malignant transformation in galectin-3 deficient mice challenged by the carcinogen 4-nitroquniline-n-oxide. AB - Galectin-3 (Gal3) has been implicated in the development of different tumors because of its involvement in the Wnt signaling pathway by promoting beta-catenin translocation into the nucleus. The APC protein, a negative regulator of this pathway, has been strongly implicated in the development of colon cancer, but still has an undetermined role in the formation of oral cancer. Therefore, this study aimed to evaluate the relationship between Gal3, the Wnt signaling pathway, and APC expression in dysplasias and carcinomas developed experimentally in mice. Sixty galectin-3-deficient (Gal3(-/-)) and 60 wild-type (Gal3(+/+)) mice were early employed to be treated with the carcinogen 4NQO for 16 weeks and killed at either week 16 or week 32. Tongues were removed, processed and embedded in paraffin blocks. Sections 5 MUm thick were made, and then stained by H&E to establish the diagnosis of dysplasia and carcinoma. Sections of 2 MUm thickness were made to detect APC expression in these lesions by immunohistochemistry. Oral carcinogenesis occurred in both groups of mice, but no statistical difference was reached. APC expression was exclusively seen in the cytoplasm of all lesions studied. In the intragroup analysis, the majority of dysplasias and carcinomas exhibiting higher APC immunoreactivity was observed in Gal3(-/-) mice compared to Gal3(+/+) mice, but no significant difference was found. However, a statistical difference was only observed between dysplastic lesions from two mice. Our results showed that neither the absence of Gal3 nor the APC protein appears to play a role in malignant transformation of the tongue. PMID- 25031747 TI - IgM expression in paraffin sections distinguishes follicular lymphoma from reactive follicular hyperplasia. AB - The trapping of IgM-containing immune complexes (ICs) by follicular dendritic cells (FDCs) serves as an important step in promoting germinal center (GC) formation. Thus, the deposition of IgM-containing ICs on FDCs can be detected by antibodies recognizing IgM. The present investigation provides the first comprehensive report on the IgM staining pattern in follicular lymphoma (FL, n = 60), with comparisons to reactive follicular hyperplasias (RFH, n = 25), demonstrating that immunohistochemical staining for IgM in paraffin-embedded sections seems to be an additional tool for differentiating between FL and RFH. In RFH, IgM highlighted processes of FDCs, with stronger and more compact staining in light than in dark zones, with occasional very dim staining of GC B cells. In FL, IgM expression patterns were of three types. Pattern I (38 cases) stained tumor cells within neoplastic follicles, with no staining of FDCs. Pattern II (15 cases) stained neither tumor cells nor FDCs. Pattern III (7 cases) stained tumor cells with (3 cases) or without (4 cases) IgM expression; however, variable and attenuated IgM expression was observed on FDCs in each case. Interestingly, significant numbers of IgD+ mantle cells were preserved around the neoplastic follicles in these 7 cases. The data suggested that a complete or considerable loss of IgM expression in FDCs, reflecting the loss of IgM containing ICs in FDCs, is a typical feature of FL. Increased IgM expression by GC B cells can also serve as an indicator of immunophenotypic abnormality in FL. PMID- 25031748 TI - Clinicopathological significance of aberrant Notch receptors in intrahepatic cholangiocarcinoma. AB - Notch signaling has been reported to be activated to promote biliary epithelial cell differentiation and tubulogenesis during bile duct development. In this study, clinicopathological significance of aberrant expression of Notch receptors in intrahepatic cholangiocarcinoma (ICC) was investigated. Thus, forty-one ICC specimens were examined by immunohistochemistry using anti-Notch1-4 antibodies, respectively. Expression of Notch receptors was scored by percentage of positive tumor cells and intensity of immunostaining. Clinicopathological parameters and survival data were compared with the expression of Notch receptors, respectively. Expression of Notch receptors was identified in cancer cells, as well as in non neoplastic cells. Compared with adjacent non-tumor liver tissues, Notch1 and 4 were up regulated, and Notch2 and 3 were relatively weaker. Positive immunostaining of Notch1 in ICC cells was detected in 34 cases (82.9%), Notch2 in 23 (56.1%), Notch3 in 16 (39.0%) and Notch4 in 14 (34.1%). Notch1 was overexpressed in cases with tumor size > 5 cm (P = 0.036). Expression of Notch2 was correlated inversely with histological grade (P = 0.016). Overexpression of Notch4 was more common in cases with serum CA125 > 35 U/ml than cases with CA125 <= 35 U/ml (P = 0.048). Expression of Notch3 was not correlated with any other clinicopathological parameters. Moreover, Notch4 was related to poor survival (P < 0.001). To conclude, this study reveals that aberrant expression of Notch receptors 1 and 4 might play important roles during ICC progression. PMID- 25031749 TI - Distribution of lymphomas in Poland according to World Health Organization classification: analysis of 11718 cases from National Histopathological Lymphoma Register project - the Polish Lymphoma Research Group study. AB - Most national lymphoma registers rely on broad classifications which include Hodgkin and non-Hodgkin lymphomas (NHL), multiple myeloma and leukaemia. In Poland the National Histopathological Lymphoma Register project (NHLR) was implemented by hematopathologists in accordance with the 2008 WHO classification into haematopoietic and lymphoid tissues. We present the NHLR data and compare lymphoma distribution in Poland, Europe, as well as in North Central and South America. Records of 11718 patients diagnosed in 24 pathology departments from all over the country were retrieved and reclassified into indolent and aggressive lymphomas according to the 2008 revised WHO classification system. DLBCL (32.9%; 2587), CLL/SLL (31.84%; 2504) and MCL (9.04%; 711) were the three most frequent NHL. The ratio of indolent to aggressive NHL was 1.72; 63.25% (4809) to 36.25% (2794) of cases respectively. Multiple myeloma was less frequent as compared to the data from population-based national cancer register (13.32% vs. 28.94%). Major differences between NHLR and European and American data on NHL subtypes concered: higher incidence of aggressive B-cell lymphomas including DLBCL, lower FL and MALT incidence rate. The percentage of unclassified lymphomas in the study was minimal due to participation of hematopathologists. PMID- 25031750 TI - Decreased expression of miR-204 is associated with poor prognosis in patients with breast cancer. AB - The identification of biomarkers in breast cancer diagnosis and therapy is important in achieving early cancer diagnosis and improving patient outcomes. The aim of this study was to examine clinical significance of miR-204 expression in tissues from breast cancer patients. The relationship between miR-204 expression and clinicopathological characteristics was investigated. MiR-204 expression was significantly associated with TNM stage and metastasis. Patients with low miR-204 expression had poorer overall survival time and disease free survival time than those with high miR-204 expression. Furthermore, miR-204 expression was correlated with chemotherapeutic resistance of breast cancer patients. In conclusion, the miR-204 may be a potential diagnostic and prognostic biomarker of breast cancer. PMID- 25031751 TI - S-1 monotherapy as second line chemotherapy in advanced gastric cancer patients previously treated with cisplatin/infusional fluorouracil. AB - The treatment choice of advanced gastric carcinoma after failure from first-line therapy is quite limited. To evaluate the efficacy and toxicity of S-1 monotherapy in patients with advanced gastric cancer after failure of first line cisplatin and fluorouracil combination (CF). S-1 monotherapy as a second line treatment was given to the patients who had failed to CF combination in SC-101 study. The efficacy and toxicity of S-1 monotherapy were evaluated exploratory. The results indicated that forty-one patients received S-1 as a second line therapy after disease progression. The overall response rate and disease control rate were 14.6% and 41.5%, respectively. The median progression free survival (PFS) was 5.1 months (range: 2.9~6.2 month). The median overall survival time was 6.4 months. The survival rates at 6 month and 1 year were 56% and 7.3%, respectively. Grade 3/4 adverse events were uncommonly occurred, including anemia (2.4%), neutropenia (2.4%), thrombocytopenia (4.9%) and rash (2.4%). There were no unexpected or life-threatening toxicities. Only one patient experienced dose reduction due to grade 3 rash. In conclusion, S-1 monotherapy provided a mild response rate and overall survival, and a favorable toxicity profile in the second line setting after the first line failure to cisplatin and fluorouracil combination. PMID- 25031752 TI - Prognostic value of glomerular C4d staining in patients with IgA nephritis. AB - INTRODUCTION: Mesangial IgA deposition is the initiative factor in the pathogenesis of IgA nephropathy (IgAN). Glomerular IgA depositon leads to activation local complement system. C4d positivity shows that complement activation occurs via alternative pathway. C4d positivity at the time of renal biopsy can be associated with poor prognosis in IgA nephropathy. We aimed to evaluate C4d deposition and renal outcome in patients with IgA nephritis. METHODS: Between January 2005 and December 2009, 40 patients with IgA nephritis were enrolled. Renal biopsy specimens of 33 patients have been evaluated. C4d immunohistochemical staining was performed 3-MUm deparaffinized and rehydrated sections of formaldehyde-fixed renal tissues, using rabbit polyclonal anti-human C4d as the antibody. Baseline demographical, clinical and laboratory data were recorded retrospectively. RESULTS: Mean age of the patients was 35.9 +/- 12.9 years and female/male ratio was 19/21. Mean duration of follow-up was 32.8 (12 60) months. Baseline glomerular filtration ratio (GFR) and proteinuria were 55.8 ml/min and 2.44 gr/day respectively at the time of renal biopsy. Eleven patients were C4d positive. Presence of hypertension (p=0.133), proteinuria (p=0.007), serum creatinine levels (p=0.056) and glomerulosclerosis (p=0.004), mesengial hypersellularity (p=0.0001) and interstitial fibrosis (p=0.006) at the time of renal biopsy were higher in C4d positive group rather than negative group. Evolution to renal failure were 63.6% in C4d positive group and 13.6% in negative group (p=0.006). Renal survival at 3 years was 39% in C4d-positive patients versus 66.7% in the C4d-negative patients (log rank- p=0.0072). PMID- 25031753 TI - Cytoplasmic HSP90alpha expression is associated with perineural invasion in pancreatic cancer. AB - Pancreatic cancer (PC) is an aggressive and devastating disease with a dismal prognosis. The study aimed to investigate the role of HSP90alpha and PDIA3 in patients with PC. Immunohistochemistry was performed on tissue microarrays containing 186 pairs of PC and normal pancreatic tissues to assess the expression levels of HSP90alpha and PDIA3. The expression levels of cytoplasmic HSP90alpha (P = 0.032) and PDIA3 (P = 0.043) in PCs were significantly higher than those in normal pancreas tissues, but nuclear HSP90alpha showed lower expression in PC tissues (P = 0.002). In addition, cytoplasmic expression of HSP90alpha and PDIA3 was significantly associated with perineural invasion (PNI) (P = 0.004) and sex (P = 0.014), respectively. These results indicate that cytoplasmic HSP90alpha may serve as a biomarker for PNI in PCs. PMID- 25031754 TI - Phosphorylation status of Akt and caspase-9 in gastric and colorectal carcinomas. AB - The serine/threonine protein kinase B/Akt plays a central role in the coordination of multiple signal transduction processes involved in transcriptional regulation, cell survival, and apoptosis. Activation of Akt kinase is a prognostic factor in several types of cancers; however, its role in gastrointestinal cancers is not fully understood. Caspase-9 is an Akt substrate that belongs to the caspase family of proteases, which function as initiators of the mitochondrial apoptotic pathway. Little is known about the role of caspase-9 phosphorylation, which downregulates the apoptotic activity of the enzyme. In this study, we investigated the expression of phosphorylated (p)-Akt and phosphorylated (p)-caspase-9 in gastric and colorectal carcinoma and the relationship between p-Akt and p-caspase-9 expression and clinicopathological parameters of gastric and colorectal cancer patients. In total, 75 samples of advanced gastric adenocarcinoma (37 well-to-moderately differentiated and 38 poorly differentiated) and 76 samples of advanced colorectal adenocarcinoma (69 well-to-moderately differentiated and 7 poorly differentiated) were analyzed for p-Akt and p-caspase-9 expression by immunohistochemistry. Our results reveal a correlation between p-Akt and p-caspase-9 expression in gastric and colorectal cancers. Levels of p-caspase-9 were significantly higher in colorectal cancer than in gastric cancer, indicating tumor-specific regulation. Although the biological role of p-Akt/p-caspase-9 signaling remains unclear, we suggest that phosphorylation of caspase-9 may be a useful tool to assess the state of gastrointestinal cancer and the effects of anti-cancer therapy. PMID- 25031755 TI - Up-regulation of miR-630 in clear cell renal cell carcinoma is associated with lower overall survival. AB - INTRODUCTION: MicroRNAs (miRNAs) are noncoding RNAs that regulate multiple cellular processes during cancer progression. MiR-630 has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer and gastric cancer. However, the regulation of miR-630 in clear cell renal cell carcinoma (ccRCC) has not yet been reported before. METHODS: Expression of miR 630 was evaluated by quantitative real-time PCR in tumour and their normal matched tissues in n = 92 ccRCC patients, and its association with overall survival of patients was analyzed by statistical analysis. RESULTS: The expression level of miR-630 was significantly higher in renal cancer in comparison to normal matched tissue (P < 0.05). It is also proved that miR-630 expression was to be associated with renal cancer histologic grade, lymphnode metastasis, distant metastasis (P < 0.05). In addition, the Kaplan-Meier survival curves revealed that high miR-630 expression was associated with poor prognosis in ccRCC patients. miR-630 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis. CONCLUSIONS: The study proves for the first time that miR-630 is upregulated in a majority of ccRCC patients. It also shows that miR-630 expression is an independent prognostic factor for patients with renal cancer, which might be a potential valuable biomarker for ccRCC. PMID- 25031756 TI - Protective effects of bifidobacterial adhesin on intestinal mucosa of stressed male rats via modulation of inflammation. AB - This study aimed to assess BA impact on inflammation markers and repair of intestinal mucosa. Forty-eight rats were randomly divided into stress (n = 24) and BA (n = 24) groups. Stress was induced by fettering in all animals, fed enterally with 125.4 kJ/kg/d and 0.2 g/kg/d nitrogen. Then, rats were treated for 8 days with 5 mg/kg/d BA (BA group) or 5 mg/kg/d saline (Stress group). Levels of NF-kappaB, IL-10, TNF-alpha, and IFN-gamma were measured at different time points, in plasma and intestinal mucosa samples. Changes in intestinal mucosa morphology were observed by electron microscopy. Plasma and/or mucosal levels of NF-kappaB, TNF-alpha, and IFN-gamma were significantly higher in both groups after stress induction (P < 0.05). These high levels persisted in control animals throughout the experiment, and were significantly reduced in the BA group, 3 and 8 days after stress induction (P < 0.05). Interestingly, IL-10 levels were increased after BA treatment (P < 0.05). At day 8, ileal mucosal villi and crypt structure were significantly restored in the BA group. Bifidobacterial adhesin plays a role in repairing intestinal mucosa injury after stress by regulating the release of inflammatory mediators in the intestinal mucosa. PMID- 25031758 TI - Three-year follow-up results for non-surgical root canal therapy of idiopathic external root resorption on a maxillary canine with MTA: a case report. AB - External root resorption (ERR) is an uncommon and intractable disease. Treatment alternatives are case-dependant and aim for the repair of the resorptive lesion and long-term retention of the tooth. A forty-year-old Asian female was diagnosed with idiopathic ERR on tooth #11 (the left maxillary canine) by CBCT. Non surgical root canal therapy was completed with the aid of an operating microscope. The apical third of the root canal was filled with warm gutta-percha and the resorption defect was filled with mineral trioxide aggregate (MTA). The periapical radiographs were taken immediately after operation, one-month follow up, six-month follow-up and three-year follow-up, respectively. Clinically, the canine was asymptomatic, and no evidence of any further resorption was found. The six-month follow-up radiograph showed initial healing of the bony lesion, while the three-year follow-up radiograph manifested almost complete healing. MTA can be a superior material to be successfully used in the non-surgical treatment of ERR. CBCT is very useful for evaluating the true nature and severity of absorption lesions in root resorption. It is the first complete case report from China about non-surgical treatment of severe ERR along with a relatively long term follow-up. PMID- 25031757 TI - Small cell carcinoma of the endometrium: a case report with emphasis on the cytological features. PMID- 25031759 TI - Intraneural perineurioma affecting multiple nerves: a case report and literature review. AB - Intraneural perineurioma is a neoplasm of perineurial cells, corresponding to WHO grade I. We present a case of intraneural perineurioma affecting multiple nerves, which usually involved one or two of major nerve trunks in one patient. We describe the clinical presentation, magnetic resonance (MR) neurography characteristics, and pathological characteristics. The differential diagnosis with other diseases, such as neurofibroma, Schwannomatosis and HNPP, will also be discussed. We also review the literature in efforts to highlight recent studies on intraneural perineurioma and heighten and awareness for the possible presentations of this disorder. PMID- 25031760 TI - An autopsy case of infantile-onset vanishing white matter disease related to an EIF2B2 mutation (V85E) in a hemizygous region. AB - We report a rare autopsy case of early infantile-onset vanishing white matter disease, with a submicroscopic deletion of 14q24.3, which included EIF2B2 and a missense mutation of EIF2B2 (V85E) of the remaining allele. The patient was a 4 year-old boy, who was found to have suddenly died during sleep. Physical and mental development began to deteriorate after convulsions at 10 month of age, and did not recover to baseline measurements. At autopsy, the brain showed a marked decrease in volume of white matter, with no typical cystic rarefaction. Histopathologically, the affected white matter showed diffuse loss of myelin fibers, meager astrogliosis with dysmorphic astrocytes, and loss of oligodendrocytes. Proliferative and apoptotic markers were negative for oligodendrocytes in the severely affected area. These findings may be related to the severity of the disease, and might be a feature of the EIF2B2 mutation pattern of the patient. Additionally, unusual fatty infiltration of both ventricles of the heart was found. These findings were suspected as early pathology of arrhythmogenic right ventricular cardiomyopathy due to characteristic gene mutation in the present case. In the present case, the defect EIF2B2 caused by hemizygosity may be related to early onset of the disease and the unusual pathological changes with vulnerability of oligodendrocytes and astrocytes, as well as cardiac abnormalities and sudden unexpected death. PMID- 25031761 TI - Intravascular large B-cell lymphoma with pontine involvement successfully treated with R-CHOP therapy and intrathecal administration: a case report and review of literature. AB - A 46-year-old man developed a fever and cough, and computed tomography showed multiple, nodular infiltrative shadows in lungs. He was diagnosed as having intravascular large B-cell lymphoma (IVLBCL). Brain magnetic resonance imaging (MRI, T2W1) showed an abnormal signal area in the pons, which was IVLBCL involvement. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy and intrathecal (I.T.) injection of methotrexate, cytarabine and prednisolone were selected. Complete remission (CR) was achieved and pontine involvement disappeared. A total of 8 courses of R-CHOP therapy and 4 courses of I.T. were performed. CR has been maintained for 1 year and 2 months. PMID- 25031762 TI - Perineal lipoblastoma: a case report and review of literature. AB - Lipoblastoma is a rare benign mesenchymal tumor that composes of embryonal white fat tissue and typically occurs in infants or young children under 3 years of age. It usually affects the extremities, trunk, head, and neck. The perineum is a rare location with only 7 cases reported in the literature. We describe a case of 3-year-old girl with a lipoblastoma arising from perineum. An approximately 4.5 cm * 3.5 cm * 2.5 cm nodule was resected in left perineum with satisfied results. Pathological examination showed that it was composed of small lobules of mature and immature fat cells, separated by fibrous septa containing small dilated blood vessels. The left perineal lipoblastoma, although rare, should be differentiated from some other mesenchymal tumors with similar histologic and cytological features. PMID- 25031763 TI - Pseudomembranous trigonitis in a male with Klinefelter syndrome: a case report and evidence of a hormonal etiology. AB - Klinefelter syndrome is a clinical syndrome with a distinct 47, XXY karyotype. Patients are characterized by a tall eunuchoid stature, small testes, hypergonotrophic hypogonadism, gynecomastia, learning difficulties and infertility. These patients have also been found to have raised estrogen levels. We report a 16 year old boy with Klinefelter syndrome presenting to our institution with gross hematuria. Cystoscopy and biopsy revealed the diagnosis of pseudomembranous trigonitis. Immunohistochemical stains showed an increase in estrogen and progesterone receptors in the trigone area but not in the rest of the bladder. In view of the patient's mildly raised estrogen levels and the histological findings, we postulate that estrogen is the driver of the development of pseudomembranous trigonitis. This is the first reported case of pseudomembranous trigonitis seen in association with Klinefelter syndrome, and also the first case of pseudomembranous trigonitis occurring within the male adolescent age group. PMID- 25031764 TI - Gastroblastoma in a 12-year-old Chinese boy. AB - Gastrablastoma is a rare epitheliomesenchymal biphasic tumor of stomach in children and young adults first reported by Miettinen et al in 2009. Five cases have been reported up to date including only one case with the nodal metastasis and distant metastases. With little atypism gastroblastoma is suggested to be a low-grade malignancy. Here we report one case of gastroblastoma in a 12-year-old boy with review of the literature. This is the first case of gastroblastoma in Chinese to our knowledge. PMID- 25031765 TI - Primary multiple clear cell variant urothelial carcinomas of urinary bladder: a rare case report. AB - Clear cell variant urothelial carcinoma of urinary bladder was very rare. There were only 6 report articles included by Pubmed and total 8 cases had been described till now. All of the past reports described single tumor of urinary bladder, but multiple carcinomas had not been reported. Here we reported a 65 years-old Chinese man who complained of intermittent gross hematuria and odynuria for more than 2 months in January 2013. Only one cauliflower-like tumor was detected approximately in the left wall of the urinary bladder with cystoscopy and the biopsy specimen was diagnosed as "urothelial carcinoma, high grade". However, three tumors were found in anterior wall (*2) near neck of urinary bladder and posterior wall (*1) of the urinary bladder during transurethral resection of the bladder tumor. Typical urothelial carcinoma with partial clear cell appearance made it difficult to make a precise pathological diagnosis and immunohistochemical stain helped to diagnose the case as clear cell variant urothelial carcinoma, but not metastasis of the renal cell carcinoma. Finally, computerized tomographic scanning confirmed that there was no primary tumor in the kidney. The clinical and pathological characteristic had not been identified for the limited reports. More work should be done to know this kind of tumor well for guiding clinical therapy. PMID- 25031766 TI - Expression of autophagy related proteins in invasive lobular carcinoma: comparison to invasive ductal carcinoma. AB - The aim of this study is to compare the expression of autophagy related proteins in invasive lobular carcinoma (ILC) with that of autophagy related proteins in invasive ductal carcinoma (IDC), and to determinate its implication. Tissue microarray containing 114 ILC and 692 IDC was constructed, and immunohistochemistry was performed for autophagy related protein (beclin-1, LC3A, LC3B, p62) and Ki-67. No significant difference in expression of autophagy related proteins between pleomorphic type (n = 12) and classic type (n = 102) of ILC was observed, whereas ILC and IDC showed distinguished features that tumoral beclin-1, stromal LC3A, tumoral LC3B, tumoral p62 were highly expressed in IDC and tumoral BNIP3 was highly expressed in ILC (P < 0.001). Beclin-1 expression was correlated with ER negativity (P = 0.016) and TNBC type (P = 0.024). BNIP3 expression was correlated with ER positivity (p = 0.040). Using multivariate Cox analysis, shorter overall survival was associated with tumoral beclin-1 positivity (hazard ratio: 21.19, 95% CI: 1.098-409.1, P = 0.043). In conclusion, ILC and IDC showed different expression pattern of autophagy-related proteins in tumor and stroma that demonstrated by higher expression of tumoral beclin-1, stromal LC3A, tumoral LC3B, tumoral p62 in IDC, and higher expression of tumoral BNIP3 in ILC. PMID- 25031767 TI - Features of intraventricular tanycytic ependymoma: report of a case and review of literature. AB - Tanycytic ependymoma is the rarest variant of ependymoma and occurs primarily in the spinal cord. Intracranial cases are even rarer. Only 9 ventricular and 5 subcortical tanycytic ependymoma have been reported in the literature. Amongst the 9 ventricular cases, only one tumor arose from the third ventricle. We report here another case of tanycytic ependymoma arising from the third ventricle completed with immunohistochemical, ultrastructural, and molecular pathology study. The patient was a 44 year-old male who presented with headache, nausea and visual disturbances of a few months duration. Neuroradiological findings showed a well-defined mass arising from the posterolateral wall of third ventricle. Histologically the tumor was composed of monotonous spindle cells arranged in fascicles without definitive perivascular rosettes. The tumor cells were diffusely positive for glial fibrillary acidic protein and epithelial membrane antigen, showed faint immunoreactivity for synaptophysin but were negative for neurofilament proteins and Ki-67 was less than 1%. Molecular studies showed absence of isocitrate dehydrogenase gene 1 and 2 mutation. A diagnosis of tanycytic ependymoma (TE) was made. From literature review with our current case included, intraventricular tanycytic ependymomas ranged from 1.8 to 4.0 cm. The age of patients ranged from 3.5 to 75 years with a mean age of 37.5 and a male predominance. The tumors occurred as well-defined, solitary ventricular mass without significant peritumoral edema with or without cystic changes. Histopathology and immunohistochemical profile are rather similar among different tumors. The immediate to short term outcome is excellent but long term follow up data is lacking. PMID- 25031768 TI - Rosai-Dorfman disease of the pericardium: a case report and review of literature. AB - Rosai-Dorfman disease (RDD) is an uncommon histiocytic disease of unknown etiology. It typically presents as massive lymphadenopathy with a predilection for the cervical lymph nodes of children and young adults. However, extranodal involvement is not uncommon and may cause confusion with other neoplasms or reactive disease. We describe here a unique case of extranodal RDD manifesting as a pericardial mass in a 69-year-old man. The lesion was detected by computed tomography during a periodic examination of the chest. Subsequently positron emission tomography scan showed mild increase of flurodeoxyglucose uptake. Clinically, it was supposed to be a mesothelioma. Histological examination showed the typical features of RDD confirmed by the staining of S100 protein, which highlighted the emperipolesis of the characteristic histiocytes. To the best of our knowledge, pericardial RDD represents an extremely rare condition and should be included in the differential diagnosis of pericardial neoplasms. PMID- 25031769 TI - HHV-6-associated acute lymphadenitis in immunocompetent patients: a case report and review of literature. AB - Human herpesvirus type 6 (HHV-6) has been well described as an agent in immunocompromised hosts, but is a rare cause of acute lymphadenitis in immunocompetent adults. We report an immunocompetent adult with HHV-6-associated acute lymphadenitis. The patient was an elderly man who presented with fever and generalized lymphadenopathy. Microscopically, the lymph node showed diffuse paracortical expansion and scattered large atypical lymphoid cells with large nucleus and eosinophilic nucleoli, resembled immunoblasts. Intranuclear eosinophilic viral inclusions can be found. Immunohistochemical study showed that the large atypical lymphoid cells were positive for CD3 and CD4, but negative for CD8, CD20, CD79a, CD30, ALK, CK, EBV-LMP, and CD56. The antibody against HHV-6 envelope glycoprotein highlighted the viral inclusions which were mostly cytoplasmic with a Golgi distribution. Literatures of HHV-6 associated acute lymphadenitis in immunocompetent patients were reviewed. PMID- 25031770 TI - Multilocular bronchogenic cyst of the bilateral adrenal: report of a rare case and review of literature. AB - PURPOSE: Bronchogenic cysts are rare benign congenital anomalies, originating from the embryonic foregut ventral segment. Adrenal bronchogenic cyst is a rare form of this anomaly. One extremely rare case of bilateral adrenal multilocular bronchogenic cyst in our hospital was reported and the relevant literatures were reviewed. Significant findings: A 51-year-old man suffered from an intermittent vague headache, fatigue and hypertension history for 2 years, which were gradually worsened in a week. Imaging tests showed bilateral suprarenal mass and left renal cysts. After underwent two retroperitoneal laparoscopic adrenal gland tumor separately, they were all proved to be both the multilocular bronchogenic cyst located in bilateral adrenal gland by histopathological examination. CONCLUSIONS: This report confirms the bronchogenic cyst that can be involved bilateral joint in the adrenal gland. And we demonstrated retroperitoneoscopic surgical management is effective in the treatment of the disease. PMID- 25031771 TI - Six cases of aggressive natural killer-cell leukemia in a Chinese population. AB - Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy that is particularly common among the Asian population. In the current study, we retrospectively evaluated six Chinese ANKL patients, including five males and one female, with a median age of 42 years (range 22 to 50 years). A number of unusual pathogenic manifestations were found in these ANKL patients, such as isolated extraocular muscle involvement, and hemophagocytic syndrome (HPS) with acute renal failure and multiple cavity effusion. Four of the patients died between two and six months after the diagnosis; however, there were two ANKL cases whose clinical behavior differed from the typical clinical course. One survived for over 30 months after splenectomy and chemotherapy treatment, and another ANKL case derived from chronic lymphoproliferative disorders of NK-cells (CLPD-NK) was treated with allogeneic bone marrow transplant (allo-BMT) and survived over 18 months. In conclusion, four cases experienced an aggressive clinical course whereas two demonstrated an indolent manifestation of their disease. New therapeutic regimens including allo-BMT should be optimized in order to improve outcomes of this disease. PMID- 25031772 TI - Development of angioimmunoblastic T-cell lymphoma after treatment of diffuse large B-cell lymphoma: a case report and review of literature. AB - Cases of diffuse large B-cell lymphoma (DLBCL) arising after the initial diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and DLBCL synchronous with AITL have been reported. To date, there is no report on the subsequent development of AITL in patients with DLBCL. Here we presented a rare case of AITL developing six months after the initial diagnosis of DLBCL. In order to investigate the clinical and molecular features of patients with AITL and DLBCL, we also reviewed the literature on AITL patients developing DLBCL, and patients with composite AITL and DLBCL. PMID- 25031773 TI - Mast cell leukemia with prolonged survival on PKC412/midostaurin. AB - Mast cell leukemia (MCL) is a rare and aggressive form of systemic mastocytosis. There are approximately 50 reported cases since 1950s. MCL is refractory to cytoreduction chemotherapy and the average survival is only six months. We report a MCL case in a 71 year-old woman with high tumor load at the initial presentation in 2005, who did not respond to either interleukin-2 or dasatinib therapy. After enrolled in a clinical trial of PKC412 (or Midostaurin) with a daily dose of 100 mg, the patient responded well to PKC412 and became transfusion independent in three months. Since then, her disease had been stably controlled. This is the first report of a high-tumor-load MCL case which achieved prolonged survival (101 months) by PKC 412. The 101-month overall survival is the longest among reported MCL cases in the English literature. PMID- 25031774 TI - Solitary fibrous tumor of the central nervous system: report of 2 cases and review of literature. AB - Solitary fibrous tumors (SFTs) rarely occur in the central nervous system (CNS). Involvement of the brainstem and pineal gland is rarely recorded. Herein, we represent 2 cases of SFTs and firstly report SFT of the pineal gland. Cranial MR imaging showed isointense to hypointense signal intensity, and marked enhancement. Microscopically, the tumors showed characteristic "patternless pattern" architecture. Elongated tumour cells formed fascicles alternating with hypocellular densely collagenous stroma. Immunohistochemistry for CD34, BCL2, and CD99 favors the definitive diagnosis of SFT. It is difficult to predict prognosis in patients with intraventricular SFT. In general, complete surgical resection may offer the best chance of a favorable clinical outcome. PMID- 25031775 TI - Pulmonary mucormycosis with embolism: two autopsied cases of acute myeloid leukemia. AB - Mucormycosis is an increasingly important cause of morbidity and mortality for patients with hematological malignancies. The diagnosis of mucormycosis usually requires mycological evidence through tissue biopsy or autopsy because the signs and symptoms are nonspecific and there are currently no biomarkers to identify the disease. We herein present two autopsied cases of acute myeloid leukemia with prolonged neutropenia who developed invasive mucormycosis accompanied by pulmonary artery embolism. Our cases were featured by unexplained fever and rapidly progressive dyspnea. Computed tomography scan detected nodular lesions or nonspecific consolidations in the lungs. Cultures, cytological study, and serum fungal markers consistently gave negative results. Autopsy revealed embolism of the pulmonary artery which consisted of fibrin clots by filamentous fungi. Genomic DNA was extracted from the paraffin-embedded clots and was applied to polymerase chain reaction amplification, leading to the diagnosis of infection by Rhizopus microsporus. We should carefully search for life-threatening pulmonary embolism when patients with hematological malignancies develop pulmonary mucormycosis. PMID- 25031776 TI - Paneth cell-like change in benign prostate can account for P504S (AMACR) reactivity. AB - Paneth cell-like neuroendocrine metaplasia of benign and cancerous prostate was described in 1992. Here, we note that P504S (AMACR), the cytoplasmic marker for prostate cancer used alone or in concert with basal cell markers, can be strongly reactive in benign prostatic acini with Paneth cell-like change. PMID- 25031777 TI - Pigmented anal squamous intraepithelial neoplasia: a case report and review of literature. PMID- 25031778 TI - Blocking TRAIL-DR5 signaling with soluble DR5 alleviates acute kidney injury in a severely burned mouse model. AB - Acute kidney injury (AKI) predicts high mortality in severely burned patients. Apoptosis plays a significant role during AKI; however, the apoptotic mechanisms underlying AKI induced by burn injury are not clear. Here, we report a critical role for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) Death receptor 5 (DR5) signaling in the pathogenesis of AKI. C57BL/6 male mice were subjected to full thickness scald burn. Apoptosis was significantly up regulated in mouse kidney 24 h after the burn. Meanwhile, the TRAIL and DR5 expression levels were significantly increased in the kidney 24 h after the burn. Soluble DR5 treatment reduced apoptotic cell death and alleviated kidney injury induced by the burn through blocking the interaction of endogenous TRAIL with DR5. These results demonstrated that TRAIL plays a deleterious role in AKI pathogenesis induced by scald burns. Inhibition of TRAIL function in the kidney may represent a novel protective strategy to treat AKI in patients with burns. PMID- 25031779 TI - MT2-MMP expression associates with tumor progression and angiogenesis in human lung cancer. AB - Matrix metalloproteinases (MMPs) are a family of important proteolytic enzymes that play an important role in the remodeling of the tumor microenvironment and associate with tumorigenesis and metastasis. We previously reported that membrane type-2 MMP (MT2-MMP) is highly expressed in human esophageal cancer tissues, and its expression level is positively correlated to tumor size and intratumoral angiogenesis. In order to reveal whether MT2-MMP expression is operative in human lung cancer and its underlying physio-pathological role, in the present study, we examined both mRNA and protein expression levels of MT2-MMP in non-small cell lung caner (NSCLC) tissues and in adjacent normal tissues by using real-time RT PCR and immunohistochemistry respectively, which showed that both MT2-MMP mRNA (P=0.0359) and protein (P<0.0001) expression levels were significantly increased in cancer tissues in contrast to adjacent normal tissues. Moreover, we also found that the MT2-MMP protein level in cancer tissues positively correlated to lymph node metastasis (P=0.0483), tumor stage (P=0.0483), intra-tumoral microvessel density (MVD) (P=0.0445). We have not found statistically significant correlation between MT2-MMP expression and patients' prognoses, but we found that the patients with both higher MT2-MMP protein expression and higher intra-tumoral microvessel density showed better prognoses than that of the patients with either higher MT2-MMP protein expression or higher intra-tumoral microvessel density (P=0.0311). Thus, our data suggest that MT2-MMP expression positively involves in NSCLC, and might play an important role in promoting the tumor progression and intra-tumoral angiogenesis in NSCLC. PMID- 25031780 TI - miR-21 inhibitor suppresses proliferation and migration of nasopharyngeal carcinoma cells through down-regulation of BCL2 expression. AB - This study is to investigate the expression of miR-21 in nasopharyngeal carcinoma (NPC) cells, and the effect of miR-21 in the biological behavior and expression of B-cell lymphoma 2 (BCL2) in NPC cells. Paired NPC and adjacent non-tumor tissues were obtained from 53 patients who underwent primary surgical resection of NPC tissues. Luciferase reporter assay was performed to test whether BCL2 is a direct target of miR-21. Methylthiazolyl blue tetrazolium assay and colony assay were used to evaluate the effect of miR-21 on NPC cell proliferation. Transwell and wound-healing assays were carried out to test the effect of low expression of miR-21 on cancer cell migration and invasion. QRT-PCR and Western blotting were used to measure the levels of mRNA and protein expression, respectively. Tumor tissues showed a positive correlation between the levels of miR-21 and BCL2 protein expression. Cells transfected with miR-21 inhibitor healed slower compared the control (P < 0.05). In addition, cell migration was notably inhibited by the down-regulation of miR-21 in vitro (P < 0.05). The reduction in miR-21 expression showed a remarkable effect on the biological behavior of NPC cell clone formation (P < 0.05). Low expression of miR-21 by transfection with miRNA expression plasmid led to a decrease in BCL2 expression, which was accompanied by reduced migration and proliferation of the cancer cells. Our results demonstrated that miR-21 inhibitor down-regulated BCL2 expression level, suggesting that BCL2 might be a target gene for the initiation and development of NPC cells. PMID- 25031781 TI - Analysis of male reproductive parameters in a murine model of mucopolysaccharidosis type I (MPS I). AB - Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder (LSD) that is characterised by alpha-L-iduronidase (Idua) deficiency and continuous deposition of glycosaminoglycans (GAGs), which consequently interferes with cell signalling mechanisms and results in multisystemic and progressive symptoms. The animal model of MPS I (Idua-/-) has been widely studied to elucidate the consequences and progression of the disorder; however, studies specifically assessing the male reproductive tract are lacking. The aim of this study was to evaluate some of the reproductive characteristics of male MPS I mice in two phases of life. Reproductive organ biometry, sperm counts, sperm morphological evaluation, plasma testosterone measurements and histopathological, histomorphometrical and immunohistochemical analysis were performed in 3- and 6-month-old C57BL/6 Idua+/+ and Idua-/- mice. Seminal vesicle weights were decreased in both the 3- and 6 month-old Idua-/- mice. Decrease in sperm counts and the majority of the histopathological signs were observed in the 6-month-old Idua-/- mice. No differences were detected in the sperm morphological analysis. Immunohistochemistry revealed that seminiferous tubules from 3-month-old Idua-/- mice were more intensely stained with anti-caspase-3 than 3-month-old Idua+/+ mice, but no difference was found at 6 months. These results suggest that MPS I interferes with male reproductive parameters both in 3 and 6-month-old animals and histopathological signs are more pronounced in 6-month-old mice, indicating that the effects of the disorder may intensify with the disease progression. PMID- 25031782 TI - Increased expression of miRNA-182 in colorectal carcinoma: an independent and tissue-specific prognostic factor. AB - Increasing evidence has revealed that miRNAs play a pivotal role in multiple processes of carcinogenesis, and are being explored as diagnostic, prognostic and predictive biomarker. In this study, we investigated the status of miR-182 expression in colorectal carcinoma (CRC) by in situ hybridization and its underlying clinicopathologic significance for patients with CRC. We found that 79/138 (57.25%) CRCs had high-level expression of miR-182, while 17/67 (25.37%) normal mucosa tissues had high-level expression of miR-182. The expression level of miR-182 was remarkably up-regulated in CRC tissues compared with non neoplastic normal tissues (P < 0.001). The over-expression of miR-182 in cancer parenchyma cells in CRC were strongly correlated with T-stage (P = 0.020), lymph node metastasis (P = 0.003), distant metastasis (P = 0.002), and Dukes' stage (P = 0.005) in patients with CRC. Patients with high-level expression of miR-182 had short overall survival time than those with low-level expression of miR-182 (P < 0.001). Univariate and multivariate survival analyses further showed that miR-182 expression was a potential unfavorable prognostic factor for CRC, suggesting a potential application of miR-182 in prognosis prediction and therapeutic application in CRC. PMID- 25031783 TI - Recurrent epistaxis caused by an intranasal supernumerary tooth in a young adult. AB - PATIENT: Male, 27. FINAL DIAGNOSIS: Recurrent epistaxis. SYMPTOMS: Nasal bleeding. MEDICATION: -. CLINICAL PROCEDURE: -. SPECIALTY: Pediatrics and Neonatology. OBJECTIVE: Congenital defects/diseases. BACKGROUND: Recurrent epistaxis is a common disorder among children and young adults. We report an unusual cause, intranasal supernumerary tooth causing friction with Little's area of the nasal septum. CASE REPORT: A 22-year-old male presented with recurrent, mild, unilateral left-sided epistaxis once to twice per month for 3 years. This usually occurred after minor nasal trauma or rubbing his nose. The patient also suffered from recurrent tonsillitis. There was neither history of blood transfusion or nasal packing, nor a history suggestive of bleeding diathesis. Anterior rhinoscopy revealed ivory white nasal mass antero-inferiorly in the left nasal cavity touching Little's area. There was no bleeding. Nasal endoscopy showed a white cylindrical bony mass 1 cm long arising from the floor of the nose, with no attachment to the nasal septum or the lateral wall of the nose. Examination of the right nasal cavity was unremarkable. CONCLUSIONS: Nasal teeth result from the ectopic eruption of supernumerary teeth and may cause a variety of symptoms including recurrent epistaxis. Their clinical and radiologic presentation is so characteristic that their diagnosis is not difficult. CT scan is helpful in planning management. Early extraction prevents further complications and prevents further attacks of epistaxis. PMID- 25031784 TI - Oxidative stress and antioxidant strategies in cardiovascular disease. PMID- 25031785 TI - Management of early asymptomatic gastrointestinal stromal tumors of the stomach. AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract. Approximately two thirds of clinically manifest tumors occur in the stomach, nearly one third in the small bowel, and the rest in the colorectal region with a few cases in the esophagus. GIST originate within the smooth muscle layer in the wall of the tubular gastrointestinal tract and grow mostly toward the serosa, far less often toward the mucosa. In the latter case, ulceration may develop and can cause gastrointestinal bleeding as the cardinal symptom. However, most GIST of the stomach are asymptomatic. They are increasingly detected incidentally as small intramural or submucosal tumors during endoscopy and particularly during endoscopic ultrasound. Epidemiological and molecular genetic findings suggest that early asymptomatic GIST of the stomach (< 1 cm) show self-limiting tumorigenesis. Thus, early (< 1 cm) asymptomatic gastric GIST (synonym: micro-GIST) are found in 20%-30% of the elderly. The mostly elderly people with early gastric GIST have an excellent GIST specific prognosis. Patients with early GIST of the stomach can therefore be managed by endoscopic surveillance. PMID- 25031787 TI - Advanced endoscopic submucosal dissection with traction. AB - Endoscopic submucosal dissection (ESD) has been established as a standard treatment for early stage gastric cancer (EGC) in Japan and has spread worldwide. ESD has been used not only for EGC but also for early esophageal and colonic cancers. However, ESD is associated with several adverse events, such as bleeding and perforation, which requires more skill. Adequate tissue tension and clear visibility of the tissue to be dissected are important for effective and safe dissection. Many ESD methods using traction have been developed, such as clip with-line method, percutaneous traction method, sinker-assisted method, magnetic anchor method, external forceps method, internal-traction method, double-channel scope method, outerroute method, double-scope method, endoscopic-surgical platform, and robot-assisted method. Each method has both advantages and disadvantages. Robotic endoscopy, enabling ESD with a traction method, will become more common due to advances in technology. In the near future, simple, noninvasive, and effective ESD using traction is expected to be developed and become established as a worldwide standard treatment for superficial gastrointestinal neoplasias. PMID- 25031786 TI - Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer. AB - Pancreatic cancer is a highly lethal disease with a genetic susceptibility and familial aggregation found in 3%-16% of patients. Early diagnosis remains the only hope for curative treatment and improvement of prognosis. This can be reached by the implementation of an intensive screening program, actually recommended for individuals at high-risk for pancreatic cancer development. The aim of this strategy is to identify pre-malignant precursors or asymptomatic pancreatic cancer lesions, curable by surgery. Endoscopic ultrasound (EUS) with or without fine needle aspiration (FNA) seems to be the most promising technique for early detection of pancreatic cancer. It has been described as a highly sensitive and accurate tool, especially for small and cystic lesions. Pancreatic intraepithelial neoplasia, a precursor lesion which is highly represented in high risk individuals, seems to have characteristics chronic pancreatitis-like changes well detected by EUS. Many screening protocols have demonstrated high diagnostic yields for pancreatic pre-malignant lesions, allowing prophylactic pancreatectomies. However, it shows a high interobserver variety even among experienced endosonographers and a low sensitivity in case of chronic pancreatitis. Some new techniques such as contrast-enhanced harmonic EUS, computer-aided diagnostic techniques, confocal laser endomicroscopy miniprobe and the detection of DNA abnormalities or protein markers by FNA, promise improvement of the diagnostic yield of EUS. As the resolution of imaging improves and as our knowledge of precursor lesions grows, we believe that EUS could become the most suitable method to detect curable pancreatic neoplasms in correctly identified asymptomatic at-risk patients. PMID- 25031788 TI - Laparoscopic management of gastric gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) are the most frequent gastrointestinal tumors of mesodermal origin. Gastric GISTs represent approximately 70% of all gastrointestinal GISTs. The only curative option is surgical resection. Many surgical groups have shown good results with the laparoscopic approach. There have not been any randomized controlled trials comparing the open vs laparoscopic approach, and all recommendations have been based on observational studies. The experience obtained from gastric laparoscopic surgery during recent decades and the development of specific devices have allowed the treatment of most gastric GISTs through the laparoscopic approach. PMID- 25031789 TI - Histology assessment of bipolar coagulation and argon plasma coagulation on digestive tract. AB - AIM: To analyze the effect of bipolar electrocoagulation and argon plasma coagulation on fresh specimens of gastrointestinal tract. METHODS: An experimental evaluation was performed at Hospital das Clinicas of the University of Sao Paulo, on 31 fresh surgical specimens using argon plasma coagulation and bipolar electrocoagulation at different time intervals. The depth of tissue damage was histopathologically analyzed by single senior pathologist unaware of the coagulation method and power setting applied. To analyze the results, the mucosa was divided in superficial mucosa (epithelial layer of the esophagus and superficial portion of the glandular layer of the stomach and colon) intermediate mucosa (until the lamina propria of the esophagus and until the bottom of the glandular layer of the stomach and colon) and muscularis mucosa. Necrosis involvement of the layers was compared in several combinations of power and time interval. RESULTS: Involvement of the intermediate mucosa of the stomach and of the muscularis mucosa of the three organs was more frequent when higher amounts of energy were used with argon plasma. In the esophagus and in the colon, injury of the intermediate mucosa was frequent, even when small amounts of energy were used. The use of bipolar electrocoagulation resulted in more frequent involvement of the intermediate mucosa and of the muscularis mucosa of the esophagus and of the colon when higher amounts of energy were used. In the stomach, these involvements were rare. The risk of injury of the muscularis propria was significant only in the colon when argon plasma coagulation was employed. CONCLUSION: Tissue damage after argon plasma coagulation is deeper than bipolar electrocoagulation. Both of them depend on the amount of energy used. PMID- 25031790 TI - Improved endoscopic retrograde cholangiopancreatography brush increases diagnostic yield of malignant biliary strictures. AB - AIM: To determine if a new brush design could improve the diagnostic yield of biliary stricture brushings. METHODS: Retrospective chart review was performed of all endoscopic retrograde cholangiopancreatography procedures with malignant biliary stricture brushing between January 2008 and October 2012. A standard wire guided cytology brush was used prior to protocol implementation in July 2011, after which, a new 9 French wire-guided cytology brush (Infinity sampling device, US Endoscopy, Mentor, OH) was used for all cases. All specimens were reviewed by blinded pathologists who determined whether the sample was positive or negative for malignancy. Cellular yield was quantified by describing the number of cell clusters seen. RESULTS: Thirty-two new brush cases were compared to 46 historical controls. Twenty-five of 32 (78%) cases in the new brush group showed abnormal cellular findings consistent with malignancy as compared to 17 of 46 (37%) in the historical control group (P = 0.0003). There was also a significant increase in the average number of cell clusters of all sizes (21.1 vs 9.9 clusters, P = 0.0007) in the new brush group compared to historical controls. CONCLUSION: The use of a new brush design for brush cytology of biliary strictures shows increased diagnostic accuracy, likely due to improved cellular yield, as evidenced by an increase in number of cellular clusters obtained. PMID- 25031791 TI - Conservative approach in Peutz-Jeghers syndrome: Single-balloon enteroscopy and small bowel polypectomy. AB - AIM: To assess the usefulness of the balloon assisted enteroscopy in preventing surgical intervention in patients with Peutz-Jeghers syndrome (PJS) having a small bowel large polyps. METHODS: Seven consecutive asymptomatic pts (age 15-38 years) with PJS have been collected; six underwent polypectomy using single balloon enteroscopy (Olympus SIF Q180) with antegrade approach using push and pull technique. SBE system consists of the SIF-Q180 enteroscope, an overtube balloon control unit (OBCU Olympus Balloon Control Unit) and a disposable silicone splinting tube with balloon (ST-SB1). All procedures were performed under general anesthesia. Previously all pts received wireless capsule endoscopy (WCE). Prophylactic polypectomy was reserved mainly in pts who had polyps > 15 mm in diameter. The balloon is inflated and deflated by a balloon control unit with a safety pressure setting range from -6.0 kPa to +5.4 kPa. Informed consent has been obtained from pts or parents for each procedure. RESULTS: Six pts underwent polypectomy of small bowel polyps; in 5 pts a large polyp > 15 mm (range 20-50 mm in diameter) was resected; in 1 patient with WCE negative, SBE was performed for previous surgical resection of gastrointestinal stromal tumors. In 2 pts endoscopic clips were placed due to a polypectomy. No surgical complication have been reported. SBE with resection of small bowel large polyps in PJS pts was useful to avoid gastrointestinal bleeding and emergency laparotomy due to intestinal intussusceptions. No gastrointestinal tumors were found in subsequent enteroscopic surveillance in all seven pts. In order surveillance, all pts received WCE, upper endoscopy, ileocolonoscopy every 2 years. No pts had extraintestinal malignant lesions. SBE was performed when WCE was positive for significant polyps (> 15 mm). CONCLUSION: The effective of prophylactic polypectomy of small bowel large polyps (> 15 mm) could be the first line treatment for conservative approach in management of PJS patients. PMID- 25031792 TI - Endoscopic and imaging appearance after injection of an ano-rectal bulking agent. AB - The use of hyaluronic acid and dextranomer (Solesta, Salix) injection in the anal canal is an emerging modality in the treatment of fecal incontinence. However, little is known regarding the endoscopic and radiological appearance following injection of this ano-rectal bulking agent. We report computed tomography and endoscopic findings after hyaluronic acid/dextranomer injection in the ano-rectal area. PMID- 25031793 TI - Intraductal papillary mucinous neoplasm of the bile duct with gastric and duodenal fistulas. AB - Intraductal papillary mucinous neoplasm (IPMN) of the bile duct is still rare and not yet understood despite of its increased incidence and similar clinicopathologic characteristics compared with IPMN of the pancreas. The fistula formation into other organs can occur in IPMN, especially the pancreatic type. To our knowledge, only two cases of IPMN of the bile duct with a choledochoduodenal fistula were reported and we have recently experienced a case of IPMN of the bile duct penetrating into two neighboring organs of the stomach and duodenum presenting with abdominal pain and jaundice. Endoscopy showed thick mucin extruding from two openings of the fistulas. Endoscopic suction of thick mucin using direct peroral cholangioscopy with ultra-slim endoscope through choledochoduodenal fistula was very difficult and ineffective because of very thick mucin and next endoscopic suction through the stent after prior insertion of biliary metal stent into choledochogastric fistula also failed. Pathologic specimen obtained from the proximal portion of the choledochogastric fistula near left intrahepatic bile duct through the metal stent showed a low grade adenoma. The patient declined the surgical treatment due to her old age and her abdominal pain with jaundice was improved after percutaneous transhepatic biliary drainage with the irrigation of N-acetylcysteine three times daily for 10 d. PMID- 25031794 TI - Current status of 3-dimensional speckle tracking echocardiography: a review from our experiences. AB - Cardiac function analysis is the main focus of echocardiography. Left ventricular ejection fraction (LVEF) has been the clinical standard, however, LVEF is not enough to investigate myocardial function. For the last decade, speckle tracking echocardiography (STE) has been the novel clinical tool for regional and global myocardial function analysis. However, 2-dimensional imaging methods have limitations in assessing 3-dimensional (3D) cardiac motion. In contrast, 3D echocardiography also has been widely used, in particular, to measure LV volume measurements and assess valvular diseases. Joining the technology bandwagon, 3D STE was introduced in 2008. Experimental studies and clinical investigations revealed the reliability and feasibility of 3D-STE-derived data. In addition, 3D STE provides a novel deformation parameter, area change ratio, which have the potential for more accurate assessment of overall and regional myocardial function. In this review, we introduced the features of the methodology, validation, and clinical application of 3D-STE based on our experiences for 7 years. PMID- 25031795 TI - Comparison of the impact of the anesthesia induction using thiopental and propofol on cardiac function for non-cardiac surgery. AB - BACKGROUND: Thiopental and propofol have been widely used for general anesthesia induction, but their impacts on cardiac function have not been well described. A recent study speculated that anesthesia induction using propofol 2 mg/kg transiently reduced left ventricular (LV) contraction by analyzing tissue Doppler derived imaging (TDI) during induction phase. The purpose of this study was to analyze and to compare the impacts of propofol- and thiopental-induction on LV function. METHODS: Twenty-four female patients with normal LV function undergoing non-cardiac surgery were randomly administered intravenous bolus thiopental (5 mg/kg, Thiopental-group, n = 12) or propofol (2 mg/kg, Propofol-group, n = 12) for anesthesia-induction. TDI of septal mitral annular velocity during systole (S'), early diastole (e') and atrial contraction (a') were determined by transthoracic echocardiography before and 1, 3, and 5 minutes after thiopental/propofol administration (T0, T1, T2, and T3, respectively). RESULTS: The bispectral index and systolic blood pressure declined significantly during anesthesia induction in both groups, however, more depressed in Thiopental-group compared with those in Propofol-group at T2 and T3 (all, p < 0.05). Among TDI two parameters demonstrated a significant inter-group difference: the S' in propofol was lower than that in Thiopental-group at T3 (p = 0.002), and a' velocities were persistently lower in Propofol-group, compared with same time values in Thiopental-group (T1, T2, and T3: p = 0.025, 0.007, and 0.009, respectively). CONCLUSION: Anesthesia induction using propofol revealed a more persistent and profound decline of LV and atrial contraction than that using thiopental. Further studies are needed to understand the clinical implication. PMID- 25031796 TI - A comparison of different techniques of two-dimensional speckle-tracking strain measurements of right ventricular systolic function in patients with acute pulmonary embolism. AB - BACKGROUND: Speckle-tracking echocardiography has been applied to measure right ventricular (RV) systolic function in various diseases. However, variations in strain measurement by different vendors have limited the application of these techniques for assessment of RV function. We sought to compare two methods for the assessment of RV systolic function in patients with acute pulmonary embolism (PE). METHODS: From August 2007 to May 2011, all consecutive PE patients were prospectively included in this cohort study. Global longitudinal strains of RV measured with EchoPAC PC software (GLSRV-EchoPAC; GE Medical Systems) and velocity vector imaging (GLSRV-VVI; Siemens Medical Systems) were recorded on the same set of echocardiographic images. RESULTS: We analyzed a total of 50 patients (12 males, 68 +/- 14 years) with acute PE in this study. GLSRV-EchoPAC and GLSRV VVI were correlated (r = 0.793, p < 0.001) and they showed significant correlations with conventional echocardiographic parameters of RV systolic function and Log B-type natriuretic peptide (BNP) level. However, GLSRV-VVI only showed significant correlations with cardiac biomarkers as serum creatinine kinase-MB (r = 0.367, p = 0.010) and tropoinin-I concentrations (r = 0.294, p = 0.040). CONCLUSION: GLSRV-VVI and GLSRV-EchoPAC showed significant correlations with conventional echocardiographic parameters of RV systolic function and LogBNP value in patients with PE. PMID- 25031797 TI - Association of myocardial angiogenesis with structural and functional ventricular remodeling in aortic stenosis patients with normal ejection fraction. AB - BACKGROUND: Although rarefaction of myocardial angiogenesis has been shown to be associated with left ventricular (LV) systolic dysfunction in animal models of ventricular hypertrophy, this relationship has not been investigated in depth nor validated in humans. We aimed to analyze the relationship of myocardial angiogenesis with various functional and structural ventricular remodeling parameters in moderate to severe aortic stenosis (AS) patients with normal LV ejection fraction (LVEF). METHODS: A total of 38 moderate or severe AS patients with LVEF > 50% were enrolled for the current study and all patients underwent LV endomyocardial biopsy at the septum during aortic valve replacement. The biopsy specimens were stained for platelet endothelial cell adhesion molecule-1 (CD31) to analyze the density of blood vessels in the myocardium. RESULTS: The degree of myocardial angiogenesis tended to increase with worse myocardial systolic function, LV filling pressure and progressed ventricular hypertrophy (Spearman's rho = -0.388, p = 0.016 for LVEF; Spearman's rho = 0.442, p = 0.007 for E/e'; Spearman's rho = 0.424, p = 0.008 for LV mass index). The degree of myocardial angiogenesis was also significantly associated with the degree of aortic valve stenosis (Spearman's rho = -0.368, p = 0.023). There was significant difference in the degree of myocardial angiogenesis according to the LV geometry (p = 0.016 for mean difference between different LV geometry groups by analysis of variance). Significant predictors of myocardial blood vessel density were LV mass index (beta = 0.398, p = 0.010) and LVEF (beta = -0.313, p = 0.028). CONCLUSION: There is a close relationship between myocardial angiogenesis and LV remodeling in moderate to severe AS patients with normal LVEF, with angiogenesis increasing with LV hypertrophy. Further studies to demonstrate the mechanism underlying this phenomenon is warranted. PMID- 25031798 TI - Pheochromocytoma as a rare hidden cause of inverted stress cardiomyopathy. AB - Stress cardiomyopathy (SCMP) is characterized by a transient left ventricular dysfunction associated with apical ballooning and compensatory hyperkinesias of the basal segments after emotional or physical stress, but inverted or mid ventricular variants of SCMP have also been described. Although catecholamine excess has been suggested as a possible pathophysiologic mechanism of SCMP, the etiology of SCMP is still unknown. Here, we report a case of inverted type of SCMP with clinical presentation mimicking acute coronary syndromes. The cause or precipitating stressor was unclear initially, but pheochromocytoma has been demonstrated as a cause of SCMP during clinical follow-up at out-patient clinic in the present case. Catecholamine-producing tumors should be included in the evaluation or management of SCMP, even though initial clinical manifestations are not suggestive for pheochromocytoma. PMID- 25031799 TI - Massive Cardiomegaly due to Dilated Cardiomyopathy Causing Bronchial Obstruction in an Infant. AB - Dilated cardiomyopathy (DCMP) remains a life threatening disease in young patients and is often difficult to differentiate from myocarditis. Early recognition and treatment of DCMP are crucial for good prognoses in this patient population. The clinical course of patients with DCMP that result in cardiogenic shock varies according to the etiology as well as patient age. The volumetric expansion of the enlarged heart can compress adjacent structures causing a number of related symptoms, especially in infants with soft cartilaginous bronchi. Therapeutic strategies for treating these issues vary according to the type of complication encountered. We report a case of severe DCMP with sudden onset of massive cardiomegaly with heart failure complicated by bronchial obstruction in an infant. PMID- 25031800 TI - Exercise-Induced Intrapulmonary Arteriovenous Shunt in a Patient Complaining of Dyspnea during Strenuous Exercise. AB - A 51-year-old highly fit man presented for dyspnea with strenuous aerobic exercise. The patient was asymptomatic and all tests were normal at rest. With increasing exercise intensity, he suddenly complained of dyspnea and showed a severe exercise-induced hypoxemia with an excessive alveolar-arterial oxygen tension difference. In agitated saline contrast echocardiography at peak exercise, a large amount of left to right shunt was identified after > 5 cardiac cycles, which suggests the presence of exercise-induced intrapulmonary arteriovenous shunt in this patient. PMID- 25031801 TI - Streptococcus constellatus community acquired pneumonia with subsequent isolated pulmonic valve endocarditis and abscess formation in a structurally normal heart. AB - Pulmonic valve infective endocarditis in isolation is a rare clinical entity. The formation of an abscess in the right ventricular outflow tract as a consequence of vegetations affecting the pulmonic valve in a structurally normal heart is extremely rare and has not been reported. We report a case of isolated pulmonic valve endocarditis complicated by a regional abscess formed within the right ventricular outflow tract caused by Streptococcus Constellatus (S. Constellatus), a member of the Streptococcus Milleri group in a young male whose risk factor was alcohol abuse and he was treated medically, a comprehensive literature review on the subject is also reported. Our case is the first reported in literature with infective endocarditis caused by S. Constellatus affecting the pulmonic valve, and the first with pulmonic valve endocarditis and perivalvular abscess formation in a structurally normal heart. PMID- 25031802 TI - Efficacy of inhaled iloprost in cor pulmonale and severe pulmonary hypertension associated with tuberculous destroyed lung. AB - Chronic obstructive pulmonary disease (COPD) is one of the causes of cor pulmonale. Cor pulmonale patients with pulmonary hypertension have a significant lower survival rate than patients without. However, there is no conclusive treatment options in cor pulmonale and pulmonary hypertension associated with COPD until now. We report a patient with cor pulmonale and pulmonary hypertension associated with severe form of COPD and tuberculous destroyed lung who achieved marked clinical, functional and echocardiographic hemodynamic improvements with inhaled iloprost for six months. PMID- 25031803 TI - Vanishing left ventricular thrombi in severe aortic stenosis with dilated cardiomyopathy. PMID- 25031804 TI - Epidural steroid injection: a need for a new clinical practice guideline. PMID- 25031805 TI - Current evidence for spinal opioid selection in postoperative pain. AB - BACKGROUND: Spinal opioid administration is an excellent option to separate the desirable analgesic effects of opioids from their expected dose-limiting side effects to improve postoperative analgesia. Therefore, physicians must better identify either specific opioids or adequate doses and routes of administration that result in a mainly spinal site of action rather than a cerebral analgesic one. METHODS: The purpose of this topical review is to describe current available clinical evidence to determine what opioids reach high enough concentrations to produce spinally selective analgesia when given by epidural or intrathecal routes and also to make recommendations regarding their rational and safety use for the best management of postoperative pain. To this end, a search of Medline/Embase was conducted to identify all articles published up to December 2013 on this topic. RESULTS: Recent advances in spinal opioid bioavailability, based on both animals and humans trials support the theory that spinal opioid bioavailability is inversely proportional to the drug lipid solubility, which is higher in hydrophilic opioids like morphine, diamorphine and hydromorphone than lipophilic ones like alfentanil, fentanyl and sufentanil. CONCLUSIONS: Results obtained from meta-analyses of RTCs is considered to be the 'highest' level and support their use. However, it's a fact that meta-analyses based on studies about treatment of postoperative pain should explore clinical surgery heterogeneity to improve patient's outcome. This observation forces physicians to use of a specific procedure surgical-based practical guideline. A vigilance protocol is also needed to achieve a good postoperative analgesia in terms of efficacy and security. PMID- 25031806 TI - Brachial plexus injury as a complication after nerve block or vessel puncture. AB - Brachial plexus injury is a potential complication of a brachial plexus block or vessel puncture. It results from direct needle trauma, neurotoxicity of injection agents and hematoma formation. The neurological presentation may range from minor transient pain to severe sensory disturbance or motor loss with poor recovery. The management includes conservative treatment and surgical exploration. Especially if a hematoma forms, it should be removed promptly. Comprehensive knowledge of anatomy and adept skills are crucial to avoid nerve injuries. Whenever possible, the patient should not be heavily sedated and should be encouraged to immediately inform the doctor of any experience of numbness/paresthesia during the nerve block or vessel puncture. PMID- 25031807 TI - Therapeutic effect of epidurally administered lipo-prostaglandin e1 agonist in a rat spinal stenosis model. AB - BACKGROUND: A lipo-prostaglandin E1 agonist is effective for the treatment of neurological symptoms of spinal stenosis when administered by an oral or intravenous route. we would like to reveal the therapeutic effect of an epidural injection of lipo-prostaglandin E1 on hyperalgesia in foraminal stenosis. METHODS: A total of 40 male Sprague-Dawley rats were included. A small stainless steel rod was inserted into the L5/L6 intervertebral foramen to produce intervertebral foraminal stenosis and chronic compression of the dorsal root ganglia (DRG). The rats were divided into three groups: epidural PGE1 (EP) (n = 15), saline (n = 15), and control (n = 10). In the EP group, 0.15 ug.kg-1 of a lipo-PGE1 agonist was injected daily via an epidural catheter for 10 days from postoperative day 3. In the saline group, saline was injected. Behavioral tests for mechanical hyperalgesia were performed for 3 weeks. Then, the target DRG was analyzed for the degree of chromatolysis, chronic inflammation, and fibrosis in light microscopic images. RESULTS: From the fifth day after lipo-PGE1 agonist injection, the EP group showed significant recovery from mechanical hyperalgesia, which was maintained for 3 weeks (P < 0.05). Microscopic analysis showed much less chromatolysis in the EP group than in the saline or control groups. CONCLUSIONS: An epidurally administered lipo-PGE1 agonist relieved neuropathic pain, such as mechanical hyperalgesia, in a rat foraminal stenosis model, with decreasing chromatolysis in target DRG. We suggest that epidurally administered lipo-PGE1 may be a useful therapeutic candidate for patients with spinal stenosis. PMID- 25031808 TI - Bupivacaine-induced Vasodilation Is Mediated by Decreased Calcium Sensitization in Isolated Endothelium-denuded Rat Aortas Precontracted with Phenylephrine. AB - BACKGROUND: A toxic dose of bupivacaine produces vasodilation in isolated aortas. The goal of this in vitro study was to investigate the cellular mechanism associated with bupivacaine-induced vasodilation in isolated endotheliumdenuded rat aortas precontracted with phenylephrine. METHODS: Isolated endothelium denuded rat aortas were suspended for isometric tension recordings. The effects of nifedipine, verapamil, iberiotoxin, 4-aminopyridine, barium chloride, and glibenclamide on bupivacaine concentration-response curves were assessed in endothelium-denuded aortas precontracted with phenylephrine. The effect of phenylephrine and KCl used for precontraction on bupivacaine-induced concentration-response curves was assessed. The effects of verapamil on phenylephrine concentration-response curves were assessed. The effects of bupivacaine on the intracellular calcium concentration ([Ca(2+)]i) and tension in aortas precontracted with phenylephrine were measured simultaneously with the acetoxymethyl ester of a fura-2-loaded aortic strip. RESULTS: Pretreatment with potassium channel inhibitors had no effect on bupivacaine-induced relaxation in the endothelium-denuded aortas precontracted with phenylephrine, whereas verapamil or nifedipine attenuated bupivacaine-induced relaxation. The magnitude of the bupivacaine-induced relaxation was enhanced in the 100 mM KCl-induced precontracted aortas compared with the phenylephrine-induced precontracted aortas. Verapamil attenuated the phenylephrine-induced contraction. The magnitude of the bupivacaine-induced relaxation was higher than that of the bupivacaine induced [Ca(2+)]i decrease in the aortas precontracted with phenylephrine. CONCLUSIONS: Taken together, these results suggest that toxic-dose bupivacaine induced vasodilation appears to be mediated by decreased calcium sensitization in endothelium-denuded aortas precontracted with phenylephrine. In addition, potassium channel inhibitors had no effect on bupivacaine-induced relaxation. Toxic-dose bupivacaine- induced vasodilation may be partially associated with the inhibitory effect of voltage-operated calcium channels. PMID- 25031809 TI - Intrathecal administration of mesenchymal stem cells reduces the reactive oxygen species and pain behavior in neuropathic rats. AB - BACKGROUND: Neuropathic pain induced by spinal or peripheral nerve injury is very resistant to common pain killers, nerve block, and other pain management approaches. Recently, several studies using stem cells suggested a new way to control the neuropatic pain. In this study, we used the spinal nerve L5 ligation (SNL) model to investigate whether intrathecal rat mesenchymal stem cells (rMSCs) were able to decrease pain behavior, as well as the relationship between rMSCs and reactive oxygen species (ROS). METHODS: Neuropathic pain of the left hind paw was induced by unilateral SNL in Sprague-Dawley rats (n = 10 in each group). Mechanical sensitivity was assessed using Von Frey filaments at 3, 7, 10, 12, 14, 17, and 24 days post-ligation. rMSCs (10 ul, 1 * 10(5)) or phosphate buffer saline (PBS, 10 ul) was injected intrathecally at 7 days post-ligation. Dihydroethidium (DHE), an oxidative fluorescent dye, was used to detect ROS at 24 days post-ligation. RESULTS: Tight ligation of the L5 spinal nerve induced allodynia in the left hind paw after 3 days post-ligation. ROS expression was increased significantly (P < 0.05) in spinal dorsal horn of L5. Intrathecal rMSCs significantly (P < 0.01) alleviated the allodynia at 10 days after intrathecal injection (17 days post-ligation). Intrathecal rMSCs administration significantly (P < 0.05) reduced ROS expression in the spinal dorsal horn. CONCLUSIONS: These results suggest that rMSCs may modulate neuropathic pain generation through ROS expression after spinal nerve ligation. PMID- 25031810 TI - The Attenuation of Pain Behavior and Serum COX-2 Concentration by Curcumin in a Rat Model of Neuropathic Pain. AB - BACKGROUND: Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. There is a lack of effective treatment for neuropathic pain, which may possibly be related to poor understanding of pathological mechanisms at the molecular level. Curcumin, a therapeutic herbal extract, has shown to be effectively capable of reducing chronic pain induced by peripheral administration of inflammatory agents such as formalin. In this study, we aimed to show the effect of curcumin on pain behavior and serum COX-2 level in a Chronic Constriction Injury (CCI) model of neuropathic pain. METHODS: Wistar male rats (150-200 g, n = 8) were divided into three groups: CCI vehicle-treated, sham-operated, and CCI drug-treated group. Curcumin (12.5, 25, 50 mg/kg, IP) was injected 24 h before surgery and continued daily for 7 days post-surgery. Behavioral tests were performed once before and following the days 1, 3, 5, 7 after surgery. The serum COX-2 level was measured on day 7 after the surgery. RESULTS: Curcumin (50 mg/kg) decreased mechanical and cold allodynia (P < 0.001) and produced a decline in serum COX-2 level (P < 0.001). CONCLUSIONS: A considerable decline in pain behavior and serum COX-2 levels was seen in rat following administration of curcumin in CCI model of neuropathic pain. High concentration of Curcumin was able to reduce the chronic neuropathic pain induced by CCI model and the serum level of COX-2. PMID- 25031811 TI - Morphologic diversities of sacral canal in children; three-dimensional computed tomographic study. AB - BACKGROUND: Caudal block is a common technique in children for reducing postoperative pain, and there have been several reports on the variations of the sacral canal in children. However, previous studies have mainly focused on the needle trajectory for caudal block, and there is limited information on the structural variations of the sacrum in children. The purpose of this study was to analyze the anatomic variations of sacral canals in children. METHODS: Three dimensional computed tomographic images were analyzed. The data from the images included 1 fusion of the sacral vertebral laminae and the sacral intervertebral space 2 existence of the sacral cornua and 3 the types of sacral hiatus. The types of sacral hiatus were classified into 3 groups: group I (fusion of S3 or S4 vertebral laminae), group II (unfused vertebral arch with the distance of the S3 and S4 vertebral laminae < 50% of the distance between the cornua), and group III (unfused vertebral arch with the distance of the S3 or S4 vertebral laminae >= 50% of the distance between the cornua). RESULTS: A total of 143 children were included in this study. All of the sacral vertebral arches were not fused in 22 children (15.4%). Cornua were not identified bilaterally in 5 (3.5%) and unilaterally in 6 (4.2%) children. In the sacral hiatus, group II and group III were identified in 22 (15.4%) and 31 (21.7%) children, respectively. CONCLUSIONS: The sacral canal has various anatomical variations in children. Careful attention must be paid to identify the correct anatomic landmark. PMID- 25031812 TI - Experience with conventional radiofrequency thermorhizotomy in patients with failed medical management for trigeminal neuralgia. AB - BACKGROUND: To evaluate the results of conventional radiofrequency thermorhizotomy (CRT) for trigeminal neuralgia (TN) in patients with failed medical management. METHODS: Patients with Trigeminal neuralgia who were referred to us for 'limited intervention' during the time frame July-2011 to Jan-2013 were enrolled for this study. CRT was administered by the Sweet technique. Pain relief was evaluated by the principle investigator. RESULTS: Eighteen patients were enrolled and completed a mean follow-up of 18.0 months. Pain relief was observed in 14 of 18 (77.8%) patients on the post-operative day, 14 of 18 (77.8%) at 1 month follow-up, 14 of 17 (82.4%) at 3-months follow-up, 12 of 15 (80%) at 6 months follow-up, 7 of 11 (63.6%) at 1-year follow-up and 2 of 6 (33.3%) 1.5 years of follow-up. Four patients required a repeat cycle of CRT; two at six months of follow-up and two at one year of follow-up. One patient was transferred for surgical intervention at six months of follow-up. Side-effects included facial hypoesthesia (n = 6); nausea/vomiting (n = 2), diminished corneal reflex (n = 13) and difficulty in chewing (n = 11). Severity of adverse effects gradually diminished and none of the patients who are beyond 6 months of follow up have any functional limitation. CONCLUSIONS: CRT is an effective method of pain relief for patients with Trigeminal neuralgia. Successful outcome (excellent or good) can be expected in 66.7% of patients after first cycle of CRF. The incidence and severity of adverse effects is less and the procedure is better tolerated by the patients. PMID- 25031813 TI - Variations in Entrance of Vertebral Artery in Korean Cervical Spine: MDCT-based Analysis. AB - BACKGROUND: Knowledge of the anatomical variation of the vertebral artery has clinical importance not only for the performance of interventional or surgical procedures itself but also to ensure their safety. We conducted a study of the anatomical variation by reviewing multi-detector computed tomography (MDCT) images of the cervical spine from 460 Korean patients. METHODS: 16-row MDCT data from 460 patients were used in this study. We observed 920 vertebral arteries. Examination points included level of entrance of the artery into the transverse foramen of the cervical vertebra, origin site of the vertebral artery, course of a vertebral artery with aberrant entrance. RESULT: The vertebral artery in 2 (0.2%) cases in this study entered into the transverse foramen of the 7th cervical vertebra from the left. In 45 (4.9%) cases, the vertebral artery entered into the transverse foramen of the 5th cervical vertebra. Of these, the entrance was on the right in 15 (1.6%) and on the left in 30 (3.3%). We found 17 (1.8%) cases in which the artery entered into the transverse foramen of the 4th cervical vertebra, 10 (1.1%) on the right and 7 (0.7%) on the left side. As is commonly acknowledged, the 6th cervical vertebra was the most common site of entry; the vertebral artery entered the transverse foramen of the 6th cervical vertebra in the remaining 855 (93.0%) cases, on the right in 434 (47.2%) and on the left in 421 (45.8%). CONCLUSIONS: In conclusion, the possibility of an atypical course of the vertebral artery in segments V1 and V2 should be evaluated with magnetic resonance imaging (MRI) or CT images before carrying out procedures involving the anterior cervical vertebrae. PMID- 25031814 TI - Intravenous Patient-controlled Analgesia Has a Positive Effect on the Prognosis of Delirium in Patients Undergoing Orthopedic Surgery. AB - BACKGROUND: Postoperative delirium is relatively common. However, the relationship between intravenous patient-controlled analgesia (IV-PCA) and delirium has not been thoroughly investigated. The aim of this study was to evaluate the effects of IV-PCA on the prognosis of postoperative delirium in patients undergoing orthopedic surgery. METHODS: Medical records of 129 patients with postoperative delirium were reviewed. Patients were divided into two groups according to whether they used IV-PCA with fentanyl and ketorolac. The IV-PCA group consisted of 73 patients who were managed with IV-PCA; the NO-PCA group consisted of 56 patients who were managed without PCA. RESULTS: Incidences of multiple psychiatric consultations and prolonged delirium were significantly lower in patients using IV-PCA with fentanyl and ketorolac than in those without PCA. CONCLUSIONS: We recommend the use of IV-PCA for pain control and management of delirium in patients with postoperative delirium. PMID- 25031815 TI - Evaluation of the Efficacy of Methylprednisolone, Etoricoxib and a Combination of the Two Substances to Attenuate Postoperative Pain and PONV in Patients Undergoing Laparoscopic Cholecystectomy: A Prospective, Randomized, Placebo controlled Trial. AB - BACKGROUND: Establishment of laparoscopic cholecystectomy as an outpatient procedure has accentuated the clinical importance of reducing early postoperative pain, as well as postoperative nausea and vomiting (PONV). We therefore planned to evaluate the role of a multimodal approach in attenuating these problems. METHODS: One hundred and twenty adult patients of ASA physical status I and II and undergoing elective laparoscopic cholecystectomy were included in this prospective, randomized, placebo-controlled study. Patients were divided into four groups of 30 each to receive methylprednisolone 125 mg intravenously or etoricoxib 120 mg orally or a combination of methylprednisolone 125 mg intravenously and etoricoxib 120 mg orally or a placebo 1 hr prior to surgery. Patients were observed for postoperative pain, fentanyl consumption, PONV, fatigue and sedation, and respiratory depression. Results were analyzed by the ANOVA, a Chi square test, the Mann Whitney U test and by Fisher's exact test. P values of less than 0.05 were considered to be significant. RESULTS: Postoperative pain and fentanyl consumption were significantly reduced by methylprednisolone, etoricoxib and their combination when compared with placebo (P<0.05). The methylprednisolone + etoricoxib combination caused a significant reduction in postoperative pain and fentanyl consumption as compared to methylprednisolone or etoricoxib alone (P<0.05); however, there was no significant difference between the methylprednisolone and etoricoxib groups (P>0.05). The methylprednisolone and methylprednisolone + etoricoxib combination significantly reduced the incidence and severity of PONV and fatigue as well as the total number of patients requiring an antiemetic treatment compared to the placebo and etoricoxib (P<0.05). CONCLUSIONS: A preoperative single-dose administration of a combination of methylprednisolone and etoricoxib reduces postoperative pain along with fentanyl consumption, PONV, antiemetic requirements and fatigue more effectively than methylprednisolone or etoricoxib alone or a placebo. PMID- 25031816 TI - Repetitive transcranial magnetic stimulation to treat depression and insomnia with chronic low back pain. AB - Transcranial magnetic stimulation (TMS) is a noninvasive and safe technique for motor cortex stimulation. TMS is used to treat neurological and psychiatric disorders, including mood and movement disorders. TMS can also treat several types of chronic neuropathic pain. The pain relief mechanism of cortical stimulation is caused by modifications in neuronal excitability. Depression is a common co-morbidity with chronic pain. Pain and depression should be treated concurrently to achieve a positive outcome. Insomnia also frequently occurs with chronic lower back pain. Several studies have proposed hypotheses for TMS pain management. Herein, we report two cases with positive results for the treatment of depression and insomnia with chronic low back pain by TMS. PMID- 25031817 TI - Pulsed radiofrequency ablation under ultrasound guidance for huge neuroma. AB - Amputation neuroma can cause very serious, intractable pain. Many treatment modalities are suggested for painful neuroma. Pharmacologic treatment shows a limited effect on eliminating the pain, and surgical treatment has a high recurrence rate. We applied pulsed radiofrequency treatment at the neuroma stalk under ultrasonography guidance. The long-term outcome was very successful, prompting us to report this case. PMID- 25031818 TI - Antidepressant-induced Burning Mouth Syndrome: A Unique Case. AB - Burning Mouth Syndrome (BMS) is defined as a chronic orofacial pain syndrome, without evidence of mucosal lesions and other clinical signs of disease or laboratory abnormalities. Patients with BMS complain of burning pain in the mouth, xerostomia and taste disturbances. It is more common among women and the median age of occurrence is about 60 years. BMS may be primary or secondary to other diseases. The mainstay in the treatment of BMS includes antidepressants, benzodiazepines, and anticonvulsants. A few cases of BMS caused due to medication have been reported. The causative drugs include angiotensin-converting enzyme inhibitors, anticoagulants, antipsychotics, antiretrovirals, and benzodiazepines. This is a case report of a patient on antidepressants who developed symptoms of BMS thereby causing a dilemma in management. PMID- 25031819 TI - The long-term safety and efficacy of intrathecal therapy using sufentanil in chronic intractable non-malignant pain. AB - This report describes the long term safety and efficacy of intrathecal therapy using Sufentanil for the management of chronic intractable neuropathic pain in 12 chronic pain patients. Standardized psychological screening was used to determine treatment suitability. Evaluation data included the Visual Analog Scale (VAS), Wong-Baker Faces Scale, Brief Pain Inventory (BPI), Disability of Arm, Shoulder, and Hand (DASH), McGill Quality of Life Questionnaire, and complications (granulomas, toxicity, withdrawal, or deaths). SPSS version 18 was used for data analysis. Pre- and post- treatment BPI measures and pain scale scores showed a statistically significant difference. There were no complications directly related to drug toxicity, nor drug withdrawals, granulomas, or deaths. Intrathecal therapy with Sufentanil therapy offers a good treatment alternative for those cases that have failed both surgery and standard pain treatment. Strict patient selection based on psychological screening, control of co-morbidities, a proper pain management may contribute to successful outcome. PMID- 25031820 TI - The potential role of intrathecal nefopam in the management of neuropathic pain. PMID- 25031821 TI - The Impact of Stress Hormones on Post-traumatic Stress Disorders Symptoms and Memory in Cardiac Surgery Patients. AB - The relationship and interactions between stress hormones and post-traumatic stress disorder (PTSD) are well established from both animal and human research studies. This interaction is especially important in the post-operative phase of cardiac surgery where the development of PTSD symptoms will result in increased morbidity and mortality and prolong length of stay for critically ill cardiac surgery patients. Cardiopulmonary bypass itself will independently result in massive inflammation response and release of stress hormones in the perioperative period. Glucocorticoid may reduce this response and result in reduction of PTSD symptom clusters and therefore improve health outcome. In this review, we plan to conduct a systemic review and analysis of the literatures on this topic. PMID- 25031822 TI - Variations of QRS Morphology in Patients with Dilated Cardiomyopathy; Clinical and Prognostic Implications. AB - The QRS represents the simultaneous activation of the right and left ventricles, although most of the QRS waveform is derived from the larger left ventricular musculature. Although normal QRS duration is <100 millisecond (ms), its duration and shape are quite variable from patient to patient in idiopathic dilated cardiomyopathy (IDCM). Prolongation of QRS occurs in 14% to 47% of heart failure (HF) patients. Left bundle branch block (LBBB) is far more common than right bundle branch block (RBBB). Dyssynchronous left ventricular activation due to LBBB and other intraventricular conduction blocks provides the rationale for the use of cardiac resynchronization therapy with biventricular pacing in patients with IDCM. Fragmented QRS (fQRS) is a marker of depolarization abnormality and present in significant number of the patients with IDCM and narrow QRS complexes. It is associated with arrhythmic events and intraventricular dyssynchrony. The purpose of this manuscript is to present an overview on some clinical, echocardiographic and prognostic implications of various QRS morphologies in patients with IDCM. PMID- 25031823 TI - Haemostatic Role of TachoSil Surgical Patch in Cardiac Surgery. AB - INTRODUCTION: Excessive bleeding presents a risk for the patient in cardiovascular surgery. Local haemostatic agents are of great value to reduce bleeding and related complications. TachoSil (Nycomed, Linz, Austria) is a sterile, haemostatic agent that consists of an equine collagen patchcoated with human fibrinogen and thrombin. This study evaluated the safety and efficacy of TachoSil compared to conventional technique. METHODS: Forty-two patients scheduled for open heart surgeries, were entered to this study from August 2010 to May 2011. After primary haemostatic measures, patients divided in two groups based on surgeon's judgment. Group A: 20 patients for whom TachoSil was applied and group B: 22 patients that conventional method using Surgicel (13 patients) or wait and see method (9 cases), were performed in order to control the bleeding. In group A, 10 patients were male with mean age of 56.95+/-15.67 years and in group B, 9 cases were male with mean age of 49.95+/-14.41 years. In case group 70% (14/20) of the surgeries were redo surgeries versus 100% (22/22) in control group. RESULTS: Baseline characteristics were similar in both groups. In TachoSil group 75% of patients required transfusion versus 90.90% in group B (P=0.03).Most transfusions consisted of packed red blood cell; 2+/-1.13 units in group A versus 3.11+/-1.44 in group B (P=0.01), however there were no significant differences between two groups regarding the mean total volume of intra and post-operative bleeding. Re-exploration was required in 10% in group A versus 13.63% in group B (P=0.67). CONCLUSION: TachoSil may act as a superior alternative in different types of cardiac surgery in order to control the bleeding and therefore reducing transfusion requirement. PMID- 25031824 TI - Activated clotting time level with weight based heparin dosing during percutaneous coronary intervention and its determinant factors. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) may be associated with Thrombotic complications. Unfractionated heparin (UFH) is a potent and preferable antithrombotic agent during this procedure. Activated clotting time (ACT) is a good assay for accurate titration of UFH during PCI. The aim of this study was to evaluate ACT levels 10 minutes after administration of 100U/kg IV heparin and determining its associated factors. METHODS: This study was performed in Madani hospital, Tabriz, Iran between January 2013 to January 2014. One hundred and two patients candidates for elective PCI were enrolled in the study. Data including demographic and risk factors were collected. RESULT: The range of ACT was between 165 to 750 seconds (mean 319.8 seconds), 52 (51%) patients had ACT levels lower than 300sec and 12 (11.8%) patients had ACT levels between 300 to 350 seconds which is known optimal range and 38 (37.2%) cases had ACT levels above this value. Major risk factors had no effect on ACT value, but there was a trend to higher levels with increasing age (P=0.06). There was no difference in the rate of major or minor bleeding with respect to ACT levels (P=0.52). There was a trend to higher rate of minimal bleeding in those with ACT >350 sec (P=0.06). CONCLUSION: Weight based UFH injection may result in suboptimal anticoagulation during the procedure. Routine ACT measurement may be necessary to ascertain adequate anticoagulation. Major risk factors had no effect on ACT level and it was not associated with the rate of bleeding. PMID- 25031825 TI - Difference between Outcome of Left Circumflex Artery and Right Coronary Artery Related Acute Inferior Wall Myocardial Infarction in Patients Undergoing Adjunctive Angioplasty after Fibrinolysis. AB - INTRODUCTION: Prognostic differences between anterior and inferior wall Myocardial Infarction (MI) has been extensively investigated, but there is limited information about similar comparison between inferior wall MI caused by right coronary artery (RCA) and left circumflex artery (LCX) occlusion. The aim of present study was to compare prognostic differences between LCX- and RCA related acute inferior wall ST-segment elevation MI (STEMI) treated by routine adjunctive angioplasty after receiving thrombolytic therapy (TLT). METHODS: Between March 2012 and June 2013 one hundred fifty consecutive patients with acute inferior wall STEMI were studied. Patients were divided into two groups according to the infarct related artery (LCX vs. RCA). All patients underwent routine adjunctive angioplasty after TLT during the index hospitalization and clinical characteristics and outcomes were compared. RESULTS: RCA and LCX arteries were occluded in 97 (64.7%) and 53 (35.3%) of patients, respectively. Two groups were similar in baseline characteristics except multiple-vessel disease was more prevalent with LCX occlusion (p= 0.008). There was a higher cardiac enzyme release (p< 0.001), more significant mitral regurgitation (MR) (p= 0.015), and lower left ventricular ejection fraction (LVEF) (p= 0.01) in patients with LCX occlusion. Multivariate analysis showed cTn-I release, occurrence of MR, and lower LVEF as independent factors leading to poor outcome. CONCLUSIONS: There were higher cTn-I release, MR occurrence, and lower LVEF in LCX-related acute inferior wall STEMI, all associated with poor outcome. Therefore, patients with ECG finding in favour of LCX occlusion should be considered as high risk and an invasive approach should be planned. PMID- 25031826 TI - Early and Mid-term Outcomes in Female Patients Undergoing Isolated Conventional Coronary Surgery. AB - INTRODUCTION: Several observational studies comparing outcomes between female and male patients after coronary artery bypass grafting (CABG) have shown that operative mortality rate is higher among female patients than in male patients. However, some conflicting studies report that early mortality among female patients is equivalent to that among male patients. We investigated predictive factors of morbidity, mortality and survival in female patients undergoing isolated conventional CABG. METHODS: Between January 2002 and December 2009, 1657 patients underwent isolated conventional CABG in our clinic. 21.8% (n=361) of patients were female and 78.2% (n=1296) males. RESULTS: Advanced age (P<0.0001), hypertension (P<0.0001), diabetes (P<0.0001), and hyperlipidemia (P<0.0001) were the independent predictive factors among female patients. Mean in-hospital mortality rates were 5.8% and 3.2%; for females and males, respectively (P=0.029). Prolonged ventilatory support (P=0.009) and postoperative atrial fibrillation (P=0.049) were the independent predictive factors of in-hospital mortality in female patients. Cardiopulmonary bypass time (P=0.041), prolonged ventilatory support (P<0.0001), and postoperative atrial fibrillation (P=0.031) were the independent predictive factors of in-hospital mortality in male patients. Mean follow-up was 47.51+/-25.06 months and 48.42+/-25.21 months among female and male patients (P=0.820). In follow-up, mortality rate was 6.1% (n=22) among female patients and 4.6% (n=60) among male patients (P=0.272). Left internal thoracic artery (LITA) usage (P=0.001) was the independent predictive factor of survival in female patients. CONCLUSION: In-hospital mortality rate was higher in female patients. Length of ICU and hospital stay, and mid-term survival was similar between female and male patients. PMID- 25031827 TI - Diagnostic Values of Plasma, Fresh and Frozen Urine NT-proBNP in Heart Failure Patients. AB - INTRODUCTION: The plasma N-terminal probrain natriuretic peptide (NT-proBNP) level is an important diagnostic and prognostic marker of heart failure. Recent studies have suggested urinary NT-proBNP as a new and simple test for diagnosis of heart failure. We aim to compare diagnostic value of plasma, fresh and frozen urine levels of N-terminal probrain natriuretic peptide (NT-proBNP) for detecting heart failure. METHODS: Between January 2010 and January 2012, we measured urine and plasma levels of NTproBNP in 98 patients with chronic heart failure (CHF) and 29 age- and sex-matched healthy control subjects. RESULTS: There were significant correlations between plasma NT-proBNP and fresh (r=0.45, p<0.001) and frozen (r=0.42, p<0.001) urine NT-proBNP concentrations in CHF patients. Due to receiver operating curve analysis, fresh and frozen urine NT-proBNP could diagnose HF with are aunder curve (AUC) of 0.73+/-0.04 (p<0.001) and 0.65+/-0.05 (p=0.01) with sensitivity and specificity of 73.97%, 58.62%, and 65.31%, 62.07%, for a cut-off of 94.2 and 96 pg/mL, respectively. Plasma NT-proBNP had greater AUC (0.94+/ 0.02, p<0.001) and better sensitivity and specificity (94.9%, 89.66% for cut-off of 414.5 pg/mL). There was no significant correlation between LVEF and plasma, fresh and frozen urine NT-proBNP levels in CHF patients. CONCLUSION: Plasma NT proBNP is still the best diagnostic marker with high sensitivity and specificity; however, urinary especially fresh urine NT-proBNP may be a surrogate to plasma NTproBNP for diagnosing HF with acceptable accuracy. PMID- 25031828 TI - Procedural Outcome and One Year Follow up of Patients Undergoing Endovascular Stenting for Coarctation of Aorta: A Single Center Study. AB - INTRODUCTION: Coarctation of aorta is the fourth most common cardiac lesion requiring intervention. While surgery used to be the only treatment option, endovascular intervention is now considered the first option in simple coarctation lesions. Despite increased popularity, there are currently no FDA approved stents for use in coarctation of aorta and data on the outcome of this procedure is still sparse. METHODS: Between October 2004 and June 2010, 33 patients who underwent treatment with Cheatham-Platinum stents for coarctation of aorta were retrospectively studied. All the patients underwent control CT scans at 6 month and echocardiography at 1 year follow-up. RESULTS: There were 17 females and 16 males with a mean age of 26.64 +/- 16.30 years (range 2-71 years). The mean stent length and balloon diameter were 3.18 +/- 0.56 mm and 15.7 +/- 3.12 mm respectively. We achieved an immediate success rate of 96.9% with the only complication of aortic rupture which led to our single mortality in this series. At 6 month follow up no complications were noted in the CT scans. The mean echocardiographic aortic arch gradient at one year follow up was 21.73 +/- 11.06 mmHg. CONCLUSION: This study is one of the few cohorts of patients with stenting for coarctation of aorta in Iranian population which comprised a diverse group of patients from early childhood to elderly. It was demonstrated in this study that stenting for coarctation of aorta is a safe and effective procedure if done carefully and performed in selected patients. PMID- 25031829 TI - Body Mass Index or Serum Albumin Levels: Which is further Prognostic following Cardiac Surgery? AB - INTRODUCTION: Patients with low serum albumin and abnormal BMI may be at the risk of death and other complications after surgery. This could be remarkable in patients with coronary arteries bypass graft surgery. Therefore, we decided to evaluate the impact of these factors associated with survival and outcome after cardiac surgery. METHODS: A cross-sectional study was performed from 2009 until 2012 on 345 patients who underwent coronary artery bypass grafts. Also Patients were monitored for a year. Patients' information was collected and then the patients were analyzed for body mass index (BMI) and serum albumin and their effects on postoperative outcomes. P value <0.05 was considered statistically significant. RESULTS: Mortality after CABG operation was not of a significant relation in patients with low BMI (BMI <20), normal and high (BMI> 30). Obese patients are more susceptible to myocardial infarction in postoperative period (P=0.02). Pneumonia after surgery in these patients was more common than others (P= 0.023); however, low serum albumin was significantly associated with mortality following operation (P<0.001). Reoperation due to bleeding (P<0.001) and required mechanical ventilation for more than a day (P=0.019) were significantly associated with low serum albumin. CONCLUSION: In conclusion, the high or low BMI alone did not increase mortality after cardiac surgery. However, postoperative morbidity in obese patients may be greater than others. Low serum albumin may increase the risk of mortality and postoperative complications as well. Therefore, it seems ameliorating serum albumin can be effective more than body mass index in improving the outcome of patients after CABG surgery. PMID- 25031830 TI - Anomalous origin of right coronary artery from distal left circumflex artery: a case study and a review of its clinical significance. AB - Single coronary arteries are rare congenital anomalies in which the whole heart circulation is supplied by a coronary artery arising from a single ostium. Single left coronary artery with right coronary artery (RCA) originating from distal left circumflex artery (LCX) is a very rare anomaly with only few cases reported in the literature. We report a 44 years old male presenting with anterior myocardial infarction who was found to have a single left coronary artery during angiography. RCA had an abnormal origin arising from distal of a dominant LCX that retrogradely followed the course of a normal RCA to the base of the heart. A brief review of the reported cases with emphasis on the clinical significance of this unusual anomaly is presented. PMID- 25031831 TI - What is the clinical benefit of neutrophil-lymphocyte ratio in cardiovascular patients? PMID- 25031832 TI - Functional autonomic nervous system profile in children with autism spectrum disorder. AB - BACKGROUND: Autonomic dysregulation has been recently reported as a feature of autism spectrum disorder (ASD). However, the nature of autonomic atypicalities in ASD remain largely unknown. The goal of this study was to characterize the cardiac autonomic profile of children with ASD across four domains affected in ASD (anxiety, attention, response inhibition, and social cognition), and suggested to be affected by autonomic dysregulation. METHODS: We compared measures of autonomic cardiac regulation in typically developing children (n = 34) and those with ASD (n = 40) as the children performed tasks eliciting anxiety, attention, response inhibition, and social cognition. Heart rate was used to quantify overall autonomic arousal, and respiratory sinus arrhythmia (RSA) was used as an index of vagal influences. Associations between atypical autonomic findings and intellectual functioning (Weschler scale), ASD symptomatology (Social Communication Questionnaire score), and co-morbid anxiety (Revised Children's Anxiety and Depression Scale) were also investigated. RESULTS: The ASD group had marginally elevated basal heart rate, and showed decreased heart rate reactivity to social anxiety and increased RSA reactivity to the social cognition task. In this group, heart rate reactivity to the social anxiety task was positively correlated with IQ and task performance, and negatively correlated with generalized anxiety. RSA reactivity in the social cognition task was positively correlated with IQ. CONCLUSIONS: Our data suggest overall autonomic hyperarousal in ASD and selective atypical reactivity to social tasks. PMID- 24860645 TI - Recommendations to enable drug development for inherited neuropathies: Charcot Marie-Tooth and Giant Axonal Neuropathy. AB - Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can envision treatment options for these rare diseases in the near future. PMID- 25031834 TI - Hemiballism-hemichorea induced by ketotic hyperglycemia: case report with PET study and review of the literature. AB - Hemiballism-hemichorea (HB-HC) is commonly used to describe the basal ganglion dysfunction in non-ketotic hyperglycemic elderly patients. Here we report two elderly female patients with acute onset of involuntary movements induced by hyperglycemia with positive urine ketones. We described the computed tomography and magnetic resonance imaging findings in these two patients, which is similar to that of non-ketotic hyperglycemic HB-HC patients. FDG-PET was performed and the glucose metabolism in the corresponding lesion in these two patients was contradictory with each other. We tried to clarify the underlying mechanisms of HB-HC and explain the contradictory neuroradiological findings in FDG-PET as being performed at different clinical stages. PMID- 25031835 TI - Implementation of an Interleukin-2 National Registry: an opportunity to improve cancer outcomes. AB - Cancer registries have proven valuable with respect to validating therapeutic safety and drug efficacy, uncovering real-world implementation practices, and their evolution over time. Modern cancer therapeutics are approved as single agents oftentimes compared to the least active approved standard agent in randomized trials. However, the burgeoning diversity and number of drugs introduces a complexity that quickly outstrips the knowledge provided by these pivotal trials. This gap in information is particularly relevant when survival is the primary therapeutic endpoint. In addition, the inherent complexity of the immune response will make registries a particularly important tool in expeditiously understanding solid tumor immunotherapy and patient outcomes. PMID- 25031836 TI - Reversible alterations in cardiac morphology and functions in a patient with Cushing's syndrome. AB - A 45-year-old female was referred for endocrine evaluation of an incidental mass (31*24 mm in diameter) on the right adrenal gland. The patient was normotensive and nondiabetic, and had no history of generalised obesity (body weight, 46 kg at 20 years of age and 51.2 kg on admission); however, her waist-to-hip ratio was 0.97. Elevated urinary free cortisol levels (112-118 MUg/day) and other findings indicated adrenocorticotrophic hormone-independent Cushing's syndrome due to right adrenocortical adenoma. Echocardiography before adrenalectomy revealed concentric left ventricular (LV) hypertrophy with a particular increase in interventricular septum thickness leading to impaired systolic and diastolic functions. Upon surgical remission of hypercortisolism, the asymmetric hypertrophy disappeared and the cardiac dysfunctions were considerably ameliorated. Although the mechanism(s) by which excessive cortisol contributes to LV wall thickness remain(s) unclear, serial echocardiography and cardiac multidetector-row computed tomography may support the notion that abnormal fat deposition in the myocardium owing to hypercortisolism appears to be an important factor for the reversible change in the cardiac morphology. LEARNING POINTS: Patients with Cushing's syndrome occasionally exhibit severe LV hypertrophy related to systolic and diastolic dysfunctions although they have neither hypertension nor diabetes mellitus.Biological remission of hypercortisolism can normalise structural and functional cardiac parameters and help in differentiating the cardiac alterations induced by excessive cortisol from those induced by other diseases.Excessive lipid accumulation within the heart before myocardial fibrosis may be implicated in reversible alterations in the cardiac morphology by Cushing's syndrome.Early diagnosis and treatment of Cushing's syndrome appear to be pivotal in preventing irreversible cardiac dysfunctions subsequent to cardiovascular events and heart failure. PMID- 25031837 TI - A case of pituitary apoplexy in pregnancy. AB - Pituitary apoplexy is a rare event in pregnancy. A 41-year-old woman with a known pituitary microadenoma presented with visual disturbance and headache during the second trimester of pregnancy. Magnetic resonance imaging (MRI) demonstrated pituitary apoplexy with chiasmal compression. After treatment with corticosteroid therapy, she underwent transsphenoidal excision of the pituitary adenoma. Visual abnormalities were completely restored and pituitary function preserved. There was no evidence of impact on the foetus. The literature on the subject is reviewed with emphasis on the management of the apoplectic patient with mild and stable neuro-ophthalmological signs. LEARNING POINTS: There are no clear guidelines on the management of pituitary apoplexy in pregnancy. A multidisciplinary approach can minimise morbidity and mortality.Pituitary apoplexy has an unpredictable clinical course and determining which clinical situations warrant early surgery needs to take into consideration the presence and severity of neurological signs and their stability.The management of conscious apoplectic patients with absent or mild and stable neuro ophthalmological signs is controversial. PMID- 25031838 TI - Aerobic exercise modulates intracortical inhibition and facilitation in a nonexercised upper limb muscle. AB - BACKGROUND: Despite growing interest in the relationship between exercise and short-term neural plasticity, the effects of exercise on motor cortical (M1) excitability are not well studied. Acute, lower-limb aerobic exercise may potentially modulate M1 excitability in working muscles, but the effects on muscles not involved in the exercise are unknown. Here we examined the excitability changes in an upper limb muscle representation following a single session of lower body aerobic exercise. Investigating the response to exercise in a non-exercised muscle may help to determine the clinical usefulness of lower body exercise interventions for upper limb neurorehabilitation. METHODS: In this study, transcranial magnetic stimulation was used to assess input-output curves, short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF) in the extensor carpi radialis muscle in twelve healthy individuals following a single session of moderate stationary biking. Additionally, we examined whether the presence of a common polymorphism of the brain-derived neurotrophic factor (BDNF) gene would affect the response of these measures to exercise. RESULTS: We observed significant increases in ICF and decreases in SICI following exercise. No changes in LICI were detected, and no differences were observed in input-output curves following exercise, or between BDNF groups. CONCLUSIONS: The current results demonstrate that the modulation of intracortical excitability following aerobic exercise is not limited to those muscles involved in the exercise, and that while exercise does not directly modulate the excitability of motor neurons, it may facilitate the induction of experience-dependent plasticity via a decrease in intracortical inhibition and increase in intracortical facilitation. These findings indicate that exercise may create favourable conditions for adaptive plasticity in M1 and may be an effective adjunct to traditional training or rehabilitation methods. PMID- 25031839 TI - Comparison of three generations of ActiGraph activity monitors under free-living conditions: do they provide comparable assessments of overall physical activity in 9-year old children? AB - BACKGROUND: A recent review concludes that the agreement of data across ActiGraph accelerometer models for children and youth still is uncertain. The aim of this study was to evaluate the agreement of three generations of ActiGraph accelerometers in children in a free-living condition. METHODS: Sixteen 9-year olds wore the ActiGraph AM7164, GT1M and GT3X+ simultaneously for three consecutive days. We compared mean counts per minute (mcpm) and time spent at different intensities from the three generations of monitors, and the agreement of outputs were evaluated by intra-class correlation coefficients (ICC) and Bland Altman plots. RESULTS: The ICC for mcpm was 0.985 (95% CI = 0.898, 0.996). We found a relative difference of 11.6% and 9.8% between the AM7164 and the GT1M and AM7164 and the GT3X+, respectively. The relative difference between mcpm assessed by the GT1M and GT3X+ was 1.7%. The inter-generation differences varied in magnitude and direction across intensity levels, with the largest difference found in the highest intensities. CONCLUSION: We found that the ActiGraph model AM7164 yields higher outputs of mean physical activity intensity (mcpm) than the models GT1M and GT3X+ in children in free-living conditions. The generations GT1M and GT3X+ provided comparable outputs. The differences between the old and the newer monitors were more complex when investigating time spent at different intensities. Comparisons of data assessed by the AM7164 with data assessed by newer generations ActiGraphs should be done with caution. PMID- 25031840 TI - Removal of phenol and bisphenol-A catalyzed by laccase in aqueous solution. AB - BACKGROUND: Elimination of hazardous phenolic compounds using laccases has gained attention during recent decades. The present study was designed to evaluate the ability of the purified laccase from Paraconiothyrium variabile (PvL) for elimination of phenol and the endocrine disrupting chemical bisphenol A. Effect of laccase activity, pH, and temperature on the enzymatic removal of the mentioned pollutants were also investigated. RESULTS: After 30 min treatment of the applied phenolic pollutants in the presence of PvL (5 U/mL), 80% of phenol and 59.7% of bisphenol A was removed. Increasing of laccase activity enhanced the removal percentage of both pollutants. The acidic pH of 5 was found to be the best pH for elimination of both phenol and bisphenol A. Increasing of reaction temperature up to 50 degrees C enhanced the removal percentage of phenol and bisphenol A to 96.3% and 88.3%, respectively. CONCLUSIONS: To sum up, the present work introduced the purified laccase of P. variabile as an efficient biocatalyst for removal of one of the most hazardous endocrine disruptor bisphenol A. PMID- 25031841 TI - Mean platelet volume and red cell distribution width as a diagnostic marker in acute appendicitis. AB - BACKGROUND: Acute appendicitis (AA) is one of the most common causes of emergent surgeries. Many methods are used for its diagnosis. OBJECTIVES: This study was conducted to investigate the diagnostic value of MPV and RDW in acute appendicitis. PATIENTS AND METHODS: This study was a retrospective multi-center cross sectional planned study. The study included 260 patients operated for AA and 158 patients as the control group. Groups were compared in terms of MPV, RDW, white blood cell count (WBC), neutrophil predominance (NP) and platelet count (PC). RESULTS: MPV was significantly lower in AA group, compared to the control group (P < 0.001). The best cut-off level for MVP in AA was <= 7.3 fL and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy ratio were 45%, 89.2%, 87.3%, 49.6% and 61.7%, respectively. There was no significant difference between the two groups in terms of RDW and platelet values. CONCLUSIONS: MPV is a routinely measured parameter in complete blood count (CBC) and requires no additional cost. It significantly decreased in AA, having a greater sensitivity and NPV when combined with WBC and NP. PMID- 25031842 TI - Investment on education of future parents: the best measure for enhancement of a community disaster resiliency. PMID- 25031843 TI - Antibiotic Susceptibility Patterns and Molecular Epidemiology of Metallo-beta Lactamase Producing Pseudomonas Aeruginosa Strains Isolated From Burn Patients. AB - BACKGROUND: Failure in the treatment of burn patients infected with Pseudomonas aeruginosa could happen as a result of the acquisition of antibiotic resistance, including carbapenems. OBJECTIVES: The aim of the present study was to investigate the phenotypic and genotypic characteristics of the Pseudomonas aeruginosa strains, isolated from burn patients. PATIENTS AND METHODS: During a 12 month period, in this cross-sectional study, two hundred seventy strains of Pseudomonas aeruginosa were isolated from the burn patients in Ghotbeddin Burn Hospital, Shiraz, Iran. Screening for the carbapenem resistance in the isolates was carried out by the E test method. Sensitivity patterns of metallo-beta lactamase (MbetaLs) producing strains of pseudomonas to eleven antibiotics were determined by the mentioned method. The epidemiological associations of these strains were determined by Pulsed-field gel electrophoresis (PFGE). RESULTS: Of the 270 strains, 60 (22.2%) were resistant to imipenem and meropenem, classified as MbetaLs producing. MbetaLs producing strains of pseudomonas were completely resistant to five tested antibiotics while their sensitivities to the three most effective antibiotics including ceftazidime, amikacin and ciprofloxacin were 23.4%, 6.7 % and 1.7%, respectively. In PFGE, 37 patterns from the genome of Pseudomonas aeruginosa were observed. Majority of the strains (43; 71.6%) exhibited more than 80% similarity, based on the drawn dendrogram. CONCLUSIONS: According to the results, none of the tested antibiotics is safe to prescribe. As PFGE revealed, a limited number of Pseudomonas aeruginosa types are predominant in the hospitals which infect the burn patients. PMID- 25031844 TI - Eligibility assessment for intravenous thrombolytic therapy in acute ischemic stroke patients; evaluating barriers for implementation. AB - BACKGROUND: Intravenous thrombolysis is an approved treatment method for patients with acute ischemic stroke (AIS) and is recommended by multiple guidelines. However, it seems that it is less frequently used in the developing countries compared to the developed countries. OBJECTIVES: The purpose of this study was to estimate the percentage of patients with AIS, eligible for intravenous thrombolytic therapy, at the main referral center in Northwest Iran and to determine the main barriers for implementation of this method. PATIENTS AND METHODS: Over one year, 647 patients who were admitted to the emergency department and met the Cincinnati Stroke Scale were enrolled into the study. The center to which patients were admitted, is a tertiary university hospital that has the required infrastructure for thrombolytic therapy in AIS. Factors recorded were neurological examinations and time between onset of symptoms and hospital arrival, hospital arrival and performance of brain computed tomography (CT) scanning, and hospital arrival to complete the investigations. Patients eligible for intravenous thrombolytic therapy were identified according to the American Heart Association (AHA) guidelines. RESULTS: Mean time interval between hospital arrival and completion of brain CT scanning was 91 minutes (range: 20-378 minutes) and mean time from hospital arrival to completion of investigations was 150 minutes (range: 30-540 minutes). A total of 159 (31.3%) patients arrived at hospital within 3 hours of the onset of symptoms (early enough for intravenous thrombolytic therapy). However, 81.7% (130/159) of these patients missed thrombolytic therapy due to delayed performance of brain CT scanning and laboratory tests and 38.3% (61/159) had contraindications. The remaining 16 patients (10% of those who arrived within 3 hours and 3.1% of all cases) were eligible for thrombolytic therapy. CONCLUSIONS: The major barriers for thrombolytic therapy for patients with AIS in this setting were delays in the provision of in-hospital services, like initial patient assessment, CT scans or laboratory studies. These results were in contrast with previous reports. PMID- 25031845 TI - The Ameliorative Effect of Zingiber officinale in Diabetic Nephropathy. PMID- 25031846 TI - Intraspinal lipomas without associated spinal dysraphism. AB - INTRODUCTION: The aim of this study was to report surgical strategies and clinical outcomes for thoraco-lumbar intradural lipomas. Intraspinal lipomas are rare congenital histologically benign neoplasms, which account for less than 1% of all spinal cord tumors. These tumors are most frequently found in the lumbosacral area as components of a dysraphic state, however, intramedullary lipomas are not associated with spina bifida or cutaneous malformations and have only been described as isolated cases among spinal lipomas, where the thoracolumbar region is rarely affected. CASE PRESENTATION: Three patients with thoracolumbar intradural lipomas were admitted to our clinic at different points of time. Partial resections and debulking of the tumors were achieved with the guidance of an operating microscope. We performed laminectomies or laminoplasties, for tumor resections. DISCUSSION: Postoperatively, the patients demonstrated significant clinical improvements. In this manuscript we presented our surgical experiences for intraspinal lipomas. PMID- 25031847 TI - Transdermal fentanyl patches versus patient-controlled intravenous morphine analgesia for postoperative pain management. AB - BACKGROUND: Acute and severe pain is common in patients postoperatively and should be correctly managed. In the past years studies on preparing better postoperative pain control have resulted in development of postoperative pain management guidelines. Perhaps, one of the major improvements in managing postoperative pain is the development of the patient-controlled analgesia systems (PCA), especially through intra venous (IV), extradural and transdermal routes, which has resulted in marked improvements in acute postoperative pain management. Physicians administrate potent opioids for moderate to severe post-surgical pains. Morphine is the most commonly IV-PCA administrated analgesic. The fentanyl iontophoretic transdermal system (fentanyl ITS) is also another efficient option for pain management. OBJECTIVES: The aim of this study was to compare the analgesic effects of these two routine postoperative pain control systems. PATIENTS AND METHODS: We enrolled 281 patients (224 males, 57 females) in this blind randomized controlled clinical trial, who had undergone an orthopedic surgery, with the mean age of 33.91 +/- 14.45 years. Patients were randomly divided into two groups; in group A patients received IV-morphine PCA pump and in group B fentanyl transdermal patches were attached on patients' arms. The severity of the pain was registered according to Visual Analogue Scale in specially designed forms by pain-trained nurses in two steps; first after the surgery and next before the beginning of analgesic effects. After 24 hours, the pain score was assessed again. RESULTS: No significant difference was observed in mean pain intensity score at the first patient assessment. Mean pain intensity scores were also similar in both groups at the last measured time point (P > 0.05). Differential pain intensity scores, showing the impacts of analgesic system on the pain experience of the patients was also similar between fentanyl patches (6.48 +/- 2.20) and morphine PCIA (6.40 +/- 1.80). (P > 0.05) Mean patient satisfactory score (scale: 0-100) was also similar in both groups (P > 0.05). The percentage of patients, whose differential pain intensity scores at 24 hours reached our pain management goal was similar between fentanyl and morphine groups (P > 0.05). The percentage of patients with at least one adverse event was significantly higher in fentanyl group (P < 0.05). The most frequent adverse events were nausea, vomiting and itching. In none of the groups, no patient experienced serious adverse events related to the studied medications. CONCLUSIONS: Although both pain killing therapeutic regimens are safe and effective for postoperative pain management, regarding the easy usage of the patches, lower risk of abuse and cost-effectiveness in the Iranian market, it is recommended for use in Iranian hospitals and trauma centers and in countries with similar socioeconomic situations. PMID- 25031848 TI - Environmental determinants of cardiovascular diseases risk factors: a qualitative directed content analysis. AB - BACKGROUND: Cardiovascular diseases (CVDs) are the number one cause of death in the world. In most analyses of health problems, environment plays a significant and modifiable role in causing the problem either directly or indirectly through behavior. OBJECTIVES: This study aims to understand the patients and healthcare providers' experiences about the environmental determinants of CVD risk factors based on the Precede Model. PATIENTS AND METHODS: This qualitative study conducted over six months in 2012 at Diabetes Units of Health Centers associated with Alborz University of Medical Sciences and Health Services which is located in Karaj, Iran. The data were collected based on individual semi-structured interviews with 50 patients and 12 healthcare providers. Data analysis was performed simultaneous with data collection using the content analysis directed method. RESULTS: Lack of behaviors like stress control, healthy eating and physical activity were the roots of the risk factors for CVD. The environmental factor is one of the barriers for conducting these behaviors. The environmental barriers included of structural environment including "availability and accessibility of health resources", "new skills", and "law and policies" which are located in enabling category and social environment including "social support", "motivation to comply" and "consequences of behavior" which are located in reinforcing category. The most barriers to performing health behaviors were often structural. CONCLUSIONS: The environmental factors were barriers for doing healthy behaviors. These factors need to be considered to design health promotion interventions. Policymakers should not only focus on patients' education but also should provide specific facilities to enhance economic, social and cultural status. PMID- 25031849 TI - Comparison of QT Dispersion With Left Ventricular Mass Index in Early Diagnosis of Cardiac Dysfunction in Patients With beta-Thalassemia Major. AB - BACKGROUND: In electrocardiography (ECG), QT is the interval between the onset of Q wave to the end of the T wave. This interval may be a sign of changes in the ventricular structure in hematologic disorders such as thalassemia major. OBJECTIVES: The main goal of this study was to compare the diagnostic value of corrected QT dispersion (QTcd) and QT dispersion (QTd) with left ventricular mass (LVM) and left ventricular mass index (LVMI) as well as to determine their sensitivity and specificity in early detection of the cardiac involvement in patients with beta-thalassemia major. PATIENTS AND METHODS: In a case-control study, 60 patients older than ten years of age with thalassemia major who received regular blood transfusion and iron chelators were selected as the case group and were compared with 60 healthy age- and sex-matched subjects. All patients had myocardial performance index (MPI) of more than 0.5 and MPI for controls was less than 0.5. Echocardiography and ECG were performed for both groups and data were analyzed using appropriate statistical tests. RESULTS: The mean age of cases and controls were 16 +/- 2.8 and 16.08 +/- 3.01 years, respectively. Male to female ratio was 33:27 in case group and 31:29 in the control group. LVMI in the case group was greater than control group. QTd and QTcd were larger in case group than in control group. The sensitivity and specificity of LVM, LVMI, QTd, and QTcd were as follows: 88.3%, 77.1%; 86.7%, 80%; 93.8%, 80%; and 91.7%, 86.7%, respectively. CONCLUSIONS: This study showed acceptable sensitivity and specificity of QTcd and QTd in comparison to LVMI; it seems that standard ECG can be used for early diagnosis of cardiac involvement in asymptomatic patients with thalassemia major. PMID- 25031850 TI - Perceived concerns of azeri menopausal women in iran. AB - BACKGROUND: Menopause is a complex biological phenomenon which is affected by socio-cultural and physiological factors. These factors may cause different experiences and concerns for menopausal women from different countries and even among women of diverse ethnic groups living in the same country. The signs and symptoms of menopause are exacerbated by the negative attitude of menopausal women and their deep concerns. OBJECTIVES: We aimed to explore self-experienced concerns of Iranian menopausal women residing in Tabriz. MATERIALS AND METHODS: Phenomenological approach was used for analyzing the participants' experiences and perceptions about menopause. Data were collected through 18 semi-structured in-depth interviews; carried out from February to July 2012. Participants were menopausal women aged between 46-57 years who experienced menopause no more than 4 years before the interview. All interviews were audio recorded and transcribed verbatim. Constant comparative analysis of the data was conducted using MAXQDA 10. RESULTS: Participants' concerns were classified into 4 main themes, including: inability, aging, isolation, and healthiness. CONCLUSIONS: Understanding these concerns might contribute to the enrichment of the existing literature by providing evidences from a different culture, assisting to design effective supportive strategies, planning training programs and appropriate infrastructures for women to improve their quality of life during the menopausal period. PMID- 25031851 TI - Perinatal outcome after diagnosis of oligohydramnious at term. AB - BACKGROUND: Oligohydramnious is threatening condition to fetal health for which some treatment are available and some are under evaluation. Oligohydramnious, is associated with increased pregnancy complication, congenital anomalies and perinatal mortality. There is an inverse relationship between the amniotic fluid index (AFI) and the adverse perinatal outcome. Oligo hydramnlious is clinical condition characteries by amniotic fluid index (AFI) of 5cm or less. Its incidence is 3-5 % of all the pregnancies an accurate and reproducible method of determining abnormality in amniotic fluid volume (AFI) is sonographic asessment of amniotic fluid index (AFI). It often increase the risk of small for gestational age (SGA) and also the incidence of cesarean section, meconium stained, low apgar score and Neonatal intensive care (NICU) admission. OBJECTIVES: The aim of study was to analyze the fetal out come in low risk pregnant women with oligohydramnious at term. This is a prospective, descriptive study. MATERIALS AND METHODS: The study was conducted at Amiralmomenin hospital in Zabol for a period of 8 months from 2012/Mar/27 to 2012/Nov/5.It included 100 pregnant women diagnosed with the AFI of or less than 5cm at term. Control group included 300 pregnant women with AFI more than 8cm. Comparison was done between the study group and the control group. Regarding the fetal and pregnancy outcome using chi square and p value, detail were recorded in terms of fetal weight, apgar score at 1 and 5 minutes. RESULTS: Mode of delivery, NICU admission neonatal death and induction of labour. Oligohydramnious is associated with a high rate of pregnancy complication and increased preinatal morbidity and mortality. Women with oligohydramnious usually have low birth babies. CONCLUSIONS: However, it can expect a safe and good outcome for which proper fetal surveillance and regular antenatal care visits are required. PMID- 25031852 TI - Forecasting tuberculosis incidence in iran using box-jenkins models. AB - BACKGROUND: Predicting the incidence of tuberculosis (TB) plays an important role in planning health control strategies for the future, developing intervention programs and allocating resources. OBJECTIVES: The present longitudinal study estimated the incidence of tuberculosis in 2014 using Box-Jenkins methods. MATERIALS AND METHODS: Monthly data of tuberculosis cases recorded in the surveillance system of Iran tuberculosis control program from 2005 till 2011 was used. Data was reviewed regarding normality, variance equality and stationary conditions. The parameters p, d and q and P, D and Q were determined, and different models were examined. Based on the lowest levels of AIC and BIC, the most suitable model was selected among the models whose overall adequacy was confirmed. RESULTS: During 84 months, 63568 TB patients were recorded. The average was 756.8 (SD = 11.9) TB cases a month. SARIMA (0,1,1)(0,1,1)12 with the lowest level of AIC (12.78) was selected as the most adequate model for prediction. It was predicted that the total nationwide TB cases for 2014 will be about 16.75 per 100,000 people. CONCLUSIONS: Regarding the cyclic pattern of TB recorded cases, Box-Jenkins and SARIMA models are suitable for predicting its prevalence in future. Moreover, prediction results show an increasing trend of TB cases in Iran. PMID- 25031853 TI - Indications and overuse of computed tomography in minor head trauma. AB - BACKGROUND: Computed Tomography (CT) is a useful diagnostic technology, particularly in accident and emergency departments. OBJECTIVES: To identify a comprehensive list of indications for application of CT in patients with minor head trauma (MHT) and to determine appropriateness of its use on the basis of this list. MATERIALS AND METHODS: A cross-sectional study was conducted in three Imaging centers in Tehran. A panel of experts developed a list of CT indications for MHT by reviewing documents. A pre-structured checklist was designed and incorporated into a structured form. Four hundred consecutive patients referring to three imaging centers for performing CT due to MHT completed the questionnaire. RESULTS: Of 400 patients who underwent CT after MHT, 187 (46.8%) patients had Glasgow coma scale (GCS) score of 13 or 14 at two hours post-trauma and 37 (19.8%) of these patients did not have any indication of imaging. In addition, 213 (53.2%) patients had GCS score of 15 out of which 110 (51.6%) patients did not have any indication of imaging. Patients with a GCS score of 15 had a noticeably lower proportion of abnormal CT results in comparison to patients with a GCS score of 13 or 14, (odds ratio, 19.07; 95% confidence interval, 6.74-54.00; and P < 0.001). There was a statistically significant association between abnormal CT results and the presence of indications including vomiting, dangerous mechanism of injury, visible signs of trauma above the clavicles, signs of skull base fracture, and suspected skull fracture (P < 0.001). CONCLUSIONS: On average, about 37% of the patients with MHT referring to the emergency departments had no indication of CT and approximately 86.5% of CT results were normal. Improving this situation can result in a significant saving in health care costs. PMID- 25031854 TI - Self-directed Learning and Its Impact on Menopausal Symptoms. AB - BACKGROUND: One of the main criteria to verify the effectiveness of a health training program is to measure quality of life in menopausal women. OBJECTIVES: Hence the aim of this review was to evaluate the effects of self-directed learning (SDL) on MENQOl. PATIENTS AND METHODS: The present single blind field study was conducted in Saadatmandi Health Center of Robat Karim (Iran, Southwest of Tehran Province) from August to December 2010. One handred and ten menopausal women were selected using convenience sampling method and then divided into two experimental (Self-directed Learning) and control groups of 55 each. Four manuals were developed to guide the women in the experimental group containing practical ways to treat menopausal symptoms. They were distributed among the participants for four weeks on a specific day. Menopausal Specific Quality of Life Questionnaire (MENQOL) was used to determine and compare quality of life scores of these women (before and three months after intervention sessions). The control group did not receive any intervention. Statistical analysis was performed by SPSS/16 software using Kolmogorov-Sminov, ANOVA, independent paired t test and Chi-square test. RESULTS: There were significant statistical differences between two groups regarding the age of subjects; age of menopause; economic, educational and employment status; number of dead and living children; BMI and vasomotor, physical, sexual and psycho-social postmenopausal symptoms. The implementation of Self-directed Learning (SDL) model leads to a significant statistical difference in scores of vasomotor symptoms (16.32 +/- 5.92 to 13.26 +/- 5.31), psychosocial symptoms (34.8 +/- 11 to 27.18 +/- 10.83), physical symptoms (75.02 +/- 18.07 to 61.42 +/- 15.49), sexual symptoms (15.36 +/- 6.10 to 12.00 +/- 4.97) and the overall score for quality of life (141.5 +/- 41.09 to 113.86 +/- 36.6) (P < 0.001). No significant changes were found in the QOL scores of the control group. CONCLUSIONS: Implementation of self-directed learning provides a useful strategy that should be included in health intervention and national surveillance programs in order to improve health and therapeutic compliance in postmenopausal women. PMID- 25031855 TI - The Voluntary Response Index in Electromyographic Study During Landing Test of the Patients With ACL Deficiency: A New Study Protocol. AB - BACKGROUND: Daily Increased rate of anterior cruciate ligament (ACL) injuries in athletes calls for more investigation in these patients to differentiate copers from noncoper ACL-deficient (ACLD) knees as soon as possible. OBJECTIVES: The current study aims to introduce a new electromyographic protocol, named voluntary response index (VRI), that might help to categorize and differentiate patients with ACLD knee from others in the early stage. MATERIALS AND METHODS: Thirty-four patients with ACLD knee were allocated into two equal groups, namely, coper and noncoper groups, based upon their ability to return to sport during the preceding six months. The patients with ACLD knee were asked to perform a jump on a force platform from a 75-cm distance. RESULTS: The results were compared with 17 matched healthy participants. The electromyographic disposable electrodes were attached to the seven muscles of the lower extremity of the participants before performing the test. The outcome measures were the magnitude and similarity index of the VRI, time to stop, vertical ground reaction force, the displacement of the center of pressure's (COP) path line length, and the participants' Tegner, IKDC (International Knee Documentation Committee) as well as KOOS (Knee injury and Osteoarthritis Outcome Score) questionnaires scores. Using the appropriate statistical analysis, the electromyographic and force plate data were compared among the three groups. All efforts went into determining whether an association exists between the findings of each group and the participants' functional questionnaires scores. CONCLUSIONS: The results of this study would be helpful in objectively differentiating the patients with ACLD knee into coper and noncoper groups to receive appropriate treatments before their return to the competitions. PMID- 25031856 TI - Prevalence of internet addiction and associated factors among medical students from mashhad, iran in 2013. AB - BACKGROUND: Problematic internet use is on the increase and has caused serious problems in many areas. This issue seems to be more important for medical students. OBJECTIVES: This study was designed to explore the prevalence of internet addiction and its related factors among the students of Mashhad University of Medical Sciences. MATERIALS AND METHODS: A cross sectional study was conducted on 383 medical students of Mashhad in 2013. Four hundred participants were selected through two-stage stratified sampling method proportional to the number of students in each stage of education. Data Collection was done through using the Chen Internet Addiction Scale (CIAS) and a checklist of demographic details and characteristics of internet usage behavior. RESULTS: It was found that 2.1% of the studied population were at risk and 5.2% were addicted users. Chatting with new people, communicating with friends and families, and playing games were the most popular activities in these groups. The factors related to internet addiction included: male sex, stage of education, daily time spent on using internet, most frequent time of internet use, monthly cost of use, and tea consumption. CONCLUSIONS: Although our study showed the prevalence of internet addiction was not more than other populations and universities, since the prevalence of internet addiction is rapidly increasing worldwide, this population might also be at risk of addiction. Thus, focusing on related factors can help us in designing more effective interventions and treatments for this susceptible group. PMID- 25031857 TI - Detecting and Accommodating Outliers in Meta-Analysis for Evaluating Effect of Albendazole on Ascaris lumbricoides Infection. AB - BACKGROUND: Meta-analysis is a statistical technique in which the results of two or more independent studies, with similar objectives, are mathematically combined in order to improve the reliability of the results. The outliers, which may exist even in random models, can affect the validity and strength of meta-analysis results. OBJECTIVES: The current study uses "random effects variance shift model" to evaluate and correct the outliers in performing a meta-analysis study of the effect of albendazole in treating patients with Ascaris lumbricoides infection. PATIENTS AND METHODS: The study used data from 14 clinical trials; each article was composed of two groups, a treatment group and a placebo group. These articles compared the effect of single dose intakes of 400 mg albendazole in treating two groups of patients with Ascaris lumbricoides infection. The articles were published in a number of internationally indexed journals between 1983 to 2013. For both groups in each article, the total number of participants, the number of those with Ascaris lumbricoides infection, and the number of those recovered following the intake of albendazole were identified and recorded. The relative risk (RR) and variance were computed for each article individually. Then, using meta-analysis, the RR was computed for all the articles together. In order to detect outliers the "random effects variance shift model" and "likelihood ratio test" (LRT) were used. Adopting the bootstrap method, the accuracy rates for sampling distribution of the tests, which were used for multiple testing, were obtained and the relevant graphs were depicted. For data analysis, STATA and R software were used. RESULTS: According to meta-analysis results, the estimate for RR was 2.91, with a 95% confidence interval of 2.6 to 3.25. According to the method used in this study, three articles (articles number 4, 7, and 12) were outliers and, as such, they were detected in the graphs. CONCLUSIONS: We can detect and accommodate outliers in meta-analysis by using random effects variance shift model and likelihood ratio test. PMID- 25031858 TI - Hydro-methanolic extract of cornus MAS L. And blood glucose, lipid profile and hematological parameters of male rats. AB - BACKGROUND: Cornus mas L, an olive-shaped red-colored single-seeded fruit, is used in traditional medicine in different parts of Europe and Asia. OBJECTIVES: In the present study, 40 male Wistar rats were randomly divided into five groups, and the effects of 21 days of intraperitoneally (IP) administration of 50, 200 and 400 mg/kg body weight of C. mas hydro-methanolic extract on the rats hematological and biochemical parameters were investigated. The experimental study was carried out in Tabriz, Iran. MATERIALS AND METHODS: The hematology and biochemical tests were performed by the Technicon H1 Hematology Analyzer and enzymatic methods, respectively. RESULTS: The results indicated that all doses of the extract caused significant (P < 0.05) decreases in the hemoglobin distribution width (HDW) (2.3 +/- 0.2 vs. 2.5 +/- 0.2, P = 0.049) and platelet distribution width (PDW) (56.5 +/- 1.8 vs. 63.9 +/- 3.6, P = 0.001) of the treated groups vs. control group, whereas only high doses caused significant elevation in the mean corpuscular hemoglobin concentration (MCHC) (30.3 +/- 0.8 vs. 28.6 +/- 0.6, P = 0.047), mean platelet volume (MPV) (5.0 +/- 0.6 vs. 4.1 +/- 0.3, P = 0.002), total platelet mass (PCT) (0.33 +/- 0.07 vs. 0.26 +/- 0.01, P = 0.050), and significant decrease in the red cell distribution width (RDW) (13.8 +/- 0.4 vs. 14.7 +/- 1.3, P = 0.048) of the treated groups vs. control group. CONCLUSIONS: Decreasing effect of the extract on platelet activity might classify it as an alternative for antiplatelet therapy in cardiovascular diseases (CVD). The results of this study suggested that further investigations with higher doses of C. mas fruit extract are necessary to obtain significant protective and nonprotective changes in hematological and biochemical parameters. PMID- 25031859 TI - Tracheobronchial foreign body aspiration demonstrating serial bronchopulmonary changes on computed tomography. AB - INTRODUCTION: Tracheobronchial foreign body may often be treated as asthma, chronic bronchitis or etc. especially in patients with no memories of aspiration episodes. CASE PRESENTATION: A 74-year-old woman, suffering from persistent cough, was temporarily misdiagnosed with allergic bronchopulmonary aspergillosis and treated for six months. During this period, computed tomography (CT) findings changed from thickened bronchial walls and a "tree-in-bud" pattern to clubbing bronchiectasis and atelectasis, and no significant bacteria was detected. Finally, a vegetable core was subsequently extracted via flexible bronchofiberscopy. Although the patient's symptoms improved dramatically, the bronchopulmonary lesion remained practically. CONCLUSIONS: We assume that chronologic CT findings of the bronchopulmonary damage by aspiration of a vegetable core, without significant detection of bacteria during the course, will be quite valuable for clinicians. PMID- 25031860 TI - Changes in risk factors and exercise capacity after cardiac rehabilitation and its effect on hospital readmission. AB - BACKGROUND: Despite the positive outcomes reported with cardiac rehabilitation (CR), its impacts have been reported to be different from a region or country to another, which may be due to the different contents of rehabilitation programs. OBJECTIVES: To investigate the effect of CR on cardiovascular risk factors. PATIENTS AND METHODS: This is a retrospective cohort study on the data from Imam Ali Cardiac Rehabilitation Center in Kermanshah province, Iran from 2001 to 2008. We used paired t-test to evaluate the effect of CR on cardiovascular risk factors. Logistic regression or t-test (unequal variance) were used to assess the factors influencing re-admission (due to cardiac problems). The relationship between different variables and death was studied using univariate cox proportional hazard. P values < 0.05 were considered significant for all analyses. RESULTS: Out of 504 patients who completed rehabilitation, a total of 499 were analyzed. These 499 patients consisted of 383 men and 116 women. All anthropometric measurements, blood lipids (except HDL cholesterol), systolic and diastolic blood pressure, depression, anxiety and exercise capacity improved after rehabilitation (P < 0.05 for all cases). The improvement was observed in both sexes. A total of 39 patients were re-admitted to hospital after rehabilitation. Being female (OR = 2.40; 95%CI: 1.22-4.68) and history of diabetes (OR = 2.04; 95%CI: 1.04-4.02) increased the risk of re-admission significantly. Patients who were readmitted had higher anthropometric measurements at the beginning and the end of the program. Moreover, the initial exercise capacity of readmitted patients was lower than those who were not readmitted. After a maximal follow-up period of 6.3 years (median = 2.99 years), only eight patients expired (survival rate: 97.5%; 95%CI: 94.7-98.8). None of the variables in our study was significantly related to the survival rate. CONCLUSIONS: The comprehensive CR program in Imam Ali Center efficiently reduces cardiovascular risk factors and improves exercise capacity. PMID- 25031861 TI - Delayed polyneuropathy in farm sprayers due to chronic low dose pesticide exposure. AB - BACKGROUND: The use of organophosphates (OPs) in developing countries is rising in large quantities and non-secure methods. This problem not only causes acute poisoning but also may lead to chronic diseases such as polyneuropathy. In Iran, 60% of pesticides are organophosphate compounds that may lead to delayed polyneuropathy. OBJECTIVES: The purpose of the current study was to evaluate delayed polyneuropathy in farm sprayers due to chronic low dose pesticide exposure. PATIENTS AND METHODS: In our cross-sectional study, non-randomized sampling method was performed and 100 farm sprayers (cases) and 100 hospital personnel (controls) after precise systemic and neurological examination were recruited to this study from June 2011 to august 2011. The nerve conduction studies were performed and these indices were recorded: Compound Muscle Action Potential (CMAP), amplitude and Distal Latency (DL) and Nerve Conduction Velocity (NCV) of common peroneal nerve, Peak Latency (PL) and amplitude of Sensory Nerve Action Potential (SNAP) and Nerve Conduction Velocity (NCV) of sural and radial sensory nerves. RESULTS: Among 100 cases, 55 farm sprayers complained of non neurological problems including: ophthalmologic, dermatologic and pulmonary complications. The ophthalmologic complaints (44%) were the most. The mean peroneal CMAP amplitude and NCV, sural PL, radial SNAP amplitude, PL and NCV in the case group were significantly different compared to control group. Mean exposure time to OPs in farm sprayers without neurological problem (40%) was 11.81 +/- 5.84 years but in farm sprayers with neurological problems (60%) was 15.70 +/- 9.08 years, which represents the effect of OPs exposure duration on neurologic problems. CONCLUSIONS: Chronic low dose pesticide exposure could lead to delayed peripheral neuropathy as well as systemic (skin, eyes and lungs) complications. In farm sprayers electrodiagnostic indices were significantly abnormal as compared to control group. The normal indices did not rule out neurologic involvement and it seems that measurement of these indices at the beginning of the farm sprayers employment and intermittently during their work is helpful for detecting delayed polyneuropathy. PMID- 25031862 TI - Comparison of Problem-based Learning With Lecture-based Learning. AB - BACKGROUND: Problem-based learning (PBL) is one of the most commonly used educational methods in medical schools of different countries. By working through this method, students think critically, generate ideas, and acquire the knowledge and skills required to become a doctor. OBJECTIVES: This study aimed to compare problem-based learning with lecture-based learning in the education of medical students. MATERIALS AND METHODS: This crossover interventional study was conducted on 40 medical students in pediatric ward of Zanjan University of Medical Sciences. All of the students were enrolled in the study and divided into two groups by simple randomization. Then two topics in pediatric courses were chosen. One of the topics was presented as LBL for the first group and as PBL for the second group. The other topic was presented as PBL for the first group and as LBL for the second group. RESULTS: The median score of the exam was higher in the intervention group compare to the control group for both topics. However, the difference was not statistically significant. Students preferred problem-based learning over lecture-based learning because of motivation boost, a higher quality of education, knowledge retention, class attractiveness, and practical use. CONCLUSIONS: Students' knowledge was similar in both methods. PMID- 25031863 TI - Quality of Life in Iranian Chemical Warfare Veteran's. AB - BACKGROUND: Mustard gas has different effects on different body systems such as respiratory tract, blood, gastrointestinal, skin, eye, endocrine and peripheral nervous system. OBJECTIVES: The purpose of this study was to determine the quality of life in chemical warfare veterans due to sulfur mustard exposure. PATIENTS AND METHODS: In a cross-sectional and analytic study, 242 patients who had a chemical injury during the Iran-Iraq war (1980-1983) and their lung damage was proven were investigated in our study. The quality of life was measured in these patients using an extensively validated Iranian version of SF-36. RESULTS: The mean age of veterans was 44.12 +/- 4.9 ranging from 22 to 62 years. Our results showed that chemical warfare had a decreased quality of life in all subscales of the SF-36. The lowest scores in SF-36 subscales were related to role physical and general health. The data also showed a significant relationship between the number of organs involved and the quality of life in these patients (P < 0.001, r = - 0.33). So that the patients who had more than three organs involved had lower quality of life. 95.4% of our participants experienced another complication with respiratory complication and the ophthalmologic complications were the most frequent accompanying condition. CONCLUSIONS: The results imply that chemical warfare survivors suffering from late complications have a low health related quality of life. PMID- 25031864 TI - Metabolic syndrome, insulin resistance and Fatty liver in obese Iranian children. AB - BACKGROUND: Obesity is a global epidemic and its morbidities such as metabolic syndrome, insulin resistance, and fatty liver leads to a spectrum of psycho social and medical consequences. OBJECTIVES: The objective of this study was to investigate the prevalence of fatty liver in obese Iranian children and its' association with metabolic syndrome and insulin resistance. PATIENTS AND METHODS: 102 obese Iranian children, referred to pediatric clinics from March 2011 to March 2012, were enrolled in this cross-sectional study. All the patients were visited by a pediatric endocrinologist, a pediatric gastroenterologist and an expert radiologist in the evaluation of fatty liver grading. RESULTS: The grade of fatty liver was higher in older children (P = 0.001). It was also more in taller and heavier children (P = 0.000). The more the BMI was, the more the fatty liver grade was (P = 0.002). Severity of fatty liver according to liver sonography in patient had a positive relationship with waist circumference, hip circumference, serum TG, serum FBS, serum fasting insulin, serum ALT, systolic blood pressure and HOMA index and had a negative correlation with the level of alkaline phosphatase. Severity of fatty liver also had a close relationship with the presence of acanthosis nigricans and HOMA index. CONCLUSIONS: Prevalence of fatty liver is high in our obese children. It was associated with criteria of metabolic syndrome and insulin resistance, so visceral fat may participate in the pathogenesis of the metabolic syndrome or merely serve as a marker of increased risk for the metabolic complications of obesity. PMID- 25031865 TI - Leech therapy in nearly total amputation of fingers without vascular repair: a case report. AB - INTRODUCTION: In the absence of microvascular replantation or in crash injury cases in which obtaining an acceptable function is not possible, amputation of the injured finger seems to be the best treatment modality. Some studies recommended leech therapy for this kind of injury after vascular repair to decrease venous congestion. CASE PRESENTATION: In this case report, the authors presented a case of leech therapy after near total amputation of the fingers. A 25-year-old patient was admitted following a sawing injury with crashed bundles of the third, fourth and fifth fingers. Microvascular surgery was not performed because of crush injury. DISCUSSION: After a simple repair and pin fixation, the patient was treated using leech therapy. The result was satisfactory. The third and fourth fingers were salvaged. It seems that in cases where a small part of the skin is still attached to the amputated part, even with complete crash of both bundles, leech therapy can help salvage the amputated fingers. PMID- 25031866 TI - Maternal quality of life during the transition to motherhood. AB - BACKGROUND: One of the elements of the broadening focus of health care beyond its traditional and restricted concept has been the increasing adoption quality of life approach to health care research and practice. OBJECTIVES: To investigate the QOL of women in the third trimester of pregnancy and at 8 weeks postpartum and factors associated with the overall QOL. MATERIALS AND METHODS: Three hundred and fifty seven pregnant women attending urban health centers in Shahroud city, located in Northeast of Iran, completed the World Health Organization Quality of Life questionnaire (WHOQOL)-BREF and General Health Questionnaire (GHQ28) in the third trimester of pregnancy and at 8 weeks postpartum. Also, breastfeeding difficulties were assessed at 4 weeks postpartum. Statistical analysis was performed using SPSS 18 for descriptive statistics, paired t-test, linear regression and multiple regression analysis. RESULTS: There were significant differences between the ante-and postnatal periods in mean scores in the physical (P < 0.001) and social relationship (P = 0.033) aspects of QOL. Multiple regression analysis revealed that factor adversely affected the global score of the QOL in the antenatal period was antepartum psychological disorders. Factors that adversely affected the global score of QOL in the postnatal period were postpartum psychological disorders, breastfeeding difficulties, multiparity, higher pregnancy weight gain, and cesarean. CONCLUSIONS: Results indicated that in this low risk group of women physical health and social relationship improved from pregnancy to postpartum. Interventions to promote psychological status during pregnancy and early postpartum should be designed. PMID- 25031867 TI - Effects of recombinant human erythropoietin on revascularization of full thickness skin grafts in rat. AB - BACKGROUND: Autologous skin graft is frequently used in the field of plastic, and reconstructive surgery. The engraftment is dependent upon revascularization and angiogenesis, which can be regulated by different factors. In addition to its hematopoietic effects, erythropoietin is shown to positively affect the wound healing process. OBJECTIVES: We studied effects of human erythropoietin on revascularization of full thickness skin grafts in rat. MATERIALS AND METHODS: Forty adult Albino male rats were selected for this study. Full thickness skin graft was performed for them, and the effects of systemic, and localized administration of erythropoietin on vascularization of the graft area were evaluated in four groups as following: inverse group underwent full thickness skin graft; in normal saline group normal saline was injected under the fascia of grafted area for seven days; systemic EPO group received systemic erythropoietin for seven days after the surgery; and in graft EPO group, erythropoietin was injected under the fascia of grafted area after full thickness skin grafting for seven days. RESULTS: Forty adult Albino male rats (n = 40), with weights ranging from 356 to 469 g (mean 391.5 +/- 29.6 g) were included. The vascular densities of central margins were significantly different between inverse group and graft EPO groups (P value = 0.01), and vascular density of central margins of normal saline group and graft EPO groups were significantly different too (P value = 0.04). CONCLUSIONS: EPO can stimulate angiogenesis which has an important role in wound healing. So, local administration of EPO seems to be beneficial in engraftment. PMID- 25031868 TI - Role of occupational stress and burnout in prevalence of musculoskeletal disorders among embassy personnel of foreign countries in iran. AB - BACKGROUND: Occupation is one of the major parts of our daily lives that might cause a great amount of stress. Stress and job burnout are linked together. The association between musculoskeletal disorders (MSD) and burnout syndrome as a psychosocial factor was investigated previously. OBJECTIVES: The aim of this study was to identify the role of occupational stress and burnout in musculoskeletal complaint among diplomatic employees of different embassies in Iran. MATERIALS AND METHODS: In a cross-sectional study, we assessed 200 employees of the foreign countries embassies in Iran. The participants were selected randomly from all the embassy personnel. Study questionnaires were delivered to the participants and finally 161 questionnaires were returned to the researchers (response rate: 80.5%). An assessment of burnout and MSD were made using the Maslach Burnout Inventory (MBI) and Nordic questionnaires. The work place stress was measured by the work place stress questionnaire. RESULTS: Mean occupational stress was significantly higher among embassy personnel with MSD than among the personnel without this syndrome during the preceding week (17.18 +/- 3.42 and 16.06 +/- 2.19, respectively; P = 0.02) and the preceding year (17.17 +/- 3.11 and 16.74 +/- 3.03, respectively; P < 0.01) to the study. Only smoking and occupational stress were identified as independent predictors of MSD among embassy personnel. CONCLUSIONS: It seems that association between musculoskeletal complaints and burnout syndrome was more complex than being attributed to only occupation stress. Further studies are recommended to determine other related factors to this association. PMID- 25031869 TI - Incidental intrathecal injection of meglumine diatrizoate. AB - INTRODUCTION: Myelograghy is a process of instilling contrast medium to the subarachnoid space for evaluating the spinal column by radiography. There are various contrast solutions for different radiographic studies but not all of them are suitable for spinal column evaluation. CASE PRESENTATION: Our patient was a 60-year-old man who developed severe pain, tonic clonic convulsions and cardiopulmonary arrest after intrathecal injection of 14 mL of meglumine diatrizoate during an elective myelography procedure. Many of these cases would die or suffer from permanent sequelae if appropriate treatment is not received. CONCLUSIONS: Our subject recovered completely without any sequelae after receiving appropriate treatment in a multidisciplinary intensive care unit. PMID- 25031870 TI - Systemic endothelial function in primary open-angle glaucoma. AB - Objective. We aimed to assess peripheral vascular endothelial function in open angle glaucoma (POAG) by measuring flow-mediated dilatation (FMD). Materials and Methods. The study included 20 cases with POAG (group 1, mean age 58.68 +/- 13.3 years) and 30 healthy individuals (group 2, mean age 58.68 +/- 13.6 years). In all cases, responses of endothelial function were assessed by a cardiologist through measurement of FMD following brachial artery occlusion. Results. Mean percent of FMD, an indicator of endothelial function, was found to be 11.9 +/- 4.2% in group 1 and 12.3 +/- 4.4% in group 2 (P = 0.86). Conclusion. No impairment in systemic vascular function of cases with POAG suggests that POAG could be a local disorder rather than being a component of systemic disease. PMID- 25031871 TI - Phagocytized neutrophil fragments in the bone marrow: a phenomenon most commonly associated with hodgkin lymphoma. AB - Bone marrow macrophages containing other cells, or large pieces of other cells, represent a distinctive feature of diseases such as Hemophagocytic Lymphohistiocytosis (HLH) and Rosai-Dorfman disease. We describe a distinct variation of phagocytic histiocyte morphology, featuring histiocytes containing predominantly fragments of neutrophil nuclei. We retrospectively reviewed initial bone marrow samples for Hodgkin lymphoma, Burkitt lymphoma, Ewing sarcoma, or evaluation for nonneoplastic conditions, scoring the presence or absence of the above-described histiocytes. We find that these histiocytes, which we term "fragmentophages," are associated with staging marrow sampling for malignancy, especially Hodgkin lymphoma (Hodgkin lymphoma: 28/34 or 82.4%, Ewing sarcoma: 11/26 or 42.3%, Burkitt lymphoma: 4/13 or 30.8%). These cells are significantly less common in marrow samples for nonneoplastic conditions (4/21 or 19.0%). Fragmentophages are significantly associated with malignancy, especially Hodgkin lymphoma, and their recognition has the potential to provide a clue to an underlying malignancy. PMID- 25031872 TI - Spinal fMRI of interoceptive attention/awareness in experts and novices. AB - Many disciplines/traditions that promote interoceptive (inner sensation of body parts) attention/awareness (IAA) train practitioners to both attend to and be aware of interoceptive sensory experiences in body parts. The effect of such practices has been investigated in previous imaging studies but limited to cerebral neural activity. Here, for the first time, we studied the impact of these practices on the spinal neural activity of experts and novices. We also attempted to clarify the effect of constant and deep breathing, a paradigm utilized in concentration practices to avoid mind wandering, on IAA-related spinal neural activity. Subjects performed IAA tasks with and without a deep and constant breathing pattern in two sessions. Results showed that neural activity in the spinal segment innervating the attended-to body area increased in experts (P = 0.04) when they performed IAA and that this increase was significantly larger for experts versus novices in each of the sessions (P = 0.024). The significant effects of IAA and expertise on spinal neural activity are consistent with and elaborate on previous reports showing similar effects on cerebral neural activity. As the spinal cord directly innervates body parts, the results might indicate that IAA has an instantaneous (possibly beneficial) effect on the physical body after extended training. PMID- 25031873 TI - Geometric Structure of 3D Spinal Curves: Plane Regions and Connecting Zones. AB - This paper presents a new study of the geometric structure of 3D spinal curves. The spine is considered as an heterogeneous beam, compound of vertebrae and intervertebral discs. The spine is modeled as a deformable wire along which vertebrae are beads rotating about the wire. 3D spinal curves are compound of plane regions connected together by zones of transition. The 3D spinal curve is uniquely flexed along the plane regions. The angular offsets between adjacent regions are concentrated at level of the middle zones of transition, so illustrating the heterogeneity of the spinal geometric structure. The plane regions along the 3D spinal curve must satisfy two criteria: (i) a criterion of minimum distance between the curve and the regional plane and (ii) a criterion controlling that the curve is continuously plane at the level of the region. The geometric structure of each 3D spinal curve is characterized by the sizes and orientations of regional planes, by the parameters representing flexed regions and by the sizes and functions of zones of transition. Spinal curves of asymptomatic subjects show three plane regions corresponding to spinal curvatures: lumbar, thoracic and cervical curvatures. In some scoliotic spines, four plane regions may be detected. PMID- 25031874 TI - Pedicle-Screw-Based Dynamic Systems and Degenerative Lumbar Diseases: Biomechanical and Clinical Experiences of Dynamic Fusion with Isobar TTL. AB - Dynamic systems in the lumbar spine are believed to reduce main fusion drawbacks such as pseudarthrosis, bone rarefaction, and mechanical failure. Compared to fusion achieved with rigid constructs, biomechanical studies underlined some advantages of dynamic instrumentation including increased load sharing between the instrumentation and interbody bone graft and stresses reduction at bone-to screw interface. These advantages may result in increased fusion rates, limitation of bone rarefaction, and reduction of mechanical complications with the ultimate objective to reduce reoperations rates. However published clinical evidence for dynamic systems remains limited. In addition to providing biomechanical evaluation of a pedicle-screw-based dynamic system, the present study offers a long-term (average 10.2 years) insight view of the clinical outcomes of 18 patients treated by fusion with dynamic systems for degenerative lumbar spine diseases. The findings outline significant and stable symptoms relief, absence of implant-related complications, no revision surgery, and few adjacent segment degenerative changes. In spite of sample limitations, this is the first long-term report of outcomes of dynamic fusion that opens an interesting perspective for clinical outcomes of dynamic systems that need to be explored at larger scale. PMID- 25031875 TI - Irinotecan Plus S-1 Followed by Hepatectomy for a Patient with Initially Unresectable Colorectal Liver Metastases, Who Showed Severe Drug Rash with Oxaliplatin Plus 5-FU and Leucovorin (FOLFOX). AB - For unresectable colorectal liver metastases (CRLM), hepatic resection with or without chemotherapy is the only curative treatment that sufficiently achieves long-term survival. However, occasional severe allergic responses to anticancer drugs necessitate treatment discontinuation. A 45-year-old woman presented with metachronous unresectable colorectal liver metastases. Chemotherapy with oxaliplatin plus 5-FU and leucovorin (FOLFOX) was initiated, but severe allergic dermatitis developed after the second cycle. Although she reported no prior history of adverse reactions to tegafur-uracil, a drug lymphocyte stimulation test showed an allergic response to 5-FU. We subsequently replaced with Irinotecan plus S-1 (IRIS) chemotherapy which was well tolerated and resulted in a partial response after 3 cycles. As a result, right trisectionectomy was successfully performed and no recurrence was detected in the following 3 years. A severe allergic reaction to intravenous 5-FU-containing drug regimens can be successfully alleviated by switching to S-1-containing regimens such as IRIS or S 1 plus oxaliplatin (SOX). PMID- 25031876 TI - High-dose methotrexate for the treatment of relapsed central nervous system erdheim-chester disease. AB - Erdheim-Chester disease (ECD) is a rare multisystem non-Langerhans histiocytosis. CNS involvement is a major complication, which is often rapidly progressive and confers a poor prognosis. However, treatment of CNS ECD is difficult due to poor CNS penetrance by the most effective chemotherapeutic drugs commonly used in this disorder (e.g., interferon and cladribine). We describe a case of a 60-year-old lady with a 5-year history of stable systemic ECD who presented with new brainstem lesions and rapid, steroid-refractory neurological deterioration which required immediate intervention. High-dose methotrexate was chosen due to its rapid onset of action and excellent CNS penetration. Her neurological deterioration was quickly arrested with significant functional improvement, which was sustained for 4 months with consolidation doses of high-dose methotrexate. Subsequent treatment with cladribine and interferon did not confer any appreciable clinical improvement. High-dose methotrexate is effective in controlling rapidly progressive CNS ECD and should be considered as a salvage agent prior to commencement of more definitive treatment. PMID- 25031877 TI - Microcystic variant of an intraosseous meningioma in the frontal area: a case report. AB - Meningiomas located inside the bone of the calvaria belong to the group of rare types of tumours. The microcystic variant is the least common in this area. Due to their similarity to other tumours in this area, the imaging test of those tumours may constitute the source of an improper preoperative diagnosis. According to the records of the Department of Neurosurgery in Bielsko-Biala, 133 patients diagnosed with an intracranial meningioma confirmed by a histopathological test were operated in the last 10 years (2004-2014). In the histopathological test, three patients were diagnosed with the microcystic variant, which constitutes 2.25% of the cases. Only one variant of microcystic meningioma was located inside the bone, which constitutes 0.75% of all the meningiomas operated. PMID- 25031878 TI - Unilateral cataract and vitreoretinopathy in a case with klippel-trenaunay syndrome. AB - Purpose. We present a case with Klippel-Trenaunay (KT) syndrome that had unilateral mature cataract and vitreoretinopathy. Case Report. A 17-year-old boy with KT syndrome presented to the clinic of ophthalmology for low vision in the right eye. His best corrected visual acuity (BCVA) was hand motion in the right eye and 20/20 in the left eye. Anterior segment examination revealed mature cataract in the right. During the physical examination, port-wine stains were noted over right side of his face, ankle, and toes. He had asymmetric face and his head was larger on the right side. Leg lengths were symmetrical, although he had skin hypertrophy. Cranial magnetic resonance imaging studies showed cortical atrophy discordant to his age, asymmetric vascular dilatations in the right hemisphere, hypertrophy in the right periorbital soft tissue, and choroidal plexus. The patient received an uncomplicated cataract surgery. His BCVA in the right eye improved to 20/200 after the surgery. After removing cataractous lens, we were able to examine the fundus that revealed severe vitreoretinopathy and choroidal hemangioma. Conclusion. This case emphasizes the importance of prompt ophthalmic examination in patients with KT syndrome. PMID- 25031879 TI - Tofacitinib citrate for ulcerative keratitis in a patient with rheumatoid arthritis. AB - Purpose. To report a case of a patient with rheumatoid arthritis (RA) treated with tofacitinib citrate. Methods. Observational case report. Results. A 59-year old patient, with a history of rheumatoid arthritis, on methotrexate 10 mg PO qwk and IV abatacept 750 mg/month, presented with photosensitivity, foreign body sensation, pain, redness, and blurry vision of her right eye (RE). Visual acuity of the RE was 20/200 and 20/20 of the left eye (LE). The slit lamp examination of the RE revealed dryness, 2+ injection of the conjunctiva, and pericentral ulceration of the cornea with 20-30% stromal thinning, pannus, and diffuse punctate epithelial erosions. The anterior chamber appeared normal. Laboratory values revealed elevated levels of rheumatoid factor, anticyclic citrullinated peptide antibodies, and C-reactive protein. The patient was switched to tofacitinib citrate 5 mg PO b.i.d, underwent corneal gluing, and was given prednisone acetate 1% gt TID, polytrim gt TID, neomycin-polymyxin-dexameth gt QD, FreshKote lubricant 1.8% gt QID, moxifloxacin 0.5% gt QID, and preservative free artificial tears Q1H. Within one week, laboratory values normalized, symptoms diminished, and the cornea reepithelialized. Conclusion. RA can present with ulcerative keratitis. Tofacitinib citrate, steroids, and corneal gluing were found to halt the progression of keratolysis and promote reepithelialization. PMID- 25031880 TI - Investigation of Bacterial Cellulose Biosynthesis Mechanism in Gluconoacetobacter hansenii. AB - The present study explores the mechanism of cellulose biosynthesis in Gluconoacetobacter hansenii. The cellulose synthase enzyme was purified as membrane fraction and solubilized by treatment with 0.1% digitonin. The enzyme was separated by native-gel electrophoresis and beta -D-glucan analysis was carried out using in vitro gel assay. The cellulose synthase has glycoprotein nature and composed two polypeptide subunits of 93 KDa and 85 KDa. The confirmation of beta -1,4-glucan (cellulose) was performed in whole and hydrolyzed monomeric sugar form. Tinopal and Congo red were used for cellulose detection on the gel. Thus the in vitro cellulose synthesis assay with cell free enzyme fraction was attempted to improve the understanding of cellulose biosynthesis. PMID- 25031882 TI - Transcriptional regulation of fibroblast growth factor 21 expression. AB - Fibroblast growth factor 21 (FGF21) is an attractive target for treating metabolic disease due to its wide-ranging beneficial effects on glucose and lipid metabolism. Circulating FGF21 levels are increased in insulin-resistant states; however, endogenous FGF21 fails to improve glucose and lipid metabolism in obesity, suggesting that metabolic syndrome is an FGF21-resistant state. Therefore, transcription factors for FGF21 are potential drug targets that could increase FGF21 expression in obesity and reduce FGF21 resistance. Despite many studies on the metabolic effects of FGF21, the transcriptional regulation of FGF21 gene expression remains controversial and is not fully understood. As the FGF21 transcription factor pathway is one of the most promising targets for the treatment of metabolic syndrome, further investigation of FGF21 transcriptional regulation is required. PMID- 25031881 TI - Phage therapy: eco-physiological pharmacology. AB - Bacterial virus use as antibacterial agents, in the guise of what is commonly known as phage therapy, is an inherently physiological, ecological, and also pharmacological process. Physiologically we can consider metabolic properties of phage infections of bacteria and variation in those properties as a function of preexisting bacterial states. In addition, there are patient responses to pathogenesis, patient responses to phage infections of pathogens, and also patient responses to phage virions alone. Ecologically, we can consider phage propagation, densities, distribution (within bodies), impact on body-associated microbiota (as ecological communities), and modification of the functioning of body "ecosystems" more generally. These ecological and physiological components in many ways represent different perspectives on otherwise equivalent phenomena. Comparable to drugs, one also can view phages during phage therapy in pharmacological terms. The relatively unique status of phages within the context of phage therapy as essentially replicating antimicrobials can therefore result in a confluence of perspectives, many of which can be useful towards gaining a better mechanistic appreciation of phage therapy, as I consider here. Pharmacology more generally may be viewed as a discipline that lies at an interface between organism-associated phenomena, as considered by physiology, and environmental interactions as considered by ecology. PMID- 25031883 TI - Neurocognitive changes and their neural correlates in patients with type 2 diabetes mellitus. AB - As the prevalence and life expectancy of type 2 diabetes mellitus (T2DM) continue to increase, the importance of effective detection and intervention for the complications of T2DM, especially neurocognitive complications including cognitive dysfunction and dementia, is receiving greater attention. T2DM is thought to influence cognitive function through an as yet unclear mechanism that involves multiple factors such as hyperglycemia, hypoglycemia, and vascular disease. Recent developments in neuroimaging methods have led to the identification of potential neural correlates of T2DM-related neurocognitive changes, which extend from structural to functional and metabolite alterations in the brain. The evidence indicates various changes in the T2DM brain, including global and regional atrophy, white matter hyperintensity, altered functional connectivity, and changes in neurometabolite levels. Continued neuroimaging research is expected to further elucidate the underpinnings of cognitive decline in T2DM and allow better diagnosis and treatment of the condition. PMID- 25031884 TI - Regulation of Adipocyte Differentiation via MicroRNAs. AB - Adipocyte differentiation, termed adipogenesis, is a complicated process in which pluripotent mesenchymal stem cells differentiate into mature adipocytes. The process of adipocyte differentiation is tightly regulated by a number of transcription factors, hormones and signaling pathway molecules. Recent studies have demonstrated that microRNAs, which belong to small noncoding RNA species, are also involved in adipocyte differentiation. In vivo and in vitro studies have revealed that various microRNAs affect adipogenesis by targeting several adipogenic transcription factors and key signaling molecules. In this review, we will summarize the roles of microRNAs in adipogenesis and their target genes associated with each stage of adipocyte differentiation. PMID- 25031885 TI - Diagnostic Modalities for FGF23-Producing Tumors in Patients with Tumor-Induced Osteomalacia. AB - Fibroblast growth factor 23 (FGF23) is a hormone that is produced by osteocytes and regulates phosphate and vitamin D metabolism through binding to the Klotho FGF receptor complex. Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. Tumor-induced rickets/osteomalacia (TIO) is a paraneoplastic syndrome caused by overproduction of FGF23 from the responsible tumors. Because TIO is cured by complete resection of the causative tumors, it is of great clinical importance to locate these tumors. Several imaging methods including skeletal survey by magnetic resonance imaging and octreotide scintigraphy have been used to identify the tumors that cause TIO. However, none of these imaging studies indicate that the detected tumors are actually producing FGF23. Recently, systemic venous sampling was conducted for locating FGF23-producing tumor in suspected patients with TIO and demonstrated that this test might be beneficial to a subset of patient. Further studies with more patients are necessary to establish the clinical utility of venous sampling in patients with TIO. PMID- 25031886 TI - The biochemical prognostic factors of subclinical hypothyroidism. PMID- 25031887 TI - Genetic Analysis of Multiple Endocrine Neoplasia Type 1 (MEN1) Leads to Misdiagnosis of an Extremely Rare Presentation of Intrasellar Cavernous Hemangioma as MEN1. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder characterized by the simultaneous occurrence of endocrine tumors in target tissues (mainly the pituitary, endocrine pancreas, and parathyroid glands). MEN1 is caused by mutations in the MEN1 gene, which functions as a tumor suppressor and consists of one untranslated exon and nine exons encoding the menin protein. This condition is usually suspected when we encounter patients diagnosed with tumors in multiple endocrine organs, as mentioned above. METHODS: A 65-year-old woman who underwent surgery for a pancreatic tumor (serous cystadenoma) 5 years previously was referred to our hospital due to neurologic symptoms of diplopia and left ptosis. Brain magnetic resonance imaging revealed a 3.4-cm lesion originating from the cavernous sinus wall and extending into the sellar region. It was thought to be a nonfunctioning tumor from the results of the combined pituitary function test. Incidentally, we found that she also had a pancreatic tumor, indicating the necessity of genetic analysis for MEN1. RESULTS: Genomic analysis using peripheral leukocytes revealed a heterozygous c.1621G>A mutation in the MEN1 gene that was previously reported to be either a pathogenic mutation or a simple polymorphism. We pursued a stereotactic approach to the pituitary lesion, and microscopic findings of the tumor revealed it to be an intrasellar cavernous hemangioma, a rare finding in the sellar region and even rarer in relation to oculomotor palsy. The patient recovered well from surgery, but refused further evaluation for the pancreatic lesion. CONCLUSION: There is great emphasis placed on genetic testing in the diagnosis of MEN1, but herein we report a case where it did not assist in diagnosis, hence, further discussion on the role of genetic testing in this disease is needed. Also, in cases of pituitary tumor with cranial nerve palsy, despite its low prevalence, intrasellar cavernous hemangioma could be suspected. PMID- 25031888 TI - The biochemical prognostic factors of subclinical hypothyroidism. AB - BACKGROUND: Patients with subclinical hypothyroidism (SHT) are common in clinical practice. However, the clinical significance of SHT, including prognosis, has not been established. Further clarifying SHT will be critical in devising a management plan and treatment guidelines for SHT patients. Thus, the aim of this study was to investigate the prognostic factors of SHT. METHODS: We reviewed the medical records of Korean patients who visited the endocrinology outpatient clinic of Severance Hospital from January 2008 to September 2012. Newly-diagnosed patients with SHT were selected and reviewed retrospectively. We compared two groups: the SHT maintenance group and the spontaneous improvement group. RESULTS: The SHT maintenance group and the spontaneous improvement group had initial thyroid-stimulating hormone (TSH) levels that were significantly different (P=0.035). In subanalysis for subjects with TSH levels between 5 to 10 uIU/mL, the spontaneous improvement group showed significantly lower antithyroid peroxidase antibody (anti-TPO-Ab) titer than the SHT maintenance group (P=0.039). Regarding lipid profiles, only triglyceride level, unlike total cholesterol and low density lipoprotein cholesterol, was related to TSH level, which is correlated with the severity of SHT. Diffuse thyroiditis on ultrasonography only contributed to the severity of SHT, not to the prognosis. High sensitivity C reactive protein and urine iodine excretion, generally regarded as possible prognostic factors, did not show any significant relation with the prognosis and severity of SHT. CONCLUSION: Only initial TSH level was a definite prognostic factor of SHT. TPO-Ab titer was also a helpful prognostic factor for SHT in cases with mildly elevated TSH. Other than TSH and TPO-Ab, we were unable to validate biochemical prognostic factors in this retrospective study for Korean SHT patients. PMID- 25031889 TI - Insulin Phosphorylates Tyrosine Residue 464 of Tub and Translocates Tubby into the Nucleus in HIRcB Cells. AB - BACKGROUND: The tubby protein has a motif that might be relevant for its action in the insulin signaling pathway. Previous studies have indicated that tubby undergoes phosphorylation on tyrosine residues in response to several stimuli and is known to localize in the nucleus as well as in the plasma membrane. However, the relationship between phosphorylation and nuclear translocation is not well understood. Here, we report that insulin directly phosphorylates tubby, which translocates into the nucleus. METHODS: The effects of insulin on Tubby were performed with Western blot. The immunoprecipitation and confocal microscopy were performed to prove phosphorylation and nuclear translocation. RESULTS: Mutation study reveals that tyrosine residue 464 of tubby gene (Tub) is a phosphorylation site activated by insulin. In addition, major portions of tubby protein in the plasma membrane are translocated into the nucleus after insulin treatment. Tyrosine kinase inhibitor pretreatment blocked insulin-induced tubby translocation, suggesting that phosphorylation is important for nuclear translocation. Moreover, mutant tyrosine residue 464 did not translocate into the nucleus in respond to insulin. These findings demonstrate that insulin phosphorylates tyrosine residue 464 of Tub, and this event is important for insulin-induced tubby nuclear translocation. CONCLUSION: Insulin phosphorylates tyrosine residue 464 of Tub and translocates tubby into the nuclei of HIRcB cells. PMID- 25031890 TI - Highly Palatable Food during Adolescence Improves Anxiety-Like Behaviors and Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Rats that Experienced Neonatal Maternal Separation. AB - BACKGROUND: This study was conducted to examine the effects of ad libitum consumption of highly palatable food (HPF) during adolescence on the adverse behavioral outcome of neonatal maternal separation. METHODS: Male Sprague-Dawley pups were separated from dam for 3 hours daily during the first 2 weeks of birth (maternal separation, MS) or left undisturbed (nonhandled, NH). Half of MS pups received free access to chocolate cookies in addition to ad libitum chow from postnatal day 28 (MS+HPF). Pups were subjected to behavioral tests during young adulthood. The plasma corticosterone response to stress challenge was analyzed by radioimmunoassay. RESULTS: Daily caloric intake and body weight gain did not differ among the experimental groups. Ambulatory activities were decreased defecation activity and rostral grooming were increased in MS controls (fed with chow only) compared with NH rats. MS controls spent less time in open arms, and more time in closed arms during the elevated plus maze test, than NH rats. Immobility duration during the forced swim test was increased in MS controls compared with NH rats. Cookie access normalized the behavioral scores of ambulatory and defecation activities and grooming, but not the scores during the elevated plus maze and swim tests in MS rats. Stress-induced corticosterone increase was blunted in MS rats fed with chow only, and cookie access normalized it. CONCLUSION: Prolonged access to HPF during adolescence and youth partly improves anxiety-related, but not depressive, symptoms in rats that experienced neonatal maternal separation, possibly in relation with improved function of the hypothalamic-pituitary-adrenal (HPA) axis. PMID- 25031891 TI - Gene expression regulation by agonist-independent constitutive signaling of melanocortin-1 receptor. AB - BACKGROUND: Melanocortin-1 receptor (Mc1r), a key signaling receptor for melanogenesis, has been reported to mediate migration of B16F10 melanoma cells. Interestingly, this activity appears to be a part of the constitutive signaling of Mc1r. METHODS: We carried out small interfering RNA-mediated knock-down of Mc1r on murine melanoma B16F10 cells and performed microarray analysis to characterize changes in the gene expression profile. RESULTS: We isolated 22 and four genes whose expression decreased and increased, respectively, by 2.5-fold or higher as the result of Mc1r knock-down. Several down-regulated genes have been proposed to be involved in cell migration. Among these genes are several members of the chemokine gene family. CONCLUSION: We provide a gene set for further functional analyses of Mc1r. The Mc1r target genes we present may be particularly relevant for understanding the ligand-independent activity of Mc1r. Further examination of the mode of action may lead to novel strategies in regulating the migration and metastasis of melanoma cells. PMID- 25031892 TI - A Novel Cytosolic Isoform of Mitochondrial Trans-2-Enoyl-CoA Reductase Enhances Peroxisome Proliferator-Activated Receptor alpha Activity. AB - BACKGROUND: Mitochondrial trans-2-enoyl-CoA reductase (MECR) is involved in mitochondrial synthesis of fatty acids and is highly expressed in mitochondria. MECR is also known as nuclear receptor binding factor-1, which was originally reported with yeast two-hybrid screening as a binding protein of the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha). However, MECR and PPARalpha are localized at different compartment, mitochondria, and the nucleus, respectively. Therefore, the presence of a cytosolic or nuclear isoform of MECR is necessary for functional interaction between MECR and PPARalpha. METHODS: To identify the expression pattern of MECR and the cytosolic form of MECR (cMECR), we performed reverse transcription polymerase chain reaction (RT-PCR) with various tissue samples from Sprague-Dawley rats. To confirm the interaction between cMECR and PPARalpha, we performed several binding assays such as yeast two-hybrid, coimmunoprecipitation, and bimolecular fluorescence complementation. To observe subcellular localization of these proteins, immunocytochemistry was performed. A luciferase assay was used to measure PPARalpha activity. RESULTS: We provide evidence of an alternatively spliced variant of the rat MECR gene that yields cMECR. The cMECR lacks the N terminal 76 amino acids of MECR and shows uniform distribution in the cytoplasm and nucleus of HeLa cells. cMECR directly bound PPARalpha in the nucleus and increased PPARalpha-dependent luciferase activity in HeLa cells. CONCLUSION: We found the cytosolic form of MECR (cMECR) was expressed in the cytosolic and/or nuclear region, directly binds with PPARalpha, and enhances PPARalpha activity. PMID- 25031893 TI - A Novel PHEX Gene Mutation in a Patient with Sporadic Hypophosphatemic Rickets. AB - Phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) is a common cause of X-linked hypophosphatemic (XLH) rickets. Diverse PHEX gene mutations have been reported; however, gene mutations in sporadic rickets are less common than in XLH rickets. Herein, we describe a 50-year-old female patient with sporadic hypophosphatemic rickets harboring a novel splicing-site mutation in the PHEX gene (c.663+1G>A) at the exon 5-intron 5 boundary. The patient had recently suffered from right thigh pain and an aggravated waddling gait. She also presented with very short stature, generalized bone pain, and muscle weakness. Despite low serum phosphate levels, her phosphate reabsorption rate was lower than normal. Additionally, her 1,25-dihydroxyvitamin D3 concentration was lower than normal, although FGF23 level was normal. After treatment with alfacalcidol and elemental phosphate, her rachitic symptoms subsided, and callus formation was observed in the fracture site on the right femur. PMID- 25031894 TI - Recurrent hypoglycemia triggered by sorafenib therapy in a patient with hemangiopericytoma. AB - Targeted therapy has been proven to be one of the most effective cancer treatments. However, some endocrine disorders can occur during treatment with targeted agents. We report the case of a patient who exhibited a wax and wane pattern of hypoglycemia that was attributed to sorafenib therapy. A 32-year-old woman with metastatic hemangiopericytoma visited the emergency department in a stuporous state. Nonhyperinsulinemic hypoglycemia was diagnosed, was exacerbated shortly after sorafenib therapy, and was improved by the cessation of sorafenib with additional glucocorticoid therapy. Patients with metastatic hemangiopericytoma should be carefully monitored with particular attention to hypoglycemia when sorafenib therapy is initiated. PMID- 25031895 TI - Letter: Diagnostic Whole-Body Scan May Not Be Necessary for Intermediate-Risk Patients with Differentiated Thyroid Cancer after Low-Dose (30 mCi) Radioactive Iodide Ablation (Endocrinol Metab 2014;29:33-9, Eon Ju Jeon et al.). PMID- 25031896 TI - Response: Diagnostic Whole-Body Scan May Not Be Necessary for Intermediate-Risk Patients with Differentiated Thyroid Cancer after Low-Dose (30 mCi) Radioactive Iodide Ablation (Endocrinol Metab 2014;29:33-9, Eon Ju Jeon et al.). PMID- 25031897 TI - Osteogenesis imperfecta: a case report and review of literature. AB - Osteogenesis imperfecta (OI) is a group of rare inherited disorders of connective tissue with the common feature of excessive fragility of bones caused by mutations in collagen. Diagnosis is mainly based on the clinical features of the disorder. We report, the case of a male neonate delivered to a 33-year-old para 2 female at University of Nigeria Teaching Hospital, Enugu with no family history suggestive of OI. He had clinical features of a type II OI and severe birth asphyxia. Multidisciplinary management was instituted, but he died on the 7(th) day of life. PMID- 25031898 TI - The complexity of stromal changes in desmoplastic ameloblastoma. AB - Ameloblastoma is usually considered a homogenous neoplasm and is thought of as the most primitive of all odontogenic neoplasms. However, detailed investigations have proven clinicopathological diversity in a significant number of cases, thus mounting the evidence in favor of considering ameloblastoma as a mysterious lesion. The purpose of this article is to report a unique case of desmoplastic ameloblastoma and to throw light on the atypical changes noticed in the stromal component. The findings of this case have served to add interesting parameters to the study of stromal changes associated with this perplexing odontogenic tumor. PMID- 25031899 TI - Gingival recession in a child-patient; easily missed etiologies: case report with video. AB - Gingival recession is commonly associated with plaque-induced inflammation and calculus. A high frenal attachment is more important in gingival recession in the child-patient. A healthy child-patient with impeccable oral hygiene presented with localized gingival recession without plaque-induced inflammation which led to the exploration of other possible etiologies. Multiple factors appeared to be acting in consonance (Concomitant multiple etiologies [CME]). The factors were a high frenal attachment, traumatic overbite and bruxism induced by premature tooth contacts. Pedodontists and periodontists should rule out CME in cases of gingival recession in the child-patient. PMID- 25031900 TI - "Watch out! Pneumonia secondary to achromobacter denitrificans". AB - Pneumonia is the cause of significant morbidity and mortality especially in developing countries. The frequency and importance of emerging new pathogens have significant implications for therapy. We report a case of pneumonia caused by a very rare organism, Achromobacter denitrificans which was treated successfully with intravenous meropenem injections for 14 days. Review of available literature has documentation of isolation of Achromobacter xylosoxidans from endotracheal aspirate culture but this is probably the first case of pneumonia due to A. denitrificans. PMID- 25031901 TI - Assessment of red blood cell parameters and peripheral smear at different temperatures in case of cold agglutination disease. AB - Cold agglutination disease (CAD) is characterized by an auto-antibody which is able to agglutinate red blood cells (RBCs) at temperatures lower than that of the body, and subsequently to activate the complement system responsible for lysis of RBCs. Patients show hemolytic anemia of varying degrees of severity, which arise or worsen upon exposure to low temperatures. We describe a case who presented with fever and symptoms of asthenia. His investigations yielded bizarre RBC parameters which led to suspicion of a rare CAD, which was confirmed on reviewing RBC parameters, peripheral smear and direct Coomb's test at different temperatures. Hence, we suggest assessment of bizarre RBC parameters and peripheral smear can help in laboratory testing and diagnosis of CAD. It should also not pose embarrassment in laboratory testing to the pathologist for making an early and accurate diagnosis, thus emphasizing the need for an early treatment of CAD. PMID- 25031902 TI - Rare case of double looped ansa cervicalis associated with its deep position in the carotid triangle of the neck. AB - Ansa cervicalis (AC) frequently shows its variations in the formation and distribution pattern. However, variation in its looping pattern associated with abnormal topographic disposition is relatively rare. Knowledge on the possible deviations in the looping pattern is clinically important, to avoid iatrogenic injuries in surgical procedures. We report here a concurrent rare case of double looped AC located deep to internal jugular vein. Anatomy of its superior root was normal, but the usual appearance of inferior root had gone astray due to formation of double loop. AC is being popularly used for nerve reconstructive surgery in treating paralyzed larynx, tongue hemiatrophy. Anatomical variation of it may potentially jeopardize the surgical procedures. Therefore, it is essential to the surgeons to be familiar with its unusual variations. PMID- 25031903 TI - Comparison between Three Rare Cases of Co-Infection with Dengue, Leptospira and Hepatitis E: Is Early Endothelial Involvement the Culprit in Mortality? AB - Co-infection in immunocompetent patients is rare. Though co-infection with dengue and leptospira cases is increasingly reported, a co-infection of this combination along with hepatitis E is rarely thought of. Until date only two case of triple co-infection have been reported world-wide. Here, we are reporting a patient with co-infection of dengue, leptospirosis and hepatitis E admitted to our intensive care unit. Early septic shock and increasing procalcitonin in dengue patient raised suspicion of co-infection. Our aim is to educate intensivists about this rare co-infection and hence that timely initiation of appropriate diagnostic, therapeutic and supportive measures can alter outcome favorably. PMID- 25031904 TI - Mandibular facial talon cusp: a rare case report. AB - Talon cusp (TC) is a relatively uncommon developmental anomaly characterized by cusp-like projections from the cemento-enamel junction to a variable distance toward the incisal edge of an anterior tooth. It usually presents on palatal/lingual surface of the anterior teeth. Studies have revealed that it consists of enamel, dentine and a variable amount of pulp tissue. Presence of this cusp on the facial surface of an anterior tooth is a rare finding with very few cases being reported in the literature. The effects of TCs are mainly aesthetic and functional. The management requires a sufficient knowledge of the present clinical entity and the problems associated with it. Early detection and treatment plays a very vital role in avoiding the future complications. The present case reports a 25-year-old male patient with a facial TC on the mandibular left central incisor in which a prophylactic enameloplasty was carried out to avoid the stagnation of debris and stain. PMID- 25031905 TI - Unresolving short stature in a possible case of mucopolysccharidosis. AB - We present a metabolic disorder with main complaints of unresolving short stature following prolonged treatment for rickets. ES is a 4-year-old male who first presented to our hospital on self-referral but had been seen previously at another tertiary health facility. The complaints were a swelling on the back and poor growth since 1 year of age with associated skeletal deformities: Chest wall, wrists, knees and ankle joints, which were progressive. Examination revealed a severely stunted child with a large head and caput quadratum, craniofacial disproportion, coarse facial features, saddle-shaped nose, thick lips and bilateral corneal clouding/opacities. He had very poor language development for his age. His diagnoses based on clinical and radiological assessment was in keeping with Hurlers type of mucopolysaccharidoses. We highlight this case to emphasize the need for early consideration of other possible rare differential diagnoses in metabolic conditions in children. PMID- 25031906 TI - Is Dysguesia Going to be a Rare or a Common Side-effect of Amlodipine? AB - A very rare side-effect of amlodipine is dysguesia. A review of the literature produced only one case. We report a case about a female with essential hypertension on drug treatment with amlodipine developed loss of taste sensation. Condition moderately improved on stoppage of the drug for 25 days. We conclude that amlodipine can cause dysguesia. Here, we describe the clinical presentation and review the relevant literature on amlodipine and dysguesia. PMID- 25031907 TI - Report of a rare case of an odontogenic myxoma of the maxilla and review of literature. AB - Odontogenic myxoma (OM) is a mesenchymal tissue benign neoplasia, being relatively rare which is almost exclusively seen in tooth-bearing areas. OM commonly occurs in the 2(nd) and 3(rd) decade and the mandible is involved more commonly than the maxilla. The lesion often grows without symptoms and presents as a painless swelling. Radiographically, the myxoma appears as a unilocular or multilocular radiolucency. This article presents a rare case of OM occurring in the maxilla of a 28-year-old female patient with a brief review of the literature. PMID- 25031908 TI - Mesenchymal chondrosarcoma of posterior maxilla: report of a case with brief literature review. AB - Mesenchymal chondrosarcomas (MCs) are infrequent, slow-growing malignant tumors of head and neck region affecting both bone and soft tissues. It represents approximately 1% of all chondrosarcomas. They usually occur in the middle aged individuals, but rarely seen in young patients. It is commonly found in the ribs and jaws. Involvement of the jaws is evident in 22-27% of cases of MC. Most commonly, MCs are painless and occurs in the anterior portion of maxilla. Maxillofacial MCs are aggressive, has a tendency for recurrence and late metastasis to lung, bone, and lymph nodes, and is associated with an overall poor prognosis. Histopathologically, it is characterized by a biphasic pattern consisting of areas of hyaline cartilage mixed with small cell malignancy. Very few case reports involving the posterior maxillary region has been reported. This article reports a rare case of MC along with a review of the pertinent literature. PMID- 25031909 TI - Male urethral diverticulum having multiple stones. AB - Congenital diverticulum of male urethra is an uncommon entity. Neglected management complicates the process in the form of calculi formation and recurrent urinary infection. A 10-year-old boy presented with urinary voiding disturbances and development of a painless hard lump at the penoscrotal junction. Imaging demonstrated presence of anterior urethral diverticulum with contained calculi in it. Open urethral diverticulectomy, extraction of multiple calculi, and primary urethral reconstruction over a Foley catheter was carried out. Early diagnosis and individualized surgical management of congenital male urethral diverticulum is the key to a successful outcome. PMID- 25031910 TI - Epicardial adipose tissue thickness in young Indian overweight and obese individuals. AB - Epicardial adipose tissue (EAT) has been found to be an important reliable marker for future coronary events. Deposition of the EAT in young individuals is not well known. We studied EAT in 25 young overweight or obese individuals. In spite of the high visceral fat and total body fat, EAT thickness was not found to be high in the participants of our study. PMID- 25031911 TI - High level resistance to aminoglycosides in urinary isolates of enterococci. PMID- 25031912 TI - Endomyocardial fibrosis in northern nigerian girl. AB - Endomyocardial fibrosis (EMF) is a disease of the tropics and subtropics; and the most common cause of restrictive cardiomyopathy. In Nigeria, it is more common in the rain forest zone; though few case reports have been documented in the Northern part of Nigeria; it is often more common amongst adolescents and young adults and in individuals of low socio-economic class. They may be asymptomatic for years with many presenting late in the course of the disease. However, a case of EMF in a 10-year-old Hausa girl who first presented at the age of 8-years and was also from a middle class family fully domiciled in northern Nigeria is reported. PMID- 25031913 TI - Breast self-examination among market women. PMID- 25031914 TI - Exploring the role of health sector in prevention of human trafficking. PMID- 25031915 TI - Need for motivation of plateletpheresis donors: a tertiary care cancer center experience from eastern India. PMID- 25031916 TI - Screening of retinopathy of prematurity: a neglected public health issue. PMID- 25031917 TI - Unusual cause of asymptomatic neck swelling. PMID- 25031918 TI - Three-way Stopcock: An Effective Air-tight Connecter for Laparoscopic Gas Insufflation. PMID- 25031919 TI - Human manganese superoxide dismutase target sequence polymorphism and ovarian cancer. PMID- 25031920 TI - Predictable biomechanics and implications of implant crest module: a clinical note. PMID- 25031922 TI - The role of the physician assistant in oncology. PMID- 25031921 TI - Trevor Disease (Hemimelic Epiphyseal Displasia): 12-year Follow-up Case Report and Literature Review. AB - Trevor disease or hemimelic epiphyseal dysplasia is a rare skeletal developmental disorder characterized by asymmetric overgrowth of cartilage in the epiphyses. Histologically, it is an epiphysis osteochondroma. The symptom onset occurs primarily during childhood. Males are 3 times more affected than females. The most common symptom is a painless bony mass around the ankle or knee, followed by swelling, restricted range of motion and deformity. Imaging diagnosis is based on plain radiographs, computed tomography scans and magnetic resonance imaging. Treatment depends on the deformities, symptoms, location and amount of epiphysis involvement. Asymptomatic patients require no treatment. When no deformities are identified, simple mass excision is the treatment choice. If the mass causes epiphyses asymmetry, resection must be combined with osteotomies. The present study reports a case of Trevor disease in a female patient with 12-year follow up. A general review of Trevor disease was also performed. PMID- 25031923 TI - Neurotoxicity associated with cancer therapy. AB - Neurologic complications can result from direct or indirect effects of cancer therapy. Treatment toxicity may affect both the central nervous system and the peripheral nervous system. Early recognition of these toxicities plays an important role in the management of patients with cancer. PMID- 25031924 TI - Venous thromboembolism in the cancer population: pathology, risk, and prevention. AB - Patients with cancer have an increased risk of developing venous thromboembolism (VTE) and the incidence of these events has been increasing over the past decade. Venous thromboembolic events include both deep venous thrombosis and pulmonary embolism. These events contribute to higher morbidity and mortality rates. Understanding the complex pathogenesis of and risk factors for cancer-associated VTE will help guide advanced practitioners to improve outcomes with prophylaxis. The American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the European Society of Medical Oncology have utilized this information and developed evidence-based guidelines for prophylactic management for those who are at highest risk of developing cancer-associated VTE. This review will discuss the impact of cancer-associated VTE as well as its underlying pathogenesis, risk factors, and current recommendations for prophylaxis. PMID- 25031925 TI - Transition to a new cancer care delivery system: opportunity for empowerment of the role of the advanced practice provider. AB - The purpose of the study was to obtain an in-depth understanding of the perceptions of advanced practice providers (APPs) with respect to their current roles in the context of the transition to a new cancer care delivery system, as well as factors that may influence their ability to practice at their level of training and education. Five focus groups were conducted with 15 APPs (11 nurse practitioners, 4 physician assistants). Data were collected by a recorder at each focus group. Four investigators reviewed the data from each group for accuracy and to generate an initial set of codes. Codes were compared across reviewers until consensus was reached and final themes were agreed upon. The mean age of the participants was 43.5 years (range: 27 to 63 years). The APPs practiced for an average of 11 years (range: 1 to 27 years), with a mean of 6.5 years in oncology (range: 1 to 11 years). Six themes were generated from the data related to the APP role during the transition to a new oncology care system: experiencing role tension, facing communication barriers, seeking mentorship, dealing with fragmented care, recognizing the need for professional growth, and navigating a new system. Our findings may inform administrators about the role of the APP in quality care delivery. These findings may empower APPs to practice to the full scope of their training and educational preparation, thereby facilitating their goals for professional development. PMID- 25031926 TI - The ASCO Study of Collaborative Practice Arrangements: A Physician Assistant's Perspective. PMID- 25031927 TI - The ASCO Study of Collaborative Practice Arrangements: A Nurse Practitioner's Point of View. PMID- 25031928 TI - Plerixafor. PMID- 25031929 TI - Dietary resource information for the oncology patient: tips and tools. PMID- 25031930 TI - Diagnostic snapshot: dyspnea in the oncology patient. PMID- 25031931 TI - Electronic technologies: can they alter the human aspect of medical care? PMID- 25031932 TI - Vaccination recommendations for the hematology and oncology and post-stem cell transplant populations. AB - Vaccination is a simple yet important process used to prevent many infections in the general population. For patients with suppressed immune systems, especially those who are undergoing chemotherapy or who have undergone stem cell transplant, repeat vaccination or boosters may be crucial in prolonging and/or extending immunity. The purpose of this review is to examine the need for each vaccine in two separate oncology populations: patients receiving concurrent chemotherapy and post-stem cell transplant patients. In addition, the importance of avoiding live vaccines and criteria for reconsideration at a future time will also be discussed. PMID- 25031933 TI - Pregnancy in a patient with cancer and heart failure: challenges and complexities. AB - A 24-year-old African American female (L.R.) with a history of smoking and gestational diabetes was diagnosed with Hodgkin lymphoma. She received multiple chemotherapies, including six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), followed by radiation therapy to left inguinal areas for a total of 30.6 Gy in 17 fractions; she obtained complete remission. Two years later, L.R. had disease relapse in the mediastinum and received two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) followed by etoposide and ifosfamide. She then received BEAM (carmustine, etoposide, cytarabine, and melphalan) as a conditioning regimen and underwent autologous bone marrow transplant. Her post-transplant course was complicated by cytomegalovirus antigenemia, aspergillus pneumonia, and congestive heart failure with left ventricular ejection fraction (LVEF) of 20%-25%. She was treated with an ACE inhibitor (lisinopril) and a beta-blocker (carvedilol) with improvement of her LVEF to 30%-35%. A follow-up chest x-ray showed an increase in the size of the anterior mediastinal adenopathy suspicious for relapse of lymphoma, and at the same time she was also found to be 5 weeks pregnant. Given her cardiomyopathy, significant obesity, poorly controlled diabetes, and cancer recurrence, L.R. was advised by her gynecologist that the pregnancy was very high risk and might not be viable. The oncologists advised her to terminate the pregnancy within the first trimester, as she needed salvage radiotherapy treatment to the mediastinum and chemotherapy treatments that might endanger the fetus. However, the patient decided to continue with the pregnancy. A multidisciplinary team-which included a cardiologist, oncologist, high-risk obstetrician, pharmacist, and nurse practitioner-was then involved to provide care during the pregnancy. A social worker was also solicited to help with home and financial issues because L.R. was a single mother with a 2-year-old son. L.R. was treated with carvedilol and furosemide, with monthly cardiology clinical follow-up during the first and second trimesters, then every 2 weeks starting with the 28th week, and weekly thereafter until delivery. Between visits, she notified the clinic for symptoms of heart failure exacerbation and was seen as necessary. The possible in utero effects of both medications were discussed with the patient. L.R. had a normal uncomplicated pregnancy and delivered a 6-pound, 10-ounce healthy boy at 39 weeks via vaginal delivery and was discharged home 2 days later. A week after delivery, L.R. presented to the cardiology clinic in good spirits and was excited to show pictures of her newborn baby. She had no cardiac complaints and the repeat echocardiogram showed an unchanged LVEF of 30% 35%. PMID- 25031934 TI - Oncology drug shortages in america. PMID- 25031935 TI - A new targeted treatment for lung cancer patients. PMID- 25031936 TI - Understanding waterfall plots. PMID- 25031937 TI - Vandetanib. PMID- 25031938 TI - What is the Cause of This Patient's Symptoms? PMID- 25031939 TI - Avoiding plagiarism in professional writing. PMID- 25031940 TI - Dermatologic toxicities in epidermal growth factor receptor and multikinase inhibitors. AB - Targeted therapies have produced significant treatment advances for patients diagnosed with a variety of tumor types. These therapies are associated with unique dermatologic toxicities that may hamper treatment efforts and cause significant discomfort for patients. Prevention and management of these toxicities can allow patients to remain on therapy and hence receive maximum clinical benefit from the drug. PMID- 25031941 TI - Interpreting molecular monitoring results and international standardization in chronic myeloid leukemia. AB - Important advances in the understanding of the molecular basis of chronic myeloid leukemia have resulted in the development of new therapies and changed the paradigm for managing this myeloproliferative disease. Translocation of chromosomes 9 and 22 (known as the Philadelphia chromosome) results in a fusion BCR-ABL gene that produces a dysregulated BCR-ABL tyrosine kinase protein and triggers events leading to malignant transformation. The tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib block the BCR-ABL protein and prevent activation of the transformation pathways. Molecular monitoring, the most sensitive approach currently available to assess treatment response, measures BCR ABL messenger RNA levels and serves as a surrogate marker of disease. Further, molecular responses are predictive of patient outcomes. It is important for advanced practitioners to become familiar with the technology and interpretation of molecular monitoring results as well as efforts to standardize this type of testing so they can educate their patients and aid their understanding of test results. Undetectable BCR-ABL levels can bring feelings of relief, whereas an increasing level can lead to anxiety. Advanced practitioners, therefore, are an important resource for interpreting results for patients, answering questions, alleviating concerns, and encouraging continued adherence to treatment. PMID- 25031942 TI - Management of refractory metastatic anal squamous cell carcinoma following disease progression on traditional chemoradiation therapy. AB - Case Study Ms. S.G., a 56-year-old woman with a poorly differentiated squamous cell carcinoma of the anal canal, American Joint Committee on Cancer stage III (T2, N1, M0), was initially diagnosed in December, 2007 at an outside institution after she had noted blood in her stool for approximately 6 months. Her medical history was unremarkable. She had no known history of HIV or other sexually transmitted diseases. At the time of presentation, Ms. S.G. had an Eastern Cooperative Oncology Group performance status of 1 related to cancer-related pain. Her appetite and weight were both stable. A complete colonoscopy demonstrated a large, immobile, ulcerated, firm, 4-cm lesion in the distal rectum, arising from the anal canal. Initial staging positron emission tomography/computed tomography (PET/CT) scan revealed a hypermetabolic inferior anorectal mass with left perirectal and presacral nodal metastases. There was no definite evidence of distant metastatic disease. Ms. S.G. received chemoradiation treatment following her diagnostic studies, with a total dose of 45 Gy over 26 fractions to the pelvis with concurrent infusional fluorouracil (5-FU; 2, 450 mg over 7 days) and mitomycin C (12 mg/m(2) on day 1) at an outside institution. However, during her chemoradiation therapy, Ms. S.G. experienced a 3-week treatment break due to severe radiation dermatitis, as recommended by her outside treating oncologist. Upon treatment completion, Ms. S.G. underwent a biopsy of the anal canal, which revealed no evidence of residual malignancy. As recommended by her treating oncologist, she received four additional cycles of adjuvant infusional 5-FU in combination with leucovorin. Shortly thereafter, Ms. S.G. developed progressive pelvic pain. She underwent a second PET/CT scan, revealing mixed findings: interval resolution of abnormal standardized uptake value (SUV) activity at the primary tumor in the anal canal, but an increase in the size and SUV of nodal disease within the left perirectal and presacral regions. A CT guided biopsy noted a perirectal abscess requiring drainage but was inconclusive for disease recurrence; Ms. S.G. was treated with IV antibiotics. Six weeks later, repeat radiographic imaging noted additional changes suspicious for regional recurrence, which was biopsy-confirmed. Ms. S.G. was subsequently referred to MD Anderson Cancer Center for consideration of salvage pelvic exenteration. On physical exam a mass was palpated in the left lower quadrant, but there was no evidence of inguinal adenopathy. On digital rectal exam there was notable external erythema with a fixed mass and moderate sphincter tone. A chest CT scan showed no definite evidence of metastatic disease, but an MRI of the abdomen/pelvis indicated the presence of a complex partially necrotic mass (7.6 * 4.9 * 7.3 cm(3)) extending to the rectosigmoid junction, inseparable from the left lateral bowel wall, with partial encasement of the bowel. In addition, there was infiltration of the left piriformis muscle and cervix consistent with local recurrence. She was referred to medical oncology and radiation oncology for consideration of reirradiation with concurrent neoadjuvant chemotherapy for palliation and possible surgical resection. In early December 2008, Ms. S.G. received intensity-modulated radiation therapy (IMRT), with a total dose of 27 Gy over 18 fractions. She received concurrent infusional 5-FU at 300 mg/m(2)/day, from Monday to Friday, on the days of radiation. She also received a weekly bolus dose of cisplatin at 20 mg/m(2). The intent was to treat to 30 Gy, but the patient deferred further treatment early due to anorectal irritation. She then underwent restaging with a PET/CT scan and a pelvic MRI in February 2009, revealing radiographic partial response of the known pelvic recurrence and reduced pelvic pain (Figures 1A and 1B). Figure 1 Figure 1. Contrast-enhanced axial MRI image of the lower pelvis. (A) Pretreatment, complex mass at the rectosigmoid junction measuring approximately 7.6 * 4.9 * 7.3 cm3. (B) Posttreatment, large necrotic mass measuring 3-4 cm in greatest dimension. Unfortunately, in the interim, she developed multiple bilateral liver lesions and punctate pulmonary nodules consistent with distant disease (Figures 2A, 2B, and 3A). Figure 2 Figure 2. Contrast-enhanced axial CT images of the lung. (A) Subcentimeter nodular opacity in the left upper lobe. (B) Subcentimeter opacity in the right upper lung lobe. Figure 3 Figure 3. Contrast-enhanced axial CT image of the liver. (A) Pretreatment, multiple bilateral liver lesions. (B) Posttreatment, near-complete resolution of liver lesions. Ms. S.G. proceeded to undergo systemic chemotherapy with carboplatin at an area under the concentration time curve of 5 and paclitaxel at 175 mg/m(2) day 1, every 21 days. She tolerated the treatment well. After three cycles of chemotherapy, radiographic imaging indicated a mixed response to treatment: interval resolution of the pulmonary nodules, stability of disease in the pelvic mass, but progression of the hepatic metastases. Given Ms. S.G.'s continuing excellent performance status, further treatment was recommended. Based on recent published literature, a regimen of cisplatin at 80 mg/m(2) day 1, vinorelbine at 25 mg/m(2) day 1 (repeated every 28 days), and weekly cetuximab (VCC) at 250 mg/m(2) was initiated. Remarkably, following three cycles of treatment, despite receiving multiple prior lines of chemotherapy, her restaging CT scan demonstrated complete radiographic response of the intrathoracic disease, stable response of the anorectal mass, and near complete resolution of the hepatic lesions (Figures 3A and 3B). Overall, Ms. S.G. had tolerated her treatment very well. Given her response and tolerability, she was evaluated again for curative surgical resection. However, she opted to receive the VCC regimen closer to home and was lost to follow-up. Unfortunately, we were unable to obtain medical records confirming if she indeed received additional treatment as recommended. Ms. S.G. was noted to have passed away due to progression of her disease approximately 6 months later. PMID- 25031943 TI - Acupuncture for the management of chemotherapy-induced peripheral neuropathy. PMID- 25031944 TI - Threats to validity in retrospective studies. PMID- 25031945 TI - Brentuximab vedotin in hodgkin lymphoma and anaplastic large cell lymphoma. PMID- 25031946 TI - Nutrition screening and counseling in patients with lung cancer in an outpatient setting. PMID- 25031947 TI - Back pain in a patient with lung cancer. PMID- 25031948 TI - Improvement needed: cancer pain management in 2012. PMID- 25031949 TI - Myeloid toxicity of cancer treatment. AB - Myelotoxicity is one of the most common treatment-related adverse events for patients receiving systemic antineoplastic therapy or radiotherapy to bone marrow producing regions. Myeloid cytopenias, including neutropenia, thrombocytopenia, and anemia, are the most common manifestations of treatment-related myelotoxicity and one of the most common reasons for dose modifications, dose delays, or discontinuation of therapy, potentially limiting therapeutic benefit. Risk factors for myelotoxicity can be broadly categorized into three types: disease related, host-related, and treatment- related. Familiarity with factors predictive of high-risk febrile neutropenia, bleeding due to thrombocytopenia, and cardiopulmonary compromise due to anemia will provide the advanced practitioner (AP) in oncology with critical tools for rapid identification of patients at risk, prompt implementation of established guidelines for management, and avoidance of clinical deterioration. The AP in oncology is often the primary point of contact for management of cytopenias, including administration of myeloid growth factors, transfusion of blood products, and management of acute events such as neutropenic fevers. Each of these interventions requires familiarity with the risk and benefits of treatment. This article will review the physiology of the bone marrow, risk factors for cytopenias, and current guidelines and recommendations for prevention and treatment of myeloid toxicity of cancer treatment. PMID- 25031951 TI - Intraventricular topotecan for the treatment of neoplastic meningitis: five case studies. AB - Many systemic cytotoxic agents cannot penetrate the blood-brain barrier. Because of this, in approximately 5% of cancer cases, metastatic disease is seen in the leptomeninges. Without treatment, patients with neoplastic meningitis (NM) generally survive for only a matter of weeks. In the treatment of NM, intraventricular (IVT) topotecan results in progression-free and overall survival outcomes similar to those seen with other IVT chemotherapies, while being particularly well tolerated by most patients. In this article, we present the case studies of five patients with NM, with various primary malignancies, who received treatment with IVT topotecan. PMID- 25031950 TI - Guide to interpreting disease responses in chronic myeloid leukemia. AB - With the introduction of tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia, the course of the disease has been altered from an acute, rapidly progressive terminal disorder to a serious condition with high remission rates when patients are compliant with long-term treatment. The goal of therapy is to prevent transformation to the accelerated or blast crisis phases, which are associated with poor survival. Knowledge of the appropriate monitoring tests and treatment milestones, as well as the ability to interpret responses, allows advanced practitioners (APs) to effectively communicate key aspects of management to their patients. Monitoring patient responses to TKIs and identifying suboptimal responses early on offer APs the opportunity to reevaluate and adjust therapeutic treatment options. One of the causes of treatment failure is noncompliance; thus, educating patients on the importance of adhering to treatment and identifying reasons for noncompliance are of major importance. Because intolerance to TKIs may lead to discontinuation, frequent monitoring of side effects and response to treatment, open communication, patient education, and careful management are all essential in helping patients remain compliant with therapy. This review discusses the AP's role in helping patients achieve their best response to TKI therapy and optimize their long-term outcomes. PMID- 25031952 TI - Vitamin d in the prevention of aromatase inhibitor-induced musculoskeletal symptoms: is it ready for practice? PMID- 25031953 TI - Cholecalciferol and Cancer: Is It a Big D3-eal? PMID- 25031954 TI - Bone marrow aspiration and biopsy: a guideline for procedural training and competency assessment. AB - The growing role of nurse practitioners (NPs) in today's demanding health-care system has allowed for a more comprehensive and complementary approach to patient care. Within the past few years, NPs have expanded their role to include invasive procedures. Limited research in the utilization of NPs has suggested equality among procedures performed by NPs when compared with those conducted by their physician counterparts. Nurse practitioners and their colleagues need to take an active role in developing protocols to train practitioners and assess their procedural competency. We suggest such a guideline for training NPs to perform invasive procedures and to confirm procedural competency, using bone marrow biopsies and aspirates as an example. Future research should be directed not only at the overall quality of biopsies obtained, but also toward patient satisfaction scores in procedures performed by NPs. PMID- 25031955 TI - Crizotinib: a breakthrough for targeted therapies in lung cancer. PMID- 25031956 TI - Can you identify this lesion seen in a patient with melanoma? PMID- 25031957 TI - Advanced practitioners are not mid-level providers. PMID- 25031958 TI - Fertility issues of breast cancer survivors. AB - In the United States, more women are diagnosed with breast cancer than any other type of cancer. More than 11,000 of these women will be younger than 40, and many of these women will want to have children in the future. A significant number of these young breast cancer patients will require treatment that can cause ovarian failure or premature menopause. Several options do exist for fertility preservation, both standard and investigational. Embryo cryopreservation is the most established intervention. Investigational interventions include oocyte cryopreservation, ovarian tissue transplantation, ovarian suppression with a gonadotropin-releasing hormone agonist, and harvesting of immature follicles with in vitro maturation and cryopreservation. Although pregnancy during cancer treatment is not recommended, pregnancies occurring after completion of therapy have not been linked to increased cancer recurrence. Young women diagnosed with breast cancer need evidence-based information presented in a timely manner in order to make decisions regarding fertility preservation prior to the initiation of treatment. The oncology advanced practitioner must be knowledgeable about fertility preservation options available to these women as well as comfortable with ethical and financial concerns that can arise. The informed practitioner can effectively counsel patients and refer to fertility specialists when appropriate. PMID- 25031959 TI - Response to degarelix after resistance to leuprolide in a patient with metastatic prostate cancer. PMID- 25031960 TI - Predictors of practice patterns for lymphedema care among oncology advanced practice nurses. AB - Lymphedema, a debilitating and chronic condition, is considered to be one of the most distressing adverse effects of cancer treatment. The purpose of this study was to understand the practice patterns in lymphedema care and identify predictors influencing those patterns among oncology nurses, with a focus on advanced practice nurses. Random and purposive sampling was utilized to recruit 238 oncology nurses who completed the Web-based study. Participants included advanced practice nurses (nurse practitioners and clinical nurse specialists), nurse navigators/case managers, staff nurses, and directors/managers/coordinators. Data focused on perceived knowledge of and perceived competence in risk reduction, treatment, and self-management of lymphedema and practice patterns in lymphedema care. Actual knowledge of lymphedema care was evaluated. Descriptive, comparative, and regression analyses were performed. The study showed that perceived knowledge and perceived competence were highly correlated. Perceived competence was a predictor of practicing lymphedema care. Advanced practice nurses scored in the midrange for perceived knowledge and perceived competence in risk reduction and self management, but obtained lower scores in perceived knowledge and perceived competence for treatment. The odds of advanced practice nurses delivering lymphedema care were less than those of staff nurses. This study identifies gaps and opportunities for advanced practice nurses to play an important role in providing lymphedema care, an essential aspect of cancer survivorship. PMID- 25031961 TI - Nurse self-evaluation of assessment of chemotherapy-induced peripheral neuropathy in patients with cancer. AB - The focus of this study was to assess the feasibility and clinical implementation of a standardized assessment for chemotherapy-induced peripheral neuropathy (CIPN) by registered nurses in patients undergoing neurotoxic chemotherapy. A total of 24 registered nurses from 4 different institutions were enrolled into the study. A pre- and posttest design was used to assess changes in nurses' attitudes, knowledge, and perceived skill in CIPN assessment. Using selected data collection instruments, nurses performed standardized assessments during the course of chemotherapy treatments. Patient-reported symptoms, vibratory sensation, deep-tendon reflexes, and touch were collected at three time points during chemotherapy treatment. Results indicated there was no statistically significant change in knowledge of chemotherapy-induced peripheral neuropathy from baseline to the end of the study. However, this finding may be due to poor internal consistency noted among the items of the Nurse Knowledge and Attitudes CIPN Assessment. Implementation of a standardized subjective and objective nursing assessment of CIPN was feasible with a total mean feasibility score of 3.76 (range 0-5) with each individual item scoring between 3.35 and 3.91. The intervention did improve pretest and posttest confidence in performing assessment for CIPN (p = .003). PMID- 25031962 TI - Tips for transitioning to a new electronic health record system. PMID- 25031963 TI - Axitinib: newly approved for renal cell carcinoma. PMID- 25031964 TI - Continuing education resources and tools for the advanced practitione. AB - Are you looking for some continuing education (CE) credits? Maybe you want to learn about a certain topic? Visit www.advancedpractitioner.com to access JADPRO's current CE offerings, but take advantage of the great (mostly free) resources listed here as well. Then sit down and get ready to learn! PMID- 25031965 TI - Can You Determine the Cause of This Patient's Skin Changes? PMID- 25031966 TI - Integrative and complementary therapies: do you know what your patients are taking? PMID- 25031968 TI - Incorporating clinical trial data into daily cancer care. AB - The objective of clinical trials is to determine the effectiveness and safety of specific interventions. Regulatory agencies, clinicians, and patients depend on clinical trials because they provide the most reliable information about treatment outcomes. The ability to predict how a patient may respond to a given treatment and what potential types, degree, and frequency of adverse events could occur is invaluable. Although data from clinical trials can determine effective treatment options for patients, it is the explanation of what to expect from treatment and how it may affect quality of life that will determine which option a patient chooses. Translating clinical trial data into "real life" can be challenging for the oncology advanced practitioner (AP) because primary and secondary endpoints may differ among clinical trials. This variability can produce confusion when comparing, contrasting, and translating clinical evidence into clinical practice. This article reviews clinical trial endpoints and surrogate markers and describes how findings can influence decision-making and patient care. With social media increasing patients' awareness and encouraging active participation in their own care, it is imperative that APs be able to articulate clinical trial outcomes along with their strengths, limitations, and life impact. PMID- 25031969 TI - Superior vena cava syndrome in the cancer patient: a case study. PMID- 25031967 TI - Mind-body therapies: evidence and implications in advanced oncology practice. AB - The idea that thoughts and emotions influence health outcomes is an ancient concept that was initially abandoned by Western medicine researchers. Today, researchers are showing a renewed interest in the interactions of the mind and body and the role these interactions play in disease formation and recovery. Complementary and alternative interventions, such as mind-body therapies, are increasingly being used by cancer survivors for disease prevention, immune system enhancement, and symptom control. Traditional training has not been structured to provide advanced practitioners with an in-depth knowledge of the clinical applications of mind-body therapies. The aim of this article is to acquaint the reader with common mind-body modalities (meditation/mindfulness-based stress reduction, relaxation therapy, cognitive-behavioral therapy, hypnosis, biofeedback, music therapy, art therapy, support groups, and aromatherapy) and to examine important evidence in support of or against their clinical application. PMID- 25031970 TI - Pertuzumab in metastatic breast cancer. PMID- 25031971 TI - Effects of aspirin on colorectal cancer related to lynch syndrome. AB - This article is a review of "Long-term effects of aspirin on cancer risk in carriers of hereditary colorectal cancer: An analysis from the CAPP2 randomised controlled trial" by Burn et al. (2011), Lancet, 378, 2081-2087. For another perspective on the Burn et al. article as well as a discussion of challenges faced when interpreting a large prospective trial, please see the related article by Rita Wickham. PMID- 25031972 TI - Aspirin and decreased colon cancer risk: challenges interpreting a large prospective trial. PMID- 25031973 TI - Subcutaneous administration of bortezomib: strategies to reduce injection site reactions. AB - Bortezomib (Velcade) is approved by the FDA for IV or SC injection in select patients with multiple myeloma or mantle cell lymphoma. The SC route functions as an alternative to IV administration for patients with poor IV access. Learn about effective strategies used to reduce injection site reactions that can occur with SC delivery. PMID- 25031974 TI - Random periareolar fine-needle aspiration: the new pap smear of the breast? AB - Random periareolar fine-needle aspiration continues to gain scientific credence in the short-term identification of women at increased risk for breast cancer. As this technique becomes more widely used, APs may seek to be trained in an effort to expand clinical trials, and someday provide a "Pap smear of the breast" for the women who need it most. PMID- 25031975 TI - Can You Determine the Cause of This Patient's Vision Changes? PMID- 25031976 TI - How much does that treatment cost? PMID- 25031977 TI - Screening for prostate cancer: the debate continues. AB - Other than skin cancer, prostate cancer is the most frequently diagnosed cancer in men, and it is the second leading cause of cancer-related death for males in the United States. Screening for prostate cancer using prostate-specific antigen testing became widely used by the late 1980s, augmenting the digital rectal exam. This led to a decline in the percentage of prostate cancer cases that were metastatic at diagnosis and a decrease in prostate cancer mortality. But some argued it led to overtreatment of prostate cancers as well. Recently, the U.S. Preventive Services Task Force (USPSTF) issued recommendations against routine prostate cancer screening in asymptomatic patients. The recent recommendations have created much controversy among medical professionals, patient advocate groups, and the general public. Most prostate cancer screening recommendations from professional organizations agree that an informed discussion and review of each individual patient's clinical situation should drive the decision to screen or not to screen, but the current USPSTF recommendations largely remove patient and provider autonomy in this regard. They do not contribute toward personalized screening based on individualized patient risk profiles, characteristics, and preferences. PMID- 25031978 TI - Bisphosphonate-related osteonecrosis of the jaw: historical, ethical, and legal issues associated with prescribing. AB - The long-term effects of many drugs are unknown. Established risks are communicated to patients who participate in clinical trials during the informed consent process. However, unknown and unanticipated side effects of medications may occur years after treatment. Patients with metastatic bone cancer experience an imbalance between tumor cells and the bone marrow microenvironment. Increased cytokine release, osteoclastic activity, and uncoupled osteoblastic activity lead to weakened bone structure and osteolytic lesions. The bisphosphonates are a class of drugs available in IV and oral formulations to treat and prevent bone loss and decrease the risk of skeletal-related events. Intravenous bisphosphonates such as zoledronic acid and pamidronate disodium are approved by the US Food and Drug Administration for the treatment of bone pain and hypercalcemia of malignancy and the prevention of painful bone fractures in patients with metastatic bone cancer. Oral bisphosphonates such as alendronate, risedronate, and etidronate are used to reduce the risk of skeletal fractures in patients with osteoporosis and in breast cancer. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but painful complication of treatment characterized by infection, exposed bone, and poor wound healing. In this article, we discuss BRONJ and identify past, present, and future ethical and legal issues surrounding bisphosphonate administration. PMID- 25031979 TI - Multiple Myeloma: Cast Nephropathy, VTE, and Neurologic Complications. AB - Multiple myeloma accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. Complications often associated with MM include neurologic and hematologic issues, infections, renal insufficiency, and bone involvement. It is crucial for advanced practice professionals caring for myeloma patients to assess patients accurately, be keenly aware of possible associated complications, and be familiar with appropriate interventions to prevent further injury. This article will provide an overview of MM-related renal insufficiency, with a focus on cast nephropathy, venous thromboembolism, and neurologic complications along with various causes and treatment options; a future article will address additional complications associated with MM. PMID- 25031980 TI - Having Difficult Conversations: The Advanced Practitioner's Role. AB - Throughout the course of their disease, patients with cancer and their families look to the oncology advanced practitioner (AP) for support and guidance as they struggle with the emotional impact of a life-limiting illness, complex treatment decisions, and the challenge of sustaining hope while maintaining realistic goals. At various points along the disease trajectory, difficult conversations between the AP and the patient are essential. In this case report of a 43-year old woman with metastatic breast cancer, we model the use of various strategies available for the AP to help make these difficult conversations as productive, relevant, and emotionally safe for the patient as possible. PMID- 25031981 TI - Pazopanib: approval for soft-tissue sarcoma. PMID- 25031982 TI - New cervical cancer screening guidelines: was the annual pap too much of a good thing? PMID- 25031983 TI - Guideline evaluation. PMID- 25031984 TI - A computerized tool to support survivorship care. PMID- 25031985 TI - The continuing impact of oncology drug shortages. PMID- 25031986 TI - Hypnosis: adjunct therapy for cancer pain management. AB - Pain is a symptom associated with prolonged recovery from illness and procedures, decreased quality of life, and increased health-care costs. While there have been advances in the management of cancer pain, there is a need for therapeutic strategies that complement pharmaceutical management without significantly contributing to the side-effect profile of these agents. Hypnosis provides a safe and efficacious supplement to pharmaceutical management of cancer pain. One barrier to the regular use of hypnosis is health-care providers' lack of current knowledge of the efficacy and safety of hypnosis. Advanced practitioners who are well-informed about hypnosis have an opportunity to increase the treatment options for patients who are suffering with cancer pain by suggesting to the health-care team that hypnosis be incorporated into the plan of care. Integration of hypnosis into the standard of care will benefit patients, caregivers, and survivors by reducing pain and the suffering associated with it. PMID- 25031987 TI - Efficacy of palifermin in the hematopoietic stem cell transplant setting. AB - Palifermin is a recombinant human keratinocyte growth factor that stimulates proliferation and differentiation of epithelial cells. Palifermin's biological activity exerts cytoprotective and healing effects that decrease cell injury caused by chemotherapy and radiation therapy. In randomized, placebo-controlled trials, palifermin significantly reduced the incidence and duration of severe oral mucositis. Based on these findings, the US Food and Drug Administration approved palifermin for patients with hematologic malignancies undergoing myeloablative therapy followed by hematopoietic stem cell transplant (HSCT). However, researchers testing the efficacy of palifermin in postapproval studies using various conditioning regimens have debated the extrapolation of palifermin dosage and dosing frequency used in the registration study as inappropriate for less mucotoxic agents. In addition, modifying the dosing intervals and frequency of palifermin has been proposed to decrease adverse events and achieve the highest clinical benefits for less mucotoxic regimens. The incidence and severity of oral mucositis vary significantly across different conditioning regimens. Hence, cost-effectiveness and the clinical benefits of palifermin among various conditioning regimens have also been debated. This article reviews the published literature on the efficacy of palifermin and makes evidence-based recommendations for the use of palifermin in the HSCT setting. PMID- 25031988 TI - Prevention and management of tumor lysis syndrome in adults with malignancy. AB - Tumor lysis syndrome (TLS), an oncologic emergency that typically occurs after the treatment of a malignancy with chemotherapy and/or radiotherapy, is the result of extreme tumor cell lysis with the release of intracellular potassium, nucleic acids, and phosphorus into the systemic circulation. Tumor lysis syndrome occurs most often after administration of cytotoxic therapy in patients with high grade lymphomas and acute lymphoblastic leukemia, but it can also occur spontaneously in tumor types that have a high proliferative rate and/or a large tumor burden. The metabolic disturbances of TLS include hyperkalemia, hyperphosphatemia, secondary hypocalcemia, hyperuricemia, and acute renal failure. The most important treatment for TLS is prevention. The mainstays of TLS prevention include aggressive hydration, control of hyperuricemia with allopurinol and rasburicase treatment, and close monitoring of electrolyte abnormalities. It is crucial for clinicians to prevent, detect, and treat TLS early to prevent life-threatening complications such as acute renal failure, cardiac dysrhythmia, and seizures. The purpose of this article is to explain the pathophysiology of TLS, identify patients at risk for TLS, and detail strategies for prevention and management of this oncologic emergency. PMID- 25031989 TI - Polypharmacy in older adults: the role of the advanced practitioner in oncology. PMID- 25031990 TI - Breast cancer and autism. AB - Case Study Amy is a 44-year-old woman with severe autism. She lives with her sister Susan, who is her caregiver and guardian. Amy is ambulatory and able to dress and feed herself. She is a healthy individual with no other significant comorbidities. She walks daily and enjoys her sister's company. Amy's life expectancy is greater than 10 years. However, she is difficult to care for medically, as she will not allow a physical examination and strikes out when strangers try to touch her. She is nonverbal and unable to participate in decision-making. INITIAL DIAGNOSIS Amy has a history of breast cancer diagnosed 2 years ago, originally presenting as a stage I lesion (T2N0) that was palpated by her caregiver while bathing. She underwent right simple mastectomy with sentinel lymph node resection. Susan recalls that the mastectomy was a very challenging ordeal, as Amy kept pulling out IV lines, drains, and dressings. Susan felt that Amy withdrew from her after the procedure as she most likely associated Susan with the cause of the pain, making her role as caregiver more difficult. Pathology confirmed an invasive ductal carcinoma, moderately differentiated, 2.4 cm, estrogen/progesterone receptor negative, HER2/neu negative, with negative surgical margins. Two right axillary sentinel lymph nodes were negative for disease. The standard of care for a patient with these tumor features is surgery plus adjuvant chemotherapy (National Comprehensive Cancer Network [NCCN], 2012). According to the Adjuvant Online! database (2012), Amy's risk for relapse was approximately 40% without adjuvant treatment; her risk for mortality was approximately 29%. After meeting with a medical oncologist, Amy did not receive adjuvant chemotherapy. According to Susan, she was not offered the choice, and the decision was not explained to them. She was simply told that it was not necessary. Aside from pathology, previous records were unavailable for review. Medical assessment of Amy's level of autism reveals marked impairments in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body posture, and gestures to regulate social interaction. She exhibits a total lack of development of spoken language, with no attempt to compensate through alternative modes of communication such as gesture. During the visit, she occupies herself with repetitive motor mannerisms. Susan believes that Amy struggles with overstimulation from tactile input. Therefore, she is combative with health-care providers and intolerant of invasive devices. Susan has an intimate understanding of Amy's ability to communicate her needs and wants through nonverbal changes. RECURRENCE Approximately 2 months ago, Amy began favoring her right arm and appeared to be in pain when participating in various activities. Susan became aware of Amy's pain issues by noticing that her posture was slightly altered and she was carrying herself differently. Further investigation with a CT scan showed concern for local disease recurrence involving the axillary lymph nodes. No distant metastases were seen. The standard of care for this diagnosis is surgical resection and consideration of radiation therapy, followed by adjuvant chemotherapy (NCCN, 2012). Susan does not want Amy to undergo further surgery and believes radiation would be too difficult to maneuver. The next best option would be a medical approach with chemotherapy as the main modality. DIFFICULT DECISIONS If treatment is pursued, the advanced practitioner will need to perform regular examinations and prescribe and monitor chemotherapy. The delivery of therapy, requiring frequent blood draws and IV access, will be a challenge for the health-care staff. The APN is apprehensive about the ability to accomplish these tasks safely given Amy's limited capacity to participate. The APN is also concerned with how treatment will affect Amy's life. The APN may have her own individual conflict of morals to contend with, given the limited understanding of the patient vs. nontreatment of a potentially curative malignancy. Chemotherapy is not an easy task for any patient to undertake, especially for a patient with challenges such as Amy has. Although Susan can give legal consent for her sister, Amy is unable to participate in this decision-making. Susan strongly believes that Amy's quality of life is much more important than the quantity. Withholding treatment may shorten the natural course of Amy's life, yet administering chemotherapy will alter the quality of life that she now enjoys without her understanding or consent. Should Amy receive chemotherapy or should Susan refuse treatment on her behalf? PMID- 25031992 TI - Credible complementary and alternative medicine websites. PMID- 25031993 TI - Youth and tanning: a dangerous combination. PMID- 25031991 TI - Regorafenib: Adding to the Armamentarium for Refractory Colorectal Cancer and GIST. PMID- 25031994 TI - Energy therapies in advanced practice oncology: an evidence-informed practice approach. AB - Advanced practitioners in oncology want patients to receive state-of-the-art care and support for their healing process. Evidence-informed practice (EIP), an approach to evaluating evidence for clinical practice, considers the varieties of evidence in the context of patient preference and condition as well as practitioner knowledge and experience. This article offers an EIP approach to energy therapies, namely, Therapeutic Touch (TT), Healing Touch (HT), and Reiki, as supportive interventions in cancer care; a description of the author's professional experience with TT, HT, and Reiki in practice and research; an overview of the three energy healing modalities; a review of nine clinical studies related to oncology; and recommendations for EIP. These studies demonstrate a response to previous research design critiques. Findings indicate a positive benefit for oncology patients in the realms of pain, quality of life, fatigue, health function, and mood. Directionality of healing in immune response and cell line studies affirms the usual explanation that these therapies bring harmony and balance to the system in the direction of health. Foremost, the research literature demonstrates the safety of these therapies. In order to consider the varieties of evidence for TT, HT, and Reiki, EIP requires a qualitative examination of patient experiences with these modalities, exploration of where these modalities have been integrated into cancer care and how the practice works in the oncology setting, and discovery of the impact of implementation on provider practice and self-care. Next steps toward EIP require fleshing out the experience of these modalities by patients and health-care providers in the oncology care setting. PMID- 25031995 TI - How to recognize and treat neoplastic meningitis. PMID- 25031996 TI - The need for communication skills training in oncology. AB - Communication between health-care professionals and their patients is an element that can make all the difference in how those patients navigate their cancer journey. In a 2011 issue of the Annals of Oncology, Barth and Lannen reported on their systematic review and meta-analysis of the efficacy of communication skills training courses in oncology. In this issue of JADPRO, two authors share their perspectives on the findings of Barth and Lannen and what advanced practitioners (APs) can learn from their research. PMID- 25031997 TI - Communication skills training: using evidence to develop programs that improve patient outcomes. PMID- 25031998 TI - Understanding the implications of the breast cancer pathology report: a case study. AB - Case Study A.K. is a 50-year-old Caucasian female who was recently diagnosed with breast cancer and is presenting for an opinion regarding adjuvant therapy following a right segmental mastectomy and sentinel lymph node biopsy. The advanced practitioner (AP) in the outpatient oncology treatment center will be expected to participate in the discussion regarding the patient's care plan. In her review of the final pathology, the AP notes that the breast tumor is infiltrating ductal carcinoma, the most common type of invasive breast cancer. It starts in the cells that line the milk ducts in the breast, grows outside the ducts, and often spreads to the lymph nodes. Infiltrating ductal carcinoma represents 65% to 85% of all breast cancer cases (College of American Pathologists, 2011). The breast tumor measures 1.2 * 0.9 * 1.0 cm(3) (T1), is estrogen receptor positive with an H score of 280, is progesterone receptor negative with an H score of 0, and is HER2 equivocal 2+ by immunohistochemistry with a fluorescence in situ hybridization ratio of 1.9 with a copy number of 5. The Ki-67 proliferation rate is 60%, and the nuclear grade is 2/3, with a Nottingham score of 5/9. The surgical margins from the segmental mastectomy are clear by 0.4 mm. There is lymphovascular invasion present. Of two sentinel lymph nodes, none is positive (N0). There has been no workup for metastatic disease. Additionally, the AP notes that the patient is premenopausal and that A.K.'s family history is positive for a maternal aunt diagnosed with a stage I breast cancer at age 75. What is the recommended plan of care for A.K.? PMID- 25031999 TI - Enzalutamide: a new agent for the prostate cancer treatment armamentarium. PMID- 25032000 TI - The ASCO University Website: Online Education for the Oncology Advanced Practitioner. PMID- 25032001 TI - Publishing in open-access journals: potential pitfalls. PMID- 25032002 TI - Peripheral neuropathy caused by Paclitaxel and docetaxel: an evaluation and comparison of symptoms. AB - The purpose of this study was to explore the prevalence, severity, distress, and timing of neuropathic symptoms in cancer patients receiving taxanes and to explore neuropathy-related interference with activities. In this descriptive, cross-sectional study, 68 adult outpatients receiving paclitaxel (n = 36) and docetaxel (n = 32) completed the Chemotherapy Induced Peripheral Neuropathy Assessment Tool and a demographic questionnaire. Muscle or joint aches were the most prevalent symptom. Muscle or joint aches were also the most severe and distressing symptom in persons receiving paclitaxel. Participants receiving paclitaxel reported that neuropathic symptoms interfered with a mean of 7.3 (standard deviation [SD] = 4.1) of 14 activities. Nerve pain was the most severe and distressing symptom in persons receiving docetaxel. Participants receiving docetaxel reported that neuropathic symptoms interfered with a mean of 7.1 (SD = 4.1) of 14 activities. Numbness in the feet was the most frequent or constant symptom in persons receiving paclitaxel or docetaxel. Patients receiving paclitaxel and docetaxel experienced similar symptoms of peripheral neuropathy and interference with activities. Continued focus on treatment of painful neuropathy including myalgias and arthralgias is needed. PMID- 25032003 TI - Complementary strategies for the management of radiation therapy side effects. AB - Patients with cancer utilize complementary and alternative medicine (CAM) for a variety of purposes, one of which is the reduction of side effects of conventional treatment. With a large number of their patients using CAM, it is important for advanced practitioners in oncology to have an understanding of these therapies to better guide their patients. Side effects of radiation therapy that may have dose-limiting poten-tial include diarrhea, mucositis, skin toxicity, and xerostomia. A com-mon side effect that is not necessarily dose limiting but considerably troublesome to patients is cancer- and treatment related fatigue. The CAM therapies that may alleviate some of the side effects of radiation therapy include probiotics, psyllium, exercise, melatonin, honey, acu puncture, and calendula. Therapies that require more research or have been shown to be ineffective include aloe vera, glutamine, and deglyc-yrrhizinated licorice. This article provides an overview of these thera-pies as well as related research and analysis. PMID- 25032005 TI - Two Patients With Brain Tumors Who Received Bevacizumab and Radiotherapy: Optic Neuropathy and Quality-of-Life Issues. PMID- 25032004 TI - Optimizing adherence to adjuvant imatinib in gastrointestinal stromal tumor. AB - The increasing use of patient-administered oral anticancer drugs is paralleled by new challenges in maintaining treatment adherence. These challenges are particularly significant with adjuvant therapies for prevention of disease recurrence, where the benefits of ongoing treatment are not readily apparent to patients. Nurse practitioners and physician assistants (collectively referred to as advanced practitioners) play integral roles in providing education on disease and treatment to patients that can increase adherence to oral therapies and ideally improve outcomes. For patients with gastrointestinal stromal tumor (GIST), the oral targeted therapy imatinib has become the mainstay of treatment for advanced and recurrent disease and as adjuvant therapy following surgical resection. Recent data indicate significantly improved overall survival with 3 years vs. 1 year of adjuvant imatinib therapy. Continuous dosing with imatinib is needed for optimal efficacy and to limit additional health-care costs associated with management of disease progression in GIST. However, longer duration of therapy increases the risk of nonadherence. Imatinib adherence rates, as well as factors contributing to nonadherence to adjuvant therapy in routine clinical practice, are discussed in this review. Also explored are practical approaches for improving adherence to adjuvant imatinib therapy through greater patient education, in light of the increased duration of therapy in select patients. PMID- 25032006 TI - Omacetaxine mepesuccinate: a new treatment option for patients with chronic myelogenous leukemia. PMID- 25032007 TI - Basic review of the cytochrome p450 system. PMID- 25032008 TI - Deadly viruses with beneficial uses: the poliovirus as therapy. PMID- 25032009 TI - Understanding CAM Natural Health Products: Implications of Use Among Cancer Patients and Survivors. AB - Herbs, vitamins, and other natural health products are being used by cancer patients and survivors with increasing prevalence in the United States. These complementary and alternative medicine (CAM) products, which are also referred to as natural health products in Canada and abroad, are used during cancer treatment and the survivorship period to ease the burden of symptoms such as pain, fatigue, insomnia, anxiety, and depression and hence improve overall quality of life. Data indicate that while patients choose these products for self-treatment, they often do not inform their health-care providers, thereby presenting the potential for negative interactions. This article gives an overview of CAM natural health products, including discussion of herbs, vitamins, and other supplements such as minerals, enzymes, and more. Related research is presented, and implications for advanced practitioners are discussed. Insights into guiding safe and effective use among patients as well as appropriate decision-making strategies are explored. PMID- 25032010 TI - Novel agents for the treatment of multiple myeloma: proteasome inhibitors and immunomodulatory agents. AB - The integration of novel agents into the treatment of multiple myeloma (MM) has shifted the focus from an incurable disease to one that is chronic, with a realistic hope of someday achieving a cure. Proteasome inhibitors and immunomodulatory agents are the backbone of novel therapies for MM. These agents are particularly important for patients with relapsed or refractory disease, a fate faced by the majority of myeloma patients over the course of their disease. Review of recent clinical trial data for the proteasome inhibitors and immunomodulatory agents, including clinical efficacy and safety information, will assist the advanced practitioner in oncology with integrating these data into the current treatment guidelines for MM. PMID- 25032011 TI - Testing women with endometrial cancer for lynch syndrome: should we test all? AB - Women with Lynch syndrome (LS) are at equal or higher risk for gynecologic cancers compared with their risk for colorectal cancer (CRC). Endometrial cancer (EC) often precedes CRC as patients' sentinel malignancy. Identifying these patients is believed to reduce their substantial risk for synchronous and metachronous tumors and has profound implications for reducing cancer-related morbidity and mortality in other family members. Routine screening of patients with CRC for LS has become increasingly common, but routine screening for LS in women with EC is rarely performed. Current screening guidelines for identifying LS in women with EC vary but rely heavily on patient age and personal/family history, with or without incorporation of tumor pathology. Because each of these strategies misses a significant proportion of women with LS, more inclusive screening strategies that make good economic and clinical sense are needed. In recent years, emerging medicoeconomic evidence supports the fact that screening EC patients for LS may be cost-effective. Implementation of such a strategy requires multidisciplinary collaboration and partnership. PMID- 25032012 TI - Sexuality, lung cancer, and the older adult: an unlikely trio? AB - Case Study Mrs. L. is a 60-year-old retired female teacher with stage IIIA squamous cell carcinoma of the lung, status postchemoradiation. She recently developed radiation pneumonitis, which was managed conservatively, and she did not require steroids. Mrs. L. has noted some progression of her underlying dyspnea. She is monitoring her oxygen saturation at home, and most of the time it is in the range of 94% to 96%. On one occasion only, her oxygen dropped to 88% and rapidly improved to the mid-90s. Her cough has improved for the past 4 to 6 weeks. She denies sputum production, congestion, or fever. Mrs. L. does not require a walker and uses a wheelchair only for long distances. She has occasional, slight dysphagia. A recent CT scan shows stable disease, and she is to return to the clinic in 2 months for restaging and possible further chemotherapy. Mrs. L. and her husband have been married for 33 years, and they have been very close. Until recently, they have continued to be sexually active and very intimate with each other. Since Mrs. L.'s diagnosis, and during treatment, the couple have become extremely stressed and psychologically spent. The act of sexual intercourse has ceased, yet they have attempted to remain close and maintain open communication. In addition to Mrs. L.'s increasing dyspnea, she has also suffered a great deal of fatigue and depression, along with alopecia and vaginal atrophy, due to the chemotherapy and radiation treatments. Both Mr. and Mrs. L. are very distressed over the change in their sexual lives. Mr. L. has mentioned that he now feels more like a "nursemaid" than a husband or lover. Mrs. L. has made concerted efforts to maintain intimacy with her husband, but her fatigue is profound. She has taken to sleeping in the living room, sitting up on the couch, as it relieves her dyspnea to some degree. PMID- 25032013 TI - Ziv-aflibercept use in metastatic colorectal cancer. PMID- 25032014 TI - Oral cancer therapy: policy implications for the uninsured and underinsured populations. PMID- 25032015 TI - Review of a study of duloxetine for painful chemotherapy-induced peripheral neuropathy. PMID- 25032016 TI - Challenges in the conduct of research: chemotherapy-induced peripheral neuropathy. PMID- 25032017 TI - Cancer genetic resources. PMID- 25032018 TI - Can ginseng alleviate cancer-related fatigue? PMID- 25032019 TI - Ceftazidime for neutropenic fevers: is it still an appropriate choice? AB - Infection continues to rank as a primary cause of treatment-related mortality in patients with cancer. For patients with neutropenic fevers, immediate empiric treatment with antibiotics is standard care. However, which specific antibiotic is best for initial treatment of high-risk patients has been much debated without consensus. Many major health centers use intravenous ceftazidime as first-line therapy for these patients. Yet updates to guidelines published by the Infectious Diseases Society of America and the National Comprehensive Cancer Network suggest that ceftazidime may no longer be an optimal choice. This article reviews the literature regarding ceftazidime therapy for the treatment of high-risk neutropenic patients with fevers. This critical analysis of existing research reveals significant pharmacologic, physiologic, social, and financial implications, and recommendations for further studies are made. PMID- 25032020 TI - Lung Cancer Screening With Low-Dose CT: Its Effect on Smoking Behavior. AB - Lung cancer screening provides an opportunity for smoking cessation interventions. A review of the literature found that smokers who participated in lung cancer screening had a higher smoking cessation rate compared with smokers in the general population. However, the randomized controlled trials included in the review did not identify any difference in smoking cessation rates between the individuals who had a CT scan to screen for lung cancer and unscreened control groups. Multiple studies observed participants for lengths of time ranging from 1 to 36 months and concluded that individuals who received abnormal CT results had a higher smoking cessation rate compared with participants with normal CT results. A single study that observed participants for 6 years initially found similar increased cessation rates among those with abnormal CT results, but at the conclusion of the study the difference in cessation rates had dissipated. Lung cancer screening produces a teachable moment when individuals may be more receptive to smoking cessation interventions. Advanced practitioners should take an active role in promoting smoking cessation interventions and fostering this teachable moment created by lung cancer screening. PMID- 25032021 TI - Breathlessness with pulmonary metastases: a multimodal approach. AB - Case Study Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away. SECOND CANCER DIAGNOSIS One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2 cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung. As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery. DISEASE RECURRENCE After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah's 1-year follow-up exam revealed a 2 cm * 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning "pins and needles" sensation at the surgical chest wall site that was bothersome and would wake her up at night. Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah's breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel "air hungry." She rated her breathlessness at 4/10 on the Borg scale. SECOND RECURRENCE: MULTIPLE PULMONARY NODULES Sarah's chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah's cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough. Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah's breathlessness was lacking. END OF LIFE Sarah's disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed. Sarah's daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah's daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress. PMID- 25032023 TI - Education of hematopoietic stem cell transplant caregivers in preparation for their role. PMID- 25032022 TI - Group appointments in a breast cancer survivorship clinic. PMID- 25032024 TI - Locally advanced rectal cancer: does assessment of response after neoadjuvant chemoradiotherapy impact management? PMID- 25032025 TI - Assessment of pathologic response in patients with locally advanced rectal cancer: implications of the park et Al. Study. PMID- 25032026 TI - Bosutinib: a novel src/abl kinase inhibitor for chronic myelogenous leukemia. PMID- 25032027 TI - Screening for intimate partner violence in an oncology population. PMID- 25032028 TI - Increasing use of advanced practitioners: strategizing for the future. PMID- 25032029 TI - Improving pain management at the nursing education level: evaluating knowledge and attitudes. AB - Unmanaged pain is a prevalent problem faced by many cancer patients. One part of this problem centers on a lack of emphasis on pain management in the undergraduate nursing curriculum. This study examined the knowledge and attitudes of 41 undergraduate nursing students regarding pain management. Students voluntarily completed a demographic data form, the Nurses' Attitude Survey, and the Pain Management Principles Assessment Tool. A mean score of 19.4 out of a possible 31 was achieved on the knowledge test, whereas a mean score of 17.0 was achieved on the Nurses' Attitude Survey. A weak-to-moderate relationship between knowledge and attitudes was found. Although students had positive attitudes regarding pain management, many still lacked the fundamental knowledge essential for adequately managing pain. The sample size was relatively small and not demographically diverse, but the response from the sample was sufficient to provide statistically meaningful data. In the quest to improve patient outcomes, these findings suggest the need to develop specific strategies to effectively teach undergraduate nursing students about pain management. PMID- 25032030 TI - Olanzapine: an antiemetic option for chemotherapy-induced nausea and vomiting. AB - Despite the appropriate use of pharmacologic and nonpharmacologic preventative measures, chemotherapy-induced nausea and vomiting (CINV) can be debilitating and can decrease quality of life for many patients. In addition, patients may be unwilling to continue chemotherapy treatment due to the uncontrollable nausea and vomiting associated with their therapy. Refractory CINV can occur at any point in a treatment cycle, despite adequate therapy for acute and delayed CINV. Current prevention strategies include using serotonin (5-HT3) receptor antagonists, corticosteroids, and/or neurokinin-1 receptor antagonists. Unfortunately, more pharmacologic options are needed to treat refractory CINV. The current standard of care for the treatment of refractory CINV includes phenothiazines, metoclopramide, butyrophenones, corticosteroids, cannabinoids, anticholinergics, and 5-HT3 receptor antagonists. Olanzapine, an atypical antipsychotic agent of the thiobenzodiazepine class, has the ability to target many different receptors, making it an attractive antiemetic agent. PMID- 25032031 TI - Predictors of cervical cancer screening adherence in the United States: a systematic review. AB - Cervical cancer incidence rates have decreased dramatically since the implementation of the Papanicolaou (Pap) smear. Nevertheless, the American Cancer Society (ACS) estimates for 2013 predicted more than 12,000 new cases of cervical cancer in the United States. Given that some subpopulations in the United States are at a higher risk for cervical cancer than others, efforts to increase screening adherence are warranted. Many studies have explored the demographics of underscreened women, but no systematic reviews of screening demographics in adult US women were identified in the past 10 years, after release of the 2002 ACS cervical cancer screening guidelines. Knowledge of adherence to these guidelines becomes important as new guidelines were developed and released in 2012. The purpose of this systematic review of relevant studies was to identify factors that predict the use of cervical cancer screening in US women. Variables found to be significantly associated with adherence to screening included education, financial status, acculturation, psychosocial issues, and marital status. Using this information, nurse practitioners and other providers can target specific at risk populations to increase screening by educating women about the need for cervical cancer screening and ensuring access to methods for prevention and early detection of the disease. PMID- 25032032 TI - Integrating Nurse Practitioners Into Radiation Oncology: One Institution's Experience. PMID- 25032033 TI - Cabozantinib for the treatment of metastatic medullary thyroid carcinoma. PMID- 25032034 TI - Pomalidomide for the treatment of multiple myeloma. PMID- 25032035 TI - The Long and Short of Tamoxifen Therapy: A Review of the ATLAS Trial. AB - Review of "Long term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial" by Davies et al. (2013), Lancet, 381, 805-816. For another perspective on the ATLAS trial, please see the article on randomization and adjusting for covariates by Dustin Dickerson starting on page 61. PMID- 25032036 TI - Randomized allocation to treatment groups and the importance of adjusting for covariates. PMID- 25032037 TI - A case of complicated survivorship care. AB - At age 34, Ms. P., a premenopausal African American woman, was diagnosed with stage IA poorly differentiated invasive ductal carcinoma of the left breast. Her tumor was estrogen and progesterone receptor (PR) positive but HER2 negative. Ms. P.'s treatment included a partial mastectomy, radiation therapy, and 2 years of tamoxifen, although tamoxifen was discontinued due to pregnancy. She was then lost to follow-up. At age 40, Ms. P. discovered a mass in her left breast upon self- exam. There was a delay in diagnosis due to pregnancy, which was terminated. A core biopsy was performed, and the pathology was positive for poorly differentiated invasive ductal carcinoma that was ER and PR positive but HER2 negative. She was clinically stage IIIB, with the tumor fixed to the chest wall. Ms. P.'s family history included premenopausal breast cancer in her mother, three of her maternal aunts, and her maternal grandmother. Genetic testing was performed; she was found to have a BRCA2 deleterious mutation. After an intrauterine device (IUD) was placed to prevent pregnancy, Ms. P. began neoadjuvant chemotherapy consisting of doxorubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 4 cycles. She then underwent a left salvage mastectomy and sentinel lymph node biopsy. After treatment, she was assessed at pathologic stage IA. Tamoxifen was reinitiated. After completing treatment, Ms. P. presented for a survivorship visit accompanied by her fiance. PMID- 25032038 TI - There's an App for That! PMID- 25032039 TI - Hyperpigmentation of the tongue. PMID- 25032040 TI - Celebrities and medicine: a potent combination. PMID- 25032041 TI - The Launch of the Advanced Practitioner Society for Hematology and Oncology (APSHO). PMID- 25032042 TI - Leaders of ASCO, ASH, ASTRO, and NCCN Embrace Collaboration With Advanced Practitioners. PMID- 25032043 TI - Advanced practitioners in oncology: diverse experiences, shared challenges. PMID- 25032044 TI - Improving surgical outcomes in pancreatic surgery with preoperative nutrition. AB - The purposes of this study were (1) to describe the relationship between preoperative physical status and postoperative outcomes in patients undergoing Whipple resection, and (2) to determine if the use of specialized immunonutrition with IMPACT Advanced Recovery supplementation improved postoperative outcomes (pancreatic leak rate, length of stay, and postoperative complications) in patients undergoing Whipple resection. The trial was a case-controlled prospective pilot study that took place in an outpatient gastrointestinal surgical oncology office in an urban community hospital in the northeast United States. The study population consisted of nine patients undergoing Whipple surgery. Patients were given IMPACT Advanced Recovery supplementation 4 days prior to Whipple surgery. Prospective data were collected on all patients and then compared to national averages in terms of outcomes. Study approval was obtained from the Fairfield University Institutional Review Board (IRB), though IRB approval was not required by the study facility due to the fact that this was a pilot study. Consent was also not required for retrospective chart review. Patients with lower scores according to the American Society of Anesthesiologists Physical Status Classification System have a shorter operating time in the setting of preoperative nutrition. Patients in this study who received preoperative nutrition with IMPACT Advanced Recovery supplementation had outcomes comparable to the national average. This pilot study suggests that there is a need for a multi-institutional randomized study powered to further evaluate the effectiveness of preoperative nutrition in pancreatic surgery. The literature supports the fact that preoperative nutritional supplementation should be offered to patients undergoing Whipple surgery. Optimization of nutritional status can translate to decreased length of stay and cost savings. PMID- 25032045 TI - Distress screening in chronic disease: essential for cancer survivors. AB - Distress is a psychological state that is often observed in patients with chronic disease. Many cancers are considered chronic in nature, with patients experiencing long, disease-free states and intervals of metastatic disease. Distress can negatively affect the biopsychosocial balance in cancer survivors and impede their progress along the cancer trajectory. Distress can also affect medical and psychological outcomes and hinder advancement into long-term survivorship. Distress may contribute to disease progression, although despite research findings, health-care providers seldom screen for indications of persistent or unresolved distress. This article discusses research findings related to the prevalence of distress in multiple chronic diseases. Validated instruments used to screen for distress in cancer survivors, such as the Distress Thermometer and symptom checklist from the National Comprehensive Cancer Network, are reviewed. With the availability of brief and concise instruments to screen for distress, providers have the ability to provide holistic and comprehensive care for cancer survivors. The overall financial impact of cancer-related distress is understudied, although similar psychological studies indicate that prevention or elimination of distress is beneficial. Cancer is a lifelong, chronic disease; patients have ongoing needs and varied sources of distress. As the number of cancer survivors exponentially increases, their psychosocial needs will likewise expand. PMID- 25032046 TI - Calculating your worth: understanding productivity and value. PMID- 25032048 TI - Abstracts From the First Annual JADPRO Live Transforming Oncology Practice Meeting. AB - Renaissance Vinoy, St.Petersburg, Florida January 24-26, 2014. PMID- 25032047 TI - Ado-Trastuzumab Emtansine in Metastatic HER2-Positive Breast Cancer. PMID- 25032049 TI - What is the Etiology of Dysarthria and Ataxia in a Woman With Cancer? PMID- 25032050 TI - Spontaneous uterine rupture at 15 weeks' gestation in a patient with a history of cesarean delivery after removal of shirodkar cerclage. AB - A pregnant woman presented with acute upper abdominal pain and nausea at 15 weeks' gestation. She had a history of cesarean delivery for abruption after the removal of a Shirodkar cerclage that was placed because of cervical shortening caused by conization. She became pregnant again 14 months later. Ultrasonography revealed no significant findings, and a single intrauterine pregnancy with positive fetal heart activity was confirmed. An intestinal obstruction was suspected because abdominal radiography showed multiple air-fluid levels in the colon. Over the 3 hours following admission, her symptoms gradually worsened, and plain abdominal computed tomography (CT) showed a large hemorrhage in the abdominal cavity, but the uterine wall appeared intact at this time. Subsequently, dynamic CT revealed discontinuity of the uterine muscle layer. During laparotomy, uterine rupture with complete opening of the uterine wall at the site of the previous transverse scar was identified. A dead fetus was located within the amniotic sac in a blood-filled abdominal cavity. She received a total of 10 units of packed red blood cells and 6 units of fresh frozen plasma for the resuscitation. She was discharged on the eighth postoperative day without any complications. PMID- 25032051 TI - Successful management of an extremely premature infant with congenital candidiasis. AB - Congenital candidiasis, which presents with a variety of clinical symptoms, is very rare in both term and preterm infants, and less than 100 neonatal cases have been reported in the medical literature. We describe the case of an extremely premature infant with congenital candidiasis, who was successfully treated and survived without major sequelae. A male infant was born at 25 weeks' gestation (weight, 834 g). He exhibited diffuse erythematous papules. Samples of his skin, pharyngeal mucus, gastric fluid, and tracheal aspirate were found to be Candida albicans-positive while blood cultures were negative. Further histopathological examinations revealed that Candida albicans mycelia had invaded the umbilical cord. After prompt antifungal therapy, the patient's skin lesions improved markedly, and he was discharged from hospital without any major complications. This report highlights the importance of characteristic skin lesions for the early diagnosis of Candida infections, especially in extremely premature infants. PMID- 25032052 TI - Repair of Uterine Rupture during Second Trimester Leading to Successful Pregnancy Outcome: Case Study and Literature's Review. AB - It was thought to be impossible to prolong the pregnancy in a case of uterine rupture in the second trimester. We encountered a case of rupture of the pregnant uterus in early mid-trimester, which we repaired with suture and overlapping of collagen fleece coated with fibrin glue, resulting in pregnancy prolongation until the 34th week. Our case and five previously reported cases were reviewed. Pregnant uterine rupture in mid-trimester could be repaired with suture and overlapping of collagen fleece in the absence of placenta percreta. PMID- 25032053 TI - Miller-dieker syndrome associated with congenital lobar emphysema. AB - Miller-Dieker syndrome (MDS) is a rare genetic syndrome associated with lissencephaly, developmental delay, and high mortality. We describe a patient who was diagnosed postnatally with both MDS and congenital lobar emphysema. We believe that this is the first reported case of the two conditions presenting in the same patient. PMID- 25032054 TI - Administration of Gemcitabine for Metastatic Adenocarcinoma during Pregnancy: A Case Report and Review of the Literature. AB - We present the case of a 38-year-old woman diagnosed with metastatic adenocarcinoma of the biliary tract in the 18th week of pregnancy. Chemotherapy based on cisplatin and gemcitabine was administered, reaching disease stabilization until late-preterm delivery at 35 + 0 weeks of gestation. The infant was healthy and showed no malformations. Her head circumference was small, yet no neurological and behavioral defects have been detected. Development was normal during 14 months of follow-up. We discuss the implications of metastatic cancer in pregnancy with focus on therapeutic options for metastatic adenocarcinoma of the biliary tract. In this context, available data for the active regimens in biliary tract cancers-platinum compounds and gemcitabine-are discussed. This report is the fourth in the literature detailing the application of gemcitabine during pregnancy and the first presenting longer term follow-up, complementing available evidence that gemcitabine-based regimens are feasible in this situation. PMID- 25032055 TI - Low cardiac output secondary to a malpositioned umbilical venous catheter: value of targeted neonatal echocardiography. AB - Systemic hypotension is common in very low birthweight preterm infants but the nature of the precipitating cause may be unclear. Targeted neonatal echocardiography (TnEcho) is being increasingly used to support hemodynamic decisions in the neonatal intensive care unit (NICU), including identifying impairments in the transitional circulation of preterm infants, providing timely re-evaluation after institution of therapies and evaluating the placement of indwelling catheters. We present a case of a preterm infant with systemic hypotension and low cardiac output secondary to a large transatrial shunt induced by a malpositioned umbilical venous catheter. Repositioning of the line led to resolution of the hemodynamic disturbance and clinical instability, highlighting the utility of TnEcho in the NICU. PMID- 25032056 TI - Interstitial pregnancy resulting in a viable infant coexistent with massive perivillous fibrin deposition: a case report and literature review. AB - Objective The objective of this report is to describe a rare case of interstitial pregnancy ultimately resulting in a viable infant coexistent with massive perivillous fibrin deposition (MPFD). Study Design This study is a case report and literature review. Results A 35-year-old female patient underwent cesarean section at 32 weeks of gestation due to fetal growth restriction (FGR) and breech presentation. During the operation, a diagnosis of interstitial pregnancy was established. There was no evidence of placental separation. We decided to complete surgery without removal of the placenta and waited until the placenta delivered spontaneously. The conservative management was successful, and the patient was discharged on postoperative day 13. The pathologic examination showed MPFD. Conclusion If interstitial pregnancies are not diagnosed at an early gestational age, it can result in a viable fetus, but such pregnancies may be associated with FGR or placenta accreta. PMID- 25032057 TI - Cloaca in discordant monoamniotic twins: prenatal diagnosis and consequence for fetal lung development. AB - Objective Describe a case of cloaca prenatally diagnosed in one of a set of monoamniotic twins. Study Design Retrospective review of a case. Results Cloaca is one of the most complex and severe degrees of anorectal malformations in girls. We present a discordant cloaca in monoamniotic twins. Fetal ultrasound showed a female fetus with a pelvic midline cystic mass, a phallus-like structure, a probable anorectal atresia with absence of anal dimple and a flat perineum, and renal anomalies. The diagnosis was confirmed by fetal magnetic resonance imaging postnatally. Conclusions The rarity of the malformation in a monoamniotic pregnancy, the difficulties of prenatal diagnosis, the pathogenic assumptions, and the consequences of adequate amniotic fluid for fetal lung development are discussed. PMID- 25032058 TI - Vaginal Myomectomy for Semipedunculated Cervical Myoma during Pregnancy. AB - Objective Cases of prolapsed myoma in which pregnancy was carried to full term or near term after vaginal myomectomy are very rare. Previously, only two such cases have been reported. In addition, both those patients had a pedunculated leiomyoma, which could be treated by twisting or clamping. Here, we report a case of a patient who was able to carry her pregnancy to term despite vaginal myomectomy for semipedunculated myoma at 13 weeks of pregnancy. Study Design This study is a case presentation. Results The myoma nucleus was removed by making an incision on the surface of the mass. Systemic and transvaginal antibiotics were prescribed after the surgery. Uterine contractions, short cervix, or cervical funneling was not observed in the remaining duration of pregnancy. Conclusion While performing myomectomy during pregnancy, removal of the myoma nucleus is safer than twisting. In addition, postoperative administration of local or systemic antibiotic agents does not adversely affect pregnancy. PMID- 25032059 TI - Emergent thrombectomy in a neonate with an upper extremity arterial thrombus. AB - Case This case report is of a 39 (4/7)weeks infant who presented at the time of birth with an immobile, cyanotic right upper extremity consistent with ischemia but without evidence of gangrene. Doppler examination identified pulses in the axillary but not the brachial or radial arteries. Extremity arterial ultrasound confirmed the diagnosis of an arterial thrombosis extending from the right axillary artery to the brachial artery bifurcation. An emergent balloon thrombectomy was performed successfully with immediate return of blood flow. Intraoperative ultrasound demonstrated patent axillary and brachial arteries with forward flow. A retroperitoneal ultrasound and limited hypercoagulable workup failed to identify a source of the arterial thrombus. The infant had normal return of function without residual limb effects. Conclusion Emergent balloon thrombectomy should be heavily considered in neonates with an extremity arterial thrombosis of undeterminable duration both for limb salvage, preserve function, and to prevent long-term growth discordance. PMID- 25032060 TI - A case of fetal diagnosis of noncompaction cardiomyopathy and coarctation of the aorta. AB - Background Left ventricular noncompaction (LVNC) cardiomyopathy is a rare form of cardiomyopathy. It is difficult to diagnose prenatally and therefore not well described in the fetal population. There have been a few reports in the literature detailing isolated cases of fetal and neonatal LVNC cardiomyopathy. Case Report We present a case of LVNC cardiomyopathy and coarctation of the aorta detected prenatally at 29 + 6 weeks of gestation with survival in infancy. This is the first case report in the literature describing the fetal diagnosis of noncompaction cardiomyopathy and associated coarctation of the aorta; a rare combination. Conclusion With a high index of suspicion, the antenatal diagnosis of noncompaction cardiomyopathy may improve neonatal morbidity and mortality. PMID- 25032061 TI - Thoracic ganglioneuromas resulting in nonimmune hydrops fetalis. AB - Introduction Most often, ganglioneuromas affect older pediatric and adult patients. They are typically slow growing tumors that remain clinically silent until they become large enough to cause symptoms by compression of adjacent structures. Case We report a case of a 22-year-old Hispanic gravida 2 para 1 female patient who was found to have massive hydrops fetalis at 20 completed gestational weeks. Fetal echocardiography revealed a narrowed distal ductal arch and proximal descending aorta. Cesarean delivery was undertaken at 29 completed gestational weeks for refractory labor and nonreassuring fetal status. The neonate expired at 47 minutes of life despite aggressive resuscitation. At autopsy, multiple thoracic masses were found adjacent to a compressed proximal descending aorta. Histological and immunohistochemical analysis confirmed the diagnosis of a ganglioneuroma, a rare type of neural crest tumor. Discussion A variety of intrathoracic masses have previously been reported to cause hydrops fetalis including teratomas, fibrosarcomas, and lymphangiomas. To our knowledge, this case is the first description of hydrops fetalis caused by ganglioneuromas. We propose that multiple thoracic ganglioneuromas led to biventricular distal outflow tract obstruction and hydrops fetalis. PMID- 25032062 TI - Conservative management of an advanced abdominal pregnancy at 22 weeks. AB - Objective We report an uneventful conservative approach of an advanced abdominal pregnancy discovered at 22 weeks of gestation. Study Design This study is a case report. Results Attempting to extend gestation of an advanced abdominal pregnancy is not a common strategy and is widely questioned. According to the couple's request, the management consisted in continuous hospitalization, regular ultrasound scan, and antenatal corticosteroids. While the woman remained asymptomatic, surgery was planned at 32 weeks, leading to the birth of a preterm child without any long-term complications. Placenta was left in situ with a prophylactic embolization, and its resorption was monitored. Conclusion Depending on multidisciplinary cares and agreement of the parents, when late discovered, prolonging advanced abdominal pregnancy appears to be a reasonable option. PMID- 25032063 TI - Coping Mediates the Association Between Marital Instability and Depression, but Not Marital Satisfaction and Depression. AB - The association between marital discord and depression is well established. Marital discord is hypothesized to be a stressful life event that would evoke one's efforts to cope with it. In an effort to further understand the nature of this association, the current study investigated coping as a mediating variable between marital dissatisfaction and depression and between marital instability and depression. Both marital dissatisfaction and instability, reflecting orthogonal dimensions of marital discord, were included in the model examined to elucidate a more complete picture of marital functioning. Structural Equation Modeling analyses revealed that coping mediated the association between marital instability and depression, but not marital dissatisfaction and depression, suggesting that coping traditionally considered adaptive for individuals in the context of controllable stressors may not be adaptive in the context of couple relationship instability. The findings also have implications for interventions focusing on decreasing maladaptive coping strategies in couples presenting for marital therapy or depression in addition to efforts directed at improving marital quality. PMID- 25032065 TI - Oral Stem Cells: The Fountain of Youth for Epithelialization and Wound Therapy? AB - Significance: The oral cavity represents a novel source of a large number of stem cells. Recent Advances: Stem cell populations have been identified in dental pulp, gingival epithelium, gingival lamina propria, and the periodontal ligament. Critical Issues: The utility of using tissues of the oral cavity as a source of stem cells has been only partially explored. Much remains to be learned about the capability of these cells and the differences between cells derived from dissimilar oral locations. Future Directions: The feasibility of using orally derived stem cells to support tissue regeneration and wound repair is a promising concept that requires additional investigation. PMID- 25032064 TI - Epithelialization in Wound Healing: A Comprehensive Review. AB - Significance: Keratinocytes, a major cellular component of the epidermis, are responsible for restoring the epidermis after injury through a process termed epithelialization. This review will focus on the pivotal role of keratinocytes in epithelialization, including cellular processes and mechanisms of their regulation during re-epithelialization, and their cross talk with other cell types participating in wound healing. Recent Advances: Discoveries in epidermal stem cells, keratinocyte immune function, and the role of the epidermis as an independent neuroendocrine organ will be reviewed. Novel mechanisms of gene expression regulation important for re-epithelialization, including microRNAs and histone modifications, will also be discussed. Critical Issues: Epithelialization is an essential component of wound healing used as a defining parameter of a successful wound closure. A wound cannot be considered healed in the absence of re-epithelialization. The epithelialization process is impaired in all types of chronic wounds. Future Directions: A comprehensive understanding of the epithelialization process will ultimately lead to the development of novel therapeutic approaches to promote wound closure. PMID- 25032066 TI - The Epigenetic Regulation of Wound Healing. AB - Significance: Epigenetic regulatory mechanisms are essential for epidermal homeostasis and contribute to the pathogenesis of many skin diseases, including skin cancer and psoriasis. However, while the epigenetic regulation of epidermal homeostasis is now becoming active area of research, the epigenetic mechanisms controlling the wound healing response remain relatively untouched. Recent Advances: Substantial progress achieved within the last two decades in understanding epigenetic mechanisms controlling gene expression allowed defining several levels, including covalent DNA and histone modifications, ATP-dependent and higher-order chromatin chromatin remodeling, as well as noncoding RNA- and microRNA-dependent regulation. Research pertained over the last few years suggests that epigenetic regulatory mechanisms play a pivotal role in the regulation of skin regeneration and control an execution of reparative gene expression programs in both skin epithelium and mesenchyme. Critical Issues: Epigenetic regulators appear to be inherently involved in the processes of skin repair, and are able to dynamically regulate keratinocyte proliferation, differentiation, and migration, together with influencing dermal regeneration and neoangiogenesis. This is achieved through a series of complex regulatory mechanisms that are able to both stimulate and repress gene activation to transiently alter cellular phenotype and behavior, and interact with growth factor activity. Future Directions: Understanding the molecular basis of epigenetic regulation is a priority as it represents potential therapeutic targets for the treatment of both acute and chronic skin conditions. Future research is, therefore, imperative to help distinguish epigenetic modulating drugs that can be used to improve wound healing. PMID- 25032067 TI - Eicosanoids and Keratinocytes in Wound Healing. AB - Significance: Eicosanoids are biologically active lipid mediators derived from arachidonic acid that are important in injury and inflammatory responses. Cyclooxygenase-1 and cyclooxygenase-2 mediate the production of prostanoids, whereas 5-lipoxygenase mediates the production of leukotrienes and hydroxyeicosatetraenoic acids. These lipid mediators have traditionally been known to recruit cells of the immune system to a site of injury and inflammation. However, they also interact with various cells that are resident to the wound bed, including modulation of keratinocyte activity. Recent Advances: Recent work has identified multiple prostanoid and leukotriene receptors on keratinocytes, indicating that eicosanoids directly interact with them. Recent work also shows that keratinocytes are capable of producing prostanoids and leukotrienes. Critical Issues: Much of the critical work has been performed in cell culture and mouse in vivo models. This has greatly expanded our understanding of the eicosanoid interactions with keratinocytes and wound healing in general. However, few of these in vivo models have been able to critically evaluate keratinocyte migration and re-epithelialization. Future Directions: As research continues in this exciting field, the cellular pathways stimulated by the eicosanoids will become better defined. Future research with excisional wound models in mice and pigs and ex vivo human skin models will better isolate the contribution of eicosanoid-mediated effects on keratinocyte migration and re-epithelialization. PMID- 25032068 TI - The Role of TGFbeta Signaling in Wound Epithelialization. AB - Significance: Transforming growth factor beta (TGFbeta) has a crucial role in maintaining skin homeostasis. TGFbeta signaling is important for re epithelialization, inflammation, angiogenesis, and granulation tissue formation during wound healing. This review will discuss the most important findings regarding the role of TGFbeta in epidermal maintenance and its restoration after injury. Recent Advances: Latest findings on the role of TGFbeta signaling in normal and impaired wound healing, including the role of TGFbeta pathway in tissue regeneration observed in super-healer animal models, will be reviewed. Critical Issues: The TGFbeta pathway is attenuated in nonhealing wounds. Observed suppression of TGFbeta signaling in chronic ulcers may contribute to the loss of tissue homeostasis and the inability of keratinocytes to migrate and close a wound. Future Directions: A better understanding of TGFbeta signaling may provide new insights not only in the normal epithelialization process, but also in tissue regeneration. Future studies focused on TGFbeta-mediated crosstalk between multiple cell types involved in wound healing may lead to development of novel therapeutic advances for chronic wounds. PMID- 25032069 TI - Innate and Adaptive Immune Responses in Wound Epithelialization. AB - Significance: Over the years, it has become clear that, in addition to performing their regular duties in immune defense, the innate and adaptive arms of the immune system are important regulators of the complex series of events that lead to wound healing. Immune cells modulate wound healing by promoting cellular cross talk; they secrete signaling molecules, including cytokines, chemokines, and growth factors. In line with the major effort in wound healing research to find efficient therapeutic agents for the constantly increasing number of patients with chronic wounds, findings regarding the contributions of innate and adaptive immune responses to the re-epithelialization of damaged skin may bring novel therapeutics. Recent Advances: Increasing evidence suggests that induction of the adaptive immune response requires activation of innate immunity and that there is a dependent relationship between the two systems. Consequently, the bridge between the innate and the acquired immune systems has become an area of emerging exploration. It is clear that a better understanding of the epithelial cells (keratinocytes), immune cells, and mechanisms that contribute to an effective wound healing process is necessary so that new strategies for successful wounds treatment can be devised. Critical Issues: A greater understanding of the biology of skin innate and adaptive immune cells during wound epithelialization may have an impact on development of novel strategies for significant improvements in the quality of tissue repair. Future Directions: Future studies should clarify the importance of particular molecules and mechanisms utilized for development and functions of skin-resident gammadeltaT and Langerhans cells, as well as identify therapeutic targets for manipulation of these cells to combat epithelial diseases. PMID- 25032070 TI - The Wound Microbiome: Modern Approaches to Examining the Role of Microorganisms in Impaired Chronic Wound Healing. AB - Significance: Bacterial burden is believed to play a significant role in impaired wound healing of chronic wounds and the development of infection-related complications. The standard of care in the clinic relies upon cultivation dependent methods to identify microorganisms. These assays are biased toward microorganisms that thrive in isolation under laboratory conditions. Recent Advances: Significant advances in genomic technologies have enabled less-biased, culture-independent approaches to characterize microbial communities, or microbiomes. The aggregate sequencing and analysis of 16S ribosomal RNA genes has demonstrated that cultures under-represent true microbial diversity and load. Critical Issues: Despite recent advances that enable culture-independent analyses of microbiomes, those organisms that are important in impaired healing remain ambiguous. Inconsistent findings across various studies highlight the need to characterize microbiomes of chronic wounds with homogenous etiology to determine differences in microbiomes that may be driven by the wound environment and that may affect wound outcomes. Rigorous analyses of wound microbiomes in light of the three dimensions of bioburden (microbial diversity, microbial load, and pathogenic organisms), clinical metadata, and wound outcomes will be a significant step forward in our quest to understand the role of microorganisms in impaired healing. Future Directions: Longitudinal studies employing serial sampling are needed to appreciate the role of the dynamic microbial community in chronic wound healing. The value of clinical metadata needs to be examined as potential biomarkers of problematic microbiota and wound outcomes. Lastly, better characterization and understanding of wound microbiomes will open avenues for improved diagnostic and therapeutic tools for the nonhealing wound. PMID- 25032072 TI - Ulnar shortening osteotomy. PMID- 25032071 TI - Modelling of a genetically diverse evolution of Systemic Mastocytosis with Chronic Myelomonocytic Leukemia (SM-CMML) by Next Generation Sequencing. AB - BACKGROUND: Systemic mastocytosis (SM) is a heterogenous, clonal mast cell (MC) proliferation, rarely associated with clonal hematologic non-mast cell lineage disease (SM-AHNMD). KIT (D816V) is regarded as driver-mutation in SM-AHNMD. METHODS: DNA isolated from peripheral blood (PB) of an SM-CMML patient was investigated with targeted next generation sequencing. Variants were verified by Sanger sequencing and further characterized in the SM part of the bone marrow trephine (BMT), normal tissue, and FACS sorted PB cell subpopulations. FINDINGS: Low coverage deep-sequencing (mean 10x) on a GS 454 Junior revealed two as yet unreported SNVs (CBFA2T3 and CLTCL1), both germ-line mutations. High coverage (mean 1674x) targeted re-sequencing on an Ion Proton revealed 177 variants in coding regions. Excluding SNPs, the final list comprised 11 variants. Among these, TET2 (p.Thr1027fs, p.Cys1263Ser) and RUNX1 (p.Asn109Ser) were identified in in the peripheral blood and the SM part of BMT, but not in normal tissue. Furthermore, Sanger sequencing of PB cells revealed similar signal intensities for both TET2 mutations in FACS sorted CD34+ precursor cells and CD16+ granulocytes comparable to signals in the SM part of BMT. In contrast, RUNX1 exhibited a double intensity in CD34+ cells compared to the SM part of BMT and a homozygous variant signal in granulocytes. Both TET2 and RUNX1 mutations were not detectable in B- and T-cells. CONCLUSION: We present a heterozygous triple mutation pattern (KIT, TET2, RUNX1) in mast cells (SM disease part) with additional LOH of RUNX1 in granulocytes (CMML disease part). These identified mutations allow a more detailed insight into a multistep pathogenesis which suggests a common tumor progenitor in SM-CMML. PMID- 25032073 TI - An italian experience delving inside the wrist. PMID- 25032074 TI - Ulnar shortening osteotomy for ulnar impaction syndrome. AB - Background Ulnar impaction syndrome is a condition in which the ulna impacts on the ulnar carpus. This most commonly occurs when the ulna is longer than the radius, but it can also occur in wrists with ulnar neutral and ulnar negative variance. Materials and Methods In this paper we outline our surgical technique for ulnar shortening osteotomy. A previously published retrospective case series of 28 patients treated at our center is presented. Fifty consecutive patients who underwent ulnar shortening osteotomy (USO) for ulnar impaction syndrome were approached for study, and 28 consented to review. Mean preoperative ulnar variance was +2.3 mm, and mean postoperative ulnar variance was -0.8 mm. Mean follow-up time was 21.2 months (8 to 41 months) and ten of 28 were receiving workers' compensation. Mean preoperative pain score (visual analog scale; VAS) was 7.9. Univariate analysis was performed to assess clinical and demographic data. In addition, subgroup analysis of workers' compensation patients and smokers was performed. Description of Technique A longitudinal incision over the subcutaneous border of the ulna is used to expose the ulna between the distal and middle third of the ulna from the ulna styloid. Preoperative posteroanterior (PA) X-rays are reviewed to determine the amount of shortening required, with a goal of creating -2 mm variance postoperatively. A 6-hole dynamic compression plate is predrilled distally prior to performing two oblique osteotomies separated by the desired shortening length. The fragments are reduced, controlling for rotation, and plated using compression. In some cases, a lag screw is employed across the oblique osteotomy site. Results Mean pain scores were significantly reduced postoperatively (VAS 7.9 versus 3.1, P < 0.0001). The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 37.2 postoperatively. Flexion, extension, and supination were reduced compared with the contralateral unaffected extremity (84.6%, 85.3%, and 86.9% of normal). Patients receiving workers' compensation and smokers had significantly more pain postoperatively (VAS 5.2 vs. 2.0, P = 0.0002 and VAS 4.4 vs 2.4, P < 0.05, respectively). Eleven of 28 patients required hardware removal for plate irritation, and five of 28 patients had a nonunion. Conclusion We present our surgical technique for ulnar shortening osteotomy. Pain was significantly improved in our population; however, patients receiving workers' compensation and smokers had less improvement in pain and higher disability scores. PMID- 25032075 TI - Ulnar Impaction Syndrome: Ulnar Shortening vs. Arthroscopic Wafer Procedure. AB - The outcome of ulnar shortenings was compared with that of arthroscopic wafer resections for ulnar impaction (or abutment) syndrome in patients with a positive ulnar variance. The outcome was measured by DASH score, visual analog scale for pain, and working incapacity. The mean DASH score in the ulnar shortening group was 26; in the wafer group it was 36. The VAS scores were respectively 4.4 and 4.6. The working incapacity was 7?months in the ulnar shortening group and 6.1 months in the wafer group. The differences between the two groups were not statistically significant. PMID- 25032076 TI - Periprosthetic osteolysis after total wrist arthroplasty. AB - Background and Literature Review Periprosthetic osteolysis (PPO) after second- or third-generation total wrist arthroplasty (TWA), with or without evident loosening of the implant components, has previously been reported in the literature, but rarely in a systematic way. Purpose The purpose of this study was to analyze the prevalence, location, and natural history of PPO following a TWA and to determine whether this was associated with prosthetic loosening. Patients and Methods We analyzed 44 consecutive cases in which a RE-MOTION TWA (Small Bone Innovations Inc., Morrisville, PA, USA) had been done. Results We found significant periprosthetic radiolucency (more than 2 mm in width) at the radial component side in 16 of the cases and at the carpal component side in 7. It developed gradually juxta-articularly around the prosthetic components regardless of the primary diagnosis, and seemed to stabilize in most patients after 1-3 years. In a small percentage of the patients, the periprosthetic area of bone resorption was markedly larger. In general, radiolucency was not related to evident loosening of the implant components, and only five carpal components and one radial had subsided or tilted. Conclusion Periprosthetic loosening is frequent following a TWA. In our series it was not necessarily associated with implant loosening and seemed to stabilize within 3 years. Close and continued observation is, however, recommended. Level of Evidence Therapeutic IV. PMID- 25032077 TI - Arthroscopic Resection Arthroplasty of the Radial Column for SLAC Wrist. AB - Background Symptomatic advanced scapholunate advanced collapse (SLAC) wrists are typically treated with extensive open procedures, including but not limited to scaphoidectomy plus four-corner fusion (4CF) and proximal row carpectomy (PRC). Although a minimally invasive arthroscopic option would be desirable, no convincing reports exist in the literature. The purpose of this paper is to describe a new surgical technique and outcomes on 14 patients who underwent arthroscopic resection arthroplasty of the radial column (ARARC) for arthroscopic stage II through stage IIIB SLAC wrists and to describe an arthroscopic staging classification of the radiocarpal joint for patients with SLAC wrist. Patients and Methods Data were collected prospectively on 17 patients presenting with radiographic stage I through III SLAC wrist who underwent ARARC in lieu of scaphoidectomy and 4CF or PRC. Fourteen patients (12 men and 2 women) subject to 1-year follow-up were included. The average age was 57 years (range 41 to 78). The mean follow-up was 24 months (range 12 to 61). Arthroscopic resection arthroplasty of the radial column is described for varying stages of arthritic changes of the radioscaphoid joint. Midcarpal resection was not performed. Results The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 66 preoperatively and 28 at final follow-up. The mean satisfaction (0 = not satisfied, 5 = completely satisfied) at final follow-up was 4.5 (range 3 to 5). The pain level (on 0-10 scale) improved from 6.6 to 1.3. The total arc of motion changed from 124 degrees preoperatively to 142 degrees postoperatively following an ARARC. Grip was 16 kg preoperatively and 18 kg postoperatively. Radiographic stages typically underestimated arthroscopic staging. Although four of our patients appeared to be radiographic stage I, all were found to have arthritis involving some or all of the radioscaphoid articulation at the time of arthroscopy. Clinical Relevance Pain relief is rapid and remains consistent over time following ARARC. ARARC may be a viable surgical option for patients with SLAC wrist who desire a minimally invasive procedure. Radiographic stages underestimate the degree of arthritic change. Accurate staging requires arthroscopy. The indications and long-term outcome are not well defined; continued surveillance is warranted. Level of Evidence Level IV, Therapeutic study. PMID- 25032078 TI - How to Avoid Ulnar Nerve Injury When Setting the 6U Wrist Arthroscopy Portal. AB - The dorsal sensory branch of the ulnar nerve (DSBUN) is at risk in setting the 6U wrist arthroscopy portal. Although surgeons know the risk and are careful when they set the 6U portal, DSBUN injuries still occur. The purpose of the present anatomical study was to evaluate the possibility that DSBUN undergoes dynamic anatomical variations in its location during wrist arthroscopy. The goal of the study was to clarify (1) whether the nerve-to-portal (NTP) distance changes with flexion/extension wrist and/or hand/forearm rotation, and (2) whether there is any particular combination of flexion-extension/hand-forearm rotation where the NTP distance is maximal. Six fresh cadaver arms were suspended in a traction tower with forearm rotation locked, the skin and subcutaneous tissue around the ulnar head was removed, and the NTP distance measured in three predetermined loading/positional conditions. Of all options, the one that consistently showed the longest and safest NTP distance involved wrist flexion and radiocarpal supination when forearm rotation is limited. In conclusion, when an arthroscopic traction device restricts the forearm rotation, the 6U portal should not be set under traction with the hand passively pronated. Failure to observe this precaution can result in serious neuropathic pain. PMID- 25032079 TI - Isolated lunocapitate osteoarthritis-an alternative pattern of osteoarthritis. AB - Introduction Osteoarthritis (OA) in the wrist usually develops in a pattern described as scapholunate advanced collapse (SLAC). We observed an alternative pattern of OA that involves the lunocapitate joint in isolation with minimal involvement of the radioscaphoid articulation. Case Series The series was observed from a series of 100 wrist radiographs that were retrospectively reviewed. In order to characterize the alternative pattern of OA, we compared demographic data, presentation, and physical and radiographic examination characteristics between the patients with lunocapitate OA and SLAC wrists. Fifteen radiographs showed OA, nine had a SLAC pattern, and six had lunocapitate OA. The demographics were similar, but the clinical presentation was different. The patients with lunocapitate OA had less tenderness over the snuffbox (P < 0.03), and a lower percentage of a positive scaphoid shift test (P < 0.005). Isolated lunocapitate OA had a higher association with scaphotrapeziotrapezoidal (STT) arthritis (P < 0.004). The SLAC group had an increased scapholunate gap (P = 0.0003). Discussion The presentation of lunocapitate OA differs from SLAC wrist in a number of ways. Further study is necessary to understand the clinical implications of this pattern. Level IV evidence Case series. PMID- 25032080 TI - Spontaneous flexor tendon rupture due to atraumatic chronic carpal instability. AB - Background Spontaneous flexor tendon rupture is considered to be invariably associated with previous hand/wrist injury or systemic disease such as rheumatoid arthritis. Case Description A 54-year-old man presented with a 4-month history of mild ulnar wrist pain and spontaneous left little finger flexion loss in the absence of distant/recent trauma and systemic arthropathy. Surgical exploration confirmed a zone IV left little finger flexor digitorum profundus (FDP5) attritional rupture (100%), ring finger flexor digitorum profundus (FDP4) attenuation (40%) and a disrupted lunotriquetral ligament and volar-ulnar wrist capsule. Volar subluxation of the narrowed carpal tunnel resulted in flexor tendon attrition against the hamate hook. A side-to-side tendon transfer was performed along with a lunotriquetral ligament repair and temporary Kirschner wire fixation. At 6 months the patient had full active, synchronous flexion of the ring and little fingers and reduced wrist pain. Literature Review Traumatic flexor tendon ruptures have been reported following distal radius/hamate hook fractures, from carpal bone osteophytes, accessory carpal bones and intraosseous ganglia. Attritional ruptures caused by chronic, degenerative carpal pathology are less common. Clinical Relevance This case highlights an unusual cause of flexor tendon rupture due to chronic carpal instability. PMID- 25032081 TI - Comments on: Dorsal Capsuloplasty for Dorsal Instability of the Distal Ulna (J Wrist Surg 2013;2(2):168-175). PMID- 25032084 TI - Establishment of intestinal bacteriology. AB - Research on intestinal bacteria began around the end of the 19th century. During the last 5 decades of the 20th century, research on the intestinal microbiota made rapid progress. At first, in my work, I first developed a method of comprehensive analysis of the intestinal microbiota, and then I established classification and identification methods for intestinal anaerobes. Using these methods I discovered a number of ecological rules governing the intestinal microbiota and the role of the intestinl microbiota in health and disease. Moreover, using germfree animals, it was proven that the intestinal microbiota has a role in carcinogenesis and aging in the host. Thus, a new interdisciplinary field, "intestinal bacteriology" was established. PMID- 25032085 TI - Development of functional foods. AB - Recent advances in intestinal microbiota research are the background for the appearance of functional foods. Lactic fermentation products are included in the functional foods and classified into 3 groups based on their mechanisms of action: probiotics, prebiotics and biogenics. Probiotics are viable microorganisms, such as lactobacilli and bifidobacteria, that beneficially affect the host by improving the intestinal bacterial balance. Prebiotics are nondigestible food ingredients, such as oligosaccharides and dietary fiber, that beneficially affect the host by selectively stimulating the growth or activities of beneficial intestinal bacteria in the colon and thus improve the health of the hosts. Biogenics are biologically active peptides, including immunopotentiators (biological response modifier: BRM), plant flavonoids, etc. They act directly or indirectly through modulation of intestinal microbiota on the health of the hosts. Thus, functional foods enhance bioregulation such as stresses, appetite and absorption; biodefence, such as immunity and suppression of allergies; prevent diseases, including diarrhea, constipation, cancer, cholesterolemia and diabetes; and suppress aging through immunostimulation as well as suppression of mutagenesis, carcinogenesis, oxidation processes, intestinal putrefaction, and cholesterolemia. PMID- 25032083 TI - The Mechanisms of M-cell Differentiation. AB - Intestinal M (microfold or membranous) cells are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. Due to their rarity, the mechanisms of M-cell function and differentiation are poorly understood. To overcome this problem, experimental strategies to enrich for M-cells have been established. Transcriptome analyses have provided valuable insight, especially on the receptors for antigen uptake, and such studies have broadened our knowledge of M cell function. In another line of investigation, we and others have begun to dissect the molecular pathways of M-cell differentiation. Among them, receptor activator of NF-kappaB ligand (RANKL) has been identified as an essential factor for M-cell differentiation. We have focused on the M-cell inducible activity of RANKL and have been able to observe temporal transitions during M-cell differentiation by using in vivo ectopic M-cell differentiation induced by exogenous RANKL treatment. We have found that the ets-family transcription factor Spi-B is essential for functional maturation of M cells. In the absence of Spi-B, the immune response to Salmonella Typhimurium is severely impaired, suggesting that M cells are important for maintaining intestinal homeostasis. PMID- 25032086 TI - Technical Aspects of Nominal Partitions on Accuracy of Data Mining Classification of Intestinal Microbiota - Comparison between 7 Restriction Enzymes. AB - The application of data mining analyses (DM) is effective for the quantitative classification of human intestinal microbiota (HIM). However, there remain various technical problems that must be overcome. This paper deals with the number of nominal partitions (NP) of the target dataset, which is a major technical problem. We used here terminal restriction fragment length polymorphism data, which was obtained from the feces of 92 Japanese men. Data comprised operational taxonomic units (OTUs) and subject smoking and drinking habits, which were effectively classified by two NP (2-NP; Yes or No). Using the same OTU data, 3-NP and 5-NP were examined here and results were obtained, focusing on the accuracies of prediction, and the reliability of the selected OTUs by DM were compared to the former 2-NP. Restriction enzymes for PCR were further affected by the accuracy and were compared with 7 enzymes. There were subjects who possess HIM at the border zones of partitions, and the greater the number of partitions, the lower the obtained DM accuracy. The application of balance nodes boosted and duplicated the data, and was able to improve accuracy. More accurate and reliable DM operations are applicable to the classification of unknown subjects for identifying various characteristics, including disease. PMID- 25032087 TI - Laparoscopic placement of a tined lead electrode on the pudendal nerve with urodynamic monitoring of bladder function during electrical stimulation: an acute experimental study in healthy female pigs. AB - PURPOSE: The aim of this study was to develop a method for standard laparoscopic access to the pudendal nerve in pigs to implant an electrode for chronic neuromodulation studies. METHODS: Using routine laparoscopic surgical techniques, the pudendal nerve was located in 10 female pigs using standardized anatomical landmarks. A tined lead electrode was placed in parallel to the exposed pudendal nerve, and acute unilateral electrical stimulation was performed consecutively on both pudendal nerves. Bladder pressure and perineal skeletal muscle response was monitored during stimulation. RESULTS: Standard access to the pudendal nerve was successfully established in the pig model with surgical times of approximately 45 minutes for bilateral electrode placement. Acute unilateral stimulation did not evoke bladder responses but resulted in reliable stimulation-dependent activity of the perineal skeletal muscles. The structural integrity of the pudendal nerves was confirmed in all cases. CONCLUSIONS: These results illustrate the effectiveness of laparoscopy for standardised, safe nerve localisation and electrode implantation at the pudendal nerve in pigs. Laparoscopic implantation represents an alternative approach for performing electrode implantation under optical guidance versus the standard approach of percutaneous, neuro physiological monitored implantation. In the future, pudendal neuromodulation may be used as a supplement to sacral neuromodulation or as a standalone therapeutic approach, depending on the underlying bladder dysfunction. PMID- 25032088 TI - Mitigating role of thymoquinone rich fractions from Nigella sativa oil and its constituents, thymoquinone and limonene on lipidemic-oxidative injury in rats. AB - Therapeutic role of Nigella sativa (NS) seed oil fractions, methanolic extract (ME) and volatile oil (VO) and their constituents, thymoquinone (TQ) and limonene (LMN) in relation to lipidemic-oxidative stress in Wistar rats was determined. The total phenolic contents of NS seed oil and their ME and VO extracts were 320.00 +/- 3.00, 300.12 +/- 0.04 and 288.41 +/- 0.01 mg gallic acid equivalents per 100 g of NS oil, respectively. Their Fe(+2) chelating activities were 870.00 +/- 2.00, 222.31 +/- 5.80 and 38.59 +/- 1.43 mg EDTA equivalents per 100 g of NS oil, respectively. These fractions and compounds exhibited strong antioxidant activities against 2,2-diphenyl-1-picryl hydrazyl, 2,2-azinobis-3 ethylbenzothiazoline-6-sulfonic acid, nitric oxide and hydroxyl radicals. Potential antiperoxidative effects of these fractions and compounds were also observed in liposome, and lipidemic-induced lipid peroxidation in atherogenic suspension fed rats, pretreated with 100 mg ME, 20 mg VO, 10 mg pure TQ or 200 mg LMN for 30 days. ME containing omega-6 linoleic acid and palmitic acid natural compounds was highly effective against lipidemic oxidative stress than VO extract possessing thymol and isothymol phenolic natural antioxidant compounds. TQ, principal compound shared to both the extracts. The test fractions and compounds effectively reduced the erythrocyte and liver lipid peroxidation markers, conjugated diene, lipid hydroperoxide and malondialdehyde to near normal levels in the order ME > TQ > VO > LMN, by directly counteracting free radicals as well as suppressing hepatic HMG-CoA reductase activity. Our findings demonstrated that these natural products, preferably ME possess significant antioxidant activities, and may be recommended as new potential sources of natural antioxidants. PMID- 25032089 TI - Confidentiality and treatment decisions of minor clients: a health professional's dilemma & policy makers challenge. AB - Issues relating to confidentiality and consent for physical and mental health treatment with minor clients can pose challenges health care providers. Decisions need to be made regarding these issues despite the absence of clear, direct, or comprehensive policies and legislation. In order to fully understand the scope of this topic, a systemic review of several pieces of legislation and guidelines related to this topic are examined. These include the: Canadian Human Rights Act, Children's Rights: International and National Laws and Practices, Health Information Act, Gillick Competence and Medical Emancipation, Freedom of Information and Protection of Privacy Act, Child, Youth and Family Enhancement Act, Common Law Mature Minor Doctrine, and Alberta Health Services Consent to Treatment/Practice(s) Minor/Mature Minor. In order to assist health professionals with decisions regarding confidentiality and treatment with minor clients a case study and guide for decision-making is also presented. PMID- 25032090 TI - Retention and mitigation of metals in sediment, soil, water, and plant of a newly constructed root-channel wetland (China) from slightly polluted source water. AB - Constructed root-channel wetland (CRCW) is a term for pre-pond/wetland/post-pond complexes, where the wetland includes plant-bed/ditch landscape and root-channel structure. Source water out of pre-ponds flows through alternate small ditches and plant beds with root-channels via a big ditch under hydraulic regulation. Then source water flows into post-ponds to finish final polishing. This article aims to explore the potential of components of a pilot CRCW in China on mitigating metals in micro-polluted source water during its initial operation stage. We investigated six heavy metals (Cd, Cr, Cu, Ni, Zn, and Pb) in surface sediment, plant-bed subsurface soil, water, and aquatic plants during 2012-2013. Monitoring results showed that pond/ditch sediments and plant-bed soil retained a significant amount of Cr, Ni, and Zn with 93.1%, 72.4%, and 57.5% samples showing contamination factor above limit 1 respectively. Remarkably the high values of metal enrichment factor (EF) occurred in root-channel zones. Water monitoring results indicated that Ni, Zn, and Pb were removed by 78.5% (66.7%), 57.6% (59.6%), and 26.0% (7.5%) in east (west) wetland respectively. Mass balance estimation revealed that heavy metal mass in the pond/ditch sediments accounted for 63.30% and that in plant-bed soil 36.67%, while plant uptake occupied only 0.03%. The heavy metal accretion flux in sediments was 0.41 - 211.08 MUg . cm(-2) . a(-1), less than that in plant-bed soil (0.73 - 543.94 MUg . cm(-2) . a(-1)). The 1.83 ha wetland has retained about 86.18 kg total heavy metals within 494 days after operation. This pilot case study proves that constructed root-channel wetland can reduce the potential ecological risk of purified raw water and provide a new and effective method for the removal of heavy metals from drinking water sources. PMID- 25032091 TI - Study protocol of the Going to Stay at Home program: evaluation of a residential carer training program to reduce dementia carer distress and burden. AB - BACKGROUND: Caring for a person with dementia has profound physical, psychological, social and financial impacts on the carer, while morbidity in carers has detrimental effects on outcomes in people with dementia. A 10-day hospital-based residential carer training program (BMJ 299(6712):1375-1379, 1989) delayed residential care placement, delayed mortality, reduced carer's psychological morbidity and lowered care costs. This study aims to evaluate the effects of a similar program adapted for use with residential respite. METHODS/DESIGN: This is a single-arm longitudinal study conducted at a residential aged care facility involving 100 people with dementia and their primary carers. In a 7-day residential program, carers will attend intensive training sessions while the people with dementia are engaged in daily activities. Data will be collected at the start of the residential program (baseline), at 6 months (post 1) and at 12 months (post 2) after completion of the program. The primary outcome is carer psychological distress. Secondary outcomes include carer burden, carer quality of life and time to residential care placement. DISCUSSION: This study will provide evidence on the effectiveness of the program in reducing carer distress and burden as well as delaying institutionalisation of the person with dementia, which may have important implications for policy. PMID- 25032092 TI - Age group performances in 100 km and 100 miles ultra-marathons. AB - Improved performance has been reported for master runners (i.e. athletes older than 40 years) in both single marathons and single ultra-marathons. This study investigated performance trends of age group ultra-marathoners competing in all 100 km and 100 miles races held worldwide between 1971 and 2013. Changes in running speeds across years were investigated for the annual ten fastest 5-year age group finishers using linear, non-linear and multi-level regression analyses. In 100 km, running speed remained unchanged in women in 25-29 years, increased non-linearly in 30-34 to 55-59 years, and linearly in 60-64 years. In men, running speed increased non-linearly in 18-24 to 60-64 years and linearly in 65 69 to 75-79 years. In 100 miles, running speed increased in women linearly in 25 29 and 30-34 years, non-linearly in 35-39 to 45-49 years, and linearly in 50-54 and 55-59 years. For men, running speed increased linearly in 18-24 years, non linearly in 25-29 to 45-49 years, and linearly in 50-54 to 65-69 years. Overall, the faster race times over the last 30 years are a result of all top ten finishers getting faster. These findings suggest that athletes in younger to middle age groups (i.e. 25-35 to 50-65 years depending upon sex and distance) have reached their limits due to a non-linear increase in running speed whereas runners in very young (i.e. younger than 25-35 years) and older age groups (i.e. older than 50-65 years) depending upon sex and distance might still improve their performance due to a linear increase in running speed. PMID- 25032093 TI - Prospective comparison of one year follow-up outcomes for the open complete intrafascial retropubic versus interfascial nerve-sparing radical prostatectomy. AB - Current work provides a prospective direct comparison between Open complete intrafascial-radical-prostatectomy (OIF-RP) and interfascial-RP in all outcomes in single centre series. Both techniques were done prospectively in 430 patients. Inclusion criteria for OIF-RP (n=241 patients) were biopsy Gleason-score <=6 and PSA <=10 ng/ml while for interfascial-RP (n=189) were Gleason-score <=7 and PSA <=15. The perioperative parameters (e.g. operative time, complications etc.), pathologic results, surgical margins and revisions were reviewed. Pre- and postoperative (3 and 12 months) evaluation of continence and potency was performed. All patients have preoperative IIEF-score of >=15. Continence was classified as complete (no pads), mild (1-2 pads/day) and incontinence (>2 pads/day). Median patients' age was 63.7 vs. 64.5 years for OIF-RP vs. Interfascial-RP, respectively. Preoperative PSA-level was significantly lower in OIF-RP (5.8 vs. 7.1), otherwise, similar perioperative data in both groups except for more frequent pT3-tumors in interfascial-RP group (18%). No statistical significance regarding continence was observed between OIF-RP vs. Interfascial-RP groups at 3 (82% vs. 85%) and 12 months (98% vs. 96%) postoperatively. Potency rates (IIEF >=15) after OIF-RP were 96% (<=55 years), 72% (55-65), and 75% (>65 years) at 12 months. The respective rates for interfascial-group were 58%, 61% and 51%. There was an advantage for OIF-RP potency-outcomes without significance over Interfascial-RP in weak potency patients (IIEF=15-18). We conclude that OIF RP is associated with better functional results without compromising early oncological results compared to interfascial-RP. Complete preservation of periprostatic fasciae provides significantly better postoperative recovery of sexual function even for weak potency patients. Longer follow-up is mandatory to further evaluate the outcome results of this technique. PMID- 25032094 TI - Organ assessment and repair centers: The future of transplantation is near. AB - Solid organ transplantation is limited by suitable donor organ availability and the geographic limitations that lead to prolonged ischemic times. Ex vivo organ perfusion is an evolving technology that enables assessment of organ function prior to transplantation. As a byproduct, overall out of body organ times are able to be extended. The future implications organ assessment and repair centers utilizing this technology are discussed. PMID- 25032095 TI - Selecting suitable solid organ transplant donors: Reducing the risk of donor transmitted infections. AB - Selection of the appropriate donor is essential to a successful allograft recipient outcome for solid organ transplantation. Multiple infectious diseases have been transmitted from the donor to the recipient via transplantation. Donor transmitted infections cause increased morbidity and mortality to the recipient. In recent years, a series of high-profile transmissions of infections have occurred in organ recipients prompting increased attention on the process of improving the selection of an appropriate donor that balances the shortage of needed allografts with an approach that mitigates the risk of donor-transmitted infection to the recipient. Important advances focused on improving donor screening diagnostics, using previously excluded high-risk donors, and individualizing the selection of allografts to recipients based on their prior infection history are serving to increase the donor pool and improve outcomes after transplant. This article serves to review the relevant literature surrounding this topic and to provide a suggested approach to the selection of an appropriate solid organ transplant donor. PMID- 25032096 TI - Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies. AB - Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus. PMID- 25032097 TI - Pre-and-post transplant considerations in patients with nonalcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression. PMID- 25032098 TI - Coronary microvasculopathy in heart transplantation: Consequences and therapeutic implications. AB - Despite the progress made in the prevention and treatment of rejection of the transplanted heart, cardiac allograft vasculopathy (CAV) remains the main cause of death in late survival transplanted patients. CAV consists of a progressive diffuse intimal hyperplasia and the proliferation of vascular smooth muscle cells, ending in wall thickening of epicardial vessels, intramyocardial arteries (50-20 MUm), arterioles (20-10 MUm), and capillaries (< 10 MUm). The etiology of CAV remains unclear; both immunologic and non-immunologic mechanisms contribute to endothelial damage with a sustained inflammatory response. The immunological factors involved are Human Leukocyte Antigen compatibility between donor and recipient, alloreactive T cells and the humoral immune system. The non immunological factors are older donor age, ischemia-reperfusion time, hyperlipidemia and CMV infections. Diagnostic techniques that are able to assess microvascular function are lacking. Intravascular ultrasound and fractional flow reserve, when performed during coronary angiography, are able to detect epicardial coronary artery disease but are not sensitive enough to assess microvascular changes. Some authors have proposed an index of microcirculatory resistance during maximal hyperemia, which is calculated by dividing pressure by flow (distal pressure multiplied by the hyperemic mean transit time). Non invasive methods to assess coronary physiology are stress echocardiography, coronary flow reserve by transthoracic Doppler echocardiography, single photon emission computed tomography, and perfusion cardiac magnetic resonance. In this review, we intend to analyze the mechanisms, consequences and therapeutic implications of microvascular dysfunction, including an extended citation of relevant literature data. PMID- 25032099 TI - Transplant options for patients with type 2 diabetes and chronic kidney disease. AB - Chronic kidney disease (CKD) has become a real epidemic around the world, mainly due to ageing and diabetic nephropathy. Although diabetic nephropathy due to type 1 diabetes mellitus (T1DM) has been studied more extensively, the vast majority of the diabetic CKD patients suffer from type 2 diabetes mellitus (T2DM). Renal transplantation has been established as a first line treatment for diabetic nephropathy unless there are major contraindications and provides not only a better quality of life, but also a significant survival advantage over dialysis. However, T2DM patients are less likely to be referred for renal transplantation as they are usually older, obese and present significant comorbidities. As pre emptive renal transplantation presents a clear survival advantage over dialysis, all T2DM patients with CKD should be referred for early evaluation by a transplant center. The transplant center should have enough time in order to examine their eligibility focusing on special issues related with diabetic nephropathy and explore the best options for each patient. Living donor kidney transplantation should always be considered as the first line treatment. Otherwise, the patient should be listed for deceased donor kidney transplantation. Recent progress in transplantation medicine has improved the "transplant menu" for T2DM patients with diabetic nephropathy and there is an ongoing discussion about the place of simultaneous pancreas kidney (SPK) transplantation in well selected patients. The initial hesitations about the different pathophysiology of T2DM have been forgotten due to the almost similar short- and long-term results with T1DM patients. However, there is still a long way and a lot of ethical and logistical issues before establishing SPK transplantation as an ordinary treatment for T2DM patients. In addition recent advances in bariatric surgery may offer new options for severely obese T2DM patients with CKD. Nevertheless, the existing data for T2DM patients with advanced CKD are rather scarce and bariatric surgery should not be considered as a cure for diabetic nephropathy, but only as a bridge for renal transplantation. PMID- 25032100 TI - Human amniotic membrane transplantation: Different modalities of its use in ophthalmology. AB - The amniotic membrane (AM) is the inner layer of the fetal membranes and consist of 3 different layers: the epithelium, basement membrane and stroma which further consists of three contiguous but distinct layers: the inner compact layer, middle fibroblast layer and the outermost spongy layer. The AM has been shown to have anti-inflammatory, anti-fibrotic, anti-angiogenic as well as anti-microbial properties. Also because of its transparent structure, lack of immunogenicity and the ability to provide an excellent substrate for growth, migration and adhesion of epithelial corneal and conjunctival cells, it is being used increasingly for ocular surface reconstruction in a variety of ocular pathologies including corneal disorders associated with limbal stem cell deficiency, surgeries for conjunctival reconstruction, as a carrier for ex vivo expansion of limbal epithelial cells, glaucoma surgeries and sceral melts and perforations. However indiscriminate use of human AM needs to be discouraged as complications though infrequent can occur. These include risk of transmission of bacterial, viral or fungal infections to the recipient if the donors are not adequately screened for communicable diseases, if the membrane is not processed under sterile conditions or if storage is improper. Optimal outcomes can be achieved only with meticulous case selection. This review explores the ever expanding ophthalmological indications for the use of human AM. PMID- 25032101 TI - Multiple indications for everolimus after liver transplantation in current clinical practice. AB - AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice. METHODS: From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy four patients (7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation and post-conversion survival were analyzed. RESULTS: Mean age at the time of conversion to everolimus was 57.7 +/- 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo (range: 0.10-192). Mean follow-up post-conversion was 22 +/- 19 mo (range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients. CONCLUSION: Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation. PMID- 25032102 TI - Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients. AB - AIM: To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen. METHODS: This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-beta (TGF-beta), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages. RESULTS: A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-alpha, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-beta [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-beta1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-beta1, P = 0.009; HA: P = 0.01), according to time since LT (> than 5 years, TFG-beta1: P = 0.001; HA: P = 0.002), related to previous history of biliary complications (HA: P = 0.01) and HCV recurrence (HA: P = 0.004). Liver transplant recipients with everolimus monotherapy had less serum expression of TGF-beta y HA than matched patients with anti-calcineurins. This difference remains when classifying patients according to donor age and time since LT. Due to the small sample size, when examining patients with a prior history of biliary complications or recurrent HCV, the difference was non-significant but trends towards the lower expression of TFG-beta1 in the everolimus group. Mammalian target of rapamycin (mTOR) plays a role in the transformation of quiescent hepatocellular stellate cell to their active profibrotic state, and experimental models have demonstrated the potential activity of mTOR inhibition in attenuating fibrogenesis. CONCLUSION: This study supports a possible role of everolimus in liver fibrosis modulation after LT in a clinical setting and suggests that tailoring immunosuppression could avoid fibrosis progression in the allograft. PMID- 25032103 TI - Impact of transplant nephrectomy on peak PRA levels and outcome after kidney re transplantation. AB - AIM: To determine the impact of transplant nephrectomy on peak panel reactive antibody (PRA) levels, patient and graft survival in kidney re-transplants. METHODS: From 1969 to 2006, a total of 609 kidney re-transplantations were performed at the University of Freiburg and the Campus Benjamin Franklin of the University of Berlin. Patients with PRA levels above (5%) before first kidney transplantation were excluded from further analysis (n = 304). Patients with graft nephrectomy (n = 245, NE+) were retrospectively compared to 60 kidney re transplants without prior graft nephrectomy (NE-). RESULTS: Peak PRA levels between the first and the second transplantation were higher in patients undergoing graft nephrectomy (P = 0.098), whereas the last PRA levels before the second kidney transplantation did not differ between the groups. Age adjusted survival for the second kidney graft, censored for death with functioning graft, were comparable in both groups. Waiting time between first and second transplantation did not influence the graft survival significantly in the group that underwent nephrectomy. In contrast, patients without nephrectomy experienced better graft survival rates when re-transplantation was performed within one year after graft loss (P = 0.033). Age adjusted patient survival rates at 1 and 5 years were 94.1% and 86.3% vs 83.1% and 75.4% group NE+ and NE-, respectively (P < 0.01). CONCLUSION: Transplant nephrectomy leads to a temporary increase in PRA levels that normalize before kidney re-transplantation. In patients without nephrectomy of a non-viable kidney graft timing of re-transplantation significantly influences graft survival after a second transplantation. Most importantly, transplant nephrectomy is associated with a significantly longer patient survival. PMID- 25032104 TI - Intra-abdominal desmoid tumor after liver transplantation: A case report. AB - We are reporting the first documented case of an abdominal desmoid tumor presenting primarily after liver transplantation. This tumor, well described in the literature as occurring both in conjunction with familial adenomatous polyposis as well as in the post-surgical patient, has never been noted after solid organ transplantation and was therefore not included in our differential upon presentation. Definitive diagnosis required the patient to undergo surgical excision and immunochemical staining of the mass for confirmation. A review of the literature showed no primary tumors after transplantation. In a population of patients who received a small bowel transplant after they developed short gut post radical resection of aggressive fibromatosis, only rare recurrences were seen. No connection of tumor development with immunosuppression or need to decrease immunosuppressant treatment has been demonstrated in these patients. Our case and the literature show the risk of this tumor presenting in the post transplantation patient and the need for a high index of suspicion in patients who present with a complex mass after transplantation to prevent progression of the disease beyond a resectable lesion. Results of a thorough search of the literature are detailed and the medical and surgical management of both resectable and unresectable lesions is reviewed. PMID- 25032105 TI - Diagnosis and management of laryngo-pharyngeal reflux. AB - The aim of the present paper was to analyze laryngo-pharyngeal reflux (LPR) manifestations in ENT patients, and present a diagnostic and treatment algorithm for appropriate management. Retrospective chart review of 150 patients, who had initially presented with symptoms suggestive of LPR. Treatment included the administration of omeprazole 20 mg twice daily for at least 4 weeks. Unresponsive patients were also given metoclopramide 10 mg twice daily for four additional weeks, and the dose of omeprazole was increased to 40 mg twice daily, if they did not achieve complete symptom resolution. Only patients who became completely asymptomatic after LPR treatment were included in the study. As many as 18 % of patients attending an ENT outpatient department benefited from anti-reflux treatment. A need to clear the throat represented the most common symptom, whereas interarytenoid oedema/congestion was the most common finding on flexible naso-endoscopy (62.67 and 72.7 % of patients, respectively). The vast majority of patients responded after 4 weeks of treatment with omeprazole, however, as many as 32 % of LPR patients achieved complete symptom control after the initial 4 week trial period. LPR seems to be more common than previously reported in the literature. Appropriate management of LPR can prevent the symptomatic use of various medical treatments for related manifestations, and even surgical interventions, thus decreasing the overall patient morbidity. PMID- 25032106 TI - Evaluation of the validity of high serum antistreptolysin o titre only, as an indication for tonsillectomy. AB - Serum Antistreptolysin O (ASO) titre is raised when there is infection of any organ of the body, by Group A beta haemolytic streptococci (GABHS), Group C or Group G streptococci [1]. Increased serum ASO titre should not be the only deciding criterion for tonsillectomy if GABHS is not present in the palatine tonsils. In this study, we evaluate the rationality of performing tonsillectomy in raised serum ASO titre only, in absence of GABHS in palatine tonsil. The study was designed as a prospective cohort study in which the main out come measure is to find out: The main outcome measure is to find out whether only the raised serum ASO titre is to be considered to perform tonsillectomy or not. Fifty consecutive patients (both children and adults) clinically diagnosed to have chronic tonsillitis were included in this prospective cohort study. Throat swab culture, tonsilar core tissue culture and Serum ASO titre tests were performed in all the patients. The results showed that out of the 50 patients 45 had raised ASO titre and 5 patients had normal ASO titre. GABHS was found in 5 cases (10 %) in throat swab culture and 8 cases (16 %) in FNA of tonsil core culture. The sensitivity of throat swab culture as compared to FNA Tonsil core culture was 62.5 % and positive predictive value was 100 %. The sensitivity of ASO titre as compared to core culture was 100 % and positive predictive value was 17.8 %. Specificity was only 12 %. From the results of this study, it is evident that FNA culture of the tonsil core is a valid and a reliable test for the diagnosis of bacterial micro flora in recurrent tonsillitis. One should perform throat swab culture and FNA culture from tonsil core along with ASO titre before doing tonsillectomy in absence of any other indications. Identifying GABHS in the tonsil by FNA test and/or in the throat swab culture along with high serum ASO titre may be one of the ideal indications for tonsillectomy. PMID- 25032107 TI - The correlation between clinical prediagnosis and pathology results in the diagnosis of neck masses. AB - The importance of clinical assessment and its contribution to the diagnosis of neck masses was investigated in patients presenting with a neck mass. In our study, we collected the medical history of a total of 127 patients, including 66 males and 61 females, who presented with a neck mass. Physical exams, endoscopic examinations, laboratory tests, a variety of imaging studies, and fine-needle aspiration biopsies were performed. The relationship between age, duration and location of the neck mass, FNAB results, and definitive histopathological diagnosis were investigated as well as the correlation between the consensus diagnosis reached after the evaluation of the medical history, physical examination and imaging studies, and definitive histopathological diagnosis. A strong and positive relationship (p < 0.01) was found between patients' ages and the definitive diagnosis established by histopathological examination. There was no statistically significant relationship (p > 0.05) between the duration and location of the neck mass and definitive diagnosis established by histopathological examination. And no statistically significant relationship (p > 0.05) was found between FNAB results and definitive histopathological diagnosis. Although no statistically significant relationship was found between the characteristics of neck masses and age, duration and location of masses and FNAB results, there was a statistically significant correlation between the pre diagnosis estimated by ENT specialists and definitive diagnosis established by histopathological examination. A strong and positive relationship (p < 0.01) was found between clinical pre-diagnosis and definitive diagnosis established by histopathological examination. In patients presenting with a neck mass, the diagnosis should be made based on the medical history, physical examination, radiologic imaging and FNAB results, treatment decisions should be based on those findings. PMID- 25032108 TI - Esthesioneuroblastoma: Good Local Control of Disease by Endoscopic and Endoscope Assisted Approach. Is it Possible? AB - To present a short report on nine patients of esthesioneuroblastoma, managed endoscopically or endoscope assisted. To describe the technique and discuss the results at an average of 36.7 months of follow up. A retrospective study in a tertiary care centre. The present communication describes a series of 9 cases harbouring esthesioneuroblastoma, 6 managed endoscopically and 3 endoscope assisted between January 2005 and December 2009. All the nine patients remained free of disease at the primary site by endoscopic and radiological evaluation on an average of 36.7 months of follow up. One of the patients developed cutaneous and systemic metastasis for which she received chemotherapy and another one died during post-operative period due to unrelated causes. None of the patients showed recurrence or residual disease locally. Endoscopic and endoscope assisted approach provides a cosmetically better and surgically comparable outcome for local control of disease in early stages of esthesioneuroblastoma in expert hands without significant complications. PMID- 25032109 TI - Efficacy of the modified endoscopic frontal sinus surgery for recurrent chronic frontal sinusitis. AB - To modify the endoscopic frontal sinus surgery and improve the therapeutic effect of recurrent chronic frontal sinusitis (RCFS). Eighty-five patients with RCFS were divided into two groups. Endoscopic frontal sinus surgery through an approach of Frontomaxillary Process-Agger Nasi, a modified Draf IIb procedure, was carried out in 51 patients (Group A), and conservative medication was applied in 34 patients as control (Group B). The therapeutic effect was prospectively evaluated with statistically validated measures of sinusitis-specific quality of life, sino-nasal outcome test-20 questionnaire (SNOT-20). Compared with pre treatment, the average total score of SNOT-20 in RCFS patients was significantly decreased at the time of 6, 12 months after modified endoscopic frontal sinus surgery and medical treatments (p < 0.05). However, the total score of SNOT20 was significantly lower in group A than group B at the same period of the follow-up after treatments (p < 0.05). The overall efficacy evaluated by patients' self showed that the rate of "much improved" and "improved" was respectively 68.6 and 17.6 % in group A, and significantly better than group B (p < 0.001). Furthermore, the frontal sinus patency rate in group A was 85 %, and significantly higher than group B (p < 0.001). Endoscopic frontal sinus surgery through an approach of Frontomaxillary Process-Agger Nasi, a modified Draf IIb procedure, is an effective procedure to treat the RCFS. PMID- 25032110 TI - Assessment of knowledge of harmful effects and exposure to recreational music in college students of delhi: a cross sectional exploratory study. AB - Exposure to loud sounds results in a mild to profound degree of temporary or permanent hearing loss. Though occupational noise exposure remains the most commonly identified cause of noise-induced hearing loss, potentially hazardous noise can be encountered during recreational activities. Unfortunately not much attention is being given to the increasing trend of prolonged exposure to noisy environment, in the younger generation of Indians. The purpose of our study was to know the knowledge of college students about the harmful effects of loud music, prevailing practices with regard to exposure to recreational music and the subjective effects that this exposure is causing if any. Cross Sectional survey of College Students (n = 940), from randomly selected colleges of Delhi University. Majority of students listened to music using music-enabled phones; earphones were preferred and 56.6 % participants listened to music on a loud volume. Effects experienced due to loud sound were headache (58 %), inability to concentrate (48 %), and ringing sensation in the ear (41.8 %). Only 2.7 % respondents used ear protection device in loud volume settings. Twenty-three percent respondents complained of transient decreased hearing and other effects after exposure to loud music. 83.8 % knew that loud sound has harmful effect on hearing but still only 2.7 % used protection device. The survey indicates that we need to generate more such epidemiological data and follow up studies on the high risk group; so as to be able to convincingly sensitize the Indian young generation to take care of their hearing and the policy makers to have more information and education campaigns for this preventable cause of deafness. PMID- 25032111 TI - Sinonasal anatomical variations: their relationship with chronic rhinosinusitis and effect on the severity of disease-a computerized tomography assisted anatomical and clinical study. AB - ABSTRACT: The anatomy of the sinonasal area has a very wide rage of anatomical variations. The significance of these anatomical variations in pathogenesis of rhinosinusitis, which is the commonest disease in the region, is still unclear. The aims of the study were to compare the rate of sinonasal anatomical variations with development and severity of chronic rhinosinusitis patients. CT scan of paranasal sinuses images of 99 individuals were retrospectively reviewed. 65 cases of chronic rhinosinusitis (study group) who had undergone endoscopic sinus surgery were compared with 34 cases without chronic rhinosinusitis (control group). Also in study group Lund-Mackay score of the sinus disease were calculated and compared to the rate of related anatomical variations. There were 74 (74.7 %) males and 25 (25.2 %) females with ages ranging from 13 to 70 years (mean 32.2 years). The anatomical variations recorded were: Septal deviation 47 (72.3) in study and 25 (73.5 %) in control group, concha bullosa 27 (41.5 %) in study and 18 (52.9 %) in control group, overpneumatized ethmoid bulla 17 (26.1 %) in study and 14 (41.1 %) in control group, pneumatized uncinate 3 (4.6 %) in study and 3 (8.8 %) in control group, agger nasi 42 (64.6 %) in study and 19 (55.8 %) in control group, paradoxical middle turbinates 9 (13.8 %) in study and 4 (11.7 %) in control group, Onodi cell 6 (9.2 %) in study and 2 (5.8 %) in control group, Haller's cells (infraorbital ethmoid cell) 9 (13.8 %) in study and 7 (20.5 %) in control group. None of these results were statistically significant between study and control group (p > 0.05). Lund-Mackay score (which was assumed to show the severity of the disease) of the maxillary, ethmoid and frontal sinus were calculated and compared to rate of septal deviation, concha bullosa, agger nasi cells. No significant correlation was conducted (p > 0.05). The results of study showed no statistically significant correlation between sinonasal anatomical variations and pathologies of the paranasal sinus. Also these anatomical variations did not increase the severity of pre-existing sinusitis significantly. LEVEL OF EVIDENCE: This is a retrospective cohort study (2b). PMID- 25032112 TI - Clinical effect analysis of microscopic surgery for epiglottis cysts with coblation. AB - This study aims to explore the effects and advantages of coblation combined with microscopy to treat epiglottis cysts. Ninety patients with epiglottis cysts were randomly assigned to three groups: the first group: marsupialisation + electric coagulation group, n = 30; the second group: marsupialisation + coblation, n = 30; and the third group: marsupialisation + coblation + microsurgery, n = 30. To compare the cure rate, intraoperative bleeding volume, postoperative pain, operation time and postoperative complications were investigated among these three groups. The comparison among three procedures showed a significant difference for intraoperative bleeding volume, operation time and postoperative pain (P < 0.05), whereas no significant difference was observed for cure rate (P > 0.05). These three procedures are effective in treating epiglottis cysts. Microscopic surgery with coblation has the advantages of less bleeding, short procedure duration, less pain and few complications. Thus, microscopic surgery is worthy of clinical application. PMID- 25032113 TI - Choanal Atresia: Surgical Management by Hegar's Dilators. AB - Choanal atresia is one of the more commonly observed congenital abnormalities of the nose. The condition is predominantly found in females with a M:F ratio of 1:2. 65-75 % of patients with choanal atresia are unilateral, and the rest are bilateral. About 50 % of the cases are associated with other congenital anomalies, the most common being coloboma, Heart disease, choanal atresia, mental and growth retardation, genital hypoplasia, ear deformities syndrome. The embryonic origin of choanal atresia is due to persistent bucco-pharyngeal or naso buccal membrane. Our study was a retrospective study of 14 cases of choanal atresia. All the cases were operated by the first author. Each patient was investigated in detail and recorded by stratifying in sex of patient, age of presentation, type and site of atresia, and associated other congenital anomalies. Patient were operated under general anesthesia and Hegar's dilators were used to perforate the atretic plate as Hegar's dilators are believed to have ideal curvature with respect to the sloping contour of the nasal floor. Out of the total 14 cases, 9 (64 %, n = 14) cases were male and 5 (36 %, n = 14) females. The age variations varied from youngest of 3 days to the oldest 31 year old female. Stents were kept for a period of 6-8 weeks and regular follow up nasal endoscopy was done weekly for suctioning and visualizing the size of the airway. There are five different surgical approaches that have been described for surgical treatment of choanal atresia: (1) trans-nasal, (2) trans-palatal, (3) trans-septal, (4) trans-antral and (5) sublabial-transnasal. In our study M:F ratio was 1.8:1 which is comparable Gosepath et al. (Rhinology 45:158-163, 2007) (2:1). In our study bilateral atresia was seen in 43 % (6, n = 14) and unilateral in 57 % (8, n = 14) which is comparable to Newman et al. (44 % bilateral cases, n = 43). Amicable and prompt referral to the ENT surgeon can be of immense value so as to buy adequate time for the surgeon to decide and act as per the patient's clinical and radiological findings. Hegar's dilator is passed along the floor of the nose, pushed against the septum so as to avoid penetrating the basal sphenoid. PMID- 25032114 TI - Pediatric Endoscopic DCR: The Outcome in 50 Patients. AB - Congenital nasolacrimal duct obstruction is a very common condition affecting 20 % of infants. Pediatric DCR is indicated when there is no response to previous therapy like probing, or is associated with recurrent dacryocystitis. This is a retrospective case series study of 50 pediatric patients who underwent endoscopic DCR in two centers, Jordan University Hospital/Jordan, and Mosul teaching and private hospitals/Iraq. The age ranged from 3 to 12 years with a mean of 6.2 years. The overall success rate of endoscopic DCR was 90 %, and failed cases were mainly due to presaccal obstruction. No major complications were reported, but minor complications occurred in about 60 % of cases. As a conclusion, endoscopic DCR is a safe and effective procedure in pediatric age group. PMID- 25032115 TI - Comparison of submucosal resection and radiofrequency turbinate volume reduction for inferior turbinate hypertrophy: evaluation by magnetic resonance imaging. AB - Inferior turbinate hypertrophy is a frequent cause of nasal airway obstruction and drastically impairs patients' quality of life. Surgical reduction of the inferior turbinates can be used for patients who did not respond to medical therapy. A number of studies have been performed to identify the most effective technique. The aim of this study was to compare the effectiveness of submucosal resection (SMR) and radiofrequency turbinate volume reduction (RFTVR) in patients with inferior turbinate hypertrophy. A prospective, randomized case-control study was conducted. Sixty patients with inferior turbinate hypertrophy refractory to medical therapy were prospectively and randomly assigned to two groups: SMR and RFTVR. A visual analog scale (VAS) and the nasal inspiratory peak flow (NPIF) were analyzed pre- and postoperatively at the first week and second month. Magnetic resonance imaging was performed pre- and postoperatively at the second month. The surgical outcomes were compared statistically using subjective and objective measures. Significant turbinate volume reduction was achieved in both the SMR and RFTVR groups. However, turbinate volume reduction was significantly greater in the SMR than in the RFTVR group at the second month postoperatively. NIPF and VAS scores were improved after both procedures at the second month postoperatively. Beside this, surgical outcomes were significantly better after SMR in terms of NIPF and VAS scores. In this study, we demonstrated that both SMR and RFTVR are effective for inferior turbinate hypertrophy. Turbinate volume reduction, improvement of subjective nasal obstruction symptoms, and NIPF after SMR were significantly superior to those after RFTVR. PMID- 25032116 TI - Endoscopic endonasal transsphenoidal hypophysectomy: two hand versus four hand technique: our experience. AB - An endoscope was used in transsphenoidal surgery and eventually replaced the operating microscope as a tool for visualization. Initially patients underwent operation via a sublabial transseptal approach using a rigid endoscope in conjunction with an operating microscope. The subsequent operations were performed through a nostril using only rigid endoscopes, initially through single nostril by one surgeon (two hands) and later through both nostrils by two surgeons (four surgeons). This is a retrospective study of 96 patients who had pituitary adenomas in last ten years. Postoperatively all patients who had undergone endonasal endoscopic surgery had unobstructed nasal airways with minimal discomfort. More than half of the patients required only an overnight hospitalization. PMID- 25032117 TI - Cartilage support for fascia graft in type I tympanoplasty. AB - To evaluate the success rate, in terms of anatomical and functional results, in our technique of cartilage support for fascia graft in type I tympanoplasty. Retrospective study of tragal cartilage support for fascia graft in tympanoplasty for large central perforation in 748 patients was carried at an academic institution during January 2004 to March 2012. Patients' age ranged from 11 to 65 years. 325 (43.4 %) male and 423 (56.6 %) female patients were operated and mean post-operative follow up was of 24 months (range 6-48 months). The inclusion criteria were large central or subtotal perforation, anterior quadrant perforation, anterior tympanosclerotic patch with perforation and revision myringoplasty. Small central perforation, posterior perforations, traumatic perforations and Ossiculplasty were excluded from this study. In this technique, a piece of tragal cartilage carved in semi lunar shape is inserted medial to anterior remnant of tympanic membrane. Temporalis fascia graft is sandwiched between cartilage and anterior remnant of tympanic membrane. Post-operative closure of perforation was noted. Pure-tone average pre and post-operative air bone gap in dB at 250, 500, 1000, 2000, and 4,000 Hz were compared. The overall success rate of our technique was 98.3 % in terms of graft uptake and within 13.35 +/- 5.22 dB of air bone gap closure in terms of hearing improvement. This study reveals that cartilage support for fascia graft in type I tympanoplasty is a highly reliable technique and gives significant improvement in graft take-up and hearing status. PMID- 25032118 TI - Exclusion of TNFRSF11B as Candidate Gene for Otosclerosis in Campania Population. AB - The etiology of otosclerosis is unknown. The etiopathogenesis of otosclerosis seems similar to that occurring in Paget's disease of bone, for which mutations or polymorphisms in several genes have been identified. Among these, TNFRSF11B gene encoding the osteoprotegerin is produced at high levels in the normal inner ear and at low level in active otosclerotic stapes footplates. The aim of this work was to verify the presence of a correlation between the rs2073618 (N3K) polymorphism in the TNFRSF11B gene and otosclerosis. Mutational screening in the TNFRSF11B gene was performed by direct sequencing. SNPs analysis was performed by PCR and by specific restriction enzyme assay with HpaI. The significance of the association was analyzed by statistical specific software. No causative mutation has been identified but the data suggested a strong correlation between the rs2073618 (N3K) polymorphism and otosclerosis. This correlation, however, has been excluded in a case-control study. This study excluded the association between the N3K polymorphism and otosclerosis in Campania region population. PMID- 25032119 TI - Urinary neopterin levels in patients with thyroid cancer. AB - Increased urinary neopterin concentrations have been described in many cancers. We aimed to evaluate the urinary neopterin levels in thyroid cancer. Sixty-nine patients with thyroid cancer, 76 patients with benign thyroid pathology and 33 healthy subjects were evaluated. First morning urine samples were collected from the patients and normal subjects for neopterin and creatinine measurement and stored at -80 degrees C until analysed. Neopterin levels were 149.3 (15.2 1,602.2) MUmol/mol creatinine in the malignant group, 32 (5.2-275.6) MUmol/mol creatinine in the benign group and 9.2 (2.7-78.7) MUmol/mol creatinine in normal subjects (p <= 0.001). Urinary neopterin levels were significantly higher in patients with thyroid cancer than patients with benign thyroid pathologies and normal subjects. Also the patients with benign thyroid pathologies had a higher urinary neopterin level than the normal subjects. Malignant group was divided to two groups; patients with/without chronic thyroiditis (confirmed histologically). There were 22 (31.9 %) patients with and 47 (68.1 %) patients without chronic thyroiditis. Urinary levels of neopterin didn't differ in both groups (168.6 (21.3-716.8) MUmol/mol creatinine and 135.3 (15.2-1,602.2) MUmol/mol creatinine respectively; p = 0.381). Urinary neopterin levels are high in thyroid cancer patients independently from the presence of chronic thyroiditis. PMID- 25032120 TI - Cartilage palisades in type 3 tympanoplasty: functional and hearing results. AB - To evaluate the functional and hearing outcomes using full thickness broad cartilage palisades for tympanic membrane reconstruction in type 3 tympanoplasty with titanium prostheses. The retrospective study performed at a tertiary referral institute included 30 patients with posterior mesotympanic retraction pockets or tympanic membrane perforations requiring tympanic membrane and type 3 ossicular reconstruction. Patients with disease extending beyond the aditus requiring canal wall down mastoidectomy were excluded. Disease removal from posterior mesotympanic and epitympanic recesses was confirmed using angled endoscopy and ossicular reconstruction was performed using titanium partial or total ossicular replacement prostheses. Tympanic membrane reconstruction was done, with or without attic reconstruction, using full thickness broad cartilage palisades harvested from the tragus with perichondrium attached laterally. Patients were assessed at 24 and 48 weeks for graft status and any evidence of implant extrusion. Hearing evaluation was done using subjective assessment and pure tone audiometry. In total, 27 out of 30 patients had intact and completely healed grafts at 48 weeks postoperatively (a success rate of 90 %) showing full union and epithelialization of palisades, and with three patients displaying small defects. The mean pure tone air bone gap pre- and postoperatively was 32.4 and 8.8 dB, respectively, with most patients reporting satisfactory postoperative hearing. No evidence of implant extrusion was found in the 48-week period. Tympanic membrane reconstruction using full thickness palisades of tragal cartilage provides good functional and hearing outcomes in type 3 tympanoplasty with titanium prostheses. PMID- 25032121 TI - The protective role of molsidomine on the Cisplatin-induced ototoxicity. AB - This experimental study was designed to investigate the protective effects of molsidomine (MOL) on against cisplatin-induced ototoxicity (CIO). To examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status [including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPX), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] were evaluated. Thirty-two female wistar albino rats were divided into four groups including; control (Group K), cisplatin (Group C), cisplatin plus MOL group (Group CM), and MOL group (Group M). DPOAEs measurements between 0.9961 and 8.0003 Hz as DP-gram and input/output (I/O) functions were performed in the same (left) ear of all rats on days 0, 1st, 5th and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. In the C group, statistically significant DPOAE amplitude reductions were detected at 2.5195, 3.1758, 3.9961, 5.0391, 6.3516 and 8.0039 Hz frequencies (p < 0.05) between 0th and 1st, 0th and 5th and 0th and 12th days' measurements (p < 0.05). Serum level of MDA, TAC and OSI levels were significantly higher in the C group versus K group (p < 0.05). In the CM group, there were no significant differences at all frequencies between 0th and other days' measurements (p > 0.05) and the serum levels of all biochemical parameters were shifted toward normal values, similar to the K group (p < 0.05). No significant differences were detected in the either M or K group's measurements. According to these results, cisplatin-related ototoxicity has been significantly prevented by MOL. PMID- 25032122 TI - Three-dimensional Anatomical Analysis of Surgical Landmarks for the Middle Cranial Fossa Approach. AB - This study describes the microsurgical anatomy of the middle cranial fossa approach using temporal bone three-dimensional (3D) computed tomography (CT) reconstruction, which should contribute to determining the drilling point for the internal auditory meatus (IAM) when bony landmarks are absent. Thirty temporal bone CT scans were reviewed retrospectively. We measured the shortest and longest distances to IAM from the petrous ridge, and measured the angle between the facial nerve and various labyrinth structures. Three-dimensional reconstructed images were obtained using high-resolution axial temporal bone CT (0.7-mm-thick slices, FOV 90 * 90, KVp 120, 305 mA, width 2,800, and level 800). The mean shortest and longest distances to IAM from the petrous ridge were 5.22 and 10.1 mm, respectively. The mean distance to the IAM from the cochlea was 9.91 mm. The mean angle between the IAM and superior semicircular canal was 47.21 degrees , which was more acute than previously reported. The mean angle between the IAM and geniculate ganglion (GG) and external auditory canal was 113.8 degrees , and the mean distance from the GG to the IAM was 15.44 mm. Understanding the 3D relationships among the microsurgical structures will help to decide the drilling point for the IAM when bony landmarks are absent. A preoperative evaluation might be useful for preserving important neurovascular structures while approaching the middle fossa. PMID- 25032123 TI - Distortion Product Otoacoustic Emission (DPOAE) as an Appropriate Tool in Assessment of Otoprotective Effects of Antioxidants in Noise-Induced Hearing Loss (NIHL). AB - Distortion product otoacoustic emission (DPOAE) appears to be an objective sensitive test of cochlear function. The aim of this study was to investigate whether DPOAE is an appropriate tool for assessment of minute changes in cochlea due to usage of antioxidant material. 48 workers exposed to continuous noise in a textile factory were randomly assigned into three groups: (1) The Control group (n = 16) received no antioxidant drugs, (2) The N-acetyl-cysteine (NAC) group (n = 16) received oral antioxidant NAC (1200 mg/day), (3) The Ginseng group (n = 16) received oral antioxidant Ginseng (200 mg/day). All three groups had a follow-up period of 2 weeks. The cochlear changes were assessed using DPOAE test before starting the daily work shift on first and 15th day. The associations between groups and DPOAE amplitudes after 2 weeks were analyzed using linear regression analysis. Four separate models were fitted by side of ears and frequency. All models were adjusted for baseline amplitude. Reduced (better) amplitude at DPOAE test was found for NAC and Ginseng groups at high frequencies (4 and 6 kHz) in both ears after 2 weeks compared to control group. Moreover, NAC group showed better DPOAE amplitude than Ginseng group. In conclusion, DPOAE seems to be an appropriate tool in assessing minute changes in the cochlea after antioxidant drugs administration. PMID- 25032124 TI - Endoscopic and computed tomographic evaluation of influence of nasal septal deviation on lateral wall of nose and its relation to sinus diseases. AB - To correlate symptoms of deviated nasal septum (DNS) and chronic rhinosinusitis with the findings of nasal endoscopy and computed tomographic (CT) imaging. To evaluate the influence of degree of septal angle deviation on the severity of lateral nasal wall abnormalities. A prospective study was conducted on 67 patients with clinical evidence of DNS and chronic sinusitis attending ENT OPD between January 2012 and September 2013. All these patients underwent nasal endoscopy and CT scan PNS coronal sections. Direction and degree of DNS was recorded. Range of sinus mucosal thickening on CT scan films was also recorded. Chronic sinusitis is common in the age group between 21 and 40 years (50.74 %) with male preponderance (55.22 %), chief symptoms being nasal obstruction (86.56 %), headache (73.13 %) and nasal discharge (52.23 %). Left sided DNS is more common (64.17 %). Most of the patients have moderate DNS, i.e. 6 degrees -10 degrees (56.7 %), followed by severe (22.4 %) and then mild (20.9 %). DNS results in compensatory structural changes in the turbinates and/or lateral nasal wall which causes ostiomeatal complex (OMC) obstruction resulting in sinusitis. Contralateral concha bullosa and ethmoid bulla prominence was noted. Maxillary sinus is most commonly affected sinus (73.13 %). Patients with increasing septal angles were associated with a higher incidence of maxillary sinus mucosal changes (p < 0.05). Present study reemphasized the concept that septal deviation causes obstruction at OMC which results in an increased incidence and severity of bilateral chronic sinus disease. PMID- 25032125 TI - What is the Role of Diffusion Weigh Magnetic Resonance Imaging in Evaluation of Thyroid Nodules? AB - This study aimed to compare ultrasonography (US), contrast-enhanced computed tomography (CCT) of the neck, and diffusion-weigh magnetic resonance imaging (DW MRI) in differentiating between benign and malignant nodules while approaching to thyroid nodules, and to estimate sensitivity and specificity of these methods. On thyroid US, echogenicity, calcification, presence/absence of halo, nodule size being larger/smaller than 20 mm, and nodule nature (cystic/solid nature) were evaluated. Findings on CCT of the neck were grouped according to the heterogeneity/homogeneity, presence/absence of enhancement, and intensity. On DW MRI, diffusion restriction was evaluated. The findings of these tests were compared with postoperative histopathological findings, and specificity and sensitivity of the tests in differentiating malignant and benign nodules were assessed. The study included 38 patients (34 females, 4 males). The sensitivity and specificity of DW-MRI were 20 and 75 %, respectively. Presence of a >20 mm nodule in thyroid US had the highest sensitivity, whereas thyroid fine-needle aspiration biopsy (FNAB) had the highest specificity in detecting malignancy. The sensitivities and specificities of CCT of the neck and DW-MRI appeared relatively low. Evaluation of thyroid US findings together with thyroid FNAB findings provided high specificity and sensitivity and yielded better results than findings of CCT of the neck and DW-MRI. PMID- 25032126 TI - Study of outcome of tympanoplasties in relation to size and site of tympanic membrane perforation. AB - There are not many studies on the effect of the site and size of the perforation on the hearing loss. This study is set to investigate the relationship between the size and site of perforation and hearing loss. This study was carried out between September 2011 to September 2013, at a tertiary care centre during which 100 cases of chronic otitis media tubotympanic type having central perforation were selected. All patients underwent, tympanoplasty using temporalis fascia/cartilage graft, underlay technique with or without simple mastoidectomy/modified radical mastoidectomy and followed up for 3 months and evaluated for graft uptake and hearing improvement with respect to size and site of TM perforation. To measure the size of perforation intra-operatively, thin transparency sheet was used, on which a graph paper of 1 * 1 mm(2) size was printed. Significant relationship was observed between size and site of tympanic membrane perforation with hearing loss. Perforations which were involving all four quadrants (AS + AI + PS + PI) are having maximum residual perforations after the surgery. In relation with size, subtotal perforation were having more residual perforations postoperatively, followed by medium sized perforations. An inherent relationship noted between ossicular involvement and hearing loss, maximum average hearing loss was observed in those cases, where all three ossicles (malleus, incus & stapes) were involved, also more hearing loss was noted in posterior perforations. PMID- 25032127 TI - The effect of alprazolam on acoustic stapedius reflex thresholds in healthy volunteers. AB - Alprazolam, a widely used drug, has widespread, nonspecific depressant effects on the central nervous system, similar to other benzodiazepines. This inhibitor effect may cause changes in reflex thresholds by affecting the acoustic stapedial reflex (ASR) arc. This study was performed on 31 healthy volunteers. Initially, the basal ASR thresholds were measured and measured again 2 h after oral intake of 1 mg of alprazolam; by measuring the reflex thresholds once again the mean values of thresholds before and after the drug were compared. Only the left ipsilateral and contralateral 2,000 Hz increases were significantly different. The left ipsilateral and contralateral 500, 1000, and 4000 Hz, and the right ipsilateral and contralateral 500, 1000, 2000, and 4000 Hz measurements showed no differences. Although an increase in ART thresholds was generally observed after the intake of alprazolam, it was not significant. Its use in healthy adults does not statistically produce an additional risk of acoustic trauma at most of the frequencies, but its use with the agents potentiating the effect of alprazolam may increase this risk. PMID- 25032128 TI - New challenges in dietary pattern analysis: combined dietary patterns and calorie adjusted factor analysis in type 2 diabetic patients. AB - BACKGROUND: Some variability for dietary pattern analysis due to subjective procedures (e.g. arbitrary food categorization and number of factors extraction) was reported. The aim of this study was to present or design a new approach to challenge the conventional dietary pattern analysis through new classification of dietary patterns according to the possibility of the high adherence to more than one dietary pattern and calorie adjusted factor extracting. METHODS: This cross sectional study conducted on 734 type2 diabetic patients. Factor analysis defined three major dietary patterns (Western like, Asian like and Traditional like) and the associations of each pattern were assessed with glycemic control and lipid profiles among tertiles of each pattern. In order to compare variables in highest tertile of three defined dietary patterns, eight new different groups were classified according to the high adherence to one or more patterns and ANOVA and ANCOVA were used to compare them. Also, calorie adjusted factor extracting were done to find out if the same factor loadings would be extract. RESULTS: Among three major dietary patterns, only Western like showed a significant association with fasting blood sugar (p = 0.03, 12.49 +/- 5.99), serum total cholesterol (p = 0.02, 8.71 +/- 3.81) and LDL cholesterol (p = 0.04, 5.04 +/- 2.40). While comparison of new classified patterns, showed no significant differences, except a high blood glucose in Western like- Asian like versus traditional like dietary pattern (p = 0.04). Also, calorie adjusted factor extracting showed different factor loadings. CONCLUSIONS: Results showed that the conventional dietary pattern analysis method may have substantial limitations in interpreting the results and may lead to inappropriate conclusions. PMID- 25032129 TI - Chronic graft loss and death in patients with post-transplant malignancy in living kidney transplantation: a competing risk analysis. AB - BACKGROUND: Malignancy is a common complication after renal transplantation. Death with functioning graft and chronic graft loss are two competing outcomes in patients with post-transplant malignancies. OBJECTIVES: The purpose of our study was to evaluate the risk factors associated with cumulative incidence of these two outcomes. PATIENTS AND METHODS: Fine-Gray model was used for 266 cases with post-transplant malignancy in Iran. These patients were followed-up from the diagnosis until the date of last visit, chronic graft loss, or death, subsequently. RESULTS: At the end of the study, as competing events, chronic graft loss and death with functioning graft were seen in 27 (10.2%) and 53 cases (19.9%), respectively, while 186 cases (69.9%) were accounted as censored. The incidence rate of death was approximately two-time of the incidence rate of chronic graft loss (8.6 vs. 4.4 per 100 person-years). In multivariate analysis, significant risk factors associated with cumulative incidence of death included age (P < 0.007, subhazard ratio (SHR) = 1.03), type of cancer (P < 0.0001), and response to treatment (P < 0.0001, SHR = 0.027). The significant risk factors associated with cumulative incidence of chronic graft loss were gender (P = 0.05, SHR = 0.37), treatment modality (P < 0.0001), and response to treatment (P = 0.048, SHR = 0.47). CONCLUSIONS: Using these factors, nephrologists may predict the occurrence of graft loss or death. If the probability of graft loss was higher, physicians can decrease the immunosuppressive medications dosage to decrease the incidence of graft loss. PMID- 25032130 TI - Urinary prognostic biomarkers in patients with focal segmental glomerulosclerosis. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a type of nephrotic syndrome which is diagnosed by renal biopsy. Degree of the proteinuria, renal dysfunction, histologic findings and the response to therapy are some factors used for evaluating the prognosis of FSGS. OBJECTIVES: In the present study, we attempted to discover some protein candidates for disease prognosis related to glomerular filtration rate (renal dysfunction). PATIENTS AND METHODS: Urine samples were collected from ten patients. Urine proteome was extracted and trypsinated. Digested peptides were separated and identified by nano-flow LC MS/MS. Protein content were determined using label-free quantification method. Protein profiles were analyzed using supervised multivariate statistical method. RESULTS: Output of a predictive model was 54 significant proteins of which ribonuclease 2 and haptoglobin had the greatest fold change in terms of overrepresentation and underrepresentation in patients with the best and worse prognosis, respectively. Complement and coagulation cascades were the only significant pathways which were impaired in FSGS. CONCLUSIONS: Urinary biomarkers can potentially be used as non-invasive prognostic markers. However these candidate biomarkers need further validation by an alternative method and in a larger cohort. PMID- 25032131 TI - Editorial comment: health-related quality of life in hemodialysis patients: an Iranian multi-center study. PMID- 25032132 TI - Association of the serum vascular endothelial growth factor levels with benign prostate hyperplasia and prostate malignancies. AB - BACKGROUND: Recently, the development of new biomarkers as prognostic and predictive markers in prostate cancer has been crucial. OBJECTIVES: This study was aimed to determine whether serum vascular endothelial growth factor (VEGF) levels would be a prognostic marker or risk assessment factor in patients with prostate cancer and to investigate whether it could differentiate cancerous tissue from benign prostate hyperplasia (BPH). PATIENTS AND METHODS: We enrolled 44 patients with prostate cancer, 57 patients with BPH, and 57 healthy individuals. Serum VEGF levels was measured by ELISA and was compared among all groups; then, its correlation with PSA and Gleason score in cancerous group was assessed. In addition, by using receiver operating characteristic (ROC) curve and area under curve (AUC), we determined the sensitivity and specificity of VEGF as well as combined variable of VEGF and PSA as a diagnostic marker of prostate cancer. RESULTS: Serum VEGF level was significantly higher in patients with prostate cancer in comparison to the other groups (P value < 0.001); however, it was not different between BPH and control groups. Only in cancerous group a significant correlation between VEGF and PSA was found (r = 0.425, P = 0.004). Assessing the risk of prostate cancer, we found a powerful correlation between the VEGF alone as well as the combination of VEGF and PSA with prostate cancer. CONCLUSIONS: VEGF may be a diagnostic biomarker of prostate cancer. In addition, it may differentiate the cancerous tissue from BPH. We suggest that VEGF combined with PSA may be used as a screening test of prostate cancer. PMID- 25032133 TI - Bilateral laparoscopic gonadectomy in a patient with complete androgen insensitivity syndrome and bilateral sertoli-leydig cell tumor: a case report and brief review of the literature. AB - INTRODUCTION: Complete androgen insensitivity syndrome (previously called testicular feminization) is specified by a 46 XY karyotype and negative sex chromatin, bilateral undescended testes, female genitalia appearance, and lack of mullerian derivatives. CASE PRESENTATION: A 28-year-old woman with complete (severe) androgen resistance underwent prophylactic laparoscopic bilateral gonadectomy because of the eventually increased risk of gonadal malignancy. Although the gonads appeared grossly normal, microscopic examination revealed bilateral well differentiated sertoli-leydig cell tumor (SLCT). DISCUSSION: Our Medline search revealed that this is the first reported case of bilateral sertoli leydig cell tumor (SLCT) in androgen insensitivity syndrome. PMID- 25032134 TI - The effects of varicocelectomy on the patients with premature ejaculation. AB - BACKGROUND: Premature ejaculation is one of the most problems in clinical practice. The association between varicocele and premature ejaculation was poorly understood. The effects of varicocelectomy on premature ejaculation in varicocele patient was studied. OBJECTIVES: The aim of this study was to determine the impacts of varicocelectomy on patients with both premature ejaculation and varicoceles. PATIENTS AND METHODS: This was a clinical trial study, conducted on 124 patients (20-35 years old), with varicoceles and premature ejaculation (PE), since March 2011 to April 2013. Inguinal and sub inguinal varicocelectomy were performed for them. All patients had both impairment of spermiogram and PE. These patients were followed up for about 2 years and evaluated for PE, in addition to parameters of spermiogram, before and after the surgery. RESULTS: A total number of 124 patients with varicoceles and PE were enrolled into the study. Following the surgery 46 patients (37%) were fully treated (P < 0.001), 78 patients (63%) had improvements in PE symptoms changed to early ejaculation (P < 0.05) and 89 patients (72%) had improved parameters of spermiogram (P < 0.002). CONCLUSIONS: In a significant number of patients who had clinical varicocele and not well responded to medical treatments for PE, varicocelectomy could effectively improve PE and spermiogram parameters. PMID- 25032135 TI - Local graft irradiation for kidney allograft rejection: a case series and review of the literature. AB - INTRODUCTION: Due to its immunosuppressive properties, local graft irradiation (LGI) has been proposed as a second line therapy for treatment of acute kidney rejection. CASE PRESENTATION: In this case-series we report 6 patients with biopsy proven acute kidney allograft rejection refractory to conventional antirejection therapy who underwent LGI for treatment of acute rejection at our center. Three of these patients had living donor transplants, 2 had deceased donor transplants, and one had received a simultaneous kidney/pancreas transplant. All patients were treated with anti thymocyte-globulin or muromonab CD3, and intravenous steroids for initial treatment of rejection. Three patients also received intravenous immunoglobulin. LGI was tried as a last resort and was well tolerated and resulted in either improvement or stabilization of renal function in 5 patients. One patient could not be given the complete course of chemical immunosuppression for treatment of rejection due to concomitant cryptococcal meningitis and was switched to LGI with good short-term response. DISCUSSION: Our results suggest that LGI could be considered a second line therapy to the conventional anti-rejection therapy for patients with refractory acute kidney allograft rejection, or for patients who cannot receive systemic immunosuppression due to severe infection. PMID- 25032136 TI - Evaluation of malnutrition and its association with biochemical parameters in patients with end stage renal disease undergoing hemodialysis using subjective global assessment. AB - BACKGROUND: Malnutrition is a common problem in patients with end stage renal disease (ESRD) undergoing hemodialysis that increases morbidity and mortality rate in them. Subjective global assessment (SGA) is a tool used by health care providers to assess nutritional status in these patients. In addition, biochemical parameters are used to assess the nutritional status in all people. OBJECTIVES: In this study, we evaluated the nutritional status of patients with ESRD undergoing hemodialysis using SGA and assessed probable association between biochemical parameters and malnutrition in this population. PATIENTS AND METHODS: Using SGA, the nutritional status of 105 patients (60 males and 45 females) of two dialysis centers in Sari, Iran, was evaluated during years 2007-2008. It is a semiquantitative scoring system that has seven variables derived from medical history and physical examination. The biochemical parameters including hemoglobin, albumin, cholesterol, BUN, and creatinine were also measured. RESULTS: Among 105 patients, 98 (93.33%) patients consisted of 56 males and 42 females had mild to moderate malnutrition and 3 (2.86%) women had severe malnutrition. In addition, all of the patients without malnutrition were men. We found significant association between patient's sex and the SGA score (P = 0.03) but no significant association was seen between age and duration of hemodialysis with SGA score. In addition, we did not find significant association between the measured biochemical parameters and malnutrition. CONCLUSIONS: According to high prevalence of malnutrition in our patients with ESRD undergoing hemodialysis, periodic assessment of nutritional status is necessary in them. Meanwhile we found SGA as the best tool to assess nutritional status in patients with ESRD undergoing hemodialysis, because it can recognize various degrees of malnutrition that may remain undetected by a single laboratory assessment. PMID- 25032137 TI - Ubiquinol effect on sperm parameters in subfertile men who have astheno teratozoospermia with normal sperm concentration. AB - BACKGROUND: Considering all the couples willing and trying to get pregnant, the incidence of infertility is 15% of which approximately half of the cases are due to the male factors. OBJECTIVES: The aim of this study was the investigation of the effects of ubiquinol, reduced form of coenzyme Q10 (Co-Q10), an empiric treatment modality, on sperm parameters in idiopathic subfertility. PATIENTS AND METHODS: In this retrospective study, 62 patients who had received 100 mg ubiquinol twice a day for six months due to idiopathic infertility since January 2012 to January 2013 were included. Only infertile patients with astheno teratozoospermia without any identified etiology and with a spermatozoa concentration of greater than 13 * 10(6)/mL were included. RESULTS: The increase in mean values of concentration after the ubiquinol treatment was not statistically significant (P value = 0.065). However, the changes in morphology and motility (fast progressive [a] and a + slow progressive [b]) were statistically significant (P < 0.00). CONCLUSIONS: The weakness of the literature with regard to coenzyme Q10 is about its effects in patients with severely diminished sperm densities and the physiologic steps of morphologic improvements. PMID- 25032138 TI - Where do patients go for treatment of urethritis? AB - BACKGROUND: Urethritis is characterized by urethral inflammation, and it can result from both infectious and noninfectious conditions. Physicians and other health care providers play a critical role in preventing and treating urethritis. OBJECTIVES: The aim of this study was to describe and identify predictors of health care seeking behavior among men with urethritis. PATIENTS AND METHODS: In total, 98 male patients aged between 16 to 52 years-of-age (mean 30.9 +/- 8.0 years), who attended our clinic with symptoms of urethritis, were included in the study. We conducted face-to-face interviews with the patients using a 9-item survey questionnaire. Patients were divided into three groups according to their level of education as follows: group I (n = 44), elementary school; group II (n = 38), high school; and group III (n = 16), university. RESULTS: Among the 98 patients evaluated, the source of treatment was physicians in 44 patients (44.9%), drugstores in 38 cases (38.77%), and friends in 16 patients (16.32%). There was a statistically significant difference found between the groups according to the source of treatment (P < 0.001). The most common factors associated with seeking care from other sources, rather than physicians, were economic reasons in 19 patients (35.18%), confidentiality concerns in 24 (44.4%), and ease of access in 11 patients (20.37%). CONCLUSIONS: A substantial proportion of patients with urethritis sought help from other sources, rather than physicians. The results of our study show that the patients with higher levels of education were more likely to seek help from health care services. It is important to promote the public's knowledge through informative studies and educational materials in order to encourage patients to seek rapid and effective treatment from proper sources. PMID- 25032139 TI - Large clitoral leiomyoma in a forty-two years old premenopausal woman. AB - INTRODUCTION: Clitromegaly can be congenital or acquired with the former type being more prevalent. The main etiology behind the acquired type is hormonal imbalance affecting mainly adult women. This type is seen mostly in association with polycystic ovarian syndrome, hyperthecosis, ovarian tumors, and clitoral cysts or it can be drug-induced. Clitoral leiomyoma is a rare benign tumor of female genitalia and is an uncommon cause of clitromegaly. CASE REPORT: We reported a 42-year-old premenopausal woman with a progressively increasing mass since five years ago, who had attended our clinic with urinary retention. It was a fungating mass with ulceration arising from the crus of the clitoris with the size was 11 * 9 cm. After detailed laboratory investigations, she had normal karyotyping. Hormonal assay for testosterone, dehydroepiandrosterone sulphate, and follicle stimulating hormone, luteinizing hormone, parathormone, and prolactin levels revealed values within the normal range. Twenty-four hours urinary excretion levels of free cortisol and ketosteroids were within normal limits. Beta-hCG level was also in normal range. Thyroid function tests and X-ray chest results were normal. Contrast enhanced computed tomography (CECT) of the abdomen showed no abnormality in adrenals and there was no pituitary enlargement on brain MRI. Pelvis MRI showed a large 11 * 9 * 8 cm clitoral mass. Diagnostic biopsy done from ulcer margin was suggestive of leiomyoma. The mass was completely excised preserving the tip of clitoris. The histopathology showed spindle-shaped cells arranged in palisading form. On immunohistochemistry, tumor cells were positive for smooth muscle actin (SMA) as well as for estrogen and progesterone receptor (ER/PR), confirming the diagnosis of leiomyoma. The patient was regularly followed, and was doing well with no voiding difficulty. CONCLUSIONS: We reported the world largest clitoral leiomyoma presenting with symptoms of acute urinary retention. MRI has important role in diagnosis and biopsy is confirmative with spindle-shaped cells arranged in palisading pattern and simple excision would be curative. PMID- 25032140 TI - Page kidney secondary to large splenic artery aneurysm bleeding and its management by angioembolization. AB - INTRODUCTION: The Page kidney is a rare phenomenon that refers to hypertension resulting from any external compression of a kidney by a hematoma, tumor, lymphocele, or urinoma. The activation of the renin-angiotensin-aldosterone system is believed to be the main mechanism responsible for development of resistant hypertension in Page kidney. CASE PRESENTATION: We reported a patient with chronic pancreatitis who presented with hypotension due to splenic artery aneurysmal bleed; following the resuscitation, accelerated hypertension secondary to Page kidney caused by perinephric hematoma presented. Early diagnosis by contrast-enhanced computed tomography of the abdomen and renal angiogram was followed by therapeutic angioembolization. However, ultrasound guided aspiration was not done because of denial by the patient for further treatment. Follow-up showed normalization of blood pressure and resolution of hematoma on subsequent abdomen ultrasound evaluation. DISCUSSION: Splenic artery aneurysm is a very uncommon cause of Page kidney and to our knowledge, it was the first case of its kind ever reported in the literature. PMID- 25032141 TI - Oral midazolam for voiding dysfunction in children undergoing voiding cystourethrography: a controlled randomized clinical trial. AB - BACKGROUND: Voiding Cystourethrography (VCUG) is the gold standard of detecting and grading the vesicoureteral reflux. Moreover, VCUG is a part of the standard review for infants and children with a urinary tract infection and urinary dysfunction. OBJECTIVES: The purpose of our study was to compare using oral midazolam in contrast to prescribing no sedative medication for voiding dysfunction in children undergoing VCUG. PATIENTS AND METHODS: In a clinical trial, we studied 84 children referred for VCUG. Children were allocated randomly into two equal groups. The intervention group received 0.5 mg/kg midazolam orally half an hour before the VCUG procedure. Then both groups were compared using statistical methods. RESULTS: Then both groups were compared using statistical methods. In more than half of the patients, the main cause of performing VCUG was urinary tract infection. Dysuria was evaluated immediately after VCUG and was more frequent in girls than in boys (P = 0.006). After one week, the urinary irritation and restlessness in the intervention group was significantly lower than the control group. CONCLUSION: The use of midazolam 0.5 mg/kg reduced children's stress and increased their cooperation during the procedure. PMID- 25032142 TI - Pulmonary and chest wall metastasectomy in urogenital tumors: a single center experience and review of literature. AB - BACKGROUND: Pulmonary metastases are often found in advanced malignancies. Urogenital malignancies originating from kidney, prostate, testes, and bladder all metastasize preferentially to the lungs. OBJECTIVES: This retrospective study aimed to evaluate the results of pulmonary and chest wall metastasectomy in patients with primary urogenital Tumors. PATIENTS AND METHODS: The patients who underwent pulmonary metastasectomy in Ghaem Hospital from 1996 to 2011 were examined. Thirteen out of 79 patients referred for pulmonary metastasectomy to a single thoracic surgeon had metastases from urogenital tumors; two cases with metastasis from urogenital tumors were inoperable. We reviewed their demographic data and also clinicopathological features. Disease free interval (DFI) was defined as the time between the first curative surgery and the appearance of the signs and symptoms of pulmonary metastasis. RESULTS: Among 11 patients who underwent surgery consisted of eight males and three females. Their metastasis originated from testis tumors (n = 5), renal cell carcinoma (RCC; n = 4), bladder tumor (n = 1), and prostate cancer (n = 1). Their mean age was 41.27 years (range, 21-67). The mean age of the patients with RCC and testis tumor at the time of diagnosing metastasis was 54 and 24.8 years, respectively. There were two other patients (a 62-year-old female and a 54-year-old male) with pleural effusion due to metastatic RCC whose tumor was inoperable because of their poor general condition and hence, were referred for chemotherapy. CONCLUSIONS: Pulmonary metastasectomy is feasible in selected cases. PMID- 25032143 TI - Effect of selenium supplementation on glutathione peroxidase enzyme activity in patients with chronic kidney disease: a randomized clinical trial. AB - BACKGROUND: Plasma selenium (Se) concentration and glutathione peroxidase (GSH Pxs) enzyme activity of the patients with chronic kidney disease (CKD) are usually lower than healthy individuals; however, the effect of Se supplementation on the GSH-Pxs activity in those patients remains unclear. OBJECTIVES: This study aimed to assess the effect of Se supplementation on plasma Se concentration and red blood cell (RBC) GSH-Pxs activity in patients with different stages of CKD. PATIENTS AND METHODS: In this randomized clinical trial, forty-five patients with CKD who attended in a nephrology clinic were recruited. The patients were randomly allocated into three groups according to their creatinine clearance rate and were supplemented with daily Se 200 mcg for three months. Plasma Se concentration and RBC GSH-Pxs activity were measured in each patient at the beginning and at the end of the study. This clinical trial was registered in the Iranian Registry of Clinical Trials (www.irct.ir) with registration number ID of IRCT201305318501N2. RESULTS: Plasma Se concentration and RBC GSH-Pxs activity increased significantly in all three groups of patients with CKD (P < 0.05). There were no significant differences between three groups regarding baseline plasma Se (P = 0.268) and RBC GSH-Pxs activity (P = 0.741). CONCLUSIONS: Se supplementation can increase plasma Se concentration and RBC GSH-Pxs activity in patients with different stages of CKD. PMID- 25032144 TI - Phosphate metabolism modulation in chronic kidney disease: when, how and to what extent? PMID- 25032145 TI - Which outcome in chronic kidney disease-mineral and bone disorder patients? PMID- 25032146 TI - Complications of primary realignment of posterior urethral disruption after pelvic trauma. AB - BACKGROUND: There are two fundamental selections for the management of traumatic posterior urethral injury, delayed repair or early primary realignment. OBJECTIVES: The aim of this study was to assess the complications of primary realignment of posterior urethral disruption. PATIENTS AND METHODS: This retrospective descriptive cross-sectional study was done at the Shohada-ye Ashayer University Hospital in Khorramabad. All male patients admitted to the hospital with posterior urethral disruption and had undergone primary realignment of the urinary tract between 2003 and 2010 were included. Primary realignment of the urinary tract was done up to 24 hours after injury. The patients underwent open cystostomy and then a nelaton catheter was inserted from the bladder neck to the distal urethra anterogradely. Upon voiding from the catheter, another nelaton catheter was fixed to it and was pulled into the bladder. The catheter was removed if the urethra was intact in the retrograde urethrography after three weeks. The patients were followed for six months. The data were presented as mean and percentage. RESULTS: A total of 24 patients were evaluated while seven, eleven, four, and two patients were aged under 20, 20 to 39, 40 to 59, and over 60 years old, respectively. Thirteen patients (54.16%) had urinary tract stenosis after the primary realignment. Erectile dysfunction was reported in three of them. Urinary incontinence did not occur in patients without stenosis. CONCLUSIONS: Early primary realignment of posterior urethral disruption had significant complications. In this study we did not have a control group, thus we could not compare the complications of delayed repair and early primary realignment of the posterior urethra. We recommend further case-control studies with larger sample size. PMID- 25032147 TI - Clinical and radiological results of fixation of acromioclavicular joint dislocation by hook plates retained for more than five months. AB - BACKGROUND: Hook plates are used to treat acromioclavicular joint dislocations. Our study took into consideration the patients' outcome following treatment with clavicular hook plates retained for more than five months. OBJECTIVES: Our aim was to assess the response to treatment of acromioclavicular joint dislocation by clavicular hook plate when retained for more than five months. PATIENTS AND METHODS: We treated 24 patients who had acromioclavicular joint dislocation with a clavicular hook plate between 2008 and 2012 at our hospital. We did not repair the coracoclavicular ligament. In all patients, the plate remained more than five months because they did not come back at the recommended time for removal of their plates. The follow-up period ranged from five to thirty three months with a mean of nineteen months. RESULTS: The main complication was osteolysis that was seen in two patients. The mean constant score was 94.5 +/- 8.77 out of 100 with a range between 70 and 100. CONCLUSIONS: Our study showed that the use of clavicular hook plates was a good treatment option for acromioclavicular joint dislocation. However, scores were lower in case of prolonged presence of plates. PMID- 25032148 TI - Oral Care in Trauma Patients Admitted to the ICU: Viewpoints of ICU Nurses. AB - BACKGROUND: Many patients with severe traumatic injuries are admitted to intensive care units (ICU). These patients usually require prolonged mechanical ventilation. These interventions require oral intubation and leave the mouth open which consequently impairs the natural antimicrobial activity in the mouth and airways. These patients are also prone to ventilator-associated pneumonia (VAP). Evidence shows that paying attention to oral hygiene in patients under mechanical ventilation is important in helping to prevent VAP. OBJECTIVES: The present study was conducted to assess the viewpoints and performance of ICU nurses at Birjand hospitals towards oral care of patients under mechanical ventilation. PATIENTS AND METHODS: A cross-sectional study was conducted at ICUs of Imam-Reza and Vali Asr hospitals, Birjand, Iran. Sampling was done through a census in which 53 ICU nurses participated. Descriptive statistics, Kolmogorov-Smirnov test, Mann Whitney U tests and Kendall's correlation coefficient were used to analyze the data. RESULTS: A total of 53 nurses participated in this study. Most of the nurses had been trained to provide oral care during their university education. According to the participants' opinions, oral care with an average score of 5.72 ranked second among the 10 nursing care domains. The most frequent oral care provided was oral suctioning, normal saline irrigation, and chlorhexidine rinse with 95%, 90%, and 81.3% frequency, respectively. CONCLUSIONS: Nurses participating in this study considered oral care to be of prime importance. Most of the participants although trained in this area felt the need for continuing training courses. PMID- 25032149 TI - Patellar Tendinopathy May not Be the Proper Term for Patients With Clinical Diagnosis of Patellar Tendon Disorder. PMID- 25032150 TI - Breaching medical ethics in research. PMID- 25032152 TI - Statistics in trauma research. PMID- 25032151 TI - Platelet-Rich Plasma in Treatment of Zoledronic Acid-Induced Bisphosphonate related Osteonecrosis of the Jaws. AB - BACKGROUND: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a well known challenging entity warranting management. Platelet-Rich Plasma (PRP) plays an important role in bone biology by enhancing bone repair and regeneration. OBJECTIVES: The aim of this animal study was to evaluate the effects of PRP on zoledronic acid-induced BRONJ. MATERIALS AND METHODS: Seven rats were given 0.04 mg Zoledronic acid intravenously once a week for five weeks. Two weeks later, the animals underwent extraction of their first lower molars, bilaterally. After clinical confirmation of the osteonecrosis, PRP was injected randomly into one of the extraction sockets of each rat. Three weeks later, all rats were sacrificed in order to obtain histological sections. The analysis of epithelialization was performed by McNamar's test, and the analysis of osteogenesis and angiogenesis was performed by the Wilcoxon Sign Rank test. P value was set at 0.05. RESULTS: We found no significant differences between the two groups regarding the amount of epithelialization, angiogenesis or sequestrum formation (P > 0.05), but a significant difference was seen between the two groups regarding the amount of existing vital bone (P < 0.05). CONCLUSIONS: Our study demonstrates positive results (preservation or regeneration of bone) using PRP in treatment of BRONJ. Although PRP may enhance osseous regeneration, long-term follow-ups are required to confirm its benefits. PMID- 25032153 TI - Fish hook injury: removal by ''push through and cut off'' technique: a case report and brief literature review. AB - INTRODUCTION: Fishing is a leisure activity for some people around the world. Accidently the fish hook can get hooked in the hand. If the hook is barbed, removal becomes difficult. We report a case of such a injury in the hand and discuss the technique for its removal with a brief review of the literature. CASE PRESENTATION: A thirty-two year old male accidently suffered a fishhook injury to his hand. He came to the orthopaedic ward two hours after the incident with pain; the fish hook was hanging from the hand. Unsuccessful attempts to remove it were made by his relatives. A push-through and cut-off technique was used for removal of barbed hook. DISCUSSION: Barbed hooks are to be removed atraumatically with controlled incision over properly anaesthetised skin. Proper wound management and prophylactic antibiotics suitable for treatment of Aeromonas species should be initiated to prevent complications. PMID- 25032154 TI - Effects of KTP Laser Bleaching on Traumatized Tooth Enamel. AB - BACKGROUND: Bleaching of traumatized discolored teeth is considered an important issue in esthetic dentistry. Various methods have been introduced for bleaching, some of which may have adverse effects on soft or hard tissues of the tooth. OBJECTIVES: The objective of the study was to evaluate the effects of KTP laser bleaching on enamel of traumatized teeth. MATERIALS AND METHODS: A square of 36 mm(2) was chosen on the labial surface of 32 extracted teeth. The corners were drilled in order to indicate the location precisely. The shade of each sample was recorded and the teeth were divided into four groups, each with eight teeth: group A (Smartbleach with KTP laser for 30 seconds), group B (Smartbleach with G Light for 5 minutes), group C (only Smartbleach for 10 minutes) and group D (control group with no bleaching). After one session of bleaching, shade assessment was performed again. In another experiment on nine teeth, Smartbleach with KTP laser was used for 150 seconds to 1500 seconds. The samples were critically processed and observed by using scanning electron microscope (SEM) to assess enamel damage. Data was statistically analyzed using Kruskal-Wallis test (confidence interval level were set at 95%). RESULTS: Smartbleach was highly effective when used with KTP laser (P = 0.0419). Enamel damage was observed after frequent KTP bleaching and 750 seconds of KTP bleaching was recognized as the limit by morphological evaluation via SEM, indicating a major difference between under and over 750 seconds of bleaching. CONCLUSIONS: Application of KTP laser may increase the bleaching effect of Smartbleach, nevertheless it may cause some enamel damage. PMID- 25032155 TI - Pre-adapted Arch Bar Revisited for Open Reduction and Internal Fixation in Mandibular Fractures at Tooth-Bearing Sites. PMID- 25032156 TI - Foreign body in the vagina of a four-year-old-girl: a childish prank or sexual abuse. AB - INTRODUCTION: Foreign body in the vagina is a common cause of vaginal discharge, which may be either purulent or hemorrhagic. CASE PRESENTATION: This problem may produce symptoms or be asymptomatic for long periods of time and may result from ignorance, accident, malice, psychotic tendencies, attempts at sexual stimulation or sexual abuse. The current report presents the case of a girl that had inserted a foreign body in her vagina probably due to childish prank. CONCLUSIONS: The clinicians should always think of foreign bodies in the vagina in cases of chronic, antibiotic resistant vaginal discharge and lower abdominal pain especially in young girls. PMID- 25032157 TI - Vulnerability to substance abuse and the risk of suicide in students of region 12 of islamic azad university. AB - BACKGROUND: Substance abuse prevalence and the number of suicides among university students is less than public population; however the sensitivity of society regarding the occurrence of such damages among students puts special emphasis on appraising these variables. More than 30% of Iranian students study in Islamic Azad University. OBJECTIVES: The current research aimed to appraise the vulnerability of substance abuse and the risk of suicide in students of region 12 of Islamic Azad University. PATIENTS AND METHODS: In the current study, 1053 students (606 boys and 447 girls) with the average age of 22.55 years were selected through stratified sampling from Karaj, Takestan, Qazvin and Qom branches of Islamic Azad University. In order to assess the variables, Mental Health Worksheet of Central Counseling Office of the Ministry Science, Research and Technology was utilized. RESULTS: Average, standard deviation, minimum and maximum scores in substance abuse vulnerability of the students in region 12 were measured as 36.28, 14.68, 11.22 and 92.87; and the same for risk of suicide were 31.29, 15.61, 7.93 and 96.30, respectively. Students in Qom branch were significantly less vulnerable to substance abuse and less exposed to the risk of suicide than their peers in Karaj, Qazvin and Takestan branches. CONCLUSIONS: Less significant possibility of substance abuse and risk of suicide in students of Qom branch in comparison with other branches could be due to numerous variables particularly their religious attitudes. Nevertheless the average of these variables among the students of region 12 were higher than the reported scores of their peers in the state universities which reflects the serious need for precise assessments and providing preventive services and mental health interventions. PMID- 25032158 TI - Comparison between family power structure and the quality of parent-child interaction among the delinquent and non-delinquent adolescents. AB - BACKGROUND: Few studies indicate that most behavioral problems are due to family dysfunction and inappropriate family environment. It seems that the family of the delinquent adolescent is unbalanced in the power structure and parenting style. OBJECTIVES: The present study compares the family power structure and parent child relationship quality in delinquent and non-delinquent young subjects in Tehran. PATIENTS AND METHODS: Eighty students of secondary schools aged between 15 and 18 in Tehran were enrolled with cluster sampling method and 80 delinquent adolescents of the Correction and Rehabilitation Centers aged between 15 and 18 were chosen with a convenience sampling method. They responded to an instrument of family power structure (Child-parents relationship inventory). Data was compared between these two groups by utilizing the independent and dependent t test and Levene's test. RESULTS: The findings indicated there is a significant difference between delinquent and non-delinquent adolescents in family power structure and its subscales (P < 0.001) and father-child relationship quality (P < 0.005). Also, there is no statistically significant difference between these two groups in mother-child relationship quality (P < 0.005). Besides, the results revealed that delinquent adolescents were significantly different regarding the quality of parent-child relationship (P < 0.001). CONCLUSIONS: These results emphasize that an inappropriate decision making process pattern in a family has a significant effect on deviant behavior in adolescents. The fathers' parenting is more strongly linked to their sons' delinquency. So, family power structure and parent-child relationship can be considered in therapeutic interventions (prevention and treatment) for adolescents' delinquency. PMID- 25032159 TI - High risk situations predicting relapse in self-referred addicts to bushehr province substance abuse treatment centers. AB - BACKGROUND: Relapse prevention is a medical intervention designed for educating cognitive and behavioral skills to avoid continued drug abuse and relapse. OBJECTIVES: This study examined high risk situations for relapse for self referred addicts are related in Bushehr province substance abuse treatment centers. PATIENTS AND METHODS: The present study is descriptive cross-sectional. The sample size consisted of 609 self-referred addicts to Bushehr province substance abuse centers. IDTS Marlatt questionnaire was used. Analytical and descriptive statistics were used to analyze the data. RESULTS: The findings showed that 73.1% of addicts have used substance during the past 12 months, and 72% have experienced a full relapse. Unpleasant emotions and physical discomfort was the most important reason for relapse and testing personal control and pleasure emotions the least important reason. Interpersonal factors have also a great role in this regard. CONCLUSIONS: Considering the high rates of relapse, more attention should be paid to reasons for relapse. It seems necessary that both clinical and psychological approaches would be undertaken simultaneously. PMID- 25032160 TI - Cognitive failure and alexithymia and predicting high-risk behaviors of students with learning disabilities. AB - BACKGROUND: One of the threatening health issues is prevalence of high-risk behaviors in various groups. Because of rapid social changes, it has been considered as of the most important problems of society by health organizations, administrative laws, and social policymakers. OBJECTIVES: The aim of this study was to determine the role of cognitive failure and alexithymia in predicting high risk behaviors of students with learning disabilities. PATIENTS AND METHODS: This was a correlational research including all 14-16 years old students during 2012 2013 school year in Arak, IR Iran. Eighty students with learning disabilities were sampled by simply random sampling. The data were collected by cognitive failures questionnaire, Toronto alexithymia scale, and high-risk behavior questionnaire. RESULTS: The results showed that high-risk behaviors had significant positive correlations with difficulty identifying feelings (r = 0.321), difficulty describing feelings (r = 0.336), externally oriented thinking (r = 0.248), distractibility (0.292), memory distortion (r = 0.374), blunders (r = 0.335), and names amnesia (r = 0.275). Multiple regression analysis showed that cognitive failure and alexithymia predicted 32% of the total variance of high risk behaviors. CONCLUSIONS: These findings demonstrated that cognitive failure and alexithymia had important roles in strengthening and appearance of high-risk behaviors in students with learning disabilities. Therefore, considering those problems, precautionary actions might be necessary. PMID- 25032161 TI - Cannabis consumption systemic adverse effects. PMID- 25032162 TI - Effectiveness of Educational Programs on Nutritional Behavior in Addicts Referring to Baharan Hospital, Zahedan (Eastern of IR Iran). AB - BACKGROUND: There are many factors which affect nutritional status of addicted such as lack o f knowledge, incorrect attitude toward modification of food pattern, and careless to food intake. OBJECTIVES: The aim of this study was to determine the effectiveness of educational program on nutritional behavior in addicts referring to Baharan hospital in Zahedan. PATIENTS AND METHODS: Thirty six addict patients were selected randomly. After recording general demographic data of patients, nutritional behaviors were determined. To determine the effectiveness of nutritional educational program, pre and post-tests were performed. Evaluation of nutritional behavior was determined as poor, fair and satisfactory levels. Statically analysis was performed by SPSS software. RESULTS: Most addict patients had a medium level of education. Improvement in knowledge, attitude and practice (KAP) of patients after intervention was observed as follows; decreasing KAP in poor level (2.8% vs. 30.6%), (3% vs. 50%), (25% vs. 80.6%), respectively; also, increasing KAP in fair level (7% vs. 55.6 %), (15% vs. 15%), (19% vs. 7%), respectively and increasing KAP in satisfactory levels (77.8% vs. 13.8%), (50% vs. 8.3%), and (22.2% vs. 0%), respectively (P < 0.0001). There was a significant difference regarding the grade of KAP in patients based on gender, marital status, and education level after education (P < 0.0001). CONCLUSIONS: This study showed that nutritional KAP was improved in addicts. After intervention, there was a significant difference in the score of knowledge, attitude, and practice scores in patients in the current study. KAP was improved in patients after intervention including; decreased KAP in poor level and increased KAP in fair and satisfactory levels. This finding indicates that addict patients would like to modify their life style. PMID- 25032163 TI - Associations of Alcohol Consumption and Chronic Diseases With Sleep Apnea Among US Adults. AB - BACKGROUND: Sleep apnea (SA) is a common sleep disorder among US adults. Associations of SA with alcohol consumption and some chronic diseases have been inconsistent. OBJECTIVES: This study aimed to estimate prevalence of SA and examine its associations with potential factors including alcohol consumption, asthma, diabetes, and hypertension. PATIENTS AND METHODS: This was a cross sectional study on 823 adults with SA and 38,638 controls from the 2011 National Survey on Drug Use and Health Data. Weighted univariate and multiple logistic regression analyses were used to examine the associations of SA with the potential factors. RESULTS: The prevalence of SA was higher in males (4.01%) than in females (2.61%), while the prevalence increased with age (0.86%, 3.50%, and 4.47% for age groups of 18-25, 26-64, and >= 65, respectively). Univariate analysis revealed that all factors except for income and education were associated with SA (P < 0.05). In multivariable analyses, participants who were current and past alcohol consumers had significantly higher odds of having SA (OR = 1.52, 95% CI = 1.03-2.23; OR = 1.65, 95% CI = 1.09-2.49, respectively) than non alcohol drinker. Furthermore, asthma (OR = 2.77, 95% CI = 2.04-3.75), diabetes (OR = 2.89, 95% CI = 2.19-3.83), and hypertension (OR = 2.42, 95% CI = 1.91-3.07) were significantly associated with SA. CONCLUSIONS: Age, alcohol consumption, asthma, diabetes, and hypertension, were positively associated with SA. More efforts should be directed to promoting screening for SA and finding possible treatments for SA among these vulnerable groups. PMID- 25032164 TI - Sociocultural reasons for smokeless tobacco use behavior. PMID- 25032165 TI - Impulsivity: a predisposition toward risky behaviors. PMID- 25032166 TI - Queuing theory to decrease waiting times in emergency department. PMID- 25032167 TI - Functional abdominal pain syndrome in morbidly obese patients following laparoscopic gastric bypass surgery. AB - BACKGROUND: Roux-en-Y gastric bypass surgery (RYGBP) is one of the most common bariatric surgeries, which is being performed using various techniques like gastrojejunostomy by hand swen, linear or circular stapler. Abdominal pain is a common complaint following laparoscopic gastric bypass procedure (LGBP), which has different aetiologies, such as overeating, adhesion, internal herniation, bile reflux and many more. In this study LGBP was performed in an ante-colic ante gastric pattern in a double loop manner and the prevalence and distribution of pain in morbidly obese patients undergoing LGBP was assessed. OBJECTIVES: The aim of this study was to analyze the distribution and frequency of post LGBP pain in morbidly obese patients. PATIENTS AND METHODS: This study was performed on 190 morbidly obese patients referred to Hazrat Rasoul Hospital in Tehran. After LGBP, pain was measured in the following intervals: 24 hours, one week and one month after the operation. Before the operation onset, 2 mg Keflin and 5000 IU subcutaneous heparin were administered as prophylaxis. LGBP was performed using five ports including: one 11 mm port was placed 15-20 cm far from the xiphoid, one 12-mm port in mid-clavicular line at the level of camera port, one 5-mm port in subcostal area in ante-axillary region in the left, another 5-mm port in the right mid-clavicular area and a 5-mm port in sub-xyphoid. All operations were done by the same team. Staple was used for all anastomoses and hand sewn technique to close the staple insertion site. The mesenteric defect was left open and no effort was made to repair it. RESULTS: The results of this study showed that 99.94 % of the patients had complains of pain in the first 24 hours of post operation, about 60% after one week and 29.5 % still had pain after one month. In addition, left upper quadrant (LUQ) was found to be the most prevalent site for the pain in 53.7% of the patients in the first 24 hours, 59.6% after one week and 16.8% after one month (except for obscure pain) with a significance of < 0.05. CONCLUSIONS: In this study, the authors analyzed the location and disturbance level of pain after LGBP, which could serve as a cornerstone for further researches. The authors suggest that long-term follow-up (for more than a year after operation) should be considered in future studies and also the relationship between the drainage site and pain should be investigated. PMID- 25032168 TI - Traumatic arteriovenous fistula after kickboxing injury: a case report and review of the literature. AB - INTRODUCTION: A traumatic arteriovenous fistula (AVF) after repetitive blunt trauma has not been described previously. In a 34-year-old male, the first reported case of such an injury after repetitive blunt trauma is described. CASE PRESENTATION: A 34-year-old gentleman presented with a non-healing ulcer near his medial malleolus. A bone scan was performed and then treated for presumed osteomyelitis. An arteriogram confirmed an AVF, and coil embolization was performed with complete occlusion of the AVF. Subsequently, the ulcer healed rapidly with no complication. Along with the cause of AVF, this case is notable for symptom presentation. CONCLUSIONS: Arteriovenous fistula after blunt trauma can present as a non-healing venous stasis ulcer, which could be treated non invasively. PMID- 25032169 TI - Agreement of cerebral state index and glasgow coma scale in brain-injured patients. AB - BACKGROUND: Variables derived from electroencephalogram like cerebral state index (CSI) have been used to monitor the anesthesia depth during general anesthesia. Observed evidences show such variables have also been used as a detector of brain death or outcome predictor in traumatic brain-injured (TBI) patients. OBJECTIVES: The current study was designed to determine the correlation between Glasgow coma score (GCS) and CSI among TBI patients. PATIENTS AND METHODS: In 60 brain-injured patients who did not need and receive sedatives, GCS and CSI were daily measured during the first ten days of their hospital stay. Correlation between GCS and CSI was studied using the Pearson's correlation test. The Gamma agreement coefficient was also calculated between the two variables for the first day of hospitalization. RESULTS: A significant correlation coefficient of 0.611-0.796 was observed between CSI and GCS in a ten-day period of the study (P < 0.001). Gamma agreement coefficient was 0.79 (P < 0.001) for CSI and GCS for the first day of hospitalization. An increased daily correlation was observed in both CSI and GCS values. However, this increase was less significant in CSI compared with the GCS. CONCLUSIONS: A statistically significant correlation and agreement was found between GCS and CSI in the brain-injured patients and GCS was also found to be more consistent and reliable compared with CSI. PMID- 25032170 TI - Disabilities and activities of daily living among veterans with old hip disarticulation and transpelvic amputation. AB - BACKGROUND: The Iran-Iraq imposed war lasted eight years and was one of the longest wars of the last century. Twenty-three years have passed since the war ended, but little has been discussed about the long-term results of war amputations in the literature. OBJECTIVES: In this long-term study, we have evaluated the activities of daily living among veterans with hip or hemipelvis amputations. PATIENTS AND METHODS: A cross-sectional study was performed on Iran Iraq war veterans with hip or hemipelvis amputations in Iran. Eighty-four (96.5%) veterans out of 87 registered veterans with hip or hemipelvis amputations participated in the study. The degree of independence for activities of daily living (ADL) was assessed by the Barthel index. The degree of independence for instrumental activities of daily living (IADL) was assessed by the Lawton-Brody scale. RESULTS: The average follow-up time was 26.6 +/- 3.7 years. The average age of veterans was 44.1+/-7 years old. Of 84 amputees, 57 (67.85%) had limitations in at least one domain of the ADL. The most common single item that affected the patients was ascending and descending stairs seen in 45 (78.9%) veterans, followed by eating seen in 4 (7.01%) veterans. In addition, 70 (83.33%) had limitations in at least one domain of the IADL. The most common single item that affected the veterans was shopping seen in 56 (80%), followed by responsibility for own medications seen in 13 (18.57%) veterans. Spearman correlation coefficient of the sum scores of ADL and IADL showed an intermediate to strong correlation (r = 0.58). CONCLUSIONS: Increasing dependency in ADL is accompanied by increasing dependency in IADL. In the past, the duty of health care providers was saving the life of veterans due to injuries while at present, because these injuries occurred in young and healthy individuals, the need for increased function is being highlighted. PMID- 25032171 TI - The reliability of red flags in spinal cord compression. AB - BACKGROUND: Acute low back pain is a common cause for presentation to the emergency department (ED). Since benign etiologies account for 95% of cases, red flags are used to identify sinister causes that require prompt management. OBJECTIVES: We assessed the effectiveness of red flag signs used in the ED to identify spinal cord and cauda equine compression. PATIENTS AND METHODS: It was a retrospective cohort study of 206 patients with acute back pain admitted from the ED. The presence or absence of the red flag symptoms was assessed against evidence of spinal cord or cauda equina compression on magnetic resonance imaging (MRI). RESULTS: Overall, 32 (15.5%) patients had compression on MRI. Profound lower limb neurologic examination did not demonstrate a statistically significant association with this finding. The likelihood ratio (LR) for bowel and bladder dysfunction (sensitivity of 0.65 and specificity of 0.73) was 2.45. Saddle sensory disturbance (sensitivity of 0.27 and specificity of 0.87) had a LR of 2.11. When both symptoms were taken together (sensitivity of 0.27 and specificity of 0.92), they gave a LR of 3.46. CONCLUSIONS: The predictive value of the two statistically significant red flags only marginally raises the clinical suspicion of spinal cord or cauda equina compression. Effective risk stratification of patients presenting to the ED with acute back pain is crucial; however, this study did not support the use of these red flags in their current form. PMID- 25032172 TI - Traumatic dental injuries among 12-15-year-old-school children in panchkula. AB - BACKGROUND: Traumatic dental injury (TDI) in children and adolescents has become one of the most serious dental public health problems. Despite such a high prevalence of dental trauma, very less attention has been paid to TDI, its etiology, and prevention. OBJECTIVES: To determine the prevalence of anterior tooth traumatic dental injuries in 12-15-year-old school children of Panchkula district, India, and to find any correlation with the cause, gender, extent of overbite as well as over-jet, and previous treatment. PATIENTS AND METHODS: A multistage sample of 12-15-year-old school children (n = 810) in Panchkula district, Haryana, was selected. The children were screened using WHO criteria for oral examination and a trained dental surgeon examined the children. Those with clinical TDI were examined further for the type of traumatic injuries using Elis classification modified by Holland. Overjet and overbite were recorded. After examination, questions regarding the cause of trauma and its treatment were asked. Data were subjected to statistical analysis using the Chi square and Mantel-Haenszel tests by SPSS version 20.0. RESULTS: The results showed that out of 810 children, 86 (10.2 %) had TDI. Males had higher prevalence of trauma than females (P < 0.05). The common cause of trauma was fall (51.11%) followed by sports injuries (41.86%). Enamel-dentin fracture without pulpal involvement was the most common type of trauma and the most frequent involved teeth were maxillary central incisors. A significant association was observed between overjet and overbite and trauma. Only 3.5% of the children affected with trauma had received treatment. CONCLUSIONS: The prevalence of traumatic injuries to permanent incisors in 12-15-year-old Panchkula school children was relatively high. TDI was associated with gender, overjet, and lip competence. There was a great unmet treatment need. PMID- 25032173 TI - Validity and reliability of behavioral pain scale in patients with low level of consciousness due to head trauma hospitalized in intensive care unit. AB - BACKGROUND: Estimating pain in patients of intensive care unit (ICU) is essential, but because of their special situation, verbal scales cannot be used. Therefore, to estimate the level of pain, behavioral pain scale was developed by Payen in 2001. OBJECTIVES: The aim of this study was to investigate the validity and reliability of behavioral pain scale in patients with low level of consciousness due to head trauma hospitalized in ICU. PATIENTS AND METHODS: This descriptive prospective study was performed in Yazd in 2013. In this study, fifty patients, including thirteen women and thirty seven men, were involved. To collect the data a questionnaire including demographic and Glasgow coma scale (GCS) information as well as a list of behavioral pain scale (BPS) were used. SPSS software (version 18) was used to analyze the data. RESULTS: There was no significant difference in reliability proving of average score of BPS recorded by two day and night assessors (P > 5). Cronbach's alpha was 85 for painful procedures and 76 for non-painful procedures. In addition, known groups' technique (painful and non-painful procedures) was used to assess validity. The average scores were 7.75 during painful procedures and 3.28 during non-painful procedures (P = 0.001). The results stated that BPS scores during these two procedures were significantly different. CONCLUSIONS: BPS in patients with low level of consciousness due to head trauma has strong reliability and validity. Therefore, this scale can be used for patients hospitalized in ICU to assess the level of pain. PMID- 25032174 TI - The path of science. PMID- 25032175 TI - Gabapentin in burns. PMID- 25032176 TI - Adult bipolar diathermy circumcision and related procedures in adults - a safe and efficient technique. AB - OBJECTIVES: To present our novel technique and step-by-step approach to bipolar diathermy circumcision and related procedures in adult males. METHODS: We reviewed our technique of bipolar circumcision and related procedures in 54 cases over a 22-month period at our day procedure center. Bipolar diathermy cutting and hemostasis was performed using bipolar forceps with a Valleylab machine set at 15. Sleeve circumcision was used. A dorsal slit was made, followed by frenulum release and ventral slit, and was completed with bilateral circumferential cutting. Frenuloplasties released the frenulum. Preputioplasties used multiple 2 3 mm longitudinal cuts to release the constriction, with frenulum left intact. All wounds were closed with interrupted 4/0 Vicryl RapideTM. RESULTS: A total of 54 nonemergency bipolar circumcision procedures were carried out from November 2010-August 2012 (42 circumcisions, eight frenuloplasties, and four preputioplasties). Patients were aged 18-72 years (mean, 34 years). There was minimal to no intraoperative bleeding in all cases, allowing for precise dissection. All patients were requested to attend outpatient reviews; three frenuloplasty and two circumcision patients failed to return. Of the remaining 49, mean interval to review was 49 days, with a range of 9-121 days. Two circumcision patients reported mild bleeding with nocturnal erections within a week postoperatively, but they did not require medical attention. Two others presented to family practitioners with possible wound infections which resolved with oral antibiotics. All 49 patients had well-healed wounds. CONCLUSION: The bipolar diathermy technique is a simple procedure, easily taught, and reproducible. It is associated with minimal bleeding, is safe and efficient, uses routine operating equipment and is universally applicable to circumcision/frenuloplasty/preputioplasty. In addition, it has minimal postoperative complications, and has associated excellent cosmesis. PMID- 25032177 TI - Bilateral spermatocytic seminoma: a case report. AB - Spermatocytic seminoma (SS) is a rare entity, accounting for 2%-12% of all seminomas; amongst those, fewer than 10% are bilateral. These may occur synchronously or metachranously. We report here a case of bilateral SS in a 63 year-old patient, who initially presented with bilateral testicular masses. In our search of the literature, this represents the fifth documented case of synchronous, bilateral SS. PMID- 25032180 TI - Are patients with alcohol-related fatty liver at increased risk of coronary heart disease? PMID- 25032179 TI - Overview and recent trends of systematic reviews and meta-analyses in hepatology. AB - A systematic review (SR) is a research methodology that involves a comprehensive search for and analysis of relevant studies on a specific topic. A strict and objective research process is conducted that comprises a systematic and comprehensive literature search in accordance with predetermined inclusion/exclusion criteria, and an assessment of the risk of bias of the selected literature. SRs require a multidisciplinary approach that necessitates cooperation with clinical experts, methodologists, other experts, and statisticians. A meta-analysis (MA) is a statistical method of quantitatively synthesizing data, where possible, from the primary literature selected for the SR. Review articles differ from SRs in that they lack a systematic methodology such as a literature search, selection of studies according to strict criteria, assessment of risk bias, and synthesis of the study results. The importance of evidence-based medicine (EBM) in the decision-making for public policy has recently been increasing thanks to the realization that it should be based on scientific research data. SRs and MAs are essential for EBM strategy and evidence based clinical practice guidelines. This review addresses the current trends in SRs and MAs in the field of hepatology via a search of recently published articles in the Cochrane Library and Ovid-MEDLINE. PMID- 25032181 TI - Alcoholic fatty liver disease elevates estimated coronary heart disease risk to levels comparable with those of nonalcoholic fatty liver disease in the Korean population: a cross-sectional study. AB - BACKGROUND/AIMS: A close relationship has been established between nonalcoholic fatty liver disease (NAFLD) and an elevated risk of coronary heart disease (CHD), but little is known about the association between alcoholic fatty liver disease (AFLD) and CHD risk. The aim of this study was to determine whether AFLD is associated with elevated CHD risk. METHODS: We retrospectively enrolled 10,710 subjects out of 11,469 individuals who visited the Konkuk University Health Care Center for a routine health checkup in 2010. AFLD was diagnosed made when the usual amount of alcohol consumption exceeded 210 g/week in males and 140 g/week in females for the previous 2 years and when hepatic steatosis was detected by liver ultrasonography. The 10-year risk for CHD was estimated using the Framingham Risk Score. RESULTS: Hepatic steatosis was diagnosed in 4,142 of the 10,710 individuals (38.7%); the remainder (i.e., n=6,568) became the control group. The 4,142 individuals with hepatic steatosis were divided into two groups: NAFLD (n=2,953) and AFLD (n=1,189). The risk of CHD was higher in AFLD (6.72+/ 0.12) than in the control group (5.50+/-0.04, P<0.001), and comparable to that in NAFLD (7.32+/-0.07, P=0.02). CONCLUSIONS: Individuals with AFLD have an elevated 10-year risk of CHD that is comparable to those with NAFLD. Therefore, AFLD should be considered a significant risk for future CHD, and preventive measures should be considered earlier. PMID- 25032182 TI - Changes in the seroprevalence of IgG anti-hepatitis A virus between 2001 and 2013: experience at a single center in Korea. AB - BACKGROUND/AIMS: The incidence of symptomatic hepatitis A reportedly increased among 20- to 40-year-old Korean during the late 2000s. Vaccination against hepatitis A was commenced in the late 1990s and was extended to children aged <10 years. In the present study we analyzed the changes in the seroprevalence of IgG anti-hepatitis A virus (HAV) over the past 13 years. METHODS: Overall, 4903 subjects who visited our hospital between January 2001 and December 2013 were studied. The seroprevalence of IgG anti-HAV was analyzed according to age and sex. In addition, the seroprevalence of IgG anti-HAV was compared among 12 age groups and among the following time periods: early 2000s (2001-2003), mid-to-late 2000s (2006-2008), and early 2010s (2011-2013). The chi-square test for trend was used for statistical analysis. RESULTS: The seroprevalence of IgG anti-HAV did not differ significantly between the sexes. Furthermore, compared to the seroprevalence of IgG anti-HAV in the early 2000s and mid-to-late 2000s, that in the early 2010s was markedly increased among individuals aged 1-14 years and decreased among those aged 25-44 years (P<0.01). We also found that the seroprevalence of IgG anti-HAV in individuals aged 25-44 years in the early 2010s was lower than that in the early 2000s and mid-to-late 2000s. CONCLUSIONS: The number of symptomatic HAV infection cases in Korea is decreasing, but the seroprevalence of IgG anti-HAV is low in the active population. PMID- 25032183 TI - Rescue therapy with adefovir in decompensated liver cirrhosis patients with lamivudine-resistant hepatitis B virus. AB - BACKGROUND/AIMS: Adefovir dipivoxil (ADV) is a nucleotide analogue that is effective against lamivudine-resistant hepatitis B virus (HBV). The aim of this study was to determine the long-term clinical outcomes after ADV rescue therapy in decompensated patients infected with lamivudine-resistant HBV. METHODS: In total, 128 patients with a decompensated state and lamivudine-resistant HBV were treated with ADV at a dosage of 10 mg/day for a median of 33 months in this multicenter cohort study. RESULTS: Following ADV treatment, 86 (72.3%) of 119 patients experienced a decrease in Child-Pugh score of at least 2 points, and the overall end-stage liver disease score decreased from 16+/-5 to 14+/-10 (mean +/- SD, P<0.001) during the follow-up period. With ADV treatment, 67 patients (56.3%) had undetectable serum HBV DNA (detection limit, 0.5 pg/mL). Virologic breakthrough occurred in 38 patients (36.1%) and 9 patients had a suboptimal ADV response. The overall survival rate was 89.9% (107/119), and a suboptimal response to ADV treatment was associated with both no improvement in Child-Pugh score (>=2 points; P=0.001) and high mortality following ADV rescue therapy (P=0.012). CONCLUSIONS: Three years of ADV treatment was effective and safe in decompensated patients with lamivudine-resistant HBV. PMID- 25032178 TI - KASL clinical practice guidelines: management of hepatitis C. PMID- 25032184 TI - No association between the IL28B SNP and response to peginterferon plus ribavirin combination treatment in Korean chronic hepatitis C patients. AB - BACKGROUND/AIMS: There are few available data regarding the association between the single nucleotide polymorphisms (SNPs) of the gene encoding interleukin 28B (IL28B) and a sustained virologic response (SVR) to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy in Korean chronic hepatitis C patients. METHODS: This was a retrospective cohort study of 156 patients with chronic hepatitis C virus (HCV) infection who received combination treatment of PEG-IFN plus RBV. Blood samples from these patients were analyzed to identify the IL28B SNPs at rs12979860, rs12980275, rs8099917, and rs8103142. Association analyses were performed to evaluate the relationships between each IL28B SNP and SVRs. RESULTS: Seventy six patients with HCV genotype 1 and 80 with genotype non-1 were enrolled. The frequencies of rs12979860 CC and CT genotypes were 90.4% and 9.6%, respectively; those of rs12980275 AA and AG genotypes were 87.2% and 12.8%, respectively; those of rs8099917 TT and TG genotypes were 92.3% and 7.7%, respectively; and those of rs8103142 TT and CT genotypes were 90.4% and 9.6%, respectively. Among the patients with HCV genotype 1, the SVR rates were 69.7% and 80.0% for rs12979860 CC and CT, respectively (P=0.71). Among the HCV genotype non-1 patients, SVR rates were 88.0% and 100% for rs12979860 CC and CT (P=1.00), respectively. CONCLUSIONS: Genotypes of the IL28B SNP that are known to be favorable were present in most of the Korean patients with chronic hepatitis C in this study. Moreover, the IL28B SNP did not influence the SVR rate in either the HCV genotype 1 or non-1 patients. Therefore, IL28B SNP analysis might be not useful for the initial assessment, prediction of treatment outcomes, or treatment decision making of Korean chronic hepatitis C patients. PMID- 25032185 TI - Prevalence of renal dysfunction in patients with cirrhosis according to ADQI-IAC working party proposal. AB - BACKGROUND/AIMS: A revised classification system for renal dysfunction in patients with cirrhosis was proposed by the Acute Dialysis Quality Initiative and the International Ascites Club Working Group in 2011. The aim of this study was to determine the prevalence of renal dysfunction according to the criteria in this proposal. METHODS: The medical records of cirrhotic patients who were admitted to Konkuk University Hospital between 2006 and 2010 were reviewed retrospectively. The data obtained at first admission were collected. Acute kidney injury (AKI) and chronic kidney disease (CKD) were defined using the proposed diagnostic criteria of kidney dysfunction in cirrhosis. RESULTS: Six hundred and forty-three patients were admitted, of whom 190 (29.5%), 273 (42.5%), and 180 (28.0%) were Child-Pugh class A, B, and C, respectively. Eighty-three patients (12.9%) were diagnosed with AKI, the most common cause for which was dehydration (30 patients). Three patients had hepatorenal syndrome type 1 and 26 patients had prerenal-type AKI caused by volume deficiency after variceal bleeding. In addition, 22 patients (3.4%) were diagnosed with CKD, 1 patient with hepatorenal syndrome type 2, and 3 patients (0.5%) with AKI on CKD. CONCLUSIONS: Both AKI and CKD are common among hospitalized cirrhotic patients, and often occur simultaneously (16.8%). The most common type of renal dysfunction was AKI (12.9%). Diagnosis of type 2 hepatorenal syndrome remains difficult. A prospective cohort study is warranted to evaluate the clinical course in cirrhotic patients with renal dysfunction. PMID- 25032186 TI - Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation. AB - BACKGROUND/AIMS: The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated. METHODS: Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 +/- 1.3 ng/mL (mean +/- SD). RESULTS: The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive (18)fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05). CONCLUSIONS: Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients. PMID- 25032187 TI - Pure red-cell aplasia and autoimmune hemolytic anemia in a patient with acute hepatitis A. AB - Pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) have rarely been reported as an extrahepatic manifestation of acute hepatitis A (AHA). We report herein a case of AHA complicated by both PRCA and AIHA. A 49-year-old female with a diagnosis of AHA presented with severe anemia (hemoglobin level, 6.9 g/dL) during her clinical course. A diagnostic workup revealed AIHA and PRCA as the cause of the anemia. The patient was treated with an initial transfusion and corticosteroid therapy. Her anemia and liver function test were completely recovered by 9 months after the initial presentation. We review the clinical features and therapeutic strategies for this rare case of extrahepatic manifestation of AHA. PMID- 25032188 TI - A case of obstructive jaundice caused by tuberculous lymphadenitis: a literature review. AB - Obstructive jaundice caused by tuberculous lymphadenitis is a rare manifestation of tuberculosis (TB), with 15 cases having been reported in Korea. We experienced a case of obstructive jaundice caused by pericholedochal tuberculous lymphadenitis in a 30-year-old man. The patient's initial serum total bilirubin level was 21.1 mg/dL. Abdominal computed tomography revealed narrowing of the bile duct by a conglomerated soft-tissue mass involving the main portal vein. Abrupt obstruction of the common bile duct was observed on cholangiography. Pathologic analysis of a ultrasonography-guided biopsy sample revealed chronic granulomatous inflammation, and an endoscopic examination revealed esophageal varices and active duodenal ulceration, the pathology of which was chronic noncaseating granulomatous inflammation. Hepaticojejunostomy was performed and pathologic analysis of the conglomerated soft-tissue mass revealed chronic granulomatous inflammation with caseation of the lymph nodes. Tuberculous lymphadenitis should be considered in patients presenting with obstructive jaundice in an endemic area. PMID- 25032189 TI - Intrahepatic cholangiocarcinoma with predominant ductal plate malformation pattern. PMID- 25032190 TI - Magnetic resonance imaging following treatment of advanced hepatocellular carcinoma with sorafenib. AB - Hepatocellular carcinomas are highly vascular tumors, showing progressive hypervascularity by the process of neoangiogenesis. Tumor angiogenesis is critical for tumor growth as well as metastatic spread therefore, imaging and quantification of tumor neo-angiogenesis is essential for monitoring response to targeted therapies and predicting disease progression. Sorafenib is a molecular targeting agent used for treating hypervascular tumors. This drug is now the standard of care in treatment of patients with advanced hepatocellular carcinoma. Due to its anti-angiogenic and anti-proliferative actions, imaging findings following treatment with Sorafenib are quite distinct when compared to conventional chemotherapeutic agents. Liver MRI is a widely adopted imaging modality for assessing treatment response in hepatocellular carcinoma and imaging features may reflect pathophysiological changes within the tumor. In this mini review, we will discuss MRI findings after Sorafenib treatment in hepatocellular carcinoma and review the feasibility of MRI as an early biomarker in differentiating responders from non-responders after treatment with molecular targeting agents. PMID- 25032191 TI - Current role of treatment in men with lower urinary tract symptoms combined with overactive bladder. AB - Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in older men. The storage subcategory of LUTS is synonymous with overactive bladder (OAB) syndrome, which is an empirical diagnosis. Traditionally, alpha-blockers are widely prescribed to manage the LUTS of BPH, although storage symptoms may persist in many men despite treatment. Therefore, because therapies that target the prostate often fail to alleviate storage symptoms, they may not be the appropriate therapy for OAB. In past years, most physicians appeared to give more weight in elderly men to voiding symptoms than to storage symptoms and to be more concerned with initial treatment with anticholinergics for males with storage symptoms. Considering the recent increase in data on the efficacy and safety of combination treatment with alpha receptor antagonists and antimuscarinic agents, the standard pharmacologic treatment of patients with LUTS combined with OAB should be an alpha receptor antagonist and an antimuscarinic agent. Beta-3 adrenoreceptor agonists may also potentially be useful for the treatment of male LUTS combined with OAB. PMID- 25032192 TI - Predictive factors of unfavorable prostate cancer in patients who underwent prostatectomy but eligible for active surveillance. AB - PURPOSE: To investigate the predictive factors of unfavorable prostate cancer in Korean men who underwent radical prostatectomy but eligible for active surveillance according to Epstein criteria. METHODS: We retrospectively reviewed the medical records of 2,036 patients who underwent radical prostatectomy for prostate cancer between 1994 and 2011. Among these, 233 patients were eligible for active surveillance based on Epstein criteria. Unfavorable prostate cancer was defined as pathologic Gleason sum >=7 or non-organ-confined disease. We investigated pathologic outcomes and predictive factors for unfavorable prostate cancer. RESULTS: Of 233 cases, 91 patients (39.1%) were pathologic Gleason sum >=7, 11 (4.7%) had extracapsular extension, and three (1.3%) had seminal vesicle invasion. Ninety-eight patients (42.1%) had unfavorable prostate cancer. When comparing clinically insignificant and significant prostate cancer, there were significant differences in mean age (P=0.007), prostate volume (P=0.021), prostate-specific antigen (PSA) density (P=0.03), maximum tumor volume in biopsy core (P<0.001), and rate of two positive cores (P=0.001). On multivariate analysis, age (P=0.015), PSA density (P=0.017) and two positive cores (P=0.001) were independent predictive factors for unfavorable prostate cancer. CONCLUSIONS: A significant proportion of patients who were candidates for active surveillance had unfavorable prostate cancer. Age, PSA density, and two positive cores were independent significant predictive factors for unfavorable prostate cancer. These factors should be considered when performing active surveillance. PMID- 25032193 TI - Analysis of different tumor volume thresholds of insignificant prostate cancer and their implications for active surveillance patient selection and monitoring. AB - PURPOSE: We compared oncological outcomes according to tumor volume (TV) thresholds defining both classical and updated insignificant prostate cancer (IPC), since the TV threshold can be used as clinical parameter for active surveillance. METHODS: Between 2001 and 2012, we retrospectively analyzed 331 organ-confined prostate cancer patients who had preoperative Gleason score 6, preoperative PSA under 10 ng/mL and pathologic TV less than 1.3 mL. Among them, 81 of 331 (24.5%) had Gleason grade 4/5 disease postoperatively. Patients were stratified into two groups: (1) TV less than 0.5 mL, using the classical definition; and (2) TV between 0.5 mL and 1.3 mL, using the range of updated definition. We compared biochemical recurrence (BCR)-free survival and identified independent predictors of BCR in each group. RESULTS: Group 2 had more Gleason grade 4/5 disease than group 1 (P<0.001). On multivariate analysis, Gleason grade 4/5 disease was not associated with BCR in group 1 (P=0.132). However, it was an independent predictor for BCR in group 2 (P=0.042). BCR-free survival were not significantly different according to the presence of Gleason grade 4/5 disease in group 1 (P=0.115). However, in group 2, it was significantly different according to the presence of Gleason grade 4/5 disease (P=0.041). CONCLUSIONS: Although the TV thresholds of the two definitions of IPC vary only slightly, this difference was enough to result in different clinical course if Gleason grade 4/5 disease was present. Therefore, the updated IPC TV threshold should be carefully applied as clinical parameter for active surveillance. PMID- 25032194 TI - Robotic assisted laparoscopic radical prostatectomy following transurethral resection of the prostate: perioperative, oncologic and functional outcomes. AB - PURPOSE: The aim of this study was to assess surgical, oncologic and functional results after robotic-assisted laparoscopic radical prostatectomy (RALP) with and without previous transurethral resection of the prostate (TURP). METHODS: Between December 2005 and January 2010, 200 patients underwent RALP, of whom 16 (8%) had received previous TURP and 184 (92%) had not. Perioperative and postoperative data were compared between those with previous TURP (group 1) and those without previous TURP (group 2). All patients included in the study had at least 1-year follow-up. RESULTS: Preoperative clinical parameters were comparable between both groups. Group 1 patients were found to have significantly more need for bladder neck reconstruction (93.75 % vs. 15.21%, P <0.001), more rectal injury (18.75% vs. 0%, P <0.001), higher incidence of major complications (18.8% vs. 1.1%, P<0.001), and smaller specimen volume (31.63 mL vs. 45.49 mL, P<0.001) than group 2. The 12-month continence rate was 93.8 % in group 1 and 97.8% in group 2 (P =0.344). A nerve-sparing technique was significantly less successfully performed in group 1 patients than in group 2 (33.3% vs. 92.0 %, P=0.001). CONCLUSIONS: Performing RALP for prostate cancer in patients who have had previous TURP is a technically demanding procedure and may be potentially associated with a higher perioperative major complication rate in short-term follow-up. Neurovascular bundle preservation is technically more challenging. PMID- 25032195 TI - Role of cyclin D1 immunoreactivity and AgNOR staining in the evaluation of benign and malignant lesions of the prostate. AB - PURPOSE: Prostatic carcinoma is a common and growing public health problem. Histological evaluation is fairly adequate for assessing tumor differentiation, but tumor proliferative activity is difficult to measure. Increasing evidence suggests that the factors controlling cell cycle progression also modulate the rate of ribosome biogenesis. Despite the influence of cyclin D1 and argyrophilic nuclear organizer region (AgNOR) on prostate cancer proliferation, few studies have evaluated the diagnostic importance of these markers. Therefore, the present study was carried out to analyze the diagnostic value of the proliferative markers cyclin D1 and AgNOR in various prostatic lesions and to determine whether any association or relation between these markers and different Gleason grades exists. METHODS: A total 50 cases of various prostatic lesions were studied. Tumor grade, AgNOR staining, and cyclin D1 expression were evaluated in all cases. Correlations between the intensity and differential localization of these markers and Gleason grades were evaluated. RESULTS: The mean AgNOR count in cases of prostatic intraepithelial neoplasia was high compared with cases of benign prostatic hyperplasia (BPH) but lower than that of carcinoma cases. The intensity of cyclin D1 expression was high in carcinoma. A total of 14 cases (46.67%) showed strong positivity. No significant correlation was found between the intensity of cyclin D1 expression, AgNOR count, and histologic grades of prostatic carcinoma, whereas a significant correlation was observed between intensity and percentage expression of cyclin D1 in BPH and carcinoma (P<0.01). Nuclear as well as cytoplasmic positivity was seen among various grades of carcinoma. CONCLUSIONS: AgNOR count and cyclin D1 may be helpful in distinguishing between BPH and carcinoma of the prostate but may not be used as reliable indicators of the grade of prostatic adenocarcinoma because of overlapping values in various grades. However, further studies on larger samples are required to elucidate the role of these markers in identification of premalignant lesions. PMID- 25032196 TI - Management of male lower urinary tract symptoms suggestive of benign prostatic hyperplasia by general practitioners in Jakarta. AB - PURPOSE: This study was performed to describe and evaluate the management of male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) by general practitioners (GPs) in Jakarta. METHODS: This observational cross-sectional study was peformed between January 2013 and August 2013 in Jakarta. We developed a questionnaire consisting of 10 questions describing the management of male LUTS suggestive of BPH by GPs in their daily practice in the previous month. We collected questionnaires from 200 GPs participating in 4 urology symposiums held in Cipto Mangunkusumo Hospital, Jakarta. RESULTS: Most GPs were aged between 25 and 35 years (71.5%) and had worked for more than 1 year (87.5%). One to 5 cases of male LUTS suggestive of BPH were treated by 81% of GPs each month. At diagnosis, the most common symptoms found were urinary retention (55.5%), frequency (48%), and nocturia (45%). The usual diagnostic workup included digital rectal examination (65%), scoring system (44%), measurement of prostate-specific antigen (PSA) level (23.5%), and renal function assessment (20%). Most GPs referred their male patients with LUTS suggestive of BPH to a urologist (59.5%) and 46.5% of GPs prescribed drugs as an initial therapy. Alpha adrenergic antagonist monotherapy (71.5%) was the most common drug prescribed. Combination therapy with alpha-adrenergic antagonists and 5alpha-reductase inhibitors was not routinely prescribed (13%). Thirty-eight percent of GPs referred their patients when recurrent urinary retention was present and 33% when complications were present. CONCLUSIONS: Our study provides evidence that the management of male LUTS suggestive of BPH by GPs in Jakarta suggests referral in part to available guidelines in terms of diagnostic methods and initial therapy. However, several aspects of the guidelines, such as PSA level measurement, renal function assessment, urinalysis, ultrasound examination, and prescription of combination therapies, are still infrequently performed. PMID- 25032198 TI - Is there a role for fish oil in inflammatory bowel disease? AB - A number of animal and human studies suggest omega 3-fatty acids are anti inflammatory. As a result they may have a therapeutic role in inflammatory bowel disease (IBD). The aim of this review is to briefly assess the literature about the utility of poly-unsaturated fatty acids (PUFAs) in the management of IBD. Taken together, almost all studies suggest some beneficial effects of n-3 PUFAs in IBD but the mechanism remains controversial. In addition, clinical benefit seems to be largely confined to ulcerative colitis. However all studies have concluded that these compounds have no potential for a steroid/aminosalicylic acid sparing effect or to maintain remission. Now the question arises as to whether this treatment is of real value to IBD patients? Clearly they have some therapeutic potential but further work is needed. PMID- 25032197 TI - Infectious burden and atherosclerosis: A clinical issue. AB - Atherosclerotic cardiovascular diseases, chronic inflammatory diseases of multifactorial etiology, are the leading cause of death worldwide. In the last decade, more infectious agents, labeled as "infectious burden", rather than any single pathogen, have been showed to contribute to the development of atherosclerosis through different mechanisms. Some microorganisms, such as Chlamydia pneumoniae (C. pneumoniae), human cytomegalovirus, etc. may act directly on the arterial wall contributing to endothelial dysfunction, foam cell formation, smooth muscle cell proliferation, platelet aggregation as well as cytokine, reactive oxygen specie, growth factor, and cellular adhesion molecule production. Others, such as Helicobacter pylori (H. pylori), influenza virus, etc. may induce a systemic inflammation which in turn may damage the vascular wall (e.g., by cytokines and proteases). Moreover, another indirect mechanism by which some infectious agents (such as H. pylori, C. pneumoniae, periodontal pathogens, etc.) may play a role in the pathogenesis of atherosclerosis is molecular mimicry. Given the complexity of the mechanisms by which each microorganism may contribute to atherosclerosis, defining the interplay of more infectious agents is far more difficult because the pro-atherogenic effect of each pathogen might be amplified. Clearly, continued research and a greater awareness will be helpful to improve our knowledge on the complex interaction between the infectious burden and atherosclerosis. PMID- 25032199 TI - Critical review of topical management of oral hairy leukoplakia. AB - Oral hairy leukoplakia (OHL) is a disease associated with Epstein-Barr virus and human immunodeficiency virus infections. OHL is usually an asymptomatic lesion, but in some cases treatment is recommended to reestablish the normal characteristics of the tongue, to eliminate pathogenic microorganisms, to improve patient comfort and for cosmetic reasons. Proposed treatments for this condition include surgery, systemic antiviral treatment and topical management. Topical treatment is an inexpensive and safe therapy that is easy to apply, noninvasive, free of systemic adverse effects and effective over a long period of time. The aim of this study was to present a review of the literature for topical therapy for OHL. Gentian violet, retinoids, podophyllin, acyclovir and podophyllin associated with topical antiviral drugs were used to treat OHL. Reports with this focus are limited, and since 2010, no new studies have been published that discuss the efficacy of topical treatments for OHL. Podophyllin with acyclovir cream was found to be effective, causing regression of lesions with no recurrences. Additional searches are necessary to provide clinical evidence of topical management effectiveness. PMID- 25032200 TI - Association between resting energy expenditure, psychopathology and HPA-axis in eating disorders. AB - AIM: To investigate the complex relationships between resting energy expenditure (REE), eating psychopathology, and Hypothalamus Pituitary Adrenal axis functioning in patients with eating disorders. METHODS: The study was designed as a cross-sectional survey, and it was planned by the Clinic for Eating Disorders of the University of Florence (Italy). The protocol was approved by the Ethics Committee of the Institution. Twenty two anorexia nervosa and twenty one Bulimia Nervosa patients were assessed by means of a clinical interview and the structured clinical interview for diagnostic and statistical manual of mental disorders, fourth edition. Eating attitudes and behaviour were specifically investigated by means of the eating disorder examination questionnaire (EDE-Q). Patients were also evaluated by means of the symptom checklist (SCL 90-R), REE was measured by means of indirect calorimetry, and blood cortisol morning levels were evaluated. RESULTS: Both anorexia nervosa and bulimia nervosa patients showed a reduced REE as compared with predicted REE. Body mass index (BMI) was positively associated with resting energy expenditure in Bulimics, whereas a strong, negative association between BMI and REE was observed in Anorectics. The pattern of associations between variables supported a mediation model, where shape concern accounted for variations in REE and cortisol levels (mediator), and variations in the mediator significantly accounted for variations in REE. When these associations where taken into account together, the relationship between shape concern and REE was no longer significant, whereas the association between cortisol levels and REE retained its significance, showing strong evidence for a single, dominant mediator. Anorectics and Bulimics showed an opposite pattern of association between BMI and REE. In Anorectics only, a higher REE was associated with a more severe eating disorder specific psychopathology, and cortisol levels represent a possible mediating factor for this relationship. CONCLUSION: The data supported a mediation model where cortisol levels mediated the relationship between eating psychopathology (concern about body shape) and REE. PMID- 25032201 TI - Role of ethnicity in social anxiety disorder: A cross-sectional survey among health science students. AB - AIM: To investigate the influence of ethnicity in social anxiety disorder (SAD), and the relationship with symptom severity, depression and substance use or abuse, in health sciences' students . METHODS: This was a cross-sectional survey of 112 1(st), 2(nd) and 3(rd) year students from the Faculty of Medicine and Health Sciences at Stellenbosch University, Cape Town, South Africa. The self reported Social Anxiety Spectrum questionnaire was used to assess for SAD. The Social Phobia Inventory (SPIN) was adapted to a version called the E-SPIN (Ethnic SPIN) in order to evaluate the effects of ethnicity. Two sub-questions per stem question were included to assess whether SAD symptoms in social interactions were ethnicity dependent. Substance use was assessed with the Alcohol Use Disorders Identification Test and Drug Use Disorders Identification Test, and depression with the Centre for Epidemiological Studies Depression Scale. RESULTS: Of 112 students who completed the E-SPIN questionnaire, 54.4% (n = 61) met criteria for SAD, with significantly more females than males meeting criteria. Ethnicity had a significant effect on SAD symptomatology, but there was no effect of ethnicity on the rates of drug and alcohol abuse in students with and without SAD. Overall significantly more students with SAD met criteria for depression compared with students without the disorder. CONCLUSION: Among university students, SAD is prevalent regardless of whether interactions are with individuals of the same or different ethnic group. However, ethnicity may be an important determinant of social anxiety for some ethnic groups. SAD was significantly associated with major depression but not significantly associated with drug or alcohol abuse. PMID- 25032202 TI - Cut-off of body mass index and waist circumference to predict hypertension in Indian adults. AB - AIM: To determine the cut-off values of body mass index (BMI) and waist circumference to predict hypertension in adults in north India. METHODS: A community based cross-sectional study was conducted in 801 subjects in Kanpur, aged 20 years and above, using multistage stratified random sampling technique. A pre-tested structured questionnaire was used to elicit the required information from the study participants and the diagnostic criteria for hypertension were taken according to the Seventh Joint National Committee Report on Hypertension (JNC-7). Receiver operating characteristic (ROC) analysis was used to estimate the cut-off values of BMI and waist circumference to predict hypertension. RESULTS: The ROC analysis revealed that BMI is a good predictor of hypertension for both men (area under the ROC curve 0.714) and women (area under the ROC curve 0.821). The cut-off values of BMI for predicting hypertension were identified as >= 24.5 kg/m(2) in men and >= 24.9 kg/m(2) in women. Similarly, the ROC analysis for waist circumference showed that it is a good predictor of hypertension both for men (area under the ROC curve 0.784) and women (area under the ROC curve 0.815). The cut-offs for waist circumference for predicting hypertension were estimated as >= 83 cm for men and >= 78 cm for women. Adults with high BMI or high waist circumference had a higher prevalence of hypertension, respectively. CONCLUSION: Simple anthropometric measurements such as BMI and waist circumference can be used for screening people at increased risk of hypertension in order to refer them for more careful and early diagnostic evaluation. Policies and programs are required for primary and secondary prevention of hypertension. PMID- 25032203 TI - Perirenal extra-adrenal myelolipoma. AB - Myelolipomas are rare tumors consisting of both adipose and hematopoietic tissue and are typically found within the adrenal gland. Extra-adrenal involvement is rare, especially those tumors involving the perirenal space and collecting system. We report a case of a patient with an incidentally discovered perirenal mass that was initially concerning for a retroperitoneal liposarcoma. Following surgical resection and pathological analysis, the lesion was found to be an extra adrenal myelolipoma. This case report and review of the literature demonstrates the importance of the proper work-up and management of perirenal lipoma variants while addressing the issues of tissue biopsy, surgical intervention, and pre- and post-operative surveillance. PMID- 25032204 TI - Verrucous carcinoma of the esophagus: A case report and literature review. AB - Verrucous carcinoma of the esophagus is a variant of a squamous cell cancer. Our case is a 78-year-old male patient comes in with the dysphagia and weight loss, and on endoscopy (EGD) he is found to have an irregular intraluminal mass at the distal esophagus. With the deep EGD assisted biopsy, diagnosis of the verrucous carcinoma is made. Due to multiple co morbidities and possible infiltration to the pericardium, patient is taken for the esophageal stent placement and is being referred for the chemo-radiation treatment. The diagnosis can be very difficult to make with the superficial biopsies due to very non specific histological changes and requires very high clinical suspicion and deep mucosal biopsies are required for accurate diagnosis of the tumor. Chronic and local disease process is the main risk factor for the development of the verrucous carcinoma of the esophagus. Surgery is the treatment of the choice for the early stage tumor and advanced cases are treated with the palliation and possibly chemo- radiation. The prognosis is usually guarded and needs long term follow up. PMID- 25032205 TI - 360 degrees fusion for realignment of high grade cervical kyphosis by one step surgery: Case report. AB - Surgical treatment for cervical kyphotic deformity is still controversial. Circumferential approach has been well described in the literature but long terms outcomes are not well reported. Important to decide the correct treatment option is the preoperative radiological exams to value the type of deformity (flexible or fixed). We report the case of a 67-year-old woman affected by a severe cervical kyphotic deformity who underwent combined anterior/posterior surgical approach, getting a good reduction of the deformity and an optimal stability in a long term follow up. PMID- 25032206 TI - Focal epithelial hyperplasia in a human immuno-deficiency virus patient treated with laser surgery. AB - Focal epithelial hyperplasia (FEH), or Heck's disease, is a rare disease of the oral mucosa; it is mostly found in children or young adults who are immunosuppressed and who live in regions with low socioeconomic status. It is characterized by asymptomatic papules on the oral mucosa, gingiva, tongue, and lips. Healing can be spontaneous, and treatment is indicated if there are aesthetic or functional complications. Human papillomavirus, especially genotypes 13 and 32, has been associated with FEH and is detected in the majority of lesions. Histopathologically, FEH is characterized by parakeratosis, epithelial hyperplasia, focal acanthosis, and fusion and horizontal outgrowth of epithelial ridges. A 37-year-old male patient was referred to the Department of Oral and Maxillofacial Sciences at the Sapienza University of Rome, complaining of numerous exophytic lesions in his mouth. He stated that the lesions were not painful but he had experienced occasional bleeding after incidental masticatory trauma. He had received no previous treatment for the oral lesions. His medical history revealed that he was human immuno-deficiency virus positive and was a smoker with numerous, asymptomatic oral papules clinically and histologically corresponding to FEH. The labial and buccal mucosa were especially affected by lesions. Surgical treatment was performed using a 532-nm potassium titanyl phosphate laser (SmartLite, Deka, Florence, Italy) in continuous mode with a 300 MUm fiber and power of 1.4 W (power density 1980.22 W/cm(2)). After anesthesia without vasoconstrictors, the lesions were tractioned with sutures or an Allis clamp and then completely excised. The lesions were preserved in 10% formalin for histological examination, which confirmed the clinical diagnosis of FEH. In this case, the laser allowed excellent control of bleeding, without postoperative sutures, and optimal wound healing. PMID- 25032207 TI - Optimal management of a patient with recurrent nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma is rare in western countries, accounting for less than 1% of all malignancies. Despite prognosis is satisfactory for newly diagnosed, non-metastatic disease, management of recurrent disease is challenging, with a survival expectancy of approximately 6 mo with the use of chemotherapy as the sole salvage treatment. We report a case of recurrent nasopharyngeal carcinoma treated with a combination of chemotherapy, radiotherapy and surgery in the context of a multidisciplinary approach. A durable complete response was achieved. PMID- 25032208 TI - Disseminated infection due to Mycobacterium bovis after intravesical BCG instillation. AB - Intravesical bacillus Calmette-Guerin (BCG) instillation has been adopted for the treatment of patients with superficial bladder cancer. Severe adverse events due to local instillation of BCG are uncommon, with an overall rate of serious complications of less than 5%. We report the case of an immunocompetent adult patient with multi-system effects, namely pneumonitis, granulomatous hepatitis and meningitis, who responded well to standard treatment for Mycobacterium bovis. This case highlights the importance of a thorough assessment of this type of patient. PMID- 25032209 TI - One-stage revision in two cases of Salmonella prosthetic hip infection. AB - We describe two cases of prosthetic joint infection (PJI) of the hip due to Salmonella. The first patient presented with an early infection 5 d after being discharged following a total hip replacement and the second patient presented at the emergency ward with a late infection, thirteen years following a total hip replacement. Both cases occurred within one month of each other at our institution and both were successfully treated with a one-stage revision. PJI caused by Salmonella species is very rare: so far only 20 Salmonella PJIs of the hip have been described. Therefore, full consensus on the best treatment approach has not yet been reached. An aggressive two-stage approach is advised because of the virulence of Salmonella, although a limited number of successful one-stage approaches have been described as well. According to the latest guidelines, one stage revision has comparable success rates and less morbidity compared to two stage treatment, when selecting the right patients. In our opinion, PJI caused by Salmonella should be treated just as PJI caused by other bacteria, with consideration of the selection criteria as mentioned in several treatment guidelines. As illustrated by these two cases, one-stage revision can be successful in both early and late Salmonella PJI of the hip. PMID- 25032210 TI - Passage of nasogastric tube through tracheo-esophageal fistula into stomach: A rare event. AB - Esophageal atresia with tracheo-oesophageal fistula (TEF) occurs in 1 in 3500 live births. Anorectal malformation is found to be associated with 14% of TEF. Esophageal atresia with TEF is a congenital anomaly which classically presents as excessive frothing from the mouth and respiratory distress. Rarely gastric position of the feeding tube in a case of TEF can be obtained delaying the diagnosis of TEF. We had an uncommon situation where a nasogastric tube reached the stomach through the trachea and tracheo-esophageal fistula, leading to misdiagnosis in a case of esophageal atresia with tracheoesophageal fistula. By using a stiff rubber catheter instead of a soft feeding tube for the diagnosis of esophageal atresia and TEF, such situation can be avoided. PMID- 25032211 TI - Diagnostic pitfall of sebaceous gland metaplasia of the esophagus. AB - We investigated the sebaceous gland metaplasia (SGM) of the esophagus and clarified the evidence of misdiagnosis and its diagnosis pitfall. Cases of pathologically proven SGM were enrolled in the clinical analysis and reviewed description of endoscope. In the current study, we demonstrated that SGM is very rare esophageal condition with an incidence around 0.00465% and an occurrence rate of 0.41 per year. There were 57.1% of senior endoscopists identified 8 episodes of SGM. In contrast, 7.7% of junior endoscopists identified SGM in only 2 episodes. Moreover, we investigated the difference in endoscopic biopsy attempt rate between the senior and junior endoscopist (P = 0.0001). The senior endoscopists had more motivation to look for SGM than did junior endoscopists (P = 0.01). We concluded that SGM of the esophagus is rare condition that is easily and not recognized in endoscopy studies omitting pathological review. PMID- 25032212 TI - Seroprevalence of antibodies against Pkn1, a novel potential immunogen, in Chlamydia trachomatis-infected Macaca nemestrina and human patients. AB - Chlamydia trachomatis (CT) is an important cause of sexually transmitted genital tract infections (STIs) and trachoma. Despite major research into chlamydial pathogenesis and host immune responses, immunoprotection has been hampered by the incomplete understanding of protective immunity in the genital tract. Characterized vaccine candidates have shown variable efficacy ranging from no protection to partial protection in vivo. It is therefore a research priority to identify novel chlamydial antigens that may elicit protective immune responses against CT infection. In the present study we assessed the seroprevalence of antibodies against protein kinase1 (Pkn1), DNA ligaseA (LigA), and major outer membrane protein A (OmpA) following natural CT infection in humans and in experimentally induced CT infection in Macaca nemestrina. Antigenic stretches of Pkn1, LigA, and OmpA were identified using bioinformatic tools. Pkn1, LigA, and OmpA genes were cloned in bacterial expression vector and purified by affinity chromatography. Our results demonstrate significantly high seroprevalence of antibodies against purified Pkn1 and OmpA in sera obtained from the macaque animal model and human patients infected with CT. In contrast no significant seroreactivity was observed for LigA. The seroprevalence of antibodies against Pkn1 suggest that nonsurface chlamydial proteins could also be important for developing vaccines for C. trachomatis. PMID- 25032213 TI - Attenuation of collagen-induced arthritis in mice by salmon proteoglycan. AB - Rheumatoid arthritis (RA) is a serious autoimmune disease caused by chronic inflammation of connective tissues. The basic principle of RA treatment is aimed to reduce joint inflammation. Our previous studies demonstrated that salmon cartilage proteoglycan (PG) suppresses excess inflammation in different mouse inflammatory diseases. In this study, we investigated the prophylactic effect of PG on the progression of RA using an experimental mouse model, collagen-induced arthritis (CIA). Clinical and histological severity of CIA was attenuated by daily oral administration of PG. In the joints of PG-administered mice, infiltration of macrophages and neutrophils and also osteoclast accumulation were limited. In comparison to nonadministered mice, anti-collagen antibodies in the sera of PG-administered mice did not alter. On the other hand, local expression of interleukin-17A (IL-17A), IL-6, IL-1 beta, interferon- gamma (IFN- gamma), C-C chemokine ligand 2 (CCL2), C-X-C chemokine ligand 1 (CXCL1), and CXCL2 in the joints of PG-administered mice decreased. Moreover, in the response of type II collagen- (CII-) restimulation ex vivo, IL-17A and IFN- gamma production by splenocytes from PG-administered mice was less than that of control mice. These data suggested that daily ingested PG attenuated CIA pathogenesis by modulating immune response of splenocytes to CII stimulation and local production inflammatory cytokines and chemokines in the joints. PMID- 25032214 TI - Strontium chloride: can it be a new treatment option for ulcerative colitis? AB - BACKGROUND/AIMS: Patients with ulcerative colitis still need effective therapy without major side effects. It has been found that strontium can suppress NFkappaB activation induced by TNF-alpha. This opens a gate to a new anti-TNF agent which is cheap and can be given orally. We for the first time aimed to investigate the effect of strontium chloride (SrCl2) on inflammation in experimental colitis. METHODS: Thirty female Wistar albino rats were divided into 5 groups each containing 6 rats. The rats in groups 1 and 2 served as the healthy control and colitis group, respectively. The rats in groups 3, 4, and 5 had colitis and received 40 mg/kg SrCl2, 160 mg/kg SrCl2, and 1 mg/kg prednisolone by oral gavage, respectively. The rats were sacrificed for histological evaluation and determination of serum neopterin, TNF-alpha, and IFN-gamma levels. RESULTS: The neopterin, TNF-alpha and IFNgamma levels of group 2 was significantly higher than the other groups. The neopterin, TNF-alpha, and IFN-gamma levels of controls and other treatment groups were comparable. There were a significant difference in macroscopic and microscopic healing between group 2 and other groups histologically. But there was not a significant difference within treatment receiving groups. CONCLUSION: SrCl2 had comparable therapeutic efficiency with prednisolone. PMID- 25032215 TI - Statistical approach for production of PUFA from Kocuria sp. BRI 35 isolated from marine water sample. AB - In this study, Plackett-Burman design was used to identify the most influential parameters affecting PUFA production by Kocuria sp. BRI 35 isolated from Antarctic water sample. Amongst 10 variables evaluated, magnesium chloride, protease peptone, glucose, and temperature were significant. Response surface methodology consisting of a central composite design was developed to study the interactions between the variables and to determine optimal values of significant variables. A quadratic model (R = 0.9652, F = 14.64, P < 0.0001) was built. The contour plots indicated that the isolate produced maximum PUFA at lower concentrations of magnesium sulfate (0.9 g/L) and higher concentrations of protease peptone (5 g/L) and glucose (10 g/L) at 15 degrees C. MgSO4 and glucose exhibited quadratic as well as interactive effect on PUFA production whereas protease peptone and temperature showed interactive effects only. After optimization, PUFA production per unit biomass increased from 0.94 mg/g to 11.12 mg/g. This represented an increase from 3% to 58.62% of the total fatty acids. Among PUFAs, the yield of omega -6 fatty acids increased from 9.66 mg/L to 107.71 mg/L with significant increase in linoleic acid (20.36 mg/L) whereas omega -3 fatty acids increased up to 12.37 mg/L with DHA being the major omega -3 fatty acid produced. PMID- 25032216 TI - Role of IL-33 and its receptor in T cell-mediated autoimmune diseases. AB - Interleukin-33 (IL-33) is a new cytokine of interleukin-1 family, whose specific receptor is ST2. IL-33 exerts its functions via its target cells and plays different roles in diseases. ST2 deletion and exclusion of IL-33/ST2 axis are accompanied by enhanced susceptibility to dominantly T cell-mediated organ specific autoimmune diseases. It has been reported that IL-33/ST2 pathway plays a key role in host defense and immune regulation in inflammatory and infectious diseases. This review focuses on new findings in the roles of IL-33 and ST2 in several kinds of T cell-mediated autoimmune diseases. PMID- 25032217 TI - Current approaches for predicting a lack of response to anti-EGFR therapy in KRAS wild-type patients. AB - Targeting epidermal growth factor receptor (EGFR) has been one of the most effective colorectal cancer strategies. Anti-EGFR antibodies function by binding to the extracellular domain of EGFR, preventing its activation, and ultimately providing clinical benefit. KRAS mutations in codons 12 and 13 are recognized prognostic and predictive biomarkers that should be analyzed at the clinic prior to the administration of anti-EGFR therapy. However, still an important fraction of KRAS wild-type patients do not respond to the treatment. The identification of additional genetic determinants of primary or secondary resistance to EGFR targeted therapy for further improving the selection of patients is urgent. Herein, we review the latest published literature highlighting the most important genes that may predict resistance to anti-EGFR monoclonal antibodies in colorectal cancer patients. According to the available findings, the evaluation of BRAF, NRAS, PIK3CA, and PTEN status could be the right strategy to select patients who are likely to respond to anti-EGFR therapies. In the future, the combination of those biomarkers will help establish consensus that can be introduced into clinical practice. PMID- 25032219 TI - Performance studies on distributed virtual screening. AB - Virtual high-throughput screening (vHTS) is an invaluable method in modern drug discovery. It permits screening large datasets or databases of chemical structures for those structures binding possibly to a drug target. Virtual screening is typically performed by docking code, which often runs sequentially. Processing of huge vHTS datasets can be parallelized by chunking the data because individual docking runs are independent of each other. The goal of this work is to find an optimal splitting maximizing the speedup while considering overhead and available cores on Distributed Computing Infrastructures (DCIs). We have conducted thorough performance studies accounting not only for the runtime of the docking itself, but also for structure preparation. Performance studies were conducted via the workflow-enabled science gateway MoSGrid (Molecular Simulation Grid). As input we used benchmark datasets for protein kinases. Our performance studies show that docking workflows can be made to scale almost linearly up to 500 concurrent processes distributed even over large DCIs, thus accelerating vHTS campaigns significantly. PMID- 25032218 TI - Preventive strategies against bleeding due to nonvitamin K antagonist oral anticoagulants. AB - Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures. PMID- 25032220 TI - Foot placement and arm position affect the five times sit-to-stand test time of individuals with chronic stroke. AB - OBJECTIVES: To investigate the effect of two foot placements (normal or posterior placement) and three arm positions (hands on the thighs, arms crossed over chest, and augmented arm position with elbow extended) on the five times sit-to-stand (FTSTS) test times of individuals with chronic stroke. DESIGN: Cross-sectional study. Setting. University-based rehabilitation clinic. PARTICIPANTS: A convenience sample of community-dwelling individuals with chronic stroke (N = 45). METHODS: The times in completing the FTSTS with two foot placements and the three arm positions were recorded by stopwatch. RESULTS: Posterior foot placement led to significantly shorter FTSTS times when compared with normal foot placement in all the 3 arm positions (P <= 0.001). In addition, hands on thigh position led to significantly longer FTSTS times than the augmented arm position (P = 0.014). CONCLUSION: Our results showed that foot placement and arm position could influence the FTSTS times of individuals with chronic stroke. Standardizing the foot placement and arm position in the test procedure is essential, if FTSTS test is intended to be used repeatedly on the same subject. PMID- 25032221 TI - Sequence variation in the E2-binding domain of HPV16 and biological function evaluation in Tunisian cervical cancers. AB - HPV16 E2 variants have different effects on the transcriptional activity of the LCR. In this study, we examined the nucleotide and amino acid sequence variation within the HPV16 E2 gene and to correlate with disease progression. E2 gene disruption was detected by PCR amplification of the entire E2 gene using a single set of primers. Nucleotide variations were analyzed by bidirectional sequencing. mRNA expression patterns of E6 and E7 gene transcripts were evaluated by a reverse transcriptase-PCR method (RT-PCR). The detection of intact E2 genes was significantly higher among controls than cases (81.8% versus 37.5%, resp., P < 0.05). Among the E subgroup, variation at position 3684 C>A results in the amino acid substitution T310K and was more common among the E2 undisrupted cases (7/9; 77.7%), compared to controls (2/9; 22.2%). In addition, specific sequence variations identified in the E2 ORF at positions 3684 C>A were associated with increased viral oncogenes E6-E7 production. Besides HPV16 E2 disruption, the 3684 C>A variation within undisrupted E2 genes could be involved in an alternative mechanism for deregulating the expression of the HPV16 E6 and E7 oncogenes and appears to be a major factor contributing to the development of cervical cancer in Tunisian women. PMID- 25032224 TI - Vegetable oil derived solvent, and catalyst free "click chemistry" thermoplastic polytriazoles. AB - Azide-alkyne Huisgen "click" chemistry provides new synthetic routes for making thermoplastic polytriazole polymers-without solvent or catalyst. This method was used to polymerize three diester dialkyne monomers with a lipid derived 18 carbon diazide to produce a series of polymers (labelled C18C18, C18C9, and C18C4 based on monomer chain lengths) free of residual solvent and catalyst. Three diester dialkyne monomers were synthesized with ester chain lengths of 4, 9, and 18 carbons from renewable sources. Significant differences in thermal and mechanical properties were observed between C18C9 and the two other polymers. C18C9 presented a lower melting temperature, higher elongation at break, and reduced Young's modulus compared to C18C4 and C18C18. This was due to the "odd-even" effect induced by the number of carbon atoms in the monomers which resulted in orientation of the ester linkages of C18C9 in the same direction, thereby reducing hydrogen bonding. The thermoplastic polytriazoles presented are novel polymers derived from vegetable oil with favourable mechanical and thermal properties suitable for a large range of applications where no residual solvent or catalyst can be tolerated. Their added potential biocompatibility and biodegradability make them ideal for applications in the medical and pharmaceutical industries. PMID- 25032223 TI - Caffeic acid phenethyl ester protects against amphotericin B induced nephrotoxicity in rat model. AB - The present study was conducted to investigate whether caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has a protective effect on amphotericin B induced nephrotoxicity in rat models. Male Wistar-Albino rats were randomly divided into four groups: (I) control group (n = 10), (II) CAPE group (n = 9) which received 10 MUmol/kg CAPE intraperitoneally (i.p.), (III) amphotericin B group (n = 7) which received one dose of 50 mg/kg amphotericin B, and (IV) amphotericin B plus CAPE group (n = 7) which received 10 MUmol/kg CAPE i.p. and one dose of 50 mg/kg amphotericin B. The left kidney was evaluated histopathologically for nephrotoxicity. Levels of malondialdehyde (MDA), nitric oxide (NO), enzyme activities including catalase (CAT), and superoxide dismutase (SOD) were measured in the right kidney. Histopathological damage was prominent in the amphotericin B group compared to controls, and the severity of damage was lowered by CAPE administration. The activity of SOD, MDA, and NO levels increased and catalase activity decreased in the amphotericin B group compared to the control group (P = 0.0001, P = 0.003, P = 0.0001, and P = 0.0001, resp.). Amphotericin B plus CAPE treatment caused a significant decrease in MDA, NO levels, and SOD activity (P = 0.04, P = 0.02, and P = 0.0001, resp.) and caused an increase in CAT activity compared with amphotericin B treatment alone (P = 0.005). CAPE treatment seems to be an effective adjuvant agent for the prevention of amphotericin B nephrotoxicity in rat models. PMID- 25032222 TI - Silibinin inhibits ICAM-1 expression via regulation of N-linked and O-linked glycosylation in ARPE-19 cells. AB - To evaluate the effects of silibinin on intercellular adhesion molecule-1 (ICAM 1) expression, we used ARPE-19 cells as a model in which tumor necrosis factor (TNF-alpha) and interferon (IFN-gamma) enhanced ICAM-1 expression. This upregulation was inhibited by silibinin. In an adherence assay using ARPE-19 and THP-1 cells, silibinin inhibited the cell adhesion function of ICAM-1. The inhibitory effects of silibinin on ICAM-1 expression were mediated via the blockage of nuclear translocation of p65 proteins in TNF-alpha and phosphorylation of STAT1 in IFN-gamma-stimulated cells. In addition, silibinin altered the degree of N-linked glycosylation posttranslationally in ARPE-19 cells by significantly enhancing MGAT3 gene expression. Silibinin can increase the O GlcNAc levels of glycoproteins in ARPE-19 cells. In a reporter gene assay, PUGNAc, which can also increase O-GlcNAc levels, inhibited NF-kappaB reporter activity in TNF-alpha-induced ARPE-19 cells and this process was augmented by silibinin treatment. Overexpression of OGT gene was associated with reduced TNF alpha-induced ICAM-1 levels, which is consistent with that induced by silibinin treatment. Taken together, silibinin inhibits ICAM-1 expression and its function through altered O-linked glycosylation in NF-kappaB and STAT1 signaling pathways and decreases the N-linked glycosylation of ICAM-1 transmembrane protein in proinflammatory cytokine-stimulated ARPE-19 cells. PMID- 25032225 TI - Formulation and evaluation of thermosensitive biogels for nose to brain delivery of doxepin. AB - Thermoreversible biogels can serve as effective systems for delivery of drugs through nose with increased nasal residence time. The objective of this study was to use chitosan and glycerophosphate based thermoreversible systems for delivery of doxepin to brain through intranasal administration. Formulations were prepared by admixture of suitable dilutions of chitosan and glycerophosphate with or without polyethylene glycol, followed by addition of the antidepressant doxepin hydrochloride. Both systems were evaluated for gelling characteristics, rheology, mucoadhesion, in vitro release, and ex vivo permeation through sheep nasal mucosa. In vivo efficacy was evaluated in Swiss albino mice through the forced swim test. Nasal tissues of mice subjected to repeated exposure to formulation were evaluated histopathologically. Both formulations gelled rapidly at 37 degrees C, returned to sol state on cooling, and exhibited thixotropy. Addition of polyethylene glycol decreased the glycerophosphate content required for gelation and rendered the formulation isotonic. Both gels showed good mucoadhesion, enhanced drug permeation, and provided prolonged in vitro release at 37 degrees C. Efficacy of the formulation in treated groups was inferred from the measured pharmacodynamic parameter and histopathological reports of formulation treated groups showed no significant local toxicity. The biogels could be potential systems for effective drug delivery to brain via nose. PMID- 25032226 TI - In vivo inflammatory effects of ceria nanoparticles on CD-1 mouse: evaluation by hematological, histological, and TEM analysis. AB - The attention on CeO2-NPs environmental and in vivo effects is due to their presence in diesel exhaust and in diesel filters that release a more water soluble form of ceria NPs, as well as to their use for medical applications. In this work, acute and subacute in vivo toxicity assays demonstrate no lethal effect of these NPs. Anyhow, performing in vivo evaluations on CD-1 mouse systems, we demonstrate that it is even not correct to assert that ceria NPs are harmless for living systems as they can induce status of inflammation, revealed by hematological-chemical-clinical assays as well as histological and TEM microscope observations. TEM analysis showed the presence of NPs in alveolar macrophages. Histological evaluation demonstrated the NPs presence in lungs tissues and this can be explained by assuming their ability to go into the blood stream and lately into the organs (generating inflammation). PMID- 25032227 TI - Fuzzy logic and its application in football team ranking. AB - Fuzzy set theory and fuzzy logic are a highly suitable and applicable basis for developing knowledge-based systems in physical education for tasks such as the selection for athletes, the evaluation for different training approaches, the team ranking, and the real-time monitoring of sports data. In this paper, we use fuzzy set theory and apply fuzzy clustering analysis in football team ranking. Based on some certain rules, we propose four parameters to calculate fuzzy similar matrix, obtain fuzzy equivalence matrix and the ranking result for our numerical example, T 7, T 3, T 1, T 9, T 10, T 8, T 11, T 12, T 2, T 6, T 5, T 4, and investigate four parameters sensitivity analysis. The study shows that our fuzzy logic method is reliable and stable when the parameters change in certain range. PMID- 25032228 TI - The natural science underlying big history. AB - Nature's many varied complex systems-including galaxies, stars, planets, life, and society-are islands of order within the increasingly disordered Universe. All organized systems are subject to physical, biological, or cultural evolution, which together comprise the grander interdisciplinary subject of cosmic evolution. A wealth of observational data supports the hypothesis that increasingly complex systems evolve unceasingly, uncaringly, and unpredictably from big bang to humankind. These are global history greatly extended, big history with a scientific basis, and natural history broadly portrayed across ~14 billion years of time. Human beings and our cultural inventions are not special, unique, or apart from Nature; rather, we are an integral part of a universal evolutionary process connecting all such complex systems throughout space and time. Such evolution writ large has significant potential to unify the natural sciences into a holistic understanding of who we are and whence we came. No new science (beyond frontier, nonequilibrium thermodynamics) is needed to describe cosmic evolution's major milestones at a deep and empirical level. Quantitative models and experimental tests imply that a remarkable simplicity underlies the emergence and growth of complexity for a wide spectrum of known and diverse systems. Energy is a principal facilitator of the rising complexity of ordered systems within the expanding Universe; energy flows are as central to life and society as they are to stars and galaxies. In particular, energy rate density contrasting with information content or entropy production-is an objective metric suitable to gauge relative degrees of complexity among a hierarchy of widely assorted systems observed throughout the material Universe. Operationally, those systems capable of utilizing optimum amounts of energy tend to survive, and those that cannot are nonrandomly eliminated. PMID- 25032229 TI - Improving phosphorus availability in an acid soil using organic amendments produced from agroindustrial wastes. AB - In acid soils, soluble inorganic phosphorus is fixed by aluminium and iron. To overcome this problem, acid soils are limed to fix aluminium and iron but this practice is not economical. The practice is also not environmentally friendly. This study was conducted to improve phosphorus availability using organic amendments (biochar and compost produced from chicken litter and pineapple leaves, resp.) to fix aluminium and iron instead of phosphorus. Amending soil with biochar or compost or a mixture of biochar and compost increased total phosphorus, available phosphorus, inorganic phosphorus fractions (soluble inorganic phosphorus, aluminium bound inorganic phosphorus, iron bound inorganic phosphorus, redundant soluble inorganic phosphorus, and calcium bound phosphorus), and organic phosphorus. This was possible because the organic amendments increased soil pH and reduced exchangeable acidity, exchangeable aluminium, and exchangeable iron. The findings suggest that the organic amendments altered soil chemical properties in a way that enhanced the availability of phosphorus in this study. The amendments effectively fixed aluminium and iron instead of phosphorus, thus rendering phosphorus available by keeping the inorganic phosphorus in a bioavailable labile phosphorus pool for a longer period compared with application of Triple Superphosphate without organic amendments. PMID- 25032230 TI - Microstructure formation and fracturing characteristics of grey cast iron repaired using laser. AB - The repairing technology based on laser rapid fusion is becoming an important tool for fixing grey cast iron equipment efficiently. A laser repairing protocol was developed using Fe-based alloy powders as material. The microstructure and fracturing feature of the repaired zone (RZ) were analyzed. The results showed that regionally organized RZ with good density and reliable metallurgical bond can be achieved by laser repairing. At the bottom of RZ, dendrites existed in similar direction and extended to the secondary RZ, making the grains grow extensively with inheritance with isometric grains closer to the surface substrate. The strength of the grey cast iron base material was maintained by laser repairing. The base material and RZ were combined with robust strength and fracture resistance. The prevention and deflection of cracking process were analyzed using a cracking process model and showed that the overall crack toughness of the materials increased. PMID- 25032231 TI - Signal waveform detection with statistical automaton for internet and web service streaming. AB - In recent years, many approaches have been suggested for Internet and web streaming detection. In this paper, we propose an approach to signal waveform detection for Internet and web streaming, with novel statistical automatons. The system records network connections over a period of time to form a signal waveform and compute suspicious characteristics of the waveform. Network streaming according to these selected waveform features by our newly designed Aho Corasick (AC) automatons can be classified. We developed two versions, that is, basic AC and advanced AC-histogram waveform automata, and conducted comprehensive experimentation. The results confirm that our approach is feasible and suitable for deployment. PMID- 25032232 TI - Multiple R&D projects scheduling optimization with improved particle swarm algorithm. AB - For most enterprises, in order to win the initiative in the fierce competition of market, a key step is to improve their R&D ability to meet the various demands of customers more timely and less costly. This paper discusses the features of multiple R&D environments in large make-to-order enterprises under constrained human resource and budget, and puts forward a multi-project scheduling model during a certain period. Furthermore, we make some improvements to existed particle swarm algorithm and apply the one developed here to the resource constrained multi-project scheduling model for a simulation experiment. Simultaneously, the feasibility of model and the validity of algorithm are proved in the experiment. PMID- 25032233 TI - Design and experimental evaluation on an advanced multisource energy harvesting system for wireless sensor nodes. AB - An effective multisource energy harvesting system is presented as power supply for wireless sensor nodes (WSNs). The advanced system contains not only an expandable power management module including control of the charging and discharging process of the lithium polymer battery but also an energy harvesting system using the maximum power point tracking (MPPT) circuit with analog driving scheme for the collection of both solar and vibration energy sources. Since the MPPT and the power management module are utilized, the system is able to effectively achieve a low power consumption. Furthermore, a super capacitor is integrated in the system so that current fluctuations of the lithium polymer battery during the charging and discharging processes can be properly reduced. In addition, through a simple analog switch circuit with low power consumption, the proposed system can successfully switch the power supply path according to the ambient energy sources and load power automatically. A practical WSNs platform shows that efficiency of the energy harvesting system can reach about 75-85% through the 24-hour environmental test, which confirms that the proposed system can be used as a long-term continuous power supply for WSNs. PMID- 25032234 TI - Phytotoxic activity of Ocimum tenuiflorum extracts on germination and seedling growth of different plant species. AB - Phytotoxic activity of Ocimum tenuiflorum (Lamiaceae) plant extracts was investigated against the germination and seedling growth of cress (Lepidium sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), Italian ryegrass (Lolium multiflorum), barnyard grass (Echinochloa crus-galli), and timothy (Phleum pratense) at four different concentrations. The plant extracts at concentrations greater than 30 mg dry weight equivalent extract mL(-1) reduced significantly the total germination percent (GP), germination index (GI), germination energy (GE), speed of emergence (SE), seedling vigour index (SVI), and coefficient of the rate of germination (CRG) of all test species except barnyard grass and GP of lettuce. In contrast, time required for 50% germination (T 50) and mean germination time (MGT) were increased at the same or higher than this concentration. The increasing trend of T 50 and MGT and the decreasing trend of other indices indicated a significant inhibition or delay of germination of the test species by O. tenuiflorum plant extracts and vice versa. In addition, the shoot and root growth of all test species were significantly inhibited by the extracts at concentrations greater than 10 mg dry weight equivalent extract mL( 1). The I 50 values for shoot and root growth were ranged from 26 to 104 mg dry weight equivalent extract mL(-1). Seedling growth was more sensitive to the extracts compared to seed germination. Results of this study suggest that O. tenuiflorum plant extracts have phytotoxic properties and thus contain phytotoxic substances. Isolation and characterization of those substances from this plant may act as a tool for new natural, biodegradable herbicide development to control weeds. PMID- 25032235 TI - Emerging trends in soft computing models in bioinformatics and biomedicine. PMID- 25032236 TI - The need for specific penalties for hacking in criminal law. AB - In spite of the fact that hacking is a widely used term, it is still not legally established. Moreover, the definition of the concept of hacking has been deployed in a wide variety of ways in national literature. This ambiguity has led to various side effects. Recently in the United States, reforms collectively known as Aaron's Law were proposed as intended amendments to the Computer Fraud and Abuse Act (CFAA). Most experts expect that this change will put the brakes on the CFAA as a severe punishment policy, and result in a drop in controversial court decisions. In this study, we analyze the definitions and the penalties for hacking for each country and compare them with the national law and then make suggestions through more specific legislation. We expect it will reduce legal controversy and prevent excessive punishment. PMID- 25032237 TI - Richness and cover of nontimber economic plants along altitude in temperate Himalayan forest-use types. AB - Pakistani Himalaya stretches over a wide range of altitudinal gradients and supports high diversity of medicinal plants that are an important source for rural livelihood. Altitudinal effects on ground vegetation have already been indicated but ground vegetation is also under severe threat of grazing and over collection. The present study investigated the effect of altitude on medicinal plants abundance in both old-growth and derived woodland forests. Each of the five line transects was selected in old-growth and derived woodland forests. Each line transect consisted of four plots distributed at four altitudinal levels (2200, 2300, 2400, and 2500 m asl). Species richness under derived woodland had shown strong negative correlation (r = -0.95) with altitude while it was found to be nonsignificant under old-growth. Cover of most of the species such as Veronica laxa (r = -0.95, P <= 0.05) had shown significant negative correlation with altitude under derived woodland. Cover abundance of some species like Valeriana jatamansi and Viola canescens has also shown significant negative correlation under old-growth forest. Derived woodland can decrease the cover abundance of valuable medicinal plants towards extension at higher altitudes. Thus, protection of the derived woodland could serve as a tool for the improvement of rural livelihood and ecological restoration. PMID- 25032238 TI - Structural monitoring of metro infrastructure during shield tunneling construction. AB - Shield tunneling construction of metro infrastructure will continuously disturb the soils. The ground surface will be subjected to uplift or subsidence due to the deep excavation and the extrusion and consolidation of the soils. Implementation of the simultaneous monitoring with the shield tunnel construction will provide an effective reference in controlling the shield driving, while how to design and implement a safe, economic, and effective structural monitoring system for metro infrastructure is of great importance and necessity. This paper presents the general architecture of the shield construction of metro tunnels as well as the procedure of the artificial ground freezing construction of the metro tunnel cross-passages. The design principles for metro infrastructure monitoring of the shield tunnel intervals in the Hangzhou Metro Line 1 are introduced. The detailed monitoring items and the specified alarming indices for construction monitoring of the shield tunneling are addressed, and the measured settlement variations at different monitoring locations are also presented. PMID- 25032239 TI - Reduction of fuel consumption and exhaust pollutant using intelligent transport systems. AB - Greenhouse gas emitted by the transport sector around the world is a serious issue of concern. To minimize such emission the automobile engineers have been working relentlessly. Researchers have been trying hard to switch fossil fuel to alternative fuels and attempting to various driving strategies to make traffic flow smooth and to reduce traffic congestion and emission of greenhouse gas. Automobile emits a massive amount of pollutants such as Carbon Monoxide (CO), hydrocarbons (HC), carbon dioxide (CO2), particulate matter (PM), and oxides of nitrogen (NO x ). Intelligent transport system (ITS) technologies can be implemented to lower pollutant emissions and reduction of fuel consumption. This paper investigates the ITS techniques and technologies for the reduction of fuel consumption and minimization of the exhaust pollutant. It highlights the environmental impact of the ITS application to provide the state-of-art green solution. A case study also advocates that ITS technology reduces fuel consumption and exhaust pollutant in the urban environment. PMID- 25032240 TI - Hydraulic fracture extending into network in shale: reviewing influence factors and their mechanism. AB - Hydraulic fracture in shale reservoir presents complex network propagation, which has essential difference with traditional plane biwing fracture at forming mechanism. Based on the research results of experiments, field fracturing practice, theory analysis, and numerical simulation, the influence factors and their mechanism of hydraulic fracture extending into network in shale have been systematically analyzed and discussed. Research results show that the fracture propagation in shale reservoir is influenced by the geological and the engineering factors, which includes rock mineral composition, rock mechanical properties, horizontal stress field, natural fractures, treating net pressure, fracturing fluid viscosity, and fracturing scale. This study has important theoretical value and practical significance to understand fracture network propagation mechanism in shale reservoir and contributes to improving the science and efficiency of shale reservoir fracturing design. PMID- 25032241 TI - Adaptive MANET multipath routing algorithm based on the simulated annealing approach. AB - Mobile ad hoc network represents a system of wireless mobile nodes that can freely and dynamically self-organize network topologies without any preexisting communication infrastructure. Due to characteristics like temporary topology and absence of centralized authority, routing is one of the major issues in ad hoc networks. In this paper, a new multipath routing scheme is proposed by employing simulated annealing approach. The proposed metaheuristic approach can achieve greater and reciprocal advantages in a hostile dynamic real world network situation. Therefore, the proposed routing scheme is a powerful method for finding an effective solution into the conflict mobile ad hoc network routing problem. Simulation results indicate that the proposed paradigm adapts best to the variation of dynamic network situations. The average remaining energy, network throughput, packet loss probability, and traffic load distribution are improved by about 10%, 10%, 5%, and 10%, respectively, more than the existing schemes. PMID- 25032242 TI - Prevalence and correlates of video and internet gaming addiction among Hong Kong adolescents: a pilot study. AB - This pilot study investigated the patterns of video and internet gaming habits and the prevalence and correlates of gaming addiction in Hong Kong adolescents. A total of 503 students were recruited from two secondary schools. Addictive behaviors of video and internet gaming were assessed using the Game Addiction Scale. Risk factors for gaming addiction were examined using logistical regression. An overwhelming majority of the subjects (94%) reported using video or internet games, with one in six (15.6%) identified as having a gaming addiction. The risk for gaming addiction was significantly higher among boys, those with poor academic performance, and those who preferred multiplayer online games. Gaming addiction was significantly associated with the average time spent gaming per week, frequency of spending money on gaming, period of spending money on gaming, perceived family disharmony, and having more close friends. These results suggest that effective educational and preventative programs or strategies are needed. PMID- 25032243 TI - A study on strategic provisioning of cloud computing services. AB - Cloud computing is currently emerging as an ever-changing, growing paradigm that models "everything-as-a-service." Virtualised physical resources, infrastructure, and applications are supplied by service provisioning in the cloud. The evolution in the adoption of cloud computing is driven by clear and distinct promising features for both cloud users and cloud providers. However, the increasing number of cloud providers and the variety of service offerings have made it difficult for the customers to choose the best services. By employing successful service provisioning, the essential services required by customers, such as agility and availability, pricing, security and trust, and user metrics can be guaranteed by service provisioning. Hence, continuous service provisioning that satisfies the user requirements is a mandatory feature for the cloud user and vitally important in cloud computing service offerings. Therefore, we aim to review the state-of the-art service provisioning objectives, essential services, topologies, user requirements, necessary metrics, and pricing mechanisms. We synthesize and summarize different provision techniques, approaches, and models through a comprehensive literature review. A thematic taxonomy of cloud service provisioning is presented after the systematic review. Finally, future research directions and open research issues are identified. PMID- 25032244 TI - Nonlinear quantitative radiation sensitivity prediction model based on NCI-60 cancer cell lines. AB - We proposed a nonlinear model to perform a novel quantitative radiation sensitivity prediction. We used the NCI-60 panel, which consists of nine different cancer types, as the platform to train our model. Important radiation therapy (RT) related genes were selected by significance analysis of microarrays (SAM). Orthogonal latent variables (LVs) were then extracted by the partial least squares (PLS) method as the new compressive input variables. Finally, support vector machine (SVM) regression model was trained with these LVs to predict the SF2 (the surviving fraction of cells after a radiation dose of 2 Gy gamma-ray) values of the cell lines. Comparison with the published results showed significant improvement of the new method in various ways: (a) reducing the root mean square error (RMSE) of the radiation sensitivity prediction model from 0.20 to 0.011; and (b) improving prediction accuracy from 62% to 91%. To test the predictive performance of the gene signature, three different types of cancer patient datasets were used. Survival analysis across these different types of cancer patients strongly confirmed the clinical potential utility of the signature genes as a general prognosis platform. The gene regulatory network analysis identified six hub genes that are involved in canonical cancer pathways. PMID- 25032245 TI - Superficial radiotherapy for multiple keratoacanthomas. AB - We report the case of a 76-year-old Caucasian woman who attended our clinic with multiple keratoacanthomas. Radiotherapy was considered a viable and effective option in such an old patient, who could not be a good surgical candidate for number and distribution of the lesions, and for the age. After a 12-month follow up, we observed the complete and global disappearance of the lesions; the patient was therefore very satisfied especially in view of the clinical outcome. According to our point of view, radiotherapy allows the physician to obtain a good oncological radicality and excellent cosmetic results too. PMID- 25032246 TI - Nordic and international efforts. PMID- 25032247 TI - The viscoelastic properties of the cervical mucus plug. AB - OBJECTIVE: To characterize the viscoelastic properties of cervical mucus plugs(CMPs) shed during labor at term. DESIGN: Experimental research. SETTING: Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark. POPULATION/SAMPLE: Spontaneously shed CMPs from 18 healthy women in active labor. METHODS: Viscoelastic properties of CMPs were investigated with a dynamic oscillatory rheometer using frequency and stress sweep experiments within the linear viscoelastic region. MAIN OUTCOME MEASURES: The rheological variables obtained were as follows: elastic modulus (G'), viscous modulus (G") and tan delta (G"/G'). Random-effects regression was used for statistical analysis. RESULTS: All CMPs showed solid-like viscoelastic behavior.This was substantiated by the elastic modulus which was three to four times greater than the viscous modulus and by tan delta, which was <1 at all frequencies.Mean tan delta at 0.01 Hz was 0.38 (95% CI 0.34-0.43) and 0.27(95% CI 0.23-0.32) at 1 Hz. The elastic modulus could be described by the relation G'(omega) = K(omega)(A) [mean R2 0.95 (95% CI 0.93-0.98)]. Despite relatively large variation in the rheological properties within CMPs, rheological variables obtained from frequency sweeps differed significantly among CMPs (p < 0.05). CONCLUSION: The CMPs are solid-like viscoelastic structures. These rheological characteristics are probably essential for the CMP's ability to form and sustain a plug in the cervical canal during pregnancy, thereby reducing the risk of ascending infections. The technique described here might be used for evaluation of an association between CMP viscoelasticity and preterm delivery. PMID- 25032248 TI - Vitamin D for preventing cancer: evidence and health beliefs. PMID- 25032249 TI - Not too little, not too much: delivering the right amount of anaesthesia during surgery. PMID- 25032250 TI - Treating metastatic breast cancer: the evidence for targeted therapy. PMID- 25032251 TI - Dermoscopic features of actinic keratosis and follow up with dermoscopy: a pilot study. AB - Actinic keratosis (AK) is a common precursor of sun-related squamous cell carcinoma. AK is difficult to be differentiated from other malignancies with the naked eyes. Dermoscopic features of AK were previously described in some studies, but not extensively investigated. We investigated the dermoscopic features of AK in Asians and assessed dermoscopy as a post-treatment monitoring tool of AK. We retrospectively examined 34 AK lesions which had been diagnosed by histology. The changes of dermoscopic features and histopathological findings were assessed in all these lesions before and after treatment. Before treatment, 18 lesions were pigmented and 16 lesions were non-pigmented AK dermoscopically. The frequent dermoscopic features of AK were keratin/ scales (79.4%), red pseudonetwork (73.5%), targetoid-like appearance (55.9%), rosette sign (38.2%) and absent fissures/ridges, crypts and milia-like cysts. All the lesions had been treated with either photodynamic therapy, cryotherapy or 5% imiquimod cream. After treatment, dermoscopic features of 33 AK lesions were decreased or disappeared, and skin biopsies confirmed that atypical keratinocytes disappeared. One lesion showed accentuated and new dermoscopic features after treatment, and skin biopsy also showed progressing squamous cell carcinoma. In conclusion, scales, red pseudonetwork, targetoid-like appearance and rosette sign were common dermoscopic findings of AK in Asians. In most cases, the treatment response correlated with the changes in dermoscopic features. These findings suggest that dermoscopy is a useful tool to monitor AK. PMID- 25032252 TI - Hysterectomy and other highlights. PMID- 25032254 TI - Traditional plant aphrodisiacs and male sexual dysfunction. AB - INTRODUCTION: There has been a long history of man's fascination with better and stronger sex drive and performance across different cultures. Several literature texts from the Hindu, Egyptian, Chinese and Roman civilizations document the human endless search for substances that can enhance sexual experiences and/or treat erectile dysfunction. AIM: This review will discuss the current research done on the most popular plant aphrodisiacs and provide evidence to support or discourage the use of any of them to enhance sexual desire and/or function in men. METHODS: We review the current evidence on the use of natural substances as aphrodisiacs. RESULTS: We found very little evidence to support the use of plant aphrodisiacs in the treatment of male sexual dysfunction. The vast majority of studies were conducted on animals with very few clinical studies. Available data suggest a beneficial effect of ginseng as a pro-sexual supplement and not an independent treatment for male sexual dysfunction. CONCLUSIONS: Trans-culturally, many herbal therapies show some potential benefits in improving men's sexual function; however, adequate studies on the specific benefits and health risks associated with their use are needed. We strongly recommend the design and execution of well-controlled clinical studies to determine the efficacy and safety of plant aphrodisiacs. PMID- 25032253 TI - Does clear cell carcinoma of stomach exist? Clinicopathological and prognostic significance of clear cell changes in gastric adenocarcinomas. AB - AIMS: In contrast to clear cell carcinomas developing in other organs (e.g. ovary and uterus), gastric adenocarcinomas with clear cell features are not well characterized. METHODS AND RESULTS: We evaluated a series of 762 gastric adenocarcinomas for the presence of clear cell changes; and investigated the nature of the changes using several histochemical and immunohistochemical markers, their association with various clinicopathological features, and their prognostic significance. Clear cell changes were observed in 8.5% (n = 65) of gastric cancers. Cases with clear cell changes (GCC) were associated significantly with older age, intestinal type histology, body/fundic location, greater depth of invasion, lymph node metastases and lymphovascular invasion. An increasing proportion of clear cell changes indicated a worsening prognosis, and was identified as an independent marker of poor prognosis using the Cox proportional hazard model (hazard ratio, 0.462; P = 0.003). Of 62 GCCs subjected to special staining, 35 cases (55.6%) displayed cytoplasmic accumulation of glycogen, while 21 (33.3%) contained mucin. GCCs showing glycogen accumulation expressed AFP, glypican-3 and CD10 more commonly than those with mucin, which commonly expressed Muc5AC and Muc6. CONCLUSION: Clear cell gastric adenocarcinoma is a unique subgroup of gastric cancer which, although heterogeneous, has a poor prognosis. PMID- 25032255 TI - Targeted metabolomic study indicating glycyrrhizin's protection against acetaminophen-induced liver damage through reversing fatty acid metabolism. AB - The present study aimed to give a short report on a possible mechanism of glycyrrhizin to acetaminophen-induced liver toxicity. Seven-day intraperitoneal administration of glycyrrhizin (400 mg/kg/day) to 2- to 3-month-old male C57BL/6N mice (mean weight 27 g) significantly prevents acetaminophen-induced liver damage, as indicated by the activity of alanine transaminase and aspartate aminotransferase. Metabolomics analysis and principal component analysis (PCA) using ultra-fast liquid chromatography coupled to triple time-of-flight mass spectrometer were performed. PCA separated well the control, glycyrrhizin treated, acetaminophen-treated, and glycyrrhizin+acetaminophen-treated groups. Long-chain acylcarnitines were listed as the top ions that contribute to this good separation, which include oleoylcarnitine, palmitoylcarnitine, palmitoleoylcarnitine, and myristoylcarnitine. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by acetaminophen administration. In conclusion, this metabolomic study indicates a significant glycyrrhizin protection effect against acetaminophen-induced liver damage through reversing fatty acid metabolism. PMID- 25032256 TI - Outsmarting cancer: the power of hybrid genomic/proteomic biomarkers to predict drug response. AB - A recent study by Niepel and colleagues describes a novel approach to predicting response to targeted anti-cancer therapies. The authors used biochemical profiling of signaling activity in basal and ligand-stimulated states for a panel of receptor and intracellular kinases to develop predictive models of drug sensitivity. In some cases, the response to ligand stimulation predicted drug response better than did target abundance or genomic alterations in the targeted pathway. Furthermore, combining biochemical profiles with genomic information was better at predicting drug response. This work suggests that incorporating biochemical signaling profiles with genomic alterations should provide powerful predictors of response to molecularly targeted therapies. PMID- 25032257 TI - Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives. AB - Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio banks of biopsy material taken from metastatic sites. We believe that such bio banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue. PMID- 25032258 TI - Status of adjuvant endocrine therapy for breast cancer. AB - Adjuvant endocrine therapy reduces the risk of recurrence and death from breast cancer in women with hormone receptor-positive early breast cancer.Tamoxifen has been the standard therapy for decades, and this is still the case for pre menopausal women.Ovarian suppression is of similar efficacy but currently there is no strong evidence for adding this to tamoxifen and the additional morbidity can be considerable. Results from two important trials addressing this issueare imminent. In post-menopausal women, aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane)are superior to tamoxifen in preventing recurrence but only letrozole has been shown to improve survival. The main gain is against high risk cancers, and tamoxifen gives very similar benefit for low-risk disease. Traditionally, treatment has been given for around 5 years, but many women remain at risk of relapse for 10 years or more.The AIs, and more recently tamoxifen, have been shown to reduce further the risk of late recurrence in women still in remission after 5 years of tamoxifen if given for a further 5 years. The comparative benefits of these two options and the selection of patients most likely to benefit from long-term adjuvant endocrine therapy are important topics for further research, as is the optimum duration of AI therapy started upfront. PMID- 25032260 TI - Obituary - JDG Troup. PMID- 25032261 TI - Stem cell epigenetics: looking forward. PMID- 25032259 TI - Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters. AB - The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression.Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible. PMID- 25032262 TI - In silico analysis of microRNA-510 as a potential oncomir in human breast cancer. PMID- 25032263 TI - Early but not late pregnancy induces lifelong reductions in the proportion of mammary progesterone sensing cells and epithelial Wnt signaling. PMID- 25032264 TI - Role of IFN-ks, IFN-ks related genes and the DEPDC5 gene in Hepatitis B virus related liver disease. AB - Recent studies have associated genetic variation near the interleukin 28B (IL28B/IFN-lambda3) gene with natural clearance of the hepatitis C virus (HCV) infection, and a common variant in the DEP domain containing 5 (DEPDC5) locus on chromosome 22 has been shown to affect susceptibility to hepatocellular carcinoma (HCC) in Japanese individuals with chronic HCV infection. This study was conducted to determine whether polymorphisms near or in interferon-lambda (IFN lambdas) genes and their receptor genes such as interleukin 28 receptor, alpha (IL28RA) and interleukin 10 receptor, beta (IL10RB) as well as p21-activated kinases 4 (PAK4) and iron/zinc purple acid phosphatase-like protein (PAPL), which are locate upstream of IFN-lambdas, and lastly the DEPDC5 gene are associated with hepatitis B virus-related liver disease in Han Chinese. The study subjects included 507 normal healthy controls, 350 individuals with natural clearance of HBV and 792 HBV-infected patients. The patients were categorized into 157 inactive carriers (Case I), 216 active carriers (Case II), 111 cirrhotics (Case III) and 308 HCC patients (Case IV) subgroups. Seven single nucleotide polymorphisms (SNPs) were genotyped using the Matrix-assisted Laser Desorption/Ionisation mass spectrometric (MALDI-TOF MS) SNP genotyping assay. Rs423058 upstream of PAPL, rs2834167 in IL10RB and rs1012068 in DEPDC5 were associated with chronic HBV status, HBV natural clearance and the presence of HCC (P = 0.0004-0.024), respectively. PAPL, IL10RB and DEPDC5 polymorphisms have an impact on progression of HBV-related liver disease. However, IFN-lambdas genes as a tool to differentiate between different clinical courses of HBV infection were not useful in the Han Chinese population. PMID- 25032266 TI - Spatial segmentation and the black middle class. AB - Ethnographic studies of the black middle class focus attention on the ways in which residential environments condition the experiences of different segments of the black class structure. This study places these arguments in a larger demographic context by providing a national analysis of neighborhood inequality and spatial inequality of different racial and ethnic groups in urban America. The findings show that there has been no change over time in the degree to which majority-black neighborhoods are surrounded by spatial disadvantage. Predominantly black neighborhoods, regardless of socioeconomic composition, continue to be spatially linked with areas of severe disadvantage. However, there has been substantial change in the degree to which middle- and upper-income African-American households have separated themselves from highly disadvantaged neighborhoods. These changes are driven primarily by the growing segment of middle- and upper-income African-Americans living in neighborhoods in which they are not the majority group, both in central cities and in suburbs. PMID- 25032265 TI - Influence of regular physical activity on warfarin dose and risk of hemorrhagic complications. AB - OBJECTIVE: To determine the influence of regular physical activity on stable warfarin dose and risk of major hemorrhage in patients on chronic anticoagulation therapy. DESIGN: Regular physical activity (maintained over > 80% of visits) was ascertained by self-report at initiation of warfarin therapy (target international normalized ratio [INR] = 2-3) in 1272 patients, with changes documented at monthly anticoagulation clinic visits in a population-based prospective cohort. Multi-variable linear regression and survival analysis, respectively, were used to assess influence on warfarin and risk of hemorrhage. SETTING: Outpatient anticoagulation clinic PARTICIPANTS: 1272 anticoagulated patients MEASUREMENT AND MAIN RESULTS: There were 683 (53.7%) patients who were regularly physically active (>= 30 min >= 3 times/week). Physically active patients required warfarin doses that were 6.9% higher (p=0.006) than in physically inactive patients after controlling for sociodemographic factors, vitamin K intake, clinical factors, and genetic variations.The overall incidence of major hemorrhagic events was 7.6/100 person-years (p-yrs, 95% confidence interval [CI] 6.4-8.9) in our population. The incidence was lower for physically active patients (5.6/100 p-yrs, 95% CI 4.2-7.2) than in inactive patients (10.3/100 p-yrs, 95% CI 8.2-12.9, p=0.0004). Active patients had a 38% lower risk of hemorrhage (hazard ratio 0.62, 95% CI 0.42-0.98, p=0.03) compared with inactive patients. CONCLUSIONS: Regular physical activity is associated with higher warfarin dose requirements and lower risk of hemorrhage. The influence of physical activity on drug response needs to be further explored, and the mechanisms through which it exerts these effects need to be elucidated PMID- 25032267 TI - Job displacement among single mothers: effects on children's outcomes in young adulthood. AB - Given the recent era of economic upheaval, studying the effects of job displacement has seldom been so timely and consequential. Despite a large literature associating displacement with worker well-being, relatively few studies focus on the effects of parental displacement on child well-being, and fewer still focus on implications for children of single-parent households. Moreover, notwithstanding a large literature on the relationship between single motherhood and children's outcomes, research on intergenerational effects of involuntary employment separations among single mothers is limited. Using 30 years of nationally representative panel data and propensity score matching methods, the authors find significant negative effects of job displacement among single mothers on children's educational attainment and social-psychological well being in young adulthood. Effects are concentrated among older children and children whose mothers had a low likelihood of displacement, suggesting an important role for social stigma and relative deprivation in the effects of socioeconomic shocks on child well-being. PMID- 25032268 TI - Red states, blue states, and divorce: understanding the impact of conservative Protestantism on regional variation in divorce rates. AB - Why do states with larger proportions of religious conservatives have higher divorce rates than states with lower proportions of religious conservatives? This project examines whether earlier transitions to marriage and parenthood among conservative Protestants (known risk factors for divorce) contribute to this paradox while attending to other plausible explanations. County-level demographic information from all 50 states is combined from a variety of public data sources and merged with individual records from the National Surveys of Family Growth to estimate both aggregated county and multilevel individual models of divorce. Results show that individual religious conservatism is positively related to individual divorce risk, solely through the earlier transitions to adulthood and lower incomes of conservative Protestants. However, the proportion of conservative Protestants in a county is also independently and positively associated with both the divorce rate in that county and an individual's likelihood of divorcing. The earlier family formation and lower levels of educational attainment and income in counties with a higher proportion of conservative Protestants can explain a substantial portion of this association. Little support is found for alternative explanations of the association between religious conservatism and divorce rates, including the relative popularity of marriage versus cohabitation across counties. PMID- 25032269 TI - Hybrid activism: social movement mobilization in a multimovement environment. AB - Social movement organizations often struggle to mobilize supporters from allied movements in their efforts to achieve critical mass. The authors argue that organizations with hybrid identities--those whose organizational identities span the boundaries of two or more social movements, issues, or identities--are vital to mobilizing these constituencies. They use original data from their study of the post-9/11 U.S. antiwar movement to show that individuals with past involvement in nonantiwar movements are more likely to join hybrid organizations than are individuals without involvement in nonantiwar movements. In addition, they show that organizations with hybrid identities occupy relatively more central positions in interorganizational cocontact networks within the antiwar movement and thus recruit significantly more participants in demonstrations than do nonhybrid organizations. Contrary to earlier research, they do not find that hybrid organizations are subject to an illegitimacy discount; instead, they find that hybridization can augment the ability of social movement organizations to mobilize their supporters in multimovement environments. PMID- 25032270 TI - The new immigration contestation: social movements and local immigration policy making in the United States, 2000-2011. AB - Analyzing oppositional social movements in the context of municipal immigration ordinances, the authors examine whether the explanatory power of resource mobilization, political process, and strain theories of social movements' impact on policy outcomes differs when considering proactive as opposed to reactive movements. The adoption of pro-immigrant (proactive) ordinances was facilitated by the presence of immigrant community organizations and of sympathetic local political allies. The adoption of anti-immigrant (reactive) ordinances was influenced by structural social changes, such as rapid increases in the local Latino population, that were framed as threats. The study also finds that pro immigrant protest events can influence policy in two ways, contributing both to the passage of pro-immigrant ordinances in the locality where protests occur and also inhibiting the passage of anti-immigrant ordinances in neighboring cities. PMID- 25032478 TI - What the future holds for women after menopause: where we have been, where we are, and where we want to go. AB - With an increasing world population of postmenopausal women, providers of health care need to focus on improving the quality of life as well as the longevity of women. This review emphasizes the importance of health care for postmenopausal women, particularly the role of menopausal hormonal therapy (MHT), from the perspective of where we have been, where we are now, and where we can expect to be in the future. Use of MHT increased dramatically in the 1980s and then fell very abruptly in the early 2000s with the publications of various randomized hormonal trials, including the Women's Health Initiative (WHI). The recent publications from the WHI with 13 years of follow-up are different from the initial reports and do not show an increase in cardiovascular risk in any age group (with the exception of venous thrombosis). Breast cancer risk increased marginally with estrogen/progestogen therapy, related to duration of use, but with estrogen-alone therapy, breast cancer risk decreased significantly, as did mortality. For younger women receiving estrogen alone, there is great consistency between all randomized trials, including the WHI and observational data showing a coronary benefit and a decrease in all-cause mortality. Recent data also confirm the 'timing hypothesis', suggesting that younger women benefit from MHT, while older women do not exhibit this effect. In the future, we will have many more genetic and molecular tools to guide therapy and risk assessment, as we move into an era of personalized medicine. An important opportunity presents at the onset of menopause to prevent diseases which usually occur some 10 years later. Part of this preventative strategy may involve MHT. PMID- 25032479 TI - Surface-induced hybridization between graphene and titanium. AB - Carbon-based materials such as graphene sheets and carbon nanotubes have inspired a broad range of applications ranging from high-speed flexible electronics all the way to ultrastrong membranes. However, many of these applications are limited by the complex interactions between carbon-based materials and metals. In this work, we experimentally investigate the structural interactions between graphene and transition metals such as palladium (Pd) and titanium (Ti), which have been confirmed by density functional simulations. We find that the adsorption of titanium on graphene is more energetically favorable than in the case of most metals, and density functional theory shows that a surface induced p-d hybridization occurs between atomic carbon and titanium orbitals. This strong affinity between the two materials results in a short-range ordered crystalline deposition on top of graphene as well as chemical modifications to graphene as seen by Raman and X-ray photoemission spectroscopy (XPS). This induced hybridization is interface-specific and has major consequences for contacting graphene-nanoelectronic devices as well as applications toward metal-induced chemical functionalization of graphene. PMID- 25032480 TI - Weighted Interaction SNP Hub (WISH) network method for building genetic networks for complex diseases and traits using whole genome genotype data. AB - BACKGROUND: High-throughput genotype (HTG) data has been used primarily in genome wide association (GWA) studies; however, GWA results explain only a limited part of the complete genetic variation of traits. In systems genetics, network approaches have been shown to be able to identify pathways and their underlying causal genes to unravel the biological and genetic background of complex diseases and traits, e.g., the Weighted Gene Co-expression Network Analysis (WGCNA) method based on microarray gene expression data. The main objective of this study was to develop a scale-free weighted genetic interaction network method using whole genome HTG data in order to detect biologically relevant pathways and potential genetic biomarkers for complex diseases and traits. RESULTS: We developed the Weighted Interaction SNP Hub (WISH) network method that uses HTG data to detect genome-wide interactions between single nucleotide polymorphism (SNPs) and its relationship with complex traits. Data dimensionality reduction was achieved by selecting SNPs based on its: 1) degree of genome-wide significance and 2) degree of genetic variation in a population. Network construction was based on pairwise Pearson's correlation between SNP genotypes or the epistatic interaction effect between SNP pairs. To identify modules the Topological Overlap Measure (TOM) was calculated, reflecting the degree of overlap in shared neighbours between SNP pairs. Modules, clusters of highly interconnected SNPs, were defined using a tree cutting algorithm on the SNP dendrogram created from the dissimilarity TOM (1 TOM). Modules were selected for functional annotation based on their association with the trait of interest, defined by the Genome-wide Module Association Test (GMAT). We successfully tested the established WISH network method using simulated and real SNP interaction data and GWA study results for carcass weight in a pig resource population; this resulted in detecting modules and key functional and biological pathways related to carcass weight. CONCLUSIONS: We developed the WISH network method which is a novel 'systems genetics' approach to study genetic networks underlying complex trait variation. The WISH network method reduces data dimensionality and statistical complexity in associating genotypes with phenotypes in GWA studies and enables researchers to identify biologically relevant pathways and potential genetic biomarkers for any complex trait of interest. PMID- 25032481 TI - Lanthanide luminescence enhancements in porous silicon resonant microcavities. AB - In this paper, the covalent immobilization and luminescence enhancement of a europium (Eu(III)) complex in a porous silicon (pSi) layer with a microcavity (pSiMC) structure are demonstrated. The alkyne-pendant arm of the Eu(III) complex was covalently immobilized on the azide-modified surface via ligand-assisted "click" chemistry. The design parameters of the microcavity were optimized to obtain an efficient luminescence-enhancing device. Luminescence enhancements by a factor of 9.5 and 3.0 were observed for Eu(III) complex bound inside the pSiMC as compared to a single layer and Bragg reflector of identical thickness, respectively, confirming the increased interaction between the immobilized molecules and the electric field in the spacer of the microcavity. When comparing pSiMCs with different resonance wavelength position, luminescence was enhanced when the resonance wavelength overlapped with the maximum emission wavelength of the Eu(III) complex at 614 nm, allowing for effective coupling between the confined light and the emitting molecules. The pSiMC also improved the spectral color purity of the Eu(III) complex luminescence. The ability of a pSiMC to act as an efficient Eu(III) luminescence enhancer, combined with the resulting sharp linelike emission, can be exploited for the development of ultrasensitive optical biosensors. PMID- 25032482 TI - Noncovalent interaction of carbon nanostructures. AB - The potential application of carbon nanomaterials in biology and medicine increases the necessity to understand the nature of their interactions with living organisms and the environment. The primary forces of interaction at the nano-bio interface are mostly noncovalent in nature. Quantifying such interactions and identifying various factors that influence such interactions is a question of outstanding fundamental interest in academia and industry. In this Account, we have summarized our recent studies in understanding the noncovalent interactions of carbon nanostructures (CNSs), which were obtained by employing first-principles calculations on various model systems representing carbon nanotubes (CNTs) and graphene. Bestowed with an extended sp(2) carbon network, which is a common feature in all of these nanostructures, they exhibit pi-pi interactions with aromatic molecules (benzene, naphthalene, nucleobases, amino acids), cation-pi type of interactions with metal ions, anion-pi interactions with anions, and other XH...pi type of interactions with various small molecules (H2O, NH3, CH4, H2, etc.). CNTs are wrapped-up forms of two-dimensional graphene, and hence, it is interesting to compare the binding abilities of these two allotropes that differ in their curvature. The chirality and curvature of CNSs appear to play a major role in determining the structural, energetic, and functional properties. Flat graphene shows stronger noncovalent interactions than the curved nanotubes toward various substrates. Understanding the interactions of CNSs with organic molecules and biomolecules has gained a great deal of research interest because of their potential applications in various fields. Aromatic hydrocarbons show a strong propensity to interact with CNSs via the pi-pi mode of interaction rather than CH...pi interaction. As DNA sequencing appears to be one of the most important potential applications of carbon nanomaterials, the study of CNS-nucleobase interactions has become quite important. The nucleobases are physisorbed on the surface of CNSs in the order G > T ~ A > C > U, exhibiting pi pi-stacking type of interaction. These interactions become stronger as the curvature of the CNSs decreases. It is also indispensable to study the interaction of nanomaterials with proteins and especially with amino acids at a molecular level to understand the drug delivery mechanism of CNSs. We have shown that the CNSs interact with small molecules by means of physisorption and thus show potential for sensor applications. The prime requisite for the exploitation of these CNSs in nanoelectronics is the tunable energy gap. We have revealed that metal ion doping modulates the HOMO-LUMO energy gap of the nanotubes significantly and thus provides a handle to tune the electronic and conductivity properties of CNTs. Moreover, metal ions tend to selectively bind with nanotubes of different chirality such as armchair and zigzag nanotubes. The reduction of planar hydrocarbon materials by lithium atoms has also been studied very systematically. We also illustrate the way in which noncovalent interactions can be used to optimize and fine-tune the properties of CNSs. PMID- 25032483 TI - Flavonoids from Jovibarba globifera (Crassulaceae) rosette leaves and their antioxidant activity. AB - Seven flavonoids new for the genus Jovibarba, kaempferol 1, kaempferol 3-O galactopyranosyl-(1 -> 2)-O-alpha-L-rhamnopyranoside 2, kaempferol 3-O-beta-D glucoside 3, kaempferol 3-O-alpha-L-rhamnopyranosyl-7-O-alpha-D-glucofuranosyl-(1 -> 2)-O-alpha-L-rhamnopyranoside 4, kaempferol 3-O-beta-D-glucopyranoside-7-O alpha-L-rhamnopyranoside 5, kaempferol 3,7,4'-O-trimethyl ether 6 and quercetin 7, were isolated from fresh and dried leaves of J.ovibarba globifera subsp. globifera. The structures of these compounds were established by analysis of their spectroscopic ((1)H and (13)C NMR) and spectrometric (MS) data, as well as by comparison of these with those reported in the literature. All of the flavonoids are reported for the first time from the investigated taxon. In addition the antioxidant activities in DPPH test of selected compounds were evaluated. PMID- 25032484 TI - Solid-state semiconductor optical cryocooler based on CdS nanobelts. AB - We demonstrate the laser cooling of silicon-on-insulator (SOI) substrate using CdS nanobelts. The local temperature change of the SOI substrate exactly beneath the CdS nanobelts is deduced from the ratio of the Stokes and anti-Stokes Raman intensities from the Si layer on the top of the SOI substrate. We have achieved a 30 and 20 K net cooling starting from 290 K under a 3.8 mW 514 nm and a 4.4 mW 532 nm pumping, respectively. In contrast, a laser heating effect has been observed pumped by 502 and 488 nm lasers. Theoretical analysis based on the general static heat conduction module in the Ansys program package is conducted, which agrees well with the experimental results. Our investigations demonstrate the laser cooling capability of an external thermal load, suggesting the applications of II-VI semiconductors in all-solid-state optical cryocoolers. PMID- 25032485 TI - Hormones, polyamines, and cell wall metabolism during oil palm fruit mesocarp development and ripening. AB - Oil palm is one of the most productive oil-producing crops and can store up to 90% oil in its fruit mesocarp. Oil palm fruit is a sessile drupe consisting of a fleshy mesocarp from which palm oil is extracted. Biochemical changes in the mesocarp cell walls, polyamines, and hormones at different ripening stages of oil palm fruits were studied, and the relationship between the structural and the biochemical metabolism of oil palm fruits during ripening is discussed. Time course analysis of the changes in expression of polyamines, hormones, and cell wall-related genes and metabolites provided insights into the complex processes and interactions involved in fruit development. Overall, a strong reduction in auxin-responsive gene expression was observed from 18 to 22 weeks after pollination. High polyamine concentrations coincided with fruit enlargement during lipid accumulation and latter stages of maturation. The trend of abscisic acid (ABA) concentration was concordant with GA4 but opposite to the GA3 profile such that as ABA levels increase the resulting elevated ABA/GA3 ratio clearly coincides with maturation. Polygalacturonase, expansin, and actin gene expressions were also observed to increase during fruit maturation. The identification of the master regulators of these coordinated processes may allow screening for oil palm variants with altered ripening profiles. PMID- 25032486 TI - Cost-effectiveness of socioeconomic support as part of HIV care for the poor in an urban community-based antiretroviral program in Uganda. AB - BACKGROUND: Socioeconomic support reduced nonretention in a community-based antiretroviral therapy (ART) program in Uganda. However, resource implications of expanding socioeconomic support are large, and cost-effectiveness analysis can inform budget priorities. We compared the incremental benefits and costs of providing education, food, or both forms of support (dual support) with existing ART services from a health care provider's perspective. METHODS: Costs and outcome data were collected from a cohort of 2371 adult patients with HIV receiving education, food, or dual support from Reach Out Mbuya between 2004 and 2010. The primary outcome was averted loss to follow-up. The number of follow-up days was calculated for each patient along with accrued service and fixed program costs for the alternative forms of socioeconomic support in USD by standard costing methods. The socioeconomic support types were compared incrementally over the study period. RESULTS: After 7 years, 762 (33%) of the patients were loss to follow-up with 42% of them receiving food. In the presence of providing ART, education support was less costly and more effective than the alternatives. The average unit cost for education, food, and dual support were $237, $538, and $776, respectively. The average total annual costs were $88,643 for education, $538,005 for food, and $103,045 for dual support. CONCLUSIONS: Compared with food or dual support, investing in education of the children of ART patients is less costly and more effective in improving patient retention. Reach Out Mbuya should embrace this paradigm shift and channel its resources more efficiently and effectively by focusing on education support. PMID- 25032487 TI - Efficacy of systemic therapy on adults with mental disorders: A meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of systemic therapy on psychiatric disorders in adulthood. METHODS: This meta-analysis integrates results of 37 randomized controlled trials (RCT) of therapy with an explicit systemic focus on adults with psychiatric disorders. Studies were identified through systematic searches in electronic databases and cross-referencing. RESULTS: On average, systemic therapy had stronger short-term (g = .51) and long-term (g = .55) efficacies than control groups without alternative treatment and stronger short-term effects than alternative active treatments (g = .25). In addition, efficacy of systemic therapy was similar to those of other bona fide psychotherapies. Individuals receiving systemic therapy plus medication showed stronger improvements at posttest (g = .71) and follow-up (g = .87) than those receiving only medication. Illness-specific analyses showed positive short-term efficacy of systemic therapy on eating disorders, mood disorders, obsessive-compulsive disorders, schizophrenia, and somatoform disorders. At follow-up, efficacy of systemic therapy was only found on eating disorders, mood disorders, and schizophrenia. In addition, systemic therapy had lower dropout rates than alternative treatments. For certain comparisons, effect sizes were moderated by participant age, study quality, and year of publication. CONCLUSIONS: We conclude that the present meta analysis found some evidence for the efficacy of systemic therapy on five disorders, but the number of available RCT is still limited. More research is needed on systemic therapy of other disorders, such as anxiety disorders and substance use disorders. PMID- 25032488 TI - Applications of the bayesian prior information to evaluation of equivalence of similar biological medicinal products. AB - In 2014, there are a number of patents of best-selling biotech drugs around the world about to expire. Large commercial interests will inevitably set off international competition among major pharmaceutical companies. The European Union, the United States, and other countries with advanced medical techniques have paid a high degree of attention to biological similarity (biosimilarity) for drug development and market management and have started to take corresponding measures. Because of the diverse definitions of biosimilarity between countries, which can determine whether the medicines on sale are in the review of the base grant, the competent authority will also encounter varying degrees of standards. Governments should review the corresponding guidelines as soon as possible because many countries around the world have actively amended the law in response to management need of biological similarity. The similarity of biological drugs should be assessed by clinical trial under current regulations. Pharmaceutical companies try to lower the cost of generic drugs to increase the competitiveness of their products. To reduce the number of subjects in the clinical trials for development of generic drugs, we refer to the clinical trial for evaluation of bridging studies. Hsiao et al. (2007) has proposed the use of Bayes method in evaluation of bridging studies. Prior information on the original region is used to reduce the number of subjects to lower the cost of biosimilar drug development. Take the results of the approval biologics as a priori information, and the information is appropriate to be embedded into the model evaluating the similar products in order to reduce the sample size required for the assessment of the test sample. PMID- 25032489 TI - Pulse-heating ionization for protein on-chip mass spectrometry. AB - An on-chip pulse-heating ionization source for protein samples was developed for the realization of miniaturized mass spectrometry. A protein analyte was ionized on a chip by applying only thermal energy to the solid phase sample without a laser, high voltage, or heated ambient gases. A fabricated ionization source consisting of a Pt/Cr microheater (width: 30 MUm; length: 100 MUm) on a silicon substrate was coupled with a time-of-flight mass filter to analyze a protein sample of bovine serum albumin (BSA, M = 66 kDa). A singly charged BSA ion and other multiply charged BSA ions were generated in the presence of 2,5 dihydroxybenzoic acid as a matrix. To detect the singly charged BSA ion, the required surface energy density of 1.65 * 10(-2) MUJ/MUm(2) was applied to the microheater for 500 ns. The use of the 2,5-dihydroxyacetophenone matrix resulted in the generation of the multiply charged protein analyte, while the use of the sinapic acid matrix showed abundant peaks in the low m/z region. PMID- 25032490 TI - Embodied cognition and mirror neurons: a critical assessment. AB - According to embodied cognition theories, higher cognitive abilities depend on the reenactment of sensory and motor representations. In the first part of this review, we critically analyze the central claims of embodied theories and argue that the existing behavioral and neuroimaging data do not allow investigators to discriminate between embodied cognition and classical cognitive accounts, which assume that conceptual representations are amodal and symbolic. In the second part, we review the main claims and the core electrophysiological findings typically cited in support of the mirror neuron theory of action understanding, one of the most influential examples of embodied cognition theories. In the final part, we analyze the claim that mirror neurons subserve action understanding by mapping visual representations of observed actions on motor representations, trying to clarify in what sense the representations carried by these neurons can be claimed motor. PMID- 25032492 TI - The perirhinal cortex. AB - Anatomically, the perirhinal cortex sits at the boundary between the medial temporal lobe and the ventral visual pathway. It has prominent interconnections not only with both these systems, but also with a wide range of unimodal and polymodal association areas. Consistent with these diverse projections, neurophysiological studies reveal a multidimensional set of mnemonic signals that include stimulus familiarity, within- and between-domain associations, associative recall, and delay-based persistence. This wide range of perirhinal memory signals not only includes signals that are largely unique to the perirhinal cortex (i.e., object familiarity), consistent with dual-process theories, but also includes a range of signals (i.e., associative flexibility and recall) that are strongly associated with the hippocampus, consistent with single process theories. These neurophysiological findings have important implications for bridging the gap between single-process and dual-process models of medial temporal lobe function. PMID- 25032491 TI - Translational control in synaptic plasticity and cognitive dysfunction. AB - Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction. PMID- 25032493 TI - Reassessing models of basal ganglia function and dysfunction. AB - The basal ganglia are a series of interconnected subcortical nuclei. The function and dysfunction of these nuclei have been studied intensively in motor control, but more recently our knowledge of these functions has broadened to include prominent roles in cognition and affective control. This review summarizes historical models of basal ganglia function, as well as findings supporting or conflicting with these models, while emphasizing recent work in animals and humans directly testing the hypotheses generated by these models. PMID- 25032495 TI - Neural coding of uncertainty and probability. AB - Organisms must act in the face of sensory, motor, and reward uncertainty stemming from a pandemonium of stochasticity and missing information. In many tasks, organisms can make better decisions if they have at their disposal a representation of the uncertainty associated with task-relevant variables. We formalize this problem using Bayesian decision theory and review recent behavioral and neural evidence that the brain may use knowledge of uncertainty, confidence, and probability. PMID- 25032494 TI - Coupling mechanism and significance of the BOLD signal: a status report. AB - Functional magnetic resonance imaging (fMRI) provides a unique view of the working human mind. The blood-oxygen-level-dependent (BOLD) signal, detected in fMRI, reflects changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation, which are coupled to underlying neuronal activity by a process termed neurovascular coupling. Over the past 10 years, a range of cellular mechanisms, including astrocytes, pericytes, and interneurons, have been proposed to play a role in functional neurovascular coupling. However, the field remains conflicted over the relative importance of each process, while key spatiotemporal features of BOLD response remain unexplained. Here, we review current candidate neurovascular coupling mechanisms and propose that previously overlooked involvement of the vascular endothelium may provide a more complete picture of how blood flow is controlled in the brain. We also explore the possibility and consequences of conditions in which neurovascular coupling may be altered, including during postnatal development, pathological states, and aging, noting relevance to both stimulus-evoked and resting-state fMRI studies. PMID- 25032498 TI - Motion-detecting circuits in flies: coming into view. AB - Visual motion cues provide animals with critical information about their environment and guide a diverse array of behaviors. The neural circuits that carry out motion estimation provide a well-constrained model system for studying the logic of neural computation. Through a confluence of behavioral, physiological, and anatomical experiments, taking advantage of the powerful genetic tools available in the fruit fly Drosophila melanogaster, an outline of the neural pathways that compute visual motion has emerged. Here we describe these pathways, the evidence supporting them, and the challenges that remain in understanding the circuits and computations that link sensory inputs to behavior. Studies in flies and vertebrates have revealed a number of functional similarities between motion-processing pathways in different animals, despite profound differences in circuit anatomy and structure. The fact that different circuit mechanisms are used to achieve convergent computational outcomes sheds light on the evolution of the nervous system. PMID- 25032496 TI - Neural tube defects. AB - Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies. PMID- 25032497 TI - Basal ganglia circuits for reward value-guided behavior. AB - The basal ganglia are equipped with inhibitory and disinhibitory mechanisms that enable a subject to choose valuable objects and actions. Notably, a value can be determined flexibly by recent experience or stably by prolonged experience. Recent studies have revealed that the head and tail of the caudate nucleus selectively and differentially process flexible and stable values of visual objects. These signals are sent to the superior colliculus through different parts of the substantia nigra so that the animal looks preferentially at high valued objects, but in different manners. Thus, relying on short-term value memories, the caudate head circuit allows the subject's gaze to move expectantly to recently valued objects. Relying on long-term value memories, the caudate tail circuit allows the subject's gaze to move automatically to previously valued objects. The basal ganglia also contain an equivalent parallel mechanism for action values. Such flexible-stable parallel mechanisms for object and action values create a highly adaptable system for decision making. PMID- 25032499 TI - Neuromodulation of circuits with variable parameters: single neurons and small circuits reveal principles of state-dependent and robust neuromodulation. AB - Neuromodulation underlies many behavioral states and has been extensively studied in small circuits. This has allowed the systematic exploration of how neuromodulatory substances and the neurons that release them can influence circuit function. The physiological state of a network and its level of activity can have profound effects on how the modulators act, a phenomenon known as state dependence. We provide insights from experiments and computational work that show how state dependence can arise and the consequences it can have for cellular and circuit function. These observations pose a general unsolved question that is relevant to all nervous systems: How is robust modulation achieved in spite of animal-to-animal variability and degenerate, nonlinear mechanisms for the production of neuronal and network activity? PMID- 25032501 TI - Neuropeptidergic control of sleep and wakefulness. AB - Sleep and wake are fundamental behavioral states whose molecular regulation remains mysterious. Brain states and body functions change dramatically between sleep and wake, are regulated by circadian and homeostatic processes, and depend on the nutritional and emotional condition of the animal. Sleep-wake transitions require the coordination of several brain regions and engage multiple neurochemical systems, including neuropeptides. Neuropeptides serve two main functions in sleep-wake regulation. First, they represent physiological states such as energy level or stress in response to environmental and internal stimuli. Second, neuropeptides excite or inhibit their target neurons to induce, stabilize, or switch between sleep-wake states. Thus, neuropeptides integrate physiological subsystems such as circadian time, previous neuron usage, energy homeostasis, and stress and growth status to generate appropriate sleep-wake behaviors. We review the roles of more than 20 neuropeptides in sleep and wake to lay the foundation for future studies uncovering the mechanisms that underlie the initiation, maintenance, and exit of sleep and wake states. PMID- 25032502 TI - Tips and tricks for successful electroretinography in children. AB - PURPOSE OF REVIEW: The role of electroretinography in pediatric practice, and to offer suggestions for successful electroretinography recordings in children. RECENT FINDINGS: Electroretinography can be usually be obtained in infants without resorting to general anesthesia. When general anesthesia is required, modifications to standard protocols can often reduce total anesthesia time without compromising the clinical value of the study. SUMMARY: With appropriate technique, electroretinography methods could be made more widely available for pediatric diagnosis. PMID- 25032503 TI - Palladium-catalyzed alkenylation of ketone enolates under mild conditions. AB - A protocol for a mild, catalytic, intermolecular alkenylation of ketone enolates has been developed using a Pd/Q-Phos catalyst. Efficient intermolecular coupling of a variety of ketones with alkenyl bromides was achieved with a slight excess of LiHMDS and temperatures down to 0 degrees C. PMID- 25032504 TI - A general strategy for synthesizing colloidal semiconductor zinc chalcogenide quantum rods. AB - Quasi-one-dimensional (1D) semiconductor nanocrystals manifest linearly polarized emission, reduced lasing threshold, and improved charge transport compared with their counterparts such as spherical quantum dots. Present investigations of colloidal semiconductor quantum rods are mainly based on cadmium chalcogenide systems because of their facile synthetic accessibility. However, it is still a big challenge to fabricate quasi-1D zinc chalcogenide nanocrystals with controlled aspect ratios. Here we report a general strategy for synthesizing zinc chalcogenide quantum rods via a colloidal chemical synthetic approach. Unlike the most common growth mechanisms of quasi-1D colloidal nanocrystals such as monomer attachment and particle coalescence, the synthesis of zinc chalcogenide quantum rods is performed by a ripening process starting from their respective ultrathin nanowires through thermodynamically driven material diffusion. We anticipate that this strategy is general and could be applied to other systems to construct quasi 1D nanostructures. Moreover, the presence of cadmium-free (or "green") zinc chalcogenide quantum rods synthesized through this strategy provides a desirable platform for eco-friendly photocatalysis, optoelectronic devices, biolabeling, and other applications. PMID- 25032500 TI - Meta-analysis in human neuroimaging: computational modeling of large-scale databases. AB - Spatial normalization--applying standardized coordinates as anatomical addresses within a reference space--was introduced to human neuroimaging research nearly 30 years ago. Over these three decades, an impressive series of methodological advances have adopted, extended, and popularized this standard. Collectively, this work has generated a methodologically coherent literature of unprecedented rigor, size, and scope. Large-scale online databases have compiled these observations and their associated meta-data, stimulating the development of meta analytic methods to exploit this expanding corpus. Coordinate-based meta-analytic methods have emerged and evolved in rigor and utility. Early methods computed cross-study consensus, in a manner roughly comparable to traditional (nonimaging) meta-analysis. Recent advances now compute coactivation-based connectivity, connectivity-based functional parcellation, and complex network models powered from data sets representing tens of thousands of subjects. Meta-analyses of human neuroimaging data in large-scale databases now stand at the forefront of computational neurobiology. PMID- 25032505 TI - Pathologizing suffering and the pursuit of a peaceful death. AB - The specialty of psychiatry has a long-standing, virtually monolithic view that a desire to die, even a desire for a hastened death among the terminally ill, is a manifestation of mental illness. Recently, psychiatry has made significant inroads into hospice and palliative care, and in doing so brings with it the conviction that dying patients who seek to end their suffering by asserting control over the time and manner of their inevitable death should be provided with psychotherapeutic measures rather than having their expressed wishes respected as though their desire for an earlier death were the rational choice of someone with decisional capacity. This article reviews and critiques this approach from the perspective of recent clinical data indicating that patients who secure and utilize a lethal prescription are generally exercising an autonomous choice unencumbered by clinical depression or other forms of incapacitating mental illness. PMID- 25032506 TI - Selenium speciation in framboidal and euhedral pyrites in shales. AB - The release of Se from shales is poorly understood because its occurrence, distribution, and speciation in the various components of shale are unknown. To address this gap we combined bulk characterization, sequential extractions, and spatially resolved MU-focus spectroscopic analyses and investigated the occurrence and distribution of Se and other associated elements (Fe, As, Cr, Ni, and Zn) and determined the Se speciation at the MU-scale in typical, low bulk Se containing shales. Our results revealed Se primarily correlated with the pyrite fraction with exact Se speciation highly dependent on pyrite morphology. In euhedral pyrites, we found Se(-II) substitutes for S in the mineral structure. However, we also demonstrate that Se is associated with framboidal pyrite grains as a discrete, independent FeSex phase. The presence of this FeSex species has major implications for Se release, because FeSex species oxidize much faster than Se substituted in the euhedral pyrite lattice. Thus, such an FeSex species will enhance and control the dynamics of Se weathering and release into the aqueous environment. PMID- 25032508 TI - Positive roles of compartmentalization in internal reactions. AB - Recently, many researchers have attempted to construct artificial cell models using a bottom-up approach in which various biochemical reactions that involve a defined set of molecules are reconstructed in cell-like compartments, such as liposomes and water-in-oil droplets. In many of these studies, the cell-like compartments have acted only as containers for the encapsulated biochemical reactions, whereas other studies have indicated that compartmentalization improves the rates and yields of these reactions. Here, we introduce two ways in which compartmentalization can improve internal reactions: the isolation effect and the condensation effect. These positive effects of compartmentalization might have played an important role in the genesis of the first primitive cell on early Earth. PMID- 25032507 TI - Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. AB - The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response. In addition to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis by deregulating PCNA expression. However, selective inhibitors of SETD8 are scarce. The only known selective inhibitor of SETD8 to date is nahuoic acid A, a marine natural product, which is competitive with the cofactor. Here, we report the discovery of the first substrate-competitive inhibitor of SETD8, UNC0379 (1). This small-molecule inhibitor is active in multiple biochemical assays. Its affinity to SETD8 was confirmed by ITC (isothermal titration calorimetry) and SPR (surface plasmon resonance) studies. Importantly, compound 1 is selective for SETD8 over 15 other methyltransferases. We also describe structure-activity relationships (SAR) of this series. PMID- 25032509 TI - Laser interferometric analysis of glucose and sucrose diffusion in agarose gel. AB - The paper presents the investigation results of glucose and sucrose diffusion in agarose gel studied with laser interferometry method and the results of fluorescence analysis of the macroscopic gel structure. The diffusion kinetics of these substances released from aqueous solutions of a molar concentration of 0.05 M into the agarose solutions of concentrations of 0.5% and 3% in two gravitational configurations of measuring system was analysed. In the first configuration the solute diffused according, whereas in the second one - opposite to the gravitational force. The diffusion was analysed in the time period between 120 and 2400 s with a time interval of Deltat = 120 s. We observed that the convective instabilities were damped well by the agarose gel, which gives the possibility of the interferometric studies of the diffusive transport for other substances in different gravitational configurations of the system. The time characteristics of glucose and sucrose fluxes in both configurations of the system and the gravitational polarisation coefficient values were obtained. The substantial differences in fluxes of glucose and sucrose diffused according and opposite to the gravitational force were observed. Additionally, we observed the differences between the diffusive fluxes of these substances in both configurations in dependence on the gel solution concentration (which is associated with gel porosity dependent on its concentration) and the kind of diffused substance. PMID- 25032510 TI - Sodium tungstate alleviates biomechanical properties of diabetic rat femur via modulation of oxidative stress. AB - Diabetes mellitus leads to bone disorders such as osteopenia and osteoporosis that can increase fracture risk. On the other hand, sodium tungstate is an inorganic compound which exerts anti-diabetic activity in experimental studies due to its suggested insulin-mimetic or antioxidant activity. Therefore this study was designed to investigate the effect of tungstate on bone quality in diabetic rat femurs. The rats were divided into four groups: Control (C), tungstate-treated control (C+Tung), diabetes (STZ-D) and tungstate-treated diabetes (STZ-D+Tung). Diabetes mellitus was induced by single injection of streptozotocin (50 mg/kg). The treated rats received 150 mg/kg/day of sodium tungstate for 12 weeks. Sodium tungstate achieved a little (17%) but significant reduction on blood glucose levels, while it didn't recover the reduced body weights of diabetic rats. In addition, impaired bone mechanical quality was reversed, despite the unchanged mineral density. Sodium tungstate administration significantly lowered the 2-thiobarbituric acid reactive substances and restored the activity of tissue antioxidant enzymes such as glutathione peroxidase, catalase and superoxide dismutase in diabetic rats. On the other hand, glutathione levels didn't change in either case. These findings indicate that tungstate can improve the reduced mechanical quality of diabetic rat femurs due probably to reduction of reactive oxygen species and modulation of antioxidant enzymes as well as reduction in blood glucose levels. PMID- 25032511 TI - Ionizing radiation as preconditioning against transient cerebral ischemia in rats. AB - Induction of ischemic tolerance (IT), the ability of an organism to survive an otherwise lethal ischemia, is the most effective known approach to preventing postischemic damage. IT can be induced by exposing animals to a broad range of stimuli. In this study we tried to induce IT of brain neurons using ionizing radiation (IR). A preconditioning (pre-C) dose of 10, 20, 30 or 50 Gy of gamma rays was used 2 days before an 8 min ischemia in adult male rats. Ischemia alone caused the degeneration of almost one half of neurons in CA1 region of hippocampus. However, a significant decrease of the number of degenerating neurons was observed after higher doses of radiation (30 and 50 Gy). Moreover, ischemia significantly impaired the spatial memory of rats as tested in Morris's water maze. In rats with a 50 Gy pre-C dose, the latency times were reduced to values close to the control level. Our study is the first to reveal that IR applied in sufficient doses can induce IT and thus allow pyramidal CA1 neurons to survive ischemia. In addition, we show that the beneficial effect of IR pre-C is proportional to the radiation dose. PMID- 25032512 TI - Construction and application of a Rh-Pt DNA metalloinsertor conjugate. AB - We report the synthesis and characterization of a bimetallic conjugate (RhPt) in which an oxaliplatin derivative is tethered to a rhodium metalloinsertor through an aminomalonate leaving group ligand. The complex interacts with DNA through metalloinsertion at a base pair mismatch followed by formation of a covalent Pt DNA adduct. Characterization of RhPt in mismatch repair-deficient HCT116O cells reveals increased cytotoxicity compared to cisplatin and oxaliplatin as well as relative to the unconjugated rhodium and platinum counterparts. Caspase and poly ADP ribose polymerase inhibition assays indicate that RhPt induces apoptotic cell death. Inductively coupled plasma mass spectrometry (ICP-MS) experiments reveal that RhPt exhibits enhanced cellular uptake properties that contribute to its increased efficacy. PMID- 25032513 TI - The nutritional energy to clinical outcome relation revisited. AB - In the previous issue of Critical Care, Dr Bellomo and colleagues reported an observational study of the relationship between nutritional intake and survival in the RENAL randomized controlled trial. In summary, the total energy intake in a very large and severely ill patient population was low. Higher average daily caloric energy intake was not associated with improved survival. The study illustrates the complexity of the interaction between disease and nutrition. PMID- 25032514 TI - Antifibrotic role of alphaB-crystallin inhibition in pleural and subpleural fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix accumulation. IPF typically starts in subpleural lung regions, and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts (mesothelio-mesenchymal transition) is induced by the profibrotic cytokine, transforming growth factor (TGF)-beta1, and is thought to play a role in the development and progression of IPF. The Mothers Against Decapentaplegic homolog (Smad)-dependent pathway is the main TGF-beta1 pathway involved in fibrosis. alphaB-crystallin is constitutively expressed in the lungs, and is inducible by stress, acts as a chaperon, and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of alphaB-crystallin hampered TGF-beta1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here, for the first time, that alphaB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from patients with IPF and in rodent models of pleural/subpleural fibrosis. alphaB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-beta1 or the intrapleural injection of bleomycin combined with carbon particles. We show that alphaB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of mesothelio-mesenchymal transition. alphaB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts, thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that alphaB-crystallin may be a key target for the development of specific drugs in the treatment of IPF. PMID- 25032515 TI - Glutamine supplementation in the critically ill: friend or foe? AB - In the previous issue of Critical Care, Mori and colleagues demonstrate that glutamine supplementation in mechanically ventilated patients as part of parenteral nutrition increases plasma glutamine concentration and glutamine utilization, but does not mitigate protein degradation and even increases de novo glutamine production. Studies suggest that protein degradation is regulated by the degree of inflammation. Immune cells utilize large amounts of glutamine and derive their glutamine requirements from muscle protein degradation. We hypothesize that the effects of glutamine supplementation depend on the degree of inflammation. Infusing large amounts of exogenous glutamine into patients with inflammatory conditions like sepsis and multiple organ failure may not only enhance immune competence, but may potentially augment the inflammatory response and thereby negatively influence outcome. PMID- 25032516 TI - Discovery of lipids from B. longum subsp. infantis using whole cell MALDI analysis. AB - Bifidobacteria are dominant members of the microbial community in the intestinal tract of infants, and studies have shown that glycolipids extracted from the cell surface of these bacteria elicit beneficial immune responses. Accordingly, the identification and structural characterization of glycolipids from the cell wall of bifidobacteria is the first step in correlating glycolipid structure with biological activity. Using whole cell MALDI as a screening tool, we herein present for the first time the identification and structural elucidation of the major polar lipids from Bifidobacterium longum subs. infantis. The lipids identified include an unprecedented plasmenyl cyclophosphatidic acid and a mixed acetal glycolipid, with the latter subsequently being isolated and found to suppress the innate immune response. PMID- 25032517 TI - A facile access to substituted benzo[a]fluorenes from o-alkynylbenzaldehydes via in situ formed acetals. AB - In situ formed acetal changes the course of Bronsted acid-catalyzed reaction of ortho-alkynylbenzaldehydes with arylalkynes altogether. By utilizing this, an efficient domino approach for the regioselective synthesis of substituted benzo[a]fluorenes has been developed under mild reaction conditions. In situ formed acetal facilitates the intermolecular heteroalkyne metathesis and subsequent trans to cis isomerization of a double bond to effect the intramolecular annulation. PMID- 25032518 TI - A bifunctional copolymer additive to utilize photoenergy transfer and to improve hole mobility for organic ternary bulk-heterojunction solar cell. AB - To realize the high efficiency organic photovoltaics (OPVs), two critical requirements have to be fulfilled: (1) increasing the photon energy absorption range of the active layer, and (2) improving charge separation and transport in the active layer. This study reports the utilization of THC8, a novel fluorescence-based polymer containing propeller-shaped di-triarylamine and fluorene moieties in the active layer consisting of poly-3-hexylthiophene and [6,6]-phenyl-C61-butyric acid methyl ester to form a ternary bulk heterojunction. The results showed that the high absorbance and strong fluorescence of THC8 at 420 and 510 nm, respectively, broadened the spectral absorption of the OPV, possibly through Forster resonance energy transfer. In addition, the morphology of the device active layer was improved with the addition of a suitable amount of THC8. Consequently, the charge transport property of the active layer was improved. The best power conversion efficiency (PCE) of the device with THC8 was 3.88%, a 25% increase compared to the PCE of a pristine OPV. PMID- 25032519 TI - Audiological evaluation in patients with Behcet's disease. AB - OBJECTIVE: This study aimed to determine the characteristics of hearing loss in patients with Behcet's disease. METHODS: Twenty-six consecutive patients with Behcet's disease and a control group consisting of 25 age-matched healthy subjects were prospectively included in this study. Pure tone and speech audiometry, tympanometry, distortion product otoacoustic emission testing, and auditory brainstem-evoked response assessment were performed in the patients and controls. RESULTS: The pure tone audiograms and the results of distortion product otoacoustic emission testing showed statistically significant hearing loss in the Behcet's disease patients (p < 0.05). Auditory brainstem-evoked response results were not significantly different between the patients and controls (p > 0.05). CONCLUSION: The findings of the present study demonstrated that audiological involvement is more frequent in patients with Behcet's disease than in healthy controls. Therefore, all patients with Behcet's disease should be regularly monitored by an otolaryngologist and be given information about the possibility of inner-ear involvement. PMID- 25032520 TI - Guest editorial: funding for innovative cancer-relevant technology development. PMID- 25032521 TI - Prognostic significance of visceral pleural involvement in early-stage lung cancer. AB - BACKGROUND: Visceral pleural invasion (VPI) may impact non-small cell lung cancer (NSCLC) survival. However, previous studies are mixed as to whether VPI is an independent prognostic factor in early-stage cancers and whether its effect is size dependent. In the current American Joint Committee on Cancer (AJCC) staging system, VPI leads to upstaging of cancers < 3 cm but not of those 3 to 7 cm in size. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) registry, we identified 16,315 patients with stage I-II NSCLC treated with lobectomy. We used the Kaplan-Meier method and Cox regression to assess the association of VPI with lung cancer-specific (primary outcome) and overall survival. Based on these results, we created a revised VPI staging classification. RESULTS: Overall, 3,389 patients (21%) had VPI. Kaplan-Meier analysis stratified by tumor size showed worse cancer-specific survival in patients with VPI (P < .0001). VPI was independently associated with decreased lung cancer-specific survival (hazard ratio, 1.38; 95% CI, 1.29-1.47) after controlling for tumor size and other confounders; this effect was not size dependent. In our revised classification, tumors < 7 cm with VPI were upstaged to the next T category. CONCLUSIONS: VPI is a prevalent finding associated with worse prognosis in early-stage lung cancer, even among patients with tumors > 3 cm, a factor not captured in the current staging system. Patients with VPI may be considered candidates for more aggressive treatment. PMID- 25032522 TI - Breaking down the silos of medicine: the future of vascular neurosurgery. PMID- 25032523 TI - Spinal dural arteriovenous fistulas: how, when, and why. PMID- 25032524 TI - The perils of comparative effectiveness, cost-effectiveness, and value of care research: lessons learned from Washington State. PMID- 25032525 TI - Spine metastases: from radiotherapy, surgery, to radiosurgery. PMID- 25032526 TI - Spinal technologies not available in the United States: an editorial. PMID- 25032527 TI - Spinal cord injury: debating the efficacy of methylprednisolone. PMID- 25032528 TI - Methylprednisolone for the treatment of acute spinal cord injury: point. PMID- 25032529 TI - Methylprednisolone for the treatment of acute spinal cord injury: counterpoint. PMID- 25032530 TI - Tackling technical challenges for microsurgical clip ligation of complex aneurysms during the endovascular era: a personal perspective. PMID- 25032531 TI - Epilepsy surgery and the evolution of clinical and translational science. PMID- 25032532 TI - The evolution of technology and neurosurgery: Presidential address of the 2013 CNS Annual Meeting. PMID- 25032533 TI - How radiosurgery changed neurosurgery and the changes that lie ahead. PMID- 25032535 TI - Open vs endoscopic: when to use which. PMID- 25032536 TI - Expanding the operative corridor for difficult-to-reach tumors: the concept of operative working angles to minimize brain transgression. PMID- 25032534 TI - Evolution of malignant glioma treatment: from chemotherapy to vaccines to viruses. PMID- 25032537 TI - The continuing evolution: biology and treatment of brain tumors. PMID- 25032538 TI - Three steps forward and 2 steps back: the Echternach procession toward optimal hydrocephalus treatment. PMID- 25032539 TI - Revolution in aneurysm treatment: flow diversion to cure aneurysms: a paradigm shift. PMID- 25032540 TI - Open vs endovascular approach to intracranial aneurysms. PMID- 25032541 TI - Reconsideration of cavernous sinus surgeries. PMID- 25032542 TI - Investing in neurosurgery innovations: an editorial. PMID- 25032544 TI - Skull base chondrosarcoma radiosurgery: a literature review. PMID- 25032543 TI - 3.0-T intraoperative magnetic resonance imaging-guided resection in cerebral glioma surgery: interim analysis of a prospective, randomized, triple-blind, parallel-controlled trial. PMID- 25032545 TI - Rate and time course of improvement in endocrine function after more than 1000 pituitary operations. PMID- 25032546 TI - High cervical fractional anisotropy as an imaging marker for spinal cord injury. PMID- 25032547 TI - Predictive value of somatosensory evoked potentials for patients with severe traumatic brain injury. PMID- 25032548 TI - Deep brain stimulation for pain: distinguishing dorsolateral somesthetic and ventromedial affective targets. PMID- 25032659 TI - Findings from the natural history of central nervous system hemangioblastomas in von Hippel-Lindau disease. PMID- 25032549 TI - Lim mineralization protein-1 knockout mice have reduced spine trabecular bone density on microcomputed tomography due to decreased bone morphogenetic protein responsiveness. PMID- 25032666 TI - Desilylative activation of TMSCN in chemoselective Strecker-Ugi type reaction: functional fused imidazoles as building blocks as an entry route to annulated purines. AB - A pathway of desilylative activation of TMSCN as a functional isonitrile equivalent, and DABCO-THF as an appropriate system for activation in a chemoselective Strecker-Ugi type reaction, has rendered ethyl glyoxalate and various heterocyclic-2-amidines as feasible substrates, and afforded the successful synthesis of 3-amino-2-carboxyethyl substituted fused imidazoles as useful building blocks. This class of functional scaffold has provided, via construction of the fused pyrimidinone motif, the synthesis of biologically important C8-N9 annulated purines, adenines and their oxo/thio analogs. This new approach is convenient and flexible for the preparation of versatile purine condensed heterocycles. PMID- 25032667 TI - Amnestic mild cognitive impairment and incident dementia and Alzheimer's disease in geriatric depression. AB - BACKGROUND: Memory impairment in geriatric depression is understudied, but may identify individuals at risk for development of dementia and Alzheimer's disease (AD). Using a neuropsychologically based definition of amnestic mild cognitive impairment (aMCI) in patients with geriatric depression, we hypothesized that patients with aMCI, compared with those without it, would have increased incidence of both dementia and AD. METHODS: Participants were aged 60 years and older and consisted of depressed participants and non-depressed volunteer controls. The depressed cohort met criteria for unipolar major depression. All participants were free of dementia and other neurological illness at baseline. At study entry, participants were administered a standardized clinical interview, a battery of neurocognitive tests, and provided a blood sample for determination of apolipoprotein E genotype. A cognitive diagnosis was assigned by a panel of experts who convened annually and reviewed available clinical, neuropsychological and laboratory data to achieve a consensus cognitive diagnosis to determine a consensus diagnosis. Survival analysis examined the association between aMCI and later dementia (all-cause) and AD. RESULTS: Among 295 depressed individuals, 63 (21.36%) met criteria for aMCI. Among 161 non-depressed controls, four (2.48%) met aMCI criteria. Participants were followed for 6.28 years on average. Forty three individuals developed dementia, including 40 (13.6%) depressed and three (1.9%) control participants. Both aMCI and age were associated with incident dementia and AD. CONCLUSIONS: The presence of aMCI is a poor prognostic sign among patients with geriatric depression. Clinicians should carefully screen elderly depressed adults for memory impairment. PMID- 25032668 TI - Association of vision loss and work status in the United States. AB - IMPORTANCE: Working is critical to personal health and well-being. We examine the association of vision measured objectively with work status using a nationally representative sample of working-age Americans. OBSERVATION: A total of 19 849 participants from the 1999-2008 National Health and Nutrition Examination Survey completed a vision examination and employment/demographic questionnaires. Employment rates for men with visual impairment, uncorrected refractive error, and normal vision were 58.7%, 66.5%, and 76.2%, respectively; employment rates for women with visual impairment, uncorrected refractive error, and normal vision were 24.5%, 56.0%, and 62.9%, respectively. In multivariable models adjusting for age, sex, race/ethnicity, and chronic disease status, both uncorrected refractive error (odds ratio [OR], 1.36; 95% CI, 1.15-1.60) and visual impairment (OR, 3.04; 95% CI, 1.93-4.79) were associated with a higher likelihood of not working. Subgroups in which visual impairment was associated with even higher odds of not working included women (OR, 4.9; 95% CI, 2.5-9.6), participants younger than 55 years (OR, 4.3; 95% CI, 2.9-6.5), and diabetic individuals (OR, 14.8; 95% CI, 5.8 37.3). CONCLUSIONS AND RELEVANCE: Decreased vision is associated with a significantly higher likelihood of not working. Visually impaired diabetic individuals, women, and those younger than 55 years have a particularly high risk of not working. Further investigation is warranted to understand barriers for employment in individuals with decreased vision. PMID- 25032669 TI - Predominant role of GIP in the development of a metabolic syndrome-like phenotype in female Wistar rats submitted to forced catch-up growth. AB - Catch-up growth has been associated with the appearance of metabolic dysfunctions such as obesity and type 2 diabetes in adulthood. Because the entero-insular axis is critical to glucose homeostasis control, we explored the relevance of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the development of these pathologies. Offspring of rat dams fed ad libitum (control [C]) or 65% food-restricted during pregnancy and suckling time (undernourished [U]) were weaned onto a high-fat (HF) diet (CHF and UHF, respectively) to drive catch-up growth. Both male and female UHF rats showed an obese phenotype characterized by hyperphagy, visceral fat accumulation, and adipocyte hypertrophy. High-fat diet induced deterioration of glucose tolerance in a sex-dependent manner. Female UHF rats experienced much more severe glucose intolerance than males, which was not compensated by insulin hypersecretion, suggesting insulin resistance, as shown by homeostatic model assessment of insulin resistance values. Moreover, female, but not male, UHF rats displayed enhanced GIP but not GLP-1 secretion during oral glucose tolerance test. Administration of the GIP receptor antagonist (Pro3)GIP to UHF female rats over 21 days markedly reduced visceral fat mass and adipocyte hypertrophy without variations in food intake or body weight. These changes were accompanied by improvement of glucose tolerance and insulin sensitivity. In conclusion, the exacerbated production and secretion of GIP after the catch-up growth seems to represent the stimulus for insulin hypersecretion and insulin resistance, ultimately resulting in derangement of glucose homeostasis. Overall, these data evidence the role of GIP as a critical link between catch-up growth and the development of metabolic disturbances. PMID- 25032670 TI - Small things make a big difference: binder effects on the performance of Li and Na batteries. AB - Li and Na batteries are very important as energy storage devices for electric vehicles and smart grids. It is well known that, when an electrode is analysed in detail, each of the components (the active material, the conductive carbon, the current collector and the binder) makes a portion of contribution to the battery performance in terms of specific capacity, rate capability, cycle life, etc. However, there has not yet been a review on the binder, though there are already many review papers on the active materials. Binders make up only a small part of the electrode composition, but in some cases, they play an important role in affecting the cycling stability and rate capability for Li-ion and Na-ion batteries. Poly(vinylidene difluoride) (PVDF) has been the mainstream binder, but there have been discoveries that aqueous binders can sometimes make a battery perform better, not to mention they are cheaper, greener, and easier to use for electrode fabrication. In this review, we focus on several kinds of promising electrode materials, to show how their battery performance can be affected significantly by binder materials: anode materials such as Si, Sn and transitional metal oxides; cathode materials such as LiFePO4, LiNi1/3Co1/3Mn1/3O2, LiCoO2 and sulphur. PMID- 25032671 TI - Pediatric hospice and palliative care: designing a mobile app for clinical practice. PMID- 25032672 TI - Elsevier clinical practice model achieves milestone successes to advance clinical decision support and evidence-based practice. PMID- 25032674 TI - Probing and analyzing buried interfaces of multifunctional oxides using a secondary electron energy analyzer. AB - A contactless method of probing and analyzing multifunctional oxide interfaces using an electron energy analyzer inside a scanning electron microscope is presented. High contrast experimental secondary electron analyzer signals are used to detect changes in the interface conductivity of a LaAlO3/SrTiO3 sample. Monte Carlo simulations of the primary beam/specimen interaction are carried out and correlated with the experimental results in order to help understand the role of the primary beam energy and adjust it to enhance contrast. PMID- 25032675 TI - Are the Italian municipal Registries of Advance Directives going in the right direction? PMID- 25032676 TI - Measurement of the nociceptive balance by Analgesia Nociception Index and Surgical Pleth Index during sevoflurane-remifentanil anesthesia. AB - BACKGROUND: Evaluation of the nociception-anti-nociception balance during anesthesia is still challenging and routinely based on clinical criteria such as movement or vegetative response. Recently, the Analgesia Nociception Index (ANI) derived from heart rate variability and the Surgical Pleth Index (SPI) derived from photoplethysmographic signal were introduced for quantification of the analgesic component of anesthesia. METHODS: After obtaining informed consent, we studied twenty-four patients (ASA I-II) scheduled for elective surgery during induction of anesthesia with sevoflurane and a stepwise increase of remifentanil effect site concentrations. Insertion of a laryngeal mask, tetanic stimulations as well as tracheal intubation were studied as nociceptive events. RESULTS: A total of 120 events were analysed. Both ANI and SPI enabled consistent detection of nociceptive events by significant changes (?). Further, ?ANI and ?SPI significantly indicated patient's movement after tetanic stimulation with a prediction probability of 0.74 and 0.84. CONCLUSION: Non-invasive monitoring of ANI and SPI reflected nociceptive stimulation during sevoflurane-remifentanil anesthesia and therefore may indicate the nociception - anti-nociception balance. Whether guidance of anesthesia by these variables will improve anesthesia care during surgery needs to be further evaluated. PMID- 25032677 TI - Anaerobic bacteria in pneumonia in surgical intensive care unit. PMID- 25032679 TI - An aptamer-based dipstick assay for the rapid and simple detection of aflatoxin B1. AB - A rapid and simple dipstick assay based on an aptamer has been developed for the determination of aflatoxin B1 (AFB1). The dipstick assay format was based on a competitive reaction of the biotin-modified aptamer specific to AFB1 between target and cy5-modified DNA probes. Streptavidin and anti-cy5 antibody as capture reagents were immobilized at test and control lines on a membrane of the dipstick assay. After optimization, the limit of detection for the dipstick assay was 0.1 ng/ml AFB1 in buffer. The method was confirmed to be specific to AFB1, and the entire process of the assay can be completed within 30 min. Aqueous methanol (20%) provided a good extraction efficiency, and the matrix influence from corn extracts was successfully reduced through 2-fold dilution. The results of AFB1 analysis for corn samples spiked with known concentration of AFB1 by the dipstick assay and ELISA showed good agreement. The cut-off value of the dipstick assay for corn samples was 0.3 ng/g AFB1. Therefore, the dipstick assay is first reported and considered as a rapid, simple, on-site and inexpensive screening tool for AFB1 determination in grains as well as a corn. PMID- 25032678 TI - The impact of the human genome project on complex disease. AB - In the decade that has passed since the initial release of the Human Genome, numerous advancements in science and technology within and beyond genetics and genomics have been encouraged and enhanced by the availability of this vast and remarkable data resource. Progress in understanding three common, complex diseases: age-related macular degeneration (AMD), Alzheimer's disease (AD), and multiple sclerosis (MS), are three exemplars of the incredible impact on the elucidation of the genetic architecture of disease. The approaches used in these diseases have been successfully applied to numerous other complex diseases. For example, the heritability of AMD was confirmed upon the release of the first genome-wide association study (GWAS) along with confirmatory reports that supported the findings of that state-of-the art method, thus setting the foundation for future GWAS in other heritable diseases. Following this seminal discovery and applying it to other diseases including AD and MS, the genetic knowledge of AD expanded far beyond the well-known APOE locus and now includes more than 20 loci. MS genetics saw a similar increase beyond the HLA loci and now has more than 100 known risk loci. Ongoing and future efforts will seek to define the remaining heritability of these diseases; the next decade could very well hold the key to attaining this goal. PMID- 25032680 TI - Silver quartz crystal microbalance for differential diagnosis of Plasmodium falciparum and Plasmodium vivax in single and mixed infection. AB - The most severe form of malaria is cerebral malaria caused by Plasmodium falciparum. Standard malaria diagnosis is Giemsa stained peripheral blood smear but false negative findings are always reported. Moreover, mixed infections are underestimated by routine microscopy. Many methods have been developed to overcome these disadvantages and the most specific and sensitive is molecular diagnosis. Specific malaria genes are amplified by polymerase chain reaction (PCR) and many post-PCR methods have been created. We developed a gold fabricated quartz crystal microbalance (QCM) as a post-PCR method of malaria diagnosis. In this work a cheaper silver fabricated QCM was developed to identify both single and mixed infection of P. falciparum and Plasmodium vivax. The biotinylated malaria probe was immobilized on silver surface via specific avidin-biotin interaction. The target DNA fragment of 18s rRNA gene was amplified and hybridized with a QCM immobilized probe. Mass changes due to DNA hybridization were indicated by changes of quartz resonance frequencies. Validation showed that malaria silver QCM had high diagnostic potency. Evaluation of suspected 67 febrile blood samples from malaria endemic area demonstrated that the malaria silver QCM could identify both false negative and misdiagnosis cases of routine microscopy. The analysis cost of malaria silver QCM was $1/sample and analysis time was 30 min after blood collection. The malaria silver QCM is stable at tropical temperature for up to 6 months. Thus, it can be transported to be used in a remote endemic area. Thus, the malaria silver QCM is accurate, precise, rapid, cheap, and field applicable. PMID- 25032681 TI - Visual detection of blood glucose based on peroxidase-like activity of WS2 nanosheets. AB - Tungsten disulfide (WS2) nanosheets were discovered to possess intrinsic peroxidase-like activity and catalyze the peroxidase substrate 3,3',5,5' tetramethylbenzidine (TMB) to produce a color reaction in the presence of H2O2. Based on this finding, a colorimetric method and a portable test kit for the visual detection of blood glucose have been developed by using glucose oxidase (GOx) and WS2 nanosheets-catalyzed reactions. The linear range for glucose was ranged from 5 to 300 MUM (R(2)=0.999) with the detection limit of 2.9 MUM. The portable test kit was successfully evaluated glucose levels in serum samples from normal persons and diabetes persons by the observable color change from pale yellow to yellow-green, blue-green. PMID- 25032682 TI - A batch-mode cube microbial fuel cell based "shock" biosensor for wastewater quality monitoring. AB - A single chamber batch-mode cube microbial fuel cell (CMFC) was explored as a novel self-sustained biosensor for real-time monitoring the toxicity shocks (sudden change in toxins concentration) of representative toxic metals in wastewater influent. Four types of shocks, including chromium, iron, nitrate, and sodium acetate, were selected to represent the shocks of acute-toxic heavy metal, low-toxic metal, common nutrient, and organic contaminant in wastewater, respectively. Wastewater was used as the inoculum in CMFCs for anodic electrogenic bacteria that were fully acclimated within 3 days, which indicated that this self-powered sensor can be quickly adapted to wastewater. The results showed that the CMFC was able to distinguish shocks of toxins from non-toxins based on voltage signal changes. Anode open circuit potential (OCP) values were well correlated with the CMFC voltage changes, indicating that the voltage changes were mainly dependent on the activity of the electrogenic bacteria on the anode surfaces. PMID- 25032683 TI - Characterizing the impact of category uncertainty on human auditory categorization behavior. AB - Categorization is an important cognitive process. However, the correct categorization of a stimulus is often challenging because categories can have overlapping boundaries. Whereas perceptual categorization has been extensively studied in vision, the analogous phenomenon in audition has yet to be systematically explored. Here, we test whether and how human subjects learn to use category distributions and prior probabilities, as well as whether subjects employ an optimal decision strategy when making auditory-category decisions. We asked subjects to classify the frequency of a tone burst into one of two overlapping, uniform categories according to the perceived tone frequency. We systematically varied the prior probability of presenting a tone burst with a frequency originating from one versus the other category. Most subjects learned these changes in prior probabilities early in testing and used this information to influence categorization. We also measured each subject's frequency discrimination thresholds (i.e., their sensory uncertainty levels). We tested each subject's average behavior against variations of a Bayesian model that either led to optimal or sub-optimal decision behavior (i.e. probability matching). In both predicting and fitting each subject's average behavior, we found that probability matching provided a better account of human decision behavior. The model fits confirmed that subjects were able to learn category prior probabilities and approximate forms of the category distributions. Finally, we systematically explored the potential ways that additional noise sources could influence categorization behavior. We found that an optimal decision strategy can produce probability-matching behavior if it utilized non-stationary category distributions and prior probabilities formed over a short stimulus history. Our work extends previous findings into the auditory domain and reformulates the issue of categorization in a manner that can help to interpret the results of previous research within a generative framework. PMID- 25032684 TI - Recombinant antigens expressed in Pichia pastoris for the diagnosis of sleeping sickness caused by Trypanosoma brucei gambiense. AB - BACKGROUND: Screening tests for gambiense sleeping sickness, such as the CATT/T. b. gambiense and a recently developed lateral flow tests, are hitherto based on native variant surface glycoproteins (VSGs), namely LiTat 1.3 and LiTat 1.5, purified from highly virulent trypanosome strains grown in rodents. METHODOLOGY/PRINCIPAL FINDINGS: We have expressed SUMO (small ubiquitin-like modifier) fusion proteins of the immunogenic N-terminal part of these antigens in the yeast Pichia pastoris. The secreted recombinant proteins were affinity purified with yields up to 10 mg per liter cell culture. CONCLUSIONS/SIGNIFICANCE: The diagnostic potential of each separate antigen and a mixture of both antigens was confirmed in ELISA on sera from 88 HAT patients and 74 endemic non-HAT controls. Replacement of native antigens in the screening tests for sleeping sickness by recombinant proteins will eliminate both the infection risk for the laboratory staff during antigen production and the need for laboratory animals. Upscaling production of recombinant antigens, e.g. in biofermentors, is straightforward thus leading to improved standardisation of antigen production and reduced production costs, which on their turn will increase the availability and affordability of the diagnostic tests needed for the elimination of gambiense HAT. PMID- 25032685 TI - Contrasting the community structure of arbuscular mycorrhizal fungi from hydrocarbon-contaminated and uncontaminated soils following willow (Salix spp. L.) planting. AB - Phytoremediation is a potentially inexpensive alternative to chemical treatment of hydrocarbon-contaminated soils, but its success depends heavily on identifying factors that govern the success of root-associated microorganisms involved in hydrocarbon degradation and plant growth stimulation. Arbuscular mycorrhizal fungi (AMF) form symbioses with many terrestrial plants, and are known to stimulate plant growth, although both species identity and the environment influence this relationship. Although AMF are suspected to play a role in plant adaptation to hydrocarbon contamination, their distribution in hydrocarbon contaminated soils is not well known. In this study, we examined how AMF communities were structured within the rhizosphere of 11 introduced willow cultivars as well as unplanted controls across uncontaminated and hydrocarbon contaminated soils at the site of a former petrochemical plant. We obtained 69 282 AMF-specific 18S rDNA sequences using 454-pyrosequencing, representing 27 OTUs. Contaminant concentration was the major influence on AMF community structure, with different AMF families dominating at each contaminant level. The most abundant operational taxonomic unit in each sample represented a large proportion of the total community, and this proportion was positively associated with increasing contamination, and seemingly, by planting as well. The most contaminated soils were dominated by three phylotypes closely related to Rhizophagus irregularis, while these OTUs represented only a small proportion of sequences in uncontaminated and moderately contaminated soils. These results suggest that in situ inoculation of AMF strains could be an important component of phytoremediation treatments, but that strains should be selected from the narrow group that is both adapted to contaminant toxicity and able to compete with indigenous AMF species. PMID- 25032686 TI - T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. AB - CD8(+) T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8(+) T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8(+) T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8(+) T cells was elevated in chronically infected individuals and highly associated with a T-bet(dim)Eomes(hi) expressional profile. Interestingly, both resting and activated HIV-specific CD8(+) T cells in chronic infection were almost exclusively T-bet(dim)Eomes(hi) cells, while CMV-specific CD8(+) T cells displayed a balanced expression pattern of T-bet and Eomes. The T bet(dim)Eomes(hi) virus-specific CD8(+) T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8(+) T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8(+) T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8(+) T cells to control the viral replication post-ART cessation. PMID- 25032688 TI - Influenza-like-illness and clinically diagnosed flu: disease burden, costs and quality of life for patients seeking ambulatory care or no professional care at all. AB - This is one of the first studies to (1) describe the out-of-hospital burden of influenza-like-illness (ILI) and clinically diagnosed flu, also for patients not seeking professional medical care, (2) assess influential background characteristics, and (3) formally compare the burden of ILI in patients with and without a clinical diagnosis of flu. A general population sample with recent ILI experience was recruited during the 2011-2012 influenza season in Belgium. Half of the 2250 respondents sought professional medical care, reported more symptoms (especially more often fever), a longer duration of illness, more use of medication (especially antibiotics) and a higher direct medical cost than patients not seeking medical care. The disease and economic burden were similar for ambulatory ILI patients, irrespective of whether they received a clinical diagnosis of flu. On average, they experienced 5-6 symptoms over a 6-day period; required 1.6 physician visits and 86-91% took medication. An average episode amounted to ?51-?53 in direct medical costs, 4 days of absence from work or school and the loss of 0.005 quality-adjusted life-years. Underlying illness led to greater costs and lower quality-of-life. The costs of ILI patients with clinically diagnosed flu tended to increase, while those of ILI patients without clinically diagnosed flu tended to decrease with age. Recently vaccinated persons experienced lower costs and a higher quality-of-life, but this was only the case for patients not seeking professional medical care. This information can be used directly to evaluate the implementation of cost-effective prevention and control measures for influenza. In particular to inform the evaluation of more widespread seasonal influenza vaccination, including in children, which is currently considered by many countries. PMID- 25032689 TI - Glioblastoma: a pathogenic crosstalk between tumor cells and pericytes. AB - Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Much evidence suggests stromal cells play a central role in tumor initiation and progression. Brain perivascular cells (pericytes) are contractile and function normally to regulate vessel tone and morphology, have stem cell properties, are interconvertible with macrophages and are involved in new vessel formation during angiogenesis. Nevertheless, how pericytes contribute to brain tumor infiltration is not known. In this study we have investigated the underlying mechanism by which the most lethal brain cancer, Glioblastoma Multiforme (GBM) interacts with pre-existing blood vessels (co option) to promote tumor initiation and progression. Here, using mouse xenografts and laminin-coated silicone substrates, we show that GBM malignancy proceeds via specific and previously unknown interactions of tumor cells with brain pericytes. Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42 dependent and actin-based cytoplasmic extensions, that we call flectopodia, to modify the normal contractile activity of pericytes. This results in the co option of modified pre-existing blood vessels that support the expansion of the tumor margin. Furthermore, our data provide evidence for GBM cell/pericyte fusion hybrids, some of which are located on abnormally constricted vessels ahead of the tumor and linked to tumor-promoting hypoxia. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favoring an innate immune response against the tumor. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumor suppressor to tumor-promoter, indicating that GBM may harbor the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option (preventing incorporation and modification of pre existing blood vessels), possibly in combination with anti-angiogenesis (blocking new vessel formation), which could lead to improved vascular targeting not only in Glioblastoma but also for other cancers. PMID- 25032690 TI - beta-Hydroxy beta-methylbutyrate improves dexamethasone-induced muscle atrophy by modulating the muscle degradation pathway in SD rat. AB - Skeletal muscle atrophy results from various conditions including high levels of glucocorticoids, and beta-hydroxy beta-methylbutyrate (HMB; a metabolite of leucine) is a potent therapeutical supplement used to treat various muscle disorders. Recent studies have demonstrated that HMB inhibits dexamethasone induced atrophy in cultured myotubes, but its effect on dexamethasone-induced muscle atrophy has not been determined in vivo. In the present study, we investigated the effect of HMB on dexamethasone-induced muscle atrophy in rats. Treatment with dexamethasone weakened grip strengths and increased muscle damage as determined by increased serum creatine kinase levels and by histological analysis. Dexamethasone treatment also reduced both soleus and gastrocnemius muscle masses. However, HMB supplementation significantly prevented reductions in grip strengths, reduced muscle damage, and prevented muscle mass and protein concentration decrease in soleus muscle. Biochemical analysis demonstrated that dexamethasone markedly increased levels of MuRF1 protein, which causes the ubiquitination and degradation of MyHC. Indeed, dexamethasone treatment decreased MyHC protein expression and increased the ubiquitinated-MyHC to MyHC ratio. However, HMB supplementation caused the down-regulations of MuRF1 protein and of ubiquitinated-MyHC. Furthermore, additional experiments provided evidence that HMB supplementation inhibited the nuclear translocation of FOXO1 induced by dexamethasone, and showed increased MyoD expression in the nuclear fractions of soleus muscles. These findings suggest that HMB supplementation attenuates dexamethasone-induced muscle wasting by regulating FOXO1 transcription factor and subsequent MuRF1 expression. Accordingly, our results suggest that HMB supplementation could be used to prevent steroid myopathy. PMID- 25032692 TI - Use of physiologically-based pharmacokinetic modeling to simulate the profiles of 3-hydroxybenzo(a)pyrene in workers exposed to polycyclic aromatic hydrocarbons. AB - Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models were constructed from in vivo experimental data in rats and then extrapolated from animals to humans after assessing and adjusting the most sensitive model parameters as well as species specific physiological parameters. Repeated urinary voids from workers exposed to polycyclic aromatic hydrocarbons (PAHs) have been collected over the course of a typical workweek and during subsequent days off work; urinary concentrations of 3-OHBaP were then determined. Based on the information obtained for each worker (BaP air concentration, daily shift hours, tasks, protective equipment), the time courses of 3-OHBaP in the urine of the different workers have been simulated using the PBPK and toxicokinetic models, considering the various possible exposure routes, oral, dermal and inhalation. Both models were equally able to closely reproduce the observed time course of 3-OHBaP in the urine of workers and predicted similar exposure scenarios. Simulations of various scenarios suggest that the workers under study were exposed mainly by the dermal route. Comparison of measured air concentration levels of BaP with simulated values needed to obtain a good approximation of observed time course further pointed out that inhalation was not the main route of exposure for most of the studied workers. Both kinetic models appear as a useful tool to interpret biomonitoring data of PAH exposure on the basis of 3-OHBaP levels. PMID- 25032691 TI - Development and validation of intracranial thrombus segmentation on CT angiography in patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Thrombus characterization is increasingly considered important in predicting treatment success for patients with acute ischemic stroke. The lack of intensity contrast between thrombus and surrounding tissue in CT images makes manual delineation a difficult and time consuming task. Our aim was to develop an automated method for thrombus measurement on CT angiography and validate it against manual delineation. MATERIALS AND METHODS: Automated thrombus segmentation was achieved using image intensity and a vascular shape prior derived from the segmentation of the contralateral artery. In 53 patients with acute ischemic stroke due to proximal intracranial arterial occlusion, automated length and volume measurements were performed. Accuracy was assessed by comparison with inter-observer variation of manual delineations using intraclass correlation coefficients and Bland-Altman analyses. RESULTS: The automated method successfully segmented the thrombus for all 53 patients. The intraclass correlation of automated and manual length and volume measurements were 0.89 and 0.84. Bland-Altman analyses yielded a bias (limits of agreement) of -0.4 (-8.8, 7.7) mm and 8 (-126, 141) mm3 for length and volume, respectively. This was comparable to the best interobserver agreement, with an intraclass correlation coefficients of 0.90 and 0.85 and a bias (limits of agreement) of -0.1 (-11.2, 10.9) mm and -17 (-216, 185) mm3. CONCLUSIONS: The method facilitates automated thrombus segmentation for accurate length and volume measurements, is relatively fast and requires minimal user input, while being insensitive to high hematocrit levels and vascular calcifications. Furthermore, it has the potential to assess thrombus characteristics of low-density thrombi. PMID- 25032693 TI - Limitation of number of strains and persistence of false positive loci in QTL mapping using recombinant inbred strains. AB - While the identification of causal genes of quantitative trait loci (QTL) remains a difficult problem in the post-genome era, the number of QTL continues to accumulate, mainly identified using the recombinant inbred (RI) strains. Over the last decade, hundreds of publications have reported nearly a thousand QTL identified from RI strains. We hypothesized that the inaccuracy of most of these QTL makes it difficult to identify causal genes. Using data from RI strains derived from C57BL/6J (B6) X DBA/2J (D2), we tested the possibility of detection of reliable QTL with different numbers of strains in the same trait in five different traits. Our results indicated that studies using RI strains of less than 30 in general have a higher probability of failing to detect reliable QTL. Errors in many studies could include false positive loci, switches between QTL with small and major effects, and missing the real major loci. The similar data was obtained from a RI strain population derived from a different pair of parents and a RI strain population of rat. Thus, thousands of reported QTL from studies of RI strains may need to be double-checked for accuracy before proceeding to causal gene identification. PMID- 25032694 TI - Ciliary body medulloepithelioma association with pleuropulmonary blastoma in a familial tumor predisposition syndrome. AB - Ciliary body medulloepithelioma can rarely present in association with pleuropulmonary blastoma as part of a familial tumor predisposition syndrome. This is thought to occur secondary to a germline mutation in the DICER1 gene. The authors describe a case of ciliary body medulloepithelioma in a 9-year-old girl with a known medical history of pleuropulmonary blastoma. PMID- 25032695 TI - Limited ocular motility in a child with 3q23 microdeletion ("blepharophimosis syndrome plus"). AB - Blepharophimosis syndrome is a recognizable ocular phenotype (blepharophimosis, telecanthus, ptosis, and epicanthus inversus) caused by heterozygous (dominant) intragenic mutation in FOXL2 (chromosome 3q23), which can also cause premature ovarian failure. A deletion that involves not only FOXL2 but also adjacent genes can result in additional clinical features ("blepharophimosis syndrome plus"). Studies of such patients are useful because observed additional clinical features suggest potential functions of genes adjacent to FOXL2. The authors describe a boy with blepharophimosis syndrome plus from a de novo heterozygous 3q22.3-q24 11.2 Mb microdeletion. Among his additional clinical features was bilateral limitation of abduction and supraduction, which suggests that the deleted area includes a gene responsible for ocular motility. PMID- 25032697 TI - Haiti National Program for the elimination of lymphatic filariasis--a model of success in the face of adversity. PMID- 25032699 TI - Magneto-chemotaxis in sediment: first insights. AB - Magnetotactic bacteria (MTB) use passive alignment with the Earth magnetic field as a mean to increase their navigation efficiency in horizontally stratified environments through what is known as magneto-aerotaxis (M-A). Current M-A models have been derived from MTB observations in aqueous environments, where a >80% alignment with inclined magnetic field lines produces a one-dimensional search for optimal living conditions. However, the mean magnetic alignment of MTB in their most widespread living environment, i.e. sediment, has been recently found to be <1%, greatly reducing or even eliminating the magnetotactic advantage deduced for the case of MTB in water. In order to understand the role of magnetotaxis for MTB populations living in sediment, we performed first M-A observations with lake sediment microcosms. Microcosm experiments were based on different combinations of (1) MTB position with respect to their preferred living depth (i.e. above, at, and below), and (2) magnetic field configurations (i.e. correctly and incorrectly polarized vertical fields, horizontal fields, and zero fields). Results suggest that polar magnetotaxis is more complex than implied by previous experiments, and revealed unexpected differences between two types of MTB living in the same sediment. Our main findings are: (1) all investigated MTB benefit of a clear magnetotactic advantage when they need to migrate over macroscopic distances for reaching their optimal living depth, (2) magnetotaxis is not used by all MTB under stationary, undisturbed conditions, (3) some MTB can rely only on chemotaxis for macroscopic vertical displacements in sediment while other cannot, and (4) some MTB use a fixed polar M-A mechanisms, while other can switch their M-A polarity, performing what can be considered as a mixed polar axial M-A. These observations demonstrate that sedimentary M-A is controlled by complex mechanical, chemical, and temporal factors that are poorly reproduced in aqueous environments. PMID- 25032698 TI - Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress. AB - Mammalian Peptidoglycan Recognition Proteins (PGRPs) are a family of evolutionary conserved bactericidal innate immunity proteins, but the mechanism through which they kill bacteria is unclear. We previously proposed that PGRPs are bactericidal due to induction of reactive oxygen species (ROS), a mechanism of killing that was also postulated, and later refuted, for several bactericidal antibiotics. Here, using whole genome expression arrays, qRT-PCR, and biochemical tests we show that in both Escherichia coli and Bacillus subtilis PGRPs induce a transcriptomic signature characteristic of oxidative stress, as well as correlated biochemical changes. However, induction of ROS was required, but not sufficient for PGRP killing. PGRPs also induced depletion of intracellular thiols and increased cytosolic concentrations of zinc and copper, as evidenced by transcriptome changes and supported by direct measurements. Depletion of thiols and elevated concentrations of metals were also required, but by themselves not sufficient, for bacterial killing. Chemical treatment studies demonstrated that efficient bacterial killing can be recapitulated only by the simultaneous addition of agents leading to production of ROS, depletion of thiols, and elevation of intracellular metal concentrations. These results identify a novel mechanism of bacterial killing by innate immunity proteins, which depends on synergistic effect of oxidative, thiol, and metal stress and differs from bacterial killing by antibiotics. These results offer potential targets for developing new antibacterial agents that would kill antibiotic-resistant bacteria. PMID- 25032700 TI - NCI-60 whole exome sequencing and pharmacological CellMiner analyses. AB - Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among the richest genomic and pharmacological publicly available cancer cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants that are either enriched or depleted compared to non-cancerous genomes, and thus may be influential in cancer progression and differential drug response were identified for 2,546 genes. Potential gene knockouts are made available. Assessment of cell line response to 19,940 compounds, including 110 FDA-approved drugs, reveals ~80-fold range in resistance versus sensitivity response across cell lines. 103,422 gene variants were significantly correlated with at least one compound (at p<0.0002). These include genes of known pharmacological importance such as IGF1R, BRAF, RAD52, MTOR, STAT2 and TSC2 as well as a large number of candidate genes such as NOM1, TLL2, and XDH. We introduce two new web-based CellMiner applications that enable exploration of variant-to-compound relationships for a broad range of researchers, especially those without bioinformatics support. The first tool, "Genetic variant versus drug visualization", provides a visualization of significant correlations between drug activity-gene variant combinations. Examples are given for the known vemurafenib BRAF, and novel ifosfamide-RAD52 pairings. The second, "Genetic variant summation" allows an assessment of cumulative genetic variations for up to 150 combined genes together; and is designed to identify the variant burden for molecular pathways or functional grouping of genes. An example of its use is provided for the EGFR-ERBB2 pathway gene variant data and the identification of correlated EGFR, ERBB2, MTOR, BRAF, MEK and ERK inhibitors. The new tools are implemented as an updated web-based CellMiner version, for which the present publication serves as a compendium. PMID- 25032701 TI - Changing patterns of human anthrax in Azerbaijan during the post-Soviet and preemptive livestock vaccination eras. AB - We assessed spatial and temporal changes in the occurrence of human anthrax in Azerbaijan during 1984 through 2010. Data on livestock outbreaks, vaccination efforts, and human anthrax incidence during Soviet governance, post-Soviet governance, preemptive livestock vaccination were analyzed. To evaluate changes in the spatio-temporal distribution of anthrax, we used a combination of spatial analysis, cluster detection, and weighted least squares segmented regression. Results indicated an annual percent change in incidence of (+)11.95% from 1984 to 1995 followed by declining rate of -35.24% after the initiation of livestock vaccination in 1996. Our findings also revealed geographic variation in the spatial distribution of reporting; cases were primarily concentrated in the west early in the study period and shifted eastward as time progressed. Over twenty years after the dissolution of the Soviet Union, the distribution of human anthrax in Azerbaijan has undergone marked changes. Despite decreases in the incidence of human anthrax, continued control measures in livestock are needed to mitigate its occurrence. The shifting patterns of human anthrax highlight the need for an integrated "One Health" approach that takes into account the changing geographic distribution of the disease. PMID- 25032703 TI - Protection from hemolytic uremic syndrome by eyedrop vaccination with modified enterohemorrhagic E. coli outer membrane vesicles. AB - We investigated whether eyedrop vaccination using modified outer membrane vesicles (mOMVs) is effective for protecting against hemolytic uremic syndrome (HUS) caused by enterohemorrhagic E. coli (EHEC) O157:H7 infection. Modified OMVs and waaJ-mOMVs were prepared from cultures of MsbB- and Shiga toxin A subunit (STxA)-deficient EHEC O157:H7 bacteria with or without an additional waaJ mutation. BALB/c mice were immunized by eyedrop mOMVs, waaJ-mOMVs, and mOMVs plus polymyxin B (PMB). Mice were boosted at 2 weeks, and challenged peritoneally with wild-type OMVs (wtOMVs) at 4 weeks. As parameters for evaluation of the OMV mediated immune protection, serum and mucosal immunoglobulins, body weight change and blood urea nitrogen (BUN)/Creatinin (Cr) were tested, as well as histopathology of renal tissue. In order to confirm the safety of mOMVs for eyedrop use, body weight and ocular histopathological changes were monitored in mice. Modified OMVs having penta-acylated lipid A moiety did not contain STxA subunit proteins but retained non-toxic Shiga toxin B (STxB) subunit. Removal of the polymeric O-antigen of O157 LPS was confirmed in waaJ-mOMVs. The mice group vaccinated with mOMVs elicited greater humoral and mucosal immune responses than did the waaJ-mOMVs and PBS-treated groups. Eyedrop vaccination of mOMVs plus PMB reduced the level of humoral and mucosal immune responses, suggesting that intact O157 LPS antigen can be a critical component for enhancing the immunogenicity of the mOMVs. After challenge, mice vaccinated with mOMVs were protected from a lethal dose of wtOMVs administered intraperitoneally, conversely mice in the PBS control group were not. Collectively, for the first time, EHEC O157-derived mOMV eyedrop vaccine was experimentally evaluated as an efficient and safe means of vaccine development against EHEC O157:H7 infection-associated HUS. PMID- 25032704 TI - Metallothionein 2 (SaMT2) from Sedum alfredii Hance confers increased Cd tolerance and accumulation in yeast and tobacco. AB - Metallothioneins are cysteine-rich metal-binding proteins. In the present study, SaMT2, a type 2 metallothionein gene, was isolated from Cd/Zn co-hyperaccumulator Sedum alfredii Hance. SaMT2 encodes a putative peptide of 79 amino acid residues including two cysteine-rich domains. The transcript level of SaMT2 was higher in shoots than in roots of S. alfredii, and was significantly induced by Cd and Zn treatments. Yeast expression assay showed SaMT2 significantly enhanced Cd tolerance and accumulation in yeast. Ectopic expression of SaMT2 in tobacco enhanced Cd and Zn tolerance and accumulation in both shoots and roots of the transgenic plants. The transgenic plants had higher antioxidant enzyme activities and accumulated less H2O2 than wild-type plants under Cd and Zn treatment. Thus, SaMT2 could significantly enhance Cd and Zn tolerance and accumulation in transgenic tobacco plants by chelating metals and improving antioxidant system. PMID- 25032705 TI - Poisson-like spiking in circuits with probabilistic synapses. AB - Neuronal activity in cortex is variable both spontaneously and during stimulation, and it has the remarkable property that it is Poisson-like over broad ranges of firing rates covering from virtually zero to hundreds of spikes per second. The mechanisms underlying cortical-like spiking variability over such a broad continuum of rates are currently unknown. We show that neuronal networks endowed with probabilistic synaptic transmission, a well-documented source of variability in cortex, robustly generate Poisson-like variability over several orders of magnitude in their firing rate without fine-tuning of the network parameters. Other sources of variability, such as random synaptic delays or spike generation jittering, do not lead to Poisson-like variability at high rates because they cannot be sufficiently amplified by recurrent neuronal networks. We also show that probabilistic synapses predict Fano factor constancy of synaptic conductances. Our results suggest that synaptic noise is a robust and sufficient mechanism for the type of variability found in cortex. PMID- 25032706 TI - LIN-42, the Caenorhabditis elegans PERIOD homolog, negatively regulates microRNA transcription. AB - During C. elegans development, microRNAs (miRNAs) function as molecular switches that define temporal gene expression and cell lineage patterns in a dosage dependent manner. It is critical, therefore, that the expression of miRNAs be tightly regulated so that target mRNA expression is properly controlled. The molecular mechanisms that function to optimize or control miRNA levels during development are unknown. Here we find that mutations in lin-42, the C. elegans homolog of the circadian-related period gene, suppress multiple dosage-dependent miRNA phenotypes including those involved in developmental timing and neuronal cell fate determination. Analysis of mature miRNA levels in lin-42 mutants indicates that lin-42 functions to attenuate miRNA expression. Through the analysis of transcriptional reporters, we show that the upstream cis-acting regulatory regions of several miRNA genes are sufficient to promote highly dynamic transcription that is coupled to the molting cycles of post-embryonic development. Immunoprecipitation of LIN-42 complexes indicates that LIN-42 binds the putative cis-regulatory regions of both non-coding and protein-coding genes and likely plays a role in regulating their transcription. Consistent with this hypothesis, analysis of miRNA transcriptional reporters in lin-42 mutants indicates that lin-42 regulates miRNA transcription. Surprisingly, strong loss-of function mutations in lin-42 do not abolish the oscillatory expression patterns of lin-4 and let-7 transcription but lead to increased expression of these genes. We propose that lin-42 functions to negatively regulate the transcriptional output of multiple miRNAs and mRNAs and therefore coordinates the expression levels of genes that dictate temporal cell fate with other regulatory programs that promote rhythmic gene expression. PMID- 25032707 TI - Brain MRI CO2 stress testing: a pilot study in patients with concussion. AB - BACKGROUND: There is a real need for quantifiable neuro-imaging biomarkers in concussion. Here we outline a brain BOLD-MRI CO2 stress test to assess the condition. METHODS: This study was approved by the REB at the University of Manitoba. A group of volunteers without prior concussion were compared to post concussion syndrome (PCS) patients--both symptomatic and recovered asymptomatic. Five 3-minute periods of BOLD imaging at 3.0 T were studied--baseline 1 (BL1--at basal CO2 tension), hypocapnia (CO2 decreased ~5 mmHg), BL2, hypercapnia (CO2 increased ~10 mmHg) and BL3. Data were processed using statistical parametric mapping (SPM) for 1st level analysis to compare each subject's response to the CO2 stress at the p = 0.001 level. A 2nd level analysis compared each PCS patient's response to the mean response of the control subjects at the p = 0.05 level. RESULTS: We report on 5 control subjects, 8 symptomatic and 4 asymptomatic PCS patients. Both increased and decreased response to CO2 was seen in all PCS patients in the 2nd level analysis. The responses were quantified as reactive voxel counts: whole brain voxel counts (2.0+/-1.6%, p = 0.012 for symptomatic patients for CO2 response < controls and 3.0+/-5.1%, p = 0.139 for CO2 response > controls: 0.49+/-0.31%, p = 0.053 for asymptomatic patients for CO2 response < controls and 4.4+/-6.8%, p = 0.281 for CO2 response > controls). CONCLUSIONS: Quantifiable alterations in regional cerebrovascular responsiveness are present in concussion patients during provocative CO2 challenge and BOLD MRI and not in healthy controls. Future longitudinal studies must aim to clarify the relationship between CO2 responsiveness and individual patient symptoms and outcomes. PMID- 25032708 TI - Screening and characterisation of antimicrobial properties of semisynthetic betulin derivatives. AB - Betulin (lup-20(29)-ene-3beta, 28-diol) is a naturally occurring triterpene, which is found in substantial amounts from the outer bark of birch trees. A library of 51 structurally diverse semisynthetic betulin derivatives was screened against five bacterial strains, Enterobacter aerogenes, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and a fungal strain Candida albicans, using broth microdilution assays. Primary antimicrobial screening at 50 uM concentration led to the identification of five compounds showing antimicrobial properties (inhibition of growth by >70% against one or more microbial strains). According to the dose-response results, 28-O-(N acetylanthraniloyl)betulin (compound 5) was the most active, showing MIC90 of 6.25 uM against two Gram-positive bacteria, E. faecalis and S. aureus. However, the activity of this compound was affected by albumin binding, which was demonstrated by the loss of activity in a host-pathogen co-culture assay as well as in the antibacterial assay in the presence of increased concentration of albumin. Furthermore, the effects on mammalian cells were evaluated by cytotoxicity assessment on hepatocyte cell culture after 24 h exposure to the compounds. Betulinic aldehyde (18), betulin-28-oxime (31) and hetero cycloadduct with acetoxy groups at carbon atoms 3 and 28 and ethyl substituent at the triazolo ring (43) displayed cytotoxicity towards hepatocytes, with IC50 values of 47, 25 and 16 uM, respectively. The IC50 value for 28-O-(N acetylanthraniloyl)betulin (5) was 56 uM. The current study presents an insight into using betulin scaffold for developing derivatives with antibacterial potential, and furthermore the necessity of in-depth analysis of found actives through selectivity profiling and follow-up studies including in silico ADMET predictions. PMID- 25032710 TI - A qualitative assessment of program characteristics for preventing secondary conditions in individuals with fetal alcohol spectrum disorders. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASD) are a major public health problem that affects 2 to 5 percent of the population. Individuals with FASD are at high risk for secondary conditions, such as mental health problems, school disruptions, and trouble with the law. Evidence-based intervention programs are needed to prevent and treat secondary conditions in this population. OBJECTIVES: The purpose of this study was to identify intervention program characteristics for preventing secondary conditions in individuals with FASD from the perspectives of parents and service providers. METHODS: This qualitative study utilized a phenomenological approach to identify program characteristics for preventing secondary conditions. Twenty-five parents of children (ages 3 to 33) with FASD and 18 service providers participated in focus groups or individual interviews. Data was systematically analyzed using a framework approach. Themes did not differ by participant type. RESULTS: Participants emphasized five primary characteristics of intervention programs for individuals with FASD. Programs need to 1) be available to individuals across the lifespan, 2) have a prevention focus, 3) be individualized, 4) be comprehensive, and 5) be coordinated across systems and developmental stages. Participants discussed a variety of specific intervention strategies for each developmental stage and setting. CONCLUSIONS: Program characteristics identified in this study are consistent with a positive behavior support framework. This framework is discussed in the context of research on existing interventions for individuals with FASD, and recommendations for future intervention development and evaluation are highlighted. PMID- 25032709 TI - HMGB1 promotes the development of pulmonary arterial hypertension in rats. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated. OBJECTIVES: To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH. METHODS: Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested. RESULTS: HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-alpha, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats. CONCLUSIONS: Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH. PMID- 25032711 TI - Dignity and the ownership and use of body parts. AB - Property-based models of the ownership of body parts are common. They are inadequate. They fail to deal satisfactorily with many important problems, and even when they do work, they rely on ideas that have to be derived from deeper, usually unacknowledged principles. This article proposes that the parent principle is always human dignity, and that one will get more satisfactory answers if one interrogates the older, wiser parent instead of the younger, callow offspring. But human dignity has a credibility problem. It is often seen as hopelessly amorphous or incurably theological. These accusations are often just. But a more thorough exegesis exculpates dignity and gives it its proper place at the fountainhead of bioethics. Dignity is objective human thriving. Thriving considerations can and should be applied to dead people as well as live ones. To use dignity properly, the unit of bioethical analysis needs to be the whole transaction rather than (for instance) the doctor-patient relationship. The dignity interests of all the stakeholders are assessed in a sort of utilitarianism. Its use in relation to body part ownership is demonstrated. Article 8(1) of the European Convention of Human Rights endorses and mandates this approach. PMID- 25032712 TI - Demoralization: a systematic review on its clinical characterization. AB - BACKGROUND: Demoralization has been described as a psychological state characterized by helplessness, hopelessness, a sense of failure and the inability to cope. METHODS: We conducted a systematic review with qualitative data analysis following PRISMA criteria with the following aims: to review validated assessment instruments of the demoralization syndrome, report main findings regarding demoralization as measured by validated instruments that emerge in the literature, compare and report evidence for the clinical utility of the identified instruments. Utilizing the key word 'demoralization' in PubMed and PsycINFO databases, an electronic search was performed, supplemented by Web of Science and manual searches. Study selection criteria included the assessment of medical patients and use of instruments validated to assess demoralization. Seventy-four studies were selected. RESULTS: Four instruments emerged in the literature. Main findings concern prevalence rates of demoralization, evidence of discriminant validity from major depression, factors associated with demoralization and evidence of clinical utility. The instruments vary in their definition, the populations they aim to assess, prevalence rates they estimate and their ability to discriminate between different conditions. Nonetheless, demoralization appears to be a distinctive psychological state characterized by helplessness, hopelessness, giving up and subjective incompetence. It is not limited to life-threatening diseases such as cancer, but may occur in any type of clinical situation. It is associated with stress and adverse health outcomes. CONCLUSIONS: Studies addressing the incremental value of demoralization in psychiatry and psychology are needed. However, demoralization appears to entail specific clinical features and may be a distinct condition from major depression. PMID- 25032713 TI - High-dose atorvastatin for preventing contrast-induced nephropathy in primary percutaneous coronary intervention. AB - AIMS: To evaluate the efficacy of high-dose atorvastatin on contrast-induced nephropathy (CIN) occurrence in patients with ST-elevation myocardial infarction undergoing primary angioplasty. METHODS: We studied whether 80 mg atorvastatin loading and its subsequent use for 5 days (high-dose group) could prevent CIN as compared to those who received 10 mg atorvastatin (regular-dose group) in patients with ST-elevation myocardial infarction undergoing primary angioplasty. The primary endpoint was incidence of CIN, defined as an at least 25% or at least 0.5 mg/dl increase in baseline serum creatinine within 5 days after contrast administration. The secondary endpoint was an in-hospital 1 and 6-month renal function change, and a composite of all-cause mortality, myocardial infarction, renal failure requiring dialysis, heart failure, and target vessel revascularization. RESULTS: One hundred and ten patients were allocated to high dose and 108 to regular dose from August 2007 to February 2009. CIN incidence was 5.5% (6/110) in the high-dose group and 10.2% (11/108) in the regular-dose group, which is a nonsignificant difference (P = 0.193). CIN occurred significantly less in the high-dose than in the regular-dose group in subgroups of renal insufficiency (creatinine clearance <=60 ml/min) [0% (0/28) vs. 16.7% (5/30); P = 0.024] and in the elderly patients who were at least 70 years old [4% (1/25) and 23.1% (6/26); P = 0.048]. Serum creatinine level tended to decrease in the high-dose group and increase in the regular-dose group, but the change was not statistically different (P = 0.093). The composite of clinical outcomes at 6 months was comparable in the high-dose and regular-dose groups (7.9 and 13.1%; P = 0.26). CONCLUSION: High-dose atorvastatin pretreatment does not seem to prevent CIN in patients receiving primary angioplasty. However, it has the potential to lower CIN in patients with renal insufficiency and in the elderly. PMID- 25032714 TI - 9p21.3 risk locus is associated with first-ever myocardial infarction in an Austrian cohort. AB - AIMS: Atherosclerosis often presents as a complex systemic disease that is strongly influenced by lifestyle factors, but also by the genetic background. The sequence variant rs1333049 affects the expression of ANRIL, a noncoding RNA transcript playing a key role in the regulation of inflammatory processes. We thus aimed to replicate the predictive value of genetic information on this variant regarding the development of cardiovascular events in an Austrian high risk cohort. METHODS: Nine hundred and eighty-eight patients from an angiologic outpatient ward at a large University hospital were genotyped by means of the 5' nuclease assay. Relative risk ratios were assessed for carriers of different alleles. Statistical independence of genetic information was evaluated in multivariable analysis including known risk markers. RESULTS: In patients carrying the [G]-allele, metabolic parameters (serum low-density lipoprotein, total cholesterol) significantly decreased during the initial 6 months of the observation period (P < 0.01). Likewise, homozygous [C]-allele carriers were at a higher risk of suffering myocardial infarction (relative risk = 2.681, 95% confidence interval 1.418-5.070). In contrast, we found no interaction between rs1333049 genotype and progression of carotid atherosclerosis or stroke. CONCLUSIONS: These results are in line with the previous findings, suggesting that genetic information on the rs1333049 variant might be a useful predictor of adverse cardiac events. Thus, we could successfully replicate the predictive value of the 9p21 risk allele in an Austrian cohort. PMID- 25032715 TI - Impact of remote monitoring on the management of arrhythmias in patients with implantable cardioverter-defibrillator. AB - BACKGROUND: In the last decade, there has been an exponential increase in cardioverter-defibrillator (ICD) implants. Remote monitoring systems, allow daily follow-ups of patients with ICD. OBJECTIVE: To evaluate the impact of remote monitoring on the management of cardiovascular events associated with supraventricular and ventricular arrhythmias during long-term follow-up. METHODS: A total of 207 patients undergoing ICD implantation/replacement were enrolled: 79 patients received remote monitoring systems and were followed up every 12 months, and 128 patients were followed up conventionally every 6 months. All patients were followed up and monitored for the occurrence of supraventricular and ventricular arrhythmia-related cardiovascular events (ICD shocks and/or hospitalizations). RESULTS: During a median follow-up of 842 days (interquartile range 476-1288 days), 32 (15.5%) patients experienced supraventricular arrhythmia related events and 51 (24.6%) patients experienced ventricular arrhythmia-related events. Remote monitoring had a significant role in the reduction of supraventricular arrhythmia-related events, but it had no effect on ventricular arrhythmia-related events. In multivariable analysis, remote monitoring remained as an independent protective factor, reducing the risk of supraventricular arrhythmia-related events of 67% [hazard ratio, 0.33; 95% confidence interval (CI), 0.13-0.82; P = 0.017]. CONCLUSION: Remote monitoring systems improved outcomes in patients with supraventricular arrhythmias by reducing the risk of cardiovascular events, but no benefits were observed in patients with ventricular arrhythmias. PMID- 25032717 TI - Risk factors for the development of Clostridium difficile infection in hospitalized children. AB - PURPOSE OF REVIEW: This article defines the risk factors for Clostridium difficile infection (CDI) in hospitalized children in light of recent studies demonstrating a change in the epidemiology of these infections in both adults and children. RECENT FINDINGS: Antibiotic exposure within the past 4-12 weeks was noted in a majority of published cases of pediatric CDI, and that remains a key risk factor for infection. Past and/or prolonged hospitalization increase a child's risk for CDI as they increase potential contact with C. difficile spores. Of all CDI, hospital-acquired infection remains more common. Many comorbid conditions have been linked with CDI, with the strongest association existing in children with cancer and inflammatory bowel disease. Severe infections occur infrequently in pediatric patients. Markers established in adults for severe CDI resulting in colectomy or transfer to ICU have not been shown to correlate in pediatric patients. SUMMARY: Recent antibiotic exposure and hospitalization remain key risk factors for CDI in the hospitalized pediatric patient. Patients with comorbid conditions such as malignancy and inflammatory bowel disease are at higher risk for CDI. Resistant infections and severe outcomes are not common in the pediatric population. PMID- 25032718 TI - Just say "yes". PMID- 25032719 TI - Sleep deprivation in children: a growing public health concern. PMID- 25032720 TI - New opportunities in the changing landscape of prevention. PMID- 25032721 TI - A case of neonatal myocardial infarction: left coronary artery thrombus resolution and normalisation of ventricular function by intracoronary low-dose tissue plasminogen activator. AB - Neonatal myocardial infarction is a rare clinical entity that is associated with high mortality. Reported treatment strategies include supportive care, extracorporeal membrane oxygenation, thrombolytics, and surgical thrombectomy. Herein we report a neonate who developed an acute myocardial infarction owing to a thrombus in the proximal left coronary artery. At 24 hours of life, he was treated with local (intracoronary) thrombolytic therapy at a lower dose than previously reported, as well as with systemic anticoagulation. There was subsequent angiographic resolution of the thrombus and normalisation of left ventricular function. PMID- 25032722 TI - Central Lung Cancer Management: Impact of Bronchial Resection Margin Length. AB - PURPOSE: The purpose of this study was to analyze the clinical impact of bronchial resection margin length in centrally located, non-small cell lung cancer. MATERIALS AND METHODS: A total of 1,854 pulmonary resections were performed between January 1994 and December 2005. Central lung cancer was defined as a tumor that was confirmed by bronchoscopy or a malignancy proven by bronchoscopic washing. Cases with neoadjuvant treatment that could alter the malignancy on the margin and those without documentation of margin length were excluded. To divide the study group into two groups, the cutoff value for the margin length was calculated by the minimum p-value approach. Clinical variables were then compared between the two groups and prognostic factors for survival were analyzed. RESULTS: A total of 573 patients were included. The patients were divided into two groups based on margin length, short (< 19 mm) and long (>= 19 mm). Overall survival and disease-free survival were superior in the short length group by univariate analysis (p = 0.03, 0.02). With multivariate analysis, advanced age (p < 0.00, 0.00), pneumonectomy (p < 0.00, 0.00), advanced pathologic stage (p < 0.00, 0.00), and no adjuvant chemotherapy (p < 0.00, 0.01) were poor prognostic factors for survival; however, bronchial resection margin length was not a statistically significant factor (p = 0.90, 0.96). CONCLUSION: A long bronchial resection margin length may not guarantee better oncologic outcomes in central lung cancer patients. Rather, avoiding pneumonectomy and the application of adjuvant chemotherapy should be considered to survival. PMID- 25032723 TI - Intraoperative Measurement of Fractional Flow Reserve in Off-Pump Coronary Artery Bypass: A Pilot Study. AB - BACKGROUNDS: Fractional flow reserve of myocardium (FFRmyo) is a functional study of significant coronary artery stenosis, defined as the ratio of the pressure distal to the stenosis (poststenosis) divided by the pressure of aortic root (prestenosis). Instead of cath laboratory, we could measure it in operating room for off-pump coronary artery bypass (OPCAB) surgery and here shared our methods in the pilot study. METHODS AND RESULTS: We used needles, catheters, and pressure tracing but without guidewires or fluoroscopy to measure FFRmyo during OPCAB. In February 2010, we conducted the pilot study and collected 32 anastomosis data from 10 patients. Without revising the anastomosis plans based on coronary angiographies, 24 FFRmyo of the 32 anastomoses (75%) were less than 0.75, which represented significant functional stenosis. The FFRmyo measurements did not lead to any adverse events. CONCLUSION: The measurement of fractional flow reserve in OPCAB is safe and feasible. It can serve as a functional assessment of coronary artery stenosis in adjuvant to conventional coronary angiography. PMID- 25032724 TI - Left atrial anatomy and physiology: echo/Doppler assessment. AB - PURPOSE OF REVIEW: This article provides a state-of-the-art perspective of left atrial anatomy and physiology. RECENT FINDINGS: Left atrial structure and function can be used to reflect and quantify the physiologic state of complex disease processes. No single left atrial anatomic, functional, or clinical feature will adequately define a complex system. The state of combined left atrial structural and functional features (i.e., systems biology) defines disease clustering (i.e., commonality of underlying left atrial pathophysiology), cause and effect (i.e., left atrial dynamics impute disease events as consequences), disease classification (e.g., primary vs. secondary atrial fibrillation), and intensity of a pathophysiologic state (i.e., quantifiably infer the magnitude of a pathophysiologic perturbation), and helps explain complex pathophysiology (e.g., myocyte death vs. hibernation). SUMMARY: Individual left atrial structural and functional features do not define the state of complex systems. Systems biology and multifeature profiles of left atrial anatomy and physiology should be used to assist the prediction, management, and, ultimately, prevention of preclinical and overt complex disease processes. PMID- 25032725 TI - Left atrial volume and function in patients with atrial fibrillation. AB - PURPOSE OF REVIEW: This review of emerging approaches to left atrial imaging in atrial fibrillation is relevant because there has been considerable recent development in the noninvasive characterization of left atrial structure and function. Concurrently, the identification and treatment of atrial fibrillation and the prevention of thromboembolism are evolving. Thus, it is timely to summarize how the advances in these two areas might be synergistic in the treatment of atrial fibrillation. RECENT FINDINGS: This article will summarize recent developments in left atrial imaging that play a role in patients with atrial fibrillation, with particular emphasis on echocardiography, and with reference made to important advances in cardiac computed tomography and cardiac magnetic resonance. The evidence that these modalities can predict who will develop atrial fibrillation, who will achieve sustained sinus rhythm after cardioversion or catheter ablation, and who will have thromboembolic risk will be reviewed. SUMMARY: Although existing evidence is promising, the clinical role of cardiac imaging to predict atrial fibrillation occurrence, atrial fibrillation recurrence after treatment, and thromboembolism from atrial fibrillation remains to be confirmed in large-scale studies and clinical trials. PMID- 25032726 TI - Left atrial function in heart failure with impaired and preserved ejection fraction. AB - PURPOSE OF REVIEW: Left atrial structural and functional changes in heart failure are relatively ignored parts of cardiac assessment. This review illustrates the pathophysiological and functional changes in left atrium in heart failure as well as their prognostic value. RECENT FINDINGS: Heart failure can be divided into those with systolic dysfunction and heart failure with preserved ejection fraction (HFPEF). Left atrial enlargement and dysfunction commonly occur in systolic heart failure, in particular, in idiopathic dilated cardiomyopathy. Atrial enlargement and dysfunction also carry important prognostic value in systolic heart failure, independently of known parameters such as left ventricular ejection fraction. In HFPEF, there is evidence of left atrial enlargement, impaired atrial compliance, and reduction of atrial pump function. This occurs not only at rest but also during exercise, indicating significant impairment of atrial contractile reserve. Furthermore, atrial dyssynchrony is common in HFPEF. These factors further contribute to the development of new onset or progression of atrial arrhythmias, in particular, atrial fibrillation. SUMMARY: Left atrial function is an integral part of cardiac function and its structural and functional changes in heart failure are common. As changes of left atrial structure and function have different clinical implications in systolic heart failure and HFPEF, routine assessment is warranted. PMID- 25032727 TI - Prospection of genomic regions divergently selected in racing line of Quarter Horses in relation to cutting line. AB - Selection of Quarter Horses for different purposes has led to the formation of lines, including racing and cutting horses. The objective of this study was to identify genomic regions divergently selected in racing line of Quarter Horses in relation to cutting line applying relative extended haplotype homozygosity (REHH) analysis, an extension of extended haplotype homozygosity (EHH) analysis, and the fixation index (F ST) statistic. A total of 188 horses of both sexes, born between 1985 and 2009 and registered at the Brazilian Association of Quarter Horse Breeders, including 120 of the racing line and 68 of the cutting line, were genotyped using single nucleotide polymorphism arrays. On the basis of 27 genomic regions identified as selection signatures by REHH and F ST statistics, functional annotations of genes were made in order to identify those that could have been important during formation of the racing line and that could be used subsequently for the development of selection tools. Genes involved in muscle growth (n=8), skeletal growth (n=10), muscle energy metabolism (n=15), cardiovascular system (n=14) and nervous system (n=23) were identified, including the FKTN, INSR, GYS1, CLCN1, MYLK, SYK, ANG, CNTFR and HTR2B. PMID- 25032728 TI - Congenital lamellar cataract. PMID- 25032729 TI - Bone mineral density in midlife women: the Study of Women's Health in Qatar. AB - OBJECTIVES: The aim of this study is to investigate bone mineral density (BMD) for a large cross-section of midlife Arab women living in Qatar and to evaluate the association of body mass index (BMI), menopause status, and nationality, on BMD of the spine and femur. STUDY DESIGN: A cross-sectional study was conducted among women aged 40-60 years recruited from nine primary-care health centers in Qatar. BMD (g/m(2)) was assessed at the lumbar spine and the femur. RESULTS: The combined prevalence of osteopenia and osteoporosis was 4% at the femur and 16.2% at the spine. BMI and menstrual status were both independently associated with BMD at the spine and at the femur (all p values < 0.001). As BMI increased, BMD increased at both the spine and femur. Women who menstruated in the past 12 months had 0.82 g/cm(2) and 0.61 g/cm(2) greater BMD at the spine and femur, respectively, compared with women who had not menstruated in 12 months. Nationality was not associated with mean BMD of the spine or the femur. CONCLUSIONS: No significant differences were observed between Qatari and non Qatari women in terms of mean BMD values at the spine and the femur except for the femur in the age group 55-60, where values were lower among non-Qataris (p = 0.04). Multivariable analyses showed that BMI and menstrual status were found to be strongly associated with BMD levels at the spine and femur. The high prevalence of obesity observed in this sample may explain the low levels of osteopenia and osteoporosis observed. PMID- 25032730 TI - DNA methylation analysis in self-sampled brush material as a triage test in hrHPV positive women. AB - BACKGROUND: Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed. METHODS: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. RESULTS: In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (kappa=0.75, P<0.001) and 90% for C13ORF18 (kappa=0.77; P<0.001). CONCLUSIONS: DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing. PMID- 25032731 TI - Concurrent analysis of human equilibrative nucleoside transporter 1 and ribonucleotide reductase subunit 1 expression increases predictive value for prognosis in cholangiocarcinoma patients treated with adjuvant gemcitabine-based chemotherapy. AB - BACKGROUND: The aim of this study was to investigate the predictive and prognostic values of intratumoural human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase subunit 1 (RRM1) expression in advanced cholangiocarcinoma patients treated with adjuvant gemcitabine-based chemotherapy (AGC). METHODS: Intratumoural hENT1 and RRM1 expression levels were investigated immunohistochemically in 127 patients with advanced cholangiocarcinoma who underwent surgical resection (68 with AGC and 59 without AGC). The impacts of hENT1 and RRM1 expression on survival were evaluated. RESULTS: High intratumoural hENT1 and RRM1 expression levels were observed in 86 (68%) and 67 (53%) patients, respectively. In a multivariate analysis of 68 patients who received AGC, high hENT1 (P=0.044) and low RRM1 expression (P=0.009) were independently associated with prolonged disease-free survival (DFS), whereas low RRM1 expression (P=0.024) was independently associated with prolonged overall survival (OS). Moreover, concurrent high hENT1 and low RRM1 expression was a powerful independent predictor of prolonged DFS (P<0.001) and OS (P=0.001) when the combined classification of hENT1 and RRM1 was introduced. CONCLUSIONS: Concurrent analysis of hENT1 and RRM1 expression may increase the predictive value of these biomarkers for survival of advanced cholangiocarcinoma patients treated with AGC. PMID- 25032732 TI - COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1. AB - BACKGROUND: Chicken ovalbumin upstream promoter-transcription factor II (COUP TFII, also known as NR2F2) promotes metastasis by functioning in the tumour microenvironment; however, the role of COUP-TFII in colorectal cancer remains unknown. METHODS: Human colon adenocarcinoma tissues were collected to test COUP TFII expression. Wound-healing and cell invasion assay were used to evaluate migration and invasion of cells. Chicken ovalbumin upstream promoter transcription factor II and related protein expression was assessed by immunostaining, immunoblotting and real-time PCR assay. Tamoxifen-inducible COUP TFII knockout mice were employed to test COUP-TFII functions on colon cancer metastasis in vivo. RESULTS: Elevated expression of COUP-TFII in colorectal adenocarcinoma tissue correlated with overexpression of the Snail1 transcription factor. High COUP-TFII expression correlated with metastasis and shorter patient survival. Chicken ovalbumin upstream promoter-transcription factor II regulated the migration and invasion of cancer cells. With Snail1, COUP-TFII inhibited expression of adherence molecules such as ZO-1, E-cadherin and beta-catenin in colorectal cancer cells. Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo. Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes. CONCLUSIONS: Chicken ovalbumin upstream promoter-transcription factor II was crucial for colorectal cancer metastasis and regulated cell migration and metastasis in conjunction with Snail1. Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis. PMID- 25032735 TI - Sample size calculations for the development of biosimilar products. AB - The most widely used design for a Phase III comparative study for demonstrating the biosimilarity between a biosimilar product and a renovator biological product is the equivalence trial, whose aim is to show that the difference between two population means of a primary endpoint is less than a prespecified equivalence margin. A well-known sample size formula for the equivalence trial is given by [Formula: see text] Since this formula is obtained based on the approximate power rather than the exact power, we investigate in this article the accuracy of the sample size formula. We conclude that the sample size formula is very conservative. Specifically, we show that the exact power based on the sample size calculated from the formula to have power [Formula: see text] is actually [Formula: see text] under some conditions. Therefore, the use of the sample size formula may cause a huge extra cost to biotechnology companies. We propose that the sample size should be calculated based on the exact power precisely and numerically. The R code to calculate the sample size numerically is provided in this article. PMID- 25032734 TI - Identification of chemoresistant factors by protein expression analysis with iTRAQ for head and neck carcinoma. AB - BACKGROUND: Cisplatin and other anticancer drugs are important in the treatment of head and neck squamous cell carcinoma; however, some tumours develop drug resistance. If chemoresistance could be determined before treatment, unnecessary drug administration would be avoided. Here, we investigated chemoresistance factors by comprehensive analyses at the protein level. METHODS: Four human carcinoma cell lines were used: cisplatin-sensitive UM-SCC-23, UM-SCC-23-CDDPR with acquired cisplatin resistance, naturally cisplatin-resistant UM-SCC-81B, and UM-SCC-23/WR with acquired 5-fluorouracil resistance. Extracted proteins were labelled with iTRAQ and analysed by tandem mass spectrometry to identify resistance. Protein expression was confirmed by western blotting and functional analysis was carried out using siRNA. RESULTS: Thirteen multiple-drug resistance proteins were identified, as well as seven proteins with specific resistance to cisplatin, including alpha-enolase. Differential expression of these proteins in cisplatin-resistant and -sensitive cell lines was confirmed by western blotting. Functional analysis for alpha-enolase by siRNA showed that cisplatin sensitivity significantly was increased in UM-SCC-81B and slightly in UM-SCC-23-CDDPR but not in UM-SCC-23/WR cells. CONCLUSIONS: We identified proteins thought to mediate anticancer drug resistance using recent proteome technology and identified alpha enolase as a true cisplatin chemoresistance factor. Such proteins could be used as biomarkers for anticancer agent resistance and as targets of cancer therapy. PMID- 25032733 TI - Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error. AB - BACKGROUND: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. METHODS: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. RESULTS: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. CONCLUSIONS: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness. PMID- 25032736 TI - Patient Characteristics by Type of Hypersexuality Referral: A Quantitative Chart Review of 115 Consecutive Male Cases. AB - Hypersexuality remains an increasingly common but poorly understood patient complaint. Despite diversity in clinical presentations of patients referred for hypersexuality, the literature has maintained treatment approaches that are assumed to apply to the entire phenomenon. This approach has proven ineffective, despite its application over several decades. The present study used quantitative methods to examine demographic, mental health, and sexological correlates of common clinical subtypes of hypersexuality referrals. Findings support the existence of subtypes, each with distinct clusters of features. Paraphilic hypersexuals reported greater numbers of sexual partners, more substance abuse, initiation to sexual activity at an earlier age, and novelty as a driving force behind their sexual behavior. Avoidant masturbators reported greater levels of anxiety, delayed ejaculation, and use of sex as an avoidance strategy. Chronic adulterers reported premature ejaculation and later onset of puberty. Designated patients were less likely to report substance abuse, employment, or finance problems. Although quantitative, this article nonetheless presents a descriptive study in which the underlying typology emerged from features most salient in routine sexological assessment. Future studies might apply purely empirical statistical techniques, such as cluster analyses, to ascertain to what extent similar typologies emerge when examined prospectively. PMID- 25032737 TI - Camouflage treatment of skeletal class III malocclusion with asymmetry using a bone-borne rapid maxillary expander. AB - This case report presents the successful use of palatal mini-implants for rapid maxillary expansion and mandibular distalization in a skeletal Class III malocclusion. The patient was a 13-year-old girl with the chief complaint of facial asymmetry and a protruded chin. Camouflage orthodontic treatment was chosen, acknowledging the possibility of need for orthognathic surgery after completion of her growth. A bone-borne rapid expander (BBRME) was used to correct the transverse discrepancy and was then used as indirect anchorage for distalization of the lower dentition with Class III elastics. As a result, a Class I occlusion with favorable inclination of the upper teeth was achieved without any adverse effects. The total treatment period was 25 months. Therefore, BBRME can be considered an alternative treatment in skeletal Class III malocclusion. PMID- 25032738 TI - Extraction optimisation and isolation of triterpenoids from Ganoderma lucidum and their effect on human carcinoma cell growth. AB - The response surface methodology was used to optimise the extraction conditions of Ganoderma lucidum based on a Box-Behnken design. A quadratic model sufficiently simulated the response of ganoderic acid H with a determination coefficient (R(2)) of 0.98. The optimal condition for extracting triterpenoids was determined to be 100.00% ethanol at 60.22 degrees C for 6.00 h, under which the yield of the reference triterpenoid ganoderic acid H increased from 0.88 to 2.09 mg/g powder. Following extraction, triterpenoid-enriched fraction was further isolated into 23 fractions, and 7 fractions were identified as ganoderic acids A, B, D, G, H and I and ganoderenic acid D. Of the seven triterpenoids, ganoderenic acid D was most cytotoxic with IC50 values of 0.14 +/- 0.01, 0.18 +/- 0.02 and 0.26 +/- 0.03 mg/mL in Hep G2, Hela and Caco-2 cells, respectively. While ganoderic acids A, G and H were relatively non-cytotoxic. The variation of inhibitory effects for these triterpenoids was likely related to their chemical structures. PMID- 25032739 TI - A survey of exposure level and lifestyle factors for perfluorooctanoate and perfluorooctane sulfonate in human plasma from selected residents in Korea. AB - Following few decades of commercial use, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) have been found in human blood and serum. We determined the amounts of PFOA and PFOS in human plasma (n = 183) and the effects of multiple uses of food-contact materials and smoking habits and alcohol consumption using liquid chromatography time-of-flight mass spectrometry (LC/TOF MS). For the paper cups, the PFOA level in the plasma of the heavy user group was 1.37 times higher than that of the light user group. However, no association between the effects of multiple uses of food-contact materials and the plasma levels of PFOA and PFOS was found, except for paper cups. Active smokers had lower plasma levels of PFOA and PFOS than non-smokers. We show that multiple uses of food-contact materials do not appear to be a significant source of PFOA and PFOS. PMID- 25032740 TI - Increasing incidence of canine leptospirosis in Switzerland. AB - A marked increase in canine leptospirosis was observed in Switzerland over 10 years with a peak incidence of 28.1 diagnosed cases/100,000 dogs/year in the most affected canton. With 95% affected dogs living at altitudes <800 m, the disease presented a seasonal pattern associated with temperature (r2 0.73) and rainfall (r2 0.39), >90% cases being diagnosed between May and October. The increasing yearly incidence however was only weakly correlated with climatic data including number of summer (r2 0.25) or rainy days (r2 0.38). Serovars Australis and Bratislava showed the highest seropositivity rates with 70.5% and 69.1%, respectively. Main clinical manifestations included renal (99.6%), pulmonary (76.7%), hepatic (26.0%), and hemorrhagic syndromes (18.2%), leading to a high mortality rate (43.3%). Similar to the human disease, liver involvement had the strongest association with negative outcome (OR 16.3). Based on these data, canine leptospirosis presents similar features and severity as the human infection for which it therefore can be considered a model. Its re-emergence in a temperate country with very high incidence rates in canines should thus be viewed as a warning and emphasize the need for increased awareness in other species. PMID- 25032742 TI - Physical activity, body mass index, and cardiorespiratory fitness among school children in Taiwan: a cross-sectional study. AB - There is evidence that cardiorespiratory fitness and physical activity significantly reduce cardiovascular risks in adults. A better understanding of the association between cardiorespiratory fitness, physical activity, and childhood obesity is vital in assessing the benefits of interventions to prevent obesity. This study was to examine the relationship between physical activity, body mass index, and cardiorespiratory fitness levels in Taiwanese children. A cross-sectional study was designed. Study participants consisted of 2419 school children (1230 males and 1189 females) aged 12 years old living in a southern Taiwan county with one the highest countrywide rates of childhood obesity. The weight status of the participants was defined as underweight, normal, overweight, or obese according to specific criteria. Cardiorespiratory fitness was then assessed by an 800-m run. Participants were queried on their physical activity habits via a questionnaire survey. The overall prevalence of overweight/obesity was 29.6%. Normal, underweight and overweight boys and girls had an increased odds ratio of being categorized with higher cardiorespiratory fitness than obese one for both gender. A significantly higher level of cardiorespiratory fitness was found in children who engaged in regular physical activity than in children who engaged only in irregular physical activity. Obese children are more likely to lack cardiorespiratory fitness. Physically active children have significantly better cardiorespiratory fitness levels than inactive children. This study supports the conclusion that BMI and physical activity are significantly correlated with cardiorespiratory fitness levels. Findings may provide educational professionals with information to assist their developing effective health promotion programs to healthy weight and improving cardiorespiratory fitness for children. PMID- 25032741 TI - Transgenerational exposure to environmental tobacco smoke. AB - Traditionally, nicotine from second hand smoke (SHS), active or passive, has been considered the most prevalent substance of abuse used during pregnancy in industrialized countries. Exposure to environmental tobacco smoke (ETS) is associated with a variety of health effects, including lung cancer and cardiovascular diseases. Tobacco is also a major burden to people who do not smoke. As developing individuals, newborns and children are particularly vulnerable to the negative effects of SHS. In particular, prenatal ETS has adverse consequences during the entire childhood causing an increased risk of abortion, low birth weight, prematurity and/or nicotine withdrawal syndrome. Over the last years, a decreasing trend in smoking habits during pregnancy has occurred, along with the implementation of laws requiring smoke free public and working places. The decrease in the incidence of prenatal tobacco exposure has usually been assessed using maternal questionnaires. In order to diminish bias in self-reporting, objective biomarkers have been developed to evaluate this exposure. The measurement of nicotine and its main metabolite, cotinine, in non conventional matrices such as cord blood, breast milk, hair or meconium can be used as a non-invasive measurement of prenatal SMS in newborns. The aim of this review is to highlight the prevalence of ETS (prenatal and postnatal) using biomarkers in non-conventional matrices before and after the implementation of smoke free policies and health effects related to this exposure during foetal and/or postnatal life. PMID- 25032743 TI - Heavy metal contamination assessment and partition for industrial and mining gathering areas. AB - Industrial and mining activities have been recognized as the major sources of soil heavy metal contamination. This study introduced an improved Nemerow index method based on the Nemerow and geo-accumulation index. Taking a typical industrial and mining gathering area in Tianjin (China) as example, this study then analyzed the contamination sources as well as the ecological and integrated risks. The spatial distribution of the contamination level and ecological risk were determined using Geographic Information Systems. The results are as follows: (1) Zinc showed the highest contaminant level in the study area; the contamination levels of the other seven heavy metals assessed were relatively lower. (2) The combustion of fossil fuels and emissions from industrial and mining activities were the main sources of contamination in the study area. (3) The overall contamination level of heavy metals in the study area ranged from heavily contaminated to extremely contaminated and showed an uneven distribution. (4) The potential ecological risk showed an uneven distribution, and the overall ecological risk level ranged from low to moderate. This study also emphasized the importance of partition in industrial and mining areas, the extensive application of spatial analysis methods, and the consideration of human health risks in future studies. PMID- 25032744 TI - Antibacterial, antioxidant and hypoglycaemic effects of Thymus capitatus (L.) Hoffmanns. et Link leaves' fractions. AB - The aim of this study was to examine the bioactivity of the methanol fraction (MF) and n-hexane fraction (HF) of Thymus capitatus leaves in relation to their constituents analysed by gas chromatography and gas chromatography-mass spectrometry. The effects of T. capitatus on the growth of pathogenic bacteria associated with respiratory diseases (13 gram-positive and 4 gram-negative) were determined using a microdilution method. The MF was particularly effective on Streptococcus pneumoniae and Moraxella catarrhalis. The antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline 6-sulphonic acid), ferric-reducing antioxidant power and beta-carotene bleaching assays. A strong activity using beta-carotene bleaching test was observed with the MF (IC50 of 0.7 MUg/mL after 30 min of incubation). In the hypoglycaemic test, a selective alpha-amylase inhibitory activity was detected with the HF begging the most active (IC50 of 422.5 MUg/mL). T. capitatus may represent a source of natural bioactive compounds. PMID- 25032745 TI - Quinoline and quinolones: promising scaffolds for future antimycobacterial agents. AB - Tuberculosis (TB) is still a major health concern worldwide. The increasing incidences of multi-drug-resistant tuberculosis (MDR-TB) necessitate the development of new anti-TB drugs acting via novel mode of action. The search of newer drugs for TB led to the identification of several quinoline-based antimycobacterial agents against both the drug-sensitive and MDR-TB. These agents have been designed by substituting quinoline scaffold with diverse chemical functionalities as well as by modifying quinoline/quinolone-based antibacterial drugs. Several of quinoline/quinolone derivatives displayed excellent antimycobacterial activity and were found free of cytotoxicity. This review highlights the critical aspects of design and structure-activity relationship of quinoline- and quinolone-based antimycobacterial agents. PMID- 25032746 TI - Biochemical characterization of recombinant beta-carbonic anhydrase (PgiCAb) identified in the genome of the oral pathogenic bacterium Porphyromonas gingivalis. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the alpha-, beta-, gamma-, delta- and zeta-CAs are ubiquitous metalloenzymes present in prokaryotes and eukaryotes. CAs started to be investigated in detail only recently in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many such organisms they are essential for the life cycle of the organism. CA inhibition leads to growth impairment or growth defects in several pathogenic bacteria. The microbiota of the human oral mucosa consists of a myriad of bacterial species, Porphyromonas gingivalis being one of them and the major pathogen responsible for the development of chronic periodontitis. The genome of P. gingivalis encodes for a beta- and a gamma-CAs. Recently, our group purified the recombinant gamma-CA (named PgiCA) which was shown to possess a significant catalytic activity for the reaction that converts CO2 to bicarbonate and protons, with a kcat of 4.1 * 10(5 )s(-1) and a kcat/Km of 5.4 * 10(7 )M(-1 )* s(-1). We have also investigated its inhibition profile with a range of inorganic anions such as thiocyanate, cyanide, azide, hydrogen sulfide, sulfamate and trithiocarbonate. Here, we describe the cloning, purification and kinetic parameters of the other class of CA identified in the genome of P. gingivalis, the beta-CA, named PgiCAb. This enzyme has a good catalytic activity, with a kcat of 2.8 * 10(5 )s(-1) and a kcat/Km of 1.5 * 10(7 )M(-1 )* s(-1). PgiCAb was also inhibited by the clinically used sulfonamide acetazolamide, with an inhibition constant of 214 nM. The role of CAs as possible virulence factors of P. gingivalis is poorly understood at the moment but their good catalytic activity and the fact that they might be inhibited by a large number of compounds, which may pave the way for finding inhibitors with antibacterial activity that may elucidate these phenomena and lead to novel antibiotics. PMID- 25032747 TI - Kernel-PCA data integration with enhanced interpretability. AB - BACKGROUND: Nowadays, combining the different sources of information to improve the biological knowledge available is a challenge in bioinformatics. One of the most powerful methods for integrating heterogeneous data types are kernel-based methods. Kernel-based data integration approaches consist of two basic steps: firstly the right kernel is chosen for each data set; secondly the kernels from the different data sources are combined to give a complete representation of the available data for a given statistical task. RESULTS: We analyze the integration of data from several sources of information using kernel PCA, from the point of view of reducing dimensionality. Moreover, we improve the interpretability of kernel PCA by adding to the plot the representation of the input variables that belong to any dataset. In particular, for each input variable or linear combination of input variables, we can represent the direction of maximum growth locally, which allows us to identify those samples with higher/lower values of the variables analyzed. CONCLUSIONS: The integration of different datasets and the simultaneous representation of samples and variables together give us a better understanding of biological knowledge. PMID- 25032748 TI - Extracorporeal life support devices and strategies for management of acute cardiorespiratory failure in adult patients: a comprehensive review. AB - Evolution of extracorporeal life support (ECLS) technology has added a new dimension to the intensive care management of acute cardiac and/or respiratory failure in adult patients who fail conventional treatment. ECLS also complements cardiac surgical and cardiology procedures, implantation of long-term mechanical cardiac assist devices, heart and lung transplantation and cardiopulmonary resuscitation. Available ECLS therapies provide a range of options to the multidisciplinary teams who are involved in the time-critical care of these complex patients. While venovenous extracorporeal membrane oxygenation (ECMO) can provide complete respiratory support, extracorporeal carbon dioxide removal facilitates protective lung ventilation and provides only partial respiratory support. Mechanical circulatory support with venoarterial (VA) ECMO employed in a traditional central/peripheral fashion or in a temporary ventricular assist device configuration may stabilise patients with decompensated cardiac failure who have evidence of end-organ dysfunction, allowing time for recovery, decision making, and bridging to implantation of a long-term mechanical circulatory support device and occasionally heart transplantation. In highly selected patients with combined severe cardiac and respiratory failure, advanced ECLS can be provided with central VA ECMO, peripheral VA ECMO with timely transition to venovenous ECMO or VA-venous ECMO upon myocardial recovery to avoid upper body hypoxia or by addition of an oxygenator to the temporary ventricular assist device circuit. This article summarises the available ECLS options and provides insights into the principles and practice of these techniques. One should emphasise that, as is common with many emerging therapies, their optimal use is currently not backed by quality evidence. This deficiency needs to be addressed to ensure that the full potential of ECLS can be achieved. PMID- 25032749 TI - ZEB1 knockdown mediated using polypeptide cationic micelles inhibits metastasis and effects sensitization to a chemotherapeutic drug for cancer therapy. AB - Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced metastasis in the lung. When DOX and siRNA were co-delivered by the nanocarriers (siRNA-DOX-NP), a synergistic therapeutic effect was observed, resulting in dramatic inhibition of tumor growth in a H460 xenograft model. These results demonstrated that the siRNA-NP or siRNA-DOX-NP complex targeting ZEB1 could be developed into a new therapeutic approach for non-small cell lung cancer (NSCLC) treatment. PMID- 25032750 TI - Evaluation of a protocol for resuscitation in burn patients. PMID- 25032751 TI - Polymeric nanoporous materials fabricated with supercritical CO2 and CO2-expanded liquids. AB - Both academia and industries have put great efforts into developing non destructive technologies for the fabrication of polymeric nanoporous materials. Such non-destructive technologies developed with supercritical CO2 (scCO2) and CO2-expanded liquids (CXLs) have been attracting more and more attention because they have been demonstrated to be green and effective media for porous polymer preparation and processing. In this tutorial review, we present several such new technologies with scCO2 and CXLs, which have the capacity to prepare polymeric nanoporous materials with unique morphologies. The fabricated nanoporous polymers have significantly improved the performance of polymeric monoliths and films, and have found wide applications as templates, antireflection coatings, low-k materials, tissue engineering scaffolds and filtration membranes. This tutorial review also introduces the associated characterization methods, including the imaging, scattering and physisorption techniques. PMID- 25032752 TI - Selective photocatalytic oxidation of benzene for the synthesis of phenol using engineered Au-Pd alloy nanoparticles supported on titanium dioxide. AB - The selectivity of photocatalytic phenol production from the direct oxidation of benzene can be enhanced by fine adjustment of the morphology and composition of Au-Pd metal nanoparticles supported on titanium dioxide thereby suppressing the decomposition of benzene and evolution of phenolic compounds. PMID- 25032753 TI - TBAI-catalyzed oxidative synthesis of benzamides from acetophenones and carbinols. AB - An interesting and convenient procedure for the oxidative transformation of acetophenones and carbinols to primary benzamides has been developed. By using tetra-n-butylammonium iodide (TBAI) as the catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant, the desired benzamides were isolated in moderate to good yields in aqueous solution. Notably, not only acetophenones but also propiophenones can be applied as substrates as well. Hence, we believe that this new procedure is not just a catalytic version of the iodine-based method. PMID- 25032754 TI - Reduced expression of osteonectin and increased natural killer cells may contribute to the pathophysiology of aplastic anemia. AB - Normal hematopoiesis involves complex interactions between hematopoietic cells and the bone marrow (BM) microenvironment. The exact causes and mechanisms involved in aplastic anemia (AA) are not known. For better understanding of the pathophysiology of AA, we investigated changes in the hematopoietic stem cell (HSC) compartment and the BM microenvironment in patients with AA by immunohistochemical analysis. A total of 10 AA patients and 10 controls were enrolled. Using BM biopsy specimen, we performed immunohistochemistry for osteopontin, osteonectin, osteocalcin, nestin, stromal-derived factor-1 (SDF-1), lymphocytes, macrophage, and HSCs. Numbers of HSCs and T/B lymphocytes were significantly lower in the AA specimens than the controls, and the AA specimens contained more natural killer cells (CD56(+) cells) (P < 0.01). The 2 groups had similar levels of expression of osteopontin, osteocalcin, nestin, and SDF-1. However, the number of osteonectin(+) cells in the AA specimens was significantly lower than in the control specimens (P<0.01). Our findings support the hypothesis that defects in the stromal cells contribute to the pathogenesis of AA by damaging HSC niche. Immune-mediated natural killer cells may also play a role in the pathogenesis of AA. PMID- 25032755 TI - Overexpression of beta3 Chains of Laminin-332 is Associated With Clinicopathologic Features and Decreased Survival in Patients With Pancreatic Adenocarcinoma. AB - BACKGROUND: Laminin-332 (LM-332, formerly termed laminin-5) is a heterotrimeric glycoprotein that promotes cellular adhesion and migration. The heterotrimer consists of an alpha3, a beta3, and a gamma2 chain. The aim of this investigation was to clarify the clinicopathologic significance of laminin-332beta3 (LNbeta3) chain expression and determine its influence on survival in pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction was used to validate and detect the expression of LNbeta3 mRNA in 37 pancreatic carcinoma tissue specimens and non-neoplastic pancreatic tissue samples. In addition, the protein expression of LNbeta3 was detected by immunohistochemistry methods in 96 pancreatic carcinoma specimens and 90 non neoplastic pancreatic tissues. We analyzed the association between immunohistochemically detected LNbeta3 expression in pancreatic ductal adenocarcinoma and clinicopathologic characteristics. Survival curves were completed using the Kaplan-Meier method and compared using log-rank analysis. RESULTS: Quantitative real-time polymerase chain reaction indicated that the relative value of LNbeta3 mRNA was 1.427+/-1.554 and 1.423+/-1.439 by 2 in pancreatic carcinoma and non-neoplastic pancreatic tissues, respectively, values that were not statistically associated (P=0.991). Immunostaining for LNbeta3 was expressed in all patients with pancreatic ductal adenocarcinoma. LNbeta3 expression was related to differentiation (P=0.000) and advanced stage (P=0.034). Tumors with low expression of LNbeta3 had a survival advantage compared with tumors that had high expression of LNbeta3 (P=0.016). Multivariate analysis indicated that location is an independent predictor of overall survival, whereas other clinicopathologic characteristics such as tumor size, duodenal invasion, differentiation, extent of invasion, hepatic metastasis, and expression of LNbeta3 were not. CONCLUSION: Our results suggest that LNbeta3 expression may play a key role in the progression and prognosis of pancreatic ductal adenocarcinoma. PMID- 25032756 TI - Does disruptive innovation enhance our paradigm shifts? PMID- 25032757 TI - The effect of air abrasion of metal implant abutments on the tensile bond strength of three luting agents used to cement implant superstructures: an in vitro study. AB - PURPOSE: To assess the effect of airborne particle abrasion of metal implant abutments on tensile bond strength (TBS) of TempBond, Retrieve, and Premier implant cements. MATERIALS AND METHODS: Specimens were designed to replicate a single metal implant crown cemented to both smooth and airborne particle-abraded Osteo-Ti implant abutments with zero degrees of taper. Twenty castings were fabricated and cemented to either a smooth surface abutment (SSA) or to an airborne particle-abraded abutment (AAA). TBS was measured with a 50-kg load and a crosshead speed of 0.5 cm/min in a universal testing machine. Each cement was tested 10 times on both abutment types. RESULTS: The mean TBS values (standard deviations, 95% confidence intervals) of SSAs for TempBond, Retrieve, and Premier cements were 115.89 N (26.44, 96.98-134.81), 134.43 N (36.95, 108.25-160.60), and 132.51 N (55.10, 93.09-171.93), respectively. The corresponding values for AAAs were 129.69 N (30.39, 107.95-151.43), 298.67 N (80.36, 241.19-356.16), and 361.17 N (133.23, 265.86-456.48), respectively. There was no significant difference in TBS among the dental cements when used with an SSA. Air abrasion of abutments did not increase the TBS of TempBond but significantly increased crown retention with Retrieve and Premier. For SSAs, all failures were adhesive on the abutment surface; for AAAs, mostly cohesive cement failures occurred. CONCLUSION: The retention of copings cemented with Retrieve or Premier to zero-degree-taper abutments was significantly increased after airborne particle abrasion of the abutments. However, this was not significant when TempBond was used. Airborne particle abrasion of abutments and the use of Retrieve or Premier can be recommended for nonretrievable prostheses. Although TempBond functioned similarly to the two other cements in SSAs, it is advisable to limit its use to provisional prostheses; its long-term performance needs to be assessed clinically. PMID- 25032758 TI - Changes in the abutment-implant interface in Morse taper implant connections after mechanical cycling: a pilot study. AB - PURPOSE: The aim of this study was to measure and compare, using scanning electron microscopy, the abutment-implant interface of a Morse taper system before and after cyclic loading. MATERIALS AND METHODS: Four Morse cone implants and four solid abutments were used. These abutments had been machined to reduce the diameter of the part corresponding to the site of prosthesis cementation. They were then screwed onto the implants and torqued to 25 N. Under a scanning electron microscope, 32 images (16 before and 16 after cycling) of the interfaces were obtained under *1,000 and *5,000 magnification. The samples were subjected to 345,600 cycles with a fatigue testing machine, in which the applied load was 80 N and the frequency was 4 Hz, to simulate chewing. With appropriate software (Image Tool 3.0), the marginal gaps of the interfaces before and after load cycling were measured. The data were analyzed with the Student t test at a significance level of 5%. RESULTS: Significant differences were found between interfaces before and after cycling. Prior to mechanical cycling, the Morse taper implant/abutment assemblies exhibited an average gap size of 3.34 +/- 2.17 MUm, whereas the average gap size after mechanical cycling was 1.35 +/- 0.64 MUm. CONCLUSION: After mechanical cycling, there was a significant decrease in the size of the gap, which indicated better adaptation and sealing ability at the level of the microgap. PMID- 25032759 TI - A dental implant-based registration method for measuring mandibular kinematics using cone beam computed tomography-based fluoroscopy. AB - PURPOSE: This study aimed to develop and evaluate experimentally an implant-based registration method for measuring three-dimensional (3D) kinematics of the mandible and dental implants in the mandible based on dental cone beam computed tomography (CBCT), modified to include fluoroscopic function. MATERIALS AND METHODS: The proposed implant-based registration method was based on the registration of CBCT data of implants/bones with single-plane fluoroscopy images. Seven registration conditions that included one to three implants were evaluated experimentally for their performance in a cadaveric porcine headmodel. RESULTS: The implant-based registration method was shown to have measurement errors (SD) of less than -0.2 (0.3) mm, 1.1 (2.2) mm, and 0.7 degrees (1.3 degrees) for the in-plane translation, out-of-plane translation, and all angular components, respectively, regardless of the number of implants used. The corresponding errors were reduced to less than -0.1 (0.1) mm, -0.3 (1.7) mm, and 0.5 degree (0.4 degree) when three implants were used. CONCLUSION: An implant-based registration method was developed to measure the 3D kinematics of the mandible/implants. With its high accuracy and reliability, the new method will be useful for measuring the 3D motion of the bones/implants for relevant applications. PMID- 25032760 TI - An in vitro evaluation of impression techniques for multiple internal- and external-connection implant prostheses. AB - PURPOSE: This in vitro study evaluated the accuracy of three different impression techniques, using polyether impression material, to obtain a precise definitive cast for a multiple-unit implant restoration with internal- or external connection implants. MATERIALS AND METHODS: Two reference resin models, one with four internal-connection implants (RRMI) and one with four external-connection implants (RRME), were fabricated. The longitudinal axes of all implants diverged by 15 to 20 degrees from the midline toward the labial/buccal. Six groups of 15 specimens each (45 RRMI, 45 RRME) were made with medium-consistency polyether: nonmodified square impression copings (NMIC and NMEC groups), square impression copings joined together with autopolymerizing acrylic resin before the impression procedure (RIC and REC groups), and square impression copings that were airborne particle-abraded and coated with impression adhesive (MIC and MEC groups). A single calibrated examiner evaluated the positional accuracy of the implant replica heads with a profile projector. These measurements were compared to the measurements calculated on the RRMI and RRME, which served as controls. All differences between the distances measured on the RRMI and on the RRME and those measured on the definitive casts of the six groups were transformed into the differences in microns each 1,000 MUm of length (per mil difference) and statistically analyzed. RESULTS: Considering anterior and posterior per mil median differences together, the highest precision of the definitive casts was in the groups MEC, REC, and RIC. CONCLUSION: Within the limitations of this study, splinted square impression copings (RIC and REC) and airborne particle-abraded and coated (MIC and MEC) impression techniques showed greater accuracy in replicating the control models (RRMI and RRME) than the nonmodified technique (NMIC and NMEC). The definitive casts of the model with internal-connection implants achieved the highest precision with splinted square impression copings (RIC). PMID- 25032761 TI - Microcomputed tomographic and biomechanical analysis of orthodontic microscrew stability under continuous or intermittent force. AB - PURPOSE: To evaluate and compare the influence of continuous and intermittent forces on stability of titanium microscrews. MATERIALS AND METHODS: One hundred forty-four microscrews were inserted bilaterally in the intraradicular zones of the maxillary first molar and second premolar in 36 beagles. Loads were delivered consecutively in the continuous group (n = 12), in cycles of 12 hours on/paused for 12 hours in intermittent group A (n = 12), and in cycles of 24 hours on/paused for 24 hours in intermittent group B (n = 12). The on/off cycles were repeated for 1, 3, 5, or 7 weeks, after which the animals were sacrificed, and microcomputed tomography (micro-CT) and pull-out testing were performed. RESULTS: The micro-CT parameters of the microscrews in all three groups increased gradually with loading time. The value of peak load at extraction (Fmax) increased and reached a peak at week 5 but dropped slightly at week 7. In the continuous group, all measurements were lower than those in the intermittent groups at all times examined. All values in intermittent group A were higher than those in intermittent group B. CONCLUSION: An intermittent loading regimen appears to be more favorable for obtaining stability than continuous loading, and a 12-hour/12-hour on/off loading cycle is superior to a 24-hour/24-hour on/off protocol in promoting bone-implant contact. PMID- 25032762 TI - Microcomputed tomographic and histomorphometric analyses of novel titanium mesh membranes for guided bone regeneration: a study in rat calvarial defects. AB - PURPOSE: The objective of this study was to evaluate the optimal thickness and porosity of novel titanium mesh membranes to enhance bone augmentation, prevent soft tissue ingrowth, and prevent membrane exposure. MATERIALS AND METHODS: Six types of novel titanium meshes with different thicknesses and pore sizes, along with three commercially available membranes, were used to cover surgically created calvarial defects in 6-week-old Sprague-Dawley rats. The animals were killed after 4 or 8 weeks. Microcomputed tomographic analyses were performed to analyze the three-dimensional bone volume and bone mineral density. Soft tissue ingrowth was also evaluated histologically and histomorphometrically. RESULTS: The novel titanium membranes used in this study were as effective at augmenting bone in the rat calvarial defect model as the commercially available membranes. The greatest bone volume was observed on 100-MUm-thick membranes with larger pores, although these membranes promoted growth of bone with lower mineral density. Soft tissue ingrowth when 100-MUm membranes were used was increased at 4 weeks but decreased again by 8 weeks to a level not statistically significantly different from other membranes. CONCLUSION: Membrane thickness affects the total amount of new bone formation, and membrane porosity is an essential factor for guided bone regeneration, especially during the initial healing period, although the final bone volume obtained is essentially the same. Newly developed titanium mesh membranes of 100 MUm in thickness and with large pores appear to be optimal for guided bone regeneration. PMID- 25032763 TI - Accuracy of implant impressions for partially and completely edentulous patients: a systematic review. AB - PURPOSE: To compare the accuracy of digital and conventional impression techniques for partially and completely edentulous patients and to determine the effect of different variables on the accuracy outcomes. MATERIALS AND METHODS: An electronic and manual search was conducted to identify studies reporting on the accuracy of implant impressions. Pooled data were descriptively analyzed. Factors affecting the accuracy were identified, and their impact on accuracy outcomes was assessed. RESULTS: The 76 studies that fulfilled the inclusion criteria featured 4 clinical studies and 72 in vitro studies. Studies were grouped according to edentulism; 41 reported on completely edentulous and 35 on partially edentulous patients. For completely edentulous patients, most in vitro studies and all three clinical studies demonstrated better accuracy with the splinted vs the nonsplinted technique (15 studies, splint; 1, nonsplint; 9, no difference). One clinical study and half of the in vitro studies reported better accuracy with the open-tray vs the closed-tray technique (10 studies, open-tray; 1, closed-tray; 10, no difference). For partially edentulous patients, one clinical study and most in vitro studies showed better accuracy with the splinted vs the nonsplinted technique (8 studies, splint; 2, nonsplint; 3, no difference). The majority of in vitro studies showed better accuracy with the open-tray vs the closed-tray technique (10 studies, open-tray; 1, closed-tray; 7, no difference), but the only clinical study reported no difference. CONCLUSION: The splinted impression technique is more accurate for both partially and completely edentulous patients. The open-tray technique is more accurate than the closed-tray for completely edentulous patients, but for partially edentulous patients there seems to be no difference. The impression material (polyether or polyvinylsiloxane) has no effect on the accuracy. The implant angulation affects the accuracy of implant impressions, while there are insufficient studies for the effect of implant connection type. Further accuracy studies are needed regarding digital implant impressions. PMID- 25032764 TI - Tolerance measurements on internal- and external-hexagon implants. AB - PURPOSE: To measure the horizontal machining tolerances of the interface between internal- and external-hexagon implants and analogs with corresponding components after delivery from the manufacturer. These values may be a valuable tool for evaluating increasing misfit caused by fabrication, processing, and wear. MATERIALS AND METHODS: Seven implants and seven analogs with external- and internal-hexagon connections (Biomet 3i) with corresponding prefabricated gold cylinders and gold screws, prefabricated cylindric plastic cylinders, and laboratory screws were studied. One set of components from the external and internal groups was measured manually and digitally. Measurements from the test subjects were compared with identical measurements from the virtual model to obtain threshold values. The virtual model was then used to obtain optimally oriented cuts. RESULTS: The horizontal machining tolerances for castable plastic abutments on external implants were 12 +/- 89 MUm, and for internal implants they were 86 +/- 47 MUm. Tolerance measurements on prefabricated gold abutments for external implants were 44 +/- 9 MUm, and for internal implants they were 58 +/- 28 MUm. CONCLUSION: The groups with metallic components showed the smallest tolerance at < 50 MUm for the external group and < 90 MUm for the internal group. The prefabricated plastic cylinder groups ranged from < 100 MUm for external and < 130 MUm for internal connection. PMID- 25032765 TI - Accuracy of a digital impression system based on parallel confocal laser technology for implants with consideration of operator experience and implant angulation and depth. AB - PURPOSE: To evaluate the accuracy of a digital impression system based on parallel confocal red laser technology, taking into consideration clinical parameters such as operator experience and angulation and depth of implants. MATERIALS AND METHODS: A maxillary master model with six implants (located bilaterally in the second molar, second premolar, and lateral incisor positions) was fitted with six polyether ether ketone scan bodies. One second premolar implant was placed with 30 degrees of mesial angulation; the opposite implant was positioned with 30 degrees of distal angulation. The lateral incisor implants were placed 2 or 4 mm subgingivally. Two experienced and two inexperienced operators performed intraoral scanning. Five different interimplant distances were then measured. The files obtained from the scans were imported with reverse engineering software. Measurements were then made with a coordinate measurement machine, with values from the master model used as reference values. The deviations from the actual values were then calculated. The differences between experienced and inexperienced operators and the effects of different implant angulations and depths were compared statistically. RESULTS: Overall, operator 3 obtained significantly less accurate results. The angulated implants did not significantly influence accuracy compared to the parallel implants. Differences were found in the amount of error in the different quadrants. The second scanned quadrant had significantly worse results than the first scanned quadrant. Impressions of the implants placed at the tissue level were less accurate than implants placed 2 and 4 mm subgingivally. CONCLUSIONS: The operator affected the accuracy of measurements, but the performance of the operator was not necessarily dependent on experience. Angulated implants did not decrease the accuracy of the digital impression system tested. The scanned distance affected the predictability of the accuracy of the scanner, and the error increased with the increased length of the scanned section. PMID- 25032766 TI - Bone recontouring in fresh sockets with buccal bone loss: a cone beam computed tomography study. AB - PURPOSE: The aim of this study was to assess buccal bone plate recontouring in maxillary fresh extraction sockets with buccal bone loss using cone beam computed tomography (CBCT). MATERIALS AND METHODS: Healthy patients who required the extraction of one tooth with buccal bone loss in the maxilla were included in this study. CBCT examinations were made before extractions and after 3 months. The alveolar bone levels were assessed from the most coronal, buccal, and palatal bone in which the crest was identified. Buccolingual width at the apical and coronal level was also measured. RESULTS: Fifty healthy patients underwent 50 extractions. Mean bone levels for both single-rooted and multiple-rooted teeth, from a buccopalatal perspective, showed no statistically significant difference between preextraction status and 3 months later. However, in both groups, mean bone levels of the buccal bone plate showed statistically significant differences between extraction and 3 months later. In single-rooted teeth, a mean bone gain of 5.36 +/- 2.65 mm was seen after 3 months, and for multiple-rooted teeth, a mean bone gain of 5.89 +/- 2.88 mm was seen. Growth in buccolingual width was seen; nevertheless, volume dimensional changes were reported after tooth extraction. CONCLUSIONS: In the first months after extraction, it is possible to observe the formation of buccal bone in sockets with previous buccal bone loss. PMID- 25032767 TI - Accuracy of impressions of multiple implants in the edentulous arch: a systematic review. AB - PURPOSE: Because there is a paucity of clear-cut evidence regarding which materials and techniques are most accurate for complete-arch, multiple-implant impressions, the current study sought to analyze the data and draw useful conclusions based on the evidence for application in clinical practice. MATERIALS AND METHODS: Relevant studies published between 1990 and December 2012 were included in the review. The articles were located through PubMed and manually through reviewing references in the literature. Papers examining implant impression accuracy in completely edentulous arches (three or more implants) were included. Clinical case reports, technique articles, abstracts, and review papers were excluded. RESULTS: One of the 34 studies selected for evaluation was clinical; the remaining 33 were in vitro investigations. Ten studies compared polyvinyl siloxane (PVS) and polyether (PE); eight found that these were statistically equal in terms of impression accuracy. The splint effect was examined by 24 studies; 10 failed to observe any differences between splinted and nonsplinted impressions, whereas 7 (> 25%) showed that the splinted technique was better than the nonsplinted technique. Thirteen studies investigated the differences between pickup and transfer impression techniques; six favored pickup over transfer, and five found insignificant differences between the techniques. The effect of nonparallel implants on edentulous multiple-implant impression accuracy was examined by only two studies. Significant differences in accuracy were observed for 15 degrees of angulation. CONCLUSION: Most of the evidence supports PVS and PE as the most accurate impression materials for edentulous multiple-implant situations, with no clear advantage of either. Conflicting evidence exists regarding the most accurate impression technique (splinted/nonsplinted, pickup/transfer), and no clear recommendation can be made. Inadequate research exists regarding several other factors that might affect edentulous implant impression accuracy. There is a lack of clinical research to support in vitro findings. PMID- 25032768 TI - Volume changes of maxillary sinus augmentations over time: a systematic review. AB - PURPOSE: The objective of this study was to systematically review the available literature on three-dimensional time-dependent graft volume changes after sinus augmentation (SA) with different biomaterials in humans. MATERIALS AND METHODS: MEDLINE, EMBASE, and CENTRAL were searched for related literature. Controlled and uncontrolled studies reporting volume changes of more than 10 SAs after at least 6 months, assessed by computed tomography (CT) or cone beam CT (CBCT), were eligible for inclusion. The primary outcome of interest was time-dependent percentage change in augmentation volume. RESULTS: Seven controlled and five uncontrolled studies (n = 234 SAs) with a high risk of bias were included and reported on a range of graft materials. Autogenous bone (AB) was used in the particulate or block form. Bone substitutes (BS) were used either alone or in combination with other materials as composite grafts (CG). All studies reported reductions in augmentation volumes over time (AVR), generally after short observation periods (range, 6 months to 6 years). Substantial AVRs (approximately 45% in 77 SAs) were reported for AB after 6 months and up to 2 years. AVRs for solely BS or CG were relatively lower (approximately 18% to 22% in 142 SAs) after a similar time period. All studies reported a wide range of volume reductions. No significant differences in AVR were observed between different graft materials. Because of insufficient long-term data, a reliable association between volume reduction and time could not be established. CONCLUSION: Some loss of augmentation volume always occurs after SA during early healing times. In general, less AVR may be expected after SA with BS or CG compared to SA with AB. Augmentation volume loss does not seem to compromise implant placement or survival. PMID- 25032770 TI - Radiographic bone level changes of implant-supported restorations in edentulous and partially dentate patients: 5-year results. AB - PURPOSE: To evaluate and compare crestal bone level changes and peri-implant status of implant-supported reconstructions in edentulous and partially dentate patients after a minimum of 5 years of loading. MATERIALS AND METHODS: All patients who received a self-tapping implant with a microstructured surface during the years 2003 and 2004 at the Department of Prosthodontics, University of Bern, were included in this study. The implant restorations comprised fixed and removable prostheses for partially and completely edentulous patients. Radiographs were taken immediately after surgery, at impression making, and 1 and 5 years after loading. Crestal bone level (BIC) was measured from the implant shoulder to the first bone contact, and changes were calculated over time (DeltaBIC). The associations between pocket depth, bleeding on probing (BOP), and DeltaBIC were assessed. RESULTS: Sixty-one implants were placed in 20 patients (mean age, 62 +/- 7 years). At the 5-year follow-up, 19 patients with 58 implants were available. Implant survival was 98.4% (one early failure; one patient died). The average DeltaBIC between surgery and 5-year follow-up was 1.5 +/- 0.9 mm and 1.1 +/- 0.6 mm for edentulous and partially dentate patients, respectively. Most bone resorption (50%, 0.7 mm) occurred during the first 3 months (osseointegration) and within the first year of loading (21%, 0.3 mm). Mean annual bone loss during the 5 years of loading was < 0.12 mm. Mean pocket depth was 2.6 +/- 0.7 mm. Seventeen percent of the implant sites displayed BOP; the frequency was significantly higher in women. None of the variables were significantly associated with crestal bone loss. CONCLUSION: Crestal bone loss after 5 years was within the normal range, without a significant difference between edentulous and partially dentate patients. In the short term, this implant system can be used successfully for various prosthetic indications. PMID- 25032769 TI - Configuration and corticalization of the mandibular bifid canal in a Taiwanese adult population: a computed tomography study. AB - PURPOSE: The configuration and degree of corticalization of bifid mandibular canals were examined using medical computed tomography (CT) images from 170 hemimandibles obtained from 308 Taiwanese adults. MATERIALS AND METHODS: The configurations of the bifid canals were assessed according to their anatomical position in relation to the ramus, molars, premolars, and mental foramen; their course (anterior/posterior or superior/inferior); the presence or absence of confluence with the main mandibular canal; and the presence or absence of penetration through the mandible to form an accessory foramen. The percentage of the canal length that was corticalized was measured. Two different classifications of bifid canals were also briefly summarized and compared. RESULTS: When bifid canals are present (41.2% of patients; 27.6% of hemimandibles), the bifid canals were primarily located in the ramus and retromolar regions (67.7%) running anteriorly (95.9%) and superiorly (95.9%) without confluence with the main mandibular canal (91.1%). Up to 16.5% of bifid canals form accessory foramina on the cortical surface of the mandible. Approximately 78% of the bifid canals have varied degrees of corticalization around the bifid canals. CONCLUSION: The configuration and course of 170 mandibular bifid canals were evaluated with CT images. The bifid canals were primarily located in the ramus and retromolar regions; however, 32.4% of the bifid canals were located in potential positions for dental implant placement. Most of the bifid canals ran anteriorly superior to the main mandibular canal, did not rejoin with the main mandibular canal, and diminished within the mandibular body. Approximately half of the bifid canals (45%) were completely corticated. PMID- 25032771 TI - Bone level variation after vertical ridge augmentation: resorbable barriers versus titanium-reinforced barriers. A 6-year double-blind randomized clinical trial. AB - PURPOSE: To compare the efficacy of two different techniques for vertical bone regeneration at implant placement with particulate autogenous bone at 6 years after loading by means of a double-blind, superiority, parallel-group randomized clinical trial. MATERIALS AND METHODS: The study was conducted in a private center in Italy between April 2004 and December 2011. Patients in whom vertical bone augmentation was indicated in combination with the placement of single or multiple implants were eligible for inclusion in this trial. Patients were randomized to receive either resorbable collagen barriers supported by an osteosynthesis plate (test group) or nonresorbable titanium-reinforced expanded polytetrafluoroethylene barriers (control group). The outcome variables radiographic bone variation at implant sites, implant failures, and complications were evaluated 6 years after loading. Randomization was done by computer, with allocation concealed by opaque sequentially numbered sealed envelopes. The patients and the radiographic examiner were blinded to group assignment. RESULTS: Twenty-two patients were randomized: 11 to the resorbable barrier group and 11 to the nonresorbable (control) group. One control group patient dropped out. The mean bone level 6 years after surgery was 1.33 mm for the resorbable group and 1.00 mm for the nonresorbable group. The adjusted difference in bone changes between groups was 0.15 mm (95% confidence interval, -0.39 to 0.69, P = .5713). No implant failures or complications occurred after loading. CONCLUSION: No differences were observed in this comparison of resorbable and nonresorbable barriers with simultaneous implant placement for vertical ridge augmentation. PMID- 25032772 TI - Zirconia dental implants: a clinical, radiographic, and microbiologic evaluation up to 3 years. AB - PURPOSE: To retrospectively evaluate the clinical performance of zirconia endosseous implants. MATERIALS AND METHODS: Partially edentulous patients with adequate bone volume to fit yttria tetragonal zirconia polycrystal (Y-TZP) implants at least 3.5 mm wide and 8.0 mm long were included. Full-mouth probing pocket depth (PPDs) and percentage bleeding on probing (BOP) scores around teeth and implant(s) were assessed and compared. Marginal bone loss/gain relative to baseline was measured on intraoral radiographs, and the prevalence and quantities of seven periodontal bacteria were assessed around implants and teeth in the same patient. RESULTS: Seventy-four consecutively treated patients with 121 zirconia implants (66 two-piece implants and 55 one-piece implants) were clinically evaluated after a mean observation period of 18 months. Three implants had failed and had been removed, for a cumulative implant survival rate of 96.5% (+/- 2.0%) after 3 years. The 118 surviving implants demonstrated healthy mucosal conditions, with low mean PPDs (1.8 +/- 0.4 mm) and mean BOP scores (4.1% +/- 4.2%). PPD and BOP were statistically significantly lower around implants than around teeth. BOP and PPD around implants and teeth were significantly correlated. Stable marginal bone levels were observed (mean bone loss of 0.1 +/- 0.6 mm after 3 years). The frequency of isolation of all marker bacteria was similar at tooth and implant sites. CONCLUSION: Zirconia endosseous implants can achieve a 3-year implant survival rate in partially edentulous patients, similar to that of titanium implants, with healthy and stable soft and hard tissues. PMID- 25032773 TI - The role played by a suspended external-internal suture in reducing marginal flap tension after bone reconstruction: a clinical prospective cohort study in the maxilla. AB - PURPOSE: To define the role played by a suspended external-internal (SEI) suture in reducing marginal flap tension after bone augmentation in the maxilla and in enhancing primary wound healing. MATERIALS AND METHODS: Twenty partially edentulous patients requiring bone augmentation (either guided bone regeneration or autogenous bone block placement) before or simultaneous with implant insertion in the maxilla were enrolled in this clinical prospective cohort study. Flap tension was measured by a dynamometer, which was accurate to within 1 g. The force recorded was that needed to enable the vestibular extensible flap to reach the edge of the palatal nonextensible flap. Flap tension was recorded after the periosteum-releasing incision was made (before application of any suture; T1), and after the SEI suture was applied (T2). Final marginal flap adaptation was accomplished via horizontal mattress sutures and simple stitches. Wound healing was monitored at 1, 2, 4, and 16 weeks and classified as "obtained primary closure" or "compromised" as a result of dehiscence or marginal flap necrosis. RESULTS: The mean flap tension measured at T1 was 32.9 +/- 7.7 g. After the SEI suture was applied, the mean marginal flap tension decreased to 4.1 +/- 1.5 g. The marginal flap tension was reduced by 87.6% compared to the initial strain. All patients healed uneventfully, and no complications such as dehiscences or marginal flap necrosis were recorded. CONCLUSION: The application of the SEI suture reduced the tension on the margins of the flaps and played a decisive role in obtaining primary wound healing. In case of passive wound closure (strain < 5 g), the type of augmentation procedure (guided bone regeneration or autogenous block) was revealed to have no impact on the quality of wound healing. PMID- 25032774 TI - Three-dimensional accuracy of a digitally coded healing abutment implant impression system. AB - PURPOSE: This study examined the three-dimensional (3D) accuracy of the Encode Impression System (EN) in transferring the locations of two implants from master models to test models and compared this to the direct impression (DI) technique. The effect of interimplant angulation on the 3D accuracy of both impression techniques was also evaluated. MATERIALS AND METHODS: Seven sectional polymethyl methacrylate mandibular arch master models were fabricated with implants in the first premolar and first molar positions. The implants were placed parallel to each other or angulated mesiodistally or buccolingually with total divergent angles of 10, 20, or 30 degrees. Each master model was secured onto an aluminum block containing a gauge block, which defined the local coordinate references. Encode healing abutments were attached to the implants before impressions were made for the EN test models; pickup impression copings were attached for the DI test models. For the seven test groups of each impression technique, a total of 70 test models were fabricated (n = 5). The EN test models were sent to Biomet 3i for implant analog placement. The centroid of each implant or implant analog and the angular orientation of the long axis relative to the x- and y-axes were measured with a coordinate measuring machine. Statistical analyses were performed. RESULTS: Impression technique had a significant effect on y distortion, global linear distortion, and absolute xz and yz angular distortions. Interimplant angulation had significant effects on x and y distortions. However, neither impression technique nor interimplant angulation had a significant effect on z distortion. CONCLUSIONS: Distortions were observed with both impression techniques. However, the results suggest that EN was less accurate than DI. PMID- 25032775 TI - Loss of teeth opposing implant-supported prostheses in the posterior mandible: a retrospective survey in dental clinics. AB - PURPOSE: The main aim of this study was to investigate the loss of maxillary teeth opposing mandibular implant-supported prostheses (ISPs) placed at dental clinics. MATERIALS AND METHODS: Participating dentists were asked to provide information on implant procedures they had undertaken between January 1, 1990, and December 31, 2009. Data were requested for procedures in which implants were inserted into only one side of the mandible in posterior regions and no implants were inserted in other regions. RESULTS: Data on a total of 383 patients were analyzed. Participants in this study consisted of 170 men and 213 women ranging from 20 to 78 years of age (mean age, 51.0 years). Natural teeth were divided into three groups: opposing teeth (teeth opposing ISPs), control teeth (teeth of the same type as the opposing teeth but on the other side of the maxilla), and other teeth. The mean observation period was 72 months. One hundred six teeth were lost during the observation period. Fourteen opposing teeth were lost (1.72%, 14/816), 15 control teeth were lost (1.84%, 15/816), and 77 other teeth were lost (0.98%, 77/7,891). The percentage of opposing teeth lost was significantly higher than that of other teeth. However, there was no difference in the rates of loss of opposing and control teeth. CONCLUSION: ISPs in posterior mandibular regions are not a risk factor for the loss of opposing teeth. PMID- 25032776 TI - Influence of the cutting edge angle of a titanium instrument on chip formation in the machining of trabecular and cortical bone. AB - PURPOSE: The placement of self-tapping implants is associated with microfractures and the formation of bone chips along the cutting flutes. This study was conducted to investigate the effect of different cutting edge angles on chip formation during the machining of trabecular and cortical bone using instruments with a rough titanium surface. MATERIALS AND METHODS: Mandibular cortical and trabecular bone specimens were obtained from freshly slaughtered domestic pigs. A predefined thrust force was applied to the specimens. Four specially designed cutting instruments that simulated dental implants and had a rough titanium surface were allowed to complete one full revolution at cutting edge angles of 55, 65, 75, and 85 degrees, respectively. Torque and thrust were measured during the cutting process. Bone chips were measured and weighed under a microscope. RESULTS: Different cutting edge angles did not lead to significant differences in torque. The lowest torque values were measured when the cutting edges were positioned at 65 degrees in trabecular bone and at 85 degrees in cortical bone. Bone chips were significantly larger and heavier at angles of 55 and 65 degrees than at angles of 75 and 85 degrees in trabecular bone. CONCLUSION: Instruments with a rough titanium surface show considerable angle-dependent differences in chip formation. In addition to bone density, the angle of the cutting edges should be taken into consideration during the placement of dental implants. Good results were obtained when the cutting edges were positioned at an angle of 65 degrees. This angle can have positive effects on osseointegration. PMID- 25032777 TI - Effect of avocado/soybean unsaponifiables on osseointegration: a proof-of principle preclinical in vivo study. AB - PURPOSE: To evaluate the influence of administration of avocado/soybean unsaponifiables (ASU) on implant osseointegration in rat tibiae. MATERIALS AND METHODS: Thirty rats were randomly assigned into one of three equal-sized groups: (1) ASU1: administration of ASU starting 7 days prior to implant placement; (2) ASU2: administration of ASU starting on the day of implant placement, and (3) CTL: administration of saline solution. In all animals, one titanium implant was placed in each tibia. All animals received ASU or saline solution by gavage daily until sacrifice 60 days postoperatively. Implant osseointegration and bone maturation were assessed by biomechanical and radiographic bone density analysis; descriptive histology; immunohistochemistry for bone morphogenetic protein 2 (BMP 2), transforming growth factor beta 1 (TGF-beta1), and osteocalcin; and histomorphometric evaluation of bone-to-implant contact (BIC) and mineralized bone area fraction within the threads of the implant. RESULTS: ASU1 and ASU2 showed three times higher expression of BMP-2 and nine times higher expression of TGF-beta1 compared with CTL (P < .05). Histomorphometric analysis, however, showed that both ASU1 and ASU2 groups presented significantly higher BIC values only in the cortical bone compartment when compared to CTL (P < .05). CONCLUSION: ASU consumption seems to exert only a subtle effect on implant osseointegration. PMID- 25032778 TI - Xenograft impregnated with bone marrow mononuclear fraction for appositional bone regeneration in rabbit calvaria: a clinical and histomorphometric study. AB - PURPOSE: This study investigated the combination of a bone marrow mononuclear fraction with a bone xenograft material in an appositional bone regeneration technique. MATERIALS AND METHODS: Twelve New Zealand rabbits were randomly divided into two groups of six animals each. Bone reconstruction situations were created using titanium cylinders; these were filled with xenograft in group 1 animals and xenograft enriched with bone marrow mononuclear fraction in group 2 animals. Two cylinders were adapted onto the calvaria of each animal. Bone marrow aspirate was obtained from the tibia of every animal. After 8 weeks, the animals were sacrificed and the parietal bone and cylinders were fixed in 10% formalin for analysis of clinical measurement of the bone volume formed inside the cylinders and histomorphometric evaluation of parameters such as vital mineralized tissue (VMT), nonvital mineralized tissue (NVMT), nonmineralized tissue (NMT), and vital mineralized tissue in contact with titanium (VMTCT). RESULTS: Clinically, groups 1 and 2 demonstrated bone volume gains of 88.29% +/- 25.97% and 98.96% +/- 0.00%, respectively. Histomorphometry for groups 1 and 2, respectively, demonstrated the following mean values: VMT, 18.96% +/- 8.99% and 28.02% +/- 8.76%; NVMT, 28.43% +/- 2.44% and 25.57% +/- 2.33%; NMT, 52.61% +/- 10.80% and 46.42% +/- 10.06%; and VMTCT, 4.98% +/- 4.30% and 27.29% +/- 9.58%. CONCLUSION: The results of this study suggest that the use of the bone marrow mononuclear fraction can improve bone healing and the level of osseointegration. PMID- 25032779 TI - The effect of patient age on bone formation using a fully synthetic nanocrystalline bone augmentation material in maxillary sinus grafting. AB - PURPOSE: Maxillary sinus floor augmentation is a treatment that has been proposed for patients in whom the alveolar bone height is insufficient. This procedure is commonly used in patients aged 40 to 70 years and older. However, little information exists whether the factor of age might influence the outcome of augmentation procedures. The aim of this study was to investigate whether the patient's age has an effect on bone formation and incorporation in maxillary sinus floor augmentation procedures. MATERIALS AND METHODS: A fully synthetic nanocrystalline bone augmentation material (NanoBone, Artoss) was used for sinus floor augmentation in patients with a subantral vertical bone height of at least 3 mm and maximum of 7 mm. After 7 months healing time, biopsy specimens were taken and were divided into two groups according to the patient's age. Exclusion criteria were poor general health (eg, severe renal/and or liver disease), history of a radiotherapy in the head region, chemotherapy at the time of surgical procedure, noncompensated diabetes mellitus, symptoms of a maxillary sinus disease, active periodontal or systemic diseases, smoking, and poor oral hygiene. Histologic analyses with hematoxylin-eosin stain were performed. Multinucleated osteoclast-like cells were identified by histochemical staining (tartrate-resistant acid phosphatase [TRAP]). Quantitative and age-dependent assessment of bone formation, residual bone grafting material, and soft tissue formation following sinus augmentation was performed using histomorphometric analysis and the Bonferroni adjustment of the Student t test. RESULTS: Twenty biopsy specimens from 17 patients were taken and divided into two groups according to age (group 1: 41 to 52 years; group 2: 66 to 71 years) containing 10 specimens each, which were analyzed in triplicate resulting in a total of 30 specimens per group. A regeneration process with varying amounts of newly formed bone surrounded by marrow-like tissue was present in all augmented regions. No signs of inflammation or immune reactions were visible. Residual particles of the augmentation material could be observed within the specimens. An age-dependent difference in investigated parameters between the two age groups could not be documented. CONCLUSION: The histologic examinations confirm that the fully synthetic nanocrystalline bone augmentation material used in this study is biocompatible and allows maxillary sinus augmentation in patients aged 41 to 70 years. PMID- 25032780 TI - Study on the resistance distribution at the contact between molybdenum disulfide and metals. AB - Contact resistance hinders the high performance of electrical devices, especially devices based on two-dimensional (2D) materials, such as graphene and transition metal dichalcogenide. To engineer contact resistance, understanding the resistance distribution and carrier transport behavior at the contact area is essential. Here, we developed a method that can be used to obtain some key parameters of contact, such as transfer length (Lt), sheet resistance of the 2D materials beneath the contacting metal (Rsh), and contact resistivity between the 2D materials and the metal electrode (rhoc). Using our method, we studied the contacts between molybdenum disulfide (MoS2) and metals, such as titanium and gold, in bilayer and few-layered MoS2 devices. Especially, we found that Rsh is obviously larger than the sheet resistance of the same 2D materials in the channel (Rch) in all the devices we studied. With the increasing of the back-gate voltage, Lt increases and Rsh, rhoc, Rch, and the contact resistance Rc decrease in all the devices we studied. Our results are helpful for understanding the metal-MoS2 contact and improving the performances of MoS2 devices. PMID- 25032781 TI - Iridium-catalyzed oxidative olefination of furans with unactivated alkenes. AB - The oxidative coupling of arenes and alkenes is an attractive strategy for the synthesis of vinylarenes, but reactions with unactivated alkenes have typically occurred in low yield. We report an Ir-catalyzed oxidative coupling of furans with unactivated olefins to generate branched vinylfuran products in high yields and with high selectivities with a second alkene as the hydrogen acceptor. Detailed mechanistic experiments revealed catalyst decomposition pathways that were alleviated by the judicious selection of reaction conditions and application of new ligands. PMID- 25032782 TI - UHPLC-PDA-ESI/HRMSn profiling method to identify and quantify oligomeric proanthocyanidins in plant products. AB - Oligomeric proanthocyanidins were successfully identified by UHPLC-PDA-HRMS(n) in a selection of plant-derived materials (jujube fruit, Fuji apple, fruit pericarps of litchi and mangosteen, dark chocolate, and grape seed and cranberry extracts). The identities of 247 proanthocyanidins were theoretically predicted by computing high-accuracy masses based on the degree of polymerization, flavan-3-ol components, and the number of A type linkages and galloyls. MS(n) fragments allowed characterization on flavan-3-ol based on the monomer, connectivity, and location of A-type bonds. Identification of doubly or triply charged ions of 50 PAs was made on the basis of theoretical calculations. A single catechin standard and molar relative response factors (MRRFs) were used to quantify the well separated PAs. The ratios of the SIM peak counts were used to quantify each of the unseparated isomers. This is the first report of direct determination of each of the proanthocyanidins in plant-derived foods and proanthocyanidins containing an epifisetinidol unit in grape seeds. PMID- 25032783 TI - Fluorescence-based assessment of plasma-induced hydrophilicity in microfluidic devices via Nile Red adsorption and depletion. AB - We present a simple method, called fluorescence-based assessment of plasma induced hydrophilicity (FAPH), that enables spatial mapping of the local hydrophilicity of surfaces normally inaccessible by traditional contact angle measurement techniques. The method leverages the change in fluorescence of a dye, Nile Red, which is adsorbed on an oxygen plasma-treated surface, and its correlation with the contact angle of water. Using FAPH, we explored the effect of microchannel geometries on the penetration distance of oxygen plasma into a microchannel and found that entrance effects prevent uniform treatment. We showed that these variations have a significant impact on cell culture, and thus the design of cell-based microfluidic assays must consider this phenomenon to obtain repeatable and homogeneous results. PMID- 25032784 TI - Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ 40411813): a novel positive allosteric modulator of the metabotropic glutamate 2 receptor. AB - We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders. PMID- 25032785 TI - Carboxylic acids as a traceless activation group for conjugate additions: a three step synthesis of (+/-)-pregabalin. AB - The direct application of carboxylic acids as a traceless activation group for radical Michael additions has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidation of a broad series of carboxylic acids, including hydrocarbon-substituted, alpha-oxy, and alpha-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addition strategy. An application of this technology to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented. PMID- 25032786 TI - Iron-catalyzed directed alkylation of aromatic and olefinic carboxamides with primary and secondary alkyl tosylates, mesylates, and halides. AB - Alkenes, arenes, and heteroarenes possessing an 8-quinolylamide group as the directing group are alkylated with primary and secondary alkyl tosylates, mesylate, and halides in the presence of Fe(acac)3/diphosphine as a catalyst and ArZnBr as a base. The reaction proceeds stereospecifically for alkene substrates and takes place without loss of regiochemical integrity of the starting secondary tosylate, but with loss of the stereochemistry of the chiral center. PMID- 25032787 TI - A copper-catalyzed three-component reaction of triethoxysilanes, sulfur dioxide, and hydrazines. AB - A three-component reaction of triethoxysilanes, sulfur dioxide, and hydrazines catalyzed by copper(II) acetate is reported, leading to N-aminosulfonamides in good yields. Not only triethoxy(aryl)silanes but also triethoxy(alkyl)silanes are compatible during the process of insertion of sulfur dioxide. Additionally, diethoxydiarylsilanes are suitable under the conditions as well. PMID- 25032788 TI - Metal-free reduction of secondary and tertiary N-phenyl amides by tris(pentafluorophenyl)boron-catalyzed hydrosilylation. AB - Tris(pentafluorophenyl)boron B(C6F5)3 is an effective catalyst for the hydrosilylative reduction of tertiary and N-phenyl secondary amides. It allows for the mild reduction of a variety of these amides in near quantitative yield, with minimal purification, at low temperatures, and with short reaction times. This reduction shows functional group tolerance for alkenes, nitro groups, and aryl halides, including aryl iodides. PMID- 25032789 TI - Diamonds are a spectroscopist's best friend: thin-film diamond mid-infrared waveguides for advanced chemical sensors/biosensors. AB - The first combination of mid-infrared (MIR) tunable quantum cascade lasers (tQCLs) with thin-film diamond strip waveguides (DSWGs) suitable for advanced chemical sensing/biosensing is demonstrated. The sensing system is composed of thin diamond films grown on surface-passivated Si wafers via chemical vapor deposition (CVD) and microstructured using inductively coupled plasma (ICP) etching, serving as photonic waveguides for radiation emitted by a broadly tunable quantum cascade laser (tQCL) in the spectral regime of 5.78-6.35 MUm (1570-1730 cm(-1)). The characterization of the free-standing diamond waveguides reveals excellent transmission properties across a broad MIR band. As a proof of concept, the detection of acetone in D2O via evanescent field absorption is demonstrated achieving a limit of detection (LOD) as low as 200 pL, which indicates a significant sensitivity improvement compared to conventional MIR slab/strip waveguides reported to date. Providing characteristic absorption features within the tuning range of the tQCL, studies using anisaldehyde as an analyte further corroborate the potential of tQCL-DSWG-based chemical sensors/biosensors. PMID- 25032791 TI - Stimulation of gene transfection by silicon nanowire arrays modified with polyethylenimine. AB - In this work, a novel gene delivery strategy was proposed based on silicon nanowire arrays modified with high-molecular-weight 25 kDa branched polyethylenimine (SN-PEI). Both the plasmid DNA (pDNA) binding capacity and the in vitro gene transfection efficiency of silicon nanowire arrays (SiNWAs) were significantly enhanced after modification with high-molecular-weight bPEI. Moreover, the transfection efficiency was substantially further increased by the introduction of free pDNA/PEI complexes formed by low-molecular-weight branched PEI (bPEI, 2 kDa). Additionally, factors affecting the in vitro transfection efficiency of the novel gene delivery system were investigated in detail, and the transfection efficiency was optimized on SN-PEI with a bPEI grafting time of 3 h, an incubation time of 10 min for tethered pDNA/PEI complexes consisting of high molecular-weight bPEI grafted onto SiNWAs, and with an N/P ratio of 80 for free pDNA/PEI complexes made of low-molecular-weight bPEI. Together, our results indicate that high-molecular-weight bPEI modified SiNWAs can serve as an efficient platform for gene delivery. PMID- 25032790 TI - LipidWrapper: an algorithm for generating large-scale membrane models of arbitrary geometry. AB - As ever larger and more complex biological systems are modeled in silico, approximating physiological lipid bilayers with simple planar models becomes increasingly unrealistic. In order to build accurate large-scale models of subcellular environments, models of lipid membranes with carefully considered, biologically relevant curvature will be essential. In the current work, we present a multi-scale utility called LipidWrapper capable of creating curved membrane models with geometries derived from various sources, both experimental and theoretical. To demonstrate its utility, we use LipidWrapper to examine an important mechanism of influenza virulence. A copy of the program can be downloaded free of charge under the terms of the open-source FreeBSD License from http://nbcr.ucsd.edu/lipidwrapper. LipidWrapper has been tested on all major computer operating systems. PMID- 25032792 TI - Analytic methods in assessment of optic nerve cupping. AB - The intent of this paper is to provide a systems-based analysis of the methods used to evaluate optic nerve cupping, identify potential flaws in these systems, and propose alternatives better to assess this anatomic quantity. Estimation of optic nerve cupping requires an analytic understanding of both the psychophysical as well as the mathematical bases inherent in this measure. When the (decimal based) cup-to-disc ratio is used to quantitate optic nerve cupping, a one dimensional, linear estimate is produced, which in turn is derived from two- or three-dimensional, non-linear physical quantities of area or volume, respectively. When extrapolating from volume, to area, to linear measures, due to the psychophysical constraints which limit this task, such a data-compressed estimate of optic nerve cupping may neither accurately reflect, nor correctly represent, the true amount of cupping actually present in the optic nerve head. This type of one-dimensional metric (when comparing calculations from two- or three-dimensional measures over a range of optic nerve cupping), appears to introduce errors which, while most pronounced earlier on in the disease progression, often overestimate the amount of relative cupping (percent cupping) present in a pathological process like glaucoma. The same systemic errors can also lead to overestimation of the progression in cupping, especially in optic nerves with low cup-to disc values. To provide clinically meaningful estimates of optic nerve cupping, the practitioner needs to be aware of psychophysical and mathematical limitations inherent in using a linear cup-to-disc ratio to estimate the amount of cupping observed in a physical structure like the optic disc. The resultant flaws introduced by observer extrapolation from three, to two, to one dimensions (volume, area, and linear); transposition from non-linear to linear quantities; and optical illusions, caused by factors like disc topology, morphology, and ametropia, can all influence subjective-based estimates of optic nerve cupping. To improve clinical outcomes, a non-linear mathematical technique is proposed which utilizes two- or three-dimensional objective measures of optic nerve cupping to describe, more accurately and more precisely, the anatomic quantities (disc, cup, and rim) under discussion. The authors acknowledge that any proposed technique is only a beginning to the work required to improve the clinical value of this type of measure. PMID- 25032793 TI - [Comparison of measurement of intraocular pressure by ICARE PRO(r) tonometer and Goldman applanation tonometer]. AB - The paper compares a concordance in measuring the intraocular pressure (IOP) using two different tonometers, Goldman applanation tonometer (GAT) and ICARE PRO(r) tonometer. GAT is nowadays considered a standard device for measuring the IOP at the offices of ophthalmologists. Options of the measurements are however limited by necessary installation as well as use of a slit lamp where the evaluation is made subjectively by the examiner. The ICARE PRO(r) tonometer is a light and mobile device that allows to perform the measurement horizontally as well as vertically. The results are calculated automatically. The data for the paper was collected by IOP measurements in right and left eye in 45 individuals at the age range of 8-84 years. They were all diagnosed for glaucoma or were suspected to have glaucoma. The measurements were carried out always at the same day time. The acquired data was compared by a double select paired t-test with a significance level p = 0.05 and then analyzed by Bland-Altman method. There was no statistically important difference (p > 0.26) between the two devices. The average IOP measured by the ICARE PRO(r) tonometer was 18.19 mm Hg with standard deviation 3.70 mm Hg, whereas the average IOP measured by GAT was 17.94 mm Hg with standard deviation 3.66 mm Hg. It was observed that the difference in the measurements was not related to the IOP. The results show an acceptable concordance of measurements performed by the two devices. The ICARE PRO(r) tonometer, in comparison with its predecessor ICARE(r) TA01 evaluated in the past, shows a much smaller average difference in collected values compared with GAT. Based on the analysis of the collected data it may be stated that measuring the IOP by ICARE PRO(r) tonometer is clinically acceptable alternative to the use of GAT. PMID- 25032794 TI - [Preservative substances - the daily dose of benzalkonium chloride in glaucoma treatment from the patients point of view]. AB - The author calculated the daily dose of Benzalkonium Chloride (BAC) in eye drops used in glaucoma treatment from the patients point of view, which means the real amount of BAC applied in the conjunctival sac. The information about BAC concentration in 1 milliliter (mL) do not offer sufficient picture about real circumstances, because the size of the drop, especially after the introducing of the use of generic products in clinical practice in specific anti-glaucomatic drugs, differs significantly. The daily dose of BAC may have substantial significance in the patients treatment tolerance. The overview of BAC daily dose in single therapeutic groups and drugs follows: betablockers: Timo-COMOD 0, Arutimol 2.6, Vistagan 2.8, Timolol-POS 3.0, Arteoptic 3.7, Betoptic S 4.8, Timoptol MSD 6.3, Betoptic 10.0; alpha-mimetics: Alphagan 3.5, Luxfen 3.5, Aruclonin 7.1; derivates of prostaglandine, prostamides: Taflotan 0, Monopost 0, Lumigan 1.4, Unilat 3.1, Travatan 3.9, Latanoprost Apotex 4.3, Rescula 5.8, Latanoprost POS 5.9, Xalatan 6.0, Latanoprost Ratiopharm 6.0, Latanoprost Actavis 6.0, Latanoprost Arrow 6.0, Arulatan 5.4, Latalux 6.0, Glaucotens 6.0, Xaloptic 6.0, Solusin 6.1; carboanhydrase inhibitors: Batidor 3.8, Azopt 4.8, Trusopt 5.4, Oftidor 8.1; fixed combinations: Ganfort 1.4, Dorzolamid/timolol TEVA 2.8, Combigan 3.2, Duotrav 4.3, Cosopt 5.6, Xalacom 6.0, Glaucotima 6.0, Latanoprost/timolol Apotex 6.3, Azarga 6.4, Dorzogen Combi 6.5, and Dozotima 8.8 ul. PMID- 25032795 TI - [Internal limiting membrane peeling as prophylaxis of epimacular membrane formation in eyes undergoing vitrectomy for rhegmatogenous retinal detachement]. AB - PURPOSE: Rhegmatogenous retinal detachment is a serious condition that can significantly impair visual function, even after a successful surgery. One of the complications that can significantly impair visual acuity in the postoperative period is a development of the epimacular membrane (ERM). The aim of this work is to monitor the effect of peeling of the internal limiting membrane (ILM) in the macula at the anatomical and functional results in the postoperative period, especially with regard to the development of ERM. METHODS: Prospective study of 21 eyes, which underwent peeling of ILM during pars plana vitrectomy for rhegmatogenous retinal detachment (on detached macula). The ILM peeling was done without using decalin during this procedure. We tested best corrected visual acuity (BCVA) and followed fundus biomicroscopic findings. Proliferative vitreoretinopathy (PVR) was evaluated according to the recommendations of the Retina Society Terminology Committee. To exclude the development of ERM in the macula optical coherence tomography (OCT) was performed at the end of the 18 month follow-up period. RESULTS: In total, the results of 21 eyes of 21 patients who underwent PPV for rhegmatogenous retinal detachment were evaluated. In all of them was during PPV performed ILM peeling on detached macula, these are followed prospectively. ILM peeling without using decalin was sufficient in all eyes. All eyes with ILM peeling did not develop ERM at the end of the follow-up period. CONCLUSIONS: ILM peeling during PPV for rhegmatogenous retinal detachment reduces the risk of developing secondary ERM. PMID- 25032796 TI - [Surgical treatment of severe degree of ptosis of the upper eyelid using a Fronto tarsal sling of biocompatible PVC]. AB - PURPOSE: ptosis is anomalous drop of the upper eyelid. Depending on the cause of the state and especially according to the results of clinical findings (dominated significance of elevation of the upper eyelid) we can be perform various surgical procedures. Operation under Fasanella-Servat is suitable for the easiest cases - function of the upper eye-lid levator muscle (levator) is at least 10 mm and a maximum of 2 mm ptosis. Aponeurosis advancement has good results in all types of involutional origin. Eyelid levator resection is performed when the levator function is better than 5 mm. Eye-lid sling to brow lift mechanism is designed for the toughest conditions, when the levator function is worse than 4 mm. The authors present the results of surgery for ptosis with biocompatible PVC tube fronto-tarsal sling. METHODS: case-reports of 4 eyes in 3 adult patients were prospectively monitored. It was a one man and two women with different etiologies of ptosis. The principle of operation is suspension the upper eyelid to eyebrow levators using PVC tubes in the subcutaneous tissue. Monitored parameters were: best corrected visual acuity, clinical finding of the front segment (with an emphasis on lagophthalmos in the postoperative period), eye-fissure height and levator function in millimeters (mm). RESULTS: there was the most severe degree of ptosis in all cases. In terms of functional and cosmetic effect treatment were surgeries successful in all patients. One half of the cases (2 of 4 eyes) had transient postoperative lagophtalmos, which in one case was solved with moisture chamber. None of exposure keratopathy developed. In one case, it was after 9 months after the operation, we had to extract one implant due to extruzion of the tube. CONCLUSIONS: The fronto-tarsal tubing with biocompatible PVC is effective and relatively safe technique in cases of severe degree of ptosis of the upper eyelid. The material appears to be well tolerated by the surrounding tissue. PMID- 25032797 TI - [Scleral buckling for Rhegmatogenous retinal detachment]. AB - Rhegmatogenous retinal detachment (RRD) is the separation of the sensory retina from the pigment epithelium (RPE). RRD is caused by a retinal tear in the periphery and the vitreoretinal (VR) traction, which allows access of the vitreous fluid to the subretinal space. Treatment of symptomatic retinal detachment is currently surgical only. Surgical options are intraocular and extraocular. This is the retrospective evaluation of the group of 17 eyes of 17 patients with RRD, which were operated by scleral buckling. Patients were 9 men and 8 women, age range 19-61 (median 46) years. The observation period is 1-13 months (median 7). The possible types of external interventions procedure were used only two: the radial plombage (in one case double) and cerclage. 15 patients (88 %) were phakic, and 2 were pseudophakic. In 12 eyes (71 %) were the quadrant RRDs, 2 eyes had dialysis in periphery of the retina, 1x it was the top half and 1x bottom half, and 1 patient had a subtotal RRD. In 9 (53 %) cases were used type of operation cryocoagulation with radial buckle and in 8 cases cryocoagulation with the cerclage. In four cases, was injected the gas tamponade into the vitreous at the end of the surgery. Primary attaching the retina occurred in 16 cases (94 %) and the retina remained flat in 14 eyes (82.4% ), in 2 cases occurred re-detachment (11.7 %). Preoperative best corrected visual acuity (BCVA) ranged from hand movement to 20/20 (average Snellen equivalent 20/63) and postoperative BCVA was 1/50 - 20/20 (average 20/50). Improving BCVA was statistically significant (Wilcoxon p=0.01). We consider the cryosurgical procedure for phakic eyes as the gold standard of the surgical treatment of uncomplicated rhegmatogenous retinal detachment. The main reason for the eventual failure of this technique is persistent vitreous traction and proliferative vitreoretinopathy (PVR). PMID- 25032798 TI - [Rare ocular manifestation with suspect alport syndrome]. AB - The authors mention a case report of a 13 year old girl with renal disease, who visited the outpatient Department of Pediatric Ophthalmology, University Hospital Brno with subjective complaints on decreased vision of both eyes. Ophthalmologic examination showed physiological foveolar reflex on fundus and very discrete changes of the retinal pigment epithelium in macula, the fundus periphery was without pathology. OCT images showed bilateral atrophy of central macula and changes at the level of the photoreceptors. The authors describe a rare ocular manifestation of macular atrophy with suspect Alport syndrome, which strengthened the suspicion of this disease. The authors also mention other possible ocular manifestations of Alport syndrome and compare the findings with the up to date international references. Key words: Alport syndrome, X heterozygot Alport syndrome, macular atrophy, lentikonus. PMID- 25032799 TI - Growth of c-axis-oriented superconducting KFe2As2 thin films. AB - KFe2As2, an iron-based superconductor, is expected to exhibit large spin Hall conductivity, and fabrication of high-quality thin films is requisite for evaluation of this effect and application to spintronics devices. Thin-film growth of KFe2As2 is difficult because of two intrinsic properties; its extremely hygroscopic nature and the high vapor pressure of potassium. We solved these issues by combining room-temperature pulsed laser deposition using K-rich KFe2As2 targets with thermal crystallization in KFe2As2 powder after encapsulation in an evacuated silica-glass tube with all of the processes conducted in a vacuum chamber and a dry Ar atmosphere in a glovebox. The optimized KFe2As2 films on (La,Sr)(Al,Ta)O3 single-crystal substrates were obtained by crystallization at 700 degrees C, and they were strongly c-axis oriented. The electrical measurements were performed with thin films protected by grease passivation to block reaction with the atmosphere. The KFe2As2 films exhibited a superconductivity transition at 3.7 K. PMID- 25032800 TI - Improvement of agricultural life cycle assessment studies through spatial differentiation and new impact categories: case study on greenhouse tomato production. AB - This paper presents the inclusion of new, relevant impact categories for agriculture life cycle assessments. We performed a specific case study with a focus on the applicability of spatially explicit characterization factors. The main goals were to provide a detailed evaluation of these new impact category methods, compare the results with commonly used methods (ReCiPe and USEtox) and demonstrate how these new methods can help improve environmental assessment in agriculture. As an overall conclusion, the newly developed impact categories helped fill the most important gaps related to land use, water consumption, pesticide toxicity, and nontoxic emissions linked to fertilizer use. We also found that including biodiversity damage due to land use and the effect of water consumption on wetlands represented a scientific advance toward more realistic environmental assessment of agricultural practices. Likewise, the dynamic crop model for assessing human toxicity from pesticide residue in food can lead to better practice in pesticide application. In further life cycle assessment (LCA) method developments, common end point units and normalization units should be agreed upon to make it possible to compare different impacts and methods. In addition, the application of site-specific characterization factors allowed us to be more accurate regarding inventory data and to identify precisely where background flows acquire high relevance. PMID- 25032801 TI - Should we hold the obese responsible? - some key issues. AB - It is a common belief that obesity is wholly or partially a question of personal choice and personal responsibility. It is also widely assumed that when individuals are responsible for some unfortunate state of affairs, society bears no burden to compensate them. This article focuses on two conceptualizations of responsibility: backward-looking and forward-looking conceptualizations. When ascertaining responsibility in a backward-looking sense, one has to determine how that state of affairs came into being or where the agent stood in relation to it. In contrast, a forward-looking conceptualization of responsibility puts aside questions of the past and holds a person responsible by reference to some desirable future state of affairs and will typically mean that he or she is subjected to criticism, censure, or other negative appraisals or that he or she is held cost-responsible in some form, for example, in terms of demanded compensation, loss of privileges, or similar. One example of this view is the debate as to whether the obese should be denied, wholly or partially, free and equal access to healthcare, not because they are somehow personally responsible in the backward-looking sense but simply because holding the obese responsible will have positive consequences. Taking these two conceptions of responsibility into account, the authors turn their analysis toward examining the relevant moral considerations to be taken into account when public policies regarding obesity rely on such a conception of responsibility. PMID- 25032803 TI - Intrapartum ultrasound prior to Kristeller maneuver: an observational study. AB - OBJECTIVES: To evaluate the accuracy of criteria followed by obstetricians when performing a Kristeller maneuver in cases of prolonged second stage of labor. METHODS: In this prospective observational study, the station of the fetal head was measured using the angle of progression (intrapartum ultrasound) just prior to the intervention of the managing obstetrician in 52 women with prolonged second stage of labor. The managing obstetricians were blinded to the sonographic results. The decision of performing a Kristeller maneuver was taken by the obstetricians based on digital palpation and their experience. Delivery mode, Apgar score, umbilical artery pH value, episiotomy, perineal tears, bleeding, and time to delivery were recorded. RESULTS: Kristeller maneuver was performed in 36/52 (69.2%) cases. There were no significant differences between the Kristeller and the non-Kristeller group regarding the angle of progression. There were no significant differences between both groups with respect to delivery mode, perineal tears, episiotomy, bleeding, Apgar score, and umbilical artery pH value. CONCLUSIONS: Our study failed to define any criteria followed by obstetricians when performing a Kristeller maneuver in cases of prolonged second stage of labor. There was no relation between the angle of progression and the decision to perform a Kristeller maneuver. PMID- 25032802 TI - Shift in phenotypic characteristics of enterotoxigenic Escherichia coli (ETEC) isolated from diarrheal patients in Bangladesh. AB - BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of bacterial diarrhea. Over the last decade, from 1996 to 2012, changes in the virulence antigen properties of ETEC such as heat labile (LT) and heat stable (ST) toxins, colonization factors (CFs), and 'O'-serogroups have been observed. The aim of this prospective study was to compare changes in antigenic profiles of ETEC strains isolated from a 2% surveillance system at the icddr,b hospital in Dhaka, Bangladesh between 2007-2012 and an earlier time period of 1996-1998 conducted at the same surveillance site. METHODOLOGY: In the surveillance system every 50th patient attending the hospital was screened for major enteric pathogens including ETEC, Vibrio cholerae, Shigella spp. and Salmonella spp. from January 2007 to December 2012. PRINCIPAL FINDINGS: Of the 15,152 diarrheal specimens tested between 2007-2012, the overall rate of ETEC isolation was 11%; of these, 43% were LT/ST, 27% LT and 30% ST positive. Isolation rate of ST-ETEC (p<0.009) and LT/ST ETEC (p<0.011) during 2007-2012 period differed significantly compared to those seen between 1996-1998. In comparison to the 1996-1998 period, difference in CF profile of ETEC isolates during 2007-2012 was observed particularly for strains expressing CS7 (12.4%), CS14 (9.5%) and CS17 (10.0%). The predominant CF types were CS5+CS6, CFA/I, CS7, CS17, CS1+CS3, CS6 and CS14. The most common serogroups among the CF positive ETEC isolates were O115, O114, O6, O25 and O8. A strong association was found between CFs and 'O' serogroups i.e. between CS5+CS6 and (O115 and O126); CS7 and (O114), CFA/I and (O78 and O126), CS17 and (O8 and O167) and CS1/CS2+CS3 and (O6). CONCLUSION: The analyses show a shift in prevalence of antigenic types of ETEC over the study period; the information is important in designing effective ETEC vaccines with broad protective coverage. PMID- 25032804 TI - Comparison of Abbott Architect high-sensitivity troponin I in Rapid Serum Tubes and plasma. PMID- 25032806 TI - Oncological applications of dual-energy computed tomography imaging. AB - Dual-energy computed tomography (DECT) imaging is a promising method used in oncology for accurate detection/diagnosis of malignant and benign lesions. Use of dual-energy spectral, weighted average, color-coded map, and virtual unenhanced images provides increased visual detection and easy lesion delineation. Lesion detectability, sensitivity, and conspicuity are significantly improved using DECT. Material characterization and decomposition are promising using DECT. Both anatomical and functional information related to oncology can be provided by DECT using single contrast-enhanced CT. PMID- 25032805 TI - Diagnostic quality of dual-source coronary CT examinations performed without heart rate control: importance of obesity and heart rate on image quality. AB - OBJECTIVES: For dual-source cardiac computed tomography (CT) scans without heart rate (HR) control, the influence of body habitus on quality is uncertain. We evaluated study quality across a range of HRs and body size. METHODS: One hundred sixty subjects were randomly selected for 4 HR groups (<70, 70-79, 80-89, >=90 beats per minute) from 703 subjects who underwent cardiac CT without premedication. Coronary visualization quality was scored on a 3-point scale (1, nondiagnostic; 2, diagnostic; 3, excellent). RESULTS: Ninety-nine percent of coronaries were diagnostic quality. Six vessels were nondiagnostic, mostly due to motion. Nondiagnostic or diagnostic scores (<3) were greatest in the group with HR of more than or equal to 90 beats per minute. All normal weight subjects had excellent quality, but 6% of vessels in overweight and 17% in obese subjects had diagnostic scores less than 3. The mean effective dose was 11.4 mSv and correlated with body size. CONCLUSIONS: Diagnostic quality cardiac CT examinations can be obtained without premedication regardless of body size. PMID- 25032807 TI - Risk of suicide and suicide attempts associated with physical disorders: a population-based, balancing score-matched analysis. AB - BACKGROUND: The association between physical disorders and suicide remains unclear. The aim of this study was to examine the relationship between physical disorders and suicide after accounting for the effects of mental disorders. METHOD: Individuals who died by suicide (n = 2100) between 1996 and 2009 were matched 3:1 by balancing score to general population controls (n = 6300). Multivariate conditional logistic regression compared the two groups across physician-diagnosed physical disorders [asthma, chronic obstructive pulmonary disease (COPD), ischemic heart disease, hypertension, diabetes, cancer, multiple sclerosis and inflammatory bowel disease], adjusting for mental disorders and co morbidity. Secondary analyses examined the risk of suicide according to time since first diagnosis of each physical disorder (1-90, 91-364, ? 365 days). Similar analyses also compared individuals with suicide attempts (n = 8641) to matched controls (n = 25 923). RESULTS: Cancer was associated with increased risk of suicide [adjusted odds ratio (AOR) 1.40, 95% confidence interval (CI) 1.03 1.91, p < 0.05] even after adjusting for all mental disorders. The risk of suicide with cancer was particularly high in the first 90 days after initial diagnosis (AOR 4.10, 95% CI 1.71-9.82, p < 0.01) and decreased to non significance after 1 year. Women with respiratory diseases had elevated risk of suicide whereas men did not. COPD, hypertension and diabetes were each associated with increased odds of suicide attempts in adjusted models (AORs ranged from 1.20 to 1.73). CONCLUSIONS: People diagnosed with cancer are at increased risk of suicide, especially in the 3 months following initial diagnosis. Increased support and psychiatric involvement should be considered for the first year after cancer diagnosis. PMID- 25032808 TI - Relationships of biomass with environmental factors in the grassland area of Hulunbuir, China. AB - Many studies have focused on the relationship between vegetation biomass and environmental factors in grassland. However, several questions remain to be answered, especially with regards to the spatial pattern of vegetation biomass. Thus, the distributed mechanism will be explored in the present study. Here, plant biomass was measured at 23 sites along a transect survey during the peak growing season in 2006. The data were analyzed with a classification and regression tree (CART) model. The structural equation modeling (SEM) was conducted to explicitly evaluate the both direct and indirect effects of these critical environmental elements on vegetation biomass. The results demonstrated that mean annual temperature (MAT) affected aboveground biomass (AGB) scored at 0.811 (P<0.05). The direct effect of MAT on belowground biomass (BGB) was -0.490 (P<0.05). The results were determined by SEM. Our results indicate that AGB and BGB in semi-arid ecosystems is strongly affected by precipitation and temperature. Future work shall attempt to take into account the integrated effects of precipitation and temperature. Meanwhile, partitioning the influences of environmental variations and vegetation types are helpful in illuminating the internal mechanism of biomass distribution. PMID- 25032810 TI - Risk factors for acute respiratory infection in the Australian community. AB - OBJECTIVES: The objective of this study was to identify the risk factors for ARI in the Australian community. METHODS: We used a national survey of 7578 randomly selected respondents in 2008-2009 to identify the risk factors of ARI. A case was defined as a person experiencing cold or flu with one or more symptoms of: fever, chills, sore throat, runny nose, or cough in the previous four weeks. RESULTS: There were 19.8% (1505/7578) of respondents who reported ARI in the four weeks prior to the survey. Age was an independent risk factor for ARI, with the risk of acquiring ARI decreasing as age increased. Respondents reporting asthma (OR 1.4, 95%CI: 1.2-1.7) or having someone in their house attending childcare (OR 1.6, 95%CI: 1.2-2.1) were more likely to report ARI. CONCLUSIONS: It is important to identify ways of interrupting transmission of ARI amongst children. Improving identification of risk factors will enable targeted interventions for this exceedingly common syndrome. PMID- 25032811 TI - FRET based quantification and screening technology platform for the interactions of leukocyte function-associated antigen-1 (LFA-1) with intercellular adhesion molecule-1 (ICAM-1). AB - The interaction between leukocyte function-associated antigen-1(LFA-1) and intercellular adhesion molecule-1 (ICAM-1) plays a pivotal role in cellular adhesion including the extravasation and inflammatory response of leukocytes, and also in the formation of immunological synapse. However, irregular expressions of LFA-1 or ICAM-1 or both may lead to autoimmune diseases, metastasis cancer, etc. Thus, the LFA-1/ICAM-1 interaction may serve as a potential therapeutic target for the treatment of these diseases. Here, we developed one simple 'in solution' steady state fluorescence resonance energy transfer (FRET) technique to obtain the dissociation constant (Kd) of the interaction between LFA-1 and ICAM-1. Moreover, we developed the assay into a screening platform to identify peptides and small molecules that inhibit the LFA-1/ICAM-1 interaction. For the FRET pair, we used Alexa Fluor 488-LFA-1 conjugate as donor and Alexa Fluor 555-human recombinant ICAM-1 (D1-D2-Fc) as acceptor. From our quantitative FRET analysis, the Kd between LFA-1 and D1-D2-Fc was determined to be 17.93+/-1.34 nM. Both the Kd determination and screening assay were performed in a 96-well plate platform, providing the opportunity to develop it into a high-throughput assay. This is the first reported work which applies FRET based technique to determine Kd as well as classifying inhibitors of the LFA-1/ICAM-1 interaction. PMID- 25032812 TI - Pulmonary vascular complications of hereditary haemorrhagic telangiectasia. AB - PURPOSE OF REVIEW: The purpose of this study is to present the latest advances and recommendations in the diagnosis and treatment of pulmonary vascular complications associated with hereditary haemorrhagic telangiectasia (HHT): pulmonary arteriovenous malformations (PAVMs), pulmonary arterial hypertension (PAH), pulmonary hypertension associated with high output cardiac failure or liver vascular malformations, haemoptysis, haemothorax and thromboembolic disease. RECENT FINDINGS: Transthoracic contrast echocardiography has been validated as a screening tool for PAVM in patients with suspected HHT. Advancements in genetic testing support its use in family members at risk as a cost-effective measure. Therapy with bevacizumab in patients with high output cardiac failure and severe liver AVMs showed promising results. PAH tends to be more aggressive in HHT type 2 patients. SUMMARY: Patients suffering from this elusive disease should be referred to HHT specialized centres to ensure a standardized and timely approach to diagnosis and management. PMID- 25032813 TI - Acute exacerbations complicating interstitial lung disease. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF), with a specific focus on new data regarding the cause, clinical features, management and prognosis of AE IPF. In addition, the limitations of the current definition of AE-IPF are discussed and a novel classification schema is proposed. RECENT FINDINGS: AE-IPF occurs in up to 15% of IPF patients annually and has a mortality of approximately 50%. The incidence of AE-IPF is higher in patients with worse lung function and may be increased in some populations. Emerging data suggest that exacerbations may be secondary to subclinical triggers such as infection, aspiration, mechanical injury and air pollution. Management of AE-IPF typically includes high dose corticosteroids and antimicrobials; however, there are limited data to support these or other therapies. Prevention of AE-IPF with antifibrotic medications may be feasible and warrants further study. SUMMARY: AE-IPF is associated with significant morbidity and mortality; however, there remains a paucity of clinical data. The current definition of AE-IPF has limitations and a new classification schema should be considered. PMID- 25032814 TI - Treatment strategies for idiopathic interstitial pneumonias. AB - PURPOSE OF REVIEW: With recent changes in diagnostic algorithms in idiopathic pulmonary fibrosis (IPF) guidelines and treatment advances in IPF, it is now necessary to reappraise the way in which clinicians should formulate treatment strategies in the idiopathic interstitial pneumonias. RECENT FINDINGS: The idiopathic interstitial pneumonias can usefully be subdivided into the following categories: first, definite IPF, second, probable IPF with major differential diagnoses of fibrotic nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis and third, apparently idiopathic interstitial pneumonias other than IPF. In definite IPF, the therapeutic landscape has irrevocably changed with the identification of robust treatment effects with pirfenidone and nintedanib, consisting of the prevention of approximately 50% of disease progression (as judged by serial forced vital capacity trends). In probable IPF, generally equating with high resolution computed tomography findings of 'possible usual interstitial pneumonia' and the nonperformance of a diagnostic surgical biopsy, management is based on multidisciplinary evaluation, integrating all available information, with a final 'working diagnosis' made for treatment purposes. In other idiopathic interstitial pneumonias and their major differentials, removal of potential triggers and immunomodulation remain the cornerstones of therapy, with treatment goals usefully designated using a disease behaviour classification. In mild disease, an initial policy of observation is often appropriate. SUMMARY: The striking recent treatment effects reported in IPF will have major management implications in the idiopathic interstitial pneumonia in general, whenever IPF is in the differential diagnosis. PMID- 25032816 TI - Serum metabolomic response of myasthenia gravis patients to chronic prednisone treatment. AB - Prednisone is often used for the treatment of autoimmune and inflammatory diseases but they suffer from variable therapeutic responses and significant adverse effects. Serum biological markers that are modulated by chronic corticosteroid use have not been identified. Myasthenia gravis is an autoimmune neuromuscular disorder caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction resulting in weakness. The patients with myasthenia gravis are primarily treated with prednisone. We analyzed the metabolomic profile of serum collected from patients prior to and after 12 weeks of prednisone treatment during a clinical trial. Our aim was to identify metabolites that may be treatment responsive and be evaluated in future studies as potential biomarkers of efficacy or adverse effects. Ultra-performance liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry was used to obtain comparative metabolomic and lipidomic profile. Untargeted metabolic profiling of serum showed a clear distinction between pre- and post-treatment groups. Chronic prednisone treatment caused upregulation of membrane associated glycerophospholipids: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, 1, 2-diacyl-sn glycerol 3 phosphate and 1-Acyl-sn-glycero-3-phosphocholine. Arachidonic acid (AA) and AA derived pro inflammatory eicosanoids such as 18-carboxy dinor leukotriene B4 and 15 hydroxyeicosatetraenoic acids were reduced. Perturbations in amino acid, carbohydrate, vitamin and lipid metabolism were observed. Chronic prednisone treatment caused increase in membrane associated glycerophospholipids, which may be associated with certain adverse effects. Decrease of AA and AA derived pro inflammatory eicosanoids demonstrate that immunosuppression by corticosteroid is via suppression of pro-inflammatory pathways. The study identified metabolomic fingerprints that can now be validated as prednisone responsive biomarkers for the improvement in diagnostic accuracy and prediction of therapeutic outcome. PMID- 25032815 TI - Novel Drosophila viruses encode host-specific suppressors of RNAi. AB - The ongoing conflict between viruses and their hosts can drive the co-evolution between host immune genes and viral suppressors of immunity. It has been suggested that an evolutionary 'arms race' may occur between rapidly evolving components of the antiviral RNAi pathway of Drosophila and viral genes that antagonize it. We have recently shown that viral protein 1 (VP1) of Drosophila melanogaster Nora virus (DmelNV) suppresses Argonaute-2 (AGO2)-mediated target RNA cleavage (slicer activity) to antagonize antiviral RNAi. Here we show that viral AGO2 antagonists of divergent Nora-like viruses can have host specific activities. We have identified novel Nora-like viruses in wild-caught populations of D. immigrans (DimmNV) and D. subobscura (DsubNV) that are 36% and 26% divergent from DmelNV at the amino acid level. We show that DimmNV and DsubNV VP1 are unable to suppress RNAi in D. melanogaster S2 cells, whereas DmelNV VP1 potently suppresses RNAi in this host species. Moreover, we show that the RNAi suppressor activity of DimmNV VP1 is restricted to its natural host species, D. immigrans. Specifically, we find that DimmNV VP1 interacts with D. immigrans AGO2, but not with D. melanogaster AGO2, and that it suppresses slicer activity in embryo lysates from D. immigrans, but not in lysates from D. melanogaster. This species-specific interaction is reflected in the ability of DimmNV VP1 to enhance RNA production by a recombinant Sindbis virus in a host-specific manner. Our results emphasize the importance of analyzing viral RNAi suppressor activity in the relevant host species. We suggest that rapid co-evolution between RNA viruses and their hosts may result in host species-specific activities of RNAi suppressor proteins, and therefore that viral RNAi suppressors could be host specificity factors. PMID- 25032818 TI - Ductal closure with radiofrequency energy: the first in-human report. AB - BACKGROUND: Vascular obstruction is one of the complications of radiofrequency ablation. Following our previous report on the use of radiofrequency energy for vascular closure in an animal model in this journal, we herein present the first ever in-human report. Patient and method The patient was a 3-year-old boy, who received a permanent endocardial pacemaker for congenital complete heart block. He also had a conical patent ductus arteriosus. The ductus was occluded with radiofrequency energy on the arterial side with no complications. CONCLUSION: Closure of patent ductus arteriosus and probably other problematic small vessels could be achieved with radiofrequency energy. Further experience will elucidate the future scope of this novel technique. PMID- 25032817 TI - HIV-1 tropism dynamics and phylogenetic analysis from longitudinal ultra-deep sequencing data of CCR5- and CXCR4-using variants. AB - OBJECTIVE: Coreceptor switch from CCR5 to CXCR4 is associated with HIV disease progression. The molecular and evolutionary mechanisms underlying the CCR5 to CXCR4 switch are the focus of intense recent research. We studied the HIV-1 tropism dynamics in relation to coreceptor usage, the nature of quasispecies from ultra deep sequencing (UDPS) data and their phylogenetic relationships. METHODS: Here, we characterized C2-V3-C3 sequences of HIV obtained from 19 patients followed up for 54 to 114 months using UDPS, with further genotyping and phylogenetic analysis for coreceptor usage. HIV quasispecies diversity and variability as well as HIV plasma viral load were measured longitudinally and their relationship with the HIV coreceptor usage was analyzed. The longitudinal UDPS data were submitted to phylogenetic analysis and sampling times and coreceptor usage were mapped onto the trees obtained. RESULTS: Although a temporal viral genetic structuring was evident, the persistence of several viral lineages evolving independently along the infection was statistically supported, indicating a complex scenario for the evolution of viral quasispecies. HIV X4 using variants were present in most of our patients, exhibiting a dissimilar inter- and intra-patient predominance as the component of quasispecies even on antiretroviral therapy. The viral populations from some of the patients studied displayed evidences of the evolution of X4 variants through fitness valleys, whereas for other patients the data favored a gradual mode of emergence. CONCLUSIONS: CXCR4 usage can emerge independently, in multiple lineages, along the course of HIV infection. The mode of emergence, i.e. gradual or through fitness valleys seems to depend on both virus and patient factors. Furthermore, our analyses suggest that, besides becoming dominant after population-level switches, minor proportions of X4 viruses might exist along the infection, perhaps even at early stages of it. The fate of these minor variants might depend on both viral and host factors. PMID- 25032819 TI - Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry. AB - BACKGROUND: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS: 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation. RESULTS: A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year. CONCLUSIONS: This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results. PMID- 25032820 TI - Water-based exercise for adults with asthma. AB - BACKGROUND: Asthma is a common condition characterised by airway inflammation and airway narrowing, which can result in intermittent symptoms of wheezing, coughing and chest tightness, possibly limiting activities of daily life. Water-based exercise is believed to offer benefits for people with asthma through pollen-free air, humidity and effects of exercise on physical function. OBJECTIVES: To evaluate the effectiveness and safety of water-based exercise for adults with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials (CAGR), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), PsycINFO, the Latin American and Caribbean Health Science Information Database (LILACS), the Physiotherapy Evidence Database (PEDro), the System for Information on Grey Literature in Europe (SIGLE) and Google Scholar on 13 May 2014. We handsearched ongoing clinical trial registers and meeting abstracts of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the British Thoracic Society (BTS). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of adults with asthma comparing a water-based exercise group versus one or more of the following groups: usual care, land-based exercise, non-exercise. DATA COLLECTION AND ANALYSIS: Two review authors (AJG, VS) independently extracted data from the primary studies using a standard form developed for this purpose, which includes methods, participants, interventions and outcomes. We contacted trial authors to request additional data. Data were input by one review author and were double-checked by a second review author. MAIN RESULTS: In this systematic review, we provide a narrative synthesis of available evidence from three small studies including 136 adult participants. The studies were at high risk of bias. No meta-analysis was possible because of methodological and interventional heterogeneity between included studies. The primary outcomes of quality of life and exacerbations leading to use of steroids were not reported by these studies. For exacerbations leading to health centre/hospital visits, uncertainty was wide because a very small number of events was reported (in a single study). Secondary outcomes symptoms, lung function, changes in medication and adverse effects, where available, described for each included study. The overall quality of the studies was very low, and no clear differences were noted between water-based exercise and comparator treatments. Therefore, we remain very uncertain about the effects of water-based exercise for adults with asthma. AUTHORS' CONCLUSIONS: The small number of participants in the three included studies, the clinical and methodological heterogeneity observed and the high risk of bias assessed mean that we are unable to assess the place of water-based exercise in asthma. Randomised controlled trials are needed to assess the efficacy and safety of water-based exercise for adults with asthma. For future research, we suggest greater methodological rigour (participant selection, blinding of outcome assessors, reporting of all outcomes analysed and registering of the study protocol). PMID- 25032821 TI - Infection control measures to decrease the burden of antimicrobial resistance in the critical care setting. AB - PURPOSE OF REVIEW: The prevalence of multidrug-resistant organisms (MDROs) in ICUs is increasing worldwide. This review assesses the role of infection control measures, excluding antibiotic stewardship programs, in reducing the burden of resistance in ICUs. RECENT FINDINGS: The knowledge base about the effect of increased hand hygiene compliance in reducing the burden of methicillin-resistant Staphylococcus aureus in ICUs has been improved. Universal decolonization with chlorhexidine body washing was associated with significant reduction in MDRO prevalence, but vigilance for emerging chlorhexidine resistance is required. A significant reduction of resistance for Gram-negative bacilli has been demonstrated with the use of selective decontamination, but further clinical trials are necessary before definitive conclusions can be drawn regarding long term risk/benefit ratios. SUMMARY: In the recent years, several high-quality clinical studies have assessed the ability of various infection control measures in reducing the burden of antimicrobial resistance. Significant progress has been made in identifying interventions effective in preventing transmission of MDROs in ICUs, in particular, decolonization. However, it still remains impossible to determine the exact and relative importance of different infection control measures. Any approach must ultimately be tailored to the local epidemiology of the targeted ICU. PMID- 25032822 TI - Mechanical characterization of microcapsules with membrane permeability by using indentation analysis. AB - Mechanical modeling of the deformation of a liquid-filled spherical microcapsule indented by a sharp truncated-cone indenter was proposed, in which membrane permeability was taken into account. The change in the internal volume of the microcapsule due to fluid permeation was calculated on the basis of Kedem and Katchalsky equations (1958, "Thermodynamic Analysis of the Permeability of Biological Membranes to Non-electrolytes," Biochim. Biophys. Acta, 27, pp. 229 246). The membrane hydraulic permeability, membrane initial stretch, and effective osmotic pressure difference across the membrane of an alginate poly(l)lysine-alginate (APA) microcapsule were identified by fitting calculated and measured force-displacement curves. The difference between deformed shapes with and without membrane permeability was shown, suggesting the spatial resolution of image analysis performed to measure the membrane permeability from the volume loss. The influences of changes in permeability, initial stretch, and a parameter beta, used for determining the effective osmotic pressure difference, on the force-displacement relationship were examined, and mechanisms causing changes in the force-displacement relationship were discussed. PMID- 25032823 TI - Comparative phylogenomics uncovers the impact of symbiotic associations on host genome evolution. AB - Mutualistic symbioses between eukaryotes and beneficial microorganisms of their microbiome play an essential role in nutrition, protection against disease, and development of the host. However, the impact of beneficial symbionts on the evolution of host genomes remains poorly characterized. Here we used the independent loss of the most widespread plant-microbe symbiosis, arbuscular mycorrhization (AM), as a model to address this question. Using a large phenotypic approach and phylogenetic analyses, we present evidence that loss of AM symbiosis correlates with the loss of many symbiotic genes in the Arabidopsis lineage (Brassicales). Then, by analyzing the genome and/or transcriptomes of nine other phylogenetically divergent non-host plants, we show that this correlation occurred in a convergent manner in four additional plant lineages, demonstrating the existence of an evolutionary pattern specific to symbiotic genes. Finally, we use a global comparative phylogenomic approach to track this evolutionary pattern among land plants. Based on this approach, we identify a set of 174 highly conserved genes and demonstrate enrichment in symbiosis-related genes. Our findings are consistent with the hypothesis that beneficial symbionts maintain purifying selection on host gene networks during the evolution of entire lineages. PMID- 25032824 TI - Azelnidipine inhibits cultured rat aortic smooth muscle cell death induced by cyclic mechanical stretch. AB - Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. Clarifying the detailed mechanism for aortic dissection is of great significance for establishing effective pharmacotherapy for this high mortality disease. In the present study, we evaluated the influence of biomechanical stretch, which mimics an acute rise in blood pressure using an experimental apparatus of stretching loads in vitro, on rat aortic smooth muscle cell (RASMC) death. Then, we examined the effects of azelnidipine and mitogen-activated protein kinase inhibitors on mechanical stretch-induced RASMC death. The major findings of the present study are as follows: (1) cyclic mechanical stretch on RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch on RASMC induced c Jun N-terminal kinase (JNK) and p38 activation with peaks at 10 min; (3) azelnidipine inhibited RASMC death in a concentration-dependent manner as well as inhibited JNK and p38 activation by mechanical stretch; and (4) SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) protected against stretch-induced RASMC death; (5) Antioxidants, diphenylene iodonium and tempol failed to inhibit stretch-induced RASMC death. On the basis of the above findings, we propose a possible mechanism where an acute rise in blood pressure increases biomechanical stress on the arterial walls, which induces RASMC death, and thus, may lead to aortic dissection. Azelnidipine may be used as a pharmacotherapeutic agent for prevention of aortic dissection independent of its blood pressure lowering effect. PMID- 25032825 TI - eulerAPE: drawing area-proportional 3-Venn diagrams using ellipses. AB - Venn diagrams with three curves are used extensively in various medical and scientific disciplines to visualize relationships between data sets and facilitate data analysis. The area of the regions formed by the overlapping curves is often directly proportional to the cardinality of the depicted set relation or any other related quantitative data. Drawing these diagrams manually is difficult and current automatic drawing methods do not always produce appropriate diagrams. Most methods depict the data sets as circles, as they perceptually pop out as complete distinct objects due to their smoothness and regularity. However, circles cannot draw accurate diagrams for most 3-set data and so the generated diagrams often have misleading region areas. Other methods use polygons to draw accurate diagrams. However, polygons are non-smooth and non symmetric, so the curves are not easily distinguishable and the diagrams are difficult to comprehend. Ellipses are more flexible than circles and are similarly smooth, but none of the current automatic drawing methods use ellipses. We present eulerAPE as the first method and software that uses ellipses for automatically drawing accurate area-proportional Venn diagrams for 3-set data. We describe the drawing method adopted by eulerAPE and we discuss our evaluation of the effectiveness of eulerAPE and ellipses for drawing random 3-set data. We compare eulerAPE and various other methods that are currently available and we discuss differences between their generated diagrams in terms of accuracy and ease of understanding for real world data. PMID- 25032826 TI - Visceral leishmaniasis as an AIDS defining condition: towards consistency across WHO guidelines. PMID- 25032828 TI - Mitogenomes of polar bodies and corresponding oocytes. AB - The objective of the present study was to develop an approach that could assess the chromosomal status and the mitochondrial DNA (mtDNA) content of oocytes and their corresponding polar bodies (PBs) with the goal of obtaining a comparative picture of the segregation process both for nuclear and mtDNA. After Whole Genome Amplification (WGA), sequencing of the whole mitochondrial genome was attempted to analyze the segregation of mutant and wild-type mtDNA during human meiosis. Three triads, composed of oocyte and corresponding PBs, were analyzed and their chromosome status was successfully assessed. The complete mitochondrial genome (mitogenome) was almost entirely sequenced in the oocytes (95.99% compared to 98.43% in blood), while the percentage of sequences obtained in the corresponding PB1 and PB2 was lower (69.70% and 69.04% respectively). The comparison with the mtDNA sequence in blood revealed no changes in the D-loop region for any of the cells of each triad. In the coding region of blood mtDNA and oocyte mtDNA sequences showed full correspondence, whereas all PBs had at least one change with respect to the blood-oocyte pairs. In all, 9 changes were found, either in PB1 or PB2: 4 in MT-ND5, 2 in MT-RNR2, and 1 each in MT-ATP8, MT-ND4, MT-CYTB. The full concordance between oocyte and blood in the 3 triads, and the relegation of changes to PBs, revealed the unexpected coexistence of different variants, giving a refined estimation of mitochondrial heteroplasmy. Should these findings be confirmed by additional data, an active mechanism could be postulated in the oocyte to preserve a condition of 'normality'. PMID- 25032829 TI - Serology of paracoccidioidomycosis due to Paracoccidioides lutzii. AB - Paracoccidioides lutzii is a new agent of paracoccidioidomycosis (PCM) and has its epicenter localized to the Central-West region of Brazil. Serological diagnosis of PCM caused by P. lutzii has not been established. This study aimed to develop new antigenic preparations from P. lutzii and to apply them in serological techniques to improve the diagnosis of PCM due to P. lutzii. Paracoccidioides lutzii exoantigens, cell free antigen (CFA), and a TCA precipitated antigen were evaluated in immunodiffusion (ID) tests using a total of 89 patient sera from the Central-West region of Brazil. Seventy-two sera were defined as reactive for P. brasiliensis using traditional antigens (AgPbB339 and gp43). Non-reactive sera for traditional antigens (n = 17) were tested with different P. lutzii preparations and P. lutzii CFA showed 100% reactivity. ELISA was found to be a very useful test to titer anti-P. lutzii antibodies using P. lutzii-CFA preparations. Sera from patients with PCM due to P. lutzii presented with higher antibody titers than PCM due to P. brasiliensis and heterologous sera. In western blot, sera from patients with PCM due to P. lutzii were able to recognize antigenic molecules from the P. lutzii-CFA antigen, but sera from patients with PCM due to P. brasiliensis could not recognize any P. lutzii molecules. Due to the facility of preparing P. lutzii CFA antigens we recommend its use in immunodiffusion tests for the diagnosis of PCM due to P. lutzii. ELISA and western blot can be used as complementary tests. PMID- 25032830 TI - Optic disc pit maculopathy recurring in the absence of vitreous gel. PMID- 25032832 TI - Graph theoretical representation of atomic asymmetry and molecular chirality of benzenoids in two-dimensional space. AB - In order to explore atomic asymmetry and molecular chirality in 2D space, benzenoids composed of 3 to 11 hexagons in 2D space were enumerated in our laboratory. These benzenoids are regarded as planar connected polyhexes and have no internal holes; that is, their internal regions are filled with hexagons. The produced dataset was composed of 357,968 benzenoids, including more than 14 million atoms. Rather than simply labeling the huge number of atoms as being either symmetric or asymmetric, this investigation aims at exploring a quantitative graph theoretical descriptor of atomic asymmetry. Based on the particular characteristics in the 2D plane, we suggested the weighted atomic sum as the descriptor of atomic asymmetry. This descriptor is measured by circulating around the molecule going in opposite directions. The investigation demonstrates that the weighted atomic sums are superior to the previously reported quantitative descriptor, atomic sums. The investigation of quantitative descriptors also reveals that the most asymmetric atom is in a structure with a spiral ring with the convex shape going in clockwise direction and concave shape going in anticlockwise direction from the atom. Based on weighted atomic sums, a weighted F index is introduced to quantitatively represent molecular chirality in the plane, rather than merely regarding benzenoids as being either chiral or achiral. By validating with enumerated benzenoids, the results indicate that the weighted F indexes were in accordance with their chiral classification (achiral or chiral) over the whole benzenoids dataset. Furthermore, weighted F indexes were superior to previously available descriptors. Benzenoids possess a variety of shapes and can be extended to practically represent any shape in 2D space-our proposed descriptor has thus the potential to be a general method to represent 2D molecular chirality based on the difference between clockwise and anticlockwise sums around a molecule. PMID- 25032833 TI - A comparative pan-genome perspective of niche-adaptable cell-surface protein phenotypes in Lactobacillus rhamnosus. AB - Lactobacillus rhamnosus is a ubiquitously adaptable Gram-positive bacterium and as a typical commensal can be recovered from various microbe-accessible bodily orifices and cavities. Then again, other isolates are food-borne, with some of these having been long associated with naturally fermented cheeses and yogurts. Additionally, because of perceived health benefits to humans and animals, numerous L. rhamnosus strains have been selected for use as so-called probiotics and are often taken in the form of dietary supplements and functional foods. At the genome level, it is anticipated that certain genetic variances will have provided the niche-related phenotypes that augment the flexible adaptiveness of this species, thus enabling its strains to grow and survive in their respective host environments. For this present study, we considered it functionally informative to examine and catalogue the genotype-phenotype variation existing at the cell surface between different L. rhamnosus strains, with the presumption that this might be relatable to habitat preferences and ecological adaptability. Here, we conducted a pan-genomic study involving 13 genomes from L. rhamnosus isolates with various origins. In using a benchmark strain (gut-adapted L. rhamnosus GG) for our pan-genome comparison, we had focused our efforts on a detailed examination and description of gene products for certain functionally relevant surface-exposed proteins, each of which in effect might also play a part in niche adaptability among the other strains. Perhaps most significantly of the surface protein loci we had analyzed, it would appear that the spaCBA operon (known to encode SpaCBA-called pili having a mucoadhesive phenotype) is a genomic rarity and an uncommon occurrence in L. rhamnosus. However, for any of the so piliated L. rhamnosus strains, they will likely possess an increased niche specific fitness, which functionally might presumably be manifested by a protracted transient colonization of the gut mucosa or some similar microhabitat. PMID- 25032834 TI - Long-term culture of rat hippocampal neurons at low density in serum-free medium: combination of the sandwich culture technique with the three-dimensional nanofibrous hydrogel PuraMatrix. AB - The primary culture of neuronal cells plays an important role in neuroscience. There has long been a need for methods enabling the long-term culture of primary neurons at low density, in defined serum-free medium. However, the lower the cell density, the more difficult it is to maintain the cells in culture. Therefore, we aimed to develop a method for long-term culture of neurons at low density, in serum-free medium, without the need for a glial feeder layer. Here, we describe the work leading to our determination of a protocol for long-term (>2 months) primary culture of rat hippocampal neurons in serum-free medium at the low density of 3*10(4) cells/mL (8.9*10(3) cells/cm2) without a glial feeder layer. Neurons were cultured on a three-dimensional nanofibrous hydrogel, PuraMatrix, and sandwiched under a coverslip to reproduce the in vivo environment, including the three-dimensional extracellular matrix, low-oxygen conditions, and exposure to concentrated paracrine factors. We examined the effects of varying PuraMatrix concentrations, the timing and presence or absence of a coverslip, the timing of neuronal isolation from embryos, cell density at plating, medium components, and changing the medium or not on parameters such as developmental pattern, cell viability, neuronal ratio, and neurite length. Using our method of combining the sandwich culture technique with PuraMatrix in Neurobasal medium/B27/L-glutamine for primary neuron culture, we achieved longer neurites (>=3,000 um), greater cell viability (>=30%) for 2 months, and uniform culture across the wells. We also achieved an average neuronal ratio of 97%, showing a nearly pure culture of neurons without astrocytes. Our method is considerably better than techniques for the primary culture of neurons, and eliminates the need for a glial feeder layer. It also exhibits continued support for axonal elongation and synaptic activity for long periods (>6 weeks). PMID- 25032835 TI - Screening for cardiovascular risk in asymptomatic users of the primary health care network in Lebanon, 2012-2013. AB - INTRODUCTION: In 2012, the Ministry of Public Health in Lebanon piloted a service of multifactorial cardiovascular screening in the publicly subsidized Primary Health Care (PHC) Network. We present an epidemiological analysis of data produced during this pilot to justify the inclusion of this service in the package of essential services offered through PHC and to present a preliminary cardiovascular risk profile in an asymptomatic population. METHODS: A total of 4,205 participants (two-thirds of which were women) aged at least 40 years and reportedly free from diabetes, hypertension, dyslipidemia, and cardiovascular disease (CVD) were screened. The screening protocol used a questionnaire and direct measurements to assess 5 modifiable cardiovascular risk factors; total cardiovascular risk score was calculated according to a paper-based algorithm developed by the World Health Organization and the International Society of Hypertension. RESULTS: Approximately 25% of the sample displayed metabolic impairments (11% for impaired blood glucose metabolism and 17% for impaired systolic blood pressure), and 6.6% were classified at total cardiovascular risk of 10% or more. Just over one-quarter of the sample was obese, almost half had a substantially elevated waist circumference, and 41% were smokers. Men were significantly more likely to screen positive for metabolic impairment than women, and women were more likely to be obese. CONCLUSION: The implementation of a multifactorial screening for CVD among asymptomatic subjects detected a substantial proportion of previously undiagnosed cases of high metabolic risk, people who could now be referred to optimal medical follow-up. PMID- 25032836 TI - Association between contraceptive use and gestational diabetes: Missouri Pregnancy Risk Assessment Monitoring System, 2007-2008. AB - INTRODUCTION: The efficacy and safety of contraceptives have been questioned for decades; however, whether a relationship exists between hormonal contraceptives and gestational diabetes (GDM) is undetermined. The aim of this study was to investigate whether maternal risk for GDM was influenced by type of contraceptive method used before pregnancy. METHODS: Data collected in 2007 and 2008 by the Missouri Pregnancy Risk Assessment Monitoring System (PRAMS) were analyzed to determine if type of contraception before pregnancy influenced maternal risk for GDM. We used a logistic regression model to determine the adjusted odds for GDM given exposure to hormonal forms of contraception. RESULTS: Of the 2,741 women who completed the 2007-2008 PRAMS survey, 8.3% were diagnosed with gestational diabetes, and 17.9% of the respondents had used hormonal contraceptive methods. Women who used hormonal methods of birth control had higher odds for gestational diabetes (adjusted odds ratio [AOR] = 1.43; 95% confidence interval [CI], 1.32 1.55) than did women who used no contraception. A protective effect was also observed for women who had used barrier methods of contraception (AOR = 0.79; 95% CI, 0.72-0.86). CONCLUSION: Findings suggest there may be a relationship between type of contraceptive method and GDM. More research is needed to verify contraception as a potential risk factor for GDM. PMID- 25032837 TI - Impact of San Francisco's toy ordinance on restaurants and children's food purchases, 2011-2012. AB - INTRODUCTION: In 2011, San Francisco passed the first citywide ordinance to improve the nutritional standards of children's meals sold at restaurants by preventing the giving away of free toys or other incentives with meals unless nutritional criteria were met. This study examined the impact of the Healthy Food Incentives Ordinance at ordinance-affected restaurants on restaurant response (eg, toy-distribution practices, change in children's menus), and the energy and nutrient content of all orders and children's-meal-only orders purchased for children aged 0 through 12 years. METHODS: Restaurant responses were examined from January 2010 through March 2012. Parent-caregiver/child dyads (n = 762) who were restaurant customers were surveyed at 2 points before and 1 seasonally matched point after ordinance enactment at Chain A and B restaurants (n = 30) in 2011 and 2012. RESULTS: Both restaurant chains responded to the ordinance by selling toys separately from children's meals, but neither changed their menus to meet ordinance-specified nutrition criteria. Among children for whom children's meals were purchased, significant decreases in kilocalories, sodium, and fat per order were likely due to changes in children's side dishes and beverages at Chain A. CONCLUSION: Although the changes at Chain A did not appear to be directly in response to the ordinance, the transition to a more healthful beverage and default side dish was consistent with the intent of the ordinance. Study results underscore the importance of policy wording, support the concept that more healthful defaults may be a powerful approach for improving dietary intake, and suggest that public policies may contribute to positive restaurant changes. PMID- 25032838 TI - Development of a logic model for a physical activity-based employee wellness program for mass transit workers. AB - Transportation workers, who constitute a large sector of the workforce, have worksite factors that harm their health. Worksite wellness programs must target this at-risk population. Although physical activity is often a component of worksite wellness logic models, we consider it the cornerstone for improving the health of mass transit employees. Program theory was based on in-person interviews and focus groups of employees. We identified 4 short-term outcome categories, which provided a chain of responses based on the program activities that should lead to the desired end results. This logic model may have significant public health impact, because it can serve as a framework for other US mass transit districts and worksite populations that face similar barriers to wellness, including truck drivers, railroad employees, and pilots. The objective of this article is to discuss the development of a logic model for a physical activity-based mass-transit employee wellness program by describing the target population, program theory, the components of the logic model, and the process of its development. PMID- 25032839 TI - Stability curve prediction of homologous proteins using temperature-dependent statistical potentials. AB - The unraveling and control of protein stability at different temperatures is a fundamental problem in biophysics that is substantially far from being quantitatively and accurately solved, as it requires a precise knowledge of the temperature dependence of amino acid interactions. In this paper we attempt to gain insight into the thermal stability of proteins by designing a tool to predict the full stability curve as a function of the temperature for a set of 45 proteins belonging to 11 homologous families, given their sequence and structure, as well as the melting temperature (Tm) and the change in heat capacity (DeltaCP) of proteins belonging to the same family. Stability curves constitute a fundamental instrument to analyze in detail the thermal stability and its relation to the thermodynamic stability, and to estimate the enthalpic and entropic contributions to the folding free energy. In summary, our approach for predicting the protein stability curves relies on temperature-dependent statistical potentials derived from three datasets of protein structures with targeted thermal stability properties. Using these potentials, the folding free energies (DeltaG) at three different temperatures were computed for each protein. The Gibbs-Helmholtz equation was then used to predict the protein's stability curve as the curve that best fits these three points. The results are quite encouraging: the standard deviations between the experimental and predicted Tm's, DeltaCP's and folding free energies at room temperature (DeltaG25) are equal to 13 degrees C, 1.3 kcal/(mol degrees C) and 4.1 kcal/mol, respectively, in cross validation. The main sources of error and some further improvements and perspectives are briefly discussed. PMID- 25032840 TI - Passive smoking is associated with lower age at menopause. AB - OBJECTIVE: The aim of the study was to investigate the age at menopause in women exposed to passive smoking. METHODS: The study was designed as a case-control study. The main outcome measure was to compare the age at menopause of women exposed to second-hand smoking to non-exposed women. RESULTS: The age at menopause in the group exposed to second-hand smoking was significantly lower than that of women in the non-exposed group (47.0 +/- 4.7 vs. 48.1 +/- 5.2 years, p = 0.002). In regression analyses, the age at menopause had an inverse correlation with second-hand smoking, and a positive correlation with the mother's age at menopause. We further stratified women according to their smoking status. Women exposed to second-hand smoking who had never smoked had a significantly lower age at menopause than the non-exposed women only when the duration of exposure exceeded 20 years (46.6 +/- 5.6 vs. 48.4 +/- 3.7 years, p = 0.008). Furthermore, women who had never smoked and who were exposed to >= 10 cigarettes per day had a significantly lower mean age at menopause than non exposed women who had never smoked. These differences were not observed among women who had ever smoked. CONCLUSIONS: Our findings suggest that earlier age at menopause should be added to the negative effects of passive smoking, in addition to increased risks for overall, cardiovascular and cancer mortality as well as increased risk for osteoporosis. PMID- 25032841 TI - Genetic variation associated with differential educational attainment in adults has anticipated associations with school performance in children. AB - Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10(-10)) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79*10(-04) and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment. PMID- 25032842 TI - Oxygen transport and stem cell aggregation in stirred-suspension bioreactor cultures. AB - Stirred-suspension bioreactors are a promising modality for large-scale culture of 3D aggregates of pluripotent stem cells and their progeny. Yet, cells within these clusters experience limitations in the transfer of factors and particularly O2 which is characterized by low solubility in aqueous media. Cultured stem cells under different O2 levels may exhibit significantly different proliferation, viability and differentiation potential. Here, a transient diffusion-reaction model was built encompassing the size distribution and ultrastructural characteristics of embryonic stem cell (ESC) aggregates. The model was coupled to experimental data from bioreactor and static cultures for extracting the effective diffusivity and kinetics of consumption of O2 within mouse (mESC) and human ESC (hESC) clusters. Under agitation, mESC aggregates exhibited a higher maximum consumption rate than hESC aggregates. Moreover, the reaction-diffusion model was integrated with a population balance equation (PBE) for the temporal distribution of ESC clusters changing due to aggregation and cell proliferation. Hypoxia was found to be negligible for ESCs with a smaller radius than 100 um but became appreciable for aggregates larger than 300 um. The integrated model not only captured the O2 profile both in the bioreactor bulk and inside ESC aggregates but also led to the calculation of the duration that fractions of cells experience a certain range of O2 concentrations. The approach described in this study can be employed for gaining a deeper understanding of the effects of O2 on the physiology of stem cells organized in 3D structures. Such frameworks can be extended to encompass the spatial and temporal availability of nutrients and differentiation factors and facilitate the design and control of relevant bioprocesses for the production of stem cell therapeutics. PMID- 25032843 TI - Diurnal profiles of melatonin synthesis-related indoles, catecholamines and their metabolites in the duck pineal organ. AB - This study characterizes the diurnal profiles of ten melatonin synthesis-related indoles, the quantitative relations between these compounds, and daily variations in the contents of catecholamines and their metabolites in the domestic duck pineal organ. Fourteen-week-old birds, which were reared under a 12L:12D cycle, were killed at two-hour intervals. The indole contents were measured using HPLC with fluorescence detection, whereas the levels of catecholamines and their metabolites were measured using HPLC with electrochemical detection. All indole contents, except for tryptophan, showed significant diurnal variations. The 5 hydroxytryptophan level was approximately two-fold higher during the scotophase than during the photophase. The serotonin content increased during the first half of the photophase, remained elevated for approximately 10 h and then rapidly decreased in the middle of the scotophase. N-acetylserotonin showed the most prominent changes, with a more than 15-fold increase at night. The melatonin cycle demonstrated only an approximately 5-fold difference between the peak and nadir. The 5-methoxytryptamine content was markedly elevated during the scotophase. The 5-hydroxyindole acetic acid, 5-hydroxytryptophol, 5-methoxyindole acetic acid and 5-methoxytryptophol profiles were analogous to the serotonin rhythm. The norepinephrine and dopamine contents showed no significant changes. The DOPA, DOPAC and homovanillic acid levels were higher during the scotophase than during the photophase. Vanillylmandelic acid showed the opposite rhythm, with an elevated level during the daytime. PMID- 25032845 TI - Sample size determination for equivalence assessment with multiple endpoints. AB - Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints. PMID- 25032844 TI - Alzheimer's disease--a panorama glimpse. AB - The single-mutation of genes associated with Alzheimer's disease (AD) increases the production of Abeta peptides. An elevated concentration of Abeta peptides is prone to aggregation into oligomers and further deposition as plaque. Abeta plaques and neurofibrillary tangles are two hallmarks of AD. In this review, we provide a broad overview of the diverses sources that could lead to AD, which include genetic origins, Abeta peptides and tau protein. We shall discuss on tau protein and tau accumulation, which result in neurofibrillary tangles. We detail the mechanisms of Abeta aggregation, fibril formation and its polymorphism. We then show the possible links between Abeta and tau pathology. Furthermore, we summarize the structural data of Abeta and its precursor protein obtained via Nuclear Magnetic Resonance (NMR) or X-ray crystallography. At the end, we go through the C-terminal and N-terminal truncated Abeta variants. We wish to draw reader's attention to two predominant and toxic Abeta species, namely Abeta4-42 and pyroglutamate amyloid-beta peptides, which have been neglected for more than a decade and may be crucial in Abeta pathogenesis due to their dominant presence in the AD brain. PMID- 25032846 TI - CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2. AB - Apoptosis-stimulating protein of p53-2 (ASPP2) induces apoptosis by promoting the expression of pro-apoptotic genes via binding to p53 or p73; however, the exact mechanisms by which ASPP2 induces apoptotic death in hepatoma cells are still unclear. Here, we show that the transient overexpression of ASPP2 induces autophagic apoptosis in hepatoma cells by promoting p53- or p73-independent C/EBP homologous protein (CHOP) expression. CHOP expression decreases the expression of Bcl-2; this change releases Beclin-1 from cytoplasmic Bcl-2-Beclin-1 complexes and allows it to initiate autophagy. However, transient overexpression of Beclin 1 can induce autophagy but not apoptosis. Our results show that ASPP2 induces the expression of damage-regulated autophagy modulator (DRAM), another critical factor that cooperates with free Beclin-1 to induce autophagic apoptosis. The effect of CHOP on the translocation and sequestration of Bcl-2 in the nucleus, which requires the binding of Bcl-2 to ASPP2, is also critical for ASPP2-induced autophagic apoptosis. Although the role of nuclear ASPP2-Bcl-2 complexes is still unclear, our results suggest that nuclear ASPP2 can prevent the translocation of the remaining Bcl-2 to the cytoplasm by binding to Bcl-2 in a CHOP-dependent manner, and this effect also contributes to Beclin-1-initiated autophagy. Thus, CHOP is critical for mediating ASPP2-induced autophagic apoptosis by decreasing Bcl-2 expression and maintaining nuclear ASPP2-Bcl-2 complexes. Our results, which define a mechanism whereby ASPP2 overexpression induces autophagic apoptosis, open a new avenue for promoting autophagy in treatments to cure hepatocellular carcinoma. PMID- 25032847 TI - Integrative epigenome analysis identifies a Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in colorectal cancer. AB - Aberrant DNA hypermethylation in human cancer has been associated with Polycomb target genes in embryonic stem (ES) cells, but a functional link of the Polycomb targeted differentiation program to tumorigenesis remains to be established. Here, through epigenome analysis correlating DNA hypermethylation in colon cancer with ES cell pluripotency and differentiation, we identified a set of DNA hypermethylated genes in cancer cells that are Polycomb targets strongly associated with ES cell differentiation, including HAND1, a developmental regulator. Intriguingly, HAND1 is silenced in over 90% of human primary colorectal tumors, and re-expression of HAND1 in colon cancer cells induces terminal differentiation, inhibits proliferation and prevents xenograft tumor formation. Moreover, hypermethylated HAND1 has a minimum enrichment of EZH2 H3K27me3 in cancer cells, but becomes EZH2 bound and bivalent upon the loss of DNA methylation, suggesting a sequential gene silencing event during oncogenesis. These findings established a functional role of Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in human cancer. PMID- 25032849 TI - Caveolin-1 is required for TGF-beta-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17. AB - Transforming growth factor-beta (TGF-beta) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-beta in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-beta receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-beta-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1(-/-) hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-beta, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-beta-induced survival signals in Cav1(-/-) hepatocytes, such as AKT and ERK1/2 phosphorylation and NFkappa-B activation. Transactivation of the EGFR pathway by TGF-beta was impaired in Cav1(-/-) hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1(-/-) hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1(+/+) cells, which was not the case in Cav1(-/-) cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-beta treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-beta-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-beta pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-beta in liver cancer cells. PMID- 25032850 TI - MicroRNA-34a: a potential therapeutic target in human cancer. AB - MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression by binding to the three untranslated regions of their target mRNAs. Deregulations of miRs were shown to play pivotal roles in tumorigenesis and progression. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the therapeutic outcome of patients with cancer. MiR-34a is a highly conserved miR throughout many different species. In humans, there are three homologs (hsa-miR34a, hsa-miR-34b and hsa-miR 34c). Early studies have shown that miR-34a acts as a tumor-suppressor gene by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-34a, including regulating its expression, its known functions in cancer and future challenges as a potential therapeutic target in human cancers. PMID- 25032848 TI - Small molecules, big effects: the role of microRNAs in regulation of cardiomyocyte death. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranscriptional regulation of gene expression, and exerting regulatory roles in plethora of biological processes. In recent years, miRNAs have received increased attention for their crucial role in health and disease, including in cardiovascular disease. This review summarizes the role of miRNAs in regulation of cardiac cell death/cell survival pathways, including apoptosis, autophagy and necrosis. It is envisaged that these miRNAs may explain the mechanisms behind the pathogenesis of many cardiac diseases, and, most importantly, may provide new avenues for therapeutic intervention that will limit cardiomyocyte cell death before it irreversibly affects cardiac function. Through an in-depth literature analysis coupled with integrative bioinformatics (pathway and synergy analysis), we dissect here the landscape of complex relationships between the apoptosis regulating miRNAs in the context of cardiomyocyte cell death (including regulation of autophagy-apoptosis cross talk), and examine the gaps in our current understanding that will guide future investigations. PMID- 25032851 TI - Autophagy and mitochondrial alterations in human retinal pigment epithelial cells induced by ethanol: implications of 4-hydroxy-nonenal. AB - Retinal pigment epithelium has a crucial role in the physiology and pathophysiology of the retina due to its location and metabolism. Oxidative damage has been demonstrated as a pathogenic mechanism in several retinal diseases, and reactive oxygen species are certainly important by-products of ethanol (EtOH) metabolism. Autophagy has been shown to exert a protective effect in different cellular and animal models. Thus, in our model, EtOH treatment increases autophagy flux, in a concentration-dependent manner. Mitochondrial morphology seems to be clearly altered under EtOH exposure, leading to an apparent increase in mitochondrial fission. An increase in 2',7' dichlorofluorescein fluorescence and accumulation of lipid peroxidation products, such as 4-hydroxy-nonenal (4-HNE), among others were confirmed. The characterization of these structures confirmed their nature as aggresomes. Hence, autophagy seems to have a cytoprotective role in ARPE-19 cells under EtOH damage, by degrading fragmented mitochondria and 4-HNE aggresomes. Herein, we describe the central implication of autophagy in human retinal pigment epithelial cells upon oxidative stress induced by EtOH, with possible implications for other conditions and diseases. PMID- 25032853 TI - Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis. AB - Intestinal ischemia has a high mortality and often causes acute lung injury (ALI), which is a serious complication, and is accompanied by high mortality up to 40%. An intense local and systemic inflammation occurs during intestinal ischemia/reperfusion (IR)-induced lung injury resulting from activation of immune responses. It has been reported that one component of complement, C5a, is indispensable for the full development of IR-induced lung injury, whereas the detailed molecular mechanism remains to be elucidated. In this study, we found that intestinal IR induced ALI-like symptoms, and C5a receptor (C5aR) expression was upregulated in alveolar macrophages, which are resident macrophages in lung tissue and are important in pulmonary homeostasis. C5a produced during lung injury binds to C5aR in alveolar macrophages, initiates downstream signaling that promotes autophagy, leading to apoptosis of alveolar macrophages. Using Mphi ATG5(-/-) mice, in which the atg5 is deficient specifically in macrophages and autophagy is inhibited, we confirmed that in vivo C5a interacting with C5aR induced autophagy in alveolar macrophages, which promoted alveolar macrophage apoptosis. Further study indicated that autophagy was induced through C5aR mediated degradation of bcl-2. Taken together, our results demonstrated that C5aR mediated autophagy induced apoptosis in alveolar macrophages, disrupting pulmonary homeostasis and contributing to the development of ALI. This novel mechanism suggests new therapeutic potential of autophagy regulation in ALI. PMID- 25032854 TI - Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype. AB - TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved in the induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement of damaged areas and prominent inflammation. As ischemic preconditioning reduces inflammatory response to brain ischemia and ameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in stroke and ischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achieve this aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middle cerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia was preceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that the neuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors and downregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animals resulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on the mechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new molecular targets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the death receptors, or to activate the decoy receptors open new perspectives for the treatment of stroke. PMID- 25032855 TI - Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor. AB - We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell's responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig 1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress. PMID- 25032856 TI - Renin-angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma. AB - Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). In the present study, we found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) are increased in RGCs and retinal Muller glia in EAAC1-deficient (KO) mice. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions in the EAAC1 KO mouse retina. Sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with candesartan was effective for RGC protection in EAAC1 KO mice without affecting IOP. In cultured Muller glia, candesartan suppressed LPS-induced iNOS production by inhibiting the TLR4-apoptosis signal-regulating kinase 1 pathway. These results suggest that the renin-angiotensin system is involved in the innate immune responses in both neural and glial cells, which accelerate neural cell death. Our findings raise intriguing possibilities for the management of glaucoma by utilizing widely prescribed drugs for the treatment of high blood pressure, in combination with conventional treatments to lower IOP. PMID- 25032857 TI - Zinc finger protein 637 protects cells against oxidative stress-induced premature senescence by mTERT-mediated telomerase activity and telomere maintenance. AB - Oxidative stress is believed to be an important inducer of cellular senescence and aging. Zinc finger protein 637 (Zfp637), which belongs to the Kruppel-like protein family, has been hypothesized to play a role in oxidative stress. Nevertheless, the precise function of Zfp637 has seldom been reported, and it remains unclear whether Zfp637 is involved in oxidative stress-induced premature senescence. In this study, we show that the endogenous expression levels of Zfp637 and mouse telomerase reverse transcriptase (mTERT) are downregulated during oxidative stress-induced premature senescence and in senescent tissues from naturally aged mice. The overexpression of Zfp637 markedly increases mTERT expression and telomerase activity, maintains telomere length, and inhibits both H2O2 and D-galactose-induced senescence accompanied by a reduction in the production of reactive oxygen species (ROS). In contrast, the knockdown of Zfp637 significantly aggravates cellular senescence by downregulating mTERT and telomerase activity, accelerating telomere shortening, and increasing ROS accumulation. In addition, the protective effect of Zfp637 against premature senescence is abrogated in the absence of mTERT. We further confirm that Zfp637 binds to and transactivates the mTERT promoter (-535/-502) specifically. As a result, the mTERT-mediated telomerase activity and telomere maintenance are responsible for the protective effect of Zfp637 against oxidative stress-induced senescence. We therefore propose that Zfp637 prevents oxidative stress-induced premature senescence in an mTERT-dependent manner, and these results provide a new foundation for the investigation of cellular senescence and aging. PMID- 25032858 TI - miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition. AB - Recently, the role of miR-29b in colorectal carcinoma (CRC) development appears to be controversial. Until now, the expression and function of miR-29b in CRC have not been clarified clearly. We showed that decreased expression of miR-29b usually occurred in CRC cell lines and tissue samples. Loss- and gain-of-function assays in vitro revealed suppressive effects of miR-29b on cell proliferation and migration. Endogenous overexpression of miR-29b was sufficient to suppress aggressive behavioral phenotypes in mice. Proteomic analysis showed that miR-29b involved in integrate several key biological processes. In addition, miR-29b mediated the inhibition of epithelial-mesenchymal transition (EMT) and the inactivation of mitogen-activated protein kinase and phosphatidylinositol-4,5 bisphosphate 3-kinase/AKT signal transduction pathway. Further studies found that T lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct target of miR-29b. In contrast to the phenotypes induced by miR-29b restoration, Tiam1 induced cell proliferation and migration partly rescued miR-29b-mediated biological behaviors. Our results illustrated that miR-29b as a suppressor has a critical role in CRC progression, which suggests its potential role in the molecular therapy of patients with advanced CRC. PMID- 25032859 TI - Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2 deoxyglucose treatment. AB - A number of studies suggest that cancer stem cells are essential for tumour growth, and failure to target these cells can result in tumour relapse. As this population of cells has been shown to be resistant to radiation and chemotherapy, it is essential to understand their biology and identify new therapeutic approaches. Targeting cancer metabolism is a potential alternative strategy to counteract tumour growth and recurrence. Here we applied a proteomic and targeted metabolomic analysis in order to point out the main metabolic differences between breast cancer cells grown as spheres and thus enriched in cancer stem cells were compared with the same cells grown in adherent differentiating conditions. This integrated approach allowed us to identify a metabolic phenotype associated with the stem-like condition and shows that breast cancer stem cells (BCSCs) shift from mitochondrial oxidative phosphorylation towards fermentative glycolysis. Functional validation of proteomic and metabolic data provide evidences for increased activities of key enzymes of anaerobic glucose fate such as pyruvate kinase M2 isoform, lactate dehydrogenase and glucose 6-phopshate dehydrogenase in cancer stem cells as well as different redox status. Moreover, we show that treatment with 2-deoxyglucose, a well known inhibitor of glycolysis, inhibits BCSC proliferation when used alone and shows a synergic effect when used in combination with doxorubicin. In conclusion, we suggest that inhibition of glycolysis may be a potentially effective strategy to target BCSCs. PMID- 25032860 TI - 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. AB - The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP and anabolic substrates at distinct phases of the cell cycle. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of 6-phosphofructo-1-kinase (Pfk-1). PFKFB3 is overexpressed in human cancers, regulated by HIF-1alpha, Akt and PTEN, and required for the survival and growth of multiple cancer types. Although most functional studies of the role of PFKFB3 in cancer progression have invoked its well-recognized function in the regulation of glycolysis, recent observations have established that PFKFB3 also traffics to the nucleus and that its product, F2,6BP, activates cyclin-dependent kinases (Cdks). In particular, F2,6BP stimulates the Cdk-mediated phosphorylation of the Cip/Kip protein p27 (threonine 187), which in turn results in p27's ubiquitination and proteasomal degradation. As p27 is a potent suppressor of the G1/S transition and activator of apoptosis, we hypothesized that the known requirement of PFKFB3 for cell cycle progression and prevention of apoptosis may be partly due to the ability of F2,6BP to activate Cdks. In this study, we demonstrate that siRNA silencing of endogenous PFKFB3 inhibits Cdk1 activity, which in turn stabilizes p27 protein levels causing cell cycle arrest at G1/S and increased apoptosis in HeLa cells. Importantly, we demonstrate that the increase in apoptosis and suppression of the G1/S transition caused by siRNA silencing of PFKFB3 expression is reversed by co-siRNA silencing of p27. Taken together with prior publications, these observations support a model whereby PFKFB3 and F2,6BP function not only as regulators of Pfk-1 but also of Cdk1 activity, and therefore serve to couple glucose metabolism with cell proliferation and survival in transformed cells. PMID- 25032861 TI - The androgen receptor mediates antiapoptotic function in myometrial cells. AB - During pregnancy, myometrial phenotype is programmed into three characteristic stages referred to as the early proliferative, the midterm hypertrophic, and the late contractile stage. Increased myometrial growth in the early and midterm of pregnancy involves a complex process of cell proliferation, antiapoptosis and differentiation. We have previously demonstrated that the androgen receptor (AR) is required for myometrial cell proliferation by modulating IGF-1 signaling during early pregnancy. Here, we report that AR also exerts its antiapoptotic function in human myometrial cells. Enhanced AR expression protects, whereas AR silencing sensitizes myometrial cells to both intrinsic and extrinsic apoptotic stimuli. AR agonist inhibits, whereas AR antagonist induces myometrial cells to undergo apoptotic cell death. Gene microarray analysis confirms that the central functions of AR in myometrial cells are to regulate cell cycling and apoptosis through three major gene groups involving the epidermal growth factor (EGF) signaling, RNA splicing and DNA repair processes. AR mediates its antiapoptotic function through two distinct pathways. In the receptor-dependent pathway, AR is required for the expression of several protein factors within the EGF signaling pathway. Through the PI3K/Akt pathway, AR enhances the expression of the antiapoptotic protein Mcl-1. In the ligand-dependent pathway, AR agonist triggers the activation of Src kinase, which in turn phosphorylates STAT3 to increase Mcl 1 expression. We conclude from these results that the AR signaling exerts antiapoptotic function in myometrial cells, further supporting its key role in programming of myometrial phenotype. PMID- 25032862 TI - ATG5 can regulate p53 expression and activation. PMID- 25032863 TI - Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide induced cell death. AB - The promyelocytic leukemia protein (PML) is a tumor suppressor that is expressed at a low level in various cancers. Although post-translational modifications including SUMOylation, phosphorylation, and ubiquitination have been found to regulate the stability or activity of PML, little is known about the role of its acetylation in the control of cell survival. Here we demonstrate that acetylation of lysine 487 (K487) and SUMO1 conjugation of K490 at PML protein are mutually exclusive. We found that hydrogen peroxide (H2O2) promotes PML deacetylation and identified SIRT1 and SIRT5 as PML deacetylases. Both SIRT1 and SIRT5 are required for H2O2-mediated deacetylation of PML and accumulation of nuclear PML protein in HeLa cells. Knockdown of SIRT1 reduces the number of H2O2-induced PML-nuclear bodies (NBs) and increases the survival of HeLa cells. Ectopic expression of wild type PML but not the K487R mutant rescues H2O2-induced cell death in SIRT1 knockdown cells. Furthermore, ectopic expression of wild-type SIRT5 but not a catalytic defective mutant can also restore H2O2-induced cell death in SIRT1 knockdown cells. Taken together, our findings reveal a novel regulatory mechanism in which SIRT1/SIRT5-mediated PML deacetylation plays a role in the regulation of cancer cell survival. PMID- 25032864 TI - Brimonidine prevents neurodegeneration in a mouse model of normal tension glaucoma. AB - Glaucoma is one of the leading causes of irreversible blindness that is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino-acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). Brimonidine (BMD) is an alpha2-adrenergic receptor agonist and it is commonly used in a form of eye drops to lower IOP in glaucoma patients. Recent studies have suggested that BMD has direct protective effects on RGCs involving IOP-independent mechanisms, but it is still controversial. In the present study, we examined the effects of BMD in EAAC1-deficient (KO) mice, an animal model of normal tension glaucoma. BMD caused a small decrease in IOP, but sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with BMD was highly effective for RGC protection in EAAC1 KO mice. BMD suppressed the phosphorylation of the N-methyl-D-aspartate receptor 2B (NR2B) subunit in RGCs in EAAC1 KO mice. Furthermore, in cultured Muller glia, BMD stimulated the production of several neurotrophic factors that enhance RGC survival. These results suggest that, in addition to lowering IOP, BMD prevents glaucomatous retinal degeneration by stimulating multiple pathways including glia-neuron interactions. PMID- 25032865 TI - Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency. AB - Loss of ataxia telangiectasia mutated (ATM) kinase, a key factor of the DNA damage response (DDR) pathway, causes the cancer predisposing and neurodegenerative syndrome ataxia-telangiectasia (A-T). To investigate the mechanisms of neurodegeneration, we have reprogrammed fibroblasts from ATM-null A T patients and normal controls to pluripotency (human-induced pluripotent stem cells), and derived from these neural precursor cells able to terminally differentiate into post-mitotic neurons positive to >90% for beta-tubulin III+/microtubule-associated protein 2+. We show that A-T neurons display similar voltage-gated potassium and sodium currents and discharges of action potentials as control neurons, but defective expression of the maturation and synaptic markers SCG10, SYP and PSD95 (postsynaptic density protein 95). A-T neurons exhibited defective repair of DNA double-strand breaks (DSBs) and repressed phosphorylation of ATM substrates (e.g., gammaH2AX, Smc1-S966, Kap1-S824, Chk2 T68, p53-S15), but normal repair of single-strand breaks, and normal short- and long-patch base excision repair activities. Moreover, A-T neurons were resistant to apoptosis induced by the genotoxic agents camptothecin and trabectedin, but as sensitive as controls to the oxidative agents. Most notably, A-T neurons exhibited abnormal accumulation of topoisomerase 1-DNA covalent complexes (Top1 ccs). These findings reveal that ATM deficiency impairs neuronal maturation, suppresses the response and repair of DNA DSBs, and enhances Top1-cc accumulation. Top1-cc could be a risk factor for neurodegeneration as they may interfere with transcription elongation and promote transcriptional decline. PMID- 25032866 TI - Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis. PMID- 25032868 TI - Bone marrow-derived clonal mesenchymal stem cells inhibit ovalbumin-induced atopic dermatitis. AB - Mesenchymal stem cells (MSCs) possess immunomodulatory activities, including suppression of T- and B-cell activation. However, their effects on atopic dermatitis (AD) have not yet been studied. Using an ovalbumin-induced AD mouse model, we investigated whether MSCs can be used as therapeutics in AD. We isolated both allogeneic and syngeneic clonal MSCs (cMSCs) from mouse bone marrow according to the subfractionation culturing method. Our cMSCs suppressed both T- and B-cell activation. T-cell proliferation and cytokine production, including interferon (IFN)-gamma and interleukin (IL)-4, were suppressed by inhibition of transcription factors, such as T-bet, GATA-3, and c-Maf. Those transcription factors were nitric oxide dependent. Immunoglobulin E (IgE) suppression occurred through downregulation of AID and BLIMP-1, important regulators for isotype class switch and B-cell differentiation. The cMSCs were injected intravenously into ovalbumin-induced AD mouse model, and the therapeutic effects were analyzed. Injection of both allogeneic and syngeneic cMSCs in an AD mouse model inhibited cell infiltration in skin lesions and decreased the serum level of IgE. IL-4 expression was also suppressed by cMSCs in both the lymph node and skin. The cMSCs migrated to skin lesions and draining lymph nodes. Taken together, these data demonstrated that cMSCs, which suppressed T- and B-cell functions, can be used for the treatment of AD in mice. PMID- 25032869 TI - FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway. AB - Ovarian cancer (OC) can be classified into five biologically distinct molecular subgroups: epithelial-A (Epi-A), Epi-B, mesenchymal (Mes), Stem-A and Stem-B. Among them, Stem-A expresses genes relating to stemness and is correlated with poor clinical prognosis. In this study, we show that frizzled family receptor 7 (FZD7), a receptor for Wnt signalling, is overexpressed in the Stem-A subgroup. To elucidate the functional roles of FZD7, we used an RNA interference gene knockdown approach in three Stem-A cell lines: CH1, PA1 and OV-17R. Si-FZD7 OC cells showed reduced cell proliferation with an increase in the G0/G1 sub population, with no effect on apoptosis. The cells also displayed a distinctive morphologic change by colony compaction to become more epithelial-like and polarised with smaller internuclear distances and increased z-axis height. Immunofluorescence (IF) staining patterns of pan-cadherin and beta-catenin suggested an increase in cadherin-based cell-cell adhesion in si-FZD7 cells. We also observed a significant rearrangement in the actin cytoskeleton and an increase in tensile contractility in si-FZD7 OC cells, as evident by the loss of stress fibres and the redistribution of phospho-myosin light chain (pMLC) from the sites of cell-cell contacts to the periphery of cell colonies. Furthermore, there was reciprocal regulation of RhoA (Ras homolog family member A) and Rac1 (Ras-related C3 botulinum toxin substrate 1 (Rho family, small GTP-binding protein Rac1)) activities upon FZD7 knockdown, with a significant reduction in RhoA activity and a concomitant upregulation in Rac1 activity. These changes in pMLC and RhoA, as well as the increased TopFlash reporter activities in si-FZD7 cells, suggested involvement of the non-canonical Wnt/planar cell polarity (PCP) pathway. Selected PCP pathway genes (cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3), prickle homolog 4 (Drosophila) (PRICKLE4), dishevelled-associated activator of morphogenesis 1 (DAAM1), profilin 2 (PFN2), protocadherin 9 (PCDH9), protocadherin alpha1 (PCDHA1), protocadherin beta17 pseudogene (PCDHB17), protocadherin beta3 (PCDHB3), sprouty homolog 1 (SPRY1) and protein tyrosine kinase 7 (PTK7)) were found to be more highly expressed in Stem-A than non Stem-A subgroup of OC. Taken together, our results suggest that FZD7 might drive aggressiveness in Stem-A OC by regulating cell proliferation, cell cycle progression, maintenance of the Mes phenotype and cell migration via casein kinase 1E-mediated non-canonical Wnt/PCP pathway. PMID- 25032870 TI - The transient expression of miR-203 and its inhibiting effects on skeletal muscle cell proliferation and differentiation. AB - Previous studies have shown that miR-203 is a skin-specific microRNA (miRNA) with a profound role in skin cell differentiation. However, emerging microarray and deep sequencing data revealed that miR-203 is also expressed in embryonic skeletal muscle and myoblasts. In this study, we found that miR-203 was transiently upregulated in chicken embryos on days 10 to 16 (E10-E16) and was sharply downregulated and even not expressed after E16 in chicken embryonic skeletal muscle. Histological profiles and weight variations of embryo skeletal muscle revealed that miR-203 expression is correlated with muscle development. In vitro experiments showed that miR-203 exhibited downregulated expression during myoblast differentiation into myotubes. miR-203 overexpression inhibited myoblast proliferation and differentiation, whereas its loss-of-function increased myoblast proliferation and differentiation. During myogenesis, miR-203 can target and inhibit the expression of c-JUN and MEF2C, which were important for cell proliferation and muscle development, respectively. The overexpression of c-JUN significantly promoted myoblast proliferation. Conversely, knockdown of c-JUN by siRNA suppressed myoblast proliferation. In addition, the knockdown of MEF2C by siRNA significantly inhibited myoblast differentiation. Altogether, these data not only suggested that the expression of miR-203 is transitory during chicken skeletal muscle development but also showed a novel role of miR-203 in inhibiting skeletal muscle cell proliferation and differentiation by repressing c-JUN and MEF2C, respectively. PMID- 25032871 TI - Time to reconsider transplant criteria for candidacy? Lung transplantation feasibility in HIV-infected patients. PMID- 25032873 TI - A cagey diagnosis. PMID- 25032872 TI - Pneumococcal vaccines: understanding centers for disease control and prevention recommendations. AB - Streptococcus pneumoniae infection is a common and serious health problem that is best prevented by the pneumococcal vaccine. The first vaccine approved by the U.S. Federal Drug Administration in 1977 contained 14 polysaccharide antigens. An improved vaccine introduced in 1983 included 23 polysaccharide antigens. Both vaccines were effective for immunocompetent adults; however, young children and immunocompromised adults remained susceptible. A pediatric vaccine was developed consisting of the capsular antigens of seven pneumococcal serotypes commonly found in children. The antigens in this preparation are covalently conjugated to diphtheria protein to make them more antigenic. The conjugate vaccine was expanded to include 13 serotypes by 2010. Although more immunogenic, the conjugate vaccine has fewer serotypes than the older 23-valent vaccine. The U.S. Centers for Disease Control and Prevention recommend that children at risk for pneumococcal pneumonia as defined by the presence of chronic disease should receive the 13-valent conjugated vaccine. Adults at risk for pneumococcal pneumonia, which includes those over 65 years of age and those who have a chronic disease, should receive the 23-polysaccharide vaccine. Immunosuppressed patients of any age should receive both vaccines. Adults should be revaccinated once at age 65 years or older with the 23-polysaccharide vaccine provided that at least 5 years have elapsed since the previous vaccination. PMID- 25032874 TI - Tough to ventilate. PMID- 25032875 TI - Extracorporeal life support. PMID- 25032876 TI - Reply: extracorporeal life support. PMID- 25032877 TI - Refractory hypoxemia due to sodium polystyrene sulfonate (kayexalate) aspiration. PMID- 25032878 TI - Severe asthma. PMID- 25032882 TI - Stress, Depression, and Lifestyle Behaviors in Korean Adults: A Latent Means and Multi-Group Analysis on the Korea Health Panel Data. AB - It has been reported that stress can induce depression, with the patient's age and sex as moderating factors. Associations between depression and lifestyle in Korean adults have not been addressed. This study was designed to examine if the relationships among stress, problem drinking, exercise, and depression differ by age and sex. For this study, the Korea health panel data was utilized, and a structural equation model using AMOS was employed. The major findings were as follows: women were more likely to experience stress and depression than men. Individuals over 40 showed a higher tendency toward stress and depression than those under 40. Age- and sex-specific paths from stress to problem drinking, exercise, and depression were positively inter-correlated; the path from exercise to depression indicated an inverse association. These results indicate the need for evidence-based stress-management programs for the psychological well-being of Korean adults. PMID- 25032883 TI - End-stage renal disease with atrial fibrillation: uncharted territory in the modern world of anticoagulants. AB - INTRODUCTION: End-stage renal disease (ESRD) and atrial fibrillation are increasingly common concurrent findings among many patients. Coexisting ESRD and atrial fibrillation can further exacerbate each disease process; thus, evidence based medicine protocols are needed for the treatment of patients with both ESRD and new-onset atrial fibrillation to clarify the appropriate anticoagulant management of such patients. AREAS COVERED: The manuscript surveys the literature to look for a suitable answer to the pressing question that requires development of an evidence-based protocol: 'Which anticoagulant is best for the patient with ESRD and atrial fibrillation?' EXPERT OPINION: Unlike many disease processes that have ample evidence available in order to better manage the patient, in the patient with end-stage kidney disease and new onset of atrial fibrillation, the situation becomes much more complicated. We believe randomized controlled trials for both the classical and the newer oral anticoagulants could provide evidence based medicine protocols for the treatment of patients with ESRD and new-onset atrial fibrillation. PMID- 25032884 TI - Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update. AB - INTRODUCTION: Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. AREAS COVERED: Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. EXPERT OPINION: Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated. PMID- 25032885 TI - Pharmacotherapy for hyperammonemia. AB - INTRODUCTION: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that is seen in patients with liver failure. The pathogenesis of HE is not entirely understood, but several hypotheses have emerged and persisted during the years. Despite the many prevalent hypotheses, most of the existing evidence point to ammonia as the main culprit behind primary and secondary symptoms making it the center of potential therapeutic options for the treatment of HE. Most treatments of hyperammonemia target the organs and metabolic processes involved in ammonia detoxification. AREAS COVERED: This article provides a review of the current targets of therapy as well as the drugs used for hyperammonemia treatment. EXPERT OPINION: Lactulose and rifaximin have a proven role as measures to use for secondary prophylaxis and are the mainstay of current therapy. The use of molecular adsorbent recirculating system in patients with severe HE has been proven to be efficacious, but through mechanisms that appear to be independent of ammonia. The main challenge that faces the further development of treatments for HE is finding appropriate end points, and the next step would be to provide evidence of the effectiveness of established treatments and define the role of emerging new treatments. PMID- 25032886 TI - Efficacy of S-1 in colorectal cancer. AB - INTRODUCTION: S-1 is an oral fluoropyrimidine that consists of tegafur, 5-chloro 2, 4-dihydroxypyridine and potassium oxonate. It has been developed as a prodrug of 5-fluorouracil with the goal of improving therapeutic efficacy and tolerability. AREAS COVERED: This review aims to provide an evidence-based update of clinical trials that have investigated the clinical efficacy, adverse-event profile, dosage and administration of S-1, given alone or in combination with conventional chemotherapeutics and new target-oriented drugs, in the management of colorectal cancer (CRC). Additionally, differences in the tolerability and pharmacokinetics of S-1 between Caucasians and Asians have been described. Finally, the therapeutic efficacy of S-1 regarding metastatic CRC or postoperative CRC has been discussed. Available data have stimulated further research, including Phase III trials for the treatment of advanced CRC. EXPERT OPINION: Treatment using S-1 combined with oxaliplatin (+/- bevacizumab) and irinotecan has achieved promising results in terms of feasibility, safety and effectiveness. Furthermore, S-1 is an acceptable treatment as adjuvant chemotherapy for colon cancer. PMID- 25032887 TI - Efficacy of motesanib diphosphate in non-small-cell lung cancer. AB - INTRODUCTION: Angiogenesis plays a crucial role in the proliferation and in the metastatic spread of tumour cells. Several agents with anti-angiogenic activity have been tested in advanced non-small-cell lung cancer (NSCLC) patients. Motesanib (AMG 706) is a promising anti-angiogenic multi-targeted tyrosine kinase inhibitor (TKI), which has been investigated as a monotherapy or in combination with chemotherapy, in several types of cancer. AREAS COVERED: We have reviewed the literature, and we have presented the results of clinical trials that have investigated the administration of motesanib in advanced NSCLC patients. EXPERT OPINION: Encouraging results have been described with the administration of motesanib as first-line treatment in combination with carboplatin and paclitaxel in Asian patients with non-squamous advanced NSCLC. Further studies are needed in order to identify the predictive biomarkers of response and to select patients who may benefit from this anti-angiogenic treatment. PMID- 25032890 TI - Platelet membrane potential: unable to pull the plug on sepsis. PMID- 25032889 TI - Pathway network inference from gene expression data. AB - BACKGROUND: The development of high-throughput omics technologies enabled genome wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules. RESULTS: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example. CONCLUSIONS: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network's topology obtained for the yeast cell cycle data. PMID- 25032891 TI - Enhanced radiation therapy with internalized polyelectrolyte modified nanoparticles. AB - A challenge of X-ray radiation therapy is that high dose X-ray under therapeutic conditions damages normal cells. This paper describes a nanoparticle-based method to enhance X-ray radiation therapy by delivering radio-sensitizing gold nanoparticles into cancer cells. The nanoparticles have been modified with cationic polyelectrolytes to allow internalization. Upon X-ray irradiation of nanoparticles, more photoelectrons and Auger electrons are generated to cause water ionization, leading to formation of free radicals that damage DNA of cancer cells. The X-ray dose required for DNA damage and cell killing is reduced by delivering gold nanoparticles inside cancer cells. PMID- 25032892 TI - Imaging opens possibilities both to target and to evaluate nutrition in critical illness. PMID- 25032893 TI - Self-assembly of NH2-(alpha,L-lysine)5-COOH and SDS into nanodiscs or nanoribbons regulated by pH. AB - NH2-(alpha,l-lysine)5-COOH and SDS can self-assemble into nanodiscs or nanoribbons. We show that pH can regulate not only the diameter of nanodiscs but also the conversion between nanodiscs and nanoribbons. This system can be used as two different templates for fabricating platinum nanowires and nanodiscs. PMID- 25032894 TI - Alkaline earth metal-based metal-organic framework: hydrothermal synthesis, X-ray structure and heterogeneously catalyzed Claisen-Schmidt reaction. AB - Two alkaline earth metal-based carboxylate systems, [Mg(HL)(H2O)2]n (1) and [Ca(H2L)2]n (2) (H3L = chelidamic acid) have been hydrothermally synthesized, and characterized by single-crystal X-ray diffraction, IR, elemental analysis, and thermo-gravimetric analysis. Compound 1 has a 2D structure incorporating two water molecules. The dehydrated species, 1a, generated from 1 by removal of the coordinated water, has been characterized by thermo-gravimetric analysis, IR, elemental analysis and variable temperature powder X-ray diffraction. Both 1 and its dehydrated species 1a catalyze the Claisen-Schmidt reaction under heterogeneous conditions, but 1a is a more effective catalyst under environmentally friendly conditions. The catalyst can readily be recovered and reused in successive cycles without detectable loss of activity. Compound 2 has a 3D structure and is thermally stable up to 540 degrees C, but is inactive catalytically. PMID- 25032895 TI - Effect of exogenous amylolytic enzymes on the accumulation of chlorogenic acid isomers in wounded potato tubers. AB - Potato tubers under wounding stress synthesize chlorogenic acid isomers, which are phenolic compounds that prevent chronic diseases. The biosynthesis of phenolic compounds in plants requires aromatic amino acids that are produced from sugars. Therefore, in this study, we hypothesized that the wound-induced accumulation of chlorogenic acid isomers in potatoes could be enhanced if the availability of sugars is increased by exogenous amylolytic enzymes applied to the surface of the site of wounding. To test this hypothesis, wounded potatoes stored at 20 degrees C were treated with amylolytic enzymes (pullulanase and amyloglucosidase, 282 units/mL, 10 mL/kg) after being stored for 0 (E0h), 48 (E48h), or 96 h (E96h). The highest level of accumulation of total chlorogenic acid isomers (~210% higher than that of time 0 h samples) was observed after storage for 120 h for the E96h treatment. The results suggest that increasing the availability of carbon sources needed for the biosynthesis of phenolic compounds would trigger their accumulation in wounded plants. PMID- 25032897 TI - Facile and mild synthesis of linear and cyclic peptides via thioesters. AB - Thioester-mediated peptide bond formation has recently garnered a lot of attention, most notably in its relevance to condensation of large peptide fragments. Herein, a simple and general ligation method for the preparation of linear and cyclic peptides, starting from peptide thioester, mainly p chlorophenyl, precursors is reported. The inherent advantages of this method are the low epimerization, reduced dimerization, use of mild reaction conditions, and elimination of superfluous coupling reagents. PMID- 25032896 TI - A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs. AB - A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models. PMID- 25032898 TI - One-pot regioselective synthesis of meta-terphenyls via [3 + 3] annulation of nitroallylic acetates with alkylidenemalononitriles. AB - A highly efficient one-pot method has been developed for the synthesis of meta terphenyls via a regioselective [3 + 3] annulation-elimination sequence involving Morita-Baylis-Hillman (MBH) acetates of nitroalkenes and alkylidenemalononitriles. The reaction takes place in a regioselective manner under mild conditions (Et3N, room temperature) to afford a wide variety of meta terphenyls bearing aryl, heteroaryl and styrenyl groups. This novel [3 + 3] annulation takes advantage of the 1,3-bielectrophilic character of MBH acetates and 1,3-binucleophilic character of alkylidenemalononitriles and proceeds in a cascade fashion comprising an SN2' substitution, intramolecular 6-endo-trig Michael addition and double elimination. Representative synthetic transformations of the products, for instance, to meta-terphenyl derived isoindolinones have also been demonstrated. PMID- 25032899 TI - Influences of peers, teachers, and climate on students' willingness to intervene when witnessing anti-transgender harassment. AB - Transgender young people are at increased risk for bullying, harassment, and negative mental health and academic outcomes compared to the general population as well as compared to other members of lesbian, gay, bisexual, transgender, queer, questioning, and similarly identified (LGBTQQ) communities. To inform interventions to support transgender students, the present study investigates students' willingness to intervene when witnessing anti-transgender harassment, using data collected from a participatory action research project investigating school climate. Multi-step linear regression was used to test the impacts of hearing transphobic language and witnessing teachers and others students intervene, while controlling for demographics and school. Hostile climate negatively predicted intervention intentions while witnessing peer intervention positively predicted likelihood to intervene. Witnessing teacher intervention did not significantly predict the outcome. These findings suggest that youth-led interventions in peer networks might be effective in diminishing transphobic bullying and supporting the healthy development of transgender young people. PMID- 25032900 TI - Combined effect of the body mass index and implant size on the wear of retrieved total knee prostheses. AB - Total Knee Arthroplasty is a well-established surgical procedure performed to relieve pain and to restore function in knee osteoarthritis. A proper choice of the implant size is mandatory in order to guarantee the success of the implant and to respect the bone stock of tibial plateau and femoral condyles. The aim of this study was to investigate the combined effect of Body Mass Index and implant size on the wear damage of retrieved knee implants, a still debated subject. To this purpose, twelve total knee prostheses of the same design (NexGen, Zimmer, Warsaw, Indiana) but with different sizes were investigated. These prostheses were all cemented fixed bearing inserts and posterior stabilised. Roughness analyses were performed on femoral components to assess surface modifications. Micro-Raman spectroscopic characterization was performed on polyethylene inserts to evaluate crystallinity changes. A worsening of the surface and a nonhomogeneous aspect was observed in the prostheses characterized by a high ratio between preoperative Body Mass Index and implant size, which we called F factor. Delamination, a good indicator for polyethylene osteolysis, was more pronounced in the inserts having a high F than in those with a low F. Micro-Raman analyses showed more significant crystallinity changes in the prostheses of lower size, in agreement with the results previously obtained in vitro. The findings of the present study suggested that the F factor can be considered a predictor factor of the Total Knee Arthroplasty overall performance. Potentially, it could be used as a discriminating factor to redact Total Knee Arthroplasty outcome and prevent complications. PMID- 25032901 TI - Exploring the vinylogous reactivity of cyclohexenylidene malononitriles: switchable regioselectivity in the organocatalytic asymmetric addition to enals giving highly enantioenriched carbabicyclic structures. AB - Modulation of the complex reactivity of cyclohexenylidene malononitriles using diverse beta-aryl-substituted enals and proper organocatalytic modalities resulted in divergent asymmetric reaction patterns to furnish angularly fused or bridged carbabicyclic frameworks. In particular, use of remotely enolizable dicyanodienes 1, under one-pot sequential amine/NHC catalysis, led to [3 + 2] cycloaddition to afford epsilon,delta-bonded spiro[4.5]decanone structures 5. Alternatively, modifying the standard amine catalysis by adding a suitable chemical stimulus (p-nitrophenol cocatalyst) switched the reactivity decidedly toward a domino [4 + 2] cycloaddition to afford gamma',delta-bonded bicyclo[2.2.2]octane carbaldehydes 8. Products invariably formed in good yields, with rigorous chemo-, regio-, diastereo-, and enantiocontrol. Experimental evidence, including carbon isotope effects measured by (13)C NMR, were indicative of the rate (and stereochemistry) determining step of these transformations and suggested a stepwise mechanism for the [4 + 2] cycloadditive pathway. PMID- 25032902 TI - Diversity and specificity: auxin perception and signaling through the TIR1/AFB pathway. AB - Auxin is a versatile plant hormone that plays an essential role in most aspects of plant growth and development. Auxin regulates various growth processes by modulating gene transcription through a SCF(TIR1/AFB)-Aux/IAA-ARF nuclear signaling module. Recent work has generated clues as to how multiple layers of regulation of the auxin signaling components may result in diverse and specific response outputs. In particular, interaction and structural studies of key auxin signaling proteins have produced novel insights into the molecular basis of auxin regulated transcription and may lead to a refined auxin signaling model. PMID- 25032904 TI - A novel argument for the Universality of Parsing principles. AB - Previous work on Relative Clause attachment has overlooked a crucial grammatical distinction across both the languages and structures tested: the selective availability of Pseudo Relatives. We reconsider the literature in light of this observation and argue that, all else being equal, local attachment is found with genuine Relative Clauses and that non-local attachment emerges when their surface identical imposters, Pseudo Relatives, are available. Hence, apparent cross linguistic variation in parsing preferences is reducible to grammatical factors. The results from two novel experiments in Italian are presented in support of these conclusions. PMID- 25032903 TI - Interpersonal stressors predict ghrelin and leptin levels in women. AB - OBJECTIVE: Stressful events enhance risk for weight gain and adiposity. Ghrelin and leptin, two hormones that are implicated in appetite regulation, may link stressful events to weight gain; a number of rodent studies suggest that stressors increase ghrelin production. The present study investigated the links among daily stressors, ghrelin and leptin, and dietary intake in humans. METHOD: Women (n=50) completed three study appointments that were scheduled at least 2 weeks apart. At each visit, women arrived fasting and ate a standardized breakfast and lunch. Blood samples were collected 45min after each meal. Women completed a self-report version of the Daily Inventory of Stressful Events (DISE) at each appointment. Two composites were created from the DISE data, reflecting the number of stressors that did and did not involve interpersonal tension. RESULTS: Women who experienced more stressors involving interpersonal tension had higher ghrelin and lower leptin levels than those who experienced fewer interpersonal stressors. Furthermore, women who experienced more interpersonal stressors had a diet that was higher in calories, fat, carbohydrates, protein, sugar, sodium, and fiber, and marginally higher in cholesterol, vegetables (but not fruits), vitamin A, and vitamin C. Stressors that did not involve interpersonal tension were unrelated to ghrelin and leptin levels or any of the dietary components examined. CONCLUSIONS: These data suggest that ghrelin and leptin may link daily interpersonal stressors to weight gain and obesity. PMID- 25032905 TI - Prediction of peptide fragment ion mass spectra by data mining techniques. AB - Accurate prediction of peptide fragment ion mass spectra is one of the critical factors to guarantee confident peptide identification by protein sequence database search in bottom-up proteomics. In an attempt to accurately and comprehensively predict this type of mass spectra, a framework named MS(2)PBPI is proposed. MS(2)PBPI first extracts fragment ions from large-scale MS/MS spectra data sets according to the peptide fragmentation pathways and uses binary trees to divide the obtained bulky data into tens to more than 1000 regions. For each adequate region, stochastic gradient boosting tree regression model is constructed. By constructing hundreds of these models, MS(2)PBPI is able to predict MS/MS spectra for unmodified and modified peptides with reasonable accuracy. Moreover, high consistency between predicted and experimental MS/MS spectra derived from different ion trap instruments with low and high resolving power is achieved. MS(2)PBPI outperforms existing algorithms MassAnalyzer and PeptideART. PMID- 25032906 TI - Diversity in structure and functions of antibody sialylation in the Fc. AB - Terminal sialic acid residues of glycoconjugates exhibit remarkable functional and structural diversity. They affect biological activity, serum half-life and structural stability of glycoproteins. Alternatively, they act as mediators for pathogens to invade host systems. These surface exposed N-glycans are easily accessible for interactions with receptors, enzymes, etc. In contrast, Fc N glycans of IgGs are sequestered within the two CH2 domains and exhibit high degree of heterogeneity. They are required for antibody effector functions including binding to C1q protein. Biological significance of Fc glycans has been extensively studied and importance of terminal galactose, bisecting GlcNAc and core fucose has been realized. This review focuses on the recent advances in structure and functions of terminal sialic acid residues of Fc glycans. PMID- 25032907 TI - Measurement and control of host cell proteins (HCPs) in CHO cell bioprocesses. AB - Chinese hamster ovary (CHO) cells are widely used for the production of biotherapeutic recombinant proteins for a range of molecules including monoclonal antibodies and Fc-fusion proteins. Regulatory requirements for the final product include the removal of host cell proteins (HCPs) to acceptable amounts (<100ppm). Recent research has begun to unravel the extent to which upstream process conditions and subsequent product recovery and purification processes impact upon the HCP profile. A number of upstream parameters, including the selection of the cell line, the culturing process (e.g. feeding regime, culture temperature), cell viability at time of harvest/culture duration and cell shear sensitivity can all influence the resulting HCP profile. Further, the molecule itself plays an important role in determining those HCPs that are retained throughout a bioprocess and HCPs can co-elute with the target product during purification. Measurement and monitoring of HCPs is usually undertaken using ELISA technology, however alternative approaches are also now emerging that complement ELISA and allow the detection, identification and monitoring of specific HCPs. Here we discuss our understanding of how the process itself influences those HCPs present throughout the production process and the challenges in their monitoring, measurement and removal. PMID- 25032909 TI - Small heterocycles in multicomponent reactions. PMID- 25032910 TI - Novel CO2-capture derived from the basic ionic liquids orientated on mesoporous materials. AB - Two new basic ionic liquids (ILs) are designed and synthesized in order to conquer the challenge arising from the capture of CO2 in flue gas whose temperature is over 373 K, and they possess a suitable basic strength to adsorb CO2 at 393 K with the capacity of 22-49 mg g(-1). After these ILs are immobilized on mesoporous alumina or silica, equimolar CO2 capture is realized at 393 K for the first time. Besides, these adsorbents can be regenerated at 443 K to form a feasible cycle for controlling CO2 emission in flue gas. Theoretical calculations indicated the key role played by the mesoporous support in promoting CO2 adsorption via electrostatic interactions between support and ILs. An unwonted promotion of the support's zeta-potential on the performance of ILs is revealed, which induces the immobilized ILs to be oriented in a favorable dispersion, enhancing the efficiency of ILs in the CO2 adsorption at elevated temperature. This study proposes a new strategy for the sustainable development of novel adsorbent. PMID- 25032908 TI - Protein folding and secretion: mechanistic insights advancing recombinant protein production in S. cerevisiae. AB - The emergence of genomic approaches coupled to recombinant DNA technologies have identified the quality control systems that regulate proteostasis - biological pathways that modulate protein biogenesis, maturation, trafficking, and degradation. The elucidation of these pathways has become of growing importance in therapeutics as loss of proteostasis has been suggested to lead to a number of human diseases including Alzheimer's, Parkinson's Disease and Type II Diabetes. We anticipate that the most successful strategies for protein expression and therapeutics development may involve integration of protein engineering strategies with host manipulation, to exploit the cell's native stress response pathways and trafficking mechanisms. This review will highlight recent findings and mechanistic detail correlated to quality control in the early secretory pathway of Saccharomyces cerevisiae. PMID- 25032911 TI - Fourier transform for fermionic systems and the spectral tensor network. AB - Leveraging the decomposability of the fast Fourier transform, I propose a new class of tensor network that is efficiently contractible and able to represent many-body systems with local entanglement that is greater than the area law. Translationally invariant systems of free fermions in arbitrary dimensions as well as 1D systems solved by the Jordan-Wigner transformation are shown to be exactly represented in this class. Further, it is proposed that these tensor networks be used as generic structures to variationally describe more complicated systems, such as interacting fermions. This class shares some similarities with the Evenbly-Vidal branching multiscale entanglement renormalization ansatz, but with some important differences and greatly reduced computational demands. PMID- 25032912 TI - Optimal control of effective Hamiltonians. AB - We present a systematic scheme for the optimization of quantum simulations. Specifically, we show how polychromatic driving can be used to significantly improve the driving of Raman transitions in the Lambda system, which opens new possibilities for controlled driving-induced effective dynamics. PMID- 25032913 TI - Information theoretical analysis of quantum optimal control. AB - We study the relations between classical information and the feasibility of accurate manipulation of quantum system dynamics. We show that if an efficient classical representation of the dynamics exists, optimal control problems on many body quantum systems can be solved efficiently with finite precision. In particular, one-dimensional slightly entangled dynamics can be efficiently controlled. We provide a bound for the minimal time necessary to perform the optimal process given the bandwidth of the control pulse, which is the continuous version of the Solovay-Kitaev theorem. Finally, we quantify how noise affects the presented results. PMID- 25032914 TI - Quench dynamics of one-dimensional interacting bosons in a disordered potential: elastic dephasing and critical speeding-up of thermalization. AB - The dynamics of interacting bosons in one dimension following the sudden switching on of a weak disordered potential is investigated. On time scales before quasiparticles scatter (prethermalized regime), the dephasing from random elastic forward scattering causes all correlations to decay exponentially fast, but the system remains far from thermal equilibrium. For longer times, the combined effect of disorder and interactions gives rise to inelastic scattering and to thermalization. A novel quantum kinetic equation accounting for both disorder and interactions is employed to study the dynamics. Thermalization turns out to be most effective close to the superfluid-Bose-glass critical point where nonlinearities become more and more important. The numerically obtained thermalization times are found to agree well with analytic estimates. PMID- 25032915 TI - Cosmological constraints on Brans-Dicke theory. AB - We report strong cosmological constraints on the Brans-Dicke (BD) theory of gravity using cosmic microwave background data from Planck. We consider two types of models. First, the initial condition of the scalar field is fixed to give the same effective gravitational strength Geff today as the one measured on Earth, GN. In this case, the BD parameter omega is constrained to omega>692 at the 99% confidence level, an order of magnitude improvement over previous constraints. In the second type, the initial condition for the scalar is a free parameter leading to a somewhat stronger constraint of omega>890, while Geff is constrained to 0.9811 accounts for theoretical uncertainty). If fa>HI/2pi then vacuum fluctuations of the axion field place conflicting demands on axion DM: isocurvature constraints require a DM abundance which is too small to be reached when the backreaction of fluctuations is included. High-fa QCD axions are thus ruled out. Constraints on axionlike particles, as a function of their mass and DM fraction, are also considered. For heavy axions with ma?10(-22) eV we find Omegaa/Omegad?10(-3), with stronger constraints on heavier axions. Lighter axions, however, are allowed and (inflationary) model-independent constraints from the CMB temperature power spectrum and large scale structure are stronger than those implied by tensor modes. PMID- 25032919 TI - Axion cold dark matter in view of BICEP2 results. AB - The properties of axions that constitute 100% of cold dark matter (CDM) depend on the tensor-to-scalar ratio r at the end of inflation. If r=0.20(-0.05)(+0.07) as reported by the BICEP2 Collaboration, then "half" of the CDM axion parameter space is ruled out. Namely, in the context of single-field slow-roll inflation, for axions to be 100% of the CDM, the Peccei-Quinn symmetry must be broken after the end of inflation, so that axion nonadiabatic primordial fluctuations are compatible with observational constraints. The cosmic axion density is then independent of the tensor-to-scalar ratio r, and the axion mass is expected to be in a narrow range that, however, depends on the cosmological model before primordial nucleosynthesis. In the standard Lambda CDM cosmology, the CDM axion mass range is ma=(71+/-2 MUeV)(alphadec+1)6/7, where alphadec is the fractional contribution to the cosmic axion density from decays of axionic strings and walls. PMID- 25032920 TI - Evidence for polarization of gluons in the proton. AB - We discuss the impact of recent high-statistics Relativistic Heavy Ion Collider data on the determination of the gluon polarization in the proton in the context of a global QCD analysis of polarized parton distributions. We find evidence for a nonvanishing polarization of gluons in the region of momentum fraction and at the scales mostly probed by the data. Although information from low momentum fractions is presently lacking, this finding is suggestive of a significant contribution of gluon spin to the proton spin, thereby limiting the amount of orbital angular momentum required to balance the proton spin budget. PMID- 25032922 TI - Evidence for triangular D3h symmetry in 12C. AB - We report a measurement of a new high spin Jpi=5- state at 22.4(2) MeV in 12C which fits very well to the predicted (ground state) rotational band of an oblate equilateral triangular spinning top with a D3h symmetry characterized by the sequence 0+, 2+, 3-, 4+/-, 5- with almost degenerate 4+ and 4- (parity doublet) states. Such a D3h symmetry was observed in triatomic molecules, and it is observed here for the first time in nuclear physics. We discuss a classification of other rotation-vibration bands in 12C such as the (0+) Hoyle band and the (1-) bending mode band and suggest measurements in search of the predicted ("missing") states that may shed new light on clustering in 12C and light nuclei. In particular, the observation (or nonobservation) of the predicted ("missing") states in the Hoyle band will allow us to conclude the geometrical arrangement of the three alpha particles composing the Hoyle state at 7.654 MeV in 12C. PMID- 25032923 TI - All-optical vector atomic magnetometer. AB - We demonstrate an all-optical magnetometer capable of measuring the magnitude and direction of a magnetic field using nonlinear magneto-optical rotation in cesium vapor. Vector capability is added by effective modulation of the field along orthogonal axes and subsequent demodulation of the magnetic-resonance frequency. This modulation is provided by the ac Stark shift induced by circularly polarized laser beams. The sensor exhibits a demonstrated rms noise floor of ~65 fT/?[Hz] in measurement of the field magnitude and 0.5 mrad/?[Hz] in the field direction; elimination of technical noise would improve these sensitivities to 12 fT/?[Hz] and 10 MUrad/?[Hz], respectively. Applications for this all-optical vector magnetometer would include magnetically sensitive fundamental physics experiments, such as the search for a permanent electric dipole moment of the neutron. PMID- 25032921 TI - Isospin character of low-lying pygmy dipole states in 208Pb via inelastic scattering of 17O ions. AB - The properties of pygmy dipole states in 208Pb were investigated using the 208Pb(17O, 17O'gamma) reaction at 340 MeV and measuring the gamma decay with high resolution with the AGATA demonstrator array. Cross sections and angular distributions of the emitted gamma rays and of the scattered particles were measured. The results are compared with (gamma, gamma') and (p, p') data. The data analysis with the distorted wave Born approximation approach gives a good description of the elastic scattering and of the inelastic excitation of the 2+ and 3- states. For the dipole transitions a form factor obtained by folding a microscopically calculated transition density was used for the first time. This has allowed us to extract the isoscalar component of the 1- excited states from 4 to 8 MeV. PMID- 25032924 TI - Bright solitonic matter-wave interferometer. AB - We present the first realization of a solitonic atom interferometer. A Bose Einstein condensate of 1*10(4) atoms of rubidium-85 is loaded into a horizontal optical waveguide. Through the use of a Feshbach resonance, the s-wave scattering length of the 85Rb atoms is tuned to a small negative value. This attractive atomic interaction then balances the inherent matter-wave dispersion, creating a bright solitonic matter wave. A Mach-Zehnder interferometer is constructed by driving Bragg transitions with the use of an optical lattice colinear with the waveguide. Matter-wave propagation and interferometric fringe visibility are compared across a range of s-wave scattering values including repulsive, attractive and noninteracting values. The solitonic matter wave is found to significantly increase fringe visibility even compared with a noninteracting cloud. PMID- 25032926 TI - Nonlinear inverse synthesis and eigenvalue division multiplexing in optical fiber channels. AB - We scrutinize the concept of integrable nonlinear communication channels, resurrecting and extending the idea of eigenvalue communications in a novel context of nonsoliton coherent optical communications. Using the integrable nonlinear Schrodinger equation as a channel model, we introduce a new approach the nonlinear inverse synthesis method-for digital signal processing based on encoding the information directly onto the nonlinear signal spectrum. The latter evolves trivially and linearly along the transmission line, thus, providing an effective eigenvalue division multiplexing with no nonlinear channel cross talk. The general approach is illustrated with a coherent optical orthogonal frequency division multiplexing transmission format. We show how the strategy based upon the inverse scattering transform method can be geared for the creation of new efficient coding and modulation standards for the nonlinear channel. PMID- 25032925 TI - Exploring a new regime for processing optical qubits: squeezing and unsqueezing single photons. AB - We implement the squeezing operation as a genuine quantum gate, deterministically and reversibly acting "online" upon an input state no longer restricted to the set of Gaussian states. More specifically, by applying an efficient and robust squeezing operation for the first time to non-Gaussian states, we demonstrate a two-way conversion between a particlelike single-photon state and a wavelike superposition of coherent states. Our squeezing gate is reliable enough to preserve the negativities of the corresponding Wigner functions. This demonstration represents an important and necessary step towards hybridizing discrete and continuous quantum protocols. PMID- 25032927 TI - Harnessing buckling to design tunable locally resonant acoustic metamaterials. AB - We report a new class of tunable and switchable acoustic metamaterials comprising resonating units dispersed into an elastic matrix. Each resonator consists of a metallic core connected to the elastomeric matrix through elastic beams, whose buckling is intentionally exploited as a novel and effective approach to control the propagation of elastic waves. We first use numerical analysis to show the evolution of the locally resonant band gap, fully accounting for the effect of nonlinear pre-deformation. Then, we experimentally measure the transmission of vibrations as a function of the applied loading in a finite-size sample and find excellent agreement with our numerical predictions. The proposed concept expands the ability of existing acoustic metamaterials by enabling tunability over a wide range of frequencies. Furthermore, we demonstrate that in our system the deformation can be exploited to turn on or off the band gap, opening avenues for the design of adaptive switches. PMID- 25032928 TI - Influence of slip on the Rayleigh-Plateau rim instability in dewetting viscous films. AB - A dewetting viscous film develops a characteristic fluid rim at its receding edge due to mass conservation. In the course of the dewetting process, the rim becomes unstable via an instability of Rayleigh-Plateau type. An important difference exists between this classic instability of a liquid column and the rim instability in a thin film as the growth of the rim is continuously fueled by the receding film. We explain how the development and macroscopic morphology of the rim instability are controlled by the slip of the film on the substrate. A single thin-film model captures quantitatively the characteristics of the complete evolution of the rim observed in the experiments. PMID- 25032929 TI - Anomalous radiative trapping in laser fields of extreme intensity. AB - We demonstrate that charged particles in a sufficiently intense standing wave are compressed toward, and oscillate synchronously at, the antinodes of the electric field. We call this unusual behavior anomalous radiative trapping (ART). We show using dipole pulses, which offer a path to increased laser intensity, that ART opens up new possibilities for the generation of radiation and particle beams, both of which are high energy, directed, and collimated. ART also provides a mechanism for particle control in high-intensity quantum-electrodynamics experiments. PMID- 25032930 TI - Excitation spectrum of the Lieb-Liniger model. AB - We study the integrable model of one-dimensional bosons with contact repulsion. In the limit of weak interaction, we use the microscopic hydrodynamic theory to obtain the excitation spectrum. The statistics of quasiparticles changes with the increase of momentum. At lowest momenta good quasiparticles are fermions, while at higher momenta they are Bogoliubov bosons, in accordance with recent studies. In the limit of strong interaction, we analyze the exact solution and find exact results for the spectrum in terms of the asymptotic series. Those results undoubtedly suggest that fermionic quasiparticle excitations actually exist at all momenta for moderate and strong interaction and also at lowest momenta for arbitrary interaction. Moreover, at strong interaction we find highly accurate analytical results for several relevant quantities of the Lieb-Liniger model. PMID- 25032931 TI - Quantum anomalous Hall insulator of composite fermions. AB - We show that a weak hexagonal periodic potential can transform a two-dimensional electron gas with an even-denominator magnetic filling factor into an quantum anomalous hall insulator of composite fermions, giving rise to the fractionally quantized Hall effect. The system provides a realization of the Haldane honeycomb net model, albeit in a composite fermion system. We further propose a trial wave function for the state, and numerically evaluate its relative stability against the competing Hofstadter state. Possible sets of experimental parameters are proposed. PMID- 25032932 TI - Dielectric effects in the self-assembly of binary colloidal aggregates. AB - Electrostatic interactions play an important role in numerous self-assembly phenomena, including colloidal aggregation. Although colloids typically have a dielectric constant that differs from the surrounding solvent, the effective interactions that arise from inhomogeneous polarization charge distributions are generally neglected in theoretical and computational studies. We introduce an efficient technique to resolve polarization charges in dynamical dielectric geometries, and demonstrate that dielectric effects qualitatively alter the predicted self-assembled structures, with surprising colloidal strings arising from many-body effects. PMID- 25032933 TI - Measurement of proton tunneling in short hydrogen bonds in single crystals of 3,5 pyridinedicarboxylic acid using nuclear magnetic resonance spectroscopy. AB - In this Letter, we present NMR spin-lattice and relaxometry data for proton transfer in one of the shortest known N-H?O hydrogen bonds in a single crystal of 3,5 pyridinedicarboxylic acid (35PDCA). It is widely believed that proton transfer by quantum tunneling does not occur in short hydrogen bonds since the ground state energy level lies above the potential barrier, yet these data show a temperature independent, proton tunneling rate below 77 K and a clear deviation from classical dynamics below 91 K. This study therefore suggests that proton tunneling occurs in all hydrogen bonds at low temperature and the crossover temperature to classical hopping must be determined when evaluating whether proton tunneling persists at higher temperature, for example in enzyme catalysis under physiological conditions. PMID- 25032934 TI - Comment on "Exotic paired states with anisotropic spin-dependent Fermi surfaces". PMID- 25032935 TI - Feiguin and Fisher reply. PMID- 25032936 TI - Retraction: Observation of topological structures in photonic quantum walks [phys. Rev. Lett. 112, 120502 (2014)]. AB - Because of serious theoretical errors that have consequently led to misinterpretations of experimental data, the main result of our recent Letter concerning the observation of topological structures and localization in photonics quantum walks is incorrect and has to be withdrawn. PMID- 25032937 TI - The long and viscous road: uncovering nuclear diffusion barriers in closed mitosis. AB - Diffusion barriers are effective means for constraining protein lateral exchange in cellular membranes. In Saccharomyces cerevisiae, they have been shown to sustain parental identity through asymmetric segregation of ageing factors during closed mitosis. Even though barriers have been extensively studied in the plasma membrane, their identity and organization within the nucleus remains poorly understood. Based on different lines of experimental evidence, we present a model of the composition and structural organization of a nuclear diffusion barrier during anaphase. By means of spatial stochastic simulations, we propose how specialised lipid domains, protein rings, and morphological changes of the nucleus may coordinate to restrict protein exchange between mother and daughter nuclear lobes. We explore distinct, plausible configurations of these diffusion barriers and offer testable predictions regarding their protein exclusion properties and the diffusion regimes they generate. Our model predicts that, while a specialised lipid domain and an immobile protein ring at the bud neck can compartmentalize the nucleus during early anaphase; a specialised lipid domain spanning the elongated bridge between lobes would be entirely sufficient during late anaphase. Our work shows how complex nuclear diffusion barriers in closed mitosis may arise from simple nanoscale biophysical interactions. PMID- 25032939 TI - Why physicians should not be involved in hostile interrogations - a response to Heilig's editorial. AB - The purpose of this article is to provide a moral foundation for Heilig's argument (published in the same issue) that physician participation in torture is a violation of medical ethics. The argument needs a moral foundation because it is unconventional by the standards of academic biomedical ethics. There is little about the "principles of bioethics", the nature of medicine, the physician patient relationship, the physician's "social role," or the like. Instead, Heilig rests his argument primarily on the AMA's Code of Ethics (and international equivalents)--what most bioethicists tend to treat as mere custom, etiquette, law, or statements of opinion (when they do not ignore it altogether). This article explains why the AMA Code of Ethics can set the standard for ethical conduct for physicians--given a certain understanding of "ethics" and "profession" largely absent from biomedical ethics but common in professional ethics generally. The article also responds to six likely objections. PMID- 25032940 TI - Deflection corridors of abdomen and thorax in oblique side impacts using equal stress equal velocity approach: comparison with other normalization methods. AB - The first objective of the study was to determine the thorax and abdomen deflection time corridors using the equal stress equal velocity approach from oblique side impact sled tests with postmortem human surrogates fitted with chestbands. The second purpose of the study was to generate deflection time corridors using impulse momentum methods and determine which of these methods best suits the data. An anthropometry-specific load wall was used. Individual surrogate responses were normalized to standard midsize male anthropometry. Corridors from the equal stress equal velocity approach were very similar to those from impulse momentum methods, thus either method can be used for this data. Present mean and plus/minus one standard deviation abdomen and thorax deflection time corridors can be used to evaluate dummies and validate complex human body finite element models. PMID- 25032941 TI - The role of preoperative imaging for cochlear implantation in postlingually deafened adults. AB - BACKGROUND: Preoperative imaging is standard practice for cochlear implant candidacy. Postlingually deafened adults rarely have temporal bone abnormalities that alter management. OBJECTIVES/HYPOTHESIS: To determine the role of preoperative imaging for cochlear implantation in postlingually deafened adults. We hypothesize that imaging does not alter management in the absence of history or physical examination findings suggestive of an anatomic abnormality. STUDY DESIGN: Nested case-control study. METHODS: We identified postlingually deafened adults with preoperative imaging and cochlear implantation at our institution from 1995 to 2008. Controls had a negative history and normal exam. Cases had suggestive history or exam. Imaging studies and operative records were reviewed. RESULTS: Approximately 164 patients met inclusion criteria-59 cases and 109 controls. Mean age at onset of hearing loss was 30.4 years (range, 0-73 yr), mean age at onset of deafness was 54.1 years (range, 9-89 yr), and mean age at implantation was 61.5 years (range, 20.6-89.7 yr). Twenty cases (34%) and 17 controls (16%) had abnormal imaging (p = 0.001). Six cases (8.5%) and 2 controls (1.8%) had changes in their management as a result of the imaging findings (p = 0.023). Both control patients had incidentally detected acoustic neuromas, which altered the side of the cochlear implantation. There was a strong association between preoperative history and exam findings and abnormality on imaging (p = 0.007). Abnormalities were 3 times more likely in patients with a positive history or exam (OR = 2.98; 95% CI, 1.36-6.54). CONCLUSION: In patients with a negative history and examination, imaging rarely alters management. MRI may detect incidental vestibular schwannomas in patients with asymmetric hearing losses. LEVEL OF EVIDENCE: 3b, Individual case-control study. PMID- 25032938 TI - NMR structures of membrane proteins in phospholipid bilayers. AB - Membrane proteins have always presented technical challenges for structural studies because of their requirement for a lipid environment. Multiple approaches exist including X-ray crystallography and electron microscopy that can give significant insights into their structure and function. However, nuclear magnetic resonance (NMR) is unique in that it offers the possibility of determining the structures of unmodified membrane proteins in their native environment of phospholipid bilayers under physiological conditions. Furthermore, NMR enables the characterization of the structure and dynamics of backbone and side chain sites of the proteins alone and in complexes with both small molecules and other biopolymers. The learning curve has been steep for the field as most initial studies were performed under non-native environments using modified proteins until ultimately progress in both techniques and instrumentation led to the possibility of examining unmodified membrane proteins in phospholipid bilayers under physiological conditions. This review aims to provide an overview of the development and application of NMR to membrane proteins. It highlights some of the most significant structural milestones that have been reached by NMR spectroscopy of membrane proteins, especially those accomplished with the proteins in phospholipid bilayer environments where they function. PMID- 25032942 TI - Testing a conceptual model on early opening of the microcirculation in severe sepsis and septic shock: a randomised controlled pilot study. AB - BACKGROUND: Organ failure in severe sepsis and septic shock may be caused by microcirculatory failure. OBJECTIVE: The objective of this study is to test a conceptual model of microcirculatory failure by using a resuscitation strategy targeting early opening of the constricted microcirculation with active vasodilatation. DESIGN: A randomised controlled pilot study. SETTING: Single centre mixed medical and surgical tertiary ICU. PATIENTS: Ninety severe sepsis and septic shock patients randomised to early opening microcirculation resuscitation group or standard resuscitation group. INTERVENTIONS: Standard resuscitation group: fluids, noradrenaline, dobutamine and hydrocortisone were given to achieve a mean arterial pressure (MAP) of more than 60 mmHg, cardiac index more than 2.5 l min m and ScvO2 more than 70%. Microcirculation resuscitation group: nitroglycerin, enoximone, dopamine and dexamethasone targeting a microvascular flow index (MFI), measured by sublingual side-stream dark field imaging, more than 2.5. MAIN OUTCOME MEASURE: A decrease in organ failure score (SOFA) on day four of ICU treatment. RESULTS: Data from 37 microcirculation resuscitation and 28 standard resuscitation patients were analysed. In the microcirculation resuscitation group, MFI of more than 2.5 was achieved after a mean +/- SD of 7.0 +/- 4.6 h. The microcirculation resuscitation group received more fluids, and noradrenaline was equally prescribed in both groups. Per protocol, the decrease in SOFA score at day 4 was not different between groups (P = 0.64). There was a significant reduction in SOFA score in both groups compared with admission (1.2 and 1.6 in microcirculation resuscitation and standard resuscitation groups, respectively; P = 0.028 and P = 0.045). CONCLUSION: Early opening of the microcirculation in patients with severe sepsis and septic shock using nitroglycerin, enoximone, dopamine and corticosteroids did not result in a faster reduction in organ failure than standard resuscitation. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00484133. PMID- 25032943 TI - Spinal anaesthesia with low-dose bupivacaine in marginally hyperbaric solutions for caesarean section: A randomised controlled trial. AB - BACKGROUND: Conventional hyperbaric spinal anaesthesia solution (SAS) with 8% glucose and low-dose bupivacaine may reduce the incidence of hypotension in caesarean section compared to standard doses, and marginally hyperbaric SAS (<=0.8% glucose) can induce a lower block level and a lower incidence of hypotension in nonobstetric patients than conventional 8% glucose SAS. OBJECTIVE: The objective of this study was to evaluate the clinical efficacy of marginally hyperbaric low-dose bupivacaine solutions used for spinal anaesthesia during caesarean section. DESIGN: A randomised, controlled clinical trial. SETTING: Single medical centre. PATIENTS: One hundred twenty women scheduled for elective caesarean section were randomised into four groups. INTERVENTIONS: Caesarean section after combined spinal-epidural anaesthesia using hyperbaric preparations of low-dose SAS (7.2 mg bupivacaine and 2 MUg 1.6 ml sufentanil in one of the following: 8%, 0.8%, 0.5% or 0.33% glucose solution. MAIN OUTCOME MEASURES: The dermatomal sensory block and degree of motor block of the lower extremities and adverse effects of anaesthesia were recorded. RESULTS: The maximum cephalad sensory block level and the incidence of hypotension decreased as the density of SAS fell (T1, T2, T4 and T6, P < 0.001; 48.3, 30, 13.3 and 10.3%, P = 0.003). The incidence of shivering reduced with decreasing density of SAS (P < 0.05). There was no significant difference in the quality of anaesthesia (efficacy of motor block and sensory block) between the groups (P > 0.05). CONCLUSION: Compared with conventional 8% glucose hyperbaric SAS, marginally hyperbaric (0.5 or 0.33% glucose) low-dose bupivacaine solutions led to a significantly lower height of cephalad spread and incidence of hypotension with no impact on the efficacy of spinal anaesthesia for caesarean section. PMID- 25032944 TI - Mitochondrial DNA mutations in ageing and disease: implications for HIV? AB - Mitochondrial DNA (mtDNA) mutations cause neurological and multisystem disease. Somatic (acquired) mtDNA mutations are also associated with degenerative diseases and with normal human ageing. It is well established that certain nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral drugs cause inhibition of the mtDNA polymerase, pol gamma, leading to a reduction in mtDNA content (depletion). Given this effect of NRTI therapy on mtDNA replication, it is plausible that NRTI treatment may also lead to increased mtDNA mutations. Here we review recent evidence for an effect of HIV infection or NRTI therapy on mtDNA mutations, as well as discussing the methodological challenges in addressing this question. Finally, we discuss the possible implications for HIV-infected persons, with particular reference to ageing. PMID- 25032945 TI - Lower limb neuromuscular function and blood flow characteristics in AFO-using survivors of stroke. AB - BACKGROUND AND PURPOSE: Ankle-foot orthoses (AFOs) and gait aids are commonly used by survivors of stroke to ambulate, but they have not been used as inclusion or exclusion criteria for physiological studies. The purpose of this study was to examine differences in neuromuscular function and blood flow characteristics between the lower limbs of ambulatory, AFO-using survivors of stroke (n = 9). METHODS: The subjects were, on average, 14 years poststroke and had used an AFO for about 7 years. We used the following measures to assess both lower limbs: quadriceps muscular strength (manual muscle testing, 1RM), calf muscular endurance (single-leg heel raises), lower limb soft tissue composition and muscle cross-sectional area, calf resting blood flow (strain gauge plethysmography), and central neural drive of the plantar flexors (nerve stimulation). The sound limb was defined as the control. RESULTS: Quadriceps strength, triceps surae endurance, and calf cross-sectional area all were greater in the sound limb than in the affected limb (relative differences: 76.3% +/- 16.6%, 146.4% +/- 24.6%, and 25.6% +/- 5.7%, respectively). In addition, resting blood flow, peak torque, and central neural drive of the plantar flexors were significantly greater (relative differences: 38.7% +/- 5.9%, 94.4% +/- 17.9%, and 43.6% +/- 12.0%, respectively) in the sound calf. DISCUSSION: Our findings confirm that significant decrements in muscle performance, size, and blood flow persist in the affected limb many years after stroke despite a resumption of ambulation. CONCLUSIONS: This cohort of ambulatory AFO users exhibited large variations in functional abilities. We recommend that future studies in stroke survivors consider AFO use in their research designs. PMID- 25032946 TI - The new mission of forensic mental health systems: managing violence as a medical syndrome in an environment that balances treatment and safety. AB - The association between violence and mental illness is well-studied, yet remains highly controversial. Currently, there appears to be a trend of increasing violence in state hospital settings, including both civilly and forensically committed populations. In fact, physical aggression is the primary reason for admission to many state hospitals. Given that violence is now often both a reason for admission and a barrier to discharge, there is a case to be made for psychiatric violence to be re-conceptualized dimensionally, as a primary syndrome, not as the byproduct of one. Furthermore, treatment settings need to be enhanced to address the new types of violence exhibited in inpatient environments, and this modification needs to be geared toward balancing safety with treatment. PMID- 25032947 TI - Submucosal endoscopy: the new frontier of therapeutic endoscopy. AB - PURPOSE OF REVIEW: Peroral endoscopic myotomy (POEM) and submucosal tunneling and endoscopic resection (STER) have been recently described as minimally invasive therapies for achalasia and gastrointestinal subepithelial tumors originating from the muscularis propria, respectively. This review illustrates the latest developments in the field of submucosal endoscopy, focuses on POEM and sheds light on STER. RECENT FINDINGS: Multiple studies from the United States, Asia and Europe have shown that POEM is an effective and safe procedure for achalasia when performed by experienced operators with adequate clinical response in 80-90% of patients. Nonetheless, POEM requires a demanding skill set that involves both advanced endoscopic skills and knowledge of surgical anatomy. In addition, the endoscopist must have the capability to manage procedural complications. Similarly, STER appears to be an effective therapy for treatment of small and medium sized gastrointestinal tumors originating from the muscularis propria. SUMMARY: POEM and STER offer minimally invasive and effective treatment alternatives for patients with achalasia, spastic esophageal disorders and upper gastrointestinal tumors originating from the muscularis propria. PMID- 25032948 TI - Chronic pancreatitis. AB - PURPOSE OF REVIEW: We review selected important clinical observations in chronic pancreatitis reported in 2013. RECENT FINDINGS: Early diagnosis of chronic pancreatitis remains difficult, although newer techniques utilizing endoscopic ultrasonography-elastography and MRI hold promise. Patients with chronic pancreatitis are at risk of nutritional deficiencies. Osteoporosis, osteopenia, and bone fracture are particularly common in these patients, and require active intervention and treatment. Diabetes caused by chronic pancreatitis, type 3c diabetes, has specific characteristics and requires careful management. Antioxidants and neuromodulators may decrease pain in some patients with chronic pancreatitis. Endoscopic treatment is effective and can be utilized in patients with painful chronic pancreatitis, although randomized trials demonstrate that surgical therapy is somewhat more durable and effective. Although surgery has typically been a last resort, some advocate early surgical intervention but the optimal time remains unknown. SUMMARY: Early diagnosis of pancreatitis may be improved by newer techniques associated with endoscopic ultrasonography imaging. Treatment of nutritional deficiencies and diabetes is an important aspect of treating chronic pancreatitis. Pain relief with adjunct means of pain modulation should be tried before starting narcotics for pain control. Endoscopic therapy is appropriate for treating chronic pancreatitis and its local complications and surgical intervention can be considered early in carefully selected individuals. PMID- 25032916 TI - Search for gravitational waves associated with gamma-ray bursts detected by the interplanetary network. AB - We present the results of a search for gravitational waves associated with 223 gamma-ray bursts (GRBs) detected by the InterPlanetary Network (IPN) in 2005-2010 during LIGO's fifth and sixth science runs and Virgo's first, second, and third science runs. The IPN satellites provide accurate times of the bursts and sky localizations that vary significantly from degree scale to hundreds of square degrees. We search for both a well-modeled binary coalescence signal, the favored progenitor model for short GRBs, and for generic, unmodeled gravitational wave bursts. Both searches use the event time and sky localization to improve the gravitational wave search sensitivity as compared to corresponding all-time, all sky searches. We find no evidence of a gravitational wave signal associated with any of the IPN GRBs in the sample, nor do we find evidence for a population of weak gravitational wave signals associated with the GRBs. For all IPN-detected GRBs, for which a sufficient duration of quality gravitational wave data are available, we place lower bounds on the distance to the source in accordance with an optimistic assumption of gravitational wave emission energy of 10(-2)M?c(2) at 150 Hz, and find a median of 13 Mpc. For the 27 short-hard GRBs we place 90% confidence exclusion distances to two source models: a binary neutron star coalescence, with a median distance of 12 Mpc, or the coalescence of a neutron star and black hole, with a median distance of 22 Mpc. Finally, we combine this search with previously published results to provide a population statement for GRB searches in first-generation LIGO and Virgo gravitational wave detectors and a resulting examination of prospects for the advanced gravitational wave detectors. PMID- 25032949 TI - Rapid characterization of naphthenic acids using differential mobility spectrometry and mass spectrometry. AB - To analyze the naphthenic acid content of environmental waters quickly and efficiently, we have developed a method that employs differential mobility spectrometry (DMS) coupled to mass spectrometry (MS). This technique combines the benefits of infusion-based MS experiments (parallel, on-demand access to individual components) with DMS's ability to provide liquid chromatography-like separations of isobaric and isomeric compounds in a fraction of the time. In this study, we have applied a DMS-MS workflow to the rapid gas-phase separation of naphthenic acids (NAs) within a technical standard and a real-world oil sands process-affected water (OSPW) extract. Among the findings provided by this workflow are the rapid characterization of isomeric NAs (i.e., same molecular formulas) in a complex OSPW sample, the ability to use DMS to isolate individual NA components (including isomeric NAs) for in-depth structural analyses, and a method by which NA analytes, background ions, and dimer species can be characterized by their distinct behaviors in DMS. Overall, the profiles of the NA content of the technical and OSPW samples were consistent with published values for similar samples, such that the benefits of DMS technology do not detract from the workflow's accuracy or quality. PMID- 25032950 TI - Visual speech perception in foveal and extrafoveal vision: further implications for divisions in hemispheric projections. AB - When observing a talking face, it has often been argued that visual speech to the left and right of fixation may produce differences in performance due to divided projections to the two cerebral hemispheres. However, while it seems likely that such a division in hemispheric projections exists for areas away from fixation, the nature and existence of a functional division in visual speech perception at the foveal midline remains to be determined. We investigated this issue by presenting visual speech in matched hemiface displays to the left and right of a central fixation point, either exactly abutting the foveal midline or else located away from the midline in extrafoveal vision. The location of displays relative to the foveal midline was controlled precisely using an automated, gaze contingent eye-tracking procedure. Visual speech perception showed a clear right hemifield advantage when presented in extrafoveal locations but no hemifield advantage (left or right) when presented abutting the foveal midline. Thus, while visual speech observed in extrafoveal vision appears to benefit from unilateral projections to left-hemisphere processes, no evidence was obtained to indicate that a functional division exists when visual speech is observed around the point of fixation. Implications of these findings for understanding visual speech perception and the nature of functional divisions in hemispheric projection are discussed. PMID- 25032951 TI - R-type calcium channels are crucial for semaphorin 3A-induced DRG axon growth cone collapse. AB - Semaphorin 3A (Sema3A) is a secreted protein involved in axon path-finding during nervous system development. Calcium signaling plays an important role during axonal growth in response to different guidance cues; however it remains unclear whether this is also the case for Sema3A. In this study we used intracellular calcium imaging to figure out whether Sema3A-induced growth cone collapse is a Ca2+ dependent process. Intracellular Ca2+ imaging results using Fura-2 AM showed Ca2+ increase in E15 mice dorsal root ganglia neurons upon Sema3A treatment. Consequently we analyzed Sema3A effect on growth cones after blocking or modifying intracellular and extracellular Ca2+ channels that are expressed in E15 mouse embryos. Our results demonstrate that Sema3A increased growth cone collapse rate is blocked by the non-selective R- and T- type Ca2+ channel blocker NiCl2 and by the selective R-type Ca2+ channel blocker SNX482. These Ca2+ channel blockers consistently decreased the Sema3A-induced intracellular Ca2+ concentration elevation. Overall, our results demonstrate that Sema3A-induced growth cone collapses are intimately related with increase in intracellular calcium concentration mediated by R-type calcium channels. PMID- 25032953 TI - Human genetic evidence for involvement of CD137 in atherosclerosis. AB - Atherosclerosis is an inflammatory disease and the main cause of cardiovascular disease. Inflammation promotes plaque instability and clinical disease, such as myocardial infarction, stroke and peripheral vascular disease. Subclinical atherosclerosis begins with thickening of the arterial intimal layer, and increased intima-media thickness (IMT) in the carotid artery is a widely used measurement of subclinical atherosclerosis. Activation of CD137 (tumor necrosis factor receptor super family 9) promotes inflammation and disease development in murine atherosclerosis. CD137 is expressed in human atherosclerosis, but its role is largely unknown. This study uses a genetic approach to investigate CD137 in human atherosclerotic disease. In publicly available data on genotype and gene expression from the HapMap project, the minor T allele of rs2453021, a single nucleotide polymorphism in CD137, was significantly associated with CD137 gene expression. In the PROCARDIS and Wellcome Trust Case Control Consortium (WTCCC) cohorts of 13,029 cases and controls, no significant association was detected between the minor T allele of rs2453021 and risk for coronary artery disease or myocardial infarction. However, in the IMPROVE multicenter study of 3,418 individuals, the minor T allele of rs2453021 was associated with increased IMT of the common carotid artery (CCA), as measured by ultrasonography, with presence of plaque in CCA and with increased incidence of adverse noncardiac vascular events. Taken together, this study shows that the minor T allele of rs2453021 is associated with increased IMT in the CCA and increased risk of incident noncardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis. PMID- 25032954 TI - Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular alpha1-adrenergic receptor function. AB - Chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor (ACKR) 3 ligands have been reported to modulate cardiovascular function in various disease models. The underlying mechanisms, however, remain unknown. Thus, it was the aim of the present study to determine how pharmacological modulation of CXCR4 and ACKR3 regulate cardiovascular function. In vivo administration of TC14012, a CXCR4 antagonist and ACKR3 agonist, caused cardiovascular collapse in normal animals. During the cardiovascular stress response to hemorrhagic shock, ubiquitin, a CXCR4 agonist, stabilized blood pressure, whereas coactivation of CXCR4 and ACKR3 with CXC chemokine ligand 12 (CXCL12), or blockade of CXCR4 with AMD3100 showed opposite effects. While CXCR4 and ACKR3 ligands did not affect myocardial function, they selectively altered vascular reactivity upon alpha1 adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced alpha1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized alpha1-AR mediated vasoconstriction. The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically. CXCR4 and ACKR3 ligands did not affect vasoconstriction upon activation of voltage-operated Ca(2+) channels or endothelin receptors. Effects of CXCR4 and ACKR3 agonists on vascular alpha1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate alpha1-AR reactivity in vascular smooth muscle and regulate hemodynamics in normal and pathological conditions. Our observations point toward CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure. PMID- 25032956 TI - Regression of choroidal metastasis from breast carcinoma treated with gamma knife radiosurgery. PMID- 25032955 TI - The role of estrogen receptor beta in prostate cancer. AB - Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor beta (ERbeta) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERbeta splice variants have been associated with prostate cancer initiation and progression mechanisms. ERbeta is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the recent experimental findings of ERbeta signaling in the prostate. PMID- 25032957 TI - Distinct distribution pattern of hepatitis B virus genotype C and D in liver tissue and serum of dual genotype infected liver cirrhosis and hepatocellular carcinoma patients. AB - AIMS: The impact of co-infection of several hepatitis B virus (HBV) genotypes on the clinical outcome remains controversial. This study has for the first time investigated the distribution of HBV genotypes in the serum and in the intrahepatic tissue of liver cirrhotic (LC) and hepatocellular carcinoma (HCC) patients from India. In addition, the genotype-genotype interplay and plausible mechanism of development of HCC has also been explored. METHODS: The assessment of HBV genotypes was performed by nested PCR using either surface or HBx specific primers from both the circulating virus in the serum and replicative virus that includes covalently closed circular DNA (cccDNA) and relaxed circular DNA (rcDNA) of HBV from the intrahepatic tissue. The integrated virus within the host chromosome was genotyped by Alu-PCR method. Each PCR products were cloned and sequences of five randomly selected clones were subsequently analysed. RESULTS: HBV/genotype D was detected in the serum of all LC and HCC patients whereas the sequences of the replicative HBV DNA (cccDNA and rcDNA) from the intrahepatic tissue of the same patients revealed the presence of both HBV/genotype C and D. The sequences of the integrated viruses exhibited the solo presence of HBV/genotype C in the majority of LC and HCC tissues while both HBV/genotype C and D clones were found in few patients in which HBV/genotype C was predominated. Moreover, compared to HBV/genotype D, genotype C had higher propensity to generate double strand breaks, ER stress and reactive oxygen species and it had also showed higher cellular homologous-recombination efficiency that engendered more chromosomal rearrangements, which ultimately led to development of HCC. CONCLUSIONS: Our study highlights the necessity of routine analysis of HBV genotype from the liver tissue of each chronic HBV infected patient in clinical practice to understand the disease prognosis and also to select therapeutic strategy. PMID- 25032958 TI - BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei. AB - While the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are thought to primarily depend on glycolysis for ATP synthesis, recent studies have shown that they can fully catabolize glucose in a canonical TCA cycle. However, these parasites lack a mitochondrial isoform of pyruvate dehydrogenase and the identity of the enzyme that catalyses the conversion of pyruvate to acetyl-CoA remains enigmatic. Here we demonstrate that the mitochondrial branched chain ketoacid dehydrogenase (BCKDH) complex is the missing link, functionally replacing mitochondrial PDH in both T. gondii and P. berghei. Deletion of the E1a subunit of T. gondii and P. berghei BCKDH significantly impacted on intracellular growth and virulence of both parasites. Interestingly, disruption of the P. berghei E1a restricted parasite development to reticulocytes only and completely prevented maturation of oocysts during mosquito transmission. Overall this study highlights the importance of the molecular adaptation of BCKDH in this important class of pathogens. PMID- 25032959 TI - Effects of exogenous recombinant APC in mouse models of ischemia reperfusion injury and of atherosclerosis. AB - Activated protein C (APC) is a serine protease that has both anticoagulant and cytoprotective properties. The cytoprotective effects are protease activated receptor 1 (PAR-1) and endothelial protein C receptor (EPCR) dependent and likely underlie protective effects of APC in animal models of sepsis, myocardial infarction and ischemic stroke. S360A-(A)PC, a variant (A)PC that has no catalytic activity, binds EPCR and shifts pro-inflammatory signaling of the thrombin-PAR-1 complex to anti-inflammatory signaling. In this study we investigated effects of human (h)wt-PC, hS360A-PC, hwt-APC and hS360A-APC in acute (mouse model of acute myocardial ischemia/reperfusion (I/R) injury) and chronic inflammation (apoE-/- mouse model of atherosclerosis). All h(A)PC variants significantly reduced myocardial infarct area (p<0.05) following I/R injury. IL-6 levels in heart homogenates did not differ significantly between sham, placebo and treatment groups in I/R injury. None of the h(A)PC variants decreased number and size of atherosclerotic plaques in apoE-/- mice. Only hS360A APC slightly affected phenotype of plaques. IL-6 levels in plasma were significantly (p<0.001) decreased in hwt-APC and hS360A-PC treated mice. In the last group levels of monocyte chemotactic protein 1 (MCP-1) were significantly increased (p<0.05). In this study we show that both hwt and hS360A-(A)PC protect against acute myocardial I/R injury, which implies that protection from I/R injury is independent of the proteolytic activity of APC. However, in the chronic atherosclerosis model hwt and hS360-(A)PC had only minor effects. When the dose, species and mode of (A)PC administration will be adjusted, we believe that (A)PC will have potential to influence development of chronic inflammation as occurring during atherosclerosis as well. PMID- 25032960 TI - Pharmacologic inhibition of sphingomyelin synthase (SMS) activity reduces apolipoprotein-B secretion from hepatocytes and attenuates endotoxin-mediated macrophage inflammation. AB - Sphingomyelin synthase (SMS) plays an important role in plasma atherogenic lipoprotein metabolism, inflammation, and the development of atherosclerosis. To understand whether the impaired apoB secretion and inflammation response is a direct result from lack of SMS activity, in this study, we prepared a series of compounds that inhibit SMS activity. Further, we characterized Dy105, the most potent inhibitor. We found that Dy105 treatment significantly reduces SM levels in SM-rich microdomain on cell membranes. Moreover, we found that SMS inhibition reduces apoB secretion in a human hepatoma cell line and reduces the activation of NFkappaB and p38, a MAP kinase, in bone marrow derived macrophages. These studies provided further evidence that SMS activity regulates atherogenic lipoprotein metabolism and inflammatory responses. Pharmacologic inhibition of SMS may be a new therapy for atherosclerosis by reducing apoB secretion, and reducing inflammation. PMID- 25032961 TI - Decay-accelerating factor 1 deficiency exacerbates leptospiral-induced murine chronic nephritis and renal fibrosis. AB - Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1-/- mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1-/- mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1-/- mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of alpha-smooth muscle actin, galectin-3, TGF-beta1, IL-17, IFN-gamma, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1-/- mice was accompanied by high expression of alpha-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-gamma, similar levels of TGF-beta1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1. PMID- 25032962 TI - Glaucomatous and age-related changes in corneal pulsation shape. The ocular dicrotism. AB - PURPOSE: To ascertain whether the incidence of ocular dicrotic pulse (ODP) increases with age, it is more pronounced in glaucomatous than in normal eyes and whether it is related to cardiovascular activity. METHODS: 261 subjects aged 47 to 78 years were included in the study and classified into four groups: primary open angle glaucoma (POAG), primary angle-closure glaucoma (PACG), glaucoma suspects with glaucomatous optic disc appearance (GODA) and the controls (CG). Additionally, in each group, subjects with ODP were divided into two age subgroups around the median age. A non-contact ultrasonic method was used to measure corneal indentation pulse (CIP) synchronically with the acquisition of electrocardiography (ECG) and blood pulse signals. ODP was assessed from the acquired signals that were numerically processed in a custom written program. RESULTS: ODP incidence was about 78%, 66%, 66% and 84% for CG, GODA, POAG, and PACG group, respectively. With advancing age, the ODP incidence increased for all subjects (Delta = 12%), the highest being for the PACG and POAG groups (Delta = 30%). GODA group did not show an age-related increase in the incidence of ODP. CONCLUSIONS: The ocular dicrotism, measured with non-contact ultrasonic method, was found to be a common phenomenon in elderly subjects. The increased ODP incidence in PACG and POAG group may correspond to either higher stiffness of glaucoma eyes, biochemical abnormalities in eye tissues, changes in ocular hemodynamics, may reflect the effect of medications or be a combination of all those factors. The results of GODA group suggest different mechanisms governing their ocular pulse that makes them less susceptible to generating ODP and having decreased predisposition to glaucoma. PMID- 25032963 TI - Decoding vigilance with NIRS. AB - Sustained, long-term cognitive workload is associated with variations and decrements in performance. Such fluctuations in vigilance can be a risk factor especially during dangerous attention demanding activities. Functional MRI studies have shown that attentional performance is correlated with BOLD-signals, especially in parietal and prefrontal cortical regions. An interesting question is whether these BOLD-signals could be measured in real-world scenarios, say to warn in a dangerous workplace whenever a subjects' vigilance is low. Because fMRI lacks the mobility needed for such applications, we tested whether the monitoring of vigilance might be possible using Near-Infrared Spectroscopy (NIRS). NIRS is a highly mobile technique that measures hemodynamics in the surface of the brain. We demonstrate that non-invasive NIRS signals correlate with vigilance. These signals carry enough information to decode subjects' reaction times at a single trial level. PMID- 25032965 TI - Paleohistology and lifestyle inferences of a dyrosaurid (Archosauria: Crocodylomorpha) from Paraiba Basin (northeastern Brazil). AB - Among the few vertebrates that survived the mass extinction event documented at the Cretaceous-Paleocene boundary are dyrosaurid crocodylomorphs. Surprisingly, there is little information regarding the bone histology of dyrosaurids, despite their relatively common occurrence in the fossil record, and the potential to gain insight about their biology and lifestyle. We provide the first description of the long bone histology of the dyrosaurids. Specimens were collected from the Maria Farinha Formation, in the Paraiba Basin of northeast Brazil. Thin sections of a right femur and left tibia were made. In the left tibia, the cortex consists of lamellar-zonal bone with five lines of arrested growth (LAGs), spaced ~300 um apart. The tibia contains a small to medium-sized organized vascular network of both simple vascular canals and primary osteons that decrease in density periostially. The femur exhibits a similar histological pattern overall but has double-LAGs, and an EFS layer (the latter is rare in living crocodylians). Secondary osteons occur in the deep cortex near and inside the spongiosa as a result of remodeling in both bones. This tissue pattern is fairly common among slow-growing animals. These specimens were a sub-adult and a senescent. Patterns in the distribution of bone consistent with osteosclerosis suggest that these animals probably hada fast-swimming ecology. Although these results are consistent with the histology in anatomically convergent taxa, it will be necessary to make additional sections from the mid-diaphysis in order to assign their ecology. PMID- 25032964 TI - Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of duchenne muscular dystrophy. AB - SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1alpha, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1alpha targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases. PMID- 25032966 TI - Studies in balance function testing: the American Balance Society (ABS). PMID- 25032967 TI - Jendrassik maneuver facilitates cVEMP amplitude: some preliminary observations. AB - BACKGROUND: The cervical vestibular evoked myogenic potential (cVEMP) is an acoustically driven electrophysiological measure of saccular and inferior nerve function that requires tonic sternocleidomastoid muscle (SCM) activity in order to be elicited. The cVEMP is gaining increased interest in the clinical and research communities based on the anatomical specificity it adds to vestibular test batteries, because it is noninvasive, and since it can be performed with instrumentation commonly found in audiology clinics worldwide. PURPOSE: Because maintaining a constant level of tonic background electromyography (EMG) over the entire course of the recording epoch is a requirement for response elicitation, active participation for some individuals including the elderly and those with cervical problems can be difficult. As a way to facilitate the response for some clinical populations, this study addressed whether cVEMPs could be modulated by remote or local changes in EMG related neural activity by applying various maneuvers during the course of the recording epoch. RESEARCH DESIGN: Keeping acoustic stimulation and recording parameters constant, three separate experimental conditions, Jendrassik maneuver, jaw (teeth) clenching, and forced eye closure, were used to determine whether cVEMP amplitudes could be enhanced from the control condition. STUDY SAMPLE: Nine adults (2 males; 7 females) ranging in age from 24 to 42 yr with normal pure-tone hearing sensitivity and a negative history of otological disease, neurological disease, and head trauma. DATA COLLECTION AND ANALYSIS: Cervical vestibular evoked myogenic potentials were recorded from the SCM using surface electrodes in response to suprathreshold 500 Hz Blackman windowed tone bursts under a control and three experimental conditions. Three separate one-way repeated measures analyses of variance (ANOVAs) were used to evaluate the effects of these maneuvers on P1/N1 peak-to peak amplitudes and P1 and N1 peak latencies. RESULTS: A significant main effect of experimental condition was shown to increase P1/N1 peak-to-peak cVEMP amplitude. Post hoc analysis found that Jendrassik maneuver versus control was the only the condition that produced significantly increased response amplitudes in comparison to all other post hoc contrasts. P1 and N1 peak latencies were unchanged across the various experimental conditions. CONCLUSIONS: In adults with normal hearing sensitivity and a negative history of otological disease, neurological disease, and head trauma, Jendrassik maneuver increased cVEMP amplitude by over 39% in comparison to the control condition. Such a simple modulation effect warrants further investigation for application in clinical studies. PMID- 25032968 TI - Normative data and test-retest reliability of the SYNAPSYS video head impulse test. AB - BACKGROUND: The observation or measurement of eye movement can aid in the detection and localization of vestibular pathology due to the relationship between the function of the vestibular sensory receptors in the inner ear and the eye movements produced by the vestibulo-ocular reflex (VOR). The majority of bedside and laboratory tests of vestibular function involve the observation or measurement of horizontal eye movements (i.e., horizontal VOR) produced by stimuli that activate the horizontal semicircular canals (SCCs) and the superior vestibular nerve. The video head impulse test (vHIT) is a new clinical test of dynamic SCC function that uses a high-speed digital video camera to record head and eye movement during and immediately after passive head rotations. The SYNAPSYS Inc. vHIT device measures the "canal deficit" (deviation in gaze) during passive head impulses in the horizontal and diagonal (vertical) planes. There is, however, a paucity of data that has been reported using this device. PURPOSE: The purpose of this study was to obtain normative data and assess the test-retest reliability of the SYNAPSYS vHIT (version 2.0). RESEARCH DESIGN: A prospective repeated measures design was utilized. STUDY SAMPLE: Thirty young adults with normal hearing, normal caloric test results, and a negative history of vestibular disorder, neurological disease, open or closed head injury, or cervical spine injury participated in the study. DATA COLLECTION AND ANALYSIS: A single examiner manually rotated each participant's head in the horizontal and diagonal planes in two directions (left and right in the horizontal plane; downward and upward in each diagonal plane) resulting in the stimulation of each of the six SCCs. Each participant returned for repeat testing to assess test-retest reliability. The effects of ear, session, and semicircular canal (horizontal, anterior, posterior) on the magnitude of canal deficit during the vHIT were assessed using repeated measures analysis of variance. RESULTS: The mean canal deficit of the horizontal canals (8.3%) was significantly lower than the mean canal deficit of the anterior canals (16.5%) and the posterior canals (15.2%); there was no significant difference between the mean canal deficits of the anterior and posterior canals. The main effects of session and ear on canal deficit were not significant, and there were no significant interaction effects. There was no significant difference between the mean canal deficit for session 1 and session 2 for the horizontal, anterior, and posterior canals. The 95th percentiles for canal deficit were 19, 26, and 22% for the horizontal, anterior, and posterior SCCs, respectively. CONCLUSIONS: Testing of all six SCCs was completed in most participants in ~10 min and was well-tolerated. The vHIT has some important advantages relative to more established laboratory tests of horizontal SCC function including the ability to assess the vertical SCCs, lower cost, shorter test time, greater portability, minimal space requirements, and increased patient comfort. Additional data, however, should be obtained from older participants with normal vestibular function and from patients with vestibular disorders. Within-subject comparisons between the results of the vHIT and the caloric and rotary chair tests will be important in determining the role of the vHIT in the vestibular test battery. PMID- 25032969 TI - Subjective visual vertical (SVV) patterns obtained using different translation times during unilateral centrifugation (UC) testing. AB - BACKGROUND: Unilateral centrifugation (UC) is a test of utricular function that involves the eccentric displacement of a patient while undergoing high velocity rotation. These off-center placements permit evaluation of utricles as only one organ is subjected to linear stimulation. Currently, several different protocols are used for translation times between positions (e.g., Clarke et al, 1996; Wuyts et al, 2003). PURPOSE: This study examined the effects of different translation times between eccentric and centric positions during UC on an individual's perceived subjective visual vertical (SVV). RESEARCH DESIGN: A prospective repeated measures design was used in this study. STUDY SAMPLE: Forty-three young adults with no history or complaints of vestibular or neurological disorders participated in this study. DATA COLLECTION: All testing was performed on a Neuro Kinetics Inc. (Pittsburgh, PA) Neuro-Otologic Test Center (NOTC) rotational chair at the Bloomsburg University of Pennsylvania Vestibular Clinic. Each participant completed six SVV trials in the static condition (sSVV) as a baseline of function. In addition, each participant completed UC trials using a rotational velocity of 300 degrees /sec with 4 cm eccentric lateral displacements that were maintained for 60 sec per position. Translations of 5, 10, 15, 20, 25, and 30 sec were randomized. The maximum velocity was maintained for 90 sec prior to the eccentric placement. Multiple estimations of dynamic subjective visual vertical (dSVV) were performed for each position. RESULTS: dSVV data yielded several trends. At 5 sec translations, dSVV values had greater variability and required longer for participant responses to stabilize. Regardless of UC translation time, initial trial values were often quite different from the remaining trials. Shorter UC translation times were associated with more eccentric dSVV values outside of the clinical norms. While not statistically significant, more variance was associated with the shortest UC translation times, while 15 and 25 sec translation data demonstrated the best correlations and lowest variances. DISCUSSION: Findings suggest that incorporating sSVV data to normalize dSVV data should be considered to reduce the influence of the underlying baseline static otolithic function on the UC results. The presence of a clear tendency for shorter UC translation times to be associated with larger numbers of clinically abnormal findings may indicate that very short UC translation times may not be ideal for clinical applications. This is supported by our finding that longer UC translation times elicited more consistent SVV results and less response variability. While some of these findings were not statistically significant, the results do suggest that clinical UC testing may benefit from optimization of translation time as well as inclusion of sSVV in response interpretation. PMID- 25032970 TI - The influence of caffeine on calorics and cervical vestibular evoked myogenic potentials (cVEMPs). AB - BACKGROUND: Prior to undergoing vestibular function testing, it is not uncommon for clinicians to request that patients abstain from caffeine 24 hr prior to the administration of the tests. However, there is little evidence that caffeine affects vestibular function. PURPOSE: To evaluate whether the results from two tests commonly used in a clinical setting to assess vestibular function (i.e., calorics and the cervical vestibular evoked myogenic potential [cVEMP]) are affected by caffeine. RESEARCH DESIGN: Subjects were tested with and without consuming a moderate amount of caffeine prior to undergoing calorics and cVEMPs. STUDY SAMPLE: Thirty young healthy controls (mean = 23.28 yr; females = 21). Subjects were excluded if they reported any history of vestibular/balance impairment. DATA COLLECTION AND ANALYSIS: The Variotherm Plus Caloric Irrigator was used to administer the water, while the I-Portal VNG software was used to collect and analyze subjects' eye movements. The TECA Evoked Potential System was used for the cVEMP stimulus presentation as well as for the data collection. During cVEMP collection, subjects were asked to monitor their sternocleidomastoid muscle contraction with a Delsys EMG monitor. IBM SPSS Statistics 20 was used to statistically analyze the results via paired t-tests. RESULTS: Analysis of the data revealed that ingestion of caffeine did not significantly influence the results of either test of vestibular function. CONCLUSIONS: The results revealed that a moderate amount of caffeine does not have a clinically significant effect on the results from caloric and cVEMP tests in young healthy adults. Future research is necessary to determine whether similar results would be obtained from individuals with a vestibular impairment, as well as older adults. PMID- 25032971 TI - Amplitude normalization reduces cervical vestibular evoked myogenic potential (cVEMP) amplitude asymmetries in normal subjects: proof of concept. AB - BACKGROUND: The cervical vestibular evoked myogenic potential (cVEMP) is an acoustically synchronized, signal averaged, brief inhibitory response of a contracted muscle usually resulting from an acoustic stimulus. The cVEMP is recorded from the tonically contracted sternocleidomastoid muscle (SCM). The presence and amplitude of the cVEMP is related to both the integrity of the sacculo-collic pathway and magnitude of electromyographic (EMG) activity at the time of recording. Measurement variables include the absolute latency of the primary positive going component (referred to as P13) and interaural (i.e., left versus right) latency differences. Also measured is the peak-to-peak interaural amplitude asymmetry (IAA; percent difference in amplitude, left versus right). It is known that the amplitude of the cVEMP is positively correlated with the magnitude of tonic EMG from which the evoked potential is extracted. Thus, if EMG amplitude is uncontrolled, one cannot determine whether cVEMP asymmetries are occurring due to unilateral end organ disease or asymmetric tonic EMG activity. Two methods have been suggested to control for tonic EMG activity. These include (1) patient self-monitoring of EMG activity with biofeedback and (2) mathematical correction (i.e., amplitude normalization) of the left and right cVEMP waveforms. Currently, it is unknown how effective amplitude normalization techniques are at reducing cVEMP amplitude asymmetry in the presence of varying levels of EMG. PURPOSE: The purpose of this investigation was to determine whether the use of amplitude correction techniques would reduce significantly the P13-N23 IAA data in otologically and neurologically intact adults when the level of EMG was varied between right and left sides. RESEARCH DESIGN: A prospective, repeated measures design was used for three different investigations in which cVEMPs were recorded and then processed using amplitude correction. STUDY SAMPLE: Subjects were 20 otologically and neurologically health young adults between 21 and 29 yr of age. INTERVENTION: cVEMPs were recorded at four different EMG target levels ranging from 100 to 400 MUV. The absolute peak-to-peak amplitude of P13-N23, absolute latency of P13, and the left/right amplitude asymmetry of P13-N23 were measured both with and without the use of EMG amplitude correction techniques. IAAs were calculated using 10 different conditions of varying EMG asymmetry with and without amplitude correction. DATA COLLECTION AND ANALYSIS: Data were analyzed using repeated measures analysis of variance (ANOVA) to detect tonic EMG level dependent differences separately for P13 latency, P13-N23 peak-to-peak amplitude, and mean root mean square (RMS) amplitude cVEMP responses. The amplitude of cVEMP responses from the left and right side were used to calculate IAA for subsequent analyses. Linear regression analyses compared level of tonic EMG with cVEMP amplitude. A one-way multivariate analysis of variance (MANOVA) was used to determine if IAAs were significantly reduced following amplitude correction. Any differences found were investigated using unplanned linear contrasts. RESULTS: The uncorrected cVEMP amplitude and RMS EMG all increased significantly with increases in the EMG target levels. With amplitude correction, cVEMP amplitude did not change significantly with changes in RMS EMG or EMG target levels. CONCLUSIONS: These findings suggest that the use of amplitude correction techniques represent an effective method of neutralizing the factor of variability in tonic EMG level on the cVEMP that would be otherwise uncontrolled. Indeed when correction is employed in cases of extreme tonic EMG asymmetry, the upper limit of percent IAA is roughly half of that when EMG correction techniques are not used. Our findings are also in agreement with those of Bogle et al (2013) showing that the input/output growth function for P13/N23 amplitude is not linear but, in fact, saturates at supra-maximal stimulation levels. Accordingly, and contrary to what has been published previously, achieving maximum muscle activation may produce a paradoxically inferior signal-to-noise ratio and in some cases result in an artificially small (or undetectable) corrected cVEMP amplitude. cVEMP amplitude either asymptotes (if maximum EMG amplitude saturation occurs at the same stimulus intensity as yields the maximum cVEMP amplitude), or the cVEMP can become smaller if EMG amplitude can increase further beyond the stimulus intensity that yields that largest P1-N1 amplitude. In the latter case the noise increases further to reach maximum and creates a disadvantageous signal (cVEMP) to noise (tonic EMG) ratio. PMID- 25032972 TI - Cervical VEMP threshold response curve in the identification of Meniere's disease. AB - PURPOSE: To investigate the sensitivity/specificity of a shift upward in the most sensitive frequency of the cervical vestibular evoked myogenic potential (cVEMP) threshold-response curve in the identification of Meniere's disease (MD). A secondary purpose was to investigate the clinical characteristics that had an impact on the sensitivity/specificity and to adjust the criteria for a positive shift upward in the cVEMP curve to maximize performance of the test. RESEARCH DESIGN: A retrospective review of patients diagnosed with MD and those without MD. STUDY SAMPLE: Two hundred ninety-four patients met the inclusion criteria of symptom complaints of spontaneous events of vertigo and a full vestibular and balance evaluation with cVEMP threshold-response curve testing. Two hundred six of these patients were diagnosed with MD, and 88 patients were determined to be non-MD. DATA COLLECTION AND ANALYSIS: Review of the patients' medical records was used to extract data on the results of the cVEMP curve, age, gender, duration from time of onset of spontaneous events, pure tone average from hearing test, and water caloric asymmetry. Student's t-test, chi2 test, receiver operating characteristic (ROC) curve with area under the curve (AUC), Pearson correlation coefficient, and sensitivity/specificity from 2 * 2 tables were all used in the analysis. RESULTS: Basic sensitivity/specificity for a shift upward in the most sensitive frequency to 1000 Hz in the cVEMP threshold-response curve was 0.47/0.64 respectively. Clinical characteristics that were found to have a significant impact on the sensitivity/specificity were age equal to or above 60 yr and a caloric asymmetry >=25%. Various combinations of age and caloric with the requirement of a shift upward in the cVEMP curve most sensitive frequency to 1000 Hz resulted in significant but modest improvements in sensitivity/specificity. However, the overall performance was not shown acceptable for routine clinical use with maximum sensitivity at 0.73. Therefore, placing an emphasis on specificity over sensitivity results showed specificity of 0.95 for those under 60 yr and 0.90 for those 60 yr of age or older with sensitivity at 0.20, but only in the context of a >=25% caloric asymmetry. CONCLUSIONS: We recommend the use of the shift upward to 1000 Hz with a caloric asymmetry as the clinical protocol to maximize the use of the cVEMP threshold response curve for assistance in the identification of MD, in the context of a >=25% caloric asymmetry. This implies that if the test is negative no interpretation of identification of MD can be made. If the test is positive the results can be used to increase the argument for MD since the probability of the result being a false positive is only 5-10%. PMID- 25032973 TI - Genetics of peripheral vestibular dysfunction: lessons from mutant mouse strains. AB - BACKGROUND: A considerable amount of research has been published about genetic hearing impairment. Fifty to sixty percent of hearing loss is thought to have a genetic cause. Genes may also play a significant role in acquired hearing loss due to aging, noise exposure, or ototoxic medications. Between 1995 and 2012, over 100 causative genes have been identified for syndromic and nonsyndromic forms of hereditary hearing loss. Mouse models have been extremely valuable in facilitating the discovery of hearing loss genes and in understanding inner ear pathology due to genetic mutations or elucidating fundamental mechanisms of inner ear development. PURPOSE: Whereas much is being learned about hereditary hearing loss and the genetics of cochlear disorders, relatively little is known about the role genes may play in peripheral vestibular impairment. Here we review the literature with regard to genetics of vestibular dysfunction and discuss what we have learned from studies using mutant mouse models and direct measures of peripheral vestibular neural function. RESULTS: Several genes are considered that when mutated lead to varying degrees of inner ear vestibular dysfunction due to deficits in otoconia, stereocilia, hair cells, or neurons. Behavior often does not reveal the inner ear deficit. Many of the examples presented are also known to cause human disorders. CONCLUSIONS: Knowledge regarding the roles of particular genes in the operation of the vestibular sensory apparatus is growing, and it is clear that gene products co-expressed in the cochlea and vestibule may play different roles in the respective end organs. The discovery of new genes mediating critical inner ear vestibular function carries the promise of new strategies in diagnosing, treating, and managing patients as well as predicting the course and level of morbidity in human vestibular disease. PMID- 25032976 TI - Equivalence assessment for interchangeability based on two-sided tests. AB - Interchangeability was originally developed in order to assess drug bioequivalence beyond average bioequivalence. In 2003, the Food and Drug Administration (FDA) published a Guidance documenting the procedures on using in vivo bioequivalence crossover trial to assess interchangeability between test and reference products. In general, this FDA Guidance describes interchangeability in terms of population and individual bioequivalence. The Guidance procedures were criticized for their lack of sampling distribution of the test statistics. As a result, the critical points were generated from simulation studies without adjusting for sample size. Further more, they lack consistency with average bioequivalence required in the 1992 FDA Guidance. Alternative interchangeability or interchangeability procedures were proposed to measure the probability of individual response difference under two treatments within prespecified lower and upper limits. Interchangeability is claimed if this probability is greater than a prespecified threshold. Tse et al. (2006) proposed an approximate distribution of the estimated probability based on the second-order Taylor expansion. For the same interchangeability probability hypothesis, Liu and Chow (1997) and Tsong and Shen (2007) also proposed a tolerance interval-based approach that can be extended to clinical trials with parallel arm design under the normality assumption. In this article, we first generalized the two-sided tolerance interval based interchangeability without equal sample size and variance assumption. We also derived a power function for the proposed method, and performed simulation studies to compare the type I error rate, power, and sample size between the Tse approximated test and the generalized tolerance interval approach for interchangeability assessment. PMID- 25032975 TI - Oroya fever and verruga peruana: bartonelloses unique to South America. AB - Bartonella bacilliformis is the bacterial agent of Carrion's disease and is presumed to be transmitted between humans by phlebotomine sand flies. Carrion's disease is endemic to high-altitude valleys of the South American Andes, and the first reported outbreak (1871) resulted in over 4,000 casualties. Since then, numerous outbreaks have been documented in endemic regions, and over the last two decades, outbreaks have occurred at atypical elevations, strongly suggesting that the area of endemicity is expanding. Approximately 1.7 million South Americans are estimated to be at risk in an area covering roughly 145,000 km2 of Ecuador, Colombia, and Peru. Although disease manifestations vary, two disparate syndromes can occur independently or sequentially. The first, Oroya fever, occurs approximately 60 days following the bite of an infected sand fly, in which infection of nearly all erythrocytes results in an acute hemolytic anemia with attendant symptoms of fever, jaundice, and myalgia. This phase of Carrion's disease often includes secondary infections and is fatal in up to 88% of patients without antimicrobial intervention. The second syndrome, referred to as verruga peruana, describes the endothelial cell-derived, blood-filled tumors that develop on the surface of the skin. Verrugae are rarely fatal, but can bleed and scar the patient. Moreover, these persistently infected humans provide a reservoir for infecting sand flies and thus maintaining B. bacilliformis in nature. Here, we discuss the current state of knowledge regarding this life-threatening, neglected bacterial pathogen and review its host-cell parasitism, molecular pathogenesis, phylogeny, sand fly vectors, diagnostics, and prospects for control. PMID- 25032978 TI - Metabolite Profiling of Root Exudates of Common Bean under Phosphorus Deficiency. AB - Root exudates improve the nutrient acquisition of plants and affect rhizosphere microbial communities. The plant nutrient status affects the composition of root exudates. The purpose of this study was to examine common bean (Phaseolus vulgaris L.) root exudates under phosphorus (P) deficiency using a metabolite profiling technique. Common bean plants were grown in a culture solution at P concentrations of 0 (P0), 1 (P1) and 8 (P8) mg P L-1 for 1, 10 and 20 days after transplanting (DAT). Root exudates were collected, and their metabolites were determined by capillary electrophoresis time-of-flight mass spectrometry (CE-TOF MS). The shoot P concentration and dry weight of common bean plants grown at P0 were lower than those grown at P8. One hundred and fifty-nine, 203 and 212 metabolites were identified in the root exudates, and 16% (26/159), 13% (26/203) and 9% (20/212) of metabolites showed a P0/P8 ratio higher than 2.0 at 1, 10 and 20 DAT, respectively. The relative peak areas of several metabolites, including organic acids and amino acids, in root exudates were higher at P0 than at P8. These results suggest that more than 10% of primary and secondary metabolites are induced to exude from roots of common bean by P deficiency. PMID- 25032977 TI - Antimony resistant Leishmania donovani but not sensitive ones drives greater frequency of potent T-regulatory cells upon interaction with human PBMCs: role of IL-10 and TGF-beta in early immune response. AB - In India the sand fly, Phlebotomus argentipes, transmitted parasitic disease termed kala-azar is caused by Leishmania donovani (LD) in humans. These immune evading parasites have increasingly developed resistance to the drug sodium antimony gluconate in endemic regions. Lack of early diagnosis methods for the disease limits the information available regarding the early interactions of this parasite with either human tissues or cell lineages. We reasoned that peripheral blood mononuclear cells (PBMCs) from healthy human beings could help compare some of their immune signatures once they were exposed for up to 8 days, to either pentavalent antimony sensitive (Sb(S)-LD) or resistant (Sb(R)-LD) Leishmania donovani isolates. At day 2, PBMC cultures exposed to Sb(S)-LD and Sb(R)-LD stationary phase promastigotes had four and seven fold higher frequency of IL-10 secreting monocyte-macrophage respectively, compared to cultures unexposed to parasites. Contrasting with the CD4(+)CD25-CD127- type-1 T-regulatory (Tr1) cell population that displayed similar features whatever the culture conditions, there was a pronounced increase in the IL-10 producing CD4(+)CD25(+)CD127low/- inducible T-regulatory cells (iTregs) in the PBMC cultures sampled at day 8 post addition of Sb(R)-LD. Sorted iTregs from different cultures on day 8 were added to anti-CD3/CD28 induced naive PBMCs to assess their suppressive ability. We observed that iTregs from Sb(R)-LD exposed PBMCs had more pronounced suppressive ability compared to Sb(S)-LD counterpart on a per cell basis and is dependent on both IL-10 and TGF-beta, whereas IL-10 being the major factor contributing to the suppressive ability of iTregs sorted from PBMC cultures exposed to Sb(S)-LD. Of note, iTreg population frequency value remained at the basal level after addition of genetically modified Sb(R)-LD lacking unique terminal sugar in surface glycan. Even with limitations of this artificial in vitro model of L. donovani-human PBMC interactions, the present findings suggest that Sb(R)-LD have higher immunomodulatory capacity which may favour aggressive pathology. PMID- 25032980 TI - Predicting the impact of biocorona formation kinetics on interspecies extrapolations of nanoparticle biodistribution modeling. AB - AIM: To assess the impact of biocorona kinetics on expected tissue distribution of nanoparticles (NPs) across species. MATERIALS & METHODS: The potential fate of NPs in vivo is described through a simple and descriptive pharmacokinetic model using rate processes dependent upon basal metabolic rate coupled to dynamics of protein corona. RESULTS: Mismatch of time scales between interspecies allometric scaling and the kinetics of corona formation is potentially a fundamental issue with interspecies extrapolations of NP biodistribution. The impact of corona evolution on NP biodistribution across two species is maximal when corona transition half-life is close to the geometric mean of NP half-lives of the two species. CONCLUSION: While engineered NPs can successfully reach target cells in rodent models, the results may be different in humans due to the fact that the longer circulation time allows for further biocorona evolution. PMID- 25032981 TI - Unexplained infertility patients have increased serum IL-2, IL-4, IL-6, IL-8, IL 21, TNFalpha, IFNgamma and increased Tfh/CD4 T cell ratio: increased Tfh and IL 21 strongly correlate with presence of autoantibodies. AB - Infertility is a disease of the reproductive system that affects millions of people globally. Reproductive failure is a major medical issue adversely affecting human health in the 21st century. Many factors contribute to infertility, including immune conditions which may lead to immune infertility (immunologic infertility). It is known that specific T helper cells (Th) and their cytokines are involved in the stages of infertility. The aim of this study is to provide a new diagnostic approach to immunologic infertility by investigating the correlation of follicular helper T cells (Tfh) and their secreted cytokines with the autoantibodies in peripheral blood samples from immunologically infertile patients. Thirty (30) patients suffering from immune infertility and 20 control subjects were selected as the sample base for this study. The levels of Tfh, 20 cytokines and 4 antibodies were evaluated for this investigation and evaluated using flow cytometry, antibody chip and ELISA technologies. It was found that, in immunologically infertile patients, Tfh cell numbers were significantly higher than those in the control group. Likewise, seven (7) serum cytokines were expressed to a greater degree in infertile patients compared to the control group. Finally, four (4) antibodies were found to be higher in immunologically infertile patients. The results show that, among patients with immunologic infertility, the levels of Tfh cells and IL-21 were increased significantly in peripheral blood samples and correlate positively with the autoantibodies. IL-12 was positively correlated with the two antibodies, while TNFalpha was negatively correlated with two additional antibodies. The detection and quantification of Tfh cells, IL-21, IL-12 and TNFalpha may provide new diagnostic indicators to screen for immunologic infertility. PMID- 25032982 TI - Therapies for onychomycosis a systematic review and network meta-analysis of mycological cure. AB - New therapies for onychomycosis continue to be developed, yet treatments are seldom directly compared in randomized controlled trials. The objective of this study was to compare the rates of mycological cure for oral and topical onychomycosis treatments using network meta-analysis. A systematic review of the literature on onychomycosis treatments published before March 25, 2013, was performed, and data were analyzed using network meta-analysis. Terbinafine, 250 mg, therapy was significantly superior to all treatments except itraconazole, 400 mg, pulse therapy; itraconazole, 200 mg, therapy was significantly superior to fluconazole and the topical treatments; and fluconazole, efinaconazole, ciclopirox, terbinafine nail solution, and amorolfine treatments were significantly superior to only placebo. These results support the superiority of 12-week continuous terbinafine, 250 mg, therapy and itraconazole, 400 mg, pulse therapy (1 week per month for 3 months) while suggesting the equivalence of topical therapies. These results reflect findings from the literature and treatment efficacy observed in clinical practice. PMID- 25032985 TI - Improved molecular diagnosis by the detection of exonic deletions with target gene capture and deep sequencing. AB - PURPOSE: We aimed to demonstrate the detection of exonic deletions using target capture and deep sequencing data. METHODS: Sequence data from target gene capture followed by massively parallel sequencing were analyzed for the detection of exonic deletions using the normalized mean coverage of individual exons. We compared the results with those obtained from high-density exon-targeted array comparative genomic hybridization and applied similar analysis to examine samples from patients with pathogenic exonic deletions. RESULTS: Thirty-eight samples, each containing 2,134, 2,833, or 4,688 coding exons from different panels, with a total of 103,863 exons, were analyzed by capture-massively parallel sequencing and array comparative genomic hybridization. Ten deletions detected by array comparative genomic hybridization were all detected by massively parallel sequencing, whereas only two of three duplications were detected. We were able to detect all pathogenic exonic deletions in 11 positive cases. Thirty-one exonic copy number changes from nine perspective clinical samples were also identified. CONCLUSION: Our results demonstrated the feasibility of using the same set of sequence data to detect both point mutations and exonic deletions, thus improving the diagnostic power of massively parallel sequencing-based assays. PMID- 25032986 TI - The genetics of luck. PMID- 25032984 TI - Hypoxic preconditioning differentially affects GABAergic and glutamatergic neuronal cells in the injured cerebellum of the neonatal rat. AB - In this study we examined cerebellar alterations in a neonatal rat model of hypoxic-ischemic brain injury with or without hypoxic preconditioning (Pc). Between postnatal days 7 and 15, the cerebellum is still undergoing intense cellular proliferation, differentiation and migration, dendritogenesis and synaptogenesis. The expression of glutamate decarboxylase 1 (GAD67) and the differentiation factor NeuroD1 were examined as markers of Purkinje and granule cells, respectively. We applied quantitative immunohistochemistry to sagittal cerebellar slices, and Western blot analysis of whole cerebella obtained from control (C) rats and rats submitted to Pc, hypoxia-ischemia (L) and a combination of both treatments (PcL). We found that either hypoxia-ischemia or Pc perturbed the granule cells in the posterior lobes, affecting their migration and final placement in the internal granular layer. These effects were partially attenuated when the Pc was delivered prior to the hypoxia-ischemia. Interestingly, whole nuclear NeuroD1 levels in Pc animals were comparable to those in the C rats. However, a subset of Purkinje cells that were severely affected by the hypoxic ischemic insult--showing signs of neuronal distress at the levels of the nucleus, cytoplasm and dendritic arborization--were not protected by Pc. A monoclonal antibody specific for GAD67 revealed a three-band pattern in cytoplasmic extracts from whole P15 cerebella. A ~110 kDa band, interpreted as a potential homodimer of a truncated form of GAD67, was reduced in Pc and L groups while its levels were close to the control animals in PcL rats. Additionally we demonstrated differential glial responses depending on the treatment, including astrogliosis in hypoxiated cerebella and a selective effect of hypoxia-ischemia on the vimentin-immunolabeled intermediate filaments of the Bergmann glia. Thus, while both glutamatergic and GABAergic cerebellar neurons are compromised by the hypoxic-ischemic insult, the former are protected by a preconditioning hypoxia while the latter are not. PMID- 25032987 TI - Multiplex genetic testing: reconsidering utility and informed consent in the era of next-generation sequencing. PMID- 25032988 TI - Horizontal integration of OMIM across the medical school preclinical curriculum for early reinforcement of clinical genetics principles. AB - PURPOSE: With the relentless expansion of genetics into every field of medicine, stronger preclinical and clinical medical student education in genetics is needed. The explosion of genetic information cannot be addressed by simply adding content hours. We proposed that students be provided a tool to access accurate clinical information on genetic conditions and, through this tool, build life long learning habits to carry them through their medical careers. METHODS: Surveys conducted at the Johns Hopkins University School of Medicine revealed that medical students in all years lacked confidence when approaching genetic conditions and lacked a reliable resource for accurate genetic information. In response, the school created a horizontal thread that stretches across the first year curriculum and is devoted to teaching students how to use Online Mendelian Inheritance in Man (OMIM) (http://omim.org) and the databases to which it links as a starting point for approaching genetic conditions. RESULTS: The thread improved the first-year students' confidence in clinical genetics concepts and encouraged use of OMIM as a primary source for genetic information. Most students showed confidence in OMIM as a learning tool and wanted to see the thread repeated in subsequent years. CONCLUSION: Incorporating OMIM into the preclinical curriculum improved students' confidence in clinical genetics concepts. PMID- 25032989 TI - Hepatitis C virus testing in adults living with HIV: a need for improved screening efforts. AB - OBJECTIVES: Guidelines recommend hepatitis C virus (HCV) screening for all people living with HIV (PLWH). Understanding HCV testing practices may improve compliance with guidelines and can help identify areas for future intervention. METHODS: We evaluated HCV screening and unnecessary repeat HCV testing in 8,590 PLWH initiating care at 12 U.S. HIV clinics between 2006 and 2010, with follow-up through 2011. Multivariable logistic regression examined the association between patient factors and the outcomes: HCV screening (>=1 HCV antibody tests during the study period) and unnecessary repeat HCV testing (>=1 HCV antibody tests in patients with a prior positive test result). RESULTS: Overall, 82% of patients were screened for HCV, 18% of those screened were HCV antibody-positive, and 40% of HCV antibody-positive patients had unnecessary repeat HCV testing. The likelihood of being screened for HCV increased as the number of outpatient visits rose (adjusted odds ratio 1.02, 95% confidence interval 1.01-1.03). Compared to men who have sex with men (MSM), patients with injection drug use (IDU) were less likely to be screened for HCV (0.63, 0.52-0.78); while individuals with Medicaid were more likely to be screened than those with private insurance (1.30, 1.04 1.62). Patients with heterosexual (1.78, 1.20-2.65) and IDU (1.58, 1.06-2.34) risk compared to MSM, and those with higher numbers of outpatient (1.03, 1.01 1.04) and inpatient (1.09, 1.01-1.19) visits were at greatest risk of unnecessary HCV testing. CONCLUSIONS: Additional efforts to improve compliance with HCV testing guidelines are needed. Leveraging health information technology may increase HCV screening and reduce unnecessary testing. PMID- 25032990 TI - Data integration in the era of omics: current and future challenges. AB - To integrate heterogeneous and large omics data constitutes not only a conceptual challenge but a practical hurdle in the daily analysis of omics data. With the rise of novel omics technologies and through large-scale consortia projects, biological systems are being further investigated at an unprecedented scale generating heterogeneous and often large data sets. These data-sets encourage researchers to develop novel data integration methodologies. In this introduction we review the definition and characterize current efforts on data integration in the life sciences. We have used a web-survey to assess current research projects on data-integration to tap into the views, needs and challenges as currently perceived by parts of the research community. PMID- 25032991 TI - Molecular mechanism of thiazolidinedione-mediated inhibitory effects on osteoclastogenesis. AB - Thiazolidinediones are synthetic peroxisome proliferator-activated receptor gamma agonists used to treat type 2 diabetes mellitus. Clinical evidence indicates that thiazolidinediones increase fracture risks in type 2 diabetes mellitus patients, but the mechanism by which thiazolidinediones augment fracture risks is not fully understood. Several groups recently demonstrated that thiazolidinediones stimulate osteoclast formation, thus proposing that thiazolidinediones induce bone loss in part by prompting osteoclastogenesis. However, numerous other studies showed that thiazolidinediones inhibit osteoclast formation. Moreover, the molecular mechanism by which thiazolidinediones modulate osteoclastogenesis is not fully understood. Here we independently address the role of thiazolidinediones in osteoclastogenesis in vitro and furthermore investigate the molecular mechanism underlying the in vitro effects of thiazolidinediones on osteoclastogenesis. Our in vitro data indicate that thiazolidinediones dose dependently inhibit osteoclastogenesis from bone marrow macrophages, but the inhibitory effect is considerably reduced when bone marrow macrophages are pretreated with RANKL. In vitro mechanistic studies reveal that thiazolidinediones inhibit osteoclastogenesis not by impairing RANKL-induced activation of the NF-kappaB, JNK, p38 and ERK pathways in bone marrow macrophages. Nonetheless, thiazolidinediones inhibit osteoclastogenesis by suppressing RANKL-induced expression of NFATc1 and c-Fos, two key transcriptional regulators of osteoclastogenesis, in bone marrow macrophages. In addition, thiazolidinediones inhibit the RANKL-induced expression of osteoclast genes encoding matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphatase and carbonic anhydrase II in bone marrow macrophages. However, the ability of thiazolidinediones to inhibit the expression of NFATc1, c-Fos and the four osteoclast genes is notably weakened in RANKL-pretreated bone marrow macrophages. These in vitro studies have not only independently demonstrated that thiazolidinediones exert inhibitory effects on osteoclastogenesis but have also revealed crucial new insights into the molecular mechanism by which thiazolidinediones inhibit osteoclastogenesis. PMID- 25032992 TI - Modeling bi-modality improves characterization of cell cycle on gene expression in single cells. AB - Advances in high-throughput, single cell gene expression are allowing interrogation of cell heterogeneity. However, there is concern that the cell cycle phase of a cell might bias characterizations of gene expression at the single-cell level. We assess the effect of cell cycle phase on gene expression in single cells by measuring 333 genes in 930 cells across three phases and three cell lines. We determine each cell's phase non-invasively without chemical arrest and use it as a covariate in tests of differential expression. We observe bi modal gene expression, a previously-described phenomenon, wherein the expression of otherwise abundant genes is either strongly positive, or undetectable within individual cells. This bi-modality is likely both biologically and technically driven. Irrespective of its source, we show that it should be modeled to draw accurate inferences from single cell expression experiments. To this end, we propose a semi-continuous modeling framework based on the generalized linear model, and use it to characterize genes with consistent cell cycle effects across three cell lines. Our new computational framework improves the detection of previously characterized cell-cycle genes compared to approaches that do not account for the bi-modality of single-cell data. We use our semi-continuous modelling framework to estimate single cell gene co-expression networks. These networks suggest that in addition to having phase-dependent shifts in expression (when averaged over many cells), some, but not all, canonical cell cycle genes tend to be co-expressed in groups in single cells. We estimate the amount of single cell expression variability attributable to the cell cycle. We find that the cell cycle explains only 5%-17% of expression variability, suggesting that the cell cycle will not tend to be a large nuisance factor in analysis of the single cell transcriptome. PMID- 25032993 TI - A hierarchical classification of benthic biodiversity and assessment of protected areas in the Southern Ocean. AB - An international effort is underway to establish a representative system of marine protected areas (MPAs) in the Southern Ocean to help provide for the long term conservation of marine biodiversity in the region. Important to this undertaking is knowledge of the distribution of benthic assemblages. Here, our aim is to identify the areas where benthic marine assemblages are likely to differ from each other in the Southern Ocean including near-shore Antarctica. We achieve this by using a hierarchical spatial classification of ecoregions, bathomes and environmental types. Ecoregions are defined according to available data on biogeographic patterns and environmental drivers on dispersal. Bathomes are identified according to depth strata defined by species distributions. Environmental types are uniquely classified according to the geomorphic features found within the bathomes in each ecoregion. We identified 23 ecoregions and nine bathomes. From a set of 28 types of geomorphic features of the seabed, 562 unique environmental types were classified for the Southern Ocean. We applied the environmental types as surrogates of different assemblages of biodiversity to assess the representativeness of existing MPAs. We found that 12 ecoregions are not represented in MPAs and that no ecoregion has their full range of environmental types represented in MPAs. Current MPA planning processes, if implemented, will substantially increase the representation of environmental types particularly within 8 ecoregions. To meet internationally agreed conservation goals, additional MPAs will be needed. To assist with this process, we identified 107 spatially restricted environmental types, which should be considered for inclusion in future MPAs. Detailed supplementary data including a spatial dataset are provided. PMID- 25032994 TI - Balance asymmetry in Parkinson's disease and its contribution to freezing of gait. AB - Balance control (the ability to maintain an upright posture) is asymmetrically controlled in a proportion of patients with Parkinson's disease. Gait asymmetries have been linked to the pathophysiology of freezing of gait. We speculate that asymmetries in balance could contribute to freezing by a) hampering the unloading of the stepping leg and/or b) leading to a preferred stance leg during gait, which then results in asymmetric gait. To investigate this, we examined the relationship between balance control and weight-bearing asymmetries and freezing. We included 20 human patients with Parkinson (tested OFF medication; nine freezers) and nine healthy controls. Balance was perturbed in the sagittal plane, using continuous multi-sine perturbations, applied by a motion platform and by a force at the sacrum. Applying closed-loop system identification techniques, relating the body sway angle to the joint torques of each leg separately, determined the relative contribution of each ankle and hip joint to the total amount of joint torque. We also calculated weight-bearing asymmetries. We determined the 99-percent confidence interval of weight-bearing and balance control asymmetry using the responses of the healthy controls. Freezers did not have larger asymmetries in weight bearing (p = 0.85) nor more asymmetrical balance control compared to non-freezers (p = 0.25). The healthy linear one-to one relationship between weight bearing and balance control was significantly different for freezers and non-freezers (p = 0.01). Specifically, non-freezers had a significant relationship between weight bearing and balance control (p = 0.02), whereas this relation was not significant for freezers (p = 0.15). Balance control is asymmetrical in most patients (about 75 percent) with Parkinson's disease, but this asymmetry is not related to freezing. The relationship between weight bearing and balance control seems to be less pronounced in freezers, compared to healthy controls and non-freezers. However, this relationship should be investigated further in larger groups of patients. PMID- 25032996 TI - An insight into fluorescent transition metal complexes. AB - The emission from transition metal complexes is usually produced from triplet excited states. Owing to strong spin-orbit coupling (SOC), the fast conversion of singlet to triplet excited states via intersystem crossing (ISC) is facilitated. Hence, in transition metal complexes, emission from singlet excited states is not favoured. Nevertheless, a number of examples of transition metal complexes that fluoresce with high intensity have been found and some of them were even comprehensively studied. In general, three common photophysical characteristics are used for the identification of fluorescent emission from a transition metal complex: emission lifetimes on the nanosecond scale; a small Stokes shift; and intense emission under aerated conditions. For most of the complexes reviewed here, singlet emission is the result of ligand-based fluorescence, which is the dominant emission process due to poor metal-ligand interactions leading to a small metal contribution in the excited states, and a competitive fluorescence rate constant when compared to the ISC rate constant. In addition to the pure fluorescence from metal complexes, another two types of fluorescent emissions were also reviewed, namely, delayed fluorescence and fluorescence-phosphorescence dual emissions. Both emissions also have their respective unique characteristics, and thus they are discussed in this perspective. PMID- 25032995 TI - A diVIsive Shuffling Approach (VIStA) for gene expression analysis to identify subtypes in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: An important step toward understanding the biological mechanisms underlying a complex disease is a refined understanding of its clinical heterogeneity. Relating clinical and molecular differences may allow us to define more specific subtypes of patients that respond differently to therapeutic interventions. RESULTS: We developed a novel unbiased method called diVIsive Shuffling Approach (VIStA) that identifies subgroups of patients by maximizing the difference in their gene expression patterns. We tested our algorithm on 140 subjects with Chronic Obstructive Pulmonary Disease (COPD) and found four distinct, biologically and clinically meaningful combinations of clinical characteristics that are associated with large gene expression differences. The dominant characteristic in these combinations was the severity of airflow limitation. Other frequently identified measures included emphysema, fibrinogen levels, phlegm, BMI and age. A pathway analysis of the differentially expressed genes in the identified subtypes suggests that VIStA is capable of capturing specific molecular signatures within in each group. CONCLUSIONS: The introduced methodology allowed us to identify combinations of clinical characteristics that correspond to clear gene expression differences. The resulting subtypes for COPD contribute to a better understanding of its heterogeneity. PMID- 25032997 TI - Synthesis of Bi nanowire networks and their superior photocatalytic activity for Cr(vi) reduction. AB - Interconnected Bi nanowire networks were synthesized for the first time via a solvothermal route by using ethylene glycol (EG) as both a solvent and a reducing agent, and citric acid (CA) as a stabilizing agent at a molar ratio of CA/Bi(3+) = 5. Among various reaction conditions including the temperature, reaction time and precursor concentration, the molar ratio of CA/Bi(3+) was the dominant experimental parameter to influence the morphology and structures of the Bi crystals. Highly dispersed Bi microspheres and network-like Bi thick wires were obtained if the molar ratio of CA/Bi(3+) was changed to 2.5 and 10, respectively. As compared to other additives including trisodium citrate, cetyltrimethylammonium bromide (CTAB) and oxalic acid, good solubility of CA in EG together with its coordination effect played a crucial role in the formation of network-like Bi nanowires. The Bi nanowire networks exhibited excellent photocatalytic performance for Cr(vi) reduction. Cr(vi) was completely reduced to less toxic Cr(iii) after 8 min and 55 min of UV and visible-light irradiation, respectively. PMID- 25032998 TI - Savoring every drop - vampire or mosquito? AB - Blood safety with respect to infectious complications has reached very high standards. Nevertheless, reports on transfusion-associated morbidity and mortality gain momentum. Multidisciplinary patient blood management programs can minimize unnecessary exposure to allogeneic blood products by strengthening and conserving patients' own resources. This article outlines concepts designed to maintain hemoglobin concentration, to optimize hemostasis, and to minimize blood loss in ICUs. These measures prevent or at least alleviate hospital-acquired anemia, reduce the need for blood transfusions, and therefore have great potential to improve patient safety and medical outcome. PMID- 25032999 TI - Using procalcitonin to guide antimicrobial duration in sepsis: asking the same questions will not bring different answers. AB - Severe sepsis is a major healthcare problem and the early initiation of antimicrobials is one of the few measures associated with improved outcomes. However, antibiotic overuse is an increasing problem in critical care. Of several potential biomarkers for antibiotic stewardship, procalcitonin represents the most widely studied and validated. In this commentary we address the current literature on the use of biomarkers to guide antimicrobial therapy in the critically ill and discuss its limitations and future directions. PMID- 25033000 TI - Anticoagulation: foreward. PMID- 25033001 TI - Anticoagulation: indications and risk classification schemes. AB - Anticoagulation is an important component of the management strategy for several common medical conditions. It is indicated for the prevention of recurrent thrombosis in patients with venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism, and ischemic stroke. Many surgical procedures also put patients at increased risk of VTE. Patients undergoing major orthopedic surgery should receive short-term anticoagulation. The Caprini Risk Assessment Model score can be used to estimate VTE risk and guide anticoagulation therapy recommendations for most nonorthopedic surgical patients. For patients with atrial fibrillation, assessment with the CHADS2 (Congestive heart failure, Hypertension, Age at least 75 years, Diabetes, previous Stroke or transient ischemic attack) score or a similar risk score is used to guide the decision on anticoagulation for stroke prevention. Anticoagulation also is used to prevent VTE in nonsurgical hospitalized patients at increased risk because of immobility or other factors. Patients with acute coronary syndrome should receive short-term anticoagulation. For patients with VTE in whom a reversible risk factor is identified, anticoagulation can be discontinued after 3 months. All patients with mechanical heart valves should receive lifelong anticoagulation. PMID- 25033002 TI - Anticoagulation: choosing the optimal anticoagulant. AB - The risks of bleeding and thrombosis should be considered in decisions on whether to initiate anticoagulation therapy. Oral anticoagulation is indicated for patients with nonvalvular atrial fibrillation who are at intermediate or high risk of stroke (CHADS2 [Congestive heart failure, Hypertension, Age at least 75 years, Diabetes, previous Stroke or transient ischemic attack] score of 1 or higher). Apixaban, dabigatran, rivaroxaban, or warfarin can be considered for the prevention of stroke and systemic embolism in these patients. Hospitalized patients at high risk of thrombosis should receive prophylaxis with low-molecular weight heparin, low-dose unfractionated heparin, or fondaparinux, whereas those at low risk should not receive pharmacologic prophylaxis. Pharmacologic prophylaxis with low-molecular-weight heparin or low-dose unfractionated heparin is indicated for patients undergoing nonorthopedic surgery who are at high risk of thrombosis and those undergoing orthopedic surgery whose risk of bleeding is low. Patients presenting with acute coronary syndrome should receive intravenous unfractionated heparin or enoxaparin at hospital admission. Anticoagulation with warfarin is appropriate for patients with mechanical heart valves. Patients with deep venous thrombosis or pulmonary embolism should receive rivaroxaban, dabigatran, or warfarin. PMID- 25033003 TI - Anticoagulation: monitoring of patients receiving anticoagulation. AB - For patients with acute venous thromboembolism treated with warfarin, parenteral anticoagulation should be continued for a minimum of 5 days and until the international normalized ratio (INR) is 2 or greater for at least 24 hours. Early initiation of warfarin therapy is recommended. The goal therapeutic INR range for patients treated with warfarin is most commonly 2 to 3. During maintenance warfarin therapy, validated decision-support tools should be used to guide dosing. For patients with stable INRs, frequency of INR testing can be extended from every 4 weeks to up to 12 weeks. Self-testing and self-management can be safe options for patients receiving warfarin who are motivated and show competence. Patients starting anticoagulation therapy should receive education on treatment goals, adverse effects, and monitoring strategy. Physicians deciding whether to prescribe one of the new oral anticoagulants instead of warfarin should assess for possible drug interactions and for renal and hepatic impairment and should consider the financial cost to the patient. No routine coagulation assay monitoring is required for patients receiving apixaban, dabigatran, or rivaroxaban. Physicians who oversee oral anticoagulation therapy should do so in a systematic and coordinated fashion. PMID- 25033004 TI - Anticoagulation: managing adverse events in patients receiving anticoagulation and perioperative care. AB - When patients present with major or life-threatening bleeding due to warfarin use, rapid reversal with coagulation factors and vitamin K often is warranted. Oral vitamin K should be administered if the international normalized ratio is greater than 10 with no evidence of bleeding, but its use is not recommended if international normalized ratios are between 4.5 and 10. The most important factor in the risk of hemorrhage is the intensity of warfarin therapy. Increasing the time in the therapeutic range results in lower rates of thrombosis and bleeding. There are no available specific reversal agents or pharmacologic antidotes for the new oral anticoagulants. Use of anticoagulation management services (eg, intervention using automated hospital information system-generated triggers from laboratory and pharmacy data) in the outpatient and inpatient settings can be considered to decrease the risk of complications for patients taking anticoagulants. Services that incorporate clear communication, evidence-based drug management, and patient education are important to ensure safe use of anticoagulants. Management of heparin-induced thrombocytopenia should include heparin discontinuation and initiation of a nonheparin anticoagulant. PMID- 25033005 TI - In situ TEM observation of the structural transformation of rutile TiO2 nanowire during electrochemical lithiation. AB - We present the first direct experimental proof that phase changes occur during the real-time lithiation of rutile TiO2 nanostructures, functioning as the anode of a solid Li-ion battery inside a transmission electron microscope. PMID- 25033006 TI - Addition reaction-induced cluster-to-cluster transformation: controlled self assembly of luminescent polynuclear gold(I) MU3-sulfido clusters. AB - Unprecedented addition reaction-induced gold(I) cluster-to-cluster transformation has been observed in the present work. Reaction of the chlorogold(I) precursor, [vdpp(AuCl)2] (vdpp = vinylidenebis(diphenylphosphine)) containing the diphosphine with unsaturated C?C bond, with H2S resulted in a series of polynuclear gold(I) MU3-sulfido clusters bearing Au(I)...Au(I) interactions; the identities of which have been fully characterized by NMR, electrospray-ionization mass spectrometry, elemental analysis, and single crystal X-ray diffraction analysis. Diverse research methods, including UV-vis absorption, (1)H NMR, and (31)P NMR spectroscopy, were employed to detect and monitor the transformation and assembly processes. Supported by single crystal structures, the existence of Au(I)...Au(I) bonding interactions sustains the diverse array of sophisticated polynuclear cluster structures and endues them with rich luminescence features. PMID- 25033007 TI - Inert and oxidative subcritical water hydrolysis of insoluble egg yolk granular protein, functional properties, and comparison to enzymatic hydrolysis. AB - The use of enzymes to recover soluble peptides with functional properties from insoluble proteins could prove to be very expensive, implying high reaction times and low yields. In this study, the insoluble granular protein, previously delipidated, was hydrolyzed using enzymes (trypsin) as a comparison to the proposed alternative method: subcritical water hydrolysis (SWH) using both nitrogen and oxygen streams. The result of the hydrolysis was characterized in terms of the yield and peptide size distribution as well as different functional properties. The SWH of the delipidated granules resulted in a higher recovery yield than that obtained by enzymatic hydrolysis in half of the time. The foaming capacity of the peptides obtained by SWH was higher than that obtained by trypsin hydrolysis, although the foam stability was lower. Slight differences were detected between these peptides in terms of their emulsifying properties. PMID- 25033008 TI - Immunohistochemical expression of sperm-associated antigen 9 in nonmelanoma skin cancer. AB - Sperm-associated antigen 9 (SPAG9) is a scaffold protein for c-Jun-NH2-kinases, which play an important role in cell survival, proliferation, apoptosis, and tumor development. SPAG9 was claimed to be involved in the pathogenesis of carcinoma in different organs. The aim of this work was to investigate its role in the pathogenesis of nonmelanoma skin cancer (NMSC) through its immunohistochemical (IHC) localization in skin biopsies of these tumors. This retrospective and prospective study included 67 cutaneous specimens; 42 of NMSC [20 cases with basal cell carcinoma (BCC) and 22 cases with squamous cell carcinoma (SCC)] and 25 normal sun-exposed skin biopsies from age and gender matched healthy subjects as a control group. SPAG9 expression was evaluated using standard IHC techniques. SPAG9 was expressed in 90% of BCC cases and in 81.8% of SCC cases. Positive expression in inflammatory cells was detected in 100% and 63.6% of BCC and SCC cases, respectively. Positive stromal expression was detected in 20% of BCC cases and was absent in all SCC cases. A significant negative correlation (r = -0.55, P = 0.008) was noted between SPAG9 H score and SCC histological grade and a significant association between SPAG9 H score and tumor grade was also detected where higher values were present in grade I tumors (P = 0.001). SPAG9 was upregulated in NMSC when compared with normal skin. In conclusion, SPAG9 is expressed in NMSC cases. It should be evaluated in large scale studies to determine if it plays an active pathogenic role or its expression is an epiphenomenon not related to NMSC pathogenesis. Large-scale studies are warranted to determine its potential utility in guiding treatment decisions and following disease progression in theses cases. Its expression in normal skin needs further investigation. PMID- 25033009 TI - Delayed onset of the Jarisch-Herxheimer reaction in doxycycline-treated disease: a case report and review of its histopathology and implications for pathogenesis. AB - The Jarisch-Herxheimer reaction (JHR) is a transient inflammatory syndrome triggered hours after the start of antibiotic treatment of spirochete infections, namely syphilis. Clinically, JHR manifests as an abrupt onset of constitutional symptoms and exacerbation of cutaneous lesions that resolve without intervention. JHR's pathogenesis is unclear and it is histopathologically rarely reported. Herein, the authors report a 47-year-old woman, with solitary erythema migrans and positive Lyme disease serology, who presented for medical care 14 days after commencement of doxycycline therapy. She complained of malaise, facial flushing, gingival erythema, and acquisition of additional plaques characterized by swelling, increased erythema, pruritus, and exfoliative scale. Punch biopsies demonstrated subacute to chronic spongiotic psoriasiform reaction patterns with a superficial lymphocytic infiltrate. By Borrelia-specific immunohistochemistry, spirochetes were found in the deep dermis, unassociated with inflammation, and focally in the upper spinous layer, associated with spongiosis. Borrelia burgdorferi DNA was detected by nested polymerase chain reaction. Doxycycline was discontinued, and symptoms and signs resolved within a few days. Liberation of endotoxin-like materials (eg, lipoproteins) from degenerating spirochetes and concomitant cytokine production is the suspected cause of JHR and supported by the finding of lesional spirochetes. Alternatively, a reversal reaction with a delayed-type hypersensitivity reaction is also a plausible cause based on spirochetes found in the lymphocytic spongiotic dermatitis. PMID- 25033010 TI - Perivascular basophilic rim as a histopathological clue of cutaneous Pseudomona aeruginosa sepsis. PMID- 25033011 TI - Fibrolipomatous Hamartoma of the Nerve Arising in the Neck: A Case Report With Review of the Literature and Differential Diagnosis. AB - We report an unusual case of a fibrolipomatous hamartoma that arose in a nuchal nerve. Typically, fibrolipomatous hamartoma, otherwise known as a neural fibrolipoma or lipomatosis of nerve, arises in the median nerve, brachial plexus, cranial nerves, or plantar nerves. The differential diagnosis is broad and includes benign and malignant spindle cell lesions, such as spindle cell lipoma, perineurioma, and myxoid liposarcoma. We were able to identify the lesion based on the typical histology, including triphasic composition with spindle cell, neural, and adipocytic components and whorled architecture. Because of the atypical location in the neck, detailed immunohistochemical staining was performed. The lesional spindle cells were negative for SMA, CD10, CD68, EMA, S100, PGP9.5, CD34, CD56, and beta-catenin. Colloidal iron stain highlighted marked intralesional mucin deposition. This detailed immunohistochemical profile is a useful diagnostic aid and to our knowledge has not been previously described. PMID- 25033012 TI - Drug-induced pseudo-Sezary syndrome: a case report and literature review. AB - Pseudo-Sezary syndrome is a benign lymphoproliferative disorder, which clinically and pathologically mimics true Sezary syndrome. In this article, a case of pseudo Sezary syndrome and review the literature has been reported. The patient was a 51 year-old man who developed erythroderma and palmoplantar keratoderma. The patient's medication history included fosinopril and combination metoprolol/hydrochlorothiazide. Flow cytometry showed a population of 2500 "Sezary-like" CD4726 T cells per microliter in the peripheral blood. Skin biopsy showed numerous atypical lymphocytes with epidermotropism, and there was matching dominant T-cell clonality in the skin and peripheral blood. After stopping all antihypertensive medications, the eruption resolved in its entirety. PMID- 25033013 TI - Structural basis for rational design of inhibitors targeting Trypanosoma cruzi sterol 14alpha-demethylase: two regions of the enzyme molecule potentiate its inhibition. AB - Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14alpha-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of beta-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50=1.2 nM, vs (S)-2/(S)-3, EC50=1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs. PMID- 25033014 TI - Multiphysics simulation of ion concentration polarization induced by nanoporous membranes in dual channel devices. AB - Many microfluidic devices have been utilizing ion concentration polarization (ICP) phenomena by using a permselective, nanoporous membrane with electric fields for a variety of preconcentration applications. However, numerical analyses on the ICP phenomena have not drawn sufficient attention, although they are an intriguing and interdisciplinary research area. In this work, we propose a 2-D model and present numerical simulation results on the ICP, which were obtained by solving three coupled governing equations: Nernst-Planck, Navier Stokes, and Poisson. With improved boundary conditions and assumptions, we demonstrated that the simulation results not only are consistent with other experimental results but also make it possible to thoroughly understand the ICP phenomena. In addition, we demonstrated that the preconcentration of analytes can be simulated and quantified in terms of concentration enhancement factors (CEFs) that were related to many factors, such as ionic concentration distribution, electric fields, and flow fields including vortex flows across the membrane. Furthermore, we demonstrated that a high electrophoretic mobility (EPM) of counterions in the membrane plays the most important role in producing accurate simulation results while the effect of the charge density of the membrane is relatively insignificant. Hence, it is believed that the model and simulation results would provide good guidelines to better develop microfluidic preconcentration devices based on the ICP phenomena. PMID- 25033015 TI - A facile synthetic route to poly(p-phenylene terephthalamide) with dual functional groups. AB - Claisen rearrangement reaction was employed for the first time to obtain a novel PPTA bearing reactive allyl and hydroxyl groups which may act as a sizing agent of Kevlar fibers to improve the interface structure and interfacial adhesion of rubber or epoxy based composites. PMID- 25033016 TI - A minor diterpenoid with a new 6/5/7/3 fused-ring skeleton from Euphorbia micractina. AB - A novel diterpenoid with an unprecedented 6/5/7/3 fused-ring skeleton, euphorbactin (1), was isolated from an ethanol extract of the roots of Euphorbia micractina. The structure was determined by extensive spectroscopic studies, especially by 2D NMR and CD data analysis. A proposed biosynthetic pathway and preliminary investigations of the biological activity of compound 1 are also discussed. PMID- 25033017 TI - Phosphine-catalyzed anti-carboboration of alkynoates with alkyl-, alkenyl-, and arylboranes. AB - We found that trialkylphosphine organocatalysts promoted unprecedented anti carboboration of alkynoates with alkyl-, alkenyl-, or arylboranes to form beta boryl acrylates. The regioselectivity of the carboboration across the polar C-C triple bond exhibited inverse electronic demand, with the less electronegative B atom being delivered to the positively charged beta carbon atom. The regioselectivity and the anti stereoselectivity were both complete and robust. In addition, the substrate scope was broad with excellent functional group compatibility. PMID- 25033018 TI - Impact of solar UV radiation on toxicity of ZnO nanoparticles through photocatalytic reactive oxygen species (ROS) generation and photo-induced dissolution. AB - The present study investigated the impact of solar UV radiation on ZnO nanoparticle toxicity through photocatalytic ROS generation and photo-induced dissolution. Toxicity of ZnO nanoparticles to Daphnia magna was examined under laboratory light versus simulated solar UV radiation (SSR). Photocatalytic ROS generation and particle dissolution were measured on a time-course basis. Two toxicity mitigation assays using CaCl2 and N-acetylcysteine were performed to differentiate the relative importance of these two modes of action. Enhanced ZnO nanoparticle toxicity under SSR was in parallel with photocatalytic ROS generation and enhanced particle dissolution. Toxicity mitigation by CaCl2 to a less extent under SSR than under lab light demonstrates the role of ROS generation in ZnO toxicity. Toxicity mitigation by N-acetylcysteine under both irradiation conditions confirms the role of particle dissolution and ROS generation. These findings demonstrate the importance of considering environmental solar UV radiation when assessing ZnO nanoparticle toxicity and risk in aquatic systems. PMID- 25033020 TI - Targeting proteins with toxic azo dyes: a microcalorimetric characterization of the interaction of the food colorant amaranth with serum proteins. AB - The interaction of amaranth with two homologous serum albumins from human and bovine (HSA and BSA) was studied by microcalorimetry. The binding stoichiometry for the complexation of amaranth to both BSA and HSA was around 1, and the equilibrium constants were (5.79 +/- 0.07) * 10(5) and (1.76 +/- 0.05) * 10(5) M( 1), respectively. The binding reaction to HSA at 298.15 K was driven by a large negative enthalpic contribution and a small but positive entropic contribution, while to BSA, it was entirely enthalpy-driven and the entropic contribution was unfavorable. Parsing of the standard molar Gibbs energy revealed that the complexation was dominated by non-polyelectrolytic forces. Temperature-dependent isothermal titration calorimetry studies revealed that the enthalpic contribution increased and the entropic contribution decreased with the rise in the temperature but the Gibbs energy change remained almost unaltered. Differential scanning calorimetry results revealed that the binding reaction stabilized the serum albumins significantly against thermal unfolding. PMID- 25033019 TI - High-throughput sequencing for the study of bacterial pathogen biology. AB - A revolution in sequencing technologies in recent years has led to dramatically increased throughput and reduced cost of bacterial genome sequencing. An increasing number of applications of the new technologies are providing broad insights into bacterial evolution, epidemiology, and pathogenesis. For example, the capacity to sequence large numbers of bacterial isolates is enabling high resolution phylogenetic analyses of bacterial populations leading to greatly enhanced understanding of the emergence, adaptation, and transmission of pathogenic clones. In addition, RNA-seq offers improved quantification and resolution for transcriptomic analysis, and the combination of high-throughput sequencing with transposon mutagenesis is a powerful approach for the identification of bacterial determinants required for survival in vivo. In this concise review we provide selected examples of how high throughput sequencing is being applied to understand the biology of bacterial pathogens, and discuss future technological advances likely to have a profound impact on the field. PMID- 25033021 TI - Numerical models of net-structure stents inserted into arteries. AB - INTRODUCTION: Restenosis is strongly attributed to stresses caused by stent artery interactions generated in the artery after balloon angioplasty. Numerical methods are often used to examine the stent-artery mechanical interactions. To overcome the extensive computational requirements demanded by these simulations, simplifications are needed. OBJECTIVE: We introduce simplified models to calculate the mechanical interactions between net-structured stents and arteries, and discuss their validity and implications. METHODS: 2D simplified numerical models are suggested, which allow cost effective assessment of arterial stresses and the potential damage factor (DF). In these models, several contact problems were solved for arteries with hyper elastic mechanical properties. Stresses were calculated for a large range of cases and for different numerical model types. The effects of model simplifications, oversizing mismatch and stenosis rate and length and symmetry on the resulting stresses were analyzed. RESULTS & CONCLUSIONS: Results obtained from planar 2D models were found in good agreement with results obtained from complex 3D models for cases with axisymmetric constant or varying stenosis. This high correlation between the results of 3D cases with varying stenosis and the more simple 2D cases can be used as a simplified and convenient tool for calculating the arterial wall stresses in complex cases. Maximal stresses obtained by the 2D model with an asymmetric stenosis are lower than the maximal stresses obtained in the axisymmetric case with the same stenosis percentage. Therefore, axisymmetric models may provide the worst-case estimation values for a stent of interest. PMID- 25033022 TI - A correction method using a support vector machine to minimize hematocrit interference in blood glucose measurements. AB - Point-of-care testing glucose meters are widely used, important tools for determining the blood glucose levels of people with diabetes, patients in intensive care units, pregnant women, and newborn infants. However, a number of studies have concluded that a change in hematocrit (Hct) levels can seriously affect the accuracy of glucose measurements. The aim of this study was to develop an algorithm for glucose calculation with improved accuracy using the Hct compensation method that minimizes the effects of Hct on glucose measurements. The glucose concentrations in this study were calculated with an adaptive calibration curve using linear fitting prediction and a support vector machine, which minimized the bias in the glucose concentrations caused by the Hct interference. This was followed by an evaluation of performance according to the international organization for standardization (ISO) 15197:2013 based on bias with respect to the reference method, the coefficient of variation, and the valid blood samples/total blood samples within the +/-20% and 15% error grids. Chronoamperometry was performed to verify the effect of Hct variation and to compare the proposed method. As a result, the average coefficients of variation for chronoamperometry and the Hct compensation method were 2.43% and 3.71%, respectively, while the average biases (%) for these methods were 12.08% and 5.69%, respectively. The results of chronoamperometry demonstrated that a decrease in Hct levels increases glucose concentrations, whereas an increase in Hct levels reduces glucose concentrations. Finally, the proposed method has improved the accuracy of glucose measurements compared to existing chronoamperometry methods. PMID- 25033023 TI - Quantitative response relationships between nitrogen transformation rates and nitrogen functional genes in a tidal flow constructed wetland under C/N ratio constraints. AB - The present study explored treatment performance and nitrogen removal mechanisms of a novel tidal flow constructed wetland (TF CW) under C/N ratios ranging from two to 12. High and stable COD (83-95%), [Formula: see text] (63-80%), and TN (50 82%) removal efficiency were simultaneously achieved in our single-stage TF CW without costly aeration. Results showed that a C/N ratio exceeding six was required to achieve complete denitrification without [Formula: see text] and [Formula: see text] accumulation in the system. Molecular biological analyses revealed aerobic ammonia oxidation was the dominant [Formula: see text] removal pathway when the C/N ratio was less than or equal to six. However, when the C/N ratio was greater than six, anammox was notably enhanced, resulting in another primary [Formula: see text] removal pathway, in addition to the aerobic ammonia oxidation. Quantitative response relationships between nitrogen transformation rates and nitrogen functional genes were established, and these relationships confirmed that different nitrogen transformation processes were coupled at the molecular level (functional genes), and collaboratively contributed to nitrogen removal in the TF CW. Specifically, [Formula: see text] transformation rates were collectively determined by amoA, nxrA, anammox, narG, nirS, nirK, and nosZ; and TN removal was influenced primarily by amoA and anammox. PMID- 25033024 TI - Homogeneous bispecifics by disulfide bridging. AB - We report on a chemical platform to generate site-specific, homogeneous, antibody antibody conjugates by targeting and bridging disulfide bonds. A bispecific antibody construct was produced in good yield through simple reduction and bridging of antibody fragment disulfide bonds, using a readily synthesized bis dibromomaleimide cross-linker. Binding activity of antibodies was maintained, and in vitro binding of target antigens was observed. This technology is demonstrated through linking scFv and Fab antibody fragments, showing its potential for the construction of a diverse range of bispecifics. PMID- 25033026 TI - Impact of Sn(S,Se) secondary phases in Cu2ZnSn(S,Se)4 solar cells: a chemical route for their selective removal and absorber surface passivation. AB - The control and removal of secondary phases is one of the major challenges for the development of Cu2ZnSn(S,Se)4 (CZTSSe)-based solar cells. Although etching processes have been developed for Cu(S,Se), Zn(S,Se), and CuSn(S,Se) secondary phases, so far very little attention has been given to the role of Sn(S,Se). In this paper, we report a chemical route using a yellow (NH4)2S solution to effectively remove Sn(S,Se). We found that Sn(S,Se) can form on the surface either because of stoichiometric deviation or by condensation. After etching, the efficiency of devices typically increases between 20 and 65% relative to the before etch efficiencies. We achieved a maximum 5.9% efficiency in Se-rich CZTSSe based devices. It is confirmed that this feature is related not only to the removal of Sn(S,Se) but also to the unexpected passivation of the surface. We propose a phenomenological model for this passivation, which may open new perspectives for the development of CZTSSe-based solar cells. PMID- 25033025 TI - Circadian clock: linking epigenetics to aging. AB - Circadian rhythms are generated by an intrinsic cellular mechanism that controls a large array of physiological and metabolic processes. There is erosion in the robustness of circadian rhythms during aging, and disruption of the clock by genetic ablation of specific genes is associated with aging-related features. Importantly, environmental conditions are thought to modulate the aging process. For example, caloric restriction is a very strong environmental effector capable of delaying aging. Intracellular pathways implicating nutrient sensors, such as SIRTs and mTOR complexes, impinge on cellular and epigenetic mechanisms that control the aging process. Strikingly, accumulating evidences indicate that these pathways are involved in both the modulation of the aging process and the control of the clock. Hence, innovative therapeutic strategies focused at controlling the circadian clock and the nutrient sensing pathways might beneficially influence the negative effects of aging. PMID- 25033027 TI - Polymorphisms of glutathione peroxidase 1 (GPX1 Pro198Leu) and catalase (CAT C 262T) in women with spontaneous abortion. AB - About 10%-15% of conceptions are lost spontaneously prior to 20 weeks. Apart from the clinical problems, genetic variations have also been proposed as a susceptibility factor to miscarriage. Glutathione peroxidase 1 (GPX1) and catalase (CAT) encode two antioxidant enzymes that detoxify H2O2 and protect the cells from oxidative damage. A functional polymorphism at codon 198 of the GPX1 gene causes a C/T substitution in exon 2, which encodes for either proline or leucine (Pro198Leu). The CAT gene has a polymorphic site in the promoter region at position -262 (C-262T) which alters the expression and enzyme blood levels, leading to some pathological clinical conditions. In this study, we evaluated the association of these two polymorphisms with the risk of spontaneous abortion. Genomic DNA from 105 cases with spontaneous abortion and 90 healthy women were genotyped using allele-specific PCR (AS-PCR) and polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). The genetic distributions for GPX1 did not differ significantly between cases and controls (p = 0.680). However, C-262T polymorphism was significantly associated with the risk of the disease (OR, 5.50; 95% CI, 1.43-21.09; p = 0.012). In conclusion, this study indicates that CAT -262T/T genotype confers less susceptibility to spontaneous abortion, while GPX1 Pro198Leu polymorphism may not be correlated with the disease. PMID- 25033028 TI - "Brain death," "dead," and parental denial - the case of Jahi McMath. PMID- 25033029 TI - Trunk angular kinematics during slip-induced backward falls and activities of daily living. AB - Prior to developing any specific fall detection algorithm, it is critical to distinguish the unique motion features associated with fall accidents. The current study aimed to investigate the upper trunk angular kinematics during slip induced backward falls and activities of daily living (ADLs). Ten healthy older adults (age = 75 +/- 6 yr (mean +/- SD)) were involved in a laboratory study. Sagittal trunk angular kinematics were measured using optical motion analysis system during normal walking, slip-induced backward falls, lying down, bending over, and various types of sitting down (SN). Trunk angular phase-plane plots were generated to reveal the motion features of falls. It was found that backward falls were characterized by a simultaneous occurrence of a slight trunk extension and an extremely high trunk extension velocity (peak average = 139.7 deg/s), as compared to ADLs (peak average = 84.1 deg/s). It was concluded that the trunk extension angular kinematics of falls were clearly distinguishable from those of ADLs from the perspective of angular phase-plane plot. Such motion features can be utilized in future studies to develop a new prior-to-impact fall detection algorithm. PMID- 25033030 TI - Examining ethics - developing a comprehensive exam for a bioethics master's program. AB - Assessing mastery of bioethics in a graduate program requires careful attention not simply to the content knowledge and skill development of students but also to the principles of sound assessment processes. In this article, we describe the rationale, development process, and features of the comprehensive exam we created as a culminating experience of a master's program in bioethics. The exam became the students' opportunity to demonstrate the way they were able to integrate course, textual, and practical knowledge gained throughout the experience of the program. Additionally, the exam assessed students' proficiency in the field of bioethics and their ability to critically and constructively analyze bioethical issues. In this article, we offer tips to other exam creators regarding our experiences with question and answer development, scoring of the exam, and relationships between coursework and exam preparation and completion. We also include a sample rubric for others to see how we determined which student answers were satisfactory. PMID- 25033031 TI - Quantifying metastatic inefficiency: rare genotypes versus rare dynamics. AB - We introduce and solve a 'null model' of stochastic metastatic colonization. The model is described by a single parameter theta: the ratio of the rate of cell division to the rate of cell death for a disseminated tumour cell in a given secondary tissue environment. We are primarily interested in the case in which colonizing cells are poorly adapted for proliferation in the local tissue environment, so that cell death is more likely than cell division, i.e. theta < 1. We quantify the rare event statistics for the successful establishment of a metastatic colony of size N. For N >> 1, we find that the probability of establishment is exponentially rare, as expected, and yet the mean time for such rare events is of the form ~log (N)/(1 - theta) while the standard deviation of colonization times is ~1/(1 - theta). Thus, counter to naive expectation, for theta < 1, the average time for establishment of successful metastatic colonies decreases with decreasing cell fitness, and colonies seeded from lower fitness cells show less stochastic variation in their growth. These results indicate that metastatic growth from poorly adapted cells is rare, exponentially explosive and essentially deterministic. These statements are brought into sharper focus by the finding that the temporal statistics of the early stages of metastatic colonization from low-fitness cells (theta < 1) are statistically indistinguishable from those initiated from high-fitness cells (theta > 1), i.e. the statistics show a duality mapping (1 - theta) --> (theta - 1). We conclude our analysis with a study of heterogeneity in the fitness of colonising cells, and describe a phase diagram delineating parameter regions in which metastatic colonization is dominated either by low or high fitness cells, showing that both are plausible given our current knowledge of physiological conditions in human cancer. PMID- 25033032 TI - The clinical utility and specificity of parent report of executive function among children with prenatal alcohol exposure. AB - Prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) result in behavioral issues related to poor executive function (EF). This overlap may hinder clinical identification of alcohol-exposed children. This study examined the relation between parent and neuropsychological measures of EF and whether parent ratings aid in differential diagnosis. Neuropsychological measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), were administered to four groups of children (8-16 years): alcohol-exposed with ADHD (AE+, n=80), alcohol-exposed without ADHD (AE-, n=36), non-exposed with ADHD (ADHD, n=93), and controls (CON, n=167). Primary caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF). For parent ratings, multivariate analyses of variance revealed main effects of Exposure and ADHD and an interaction between these factors, with significant differences between all groups on nearly all BRIEF scales. For neuropsychological measures, results indicated main effects of Exposure and ADHD, but no interaction. Discriminant function analysis indicated the BRIEF accurately classifies groups. These findings confirm compounded behavioral, but not neuropsychological, effects in the AE+ group over the other clinical groups. Parent-report was not correlated with neuropsychological performance in the clinical groups and may provide unique information about neurobehavior. Parent-report measures are clinically useful in predicting alcohol exposure regardless of ADHD. Results contribute to a neurobehavioral profile of prenatal alcohol exposure. PMID- 25033033 TI - A novel nutritional predictor links microbial fastidiousness with lowered ubiquity, growth rate, and cooperativeness. AB - Understanding microbial nutritional requirements is a key challenge in microbiology. Here we leverage the recent availability of thousands of automatically generated genome-scale metabolic models to develop a predictor of microbial minimal medium requirements, which we apply to thousands of species to study the relationship between their nutritional requirements and their ecological and genomic traits. We first show that nutritional requirements are more similar among species that co-habit many ecological niches. We then reveal three fundamental characteristics of microbial fastidiousness (i.e., complex and specific nutritional requirements): (1) more fastidious microorganisms tend to be more ecologically limited; (2) fastidiousness is positively associated with smaller genomes and smaller metabolic networks; and (3) more fastidious species grow more slowly and have less ability to cooperate with other species than more metabolically versatile organisms. These associations reflect the adaptation of fastidious microorganisms to unique niches with few cohabitating species. They also explain how non-fastidious species inhabit many ecological niches with high abundance rates. Taken together, these results advance our understanding microbial nutrition on a large scale, by presenting new nutrition-related associations that govern the distribution of microorganisms in nature. PMID- 25033034 TI - CogSMART Compensatory Cognitive Training for Traumatic Brain Injury: Effects Over 1 Year. AB - OBJECTIVE: There are very few evidence-based treatments for individuals with mild to moderate traumatic brain injuries. We developed and tested a 12-week, manualized, compensatory cognitive training intervention, Cognitive Symptom Management and Rehabilitation Therapy (CogSMART), which targeted postconcussive symptom management, prospective memory, attention, learning/memory, and executive functioning. The intervention focused on psychoeducation and compensatory strategies such as calendar use, self-talk, note taking, and a 6-step problem solving method. SETTING: VA Healthcare System. PARTICIPANTS: A total of 50 Veterans with mild to moderate traumatic brain injuries receiving supported employment. DESIGN: Twelve-month randomized controlled trial with participants assigned to receive CogSMART or additional supported employment sessions for the first 12 weeks. Outcome assessments were administered at baseline and 3, 6, and 12 months. MAIN MEASURES: Assessments measured postconcussive symptoms, neuropsychological performance, functional capacity, psychiatric symptom severity, quality of life, and weeks worked during the 12-month trial. RESULTS: Hierarchical linear modeling analyses using all 4 time points demonstrated significant CogSMART-associated reductions in postconcussive symptoms (r = -0.28, P = .026, d = 0.64) and improvements in prospective memory (r = 0.35, P = .031, d = 0.55) and quality of life (r = 0.34, P = .009, d = 1.0). The groups did not differ on weeks worked during the trial. CONCLUSION: CogSMART has the potential to improve postconcussive symptoms, cognitive performance, and self-rated quality of life in individuals with mild to moderate traumatic brain injuries. PMID- 25033035 TI - Functional Recovery and Life Satisfaction in the First Year After Severe Traumatic Brain Injury: A Prospective Multicenter Study of a Norwegian National Cohort. AB - OBJECTIVES: (1) To examine the impact of demographic and acute injury-related variables on functional recovery and life satisfaction after severe traumatic brain injury (sTBI) and (2) to test whether postinjury functioning, postconcussive symptoms, emotional state, and functional improvement are related to life satisfaction. DESIGN: Prospective national multicenter study. SETTING: Level 1 trauma centers in Norway. PARTICIPANTS: 163 adults with sTBI. MAIN MEASURES: Functional recovery between 3 and 12 months postinjury measured with Glasgow Outcome Scale Extended, Rivermead Postconcussion Symptoms Questionnaire, Hospital Anxiety and Depression Scale, and satisfaction with life situation. RESULTS: 60% of cases experienced functional improvement from 3 to 12 months postinjury. Multivariate logistic regression analysis revealed that discharge to a rehabilitation department from acute care (odds ratio [OR] = 2.14; P < .05) and fewer days with artificial ventilation (OR = 1.04; P < .05) were significantly related to improvement. At 12 months postinjury, 85% were independent in daily activities. Most participants (63%) were satisfied with their life situation. Regression analysis revealed that older age (>65 years), low education, better functional outcome, and the absence of depressive and postconcussion symptoms were significant (P < .05) predictors of life satisfaction. Functional improvement was significantly associated with emotional state but not to life satisfaction. CONCLUSION: Following sTBI, approximately two-thirds of survivors improve between 3 and 12 months postinjury and are satisfied with their life. Direct discharge from acute care to specialized rehabilitation appears to increase functional recovery. PMID- 25033036 TI - Ocean acidification increases copper toxicity to the early life history stages of the polychaete Arenicola marina in artificial seawater. AB - The speciation and therefore bioavailability of the common pollutant copper is predicted to increase within the pH range anticipated under near-future ocean acidification (OA), hence the potential exists for copper toxicity to marine organisms to also increase. We investigated the impact of OA (seawater pH values of 7.77 (pCO2 1400 MUatm) and 7.47 (pCO2 3000 MUatm)) upon copper toxicity responses in early life history stages of the polychaete Arenicola marina and found both synergistic and additive toxicity effects of combined exposures depending on life history stage. The toxicity of copper on sperm DNA damage and early larval survivorship was synergistically increased under OA conditions. Larval survival was reduced by 24% when exposed to both OA and copper combined compared to single OA or copper exposures. Sperm motility was negatively affected by both OA and copper singularly with additive toxicity effects of the two stressors when combined. Fertilization success was also negatively affected by both OA and copper individually, but no additive effects when exposed as combined stressors were present for this stage. These findings add to the growing body of evidence that OA will act to increase the toxicity of copper to marine organisms, which has clear implications for coastal benthic ecosystems suffering chronic metal pollution as pCO2 levels rise and drive a reduction in seawater pH. PMID- 25033037 TI - A cost-minimization analysis comparing immediate sequential cataract surgery and delayed sequential cataract surgery from the payer, patient, and societal perspectives in the United States. AB - IMPORTANCE: The cost difference is evaluated between delayed sequential cataract surgery (DSCS) and immediate sequential cataract surgery (ISCS) in the United States for patients covered by Medicare. OBJECTIVE: To perform a cost minimization analysis comparing ISCS with DSCS in the United States from the payer, patient, and societal perspectives for the West Tennessee region and nationally. DESIGN, SETTING, AND PARTICIPANTS: A cost-minimization analysis using cataract surgery volume and eligibility estimates, 2012 Medicare reimbursement schedules, and actual or estimated patient cost data for the West Tennessee region and nationally was performed comparing ISCS with DSCS. The West Tennessee model was set in a mixed small city and rural private practice setting and was extrapolated to a national model. Ambulatory surgery center and hospital outpatient department setting costs were evaluated. MAIN OUTCOMES AND MEASURES: West Tennessee and national Medicare payer costs per patient and the total national Medicare payer cost for DSCS and for ISCS, as well as West Tennessee and national Medicare patient (direct medical, travel, and lost wages) costs for DSCS and for ISCS. RESULTS: Nationally, Medicare was estimated to reduce costs by approximately $522 million with the switch from DSCS to ISCS in 2012. With a change to ISCS, a West Tennessee Medicare patient was estimated to reduce costs by $174 for direct medical costs, $40 for travel costs, and $138 for lost wages (total cost reduction range, $329-$649). The total Medicare-based societal cost reduction was $783 million. CONCLUSIONS AND RELEVANCE: Payers and patients would benefit from an economic standpoint by switching from DSCS to ISCS. Patients and their families would benefit from fewer visits. This becomes important given the increasing number of future cataract surgical procedures that will be performed as the baby boomer generation ages, especially given the fact that Medicare is already financially strained. Further research is needed to evaluate the effect of switching to ISCS from the physician and surgical facility perspectives. PMID- 25033038 TI - The beet cyst nematode Heterodera schachtii modulates the expression of WRKY transcription factors in syncytia to favour its development in Arabidopsis roots. AB - Cyst nematodes invade the roots of their host plants as second stage juveniles and induce a syncytium which is the only source of nutrients throughout their life. A recent transcriptome analysis of syncytia induced by the beet cyst nematode Heterodera schachtii in Arabidopsis roots has shown that thousands of genes are up-regulated or down-regulated in syncytia as compared to root segments from uninfected plants. Among the down-regulated genes are many which code for WRKY transcription factors. Arabidopsis contains 66 WRKY genes with 59 represented by the ATH1 GeneChip. Of these, 28 were significantly down-regulated and 6 up-regulated in syncytia as compared to control root segments. We have studied here the down-regulated genes WRKY6, WRKY11, WRKY17 and WRKY33 in detail. We confirmed the down-regulation in syncytia with promoter::GUS lines. Using various overexpression lines and mutants it was shown that the down-regulation of these WRKY genes is important for nematode development, probably through interfering with plant defense reactions. In case of WRKY33, this might involve the production of the phytoalexin camalexin. PMID- 25033040 TI - Intersex occurrence in rainbow trout (Oncorhynchus mykiss) male fry chronically exposed to ethynylestradiol. AB - This study aimed to investigate the male-to-female morphological and physiological transdifferentiation process in rainbow trout (Oncorhynchus mykiss) exposed to exogenous estrogens. The first objective was to elucidate whether trout develop intersex gonads under exposure to low levels of estrogen. To this end, the gonads of an all-male population of fry exposed chronically (from 60 to 136 days post fertilization--dpf) to several doses (from environmentally relevant 0.01 ug/L to supra-environmental levels: 0.1, 1 and 10 ug/L) of the potent synthetic estrogen ethynylestradiol (EE2) were examined histologically. The morphological evaluations were underpinned by the analysis of gonad steroid (testosterone, estradiol and 11-ketotestosterone) levels and of brain and gonad gene expression, including estrogen-responsive genes and genes involved in sex differentiation in (gonads: cyp19a1a, ER isoforms, vtg, dmrt1, sox9a2; sdY; cyp11b; brain: cyp19a1b, ER isoforms). Intersex gonads were observed from the first concentration used (0.01 ug EE2/L) and sexual inversion could be detected from 0.1 ug EE2/L. This was accompanied by a linear decrease in 11-KT levels, whereas no effect on E2 and T levels was observed. Q-PCR results from the gonads showed downregulation of testicular markers (dmrt1, sox9a2; sdY; cyp11b) with increasing EE2 exposure concentrations, and upregulation of the female vtg gene. No evidence was found for a direct involvement of aromatase in the sex conversion process. The results from this study provide evidence that gonads of male trout respond to estrogen exposure by intersex formation and, with increasing concentration, by morphological and physiological conversion to phenotypic ovaries. However, supra-environmental estrogen concentrations are needed to induce these changes. PMID- 25033041 TI - QbD-based carbopol transgel formulation: characterization, pharmacokinetic assessment and therapeutic efficacy in diabetes. AB - In order to develop transdermal drug delivery system that facilitates the skin permeation of Pioglitazone (PZ) encapsulated in carbopol-based transgel system (proniosomes/niosome). The developed formulations were optimized using quality by design (QbD) approach and particle size, percentage entrapment and transdermal flux were determined. It was found to be more efficient delivery carriers with high encapsulation and enhanced flux value demonstrated that the permeation of PZ through skin was significantly increased with developed formulation. The transdermal enhancement from proniosome was 3.16 times higher than that of PZ from control formulation (ethanol buffer formulation, 3:7), which was further confirmed by confocal laser scanning microscopy. In vivo pharmacokinetic study of carbopol transgel showed a significant increase in bioavailability (2.26 times) compared with tablet formulation. It also showed better antidiabetic activity in comparison to marketed tablet, so our results suggest that carbopol-based transgel are an efficient carrier for delivery of pioglitazone through skin. PMID- 25033042 TI - Development, characterization and toxicological evaluations of phospholipids complexes of curcumin for effective drug delivery in cancer chemotherapy. AB - The purpose of this study was to prepare and characterize the complexes between curcumin (CU) phosphatidylcholine (PC) and hydrogenated soya phosphatidylcholine (HSPC) and to evaluate their anticancer activity. These CU-PC and CU-HSPC complexes (CU-PC-C and CU-HSPC-C) were evaluated for various physical parameters like Fourier transform infrared spectroscopy, melting point, solubility, scanning electron microscopy and the in vitro drug release study. These data confirmed the formation of phospholipids complexes. The in vitro hemolysis study showed that the complex was non-hemolytic. The anti-cancer potential of the complexes was demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay in MCF-7 cell line. This increase may be due to the amphiphilic nature of the complexes, which significantly enhances the water and lipid solubility of the CU. Unlike the free CU (which showed a total of only 90% drug release at the end of 8 h), complex showed around 40-60% release at the end of 8 h in dissolution studies. It showed that (when given in equimolar doses) complexes have significantly decreased the amount of CU available for absorption as compared with CU-free drug. Both CU-PC-C and CU-HSPC-C were found to be non-toxic at the dose equivalent to 2000 mg/kg of body weight of CU in the toxicity study. Acute and subacute toxicity studies confirmed the oral safety of the formulation. A series of genotoxicity studies was conducted, which revealed the non-genotoxicity potential of the developed complexes. Thus, it can be concluded that the phospholipid complexes of CU may be a promising candidate in cancer therapy. PMID- 25033043 TI - Intact dendritic cell pathogen-recognition receptor functions associate with chronic hepatitis C treatment-induced viral clearance. AB - Although studies have addressed the exhaustion of the host's immune response to HCV and its role in treatment, there is little information about the possible contribution of innate immunity to treatment-induced clearance. We hypothesized that because intact myeloid dendritic cell (MDC) pathogen sensing functions are associated with improved HCV-specific CD8+ T cell functionality in some chronically infected patients, it might enhance HCV clearance rate under standard interferon therapy. To investigate this hypothesis, TLR-induced MDC activation and HCV-specific CD8+ T cell response quality were monitored longitudinally at the single-cell level using polychromatic flow cytometry in chronically infected patients undergoing interferon therapy. We correlated the immunological, biochemical and virological data with response to treatment. We demonstrate that the clinical efficacy of interferon-induced viral clearance is influenced by the extent to which HCV inhibits MDC functions before treatment, rather than solely on a breakdown of the extrinsic T cell immunosuppressive environment. Thus, viral inhibition of MDC functions before treatment emerges as a co-determining factor in the clinical efficacy of interferon therapy during chronic HCV infection. PMID- 25033044 TI - A novel mouse model of Campylobacter jejuni gastroenteritis reveals key pro inflammatory and tissue protective roles for Toll-like receptor signaling during infection. AB - Campylobacter jejuni is a major source of foodborne illness in the developed world, and a common cause of clinical gastroenteritis. Exactly how C. jejuni colonizes its host's intestines and causes disease is poorly understood. Although it causes severe diarrhea and gastroenteritis in humans, C. jejuni typically dwells as a commensal microbe within the intestines of most animals, including birds, where its colonization is asymptomatic. Pretreatment of C57BL/6 mice with the antibiotic vancomycin facilitated intestinal C. jejuni colonization, albeit with minimal pathology. In contrast, vancomycin pretreatment of mice deficient in SIGIRR (Sigirr(-/-)), a negative regulator of MyD88-dependent signaling led to heavy and widespread C. jejuni colonization, accompanied by severe gastroenteritis involving strongly elevated transcription of Th1/Th17 cytokines. C. jejuni heavily colonized the cecal and colonic crypts of Sigirr(-/-) mice, adhering to, as well as invading intestinal epithelial cells. This infectivity was dependent on established C. jejuni pathogenicity factors, capsular polysaccharides (kpsM) and motility/flagella (flaA). We also explored the basis for the inflammatory response elicited by C. jejuni in Sigirr(-/-) mice, focusing on the roles played by Toll-like receptors (TLR) 2 and 4, as these innate receptors were strongly stimulated by C. jejuni. Despite heavy colonization, Tlr4(-/-)/Sigirr(-/-) mice were largely unresponsive to infection by C. jejuni, whereas Tlr2(-/-)/Sigirr(-/-) mice developed exaggerated inflammation and pathology. This indicates that TLR4 signaling underlies the majority of the enteritis seen in this model, whereas TLR2 signaling had a protective role, acting to promote mucosal integrity. Furthermore, we found that loss of the C. jejuni capsule led to increased TLR4 activation and exaggerated inflammation and gastroenteritis. Together, these results validate the use of Sigirr(-/-) mice as an exciting and relevant animal model for studying the pathogenesis and innate immune responses to C. jejuni. PMID- 25033045 TI - Diagnostic utility of neutrophil CD64 as a marker for early-onset sepsis in preterm neonates. AB - INTRODUCTION: Neutrophil CD64 has been proposed as an early marker of sepsis. This study aims to evaluate the diagnostic utility of neutrophil CD64 for identification of early-onset sepsis in preterm neonates. METHODS: The prospective study was conducted in a neonatal intensive care unit between November 2010 and June 2011. Preterm neonates in whom infection was suspected when they were <12 hours of age were enrolled. Complete blood count with differential, blood culture, neutrophil CD11b and CD64 measurement were performed. Receiver operating characteristic curve analysis was performed to evaluate the performance of neutrophil CD64 as biomarker of sepsis. RESULTS: A total of 158 preterm neonates was enrolled, 88 of whom were suspected infection. The suspected sepsis group was of lesser gestational age (P<0.001) and lower birth weight (P<0.001), compared with controls. The hematologic profiles of the suspected sepsis group were characterized by higher white blood cell count, neutrophil counts and C-reactive protein. The suspected sepsis neonates had significantly higher neutrophil CD64 expression compared with controls. Neutrophil CD64 had an area value under the curve of 0.869 with an optimal cutoff values of 1010 phycoerythrin molecules bound/cell and it had a high sensitivity (81.82%) and negative predictive value (77.4%). The level of neutrophil CD64 was independent of antibiotic therapy within 24 hours after the onset of sepsis in preterm neonates. CONCLUSIONS: Neutrophil CD64 is a highly sensitive marker for suspected early-onset sepsis in preterm neonates. Our study suggests that neutrophil CD64 may be incorporated as a valuable marker to diagnose infection. PMID- 25033046 TI - The effect of HIV-hepatitis C co-infection on bone mineral density and fracture: a meta-analysis. AB - OBJECTIVE: There is a variable body of evidence on adverse bone outcomes in HIV patients co-infected with hepatitis C virus (HCV). We examined the association of HIV/HCV co-infection on osteoporosis or osteopenia (reduced bone mineral density; BMD) and fracture. DESIGN: Systematic review and random effects meta-analyses. METHODS: A systematic literature search was conducted for articles published in English up to 1 April 2013. All studies reporting either BMD (g/cm2, or as a T score) or incident fractures in HIV/HCV co-infected patients compared to either HIV mono-infected or HIV/HCV uninfected/seronegative controls were included. Random effects meta-analyses estimated the pooled odds ratio (OR) and the relative risk (RR) and associated 95% confidence intervals (CI). RESULTS: Thirteen eligible publications (BMD N = 6; Fracture = 7) of 2,064 identified were included with a total of 427,352 subjects. No publications reported data on HCV mono-infected controls. Meta-analysis of cross-sectional studies confirmed that low bone mineral density was increasingly prevalent among co-infected patients compared to HIV mono-infected controls (pooled OR 1.98, 95% CI 1.18, 3.31) but not those uninfected (pooled OR 1.47, 95% CI 0.78, 2.78). Significant association between co-infection and fracture was found compared to HIV mono-infected from cohort and case-control studies (pooled RR 1.57, 95% CI 1.33, 1.86) and compared to HIV/HCV uninfected from cohort (pooled RR 2.46, 95% CI 1.03, 3.88) and cross sectional studies (pooled OR 2.30, 95% CI 2.09, 2.23). CONCLUSIONS: The associations of co-infection with prevalent low BMD and risk of fracture are confirmed in this meta-analysis. Although the mechanisms of HIV/HCV co infection's effect on BMD and fracture are not well understood, there is evidence to suggest that adverse outcomes among HIV/HCV co-infected patients are substantial. PMID- 25033047 TI - Invasive cane toads: social facilitation depends upon an individual's personality. AB - Individual variation in behavioural traits (including responses to social cues) may influence the success of invasive populations. We studied the relationship between sociality and personality in invasive cane toads (Rhinella marina) from a recently established population in tropical Australia. In our field experiments, we manipulated social cues (the presence of a feeding conspecific) near a food source. We captured and compared toads that only approached feeding sites where another toad was already present, with conspecifics that approached unoccupied feeding sites. Subsequent laboratory trials showed correlated personality differences (behavioural syndromes) between these two groups of toads. For example, toads that approached already-occupied rather than unoccupied feeding sites in the field, took longer to emerge from a shelter-site in standardized trials, suggesting these individuals are 'shy' (whereas toads that approached unoccupied feeding stations tended to be 'bold'). Manipulating hunger levels did not abolish this difference. In feeding trials, a bold toad typically outcompeted a shy toad under conditions of low prey availability, but the outcome was reversed when multiple prey items were present. Thus, both personality types may be favored under different circumstances. This invasive population of toads contains individuals that exhibit a range of personalities, hinting at the existence of a wide range of social dynamics in taxa traditionally considered to be asocial. PMID- 25033048 TI - Correlations between transmembrane 4 L6 family member 5 (TM4SF5), CD151, and CD63 in liver fibrotic phenotypes and hepatic migration and invasive capacities. AB - Transmembrane 4 L6 family member 5 (TM4SF5) is overexpressed during CCl4-mediated murine liver fibrosis and in human hepatocellular carcinomas. The tetraspanins form tetraspanin-enriched microdomains (TEMs) consisting of large membrane protein complexes on the cell surface. Thus, TM4SF5 may be involved in the signal coordination that controls liver malignancy. We investigated the relationship between TM4SF5-positive TEMs with liver fibrosis and tumorigenesis, using normal Chang hepatocytes that lack TM4SF5 expression and chronically TGFbeta1-treated Chang cells that express TM4SF5. TM4SF5 expression is positively correlated with tumorigenic CD151 expression, but is negatively correlated with tumor-suppressive CD63 expression in mouse fibrotic and human hepatic carcinoma tissues, indicating cooperative roles of the tetraspanins in liver malignancies. Although CD151 did not control the expression of TM4SF5, TM4SF5 appeared to control the expression levels of CD151 and CD63. TM4SF5 interacted with CD151, and caused the internalization of CD63 from the cell surface into late lysosomal membranes, presumably leading to terminating the tumor-suppressive functions of CD63. TM4SF5 could overcome the tumorigenic effects of CD151, especially cell migration and extracellular matrix (ECM)-degradation. Taken together, TM4SF5 appears to play a role in liver malignancy by controlling the levels of tetraspanins on the cell surface, and could provide a promising therapeutic target for the treatment of liver malignancies. PMID- 25033049 TI - Wideband LTE power amplifier with integrated novel analog pre-distorter linearizer for mobile wireless communications. AB - For the first time, a new circuit to extend the linear operation bandwidth of a LTE (Long Term Evolution) power amplifier, while delivering a high efficiency is implemented in less than 1 mm2 chip area. The 950 um * 900 um monolithic microwave integrated circuit (MMIC) power amplifier (PA) is fabricated in a 2 um InGaP/GaAs process. An on-chip analog pre-distorter (APD) is designed to improve the linearity of the PA, up to 20 MHz channel bandwidth. Intended for 1.95 GHz Band 1 LTE application, the PA satisfies adjacent channel leakage ratio (ACLR) and error vector magnitude (EVM) specifications for a wide LTE channel bandwidth of 20 MHz at a linear output power of 28 dBm with corresponding power added efficiency (PAE) of 52.3%. With a respective input and output return loss of 30 dB and 14 dB, the PA's power gain is measured to be 32.5 dB while exhibiting an unconditional stability characteristic from DC up to 5 GHz. The proposed APD technique serves to be a good solution to improve linearity of a PA without sacrificing other critical performance metrics. PMID- 25033050 TI - Evidence and policy for influenza control. PMID- 25033051 TI - Effectiveness of trivalent seasonal influenza vaccine in preventing laboratory confirmed influenza in primary care in the United Kingdom: 2012/13 end of season results. AB - The effectiveness of the 2012/13 trivalent seasonal influenza vaccine (TIV) was assessed using a test-negative case-control study of patients consulting primary care with influenza-like illness in the United Kingdom. Strain characterisation was undertaken on selected isolates. Vaccine effectiveness (VE) against confirmed influenza A(H3N2), A(H1N1) and B virus infection, adjusted for age, sex, surveillance scheme (i.e. setting) and month of sample collection was 26% (95% confidence interval (CI): -4 to 48), 73% (95% CI: 37 to 89) and 51% (95% CI: 34 to 63) respectively. There was an indication, although not significant, that VE declined by time since vaccination for influenza A(H3N2) (VE 50% within three months, 2% after three months, p=0.25). For influenza A(H3N2) this is the second season of low VE, contributing to the World Health Organization (WHO) recommendation that the 2013/14 influenza vaccine strain composition be changed to an A(H3N2) virus antigenically like cell-propagated prototype 2012/13 vaccine strain (A/Victoria/361/2011). The lower VE seen for type B is consistent with antigenic drift away from the 2012/13 vaccine strain. The majority of influenza B viruses analysed belong to the genetic clade 2 and were antigenically distinguishable from the 2012/13 vaccine virus B/Wisconsin/1/2010 clade 3. These findings supported the change to the WHO recommended influenza B vaccine component for 2013/14. PMID- 25033052 TI - Y155H amino acid substitution in influenza A(H1N1)pdm09 viruses does not confer a phenotype of reduced susceptibility to neuraminidase inhibitors. AB - The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1) pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1) pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients. PMID- 25033053 TI - Till receipts--a new approach for investigating outbreaks? Evaluation during a large Salmonella Enteritidis phage type 14b outbreak in a North West London takeaway restaurant, September 2009. AB - Selecting suitable controls for outbreak investigations is often difficult and if done inappropriately will lead to biased inferences. Till receipts and other sales records are frequently available on food premises, but their applicability has not been fully explored. Using data from an investigation into a Salmonella outbreak affecting 66 individuals exposed in a London takeaway restaurant, this study aimed to evaluate the use of till receipts to assess associations between sales and illness. Cases identified through local case-finding were subjected to a standardised exposure questionnaire. Till receipts over the time period when cases arose were analysed. Estimated food exposures from sales were compared to case reported exposures and till receipts analysis showed strong association between illness and consumption of rotisserie chicken (odds ratio (OR): 2.75; confidence interval (CI): 1.7-4.5). Chicken sales immediately prior to food consumption for cases were compared to two control periods in an ecological case crossover design. On average there was an estimated increase of 3.7 (CI: 2.2-5.2) extra chickens sold in the hour immediately prior to the consumption in the cases (p<0.0001) and the risk of becoming ill at busy times increased by 5% with each additional chicken quarter sold per hour (OR: 1.05; CI: 1.03-1.08). Microbiological and environmental investigations revealed Salmonella Enteritidis phage type (PT)14b in all available cases' stool samples, two environmental samples and leftover chicken from the takeaway. The feasibility of this novel approach to obtain exposure information in the population at risk has been demonstrated, and its limitations are discussed. Further validation is required, comparing results with those in a concurrent classic case-control study. PMID- 25033056 TI - Arabidopsis thaliana WAPL is essential for the prophase removal of cohesin during meiosis. AB - Sister chromatid cohesion, which is mediated by the cohesin complex, is essential for the proper segregation of chromosomes in mitosis and meiosis. The establishment of stable sister chromatid cohesion occurs during DNA replication and involves acetylation of the complex by the acetyltransferase CTF7. In higher eukaryotes, the majority of cohesin complexes are removed from chromosomes during prophase. Studies in fly and human have shown that this process involves the WAPL mediated opening of the cohesin ring at the junction between the SMC3 ATPase domain and the N-terminal domain of cohesin's alpha-kleisin subunit. We report here the isolation and detailed characterization of WAPL in Arabidopsis thaliana. We show that Arabidopsis contains two WAPL genes, which share overlapping functions. Plants in which both WAPL genes contain T-DNA insertions show relatively normal growth and development but exhibit a significant reduction in male and female fertility. The removal of cohesin from chromosomes during meiotic prophase is blocked in Atwapl mutants resulting in chromosome bridges, broken chromosomes and uneven chromosome segregation. In contrast, while subtle mitotic alterations are observed in some somatic cells, cohesin complexes appear to be removed normally. Finally, we show that mutations in AtWAPL suppress the lethality associated with inactivation of AtCTF7. Taken together our results demonstrate that WAPL plays a critical role in meiosis and raises the possibility that mechanisms involved in the prophase removal of cohesin may vary between mitosis and meiosis in plants. PMID- 25033057 TI - Biotransformation and in vitro metabolic profile of bioactive extracts from a traditional Miao-nationality herbal medicine, Polygonum capitatum. AB - Polygonum capitatum Buch.-Ham.ex D. Don, a traditional Miao-nationality herbal medicine, has been widely used in the treatment of various urologic disorders. Recent pharmacological studies demonstrated that a pure compound, FR429, isolated from the ethanol extracts of P. capitatum could selectively inhibit the growth of four hepatocellular carcinoma (HCC) cell lines in a dose-dependent manner. Thus, P. capitatum probably exhibits potential antitumor activity. However, there is very little information on the metabolism of substances present in P. capitatum extracts. In this study, gallic acid, quercetrin, ethanol extracts and ethyl acetate fraction of ethnolic extract (EtOAc fraction) of P. capitatum were cultured anaerobically with rat intestinal bacteria. A highly sensitive and selective liquid chromatography electrospray ionization-ion trap-time of fight mass spectrometry (LC/MSn-IT-TOF) technique was employed to identify and characterize the resulting metabolites. A total of 22 metabolites (M1-M22), including tannins, phenolic acids and flavonoids, were detected and characterized. The overall results demonstrated that the intestinal bacteria played an important role in the metabolism of P. capitatum, and the main metabolic pathways were hydrolysis, reduction and oxidation reactions. Our results provided a basis for the estimation of the metabolic transformation of P. capitatum in vivo. PMID- 25033058 TI - Simultaneous quantitation and validation of triterpenoids and phytosteroids in Phaseolus angularis seeds. AB - A reproducible analytical method using reverse-phase high liquid performance chromatography combined with UV detecting was developed for the quantitative determination of four compounds isolated from the ethanol extract of Phaseolus angularis seeds (PASE): oleanolic acid (1), oleanolic acid acetate (2), stigmasterol (3) and beta-sitosterol (4). This method was fully validated in terms of linearity (r2 > 0.999), accuracy (98.5%-100.8%), precision (<0.92%), LOD (<0.0035 mg/mL), and LOQ (<0.0115 mg/mL). The effects of the PASE and isolated compounds 1-4 on TLR4 activation were tested in THP1-Blue cells. Among the tested substances, compound 2 showed potent inhibitory activity with an IC50 value of 3.89 +/- 0.17 uM. PMID- 25033059 TI - Microextraction techniques coupled to liquid chromatography with mass spectrometry for the determination of organic micropollutants in environmental water samples. AB - Until recently, sample preparation was carried out using traditional techniques, such as liquid-liquid extraction (LLE), that use large volumes of organic solvents. Solid-phase extraction (SPE) uses much less solvent than LLE, although the volume can still be significant. These preparation methods are expensive, time-consuming and environmentally unfriendly. Recently, a great effort has been made to develop new analytical methodologies able to perform direct analyses using miniaturised equipment, thereby achieving high enrichment factors, minimising solvent consumption and reducing waste. These microextraction techniques improve the performance during sample preparation, particularly in complex water environmental samples, such as wastewaters, surface and ground waters, tap waters, sea and river waters. Liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) and time-of-flight mass spectrometric (TOF/MS) techniques can be used when analysing a broad range of organic micropollutants. Before separating and detecting these compounds in environmental samples, the target analytes must be extracted and pre-concentrated to make them detectable. In this work, we review the most recent applications of microextraction preparation techniques in different water environmental matrices to determine organic micropollutants: solid-phase microextraction SPME, in-tube solid-phase microextraction (IT-SPME), stir bar sorptive extraction (SBSE) and liquid-phase microextraction (LPME). Several groups of compounds are considered organic micropollutants because these are being released continuously into the environment. Many of these compounds are considered emerging contaminants. These analytes are generally compounds that are not covered by the existing regulations and are now detected more frequently in different environmental compartments. Pharmaceuticals, surfactants, personal care products and other chemicals are considered micropollutants. These compounds must be monitored because, although they are detected in low concentrations, they might be harmful toward ecosystems. PMID- 25033060 TI - Vitamin D as a neurosteroid affecting the developing and adult brain. AB - Vitamin D deficiency is prevalent throughout the world, and growing evidence supports a requirement for optimal vitamin D levels for the healthy developing and adult brain. Vitamin D has important roles in proliferation and differentiation, calcium signaling within the brain, and neurotrophic and neuroprotective actions; it may also alter neurotransmission and synaptic plasticity. Recent experimental studies highlight the impact that vitamin D deficiency has on brain function in health and disease. In addition, results from recent animal studies suggest that vitamin D deficiency during adulthood may exacerbate underlying brain disorders and/or worsen recovery from brain stressors. An increasing number of epidemiological studies indicate that vitamin D deficiency is associated with a wide range of neuropsychiatric disorders and neurodegenerative diseases. Vitamin D supplementation is readily available and affordable, and this review highlights the need for further research. PMID- 25033062 TI - The emerging role of microRNAs and nutrition in modulating health and disease. AB - Understanding the molecular mechanisms that inform how diet and dietary supplements influence health and disease is an active research area. One such mechanism concerns the role of diet in modulating the activity and function of microRNAs (miRNAs). miRNAs are small noncoding RNA molecules that are involved in posttranscriptional gene silencing and have been shown to control gene expression in diverse biological processes including development, differentiation, cell proliferation, metabolism, and inflammation as well as in human diseases. Recent evidence described in this review highlights how dietary factors may influence cancer, cardiovascular disease, type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver disease through modulation of miRNA expression. Additionally, circulating miRNAs are emerging as putative biomarkers of disease, susceptibility, and perhaps dietary exposure. Research needs to move beyond associations in cells and animals to understanding the direct effects of diet and dietary supplements on miRNA expression and function in human health and disease. PMID- 25033063 TI - Regulation of intestinal lipid absorption by clock genes. AB - Plasma levels of triacylglycerols and diacylglycerols, the lipoproteins that transport them, and proteins involved in their absorption from the intestinal lumen fluctuate in a circadian manner. These changes are likely controlled by clock genes expressed in the intestine that are probably synchronized by neuronal and humoral signals from the suprachiasmatic nuclei, which constitute a master clock entrained by light signals from the eyes and from the environment, e.g., food availability. Acute changes in circadian rhythms--e.g., due to nonsynchronous work schedules or a transcontinental flight--may trigger intestinal discomfort. Chronic disruptions in circadian control mechanisms may predispose the individual to irritable bowel syndrome, gastroesophageal reflux disease, and peptic ulcer disease. A more detailed understanding of the molecular mechanisms underlying temporal changes in intestinal activity might allow us to identify novel targets for developing therapeutic approaches to these disorders. PMID- 25033064 TI - Using denosumab to treat immobilization hypercalcemia in a post-acute care patient. AB - BACKGROUND: Hypercalcemia in adults has several less common causes. Management in patients with chronic kidney disease (CKD) is challenging because bisphosphonates are contraindicated. This case presents an uncommon cause of hypercalcemia in a subacute rehabilitation patient who was managed with denosumab. CASE REPORT: A 79 year-old female with CKD stage 4 was admitted to a skilled nursing facility with a limited-weight-bearing status after right-hip arthroplasty. Four weeks later, she developed hypercalcemia (11.5 mg/dL; normal, 7.9-9.9 mg/dL) with serum albumin of 2.5 g/dL (corrected calcium, 12.7 mg/dL). Despite iv fluids, hypercalcemia worsened (corrected serum calcium, 14.5 mg/dL), and she was rehospitalized. Additional studies eliminated common causes of hypercalcemia, leading to the diagnosis of immobilization hypercalcemia. Due to CKD, a bisphosphonate was not given. She received 10 doses of calcitonin s.c. with mild improvement in her calcium, and she returned to the skilled nursing facility. Because hypercalcemia worsened within days, denosumab 60 mg was administered s.c., and her serum calcium level normalized. Over the next several weeks, her surgical wound worsened. Hip x-ray showed osteolysis of her residual right femoral head. In retrospect, hip x-ray during her hospitalization for hypercalcemia showed osteolysis, likely from osteomyelitis. A contribution of osteomyelitis to hypercalcemia could not be excluded. Despite resolution of hypercalcemia, she succumbed to sepsis. CONCLUSION: Immobilization hypercalcemia is underappreciated in post-acute care older adults. In this patient with CKD, denosumab reversed her hypercalcemia; however, the case highlights potential risks and limitations with this therapy and emphasizes the need for further studies in medically complex older adults. PMID- 25033065 TI - Maximum dose rate is a determinant of hypothyroidism after 131I therapy of Graves' disease but the total thyroid absorbed dose is not. AB - CONTEXT: The determinants of successful (131)I therapy of Graves' disease (GD) are unclear. OBJECTIVE: To relate dosimetry parameters to outcome of therapy to identify significant determinants eu- and/or hypothyroidism after (131)I therapy in patients with GD. SETTING AND DESIGN: A retrospective study in which 206 Patients with GD treated in University Hospital between November 1999 and January 2011. All received (131)I therapy aiming at a total absorbed dose to the thyroid of 250 Gy based on pre-therapeutic dosimetry. Post-therapy dosimetric thyroid measurements were performed twice daily until discharge. From these measurements, thyroid (131)I half-life, the total thyroid absorbed dose, and the maximum dose rate after (131)I administration were calculated. RESULTS: In all, 48.5% of patients were hypothyroid and 28.6% of patients were euthyroid after (131)I therapy. In univariate analysis, nonhyperthyroid and hyperthyroid patients only differed by sex. A lower thyroid mass, a higher activity per gram thyroid tissue, a shorter effective thyroidal (131)I half-life, and a higher maximum dose rate, but not the total thyroid absorbed dose, were significantly associated with hypothyroidism. In multivariate analysis, the maximum dose rate remained the only significant determinant of hypothyroidism (P < .001). Maximum dose rates of 2.2 Gy/h and higher were associated with a 100% hypothyroidism rate. CONCLUSIONS: Not the total thyroid absorbed dose, but the maximum dose rate is a determinant of successfully achieving hypothyroidism in Graves' disease. Dosimetric concepts aiming at a specific total thyroid absorbed dose will therefore require reconsideration if our data are confirmed prospectively. PMID- 25033066 TI - A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone. AB - CONTEXT: Fibrous dysplasia (FD) is a rare skeletal disorder, resulting in deformity, fracture, functional impairment, and pain. Bisphosphonates have been advocated as a potential treatment. OBJECTIVE: To determine the efficacy of alendronate for treatment of FD. DESIGN: Two-year randomized, double-blind, placebo-controlled trial. SETTING: Clinical research center. PATIENTS: Forty subjects with polyostotic FD (24 adults, 16 children). Subjects were randomized and stratified by age. INTERVENTIONS: Study drug was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). Alendronate dosing was stratified: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. MAIN OUTCOME MEASURES: Primary endpoints were bone turnover markers, including serum osteocalcin, and urinary NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-min walk test and manual muscle testing. RESULTS: Clinical data was collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (P = .006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (P = .006), and in predetermined regions of FD (P < .001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups. CONCLUSIONS: Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but no significant effect on serum osteocalcin, pain, or functional parameters. PMID- 25033067 TI - Hyperglycemia and insulin resistance in cardiac arrest patients treated with moderate hypothermia. AB - CONTEXT: It is unknown whether the hyperglycemia that follows cardiac arrest and during therapeutic hypothermia (TH) is due to the arrest or the TH, whether it is associated with adverse outcomes, or whether its treatment affects outcomes. OBJECTIVE: The objective of the study was to determine the effects of TH on the blood glucose (BG) levels in postcardiac arrest patients and the effects of hyperglycemia on mortality. DESIGN: This was a chart review of 62 patients undergoing TH after cardiac arrest between September 2005 and April 2008. BG levels from 72 hours before the arrest to 48 hours after TH and iv insulin infusion rates were analyzed and correlated with survival to discharge from hospital. SETTING: The study was conducted at a tertiary, university referral center. PATIENTS: PATIENTS undergoing TH after cardiac arrest participated in the study. INTERVENTIONS: TH consisted of cooling as rapidly as possible to 33 degrees C, holding that temperature for 24 hours, and then controlled rewarming to 37 degrees C over 8 or 16 hours. Hyperglycemia was managed with iv insulin drip protocols. MAIN OUTCOME MEASURE: The relationship of cardiac arrest and hypothermia to hyperglycemia, with a key secondary outcome being the relationship of hyperglycemia to survival to discharge, was measured. RESULTS: Analysis of glucose patterns showed no independent effect of TH on BG levels. Mean BG levels between cardiac arrest and the initiation of hypothermia were higher in nonsurvivors (253 +/- 112 mg/dL, n = 48) than in survivors (192 +/- 69 mg/dL, n = 24, P = .016). BG, insulin infusion rates, and insulin resistance during hypothermia, during rewarming, and 24-48 hours after hypothermia were not significantly different between the 2 groups. CONCLUSIONS: In patients treated with TH, the TH had no independent effect on BG levels. Mortality was associated with increased BG levels after cardiac arrest but before initiation of TH or an insulin drip. Likely, it is the severity of stress from the cardiac arrest that causes the hyperglycemia in these patients. PMID- 25033061 TI - Sulfur as a signaling nutrient through hydrogen sulfide. AB - Hydrogen sulfide (H2S) has emerged as an important signaling molecule with beneficial effects on various cellular processes affecting, for example, cardiovascular and neurological functions. The physiological importance of H2S is motivating efforts to develop strategies for modulating its levels. However, advancement in the field of H2S-based therapeutics is hampered by fundamental gaps in our knowledge of how H2S is regulated, its mechanism of action, and its molecular targets. This review provides an overview of sulfur metabolism; describes recent progress that has shed light on the mechanism of H2S as a signaling molecule; and examines nutritional regulation of sulfur metabolism, which pertains to health and disease. PMID- 25033068 TI - The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. AB - CONTEXT: There is growing evidence that vitamin D plays a role on several tissues including skeletal muscle. OBJECTIVE: The aim was to summarize with a meta analysis, the effects of vitamin D supplementation on muscle function. DATA SOURCES: A systematic research of randomized controlled trials, performed between 1966 and January 2014 has been conducted on Medline, Cochrane Database of Systematics Reviews, Cochrane Central Register of Controlled and completed by a manual review of the literature and congressional abstracts. STUDY SELECTION: All forms and doses of vitamin D supplementation, with or without calcium supplementation, compared with placebo or control were included. Out of the 225 potentially relevant articles, 30 randomized controlled trials involving 5615 individuals (mean age: 61.1 years) met the inclusion criteria. DATA EXTRACTION: Data were extracted by two independent reviewers. DATA SYNTHESIS: Results revealed a small but significant positive effect of vitamin D supplementation on global muscle strength with a standardized mean difference (SMD) of 0.17 (P = .02). No significant effect was found on muscle mass (SMD 0.058; P = .52) or muscle power (SMD 0.057; P = .657). Results on muscle strength were significantly more important with people who presented a 25-hydroxyvitamin D level <30 nmol/L. Supplementation seems also more effective on people aged 65 years or older compared to younger subjects (SMD 0.25; 95% CI 0.01 to 0.48 vs SMD 0.03; 95% CI 0.08 to 0.14). CONCLUSIONS: Vitamin D supplementation has a small positive impact on muscle strength, but additional studies are needed to define optimal treatment modalities, including dose, mode of administration, and duration. PMID- 25033069 TI - Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. AB - CONTEXT: Gordon Holmes syndrome (GHS) is characterized by cerebellar ataxia/atrophy and normosmic hypogonadotropic hypogonadism (nHH). The underlying pathophysiology of this combined neurodegeneration and nHH remains unknown. OBJECTIVE: We aimed to provide insight into the disease mechanism in GHS. METHODS: We studied a cohort of 6 multiplex families with GHS through autozygosity mapping and whole-exome sequencing. RESULTS: We identified 6 patients from 3 independent families carrying loss-of-function mutations in PNPLA6, which encodes neuropathy target esterase (NTE), a lysophospholipase that maintains intracellular phospholipid homeostasis by converting lysophosphatidylcholine to glycerophosphocholine. Wild-type PNPLA6, but not PNPLA6 bearing these mutations, rescued a well-established Drosophila neurodegenerative phenotype caused by the absence of sws, the fly ortholog of mammalian PNPLA6. Inhibition of NTE activity in the LbetaT2 gonadotrope cell line diminished LH response to GnRH by reducing GnRH-stimulated LH exocytosis, without affecting GnRH receptor signaling or LHbeta synthesis. CONCLUSION: These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH. PMID- 25033070 TI - Tree-based model for thyroid cancer prognostication. AB - BACKGROUND: Death is uncommon in thyroid cancer patients, and the factors important in predicting survival remain inadequately studied. The objective of this study was to assess prognostic effects of patient, tumor, and treatment factors and to determine prognostic groups for thyroid cancer survival. METHODS: Using data from the Surveillance, Epidemiology, and End Results Program (SEER), we evaluated overall and disease-specific survival (DSS) in 43 392 well differentiated thyroid cancer patients diagnosed from 1998 through 2005. Multivariable analyses were performed using Cox proportional hazards regression, survival trees, and random survival forest. Similar analyses were performed using National Cancer Data Base data, with overall survival (OS) evaluated in 131 484 thyroid cancer patients diagnosed from 1998 through 2005. Relative importance of factors important to survival was assessed based on the random survival forest analyses. RESULTS: Using survival tree analyses, we identified 4 distinct prognostic groups based on DSS (P < .0001). The 5-year DSS of these prognostic groups was 100%, 98%, 91%, 64%, whereas the 10-year survival was 100%, 96%, 85%, and 50%. Based on random survival forest analyses, the most important factors for DSS were SEER stage and age at diagnosis. For OS, important prognostic factors were similar, except age at diagnosis demonstrated marked importance relative to SEER stage. Similar results for OS were found using National Cancer Data Base data. CONCLUSION: This study identifies distinct prognostic groups for thyroid cancer and illustrates the importance of patient age to both disease-specific and OS. These findings have implications for patient education and thyroid cancer treatment. PMID- 25033071 TI - Acute Candida thyroiditis complicated by abscess formation in a severely immunocompromised patient. PMID- 25033072 TI - The common ground of genomics and systems biology. AB - The rise of systems biology is intertwined with that of genomics, yet their primordial relationship to one another is ill-defined. We discuss how the growth of genomics provided a critical boost to the popularity of systems biology. We describe the parts of genomics that share common areas of interest with systems biology today in the areas of gene expression, network inference, chromatin state analysis, pathway analysis, personalized medicine, and upcoming areas of synergy as genomics continues to expand its scope across all biomedical fields. PMID- 25033074 TI - Equivalence tests for interchangeability based on two one-sided probabilities. AB - A test treatment is considered to be interchangeable with its reference treatment if they are equivalent and expected to produce the same clinical result in any given patient. To assess interchangeability, FDA Draft Guidance (1999) and Guidance for Industry (2001, 2003) recommend using individual bioequivalence (IBE) and population bioequivalence (PBE) procedures. Chow (1999) and Chow and Liu (1999) gave a discussion on the limitation of the aggregate criteria of the IBE and PBE proposed therein. They mentioned that it is not clear whether IBE or PBE can imply average bioequivalence. Alternative approaches have been proposed to address the weakness of IBE and PBE. Dong et al. (2014) discuss the tolerance interval method and an approximate test for interchangeability defined by a two sided probability. These tests may not be able to test for the two one-sided tests (TOST) with asymmetric margins around the true mean difference. In addition, the tests of two-sided probability provide no direction when failing the equivalence in interchangeability. Thus, we reexamine the statistical properties of the two one-sided tolerance interval approaches proposed by Tsong and Shen (2007, 2008). In this project, we extend their approach for parallel arms trials and paired/crossover data without the assumption of equal sample sizes and variances. We also develop the exact power function and assess the type I error rate of our proposed approach. In addition, we study the sample size determination based on the interchangeability testing utilizing the tolerance interval method. PMID- 25033073 TI - Detection of circulating parasite-derived microRNAs in filarial infections. AB - Filarial nematodes cause chronic and profoundly debilitating diseases in both humans and animals. Applications of novel technology are providing unprecedented opportunities to improve diagnosis and our understanding of the molecular basis for host-parasite interactions. As a first step, we investigated the presence of circulating miRNAs released by filarial nematodes into the host bloodstream. miRNA deep-sequencing combined with bioinformatics revealed over 200 mature miRNA sequences of potential nematode origin in Dirofilaria immitis-infected dog plasma in two independent analyses, and 21 in Onchocerca volvulus-infected human serum. Total RNA obtained from D. immitis-infected dog plasma was subjected to stem-loop RT-qPCR assays targeting two detected miRNA candidates, miR-71 and miR-34. Additionally, Brugia pahangi-infected dog samples were included in the analysis, as these miRNAs were previously detected in extracts prepared from this species. The presence of miR-71 and miR-34 discriminated infected samples (both species) from uninfected samples, in which no specific miRNA amplification occurred. However, absolute miRNA copy numbers were not significantly correlated with microfilaraemia for either parasite. This may be due to the imprecision of mf counts to estimate infection intensity or to miRNA contributions from the unknown number of adult worms present. Nonetheless, parasite-derived circulating miRNAs are found in plasma or serum even for those species that do not live in the bloodstream. PMID- 25033075 TI - Does targeted neonatal echocardiography affect hemodynamics and cerebral oxygenation in extremely preterm infants? AB - OBJECTIVE: To investigate the effect of targeted neonatal echocardiography (TnEcho) on heart rate, arterial oxygen saturation (SPO2), cerebral regional oxygen saturation (CrSO2) and cerebral fractional oxygen extraction (CFOE) in extremely preterm infants during the first 3 postnatal days. STUDY DESIGN: s a nested study in a prospective observational study, we acquired continuous data on heart rate, SPO2, CrSO2 and CFOE. Data averaged for the duration of TnEcho study were compared with the data collected during a baseline period immediately before the start of echocardiography. The duration of the baseline and study periods was the same. TnEcho evaluation included assessment of preload, afterload, contractility, left and right ventricular output, patent ductus arteriosus and foramen ovale. RESULT: We analyzed 138 data pairs before and during TnEcho in 22 extremely preterm infants (gestational age 25.9 +/- 1.2 weeks; range 23 to 27). There was no significant difference in heart rate between baseline and TnEcho period. There was a statistical, but clinically negligible, difference between baseline and TnEcho in SPO2 (median (quartile) 91.4% (88.9, 94.2) vs 91.3% (88.9, 94), P = 0.048), CrSO2 (76.8% (70.7, 81.5) vs 74.9% (69.5, 80.1), P<0.0001) and CFOE (15.8% (9.8, 23.6) vs 17.5% (11.3, 24.7), P<0.0001). The changes in the parameters monitored were similar in preterm infants who developed peri/intraventricular hemorrhage and in those who did not. CONCLUSION: Although there were statistically significant changes in SPO2, CrSO2 and CFOE, the alterations were minimal and unlikely of clinical relevance. Thus, cerebral hemodynamics and systemic and cerebral oxygenation are not perturbed during TnEcho and the procedure is well tolerated by the extremely preterm infants during the postnatal transitional period. PMID- 25033076 TI - The impact of prenatal and neonatal infection on neurodevelopmental outcomes in very preterm infants. AB - OBJECTIVE: Determine the association of prenatal and neonatal infections with neurodevelopmental outcomes in very preterm infants. STUDY DESIGN: Secondary retrospective analysis of 155 very preterm infants at a single tertiary referral center. General linear or logistic regression models were used to evaluate the association with hospital factors; brain injury, growth and development; and neurobehavioral outcome. RESULT: Necrotizing enterocolitis with sepsis was associated with reduced transcerebellar diameter (38.3 vs 48.4 mm, P<0.001) and increased left ventricular diameter (12.0 vs 8.0 mm, P=0.005). Sepsis alone was associated with higher diffusivity in the left frontal lobe (1.85 vs 1.68 * 10-3 mm2 s-1, P=0.001) and right cingulum bundle (1.52 vs 1.45 * 10-3 mm 253 s-1, P=0.002). Neurobehavioral outcomes were worse in children exposed to maternal genitourinary infection (cognitive composite: beta=-8.8, P=0.001; receptive language score: beta=-2.7, P<0.001; language composite: beta=-14.9, P<0.001) or histological chorioamnionitis (language composite: beta=-8.6, P=0.006), but not neonatal infection. CONCLUSION: Neonatal infection was associated with changes in brain structure but not with neurobehavioral outcomes, whereas the opposite pattern was observed for maternal genitourinary tract infection. These findings emphasize the potential importance of infections during pregnancy on the neurodevelopmental outcomes of preterm infants. PMID- 25033078 TI - Effects of low-level deuterium enrichment on bacterial growth. AB - Using very precise (+/-0.05%) measurements of the growth parameters for bacteria E. coli grown on minimal media, we aimed to determine the lowest deuterium concentration at which the adverse effects that are prominent at higher enrichments start to become noticeable. Such a threshold was found at 0.5% D, a surprisingly high value, while the ultralow deuterium concentrations (<=0.25% D) showed signs of the opposite trend. Bacterial adaptation for 400 generations in isotopically different environment confirmed preference for ultralow (<=0.25% D) enrichment. This effect appears to be similar to those described in sporadic but multiple earlier reports. Possible explanations include hormesis and isotopic resonance phenomena, with the latter explanation being favored. PMID- 25033077 TI - Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island. AB - BACKGROUND: Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection. METHODS: The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ <= 85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms. RESULTS: The mean DQ score was 86.3 (95%CI: 81.0-91.5) in infected children compared to 100.2 (95%CI: 98.0-102.5) in uninfected peers (P<0.001). Fifty-one percent (n = 17) of infected children had a GND compared to 15% (n = 21) of uninfected children (P<0.001). Specific neurocognitive delays in p-CHIKV infected children were as follows: coordination and language (57%), sociability (36%), movement/posture (27%). After adjustment for maternal social situation, small for gestational age, and head circumference, p-CHIKV infection was found associated with GND (incidence rate ratio: 2.79, 95%CI: 1.45-5.34). Further adjustments on gestational age or breastfeeding did not change the independent effect of CHIKV infection on neurocognitive outcome. The mean DQ of p-CHIKV infected children was lower in severe encephalopathic children than in non-severe children (77.6 versus 91.2, P<0.001). Of the 12 cases of CHIKV neonatal encephalopathy, five developed a microcephaly (head circumference <-2 standard deviations) and four matched the definition of cerebral palsy. MRI scans showed severe restrictions of white matter areas, predominant in the frontal lobes in these children. CONCLUSIONS: The neurocognitive outcome of children exposed to perinatal mother-to-child CHIKV infection is poor. Severe CHIKV neonatal encephalopathy is associated with an even poorer outcome. PMID- 25033079 TI - The science of style: in fashion, colors should match only moderately. AB - Fashion is an essential part of human experience and an industry worth over $1.7 trillion. Important choices such as hiring or dating someone are often based on the clothing people wear, and yet we understand almost nothing about the objective features that make an outfit fashionable. In this study, we provide an empirical approach to this key aesthetic domain, examining the link between color coordination and fashionableness. Studies reveal a robust quadratic effect, such that that maximum fashionableness is attained when outfits are neither too coordinated nor too different. In other words, fashionable outfits are those that are moderately matched, not those that are ultra-matched ("matchy-matchy") or zero-matched ("clashing"). This balance of extremes supports a broader hypothesis regarding aesthetic preferences-the Goldilocks principle--that seeks to balance simplicity and complexity. PMID- 25033080 TI - Use of surface enhanced blocking (SEB) electrodes for microbial cell lysis in flow-through devices. AB - By simultaneously subjecting microbial cells to high amplitude pulsed electric fields and flash heating of the cell suspension fluid, effective release of intracellular contents was achieved. The synergistic effect of the applied electric field and elevated temperature on cell lysis in a flow-through device was demonstrated for Gram-negative and Gram-positive bacteria, and Mycobacterium species. The resulting lysate is suitable for downstream nucleic acid amplification and detection without requiring further preparation. The lysis chamber employs surface enhanced blocking electrodes which possess an etched micro-structured surface and a thin layer of dielectric metal oxide which provides a large effective area and blocks transmission of electrical current. The surface enhanced blocking electrodes enable simultaneous suppression of the rapid onset of electric field screening in the bulk of the cell suspension medium and avoidance of undesired electrochemical processes at the electrode-electrolyte interface. In addition the blocking layer ensures the robustness of the cell lysis device in applications involving prolonged flow-through processing of the microbial cells. PMID- 25033081 TI - CeleST: computer vision software for quantitative analysis of C. elegans swim behavior reveals novel features of locomotion. AB - In the effort to define genes and specific neuronal circuits that control behavior and plasticity, the capacity for high-precision automated analysis of behavior is essential. We report on comprehensive computer vision software for analysis of swimming locomotion of C. elegans, a simple animal model initially developed to facilitate elaboration of genetic influences on behavior. C. elegans swim test software CeleST tracks swimming of multiple animals, measures 10 novel parameters of swim behavior that can fully report dynamic changes in posture and speed, and generates data in several analysis formats, complete with statistics. Our measures of swim locomotion utilize a deformable model approach and a novel mathematical analysis of curvature maps that enable even irregular patterns and dynamic changes to be scored without need for thresholding or dropping outlier swimmers from study. Operation of CeleST is mostly automated and only requires minimal investigator interventions, such as the selection of videotaped swim trials and choice of data output format. Data can be analyzed from the level of the single animal to populations of thousands. We document how the CeleST program reveals unexpected preferences for specific swim "gaits" in wild-type C. elegans, uncovers previously unknown mutant phenotypes, efficiently tracks changes in aging populations, and distinguishes "graceful" from poor aging. The sensitivity, dynamic range, and comprehensive nature of CeleST measures elevate swim locomotion analysis to a new level of ease, economy, and detail that enables behavioral plasticity resulting from genetic, cellular, or experience manipulation to be analyzed in ways not previously possible. PMID- 25033083 TI - Population genetics and phylogenetic analysis of the vrs1 nucleotide sequence in wild and cultivated barley. AB - Spike morphology is a key characteristic in the study of barley genetics, breeding, and domestication. Variation at the six-rowed spike 1 (vrs1) locus is sufficient to control the development and fertility of the lateral spikelet of barley. To study the genetic variation of vrs1 in wild barley (Hordeum vulgare subsp. spontaneum) and cultivated barley (Hordeum vulgare subsp. vulgare), nucleotide sequences of vrs1 were examined in 84 wild barleys (including 10 six rowed) and 20 cultivated barleys (including 10 six-rowed) from four populations. The length of the vrs1 sequence amplified was 1536 bp. A total of 40 haplotypes were identified in the four populations. The highest nucleotide diversity, haplotype diversity, and per-site nucleotide diversity were observed in the Southwest Asian wild barley population. The nucleotide diversity, number of haplotypes, haplotype diversity, and per-site nucleotide diversity in two-rowed barley were higher than those in six-rowed barley. The phylogenetic analysis of the vrs1 sequences partially separated the six-rowed and the two-rowed barley. The six-rowed barleys were divided into four groups. PMID- 25033082 TI - HIV-1 capture and transmission by dendritic cells: the role of viral glycolipids and the cellular receptor Siglec-1. AB - Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. Paradoxically, in the case of HIV-1, DCs might contribute to viral pathogenesis through trans-infection, a mechanism that promotes viral capture and transmission to target cells, especially after DC maturation. In this review, we highlight recent evidence identifying sialyllactose-containing gangliosides in the viral membrane and the cellular lectin Siglec-1 as critical determinants for HIV-1 capture and storage by mature DCs and for DC-mediated trans-infection of T cells. In contrast, DC-SIGN, long considered to be the main receptor for DC capture of HIV-1, plays a minor role in mature DC-mediated HIV-1 capture and trans-infection. PMID- 25033085 TI - The furosemide stress test to predict renal function after continuous renal replacement therapy. PMID- 25033084 TI - An attenuated herpes simplex virus type 1 (HSV1) encoding the HIV-1 Tat protein protects mice from a deadly mucosal HSV1 challenge. AB - Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination. PMID- 25033087 TI - Ralfuranone Is Produced by an Alternative Aryl-Substituted gamma-Lactone Biosynthetic Route in Ralstonia solanacearum. AB - The aryl-substituted gamma-lactones ralfuranones A and B were isolated after feeding L-[1-(13)C]-phenylalanine to a liquid culture of the plant pathogenic bacterium Ralstonia solanacearum. (13)C NMR analysis demonstrated specific enrichment of the label at position 2 of the gamma-lactone. This labeling pattern is consistent with a biosynthetic mechanism that includes direct cyclization of two monomeric phenylpyruvate precursors into an alpha,beta-substituted lactone, but incompatible with a terphenylquinone intermediate. As the latter was shown as an intermediate in allantofuranone biosynthesis, we conclude that aryl substituted gamma-lactones can be assembled via divergent biosynthetic routes. PMID- 25033086 TI - HAb18G/CD147 regulates vinculin-mediated focal adhesion and cytoskeleton organization in cultured human hepatocellular carcinoma cells. AB - Focal adhesions (FAs), integrin-mediated macromolecular complexes located at the cell membrane extracellular interface, have been shown to regulate cell adhesion and migration. Our previous studies have indicated that HAb18G/CD147 (CD147) is involved in cytoskeleton reorganization and FA formation in human hepatocellular carcinoma (HCC) cells. However, the precise mechanisms underlying these processes remain unclear. In the current study, we determined that CD147 was involved in vinculin-mediated FA focal adhesion formation in HCC cells. We also found that deletion of CD147 led to reduced vinculin-mediated FA areas (P<0.0001), length/width ratios (P<0.0001), and mean intensities (P<0.0001). CD147 promoted lamellipodia formation by localizing Arp2/3 to the leading edge of the cell. Deletion of CD147 significantly reduced the fluorescence (t1/2) recovery times (22.7+/-3.3 s) of vinculin-mediated focal adhesions (P<0.0001). In cell-spreading assays, CD147 was found to be essential for dynamic focal adhesion enlargement and disassembly. Furthermore, the current data showed that CD147 reduced tyrosine phosphorylation in vinculin-mediated focal adhesions, and enhanced the accumulation of the acidic phospholipid phosphatidylinositol-4, 5-bisphosphate (PIP2). Together, these results revealed that CD147 is involved in vinculin mediated focal adhesion formation, which subsequently promotes cytoskeleton reorganization to facilitate invasion and migration of human HCC cells. PMID- 25033088 TI - Fabrication of transparent-conducting-oxide-coated inverse opals as mesostructured architectures for electrocatalysis applications: a case study with NiO. AB - Highly ordered, and conductive inverse opal arrays were made with silica and subsequently coated with tin-doped indium oxide (ITO) via atomic layer deposition (ALD). We demonstrate the utility of the resulting mesostructured electrodes by further coating them with nickel oxide via ALD. The NiO-coated arrays are capable of efficiently electrochemically evolving oxygen from water. These modular, crack free, transparent, high surface area, and conducting structures show promise for many applications including electrocatalysis, photocatalysis, and dye-sensitized solar cells. PMID- 25033089 TI - A theoretical and experimental study on meridional-facial isomerization of tris(quinolin-8-olate)aluminum (Alq3). AB - The rationale behind the stereospecific synthesis of a facial isomer of tris(quinolin-8-olate)aluminum (Alq3) is studied by density functional theory (DFT) calculations, which predict the favourable influence of an H3O(+) ion on the distribution ratio between a meridional and a thermodynamically unstable facial isomer. PMID- 25033090 TI - Fitness cost and realized heritability of resistance to spinosad in Chrysoperla carnea (Neuroptera: Chrysopidae). AB - The common green lacewing Chrysoperla carnea is a key biological control agent employed in integrated pest management (IPM) programs for managing various insect pests. Spinosad is used for the management of pests in ornamental plants, fruit trees, vegetable and field crops all over the world, including Pakistan. A field collected population of C. carnea was selected with spinosad and fitness costs and realized heritability were investigated. After selection for five generations, C. carnea developed 12.65- and 73.37-fold resistance to spinosad compared to the field and UNSEL populations. The resistant population had a relative fitness of 1.47, with substantially higher emergence rate of healthy adults, fecundity and hatchability and shorter larval duration, pupal duration, and development time as compared to a susceptible laboratory population. Mean relative growth rate of larvae, intrinsic rate of natural population increase and biotic potential was higher for the spinosad-selected population compared to the susceptible laboratory population. Chrysoperla species are known to show resistance to insecticides which makes the predator compatible with most IPM systems. The realized heritability (h 2) value of spinosad resistance was 0.37 in spinosad-selected population of C. carnea. PMID- 25033091 TI - STATegra EMS: an Experiment Management System for complex next-generation omics experiments. AB - High-throughput sequencing assays are now routinely used to study different aspects of genome organization. As decreasing costs and widespread availability of sequencing enable more laboratories to use sequencing assays in their research projects, the number of samples and replicates in these experiments can quickly grow to several dozens of samples and thus require standardized annotation, storage and management of preprocessing steps. As a part of the STATegra project, we have developed an Experiment Management System (EMS) for high throughput omics data that supports different types of sequencing-based assays such as RNA-seq, ChIP-seq, Methyl-seq, etc, as well as proteomics and metabolomics data. The STATegra EMS provides metadata annotation of experimental design, samples and processing pipelines, as well as storage of different types of data files, from raw data to ready-to-use measurements. The system has been developed to provide research laboratories with a freely-available, integrated system that offers a simple and effective way for experiment annotation and tracking of analysis procedures. PMID- 25033092 TI - Severe and early quadriceps weakness in mechanically ventilated patients. PMID- 25033093 TI - Facile and cost effective synthesis of mesoporous spinel NiCo2O4 as an anode for high lithium storage capacity. AB - To fulfill the high power and high energy density demands for Li-ion batteries (LIBs) new anode materials need to be explored to replace conventional graphite. Herein, we report the urea assisted facile co-precipitation synthesis of spinel NiCo2O4 and its application as an anode material for LIBs. The synthesized NiCo2O4 exhibited an urchin-like microstructure and polycrystalline and mesoporous nature. In addition, the mesoporous NiCo2O4 electrode exhibited an initial discharge capacity of 1095 mA h g(-1) and maintained a reversible capacity of 1000 mA h g(-1) for 400 cycles at 0.5 C-rate. The reversible capacity of NiCo2O4 could still be maintained at 718 mA h g(-1), even at 10 C. The mesoporous NiCo2O4 exhibits great potential as an anode material for LIBs with the advantages of unique performance and facile preparation. PMID- 25033094 TI - Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with amines: rapid access to 2-substituted 4-hydroxyindole. AB - An efficient ring-opening cyclization of cyclohexane-1,3-dione-2 spirocyclopropanes with primary amines has been developed. The reaction proceeded at room temperature without any additives to provide 2-substituted tetrahydroindol-4-ones in good to excellent yields without the formation of the 3 substituted isomers. The obtained product was readily converted into a 2 substituted 4-hydroxyindole derivative via a synthetically useful indoline intermediate. PMID- 25033095 TI - Pillararene-based supramolecular polymers: from molecular recognition to polymeric aggregates. AB - Pillar[n]arenes (P[n]As) and their derivatives, consisting of (substituted) hydroquinone units linked by methylene bridges at para-positions, are new type of cyclophane hosts developed in 2008. Their intrinsic characteristics and properties, such as facile preparation and flexible modification, symmetrical and columnar architectures, very rigid and pi-rich cavities, as well as intriguing and peculiar guest complexation capability, make them ideal building blocks for the fabrication of polymeric supramolecules. This Feature Article provides an overview of the construction of pillararene-based supramolecular polymers and covers recent research endeavors of the marriage between pillararene-based host guest pairs and polymeric aggregates. These polymers are classified into two major classes according to the different types of guest species: (1) supramolecular polymers relying on pillararene-based cationic guest recognition; (2) supramolecular polymers relying on pillararene-based neutral guest recognition. The host-guest motifs, building strategies, topological architectures, stimuli-responsiveness and functionalities are comprehensively discussed. PMID- 25033096 TI - Improved ligation-mediated PCR method coupled with T7 RNA polymerase for sensitive DNA detection. AB - The ligation-mediated polymerase chain reaction (PCR) method is widely applied for detecting short-length DNA target. The primary principle of this method is based on the linkage of two separated DNA probes as PCR templates via simultaneous hybridization with DNA target by DNA ligase. Even before taking into account low ligation efficiency, a 1:1 stoichiometric ratio between DNA target and the produced PCR template would put an intrinsic limitation on the detection sensitivity. In order to solve this problem, we have developed an improved ligation-mediated PCR method. It is designed such that a transcription reaction by T7 RNA polymerase is integrated into the ligation reaction. In this way, the produced joint DNA strand composed by two DNA probes can be used as a template both in the transcription reaction and the following PCR process. Then a great number of RNA strands containing the same sequence as DNA target are transcribed to act as a target to initiate new cyclic reactions of ligation and transcription. The results indicate that our proposed method can improve the detection sensitivity by ~2 orders of magnitude compared with the conventional ligation-mediated PCR method. PMID- 25033097 TI - New conjugated molecular scaffolds based on [2,2]paracyclophane as electron acceptors for organic photovoltaic cells. AB - Two conjugated molecules with a [2,2]paracyclophane core were designed as non fullerene electron acceptors for photovoltaic cells. Using as the donor, a high power conversion efficiency (2.69%) is achieved for the blending thin film of with , which is relatively high for solution-processed OPVs based on small molecular non-fullerene acceptors and as the electron donor. PMID- 25033098 TI - Interventional pain management skills competency in pain medicine fellows: a method for development and assessment. AB - The purposes of this project were to propose an educational module to instruct pain medicine fellows in the appropriate performance of interventional pain management techniques and to verify procedural competency through objective evaluation methodology. Eight board-certified pain medicine physicians spanning two fellowship programs trained seven fellows using a standardized competency based module. Assessment tools address the basic competencies outlined by the Accreditation Council for Graduate Medical Education (American Board of Anesthesiology Pain Medicine Content Outline). The seven fellows demonstrated proficiency in every segment of the evaluation module. Objective measures compared the fellows' performance on standardized procedure checklists administered 9 mos into training; fellows in the 2012-2013 academic year also received testing at the 3-mo mark. Support for the assessment module is demonstrated by appropriate performance of interventional procedures, with improvement noted from 3-mo to 9-mo testing, successful completion of chart stimulated oral examinations, proper performance of relevant physical examination maneuvers, and completion of program-specific medical knowledge written tests. The fellows were evaluated via patient surveys and 360-degree global rating scales, maintained procedure logs, and completed two patient-care reports; these were reviewed by program directors to ensure adequate completion. The standardized educational module and evaluation methodology presented provide a potential framework for the definition of baseline competency in the clinical skill area of interventional pain management. PMID- 25033100 TI - Phenylenediamine-based FeN(x)/C catalyst with high activity for oxygen reduction in acid medium and its active-site probing. AB - High-temperature pyrolyzed FeN(x)/C catalyst is one of the most promising nonprecious metal electrocatalysts for oxygen reduction reaction (ORR). However, it suffers from two challenging problems: insufficient ORR activity and unclear active site structure. Herein, we report a FeN(x)/C catalyst derived from poly-m phenylenediamine (PmPDA-FeN(x)/C) that possesses high ORR activity (11.5 A g(-1) at 0.80 V vs RHE) and low H2O2 yield (<1%) in acid medium. The PmPDA-FeN(x)/C also exhibits high catalytic activity for both reduction and oxidation of H2O2. We further find that the ORR activity of PmPDA-FeN(x)/C is not sensitive to CO and NO(x) but can be suppressed significantly by halide ions (e.g., Cl(-), F(-), and Br(-)) and low valence state sulfur-containing species (e.g., SCN(-), SO2, and H2S). This result reveals that the active sites of the FeN(x)/C catalyst contains Fe element (mainly as Fe(III) at high potentials) in acid medium. PMID- 25033099 TI - Organophosphate flame retardants and plasticizers in the air and dust in German daycare centers and human biomonitoring in visiting children (LUPE 3). AB - Organophosphate (OP) flame retardants and plasticizers are chemicals that have been used in large quantities in diverse consumer and building-related products for decades. In the present study, OPs were measured in paired indoor air and dust samples from 63 daycare centers in Germany. Moreover, the urine of 312 children between 22 and 80 months old who attend these facilities was analyzed for the presence of eight OP metabolites. Tri-(2-butoxyethyl)-phosphate (TBEP), tris-(2-chloroisopropyl) phosphate (TCPP), and tri-n-butyl-phosphate (TnBP) were present in low concentrations in indoor air, with median values of 49 ng/m(3), 2.7 ng/m(3), and 2.2 ng/m(3), respectively. In dust, median values of 225 mg/kg for TBEP, 2.7 mg/kg for TCPP, 1.1mg/kg for diphenyl(2-ethylhexyl) phosphate, and 0.5mg/kg for tri-phenyl-phosphate (TPhP) were found. In the urine samples, the metabolites di-phenyl-phosphate, di-n-butyl-phosphate, and di-(2-butoxyethyl) phosphate had median values (95th percentiles) of 0.8 MUg/l (4.0 MUg/l), 0.2 MUg/l (0.9 MUg/l), and 2.0 MUg/l (10.7 MUg/l), respectively. A significant correlation was found between the dust and air samples in the levels of TnBP, tris(2-chloroethyl) phosphate (TCEP), and TBEP. For TCEP and TBEP, significant correlations were also observed between the levels in dust and the respective metabolite levels in urine. For TCEP, there was also a significant correlation between the concentration in indoor air and metabolite levels in urine. Based on the 95th percentile in dust and air in our study and data from residences in a previously published study, the daily intake of the most abundant OP (TBEP) is high (i.e., 3.2 MUg/kg b.w.). This level is approximately 6.4% of the reference dose (RfD) established by the NSF, U.S.A. Overall, our study shows that daycare centers are indoor environments that contribute to OP exposure. PMID- 25033101 TI - First-in-man late partial recanalisation after LARIAT suturing of the left atrial appendage successfully treated with an AMPLATZERa septal occluder device. PMID- 25033102 TI - Clinical results with the Resolute zotarolimus-eluting stent in total coronary occlusions. AB - AIMS: We conducted a pooled post hoc analysis (RESOLUTE All Comers and RESOLUTE International) of patients who had the Resolute(r) zotarolimus-eluting stent (R ZES) implanted in revascularised total occlusions (TO) compared with patients treated with R-ZES for non-occluded lesions. METHODS AND RESULTS: Patients were divided into three groups: chronic TO (CTO; n=256), non-chronic TO (n=292), and no occlusion (n=2,941). Clinical and safety outcomes assessed through two years included target lesion failure (TLF: cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularisation) and Academic Research Consortium definite or probable stent thrombosis. The rate of TLF at two years was not significantly different among patients in the CTO (9.1%), TO (9.8%), and no occlusion (10.4%) groups (log-rank p=0.800); neither were the components of TLF. Definite or probable stent thrombosis occurred more frequently in the TO group (2.8% vs. 1.2% in the CTO and 1.1% in the group with no occlusion, p=0.027). There were 10 late and six very late stent thrombosis events. CONCLUSIONS: Apart from a higher rate of stent thrombosis in patients with TO, patients with totally occluded coronary arteries who receive revascularisation with an R-ZES have clinical outcomes comparable to those who receive a similar stent in non-occluded lesions. PMID- 25033103 TI - Re: "Transcatheter treatment for refractory angina with the coronary sinus Reducer" by Maayan Konigstein et al. PMID- 25033104 TI - Left atrial appendage closure monitoring without sedation: a pilot study using intracardiac echocardiography through the oesophageal route. AB - Aims: We evaluated the safety and feasibility of an intracardiac echocardiography probe through the oesophageal route (ICE-TEE) for the monitoring of left atrial appendage (LAA) closure to avoid general anaesthesia. Methods and results: The study included 16 consecutive patients (75+/-7 years) in atrial fibrillation with high embolism (CHADS-VASc=5+/-1.4) and bleeding risk (HAS-BLED=4+/-0.9) referred for LAA closure (Amplatzer Cardiac Plug [ACP]). Standard TEE was performed before device implantation for LAA analysis. During the procedure, ICE-TEE was used under local anaesthesia to determine LAA size and monitor ACP positioning. Maximum and minimum LAA diameter by standard TEE averaged 21+/-3 mm and 18+/-1 mm, respectively. Eccentricity index (1.1+/-0.2) increased with LAA diameter (r=0.73, p=0.001). Maximum LAA size (21+/-3 mm) obtained by ICE-TEE during the procedure closely correlated with standard TEE measurement (r=0.9, p<0.0001). LAA closure was successfully performed in 15 patients without complication (one failed despite testing three ACP). Implanted ACP size averaged 25+/-3 mm (range 22-30 mm) and correlated with the size predicted by ICE-TEE (r=0.89) and standard TEE (r=0.57). Procedure duration (62+/-27 min) correlated with LAA size by ICE TEE (r=0.71, p=0.002) and eccentricity index (r=0.58, p=0.02). Conclusions: An ICE-TEE probe through the oesophageal route without general anaesthesia may be used for the monitoring of ACP device implantation. PMID- 25033105 TI - Optical coherence tomography assessment of a PLGA-polymer with electro-grafting base layer versus a PLA-polymer sirolimus-eluting stent at three-month follow-up: the BuMA-OCT randomised trial. AB - AIMS: To compare stent strut coverage using optical coherence tomography (OCT) at three-month follow-up between a PLGA-polymer with electro-grafting base layer sirolimus-eluting stent (SES) (BuMA) and a PLA-polymer SES (EXCEL). METHODS AND RESULTS: This prospective, single-centre, non-inferiority randomised BuMA-OCT trial enrolled patients with de novo coronary artery lesions, treated with either the BuMA or the EXCEL stent. The study primary endpoint was OCT-evaluated stent strut coverage at three months. Secondary endpoints were neointimal thickness of stent struts, and incomplete stent apposition evaluated with OCT. A total of 80 patients were randomly assigned to receive the BuMA (n=40) or the EXCEL (n=40) stent. In OCT follow-up (achieved in 86.3% of cases: BuMA, n=33; EXCEL, n=36), the percentage of stent strut coverage was significantly higher in the BuMA vs. the EXCEL group (strut level: 94.2% vs. 90.0%, p<0.01; p(non-inferiority)<0.0001; p(superiority) <0.0001), while the proportion of malapposed struts (strut level: 1.28% vs. 1.80%, p=0.51) and the mean neointimal thickness (strut level: 0.07+/ 0.03 mm vs. 0.06+/-0.02 mm, p=0.31) were similar. Rates of myocardial infarction (periprocedural non-Q-wave, 7.5% vs. 7.5%, p=1.00) and target lesion failure (7.5% vs. 7.5%, p=1.00) were similar between groups, with no cardiac death or stent thrombosis. CONCLUSIONS: In the BuMA-OCT randomised trial, the novel BuMA PLGA-polymer with electro-grafting base layer SES was superior to the EXCEL PLA polymer SES in the primary endpoint of stent strut coverage at three-month follow up. PMID- 25033106 TI - Invasive management without stents in selected acute coronary syndrome patients with a large thrombus burden: a prospective study of optical coherence tomography guided treatment decisions. AB - AIMS: To assess whether a strategy of invasive management without stents in selected acute coronary syndrome (ACS) patients with a large thrombus burden (LTB) might be feasible and safe. METHODS AND RESULTS: We performed a prospective non-randomised observational cohort study of invasive treatment decisions guided by optical coherence tomography (OCT) in selected ACS patients with LTB. Among 852 ACS patients who had undergone invasive coronary angiography, 101 (11.8%) patients with large thrombus burden on initial angiography underwent thrombectomy to restore TIMI 3 flow without stenting. All of these patients then had repeat angiography with OCT (days 0-2 [Group 1], days 3-6 [Group 2] or days 7-30 [Group 3]). No adverse events occurred between the initial and second angiograms. Residual thrombus was detected in 68% of patients with OCT (respectively, 94%, 79% and 32% in Group 1, Group 2 and Group 3), and 20% of cases with angiography. Plaque rupture was detected by OCT in 65% of cases. Minimal lumen area was 2.81 mm2, 3.40 mm2 and 4.89 mm2 in Group 1, Group 2 and Group 3, respectively. Sixty two percent of patients were stented (respectively, 76%, 61% and 50%). During a minimum follow-up period of 12 months in all patients, one non-fatal MI occurred and one PCI was performed for angina. CONCLUSIONS: Medical management without stents is safe and feasible in selected ACS patients with LTB. OCT revealed culprit lesion characteristics that were not disclosed by angiography and facilitated treatment decisions. PMID- 25033107 TI - Lentinan degradation in the Lentinula edodes fruiting body during postharvest preservation is reduced by downregulation of the exo-beta-1,3-glucanase EXG2. AB - Lentinan from Lentinula edodes fruiting bodies (shiitake mushrooms) is a valuable beta-glucan for medical purposes based on its anticancer activity and immunomodulating activity. However, lentinan content in fruiting bodies decreases after harvesting and storage due to an increase in glucanase activity. In this study, we downregulated the expression of an exo-beta-1,3-glucanase, exg2, in L. edodes using RNA interference. In the wild-type strain, beta-1,3-glucanase activity in fruiting bodies remarkably increased after harvesting, and 41.7% of the lentinan content was lost after 4 days of preservation. The EXG2 downregulated strain showed significantly lower lentinan degrading activity (60 70% of the wild-type strain) in the fruiting bodies 2-4 days after harvesting. The lentinan content of fresh fruiting bodies was similar in the wild-type and EXG2 downregulated strains, but in the downregulated strain, only 25.4% of the lentinan was lost after 4 days, indicating that downregulation of EXG2 enables keeping the lentinan content high longer. PMID- 25033108 TI - Polybrominated diphenyl ethers (PBDEs) in soil and outdoor dust from a multi functional area of Shanghai: levels, compositional profiles and interrelationships. AB - In this study, 14 polybrominated diphenyl ethers (PBDEs) congeners were investigated in soil and outdoor dust taken from Jiading District, Shanghai City. The concentrations of Sigma13PBDEs (BDE-17, BDE-28, BDE-47, BDE-66, BDE-71, BDE 85, BDE-99, BDE-100, BDE-138, BDE-153, BDE-154, BDE-183 and BDE-190) and BDE-209 ranged from 0.37 to 32.9ngg(-1) and 4.31 to 141.8ngg(-1) dry weight (dw) in soil. Concentrations in outdoor dust ranged from 1.03 to 112.5ngg(-1) and 6.71 to 342.1ngg(-1) (dw) for Sigma13PBDEs and BDE-209. BDE-209 was the predominant congener both in soil and outdoor dust, but the BDE-209 contribution was much lower in dust compared with that in soil. A significant correlation between PBDEs congeners and specific land use type was observed, and principal component analysis (PCA) revealed that the major source of PBDE in samples was associated with prevalent use of technical Deca-BDE, which also suggested the contributions from Penta-BDE and Octa-BDE mixtures. Canonical correlation analysis suggested the two sets of PBDEs data (soil and outdoor dust) were uncorrelated, and Spearman correlation coefficient matrix implied that the degradation pathways of PBDEs were different between soil and outdoor dust. PMID- 25033109 TI - The evolution of vocal learning. AB - Vocal learning, in which animals modify their vocalizations to imitate those of others, has evolved independently in scattered lineages of birds and mammals. Comparative evidence supports two hypotheses for the selective advantages leading to the origin of vocal learning. The sexual selection hypothesis proposes that vocal learning evolves to allow expansion of vocal repertoires in response to mating preferences for more complex vocalizations. The information-sharing hypothesis also proposes that vocal learning evolves to allow expansion of vocal repertoires, but in this case in response to kin selection favoring sharing of information among relatives. PMID- 25033110 TI - The mechanism of sound production in tungara frogs and its role in sexual selection and speciation. AB - Sexual communication can evolve in response to sexual selection, and it can also cause behavioral reproductive isolation between populations and thus drive speciation. Anurans are an excellent system to investigate these links between behavior and evolution because we have detailed knowledge of how neural mechanisms generate behavioral preferences for calls and how these preferences then generate selection on call variation. But we know far less about the physical mechanisms of call production, especially how different laryngeal morphologies generate call variation. Here we review studies of a group of species that differ in the presence of a secondary call component that evolved under sexual selection. We discuss how the larynx produces this call component, and how laryngeal morphology generates sexual selection and can contribute to speciation. PMID- 25033112 TI - From the editors - what's in a name? PMID- 25033111 TI - Ethynylflavones, highly potent, and selective inhibitors of cytochrome P450 1A1. AB - The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3'-Ethynylflavone, 4'-ethynylflavone, 6-ethynylflavone, and 7 ethynylflavone (KI values of 0.035-0.056 MUM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (KI value of 0.51 MUM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4'-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a Ki value of 0.035 MUM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes. PMID- 25033113 TI - The effect of cognitive therapy on structural social capital: results from a randomized controlled trial among sexual violence survivors in the Democratic Republic of the Congo. AB - OBJECTIVES: We evaluated changes in social capital following group-based cognitive processing therapy (CPT) for female survivors of sexual violence. METHODS: We compared CPT with individual support in a cluster-randomized trial in villages in South Kivu province, Democratic Republic of the Congo. Local psychosocial assistants delivered the interventions from April through July 2011. We evaluated differences between CPT and individual support conditions for structural social capital (i.e., time spent with nonkin social network, group membership and participation, and the size of financial and instrumental support networks) and emotional support seeking. We analyzed intervention effects with longitudinal random effects models. RESULTS: We obtained small to medium effect size differences for 2 study outcomes. Women in the CPT villages increased group membership and participation at 6-month follow-up and emotional support seeking after the intervention compared with women in the individual support villages. CONCLUSIONS: Results support the efficacy of group CPT to increase dimensions of social capital among survivors of sexual violence in a low-income conflict affected context. PMID- 25033114 TI - Health disparities calculator: a methodologically rigorous tool for analyzing inequalities in population health. AB - Historically, researchers and policy planners have selected a single indicator to measure trends in social inequalities. A more rigorous approach is to review the literature and data, select appropriate inequality measures to address the research question, compute results from various indices, and graphically compare resulting trends. The Health Disparities Calculator (HD*Calc, version 1.2.4; National Cancer Institute, Bethesda, MD) computes results from different indices and graphically displays them, making an arduous task easier, more transparent, and more accessible. PMID- 25033115 TI - The social justice agenda. PMID- 25033116 TI - Maternal depression as a risk factor for family homelessness. AB - OBJECTIVES: We estimated the effects of maternal depression during the postpartum year, which is often an unexpected event, on subsequent homelessness and risk of homelessness in a national sample of urban, mostly low-income mothers. METHODS: We used logistic regression models to estimate associations between maternal depression during the postpartum year and both homelessness and risk of homelessness 2 to 3 years later, controlling for maternal and family history of depression, prenatal housing problems, and other covariates. Risk factors for homelessness included experiencing evictions or frequent moves and moving in with family or friends and not paying rent. RESULTS: We found robust associations between maternal depression during the postpartum year and subsequent homelessness and risk of homelessness, even among mothers who had no history of mental illness, whose own mothers did not have a history of depressive symptoms, and who had no previous housing problems. CONCLUSIONS: This study provides robust evidence that maternal mental illness places families with young children at risk for homelessness, contributes to the scant literature elucidating directional and causal links between mental illness and homelessness, and contributes to a stagnant but important literature on family homelessness. PMID- 25033117 TI - Supporting replication and scale-up of evidence-based home visiting programs: assessing the implementation knowledge base. AB - In recent years, researchers, policymakers, and practitioners have expressed a growing interest in the use of interventions with scientific evidence of effectiveness. Reproducing positive effects shown in research, however, requires more than simply adopting an evidence-based program. There is growing recognition across disciplines of the importance of implementation research to guide adoption, replication, and scale-up of evidence-based interventions. We evaluate the state of the knowledge base supporting replication and scale-up of evidence based programs by reviewing information on implementation included in the research literature on 22 home visiting programs that have or are building an evidence base. We used the Interactive Systems Framework for Dissemination and Implementation to assess programs. PMID- 25033118 TI - Utilitarian walking, neighborhood environment, and risk of outdoor falls among older adults. AB - OBJECTIVES: We examined the roles of utilitarian and recreational walking in relation to occurrence of outdoor falls in older adults. METHODS: We analyzed data on walking habits, falls, and fall injuries among participants of MOBILIZE Boston, a prospective cohort study of 765 community-dwelling women and men, mainly aged 70 years or older, in Boston, Massachusetts. Neighborhood socioeconomic status (SES) indicators were assessed at census block group level. Falls were recorded during a total of 2066.5 person-years of follow-up (September 2005-December 2009), and the median length of follow-up was 2.9 years (range = 0.04-4.3). RESULTS: . Lower neighborhood SES indicators were associated with more utilitarian walking and higher rates of falls on sidewalks, streets, and curbs. Falls on sidewalks and streets were more likely to result in an injury than were falls in recreational areas. Utilitarian-only walkers tended to live in neighborhoods with the lowest neighborhood SES and had the highest rate of outdoor falls despite walking 14 and 25 fewer blocks per week than the recreational-only and dual walkers, respectively. CONCLUSIONS: . Improving the safety of walking environments in areas where older adults shop and do other errands of necessity is an important component of fall prevention. PMID- 25033119 TI - The promise of community-based participatory research for health equity: a conceptual model for bridging evidence with policy. AB - Insufficient attention has been paid to how research can be leveraged to promote health policy or how locality-based research strategies, in particular community based participatory research (CBPR), influences health policy to eliminate racial and ethnic health inequities. To address this gap, we highlighted the efforts of 2 CBPR partnerships in California to explore how these initiatives made substantial contributions to policymaking for health equity. We presented a new conceptual model and 2 case studies to illustrate the connections among CBPR contexts and processes, policymaking processes and strategies, and outcomes. We extended the critical role of civic engagement by those communities that were most burdened by health inequities by focusing on their political participation as research brokers in bridging evidence and policymaking. PMID- 25033120 TI - Statistics at the forefront of public health analysis and reporting. PMID- 25033121 TI - Age at menarche: 50-year socioeconomic trends among US-born black and white women. AB - OBJECTIVES: We investigated 50-year US trends in age at menarche by socioeconomic position (SEP) and race/ethnicity because data are scant and contradictory. METHODS: We analyzed data by income and education for US-born non-Hispanic Black and White women aged 25 to 74 years in the National Health Examination Survey (NHES) I (1959-1962), National Health Examination and Nutrition Surveys (NHANES) I-III (1971-1994), and NHANES 1999-2008. RESULTS: In NHES I, average age at menarche among White women in the 20th (lowest) versus 80th (highest) income percentiles was 0.26 years higher (95% confidence interval [CI] = -0.09, 0.61), but by NHANES 2005-2008 it had reversed and was -0.33 years lower (95% CI = 0.54, -0.11); no socioeconomic gradients occurred among Black women. The proportion with onset at younger than 11 years increased only among women with low SEP, among Blacks and Whites (P for trend < .05), and high rates of change occurred solely among Black women (all SEP strata) and low-income White women who underwent menarche before 1960. CONCLUSIONS: Trends in US age at menarche vary by SEP and race/ethnicity in ways that pose challenges to several leading clinical, public health, and social explanations for early age at menarche and that underscore why analyses must jointly include data on race/ethnicity and socioeconomic position. Future research is needed to explain these trends. PMID- 25033122 TI - A ride in the time machine: information management capabilities health departments will need. AB - We have proposed needed information management capabilities for future US health departments predicated on trends in health care reform and health information technology. Regardless of whether health departments provide direct clinical services (and many will), they will manage unprecedented quantities of sensitive information for the public health core functions of assurance and assessment, including population-level health surveillance and metrics. Absent improved capabilities, health departments risk vestigial status, with consequences for vulnerable populations. Developments in electronic health records, interoperability and information exchange, public information sharing, decision support, and cloud technologies can support information management if health departments have appropriate capabilities. The need for national engagement in and consensus on these capabilities and their importance to health department sustainability make them appropriate for consideration in the context of accreditation. PMID- 25033123 TI - Preventing childhood obesity: what are we doing right? AB - After decades of increases, the prevalence of childhood obesity has declined in the past decade in New York City, as measured in children participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and public school students, with the greatest reductions occurring in the youngest children. Possible explanations were changes in demographics; WIC, day care, and school food policies; citywide obesity prevention policies, media messages; and family and community food consumption. Although the decreases cannot be attributed to any one cause, the most plausible explanation is changes in food consumption at home, prompted by media messages and reinforced by school and child care center policy changes. Continued media messages and policy changes are needed to sustain these improvements and extend them to other age groups. PMID- 25033124 TI - Health preemption behind closed doors: trade agreements and fast-track authority. AB - Noncommunicable diseases result from consuming unhealthy products, including tobacco, which are promoted by transnational corporations. The tobacco industry uses preemption to block or reverse tobacco control policies. Preemption removes authority from jurisdictions where tobacco companies' influence is weak and transfers it to jurisdictions where they have an advantage. International trade agreements relocate decisions about tobacco control policy to venues where there is little opportunity for public scrutiny, participation, and debate. Tobacco companies are using these agreements to preempt domestic authority over tobacco policy. Other transnational corporations that profit by promoting unhealthy foods could do the same. "Fast-track authority," in which Congress cedes ongoing oversight authority to the President, further distances the public from the debate. With international agreements binding governments to prioritize trade over health, transparency and public oversight of the trade negotiation process is necessary to safeguard public health interests. PMID- 25033125 TI - Unaccompanied evacuation and adult mortality: evaluating the finnish policy of evacuating children to foster care during World War II. AB - OBJECTIVES: I examined associations between evacuation of Finnish children to temporary foster care in Sweden during World War II and all-cause mortality between ages 38 and 78 years. METHODS: I used a Cox proportional hazards model to estimate mortality risk according to whether the individual was evacuated during childhood or not. I used within-sibling analysis to control for all unobserved socioeconomic and genetic characteristics shared among siblings. Individual-level data for Finnish cohorts born in 1933 to 1944 were derived from wartime government records, Finnish census data from 1950 and 1970, and death cause registry from 1971 to 2011. RESULTS: I found no statistically significant association between evacuation and all-cause mortality when all exposed individuals were included in the analysis. However, subgroup analysis showed that men evacuated before age 4 years had a 1.31 higher mortality risk (95% confidence interval = 1.01, 1.69) than their nonevacuated counterparts. CONCLUSIONS: In the aggregate, individuals do not have elevated mortality risk as a consequence of foster care during early childhood owing to the onset of sudden external shocks (e.g., wars). PMID- 25033126 TI - A national cohort study of the association between the polytrauma clinical triad and suicide-related behavior among US Veterans who served in Iraq and Afghanistan. AB - OBJECTIVES: We examined the association of posttraumatic stress disorder (PTSD), traumatic brain injury, and chronic pain-the polytrauma clinical triad (PCT) independently and with other conditions, with suicide-related behavior (SRB) risk among Operation Enduring Freedom (OEF; Afghanistan) and Operation Iraqi Freedom (OIF) veterans. METHODS: We used Department of Veterans Affairs (VA) administrative data to identify OEF and OIF veterans receiving VA care in fiscal years 2009-2011; we used International Classification of Diseases, Ninth Revision, Clinical Modification codes to characterize 211652 cohort members. Descriptive statistics were followed by multinomial logistic regression analyses predicting SRB. RESULTS: Co-occurrence of PCT conditions was associated with significant increase in suicide ideation risk (odds ratio [OR] = 1.9; 95% confidence interval [CI]=1.5, 2.4) or attempt and ideation (OR=2.6; 95% CI=1.5, 4.6), but did not exceed increased risk with PTSD alone (ideation: OR=2.3; 95% CI=2.0, 2.6; attempt: OR=2.0; 95% CI=1.4, 2.9; ideation and attempt: OR=1.8; 95% CI=1.2, 2.8). Ideation risk was significantly elevated when PTSD was comorbid with depression (OR=4.2; 95% CI=3.6, 4.8) or substance abuse (OR=4.7; 95% CI = 3.9, 5.6). CONCLUSIONS: Although PCT was a moderate SRB predictor, interactions among PCT conditions, particularly PTSD, and depression or substance abuse had larger risk increases. PMID- 25033128 TI - Untangling gestational weight gain from gestational age in infant mortality studies. PMID- 25033127 TI - Recent violence in a community-based sample of homeless and unstably housed women with high levels of psychiatric comorbidity. AB - OBJECTIVES: We determined associations between co-occurring psychiatric conditions and violence against homeless and unstably housed women. METHODS: Between 2008 and 2010, we interviewed homeless and unstably housed women recruited from community venues about violence, socioeconomic factors, and psychiatric conditions. We used multivariable logistic regression to determine independent correlates of violence. RESULTS: Among 291 women, 97% screened positive for 1 or more psychiatric conditions. Types of violence perpetrated by primary partners and persons who were not primary partners (non-primary partners) included emotional violence (24% vs 50%; P < .01), physical violence (11% vs 19%; P < .01), and sexual violence (7% vs 22%; P < .01). The odds of primary partner and non-primary partner violence increased with each additional psychiatric diagnosis and decreasing levels of social isolation. CONCLUSIONS: All types of violence were more commonly perpetrated by non-primary partners, suggesting that an exclusive focus on domestic violence screening in health care or social service settings will miss most of the violence in this population. Contrary to some previous studies, the odds of violence decreased as social isolation increased, suggesting that social isolation may be protective in homeless and unstably housed communities with high levels of comorbidity and limited options. PMID- 25033129 TI - The association between race/ethnicity and major birth defects in the United States, 1999-2007. AB - OBJECTIVES: We investigated the relationship between race/ethnicity and 27 major birth defects. METHODS: We pooled data from 12 population-based birth defects surveillance systems in the United States that included 13.5 million live births (1 of 3 of US births) from 1999 to 2007. Using Poisson regression, we calculated prevalence estimates for each birth defect and 13 racial/ethnic groupings, along with crude and adjusted prevalence ratios (aPRs). Non-Hispanic Whites served as the referent group. RESULTS: American Indians/Alaska Natives had a significantly higher and 50% or greater prevalence for 7 conditions (aPR = 3.97; 95% confidence interval [CI] = 2.89, 5.44 for anotia or microtia); aPRs of 1.5 to 2.1 for cleft lip, trisomy 18, and encephalocele, and lower, upper, and any limb deficiency). Cubans and Asians, especially Chinese and Asian Indians, had either significantly lower or similar prevalences of these defects compared with non-Hispanic Whites, with the exception of anotia or microtia among Chinese (aPR = 2.08; 95% CI = 1.30, 3.33) and Filipinos (aPR = 1.90; 95% CI = 1.10, 3.30) and tetralogy of Fallot among Vietnamese (aPR = 1.60; 95% CI = 1.11, 2.32). CONCLUSIONS: This is the largest population-based study to our knowledge to systematically examine the prevalence of a range of major birth defects across many racial/ethnic groups, including Asian and Hispanic subgroups. The relatively high prevalence of birth defects in American Indians/Alaska Natives warrants further attention. PMID- 25033130 TI - Characterization of dementia and Alzheimer's disease in an older population: updated incidence and life expectancy with and without dementia. AB - OBJECTIVES: We estimated dementia incidence rates, life expectancies with and without dementia, and percentage of total life expectancy without dementia. METHODS: We studied 3605 members of Group Health (Seattle, WA) aged 65 years or older who did not have dementia at enrollment to the Adult Changes in Thought study between 1994 and 2008. We estimated incidence rates of Alzheimer's disease and dementia, as well as life expectancies with and without dementia, defined as the average number of years one is expected to live with and without dementia, and percentage of total life expectancy without dementia. RESULTS: Dementia incidence increased through ages 85 to 89 years (74.2 cases per 1000 person years) and 90 years or older (105 cases per 1000 person-years). Life expectancy without dementia and percentage of total life expectancy without dementia decreased with age. Life expectancy with dementia was longer in women and people with at least a college degree. Percentage of total life expectancy without dementia was greater in younger age groups, men, and those with more education. CONCLUSIONS: Efforts to delay onset of dementia, if successful, would likely benefit older adults of all ages. PMID- 25033131 TI - The cost-effectiveness of school-based eating disorder screening. AB - OBJECTIVES: We aimed to assess the value of school-based eating disorder (ED) screening for a hypothetical cohort of US public school students. METHODS: We used a decision-analytic microsimulation model to model the effectiveness (life years with ED and quality-adjusted life-years [QALYs]), total direct costs, and cost-effectiveness (cost per QALY gained) of screening relative to current practice. RESULTS: The screening strategy cost $2260 (95% confidence interval [CI] = $1892, $2668) per student and resulted in a per capita gain of 0.25 fewer life-years with ED (95% CI = 0.21, 0.30) and 0.04 QALYs (95% CI = 0.03, 0.05) relative to current practice. The base case cost-effectiveness of the intervention was $9041 per life-year with ED avoided (95% CI = $6617, $12,344) and $56,500 per QALY gained (95% CI = $38,805, $71,250). CONCLUSIONS: At willingness-to-pay thresholds of $50,000 and $100,000 per QALY gained, school based ED screening is 41% and 100% likely to be cost-effective, respectively. The cost-effectiveness of ED screening is comparable to many other accepted pediatric health interventions, including hypertension screening. PMID- 25033132 TI - Davis et al. respond. PMID- 25033133 TI - New walking and cycling routes and increased physical activity: one- and 2-year findings from the UK iConnect Study. AB - OBJECTIVES: We evaluated the effects of providing new high-quality, traffic-free routes for walking and cycling on overall levels of walking, cycling, and physical activity. METHODS: 1796 adult residents in 3 UK municipalities completed postal questionnaires at baseline (2010) and 1-year follow-up (2011), after the construction of the new infrastructure. 1465 adults completed questionnaires at baseline and 2-year follow-up (2012). Transport network distance from home to infrastructure defined intervention exposure and provided a basis for controlled comparisons. RESULTS: Living nearer the infrastructure did not predict changes in activity levels at 1-year follow-up but did predict increases in activity at 2 years relative to those living farther away (15.3 additional minutes/week walking and cycling per km nearer; 12.5 additional minutes/week of total physical activity). The effects were larger among participants with no car. CONCLUSIONS: These new local routes may mainly have displaced walking or cycling trips in the short term but generated new trips in the longer term, particularly among those unable to access more distant destinations by car. These findings support the potential for walking and cycling infrastructure to promote physical activity. PMID- 25033134 TI - Assessing the connection between health and education: identifying potential leverage points for public health to improve school attendance. AB - OBJECTIVES: We examined multiple variables influencing school truancy to identify potential leverage points to improve school attendance. METHODS: A cross sectional observational design was used to analyze inner-city data collected in Los Angeles County, California, during 2010 to 2011. We constructed an ordinal logistic regression model with cluster robust standard errors to examine the association between truancy and various covariates. RESULTS: The sample was predominantly Hispanic (84.3%). Multivariable analysis revealed greater truancy among students (1) with mild (adjusted odds ratio [AOR] = 1.57; 95% confidence interval [CI] = 1.22, 2.01) and severe (AOR = 1.80; 95% CI = 1.04, 3.13) depression (referent: no depression), (2) whose parents were neglectful (AOR = 2.21; 95% CI = 1.21, 4.03) or indulgent (AOR = 1.71; 95% CI = 1.04, 2.82; referent: authoritative parents), (3) who perceived less support from classes, teachers, and other students regarding college preparation (AOR = 0.87; 95% CI = 0.81, 0.95), (4) who had low grade point averages (AOR = 2.34; 95% CI = 1.49, 4.38), and (5) who reported using alcohol (AOR = 3.47; 95% CI = 2.34, 5.14) or marijuana (AOR = 1.59; 95% CI = 1.06, 2.38) during the past month. CONCLUSIONS: Study findings suggest depression, substance use, and parental engagement as potential leverage points for public health to intervene to improve school attendance. PMID- 25033135 TI - Medicaid enrollment gap length and number of Medicaid enrollment periods among US children. AB - OBJECTIVES: We examined gap length, characteristics associated with gap length, and number of enrollment periods among Medicaid-enrolled children in the United States. METHODS: We linked the 2004 National Health Interview Survey to Medicaid Analytic eXtract files for 1999 through 2008. We examined linkage-eligible children aged 5 to 13 years in the 2004 National Health Interview Survey who disenrolled from Medicaid. We generated Kaplan-Meier curves of time to reenrollment. We used Cox proportional hazards models to assess the effect of sociodemographic variables on time to reenrollment. We compared the percentage of children enrolled 4 or more times across sociodemographic groups. RESULTS. Of children who disenrolled from Medicaid, 35.8%, 47.1%, 63.5%, 70.8%, and 79.1% of children had reenrolled in Medicaid by 6 months, 1, 3, 5, and 10 years, respectively. Children who were younger, poorer, or of minority race/ethnicity or had lower educated parents had shorter gaps in Medicaid and were more likely to have had 4 or more Medicaid enrollment periods. CONCLUSIONS: Nearly half of US children who disenrolled from Medicaid reenrolled within 1 year. Children with traditionally high-risk demographic characteristics had shorter gaps in Medicaid enrollment and were more likely to have more periods of Medicaid enrollment. PMID- 25033136 TI - Mortality risks among persons reporting same-sex sexual partners: evidence from the 2008 General Social Survey-National Death Index data set. AB - OBJECTIVES: We investigated the possibility that men who have sex with men (MSM) and women who have sex with women (WSW) may be at higher risk for early mortality associated with suicide and other sexual orientation-associated health risks. METHODS: We used data from the 1988-2002 General Social Surveys, with respondents followed up for mortality status as of December 31, 2008. The surveys included 17 886 persons aged 18 years or older, who reported at least 1 lifetime sexual partner. Of these, 853 reported any same-sex partners; 17 033 reported only different-sex partners. Using gender-stratified analyses, we compared these 2 groups for all-cause mortality and HIV-, suicide-, and breast cancer-related mortality. RESULTS: The WSW evidenced greater risk for suicide mortality than presumptively heterosexual women, but there was no evidence of similar sexual orientation-associated risk among men. All-cause mortality did not appear to differ by sexual orientation among either women or men. HIV-related deaths were not elevated among MSM or breast cancer deaths among WSW. CONCLUSIONS: The elevated suicide mortality risk observed among WSW partially confirms public health concerns that sexual minorities experience greater burden from suicide related mortality. PMID- 25033137 TI - Project HOPE: online social network changes in an HIV prevention randomized controlled trial for African American and Latino men who have sex with men. AB - OBJECTIVES: We examined whether and how an HIV prevention diffusion-based intervention spread throughout participants' online social networks and whether changes in social network ties were associated with increased HIV prevention and testing behaviors. METHODS: We randomly assigned 112 primarily racial/ethnic minority men who have sex with men (MSM) to receive peer-delivered HIV (intervention) or general health (control) information over 12 weeks through closed Facebook groups. We recorded participants' public Facebook friend networks at baseline (September 2010) and follow-up (February 2011), and assessed whether changes in network growth were associated with changes in health engagement and HIV testing. RESULTS: Within-group ties increased in both conditions from baseline to follow-up. Among the intervention group, we found a significant positive relation between increased network ties and using social media to discuss sexual behaviors. We found a positive trending relationship between increased network ties and likelihood of HIV testing, follow-up for test results, and participation in online community discussions. No significant differences were seen within control groups. CONCLUSIONS: Among high-risk MSM, peer-led social media HIV prevention interventions can increase community cohesion. These changes appear to be associated with increased HIV prevention and testing behaviors. PMID- 25033138 TI - Skin cancer risk behaviors among US men: the role of sexual orientation. AB - The current study assessed skin cancer risk behaviors by sexual orientation in a nationally representative prospective sample of US men (n = 1767), sampled at ages 16 and 29 years. At age 16 years, sexual minority men were 3.9 times as likely as heterosexual men to indoor tan. Participants did not significantly differ in the use of sunscreen or the frequency of outdoor tanning. Thus, sexual minority men might be an at-risk group for developing skin cancers because of their indoor tanning behaviors. PMID- 25033139 TI - HIV diagnoses among men who have sex with men and women-United States and 6 dependent areas, 2008-2011. AB - OBJECTIVES: We sought to describe HIV diagnoses among men who have sex with men and women (MSMW), who have the potential to bridge HIV transmission risk from men who have sex with men (MSM) to women. METHODS: Applying National HIV Surveillance System data for persons aged 13 years and older, we examined estimated numbers and percentages of HIV diagnoses among MSMW and MSM only (MSMO) from 2008 to 2011, and estimated the annual percentage change and 95% confidence intervals, by age and race/ethnicity. RESULTS: In 2011, 26.4% of 30,896 MSM diagnosed with HIV infection also had had sex with women. A larger percentage of MSMW were Black/African American (44.5%) compared with MSMO (36.0%), and fewer MSMW were White (26.4%) compared with MSMO (36.2%); similar percentages were classified as either MWMW or MSMO among other racial/ethnic groups. Among MSMW, HIV diagnoses were relatively stable and MSMO increased more than 6% annually among those aged 13 to 29 years. CONCLUSIONS: Many MSM diagnosed with HIV infection had also had sex with women. Intensified interventions are needed to decrease HIV infections overall for MSMW and reverse the increasing trends among young MSMO. PMID- 25033140 TI - Mortality and economic costs from regular cigar use in the United States, 2010. AB - OBJECTIVES: We estimated annual mortality, years of potential life lost, and associated economic costs attributable to regular cigar smoking among US adults aged 35 years or older. METHODS: We estimated cigar-attributable mortality for the United States in 2010 using the Centers for Disease Control and Prevention's Smoking-Attributable Mortality, Morbidity, and Economic Costs methodology for smoking-related causes of death. We obtained cigar prevalence from the National Adult Tobacco Survey, relative risks from the Cancer Prevention Studies I and II, and annual US deaths from the National Vital Statistics System. We also estimated the economic cost of this premature mortality using the value of a statistical life-year. RESULTS: Regular cigar smoking was responsible for approximately 9000 premature deaths and more than 140,000 years of potential life lost among US adults aged 35 years or older in 2010. These years of life had an economic value of approximately $23 billion. CONCLUSIONS: . The health and economic burden of cigar smoking in the United States is large and may increase over time because of the increasing consumption of cigars in the United States. PMID- 25033141 TI - Caloric beverage intake among adult supplemental nutrition assistance program participants. AB - OBJECTIVES: We compared sugar-sweetened beverage (SSB), alcohol, and other caloric beverage (juice and milk) consumption of Supplemental Nutrition Assistance Program (SNAP) participants with that of low-income nonparticipants. METHODS: We used 1 day of dietary intake data from the 2005-2008 National Health and Nutrition Examination Survey for 4594 adults aged 20 years and older with household income at or below 250% of the federal poverty line. We used bivariate and multivariate methods to compare the probability of consuming and the amount of calories consumed for each beverage type across 3 groups: current SNAP participants, former participants, and nonparticipants. We used instrumental variable methods to control for unobservable differences in participant groups. RESULTS: After controlling for observable characteristics, SNAP participants were no more likely to consume SSBs than were nonparticipants. Instrumental variable estimates showed that current participants consumed fewer calories from SSBs than did similar nonparticipants. We found no differences in alcoholic beverage consumption, which cannot be purchased with SNAP benefits. CONCLUSIONS: SNAP participants are not unique in their consumption of SSBs or alcoholic beverages. Purchase restrictions may have little effect on SSB consumption. PMID- 25033142 TI - Assessment of hepatitis C risk factors and infection prevalence in a jail population. AB - OBJECTIVES: We sought to validate previous reports of HCV prevalence in jails, identify HCV risk factors prevalence, and identify risk factors associated with HCV infection in this population. METHODS: Inmates at the Buzz Westfall Justice Center (BWJC) in St. Louis, Missouri, were offered risk factor screening for HCV and anti-HCV antibody testing from December 2012 through May 2013. Demographic and risk factor information were assessed for significant associations with positive HCV antibody results. Risk factors that were significantly associated in univariate analysis were assessed using binary logistic regression to model the relationship between positive HCV results and the risk factors and demographics. RESULTS: Fifty of 304 inmates were positive for HCV, with a prevalence of 16.4%. The risk factors significantly associated with increased risk for positive HCV antibody were age (odds ratio [OR] = 1.09; 95% confidence interval [CI] = 1.04, 1.15 for each year), injection drug use (OR = 53.87; 95% CI = 17.78, 163.21), sex with HCV-positive partner (OR = 7.35; 95% CI = 1.41, 38.20), and tattoos by a nonlicensed provider (OR = 2.62; 95% CI = 1.09, 6.33). Prevalence for women was 3 times that of men (38% vs 12%). CONCLUSIONS: Prevalence of HCV at BWJC was similar to previous jail studies, which is lower than reported prison rates and higher than the general population. PMID- 25033143 TI - Trends in mental health services utilization and stigma in US soldiers from 2002 to 2011. AB - OBJECTIVES: We characterized trends in mental health services utilization and stigma over the course of the Afghanistan and Iraq wars among active-component US soldiers. METHODS: We evaluated trends in mental health services utilization and stigma using US Army data from the Health-Related Behavior (HRB) surveys from 2002, 2005, and 2008 (n = 12,835) and the Land Combat Study (LCS) surveys administered to soldiers annually from 2003 to 2009 and again in 2011 (n = 22,627). RESULTS: HRB and LCS data suggested increased mental health services utilization and decreased stigma in US soldiers between 2002 and 2011. These trends were evident in soldiers with and without posttraumatic stress disorder (PTSD), major depressive disorder (MDD), or PTSD and MDD. Despite the improving trends, more than half of soldiers with mental health problems did not report seeking care. CONCLUSIONS: Mental health services utilization increased and stigma decreased over the course of the wars in Iraq and Afghanistan. Although promising, these findings indicate that a significant proportion of US soldiers meeting criteria for PTSD or MDD do not utilize mental health services, and stigma remains a pervasive problem requiring further attention. PMID- 25033144 TI - Retention in care and viral suppression among persons living with HIV/AIDS in New York City, 2006-2010. AB - OBJECTIVES: We estimated the proportions of persons living with HIV/AIDS (PLWHA) in New York City (NYC) retained in care and virally suppressed. METHODS: We used routinely reported laboratory surveillance data to measure trends in retention in care and viral suppression in PLWHA in NYC from 2006 through 2010. Our denominator excluded persons lacking any HIV-related laboratory tests during the 5 years prior to the year of analysis. RESULTS: The proportion of patients retained in care (>= 1 care visit in a calendar year) was stable, at 82.5% in 2006 and 81.8% in 2010. However, the proportion of persons with evidence of viral suppression increased significantly, from 44.3% to 59.1%. Blacks were least likely to have viral suppression (adjusted prevalence ratio [APR] = 0.89; 95% confidence interval [CI] = 0.87, 0.90). A U-shaped relationship between age and viral suppression was observed, with the 20- to 29-year age group least likely to have a suppressed viral load. CONCLUSIONS: Higher and more plausible proportions retained in care and virally suppressed than national estimates may reflect the difference in methodology and our comprehensive HIV-related laboratory reporting system. PMID- 25033145 TI - Prevalence of undiagnosed acute and chronic HIV in a lower-prevalence urban emergency department. AB - OBJECTIVES: We estimated the seroprevalence of both acute and chronic HIV infection by using a random sample of emergency department (ED) patients from a region of the United States with low-to-moderate HIV prevalence. METHODS: This cross-sectional seroprevalence study consecutively enrolled patients aged 18 to 64 years within randomly selected sampling blocks in a Midwestern urban ED in a region of lower HIV prevalence in 2008 to 2009. Participants were compensated for providing a blood sample and health information. After de-identification, we assayed samples for HIV antibody and nucleic acid. RESULTS: There were 926 participants who consented and enrolled. Overall, prevalence of undiagnosed HIV was 0.76% (95% confidence interval [CI] = 0.30%, 1.56%). Three participants (0.32%; 95% CI = 0.09%, 0.86%) were nucleic acid-positive but antibody-negative and 4 (0.43%; 95% CI = 0.15%, 1.02%) were antibody-positive. CONCLUSIONS: Even when the absolute prevalence is low, a considerable proportion of undetected HIV cases in an ED population are acute. Identification of acute HIV in ED settings should receive increased priority. PMID- 25033146 TI - Older jail inmates and community acute care use. AB - OBJECTIVES: We examined older jail inmates' predetainment acute care use (emergency department or hospitalization in the 3 months before arrest) and their plans for using acute care after release. METHODS: We performed a cross-sectional study of 247 jail inmates aged 55 years or older assessing sociodemographic characteristics, health, and geriatric conditions associated with predetainment and anticipated postrelease acute care use. RESULTS: We found that 52% of older inmates reported predetainment acute care use and 47% planned to use the emergency department after release. In modified Poisson regression, homelessness was independently associated with predetainment use (relative risk = 1.42; 95% confidence interval = 1.10, 1.83) and having a primary care provider was inversely associated with planned use (relative risk = 0.69; 95% confidence interval = 0.53, 0.89). CONCLUSIONS: The Affordable Care Act has expanded Medicaid eligibility to all persons leaving jail in an effort to decrease postrelease acute care use in this high-risk population. Jail-to-community transitional care models that address the health, geriatric, and social factors prevalent in older adults leaving jail, and that focus on linkages to housing and primary care, are needed to enhance the impact of the act on acute care use for this population. PMID- 25033147 TI - Effect of acculturation on variations in having a usual source of care among Asian Americans and non-Hispanic whites in California. AB - OBJECTIVES: We examined variations in having a usual source of care (USC) among non-Hispanic White and Asian American adults in California. METHODS: Data were from the 2005 and 2009 California Health Interview Survey. Using a modified Anderson model, we used multiple logistic regression to compare odds of having a USC between non-Hispanic White (n=38554) and Asian American adults (n=7566) and to examine associations with acculturation factors (English proficiency, length of residence, residence in a racially concordant neighborhood) and key enabling (employment, income, insurance) and predisposing (education) factors. RESULTS: Race-related disparities between Asian Americans and non-Hispanic Whites in having a USC were no longer significant after accounting for acculturation factors. Limited English proficiency and short time in the United States (<5 years) were significantly associated with not having a USC for both races. Increasing levels of education and insurance were not associated with better access among Asian Americans. CONCLUSIONS: Key differences exist in how Asian American and non-Hispanic White adults access care. Acculturation factors are key drivers of disparities and should be included in access-to-care models with Asians. Insurance and education are differentially significant for Asian Americans and non-Hispanic Whites. PMID- 25033148 TI - Increase in suicides associated with home eviction and foreclosure during the US housing crisis: findings from 16 National Violent Death Reporting System States, 2005-2010. AB - OBJECTIVES: We aimed to determine the frequency, characteristics, and precipitating circumstances of eviction- and foreclosure-related suicides during the US housing crisis, which resulted in historically high foreclosures and increased evictions beginning in 2006. METHODS: We examined all eviction- and foreclosure-related suicides in the years 2005 to 2010 in 16 states in the National Violent Death Reporting System, a surveillance system for all violent deaths within participating states that abstracts information across multiple investigative sources (e.g., law enforcement, coroners, medical examiners). RESULTS: We identified 929 eviction- or foreclosure-related suicides. Eviction- and foreclosure-related suicides doubled from 2005 to 2010 (n=88 in 2005; n=176 in 2010), mostly because of foreclosure-related suicides, which increased 253% from 2005 (n=30) to 2010 (n=106). Most suicides occurred before the actual housing loss (79%), and 37% of decedents experienced acute eviction or foreclosure crises within 2 weeks of the suicide. CONCLUSIONS: Housing loss is a significant crisis that can precipitate suicide. Prevention strategies include support for those projected to lose homes, intervention before move-out date, training financial professionals to recognize warning signs, and strengthening population-wide suicide prevention measures during economic crises. PMID- 25033149 TI - Potential effects of California's new vaccine exemption law on the prevalence and clustering of exemptions. AB - Exemptions from childhood immunizations required for school entry have continued to increase among California kindergartners, and exemptions show spatial clustering within the state. A 2014 change in California's school-entry vaccine exemption law requires parents filing for an exemption to submit signed documents from a health care provider. However, the evidence presented here suggests that the policy change will probably not be sufficient to reverse the growing trend in vaccine refusals. PMID- 25033150 TI - The effect of a "maintain, don't gain" approach to weight management on depression among black women: results from a randomized controlled trial. AB - OBJECTIVES: We evaluated the effect of a weight gain prevention intervention (Shape Program) on depression among socioeconomically disadvantaged overweight and obese Black women. METHODS: Between 2009 and 2012, we conducted a randomized trial comparing a 12-month electronic health-based weight gain prevention intervention to usual primary care at 5 central North Carolina community health centers. We assessed depression with the Patient Health Questionnaire (PHQ-8). We analyzed change in depression score from baseline to 12- and 18-month follow-up across groups with mixed models. We used generalized estimating equation models to analyze group differences in the proportion above the clinical threshold for depression (PHQ-8 score >= 10). RESULTS: At baseline, 20% of participants reported depression. Twelve-month change in depression scores was larger for intervention participants (mean difference = -1.85; 95% confidence interval = 3.08, -0.61; P = .004). There was a significant reduction in the proportion of intervention participants with depression at 12 months with no change in the usual-care group (11% vs 19%; P = .035). All effects persisted after we controlled for weight change and medication use. We saw similar findings at 18 months. CONCLUSIONS: The Shape Program, which includes no mention of mood, improved depression among socioeconomically disadvantaged Black women. PMID- 25033151 TI - Determinants of mental health and self-rated health: a model of socioeconomic status, neighborhood safety, and physical activity. AB - OBJECTIVES: We investigated the underlying mechanisms of the influence of socioeconomic status (SES) on mental health and self-rated health (SRH), and evaluated how these relationships might vary by race/ethnicity, age, and gender. METHODS: We analyzed data of 44 921 adults who responded to the 2009 California Health Interview Survey. We used a path analysis to test effects of SES, neighborhood safety, and physical activity on mental health and SRH. RESULTS: Low SES was associated with greater neighborhood safety concerns, which were negatively associated with physical activity, which was then negatively related to mental health and SRH. This model was similar across different racial/ethnic and gender groups, but mean levels in the constructs differed across groups. CONCLUSIONS: SES plays an important role in SRH and mental health, and this effect is further nuanced by race/ethnicity and gender. Identifying the psychological (neighborhood safety) and behavioral (physical activity) factors that influence mental health and SRH is critical for tailoring interventions and designing programs that can improve overall health. PMID- 25033152 TI - Community characteristics and mortality: the relative strength of association of different community characteristics. AB - OBJECTIVES: We compared the strength of association between average 5-year county level mortality rates and area-level measures, including air quality, sociodemographic characteristics, violence, and economic distress. METHODS: . We obtained mortality data from the National Vital Statistics System and linked it to socioeconomic and demographic data from the Census Bureau, air quality data, violent crime statistics, and loan delinquency data. We modeled 5-year average mortality rates (1998-2002) for all-cause, cancer, heart disease, stroke, and respiratory diseases as a function of county-level characteristics using ordinary least squares regression models. We limited analyses to counties with population of 100,000 or greater (n = 458). RESULTS: Demographic and socioeconomic characteristics, particularly the percentage older than 65 years and near poor, were top predictors of all-cause and condition-specific mortality, as were a high concentration of construction and service workers. We found weaker associations for air quality, mortgage delinquencies, and violent crimes. Protective characteristics included the percentage of Hispanics, Asians, and married residents. CONCLUSIONS: Multiple factors influence county-level mortality. Although county demographic and socioeconomic characteristics are important, there are independent, although weaker, associations of other environmental characteristics. Future studies should investigate these factors to better understand community mortality risk. PMID- 25033153 TI - The impact of public housing on social networks: a natural experiment. AB - OBJECTIVES: We assessed whether 2 types of public housing-scattered among market rate housing developments or clustered in small public housing projects-were associated with the perceived health and health behaviors of residents' social networks. METHODS: Leveraging a natural experiment in Montgomery County, Maryland, in which residents were randomly assigned to different types of public housing, we surveyed 453 heads of household in 2011. We asked residents about their own health as well as the perceived health of their network members, including their neighbors. RESULTS: Residents in scattered-site public housing perceived that their neighbors were more likely to exercise than residents of clustered public housing (24.7% of network members vs 14.0%; P < .001). There were no significant differences in the proportion of network members who were perceived to have major health problems, depressed mood, poor diet, or obesity. Having more network members who smoked was associated with a significantly higher likelihood of smoking. CONCLUSIONS: Different types of public housing have a modest impact on the health composition of one's social network, suggesting the importance of housing policy for health. PMID- 25033155 TI - Promoting public health through public art in the digital age. PMID- 25033154 TI - Insurance continuity and human papillomavirus vaccine uptake in Oregon and California federally qualified health centers. AB - OBJECTIVES: We examined the association between insurance continuity and human papillomavirus (HPV) vaccine uptake in a network of federally qualified health clinics (FQHCs). METHODS: We analyzed retrospective electronic health record data for females, aged 9-26 years in 2008 through 2010. Based on electronic health record insurance coverage information, patients were categorized by percent of time insured during the study period (0%, 1%-32%, 33%-65%, 66%-99%, or 100%). We used bilevel multivariable Poisson regression to compare vaccine-initiation prevalence between insurance groups, stratified by race/ethnicity and age. We also examined vaccine series completion among initiators who had at least 12 months to complete all 3 doses. RESULTS: Significant interactions were observed between insurance category, age, and race/ethnicity. Juxtaposed with their continuously insured peers, patients were less likely to initiate the HPV vaccine if they were insured for less than 66% of the study period, aged 13 years or older, and identified as a racial/ethnic minority. Insurance coverage was not associated with vaccine series completion. CONCLUSIONS: Disparities in vaccine uptake by insurance status were present in the FQHCs studied here, despite the fact that HPV vaccines are available to many patients regardless of ability to pay. PMID- 25033156 TI - An analysis of state public health emergency declarations. AB - Disaster responses often involve coordination among multiple levels of government and public and private sector collaboration. When emergencies raise health concerns, governments must include public health and health care systems in their response. A state government's declaration of "public health emergency" can provide that state's health sector with flexibility and guidance about response parameters. Although events including Hurricanes Katrina and Sandy and the H1N1 influenza outbreak provided opportunities for states to deploy their public health emergency powers, little has been reported about how states have used their authority to declare a public health emergency. I present a systematic identification and analysis of states' public health emergency declarations, examine why these declarations were issued, and discuss their potential value. PMID- 25033157 TI - Ludwik Rajchman (1881-1965): world leader in social medicine and director of the League of Nations Health Organization. PMID- 25033159 TI - Glycated collagen decreased endothelial cell fibronectin alignment in response to cyclic stretch via interruption of actin alignment. AB - Hyperglycemia is a defining characteristic of diabetes, and uncontrolled blood glucose in diabetes is associated with accelerated cardiovascular disease. Chronic hyperglycemia glycates extracellular matrix (ECM) collagen, which can lead to endothelial cell dysfunction. In healthy conditions, endothelial cells respond to mechanical stimuli such as cyclic stretch (CS) by aligning their actin cytoskeleton. Other cell types, specifically fibroblasts, align their ECM in response to CS. We previously demonstrated that glycated collagen inhibits endothelial cell actin alignment in response to CS. The aim of this study was to determine the effect of glycated collagen on ECM remodeling and protein alignment in response to stretch. Porcine aortic endothelial cells (PAEC) seeded on native or glycated collagen coated elastic substrates were exposed to 10% CS. Cells on native collagen aligned subcellular fibronectin fibers in response to stretch, whereas cells on glycated collagen did not. The loss of fibronectin alignment was due to inhibited actin alignment in response to CS, since fibronectin alignment did not occur in cells on native collagen when actin alignment was inhibited with cytochalasin. Further, while ECM protein content did not change in cells on native or glycated collagen in response to CS, degradation activity decreased in cells on glycated collagen. Matrix metalloproteinase 2 (MMP-2) and membrane associated type 1 matrix metalloproteinase (MT1-MMP) protein levels decreased, and therefore MMP-2 activity also decreased. These MMP changes may relate to c Jun N-terminal kinase (Jnk) phosphorylation inhibition with CS, which has previously been linked to focal adhesion kinase (FAK). These data demonstrate the importance of endothelial cell actin tension in remodeling and aligning matrix proteins in response to mechanical stimuli, which is critical to vascular remodeling in health and disease. PMID- 25033158 TI - Role of health insurance on the survival of infants with congenital heart defects. AB - OBJECTIVES: We examined the association between health insurance and survival of infants with congenital heart defects (CHDs), and whether medical insurance type contributed to racial/ethnic disparities in survival. METHODS: We conducted a population-based, retrospective study on a cohort of Florida resident infants born with CHDs between 1998 and 2007. We estimated neonatal, post-neonatal, and infant survival probabilities and adjusted hazard ratios (AHRs) for individual characteristics. RESULTS: Uninsured infants with critical CHDs had 3 times the mortality risk (AHR = 3.0; 95% confidence interval = 1.3, 6.9) than that in privately insured infants. Publicly insured infants had a 30% reduced mortality risk than that of privately insured infants during the neonatal period, but had a 30% increased risk in the post-neonatal period. Adjusting for insurance type reduced the Black-White disparity in mortality risk by 50%. CONCLUSIONS: Racial/ethnic disparities in survival were attenuated significantly, but not eliminated, by adjusting for payer status. PMID- 25033160 TI - Characterization of freshly retrieved preantral follicles using a low-invasive, mechanical isolation method extended to different ruminant species. AB - Due to the increased interest in preantral follicular physiology, non-invasive retrieval and morphological classification are crucial. Therefore, this study aimed: (1) to standardize a minimally invasive isolation protocol, applicable to three ruminant species; (2) to morphologically classify preantral follicles upon retrieval; and (3) to describe morphological features of freshly retrieved follicles compared with follicle characteristics using invasive methods. Bovine, caprine and ovine ovarian cortex strips were retrieved from slaughterhouse ovaries and dispersed. This suspension was filtered, centrifuged, re-suspended and transferred to a Petri dish, to which 0.025 mg/ml neutral red (NR) was added to assess the viability of the isolated follicles. Between 59 and 191 follicles per follicle class and per species were collected and classified by light microscopy, based on follicular cell morphology. Subsequently, follicle diameters were measured. The proposed isolation protocol was applicable to all three species and showed a significant, expected increase in diameter with developmental stage. With an average diameter of 37 +/- 5 MUm for primordial follicles, 47 +/- 6.3 MUm for primary follicles and 67.1 +/- 13.1 MUm for secondary follicles, no significant difference in diameter among the three species was observed. Bovine, caprine and ovine follicles (63, 59 and 50% respectively) were graded as viable upon retrieval. Using the same morphological characteristics as determined by invasive techniques [e.g. haematoxylin-eosin (HE) sections], cumulus cell morphology and follicle diameter could be used routinely to classify freshly retrieved follicles. Finally, we applied a mechanical, minimally invasive, follicle isolation protocol and extended it to three ruminant species, yielding viable preantral follicles without compromising further in vitro processing and allowing routine follicle characterization upon retrieval. PMID- 25033161 TI - High self-efficacy predicts adherence to surveillance colonoscopy in inflammatory bowel disease. AB - BACKGROUND: Patients with extensive ulcerative colitis or Crohn's disease of the colon have an increased risk of colon cancer and require colonoscopic surveillance. In this study, we assessed individual self-efficacy (SE) to estimate the probability of adherence to surveillance colonoscopies. METHODS: Three hundred seventy-eight patients with ulcerative colitis or Crohn's disease of the colon for at least 7 years and with at least one third of the colon involved participated in this cross-sectional questionnaire study performed at 3 tertiary referral inflammatory bowel disease clinics. Medical charts were abstracted for demographic and clinical variables. The questionnaire contained a group of items assessing SE for undergoing colonoscopy. RESULTS: We validated our 20-question SE scale and used 8 of the items that highlighted scheduling, preparation, and postprocedure recovery, to develop 2 shorter SE scales. All 3 scales were reliable with Cronbach's alpha ranging from 0.845 to 0.905 and correlated with chart-documented adherence to surveillance colonoscopy (P < 0.001). We then developed logistic regression models to predict adherence to surveillance colonoscopy using each scale separately along with other key variables (i.e., disease location, knowledge of correct adherence intervals, and information sources of patients consulted regarding Crohn's disease and ulcerative colitis) and demonstrated model accuracy up to 74%. CONCLUSIONS: SE, as measured by our validated scales, correlates with chart-adherence to surveillance colonoscopy. Our adherence model, which includes SE, predicts adherence with 74% certainty. An 8-item validated clinical questionnaire can be administered to assess whether patients in this population may require further intervention for adherence. PMID- 25033163 TI - Age of onset as a moderator of cognitive decline in pediatric-onset multiple sclerosis. AB - Cognitive impairment is often reported in pediatric-onset multiple sclerosis (MS). Using serial cognitive data from 35 individuals with pediatric-onset MS, this study examined how age at disease-onset and proxies of cognitive reserve may impact cognitive maturation over the course of childhood and adolescence. Neuropsychological evaluations were conducted at baseline and up to four more assessments. Of the 35 participants, 7 completed only one assessment, 5 completed two assessments, 13 completed three assessments, 10 completed four or more assessments. Growth curve modeling was used to assess longitudinal trajectories on the Trail Making Test-Part B (TMT-B) and the Symbol Digit Modalities (SDMT; oral version) and to examine how age at disease onset, baseline Full Scale IQ, and social status may moderate rate of change on these measures. Mean number of evaluations completed per patient was 2.8. Younger age at disease onset was associated with a greater likelihood of cognitive decline on both the TMT-B (p=.001) and SDMT (p=.005). Baseline IQ and parental social status did not moderate any of the cognitive trajectories. Findings suggest that younger age at disease-onset increases the vulnerability for disrupted performance on measures of information processing, visual scanning, perceptual/motor speed, and working memory. Proxies of cognitive reserve did not protect against the progression of decline on these measures. Young patients with MS should be advised to seek follow-up cognitive evaluation to assess cognitive maturation and to screen for the potential late emergence of cognitive deficits. (JINS, 2014, 20, 1-9). PMID- 25033166 TI - Development of albuminuria and enhancement of oxidative stress during chronic renin-angiotensin system suppression. AB - OBJECTIVE: Albuminuria has been recently described in hypertensive patients under chronic renin-angiotensin system (RAS) suppression. We investigated whether this fact could be related to an increase in oxidative stress. METHODS: We examined normoalbuminuric and albuminuric patients in stage 2 chronic kidney disease, both with more than 2 years of RAS blockade. The relationship between albuminuria and circulating biomarkers for both oxidative damage, that is carbonyl and malondialdehyde, as well as antioxidant defense, that is reduced glutathione, thiol groups, uric acid, bilirubin, or catalase, and superoxide scavenging activity, was assessed. RESULTS: We found that only patients with albuminuria showed an important increase in carbonyls (P < 0.001) and malondialdehyde (P < 0.05) compared to normoalbuminuric patients. This increase in oxidative damage was also accompanied by a rise in catalase activity (P < 0.05) and low-molecular weight antioxidants only when they were measured as total antioxidant capacity (P < 0.01). In order to establish the specific oxidative status of each group, new indexes of oxidative damage and antioxidant defense were calculated with all these markers following a mathematical and statistical approach. Although both pro-oxidant and antioxidant indexes were significantly increased in patients with albuminuria, only the oxidative damage index positively correlated with the increase of albumin/creatinine ratio (P = 0.0024). CONCLUSIONS: We conclude that albuminuria is accompanied by an amplified oxidative damage in patients in early stages of chronic kidney disease. These results indicate that chronic RAS protection must be directed to avoid development of albuminuria and oxidative damage. PMID- 25033167 TI - Structures, vibrational frequencies, and stabilities of halogen cluster anions and cations, X(n)(+/-), n = 3, 4, and 5. AB - The structures, vibrational frequencies, and thermodynamic stabilities of the homonuclear polyhalogen ions, X3(+), X3(-), X4(+), X4(-), X5(+), and X5(-) (X = Cl, Br, I), have been calculated at the CCSD(T) level. The energetics were calculated using the Feller-Peterson-Dixon approach for the prediction of reliable enthalpies of formation. The calculations allow the following predictions where stabilities are defined in terms of thermodynamic quantities. (1) The X3(+) cations are stable toward loss of X2; (2) the X3(-) anions are marginally stable toward loss of X2 with Cl3(-) being the least stable; (3) the X4(+) cations and X4(-) anions are only weakly bound dimers of X2(+1/2) and X2( 1/2) units, respectively, but the cations are marginally stable toward decomposition to X3(+) and X, with I4(+) having the lowest dissociation energy, whereas the X4(-) anions decompose spontaneously to X3(-) and X; (4) the X5(+) cations are only marginally stable at low temperatures toward loss of X2, with Cl5(+) being the least stable; and (5) the X5(-) anions are also only stable at low temperatures toward loss of X2, with Cl5(-) being the least stable. PMID- 25033168 TI - Retinal metastasis from systemic cancer in 8 cases. AB - IMPORTANCE: Metastatic tumors of the retina are rare, simulate retinitis, and are associated with poor patient survival. OBJECTIVE: To describe the clinical features and outcomes of patients with retinal metastasis from systemic cancer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 8 patients with retinal metastasis from cutaneous melanoma (n = 4), breast cancer (n =2), esophageal cancer (n =1), and lung cancer (n = 1). At presentation, the mean patient age was 62 years and all were white. INTERVENTION: Treatment included plaque radiotherapy (n = 1) for localized disease or enucleation (n =3) for extensive tumor hemorrhage (n = 1), total retinal detachment (n = 1), or pain (n = 1). For 4 preterminal patients, observation was preferred. MAIN OUTCOMES AND MEASURES: Clinical features and systemic outcomes. RESULTS: The mean interval from primary cancer diagnosis to retinal metastasis was 63 months. Initial misdiagnosis as retinitis (n = 5), hemangioma (n = 1), choroidal neovascular membrane (n = 1), or nerve fiber layer infarction (n = 1) for a mean interval of 5 months was recorded. Visual acuity in the affected eye was 20/40 to 20/60 (n = 5) or 20/400 to light perception (n = 3). The tumors were unilateral (n = 7), involved the macula (n = 3), and had a mean distance to the foveola of 6 mm. In one case, dense vitreous blood precluded fundus visualization. The mean tumor basal dimension was 7.4 mm, and the mean thickness was 2.3 mm. The tumors appeared white (n = 2), yellow (n = 4), or brown (n = 1); were located in the inner retina (n = 6) or full-thickness retina (n = 1); and had vitreous seeds (n = 3), vitreous hemorrhage (n = 2), retinal hemorrhage (n = 4), subretinal fluid (n = 4), and/or intraretinal exudation (n = 1). Fluorescein angiography disclosed early retinal hypofluorescence and late hyperfluorescence with staining. Fine needle aspiration biopsy confirmed the diagnoses (n = 4). Metastasis-related death occurred in 5 patients within 1 month in each case. Of the remaining 3 patients, 2 were alive at 4 and 17 months and 1 was too sick to return. CONCLUSIONS AND RELEVANCE: Retinal metastases resemble retinitis, often with delay in diagnosis and poor life prognosis. PMID- 25033169 TI - Coronaviruses: severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus in travelers. AB - PURPOSE OF REVIEW: Middle East respiratory syndrome coronavirus (MERS-CoV) is currently the focus of global attention. In this review, we describe virological, clinical, epidemiological features and interim travel advice and guidelines regarding MERS-CoV. We compare and contrast these with the severe acute respiratory syndrome coronavirus (SARS-CoV). RECENT FINDINGS: MERS-CoV is a novel beta CoV that causes a spectrum of clinical illness from asymptomatic to the rapidly fatal disease mainly in those with comorbid conditions. Epidemiological and genomic studies show zoonotic transmission to humans from camels and possibly bats. In contrast to the SARS-CoV pandemic, very limited global spread of fatal MERS-CoV has occurred outside the Arabian Peninsula. Although mainly currently restricted to Middle Eastern countries, MERS-CoV was reported from at least 10 other countries in Europe, Asia and the United States. All primary cases have been linked to travel to the Middle East. Nosocomial transmission of MERS-CoV has occurred because of poor infection control measures. Specific molecular diagnostic tests are available. Currently, there are no specific drugs for prevention or treatment for MERS-CoV and vaccine development is in the early stages. Advice and guidance for travelers to the Middle East are updated regularly by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). SUMMARY: Like SARS-CoV, MERS-CoV threatens global health security. All physicians and travelers to the Middle East should be aware of the new threat caused by MERS-CoV and follow CDC and WHO guidelines. Those who develop ill health during their trip or soon after their return should seek medical care. PMID- 25033170 TI - Role of extracapsular dissection in surgical management of benign parotid tumors. AB - Hypothesis: Extracapsular dissection is a safe and effective surgical technique in the management of benign parotid neoplasms. PMID- 25033172 TI - MicroRNA-mediated repression combats depression. AB - Precisely how SSRIs induce long-term modifications in serotonin transmission to elicit their antidepressant actions is unclear. In this issue of Neuron, Issler et al. (2014) identify a key role for microRNA-135a [corrected] in the raphe nuclei in the molecular mechanisms underlying the therapeutic actions of SSRIs. PMID- 25033171 TI - P-loop conformation governed crizotinib resistance in G2032R-mutated ROS1 tyrosine kinase: clues from free energy landscape. AB - Tyrosine kinases are regarded as excellent targets for chemical drug therapy of carcinomas. However, under strong purifying selection, drug resistance usually occurs in the cancer cells within a short term. Many cases of drug resistance have been found to be associated with secondary mutations in drug target, which lead to the attenuated drug-target interactions. For example, recently, an acquired secondary mutation, G2032R, has been detected in the drug target, ROS1 tyrosine kinase, from a crizotinib-resistant patient, who responded poorly to crizotinib within a very short therapeutic term. It was supposed that the mutation was located at the solvent front and might hinder the drug binding. However, a different fact could be uncovered by the simulations reported in this study. Here, free energy surfaces were characterized by the drug-target distance and the phosphate-binding loop (P-loop) conformational change of the crizotinib ROS1 complex through advanced molecular dynamics techniques, and it was revealed that the more rigid P-loop region in the G2032R-mutated ROS1 was primarily responsible for the crizotinib resistance, which on one hand, impaired the binding of crizotinib directly, and on the other hand, shortened the residence time induced by the flattened free energy surface. Therefore, both of the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the kinase resistance. PMID- 25033173 TI - Astrocyte morphology is controlled by neuron-derived FGF. AB - The highly ramified processes of astrocytes enable cellular interactions and extracellular homeostasis. In this issue of Neuron, Stork et al. (2014) report that extension and elaboration of astrocyte processes in Drosophila is controlled by the release of FGF by neurons. PMID- 25033174 TI - Slow neuromodulation mediated by ATP P2X receptors. AB - ATP-gated P2X receptors are widely expressed in the nervous system, but their physiological roles are not fully understood. New insights from Pougnet et al. (2014) in this issue of Neuron show that postsynaptic P2X receptors may be activated by ATP released from astrocytes and function to downregulate synaptic AMPA receptors in hippocampal neurons. PMID- 25033175 TI - Controlling brain states. AB - Neurons in mouse V1 increase their response to visual stimulation during locomotion. In this issue of Neuron, Lee et al. (2014) show that subthreshold optogenetic stimulation of a brainstem locomotion area can mimic the effect of locomotion on sensory processing. PMID- 25033176 TI - Insights about adolescent behavior, plasticity, and policy from neuroscience research. AB - Adolescent brain research has offered an explanation of adolescent behavior relevant for parents, society, and policymakers. As the science continues to evolve, it will advance understanding of adolescent potential and individual variation to further generate developmentally appropriate expectations, policies, and sanctions. PMID- 25033177 TI - DNA damage and its links to neurodegeneration. AB - The integrity of our genetic material is under constant attack from numerous endogenous and exogenous agents. The consequences of a defective DNA damage response are well studied in proliferating cells, especially with regards to the development of cancer, yet its precise roles in the nervous system are relatively poorly understood. Here we attempt to provide a comprehensive overview of the consequences of genomic instability in the nervous system. We highlight the neuropathology of congenital syndromes that result from mutations in DNA repair factors and underscore the importance of the DNA damage response in neural development. In addition, we describe the findings of recent studies, which reveal that a robust DNA damage response is also intimately connected to aging and the manifestation of age-related neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. PMID- 25033179 TI - Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. AB - The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month-old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month-old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro or in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired dedifferentiation, myelin clearance, and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance. PMID- 25033180 TI - ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice. AB - The serine hydrolase alpha/beta-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy. PMID- 25033181 TI - Subdomain-mediated axon-axon signaling and chemoattraction cooperate to regulate afferent innervation of the lateral habenula. AB - A dominant feature of neural circuitry is the organization of neuronal projections and synapses into specific brain nuclei or laminae. Lamina-specific connectivity is controlled by the selective expression of extracellular guidance and adhesion molecules in the target field. However, how (sub)nucleus-specific connections are established and whether axon-derived cues contribute to subdomain targeting are largely unknown. Here, we demonstrate that the lateral subnucleus of the habenula (lHb) determines its own afferent innervation by sending out efferent projections that express the cell adhesion molecule LAMP to reciprocally collect and guide dopaminergic afferents to the lHb-a phenomenon we term subdomain-mediated axon-axon signaling. This process of reciprocal axon-axon interactions cooperates with lHb-specific chemoattraction mediated by Netrin-1, which controls axon target entry, to ensure specific innervation of the lHb. We propose that cooperation between pretarget reciprocal axon-axon signaling and subdomain-restricted instructive cues provides a highly precise and general mechanism to establish subdomain-specific neural circuitry. PMID- 25033178 TI - Glial development: the crossroads of regeneration and repair in the CNS. AB - Given the complexities of the mammalian CNS, its regeneration is viewed as the holy grail of regenerative medicine. Extraordinary efforts have been made to understand developmental neurogenesis, with the hopes of clinically applying this knowledge. CNS regeneration also involves glia, which comprises at least 50% of the cellular constituency of the brain and is involved in all forms of injury and disease response, recovery, and regeneration. Recent developmental studies have given us unprecedented insight into the processes that regulate the generation of CNS glia. Because restorative processes often parallel those found in development, we will peer through the lens of developmental gliogenesis to gain a clearer understanding of the processes that underlie glial regeneration under pathological conditions. Specifically, this review will focus on key signaling pathways that regulate astrocyte and oligodendrocyte development and describe how these mechanisms are reutilized in these populations during regeneration and repair after CNS injury. PMID- 25033182 TI - Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes. AB - Astrocytes are critically important for neuronal circuit assembly and function. Mammalian protoplasmic astrocytes develop a dense ramified meshwork of cellular processes to form intimate contacts with neuronal cell bodies, neurites, and synapses. This close neuron-glia morphological relationship is essential for astrocyte function, but it remains unclear how astrocytes establish their intricate morphology, organize spatial domains, and associate with neurons and synapses in vivo. Here we characterize a Drosophila glial subtype that shows striking morphological and functional similarities to mammalian astrocytes. We demonstrate that the Fibroblast growth factor (FGF) receptor Heartless autonomously controls astrocyte membrane growth, and the FGFs Pyramus and Thisbe direct astrocyte processes to ramify specifically in CNS synaptic regions. We further show that the shape and size of individual astrocytes are dynamically sculpted through inhibitory or competitive astrocyte-astrocyte interactions and Heartless FGF signaling. Our data identify FGF signaling through Heartless as a key regulator of astrocyte morphological elaboration in vivo. PMID- 25033183 TI - Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. AB - Amphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons. Consistent with this decrease in surface EAAT3, amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin- and Rho-mediated and requires a unique sequence in the cytosolic C terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission. PMID- 25033184 TI - ATP P2X receptors downregulate AMPA receptor trafficking and postsynaptic efficacy in hippocampal neurons. AB - P2X receptors (P2XRs) are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons or glia. Although purinergic signaling has multiple effects on synaptic transmission and plasticity, P2XR function at brain synapses remains to be established. Here, we show that activation of postsynaptic P2XRs by exogenous ATP or noradrenaline dependent glial release of endogenous ATP decreases the amplitude of miniature excitatory postsynaptic currents and AMPA-evoked currents in cultured hippocampal neurons. We also observed a P2X-mediated depression of field potentials recorded in CA1 region from brain slices. P2X2Rs trigger dynamin-dependent internalization of AMPA receptors (AMPARs), leading to reduced surface AMPARs in dendrites and at synapses. AMPAR alteration required calcium influx through opened ATP-gated channels and phosphatase or CamKII activities. These findings indicate that postsynaptic P2XRs play a critical role in regulating the surface expression of AMPARs and thereby regulate the synaptic strength. PMID- 25033185 TI - Identification of a brainstem circuit regulating visual cortical state in parallel with locomotion. AB - Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual responses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold for overt movement similarly changed cortical processing, revealing that MLR's effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demonstrate that the MLR regulates cortical state in parallel with locomotion. PMID- 25033187 TI - A model of grid cell development through spatial exploration and spike time dependent plasticity. AB - Grid cell responses develop gradually after eye opening, but little is known about the rules that govern this process. We present a biologically plausible model for the formation of a grid cell network. An asymmetric spike time dependent plasticity rule acts upon an initially unstructured network of spiking neurons that receive inputs encoding animal velocity and location. Neurons develop an organized recurrent architecture based on the similarity of their inputs, interacting through inhibitory interneurons. The mature network can convert velocity inputs into estimates of animal location, showing that spatially periodic responses and the capacity of path integration can arise through synaptic plasticity, acting on inputs that display neither. The model provides numerous predictions about the necessity of spatial exploration for grid cell development, network topography, the maturation of velocity tuning and neural correlations, the abrupt transition to stable patterned responses, and possible mechanisms to set grid period across grid modules. PMID- 25033186 TI - Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations. AB - High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus. PMID- 25033189 TI - Research on a power management system for thermoelectric generators to drive wireless sensors on a spindle unit. AB - Thermoelectric energy harvesting is emerging as a promising alternative energy source to drive wireless sensors in mechanical systems. Typically, the waste heat from spindle units in machine tools creates potential for thermoelectric generation. However, the problem of low and fluctuant ambient temperature differences in spindle units limits the application of thermoelectric generation to drive a wireless sensor. This study is devoted to presenting a transformer based power management system and its associated control strategy to make the wireless sensor work stably at different speeds of the spindle. The charging/discharging time of capacitors is optimized through this energy harvesting strategy. A rotating spindle platform is set up to test the performance of the power management system at different speeds. The experimental results show that a longer sampling cycle time will increase the stability of the wireless sensor. The experiments also prove that utilizing the optimal time can make the power management system work more effectively compared with other systems using the same sample cycle. PMID- 25033188 TI - Eye movement preparation modulates neuronal responses in area V4 when dissociated from attentional demands. AB - We examined whether the preparation of saccadic eye movements, when behaviorally dissociated from covert attention, modulates activity within visual cortex. We measured single-neuron and local field potential (LFP) responses to visual stimuli in area V4 while monkeys covertly attended a stimulus at one location and prepared saccades to a potential target at another. In spite of the irrelevance of visual information at the saccade target, visual activity at that location was modulated at least as much as, and often more than, activity at the covertly attended location. Modulations of activity at the attended and saccade target locations were qualitatively similar and included increased response magnitude, stimulus selectivity, and spiking reliability, as well as increased gamma and decreased low-frequency power of LFPs. These results demonstrate that saccade preparation is sufficient to modulate visual cortical representations and suggest that the interrelationship of oculomotor and attention-related mechanisms extends to posterior visual cortex. PMID- 25033190 TI - (18)F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. AB - PURPOSE: To present data from the first prospective pilot phase trial of breast cancer participants imaged with fluorine 18 ((18)F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid ( RGD arginine-glycine-aspartic acid ) peptide (PEG3-E[c{ RGD arginine-glycine-aspartic acid yk}]2) ( FPPRGD2 2 fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) ), a radiopharmaceutical agent used in positron emission tomographic (PET) imaging. MATERIALS AND METHODS: The local institutional review board approved the HIPAA compliant protocol. Written informed consent was obtained from each patient. Eight women (age range, 44-67 years; mean age, 54.3 years +/- 8.8 [standard deviation]) with newly diagnosed or recurrent breast cancer were recruited between November 2010 and February 2011. (18)F- FPPRGD2 2-fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) PET/computed tomographic (CT) and (18)F-fluorodeoxyglucose ( FDG fluorine 18 fluorodeoxyglucose ) PET/CT examinations were performed within 3 weeks of each other. Dynamic (18)F- FPPRGD2 2-fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) PET and two whole-body static (18)F- FPPRGD2 2-fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) PET/CT scans were obtained. During this time, vital signs and electrocardiograms were recorded at regular intervals. Blood samples were obtained before the injection of (18)F- FPPRGD2 2 fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) and at 24 hours and 1 week after injection to evaluate for toxicity. A nonparametric version of multivariate analysis of variance was used to assess the safety outcome measures simultaneously across time points. A paired two-sample t test was performed to compare the maximum standardized uptake values ( SUVmax maximum standardized uptake value ). RESULTS: (18)F- FPPRGD2 2-fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) was well tolerated, without noticeable changes in vital signs, on electrocardiograms, or in laboratory values. A total of 30 lesions were evaluated at (18)F- FDG fluorine 18 fluorodeoxyglucose PET/CT and (18)F- FPPRGD2 2-fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) PET/CT. The primary breast lesions had (18)F- FPPRGD2 2-fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3 E[c{RGDyk}]2) uptake with SUVmax maximum standardized uptake value of 2.4-9.4 (mean, 5.6 +/- 2.8) 60 minutes after injection, compared with (18)F- FDG fluorine 18 fluorodeoxyglucose uptake with SUVmax maximum standardized uptake value of 2.8 18.6 (mean, 10.4 +/- 7.2). Metastatic lesions also showed (18)F- FPPRGD2 2 fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) uptake, with SUVmax maximum standardized uptake value of 2.4-9.7 (mean, 5.0 +/- 2.3) at 60 minutes, compared with (18)F- FDG fluorine 18 fluorodeoxyglucose uptake with SUVmax maximum standardized uptake value of 2.2-14.6 (mean, 6.6 +/- 4.2). CONCLUSION: Data from this pilot phase study suggest that (18)F- FPPRGD2 2 fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) is a safe PET radiopharmaceutical agent. Evaluation of (18)F- FPPRGD2 2 fluoropropionyl labeled PEGylated dimeric RGD peptide (PEG3-E[c{RGDyk}]2) in participants with breast cancer demonstrated significant uptake in the primary lesion and in the metastases. Larger cohorts are required to confirm these preliminary findings. PMID- 25033191 TI - Estimation and approximation approaches for biosimilar index based on reproducibility probability. AB - In recent years, quantitative evaluation for biosimilarity has been taken seriously due to the development of biosimilar products. The concept for assessment of biological products is very different from that of small-molecule drug products because of the variability with respect to the manufacturing process and environmental factors of the biological products. In this article, we propose an estimate method for a biosimilar index and the related lower bound based on the concept of reproducibility probability by assessing power. In addition, some approximations are proposed and compared in regard to simplicity and accuracy. PMID- 25033192 TI - Respiratory syncytial virus can infect basal cells and alter human airway epithelial differentiation. AB - Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality worldwide, causing severe respiratory illness in infants and immune compromised patients. The ciliated cells of the human airway epithelium have been considered to be the exclusive target of RSV, although recent data have suggested that basal cells, the progenitors for the conducting airway epithelium, may also become infected in vivo. Using either mechanical or chemical injury models, we have demonstrated a robust RSV infection of p63+ basal cells in air-liquid interface (ALI) cultures of human bronchial epithelial cells. In addition, proliferating basal cells in 2D culture were also susceptible to RSV infection. We therefore tested the hypothesis that RSV infection of this progenitor cell would influence the differentiation status of the airway epithelium. RSV infection of basal cells on the day of seeding (MOI<=0.0001), resulted in the formation of an epithelium that showed a profound loss of ciliated cells and gain of secretory cells as assessed by acetylated alpha-tubulin and MUC5AC/MUC5B immunostaining, respectively. The mechanism driving the switch in epithelial phenotype is in part driven by the induced type I and type III interferon response that we demonstrate is triggered early following RSV infection. Neutralization of this response attenuates the RSV-induced loss of ciliated cells. Together, these data show that through infection of proliferating airway basal cells, RSV has the potential to influence the cellular composition of the airway epithelium. The resulting phenotype might be expected to contribute towards both the severity of acute infection, as well as to the longer-term consequences of viral exacerbations in patients with pre-existing respiratory diseases. PMID- 25033193 TI - Use of prior knowledge for the analysis of high-throughput transcriptomics and metabolomics data. AB - BACKGROUND: High-throughput omics technologies have enabled the measurement of many genes or metabolites simultaneously. The resulting high dimensional experimental data poses significant challenges to transcriptomics and metabolomics data analysis methods, which may lead to spurious instead of biologically relevant results. One strategy to improve the results is the incorporation of prior biological knowledge in the analysis. This strategy is used to reduce the solution space and/or to focus the analysis on biological meaningful regions. In this article, we review a selection of these methods used in transcriptomics and metabolomics. We combine the reviewed methods in three groups based on the underlying mathematical model: exploratory methods, supervised methods and estimation of the covariance matrix. We discuss which prior knowledge has been used, how it is incorporated and how it modifies the mathematical properties of the underlying methods. PMID- 25033194 TI - mCLCA3 modulates IL-17 and CXCL-1 induction and leukocyte recruitment in murine Staphylococcus aureus pneumonia. AB - The human hCLCA1 and its murine ortholog mCLCA3 (calcium-activated chloride channel regulators) are exclusively expressed in mucus cells and linked to inflammatory airway diseases with increased mucus production, such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Both proteins have a known impact on the mucus cell metaplasia trait in these diseases. However, growing evidence points towards an additional role in innate immune responses. In the current study, we analyzed Staphylococcus aureus pneumonia, an established model to study pulmonary innate immunity, in mCLCA3-deficient and wild-type mice, focusing on the cellular and cytokine-driven innate inflammatory response. We compared clinical signs, bacterial clearance, leukocyte immigration and cytokine responses in the bronchoalveolar compartment, as well as pulmonary vascular permeability, histopathology, mucus cell number and mRNA expression levels of selected genes (mClca1 to 7, Muc5ac, Muc5b, Muc2, Cxcl-1, Cxcl-2, Il-17). Deficiency of mCLCA3 resulted in decreased neutrophilic infiltration into the bronchoalveolar space during bacterial infection. Only the cytokines IL-17 and the murine CXCL-8 homolog CXCL-1 were decreased on mRNA and protein levels during bacterial infection in mCLCA3-deficient mice compared to wild-type controls. However, no differences in clinical outcome, histopathology or mucus cell metaplasia were observed. We did not find evidence for regulation of any other CLCA homolog that would putatively compensate for the lack of mCLCA3. In conclusion, mCLCA3 appears to modulate leukocyte response via IL-17 and murine CXCL-8 homologs in acute Staphylococcus aureus pneumonia which is well in line with the proposed function of hCLCA1 as a signaling molecule acting on alveolar macrophages. PMID- 25033195 TI - Plant surface cues prime Ustilago maydis for biotrophic development. AB - Infection-related development of phytopathogenic fungi is initiated by sensing and responding to plant surface cues. This response can result in the formation of specialized infection structures, so-called appressoria. To unravel the program inducing filaments and appressoria in the biotrophic smut fungus Ustilago maydis, we exposed cells to a hydrophobic surface and the cutin monomer 16 hydroxy hexadecanoic acid. Genome-wide transcriptional profiling at the pre penetration stage documented dramatic transcriptional changes in almost 20% of the genes. Comparisons with the U. maydis sho1 msb2 double mutant, lacking two putative sensors for plant surface cues, revealed that these plasma membrane receptors regulate a small subset of the surface cue-induced genes comprising mainly secreted proteins including potential plant cell wall degrading enzymes. Targeted gene deletion analysis ascribed a role to up-regulated GH51 and GH62 arabinofuranosidases during plant penetration. Among the sho1/msb2-dependently expressed genes were several secreted effectors that are essential for virulence. Our data also demonstrate specific effects on two transcription factors that redirect the transcriptional regulatory network towards appressorium formation and plant penetration. This shows that plant surface cues prime U. maydis for biotrophic development. PMID- 25033196 TI - Insights into alpha-hemolysin (Hla) evolution and expression among Staphylococcus aureus clones with hospital and community origin. AB - BACKGROUND: Alpha-hemolysin (Hla) is a major virulence factor in the pathogenesis of Staphylococcus aureus infection, being active against a wide range of host cells. Although hla is ubiquitous in S. aureus, its genetic diversity and variation in expression in different genetic backgrounds is not known. We evaluated nucleotide sequence variation and gene expression profiles of hla among representatives of hospital (HA) and community-associated (CA) S. aureus clones. METHODS: 51 methicillin-resistant S. aureus and 22 methicillin-susceptible S. aureus were characterized by PFGE, spa typing, MLST and SCCmec typing. The internal regions of hla and the hla promoter were sequenced and gene expression was assessed by RT-PCR. RESULTS: Alpha-hemolysin encoding- and promoter sequences were diverse, with 12 and 23 different alleles, respectively. Based on phylogenetic analysis, we suggest that hla may have evolved together with the S. aureus genetic background, except for ST22, ST121, ST59 and ST93. Conversely, the promoter region showed lack of co-evolution with the genetic backgrounds. Four non-synonymous amino acid changes were identified close to important regions of hla activity. Amino acid changes in the RNAIII binding site were not associated to hla expression. Although expression rates of hla were in general strain specific, we observed CA clones showed significantly higher hla expression (p = 0.003) when compared with HA clones. CONCLUSION: We propose that the hla gene has evolved together with the genetic background. Overall, CA genetic backgrounds showed higher levels of hla expression than HA, and a high strain-to-strain variation of gene expression was detected in closely related strains. PMID- 25033198 TI - The ethanol-induced stimulation of rat duodenal mucosal bicarbonate secretion in vivo is critically dependent on luminal Cl-. AB - Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS) is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of 51Cr-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTRinh172 (i.p. or i.v.) did not change the secretory response to ethanol, while removing Cl- from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v.) but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl- and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms. PMID- 25033199 TI - Improved yield of high molecular weight DNA coincides with increased microbial diversity access from iron oxide cemented sub-surface clay environments. AB - Despite over three decades of progress, extraction of high molecular weight (HMW) DNA from high clay soils or iron oxide cemented clay has remained challenging. HMW DNA is desirable for next generation sequencing as it yields the most comprehensive coverage. Several DNA extraction procedures were compared from samples that exhibit strong nucleic acid adsorption. pH manipulation or use of alternative ion solutions offered no improvement in nucleic acid recovery. Lysis by liquid N2 grinding in concentrated guanidine followed by concentrated sodium phosphate extraction supported HMW DNA recovery from clays high in iron oxides. DNA recovered using 1 M sodium phosphate buffer (PB) as a competitive desorptive wash was 15.22+/-2.33 ug DNA/g clay, with most DNA consisting of >20 Kb fragments, compared to 2.46+/-0.25 ug DNA/g clay with the Powerlyzer system (MoBio). Increasing PB concentration in the lysis reagent coincided with increasing DNA fragment length during initial extraction. Rarefaction plots of 16S rRNA (V1-V3 region) pyrosequencing from A-horizon and clay soils showed an ~80% and ~400% larger accessed diversity compared to the Powerlyzer soil DNA system, respectively. The observed diversity from the Firmicutes showed the strongest increase with >3-fold more operational taxonomic units (OTU) recovered. PMID- 25033201 TI - Mapping of quantitative trait locus (QTLs) that contribute to germination and early seedling drought tolerance in the interspecific cross Setaria italica*Setaria viridis. AB - Drought tolerance is an important breeding target for enhancing the yields of grain crop species in arid and semi-arid regions of the world. Two species of Setaria, domesticated foxtail millet (S. italica) and its wild ancestor green foxtail (S. viridis) are becoming widely adopted as models for functional genomics studies in the Panicoid grasses. In this study, the genomic regions controlling germination and early seedling drought tolerance in Setaria were identified using 190 F7 lines derived from a cross between Yugu1, a S. italica cultivar developed in China, and a wild S. viridis genotype collected from Uzbekistan. Quantitative trait loci were identified which contribute to a number of traits including promptness index, radical root length, coleoptile length and lateral root number at germinating stage and seedling survival rate was characterized by the ability of desiccated seedlings to revive after rehydration. A genetic map with 128 SSR markers which spans 1293.9 cM with an average of 14 markers per linkage group of the 9 linkage groups was constructed. A total of eighteen QTLs were detected which included nine that explained over 10% of the phenotypic variance for a given trait. Both the wild green foxtail genotype and the foxtail millet cultivar contributed the favorite alleles for traits detected in this trial, indicating that wild Setaria viridis populations may serve as a reservoir for novel stress tolerance alleles which could be employed in foxtail millet breeding. PMID- 25033202 TI - Blended working: for whom it may (not) work. AB - Similarly to related developments such as blended learning and blended care, blended working is a pervasive and booming trend in modern societies. Blended working combines on-site and off-site working in an optimal way to improve workers' and organizations' outcomes. In this paper, we examine the degree to which workers feel that the two defining features of blended working (i.e., time independent working and location-independent working) enhance their own functioning in their jobs. Blended working, enabled through the continuing advance and improvement of high-tech ICT software, devices, and infrastructure, may be considered beneficial for workers' perceived effectiveness because it increases their job autonomy. However, because blended working may have downsides as well, it is important to know for whom blended working may (not) work. As hypothesized, in a sample of 348 workers (51.7% women), representing a wide range of occupations and organizations, we found that the perceived personal effectiveness of blended working was contingent upon workers' psychological need strength. Specifically, the perceived effectiveness of both time-independent working and location-independent working was positively related to individuals' need for autonomy at work, and negatively related to their need for relatedness and need for structure at work. PMID- 25033200 TI - Identification of a new target of miR-16, Vacuolar Protein Sorting 4a. AB - RATIONALE: The rationale was to utilize a bioinformatics approach to identify miRNA binding sites in genes with single nucleotide mutations (SNPs) to discover pathways in heart failure (HF). OBJECTIVE: The objective was to focus on the genes containing miRNA binding sites with miRNAs that were significantly altered in end-stage HF and in response to a left ventricular assist device (LVAD). METHODS AND RESULTS: BEDTools v2.14.3 was used to discriminate SNPs within predicted 3'UTR miRNA binding sites. A member of the miR-15/107 family, miR-16, was decreased in the circulation of end-stage HF patients and increased in response to a LVAD (p<0.001). MiR-16 decreased Vacuolar Protein Sorting 4a (VPS4a) expression in HEK 293T cells (p<0.01). The SNP rs16958754 was identified in the miR-15/107 family binding site of VPS4a which abolished direct binding of miR-16 to the 3'UTR of VPS4a (p<0.05). VPS4a was increased in the circulation of end-stage HF patients (p<0.001), and led to a decrease in the number of HEK 293T cells in vitro (p<0.001). CONCLUSIONS: We provide evidence that miR-16 decreases in the circulation of end-stage HF patients and increases with a LVAD. Modeling studies suggest that miR-16 binds to and decreases expression of VPS4a. Overexpression of VPS4a decreases cell number. Together, these experiments suggest that miR-16 and VPS4a expression are altered in end-stage HF and in response to unloading with a LVAD. This signaling pathway may lead to reduced circulating cell number in HF. PMID- 25033203 TI - Microsatellite interruptions stabilize primate genomes and exist as population specific single nucleotide polymorphisms within individual human genomes. AB - Interruptions of microsatellite sequences impact genome evolution and can alter disease manifestation. However, human polymorphism levels at interrupted microsatellites (iMSs) are not known at a genome-wide scale, and the pathways for gaining interruptions are poorly understood. Using the 1000 Genomes Phase-1 variant call set, we interrogated mono-, di-, tri-, and tetranucleotide repeats up to 10 units in length. We detected ~26,000-40,000 iMSs within each of four human population groups (African, European, East Asian, and American). We identified population-specific iMSs within exonic regions, and discovered that known disease-associated iMSs contain alleles present at differing frequencies among the populations. By analyzing longer microsatellites in primate genomes, we demonstrate that single interruptions result in a genome-wide average two- to six fold reduction in microsatellite mutability, as compared with perfect microsatellites. Centrally located interruptions lowered mutability dramatically, by two to three orders of magnitude. Using a biochemical approach, we tested directly whether the mutability of a specific iMS is lower because of decreased DNA polymerase strand slippage errors. Modeling the adenomatous polyposis coli tumor suppressor gene sequence, we observed that a single base substitution interruption reduced strand slippage error rates five- to 50-fold, relative to a perfect repeat, during synthesis by DNA polymerases alpha, beta, or eta. Computationally, we demonstrate that iMSs arise primarily by base substitution mutations within individual human genomes. Our biochemical survey of human DNA polymerase alpha, beta, delta, kappa, and eta error rates within certain microsatellites suggests that interruptions are created most frequently by low fidelity polymerases. Our combined computational and biochemical results demonstrate that iMSs are abundant in human genomes and are sources of population specific genetic variation that may affect genome stability. The genome-wide identification of iMSs in human populations presented here has important implications for current models describing the impact of microsatellite polymorphisms on gene expression. PMID- 25033204 TI - Endothelial arginine resynthesis contributes to the maintenance of vasomotor function in male diabetic mice. AB - AIM: Argininosuccinate synthetase (ASS) is essential for recycling L-citrulline, the by-product of NO synthase (NOS), to the NOS substrate L-arginine. Here, we assessed whether disturbed arginine resynthesis modulates endothelium-dependent vasodilatation in normal and diabetic male mice. METHODS AND RESULTS: Endothelium selective Ass-deficient mice (Assfl/fl/Tie2Cretg/- = Ass-KOTie2) were generated by crossing Assfl/fl mice ( = control) with Tie2Cre mice. Gene ablation in endothelial cells was confirmed by immunohistochemistry. Blood pressure (MAP) was recorded in 34-week-old male mice. Vasomotor responses were studied in isolated saphenous arteries of 12- and 34-week-old Ass-KOTie2 and control animals. At the age of 10 weeks, diabetes was induced in control and Ass-KOTie2 mice by streptozotocin injections. Vasomotor responses of diabetic animals were studied 10 weeks later. MAP was similar in control and Ass-KOTie2 mice. Depletion of circulating L-arginine by arginase 1 infusion or inhibition of NOS activity with L-NAME resulted in an increased MAP (10 and 30 mmHg, respectively) in control and Ass-KOTie2 mice. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in healthy control and Ass-KOTie2 mice. However, in diabetic Ass KOTie2 mice, relaxation responses to acetylcholine and endothelium-derived NO (EDNO) were significantly reduced when compared to diabetic control mice. CONCLUSIONS: Absence of endothelial citrulline recycling to arginine did not affect blood pressure and systemic arterial vasomotor responses in healthy mice. EDNO-mediated vasodilatation was significantly more impaired in diabetic Ass KOTie2 than in control mice demonstrating that endothelial arginine recycling becomes a limiting endothelial function in diabetes. PMID- 25033205 TI - What's pregnancy got to do with it? Late presentation to HIV/AIDS services in Northeastern Brazil. AB - Despite the known benefits of early treatment initiation for individual morbidity and mortality, as well as for reducing the risk of transmission, late presentation (LP) to HIV/AIDS services remains a major concern in many countries. There is little information on LP from middle- and low-income countries and studies that do evaluate LP commonly disaggregate data by sex. It is rare, however, for researchers to further disaggregate the data by pregnancy status so it remains unclear if pregnancy status modifies the effects associated with sex. The study was conducted at the only State Reference Center for HIV/AIDS in Salvador, Brazil's third largest city. LP was defined as a patient accessing services with a CD4 < 350 cells/mm(3). Data were abstracted from the electronic medical records of 1421 patients presenting between 2007 and 2009. CD4 counts and viral load (VL) information was validated with data from the National CD4/VL Database. Descriptive and bivariate statistics were conducted to inform the multivariate analysis. Adjusted prevalence ratios (APR) were estimated using generalized linear models due to the high frequency of the outcome. Half of the sample (52.5%; n = 621) was classified as LP. Compared to the prevalence among pregnant women (21.1%), the prevalence of LP was more than twice as high among non-pregnant women (56.0%) and among men (55.4%). The multivariate analysis demonstrated no statistical difference between men and nonpregnant women (APR 1.04; 95%CI 0.92-1.19), but the APR of LP for nonpregnant women was 53% less than men (APR 0.47; 95%CI 0.33-0.68). These results highlight the importance of analyzing data disaggregated not only by sex but also by pregnancy status to accurately identify the risk factors associated with LP so that programs and policies can effectively and efficiently address LP in Brazil and beyond. PMID- 25033206 TI - Eosinophil granule proteins ECP and EPX as markers for a potential early-stage inflammatory lesion in female genital schistosomiasis (FGS). AB - BACKGROUND: Genital granulomas induced by Schistosoma haematobium eggs can manifest as different lesion types visible by colposcopy; rubbery papules (RP), homogenous sandy patches (HSP) and grainy sandy patches (GSP). Pronounced tissue eosinophilia is a candidate marker for active S. haematobium pathology, as viable schistosome egg granulomas often are eosinophil rich. Here it was investigated whether eosinophil granule proteins ECP (eosinophil cationic protein) and EPX (eosinophil protein-X) in urine and genital lavage can be used as markers for active FGS lesions. METHODS: Uro-genital samples from 118 Malagasy women were analysed for ECP and EPX by standard sandwich avidin/biotin amplified ELISA. PRINCIPAL FINDINGS: The women with RP lesions had significantly higher levels of ECP and EPX in both lavage and urine. Furthermore, women with RP lesions were significantly younger than those with GSP. This could indicate that RP lesions might be more recently established and thus represent an earlier inflammatory lesion stage. CONCLUSION: ECP in genital lavage might be a future tool aiding the identification of FGS pathology at a stage where reversibility remains a possibility following praziquantel treatment. PMID- 25033207 TI - A nanoparticle formula for delivering siRNA or miRNAs to tumor cells in cell culture and in vivo. AB - To improve RNA delivery, we present a protocol to produce an RNA carrier based on a Zn(II)-dipicolylamine (Zn-DPA) analog, which is an artificial receptor for phosphate anion derivatives. We further functionalized this Zn-DPA analog to hyaluronic acid (HA)-based self-assembled nanoparticles (HA-NPs) with a hydrodynamic diameter of 100 nm by conjugating amine-functionalized Zn-DPA molecules onto the HA-NPs through amide formation, resulting in efficient tumor targeted delivery of RNAs (siRNAs, miRNA or other short oligoribonucleotides) and small-molecule drugs. The functional group of Zn-DPA can be converted into other groups such as a carboxylic or thiol group, and the DPA analog can be covalently attached to a variety of existing and novel platforms or formulations for the development of multifunctional materials via standard bioconjugation techniques. Protocols for RNA formulation and delivery into tumor tissues and tumor cells are also described. Our design strategy offers a versatile and practical method for delivering both RNA and chemotherapeutics to tumor cells and expands existing nanomaterial capabilities to further the field of drug and gene delivery. PMID- 25033208 TI - iMAD, a genetic screening strategy for dissecting complex interactions between a pathogen and its host. AB - Insertional mutagenesis and depletion (iMAD) is a genetic screening strategy for dissecting complex interactions between two organisms. The simultaneous genetic manipulation of both organisms allows the identification of aggravating and alleviating genetic interactions between pairs of gene disruptions, one from each organism. Hierarchial clustering and genetic interaction networks are then used to identify common behavioral patterns among subsets of genes, which allow functional relationships between proteins and their component pathways to be elucidated. Here we present a protocol for dissecting the interaction between a pathogen (Legionella pneumophila) and its host (cultured Drosophila melanogaster cells) using bacterial mutagenesis and host RNAi. The key stages covered in the PROCEDURE include the design, execution and data analysis of an iMAD screen; details for determining the abundance of individual mutants by microarray analysis and next-generation sequencing are not included because detailed protocols have been published elsewhere. Adapting and optimizing iMAD to a specific experimental system can require 6-18 months. Once a bacterial mutant library, host cell factor depletion strategies and conditions to monitor the interaction are established, an iMAD screen can be completed in 4-8 weeks, depending on the organisms' growth rates, the duration of the interaction and the types of data analysis performed. PMID- 25033209 TI - Quantitative and unbiased analysis of directional persistence in cell migration. AB - The mechanism by which cells control directional persistence during migration is a major question. However, the common index measuring directional persistence, namely the ratio of displacement to trajectory length, is biased, particularly by cell speed. An unbiased method is to calculate direction autocorrelation as a function of time. This function depends only on the angles of the vectors tangent to the trajectory. This method has not been widely used, because it is more difficult to compute. Here we discuss biases of the classical index and introduce a custom-made open-source computer program, DiPer, which calculates direction autocorrelation. In addition, DiPer also plots and calculates other essential parameters to analyze cell migration in two dimensions: it displays cell trajectories individually and collectively, and it calculates average speed and mean square displacements (MSDs) to assess the area explored by cells over time. This user-friendly program is executable through Microsoft Excel, and it generates plots of publication-level quality. The protocol takes ~15 min to complete. We have recently used DiPer to analyze cell migration of three different mammalian cell types in 2D cultures: the mammary carcinoma cell line MDA-MB-231, the motile amoeba Dictyostelium discoideum and fish-scale keratocytes. DiPer can potentially be used not only for random migration in 2D but also for directed migration and for migration in 3D (direction autocorrelation only). Moreover, it can be used for any types of tracked particles: cellular organelles, bacteria and whole organisms. PMID- 25033210 TI - Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV infected Chinese rhesus macaques. AB - OBJECTIVES: Viral reservoirs-persistent residual virus despite combination antiretroviral therapy (cART)-remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA). METHODS: SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L 870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations. RESULTS: Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters. CONCLUSIONS: The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations. PMID- 25033211 TI - Elevated levels of G-quadruplex formation in human stomach and liver cancer tissues. AB - Four-stranded G-quadruplex DNA secondary structures have recently been visualized in the nuclei of human cultured cells. Here, we show that BG4, a G-quadruplex specific antibody, can be used to stain DNA G-quadruplex structures in patient derived tissues using immunohistochemistry. We observe a significantly elevated number of G-quadruplex-positive nuclei in human cancers of the liver and stomach as compared to background non-neoplastic tissue. Our results suggest that G quadruplex formation can be detected and measured in patient-derived material and that elevated G-quadruplex formation may be a characteristic of some cancers. PMID- 25033212 TI - Detection of oral human papillomavirus in HIV-positive men who have sex with men 3 years after baseline: a follow up cross-sectional study. AB - BACKGROUND: Human papillomavirus (HPV) is a causative agent in oropharyngeal squamous cell carcinoma. The natural history of oral HPV in HIV-positive men who have sex with men (MSM) is unclear. METHODS: Detection of oral human papillomavirus in 173 HIV-positive MSM using oral rinse samples 3 years apart was investigated. HPV DNA was detected by polymerase chain reaction, and genotyped by Roche Linear Array. RESULTS: Of 173 men tested in 2010, 30 had at least one HPV genotype (17%, 95% CI: 12-23), 15 at least one hr-HPV (9%, 95% CI: 5-14) and 8 had HPV 16 (5%, 95% CI: 2-9) detected. In 2013, 33 had at least one HPV genotype (19%, 95% CI: 14-26), 20 had at least one hr-HPV (12%, 95% CI: 7-17) and 7 had HPV 16 (4%, 95% CI: 2-8) detected. Of 30 men at baseline (2010) with any HPV detected, 14 (47%, 95% CI: 28-66) had at least one persistent genotype. Of the 15 men in 2010 with high risk (hr-) HPV, 6 men (40%, 95% CI: 16-68) had at least one persistent hr-HPV genotype. The incidence rate of detection of at least one new HPV genotype was 4.8 per 100 person years (95% CI: 3.1-7.0), of at least one hr HPV genotype was 3.2 per 100 person years (95% CI: 1.8-5.1) and of HPV 16 was 0.8 per 100 person years (95% CI: 0.2-2.0). The clearance rate was 14.9 per 100 person years (95% CI: 8.2-24.2) for any HPV, 18.2 per 100 person years (95% CI: 8.2-32.7) for hr-HPV and 17.4 per 100 person years (95% CI: 5.0-38.8) for HPV-16. Persistent HPV detection was associated with duration of HIV (OR 1.13 (per additional year), 95% CI: 1.00-1.26) and tonsillectomy (OR 8.17, 95% CI: 1.30 51.40). CONCLUSION: The same oral HPV genotype was detected again after 3 years in nearly half of HIV-positive men who have sex with men. PMID- 25033214 TI - Rethinking transcriptional activation in the Arabidopsis circadian clock. AB - Circadian clocks are biological timekeepers that allow living cells to time their activity in anticipation of predictable daily changes in light and other environmental factors. The complexity of the circadian clock in higher plants makes it difficult to understand the role of individual genes or molecular interactions, and mathematical modelling has been useful in guiding clock research in model organisms such as Arabidopsis thaliana. We present a model of the circadian clock in Arabidopsis, based on a large corpus of published time course data. It appears from experimental evidence in the literature that most interactions in the clock are repressive. Hence, we remove all transcriptional activation found in previous models of this system, and instead extend the system by including two new components, the morning-expressed activator RVE8 and the nightly repressor/activator NOX. Our modelling results demonstrate that the clock does not need a large number of activators in order to reproduce the observed gene expression patterns. For example, the sequential expression of the PRR genes does not require the genes to be connected as a series of activators. In the presented model, transcriptional activation is exclusively the task of RVE8. Predictions of how strongly RVE8 affects its targets are found to agree with earlier interpretations of the experimental data, but generally we find that the many negative feedbacks in the system should discourage intuitive interpretations of mutant phenotypes. The dynamics of the clock are difficult to predict without mathematical modelling, and the clock is better viewed as a tangled web than as a series of loops. PMID- 25033215 TI - Defensins and viral infection: dispelling common misconceptions. PMID- 25033216 TI - An endoparasitoid avoids hyperparasitism by manipulating immobile host herbivore to modify host plant morphology. AB - Many parasitic organisms have an ability to manipulate their hosts to increase their own fitness. In parasitoids, behavioral changes of mobile hosts to avoid or protect against predation and hyperparasitism have been intensively studied, but host manipulation by parasitoids associated with endophytic or immobile hosts has seldom been investigated. We examined the interactions between a gall inducer Masakimyia pustulae (Diptera: Cecidomyiidae) and its parasitoids. This gall midge induces dimorphic leaf galls, thick and thin types, on Euonymus japonicus (Celastraceae). Platygaster sp. was the most common primary parasitoid of M. pustulae. In galls attacked by Platygaster sp., whole gall thickness as well as thicknesses of upper and lower gall wall was significantly larger than unparasitized galls, regardless of the gall types, in many localities. In addition, localities and tree individuals significantly affected the thickness of gall. Galls attacked by Platygaster sp. were seldom hyperparasitized in the two gall types. These results strongly suggest that Platygaster sp. manipulates the host plant's development to avoid hyperparasitism by thickening galls. PMID- 25033217 TI - In vitro antioxidant activity of Retama monosperma (L.) Boiss. AB - The relationship between the antioxidant activity and the phenolic contents (total polyphenol, flavonoid and condensed tannin) of Retama monosperma (Fabaceae), used commonly in the traditional medicine of Mediterranean regions, was investigated. The antioxidant activities of the various fractions (toluene, chloroform, ethyl acetate and butanol) of the hydromethanolic extract of the seeds, stems and flowers have been evaluated using in vitro 2,2-diphenyl-1 picrylhydrazyl radical (DPPH) radical scavenging activities and Phosphomolybdic acid assays and were compared to ascorbic acid. A significant high Pearson's correlations between flavonoid content and antioxidant activities (r = 0.91) with Phosphomolybdic acid assays and (r = - 0.79) with IC50 DPPH radical scavenging activities. However, there was no correlation between condensed tannin and antioxidant activities. The results obtained in the present study indicate that the ethyl acetate fraction of seeds is a potential source of natural antioxidant for R. monosperma. PMID- 25033218 TI - In vitro and in vivo miltefosine susceptibility of a Leishmania amazonensis isolate from a patient with diffuse cutaneous leishmaniasis. AB - Miltefosine was the first oral compound approved for visceral leishmaniasis chemotherapy, and its efficacy against Leishmania donovani has been well documented. Leishmania amazonensis is the second most prevalent species causing cutaneous leishmaniasis and the main etiological agent of diffuse cutaneous leishmaniasis in Brazil. Driven by the necessity of finding alternative therapeutic strategies for a chronic diffuse cutaneous leishmaniasis patient, we evaluated the susceptibility to miltefosine of the Leishmania amazonensis line isolated from this patient, who had not been previously treated with miltefosine. In vitro tests against promastigotes and intracellular amastigotes showed that this parasite isolate was less susceptible to miltefosine than L. amazonensis type strains. Due to this difference in susceptibility, we evaluated whether genes previously associated with miltefosine resistance were involved. No mutations were found in the miltefosine transporter gene or in the Ros3 or pyridoxal kinase genes. These analyses were conducted in parallel with the characterization of L. amazonensis mutant lines selected for miltefosine resistance using a conventional protocol to select resistance in vitro, i.e., exposure of promastigotes to increasing drug concentrations. In these mutant lines, a single nucleotide mutation G852E was found in the miltefosine transporter gene. In vivo studies were also performed to evaluate the correlation between in vitro susceptibility and in vivo efficacy. Miltefosine was effective in the treatment of BALB/c mice infected with the L. amazonensis type strain and with the diffuse cutaneous leishmaniasis isolate. On the other hand, animals infected with the resistant line bearing the mutated miltefosine transporter gene were completely refractory to miltefosine chemotherapy. These data highlight the difficulties in establishing correlations between in vitro susceptibility determinations and response to chemotherapy in vivo. This study contributed to establish that the miltefosine transporter is essential for drug activity in L. amazonensis and a potential molecular marker of miltefosine unresponsiveness in leishmaniasis patients. PMID- 25033219 TI - Retention of single crystals of two Co(II) complexes during chemical reactions and rearrangement. AB - Monomeric [Co(II)(hep-H)(H2O)4]SO4 [1]SO4 and [Co(II)(hep-H)2(H2O)2](NO3)2 [2](NO3)2 have been developed from 2-(2-hydroxyethyl)pyridine (hep-H) and CoSO4.7H2O/Co(NO3)2.6H2O, respectively, at 298 K. On exposure to heat (120 degrees C), the light orange single crystal of [1]SO4 transforms to a pink single crystal corresponding to the neutral sulfato bridged dimeric complex [(Co(II)(hep H)(H2O)2(MU2-sulfato-O,O'))2](3). However, the orange single crystal of [2](NO3)2 transforms to the single crystal of monomeric [Co(II)(hep-H)2(NO3)]NO3 [4]NO3 (orange) upon exposure to heat (110 degrees C) where one of the NO3(-) counter anions in [2](NO3)2 moves to the coordination sphere. The facile SCSC transformations of [1]SO4 (orange) -> 3 (pink) and [2](NO3)2 (orange) -> [4]NO3 (orange) involve intricate multiple bond breaking and bond forming processes without losing the crystallinity. Moreover, the immersion of the pink single crystal of 3 in 1 N HCl results in a green single crystal of ionic monomeric [Co(II)(H2O)6].SO4[5]SO4, which indeed demonstrates the unprecedented unique two step SCSC transformations. PMID- 25033220 TI - Body cell mass evaluation in critically ill patients: killing two birds with one stone. AB - Body cell mass (BCM) is the metabolically active cell mass involved in O2 consumption, CO2 production and energy expenditure. BCM measurement has been suggested as a tool for the evaluation of nutritional status. Since BCM is closely related to energy expenditure, it could also represent a good reference value for the calculation of nutrient needs. In a recent issue of Critical Care, Ismael and colleagues used bioelectrical impedance analysis parameters and anthropometric variables to evaluate BCM in patients with acute kidney injury, before and after a hemodialysis session. The results of this study suggest that BCM is relatively insensitive to major body fluid shifts, a well known factor interfering with nutritional evaluation/monitoring and energy need calculations in the ICU. Thus, BCM seems to be a more 'stable' nutritional variable, as it is apparently less influenced by non-nutritional factors. The results of this paper emphasize the need to identify biologically sound parameters for nutritional status evaluation and energy need calculation in critically ill patients; in this regard, BCM could fulfill these expectations. PMID- 25033221 TI - Pseudorotaxane orientational stereoisomerism driven by pi-electron density. AB - Pseudo[2]rotaxane orientational isomers were formed in a stereocontrolled way by exploiting the electron-withdrawing (EW) or electron-donating (ED) effects of para-substituted dibenzylammonium axles threaded through the pi-electron rich calixarene cavity, which allow the fine tuning of the weak pi-pi interactions. PMID- 25033222 TI - Personalized organ donation directives: saving lives with PODDs. PMID- 25033223 TI - The life cycle of Prosorhynchoides carvajali (Trematoda: Bucephalidae) involving species of bivalve and fish hosts in the intertidal zone of central Chile. AB - We describe the life cycle of the bucephalid Prosorhynchoides carvajali from the intertidal rocky zone of central Chile. To elucidate the life cycle of this digenean, two mytilid bivalves, Semimytilus algosus and Perumytilus purpuratus, and ten intertidal fish species belonging to the families Blenniidae, Tripterygiidae, Labrisomidae, Kyphosidae and Gobiesocidae were analysed for natural infections. In addition, experimental infections of fish were undertaken and molecular analyses were performed of several developmental stages of the digeneans in various host species. Experimental infections of fish were made from infected mytilids to determine which fish species were suitable for the metacercarial stage of Prosorhynchoides. We also determined the abundance and prevalence of metacercariae in natural infections in fish and found that they were lower than in the experimental infections. A molecular analysis showed that sporocysts from S. algosus were identical to metacercariae from five fish species and P. carvajali adults. Sporocysts isolated from P. purpuratus were similar to metacercaria found in one fish species only (G. laevifrons) but were different from P. carvajali, with 1.9-2.0% genetic divergence. Therefore, the complete life cycle of P. carvajali consists of the mytilid species S. algosus as the first intermediate host, at least five intertidal fish species as second intermediate hosts (Scartichthys viridis, Auchenionchus microcirrhis, Hypsoblennius sordidus, Helcogrammoides chilensis and Gobiesox marmoratus), two carnivorous fish as definitive hosts (Auchenionchus microcirrhis and A. variolosus) and one occasional definitive host (Syciases sanguineus). This is the second description of a life cycle of a marine digenean from Chile. PMID- 25033224 TI - An integration of condensation/Ullmann-type coupling/bicyclization sequences: copper-catalyzed three-component direct synthesis of [1,2,4]triazolo[1,5 b]isoquinolin-5(1H)-ones. AB - A highly efficient three-component domino protocol has been developed for the synthesis of [1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-ones from simple and readily available o-halogenated benzohydrazides, aldehydes and nitriles. This domino process involves sequential selective condensation, copper-catalyzed intermolecular C-arylation and bicyclization. Notably, the use of ligands and anaerobic conditions can be avoided in this reaction. PMID- 25033225 TI - Patient safety begins with me. PMID- 25033226 TI - Ionic liquid-induced three-dimensional macroassembly of graphene and its applications in electrochemical energy storage. AB - Ionic liquid (IL)-induced three-dimensional macroassembly of graphene (GN) has been achieved through one-step hydrothermal treatment. Significantly, the three dimensional GN-IL (TGN-IL) nanostructures provide ideal electrode materials for supercapacitors because they combine the unique properties of GN and IL in overcoming the restacking of GN, enlarging the specific surface area, improving the GN conductivity and ensuring the high electrochemical utilization of GN as well as the open channels provided by 3D nanostructures. PMID- 25033227 TI - Infrared spectra and structures of the neutral and charged CrCO2 and Cr(CO2)2 isomers in solid neon. AB - The reactions from codeposition of laser-ablated chromium atoms with carbon dioxide in excess neon are studied by infrared absorption spectroscopy. The species formed are identified by the effects of isotopic substitution on their infrared spectra. Density functional calculations are performed to support the spectral assignments and to interpret the geometric and electronic structures of the experimentally observed species. Besides the previously reported insertion products OCrCO and O2Cr(CO)2, the one-to-one Cr(CO2) complex and the one-to-two Cr(CO2)2 complex as well as the CrOCrCO and OCCrCO3 complexes are also formed. The Cr(CO2) complex is characterized to be side-on eta(2)-C,O-coordinated. The Cr(CO2)2 complex is identified to involve a side-on eta(2)-C,O-coordinated CO2 and an end-on eta(1)-O-coordinated CO2. OCCrCO3 is a carbonate carbonyl complex predicted to have a planar structure with a eta(2)-O,O-coordinated carbonate ligand. The CrOCrCO complex is predicted to be linear with a high-spin ground state. Besides the neutral molecules, charged species are also produced. The Cr(CO2)(+) and Cr(CO2)2(+) cation complexes are characterized to have linear end on eta(1)-O-coordinated structures with blue-shifted antisymmetric CO2 stretching vibrational frequencies. The OCrCO(-) anion is bent with the Cr-O and CO stretching frequencies red-shifted from those of OCrCO neutral molecule. PMID- 25033228 TI - Dendritic, transferable, strictly monolayer MoS2 flakes synthesized on SrTiO3 single crystals for efficient electrocatalytic applications. AB - Controllable synthesis of macroscopically uniform, high-quality monolayer MoS2 is crucial for harnessing its great potential in optoelectronics, electrocatalysis, and energy storage. To date, triangular MoS2 single crystals or their polycrystalline aggregates have been synthesized on insulating substrates of SiO2/Si, mica, sapphire, etc., via portable chemical vapor deposition methods. Herein, we report a controllable synthesis of dendritic, strictly monolayer MoS2 flakes possessing tunable degrees of fractal shape on a specific insulator, SrTiO3. Interestingly, the dendritic monolayer MoS2, characterized by abundant edges, can be transferred intact onto Au foil electrodes and serve as ideal electrocatalysts for hydrogen evolution reaction, reflected by a rather low Tafel slope of ~73 mV/decade among CVD-grown two-dimensional MoS2 flakes. In addition, we reveal that centimeter-scale uniform, strictly monolayer MoS2 films consisting of relatively compact domains can also be obtained, offering insights into promising applications such as flexible energy conversion/harvesting and optoelectronics. PMID- 25033229 TI - Platinum-tin oxide core-shell catalysts for efficient electro-oxidation of ethanol. AB - Platinum-tin (Pt/Sn) binary nanoparticles are active electrocatalysts for the ethanol oxidation reaction (EOR), but inactive for splitting the C-C bond of ethanol to CO2. Here we studied detailed structure properties of Pt/Sn catalysts for the EOR, especially CO2 generation in situ using a CO2 microelectrode. We found that composition and crystalline structure of the tin element played important roles in the CO2 generation: non-alloyed Pt46-(SnO2)54 core-shell particles demonstrated a strong capability for C-C bond breaking of ethanol than pure Pt and intermetallic Pt/Sn, showing 4.1 times higher CO2 peak partial pressure generated from EOR than commercial Pt/C. PMID- 25033230 TI - New insights into disease-specific absence of complement factor H related protein C in mouse models of spontaneous autoimmune diseases. AB - Complement factor H (CFH) protein is an inhibitor of the alternative pathway of complement (AP) both in the fluid phase and on the surface of host cells. Mouse and human complement factor H-related (CFHR) proteins also belong to the fH family of plasma glycoproteins. The main goal of the current study was to compare the presence of mRNA for two mCFHR proteins in spontaneously developing autoimmune diseases in mice such as dense deposit disease (DDD), diabetes mellitus (DM), basal laminar deposits (BLD), collagen antibody-induced arthrits (CAIA) and systemic lupus erythematosus (SLE). Here we report for the first time that the CFHR-C mRNA was universally absent in the liver from three strains of lupus-prone mice and in a diabetic-prone mouse strain. The mRNA levels (pg/ng) for CFH and CFHR-B in MRL-lpr/lpr, at 9 wks and 23 wks were 707.2+/-44.4, 54.5+/ 5.75 and 729+/-252.9, 74.04+/-22.76, respectively. The mRNA levels for CFH and CFHR-B in NZB/NZW mice, at 9 wks and 54 wks were 579.9+/-23.8, 58.8+/-1.41 and 890.3+/-135.2, 63.30+/-9.2, respectively. CFHR-C protein was absent in the circulation of MRL-lpr/lpr and NZB/NZW mice before and after the development of lupus. Similarly, mRNA and protein for CFHR-C was universally absent in liver and other organs and in the circulation of NOD mice before and after the development of DM. In contrast, the mRNAs for CFH, CFHR-B and CFHR-C were universally present in the liver from mice with and without DDD, BLD and CAIA. The levels of mRNA for CFHR-B in mice with and without BLD were ~4 times higher than the mice with lupus. The complete absence of mRNA for CFHR-C in lupus and diabetic-prone strains indicates that polymorphic variation within the mouse CFHR family exists and raises the possibility that such variation contributes to lupus and diabetic phenotypes. PMID- 25033231 TI - Sensitive, selective analysis of selenium oxoanions using microchip electrophoresis with contact conductivity detection. AB - The common selenium oxoanions selenite (SeO3(2-)) and selenate (SeO4(2-)) are toxic at intake levels slightly below 1 mg day(-1). These anions are currently monitored by a variety of traditional analytical techniques that are time consuming, expensive, require large sample volumes, and/or lack portability. To address the need for a fast and inexpensive analysis of selenium oxoanions, we present the first microchip capillary zone electrophoresis (MCE) separation targeting these species in the presence of chloride, sulfate, nitrate, nitrite, chlorate, sulfamate, methanesulfonate, and fluoride, which can be simultaneously monitored. The chemistry was designed to give high selectivity in nonideal matrices. Interference from common weak acids is avoided by operating near pH 4. Separation resolution from chloride was enhanced to improve tolerance of high salinity matrices. As a result, selenate can be quantified in the presence of up to 1.5 mM NaCl, and selenite analysis is even more robust against chloride. Using contact conductivity detection, detection limits for samples with conductivity equal to the background electrolyte are 53 nM (4.2 ppb Se) and 380 nM (30 ppb) for selenate and selenite, respectively. Analysis time, including injection, is ~2 min. The MCE method was validated against ion chromatography (IC) using spiked samples of dilute BBL broth and slightly outperformed the IC in accuracy while requiring <10% of the analysis time. The applicability of the technique to real samples was shown by monitoring the consumption of selenite by bacteria incubated in LB broth. PMID- 25033232 TI - Enantiospecific total synthesis of macrolactone Sch 725674. AB - The enantiospecific total synthesis of 14-membered macrolactone Sch 725674 was accomplished from tartaric acid. Key reactions in the synthesis include the Ley's dithiaketalization of an alkynone derived from the bis-Weinreb amide of tartaric acid, Boord olefination, and ring-closing metathesis of an acrylate ester. PMID- 25033233 TI - Consensus on use of the term "App" versus "Application" for reporting of mHealth research. PMID- 25033234 TI - Development of a multiplex real-time PCR for the rapid detection of the predominant beta-lactamase genes CTX-M, SHV, TEM and CIT-type AmpCs in Enterobacteriaceae. AB - Beta-lactamase resistant bacteria and especially ESBL producing Enterobacteriaceae are an increasing problem worldwide. For this reason a major interest in efficient and reliable methods for rapid screening of high sample numbers is recognizable. Therefore, a multiplex real-time PCR was developed to detect the predominant class A beta-lactamase genes blaCTX-M, blaSHV, blaTEM and CIT-type AmpCs in a one-step reaction. A set of 114 Enterobacteriaceae containing previously identified resistance gene subtypes and in addition 20 undefined animal and environmental isolates were used for the validation of this assay. To confirm the accessibility in variable settings, the real-time runs were performed analogous in two different laboratories using different real-time cyclers. The obtained results showed complete accordance between the real-time data and the predetermined genotypes. Even if sequence analyses are further necessary for a comprehensive characterization, this method was proofed to be reliable for rapid screening of high sample numbers and therefore could be an important tool for e. g. epidemiological purposes or support infection control measures. PMID- 25033235 TI - Raman spectroscopy as a tool in differentiating conjugated polyenes from synthetic and natural sources. AB - This work presents the Raman spectroscopic characterization of synthetic analogs of natural conjugated polyenals found in octocorals, focusing the unequivocal identification of the chemical species present in these systems. The synthetic material was produced by the autocondensation reaction of crotonaldehyde, generating a demethylated conjugated polyene containing 11 carbon-carbon double bonds, with just a methyl group on the end of the carbon chain. The resonance Raman spectra of such pigment has shown the existence of enhanced modes assigned to nu1(CC) and nu2(CC) modes of the main chain. For the resonance Raman spectra of natural pigments from octocorals collected in the Brazilian coast, besides the previously cited bands, it could be also observed the presence of the nu4(CCH3), related to the vibrational mode who describes the vibration of the methyl group of the central carbon chain of carotenoids. Other interesting point is the observation of overtones and combination bands, which for carotenoids involves the presence of the nu4 mode, whereas for the synthetic polyene this band, besides be seen at a slightly different wavenumber position, does not appear as an enhanced mode and also as a combination, such as for the natural carotenoids. Theoretical molecular orbital analysis of polyenal-11 and lycopene has shown the structural differences which are also responsible for the resonance Raman data, based on the appearance of the (CH3) vibrational mode in the resonant transition only for lycopene. At last, the Raman band at ca. 1010 cm(-1), assigned to the (CH3) vibrational mode, can be used for attributing the presence of each one of the conjugated polyenes: the resonance Raman spectrum containing the band at ca. 1010 cm(-1) refers to the carotenoid (in this case lycopene), and the absence of such band in resonance conditions refers to the polyenal (in this case the polyenal-11). PMID- 25033236 TI - Physicochemical analysis of urinary stones from Dharmapuri district. AB - Nephrolithiasis is a common disease caused by the multifactorial components such as geographical location, bacterial infection, low urine volume, and low intake of water. This disease induces severe metabolic abnormalities in the human body. As the prevalence of this disease was high in Dharmapuri district located in Tamil Nadu, urinary stones removed from the patients pertaining to this district were collected and to identify the toxic elements present in the stones. The presence of functional groups and phases of the stones were analyzed using X-ray diffraction (XRD), Fourier transform Raman spectroscopy and Fourier transform infrared spectroscopy (FT-IR). The majority of stones were found to be calcium oxalate monohydrate (COM) and mixed stones having minor existence of struvite and uric acid. Hexagonal shaped COM crystals, needle shaped uric acid crystals and layered arrangement of struvite crystals in the core region were revealed by Scanning Electron Microscopy (SEM). Thermo Gravimetric Analysis (TGA) was used to determine the thermal stability and the hardness of the stone which was measured using Vickers hardness (HV). The presence of toxic elements in stones such as zirconium and mercury was identified using Energy Dispersive X-ray Spectroscopy (EDS). The EDS analysis showed higher concentration of zirconium in the core region compared to the periphery. The percentage of zirconium was relatively high compared to other toxic elements in the stones. The Vickers hardness results indicated that high HV values in the core region than the periphery and this might be due to the presence of zirconium. PMID- 25033237 TI - Spectrofluorimetric analysis of famotidine in pharmaceutical preparations and biological fluids by derivatization with benzoin. AB - A sensitive and simple spectrofluorimetric method has been developed for the analysis of famotidine, from pharmaceutical preparations and biological fluids after derivatization with benzoin. The reaction was carried out in alkaline medium with measurement of fluorescence intensity at 446 nm with excitation wavelength at 286 nm. Linear calibration was obtained with 0.5-15 MUg/ml with coefficient of determination (r(2)) 0.997. The factors affecting the fluorescence intensity were optimized. The pharmaceutical additives and amino acid did not interfere in the determination. The mean percentage recovery (n=4) calculated by standard addition from pharmaceutical preparation was 94.8-98.2% with relative standard deviation (RSD) 1.56-3.34% and recovery from deproteinized spiked serum and urine of healthy volunteers was 98.6-98.9% and 98.0-98.4% with RSD 0.34-0.84% and 0.29-0.87% respectively. PMID- 25033238 TI - Vibrational spectra, molecular structure, natural bond orbital, first order hyperpolarizability, thermodynamic analysis and normal coordinate analysis of Salicylaldehyde p-methylphenylthiosemicarbazone by density functional method. AB - The thiosemicarbazone compound, Salicylaldehyde p-methylphenylthiosemicarbazone (abbreviated as SMPTSC) was synthesized and characterized by FTIR, FT-Raman and UV. Density functional (DFT) calculations have been carried out for the title compound by performing DFT level of theory using B3LYP/6-31++G(d,p) basis set. The molecular geometry and vibrational frequencies were calculated and compared with the experimental data. The detailed interpretation of the vibrational spectra has been carried out with aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology. The electronic dipole moment (MUD) and the first hyperpolarizability (betatot) values of the investigated molecule were computed using density functional theory (DFT/B3LYP) with 6-311++G(d,p) basis set. The stability and charge delocalization of the molecule was studied by natural bond orbital (NBO) analysis. Thearomaticities of the phenyl rings were studied using the standard harmonic oscillator model of aromaticity (HOMA) index. Mulliken population analysis on atomic charges is also calculated. The molecule orbital contributions are studied by density of energy states (DOSs). PMID- 25033239 TI - Development and evaluation of a molecularly imprinted polymer for the detection and cleanup of benzylpenicillin in milk. AB - A molecularly imprinted polymer (MIP) was designed for benzylpenicillin via suspension polymerization. The specific absorption of benzylpenicillin to the MIP, applied in a molecularly imprinted solid-phase extraction (MISPE), was compared to the nonspecific binding using a NIP (nonimprinted polymer without a target molecule) in a non-molecularly imprinted solid-phase extraction. This validation was performed successfully in acetonitrile solutions and milk extracts spiked with benzylpenicillin. Significant differences in absorption were observed. In acetonitrile, the recoveries using MISPE (90-95%) were a fraction higher than those in milk extracts (70-80%). The validation revealed the limit of detection and the limit of quantitation for the MISPE application in milk samples to be 0.51 and 1.02 MUg/kg, respectively. In addition, comparing the results of the analysis of positive milk samples using MISPE with those using a classic sample preparation step showed a Pearson correlation of 0.989. Finally, cross reactivity tests using other antibiotics showed a certain cross reactivity, but non-beta-lactams were barely bound. PMID- 25033240 TI - Earth's field NMR flow meter: preliminary quantitative measurements. AB - In this paper we demonstrate the use of Earth's field NMR (EF NMR) combined with a pre-polarising permanent magnet for measuring fast fluid velocities. This time of flight measurement protocol has a considerable history in the literature; here we demonstrate that it is quantitative when employing the Earth's magnetic field for signal detection. NMR signal intensities are measured as a function of flow rate (0-1m/s) and separation distance between the permanent magnet and the EF NMR signal detection. These data are quantitatively described by a flow model, ultimately featuring no free parameters, that accounts for NMR signal modulation due to residence time inside the pre-polarising magnet, between the pre polarising magnet and the detection RF coil and inside the detection coil respectively. The methodology is subsequently demonstrated with a metallic pipe in the pre-polarising region. PMID- 25033241 TI - Occurrence and distribution of monomethylalkanes in the freshwater wetland ecosystem of the Florida Everglades. AB - A series of mono-methylalkanes (MMAs) with carbon numbers from C10 to C23 and C29 were detected in freshwater wetlands of the Everglades. A decrease in concentration and molecular complexity was observed in the order from periphyton and floc, to surface soil and deeper soil horizons. These compounds were present in varying amounts up to 27 MUg gdw(-1) in periphyton, 74 MUg gdw(-1) in floc, 1.8 MUg gdw(-1) in surface soil, <0.03 MUg gdw(-1) in deeper soils (12-15 cm). A total of 46 MMAs, including three iso and three anteiso-alkanes, were identified. Compound specific carbon isotopes values were determined for some dominant MMAs, and suggest that they originate from microbial sources, including cyanobacteria. Potential decarboxylation from fatty acids could also potentially contribute to the MMAs detected. Early diagenetic degradation was suggested to affect the accumulation of MMAs in soils and further studies are needed to address their applications as biomarkers. PMID- 25033242 TI - Retention and leaching of nitrite by municipal solid waste incinerator bottom ash under the landfill circumstance. AB - The retention and leaching of nitrite by municipal solid waste incinerator (MSWI) bottom ash could affect its migration in the landfill. In this study, the effect of the dosage of MSWI bottom ash as well as the variation of the landfill environmental parameters including pH, anions and organic matter on the nitrite retention and leaching behavior was investigated by batch experiments. The highest removal percentage (73.0%) of nitrite was observed when the dosage of MSWI bottom ash was 10 g L(-1) in 2 mg L(-1) nitrite solution. Further increase of the dosage would retard the retention, as the nitrite leaching from MSWI bottom ash was enhanced. The optimum retention of nitrite was observed when the pH was 5.0, while the leaching of nitrite showed a consistent reduction with the increase of pH. Besides, the presence of Cl(-), SO4(2)(-) and acetic acid could enhance the leaching of nitrite and mitigate the retention process. However, the retention of nitrite was enhanced by PO4(3)(-), which was probably due to the formation of the apatite, an active material for the adsorption of the nitrite. These results suggested that MSWI bottom ash could affect the migration of nitrite in the landfill, which was related to the variation of the landfill circumstance. PMID- 25033244 TI - Gill remodeling in three freshwater teleosts in response to high environmental ammonia. AB - The present study aimed to determine whether gill macro- and microstructure show compensatory responses in three freshwater fish differing in their sensitivity to high environmental ammonia (HEA). The highly ammonia-sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less ammonia-sensitive cyprinid Cyprinus carpio (common carp) and the highly ammonia-resistant cyprinid Carassius auratus (goldfish) were used as test species and were exposed for 0 h (control), 3h, 12h, 24h, 48 h, 84 h and 180 h to 1mM ammonia (as NH4HCO3; pH 7.9). In cyprinids, dramatic alterations were initiated quickly evident by thickening of filaments and lamellae, retraction of lamellae, enlargement of interlamellar cell mass (ILCM), and increase in the water-blood diffusion distance; while in trout, these modifications were absent or developed very slowly. These reorganizations may attempt to reduce the surface area presumably protecting against the water borne ammonia; and were more pronounced in goldfish marked by momentous enlargement of ILCM volume and the presence of rudimental and almost fused lamellae. Extensive mucus production in the gills of goldfish and carp and to a limited extent in trout may have been part of general stress response and/or may have played a protective role. While goldfish and carp showed shrinkage of apical crypts of mitochondrion rich cells (MRCs), probably aiding to regulate ion status, trout showed enlarged apical crypts of MRCs. All species displayed changes in the pattern of the microridges on the surface of pavement cells (PVCs). Overall, the present results connote that the goldfish with its minimal respiratory surface area and a large population of the MRCs with small apical crypts located on the edge of ILCM is better prepared for survival in ammonia polluted water compared to carp which maintain larger lamellae and especially the trout that did not show gill remodeling. PMID- 25033243 TI - Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS. AB - Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: (1) identify transcriptional biomarkers of exposure; and (2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences. PMID- 25033245 TI - Coarsening of the pore network in drying latex films upon interparticle aggregation. AB - The lateral drying front observed during film formation from latex dispersions with a Tg of the polymer around room temperature is composed of three three distinct lines. The lines are characterized by a decrease in turbidity, a renewed sharp increase in turbidity, and a more gradual decrease in turbidity at the end of what can be called a "halo". Microcracks with herringbone morphology develop at the first line, where the turbidity decreases. If macrocracks are present, these nucleate close to the end of the halo. At the line, where the turbidity sharply increases, one also observes an increase in stress birefringence. The substructure of the drying front is characteristically different from the structures described previously for films drying from hard particles. In particular, the renewed increase in turbidity cannot be explained as pore opening, but rather is the consequence of a coarsening of the pore network after the particles jump into contact. A capillary instability sets in, by which the small pores collapse under the polymer/water interfacial energy, while the larger pores expand correspondingly. The instability (related to the Rayleigh instability of liquid jets) makes the films appear turbid. Also, the induced mechanical heterogeneity prevents straight macrocracks from penetrating into the halo because crack deflection and crack branching would result, which is energetically unfavorable. PMID- 25033247 TI - Engineered proteins with desired specificity: DARPins, other alternative scaffolds and bispecific IgGs. AB - Specific binding proteins have become essential for diagnostic and therapeutic applications, and traditionally these have been antibodies. Nowadays an increasing number of alternative scaffolds have joined these ranks. These additional folds have raised a lot of interest and expectations within the last decade. It appears that they have come of age and caught up with antibodies in many fields of applications. The last years have seen an exploration of possibilities in research, diagnostics and therapy. Some scaffolds have received further improvements broadening their fields of application, while others have started to occupy their respective niche. Protein engineering, the prerequisite for the advent of all alternative scaffolds, remains the driving force in this process, for both non-immunoglobulins and immunoglobulins alike. PMID- 25033246 TI - Differential activation of intracellular versus plasmalemmal CB2 cannabinoid receptors. AB - The therapeutic and psychoactive properties of cannabinoids have long been recognized. The type 2 receptor for cannabinoids (CB2) has emerged as an important therapeutic target in several pathologies, as it mediates beneficial effects of cannabinoids while having little if any psychotropic activity. Difficulties associated with the development of CB2-based therapeutic agents have been related to its intricate pharmacology, including the species specificity and functional selectivity of the CB2-initiated responses. We postulated that a plasmalemmal or subcellular location of the receptor may contribute to the differential signaling pathways initiated by its activation. To differentiate between these two, we used extracellular and intracellular administration of CB2 ligands and concurrent calcium imaging in CB2-expressing U2OS cells. We found that extracellular administration of anandamide was ineffective, whereas 2 arachidonoyl glycerol (2-AG) and WIN55,212-2 triggered delayed, CB2-dependent Ca(2+) responses that were Gq protein-mediated. When microinjected, all agonists elicited fast, transient, and dose-dependent elevations in intracellular Ca(2+) concentration upon activation of Gq-coupled CB2 receptors. The CB2 dependency was confirmed by the sensitivity to AM630, a selective CB2 antagonist, and by the unresponsiveness of untransfected U2OS cells to 2-AG, anandamide, or WIN55,212-2. Moreover, we provide functional and morphological evidence that CB2 receptors are localized at the endolysosomes, while their activation releases Ca(2+) from inositol 1,4,5-trisphosphate-sensitive- and acidic-like Ca(2+) stores. Our results support the functionality of intracellular CB2 receptors and their ability to couple to Gq and elicit Ca(2+) signaling. These findings add further complexity to CB2 receptor pharmacology and argue for careful consideration of receptor localization in the development of CB2-based therapeutic agents. PMID- 25033248 TI - Structure- and concentration-specific assessment of the physiological reactivity of alpha-dicarbonyl glucose degradation products in peritoneal dialysis fluids. AB - In peritoneal dialysis (PD), glucose degradation products (GDPs), which are formed during heat sterilization of dialysis fluids, lead to structural and functional changes in the peritoneal membrane, which eventually result in the loss of its ultrafiltration capacity. To determine the molecular mechanisms behind these processes, the present study tested the influence of the six major alpha-dicarbonyl GDPs in PD fluids, namely, glyoxal, methylglyoxal, 3 deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), and glucosone with respect to their potential to impair the enzymatic activity of RNase A as well as their effects on cell viability. For comprehensive risk assessment, the alpha-dicarbonyl GDPs were applied separately and in concentrations as present in conventional PD fluids. Thus, it was shown that after 5 days, glucosone impaired RNase A activity most distinctly (58% remaining activity, p < 0.001 compared to that of the control), followed by 3,4-DGE (62%, p < 0.001), 3-DGal (66%, p < 0.001), and 3-DG (76%, p < 0.01). Methylglyoxal and glyoxal caused weaker inactivation with significant effects only after 10 days of incubation (79%, 81%, p < 0.001). Profiling of the advanced glycation end products formed during the incubation of RNase A with methylglyoxal revealed predominant formation of the arginine modifications imidazolinone, CEA/dihydroxyimidazoline, and tetrahydropyrimidine at Arg10, Arg33, Arg39, and Arg85. Particularly, modification at Arg39 may severely affect the active site of the enzyme. Additionally, structure- and concentration-specific assessment of the cytotoxicity of the alpha-dicarbonyl GDPs was performed. Although present at very low concentration, the cytotoxic effect of PD fluids after 2 days of incubation was exclusively caused by 3,4-DGE (14% cell viability, p < 0.001). After 4 days of incubation, 3-DGal (13% cell viability, p < 0.001), 3-DG (24%, p < 0.001), and, to a lower extent, glyoxal and methylglyoxal (both 57%, p < 0.01) also reduced cell viability significantly. In conclusion, 3,4-DGE, 3-DGal, and glucosone appear to be the most relevant parameters for the biocompatibility of PD fluids. PMID- 25033249 TI - The ethical imperative to think about thinking - diagnostics, metacognition, and medical professionalism. AB - While the medical ethics literature has well explored the harm to patients, families, and the integrity of the profession in failing to disclose medical errors once they occur, less often addressed are the moral and professional obligations to take all available steps to prevent errors and harm in the first instance. As an expanding body of scholarship further elucidates the causes of medical error, including the considerable extent to which medical errors, particularly in diagnostics, may be attributable to cognitive sources, insufficient progress in systematically evaluating and implementing suggested strategies for improving critical thinking skills and medical judgment is of mounting concern. Continued failure to address pervasive thinking errors in medical decisionmaking imperils patient safety and professionalism, as well as beneficence and nonmaleficence, fairness and justice. We maintain that self reflective and metacognitive refinement of critical thinking should not be construed as optional but rather should be considered an integral part of medical education, a codified tenet of professionalism, and by extension, a moral and professional duty. PMID- 25033250 TI - Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea. AB - RATIONALE: Obstructive sleep apnea (OSA) has been associated with kidney function loss, which may be related to changes in the renin-angiotensin system (RAS). OBJECTIVES: We sought to determine the effect of continuous positive airway pressure (CPAP) of patients with OSA on renal hemodynamics at baseline and in response to angiotensin II (AngII), which reflects RAS activity. METHODS: Twenty normotensive, nondiabetic, newly diagnosed OSA subjects (15 men, 5 women, 50 +/- 2 yr, respiratory disturbance index [RDI] > 15 h(-1)) with nocturnal hypoxemia (SaO2 < 90% for >12% of the night) were studied in high-salt balance pre- and post-CPAP therapy (>4 h CPAP use/night for 1 mo). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) (a surrogate marker for intraglomerular pressure) were measured pre- and post-CPAP using inulin and para-aminohippurate clearance techniques at baseline and in response to graded AngII infusion (3 ng/kg/min * 30 min and 6 ng/kg/min * 30 min, respectively). MEASUREMENTS AND MAIN RESULTS: CPAP corrected OSA and hypoxemia (RDI: 42 +/- 4 vs. 4 +/- 1 h(-1), P < 0.001; duration SaO2 < 90%: 36% +/- 5% vs. 6 +/- 2%, P < 0.001). CPAP reduced GFR (124 +/- 8 ml/min vs. 110 +/- 6 ml/min, P = 0.014), increased RPF (692 +/- 36 ml/min vs. 749 +/- 40 ml/min, P = 0.059), and reduced baseline FF (18.9 +/- 1.6% vs. 15.3 +/- 1.0%, P = 0.004). Post-CPAP demonstrated a blunted GFR response (-9 +/- 3 ml/min vs. -2 +/- 2 ml/min, P = 0.033) and augmented RPF response (-182 +/- 22 ml/min vs. -219 +/- 25 ml/min, P = 0.024) to AngII. FF response was maintained (P = 0.4). CPAP reduced baseline mean arterial pressure (94 +/- 2 vs. 89 +/- 2 mm Hg, P = 0.002), plasma aldosterone (149 +/- 18 vs. 109 +/- 10 pmol/L, P = 0.003), and urinary protein excretion (61 [39-341] mg/day vs. 56 [22-204] mg/d, P = 0.003). CONCLUSIONS: CPAP therapy was associated with improved renal hemodynamics and down-regulation of renal RAS activity, suggesting a potential therapeutic benefit for kidney function. PMID- 25033253 TI - Bronzino and the evolution of a portrait, Barbara Williams, by Gillian M. Dunlop. PMID- 25033254 TI - Jog Your Mind: methodology and challenges of conducting evaluative research in partnership with community organizations. AB - BACKGROUND: Jog Your Mind is a community-based program aiming at empowering elderly people to maintain their cognitive abilities using a multi-strategic approach including cognitively stimulating activities, mnemonic strategies, and strategies to promote healthy behaviors. It is offered to elderly individuals without known or diagnosed cognitive impairment by volunteers or community practitioners over ten weekly sessions. This paper describes the protocol of a quasi-experimental study designed to evaluate Jog Your Mind. METHODS: Community responsible to recruit participants were either assigned to the experimental group (participating in the Jog Your Mind program) or to the control group (one year waiting list). All participants were interviewed at baseline (T1), after the program (T2), and 12 months after the baseline (T3). Primary outcomes were the use of everyday memory strategies and aids and subjective memory functioning in daily life. Secondary outcomes included attitudes, knowledge, and behaviors related to cognitive vitality and cognitive abilities (memory and executive functions). Program delivery, organizational and environmental variables were recorded to document the implementation process. RESULTS: Twenty-three community organizations recruited 294 community-dwelling elderly individuals in total at T1. Between T1 and T3, an attrition rate of 15.2% was obtained. CONCLUSIONS: Jog Your Mind is one of the only programs targeting cognition among older adults being offered in community settings by community practitioners. The protocol described was designed with a focus on maximizing broad generalizations of the results while achieving scientific rigor. It can serve as an example to guide future research aiming to evaluate health interventions under natural conditions. PMID- 25033255 TI - A systematic review of quality of life and sexual function of patients with cervical cancer after treatment. AB - OBJECTIVES: Quality of life (QoL) and sexual health have become increasingly important in cervical cancer survivors (CCSs). The aims of this review were to summarize research findings of QoL and sexual function in CCSs after treatment on the basis of self-reported questionnaires and to update the current knowledge of overall QoL and sexual function in CCSs. METHODS: Studies from electronic database between May 1966 and May 2013 were rated on their internal validity as methodological assessment. Thirty-two studies were included, wherein 15 studies had a relatively good methodology. RESULTS: Anorectal function, urinary symptoms, and lymphedema were commonly reported as physical symptoms. As to psychosocial domains, the studies illustrated that anxiety decreased with age, whereas depression generally increased with age. Sexual function was involved in most of the studies. Vaginal dryness, dyspareunia, short vagina, and sexual dissatisfaction were prominent issues of sexual dysfunction and vaginal changes in CCSs. In terms of treatment modality, radiotherapy was thought to be associated with worse QoL and sexual function in CCSs. CONCLUSIONS: The studies showed that QoL and sexual function in CCSs were compromised compared with the general population to different extents. Quality of life and sexual function should be paid with more attention in patients with cervical cancer after treatment. PMID- 25033256 TI - Preoperative neutrophil-lymphocyte ratio before platelet-lymphocyte ratio predicts clinical outcome in patients with cervical cancer treated with initial radical surgery. AB - OBJECTIVE: Several inflammatory parameters are applied to predict the survival of patients with various cancers. Neutrophil-lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) are 2 nonspecific markers of systemic inflammation. This study aimed to evaluate the clinicopathologic and prognostic values of NLR and PLR in patients with cervical cancer undergoing primary radical hysterectomy with pelvic lymphadenectomy. METHODS: A total of 460 cervical cancer patients were enrolled in this study. These patients were histologically confirmed with cervical cancer from February 2005 to June 2008, at the Department of Gynecology, the Third Affiliated Hospital of Harbin Medical University, China. Their clinical and histopathological markers and complete blood counts were collected and analyzed. Prognostic factors were assessed by univariate and multivariate analyses. RESULTS: The median NLR and PLR were 2.213 and 150.9, respectively. The clinicopathologic analysis showed that NLR was highly associated with depth of stromal infiltration (P = 0.007) and lymph node metastasis (P = 0.003), and PLR was significantly related to tumor size (P = 0.020) and lymph node metastasis (P = 0.027).Univariate analysis identified high NLR as a statistically significant poor predictive factor for the progression-free survival (PFS) (P = 0.008) and overall survival (OS) (P = 0.014), and PLR exhibited no significance on PFS (P = 0.075) and OS (P = 0.110).Multivariable analysis showed that the NLR was an independent prognostic marker for PFS (hazard ratio, 1.799; 95% confidence interval, 1.069-3.028; P = 0.027), but not for OS (hazard ratio, 1.631; 95% confidence interval, 0.968-2.750; P = 0.066). CONCLUSIONS: Preoperative NLR and PLR were found to be correlated to unfavorable histopathologic features of cervical cancer. The preoperative NLR, but not PLR, may be used as a potential and easy biomarker for survival prognosis in patients with cervical cancer receiving initial radical hysterectomy with pelvic lymphadenectomy. PMID- 25033257 TI - Gynecologic Cancer InterGroup (GCIG) consensus review for endometrial stromal sarcoma. AB - Endometrial stromal sarcoma (ESS) accounts for approximately 20% of all uterine sarcomas and presents, at a mean age, around 50 years of age. Half of the patients are premenopausal. ESS often manifests as an endometrial polyp and 60% of cases present with FIGO stage I disease. The natural history is one of slow growing indolent disease. Typical microscopic findings include a uniform population of endometrial stromal-type cells invading the myometrium and myometrial vessels. Imaging studies cannot reliably diagnose ESS preoperatively, so surgical resection for a presumed fibroid is a common scenario. Hysterectomy is the cornerstone of treatment for localized ESS, but morcellation should be avoided. Systematic lymphadenectomy in ESS does not improve the outcome. Leaving the ovaries in situ does not worsen survival and this is of importance especially for young women. The data support the current practice to administer adjuvant hormonal treatment, although several questions remain, such as optimal doses, regimens (progestins or aromatase inhibitors) and duration of therapy. Repeat surgery for recurrent disease that is indolent and hormone sensitive appears to be an acceptable approach. Systemic treatment for recurrent disease is mainly hormonal. PMID- 25033259 TI - A method to test the performance of an energy-dispersive X-ray spectrometer (EDS). AB - A test material for routine performance evaluation of energy-dispersive X-ray spectrometers (EDS) is presented. It consists of a synthetic, thick coating of C, Al, Mn, Cu, and Zr, in an elemental composition that provides interference-free characteristic X-ray lines of similar intensities at 10 kV scanning electron microscope voltage. The EDS energy resolution at the C-K, Mn-Lalpha, Cu-Lalpha, Al-K, Zr-Lalpha, and Mn-Kalpha lines, the calibration state of the energy scale, and the Mn-Lalpha/Mn-Kalpha intensity ratio as a measure for the low-energy detection efficiency are calculated by a dedicated software package from the 10 kV spectrum. Measurements at various input count rates and processor shaping times enable an estimation of the operation conditions for which the X-ray spectrum is not yet corrupted by pile-up events. Representative examples of EDS systems characterized with the test material and the related software are presented and discussed. PMID- 25033258 TI - Posttransplant soluble B-cell activating factor kinetics in pediatric recipients of first kidney allograft. AB - BACKGROUND: Development of de novo donor-specific antibodies (dnDSA) is associated with late or chronic antibody-mediated rejection (CAMR) and poor graft outcome in low-risk kidney transplant recipients. High-level soluble B-cell activating factor (sBAFF) was observed in kidney recipients at higher risk of developing dnDSA. METHODS: We longitudinally analyzed sBAFF levels in 81 consecutive primary pediatric kidney recipients monitored for de novo human leukocyte antigen (HLA) antibody (Ab) occurrence to gain insight into the events conditioning B-cell activation posttransplant and to analyze the usefulness of paired DSA-sBAFF monitoring in this clinical setting. RESULTS: At a median follow up of 65 months, 23 patients (28%) developed dnDSA, with 13 of 23 developing CAMR. Irrespective of HLA Ab status, sBAFF levels progressively increased in all patients in the first posttransplant year, thereafter reaching a plateau. sBAFF levels were influenced by the degree of HLA class I antigen match and donor age. Despite higher levels of sBAFF in HLA Ab-positive patients (median and 95% confidence interval sBAFF in DSA+non-DSA patients: 568, 534-608 pg/mL vs. 502, 422-548 pg/mL in Ab-negative patients; P<0.05), we found that sBAFF monitoring could not predict DSA development by a time to event longitudinal analysis. Moreover, sBAFF kinetics up to CAMR onset could not anticipate CAMR development in the DSA cohort. CONCLUSION: Our findings provide evidence of early posttransplant B-cell activation even in unsensitized recipients of first kidney allograft. The significance of this activation, likely induced by exposition to the allograft, is yet unclear. PMID- 25033260 TI - Surface electromyographic mapping of the orbicularis oculi muscle for real-time blink detection. AB - IMPORTANCE: Facial paralysis is a life-altering condition that significantly impairs function, appearance, and communication. Facial rehabilitation via closed loop pacing represents a potential but as yet theoretical approach to reanimation. A first critical step toward closed-loop facial pacing in cases of unilateral paralysis is the detection of healthy movements to use as a trigger to prosthetically elicit automatic artificial movements on the contralateral side of the face. OBJECTIVES: To test and to maximize the performance of an electromyography (EMG)-based blink detection system for applications in closed loop facial pacing. DESIGN, SETTING, AND PARTICIPANTS: Blinking was detected across the periocular region by means of multichannel surface EMG at an academic neuroengineering and medical robotics laboratory among 15 healthy volunteers. MAIN OUTCOMES AND MEASURES: Real-time blink detection was accomplished by mapping the surface of the orbicularis oculi muscle on one side of the face with a multichannel surface EMG. The biosignal from each channel was independently processed; custom software registered a blink when an amplitude-based or slope based suprathreshold activity was detected. The experiments were performed when participants were relaxed and during the production of particular orofacial movements. An F1 score metric was used to analyze software performance in detecting blinks. RESULTS: The maximal software performance was achieved when a blink was recorded from the superomedial orbit quadrant. At this recording location, the median F1 scores were 0.89 during spontaneous blinking, 0.82 when chewing gum, 0.80 when raising the eyebrows, and 0.70 when smiling. The overall performance of blink detection was significantly better at the superomedial quadrant (F1 score, 0.75) than at the traditionally used inferolateral quadrant (F1 score, 0.40) (P < .05). CONCLUSIONS AND RELEVANCE: Electromyographic recording represents an accurate tool to detect spontaneous blinks as part of closed-loop facial pacing systems. The early detection of blink activity may allow real-time pacing via rapid triggering of contralateral muscles. Moreover, an EMG detection system can be integrated in external devices and in implanted neuroprostheses. A potential downside to this approach involves cross talk from adjacent muscles, which can be notably reduced by recording from the superomedial quadrant of the orbicularis oculi muscle and by applying proper signal processing. LEVEL OF EVIDENCE: NA. PMID- 25033263 TI - Post-walking exercise hypotension in patients with intermittent claudication. AB - PURPOSE: This study aimed to investigate the acute effect of intermittent walking exercise (WE) on blood pressure (BP) responses in patients with intermittent claudication (IC). Secondly, this study aimed to gain improved insight into the physiological mechanisms controlling BP regulation after intermittent WE in this patient group. METHODS: Twenty patients with IC participated in two experimental sessions in a random order, as follows: WE (15 * 2-min bouts of WE interpolated with 2-min rest intervals) and control (standing rest on a treadmill for 60 min). BP, cardiac output (CO: CO2 rebreathing), and cardiovascular autonomic modulation (spectral analysis of HR variability) were assessed before and after both experimental sessions during supine rest, and stroke volume (SV) and systemic vascular resistance (SVR) were calculated. Data were analyzed using two-way ANOVA. RESULTS: WE decreased systolic, diastolic, and mean BP, with net effects of -13 +/- 2, -5 +/- 2, and -7 +/- 2 mm Hg versus control, respectively (all P < 0.05). WE also decreased SV (-5.62 +/- 1.97 mL, P < 0.05) and CO (-0.05 +/- 0.13 L.min(-1), P < 0.05) versus preintervention and prevented the observed increase in SVR in the control condition (+4.2 +/- 1.4 U, P < 0.05). HR showed a decrease (P < 0.05), consistent with evidence of increased vagal modulation, in the control condition. BP measurements over the subsequent 24 h were similar between experimental conditions. CONCLUSIONS: In patients with IC, WE induced a postexercise hypotension response that had a significant magnitude versus control but was not maintained over the next 24 h of daily activities. The acute postexercise hypotension response was mediated by a decrease in CO and SV, which was not compensated by an augmentation of SVR, as observed in the control arm of the study. PMID- 25033262 TI - Analysis of the protein domain and domain architecture content in fungi and its application in the search of new antifungal targets. AB - Over the past several years fungal infections have shown an increasing incidence in the susceptible population, and caused high mortality rates. In parallel, multi-resistant fungi are emerging in human infections. Therefore, the identification of new potential antifungal targets is a priority. The first task of this study was to analyse the protein domain and domain architecture content of the 137 fungal proteomes (corresponding to 111 species) available in UniProtKB (UniProt KnowledgeBase) by January 2013. The resulting list of core and exclusive domain and domain architectures is provided in this paper. It delineates the different levels of fungal taxonomic classification: phylum, subphylum, order, genus and species. The analysis highlighted Aspergillus as the most diverse genus in terms of exclusive domain content. In addition, we also investigated which domains could be considered promiscuous in the different organisms. As an application of this analysis, we explored three different ways to detect potential targets for antifungal drugs. First, we compared the domain and domain architecture content of the human and fungal proteomes, and identified those domains and domain architectures only present in fungi. Secondly, we looked for information regarding fungal pathways in public repositories, where proteins containing promiscuous domains could be involved. Three pathways were identified as a result: lovastatin biosynthesis, xylan degradation and biosynthesis of siroheme. Finally, we classified a subset of the studied fungi in five groups depending on their occurrence in clinical samples. We then looked for exclusive domains in the groups that were more relevant clinically and determined which of them had the potential to bind small molecules. Overall, this study provides a comprehensive analysis of the available fungal proteomes and shows three approaches that can be used as a first step in the detection of new antifungal targets. PMID- 25033264 TI - Aspects of respiratory muscle fatigue in a mountain ultramarathon race. AB - PURPOSE: Ultramarathon running offers a unique possibility to investigate the mechanisms contributing to the limitation of endurance performance. Investigations of locomotor muscle fatigue show that central fatigue is a major contributor to the loss of strength in the lower limbs after an ultramarathon. In addition, respiratory muscle fatigue is known to limit exercise performance, but only limited data are available on changes in respiratory muscle function after ultramarathon running and it is not known whether the observed impairment is caused by peripheral and/or central fatigue. METHODS: In 22 experienced ultra trail runners, we assessed respiratory muscle strength, i.e., maximal voluntary inspiratory and expiratory pressures, mouth twitch pressure (n = 16), and voluntary activation (n = 16) using cervical magnetic stimulation, lung function, and maximal voluntary ventilation before and after a 110-km mountain ultramarathon with 5862 m of positive elevation gain. RESULTS: Both maximal voluntary inspiratory (-16% +/- 13%) and expiratory pressures (-21% +/- 14%) were significantly reduced after the race. Fatigue of inspiratory muscles likely resulted from substantial peripheral fatigue (reduction in mouth twitch pressure, -19% +/- 15%; P < 0.01), as voluntary activation (-3% +/- 6%, P = 0.09) only tended to be decreased, suggesting negligible or only mild levels of central fatigue. Forced vital capacity remained unchanged, whereas forced expiratory volume in 1 s, peak inspiratory and expiratory flow rates, and maximal voluntary ventilation were significantly reduced (P < 0.05). CONCLUSIONS: Ultraendurance running reduces respiratory muscle strength for inspiratory muscles shown to result from significant peripheral muscle fatigue with only little contribution of central fatigue. This is in contrast to findings in locomotor muscles. Whether this difference between muscle groups results from inherent neuromuscular differences, their specific pattern of loading or other reasons remain to be clarified. PMID- 25033266 TI - Diarylethene-containing carbon-rich ruthenium organometallics: tuning of electrochromism. AB - The association of a dithienylethene (DTE) system with ruthenium carbon-rich systems allows reaching sophisticated and efficient light- and electro-triggered multifunctional switches R-[Ru]-C=C-DTE-C=C-[Ru]-R, featuring multicolor electrochromism and electrochemical cyclization at remarkably low voltage. The spin density on the DTE ligand and the energetic stabilization of the system upon oxidation could be manipulated to influence the closing event, owing to the noninnocent behavior of carbon-rich ligands in the redox processes. A combination of spectroscopic (UV-vis-NIR-IR and EPR) and electrochemical studies, with the help of quantum chemical calculations, demonstrates that one can control and get a deeper understanding of the electrochemical ring closure with a slight modification of ligands remote from the DTE unit. This electrochemical cyclization was established to occur in the second oxidized state (EEC mechanism), and the kinetic rate constant in solution was measured. Importantly, these complexes provide an unprecedented experimental means to directly probe the remarkable efficiency of electronic (spin) delocalization between two trans carbon-rich ligands through a metal atom, in full agreement with the theoretical predictions. In addition, when no cyclization occurs upon oxidation, we could achieve a redox-triggered magnetic switch. PMID- 25033265 TI - Free glycogen in vaginal fluids is associated with Lactobacillus colonization and low vaginal pH. AB - OBJECTIVE: Lactobacillus dominates the lower genital tract microbiota of many women, producing a low vaginal pH, and is important for healthy pregnancy outcomes and protection against several sexually transmitted pathogens. Yet, factors that promote Lactobacillus remain poorly understood. We hypothesized that the amount of free glycogen in the lumen of the lower genital tract is an important determinant of Lactobacillus colonization and a low vaginal pH. METHODS: Free glycogen in lavage samples was quantified. Pyrosequencing of the 16S rRNA gene was used to identify microbiota from 21 African American women collected over 8-11 years. RESULTS: Free glycogen levels varied greatly between women and even in the same woman. Samples with the highest free glycogen had a corresponding median genital pH that was significantly lower (pH 4.4) than those with low glycogen (pH 5.8; p<0.001). The fraction of the microbiota consisting of Lactobacillus was highest in samples with high glycogen versus those with low glycogen (median = 0.97 vs. 0.05, p<0.001). In multivariable analysis, having 1 vs. 0 male sexual partner in the past 6 months was negatively associated, while BMI >=30 was positively associated with glycogen. High concentrations of glycogen corresponded to higher levels of L. crispatus and L. jensenii, but not L. iners. CONCLUSION: These findings show that free glycogen in genital fluid is associated with a genital microbiota dominated by Lactobacillus, suggesting glycogen is important for maintaining genital health. Treatments aimed at increasing genital free glycogen might impact Lactobacillus colonization. PMID- 25033269 TI - Inference of equivalence for the ratio of two normal means with unspecified variances. AB - Equivalence trials aim to demonstrate that new and standard treatments are equivalent within predefined clinically relevant limits. We focus on when inference of equivalence is made in terms of the ratio of two normal means. In the presence of unspecified variances, methods such as the likelihood-ratio test use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit the knowledge on the extent to which equivalence is affected by variability of the parameter of interest. In this article, we propose a likelihood approach that retains the unspecified variances in the model and partitions the likelihood function into two components: F-statistic function for variances, and t-statistic function for the ratio of two means. By incorporating unspecified variances, the proposed method can help identify a numeric range of variances where equivalence is more likely to be achieved, which cannot be accomplished by current analysis methods. By partitioning the likelihood function into two components, the proposed method provides more inference information than a method that relies solely on one component. Using a published set of real example data, we show that the proposed method produces the same results as the likelihood-ratio test and is comparable to Bayesian analysis in the general case. In a special case where the ratio of two variances is directly proportional to the ratio of two means, the proposed method yields better results in inference about equivalence than either the likelihood-ratio test or the Bayesian method. Using a published set of real example data, the proposed likelihood method is shown to be a better alternative than current analysis methods for equivalence inference. PMID- 25033267 TI - Influence of ND10 components on epigenetic determinants of early KSHV latency establishment. AB - We have previously demonstrated that acquisition of intricate patterns of activating (H3K4me3, H3K9/K14ac) and repressive (H3K27me3) histone modifications is a hallmark of KSHV latency establishment. The precise molecular mechanisms that shape the latent histone modification landscape, however, remain unknown. Promyelocytic leukemia nuclear bodies (PML-NB), also called nuclear domain 10 (ND10), have emerged as mediators of innate immune responses that can limit viral gene expression via chromatin based mechanisms. Consequently, although ND10 functions thus far have been almost exclusively investigated in models of productive herpesvirus infection, it has been proposed that they also may contribute to the establishment of viral latency. Here, we report the first systematic study of the role of ND10 during KSHV latency establishment, and link alterations in the subcellular distribution of ND10 components to a temporal analysis of histone modification acquisition and host cell gene expression during the early infection phase. Our study demonstrates that KSHV infection results in a transient interferon response that leads to induction of the ND10 components PML and Sp100, but that repression by ND10 bodies is unlikely to contribute to KSHV latency establishment. Instead, we uncover an unexpected role for soluble Sp100 protein, which is efficiently and permanently relocalized from nucleoplasmic and chromatin-associated fractions into the insoluble matrix. We show that LANA expression is sufficient to induce Sp100 relocalization, likely via mediating SUMOylation of Sp100. Furthermore, we demonstrate that depletion of soluble Sp100 occurs precisely when repressive H3K27me3 marks first accumulate on viral genomes, and that knock-down of Sp100 (but not PML or Daxx) facilitates H3K27me3 acquisition. Collectively, our data support a model in which non-ND10 resident Sp100 acts as a negative regulator of polycomb repressive complex-2 (PRC2) recruitment, and suggest that KSHV may actively escape ND10 silencing mechanisms to promote establishment of latent chromatin. PMID- 25033270 TI - Effective automated feature construction and selection for classification of biological sequences. AB - BACKGROUND: Many open problems in bioinformatics involve elucidating underlying functional signals in biological sequences. DNA sequences, in particular, are characterized by rich architectures in which functional signals are increasingly found to combine local and distal interactions at the nucleotide level. Problems of interest include detection of regulatory regions, splice sites, exons, hypersensitive sites, and more. These problems naturally lend themselves to formulation as classification problems in machine learning. When classification is based on features extracted from the sequences under investigation, success is critically dependent on the chosen set of features. METHODOLOGY: We present an algorithmic framework (EFFECT) for automated detection of functional signals in biological sequences. We focus here on classification problems involving DNA sequences which state-of-the-art work in machine learning shows to be challenging and involve complex combinations of local and distal features. EFFECT uses a two stage process to first construct a set of candidate sequence-based features and then select a most effective subset for the classification task at hand. Both stages make heavy use of evolutionary algorithms to efficiently guide the search towards informative features capable of discriminating between sequences that contain a particular functional signal and those that do not. RESULTS: To demonstrate its generality, EFFECT is applied to three separate problems of importance in DNA research: the recognition of hypersensitive sites, splice sites, and ALU sites. Comparisons with state-of-the-art algorithms show that the framework is both general and powerful. In addition, a detailed analysis of the constructed features shows that they contain valuable biological information about DNA architecture, allowing biologists and other researchers to directly inspect the features and potentially use the insights obtained to assist wet laboratory studies on retainment or modification of a specific signal. Code, documentation, and all data for the applications presented here are provided for the community at http://www.cs.gmu.edu/~ashehu/?q=OurTools. PMID- 25033271 TI - Preventing phrenic nerve stimulation by a patch insulation in an intact swine heart model. AB - INTRODUCTION: Phrenic nerve stimulation (PNS) could be prevented by a silastic patch over the epicardial lead. We studied the effects in preventing PNS by placing a silastic patch directly over an epicardial lead or placing a graft around the phrenic nerve (PN). METHODS AND RESULTS: Fourteen Lanyu swine were enrolled. A bipolar lead was placed epicardially on the left ventricle (LV) inferior to the PN. An implantable cardioverter-defibrillator (ICD) lead was placed into the right ventricle (RV). The maximal influential distance (MID) was measured under 3 pacing configurations to express the influential electrical field on the PN. The threshold of the LV and PN were evaluated epicardially. Then, PTFE patches of different sizes (10*10 mm, 20*20 mm and 30*30 mm) were placed between the LV lead and PN to study the rise in PN threshold in 7 swine. On the other hand, the PN were surrounded by a PTFE graft of different lengths (10 mm, 20 mm, and 30 mm) in the remaining 7 swine. LV-bipolar pacing showed the shortest MID when compared to the other 2 unipolar pacing configurations at pacing voltage of 10 V. The patch was most effective in preventing PNS during LV bipolar pacing. PNS was prevented under all circumstances with a larger PTFE patch (30*30 mm) or long graft (30 mm). CONCLUSIONS: PNS was avoided by placing a PTFE patch over the LV lead or a graft around the PN despite pacing configurations. Hence if PNS persisted during CRT implantation, a PTFE patch on the LV lead or a graft around the PN could be considered. PMID- 25033272 TI - Internal consistency of event-related potentials associated with cognitive control: N2/P3 and ERN/Pe. AB - Recent studies in psychophysiology show an increased attention for examining the reliability of Event-Related Potentials (ERPs), which are measures of cognitive control (e.g., Go/No-Go tasks). An important index of reliability is the internal consistency (e.g., Cronbach's alpha) of a measure. In this study, we examine the internal consistency of the N2 and P3 in a Go/No-Go task. Furthermore, we attempt to replicate the previously found internal consistency of the Error-Related Negativity (ERN) and Positive-Error (Pe) in an Eriksen Flanker task. Healthy participants performed a Go/No-Go task and an Eriksen Flanker task, whereby the amplitudes of the correct No-Go N2/P3, and error trials for ERN/Pe were the variables of interest. This study provides evidence that the N2 and P3 in a Go/No Go task are internally consistent after 20 and 14 trials are included in the average, respectively. Moreover, the ERN and Pe become internally consistent after approximately 8 trials are included in the average. In addition guidelines and suggestions for future research are discussed. PMID- 25033274 TI - Disability and HIV: a systematic review and a meta-analysis of the risk of HIV infection among adults with disabilities in Sub-Saharan Africa. AB - More than one billion people worldwide are estimated to be living with a disability. A significant proportion of them lives in Sub-Saharan Africa where they are reported to be at increased risk of HIV. However, quantitative evidence on this remains scarce. A systematic review and a meta-analysis of the risk of HIV infection among people with disabilities living in Sub-Saharan Africa were undertaken. We searched all published or unpublished studies and national surveys reporting HIV prevalence among adults with disabilities living in Sub-Saharan Africa between 2000 and 2013. The risk ratio (RR) of HIV infection in people with disabilities versus people without disabilities was estimated through a random effects meta-analysis. Of the 12,252 references screened, 13 studies were selected. HIV prevalence varied widely across studies from 1.1% to 29%. Pooled RRs of HIV infection in people with disabilities compared to the general population were 1.31 (1.02-1.69) overall; 1.16 (0.71-1.87) among people with mental illness or intellectual disabilities and 1.07 (0.58-1.95) among people with hearing disabilities. This meta-analysis provides evidence that people with disabilities do not have a lower risk of HIV when compared to the general population, and that women with disabilities are especially affected. A clear increasing gradient in the risk of HIV according to gender and disability status was also observed. The important heterogeneity across studies and their varying quality warrant a closer look at the intersection between disability and HIV. Additional studies with more systematic approaches and with higher-quality methodologies are required to further address this knowledge gap. PMID- 25033273 TI - Toxicity of parasporin-4 and health effects of pro-parasporin-4 diet in mice. AB - Parasporin-4 (PS4) is an aerolysin-type beta-pore-forming toxin produced by Bacillus thuringiensis strain A1470. It exhibits specific cytotoxicity against human cancer cell lines; therefore, it is expected to be useful for the diagnosis and treatment of particular types of cancer cells. We examined the acute toxicity of PS4 on ICR mice. The LD50 value was 160 MUg/kg by a subcutaneous route. Potassium, ammonium, magnesium ion, creatinine, and urea nitrogen decreased in urine by the injection of PS4. Simultaneously, creatinine and urea nitrogen in mice serum increased. These results imply that PS4 impairs kidney function in mice. PS4 is obtained from Pro-parasporin-4 (ProPS4) by processing, and ProPS4 is produced by recombinant Escherichia coli as the inclusion body. The inclusion body of ProPS4 can be solubilized in a weak acid solution and activated by pepsin, implying that it would be solubilized and activated in the stomach of mammals after oral administration. Thus, the influence of the oral administration of it by C57BL/6J mice was examined. Although ProPS4 was activated to PS4 in the mouse digestive tract, any serious health hazard was not observed and there was no significant difference in body weight change. PMID- 25033275 TI - Factors predicting adherence to antidepressant treatment. AB - PURPOSE OF REVIEW: Poor adherence and discontinuation of treatment are the major challenges of pharmacotherapy among patients with depression. This article reviews the factors predicting adherence to and persistence of antidepressant treatment identified in recent years. RECENT FINDINGS: Study populations have been extended to subgroups of patients with depression or depressive patients with comorbid medical conditions. Some studies have investigated the issues by analysing medical claims databases. Socio-demographic variables, clinical features of depression, comorbidities, pharmacological factors, attitudes towards antidepressants, previous experiences of antidepressant treatment, patient professional relationship and genes were found to be common factors. An older age, positive attitudes to antidepressants and previous experiences and vicarious experiences of depression or treatment were found to be factors predicting better adherence or persistence. Conversely, patients in minority groups, those with a low family income, pregnancy, experience of side effects, dissatisfaction with treatment and a poor patient-professional relationship were found to be associated with poorer adherence or persistence. SUMMARY: The factors predicting adherence and persistence are complex and interactive. Different methods of studies have limitations in terms of exploring all these factors. Future studies should integrate these factors simultaneously and explore specific factors predicting adherence and persistence among subgroups of patients with depression. PMID- 25033276 TI - Prevention of domestic violence against women and children in low-income and middle-income countries. AB - PURPOSE OF REVIEW: Violence against women and children is increasingly recognized as an important and urgent public health, social and human rights issue cutting across geographical, socioeconomic and cultural boundaries. There is a large and growing body of literature that demonstrates the negative impact of such violence on the victim's mental and physical health, as well as several other consequences on them, their families and communities. However, this literature for the most part comes from the so-called 'developed countries'. This review, at the opposite, focused on current literature on prevention of domestic/family violence against children and women in low and middle income countries (LMICs). RECENT FINDINGS: Establishing effective prevention programmes for domestic violence against women and children in LMICs requires an understanding of the sociopolitical, economic and cultural settings and a multilevel collaboration among various stakeholders. SUMMARY: This review confirms the lack of research in the so-called 'developing countries' and provides suggestions for further research and prevention efforts in this setting. PMID- 25033279 TI - Accounting for heterogeneity among treatment sites and time trends in developing crash modification functions. AB - Collision modification factors (CMFs) are commonly used to quantify the impact of safety countermeasures. The CMFs obtained from observational before-after (BA) studies are usually estimated by averaging the safety impact (i.e., index of effectiveness) for a group of treatment sites. The heterogeneity among the treatment locations, in terms of their characteristics, and the effect of this heterogeneity on safety treatment effectiveness are usually ignored. This is in contrast to treatment evaluations in other fields like medical statistics where variations in the magnitude (or in the direction) of response to the same treatment given to different patients are considered. This paper introduces an approach for estimating a CMFunction from BA safety studies that account for variable treatment location characteristics (heterogeneity). The treatment sites heterogeneity was incorporated into the CMFunction using fixed-effects and random effects regression models. In addition to heterogeneity, the paper also advocates the use of CMFunctions with a time variable to acknowledge that the safety treatment (intervention) effects do not occur instantaneously but are spread over future time. This is achieved using non-linear intervention (Koyck) models, developed within a hierarchical full Bayes (FB) context. To demonstrate the approach, a case study is presented to evaluate the safety effectiveness of the "Signal Head Upgrade Program" recently implemented in the city of Surrey (British Columbia, Canada), where signal visibility was improved at several urban signalized intersections. The results demonstrated the importance of considering treatment sites heterogeneity and time trends when developing CMFunctions. PMID- 25033282 TI - Preference for male traits differ in two female morphs of the tree lizard, Urosaurus ornatus. AB - Non-random female mating preferences may contribute to the maintenance of phenotypic variation in color polymorphic species. However, the effect of female preference depends on the types of male traits used as signals by receptive females. If preference signals derive from discrete male traits (i.e., morph specific), female preferences may rapidly fix to a morph. However, female preference signals may also include condition-dependent male traits. In this scenario, female preference may differ depending on the social context (i.e., male morph availability). Male tree lizards (Urosaurus ornatus) exhibit a dewlap color polymorphism that covaries with mating behavior. Blue morph males are aggressive and defend territories, yellow males are less aggressive and defend smaller territories, and orange males are typically nomadic. Female U. ornatus are also polymorphic in dewlap color, but the covariation between dewlap color and female behavior is unknown. We performed an experiment to determine how female mate choice depends on the visual and chemical signals produced by males. We also tested whether female morphs differ in their preferences for these signals. Female preferences involved both male dewlap color and size of the ventral color patch. However, the female morphs responded to these signals differently and depended on the choice between the types of male morphs. Our experiment revealed that females may be capable of distinguishing among the male morphs using chemical signals alone. Yellow females exhibit preferences based on both chemical and visual signals, which may be a strategy to avoid ultra-dominant males. In contrast, orange females may prefer dominant males. We conclude that female U. ornatus morphs differ in mating behavior. Our findings also provide evidence for a chemical polymorphism among male lizards in femoral pore secretions. PMID- 25033281 TI - Current approaches and recent developments in the management of head and neck paragangliomas. AB - Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors belonging to the family of pheochromocytoma/paraganglioma neoplasms. Despite advances in understanding the pathogenesis of these tumors, the growth potential and clinical outcome of individual cases remains largely unpredictable. Over several decades, surgical resection has long been the treatment of choice for HNPGLs. However, increasing experience in various forms of radiosurgery has been reported to result in curative-like outcomes, even for tumors localized in the most inaccessible anatomical areas. The emergence of such new therapies challenges the traditional paradigm for the management of HNPGLs. This review will assist and guide physicians who encounter patients with such tumors, either from a diagnostic or therapeutic standpoint. This review will also particularly emphasize current and emerging knowledge in genetics, imaging, and therapeutic options as well as the health-related quality of life for patients with HNPGLs. PMID- 25033283 TI - Bird fruit preferences match the frequency of fruit colours in tropical Asia. AB - While many factors explain the colour of fleshy fruits, it is thought that black and red fruits are common in part because frugivorous birds prefer these colours. We examined this still controversial hypothesis at a tropical Asian field site, using artificial fruits, fresh fruits, four wild-caught resident frugivorous bird species, and hand-raised naive birds from three of the same species. We demonstrate that all birds favored red artificial fruits more than yellow, blue, black and green, although the artificial black colour was found subsequently to be similar to the artificial blue colour in its spectral reflectance. Wild-caught birds preferred both black and red fleshy natural fruits, whereas hand-raised naive birds preferred black to red natural fleshy fruits and to those of other colours. All birds avoided artificial and naturally ripe green fruits. The inter individual variation in colour choice was low and the preferences were constant over time, supporting the hypothesis that bird colour preferences are a contributing factor driving fruit colour evolution in tropical Asia. PMID- 25033284 TI - Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. AB - The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions. PMID- 25033285 TI - Follow-Up Visit Patterns in an Antiretroviral Therapy (ART) programme in Zomba, Malawi. AB - BACKGROUND: Identifying follow-up (FU) visit patterns, and exploring which factors influence them are likely to be useful in determining which patients on antiretroviral therapy (ART) may become Lost to Follow-Up (LTFU). Using an operation and implementation research approach, we sought 1) to describe the timing of FU visits amongst patients who have been on ART for shorter and longer periods of time; and 2) to determine the median time to late visits, and 3) to identify specific factors that may be associated with these patterns in Zomba, Malawi. METHODS AND FINDINGS: Using routinely collected programme monitoring data from Zomba District, we performed descriptive analyses on all ART visits among patients who initiated ART between Jan. 1, 2007-June 30, 2010. Based on an expected FU date, each FU visit was classified as early (>=4 day before an expected FU date), on time (3 days before an expected FU date/up to 6 days after an expected FU date), or late (>=7 days after an expected FU date). In total, 7,815 patients with 76417 FU visits were included. Ninety-two percent of patients had >=2 FU visits. At the majority of visits, patients were either on time or late. The median time to a first late visit among those with 2 or more visits was 216 days (IQR: 128-359). Various patient- and visit-level factors differed significantly across Early, On Time, and Late visit groups including ART adherence and frequency of, and type of side effects. DISCUSSION: The majority of patients do not demonstrate consistent FU visit patterns. Individuals were generally on ART for at least 6 months before experiencing their first late visit. Our findings have implications for the development of effective interventions that meet patient needs when they present early and can reduce patient losses to follow-up when they are late. In particular, time-varying visit characteristics need further research. PMID- 25033286 TI - Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. AB - Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors. PMID- 25033287 TI - Can serum levels of alkaline phosphatase and phosphate predict cardiovascular diseases and total mortality in individuals with preserved renal function? A systemic review and meta-analysis. AB - BACKGROUND: It is demonstrated that elevated serum levels of alkaline phosphatase (ALP) and phosphate indicate a higher risks of cardiovascular disease (CVD) and total mortality in population with chronic kidney disease (CKD), but it remains unclear whether this association exists in people with normal or preserved renal function. METHOD: Clinical trials were searched from Embase and PubMed from inception to 2013 December using the keywords "ALP", "phosphate", "CVD", "mortality" and so on, and finally 24 trials with a total of 147634 patients were included in this study. Dose-response and semi-parametric meta-analyses were performed. RESULTS: A linear association of serum levels of ALP and phosphate with risks of coronary heart disease (CHD) events, CVD events and deaths was identified. The relative risk (RR) of ALP for CVD deaths was 1.02 (95% confidence interval [CI], 1.01-1.04). The RR of phosphate for CVD deaths and events was 1.05 (95% CI, 1.02-1.09) and 1.04 (95% CI: 1.03-1.06), respectively. A non-linear association of ALP and phosphate with total mortality was identified. Compared with the reference category of ALP and phosphate, the pooled RR of ALP for total mortality was 1.57 (95% CI, 1.27-1.95) for the high ALP group, while the RR of phosphate for total mortality was 1.33 (95% CI, 1.21-1.46) for the high phosphate group. It was observed in subgroup analysis that higher levels of serum ALP and phosphate seemed to indicate a higher mortality rate in diabetic patients and those having previous CVD. The higher total mortality rate was more obvious in the men and Asians with high ALP. CONCLUSION: A non-linear relationship exists between serum levels of ALP and phosphate and risk of total mortality. There appears to be a positive association of serum levels of ALP/phosphate with total mortality in people with normal or preserved renal function, while the relationship between ALP and CVD is still ambiguous. PMID- 25033288 TI - Bioinformatic analysis of proteomics data. AB - Most biochemical reactions in a cell are regulated by highly specialized proteins, which are the prime mediators of the cellular phenotype. Therefore the identification, quantitation and characterization of all proteins in a cell are of utmost importance to understand the molecular processes that mediate cellular physiology. With the advent of robust and reliable mass spectrometers that are able to analyze complex protein mixtures within a reasonable timeframe, the systematic analysis of all proteins in a cell becomes feasible. Besides the ongoing improvements of analytical hardware, standardized methods to analyze and study all proteins have to be developed that allow the generation of testable new hypothesis based on the enormous pre-existing amount of biological information. Here we discuss current strategies on how to gather, filter and analyze proteomic data sates using available software packages. PMID- 25033289 TI - Chronic granulomatous otitis externa as an initial presentation of cutaneous Crohn disease. AB - IMPORTANCE: In the limited number of Crohn disease cases involving the head and neck, there is a predilection for mucosal surfaces and rare reports of involvement in the postauricular region. To our knowledge, in all previously reported cases involving the head and neck, the patients had a known diagnosis of Crohn disease. OBSERVATIONS: This case describes a 10-year-old boy with a history of psoriasis and psoriasiform dermatitis who presented with bilateral chronic granulomatous otitis externa, obliteration of the external auditory canal, and fissuring, resulting in separation of the lobule from the preauricular skin. CONCLUSIONS AND RELEVANCE: Pathologic examination results were consistent with granulomatous dermatitis concerning for cutaneous Crohn disease, and a subsequent gastroenterologic workup confirmed the diagnosis of Crohn disease. This is a report of chronic granulomatous otitis as the initial presentation of cutaneous Crohn disease in a child. PMID- 25033290 TI - Glaucocalyxin A: a review. AB - Glaucocalyxin A is a natural ent-Kaurane diterpenoid. It has been widely studied for some important biological activities like cytotoxicity and anti-tumour, anti bacterial, anti-oxidative, anti-coagulative, anti-thrombotic, immune and anti neuroinflammatory activities. The aim of the present article is to review the available information on Glaucocalyxin A including sources, biological activities and derivatives and also have a look at the future perspectives. PMID- 25033291 TI - Praziquantel, mefloquine-praziquantel, and mefloquine-artesunate-praziquantel against Schistosoma haematobium: a randomized, exploratory, open-label trial. AB - BACKGROUND: Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel. Hence, there is a pressing need to develop additional therapeutics against schistosomiasis. The antimalarial drug mefloquine shows antischistosomal activity in animal models and clinical trials, which calls for further investigations. METHODOLOGY: We comparatively assessed the efficacy and tolerability of the following treatments against Schistosoma haematobium in school-aged children in Cote d'Ivoire: (i) praziquantel (40 mg/kg; standard treatment); (ii) mefloquine (25 mg/kg) combined with praziquantel (40 mg/kg); and (iii) mefloquine-artesunate (3* (100 mg artesunate +250 mg mefloquine)) combined with praziquantel (40 mg/kg) (treatments administered on subsequent days). Two urine samples were collected before, and on days 21-22 and 78-79 after the first dosing. PRINCIPAL FINDINGS: Sixty-one children were present on all examination time points and had complete datasets. No difference in efficacy was observed between the three treatment groups on either follow-up. On the 21-22 day posttreatment follow-up, based on available case analysis, cure rates of 33% (95% confidence interval (CI) 11-55%), 29% (95% CI 8-50%), and 26% (95% CI 5-48%) were observed for praziquantel, mefloquine-artesunate-praziquantel, and mefloquine praziquantel, respectively. The corresponding egg reduction rates were 94% and above. On the second follow-up, observed cure rates ranged from 19% (praziquantel) to 33% (mefloquine-artesunate-praziquantel), and egg reduction rates were above 90%. Praziquantel monotherapy was the best tolerated treatment. In the mefloquine-artesunate-praziquantel group, adverse events were reported by 91% of the participants, and in the mefloquine-praziquantel group, 95% experienced adverse events. With the exception of abdominal pain at moderate severity, adverse events were mild. CONCLUSIONS/SIGNIFICANCE: The addition of mefloquine or mefloquine-artesunate does not increase the efficacy of praziquantel against chronic S. haematobium infection. Additional studies are necessary to elucidate the effect of the combinations against acute schistosomiasis. PMID- 25033292 TI - Fearfulness affects quail maternal care and subsequent offspring development. AB - Our study investigated relationships between a precocial bird's fearfulness and maternal care, and the implication of maternal care as a vector for non-genomic transmission of fearfulness to chicks. We compared care given to chicks between two sets of female Japanese quail selected to present either high (LTI) or low fearfulness (STI). Chicks, from a broiler line, were adopted by these females following a sensitization procedure. Chicks' fearfulness after separation from their mother was assessed by well-established procedures. LTIs took longer to present maternal responses, pecked chicks more during the first days post-hatch, presented impaired maternal vocal behaviour and were globally less active than STI females. Chicks mothered by LTIs presented more fearful reactions than did chicks mothered by STIs, supporting the hypothesis of a non-genetic maternal transmission of fearfulness. We suggest that the longer latencies required by LTIs to become maternal are a consequence of their greater fear of chicks, and that their lower general and vocal activity could be components of a heightened antipredatory strategy. We discuss the transmission of maternal fearfulness to fostered chicks, taking into account the possible implication of several well known mechanisms underlying maternal effects. PMID- 25033293 TI - Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse. AB - Previous analysis of the Cerberus like 2 knockout (Cerl2-/-) mouse revealed a significant mortality during the first day after birth, mostly due to cardiac defects apparently associated with randomization of the left-right axis. We have however, identified Cerl2-associated cardiac defects, particularly a large increase in the left ventricular myocardial wall in neonates that cannot be explained by laterality abnormalities. Therefore, in order to access the endogenous role of Cerl2 in cardiogenesis, we analyzed the embryonic and neonatal hearts of Cerl2 null mutants that did not display a laterality phenotype. Neonatal mutants obtained from the compound mouse line Cer2-/-::Mlc1v-nLacZ24+, in which the pulmonary ventricle is genetically marked, revealed a massive enlargement of the ventricular myocardium in animals without laterality defects. Echocardiography analysis in Cerl2-/- neonates showed a left ventricular systolic dysfunction that is incompatible with a long lifespan. We uncovered that the increased ventricular muscle observed in Cerl2-/- mice is caused by a high cardiomyocyte mitotic index in the compact myocardium which is mainly associated with increased Ccnd1 expression levels in the left ventricle at embryonic day (E) 13. Interestingly, at this stage we found augmented left ventricular expression of Cerl2 levels when compared with the right ventricle, which may elucidate the regionalized contribution of Cerl2 to the left ventricular muscle formation. Importantly, we observed an increase of phosphorylated Smad2 (pSmad2) levels in embryonic (E13) and neonatal hearts indicating a prolonged TGFbetas/Nodal signaling activation. Concomitantly, we detected an increase of Baf60c levels, but only in Cerl2-/- embryonic hearts. These results indicate that independently of its well-known role in left-right axis establishment Cerl2 plays an important role during heart development in the mouse, mediating Baf60c levels by exerting an important control of the TGFbetas/Nodal-signaling pathway. PMID- 25033294 TI - The neuro-ecology of Drosophila pupation behavior. AB - Many species of Drosophila form conspecific pupa aggregations across the breeding sites. These aggregations could result from species-specific larval odor recognition. To test this hypothesis we used larval odors of D. melanogaster and D. pavani, two species that coexist in the nature. When stimulated by those odors, wild type and vestigial (vg) third-instar larvae of D. melanogaster pupated on conspecific larval odors, but individuals deficient in the expression of the odor co-receptor Orco randomly pupated across the substrate, indicating that in this species, olfaction plays a role in pupation site selection. Larvae are unable to learn but can smell, the Syn97CS and rut strains of D. melanogaster, did not respond to conspecific odors or D. pavani larval cues, and they randomly pupated across the substrate, suggesting that larval odor-based learning could influence the pupation site selection. Thus, Orco, Syn97CS and rut loci participated in the pupation site selection. When stimulated by conspecific and D. melanogaster larval cues, D. pavani larvae also pupated on conspecific odors. The larvae of D. gaucha, a sibling species of D. pavani, did not respond to D. melanogaster larval cues, pupating randomly across the substrate. In nature, D. gaucha is isolated from D. melanogaster. Interspecific hybrids, which result from crossing pavani female with gaucha males clumped their pupae similarly to D. pavani, but the behavior of gaucha female x pavani male hybrids was similar to D. gaucha parent. The two sibling species show substantial evolutionary divergence in organization and functioning of larval nervous system. D. melanogaster and D. pavani larvae extracted information about odor identities and the spatial location of congener and alien larvae to select pupation sites. We hypothesize that larval recognition contributes to the cohabitation of species with similar ecologies, thus aiding the organization and persistence of Drosophila species guilds in the wild. PMID- 25033295 TI - Larger mammalian body size leads to lower retroviral activity. AB - Retroviruses have been infecting mammals for at least 100 million years, leaving descendants in host genomes known as endogenous retroviruses (ERVs). The abundance of ERVs is partly determined by their mode of replication, but it has also been suggested that host life history traits could enhance or suppress their activity. We show that larger bodied species have lower levels of ERV activity by reconstructing the rate of ERV integration across 38 mammalian species. Body size explains 37% of the variance in ERV integration rate over the last 10 million years, controlling for the effect of confounding due to other life history traits. Furthermore, 68% of the variance in the mean age of ERVs per genome can also be explained by body size. These results indicate that body size limits the number of recently replicating ERVs due to their detrimental effects on their host. To comprehend the possible mechanistic links between body size and ERV integration we built a mathematical model, which shows that ERV abundance is favored by lower body size and higher horizontal transmission rates. We argue that because retroviral integration is tumorigenic, the negative correlation between body size and ERV numbers results from the necessity to reduce the risk of cancer, under the assumption that this risk scales positively with body size. Our model also fits the empirical observation that the lifetime risk of cancer is relatively invariant among mammals regardless of their body size, known as Peto's paradox, and indicates that larger bodied mammals may have evolved mechanisms to limit ERV activity. PMID- 25033296 TI - DNA/protein interaction and cytotoxic activity of imidazole terpyridine derived Cu(II)/Zn(II) metal complexes. AB - Two imidazole terpyridine (itpy) based complexes, [Cu(itpy)(OAc)(H2O)]NO3.H2O (1) and [Zn(itpy)(OAc)]OAc (2) have been synthesised and characterized. The crystal structure of complex 1 shows distorted octahedral geometry with an anti-parallel stacking arrangement. The interactions of the two complexes with Calf thymus DNA (ctDNA) have been studied using absorption titration and circular dichroism. Complex 1 shows coordinate binding to DNA bases, and complex 2 shows an intercalative mode of binding with DNA. Complex 1 cleaves the DNA via an oxidative pathway in the presence of additives, because of the presence of a redox active copper(II) centre. However, complex 2 cleaves DNA hydrolytically. Interactions of the two complexes with bovine serum albumin have been studied using fluorescence quenching and circular dichroism experiments. Circular dichroic analysis reveals that both the complexes strongly influence the secondary structure of the protein. Fluorescence quenching experiments indicate that there are different binding sites for complexes 1 and 2 on the protein. Furthermore, the complexes show potential cytotoxicity towards the A549 lung cancer cell line. Both the complexes have been found to induce apoptosis. PMID- 25033297 TI - Deeper understanding of mechanisms contributing to sepsis-induced myocardial dysfunction. AB - The inflammatory response of sepsis results in organ dysfunction, including myocardial dysfunction. Myocardial dysfunction is particularly important in patients with severe septic shock who progress to a hypodynamic pre-terminal phase. Multiple aspects of this septic inflammatory response contribute to the pathogenesis of decreased ventricular contractility. Inflammatory cytokines released by inflammatory cells contribute as does nitric oxide released by vascular endothelium and by cardiomyocytes. Endotoxins and other pathogen molecules induce an intramyocardial inflammatory response by binding Toll-like receptors on cardiomyocytes that then signal via NF-kappaB. These processes alter cardiomyocyte depolarization and, therefore, contractility. The particular role of the cardiomyocyte sodium current has not been characterized. Now new information suggests that the septic inflammatory response impairs normal depolarization by altering the cardiomyocyte sodium current. This results in decreased ventricular contractility. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated. PMID- 25033300 TI - Polymer-grafted multiwall carbon nanotubes functionalized by nitrene chemistry: effect on cooperativity and phase miscibility. AB - The demixing of polystyrene (PS) and poly(vinyl methylether) (PVME) was systematically investigated in the presence of surface functionalized multiwall carbon nanotubes (MWNTs) by melt rheology. As PS-PVME blends are weakly interacting blends, the contribution of conformational entropy increases, resulting in thermo-rheological complexity wherein the concentration fluctuation persists even beyond the critical demixing temperature. These phenomenal changes were followed here in the presence of MWNTs with different surface functional groups. Polystyrene was synthesised by atom transfer radical polymerization and was immobilized onto carboxyl acid functionalized multiwall carbon nanotubes (COOH-MWNTs) via nitrene chemistry in order to improve the phase miscibility in PS-PVME blends. Interestingly, blends with 0.25 wt% polystyrene grafted multiwall carbon nanotubes (PS-g-MWNTs) delayed the spinodal decomposition temperature in the blends by ~33 degrees C with respect to both control blends and those with COOH-MWNTs. While the localization of COOH-MWNTs in PVME was explained from a thermodynamic point of view, the localization of PS-g-MWNTs was understood to result from favorable PS-PVME contact and the degree of surface coverage of PS on the surface of MWNTs. The length of the cooperative rearranging region (xi) decreased in presence of PS-g-MWNTs, suggesting confinement effects on large scale motions and enhanced interchain concentration fluctuation. PMID- 25033299 TI - Unraveling the stratification of an iron-oxidizing microbial mat by metatranscriptomics. AB - A metatranscriptomic approach was used to study community gene expression in a naturally occurring iron-rich microbial mat. Total microbial community RNA was reversely transcribed and sequenced by pyrosequencing. Characterization of expressed gene sequences provided accurate and detailed information of the composition of the transcriptionally active community and revealed phylogenetic and functional stratifications within the mat. Comparison of 16S rRNA reads and delineation of OTUs showed significantly lower values of metatranscriptomic-based richness and diversity in the upper parts of the mat than in the deeper regions. Taxonomic affiliation of rRNA sequences and mRNA genome recruitments indicated that iron-oxidizing bacteria affiliated to the genus Leptothrix, dominated the community in the upper layers of the mat. Surprisingly, type I methanotrophs contributed to the majority of the sequences in the deep layers of the mat. Analysis of mRNA expression patterns showed that genes encoding the three subunits of the particulate methane monooxygenase (pmoCAB) were the most highly expressed in our dataset. These results provide strong hints that iron-oxidation and methane-oxidation occur simultaneously in microbial mats and that both groups of microorganisms are major players in the functioning of this ecosystem. PMID- 25033298 TI - Signaling domain of Sonic Hedgehog as cannibalistic calcium-regulated zinc peptidase. AB - Sonic Hedgehog (Shh) is a representative of the evolutionary closely related class of Hedgehog proteins that have essential signaling functions in animal development. The N-terminal domain (ShhN) is also assigned to the group of LAS proteins (LAS = Lysostaphin type enzymes, D-Ala-D-Ala metalloproteases, Sonic Hedgehog), of which all members harbor a structurally well-defined Zn2+ center; however, it is remarkable that ShhN so far is the only LAS member without proven peptidase activity. Another unique feature of ShhN in the LAS group is a double Ca2+ center close to the zinc. We have studied the effect of these calcium ions on ShhN structure, dynamics, and interactions. We find that the presence of calcium has a marked impact on ShhN properties, with the two calcium ions having different effects. The more strongly bound calcium ion significantly stabilizes the overall structure. Surprisingly, the binding of the second calcium ion switches the putative catalytic center from a state similar to LAS enzymes to a state that probably is catalytically inactive. We describe in detail the mechanics of the switch, including the effect on substrate co-ordinating residues and on the putative catalytic water molecule. The properties of the putative substrate binding site suggest that ShhN could degrade other ShhN molecules, e.g. by cleavage at highly conserved glycines in ShhN. To test experimentally the stability of ShhN against autodegradation, we compare two ShhN mutants in vitro: (1) a ShhN mutant unable to bind calcium but with putative catalytic center intact, and thus, according to our hypothesis, a constitutively active peptidase, and (2) a mutant carrying additionally mutation E177A, i.e., with the putative catalytically active residue knocked out. The in vitro results are consistent with ShhN being a cannibalistic zinc-peptidase. These experiments also reveal that the peptidase activity depends on pH. PMID- 25033301 TI - Leishmania amazonensis amastigotes highly express a tryparedoxin peroxidase isoform that increases parasite resistance to macrophage antimicrobial defenses and fosters parasite virulence. AB - Professional phagocytes generate a myriad of antimicrobial molecules to kill invading microorganisms, of which nitrogen oxides are integral in controlling the obligate intracellular pathogen Leishmania. Although reactive nitrogen species produced by the inducible nitric oxide synthase (iNOS) can promote the clearance of intracellular parasites, some Leishmania species/stages are relatively resistant to iNOS-mediated antimicrobial activity. The underlying mechanism for this resistance remains largely uncharacterized. Here, we show that the amastigote form of L. amazonensis is hyper-resistant to the antimicrobial actions of cytokine-activated murine and human macrophages as compared to its promastigote counterpart. Amastigotes exhibit a marked ability to directly counter the cytotoxicity of peroxynitrite (ONOO-), a leishmanicidal oxidant that is generated during infection through the combined enzymatic activities of NADPH oxidase and iNOS. The enhanced antinitrosative defense of amastigotes correlates with the increased expression of a tryparedoxin peroxidase (TXNPx) isoform that is also upregulated in response to iNOS enzymatic activity within infected macrophages. Accordingly, ectopic over-expression of the TXNPx isoform by L. amazonensis promastigotes significantly enhances parasite resistance against ONOO cytotoxicity. Moreover, TXNPx-overexpressing parasites exhibit greater intra macrophage survival, and increased parasite growth and lesion development in a murine model of leishmaniasis. Our investigations indicate that TXNPx isoforms contribute to Leishmania's ability to adapt to and antagonize the hostile microenvironment of cytokine-activated macrophages, and provide a mechanistic explanation for persistent infection in experimental and human leishmaniasis. PMID- 25033302 TI - Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review. AB - Acute respiratory distress syndrome (ARDS) continues to have significant mortality and morbidity. The only intervention proven to reduce mortality is the use of lung-protective mechanical ventilation strategies, although such a strategy may lead to problematic hypercapnia. Extracorporeal carbon dioxide removal (ECCO2R) devices allow uncoupling of ventilation from oxygenation, thereby removing carbon dioxide and facilitating lower tidal volume ventilation. We performed a systematic review to assess efficacy, complication rates, and utility of ECCO2R devices. We included randomised controlled trials (RCTs), case control studies and case series with 10 or more patients. We searched MEDLINE, Embase, LILACS (Literatura Latino Americana em Ciencias da Saude), and ISI Web of Science, in addition to grey literature and clinical trials registries. Data were independently extracted by two reviewers against predefined criteria and agreement was reached by consensus. Outcomes of interest included mortality, intensive care and hospital lengths of stay, respiratory parameters and complications. The review included 14 studies with 495 patients (two RCTs and 12 observational studies). Arteriovenous ECCO2R was used in seven studies, and venovenous ECCO2R in seven studies. Available evidence suggests no mortality benefit to ECCO2R, although post hoc analysis of data from the most recent RCT showed an improvement in ventilator-free days in more severe ARDS. Organ failure free days or ICU stay have not been shown to decrease with ECCOvR. Carbon dioxide removal was widely demonstrated as feasible, facilitating the use of lower tidal volume ventilation. Complication rates varied greatly across the included studies, representing technological advances. There was a general paucity of high quality data and significant variation in both practice and technology used among studies, which confounded analysis. ECCO2R is a rapidly evolving technology and is an efficacious treatment to enable protective lung ventilation. Evidence for a positive effect on mortality and other important clinical outcomes is lacking. Rapid technological advances have led to major changes in these devices and together with variation in study design have limited applicability of analysis. Further well-designed adequately powered RCTs are needed. PMID- 25033303 TI - Tinnitus and its association with psychiatric disorders: systematic review. AB - OBJECTIVES: To systematically review the literature on the occurrence of psychiatric diagnoses in a tinnitus-affected population, and correlate the presence of psychiatric disorders with tinnitus-related annoyance and severity. METHOD: A systematic review of the literature published between January 2000 and December 2012 was performed using PubMed, ISI Web of Science and SciELO databases. Original articles in English and Portuguese that focused on the diagnosis of mental disorders associated with tinnitus, especially anxiety and depression, were identified. RESULTS: A total of 153 articles were found and 16 were selected. Fifteen articles showed a high prevalence of psychiatric disorders in tinnitus-affected patients, and nine showed a high correlation between the presence of a psychiatric disorder and tinnitus-related annoyance and severity. CONCLUSION: The prevalence of psychiatric disorders, especially anxiety and depression, is high in tinnitus patients, and the presence of these disorders correlates with tinnitus-related annoyance and severity. PMID- 25033304 TI - One-step synthesis of "rattle-like" polymer particles via suspension polymerization. AB - Multiple polymer particles encapsulated in a polymer shell are applied in electrophoretic ink. We demonstrate a simple one-step polymerization of polymer capsules containing small particles (rattle-like particles). In the obtained capsules, encapsulated particles independently dispersed and moved in response to the electric field. PMID- 25033305 TI - Multistimuli-responsive supramolecular vesicles based on water-soluble pillar[6]arene and SAINT complexation for controllable drug release. AB - Supramolecular binary vesicles based on the host-guest complexation of water soluble pillar[6]arene (WP6) and SAINT molecule have been successfully constructed, which showed pH-, Ca(2+)-, and thermal-responsiveness. These supramolecular vesicles can efficiently encapsulate model substrate calcein, which then can be efficiently released either by adjusting the solution pH to acidic condition due to the complete disruption of vesicular structure, or particularly, by adding a certain amount of Ca(2+) due to the Ca(2+)-induced vesicle fusion and accompanied by the structure disruption. More importantly, drug loading and releasing experiments demonstrate that an anticancer drug, DOX, can be successfully encapsulated by the supramolecular vesicles, and the resulting DOX-loaded vesicles exhibit efficient release of the encapsulated DOX with the pH adjustment or the introduction of Ca(2+). Cytotoxicity experiments suggest that the resulting DOX-loaded supramolecular vesicles exhibit comparable therapeutic effect for cancer cells as free DOX and the remarkably reduced damage for normal cells as well. The present multistimuli-responsive supramolecular vesicles have great potential applications in the field of controlled drug delivery. In addition, giant supramolecular vesicles (~3 MUm) with large internal volume and good stability can be achieved by increasing the temperature of WP6 ? SAINT vesicular solution, and they might have potential applications for bioimaging. PMID- 25033306 TI - Leadership: workforce management research in wound care. PMID- 25033307 TI - Preconference workshops offer exciting new sessions. PMID- 25033309 TI - Have you read the National Correct Coding Initiative Policy Manual for Medicare Services? PMID- 25033310 TI - The use of PriMatrix, a fetal bovine acellular dermal matrix, in healing chronic diabetic foot ulcers: a prospective multicenter study. AB - OBJECTIVE: The objective of this multicenter study was to prospectively evaluate the healing outcomes of chronic diabetic foot ulcers (DFUs) treated with PriMatrix (TEI Biosciences, Boston, Massachusetts), a fetal bovine acellular dermal matrix. METHODS: Inclusion criteria required the subjects to have a chronic DFU that ranged in area from 1 to 20 cm2 and failed to heal more than 30% during a 2-week screening period when treated with moist wound therapy. For qualifying subjects, PriMatrix was secured into a clean, sharply debrided wound; dressings were applied to maintain a moist wound environment, and the DFU was pressure off-loaded. Wound area measurements were taken weekly for up to 12 weeks, and PriMatrix was reapplied at the discretion of the treating physician. RESULTS: A total of 55 subjects were enrolled at 9 US centers with 46 subjects progressing to study completion. Ulcers had been in existence for an average of 286 days, and initial mean ulcer area was 4.34 cm2. Of the subjects completing the study, 76% healed by 12 weeks with a mean time to healing of 53.1 +/- 21.9 days. The mean number of applications for these healed wounds was 2.0 +/- 1.4, with 59.1% healing with a single application of PriMatrix and 22.9% healing with 2 applications. For subjects not healed by 12 weeks, the average wound area reduction was 71.4%. CONCLUSION: The results of this multicenter prospective study demonstrate that the use of PriMatrix integrated with standard-of-care therapy is a successful treatment regimen to heal DFUs. PMID- 25033311 TI - Psychometric properties of the Dutch National Prevalence Measurement of Care Problems used to measure quality of pressure ulcer care in Indonesian hospitals. AB - OBJECTIVE: To evaluate the psychometric properties of the Indonesian version of the Dutch National Prevalence Measurement of Care Problems. The questionnaire consists of 6 parts: patient characteristics (including pressure ulcer [PrU] risk; assessed by the Braden Scale) and care dependency (assessed by the Care Dependency Scale [CDS]), PrU categorization, prevention, treatment, and structural quality indicators at ward and hospital level. DESIGN, PARTICIPANTS, AND SETTING: A 3-phase design was used, including questionnaire translation and psychometric testing. The questionnaire was translated into Indonesian on March 2012. Content validity was assessed by 18 Indonesian experts on July 2012. The interrater agreement and reliability of the PrU categories, Braden Scale, and CDS were assessed on October 2012 in 4 Indonesian large public general hospitals. RESULTS: Most Indonesian experts (91.8%) rated the Indonesian version of the questionnaire as "good" on clarity of wording. The content validity indices of the questionnaire ranged from 0.50 to 1.00. The PrU categories assessed showed an interrater reliability of kappa = 0.92 (95% confidence interval [CI], 0.87-0.97) and an interrater agreement of po = 98.6% (95% CI, 97.5-99.3). The interrater reliability intraclass correlation coefficient (1,1) of the Braden Scale sum score was 0.90 (95% CI, 0.85-0.93). The exact proportion of agreement sum score was 39%. The interrater reliability intraclass correlation coefficient (1,1) of the CDS sum score was 0.88 (95% CI, 0.83-0.92). There was a 45% exact agreement on the CDS sum scores. CONCLUSIONS: The questionnaire can be used in Indonesian hospitals to measure the PrU prevalence and quality of PrU care. PMID- 25033312 TI - 2014 survey results: wound care and prevention. AB - The results of the 2012 Wound Care Survey are presented. A total of 647 nurses participated in this follow-up to the 2005 survey conducted by the authors. PMID- 25033314 TI - Meaningful Use: October 1, 2014 is the final deadline to meet Meaningful Use Stage 1. PMID- 25033315 TI - Light induced carbon dioxide reduction by water at binuclear ZrOCo(II) unit coupled to Ir oxide nanocluster catalyst. AB - An all-inorganic polynuclear unit consisting of an oxo-bridged binuclear ZrOCo(II) group coupled to an iridium oxide nanocluster (IrO(x)) was assembled on an SBA-15 silica mesopore surface. A photodeposition method was developed that affords coupling of the IrO(x) water oxidation catalyst with the Co donor center. The approach consists of excitation of the ZrOCo(II) metal-to-metal charge transfer (MMCT) chromophore with visible light in the presence of [Ir(acac)3] (acac: acetylacetonate) precursor followed by calcination under mild conditions, with each step monitored by optical and infrared spectroscopy. Illumination of the MMCT chromophore of the resulting ZrOCo(II)-IrO(x) units in the SBA-15 pores loaded with a mixture of (13)CO2 and H2O vapor resulted in the formation of (13)CO and O2 monitored by FT-IR and mass spectroscopy, respectively. Use of (18)O labeled water resulted in the formation of (18)O2 product. This is the first example of a closed photosynthetic cycle of carbon dioxide reduction by water using an all-inorganic polynuclear cluster featuring a molecularly defined light absorber. The observed activity implies successful competition of electron transfer between the IrO(x) catalyst cluster and the transient oxidized Co donor center with back electron transfer of the ZrOCo light absorber, and is further aided by the instant desorption of the CO and O2 product from the silica pores. PMID- 25033316 TI - Macrocyclic influences in CO2 uptake and stabilization. AB - Two 24-member diamine-tetraamido macrocycles (R = H and CH3), readily synthesized in one or two steps, were found to react with CO2 rapidly and efficiently (100% conversion within 1 min at rt). The resulting carbamate formation was demonstrated by (1)H, (13)C NMR, ESI-MS, and X-ray crystallography. The crystal structure clearly showed the carbamate group (N-CO2(-)) formed was tightly bound within the macrocyclic cavity, held by five internal hydrogen bonds, and stabilized by intramolecular carbamate-ammonium salt-bridge formation. PMID- 25033317 TI - Substrate-sensitive mid-infrared photoresponse in graphene. AB - We report mid-infrared photocurrent spectra of graphene nanoribbon arrays on SiO2 dielectrics showing dual signatures of the substrate interaction. First, hybrid polaritonic modes of graphene plasmons and dielectric surface polar phonons produce a thermal photocurrent in graphene with spectral features that are tunable by gate voltage, nanoribbon width, and light polarization. Second, phonon polaritons associated with the substrate are excited, which indirectly heat up the graphene, leading to a graphene photocurrent with fixed spectral features. Models for other commonly used substrates show that the responsivity of graphene infrared photodetectors can be tailored to specific mid-IR frequency bands by the choice of the substrate. PMID- 25033318 TI - Synthesis of methyl 2-cyano-3,12-dioxo-18beta-olean-1,9(11)-dien-30-oate analogues to determine the active groups for inhibiting cell growth and inducing apoptosis in leukemia cells. AB - Fourteen of the methyl 2-cyano-3,12-dioxo-18beta-olean-1,9(11)-dien-30-oate (CDODO-Me-12, 10d) analogues with different structures of ring C were synthesized to determine the active groups for inhibiting cell growth and inducing apoptosis in human leukemia HL-60 cells. An unsaturated group in ring C was required to maintain the ability to inhibit cell growth and induce apoptosis. Compound 10e with 9(11),12-dien in ring C displayed comparable apoptosis induction ability to 10d associated with decreased levels of c-FLIP, but not Mcl-1 and XIAP. Compound 10e had decreased ability to deplete GSH compared to compound 10d. Compound 10e represents a new active compound acting through a different mechanism from that of compound 10d. PMID- 25033319 TI - Automated combustion accelerator mass spectrometry for the analysis of biomedical samples in the low attomole range. AB - The increasing role of accelerator mass spectrometry (AMS) in biomedical research necessitates modernization of the traditional sample handling process. AMS was originally developed and used for carbon dating, therefore focusing on a very high precision but with a comparably low sample throughput. Here, we describe the combination of automated sample combustion with an elemental analyzer (EA) online coupled to an AMS via a dedicated interface. This setup allows direct radiocarbon measurements for over 70 samples daily by AMS. No sample processing is required apart from the pipetting of the sample into a tin foil cup, which is placed in the carousel of the EA. In our system, up to 200 AMS analyses are performed automatically without the need for manual interventions. We present results on the direct total (14)C count measurements in <2 MUL human plasma samples. The method shows linearity over a range of 0.65-821 mBq/mL, with a lower limit of quantification of 0.65 mBq/mL (corresponding to 0.67 amol for acetaminophen). At these extremely low levels of activity, it becomes important to quantify plasma specific carbon percentages. This carbon percentage is automatically generated upon combustion of a sample on the EA. Apparent advantages of the present approach include complete omission of sample preparation (reduced hands-on time) and fully automated sample analysis. These improvements clearly stimulate the standard incorporation of microtracer research in the drug development process. In combination with the particularly low sample volumes required and extreme sensitivity, AMS strongly improves its position as a bioanalysis method. PMID- 25033321 TI - Effect of cooking on meat proteins: mapping hydrothermal protein modification as a potential indicator of bioavailability. AB - Thermal treatment of meat proteins induces a range of observable and molecular level changes. In order to understand and track these heat-induced modifications at the amino acid level, various analytical techniques were used. Changes were observed both in the soluble and in the insoluble fractions after hydrothermal treatment of minced beef samples. Redox proteomics clearly indicated increasing oxidative modification of proteins with increased heat exposure. Collagens in the soluble fraction and myosin in the insoluble fraction were found to be highly susceptible to such modifications. Maillard reaction products in the insoluble and pyrrolidone formation in the soluble fraction steadily increased with increased heat exposure. Fluorescence studies indicated a rapid increase in fluorescence with heat, suggesting the formation of advanced glycation end products. Overall these results provide a deeper understanding of the effect of cooking on meat proteins and the possible relationship to processing conditions in meat-derived food. PMID- 25033320 TI - Taima (stop) TB: the impact of a multifaceted TB awareness and door-to-door campaign in residential areas of high risk for TB in Iqaluit, Nunavut. AB - BACKGROUND: The incidence rate of active tuberculosis (TB) disease in the Canadian Territory of Nunavut has shown a rising trend over the past 10 years. In 2010 it was 60 times greater than the national incidence rate. The objective of the Taima (translates to "stop" in Inuktitut) TB study was to implement and evaluate a public health campaign to enhance existing TB prevention efforts in Nunavut. METHODS: A TB awareness campaign followed by a door-to-door screening campaign was carried out in Iqaluit, Nunavut. The aim of the campaign was to raise awareness about TB, and to provide in-home screening and treatment for people living in residential areas at high risk for TB. Screening was based on geographic location rather than on individual risk factors. RESULTS: During the general awareness campaign an increase in the number of people who requested TB testing at the local public health clinic was observed. However, this increase was not sustained following cessation of the awareness campaign. Targeted TB screening in high risk residential areas in Iqaluit resulted in 224 individuals having TSTs read, and detection of 42 previously unidentified cases of latent TB, (overall yield of 18.8% or number needed to screen = 5.3). These cases of latent TB infection (LTBI) were extra cases that had not been picked up by traditional screening practices (34% relative increase within the community). This resulted in a 33% relative increase in the completion of LTBI treatment within the community. The program directly and indirectly identified 5/17 new cases of active TB disease in Iqaluit during the study period (29.5% of all incident cases). CONCLUSIONS: While contact tracing investigations remain a cornerstone of TB prevention, additional awareness, screening, and treatment programs like Taima TB may contribute to the successful control of TB in Aboriginal communities. PMID- 25033322 TI - Indocyanine green video-angiography in neurosurgery: a glance beyond vascular applications. AB - OBJECTIVE: Indocyanine green video angiography (ICG-VA) is a non invasive, easy to use and a very useful tool for various neurosurgical procedures. Initially introduced in vascular neurosurgery since 2003, it's applications have broadened over time, both in vascular applications and in other neurosurgical fields. The objective of our study is to review all published literature about ICG-VA, cataloguing its different applications. METHODS: A systematic review of all pertinent literature articles published from January 2003 to May 2014 using Pubmed access was performed using pertinent keywords; cross check of references of selected articles was performed in order to complete bibliographical research. Results of research were grouped by pathology. RESULTS AND CONCLUSIONS: The paper systematically analyses ICG-VA different applications in neurosurgery, from vascular neurosurgery to tumor resection and endoscopic applications, focusing on reported advantages and disadvantages, and discussing future perspectives. PMID- 25033323 TI - Lead tolerance mechanism in sterilized seedlings of Potamogeton crispus L.: subcellular distribution, polyamines and proline. AB - The effects of increasing concentrations of lead (Pb) on malondialdehyde (MDA) content, soluble protein, Pb accumulation, nutrients, polyamines (PAs) and proline metabolism were investigated in sterilized seedlings of Potamogeton crispus L. after 5d exposure. Significant oxidative stress was not caused, indicated by a little induction of MDA content and soluble proteins. Pb accumulation increased in a concentration-dependent manner and most of Pb was stored in the cell wall. Total P, Mg, Na and Zn rose and total Fe fell; total Ca increased at 25 MUM Pb but then declined. The nutrients in cell wall fraction changed in the same pattern as total nutrients, whereas those in soluble and organelle fraction declined. Total putrescine (Put) decreased markedly, while total spermidine (Spd), spermine (Spm) and (Spd+Spm)/Put ratio increased progressively but then declined. The trends for free, perchloric acid soluble conjugated (PS-conjugated) and perchloric acid insoluble bound (PIS-bound) PAs were similar to those on total PAs, except that PIS-bound Spm increased significantly. Arginine decarboxylase (ADC) and ornithine decarboxylase (ODC) activities rose gradually, while diamine oxidase (DAO) initially increased but then declined. Proline content increased initially only to decline later, due to the increase of r-glutamyl kinase (GK) activity. Meanwhile, ornithine-d aminotransferase (OAT) activity gradually reduced, while no significant change was observed in proline dehydrogenase (PDH) activity. Our results indicated that the tolerance of P. crispus to Pb stress was based on cell wall compartmentalization combined with increase of nutrients, alterations of PAs, and induction of proline. PMID- 25033324 TI - A specific pilot-scale membrane hybrid treatment system for municipal wastewater treatment. AB - A specifically designed pilot-scale hybrid wastewater treatment system integrating an innovative equalizing reactor (EQ), rotating hanging media bioreactor (RHMBR) and submerged flat sheet membrane bioreactor (SMBR) was evaluated for its effectiveness in practical, long-term, real-world applications. The pilot system was operated at a constant flux, but with different internal recycle flow rates (Q) over a long-term operating of 475 days. At 4 Q internal recycle flow rate, BOD5, CODCr, NH4(+)-N, T-N, T-P and TSS was highly removed with efficiencies up to 99.88 +/- 0.05%, 95.01 +/- 1.62%, 100%, 90.42 +/- 2.43%, 73.44 +/- 6.03%, and 99.93 +/- 0.28%, respectively. Furthermore, the effluent quality was also superior in terms of turbidity (<1 NTU), color (<15 TCU) and taste (inoffensive). The results indicated that with providing only chemically cleaned-in-place (CIP) during the entire period of operation, the membrane could continuously maintain a constant permeate flux of 22.77 +/- 2.19 L/m(2)h. In addition, the power consumption was also found to be reasonably low (0.92-1.62 k Wh/m(3)). PMID- 25033325 TI - Thermo-resistant green microalgae for effective biodiesel production: isolation and characterization of unialgal species from geothermal flora of Central Anatolia. AB - Oil content and composition, biomass productivity and adaptability to different growth conditions are important parameters in selecting a suitable microalgal strain for biodiesel production. Here, we describe isolation and characterization of three green microalgal species from geothermal flora of Central Anatolia. All three isolates, namely, Scenedesmus sp. METUNERGY1402 (Scenedesmus sp. ME02), Hindakia tetrachotoma METUNERGY1403 (H. tetrachotoma ME03) and Micractinium sp. METUNERGY1405 (Micractinium sp. ME05) are adaptable to growth at a wide temperature range (25-50 degrees C). Micractinium sp. ME05, particularly has superior properties for biodiesel production. Biomass productivity, lipid content and lipid productivity of this isolate are 0.17 g L(-1) d(-1), 22.7% and 0.04 g L(-1) d(-1), respectively. In addition, Micractinium sp. ME05 and Scenedesmus sp. ME03 mainly contain desirable fatty acid methyl esters (i.e. 16:0, 16:1, 18:0 and 18:1) for biodiesel production. All isolates can further be improved via genetic and metabolic engineering strategies. PMID- 25033326 TI - Methane production and energy evaluation of a farm scaled biogas plant in cold climate area. AB - The aim of this study was to investigate the specific methane production and the energy balance at a small farm scaled mesophilic biogas plant in a cold climate area. The main substrate was dairy cow slurry. Fish silage was used as co substrate for two of the three test periods. Energy production, substrate volumes and thermal and electric energy consumption was monitored. Methane production depended mainly on type and amount of substrates, while energy consumption depended mainly on the ambient temperature. During summer the main thermal energy consumption was caused by heating of new substrates, while covering for thermal energy losses from digester and pipes required most thermal energy during winter. Fish silage gave a total energy production of 1623 k Wh/m(3), while the dairy cow slurry produced 79 k Wh/m(3) slurry. Total energy demand at the plant varied between 26.9% and 88.2% of the energy produced. PMID- 25033327 TI - Determination of surface-accessible acidic hydroxyls and surface area of lignin by cationic dye adsorption. AB - A new colorimetric method for determining the surface-accessible acidic lignin hydroxyl groups in lignocellulose solid fractions was developed. The method is based on selective adsorption of Azure B, a basic dye, onto acidic hydroxyl groups of lignin. Selectivity of adsorption of Azure B on lignin was demonstrated using lignin and cellulose materials as adsorbents. Adsorption isotherms of Azure B on wheat straw (WS), sugarcane bagasse (SGB), oat husk, and isolated lignin materials were determined. The maximum adsorption capacities predicted by the Langmuir isotherms were used to calculate the amounts of surface-accessible acidic hydroxyl groups. WS contained 1.7-times more acidic hydroxyls (0.21 mmol/g) and higher surface area of lignin (84 m(2)/g) than SGB or oat husk materials. Equations for determining the amount of surface-accessible acidic hydroxyls in solid fractions of the three plant materials by a single point measurement were developed. A method for high-throughput characterization of lignocellulosic materials is now available. PMID- 25033328 TI - Hydrolysis and composition of recovered fibres fractionated from solid recovered fuel. AB - Fibres fractionated from solid recovered fuel (SRF), a standardised market combustion fuel produced from sorted waste, were considered as a source of lignocellulosic fermentable sugars. The fibre yield from four samples of SRF was 25-45%, and the separated material consisted of 52-54% carbohydrates, mainly glucan, with a high content of ash (12-17%). The enzymatic digestibility of recovered fibres was studied at low and high solids loading and compared with model substrates containing only chemical and mechanical pulps. Above 80% hydrolysis yield was reached at 20% solids loading in 48 h, but variation was observed between different samples of recovered fibres. Surfactants were found to improve the hydrolysis yield of recovered fibres especially in tumbling-type of mixing at low solids loading, where hydrolysis was found to stagnate without surfactants. The results suggest that SRF is a potential source of easily digestible lignocellulosic carbohydrates for use in biorefineries. PMID- 25033329 TI - Polyelectrolyte-triggered transformation of various types of AgBr microstructures into AgBr nanophotocatalysts with a single shape and size. AB - AgBr nanostructures with unified shapes and sizes were prepared using simple polyelectrolyte (PE) coatings on various AgBr microstructures that were prepared by mixing silver precursors with hexadecyltrimethylammonium bromide (CTAB) under controlled conditions. The AgBr microstructures (plates, rods, and wires), regardless of initial structures or sizes, transformed into cubic AgBr nanoparticles (CNPs) after only three PE coatings. The electrostatic interactions between the PEs and the CTAB in the AgBr microstructures are the crucial factors that control the shapes and sizes of the AgBr microstructures. During the PE coating, the AgBr microstructures were transformed and rearranged into AgBr CNPs with favorable catalytic faces that enhanced the photocatalytic activity. The size- and shape-controlled AgBr CNPs showed excellent photocatalytic performance for the degradation of methylene orange (MO) dyes under visible-light irradiation without deterioration even after multiple uses. PMID- 25033330 TI - Looking at human cytosolic sialidase NEU2 structural features with an interdisciplinary approach. AB - Circular dichroism (CD) spectra at variable temperatures have been recorded for human cytosolic sialidase NEU2 in buffered water solutions and in the presence of divalent cations. The results show the prevalence of beta-strands together with a considerable amount of alpha-helical structure, while in the solid state, from both previous X-ray diffraction analysis and our CD data on film samples, the content of beta-strands is higher. In solution, a significant change in CD spectra occurs with an increase in temperature, related to a decrease in alpha helix content and a slight increase in beta-strand content. In the same range of temperatures, the enzymatic activity decreases. Although the overall structure of the protein appears to be particularly stable, molecular dynamics simulations performed at various temperatures evidence local conformational changes possibly relevant for explaining the relative lability of enzymatic activity. PMID- 25033331 TI - Growth parameters of Penicillium expansum calculated from mixed inocula as an alternative to account for intraspecies variability. AB - The aim of this work was to compare the radial growth rate (MU) and the lag time (lambda) for growth of 25 isolates of Penicillium expansum at 1 and 20 oC with those of the mixed inoculum of the 25 isolates. Moreover, the evolution of probability of growth through time was also compared for the single strains and mixed inoculum. Working with a mixed inoculum would require less work, time and consumables than if a range of single strains has to be used in order to represent a given species. Suitable predictive models developed for a given species should represent as much as possible the behavior of all strains belonging to this species. The results suggested, on one hand, that the predictions based on growth parameters calculated on the basis of mixed inocula may not accurately predict the behavior of all possible strains but may represent a percentage of them, and the median/mean values of MU and lambda obtained by the 25 strains may be substituted by the value obtained with the mixed inoculum. Moreover, the predictions may be biased, in particular, the predictions of lambda which may be underestimated (fail-safe). Moreover, the prediction of time for a given probability of growth through a mixed inoculum may not be accurate for all single inocula, but it may represent 92% and 60% of them at 20 and 1 oC, respectively, and also their overall mean and median values. In conclusion, mixed inoculum could be a good alternative to estimate the mean or median values of high number of isolates, but not to account for those strains with marginal behavior. In particular, estimation of radial growth rate, and time for 0.10 and 0.50 probability of growth using a cocktail inoculum accounted for the estimates of most single isolates tested. For the particular case of probability models, this is an interesting result as for practical applications in the food industry the estimation of t10 or lower probability may be required. PMID- 25033333 TI - Patient informed choice for altruism. AB - Respect for persons protects patients regarding their own healthcare decisions. Patient informed choice for altruism (PICA) is a proposed means for a fully autonomous patient with decisionmaking capacity to limit his or her own treatment for altruistic reasons. An altruistic decision could bond the patient with others at the end of life. We contend that PICA can also be an advance directive option. The proxy, family, and physicians must be reminded that a patient's altruistic treatment refusal should be respected. PMID- 25033332 TI - Divergent functions of Toll-like receptors during bacterial lung infections. AB - Lower respiratory tract infections caused by bacteria are a major cause of death in humans irrespective of sex, race, or geography. Indeed, accumulated data indicate greater mortality and morbidity due to these infections than cancer, malaria, or HIV infection. Successful recognition of, followed by an appropriate response to, bacterial pathogens in the lungs is crucial for effective pulmonary host defense. Although the early recruitment and activation of neutrophils in the lungs is key in the response against invading microbial pathogens, other sentinels, such as alveolar macrophages, epithelial cells, dendritic cells, and CD4(+) T cells, also contribute to the elimination of the bacterial burden. Pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide binding oligomerization domain-like receptors, are important for recognizing and responding to microbes during pulmonary infections. However, bacterial pathogens have acquired crafty evasive strategies to circumvent the pattern recognition receptor response and thus establish infection. Increased understanding of the function of TLRs and evasive mechanisms used by pathogens during pulmonary infection will deepen our knowledge of immunopathogenesis and is crucial for developing effective therapeutic and/or prophylactic measures. This review summarizes current knowledge of the multiple roles of TLRs in bacterial lung infections and highlights the mechanisms used by pathogens to modulate or interfere with TLR signaling in the lungs. PMID- 25033336 TI - Gift horse. PMID- 25033337 TI - Davies and Welch draw unfounded conclusions about thyroid cancer from epidemiological data. PMID- 25033338 TI - Gift horse-reply. PMID- 25033339 TI - Davies and Welch draw unfounded conclusions about thyroid cancer from epidemiological data-reply. PMID- 25033340 TI - Assembly mechanisms of specialized core particles of the proteasome. AB - The 26S proteasome has a highly complicated structure comprising the 20S core particle (CP) and the 19S regulatory particle (RP). Along with the standard CP in all eukaryotes, vertebrates have two more subtypes of CP called the immunoproteasome and the thymoproteasome. The immunoproteasome has catalytic subunits beta1i, beta2i, and beta5i replacing beta1, beta2, and beta5 and enhances production of major histocompatibility complex I ligands. The thymoproteasome contains thymus-specific subunit beta5t in place of beta5 or beta5i and plays a pivotal role in positive selection of CD8+ T cells. Here we investigate the assembly pathways of the specialized CPs and show that beta1i and beta2i are incorporated ahead of all the other beta-subunits and that both beta5i and beta5t can be incorporated immediately after the assembly of beta3 in the absence of beta4, distinct from the assembly of the standard CP in which beta subunits are incorporated in the order of beta2, beta3, beta4, beta5, beta6, beta1, and beta7. The propeptide of beta5t is a key factor for this earlier incorporation, whereas the body sequence seems to be important for the earlier incorporation of beta5i. This unique feature of beta5t and beta5i may account for preferential assembly of the immunoproteasome and the thymoproteasome over the standard type even when both the standard and specialized subunits are co expressed. PMID- 25033341 TI - Prevalence of dementia and factors associated with dementia in rural Bangladesh: data from a cross-sectional, population-based study. AB - BACKGROUND: There are currently no published reports of dementia prevalence or factors associated with dementia occurrence in Bangladesh. The aims are to report the prevalence of definite and questionable dementia in rural Bangladesh, and examine factors potentially associated with dementia occurrence, including sociodemographic, clinical, social, and nutritional factors. METHODS: We used data from a population-based, cross-sectional study from Matlab, in rural Bangladesh, on 471 persons aged 60+ years. Participants underwent a clinical examination including diagnosis of somatic disorders, and a structured interview including questions about sociodemographic and social factors. Nutritional status was measured with the Mini Nutritional Assessment, and blood tests were conducted to assess a range of nutritional and clinical aspects. Age- and sex-specific dementia prevalence was calculated. Crude and adjusted logistic regression was used to examine associations between dementia and clinical, social, and nutritional factors. Dementia was diagnosed using a two-step procedure by physicians according to DSM-IV criteria. RESULTS: The prevalence of questionable dementia was 11.5% and definite dementia was 3.6%. Dementia prevalence increased with increasing years of age (adjusted OR: 1.04; 95% CI = 1.002-1.1) and decreased with more years of education (adjusted OR: 0.8; 95% CI = 0.6-0.99). Being malnourished increased the odds of dementia almost six-fold (adjusted OR: 5.9; 95% CI = 1.3-26.3), while frequent participation in social activities was associated with a decreased odds (adjusted OR: 0.5; 95% CI = 0.2-0.9). CONCLUSIONS: The prevalence of dementia in rural Bangladesh is similar to other countries in the South Asia region, but lower than reports from other world regions. Malnutrition is strongly associated with dementia occurrence, and is a relevant area for future research within low-income countries. PMID- 25033342 TI - Evaluation of retention forces and resistance to fatigue of attachment systems for overdentures: plastic and metal components. AB - PURPOSE: To compare retention forces of 3 overdenture attachment systems with metal and plastic components. MATERIALS AND METHODS: Four samples of each system evaluated (Ball-Attachment [metal]; O-Ring, and ERA [plastic]) were prepared and underwent fatigue and retention force in a universal testing machine. Maximum retention force (N) was measured at 6 time points (from 0 to 36 months-0.5 mm/min). Two-way analysis of variance and the Tukey test were used (alpha = 0.05). RESULTS: The Ball-Attachment group showed the highest retention values, statistically greater than the other systems, without differences during the trial (42.75-44.75). The ERA group had intermediate values and a statistically significant decrease during the trial (20.75-14). The lowest retention forces were found for the O-Ring group (13.75-11.75), with no statistical differences during the trial. CONCLUSION: Retention forces are significantly affected by abutment type because the metal retainer was more retentive than plastics, possibly providing better fixation of the prosthesis in position, and more difficult to remove. After 6 months of simulation, retentiveness of both plastic components was similar. There was no fracture of any component. PMID- 25033344 TI - Bridging a dichotomy. PMID- 25033343 TI - In vitro assessment of mandibular single/two implant-retained overdentures using stress-breaking attachments. AB - OBJECTIVE: This study investigated the strain surround implants and the pressure distribution of the alveolar ridge related to implant overdentures with stress breaking ball (SBB) attachments. METHODS: Simulation models of edentulous mandibles were embedded with 1 and 2 implants to simulate a single implant retained overdenture (S-IOD) and a two-implant-retained overdenture (T-IOD), respectively. The implants were connected to the denture base with the following conditions: complete separation between the denture base and implant with cover screws as a conventional complete denture (CD), 3 types of settlements with an SBB attachment between them, and a conventional ball attachment (BALL). Strain surround the implant, pressure at 5 different soft tissue areas, and displacement of the denture base were measured with loading up to 50 N. RESULTS: In S-IOD and T-IOD, the strain of each SBB attachment was less than the strain shown by the BALL. The pressure at each region of the SBB attachment was less than the pressure shown with the CD and BALL. CONCLUSIONS: SBB attachments prevented strain surround the implants in loading and provided optimal stress distribution. PMID- 25033345 TI - Implant-supported fixed prosthesis in a hypohidrotic ectodermal dysplasia patient: a case report with 3 years follow-up and review of the literature. AB - INTRODUCTION: Ectodermal dysplasia (ED) is a rare inherited disorder that affects structures derived from embryonic ectoderm. Due to associated ridge deficiency, and anodontia found in these patients, multiple surgeries are often indicated before replacement of missing teeth with implants, resulting in increased morbidity and treatment time. MATERIALS AND METHODS: In this case report, a 31 year-old woman was transitioned from failing tooth-supported fixed restorations to a fully implant-supported fixed prosthesis using immediate implants and narrow diameter implants (NDI). By using some of her existing dentition to support the provisional restorations while osseointegration took place, the patient was able to retain function during treatment. Full-fixed implant-supported prostheses were delivered, providing an esthetic and functional outcome that has been maintained for 3 years. CONCLUSION: In ED patients, NDI together with immediate implant placement can be used successfully to support a complete fixed restoration and should be considered as an alternative to major reconstruction surgeries. Key factors associated with increased predictability are discussed together with a review of the literature. PMID- 25033346 TI - Implant associated soft tissue defects in the anterior maxilla: a randomized control trial comparing subepithelial connective tissue graft and acellular dermal matrix allograft. AB - INTRODUCTION: This randomized controlled clinical pilot trial compared the efficacy of 2 soft tissue grafting methods for correcting esthetic discrepancies associated with definitively restored implant crowns. METHODS: Thirteen patients presenting with implants displaying recession, thin biotype, concavity defects, or a combination thereof associated with single crowned dental implants randomly received subepithelial connective tissue grafts (SCTG) in the control group (N = 7) or acellular dermal matrix (ADM) allografts in the test group (N = 6), both under coronally positioned flaps. Data regarding soft tissue, hard tissue, esthetics, and quality of life (QoL) parameters were collected over 6 months. RESULTS: Both groups gained tissue thickness (SCTG: 63% and ADM: 105%), reduced concavity measures (SCTG: 82% and ADM: 96%), and improved recessions (SCTG: 40% and ADM: 28%) from baseline to 6 months. Clinicians determined improvement in esthetics for both groups (P = 0.001), unlike patients who did not change their esthetic ratings. No statistical differences were noted for QoL assessment; however, ADM subjects had more eventful wound healing (P = 0.021). CONCLUSIONS: Within the limitations of this study, both SCTG and ADM result in increased mucosal thickness, reduction in concavity dimensions, and have a potential for recession reduction on definitively restored dental implants. PMID- 25033347 TI - Osteogenic ability according to the decalcified modality of auto-tooth bone grafts in peri-implant defects in dogs. AB - PURPOSE: The purpose of this study was to evaluate the bone generation capacity of the autotransplantation material with clinical and histological analyses after controlled acid treatment conditions. MATERIAL AND METHODS: Bony defects were formed in the femur. Then, autotransplantation material was grafted after hydroxyapatite-coated implant placement. Experimental groups were classified according to the acid treatment method: 2% H2SO4 (group 1), 2% HCl (group 2), 2% HNO3 (group 3), or 2% ethylenediaminetetraacetic acid (EDTA) (group 4). RESULTS: The new bone formation area and bone-implant contact (BIC) of the autotransplantation materials were measured after 8 weeks. The new bone formation area in experimental groups 2, 3, and 4 were greater than that in the control group (no graft) and in experimental group 1 at 8 weeks, and the BIC of experimental group 4 was greater than that in the control group and in experimental group 1; these differences showed statistical significance (P < 0.05). CONCLUSION: Auto-tooth bone treated with EDTA resulted in more effective bone formation in dogs' femurs than bone treated with other solutions. PMID- 25033348 TI - Calcification of the stylohyoid ligament in panoramic radiography and cone beam computed tomography among patients referred for dental implant treatment planning. AB - BACKGROUND: Calcification of the stylohyoid ligament (SHL) is a common condition noted as an incidental finding in routine radiographic examination. Due to proximity with important neurovascular structures, elongation and calcification may sometimes lead to dysphagia and pain. The objective of this study was to evaluate the incidence of calcified SHL detected on cone beam computed tomography (CBCT) scans and panoramic radiographs (PR) in patients referred for dental implant therapy. METHODS: Retrospective analysis of 30 patients referred for dental implants to the Department of Oral and Maxillofacial Radiology at the University of Connecticut School of Dental Medicine was done. Patients were imaged using Hitachi CB MercuRay CBCT machine, and PRs were obtained using Planmeca panoramic machine. CBCT reconstructions and panoramic images were evaluated for the incidence and pattern of SHL calcification. RESULTS: Nineteen patients (63.3%) had calcified SHLs, 16 of whom were reported to have bilateral involvement. PR was unable to show complete calcification of the ligament in any of the cases, whereas CBCT showed evidence of complete calcification when present (14 cases). CONCLUSION: CBCT was more accurate in determining the pattern and extent of calcification of the SHL in patients undergoing implant treatment planning. PMID- 25033349 TI - Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile. AB - OBJECTIVES: This study evaluated the influence of the immune profile on the outcome at day 28 (D28) of patients admitted to the ICU for septic shock or severe sepsis. METHODS: We conducted an observational study using a prospective multicenter database and included all patients admitted to 11 ICUs for severe sepsis or septic shock from January 1997 to August 2011. Seven profiles of immunodeficiency were defined. The prognostic analysis used a competitive risk model (Fine and Gray), in which being alive at ICU or hospital discharge before D28 competed with death. RESULTS: Among the 1,981 included patients, 607 (31%) were immunocompromised (including nonneutropenic solid tumor [19.6%], nonneutropenic hematologic malignancies [26.3%], and all-cause neutropenia [28%]). Compared with immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often with septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8% in immunocompetent patients (P = .26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (subdistribution hazard ratio [sHR], 1.37; 95% CI, 1.12-1.67). The immunodeficiency profiles independently associated with death were AIDS (sHR = 1.9), non-neutropenic solid tumor (sHR = 1.8), nonneutropenic hematologic malignancies (sHR = 1.4), and all-cause neutropenia (sHR = 1.7). CONCLUSIONS: Immunodeficiency is common in patients with severe sepsis or septic shock. Despite a similar crude mortality, immunodeficiency was associated with an increased risk of short-term mortality after multivariate analysis. Neutropenia and specific, but not all, profiles of immunodeficiency were independently associated with an increased risk of death. PMID- 25033350 TI - Quantitative fluctuation electron microscopy in the STEM: methods to identify, avoid, and correct for artifacts. AB - Fluctuation electron microscopy can reveal the nanoscale order in amorphous materials via the statistical variance in the scattering intensity as a function of position, scattering vector, and resolution. However, several sources of experimental artifacts can seriously affect the magnitude of the variance peaks. The use of a scanning transmission electron microscope for data collection affords a convenient means to check whether artifacts are present. As nanodiffraction patterns are collected in serial, any spatial or temporal dependence of the scattering intensity across the series can easily be detected. We present examples of the major types of artifact and methods to correct the data or to avoid the problem experimentally. We also re-cast the statistical formalism used to identify sources of noise in view of the present results. The present work provides a basis on which to perform fluctuation electron microscopy with a high level of reliability and confidence in the quantitative magnitude of the data. PMID- 25033351 TI - Journal club: national variability in intracranial pressure monitoring and craniotomy for children with moderate to severe traumatic brain injury. PMID- 25033352 TI - Response to journal club: national variability in intracranial pressure monitoring and craniotomy for children with moderate to severe traumatic brain injury. PMID- 25033355 TI - Plasmin in brain stroma inhibits metastatic colonization. PMID- 25033356 TI - Inducing the "will to persevere": electric stimulation as a potential treatment for apathy. PMID- 25033357 TI - Maladaptive plasticity and memory decline in temporal lobe epilepsy. PMID- 25033358 TI - "Time out" for surgical safety checklists? PMID- 25033359 TI - Bilateral representation of sensory-motor transformations. PMID- 25033360 TI - Optical coherence tomography as a potential tool for extravascular imaging in vascular neurosurgery. PMID- 25033361 TI - Targeting a heterogeneous tumor: the promise of the interleukin-13 receptor alpha2. PMID- 25033362 TI - Let there be light and muscle contraction: optogenetic restoration of muscle function. PMID- 25033363 TI - A randomized clinical trial to assess the benefit of decompressive craniectomy in older patients with a large middle cerebral artery infarction. PMID- 25033364 TI - Preventing ischemia after stroke: are pericytes the answer? PMID- 25033365 TI - A telomerase assay detects brain tumor cells in blood. PMID- 25033366 TI - In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. PMID- 25033369 TI - Ion-exchange mechanism of layered transition-metal oxides: case study of LiNi(0.5)Mn(0.5)O2. AB - An ion-exchange process can be an effective route to synthesize new quasi equilibrium phases with a desired crystal structure. Important layered-type battery materials, such as LiMnO2 and LiNi(0.5)Mn(0.5)O2, can be obtained through this method from a sodium-containing parent structure, and they often show electrochemical properties remarkably distinct from those of their solid-state synthesized equivalents. However, while ion exchange is generally believed to occur via a simple topotactic reaction, the detailed phase transformation mechanism during the process is not yet fully understood. For the case of layered LiNi(0.5)Mn(0.5)O2, we show through ex situ X-ray diffraction (XRD) that the ion exchange process consists of several sequential phase transformations. By a study of the intermediate phase, it is shown that the residual sodium ions in the final structure may greatly affect the electrochemical (de)lithiation mechanism. PMID- 25033370 TI - Clinical development and trial design of biosimilar products: a Japanese perspective. AB - In recent years, development of biosimilar products has attracted considerable attention. Because of the structural complexity of biologics, it is difficult to demonstrate that a biosimilar product is identical to the reference product. Therefore, for the development of biosimilar products, we need to adopt an approach that is different from generic product development. In this article, we discuss the guidelines for the development of biosimilar products along with the case examples of biosimilar product development in Japan. In addition, we discuss several issues of clinical trial design for demonstrating biosimilarity to a reference product. PMID- 25033372 TI - The effects of aging on lymphocyte subgroups in males and females. AB - BACKGROUND: Age-associated immune senescence is a catch-all phrase that has been used to describe a plethora of changes to the immune system across the lifespan. Aging is associated with a decline in immune function. Our aim in this study was to investigate how lymphocyte subgroups in peripheral blood are affected by aging among males and females. MATERIAL/METHODS: Study participants were 70 healthy individuals from 3 different age groups, observed from January 2010 to January 2012. The average levels of CD3+, CD4+, CD8+, CD19+, CD16+/CD56+, CD3+/CD69+, and CD19+/CD69+ were determined for each group and compared in terms of age and sex. RESULTS: We found significant reduction in the level of CD3+T cells related with age, but no significant changes in CD19+ B cell levels (p<0.005). Aging significantly reduces activated B cell (CD19+/CD69+) levels in males (p<0.005). CONCLUSIONS: Our results show that there may be differences between males and females in terms of immune senescence. PMID- 25033373 TI - Does labour market disadvantage help to explain why childhood circumstances are related to quality of life at older ages? Results from SHARE. AB - There is robust evidence that childhood circumstances are related to quality of life in older ages, but the role of possible intermediate factors is less explored. In this paper, we examine to what extent associations between deprived childhood circumstances and quality of life at older ages are due to experienced labour market disadvantage during adulthood. Analyses are based on the Survey of Health Ageing and Retirement in Europe (SHARE), with detailed retrospective information on individual life courses collected among 10,272 retired men and women in 13 European countries (2008-2009). Our assumption is that those who have spent their childhood in deprived circumstances may also have had more labour market disadvantage with negative consequences for quality of life beyond working life. Results demonstrate that advantaged circumstances during childhood are associated with lower levels of labour market disadvantage and higher quality of life in older ages. Furthermore, results of multivariate analyses support the idea that part of the association between childhood circumstances and later quality of life is explained by labour market disadvantage during adulthood. PMID- 25033374 TI - Maintenance therapy in ovarian cancer. AB - PURPOSE OF REVIEW: Targeted therapies are being used as maintenance therapy to improve the outcome of ovarian cancer following standard treatment in the first line setting and in recurrent disease. We review the different approaches being used, trial design, and the impact of maintenance treatment on survival and quality of life. RECENT FINDINGS: The greatest experience of maintenance therapy is with antiangiogenic agents. Several trials targeting vascular endothelial growth factor with bevacizumab or vascular endothelial growth factor receptor with oral tyrosine kinase inhibitors have demonstrated a prolongation in progression-free survival (PFS) following first or second-line treatment. Maintenance therapy with olaparib, a poly ADP ribose polymerase inhibitor given post-platinum therapy for recurrent disease, has led to a prolongation in PFS, particularly, in patients with a BRCA mutation. The results of immunotherapy maintenance studies, based on using cancer antigen 125 as an antigen, have been disappointing. A benefit in PFS often does not translate into overall survival improvement, largely because of crossover and postprogression therapies. This makes clinical interpretation of results more difficult. SUMMARY: The principle of using molecular targeted therapy to prolong the control of ovarian cancer has been clearly demonstrated. The greatest effect is on prolongation of PFS and, by adding to the effects of standard treatments, maintenance therapy is likely to help incrementally extend the 5-year survival of women with ovarian cancer. PMID- 25033375 TI - Bruton's tyrosine kinase inhibitors: lessons learned from bench-to-bedside (first) studies. AB - PURPOSE OF REVIEW: Targeted inhibitors of B-cell receptor signaling have emerged as the most promising therapeutic options against non-Hodgkin's lymphoma. The inhibitor agents that target Bruton's tyrosine kinase (BTK) have elicited particularly high enthusiasm given the unprecedented positive responses observed in Phase I trials. The sheer amount of clinical data published since last year now requires reinterpretation in light of recently published findings on BTK. RECENT FINDINGS: Clinical trial data pertaining to various B-cell dyscrasia forms must be interpreted with great caution. The differing response rates reported with various BTK inhibitors for a range of lymphoma subtypes most likely mirror BTK's disease-specific pivotal role in the regulation of cell survival, migration, and proliferation pathways. It must also be stressed that activating or inhibitory somatic mutations affecting other critical components of targeted signaling cascades dramatically impact BTK inhibitor efficacy, and scientific evidence is mounting that warrants patient screening to identify those who, based on B-cell receptor activation modes, most likely benefit from BTK inhibitors. SUMMARY: Recent developments in BTK-based therapeutic strategies have undoubtedly changed the way we approach lymphoma therapy. As of yet, there is no cure for indolent lymphoma, and the future of BTK inhibitor therapy will undoubtedly include rational combinations to exploit synthetic lethality in distinct lymphoma subsets. PMID- 25033376 TI - Predictors of substance use among young adults transitioning away from high school: a narrative review. AB - BACKGROUND: Young adulthood has been shown to be a time of increased substance use. Yet, not enough is known about which factors contribute to initiation and progression of substance use among young adults specifically during the transition year away from high school. OBJECTIVES: A narrative review was undertaken to increase understanding of the predictors of changes in use of tobacco, alcohol, cannabis, other illicit drugs, and mental health problems among young adults during the transition period after high school. METHODS: A review of academic literature examining predictors of the use of tobacco, alcohol and cannabis, and co-morbidities (e.g., co-occurring substance use and/or mental health issues) among young adults transitioning from high school to post secondary education or the workforce. RESULTS: Twenty six studies were included in the review. The majority of the studies (19) examined substance use during the transition from high school to post-secondary settings. Seven studies examined substance use in post-secondary settings. The studies consistently found that substance use increases among young adults as they transition away from high school. During the transition away from high school, common predictors of substance use include substance use in high school, and peer influence. Common predictors of substance use in post-secondary education include previous substance use, peer influence, psychological factors and mental health issues. Conclusions/Importance: Further research on social contextual influences on substance use, mental health issues, gender differences and availability of substances during the transition period is needed to inform the development of new preventive interventions for this age group. PMID- 25033377 TI - Family functioning and parent support trajectories and substance use and misuse among minority urban adolescents: a latent class growth analysis. AB - We sought to examine latent classes of family functioning and parent support trajectories during high school and whether these trajectories are associated with an increased risk of substance use and misuse among urban youth. A total of 850 adolescents (Mage = 15.1 years) were included in this study, assessed at baseline, 12-, 24-, and 36-months postbaseline, and completed self-report measures on past 30-day alcohol and marijuana use, binge drinking, and measures of family functioning and parent support. Latent class growth analysis revealed that trajectories of high family functioning and parent support are associated with a decreased risk of marijuana use. Findings may be helpful to inform family based preventive interventions. PMID- 25033379 TI - Cognitive impairment in chronic obstructive pulmonary disease. AB - BACKGROUND/PURPOSE: Chronic obstructive pulmonary disease (COPD), especially in severe forms, is commonly associated with multiple cognitive problems. Montreal Cognitive Assessment test (MoCA) is used to detect cognitive impairment evaluating several areas: visuospatial, memory, attention and fluency. Our study aim was to evaluate the impact of stable COPD and exacerbation (AECOPD) phases on cognitive status using MoCA questionnaire. METHODS: We enrolled 39 patients (pts), smokers with COPD group D (30 stable and 9 in AECOPD) and 13 healthy subjects (control group), having similar level of education and no significant differences regarding the anthropometric measurements. We analyzed the differences in MoCA score between these three groups and also the correlation between this score and inflammatory markers. RESULTS: Patients with AECOPD had a significant (p<0.001) decreased MoCA score (14.6+/-3.4) compared to stable COPD (20.2+/-2.4) and controls (24.2+/-5.8). The differences between groups were more accentuated for the language abstraction and attention (p<0.001) and delayed recall and orientation (p<0.001) sub-topics. No significant variance of score was observed between groups regarding visuospatial and naming score (p = 0.095). The MoCA score was significantly correlated with forced expiratory volume (r = 0.28) and reverse correlated with C-reactive protein (CRP) (r = -0.57), fibrinogen (r = -0.58), erythrocyte sedimentation rate (ESR) (r = -0.55) and with the partial pressure of CO2 (r = -0.47). CONCLUSIONS: According to this study, COPD significantly decreases the cognitive status in advanced and acute stages of the disease. PMID- 25033378 TI - Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. AB - CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system. PMID- 25033380 TI - Low dose propranolol decreases orthodontic movement. AB - OBJECTIVE: Low dose propranolol has previously been demonstrated to suppress bone remodelling. Therefore, its effect on orthodontic movement was tested. DESIGN: Rats were assigned as follows (n=5): animals with no orthodontic appliance (G1); the remaining groups were fitted with a Ni-Ti closed-coil spring ligated to the upper left first molar and connected to the incisors using metal and resin and received vehicle only (G2), 0.1mg/kg (G3) or 20mg/kg (G4) of propranolol orally. Cone Beam Computed Tomography was performed using high resolution for image capture. The distance between the first and second upper molars, both with and without the orthodontic appliance, was measured in millimetres. Gingival tissue was harvested and assessed for IL-1beta and IL-6 using ELISA and for ICAM-1 and RANKL by Western blotting. RESULTS: The orthodontic appliance induced a significant tooth movement in G2 when compared to the animals without an orthodontic appliance (G1) (p<0.05). The animals from G3 showed a significantly reduction in tooth movement (p<0.05) when compared with rats from G2. Animals treated with 20mg/kg of propranolol (G4) showed tooth movement similar to that of G2. The reduced tooth movement observed in the animals treated with 0.1mg/kg of propranolol (G3) occurred due to decreased amounts of IL-1beta and IL-6, in addition to lower ICAM-1 and RANKL expression. CONCLUSIONS: Low dose propranolol inhibits bone remodelling and orthodontic movement. PMID- 25033381 TI - Chemopreventive potential of phenolic compounds in oral carcinogenesis. AB - OBJECTIVE: To evaluate the chemopreventive potential of phenolic compounds - potassium apigenin, cocoa, catechins, eriocitrin and rosmarinic acid in oral carcinogenesis induced in hamsters by means of the topical application of 7,12 dimethylbenz(a)anthracene(DMBA). STUDY DESIGN: An experimental study at the University of Murcia. METHODS: 50 male Syrian hamsters (Mesocricetus auratus) were divided into five groups of ten: Group I (control group): 0.5% DMBA; Group II: 0.5% DMBA+1.1mg/15ml potassium apigenin; Group III: 05% DMBA+2.5mg/15ml cocoa catechins; Group IV: 0.5% DMBA+6mg/15ml eriocitrin; Group V: 0.5% DMBA+1.3mg/15ml rosmarinic acid. The flavonoids were administered orally. All the animals were sacrificed after 12 weeks. Macroscopic, microscopic and immunohistochemical (PCNA and p53) analyses of the lesions were performed. RESULTS: All the groups treated with phenolic compounds showed lower incidences of tumour, greater differentiation and lower scores in the tumour invasion front grading system in comparison with the control group. Potassium apigenin and rosmarinic acid achieved the best results, the former considerably reduced the carcinoma tumour volumes developed and both significantly reduced the intensity and aggression of the tumours. Immunoexpression of PCNA and p53 were significantly altered during DMBA-induced oral carcinogenesis. CONCLUSIONS: Animals treated with phenolic compounds, particularly potassium apigenin and rosmarinic acid, showed a lower incidence of tumours. PMID- 25033382 TI - Fetal jaw movement affects Ihh signaling in mandibular condylar cartilage development: the possible role of Ihh as mechanotransduction mediator. AB - OBJECTIVE: Jaw movement is an important mechanical factor for prenatal development of the condylar cartilage of mandible. Fetal jaw movement restriction has been shown to cause deformity of the mandibular condyle. We hypothesized that this treatment affects the expression of mechanosensitive molecules, namely Indian hedgehog (Ihh) and Parathyroid hormone related protein (PTHrP) in the condyle. EXPERIMENTAL METHODS: We restrained jaw movement by suturing the jaw of E15.5 mouse embryos and allowed them to develop until E18.5 using exo utero system, and analyzed them by immunohistochemistry and in situ hybridization methods. RESULTS: Morphological, histomorphometric and immunohistochemical study showed that the mandibular condylar cartilage was reduced and deformed, the volume and total cell numbers in the condylar cartilage were also reduced, and number and/or distribution of 5-bromo-2'-deoxyuridine-positive cells, Ihh positive cells in the mesenchymal and pre-hypertrophic zones were significantly and correspondingly decreased in the sutured group. Using in situ hybridization, reduced expression of Ihh, PTHrP and their related receptors were observed in condylar cartilage of the sutured embryos. CONCLUSIONS: Our results revealed that the altered mechanical stress induced by prenatal jaw movement restriction decreased proliferating cells, the amount of cartilage, and altered expression of the Ihh and PTHrP, suggesting that Ihh act as mechanotransduction mediators in the development of mandibular condylar cartilage. PMID- 25033383 TI - Efficacy and safety of vismodegib : a new therapeutic agent in the treatment of basal cell carcinoma. AB - INTRODUCTION: Basal cell carcinoma (BCC) is the most common human malignancy. Treatment options for the minority of patients presenting with locally advanced inoperable or metastatic BCC are very limited. The hedgehog (Hh) pathway plays a crucial role in the pathogenesis of BCC. Recent advances in targeting this pathway have led to the development of a first-in-class, small-molecule oral Hh inhibitor, vismodegib (Erivedge(r), Genentech). AREAS COVERED: In this article, we review vismodegib with regard to its mechanism of action, clinical efficacy, safety and tolerability, and we consider the causes of emerging resistance to the drug. EXPERT OPINION: Vismodegib is a welcome addition to the treatment paradigm for BCC. Approval was based on Phase II evidence, the patient number was relatively small, there was no control group or a comparator group and survival data have not been presented so longer term follow-up and larger exposure to the drug is required to fully appreciate its clinical utility into the future. With ongoing use of the drug in the nontrial population and further studies investigating its use in both early- and later-stage disease, we will get a better understanding of the drug and determine its place in the armamentarium against BCC. PMID- 25033386 TI - Motility and chemotaxis mediate the preferential colonization of gastric injury sites by Helicobacter pylori. AB - Helicobacter pylori (H. pylori) is a pathogen contributing to peptic inflammation, ulceration, and cancer. A crucial step in the pathogenic sequence is when the bacterium first interacts with gastric tissue, an event that is poorly understood in vivo. We have shown that the luminal space adjacent to gastric epithelial damage is a microenvironment, and we hypothesized that this microenvironment might enhance H. pylori colonization. Inoculation with 106 H. pylori (wild-type Sydney Strain 1, SS1) significantly delayed healing of acetic acid induced ulcers at Day 1, 7 and 30 post-inoculation, and wild-type SS1 preferentially colonized the ulcerated area compared to uninjured gastric tissue in the same animal at all time points. Gastric resident Lactobacillus spp. did not preferentially colonize ulcerated tissue. To determine whether bacterial motility and chemotaxis are important to ulcer healing and colonization, we analyzed isogenic H. pylori mutants defective in motility (DeltamotB) or chemotaxis (DeltacheY). DeltamotB (10(6)) failed to colonize ulcerated or healthy stomach tissue. DeltacheY (10(6)) colonized both tissues, but without preferential colonization of ulcerated tissue. However, DeltacheY did modestly delay ulcer healing, suggesting that chemotaxis is not required for this process. We used two-photon microscopy to induce microscopic epithelial lesions in vivo, and evaluated accumulation of fluorescently labeled H. pylori at gastric damage sites in the time frame of minutes instead of days. By 5 min after inducing damage, H. pylori SS1 preferentially accumulated at the site of damage and inhibited gastric epithelial restitution. H. pylori DeltacheY modestly accumulated at the gastric surface and inhibited restitution, but did not preferentially accumulate at the injury site. H. pylori DeltamotB neither accumulated at the surface nor inhibited restitution. We conclude that bacterial chemosensing and motility rapidly promote H. pylori colonization of injury sites, and thereby biases the injured tissue towards sustained gastric damage. PMID- 25033387 TI - Regional precipitation variability in East Asia related to climate and environmental factors during 1979-2012. AB - This paper studies the inter-annual precipitation variations in different regions of East Asia from oceans to interior areas in China during 1979 - 2012. The results computed by Empirical Orthogonal Functions (EOF) demonstrate that the annual precipitation changes are mainly related to the El Nino-Southern Oscillation, East Asian summer monsoon and aerosols. We also found that the increased Sea surface temperature (SST) could explain the precipitation changes over the Northwest Pacific in the dry season (Oct. - May) and the East China Sea and the South China Sea in the rainy season (Jun. - Sep.). The precipitation changes over the ocean unexplained by SST were likely due to the water vapor transport dominated by dynamic factors. With the increased SST, the moisture transported from oceans to interior land was likely redistributed and caused the complicated regional variability of precipitation. Moreover, the impacts of aerosols on cloud and precipitation varied with different pollution levels and different seasons. PMID- 25033388 TI - Edaravone protects against methylglyoxal-induced barrier damage in human brain endothelial cells. AB - BACKGROUND: Elevated level of reactive carbonyl species, such as methylglyoxal, triggers carbonyl stress and activates a series of inflammatory responses leading to accelerated vascular damage. Edaravone is the active substance of a Japanese medicine, which aids neurological recovery following acute brain ischemia and subsequent cerebral infarction. Our aim was to test whether edaravone can exert a protective effect on the barrier properties of human brain endothelial cells (hCMEC/D3 cell line) treated with methylglyoxal. METHODOLOGY: Cell viability was monitored in real-time by impedance-based cell electronic sensing. The barrier function of the monolayer was characterized by measurement of resistance and flux of permeability markers, and visualized by immunohistochemistry for claudin-5 and beta-catenin. Cell morphology was also examined by holographic phase imaging. PRINCIPAL FINDINGS: Methylglyoxal exerted a time- and dose-dependent toxicity on cultured human brain endothelial cells: a concentration of 600 uM resulted in about 50% toxicity, significantly reduced the integrity and increased the permeability of the barrier. The cell morphology also changed dramatically: the area of cells decreased, their optical height significantly increased. Edaravone (3 mM) provided a complete protection against the toxic effect of methylglyoxal. Co-administration of edaravone restored cell viability, barrier integrity and functions of brain endothelial cells. Similar protection was obtained by the well known antiglycating molecule, aminoguanidine, our reference compound. CONCLUSION: These results indicate for the first time that edaravone is protective in carbonyl stress induced barrier damage. Our data may contribute to the development of compounds to treat brain endothelial dysfunction in carbonyl stress related diseases. PMID- 25033390 TI - Extracapsular dissection of benign parotid tumors. PMID- 25033389 TI - Integrative omics analysis. A study based on Plasmodium falciparum mRNA and protein data. AB - BACKGROUND: Technological improvements have shifted the focus from data generation to data analysis. The availability of large amounts of data from transcriptomics, protemics and metabolomics experiments raise new questions concerning suitable integrative analysis methods. We compare three integrative analysis techniques (co-inertia analysis, generalized singular value decomposition and integrative biclustering) by applying them to gene and protein abundance data from the six life cycle stages of Plasmodium falciparum. Co inertia analysis is an analysis method used to visualize and explore gene and protein data. The generalized singular value decomposition has shown its potential in the analysis of two transcriptome data sets. Integrative Biclustering applies biclustering to gene and protein data. RESULTS: Using CIA, we visualize the six life cycle stages of Plasmodium falciparum, as well as GO terms in a 2D plane and interpret the spatial configuration. With GSVD, we decompose the transcriptomic and proteomic data sets into matrices with biologically meaningful interpretations and explore the processes captured by the data sets. IBC identifies groups of genes, proteins, GO Terms and life cycle stages of Plasmodium falciparum. We show method-specific results as well as a network view of the life cycle stages based on the results common to all three methods. Additionally, by combining the results of the three methods, we create a three-fold validated network of life cycle stage specific GO terms: Sporozoites are associated with transcription and transport; merozoites with entry into host cell as well as biosynthetic and metabolic processes; rings with oxidation reduction processes; trophozoites with glycolysis and energy production; schizonts with antigenic variation and immune response; gametocyctes with DNA packaging and mitochondrial transport. Furthermore, the network connectivity underlines the separation of the intraerythrocytic cycle from the gametocyte and sporozoite stages. CONCLUSION: Using integrative analysis techniques, we can integrate knowledge from different levels and obtain a wider view of the system under study. The overlap between method-specific and common results is considerable, even if the basic mathematical assumptions are very different. The three-fold validated network of life cycle stage characteristics of Plasmodium falciparum could identify a large amount of the known associations from literature in only one study. PMID- 25033391 TI - Analysis of the phospholipid profile of metaphase II mouse oocytes undergoing vitrification. AB - Oocyte freezing confers thermal and chemical stress upon the oolemma and various other intracellular structures due to the formation of ice crystals. The lipid profiles of oocytes and embryos are closely associated with both, the degrees of their membrane fluidity, as well as the degree of chilling and freezing injuries that may occur during cryopreservation. In spite of the importance of lipids in the process of cryopreservation, the phospholipid status in oocytes and embryos before and after freezing has not been investigated. In this study, we employed mass spectrometric analysis to examine if vitrification has an effect on the phospholipid profiles of mouse oocytes. Freshly prepared metaphase II mouse oocytes were vitrified using copper grids and stored in liquid nitrogen for 2 weeks. Fresh and vitrified-warmed oocytes were subjected to phospholipid extraction procedure. Mass spectrometric analyses revealed that multiple species of phospholipids are reduced in vitrified-warmed oocytes. LIFT analyses identified 31 underexpressed and 5 overexpressed phospholipids in vitrified mouse oocytes. The intensities of phosphatidylinositol (PI) {18?2/16?0} [M-H]- and phosphatidylglycerol (PG) {14?0/18?2} [M-H]- were decreased the most with fold changes of 30.5 and 19.1 in negative ion mode, respectively. Several sphingomyelins (SM) including SM {d38?3} [M+H]+ and SM {d34?0} [M+K]+ were decreased significantly in positive ion mode. Overall, the declining trend of multiple phospholipids demonstrates that vitrification has a marked effect on phospholipid profiles of oocytes. These results show that the identified phospholipids can be used as potential biomarkers of oocyte undergoing vitrification and will allow for the development of strategies to preserve phospholipids during oocyte cryopreservation. PMID- 25033392 TI - Triterpenoids from the fruits and leaves of the blackberry (Rubus allegheniensis) and their inhibitory activities on foam cell formation in human monocyte-derived macrophage. AB - From the methanol extract of the fruits of the blackberry (Rubus allegheniensis Port.), four triterpenoids - pomolic acid (1), tormentic acid (2), euscaphic acid (3) and 1beta-hydroxyeuscaphic acid (4) - were isolated, while six triterpenoids 2, 3, myrianthic acid (5), ziyu glycoside II (6), sericic acid (7) and 19 hydroxy-2,3-secours-12-ene-2,3,28-trioic acid 3-methyl ester (8) - were obtained from the methanol extract of the leaves of this plant. Their structures were determined on the basis of spectral data. Compounds 1-8 were examined for their inhibitory activities on foam cell formation in human monocyte-derived macrophages induced by acetylated low-density lipoproteins at a 50 MUM concentration. Among the tested compounds, 1 showed the strongest activity, with the inhibitory effect being 90%. The inhibitory activities of 2-8 were evaluated to be 30%, 32%, 33%, 4%, 48%, 4% and 24%, respectively. Further, the structure activity relationship of these compounds was investigated. PMID- 25033394 TI - AIBN-catalyzed oxidative cleavage of gem-disubstituted alkenes with O2 as an oxidant. AB - A 2,2-azobis(isobutyronitrile) (AIBN) catalyzed oxidative cleavage of gem disubstituted alkenes with molecular oxygen as the oxidant has been described. Carbonyl compounds were obtained as the desired products in high yield under mild conditions. Based on previous documents and current experimental results, a relatively reasonable mechanism is proposed. PMID- 25033393 TI - IL-7 receptor recovery on CD8 T-cells isolated from HIV+ patients is inhibited by the HIV Tat protein. AB - Expression of the IL-7 receptor alpha-chain (CD127) is decreased on CD8 T-cells in HIV infected patients and partially recovers in those receiving antiretroviral therapy with sustained viral suppression. We have shown that soluble HIV Tat protein down regulates CD127 expression on CD8 T-cells isolated from healthy HIV negative individuals. Tat is taken up by CD8 T-cells via endocytosis, exits the endosome and then translocates to the inner leaflet of the cell membrane where it binds to the cytoplasmic tail of CD127 inducing receptor internalization and degradation by the proteasome. This down regulation of CD127 by Tat results in impaired CD8 T-cell function. Interestingly, suppression of CD127 by Tat is reversible and requires the continual presence of Tat in the culture media. We thus questioned whether the low IL-7 receptor expression evident on CD8 T-cells in HIV+ patients was similarly reversible and if suppression of the receptor could be maintained ex vivo by Tat protein alone. We show here that when CD8 T cells isolated from HIV+ patients are incubated alone in fresh medium, low CD127 expression on the cell surface recovers to normal levels. This recovery of CD127, however, is completely inhibited by the addition of HIV Tat protein to the culture media. This study then provides evidence that soluble factor(s) are responsible for low CD127 expression on circulating CD8 T-cells in HIV+ individuals and further implicates Tat in suppressing this receptor essential to CD8 T-cell proliferation and function. PMID- 25033396 TI - Combined PET imaging and diffusion-weighted imaging of intermediate and high-risk primary prostate carcinomas with simultaneous [18F] choline PET/MRI. AB - PURPOSE: To characterize intermediate and high-risk prostate carcinomas with measurements of standardized uptake values (SUVs) and apparent diffusion coefficient (ADC) values by means of simultaneous [18F] choline PET/MRI. MATERIALS AND METHODS: 35 patients with primary prostate cancer underwent simultaneous [18F] choline PET/MRI. From these, 21 patients with an intermediate and high risk constellation who were not under ongoing hormonal therapy were included. Altogether 32 tumor lesions with a focal uptake of [18F] choline could be identified. Average ADC values (ADCaver) minimum ADC values (ADCmin) as well as maximum and mean SUVs (SUVmax, SUVmean) of tumor lesions were assessed with volume-of-interest (VOI) and Region-of-interest (ROI) measurements. As a reference, also ADCaver, ADCmin and SUVmax and SUVmean of non-tumorous prostate tissue were measured. Statistical analysis comprised calculation of descriptive parameters and calculation of Pearson's product moment correlations between ADC values and SUVs of tumor lesions. RESULTS: Mean ADCaver and ADCmin of tumor lesions were 0.94+/-0.22*10(-3) mm2/s and 0.65+/-0.21*10(-3) mm2/s, respectively. Mean SUVmax and SUVmean of tumor lesions were 6.3+/-2.3 and 2.6+/-0.8, respectively. These values were in each case significantly different from the reference values (p<0.001). There was no significant correlation between the measured SUVs and ADC values (SUVmax vs. ADCaver: R = -0.24, p = 0.179; SUVmax vs. ADCmin: R = -0.03, p = 0.877; SUVmean vs. ADCaver: R = -0.27, p = 0.136; SUVmean vs. ADCmin: R = -0.08, p = 0.679). CONCLUSION: Both SUVs and ADC values differ significantly between tumor lesions and healthy tissue. However, there is no significant correlation between these two parameters. This might be explained by the fact that SUVs and ADC values characterize different parts of tumor biology. PMID- 25033398 TI - Microneedle enhanced delivery of cosmeceutically relevant peptides in human skin. AB - Peptides and proteins play an important role in skin health and well-being. They are also found to contribute to skin aging and melanogenesis. Microneedles have been shown to substantially enhance skin penetration and may offer an effective means of peptide delivery enhancement. The aim of this investigation was to assess the influence of microneedles on the skin penetration of peptides using fluorescence imaging to determine skin distribution. In particular the effect of peptide chain length (3, 4, 5 amino acid chain length) on passive and MN facilitated skin penetration was investigated. Confocal laser scanning microscopy was used to image fluorescence intensity and the area of penetration of fluorescently tagged peptides. Penetration studies were conducted on excised full thickness human skin in Franz type diffusion cells for 1 and 24 hours. A 2 to 22 fold signal improvement in microneedle enhanced delivery of melanostatin, rigin and pal-KTTKS was observed. To our knowledge this is the first description of microneedle enhanced skin permeation studies on these peptides. PMID- 25033397 TI - Recombination in the human Pseudoautosomal region PAR1. AB - The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome. PMID- 25033399 TI - Postoperative pain management among surgically treated patients in an Ethiopian hospital. AB - BACKGROUND: Incidence of postoperative pain has been reported to be between 47 100%. Ineffective postoperative pain management results in tangible and intangible costs. The purpose of this study was to assess the processes and outcomes of pain management in the surgical wards of Jimma University Specialized Hospital, Ethiopia. METHODS AND FINDINGS: A prospective cross sectional study was conducted among 252 postoperative patients during February 13 to April 30, 2012. A contextually modified and validated (Cronbach's alpha coefficient of 0.78) American Pain Society Patient Outcome Questionnaire was used to assess pain experience of patients. Patients' charts were reviewed to assess the pattern of analgesic use. Incidence of postoperative pain was 91.4%, and remained high over 3 measurements (McNemar's; p<0.05), and 80.1% of the patients were undertreated. The mean pain intensity, and pain interference on functional status were 6.72+/ 1.44 and 5.61+/-1.13 on a 10 point Numerical rating scale respectively; both being strongly correlated(r = 0.86: p<0.001). Pain intensity was varied by ethnicity, education and preoperative information (ANOVA; P<0.05). Only 50% of the patients were adequately satisfied with their pain management. As needed (prn), solo analgesic, null analgesic, and intramuscular orders were noted for 31.3%, 89.29%, 9.7% and 20.1% of the prescription orders respectively. Though under dose, diclofenac and tramadol were the top prescribed medications, and only 57% of their dose was administered. Linear regression model showed that the predictors of satisfaction were sex of an individual and pain interference with functional status. CONCLUSION: Despite patients' paradoxical high satisfaction with pain management, the majority of patients were inadequately and inappropriately treated. Thus, further research is needed to determine how best to break down current barriers to effective pain management. PMID- 25033401 TI - Identification of sVSG117 as an immunodiagnostic antigen and evaluation of a dual antigen lateral flow test for the diagnosis of human African trypanosomiasis. AB - BACKGROUND: The diagnosis of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense relies mainly on the Card Agglutination Test for Trypanosomiasis (CATT). There is no immunodiagnostic for HAT caused by T. b. rhodesiense. Our principle aim was to develop a prototype lateral flow test that might be an improvement on CATT. METHODOLOGY/PRINCIPLE FINDINGS: Pools of infection and control sera were screened against four different soluble form variant surface glycoproteins (sVSGs) by ELISA and one, sVSG117, showed particularly strong immunoreactivity to pooled infection sera. Using individual sera, sVSG117 was shown to be able to discriminate between T. b. gambiense infection and control sera by both ELISA and lateral flow test. The sVSG117 antigen was subsequently used with a previously described recombinant diagnostic antigen, rISG65, to create a dual-antigen lateral flow test prototype. The latter was used blind in a virtual field trial of 431 randomized infection and control sera from the WHO HAT Specimen Biobank. CONCLUSION/SIGNIFICANCE: In the virtual field trial, using two positive antigen bands as the criterion for infection, the sVSG117 and rISG65 dual-antigen lateral flow test prototype showed a sensitivity of 97.3% (95% CI: 93.3 to 99.2) and a specificity of 83.3% (95% CI: 76.4 to 88.9) for the detection of T. b. gambiense infections. The device was not as good for detecting T. b. rhodesiense infections using two positive antigen bands as the criterion for infection, with a sensitivity of 58.9% (95% CI: 44.9 to 71.9) and specificity of 97.3% (95% CI: 90.7 to 99.7). However, using one or both positive antigen band(s) as the criterion for T. b. rhodesiense infection improved the sensitivity to 83.9% (95% CI: 71.7 to 92.4) with a specificity of 85.3% (95% CI: 75.3 to 92.4). These results encourage further development of the dual-antigen device for clinical use. PMID- 25033402 TI - Clinical characteristics of Q fever and etiology of community-acquired pneumonia in a tropical region of southern Taiwan: a prospective observational study. AB - BACKGROUND: The clinical characteristics of Q fever are poorly identified in the tropics. Fever with pneumonia or hepatitis are the dominant presentations of acute Q fever, which exhibits geographic variability. In southern Taiwan, which is located in a tropical region, the role of Q fever in community-acquired pneumonia (CAP) has never been investigated. METHODOLOGY/PRINCIPAL FINDINGS: During the study period, May 2012 to April 2013, 166 cases of adult CAP and 15 cases of acute Q fever were prospectively investigated. Cultures of clinical specimens, urine antigen tests for Streptococcus pneumoniae and Legionella pneumophila, and paired serologic assessments for Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Q fever (Coxiella burnetii) were used for identifying pathogens associated with CAP. From April 2004 to April 2013 (the pre study period), 122 cases of acute Q fever were also included retrospectively for analysis. The geographic distribution of Q fever and CAP cases was similar. Q fever cases were identified in warmer seasons and younger ages than CAP. Based on multivariate analysis, male gender, chills, thrombocytopenia, and elevated liver enzymes were independent characteristics associated with Q fever. In patients with Q fever, 95% and 13.5% of cases presented with hepatitis and pneumonia, respectively. Twelve (7.2%) cases of CAP were seropositive for C. burnetii antibodies, but none of them had acute Q fever. Among CAP cases, 22.9% had a CURB 65 score ?2, and 45.8% had identifiable pathogens. Haemophilus parainfluenzae (14.5%), S. pneumoniae (6.6%), Pseudomonas aeruginosa (4.8%), and Klebsiella pneumoniae (3.0%) were the most common pathogens identified by cultures or urine antigen tests. Moreover, M. pneumoniae, C. pneumoniae, and co-infection with 2 pathogens accounted for 9.0%, 7.8%, and 1.8%, respectively. CONCLUSIONS: In southern Taiwan, Q fever is an endemic disease with hepatitis as the major presentation and is not a common etiology of CAP. PMID- 25033404 TI - Lake sediment records on climate change and human activities in the Xingyun Lake catchment, SW China. AB - Sediments from Xinyun Lake in central Yunnan, southwest China, provide a record of environmental history since the Holocene. With the application of multi-proxy indicators (total organic carbon (TOC), total nitrogen (TN), delta13C and delta15N isotopes, C/N ratio, grain size, magnetic susceptibility (MS) and CaCO3 content), as well as accelerator mass spectrometry (AMS) 14C datings, four major climatic stages during the Holocene have been identified in Xingyun's catchment. A marked increase in lacustrine palaeoproductivity occurred from 11.06 to 9.98 cal. ka BP, which likely resulted from an enhanced Asian southwest monsoon and warm-humid climate. Between 9.98 and 5.93 cal. ka BP, a gradually increased lake level might have reached the optimum water depth, causing a marked decline in coverage by aquatic plants and lake productivity of the lake. This was caused by strong Asian southwest monsoon, and coincided with the global Holocene Optimum. During the period of 5.60-1.35 cal. ka BP, it resulted in a warm and dry climate at this stage, which is comparable to the aridification of India during the mid- and late Holocene. The intensifying human activity and land-use in the lake catchment since the early Tang Dynasty (~1.35 cal. ka BP) were associated with the ancient Dian culture within Xingyun's catchment. The extensive deforestation and development of agriculture in the lake catchment caused heavy soil loss. Our study clearly shows that long-term human activities and land-use change have strongly impacted the evolution of the lake environment and therefore modulated the sediment records of the regional climate in central Yunnan for more than one thousand years. PMID- 25033405 TI - A novel MIP gene mutation analysis in a Chinese family affected with congenital progressive punctate cataract. AB - Congenital cataracts are one of the leading causes of visual impairment and blindness in children, and genetic factors play an important role in their development. This study aimed to identify the genetic defects associated with autosomal dominant congenital progressive punctate cataracts in a Chinese family and to explore the potential pathogenesis. Detailed family history and clinical data were recorded, and all the family members' blood samples were collected for DNA extraction. Linkage analysis was performed by microsatellite markers that are associated with punctate cataracts, and logarithm (base 10) of odds (LOD) scores were calculated using the LINKAGE program. Positive two-point LOD scores were obtained at markers D12S1622 (Zmax = 2.71 at theta = 0.0), D12S1724 (Zmax = 2.71 at theta = 0.0), and D12S90 (Zmax = 2.71 at theta = 0.0), which flank the major intrinsic protein of lens fiber (MIP) gene on chromosomal region 12q13. Direct sequencing of the encoding region of the MIP gene revealed a novel mutation (G>D) in exon 4 at nucleotide 644, which caused a substitution of glycine to aspartic acid at codon 215 (p.G215D) for the MIP protein. The mutation cosegregated with all patients with congenital progressive punctate cataracts, but it was absent in the healthy members. Bioinformatics analysis predicted that the mutation affects the function of the MIP protein. The wild type (WT) and G215D mutant of MIP were transfected with green fluorescent protein (GFP) into Hela cells separately, and it was found that the G215D mutant was aberrantly located in the cytoplasm instead of in the plasma membrane. In summary, our study presented genetic and functional evidence linking the new MIP mutation of G215D to autosomal dominant congenital cataracts, which adds to the list of MIP mutations linked to congenital progressive punctate cataracts. PMID- 25033407 TI - Procalcitonin-guided therapy in severe sepsis and septic shock. PMID- 25033406 TI - Real-time imaging reveals the dynamics of leukocyte behaviour during experimental cerebral malaria pathogenesis. AB - During experimental cerebral malaria (ECM) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6C(hi) monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA)-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS). A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG)-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8(+) T lymphocytes. A critical number of CD8(+) T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8(+) T lymphocytes in regulating vascular pathology in this disease. PMID- 25033408 TI - Enhanced regulatory sequence prediction using gapped k-mer features. AB - Oligomers of length k, or k-mers, are convenient and widely used features for modeling the properties and functions of DNA and protein sequences. However, k mers suffer from the inherent limitation that if the parameter k is increased to resolve longer features, the probability of observing any specific k-mer becomes very small, and k-mer counts approach a binary variable, with most k-mers absent and a few present once. Thus, any statistical learning approach using k-mers as features becomes susceptible to noisy training set k-mer frequencies once k becomes large. To address this problem, we introduce alternative feature sets using gapped k-mers, a new classifier, gkm-SVM, and a general method for robust estimation of k-mer frequencies. To make the method applicable to large-scale genome wide applications, we develop an efficient tree data structure for computing the kernel matrix. We show that compared to our original kmer-SVM and alternative approaches, our gkm-SVM predicts functional genomic regulatory elements and tissue specific enhancers with significantly improved accuracy, increasing the precision by up to a factor of two. We then show that gkm-SVM consistently outperforms kmer-SVM on human ENCODE ChIP-seq datasets, and further demonstrate the general utility of our method using a Naive-Bayes classifier. Although developed for regulatory sequence analysis, these methods can be applied to any sequence classification problem. PMID- 25033409 TI - Hexagonal ice stability and growth in the presence of glyoxal and secondary organic aerosols. AB - The presence of ice dominates the microphysics of formation of high altitude cirrus and polar stratospheric clouds, as well as the maturity of thunderstorms. We report on the hexagonal (1h) ice stability and growth in binary as well as multi-compound aerosols in atmospherically relevant conformations. The ubiquitous atmospheric trace gas glyoxal along with secondary organic aerosol (SOA) also in the presence of CO2 interacts with large ice 1h crystals of 1300-2000 water molecules. The crystals are subjected to phase transitions under superheating and supercooling conditions by Molecular Dynamics (MD) simulations. Density Functional Theory (DFT) based geometry optimization and vibrational frequency analysis are also employed for a smaller ice 1h cell of 12 water molecules. The interaction of the latter with each organic molecule reveals the extent of the mechanical stress exerted on the ordered ice structure. Full hydration of glyoxal promotes ice 1h stability and growth in wet aerosols, while partial hydration or full oxidation exerts a destabilizing effect on the ice 1h lattice. This behavior is associated with the ability of each organic phase to match the order of the ice 1h crystal. We propose that aqueous chemistry in wet aerosols may also have a strong effect on the microphysics of cloud formation. PMID- 25033411 TI - Copper catalyzed C-O bond formation via oxidative cross-coupling reaction of aldehydes and ethers. AB - A practical and efficient construction of C-O bonds via oxidative cross-coupling reaction of aldehydes and ethers has been realized under open air. When 2 mol% copper was used as the catalyst, various alpha-acyloxy ethers were obtained with up to 93% isolated yield. PMID- 25033410 TI - Hormesis effects of silver nanoparticles at non-cytotoxic doses to human hepatoma cells. AB - Silver nanoparticles (AgNPs) have attracted considerable attentions due to their unique properties and diverse applications. Although it has been reported that AgNPs have acute toxic effects on a variety of cultured mammalian cells and animal models, few studies have been conducted to evaluate the associated risk of AgNPs to human health at non-cytotoxic doses. In this paper, HepG2 cells were exposed to 10 nm and 100 nm AgNPs under non-cytotoxic conditions, and cell viability was assessed. At low doses, AgNPs displayed "hormesis" effects by accelerating cell proliferation. Further studies indicated that the activation states of MAPKs were differentially regulated in this process. Specifically, by increasing the expression of downstream genes, p38 MAPK played a central role in non-cytotoxic AgNP-induced hormesis. Moreover, the treatment of HepG2 cells with silver ions (Ag+) at the same dose levels induced distinct biological effects, suggesting that different intrinsic properties exist for AgNPs and Ag+. PMID- 25033413 TI - Novel azepino-perylenebisimides: synthesis, structure, and properties. AB - The first example of an azepine ring formation by counterintuitive nucleophilic participation of DBU was observed at the sterically crowded bay area of electron deficient perylenebisimide (PBI). This is also a rare example of the formation of a seven-membered ring via two consecutive C-N bond formations in a single step. Azepino-PBIs reveal panchromatic absorption covering the whole visible region. Further novelty of these PBIs lies within the fact that their photophysical characteristics can easily be modulated by suitable substituents. PMID- 25033412 TI - Long-term and seasonal dynamics of dengue in Iquitos, Peru. AB - INTRODUCTION: Long-term disease surveillance data provide a basis for studying drivers of pathogen transmission dynamics. Dengue is a mosquito-borne disease caused by four distinct, but related, viruses (DENV-1-4) that potentially affect over half the world's population. Dengue incidence varies seasonally and on longer time scales, presumably driven by the interaction of climate and host susceptibility. Precise understanding of dengue dynamics is constrained, however, by the relative paucity of laboratory-confirmed longitudinal data. METHODS: We studied 10 years (2000-2010) of laboratory-confirmed, clinic-based surveillance data collected in Iquitos, Peru. We characterized inter and intra-annual patterns of dengue dynamics on a weekly time scale using wavelet analysis. We explored the relationships of case counts to climatic variables with cross-correlation maps on annual and trimester bases. FINDINGS: Transmission was dominated by single serotypes, first DENV-3 (2001-2007) then DENV-4 (2008-2010). After 2003, incidence fluctuated inter-annually with outbreaks usually occurring between October and April. We detected a strong positive autocorrelation in case counts at a lag of ~ 70 weeks, indicating a shift in the timing of peak incidence year to-year. All climatic variables showed modest seasonality and correlated weakly with the number of reported dengue cases across a range of time lags. Cases were reduced after citywide insecticide fumigation if conducted early in the transmission season. CONCLUSIONS: Dengue case counts peaked seasonally despite limited intra-annual variation in climate conditions. Contrary to expectations for this mosquito-borne disease, no climatic variable considered exhibited a strong relationship with transmission. Vector control operations did, however, appear to have a significant impact on transmission some years. Our results indicate that a complicated interplay of factors underlie DENV transmission in contexts such as Iquitos. PMID- 25033414 TI - Should beta-blockers be used in septic shock? PMID- 25033415 TI - Solution-based indirect affinity selection mass spectrometry--a general tool for high-throughput screening of pharmaceutical compound libraries. AB - We show here that an automated solution-based affinity selection mass spectrometry (ASMS) system can be built exclusively from commercially available parts. The value of this technology lies in the throughput (~1 * 10(5) compounds/day) coupled with a low hit rate. The system, being a binding assay, requires little development time yielding a fast timeline between target availability and hit identification. In addition, the use of exact mass simplifies the hit identification. We demonstrate this system using carbonic anhydrase as the target and a library of 144,000 proprietary compounds. PMID- 25033416 TI - An overview on the presence of cyclopropane fatty acids in milk and dairy products. AB - A survey was carried out to determine the presence of cyclopropane fatty acids (CPFA) in various dairy products. CPFA such as lactobacillic acid and dihydrosterculic acid are components of bacterial membranes and have been recently detected in milk from cows fed with maize silage. In this paper about 200 dairy samples comprising cow, sheep, and goat milk, cheese, yogurt/fermented milk, and butter were analyzed. Results showed that cow milks were generally positive to CPFA (0.014-0.105% of total fatty acids), while goat, yak, and sheep milks were negative. Experimental yogurt and fermented milks showed the same CPFA content of the starting milk. Positive to CPFA were also the majority of samples of commercial butter and cheeses, except some PDO cheeses as Parmigiano-Reggiano and Fontina, cheeses from mountain regions, and goat and sheep cheeses. These data suggest that the presence of CPFA in dairy products could be used as a marker of silage feeding. PMID- 25033417 TI - Direct oxidative nitration of aromatic sulfonamides under mild conditions. AB - A direct nitration of aromatic sulfonamides using sodium nitrite as the nitrating agent has been developed. The reaction shows typically mono-substitution selectivity and can be enlarged to the gram scale with good yield. PMID- 25033418 TI - Synthesis, structural characterization and cytotoxic activity of ternary copper(II)-dipeptide-phenanthroline complexes. A step towards the development of new copper compounds for the treatment of cancer. AB - In the search for new compounds with antitumor activity, coordination complexes with different metals are being studied by our group. This work presents the synthesis and characterization of six copper complexes with general stoichiometry [Cu(L-dipeptide)(phen)].nH2O (were phen=1,10-phenanthroline) and their cytotoxic activities against tumor cell lines. To characterize these systems, analytical and spectroscopic studies were performed in solid state (by UV-visible, IR, X-ray diffraction) including the crystal structure of four new complexes (of the six complexes studied): [Cu(Ala-Phe)(phen)].4H2O, [Cu(Phe-Ala)(phen)].4H2O, [Cu(Phe Val)(phen)].4.5H2O and [Cu(Phe-Phe)(phen)].3H2O. In all of them, the copper ion is situated in a distorted squared pyramidal environment. The phen ligand is perpendicular to the dipeptide, therefore exposed and potentially available for interaction with biological molecules. In addition, for all the studied complexes, structural information in solution using EPR and UV-visible spectroscopies were obtained, showing that the coordination observed in solid state is maintained. The lipophilicity, DNA binding and albumin interaction were also studied. Biological experiments showed that all the complexes induce cell death in the cell lines: HeLa (human cervical adenocarcinoma), MCF-7 (human metastatic breast adenocarcinoma) and A549 (human lung epithelial carcinoma). Among the six complexes, [Cu(Ala-Phe)(phen)] presents the lowest IC50 values. Taken together all these data we hypothesize that [Cu(Ala-Phe)(phen)] may be a good candidate for further studies in vivo. PMID- 25033419 TI - Investigation of demodex species frequency in patients with a persistent itchy ear canal treated with a local steroid. AB - OBJECTIVE: To investigate the frequency of demodex species in the external acoustic meatus in patients with an itchy ear canal. METHODS: Patients were assigned to one of three groups. Group one consisted of 54 patients with an itchy ear canal who were using a local agent, while group two was composed of 51 patients with an itchy ear canal who were not using a local agent. Group three consisted of 50 healthy individuals without an itchy ear canal. RESULTS: Demodex species test results were positive in nine (5.8 per cent) of the cases. Six of these positive cases were in group one, two in group two and one in group three. The frequency of demodex species in the external acoustic meatus was similar between those patients with an itchy ear canal who did not use a local agent and the healthy individuals (p = 0.571), but it was significantly higher in those using a local steroid compared with those not using a local agent (p = 0.046). CONCLUSION: Although demodex species was not significantly higher in patients with an itchy ear canal compared with the control group, use of a local steroid increased the parasite frequency in the external ear canal of affected patients. PMID- 25033420 TI - Surfactant kinetics and their importance in nucleation events in (mini)emulsion polymerization revealed by quartz crystal microbalance with dissipation monitoring. AB - Surfactants are vital components of almost all heterogeneous polymerizations for maintaining colloidal stability, but they also play an important role in the kinetics and mechanism of particle nucleation. Despite many decades of research, the knowledge of adsorption-desorption surfactant kinetics and their application in (mini)emulsion polymerization is largely based on qualitative arguments. In this paper we show that the use of a quartz crystal microbalance with dissipation monitoring can provide quantitative information on both the adsorption equilibrium of ionic and nonionic surfactants, and also the kinetics of adsorption/desorption, that can be applied to the understanding of nucleation processes in (mini)emulsion polymerization. We show that surfactant dynamics and nucleation phenomena in (mini)emulsion polymerization are not dominated by diffusion phenomena linked to molecular size of surfactant as previously thought but rather are driven by the large differences in the rate of surfactant adsorption and desorption at the polymer-water interface. Finally, we show the application of this knowledge to explain the differences between nucleation processes for ionic and nonionic surfactants in emulsion polymerization. PMID- 25033421 TI - Electrochemical detection of the 2-isobutyl-3-methoxypyrazine model odorant based on odorant-binding proteins: the proof of concept. AB - We developed an electrochemical assay for the detection of odorant molecules based on a rat odorant-binding protein (rOBP3). We demonstrated that rOBP3 cavity binds 2-methyl-1,4-naphtoquinone (MNQ), an electrochemical probe, as depicted from the decrease of its electrochemical signal, and deduced the dissociation constant, KdMNQ=0.5(+/-0.2)MUM. The amount of MNQ displaced from rOBP3 by 2 isobutyl-3-methoxypyrazine (IBMP), a model odorant molecule, was measured using square-wave voltammetry. The release of MNQ by competition led to an increase of the electrochemical response. In addition, this method allowed determination of the dissociation constant of rOBP3 for IBMP, KdIBMP=0.5(+/-0.1)MUM. A negative control was performed with a non-binding species, caffeic acid (CA). The determined binding affinity values were confirmed using a fluorescent competitive binding assay and isothermal titration microcalorimetry. This electrochemical assay opens the way for designing robust, reliable and inexpensive odorant biosensors. PMID- 25033422 TI - Directional fluorescence emission by individual V-antennas explained by mode expansion. AB - Specially designed plasmonic antennas can, by far-field interference of different antenna elements or a combination of multipolar antenna modes, scatter light unidirectionally, allowing for directional light control at the nanoscale. One of the most basic and compact geometries for such antennas is a nanorod with broken rotational symmetry, in the shape of the letter V. In this article, we show that these V-antennas unidirectionally scatter the emission of a local dipole source in a direction opposite the undirectional side scattering of a plane wave. Moreover, we observe high directivity, up to 6 dB, only for certain well-defined positions of the emitter relative to the antenna. By employing a rigorous eigenmode expansion analysis of the V-antenna, we fully elucidate the fundamental origin of its directional behavior. All findings are experimentally verified by measuring the radiation patterns of a scattered plane wave and the emission pattern of fluorescently doped PMMA positioned in different regions around the antenna. The fundamental interference effects revealed in the eigenmode expansion can serve as guidelines in the understanding and further development of nanoscale directional scatterers. PMID- 25033423 TI - Amphiphilic graft copolymers from end-functionalized starches: synthesis, characterization, thin film preparation, and small molecule loading. AB - End-functionalized macromolecular starch reagents, prepared by reductive amination, were grafted onto a urethane-linked polyester-based backbone using copper-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry to produce novel amphiphilic hybrid graft copolymers. These copolymers represent the first examples of materials where the pendant chains derived from starch biopolymers have been incorporated into a host polymer by a grafting-to approach. The graft copolymers were prepared in good yields (63-90%) with high grafting efficiencies (66-98%). Rigorous quantitative spectroscopic analyses of both the macromolecular building blocks and the final graft copolymers provide a comprehensive analytical toolbox for deciphering the reaction chemistry. Due to the modular nature of both the urethane-linked polyester synthesis and the postpolymerization modification, the starch content of these novel hybrid graft copolymers was easily tuned from 28-53% (w/w). The uptake of two low molecular weight guest molecules into the hybrid polymer thin films was also studied. It was found that binding of 1 naphthol and pterostilbene correlated linearly with amount of starch present in the hybrid polymer. The newly synthesized graft copolymers were highly processable and thermally stable, therefore, opening up significant opportunities in film and coating applications. These results represent a proof-of-concept system for not only the construction of starch-containing copolymers, but also the loading of these novel polymeric materials with active agents. PMID- 25033424 TI - Staphylococcus aureus food-poisoning outbreak associated with the consumption of ice-cream. AB - In April 2013, a food poisoning outbreak caused by staphylococcal enterotoxins (SEs) in ice-cream occurred in Freiburg, Germany, among the 31 participants of a christening party. Of the 13 cases, seven were hospitalized or obtained ambulatory treatment. Different types of ice-cream, which was freshly produced at the hotel where the party took place, were found to contain SE and high amounts of coagulase positive staphylococci. Enterotoxigenic Staphylococcus aureus strains isolated from ice-cream and human cases were of the same spa-type (t127), harboured the sea gene and displayed identical phenotypic resistance-, Fourier transform infrared spectroscopy- (FT-IR) and microarray-profiles. Despite the strong microbiological and epidemiological evidence of ice-cream being the incriminated food vehicle of the outbreak, a common source of S. aureus from the ice-cream could not be deduced. As none of the employees carried the outbreak strain, either the equipment used for the production of the ice-cream or a contaminated ingredient is the most likely introduction source. PMID- 25033425 TI - Effectiveness of a novel spontaneous carvacrol nanoemulsion against Salmonella enterica Enteritidis and Escherichia coli O157:H7 on contaminated mung bean and alfalfa seeds. AB - Outbreaks of foodborne illness from consumption of sprouts have been linked to contaminated seeds prior to germination. Due to the long sprouting period at ambient temperatures and high humidity, germinating seeds contaminated with low pathogen levels (0.1logCFU/g) can result in sprouts with high numbers (>=10(8)CFU/g) of pathogens. Currently, the recommended treatment method involves soaking seeds in 20,000ppm (2%) calcium hypochlorite prior to germination. In this study, an alternative treatment involving soaking seeds in a carvacrol nanoemulsion was tested for its efficacy against Salmonella enterica subspecies enterica serovar Enteritidis (ATCC BAA-1045) or EGFP expressing E. coli O157:H7 (ATCC 42895) contaminated mung bean and alfalfa seeds. The antimicrobial treatment was performed by soaking inoculated seed batches in the spontaneous nanoemulsion (4000 or 8000ppm) for 30 or 60min. The spontaneous nanoemulsion was formed by titrating the oil phase (carvacrol and medium chain triglycerides) and water-soluble surfactant (Tween 80(r)) into sodium citrate buffer. Following treatment, the numbers of surviving cells were determined by suspending the seeds in TSB and performing plate counts and/or Most Probable Number (MPN) enumeration. Treated seeds were sprouted and tested for the presence of the appropriate pathogen. This treatment successfully inactivated low levels (2 and 3logCFU/g) of S. Enteritidis and E. coli on either seed types when soaked for either 30 or 60min at nanoemulsion concentrations corresponding to 4000 (0.4%) or 8000 (0.8%) ppm carvacrol. Inoculated alfalfa seeds treated with 4000ppm nanoemulsion, required a 60min treatment time to show a similar 2-3 log reduction. Complete inactivation was confirmed by germinating treated seeds and performing microbiological testing. Total sprout yield was not compromised by any of the tested treatments. These results show that carvacrol nanoemulsions may be an alternative antimicrobial treatment method for mung bean and alfalfa seeds. PMID- 25033427 TI - Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF. PMID- 25033426 TI - Synergistic up-regulation of CXCL10 by virus and IFN gamma in human airway epithelial cells. AB - Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN gamma and influenza virus. The synergism also occurred when the cells were treated with IFN gamma and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFkappaB sites, western blot analysis indicated that the combined treatment of IFN gamma and dsRNA significantly augmented NFkappaB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN gamma and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFkappaB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level. PMID- 25033428 TI - Thermosensitive hydrogel used in dual drug delivery system with paclitaxel-loaded micelles for in situ treatment of lung cancer. AB - In this study, an in situ gel-based dual drug delivery system (PEG-PCL PEG/DDP+MPEG-PCL/PTX, abbreviated as PDMP) was prepared through the combination of a cisplatin (DDP)-containing thermosensitive hydrogel (PEG-PCL-PEG/DDP, PECE/DDP) and paclitaxel (PTX)-loaded polymeric micelles (average diameter of 20.1nm). PDMP is a free-flowing solution at room temperature and forms a stationary gel at body temperature, allowing it to serve as a drug depot for the in situ treatment of lung cancer. For in vivo experiments, the xenografted lung cancer model was used to evaluate the anti-tumor efficacy of the PDMP. The results suggested that PDMP is effective at inhibiting tumor growth and prolonging the survival time of tumor-bearing BALB/c nude mice. The survival time of the PDMP-treated group (53 days) is significantly higher than that of other groups (40 days from the free DDP+PTX group, 26 days from the blank PECE group, 25 days from the normal saline group, p<0.05). Immunohistochemical analysis revealed that tumors in the PDMP group had fewer microvessels and lower proliferation activity compared with those of the control group. Thus, PDMP may have great potential for in situ treatment of lung cancer by minimally invasive injection methods. PMID- 25033429 TI - Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres as tumor-specific drug delivery system. AB - Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres have been designed via the layer-by-layer (LbL) self-assembly technique via the electrostatic interaction between the poly(ethylene glycol) grafted chitosan (CS-g-PEG) as polycation and the citrate modified ferroferric oxide nanoparticles (Fe3O4-CA) as hybrid anion onto the uniform polystyrene sulfonate (PSS) microsphere templates. The well-defined hybrid hollow microspheres ((CS-g-PEG/Fe3O4-CA)4/CS-g-PEG) were obtained after etching the templates by washing with DMF. They possessed superparamagnetic characteristics with a saturation magnetization of 37.23emu/g, and exhibited excellent stability in high ion-strength media and pH dependent DOX release. Their unique structure and outstanding performance make them potential platform for tumor-specific delivery in the tumor diagnostic and therapy. PMID- 25033430 TI - Green synthesis and physical characterization of Au nanoparticles and their interaction with bovine serum albumin. AB - In this study, we used morin as a reducing agent for the synthesis of stable and nearly spherical Au nanoparticles (M-AuNPs), which were characterized by UV-vis, transmission electron microscopy (TEM) and X-ray diffraction (XRD). The binding characteristics and molecular mechanism of the interaction between the M-AuNPs and bovine serum albumin (BSA) were explored by UV-vis absorbance, fluorescence spectroscopy, and circular dichroism spectra (CD). The results showed that the quenching mechanisms were based on static quenching. The thermodynamic parameters DeltaG, DeltaH and DeltaS, suggested that the reaction was spontaneous, and mainly driven by electrostatic interactions. Site marker competitive displacement experiments indicated that MAuNPs bound with high affinity to site I (subdomain IIA) of BSA. Synchronous fluorescence and CD spectra demonstrated that BSA conformation was slightly altered in the presence of M-AuNPs. In addition, the effect of pH, temperature, morin quantity, and reaction time were investigated. PMID- 25033431 TI - Poly(ethyleneimine) functionalized carbon nanotubes as efficient nano-vector for transfecting mesenchymal stem cells. AB - For gene and drug delivery applications, carbon nanotubes (CNTs) have to be functionalized in order to become compatible with aqueous media and bind with genetic materials. In this study, combination of polyethyleneimine (PEI) grafted multi-walled carbon nanotubes (PEI-g-MWCNTs) and chitosan substrate is used as an efficient gene delivery system for transfection of hard-to-transfect bone marrow mesenchymal stem cells (BMSCs) with enhanced green fluorescent protein (EGFP) gene. Fourier transform infrared (FT-IR) spectra, dynamic light scattering (DLS) analysis and zeta potential measurements are used to characterize binding of PEI, particle size distribution and colloidal stability of the functionalized CNTs, respectively. DNA binding affinity, cellular uptake, transfection efficiency and possible cytotoxicity are also tested by agarose gel electrophoresis, flow cytometry, cytochemisty and MTT assay. The results demonstrate that cytotoxic effect of PEI-g-MWCNTs is negligible under optimal transfection condition. In consistency with high cellular uptake (>82%), PEI-g-MWCNTs give higher delivery of EGFP into the BMSCs which results in a more sustained expression of the model gene (EGFP) in short-term culture. These results suggest that PEI-g-MWCNTs in corporation with chitosan substrates would be a promising delivery system for BMSCs, a cell type with relevancy in the regenerative medicine and clinical applications. PMID- 25033432 TI - Novel anti-infective activities of chitosan immobilized titanium surface with enhanced osteogenic properties. AB - We have covalently immobilized chitosan onto a titanium (Ti) surface to manage implant-related infection and poor osseointegration, two of the major complications of orthopedic implants. The Ti surface was first treated with sulfuric acid (SA) and then covalently grafted with chitosan. Surface roughness, contact angle and surface zeta potential of the samples were markedly increased by the sulfuric acid treatment and the subsequent chitosan immobilization. The chitosan-immobilized Ti (SA-CS-Ti) showed two novel antimicrobial roles: it (a) prevented the invasion and internalization of bacteria into the osteoblast-like cells, and (b) significantly increased the susceptibility of adherent bacteria to antibiotics. In addition, the sulfuric acid-treated Ti (SA-Ti) and SA-CS-Ti led to significantly increased (P<0.05) osteoblast-like cell attachment, enhanced cell proliferation, and better osteogenic differentiation and mineralization of osteoblast-like cells. PMID- 25033433 TI - A correlation study of protein adsorption and cell behaviors on substrates with different densities of PEG chains. AB - The adsorption of proteins, in particular fibronectin (Fn), was studied on poly(ethylene glycol) (PEG, 5kDa)-grafted surfaces, and was correlated with the adhesion behaviors of smooth muscle cells (SMCs). The PEG molecules were covalently grafted on aldehyde-activated substrates with different densities of amino groups. The thickness of PEG layer increased nearly 10 fold in a hydrated state, reaching to 27nm on the surface of highest PEG chain density with a brush configuration. On the lower PEG-grafted surfaces, however, the PEG molecules adopted a mushroom configuration. The adsorption of Fn without and with the competition of bovine serum albumin (BSA) and serum was studied by using ellipsometry, fluorescence microscopy and radio-labeling techniques. The adsorption amount of Fn in serum decreased initially with increased PEG chain density until 0.12chains/nm(2) PEG, and then slightly increased on the 0.29chains/nm(2) PEG. A series of protein preadsorption experiments were carried out under different conditions before SMCs culture in vitro. Compared with those substrates without Fn preadsorption, the cell adhesion and spreading were significantly enhanced on all the PEG surfaces preadsorbed with Fn and serum, although they overall decreased along with the increase of PEG grafting density. The adhesion force of Fn decreased monotonously with the increase of PEG grafting density, which was in accordance with the cell adhesion force. The correlation between the PEG-grafted surfaces, Fn adsorption, and cellular behaviors is finally suggested. PMID- 25033434 TI - Surface engineered nanostructured lipid carriers for efficient nose to brain delivery of ondansetron HCl using Delonix regia gum as a natural mucoadhesive polymer. AB - The objective of this investigation was to fabricate ondansetron hydrochloride [OND] loaded mucoadhesive nanostructured lipid carriers [NLCs] for efficient delivery to brain through nasal route. Mucoadhesive NLCs thereby sustaining drug release for longer time in nasal cavity. NLCs were prepared by high pressure homogenization [HPH] technique using glycerol monostearate [GMS]; as solid lipid, Capryol 90; as liquid lipid, soya lecithin; as surfactant and poloxamer 188; as cosurfactant. In the fabrication of NLCs, Delonix regia gum [DRG], isolated from seeds of D. regia belonging to family fabiaceae was used as a mucoadhesive polymer. The NLCs were evaluated for particle size, morphology, drug-entrapment efficiency [%EE], mucoadhesive strength, in vitro drug release, histological examination, ex vivo permeation study, in vivo biodistribution and pharmacokinetic studies in the brain/blood following intravenous [i.v.] and intranasal [i.n.] administration. Particle size, PDI, Zeta potential was observed in the range of 92.28-135nm, 0.32-0.46, and -11.5 to -36.2 respectively. Prepared NLCs achieved thermodynamic stability, control release pattern with minor histopathological changes in sheep nasal mucosa. The significantly [P<0.05] higher values for selected batch was observed, when administered by i.n. route showed higher drug targeting efficiency [506%] and direct transport percentage [97.14%] which confirms the development of promising OND-loaded NLC for efficient nose-to-brain delivery. PMID- 25033435 TI - Synthesis, micellization behavior, antimicrobial and intercalative DNA binding of some novel surfactant copper(II) complexes containing modified phenanthroline ligands. AB - The novel surfactant copper(II) complexes, [Cu(ip)2DA](ClO4)21, [Cu(dpqc)2DA](ClO4)22, [Cu(dppn)2DA](ClO4)23, where ip=imidazo[4,5 f][1,10]phenanthroline, dpqc=dipyrido[3,2-a:2',4'-c](6,7,8,9 tetrahydro)phenazine, dppn=benzo[1]dipyrido[3,2-a':2',3'-c]phenazine and DA dodecylamine, were synthesized and characterized by physico-chemical and spectroscopic methods. In these complexes 1-3, the geometry of copper metal ions was described as square pyramidal. The critical micelle concentration (CMC) value of these surfactant copper(II) complexes in aqueous solution was found out from conductance measurements. Specific conductivity data at different temperatures served for the evaluation of the temperature-dependent CMC and the thermodynamics of micellization (DeltaGm degrees , DeltaHm degrees and DeltaSm degrees ). The binding interaction of these complexes with DNA (calf thymus DNA) in Tris buffer was studied by physico-chemical techniques. In the presence of the DNA UV-vis spectrum of complexes showed red shift of the absorption band along with significant hypochromicity indicating intercalation of our complexes with nucleic acids. Competitive binding study with ethidium bromide (EB) shows that the complexes exhibit the ability to displace the nucleic acid-bound EB indicating that the complexes bind to nucleic acids in strong competition with EB for the intercalative binding site. Observed changes in the circular dichoric spectra of DNA in the presence of surfactant complexes support the strong binding of complexes with DNA. CV results also confirm this mode of binding. Some significant thermodynamic parameters of the binding of the titled complexes to DNA have also been determined. The results reveal that the extent of DNA binding of 3 was greater than that of 1 and 2. The antibacterial and antifungal screening tests of these complexes have shown good results compared to its precursor chloride complexes. PMID- 25033436 TI - Bioactive electrospun fish sarcoplasmic proteins as a drug delivery system. AB - Nano-microfibers were made from cod (Gadus morhua) sarcoplasmic proteins (FSP) (Mw<200kDa) using the electrospinning technique. The FSP fibers were studied by scanning electron microscopy, and the fiber morphology was found to be strongly dependent on FSP concentration. Interestingly, the FSP fibers were insoluble in water. However, when exposed to proteolytic enzymes, the fibers were degraded. The degradation products of the FSP fibers proved to be inhibitors of the diabetes-related enzyme DPP-IV. The FSP fibers may have biomedical applications, among others as a delivery system. To demonstrate this, a dipeptide (Ala-Trp) was encapsulated into the FSP fibers, and the release properties were investigated in gastric buffer and in intestinal buffer. The release profile showed an initial burst release, where 30% of the compound was released within the first minute, after which an additional 40% was released (still exponential) within the next 30min (gastric buffer) or 15min (intestinal buffer). The remaining 30% was not released in the timespan of the experiment. PMID- 25033437 TI - Biodegradable gelatin-ciprofloxacin-montmorillonite composite hydrogels for controlled drug release and wound dressing application. AB - This work reports intercalation of a sparingly soluble antibiotic (ciprofloxacin) into layered nanostructure silicate, montmorillonite (MMT) and its reaction with bone derived polypeptide, gelatin that yields three-dimensional composite hydrogel. Drug intercalation results in changes in MMT layered space and drug loaded MMT and gelatin creates 3D morphology with biodegradable composite hydrogels. These changes can be correlated with electrostatic interactions between the drug, MMT and the gelatin polypeptides as confirmed by X-ray diffraction patterns, thermal, spectroscopic analyses, computational modeling and 3D morphology revealed by SEM and TEM analysis. No significant changes in structural and functional properties of drug was found after intercalation in MMT layers and composite hydrogels. In vitro drug release profiles showed controlled release up to 150h. The drug loaded composite hydrogels were tested on lung cancer cells (A549) by MTT assay. The results of in vitro cell migration and proliferation assay were promising as composite hydrogels induced wound healing progression. In vitro biodegradation was studied using proteolytic enzymes (lysozyme and protease K) at physiological conditions. This new approach of drug intercalation into the layered nanostructure silicate by ion-exchange may have significant applications in cost-effective wound dressing biomaterial with antimicrobial property. PMID- 25033438 TI - Engineering scaffolds integrated with calcium sulfate and oyster shell for enhanced bone tissue regeneration. AB - Engineering scaffolds combinging natural biomineral and artificially synthesized material hold promising potential for bone tissue regeneration. In this study, novel bioactive calcium sulfate/oyster shell (CS/OS) composites were prepared. Comparing to CS scaffold, the CS/OS composites with a controllable degradation rate displayed enhanced mineral nodule formation, higher alkaline phosphate (ALP) activity and increased proliferation rate while treated osteocytes. In CS/OS composites group, elevated mRNA levels of key osteogenic genes including bone morphogenetic protein-2 (BMP-2), runt-related transcription factor 2 (Runx2), osterix (Osx), and osteocalcin (OCN) were observed. Furthermore, The up regulation of BMP-2 and type I collagen (COL-I) was observed for CS/OS composites relative to a CS group. Scaffolds were implanted into critical-sized femur cavity defects in rabbits to investigate the osteogenic capacity of the composites in vivo. The CS/OS scaffolds with proper suitable times and mechanical strength strongly promoted osteogenic tissue regeneration relative to the regeneration capacity of CS scaffolds, as indicated by the results of histological staining. These results suggest that the OS-modified CS engineering scaffolds with improved mechanical properties and bioactivity would facilitate the development of a new strategy for clinic bone defect regeneration. PMID- 25033439 TI - Novel Cu(I)-selective chelators based on a bis(phosphorothioyl)amide scaffold. AB - Bis(dialkyl/aryl-phosphorothioyl)amide (BPA) derivatives are versatile ligands known by their high metal-ion affinity and selectivity. Here, we synthesized related chelators based on bis(1,3,2-dithia/dioxaphospholane-2-sulfide)amide (BTPA/BOPA) scaffolds targeting the chelation of soft metal ions. Crystal structures of BTPA compounds 6 (N(-)R3NH(+)) and 8 (NEt) revealed a gauche geometry, while BOPA compound 7 (N(-)R3NH(+)) exhibited an anti-geometry. Solid state (31)P magic-angle spinning NMR spectra of BTPA 6-Hg(II) and 6-Zn(II) complexes imply a square planar or tetrahedral geometry of the former and a distorted tetrahedral geometry of the latter, while both BTPA 6-Ni(II) and BOPA 7 Ni(II) complexes possibly form a polymeric structure. In Cu(I)-H2O2 system (Fenton reaction conditions) BTPA compounds 6, 8, and 10 (NCH2Ph) were identified as most potent antioxidants (IC50 32, 56, and 29 MUM, respectively), whereas BOPA analogues 7, 9 (NEt), and 11 (NCH2Ph) were found to be poor antioxidants. In Fe(II)-H2O2 system, IC50 values for both BTPA and BOPA compounds exceeded 500 MUM indicating high selectivity to Cu(I) versus the borderline Fe(II)-ion. Neither BTPA nor BOPA derivatives showed radical scavenging properties in H2O2 photolysis, implying that inhibition of the Cu(I)-induced Fenton reaction by both BTPA and BOPA analogues occurred predominantly through Cu(I)-chelation. In addition, NMR-monitored Cu(I)- and Zn(II)-titration of BTPA compounds 8 and 10 showed their high selectivity to a soft metal ion, Cu(I), as compared to a borderline metal ion, Zn(II). In summary, lipophilic BTPA analogues are promising highly selective Cu(I) ion chelators. PMID- 25033440 TI - Use of stable isotopes to identify sources of methane in Appalachian Basin shallow groundwaters: a review. AB - Development of unconventional shale gas reservoirs in the Appalachian Basin has raised questions regarding the potential for these activities to affect shallow groundwater resources. Geochemical indicators, such as stable carbon and hydrogen isotopes of methane, stable carbon isotopes of ethane, and hydrocarbon ratios, have been used to evaluate methane sources however their utility is complicated by influences from multiple physical (e.g., mixing) and geochemical (e.g., redox) processes. Baseline sampling of shallow aquifers prior to development, and measurement of additional geochemical indicators within samples from across the Appalachian Basin, may aid in identifying natural causes for dissolved methane in shallow groundwater versus development-induced pathways. PMID- 25033441 TI - Unusual presentation of a laryngeal mass. PMID- 25033442 TI - Continuous stroke volume estimation from aortic pressure using zero dimensional cardiovascular model: proof of concept study from porcine experiments. AB - INTRODUCTION: Accurate, continuous, left ventricular stroke volume (SV) measurements can convey large amounts of information about patient hemodynamic status and response to therapy. However, direct measurements are highly invasive in clinical practice, and current procedures for estimating SV require specialized devices and significant approximation. METHOD: This study investigates the accuracy of a three element Windkessel model combined with an aortic pressure waveform to estimate SV. Aortic pressure is separated into two components capturing; 1) resistance and compliance, 2) characteristic impedance. This separation provides model-element relationships enabling SV to be estimated while requiring only one of the three element values to be known or estimated. Beat-to-beat SV estimation was performed using population-representative optimal values for each model element. This method was validated using measured SV data from porcine experiments (N = 3 female Pietrain pigs, 29-37 kg) in which both ventricular volume and aortic pressure waveforms were measured simultaneously. RESULTS: The median difference between measured SV from left ventricle (LV) output and estimated SV was 0.6 ml with a 90% range (5th-95th percentile) -12.4 ml-14.3 ml. During periods when changes in SV were induced, cross correlations in between estimated and measured SV were above R = 0.65 for all cases. CONCLUSION: The method presented demonstrates that the magnitude and trends of SV can be accurately estimated from pressure waveforms alone, without the need for identification of complex physiological metrics where strength of correlations may vary significantly from patient to patient. PMID- 25033443 TI - Comparison of methods to account for relatedness in genome-wide association studies with family-based data. AB - Approaches based on linear mixed models (LMMs) have recently gained popularity for modelling population substructure and relatedness in genome-wide association studies. In the last few years, a bewildering variety of different LMM methods/software packages have been developed, but it is not always clear how (or indeed whether) any newly-proposed method differs from previously-proposed implementations. Here we compare the performance of several LMM approaches (and software implementations, including EMMAX, GenABEL, FaST-LMM, Mendel, GEMMA and MMM) via their application to a genome-wide association study of visceral leishmaniasis in 348 Brazilian families comprising 3626 individuals (1972 genotyped). The implementations differ in precise details of methodology implemented and through various user-chosen options such as the method and number of SNPs used to estimate the kinship (relatedness) matrix. We investigate sensitivity to these choices and the success (or otherwise) of the approaches in controlling the overall genome-wide error-rate for both real and simulated phenotypes. We compare the LMM results to those obtained using traditional family based association tests (based on transmission of alleles within pedigrees) and to alternative approaches implemented in the software packages MQLS, ROADTRIPS and MASTOR. We find strong concordance between the results from different LMM approaches, and all are successful in controlling the genome-wide error rate (except for some approaches when applied naively to longitudinal data with many repeated measures). We also find high correlation between LMMs and alternative approaches (apart from transmission-based approaches when applied to SNPs with small or non-existent effects). We conclude that LMM approaches perform well in comparison to competing approaches. Given their strong concordance, in most applications, the choice of precise LMM implementation cannot be based on power/type I error considerations but must instead be based on considerations such as speed and ease-of-use. PMID- 25033445 TI - Syk signaling in dendritic cells orchestrates innate resistance to systemic fungal infection. AB - Host protection from fungal infection is thought to ensue in part from the activity of Syk-coupled C-type lectin receptors and MyD88-coupled toll-like receptors in myeloid cells, including neutrophils, macrophages and dendritic cells (DCs). Given the multitude of cell types and receptors involved, elimination of a single pathway for fungal recognition in a cell type such as DCs, primarily known for their ability to prime T cell responses, would be expected to have little effect on innate resistance to fungal infection. Here we report that this is surprisingly not the case and that selective loss of Syk but not MyD88 in DCs abrogates innate resistance to acute systemic Candida albicans infection in mice. We show that Syk expression by DCs is necessary for IL-23p19 production in response to C. albicans, which is essential to transiently induce GM-CSF secretion by NK cells that are recruited to the site of fungal replication. NK cell-derived-GM-CSF in turn sustains the anti-microbial activity of neutrophils, the main fungicidal effectors. Thus, the activity of a single kinase in a single myeloid cell type orchestrates a complex series of molecular and cellular events that underlies innate resistance to fungal sepsis. PMID- 25033446 TI - The predictive value of Golgi protein 73 in differentiating benign from malignant liver tumors. AB - INTRODUCTION: In the work up of primary solid liver lesions it is essential to differentiate correctly between benign and malignant tumors, such as hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC) respectively. A promising new marker to detect HCC is Golgi Protein 73 (GP73). Studies comparing patients with HCC and cirrhosis with normal controls suggested that GP73 is specific for patients with HCC; however, patients with other liver tumors were not included. We therefore studied the predictive value of GP73 in differentiating between solid benign and malignant liver tumors. MATERIALS AND METHODS: This study included 264 patients: 88 patients with HCC, 88 with hepatocellular adenoma (HCA), and 88 with focal nodal hyperplasia (FNH). A blood sample was collected from each patient to measure GP73 levels using a quantitative ELISA assay and differences in outcome between subgroups were compared. The receiver operating characteristic (ROC) curve, sensitivity and specificity of GP73 were calculated and compared to alpha-fetoprotein (AFP) levels. RESULTS: When comparing malignant and benign liver tumors the area under ROC was 0.701 and 0.912 for GP73 and AFP respectively. Test characteristics revealed a sensitivity of 60% for GP73 and 65% for AFP; in addition the specificity was 77% for GP73 and 96% for AFP. CONCLUSION: Although the literature suggests that GP73 is a valuable serum marker in patients with HCC, the serum concentration may also be increased in patients with solid benign liver tumors. Therefore, a GP73 assay is less suitable for discriminating between primary malignant and benign tumors of the liver. PMID- 25033447 TI - Proteomic changes of alveolar lining fluid in illnesses associated with exposure to inhaled non-infectious microbial particles. AB - BACKGROUND: Hyperresponsiveness to inhaled non-infectious microbial particles (NIMPs) has been associated with illnesses in the airways. Hypersensitivity pneumonitis (HP) is considered to be the prototype for these NIMPs-related diseases; however, there is no consensus on the definitions or diagnostic criteria for HP and the spectrum of related illnesses. METHODS AND FINDINGS: In order to identify the possible diagnostic markers for illnesses associated with NIMPs in alveolar lining fluid, we performed a proteomic analysis using a two dimensional difference gel electrophoresis on bronchoalveolar lavage (BAL) fluid from patients with exposure to NIMPs in the context of damp building-related illness (DBRI) or conditions on the borderline to acute HP, designated here as agricultural type of microbial exposure (AME). Samples from patients with HP and sarcoidosis (SARC) were included for reference. Results were compared to results of healthy subjects (CTR). Western blot was used for validation of potential marker proteins from BAL fluid and plasma. Protein expression patterns suggest a close similarity between AME and HP, while DBRI was similar to CTR. However, in DBRI the levels of the inflammation associated molecules galectin-3 and alpha-1 antitrypsin were increased. A novel finding emerging from this study was the increases of semenogelin levels in BAL fluid from patients with AME, HP and SARC. Histone 4 levels were increased in AME, HP and SARC. Elevated plasma levels of histone 2B were detected in HP and SARC, suggesting it to be a potential blood indicator for inflammatory diseases of the lungs. CONCLUSIONS: In this study, the proteomic changes in bronchoalveolar lavage of DBRI patients were distinct from other NIMP exposure associated lung diseases, while changes in AME overlapped those observed for HP patient samples. Some of the proteins identified in this study, semenogelin and histone 4, could function as diagnostic markers for differential diagnosis between DBRI and HP-like conditions. PMID- 25033449 TI - The influence of antismoking television advertisements on cessation by race/ethnicity, socioeconomic status, and mental health status. AB - Disparities in tobacco use and smoking cessation by race/ethnicity, education, income, and mental health status remain despite recent successes in reducing tobacco use. It is unclear to what extent media campaigns promote cessation within these population groups. This study aims to (1) assess whether exposure to antitobacco advertising is associated with making a quit attempt within a number of population subgroups, and (2) determine whether advertisement type differentialy affects cessation behavior across subgroups. We used data from the New York Adult Tobacco Survey (NY-ATS), a cross-sectional, random-digit-dial telephone survey of adults aged 18 or older in New York State conducted quarterly from 2003 through 2011 (N = 53,706). The sample for this study consists of 9,408 current smokers from the total NY-ATS sample. Regression methods were used to examine the effect of New York State's antismoking advertising, overall and by advertisement type (graphic and/or emotional), on making a quit attempt in the past 12 months. Exposure to antismoking advertising was measured in two ways: gross rating points (a measure of potential exposure) and self-reported confirmed recall of advertisements. This study yields three important findings. First, antismoking advertising promotes quit attempts among racial/ethnic minority smokers and smokers of lower education and income. Second, advertising effectiveness is attributable in part to advertisements with strong graphic imagery or negative emotion. Third, smokers with poor mental health do not appear to benefit from exposure to antismoking advertising of any type. This study contributes to the evidence about how cessation media campaigns can be used most effectively to increase quit attempts within vulnerable subgroups. In particular, it suggests that a general campaign can promote cessation among a range of sociodemographic groups. More research is needed to understand what message strategies might work for those with poor mental health. PMID- 25033448 TI - Shift in the microbial ecology of a hospital hot water system following the introduction of an on-site monochloramine disinfection system. AB - Drinking water distribution systems, including premise plumbing, contain a diverse microbiological community that may include opportunistic pathogens. On site supplemental disinfection systems have been proposed as a control method for opportunistic pathogens in premise plumbing. The majority of on-site disinfection systems to date have been installed in hospitals due to the high concentration of opportunistic pathogen susceptible occupants. The installation of on-site supplemental disinfection systems in hospitals allows for evaluation of the impact of on-site disinfection systems on drinking water system microbial ecology prior to widespread application. This study evaluated the impact of supplemental monochloramine on the microbial ecology of a hospital's hot water system. Samples were taken three months and immediately prior to monochloramine treatment and monthly for the first six months of treatment, and all samples were subjected to high throughput Illumina 16S rRNA region sequencing. The microbial community composition of monochloramine treated samples was dramatically different than the baseline months. There was an immediate shift towards decreased relative abundance of Betaproteobacteria, and increased relative abundance of Firmicutes, Alphaproteobacteria, Gammaproteobacteria, Cyanobacteria and Actinobacteria. Following treatment, microbial populations grouped by sampling location rather than sampling time. Over the course of treatment the relative abundance of certain genera containing opportunistic pathogens and genera containing denitrifying bacteria increased. The results demonstrate the driving influence of supplemental disinfection on premise plumbing microbial ecology and suggest the value of further investigation into the overall effects of premise plumbing disinfection strategies on microbial ecology and not solely specific target microorganisms. PMID- 25033450 TI - Unconditioned stimulus revaluation to promote conditioned fear extinction in the memory reconsolidation window. AB - The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window. PMID- 25033452 TI - Modelling the incidence of Plasmodium vivax and Plasmodium falciparum malaria in Afghanistan 2006-2009. AB - BACKGROUND: Identifying areas that support high malaria risks and where populations lack access to health care is central to reducing the burden in Afghanistan. This study investigated the incidence of Plasmodium vivax and Plasmodium falciparum using routine data to help focus malaria interventions. METHODS: To estimate incidence, the study modelled utilisation of the public health sector using fever treatment data from the 2012 national Malaria Indicator Survey. A probabilistic measure of attendance was applied to population density metrics to define the proportion of the population within catchment of a public health facility. Malaria data were used in a Bayesian spatio-temporal conditional autoregressive model with ecological or environmental covariates, to examine the spatial and temporal variation of incidence. FINDINGS: From the analysis of healthcare utilisation, over 80% of the population was within 2 hours' travel of the nearest public health facility, while 64.4% were within 30 minutes' travel. The mean incidence of P. vivax in 2009 was 5.4 (95% Crl 3.2-9.2) cases per 1000 population compared to 1.2 (95% Crl 0.4-2.9) cases per 1000 population for P. falciparum. P. vivax peaked in August while P. falciparum peaked in November. 32% of the estimated 30.5 million people lived in regions where annual incidence was at least 1 case per 1,000 population of P. vivax; 23.7% of the population lived in areas where annual P. falciparum case incidence was at least 1 per 1000. CONCLUSION: This study showed how routine data can be combined with household survey data to model malaria incidence. The incidence of both P. vivax and P. falciparum in Afghanistan remain low but the co-distribution of both parasites and the lag in their peak season provides challenges to malaria control in Afghanistan. Future improved case definition to determine levels of imported risks may be useful for the elimination ambitions in Afghanistan. PMID- 25033451 TI - Dietary methanol regulates human gene activity. AB - Methanol (MeOH) is considered to be a poison in humans because of the alcohol dehydrogenase (ADH)-mediated conversion of MeOH to formaldehyde (FA), which is toxic. Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and a modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC) from volunteers after pectin intake showed various responses for 30 significantly differentially regulated mRNAs, most of which were somehow involved in the pathogenesis of Alzheimer's disease (AD). There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte specific marker genes were not significantly expressed. A qRT-PCR analysis of volunteer WBCs after pectin and red wine intake confirmed the complicated relationship between the plasma MeOH content and the mRNA accumulation of both genes that were previously identified, namely, GAPDH and SNX27, and genes revealed in this study, including MME, SORL1, DDIT4, HBA and HBB. We hypothesized that human plasma MeOH has an impact on the WBC mRNA levels of genes involved in cell signaling. PMID- 25033453 TI - Sensitization to food and inhalant allergens in relation to atopic diseases in early childhood: a birth cohort study. AB - OBJECTIVES: A correct interpretation of sensitization to common allergens is critical in determining susceptibility to allergic diseases. The aim of this study was to investigate the patterns of sensitization to food and inhalant allergens, and their relation to the development of atopic diseases in early childhood. METHODS: Children aged 0 through 4 years from a birth cohort in the Prediction of Allergies in Taiwanese Children (PATCH) study were enrolled. Specific IgE antibody against food and inhalant allergens were measured and their association between total serum IgE levels and atopic diseases were assessed. RESULTS: A total of 182 children were regular followed up at clinics for a four year follow-up period. The prevalence of food allergen sensitization increased markedly after 6 months of age, reaching up to 47% at 1.5 years of age and then declined significantly to 10% in parallel with a considerable increase in the prevalence of sensitization to inhalant allergens up to 25% at age 4. Food allergen sensitization appeared to be mainly associated with the elevation of serum total IgE levels before age 2. A combined sensitization to food and inhalant allergens had an additive effect on serum IgE levels after age 2, and was significantly associated with the risk of developing atopic diseases at age 4. CONCLUSIONS: Sensitization to food occurs early in life, in parallel with the rising prevalence of sensitization to inhalant allergens at older age. A combined sensitization to food and inhalant allergens not only has an additive increase in serum IgE antibody production but also increases the risk of developing allergic respiratory diseases in early childhood. PMID- 25033454 TI - Leptin promotes wound healing in the oral mucosa. AB - INTRODUCTION: Leptin, a 16 kDa circulating anti-obesity hormone, exhibits many physiological properties. Recently, leptin was isolated from saliva; however, its function in the oral cavity is still unclear. In this study, we investigated the physiological role of leptin in the oral cavity by focusing on its effect on wound healing in the oral mucosa. METHODS: Immunohistochemical analysis was used to examine the expression of the leptin receptor (Ob-R) in human/rabbit oral mucosa. To investigate the effect of leptin on wound healing in the oral mucosa, chemical wounds were created in rabbit oral mucosa, and leptin was topically administered to the wound. The process of wound repair was histologically observed and quantitatively analyzed by measuring the area of ulceration and the duration required for complete healing. The effect of leptin on the proliferation, differentiation and migration of human oral mucosal epithelial cells (RT7 cells) was investigated using crystal violet staining, reverse transcription polymerase chain reaction (RT-PCR) and a wound healing assay, respectively. RESULTS: Ob-R was expressed in spinous/granular cells in the epithelial tissue and vascular endothelial cells in the subepithelial connective tissue of the oral mucosa. Topical administration of leptin significantly promoted wound healing and shortened the duration required for complete healing. Histological analysis of gingival tissue beneath the ulceration showed a denser distribution of blood vessels in the leptin-treated group. Although the proliferation and differentiation of RT7 cells were not affected by leptin, the migration of these cells was accelerated in the presence of leptin. CONCLUSION: Topically administered leptin was shown to promote wound healing in the oral mucosa by accelerating epithelial cell migration and enhancing angiogenesis around the wounded area. These results strongly suggest that topical administration of leptin may be useful as a treatment to promote wound healing in the oral mucosa. PMID- 25033455 TI - Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age. AB - Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs), we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ) pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ) events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age. PMID- 25033456 TI - Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. AB - An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 uM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 uM), and an antifolate drug (pyrimethamine, EC50 of 3.8 uM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease. PMID- 25033457 TI - Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E. AB - DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P<0.05), of which 300 134 were intergenic and 264 084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872 hypermethylated regions. Importantly, pathway analysis revealed 1693 genes associated with the identified DMRs were highly associated in diverse neurological disorders and NAD+/NADH metabolism pathways is implicated in the pathogenesis. Our results provide novel insights into the epigenetic mechanism of neurodegeneration arising from a hotspot DNMT1 mutation and reveal pathways potentially important in a broad category of neurological and psychological disorders. PMID- 25033458 TI - A mouse model of otitis media identifies HB-EGF as a mediator of inflammation induced mucosal proliferation. AB - OBJECTIVE: Otitis media is one of the most common pediatric infections. While it is usually treated without difficulty, up to 20% of children may progress to long term complications that include hearing loss, impaired speech and language development, academic underachievement, and irreversible disease. Hyperplasia of middle ear mucosa contributes to the sequelae of acute otitis media and is of important clinical significance. Understanding the role of growth factors in the mediation of mucosal hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae. METHODS: From a whole genome gene array analysis of mRNA expression during acute otitis media, we identified growth factors with expression kinetics temporally related to hyperplasia. We then tested these factors for their ability to stimulate mucosal epithelial growth in vitro, and determined protein levels and histological distribution in vivo for active factors. RESULTS: From the gene array, we identified seven candidate growth factors with upregulation of mRNA expression kinetics related to mucosal hyperplasia. Of the seven, only HB-EGF (heparin-binding-epidermal growth factor) induced significant mucosal epithelial hyperplasia in vitro. Subsequent quantification of HB-EGF protein expression in vivo via Western blot analysis confirmed that the protein is highly expressed from 6 hours to 24 hours after bacterial inoculation, while immunohistochemistry revealed production by middle ear epithelial cells and infiltrating lymphocytes. CONCLUSION: Our data suggest an active role for HB-EGF in the hyperplasia of the middle ear mucosal epithelium during otitis media. These results imply that therapies targeting HB-EGF could ameliorate mucosal growth during otitis media, and thereby reduce detrimental sequelae of this childhood disease. PMID- 25033459 TI - Suitable habitats for endangered frugivorous mammals: small-scale comparison, regeneration forest and chimpanzee density in Kibale National Park, Uganda. AB - Landscape patterns and chimpanzee (Pan troglodytes schweinfurthii) densities in Kibale National Park show important variation among communities that are geographically close to one another (from 1.5 to 5.1 chimpanzees/km2). Anthropogenic activities inside the park (past logging activities, current encroachment) and outside its limits (food and cash crops) may impact the amount and distribution of food resources for chimpanzees (frugivorous species) and their spatial distribution within the park. Spatial and temporal patterns of fruit availability were recorded over 18 months at Sebitoli (a site of intermediate chimpanzee density and higher anthropic pressure) with the aim of understanding the factors explaining chimpanzee density there, in comparison to results from two other sites, also in Kibale: Kanyawara (low chimpanzee density) and Ngogo (high density, and furthest from Sebitoli). Because of the post-logging regenerating status of the forest in Sebitoli and Kanyawara, smaller basal area (BA) of fruiting trees most widely consumed by the chimpanzees in Kanyawara and Sebitoli was expected compared to Ngogo (not logged commercially). Due to the distance between sites, spatial and temporal fruit abundance in Sebitoli was expected to be more similar to Kanyawara than to Ngogo. While species functional classes consumed by Sebitoli chimpanzees (foods eaten during periods of high or low fruit abundance) differ from the two other sites, Sebitoli is very similar to Kanyawara in terms of land-cover and consumed species. Among feeding trees, Ficus species are particularly important resources for chimpanzees at Sebitoli, where their basal area is higher than at Kanywara or Ngogo. Ficus species provided a relatively consistent supply of food for chimpanzees throughout the year, and we suggest that this could help to explain the unusually high density of chimpanzees in such a disturbed site. PMID- 25033460 TI - A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes. AB - Cytochrome P450 enzymes are found in all life forms. P450s play an important role in drug metabolism, and have potential uses as biocatalysts. Human P450s are membrane-bound proteins. However, the interactions between P450s and their membrane environment are not well-understood. To date, all P450 crystal structures have been obtained from engineered proteins, from which the transmembrane helix was absent. A significant number of computational studies have been performed on P450s, but the majority of these have been performed on the solubilised forms of P450s. Here we present a multiscale approach for modelling P450s, spanning from coarse-grained and atomistic molecular dynamics simulations to reaction modelling using hybrid quantum mechanics/molecular mechanics (QM/MM) methods. To our knowledge, this is the first application of such an integrated multiscale approach to modelling of a membrane-bound enzyme. We have applied this protocol to a key human P450 involved in drug metabolism: CYP3A4. A biologically realistic model of CYP3A4, complete with its transmembrane helix and a membrane, has been constructed and characterised. The dynamics of this complex have been studied, and the oxidation of the anticoagulant R-warfarin has been modelled in the active site. Calculations have also been performed on the soluble form of the enzyme in aqueous solution. Important differences are observed between the membrane and solution systems, most notably for the gating residues and channels that control access to the active site. The protocol that we describe here is applicable to other membrane-bound enzymes. PMID- 25033461 TI - Mechanisms of neuroblastoma cell growth inhibition by CARP-1 functional mimetics. AB - Neuroblastomas (NBs) are a clinically heterogeneous group of extra cranial pediatric tumors. Patients with high-risk, metastatic NBs have a long-term survival rate of below 40%, and are often resistant to current therapeutic modalities. Due to toxic side effects associated with radiation and chemotherapies, development of new agents is warranted to overcome resistance and effectively treat this disease in clinic. CARP-1 functional mimetics (CFMs) are an emerging class of small molecule compounds that inhibit growth of diverse cancer cell types. Here we investigated NB inhibitory potential of CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited NB cell growth, in vitro, independent of their p53 and MYCN status. CFM-4 and -5 induced apoptosis in NB cells in part by activating pro-apoptotic stress-activated kinases (SAPKs) p38 and JNK, stimulating CARP-1 expression and cleavage of PARP1, while promoting loss of the oncogenes C and N-myc as well as mitotic cyclin B1. Treatments of NB cells with CFM-4 or -5 also resulted in loss of Inhibitory kappaB (IkappaB) alpha and beta proteins. Micro-RNA profiling revealed upregulation of XIAP-targeting miR513a-3p in CFM-4-treated NB, mesothelioma, and breast cancer cells. Moreover, exposure of NB and breast cancer cells to CFM-4 or -5 resulted in diminished expression of anti-apoptotic XIAP1, cIAP1, and Survivin proteins. Expression of anti-miR513a-5p or miR513a-5p mimic, however, interfered with or enhanced, respectively, the breast cancer cell growth inhibition by CFM-4. CFMs also impacted biological properties of the NB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Our studies indicate anti-NB properties of CFM-4 and 5, and suggest that these CFMs and/or their future analogs have potential as anti-NB agents. PMID- 25033464 TI - Size-dependent excited state behavior of glutathione-capped gold clusters and their light-harvesting capacity. AB - Glutathione-protected gold clusters exhibit size-dependent excited state and electron transfer properties. Larger-size clusters (e.g., Au25GSH18) with core metal atoms display rapid (<1 ps) as well as slower relaxation (~200 ns) while homoleptic clusters (e.g., Au(10-12)GSH(10-12)) exhibit only slower relaxation. These decay components have been identified as metal-metal transition and ligand to-metal charge transfer, respectively. The short lifetime relaxation component becomes less dominant as the size of the gold cluster decreases. The long-lived excited state and ability to participate in electron transfer are integral for these clusters to serve as light-harvesting antennae. A strong correlation between the ligand-to-metal charge-transfer excited state lifetime and photocatalytic activity was evidenced from the electron transfer to methyl viologen. The photoactivity of these metal clusters shows increasing photocatalytic reduction yield (0.05-0.14) with decreasing cluster size, Au25 < Au18 < Au15 < Au(10-12). Gold clusters, Au18GSH14, were found to have the highest potential as a photosensitizer on the basis of the quantum yield of electron transfer and good visible light absorption properties. PMID- 25033462 TI - Transcriptome sequencing and developmental regulation of gene expression in Anopheles aquasalis. AB - BACKGROUND: Anopheles aquasalis is a major malaria vector in coastal areas of South and Central America where it breeds preferentially in brackish water. This species is very susceptible to Plasmodium vivax and it has been already incriminated as responsible vector in malaria outbreaks. There has been no high throughput investigation into the sequencing of An. aquasalis genes, transcripts and proteins despite its epidemiological relevance. Here we describe the sequencing, assembly and annotation of the An. aquasalis transcriptome. METHODOLOGY/PRINCIPAL FINDINGS: A total of 419 thousand cDNA sequence reads, encompassing 164 million nucleotides, were assembled in 7544 contigs of >= 2 sequences, and 1999 singletons. The majority of the An. aquasalis transcripts encode proteins with their closest counterparts in another neotropical malaria vector, An. darlingi. Several analyses in different protein databases were used to annotate and predict the putative functions of the deduced An. aquasalis proteins. Larval and adult-specific transcripts were represented by 121 and 424 contig sequences, respectively. Fifty-one transcripts were only detected in blood fed females. The data also reveal a list of transcripts up- or down-regulated in adult females after a blood meal. Transcripts associated with immunity, signaling networks and blood feeding and digestion are discussed. CONCLUSIONS/SIGNIFICANCE: This study represents the first large-scale effort to sequence the transcriptome of An. aquasalis. It provides valuable information that will facilitate studies on the biology of this species and may lead to novel strategies to reduce malaria transmission on the South American continent. The An. aquasalis transcriptome is accessible at http://exon.niaid.nih.gov/transcriptome/An_aquasalis/Anaquexcel.xlsx. PMID- 25033463 TI - LANA binds to multiple active viral and cellular promoters and associates with the H3K4methyltransferase hSET1 complex. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-herpesvirus associated with KS and two lymphoproliferative diseases. Recent studies characterized epigenetic modification of KSHV episomes during latency and determined that latency-associated genes are associated with H3K4me3 while most lytic genes are associated with the silencing mark H3K27me3. Since the latency-associated nuclear antigen (LANA) (i) is expressed very early after de novo infection, (ii) interacts with transcriptional regulators and chromatin remodelers, and (iii) regulates the LANA and RTA promoters, we hypothesized that LANA may contribute to the establishment of latency through epigenetic control. We performed a detailed ChIP-seq analysis in cells of lymphoid and endothelial origin and compared H3K4me3, H3K27me3, polII, and LANA occupancy. On viral episomes LANA binding was detected at numerous lytic and latent promoters, which were transactivated by LANA using reporter assays. LANA binding was highly enriched at H3K4me3 peaks and this co-occupancy was also detected on many host gene promoters. Bioinformatic analysis of enriched LANA binding sites in combination with biochemical binding studies revealed three distinct binding patterns. A small subset of LANA binding sites showed sequence homology to the characterized LBS1/2 sequence in the viral terminal repeat. A large number of sites contained a novel LANA binding motif (TCCAT)3 which was confirmed by gel shift analysis. Third, some viral and cellular promoters did not contain LANA binding sites and are likely enriched through protein/protein interaction. LANA was associated with H3K4me3 marks and in PEL cells 86% of all LANA bound promoters were transcriptionally active, leading to the hypothesis that LANA interacts with the machinery that methylates H3K4. Co-immunoprecipitation demonstrated LANA association with endogenous hSET1 complexes in both lymphoid and endothelial cells suggesting that LANA may contribute to the epigenetic profile of KSHV episomes. PMID- 25033466 TI - Incorporation of inorganic mercury (Hg2+) in pelagic food webs of ultraoligotrophic and oligotrophic lakes: the role of different plankton size fractions and species assemblages. AB - In lake food webs, pelagic basal organisms such as bacteria and phytoplankton incorporate mercury (Hg(2+)) from the dissolved phase and pass the adsorbed and internalized Hg to higher trophic levels. This experimental investigation addresses the incorporation of dissolved Hg(2+) by four plankton fractions (picoplankton: 0.2-2.7 MUm; pico+nanoplankton: 0.2-20 MUm; microplankton: 20-50 MUm; and mesoplankton: 50-200 MUm) obtained from four Andean Patagonian lakes, using the radioisotope (197)Hg(2+). Species composition and abundance were determined in each plankton fraction. In addition, morphometric parameters such as surface and biovolume were calculated using standard geometric models. The incorporation of Hg(2+) in each plankton fraction was analyzed through three concentration factors: BCF (bioconcentration factor) as a function of cell or individual abundance, SCF (surface concentration factor) and VCF (volume concentration factor) as functions of individual exposed surface and biovolume, respectively. Overall, this investigation showed that through adsorption and internalization, pico+nanoplankton play a central role leading the incorporation of Hg(2+) in pelagic food webs of Andean lakes. Larger planktonic organisms included in the micro- and mesoplankton fractions incorporate Hg(2+) by surface adsorption, although at a lesser extent. Mixotrophic bacterivorous organisms dominate the different plankton fractions of the lakes connecting trophic levels through microbial loops (e.g., bacteria-nanoflagellates-crustaceans; bacteria ciliates-crustaceans; endosymbiotic algae-ciliates). These bacterivorous organisms, which incorporate Hg from the dissolved phase and through their prey, appear to explain the high incorporation of Hg(2+) observed in all the plankton fractions. PMID- 25033467 TI - Multi-spectral characterization & effect of metal ions on the binding of bovine serum albumin upon interaction with a lincosamide antibiotic drug, clindamycin phosphate. AB - The interaction of clindamycin phosphate (CP) with bovine serum albumin (BSA) is studied by using fluorescence spectra, UV-visible absorption, synchronous fluorescence spectra (SFS), CD, 3D fluorescence spectra and lifetime measurements under simulated physiological conditions. CP effectively quenched intrinsic fluorescence of BSA. The binding constants KA values are 2.540*10(5), 4.960*10(5), 7.207*10(5) L mol(-1), the number of binding sites n and corresponding thermodynamic parameters DeltaG(o), DeltaH(o) and DeltaS(o) between CP and BSA were calculated at different temperatures. The interaction between CP and BSA occurs through dynamic quenching and the effect of CP on the conformation of BSA was also analyzed using SFS. The average binding distance r between the donor (BSA) and acceptor (CP) was determined based on Forster's theory. The results of fluorescence spectra, UV-vis absorption spectra and SFS show that the secondary structure of the protein has been changed in the presence of CP. PMID- 25033465 TI - Transcriptome analysis of a petal anthocyanin polymorphism in the arctic mustard, Parrya nudicaulis. AB - Angiosperms are renown for their diversity of flower colors. Often considered adaptations to pollinators, the most common underlying pigments, anthocyanins, are also involved in plants' stress response. Although the anthocyanin biosynthetic pathway is well characterized across many angiosperms and is composed of a few candidate genes, the consequences of blocking this pathway and producing white flowers has not been investigated at the transcriptome scale. We take a transcriptome-wide approach to compare expression differences between purple and white petal buds in the arctic mustard, Parrya nudicaulis, to determine which genes' expression are consistently correlated with flower color. Using mRNA-Seq and de novo transcriptome assembly, we assembled an average of 722 bp per gene (49.81% coding sequence based on the A. thaliana homolog) for 12,795 genes from the petal buds of a pair of purple and white samples. Our results correlate strongly with qRT-PCR analysis of nine candidate genes in the anthocyanin biosynthetic pathway where chalcone synthase has the greatest difference in expression between color morphs (P/W = ~7*). Among the most consistently differentially expressed genes between purple and white samples, we found 3* more genes with higher expression in white petals than in purple petals. These include four unknown genes, two drought-response genes (CDSP32, ERD5), a cold-response gene (GR-RBP2), and a pathogen defense gene (DND1). Gene ontology analysis of the top 2% of genes with greater expression in white relative to purple petals revealed enrichment in genes associated with stress responses including cold, drought and pathogen defense. Unlike the uniform downregulation of chalcone synthase that may be directly involved in the loss of petal anthocyanins, the variable expression of several genes with greater expression in white petals suggest that the physiological and ecological consequences of having white petals may be microenvironment-dependent. PMID- 25033468 TI - [Ureido-15N]citrulline UPLC-MS/MS nitric oxide synthase (NOS) activity assay: development, validation, and applications to assess NOS uncoupling and human platelets NOS activity. AB - In healthy human subjects, less than 0.2% of l-arginine is converted to l citrulline and nitric oxide (NO) by NO synthases (NOS), a metabolic pathway present in all cell types. Assessment of NOS activity in vitro and in vivo by measuring l-citrulline or NO is difficult. l-citrulline is formed from l-arginine to a much higher extent by other pathways including the urea cycle. Furthermore, NO is a very short-lived gaseous molecule and is oxidized to nitrite and nitrate which are ubiquitous. In fact, nitrite and nitrate are also derived from food and air and are major laboratory contaminants. Further, NOS (in the uncoupled state) are also able to produce superoxide in addition and/or instead of l-citrulline and NO. The difficulties of NOS assays based on l-citrulline and NO measurement can only in part be overcome by sophisticated techniques including use of radio labeled ((3)H or (14)C) and stable-isotope labeled ((15)N2 at the guanidine group) l-arginine analogs as substrates for NOS and measurement of radio-labeled l-citrulline and (15)N-labeled nitrite and nitrate, respectively. In the present work, we report on the development, validation and application of an UPLC-MS/MS method for the assessment of the activity of recombinant NOS enzymes by using [guanidino-(15)N2]-l-arginine (20 MUM for recombinant NOS, 5mM in cell systems) as the substrate and by measuring [ureido-(15)N]-l-citrulline as the reaction product (usually formed at concentrations below 1 MUM) using (2)H7-l-citrulline as the internal standard. The lower limit of detection of the method is about 80 fmol (2)H7-l-citrulline. In cell systems, exceeding [guanidino-(15)N2]-l-arginine is removed by strong cation exchanger solid-phase extraction. The method was cross-validated by a GC-MS assay that measures simultaneously (15)N-nitrite and (15)N-nitrate as pentafluorobenzyl derivatives, with unlabeled nitrite and nitrate serving as the internal standards. By means of this UPLC-MS/MS (15)N citrulline assay, N(G)-nitro-arginine (100 MUM) was found to inhibit recombinant inducible NOS (iNOS) activity (by 38%), whereas nitrite and GSSG (each at 500 MUM) did not affect iNOS activity at all. Nitrite and GSSG at pathophysiological concentrations are unlikely to uncouple NOS. NOS activity was not detectable in platelets of healthy humans by the UPLC-MS/MS and GC-MS assays. PMID- 25033469 TI - Modeling human development in 3D culture. AB - Recently human embryonic stem cell research has taken on a new dimension - the third dimension. Capitalizing on increasing knowledge on directing pluripotent cells along different lineages, combined with ECM supported three-dimensional culture conditions, it has become possible to generate highly organized tissues of the central nervous system, gut, liver and kidney. Each system has been used to study different aspects of organogenesis and function including physical forces underlying optic cup morphogenesis, the function of disease related genes in progenitor cell control, as well as interaction of the generated tissues with host tissue upon transplantation. Pluripotent stem cell derived organoids represent powerful systems for the study of how cells self-organize to generate tissues with a given shape, pattern and form. PMID- 25033470 TI - Hierarchical performance estimation in the statistical label fusion framework. AB - Label fusion is a critical step in many image segmentation frameworks (e.g., multi-atlas segmentation) as it provides a mechanism for generalizing a collection of labeled examples into a single estimate of the underlying segmentation. In the multi-label case, typical label fusion algorithms treat all labels equally - fully neglecting the known, yet complex, anatomical relationships exhibited in the data. To address this problem, we propose a generalized statistical fusion framework using hierarchical models of rater performance. Building on the seminal work in statistical fusion, we reformulate the traditional rater performance model from a multi-tiered hierarchical perspective. The proposed approach provides a natural framework for leveraging known anatomical relationships and accurately modeling the types of errors that raters (or atlases) make within a hierarchically consistent formulation. Herein, the primary contributions of this manuscript are: (1) we provide a theoretical advancement to the statistical fusion framework that enables the simultaneous estimation of multiple (hierarchical) confusion matrices for each rater, (2) we highlight the amenability of the proposed hierarchical formulation to many of the state-of-the-art advancements to the statistical fusion framework, and (3) we demonstrate statistically significant improvement on both simulated and empirical data. Specifically, both theoretically and empirically, we show that the proposed hierarchical performance model provides substantial and significant accuracy benefits when applied to two disparate multi-atlas segmentation tasks: (1) 133 label whole-brain anatomy on structural MR, and (2) orbital anatomy on CT. PMID- 25033471 TI - GR gene BclI polymorphysm changes the path, but not the level, of dexamethasone induced cortisol suppression. AB - BACKGROUND: The hypothalamo-pituitary-adrenocortical (HPA) axis self-regulation is achieved via cortisol binding to mineralocorticoid (MR) and glucocorticoid receptors (GR). It is often disturbed in mental disorders, particularly in those where traumatic stress has been implicated, such as posttraumatic stress disorder and depression. Although dexamethasone suppression test (DST) is often used as diagnostic aid, the findings still vary. In search of the factors influencing the DST outcome, we examined the glucocorticoid receptor (GR) gene BclI polymorphism. METHODS: A total of 229 male subjects were classified into three BclI groups: two groups with homozygous carriers (of the G allele, N=108, and of the C allele, N=26), and one with heterozygous carriers (N=95). Multiple hierarchical linear regression analysis was done, where the dependent variable was the dexamethasone induced cortisol suppression, and predictors included receptor variables. The interactions of the count of 'G's with the predictors were introduced to single out the effects of the G allele. RESULTS: The means of all studied variables, including suppression, are statistically the same in the three groups. However, the mechanism of suppression involves MRs only in the G allele carriers. LIMITATIONS: The subjects were selected by criteria suited for the aim of the large project whose part is this study, hence the relatively small number of CC carriers. Also, we did not assess MR functional properties that would probably sharpen the results. CONCLUSION: Our finding that MRs participate in cortisol suppression in the G allele carriers suggests that research aimed at refining HPA axis-based therapy might require its adjustment for such patients. PMID- 25033472 TI - Are childhood trauma exposures predictive of anxiety sensitivity in school attending youth? AB - BACKGROUND: Stressful life events in adolescents have been found to be longitudinally associated with higher anxiety sensitivity (AS). A question that has not been addressed is whether AS in adolescence is associated with different childhood adversity exposures. METHODS: School attending adolescents (n=1149) completed measures of anxiety sensitivity (CASI), trait anxiety (STAI-T), childhood trauma (CTQ), depression (CES-DC), alcohol (AUDIT) and drug use (DUDIT), and resilience (CD-RISC) and coping orientation (A-COPE). RESULTS: There was no significant gender difference in childhood trauma exposure, resilience levels or coping orientation. Gender differences were evident in terms of AS, trait anxiety, depression, alcohol and drug use. Depression, trait anxiety and alcohol use mediated the relationship between the amount of childhood trauma and AS and played a role in the relationship between certain childhood trauma types and AS. Neither resilience nor coping orientation had a moderating effect on the relationship between the amount of childhood trauma and AS. LIMITATIONS: Cross sectional study, over- or under-reporting of data due to use of self-report instruments, and use of a retrospective measure of childhood trauma (CTQ) that is subject to recall bias. CONCLUSIONS: Girls are at greater risk than boys for early onset anxiety disorders as girls have higher rates of AS, trait anxiety and depression despite the same rates of childhood trauma, coping orientation and resilience. Our findings, in the context of childhood trauma, underscore the influence of depression, trait anxiety and alcohol use as risk factors for the development of AS in youth. PMID- 25033473 TI - Reduction of anterior cingulate in adults with urban violence-related PTSD. AB - BACKGROUND: To evaluate differences in limbic structure volume of subjects exposed to urban violence during adulthood, between those who developed posttraumatic stress disorder (with PTSD) and resilient matched controls (without PTSD). METHODS: Limbic volumetric measures of 32 subjects with PTSD and 32 subjects without PTSD who underwent brain MRI were analyzed in an epidemiological study in the city of Sao Paulo. The hippocampus, amygdala, cingulate, and parahipocampal gyri volumes were estimated using FreeSurfer software. We also investigated the association between limbic volumetric measurements, symptom's severity, and early life stress history (measure by Early Trauma Inventory - ETI). RESULTS: Subjects with PTSD presented reduced volume of the right rostral part of the anterior cingulate, compared to subjects without PTSD, after controlling for intracranial volume, ETI, and depressive symptoms. Subjects with PTSD presented larger bilateral hippocampus and right amygdala, but secondary to the higher ETI. In PTSD group there was a positive correlation between ETI with bilateral hippocampus, bilateral amygdala, and left parahippocampus. LIMITATIONS: First, the cross-sectional study design precludes causal interpretation of limbic structure reduction in PTSD, consequence of PTSD, or other life events. Finally, since the sample size was not sufficiently large, we could not observe whether or not limbic structure volume could be related to the type of trauma. CONCLUSIONS: The present study provides evidence of a reduced anterior cingulate volume in subjects with PTSD than in resilient subjects exposed to urban violence. Enlargement of hippocampus and amygdala volume was observed in subjects with PTSD, however secondary to early trauma experience. PMID- 25033476 TI - Little-known risk factors for cardiovascular disease. Depression is the latest named; studies confirm that it raises the risk of death for patients with heart disease. PMID- 25033475 TI - Association of asthma and bipolar disorder: a nationwide population-based study in Taiwan. AB - BACKGROUND: The relationship between asthma and bipolar disorder has received little research. We sought to investigate this in a large national sample. Previous studies have found mood changes after prednisone use in asthma patients, and we therefore also investigated this exposure in relation to bipolar disorder. METHODS: Cases were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of asthma (ICD-9:493) between 2000 and 2007. Case status required the presence of any inpatient diagnosis of asthma and/or at least one year diagnosis of asthma in outpatient service. These 46,558 cases were compared to 46,558 sex-, age-, residence- and insurance premium matched controls and both groups were followed until the end of 2008 for first diagnosis of bipolar disorder (ICD-9 codes 296.0 to 296.16, 296.4 to 296.81 and 296.89). Competing risk adjusted Cox regression analyses were applied, adjusting for sex, age, residence, insurance premium, prednisone, hyperthyroidism, COPD (chronic obstructive pulmonary disease), Charlson comorbidity index, and hospital admission days for any disorder. RESULTS: Of the 93,116 subjects, 161 were ascertained as having bipolar disorder during a mean (SD) follow-up period of 5.7 (2.2) years. Asthma was an independent risk for bipolar disorder in the fully adjusted model. Higher daily dose of prednisone was a risk factor in asthma cases. LIMITATIONS: The severity of asthma and bipolar disorder, and the route/duration of prednisone treatment were not evaluated. CONCLUSIONS: Asthma was associated with increased risk of bipolar disorder. Higher daily dose of prednisone was associated with a further increased risk. PMID- 25033477 TI - HIIT moves out of the exercise lab and into the real world. A modified version of the High-Intensity Interval Training may be a time-saving, effective way for older, less fit adults to stay in shape. PMID- 25033474 TI - Altered brain network modules induce helplessness in major depressive disorder. AB - OBJECTIVE: The abnormal brain functional connectivity (FC) has been assumed to be a pathophysiological aspect of major depressive disorder (MDD). However, it is poorly understood, regarding the underlying patterns of global FC network and their relationships with the clinical characteristics of MDD. METHODS: Resting state functional magnetic resonance imaging data were acquired from 16 first episode, medication-naive MDD patients and 16 healthy control subjects. The global FC network was constructed using 90 brain regions. The global topological patterns, e.g., small-worldness and modularity, and their relationships with depressive characteristics were investigated. Furthermore, the participant coefficient and module degree of MDD patients were measured to reflect the regional roles in module network, and the impairment of FC was examined by network based statistic. RESULTS: Small-world property was not altered in MDD. However, MDD patients exhibited 5 atypically reorganized modules compared to the controls. A positive relationship was also found among MDD patients between the intra-module I and helplessness factor evaluated via the Hamilton Depression Scale. Specifically, eight regions exhibited the abnormal participant coefficient or module degree, e.g., left superior orbital frontal cortex and right amygdala. The decreased FC was identified among the sub-network of 24 brain regions, e.g., frontal cortex, supplementary motor area, amygdala, thalamus, and hippocampus. LIMITATION: The limited size of MDD samples precluded meaningful study of distinct clinical characteristics in relation to aberrant FC. CONCLUSIONS: The results revealed altered patterns of brain module network at the global level in MDD patients, which might contribute to the feelings of helplessness. PMID- 25033478 TI - Sunshine in a bottle: continuing debate over vitamin D supplements. Are low levels of vitamin D causes of disease--or just indicators of poor lifestyle choices that can foster disease? There's no clear answer yet. PMID- 25033479 TI - Gum disease linked to rare, but deadly, mouth cancer. All the more reason to maintain good oral health. PMID- 25033480 TI - Migraine risk after a stressful event. Once stress hormones subside, you may still be susceptible to a migraine attack. PMID- 25033481 TI - Ever since I began to take Coumadin for atrial fibrillation I have a fear of falling and bleeding. What can I do to improve my balance? PMID- 25033482 TI - Is there any way I can prevent having a stroke? PMID- 25033483 TI - Is it true that vitamin C is beneficial in preventing knee osteoarthritis? PMID- 25033484 TI - About technique for planning interventional treatments. PMID- 25033485 TI - Granuloma annularis revealing Wegener's granulomatosis. AB - Skin manifestations are often associated with systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display pathognomonic dermatological features, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions. Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by E. coli. PMID- 25033486 TI - Repair of an interrupted aortic arch in concomitant diseases. PMID- 25033487 TI - Answer. PMID- 25033488 TI - Early coronary artery disease as a complication of radiotherapy for Hodgkin's disease. PMID- 25033489 TI - Attitudes of prejudice as a predictor of cultural competence among baccalaureate nursing students. AB - The purpose of this study was to explore the relationship between attitudes of prejudice and cultural competence among nursing students. Using a mixed-methods design, a convenience sample of students (N = 129) currently enrolled in a baccalaureate nursing program was recruited via Web networking. Data regarding attitudes of prejudice, cultural competence, prior cultural experience, and integration of cultural competence were obtained via a Web-based survey. Multiple linear regression was used to predict cultural knowledge, attitudes, and consciousness. Although all three regression models were statistically significant, the significant predictors varied within each model. Greater prejudice was a significant predictor of less culturally competent attitudes toward providing nursing care. Existing prejudice among nursing students needs to be addressed to help promote positive cultural attitudes and, ultimately, cultural competent nursing care. PMID- 25033490 TI - Author's reply: To PMID 24486667. PMID- 25033491 TI - [Prospects of adipose tissue stem cells using in plastic surgery and regenerative medicine]. PMID- 25033492 TI - [Cervico-thoracic injuries]. PMID- 25033493 TI - [Causes and prevention of pancreatic fistulas after pancreas resection]. PMID- 25033494 TI - [Resectable rectum cancer and radiation therapy]. PMID- 25033495 TI - [Professor N.N.Elanskii -outstanding military field surgeon 120th anniversary of the birth]. PMID- 25033497 TI - Structural virology. Preface. PMID- 25033496 TI - [Case of candidemia with Candida glabrata with confirmation of the acquisition of micafungin sensitivity due to new mutation of FKS gene mutation]. PMID- 25033498 TI - "Dementia: a health crisis in the making--are we prepared"? PMID- 25033499 TI - ONA works ... so you can practice nursing! PMID- 25033500 TI - Your license at risk: an overview of the Board of Nursing disciplinary process. PMID- 25033501 TI - Healthy work environment toward civility. ANA, nurses promote strategies to prevent disruptive behaviors. PMID- 25033502 TI - Enhancing gerontology in undergraduate nursing programs: the Oklahoma Geriatric Nursing Education Workgroup (OGNEW). PMID- 25033503 TI - Introduction. Why a voice for staff is just a click away. PMID- 25033504 TI - Workforce mix. Diversity makes a difference. PMID- 25033505 TI - The leaders' views. Not just black and white. PMID- 25033506 TI - Make waiting time targets redundant. Complex, perverse and politically untouchable. PMID- 25033507 TI - Targets' pros outweigh cons. PMID- 25033508 TI - Seminar: reform. Change directions. PMID- 25033509 TI - Patient takes priority. PMID- 25033510 TI - Pragmatism can avert a cash crisis. PMID- 25033511 TI - A world without hepatitis C. PMID- 25033512 TI - Public health. A closer look at NHS Health Check. PMID- 25033514 TI - Delayed FDA rule on e-cigarettes draws fire. PMID- 25033513 TI - Staff wellbeing. The anatomy of violence. PMID- 25033515 TI - Contract standoff continues between competing UPMC and Highmark systems. PMID- 25033516 TI - CMS to weigh coverage of CT scans for smokers. PMID- 25033517 TI - Bonuses still tied to better financials. Use of CEO pay incentives for quality is uneven across for-profit hospital systems. PMID- 25033518 TI - Bridging Medicaid's medical and behavioral care chasm. PMID- 25033519 TI - Let's start paying CEO's for quality. PMID- 25033520 TI - Defining the job description for population health. PMID- 25033521 TI - Phoenix hospital offers price transparency and discounts for self-pay patients. PMID- 25033522 TI - Getting ready to manage risk and compete with insurers. PMID- 25033523 TI - [Jakub Barner (1640-1683) and his Chymia philosophica (1698): side notes on the publication of the Polish translation]. AB - The translation of Chymiaphilosophica by Jakub Barner is the second publication in Polish historiography of a printed source work on early modem chemistry (alchemy) written by a Polish citizen, well known and influencial across Europe (the first such translation comprised the treatises of Michael Sendivogius). This admirable initiative of unquestionable value to Polish historians of science resulted in an elegantly published volume, with an extensive introduction and useful appendices. The language of the translation is pleasant to read, retaining the spirit of the original by means of a moderate use of archaisms and generally accurate selection of proper terminology. A closer comparison of some fragments of the translation reveals, however, that it omits essential words, phrases and even entire sentences. The translation itself is occasionally incorrect as well, completely changing the meaning of the author's text and distorting his intentions, thereby undermining the reliability of the Polish translation as a whole. In the factual layer, identifying both chemical substances and (especially) the names of the authors cited by Barner often appear to be doubtful or problematic. Apart from numerous obvious mistakes, as well as leaving many surnames unidentified even when it was very difficult, the translators and/or editors of the Polish text created some non-existent authors as a result of errors produced while copying their surnames from the original text or due to unfounded assumptions that some chemical or botanical terms are names of chemical authors. There is also no consistency in the spelling of surnames (usually left in the Latin form, sometimes spelled with wrong inflection, but also modernised). In the biographical introduction there are also numerous factual errors and some bizarre mistranslations. Not only did its author fail to correct invalid information of earlier biographers of Barner, relying only on the most obvious and accessible publications, but also perpetuated these "historiographical myths" and even created new ones. Neither did he consult any sources apart from some other of Barners published books. Writing from the positivist perspective and on the basis of outdated literature, he also sustained the categorical distinction between alchemy and chemistry, already rejected in contemporary historiography, thus presenting the role and position of Barner in the history of science not quite adequately. If one adds to that the very numerous "typos" throughout the book, it may be regarded as a negative example of poor source editing in almost every respect, even though it makes a pleasant reading. PMID- 25033524 TI - [History and reception of the translations of Plato's Dialogues by Antoni Bronikowski]. AB - The article presents the history of translations of Plato's dialogues as made by A. Bronikowski (1817-1884), their assessment formulated by the contemporary for the translator recipients and today's opinions on them. Bronikowski began his translation work on the legacy of Plato in the '50s of the 19th century and carried them out systematically, despite the many adversities, until his death. The article presents the most important criticisms of the reviewers of Bronikowski's translations, which focused on the flaws of his style. The critics pointed out numerous shortcomings, archaisms, which hindered and prevented smooth reading of the text by readers unfamiliar with the language of the original. Most of the criticisms came from the Warsaw environment, especially from K. Kozlowski, the son of the first Polish translator of Plato, FA. Kozlowski. Among the defenders of Bronikowski there were K. Libelt and J.I. Kraszewski. They raised the subject of difficulty which the translator had to deal with and the lack of literary taste of the audience. It seems that both parties were partially right. Bronikowski's text was indeed not suitable for smooth reading in many places, however, it could serve as a useful tool for students who acquainted themselves with the Greek originals of the dialogues. PMID- 25033525 TI - [Isaac Newton's Anguli Contactus method]. AB - In this paper we discuss the geometrical method for calculating the curvature of a class of curves from the third Book of Isaac Newton's Principia. The method involves any curve which is generated from an elementary curve (actually from any curve whose curvature we known of) by means of transformation increasing the polar angular coordinate in a constant ratio, but unchanging the polar radial angular coordinate. PMID- 25033526 TI - [Some remarks on the theory of sets by Richard Dedekind and Stanislaw Lesniewski]. AB - Mereology, is a part-whole theory, also called the theory of collective sets. It was founded in 1916 by Stanislaw Lesniewski and this is an alternative theory versus the classical set theory by Georg Cantor. These two theories are usually teamed up together as Lesniewski himself was referring to the concept of the set by Cantor and Cantor is considered the "main" ideologist of the set theory. However, when analyzing the original texts of various authors, it seems that the very concept of a collective set is closer to the idea of Richard Dedekind rather than that of Georg Cantor. It is known that Cantor borrowed some concepts on the notion of set from Dedekind, whose ideas were also known to Lesniewski, however, there is no study on this topic. This work is therefore an attempt to compare some set-theoretical concepts of both of these authors, i.e. S. Lesiewski and R. Dedekind and the presentation of their convergence. PMID- 25033527 TI - [Edward Blyth (1810-1873). Father of the Indian ornitology]. AB - Edward Blyth was born on 23 December 1810. When he was ayoung man he took an interest with the zoology which became his life's passion. As a young naturalist he was a conscientious observer of the nature and a man gifted with a superb memory. Unfortunately his career was not successful in London because of the conflict with the younger of the Gray brothers. Facing the prospect of no employment in The British Museum, Blyth decided to leave England for Calcutta where he was offered a post of a museum curator. The English naturalist spent in India the years from 1841 to 1862. During that time he greatly enriched the zoological collection of the museum and consequently the place had much more visitors. Regarding his private life he got married in 1854 to Elisabeth Mary Turner Hodges. Undoubtedly the next four year were the happiest in Blyth's life. After his wife's death Blyth's health condition deteriorated. The ongoing conflicts he kept having while the first stay in India and constant struggle to improve his financial status made him decide to return to England. Blyth left India in 1862. After coming back to his homeland he continued the naturalistic passions. Nevertheless Blyth was constantly troubled by the financial problems. Also, his health, both mental and physical, systematically deteriorated. Finally the death came on 27 December 1873, in London. Blyth tried in vain to gain the recognition and join the scientific establishment of the 19th century England. Constant lack of satisfactory income and often problems with health prevented the ornithologist to be fully devote to his passion. The aim of this article is to highlight some of the most important and interesting events of Blyth's life. Moreover, another objective is to popularise Blyth and his work since he was one of the greatest naturalists of that time. PMID- 25033529 TI - Polish analytical chemistry--its history since 1945. PMID- 25033528 TI - ["adeste omnes Logicae et Mathematicae Musae". Johannes Broscius's Apology of Aristotle and Euclid (1652) and the issue of anti-Ramism at the Academy of Cracow]. AB - This article discusses a largely overlooked aspect of the last work by Johannes Broscius (1585 - 1652), his Apologia pro Aristotele et Euclide contra Petrum Ramum et alios of 1652. While the past researchers focused their attention on the evaluation of Broscius's contribution to mathematics, geometry in particular, they ignored the socio-scientific aspect of his work, that is the way Peter Ramus and his followers have been presented and how did the dark legend of Ramus have been thus revived at the Central-European university in the middle of 17th century. I am showing types of rhetorical arguments employed by Broscius and analyse the way he portrayed Ramus and depicted events related to the reception of Ramism at the Academy of Cracow. The article is followed by an appendix which contains a critical edition of excerpts from the manuscript rough draft of Apologia which has been preserved until nowadays (Jagiellonian Library MS. 3205 I). In the apparatus I identify the references and show how Broscius rewrote and rearranged the original paragraphs of his anti-Ramist work. PMID- 25033530 TI - [Tadeusz Tucholski (1898-1940). A contribution to the scientific biography]. AB - Assistant professor Tadeusz Tucholski Ph.D., murdered in Katyn, was one of the most outstanding representatives of the younger generation of Polish physical chemist scholars of the interwar period. He published over 30 scientific papers in the field of physical and chemical properties of explosions, kinetics and catalysis and also toxicology and forensics. Thesere searches were partly performed at the University of Poznan, in the period 1926-1939, at the Faculty of Medicine of the Department of Physics where Tucholski was employed as a senior assistant and was the closest associate of professor S. Kalandyk, partly at the Department of Forensic Medicine headed by professor S. Horoszkiewicz in the chemical-toxicological laboratory which Tucholski ranin the years 1931-1939, partly at the Warsaw University of Technology in the Department of Explosives Technology of the Faculty of Chemistry headed by professor T. Urbanski, where he had been lecturing "On the latest theories of explosives" since 1937 and in 1934 35 in Cambridge, as a teaching fellow of the National Culture Fund, in Colloid Science Laboratory headed by professor E.K. Rideal. In 1903 Tucholski moved with his parents to Zabaykalye, in 1911--to Brazil. He returned to Poland in 1920, joined the Polish Army and with the 14th Polish Medium Regiment fought on the fronts of the Polish-Bolshevik War. He was drafted to the School of Pyrotechnics Foremen at Corps District Command number VII (Poznan). After graduating, Tucholski remained on active duty as a professional pyrotechnic: from 1921 to 1929 he was appointed the head of the Laboratory of Chemical and Pyrotechnic Ammunition Workshop No. 2 in Poznan and as an inspector of magazines of explosives. In 1927 he was transferred to the reserves, in 1932 after having graduated from the Officer Cadet School in Jarocin, Tucholski was appointed a second lieutenant in the Army Reserve, and later moved from the officers infantry corpsto the army ordnance corps. As part of his specialty, he constantly cooperated with the army. In the years 1937-1939,Tucholski was a technical adviser to the Ministry of Military Affairs and from August 1939--an independent researcher at the Institute of Armament Technology. He took part in the works of the Explosives Commission of the Military Technical Society. Tadeusz Tucholski was a self-taught man. He passed his A-level examsin course of his military service in October 1923 and began studying chemistry at the Faculty of Mathematics and Natural Sciences of the University of Poznan. He obtained his Master's degree in 1927, the rank and the degree of Ph.D. in the field of chemical sciences and physics in 1930. In 1936, he became the Associate Professor of physical chemistry of explosives at the Faculty of Chemistry at the University of Technology in Warsaw. Tucholski invented the method of the differential thermal analysis. He is the author of the widely used differential calorimeter which records the-processes of conversion of explosives during heating, presently known as the Differential Scanning Calorimeter. PMID- 25033531 TI - [Dorota Zamojska, Ph.D. (Oct. 12, 1960 - Dec. 25, 2013) - in memory]. PMID- 25033532 TI - [Memoirs of the late Prof. Hojo Teruyuki]. PMID- 25033533 TI - [Memoirs of the late Prof. Susumu Shibasaki]. PMID- 25033534 TI - [Memoirs of the late Prof. Shin-ichi Mikami]. PMID- 25033535 TI - [Memoirs of the late Prof. Hiroshi Outi]. PMID- 25033536 TI - [On taking office as a professor at Asahi University School of Dentistry (my ambition for a study and the education)]. PMID- 25033537 TI - [National news]. PMID- 25033538 TI - [245th birth anniversary celebration for Jedrzej Sniadecki in Horodnik]. PMID- 25033539 TI - [Fifty years of cooperation--FEBS and Polish Biochemical Society]. AB - This year, the Federation of European Biochemical Societies (FEBS) celebrates its 50th anniversary. The Polish Biochemical Society, represented by the Society's President, Kazimierz Zakrzewski, was a founding member of the organization. The text presents a history of collaboration between FEBS and Polish Biochemical Society, the participation of Polish Biochemical Society members in different FEBS activities, as well as the role they played in running the Federation. Author describes FEBS Congresses which taken place in Warsaw, the first 3rd FEBS Meeting in 1966 and then 29th Congress in 2004. The profiles of Jakub Karol Parnas, the founding father of the Polish biochemistry and some crucial Presidents of the Society, are also presented. The text describes Parnas Conferences, organized jointly by Polish and Ukrainian Biochemical Societies from 1996, and growing from 2011 into three-nation event with participation of Ukrainian, Israeli and Polish scientists, largely due to significant help from FEBS. Summarizing the last few years, author judge the cooperation between the Federation and the Polish Biochemical Society as optimal. PMID- 25033540 TI - [Half century of the concept of "chemiosmotic" energy coupling ,]. AB - History of the formulation of the "chemiosmotic" energy coupling concept of oxidative phosphorylation and photophosphorylation is described. A short CV of its author Peter Mitchell is also presented. PMID- 25033541 TI - [Molecular mechanisms of protein biosynthesis initiation--biochemical and biomedical implications of a new model of translation enhanced by the RNA hypoxia response element (rHRE)]. AB - Translation initiation is a key rate-limiting step in cellular protein synthesis. A cap-dependent initiation is the most effective mechanism of the translation. However, some physiological (mitosis) and pathological (oxidative stress) processes may switch the classic mechanism to an alternative one that is regulated by an mRNA element such as IRES, uORF, IRE, CPE, DICE, AURE or CITE. A recently discovered mechanism of RNA hypoxia response element (rHRE)-dependent translation initiation, may change the view of oxygen-regulated translation and give a new insight into unexplained biochemical processes. Hypoxia is one of the better-known factors that may trigger an alternative mechanism of the translation initiation. Temporal events of oxygen deficiency within tissues and organs may activate processes such as angiogenesis, myogenesis, regeneration, wound healing, and may promote an adaptive response in cardiovascular and neurodegenerative diseases. On the other hand, growth of solid tumors may be accompanied by cyclic hypoxia, allowing for synthesis of proteins required for further progression of cancer cells. This paper provides a review of current knowledge on translational control in the context of alternative models of translation initiation. PMID- 25033542 TI - [Participation of annexins in endocytosis and EGFR-mediated signal transduction]. AB - Annexins are a family of membrane interacting proteins, widely distributed in vertebrates. Their involvement in the endosomal transport is due to annexin capability of binding cellular constituents such as membrane phospholipids and intracellular protein partners in a calcium dependent manner. Furthermore, annexins, through endosomal transport of particular receptors and specific cargo, may regulate various processes involved in signal transduction. Cell surface receptors after activation by signal molecule are internalized during endocytosis and transduce signal downstream the signaling pathway. The optimal conditions to modulate the signal are provided by the compartment specific membrane platforms carrying signal transducing complexes. In this review we describe a role of some members of the annexin family, annexin A1 (AnxA1), annexin A2 (AnxA2), annexin A6 (AnxA6) and annexin A8 (AnxA8) in the epidermal growth factor (EGF) signal transduction pathway. Annexins due to their specialized structure and specific localization in the cell may modulate signal transduction either directly, by interacting with EGF receptor (EGFR) or indirectly by interacting with EGF pathway regulators and effectors, by participating in formation and stabilization of the cholesterol enriched signal transduction platforms and by participating in EGFR transport and degradation. PMID- 25033543 TI - Biogenesis of invadopodia and their cellular functions. AB - Cancer cells degrade the extracellular matrix (ECM) in the basement membrane and blood vessel walls to emigrate and invade from original to peripheral tissues. This invasion of cells through ECM layers is a key step not only in tumor metastasis but also in other processes such as inflammation and development. All of them seem to be facilitated by the formation of small cellular protrusions of localized protease activity, termed podosomes in non-malignant cells and invadopodia in cancer cells. Understanding the mechanisms that lead to functional invadopodia is nowadays a subject of intense study. Herein, a brief overview of the molecular components and regulators of invadopodia will be provided. In this review we will summarize recent achievements and the latest methods of visualizing invadopodia formation and functions, with a strong emphasis on advanced microscopy approaches. PMID- 25033544 TI - [The role of NADPH oxidase NOX4 in regulation of proliferation, senescence and differentiation of the cells]. AB - NADPH oxidase NOX4 is a source of reactive oxygen species in many tissue of human body. NOX4 products of activity are connected with various processes that take on the cellular and tissue level. One of them is cellular senescence. The role of this oxidase in the regulation of replicative and oncogene-induced senescence was shown in both normal and cancer cells. On the other hand NOX4 also stimulates to proliferation various types of cancer and primary cells, what promotes pathologies. NOX4 participates in epithelial-mesenchymal transition, important for tumor cells invasion and metastasis. Many research concern the role of NOX4 in the physiology and pathology of the cardiovascular system. It was shown that NOX4 has an impact on vasoconstriction, atherosclerosis development, vascular cells hypertrophy, apoptosis and differentiation. NOX4 plays both positive and negative role in the organism. Better understanding of NOX4 regulation and its involvement in signaling pathways give a hope to control the development of many diseases. PMID- 25033545 TI - [Filamin A as a mediator of alterations in cancer cells]. AB - Filamin A (FLNA, filamin-1) is a homodimeric protein, commonly expressed in animal organisms. Its basic function in the cell is actin crosslinking and forming 3D cytoskeleton structure. Filamin-1 interacts with more than 60 different proteins with various functions such as: cell membrane and cytoskeleton formation, maintaining cell shape, intracellular signaling, nuclear functions or GTP-binding proteins regulation. FLNA interactions with oncogenesis- and metastasis-related proteins, such as K-RAS, TRAF2 or NIK indicate its crucial role in cancer progression. Filamin-1 undergoes proteolytic fragmentation producing products, translocation of which to the nucleus may be related to alterations in the cell metastatic ability. It was also demonstrated that FLNA dysfunctions can lead to sensitization of cells to ionizing irradiation or common chemotherapeutics: bleomycin and cisplatin. These findings indicate that FLNA can be considered as a novel target in anti-cancer therapy. PMID- 25033546 TI - [Lunasin--a novel chemopreventive peptide]. AB - Lunasin is a bioactive peptide originally isolated from soybean and has demonstrated chemopreventive and anticancer properties against: skin, colon, prostate and breast cancers. Lunasin by binding to the receptors of colon cancer cells prevents its adhesion to the liver tissue. When the receptor is blocked, new blood vessels cannot differentiate which prevent the spread of cancer. In the model estrogen-independent breast cancer, lunasin and aspirin administration inhibits cell proliferation, arrest cell cycle in S-phase as well as a decreases expression of cancer genes. Lunasin has also been found to exert potent antioxidant properties, reducing lipopolysaccharide induced production of ROS by macrophage cells, and acting as a potent free radical scavenger. Using the modifying the of DNA method it has been demonstrated that CpG islands were hypomethylated in RWPE-1 cell lines and hypermethylated RWPE-2 in cell line.Despite of numerous and promising evidence of antitumor activity of lunasin, there are still not explained all the mechanisms of its action in the processes of carcinogenesis. PMID- 25033547 TI - [The mysterious properties of renalase]. AB - Renalase, a recently discovered protein participating in the catecholamine metabolism and belonging to oxidoreductases, possess also antihypertensive and cardioprotective properties, confirmed in several studies on animal models. In human, rat and mouse renalase is thought to be produced mainly by kidney, but increasing number of reports indicates that large quantities of this enzyme, depending on species, are produced by other organs, primarily heart and gonads. However, there are still many uncertainties regarding the mechanism of in vivo action of renalase. The discrepancies in the results of measurement of its concentration in patients with chronic kidney disease exist. Moreover, the site of production and the potential biological function of the renalase isoforms, except isoform 1, are still not determined. PMID- 25033548 TI - [Fructose transporter in yeasts]. AB - Study of hexoses transporter started with discovery of galactose permease in Saccharomyces cerevisiae. Glucose, fructose and mannose assimilation is assumed by numerous proteins encoded by different genes. To date over 20 hexoses transporters, belonging to Sugar Porter family and to Major Facilitator Superfamily, were known. Genome sequence analysis of Candida glabrata, Kluyveromyces lactis, Yarrowia lipolytica, S. cerevisaie and Debaryomyces hansenii reveled potential presence of 17-48 sugar porter proteins. Glucose transporters in S. cerevisiae have been already characterized. In this paper, hexoses transporters, responsible for assimilation of fructose by cells, are presented and compared. Fructose specific transporter are described for yeasts: Zygosaccharomyces rouxii, Zygosaccharomyces bailli, K. lactis, Saccharomyces pastorianus, S. cerevisiae winemaking strain and for fungus Botritys cinerea and human (Glut5p). Among six yeasts transporters, five are fructose specific, acting by facilitated diffusion or proton symport. Yeasts monosaccharides transporter studies allow understanding of sugars uptake and metabolism important aspects, even in higher eukaryotes cells. PMID- 25033549 TI - [Biarsenical probes for specific and multifunctional modification of proteins]. AB - Chemical modifications of proteins are crucial for studying their functions, biophysical properties and cellular localization. The most important is the protein fluorescent modification utilized in biochemistry, molecular biology and medicinal diagnostics. Precision of fluorophore attachment in certain part of the protein or amino acid sequence is very important for the labeling and subsequent characterization or protein applications. One of the most important type of probes used for fluorescent protein labeling are biarsenical probes. They are not only to localize proteins in cell but based on their chemical properties they are widely applied for studying protein folding, degradation, control of the activity, protein inactivation with singlet oxygen, oligomerization and protein purification. Here, author presents principles of protein labeling with biarsenical probes with special attention to factors affecting proper protein modification. Review includes the most interesting applications of biarsenical probes in molecular biology, molecular diagnostics and analytical biochemistry. PMID- 25033550 TI - [ATP-sensitive K(+)-channels in muscle cells: features and physiological role]. AB - ATP-sensitive K(+)-channels of plasma membranes belong to the inward rectifier potassium channels type. They are involved in coupling of electrical activity of muscle cell with its metabolic state. These channels are heterooctameric and consist of two types of subunits: four poreforming (Kir 6.x) and four regulatory (SUR, sulfonylurea receptor). The Kir subunits contain highly selective K+ filter and provide for high-velocity K+ currents. The SUR subunits contain binding sites for activators and blockers and have metabolic sensor, which enables channel activation under conditions of metabolic stress. ATP blocks K+ currents through the ATP-sensitive K(+)-channels in the most types of muscle cells. However, functional activity of these channels does not depend on absolute concentration of ATP but on the ATP/ADP ratio and presence of Mg2+. Physiologically active substances, such as phosphatidylinositol bisphosphate and fatty acid esters can regulate the activity of these structures in muscle cells. Activation of these channels under ischemic conditions underlies their cytoprotective action, which results in prevention of Ca2+ overload in cytosol. In contrast to ATP-sensitive K(+)-channels of plasma membranes, the data regarding the structure and function of ATP-sensitive K(+)-channels of mitochondrial membrane are contradictory. Pore forming subunits of this channel have not been firmly identified yet. ATP sensitive K+ transport through the mitochondrial membrane is easily tested by different methods, which are briefly reviewed in this paper. Interaction of mitoK(ATP) with physiological and pharmacological ligands is discussed as well. PMID- 25033551 TI - [Structure and functions of glutathione transferases]. AB - Data about classification, nomenclature, structure, substrate specificity and role of many glutathione transferase's isoenzymes in cell functions have been summarised. The enzyme has been discovered more than 50 years ago. This family of proteins is updated continuously. It has very different composition and will have demand for system analysis for many years. PMID- 25033552 TI - Ribonuclease activity of buckwheat plant (Fagopyrum esculentum) cultivars with different sensitivities to buckwheat burn virus. AB - Ribonucleases (RNases) are present in base-level amounts in intact plants, but this level is able to increase greatly under stress conditions. The possible cause for such an increase is protection against plant RNA-virus attack. Buckwheat burn virus (BBV) is a highly virulent pathogen that belongs to Rhabdoviridae family. In our study, we have analyzed the correlation between RNase activity and resistance of different buckwheat cultivars to BBV infection. Two cultivars, Kara-Dag and Roksolana, with different sensitivities to BBV have been used. Kara-Dag is a cultivar with medium sensitivity to virus and Roksolana is a tolerant cultivar. It has been shown that the base level of RNase activity in Roksolana cultivar was in most cases higher than the corresponding parameter in Kara-Dag cultivar. Both infected and uninfected plants of Roksolana cultivar demonstrated high RNase activity during two weeks. Whereas infected plants of Kara-Dag cultivar demonstrated unstable levels of RNase activity. Significant decline in RNase activity was detected on the 7th day post infection with subsequent gradual increase in RNase activity. Decline of the RNase activity during the first week could promote the virus replication and therefore more successful infection of upper leaves of plants. Unstable levels of RNase activity in infected buckwheat plants may be explained by insufficiency of virus-resistant mechanisms that determines the medium sensitivity of the cultivar to BBV. Thus, plants of buckwheat cultivar having less sensitivity to virus, displayed in general higher RNase activity. PMID- 25033553 TI - [Ca2+/H(+)-exchange in myometrium mitochondria]. AB - Using the fluorescent probe Fluo-4 AM the authors have identified Na(+) independent Ca2+H(+)-exchange in isolated mitochondria of rat myometrium and studied its individual properties. Formation of directional protons gradient in the matrix of mitochondria causes antyporte release of Ca2+, which has been previously accumulated in energetic processes (in the presence of Mg-ATP and succinate). The functioning of Ca2+/H(+)-exchange depends on the proton gradient and is characterized by reversibility, in case of extramitochondria environment alkalization the additional accumulation of Ca2+ by organelles is recorded. Monovalent cations gradients (Na+, K+, Li+) do not cause the release of Ca2+ from mitochondria. Rate of Ca2+/H(+)-exchange is growing in terms of increasing deltapH on the mitochondria membrane and kinetics of deltapH-induced Ca2+ release from the matrix corresponds to the laws of first order reaction. Research of Ca2+/H(+)-exchange some properties in the myometrium mitochondria showed that the above transport process is of electrogenic nature, perhaps it is done in a 1: 1 stechiometry (Hill coefficient on H+ close to 1) and is able to adjust matrix Ca2+ concentration under physiological conditions (pH activation of about 6.9). Thus, in the inner membrane of the myometrium mitochondria the available system of the secondary active Ca(2+)-transport from the matrix of these organelles to myoplasm and the functioning of Ca2+/H(+)-exchanger may underlie this process. PMID- 25033554 TI - [Complexes of cobalt (II, III) with derivatives of dithiocarbamic acid--effectors of peptidases of Bacillus thuringiensis and alpha-L-rhamnozidase of Eupenicillium erubescens and Cryptococcus albidus]. AB - The influence of cobalt (II, III) coordinative compounds with derivatives of dithiocarbamic acid on Bacillus thuringiensis IMV B-7324 peptidases with elastase and fibrinolytic activity and Eupenicillium erubescens and Cryptococcus albidus alpha-L-rhamnosidases have been studied. Tested coordinative compounds of cobalt (II, III) on the basis of their composition and structure are presented by 6 groups: 1) tetrachlorocobaltates (II) of 3,6-di(R,R')-iminio-1,2,4,5-tetratiane- (RR')2Ditt[CoCl4]; 2) tetrabromocobaltates (II) of 3,6-di(R,R')-iminio-1,2,4,5 tetratiane--(RR')2Ditt[CoBr4]; 3) isothiocyanates of tetra((R,R') dithiocarbamatoisothiocyanate)cobalt (II)--[Co(RR'Ditc)4](NCS)2]; 4) dithiocarbamates of cobalt (II)--[Co(S2CNRR')2]; 5) dithiocarbamates of cobalt (III)--[Co(S2CNRR')3]; 6) molecular complexes of dithiocarbamates of cobalt (III) with iodine--[Co(S2CNRR')3] x 2I(2). These groups (1-6) are combined by the presence of the same complexing agent (cobalt) and a fragment S2CNRR' in their molecules. Investigated complexes differ by a charge of intrinsic coordination sphere: anionic (1-2), cationic (3) and neutral (4-6). The nature of substituents at nitrogen atoms varies in each group of complexes. It is stated that the studied coordination compounds render both activating and inhibiting effect on enzyme activity, depending on composition, structure, charge of complex, coordination number of complex former and also on the enzyme and strain producer. Maximum effect is achieved by activating of peptidases B. thuringiensis IMV B 7324 with elastase and fibrinolytic activity. So, in order to improve the catalytic properties of peptidase 1, depending on the type of exhibited activity, it is possible to recommend the following compounds: for elastase--coordinately nonsaturated complexes of cobalt (II) (1-4) containing short aliphatic or alicyclic substituents at atoms of nitrogen and increasing activity by 17-100% at an average; for fibrinolytic--neutral dithiocarbamates of cobalt (II, III) (4-5) (by 29-199%). For increasing the fibrinolytic activity of peptidase it is better to use dibenzyl- or ethylphenyldithiocarbamates of cobalt (III), which increase activity by 15-40% at an average. The same complexes, and also compound {(CH2)6}2Ditt[CoCl4] make an activating impact on alpha-L-rhamnosidase C. albidus (by 10-20%). PMID- 25033555 TI - Aldehydes participation in oxidative stress in rat thymocytes in vitro. AB - A variety of lipid radicals are formed under oxidative stress development. The further oxidation of these radicals leads to formation of numerous aldehydes. They can form postsynthetic modifications in proteins and nucleic acids that disrupt their functions. In the present study aldehydes role in the formation of oxidative stress parameters in rat thymocytes was investigated. Two models were used: iron-stimulated oxidative stress and exogenous aldehydes exposure to thymocytes. For oxidative stress induction, thymocytes (2 x 10(6) cells/ml HBSS, pH 7.2) were exposed to different concentrations of FeSO4 (20, 30, 40 microM) and ascorbic acid (100 microM) for 6 h. It resulted in increase of levels of aldehydes 29 times (90 +/- 6 nmol/10(7) cells), these changes led to increase of TBARS levels 4.4 times; the levels of protein CO groups 10 times, cell mitochondrial activity and low-molecular weight SH groups were decreased 1.5 and 2.3 times, respectively. Treatment with aldehydes acceptor dimedone (200 microM) significantly decreased the levels of aldehydes 3.7 times, TBARS 1.6 times and protein CO groups 5 times. It was shown that the levels of cell mitochondrial activity increase 1.4 times and the levels of SH groups 1.8 times. To compare the effects of aldehydes in induction of oxidative stress, thymocytes (2 x 10(6) cells/ml HBSS, pH 7.2) were exposed to 50-600 microM formaldehyde (FA), 50-600 microM glyoxal (GL), 50-600 microM methylglyoxal (MGL), 1-15 microM acrolein (ACR) for 6 h. TBARS levels were increased for FA 1.3 times and for other aldehydes about 5-7 times. The levels of protein CO groups were increase for FA 3.7 times, for MGL 7 times, for GL 13 times, for ACR 22 times. Levels of SH groups were decreased for FA 1.5 times, for MGL 2.6 times, for GL 3 times, for ACR 9 times. A decrease of cell mitochondrial activity 1.5 times observe for all aldehydes. Obtained results prove the aldehydes participation in the formation of oxidative stress parameters and their capability to oxidative stress induction in the rat thymocytes. PMID- 25033556 TI - [Influence of polymicroelement preparation esmin on hydrogen sulfide levels and indices of pro- and antioxidant system in the rat myocardium of different age]. AB - The influence of microelement preparation Esmin on hydrogen sulfide (H2S) levels, activity of H2S-producing enzymes and indices of pro-/antioxidant system in the myocardium of different age rats were investigated. In the process of aging the levels of H2S and activities of H2S-producing enzymes (cysteine aminotransferase, cystathionine-gamma-lyase) are reduced in the myocardium; the pro-/antioxidant balance is destabilized (NADPH-oxidase activity is increased and thioredoxin reductase activity is decreased). Esmin administration effectively reduces age related changes in the myocardium of old rats: increases H2S levels and activity of H2S-producing enzymes, restores pro-/antioxidant balance. PMID- 25033557 TI - Effect of the T-domain on intracellular transport of diphtheria toxin. AB - Subunit B of diphtheria toxin (DT), which consists of two domains: R (receptor binding) and T (transmembrane), plays an important role in toxin-receptor binding on the cell-targets and in transportation of catalytic subunit A to the cell cytosol. Recombinant analogues of the subunit B are promising representatives in the unique class of transporting proteins, able to deliver different types of biologically active molecules to cell cytosol. In the development of these protein constructs understanding of the role of each of the DT fragments in determination of transporting pathways of endocytosed complex toxin-receptor is urgently required. We have studied in this work the T-domain effect on intracellular transport of recombinant fragments of DT. We have compared intracellular transport of the R-domain and the subunit B, the last one consisted of both R-domain and T-domain. Recombinant fragments of DT used in this work were labeled with fluorescent proteins, which allowed applying colocalization technique for our study. Application of confocal microscopy technique revealed differences in transportation of recombinant derivates of DT in Vero cells: R domain moved faster than subunit B to tubular compartments. Analysis of R-domain and subunit B transportation confirmed almost linear increase of their colocalization with the time regarding to Pearsons correlation coefficient (PCC). However, amount of colocalized with R-domain subunit B were not linearly increased with time according to Manders coefficient (M1), this could indicate the ability of subunit B to transport to such compartments that R-domain do not reach. Possible role of the T-domain in intracellular transportation and compartmentalization of the toxin may be associated with the ability of the T domain to form a proton channels and its ability to interact with COPI complex. PMID- 25033558 TI - [N-stearoylethanolamine effect on the level of 11-hydroxycorticosteroids, cytokines IL-1, IL-6 and TNFalpha in rats with nonspecific inflammation caused by thermal burn of skin]. AB - The mechanisms of anti-inflammatory action of saturated N-acylethanolamine--N stearoylethanolamine (NSE) were investigated on the rat model of nonspecific inflammation (thermal burns of the skin). The results showed that the NSE application in a form of aqueous suspension (10 mg/ml) on the damaged skin area during 12 days significantly accelerated the healing process of burned wounds. NSE also prevented the increase of 11-hydroxycorticosteroids content in the blood of rats with burns. There was also found a significant decrease of cytokines (IL 1beta, IL-6 and TNFalpha) levels under the NSE action. This way may be one of the mechanisms of NSE anti-inflammatory action. PMID- 25033559 TI - [Biophysical parameters of erythrocyte membranes and mechanisms of interaction with non-opioid analgesics under acute pain syndrome]. AB - Methods of fluorescent probing, spectrophotometry and microcalorimetry were applied to investigate the alterations in biophysical parameters of erythrocytes membranes, and specifically microviscosity, surface charge, molecular organization of lipid bilayer and lipid-protein interactions under conditions of acute pain syndrome produced by experimental chemical lesion. The distinctive features of non-opiod analgesics interactions and binding to the erythrocytes membranes of rats subjected to acute nociceptive pain accompanied with oxidative stress development were investigated. The abilities of analgesics under research, and namely paracetamol, aspirin, phenazone, ketorolac, pyrodazole, ketoprofenum, natrium mefenaminate, indometacin, nimesulide to make up physico-chemical complexes with lipoperoxidation modified erythrocytes surface and protein-lipid bilayer showed marked changes. The significance of oxidative damage of biophase under conditions of acute pain syndrome for analgesics effective pharmacodynamics and pharmacokinetics realization is under consideration. PMID- 25033560 TI - [Trace elements storage peculiarities and metallothionein content in human thyroid gland under iodine deficiency euthyroid nodular goiter]. AB - Accumulation of iodine and copper in the node, paranodular and contralateral (not affected tissue by node) tissues of thyroid gland in relation to the level of metal-binding proteins, potential antioxidants and oxidative changes in tissue was investigated. To assess the severity of the pathological process the molecular markers of cytotoxicity were used. The reduction of total iodine (by 19.5%), increase of inorganic iodine fraction (by 82.4%) and total copper content (twice) in paranodular and nodular tissues compared with contrlateral part have been established. Excess of copper in goitrous-changes tissue was partially accumulated in the metallothioneins. The level of metal-binding form of metallothioneins and reserve of free thiols of these proteins was higher two three times and lower content of reduced glutathione in node-affected tissue compared to the contralateral part. Signs of cytotoxicity among them: higher cathepsine D free activity (up to 84.6% and 134.4% in paranodular tissue and node respectively) and higher level of DNA strand breaks in the node (up to 22.6%) were observed. In paranodular tissue the range of indices variability compared with parenchyma of contralateral part is shorter than in the node. Thus, under low level of iodine organification and high copper level in goitrous-modified tissue of thyroid gland metallothionein may provide a partial compensatory effect on prooxidative processes. PMID- 25033561 TI - [Antioxidant status and glutathione redox potential of erythrocytes in patients with acute coronary syndrome]. AB - Indicators of oxidative stress (OS), systemic inflammation, metabolism and redox status of glutathione (GSH) were investigated and compared in patients with ST segment elevation myocardial infarction on electrocardiograms (STEMI), and patients with unstable angina (UA). The elevated and decreased myeloperoxidase level, superoxide dismutase activity, and moderate increased plasma levels of interleukin-6, while maintaining the antioxidant potential, were found in Group 1. Disorders in pro-/antioxidant balance and systemic inflammatory response were manifested in UA. Increased GSH concentration (and total GSH) in erythrocytes has been established for STEMI patients and the decreased GSH for UA patients. Thus, a significant shift of erythrocytes redox to oxidization and increase (unlike STEMI patients) of glutathione peroxidase activity were recorded. Mechanisms of the pro- and antioxidant functions of red blood cells in acute coronary syndrome are considered. The role of red blood cell glutathione to provide more oxidized intravascular environment for S-glutathionylation and optimization of redox signaling in target cells is pronounced. PMID- 25033562 TI - [Indicators of exchange of bile pigments under the action of ecopathogenic factors on the organism and correction with liposomes]. AB - High levels of anthropogenic impact on the environment requires a detailed study of the features of the influence of heavy metals and ionizing radiation on living organisms, and provides for the development and use of effective means of protecting the body from its negative influence. The purpose of the work was to study the characteristics of the exchange of bile pigments of rats under the action of ecopathogenic factors (ionizing radiation and cadmium) on the organism and the corrective properties of liposomes on the basis of milk phospholipids. An analysis of the chromatographic studies of bilirubin and derivatives (nonconjugated bilirubin, bilirubin sulfate, billirubin glucuronide, urobilin and stercobilin) in the whole blood, liver, jejunum contents and feces under the action on the animal organism of ecopathogenic factors (ionizing radiation and cadmium) indicate material violation of the exchange bile pigments that may be due to the destabilization of the structural and functional hot hepatocytes. Correction of the liposomal form of biologically active additive (BAA) FLP-MD is recommended; the latter is a mixture of phospholipids isolated from milk, with a mixture of unsaturated fatty acids (oleic, linoleic, linolenic) and antioxidants (alpha-tocopherol and retinol acetate). The additive components exhibit the reparative effect of the action in respect of the damaged membrane structures with simultaneous improving of cholepoietic and billiation liver function, and therefore contribute to the normalization of exchange og bile pigments in terms of action on the body ecopathogenic factors. PMID- 25033563 TI - [Influence of hemantane in injectable dosage form on levodopa-induced dyskinesia in rats with model parkinsonian syndrome]. AB - Levodopa-induced heavy dyskinesia was modeled in rats with severe hemiparkinsonian syndrome induced by injection of 6-hydroxydopamine in the left medial forebrain bundle. It is established that the antidyskinetic effect of the injectable dosage form of a new antiparkinsonian drug hemantane (5 mg/kg) after a single intravenous administration is weaker than that of the most effective in clinical practice antidyskinetic drug amantadine (20 mg/kg). However, after five days of treatment, the effect of hemantane injections exceeded that of amantadine. PMID- 25033564 TI - [Insulin potentiating and antidepressant effects of 3-oxypyridine and succinic acid derivatives]. AB - The dependence of the antidepressant action of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin, and mexidol) on the insulin potentiating activity of these therapeutic agents has been studied in experiments on rats. Alpha-lipoic acid was used as a reference drug. It was established that single administration of emoxipine, reamberin, mexidol and alpha-lipoic acid in optimal doses, corresponding to the therapeutic range in humans, increased the sensitivity of animals to insulin according to the criterion of insulin coma development. Triple administration of the therapeutic agents studied in the same single dose produced an antidepressant effect according to the criterion of "desperate behavior" in Porsolt forced swimming test. Standardization of obtained data by average difference from the control and further correlation analysis demonstrated that the extent of antidepressant action of emoxipine, reamberin, mexidol and alpha-lipoic acid considerably depends on their insulin potentiating activity (r = 0.762, p = 0.004). PMID- 25033565 TI - [Studying the development of imipramine tolerance and prospects of its overcoming with the aid of tianeptine]. AB - Reaction of two groups of mice to sub-chronic imipramine administration has been studied in a series of experiments, where one (control) group received physiological saline instead of imipramine. Then, both groups were randomly divided to receive either tianeptine (two groups) or physiological saline (two groups) for three days. After this period, the reaction of mice to imipramine was assessed again by measuring the immobilization duration in the tail suspension test. It was found that sub-chronic administration of imipramine (6 days) did not reduce sensitivity of the mice to this medication. Tianeptine showed "pro depressive" action in the tail suspension test, but the administration of tianeptine increased the sensitivity of rodents to imipramine. PMID- 25033566 TI - [Influence of mydocalm on the degree of intra-abdominal hypertension and local blood circulation in the intestinal wall in experiment]. AB - The effect of mydocalm (tolperison, 5 mg/kg single dose) on the dynamics of intra abdominal hypertension (IAH), blood circulation regulation, and oxygen balance in the tissues of intestinal wall were studied in acute experiments on rabbits. Using a special stand of original design, the initial IAH level was modeled at 200 mm H2O with the subsequent stopping of further receipt of liquid during 3 hours in an elastic container in the abdominal cavity. During 3-h observation without drug administration, no changes in IAH due to the tone of muscles of the frontal abdominal wall takes place, but there is progressive deceleration of local blood flow (-35.33 + 0.99%, p < 0.01), suppressed dilation (-20.02 + 0.54%, p < 0.01) and constriction (-60.45 + 1.17%, p < 0.01) reactivity of vessels, and decreased oxygen tension (-47.18 + 0.75%, p < 0.01) in the intestinal wall at the end of experiment. The introduction of mydocalm reduces the tone of muscles of the frontal abdominal wall, which leads to a decrease in IAH (maximum effect after 1.5 hours, -20.81 + 0.84%, p < 0.01) and prevents decrease in the local blood flow (-26.77 + 0.41%, p < 0.01), suppression of dilation (-16.51 + 0.34%, p < 0.01) and constriction (-37.85 + 0.61%, p < 0.01) reactivity of vessels, and reduction in oxygen tension (-36.60 + 1.18%, p < 0.01) at the end of experiment. The administration of mydocalm can extend the limits of application of a conservative therapy for patients with IAH and to improve the results. PMID- 25033567 TI - [Comparative study of the toxicity and antiarrhythmic activity of some organic derivatives of dimethylacetamide]. AB - A comparative study of the acute toxicity and antiarrhythmic activity of new domestic derivatives of dimethylacetamide showed that the introduction of amino and carboxylic acid residues into the structure of compounds is accompanied by reduction of the toxic properties of new substances on the average 2.73 times (p = 0.002) upon intraperitoneal introduction to animals. It has been established that the derivatives are able to prevent the formation of aconitine induced arrhythmias and eliminate the arrhythmia that occurs on the second day of myocardial infarction in dogs. Original derivatives of dimethylacetamide exhibit antiarrhythmic properties and their activity increases in proportion to the acute toxicity (r = 0.83, p = 0.0043). PMID- 25033568 TI - [Preclinical study of the new anti-influenza drug candidate AV0038 (ethyl 2 (dimethylaminomethyl)-5-hydroxy-1-methyl-6-(pyridin-3-yl)-1H-indole-3 carboxylate)]. AB - In the framework of preclinical testing of AV0038, ethyl 2-(dimethylaminomethyl) 5-hydroxy-1-methyl-6-(pyridin-3-yl)-1H-indole-3-carboxylate, which showed high efficiency in the prevention and treatment of influenza A/Aichi/2/69 (H3N2) in mice, we have studied the drug solubility and stability in aqueous solutions, metabolic stability in human liver microsomes, stability in blood plasma of mice and humans, binding to plasma proteins of mice and humans, pharmacokinetics and bioavailability in mice, and the acute toxicity and the maximum tolerated dose. It is established that AV0038 has attractive pharmacological properties as anti influenza drug candidate. The therapeutic doses of AV0038 do not cause acute toxicity in mice. It is expedient to continue preclinical investigations and study the drug metabolism, metabolites, and sub-chronic toxicity in test animals. PMID- 25033569 TI - [Influence of nonsteroidal anti-inflammatory drugs on chemiluminescence of polymorphonuclear leukocytes in patients with intolerance of these drugs]. AB - We have studied the intensity of barium sulfate stimulated luminol- and lucigenin dependent chemiluminescence (SLCHL and SLCCHL) in polymorphonuclear leukocytes (PML) after pre-incubation of PML suspension with sodium salicylate, sodium metamizole, or sodium diclofenac at various concentrations in healthy donors and patients with intolerance to aspirin, and/or sodium metamizole, and/or sodium diclofenac. No significant differences of SLCHL and SLCCHL indicators in PML isolated from healthy donors and patients with intolerance to these drugs have been found, which indirectly indicates the absence of any specific features in the oxidative metabolism of PML enzymes under the influence of indicated NSAIDs in patients intolerant of these drugs as compared to donors. PMID- 25033570 TI - [Serotonin and its receptors in the cardiovascular system]. AB - Serotonin in cardiovascular system plays an important role in blood coagulation, allergy, and inflammation, as well as in blood vessel tone regulation. In this review, the mechanisms of serotonin effects upon the cells of blood vessels are considered and the list of main agonists and antagonists is presented. The signaling pathways activated by serotonin and their interaction in normal and pathological states are described. PMID- 25033571 TI - [Modern notions about the role of taurine in the central nervous system]. AB - Literature data concerning modern notions about the role of taurine in the central nervous system are analyzed. Mechanisms of the neuroprotective activity of taurine are described. Evidence showing the effects of taurine as neurotransmitter, neuromodulator, antioxidant, etc. is provided. PMID- 25033572 TI - Occupational medicine--then and now: where we could go from here. AB - Occupational medicine has a long-standing history in the region of the former Yugoslavia with seminal contributions to the theory and practice of this discipline. This tradition should be expanded to incorporate psychosocial stressors. We review the sociological work stress models and empirical evidence gleaned thereby, and then the occupational stressor index, an additive burden model developed from a cognitive ergonomics perspective. In numerous studies, the occupational stressor index is significantly associated with risk behaviors: smoking, obesity and sedentariness and clinical outcomes: hypertension, ischemic heart disease, dyslipidemia and type 2 diabetes. The occupational stressor index characterizes the work conditions of physicians including surgeons and anesthesiologists; professional drivers and other groups at elevated risk for stress-related disorders. Much of these empirical data are from this region. Work stress related health disorders are a major public health problem, with enormous human and economic costs. A more proactive role for physicians is needed vis-a vis our working environment and that of patients. We physicians face a heavy job stressor burden strongly implicated with adverse health outcomes. The challenge is to identify effective strategies to lower the risk of work-stressor related illness. The critical gap is the lack of evidence-based guidelines. Intervention studies are needed in which job stressors are ameliorated as a therapeutic/preventive modality; the logical starting point is within our own profession. We also suggest how the relevant clinical competence could be enhanced. Alongside clinical enhancement should be the full restoration of physician empowerment to implement work-related recommendations. A participatory action research perspective by physicians for physicians and for our patients is needed. PMID- 25033573 TI - Morphologic and morphometric analysis of alternations in the oral cavity caused by Candida albicans--experimental work. AB - INTRODUCTION: Candidiasis has become a human disease of increasing importance in the last decades. The aim of the study is to establish pathomorphological alterations caused by the blastospores of the Candida albicans as well as morphometric alterations. MATERIAL AND METHODS: The experiment was carried out on 2.5-month-old rats, weighting 110-130 g. The study sample was divided into the animals infected by a submucous inoculation in the periodontal region and the controls. The gingival specimens were taken, preparations were done and stained by the hematoxylin-eosin and Periodic acid Schiff methods. RESULTS: The following alterations were found out by the stereological analysis: an average volume of nuclei of the gingival epithelial cells was 111.82 microm3 (SD = 25.34) on the first day. A statistically significant increase in the volume of nuclei in the experimental group began to occur from the fourth day (202.97 microm3; SD = 31.16, p < 0.05) and the highest value of the nuclei volume was found out on the eight day of the experiment (316.83 microm3; SD = 40.15). CONCLUSION: Blastospores of Candida albicans are pathogenic for the gingival tissue where they cause degenerative necrotic alterations of the granulomatous character and after the fourth day from the inoculation, the development of the pseudohyphae was observed. The obtained values of stereologic measurement show the acute increase in the volume of nuclei. PMID- 25033574 TI - Comparative analysis of success of psoriasis treatment with standard therapeutic modalities and balneotherapy. AB - INTRODUCTION: Psoriasis is a chronic, inflammatory, immune-mediated skin disease. In addition to standard therapeutic modalities (antibiotics, cytostatics, phototherapy, photochemotherapy and retinoids), nonstandard methods can be used in the treatment of psoriasis. This includes balneotherapy which is most commonly used in combination with therapeutic resources. The aim of this research was to determine the length of remission of psoriasis in patients treated with standard therapeutic modalities, balneotherapy, and combined treatment (standard therapeutic modalities and balneotherapy). MATERIAL AND METHODS: The study analyzed 60 adult patients, of both sexes, with different clinical forms of psoriasis, who were divided into three groups according to the applied therapeutic modalities: the first group (treated with standard therapeutic modalities), the second group (treated with balneotherapy) and the third group (treated with combined therapy-standard methods therapy and balneotherapy). The Psoriasis Area and Severity Index was determined in first, third and sixth week of treatment for all patients. The following laboratory analysis were performed and monitored: C reactive protein, iron with total iron binding capacity, unsaturated iron binding capacity and ferritin, uric acid, rheumatoid factors and antibodies to streptolysin O in the first and sixth week of treatment. RESULTS: The average length of remission in patients treated with standard therapeutic modalities and in those treated with balneotherapy was 1.77 +/- 0.951 months and 1.79 +/- 0.918 months, respectively. There was a statistically significant difference in the duration of remission between the patients treated with combination therapy and patients treated with standard therapeutic modalities (p = 0.019) and balneotherapy (p = 0.032). CONCLUSION: The best results have been achieved when the combination therapy was administered. PMID- 25033575 TI - Treatment of neurosarcoidosis--innovations and challenges. AB - INTRODUCTION: Sarcoidosis affects the central nervous system more frequently than it used to be believed. While the cranial nerves are most frequently affected, neurosarcoidosis can involve other nervous system tissues as well. TREATMENT OF NEUROSARCOIDOSIS: Although a lot of drugs have proved useful in treating neurosarcoidosis, corticosteroids are still the gold standard in treatment of these patients. Therapeutic protocols differ regarding the dose of these drugs. Symptomatic neurosarcoidosis should always be treated with pulse corticosteroid therapy. People with diabetes, high blood pressure, osteoporosis and tuberculosis should be carefully monitored, as they are prone to complications associated with treatment with corticosteroids. In cases when treatment with corticosteroids does not show the desired results or therapy is discontinued due to the development of side effects, there are other pharmacologic options, such as methotrexate, mycophenolate mofetil, cyclophosphamide, chloroquine, azathioprine, thalidomide, and infliximab. It should be noted that the treatment response to the above mentioned regimens, except for infliximab, is relatively slow compared to corticosteroids; therefore, corticosteroids should be taken into account in all states and particularly in the acute phase of the disease. CONCLUSION: It is the existence of different forms of the disease, lack of local diagnostic criteria and different and non standardized therapy that makes the treatment of this disease difficult. Despite advances in pharmacotherapy and radiological diagnosis, it is necessary to develop better diagnostic strategies in order to set the optimal therapeutic approach. PMID- 25033576 TI - What kind of milk can prevent infant's sideropenic anemia--comparative study. AB - INTRODUCTION: The most common cause of sideropenic anemia in infants, during the period of their fast growth and development, is inadequate nutrition or insufficient intake of food rich in iron. The aim of this paper is to provide the insight into the problem of anemia and to emphasize nutrition as an important etiologic factor in the onset and prevention of anemia in infants. MATERIAL AND METHODS: Two retrospective studies were conducted at the Institute for Child and Youth Healthcare of Vojvodina. Department for Infant and Small Children's Pathology. The first study covered the period of eight years (1988-1995), and it included a total of 507 children, aged 1-24 months. The second study covered the period of two years (2010-2011) and a total of 290 children aged 1-12 months were included. The diagnosis of anemia was made according to clinical examination or after taking routine laboratory tests. According to the criteria of the World Health Organization, all children were divided into those with severe, moderate or mild anemia. RESULTS: Out of 507 children examined in the first study, 333 (65.68%) were breastfed, while 174 (34.32%) had never been breastfed. In the second study, 206 (71.03%) out of 290 children were breastfed, while 56 (19.31%) had never been breastfed. In both studies the highest percentage of children breastfed for the longest period was among children with mild form of anemia, while the children who were breastfed for the shortest period had severe anemia. In addition, the highest percentage of anemic children was supplementary fed with cow's milk in both studies. CONCLUSION: Short natural diet, early introduction of supplementation and choice of milk could be determining factors in the development and manifestation of anemia. PMID- 25033577 TI - Effects of phthalic acid esters on fetal health. AB - INTRODUCTION: Phthalates are synthetic industrial compounds capable of disrupting endocrine system. Effects of phthalates depend on dosage, duration of action and stage of development of the individual, thus making the fetus, newborn, and children at puberty the most vulnerable groups. METABOLISM OF PHTHALATES: Metabolism of these compounds consists of at least two steps: hydrolysis and conjugation. They are mainly excreted in urine, with a low percent being excreted through feces. EXPOSURE TO PHTHALATES: Exposure to the effects of phthalates begins at the intrauterine stage since the phthalates pass through the placental barrier. Phthalates may be found in plastic products, toys, medical equipment, industrial materials, food, and clothes. DETERMINATION OF PHTHALATE LEVELS IN HUMANS: Urine is the best sample for evaluating phthalate levels in humans because of rapid phthalate metabolism and high concentrations of metabolites in the urine. FETAL TESTICULAR DYSGENESIS SYNDROME: Fetal testicular dysgenesis syndrome involves disorders of male genital tract such as shortened anogenital distance, hypospadia, cryptorchidism, malformations of seminal vesicles, prostate, epididymis and it results from the harmful effects of phthalates. OTHER EFFECTS OF PHTHALATES ON HEALTH: Negative effects of phthalates on female health are mostly reflected in anovulation, premature puberty, changes in duration of pregnancy. There is a possible effect on neurocognitive development, occurrence of allergies, asthma, testicular carcinoma, hepatic and renal damages, insulin resistance and obesity, thyroid dysfunction. CONCLUSION: Further studies are needed to establish the safe phthalate concentration in certain products and to determine more negative consequences of exposure to phthalate. PMID- 25033578 TI - Application of fibrin rich blocks with concentrated growth factors in pre-implant augmentation procedures. AB - INTRODUCTION: Growth factors are mediators regulating the key processes of tissue regeneration, including cell proliferation and differentiation, extracellular matrix synthesis, chemotaxis and angiogenesis. In addition to the role they play in haemostasis and inflammatory processes, thrombocytes are of major importance in the reparation of mineralized and soft tissues. Application of fibrin rich blocks with concentrated growth factors is one of the latest approaches to guided bone regeneration and augmentation of lost bony structures of the alveolar ridge. CASE REPORT: This paper presents a case of a female patient who underwent reconstruction of the defect of residual alveolar ridge of the upper jaw by applying fibrin rich blocks with concentrated growth factors and subsequent placement of two titanium endosteal implants five months after wound healing. CONCLUSION: The loss of a single tooth or several teeth sometimes entails the augmentation of lost bony structures in order to provide optimal conditions for dental implant placement and subsequent prosthetic rehabilitation. A range of contemporary surgical procedures and a variety of dental materials for reconstruction of bony defects of the upper and lower jaws are available nowadays. The method described in this paper, i.e. the application of concentrated growth factors is one of the latest approaches which poses no risk of transmissible and allergic diseases and is at the same time cost effective. PMID- 25033579 TI - Severe hyperkalemia induced by propranolol. AB - INTRODUCTION: Hyperkalemia secondary to beta-adrenergic receptor blockade occurs in 1-5% of patients and is likely to develop with non-cardio-selective beta blockers. CASE REPORT: We have described hyperkalemia in a patient with angina pectoris receiving propranolol, clinically manifested as weakness, tightness behind the sternum and numbness in the limbs. Laboratory tests showed hyperkalemia (6.6 mmol/L), peaked T wave and a corrected QT interval of 510 ms. After discontinuation of propranolol, decline in potassium level, normalisation of electrocardiographic changes and clinical improvement were achieved. Causal relationship of drug related hyperkalemia has been confirmed as probable/likely according to Naranjo Adverse Drug Reaction Probability Score of 7 and the World Health Organization Uppsala Monitoring Centre Probability Scale. CONCLUSION: Hyperkalemia can be unpredictable and life-threatening complication of propranolol or a non-selective adrenergic beta blocker treatment, and requires timely identification of cause and implementation of therapeutic measures. PMID- 25033580 TI - Retinal hemorrhages as one of complications of optic disc drusen during pregnancy. AB - INTRODUCTION: Drusen of the optic nerve head are relatively benign and asymptomatic. They represent retinal hyaline corpuscles resulting from impaired axoplasmic transport of the retinal ganglion cells of optic nerve in front of the lamina cribrosa. They are usually detected accidentally, during a routine ophthalmologic examination. Most patients with optic disc drusen are not aware of the deterioration of their eyesight because of the slow progression of visual field defects. Damage in visual acuity due to optic disc drusen is rare. CASE REPORT: A 27-year-old female patient in the sixth month of pregnancy visited an ophthalmologist because of a visual impairment described as the appearance of mist and shadows over her right eye. When first examined, her visual acuity in both eyes was 20/20. The retinal hemorrhages framing the bottom half of the optic nerve were seen. Complete laboratory and clinical testing as well as specific ophthalmic examinations (photofundus, computerized visual field, optical coherence tomography, and ultrasound) were performed to exclude systemic causes and they presented no risk for the pregnancy. Echosonographic examination confirmed the presence of bilateral optic nerve head drusen. CONCLUSION: Hemodynamic changes during pregnancy are possible factors for the development of optical disc and retinal hemorrhages. Since treatment of optic disc drusen is limited, recognition of optic nerve drusen as a cause of hemorrhage during pregnancy prevents unnecessary diagnostic and therapeutic interventions. PMID- 25033581 TI - [Repetitive transcranial magnetic stimulation as an adjuvant method in the treatment of depression: preliminary results]. AB - INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) is a method of brain stimulation which is increasingly used in both clinical practice and research. Up-to-date studies have pointed out a potential antidepressive effect of rTMS, but definitive superiority over placebo has not yet been confirmed. OBJECTIVE: The aim of the study was to examine the effect of rTMS as an adjuvant treatment with antidepressants during 18 weeks of evaluation starting from the initial application of the protocol. METHODS: Four patients with the diagnosis of moderate/severe major depression were included in the study.The protocol involved 2000 stimuli per day (rTMS frequency of 10 Hz, intensity of 120% motor threshold) administered over the left dorsolateral prefrontal cortex (DLPFC) for 15 days. Subjective and objective depressive symptoms were measured before the initiation of rTMS and repeatedly evaluated at week 3, 6, 12 and 18 from the beginning of the stimulation. RESULTS: After completion of rTMS protocol two patients demonstrated a reduction of depressive symptoms that was sustained throughout the 15-week follow-up period. One patient showed a tendency of remission during the first 12 weeks of the study, but relapsed in week 18. One patient showed no significant symptom reduction at any point of follow-up. CONCLUSION: Preliminary findings suggest that rTMS has a good tolerability and can be efficient in accelerating the effect of antidepressants, particularly in individuals with shorter duration of depressive episodes and moderate symptom severity. PMID- 25033582 TI - Changes in the retrobulbar hemodynamic parameters after decreasing the elevated intraocular pressure in primary open-angle glaucoma patients. AB - INTRODUCTION: Ocular blood flow (OBF) disturbances could be involved both in the pathogenesis and in progression of glaucomatous damage. OBJECTIVE: The aim of the study was to compare the retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery (CRA) and short posterior cilliary arteries (SPCA) after decreasing the elevated intraocular pressure (IOP) in primary open angle glaucoma (POAG) patients by using color Doppler imaging (CDI). METHODS: We examined 60 patients (21 male and 39 female) with diagnosed and treated POAG. Thirty-nine patients had increased IOP (> 25 mm Hg). Peak-systolic velocity (PSV), end-diastolic velocity (EDV), Pourcelot resistance index (RI), and pulsatility index (PI) were assessed in the OA, CRA, and SPCA. IOP was measured both with the Goldmann Applanation tonometer (GAT) and with the Dynamic Contour tonometer (DCT), three times respectively. Ocular pulse amplitude (OPA) was measured using DCT. RESULTS: The retrobulbar parameters between the baseline and after IOP reduction showed no difference in measurements. After Bonferroni correction (p < or = 0.0056, alpha/9) statistical significance was recorded only in the following retrobulbar hemodynamic parameters; DCT (29.8 +/- 6.2 vs. 15.5 +/- 5.0), GAT (33.8 +/- 9.0 vs. 15.0 +/- 6.6) and OPA measurements (4.3 +/- 1.0 vs. 3.0 +/- 1.6), as compared to the baseline. There was no correlation between the changes in IOP measured with either DCT or GAT and changes in the hemodynamic parameters (p > 0.05 for all). Pearson correlation coefficient (95% CI) showed very good correlation for IOP measurements between DCT and GAT: at baseline 0.83 (0.71 to 0.90) and at the end 0.71 (0.55 to 0.83); p < 0.0001 for both measurements, but without any difference between them (p > 0.05). CONCLUSION: There was a lack of correlation between the changes in IOP measured with either DCT or GAT and the changes in the hemodynamic parameters. PMID- 25033583 TI - [Intratympanic corticosteroid perfusion in the therapy of Meniere's disease]. AB - INTRODUCTION: Over the last two decades the intratympanic perfusion of corticosteroids has been used as a minimally invasive surgical therapy of Meniere's disease. According to experimental studies the antiinflammatory, immunoprotective, antioxidant and neuroprotective role of the locally perfused corticosteroids was noticed in the inner ear structures. The recovery of action potentials in the cells of the Corti organ was confirmed as well as a decreased expression of aquaporine-1, a glycoprotein responsible for labyrinth hydrops and N and K ions derangement. OBJECTIVE: The study showed results of intratympanic perfusion therapy with dexamethasone in patients with retractable Meniere's disease who are resistant to conservative treatment. METHODS: Single doses of 4 mg/ml dexamethasone were given intratympanically in 19 patients with retractable Meniere's disease. Six single successive doses of dexamethasone were administered in the posteroinferior quadrant of the tympanic membrane. Follow-up of the patients was conducted by using a clinical questionnaire a month after completed perfusion series as well as on every third month up to one year. RESULTS: One month after completed first course of perfusions, in 78% of patients, vertigo problems completely ceased or were markedly reduced. The recovery of hearing function was recorded in 68% and marked tinnitus reduction in 84% of patients. After a year of follow-up, in 63% of patients the reduction of vertigo persisted, while hearing function was satisfactory in 52%. Tinitus reduction was present in 73% of patients. CONCLUSION: Intratympanic perfusion of dexamethasone in patients with Meniere's disease is a minimally invasive therapeutic method that contributes to the reduction of the intensity of vertigo recurrent attacks, decrease of the intensity of tinnitus and improvement of the average hearing threshold. Patients with chronic diseases and Meniere's disease who are contraindicted for systemic administration of cortocosteroids (hypertension, diabetes, glaucoma, peptic ulcer, etc.) have an additional therapeutic option by dexamethasone intratympanic perfusion. PMID- 25033584 TI - Detection of herpes simplex virus type 1 in gingival crevicular fluid of gingival sulcus/periodontal pocket using polymerase chain reaction. AB - INTRODUCTION: Pathogenesis and some characteristics of periodontitis cannot be fully explained by bacterial etiology alone. Herpes viruses may bridge the gap between clinical characteristics and molecular understanding of periodontal destruction. OBJECTIVE: The aim of this study was to investigate the prevalence of herpes simplex virus type 1 (HSV-1) in gingival crevicular fluid (GCF) of healthy and damaged periodontium in Serbian population and to explore potential correlation between the presence of this virus and the level of periodontal destruction. METHODS: Samples were collected from gingival sulcus/periodontal pockets by sterile paper points and the presence of viral DNA in gingival crevicular fluid was assessed by PCR. RESULTS: There was no statistically significant difference in HSV-1 in presence between periodontitis patients (PG = 38.9%) and healthy controls (HC = 32.3%), (Chi-square test, with Yates' correction p = 0.7574). However, HSV-1 positive patients showed significantly higher values of parameters of periodontal destruction (PPD = 7.11 +/- 2.52, CAL = 5.46 +/- 2.34) than periodontitis patients without HSV-1 in gingival crevicular fluid (PPD = 4.70 +/- 1.79, CAL = 3.39 +/- 2.65) (p values respectively, p = 0.002 and p = 0.023, Independent Samples T-Test). HSV-1 occurred more often in deeper (PPD > or = 6 mm) (69.2%) than in shallow pockets (3 mm < PPD < 6 mm) (18.2%) (Chi-square test, with Yates' correction, p = 0.008). Plaque index was lower in the HSV-1 positive group (0.84 +/- 0.69 vs. 1.43 +/- 0.76, p = 0.023, Independent Samples T-Test). CONCLUSION: This study demonstrated that the presence of HSV-1 in the gingival crevicular fluid coincides with a higher degree of tissue destruction in patients with periodontitis. PMID- 25033585 TI - Changes in subgingival microflora after placement and removal of fixed orthodontic appliances. AB - INTRODUCTION: The placement of fixed orthodontic appliances may lead to increased plaque accumulation and changes in subgingival microflora. OBJECTIVE: The aim of this study was to examine the changes in frequency of subgingival microflora that occur after placement and removal of fixed orthodontic appliance using polymerase chain reaction (PCR). METHODS: This study included 33 orthodontic patients, who were divided into two groups. Subgingival plaque samples were collected from the right upper incisor (U1) and right upper first molar (U6). In group A, the samples were taken three times: before placement appliance (T1), after one month (T2), and after 3 months (T3). In group B the samples were also taken three times: before appliance removal (T1), after one month (T2), and after three months (T3). PCR method was used to determine the presence of P. gingivalis, A. actinomycetemcomitans, T. forsythia, and P. intermedia. RESULTS: In group A the frequency of P. gingivalis showed statistically significant decrease at U1 (p = 0.049) and U6 (p = 0.008), from T1 to T2, and at U1 (p = 0.048) from T1 to T3. In group B only the frequency of T. forsythia showed a statistically significant decrease, at U6 (T1 vs.T2, p = 0.004; T1 vs.T3, p = 0.0003). Regarding other analyzed bacteria, changes in the presence were noticed but no statistical significance was found. CONCLUSION: Placement of fixed appliances may have an impact on subgingival microflora, but in the first months after the placement and removal of the appliance changes were not significant, probably due to good oral hygiene. PMID- 25033586 TI - [Mid-term results after complete surgical correction of transposition of the great arteries]. AB - INTRODUCTION: Arterial switch operation (ASO) is a cardiosurgical method of choice for complete anatomical correction of transposition of great arteries. Improvement of this procedure has made considerably improved the outcome and long term prognosis of children born with this complex congenital heart disease. OBJECTIVE: The aim of this study was to estimate the success rate of ASO through retrospective analysis of mortality and late complications. METHODS: This study included 57 children operated from 1st January 2005 until 31st December 2009. Parameters that could influence the outcome of surgery were investigated. The following late complications were investigated: neopulmonary artery stenosis, neoaortic stenosis and regurgitation, as well as clinical signs of heart failure. RESULTS: Early postoperative mortality was 15.8% (9/57 patients). During follow up (8 to 72 months, average 36.5 months) there were no lethal outcomes. On the last echocardiography examination, 73.2% patients had neoaortic regurgitation and 67.4% patients had neopulmonary regurgitation, but all of them were mild in intensity. Neopulmonary stenosis had 32.6% of patients, but only two had moderate or severe stenosis. No one had ischemic ECG changes. Three reinterventions were performed due to serious residual problems: surgical correction of neoaortic stenosis, surgical correction of neopulmonary stenosis and transcatether balloon dilatation for aortic recoarctation. At the end of the follow-up period, only one of 46 consistently followed patients had signs of heart failure which required therapy (2.2%), while the majority of patients were without any symptoms and with good effort tolerance. CONCLUSION: Arterial switch operation has been successfully performed at our institution, with acceptable perioperative mortality and excellent late outcome. PMID- 25033587 TI - The influence of hyperprolactinemia on coagulation parameters in females with prolactinomas. AB - INTRODUCTION: Currently there is little information on the effects of prolactin (PRL) on the coagulation and fibrinolytic systems. OBJECTIVE: The aim of this study was to evaluate the effects of hypeprolactinemia on the parameters of the hemostatic system and activation of the coagulation system. METHODS: We studied PRL levels, body mass index (BMI), values of activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), D-dimer level, von Willebrand factor antigen (vWFAg) and fibrinogen in 15 young female patients with microprolactinomas before and after therapy and in 15 healthy female controls. RESULTS: As expected, pretreatment PRL levels were significantly higher in patients than in controls (140.90 +/- 42.87 vs. 12.53 +/- 4.05 ng/ml; p < 0.001). PT, although still in the normal range, was prolonged in patients with hyperprolactinemia as compared to the control group (13.53 +/- 1.39 vs. 12.65 +/- 0.53 s; p = 0.03) and normalized after therapy (12.69 +/- 0.65 vs. 12.65 +/- 0.53 s; p = 0.88). TT, although in normal range, was significantly shorter in the hypeprolactinemic patients than in the controls (14.34 +/- 4.52 vs. 17.21 +/- 1.35 s; p < 0.025) and after treatment remained significantly shorter than in the controls (15.17 +/- 1.55 vs. 17.21 +/- 1.35 s; p < 0.0001). D-dimer values before treatment in the patients with hyperproplactinemia were above the normal range (239.47 +/- 107.93 vs. 131.27 +/- 50.64 ng/ml, p = 0.002) and decreased to normal values after therapy (239.47 +/- 107.93 vs. 146.60 +/- 39.15 ng/ml; p < 0.001). D dimer levels correlated with PRL (r = 0.30) and the change in serum D-dimer values significantly correlated with the change in PRL levels during therapy (r = 0.62). aPTT, vWFAg and fibrinogen were similar in patients and controls. CONCLUSION: In our study, increased thrombin generation that resulted in elevated D-dimer levels may be one of the contributing factors to the prethrombotic state in patients with hyperprolactinemia. PMID- 25033588 TI - Indications for repeated enema reduction of intussusception in children. AB - INTRODUCTION: Intussusception is a common abdominal emergency in early childhood. It is idiopathic in more than 90% of cases with incidence of 1.5-4 per 1,000 live births. The treatment of choice is nonoperative hydrostatic or air enema reduction. OBJECTIVE: The aim of the study was to evaluate the influence of clinical presentation and symptom duration in non-operative treatment, considering the indications for delayed enema reduction and its efficacy. METHODS: From the total number of 107 patients with intusussception, aged from 2 months to 14 years (median 9 months), 102 (95%) patients with ileo-colic intussusceptions were treated initially by ultrasound guided saline enema. Records were reviewed for patients with failed initial treatment and delayed repeated enemas or operative procedure. The predictor variable included duration of presenting symptoms. RESULTS: Successful treatment by hydrostatic saline enemas had 58/102 (57%) patients. Success in reduction was greater it symptom duration was < 24 hours (54/62 cases; 87%, p < 0.001), compared with > 24 hours, (4/45 cases; 9%). Despite failed initial attempts, enema reduction was reattempted in 12 patients, with success in 7/12 (60%) patients. Children with symptom duration > 24 hours had a greater risk of requiring surgery (41/45 cases; 91%, p < 0.001), including 5 (5%) patients with ileo-ileal intussusceptions. CONCLUSION: The accuracy of ultrasound guided saline enema in intussusception reduction is high. Delay in presentation decreases success of non-operative treatment. Delayed enema reduction is important therapeutic option for intussusceptions. Surgical treatment is indicated in cases of complications. PMID- 25033589 TI - Early clinical results of surgical treatment of patients with femoroacetabular impingement. AB - INTRODUCTION: Surgical treatment is the treatment of choice in patients with symptoms and radiological signs of femoroacetabular impingement. OBJECTIVE: Our experience and early results of surgical treatment of patients with signs of femoroacetabular impingement and early hip osteoarthritis are reported. METHODS: The results of treatment of 21 patients aged 23-54 years with different types of femoroacetabular impingement are presented. Safe open surgical dislocation of the hip was performed in all patients. Before and after surgery, the WOMAC score was performed, clinical and radiographic data of the operated hips were evaluated and t-tests were used for statistical analyzes of data. RESULTS: The WOMAC score improved from 70.5 points (range 56.3 to 89.8 points) to 90.3 points (range 70.3 to 100 points) at one year of follow-up (p < 0.0001), anterior impingement test was negative in all operated cases, average hip internal rotation improved significantly, no complications were found, except trochanteric nonunion at the site of osteotomy, which was reaffixed. CONCLUSION: Postoperative results have shown that the surgical approach to treating patients with femoroacetabular impingement is the method of choice. Three operated patients, with advanced osteoarthritis of the hip, had to be converted to total hip replacement. PMID- 25033590 TI - The impact of education on adolescents' sun behavior: experiences from Serbia. AB - INTRODUCTION: In Serbia, there have been no broad campaigns or educational programs focused on adolescents' sun protection. OBJECTIVE: The aim of the study was to assess whether an educational program would have impact on changes of attitudes and sun-protective behaviors of high school students. More specific aim was to examine whether sex and age differences in sun behavior exists. METHODS: Educational program was designed to provoke changes in attitudes towards sun protection and sun behavior. The investigation was carried out in Belgrade, Serbia in two educational cycles, during spring 2007 and 2008. Sixteen- and 17 year old high schools students were targeted and assessed before and after the educational intervention by means of self-report questionnaire designed for this study (about skin types and sun behavior). The students' attitudes towards sun protection and sun behavior before and after the educational intervention were compared and analyzed by the Pearson's chi-square test and logistic regression analyses. In the second educational cycle (2008) age and gender differences in sun behavior were analyzed. RESULTS: Overall 3205 students in 2007, and 2155 students in 2008 year from 11 high schools participated. A statistically significant behavior change was observed for the use of sunglasses in 2007--the number of students using them increased from 41.6% to 45.6% (p < 0.05). There were no significant changes in other ways of protection i.e. sunscreen use, protective clothes or staying in shade. CONCLUSION: Educational program had an impact, but broader activities involving schools, local communities and media are needed for significant changes in sun behavior and attitude. PMID- 25033591 TI - L-2-Hydroxyglutaric aciduria: a case report. AB - INTRODUCTION: L-2-Hydroxyglutaric aciduria (L-2-HGA) is an autosomal recessive neurometabolic disease with a slowly progressive course and characterized by increased levels of hydroxyglutaric acid in urine, cerebrospinal fluid and plasma. In this condition clinical features mainly consist of mental deterioration, ataxia and motor deficits. CASE OUTLINE: The patient is a 16-year old girl, the first and only child of healthy, non-consanguineous parents of Serbian origin. At the age of 4 years her walk became unsteady and ataxic. Other signs of cerebellar involvement were soon observed. Head circumference was above two standard deviations (55 cm). Mild mental retardation was revealed by formal intelligence testing (IQ 60). MR examination of the brain showed confluent subcortical white matter lesions spread centripetally, and atrophy of the cerebellar vermis with involvement of dentate nuclei, without deep white matter abnormalities. Laboratory investigation revealed increased amounts and a very large peak of HGA in urine and plasma. Enantiomeric analysis confirmed the L configuration (> 90%) establishing the diagnosis of L-2-HGA. The first epileptic seizure, partial with secondary generalization, occurred at age of 8 years. Favorable seizure control was achieved. A slow progression of neurological impairment was noted. Therapeutic trials with oral coenzyme Q10 and with oral riboflavin showed no biochemical and clinical effects. Recently, the diagnosis was proven by the presence of a mutation in the L-2-HGA gene. CONCLUSION: To our knowledge, this is the first report of L-2-HGA in Serbia. L-2-HGA must be considered in the differential diagnosis based on specific findings in cranial MRI. PMID- 25033592 TI - Thrombolysis of occluded femoropopliteal graft with locally delivered human plasmin. AB - INTRODUCTION: Acute lower limb ischemia results from thrombosis or embolization of diseased native artery or previously implanted bypass graft. When this occurs, several options are available to restore blood flow: catheter-directed thrombolysis, mechanical thrombectomy or open surgery. Fundamental reasons to apply percutaneous interventions are avoiding open procedures in high risk patients, and avoiding difficult dissection through scar tissue. CASE OUTLINE: A 67-year-old male was admitted at our Institution for critical limb ischemia. After performed angiography the diagnosis of occluded femoropopliteal graft was established. Occlusion was resolved by catheter-directed thrombolysis with plasmin. Culprit lesions were treated by angioplasty. CONCLUSION: Our patient underwent a successful thrombolysis of occluded femoropopliteal graft with locally-delivered human plasmin. PMID- 25033593 TI - Reconstruction of full thickness abdominal wall defect following tumor resection: a case report. AB - INTRODUCTION: Reconstruction of a full thickness abdominal wall defect is a demanding procedure for general and also for plastic surgeons, requiring vigorous planning and reconstruction of three layers. CASE OUTLINE: We present a case of a 70-year-old patient with a huge abdominal wall tumor with 40 years evolution. Surgery was performed under general anesthesia. Full thickness abdominal defect appeared after the tumor resection. Reconstruction followed in the same act. The defect was reconstructed using a combination of techniques, including omental flap, fascia lata graft, local skin flaps and skin grafts. After surgery no major complications were noted, only a partial skin flap loss, which was repaired using partial thickness skin grafts. The final result was described by the patient as very good, without hernia formation. CONCLUSION: Omenthoplasty, abdominal wall reconstruction in combination with free fascia lata graft and skin grafts can be one of good options for the reconstruction of full thickness abdominal wall defects. PMID- 25033594 TI - [Obstetric and gynecological intervention in women with Bernard-Soulier syndrome: report of two cases]. AB - Introduction Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder characterized by giant platelets thrombocytopenia, prolonged bleeding time, frequent hemorrhages with considerable morbidity. Data on the outcome of pregnancy and gynecological intervention in BSS are rare and there are no general therapeutic recommendations. CASES OUTLINE: We report two cases of BSS. In the first case a 29-year-old patient with BSS was admitted in 8 weeks of gestation. The diagnosis of BSS was made on the basis of prolonged bleeding time, giant platelets thrombocytopenia, and absent ristocetin-induced platelet aggregation. In 38 week of gestation Cesarean section, with platelets transfusion preparation, was performed. Obstetric intervention passed without complication. Postoperative course was complicated with a three-week vaginal bleeding resistant to platelet transfusion. Neonate platelet count was normal. Our second case was a 28-year-old patient with BSS, hospitalized for ovarial tumor surgery. The patient was prepared for the intervention with platelets transfusion. The surgery was uncomplicated, but on the second postoperative day a massive vaginal bleeding, resistant to the platelet transfusion, developed. Bleeding control was achieved with activated recombinant factor VII. Twelve hours the patient developed later hypertensive crisis with epileptic seizure due to subarachnoid hemorrhage. Therapy was continued with platelet transfusion, antihypertensive and antiedema drugs. PH examination of tumor tissue showed hemorrhagic ovarial cyst. CONCLUSION: Obstretic and gynecological intervention in women with BSS may be associated with a life-threatening bleeding thus requiring a multidisciplinary approach with adequate preparation. Because of the limited data in the literature, it is not possible to provide firm management recommendations and each case should be managed individually. PMID- 25033596 TI - [Death caused by heat stroke: case report]. AB - INTRODUCTION: Heat stroke is the most dangerous among numerous disorders caused by elevated environmental temperature. It is characterized by an increased body temperature of over 40 degrees C, the dysfunction of the central nervous system and the development of multiple organ failure. The aim of this paper was to highlight problems in the clinical and post-mortal diagnosis of fatal heat stroke. CASE OUTLINE: A 20-year-old male was found unconscious on the street; on admission at the Emergency Center, Clinical Center of Serbia, Belgrade, he was in a coma. The body temperature of 40 degrees C was maintained despite the applied therapy, meningeal signs were negative, tachycardia with gallop rhythm, hypotension, bleeding from the nose and mouth, and presence of skin bruises. LABORATORY FINDINGS: highly elevated LDH and creatine kinase, elevated serum creatinine, AST, and signs of DIC. Lethal outcome occurred 6 hours after admission, and the case remained clinically unsolved. Autopsy showed signs of hemorrhagic diathesis, brain and pulmonary edema, and microscopic examination revealed general congestion, internal bleeding in various organs, cerebral edema, massive blood aspiration and pulmonary edema. Toxicological and bacteriological examinations were negative. Based on these findings and subsequently obtained data on the conditions at the workplace where the young man had a part-time job, it was concluded that the violent death was caused by heat stroke. CONCLUSION: Since heat stroke is associated with a high mortality rate and high incidence of serious and permanent organ damage in survivors, it is important to make the diagnosis of heat stroke as quickly as possible and apply appropriate treatment. Misdiagnosis of heat stroke, and consequently inadequate treatment, with a potential fatal outcome for the patient, can be the reason for blaming doctors for the legal offense of medical malpractice in failing to administer first aid. PMID- 25033595 TI - Buschke-Lowenstein tumor: squamous cell carcinoma of the anogenital region. AB - INTRODUCTION: Buschke-Lowenstein tumor (BLT), as a rare form of condylomata acuminatum, was firstly described by Buschke in 1886 as a "carcinoma-like condyloma acuminatum of the penis". BLT is generally considered to be a low-grade variant of squamous cell carcinoma of the anogenital region. CASE OUTLINE: We describe a case of BLT in a 56-year-old male patient who was referred to our institute due to a large defect in the gluteal region. The biopsy of the lesion was performed and the diagnosis of BLT was made on histopathological examination. Magnetic resonance imaging of the pelvis showed the extensive vegetant lesion that significantly infiltrated pelvic organs accompanied with an enlargement of para-iliac lymph nodes. Sygmoidostomy for fecal diversion was done and chemotherapy with 5-fluorouracil and cisplatin was initiated. Unfortunately, the patient's severe condition caused fatal outcome. CONCLUSION: Our case points out that BLT should be treated at the initial stage in order to prevent untreatable condition which happened in our patient. Therefore, early diagnostics and staging of the disease using modern technologies are crucial in order to treat patients effectively. PMID- 25033597 TI - [Hard dental tissue minimal-invasive preparation using contemporary polymer rotating instruments and laser]. AB - Goal of contemporary dentistry is to decrease the patient's discomfort during treatment. Dentists aim to achieve maximum with the newly developed dental materials as well as with new cavity preparation techniques in the shortest time span. Since the development of the first constructed borer (drilling machine) for caries removal, the preparation techniques have considerably changed. The progress of dental materials as well as the cavity preparation techniques has led us to contemporary carbide tungsten and diamond borers that are used with obligatory water cooling. The innovation within this field represents newly developed polymer borers that can detect the difference between carious lesions and healthy tooth structure. In this way the cavity preparation may be performed without damaging dental healthy tissue. This is possible owing to their hardness which is lower than the hardness of intact dentin. Polymer borer preparation is painless with less vibration, while the increase in temperature is negligible. Lasers have been used in clinical dentistry since 1980s so it can be said that they represent a new technology. The function of lasers is based on ablation which requires water. Erbium lasers have shown the highest potential with their ability to produce effective ablation of hard dental tissues. Laser application in dentistry requires special training as well as some protective measures. Laser advantages, compared to traditional preparation techniques, involve the absence of vibration, painless preparation, possibility of preparation without anesthetic and easier patient's adjustment to dental intervention which is of importance, especially in pediatric dentistry. PMID- 25033598 TI - [Acute kidney injury in children]. AB - Acute kidney injury (AKI) is a clinical condition considered to be the consequence of a sudden decrease (> 25%) or discontinuation of renal function. The term AKI is used instead of the previous term acute renal failure, because it has been demonstrated that even minor renal lesions may cause far-reaching consequences on human health. Contemporary classifications of AKI (RIFLE and AKIN) are based on the change of serum creatinine and urinary output. In the developed countries, AKI is most often caused by renal ischemia, nephrotoxins and sepsis, rather than a (primary) diffuse renal disease, such as glomerulonephritis, interstitial nephritis, renovascular disorder and thrombotic microangiopathy. The main risk factors for hospital AKI are mechanical ventilation, use of vasoactive drugs, stem cell transplantation and diuretic resistant hypervolemia. Prerenal and parenchymal AKI (previously known as acute tubular necrosis) jointly account for 2/3 of all AKI causes. Diuresis and serum creatinine concentration are not early diagnostic markers of AKI. Potential early biomarkers of AKI are neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), interleukins 6, 8 and 18, and liver-type fatty acid-binding protein (L-FABP). Early detection of kidney impairment, before the increase of serum creatinine, is important for timely initiated therapy and recovery. The goal of AKI treatment is to normalize the fluid and electrolyte status, as well as the correction of acidosis and blood pressure. Since a severe fluid overload resistant to diuretics and inotropic agents is associated with a poor outcome, the initiation of dialysis should not be delayed. The mortality rate of AKI is highest in critically ill children with multiple organ failure and hemodynamically unstable patients. PMID- 25033599 TI - [Persistent human papillomavirus infection in the etiology of cervical carcinoma: the role of immunological, genetic, viral and cellular factors]. AB - The aim of this paper was to present the role of human papillomavirus (HPV) in cervical carcinogenesis from several aspects. By explaining the HPV virus lifecycle and structure, its effect on cervical cell cycle and subversion of immune response can be better understood. Early E region of the viral genome encodes proteins that are directly involved in carcinogenesis. The E6 protein binds to p53 protein (product of tumor-suppressor gene) blocking and degrading it, which in turn prevents cell cycle arrest and apoptosis induction. E6 is also capable of telomerase activation, which leads to cell immortalization; it also reacts with host proto-oncogene c-jun, responsible for transcription, shortens G1 phase and speeds up the transition from G1 to S phase of the cells infected by HPV. E7 forms bonds with retinoblastoma protein (product of tumor-suppressor gene) and inactivates it. It can inactivate cyclin inhibitors p21, p27, and abrogate the mitotic spindle checkpoint with the loss of protective effect of pRB and p53. The immune system cannot initiate early immunological reaction since the virus is non-lytic, while the concentration of viral proteins--antigens is low and has a basal intracellular position. Presentation through Langerhans cells (LC) is weak, because the number of these cells is low due to the effect of HPV. E7 HPV reduces the expression of E-cadherin, which is responsible for LC adhesion to HPV-transformed keratinocytes. Based on these considerations, it may be concluded that the process of cervical carcinogenesis includes viral, genetic, cellular, molecular-biological, endocrine, exocrine and immunological factors. PMID- 25033600 TI - [Improving blood safety: errors management in transfusion medicine]. AB - INTRODUCTION: The concept of blood safety includes the entire transfusion chain starting with the collection of blood from the blood donor, and ending with blood transfusion to the patient. The concept involves quality management system as the systematic monitoring of adverse reactions and incidents regarding the blood donor or patient. Monitoring of near-miss errors show the critical points in the working process and increase transfusion safety. OBJECTIVE: The aim of the study was to present the analysis results of adverse and unexpected events in transfusion practice with a potential risk to the health of blood donors and patients. METHODS: One-year retrospective study was based on the collection, analysis and interpretation of written reports on medical errors in the Blood Transfusion Institute of Vojvodina. RESULTS: Errors were distributed according to the type, frequency and part of the working process where they occurred. Possible causes and corrective actions were described for each error. The study showed that there were not errors with potential health consequences for the blood donor/patient. Errors with potentially damaging consequences for patients were detected throughout the entire transfusion chain. Most of the errors were identified in the preanalytical phase. The human factor was responsible for the largest number of errors. CONCLUSION: Error reporting system has an important role in the error management and the reduction of transfusion-related risk of adverse events and incidents. The ongoing analysis reveals the strengths and weaknesses of the entire process and indicates the necessary changes. Errors in transfusion medicine can be avoided in a large percentage and prevention is cost effective, systematic and applicable. PMID- 25033601 TI - [Comparative characteristics of genetic aberrations in glioblastomas in children and adults]. AB - Glioblastomas in children and adults are a heterogeneous group of tumors that can be divided into at least three different subgroups: pediatric glioblastomas, IDH1 mutant glioblastomas in adults (the most favorable prognostic subtype), and IDH1 wild type glioblastomas in adults. According to the frequency of detected cytogenetic aberrations (amplification of the MYC/MYCN, EGFR and PDGRFA oncogenes, homozygous deletion of the CDKN2A gene, and deletion of the PTEN gene), pediatric glioblastomas bear analogy to the subgroup of IDH1-mutant glioblastomas in adults. PMID- 25033602 TI - [Surgery of skull base tumors extending into the orbit, paranasal sinuses, nasal cavity, pterygopalatine and infratemporal fossas: treatment principles in certain types of tumors]. AB - Following the paper focused on surgery of skull base tumors invading the orbit, paranasal sinuses, nasal cavities, pterygopalatine and infratemporal fossae, the authors discuss particular issues of surgical treatment of the most common craniofacial mass lesions, including meningiomas, juvenile angiofibromas, trigeminal nerve tumors, chondroid tumors, and others. PMID- 25033603 TI - [Intraoperative fluorescence diagnostics upon recurrent operations for brain gliomas]. AB - The method of fluorescent diagnosis (FD) using 5-ALA has been widely employed in surgery of primary intracerebral tumors over the last years. The issue of FD application in surgery of gliomas with continued growth has remained less studied. OBJECTIVE: To investigate the efficacy of using FD with 5-ALA and laser spectral analysis in surgery of brain gliomas with continued growth. MATERIAL AND METHODS: 19 patients with Grade II-IV (WHO) gliomas with continued growth of different localization were studied. All tumors localized supratentorially. 5 Aminolevulinic acid hydrochloride "Alasens" (SSC "NIOPIK", Moscow, Russia) was used in the study. The equipment used during surgery included an operating microscope with an attachment for fluorescent navigation. Apart from expert qualitative assessment of a fluorescence extent, computer analysis of the fluorescence and light scattering (diffuse reflection) spectra was performed on a LESA-01-BIOSPEK spectrum analyzer (Russia). RESULTS: Detectable fluorescence was obtained in all the cases. PP IX fluorescence indices from 9.05 to 53.97 (the study was conducted in 12 cases) were determined by quantitative analysis of the spectrograms. The analysis of light scattering revealed its inverse relationship with respect to the fluorescence index. High sensitivity of the method in surgery of gliomas with continued growth requires clarification of method specificity because non-specific accumulation of PP IX in the area of post-radiation necrosis may occur in these patients. CONCLUSIONS: The FD method can be used for intraoperative demarcation of tumor resection boundaries in surgery of cerebral gliomas with continued growth. However, it is necessary to be critical of the high sensitivity of the method in patients with postradiation pathomorphism due to possible non-specific accumulation of PP IX in tissues. A light scattering study may provide additional information about the structure of tissues in the surgical wound. PMID- 25033604 TI - [The analysis of complications of surgical treatment of brain aneurysms in patients operated on in the late posthemorrhagic period]. AB - Most patients with brain aneurisms were operated on in the late posthemorrhagic period at the Burdenko Neurosurgical Institute. OBJECTIVE: To investigate the rate and structure of complications of microsurgical and endovascular surgery for different topographic anatomic variants of cerebral aneurysms in patients operated on in the late posthemorrhagic period in order to assess the risk of intervention in these patients. MATERIAL AND METHODS: The study group comprised 1074 patients with single brain aneurysms who had been treated at the Burdenko Neurosurgical Institute (Russian Academy of Medical Sciences) for the period from 2005 to 2012. The exclusion criterion for the study was the acute stage--21 days after the date of hemorrhage. Age of patients ranged from 18 to 75 years, with the mean of 45.3 years. The number of female patients was 552 (51.4%); the number of male patients was 522 (48.6%). Microsurgical operations were performed in 887 (82.6%) patients, endovascular--in 187 (17.4%). RESULTS: Postoperative complications were observed in 163 (15.2%) patients. Most of the complications (14.2%) were associated with cerebral disorders. Pronounced deterioration was noted in 6% of cases, death--in 0.9%. Cerebral complications were revealed in 13.8% of the patients after microsurgery and in 16% after endovascular treatment; mortality was observed in 1% and 0.5%, respectively. CONCLUSION: The overall risk of disability and death associated with recurrent hemorrhage from the aneurysm, especially at young age, is significantly higher than risks of surgical intervention in patients in the late posthemorrhagic period. Thus, the presence of a brain aneurysm that caused hemorrhage is an indication for surgical treatment, regardless of the time of its rupture. PMID- 25033605 TI - [A model of the arterial aneurysm of the brain for microneurosurgical training]. AB - Clipping of arterial aneurysms of the brain is one of technically complex neurosurgical interventions. In the available literature, there is no information about simulation models of aneurysm clipping that have tactile properties similar to the real ones. The study presents a technical rationale for the development of a new model for the aneurysm on human placental vessels to train skills of isolating and clipping under ruptured and unruptured aneurysm conditions. PMID- 25033606 TI - [Biological features and long-term results of comprehensive treatment of brain tumors in infants]. AB - Complete removal is the treatment standard for most brain tumors. Outcomes of subsequent comprehensive treatment depend on biological features, the histological structure of the tumor, and radicality of surgery. The aim of this work was to study the morphological features of brain tumors in infants and to analyze long-term outcomes of surgical and comprehensive treatment. MATERIAL AND METHODS: The study included 80 infants with brain tumors aged from 1 to 12 months who had been operated on at the Burdenko Neurosurgical Institute during the period from 2000 to 2010. RESULTS: Maximal radicality was achieved in the group of tumors of the lateral and third ventricles (85%), in the group of tumors of hemispheric localization (82%), and in the group of tumors of the posterior fossa (83%). The lowest percentage of radical tumor removal (15%) accrued to tumors of the chiasmosellar area, most of which were large visual pathway gliomas. The overall five-year survival rate associated with the treatment in the studied series of patients was 92 and 48% for Grade I-II and Grade III-IV tumors, respectively. CONCLUSION: The features of biology of brain tumors in infants include the increased proliferative activity (high Ki-67 index of 10% and higher) revealed at the diagnosis of choroid papillomas, a series of pilocytic astrocytomas of the chiasm and Grade III astrocytomas, which do not affect the clinical course. The best long-term results of the treatment were obtained in infants with complete resection of Grade I and III astrocytomas and in infants with choroid papillomas. Radical removal of such histological forms as anaplastic astrocytoma, choroidal carcinoma, and anaplastic ependymoma improves the prognosis, provides favorable conditions for adjuvant therapy, and increases the period of progression-free survival in infants. PMID- 25033607 TI - [Biportal endoscopic removal of choroid papilloma of the lateral ventricle in a child]. AB - The article is devoted to the use of minimally invasive techniques for removing intraventricular tumors; this topic is currently relevant to pediatric neurosurgery. As an example, a clinical case of complete removal of a choroid plexus papilloma in a child using the neuroendoscopic technique through the biportal approach is provided. This tumor is most commonly found in pediatric practice. Taking this into account, the use of minimally invasive surgical methods for treating this pathology is very important. The published data relating to this pathology, as well as to the use of neuroendoscopy for this disease, are fragmentary today. Therefore, one of the objectives of this work was to analyze the literature regarding etiopathogenesis, clinical presentation, diagnostic features, and some aspects of surgical treatment of choroid plexus papilloma, in connection with which this work is primarily of practical interest. PMID- 25033608 TI - [Academician Aleksandr Ivanovich Arutyunov--the founder of Ukrainian Neurosurgery (on the occasion of his 110 birthday)]. PMID- 25033609 TI - [The BION-M1 project: overview and first results]. AB - Biosatellite BION-M1 was launched on April 19 and landed on May 19, 2013. The mission program was largely a continuation of the earlier flown 11 BION projects, FOTON-M2 and FOTON-M3. The biosatellite was inhabited by a great variety of living organisms used for experiments and studies in gravitational physiology, gravitational biology, biotechnology, astrobiology and radiation biology, dosimetry and spectrometry. This was the first time in the history of national biology and physiology when male mice C57bl/6 were chosen for a long-term space experiment focused upon molecular biology investigations. Unfortunately, because of technical failures during the flight a part of the animals were lost. However, the major objectives were attained through reconsideration of biomaterial division among investigators and completion of virtually the total scope of investigations. PMID- 25033610 TI - [Experimental studies with mice on the program of the biosatellite BION-M1 mission]. AB - Purpose of the BION-M1 project was laying the evidence and technological basis for addressing the medical issues of future remote space exploration missions by humans. The program of researches with the use of mice was focused on elicitation of cellular and molecular mechanisms of the muscular, cardiovascular and immune reactions to extended exposure in microgravity. The comprehensive studies combined lifetime measurements with investigations of mice tissues and cells by dint of the cutting-edge morphological, biochemical and molecular biology techniques. Males of mice C57/BL6 aged 4 to 5 months were chosen as the object of studies. They were distributed into the flight, ground control and two vivarium (laboratory control) groups and investigated immediately on return and after 7 days of readaptation. Some of the physiological functions were recorded throughout the flight. To ensure wellbeing of the animals in the experiments and to enhance data quality, prior to launch the mice were specially trained so as to accommodate to the group living, eating space food, and in-flight stress factors. Those of the mice that were designated for lifetime investigations were tested and received training pre-launch. PMID- 25033611 TI - [Night sleep structural alteration as a function of individual strategy of adapting to 520-isolation]. AB - Purpose of the work was to establish a relationship between trends in sleep alteration and individual adaptation to the stress-factors in the 520-day isolation study. Psychological evaluations using a battery of motivation tests and L. Sobchik's modification of the Luscher personality test, and Mirror coordinograph enabled to differentiate groups reacting to the stress on the pattern of "control" (G-1) or "search" (G-2) manifested in individual styles of behavior and operator's activity. The 2 groups showed different dynamics of the night sleep structure. Difficulties with falling asleep in G-1 arose on the eve of "landing onto Mars" and end of the experiment, whereas in G-2 they were evident prior to the end only. Besides, the micro- and segmental sleep structures were more stable in G-1 suggesting the integrity of somnogenic mechanisms despite difficult sleep initiation. PMID- 25033612 TI - [Unconscious components of the psychophysiological reactions of the participants in the experiment with 520-day isolation]. AB - Six participants in MARS-500 were examined in an effort to gather information about intrapersonal conflicts and life spheres with high emotional tension associated with participation in the experiment with extended group isolation. The investigation was performed using the operational analogy-based neuro semantic psychodiagnostics which allows to regard the subconscious as a semantic filter with unstructured semantic information at the input and information structured by the inner world content at the output. The results shed light on the semantic structure of subjective experience and functioning of protective mechanisms, as well as organizational levels and modality of emotional experience. Prior to and after 520-day isolation, all the participants were shown to have intrapersonal conflicts and high emotional tension in the socio professional sphere, caused by the family/sexual and interpersonal relations and self-rating, and concerns about life and health. On the completion of isolation, the psychoemotional tension reduced quantitatively in interpersonal relations and increased in family/sexual. PMID- 25033613 TI - [Permanent proteins in healthy human's urine in the experiment with 520-day isolation]. AB - Purpose of the study was to track permanent proteins of urine proteome in the 520 day isolation experiment at the IBMP Ground-Based Test Facility with controlled environmental parameters. Object of the investigation was urine sampled from 6 normal male subjects at the age of 25 to 37 years. Second morning aliquots were gathered during baseline data collection, on days 50, 93, 124, 153, 180, 251, 274, 303, 330, 371, 400 and 427 of isolation, and in 7 days after its completion. Samples were subject to chromatography-mass spectrometry; results were analyzed with the help of bioinformatics resources. The following 7 permanent proteins were observed in urine over the entire length of the investigation: epidermal growth factor, polymer immunoglobulin receptor, plasma serine protease inhibitor, protein AMBP, keratin, type II cytoskeletal 1, collagen alpha-1 (vi) chain, serum albumin. PMID- 25033615 TI - [ Clermont military hospital during World war I]. PMID- 25033616 TI - [Vendome and its hospital during World war I]. PMID- 25033617 TI - [Dunkerque's hospital during World war I]. PMID- 25033618 TI - [1914-1918. Toulouse's hospitals kept out of the loop by military authorities]. PMID- 25033619 TI - [Claudius Regaud and Bouleuse]. PMID- 25033620 TI - [Orleans' hospital legacy]. PMID- 25033621 TI - Spending jump puzzles providers. PMID- 25033622 TI - Insurers brace for high-cost Sovaldi. PMID- 25033623 TI - IT experts push translator systems to convert doc-speak into ICD-10 codes. PMID- 25033624 TI - Texas doc boom leaves many out. PMID- 25033625 TI - Partnership for patients hospitals tout quality improvements but critics see a lost opportunity. PMID- 25033626 TI - Limited Medicare ACO quality data show sharp variations in performance. PMID- 25033627 TI - Why Sovaldi shouldn't cost $84,000. PMID- 25033628 TI - The ROI of infection prevention. PMID- 25033629 TI - Embracing 'retailification' of healthcare. PMID- 25033630 TI - Siemens CEO details hospitals' 'new normal' for purchasing capital equipment. PMID- 25033631 TI - [The advanced techniques of dentoalveolar surgery]. AB - During the recent decade, the advanced medical technology has brought the rapid development in the dentoalveolar surgery, and the medical concepts of humanity, painless, minimally invasive, safe and comfortable are gradually accepted by the patients and doctors. Many advanced techniques and equipments have been used in the dentoalveolar surgery. This paper would like to make a review on the clinical application and experience of the advanced medical technologies in the tooth extraction, such as the general anaesthetic technique, the nitrous oxide sedative technique, the computer-controlled local anesthesia delivery devices, the electrocardiogram montior, the location of embedded tooth by cone beam CT and minimally invasive surgical technique. Additionally, in this paper we also described the indication, contraindication, advantages and operating essentials of the orthodontic traction technique, ultrasonic bone surgery (piezosurgery) device and the surgery technology for alveolar bone shape and functional preservation in the extraction of tooth. Finally, we introduced the immediate implantation technique used in the dentoalveolar surgery. PMID- 25033632 TI - [In vitro study of xylitol on the growth and acid production of Actinomyces viscosus]. AB - OBJECTIVE: This research aimed to study the inhibitory effect of xylitol on the growth and acid production of Actinomyces viscosus (A. viscosus). METHODS: We cultivated A. viscosus in anaerobic conditions with different concentrations (128, 64, 32, 16, 8, and 4 g x L(-1)) of xylitol brain heart infusion liquid medium and determined the minimum inhibitory concentration (MIC). Subsequently, we measured the pH value of the control group, as well as those of 1/2, 1/4, 1/8 MIC, and MIC concentration groups at 1.5, 3, 6, 12, 24, and 48 h. The Delta pH and OD550 at 2, 4, 6, 8, 10, and 12 h were calculated. We discovered that the minimum xylitol concentrations suppressed 50% and 90% A. viscosus biofilm formation (i.e., MBIC50 and MBIC90). SPSS 19.0 was used to analyze the collected data, and conclusions were drawn afterward. RESULTS: Xylitol inhibited the growth ofA. viscosus at MIC of 64 g x L(-1). After 12 h, the differences of pH value among groups were all statistically significant (P < 0.05), and Delta pH increased when the MIC concentration decreased. Except for the 1/2 MIC and MIC groups, the differences of OD550 among groups had no statistical significance (P>0.05), and OD550 also increased when the MIC concentration decreased. These results imply that the ability ofA. viscosus to grow and produce acid in 1/2 MIC and MIC conditions will be reduced with the increase in xylitol concentration. The value of MIBC50 was 64 g x L(-1), whereas the value of MIBC90 was 128 g x L( 1). This finding indicates that the xylitol medium can restrict A. viscosus biofilm formation. CONCLUSION: Xylitolcan effectively inhibit the growth, adhesion, and acid production ofA. viscosus, protecting teeth from cariogenic bacteria and preventing caries to a certain extent. PMID- 25033633 TI - [Effect of type I transmembrane protein deletions on the cell cycle of human periodontal ligament fibroblasts cells]. AB - OBJECTIVE: To determine the effect of type I transmembrane protein (IRE1alpha) deletions on the cell cycle of human periodontal ligament fibroblasts (hPDLFs) cells. METHODS: Based on the IRE1alpha deletions, a full-length model was successfully constructed. Moreover, overlapping polymerase chain reaction mutagenesis facilitated the establishment of two deletion mutants of IREla (pD Kinase, pD-Rnase). The full-length model and two mutant eukaryotic expression vectors were transfected into hPDLFs cells. Western blot analysis was performed to identify the expression in the cells. The changes in the cell cycle of hPDLFS cells were detected by flow cytometry (FCM). RESULTS: The two deletion mutants of IRE1alpha with eukaryotic expression vectors were successfully constructed and correctly expressed in hPDLFs cells based on Western blot analysis. Under stress conditions, the FCM assay showed that cell percentage of S phases increased, whereas that of G1 phases decreased in the IRE1alpha group (P < 0.05) compared with the control group of tunicamycin (TM) treatment. Moreover, the cell percentage of the S phases decreased, whereas that of the G1 phases increased in the D-Rnase group (P < 0.05) compared with the control. The deletion mutant D Kinase had no influence on hPDLFS cell proliferation and cycle (P>0.05). CONCLUSION: Under stress conditions, IRE1alpha can improve the cell cycle of hPDLFs cells from the G1 to the S phase. The deletion mutant D-Rnase cause hPDLFs cell growth arrest at the G1 phase, whereas deletion mutant D-Kinase has no significant effect. PMID- 25033634 TI - [Influence of three primers on the shear bond strength between cast titanium and composite resin]. AB - OBJECTIVE: To investigate the influence of three primers on the shear bond strength between cast titanium (Ti) and composite resin. METHODS: The disks (n = 40) were cast by commercially pure (CP) Ti, which diameter were 8 mm and thick were 3 mm. The titanium surfaces were polished with silicon carbide sand papers under running water and then treated by sandblasting and acid (4%HF) etching. They were divided into four groups: control group (group A), treated with KH-570 (group B), treated with Alloy Primer (group C), treated with Metal photo primer (group D). After treatment, the specimens were evaluated for their shear bond strengths by universal testing machine. The values were statistically analyzed. The fractured surfaces were observed by scanning electron microscope (SEM). RESULTS: The shear bond strengths of group A, B, C, D were (9.773 +/- 0.67), (11.463 +/- 0.82), (14.224 +/- 0.75), (13.157 +/- 0.73) MPa. There were significant differences in bond strength between A and B, C, D (P < 0.01). B and C, D had significant differences (P < 0.01). C and D had no significant differences (P>0.05). CONCLUSION: KH-570, Alloy Primer, Metal photo primer significantly improve the bond strength of ceramage composite resin to cast titanium. KH-570 group bonding strength is lower than the the Alloy Primer group and Metal photo primer group. PMID- 25033635 TI - [Strengthening a dental gypsum model by infiltration of cyanoacrylate]. AB - OBJECTIVE: To explore a simple but novel method of strengthening gypsum material by cyanoacrylate infiltration. To evaluate the influence of cyanoacrylate on the mechanical properties of dental gypsum models. METHODS: Gypsum specimens were polished to the dimension of 35 mmx4 mmx4 mm. Butyl-cyanoacrylate was diluted with chloroform at different concentrations, namely 20% and 30% cyanoacrylate. Gypsum specimens were infiltrated by diluting one component of cyanoacrylate at different concentrations for 8 h and then dried for analysis. The changes in elastic modulus, fracture toughness, compressive strength, biaxial strength, brinell hardness were measured. The data were analyzed using software OriginPro 8. RESULTS: The viscosity measurements indicated that diluted cyanoacrylate were Newtonian fluids and the viscosity increased slightly within the 48 hours of preparation but still similar as water at room temperature, which could be used to infiltrating gypsum. The gypsum infiltrated with cyanoacrylate exhibited good physicochemical properties. The biaxial strength, fracture toughness, compressive strength and brinell hardness of the gypsum were improved by 39%, 30%, 63% and 18%, respectively. CONCLUSION: Cyanoacrylate can significantly improve the strength of gypsum model which indicates the potential clinical application. PMID- 25033636 TI - [Effect on secretory function of rat submandibular glands caused by ischemia reperfusion]. AB - OBJECTIVE: To investigate the injury stress responses caused by ischemia reperfusion and its effects on the salivary secretory function of rat submandibular glands. METHODS: An in situ ischemia reperfusion experimental model of rat submandibular glands was developed. The rat submandibular glands were subjected to 90 min of ischemia without denervation followed by reperfusion for 1, 12, 24, and 72 h. Salivary secretion, histological changes, reactive oxygen species (ROS) levels, and cellular apoptosis of the involved submandibular glands were detected after reperfusion. RESULTS: The secretory function of the glands decreased at 1 and 12 h, and the saliva secretion gradually had the same value as that of the control sample 72 h after reperfusion. Increasing inflammatory cells infiltration, cellular atrophy, and tissue edema were observed especially after reperfusion for 12 h. The level of ROS and the number of apoptotic cells exhibited the same tendency, and higher ROS levels and more apoptosis cells 1 and 12 h after reperfusion were observed. CONCLUSION: Our study suggests that ischemia reperfusion can cause a series of injury stress responses in submandibular glands, which might have an important function in the early phase dysfunction of transplanted submandibular glands. PMID- 25033637 TI - [Influence of cryogenic treatment and age-hardening heat treatment on the corrosion behavior of a dental casting Ag-Pd alloy]. AB - OBJECTIVE: The purpose of this study is to investigate the influence of cryogenic treatment and age-hardening heat treatment on the corrosion behavior of a dental casting Ag-Pd alloy. METHODS: A low gold content dental casting alloy composed of Ag-Pd-Cu-Au was prepared for this study. Corrosion test was performed according to ISO 10271:2001 dental metallie-corrosion test methods. Experimental specimens were casted according to a standard dental lost-wax casting procedure, treated with solution by heating the specimens to 900 degrees C, and immediately quenched in ice water. The specimens were then divided into four groups and subjected to heat treatment, cryogenic treatment, and heat treatment combined with cryogenic treatment. The specimens after the solution treatment were taken as control. The metallographic structures of the specimens were observed. The electrochemical parameters and the quantity of non-precious metallic ions released were evaluated via electrochemical and static immersion tests. RESULTS: Metallographic observation revealed that all the treatments resulted in a change in the microstructure of the alloy. The treatments were effective in improving the electrochemical parameters, such as an increase in Eocp and Ecorr and a decrease in Icorr (P < 0.05). The amount of non-noble metal ions released showed no difference compared with the control group (P > 0.05). CONCLUSION: After different treatments, the antierosion properties of the alloy satisfied the ISO requirements. Age-hardening heat treatment and cryogenic treatment improved the corrosion resistance of the alloy. PMID- 25033638 TI - [Factorial analysis of root canal irrigants and cements on coronal microleakage after cementing metal post-cores]. AB - OBJECTIVE: To evaluate the effect of different root canal irrigants and cements on coronal microleakage and the interaction effects after cementing metal post cores. METHODS: Ninety newly extracted single-rooted mandibular human premolars were endodontically treated. Post spaces were prepared in the root canals, and Co Cr post-cores were cast routinely. The specimens were randomly divided into six groups (n = 15) via a two-way factorial design method. The irrigant factors (A) included A1: no irrigant (75% alcohol wiping), A2: 3% H2O2 + 0.9% NaCl, and A3: 15% ethylenediamine tetraacetic acid (EDTA) + 5.25% NaClO. The cement factors (B) included B1: zinc polycarboxylate cement, and B2: glass ionomer cement. The specimens received treatments based on the grouping of A1B1, A1B2, A2B1, A2B2, A3B1, and A3B2. All samples were sectioned longitudinally after being immersed in India ink for three weeks. The microleakages were observed using a stereomicroscope. The SPSS 13.0 software package was used for factorial analysis. RESULTS: The mean microleakage scores and standard deviations were as follows: Group A1BI: (1,192.59 +/- 417.84) microm, Group A1B2: (1,317.38 +/- 527.35) microm, Group A2B1: (1,429.33 +/- 482.68) microm, Group A2B2: (1,026.79 +/- 459.49) microm, Group A3B1: (1,448.29 +/- 561.02) microm, and Group A3B2: (1,922.47 +/- 678.86) microm. The A2B2 group showed minimum microleakage, whereas the A3B2 group showed maximum microleakage. The microleakage degrees among different irrigants presented significant statistical difference (P < 0.05), but the two cements showed no significant difference (P > 0.05). An interactive effect on the microleakage existed between the irrigants and the cements after cementing the metal post-cores (P < 0.05). CONCLUSION: When cementing metal post cores, the coronal microleakage following 3% H2O2 + 0.9% NaCl irrigation combined with glass ionomer cement can be reduced. The combined application of 15% EDTA + 5.25% NaClO and glass ionomer cement significantly aggravates microleakage. PMID- 25033639 TI - [Craniofacial morphology of child and adult deepbite: a cross-sectional study]. AB - OBJECTIVE: To investigate the changes in the craniofacial morphology ofdeepbite from childhood to adulthood using cross-sectional methods. To analyze the maxillofacial characteristics of adult deepbite. METHODS: The sample included 159 children (with average age of 12.47 years old) and 81 adults (with average age of21.76 years old) with class III deepbite. The control group consisted of51 normal individuals (with average age of 18.41 years old). Lateral cephalometric radiographs were taken and recorded in a computer through a scanner. Cephalometric measurements were conducted by using Winceph 7.0 software, and results were analyzed with SPSS 12.0 software. RESULTS: Significant differences between child and adult deepbite were observed in the following: N-ANS, ANS-Me, A Ms, A-Ptm, Wits, Mo-Ms, Ii-Ii, A-B plane angle to the mandibular plane angle, Gonial angle, L1 to NB length, overjet, mandibular body to anterior cranial base, Mo-Mi, posterior facial height, U1 to NA length, Pog-Go, Cd-Go, occlusion plane angle to SN, and U1 to SN. In addition, significant differences between adult deepbite and normal occlusion were observed in SNB, ANB, convexity, APDI, ODI, Wits, A-B plane to mandibular plane, Gonial angle, overjet, mandibular body to anterior cranial base, S-Ptm, Mo-Mi U1 to SN; Pog-Go, Cd-Go, posterior cranial base, and occlusion plane to SN and posterior facial height. CONCLUSION: Deepbite patients have certain growth potential after puberty, but the sagittal relationship of their jaws exhibits no improvement. Adult deepbite patients exhibit significant problems in the vertical and sagittal jaw positions. PMID- 25033640 TI - [Preliminary study on the best-exerted force chance in the female menstrual cycle]. AB - OBJECTIVE: To investigate the exerted force in different phases of the female menstrual cycle, as well as the changes in estrogen (E2), osteocalcin (OCN), receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) levels in the gingival crevicular fluid (GCF) during orthodontic tooth movement, to provide a theoretical basis for the selection of the best opportunity for efficient tooth movement. METHODS: Twelve women (aged 18 years to 28 years) with extracted first premolars had been selected. Six women in the group were randomly selected as the menstrual period group, whereas the remaining six were assigned to the ovulation period group. Right canines were retracted with 1.5 N NiTi close coil spring. GCF samples were collected prior to the force exertion experiments at 0 (T0), 15 (T1), 30 (T2), and 45 d (T3). The levels of E2, OCN, OPG and RANKL in GCF were measured by chemiluminescence and enzymelinked immunosorbent assay. RESULTS: The E2 and OCN levels were significantly higher in the ovulation period group than in the menstrual period group (P < 0.05). No significant differences were found in RANKL and OPG levels between the two groups (P > 0.05). Finally, no significant difference was found in RANKL/OPG ratio between the two groups (P > 0.05). CONCLUSION: Exerted force on teeth during the menstrual period may promote rapid tooth movement. PMID- 25033641 TI - [Clinical evaluation of zirconia crowns for single posterior teeth]. AB - OBJECTIVE: To observe and evaluate the clinical performance of zirconia crowns made by CEREC inLab computer aided design/computer aided manufacturing(CAD/CAM) for posterior teeth. METHODS: A total of 242 patients were implanted with zirconia crowns fabricated by CEREC inLab CAD/CAM. The crowns were evaluated by Modified US Public Health Service criteria at baseline, 6, 12, 24, and 36 months. The chi-square test was used to analyze the survival rate. RESULTS: All but five crowns were evaluated by an independent evaluator at baseline, 6, 12, 24, and 36 months. The survival rate declined with time. The A score percentage was above 85% at 36 months. CONCLUSION: The single zirconia crowns fabricated by CEREC inLab CAD/CAM demonstrate satisfactory clinical performance during a short period. PMID- 25033642 TI - [Assessment of tooth bleaching efficacy with spectrophotometer]. AB - OBJECTIVE: To analyze the changes in CIE L*, a*, and b* at cervical, body, and incisal sites after tooth bleaching by using a spectrophotometer. METHODS: Sixty seven intact and healthy maxillary central incisors were in-vestigated. These incisors were darker than A3 according to the Vita Classical shade guide. The CIE tooth shade parameters L*, a*, and b* were simultaneously recorded at three tooth areas (cervical, body, and incisal) with a spectrophotometer before and after tooth bleaching (35%H2O2 coordinating with Beyond whitening accelerator irradiating). The shade dif-ferential (DeltaE) was calculated. ANOVA, paired t test, and Pearson correlation analysis were used for data analysis. RESULTS: The efficacy rates of tooth bleaching were satisfactory, with 86.6%, 86.6%, and 85.1% in the cervical, body, and incisal sites, respectively. The average values of DeltaE were 5.09, 4.44, and 4.40 in the cervical, body, and incisal sites. Tooth bleaching significantly increased L* and significantly decreased a* and b* in all tooth areas (P < 0.01). The decreasing range of Deltab* was more than the increasing range of DeltaL* at the cervical site; opposite results were observed at the incisal site. A positive correlation was detected between baseline b* and DeltaE. CONCLUSION: The spectrophotometer could objectively evaluate the whitening effect of tooth bleaching at the different tooth sites. The tooth bleaching system (35%H202 coordinating with Beyond whitening accelerator irradiating) exerts powerful bleaching actions in most of the tooth areas investigated. The order of tooth bleaching effectiveness is cervicalbody>incisal. Yellow coloration is decreased mainly at the cervical site, and brightness was increased mostly at theincisal site. The effectiveness of tooth bleaching increases as the baseline b* value increases. PMID- 25033643 TI - [Nursing intervention and evaluation of postoperative pain in preschool children with cleft lip and palate]. AB - OBJECTIVE: This study aimed to observe the postoperative pain rate and degree of pain in preschool children with cleft lip and palate, and investigate the effect of nursing intervention on pain relief. METHODS: A total of 120 hospitalized cases of three- to seven-year-old preschool children with cleft lip and palate were selected from May to October 2011. The subjects were randomly divided into the control group and experimental groups 1, 2, and 3. The control group used conventional nursing methods, experimental group 1 used analgesic drug treatment, experimental group 2 used psychological nursing interventions, and experimental group 3 used both psychological nursing intervention and analgesic drug treatment. After 6, 12, 24, and 48 h, pain self-assessment, pain parent assessment, and pain nurse-assessment were calculated for the four groups using the pain assessment forms, and their ratings were compared. RESULTS: The postoperative pain rates of the four groups ranged from 50.0% to 73.3%. The difference among the four groups was statistically significant (P < 0.001). The differences among the control group and experimental groups 1 and 2 were not statistically significant (P = 0.871), whereas the differences among experimental group 3 and the other groups were statistically significant (P < 0.001). CONCLUSION: Postoperative pain in preschool children with cleft lip and palate is common. Psychological nursing intervention with analgesic treatment is effective in relieving postoperative pain. PMID- 25033644 TI - [Construction and identification of a lentiviral vector of RNA interference containing human Notch-1 gene]. AB - OBJECTIVE: To construct and identify a lentiviral vector of RNA interference targeting human Notch-1 gene. METHODS: To determine the Notch-1 gene sequences, three RNAi target sequences (shRNA1-3) were designed in accordance with the RNAi sequence design principles and cloned into the lentiviral vector pLenOR-THM by endonuclease BamH I restriction, EcoR I double digestion, and T4 DNA-ligase ligation. After the transformation into competent DH5alpha bacteria, the candidate clones were identified by Kpn I and EcoR I double digestion and DNA sequencing. The recombinant and three packaging plasmids were co-transfected into human embryonic kidney cell line 293T cells by lipofectamine to produce the lentiviral particles. The viral titer was determined. The 293T cells were infected by the lentiviral particles obtained, and transfection efficiency was assessed using a fluorescent microscope. The lentiviral vector particles were also transfected into ACC-M cells. The Notch-1 expression in the transfected cells was assayed by quantitative reverse transcription polymerase chain reaction (QRT-PCR) and Western blot analysis. RESULTS: The lentiviral RNAi vector pLenOR THM-Notchl for Notch-1 gene was constructed successfully. Strong green fluorescence was observed in the 293T cells under fluorescent microscope after co transfection of the cells with the four plasmids of lentiviral vector. The virus in the supernatant reached a titer of 5.8 x 10(8) TU x mL(-1). The transfection efficiency of the collected virus exceeded 90% in 293T cells with 1 as a multiplicity of infection. The third lentiviral vector was found to significantly inhibit the Notch-1 expression at the mRNA and protein levels. CONCLUSION: The lentiviral RNAi vector of Notch-1 has been successfully constructed and identified. PMID- 25033645 TI - [Application of fluorescence probe marked by quantum dots to detect early submandibular lymph node metastasis in a nude mouse model]. AB - OBJECTIVE: A fluorescence probe marked with a specific angle protein antibody by using quantum dots QDs605-CK (AE1/AE3) was utilized to detect metastasis and micrometastasis rates of early submandibular lymph node metastatic carcinoma in a nude mouse model. The method was compared with traditional immunohistochemistry (IHC) staining and hematine-eosin (HE) staining to explore a new method for early diagnosis and treatment of tongue squamous cell carcinoma. METHODS: Human tongue Tca8113 cells were cultured and inoculated in 18 nude mice tongue body tissues (except the midline) to establish submandibular lymph node metastasis in tumor bearing nude mice models. The nude mice were sacrificed, and the mandibular lymph node was dissected after injecting tumor cells for six weeks. One lymph node was divided into two parts: one was used to create a serial section embedded by paraffin then detected in HE staining and IHC staining; the other was immediately frozen in liquid nitrogen and detected using the fluorescence probe marked with a specific angle protein antibody by using quantum dots. Lymph node metastasis and micrometastases rates were calculated. RESULTS: The rates of metastasis in the submandibular lymph node via quantum dot immunofluorescence staining, IHC staining, and HE staining showed positive values of 66.7%, 61.1%, and 27.8%, respectively. The micrometastases rates were 38.9% and 33.3% via quantum dot immunofluorescence staining and IHC staining, respectively. The positive rates of detecting lymph nodes metastasis with quantum dot labeled keratin CK (AEl/AE3) immunofluorescence and keratin CK (AE1/AE3) IHC staining were higher than that of conventional HE staining ('=6.379, P<0.05). The two methods showed no statistical difference (chi2 = 0.120, P > 0.05). CONCLUSION: Quantum dots fluorescent probe marked with the angle protein antibody CK (AE1/ AE3) can precisely locate the submandibular lymph node metastasis tumor cell of the nude mice tongue squamous cell carcinoma, and the emitted red fluorescence showed strong specificity, high resolution, and a clear background. The method could be utilized to detect submandibular lymph node metastasis and micrometastasis of tongue squamous cell carcinoma in nude mice. PMID- 25033646 TI - [An animal experimental study of the loading time on anchorage implant stability]. AB - OBJECTIVE: This study aimed to evaluate the influence of loading in different healing periods on implant stability and to establish an animal model of anchorage implant screws. METHODS: Anchorage implant screws were implanted in sheep alveolar bone to establish the implant screw animal model. The animals were randomly divided into four groups: group A, sheep without loading; group B, sheep loaded immediately after implant; group C, sheep loaded after two weeks; and group D, sheep loaded after four weeks. The maxillary and mandibular tissue specimens with implants were dissected. The maxillary tissue specimens were used to make undecalcified bone grinding slices, and the healing mode of the implant bone interface was observed by light microscope. The maximum shear strength of loose mandibular specimens was measured by a material testing machine. The differences in group data were statistically analyzed. RESULTS 1) A general difference in shear strength exists among the four groups. The shear strengths in groups A and B were lower than those in groups C and D. 2) No significant difference in healing mode was found between the pressure side and the tension side of the longitudinal-grinded bone slices with implants. Both fiber combination and osseointegration of transverse-grinded slices could be found in the interface in all four groups. The major integration mode of the implant-bone interface of groups A and D was osseointegration, whereas that of the implant bone interface of groups B and C was fibrous tissue transformation. The surrounding bone tissue regenerated toward the implants of group C. CONCLUSION: Results show that loading time influences the stability of implant anchorage. PMID- 25033647 TI - [Differential proteomics research on exosomes derived from tongue squamous cell carcinoma cells and normal mucosa cells]. AB - OBJECTIVE: This study aimed to explore further the mechanisms of tongue squamous cell carcinoma (TSCC) cell recurrence, metastasis, and diffusion, as well as to establish the experimental basis for the molecular biology research on TSSC. We intend to complete our objective through differential proteomics and preliminary analysis protein expression of exosomes derived from TSCC and normal mucosa cells. METHODS: We acquired cultured supernatant fluid in vitro in the laboratory by culturing TSCC (tongue cancer Tca8113 cell line) and human normal mucosa cells (HOK cell line). The exosomes were separated and purified through differential centrifugation. Furthermore, the different protein expressions were identified through dielectrophoresis and mass spectrometry. The functions of the different protein expressions were identified through an online database search. RESULTS: TSCC and human normal mucosa cells secrete a large amount of capsule bubble structure substances in vitro, as confirmed by electron microscopy and surface markers heat shock protein-70 and major histocompatibility complex class 1. A total of 16 oral cancer cell-derived exosomes that expressed quantity more than two times, twelve that increased their expression levels, and four that cut their expressions were identified through the differential proteomics research on the two groups. CONCLUSION: Differential proteins that were verified through the online database serve an important function in exosome formation and in the progress of cancer. PMID- 25033648 TI - [Occlusal planes of Angle's class III malocclusion impact by anterior overbite]. AB - OBJECTIVE: To investigate the correlation between Angle's class III patients' occlusion plane and anterior overbite by controlling the changes in occlusion plane during orthodontic treatment. METHODS: In total, 90 Angle's class III adult orthodontic patients were selected as the experimental group, and 30 normal adults were selected as the control group. According to the overbite, the class III patients were divided into three groups, and 14 indicators were measured. ANOVA and multiple comparison analysis were used to analyze the difference between class III patients, and linear analysis was used to analyze the correlation between anterior overbite and anterior-posterior occlusion plane. RESULTS: In class Ill patients, posterior occlusion plane and anterior overbite size were negatively correlated (r = -0.24, P < 0.05), whereas anterior occlusal plane and anterior overbite size were positive correlated (r = 0.23, P < 0.05). CONCLUSION: The shape of the occlusion plane varies in different anterior overbite patients. During orthodontic treatment in different overbite class III patients, the vertical height of the posterior teeth and the rotation of the occlusion plane should be controlled. PMID- 25033649 TI - [Effect of different polymerization methods on shear bond strength between polymethyl methacrylate and silicone soft liner]. AB - OBJECTIVE: To compare shear bond strength (SBS) between two types of silicone soft liner and polymethyl methacrylate (PMMA) under the condition of heat curing and room temperature curing. METHODS: A total of 48 PMMA specimens (50 mm x 10 mm x 3 mm) were made by water-bath heating method, and randomly divided into four groups. By using Ufi Gel P (UGP) as soft liner material, group A1 was prepared under heat curing, and group A2 was prepared under room temperature curing. To form the other two groups, Silagum-Comfort (SLC) as soft-liner material was used. Group B1 was prepared under heat curing, and group B2 was prepared under room temperature curing. Shear bond strength (SBS) was tested by using the electronic universal testing machine. The adhesives layer and surface of silastic and PMMA were observed by optical microscope and scanning electron microscopy (SEM). RESULTS: The SBS of groups A1, A2, B1, B2 were (2.39 +/- 0.24), (1.74 +/- 0.27), (3.09 +/- 0.26), and (2.21 +/- 0.29) MPa, respectively. Significant differences were found between A1 and A2, B1 and B2, A1 and B1, and A2 and B2 (P < 0.05). Optical microscope showed numerous bubbles in the cured UGP, and no air bubbles in the SLC. The surface of PMMA was rough. SEM images showed that each group had continual consistent adhesive interface and a whisker hump on the adhesive layer of A2 and B2. CONCLUSION: The SBS ofUGP, SLC, and PMMA achieved minimum clinical standard of 0.44 MPa. The SBS of UGP and PMMA were higher than that of SLC and PMMA. The polymerization method of heat curing was higher than room temperature curing. PMID- 25033650 TI - [Relationship between dental caries and salivary proteome by electrospray ionization ion-trap tandem mass spectrometry in children aged 6 to 8 years]. AB - OBJECTIVE: To explore the relationship between salivary proteome and dental caries and to promote the biomarker studies of dental caries susceptibility by comparing the salivary proteome of caries-active children and caries-free children with electrospray ionization ion-trap tandem mass spectrometry (ESI MS/MS). METHODS: Ten caries-active children and ten caries-free children were sampled. The salivary proteome of the two groups was studied, and the differential protein between the two groups was analyzed by ESI-MS/MS after sodium dodecyl sulfate polyacrylamide gel electrophoresis, filter-aided sample preparation, and liquid chromatography. RESULTS: The concentration of salivary protein was higher in the caries-active group than in the caries-free group. The polypeptide counts of thecaries-active and caries-free groups were 602 and 481, which belonged to 286 and 227 proteins, respectively. The differential polypeptide count of the two groups was 361, and the differential protein count was 118. The detected proteins included matrix metalloproteinase-9 (MMP9), mucin 7 (MUC7), lactotransferrin (LTF), carbonic anhydrase 6 (CA6), azurocidin (AZU), and cold agglutinin. CONCLUSION: The total salivary protein was higher in the caries-active group than in the caries-free group. The preliminary detection of differential proteins (MMP9, MUC7, LTF, CA6, AZU, and cold agglutinin) may lay some foundation for biomarker research of dental caries susceptibility. PMID- 25033651 TI - [Preparation and anti-bacterial tests of silver-modified titanium surface]. AB - OBJECTIVE: To deposit silver nanoparticles on a titanium surface to obtain antibacterial properties. To reduce the incidence of peri-implantitis, and improve the success rate of implantation. METHODS: A silver nanoparticle-modified titanium (Ti-nAg) surface was prepared using silanization method, and its surface was characterized by using X-ray photoelectron spectroscopy (XPS) and energy dispersive X-ray spectrometer (EDX). Two species of bacteria, namely, Staphylococcus aureus and Escherichia coli, were used to test the antibacterial effect of Ti-nAg surface. RESULTS: Scanning electron microscope (SEM) revealed that a small quantity of silver nanoparticles were deposited on the titanium surface. XPS analyses revealed that 6.8% of silver was present on the titanium surface. After 24 h of incubation, 94.23% of Staphylococcus aureus and 95.34% of Escherichia coli were killed on the Ti-nAg surface. CONCLUSION: Results suggest that silver nanoparticle-modified titanium is a promising material with an antibacterial property that may be used as an implantable biomaterial. PMID- 25033652 TI - [Effect of resin infiltration treatment on the colour of white spot lesions]. AB - OBJECTIVE: This study aimed to evaluate the effect of resin infiltration and fluoride solution on masking different demineralized white spot lesions by assessing color change. METHODS: Artificial white spot lesions were produced on 60 human molars. Each sample had at least two enamel surfaces opened (named A and B). The samples were randomly divided into groups 1, 2, and 3 according to their time of demineralization (24, 48, and 72 h). After demineralization, the A spot of each sample was treated by resin infiltration. The B spot was treated with 0.1% fluoride solution daily for 30 days. After the remineralization of the B spot, resin infiltration was used again on the B spot of each sample. Color assessment was performed by a spectrophotometer in five distinct stages: baseline, after the production of artificial caries, after resin infiltration of A spots, after 30 days of fluoride solution treatment of B spots, and after resin infiltration of remineralized B spots. RESULTS: Before demineralization, the L* values of spots A and B in all groups were not significantly different (P > 0.05), whereas the L* values of spots A and B were significantly increased after demineralization. The L* values of A spots recovered significantly after treatment by resin infiltration (P<0.05), but only groups 1 and 2 reached the baseline. The L* values of B spots had no significant differences (P > 0.05) after fluoride treatment compared with that after demineralization. After resin infiltration on B spots, the L* values recovered but could not reach the baseline nor the level of A spots treated by resin infiltration only. CONCLUSION: Resin infiltration is a more effective treatment for masking white spot lesions than traditional fluoride treatment. The effect of masking white spot lesions has certain relationships with the degree of demineralization and activity of the lesion. PMID- 25033653 TI - [Multiple enamel pearls on left maxillary third molar: a case report]. AB - Enamel pearl is an ectopic enamel, which usually occurs in the root bifurcate or approaching enamel-cementum site of the first maxillary molar. A case of multiple enamel pearls on the left maxillary third molar is reported in this paper, and relevant literature was reviewed. PMID- 25033654 TI - [Clinical study of the two-stage hollow prosthesis on restoring unilateral maxillary defect with restricting mouth opening: a case report]. AB - A case of a patient with a unilateral maxillary defect and restricted mouth opening was presented. The two-stage hollow maxillofacial prosthesis can be used to restore the above defect, thus promoting mastication, speaking, swallowing, and sucking, as well as improving the patient's appearance. Satisfactory results were achieved. PMID- 25033655 TI - [Overview of researches for Helicobacter pylori in oral cavity and stomach]. AB - Helicobacter pylori (H. pylori) is one of the most common pathogens in human and it is closely related to gastrointestinal diseases. It is essential for us to understand the transmission process of H. pylori to prevent its spreading. The oral cavity has been proposed as a reservoir for gastric H. pylori, which has been detected by culture and polymerase chain reaction (PCR) in both dental plaque and saliva. Some researchers have proposed H. pylori in oral cavity may play an important role in its transmission and reinfection. Oral-oral or fecal oral transmission are thought to be the most possible transmit way. This review will discuss the evidence for the role of the oral cavity in the transmission of H. pylori, the difficulties encountered in addressing this topic and possible directions for future research. Oral H. pylori may also play a role in the diagnosis and prevention of deceases related to H. pylori such as gastritis, gastric ulcer and gastric carcinoma. The recent progresses in this area are also reviewed. Moreover, we also discussed the relationship between oral H. pylori and oral deceases like periodontal disease and oral ulcer. PMID- 25033656 TI - Use of plant extracts to control and treat AB5 enterotoxin-related diarrhea. AB - Plants contain a broad spectrum of small molecules with potential antimicrobial properties. Here, we review the antimicrobial activities of plant extracts against enterotoxic bacteria encoding AB5 toxins, including Vibrio cholerae, Shigella dysenteriae and enterotoxic Escherichia coli strains. Several plant extracts have strong antimicrobial effects and the potential to boost Oral Rehydration Therapy, which is the first line of treatment for acute diarrhea. PMID- 25033657 TI - Quantitative expression of Candida albicans aspartyl proteinase genes SAP7, SAP8, SAP9, SAP10 in human serum in vitro. AB - The different members of the secreted aspartyl proteinase (Sap) family of the human pathogenic yeast Candida albicans are proposed to play different roles during infection and are differentially expressed at various body sites. In recent reports, expression analysis has focused on the genes SAP1-6, while the expression pattern of SAP7-10 was less well studied. We analyzed the SAP7-SAP10 expression profile of C. albicans under human serum influence that may be elucidated in the course of blood infection in humans and how this in vitro expression profile is associated with hyphal formation. The phenotypes of strains were examined under scanning electron microscopy. Quantitative RT-PCR (2 (deltadeltaC)T) was used to monitor SAP expression of C. albicans wild type cells and mutants lacking SAP9 and/or SAP10. Of the four analyzed SAP genes, only SAP7 was detectably induced in the double mutant and in the wild type strains in the model that mimics bloodstream infections. On the other hand, in the wild types (isolate 83 and CAF2-1), SAP7 was expressed 0.8- or 0.4-fold less than SAP10, respectively. Our findings suggest that Sap7 may respond to the challenge of the human blood environment. Furthermore, the results support the notion that compensatory upregulation of SAP7 and SAP8 in the deltasap9/deltasap10 mutant occurs in these conditions. SAP7-10 expression was strain-specific. Our findings point to a link between morphogenesis and expression of SAP9 in serum, where these conditions induce both hyphae and SAP9, but temporal gene expression patterns might be controlled by other factors. PMID- 25033658 TI - The effect of oleanolic and ursolic acids on the hemolytic properties and biofilm formation of Listeria monocytogenes. AB - Oleanolic acid and ursolic acid are pentacyclic triterpenoids isolated from a variety of medicinal plants, which have antibacterial activity. Listeria monocytogenes is a Gram-positive facultative pathogen, being the causative agent of listeriosis. The present study was carried out to evaluate the in vitro effect of sub-inhibitory concentrations of both triterpene acids on the pathogenicity determinants of L. monocytogenes: their hemolytic activity and biofilm forming ability. Oleanolic and ursolic acids inhibited listeriolysin O activity without influencing toxin secretion. Biofilm formation, and the viability of L. monocytogenes cells in biofilms was diminished by both compounds. Thus, both acids affected L. monocytogenes virulence. It was also demonstrated that oleanolic acid bound to the peptidoglycan of L. monocytogenes and this interaction was influenced by teichoic acids. PMID- 25033659 TI - Iron shortage and bile salts play a major role in the expression of ompK gene in Vibrio anguillarum. AB - The outer membrane protein K, OmpK first identified in Vibrio parahaemolyticus has been shown to be a receptor for a broad host range vibriophage KVP40 infecting members of the Vibrionaceae. In the study, the effect of culture conditions on the expression of ompK in V. anguillarum was studied using real time PCR. The expression increased significantly in the presence of bile salts and iron chelating agent 2, 2' bipyridine, suggesting a role for this protein in bile resistance and also in iron acquisition by V. anguillarum. OmpK induction by iron limitation and the presence of bile salts was reconfirmed by western blot technique after growing the cells in trypticase soy broth supplemented with bile salts, blood and 2, 2' bipyridine. We surmise that the expression of OmpK protein of V. anguillarum is bile salt and iron chelating agent-dependent. PMID- 25033660 TI - Development of synbiotics with inulin, palatinose, alpha-cyclodextrin and probiotic bacteria. AB - Success in creating a synbiotic depends on compatibility between the chosen components--prebiotic and probiotic. In this work the interactions between Lactobacillus sp. strains isolated from yogurts and type strains of Lactobacillus sp. and Lactococcus sp., and the dependence of their growth and antibacterial activity on three oligosaccharides (OS)--palatinose, inulin and alpha cyclodextrin were investigated. All isolated lactobacilli produce antibacterial compounds, which possibly are the bacteriocins of Lactobacillus casei ATCC334 strain. Results of growth analysis with different OS revealed that part of lactobacilli isolated from yogurts can effectively ferment inulin and may be used for the development of synbiotics. Palatinose and Lactobacillus acidophilus could be used as symbiotics with effective antibacterial activity. One of the types of Lactococcus sp. strains can assimilate palatinose and alpha-cyclodextrin, so they both can be used as components of synbiotics with the investigated lactococci. Results of this analysis suggest that the investigated isolated and type strains of Lactobacillus sp. and Lactoccocus sp. can be useful as probiotics in the development of synbiotics. Together with prebiotics--palatinose, inulin and alpha cyclodextrin, the synbiotics, which could regulate not only the growth of beneficial bacteria in the gastrointestinal tract, but also their antibacterial activity, can be created. PMID- 25033661 TI - Uropathogenic Escherichia coli isolates with different virulence genes content exhibit similar pathologic influence on Vero cells. AB - Uropathogenic Escherichia coli are the major causative agent of urinary tract infection--they may simultaneously express a number of virulence factors to cause disease. The aim of this study was to investigate the relation between virulence factors content of fifteen UPEC isolates and their pathogenic potential. The isolates belonged to the five serotypes O78:K80, O114:K90, O142:K86, O164 and O157. Nine of the virulence factors have been explored, ibeA, pap, sfa/foc, cnfl, hly, fyuA, pil, ompT and traT. Virulence factors profiling of the isolates revealed a different content ranging from 22% to 100% of the virulence genes explored. The pathogenic capacity of all fifteen isolates when tested on Vero cells showed that the cytotoxicity for all tested strains on Vero cells was approximately equal and enhanced after growth in syncase broth, leading mainly to cell lysis. The toxic effects reduced slightly after heat treatment of the toxin, and greatly after formalin detoxification, but not all the deleterious effect was abolished. Endotoxin also has cytotoxic effects on Vero cells, but longer time is needed for cytolysis which is greatly diminished with formalin treatment. In conclusion, our study revealed that pathogenic strains of UPEC can exert their pathogenic effect on live cells or system with limited virulence factors gene content. PMID- 25033662 TI - Novobiocin sensitivity of Salmonella typhimurium dam and/or seqA mutants. AB - This study was carried out to determine the effects of novobiocin, a gyrase inhibitor, on the growth, survival, motility and whole cell proteins of S. Typhimurium dam and/or seqA strains. Our results showed that the dam and seqA/dam mutants are the most sensitive to novobiocin, compared to wild type and seqA strains. Surprisingly, the motility of seqA mutants increased after exposure to novobiocin only in stationary phase cells. All the other strains showed a significant decrease in their motility. The analysis of protein profiles of all strains demonstrated several modifications as manifested by the alteration of the expression levels of certain bands. Our work is therefore of great interest in understanding the effects of novobiocin on S. Typhimurium and the involvement of DNA methylation. PMID- 25033663 TI - The antimicrobial susceptibility of Helicobacter pylori strains isolated from children and adults with primary infection in the Lower Silesia Region, Poland. AB - The resistance of microorganisms to antibiotics has become a serious issue in recent years in the therapy of bacterial infections. This problem also concerns the treatment of infections caused by Helicobacter pylori strains. The aim of this study was to evaluate the frequency of primary resistance of H. pylori strains isolated from children and adults. The subject of the research was 105 strains of H. pylori isolated from children and 60 strains from adults in the Lower Silesia Region in the years 2008-2011. Antimicrobial susceptibility to the following antibiotics was assessed: amoxicillin (AC), clarithromycin (CH), metronidazole (MZ), tetracycline (TC), levofloxacin (LEV) and rifabutin (RB). Among the strains isolated from children, 33.3% were resistant to CH, 44.8% to MZ whereas 1.9% of strains were resistant simultaneously to CH, MZ and LEV. Among 60 strains isolated from adults, 23.3% were resistant to CH, 66.7% to MZ, and 6.7% to LEV. Moreover, 16 multidrug resistant strains were isolated from adults, including 12 resistant to CH and MZ, 3 to MZ and LEV, and 1 to CH, MZ and LEV. All examined strains were susceptible to AC, TC and RB. The high incidence of resistance to CH and MZ suggests that standard triple therapies may not be useful as first-line treatment in Poland without earlier susceptibility testing. PMID- 25033664 TI - Helicobacter pylori infection in type 1 diabetes children and adolescents using 13C urea breath test. AB - There is a 10-30% prevalence of HP infection in the general pediatric population in Poland. This study aimed to determine its prevalence in T1DM children in Upper Silesia, Poland and estimate its influence on metabolic control of patients. We studied 149 (82 female) children with T1DM (duration > 12 months, mean HbA1c) and 298 (164 female) age-matched controls. In all cases height and weight z-scores and Cole's index were assessed. In T1DM patients additionally glycated hemoglobin A1c and T1DM duration were analyzed. Presence of HP infection was determined using 13C-isotope-labeled urea breath test (UBT) (fasting and 30 min after ingestion 75 mg of 13C urea). HP infection was present in 17 (11.4%) T1DM patients and in 49 (16.4%) controls (p > 0.05). T1DM patients presented higher values of anthropometric parameters than healthy controls (weight SDS 0.25[-0.46 divided by 0.84] vs. -0.25 [-1.06 divided by 0.26], height SDS 0.09 [-0.60 divided by 0.69] vs. -0.31[-1.17 divided by 0.48] and Cole's index 103% [93 divided by 111%] vs. 97% [86 divided by 106%]; for all p < 0001). Within both groups--T1DM children and controls--no differences regarding sex, age and any of the anthropometric parameters were determined. T1DM duration and HbA1c showed no relation to prevalence of HP infection. Prevalence of HP infection in pediatric T1DM patients is similar to that of healthy peers and shows no relation to glycemic control. PMID- 25033665 TI - The utility of Caco-2 cells in isolation of enteroviruses from environmental and clinical material. AB - The work presented here demonstrates the utility of Caco-2 cells in the isolation of enteroviruses (EVs) from environmental and clinical materials. Thirty-two samples of cerebrospinal fluid positive in Pan-entero RT-PCR were taken for EV strain isolation in cell culture. Out of the 32 samples analysed, 22 (68.75%) were positive for enteroviruses by isolation in Caco-2 cells, and 10 (31.25%) were positive by isolation in RD cells. High viral titre in clinical specimens resulted in rate increase for isolation in Caco-2 cells and RD cells (87.5% and 50%, respectively). Also, the probability of isolation of enteroviruses from sewage in Caco-2 cells was 20 times higher that in RD cells. We proved that Caco 2 cells were more effective than RD cells in enterovirus isolation, irrespective of the material used in the inoculation process. PMID- 25033666 TI - Psychrotrophic lipase producers from Arctic soil and sediment samples. AB - Culturable microorganisms were successfully isolated from soil and sediment samples collected in 2011 on the northern coast of Hornsund, West Spitsbergen. A total of 63 single colony isolates from three sampling sites obtained were subjected to temperature dependence study to assess whether they are obligate psychrophilic or psychrotrophic strains. From initial temperature screening, only 53 psychrotrophic isolates were selected that are capable of growing between 4-28 degrees C. The rest that were capable of tolerating higher temperatures up to 37 degrees C were not included in this study. These isolates were chosen for lipase enzyme screening confirmation with the standard plate assay of olive oil and fluorescent dye Rhodamine B. Six lipase positive isolates were also subjected for subsequent lipase enzyme plate screening on tributyrin, triolein, olive oil and palm oil agar. Lipase production by these six isolates was further assayed by using colorimetric method with palm oil and olive oil as the substrate. These isolates with promising lipase activity ranging from 20 U/ml up to 160 U/ml on palm oil and olive oil substrate were successfully identified. Molecular identification by using 16S rRNA revealed that five out of six isolates were Gram negative Proteobacteria and the other one was a Gram-positive Actinobacteria. PMID- 25033667 TI - Plant growth promotion rhizobacteria in onion production. AB - The aim of the research was to examine the effect of rhizospheric bacteria Azotobacter chroococcum, Pseudomonas fluorescens (strains 1 and 2) and Bacillus subtilis on the growth and yield of onion and on the microorganisms in the rhizosphere of onion. The ability of microorganisms to produce indole-acetic acid (IAA), siderophores and to solubilize tricalcium phosphate (TCP) was also assessed. The experiment was conducted in field conditions, in chernozem type of soil. Bacillus subtilis was the best producer of IAA, whereas Pseudomonas fluorescens strains were better at producing siderophores and solubilizing phosphates. The longest seedling was observed with the application of Azotobacter chroococcum. The height of the plants sixty days after sowing was greater in all the inoculated variants than in the control. The highest onion yield was observed in Bacillus subtilis and Azotobacter chroococcum variants. The total number of bacteria and the number of Azotobacter chroococcum were larger in all the inoculated variants then in the control. The number of fungi decreased in most of the inoculated variants, whereas the number of actinomycetes decreased or remained the same. PMID- 25033668 TI - The prevalence of Anaplasma phagocytophilum in questing Ixodes ricinus ticks in SW Poland. AB - Ticks constitute important vectors of human and animal pathogens. Besides the Lyme borreliosis and tick-borne encephalitis, other pathogens such as Babesia spp., Rickettsia spp., and Anaplasma phagocytophilum, are of increasing public health interest. In Poland, as in other European countries, Ixodes ricinus, the most prevalent tick species responsible for the majority of tick bites in humans, is the main vector of A. phagocytophilum. The aim of the study was to estimate the infection level of I. ricinus with A. phagocytophilum in selected districts, not previously surveyed for the presence of this agent. Sampling of questing ticks was performed in 12 forested sites, located in four districts (Legnica, Milicz, Luban, and Olawa) in SW Poland. Altogether, 792 ticks (151 females, 101 males, and 540 nymphs) representing I. ricinus were checked for the presence of A. phagocytophilum. The average infection level was 4.3%, with higher rate reported for adult ticks. The highest percentage of infected adults was observed in Milicz (17.4%) and the lowest in Olawa (6.8%). The abundance of questing I. ricinus in all examined sites as well as the infection with A. phagocytophilum indicate for the first time the risk for HGA transmission in SW Poland. PMID- 25033669 TI - Biocontrol efficacy of different isolates of Trichoderma against soil borne pathogen Rhizoctonia solani. AB - In this study, the biocontrol abilities of water-soluble and volatile metabolites of three different isolates of Trichoderma (T. asperellum, T. harzianum and Trichoderma spp.) against soil borne plant pathogen Rhizoctonia solani were investigated both in vitro and in vivo. The results showed for the first time that mycelial growth inhibition of the pathogen was 74.4-67.8% with water-soluble metabolites as compared to 15.3-10.6% with volatile metabolites in vitro. In vivo antagonistic activity of Trichoderma isolates against R. solani was evaluated on bean plants under laboratory and greenhouse conditions. We observed that T. asperellum was more effective and consistent, lowering disease incidence up to 19.3% in laboratory and 30.5% in green house conditions. These results showed that three isolates of Trichoderma could be used as effective biocontrol agents against R. solani. PMID- 25033670 TI - Prevalence of EBV genotypes in Polish, Taiwanese and Arabic healthy students and association between genotypes and 30-bp deletion in the LMP-1 gene phylogenetic analysis. AB - The aim of this study was to compare the prevalence of EBV genotype and del-LMP-1 in saliva from Polish, Taiwanese and Arabic healthy students. The study group consisted of 56 healthy students; 24 of them Polish, 25 Taiwanese, and 7 Arabic. Typing was carried out using PCR with EBNA-2 primers. A detection of LMP-1 variants was also performed using PCR. EBV DNA was detected in 22 investigated samples (39.3%). Type 1 of the virus was dominant in both Polish and Taiwanese group. Among 62.5% Taiwanese with EBV 1 and 55.6% Polish detected EBV with 30-bp deletion in LMP-1 gene. PMID- 25033671 TI - Microbial transformations of 3-methoxyflavone by strains of Aspergillus niger. AB - Microbial transformation of 3-methoxyflavone into 3'-hydroxyflavon-3-yloxymethyl myristate was presented. Six filamentous fungi were used as biocatalysts: a wild strain of Aspergillus niger KB, its four UV mutants (A. niger MB, SBP, SBJ, 13/5) and the strain of Penicillium chermesinum 113. The highest yields were observed for the strains of A. niger KB and A. niger SBP (69.8% and 63.1%, respectively). PMID- 25033672 TI - Zeaxanthin biosynthesis by members of the genus Muricauda. AB - Zeaxanthin, a C40xanthophyll carotenoid, has potential biological applications in nutrition and human health. In this study we characterized carotenoid composition in 5 taxonomically related marine bacterial isolates from the genus Muricauda. The pigment was characterized using high performance liquid chromatography (HPLC) and mass spectrometry, which confirmed the presence of all-trans-zeaxanthin. Muricauda strains produced zeaxanthin as a predominant carotenoid. M. flavescens JCM 11812(T) produced highest yield (4.4 +/- 0.2 mg L(-1)) when cultured on marine broth at 32 degrees C for 72 h. This is the first report on the presence of zeaxanthin among the majority of species from the genus Muricauda. PMID- 25033673 TI - [Ian Vladimirovich Bokhman and the St. Petersburg School of Oncogynecology]. AB - The article describes the history of the formation of the St. Petersburg school of oncogynecology based at the Department of Oncogynecology of the N. N. Petrov Research Institute of Oncology since 1927 until the present day. The contribution of the Heads of this Department is characterized in the creation of the St. Petersburg school of oncogynecology for the period of its existence. A brief biography of Professor Y. V. Bokhman is presented who has made the most significant contribution to the development of domestic oncogynecology. The main scientific directions of the Department of Oncogynecology are discussed in historical aspect. PMID- 25033674 TI - [Endometrial cancer, estrogens and metabolic syndrome: scenario becomes more complicated]. AB - Simultaneously with keeping one of the leading positions in the structure of oncogynecological morbidity, endometrial cancer (EC) presents for many decades 'the food for brains' of cancer endocrinologists. Step by step development of contemporary ideas and collecting the data on mechanisms of hormonal carcinogenesis, the role of excessive estrogenic stimulation and metabolic syndrome/insulin resistance as risk factors for EC, very probable gradual changing of the disease phenotype and significance of genetic damages (with PTEN mutations as one of the examples), as a consequence point at potential perspectives in the usage of preventive and therapeutic approaches in this important area. PMID- 25033675 TI - [Cervical intraepithelial neoplasia combined in pregnancy: diagnosis, management, outcomes]. AB - Cervical cancer is the leading gynecological tumor associated with pregnancy accounting for 1.2-4.5 cases per 10,000 births. Precancerous diseases of the cervix, which include cervical intraepithelial neoplasia of high severity (H-SIL) combined with pregnancy, are even more relevant since the frequency of their occurrence can achieve 5.0%. Besides the peak of dysplastic cervical changes occurs in the mean age at delivery in the Russian Federation (28 years). The features of diagnosis and management of these patients during pregnancy, delivery and postpartum require a multidisciplinary approach from doctors of different specialties. PMID- 25033676 TI - [Organ-sparing therapy for patients with borderline ovarian tumors]. AB - Contemporary possibilities of organ-sparing therapy for borderline ovarian tumors are considered. World data was analyzed on recurrence rates and fertility rates after different methods of conservative surgery. The experience with ultra conservative surgery in patients with bilateral borderline ovarian tumors at the Onco-Gynecological clinic of the P.A. Herzen Moscow Research Oncology Institute is presented. PMID- 25033677 TI - [Rationale for the approach to the choice of hormone therapy for ovarian cancer]. AB - Ovarian cancer is one of the most aggressive malignant tumors in women. The role of hormone therapy in the treatment for ovarian cancer is not fully studied up to now. The literature contains data on the efficacy and safety of treatment with antiestrogens and aromatase inhibitors for recurrent ovarian cancer. The article summarizes the epidemiology, preclinical and clinical studies related to the role of estrogen and aromatase expression in this disease as well as the role of aromatase inhibitors in the treatment for ovarian cancer. PMID- 25033678 TI - [Chemoradiotherapy for locally advanced cervical cancer]. AB - Cervical cancer takes second place in morbidity and third place in mortality from gynecological cancer. Advanced stages among newly diagnosed cases is still large. The "gold standard" of treatment for locally advanced cervical cancer is chemoradiotherapy with cisplatin that results in a lower risk of death. Improvement of radiotherapy methods allowed to bring optimal dose to the primary tumor with the inclusion of regional metastasis areas with less risk of damage to surrounding healthy tissue and organs. The search for alternative combinations of cytostatics, modes of drug administration, adjuvant chemotherapy after chemoradiotherapy showed an increase in survival of patients with locally advanced cervical cancer. PMID- 25033679 TI - [Prevalence of gynecological cancer and survival of patients]. AB - The article presents an analysis of the situation with cancer in the world, Russia and more detailed (database of the Population-based Cancer Registry) in St. Petersburg. It is presented medium-term morbidity of the population of St. Petersburg per cervical cancer, endometrial cancer and ovarian neoplasms. The use of geoinformation systems allowed presenting incidence (standardized indicators) by districts of the town. PMID- 25033680 TI - [Effectiveness of the model used for screening and early diagnosis of cervical cancer in Karelia]. AB - The article presents the results of a study of the dynamics of morbidity and mortality from cervical cancer among women in Karelia and detection rate of cancer in situ of the cervix during cytological screening in various areas of Karelia from 1998 to 2012. It is shown that cervical cancer incidence in Karelia for this period increased 3 times more. At the same time it is marked an increase of the level of cervical cancer early diagnosis by increasing the detection rate of the disease in Stages I-II from 66.1% to 77.4% and also an increase in the detection rate of preinvasive cervical cancer from 24.3% in 1998-2002 up to 62.8% in 2008-2012. On the example of Kondopoga region of Karelia it is showed that to ensure early diagnosis of cervical cancer in 95% it is necessary a coverage of the female population at least 70%. This coverage can be achieved by establishing a state program of organized cytological screening for cervical cancer. PMID- 25033681 TI - [Hormone therapy alone for pre-cancerous conditions and early endometrial cancer: pros and cons]. AB - The results of conservative treatment of 121 patients with endometrial atypical hyperplasia (EAH) and early endometrial cancer (EC) with preservation of fertility are presented. In EAH (n = 56) for 6 months the intrauterine spiral Mirena was used. The effectiveness was 91%, the recurrence rate 16%, pregnancies occurred in 16% of patients. In EC (n = 65) hormone therapy was conducted for 6 months using the intrauterine spiral Mirena and zoladex. The effectiveness was 79%, recurrence rate 22%, pregnancies occurred in 24% of patients. Based on our data and on the results of other studies, the benefits and risks of hormone therapy alone for EAH and EC are discussed in women of reproductive age. PMID- 25033682 TI - [Simultaneous prophylactic surgery for colon cancer in women. Viewpoint of the gynecologist]. AB - A 5-year survival of patients with Stage III colon cancer with prophylactic panhysterectomy in anamnesis was 83.3%, significantly higher than that of patients with Stage III colon cancer without panhysterectomy (69.3%) and than in colon cancer patients with metachronous ovarian metastases (42%). In families of patients with primary multiple malignant tumors (PMMT) of colon, endometrium and/or ovaries as well as in cases of accumulation in the same family of solitary tumors of the above locations it is necessary to carry out genetic testing to identify mutations in genes MSH2, MLH1, MSH6. Carriers of mutations in genes of mismatch repair MSH2, MLH1, MSH6 should be assumed to the high-risk group for the development of malignancies both PMMT of colon and organs of the female reproductive system and solitary tumors of the above locations. All women suffering from colon cancer, especially in the presence of mutations in genes of mismatch repair, in pre- and menopause should be undergone simultaneous prophylactic surgery: panhysterectomy. The question about the greater omentum should be decided situationally. PMID- 25033683 TI - [Immediate and long-term results of treatment after pelvic exenteration for locally advanced cervical cancer]. AB - Results of treatment after pelvic exenterations were analyzed in 73 patients with locally advanced cervical cancer: 4 patients--Stage IIIB, 24--Stage IVA, 45--with local recurrences after combined (15) or radiation therapy (30) for the period from 2007 to 2012. The median age was 51 years (22 to 77). Variants of pelvic exenterations were as follows: 30 front, 6 rear supralevatory, 37 total (full monoblock removal of the pelvic organs above the pelvic diaphragm): 6 infralevatory and 31 supralevatory. Postoperative complications were recorded in 21 patients (28.8%), postoperative lethality--6.8%. Long-term results of treatment were observed among 34 patients operated in 2007-2009. One-year survival was 50.0%, two-year--47.1%, three-year--41.2%, four-year--38.2%, five year--38.2%. Best results were observed in the group of primary patients (Stages IIIB, IVA) with only interorgan fistulas. Low survival rate was registered in the group of patients with recurrences after radiotherapy as intraoperatively, despite both data of CT and MRI and the results of express histological examination, it was impossible to assess accurately the lateral edge of the tumor growth. PMID- 25033684 TI - [Ultrasound semiotics in recurrent ovarian cancer after optimal cytoreductive surgery]. AB - Features of ultrasound picture of morphologically verified recurrence of ovarian cancer in 21 patients are presented, who received combined treatment including cytoreductive surgery in the form of hysterectomy with oophorectomy, resection of the greater omentum and 6 courses of chemotherapy CAP for ovarian cancer stage III (FIGO). In all patients cytoreductive surgery was optimal--without residual tumor. Recurrence of the disease was detected in 12-48 months in 80.9% of the cases. Three variants of recurrence was revealed by ultrasonography: isolated peritoneal dissemination, in 14.2% of the cases, which was mainly detected during the first 12 months; single entities in the projection of the small pelvis (61.9%) and mixed form (local lesions of small pelvis and peritoneal dissemination) in 23.8% of the cases. PMID- 25033685 TI - [Laparoscopic radical hysterectomy with pelvic lymph node dissection for endometrial cancer in obese patients]. AB - The results of treatment of 61 endometrial cancer patients with various forms of obesity are presented. Two groups of patients were compared: the first group comprised 26 patients who had undergone the laparoscopic surgery; the second group included 35 patients who had open surgery. Te laparoscopic approach improved the results of surgical treatment of endometrial cancer in patients with obesity. This technique allowed to reduce intraoperative blood loss, to diminish the duration of analgesics' administration, to shorten the period of bowel function recovery, 3 times to reduce the incidence of postoperative complications. PMID- 25033686 TI - [Clinical and anamnestic analysis of multiple primary neoplasms with lesions of the endometrium in women of the Novosibirsk region]. AB - Based on the study of 60 women who were treated at the gynecology department of the Novosibirsk Regional Oncology Dispensary from 2003 to 2013 with a diagnosis of primary multiple synchronous and metachronous neoplasia with endometrial lesion it was found that the most common risk factors for this disease could be considered: overweight and obesity; late age at onset of menarche; late age of menopause; concomitant cardiovascular diseases and disorders of the endocrine metabolism. PMID- 25033687 TI - [Effectiveness of platinum-based chemotherapy in ovarian cancer patients with BRCA1/2 mutations]. AB - The purpose of this study was to examine the clinical significance of mutations in BRCA1/2 in the formation of response to neoadjuvant platinum-based chemotherapy for ovarian cancer (OC). All patients who had had neoadjuvant chemotherapy (NCT) in our Institute from January 2000 till January 2013 were tested for carrier of mutations in BRCA1/2. In accordance with the BRCA-status we formed two groups--a group with hereditary advanced OC and a group with non hereditary advanced OC. In the formed groups there was studied the effectiveness of chemotherapy. Patients carriers of mutations in BRCA1/2 showed a complete clinical response in 34% of cases, compared to 4% in the non-hereditary OC. Analysis of the results of cytoreductive surgery showed that in the group of hereditary cancer it was significantly higher the percentage of performing optimal cytoreductive operations (71% vs 48%). We analyzed the cases of complete pathologic response in all patients NCT and found that full pathomorphosis significantly associated with BRCA-status and the type of ongoing chemotherapy. It was important to note that all carriers of mutations in BRCA1/2 responded to cisplatin chemotherapy. PMID- 25033688 TI - [Hyperthermic intraperitoneal chemotherapy in the treatment for recurrent ovarian cancer]. AB - There are presented data of literature and own observations of the treatment for recurrent ovarian cancer using hyperthermic intraperitoneal chemoperfusion. The possible complications during hyperthermic chemoperfusion are discussed and the effectiveness of the method is analyzed. Further studies are needed to obtain more certain criteria for abdominal chemotherapy in these patients. PMID- 25033689 TI - [The risk of neoplastic processes transformation in cervix uteri]. AB - There was performed a comparative analysis of quantitative load and physical status of human papillomavirus (HPV) type 16 in groups of patients with cervical intraepithelial neoplasia (CIN)--25 people and cervical cancer (CC)--85 people. According to the analysis there were selected criteria appropriate to a combination of adverse factors that characterized HPV- infection and at the same time estimated both quantitative load and physical status of the virus: high viral load (> 6,5 lg copies of HPV DNA per 100000 cells) in episomal form or low load (< 6,5 lg copies of HPV DNA per 100000 cells) in integrated form of the virus. According to calculations a relative chance of appearing of CC in CIN patients with unfavorable combination of factors was 7,5 times higher than in other patients. PMID- 25033690 TI - [Modern techniques of ultrasound examination in clarifying the diagnosis of endometrial cancer]. AB - There was conducted an evaluation of capabilities of integrated ultrasound examination in the diagnosis of endometrial cancer. The results indicated the high efficiency of the method to identify the special characteristics of intraorganic and tumor blood flow, which played an important role in clarifying the diagnosis and prognosis of neoplastic growth speed. PMID- 25033692 TI - [Clinical evaluation of the effectiveness of radiation treatment for cervical cancer]. AB - The study is based on data on 1756 patients with cervical cancer treated as combined (remote + contact) and only the contact exposure with low, medium and high dose rate. For comparative radiobiological evaluation of reactions of irradiated tissues there were used the following radiobiological models: factor time-dose-fractionation, the cumulative radiation effect, linear- quadratic model in the variant of biologically effective dose. Survival of cervical cancer patients undergone combined radiation treatment was determined by the stage of disease. In particular, the survival of patients with Stage IB cervical cancer was significantly higher than in Stages IIB and IIIB, while in Stage IIB was significantly higher than in Stage IIIB. Long-term results of radiation treatment of patients with Stage IB1 (T1b1N0M0) and Stage IIB (T2bN0M0) cervical cancer did not depend on whether the contact radiation exposure was combined or single. The most preferred component of radiotherapy in women suffering from cervical cancer was brachytherapy with high dose rate. PMID- 25033691 TI - [Evaluation of ovarian status in women who received anti-tumor therapy in childhood and adolescence]. AB - The paper presents the results of a study of the ovarian reserve in young women who received treatment for malignant tumors in childhood and adolescence and are in complete clinical remission. The function of the reproductive system was evaluated by serum concentrations of gonadotropins, estradiol, anti-Mullerian hormone (AMH) and inhibin B. The results were compared to the treatment, patients' age at the beginning of therapy and at the time of the examination. AMH level in serum was the most informative indicator of ovarian reserve in patients treated for malignant tumors. PMID- 25033693 TI - [Clinical evaluation of the effectiveness of radiation treatment for endometrial cancer]. AB - The study is based on data on 306 patients with endometrial cancer treated as combined (remote + contact) and only the contact exposure with low, medium and high dose rate. For comparative radiobiological evaluation of reactions of irradiated tissues there were used the following radiobiological models: factor time-dose-fractionation, the cumulative radiation effect, linear- quadratic model in the variant of biologically effective dose. Survival of endometrial cancer patients undergone combined or only the contact radiation treatment was determined by the stage of disease. In particular, the survival of patients with Stage IB endometrial cancer (combined radiation treatment) was significantly higher than in Stage IC, while in Stage IB (contact radiation treatment) was significantly higher than in Stages IC and IIB. Long-term results of radiation treatment of patients with all Stages of endometrial cancer were significantly better by 16% when only the contact radiation treatment was performed. The most preferred component of radiotherapy in women suffering from endometrial cancer with severe comorbidities was brachytherapy with high dose rate both in the combined and only contact irradiation. PMID- 25033694 TI - [Fallopian tube carcinoma: clinical and morphological features, analysis of 69 cases]. AB - Primary fallopian tube carcinoma (PFTC) is a rare gynecological malignancy accounting 0.14-1.8% cases. The purpose of the study was to assess clinical, morphological and immunohistochemical features of PFTC. All the cases of PFTC were detected during 1980-2005. 31 cases of PFTC were analyzed as to Ki-67, HER-2 expression, estrogen receptors (ER), progesterone receptors (PR), grade and stage. 69 cases of PFTC were detected with an average age of 55, 6 years (range 21-73 years). Stage I detected in 34.2% cases, Stages II and III--32.8%, Ca in situ--10%. Among 31 patients ER were positive in 75% (n = 23), PR were positive in 46% (n = 14): ER+PR+ in 12 (38%) cases, ER+PR- in 11 (36%) cases, ER-PR+ in 2 (6%) cases, ER-PR- in 6 (19.4%) cases. Only 2 cases were HER-2 positive with ER+PR+ and ER-PR- status. Ki-67 labeling index (LI, %) values ranged from 15 to 95% (median 60) with average rate 58.03% +/- 4.08. Ki-67 LI values > or = 60% were graded as high and < 60% as low. We did not find any significant differences in Ki-67 LI values among tumors of various Receptor Status. However Ki-67 L1 > 60% was associated with poor 5-year survival (14%), vs 75% in Ki-67 L1 < 60%. Primary fallopian tube carcinoma is mainly HER-2 negative, receptor positive in 79.6%. Ki-67 rate is irrespective of ER PR status. However the level of Ki-67 (> 60%) was a significant survival prognostic factor. PMID- 25033695 TI - [Clear cell (mesonephric) cancer: a rare tumor of the ovary with a mixed prognosis]. PMID- 25033696 TI - [Neoadjuvant chemoradiotherapy in the combined treatment of patients with stage IB2-III cervical cancer]. AB - There are provided own observations on the use of cisplatin and capecitabine in schemes of combined treatment of patients with cervical cancer. Their efficiency as radiosensitizing agents is showed. There are discussed possible indications for the use of cisplatin and capecitabine in cervical cancer patients with metastatic lymph nodes. PMID- 25033697 TI - [The use of letrozole in ovarian cancer]. PMID- 25033698 TI - [Surgical treatment of pregnant women with benign ovarian tumors]. AB - The article describes the features of surgery in tumors and tumor-like formations of the ovaries in pregnant women. The influence of surgery on the course and outcome of pregnancy and childbirth is presented. It is showed high efficiency of laparoscopic surgery during I and II trimesters of pregnancy. PMID- 25033699 TI - [Hydatidiform mole and malignant trophoblastic tumors initiated by hydatidiform mole. Standards and innovation of diagnosis and treatment]. AB - Malignant trophoblastic tumors are hormone and hormone-dependent allografts initiated by, in the most cases, hydatidiform mole. The absence of methodological principles for monitoring of women after evacuation of hydatidiform mole often leads to late detection of the disease, inadequate chemotherapy conducted in clinics with no experience of treatment, followed by the development of drug resistant tumors and worse prognosis. This paper analyzes the problem at the moment. PMID- 25033700 TI - Feltman: evaluating the acceptability of a diabetes education tool for Aboriginal health workers. AB - There is an urgent need to address the lack of Aboriginal-specific diabetes prevention and management resources. Following consultation with Victorian Aboriginal health workers, the Victorian Aboriginal Community Controlled Health Organisation and Diabetes Australia - Victoria developed 'Feltman', a life-sized felt body showing the main organs involved in the digestion and metabolism of food, and the main parts of the body affected by diabetes. Feltman was distributed to all Victorian Aboriginal Community Controlled Health Organisations and an additional 32 Victorian organisations. In total, 276 people from 57 organisations were trained to use Feltman. An online evaluation survey was developed and sent to all people who were trained to use Feltman in Victoria. Sixty-six people completed the survey. All respondents agreed Feltman was an appropriate tool for the Aboriginal community, 89% of health workers felt more confident in their ability to discuss diabetes with their community but would like further training to maintain skills and confidence and 70% of workers had used Feltman with the community. Qualitative feedback noted its strength as a highly visual resource that was popular with the Aboriginal community. Workers reported that Feltman was a highly acceptable diabetes education resource, which they believed had increased knowledge and improved the management of diabetes among clients. PMID- 25033701 TI - "Open lung ventilation optimizes pulmonary function during lung surgery". AB - BACKGROUND: We evaluated an "open lung" ventilation (OV) strategy using low tidal volumes, low respiratory rate, low FiO2, and high continuous positive airway pressure in patients undergoing major lung resections. MATERIALS AND METHODS: In this phase I pilot study, twelve consecutive patients were anesthetized using conventional ventilator settings (CV) and then OV strategy during which oxygenation and lung compliance were noted. Subsequently, a lung resection was performed. Data were collected during both modes of ventilation in each patient, with each patient acting as his own control. The postoperative course was monitored for complications. RESULTS: Twelve patients underwent open thoracotomies for seven lobectomies and five segmentectomies. The OV strategy provided consistent one-lung anesthesia and improved static compliance (40 +/- 7 versus 25 +/- 4 mL/cm H2O, P = 0.002) with airway pressures similar to CV. Postresection oxygenation (SpO2/FiO2) was better during OV (433 +/- 11 versus 386 +/- 15, P = 0.008). All postoperative chest x-rays were free of atelectasis or infiltrates. No patient required supplemental oxygen at any time postoperatively or on discharge. The mean hospital stay was 4 +/- 1 d. There were no complications or mortality. CONCLUSIONS: The OV strategy, previously shown to have benefits during mechanical ventilation of patients with respiratory failure, proved safe and effective in lung resection patients. Because postoperative pulmonary complications may be directly attributable to the anesthetic management, adopting an OV strategy that optimizes lung mechanics and gas exchange may help reduce postoperative problems and improve overall surgical results. A randomized trial is planned to ascertain whether this technique will reduce postoperative pulmonary complications. PMID- 25033702 TI - Low junctional adhesion molecule A expression correlates with poor prognosis in gastric cancer. AB - BACKGROUND: The aberrant expression of junctional adhesion molecule A (JAM-A), which has a close correlation with the development, progression, metastasis, and prognosis of cancer, has been frequently reported. However, neither JAM-A expression nor its correlation with clinicopathologic variables and patient survival has been defined in gastric cancers. Moreover, little is known about the role of JAM-A in gastric cancer progression. We carried out the present study to investigate the prognostic value of JAM-A expression in gastric cancer patients. Furthermore, the biological roles of JAM-A in gastric cancer progression were also investigated. METHODS: We determined JAM-A expression in 167 primary gastric cancer tissues and 94 matched adjacent non-tumor tissues by immunohistochemistry. Transwell migration assays and matrigel invasion assays were used to explore the role of JAM-A in gastric cancer cells migration and invasion. CCK-8 assays were used to examine the effect of JAM-A on the proliferation of gastric cancer cells. RESULTS: JAM-A was downregulated in gastric cancer tissues. Low JAM-A expression was significantly associated with tumor size, lymphatic vessel invasion, lymph node metastasis, and TNM stage. Low JAM-A expression was also significantly associated with poor disease-specific survival in gastric cancer patients. Multivariate analysis demonstrated low JAM-A expression as an independent factor predicting poor survival. In addition, JAM-A had the effect on inhibition of gastric cancer cells migration and invasion. However, JAM-A had no significant effects on proliferation of gastric cancer cells. CONCLUSIONS: Low JAM-A expression correlates with poor clinical outcome and promotes cell migration and invasion in gastric cancer. PMID- 25033703 TI - Rodent models of hepatic ischemia-reperfusion injury: time and percentage-related pathophysiological mechanisms. AB - Ischemia and reperfusion (IR) injury remains one of the major problems in liver surgery and transplantation, which determines the viability of the hepatic tissue after resection and of the grafted organ. This review aims to elucidate the mechanisms involved in IR injury of the liver in rodent experimental studies and the preventative methods and pharmacologic agents that have been applied. Many time- and percentage-related liver IR injury rodent models have been used to examine the pathophysiological mechanisms and the parameters implicated with different morbidity, mortality, and pathology findings. The most preferred experimental rodent model of liver IR is the induction of 70% IR for 45 min, which is associated with almost 100% survival. In this model, plasma levels of several parameters such as alanine transaminase, aspartate aminotransferase, gamma-glutamyltransferase, endothelin-1, malonodialdehyde, tumor necrosis factor alpha, interleukin 1b, inducible nitric oxide synthase, and caspases are increased. The increase of caspases is associated with the initiation of hepatic cellular apoptosis. The main injuries observed 24 h after reperfusion are nuclear pyknosis, cytoplasmic hypereosinophilia, severe necrosis, and loss of intercellular borders. Both ischemic pre- and post-conditioning preventative methods and pharmacologic agents are successfully applied to alleviate the IR injuries. The selection of the time- and percentage-related liver IR injury rodent model and the potential preventative method should be related to the clinical question being answered. PMID- 25033704 TI - Comparison of single access devices during cut and suturing tasks on simulator. AB - BACKGROUND: Published comparisons of the different available laparoendoscopic single-site surgery (LESS) devices focused on its economic cost and technical aspects. With this study, we aimed to objectively compare the use of three different LESS access devices in controlled experimental tasks. MATERIALS AND METHODS: Twenty subjects participated in simulator trials. A cut and an intracorporeal suturing task were carried out. Three single access devices (SILS: SILS(TM) Port, GPN. GelPOINT Advanced Access Platform, and XCN: XCONE) were used according to a randomized nine-session schedule. Completion time was registered and performance objectively assessed with task-specific rating scales. Two blinded expert raters worked over video recordings of the hands-on sessions. RESULTS: Participants showed improvement with all devices on total cut completion times and significantly for SILS (P = 0.017). The GPN decreased its adapted Global Rating Scale score (P = 0.002) from the first (W1) to the last week (W9). On the suture task, XCN constituted the device with longer completion times compared with SILS (P < 0.001) and to GPN (P < 0.001). There was significant improvement in times from W1 to W9 with XCN (P < 0.001), SILS (P = 0.003), and GPN (P < 0.001). On average summative score, we observed significant improvement in performance with all devices from W1 to W9 (SILS: P = 0.003; GPN: P = 0.001; and XCN: P < 0.001). CONCLUSIONS: Although we advise surgeons to focus on the specific procedures and patient characteristics to select the most adequate access device to maintain procedural safety standards, single-use devices appear to confer an easier adaptation to LESS surgery. PMID- 25033705 TI - Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study. AB - BACKGROUND: The objective of the present study was to clarify the relationship between the neuroprotective effects of curcumin and the classical wnt signaling pathway. METHOD: Using Sprague-Dawley rats at a gestational age of 14.5 d, we isolated neural stem cells from the anterior two-thirds of the fetal rat brain. The neural stem cells were passaged three times using the half media replacement method and identified using cellular immunofluorescence. After passaging for three generations, we cultured cells in media without basic fibroblast growth factor and epidermal growth factor. Then we treated cells in five different ways, including a blank control group, a group treated with IWR1 (10 MUmol/L), a group treated with curcumin (500 nmol/L), a group treated with IWR1 + curcumin, and a group treated with dimethyl sulfoxide (10 MUmol/L). We then measured the protein and RNA expression levels for wnt3a and beta-catenin using Western blotting and Reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Western blotting: after the third generation of cells had been treated for 72 h, we observed that wnt3a and beta-catenin expression was significantly increased in the group receiving 500 nmol/L curcumin but not in the other groups. Furthermore, cells in the IWR1-treated group showed decreased wnt3a and beta-catenin expression, and wnt3a and beta-catenin was also decreased in the IWR1 + 500 nmol/L curcumin group. No obvious change was observed in the dimethyl sulfoxide group. RT-PCR: RT-PCR showed similar changes to those observed with the Western blotting experiments. CONCLUSIONS: Our study suggests that curcumin can activate the wnt signaling pathway, which provides evidence that curcumin exhibits a neuroprotective effect through the classical wnt signaling pathway. PMID- 25033706 TI - Effects of sleep deprivation on pain-related factors in the temporomandibular joint. AB - BACKGROUND: The objective of this study was to investigate the effects of experimental sleep deprivation (SD) on the temporomandibular joint (TMJ) in rats by examining pain-related factors and to determine the possible involvement of estrogen and NF (nuclear factor) kappaB signaling in the TMJ synovial membrane. METHODS: The influence of SD, conducted in rats using the modified multiple platform method, was estimated by observing behavioral manifestations and examining changes in serum hormone levels. The morphologic changes of synovial tissue were observed with light microscopy and the serum levels of estrogen were measured by radioimmunoassay. Activation of NF-kappaB in the synovial membrane was examined using an immunofluorescence technique, and the expression levels of interleukin (IL) 1beta, IL-6, tumor necrosis factor alpha, cyclooxygenase 2, and inducible nitric oxide synthase were measured with real-time polymerase chain reaction. RESULTS: The SD group showed evidence of elevated anxiety and stress, and increased plasma levels of estradiol compared with the control group. The activity of NF-kappaB was significantly enhanced and translocation of NF-kappaB p65 was evident in the synovial membrane after SD. The expression of pain-related factors IL-1beta, IL-6, cyclooxygenase-2, tumor necrosis factor alpha, and inducible nitric oxide synthase in the synovial membrane significantly increased after SD. CONCLUSIONS: These results indicate that SD increases serum levels of estrogen and induces alterations in pain-related factors in the TMJ. The NF kappaB pathway has been associated with the regulation of these inflammatory cytokines and plays an important role in temporomandibular disorders. PMID- 25033707 TI - The prognostic value of liver tumor T cell infiltrates. AB - Tumor infiltrating lymphocytes (TIL) have been demonstrated to predict oncologic outcomes following resection of primary intrahepatic neoplasms and metastatic liver tumors. Despite strong immunosuppressive factors within the intrahepatic space, TIL are frequently demonstrated in liver tumors. The presence of TIL within liver tumors provides evidence of a host immune response that may be protective, but often is rendered ineffective by tumor induced immune dysfunction. In this review, we discuss techniques involved in studying TIL and subsets of TIL commonly identified. We emphasize the unique nature of the intrahepatic milieu that promotes immunosuppression, and how liver TIL and TIL ratios can be used as indicators of prognosis. Several types of primary and metastatic liver tumors are considered to highlight the similarities and important differences in TIL responses, which likely reflect how intrahepatic immunity is influenced by tumor biology. The studies we discuss indicate that tumor infiltration by suppressor cells and expression of immunoinhibitory molecules by TIL limits the anti-tumor immune function of effector T cells. Most patients fail to mount an adequate immune response to liver tumors, which provides compelling rationale for clinical study of immunotherapy for intrahepatic neoplasms. PMID- 25033708 TI - The impact of leukoreduced red blood cell transfusion on mortality of neonates undergoing extracorporeal membrane oxygenation. AB - BACKGROUND: Blood products containing leukocytes have been associated with negative immunomodulatory and infectious effects. Transfusion-related acute lung injury is partially explained by leucocyte agglutination. The Food and Drug Administration has therefore recommended leukoreduction strategies for blood product transfusion. Our institution has been using leukocyte-reduced blood via filtration for neonates on Extracorporeal Membrane Oxygenation (ECMO). We hypothesized that the use of leukocyte-reduced blood would decrease mortality and morbidity of neonatal ECMO patients. METHODS: Retrospective review of noncardiac ECMO in neonates from 1984-2011, stratified into year groups I and II (<=1996 and >=1997). Demographics, duration and type of ECMO, complications, and outcome data were collected. Blood product use data was collected. Univariate, bivariate, and multivariate analyses determined predictors of risk-adjusted mortality by year group. RESULTS: Patients (827) underwent ECMO with 65.3% (540) in group I. Overall median blood product use in mL/kg/d was 36.2 packed red blood cells (pRBC), 8.1 platelets, and 0 cyroprecipitate and/or fresh-frozen plasma. Overall mortality was 16.4%. Median pRBC used or transfused was 42.1 mL/kg/d in group I versus 19.1 mL/kg/d group II (P <0.001). On bivariate analysis, there was no difference in crude mortality between the 2 year groups (17.2% versus 16.0%, P = 0.66). However, on multivariate analysis adjusting for demographics, diagnosis, complications, and blood product use other than pRBCs, each additional transfusion of 10 mL/kg/d of pRBC was associated with a 33% increase in mortality in group I (P <0.05). Group II also showed an increase in mortality with each additional transfusion (21%) but this was not statistically significant (P = 0.07). Days on ECMO were not associated with pRBC transfusion in group I but increased in group II (additional 3 d for each 10 mL/kg/d transfused). There was no difference in infectious complications between groups I and II. CONCLUSIONS: Blood transfusion requirement has diminished in newborns undergoing ECMO at our institution. Transfusion of non leukocyte-reduced blood is associated with an increase in mortality whereas transfusion of leukocyte-reduced blood provided no benefit with a trend toward increased mortality. Further research is recommended to understand these trends. PMID- 25033709 TI - Enhanced permeation of a hydrophobic fluid through particles with hydrophobic and hydrophilic patterned surfaces. AB - The wetting properties of solid surfaces are significant in oil/gas and liquid displacement processes. It is difficult for hydrophobic fluids to permeate channels filled with hydrophilic particles and an aqueous phase, and this is thought to be the primary cause of low yields in low permeability reservoir operations. Using three-dimensional lattice Boltzmann simulations, we show that particles with hydrophobic and hydrophilic patterned surfaces can greatly improve hydrophobic fluid permeation. Specifically, a hydrophobic fluid can easily access micro-channels in the hydrophobic regions, which extend rapidly even to the hydrophilic regions and accelerate hydrophobic fluid escape. This work enriches understanding of multiphase flow in porous media at the pore scale and fracture conductivity and is expected to have great significance in the exploitation of low permeability reservoirs and shale gas. PMID- 25033710 TI - [Siblings of prepubesecent anorexic children]. AB - As professionals working in a specialised unit for prepubescent anorexic children, we are very often concerned with the siblings of our young patients who are daily faced with anorexia nervosa. Although it is an undeniable subject of prevention, research on the topic remains scarce. Based on our clinical experience, this article thus proposes to give a few landmarks to health professionals likely to support these siblings in order to prevent anxious and depressive disorders as well as eating disorders. If guided, supported and informed on anorexia nervosa, siblings can adopt adequate coping strategies when confronted to their sibling's anorexic cognitions and behaviours. We also encourage parents to pay close attention to the needs of their other children, especially to remain receptive to the youngest ones or, if unavailable to find adult carers (grandparents, family, friends). We also guide these children, who are eager to help their anorexic sibling, to remain in a brotherly role. Siblings must be informed about anorexia nervosa. Such information enables them to have a better understanding of their sister's thoughts and attitudes. It also leads to a better understanding of the reasons why anorexia has such a significant impact on family routine, among other things by reducing parental availability. Beyond enabling siblings to adopt adequate coping strategies, such provision of support also contributes to the prevention of mental illness and the maintenance of adequate sibling and family relationships. PMID- 25033711 TI - Morphological and mechanical characterisation of the hindwing nodus from the Libellulidae family of dragonfly (Indonesia). AB - In this communication, the morphologies and mechanical characteristics of nodi from the hindwings of seven Indonesian Libellulidae dragonfly species are identified. Geometrical analyses reveal that in all species, the shape of dorsal face resilin is relatively long and thin while ventral face resilin covers a greater surface area than dorsal face resilin, and is shaped like a hook. Finite element analyses reveal that the magnitude of strain energy may differ considerably between species, even though the locations of highest strain energy are usually the same. Importantly, a correlation is found to exist between the mechanical forces that build up in the resilin, the face under investigation (dorsal or ventral) and the elongational shape factor of the resilin. PMID- 25033712 TI - Effects of topical application of patchouli alcohol on the UV-induced skin photoaging in mice. AB - Ultraviolet (UV) irradiation, known to generate reactive oxygen species (ROS) excessively and elicit inflammatory response, is a potent inducer for skin photoaging. Overproduction of ROS in conjunction with the resulting inflammation stimulate the over-expression of matrix metalloproteinases (MMPs), which in turn causes degradation of extracellular matrix, leading finally to coarse wrinkling, dryness, and laxity of the skin. In this study, patchouli alcohol (PA, C15H26O), an active chemical ingredient reputed for free radical scavenging and anti inflammatory properties, was investigated for its anti-photoaging action using a mouse model whose dorsal skin was depilated. The dorsal skin areas of six-week old mice were smeared with PA solution or vehicle, followed by UV irradiation for nine consecutive weeks. Protective effects of PA were evaluated macroscopically and histologically, as well as by assaying the antioxidant enzymes (SOD, GSH-Px) activities, the contents of inflammatory factors (IL-10, IL-6, TNF-alpha), and the levels of MMP-1 and MMP-3. Our findings amply demonstrated that PA significantly accelerated the recovery of the UV-induced skin lesions, evidently through anti-oxidant and anti-inflammatory action, as well as down-regulation of the MMP-1 and MMP-3 expression. PMID- 25033713 TI - Are men difficult to find? Identifying male-specific studies in MEDLINE and Embase. AB - BACKGROUND: Systematic reviews often investigate the effectiveness of interventions for one sex. However, identifying interventions with data presented according to the sex of study participants can be challenging due to suboptimal indexing in bibliographic databases and poor reporting in titles and abstracts. The purposes of this study were to develop a highly sensitive search filter to identify literature relevant to men's health and to assess the performance of a range of sex-specific search terms used individually and in various combinations. METHODS: Comprehensive electronic searches were undertaken across a range of databases to inform a series of systematic reviews investigating obesity management for men. The included studies formed a reference standard set. A set of sex-specific search terms, identified from database-specific controlled vocabularies and from natural language used in the titles and abstracts of relevant papers, was investigated in MEDLINE and Embase. Sensitivity, precision, number needed to read (NNR) and percent reduction in results compared to searching without sex-specific terms were calculated. RESULTS: The reference standard set comprised 57 papers in MEDLINE and 63 in Embase. Seven sex-specific search terms were identified. Searching without sex-specific terms returned 31,897 results in MEDLINE and 37,351 in Embase and identified 84% (MEDLINE) and 83% (Embase) of the reference standard sets. The best performing individual sex specific term achieved 100%/98% sensitivity (MEDLINE/Embase), NNR 544/609 (MEDLINE/Embase) and reduced the number of results by 18%/17% (MEDLINE/Embase), relative to searching without sex-specific terms. The best performing filter, compromising different combinations of controlled vocabulary terms and natural language, achieved higher sensitivity (MEDLINE and Embase 100%), greater reduction in number of results (MEDLINE/Embase 24%/20%) and greater reduction in NNR (MEDLINE/Embase 506/578) than the best performing individual sex-specific term. CONCLUSIONS: The proposed MEDLINE and Embase filters achieved high sensitivity and a reduction in the number of search results and NNR, indicating that they are useful tools for efficient, comprehensive literature searching but their performance is partially dependent on the appropriate use of database controlled vocabularies and index terms. PMID- 25033714 TI - Heavy metals affect nematocysts discharge response and biological activity of crude venom in the jellyfish Pelagia noctiluca (Cnidaria, Scyphozoa). AB - BACKGROUND: Pollution of marine ecosystems and, specifically, heavy metals contamination may compromise the physiology of marine animals with events occurring on a cellular and molecular level. The present study focuses on the effect of short-term exposure to heavy metals like Zinc, Cadmium, Cobalt and Lanthanum (2-10 mM) on the homeostasis of Pelagia noctiluca (Cnidaria, Scyphozoa), a jellyfish abundant in the Mediterranean sea. This species possesses stinging organoids, termed nematocysts, whose discharge and concomitant delivery of venom underlie the survival of all Cnidaria. METHODS: Nematocysts discharge response, elicited by combined chemico-physical stimulation, was verified on excised oral arms exposed to heavy metals for 20 min. In addition, the hemolytic activity of toxins, contained in the crude venom extracted from nematocysts isolated from oral arms, was tested on human erythrocytes, in the presence of heavy metals or their mixture. RESULTS: Treatment with heavy metals significantly inhibited both nematocysts discharge response and hemolytic activity of crude venom, in a dose-dependent manner, not involving oxidative events, that was irreversible in the case of Lanthanum. CONCLUSION: Our findings show that the homeostasis of Pelagia noctiluca, in terms of nematocysts discharge capability and effectiveness of venom toxins, is dramatically and rapidly compromised by heavy metals and confirm that this jellyfish is eligible as a model for ecotoxicological investigations. PMID- 25033715 TI - MR angiography demonstrates a positive correlation between placental blood vessel volume and fetal size. AB - PURPOSE: While intrauterine growth restriction is often associated with placental dysfunction or abnormal morphology, the link between fetal weight and the placental delivery capacity of blood has not been studied in detail. The purpose of this study was to investigate the relationship between the fetal placental blood volume (FPBV) and fetal length, fetal weight and fetal head circumference using a non-invasive approach. METHODS: Placentas from normal pregnancies terminated with elective cesarean section were included. The entire fetal-side placental vasculature was filled with a solution of a gadolinium-containing contrast agent, followed by magnetic resonance angiography. FPBV was calculated from the complete 3D dataset as the sum of high-intense voxels. Areas that appeared different than the main part of the placenta were marked and evaluated by histology. FPBV of each placenta was compared to the fetal measures at birth: weight, length and head circumference. FPBV was also compared to placental weight at birth. RESULTS: We found that FPBV correlated linearly with fetal weight (p = 0.02) and fetal head circumference (p = 0.03), but found no correlation between the calculated placental blood vessel volume and the placental weight at birth. Histology revealed no pathophysiological findings in any cases. The marked areas were all those of infarctions or fibrinous sedimentation. CONCLUSION: Interestingly, we found a positive correlation between FPBV and fetal size. Fetal size was measured in fetal weight and fetal head circumference. Fetal length did not correlate with FPBV. Further studies are warranted to investigate this relationship in pregnancies with intrauterine growth restriction, and whether MRI angiography (without gadolinium-containing agents) is suitable as a novel diagnostic modality for placental dysfunction. PMID- 25033716 TI - Asthma and pregnancy: therapeutic challenges. AB - PURPOSE: Asthma in pregnancy represents a complex therapeutic challenge as it can have unfavourable consequences on both the mother and the fetus. Pregnancy can have a variable impact on asthma, and there is no general rule to predict in whom is going to be better, stable or worse. On the other hand, asthma can increase the risks of fetal malformations, low birth weight or premature birth. METHODS AND RESULTS: The review of the literature regarding the asthma pathogenic maternal and fetal effects and the current therapeutic recommendations. CONCLUSIONS: A multidisciplinary team is needed to appropriately follow up a pregnant woman with asthma and this should involve a pulmonary disease physician, a neonatologist, an obstetrician and, if necessary, an allergolocist. Most of the medications used in asthma outside pregnancy can safely be used during it. An appropriate management according to existing guidelines can minimize both maternal and fetal risks. PMID- 25033717 TI - Effect of vaginal intercourse on spontaneous labor at term: a randomized controlled trial. AB - OBJECTIVE: This study aimed at evaluating the effect of vaginal intercourse on spontaneous labor onset at term. METHODS: In a randomized controlled trial, patients with singleton, cephalic, term, and low-risk pregnancy were assigned to either vaginal intercourse at least twice a week or abstinence. The following data were assessed: demographics, parity, vaginal coitus frequency before and during pregnancy, Bishop score at 38th weeks, gestational age at delivery, mode of delivery, and days between recruitment and delivery. The primary outcome was spontaneous labor onset. RESULTS: Of the 123 patient analyzed, 63 were assigned to study group and 60 to control group. Mean interval between study recruitment and delivery was higher in sexually active women (15.05 days +/- 0.8 compared with 14.17 days +/- 0.8, p = 0.45) as well as the rate of cesarean delivery (14.3 % compared with 10 %, p = 0.58), but the differences were not statistically significant. The rate of spontaneous labor was similar in both groups (84.1 % in vaginal coitus group; 75 % in control group, p = 0.26). CONCLUSION: Our results showed that vaginal intercourse does not hasten spontaneous labor onset at term. PMID- 25033718 TI - Four-country meeting on residency in France, Germany, The Netherlands and UK: 4 countries, 4 ways. AB - The 2013 "4 countries meeting" of the British, Dutch, French, and German Societies of Gynaecology and Obstetrics (RCOG, NVOG, CNGOF, DGGG) was dedicated to "Residency and clinical guidelines". The meeting was convened to compare how residency is organised in each country and to see how the political and social issues affect how residency is organised. At the same meeting we discussed the production of clinical guidelines and their importance within Europe. This report focuses on "residency" and looks at the underlying structural differences in each country. We discuss the differences and how we might learn from each other's strengths. PMID- 25033719 TI - Live birth of twins after performing early hCG administration as a modification of natural cycle in vitro fertilization, in a women with decreased ovarian reserve. AB - PURPOSE: This case reports the first twin live births achieved in a woman with a serum FSH of such magnitude -80 IU/L, after following early hCG administration in natural cycle in vitro fertilization (IVF). METHOD: Case report. RESULTS: A 27 year-old with 2 years of primary infertility presented with regular menses since menarche. FSH following clomiphene citrate challenge test was 80 IU/L. Antral follicle count was 1. After failing two IVF cycles, natural cycle IVF with early hCG administration was attempted. Ovulation with 10,000 IU hCG was triggered when the dominant follicle was 10 mm in mean diameter. Two smaller follicles were also present. Oocyte collection was performed 38 h after hCG injection. Three mature oocytes were retrieved. Two oocytes fertilized normally. Two good-quality embryos were transferred on day 2. Bichorionic biamniotic pregnancy was achieved and healthy twins were delivered at term. CONCLUSIONS: This case suggests that natural cycles with early hCG administration should be investigated further as an option for poor responders to retrieve more than one mature oocyte, and prevent premature ovulation. We believe this case to represent the patient with the highest serum FSH level, reflective of ovarian reserve at the time of treatment, to achieve a live birth. It is also the first case report to describe this modification on the traditional natural cycle. PMID- 25033723 TI - Drug discovery and repurposing at Memorial Sloan Kettering Cancer Center: chemical biology drives translational medicine. PMID- 25033724 TI - You are what you eat: the impact of diet on overactive bladder and lower urinary tract symptoms. AB - Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. The symptoms associated with OAB are common and whilst not life threatening are known to have a significant impact on the quality of life (QoL). There is increasing evidence that diet may have a significant role in the development of OAB symptoms. Whilst fluid in-take is known to affect lower urinary tract function the effects of caffeine, carbonated drinks and artificial sweeteners are less well understood. Consequently the aim of this paper is to review the evidence and investigate the effect of diet on lower urinary tract function and dysfunction. PMID- 25033725 TI - Dysfunctional cortical inhibition in adult ADHD: neural correlates in auditory event-related potentials. AB - In recent times, the relevance of an accurate diagnosis of attention deficit/hyperactivity disorder (ADHD) in adults has been the focus of several studies. No longer considered a pathology exclusive to children and adolescents, and taking into account its social implications, developing enhanced support tools for the current diagnostic procedure becomes a priority. Here we present a method for the objective assessment of ADHD in adults using chirp-evoked, paired auditory late responses (ALRs) combined with a two-dimensional ALR denoising scheme to extract correlates of intracortical inhibition. Our method allows for an effective single-sweep denoising, thus requiring less trials to obtain recognizable physiological features, useful as pointers of cortical impairment. Results allow an optimized diagnosis, reduction of data loss and acquisition time; moreover, they do not account exclusively for critical elements within clinical evaluations, but also allow studying the pathophysiology of the condition by providing objective information regarding impaired cortical functions. PMID- 25033726 TI - The frequency and significance of WT-1 expression in serous endometrial carcinoma. AB - Serous endometrial carcinoma is an aggressive type of endometrial carcinoma. Wilms tumor gene 1 (WT-1) is commonly expressed in ovarian serous carcinomas and considered a diagnostic marker of these tumors. However, it is generally believed that WT-1 is rarely expressed by endometrial serous carcinoma. The aim of this study was to evaluate the frequency and significance of WT-1 expression in endometrial serous carcinoma. We studied the expression of WT-1 in formalin fixed, paraffin-embedded tumor sections from 77 cases of endometrial serous carcinoma. Thirty-four tumors showed positive expression for WT-1 (44%). There was a statistically significant association between the presence of WT-1 expression and disease-free survival (DFS), where patients with tumors expressing WT-1 had a shorter DFS compared with those with no WT-1 expression (P = .031; median DFS, 15 and 38 months, respectively). By multivariate Cox regression analysis, DFS was independent from other clinicopathological data (tumor stage, presence of lymphovascular space invasion, cervical involvement, and extrauterine spread), indicating that WT-1 expression is independently associated with DFS. Our study shows that WT-1 is expressed in a considerable percentage of endometrial serous carcinomas, suggesting a role for WT-1 in the pathology of these tumors. This has therapeutic significance, as WT-1 is an emerging target for immunotherapy. Moreover, our results show that WT-1 has prognostic value, being predictive of DFS. As a potential prognostic marker and therapeutic target, we recommend that WT-1 expression should be included in histopathologic reports of endometrial serous carcinoma. PMID- 25033728 TI - Contrast-enhanced postmortem computed tomography in clinical pathology: enhanced value of 20 clinical autopsies. AB - Postmortem computed tomography (PMCT) is a modern tool that complements autopsy diagnostics. In clinical autopsies, a major cause of death is cardiovascular disease. To improve the performance of PMCT in cardiovascular disease, full body angiography was developed (PMCT angiography [PMCTA]). Twenty PMCTA scans generated before autopsy were compared with native PMCT and clinical autopsy. The objective of the study was to quantify the additional diagnostic value of adding angiography to native imaging and to compare PMCT and PMCTA findings to autopsy findings. The diagnosis of the cause of death was identical or overlapped in 80% of the cases that used PMCTA and 70% that used PMCT. The additional diagnostic yield given by PMCT and PMCTA in combination with autopsy was 55%. PMCT yielded additional diagnoses in the musculoskeletal system. The greatest additional diagnostic value of PMCTA was in association with cardiovascular diagnoses. The accuracy of PMCTA for cardiac causes of death was 80%, and the positive predictive value was 90%. The findings indicate that native PMCT cannot display the cardiovascular system sufficiently clearly for high-quality diagnostic assessment. However, PMCTA is a powerful tool in autopsy cases with a history of cardiovascular disease and/or a suspected cardiovascular cause of death. The combination of PMCTA and clinical autopsy enhances diagnostic quality and completeness of the autopsy report. Furthermore, in cases without consent or with a restricted consent for clinical autopsy, PMCTA has the potential to provide information on cardiovascular causes of death. PMID- 25033727 TI - GP88 (progranulin): a novel tissue and circulating biomarker for non-small cell lung carcinoma. AB - GP88 (progranulin) is a growth and survival factor implicated in tumorigenesis and drug resistance. Previous studies showed that GP88 was expressed in breast cancer tissue in inverse correlation with survival. This study evaluates GP88 tissue expression in localized/locally advanced lung cancer and GP88 serum levels in advanced disease. GP88 expression was determined by immunohistochemistry in tumor tissue from non-small cell lung carcinoma (NSCLC) patients, 85 with localized (stage I-II), and 40 with locally advanced disease (stage IIIa) and correlated with clinical outcome. Serum GP88 levels from stage IIIb/IV patients, quantified by enzyme immunoassay were compared with GP88 levels from patients with chronic obstructive pulmonary disease and healthy individuals. GP88 was expressed in more than 80% adenocarcinoma and squamous cell carcinoma in contrast to normal lung or small cell lung cancer. There was a statistically significant inverse association of GP88 expression (GP88 immunohistochemistry score, 3+ versus < 3+) with survival for patients with localized resected NSCLC with hazard ratio (HR) = 2.28 (P = .0076) for disease-free survival and HR = 2.17 (P = .014) for overall survival. A statistically significant decrease in progression-free survival (HR = 2.9; P = .022) for GP88 scores of 3+ versus less than 3+ was observed for stage IIIa after chemoradiotherapy. In addition, serum GP88 was significantly elevated in stage IIIb/IV NSCLC compared with control subjects (49.9 ng/mL versus 28.4 ng/mL; P < .0001). This is the first study demonstrating GP88 tissue and serum expression as a prognostic biomarker in localized and advanced disease. Future research will determine utility of monitoring GP88 and the potential of GP88 expression as a predictive marker for anti-GP88 therapeutics. PMID- 25033729 TI - Recurrent chromosomal aberrations in intravenous leiomyomatosis of the uterus: high-resolution array comparative genomic hybridization study. AB - Uterine intravenous leiomyomatosis (IVL) is a distinct smooth muscle neoplasm with a potential of clinical aggressiveness due to its ability to extend into intrauterine and extrauterine vasculature. In this study, chromosomal alterations analyzed by oligonucleotide array comparative genomic hybridization were performed in 9 cases of IVL. The analysis was informative in all cases with multiple copy number losses and/or gains observed in each tumor. The most frequent recurrent loss of 22q12.3-q13.1 was observed in 6 tumors (66.7%), followed by losses of 22q11.23-q13.31, 1p36.13-p33, 2p25.3-p23.3, and 2q24.2 q32.2 and gains of 6p22.2, 2q37.3 and 10q22.2-q22.3, in decreasing order of frequency. Copy number variants were identified at 14q11.2, 15q11.1-q11.2, and 15q26.2. Genes mapping to the regions of loss include CHEK2, EWS, NF2, PDGFB, and MAP3K7IP1 on chromosome 22q, HEI10 on chromosome 14q, and succinate dehydrogenase subunit B, E2F2, ARID1A KPNA6, EIF3S2 , PTCH2, and PIK3R3 on chromosome 1p. Regional losses on chromosomes 22q and 1p and gains on chromosomes 12q showed overlaps with those previously observed in uterine leiomyosarcomas. In addition, presence of multiple chromosomal aberrations implies a higher level of genetic instability. Follow-up polymerase chain reaction (PCR) sequencing analysis of MED12 gene revealed absence of G> A transition at nucleotides c.130 or c.131 in all 9 cases, a frequent mutation found in uterine leiomyoma and its variants. In conclusion, this is the first report of high-resolution, genome-wide investigation of IVL by oligonucleotide array comparative genomic hybridization. The presence of high frequencies of recurrent regional loss involving several chromosomes is an important finding and likely related to the pathogenesis of the disease. PMID- 25033731 TI - Influence of redox non-innocent phenylenediamido ligands on chromium imido hydrogen-atom abstraction reactivity. AB - Paramagnetic CpCr[(RN)2C6H4] compounds (R = SiMe3, CH2CMe3 and Ph) were treated with R'N3 azides to generate chromium imido complexes, CpCr[(RN)2C6H4](NR'), with R' = adamantyl, aryl or SO2Ar. The H-atom abstraction reactivity of the imido complexes differed as the R and R' substituents were varied. PMID- 25033730 TI - Prognostic value of coexistence of abnormal expression of micro-RNA-200b and cyclic adenosine monophosphate-responsive element-binding protein 1 in human astrocytoma. AB - Our aim was to investigate the expression of micro-RNA-200b (miR-200b) and cAMP responsive element-binding protein 1 (CREB-1) in astrocytoma and its efficacy for predicting outcome. Both miR-200b and CREB-1 messenger RNA expression was measured in 122 astrocytomas and 30 nonneoplastic brain specimens by quantitative real-time polymerase chain reaction. Expression of miR-200b was significantly lower in astrocytoma than in nonneoplastic brain (P < .001), whereas CREB-1 messenger RNA expression was significantly elevated in the tumors (P < .001). Both miR-200b down-regulation and CREB-1 up-regulation were significantly associated with advanced pathologic grade (P = .002 and P = .006, respectively). Low miR-200b expression correlated negatively with Karnofsky performance score (P = .03), and high CREB-1 expression correlated positively with mean tumor diameter (P = .03). By Kaplan-Meier analysis, low miR-200b, high CREB-1, and coexistence of abnormal miR-200b and CREB-1 expression (low miR-200b/high CREB-1) were predictive of shorter progression-free survival and overall survival in both grade III and grade IV astrocytoma. By multivariate analysis, only low miR 200b/high CREB-1 expression was an independent prognostic factor for poor prognosis in astrocytoma of advanced grade. Both miR-200b and CREB-1 may play important cooperative roles in the progression of human astrocytoma. The efficacy of miR-200b and CREB-1 together as a predictor of prognosis in astrocytoma patients is shown for the first time. PMID- 25033733 TI - Executive dysfunction in schizophrenia and its association with mentalizing abilities. AB - INTRODUCTION: Patients with schizophrenia have been found impaired in important aspects of their basic and social cognition. Our aim in this study is to explore the relationship between executive function (EF) and theory of mind (ToM) deficiencies in patients that suffer the illness. MATERIALS AND METHODS: Twenty two Spanish-speaking inpatients and 22 healthy controls matched in age, sex, education, language dominance, and premorbid IQ were assessed in EF and ToM abilities. The former were assessed using 10 tasks that covered 5 cognitive dimensions and the latter using 3 different tasks. Correlation analyses were used to explore the level of association between executive and mentalizing abilities. A series of discriminant function analyses were carried out to examine the relative contribution of each executive and mentalizing task to discriminate between patients and controls. RESULTS: Patients showed impairments in both, executive and ToM abilities. The correlation analyses showed a virtual absence of association between EF and ToM abilities within the group of patients, and an almost opposite pattern within the healthy group. ToM performance was more accurate than executive performance to discriminate patients from controls. CONCLUSIONS: Although EFs and ToM deficits come into view together in schizophrenia, they appear to belong to different and relatively independent cognitive domains. PMID- 25033732 TI - A rabbit model of non-typhoidal Salmonella bacteremia. AB - Bacteremia is an important cause of morbidity and mortality in humans. In this study, we focused on the development of an animal model of bacteremia induced by non-typhoidal Salmonella. New Zealand White rabbits were inoculated with a human isolate of non-typhoidal Salmonella strain CVD J73 via the intra-peritoneal route. Blood samples were collected at specific time points and at euthanasia from infected rabbits. Additionally, tissue samples from the heart, lungs, spleen, gastrointestinal tract, liver and kidneys were obtained at euthanasia. All experimentally infected rabbits displayed clinical signs of disease (fever, dehydration, weight loss and lethargy). Tissues collected at necropsy from the animals exhibited histopathological changes indicative of bacteremia. Non typhoidal Salmonella bacteria were detected in the blood and tissue samples of infected rabbits by microbiological culture and real-time PCR assays. The development of this animal model of bacteremia could prove to be a useful tool for studying how non-typhoidal Salmonella infections disseminate and spread in humans. PMID- 25033734 TI - The discovery of first-in-class drugs: origins and evolution. AB - Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach. PMID- 25033735 TI - Vaccines: HIV vaccine failure due to induction of immune suppressors? PMID- 25033737 TI - Neural repair: timing is everything for Nogo-specific antibodies. PMID- 25033738 TI - Analgesia: anti-itch and anti-ouch antibody. PMID- 25033736 TI - Phenotypic screening in cancer drug discovery - past, present and future. AB - There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology. PMID- 25033739 TI - Pathological changes in the TMJ and the length of the ramus in patients with confirmed juvenile idiopathic arthritis. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) is characterized by a progressive destruction of the joints. The temporomandibular joints (TMJ) are especially likely to be affected. The often undetected arthritis in the TMJ in particular can cause significant destruction and craniofacial developmental abnormalities. The aim of this study was to analyze the destructive impact of JIA on TMJ and mandibular development. MATERIAL AND METHODS: We analyzed a total of 92 joints and mandibular rami using digital cone-beam tomography (CBT) and compared 23 consecutively treated JIA patients with 23 healthy controls, matched for age and gender. We evaluated ramus length, vertical depth of the articular fossa, anterior-posterior dimensions of the mandibular head and condylar process. The statistical analysis was performed using non-parametric Wilcoxon and Kruskal Wallis Rank Sum tests. RESULTS: The JIA patients exhibited significantly more pronounced asymmetries. However, we were unable to detect significant differences in the metric measuring distances. The different JIA subtypes exerted no statistically significant influence. CONCLUSIONS: The possible destruction arising as a result of JIA concerns the TMJ and the length of the mandibular ramus. These craniofacial anomalies demonstrate the central importance of sufficiently early detection and timely treatment in the prevention of such growth disturbances. PMID- 25033740 TI - Evaluation of factors affecting recovery period in lower lip hypoesthesia after sagittal split ramus osteotomy in mandibular prognathism patients. AB - PURPOSE: The purpose of this study was to evaluate the factors affecting the recovery period of lower lip hypoesthesia after sagittal split ramus osteotomy (SSRO) in mandibular prognathism patients using multivariate analysis, retrospectively. SUBJECTS AND METHODS: The subjects were 222 patients (444 sides) who underwent bilateral SSRO setback surgery with and without Le Fort I osteotomy. Trigeminal nerve hypoesthesia at the region of the lower lip was assessed bilaterally by the trigeminal somatosensory-evoked potential (TSEP) method pre- and post-operatively. Recovery period was determined as the time when TSEP was first measurable post-operatively. Age, sex, presence or absence of third molars, setback amount and osteotomy type and fixation method were selected as covariates in the multivariate analysis. The factor affecting the recovery period in lower lip hypoesthesia was examined with Cox's proportional hazard regression. RESULTS: Sex and osteotomy fixation method affected the recovery period in lower lip hypoesthesia significantly (P = 0.0132 and P = 0.0394). However, the other factors did not affect the recovery period. CONCLUSION: This study suggested that sex and osteotomy type and fixation method may affect the recovery period in lower lip hypoesthesia after SSRO setback surgery. PMID- 25033741 TI - Multiple reentrant glass transitions in confined hard-sphere glasses. AB - Glass-forming liquids exhibit a rich phenomenology upon confinement. This is often related to the effects arising from wall-fluid interactions. Here we focus on the interesting limit where the separation of the confining walls becomes of the order of a few particle diameters. For a moderately polydisperse, densely packed hard-sphere fluid confined between two smooth hard walls, we show via event-driven molecular dynamics simulations the emergence of a multiple reentrant glass transition scenario upon a variation of the wall separation. Using thermodynamic relations, this reentrant phenomenon is shown to persist also under constant chemical potential. This allows straightforward experimental investigation and opens the way to a variety of applications in micro- and nanotechnology, where channel dimensions are comparable to the size of the contained particles. The results are in line with theoretical predictions obtained by a combination of density functional theory and the mode-coupling theory of the glass transition. PMID- 25033742 TI - Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. AB - AIM: To characterize a new subset of early myoclonic encephalopathy usually associated with metabolic etiologies with a new genetic entity. METHODS: We describe two siblings with early myoclonic encephalopathy born to consanguineous parents of Arab Muslim origin from Israel. We used homozygosity mapping and candidate gene sequencing to reveal the genetic basis of the myoclonic syndrome. RESULTS: We found a rare missense mutation in the gene encoding one of the two mitochondrial glutamate/H symporters, SLC25A22. The phenotype of early myoclonic encephalopathy was first linked to the same mutation in 2005 in patients of the same ethnicity as our family. CONCLUSIONS: Owing to the devastating nature of this encephalopathy, we focus attention on its clinical history, epileptic semiology, distinct electroencephalography features, and genetic basis. We provide the evidence that an integrated diagnostic strategy combining homozygosity mapping with candidate gene sequencing is efficient in consanguineous families with highly heterogeneous autosomal recessive diseases. PMID- 25033743 TI - Counselling sessions increased duration of exclusive breastfeeding: a randomized clinical trial with adolescent mothers and grandmothers. AB - BACKGROUND: Considering that adolescent mothers may be more vulnerable to discontinuing exclusive breastfeeding (EBF) before 6 months and that their mothers may exert a negative influence on this practice, this study was conducted with the objective of evaluating the efficacy of breastfeeding counselling for adolescent mothers and their mothers in increasing EBF duration. METHODS: A clinical trial was performed in 323 adolescent mothers with newborns and their mothers randomized in four groups: (1) not living with mother, without intervention; (2) not living with mother, with intervention; (3) living with mother, without intervention, (4) living with mother, with intervention. The intervention consisted of five counselling sessions directed to mother and grandmother, in the maternity hospital and on follow-up. Information about feeding practices during the newborn's first six months of life was collected monthly by telephone. Intervention's efficacy was measured through Cox regression and comparison of exclusive breastfeeding medians and survival curves for the different groups. RESULTS: The intervention increased the duration of EBF by67 days for the group which included grandmothers (HR = 0.64; CI 95% = 0.46-0.90) and 46 days for the group which did not include grandmothers (HR = 0.52; CI 95% = 0.36-0.76). CONCLUSIONS: Counselling sessions in the first four months of children's lives proved to be effective in increasing EBF duration among adolescent mothers. TRIAL REGISTRATION: ClinicalTrials.gov NCT00910377. PMID- 25033744 TI - Bezold-Jarisch reflex caused by postural change. PMID- 25033745 TI - A prospective randomized double-blind study on the effects of the temperature of irrigation solutions on thermoregulation and postoperative complications in percutaneous nephrolithotomy. AB - PURPOSE: This study investigated the effects of irrigation solutions, administered at either 21 or 37 degrees C in percutaneous nephrolithotomy (PCNL), on hypothermia and related postoperative complications such as late emergence and late recovery from anesthesia, shivering, lactic acidosis, and excess bleeding. METHODS: Sixty patients who were scheduled for PCNL were enrolled in this prospective randomized double-blind study. Irrigation solutions at room temperature were administered to patients in group R (30 patients), and warmed irrigation solutions were administered to patients in group W (30 patients). The two groups were compared for core and peripheral body temperature, incidence of hypothermia, duration of emergence from anesthesia, duration of recovery from anesthesia, shivering, lactic acidosis, and hemoglobin levels. RESULTS: Hypothermia was incident in 19 patients (63.3 %) in group W and in 27 patients (90 %) in group R at the end of surgery. The difference between the initial and the final core body temperature was 0.9 +/- 0.6 degrees C group W and 1.4 +/- 0.7 degrees C in group R (p = 0.003). The extubation time was 4.4 +/ 2.2 min in group W and 5.9 +/- 3 min in group R (p = 0.032). Shivering was detected in seven patients (23.3 %) in group W and in 15 patients (50 %) in group R (p = 0.032). The recovery duration was 49.8 +/- 24.6 min in group W and 67.6 +/ 33.9 min in group R (p = 0.023). CONCLUSIONS: Administration of irrigation solutions at room temperature in PCNL operations causes the body temperature to decrease significantly, which results in postoperative complications such as late emergence from anesthesia, late recovery from anesthesia, and shivering. PMID- 25033746 TI - Longitudinal prevalence, oocyst shedding and molecular characterisation of Eimeria species in sheep across four states in Australia. AB - The prevalence of Eimeria in sheep in Australia has not been well described, therefore a quantitative PCR (qPCR) was developed, validated and used to study the prevalence and oocyst concentration in lamb faecal samples at three sampling periods (weaning, post-weaning and pre-slaughter) from eight farms across South Australia, New South Wales, Victoria and Western Australia. A total of 3412 faecal samples were collected from approximately 1182 lambs across the 4 states and screened for the presence of Eimeria using this qPCR at the 18S ribosomal RNA (rRNA) locus. A subset of positives was typed by sequence analysis at the 18S locus. The overall prevalence was 18.1% (95% CI 16.8-19.3%) and of the 616 positives, 118 were successfully genotyped. The prevalence of Eimeria was highest in NSW and peaked at 70% during the post-weaning period. The range of oocyst shedding per gram of faeces (g(-1)) at weaning, post-weaning and pre-slaughter overall across all states was 23-2.1*10(7), 23-1.3*10(7) and 23-2.1*10(5), respectively. Median Eimeria shedding g(-1) was higher during post-weaning (1.1*10(3)) and pre-slaughter (1.1*10(3)) than during weaning (206). The following species were identified: Eimeria crandallis, Eimeria ahsata, Eimeria ovinoidalis, Eimeria weybridgensis and Eimeria cylindrica. Of these, E. crandallis and E. ovinoidalis, the most pathogenic species in sheep were responsible for 58.5% of infections typed. This highlights a need for further research to quantify the production impacts of Eimeria in sheep. PMID- 25033747 TI - Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. AB - INTRODUCTION: We compare the outcomes for patients who received esmolol to those who did not receive esmolol during refractory ventricular fibrillation (RVF) in the emergency department (ED). METHODS: A retrospective investigation in an urban academic ED of patients between January 2011 and January 2014 of patients with out-of-hospital or ED cardiac arrest (CA) with an initial rhythm of ventricular fibrillation (VF) or ventricular tachycardia (VT) who received at least three defibrillation attempts, 300mg of amiodarone, and 3mg of adrenaline, and who remained in CA upon ED arrival. Patients who received esmolol during CA were compared to those who did not. RESULTS: 90 patients had CA with an initial rhythm of VF or VT; 65 patients were excluded, leaving 25 for analysis. Six patients received esmolol during cardiac arrest, and nineteen did not. All patients had ventricular dysrhythmias refractory to many defibrillation attempts, including defibrillation after administration of standard ACLS medications. Most received high doses of adrenaline, amiodarone, and sodium bicarbonate. Comparing the patients that received esmolol to those that did not: 67% and 42% had temporary return of spontaneous circulation (ROSC); 67% and 32% had sustained ROSC; 66% and 32% survived to intensive care unit admission; 50% and 16% survived to hospital discharge; and 50% and 11% survived to discharge with a favorable neurologic outcome, respectively. CONCLUSION: Beta-blockade should be considered in patients with RVF in the ED prior to cessation of resuscitative efforts. PMID- 25033748 TI - Impact of a revised appointment scheduling script on IUD service delivery in three Title X family planning clinics. AB - OBJECTIVE: The objective was to study a redesigned call script for intrauterine device (IUD) appointment scheduling. STUDY DESIGN: The script for a Title X call center was redesigned. Pre- and postintervention data were collected. RESULTS: For women with a scheduled IUD visit (n=99, pre n=57, post n=42), the preintervention IUD insertion rate was 47%; the postintervention insertion rate was 60% (p=.23). Among women <=25 years old, the preintervention rate was 41% and the postintervention rate was 68% (p=.05). No-show rates decreased (40.4% vs. 23.8%, p=.08), particularly for younger women (n=51; 46.9% vs. 15.8%, p=.04). CONCLUSION: A revised IUD appointment scheduling script improved long-acting reversible contraceptive uptake. IMPLICATIONS: Revising an appointment scheduling call script is a simple and scalable intervention to decrease administrative and clinical barriers to family planning services. As many clinics in the United States move toward computerized and centralized call centers, improving patient communication during the scheduling process may have a broad impact on clinical efficiency. PMID- 25033749 TI - Family planning since ICPD--how far have we progressed? AB - The 1994 International Conference on Population and Development (ICPD) was a pivotal global event. It established voluntary family planning as a fundamental human right. We describe the progress made and challenges faced by the family planning field in the 20 years since ICPD. We present case studies from three African countries to highlight factors affecting the evolution of family planning during the past 2 decades. Measurable progress has been made in the key family planning indicators over this interval. However, improvement has slowed in recent years, and demographic forecasts predict a greater unmet need for effective contraception in the future. With a rights-based lens, we need to better understand the nuances of fertility intentions as we offer women and couples contraceptive choices pertinent to their stage of life. With a public-health lens, we need better metrics to reflect the realities of contraceptive effectiveness. Now is the time to build on two decades of family planning progress after ICPD. PMID- 25033751 TI - Molecular determinants of pathogenicity in the polymerase complex. AB - Viral pathogenesis involves numerous interactions between viral and cellular factors. In recent years, the influenza virus polymerase complex has emerged as a major determinant of interspecies transmission and pathogenicity. The viral RNA dependent RNA polymerase, in concert with the nucleoprotein, mediates transcription and replication of the viral RNA genome in the nucleus of the infected cell. The activity by which the viral polymerase complex performs these processes in mammalian cells is considered to be a major contributor to viral pathogenicity in mammals. In this chapter, we summarise our current understanding on the pathogenicity determinants in the viral polymerase complex and highlight some of its cellular interaction partners. We particularly discuss the role of importin-alpha isoforms in host adaptation and pathogenesis as well as the role of the viral polymerase in regulating cellular responses to viral infection. PMID- 25033750 TI - Functional innovations of three chronological mesohexaploid Brassica rapa genomes. AB - BACKGROUND: The Brassicaceae family is an exemplary model for studying plant polyploidy. The Brassicaceae knowledge-base includes the well-annotated Arabidopsis thaliana reference sequence; well-established evidence for three rounds of whole genome duplication (WGD); and the conservation of genomic structure, with 24 conserved genomic blocks (GBs). The recently released Brassica rapa draft genome provides an ideal opportunity to update our knowledge of the conserved genomic structures in Brassica, and to study evolutionary innovations of the mesohexaploid plant, B. rapa. RESULTS: Three chronological B. rapa genomes (recent, young, and old) were reconstructed with sequence divergences, revealing a trace of recursive WGD events. A total of 636 fast evolving genes were unevenly distributed throughout the recent and young genomes. The representative Gene Ontology (GO) terms for these genes were 'stress response' and 'development' both through a change in protein modification or signaling, rather than by enhancing signal recognition. In retention patterns analysis, 98% of B. rapa genes were retained as collinear gene pairs; 77% of those were singly-retained in recent or young genomes resulting from death of the ancestral copies, while others were multi-retained as long retention genes. GO enrichments indicated that single retention genes mainly function in the interpretation of genetic information, whereas, multi-retention genes were biased toward signal response, especially regarding development and defense. In the recent genome, 13,302, 5,790, and 20 gene pairs were multi-retained following Brassica whole genome triplication (WGT) events with 2, 3, and 4 homoeologous copies, respectively. Enriched GO-slim terms from B. rapa homomoelogues imply that a major effect of the B. rapa WGT may have been to acquire environmental adaptability or to change the course of development. These homoeologues seem to more frequently undergo subfunctionalization with spatial expression patterns compared with other possible events including nonfunctionalization and neofunctionalization. CONCLUSION: We refined Brassicaceae GB information using the latest genomic resources, and distinguished three chronologically ordered B. rapa genomes. B. rapa genes were categorized into fast evolving, single- and multi-retention genes, and long retention genes by their substitution rates and retention patterns. Representative functions of the categorized genes were elucidated, providing better understanding of B. rapa evolution and the Brassica genus. PMID- 25033752 TI - Pathogenesis and vaccination of influenza A virus in swine. AB - Swine influenza is an acute respiratory disease of pigs caused by influenza A virus (IAV) and characterized by fever followed by lethargy, anorexia, and serous nasal discharge. The disease progresses rapidly and may be complicated when associated with other respiratory pathogens. IAV is one of the most prevalent respiratory pathogens of swine, resulting in substantial economic burden to pork producers. In the past 10-15 years, a dramatic evolution of the IAV in U.S. swine has occurred, resulting in the co-circulation of many antigenically distinct IAV strains, derived from 13 phylogenetically distinct hemagglutinin clusters of H1 and H3 viruses. Vaccination is the most common strategy to prevent influenza in pigs, however, the current diverse IAV epidemiology poses a challenge for the production of efficacious and protective vaccines. A concern regarding the use of traditional inactivated vaccines is the possibility of inducing vaccine associated enhanced respiratory disease (VAERD) when vaccine virus strains are mismatched with the infecting strain. In this review, we discuss the current epidemiology and pathogenesis of swine influenza in the United States, different vaccines platforms with potential to control influenza in pigs, and the factors associated with vaccine-associated disease enhancement. PMID- 25033754 TI - Influenza neuraminidase as a vaccine antigen. AB - Neuraminidase (NA) is the second most abundant influenza surface glycoprotein and contributes to virus replication in several ways, most notably by removing sialic acids from the host and viral glycoproteins, releasing newly formed virus particles from infected cells. Antibodies that block this enzyme activity restrict virus replication in vitro. This chapter describes foundational epidemiologic and human influenza challenge studies that provide evidence of an association between NA inhibiting antibodies and resistance to disease. Mouse challenge studies show that while NA immunity is infection-permissive, NA specific antibodies attenuate infection and prevent severe disease. NA immunity is most effective against homologous viruses but there is substantial protection against viruses with a heterologous NA (different lineage within a NA subtype). Monoclonal antibodies specific for conserved antigenic domains of subtype N1 protect against seasonal and pandemic H1N1 as well as H5N1 virus challenge. Clinical studies demonstrate that licensed seasonal vaccines contain immunogenic amounts of NA, but the contribution of this immunity to vaccine efficacy is currently not known. New types of influenza vaccines could be designed to elicit NA immunity. Because NA induces heterologous immunity, it could be an important constituent of universal influenza vaccines that aim to protect against unexpected emerging viruses. PMID- 25033755 TI - Pierisins and CARP-1: ADP-ribosylation of DNA by ARTCs in butterflies and shellfish. AB - The cabbage butterfly, Pieris rapae, and related species possess a previously unknown ADP-ribosylating toxin, guanine specific ADP-ribosyltransferase. This enzyme toxin, known as pierisin, consists of enzymatic N-terminal domain and receptor-binding C-terminal domain, or typical AB-toxin structure. Pierisin efficiently transfers an ADP-ribosyl moiety to the N(2) position of the guanine base of dsDNA. Receptors for pierisin are suggested to be the neutral glycosphingolipids, globotriaosylceramide (Gb3), and globotetraosylceramide (Gb4). This DNA-modifying toxin exhibits strong cytotoxicity and induces apoptosis in various human cell lines, which can be blocked by Bcl-2. Pierisin also produces detrimental effects on the eggs and larvae of the non-habitual parasitoids. In contrast, a natural parasitoid of the cabbage butterfly, Cotesia glomerata, was resistant to this toxin. The physiological role of pierisin in the butterfly is suggested to be a defense factor against parasitization by wasps. Other type of DNA ADP-ribosyltransferase is present in certain kinds of edible clams. For example, the CARP-1 protein found in Meretrix lamarckii consists of an enzymatic domain without a possible receptor-binding domain. Pierisin and CARP-1 are almost fully non-homologous at the amino acid sequence level, but other ADP ribosyltransferases homologous to pierisin are present in different biological species such as eubacterium Streptomyces. Possible diverse physiological roles of the DNA ADP-ribosyltransferases are discussed. PMID- 25033753 TI - The effector T cell response to influenza infection. AB - Influenza virus infection induces a potent initial innate immune response, which serves to limit the extent of viral replication and virus spread. However, efficient (and eventual) viral clearance within the respiratory tract requires the subsequent activation, rapid proliferation, recruitment, and expression of effector activities by the adaptive immune system, consisting of antibody producing B cells and influenza-specific T lymphocytes with diverse functions. The ensuing effector activities of these T lymphocytes ultimately determine (along with antibodies) the capacity of the host to eliminate the viruses and the extent of tissue damage. In this review, we describe this effector T cell response to influenza virus infection. Based on information largely obtained in experimental settings (i.e., murine models), we will illustrate the factors regulating the induction of adaptive immune T cell responses to influenza, the effector activities displayed by these activated T cells, the mechanisms underlying the expression of these effector mechanisms, and the control of the activation/differentiation of these T cells, in situ, in the infected lungs. PMID- 25033756 TI - UV and melanoma: the TP53 link. AB - Ultraviolet radiation (UVR) is a major risk factor for melanoma development, but it has been unclear exactly how UVR leads to melanomagenesis. In a recent publication in Nature, Viros et al. identify TP53/Trp53 as a UVR-target gene in melanoma and show that UVR-induced TP53/Trp53 mutations accelerate BRAF(V600E) driven melanomagenesis. PMID- 25033757 TI - How many testers are needed to assure the usability of medical devices? AB - Before releasing a product, manufacturers have to follow a regulatory framework and meet standards, producing reliable evidence that the device presents low levels of risk in use. There is, though, a gap between the needs of the manufacturers to conduct usability testing while managing their costs, and the requirements of authorities for representative evaluation data. A key issue here is the number of users that should complete this evaluation to provide confidence in a product's safety. This paper reviews the US FDA's indication that a sample composed of 15 participants per major group (or a minimum of 25 users) should be enough to identify 90-97% of the usability problems and argues that a more nuanced approach to determining sample size (which would also fit well with the FDA's own concerns) would be beneficial. The paper will show that there is no a priori cohort size that can guarantee a reliable assessment, a point stressed by the FDA in the appendices to its guidance, but that manufacturers can terminate the assessment when appropriate by using a specific approach - illustrated in this paper through a case study - called the 'Grounded Procedure'. PMID- 25033759 TI - Qualitative tests of remote eyetracker recovery and performance during head rotation. AB - What are the decision criteria for choosing an eyetracker? Often the choice is based on specifications by the manufacturer of the validity (accuracy) and reliability (precision) of measurements that can be achieved using a particular eyetracker. These specifications are mostly achieved under optimal conditions-for example, by using an artificial eye or trained participants fixed in a chinrest. Research, however, does not always take place in optimal conditions: For instance, when investigating eye movements in infants, school children, and patient groups with disorders such as attention-deficit hyperactivity disorder, it is practically impossible to restrict movement. We modeled movements often seen in infant research in two behaviors: (1) looking away from and back to the screen, to investigate eyetracker recovery, and (2) head orientations, to investigate eyetracker performance with nonoptimal orientations of the eyes. We investigated how eight eyetracking setups by three manufacturers (SMI, Tobii, and LC Technologies) coped with these modeled behaviors in adults. We report that the tested SMI eyetrackers dropped in sampling frequency when the eyes were not visible to the eyetracker, whereas the other systems did not, and discuss the potential consequences thereof. Furthermore, we report that the tested eyetrackers varied in their rates of data loss and systematic offsets during shifted head orientations. We conclude that (prospective) eye-movement researchers who cannot restrict movement or nonoptimal head orientations in their participants might benefit from testing their eyetracker in nonoptimal conditions. Additionally, researchers should be aware of the data loss and inaccuracies that might result from nonoptimal head orientations. PMID- 25033758 TI - Molecular genetics of Mullerian duct formation, regression and differentiation. AB - The Mullerian duct (MD) forms the female reproductive tract (FRT) consisting of the oviducts, uterus, cervix, and upper vagina. FRT function is vital to fertility, providing the site of fertilization, embryo implantation and fetal development. Developmental defects in the formation and diseases of the FRT, including cancer and endometriosis, are prevalent in humans and can result in infertility and death. Furthermore, because the MDs are initially formed regardless of genotypic sex, mesenchymal to epithelial signaling is required in males to mediate MD regression and prevents the development of MD-derived organs. In males, defects in MD regression result in the retention of FRT organs and have been described in several human syndromes. Although to date not reported in humans, ectopic activation of MD regression signaling components in females can result in aplasia of the FRT. Clearly, MD development is important to human health; however, the molecular mechanisms remain largely undetermined. Molecular genetics studies of human diseases and mouse models have provided new insights into molecular signaling during MD development, regression and differentiation. This review will provide an overview of MD development and important genes and signaling mechanisms involved. PMID- 25033760 TI - Correlation of HER2 gene status assessment by fluorescence in situ hybridization between histological sections and cytological specimens of breast cancer. AB - BACKGROUND: While HER2 gene detection in cytological specimens using fluorescence in situ hybridization (FISH) has been reported, the appropriate criteria for such specimens remain controversial. METHODS: Fine needle aspiration (FNA) samples collected from surgically resected breast cancer specimens were rinsed in a cytopreservative solution containing fixative. Then, slides of the FNA samples were prepared by liquid-based cytology (LBC) (ThinPrep system, Hologic) according to the manufacturer's instructions, and a PathVision HER2 DNA probe kit (Abbott) was used for FISH staining. The results were evaluated using an automated MetaCyte imaging system (MetaSystems, Altlussheim, Germany). HER2 gene amplification was scored using the HER2/chromosome enumeration probe 17 (CEP17) signal count ratio as follows: amplified, >2.2; equivocal, 1.8-2.2; and unamplified, <1.8. The cytology results were compared with the histology results from concordant cases. RESULTS: Successful results were obtained in 98 of 100 cases, and results from the FNA specimens were in agreement with those from the histological sections in 97 of these 98 cases (accuracy rate, 99 %; kappa, 0.962). CONCLUSIONS: FISH-based assessment of the HER2 gene status is consistent between histological sections and cytological specimens of breast cancer. PMID- 25033761 TI - The Boston Residue and Clearance Scale: preliminary reliability and validity testing. AB - BACKGROUND: There is no appropriately validated scale with which to rate the problem of residue after swallowing. The Boston Residue and Clearance Scale (BRACS) was developed to meet this need. Initial reliability and validity were assessed. METHODS: BRACS is an 11-point ordinal residue rating scale scoring three aspects of residue during a fiberoptic endoscopic evaluation of swallowing (FEES): (1) the amount and location of residue, (2) the presence of spontaneous clearing swallows, and (3) the effectiveness of clearing swallows. To determine inter-rater and test-retest reliability, 63 swallows from previously recorded FEES procedures were scored twice by 4 raters using (1) clinical judgment (none, mild, mild-moderate, moderate, moderate-severe, severe) and (2) BRACS. Concurrent validity was tested by correlating clinical judgment scores with BRACS scores. Internal consistency of the items in BRACS was examined. A factor analysis was performed to identify important factors that suggest grouping within the 12 location items in BRACS. RESULTS: BRACS showed excellent inter-rater reliability (intraclass correlation coefficient, ICC = 0.81), test-retest reliability (ICC: 0.82-0.92), high concurrent validity (Pearson's r = 0.76), and high internal consistency (Cronbach's alpha = 0.86). Factor analysis revealed 3 main latent factors for the 12 location items. CONCLUSION: BRACS is a valid and reliable tool that can rate the severity of residue. PMID- 25033762 TI - Quantitative ADME proteomics - CYP and UGT enzymes in the Beagle dog liver and intestine. AB - PURPOSE: Beagle dogs are used to study oral pharmacokinetics and guide development of drug formulations for human use. Since mechanistic insight into species differences is needed to translate findings in this species to human, abundances of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) drug metabolizing enzymes have been quantified in dog liver and intestine. METHODS: Abundances of enzymes were measured in Beagle dog intestine and liver using selected reaction monitoring mass spectrometry. RESULTS: Seven and two CYPs were present in the liver and intestine, respectively. CYP3A12 was the most abundant CYP in both tissues. Seven UGT enzymes were quantified in the liver and seven in the intestine although UGT1A11 and UGT1A9 were present only in the intestine and UGT1A7 and UGT2B31 were found only in the liver. UGT1A11 and UGT1A2 were the most abundant UGTs in the intestine and UGT2B31 was the most abundant UGT in the liver. Summed abundance of UGT enzymes was similar to the sum of CYP enzymes in the liver whereas intestinal UGTs were up to four times more abundant than CYPs. The estimated coefficients of variation of abundance estimates in the livers of 14 donors were separated into biological and technical components which ranged from 14 to 49% and 20 to 39%, respectively. CONCLUSIONS: Abundances of canine CYP enzymes in liver and intestine have been confirmed in a larger number of dogs and UGT abundances have been quantified for the first time. The biological variability in hepatic CYPs and UGTs has also been estimated. PMID- 25033763 TI - Nanomagnetic activation as a way to control the efficacy of nucleic acid delivery. AB - PURPOSE: To explore the potential of magnetofection in delivering pDNA to primary mouse embryonic fibroblasts (PMEFs) and porcine fetal fibroblasts (PFFs) and investigate an effect of magnetic cell labeling on transfection efficacy. METHODS: The formulation and a dose of the magnetic vector were optimized. The efficacy of the procedure was quantified by vector internalization, transgene expression and cell iron loading upon specific labeling with Ab-conjugated magnetic beads or non-specific labeling with MNPs. RESULTS: Up to sixty percent of PMEF and PFF cells were transfected at low pDNA doses of 4-16 pg pDNA/cell. Specific labeling of the PMEFs with MNPs, resulted in a 3- and 2-fold increase in pDNA internalization upon magnetofection and lipofection, respectively, that yielded a 2-4-fold increase in percent of transgene-expressing cells. Non specific cell labeling had no effect on the efficacy of the reporter expression, despite the acquisition of similar magnetic moments per cell. In PFFs, specific magnetic labeling of the cell surface receptors inhibited internalization and transfection efficacy. CONCLUSIONS: Magnetic labeling of cell-surface receptors combined with the application of an inhomogenous magnetic field (nanomagnetic activation) can affect the receptor-mediated internalization of delivery vectors and be used to control nucleic acid delivery to cells. PMID- 25033764 TI - Inflation of the type I error: investigations on regulatory recommendations for bioequivalence of highly variable drugs. AB - PURPOSE: We investigated different evaluation strategies for bioequivalence trials with highly variable drugs on their resulting empirical type I error and empirical power. The classical 'unscaled' crossover design with average bioequivalence evaluation, the Add-on concept of the Japanese guideline, and the current 'scaling' approach of EMA were compared. METHODS: Simulation studies were performed based on the assumption of a single dose drug administration while changing the underlying intra-individual variability. RESULTS: Inclusion of Add on subjects following the Japanese concept led to slight increases of the empirical alpha-error (~7.5%). For the approach of EMA we noted an unexpected tremendous increase of the rejection rate at a geometric mean ratio of 1.25. Moreover, we detected error rates slightly above the pre-set limit of 5% even at the proposed 'scaled' bioequivalence limits. CONCLUSIONS: With the classical 'unscaled' approach and the Japanese guideline concept the goal of reduced subject numbers in bioequivalence trials of HVDs cannot be achieved. On the other hand, widening the acceptance range comes at the price that quite a number of products will be accepted bioequivalent that had not been accepted in the past. A two-stage design with control of the global alpha therefore seems the better alternative. PMID- 25033766 TI - Temperature-dependent infiltration of polymers during sequential exposures to trimethylaluminum. AB - Atomic layer deposition provides the opportunity to introduce nanoscale inorganic coatings to organic polymers creating coatings of varied compositions of finish with distinctive interfaces. Prior research has shown that ALD materials nucleation on polymers varies in composition and structure based on how the precursor interacts with the polymer chemistry and the process conditions. To study this in more detail, in situ quartz crystal microgravimetry is employed to understand the infiltration and saturation behavior of trimethylaluminum in polyamide-6, poly(acrylic acid), poly(ethylene terephthalate), and poly(methyl methacrylate). Emphasis is placed on understanding reactive vapor diffusion into these polymers as the exposure temperature is varied. Finally, we propose potential growth mechanisms based on the temperature-dependent observations in this work that enables the ability to produce a customized interface for ALD materials growth on polymer substrates. PMID- 25033765 TI - Formulation design and evaluation of liposomal sepantronium bromide (YM155), a small-molecule survivin suppressant, based on pharmacokinetic modeling and simulation. AB - PURPOSE: Sepantronium bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities. METHODS: A kinetic simulation model of liposomal YM155 to predict the free drug concentration in both tumor and plasma was developed. A liposomal formulation with the target drug release rate was prepared based on the simulation. Antitumor activities of the formulation were examined in various tumor xenograft mouse models. In addition, antitumor activities of liposomal formulations with different drug release rates were compared in order to confirm the validity of the simulation-based prediction. RESULTS: Liposomal YM155 with the release half-life of 48 h was prepared as a promising formulation. This formulation showed significantly potent antitumor activities in tumor xenograft models by weekly bolus injections. Further studies demonstrated that this release rate was optimal for YM155 in terms of both efficacy and safety. CONCLUSIONS: We successfully developed a liposomal formulation of YM155 that could substitute for long-term continuous infusion of the drug solution in clinical settings by being given as weekly bolus injections. PMID- 25033767 TI - Evaluation of the predacious mite Hemicheyletia wellsina (Acari: Cheyletidae) as a predator of arthropod pests of orchids. AB - The cheyletid predator Hemicheyletia wellsina was found in association with orchid pests in a Florida greenhouse. The life history of H. wellsina was determined using the two-spotted spider mite, Tetranychus urticae, as prey in the laboratory. Hemicheyletia wellsina is arrhenotokous, with mated females producing a female-biased sex ratio of 3.4:1. Adult longevity averaged 30.2 days, with females producing an average of 18.5 eggs. Adult females live up to 17 days without food, surviving an average of 9.7 days. Hemicheyletia wellsina will readily feed on the phytoseiid Metaseiulus occidentalis, suggesting intraguild predation by H. wellsina on phytoseiids could be important in pest management programs. The average prey consumption of H. wellsina is 1.5 T. urticae females per day. The results of this study provide information on an under-studied group of mite predators. Although H. wellsina does not have the qualities that would be necessary for its use in an augmentative or classical biological control program, its use in naturally occurring biological control could be beneficial. PMID- 25033768 TI - Host finding behaviour of the coconut mite Aceria guerreronis. AB - For the coconut mite, Aceria guerreronis Keifer, its host plant, the coconut palm, is not merely a source of food, but more generally a habitat to live in for several generations. For these minute organisms, finding a new plant is difficult and risky, especially because their main mode of dispersal is passive drifting with the wind and because they are highly specialized on their host plant. Consequently, the probability of landing on a suitable host is very low, let alone to land in their specific microhabitat within the host. How coconut mites manage to find their microhabitat within a host plant is still underexplored. We tested the hypothesis that they use volatile chemical information emanating from the plant to find a specific site within their host plants and/or use non volatile plant chemicals to stay at a profitable site on the plant. This was investigated in a Y-tube olfactometer (i.e. under conditions of a directed wind flow) and on cross-shaped arenas (i.e. under conditions of turbulent air) that either allowed contact with odour sources or not. The mites had to choose between odours from specific parts (leaflet, spikelet or fruit) of a non-infested coconut plant and clean air as the alternative. In the olfactometer experiments, no mites were found to reach the upwind end of the Y-tube: <5 % of the mites were able to pass the bifurcation of the "Y". On the cross-shaped arenas, however, a large number of coconut mites was found only when the arm of the arena contained discs of fruit epidermis and contact with these discs was allowed. The results suggest that coconut mites on palm trees are not attracted to specific sites on the plant by volatile plant chemicals, but that they arrested once they contact the substrate of specific sites. Possibly, they perceive non-volatile chemicals, but these remain to be identified. PMID- 25033769 TI - Behaviour of coconut mites preceding take-off to passive aerial dispersal. AB - For more than three decades the coconut mite Aceria guerreronis Keifer is one of the most important pests of coconut palms and has recently spread to many coconut production areas worldwide. Colonization of coconut palms is thought to arise from mites dispersing aerially after take-off from other plants within the same plantation or other plantations. The underlying dispersal behaviour of the mite at take-off, in the airborne state and after landing is largely unknown and this is essential to understand how they spread from tree to tree. In this article we studied whether take-off to aerial dispersal of coconut mites is preceded by characteristic behaviour, whether there is a correlation between the body position preceding aerial dispersal and the direction of the wind, and whether the substrate (outer surface of coconut bracts or epidermis) and the wind speed matter to the decision to take-off. We found that take-off can sometimes be preceded by a raised body stance, but more frequently take-off occurs while the mite is walking or resting on its substrate. Coconut mites that become airborne assumed a body stance that had no relation to the wind direction. Take-off was suppressed on a substrate providing food to coconut mites, but occurred significantly more frequently on the outer surface of coconut bracts than on the surface of the fruit. For both substrates, take-off frequency increased with wind speed. We conclude that coconut mites have at least some degree of control over take-off for aerial dispersal and that there is as yet no reason to infer that a raised body stance is necessary to become airborne. PMID- 25033770 TI - Decreased orthostatic adrenergic reactivity in non-dipping postural tachycardia syndrome. AB - Whether non-dipping - the loss of the physiologic nocturnal drop in blood pressure - among patients with postural tachycardia syndrome (POTS) is secondary to autonomic neuropathy, a hyperadrenergic state, or other factors remains to be determined. In 51 patients with POTS (44 females), we retrospectively analyzed 24 hour ambulatory blood pressure recordings, laboratory indices of autonomic function, orthostatic norepinephrine response, 24-hour natriuresis and peak exercise oxygen consumption. Non-dipping (<10% day-night drop in systolic blood pressure) was found in 55% (n=28). Dippers and non-dippers did not differ in: 1) baseline characteristics including demographic and clinical profile, sleep duration, daytime blood pressure, 24-hour natriuresis, and peak exercise oxygen consumption; 2) severity of laboratory autonomic deficits (sudomotor, cardiovagal and adrenergic); 3) frequency of autonomic neuropathy (7/23 vs. 8/28, P=0.885); 4) supine resting heart rate (75.3+/-14.0bpm vs. 74.0+/-13.8bpm, P=0.532); or 5) supine plasma norepinephrine level (250.0+/-94.9pg/ml vs. 207.0+/-86.8pg/ml, P=0.08). However, dippers differed significantly from non-dippers in that they had significantly greater orthostatic heart rate increment (43+/-16bpm vs. 35+/ 10bpm, P=0.007) and significantly greater orthostatic plasma norepinephrine increase (293+/-136.6pg/ml vs. 209+/-91.1pg/ml, P=0.028). Our data indicate that in patients with POTS, a non-dipping blood pressure profile is associated with a reduced orthostatic sympathetic reactivity not accounted for by autonomic neuropathy. PMID- 25033771 TI - The protective effect of granulocyte colony-stimulating factor on endometrium and ovary in a rat model of diabetes mellitus. AB - AIMS: To evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on the endometrium and ovaries in an experimental diabetes mellitus (DM) rat model. METHODS: A total of 18 female Sprague-Dawley albino mature rats (8 weeks, 200-220 g) were used in this study. Diabetes was induced by intraperitoneal (i.p.) injection of streptozocin randomly in 12 rats. No drug was administered to the remainder of the rats (control group, group 1, n = 6). The other 12 rats were randomly divided into 2 groups; 1 ml/kg i.p. saline was given as vehicle to group 2 (diabetic nontreated control group, n = 6) and 100 ug/kg/day of i.p. G-CSF was given to group 3 (G-CSF-treated group, n = 6) for 4 weeks. After 4 weeks, blood samples were collected and hysterectomy with bilateral oophorectomy was performed for histopathological examination. RESULTS: The mean endometrial gland degeneration and stromal fibrosis scores were significantly higher in group 2 compared with groups 1 and 3. Ovarian follicle degeneration, stromal degeneration and stromal fibrosis scores were significantly higher in group 2 compared with groups 1 and 3. Plasma TGF-beta and malondialdehyde levels were significantly lower in groups 1 and 3 compared with group 2. Antimullerian hormone levels were significantly lower in group 2 compared with groups 1 and 3. CONCLUSION: Glucose toxicity occurred severely in the ovaries and endometrium of the DM rats. After G CSF treatment, ovarian and endometrial injury and fibrosis scores decreased significantly. The effects of G-CSF in rat models give hope to improved treatment of human DM complications such as premature ovarian failure and endometrial dysfunction. PMID- 25033772 TI - Two new cases of KIR3DP1, KIR2DL4-negative genotypes, one of which is also lacking KIR3DL2. AB - The killer immunoglobulin-like receptor (KIR) genes KIR2DL4, KIR3DL2, and KIR3DP1 are present in virtually all humans. KIR2DL4 encodes a receptor present on uterine and decidual natural killer (NK) cells and some peripheral blood NK cells. Its only known ligand is the human leukocyte antigen-G molecule expressed on extravillous trophoblasts, and on tissues in some diseases. KIR3DL2 binds HLA A*03 and HLA-A*11 as well as HLA-B*27 dimers, and microbial CpG DNA. KIR3DP1 is a pseudogene. During our immunogenetic studies we found two individuals, one from Lower Silesia district in Poland, and another from Western Ukraine, who were reproducibly negative for KIR2DL4 and KIR3DP1 genes, using three different PCR systems. Both individuals displayed very similar genotypes, possessing only KIR3DL3, KIR2DL3, KIR2DP1, KIR2DS1, and probably a rare variant of KIR2DL1. The Pole had also KIR3DL2, which the Ukrainian was apparently lacking. The Lower Silesia has been populated after the Second World War by a remarkable percentage with displaced people from Western Ukraine, which might contribute to genetic similarity of the two individuals described here. PMID- 25033773 TI - Caspases as the key effectors of inflammatory responses against bacterial infection. AB - Caspase cysteine proteases are factors widely recognized for their role in the induction of apoptotic cell death. Caspases induce apoptosis during the inflammatory response to pathogen infection; in addition, caspases such as caspase-1 and caspase-11 are known to be involved in the production of inflammatory cytokines in response to bacterial infections. Caspase-1 is activated in the inflammasome, an intracellular protein complex that is formed by the recognition of intracellular ligands or cellular stresses by sensor molecules such as NOD-like receptors. Under certain conditions, caspase-11 is required for the activation of the caspase-1 inflammasome, referred to as the non-canonical inflammasome. In addition to these caspases, accumulating evidence indicates that caspase-8 also contributes to the production of inflammatory cytokines. In contrast to caspase-1, caspase-8 is activated by receptors located on the plasma membrane including dectin-1, TLR-3/4, and Fas. Recently, Fas-mediated caspase-8 activation and inflammatory cytokine production have been shown to play a significant role in the regulation of bacterial infections. This review highlights the functional roles and activation mechanisms of caspase-1/-11 in innate immune responses against bacterial infection. In addition, we discuss the novel aspects of caspase-8 function in comparison with caspase-1/-11 during innate inflammatory responses. PMID- 25033774 TI - Biological agents database in the armed forces. AB - Rapid detection and identification of the biological agent during both, natural or deliberate outbreak is crucial for implementation of appropriate control measures and procedures in order to mitigate the spread of disease. Determination of pathogen etiology may not only support epidemiological investigation and safety of human beings, but also enhance forensic efforts in pathogen tracing, collection of evidences and correct inference. The article presents objectives of the Biological Agents Database, which was developed for the purpose of the Ministry of National Defense of the Republic of Poland under the European Defence Agency frame. The Biological Agents Database is an electronic catalogue of genetic markers of highly dangerous pathogens and biological agents of weapon of mass destruction concern, which provides full identification of biological threats emerging in Poland and in locations of activity of Polish troops. The Biological Agents Database is a supportive tool used for tracing biological agents' origin as well as rapid identification of agent causing the disease of unknown etiology. It also provides support in diagnosis, analysis, response and exchange of information between institutions that use information contained in it. Therefore, it can be used not only for military purposes, but also in a civilian environment. PMID- 25033775 TI - (Self-) infections with parasites: re-interpretations for the present. AB - Previously, scientists sometimes resorted to infecting themselves or colleagues with parasites, usually to assess the pathogenicity and obtain insight into the life cycles of the parasites, host specificity, and epidemiology. However, with recent research addressing the possible beneficial impact of intestinal helminths on a range of immune-mediated diseases in humans, these studies offer valuable information, although many are now considered unethical owing to a lack of experimental oversight and informed consent. Here, we critically review cases in which humans were deliberately infected with parasites. Moreover, we summarize the contribution of (self-) infections and propose protist and helminth candidates, chosen on the basis of several criteria, to test as possible therapy for selected human diseases. PMID- 25033776 TI - Mathematical model of stem cell differentiation and tissue regeneration with stochastic noise. AB - Differentiation and self-renewal of stem cells is an essential process for the maintenance of tissue composition. The promise of novel medical therapies combined with the complexity of this process encourage us to employ numerical and mathematical methods. This will allow us to understand better the mechanisms which regulate stem cell behaviour. Perturbations to the cellular environment may have an influence on the death rate, proliferation rate and on the fraction of self-renewal at every stage of differentiation. In this paper, we present mathematical study of the effect of stochastic noise on the process of tissue regeneration. Here, a system of Ito stochastic differential equations with linear diffusion coefficients that is based on a deterministic model of multistage cell lineages is investigated. Numerical simulations of the stochastic model are shown for a different number of stages of differentiation. Interactions between the noise, added to the different stages, are characterised using numerical simulations. The long-time behaviour of the two-dimensional version of the model is fully characterised; asymptotic stability of the related Markov semigroup is proved using the theory of the Markov semigroups and the method of the Khasminskii function. PMID- 25033777 TI - Analysis of risk-structured vaccination model for the dynamics of oncogenic and warts-causing HPV types. AB - A new deterministic model is designed and used to assess the community-wide impact of mass vaccination of new sexually active individuals on the dynamics of the oncogenic and warts-causing HPV types. Rigorous qualitative analyses of the model, which incorporates the two currently available anti-HPV vaccines, reveal that it undergoes competitive exclusion when the reproduction of one HPV risk type (low/high) exceeds unity, while that of the other HPV risk type is less than unity. For the case when the reproduction numbers of the two HPV risk types (low/high) exceed unity, the two risk types co-exist. It is shown that the sub model with the low-risk HPV types only has at least one endemic equilibrium whenever the associated reproduction threshold exceeds unity. Furthermore, this sub-model undergoes a re-infection-induced backward bifurcation under certain conditions. In the absence of the re-infection of recovered individuals and cancer-induced mortality in males, the associated disease-free equilibrium of the full (risk-structured) model is shown to be globally asymptotically stable whenever the reproduction number of the model is less than unity (that is, the full model does not undergo backward bifurcation under this setting). It is shown, via numerical simulations, that the use of the Gardasil vaccine could lead to the effective control of HPV in the community if the coverage rate is in the range of 73-95 % (84 %). If 70 % of the new sexually active susceptible females are vaccinated with the Gardasil vaccine, additionally vaccinating 34-56 % (45 %) of the new sexually active susceptible males can lead to the effective community wide control (or elimination) of the HPV types. PMID- 25033778 TI - Stochastic dynamic programming illuminates the link between environment, physiology, and evolution. AB - I describe how stochastic dynamic programming (SDP), a method for stochastic optimization that evolved from the work of Hamilton and Jacobi on variational problems, allows us to connect the physiological state of organisms, the environment in which they live, and how evolution by natural selection acts on trade-offs that all organisms face. I first derive the two canonical equations of SDP. These are valuable because although they apply to no system in particular, they share commonalities with many systems (as do frictionless springs). After that, I show how we used SDP in insect behavioral ecology. I describe the puzzles that needed to be solved, the SDP equations we used to solve the puzzles, and the experiments that we used to test the predictions of the models. I then briefly describe two other applications of SDP in biology: first, understanding the developmental pathways followed by steelhead trout in California and second skipped spawning by Norwegian cod. In both cases, modeling and empirical work were closely connected. I close with lessons learned and advice for the young mathematical biologists. PMID- 25033779 TI - Individual-based competition between species with spatial correlation and aggregation. AB - In order to clarify the theoretical relationship between individual behavior and population-level competition between two species with spatial correlation, this paper describes how discrete-time competition equations for the two species can be derived from local resource competition among individuals. Competition type of each species is either scramble, contest, or modified contest, and for various combinations of two competition types, different competition models are derived. Simple competition models that can approximate the above models when competition is weak are also derived. Furthermore, the derived models are used to investigate how coexistence conditions and coexistence probability depend on spatial correlation and aggregation of individuals. For the weak competition models, spatial aggregation and non-correlation, in terms of measures adopted here, play exactly symmetric roles in promoting coexistence. In contrast, for the fully developed models, spatial aggregation generally exerts stronger effects than non correlation on coexistence. Coexistence probability also depends greatly on competition types. For example, two species are generally more likely to coexist when they are of the same competition type than of different competition types. Coexistence probabilities from the mathematical analysis are in good agreement with those from individual-based simulations. PMID- 25033780 TI - Resource consumption, sustainability, and cancer. AB - Preserving a system's viability in the presence of diversity erosion is critical if the goal is to sustainably support biodiversity. Reduction in population heterogeneity, whether inter- or intraspecies, may increase population fragility, either decreasing its ability to adapt effectively to environmental changes or facilitating the survival and success of ordinarily rare phenotypes. The latter may result in over-representation of individuals who may participate in resource utilization patterns that can lead to over-exploitation, exhaustion, and, ultimately, collapse of both the resource and the population that depends on it. Here, we aim to identify regimes that can signal whether a consumer-resource system is capable of supporting viable degrees of heterogeneity. The framework used here is an expansion of a previously introduced consumer-resource type system of a population of individuals classified by their resource consumption. Application of the Reduction Theorem to the system enables us to evaluate the health of the system through tracking both the mean value of the parameter of resource (over)consumption, and the population variance, as both change over time. The article concludes with a discussion that highlights applicability of the proposed system to investigation of systems that are affected by particularly devastating overly adapted populations, namely cancerous cells. Potential intervention approaches for system management are discussed in the context of cancer therapies. PMID- 25033781 TI - N-Site phosphorylation systems with 2n-1 steady states. AB - Multisite protein phosphorylation plays a prominent role in intracellular processes like signal transduction, cell-cycle control and nuclear signal integration. Many proteins are phosphorylated in a sequential and distributive way at more than one phosphorylation site. Mathematical models of n-site sequential distributive phosphorylation are therefore studied frequently. In particular, in Wang and Sontag (J Math Biol 57:29-52, 2008), it is shown that models of n-site sequential distributive phosphorylation admit at most 2n - 1 steady states.Wang and Sontag furthermore conjecture that for odd n, there are at most n and that, for even n, there are at most n + 1 steady states. This, however, is not true: building on earlier work in Holstein et al. (BullMath Biol 75(11):2028-2058, 2013), we present a scalar determining equation for multistationarity which will lead to parameter values where a 3-site system has 5 steady states and parameter values where a 4-site system has 7 steady states. Our results therefore are counterexamples to the conjecture of Wang and Sontag.We furthermore study the inherent geometric properties of multistationarity in n site sequential distributive phosphorylation: the complete vector of steady state ratios is determined by the steady state ratios of free enzymes and unphosphorylated protein and there exists a linear relationship between steady state ratios of phosphorylated protein. PMID- 25033782 TI - Microtubule patterning in the presence of stationary motor distributions. AB - In this paper, we construct a novel nonlocal transport model that describes the evolution of microtubules (MTs) as they interact with stationary distributions of motor proteins. An advection term accounts for directed MT transport (sliding due to motor protein action), and an integral term accounts for reorientation of MTs due to their interactions with cross-linking motor proteins. Simulations of our model show how MT patterns depend on boundary constraints, as well as model parameters that represent motor speed, cross-linking capability (motor activity), and directionality. In large domains, and using motor parameter values consistent with experimentally-derived values, we find that patterns such as asters, vortices, and bundles are able to persist. In vivo, MTs take on aster patterns during interphase and they form bundles in neurons and polarized epithelial cells. Vortex patterns have not been observed in vivo, however, are found in in vitro experiments. In constrained domains, we find that similar patterns form (asters, bundles, and vortices). However, we also find that when two opposing motors are present, anti-parallel bundles are able to form, resembling the mitotic spindle during cell division. This model demonstrates how MT sliding and MT reorientation are sufficient to produce experimentally observed patterns. PMID- 25033783 TI - Bivalent associations in Mus domesticus 2n = 40 spermatocytes. Are they random? AB - The establishment of associations between bivalents from Mus domesticus 2n = 40 spermatocytes is a common phenomenon that shows up during the first prophase of meiotic nuclei. In each nucleus, a seemingly random display of variable size clusters of bivalents in association is observed. These associations originate a particular nuclear architecture and determine the probability of encounters between chromosome domains. Hence, the type of randomness in associations between bivalents has nontrivial consequences. We explore different models for randomness and the associated bivalent probability distributions and find that a simple model based on randomly coloring a subset of vertices of a 6-regular graph provides best agreement with microspreads observations. The notion of randomness is thereby explained in conjunction with the underlying local geometry of the nuclear envelope. PMID- 25033785 TI - Noise measurement in total knee arthroplasty. AB - Few studies have been performed to analyze noise levels produced by various surgical instruments in the operating room (OR). The highest levels of noise that have been described were due to instruments used for total knee arthroplasty (TKA). These high levels of noise might be a potential health hazard for patients and medical staff. Therefore, we aimed to measure noise levels of current instruments that are widely used worldwide. During a conventional primary TKA the levels of noise in the OR were measured using a Class 1 integrating-averaging sound level meter. The highest A-weighted equivalent level was produced when using a hammer during the implantation of the femoral and tibial components with 90.2 dBA. In total surgical instruments were used for about 10% of the total time of surgery. Noise exposure due to instrument use during TKA does not seem to be a potential health hazard for medical staff or patients. PMID- 25033784 TI - Noise-related sleep disturbances: does gender matter? AB - Women sleep differently and report differently about sleep disturbances than men. However, it is unclear whether the sleep of women and men is affected differently by traffic noise exposure. We aimed to address gender specific noise effects by using objective and subjective exposure measures as well as objective and subjective outcome data. In a questionnaire survey conducted in 2008 including 733 women and 533 men from Basel, Switzerland, with follow-up 1 year later, we collected data on subjective sleep disturbances and annoyance to road traffic noise. Objective noise exposure data was obtained using validated propagation models. In a nested diary study with 119 participants, objective sleep efficiency and sleep duration was measured by means of actigraphic devices for 1551 nights. Data were analyzed using random intercept mixed-effects multilevel regression models adjusted for relevant confounding factors. Objectively measured sleep duration in highly exposed men (>55 dB) was reduced by 1.5 h (95% confidence interval [CI]: 2.3-0.8 h) compared with low exposed men (<30 dB). No noise effect on sleep duration was observed in women. The association of modeled noise exposure with self-reported sleep quality rating was also more pronounced in men (-0.8 unit, 95% CI: -1.4 to -0.2) than in women (-0.3 unit, 95% CI: -0.8 to 0.2). However, in highly annoyed women reduction in sleep quality and well-being rating tended to be stronger than in highly annoyed men. Our study provides some indications that noise exposure affects men's sleep differently than women's sleep, which may have distinct long-term health consequences. PMID- 25033786 TI - Factoid forensics: have "more than 40" Australian families abandoned their homes because of wind farm noise? AB - Anti-wind farm activists repeatedly claim that families said to be adversely affected by noise from wind turbines "abandon" their homes. In Australia, a claim of "more than 40 families" has been made by a prominent anti-wind farm activist. Six sources (parliamentary submissions, media reports, an anti-wind farm website, wind industry sources, correspondence with known anti-wind farm activists and with three politicians opposed to wind farms) were used to find evidence of home "abandonments." Claims about 12 Australian households permanently (n = 10) or periodically (n = 2) leaving their homes were found. However, no house appears to have been permanently "abandoned" without sale, as the expression implies. These 12 cases need contextualizing against considerations that several of those involved were either dedicated activists against wind farms from times sometimes pre-dating their construction, were engaged in protracted negotiations for home purchase with wind companies, had pre-existing health problems, grievances with the wind company over employment or had left the area for unrelated reasons of employment elsewhere. The statement that "more than 40" houses have been "abandoned" because of wind turbines in Australia is a factoid promoted by wind farm opponents for dramatic, rhetorical impact. Other considerations are often involved in abandonment unrelated to the claims made about wind farm noise. PMID- 25033787 TI - Effects of high frequency noise on female rat's multi-organ histology. AB - To investigate the pathological damage of high-frequency stable noise exposure on the brain, heart, liver, and spleen of female rat's. Controlled animal intervention study. Twenty female Sprague-Dawley rats were randomly divided into experimental and control groups with 10 rats in each group. Rats in the experimental group were exposed to continuous high-frequency stable noise for 2 weeks (3 h/day)followed by the pathological damages in the rat's brain, heart, liver, and spleen were compared with those of the control group. After 2 weeks' continuous exposure to high-frequency stable noise, compared with the control group, the most prominent histopathologic changes in the brain tissue structures of the experimental group included loose disorder, hyperemia, edema, blood vessels expand, glial cell hyperplasia, mild atypia in some areas (hyperchromatic nuclei, irregular karyotype), and no degeneration and necrosis. There were dilatation and congestion of central vein, hepatic sinus, and interlobular veins of liver tissue. The structure of hepatic lobule was destroyed by inflammatory cell infiltration, as well as lymphoid nodule formation. There was hyperemia in spleen, but the structure was clear. There was extravasated blood, and the splenic sinuses were highly expanded by a blood clot. Hyperplasias of the lymphoid of white pulp were also active. There was dilation and congestion in myocardial interstitial vascular, and there was mild degeneration and hyperemia in myocardial cells. No hemorrhage and myocardial necrosis were observed. High frequency stable noise can cause pathological damage in brain, liver, spleen, and heart tissues of female rat at a various degree. PMID- 25033788 TI - Chinese-adapted youth attitude to noise scale: evaluation of validity and reliability. AB - Noise exposure is central to hearing impairment, especially for adolescents. Chinese youth frequently and consciously expose themselves to loud noise, often for many hours. Hence, a Chinese-adapted evaluative scale to measure youth's attitude toward noise could rigorously evaluate data validity and reliability. After authenticating the youth attitude to noise scale (YANS) originally developed by Olsen and Erlandsson, we purposively sampled and surveyed 642 freshmen at Capital Medical University in Beijing, China. To establish validity, we conducted confirmatory factor analysis according to Olsen's classification. To establish reliability, we calculated Cronbach's alpha coefficient and split-half coefficient. We used Bland-Altman analysis to calculate the agreement limits between test and retest. Among 642 students, 550 (85.67%) participated in statistical analysis (399 females [72.55%] vs. 151 males [27.45%]). Confirmatory factorial analysis sorted 19 items into four main subcategories (F1-F4) in terms of factor load, yielding a correlation coefficient between factors <0.40. The Cronbach's alpha coefficient (0.70) was within the desirable range, confirming the reliability of Chinese-adapted YANS. The split-half coefficient was 0.53. Furthermore, the paired t-test reported a mean difference of 0.002 (P = 0.9601). Notably, the mean overall YANS score (3.46) was similar to YANS testing in Belgium (3.10), but higher than Sweden (2.10) and Brazil (2.80). The Chinese version of the YANS questionnaire is valid, reliable, and adaptable to Chinese adolescents. Analysis of the adapted YANS showed that a significant number of Chinese youth display a poor attitude and behavior toward noise. Therefore, Chinese YANS can play a pivotal role in programs that focus on increasing youth awareness of noise and hearing health. PMID- 25033789 TI - Comparison of the effects of N-acetyl-cysteine and ginseng in prevention of noise induced hearing loss in male textile workers. AB - Previous studies revealed the role of antioxidant agents in prevention of noise induced hearing loss (NIHL). The aim of this study was to compare the protective effect of N-acetyl-cysteine (NAC) and ginseng on protection of NIHL in textile workers exposed to continuous noise in daily working. In this study, 48 participants were randomly allocated to three groups; Group I received NAC 1200 mg/day, Group II received ginseng 200 mg/day, and Group III (control group) received no supplement. Pure tone audiometry and high frequency audiometry were performed preshift before and after 14 days (on day 15). Linear regression analysis results showed reduced noise-induced temporary threshold shift (TTS) for NAC and ginseng groups at 4, 6 and 16 kHz (P < 0.001) in both ears. Furthermore, the protective effects were more prominent in NAC than ginseng. Our results show that NAC and ginseng can reduce noise induced TTS in workers exposed to occupational noise. Further studies are needed to prove antioxidants benefits in hearing conservation programs. PMID- 25033790 TI - Evaluation of community response to wind turbine-related noise in western New York state. AB - As the boundaries of harvesting wind energy expand to meet the ever-increasing societal energy demands, the number and size of wind turbines being constructed rises. As part of a larger project to monitor sound in an operating wind park in western New York State, a cross-sectional survey was conducted among individuals living in and around the wind park to characterize the perception, level of annoyance, and self-reported health effects of residents. We conducted the study in a 126 MW wind park consisting of 84 turbines spanning approximately 19 square miles of farmland. Short-term outdoor and indoor sound level measurements were also performed at each dwelling in which a questionnaire was administered. To our knowledge, this study is the first to collect sound measurements at individual residences. There was no apparent exposure-response relationship between an individual's level of annoyance and the short duration sound measurements collected at the time of the survey. There was a correlation between an individual's concern regarding health effects and the prevalence of sleep disturbance and stress among the study population. The siting process is unique to each community with varying degrees of success. Additional sound level measurements inside and outside homes in larger cohorts in concert with detailed questionnaires would be useful in verifying those exposure-response relationships found in studies using calculated sound level data. Additional research should include a detailed investigation of sleep patterns and possible disturbance in those living in and near operating wind turbine projects. PMID- 25033791 TI - The effect on recognition memory of noise cancelling headphones in a noisy environment with native and non-native speakers. AB - Noise has the potential to impair cognitive performance. For nonnative speakers, the effect of noise on performance is more severe than their native counterparts. What remains unknown is the effectiveness of countermeasures such as noise attenuating devices in such circumstances. Therefore, the main aim of the present research was to examine the effectiveness of active noise attenuating countermeasures in the presence of simulated aircraft noise for both native and nonnative English speakers. Thirty-two participants, half native English speakers and half native German speakers completed four recognition (cued) recall tasks presented in English under four different audio conditions, all in the presence of simulated aircraft noise. The results of the research indicated that in simulated aircraft noise at 65 dB(A), performance of nonnative English speakers was poorer than for native English speakers. The beneficial effects of noise cancelling headphones in improving the signal to noise ratio led to an improved performance for nonnative speakers. These results have particular importance for organizations operating in a safety-critical environment such as aviation. PMID- 25033792 TI - Noise pollution: recent challenges in Indian scenario. PMID- 25033793 TI - Effect of noise on the health of bus drivers. PMID- 25033794 TI - Accuracy of point-of-care serum creatinine devices for detecting patients at risk of contrast-induced nephropathy: a critical overview. AB - Contrast-induced nephropathy (CIN) is a common event in hospitals, with reported incidences ranging from 1 to 30%. Patients with underlying kidney disease have an increased risk of developing CIN. Point-of-care (POC) creatinine devices are handheld devices capable of providing quantitative data on a patient's kidney function that could be useful in stratifying preventive measures. This overview aims to synthesize the current evidence on diagnostic accuracy and clinical utility of POC creatinine devices in detecting patients at risk of CIN. Five databases were searched for diagnostic accuracy studies or clinical trials that evaluated the usefulness of POC devices in detecting patients at risk of CIN. Selected articles were critically appraised to assess their individual risk of bias by the use of standard criteria; 13 studies were found that addressed the diagnostic accuracy or clinical utility of POC creatinine devices. Most studies incurred a moderate to high risk of bias. Overall concordance between POC devices and reference standards (clinical laboratory procedures) was found to be moderate, with 95% limits of agreement often lying between -35.4 and +35.4 umol/L (-0.4 and +0.4 mg/dL). Concordance was shown to decrease with worsening kidney function. Data on the clinical utility of these devices were limited, but a significant reduction in time to diagnosis was reported in two studies. Overall, POC creatinine devices showed a moderate concordance with standard clinical laboratory creatinine measurements. Several biases could have induced optimism in these estimations. Results obtained from these devices may be unreliable in cases of severe kidney failure. Randomized trials are needed to address the clinical utility of these devices. PMID- 25033795 TI - An alternative to current psychiatric classifications: a psychological landscape hypothesis based on an integrative, dynamical and multidimensional approach. AB - BACKGROUND: Mental disorders as defined by current classifications are not fully supported by scientific evidence. It is unclear whether main disorders should be broken down into separate categories or disposed along a continuous spectrum. In the near future, new classes of mental disorders could be defined through associations of so-called abnormalities observed at the genetic, molecular and neuronal circuitry levels. METHODS: We propose an alternative hypothesis to these classifications based on an integrative, dynamical and multidimensional approach. RESULTS: We suggest that observed data collected in the general population can be used to build a psychological landscape. Innovative techniques issued from information processing and system dynamics can prove helpful in this task. Information preserving techniques can reduce the high dimensional data collected and provide an intrinsic map for psychological characteristics or behaviors. Dynamical patterns called attractors, which are linked to each other through continuous pathways, can be identified. Specific attractors can define mental disorders. Their causal structure can be investigated with causal networks. CONCLUSIONS: Powerful and reliable tools are available so that an alternative to current psychiatric classifications can be built based on a genuine biopsychosocial model. The proposed model is ready to be tested on real data. PMID- 25033796 TI - Exploring the experiences of client involvement in medication decisions using a shared decision making model: results of a qualitative study. AB - This qualitative study explored a newly introduced model of shared decision making (CommonGround) and how psychiatric medications were experienced by clients, prescribers, case managers and peer support staff. Of the twelve client subjects, six were highly engaged in shared decision-making and six were not. Five notable differences were found between the two groups including the presence of a goal, use of personal medicine, and the behavior of case managers and prescribers. Implications for a shared decision making model in psychiatry are discussed. PMID- 25033797 TI - Clinical features of patients of different ages with postoperative multi-space maxillofacial infection. AB - To investigate the clinical features of patients of different ages with multi space infection after maxillofacial surgery. Three hundred and seven patients with infections in multiple spaces were enrolled in the study. They were classified into the senior (n = 149) and the younger group (n = 158). The clinic data were retrospectively analyzed. Male patients accounted for 63.09 and 63.29 % of the senior and the younger group, respectively. Sex composition between the two groups was not significantly different (p > 0.05). Senior patients were associated with significantly more complications than the younger adults (p < 0.05). 46.31 and 55.70 % of patients in the respective two groups had infections involving more than two spaces. Patients in both groups visited the hospital at a similar time after the symptoms manifested (p > 0.05). Elderly patients had similar glucose levels, white blood cell counts and neutrophil cell counts compared to those of the younger groups (p > 0.05). 55.06 % of the younger patients had negative bacterial culture results, which was significantly more than those of the senior groups (p < 0.05). The bacterial compositions of the infection of two groups were also found significantly different (p < 0.05). In the event of postoperative multi-space maxillofacial infection, senior patients shared many similar clinical features with the younger adults. But they also had unique features, such as more complications. As a result, it is more difficult to treat senior patients with multi-space infections. Therefore, more medical attention is required to senior patients. PMID- 25033798 TI - The Ras superfamily G-proteins. AB - The Ras superfamily G-proteins are monomeric proteins of approximately 21kDa that act as a molecular switch to regulate a variety of cellular processes. The structure of the Ras superfamily G-proteins, their regulators as well as posttranslational modification of these proteins leading to their membrane association have been elucidated. The Ras superfamily G-proteins interact at their effector domains with their downstream effectors via protein-protein interactions. Mutational activation or overexpression of the Ras superfamily G proteins has been observed in a number of human cancer cases. Over the years, a variety of approaches to inhibit the Ras superfamily G-proteins have been developed. These different approaches are discussed in this volume. PMID- 25033799 TI - NMR study to identify a ligand-binding pocket in Ras. AB - Despite decades of intense drug discovery efforts, to date no small molecules have been described that directly bind to Ras protein and effectively antagonize its function. In order to identify and characterize small-molecule binders to KRas, we carried out a fragment-based lead discovery effort. A ligand-detected primary nuclear magnetic resonance (NMR) screen identified 266 fragments from a library of 3285 diverse compounds. Protein-detected NMR using isotopically labeled KRas protein was applied for hit validation and binding site characterization. An area on the KRas surface emerged as a consensus site of fragment binding. X-ray crystallography studies on a subset of the hits elucidated atomic details of the ligand-protein interactions, and revealed that the consensus site comprises a shallow hydrophobic pocket. Comparison among the crystal structures indicated that the ligand-binding pocket is flexible and can be expanded upon ligand binding. The identified ligand-binding pocket is proximal to the protein-protein interface and therefore has the potential to mediate functional effects. Indeed, some ligands inhibited SOS1-dependent nucleotide exchange, although with weak potency. Several Ras ligands have been published in literature, the majority of which were discovered using NMR-based methods. Mapping of the ligand-binding sites revealed five areas on Ras with a high propensity for ligand binding and the potential of modulating Ras activity. PMID- 25033800 TI - The allosteric switch and conformational states in Ras GTPase affected by small molecules. AB - Ras is a hub protein in signal transduction pathways leading to the control of cell proliferation, migration, and survival and a major target for drug discovery due to the presence of its mutants in about 20% of human cancers. Yet, the discovery of small molecules that can directly interfere with its function has been elusive in spite of intense efforts. This is most likely due to its highly flexible nature and the lack of a well-ordered active site. This chapter contains a discussion of our current understanding of conformational states in Ras-GTP, with focus on a recently discovered allosteric switch mechanism that may promote intrinsic hydrolysis of GTP in the presence of Raf. We discuss the manner in which small molecules are known to affect the equilibrium of states in Ras-GTP and suggest novel strategies to go forward in the search for inhibitors of this master signaling protein. PMID- 25033801 TI - State 1(T) inhibitors of activated Ras. AB - Oncogenic mutations in the Ras (rat sarcoma) protein lead to a permanent activation of the Ras pathway and are found in approximately 30% of all human tumors. During signal transduction, Ras is transiently activated by GTP binding and interacts with effector proteins such as Raf kinase. Ras complexed with GTP (T) occurs in at least two conformational states, states 1(T) and 2(T), where state 2(T) represents the true effector-interaction state and state 1(T) has only a low affinity for effectors. Stabilization of state 1(T) by small molecules such as metal-cyclens can reduce the affinity for effectors and thus it can lead to an interruption of the signal transduction chain. Metal-cyclens bind inside the nucleotide-binding pocket to GTP, shifting the conformational equilibrium of Ras toward state 1(T). In contrast, Zn(2+)-BPA (bis(2-picolyl)amine) binds outside the nucleotide-binding pocket but nevertheless allosterically stabilizes state 1(T) and thus inhibits Raf interaction. It shows a higher affinity for the oncogenic mutant Ras(G12V) than for wild type in contrast to other compounds such as Zn(2+)-cyclen. PMID- 25033802 TI - Sugar-based inhibitors of Ras activation: biological activity and identification of Ras-inhibitor binding interface. AB - Inhibition of oncogenic Ras activation through small molecules is a promising approach to the pharmacologic treatment of human tumors. A common strategy to block Ras activation and signal transduction is based on molecules that interfere with the guanine exchange factors (GEF)-promoted nucleotide exchange. We developed several generations of small molecules active in inhibiting Ras activation at low micromolar concentrations. Some of these compounds are more active on cell lines expressing oncogenic Ras than on normal cells and are therefore good hit compounds for anticancer drug development. The molecules belonging to the last generation are soluble in water and allowed the identification of binding site on Ras by means of NMR experiments in deuterated water. The experimentally-determined Ras-binding site comprises residues belonging to the alpha-2 helix and the beta-3 strand of the central beta-sheet in the Switch 2 region. Synthetic molecules bind Ras in a region belonging to the more extended Ras/GEF-binding site, and a possible mechanism of Ras inhibition by these compounds can be the blockade of GEF-mediated nucleotide exchange. PMID- 25033803 TI - Development of EHop-016: a small molecule inhibitor of Rac. AB - The Rac inhibitor EHop-016 was developed as a compound with the potential to inhibit cancer metastasis. Inhibition of the first step of metastasis, migration, is an important strategy for metastasis prevention. The small GTPase Rac acts as a pivotal binary switch that is turned "on" by guanine nucleotide exchange factors (GEFs) via a myriad of cell surface receptors, to regulate cancer cell migration, survival, and proliferation. Unlike the related GTPase Ras, Racs are not usually mutated, but overexpressed or overactivated in cancer. Therefore, a rational Rac inhibitor should block the activation of Rac by its upstream effectors, GEFs, and the Rac inhibitor NSC23766 was developed using this rationale. However, this compound is ineffective at inhibiting the elevated Rac activity of metastatic breast cancer cells. Therefore, a panel of small molecule compounds were derived from NSC23766 and screened for Rac activity inhibition in metastatic cancer cells. EHop-016 was identified as a compound that blocks the interaction of Rac with the GEF Vav in metastatic human breast cancer cells with an IC50 of ~1MUM. At higher concentrations (10MUM), EHop-016 inhibits the related Rho GTPase Cdc42, but not Rho, and also reduces cell viability. Moreover, EHop 016 inhibits the activation of the Rac downstream effector p21-activated kinase, extension of motile actin-based structures, and cell migration. Future goals are to develop EHop-016 as a therapeutic to inhibit cancer metastasis, either individually or in combination with current anticancer compounds. The next generation of EHop-016-based Rac inhibitors is also being developed. PMID- 25033804 TI - Aptamer-derived peptide inhibitors of Rho guanine nucleotide exchange factors. AB - Small G proteins of the Rho family and their activators the guanine nucleotide exchange factors (RhoGEFs) regulate essential cellular functions and their deregulation has been associated with an amazing variety of human disorders, including cancer, inflammation, vascular diseases, and mental retardation. Rho GTPases and RhoGEFs therefore represent important targets for inhibition, not only in basic research but also for therapeutic purposes, and strategies to inhibit their function are actively being sought. Our lab has been very active in this field and has used the peptide aptamer technology to develop the first RhoGEF inhibitor, using the RhoGEF Trio as a model. Trio function has been described mainly in cell motility and axon growth in the nervous system via Rac1 GTPase activation, but recent findings suggest it to play also a role in the aggressive phenotype of various cancers, making it an attractive target for drug discovery. The object of this chapter is to demonstrate that targeting a RhoGEF using the peptide aptamer technology represents a valid and efficient approach to inhibit cellular processes in which Rho GTPase activity is upregulated. This is illustrated here by the first description of a peptide inhibitor of the oncogenic RhoGEF Tgat, TRIP(E32G), which is functional in vivo. On a long-term perspective, these peptide inhibitors can also serve as therapeutic tools or as guides for the discovery of small-molecule drugs, using an aptamer displacement screen. PMID- 25033805 TI - Targeting the Dbl and dock-family RhoGEFs: a yeast-based assay to identify cell active inhibitors of Rho-controlled pathways. AB - The Ras-like superfamily of low molecular weight GTPases is made of five major families (Arf/Sar, Rab, Ran, Ras, and Rho), highly conserved across evolution. This is in keeping with their roles in basic cellular functions (endo/exocytosis, vesicular trafficking, nucleocytoplasmic trafficking, cell signaling, proliferation and apoptosis, gene regulation, F-actin dynamics), whose alterations are associated with various types of diseases, in particular cancer, neurodegenerative, cardiovascular, and infectious diseases. For these reasons, Ras-like pathways are of great potential in therapeutics and identifying inhibitors that decrease signaling activity is under intense research. Along this line, guanine exchange factors (GEFs) represent attractive targets. GEFs are proteins that promote the active GTP-bound state of GTPases and represent the major entry points whereby extracellular cues are converted into Ras-like signaling. We previously developed the yeast exchange assay (YEA), an experimental setup in the yeast in which activity of a mammalian GEF can be monitored by auxotrophy and color reporter genes. This assay was further engineered for medium-throughput screening of GEF inhibitors, which can readily select for cell-active and specific compounds. We report here on the successful identification of inhibitors against Dbl and CZH/DOCK-family members, GEFs for Rho GTPases, and on the experimental setup to screen for inhibitors of GEFs of the Arf family. We also discuss on inhibitors developed using virtual screening (VS), which target the GEF/GTPase interface with high efficacy and specificity. We propose that using VS and YEA in combination may represent a method of choice for identifying specific and cell-active GEF inhibitors. PMID- 25033806 TI - Inhibitors of the ROCK serine/threonine kinases: key effectors of the RhoA small GTPase. AB - Aberrant activation of the RhoA small GTPase has been implicated in cancer and other human diseases. Therefore, inhibitors of RhoA may have important therapeutic value. However, similar to the Ras small GTPases, RhoA itself is not considered a tractable target and is currently considered to be "undruggable." While recent efforts suggest that direct inhibitors of the Ras oncoprotein may yet be developed, the most promising directions for anti-Ras inhibitors involve inhibitors of protein kinases that are activated downstream of Ras. By analogy, protein kinases activated downstream of RhoA may provide more attractive directions for the development of anti-RhoA inhibitors. Among the multitude of RhoA effectors, the ROCK serine/threonine kinases have emerged as attractive targets for anti-RhoA drug discovery. In this review, we summarize the current status of the development of small molecule inhibitors of ROCK. PMID- 25033807 TI - A two-hybrid approach to identify inhibitors of the RAS-RAF interaction. AB - MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma. PMID- 25033808 TI - Inhibitors of K-Ras plasma membrane localization. AB - Oncogenic mutant K-Ras is highly prevalent in multiple human tumors. Despite significant efforts to directly target Ras activity, no K-Ras-specific inhibitors have been developed and taken into the clinic. Since Ras proteins must be anchored to the inner leaflet of the plasma membrane (PM) for full biological activity, we devised a high-content screen to identify molecules with ability to displace K-Ras from the PM. Here we summarize the biochemistry and biology of three classes of compound identified by this screening method that inhibit K-Ras PM targeting: staurosporine and analogs, fendiline, and metformin. All three classes of compound significantly abrogate cell proliferation and Ras signaling in K-Ras-transformed cancer cells. Taken together, these studies provide an important proof of concept that blocking PM localization of K-Ras is a tractable therapeutic target. PMID- 25033809 TI - Ras chaperones: new targets for cancer and immunotherapy. AB - The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib(r)) interferes with Ras membrane interactions that are crucial for Ras-dependent signaling and cellular transformation. FTS had been successfully evaluated in clinical trials of cancer patients. Interestingly, its effect is mediated by targeting Ras chaperones that serve as key coordinators for Ras proper folding and delivery, thus offering a novel target for cancer therapy. The development of new FTS analogs has revealed that the specific modifications to the FTS carboxyl group by esterification and amidation yielded compounds with improved growth inhibitory activity. When FTS was combined with additional therapeutic agents its activity toward Ras was significantly augmented. FTS should be tested not only in cancer but also for genetic diseases associated with abnormal Ras signaling, as well as for various inflammatory and autoimmune disturbances, where Ras plays a major role. We conclude that FTS has a great potential both as a safe anticancer drug and as a promising immune modulator agent. PMID- 25033810 TI - Preface. PMID- 25033812 TI - Influence of the formulations in removing eggs of Pediculus humanus capitis (Phthiraptera: Pediculidae). AB - Head lice lay eggs in human head hairs in order to reproduce. There is a difficulty associated to the process of detaching these eggs: they are tightly gripped to the hair by a secretion produced by female head lice. The physical removal of eggs has become an important part of treatment of louse infestations. The finding of new products to loosen the eggs is necessary to avoid mistaken diagnosis or reinfestations. This work aimed to compare different kinds of pediculicide formulations in order to find if their presentations represented differences in the egg remover effect. We also wanted to present a new device to test the efficacy of the egg remover formulations. Products with creamy presentations (Bio infant lice and egg remover and hair conditioner) and one containing dimethicone (Nyda) showed the lower mean forces compared with the control (lower mean forces represented best removal activity). Whereas, the Biferdil egg remover (gel) and Nopucid Tribit (hydroalcoholic lotion) had no egg removal effect, presenting the highest mean forces (177.82 and 189.99 mN, respectively) compared with the control. Additionally, we proposed a removal index (RI) to compare the efficacy of different products on the egg removal activity (RI > 0, good performance). The higher index values were for Bio infant lice and egg remover (0.72) and Biferdil hair conditioner (0.58). The lowest index values were for Biferdil egg remover (-0.26) and Nopucid Tribit (-0.35).The formulation of over the counter pediculicides in the egg remover effect was discussed. PMID- 25033811 TI - Analysis of the population genetics of Opisthorchis viverrini sensu lato in the Nam Ngum River wetland, Lao PDR, by multilocus enzyme electrophoresis. AB - A previous population genetics study of Opisthorchis viverrini from a locality in an endemic area in Thailand found little genetic variation over time and second intermediate fish host species. Since a similar comparative analysis is not available for Lao PDR, we conducted a study of O. viverrini from different endemic foci in Vientiane Province, Lao PDR, based on spatial, temporal and fish host species. A total of 620 adult O. viverrini originating from the Nam Ngum River wetland were analysed at five previously defined polymorphic enzyme loci. Of these worms, 252 were from six different localities (spatial samples), 162 worms from different years (temporal samples) and 206 worms from four different cyprinid fish species. Significant heterozygote deficiency was found in most O. viverrini populations with levels of genetic differentiation ranging between F ST 0.0000 and 0.0197 suggesting that gene flow occurred at a variable rate. The role of temporal factors and fish host species had little influence on the level of genetic differentiation. As for O. viverrini from Thailand, these findings indicate that self-fertilization and/or a clonal distribution of O. viverrini occurs in Lao PDR. Unlike the results for O. viverrini from Thailand, spatial population substructuring may be the underlying population processes for O. viverrini in Lao PDR. These findings indicate that geographical variation may contribute to the transmission dynamics of the parasite with implications for parasite control. However, other host factors, such as snail intermediate hosts and mammal reservoir hosts, as well as human beings, may also play significant roles. PMID- 25033813 TI - Acaricide activity in vitro of Acmella oleracea against Rhipicephalus microplus. AB - Cattle tick control has been limited by the resistance of these parasites to synthetic acaricides. Natural products are a possible alternative as they have different mechanisms of action. Acmella oleracea is a native plant with a large cultivated area in the Amazon region and could be easily used for large-scale preparation of a commercial product. This study evaluated the in vitro action of the hexane extract of the aerial parts of A. oleracea on larvae and engorged females of the cattle tick Rhipicephalus microplus. Spilanthol was the major constituent with a content of 14.8% in the extract. The hexane extract of A. oleracea was highly effective against larvae of R. microplus with an LC50 of 0.8 mg mL(-1). Against engorged females, hexane extract of A. oleracea reduced oviposition and hatchability of eggs with an LC50 of 79.7 mg mL(-1). Larvae and engorged females were killed by the hexane extract with high efficiency (>95%) at concentrations of 3.1 and 150.0 mg mL(-1), respectively. These results demonstrate that the hexane extract of A. oleracea has significant activity against R. microplus and has potential to be developed into formulations for tick control. PMID- 25033814 TI - Prevalence and geographic distribution of Besnoitia besnoiti infection in cattle herds in Portugal. AB - Bovine besnoitiosis, caused by the apicomplexan parasite Besnoitia besnoiti is considered an emergent disease in Europe. This study aimed to determine the prevalence and geographic distribution of B. besnoiti in cattle herds in continental Portugal and to identify potential spatial clustering of infection. A stratified two-stage cross-sectional serological survey was carried out between March 2012 and May 2013 with the five administrative NUTS II regions, Norte, Centro, Lisboa, Alentejo, and Algarve, as the stratification level. Sera from 391 herds in 220 parishes and 83 municipalities were analyzed by a serial testing strategy, with the modified agglutination test (B-MAT) as the first screening assay and the immunofluorescent antibody test (IFAT) as the confirmatory test. Within-herd prevalence of positive herds varied between 0.7 and 72.4% and was >=10.3% in half of the infected herds. Using a Bayesian approach, the true prevalence of B. besnoiti in cattle herds was determined to be 5.1% (confidence interval (CI), 3.1-7.8%) and the mean within-herd prevalence of positive herds was 33.0% (CI, 20.3-46.0%). The sensitivity and specificity of the B-MAT were estimated to be 96.9% (CI, 93.7-98.8 %) and 99.7% (CI, 99.6-99.8%), whereas those of the IFAT were 89.6% (CI, 86.0-92.5%) and 99.7% (CI, 98.5-99.9%), respectively. Spatial scan statistics analysis identified one spatial cluster covering the majority of the Alentejo region. Seropositive herds were detected for the first time outside Alentejo, in the region Centro and in the northeast of Portugal. Further epidemiological research is needed to identify eco-biological factors, which could explain the geographic clustering of B. besnoiti in Portugal. PMID- 25033815 TI - Effect of Polygonum hydropiper L. against dengue vector mosquito Aedes albopictus L. AB - The present study aimed to evaluate the essential oil and an isolated compound from the leaves of Polygonum hydropiper L. against dengue vector mosquito Aedes albopictus L. The plant material was macerated and steam distilled using clavenger apparatus for oil extraction. The essential oil was tested at different concentrations of 100, 50, 25, 12.5 and 6.25 ppm concentrations against the larvae of Ae. albopictus. The isolated compound was tested for larvicidal, ovicidal, repellent, oviposition deterrent and adulticidal activities at 10, 5, 2.5, 1.25 and 0.625 ppm concentrations. The essential oil exhibited LC50 values of 194.63 and 199.65 and confertifolin exhibited LC50 values of 2.02 and 3.16 against the second and fourth instar larvae of Ae. albopictus, respectively. The ovicidal activity of 100% on 0- to 6-h-old eggs, repellent activity of 320.6 min, oviposition deterrent activity of 98.51% and adulticidal activity of 100% at 10 ppm concentration of confertifolin were recorded. No mortality of was observed in negative control. To the best of our knowledge, this is the first report on the potential mosquitocidal activities of confertifolin against Ae. albopictus. PMID- 25033816 TI - Some secrets are revealed: parasitic keratitis amoebae as vectors of the scarcely described pandoraviruses to humans. AB - In this article, the results of a long effort to derive valuable phylogenetic data about an extraordinary spore-like infectious particle (endocytobiont) within host amoebae (Acanthamoeba sp.) recently isolated from the contact lens and the inflamed eye of a patient with keratitis are presented. The development of these endocytobionts has already been demonstrated with electron microscopic photo sequences, leading to a relevant model of its development presented here. The molecular biological investigation following the discovery of two other Pandoravirus species within aquatic sediments in 2013 led to the taxonomic affiliation of our endocytobiont with the genus Pandoravirus. A range of endocytobionts (intracellular biofilms) have been found in recent years, among which are several viruses which obligatorily proliferate within free-living amoebae. In human medicine, foreign objects which are placed in or on humans cause problems with microorganisms in biofilms. Contact lenses are especially important, because they are known as a source of a rapid formation of biofilm. These were the first Pandoraviruses described, and because this is additionally the first documented association with humans, we have clearly demonstrated how easily such (viral) endocytobionts can be transferred to humans. This case counts as an example of parasites acting as vectors of phylogenetically different microorganisms especially when living sympatric within their biocoenosis of biofilms. As the third part of the "Pandoravirus trilogy", it finally reveals the phylogenetic nature of these "extraordinary endocytobionts" within Acanthamoebae. PMID- 25033817 TI - Condom use and intimacy among Tajik male migrants and their regular female partners in Moscow. AB - This study examined condom use and intimacy among Tajik male migrants and their regular female partners in Moscow, Russia. This study included a survey of 400 Tajik male labour migrants and longitudinal ethnographic interviews with 30 of the surveyed male migrants and 30 of their regular female partners. of the surveyed male migrants, 351 (88%) reported having a regular female partner in Moscow. Findings demonstrated that the migrants' and regular partners' intentions to use condoms diminished with increased intimacy, yet each party perceived intimacy differently. Migrants' intimacy with regular partners was determined by their familiarity and the perceived sexual cleanliness of their partner. Migrants believed that Muslim women were cleaner than Orthodox Christian women and reported using condoms more frequently with Orthodox Christian regular partners. Regular partners reported determining intimacy based on the perceived commitment of the male migrant. When perceived commitment faced a crisis, intimacy declined and regular partners renegotiated condom use. The association between intimacy and condom use suggests that HIV-prevention programmes should aim to help male migrants and female regular partners to dissociate their approaches to condom use from their perceptions of intimacy. PMID- 25033818 TI - Experimental and theoretical studies on the molecular properties of ciprofloxacin, norfloxacin, pefloxacin, sparfloxacin, and gatifloxacin in determining bioavailability. AB - The aim of this investigation is to identify, by in silico and in vitro methods, the molecular determinants, e.g., solubility in an aqueous medium and lipophilic properties, which have an effect on the bioavailability of five selected fluoroquinolones. These properties were estimated by analysis of the electrostatic potential pattern and values of free energy of solvation as well as the partition coefficients of the studied compounds. The study is based on theoretical quantum-chemical methods and a simple experimental shake-flask technique with two immiscible phases, n-octanol and phosphate buffer. The solvation free energy values of compounds in both environments appeared to be negative. The wide range of electrostatic potential from negative to positive demonstrates the presence of dipole-dipole intermolecular interactions, while the high electron density at various sites indicates the possibility of hydrogen bond formation with solvent molecules. High partition coefficient values, obtained by summing the atomic contributions, did not take various correction factors into account and therefore were not accurate. Theoretical partition coefficient values based on more accurate algorithms, which included these correction factors (fragmental methods), yielded more accurate values. Theoretical methods are useful tools for predicting the bioavailability of fluoroquinolones. PMID- 25033819 TI - Correlation between dynamic contrast-enhanced MRI and quantitative histopathologic microvascular parameters in organ-confined prostate cancer. AB - OBJECTIVES: To correlate pharmacokinetic parameters of 3-T dynamic contrast enhanced (DCE-)MRI with histopathologic microvascular and lymphatic parameters in organ-confined prostate cancer. METHODS: In 18 patients with unilateral peripheral zone (pT2a) tumours who underwent DCE-MRI prior to radical prostatectomy (RP), the following pharmacokinetic parameters were assessed: permeability surface area volume transfer constant (K (trans)), extravascular extracellular volume (Ve) and rate constant (K ep). In the RP sections blood and lymph vessels were visualised immunohistochemically and automatically examined and analysed. Parameters assessed included microvessel density (MVD), area (MVA) and perimeter (MVP) as well as lymph vessel density (LVD), area (LVA) and perimeter (LVP). RESULTS: A negative correlation was found between age and K (trans) and K ep for tumour (r = -0.60, p = 0.009; r = -0.67, p = 0.002) and normal (r = -0.54, p = 0.021; r = -0.46, p = 0.055) tissue. No correlation existed between absolute values of microvascular parameters from histopathology and DCE-MRI. In contrast, the ratio between tumour and normal tissue (correcting for individual microvascularity variations) significantly correlated between K ep and MVD (r = 0.61, p = 0.007) and MVP (r = 0.54, p = 0.022). The lymphovascular parameters showed only a correlation between LVA and K ep (r = -0.66, p = 0.003). CONCLUSIONS: Significant correlations between DCE-MRI and histopathologic parameters were found when correcting for interpatient variations in microvascularity. KEY POINTS: * Normal prostate tissue shows strong heterogeneity in microvascularity. * Peripheral zone prostate cancer shows increased and less heterogeneous microvascularity. * Normal and tumour tissue shows considerable variation in microvascularity between patients. * DCE-MRI should take into account the interprostatic heterogeneity of microvasculature between patients. PMID- 25033820 TI - Biosynthesis of methylated resveratrol analogs through the construction of an artificial biosynthetic pathway in E. coli. AB - BACKGROUND: Methylated resveratrol analogs show similar biological activities that are comparable with those of the resveratrol. However, the methylated resveratrol analogs exhibit better bioavailability as they are more easily transported into the cell and more resistant to degradation. Although these compounds are widely used in human health care and in industrial materials, at present they are mainly obtained by extraction from raw plant sources. Accordingly their production can suffer from a variety of economic problems, including low levels of productivity and/or heterogeneous quality. On this backdrop, large-scale production of plant metabolites via microbial approaches is a promising alternative to chemical synthesis and extraction from plant sources. RESULTS: An Escherichia coli system containing an artificial biosynthetic pathway that produces methylated resveratrol analogues, such as pinostilbene (3,4' dihydroxy-5-methoxystilbene), 3,5-dihydroxy-4'-methoxystilbene, 3,4'-dimethoxy-5 hydroxystilbene, and 3,5,4'-trimethoxystilbene, from simple carbon sources is developed. These artificial biosynthetic pathways contain a series of codon optimized O-methyltransferase genes from sorghum in addition to the resveratrol biosynthetic genes. The E. coli cells that harbor pET-opTLO1S or pET-opTLO3S produce the one-methyl resveratrol analogues of 3,5-dihydroxy-4'-methoxystilbene and pinostilbene, respectively. Furthermore, the E. coli cells that harbor pET opTLO13S produce 3,5-dihydroxy-4'-methoxystilbene, bis-methyl resveratrol (3,4' dimethoxy-5-hydroxystilbene), and tri-methyl resveratrol (3,5,4' trimethoxystilbene). CONCLUSIONS: Our strategy demonstrates the first harness microorganisms for de novo synthesis of methylated resveratrol analogs used a single vector system joined with resveratrol biosynthetic genes and sorghum two resveratrol O-methyltransferase genes. Thus, this is also the first report on the production of the methylated resveratrol compounds bis-methyl and tri-methyl resveratrol (3,4'-dimethoxy-5-hydroxystilbene and 3,5,4'-trimethoxystilbene) in the E. coli culture. Thus, the production of the methylated resveratrol compounds was performed on the simple E. coli medium without precursor feeding in the culture. PMID- 25033821 TI - US sees no surge in new patient visits despite increase in health insurance. PMID- 25033822 TI - Undibacterium squillarum sp. nov., isolated from a freshwater shrimp culture pond. AB - A bacterial strain designated CMJ-15(T) was isolated from a freshwater shrimp culture pond in Taiwan and characterized using a polyphasic taxonomic approach. Cells of strain CMJ-15(T) were facultatively anaerobic, Gram-stain-negative and motile by a single polar flagellum and formed light-yellow colonies. Growth occurred at 20-40 degrees C (optimum, 25-30 degrees C), with 0-0.7% NaCl (optimum, 0-0.2%) and at pH 5.0-9.0 (optimum, pH 6.0-7.0). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain CMJ-15(T) belonged to the genus Undibacterium and its closest neighbour was Undibacterium oligocarboniphilum EM 1(T), with sequence similarity of 96.3%. The predominant cellular fatty acids were summed feature 3 (C16:1omega7c and/or C16:1omega6c), C16:0 and C18:1omega7c. The major cellular hydroxy fatty acid was C10:0 3-OH. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The polyamine profile was composed of the major compound putrescine and moderate amounts of 2-hydroxyputrescine. The major respiratory quinone was Q-8 and the DNA G+C content was 52.2 mol%. On the basis of these phylogenetic and phenotypic data, strain CMJ-15(T) should be classified as representing a novel species, for which the name Undibacterium squillarum sp. nov. is proposed. The type strain is CMJ-15(T) ( = BCRC 80404(T) = LMG 26892(T) = KCTC 23917(T)). PMID- 25033823 TI - Detection of West Nile virus and insect-specific flavivirus RNA in Culex mosquitoes, central Macedonia, Greece. AB - BACKGROUND: West Nile virus (WNV) emerged in central Macedonia, northern Greece, in 2010. The aim of the study was to test Culex mosquitoes for genetic detection of WNV and other flaviviruses, and to check whether the detection of WNV in mosquitoes was correlated with the occurrence of human WNV cases. METHODS: During 2013, 25 780 Culex spp. mosquitoes were collected from central Macedonia, grouped into 295 pools, according to collection site and date, and tested for the presence of flavivirus RNA. RESULTS: Thirteen (4.4%) pools were flavivirus positive. WNV lineage 2 was detected in nine (3.1%) pools, and insect-specific flaviviruses (ISFV) in four (1.4%). Three ISFV nucleotide sequences were 98% identical to Culex theileri flavivirus, previously detected in the Iberian peninsula, while the fourth sequence differed by >25% from all known flaviviruses. In most units of central Macedonia WNV detection in mosquitoes preceded the occurrence of human cases by approximately one month. CONCLUSIONS: Detection of WNV lineage 2 in mosquitoes for a fourth consecutive year suggests that the virus is established in Greece. Entomological surveillance provides an early warning system for the circulation of the virus. The detection of Culex theileri flavivirus extends the known range of this virus. PMID- 25033824 TI - Oral human papillomavirus infection and its risk factors among 5,410 healthy adults in China, 2009-2011. AB - BACKGROUND: Despite the established link between oral human papillomavirus (HPV) infection and a subset of oropharyngeal squamous cell carcinoma (OSCC), little is known about the epidemiology of oral HPV infection among healthy adults in China. METHODS: Oral swab specimens and questionnaires were collected from 5,410 individuals (ages 25-65 years). HPV DNA in oral exfoliated cells was tested by general primer-mediated (SPF1/GP6+) PCR and sequencing. Univariate and multivariate analyses were performed to assess the associations between exposure factors and oral infection. RESULTS: Alpha mucosal HPV types were detected in 0.67% [95% confidence interval (CI), 0.47%-0.93%] of 5,351 beta-globin-positive specimens, and cutaneous HPV in 5.46% (95% CI, 4.86%-6.10%). HPV 16 and 3 were the most prevalent types of alpha mucosal (0.43%; 95% CI, 0.27%-0.64%) and cutaneous HPV (4.17%; 95% CI, 3.65%-4.74%), respectively. The prevalence of alpha mucosal HPV decreased with increasing age (25-65 years) from 0.93% to 0.36% (Ptrend = 0.033), and was associated with self-reported history of oral disease [adjusted odds ratio (OR), 4.78; 95% CI, 1.07-21.41]. In 1,614 heterosexual couples, cutaneous HPV in one partner was found to increase the other partner's risk of cutaneous HPV infection (adjusted OR, 2.33; 95% CI, 1.22-4.48). CONCLUSIONS: Oral HPV infection, particularly with alpha mucosal types, is rare among healthy adults in China. A younger age and a history of oral disease imply higher risk of alpha mucosal HPV infection. IMPACT: This study addresses the paucity of epidemiological data on oral HPV infection among healthy population in China. PMID- 25033825 TI - Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single walled carbon nanotubes as tumor-targeting drug delivery system. AB - This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 +/- 5.6 nm, and drug entrapment efficiency was 86.5 +/- 3.7%. The drug release test showed that doxorubicin released more quickly at 42C than at 37C. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs. PMID- 25033827 TI - A call to action: exercise as treatment for patients with mental illness. AB - Mental illness affects the lives of a significant number of Australians. In addition to pharmacological and psychological interventions, exercise has demonstrated benefits for people with mental illness including symptom reduction, improved cardiovascular risk profile and improved physical capacity. Unfortunately, evidence shows that clinician-delivered exercise advice is not routinely offered. This is despite patient acceptability for exercise. This article summarises the recent evidence supporting the prescription of exercise for people with mental illness and offers a model incorporating basic exercise prescription, and referral pathways for specialised advice. Current exercise prescription patterns for people with mental illness may not meet patient expectations; therefore, clinicians should consider exercise referral schemes to increase the accessibility of interventions for people with a mental illness. PMID- 25033826 TI - Different mechanisms are responsible for chlorophyll dephytylation during fruit ripening and leaf senescence in tomato. AB - Chlorophyll breakdown occurs in different green plant tissues (e.g. during leaf senescence and in ripening fruits). For different plant species, the PHEOPHORBIDE A OXYGENASE (PAO)/phyllobilin pathway has been described to be the major chlorophyll catabolic pathway. In this pathway, pheophorbide (i.e. magnesium- and phytol-free chlorophyll) occurs as a core intermediate. Most of the enzymes involved in the PAO/phyllobilin pathway are known; however, the mechanism of dephytylation remains uncertain. During Arabidopsis (Arabidopsis thaliana) leaf senescence, phytol hydrolysis is catalyzed by PHEOPHYTINASE (PPH), which is specific for pheophytin (i.e. magnesium-free chlorophyll). By contrast, in fruits of different Citrus spp., chlorophyllase, hydrolyzing phytol from chlorophyll, was shown to be active. Here, we enlighten the process of chlorophyll breakdown in tomato (Solanum lycopersicum), both in leaves and fruits. We demonstrate the activity of the PAO/phyllobilin pathway and identify tomato PPH (SlPPH), which, like its Arabidopsis ortholog, was specifically active on pheophytin. SlPPH localized to chloroplasts and was transcriptionally up-regulated during leaf senescence and fruit ripening. SlPPH-silencing tomato lines were impaired in chlorophyll breakdown and accumulated pheophytin during leaf senescence. However, although pheophytin transiently accumulated in ripening fruits of SlPPH-silencing lines, ultimately these fruits were able to degrade chlorophyll like the wild type. We conclude that PPH is the core phytol-hydrolytic enzyme during leaf senescence in different plant species; however, fruit ripening involves other hydrolases, which are active in parallel to PPH or are the core hydrolases in fruits. These hydrolases remain unidentified, and we discuss the question of whether chlorophyllases might be involved. PMID- 25033828 TI - Detecting communities based on network topology. AB - Network methods have had profound influence in many domains and disciplines in the past decade. Community structure is a very important property of complex networks, but the accurate definition of a community remains an open problem. Here we defined community based on three properties, and then propose a simple and novel framework to detect communities based on network topology. We analyzed 16 different types of networks, and compared our partitions with Infomap, LPA, Fastgreedy and Walktrap, which are popular algorithms for community detection. Most of the partitions generated using our approach compare favorably to those generated by these other algorithms. Furthermore, we define overlapping nodes that combine community structure with shortest paths. We also analyzed the E. Coli. transcriptional regulatory network in detail, and identified modules with strong functional coherence. PMID- 25033829 TI - Molecular cloning, expression, and characterization of a Sophora alopecuroides lectin from Escherichia coli. AB - Sophora alopecuroides lectin (SAL) has been isolated from the seeds and confirmed to have antifungal and antitumor activities, and presently the preparation of the natural lectin was cumbersome, time-consuming, and the yield was relatively low for further analysis. In this study, the signal peptide of lectin, the modification sites, and the secondary structure were analyzed, and the three dimensional structures of SAL were modeled. The gene of SAL was amplified by the reverse transcription polymerase chain reaction, and cloned into the pET-30a vector and expressed in Escherichia coli BL21(DE3) by the induction of isopropyl beta-d-thiogalactopyranoside. Totally, 400 mg of recombinant SAL (rSAL) was purified from 1 l of bacterial culture through Ni-NTA agarose column and the purity reached 95%. The recombinant protein was further confirmed by western blot using rSAL-specific antibody. The biological activity analysis results showed that rSAL exclusively bound to d-galactose and had universal hemagglutinating activities to human A, B, O, and AB, and rabbit and mouse erythrocytes. rSAL also inhibited the growth of fungi, the proliferation of cancer cells, and the HIV-I reverse transcriptase activity. In conclusion, this study indicates that rSAL can be produced in large quantities in the prokaryotic expression system and the recombinant protein still retains the various biological activities, which will make the large-scale production of SAL recombinant protein at dramatically reduced cost possible. PMID- 25033830 TI - A new animal bioreactor for producing pharmaceutical proteins. PMID- 25033831 TI - Preliminary evaluation of near infrared spectroscopy as a method to detect plasma leakage in children with dengue hemorrhagic fever. AB - BACKGROUND: Dengue viral infections are prevalent in the tropical and sub tropical regions of the world, resulting in substantial morbidity and mortality. Clinical manifestations range from a self-limited fever to a potential life threatening plasma leakage syndrome (dengue hemorrhagic fever). The objective of this study was to assess the utility of near infrared spectroscopy (NIRS) measurements of muscle oxygen saturation (SmO2) as a possible continuous measure to detect plasma leakage in children with dengue. METHODS: Children ages 6 months to 15 years of age admitted with suspected dengue were enrolled from the dengue ward at Queen Sirikit National Institute for Child Health. Children were monitored daily until discharge. NIRS data were collected continuously using a prototype CareGuide Oximeter 1100 with sensors placed on the deltoid or thigh. Daily ultrasound of the chest and a right lateral decubitus chest x-ray the day after defervescence were performed to detect and quantitate plasma leakage in the pleural cavity. RESULTS: NIRS data were obtained from 19 children with laboratory confirmed dengue. Average minimum SmO2 decreased for all subjects prior to defervescence. Average minimum SmO2 subsequently increased in children with no ultrasound evidence of pleural effusion but remained low in children with pleural effusion following defervescence. Average minimum SmO2 was inversely correlated with pleural space fluid volume. ROC analysis revealed a cut-off value for SmO2 which yielded high specificity and sensitivity. CONCLUSIONS: SmO2 measured using NIRS may be a useful guide for real-time and non-invasive identification of plasma leakage in children with dengue. Further investigation of the utility of NIRS measurements for prediction and management of severe dengue syndromes is warranted. PMID- 25033832 TI - Interaction of amorphous silica nanoparticles with erythrocytes in vitro: role of oxidative stress. AB - BACKGROUND/AIMS: The use of engineered nanomaterials in the form of nanoparticles (NP) for various biomedical applications, as well as in consumer products, has raised concerns about their safety for human health. These NP are intended to be administered directly into the circulation following intravenous injection, or they may reach the circulation following other routes of administration such as oral or inhalation, and interact with circulating cells such as erythrocytes. However, little is known about the interaction of amorphous SiNP with erythrocytes. METHODS: We studied the interaction of amorphous silica nanoparticles (SiNP) at various concentrations (1, 5, 25 and 125 ug/ml) with mouse erythrocytes in vitro. RESULTS: Incubation of erythrocytes with SiNP caused a dose-dependent hemolytic effect. Likewise, the activity of lactate dehydrogenase was dose-dependently increased by SiNP. Transmission electron microscopy analysis revealed that SiNP are taken up by erythrocytes. Lipid erythrocyte susceptibility to in vitro peroxidation measured by malondialdehyde showed a significant and dose-dependent increase in erythrocytes. SiNP also enhanced the antioxidant activities of superoxide dismutase (SOD), catalase and reduced glutathione (GSH). Moreover, SiNP increased caspase 3, triggered annexin V-binding and caused a dose-dependent increase of cytosolic calcium concentration. CONCLUSION: It can be concluded that SiNP cause a dose-dependent hemolytic activity and are taken up by the erythrocytes. We also found that SiNP induce the occurrence of oxidative activity, apoptosis and increase cytosolic Ca(2+), which may explain their haemolytic activity. Our in vitro data suggest that SiNP may, plausibly, lead to anemia and circulatory disorders in vivo. PMID- 25033833 TI - Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling. AB - BACKGROUND: Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies. METHODS: In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells. RESULTS: SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown. CONCLUSION: We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways. PMID- 25033836 TI - (Epi)Genetic analyses of age-related macular degeneration: case-control and discordant twin studies. AB - BACKGROUND/AIMS: Phenotypic discordance in monozygotic (MZ) twin pairs can have an epigenetic or genetic basis. Although age-related macular degeneration (AMD) has a strong genetic component, few studies have addressed its epigenetic basis. METHODS: Using SNP arrays, we evaluated differences in copy number variation (CNV) and allele-specific methylation (ASM) patterns (via methyl-sensitive restriction enzyme digestion of DNA) in MZ twin pairs from the US Twin Study of AMD. Further analyses examined the relationship between ASM and CNVs with AMD by both case/control analysis of ASM at candidate regions and by analysis of ASM and CNVs in twins discordant for AMD. RESULTS: The frequency of ASM sites differs between cases and controls in regions surrounding the AMD candidate genes CFH, C2 and CFB. While ASM patterns show a substantial dependence on local sequence polymorphisms, we observed dissimilar patterns of ASM between MZ twins. The genes closest to the sites where discordant MZ twins have dissimilar patterns of ASM are enriched for genes implicated in gliosis, a process associated with neovascular AMD. Similar twin-based analyses revealed no AMD-associated CNVs. CONCLUSIONS: Our results provide evidence of epigenetic influences beyond the known genetic susceptibility and implicate inflammatory responses and gliosis in the etiology of AMD. PMID- 25033835 TI - Physiological correlates of neurobehavioral disinhibition that relate to drug use and risky sexual behavior in adolescents with prenatal substance exposure. AB - Physiological correlates of behavioral and emotional problems, substance use onset and initiation of risky sexual behavior have not been studied in adolescents with prenatal drug exposure. We studied the concordance between baseline respiratory sinus arrhythmia (RSA) at age 3 and baseline cortisol levels at age 11. We hypothesized that children who showed concordance between RSA and cortisol would have lower neurobehavioral disinhibition scores which would in turn predict age of substance use onset and first sexual intercourse. The sample included 860 children aged 16 years participating in the Maternal Lifestyle Study, a multisite longitudinal study of children with prenatal exposure to cocaine and other substances. Structural equation modeling was used to test pathways between prenatal substance exposure, early adversity, baseline RSA, baseline cortisol, neurobehavioral disinhibition, drug use, and sexual behavior outcomes. Concordance was studied by examining separate male and female models in which there were statistically significant interactions between baseline RSA and cortisol. Prenatal substance exposure was operationalized as the number of substances to which the child was exposed. An adversity score was computed based on caregiver postnatal substance use, depression and psychological distress, number of caregiver changes, socioeconomic and poverty status, quality of the home environment, and child history of protective service involvement, abuse and neglect. RSA and cortisol were measured during a baseline period prior to the beginning of a task. Neurobehavioral disinhibition, based on composite scores of behavioral dysregulation and executive dysfunction, substance use and sexual behavior were derived from questionnaires and cognitive tests administered to the child. Findings were sex specific. In females, those with discordance between RSA and cortisol (high RSA and low cortisol or low RSA and high cortisol) had the most executive dysfunction which, in turn, predicted earlier initiation of alcohol by age 16. Among boys, there also existed a significant baseline RSA by baseline cortisol interaction. Boys with low baseline RSA and high baseline cortisol had the highest levels of behavioral dysregulation. This increase in behavioral dysregulation was in turn related to initiation of alcohol use by age 16 and lower age of first sexual intercourse. We found sex-specific pathways to the initiation of alcohol use and risky sexual behavior through the combined activity of parasympathetic and neuroendocrine functioning. The study of multiple physiological systems may suggest new pathways to the study of age of onset of substance use and engagement in risky sexual behavior in adolescents. PMID- 25033837 TI - Spontaneous chiral symmetry breaking in metamaterials. AB - Spontaneous chiral symmetry breaking underpins a variety of areas such as subatomic physics and biochemistry, and leads to an impressive range of fundamental phenomena. Here we show that this prominent effect is now available in artificial electromagnetic systems, enabled by the advent of magnetoelastic metamaterials where a mechanical degree of freedom leads to a rich variety of strong nonlinear effects such as bistability and self-oscillations. We report spontaneous symmetry breaking in torsional chiral magnetoelastic structures where two or more meta-molecules with opposite handedness are electromagnetically coupled, modifying the system stability. Importantly, we show that chiral symmetry breaking can be found in the stationary response of the system, and the effect is successfully demonstrated in a microwave pump-probe experiment. Such symmetry breaking can lead to a giant nonlinear polarization change, energy localization and mode splitting, which provides a new possibility for creating an artificial phase transition in metamaterials, analogous to that in ferrimagnetic domains. PMID- 25033834 TI - APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions. AB - Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1alpha, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed. PMID- 25033838 TI - Prevalence of human papillomavirus in oropharyngeal cancer: a multicenter study in Japan. AB - BACKGROUND: The incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) have risen steadily in the USA and in northern Europe. These increases are thought to be a consequence of persistent infection with high-risk human papillomavirus (HPV) in OPSCC patients. HPV is an emerging etiologic factor in OPSCC. In Japan, the incidence of OPSCC has significantly increased over the last three decades. However, the population of HPV-positive OPSCC patients is currently unknown. We examined the nationwide trends with regard to HPV incidence in OPSCC patients at 21 specific sites, and examined the relationship between the presence of HPV and survival in OPSCC patients in Japan. METHODS: Tumor samples were obtained from patients with OPSCC prior to treatment, and HPV infection was investigated by polymerase chain reaction (PCR). Hybrid Capture 2 (HC2) was also adopted for swab examination on the surface of fresh tumors. RESULTS: HPV was detected by PCR in 79 (50.3%) out of 157 OPSCC patients. The clinical features of HPV-positive OPSCC were low differentiation, a tendency to involve the lateral wall, and high nodal staging. The sensitivity and specificity of HC2 were 93.7 and 96.2%, respectively, indicating its utility as a screening test. HPV-positive patients had significantly better overall survival and disease-free survival than HPV-negative patients. PMID- 25033839 TI - Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface between RNA polymerase I and Rrn3. AB - The interface between the polymerase I-associated factor Rrn3 and the 43-kDa subunit of RNA polymerase I is essential to the recruitment of Pol I to the preinitiation complex on the rDNA promoter. In silico analysis identified an evolutionarily conserved 22 amino acid peptide within rpa43 that is both necessary and sufficient to mediate the interaction between rpa43 and Rrn3. This peptide inhibited rDNA transcription in vitro, while a control peptide did not. To determine the effect of the peptide in cultured cells, the peptide was coupled to the HIV TAT peptide to facilitate transduction into cells. The wild-type peptide, but not control peptides, inhibited Pol I transcription and cell division. In addition, the peptide induced cell death, consistent with other observations that "nucleolar stress" results in the death of tumor cells. The 22mer is a small-molecule inhibitor of rDNA transcription that is specific for the interaction between Rrn3 and rpa43, as such it represents an original way to interfere with cell growth. IMPLICATIONS: These results demonstrate a potentially novel pharmaceutical target for the therapeutic treatment of cancer cells. PMID- 25033842 TI - Air compressor-induced pneumocephalus, pneumomediastinum, and extensive emphysema. PMID- 25033840 TI - Bioactive lipids, LPC and LPA, are novel prometastatic factors and their tissue levels increase in response to radio/chemotherapy. AB - Bioactive lipids are fundamental mediators of a number of critical biologic processes such as inflammation, proliferation, and apoptosis. Rhabdomyosarcoma (RMS) is common in adolescence with histologic subtypes that favor metastasis. However, the factors that influence metastasis are not well appreciated. Here, it is shown that lysophosphatidylcholine (LPC) and its derivative, lysophosphatidic acid (LPA), strongly enhance motility and adhesion of human RMS cells. Importantly, these metastatic-associated phenotypes were observed at physiologic concentrations of these lipids, which naturally occur in biologic fluids. Moreover, the effects of these bioactive lipids were much stronger as compared with known peptide-based prometastatic factors in RMS, such as stromal-derived factor-1 or hepatocyte growth factor/scatter factor. Finally, both LPC and LPA levels were increased in several organs after gamma-irradiation or chemotherapy, supporting the hypothesis that radio/chemotherapy induces an unwanted prometastatic environment in these organs. IMPLICATIONS: LPC and LPA play a previously underappreciated role in dissemination of RMS and suggest that antimetastatic treatment with specific molecules blocking LPC/LPA activity should be part of standard radio/chemotherapy arsenal. PMID- 25033841 TI - Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM RAR to TRADD. AB - A subset of acute promyelocytic leukemia (APL) cases has been characterized by the t(5;17)(q35;q21) translocation variant, which fuses nucleophosmin (NPM) to retinoic acid receptor alpha (RARA). The resultant NPM-RAR fusion protein blocks myeloid differentiation and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) PML-RAR fusion. The contribution of the N-terminal 117 amino acids of NPM contained within NPM-RAR has not been well studied. As a molecular chaperone, NPM interacts with a variety of proteins implicated in leukemogenesis. Therefore, a proteomic analysis was conducted to identify novel NPM-RAR-associated proteins. TNF receptor type I-associated DEATH domain protein (TRADD) was identified as a relevant binding partner for NPM-RAR. This interaction was validated by coprecipitation and colocalization analysis. Biologic assessment found that NPM-RAR expression impaired TNF-induced signaling through TRADD, blunting TNF-mediated activation of caspase-3 (CASP3) and caspase 8 (CASP8), to ultimately block apoptosis. IMPLICATIONS: This study identifies a novel mechanism through which NPM-RAR affects leukemogenesis. PMID- 25033843 TI - Endovascular treatment in acute ischemic stroke: where it stands? PMID- 25033844 TI - Clinical relevance of stem cell therapies in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS), characterized by the progressive loss of both upper and lower motor neurons, is a fatal neurodegenerative disorder. This disease is often accompanied by a tremendous physical and emotional burden not only for the patients, but also for their families and friends as well. There is no clinically relevant treatment available for ALS. To date, only one Food and Drug Administration (FDA)-approved drug, Riluzole, licensed 18 years ago, has been proven to marginally prolong patients' survival without improving the quality of their lives. Because of the lack of an effective drug treatment and the promising outcomes from several preclinical studies, researchers have highlighted this disease as a suitable candidate for stem cell therapy. This review article highlights the finding of key preclinical studies that present a rationale for the use of different types of stem cells for the treatment of ALS, and the most recent updates on the stem cell-based ALS clinical trials around the world. PMID- 25033845 TI - Practical guidelines for setting up neurosurgery skills training cadaver laboratory in India. AB - Though the necessity of cadaver dissection is felt by the medical fraternity, and described as early as 600 BC, in India, there are no practical guidelines available in the world literature for setting up a basic cadaver dissection laboratory for neurosurgery skills training. Hands-on dissection practice on microscopic and endoscopic procedures is essential in technologically demanding modern neurosurgery training where ethical issues, cost constraints, medico-legal pitfalls, and resident duty time restrictions have resulted in lesser opportunities to learn. Collaboration of anatomy, forensic medicine, and neurosurgery is essential for development of a workflow of cadaver procurement, preservation, storage, dissection, and disposal along with setting up the guidelines for ethical and legal concerns. PMID- 25033846 TI - Characteristics of CADASIL in Chinese mainland patients. AB - BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been reported in many geographical regions. However, relatively few reports about CADASIL in Chinese were reported. MATERIALS AND METHODS: We retrospectively collected and analyzed clinical characteristics, magnetic resonance (MRI) features and genetic data of 52 Chinese mainland CADASIL patients. RESULTS: Mean age of onset was 42.43 years. The primary clinical manifestations included: Ischemic stroke/transient ischemic attack (62.5%), primary intracerebral hemorrhage (25%), vertigo (25%), migraine (39.58%), dementia (18.75%) and emotional disturbance (20.83%). The most frequently observed MRI abnormalities were hyperintensity in the cerebral white matter on T2 weighted images and multiple infarcts, high-signal lesions on T2 images in anterior temporal lobes and external capsule were uncommon. The highest mutation frequency was in exon regions, 4 and 3, followed by exon 11. Granular osmiophilic material (GOM) was identified in 66.67% of the cases examined with biopsy. CONCLUSIONS: Most characteristics of Chinese mainland CADASIL patients are similar to those of CADASIL patients living in other regions. However, the prevalence of primary intracerebral hemorrhage and vertigo is much higher in Chinese mainland CADASIL patients. Significant leukoaraiosis in anterior temporal poles on T2-weighted image are uncommon. Exons 3 and 4 are the mutation hotspots. PMID- 25033847 TI - Effect of intraoperative brain protection with propofol on postoperative cognition in patients undergoing temporary clipping during intracranial aneurysm surgery. AB - BACKGROUND: Cognitive dysfunction after subarachnoid hemorrhage (SAH) has been attributable to presence of subarachnoid blood, hydrocephalus (HCP), cerebral edema, vasospasm, and temporary clipping of intracranial aneurysm. Provision of neuroprotection during temporary clipping may improve postoperative cognition in such patients. MATERIALS AND METHODS: Good-grade aneurysmal SAH patients undergoing temporary clipping during surgery were allocated either to group C (control) or group P (propofol). Patients in group P received propofol in titrated doses to attain a burst suppression ratio of 75 +/- 5% on bispectral index (BIS) monitor. The cognitive function as assessed by Hindi-language modification of mini-mental state examination (HMSE) score was evaluated preoperatively, 24 h after surgery, and at discharge from hospital. A score of <=23 was indicative of cognitive dysfunction. Perioperative complications, duration of intensive care unit (ICU) and hospital stay, and outcome at discharge were noted. RESULTS: A total of 66 patients (32 and 34 in group C and P respectively) were included in the study. 97% of the patients had anterior circulation aneurysms. At 24 h after surgery, eight and 12 patients in group C and P respectively; and at discharge, five patients in each group had cognitive dysfunction. In both groups, the trend showed a decline in cognition at 24 h followed by improvement at discharge. Glasgow outcome score in both the groups was comparable (P > 0.05). Intraoperative brain bulge, postoperative vasospasm, and cerebral infarction were found to be independent risk factors for cognitive dysfunction. CONCLUSIONS: Pharmacologic neuroprotection with propofol at the time of temporary clipping during surgery for aneurysmal SAH did not offer any advantage as far as preservation of cognition is concerned. PMID- 25033848 TI - Endovascular treatment of ruptured proximal PICA aneurysms: a single-center 5 years experience. AB - BACKGROUND AND PURPOSE: Posterior inferior cerebellar artery (PICA) like other intracranial arteries is prone to aneurysm formation. Aneurysms usually arise from the vertebral artery (VA) - PICA junction and the proximal segment of the PICA. The use of endovascular treatment as an alternative treatment to surgery has been increasing. We present our last 5 years' experience in treating the ruptured proximal PICA aneurysms. MATERIALS AND METHODS: Retrospective analysis of records of all patients with ruptured VA-PICA junction aneurysms treated at our referral center between July 2008 and July 2013 was performed. Over the last 5 years, we came across 17 patients who had aneurysms of proximal PICA or VA-PICA junction out of which 13 patients underwent endovascular treatment for ruptured saccular VA-PICA junction aneurysms and were the focus of this research. Follow up studies ranged from 6 months to 3 years. RESULTS: All the patients presented with an acute intracranial hemorrhage on NCCT. All the aneurysms were at VA-PICA junction with partial or complete incorporation of PICA origin in the sac. Endovascular treatment of all the 13 aneurysm was successful in the first attempt. Aneurysms were treated with balloon assisted coiling either by placing the balloon across the VA-PICA junction (n = 3) or in the vertebral artery proper (n = 9). Stent assisted coiling VA-PICA was performed in one aneurysm (n = 1). There was no intra-procedural rupture of the aneurysms. CONCLUSION: Endovascular therapy of ruptured proximal PICA aneurysms is possible and safe with the use of adjuvant devices and should be considered as first line treatment. PMID- 25033849 TI - Endovascular treatment of acute ischemic stroke: an Indian experience from a tertiary care center. AB - BACKGROUND: In India, late presentation due to poor awareness about stroke precludes intravenous thrombolysis (IVT). Endovascular therapy can be used in these circumstances. We present our experience of endovascular treatment of acute ischemic stroke in a tertiary care center. AIM: Endovascular treatment of acute ischemic stroke in a tertiary care center in India. SETTINGS, DESIGN, MATERIALS, AND METHODS: The study period was from 2009 till 2013. Consecutive patients with acute ischemic stroke, who either had contraindications to IVT or had failed IVT, underwent endovascular treatment. Before the publication of interventional management of stroke 3 results, we took a few patients, with large vessel occlusions, directly for endovascular treatment. After imaging, patients were considered for endovascular treatment, using either intra-arterial thrombolysis or mechanical thrombectomy, if there was a documented large vessel occlusion. Outcome was assessed at 3 months using the modified Rankin Scale. STATISTICAL ANALYSIS: Statistical analysis was done using the Statistical Package for the Social Sciences 17.0 software. RESULTS: A total of 45 patients underwent endovascular treatment. The mean age at presentation was 49 years, median National Institutes of Health Stroke Scale (NIHSS) was 19 and the most common site was the middle cerebral artery (23 patients). SolitaireTM stentriever was used in 33 patients. The median pre-procedure Thrombolysis In Myocardial Infarction (TIMI) score was 0 and the median post-procedure TIMI score was 3. Nine patients underwent decompressive craniectomy. On follow-up at 3 months, the median Modified Rankin Scale (mRS) was 0. Eight patients died during 3 months following stroke. CONCLUSION: Endovascular treatment of acute ischemic stroke is a viable treatment option in patients who either have contraindications to IVT or who fail IVT. PMID- 25033850 TI - Dynamic pituitary hormones change after traumatic brain injury. AB - OBJECTIVE: To study the dynamic changes of pituitary hormones in traumatic brain injury (TBI) and to correlate the severity and neurological outcome. PATIENTS AND METHODS: Dynamic changes in the pituitary hormones were evaluated in 164 patients with TBI on day-1, day-7, day-14, day-21, and day-28 post injury. Admission TBI severity and long-term outcome were assessed with Glasgow Coma Scale (GCS) score and Glasgow Outcome Scale (GOS) score. The pituitary hormonal changes were correlated with TBI severity and outcome. RESULTS: Of the 164 patients included in the study, pituitary dysfunction was found in 84 patients and in the remaining 80 patients pituitary function was normal. Most of the pituitary hormone deficiencies observed resolved over time; however, a significant proportion of patients had pituitary dysfunction at one month post injury. The hormones associated with poor outcome included growth hormone, thyrotropic hormone, and gonadotropic hormone. CONCLUSION: Dynamic changes of pituitary hormones in patients with TBI may reflect the severity of injury and also determine the outcome. Deficiency of growth hormone, gonadotropic hormone, and thyrotropic hormone can adversely affect neurological outcome. PMID- 25033851 TI - Phenytoin toxicity in patients with traumatic brain injury. AB - BACKGROUND: We observed that in patients with traumatic brain injury (TBI) who did not improve as expected, serum levels of phenytoin were in the toxic range and that their sensorium improved with modification of the dose. This led us to study the usage of phenytoin in patients with TBI. AIMS: To determine the prevalence of phenytoin toxicity in TBI patients and to study the suitability of using ideal body weight (IBW) to guide phenytoin dosing. SETTING AND DESIGN: Neurotrauma unit of a tertiary care centre in India. Prospective data collection from an already established protocol of drug level monitoring. MATERIALS AND METHODS: The study cohort included 100 consecutive adult patients with mild or moderate TBI who were administered phenytoin based on IBW. Trough serum phenytoin and albumin levels were measured on day 4 after administration of the loading dose and actual body weight obtained when it was possible. STATISTICAL ANALYSIS: Chi-square was used for comparing categorical variables, student's t-test for continuous variables and multivariate regression analysis to obtain independent risk factors. RESULTS: Clinical toxicity was observed in 15% of patients and biochemical toxicity in 36%, with a significant association between the two (P < 0.01). Using multivariate analysis, abdominal girth <=75 cm (P = 0.07), neck circumference <=34 cm (P = 0.025) and IV dose proportion >=80% (P = 0.003) were independent risk factors for biochemical toxicity. The plot between actual weight and IBW showed that toxicity occurred when IBW was higher than actual weight. CONCLUSION: The prevalence of biochemical phenytoin toxicity was high, with independent risk factors being a higher proportion of IV administration and overestimation of weight by IBW. Clinical suspicion of phenytoin toxicity was a good predictor of biochemical toxicity. PMID- 25033852 TI - Large/giant meningiomas of posterior third ventricular region: falcotentorial or velum interpositum? AB - Surgical excision of rare, large-to-giant posterior third ventricular (PTV) meningiomas [including velum-interpositum meningiomas (VIM; postero-superior venous complex displacement; without falco-tentorial attachment) and falco tentorial meningiomas (FTM; falco-tentorial attachment; displacing major veins antero-inferiorly)] is extremely challenging. To study the management nuances in the excision of large-to-giant PTV meningiomas. Tertiary care referral center. Four patients with large (>3 cm; n = 2) and giant (>5 cm; n = 2) meningiomas (FTM = 2; VIM = 2, mean tumor size = 4.9 cm) underwent occipital transtentorial approach (OTT) for tumor excision. One also underwent a second-stage supracerebellar infratentorial (SCIT) approach. The side of approach was determined by lateral tumor extension and venous displacement (right = 3, left = 1). Near-total removal or subtotal excision (<10% remaining) with radiotherapy was performed in 2 patients each, respectively. At follow-up (mean: 14.75 months), clinical improvement without tumor recurrence/re-growth was achieved. Extent of excision was determined by position of great vein of Galen; tumor attachment to falco-tentorium or major veins; its consistency; its lateral and inferior extent; and, presence of a good tumor-neuraxial arachnoidal plane. OTT is the preferable approach for large-to-giant meningiomas as it provides a wider corridor and better delineation of tumor-neurovascular arachnoidal interface. PMID- 25033853 TI - Congenital defect of the anterior arch of the atlas: a case report and review of the literature. PMID- 25033854 TI - Enhanced T 2 FNx weighted angiography imaging and 3-D time-resolved imaging of contrast kinetics findings in Balo's concentric sclerosis. PMID- 25033855 TI - The one-and-a-half syndrome as the presenting sign of systemic lupus erythematosus. PMID- 25033856 TI - Cerebral venous sinus thrombosis presentation in severe scrub typhus infection: a rare entity. PMID- 25033857 TI - Vertebral artery thrombosis in a case of traumatic atlanto-axial dislocation with delayed presentation: emphasis on preoperative evaluation and operative steps to prevent a catastrophe. PMID- 25033859 TI - Spinal cord involvement of Churg-Strauss syndrome with multi-organ disorders. PMID- 25033858 TI - Familial Dok7 congenital myasthenic syndrome responsive to salbutamol. PMID- 25033860 TI - Mantle cell lymphoma presented with unilateral palsy: a case report and review of literature. PMID- 25033861 TI - Hematomyelia due to ruptured intramedullary aneurysm associated with arteriovenous malformation masquerading as demyelination. PMID- 25033862 TI - Cervical spine brucellosis presenting as fever with neck stiffness and cervical compressive myelopathy: a case report. PMID- 25033863 TI - Cryptococcal myelitis: a rare manifestation in immunocompetent patients. PMID- 25033864 TI - Dysembryoplastic neuroepithelial tumor transforming into malignancy: a case report. PMID- 25033865 TI - Compressive radiculopathy due to delayed pseudomeningocele secondary to occult dural tear following tubular lumbar microdiscectomy. PMID- 25033866 TI - Multifocal cns vasculopathy due to reactivation of latent varicella: a potentially reversible complication following radiofrequency ablation for trigeminal neuralgia. PMID- 25033867 TI - Orbital infantile fibrosarcoma presenting as intraconal mass in a 2-year-old child: a case report. PMID- 25033868 TI - Anti NMDA receptor encephalitis associated with thymic hyperplasia: a case report. PMID- 25033869 TI - Pruritus: is it a predictor of relapse in neuromyelitisoptica spectrum disorder? PMID- 25033870 TI - Giant dilations of perivascular spaces in deep brain locations: a cause for parkinsonism? PMID- 25033871 TI - Remote site intracranial hemorrhage: our experience and review of literature. AB - Sudden decompression in a patient with chronically raised intracranial pressure (ICP) can very rarely lead to bleeding away from the operative site. In this retrospective review the intention is to highlight the possible causes of remote bleed. Data of six patients with remote site bleed in the postoperative period operated at our center were retrospectively reviewed. Medline and Pubmed databases were searched for similar cases and were reviewed systematically to understand the cause, management, and outcome. In our series the mean age of patients was 35.5 years. Three patients each were operated for supratentorial and infratentorial pathologies. Of the six patients, three patients were operated for tumors. Of the 89 patients with remote site bleed in the postoperative period,64 (72%) patients had supratentorial tentorial and in the remaining it was infratentorial surgery. Most common site of bleed was supratentorial in 72 {81 %) patients. The reported mortality was 28% (21 patients). Remote site intracranial bleed following cranial surgery is a rare but well-documented complication. It can prove fatal and may cause significant morbidity. We advocate keeping high index of suspicion and ear[y computed tomography(CT) scan head in postoperative period. PMID- 25033872 TI - "Boomerang sign" in rickettsial encephalitis. PMID- 25033873 TI - Cystic cavernous angioma of the cauda equina mimicking neurenteric cyst. PMID- 25033874 TI - 'Hot-cross bun' and 'inverse trident sign' in progressive multifocal leukoencephalopathy with HIV seropositivity. PMID- 25033875 TI - Central nervous system lymphoma: patterns of incidence in Indian population and effect of steroids on stereotactic biopsy yield. PMID- 25033876 TI - Computational analysis identifies a sponge interaction network between long non coding RNAs and messenger RNAs in human breast cancer. AB - BACKGROUND: Non-coding RNAs (ncRNAs) are emerging as key regulators of many cellular processes in both physiological and pathological states. Moreover, the constant discovery of new non-coding RNA species suggests that the study of their complex functions is still in its very early stages. This variegated class of RNA species encompasses the well-known microRNAs (miRNAs) and the most recently acknowledged long non-coding RNAs (lncRNAs). Interestingly, in the last couple of years, a few studies have shown that some lncRNAs can act as miRNA sponges, i.e. as competing endogenous RNAs (ceRNAs), able to reduce the amount of miRNAs available to target messenger RNAs (mRNAs). RESULTS: We propose a computational approach to explore the ability of lncRNAs to act as ceRNAs by protecting mRNAs from miRNA repression. A seed match analysis was performed to validate the underlying regression model. We built normal and cancer networks of miRNA mediated sponge interactions (MMI-networks) using breast cancer expression data provided by The Cancer Genome Atlas. CONCLUSIONS: Our study highlights a marked rewiring in the ceRNA program between normal and pathological breast tissue, documented by its "on/off" switch from normal to cancer, and vice-versa. This mutually exclusive activation confers an interesting character to ceRNAs as potential oncosuppressive, or oncogenic, protagonists in cancer. At the heart of this phenomenon is the lncRNA PVT1, as illustrated by both the width of its antagonist mRNAs in normal-MMI-network, and the relevance of the latter in breast cancer. Interestingly, PVT1 revealed a net binding preference towards the mir-200 family as the bone of contention with its rival mRNAs. PMID- 25033877 TI - Meta-analysis of GSTM1 null genotype and lung cancer risk in Asians. AB - BACKGROUND: Several molecular epidemiological studies have been conducted to examine the association between glutathione S-transferase M 1 (GSTM1) null genotype and lung cancer in Asians; however, the conclusions remained controversial. We therefore performed an extensive meta-analysis on 31 published case-control studies with a total of 5347 lung cancer cases and 6072 controls. MATERIAL/METHODS: PubMed and EMBASE were searched to identify case-control studies investigating the associations of GSTM1 null genotype with risk of lung cancer in Asians. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between lung cancer risk and polymorphism of GSTM1. RESULTS: GSTM1 null genotype was significantly associated with lung cancer risk (OR=1.43; 95% CI, 1.30-1.58). This result remained statistically significant when the adjusted ORs were combined (OR=1.38; 95% CI, 1.23-1.54). In the subgroup analysis by sex, there were significant associations in women and men. When stratifying for histology, this genotype showed increased adenocarcinoma risk and squamous cell carcinoma risk. In the subgroup analysis stratified by smoking status, lung cancer risk was increased in both smokers and non-smokers. CONCLUSIONS: This study suggests that GSTM1 null genotype is a risk factor for lung cancer in Asians. PMID- 25033878 TI - Air versus saline in the loss of resistance technique for identification of the epidural space. AB - BACKGROUND: The success of epidural anaesthesia depends on correct identification of the epidural space. For several decades, the decision of whether to use air or physiological saline during the loss of resistance technique for identification of the epidural space has been governed by the personal experience of the anaesthesiologist. Epidural block remains one of the main regional anaesthesia techniques. It is used for surgical anaesthesia, obstetrical analgesia, postoperative analgesia and treatment of chronic pain and as a complement to general anaesthesia. The sensation felt by the anaesthesiologist from the syringe plunger with loss of resistance is different when air is compared with saline (fluid). Frequently fluid allows a rapid change from resistance to non-resistance and increased movement of the plunger. However, the ideal technique for identification of the epidural space remains unclear. OBJECTIVES: * To evaluate the efficacy and safety of both air and saline in the loss of resistance technique for identification of the epidural space.* To evaluate complications related to the air or saline injected. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 9), MEDLINE, EMBASE and the Latin American and Caribbean Health Science Information Database (LILACS) (from inception to September 2013). We applied no language restrictions. The date of the most recent search was 7 September 2013. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-randomized controlled trials (quasi RCTs) on air and saline in the loss of resistance technique for identification of the epidural space. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: We included in the review seven studies with a total of 852 participants. The methodological quality of the included studies was generally ranked as showing low risk of bias in most domains, with the exception of one study, which did not mask participants. We were able to include data from 838 participants in the meta analysis. We found no statistically significant differences between participants receiving air and those given saline in any of the outcomes evaluated: inability to locate the epidural space (three trials, 619 participants) (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.33 to 2.31, low-quality evidence); accidental intravascular catheter placement (two trials, 223 participants) (RR 0.90, 95% CI 0.33 to 2.45, low-quality evidence); accidental subarachnoid catheter placement (four trials, 682 participants) (RR 2.95, 95% CI 0.12 to 71.90, low-quality evidence); combined spinal epidural failure (two trials, 400 participants) (RR 0.98, 95% CI 0.44 to 2.18, low-quality evidence); unblocked segments (five studies, 423 participants) (RR 1.66, 95% CI 0.72 to 3.85); and pain measured by VAS (two studies, 395 participants) (mean difference (MD) -0.09, 95% CI -0.37 to 0.18). With regard to adverse effects, we found no statistically significant differences between participants receiving air and those given saline in the occurrence of paraesthesias (three trials, 572 participants) (RR 0.89, 95% CI 0.69 to 1.15); difficulty in advancing the catheter (two trials, 227 participants) (RR 0.91, 95% CI 0.32 to 2.56); catheter replacement (two trials, 501 participants) (RR 0.69, 95% CI 0.26 to 1.83); and postdural puncture headache (one trial, 110 participants) (RR 0.83, 95% CI 0.12 to 5.71). AUTHORS' CONCLUSIONS: Low-quality evidence shows that results do not differ between air and saline in terms of the loss of resistance technique for identification of the epidural space and reduction of complications. Applicability might be compromised, as most of the results described in this review were obtained from parturient patients. This review underlines the need to conduct well-designed trials in this field. PMID- 25033879 TI - Probability of a false-negative HIV antibody test result during the window period: a tool for pre- and post-test counselling. AB - Failure to understand the risk of false-negative HIV test results during the window period results in anxiety. Patients typically want accurate test results as soon as possible while clinicians prefer to wait until the probability of a false-negative is virtually nil. This review summarizes the median window periods for third-generation antibody and fourth-generation HIV tests and provides the probability of a false-negative result for various days post-exposure. Data were extracted from published seroconversion panels. A 10-day eclipse period was used to estimate days from infection to first detection of HIV RNA. Median (interquartile range) days to seroconversion were calculated and probabilities of a false-negative result at various time periods post-exposure are reported. The median (interquartile range) window period for third-generation tests was 22 days (19-25) and 18 days (16-24) for fourth-generation tests. The probability of a false-negative result is 0.01 at 80 days' post-exposure for third-generation tests and at 42 days for fourth-generation tests. The table of probabilities of falsely-negative HIV test results may be useful during pre- and post-test HIV counselling to inform co-decision making regarding the ideal time to test for HIV. PMID- 25033880 TI - Prevalence of HIV-1 subtypes among men who have sex with men in China: a systematic review. AB - The distribution of prevalent HIV-1 strains are still complex in China. Men who have sex with men (MSM) play an important bridging role in spreading HIV. The aim of our study was to quantitatively evaluate the prevalence of HIV-1 subtypes among the MSM population in China from published studies. Relevant studies were searched by selection criteria from CNKI, CBM, Pubmed, etc. We computed the estimates of the pooled proportion of HIV-1 subtypes. Heterogeneity between studies was investigated and measured using Cochran's Q statistic and the I (2) statistic. All analyses were conducted by the R statistical package version 2.13.1. A meta-analysis was performed, which included 19 articles. For comprehensive analysis of env, gag and pol genes, the pooled estimates for the prevalence of subtype B was 28.25% (95% CI: 18.10-39.66%), CRF01_AE was 53.46% (95% CI: 46.11-60.74%), CRF07_BC was 18.66% (95% CI: 13.06-25.01%) and CRF08_BC was 5.85% (95% CI: 2.73-10.07%), respectively. In subgroup analysis, the proportion of subtype B decreased, while the proportion of CRF01_AE and CRF07_BC showed an increasing tendency. Beijing, Guangdong and Henan provinces had high proportions of subtype CRF01_AE while Guangdong and Hebei provinces had the highest proportions of subtype B and CRF07_BC, respectively. A high genetic variability of HIV-1 presents a serious challenge for HIV prevention and treatment strategies among MSM in China. PMID- 25033881 TI - A case of proliferative diabetic retinopathy that regressed on human immunodeficiency virus treatment. AB - We report the case of a patient with proliferative diabetic retinopathy, who was later found to have human immunodeficiency virus infection that progressed rapidly. However, we could not determine the clinical course after the onset of human immunodeficiency virus because the patient died shortly after it was detected. In this patient, the activity of proliferative diabetic retinopathy showed regression after treatment for human immunodeficiency virus was initiated. PMID- 25033882 TI - A review of how the quality of HIV clinical services has been evaluated or improved. AB - To examine approaches being used to evaluate and improve quality of HIV clinical services we searched the MEDLINE, Cochrane Library collection, EMBASE, Global Health, and Web of Science databases for articles and abstracts focused on evaluating or improving quality of HIV clinical services. We extracted country income level, targeted clinical services, and quality evaluation approaches, data sources, and criteria. Fifty journal articles and 46 meeting abstracts were included. Of the 96 studies reviewed, 65% were programme evaluations, 71% focused on low- and middle-income countries, and 65% focused on antiretroviral therapy services. With regard to quality, 45% used a quality improvement model or programme, 13% set a quality threshold, and 51% examined patient records to evaluate quality. No studies provided a definition for quality HIV care. Quality assurance and improvement of HIV clinical services is increasingly important. This review highlights gaps in knowledge for future research, and may also help countries and programmes develop their HIV care quality improvement frameworks. PMID- 25033884 TI - Classification schema of symptomatic enterogastric reflux utilizing sincalide augmentation on hepatobiliary scintigraphy. AB - Enterogastric reflux (EGR) is the reflux of duodenal contents into the stomach. Hepatobiliary scintigraphy provides physiologic assessment of the biliary system and was used to test the hypothesis that presence and timing of EGR may be associated with infusion of sincalide, a surrogate of endogenous cholecystokinin. METHODS: One hundred fifty-seven hepatobiliary scintigraphy studies were retrospectively reviewed. Data included EGR incidence on initial reports, incidence after masked second reads, and time of EGR onset in relation to sincalide infusion. EGR cases were then classified according to onset on pre-, post-, or both presincalide and postsincalide imaging. RESULTS: Time of EGR onset at 19-24 minutes after start of a 15-min sincalide infusion differed significantly from normal (p<0.0001). EGR was initially reported in 14 of 157 cases (8.9%) but found in 38 of 157 cases on masked second reads (24.2%), corresponding to a 15.3% discrepancy rate. CONCLUSION: The temporal association of EGR onset with sincalide infusion may identify patients with EGR mimicking chronic cholecystitis or biliary dyskinesia. A novel classification schema was therefore developed as a framework for future research, utilizing EGR onset in relation to pre-, post-, or both presincalide and postsincalide imaging as a hypothetical biomarker of clinically significant EGR. PMID- 25033883 TI - Fully automated production of diverse 18F-labeled PET tracers on the ELIXYS multireactor radiosynthesizer without hardware modification. AB - Fully automated radiosynthesizers are continuing to be developed to meet the growing need for the reliable production of PET tracers made under current good manufacturing practice guidelines. There is a current trend toward supporting kitlike disposable cassettes that come preconfigured for particular tracers, thus eliminating the need for cleaning protocols between syntheses and enabling quick transitions to synthesizing other tracers. Though ideal for production, these systems are often limited for the development of novel tracers because of pressure, temperature, and chemical compatibility considerations. This study demonstrated the versatile use of the ELIXYS fully automated radiosynthesizer to adapt and produce 8 different (18)F-labeled PET tracers of varying complexity. METHODS: Three-reactor syntheses of 2-deoxy-2-(18)F-fluoro-beta-d arabinofuranosylcytosine (d-(18)F-FAC), 2-deoxy-2-(18)F-fluoro-5-methyl-beta-l arabinofuranosyluracil (l-(18)F-FMAU), and 2-deoxy-2-(18)F-fluoro-5-ethyl-beta-d arabinofuranosyluracil (d-(18)F-FEAU) along with the 1-reactor syntheses of d (18)F-FEAU, (18)F-FDG, 3-deoxy-3-(18)F-fluoro-l-thymidine ((18)F-FLT), (18)F fallypride, 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)-guanine ((18)F-FHBG), and N succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB), were all produced using ELIXYS without the need for any hardware modifications or reconfiguration. Synthesis protocols were adapted and slightly modified from those in the literature but were not fully optimized. Furthermore, (18)F-FLT, (18)F-FDG, and (18)F-fallypride were produced sequentially on the same day and used for preclinical imaging of A431 tumor-bearing severe combined immunodeficient mice and wild-type BALB/c mice. To assess future translation to the clinical setting, several batches of tracers were subjected to a full set of quality control tests. RESULTS: All tracers were produced with radiochemical yields comparable to those in the literature. (18)F-FLT, (18)F-FDG, and (18)F-fallypride were successfully used to image the mice, with results consistent with those reported in the literature. All tracers that were subjected to clinical quality control tests passed. CONCLUSION: The ELIXYS radiosynthesizer facilitates rapid tracer development and is capable of producing multiple (18)F-labeled PET tracers suitable for clinical applications using the same hardware setup. PMID- 25033885 TI - Complementary role of 18F-FDG PET and 123I-ioflupane SPECT in the diagnosis of Lewy body disease. AB - We present a case demonstrating how correlative imaging with (123)I-ioflupane SPECT and (18)F-FDG PET can be used to help make the diagnosis of Lewy body disease more specific. PMID- 25033886 TI - Reduction of patient anxiety in PET/CT imaging by improving communication between patient and technologist. AB - Patients experience anxiety during imaging procedures because of the confined space, uncertainty about the procedure, worry about the results, and other concerns. When a patient experiences anxiety during PET/CT imaging, the quality of the scan can be affected in several ways. Current patient-technologist communication is limited in PET/CT because the technologist must be separated from the patient during the course of the imaging workflow. This study investigated the use of a call device enabling rapid communication to reduce patient anxiety. METHODS: Clinical patients with various oncologic indications and undergoing (18)F-FDG PET/CT imaging were asked to participate in anxiety surveys under several conditions. Metrics were tracked regarding the survey results for comparison between groups and survey conditions. During the course of this study, 2 patient surveys were used. One of the patient populations was asked to fill out a survey on personal perceptions of the use of such a device, with questions related to their comfort with the device and the degree to which they perceived the device to reduce their anxiety. The 2 remaining populations were given a standard Spielberger State Anxiety survey for anxiety assessments against control populations. RESULTS: Perception survey results indicated that 75% of the respondents experienced a reduction in anxiety and that 84% would request this type of device for other procedures. A correlation was observed between improved patient-technologist communication and perceived feelings of safety, with identical percentages of positive responses. Although responses were mostly positive, 18.8% did not perceive any reduction in anxiety, and the same number indicated they would not use the system in the future. For those patients given the standard Spielberger State Anxiety survey, a statistically significant reduction in anxiety was observed (P < 0.05) in those patients given a call device. Reductions in anxiety were observed for all patient populations, including first-time and repeated-imaging patients. CONCLUSION: Patient anxiety can be reduced through the use of a tangible device that improves communication between the patient and the imaging staff. Reducing anxiety may have a positive effect on imaging, because involuntary motion may be reduced and there may be improvement in the patients' comfort and in their overall experience with the imaging procedure. PMID- 25033887 TI - Novel human recombinant antibodies against Mycobacterium tuberculosis antigen 85B. AB - BACKGROUND: Tuberculosis is the leading cause of death due to bacterial infections worldwide, mainly caused by Mycobacterium tuberculosis. The antigen 85 complex comprises a set of major secreted proteins of M. tuberculosis, which are potential biomarkers for diagnostic. RESULTS: In this work, the first human single chain fragment variable (scFv) antibodies specific for the tuberculosis biomarker 85 B were selected by phage display from naive antibody gene libraries (HAL7/8). Produced as scFv-Fc in mammalian cells, these antibodies were further characterized and analysed for specificity and applicability in different tuberculosis antigen detection assays. Sandwich detection of recombinant 85 B was successful in enzyme linked immunosorbent assay (ELISA), lateral flow immunoassay and immunoblot. Whereas detection of M. tuberculosis cell extracts and culture filtrates was only possible in direct ELISA and immunoblot assays. It was found that the conformation of 85 B, depending on sample treatment, influenced antigen detection. CONCLUSIONS: Recombinant antibodies, selected by phage display, may be applicable for 85 B detection in various assays. These antibodies are candidates for the development of future point of care tuberculosis diagnostic kits. Using 85 B as a biomarker, the antigen conformation influenced by sample treatment is important. PMID- 25033889 TI - Percutaneous endoscopic decompression for lumbar spinal stenosis. AB - Percutaneous endoscopic lumbar discectomy has become a representative minimally invasive spine surgery for lumbar disc herniation. Due to the remarkable evolution in the techniques available, the paradigm of spinal endoscopy is shifting from treatments of soft disc herniation to those of lumbar spinal stenosis. Lumbar spinal stenosis can be classified into three categories according to pathological zone as follows: central stenosis, lateral recess stenosis and foraminal stenosis. Moreover, percutaneous endoscopic decompression (PED) techniques may vary according to the type of lumbar stenosis, including interlaminar PED, transforaminal PED and endoscopic lumbar foraminotomy. However, these techniques are continuously evolving. In the near future, PED for lumbar stenosis may be an efficient alternative to conventional open lumbar decompression surgery. PMID- 25033890 TI - Expression patterns of mitochondrial OXPHOS components, mitofusin 1 and dynamin related protein 1 are associated with human embryo fragmentation. AB - Developmental dysfunction in embryos, such as a lethal level of fragmentation, is assumed to be mitochondrial in origin. This study investigated the molecular basis of mitochondrial impairment in embryo fragmentation. Transcription patterns of factors that determine mitochondrial functionality: (i) components of the oxidative phosphorylation (OXPHOS) - complex I, cytochrome b, complex IV and ATP synthase; (ii) mitochondrial membrane potential (MMP); (iii) mitochondrial DNA (mtDNA) content and (iv) proteins involved in mitochondrial dynamics, mitofusin 1 (Mfn1) and dynamin related protein 1 (Drp1) were examined in six-cells Day 3 non fragmented (control), low-fragmented (LF) and high-fragmented (HF) human embryos. Gene expression of mitochondria-encoded components of complex I and IV, cytochrome b and mtDNA were increased in HF embryos compared with control and LF embryos. In LF embryos, expression of these molecules was decreased compared with control and HF embryos. Both classes of fragmented embryos had decreased MMP compared with control. LF embryos had increased gene expression of Mfn1 accompanied by decreased expression of Drp1, while HF embryos had decreased Mfn1 expression but increased Drp1 expression. The study revealed that each improper transcriptional (in)activation of mitochondria-encoded components of the OXPHOS during early in vitro embryo development is associated with a decrease in MMP and with embryo fragmentation. The results also showed the importance of mitochondrial dynamics in fragmentation, at least in the extent of this process. PMID- 25033888 TI - The frequency and nature of incidental findings in large-field cone beam computed tomography scans of an orthodontic sample. AB - BACKGROUND: The aim of this study is to evaluate the nature and frequency of incidental findings in large-field maxillofacial cone beam computed tomography (CBCT). METHODS: A total of 427 consecutive CBCT radiologic reports obtained for orthodontic purposes were retrospectively reviewed. Findings were summarized and categorized into six anatomic categories. RESULTS: A total of 842 incidental findings were reported in the 427 CBCT scans (1.97 findings/scan). The most prevalent findings were those located in the airway (42.3%), followed by the paranasal sinuses (30.9%), dentoalveolar (14.7%), surrounding hard/soft tissues (4.0%), temporomandibular joint (TMJ) (6.4%), and cervical vertebrae (1.3%) regions. Non-odontogenic findings, defined as those located outside the dentition and associated alveolus, represented 718 of the 842 (85.3%) findings. CONCLUSIONS: This study confirms the high occurrence of incidental findings in large-field maxillofacial CBCT scans in a sample of orthodontically referred cases. The majority are extragnathic findings, which can be normally considered outside the regions of interest of many dental clinicians. Specifically, incidental findings in the naso-oropharyngeal and paranasal air sinuses are the most frequent. This underscores the need for comprehensive review of the entire data volume and the requisite to properly document all findings, regardless of the region of interest. PMID- 25033892 TI - Psychological work characteristics, psychological workload and associated psychological and cognitive requirements of train drivers. AB - This study aimed to assess the psychological work characteristics and psychological workload of train drivers and to define the psychological and cognitive requirements of their work. A systematic literature search was performed, and expert interviews were conducted. The following work demands were specific to train drivers: high emotional and mental demands, small amount of autonomy and skill discretion. No evidence of a high emotional workload, a high mental workload or short-term stress reactivity was found. In general, the drivers' fatigue complaints and recovery needs after work were comparable to that of other workers. However, severe sleepiness and high need for recovery did affect a substantial proportion of train drivers. The ability to stay aware, to anticipate, to remain attentive and to cope with fatigue are psychological and cognitive skills that are required to adequately and safely perform the train drivers' job. Including these requirements in periodic assessments of train drivers is recommended. PRACTITIONER SUMMARY: A systematic literature search was performed, aimed at assessing the psychological work characteristics and psychological workload of train drivers. Based on this information and interviews with experts, a list of psychological and cognitive requirements that needed to perform the train drivers' job adequately and safely was proposed. PMID- 25033891 TI - Chronic kidney disease and support provided by home care services: a systematic review. AB - BACKGROUND: Chronic diseases, such as chronic kidney disease (CKD), are growing in incidence and prevalence, in part due to an aging population. Support provided through home care services may be useful in attaining a more efficient and higher quality care for CKD patients. METHODS: A systematic review was performed to identify studies examining home care interventions among adult CKD patients incorporating all outcomes. Studies examining home care services as an alternative to acute, post-acute or hospice care and those for long-term maintenance in patients' homes were included. Studies with only a home training intervention and those without an applied research component were excluded. RESULTS: Seventeen studies (10 cohort, 4 non-comparative, 2 cross-sectional, 1 randomized) examined the support provided by home care services in 15,058 CKD patients. Fourteen studies included peritoneal dialysis (PD), two incorporated hemodialysis (HD) and one included both PD and HD patients in their treatment groups. Sixteen studies focused on the dialysis phase of care in their study samples and one study included information from both the dialysis and pre dialysis phases of care. Study settings included nine single hospital/dialysis centers and three regional/metropolitan areas and five were at the national level. Studies primarily focused on nurse assisted home care patients and mostly examined PD related clinical outcomes. In PD studies with comparators, peritonitis risks and technique survival rates were similar across home care assisted patients and comparators. The risk of mortality, however, was higher for home care assisted PD patients. While most studies adjusted for age and comorbidities, information about multidimensional prognostic indices that take into account physical, psychological, cognitive, functional and social factors among CKD patients was not easily available. CONCLUSIONS: Most studies focused on nurse assisted home care patients on dialysis. The majority were single site studies incorporating small patient populations. There are gaps in the literature regarding the utility of providing home care to CKD patients and the impact this has on healthcare resources. PMID- 25033893 TI - Novel insights into the risk assessment of the nanomaterial synthetic amorphous silica, additive E551, in food. AB - This study presents novel insights in the risk assessment of synthetic amorphous silica (SAS) in food. SAS is a nanostructured material consisting of aggregates and agglomerates of primary particles in the nanorange (<100 nm). Depending on the production process, SAS exists in four main forms, and each form comprises various types with different physicochemical characteristics. SAS is widely used in foods as additive E551. The novel insights from other studies relate to low gastrointestinal absorption of SAS that decreases with increasing dose, and the potential for accumulation in tissues with daily consumption. To accommodate these insights, we focused our risk assessment on internal exposure in the target organ (liver). Based on blood and tissue concentrations in time of two different SAS types that were orally and intravenously administered, a kinetic model is developed to estimate the silicon concentration in liver in (1) humans for average-to-worst-case dietary exposure at steady state and (2) rats and mice in key toxicity studies. The estimated liver concentration in humans is at a similar level as the measured or estimated liver concentrations in animal studies in which adverse effects were found. Hence, this assessment suggests that SAS in food may pose a health risk. Yet, for this risk assessment, we had to make assumptions and deal with several sources of uncertainty that make it difficult to draw firm conclusions. Recommendations to fill in the remaining data gaps are discussed. More insight in the health risk of SAS in food is warranted considering the wide applications and these findings. PMID- 25033894 TI - Microstructural analysis and transport properties of MoO and MoC nanostructures prepared by focused electron beam-induced deposition. AB - By electron-beam-induced deposition, we have succeeded in the direct fabrication of nanowires of molybdenum oxide (MoOx) and molybdenum carbide (MoC) on a SiO2 substrate set in a scanning electron microscope. In order to prepare MoOx specimens of high purity, a precursor gas of molybdenum hexacarbonyl [Mo(CO)6] is used, mixed with oxygen gas. On the other hand, MoC is grown by mixing H2O gas with the precursor gas. The electrical transport properties of the nanowires are investigated by the DC four-terminal method. A highly resistive MoOx nanowire prepared from an as-deposited specimen by annealing in air shows nonlinear current-voltage characteristics and a high photoconductivity. The resistivity rho of an as-deposited amorphous MoC (a-MoC) nanowire takes its maximum at a temperature T ~ 10 K and decreases to ~ 0 with decreasing temperature. This behavior of rho(T) indicates the possible occurrence of superconductivity in a MoC nanowires. The characteristic of rho(T) below the superconducting transition temperature Tc ~ 4 K can be well explained by the quantum phase-slip model with a coherence length xi(0) ~ 8 nm at T = 0. PMID- 25033895 TI - MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells. AB - OBJECTIVE: We investigated the molecular mechanism underlying the role of monocyte chemoattractant protein-1 (MCP-1) in the formation and development of human abdominal aortic aneurysm (AAA). METHODS: We examined protein expression profiles using a protein array and found that MCP-1 was the most highly expressed protein in AAA tissues compared with normal aortas. To investigate the potential mechanism of MCP-1 involvement in the pathogenesis of AAA, we treated human aortic smooth muscle cells (HASMCs) with human recombinant MCP-1. RESULTS: MCP-1 was the most highly expressed protein in AAA tissues compared with normal aorta; matrix metalloproteinase-9 (MMP-9) expression was also significantly increased. Treatment with MCP-1 significantly increased the expression and activation of MMP 9 and activated the three major mitogen activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun amino terminal kinase (JNK1/2) and p38 MAPK. Furthermore, MCP-1-induced secretion of MMP-9 was inhibited by U0126 (inhibitor of the ERK 1/2 pathway) and SB203580 (inhibitor of the p38 MAPK pathway), but not SP600125 (inhibitor of the JNK1/2 pathway). CONCLUSION: These data demonstrate that MCP-1 stimulates secretion of MMP-9 directly through the ERK1/2 and p38 MAPK mediated pathways in HASMCs. Thus, inhibition of this molecular mechanism might be a potential therapeutic target in the non-surgical treatment of AAA. PMID- 25033896 TI - Iodine-125 induces apoptosis via regulating p53, microvessel density, and vascular endothelial growth factor in colorectal cancer. AB - BACKGROUND: Iodine interstitial brachytherapy has been widely reported for treating colorectal cancer (CRC). However, the inhibitory molecular mechanism of iodine-125 (I-125) on CRC has not been reported. METHODS: To illustrate the inhibitory mechanism of iodine-125 (I-125) on CRC, we established the animal models of CRC via the injection of HCT-8 cells into nude mice. Subsequently, the I-125 granules were implanted into the tumor of the animal model at different dosages. Proliferating cell nuclear antigen and terminal transferase dUTP nick end labeling were used to detect the apoptosis of the tumor cells. Immunohistochemistry SP staining was used to measure the expression of p53 protein. The protein levels were examined with western blot and ELISA. Meanwhile, microvessel density (MVD) was counted by endothelial cells immunostained by anti CD34 antibody. RESULTS: The results showed that I-125 protests against CRC via increasing the protein level of p53 and decreasing the level of vascular endothelial growth factor (VEGF), leading to the decrease of MVD in CRC (P <0.0001). An effective inhibition dosage of I-125 ranged from 0.4 to 0.8 mCi. CONCLUSIONS: The inhibitory mechanisms of iodine on CRC acted through an increase in the level of p53 and a decrease in the level of VEGF, resulting in a decrease of MVD. PMID- 25033897 TI - Whole Slide Imaging of Pap Cell Block Preparations versus Liquid-Based Thin-Layer Cervical Cytology: A Comparative Study Evaluating the Detection of Organisms and Nonneoplastic Findings. AB - OBJECTIVE: Cervical cancer is one of the most common malignancies worldwide, yet it is preventable by population screening. In a previous study, we confirmed the feasibility of utilizing whole slide imaging (WSI) of cell block (CB) preparations to overcome the limitations of digitizing cytologic samples. In this study, we evaluated the accuracy of WSI in identifying various organisms and nonneoplastic findings. STUDY DESIGN: A total of 335 WS images from Pap CB preparations were analyzed using the Aperio system. The test performance characteristics of ThinPrep (TP) and WSI samples were compared for adequacy, for the presence of bacterial vaginosis (BV), fungi, Trichomonas vaginalis (TV) and herpes simplex virus (HSV) and for nonneoplastic findings. RESULTS: The WSI samples contained optimal material from all preparations. BV was diagnosed in 33 WSI versus 36 TP samples. Budding yeasts and/or pseudohyphal forms were noted in 18 WSI versus 19 TP samples. TV organisms (10 of 11 samples) and 1 HSV case were accurately identified in the WSI and TP samples. Squamous metaplasia, keratosis and reactive/reparative and inflammatory changes were easily identified by WSI. CONCLUSIONS: The concept of WSI from Pap CB preparations is potentially feasible for adoption. Digital remote web-based technology eliminates the need for an individual on site, saving time and resources. PMID- 25033898 TI - Trendelenburg positioning with temporal approach for vitreoretinal surgery in a patient with severe kyphosis. PMID- 25033899 TI - A safety audit of the first 10 000 intravitreal ranibizumab injections performed by nurse practitioners. AB - PURPOSE: To evaluate the safety of a nurse practitioner (NP)-delivered injection service for the treatment of wet age-related macular degeneration (wAMD) with ranibizumab. METHODS: An evaluation of medical staffing resources for providing an injection service for wAMD highlighted difficulties covering lists. An alternative strategy of an NP-delivered injection service was evaluated. Two suitable NPs with previous extensive experience in minor surgical procedures were identified. The department's senior vitreo-retinal consultant supervised the NP's training programme. A prospective safety audit was conducted for the first 5.5 years of the service. RESULTS: The NPs administered 10 006 injections in the first 5.5 years of the service (1 May 2008 to 8 October 2013). This represented 84.1% of the total injections performed during this period. Four patients developed presumed infectious endophthalmitis (1 was culture positive and 3 were culture negative). The incidence of post-injection endophthalmitis was 0.04%. There was no evidence of lens touch, retinal detachment, or systemic thrombo embolic events. CONCLUSIONS: Carefully selected and well-trained NPs are capable of delivering a safe and effective wAMD injection treatment service. This work demonstrates how such a service can be established and provides safety data that other units can use as a benchmark when evaluating their own practice. PMID- 25033900 TI - Changes in corneal sensation following 20 and 23 G vitrectomy in diabetic and non diabetic patients. AB - PURPOSE: To evaluate the changes in corneal sensation (CS) following two different port sizes vitrectomy in diabetic and non-diabetic patients. PATIENTS AND METHODS: Patients prepared for pars plana vitrectomy were randomly assigned to four groups: diabetics to either 20 G or 23 G and non-diabetics to either 20 G or 23 G vitrectomy systems. CS was measured using the Cochet-Bonnet aesthesiometer at baseline preoperatively, and at 1 day, 1 week, and 1 month postoperative. RESULTS: A total of 40 eyes of 40 patients were included in this study; 20 patients (20 eyes) in each of the 20-G and 23-G groups. The mean age was 55.51+/-10 years and male/female ratio was 2:3. There were no significant difference between CS at baseline, and at 1 day, 1 week, and 1 month between both the 20-G and 23-G groups. There were significant drops in CSs at 1 day and 1 week for both groups (20 G and 23 G) with incomplete recovery for the 20-G group and complete recovery for the 23-G group. Comparing the two diabetic subgroups (20 G and 23 G) and two non-diabetic subgroups (20 G and 23 G), there were no significant differences in CS between subgroups. Diabetics' eyes had lower CSs throughout the study period in the 20-G and 23-G groups, which was significant at day1 and week 1 postoperatively. CONCLUSION: The vitrectomy procedure showed reduction in CS in the postoperative period with minimal nonsignificant difference between 20 G and 23 G systems. However, diabetics' eyes showed compromised CS preoperatively and a further significant reduction for 1 month postoperatively compared with non-diabetics. PMID- 25033901 TI - Comparison of new motorized injector vs manual injector for implantation of foldable intraocular lenses on wound integrity: an ASOCT study. AB - PURPOSE: To compare intraocular lens implantation using a motorized injector vs standard manual injector through a 2.2-mm clear corneal incision. METHODS: Patients underwent standard phacoemulsification using a 2.2-mm clear corneal incision. Hydrophobic acrylic aspheric intraocular lens (Acrysof SN60WF intraocular lens (IOL)) was inserted using D cartridge with manual monarch injector or autosert motorized injector. IOL safety, final incision size and wound integrity in terms of anterior and posterior wound gape, and descemet's membrane detachment were compared between the two groups at post-operative day 1 and at 1 month using Anterior Segment Optical Coherence Tomography. RESULTS: The study recruited 32 patients in the group I (manual injector) and 30 patients in group II (motorized injector). In group I, the final incision after IOL insertion increased by 0.12 mm (95% CI: 0.134-0.106) (P<0.0001), which was seen in 100% of the patients. In group II, the incision enlarged by 0.01 (95% CI: 0.021-0.0.001) (P=0.07) and was seen in only 6.67% of the cases. IOL nicks were seen in 9.37% of the cases in group I only. Although the incidence of descemet's membrane detachment and anterior wound gape was similar for both groups, posterior wound gape was seen more often with the manual injector in the immediate post-operative period. (P=0.018) CONCLUSION: The motorized insertion system was gentle and safe for the IOLs with lesser incidence of IOL nicks. Regarding wound safety, it caused significantly less incision enlargement and better posterior wound integrity. PMID- 25033902 TI - Emmetropization, visual acuity, and strabismus outcomes among hyperopic infants followed with partial hyperopic corrections given in accordance with dynamic retinoscopy. AB - OBJECT: To record emmetropization, visual acuity, and strabismus outcomes among hyperopic infants followed with partial hyperopic corrections given in accordance with dynamic retinoscopy (DR). METHODS: Infants (3.5-12 months of age) with >=5 D hyperopia were followed without glasses or partial hyperopic corrections prescribed according to their near dynamic accommodative abilities determined by DR responses at the initial visit and follow-ups. Refraction and binocular accommodative ability assessments were made at 3-month intervals up to the age of 1 and at 6-month intervals afterwards for a mean 35.4+/-2.1 months; main outcome measures being the development of esotropia, emmetropization rate, and visual acuity level after emmetropization period. RESULTS: Among 211, 146 were normal accommodators initially (Group 1). These infants were followed without treatment and none presented with strabismus. Sixty-five infants were hypo-accommodators (Group 2) and received minimum DR-based corrections. Of the 65 infants 31 (48%) developed strabismus (Group 2B). The remaining 34 constituted Group 2A. Each of the three groups showed an overall reduction of hyperopia by 0.37+/-0.25 days per year, 0.50+/-0.28 days per year, and 0.60+/-0.20 days per year, respectively. Visual acuity assessments among Groups 1 and 2A revealed normal values (0.2-0.0 LogMAR); among Group 2B 19% were within normal range. CONCLUSIONS: Binocular accommodative behavior at the initial visit seems to be one of the indicators for pointing out infants at risk of developing strabismus and amblyopia. Prescription of DR-based corrections to hyperopic orthotropic infants does not impede emmetropization and result in normal visual acuities after emmetropization period. PMID- 25033903 TI - Effect of intracameral phenylephrine on systemic blood pressure. PMID- 25033904 TI - Perfluropropane (C3F8) gas injection followed by deep anterior lamellar keratoplasty (DALK) in severe keratoconus. PMID- 25033905 TI - T cell memory: Metabolic self-reliance. PMID- 25033906 TI - Cytokines: Tipping TB off balance. PMID- 25033908 TI - Mucosal immunology: two routes to success. PMID- 25033907 TI - Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. AB - The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species. PMID- 25033910 TI - Two adjustment strategies for imputation across genotyping arrays. AB - Genotype imputation is a powerful approach in genome-wide association studies (GWAS) because it can provide higher resolution for associated regions and facilitate meta-analysis. However, bias can exist if different genotyping arrays are used and are unbalanced for case versus control subjects. The intersection imputation strategy [imputation based on single nucleotide polymorphisms (SNPs) available on all arrays] is a valid strategy that eliminates the bias caused by unbalanced genotyping, but achieved at the expense of reduced statistical power. In order to improve power in this situation, we introduce two new strategies: the replacement strategy based on the imputation quality score (IQS) >=0.9 and the correction strategy. The IQS is a score that we have previously introduced based on Cohen's kappa of rater agreement. The replacement strategy with IQS >=0.9 is a hybrid approach that utilizes measured genotypes for SNPs available on one or more of all arrays whenever the SNP has a high imputation quality (defined by IQS >=0.9). The correction strategy combines measured genotypes as well as imputed and corrected genotype dosages for SNPs available on one or more of all arrays. The correction strategy yields a valid statistical test, while the replacement strategy with IQS >=0.9 eliminates most spurious associations. Both strategies maintain statistical power. PMID- 25033909 TI - OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids. AB - Recent discoveries in the field of innate immunity have highlighted the existence of a family of nucleic acid-sensing proteins that have similar structural and functional properties. These include the well-known oligoadenylate synthase (OAS) family proteins and the recently identified OAS homologue cyclic GMP-AMP (cGAMP) synthase (cGAS). The OAS proteins and cGAS are template-independent nucleotidyltransferases that, once activated by double-stranded nucleic acids in the cytosol, produce unique classes of 2'-5'-linked second messenger molecules, which - through distinct mechanisms - have crucial antiviral functions. 2'-5' linked oligoadenylates limit viral propagation through the activation of the enzyme RNase L, which degrades host and viral RNA, and 2'-5'-linked cGAMP activates downstream signalling pathways to induce de novo antiviral gene expression. In this Progress article, we describe the striking functional and structural similarities between OAS proteins and cGAS, and highlight their roles in antiviral immunity. PMID- 25033911 TI - Self-assembly and modular functionalization of three-dimensional crystals from oppositely charged proteins. AB - Multicomponent crystals and nanoparticle superlattices are a powerful approach to integrate different materials into ordered nanostructures. Well-developed, especially DNA-based, methods for their preparation exist, yet most techniques concentrate on molecular and synthetic nanoparticle systems in non-biocompatible environment. Here we describe the self-assembly and characterization of binary solids that consist of crystalline arrays of native biomacromolecules. We electrostatically assembled cowpea chlorotic mottle virus particles and avidin proteins into heterogeneous crystals, where the virus particles adopt a non-close packed body-centred cubic arrangement held together by avidin. Importantly, the whole preparation process takes place at room temperature in a mild aqueous medium allowing the processing of delicate biological building blocks into ordered structures with lattice constants in the nanometre range. Furthermore, the use of avidin-biotin interaction allows highly selective pre- or post functionalization of the protein crystals in a modular way with different types of functional units, such as fluorescent dyes, enzymes and plasmonic nanoparticles. PMID- 25033912 TI - High-risk borderline ovarian tumors: analysis of clinicopathological features and prognostic impact of different follow-up strategies. AB - OBJECTIVES: Borderline ovarian tumors (BOTs) represent 10-20% of all epithelial ovarian malignancies. Most of them are comparable to benign cysts but a high-risk group has been recognized. The aim of the study was to analyze different follow up strategies in high-risk patients. METHOD: Patients with BOT treated at our institution from 1992 to 2011 were retrospectively reviewed. Clinicopathological features influencing prognosis were analyzed and two different follow-up strategies compared [6-month laparoscopic look (LPS-look): group A vs. ultrasound/CA-125 evaluation: group B]. RESULTS: 70 patients with high-risk BOTs were identified. After a median progression-free survival (PFS) of 43 months, 27% of patients experienced recurrences. Six months after diagnosis, 26 high-risk patients were submitted to LPS-look: at surgery, 6 out of 10 patients presenting evidence of disease were optimally debulked while in the remaining 4, only biopsies were performed. No difference in PFS was registered between group A and B patients, nevertheless a significant increase in PFS was registered among completely versus incompletely debulked patients with evidence of disease at laparoscopy. CONCLUSION: Clinical follow-up remains the gold standard for BOTs. These very preliminary data seem to suggest that LPS-look may have an impact on the secondary PFS in a subgroup of high-risk patients. PMID- 25033913 TI - Novel technique for pediatric ostial cardioplegia delivery. AB - Antegrade ostial cardioplegia is an important mode of cardioplegia administration in pediatric patients. We present our innovative, simple, and cost-effective method of pediatric ostial cardioplegia delivery. PMID- 25033914 TI - Rigorous patient-prosthesis matching of Perimount Magna aortic bioprosthesis. AB - BACKGROUND: Severe patient-prosthesis mismatch, defined as effective orifice area index <=0.65 cm(2) m(-2), has demonstrated poor long-term survival after aortic valve replacement. Reported rates of severe mismatch involving the Perimount Magna aortic bioprosthesis range from 4% to 20% in patients with a small annulus. METHODS: Between June 2008 and August 2011, 251 patients (mean age 70.5 +/- 10.2 years; mean body surface area 1.55 +/- 0.19 m(2)) underwent aortic valve replacement with a Perimount Magna bioprosthesis, with or without concomitant procedures. We performed our procedure with rigorous patient-prosthesis matching to implant a valve appropriately sized to each patient, and carried out annular enlargement when a 19-mm valve did not fit. The bioprosthetic performance was evaluated by transthoracic echocardiography predischarge and at 1 and 2 years after surgery. RESULTS: Overall hospital mortality was 1.6%. Only 5 (2.0%) patients required annular enlargement. The mean follow-up period was 19.1 +/- 10.7 months with a 98.4% completion rate. Predischarge data showed a mean effective orifice area index of 1.21 +/- 0.20 cm(2) m(-2). Moderate mismatch, defined as effective orifice area index <=0.85 cm(2) m(-2), developed in 4 (1.6%) patients. None developed severe mismatch. Data at 1 and 2 years showed only two cases of moderate mismatch; neither was severe. CONCLUSIONS: Rigorous patient prosthesis matching maximized the performance of the Perimount Magna, and no severe mismatch resulted in this Japanese population of aortic valve replacement patients. PMID- 25033915 TI - Unruptured right sinus of Valsalva aneurysm dissecting into ventricular septum. PMID- 25033916 TI - Right ventricular perforation caused by Swan-Ganz pacing catheter. PMID- 25033917 TI - Leiomyosarcoma of the inferior vena cava. AB - Inferior vena cava leiomyosarcoma is a rare tumor with a variety of symptoms. A 41-year-old woman was admitted with nonspecific epigastric pain. Computed tomography revealed a dense mass between the inferior vena cava and the liver. The patient underwent successful resection of the mass. The pathologic study confirmed leiomyosarcoma. Adjuvant radiation therapy was completed, and after 12 months of follow-up, the patient had no problems. PMID- 25033918 TI - The nightmare of indeterminate follicular proliferations: when liquid-based cytology and ancillary techniques are not a moon landing but a realistic plan. AB - OBJECTIVE: Thyroid nodules are a common finding in the general population, including both nonneoplastic and neoplastic entities. Fine-needle aspiration cytology (FNAC) is the first tool for evaluating thyroid nodules. In spite of its high diagnostic accuracy, 25% of nodules result in the category of follicular neoplasms (FN), with varying risk of malignancy and different management strategies. STUDY DESIGN: The use of ancillary techniques is reshaping the practice of FNAC. These tools can significantly empower the morphological diagnosis and prognosis of thyroid nodules, allowing a more accurate prediction of the nature of the lesion. Several studies have underlined the role of single or multiple testing for the category of FN as strong indicators of cancer. Every cytological preparation can be used for the application of ancillary techniques but the introduction of liquid-based cytology (LBC) might facilitate the application. RESULTS: Our experience involving an immunocytochemical panel made up of HBME-1 and galectin-3 pointed to an 81% overall diagnostic accuracy in discriminating between low and high risk of malignancy in FN. CONCLUSIONS: The application of these techniques on LBC represents an adjunct to the morphological evaluation of FN. They represent a critical and challenging, but also a feasible, tool in the preoperative diagnoses, allowing specific prognostic and predictive details regardless of the cytological preparation. (c) 2014 S. Karger AG, Basel. PMID- 25033919 TI - Acupuncture versus solifenacin for treatment of overactive bladder and its correlation with urine nerve growth factor levels: a randomized, placebo controlled clinical trial. AB - OBJECTIVE: To determine whether acupuncture is effective as an overactive bladder (OAB) treatment compared with solifenacin and placebo, and to investigate its relation with urine nerve growth factor (NGF) levels. PATIENTS AND METHODS: The study was conducted with methodological rigor based on the Consolidated Standards of Reporting Trials criteria. 90 female patients with OAB were included and randomly assigned to a solifenacin, acupuncture or placebo group. The medicated group received solifenacin 5 mg/day; the acupuncture and placebo groups were treated twice a week for 4 weeks. Symptom scores, quality of life scores, frequency of micturition and urine NGF levels were used to assess treatment efficiency. RESULTS: The study was completed with 82 patients (n = 30 in the solifenacin group, n = 28 in the acupuncture group and n = 24 in the placebo group). After treatment, comparison of the medical and acupuncture therapy groups with the placebo group showed significant differences between recovery concerning quality of life (p < 0.001 and p < 0.01, respectively) and symptom scores (p < 0.001 and p < 0.001, respectively). The decrease of NGF levels after treatment compared to before treatment was determined in each group (solifenacin, acupuncture, placebo group; p < 0.001, p < 0.001, p = 0.359, respectively). Sufficient symptomatic improvement was not achieved in 8 patients in the acupuncture group. Therefore, comparisons were assessed twice with and without including these patients, and NGF levels in the acupuncture group were higher than at first comparison in which all patients in the acupuncture group were included. CONCLUSIONS: In patients with OAB in whom anticholinergic treatment is contraindicated, acupuncture may be considered another treatment option. PMID- 25033920 TI - Long-term outcome of biologic graft: a case report. AB - INTRODUCTION: Biologic grafts have been shown to support tissue regeneration in various animal models. Very few reports in the literature exist to show tissue remodeling in patients after placement of a biologic graft. CASE PRESENTATION: We report the case of a 69-year-old Caucasian man with a history of small bowel carcinoid resection and concurrent recurrent ventral hernia repair with component separation and underlay biologic graft placement who underwent re-operation for metastatic carcinoid tumor to his liver. Complete incorporation of the biologic graft was observed. Tissue analysis of the incised midline fascia revealed tissue remodeling at the site of the previous abdominal wall defect. CONCLUSION: Placement of a biologic graft in ventral hernia repair supports tissue regeneration similar to that previously reported in animal models. PMID- 25033921 TI - Experience with new techniques for the treatment of type II endoleaks post-EVAR. AB - Endovascular aneurysm management (EVAR) is hampered by persistent arterial blood flow in the aneurysm sac after treatment, known as endoleak (EL). Type II EL consist of blood flow from one or more aortic branch vessels; they only require treatment when the aneurysm sac fails to shrink. Post-EVAR follow up is mostly done with contrast enhanced computed tomography. If a type II EL requiring treatment is found, a variety of options exist, depending on the source of EL and the anatomy. Inferior mesenteric artery EL is best treated by endovascular embolization through the superior mesenteric artery and Riolans' arc. In hypogastric to lumbar artery EL success of endovascular treatment is limited. In these cases a successful embolization of the EL can often be performed by a direct percutaneous approach to the EL inside the aneurysmal sac. CT guidance provides a good way to exactly puncture the EL percutaneously in most cases, but limited workspace and lack of fluoroscopy availability for the ensuing catheter manipulation hampers this technique. A novel way to puncture the EL and subsequently treat it is performed on flat panel detector angiography units. By a rotation around the patients these units provide the possibility to create a cone beam CT (CBCT) in the angio suite. Using the 3-dimensional dataset thus acquired, a needle path can be planned and the EL nidus can be punctured with great confidence and without danger of inadvertently perforating vital structures. After the EL has been punctured, microcatheters can be inserted to embolize the origins of branch vessels and/or the aneurysm sac can be filled with thrombogenic agents or glue. CBCT guided procedures incur lower radiation dose and have higher accuracy compared to conventional CT guided procedures. Details of CBCT guided procedures; the materials and technique used are detailed in this manuscript. PMID- 25033922 TI - Leotia cf. lubrica forms arbutoid mycorrhiza with Comarostaphylis arbutoides (Ericaceae). AB - Arbutoid mycorrhizal plants are commonly found as understory vegetation in forests worldwide where ectomycorrhiza-forming trees occur. Comarostaphylis arbutoides (Ericaceae) is a tropical woody plant and common in tropical Central America. This plant forms arbutoid mycorrhiza, whereas only associations with Leccinum monticola as well as Sebacina sp. are described so far. We collected arbutoid mycorrhizas of C. arbutoides from the Cerro de la Muerte (Cordillera de Talamanca), Costa Rica, where this plant species grows together with Quercus costaricensis. We provide here the first evidence of mycorrhizal status for the Ascomycete Leotia cf. lubrica (Helotiales) that was so far under discussion as saprophyte or mycorrhizal. This fungus formed arbutoid mycorrhiza with C. arbutoides. The morphotype was described morphologically and anatomically. Leotia cf. lubrica was identified using molecular methods, such as sequencing the internal-transcribed spacer (ITS) and the large subunit (LSU) ribosomal DNA regions, as well as phylogenetic analyses. Specific plant primers were used to confirm C. arbutoides as the host plant of the leotioid mycorrhiza. PMID- 25033923 TI - Arbuscular mycorrhiza mediates glomalin-related soil protein production and soil enzyme activities in the rhizosphere of trifoliate orange grown under different P levels. AB - Glomalin-related soil protein (GRSP) is beneficial to soil and plants and is affected by various factors. To address whether mycorrhizal-induced GRSP and relevant soil enzymes depend on external P levels, a pot study evaluated effects of the arbuscular mycorrhizal fungus (AMF) Funneliformis mosseae on GRSP production and soil enzyme activities. Three GRSP categories, as easily extractable GRSP (EE-GRSP), difficultly-extractable GRSP (DE-GRSP), and total (EE GRSP + DE-GRSP) GRSP (T-GRSP), were analyzed, together with five enzyme activities (beta-glucosidase, catalase, peroxidase, phosphatase, polyphenol oxidase) in the rhizosphere of trifoliate orange (Poncirus trifoliata) grown under 0, 3, and 30 mM KH2PO4 in a sand substrate. After 4 months, root AM colonization and substrate hyphal length decreased with increasing P levels. Shoot, root, and total biomass production was significantly increased by AM colonization, regardless of P levels, but more profound under 0 mM P than under 30 mM KH2PO4. In general, production of these three GRSP categories under 0 or 30 mM KH2PO4 was similar in non-mycorrhizosphere but decreased in mycorrhizosphere. Mycorrhization significantly increased the production of EE-GRSP, DE-GRSP and T GRSP, soil organic carbon (SOC), and activity of substrate beta-glucosidase, catalase, peroxidase, and phosphatase, but decreased polyphenol oxidase activity, irrespective of P levels. Production of EE-GRSP, DE-GRSP, and T-GRSP significantly positively correlated with SOC and beta-glucosidase, catalase, and peroxidase activity, negatively with polyphenol oxidase activity, but not with hyphal length or phosphatase activity. These results indicate that AM-mediated production of GRSP and relevant soil enzyme activities may not depend on external P concentrations. PMID- 25033924 TI - Arbuscular mycorrhizal symbiosis can mitigate the negative effects of night warming on physiological traits of Medicago truncatula L. AB - Elevated night temperature, one of the main climate warming scenarios, can have profound effects on plant growth and metabolism. However, little attention has been paid to the potential role of mycorrhizal associations in plant responses to night warming, although it is well known that symbiotic fungi can protect host plants against various environmental stresses. In the present study, physiological traits of Medicago truncatula L. in association with the arbuscular mycorrhizal (AM) fungus Rhizophagus irregularis were investigated under simulated night warming. A constant increase in night temperature of 1.53 degrees C significantly reduced plant shoot and root biomass, flower and seed number, leaf sugar concentration, and shoot Zn and root P concentrations. However, the AM association essentially mitigated these negative effects of night warming by improving plant growth, especially through increased root biomass, root to shoot ratio, and shoot Zn and root P concentrations. A significant interaction was observed between R. irregularis inoculation and night warming in influencing both root sucrose concentration and expression of sucrose synthase (SusS) genes, suggesting that AM symbiosis and increased night temperature jointly regulated plant sugar metabolism. Night warming stimulated AM fungal colonization but did not influence arbuscule abundance, symbiosis-related plant or fungal gene expression, or growth of extraradical mycelium, indicating little effect of night warming on the development or functioning of AM symbiosis. These findings highlight the importance of mycorrhizal symbiosis in assisting plant resilience to climate warming. PMID- 25033925 TI - Study protocol: a randomised placebo-controlled clinical trial to study the effect of vitamin D supplementation on glycaemic control in type 2 Diabetes Mellitus SUNNY trial. AB - BACKGROUND: Besides the classical role of vitamin D on calcium and bone homeostasis, vitamin D deficiency has recently been identified as a contributing factor in the onset of insulin resistance in type 2 diabetes mellitus. However, it is uncertain whether vitamin D deficiency and poor glycaemic control are causally interrelated or that they constitute two independent features of type 2 diabetes mellitus. There are limited clinical trials carried out which measured the effect of vitamin D supplementation on glycaemic control.The objective of this study is to investigate the effect of vitamin D supplementation on glycaemic control and quality of life in patients with type 2 diabetes mellitus. METHODS/DESIGN: In a randomised double-blind placebo-controlled trial conducted in five general practices in the Netherlands three hundred patients with type 2 diabetes mellitus treated with lifestyle advises or metformin or sulphonylurea derivatives are randomised to receive either placebo or 50,000 IU Vitamin D3 at monthly intervals. The primary outcome measure is the change in glycated haemoglobin level between baseline and six months. Secondary outcome measures include blood pressure, anthropometric parameters, lipid profile, insulin resistance, quality of life, advanced glycation end products and safety profiles. Quality of life will be measured by The Short Form (SF-36) Health Survey questionnaire. Advanced glycation end products are measured by an AGE-reader. DISCUSSION: This trial will be the first study exploring the effect of vitamin D supplementation on both glycaemic control and quality of life in patients with type 2 diabetes mellitus. Our findings will contribute to the knowledge of the relationship between vitamin D status and insulin resistance in patients with type 2 diabetes mellitus. TRIAL REGISTRATION: The Netherlands trial register: NTR3154. PMID- 25033926 TI - Description of cardiovascular event rates in patients initiating chronic opioid therapy for noncancer pain in observational cohort studies in the US, UK, and Germany. AB - INTRODUCTION: Previous observational studies in the US suggest that opioid analgesic use increases the risk of cardiovascular (CV) events. The current study provides additional background event rates for five prespecified CV outcomes of interest in patients from three countries. METHODS: Three observational cohort studies were conducted in patients from the US (N = 17,604), the UK (N = 9,823), and Germany (N = 9,412). Patients were new opioid users who had undergone >=6 months of chronic, continuous therapy. De-identified data were collated from electronic healthcare databases in the respective countries. Demographics, clinical characteristics, and opioid use were examined. Overall rates, prevalence rates in patients with established CV disease, and incidence rates in patients without established CV disease were determined for myocardial infarction (MI), stroke, transient ischemic attack, unstable angina, and congestive heart failure (CHF). RESULTS: Cardiovascular disease at baseline was more prevalent in US and German patients. Back pain and depression were prevalent preexisting comorbidities. The majority of patients were using various weak opioids (based on receptor affinities), CV medications, and antidepressants. Overall rates by individual CV outcome per 1,000 patient-years by country were greatest for CHF (US 37.2, 95% CI 24.1-40.5), unstable angina (UK 8.2, 95% CI 7.0-9.6), and stroke (Germany 5.3, 95% CI 4.1-6.7). Overall rates for MI were: US, 10.7 (95% CI 9.1 12.5), UK, 6.7 (95% CI 5.6-8.0), and Germany, 2.7 (95% CI 1.9-3.7). Overall rates for each CV outcome, prevalence rates in patients with preexisting CV disease, and incidence rates in patients without established CV disease differed by country. Rates were higher in patients with preexisting CV disease. CONCLUSIONS: CV risk for new opioid users with >=6 months of therapy was increased in patients with established CV disease compared with those without established CV disease, and the risk for specific outcomes differed by country. Assessment of CV safety events of new therapies introduced to chronic opioid users should consider sample size and population heterogeneity in the design of an observational study. PMID- 25033927 TI - The galU gene of Xanthomonas campestris pv. campestris is involved in bacterial attachment, cell motility, polysaccharide synthesis, virulence, and tolerance to various stresses. AB - Uridine triphosphate (UTP)-glucose-1-phosphate uridylyltransferase (GalU; EC 2.7.7.9) is an enzyme that catalyzes the formation of uridine diphosphate (UDP) glucose from UTP and glucose-1-phosphate. GalU is involved in virulence in a number of animal-pathogenic bacteria since its product, UDP-glucose, is indispensable for the biosynthesis of virulence factors such as lipopolysaccharide and exopolysaccharide. However, its function in Xanthomonas campestris pv. campestris, the phytopathogen that causes black rot in cruciferous plants, is unclear. Here, we characterized a galU mutant of X. campestris pv. campestris and showed that the X. campestris pv. campestris galU mutant resulted in a reduction in virulence on the host cabbage. We also demonstrated that galU is involved in bacterial attachment, cell motility, and polysaccharide synthesis. Furthermore, the galU mutant showed increased sensitivity to various stress conditions including copper sulfate, hydrogen peroxide, and sodium dodecyl sulfate. In addition, mutation of galU impairs the expression of the flagellin gene fliC as well as the attachment-related genes xadA, fhaC, and yapH. In conclusion, our results indicate involvement of galU in the virulence factor production and pathogenicity in X. campestris pv. campestris, and a role for galU in stress tolerance of this crucifer pathogen. PMID- 25033928 TI - Human recombinant factor VIIa may improve heat intolerance in mice by attenuating hypothalamic neuronal apoptosis and damage. AB - Intolerance to heat exposure is believed to be associated with hypothalamo pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 degrees C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65-270 ug/kg of body weight) and then returned to room temperature (26 degrees C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1beta, tumor necrosis factor-alpha) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated alphaUTP nick-end labeling, caspase-3 positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 degrees C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage) in mice. PMID- 25033929 TI - Comparison of metal stenting with radiofrequency ablation versus stenting alone for treating malignant biliary strictures: is there an added benefit? AB - BACKGROUND: Radiofrequency ablation (RFA) has been reported to be a beneficial treatment option for palliation of malignant biliary strictures. Biliary obstruction is a common complication in pancreatic and cholangiocarcinoma and many patients require stenting for definitive decompression. The objective of this study was to compare the survival duration of patients as well as safety and efficacy of RFA and metal stent versus stent alone. METHODS: A prospectively established database was analyzed retrospectively and extracted 64 patients with malignant biliary strictures. Patients who underwent RFA with metal stenting were compared to those who were treated conventionally with metal stenting alone. The groups were matched on age, diagnosis, performance status, and palliative chemotherapy. Immediate and 30-day adverse events were recorded. Survival and Cox proportional hazard analyses were calculated. RESULTS: RFA and control groups were closely matched in terms of age (65.5 +/- 13.4 vs. 66.8 +/- 12.16 years, p = 0.069) and diagnosis [cholangiocarcinoma (36) and pancreatic cancer (28)]. Technical success rate for both groups was 100 %. Multivariable Cox proportional regression analysis showed RFA to be an independent predictor of survival [HR 0.29 (0.11-0.76), p = 0.012] as well as age and receipt of chemotherapy [HR 1.04 (1.01-1.07), p = 0.011; HR 0.26 (0.10-0.70), p = 0.007]. Overall self-expanding metal stent patency rates were the same across both groups. CONCLUSION: RFA appears to improve survival in patients with end-stage cholangiocarcinoma and pancreatic cancer. In a disease with limited treatment options, this modality may prove to be beneficial compared to stenting alone. Randomized controlled trials and evaluation of quality of life measures should be performed to confirm these findings. PMID- 25033930 TI - Larynx during exercise: the unexplored bottleneck of the airways. AB - Exercise-induced shortness of breath is not uncommon in otherwise healthy young people. Based on the presenting symptoms alone, it is challenging to distinguish exercise-induced asthma (EIA) from exercise-induced obstruction of central airways, sometimes leading to diagnostic errors and inadequate treatment. Central airway obstruction usually presents with exercise-induced inspiratory symptoms (EIIS) during ongoing exercise. EIIS tends to peak towards the end of an exercise session or immediately after its completion, contradicting symptoms of EIA typically peaking 3-15 min after the exercise has stopped. EIIS is usually associated with some form of laryngeal obstruction. Transnasal flexible laryngoscopy performed continuously throughout an incremental exercise test from rest to exhaustion or to intolerable symptoms is usually diagnostic, and also provides information that is important for further handling and treatment. Reflecting the complex anatomy and functional features of the larynx, exercise induced laryngeal obstruction (EILO) appears to be a heterogeneous condition. Contradicting previous beliefs, recent literature suggests that laryngeal adduction in a majority of cases starts in supraglottic structures and that vocal cord adduction (VCD) most often occurs as a secondary phenomenon. However, EILO is poorly understood and more and better research is needed to unravel causal mechanisms. The evidence base for treatment of EILO is weak. Speech therapy, psychotherapy, biofeedback, muscle training, anticholinergic aerosols have all been applied, as has laser supraglottoplasty. Randomized controlled trials with well-defined and verifiable inclusion and success criteria are required to establish evidence-based treatment schemes. PMID- 25033931 TI - Videolaryngostroboscopy versus microlaryngoscopy for the diagnosis of benign vocal cord lesions: a prospective clinical study. AB - The aim of this study is to prospectively compare rigid videolaryngostroboscopy with microlaryngoscopy for the diagnosis of benign vocal cord lesions. Eighty five adult patients with benign vocal cord lesions were evaluated with videolaryngostroboscopy and later underwent microlaryngoscopy. During microlaryngoscopy, systematic examination of the glottis was conducted, including careful inspection and meticulous palpation of the vocal cords from anterior commissure to arytenoids. Preoperative and intraoperative diagnoses were analyzed. One hundred and forty-one lesions were diagnosed preoperatively with rigid videolaryngostroboscopy in 85 patients. Microlaryngoscopy revealed a total of 199 lesions in these patients, demonstrating a 41.1 % higher diagnostic yield. Forty-five (77.6 %) of the 58 additional lesions involved structural abnormalities, including sulcus vocalis, microwebs, vascular ectasia, mucosal bridges, and anterior web. The preoperative diagnosis was consistent with the postoperative diagnosis in only 29 patients (34.2 %). For the rest of the patients (n = 56, 65.8 %), the preoperative diagnosis was either changed, or new lesions were identified during microlaryngoscopy. Intraoperative diagnosis of benign vocal cord lesions differs significantly from preoperative diagnosis, regarding both the type and number of lesions present. A large proportion of patients diagnosed with videolaryngostroboscopy have additional lesions, particularly structural abnormalities. Precise inspection and palpation of vocal cords are thus essential during microlaryngoscopy. PMID- 25033932 TI - Phosphoinositide 3-kinase gamma affects LPS-induced disturbance of blood-brain barrier via lipid kinase-independent control of cAMP in microglial cells. AB - The breakdown of the blood-brain barrier (BBB) is a key event in the development of sepsis-induced brain damage. BBB opening allows blood-born immune cells to enter the CNS to provoke a neuroinflammatory response. Abnormal expression and activation of matrix metalloproteinases (MMP) was shown to contribute to BBB opening. Using different mouse genotypes in a model of LPS-induced systemic inflammation, our present report reveals phosphoinositide 3-kinase gamma (PI3Kgamma) as a mediator of BBB deterioration and concomitant generation of MMP by microglia. Unexpectedly, microglia expressing lipid kinase-deficient mutant PI3Kgamma exhibited similar MMP regulation as wild-type cells. Our data suggest kinase-independent control of cAMP phosphodiesterase activity by PI3Kgamma as a crucial mediator of microglial cell activation, MMP expression and subsequent BBB deterioration. The results identify the suppressive effect of PI3Kgamma on cAMP as a critical mediator of immune cell functions. PMID- 25033933 TI - A theoretical and methodological proposal for the descriptive assessment of therapeutic interactions. AB - OBJECTIVE: The goal of this study is to show the development of a strategy for a descriptive assessment of the therapeutic interaction. METHOD: In this study, we develop an observational methodology to analyze the dialogues that took place during 92 sessions conducted in a psychological center in Madrid, Spain, in which 19 adults were treated for various psychological problems by 9 behavioral therapists. A system was developed to codify vocal behavior of both the therapists and the clients; the software The Observer XT was used for recording. Therapeutic interactions were analyzed using sequential analysis. RESULTS: There are three main sequences that synthesize the therapist-client interaction: first, an utterance by the client preceded by a therapist's verbalization, specifically a question (discriminative morphology) and followed by an expression of approval (reinforcement morphology); second, verbalizations of failure or discomfort uttered by the client, followed most often by verbalizations of disapproval (punishing morphology) uttered by the therapist; and third, verbalizations uttered by the client that are discriminated by the therapist after an in-depth explanation and followed by different therapist's utterances (expressions of approval, technical information, etc.). CONCLUSIONS: Depending on how the client responds the results in this study present a starting point for the study of the functional sequences that form the basis of therapeutic change. PMID- 25033934 TI - Health-related determinants of happiness in Korean adults. AB - OBJECTIVES: Happiness has been associated with a range of favorable health outcomes. The aim of this study was to examine the relationships between happiness and health behaviors, stress, and environmental aspects of exercise in a Korean national representative sample. METHODS: This cross-sectional study was conducted using multiple-stratified random sampling on the Korea Census of 2005. In October 2009, investigators conducted 15-min face-to-face interviews with 1,530 South Korean volunteers aged between 30 and 69 years. The questionnaire included questions about sociodemographic factors, perceived stress, smoking, drinking, healthy diet, exercise, exercise environment, and happiness levels. RESULTS: The multivariate analysis revealed that middle-aged participants were less likely to be happy than younger and older participants, and higher happiness was associated with being part of a couple, higher income, lower stress, healthy diet, exercise, and certain exercise environments (e.g., mountain trails). CONCLUSIONS: Besides individual-level sociodemographic conditions, such as income or psychological status, community-level conditions, such as environment, should be considered when national and community public welfare policy is established. PMID- 25033935 TI - WRKY45-dependent priming of diterpenoid phytoalexin biosynthesis in rice and the role of cytokinin in triggering the reaction. AB - Plant activators such as benzothiadiazole (BTH) protect plants against diseases by priming the salicylic acid (SA) signaling pathway. In rice, the transcription factor WRKY45 plays a central role in this process. To investigate the mechanism involved in defense-priming by BTH and the role of WRKY45 in this process, we analyzed the transcripts of biosynthetic genes for diterpenoid phytoalexins (DPs) during the rice-Magnaporthe oryzae interaction. The DP biosynthetic genes were barely upregulated in BTH-treated rice plants, but were induced rapidly after M. oryzae infection in a WRKY45-dependent manner. These results indicate that the DP biosynthetic genes were primed by BTH through WRKY45. Rapid induction of the DP biosynthetic genes was also observed after M. oryzae infection to WRKY45 overexpressing (WRKY45-ox) plants. The changes in gene transcription resulted in accumulation of DPs in WRKY45-ox and BTH-pretreated rice after M. oryzae infection. Previously, we reported that cytokinins (CKs), especially isopentenyladenines, accumulated in M. oryzae-infected rice. Here, we show that DP biosynthetic genes are regulated by the SA/CK synergism in a WRKY45-dependent manner. Together, we propose that CK plays a role in mediating the signal of M. oryzae infection to trigger the induction of DP biosynthetic genes in BTH-primed plants. PMID- 25033936 TI - Positivity to p-ANCA in patients with status epilepticus. AB - BACKGROUND: Status epilepticus (SE) may occur in the setting of several internal or neurologic diseases. Anti-neutrophilic cytoplasmic antibodies (ANCA) are a group of Ig that may be observed in patients with different autoimmune disorders but are particularly associated with systemic vasculitis named ANCA-associated vasculities (AAV). We herein report 3 patients with SE and positivity to p-ANCA. CASE PRESENTATION: One patient had a catastrophic evolution and died 5 months after disease onset. The other two patients had a good outcome and remained seizure-free at 30 months and 5 years of follow-up respectively. CONCLUSION: This report highlights the importance of considering ANCA dosage in patients with SE of unclear origin. PMID- 25033937 TI - Changes of occlusal plane inclination after orthodontic treatment in different dentoskeletal frames. AB - BACKGROUND: The inclination of the occlusal plane (OP) is related to facial types and experiences physiological growth-related changes. The aims of this research were to determine if there were any differences in the inclination of OP in subjects with three types of skeletal malocclusion and to investigate the characteristics and differences of functional occlusal plane (FOP) compared to bisected occlusal plane (BOP). METHODS: A sample of 90 Caucasians patients was skeletal-classified into three (n = 30), and pre- and post-treatment cephalograms were digitized. Six linear and 8 angular cephalometric measurements were selected. The changes of OP inclination within each group and the differences among the three groups pre- and post-treatment were compared with paired t test and ANOVA test, respectively. The comparison and correlation between BOP and FOP were analyzed with paired t test and coefficient of correlation, respectively. RESULTS: The BOP angle increased in all of the three groups but only had statistically significant differences in skeletal class II patients in a mean of 1.51 degrees (p < 0.05). The FOP-SN angle showed stability (p > 0.05) in all three groups. The inclination of FOP was closely related to that of BOP (p < 0.001) but revealed discrepancies in each group. CONCLUSIONS: BOP and FOP were statistically significantly steeper in class II subjects compared to the other two groups both before and after treatment. The BOP angle statistically significantly increased by 1.51 degrees in skeletal class II patients. BOP was a more reproducible reference plane compared to FOP during cephalometric tracing process, while FOP showed stability in orthodontically treated patients with all three skeletal patterns. PMID- 25033938 TI - Malaria prophylaxis and guidelines. AB - BACKGROUND: Malaria prophylaxis recommendations issued by different health authorities in Europe are inhomogeneous, and so is the opinion of experts, but a general trend towards reducing its use is evident, and prescribers apparently adhere more easily to more restrictive recommendations. METHODS AND RESULTS: A new Italian guideline has been produced, looking both at scientific evidence (data on malaria risk and drugs' side effects) and at the opinion of experts (surveys and previously issued recommendations). CONCLUSIONS: Collecting data on imported malaria, stating a clear methodology and introduce a discussion at international level should be the next goals in order to homogenise recommendations for malaria prophylaxis in Europe. PMID- 25033939 TI - Beyond antibiotic selection: concordance with the IDSA guidelines for uncomplicated urinary tract infections. AB - The purpose of this report was to evaluate concordance with the most recent guidelines for the treatment of uncomplicated UTI based on antibiotic selection, dosage, frequency, and duration. A historical review of patients' medical records at a university-based internal medicine clinic was conducted. When aggregated across antibiotic type, frequency, and duration, overall concordance was 33.96 %. Prescribing concordance for uncomplicated UTI in the local region is suboptimal. PMID- 25033940 TI - Current evidence of temozolomide and bevacizumab in treatment of gliomas. AB - OBJECTIVE: This review article summarizes in vitro, in vivo, and clinical evidence pertaining to temozolomide (TMZ) and bevacizumab (BEV) efficacy and mechanism of action in gliomas. METHODS: Relevant publications published before June 2013 in PubMed database were reviewed. RESULTS: Temozolomide and BEV are current chemotherapeutic agents treating patients with high-grade glioma, including glioblastoma. In vitro and in vivo studies have proposed discordant cell death pathways for TMZ as either apoptosis or autophagy using different experimental setting details or cell lines. In addition, BEV may cause cell death through hypoxia-induced autophagy or unspecific indirect effects on cancer cells. The complexity of cancer cells in glioma has contributed to their resistance of both chemotherapies. In clinical trials, overall survival duration in glioma patients with recurrence (8-9 months) is lower than that in newly diagnosed patients (12-15 months). CONCLUSION: Our collected data support the addition of radiotherapy, BEV, and other targeted agents to TMZ treatment, indicating prolonged survival duration in newly diagnosed patients. However, the optimal regimen for treating high-grade glioma cannot be concluded without more clinical trials. PMID- 25033941 TI - Evaluation of three purely polypropylene meshes of different pore sizes in an onlay position in a New Zealand white rabbit model. AB - BACKGROUND: The aim of the study was to evaluate the influence of the pore size of a polypropylene mesh on the shrinkage and elasticity of the mesh-tissue complex and the inflammatory reaction to the implant in an open onlay hernia repair. MATERIALS AND METHODS: Twenty-one 10 * 10 cm samples of polypropylene meshes of a different pore size (3.0 * 2.8 mm-PP3, 1.0 * 0.8 mm-PP1 and 0.6 * 0.5 mm-PP.5) were implanted in an onlay position in 21 New Zealand white rabbits. After 90 days of implantation the shrinkage, elasticity and foreign body reaction (FBR) were assessed. RESULTS: The shrinkage of PP3 was 30.6 +/- 4.3 %, PP1 49.3 +/- 2.9 % and PP.5 49.5 +/- 2.6 %. The shrinkage of PP3 was significantly lower (PP3 * PP1 p = 0.007, PP3 * PP.5 p = 0.005), PP1 and PP.5 were similar. The elasticity was similar. The strength of FBR in mesh pores was similar. The width of foreign body granuloma layers at the mesh-tissue interface was significantly reduced with increasing pore size (inner: PP3 10.1 +/- 1.2; PP1 12.5 +/- 2.9; PP.5 17.4 +/- 5.2 and outer: PP3 21.2 +/- 2.5; PP1 30.6 +/- 6.3; PP.5 60.4 +/- 14.9). All differences between the widths of granuloma layers were statistically significant (p < 0.010). One animal (PP1) was excluded because of a mesh infection. CONCLUSIONS: Implantation of polypropylene mesh of a pore size of 3 mm in an onlay position is associated with a significant reduction of shrinkage in comparison to a 1 mm pore lightweight and 0.5 mm pore heavyweight mesh. A pore size increase to 3 mm is not sufficient for an improvement of mesh-tissue complex elasticity in comparison to a 1 mm pore lightweight and 0.5 mm heavyweight mesh. Polypropylene mesh with enlarged pores to 3 mm is associated with a similar strength of FBR in mesh pores and a reduced foreign body granuloma in comparison to a 1 mm pore lightweight and 0.5 mm pore heavyweight mesh. PMID- 25033942 TI - Effect of botulinum toxin type A in lateral abdominal wall muscles thickness and length of patients with midline incisional hernia secondary to open abdomen management. AB - PURPOSE: Abdominal wall hernia secondary to open abdomen management represents a surgical challenge. The hernia worsens due to lateral muscle retraction. Our objective was to evaluate if Botulinum Toxin Type A (BTA) application in lateral abdominal wall muscles modifies its thickness and length. METHODS: A clinical trial of male trauma patients with hernia secondary to open abdomen management was performed from January 2009 to July 2011. Thickness and length of lateral abdominal muscles were measured by a basal Computed Tomography and 1 month after BTA application. A dosage of 250 units of BTA was applied at five points at each side between the external and internal oblique muscles under ultrasonographic guidance. Statistical analysis for differences between basal and after BTA application measures was performed by a paired Student's t test (significance: p < 0.05). RESULTS: Seventeen male patients with a mean age of 35 years were included. There were muscle measure modifications in all the patients. Left muscle thickness: mean reduction of 1 +/- 0.55 cm (p < 0.001). Right muscle thickness: mean reduction of 1.00 +/- 0.49 cm (p < 0.001). Left muscle length: mean increase of 2.44 +/- 1.22 cm (p < 0.001). Right muscle length: mean increase of 2.59 +/- 1.38 cm (p < 0.001). No complications secondary to BTA or recurrences at mean follow-up of 49 months were observed. CONCLUSIONS: BTA application in lateral abdominal muscles decreases its thickness and increases its length in abdominal wall hernia patients secondary to open abdomen management. PMID- 25033943 TI - Meta-analysis and review of prospective randomized trials comparing laparoscopic and Lichtenstein techniques in recurrent inguinal hernia repair. AB - PURPOSE: The hypothesis of this meta-analysis was to assess whether laparoscopic approach shows real benefits over Lichtenstein technique in recurrent inguinal hernia repair. METHODS: A literature search for prospective randomized trials comparing laparoscopic and Lichtenstein procedure in recurrent inguinal hernia repair was performed. Trials were reviewed for primary outcome measures: re recurrence, chronic inguinal pain and ischemic orchitis; and for secondary outcome measures. Standardized mean difference (SMD) was calculated for continuous variables and odds ratio for dichotomous variables. RESULTS: Seven studies comparing laparoscopic and Lichtenstein technique were considered suitable for the pooled analysis. Overall 647 patients with recurrent inguinal hernia were randomized to either laparoscopic repair (333, 51.5 %, transabdominal preperitoneal approach, TAPP and totally extraperitoneal approach, TEP) or anterior open repair (314, 48.5 %, Lichtenstein operation). Patients who underwent laparoscopic repair experienced significantly less chronic pain (9.2 % vs. 21.5 %, p = 0.003). Patients of the laparoscopic group had a significantly earlier return to normal daily activities (13.9 vs. 18.4 days, SMD = -0.68, 95 % CI = -0.94 to -0.43, p < 0.000001). Operative time was significantly longer in laparoscopic operations (62.9 vs. 54.2 min, SMD 0.46, 95 % CI 0.03, 0.89; p = 0.04). No other differences were found. CONCLUSIONS: Laparoscopy showed reduced chronic inguinal pain and an earlier return to normal daily activities but significantly longer operative time. Despite the expected advantages, the choice between laparoscopy and other techniques still depends on local expertise availability. Only dedicated centers are able to routinely offer laparoscopy for recurrent inguinal hernia repair. PMID- 25033944 TI - Effect of combined exogenous progesterone with luteotrophic support via equine chorionic gonadotrophin (eCG) on corpus luteum development, circulating progesterone concentrations and embryo development in cattle. AB - The aim was to examine the effect of a single intramuscular (i.m.) injection of equine chorionic gonadotrophin (eCG) on Day 3 after oestrus on corpus luteum (CL) development, circulating progesterone and conceptus development in cross-bred beef heifers. In Experiment 1, heifers received: (1) saline, or a single i.m. injection of eCG on Day 3 at (2) 250IU (3) 500IU (4) 750IU or (5) 1000IU. Administration of eCG resulted in increased luteal tissue area and progesterone and oestradiol concentrations compared with controls. In Experiment 2, heifers received (1) a progesterone-releasing intravaginal device (PRID Delta) from Day 3 to 5 or (2) a PRID Delta from Day 3 to 5 plus a single injection of 750IU eCG on Day 3. In vitro-produced blastocysts (n=10 per recipient) were transferred on Day 7 and heifers were slaughtered on Day 14 to assess conceptus development. Administration of eCG reduced the number of short cycles (6.3% vs 31.3%) and increased mean luteal tissue weight (P=0.02). Insertion of a PRID Delta on Day 3 resulted in an elevation (P<0.05) in serum progesterone until removal on Day 5. Administration of eCG at the time of PRID Delta insertion resulted in higher progesterone levels (P<0.05) from Day 10 onwards. Conceptus dimensions were not affected. In conclusion, a single injection of eCG on Day 3 increased CL size and progesterone concentrations and, when given in conjunction with a progesterone releasing device, appeared to reduce the number of short cycles, presumably due to its luteotrophic nature. The implications of the elevated oestradiol concentrations for embryo quality require further study. PMID- 25033945 TI - Percutaneous segmental dilatation of portal stenosis after paediatric liver transplantation to avoid or postpone surgery: two cases and literature review. AB - PURPOSE: The authors retrospectively reviewed the results obtained with percutaneous treatment of portal stenosis. MATERIALS AND METHODS: In November 2005 and March 2008, two patients, 15 and 32 months old, underwent portal vein angioplasty at our centre. Both procedures were performed after ultrasound-guided portal vein puncture and measurement of pre- and postanastomotic pressure gradients. The diameters of the angioplasty catheters ranged from 5 to 10 mm and no stents were used. RESULTS: In both cases, it was possible to cross the stenoses, perform angioplasty and obtain an immediate reduction of the pressure gradients. There were no major complications after the procedure. In the first patient, percutaneous treatment allowed us to postpone surgical revision of the anastomosis; in the second case, angioplasty had to be repeated twice over a period of 4 years to finally achieve regular patency of the anastomosis and function of the graft. CONCLUSIONS: Percutaneous treatment of portal stenosis after paediatric liver transplantation is a safe and feasible treatment; if balloon dilatation does not guarantee functional recovery of the organ, it allows surgical revision to be postponed to a later date when the clinical condition is more stable. PMID- 25033946 TI - Parotid glands in whole-brain radiotherapy: 2D versus 3D technique for no sparing or sparing. AB - PURPOSE: Whole-brain radiotherapy is performed as standard therapy in patients with multiple brain metastases and in patients with more favourable prognosis such as lymphoma and small-cell lung carcinoma in the prophylactic setting. Because of the prognosis and the total prescribed dose, the parotid glands are not usually regarded as an organ at risk in whole-brain radiotherapy. Long-term survival can be expected in some of these patients and late toxicity can be observed, becoming essential to evaluate organs at risk, particularly the parotid glands even in metastatic patients. We compared the 2D with 3D technique to evaluate parotid glands involvement and received dose, and coverage of the clinical target volume. MATERIALS AND METHODS: Seven patients were considered. The prescribed dose was 30 Gy in ten fractions. On the same day and with the same set-up, all the treatment planning were performed using a 2D and 3D technique. A treatment plan was performed following same technical characteristics as the 2D technique. The parotid glands and whole brain were delineated. Dose-volume statistics were analysed. RESULTS: Dose-volume histograms of the parotid glands showed that 2/7 patients (28 %) received a mean dose >20 Gy. We found a lack of coverage of the clinical target volume in 6/7 patients. CONCLUSIONS: Planning whole-brain radiotherapy with only the 2D technique involves a risk of including parotid glands in the field and not covering the clinical target volume. The 3D technique should be systematically performed and the parotid glands should be regarded as an organ at risk in whole-brain radiotherapy. PMID- 25033949 TI - Convergent and divergent two-dimensional coordination networks formed through substrate-activated or quenched alkynyl ligation. AB - Metal coordination assemblies of the symmetric bi-functional 4,4'-di-(1,4-buta 1,3-diynyl)-benzoic acid are investigated by scanning tunnelling microscopy on metal surfaces. The formation of long-range ordered, short-range disordered and random phases depends on the competition between the convergent and divergent coordination motifs of the individual functional groups and is crucially influenced by the substrate. PMID- 25033948 TI - [Serous vascularized pigment epithelial detachment in exudative AMD. Morphological typing and risk of tears in the RPE]. AB - PURPOSE: Are there any morphological parameters in pigment epithelial detachment (PED) in eyes with age-related macular degeneration (AMD), which could identify the development of tears (RIP) in the retinal pigment epithelium (RPE) before initiation of anti-vascular endothelial growth factor (VEGF) therapy? METHODS: Retrospectively, the spectral domain optical coherence tomography (SD-OCT), FLA and near infrared (NIR) images of 98 eyes with PED in exudative AMD before treatment (ranibizumab or bevacizumab) were analyzed. Eyes in which a tear in the RPE (RIP group) could be observed during treatment were compared to eyes without the development of RIP (PED group) in the following morphological parameters of PED: height, number of peaks, presence of hyporeflective fissures at the base of the PED, structure of the RPE, presence of floating structures in the PED with maximum hyperreflectivity, amount and localization of hyperreflectivity in the PED and hyperreflectivity in the NIR images. RESULTS: In the 80 eyes of the PED group the mean PED height was 373.7+/- 197 um and in the 18 eyes of the RIP group the mean PED height was higher (694.2+/- 284.3 um, p < 0.0001). A difference was also seen in the number of peaks per PED (PED group 43%, RIP group 72%, p = 0.039) and in the hyperreflectivity in NIR images (PED group 68%, RIP group 94%, p = 0.033). There were no significant differences in the other morphological parameters. A classification into four types of PED was found by the parameters height and number of peaks. The PED type with a height > 350 um and one peak (RIP 43%) developed tears more often (p = 0.001) than the PED type < 350 um with one peak (RIP 0%, p = 0.001). A trend in the visual acuity over 156 weeks was seen: in PED types with heights > 350 um there was a lower increase in the visual acuity than in PED types < 350 um (rm ANOVA p = 0.18; E HH = 0.88). Furthermore, in PED types > 350 um with multiple peaks the total number of injections necessary was higher than in the other PED types (p = 0.032). CONCLUSION: Morphological parameters, such as PED height, number of peaks per PED in OCT images and hyperreflectivity in NIR images are prognostic factors for RPE tears in exudative AMD. The PED height and number of peaks per PED are useful for classification of PED in the daily routine. PMID- 25033950 TI - Combinatorial synthesis of functionalized spirooxindole pyrrolidine/pyrrolizidine/pyrrolothiazole derivatives via three-component 1,3 dipolar cycloaddition reactions. AB - A series of diverse polycyclic heterocycles containing spirooxindole, pyridine/thiophene, and pyrrolidine/pyrrolizidine/pyrrolothiazole rings have been synthesized through the 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the condensation of dicarbonyl compounds (isatin or acenaphthenequinone) and secondary amino acids with dipolarophiles. The method is simple and provides diverse and biologically interesting products with excellent yields. PMID- 25033953 TI - Tetranectin knockout mice develop features of Parkinson disease. AB - BACKGROUND/AIMS: Aggregation of insoluble alpha-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. METHODS: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN(-/-)) and measured the behavioral and histopathological features of PD. RESULTS: Aged (15-to 20-month old) TN(-/-) mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous alpha synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. CONCLUSION: The TN(-/-) mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies. PMID- 25033954 TI - Impacts of a warming marginal sea on torrential rainfall organized under the Asian summer monsoon. AB - Monsoonal airflow from the tropics triggers torrential rainfall over coastal regions of East Asia in summer, bringing flooding situations into areas of growing population and industries. However, impacts of rapid seasonal warming of the shallow East China Sea ECS and its pronounced future warming upon extreme summertime rainfall have not been explored. Here we show through cloudresolving atmospheric model simulations that observational tendency for torrential rainfall events over western Japan to occur most frequently in July cannot be reproduced without the rapid seasonal warming of ECS. The simulations also suggest that the future ECS warming will increase precipitation substantially in such an extreme event as observed in mid July 2012 and also the likelihood of such an event occurring in June. A need is thus urged for reducing uncertainties in future temperature projections over ECS and other marginal seas for better projections of extreme summertime rainfall in the surrounding areas. PMID- 25033955 TI - Treatment of eyelid nevus with CO2 laser: A double-edged sword. PMID- 25033956 TI - Systematic review and meta-analysis of the effect of alcohol intake on the risk of urolithiasis including dose-response relationship. AB - OBJECTIVE: We conducted a meta-analysis to quantitatively evaluate the correlation between alcohol consumption and the risk of urolithiasis by summarizing the results of published case-control and cohort studies and the potential dose-response association. METHODS: A systematic literature search of articles up to February 2014 was conducted via PubMed, Web of Science, Cochrane Library, Scopus, EMBASE, the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles. Fixed- or random-effect models were used to summarize the estimates of odds ratio (OR) with 95% confidence interval (95% CI) for the highest versus the lowest consumption of alcohol. A dose response meta-analysis was also conducted. RESULTS: The pooled OR estimates indicated that alcohol consumption was associated with a decreased risk of urolithiasis (OR=0.683, 95% CI 0.577-0.808). In addition, the dose-response meta analysis indicated that the rate of urolithiasis decreased by 10% for a 10 g/day increase in alcohol intake (OR=0.898, 95% CI 0.851-0.948). No evidence of publication bias was found by Begg's or Egger's test (p=0.130, p=0.130, respectively). CONCLUSION: Our meta-analysis indicated that alcohol intake is associated with a decreased risk of urolithiasis. PMID- 25033957 TI - Relationship between bladder cancer and total fluid intake: a meta-analysis of epidemiological evidence. AB - OBJECTIVES: Epidemiological findings regarding the association between total fluid intake and bladder cancer risk have yielded varying results. Our objective is to examine the possible associations between total fluid intake and bladder cancer risk. METHODS: Databases searched include the EMBASE and PUBMED, from inception to February 2014, with no limits on study language. We also reviewed the reference lists of identified studies. Stratified analyses were performed. A random-effect model was used to summarize the estimates of odds ratio (OR) with 95% confidence intervals (CI). RESULTS: Overall,17 case-control and four cohort studies were included. The overall OR of bladder cancer for the highest versus the lowest fluid intake was 1.06 (95% CI: 0.88-1.27). In the subgroup analyses, the overall ORs for coffee, green, and black tea intake were 1.17 (95% CI: 1.03 1.33), 0.76 (95% CI: 0.66-0.95), and 0.80 (95% CI: 0.65-0.97), respectively. A significantly decreased risk was observed in Asian people (OR 0.27; 95% CI: 0.10 0.72). Among smokers, a suggestive inverse association was observed between total fluid intake and overall bladder cancer risk (OR 0.80; 95% CI: 0.62-1.02). CONCLUSIONS: Although this meta-analysis suggested that greater consumption of fluid may have a protective effect on bladder cancer in Asian people, there was no convincing evidence on this association because of the limitations of the individual trials. PMID- 25033958 TI - What is the role of portion control in weight management? AB - Systematic studies have shown that providing individuals with larger portions of foods and beverages leads to substantial increases in energy intake. The effect is sustained over weeks, supporting the possibility that large portions have a role in the development of obesity. The challenge is to find strategies to effectively manage the effects of portion size. One approach involves teaching people to select appropriate portions and to use tools that facilitate portion control. Although tools such as portion-control plates have been shown in several randomized trials to improve weight loss, limited data are available on whether education and tools lead to long-term changes in eating behavior and body weight. Another approach is to use preportioned foods (PPFs) to add structure to meals and minimize decisions about the amount of food to eat. A number of randomized controlled trials have demonstrated the efficacy of both liquid meal replacements and solid PPFs for weight loss and weight loss maintenance, but it is not known if they lead to better understanding of appropriate portions. Although portion control is important for weight management, urging people simply to 'eat less' of all foods may not be the best approach as high-energy-dense foods disproportionately increase energy intake compared with those lower in energy density. A more effective strategy may be to encourage people to increase the proportion of foods low in energy density in their diets while limiting portions of high-energy-dense foods. If people lower the energy density of their diet, they can eat satisfying portions while managing their body weight. PMID- 25033959 TI - Small, medium, large or supersize? The development and evaluation of interventions targeted at portion size. AB - In the past decades, portion sizes of high-caloric foods and drinks have increased and can be considered an important environmental obesogenic factor. This paper describes a research project in which the feasibility and effectiveness of environmental interventions targeted at portion size was evaluated. The studies that we conducted revealed that portion size labeling, offering a larger variety of portion sizes, and proportional pricing (that is, a comparable price per unit regardless of the size) were considered feasible to implement according to both consumers and point-of-purchase representatives. Studies into the effectiveness of these interventions demonstrated that the impact of portion size labeling on the (intended) consumption of soft drinks was, at most, modest. Furthermore, the introduction of smaller portion sizes of hot meals in worksite cafeterias in addition to the existing size stimulated a moderate number of consumers to replace their large meals by a small meal. Elaborating on these findings, we advocate further research into communication and marketing strategies related to portion size interventions; the development of environmental portion size interventions as well as educational interventions that improve people's ability to deal with a 'super-sized' environment; the implementation of regulation with respect to portion size labeling, and the use of nudges to stimulate consumers to select healthier portion sizes. PMID- 25033960 TI - Opportunities and barriers for smaller portions in food service: lessons from marketing and behavioral economics. AB - This paper uses the frameworks and evidence from marketing and behavioral economics to highlight the opportunities and barriers for portion control in food service environments. Applying Kahneman's 'thinking fast and slow' concepts, it describes 10 strategies that can be effective in 'tricking' the consumer's fast cognitive system to make better decisions and in triggering the slow cognitive system to help prevent the fast system from making bad decisions. These strategies include shrinking defaults, elongating packages, increasing the visibility of small portions, offering more mixed virtue options, adding more small sizes, offering 'right-sized' standard portions, using meaningful size labels, adopting linear pricing, using temporal landmarks to push smaller portions and facilitating pre-commitment. For each of these strategies, I discuss the specific cost and revenue barriers that a food service operator would face if the strategy were adopted. PMID- 25033961 TI - Improving the design of nutrition labels to promote healthier food choices and reasonable portion sizes. AB - Accurate and easy-to-understand nutrition labeling is a worthy public health goal that should be considered an important strategy among many to address obesity and poor diet. Updating the Nutrition Facts Panel on packaged foods, developing a uniform front-of-package labeling system and providing consumers with nutrition information on restaurant menus offer important opportunities to educate people about food's nutritional content, increase awareness of reasonable portion sizes and motivate consumers to make healthier choices. The aims of this paper were to identify and discuss: (1) current concerns with nutrition label communication strategies; (2) opportunities to improve the communication of nutrition information via food labels, with a specific focus on serving size information; and (3) important future areas of research on nutrition labeling as a tool to improve diet. We suggest that research on nutrition labeling should focus on ways to improve food labels' ability to capture consumer attention, reduce label complexity and convey numeric nutrition information in simpler and more meaningful ways, such as through interpretive food labels, the addition of simple text, reduced use of percentages and easy-to-understand presentation of serving size information. PMID- 25033962 TI - What to do about portion sizes? Roundtable discussion at the Forefronts in Portion Size Conference. AB - As portion size has increased in the United States, greater concern has arisen regarding the positive relationship between portion size and consumption, and how this relationship may negatively impact weight management. This article is a summary of a roundtable discussion from the Forefronts in Portion Size Conference held in Philadelphia, PA, USA in May 2013. The roundtable included four discussants, five speakers who had presented research on various components of portion size at the conference, two organizers and the moderator. Topics discussed included methods to reduce portion size that can assist with reducing energy intake, societal norms about portion size, values associated with portion size and methods to promote smaller portion sizes. Areas needing additional research were also identified. PMID- 25033963 TI - Mind over platter: pre-meal planning and the control of meal size in humans. AB - It is widely accepted that meal size is governed by psychological and physiological processes that generate fullness towards the end of a meal. However, observations of natural eating behaviour suggest that this preoccupation with within-meal events may be misplaced and that the role of immediate post ingestive feedback (for example, gastric stretch) has been overstated. This review considers the proposition that the locus of control is more likely to be expressed in decisions about portion size, before a meal begins. Consistent with this idea, we have discovered that people are extremely adept at estimating the 'expected satiety' and 'expected satiation' of different foods. These expectations are learned over time and they are highly correlated with the number of calories that end up on our plate. Indeed, across a range of foods, the large variation in expected satiety/satiation may be a more important determinant of meal size than relatively subtle differences in palatability. Building on related advances, it would also appear that memory for portion size has an important role in generating satiety after a meal has been consumed. Together, these findings expose the importance of planning and episodic memory in the control of appetite and food intake in humans. PMID- 25033964 TI - Advances in understanding of colorectal liver metastasis and implications for the clinic. AB - Colorectal cancer is one of the most common cancers in both the USA and Europe. Over the course of diagnosis, treatment and surveillance, up to 50% of these patients will develop metastases to their liver. In the past 20 years alone, there have been multiple advances in the management of these colorectal metastases to the liver. These advances have been made in characterization of these tumors, diagnosis and in treatment, both locally and systemically. Because of this progress, there are subsets of patients with this stage IV disease who are cured of their disease. While significant progress has been made, there still exist limitations in the management of metastatic colorectal cancer to the liver. This review outlines current strategies and highlights recent advances in the management of colorectal liver metastases. PMID- 25033972 TI - Th17 and non-classic Th1 cells in chronic inflammatory disorders: two sides of the same coin. AB - Th17 lymphocytes, beyond their protective role in the clearance of extracellular pathogens, also play a role in the pathogenesis of several autoimmune and inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases, psoriasis and contact dermatitis. Nevertheless, they are very rare at inflammatory sites in comparison with other T cell subsets. Recently, this rarity has been explained by the finding that Th17 cells rapidly shift into the Th1 phenotype in the presence of IL-12 and/or TNF-alpha as well as by the fact that they possess self-regulatory mechanisms limiting their own expansion. Th17 lymphocytes that have shifted towards a Th1 phenotype seem to be particularly aggressive and more pathogenic than the Th17 unshifted cells. As a consequence, the Th17-derived Th1 cells, named non-classic Th1 cells, can become a possible target for the therapy of some inflammatory disorders. In particular, convincing evidence has recently been accumulated indicating that this subset can play a role in Crohn's disease and juvenile idiopathic arthritis. More importantly, it has been shown that TNF-alpha inhibitors, which are used for the treatment of such diseases, appear to be able to inhibit the transition of Th17 lymphocytes to the non-classic Th1 phenotype, and thus they possibly help to dampen inflammation and arrest disease progression. Based on this context, the definition of the soluble factors involved in the shifting from Th17 towards non classic Th1 subset as well as the comprehension of their respective pathogenic role in human inflammatory disorders would be of great help for developing novel therapeutic strategies. PMID- 25033974 TI - Longitudinal changes in circulating testosterone levels determined by LC-MS/MS and by a commercially available radioimmunoassay in healthy girls and boys during the pubertal transition. AB - BACKGROUND: Accurate and selective assessment of testosterone requires use of a sensitive LC-MS/MS method, especially at low levels as those seen in young children. METHODS: The present longitudinal study of 20 healthy children from the Copenhagen Puberty Study followed every 6 months for 5 years evaluates the longitudinal increase in serum testosterone before, during and after pubertal onset quantified by a newly developed LC-MS/MS method in comparison with immunoassay. Testosterone concentrations in serum samples (n = 177) were determined by LC-MS/MS (detection limit 0.1 nmol/l) and by immunoassay (detection limit 0.23 nmol/l). RESULTS: Serum concentrations of testosterone increased gradually with age by both methods. However, serum testosterone was quantifiable in 9/10 girls prior to pubic hair development measured with LC-MS/MS, and in 2/10 girls measured with immunoassay. In boys, testosterone was quantifiable in 10/10 boys 1 year prior to pubic hair development measured with LC-MS/MS, and only in 1/10 boys measured with immunoassay. Serum testosterone levels were quantifiable 1.5 years (range 0.5-2.5) earlier using LC-MS/MS. CONCLUSION: Assessment of longitudinal circulating levels of serum testosterone using a selective LC-MS/MS method proved to be more sensitive in predicting early peripubertal changes in healthy children compared to levels determined by immunoassay. PMID- 25033973 TI - A micro-sterile inflammation array as an adjuvant for influenza vaccines. AB - There is an urgent need of adjuvants for cutaneous vaccination. Here, we report that micro-sterile inflammation induced at inoculation sites can augment immune responses to influenza vaccines in animal models. The inoculation site is briefly illuminated with a handheld, non-ablative fractional laser before the vaccine is intradermally administered, which creates an array of self-healing microthermal zones (MTZs) in the skin. The dying cells in the MTZs send 'danger' signals that attract a large number of antigen-presenting cells, in particular, plasmacytoid dendritic cells (pDCs) around each MTZ forming a micro-sterile inflammation array. A pivotal role for pDCs in the adjuvanticity is ascertained by significant abrogation of the immunity after systemic depletion of pDCs, local application of a TNF-alpha inhibitor or null mutation of IFN regulatory factor7 (IRF7). In contrast to conventional adjuvants that cause persistent inflammation and skin lesions, micro-sterile inflammation enhances efficacy of influenza vaccines, yet with diminished adverse effects. PMID- 25033975 TI - The vascular stem cell niches and their significance in the brain. AB - AIM: This cytohistopathological study was performed for a better knowledge of phenotypes derived from pluripotent stem cells, as well as for precise location of stem cells within the vascular niche in the brain. METHODS: We used light and transmission electron microscopy to demonstrate the presence of stem cells in the vascular wall of microvessels in the cerebral and cerebellar cortex, pia mater (considered by us a cordocytic-vascular tissue), adventitia of larger cortical arteries and veins, and around vessels. We investigated multiple vascular segments and brain tissue in a variety of clinical cases, such as cerebral tumors, cerebrovascular malformations, thromboses in the carotid system, and direct laceration. RESULTS: Our morphological and ultrastructural observations pointed out many changing phenotypes, as well as cell interrelationships within the vascular niche, both for repair processes when cordocytes cooperate with mesenchymal stem cells, and pathological processes such as atherogenesis, tumorigenesis, and neurotrauma. Our results underlie the important roles of cordocytes in their interrelations with precursor/stem cells in the arterial adventitia. CONCLUSION: The cells derived from pluripotent stem cells along different lineages have had different phenotypes as they derived from hematopoietic stem cells or mesenchymal stem cells, with or without epigenetic disregulations or depending on different microenvironments. Cell interactions, phenotypes, and underlying mechanisms, as well as biological responses to different small molecules or compounds, remain to be determined by future molecular insights within the vascular niche. PMID- 25033976 TI - Minimally invasive percutaneous stabilization plus balloon kyphoplasty for the treatment of type A thoraco lumbar spine fractures: minimum 4 year's follow-up. AB - AIM: There is no consensus regarding the ideal treatment of type A thoraco-lumbar fractures. Many surgical techniques have been described but none has demonstrated its superiority over others. Recently, minimally invasive techniques have been widely used as they reduce the immediate morbidity related to the procedure. Percutaneous pedicle screw stabilization plus balloon kyphoplasty is a valuable technique, but there are only few data regarding clinical and radiological results in the long term. The purpose of this study was to report the long-term clinical and radiological outcome of patients undergoing minimally invasive management of thoracolumbar fracture in our institution. METHODS: This was a retrospective review of prospectively collected data. Between January 2006 and June 2008, 22 patients underwent short-segment percutaneous stabilization and balloon kyphoplasty for treatment of a type A fracture of the thoraco-lumbar spine. The study included 12 males and 10 females and the mean age was 50.5 years (25-75 years). The affected levels were T10 (N.=1), T11 (N.=1), T12 (N.=3), L1 (N.=9), L2 (N.=4), L3 (N.=3) and L4 (N.=1). RESULTS: The mean follow-up period was 60.9 months (50-75 months). The mean operative time was 77 min (range 55-135 min) and the bleeding was very low (<100 mL). VAS was significantly improved from 6.1 to 1.1 at last follow-up. Vertebral kyphosis decreased by 19 degrees to 7.7 degrees (ap<0.001) and local kyphosis was also significantly improved from 12.3 degrees to 4.4 degrees at last follow-up. We reported one screw misplacement that required early repositioning and 4 cement leakage, none of which was symptomatic. No patient worsened his neurological condition postoperatively. CONCLUSION: This treatment strategy is safe and effective. Clinical and radiological results seem to be stable over the time. PMID- 25033977 TI - Severity of symptoms, physical functioning and satisfaction in patients with lumbar spinal stenosis: a validation study of the Iranian version of the Swiss Spinal Stenosis Score. AB - AIM: A common cause of low back pain is lumbar spinal stenosis (LSS). The Swiss Spinal Stenosis Score (SSS) is a well-known questionnaire that measures the severity of symptoms, physical functioning and patient's satisfaction in lumbar spinal stenosis. This study aimed to translate and validate the SSS in Iran. METHODS: A prospective clinical validation study was performed. Forward-backward procedure was applied to translate the original questionnaires into Persian. A sample of patients with lumbar spinal stenosis completed the questionnaire twice: at pre- and postoperative (6 months follow-up) assessments. To test reliability the internal consistency was assessed by the Cronbach's alpha coefficient. Validity was evaluated using the known groups comparison. In addition the Oswestry Disability Index was used to perform convergent validity. RESULTS: In all 121 patients were entered into the study. The mean age of patients was 62.3 (SD=10.2) years. The Cronbach's alpha coefficient for the SSS was 0.88. Validity was performed by known groups analysis and showed satisfactory results. The instrument discriminated well between the subgroups of patients who differed in age, severity of lumbar spinal stenosis, and the Self-Paced Walking Test (SPWT). The change in the Oswestry Disability Index strongly correlated with the change in patients' scores on the SSS; lending support to its good convergent validity (r=0.82; P<0.001). CONCLUSION: The Iranian version of Swiss Spinal Stenosis Score performed well and the findings suggest that it is a valid measure of symptoms, physical functioning and satisfaction among patients with lumbar spinal stenosis. PMID- 25033978 TI - Therapeutic and survival outcomes following treatment of primary central nervous system lymphoma: a 12-year case study. AB - AIM: The study primarily aimed to investigate therapeutic and survival outcomes following definitive treatment of primary central nervous system lymphoma (PCNSL). METHODS: All patients with histopathologically proven PCNSL at our institute between 1998 and 2009 were recruited. The collated data included demographic, laboratory, neuroimaging, therapeutic and survival aspects. RESULTS: Of 85 participants with the mean age of 52.8 years, 79 underwent neurosurgical procedures endeavoring for diagnosis or decompression. Fifty patients who received definitive treatment in our institute were evaluated for therapeutic response. In multivariate analysis, there was no variable associated with good response rate. Eastern Cooperative Oncology Group (ECOG) performance status >1 and elevated cerebrospinal fluid (CSF) protein level >45 mg/dL were significant prognostic factors of poor survival outcome as estimated by Cox regression analysis. The patients treated by high-dose methotrexate (HD-MTX)-based protocols with or without radiotherapy (RT) achieved significantly longer median survival than those treated by RT alone or other kinds of chemotherapy. CONCLUSION: Neurosurgical procedure plays an important role for diagnosis of PCNSL. Surgical resection has no role in curative treatment and should be discarded unless considerable mass effect develops. HD-MTX should be considered as the primary chemotherapy for individuals agonizing from the disease. PMID- 25033979 TI - Role of p53 pathway alterations in uterine carcinosarcomas (malignant mixed Mullerian tumors). AB - Carcinosarcomas (CSs; malignant mixed Mullerian tumors) of the uterus are highly malignant neoplasms characterized by an unfavorable outcome. They represent less than 5% of all uterine malignancies, and the median patient survival rate is only 21 months. p53 pathway alterations have been studied in CSs originating from the uterus, supporting the monoclonal nature of most but not all of these neoplasms. This paper gives an overview of the current knowledge of p53 pathway distortions in patients with uterine CSs. The survival of patients with uterine CSs in relation to p53 pathway alterations is also briefly summarized. PMID- 25033980 TI - European Medicines Agency is attacked over proposal to allow technology assessment bodies to sell advice to drug industry. PMID- 25033982 TI - Determination of free fatty acids in human serum by HPLC with fluorescence detection. AB - It has been suggested that serum concentrations of polyunsaturated essential fatty acids correlate with the symptoms or severity of various diseases, including depression and Alzheimer-type dementia, and that determination of serum fatty acids might be important for disease diagnosis. Thus, we developed to analyze serum fatty acids in healthy individuals by using a high-performance liquid chromatography method with fluorescence detection, because free fatty acids have a carboxyl group that can be derivatized with a fluorescent reagent, 4 N,N-dimethylaminosulfonyl-7-N-(2-aminoethyl)amino-2,1,3-benzoxadiazole. This approach could quantify five types of free fatty acids [alpha-linolenic acid (ALA), palmitoleic acid (PLA), arachidonic acid (AA), linoleic acid (LA) and oleic acid (OA)] in human serum. The detection limits of the method were in the range of 2.29-4.75 fmol (signal-to-noise ratio 3), and absolute concentrations of ALA, PLA, AA, LA and OA were 8.27 +/- 1.04, 18.8 +/- 2.95, 49.9 +/- 4.03, 230 +/- 18.1 and 201 +/- 22.1 uM, respectively. PMID- 25033981 TI - Increased thrombin generation potential in symptomatic versus asymptomatic moderate or severe carotid stenosis and relationship with cerebral microemboli. AB - INTRODUCTION: The importance of thrombin generation in the pathogenesis of TIA or stroke and its relationship with cerebral microembolic signals (MES) in asymptomatic and symptomatic carotid stenosis has not been comprehensively assessed. METHODS: Plasma thrombin generation parameters from patients with moderate or severe (>= 50%) asymptomatic carotid stenosis were compared with those from patients with symptomatic carotid stenosis in the early (<= 4 weeks) and late phases (>= 3 months) after TIA or stroke in this prospective, pilot observational study. Thrombin generation profile was longitudinally assessed in symptomatic patients with data at each time point. Bilateral transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed whenever possible to classify patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic, 46 'early symptomatic' and 35 'late symptomatic' patients were analysed. Peak thrombin (344.2 nM vs 305.3 nM; p = 0.01) and endogenous thrombin potential (1772.4 vs 1589.7; p = 0.047) were higher in early symptomatic than asymptomatic patients. Peak thrombin production decreased in symptomatic patients followed up from the early to late phase after TIA or stroke (339.7 nM vs 308.6 nM; p = 0.02). Transcranial Doppler ultrasound data were available in 25 asymptomatic, 31 early symptomatic and 27 late symptomatic patients. Early symptomatic MES-positive patients had a shorter 'time-to-peak thrombin' than asymptomatic MES-positive patients (p=0.04), suggesting a more procoagulant state in this early symptomatic subgroup. DISCUSSION: Thrombin generation potential is greater in patients with recently symptomatic than asymptomatic carotid stenosis, and decreases over time following TIA or stroke associated with carotid stenosis. These data improve our understanding of the haemostatic/thrombotic biomarker profile in moderate-severe carotid stenosis. PMID- 25033983 TI - Danning tablets attenuates alpha-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes. AB - BACKGROUND: The Danning tablets (DNts) is commonly prescribed in China as a cholagogic formula. Our previous studies showed that DNts exerted the protective effect on alpha-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis in a dose-dependent mannar. However, the detailed molecular mechanisms of DNts against ANIT-induced cholestasis are still not fully explored. METHODS: Danning tablet (3 g/kg body weight/day) was administered orally to experimental rats for seven days before they were treated with ANIT (60 mg/kg daily via gastrogavage) which caused cholestasis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and total bile acid (TBA) were measured to evaluate the protective effect of Danning tablet at 12, 24 and 48h after ANIT treatment. Meanwhile, total bilirubin or total bile acid in the bile, urine and liver were also measured at 48h after ANIT treatment. Furthermore, the hepatic or renal mRNA and protein levels of metabolic enzymes and transports were investigated to elucidate the protective mechanisms of Danning tablet against ANIT-induced cholestasis. RESULTS: In this study, we found that DNts significantly attenuated translocation of multidrug resistance associated protein 2 (Mrp2) from the canalicular membrane into an intracellular and up-regulated the hepatic mRNA and protein expressions of metabolic enzymes including cytochrome P450 2b1(Cyp2b1) and uridine diphosphate-5c- glucuronosyltransferase (Ugt1a1)) and transporters including bile salt export pump (Bsep) and multidrug resistance protein 2 (Mdr2)) as well as renal organic solute transporter beta (Ostbeta), accompanied by further increase in urinary and biliary excretion of bile acid and bilirubin. CONCLUSIONS: DNts might promote bile acid and bilirubin elimination by regulating the expressions of hepatic and renal transporters as well as hepatic metabolic enzymes. PMID- 25033984 TI - Termination of immune activation: an essential component of healthy host immune responses. AB - The ideal immune response is rapid, proportionate and effective. Crucially, it must also be finite. An inflammatory response which is disproportionate or lasts too long risks injury to the host; chronic un-regulated inflammation in autoimmune diseases is one example of this. Thus, mechanisms to regulate and ultimately terminate immune responses are central to a healthy immune system. Despite extensive knowledge of what drives immune responses, our understanding of mechanisms of immune termination remains relatively sparse. It is clear that such processes are more complex than a one-dimensional homeostatic balance. Recent discoveries have revealed ever more nuanced mechanisms of signal termination, such as intrinsically self-limiting signals, multiple inhibitory mechanisms acting in tandem and activating proteins behaving differently in a variety of contexts. This review will summarise some important mechanisms, including termination by immunoreceptor tyrosine-based inhibitory motifs (ITIM), inhibition by soluble antagonists, receptor endocytosis or ubiquitination, and auto inhibition by newly synthesised intracellular inhibitory molecules. Several recent discoveries showing immunoreceptor tyrosine-based activation motifs transducing inhibitory signals, ITIM mediating activating responses and the possible roles of immunoreceptor tyrosine-based switch motifs will also be explored. PMID- 25033985 TI - Decreased lipid absorption due to reduced pancreatic lipase activity in aging male mice. AB - Malnutrition due to aging is partly caused by decreased absorption of nutrients by the gastrointestinal tract. However, the underlying mechanism is unclear and changes in lipid absorption with aging are poorly understood. In this study, changes in lipid absorption with aging were examined in mice aged 3 and 25 months. After overnight fasting, blood samples were collected from snipped tails and then soybean oil was administered orally. Three hours later, mice were sacrificed by decapitation and the liver, pancreas, small intestine and blood were collected. The increase in serum triacylglycerol after soybean oil administration was significantly lower in the older mice, indicating a decrease in lipid absorption with aging. Measurement of mRNA levels for triacylglycerol absorption-related genes showed that mRNA for pancreatic lipase tended to decrease in 25-month-old mice. There was no significant difference in the protein level of pancreatic lipase, but the enzyme activity showed a significant decrease in the older mice. To examine this mechanism, expression levels of mRNA for protein turnover-related genes in the pancreas were measured. The level of a proteasomal mRNA showed a significant decrease in 25-month-old mice. This suggests that the ability to degrade unfolded protein decreases in the aging pancreas, and that this leads to reduction of pancreatic lipase activity and a decrease in lipid absorption. PMID- 25033986 TI - Perfusion deficits, inflammation and aging precipitate depressive behaviour. AB - Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therapeutic interventions. PMID- 25033988 TI - Morphological characteristics influencing the orthodontic extraction strategies for Angle's class II division 1 malocclusions. AB - BACKGROUND: Extraction has now been accepted widely in various malocclusions including Angle's class II division 1. However, the levels of scientific evidence in orthodontic treatment planning have been weak, and it is unlikely to systematically provide a rationale and consistent basis in decisions of extraction. This study was retrospectively designed to investigate the initial morphologic characteristics of class II division 1 subjects involving four different extraction strategies, to determine the relevant influential factors when choosing extraction strategies with the most commonly used mechanics and the principle of simplicity in orthodontic treatment based on cases diagnosed and treated by an experienced orthodontist. METHODS: One hundred and ten samples of Angle's class II division 1 malocclusion with good facial and occlusal outcomes after orthodontic treatment were selected and divided into four groups according to different extraction patterns. For each case, pretreatment models and the lateral radiographs were analyzed. Significant variables of models and craniofacial structures of each group were identified by comparing the measurements using one-way analysis of variance (ANOVA) at a significance level of P < 0.05. Then, binary logistic regression analysis was used and a regression equation was established to quantify the correlations among the significant variables and their contributions to the extraction decisions. RESULTS: Molar relationship, lower anterior crowding, anterior Bolton index, and anterior overjet measured from models, as well as ANS-Xi-Pm, NBa-PtGn, Li-NsPog', U1-NPog and L1-NPog measured from lateral radiographs were found to be statistically significant. Binary logistic regression analysis revealed that lower anterior crowding, molar relationship, and growth pattern were the three most relevant influential factors with a declining impact contributing to the extraction decisions for Angle's class II division 1 malocclusions. CONCLUSIONS: Angle's class II division 1 malocclusions exhibit various morphological characteristics. Orthodontists should comprehensively consider the reciprocal impact of multiple factors when choosing different extraction strategies for Angle's class II division 1 malocclusions. PMID- 25033989 TI - Extracellular signal-regulated kinases 1/2 and Akt contribute to triclosan stimulated proliferation of JB6 Cl 41-5a cells. AB - Triclosan is a broad spectrum anti-bacterial agent widely used in many personal care products, household items, medical devices, and clinical settings. Human exposure to triclosan is mainly through oral and dermal routes. In previous studies, we found that sub-chronic dermal exposure of B6C3F1 mice to triclosan induced epidermal hyperplasia and focal necrosis; however, the mechanisms for these responses remain elusive. In this study, using mouse epidermis-derived JB6 Cl 41-5a cells, we found that triclosan stimulated cell growth in a concentration and time-dependent manner. Enhanced cell proliferation was demonstrated by a substantial increase in the percentage of BrdU-positive cells, an elevation in the protein levels of cyclin D1 and cyclin A, and a reduction in the protein level of p27(Kip1). Western blotting analysis revealed that triclosan induced the activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N terminal kinases (JNK), p38, and Akt. Pre-treatment of the cells with PD184352, an inhibitor of the upstream kinase MEK1/2, or with wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked triclosan-mediated phosphorylation of ERK1/2 and Akt, respectively, and substantially suppressed triclosan-stimulated cell proliferation, whereas the JNK inhibitor SP600125 or the p38 inhibitor SB203580 had little to no effect on triclosan-stimulated cell proliferation. The phosphorylation activation of ERK1/2 and Akt was further confirmed on the skin of mice dermally administered triclosan. These data suggest that the activation of ERK1/2 and Akt is involved in triclosan-stimulated proliferation of JB6 Cl 41-5a cells. PMID- 25033990 TI - Toxicological interactions between the mycotoxins deoxynivalenol, nivalenol and their acetylated derivatives in intestinal epithelial cells. AB - In case of mycotoxin contaminations, food and feedstuff are usually contaminated by more than one toxin. However toxicological data concerning the effects of mycotoxin combinations are sparse. The intestinal epithelium is the first barrier against food contaminants and this constantly renewing organ is particularly sensitive to mycotoxins. The aim of this study was to investigate the effects of deoxynivalenol (DON) and four other type B trichothecenes (TCTB), 3 acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon-X (FX) alone or in combination on intestinal epithelial cells. Proliferating, non-transformed IPEC-1 cells were exposed to increasing doses of TCTB, alone or in binary mixtures and mycotoxin-induced cytotoxicity was measured with MTT test. The toxicological interactions were assessed using the isobologram Combination index method. The five tested mycotoxins and their mixtures had a dose-dependent effect on the proliferating enterocytes. DON-NIV, DON-15-ADON and 15-ADON-3-ADON combinations were synergistic, with magnitude of synergy for 10 % cytotoxicity ranging from 2 to 7. The association between DON and 3-ADON also demonstrated a synergy but only at high doses, at lower doses antagonism was noted. Additivity was observed between NIV and FX, and antagonism between DON and FX. These results indicate that the simultaneous presence of mycotoxins in food commodities and diet may be more toxic than predicted from the mycotoxins alone. This synergy should be taken into account considering the frequent co-occurrence of TCTB in the diet. PMID- 25033991 TI - Survey of aflatoxin M1 in cows' milk from free-grazing cows in Abeokuta, Nigeria. AB - Aflatoxin M1 (AFM1) in milk from 100 different herds of free-grazing cows in Abeokuta, Nigeria, was analysed by immunoaffinity column cleanup and HPLC with fluorescence detection. AFM1 was found in 75% of the samples, the toxin levels in positive samples ranged from 9.0 to 456.0 ng/l. The mean AFM1 level in positive samples was 108.15 ng/l, exceeding, for example, the European Union maximum level by a factor of two. These results indicated that there is an urgent need to more closely control the milk of free-grazing cows for AFM1 in order to protect the health of humans consuming milk and milk products. PMID- 25033992 TI - A review of melatonin in hepatic ischemia/reperfusion injury and clinical liver disease. AB - Ischemia/reperfusion injury (IRI) can lead to cellular and, eventually, organ dysfunction, with the liver being one of the most frequently affected organs. Melatonin, a molecule that has notable antioxidant and anti-inflammatory properties, has been shown to protect against hepatic IRI. The purpose of this review is to summarize the protective effects of melatonin on hepatic IRI. The review initially summarizes the antioxidant properties of melatonin. We then discuss the protective effects of melatonin against endothelial and mitochondrial dysfunction. Thereafter, we introduce some information covering melatonin-related signaling pathways, including heme oxygenase-1 (HO-1), toll-like receptor (TLR), c-Jun N-terminal kinase (JNK), and so on. Furthermore, the clinical application of melatonin to hepatic diseases is considered. Finally, the safety of melatonin is evaluated. Taken together, the information compiled in this review will serve as a comprehensive reference regarding the pharmacological benefits of melatonin on hepatic IRI, aid in the design of future experimental research, and promote melatonin as a new therapeutic target. PMID- 25033993 TI - Split bolus technique in polytrauma: a prospective study on scan protocols for trauma analysis. AB - BACKGROUND: For the evaluation of severely injured trauma patients a variety of total body computed tomography (CT) scanning protocols exist. Frequently multiple pass protocols are used. A split bolus contrast protocol can reduce the number of passes through the body, and thereby radiation exposure, in this relatively young and vitally threatened population. PURPOSE: To evaluate three protocols for single pass total body scanning in 64-slice multidetector CT (MDCT) on optimal image quality. MATERIAL AND METHODS: Three total body CT protocols were prospectively evaluated in three series of 10 consecutive trauma patients. In Group A unenhanced brain and cervical spine CT was followed by chest-abdomen pelvis CT in portovenous phase after repositioning of the arms. Group B underwent brain CT followed without arm repositioning by a one-volume contrast CT from skull base to the pubic symphysis. Group C was identical to Group A, but the torso was scanned with a split bolus technique. Three radiologists independently evaluated protocol quality scores (5-point Likert scale), parenchymal and vascular enhancement and artifacts. RESULTS: Overall image quality was good (4.10) in Group A, more than satisfactory (3.38) in Group B, and nearly excellent (4.75) in Group C (P < 0.001). Interfering artifacts were mostly reported in Group B in the liver and spleen. CONCLUSION: In single pass total body CT scanning a split bolus technique reached the highest overall image quality compared to conventional total body CT and one-volume contrast CT. PMID- 25033994 TI - Left ventricle size quantification using non-contrast-enhanced cardiac computed tomography--association with cardiovascular risk factors and coronary artery calcium score in the general population: The Heinz Nixdorf Recall Study. AB - BACKGROUND: Increased left ventricular (LV) size is associated with cardiovascular mortality and morbidity. Once non-contrast cardiac computed tomography (CT) is performed for other purposes, information of LV size is readily available. PURPOSE: To determine the association of gated CT-derived LV size with cardiovascular risk factors and coronary artery calcification (CAC) and to describe age- and gender-specific normative values in a general population cohort. MATERIAL AND METHODS: LV area was quantified from non-contrast-enhanced CT in axial, end-diastolic images at a mid-ventricular slice in participants of the population-based Heinz Nixdorf Recall Study, free of known cardiovascular disease. LV index (LVI) was calculated by the quotient of LV area and body surface area (BSA). Crude and adjusted regression analyses were used to determine the association of LVI with risk factors and CAC. RESULTS: Overall, 3926 subjects (age 59 +/- 8 years, 53% women) were included in this analysis. From quantification in end-diastolic phase, men had larger LV index (2232 +/- 296 mm(2)/m(2) vs. 2088 +/- 251 mm(2)/m(2), both P < 0.0001). LVI was strongly correlated systolic blood pressure (men, PE [95% CI]: 22.8 [15.5-30.2] mm(2)/10 mmHg; women, 23.4 [18.1-28.6]), and antihypertensive medication (men, 45.2 [14.7 75.8] mm(2); women: 46.5 [22.7-70.2], all P < 0.005). Cholesterol levels were associated with LVI in univariate analysis, however, correlations were low (R(2) <= 0.04). In multivariable regression, blood pressure, antihypertensive medication and cholesterol levels, remained associated with LVI (P < 0.05). LVI was linked with CAC in unadjusted (men, increase of CAC + 1 by 13.0% [1.4-25.8] with increased LVI by 1 standard deviation of LVI, P = 0.03; women, 20.7% [10.0 32.3], P < 0.0001) and risk factor adjusted models (men, 14.6% [3.7-26.6], P = 0.007); women, 17.4% [7.8-27.8], P = 0.0002). CONCLUSION: Non-contrast cardiac CT derived LV index is associated with body size and hypertension. LVI is weakly linked with CAC-score. Further studies need to evaluate whether assessment of LV dimensions from cardiac CT helps identifying subjects with increased cardiovascular risk. PMID- 25033995 TI - Traumatic brain injury and early life experiences among men and women in a prison population. AB - This study examined the proportion of men and women reporting previous traumatic brain injury (TBI) in an Ontario (Canada) prison sample by demographic characteristics; adverse life experiences; and criminal, drug, and alcohol use history. Using data from The Cost of Substance Abuse in Canada study based on a random sample from four Ontario prisons, this study found 50.4% of males and 38% of females reporting previous TBI. More TBIs occurred before the first crime for women than for men. Women with TBI experienced more early physical and sexual abuse than those without TBI. Additionally, this study shows high prevalence of early life experiences among persons, particularly women, with a history of TBI. Prisoners and prison staff should be educated on TBI and best practice for rehabilitation of TBI. PMID- 25033996 TI - An education intervention in an incarcerated population to reduce the occurrence of infectious skin diseases. AB - A study conducted at a Midwest county confinement center focused on detainees' intention to wash their hands to prevent the spread of infectious skin diseases. Results of a qualitative interview and learning style inventory were used in conjunction with the theory of planned behavior to develop a Standard Precautions DVD to address hand washing, use of personal protective equipment while cleaning body fluids, and handling of laundry. A postintervention survey revealed significant knowledge-based learning among inmates. A regression model predicting behavioral intention (hand washing) with three predictor variables (attitude toward action, subjective norm, and perceived behavioral control) was developed. The highest correlation was found to be between inmates' subjective norms and their intent to wash their hands, which indicates that inmates' behavior after watching the DVD is most influenced by how others view them, with family members having the greatest influence on subjective norms. PMID- 25033997 TI - Post-thyroidectomy chronic asthenia: self-deception or disease? AB - There is clinical evidence that post-total thyroidectomy (TT) patients can present persistent asthenia. The aim of this study was to evaluate the prevalence of asthenia symptoms in such patients, assess whether a chronic asthenia syndrome could be caused by TT or become evident after it. An observational study was carried out comparing two groups of 100 patients each, all with homogeneous characteristics. Group A was treated with total lobectomy (TL), Group B with TT. All patients presented normal thyroid hormone levels. The patients were interviewed in order to identify the ones affected by post-operative asthenia persisting for at least six months, with reduced ability to perform physical and mental work, not showing improvement with rest. The severity of the symptoms has been measured by means of the brief fatigue inventory (BFI). Statistical analysis was performed to evaluate statistically significative differences between groups and prognostic factors in TT group. The incidence of post-operative asthenia was 0 % after TL and 25 % after TT, with the operation being the only significant variable. Asthenia is well known as symptom of post-thyroidectomy, but it has not been adequately investigated as consequence of surgery. We demonstrated that the complete removal of the thyroid gland could determine chronic post-thyroidectomy asthenia, although with intensity limited to low/moderate. Post-thyroidectomy asthenia is a relevant sequela interfering with quality of life of at least 25 % of patients operated, suggesting the need to identify its real causes and limit the indication to TT only when strictly required. PMID- 25033998 TI - Should we still be concerned about the potential side effects of glucagon-like peptide-1 receptor agonists on thyroid C cells? AB - In recent years, numerous novel anti-diabetic drugs have emerged. Among them, glucagon-like peptide-1 receptor (GLP-1R) agonists developed on the basis of the incretin theory are the most popular and surprising. Thus far, the clinical and experimental efficiency and safety data seem to be good. However, questions about the side effects of GLP-1R agonists, especially on thyroid C cells, still remain. In vivo and in vitro rodent experiments have shown the potential risks of GLP-1R agonists on thyroid C cells. However, the effects of GLP-1R agonists in humans, which have only been studied in experiments using untreated thyroid tissues or C cell lines, are questionable and differ from that in rodents. C-cell abnormalities are not only dependent on GLP-1R, as many other factors also influence the structure and function of thyroid C cells. Furthermore, there is not enough information from patients with diabetes or tissue samples from subjects treated with GLP-1R agonists and related drugs--especially data obtained during the prandial period or from a long-term study. Therefore, it is important to focus on the possible side effects of GLP-1R agonists on thyroid C cells. PMID- 25033999 TI - The use of everolimus to reverse tamoxifen resistance in men with metastatic breast cancer: a case report. PMID- 25034000 TI - Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi factorial drug resistant cancer cells. AB - INTRODUCTION: Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds. This work was designed to assess the cytotoxicity and the mechanism of action of flavonoids abyssinone IV (1), atalantoflavone (3) and neocyclomorusin (6) and isoflavonoids sigmoidin I (2), sophorapterocarpan A (4), bidwillon A (5) and 6alpha-hydroxyphaseollidin (7) isolated from Erythrina sigmoidea against nine drug sensitive and multidrug resistant (MDR) cancer cell lines. METHODS: The resazurin reduction assay was used to evaluate the cytotoxicity of the studied compounds whilst caspase-Glo assay was used to detect the activation of caspases enzymes by 1, 2, 4 and 7. Cell cycle, mitochondrial membrane potential and levels of reactive oxygen species were all analyzed via flow cytometry. RESULTS: The pterocarpan isoflavonoid 7 displayed the best antiproliferative activity with the IC50 values below 10 MUM obtained on the nine tested cancer cell lines. The IC50 values below 50 MUM were also recorded with compounds 1, 2 and 4 against the nine cancer cell lines whilst 3, 5 and 6 showed selective activities. The IC50 values varied from 14.43 MUM (against MDA-MB-231-pcDNA cells) to 20.65 MUM [towards HCT116 (p53(+/+)) cells] for compound 1, from 4.24 MUM (towards CCRF-CEM cells) to 30.98 MUM (towards MDA-MB-231-BCRP cells) for 2, from 3.73 MUM (towards CCRF CEM cells) to 14.81 MUM (against U87MG.DeltaEGFR cells) for 4, from 3.36 MUM (towards CCRF-CEM cells) to 6.44 MUM (against HepG2 cells) for 7, and from 0.20 MUM (against CCRF-CEM cells) and 195.12 MUM (against CEM/ADR5000 cells) for the positive control drug, doxorubicin. Compared to their corresponding sensitive cell lines, collateral sensitivity was observed with HCT116 (p53(-/-)) to 1, 2, 4, 5, and 7 and with U87MG.DeltaEGFR to 1 to 6. Compound 7 induced apoptosis in CCRF-CEM cells mediated by the activation of caspases 3/7, 8 and 9 and breakdown of MMP and increase in ROS production, whereas the apoptotic process induced by 1, 2 and 4 was mediated by the loss of MMP as well as increase in ROS production. CONCLUSIONS: Compounds from Erythrina sigmoidea and mostly 6alpha hydroxyphaseollidin are potential antiproliferative natural products that deserve more investigations to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes. PMID- 25034001 TI - Inadvertent placement of pacemaker lead into the middle cardiac vein. PMID- 25034002 TI - Racial differences in the use of extracorporeal photopheresis for mycosis fungoides. AB - BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment option for mycosis fungoides (MF) and associated with few systemic side effects. OBJECTIVE: We sought to investigate whether there were differences in rates of ECP use between African-American and Caucasian patients with stage III/IV MF. METHODS: We conducted a retrospective review of all patients treated for MF at the Johns Hopkins Hospital main campus outpatient clinic between 1999 and 2011. RESULTS: We identified 65 patients with stage III or IV disease, 20 African American and 45 Caucasian. Only 7 of 20 African-American patients (35%) compared with 30 of 45 (66%) of Caucasian patients were treated with ECP (p = 0.029). In addition, ECP was discussed as an option for 45% of African-Americans compared to 82% of Caucasians (p = 0.007). When discussed as an option, African-Americans and Caucasians had identical rates of ECP use (78% vs 81%, p = 0.841). CONCLUSIONS: Differences in rates of ECP use exist among African-American patients when compared to their Caucasian counterparts and may be related to how often ECP is offered as a treatment option. Improving physician awareness of the factors that influence treatment decision making may help diminish discrepancies in treatment regimens among patients with MF. PMID- 25034003 TI - A randomised, controlled trial of a 4% cutaneous emulsion of sodium cromoglicate in treatment of atopic dermatitis in children. AB - INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Sodium cromoglicate (SCG) is a chromone with anti-inflammatory, anti-itch and anti-allergic activity. This trial is a 12-week comparison (RCT) of a 4% SCG cutaneous emulsion with its vehicle in AD. MATERIALS AND METHODS: 208 children aged 2-12 years participated, 104 in each group. The primary endpoint was change in SCORAD score. Secondary endpoints included SASSAD score, topical steroid usage and global assessments. RESULTS: SCORAD was reduced by 28% (SCG group) and by 19% (vehicle): difference was statistically significant (p = 0.03) after 8 weeks and nearly significant (p = 0.09) after 12. A similar result occurred in SASSAD (p = 0.001 at 8 weeks). In subjects without major protocol deviations (SCG-64, vehicle 63), difference in SCORAD remained significant at 12 weeks (p = 0.04). Weight of topical steroids reduced in both groups: -0.60 +/- 1.3 g/day (35%), SCG and -0.05 +/- 1.1 g/day vehicle (p = 0.04). Treatment success, defined as investigator global opinion graded very or moderately effective, was significantly more frequent in SCG group (p = 0.025). Application site discomfort reported by 12.5% of subjects in SCG group and 16.5% in vehicle group. CONCLUSIONS: SCG 4% cutaneous emulsion provides an effective, well-tolerated, steroid-sparing treatment for AD in children. PMID- 25034004 TI - Electrochemical arsine generators for arsenic determination. AB - Arsine generation is the gateway for several sensitive and selective methods of As determination. An electrochemical arsine generator (EAG) is especially green: we report here the use of two electrode materials, aluminum and highly oriented (ordered) pyrolytic graphite (HOPG) never before used for this purpose. The first is operated on a novel constant voltage mode: current flows only when the sample, deliberately made highly conductive with acid, is injected. As a result, the cathode, despite being a highly active metal that will self-corrode in acid, lasts a long time. This EAG can be made to respond to As(III) and As(V) in an equivalent fashion and is fabricated with two readily available chromatographic T fittings. It permits the use of a wire roll as the cathode, permitting rapid renewal of the electrode. The HOPG-based EAG is easily constructed from ion chromatography suppressor shells and can convert As(III) to AsH3 quantitatively but has significantly lower response to As(V); this difference can be exploited for speciation. The success of Al, an active metal, also dispels the maxim that metals with high hydrogen overpotential are best for electrochemical hydride generation. We report construction, operation, and performance details of these EAGs. Using gas phase chemiluminescence (GPCL) with ozone as a complementary green analytical technique, we demonstrate attractive limits of detection (LODs) (S/N = 3) of 1.9 and 1.0 MUg/L As(V) and As(III) for the HOPG-based EAG and 1.4 MUg/L As(V) or As(III) for the Al-based EAG, respectively. Precision at the ~20 MUg/L As(V) level was 2.4% and 2.1% relative standard deviation (RSD) for HOPG- and Al-based EAGs, respectively. Both HOPG- and Al-based EAGs permitted a sample throughput of 12/h. For groundwater samples from West Texas and West Bengal, India, very comparable results were obtained with parallel measurements by induction coupled plasma-mass spectrometry. PMID- 25034005 TI - Pericytes in chronic lung disease. AB - Pericytes are mesenchymal cells embedded within the abluminal surface of the endothelium of microvessels such as capillaries, pre-capillary arterioles, post capillary and collecting venules, where they maintain microvascular homeostasis and participate in angiogenesis. In addition to their roles in supporting the vasculature and facilitating leukocyte extravasation, pericytes have been recently investigated as a subpopulation of mesenchymal stem cells (MSCs) due to their capacity to differentiate into numerous cell types including the classic MSC triad, i.e. osteocytes, chondrocytes and adipocytes. Other studies in models of fibrotic inflammatory disease of the lung have demonstrated a vital role of pericytes in myofibroblast activation, collagen deposition and microvascular remodelling, which are hallmark features of chronic lung diseases such as asthma, chronic obstructive pulmonary disorder, pulmonary fibrosis and pulmonary hypertension. Further studies into the mechanisms of the pericyte-to myofibroblast transition and migration to fibrotic foci will hopefully clarify the role of these cells in chronic lung disease and confirm the importance of pericytes in human fibrotic pulmonary disease. PMID- 25034006 TI - Energy deposition by heavy ions: additivity of kinetic and potential energy contributions in hillock formation on CaF2. AB - Modification of surface and bulk properties of solids by irradiation with ion beams is a widely used technique with many applications in material science. In this study, we show that nano-hillocks on CaF2 crystal surfaces can be formed by individual impact of medium energy (3 and 5 MeV) highly charged ions (Xe(22+) to Xe(30+)) as well as swift (kinetic energies between 12 and 58 MeV) heavy xenon ions. For very slow highly charged ions the appearance of hillocks is known to be linked to a threshold in potential energy (Ep) while for swift heavy ions a minimum electronic energy loss per unit length (Se) is necessary. With our results we bridge the gap between these two extreme cases and demonstrate, that with increasing energy deposition via Se the Ep-threshold for hillock production can be lowered substantially. Surprisingly, both mechanisms of energy deposition in the target surface seem to contribute in an additive way, which can be visualized in a phase diagram. We show that the inelastic thermal spike model, originally developed to describe such material modifications for swift heavy ions, can be extended to the case where both kinetic and potential energies are deposited into the surface. PMID- 25034007 TI - A comparison of cardiomyocyte cytotoxic mechanisms for 5-fluorouracil and its pro drug capecitabine. AB - 1. 5-Fluorouracil (5-FU) and its prodrug capecitabine are key chemotherapeutic agents in the treatment of many gastrointestinal tract adenocarcinomas. In addition to their beneficial antitumor effects, they also possess undesired cardiac toxicity. In the present study, we investigated the cytotoxic mechanisms of 5-FU and capecitabine in freshly isolated rat cardiomyocytes. 2. 5-FU and capecitabine cytotoxicities were associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione depletion. Increased intracellular ROS could target mitochondria, and our findings confirmed that the cardiomyocytes mitochondrial membrane potential (DeltaPsim) was rapidly decreased by 5-FU and capecitabine. Mitochondrial dysfunction subsequently initiates downstream events that trigger caspase-3 activation, and our results showed that 5-FU and capecitabine activated caspase-3 which leads to apoptosis or necrosis. However, 5-FU acted much more powerful than capecitabine at inducing several cytotoxicity markers in heart cardiomyocytes. In addition, 5-FU but not capecitabine caused lysosomal membrane leakiness when it was incubated with cardiomyocytes. All cytotoxicity markers were prevented by antioxidants, ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents and lysosomotropic agents. 3. Our findings showed that the cytotoxic action of 5-FU and capecitabine on cardiomyocytes are mediated by oxidative stress and subsequent mitochondrial dysfunction which causes caspase-3 activation and cell death. PMID- 25034008 TI - Glucuronidation of fimasartan, a new angiotensin receptor antagonist, is mainly mediated by UGT1A3. AB - 1. Fimasartan is an angiotensin receptor II antagonist used to treat patients with hypertension. This drug is mainly excreted into bile as either the parent compound or a glucuronide conjugate. In this study, we examined the glucuronidation of fimasartan and characterized the UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation. 2. Only one type of fimasartan glucuronide was observed after incubation with pooled human liver microsomes (HLMs) and was identified as an N2-glucuronide based on comparison with an authentic standard. 3. Among the 12 UGT isoforms tested, UGT1A1, UGT1A3 and UGT2B7 showed catalytic activity toward fimasartan glucuronidation. The intrinsic clearance (CLint) of UGT1A3 was 68.5- and 21.4-fold higher than that of UGT1A1 and UGT2B7, respectively, and the estimated relative contribution of UGT1A3 in human liver was 94.1%. Both chemical inhibition and correlation studies demonstrated that fimasartan glucuronidation activity in HLMs was significantly related with UGT1A3 activity. Fimasartan glucuronide was identified as a substrate for P-glycoprotein (Pgp) and breast cancer response protein (BCRP). 4. These findings collectively indicate that UGT1A3 is the major UGT isoform responsible for the glucuronidation of fimasartan, and this glucuronide is excreted from hepatocytes via MDR1 and BCRP. PMID- 25034009 TI - Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. AB - 1. Crizotinib (XALKORI(r)), an oral inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor kinase (c-Met), is currently approved for the treatment of patients with non-small cell lung cancer that is ALK-positive. 2. The metabolism, excretion and pharmacokinetics of crizotinib were investigated following administration of a single oral dose of 250 mg/100 uCi [(14)C]crizotinib to six healthy male subjects. 3. Mean recovery of [(14)C]crizotinib-related radioactivity in excreta samples was 85% of the dose (63% in feces and 22% in urine). 4. Crizotinib and its metabolite, crizotinib lactam, were the major components circulating in plasma, accounting for 33% and 10%, respectively, of the 0-96 h plasma radioactivity. Unchanged crizotinib was the major excreted component in feces (~ 53% of the dose). In urine, crizotinib and O-desalkyl crizotinib lactam accounted for ~ 2% and 5% of the dose, respectively. Collectively, these data indicate that the primary clearance pathway for crizotinib in humans is oxidative metabolism/hepatic elimination. 5. Based on plasma exposure in healthy subjects following a single dose of crizotinib and in vitro potency against ALK and c-Met, the crizotinib lactam diastereomers are not anticipated to contribute significantly to in vivo activity; however, additional assessment in cancer patients is warranted. PMID- 25034010 TI - The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys. AB - 1. Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12 mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28 L/kg, respectively) with terminal elimination half life approximately 6 h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension. 2. Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species. 3. Following oral administration to rats, [(14)C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24 h. 4. The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation. PMID- 25034011 TI - Ethyl sulphate, a chemically reactive human metabolite of ethanol? AB - 1. Ethanol consumption is known to be linked in varying degrees to numerous ailments including damage to the nervous, endocrine and musculoskeletal systems and the gastrointestinal tract as well as extensive liver injury and several cancerous events. 2. Although acetaldehyde is the presently favoured candidate, both directly and indirectly, for such deleterious outcomes, over the years many other mechanisms and suggestions have been advanced. 3. The sparse literature concerning ethyl sulphate, a recently confirmed human metabolite of ethanol, has been examined, evaluated and interpreted to put forward the new proposition that ethyl sulphate itself may be able to alkylate various biological macromolecules thereby leading to toxicity. PMID- 25034012 TI - Clustered DNA damage on subcellular level: effect of scavengers. AB - Clustered DNA damages are induced by ionizing radiation, particularly of high linear energy transfer (LET). Compared to isolated DNA damage sites, their biological effects can be more severe. We investigated a clustered DNA damage induced by high LET radiation (C 290 MeV u(-1) and Fe 500 MeV u(-1)) in pBR322 plasmid DNA. The plasmid is dissolved in pure water or in aqueous solution of one of the three scavengers (coumarin-3-carboxylic acid, dimethylsulfoxide, and glycylglycine). The yield of double strand breaks (DSB) induced in the DNA plasmid-scavenger system by heavy ion radiation was found to decrease with increasing scavenging capacity due to reaction with hydroxyl radical, linearly with high correlation coefficients. The yield of non-DSB clusters was found to occur twice as much as the DSB. Their decrease with increasing scavenging capacity had lower linear correlation coefficients. This indicates that the yield of non-DSB clusters depends on more factors, which are likely connected to the chemical properties of individual scavengers. PMID- 25034013 TI - In vitro interaction between resistin and peroxisome proliferator-activated receptor gamma in porcine ovarian follicles. AB - In the present study, using real-time polymerase chain reaction and immunoblotting methods, we quantified the expression of peroxisome proliferator activated receptor (PPAR) gamma, PPARalpha and PPARbeta in different sized ovarian follicles (small (SF), medium (MF) and large (LF) follicles) in prepubertal and adult pigs. In prepubertal pigs, PPARgamma and PPARalpha expression was highest in LF; however, PPARbeta expression did not differ among SF, MF and LF. In mature pigs, only protein expression of PPARgamma and PPARalpha increased during ovarian follicle development. Following identification of very high levels of PPARgamma expression in LF in prepubertal and adult pigs, using in vitro culture of ovarian follicles, we determined the effect of resistin at 0.1, 1 and 10ngmL(-1) on PPARgamma mRNA and protein expression and the effect of rosiglitazone at 25 and 50uM (a PPARgamma agonist) on resistin mRNA and protein expression. Resistin increased PPARgamma expression in ovarian follicles in both prepubertal and adult pigs, whereas rosiglitazone had an inhibitory effect on resistin expression. The role of PPARgamma in regulating the effects of resistin on ovarian steroidogenesis was investigated using GW9662 (a PPARgamma antagonist at dose of 1MUM). In these studies, GW9662 reversed the effect of resistin on steroid hormone secretion. The data suggest that there is local cooperation between resistin and PPARgamma expression in the porcine ovary. Resistin significantly increased the expression of PPARgamma, whereas PPARgamma decreased resistin expression; thus, PPARgamma is a new key regulator of resistin expression and function. PMID- 25034014 TI - Constrained geometric dynamics of the Fenna-Matthews-Olson complex: the role of correlated motion in reducing uncertainty in excitation energy transfer. AB - The trimeric Fenna-Mathews-Olson (FMO) complex of green sulphur bacteria is a well-studied example of a photosynthetic pigment-protein complex, in which the electronic properties of the pigments are modified by the protein environment to promote efficient excitonic energy transfer from antenna complexes to the reaction centres. By a range of simulation methods, many of the electronic properties of the FMO complex can be extracted from knowledge of the static crystal structure. However, the recent observation and analysis of long-lasting quantum dynamics in the FMO complex point to protein dynamics as a key factor in protecting and generating quantum coherence under laboratory conditions. While fast inter- and intra-molecular vibrations have been investigated extensively, the slow, conformational dynamics which effectively determine the optical inhomogeneous broadening of experimental ensembles has received less attention. The following study employs constrained geometric dynamics to study the flexibility in the protein network by efficiently generating the accessible conformational states from the published crystal structure. Statistical and principle component analyses reveal highly correlated low frequency motions between functionally relevant elements, including strong correlations between pigments that are excitonically coupled. Our analysis reveals a hierarchy of structural interactions which enforce these correlated motions, from the level of monomer-monomer interfaces right down to the alpha-helices, beta-sheets and pigments. In addition to inducing strong spatial correlations across the conformational ensemble, we find that the overall rigidity of the FMO complex is exceptionally high. We suggest that these observations support the idea of highly correlated inhomogeneous disorder of the electronic excited states, which is further supported by the remarkably low variance (typically <5%) of the excitonic couplings of the conformational ensemble. PMID- 25034016 TI - Scaphoid view radiograph of the left wrist. PMID- 25034017 TI - Evolutionary relationship of disease resistance genes in soybean and Arabidopsis specific for the Pseudomonas syringae effectors AvrB and AvrRpm1. AB - In Arabidopsis (Arabidopsis thaliana), the Pseudomonas syringae effector proteins AvrB and AvrRpm1 are both detected by the RESISTANCE TO PSEUDOMONAS MACULICOLA1 (RPM1) disease resistance (R) protein. By contrast, soybean (Glycine max) can distinguish between these effectors, with AvrB and AvrRpm1 being detected by the Resistance to Pseudomonas glycinea 1b (Rpg1b) and Rpg1r R proteins, respectively. We have been using these genes to investigate the evolution of R gene specificity and have previously identified RPM1 and Rpg1b. Here, we report the cloning of Rpg1r, which, like RPM1 and Rpg1b, encodes a coiled-coil (CC)-nucleotide-binding (NB)-leucine-rich repeat (LRR) protein. As previously found for Rpg1b, we determined that Rpg1r is not orthologous with RPM1, indicating that the ability to detect both AvrB and AvrRpm1 evolved independently in soybean and Arabidopsis. The tightly linked soybean Rpg1b and Rpg1r genes share a close evolutionary relationship, with Rpg1b containing a recombination event that combined a NB domain closely related to Rpg1r with CC and LRR domains from a more distantly related CC-NB-LRR gene. Using structural modeling, we mapped polymorphisms between Rpg1b and Rpg1r onto the predicted tertiary structure of Rpg1b, which revealed highly polymorphic surfaces within both the CC and LRR domains. Assessment of chimeras between Rpg1b and Rpg1r using a transient expression system revealed that AvrB versus AvrRpm1 specificity is determined by the C terminal portion of the LRR domain. The P. syringae effector AvrRpt2, which targets RPM1 INTERACTOR4 (RIN4) proteins in both Arabidopsis and soybean, partially blocked recognition of both AvrB and AvrRpm1 in soybean, suggesting that both Rpg1b and Rpg1r may detect these effectors via modification of a RIN4 homolog. PMID- 25034018 TI - Plant nutrition: root transporters on the move. AB - Nutrient and water uptake from the soil is essential for plant growth and development. In the root, absorption and radial transport of nutrients and water toward the vascular tissues is achieved by a battery of specialized transporters and channels. Modulating the amount and the localization of these membrane transport proteins appears as a way to drive their activity and is essential to maintain nutrient homeostasis in plants. This control first involves the delivery of newly synthesized proteins to the plasma membrane by establishing check points along the secretory pathway, especially during the export from the endoplasmic reticulum. Plasma membrane-localized transport proteins are internalized through endocytosis followed by recycling to the cell surface or targeting to the vacuole for degradation, hence constituting another layer of control. These intricate mechanisms are often regulated by nutrient availability, stresses, and endogenous cues, allowing plants to rapidly adjust to their environment and adapt their development. PMID- 25034020 TI - The safety of asthma medications during pregnancy: an update for clinicians. AB - Pregnancy may be complicated by new onset or preexisting asthma. This article reviews the recognition and management of asthma during pregnancy, as well as general principles of asthma medication use during pregnancy. PMID- 25034021 TI - Current best practice in the management of pulmonary and systemic sarcoidosis. AB - Sarcoidosis is a systemic inflammatory disease of unknown etiology that is characterized by the presence of granulomatous inflammation in affected tissues. It can affect essentially any organ system but shows a predilection for the lungs, eyes, and skin. Accurate epidemiological data are not available in the USA, but sarcoidosis is considered a 'rare disease' (prevalence less than 200,000). However, recent epidemiologic studies indicate that regional prevalence is much higher than previously estimated, especially among African American women. Additionally, mortality rates of patients with sarcoidosis are increasing by 3% per year over the past two decades. The most common causes of death are attributed to progressive lung disease and cardiac sarcoidosis, and the health of the patients is further compromised by other systemic manifestations. As such, the management of sarcoidosis requires a collaborative multidisciplinary approach. We aim to discuss the principles of managing sarcoidosis, including standards of care relating to pulmonary disease as well as recent advances relating to the detection and treatment of extrapulmonary manifestations. PMID- 25034022 TI - A renal angiomyolipoma with extension to the renal vein and asymptomatic fat pulmonary embolus. AB - Renal angiomyolipoma (AML) is a rare benign tumor that can extend into the renal vein, inferior vena cava and the right atrium. AML is a mesenchymal tumor composed of smooth muscle, fat and vascular elements. In rare instances, the tumor may release a fatty tissue to the pulmonary vasculature, which can lead to cardiopulmonary collapse and death. Only four cases of fat pulmonary embolism secondary to AML have been reported in the literature but our case was the first to present as asymptomatic. Our patient had left renal AML extending to the renal vein that was associated with fat pulmonary embolus. The patient underwent uncomplicated radical nephrectomy and was discharged home on no anticoagulation. Follow-up chest computed tomography showed no extension of the pulmonary embolism. Whether embolectomy or anticoagulation is necessary in asymptomatic pulmonary embolism secondary to renal AML is unclear. Although controversial, some surgeons prefer to place an inferior vena cava filter prior to radical nephrectomy to prevent dislodgement of new intraoperative emboli, which can lead to catastrophic outcome. PMID- 25034019 TI - The ASH1-RELATED3 SET-domain protein controls cell division competence of the meristem and the quiescent center of the Arabidopsis primary root. AB - The stem cell niche of the Arabidopsis (Arabidopsis thaliana) primary root apical meristem is composed of the quiescent (or organizing) center surrounded by stem (initial) cells for the different tissues. Initial cells generate a population of transit-amplifying cells that undergo a limited number of cell divisions before elongating and differentiating. It is unclear whether these divisions occur stochastically or in an orderly manner. Using the thymidine analog 5-ethynyl-2' deoxyuridine to monitor DNA replication of cells of Arabidopsis root meristems, we identified a pattern of two, four, and eight neighboring cells with synchronized replication along the cortical, epidermal, and endodermal cell files, suggested to be daughters, granddaughters, and great-granddaughters of the direct progeny of each stem cell. Markers of mitosis and cytokinesis were not present in the region closest to the transition zone where the cells start to elongate, suggesting that great-granddaughter cells switch synchronously from the mitotic cell cycle to endoreduplication. Mutations in the stem cell niche expressed ASH1-RELATED3 (ASHR3) gene, encoding a SET-domain protein conferring histone H3 lysine-36 methylation, disrupted this pattern of coordinated DNA replication and cell division and increased the cell division rate in the quiescent center. E2Fa/E2Fb transcription factors controlling the G1-to-S-phase transition regulate ASHR3 expression and bind to the ASHR3 promoter, substantiating a role for ASHR3 in cell division control. The reduced length of the root apical meristem and primary root of the mutant ashr3-1 indicate that synchronization of replication and cell divisions is required for normal root growth and development. PMID- 25034023 TI - Heparin/heparan sulfate controls fibrillin-1, -2 and -3 self-interactions in microfibril assembly. AB - Fibrillins form multifunctional microfibrils in most connective tissues. Deficiencies in fibrillin assembly can result in fibrillinopathies, such as Marfan syndrome. We demonstrate the presence of heparin/heparan sulfate binding sites in fibrillin-2 and -3. Multimerization of all three fibrillins drastically increased the apparent affinity of their interaction with heparin/heparan sulfate. Surprisingly, contrary to other reports heparin/heparan sulfate strongly inhibited homo- and heterotypic N-to-C-terminal fibrillin interactions. These data suggest that heparin/heparan sulfate controls the formation of microfibrils at the bead interaction stage. PMID- 25034024 TI - Therapeutic approaches for the treatment of Friedreich's ataxia. AB - Friedreich ataxia (FRDA) is an inherited, progressive, neurodegenerative disease for which there is presently no cure or effective therapeutic intervention. While physiologically complex, FRDA is caused by deficits in production and expression of frataxin (FXN), a mitochondrial protein important for regulation of iron sulfur cluster containing enzymes in the cell. Depletion of FXN is associated with dysfunction of ATP synthesis, mitochondrial iron accumulation, potentially an increase in oxidative stress, and cellular dysfunction. Therapeutic development presently focuses on improving mitochondrial function and increasing FXN expression. Gene therapy, a field which has undergone significant advances in recent years, may offer a promising treatment for FRDA in the future. This collection of approaches provides many possible opportunities for treating this multisystem disorder. PMID- 25034025 TI - Maternal obesity and its relation with the cesarean section: a hospital based cross sectional study in Iraq. AB - BACKGROUND: Obesity during pregnancy is reported in approximately one in five pregnant women worldwide. It increases the risk of pregnancy complications many of which necessitate Cesarean section (CS). This study determines the association between obesity and type of delivery. METHODS: A cross-sectional study involving 404 pregnant women was carried out at Al-Yarmouk Teaching Hospital, Baghdad, Iraq. Women with hypertension, diabetes, preterm labor, fetal presentation other than cephalic presentation and multiple gestations were excluded from the study. BMI and past obstetric history were recorded. RESULTS: The overall rate of CS was 38%. The overall mean body mass index (BMI) was 25.0 +/- 4.52 Kg/m2 and it was significantly higher among women who delivered by cesarean section. Significantly high rate of CS was found in primigravida and multigravida women with high BMI. Moreover, all obese multigravid women with history of previous CS were delivered by CS. The rate of CS was higher in women with primary level education when compared to women with secondary or tertiary education. CS was significantly lower in women with a previous history of abortion. CONCLUSION: Obese women with or without a previous history of CS are at a higher risk of having a CS and should therefore be considered as high risk and managed appropriately during pregnancy. Weight management prior to or during pregnancy could help reduce the need for CS. PMID- 25034026 TI - Synthesis of water-soluble CdSe quantum dots with various fluorescent properties and their application in immunoassay for determination of C-reactive protein. AB - Effects of various factors on synthesis and fluorescent properties of CdSe quantum dots were studied. It was shown that variation of pH, stabilizer and concentration of precursors brings to obtaining of quantum dots with various fluorescent properties. The nanoparticles prepared were conjugated with rabbit antibodies to C-Reactive protein and C-Reactive protein for competitive immunoassay for determination of CRP. It was shown that interaction of these dots as a result of antigen-antibody reaction brings to resonance energy transfer and these changes in fluorescence spectra correlate with concentration of CRP. This approach permits to determine CRP in range between 4-100 ng. PMID- 25034027 TI - The mechanism of hemifacial spasm: a new understanding of the offending artery. AB - Although neurovascular confliction was believed to be the cause of hemifacial spasm (HFS), the mechanism of the disorder remains unclear to date. Current theories, merely focusing on the facial nerve, have failed to explain the clinical phenomenon of immediate relief following a successful microvascular decompression surgery (MVD). With the experience of thousands of microvascular decompression surgeries and preliminary investigations, we have learned that the offending artery may play a more important role than the effect of merely mechanical compression in the pathogenesis of the disease. We believe that the attrition of neurovascular interface is the essence of the etiology, and the substance of the disease is emersion of ectopic action potentials from the demyelinated facial nerve fibers, which were triggered by the sympathetic endings from the offending artery wall. In this paper, we put forward evidence to support this hypothesis, both logically and theoretically. PMID- 25034028 TI - A novel means of assessing institutional adherence to blood transfusion guidelines. AB - Risk-adjusted institutional transfusion rates are not currently available on a national level. A surrogate means of benchmarking transfusion practices to use for internal quality improvement was studied. Blood utilization was prospectively studied among all colorectal surgery patients at the study institution (July 2010 November 2012), and these data were benchmarked with transfusion data from the National Surgical Quality Improvement Program (NSQIP) database by hospital type and size. Using NSQIP, the study institution's colorectal surgery transfusion rate was 16.3% (150/920 cases), which was slightly higher than the 14.3% national mean transfusion rate (12 191/85 507 cases; P = .08). When broken down by hospital type and size, the study hospital had a similar rate of blood transfusion compared with academic hospitals (P = .35) but a significantly higher rate than community hospitals, regardless of patient volume (P = .03). Benchmarking blood utilization compared with similar-type hospitals using NSQIP may be a surrogate method to assess adherence to evidence-based transfusion guidelines and identify areas for structured quality improvement initiatives. PMID- 25034029 TI - Diet-dependent gene expression in honey bees: honey vs. sucrose or high fructose corn syrup. AB - Severe declines in honey bee populations have made it imperative to understand key factors impacting honey bee health. Of major concern is nutrition, as malnutrition in honey bees is associated with immune system impairment and increased pesticide susceptibility. Beekeepers often feed high fructose corn syrup (HFCS) or sucrose after harvesting honey or during periods of nectar dearth. We report that, relative to honey, chronic feeding of either of these two alternative carbohydrate sources elicited hundreds of differences in gene expression in the fat body, a peripheral nutrient-sensing tissue analogous to vertebrate liver and adipose tissues. These expression differences included genes involved in protein metabolism and oxidation-reduction, including some involved in tyrosine and phenylalanine metabolism. Differences between HFCS and sucrose diets were much more subtle and included a few genes involved in carbohydrate and lipid metabolism. Our results suggest that bees receive nutritional components from honey that are not provided by alternative food sources widely used in apiculture. PMID- 25034030 TI - Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model. AB - BACKGROUND: Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti inflammatory actions. METHODS: Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. RESULTS: Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-kappaB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. CONCLUSIONS: Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities. PMID- 25034032 TI - Tetrabutylphosphonium ions as a new swelling/delamination agent for layered compounds. AB - The swelling and exfoliation behavior of protonated layered oxides using an organo-phosphonium base, tetrabutylphosphonium hydroxide (TBPOH), was examined for the first time. The action of the aqueous solution induced massive interlayer expansion up to ~100-fold. The swollen crystals were immediately broken and completely exfoliated into unilamellar nanosheets in 1-2 h by shaking. PMID- 25034031 TI - Genetic variants in the complement system predisposing to age-related macular degeneration: a review. AB - Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD. PMID- 25034033 TI - p600 stabilizes microtubules to prevent the aggregation of CaMKIIalpha during photoconductive stimulation. AB - The large microtubule-associated/Ca(2+)-signalling protein p600 (also known as UBR4) is required for hippocampal neuronal survival upon Ca(2+) dyshomeostasis induced by glutamate treatment. During this process, p600 prevents aggregation of the Ca(2+)/calmodulin-dependent kinase IIalpha (CaMKIIalpha), a proxy of neuronal death, via direct binding to calmodulin in a microtubuleindependent manner. Using photoconductive stimulation coupled with live imaging of single neurons, we identified a distinct mechanism of prevention of CaMKIIalpha aggregation by p600. Upon direct depolarization, CaMKIIalpha translocates to microtubules. In the absence of p600, this translocation is interrupted in favour of a sustained self aggregation that is prevented by the microtubule-stabilizing drug paclitaxel. Thus, during photoconductive stimulation, p600 prevents the aggregation of CaMKIIalpha by stabilizing microtubules. The effectiveness of this stabilization for preventing CaMKIIalpha aggregation during direct depolarization but not during glutamate treatment suggests a model wherein p600 has two modes of action depending on the source of cytosolic Ca(2+). PMID- 25034034 TI - CD39/NTPDase-1 expression and activity in human umbilical vein endothelial cells are differentially regulated by leaf extracts from Rubus caesius and Rubus idaeus. AB - Many experimental studies have demonstrated the favorable biological activities of plants belonging to the genus Rubus, but little is known of the role of Rubus leaf extracts in the modulation of the surface membrane expression and activity of endothelial apyrase. The aim of this study was to assess the influence of 1-15 MUg/ml Rubus extracts on CD39 expression and enzymatic activity, and on the activation (ICAM-1 expression) and viability of human umbilical vein endothelial cells (HUVEC). The polyphenolic contents and antioxidative capacities of extracts from dewberry (R. caesius L.) and raspberry (R. idaeus L.) leaves were also investigated. The techniques applied were flow cytometry (endothelial surface membrane expression of ICAM-1 and CD39), malachite green assay (CD39 activity), HPLC-DAD (quantitative analysis of polyphenolic extract), ABTS, DPPH and FRAP spectrometric assays (antioxidant capacity), and the MTT test (cell viability). Significantly increased CD39 expressions and significantly decreased ATPDase activities were found in the cells treated with 15 MUg/ml of either extract compared to the results for the controls. Neither of the extracts affected cell proliferation, but both significantly augmented endothelial cell ICAM-1 expression. The overall antioxidant capacities of the examined extracts remained relatively high and corresponded well to the determined total polyphenol contents. Overall, the results indicate that under in vitro conditions dewberry and raspberry leaf extracts have unfavorable impact on endothelial cells. PMID- 25034035 TI - Resectable carcinoma developing in the remnant pancreas 7 years and 10 months after distal pancreatectomy for invasive ductal carcinoma of the pancreas: report of a case. AB - BACKGROUND: Pancreatic ductal adenocarcinoma, which represents 90% of pancreatic cancers, is one of the most lethal and aggressive malignancies. Operative resection remains the only treatment providing prolonged survival, however, recurrence of pancreatic ductal adenocarcinoma occurs in up to 80% of patients with pancreatic cancer within 2 years of a potential curative resection. There are few reports of pancreatic carcinoma recurrence (primary second cancer) in the remnant pancreas after pancreatectomy. CASE PRESENTATION: A 52-year-old woman underwent a distal pancreatectomy for pancreatic cancer in September 2004. Adjuvant chemotherapy was started after surgery and continued for 4 years. In March 2012, marked elevation of DUPAN-II was observed, followed by an irregular stenotic finding in the main duct. We performed an en bloc resection of the remnant pancreas in July 2012. Histologically, the tumor contained a second primary pancreatic carcinoma with lymph node metastasis. At follow-up 20 months after the second operation, the patient was alive without recurrence. Fourteen cases of resectable cancer developing in the remnant pancreas after a pancreatectomy for cancer have been reported; a minority of these was identified as second primary tumors. Therefore, our patient's primary second cancer is a rare event. CONCLUSION: The patient is considered to have shown a rare, unique pancreatic cancer recurrence. Persistent elevation of a tumor marker and extensive imaging led to proper diagnosis and treatment. PMID- 25034036 TI - Scottish health in a post-independence world. PMID- 25034037 TI - Incorporation of heterostructured Sn/SnO nanoparticles in crumpled nitrogen-doped graphene nanosheets for application as anodes in lithium-ion batteries. AB - Sn/SnO nanoparticles are incorporated in crumpled nitrogen-doped graphene nanosheets by a simple melting diffusion method. The resulting composite exhibits large specific capacity, excellent cycling stability and high rate capability as an anode for lithium-ion batteries. PMID- 25034038 TI - Update on the optimal management of patients with vascular extension of pheochromocytoma. AB - AIM: Vascular extension of pheochromocytoma is extremely rare but highly resectable. The aim of this study was to review the available information in the literature for patients with this condition. METHODS: A systematic literature search produced individual data for 29 treated patients with vascular extension of pheochromocytoma mainly to the inferior vena cava. RESULTS: Out of 29 reported cases, 26 have been treated surgically. Nine of these patients required cardiopulmonary bypass. Two patients died untreated and one patient declined surgical treatment and discharged to follow-up. In 24 patients including nine with primarily missed diagnosis, surgery was documented as curative. CONCLUSION: Surgeons need to be aware of this extremely rare characteristic feature of pheochromocytoma and indicated medical work-up in order to properly diagnose and manage this challenging group of patients. PMID- 25034039 TI - Other Bordetellas, lessons for and from pertussis vaccines. AB - The Bordetella genus comprises nine species of which Bordetella pertussis and B. parapertussis are isolated from humans and are the most studied Bordetella species since they cause whooping cough. They both originate from B. bronchiseptica, which infects several mammals and immune compromised humans, but the intensive use of pertussis vaccines induced changes in B. pertussis and B. parapertussis populations. B. petrii and B. holmesii are other species of unknown reservoir and transmission pattern that have been described in humans. It is still unknown whether these species are pathogens for humans or only opportunistic bacteria but biological diagnosis has confirmed the presence of B. holmesii in human respiratory samples while B. petrii and the four other species have little implications for public health. PMID- 25034040 TI - Dyslexia: reconciling controversies within an integrative developmental perspective. PMID- 25034041 TI - Use patterns of health information exchange through a multidimensional lens: conceptual framework and empirical validation. AB - Insights about patterns of system use are often gained through the analysis of system log files, which record the actual behavior of users. In a clinical context, however, few attempts have been made to typify system use through log file analysis. The present study offers a framework for identifying, describing, and discerning among patterns of use of a clinical information retrieval system. We use the session attributes of volume, diversity, granularity, duration, and content to define a multidimensional space in which each specific session can be positioned. We also describe an analytical method for identifying the common archetypes of system use in this multidimensional space. We demonstrate the value of the proposed framework with a log file of the use of a health information exchange (HIE) system by physicians in an emergency department (ED) of a large Israeli hospital. The analysis reveals five distinct patterns of system use, which have yet to be described in the relevant literature. The results of this study have the potential to inform the design of HIE systems for efficient and effective use, thus increasing their contribution to the clinical decision-making process. PMID- 25034042 TI - Geniposide attenuates mitochondrial dysfunction and memory deficits in APP/PS1 transgenic mice. AB - Oxidative stress and mitochondrial dysfunction appear early and contribute to the disease progression in Alzheimer's disease (AD), which can be detected extensively in AD patients brains as well as in transgenic AD mice brains. Thus, treatments that result in attenuation of oxidative stress and mitochondrial dysfunction may hold potential for AD treatment. Geniposide, a pharmacologically active component purified from gardenia fruit, exhibits anti-oxidative, antiinflammatory and other important therapeutic properties. However, whether geniposide has any protective effect on oxidative stress and mitochondrial dysfunction in AD transgenic mouse model has not yet been reported. Here, we demonstrate that intragastric administration of geniposide significantly reduces oxidative stress and mitochondrial dysfunction in addition to improving learning and memory in APP/PS1 mice. Geniposide exerts protective effects on mitochondrial dysfunction in APP/PS1 mice through suppressing the mitochondrial oxidative damage and increasing the mitochondrial membrane potential and activity of cytochrome c oxidase. These studies indicate that geniposide may attenuate memory deficits through the suppression of mitochondrial oxidative stress. Thus, geniposide may be a potential therapeutic reagent for halting and preventing AD progress. PMID- 25034043 TI - Designing in vitro strategies and in vivo models for Alzheimer's disease - promises & challenges. AB - Protein folding is a spontaneous self-assembly process, which occurs in the biological system. Understanding this complex process not only helps in deciphering the mechanism involved in protein misfolding diseases but also helps in modeling in vitro and in vivo systems for testing the therapeutic strategies developed for the disease. Among the protein misfolding diseases, much emphasis has been given to Alzheimer's disease because of its prevalence among elderly individuals and propensity to cause external damage to neurons, an effective cure for which is yet to be designed. Though amyloid fibrils are the major cause of neurotoxicity in Alzheimer's disease, their mechanism of self-assembly during pathological conditions is still under active investigation. This review aims to understand the basic mechanism of amyloid fibril formation and how it can be characterized in different stages by various techniques. With this information, it is possible to design both in vitro and in vivo systems, which not only serves as model systems for understanding the mechanism of amyloid fibril formation but also helps to test new therapeutic strategies against the disease. This review also highlights the pros and cons of currently available in vitro and in vivo systems, which can aid the readers to select a suitable system for their further studies. PMID- 25034044 TI - Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz Pulsed Imaging. AB - The aim of this study was the evaluation of critical process parameters (CPP) for inter-tablet coating uniformity in an active pan coating process using nondestructive Terahertz Pulsed Imaging (TPI). Coating uniformity was assessed by calculating the coefficient of variation (CV) of coating thickness measured by TPI, and the CV of API content measured by high performance liquid chromatography (HPLC). A design of experiments (DoE) was performed at pilot scale with drum load, drum speed, spray rate, run duration and spray pressure as factors. Good agreement in the CV of both analytical techniques was shown. The DoE models both revealed the same CPP: a low drum load, high drum speed, low spray rate and high run duration were beneficial for coating uniformity. The spray pressure was only significant in one of the DoE models. It was further shown that the negative impact of a high drum load on the CV cannot only be compensated by high drum speed, but also be compensated by a low spray rate and long run duration. It was demonstrated that TPI is a feasible tool for the measurement of inter-tablet coating uniformity and for the evaluation of CPP in an active pan coating process. PMID- 25034045 TI - Salvianolic acid B inhibited PPARgamma expression and attenuated weight gain in mice with high-fat diet-induced obesity. AB - BACKGROUND/AIMS: Obesity contributes to the development of cardiometabolic disorders such as type 2 diabetes, fatty liver disease and cardiovascular disease. Salvianolic acid B (Sal B) is a molecule derived from the root of Salvia miltiorrhiza (Danshen), which is a traditional Chinese medicine that is widely used to treat cardiovascular diseases. However, the role of Sal B in obesity and obesity-related metabolic disorders is unknown. In this study, we aimed to investigate the effects of Sal B on high-fat diet-induced obesity and determine the possible mechanisms involved. METHODS: Male C57BL/6J mice fed a high-fat diet for 12 weeks received a supplement of Sal B (100 mg/kg/day) by gavage for a further 8 weeks. These mice were compared to control mice fed an un-supplemented high-fat diet. 3T3-L1 preadipocytes were used in vitro studies. RESULTS: Sal B administration significantly decreased body weight, white adipose tissue weight, adipocyte size and lipid (triglyceride and total cholesterol) levels in obese mice. Eight weeks of Sal B administration also improved the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) scores in high-fat diet-induced obese mice. In 3T3-L1 preadipocytes that were cultured in vitro and induced to differentiate, Sal B reduced the accumulation of lipid droplets and lipid content in a dose-dependent manner. Immunoblotting indicated that Sal B decreased peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha) expression but increased the expression of GATA binding protein 2 and 3 (GATA 2, GATA 3) both in vivo and in vitro. CONCLUSION: Our data suggest that Sal B may reduce obesity and obesity-related metabolic disorders by suppressing adipogenesis. The effects of Sal B in adipose tissue may be related to its action on PPARgamma, C/EBPalpha, GATA-2 and GATA-3. PMID- 25034047 TI - Novel mitochondrial tRNA(Ile) m.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype. AB - BACKGROUND/AIM: To investigate the underlying pathomechanism in a 33-year-old female Caucasian patient presenting with chronic progressive external ophthalmoplegia (CPEO) plus symptoms. METHODS: Histochemical analysis of skeletal muscle and biochemical measurements of individual oxidative phosphorylation (OXPHOS) complexes. Genetic analysis of mitochondrial DNA in various tissues with subsequent investigation of single muscle fibres for correlation of mutational load. RESULTS: The patient's skeletal muscle showed 20% of cytochrome c oxidase negative fibres and 8% ragged-red fibres. Genetic analysis of the mitochondrial DNA revealed a novel point mutation in the mitochondrial tRNA(Ile) (MTTI) gene at position m.4282G>A. The heteroplasmy was determined in blood, buccal cells and muscle by restriction fragment length polymorphism (RFLP) combined with a last fluorescent cycle. The total mutational load was 38% in skeletal muscle, but was not detectable in blood or buccal cells of the patient. The phenotype segregated with the mutational load as determined by analysis of single cytochrome c oxidase negative/positive fibres by laser capture microdissection and subsequent LFC RFLP. CONCLUSIONS: We describe a novel MTTI transition mutation at nucleotide position m.4282G>A associated with a CPEO plus phenotype. The novel variant at position m.4282G>A disrupts the middle bond of the D-stem of the tRNA(Ile) and is highly conserved. The conservation and phenotype-genotype segregation strongly suggest pathogenicity and is in good agreement with the MTTI gene being frequently associated with CPEO. This novel variant broadens the spectrum of MTTI mutations causing CPEO. PMID- 25034046 TI - Naproxen affects osteogenesis of human mesenchymal stem cells via regulation of Indian hedgehog signaling molecules. AB - INTRODUCTION: We previously showed that type X collagen, a marker of late stage chondrocyte hypertrophy (associated with endochondral ossification), is constitutively expressed by mesenchymal stem cells (MSCs) from osteoarthritis patients and this may be related to Naproxen (Npx), a nonsteroidal anti inflammatory drug used for therapy. Hedgehog (HH) signaling plays an important role during the development of bone. We tested the hypothesis that Npx affected osteogenic differentiation of human MSCs through the expression of Indian hedgehog (IHH), Patched-1 (PTC1) and GLI family members GLI1, GLI2, GLI3 in vitro. METHODS: MSCs were cultured in osteogenic differentiation medium without (control) or with 0.5 MUM Npx. The expression of collagen type X, alpha 1 (COL10A1), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OC), collagen type I, alpha 1 (COL1A1) was analyzed with real-time reverse transcription (RT) PCR, and the ALP activity was measured. The osteogenesis of MSCs was monitored by mineral staining and quantification with alizarin red S. To examine whether Npx affects osteogenic differentiation through HH signaling, the effect of Npx on the expression of IHH, GLI1, GLI2, GLI3 and PTC1 was analyzed with real-time RT PCR. The effect of cyclopamine (Cpn), a HH signaling inhibitor, on the expression of COL10A1, ALP, OC and COL1A1 was also determined. RESULTS: When MSCs were cultured in osteogenic differentiation medium, Npx supplementation led to a significant decrease in ALP gene expression as well as its activity, and had a tendency to decrease mineral deposition. It also decreased the expression of COL1A1 significantly. In contrast, the gene expression of COL10A1 and OPN were upregulated significantly by Npx. No significant effect was found on OC expression. The expression of IHH, PTC1, GLI1, and GLI2 was increased by Npx, while no significant difference was observed on GLI3 expression. Cpn reversed the effect of Npx on the expression of COL10A1, ALP, OPN and COL1A1. CONCLUSIONS: These results indicate that Npx can affect gene expression during osteogenic differentiation of MSCs, and downregulate mineral deposition in the extracellular matrix through IHH signaling. Therefore, Npx could affect MSC-mediated repair of subchondral bone in OA patients. PMID- 25034048 TI - Granular corneal dystrophy type 2 is associated with morphological abnormalities of meibomian glands. AB - AIMS: To investigate morphological changes in meibomian glands in patients with granular corneal dystrophy type 2 (GCD2) using non-invasive meibography. METHODS: Eleven patients (3 men and 8 women) with GCD2, and sex-matched and age-matched healthy volunteers as a controls were enrolled in this study. The diagnosis of GCD2 was confirmed by transforming growth factor beta-induced (TGFBI) gene analysis using direct sequencing in exon 4 of TGFBI gene. Meibography was performed in the right eye of the studied cases. Meiboscore was determined according to the morphology of meibomian gland and classified into four grades; grade 0 (no meibomian gland loss), grade 1 (loss less than one-third the total area of meibomian glands), grade 2 (area loss between one-third and two-thirds of the total area), and grade 3 (area loss greater than two-thirds of the total). RESULTS: R124H mutation was detected in all patients with GCD2. Extinguishing or shortening of the meibomian glands was observed in patients with GCD2. The meiboscore was 3.8+/-1.3 in patients with GCD2 and 1.3+/-1.1 in the control group, showing significant difference between two groups (Mann-Whitney U-test, p=0.042). CONCLUSIONS: In GCD2, corneal deposits, and also morphological abnormalities of meibomian glands, such as obstruction or shortening, were found. Since abnormal phospholipid deposition is noted in GCD2, these results are interesting because phospholipid is possibly secreted from the meibomian gland. PMID- 25034049 TI - Biomarkers and surrogate endpoints in glaucoma clinical trials. AB - Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. PMID- 25034050 TI - Effects of aflibercept on primary RPE cells: toxicity, wound healing, uptake and phagocytosis. AB - BACKGROUND/AIM: Anti-VEGF treatment is the therapy of choice in age-related macular degeneration, and is also applied in diabetic macular oedema or retinal vein occlusion. Recently, the fusion protein, aflibercept, has been approved for therapeutic use. In this study, we investigate the effects of aflibercept on primary RPE cells. METHODS: Primary RPE cells were prepared from freshly slaughtered pigs' eyes. The impact of aflibercept on cell viability was investigated with MTT and trypan blue exclusion assay. The influence of aflibercept on wound healing was assessed with a scratch assay. Intracellular uptake of aflibercept was investigated in immunohistochemistry and its influence on phagocytosis with a phagocytosis assay using opsonised latex beads. RESULTS: Aflibercept displays no cytotoxicity on RPE cells but impairs its wound healing ability. It is taken up into RPE cells and can be intracellularly detected for at least 7 days. Intracellular aflibercept impairs the phagocytic capacity of RPE cells. CONCLUSIONS: Aflibercept interferes with the physiology of RPE cells, as it is taken up into RPE cells, which is accompanied by a reduction of the phagocytic ability. Additionally, it impairs the wound healing capacity of RPE cells. These effects on the physiology of RPE cells may indicate possible side effects. PMID- 25034051 TI - Modern-day cataract surgery: can we match growing expectations? PMID- 25034052 TI - Pathophysiology of brain dysfunction in hyperammonemic syndromes: The many faces of glutamine. AB - Ineffective hepatic clearance of excess ammonia in the form of urea, as occurs in urea cycle enzymopathies (UCDs) and in liver failure, leads to increases in circulating and tissue concentrations of glutamine and a positive correlation between brain glutamine and the severity of neurological symptoms. Studies using 1H/13C Nuclear Magnetic Resonance (NMR) spectroscopy reveal increased de novo synthesis of glutamine in the brain in acute liver failure (ALF) but increases of synthesis rates per se do not correlate with either the severity of encephalopathy or brain edema. Skeletal muscle becomes primarily responsible for removal of excess ammonia in liver failure and in UCDs, an adaptation that results from a post-translational induction of the glutamine synthetase (GS) gene. The importance of muscle in ammonia removal in hyperammonemia accounts for the resurgence of interest in maintaining adequate dietary protein and the use of agents aimed at the stimulation of muscle GS. Alternative or additional metabolic and regulatory pathways that impact on brain glutamine homeostasis in hyperammonemia include (i) glutamine deamination by the two isoforms of glutaminase, (ii) glutamine transamination leading to the production of the putative neurotoxin alpha-ketoglutaramate and (iii) alterations of high affinity astrocytic glutamine transporters (SNATs). Findings of reduced expression of the glutamine transporter SNAT-5 (responsible for glutamine clearance from the astrocyte) in ALF raise the possibility of "glutamine trapping" within these cells. Such a trapping mechanism could contribute to cytotoxic brain edema and to the imbalance between excitatory and inhibitory neurotransmission in this disorder. PMID- 25034053 TI - Age, education and dementia related deaths. The Norwegian Counties Study and The Cohort of Norway. AB - An inverse relationship between educational level and dementia has been reported in several studies. In this study we investigated the relationship between educational level and dementia related deaths for cohorts of people all born during 1915-39. The cohorts were followed up from adulthood or old age, taking into account possible confounders and mediating paths. Our study population comprised participants in Norwegian health examination studies in the period 1974 2002; The Counties Study and Cohort of Norway (CONOR). Dementia related deaths were defined as deaths with a dementia diagnosis on the death certificate and linked using the Cause of Death Registry to year 2012. The study included 90,843 participants, 2.06 million person years and 2440 dementia related deaths. Cox regression was used to assess the association between education and dementia related deaths. Both high and middle educational levels were associated with lower dementia related death risk compared to those with low education when follow-up started in adulthood (35-49 years, high versus low education: HR=0.68, 95% confidence interval (CI) 0.50-0.93; 50-69 years, high versus low education: HR=0.52, 95% CI 0.34-0.80). However, when follow-up started at old age (70-80 years) there was no significant association between education and dementia related death. Restricting the study population to those born during a five-year period 1925-29 (the birth cohort overlapping all three age groups), gave similar main findings. The protective effects found for both high and middle educational level compared to low education were robust to adjustment for cardiovascular health and life style factors, suggesting education to be a protective factor for dementia related death. Both high and middle educational levels were associated with decreased dementia related death risk compared with low educational level when follow-up started in adulthood, but no association was observed when follow up started at old age. PMID- 25034054 TI - CNS-disease affecting the heart: brain-heart disorders. AB - There are a number of hereditary and non-hereditary central nervous system (CNS) disorders, which directly or indirectly affect the heart (brain-heart disorders). The most well-known of these CNS-disorders are epilepsy, stroke, subarachanoid bleeding, bacterial meningitis, and head injury. In addition, a number of hereditary and non-hereditary neurodegenerative disorders may impair cardiac functions. Affection of the heart may manifest as arrhythmias, cardiomyopathy, or autonomic dysfunction. Rarer cardiac complications of CNS disorders include heart failure, systolic or diastolic dysfunction, myocardial infarction, arterial hypertension, or pulmonary hypertension. Cardiomyopathy induced by hereditary CNS disease mainly include stress-induced myocardial dysfunction, known as Takotsubo syndrome (TTS). CNS disease triggering TTS includes epilepsy, ischemic stroke, subarachnoid bleeding, or PRES syndrome. Arrhythmias induced by hereditary CNS disease include supraventricular or ventricular arrhythmias leading to palpitations, dizziness, vertigo, fainting, syncope, (near) sudden cardiac death, or sudden unexplained death in epilepsy (SUDEP). Appropriate management of cardiac involvement in CNS-disorders is essential to improve outcome of affected patients. PMID- 25034055 TI - Hematoma volume as the major determinant of outcomes after intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is a leading cause of morbidity and mortality, greatly linked to hematoma volume. Understanding the characteristics and size of hematoma is integral to evaluating severity and prognosis after ICH. Examination of the literature suggests that markers for hematoma size vary, but the key range between 20-30 mL is most widely used as the cut-off for classification of hematoma volume. The role of hematoma volume in episodes of hematoma expansion and re-bleeding further impact outcomes, with increased growth associated with larger hematoma volume. Additionally, many commonly used predictors of ICH outcomes are directly related to hematoma volume, implicating it as an important variable when determining outcomes. In conclusion, hematoma volume is likely the most significant determinant of outcomes in intracerebral hemorrhage. PMID- 25034056 TI - Reduced spontaneous sympathetic nerve activity in multiple sclerosis patients. AB - For the first time, we obtained direct intra-neural measurements of muscle sympathetic nerve activity (MSNA) in relapsing-remitting multiple sclerosis (MS) patients to test the hypothesis that spontaneous resting MSNA is reduced in MS patients compared to age, sex-matched healthy controls. Spontaneous MSNA (microneurography; peroneal nerve), plasma norepinephrine, arterial blood pressure (finger photoplethysmography), and heart rate were measured at rest in three groups: 1) relapsing-remitting MS patients on disease modifying therapy only (MS-DT; n=6); 2) relapsing-remitting MS patients on disease modifying therapy and medications for MS-related symptoms that are known to effect the central nervous system (MS-DT/ST; n=5), and 3) healthy age and sex-matched controls (CON; n=6). Compared to the CON group, MSNA burst frequency (bursts/min) was significantly lower in both MS-DT (P=0.027) and MS-DT/ST groups (P=0.003). Similarly, MSNA burst incidence (bursts/100 heartbeats) was significantly reduced in both MS-DT (P=0.049) and MS-DT/ST groups (P=0.004) compared to the CON group. Burst frequency and burst incidence were not different between MS-DT and MS-DT/ST groups. Resting plasma norepinephrine was also significantly lower in both MS-DT (P=0.039) and MS-DT/ST groups (P=0.021) compared to the CON group. Reduced MSNA may signify an important dysfunction in autonomic control of cardiovascular function in patients with MS. PMID- 25034057 TI - Long-term follow-up of elective chronic total coronary occlusion angioplasty: analysis from the U.K. Central Cardiac Audit Database. AB - BACKGROUND: Chronic total occlusion (CTO) is common, being reported in 18% to 30% of patients undergoing coronary angiography. Percutaneous coronary intervention (PCI) is usually performed to relieve anginal symptoms, but data are emerging to suggest that there may also be a mortality benefit. OBJECTIVES: This study aimed to compare outcomes of patients with successful versus unsuccessful PCI to a CTO. METHODS: We analyzed the U.K. Central Cardiac Audit Database for all CTO PCI cases carried out in England and Wales between January 1, 2005, and December 31, 2009. Vital status in September 2010 was obtained from the Medical Research Information Service. RESULTS: A total of 13,443 patients (78.8% male) had a mean age of 63.5 years and underwent 14,439 CTO procedures. CTO PCI was successful in 10,199 cases (70.6%). During follow-up of 2.65 years (interquartile range: 1.59 to 3.83 years), successful PCI of at least 1 CTO was associated with improved survival (hazard ratio [HR]: 0.72; 95% CI: 0.62 to 0.83; p < 0.001). Complete revascularization was associated with improved survival compared with partial revascularization (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.002) or failed revascularization (HR: 0.61; 95% CI: 0.50 to 0.74; p < 0.001). CONCLUSIONS: Successful CTO PCI was associated with improved long-term survival. The improvement was greatest in patients when complete revascularization was achieved. The identity of the successfully treated occluded vessel was not associated with differences in outcome. PMID- 25034058 TI - Chronic total occlusion revascularization: Achilles' heel or golden opportunity for PCI? PMID- 25034059 TI - beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. AB - BACKGROUND: The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI). OBJECTIVES: The purpose of this study was to assess the association of beta-blockers with outcomes among patients with new onset CHD. METHODS: We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta blockers in the year before entry. We used time-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (p(int)) to determine whether the association differed for patients with or without a recent MI. RESULTS: A total of 26,793 patients were included, 19,843 of whom initiated beta-blocker treatment within 7 days of discharge from their initial CHD event. Over an average of 3.7 years of follow-up, 6,968 patients had an MI or died. Use of beta-blockers was associated with an adjusted HR for mortality of 0.90 (95% confidence limits [CL]: 0.84 to 0.96), and an adjusted HR for death or MI of 0.92 (CL: 0.87 to 0.97). The association between beta-blockers and outcomes differed significantly between patients with and without a recent MI (HR for death: 0.85 vs. 1.02, p(int) = 0.007; and HR for death or MI: 0.87 vs. 1.03, p(int) = 0.005). CONCLUSIONS: Use of beta-blockers among patients with new-onset CHD was associated with a lower risk of cardiac events only among patients with a recent MI. PMID- 25034060 TI - Beta-blockers in asymptomatic coronary artery disease: no benefit or no evidence? PMID- 25034061 TI - Predictors of an inadequate defibrillation safety margin at ICD implantation: insights from the National Cardiovascular Data Registry. AB - BACKGROUND: Defibrillation testing is often performed to establish effective arrhythmia termination, but predictors and consequences of an inadequate defibrillation safety margin (DSM) remain largely unknown. OBJECTIVES: The aims of this study were to develop a simple risk score predictive of an inadequate DSM at implantable cardioverter-defibrillator (ICD) implantation and to examine the association of an inadequate DSM with adverse events. METHODS: A total of 132,477 ICD Registry implantations between 2010 and 2012 were analyzed. Using logistic regression models, factors most predictive of an inadequate DSM (defined as the lowest successful energy tested <10 J from maximal device output) were identified, and the association of an inadequate DSM with adverse events was evaluated. RESULTS: Inadequate DSMs occurred in 12,397 patients (9.4%). A simple risk score composed of 8 easily identifiable variables characterized patients at high and low risk for an inadequate DSM, including (with assigned points) age <70 years (1 point); male sex (1 point); race: black (4 points), Hispanic (2 points), or other (1 point); New York Heart Association functional class III (1 point) or IV (3 points); no ischemic heart disease (2 points); renal dialysis (3 points); secondary prevention indication (1 point); and ICD type: single-chamber (2 points) or biventricular (1 point) device. An inadequate DSM was associated with greater odds of complications (odds ratio: 1.22; 95% confidence interval: 1.09 to 1.37; p = 0.0006), hospital stay >3 days (odds ratio: 1.24; 95% confidence interval: 1.19 to 1.30; p < 0.0001), and in-hospital mortality (odds ratio: 1.96; 95% confidence interval: 1.63 to 2.36; p < 0.0001). CONCLUSIONS: A simple risk score identified ICD recipients at risk for an inadequate DSM. An inadequate DSM was associated with an increased risk for in-hospital adverse events. PMID- 25034062 TI - Assessing risk of inadequate defibrillation safety margin: the strengths and limitations of the NCDR ICD Registry. PMID- 25034063 TI - A functional variant in APOA5/A4/C3/A1 gene cluster contributes to elevated triglycerides and severity of CAD by interfering with microRNA 3201 binding efficiency. AB - BACKGROUND: Recent genome-wide association studies identified the APOA5/A4/C3/A1 gene cluster polymorphisms influencing triglyceride level and risk of coronary artery disease (CAD). OBJECTIVES: The purposes of this study were to fine-map triglyceride association signals in the APOA5/A4/C3/A1 gene cluster and then explore the clinical relevance in CAD and potential underlying mechanisms. METHODS: We resequenced the APOA5/A4/C3/A1 gene cluster in 200 patients with extremely high triglyceride levels (>=10 mm/l) and 200 healthy control subjects who were ethnically matched and genotyped 20 genetic markers among 4,991 participants with Chinese Han ethnicity. Subsequently, 8 risk markers were investigated in 917 early-onset and 1,149 late-onset CAD patients, respectively. The molecular mechanism was explored. RESULTS: By resequencing, a number of newly and potentially functional variants were identified, and both the common and rare variants have remarkable cumulative effects on hypertriglyceridemia risk. Of note, gene dosage of rs2266788 demonstrated a robust association with triglyceride level (p = 1.39 * 10(-19)), modified Gensini scores (p = 1.67 * 10( 3)), and numbers of vascular lesions in CAD patients (odds ratio: 1.96, 95% confidence interval: 1.31 to 2.14, p = 8.96 * 10(-4)). Functional study demonstrated that the rs2266788 C allele destroyed microRNA 3201 binding to the 3' UTR of APOA5, resulting in prolonging the half-life of APOA5 messenger RNA and increasing its expression levels. CONCLUSIONS: Genetic variants in APOA5/A4/C3/A1 gene cluster play an important role in the regulation of plasma triglyceride levels by an increased APOA5 concentration and contribute to the severity of CAD. PMID- 25034064 TI - Single nucleotide variances can account for loss of microRNA function: the emerging cross talk between genetics and epigenetics. PMID- 25034065 TI - Alcohol consumption and risk of atrial fibrillation: a prospective study and dose response meta-analysis. AB - BACKGROUND: Although high alcohol consumption has been associated with increased risk of atrial fibrillation (AF), the role of light to moderate drinking remains unclear. OBJECTIVES: The study sought to investigate the association between alcohol consumption and AF risk in a prospective study of Swedish men and women and to conduct a meta-analysis of prospective studies to summarize available evidence. METHODS: We followed 79,019 men and women who, at baseline, were free from AF and had completed a questionnaire about alcohol consumption and other risk factors for chronic diseases. Incident AF cases were ascertained by linkage to the Swedish Inpatient Register. For the meta-analysis, studies were identified by searching PubMed through January 10, 2014, and by reviewing references of pertinent publications. Study-specific relative risks (RRs) were combined using a random effects model. RESULTS: Over 859,420 person-years of follow-up (1998 to 2009), 7,245 incident AF cases were identified in our own cohort study. The association between alcohol consumption and AF did not differ by sex (p for interaction = 0.74). Compared with current drinkers of <1 drink/week (12 g alcohol/drink), the multivariable RRs of AF were 1.01 (95% confidence interval [CI]: 0.94 to 1.09) for 1 to 6 drinks/week, 1.07 (95% CI: 0.98 to 1.17) for 7 to 14 drinks/week, 1.14 (95% CI: 1.01 to 1.28) for 15 to 21 drinks/week, and 1.39 (95% CI: 1.22 to 1.58) for >21 drinks/week. Results were similar after excluding binge drinkers. In a meta-analysis of 7 prospective studies, including 12,554 AF cases, the RRs were 1.08 (95% CI: 1.06 to 1.10) for 1 drink/day, 1.17 (95% CI: 1.13 to 1.21) for 2 drinks/day, 1.26 (95% CI: 1.19 to 1.33) for 3 drinks/day, 1.36 (95% CI: 1.27 to 1.46) for 4 drinks/day, and 1.47 (95% CI: 1.34 to 1.61) for 5 drinks/day, compared with nondrinkers. CONCLUSIONS: These findings indicate that alcohol consumption, even at moderate intakes, is a risk factor for atrial fibrillation. PMID- 25034066 TI - Alcohol consumption and risk of atrial fibrillation: how much is too much? PMID- 25034067 TI - Yield of serial evaluation in at-risk family members of patients with ARVD/C. AB - BACKGROUND: Incomplete penetrance and variable expressivity of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) complicate family screening. OBJECTIVES: The objective of the present study was to determine the optimal approach to longitudinal follow-up regarding: 1) screening interval; and 2) testing strategy in at-risk relatives of ARVD/C patients. METHODS: We included 117 relatives (45% male, age 33.3 +/- 16.3 years) from 64 families who were at risk of developing ARVD/C by virtue of their familial predisposition (72% mutation carriers [92% plakophilin-2]; 28% first-degree relatives of a mutation negative proband). Subjects were evaluated by electrocardiography (ECG), Holter monitoring, signal-averaged ECG, and cardiac magnetic resonance (CMR). Disease progression was defined as the development of a new criterion by the 2010 Task Force Criteria (not the "Hamid criteria") at last follow-up that was absent at enrollment. RESULTS: At first evaluation, 43 subjects (37%) fulfilled an ARVD/C diagnosis according to the 2010 Task Force Criteria. Among the remaining 74 subjects (63%), 11 of 37 (30%) with complete re-evaluation experienced disease progression during 4.1 +/- 2.3 years of follow-up. Electrical progression (n = 10 [27%], including by ECG [14%], Holter monitoring [11%], or signal-averaged ECG [14%]) was more frequently observed than structural progression (n = 1 [3%] on CMR). All 5 patients (14%) with clinical ARVD/C diagnosis at last follow-up had an abnormal ECG or Holter monitor recording, and the only patient with an abnormal CMR already had an abnormal ECG at enrollment. CONCLUSIONS: Over a mean follow-up of 4 years, our study showed that: 1) almost one-third of at-risk relatives have electrical progression; 2) structural progression is rare; and 3) electrical abnormalities precede detectable structural changes. This information could be valuable in determining family screening protocols. PMID- 25034068 TI - Family members of patients with ARVC: who is at risk? At what age? When and how often should we evaluate to determine risk? PMID- 25034069 TI - The MOGE(S) classification of cardiomyopathy for clinicians. AB - Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and involvement of organs other than the heart, as well as the genotype and the mode of inheritance. The recently proposed MOGE(S) nosology system embodies all of these characteristics, and describes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association functional class. The proposed nomenclature is supported by a web-assisted application and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing. It is expected that such a nomenclature would help group cardiomyopathies on their etiological basis, describe complex genetics, and create collaborative registries. PMID- 25034070 TI - Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. AB - Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as >=2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding. PMID- 25034071 TI - The critical need to share our successes. PMID- 25034072 TI - 7 lessons from fellowship. PMID- 25034073 TI - Reply: Intravenous hydration (with or without rosuvastatin) should remain the cornerstone of the prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. PMID- 25034074 TI - Intravenous hydration (with or without rosuvastatin) should remain the cornerstone of the prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. PMID- 25034075 TI - The importance of genotype variation beyond different antiplatelet therapy in nonresponder patients. PMID- 25034076 TI - Reply: The importance of genotype variation beyond different antiplatelet therapy in nonresponder patients. PMID- 25034077 TI - Is MSAFP still a useful test for detecting open neural tube defects and ventral wall defects in the era of first-trimester and early second-trimester fetal anatomical ultrasounds? AB - INTRODUCTION: To evaluate whether maternal serum alpha-fetoprotein (MSAFP) improves the detection rate for open neural tube defects (ONTDs) and ventral wall defects (VWD) in patients undergoing first-trimester and early second-trimester fetal anatomical survey. MATERIAL AND METHODS: A cohort of women undergoing screening between 2005 and 2012 was identified. All patients were offered an ultrasound at between 11 weeks and 13 weeks and 6 days of gestational age for nuchal translucency/fetal anatomy followed by an early second-trimester ultrasound at between 15 weeks and 17 weeks and 6 days of gestational age for fetal anatomy and MSAFP screening. All cases of ONTD and VWD were identified via query of billing and reporting software. Sensitivity and specificity for detection of ONTD/VWD were calculated, and groups were compared using the Fisher exact test, with p < 0.05 as significance. RESULTS: A total of 23,790 women met the criteria for inclusion. Overall, 15 cases of ONTD and 17 cases of VWD were identified; 100% of cases were diagnosed by ultrasound prior to 18 weeks' gestation; none were diagnosed via MSAFP screening (p < 0.001). First-trimester and early second-trimester ultrasound had 100% sensitivity and 100% specificity for diagnosing ONTD/VWD. DISCUSSION: Ultrasound for fetal anatomy during the first and early second trimester detected 100% of ONTD/VWD in our population. MSAFP is not useful as a screening tool for ONTD and VWD in the setting of this ultrasound screening protocol. PMID- 25034078 TI - Psychometric evaluation of dietary self-efficacy and outcome expectation scales in female college freshmen. AB - Lifestyle interventions commonly measure psychosocial beliefs as precursors to positive behavior change, but often overlook questionnaire validation. This can affect measurement accuracy if the survey has been developed for a different population, as differing behavioral influences may affect instrument validity. The present study aimed to explore psychometric properties of self-efficacy and outcome expectation scales-originally developed for younger children-in a population of female college freshmen (N = 268). Exploratory principal component analysis was used to investigate underlying data patterns and assess validity of previously published subscales. Composite scores for reliable subscales (Cronbach's alpha >= .70) were calculated to help characterize self-efficacy and outcome expectation beliefs in this population. The outcome expectation factor structure clearly comprised of positive (alpha = .81-.90) and negative outcomes (alpha = .63-.67). The self-efficacy factor structure included themes of motivation and effort (alpha = .75-.94), but items pertaining to hunger and availability cross-loaded often. Based on cross-loading patterns and low Cronbach's alpha values, respectively, self-efficacy items regarding barriers to healthy eating and negative outcome expectation items should be refined to improve reliability. Composite scores suggested that eating healthfully was associated with positive outcomes, but self-efficacy to do so was lower. Thus, dietary interventions for college students may be more successful by including skill-building activities to enhance self-efficacy and increase the likelihood of behavior change. PMID- 25034080 TI - Prevalence of cardiovascular risk factors in patients with psoriatic arthritis. AB - Psoriatic arthritis (PsA) is a chronic T cell-mediated inflammatory spondyloarthropathy affecting 10-40 % of psoriasis (PSO) patients (0.3-1.0 % of the general population). Recent epidemiological studies have shown an increased prevalence of cardiovascular (CV) risk factors and/or morbidity among PSO or PsA patients as compared to control individuals. The aim of this study is to describe the CV profile of PsA patients in Newfoundland, Canada. The possible impact of duration of chronic inflammation on CV variables was also explored. PsA patients were selected from a registry of PSO and PsA patients in Newfoundland. PsA patients diagnosed as per the CASPAR criteria are entered in the registry at the time of diagnosis, questioned on their medical history, and are followed indefinitely. Based on the duration since PsA diagnosis patients were classified as having early (<2 years) or established (>=2 years) PsA. CV risk was assessed using both conventional (hypertension, hypercholesterolemia, diabetes, obesity) and non-conventional (markers of chronic inflammation) factors. A total of 196 PsA patients were included; 42.9 % had early PsA and 57.1 % had established PsA. The prevalence of hypercholesterolemia, obesity, hypertension, diabetes mellitus, anxiety/depression, and coronary heart disease was 61.6, 59.7, 32.7, 13.8, 13.8, and 8.7 %, respectively. The prevalence of comorbidities was generally comparable between cohorts with exception of anxiety/depression, which was considerably higher in patients with established PsA compared to early PsA and obesity which was more common among male patients with established PsA. However, upon adjusting for age and gender differences, no statistically significant between-group differences were observed. Overall, these results suggest that PsA, even at early stages, is associated with significant CV comorbidity. These conditions should be taken into consideration when assessing the PsA burden of illness in epidemiological and health outcomes studies. Furthermore, early detection and management of these conditions could improve the patients' disability and quality of life. PMID- 25034079 TI - The tumor promoting activity of the EP4 receptor for prostaglandin E2 in murine skin. AB - To determine whether the EP4 receptor for prostaglandin E2 (PGE2) contributes to the tumor promoting activity of PGs in murine skin, EP4 over-expressing mice (BK5.EP4) were generated and subjected carcinogenesis protocols. An initiation/promotion protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. An increase in SCCs also occurred following treatment with initiator alone or UV irradiation. The initiator dimethylbenz[a]anthracene caused cytotoxicity in BK5.EP4, but not WT mice, characterized by sloughing of the interfollicular epidermis, regeneration and subsequent SCC development. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, supporting a pro-tumorigenic role for the EP4 receptor. PMID- 25034081 TI - Safety and efficacy of etanercept in children with the JIA categories extended oligoarthritis, enthesitis-related arthritis and psoriasis arthritis. AB - The approval of etanercept for the treatment of the juvenile idiopathic arthritis (JIA) categories extended oligoarthritis (ExtOA), enthesitis-related arthritis (ERA) and psoriasis arthritis (PsA) was recently added to the approval for the treatment of polyarticular-course JIA (PA). This study aims to evaluate the efficacy and safety of etanercept in a large number of patients with the additional JIA categories. The Biologika in der Kinderrheumatologie (BIKER) registry documents baseline demographics, clinical characteristics and disease activity parameters. Efficacy was determined using the PedACR 30/50/70 response criteria and the Juvenile Arthritis Disease Activity Score (JADAS)-10. Safety assessments were based on adverse events' reports. Until December 2012, a total of 1,678 JIA patients, incorporating 238 ERA, 315 ExtOA and 127 PsA patients were included. JADAS-10 demonstrated marked improvement compared to baseline after 3 to 24 months in ExtOA [16.1 +/- 7.6 (baseline), 5.1 +/- 5.2 (3 months), 3.0 +/- 3.5 (24 months)]; ERA (15.3 +/- 7.2, 4.4 +/- 4.7, 4.0 +/- 4.9) and PsA (14.7 +/- 6.4, 5.0 +/- 4.6, 5.3 +/- 6.4). Compared to patients with PA, the rate of serious adverse events [relative risk (RR) 1.39 (0.95-2.03, p = 0.08)] and nonserious [1.18 (1.02-1.35; p = 0.03)] adverse events were elevated. The rate of uveitis flares was significantly higher in PsA (3.3/100 patient-years), ExtOA (2.8/100 patient-years) and ERA (2.7/100 patient-years) than in rheumatoid factor (RF) negative polyarticular JIA (1.3/100 pat.yrs) or RF-positive polyarticular JIA (0.27/100 patient-years). Reports on chronic inflammatory bowel disease were numerically more frequent in ExtOA, ERA and PsA. Administration of etanercept in patients with the JIA categories ExtOA, ERA and PsA is safe and very efficacious in children. Attention should be paid to the occurrence of extraarticular autoimmunopathies. PMID- 25034082 TI - Lack of association between suppressor of cytokine signaling-3 gene polymorphism and susceptibility and curve severity of adolescent idiopathic scoliosis. AB - PURPOSE: To explore whether the suppressor of cytokine signaling-3 (SOCS3) gene polymorphisms are associated with the susceptibility and abnormal growth pattern of adolescent idiopathic scoliosis (AIS). METHODS: Three hundred and ninety eight AIS girls aged 10-18 years old were enrolled, and 367 age-matched healthy girls were recruited as controls. Only patients who had Cobb angles larger than 20o were included in this study. Anthropometric parameters including body weight, height, and body mass index (BMI) were measured for AIS girls. Rs4969198 was selected as tagSNP to cover all of the related polymorphisms on SOCS3. Genotyping was performed using PCR-based Invader assay with the probe sets designed and synthesized by third wave. The genotyping results were read with an ABI PRISM7900HT sequence detection system (Applied Biosystems, Foster City, CA). A subgroup of 322 skeletally mature AIS patients who did not received bracing or any other conservative treatment previously were analyzed to define the contribution of rs4969168 on curve severity, body height, body weight, and BMI. RESULTS: Rs4969198 was successfully genotyped. No significant difference of genotype frequencies from the Hardy-Weinberg equilibrium (HWE) test was noted for the AIS patients or the normal controls. Neither the genotype nor the allele frequencies of rs49691968 were significantly different between the AIS patients and the normal controls. Rs4969168 was not found to be associated with age, curve severity of scoliosis, and body height. AIS patients with AA genotype had significantly higher body weight and BMI than the patients with AG and GG genotype (P = 0.014). CONCLUSIONS: The SOCS3 gene polymorphisms are not associated with the occurrence of AIS, but the gene polymorphism (rs4969168) is associated with abnormal growth pattern of AIS, indicating that SOCS3 gene might be a disease-modifying gene of AIS. PMID- 25034083 TI - Clinical usefulness of electrodiagnostic study to predict surgical outcomes in lumbosacral disc herniation or spinal stenosis. AB - PURPOSE: Although surgeries have been performed for the treatment of lumbar disc herniation (LDH) or lumbar spinal stenosis (LSS), not all patients who undergo surgery are satisfied with the outcome. Electrodiagnostic study (EDX) can assess the physiological functions of nerve roots with higher specificity and relate better with clinical manifestations. The purpose of this study was to examine how EDX can predict surgical outcomes in patients with LDH and LSS and to compare the predicted values of EDX with other clinical factors and MRI findings. METHODS: Patients diagnosed with LDH or LSS without neurological deficits, who underwent EDX before lumbar surgery, were selected and analyzed. Patients were divided into groups of successful and unsuccessful surgical outcomes according to a modified MacNab classification. We obtained pre-operative clinical data, radiological results, and EDX results. RESULTS: Using EDX, radiculopathy was found in 236 patients (52.7%) in the study population. Radiculopathy on EDX was significantly related only to unsuccessful surgical outcomes. The association of spondylolisthesis showed the trends towards unsuccessful surgical outcome, despite statistical insignificance. CONCLUSIONS: EDX detected functional abnormalities of nerve roots that did not show clinical manifestation and did not appear compressed on MRI. These abnormalities are important predictive factors for surgical outcomes in patients with LDH or LSS. Therefore, pre-operative EDX is a clinically useful method to predict surgical prognosis. PMID- 25034084 TI - [Chronic inflammatory bowel diseases]. PMID- 25034085 TI - Exploring the impact of climate variability during the Last Glacial Maximum on the pattern of human occupation of Iberia. AB - The Last Glacial Maximum (LGM) was a global climate event, which had significant repercussions for the spatial distribution and demographic history of prehistoric populations. In Eurasia, the LGM coincides with a potential bottleneck for modern humans and may mark the divergence date for Asian and European populations (Keinan et al., 2007). In this research, the impact of climate variability on human populations in the Iberian Peninsula during the Last Glacial Maximum (LGM) is examined with the aid of downscaled high-resolution (16 * 16 km) numerical climate experiments. Human sensitivity to short time-scale (inter-annual) climate variability during this key time period, which follows the initial modern human colonisation of Eurasia and the extinction of the Neanderthals, is tested using the spatial distribution of archaeological sites. Results indicate that anatomically modern human populations responded to small-scale spatial patterning in climate variability, specifically inter-annual variability in precipitation levels as measured by the standard precipitation index. Climate variability at less than millennial scale, therefore, is shown to be an important component of ecological risk, one that played a role in regulating the spatial behaviour of prehistoric human populations and consequently affected their social networks. PMID- 25034087 TI - Behavioural strategies towards human disturbances explain individual performance in woodland caribou. AB - Behavioural strategies may have important fitness, ecological and evolutionary consequences. In woodland caribou, human disturbances are associated with higher predation risk. Between 2004 and 2011, we investigated if habitat selection strategies of female caribou towards disturbances influenced their calf's survival in managed boreal forest with varying intensities of human disturbances. Calf survival was 53% and 43% after 30 and 90 days following birth, respectively, and 52% of calves that died were killed by black bear. The probability that a female lose its calf to predation was not influenced by habitat composition of her annual home range, but decreased with an increase in proportion of open lichen woodland within her calving home range. At the local scale, females that did not lose their calf displayed stronger avoidance of high road density areas than females that lost their calf to predation. Further, females that lost their calf to predation and that had a low proportion of <=5-year-old cutovers within their calving home range were mostly observed in areas where these young cutovers were locally absent. Also, females that lost their calf to predation and that had a high proportion of <=5-year-old cutovers within their calving home range were mostly observed in areas with a high local density of <=5-year-old cutovers. Our study demonstrates that we have to account for human-induced disturbances at both local and regional scales in order to further enhance effective caribou management plans. We demonstrate that disturbances not only impact spatial distribution of individuals, but also their reproductive success. PMID- 25034088 TI - Analysis of radiotherapy in 1054 patients with primary central nervous system lymphoma treated from 1985 to 2009. AB - AIMS: Data on primary central nervous system lymphoma that had been collected through surveys for four consecutive periods between 1985 and 2009 were analysed to evaluate outcomes according to treatment. MATERIALS AND METHODS: All had histologically proven disease and had received radiotherapy. No patients had AIDS. Among 1054 patients, 696 died and 358 were alive or lost to follow-up. The median follow-up period for surviving patients was 37 months. RESULTS: For all patients, the median survival time was 24 months; the 5 year survival rate was 25.8%. Patients treated with methotrexate-based chemotherapy and radiation had a higher 5 year survival rate (43%) than those treated with radiation alone (14%) and those treated with non-methotrexate chemotherapy plus radiation (20%), but differences in relapse-free survival were smaller among the three groups. The 5 year survival rate was 25% for patients treated with whole-brain irradiation and 29% for patients treated with partial-brain irradiation (P = 0.80). Patients receiving a total dose of 40-49.9 Gy had a higher 5 year survival rate (32%) than those receiving other doses (21-25%, P = 0.0004) and patients receiving a whole brain dose of 30-39.9 Gy had a higher 5 year survival rate (32%) than those receiving >=40 Gy (13-22%, P < 0.0005). Patients receiving methotrexate-based chemotherapy and partial-brain radiotherapy (>=30 Gy) had a 5 year survival rate of 49%. CONCLUSIONS: The optimal total and whole-brain doses may be in the range of 40-49.9 and <40 Gy, respectively, especially in combination with chemotherapy. Patients receiving partial-brain irradiation had a prognosis similar to that of those receiving whole-brain irradiation. With methotrexate-based chemotherapy, partial-brain radiotherapy may be worth considering for non-elderly patients with a single tumour. PMID- 25034089 TI - A novel mutation (c.2735_2736delTC) in the androgen receptor gene in 46,XY females with complete androgen insensitivity syndrome in an Egyptian family. AB - BACKGROUND: Androgen insensitivity syndrome (AIS) results from resistance of the target tissues to the effect of the androgenic hormones producing a phenotype with varying degrees of feminization ranging from male infertility to completely normal female external genitalia. Androgen receptor (AR) is a transcription factor that interacts with the androgenic steroids that act as ligands activating the AR, and via different cellular mechanisms, the activated AR binds to the DNA of target tissues to induce the desired biological changes. To date, more than 800 different mutations in the AR gene have been identified in patients with AIS and the majority of these mutations are localized in the ligand-binding domain. METHODS: Here we describe an Egyptian family with 7 affected 46,XY females with complete androgen insensitivity. RESULTS: Mutational analysis of the AR gene revealed a novel frameshift mutation in exon 8 of the gene c.2735_2736delTC. CONCLUSION: This study extends the number of AR gene mutations identified so far. Further, it confirms that AR gene mutations are the most frequent cause of 46,XY disorder of sexual development, with higher frequency in the complete phenotype. PMID- 25034090 TI - Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction. AB - The interior of the neuronal cell nucleus is a highly organized three-dimensional (3D) structure where regions of the genome that are linearly millions of bases apart establish sub-structures with specialized functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice expressing GFP-tagged histone H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons caused chromocenter declustering and disrupted the association of heterochromatin with the nuclear lamina. The loss of these structures did not affect neuronal viability but was associated with specific transcriptional and behavioural deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D organization of chromatin within neuronal cells provides an additional level of epigenetic regulation of gene expression that critically impacts neuronal function. This in turn suggests that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture. PMID- 25034091 TI - Promising prospects for 44Sc-/47Sc-based theragnostics: application of 47Sc for radionuclide tumor therapy in mice. AB - In recent years, (47)Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Egamma, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of (47)Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. METHODS: (47)Sc was produced via the (46)Ca(n,gamma)(47)Ca[Formula: see text](47)Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the (47)Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. (47)Sc-labeled cm10 was tested on folate receptor-positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor-bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either (47)Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. RESULTS: Irradiation of (46)Ca resulted in approximately 1.8 GBq of (47)Ca, which subsequently decayed to (47)Sc. Separation of (47)Sc from (47)Ca was obtained with 80% yield in only 10 min. The (47)Sc was then available in a small volume (~500 MUL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. (47)Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro (47)Sc-cm10 showed folate receptor-specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received (47)Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. CONCLUSION: With this study, we demonstrated the suitability of using (47)Sc for therapeutic purposes. On the basis of our recent results obtained with (44)Sc-folate, the present work confirms the applicability of (44)Sc/(47)Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy. PMID- 25034092 TI - Ventilation-perfusion lung scanning: stuck in a rut? PMID- 25034093 TI - New targets for the development of PET tracers for imaging neurodegeneration in Alzheimer disease. AB - The field of molecular imaging has experienced significant advances in the area of Alzheimer disease (AD), the most significant being the development of PET radiotracers for imaging beta-amyloid burden in the brain of individuals at risk for or in the early stages of AD. More recent advances include the development of PET radiotracers for imaging aggregates of hyperphosphorylated tau protein in neurofibrillary tangles, a process that occurs late in the disease process. This article highlights advances in the neurobiology of AD and describes how PET can be used to study the mechanisms of neurodegeneration in AD. PMID- 25034094 TI - Possible mechanism underlying the effect of Heshouwuyin, a tonifying kidney herb, on sperm quality in aging rats. AB - BACKGROUND: Herb mixtures are used as alternatives to hormone therapy in China for the treatment of partial androgen deficiency in aging men. However, the compositions of these herb mixtures are complex and their mechanisms are often unknown. This study investigates the effect of Heshouwuyin, a Chinese herbal compound for invigorating the kidney, on the control of testosterone secretion and sperm function. METHODS: Aged Wistar rats were administered with Heshouwuyin. A Shouwu pill group and young group were used as controls. RESULTS: Morphology, chemiluminescence, fluorescence immunohistochemistry, and western blot showed that the epididymal sperm of naturally aged rats had intact plasma membranes. They also had abnormal mitochondrial function and DNA integrity, a significant decline in serum testosterone levels, and significant pathological changes in the structure of testicular tissues. Heshouwuyin significantly improved sperm function and serum testosterone levels, and improved testicular morphology. Moreover, the curative efficacy of Heshouwuyin after 60 days was better than that of Heshouwuyin after 30 days and the Shouwu pill group. CONCLUSION: Heshouwuyin exerts an important role in controlling testosterone secretion and sperm function. PMID- 25034095 TI - Gianotti-Crosti syndrome associated with Ebstein-Barr virus and Parvovirus B-19 coinfection in a male adult: case report and review of the literature. AB - Gianotti-Crosti syndrome (GCS) is a self-limiting, mostly childhood-appearing, cutaneous eruption with characteristic symmetric areal distribution. The original cases, described by Gianotti in 1955, were associated with hepatitis B virus infection, but other viral and bacterial infections, as well as immunizations, have been implied in etiology of this condition. Adult cases are rare and have been reported almost exclusively in women. We present the case of a 20-year-old Caucasian man who had typical clinical presentation: monomorphic pale, pink-to flesh - colored or erythematous papules and papulovesicles localized symmetrically over the extensor surfaces of the extremities, buttocks and the face; some lesions were detected on knees, elbows and palms, as well. Laboratory tests revealed slight bilirubin and alanine aminotransaminase elevation. Serology tests demonstrated antibodies against Epstein-Barr virus and parvovirus B-19. Histology of skin biopsy specimens revealed a vesicular dermatitis with perivascular lymphocytic infiltrate. Oral and topical corticosteroids and oral antihistamines led to complete resolution of lesions in 3 weeks. GCS is rare in adults, especially men. To the best of our knowledge, this is the fifth male adult case and the first with Parvovirus B-19 and EBV coinfection. PMID- 25034096 TI - An update on juvenile dermatomyositis. AB - Juvenile dermatomyositis (JDM) is a rare, severe, autoimmune disease characterized by a small-vessel vasculopathy that primarily affects skin and muscle, but also lung, joints, gut and heart. Nowadays prompt recognition of this entity and aggressive treatment, when needed, improves outcomes and has decreased mortality that, before corticosteroid became a mainstay in therapy, could reach 40%. PMID- 25034097 TI - The high-sensitivity modified Glasgow prognostic score is superior to the modified Glasgow prognostic score as a prognostic predictor in patients with resectable gastric cancer. AB - AIM: The aim of the present study was to evaluate the superiority of the high sensitivity modified Glasgow prognostic score (HS-mGPS) before surgery in patients with gastric cancer. PATIENTS AND METHODS: The participants of this retrospective study comprised 552 patients with gastric cancer who underwent gastrectomy at the Fukuoka University Hospital. The HS-mGPS was calculated before surgery based on cutoff values of 0.3 mg/dl for C-reactive protein and 3.5 g/dl for albumin, and correlations between the HS-mGPS and the clinicopathological parameters and prognosis were evaluated. In addition, the superiority of the HS mGPS to the mGPS as a prognostic indicator was examined in detail. RESULTS: The mGPS was 0 in 494 patients, 1 in 24 patients and 2 in 34 patients. In contrast, the HS-mGPS was 0 in 411 patients, 1 in 75 patients and 2 in 66 patients. Both the mGPS (p < 0.0001) and HS-mGPS (p < 0.0001) were good prognostic predictors in gastric cancer patients who underwent gastrectomy. Of the 494 patients with an mGPS of 0 before surgery, 51 and 32 exhibited an HS-mGPS of 1 and 2, respectively. The patients who exhibited migration in the HS-mGPS demonstrated a significantly more unfavorable prognosis than the patients with an HS-mGPS of 0 (p < 0.0001). The prognostic impact of the HS-mGPS was especially clear in stage I and IV patients (p = 0.0027, p = 0.017). The HS-mGPS was found to be a superior prognostic predictor compared to the mGPS in a multivariate analysis (p = 0.0002). CONCLUSIONS: The HS-mGPS before surgery is a superior prognostic predictor in patients with gastric cancer. PMID- 25034098 TI - Discovery of small-molecule Ras inhibitors that display antitumor activity by interfering with Ras.GTP-effector interaction. AB - Ras proteins, particularly their active GTP-bound forms (Ras.GTP), were thought "undruggable" owing to the absence of apparent drug-accepting pockets in their crystal structures. Only recently, such pockets have been found in the crystal structures representing a novel Ras.GTP conformation. We have conducted an in silico docking screen targeting a pocket in the crystal structure of M Ras(P40D).GTP and obtained Kobe0065, which, along with its analogue Kobe2602, inhibits binding of H-Ras.GTP to c-Raf-1. They inhibit the growth of H-rasG12V transformed NIH3T3 cells, which are accompanied by downregulation of not only MEK/ERK but also Akt, RalA, and Sos, indicating the blockade of interaction with multiple effectors. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma carrying K-rasG12V. The nuclear magnetic resonance structure of a complex of the compound with H-Ras(T35S).GTP confirms its insertion into the surface pocket. Thus, these compounds may serve as a novel scaffold for the development of Ras inhibitors with higher potency and specificity. PMID- 25034099 TI - An orthosteric inhibitor of the RAS-SOS interaction. AB - Rat sarcoma (RAS) proteins are signaling nodes that transduce extracellular cues into precise alterations in cellular physiology by engaging effector pathways. RAS signaling thus regulates diverse cell processes including proliferation, migration, differentiation, and survival. Owing to this central role in governing mitogenic signals, RAS pathway components are often dysregulated in human diseases. Targeted therapy of RAS pathways has generally not been successful, largely because of the robust biochemistry of the targets and their multifaceted network of molecular regulators. The rate-limiting step of RAS activation is Son of Sevenless (SOS)-mediated nucleotide exchange involving a single evolutionarily conserved catalytic helix from SOS. Structure function data of this mechanism provided a strong platform to design an SOS-derived, helically constrained peptide mimic as an inhibitor of the RAS-SOS interaction. In this chapter, we review RAS-SOS signaling dynamics and present evidence supporting the novel paradigm of inhibiting their interaction as a therapeutic strategy. We then describe a method of generating helically constrained peptide mimics of protein surfaces, which we have employed to inhibit the RAS-SOS active site interaction. The biochemical and functional properties of this SOS mimic support the premise that inhibition of RAS-nucleotide exchange can effectively block RAS activation and downstream signaling. PMID- 25034100 TI - Conformation-specific inhibitors of Raf kinases. AB - Since the discovery linking B-Raf mutations to human tumors in 2002, significant advances in the development of Raf inhibitors have been made, leading to the recent approval of two Raf inhibitor drugs. This chapter includes a brief introduction to B-Raf as a validated target and focuses on the three different binding modes observed with Raf small-molecule inhibitors. These various binding modes lock the Raf kinase in different conformations that impact the toxicity profiles of the inhibitors. Possible solutions to mitigate the side effects caused by inhibitor-induced dimerization are also discussed. PMID- 25034101 TI - Inhibitors of the ERK mitogen-activated protein kinase cascade for targeting RAS mutant cancers. AB - Although recent success in identifying direct inhibitors of mutant Ras has begun to challenge the perception that Ras is "undruggable," the successful transition of these hits to the clinic remains uncertain. Therefore, current efforts to develop anti-Ras inhibitors are focused on indirect approaches, with inhibitors of the downstream effectors of Ras signaling having attracted the greatest current interest. Of the multitude of effectors, the Raf-MEK-ERK mitogen activated protein kinase (MAPK) cascade is arguably the most attractive target for these efforts. In this chapter, we review the evidence for a key driver role for the ERK MAPK cascade in RAS mutant cancers and the status of efforts to develop inhibitors of MEK1/2 and ERK1/2 to block this pathway. PMID- 25034102 TI - Inhibiting the RAS-PI3K pathway in cancer therapy. AB - The PI3K pathway is over-activated in the majority of human cancers. This may occur through oncogenic activation of upstream RAS isoforms and tyrosine kinase receptors, or by mutational activation of components of the PI3K pathway themselves. Stimulation of the PI3K pathway enhances growth, survival, and metabolism of cancer cells. Migration, invasion, and angiogenesis are also supported by PI3K signaling. Thus, the PI3K pathway is an attractive candidate for the therapeutic targeting of tumors. Multiple kinases within the PI3Ks, AKT, and mTOR pathway have been selected for inhibition, and dual inhibitors have also been produced. Recently, the development of kinase inhibitors with enhanced specificity and improved pharmacokinetics has facilitated the investigation of PI3K pathway inhibition in clinical trials. Initial reports are encouraging, with tolerable toxicity profiles reported. PI3K inhibitors have provided some benefit as single-agent treatments of advanced solid tumors and the possibilities for enhanced effect with combination treatments look promising. In this chapter, we describe the PI3K inhibitors currently under investigation for the treatment of cancer and discuss the opportunities and obstacles that have been revealed by the latest preclinical and clinical studies. PMID- 25034104 TI - p21-activated kinase inhibitors. AB - The p21-activated kinases (PAKs) are Ser/Thr kinases in the STE20 kinase family with important roles in regulating cytoskeletal organization, cell migration, and signaling. The PAK enzyme family comprises six members subdivided into two groups: Group I, represented by PAK1, 2, and 3, and Group II, represented by PAK 4, 5, and 6, based on sequence and structural homology. Individual PAK isoforms were found to be overexpressed and amplified in a variety of human cancers, and in vitro and in vivo studies using genetically engineered systems as well as small-molecule tool compounds have suggested therapeutic utility of PAKs as oncology targets. The identification of potent and kinome-selective ATP competitive PAK inhibitors has proven challenging, likely caused by the openness and unique plasticity of the ATP-binding site of PAK enzymes. Progress in achieving increased kinase selectivity has been achieved with certain inhibitors but at the expense of increased molecular weight. Allosteric inhibitors, such as IPA-3, leverage the unique Group I PAK autoregulatory domain for selective inhibition, and this approach might provide an outlet to evade the kinase selectivity challenges observed with ATP-competitive PAK inhibitors. PMID- 25034103 TI - The RalGEF/Ral pathway: evaluating an intervention opportunity for Ras cancers. AB - Recognition that Ral guanine nucleotide exchange factors (RalGEFs) are direct Ras effectors and that Ral G-protein activation is a direct consequence of Ras activation has spurred focused efforts to establish the contribution of RalGEF/Ral signaling to oncogenic transformation. Here, we provide a broad strokes overview of the mechanistic organization of the RalGEF/Ral signaling network, evaluate the evidence for participation of this network in tumorigenic regulatory milieus, consider targeting strategies, and discuss the challenges to and opportunities for clinical development of these targeting strategies. PMID- 25034105 TI - Recent progress in developing small molecule inhibitors designed to interfere with ras membrane association: toward inhibiting K-Ras and N-Ras functions. AB - K-Ras and N-Ras are mutated in a wide range of human cancers, thus making these proteins attractive targets of anticancer drug development. However, no effective compounds have been obtained so far. One of the approaches taken to inhibit the function of K-Ras and N-Ras is to interfere with their membrane association. Various attempts have been taken. In the first example, we examine the approach conceived in early 1990s to inhibit protein prenylation that is required for their membrane association. The initial premise that the inhibition of Ras farnesylation leads to the inhibition of Ras was not realized, mainly due to alternative prenylation of K-Ras and N-Ras proteins. This led to the idea that the combined inhibition of FTase and GGTase-I can block membrane association of K Ras and N-Ras. Dual specificity inhibitors of FTase and GGTase-I (DPIs) were also developed. These compounds were tested in preclinical and clinical studies. It appears that sufficiently high concentration of the drug to inhibit K-Ras was not achieved in previous attempts. In addition, dose-limiting toxicity has been observed and this was primarily ascribed to GGTase-I inhibition. Strategies to confer cancer targeting capabilities to the inhibitors may overcome the dose limiting toxicity. In the second approach, postprenylation events were exploited. This led to the development of various inhibitors including the ICMT inhibitors. Finally, recent identification of compounds that inhibit the interaction between K-Ras and PDE-delta is discussed. PMID- 25034106 TI - Synthetic lethal genetic screens in Ras mutant cancers. AB - Mutations in the Ras family of small GTPases are among the most frequent oncogenic events in human cancer. Difficulties in targeting Ras itself and the limited efficacy in targeting its effector kinases have spurred the search for Ras synthetic lethal genes that could shed new light on the biology of Ras-driven cancer and lead to new therapeutic strategies. Advances in mammalian RNAi technology have enabled high-throughput functional screens for Ras synthetic lethal interactions. In this chapter, we summarize the strategies and findings from these screens and discuss future improvement for Ras synthetic lethality studies. PMID- 25034107 TI - Inhibitors of the Ras superfamily of small G-proteins. Preface. PMID- 25034108 TI - Retardation of C2C12 myoblast cell proliferation by exposure to low-temperature atmospheric plasma. AB - As the first step in evaluating the possibility of low-temperature atmospheric plasma for clinical applications in the treatment of rhabdomyosarcoma (RMS), we determined the effects of plasma exposure on C2C12 myoblasts. The low-temperature atmospheric plasma was generated through an electrical discharge in argon gas. One minute of plasma exposure every 24 h inhibited the cell proliferation, whereas myoblast differentiation was not affected. Plasma exposure increased the phosphorylation of ERK and JNK at 30 min after the exposure, but the phosphorylation of both was decreased to less than control levels at 1 and 4 h after the exposure. Plasma exposure increased the percentage of cells in the G2/M phase at 8 h after the exposure. In conclusion, plasma exposure retarded the proliferation of C2C12 myoblasts by G2/M arrest. Therefore, plasma exposure can be a possible treatment for the anti-proliferative effects of malignant tumors, such as RMS, without affecting differentiated skeletal muscle cells. PMID- 25034109 TI - Comparison of two devices for respiratory impedance measurement using a forced oscillation technique: basic study using phantom models. AB - Since commercial forced oscillation technique (FOT) devices became available, they have been widely used for physiological assessments, mainly of obstructive lung diseases. However, it is not known whether the impedance values measured with different devices are identical. In this study, two FOT devices-the impulse oscillometry system (IOS) and the MostGraph (MG)-were compared using phantom models. The resistance values varied up to 10% from estimated values in both devices. Additionally, there was a difference in frequency dependence for the resistance between the devices. The reactance values measured with MG were higher than those measured with IOS. The effects of ventilation on the measured impedance values were higher for IOS than for MG, especially at lower frequencies. We concluded that the devices do not always generate identical impedance values. Thus, differences between the devices should be taken into consideration when evaluating clinical data. PMID- 25034110 TI - Identification of a novel papillomavirus in a Northern Fulmar (Fulmarus glacialis) with viral production in cartilage. AB - We report the identification of a novel papillomavirus, Fulmarus glacialis papillomavirus 1 (FgPV1), present within an interdigital foot mass of a Northern Fulmar (Fulmarus glacialis). The mass of interest was composed of normal stratified and keratinized epithelium and dense mesenchymal cells with central cartilaginous islands. Within the nuclei of many chondrocytes were loose aggregates or paracrystalline arrays of virions approximately 50 nm in size. Degenerate polymerase chain reaction was used to identify the virus as a putative papillomavirus, and the entire viral genome of 8132 base pairs was subsequently amplified and sequenced. Analysis revealed canonical papillomavirus architecture, including the early open reading frames E6, E7, E1, and E2 and the 2 late proteins L1 and L2. FgPV1 is most closely related to a cluster of avian and reptilian papillomaviruses as visualized by phylogenetic trees. This observation suggests that papillomavirus virion production can occur in mesenchymal cells. PMID- 25034111 TI - The incidence of neovascular subtypes in newly diagnosed neovascular age-related macular degeneration. AB - PURPOSE: To determine the frequency of neovascularization subtypes as determined by fluorescein angiography (FA) alone vs FA and optical coherence tomography (OCT) grading in age-related macular degeneration (AMD). DESIGN: Retrospective cohort. METHODS: participants: Newly diagnosed neovascular AMD patients who initiated intravitreal anti-vascular endothelial growth factor therapy by 1 physician from October 1, 2005 to December 1, 2012. interventions: Two independent graders classified the baseline lesions using FA alone and FA+OCT. main outcome measures: Analysis of the frequency of lesion subtypes by FA alone or FA+OCT and agreement between both classification systems was performed. RESULTS: A total of 232 patients (266 eyes) fit the inclusion criteria. Mean age was 86.3 years; 67.7% of eyes (180/266) were from female patients, and 95.5% (254/266) were from white patients. The distribution using FA alone was 49.6% (132/266), 12.0% (32/266), 28.6% (76/266), and 9.8% (26/266) among occult, classic, retinal angiomatous proliferation, and mixed choroidal neovascularization, respectively. With FA+OCT, 39.9% (106/266), 9.0% (24/266), 34.2% (91/266), and 16.9% (45/266) were type 1 (sub-retinal pigment epithelium), type 2 (subretinal), type 3 (intraretinal), and mixed neovascularization (NV), respectively. The kappa statistic was 0.65 (standard error +/-0.37, P < .001) between the 2 classification systems, representing good agreement. CONCLUSION: With both FA-alone and FA+OCT grading, we found a higher incidence of type 3 NV in eyes with newly diagnosed neovascular AMD than that reported in prior studies. The kappa statistic between the 2 classification systems showed "good" agreement. The discrepancies are likely attributable to the identification of a higher frequency of type 3 and mixed NV and a lower frequency of type 1 NV with the aid of OCT. PMID- 25034112 TI - The lack of concordance between subretinal drusenoid deposits and large choroidal blood vessels. AB - PURPOSE: To evaluate the concordance between pseudodrusen as manifested by subretinal drusenoid deposits and large choroidal blood vessels using stereological analysis of spectral-domain optical coherence tomography (SD OCT) images. DESIGN: Retrospective, observational case series. METHODS: The SD OCT images of 31 consecutive patients with the clinical appearance of pseudodrusen from a private-referral retinal clinic were retrospectively reviewed. A grid of 19 evenly spaced vertical lines was randomly superimposed on each SD OCT image using ImageJ to perform systematic uniform random sampling. The main outcome measure was the likelihood of association between subretinal drusenoid deposits and large choroidal vessels. RESULTS: Uniform random systematic sampling of 589 samples found the proportion of geometric probes intersecting subretinal drusenoid deposits to be 0.28, large choroidal vessel 0.65, and both 0.19. This value was nearly identical to the product of the joint probabilities and was within the 95% confidence interval (0.15-0.21) of the point estimate as calculated by the binomial theorem, indicating mutual independence. The subretinal drusenoid deposits were associated with neither large choroidal vessels nor the intervals in between. CONCLUSIONS: Our results demonstrate that there is no concordance between subretinal drusenoid deposits and large choroidal vessels or the stroma in between. As a consequence, hypotheses postulating that subretinal drusenoid deposits are associated with large choroidal vessels or the choroidal stromal spaces should be abandoned. Stereological techniques are powerful methods used in image evaluation in other fields of study and appear to have utility in analyzing OCT findings of the retina and choroid. PMID- 25034113 TI - Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. AB - PURPOSE: To compare the corneal stromal demarcation line depth using anterior segment optical coherence tomography (AS-OCT) after corneal collagen cross linking (CXL) using 2 different treatment protocols: the standard Dresden protocol (30 minutes with 3 mW/cm(2)) and a modified-accelerated protocol (14 minutes with 9 mW/cm(2)). DESIGN: Prospective, comparative study. METHODS: Forty three keratoconic patients (52 eyes) were enrolled. All patients underwent CXL using the same high-intensity ultraviolet-A (UV-A) irradiation device. Twenty-six eyes were treated for 30 minutes with 3 mW/cm(2) according to the standard Dresden protocol (Group 1), while 26 eyes were treated with a novel modified accelerated CXL protocol for 14 minutes with 9 mW/cm(2) of UV-A irradiation intensity (Group 2). One month postoperatively, corneal stromal demarcation line depth was measured by 2 independent observers using AS-OCT. RESULTS: Corneal stromal demarcation line depth was assessed with no significant difference between observer measurements for both groups (P = .676 for Group 1 and P = .566 for Group 2). Mean corneal stromal demarcation line depth was 337.00 +/- 46.46 MUm for Group 1 and 322.91 +/- 48.28 MUm for Group 2. There was no statistically significant difference (P = .243) in the corneal stromal demarcation line depth between the 2 groups. CONCLUSIONS: Corneal stromal demarcation line depth using UV-A with 3 mW/cm(2) for 30 minutes and 9 mW/cm(2) for 14 minutes was similar. A modified-accelerated protocol of 14 minutes of CXL provided the same treatment depth as the classic Dresden protocol. PMID- 25034114 TI - Disparities in visual impairment by immigrant status in the United States. AB - PURPOSE: To examine differences in visual impairment between immigrants and natives in the United States (US). DESIGN: This is a cross-sectional study of clinical vision examination data from the 2003-2008 National Health and Nutrition Examination Survey. METHODS: Analyses compare myopia, hyperopia, astigmatism, and visual acuity between noncitizens, naturalized citizens, and US natives. Visual acuity variables included having 20/40 or better corrected vision. Differences in 20/20 vision and legal blindness (20/200 or worse) were also examined. Respondents born in the United States were defined as US natives. Foreign-born respondents were categorized as either naturalized US citizens or noncitizen residents. Multivariate logistic regression of outcomes adjusted for sex, age, race/ethnicity, poverty, insurance, diabetes, and surgical correction for eyesight. RESULTS: A smaller percentage of noncitizens than US natives had myopia (18.8% vs 30.7%) or astigmatism (22.0% vs 30.9%). However, noncitizens using corrective lenses had an adjusted odds ratio (AOR) of 0.65 of having 20/20 vision compared to US natives (95% confidence interval [CI] 0.48-0.88). Differences in visual acuity for 20/40 and better vision were not statistically significant for corrective lens users. Among nonusers of corrective lenses, noncitizens were significantly less likely than US natives to have 20/40 or better vision (AOR = 0.54; 95% CI 0.39-0.74). Noncitizens also had up to 3.5 times the odds of being legally blind relative to US natives after adjusting for confounding factors (95% CI 1.52-7.83). CONCLUSIONS: Significant differences in visual acuity exist between immigrants and US natives. More research is necessary to identify underlying factors that may explain these disparities in visual impairment. PMID- 25034115 TI - A clinical, radiologic, and immunopathologic study of five periorbital intraosseous cavernous vascular malformations. AB - PURPOSE: To correlate the clinical, radiographic, histopathologic, and immunohistochemical features of 5 primary periorbital intraosseous cavernous vascular malformations. DESIGN: Retrospective interventional case series. METHODS: Clinical and operative records and radiographic images were reviewed. Histopathologic slides were evaluated with hematoxylin-eosin, trichrome, and elastin stains. Immunohistochemical studies were performed with a spectrum of monoclonal antibodies directed at antigens of vascular cells. RESULTS: Three men and 2 women ranged in age from 36 to 64 years. Vision was unaffected and there was no proptosis or globe displacement. The slow-growing lesions measured 13-25 mm in greatest diameter (mean 16.4 mm). Computed tomographic studies revealed that 2 lesions were situated in the maxillary bone, 2 in the frontal, and 1 in the zygoma, all anteriorly and with circumscribed, lucent, honeycombed, or sunburst characteristics. Histopathologically the lesions were composed of cavernous or telangiectatic channels; 1 showed advanced fibrotic vascular involution. Immunohistochemistry demonstrated CD31/34 positivity for vascular endothelium and D2-40 negativity for lymphatic endothelium. A typically thin mural myofibroblastic cuff was smooth muscle actin positive, weakly calponin positive, and desmin negative. Glucose transporter-1 and Ki-67 were negative in the endothelium. CONCLUSIONS: Intraosseous vascular lesions resemble orbital cavernous venous malformations (not true hemangiomas), except that their vascular walls are thinner owing to the constraints imposed by neighboring bone spicules, which limit the amount of interstitium from which mural myofibroblasts can be recruited. The bony trabeculae conferred the honeycomb or sunburst appearances observed radiographically. En bloc excision of these lesions was successful and avoided complications (mean follow-up, 46 months). PMID- 25034116 TI - Prophylactic use of bevacizumab to avoid anterior segment neovascularization following proton therapy for uveal melanoma. AB - PURPOSE: To investigate whether the prophylactic use of bevacizumab reduces the rate of rubeosis after proton therapy for uveal melanoma and improves the possibility to treat ischemic, reapplicated retina with laser photocoagulation. DESIGN: Comparative retrospective case series. METHODS: Uveal melanoma patients with ischemic retinal detachment and treated with proton therapy were included in this institutional study. Twenty-four eyes received prophylactic intravitreal bevacizumab injections and were compared with a control group of 44 eyes without bevacizumab treatment. Bevacizumab injections were performed at the time of tantalum clip insertion and were repeated every 2 months during 6 months, and every 3 months thereafter. Ultra-widefield angiography allowed determination of the extent of retinal ischemia, which was treated with laser photocoagulation after retinal reapplication. Main outcome measures were the time to rubeosis, the time to retinal reattachment, and the time to laser photocoagulation of ischemic retina. RESULTS: Baseline characteristics were balanced between the groups, except for thicker tumors and larger retinal detachments in the bevacizumab group, potentially to the disadvantage of the study group. Nevertheless, bevacizumab prophylaxis significantly reduced the rate of iris rubeosis from 36% to 4% (log-rank test P = .02) and tended to shorten the time to retinal reapplication until laser photocoagulation of the nonperfusion areas could be performed. CONCLUSIONS: Prophylactic intravitreal bevacizumab in patients treated with proton therapy for uveal melanoma with ischemic retinal detachment prevented anterior segment neovascularization, until laser photocoagulation to the reapplied retina could be performed. PMID- 25034117 TI - An optical coherence tomography-based analysis of choroidal morphologic features and choroidal vascular diameter in children and adults. AB - PURPOSE: To analyze choroidal sub-layers and vascular diameter in children, and to compare these choroidal features with those of adults. DESIGN: Retrospective observational study. METHODS: This study included 96 eyes from 48 healthy children and 54 eyes from 27 healthy adults. The subfoveal choroidal thickness, large choroidal vessel layer thickness, medium choroidal vessel layer choriocapillaris layer thickness, and large choroidal vessel diameter were estimated. The ratio of thickness of the large choroidal vessel layer to total choroidal thickness was calculated. The association between subfoveal choroidal thickness and large choroidal vessel layer, as well as ratio of thickness of the large choroidal vessel layer to total choroidal thickness, was analyzed. Furthermore, the ratio and choroidal vascular diameter were compared between children and adults. RESULTS: The mean age was 6.7 +/- 1.9 years and 30.7 +/- 4.3 years in children and in adults, respectively. In children, the mean ratio was 0.71 +/- 0.08 and the mean choroidal vascular diameter was 103.1 +/- 16.0 MUm. In adults, the values were 0.73 +/- 0.08 and 122.5 +/- 20.7 MUm, respectively. The subfoveal choroidal thickness in children was significantly associated with the ratio (P < .001), whereas the association was not significant in adults (P = .173). The choroidal vascular diameter was significantly greater in adults than in children (P < .001). However, the ratio was not different between the 2 groups (P = .391). CONCLUSIONS: Choroidal morphologic features are generally comparable between children and adults. Some differences between the 2 groups may reflect changes in choroidal morphology associated with aging. PMID- 25034118 TI - Serotonin and dopamine differentially affect appetitive and aversive general Pavlovian-to-instrumental transfer. AB - RATIONALE: Human motivation and decision-making is influenced by the interaction of Pavlovian and instrumental systems. The neurotransmitters dopamine and serotonin have been suggested to play a major role in motivation and decision making, but how they affect this interaction in humans is largely unknown. OBJECTIVE: We investigated the effect of these neurotransmitters in a general Pavlovian-to-instrumental transfer (PIT) task which measured the nonspecific effect of appetitive and aversive Pavlovian cues on instrumental responses. METHODS: For that purpose, we used selective dietary depletion of the amino acid precursors of serotonin and dopamine: tryptophan (n = 34) and tyrosine/phenylalanine (n = 35), respectively, and compared the performance of these groups to a control group (n = 34) receiving a nondepleted (balanced) amino acid drink. RESULTS: We found that PIT differed between groups: Relative to the control group that exhibited only appetitive PIT, we found reduced appetitive PIT in the tyrosine/phenylalanine-depleted group and enhanced aversive PIT in the tryptophan-depleted group. CONCLUSIONS: These results demonstrate a differential involvement of serotonin and dopamine in motivated behavior. They suggest that reductions in serotonin enhance the motivational influence of aversive stimuli on instrumental behavior and do not affect the influence of appetitive stimuli, while reductions in dopamine diminish the influence of appetitive stimuli. No conclusions could be drawn about how dopamine affects the influence of aversive stimuli. The interplay of both neurotransmitter systems allows for flexible and adaptive responses depending on the behavioral context. PMID- 25034119 TI - 7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress. AB - RATIONALE: 7-Chlorokynurenic acid (7-CTKA), a NMDA receptor antagonist, has been reported as a potential rapid antidepressant with poor understanding about the molecular mechanism of its therapeutic action. MicroRNAs (miRNAs) are emerging as critical regulators of central nervous system plasticity and may play an important role in depression. OBJECTIVE: The objective of this study was to investigate the molecular mechanism of antidepressant action of 7-CTKA in chronic unpredictable mild stress (CUMS) animal model. METHODS: K252a (tropomyosin related kinase receptor B (TrkB) antagonist), U0126 (extracellular signal regulated kinase (ERK) phosphorylation inhibitor), LY294002 (serine-threonine kinase (Akt) phosphorylation inhibitor), or vehicle was given intracerebroventricularly to mice in each group 30 min before 7-CTKA or vehicle intraperitoneal injection. Behavioral changes were observed by sucrose preference test and miRNA microarray was performed to examine hippocampal miRNAs levels in mice. Quantitative RT-PCR was conducted to further confirm results in microarray study. RESULTS: 7-CTKA not only reversed the decrease in sucrose preference and multiple hippocampal miRNAs changes induced by CUMS but also mediated 15 common miRNAs via TrkB-ERK/Akt pathways. Among them, the expression levels of four miRNAs (miR-34a-5p, miR-200a-3p, miR-144-3p, miR-1894-5p) were validated by quantitative real-time PCR (qRT-PCR). The findings from qRT-PCR study support results from microarray analysis except for the non-significance of miR-1894-5p expression. CONCLUSIONS: This demonstrated that the 15 miRNA targets shared by TrkB-ERK/Akt pathways might participate in rapid-acting molecular mechanism of antidepressant 7-CTKA. PMID- 25034120 TI - "A patchwork of services"--caring for women who sustain severe perineal trauma in New South Wales--from the perspective of women and midwives. AB - BACKGROUND: Current research into severe perineal trauma (3rd and 4th degree) focuses upon identification of risk factors, preventative practices and methods of repair, with little focus on women's experiences of, and interactions with, health professionals following severe perineal trauma (SPT). The aim of this study is to describe current health services provided to women in New South Wales (NSW) who have experienced SPT from the perspective of Clinical Midwifery Consultants (CMC) and women. METHODS: This study used a descriptive qualitative design and reports on the findings of a component of a larger mixed methods study. Data were collected through a semi-structured discussion group using a variety of non-directive, open-ended questions leading CMCs of NSW. A survey was distributed prior to the discussion group to collect further information and enable a more comprehensive understanding of services provided. Data from individual interviews with twelve women who had experienced SPT during vaginal birth is used to provide greater insight into their interactions with, and ease of access to, health service providers in NSW. An integrative approach was undertaken in reporting the findings which involved comparing and analysing findings from the three sets of data. RESULTS: One overarching theme was identified: A Patchwork of Policy and Process which identified that current health services operate in a 'patchwork' manner when caring for women who sustain SPT. They are characterised by lack of consistency in practice and standardisation of care. Within the overarching theme, four subthemes were identified: Falling through the gaps; Qualifications, skills and attitudes of health professionals; Caring for women who have sustained SPT; and Gold standard care: how would it look? CONCLUSION: The findings from this study suggest that current health services in NSW represent a 'patchwork' of service provision for women who have sustained SPT. It appeared that women seek compassionate and supportive care based upon a clear exchange of information, and this should be considered when reflecting upon health service design. This study highlights the benefits of establishing multi-disciplinary collaborative specialist clinics to support women who experience SPT and associated morbidities, with the aim of providing comprehensive physiological and psychological support. PMID- 25034121 TI - Differential expression patterns of PQRFamide peptide and its two receptor genes in the brain and pituitary of grass puffer during the reproductive cycle. AB - Pain-modulatory neuropeptides, PQRFamide (PQRFa) peptides, have recently been implicated in the regulation of reproduction in fish. As a first step toward investigating the role of PQRFa peptides on reproductive function in the grass puffer Takifugu niphobles, which is a semilunar spawner, we cloned genes encoding PQRFa peptide precursor (pqrfa) and its two types of receptors (pqrfa-r1 and pqrfa-r2), and examined changes in their expression levels in the brain and pituitary over several months during the reproductive cycle. The grass puffer PQRFa peptide precursor of 126 amino acid residues contains two putative PQRFa peptides, PQRFa-1 and PQRFa-2, which correspond to NPFF and NPAF in other vertebrates, respectively. The grass puffer PQRFa-R1 and PQRFa-R2 consist of 426 and 453 amino acid residues, respectively, and contain distinct characteristics of G-protein coupled receptors. These three genes were exclusively expressed in the brain and pituitary. The expression levels of pqrfa and pqrfa-r1 were significantly increased during the late stage of sexual maturation, but low in the spawning fish just after releasing sperms and eggs. Therefore, the grass puffer PQRFa peptide may have a role in the late stage of sexual maturation before spawning via PQRFa-R1. In contrast, the pqrfa-r2 expression showed maximum levels in the spawning fish and in the post-spawning period. The present results provide fundamental data suggesting that the grass puffer PQRFa peptide may have multiple roles in the control of reproduction that are dependent on the reproductive stages. PMID- 25034122 TI - Synthesis, spectroscopic characterization, electrochemical behavior and computational analysis of mixed diamine ligand gold(III) complexes: antiproliferative and in vitro cytotoxic evaluations against human cancer cell lines. AB - The gold(III) complexes of the type [(DACH)Au(en)]Cl3, 1,2-Diaminocyclohexane ethylenediamine gold(III) chloride [where 1,2-DACH = cis-, trans-1,2- and S,S 1,2diaminocyclohexane and en = ethylenediamine] have been synthesized and characterized using various analytical and spectroscopic techniques including elemental analysis, UV-Vis and FTIR spectra; and solution as well as solid-state NMR measurements. The solid-state (13)C NMR shows that 1,2-diaminocyclohexane (1,2-DACH) and ethylenediamine (en) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was determined by (1)H and (13)C NMR spectra. Their electrochemical behavior was studied by cyclic voltammetry. The structural details and relative stabilities of the four possible isomers of the complexes were also reported at the B3LYP/LANL2DZ level of theory. The coordination sphere of these complexes around gold(III) center adopts distorted square planar geometry. The computational study also demonstrates that trans- conformations is slightly more stable than the cis conformations. The antiproliferative effects and cytotoxic properties of the mixed diamine ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 1 is the most effective antiproliferative agent among mixed ligand based gold(III) complexes 1-3. The IC50 data reveal that the in vitro cytotoxicity of complexes 1 and 3 against SGC7901 cancer cells are fairly better than that of cisplatin. PMID- 25034123 TI - Genetic animal models of dystonia: common features and diversities. AB - Animal models are pivotal for studies of pathogenesis and treatment of disorders of the central nervous system which in its complexity cannot yet be modeled in vitro or using computer simulations. The choice of a specific model to test novel therapeutic strategies for a human disease should be based on validity of the model for the approach: does the model reflect symptoms, pathogenesis and treatment response present in human patients? In the movement disorder dystonia, prior to the availability of genetically engineered mice, spontaneous mutants were chosen based on expression of dystonic features, including abnormal muscle contraction, movements and postures. Recent discovery of a number of genes and gene products involved in dystonia initiated research on pathogenesis of the disorder, and the creation of novel models based on gene mutations. Here we present a review of current models of dystonia, with a focus on genetic rodent models, which will likely be first choice in the future either for pathophysiological or for preclinical drug testing or both. In order to help selection of a model depending on expression of a specific feature of dystonia, this review is organized by symptoms and current knowledge of pathogenesis of dystonia. We conclude that albeit there is increasing need for research on pathogenesis of the disease and development of improved models, current models do replicate features of dystonia and are useful tools to develop urgently demanded treatment for this debilitating disorder. PMID- 25034124 TI - Transcriptional activity comparison of different sites in recombinant Marek's disease virus for the expression of the H9N2 avian influenza virus hemagglutinin gene. AB - Over the last two decades, much attention has been paid to MDV-vectored recombinant vaccines. Many factors have influenced their protective efficacy, and insertion site has been among the main influential factors for the expression of foreign genes in recombinant Marek's disease virus (rMDV). To compare the transcriptional activity of different sites of rMDV, an H9N2 avian influenza virus hemagglutinin gene (AIV-H9N2-HA) expression cassette that used the bi directional promoter of serotype 1 MDV (MDV1) in the 1.8kb RNA transcript direction (p1.8kb) as a promoter was inserted into 4 different regions of MDV using the bacterial artificial chromosome (BAC) vector and FLP/FRT recombination technique. The insertion regions included 3 of its own sites (US2, US10 and one of Meq genes) in the MDV genome and a foreign site (gpt gene) in the BAC vector. Quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to analyze and compare the H9N2-HA expression levels of these different rMDVs both at the mRNA level and at the protein level. The results indicated that among the four tested insertion regions, the HA expression cassette in the US2 region demonstrated the highest activity, followed by that in the Meq region, which was almost equal to that of US10. Further, the expression cassette had the lowest activity in the foreign region gpt gene. The above data could be useful for choosing proper recombinant insertion regions in the construction of rMDV to express different foreign genes, and it is a prerequisite for developing effective MDV-vectored recombinant vaccines. PMID- 25034125 TI - Ribosomal RNA depletion or exclusion has negligible effect on the detection of viruses in a pan viral microarray. AB - Pan viral DNA microarrays, which can detect known, novel and multiple viral infections, are major laboratory assets contributing to the control of infectious diseases. The large quantity of ribosomal RNA (rRNA) found in tissue samples is thought to be a major factor contributing to the comparatively lower sensitivity of detecting RNA viruses, as a sequence-independent PCR is used to amplify unknown samples for microarray analysis. This study aimed to determine whether depletion or exclusion of rRNA can improve microarray detection and simplify its analysis. Therefore, two different rRNA depletion and exclusion protocols, RiboMinusTM technology and non-rRNA binding hexanucleotides, were applied to the microarray sample processing and the outcome was compared with those of the sequence-independent amplification protocol. This study concludes that the two procedures, described to deplete or exclude rRNA, have negligible effect on the microarrays detection and analysis and might only in combination with further techniques result in a significant enhancement of sensitivity. Currently, existing protocols of random amplification and background adjustment are pertinent for the purpose of sample processing for microarray analysis. PMID- 25034126 TI - Free circulating nucleic acids in plasma and serum as a novel approach to the use of internal controls in real time PCR based detection. AB - Internal controls (ICs), are the main components of any real-time PCR based amplification methods, which are co-purified and co-amplified with the actual target. The existence of free circulating nucleic acids in plasma and serum (CNAPS) has been known for many years. The aim of this study was to verify whether CNAPS can be used as ICs in real-time PCR based detection and quantification of DNA or RNA targets in plasma and serum samples. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a housekeeping gene, was chosen at random as CNAPS to serve as an intrinsic internal control in two different real-time PCR based quantification models in plasma and serum. Viral loads of hepatitis B virus (HBV) DNA and hepatitis delta virus (HDV) RNA were quantified as actual targets in parallel to GAPDH as IC in a total of 519 serum or plasma samples including 21 healthy controls, 202 positive chronic hepatitis delta patients, 37 chronic hepatitis C patients, 168 chronic hepatitis B patients, 52 patients with hepatocellular carcinoma, and 39 patients with non-alcoholic steatohepatitis/non alcoholic fatty liver disease. GAPDH levels did not show significant variance in different patient groups and yielded positive signals in all 519 patients with persistent cycle threshold (CT) values 27.85+/-1.57 (mean+/-standard deviation (SD)). Reproducibility of the GAPDH amplification in HDV RNA and HBV DNA quantifications was shown with a SD value of CT ranging from 0.42 to 2.14 (mean SD; 1.18) and 0.24 to 1.75 (mean SD; 1.03), respectively. In conclusion, the freely circulating nucleic acids can clearly be used as internal controls for real-time PCR based detection and quantification of any RNA and mainly DNA targets (pathogens) in serum or plasma and this simply excludes the compulsory external addition of any IC molecules into the reaction. PMID- 25034127 TI - Concordance between allele-specific PCR and ultra-deep pyrosequencing for the detection of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations. AB - Recent advances in genotyping technologies have allowed for detection of HIV-1 drug resistance mutations present at low levels. The presence and percentage of Y181C and K103N drug-resistant variants in the blood of 105 subtype C HIV infected infants who failed single-dose nevirapine prophylaxis for HIV transmission were compared using two highly sensitive genotyping methods, allele specific PCR (AS-PCR) and ultra-deep pyrosequencing. Significant correlations in detection between both methods were found for both Y181C (correlation coefficients of 0.94 [95% CI 0.91-0.96]) and K103N (0.89 [95% CI 0.84-0.92]) mutations. The majority of discordant specimens (3/5 Y181C and 8/11 K103N) had wild-type variants when population sequencing was used, but mutant variants were detectable at very low levels (<=5%) with either assay. This difference is most likely due to stochastic variations in the appearance of mutant variants. Overall, both AS-PCR and ultra-deep pyrosequencing methods have proven to be sensitive and accurate, and may confidently be used where feasible. PMID- 25034128 TI - Integrin and cadherin signaling in bone: role and potential therapeutic targets. AB - Cell-cell and cell-matrix interactions mediated by cell adhesion molecules are important mechanisms controlling cell fate and function. Here, we review recent advances in the implication of the cell adhesion molecules integrins and cadherins in the control of osteoblastogenesis and bone formation. We discuss emerging evidence indicating that signaling pathways mediated by integrins and cadherins and their crosstalk with the Wnt/beta-catenin signaling pathway regulate osteogenic differentiation and mechanotransduction. We also offer a comprehensive view of the mechanisms by which some integrins and cadherins control the differentiation of cells of the osteoblast lineage in bone marrow niches. Understanding how specific integrins or cadherins may promote osteogenic cell differentiation, bone formation, and repair may lead to novel therapeutic strategies. PMID- 25034130 TI - Mitochondrial DNA damage and atherosclerosis. AB - Mitochondria are often regarded as the cellular powerhouses through their ability to generate ATP, the universal fuel for metabolic processes. However, in recent years mitochondria have been recognised as critical regulators of cell death, inflammation, metabolism, and the generation of reactive oxygen species (ROS). Thus, mitochondrial dysfunction directly promotes cell death, inflammation, and oxidative stress and alters metabolism. These are key processes in atherosclerosis and there is now evidence that mitochondrial DNA (mtDNA) damage leads to mitochondrial dysfunction and promotes atherosclerosis directly. In this review we discuss the recent evidence for and mechanisms linking mtDNA defects and atherosclerosis and suggest areas of mitochondrial biology that are potential therapeutic targets. PMID- 25034131 TI - Evaluation of sediment contamination with heavy metals: the importance of determining appropriate background content and suitable element for normalization. AB - In the present study, concentrations of heavy metals (Cd, Cu, Co, Mn, Cr, Ni, Pb, and Zn) were determined at 35 river sediments in Serbia. The anthropogenic heavy metals input and quantification of the metal enrichment degree in sediments were estimated by calculating geo-accumulation indices (I(geo)) and enrichment factors (EF). These pollution indices have been calculated using different background values (continental crust and local background values) and different element used for normalization (Al and Fe), followed by result comparison. The EF values calculated with continental crust as background (minor to extremely severe enrichment) were higher than when regional background values were used (minor to moderate enrichment). Significant influence of background values on the I(geo) values is observed. Values of geo-accumulation index (<2) revealed that studied river sediments are remaining unpolluted to moderately polluted with Co, Mn, Cr, and Ni. Significant pollution in the sediments was observed for Cd, Cu, Pb, and Zn elements. The results of this study confirm the relevance of precise and accurate determining of local background concentrations while assessing sediment pollution. The values of EFs for studied elements were more influenced by the choice of background values than selection of element used for normalization. Our recommendation would be to use the local and regional background content in quantification of metal contamination in sediments, since these values differ and are site and region dependent. PMID- 25034129 TI - Insights into obesity and diabetes at the intersection of mouse and human genetics. AB - Many of our insights into obesity and diabetes come from studies in mice carrying natural or induced mutations. In parallel, genome-wide association studies (GWAS) in humans have identified numerous genes that are causally associated with obesity and diabetes, but discovering the underlying mechanisms required in-depth studies in mice. We discuss the advantages of studying natural variation in mice and summarize several examples where the combination of human and mouse genetics opened windows into fundamental physiological pathways. A noteworthy example is the melanocortin-4 receptor (MC4R) and its role in energy balance. The pathway was delineated by discovering the gene responsible for the Agouti mutation in mice. With more targeted phenotyping, we predict that additional pathways relevant to human pathophysiology will be discovered. PMID- 25034133 TI - Subcortical morphometry and psychomotor function in euthymic bipolar disorder with a history of psychosis. AB - Psychomotor disturbances are prominent in bipolar disorder patients with a history of psychosis, but their neural correlates remain largely unexplored. We hypothesized that these psychomotor disturbances are associated with morphometric changes in functionally specific regions of the basal ganglia and thalamus. To test if psychomotor performance is associated with changes in volume and shape in these brain regions, we investigated 20 euthymic bipolar disorder patients with a history of psychosis and 20 healthy controls with structural magnetic resonance imaging and vertex-based morphometry. Within the patient group, the local shape of the basal ganglia was significantly associated with longer duration of illness, increased number of manic episodes, and treatment with antipsychotics. There were neither any statistically significant associations between psychomotor performance and morphometric measures in the patient group, nor any significant morphometric differences between patients and controls. We conclude that euthymic subjects with bipolar disorder and a previous history of psychosis show shape changes in regions of the basal ganglia associated to clinical variables that may predict psychomotor disturbances in bipolar disorder. PMID- 25034132 TI - Molecular characterization of argininosuccinate synthase and argininosuccinate lyase from the liver of the African lungfish Protopterus annectens, and their mRNA expression levels in the liver, kidney, brain and skeletal muscle during aestivation. AB - Argininosuccinate synthase (Ass) and argininosuccinate lyase (Asl) are involved in arginine synthesis for various purposes. The complete cDNA coding sequences of ass and asl from the liver of Protopterus annectens consisted of 1,296 and 1,398 bp, respectively. Phylogenetic analyses revealed that the deduced Ass and Asl of P. annectens had close relationship with that of the cartilaginous fish Callorhinchus milii. Besides being strongly expressed in the liver, ass and asl expression were detectable in many tissues/organs. In the liver, mRNA expression levels of ass and asl increased significantly during the induction phase of aestivation, probably to increase arginine production to support increased urea synthesis. The increases in ass and asl mRNA expression levels during the prolonged maintenance phase and early arousal phase of aestivation could reflect increased demand on arginine for nitric oxide (NO) production in the liver. In the kidney, there was a significant decrease in ass mRNA expression level after 6 months of aestivation, indicating possible decreases in the synthesis and supply of arginine to other tissues/organs. In the brain, changes in ass and asl mRNA expression levels during the three phases of aestivation could be related to the supply of arginine for NO synthesis in response to conditions that resemble ischaemia and ischaemia-reperfusion during the maintenance and arousal phase of aestivation, respectively. The decrease in ass mRNA expression level, accompanied with decreases in the concentrations of arginine and NO, in the skeletal muscle of aestivating P. annectens might ameliorate the potential of disuse muscle atrophy. PMID- 25034134 TI - Identity of Sarcocystis species of the water buffalo (Bubalus bubalis) and cattle (Bos taurus) and the suppression of Sarcocystis sinensis as a nomen nudum. AB - There are uncertainties concerning the identity and host species specificity of Sarcocystis species of the water buffalo (Bubalus bubalis) and cattle (Bos taurus). Currently, in cattle three species are recognized with known endogenous stages, viz.: S. cruzi (with canine definitive host), S. hirsuta (feline definitive host), and S. hominis (primate definitive host). Recently, a fourth Sarcocystis species with an unknown life cycle has been reported from cattle. In the water buffalo, four species of Sarcocystis have been described: S. fusiformis (feline definitive host), S. buffalonis (feline definitive host), S. levinei (canine definitive host), and S. dubeyi (definitive host unknown but not cat or dog). Besides, there are studies of Sarcocystis infections in buffalo and cattle from China with results that are difficult to interpret and validate. For example, some of the studies report transmission of Sarcocystis species between cattle and buffalo, but steps to preclude exogenous exposures were not reported. A species of the water buffalo, 'S. sinensis', was proposed at a Chinese national conference in 1990, and published as an abstract without figures and with no archived type specimens for verification. The International Code of Zoological Nomenclature Articles 9 and 10 state that "abstracts of articles, papers, posters, text of lectures, and similar material when issued primarily to participants at meetings, symposia, colloquia or congress does not constitute published work"; therefore, S. sinensis is a nomen nudum. PMID- 25034135 TI - Immunoinformatics study on highly expressed Mycobacterium tuberculosis genes during infection. AB - The most important targets for vaccine development are the proteins that are highly expressed by the microorganisms during infection in-vivo. A number of Mycobacterium tuberculosis (Mtb) proteins are also reported to be expressed in vivo at different phases of infection. In the present study, we analyzed multiple published databases of gene expression profiles of Mtb in-vivo at different phases of infection in animals and humans and selected 38 proteins that are highly expressed in the active, latent and reactivation phases. We predicted T- and B-cell epitopes from the selected proteins using HLAPred for T-cell epitope prediction and BCEPred combined with ABCPred for B-cell epitope prediction. For each selected proteins, regions containing both T- and B-cell epitopes were identified which might be considered as important candidates for vaccine design against tuberculosis. PMID- 25034136 TI - Physical activity and capacity at initiation of antiretroviral treatment in HIV patients in Ethiopia. AB - SUMMARY We described levels of habitual physical activity and physical capacity in HIV patients initiating antiretroviral treatment in Ethiopia and assessed the role of HIV and nutritional indicators on these outcomes. Physical activity energy expenditure (PAEE) and activity levels were measured with combined heart rate and movement sensors. Physical capacity was assessed by grip strength, sleeping heart rate and heart rate economy. Grip strength data was also available from a sex- and age-matched HIV-negative reference group. Median PAEE was 27.9 (interquartile range 17.4-39.8) kJ/kg per day and mean +/- s.d. grip strength was 23.6 +/- 6.7 kg. Advanced HIV disease predicted reduced levels of both physical activity and capacity; e.g. each unit viral load [log(1+copies/ml)] was associated with -15% PAEE (P < 0.001) and -1.0 kg grip strength (P < 0.001). Grip strength was 4.2 kg lower in patients compared to HIV-negative individuals (P < 0.001). Low body mass index (BMI) predicted poor physical activity and capacity independently of HIV status, e.g. BMI <16 was associated with -42% PAEE (P < 0.001) and -6.8 kg grip strength (P < 0.001) compared to BMI >=18.5. The study shows that advanced HIV and malnutrition are associated with considerably lower levels of physical activity and capacity in patients at initiation of antiretroviral treatment. PMID- 25034140 TI - Superovulation alters embryonic poly(A)-binding protein (Epab) and poly(A) binding protein, cytoplasmic 1 (Pabpc1) gene expression in mouse oocytes and early embryos. AB - Embryonic poly(A)-binding protein (EPAB) and poly(A)-binding protein, cytoplasmic 1 (PABPC1) play critical roles in translational regulation of stored maternal mRNAs required for proper oocyte maturation and early embryo development in mammals. Superovulation is a commonly used technique to obtain a great number of oocytes in the same developmental stages in assisted reproductive technology (ART) and in clinical or experimental animal studies. Previous studies have convincingly indicated that superovulation alone can cause impaired oocyte maturation, delayed embryo development, decreased implantation rate and increased postimplantation loss. Although how superovulation results in these disturbances has not been clearly addressed yet, putative changes in genes related to oocyte and early embryo development seem to be potential risk factors. Thus, the aim of the present study was to determine the effect of superovulation on Epab and Pabpc1 gene expression. To this end, low- (5IU) and high-dose (10IU) pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotrophin (hCG) were administered to female mice to induce superovulation, with naturally cycling female mice serving as controls. Epab and Pabpc1 gene expression in germinal vesicle (GV) stage oocytes, MII oocytes and 1- and 2-cell embryos collected from each group were quantified using quantitative reverse transcription-polymerase chain reaction. Superovulation with low or high doses of gonadotropins significantly altered Epab and Pabpc1 mRNA levels in GV oocytes, MII oocytes and 1- and 2-cell embryos compared with their respective controls (P<0.05). These changes most likely lead to variations in expression of EPAB- and PABPC1 regulated genes, which may adversely influence the quality of oocytes and early embryos retrieved using superovulation. PMID- 25034137 TI - Application of intraoperative frozen section examination in the management of female breast cancer in China: a nationwide, multicenter 10-year epidemiological study. AB - BACKGROUND: Intraoperative frozen section examination (IFSE) during breast cancer surgery can partly reflect the status of surgical treatment since the surgical method used directly determines the purpose of IFSE use in disease management. This study aims to investigate the application of, changing trends in, and factors influencing IFSE in the management of female breast cancer in China. METHODS: We collected the sociodemographic and clinical data of 4,211 breast cancer patients between 1999 and 2008 and statistically analyzed these data using chi2 or Fisher's exact tests. RESULTS: A total of 2,283 (54.22%) patients with breast cancer underwent IFSE. During the 10-year study period, IFSE use was associated with an increase in the number of sentinel lymph node biopsies (SLNB) and breast-conserving surgeries (BS) performed, with significant regional differences noted in this trend (P < 0.05). Patients' education, occupation, age, tumor size estimated by preoperative palpation, and the use of imaging examinations affected the purpose of IFSE use (P < 0.05). CONCLUSIONS: Our results show that the purpose of IFSE in the surgical treatment of breast cancer in China is gradually approaching that in developed countries. We believe that policymakers must address the differences in breast cancer treatment based on the socioeconomic status of patients. Lastly, the use of IFSE for determining tumor characteristics should be avoided as far as possible, and patient education and breast cancer screening programs tailored to the Chinese population should be established. Our findings may guide the formulation of breast cancer control strategies in China and other low-income countries. PMID- 25034141 TI - Spirituality and Its Relationship with Personality in Depressed People: Preliminary Findings. AB - The relationship between spirituality and personality in patients with depression is complex and not much explored. The aim of our study is to examine the interconnection between the spiritual quality of life (QoL) and Cloninger's psychobiological model of personality in patients with depression. The sample consisted of 85 consecutive outpatients treated for depression. The measurements used were: Beck Depression Inventory, WHO-Quality of Life-Spiritual, Religious, Personal Beliefs, and Temperament and Character Inventory. The results have shown that higher harm avoidance, lower self-directedness and lower cooperativeness are personality dimensions associated with depression. The spiritual QoL has showed to play a significant role in depression, just as it has proved to be a unique predictor of lower depressive symptoms, adjusted for personality dimensions. The spiritual QoL itself is predicted by personality dimensions, self-directedness and self-transcendence implying that spirituality is a broader construct than the character dimension. Our findings may contribute to a more comprehensive understanding of depression, spirituality and personality. PMID- 25034142 TI - Tolerability and efficacy of busulfan and fludarabine as allogeneic pretransplant conditioning therapy in acute myeloid leukemia: comparison with busulfan and cyclophosphamide regimen. AB - BACKGROUND: The aim of this study was to compare safety and efficacy of the association of busulfan with cyclophosphamide (BuCy2) versus busulfan and fludarabine (BuFlu) as a conditioning regimen in allogeneic hematopoietic progenitor cell transplantation (allo-HPCT) in patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: A total of 65 consecutive patients who received an allo-HPCT from Human Leucocyte Antigen-matched sibling donors were analyzed. The conditioning was BuCy2 in 48 patients and BuFlu in 17 patients. RESULTS: There were no significant differences between the 2 cohorts in hematological engraftment, incidence of extrahematological toxicities, and acute graft versus host disease (GVHD). The incidence of chronic GVHD was 34% in the BuCy2 group versus 57% in the BuFlu group (P = .03). Transplant-related mortality was 17% (8 patients) in the BuCy2 group versus 0 in the BuFlu arm. Disease related mortality was similar in the whole study population; in high-risk AML patients it was 11% in the BuCy2 group and 19% in the BuFlu group (P = .015). The probability of disease-free and event-free survival at 2 years was, respectively, 70% and 60% in the BuCy2 group and 59% and 58% in the BuFlu group (P = .06 and P = not significant [ns]). The probability of overall survival at 2 years was 71% in the BuCy2 group and 63% in the BuFlu group (P = ns), and in the high-risk group it was 83% and 67% in the BuCy2 and BuFlu group, respectively (P = ns). CONCLUSION: BuFlu is well tolerated and is less toxic than BuCy2 and our results did not suggest that in high-risk AML, BuCy2 should be the favorite regimen in terms of efficacy. PMID- 25034143 TI - Stereotactic radiosurgery for multiple brain metastases. AB - Stereotactic radiosurgery (SRS) alone has become one of the treatment options for patients with 1-4 metastases as the detrimental effects of whole brain radiation therapy on neurocognition and quality of life are becoming well known. Multiple randomized control trials also failed to show overall survival benefit of adding whole brain radiation therapy to SRS. However, the role of SRS in multiple brain metastases, especially those with >= 4 tumors, remains controversial. The literature is emerging, and the limited evidence suggests that the local control benefit is independent of the number of metastases, and that patients with more than four brain metastases have similar overall survival compared to those with 2 4 tumors. This review aims at summarizing the current evidence of SRS for multiple brain metastases, divided into limited (2-3) and multiple (>= 4) lesions. It also reviews the technical aspects and cost-effectiveness of SRS. PMID- 25034144 TI - Molecular analysis of chromium and cobalt-related toxicity. AB - Occupational and environmental exposure to Co and Cr has been previously linked to a wide array of inflammatory and degenerative conditions and cancer. Recently, significant health concerns have been raised by the high levels of Cr and Co ions and corrosion products released by biomedical implants. Herein, we set to analyze the biological responses associated with Co and Cr toxicity. Histological, ultrastructural, and elemental analysis, performed on Cr and Co exposed patients reveal the presence of corrosion products, metallic wear debris and metal ions at varying concentrations. Metallic ions and corrosion products were also generated in vitro following macrophage phagocytosis of metal alloys. Ex vivo redox proteomic mapped several oxidatively damaged proteins by Cr(III) and Co(II) induced Fenton reaction. Importantly, a positive correlation between the tissue amounts of Cr(III) and Co(II) ions and tissue oxidative damage was observed. Immobilized- Cr(III) and Co(II) affinity chromatography indicated that metal ions can also directly bind to several metallo and non-metalloproteins and, as demonstrated for aldolase and catalase, induce loss of their biological function. Altogether, our analysis reveals several biological mechanisms leading to tissue damage, necrosis, and inflammation in patients with Cr and Co-associated adverse local tissue reactions. PMID- 25034145 TI - Synergy of Myc, cell cycle regulators and the Akt pathway in the development of aggressive B-cell lymphoma in a mouse model. PMID- 25034146 TI - Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. AB - Refractory chronic graft-versus-host disease (cGVHD) is a significant complication resulting from allogeneic hematopoietic stem cell transplantation (HSCT). Mesenchymal stromal cells (MSCs) have shown promise for treating refractory cGVHD, but the favorable effects of MSCs therapy in cGVHD are complex and not fully understood. In this prospective clinical study, 20 of 23 cGVHD patients had a complete response or partial response in a 12-month follow-up study. The most marked improvements in cGVHD symptoms were observed in the skin, oral mucosa and liver. Clinical improvement was accompanied by a significantly increased number of interleukin (IL)-10-producing CD5+ B cells. Importantly, CD5+ B cells from cGVHD patients showed increased IL-10 expression after MSCs treatment, which was associated with reduced inflammatory cytokine production by T cells. Mechanistically, MSCs could promote the survival and proliferation of CD5+ regulatory B cells (Bregs), and indoleamine 2, 3-dioxygenase partially participates in the MSC-mediated effects on Breg cells. Thus, CD5+ Breg cells may have an important role in the process of MSC-induced amelioration of refractory cGVHD and may provide new clues to reveal novel mechanisms of action for MSCs. PMID- 25034147 TI - Monoclonal B-cell lymphocytosis is characterized by mutations in CLL putative driver genes and clonal heterogeneity many years before disease progression. PMID- 25034149 TI - Quantitative evaluation of biological reaction kinetics in confined nanospaces. AB - Evaluating the kinetics of biological reaction occurring in confined nanospaces is of great significance in studying the molecular biological processes in vivo. Herein, we developed a nanochannel-based electrochemical reactor and a kinetic model to investigate the immunological reaction in confined nanochannels simply by the electrochemical method. As a result, except for the reaction kinetic constant that was previously studied, more insightful kinetic information such as the moving speed of the antibody and the immunological reaction progress in nanochannels were successfully revealed in a quantitative way for the first time. This study would not only pave the investigation of molecular biological processes in confined nanospaces but also be promising to extend to other fields such as biological detection and clinical diagnosis. PMID- 25034148 TI - The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma. AB - The role of both autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) in the management of mantle cell lymphoma (MCL) remains to be clarified. We conducted a consensus project using the RAND-modified Delphi consensus procedure to provide guidance on how SCT should be used in MCL. With regard to autoSCT, there was consensus in support of: autoSCT is the standard first-line consolidation therapy; induction therapy should include high-dose cytarabine and Rituximab; complete or partial remission should be achieved before autoSCT; Rituximab maintenance following autoSCT is not indicated; and omission of autoSCT in 'low-risk' patients is not indicated. No consensus could be reached regarding: autoSCT in the treatment of relapsed disease following non-transplant therapy; the value of positron emission tomography scanning and minimal residual disease (MRD) monitoring; in vivo purging with Rituximab; total body irradiation conditioning for autoSCT; and preemptive Rituximab after autoSCT. For alloSCT, consensus was reached in support of: alloSCT should be considered for patients relapsing after autoSCT; reduced intensity conditioning regimens should be used; allogeneic immunotherapy should be used for MRD eradication after alloSCT; and there is a lack of prognostic criteria to guide the use of alloSCT as first-line consolidation. No consensus was reached regarding the role of alloSCT for relapsed disease following non-transplant therapy. PMID- 25034150 TI - An improved axillary staging system using the OSNA assay does not modify the therapeutic management of breast cancer patients. AB - The one-step nucleic acid amplification (OSNA) assay is a molecular procedure that can identify deposits of breast cancer (BC) cells in the sentinel lymph node (SLN). We examined the consistency of the OSNA assay with a classic hematoxylin eosin (H&E)-based immunohistochemistry (IHC) study and evaluated how OSNA-based axillary staging might impact the therapeutic management of BC patients. SLN biopsy results were considered to be positive in 60 patients (40%) in the OSNA group (N = 148) and in 43 (28%) patients in the IHC cohort (N = 153, p = 0.023). There was no difference in the macrometastasis (22% for OSNA, 15% for H&E, p = 0.139) or micrometastasis (19% for OSNA, 13% for H&E, p = 0.166) rates, but we found statistically significant differences in the number of isolated tumor cells (1% for OSNA, 11% for H&E, p < 0.001). There were no differences in the administration rate of adjuvant systemic therapy between the OSNA (66% in the SLN(+) patients) and the H&E (74% in the SLN(+) patients) groups (p = 0.159). The OSNA assay allows for the detection of SLN metastases more precisely than conventional pathologic methods but does not alter the therapeutic management of SLN(+) BC patients. PMID- 25034151 TI - Association of leptin gene -2548 G/A polymorphism with obesity: a meta-analysis. AB - BACKGROUND: A common single-nucleotide polymorphism identified in the 5' untranslated region of the leptin gene (LEP -2548 G/A polymorphism) may be associated with obesity, but the existing research findings are inconsistent, so we conducted this meta-analysis. METHODS: Medline, Embase and ISI Web of Science databases were searched to identify relevant studies. Meta-analysis of the total and subgroup populations was conducted using allelic, additive, dominant and recessive models, and odds ratios and their 95% confidence intervals were calculated in a fixed-effect model if no heterogeneity (evaluated as I(2) statistic) existed. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by ethnicity. Meta-regression and the HETRED analysis were used to explore the potential sources of between-study heterogeneity. Egger's test and influence analysis were conducted to evaluate the publication bias and study power, respectively. RESULTS: The final selection enrolled 9 studies, including 2,988 subjects (1,372 obese subjects and 1,616 controls). No significant association was identified between the LEP -2548 G/A polymorphism and obesity for all genetic models in the overall population and Caucasians. We found a significant association with allelic, additive and dominant models for subjects of mixed race from South America. Notwithstanding, this significance should be treated cautiously for it is based on a rather small sample (788 involved subjects). CONCLUSIONS: In total, the combined analysis of data from current and published studies suggested that the LEP -2548 G/A polymorphism does not contribute to the development of obesity, despite the fact that a significant association exists in a small subgroup from South America. Further studies are needed to elucidate the relationship. . PMID- 25034152 TI - Proteomics focusing on immune markers in psoriatic arthritis. AB - The immune-pathogenesis of psoriatic arthritis represents a subject of intense research, as a still unknown factor can trigger the chronic inflammation that, upon a defective immune terrain, generates this auto-immune/auto-inflammatory condition. The pathogenesis complexity of psoriatic arthritis resides in the psoriatic synovitis milieu, where intricate immune relations are emerging during disease development. Innate immune response generates inflammatory cytokines driving effectors functions for immune and non-immune cells that sustain the chronical character of the synovitis. Herein, we review the updated information regarding biomarkers/immune markers that sustain the heterogeneity and complexity of psoriatic arthritis pathogenesis, this complexity leading to multifaceted methodological approaches for disease investigation. New immune proteomic or genomic biomarkers can enlarge and identify new therapeutic targets. PMID- 25034153 TI - Environmental influences on systemic lupus erythematosus expression. AB - The etiology of systemic lupus erythematosus (SLE) is unknown, but multiple genetic, epigenetic, and environmental risk factors have been implicated. The inheritance of genes alone is not sufficient for developing SLE, suggesting the influence of environmental triggers on disease expression. Despite the tremendous amount of progress in elucidating potential environmental risk factors for SLE, much more needs to be done. An interdisciplinary approach to studies of the causes and, ultimately, prevention of SLE is needed. This article reviews what is understood about the epidemiology of the relationship between environmental exposures and SLE, in addition to emerging areas of study. PMID- 25034155 TI - Impact of race and ethnicity in the course and outcome of systemic lupus erythematosus. AB - Genetic factors seem to play a more important role early in the course of systemic lupus erythematosus (SLE), whereas nongenetic factors seem to play a more important role over the course of the disease. SLE is more frequent with less favorable outcomes in nonwhite populations. To overcome these differences and reduce the immediate-term, mediate-term, and long-term impact of SLE among disadvantaged populations, it is essential to increase disease awareness, to improve access to health care and to provide care to these patients in a consistent manner regardless of the severity of their disease. PMID- 25034154 TI - Clinical perspectives on lupus genetics: advances and opportunities. AB - In recent years, genome-wide association studies have led to an expansion in the identification of regions containing confirmed genetic risk variants within complex human diseases, such as systemic lupus erythematosus (SLE). Many of the strongest SLE genetic associations can be divided into groups based on their potential roles in different processes implicated in lupus pathogenesis, including ubiquitination, DNA degradation, innate immunity, cellular immunity, lymphocyte development, and antigen presentation. Recent advances have also shown several genetic associations with SLE subphenotypes and subcriteria. Many areas for further exploration remain to move lupus genetic studies toward clinically informative end points. PMID- 25034156 TI - The immunopathology of cutaneous lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the development of autoantibodies and immunologic attack of different organ systems, including the skin. This review aims to provide an overview of some of the pathogenic processes that may be important in the development of SLE, specifically cutaneous lupus erythematosus, and then illustrates how therapies might be tailored to modify these processes and treat disease. PMID- 25034158 TI - Systemic lupus erythematosus and malignancies: a review article. AB - The systemic lupus erythematosus (SLE) population has a unique cancer risk profile. This article presents the most recent data on risk of cancer in lupus and discusses possible contributing factors. The risk of lymphoma is particularly increased in SLE and may be mediated by immunosuppressive medication. Lung cancer risk is also increased in SLE. There is a high rate of cervical dysplasia in women with SLE. A similar pathophysiology could be responsible for the trend seen in vulvovaginal and hepatic carcinomas. There is a decreased risk in SLE for some hormone-sensitive cancers, but the cause of this remains unclear. PMID- 25034159 TI - Post-marketing experiences with belimumab in the treatment of SLE patients. AB - Belimumab (Benlysta) is a human recombinant monoclonal antibody that targets and inhibits soluble B-lymphocyte stimulator, also known as B-cell activating factor, a proliferation and survival factor for B cells. The published clinical trials data showed that in patients with active systemic lupus erythematosus (SLE), belimumab effectively reduced peripheral B-cell levels and improved disease activity. This article reviews the belimumab clinical trials and the post marketing experience with belimumab in the treatment of those lupus patients with persistent active disease despite current standard of care (SOC) therapy. PMID- 25034157 TI - Pathogenesis and treatment of atherosclerosis in lupus. AB - The prevalence of atherosclerosis (ATH) is higher in patients with systemic lupus erythematosus (SLE) and occurs at an earlier age. The lupus-related factors that account for this increased risk are likely numerous and related to the factors described in this article. Identifying of at-risk subjects and increasing the understanding of pathogenesis of ATH in SLE is critical for improving the quality of care and improving mortality in this vulnerable population. PMID- 25034160 TI - Recent clinical trials in lupus nephritis. AB - Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that the efficacy of mycophenolate mofetil may be similar to that of quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil. PMID- 25034162 TI - Improving participation in clinical trials of novel therapies: going back to basics. AB - Clinical trials in many diseases are experiencing more difficulties in achieving sufficient or timely enrollment of participants; anecdotal reports from trials of novel therapies for systemic lupus erythematosus (SLE) seem to be facing the same challenges. General factors associated with this trend include the growth of the contract research industry, increasing oversight, and high-profile accounts of scientific misconduct and fraud in research. Complicated protocols that increase participant burden, overly restrictive entry criteria, the fear of an SLE flare may also affect enrollment in SLE trials. PMID- 25034163 TI - Foreword. Systemic lupus erythematosus. PMID- 25034161 TI - The kidney biopsy in lupus nephritis: is it still relevant? AB - The kidney biopsy is the standard of care for diagnosis of lupus nephritis and remains necessary to ensure accurate diagnosis and guide treatment. Repeat biopsy should be considered when therapy modifications are necessary, as in cases with incomplete or no response, or when stopping therapy for those in remission. There are several promising biomarkers of kidney disorders; however, these markers need to be validated in a prospective clinical trial before being applied clinically. Molecular analysis may provide the information presently lacking from current evaluation of kidney disorders and may better inform on prognosis and treatment considerations. PMID- 25034164 TI - Systemic lupus erythematosus. PMID- 25034165 TI - Mechanisms underlying increased serotonin-induced contraction in carotid arteries from chronic type 2 diabetic Goto-Kakizaki rats. AB - Serotonin (5-hydroxytryptamine; 5-HT) plays important roles in the cardiovascular system; however, the relationship between 5-HT-induced vasocontraction and the arterial 5-HT system including metabolism and signal transduction, in the presence of chronic type 2 diabetes (T2D) remains unclear. Therefore, we investigated 5-HT-induced contraction and associated mechanisms in carotid arteries from chronic T2D Goto-Kakizaki (GK) rats. Contractions in response to 5 HT were examined in carotid arteries from GK rats (42-46 weeks old). To investigate the response mechanisms of arterial smooth muscle, we constructed concentration-response curves for TCB2 (5-HT2A-receptor agonist), BW723C86 (5 HT2B-receptor agonist), and 5-HT in the presence of various inhibitors using endothelium-denuded preparations. Carotid arterial expressions of monoamine oxidase-A (MAO-A), serotonin transporter (SERT), and 5-HT2A were detected by immunoblotting. 5-HT-induced contraction was increased in carotid arteries from GK compared to control Wistar rats in both endothelium-intact and -denuded preparations. In denuded preparations, we found that: (1) TCB2-induced contraction was increased in GK rat arteries (vs. Wistar); (2) MAO-A inhibitor did not affect 5-HT-induced contraction, whereas SERT inhibitor augmented such contractions in both groups; and (3) differences in 5-HT-induced contractions were abolished by p38 MAPK, PI3K, and Rho kinase inhibitors. Carotid arterial expressions of MAO-A, SERT, and 5-HT2A remained unchanged in the groups. The results suggest that 5-HT-induced contraction is augmented in T2D GK rat carotid arteries. This augmentation is due to smooth muscle activation partly mediated by p38 MAPK, PI3K, and Rho kinases, and may also be partly due to arterial SERT activity. PMID- 25034166 TI - Statin: new life for an old drug. PMID- 25034167 TI - Proposal of e-learning strategy to teach Atraumatic Restorative Treatment (ART) to undergraduate and graduate students. AB - BACKGROUND: The aim of this study was to evaluate e-learning strategy in teaching Atraumatic Restorative Treatment (ART) to undergraduate and graduate students. The sample comprised 76 participants-38 dental students and 38 pediatric dentistry students-in a specialization course. To evaluate knowledge improvement, participants were subjected to a test performed before and after the course. RESULTS: A single researcher corrected the tests and intraexaminer reproducibility was calculated (CCI = 0.991; 95% IC = 0.975-0.996). All students improved their performances after the e-learning course (Paired t-tests p < 0.001). The means of undergraduate students were 4.7 (initial) and 6.4 (final) and those of graduate students were 6.8 (initial) and 8.2 (final). The comparison of the final evaluation means showed a statistically significant difference (t tests p < 0.0001). CONCLUSIONS: The e-learning strategy has the potential of improving students' knowledge in ART. Mature students perform better in this teaching modality when it is applied exclusively via distance learning. PMID- 25034175 TI - A cross-cultural study to assess measurement invariance of the KIDSCREEN-27 questionnaire across Serbian and Iranian children and adolescents. AB - PURPOSE: The KIDSCREEN questionnaire for health-related quality of life (HRQOL) assessments in children and adolescents was simultaneously developed across 13 European countries, and it was subsequently translated and culturally adapted to over 30 different languages across the world. The aim of this study was to evaluate the measurement equivalence of the KIDSCREEN-27 across Serbian and Iranian children and adolescents. METHODS: The items in the KIDSCREEN-27 were analyzed for differential item functioning (DIF) across Iranian and Serbian populations using ordinal logistic regression with three different criteria. The sample included 330 Iranian and 329 Serbian children and adolescents and 330 and 314 of their parents, respectively. RESULTS: Across the two samples, DIF was detected in 16 (59 %) of 27 items in the child self-reports and in 20 (74 %) of 27 items in the parent/proxy report. However, using alternative criteria based on magnitude detected for DIF, only three items in the parent/proxy report showed significant DIF. CONCLUSION: Our study provided more evidence that the KIDSCREEN 27 possesses DIF items across different cultures, but their impact is probably small, and the questionnaire could be used for cross-cultural HRQOL comparisons. PMID- 25034176 TI - Lens-care-solution-induced alterations in dynamic interfacial properties of human tear-lipid films. AB - PURPOSE: To evaluate the influence of lens care solutions (LCS) on interfacial dynamics and rheological properties of human tear-lipid films. METHODS: Tear lipids were extracted from Schirmer strips collected from 6 healthy subjects. Sessile bubble tensiometry was used to study interfacial properties at 22 degrees C. Lipids were deposited on an air bubble immersed into electrolytes solution to form 90+/-20nm films. Lipid films were subjected to expansion-compression cycles for dynamic interfacial properties and to step-strain relaxations for assessments of rheological properties. LCS (BioTrue [BT], PureMoist [PM], Revitalens [RL], ClearCare [CC]) were injected into optical chamber and equilibrated for 2h without or with lipid films. Dynamic interfacial properties of films were measured. Then electrolyte solution was pumped through chamber and properties of films were re-evaluated. RESULTS: Equilibrium surface tension (EST), elasticity modulus (E), and relaxation times (tau) of tear lipids were 22+/-2.1mN/m, 10.7 14.8mN/m, and 80-150s, respectively. EST for LCS was 43.6+/-0.2 for CC, 38.3+/ 0.2 for BT, 36.5+/-1.2 for RL, and 32.8+/-0.2mN/m for PM. [corrected]. E for LCS varied within 0.5-6.7mN/m, and tau varied from 49 to 68+/-5s. For mixed lipids+LCS films, EST remained unchanged whereas E and tau were reduced for all LCS types. Exposure to PM and RL noticeably altered the shape of lipid-film iso cycles. These changes persisted after LCS washout. CONCLUSIONS: Some components of LCS bind irreversibly to lipid films and make them less viscous and less elastic. These findings suggest the possibility of tear-film destabilization upon LCS exposure. PMID- 25034177 TI - Protective effect of SGK1 in rat hippocampal neurons subjected to ischemia reperfusion. AB - BACKGROUND/AIMS: To investigate the protective effect of SGK1 (serum- and glucocorticoid-inducible protein kinase 1) in rat hippocampal neurons in vitro and in vivo following ischemia reperfusion (I/R). METHODS: Isolated rat hippocampal neurons were subjected to 2 h of oxygen and glucose deprivation (OGD) then returned to normoxic conditions for 10, 30 or 60 min. Cell apoptosis and protein expression of SGK1 were analyzed. To examine SGK1 function, we overexpressed SGK1 in rat hippocampal neurons. Finally we examined the involvement of PI3K/Akt/GSK3beta signaling by treating the cells (untransfected or transfected with expression vector encoding SGK1) with the PI3K inhibitor LY294002. Findings were confirmed in vivo in a rat model of middle cerebral artery occlusion. RESULTS: I/R caused a time-dependent increase in apoptosis, both in vitro and in vivo. SGK1 protein levels decreased significantly under the same conditions. Overexpression of SGK1 reduced apoptosis following OGD or I/R compared to cells transfected with empty vector and subjected to the same treatment, or sham-operated animals. Addition of LY294002 revealed that the action of SGK1 in suppressing apoptosis was mediated by the PI3K/Akt/GSK3beta pathway. CONCLUSION: SGK1 plays a protective role in ischemia reperfusion in rat hippocampal neurons, exerting its effects via the PI3K/Akt/GSK3beta pathway. PMID- 25034178 TI - Intraperitoneal and intravenous deliveries are not comparable in terms of drug efficacy and cell distribution in neonatal mice with hypoxia-ischemia. AB - BACKGROUND AND PURPOSE: Most therapeutic agents are administered intravenously (IV) in clinical settings and intraperitoneally (IP) in preclinical studies with neonatal rodents; however, it remains unclear whether intraperitoneal (IP) injection is truly an acceptable alternative for intravenous (IV) injection in preclinical studies. The objective of our study is to clarify the differences in the therapeutic effects of drugs and in the distribution of infused cells after an IP or IV injection in animals with brain injury. METHODS: Dexamethasone or MK 801, an N-methyl-d-aspartate receptor antagonist was administered either IP or IV in a mouse model of neonatal hypoxic-ischemic encephalopathy. Green fluorescent protein-expressing mesenchymal stem cells (MSCs) or mononuclear cells (MNCs) were injected IP or IV in the mouse model. Two hours and 24h after the administration of the cells, we investigated the cell distributions by immunohistochemical staining. We also investigated distribution of IV administered MNCs labeled with 2-[18F]fluoro-2-deoxy-d-glucose in a juvenile primate, a macaque with stroke 1h after the administration. RESULTS: IP and IV administration of dexamethasone attenuated the brain injury to a similar degree. IP administration of MK-801 attenuated brain injury, whereas IV administration of MK-801 did not. The IV group showed a significantly greater number of infused cells in the lungs and brains in the MSC cohort and in the spleen, liver, and lung in the MNC cohort compared to the IP group. In the macaque, MNCs were detected in the spleen and liver in large amounts, but not in the brain and lungs. CONCLUSIONS: This study demonstrated that the administration route influences the effects of drugs and cell distribution. Therefore, a preclinical study may need to be performed using the optimal administration route used in a clinical setting. PMID- 25034179 TI - Cutaneous or respiratory exposures to peanut allergens in mice and their impacts on subsequent oral exposure. AB - BACKGROUND: Recent data suggested that non-gastrointestinal exposure can lead to sensitisation to food allergens. We thus assessed the immune impact of respiratory or cutaneous exposure to peanut proteins on non-altered epithelium and investigated the effect of such pre-exposure on subsequent oral administration of peanut. METHODS: BALB/cJ mice were exposed to purified Ara h 1 or to a non-defatted roasted peanut extract (PE) by simple deposit of allergens solutions on non-altered skin or in the nostrils. Exposures were performed 6 times at weekly intervals. Pre-exposed mice then received intra-gastric administrations of PE alone or in the presence of the Th2 mucosal adjuvant cholera toxin (CT). The specific humoral and cellular immune response was assessed throughout the protocol. RESULTS: Both cutaneous and respiratory exposures led to the production of specific IgG1. Local and systemic IL-5 and IL 13 production were also evidenced, demonstrating activation of specific Th2 cells. This effect was dose-dependent and most efficient via the respiratory route. Moreover, these pre-exposures led to the production of specific IgE antibodies after gavage with PE, whatever the presence of CT. CONCLUSIONS: Cutaneous or respiratory exposures to peanut induce Th2 priming in mice. Moreover, pre-exposures promote further sensitisation via the oral route without the use of CT; this proposes a new adjuvant-free experimental model of sensitisation to food that may reflect a realistic exposure pattern in infants. These results also suggest that non-gastrointestinal peanut exposure should be minimised in high-risk infants, even those with non-altered skin, to potentially reduce allergic sensitisation to this major food allergen. PMID- 25034180 TI - Relationship between acid-base status and inflammation in the critically ill. AB - INTRODUCTION: There is a complex interplay between changes in acid-base components and inflammation. This manuscript aims to explore associations between plasma cytokines and chemokines and acid-base status on admission to intensive care. METHODS: We conducted a prospective cohort study in a 13-bed ICU in a tertiary-care center in Brazil. 87 unselected patients admitted to the ICU during a 2-year period were included. We measured multiple inflammatory mediators in plasma using multiplex assays and evaluated the association between mediator concentrations and acid-base variables using a variety of statistical modeling approaches, including generalized linear models, multiadaptive regression splines and principal component analysis. RESULTS: We found a positive association between strong ion gap (SIG) and plasma concentrations of interleukin (IL)6, 8, 10 and tumor necrosis factor (TNF); whereas albumin was negatively associated with IL6, IL7, IL8, IL10, TNF and interferon (IFN)alpha. Apparent strong ion difference (SIDa) was negatively associated with IL10 and IL17. A principal component analysis including SAPS 3 indicated that the association between acid base components and inflammatory status was largely independent of illness severity, with both increased SIG and decreased SIDa (both drivers of acidosis) associated with increased inflammation. CONCLUSION: Acid-base variables (especially increased SIG, decreased albumin and decreased SIDa) on admission to ICU are associated with immunological activation. These findings should encourage new research into the effects of acid-base status on inflammation. PMID- 25034181 TI - Catalytic performance of functionalized polyurethane foam on the reductive decolorization of Reactive Red K-2G in up-flow anaerobic reactor under saline conditions. AB - Soluble anthraquinone compounds including anthraquinone-2-sulfonate (AQS) and anthraquinone-2,6-disulfonate can accelerate anaerobic decolorization of azo dyes. To realize the application of these compounds, the catalytic performance and stability of AQS-modified polyurethane foam (AQS-PUF) for Reactive Red K-2G decolorization were investigated in an up-flow anaerobic bioreactor under saline conditions. The results showed that the optimal influent pH value and hydraulic retention time were 7 and 10 h, respectively, in a continuous-flow bioreactor amended with AQS-PUF (R1). Under the above conditions, R1 (93.8 % color removal) displayed better decolorization performance than the bioreactor amended with PUF (R2, 64 % color removal) in 10 days, when influent K-2G concentration was 50 mg/L. Moreover, compared with R2, R1 could more effectively cope with 50-400 mg/L K-2G and exhibited better stability with over 85 % color removal efficiency within 75 days. Further bacterial community analysis using polymerase chain reaction-denaturing gradient gel electrophoresis showed that AQS-reducing bacteria played an important role in accelerating K-2G decolorization in R1. Extracellular polymeric substances analysis found that biofilm formed on AQS-PUF had very limited negative effects on K-2G decolorization. The catalytic performance of used AQS-PUF only decreased less than 9 % in batch experiments. These findings indicate that AQS-PUF has potential application for the treatment of azo dye-containing wastewater. PMID- 25034182 TI - Comparing in situ removal strategies for improving styrene bioproduction. AB - As an important conventional monomer compound, the biological production of styrene carries significant promise with respect to creating novel sustainable materials. Since end-product toxicity presently limits styrene production by previously engineered Escherichia coli, in situ product removal by both solvent extraction and gas stripping were explored as process-based strategies for circumventing its inhibitory effects. In solvent extraction, the addition of bis(2-ethylhexyl)phthalate offered the greatest productivity enhancement, allowing net volumetric production of 836 +/- 64 mg/L to be reached, representing a 320 % improvement over single-phase cultures. Gas stripping rates, meanwhile, were controlled by rates of bioreactor agitation and, to a greater extent, aeration. A periodic gas stripping protocol ultimately enabled up to 561 +/- 15 mg/L styrene to be attained. Lastly, by relieving the effects of styrene toxicity, new insight was gained regarding subsequent factors limiting its biosynthesis in E. coli and strategies for future strain improvement are discussed. PMID- 25034183 TI - Comparison of intracardiac echocardiography and transesophageal echocardiography for imaging of the right and left atrial appendages. AB - BACKGROUND: Transesophageal echocardiography (TEE) is the standard for diagnosis of atrial thrombi and is performed before ablation of atrial arrhythmias. Intracardiac echocardiography (ICE) is routinely used during these procedures and may provide an alternative imaging modality. OBJECTIVE: The purpose of this study was to compare TEE and ICE for right atrial appendage (RAA) and left atrial appendage (LAA) anatomy and thrombus. METHODS: This prospective blinded study enrolled 71 patients with atrial arrhythmias who presented for ablation. TEE and ICE were performed simultaneously to assess the RAA and LAA for thrombi, spontaneous echo contrast, and dimensions. ICE images were acquired sequentially from the right atrium, right ventricular outflow tract, and the pulmonary artery. RESULTS: Imaging of the RAA and LAA was achieved in all 71 patients using ICE but in only in 69 patients using TEE because of inability to intubate the esophagus. A total of 4 thrombi were diagnosed (3 LAA, 1 RAA). All were detected by ICE but only 1 by TEE. Diagnostic imaging of the LAA was achieved in 71 patients (100%) with ICE and in 62 patients (87.3%) with TEE (P < .002). Spontaneous echo contrast was more commonly diagnosed with ICE (P < .01). There was strong correlation between TEE and ICE for length (r = 0.71), width (r = 0.94), and area (r = 0.88) of the LAA. Image quality with ICE was highest from the pulmonary artery and lowest from the right atrium. CONCLUSION: ICE imaging is a viable alternative to TEE for visualization of the LAA and RAA during catheter ablation procedures. PMID- 25034184 TI - High-degree atrioventricular block in patients with preexisting bundle branch block or bundle branch block occurring during transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become the standard therapy for high-risk and non-operable patients with severe aortic stenosis. However, the procedure involves several adverse effects, such as rhythm and conduction disturbances. Patients with postprocedural left bundle branch block may have an increased mortality risk, whereas patients with preprocedural right bundle branch block display a higher rate of postinterventional bradyarrhythmias. OBJECTIVE: The purpose of this study was to investigate the occurrence of high-degree atrioventricular block (AVB) in patients with preexisting bundle branch block (BBB) or BBB occurring during TAVI. METHODS: In this prospective single-center study, 50 consecutive patients undergoing TAVI with the Medtronic CoreValve Revalving System were included. Of these patients, 17 with preexisting BBB or BBB occurring during TAVI received a primary prophylactic permanent DDD pacemaker, programmed to the SafeR-mode and featuring dual-channel event counters as well as stored intracardiac electrograms. Pacemaker readouts and intracardiac electrograms were analyzed for the occurrence of high-degree AVB. RESULTS: Ten of 17 patients (58.8%) with preexisting BBB or BBB occurring during TAVI developed episodes of high-degree AVB that were immediately terminated due to switch into DDD backup pacing. In 5 of the cases (29.4%), the first documented episode of high-degree AVB occurred after hospital discharge. Mean follow-up period was 578.1 +/- 294.9 days. CONCLUSION: Development of high-degree AVB is a common complication in patients with preexisting BBB or BBB occurring during TAVI. Accordingly, intensified monitoring might be reasonable, especially in patients treated with the self-expandable Medtronic CoreValve Revalving System. PMID- 25034186 TI - Tension-type headache in Parma's adult general population: a focus on age of onset. AB - In the present paper, we focus on the age of onset for tension-type headache in a population-based sample in the Parma, distinguishing its different subtypes and considering definite and probable diagnoses. Age of headache onset is a useful clinical feature for differential diagnosis between primary headaches and between primary and secondary headache forms. A total of 904 subjects representative of the Parma's adult general population were interviewed face to face by a physician from the Parma Headache Centre, using a validated questionnaire specially designed for the diagnosis of primary headaches according to the ICHD-II criteria. In the majority of subjects diagnosed with definite tension-type headache, age of onset was 39 years or less, while mean age of onset was 29.7 years (SD 16.3 years, range 5-79 years), the median being 25 years. Both infrequent and frequent episodic definite tension-type headache first occurred in the majority of cases in the second, third and fourth decades. Subjects with chronic definite tension-type headache reported a later onset in life (i.e. fourth, fifth and sixth decades). In our study, mean age of onset for probable tension-type headache was 23.7 years (SD 9.2 years, range 10-40 years) and the median was 22 years. In no case did we find significant gender differences. Our study results are similar to most of those reported in the literature. Further research needs to be done in the Italian epidemiological context, given the lack of literature reports on this topic. PMID- 25034185 TI - Sleep disturbance and cognitive disorder: epidemiological analysis in a cohort of 263 patients. AB - The aim of this study was to investigate and describe frequency and characteristics of sleep disorders in a large cohort of community dwelling persons with several degrees and typologies of cognitive disorders. 236 patients (78 men and 158 women) were enrolled with different subtypes of dementia: Alzheimer's disease (AD), vascular dementia (VaD), mixed dementia, mild cognitive impairment (MCI), dementia with Lewy bodies (DLB), parkinson's disease dementia (PDD), and frontotemporal lobar degeneration (FTLD), respectively. The sleep disturbances evaluated were: insomnia, excessive daytime sleepiness (EDS), REM behavior disorder (RBD), restless legs syndrome (RLS), and nightmares. Every type of sleep disorder was present in each type of dementia but with significant differences. Insomnia is found to be more present and specific for AD; EDS was associated with the presence of dementia in the elderly with LBD or PDD; RLS and nightmares that were recognized mainly in FTD, LBD, and PDD patients scores; patients with MCI had a frequency of sleep disturbances of any type equal to that of patients with AD presenting mostly insomnia, nightmares or RLS more frequently; nightmares were more frequent among LBD and PDD patients. Frequency of RDB was more frequent in FTD, AD, and VaD. Our findings demonstrate that sleep disturbance was related to dementia. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. PMID- 25034187 TI - An unusual case of paradoxical embolism in a young patient affected by stroke. PMID- 25034188 TI - Non-occupational task-specific masticatory dystonia. PMID- 25034189 TI - Comparison of artificial cervical arthroplasty versus anterior cervical discectomy and fusion for one-level cervical degenerative disc disease: a meta analysis of randomized controlled trials. AB - PURPOSE: The aim of the study was to evaluate whether there is a superior clinical effect of artificial cervical arthroplasty compared with anterior cervical discectomy and fusion (ACDF) for the treatment of one-level cervical degenerative disc disease (CDDD). METHODS: A comprehensive literature search of multiple databases, including PubMed, ScienceDirect, Scopus, Embase, Cochrane Central Register of Controlled Trials, was conducted to identify studies that met the inclusion criteria. Methodological quality was assessed and relevant data were extracted, and if appropriate, meta-analysis was performed. RESULTS: Thirteen randomized controlled trials were identified. At 24 months post operatively, total disc replacement (TDR) was demonstrated to be more beneficial for patients compared with ACDF for the following outcomes: neurological success [odds ratio (OR) 1.92; 95% confidence interval (CI) 1.47-2.49; p < 0.00001], range of motion [mean differences (MD), 6.67; 95% CI 4.82-8.53; p < 0.00001], secondary surgical procedures (OR 0.50; 95% CI 0.37-0.68; p < 0.00001), and visual analogue scale neck pain scores (MD -5.99; 95% CI -10.54 to -1.45; p = 0.001) and visual analogue scale arm pain scores (MD -3.23; 95% CI -6.48 to 0.02; p = 0.004). Other outcomes, including length of the hospital stay (MD -0.03; 95% CI -0.18 to 0.12; p = 0.68), blood loss (MD 6.92 mL; 95% CI -3.09 to 16.92 mL; p = 0.18), Neck Disability Index scores (MD -1.00; 95% CI -5.28 to 3.28; p = 0.65) and rate of adverse events [risk ratio (RR), 0.93; 95% CI 0.76-1.15; p = 0.52] demonstrated no differences between the 2 groups. Although the TDR group had a significantly longer operation time than the ACDF group, it was not considered clinically important. CONCLUSIONS: For patients with one-level CDDD, TDR was found to be more superior than ACDF in terms of neurological success, secondary surgical procedures, visual analogue scale pain scores and range of motion at 24 months post-operatively. Therefore, cervical arthroplasty is a safe and effective surgical procedure for treating one-level CDDD. We suggest adopting TDR on a large scale; with failure of TDR, ACDF would be performed. PMID- 25034191 TI - Screening of biosurfactant producers from petroleum hydrocarbon contaminated sources in cold marine environments. AB - An overview of literature about isolating biosurfactant producers from marine sources indicated no such producers have been reported form North Atlantic Canada. Water and sediment samples were taken from petroleum hydrocarbon contaminated coastal and offshore areas in this region. Either n-hexadecane or diesel was used as the sole carbon source for the screening. A modified colony based oil drop collapsing test was used to cover sessile biosurfactant producers. Fifty-five biosurfactant producers belong to genera of Alcanivorax, Exiguobacterium, Halomonas, Rhodococcus, Bacillus, Acinetobacter, Pseudomonas, and Streptomyces were isolated. The first three genera were established after 1980s with interesting characteristics and limited relevant publications. Some of the 55 isolated strains were found with properties such as greatly reducing surface tension, stabilizing emulsion and producing flocculant. Isolates P6-4P and P1-5P were selected to demonstrate the performance of biosurfactant production, and were found to reduce the surface tension of water to as low as 28 dynes/cm. PMID- 25034192 TI - [Spontaneous retropharyngeal emphysema: a rare clinical entity]. PMID- 25034193 TI - [High-flow oxygen therapy in a hospital ward]. PMID- 25034194 TI - Serum paraoxonase 1 activity and oxidative stress in pediatric patients with pulmonary tuberculosis. AB - OBJECTIVES: The aim of this study was to determine the oxidative stress and paraoxonase 1 (PON1) levels in children with pulmonary tuberculosis (TB) compared to healthy controls, and to examine the association of demographical with oxidative stress. SUBJECTS AND METHODS: Forty children diagnosed with pulmonary TB and 40 age- and gender-matched healthy controls were enrolled in the study. Serum total antioxidant status (TAS), total oxidant status (TOS) and PON1 levels were measured. The oxidative stress index (OSI) was calculated to indicate the degree of oxidative stress. RESULTS: The TAS levels were lower (1.73 +/- 0.5 vs. 2.54 +/- 1.2 MUmol Trolox Eq/l) while TOS levels were significantly higher (26.9 +/- 14.4 vs. 13.4 +/- 7.7 MUmol H2O2 Eq/l) in the TB group than in the controls (p < 0.001). The OSI was significantly higher in the TB group than in the controls (21.2 +/- 5.1 vs. 6.5 +/- 4.9 units, p = 0.006). Serum PON1 levels were significantly lower in the TB group than in the controls (14.2 +/- 13.2 vs. 28.4 +/- 17.3 U/l, p < 0.001). The lower PON1 levels correlated with TAS and OSI levels but not with anthropometric parameters (r = 0.264, p = 0.018 and r = 0.255, p = 0.023, respectively). CONCLUSION: The TOS and OSI levels were higher and the TAS and PON1 levels were lower in pediatric patients with pulmonary TB when compared to healthy controls. This indicates greater oxidative stress in the patients. PMID- 25034195 TI - A highly selective water-soluble optical probe for endogenous peroxynitrite. AB - A colorimetric and fluorescent probe C-Py-1 for ONOO(-) was prepared and it could exhibit high sensitivity and excellent selectivity toward ONOO(-) among reactive oxygen species (ROS) and reactive nitrogen species (RNS) with a rapid response time in 100% water solution. Meanwhile, C-Py-1 was successfully applied in the imaging of endogenous ONOO(-) in RAW264.7 cells. PMID- 25034196 TI - Administrative data on diagnosis and mineralocorticoid receptor antagonist prescription identified patients with primary aldosteronism in Taiwan. AB - OBJECTIVES: To develop algorithms of locating patients with primary aldosteronism (PA) using insurance reimbursement data and to validate the algorithms using medical charts. STUDY DESIGN AND SETTING: We extracted National Health Insurance (NHI) reimbursement data and medical charts in seven enrolled hospitals and analyzed diagnosis-related information for 1999-2010. The NHI codes PA as 255.1x, using the International Classification of Diseases, Ninth Revision, Clinical Modification. Confirmation of PA was based on suppression tests. RESULTS: We reviewed medical charts for 1,094 cases with at least one PA diagnosis. PA was confirmed for 563 cases. Compared with patients with essential hypertension, PA patients had higher systolic blood pressure, higher aldosterone, lower renin activity, and lower potassium level (all P-values <0.05). An algorithm based on PA diagnosis reported in at least one hospital stay or three outpatient visits had modest performance (sensitivity = 0.94 and specificity = 0.20). The best additional condition for the algorithm was use of mineralocorticoid receptor antagonist (MRA; sensitivity = 0.89 and specificity = 0.88). CONCLUSION: Using information on PA diagnosis and MRA prescription reported in insurance claims data can precisely locate PA patients in high-risk groups. This algorithm can construct a reliable PA sample for conducting research in various fields, including epidemiology and clinical practice. PMID- 25034197 TI - Is there a solution to publication bias? Researchers call for changes in dissemination of clinical research results. AB - OBJECTIVES: To explore opinions of authors of published reports of clinical trials and Cochrane systematic reviews on the causes and methods of preventing publication bias. STUDY DESIGN AND SETTING: An online questionnaire was developed and sent to researchers publishing in high-impact or national general medical journals, authors of Cochrane systematic reviews, and a general population of researchers. Open-ended questions about publication bias were qualitatively analyzed. We also held a focus group with experienced researchers and/or Cochrane reviewers. RESULTS: Publication bias was common: 48 (36%) respondents had own unpublished trials and 40 (30%) admitted selective outcome reporting; but researchers felt strongly that blame rested also with the system that promotes and augments publication bias practices. Qualitative analysis of both survey responses and focus group discussion identified possible ways of reducing publication bias through increased transparency, improvements to trial registries, search engines and databases, enhancement of the role of institutional review boards, positive encouragement of scientists, and policy changes. CONCLUSION: Although well aware of the problem, clinical researchers knowingly contribute to problems of selective reporting and nonpublication of trials. They call for changes in current practices of journal-based communication of trial reporting and for systematic evaluation of measures to decrease publication bias. PMID- 25034198 TI - Scoping reviews: time for clarity in definition, methods, and reporting. AB - OBJECTIVES: The scoping review has become increasingly popular as a form of knowledge synthesis. However, a lack of consensus on scoping review terminology, definition, methodology, and reporting limits the potential of this form of synthesis. In this article, we propose recommendations to further advance the field of scoping review methodology. STUDY DESIGN AND SETTING: We summarize current understanding of scoping review publication rates, terms, definitions, and methods. We propose three recommendations for clarity in term, definition and methodology. RESULTS: We recommend adopting the terms "scoping review" or "scoping study" and the use of a proposed definition. Until such time as further guidance is developed, we recommend the use of the methodological steps outlined in the Arksey and O'Malley framework and further enhanced by Levac et al. The development of reporting guidance for the conduct and reporting of scoping reviews is underway. CONCLUSION: Consistency in the proposed domains and methodologies of scoping reviews, along with the development of reporting guidance, will facilitate methodological advancement, reduce confusion, facilitate collaboration and improve knowledge translation of scoping review findings. PMID- 25034199 TI - A summary to communicate evidence from systematic reviews to the public improved understanding and accessibility of information: a randomized controlled trial. AB - OBJECTIVES: To evaluate a new format of a summary, which presents research from synthesized evidence to patients and the public. STUDY DESIGN AND SETTING: We conducted a randomized controlled trial in 143 members of the public from five countries (Canada, Norway, Spain, Argentina, and Italy). Participants received either a new summary format (a plain language summary [PLS]) or the current format used in Cochrane systematic reviews. The new PLS presents information about the condition and intervention, a narrative summary of results, and a table of results with absolute numbers for effects of the intervention and quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: With the new PLS, more participants understood the benefits and harms and quality of evidence (53% vs. 18%, P < 0.001); more answered each of the five questions correctly (P <= 0.001 for four questions); and they answered more questions correctly, median 3 (interquartile range [IQR]: 1-4) vs. 1 (IQR: 0 1), P < 0.001). Better understanding was independent of education level. More participants found information in the new PLS reliable, easy to find, easy to understand, and presented in a way that helped make decisions. Overall, participants preferred the new PLS. CONCLUSION: This new PLS format for patients and the public is a promising tool to translate evidence from synthesized research. PMID- 25034200 TI - Percutaneous-based management of Staghorn calculi in solitary kidney: combined mini percutaneous nephrolithotomy versus retrograde intrarenal surgery. AB - INTRODUCTION: Mini percutaneous nephrolithotomy (mini-PCNL) and retrograde intrarenal surgery (RIRS) are well-established techniques with little morbidity. The combined use of standard PCNL and the mini-PCNL or the RIRS technique was evaluated and compared to investigate their own role in the management of staghorn calculi in solitary kidney. MATERIALS AND METHODS: 23 patients received combined standard PCNL and mini-PCNL (group 1), and 22 patients received combined standard PCNL and RIRS (group 2). The treatment results and complications were evaluated and compared. RESULTS: The mean operation time was 128.8 +/- 9.1 min in group 1 and 109.8 +/- 10.7 min in group 2 (p < 0.001). The decrease in hemoglobin level in group 1 was significantly higher than that in group 2 (3.5 +/- 0.6 vs. 2.1 +/- 0.5 g/dl, p < 0.001). The final stone-free rate was significantly higher (p = 0.038) in group 2 (90.9%) than in group 1 (65.2%). CONCLUSIONS: Combined standard PCNL and RIRS technique can extract the majority of staghorn calculi quickly by PCNL with EMS Lithoclast, and RIRS used simultaneously can reduce the need for multiple tracts and therefore reduce blood loss and potential morbidity related to multiple tracts, shorten the operation time and achieve a high stone free rate. PMID- 25034201 TI - Single-molecule analysis of transcription factor binding at transcription sites in live cells. AB - Although numerous live-cell measurements have shown that transcription factors (TFs) bind chromatin transiently, no measurements of transient binding have been reported at the endogenous response elements (REs) where transcription is normally induced. Here we show that at endogenous REs the transcriptionally productive specific binding of two TFs, p53 and the glucocorticoid receptor (GR), is transient. We also find that the transient residence times of GR at endogenous REs are roughly comparable to those at an artificial, multi-copy array of gene regulatory sites, supporting the use of multi-copy arrays for live-cell analysis of transcription. Finally, we find that at any moment only a small fraction of TF molecules are engaged in transcriptionally productive binding at endogenous REs. The small fraction of bound factors provides one explanation for gene bursting and it also indicates that REs may often be unoccupied, resulting in partial responses to transcriptional signals. PMID- 25034202 TI - Dizziness after sports-related concussion: can physiotherapists offer better treatment than just 'physical and cognitive rest'? PMID- 25034203 TI - Impacts of agricultural irrigation on nearby freshwater ecosystems: the seasonal influence of triazine herbicides in benthic algal communities. AB - A small hydrological basin (Lerma, NE Spain), transformed from its natural state (steppe) to rain-fed agriculture and recently to irrigation agriculture, has been monitored across four seasons of an agricultural year. The goal of this study was to assess how and whether agricultural activities impacted the nearby freshwater ecosystems via runoff. Specifically, we assessed the toxicity of three triazine herbicides, terbuthylazine, atrazine and simazine on the photosynthetic efficiency and structure of algal benthic biofilms (i.e., phototropic periphyton) in the small creek draining the basin. It was expected that the seasonal runoff of the herbicides in the creek affected the sensitivity of the periphyton in accord with the rationale of the Pollution Induced Community Tolerance (PICT): the exposure of the community to pollutants result in the replacement of sensitive species by more tolerant ones. In this way, PICT can serve to establish causal linkages between pollutants and the observed biological impacts. The periphyton presented significantly different sensitivities against terbuthylazine through the year in accord with the seasonal application of this herbicide in the crops nowadays. The sensitivity of already banned herbicides, atrazine and simazine does not display a clear seasonality. The different sensitivities to herbicides were in agreement with the expected exposures scenarios, according to the agricultural calendar, but not with the concentrations measured in water, which altogether indicates that the use of PICT approach may serve for long-term monitoring purposes. That will provide not only causal links between the occurrence of chemicals and their impacts on natural communities, but also information about the occurrence of chemicals that may escape from traditional sampling methods (water analysis). In addition, the EC50 and EC10 of periphyton for terbuthylazine or simazine are the first to be published and can be used for impact assessments. PMID- 25034204 TI - Effects of hypolimnetic oxygen addition on mercury bioaccumulation in Twin Lakes, Washington, USA. AB - Twin Lakes, located on the Confederated Tribes of the Colville Indian Reservation in eastern Washington, USA, include North Twin Lake (NT) and South Twin Lake (ST). The mesotrophic, dimictic lakes are important recreational fishing sites for both warm-water bass and cold-water trout. To improve summertime cold-water habitat for trout in NT, dissolved oxygen (DO) addition to the hypolimnion, using liquid oxygen as an oxygen gas source, started in 2009. This study assessed mercury (Hg) in the water column, zooplankton and fish, and related water quality parameters, in Twin Lakes from 2009 to 2012. Because methylmercury (MeHg) buildup in lake bottom water is commonly associated with hypolimnetic anoxia, hypolimnetic oxygenation was hypothesized to reduce Hg in bottom waters and biota in NT relative to ST. Oxygen addition led to significantly higher DO (mean hypolimnetic DO: 2-8 mg/L versus <1 mg/L) and lower MeHg (peak mean hypolimnetic MeHg: 0.05-0.2 ng/L versus 0.15-0.4 ng/L) in North Twin. In North Twin, years with higher DO (2009 and 2011) exhibited lower MeHg in bottom waters and lower total Hg in zooplankton, inferring a positive linkage between oxygen addition and lower bioaccumulation. However, when comparing between the two lakes, Hg levels were significantly higher in zooplankton (total Hg range: 100-200 versus 50-100 MUg/kg dry weight) and trout (spring 2010 stocking cohort of eastern brook trout mean total Hg: 74.9 versus 49.9 MUg/kg wet weight) in NT relative to ST. Lower Hg bioaccumulation in ST compared to NT may be related to bloom dilution in chlorophyll-rich bottom waters, a vertical disconnect between the location of zooplankton and MeHg in the water column, and high binding affinity between sulfide and MeHg in bottom waters. PMID- 25034205 TI - Pesticide monitoring in the basin of Llobregat River (Catalonia, Spain) and comparison with historical data. AB - Through an extensive sampling in the Llobregat River basin, the presence of 50 currently used pesticides in water, sediment, and biota was assessed. Pesticides were detected primarily in water (up to 56% of the analytes), whereas their presence in sediments was more intermittent, and in biota was scarce. Those at high concentrations in water were the benzimidazoles (carbendazim in 22% of the samples up to 697 ng L(-1)), the organophosphorus (malathion in 54% of the samples up to 320 ng L(-1)), and the ureas (diuron in 54% of the samples up to 159 ng L(-1)). However, this pattern differed in sediments and biota, which were contaminated primarily with organophosphorus (higher Kow) (chlorpyrifos 93% of sediments up to 131 ng g(-1)). According to the results of this study, pesticide residues in the Llobregat River basin do not seem to represent a high risk to biota, even though some algae and fish can be affected. Nevertheless, the monitoring program can be very useful to control the contamination of the river basin, as the availability of historical data on the basin confirmed background contamination in the last 20 years. PMID- 25034206 TI - Oral bioaccessibility and human exposure to anthropogenic and geogenic mercury in urban, industrial and mining areas. AB - The objective of this study was to characterize the link between bioaccessibility and fractionation of mercury (Hg) in soils and to provide insight into human exposure to Hg due to inhalation of airborne soil particles and hand-to-mouth ingestion of Hg-bearing soil. Mercury in soils from mining, urban and industrial areas was fractionated in organometallic forms; mobile; semi-mobile; and non mobile forms as well as HCl-extractable Hg. The in vitro bioaccessibility of Hg was obtained by extracting soils with (1) a simulated human gastric fluid (pH1.5), and (2) a simulated human lung fluid (pH7.4). Total soil Hg concentrations ranged from 0.72 to 1.8 mg kg(-1) (urban areas), 0.28 to 94 mg kg( 1) (industrial area) and 0.92 to 37 mg kg(-1) (mining areas). Both organometallic Hg as well as 0.1M HCl extractable Hg were lower (<0.5% of total Hg) than Hg extracted by gastric fluid (up to 1.8% of total Hg) and lung fluid (up to 12% of total Hg). In addition, Hg extracted by lung fluid was significantly higher in urban and industrial soils (average 5.0-6.6% of total Hg) compared to mining soils. Such differences were related to levels of mobile Hg species in urban and industrial soils compared to mining soils. These results strengthen the need to measure site-specific Hg fractionation when determining Hg bioaccessibility. Results also show that ingestion and/or inhalation of Hg from soil particles can contribute up to 8% of adult total Hg intake when compared to total Hg intake via consumption of contaminated fish and animal products from contaminated areas. PMID- 25034207 TI - On the evolution of AIDS/HIV treatment: an optimal control approach. AB - After more than 30 years of continuous research as well as unselfish efforts, tremendous and exciting developments have been achieved towards the evolution of HIV treatments both in the directions of antiretroviral therapy and effective vaccine for HIV positive patients. Recent research shows that triple-drug antiretroviral therapy can 'functionally cure' [1, 2] the HIV positive patients, which is a milestone in the therapeutic treatments of AIDS. Despite the significant progress on the evolution of AIDS/HIV treatments, it is still a curse for the humanity and until today the world's most serious epidemic as well as leading infectious killer disease. However, Millennium Development Goals (MDGs) Getting to Zero shows a hope to build up a new world without AIDS. In this paper we investigate and focus on those issues of the overall present scenarios of AIDS treatment for the preventive strategies of HIV infections. A mathematical model is analyzed with numerical simulations showing its importance in diseases control and preventions. Optimal control theory is applied to compare the results in the presence of state constraints. PMID- 25034209 TI - Dog ownership has unknown risks but known health benefits: we need evidence based policy. PMID- 25034208 TI - HIV infection, antiretroviral therapy initiation and longitudinal changes in biomarkers of organ function. AB - BACKGROUND: HIV is associated with end-organ diseases of aging via unclear mechanisms. Longitudinally assessing how HIV infection and ART initiation affect biomarkers of end organ function/disease could clarify these mechanisms. We investigated longitudinal changes in clinical biomarkers following 1) HIV infection and 2) ART initiation with evidence of viral suppression. METHODS: COHORT: Veterans Aging COHORT Study Virtual COHORT (VACS VC). VACS VC is a longitudinal cohort of HIV infected (HIV+) and race-ethnicity, sex, age, and clinical site-matched uninfected Veterans enrolled in the same calendar year. INCLUSION CRITERIA: a negative and successively positive (>six months) HIV antibody test. We used Wilcoxon signedrank tests to analyze 1) the effect of HIV infection on lipids, renal, hepatic and hematologic/cardiovascular biomarkers and 2)whether ART initiation with HIV-1 RNA<500 cpm reverts any changes back to pre HIV levels. RESULTS: 422 Veterans had at least 1 biomarker measurement available prior to HIV infection and prior to ART initiation. 297 had at least 1 biomarker measurement available prior to HIV infection and after ART initiation with evidence of viral suppression. Mean age prior to HIV infection was 43 years. HIV infection was associated with reduction in total cholesterol, HDL cholesterol, LDL cholesterol, serum albumin, ALT, platelet count, hemoglobin and elevation of FIB-4 score and triglycerides. These changes occurred without significant changes in BMI. ART initiation (with HIV-1 RNA<500cpm) did not reverse alteration in triglycerides, LDL cholesterol, hemoglobin, or FIB-4 to pre-HIV infection levels. CONCLUSIONS: HIV infection is associated with longitudinal changes in serum levels of several biomarkers of end-organ function/disease and mortality. Multiple biomarkers (triglycerides, LDL cholesterol, hemoglobin, and FIB-4 ) remain altered from levels prior to HIV infection levels even following inititiation of ART and evidence of viral suppression. These results give insights into underlying mechanisms of increased risk for aging-related chronic diseases in the context of HIV infection. PMID- 25034210 TI - Differential regulation of TNF receptors in maternal leukocytes is associated with severe preterm preeclampsia. AB - We tested the hypothesis that maternal peripheral blood leukocytes contribute to elevated levels of soluble TNF receptors (sTNFR) in preeclampsia (PE) with concomitant intrauterine growth restriction (IUGR). TNFR1 and TNFR2 were evaluated in a cross-sectional study comparing preeclamptic (n = 15) with or without IUGR versus normotensive pregnant women (PREG, n = 30), and non-pregnant controls (Con; n = 20). Plasma levels of sTNFR1 were higher in PE (1675.0 +/- 227.1 pg/mL) compared with PREG (1035.0 +/- 101.1 pg/mL) and Con (589.3 +/- 82.67 pg/mL), with the highest values observed in PE with IUGR (2624.0 +/- 421.4 pg/mL; n = 6). Plasma sTNFR2 was higher during pregnancy (PE: 1836.0 +/- 198.7 pg/mL; PREG: 1697.0 +/- 95.0 pg/mL) compared with Con (598.3 +/- 82.7 pg/mL). Urinary levels of sTNFR1 and sTNFR2 were higher in PE and PREG compared with the Con group. Abundance of TNFR1 mRNA in peripheral blood leukocytes was strongly correlated with plasma levels of sTNFR1 in PE. However, TNFR2 mRNA accumulation in leukocytes did not correlate with sTNFR2 plasma levels. The level of sTNFR1 in plasma was correlated with body weight of the newborn (r = -0.56). The data suggest that maternal leukocytes contribute to sTNFR1 levels in plasma in association with decreasing newborn weight and PE with concomitant IUGR. PMID- 25034211 TI - Evaluation of the transporter-mediated herb-drug interaction potential of DA 9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo. AB - BACKGROUND: Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA 9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. METHOD: The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. RESULTS: DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC50 values of 106, 174, 48.1, and 273 MUg/mL, respectively, while the other transporters were not inhibited by 300 MUg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the Cmax of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. CONCLUSION: Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb drug interactions in rats even at its maximum effective dose. PMID- 25034212 TI - Eccrine hidrocystoma of the external auditory canal. PMID- 25034213 TI - Structural dissection of the C-terminal sterile alpha motif (SAM) of human p73. AB - The alpha splice variant of p73 (p73alpha), a homologue of the tumour suppressor p53, has at its C terminus a sterile alpha motif (SAM); this domain, SAMp73, is involved in lipid binding and it is thought to mediate in protein-protein interactions. SAMp73 is composed of five helices (alpha1-alpha5). In this work, we dissected SAMp73 in fragments encompassing the different helices, to study the conformational stability of the isolated elements of secondary structure. There was no evidence of stable residual helical structure in the isolated alpha1, alpha4 and alpha5 helices in aqueous solution, as shown by 2D-(1)H NMR and far-UV CD spectroscopies; those helices acquired native-like helical structure in the presence of 40% trifluoroethanol (TFE). The population of helical structure in alpha5 seemed to be driven by the indole moiety of Trp542, and it was enhanced by the presence of alpha4. On the other hand, helices alpha2 and 310(alpha3) had a tendency to self-associate even in TFE-water solutions. However, the short, aggregation-prone 310(alpha3) helix was key to attain the native-like fold of SAMp73, as suggested by experiments with non-covalent complexes among the peptides. PMID- 25034215 TI - Role of angiogenesis in bone repair. AB - Bone vasculature plays a vital role in bone development, remodeling and homeostasis. New blood vessel formation is crucial during both primary bone development as well as fracture repair in adults. Both bone repair and bone remodeling involve the activation and complex interaction between angiogenic and osteogenic pathways. Interestingly studies have demonstrated that angiogenesis precedes the onset of osteogenesis. Indeed reduced or inadequate blood flow has been linked to impaired fracture healing and old age related low bone mass disorders such as osteoporosis. Similarly the slow penetration of host blood vessels in large engineered bone tissue grafts has been cited as one of the major hurdle still impeding current bone construction engineering strategies. This article reviews the current knowledge elaborating the importance of vascularization during bone healing and remodeling, and the current therapeutic strategies being adapted to promote and improve angiogenesis. PMID- 25034214 TI - Ion transport in pigmentation. AB - Skin melanocytes and ocular pigment cells contain specialized organelles called melanosomes, which are responsible for the synthesis of melanin, the major pigment in mammals. Defects in the complex mechanisms involved in melanin synthesis and regulation result in vision and pigmentation deficits, impaired development of the visual system, and increased susceptibility to skin and eye cancers. Ion transport across cellular membranes is critical for many biological processes, including pigmentation, but the molecular mechanisms by which it regulates melanin synthesis, storage, and transfer are not understood. In this review we first discuss ion channels and transporters that function at the plasma membrane of melanocytes; in the second part we consider ion transport across the membrane of intracellular organelles, with emphasis on melanosomes. We discuss recently characterized lysosomal and endosomal ion channels and transporters associated with pigmentation phenotypes. We then review the evidence for melanosomal channels and transporters critical for pigmentation, discussing potential molecular mechanisms mediating their function. The studies investigating ion transport in pigmentation physiology open new avenues for future research and could reveal novel molecular mechanisms underlying melanogenesis. PMID- 25034217 TI - The role of prothrombotic factors in children with hemiplegic cerebral palsy. AB - AIM: Hemiplegic cerebral palsy (HCP) is a condition occurring as a consequence of a non-progressive damage of the brain with incomplete anatomical and physical development during the early period of life. Its etiology is multifactorial, with the cause remaining unexplained in the majority of cases. This study aims to investigate whether thrombophilic factors correlates with the etiology in children with HCP. METHODS: We included 36 children with HCP in the patient group, and 41 healthy children with no neurologic disorders in the control group. No significant difference was found between the two groups in terms of factor V leiden, methylenetetrahydrofolate reductase and prothrombin 20210A mutation frequency and protein C, protein S and antithrombin III levels. RESULTS: Homocysteine levels were significantly higher in the group of patients with HCP as compared to the control group (P=0.012). Because we could not identify the origin of hyperhomocysteinemia as congenital or acquired, the impact of hyperhomocysteinemia on HCP was considered insignificant. Each thrombophilic disorder was assessed in terms of relatedness to atrophy, periventricular leukomalacia, infarct, congenital anomaly and porencephalic cyst, respectively. No significant correlation was detected between thrombophilic disorders and cranial imaging findings. CONCLUSION: Our study has shown that thrombophilic factors are not involved in the etiology of HCP. PMID- 25034216 TI - The JDRF CCTN CGM TIME Trial: Timing of Initiation of continuous glucose Monitoring in Established pediatric type 1 diabetes: study protocol, recruitment and baseline characteristics. AB - BACKGROUND: Continuous glucose monitoring (CGM) has been shown to improve glucose control in adults with type 1 diabetes. Effectiveness of CGM is directly linked with CGM adherence, which can be challenging to maintain in children and adolescents. We hypothesize that initiating CGM at the same time as starting insulin pump therapy in pump naive children and adolescents with type 1 diabetes will result in greater CGM adherence and effectiveness compared to delaying CGM introduction by 6 months, and that this is related to greater readiness for making behaviour change at the time of pump initiation. METHODS/DESIGN: The CGM TIME Trial is a multicenter randomized controlled trial. Eligible children and adolescents (5-18 years) with established type 1 diabetes were randomized to simultaneous initiation of pump (Medtronic Veo(c)) and CGM (Enlite(c)) or to standard pump therapy with delayed CGM introduction. Primary outcomes are CGM adherence and hemoglobin A1C at 6 and 12 months post pump initiation. Secondary outcomes include glycemic variability, stage of readiness, and other patient reported outcomes with follow-up to 24 months. 144 (95%) of the 152 eligible patients were enrolled and randomized. Allowing for 10% withdrawals, this will provide 93% power to detect a between group difference in CGM adherence and 86% power to detect a between group difference in hemoglobin A1C. Baseline characteristics were similar between the treatment groups. Analysis of 12 month primary outcomes will begin in September 2014. DISCUSSION: The CGM TIME Trial is the first study to examine the relationship between timing of CGM initiation, readiness for behaviour change, and subsequent CGM adherence in pump naive children and adolescents. Its findings will advance our understanding of when and how to initiate CGM in children and adolescents with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrial.gov NCT01295788. Registered 14 February 2011. PMID- 25034218 TI - Is single incision pediatric endoscopic surgery more painful than standard laparoscopy in children? Personal experience and review of the literature. AB - AIM: It has been speculated that single incision pediatric endoscopic surgery (SIPES) in children could result in more postoperative pain given the device size for a child umbilicus. Herein, we compare the postoperative pain in children who underwent SIPES or standard laparoscopy (SL). METHODS: Patients who underwent SIPES via Olympus TriPortTM Access system between 2010 and 2011 were prospectively compared with SL controls (similar age, sex and type of operation). Primary endpoint was analgesic requirement (number of doses and dose/kg). A systematic review of the literature included all articles (2008-2012) comparing postoperative pain following transumbilical SIPES and SL in children. Data were analyzed using non-parametric tests. RESULTS: Ten patients (8 males, median age 9 years, range 4-15) underwent 11 SIPES procedures: appendicectomy (N.=6), orchidopexy (N.=2), cholecystectomy (N.=2), and total colectomy (N.=1). There was no difference in paracetamol requirement between SIPES (median 74 mg/kg, range 14 149) and SL (median 59 mg/kg, range 13-108, P=0.76) patients. Morphine was required by only two patients per group (no difference in dosage or frequency). Eight studies (2010-2012) comparing 334 SIPES vs. 343 SL patients were analysed. Three studies showed advantage of SIPES, and four no difference between SIPES and SL. One randomized trial reported greater pain in SIPES appendicectomy, but no difference with SL once patients were discharged home. CONCLUSION: SIPES does not seem to be associated with more postoperative pain than SL in children. In appropriate cases, SIPES is a valid alternative to SL for a good range of pediatric procedures. PMID- 25034219 TI - Does maternal obesity have an influence on feeding behavior of obese children? AB - AIM: Although the pathogenesis of childhood obesity is multi factorial, maternal obesity and parenting have major roles. The aim of this study was to evaluate the influence of maternal obesity on feeding practices toward their obese school children. METHODS: Obese children and adolescents referred to the pediatric endocrinology department were enrolled consecutively. Height and weight of all children and their mothers were measured. Maternal feeding practices were measured using an adapted version of the Child Feeding Questionnaire (CFQ). Answers were compared between obese (Body Mass Index [BMI] >= 30 kg/m2) and non obese mothers. RESULTS: A total of 491 obese subjects (292 girls, mean age 12.0 +/- 2.8 years) and their mothers participated in this study. A direct correlation between children's BMI and their mothers' BMI was found (P<0.001) both in girls (r = 0.372) and boys (r = 0.337). While 64.4% of mothers were found obese in the study, only half of them consider themselves as obese. No difference were found in the scores of the subscales "perceived responsibility", "restriction", "concern for child's weight" and "monitoring" between obese and non-obese mothers. Child's BMI-SDS positively correlated with mothers' personal weight perception, concern for child's weight and restriction after adjustment for child's age (P < 0.001, P = 0.012 and P = 0.002, respectively). CONCLUSION: Mothers' BMI highly correlate with children's BMI-z-scores. The degree of child's obesity increases mothers' concern and food restriction behavior. While mothers of obese children have a high prevalence of obesity, maternal obesity was found to have no significant influence on feeding behavior of obese school children. PMID- 25034220 TI - Drug-related problems in cardiac children. AB - BACKGROUND: A drug-related problem (DRP) may be defined as "an event or circumstance involving drug therapy that actually or potentially interferes with the desired health outcome". Our aim was to determine the frequency and characteristics of DRPs in pediatric patients admitted to a tertiary cardiac care center in the Egyptian capital, Cairo. METHODS: A prospective observational cohort study involving review of case notes for children aged 0-18 years, admitted to the medical ward and intensive care unit (ICU), was conducted at a tertiary cardiac care center in Egypt. Data collection took place over a three month period. Daily reviews of patients' records, medication charts and laboratory data were undertaken by the clinical pharmacists to identify DRPs. RESULTS: A total of 60 patients were included in the study (mean age 4.8 years; 53.33% males). Over a three-month period, a total of 313 DRPs were recorded corresponding to an average of 5.22 problems per patient. The most commonly recorded problems related to drug-drug interaction (45.69%), prescribing unnecessary medication (31.95%), under-dosing (21.09%), inappropriate medication (0.96%) and adverse drug reaction (0.32%). Prophylactic antibiotics represented the only unnecessarily prescribed medications. Of the pharmacist suggested interventions, 65% were accepted by the responsible physician. CONCLUSIONS: DRPs occurred frequently during the study period. Drug-drug interactions, drug choice and drug dosing problems represented the majority of the identified DRPs, necessitating targeted prescriber education interventions in these areas. There is a clear need for clinical pharmacists' involvement on the ward level to identify and rectify these frequently occurring and very costly problems. PMID- 25034221 TI - From the journal archives: masseter muscle rigidity: a dose-related drug effect or an early manifestation of a rare potentially fatal pharmacogenetic disorder. AB - Plumley MH, Bevan JC, Saddler JM, Donati F, Bevan DR. Dose-related effects of succinylcholine on the adductor pollicis and masseter muscles in children. Can J Anaesth 1990; 37: 15-20. PMID- 25034222 TI - Stroke-induced synergistic phase shifting and its possible implications for recovery mechanisms. AB - Among other diminished motor capabilities, survivors of a stroke often exhibit pathological joint synergies. With respect to the upper limbs, these deficits diminish coordination in reaching, pointing, and daily task performance. Past research on pathological synergies suggests that the synergistic relationship between joints is different for flexion than in extension. One explanation for different flexion and extension synergies is that there exists a time difference between the joint being volitionally moved and the joint that moves in synergy. The goal of this research was to measure these synergistic time differences. The experiment included 11 hemiparetic subjects who performed rhythmic elbow motions at five different frequencies. A motion capture system was used to record the resulting shoulder synergies. Synergistic shoulder rotations were found to exhibit frequency-dependent phase lags (delays) and leads (advances) in the paretic arm. Furthermore, the synergistic leads and lags varied with frequency and were subject specific. We found that timing differences between joints in pathological movements are comparable to differences that were observed by other researchers for normal, able-bodied movement synergies. Moreover, the fact that pathological synergies were evident in rhythmic motion suggests that they are spinal in origin. A significant amount research exists relating to able-bodied spinal synergies. Thus, the supposition that pathological synergies are an expression of normal synergies would tie disabled movement into a larger body of work related to able-bodied synergies. The rehabilitation implications of this possible connection are discussed. PMID- 25034223 TI - From nursing home to acute care: signs, symptoms, and strategies used to prevent transfer. AB - Older adults are vulnerable to experiencing physiologic changes that may permanently decrease functional abilities when transferring from the nursing home (NH) to the acute care setting. Making the right decision about who and when to transfer from the nursing home (NH) to acute care is critical for optimizing quality care. The specific aims of this study were to identify the common signs and symptoms exhibited by NH residents at the time of transfer to acute care and to identify strategies used to prevent transfer of NH residents. Using survey methodology, this descriptive study found change in level of consciousness, chest pressure/tightness, shortness of breath, decreased oxygenation, and muscle or bone pain were the highest ranked signs/symptoms requiring action. Actions to prevent transfer focused on stabilizing resident conditions and included hydration, oxygen, antibiotics, medications, symptom management, and providing additional physical assistance. When transfer was warranted, actions concentrated on the practical tasks of getting the residents transferred. PMID- 25034224 TI - Pilot research: it is what it is! PMID- 25034225 TI - Comparison of the efficacy of gefitinib in patients with non-small cell lung cancer according to the type of epidermal growth factor receptor mutation. AB - BACKGROUND: Exon 19 deletion and L858R point mutation of the epidermal growth factor receptor (EGFR) are the most commonly encountered EGFR mutations in non small cell lung cancer (NSCLC), and predict higher clinical outcomes following treatment with gefitinib. The objective of this study was to evaluate the differential clinical outcomes of gefitinib in patients with NSCLC according to the type of active EGFR mutation, i.e. exon 19 deletion or L858R point mutation. METHODS: We identified patients with advanced NSCLC harboring the exon 19 deletion or the L858R point mutation of EGFR who were on gefitinib treatment. The clinical outcomes were evaluated. RESULTS: Of the 124 patients with NSCLC harboring active EGFR mutations, the overall response rate, progression-free survival and overall survival were 60.5%, 11.3 and 27.3 months, respectively, and did not differ significantly between patients with the exon 19 deletion (61.8%, 11.3 and 32.2 months, respectively) and those with the L858R point mutation (58.9%, 9.0 and 27.7 months, respectively). CONCLUSION: It may be considered that there is no difference in the clinical efficacy of gefitinib between NSCLC patients who harbor the exon 19 deletion and those with the L858R point mutation. PMID- 25034226 TI - Differential association of child abuse with self-reported versus laboratory based impulsivity and risk-taking in young adulthood. AB - Young adults (ages 18-26) with (n = 20) and without (n = 55) a history of child abuse (CA) completed self-report and laboratory-based measures of impulsivity and risk-taking. Relative to individuals without abuse histories, individuals with a history of CA self-reported a greater number of lifetime sexual partners as well as elevated trait impulsivity (specifically, elevated lack of premeditation and lack of perseverance). No group differences were observed for self-reported safety-related behaviors and risk-taking propensity. Notably, however, laboratory based measures suggested that individuals with a history of CA showed significantly less impulsivity and risk-taking than individuals without abuse histories. These results suggest that self-report and laboratory measures of risk taking and impulsivity measured in emerging adulthood may differentially relate to CA. Specifically, whereas laboratory-based measures may be influenced by hypervigilance or in the moment actions, self-report measures may assess more general behaviors related to real-world impulsivity and risk-taking. PMID- 25034227 TI - Gamma irradiation of pollen and eradication of Israeli acute paralysis virus. AB - Honeybees and bumblebees are the most important pollinators of agricultural crops. For this purpose honeybees and bumblebees are reared and transported. A pathogen-free status of bees in general, is crucial. Indeed anthropogenic transports of hosts carrying parasites could alter the natural host/pathogen association, inducing an extra pathogenic stress. Therefore the creation of a pathogen-free rearing environment is needed. For bumblebees this is possible, as these species are reared in a closed environment. Although, a link remains between reared bumblebees and the outside bee community, as honeybee-collected pollen is essential food for bumblebee mass rearing. Here we evaluated if gamma irradiation can minimize the risk of this potential route of exposure and can inactivate viral particles present in honeybee-collected pollen. We show that 16.9kGy gamma irradiation induced a 100-1000 fold reduction on the ability of IAPV to cause mortality after injections. This result opens avenues toward rearing pathogen-free bumblebees and towards eliminating the risks of pathogen spillover to native wild bee species. PMID- 25034228 TI - An in vivo crosslinking system for identifying mycobacterial protein-protein interactions. AB - The analysis of protein-protein interactions in Mycobacterium tuberculosis has the potential to shed light on the functions of the large number of predicted open-reading frames annotated as conserved hypothetical proteins. We have developed a formaldehyde crosslinking system to detect in vivo interactions in mycobacteria. Our Gateway-adapted vector system uses three promoter strengths, including constitutive and regulatable versions, for the expression of target proteins with either an N- or C-terminal His-Strep-Strep tag. Tandem affinity purification using the His- and Strep-tags is well-suited to the isolation of protein complexes with a high purity and no detectable background. We have validated this approach using the well-described pyruvate dehydrogenase complex. PMID- 25034229 TI - Improved resolution of bacteria by high throughput sequence analysis of the rRNA internal transcribed spacer. AB - Current high throughput sequencing (HTS) methods are limited in their ability to resolve bacteria at or below the genus level. While the impact of this limitation may be relatively minor in whole-community analyses, it constrains the use of HTS as a tool for identifying and examining individual bacteria of interest. The limited resolution is a consequence of both short read lengths and insufficient sequence variation within the commonly targeted variable regions of the small subunit rRNA (SSU) gene. The goal of this work was to improve the resolving power of bacterial HTS. We developed an assay targeting the hypervariable rRNA internal transcribed spacer (ITS) region residing between the SSU and large-subunit (LSU) rRNA genes. Comparisons of the ITS region and two SSU regions using annotated bacterial genomes in GenBank showed much greater resolving power is possible with the ITS region. This report presents a new HTS method for analyzing bacterial composition with improved capabilities. The greater resolving power enabled by the ITS region arises from its high sequence variation across a wide range of bacterial taxa and an associated decrease in taxonomic heterogeneity within its OTUs. Although the method should be adaptable to any HTS platform, this report presents PCR primers, amplification parameters, and protocols for Illumina-based analyses. PMID- 25034230 TI - Design study of a miniaturized displacement transducer (MDT) for an active middle ear implant system. AB - People suffering from moderate to severe hearing loss can be treated with active middle ear implants. A new approach in this field is to implant an electromechanical transducer onto the round window membrane in order to improve coupling and be able to treat patients with middle-ear problems. In this paper the design study for a miniaturized displacement transducer (MDT) for the round window is presented. Based on a requirement analysis, the basic principle and analytical modeling of the actuator is shown. A parameter variation study results in an optimized actuator configuration that is able to generate an amplification of 110 dB SPL theoretically. As a next step this actuator has to be manufactured and tested. PMID- 25034231 TI - Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways. AB - Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1alpha (SDF 1alpha) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1alpha/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-kappaB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1alpha-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. PMID- 25034232 TI - Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a complement-mediated hemolytic anemia, bone marrow failure, and a propensity for thrombosis. These patients experience both intra- and extravascular hemolysis in the context of underlying complement activation. Currently eculizumab effectively blocks the intravascular hemolysis PNH. There remains an unmet clinical need for a complement inhibitor with activity early in the complement cascade to block complement at the classical and alternative pathways. C1 esterase inhibitor (C1INH) is an endogenous human plasma protein that has broad inhibitory activity in the complement pathway through inhibition of the classical pathway by binding C1r and C1s and inhibits the mannose-binding lectin-associated serine proteases in the lectin pathway. In this study, we show that commercially available plasma derived C1INH prevents lysis induced by the alternative complement pathway of PNH erythrocytes in human serum. Importantly, C1INH was able to block the accumulation of C3 degradation products on CD55 deficient erythrocytes from PNH patient on eculizumab therapy. This could suggest a role for inhibition of earlier phases of the complement cascade than that currently inhibited by eculizumab for incomplete or nonresponders to that therapy. PMID- 25034233 TI - Ecological vulnerability: seasonal and spatial assessment of trace metals in soils and plants in the vicinity of a scrap metal recycling factory in Southwestern Nigeria. AB - The concentrations of selected heavy metals in the soil and vegetation in the immediate vicinity of a metal scrap recycling factory were determined in the dry and wet seasons using the Atomic Absorption Spectrophotometer. The results showed that the soil pH in all the sites indicated slight acidity (from 5.07 to 6.13), high soil organic matter content (from 2.08 to 5.60 %), and a well-drained soil of sandy loam textural composition. Soil heavy metal content in the dry season were 0.84-3.12 mg/kg for Pb, 0.26-0.46 mg/kg for Cd, 9.19-24.70 mg/kg for Zn, and 1.46-1.97 mg/kg for Cu. These values were higher than those in the wet season which ranged from 0.62-0.69 mg/kg for Pb, 0.67-0.78 mg/kg for Cd, 0.84-1.00 mg/kg for Zn, and 1.26-1.45 mg/kg for Cu. Except for cadmium in the dry season, the highest concentrations occurred in the northern side of the factory for all the elements in both seasons. An increase in the concentrations of the elements up to 350 m in most directions was also observed. There was no specific pattern in the level of the metals in the leaves of the plant used for the study. However, slightly elevated values were observed in the wet season (Pb 0.53 mg/kg, Cd 0.59 mg/kg, Cu 0.88 mg/kg) compared with the dry season values (Pb 0.50 mg/kg, Cd 0.57 mg/kg, Cu 0.83 mg/kg). This study showed that the elevated concentrations of these metals might be associated with the activities from the recycling plant, providing the basis for heavy metal pollution monitoring and control of this locality that is primarily used for agricultural purposes. PMID- 25034234 TI - Contamination assessment of arsenic and heavy metals in a typical abandoned estuary wetland--a case study of the Yellow River Delta Natural Reserve. AB - Coastal and estuarine areas are often polluted by heavy metals that result from industrial production and agricultural activities. In this study, we investigated the concentration trait and vertical pattern of trace elements, such as As, Cd, Ni, Zn, Pb, Cu, and Cr, and the relationship between those trace elements and the soil properties in coastal wetlands using 28 profiles that were surveyed across the Diaokouhe Nature Reserve (DKHNR). The goal of this study is to investigate profile distribution characteristics of heavy metals in different wetland types and their variations with the soil depth to assess heavy metal pollution using pollution indices and to identify the pollution sources using multivariate analysis and sediment quality guidelines. Principal component analysis, cluster analysis, and pollution level indices were applied to evaluate the contamination conditions due to wetland degradation. The findings indicated that the concentration of trace elements decreased with the soil depth, while Cd increases with soil depth. The As concentrations in reed swamps and Suaeda heteroptera surface layers were slightly higher than those in other land use types. All six heavy metals, i.e., Ni, Cu, As, Zn, Cr, and Pb, were strongly associated with PC1 (positive loading) and could reflect the contribution of natural geological sources of metals into the coastal sediments. PC2 is highly associated with Cd and could represent anthropogenic sources of metal pollution. Most of the heavy metals exhibited significant positive correlations with total concentrations; however, no significant correlations were observed between them and the soil salt and soil organic carbon. Soil organic carbon exhibited a positive linear relationship with Cu, Pb, and Zn in the first soil layer (0-20 cm); As, Cr, Cu, Ni, Pb, and Zn in the second layer (20-40 cm); and As, Cr, Cu, Ni, Pb, and Zn in the third layer (40-60 cm). Soil organic carbon exhibited only a negative correlation with Cd (P < 0.05), in the second and third layers. As, Cr, Cu, Ni, Pb, and Zn exhibited lower geoaccumulation index values (I geo values), which averaged less than 0 in the three soil layers, this finding indicates that the soils have remained unpolluted by these heavy metals. The mean concentrations of these trace elements were lower than Class I criteria. The degradation wetland restoration suggestions have also been provided in such a way as to restore the reserved flow path of the Yellow River. The results that are associated with trace element contamination would be helpful in providing scientific directions to restore wetlands across the world. PMID- 25034235 TI - Improving artificial forest biomass estimates using afforestation age information from time series Landsat stacks. AB - China maintains the largest artificial forest area in the world. Studying the dynamic variation of forest biomass and carbon stock is important to the sustainable use of forest resources and understanding of the artificial forest carbon budget in China. In this study, we investigated the potential of Landsat time series stacks for aboveground biomass (AGB) estimation in Yulin District, a key region of the Three-North Shelter region of China. Firstly, the afforestation age was successfully retrieved from the Landsat time series stacks in the last 40 years (from 1974 to 2013) and shown to be consistent with the surveyed tree ages, with a root-mean-square error (RMSE) value of 4.32 years and a determination coefficient (R (2)) of 0.824. Then, the AGB regression models were successfully developed by integrating vegetation indices and tree age. The simple ratio vegetation index (SR) is the best candidate of the commonly used vegetation indices for estimating forest AGB, and the forest AGB model was significantly improved using the combination of SR and tree age, with R (2) values from 0.50 to 0.727. Finally, the forest AGB images were mapped at eight epochs from 1985 to 2013 using SR and afforestation age. The total forest AGB in seven counties of Yulin District increased by 20.8 G kg, from 5.8 G kg in 1986 to 26.6 G kg in 2013, a total increase of 360 %. For the persistent forest area since 1974, the forest AGB density increased from 15.72 t/ha in 1986 to 44.53 t/ha in 2013, with an annual rate of about 0.98 t/ha. For the artificial forest planted after 1974, the AGB density increased about 1.03 t/ha a year from 1974 to 2013. The results present a noticeable carbon increment for the planted artificial forest in Yulin District over the last four decades. PMID- 25034236 TI - Insecticide residues in soil and water in coastal areas of vegetable production in Togo. AB - Some common organochlorine, organophosphorus and pyrethroid insecticides were analysed in agricultural soil samples (n = 35) and surface water and groundwater samples (n = 25) collected from coastal areas of vegetable production in Togo. Analytical methods included solvent extraction of the insecticide residues and their subsequent quantification using GC-ECD. delta-HCH, heptachlor epoxide, 4,4 DDE, endosulphan (alpha, beta and sulphate), lambda-cyalothrin and chlorpyrifos were found in the soil samples with concentrations that varied from non detectable (ND) to 26.93 MUg kg(-1) dry weight. For water samples, heptachlor epoxide, 2,4-DDD, 4,4-DDD, 4,4-DDE and endosulphan (alpha, beta, and sulphate) were found at contamination levels that varied from ND to 0.116 MUg L(-1). The concentration of insecticide residues detected in the water samples was below the limits set by the World Health Organization (WHO) and also by the European Union (EU), with the exception of the concentration of endosulphan sulphate at the Aneho site, which was 0.116 MUg L(-1). PMID- 25034237 TI - The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration. AB - Chemotactic factors direct the migration of immune cells, multipotent stem cells, and progenitor cells under physiologic and pathologic conditions. Chemokine ligand 12 and chemokine ligand 7 have been identified and investigated in multiple studies for their role in cellular trafficking in the setting of tissue regeneration. Recent early phase clinical trials have suggested that these molecules may lead to clinical benefit in patients with chronic disease. Importantly, these two proteins may play additional significant roles in directing the migration of multipotent cells, such as mesenchymal stem cells and hematopoietic progenitor cells. This article reviews the functions of these two chemokines, focusing on recruitment to sites of injury, immune function modulation, and contributions to embryonic development. Additional research would provide valuable insight into the potential clinical application of these two proteins in stem cell therapy. PMID- 25034238 TI - The Roman Empire legacy of Galen (129-200 AD). AB - INTRODUCTION: Galen of Pergamum was the physician of Roman Emperors and contributed to our early understanding of medicine and anatomy. Herein, we present a short biography of Galen and review his multiple contributions to medicine and anatomy. CONCLUSIONS: Although it has been almost 2,000 years since Galen walked the streets of the Roman Empire, his legacy continues via multiple eponyms that bare his name. PMID- 25034239 TI - The importance of microsurgery in childhood meningioma: a case report. AB - INTRODUCTION: Although meningiomas are frequently diagnosed in adults, it is a rare (intracranial) tumor in the pediatric population, with an incidence of 0.06/100,000. The pathology and treatment of meningiomas in adulthood has been a topic of increasing investigation. So far, the treatment of pediatric meningiomas has been extrapolated from these results. The question remains, however, whether translation of adult meningioma data into the childhood population is legitimate. METHODS: We present the case of a 3-year-old girl diagnosed with an intraventricular malignant meningioma and type 2 neurofibromatosis. She was operated on multiple times to achieve complete resection and received adjuvant chemotherapy. Since, she has been stable with no neurological sequelae and/or recurrence of the meningioma. CONCLUSION: Pediatric meningiomas are rare tumors and differ from their adult counterparts in various aspects. We believe that gross total resection of meningioma in the pediatric population, when possible, is the treatment of choice. In the event of a subtotal resection, repeat resection is recommended. Any adjuvant treatment with chemotherapy or radiation therapy should be carefully considered during multidisciplinary meetings. PMID- 25034240 TI - Insult of gastroesophageal reflux on airway: clinical significance of pharyngeal nozzle. AB - At the very time of global paying the highest attention to the worst insults of smoking as well as haze on the airway, everybody knows both are exogenous and noticeable. However, people mostly, including many medical personnel, do not know how badly the gastroesophageal reflux (GER) insults on our own airway. Symptoms of GER are commonly seen as heartburn and regurgitation, which can be mostly tolerated. However, when the up going gastric content reversely passes the esophagus and then the distal pharynx, where it appears a beak like stricture, serving as a nozzle, so as to produce numerous micro-particles and reach the oro nasal cavity and also the airway causing allergic rhinitis and asthmatic attacks, even pulmonary parenchyma lesions. It will reduce life quality or even jeopardize life. The point that the endogenous insult appears in the respiratory system, but originates from the digestive tract is not well known and often undiagnosed and not correctly treated. The GER induced airway challenge is a treatable and preventive entity, as soon as a diagnosis is made, a good relief could be expected by means of life style adjustment, medicine, or fixation of the patulous cardia through radiofrequency or fundoplication. The author Dr. Zhonggao Wang had suffered it for long and symptoms disappeared for 8 years after anti-reflux surgery. Here is a presentation of Dr. Zhonggao Wang and his team's work and would call attention to the public so as to recognize this relatively unknown entity - a treatable condition occurring from human itself, but not from outside surroundings as smoking or haze does. PMID- 25034241 TI - Gender differences in the relationship between plasma lipids and fasting plasma glucose in non-diabetic urban Chinese population: a cross-section study. AB - The association between dyslipidemia and elevated fasting glucose in type 2 diabetes is well known. In non-diabetes, whether this association still exists, and whether dyslipidemia is an independent risk factor for high fasting plasma glucose (FPG) levels are not clear. This cross-sectional study recruited 3460 non diabetic Chinese subjects (1027 men, and 2433 women, aged 35-75 years old) who participated in a health survey. Men and women were classified into tertiles by levels of plasma lipids respectively. In women, the prevalence of impaired fasting glucose (IFG) was decreased with increased HDL-C. A stepwise increase in HDL-C was associated with decreasing FPG levels (lowest tertiles, FPG: 5.376 +/- 0.018; middle tertiles, 5.324 +/- 0.018; highest tertiles, 5.276 +/- 0.018 mmol/L; P = 0.001). Reversely, FPG levels increased from lowest tertiles to highest tertiles of LDL-C, TC, and TG. we found that women in the first tertile with lower HDL-C level had a 1.75-fold increase in risk of IFG compared with non diabetic women in the third tertile with higher HDL-C level (OR: 1.75; 95% CI: 1.20-2.56). In men, no significant association was found. We took age, BMI, waist/hip ratio, education, smoking, alcohol drinking, and physical exercise as adjusted variables. In Chinese non-diabetic women, dyslipidemia is independently associated with high levels of FPG; TG, HDL-C, and LDL-C are predictors of IFG independent of BMI and waist/hip ratio. PMID- 25034242 TI - Too hot to trot (barefoot)... A study of burns in children caused by sun heated surfaces in Queensland, Australia. AB - The aim of this study was to quantify and describe the characteristics of burns in children caused by sun heated surfaces. Children presenting between January 2013 and February 2014 with a burn due to sun heated surfaces were included in the study. Fifteen children were identified representing 1.7% of new burns. The mean age was 18.3 months. All burns occurred during the warmer months between 11a.m. and 4p.m. and the feet were commonly involved. Most cases occurred in the child's home garden but six cases occurred in public play areas. Metal was the most common surface involved. Most burns were superficial partial thickness with two burns deep dermal partial thickness and one child needed a skin graft. Burns due to sun heated surfaces are relatively frequent. Parents need to be aware that in summer surfaces can become hot enough to cause burns to bare feet in young children. Play areas need to be shaded or covered in surfaces that do not become hot enough to cause burns and metal objects should not be left in the sun in children's play areas. PMID- 25034243 TI - Weight cycling and depressive symptoms in diabetes: a community-based study of adults with type 2 diabetes mellitus in Quebec. AB - OBJECTIVE: The problems of obesity and depression in type 2 diabetes mellitus are well documented, yet the role of weight cycling in relation to these 2 chronic conditions has not been examined. The study objective was to determine whether weight cycling predicts the development of depressive symptoms in the course of 1 year. METHODS: A cohort study of 1100 adults with type 2 diabetes participating in the Diabetes Health and Well-Being Study (telephone survey using the random digit-dialling method) had complete data at the 1-year follow up on depressive symptoms (Patient Health Questionnaire 9) and weight cycling frequency (going on a diet and losing >10 kg). RESULTS: At baseline, 56.5% of subjects reported weight cycling on at least 1 occasion in their lifetime; it was found to be associated with baseline body mass index, depression, sex and age (p<0.05). Regression analyses indicated that severe weight cycling (>=4 times) was not associated with the development of major depressive symptoms; however, it was associated with maintaining major depressive symptoms (p=0.038) but significance disappeared after adjusting for body mass index, physical activity, smoking and sociodemographic characteristics. Development and maintenance of major depressive symptoms were associated with physical inactivity (p<0.05); maintenance of major depressive symptoms was also associated with higher body mass index values (p<0.05). CONCLUSIONS: Weight cycling is a widespread phenomenon in diabetes. It was associated with depression, but severe cycling was not an independent predictor of the development and maintenance of major depressive symptoms. Clinicians should consider physical inactivity when evaluating and addressing depression in patients with type 2 diabetes. PMID- 25034244 TI - Emerging roles of dipeptidyl peptidase 4 inhibitors: anti-inflammatory and immunomodulatory effect and its application in diabetes mellitus. AB - Dipeptidyl peptidase 4 (DPP4) inhibitors have been widely used in the treatment of type 2 diabetes mellitus. It is well known that DPP4 inhibitors exert their antidiabetes effects mainly by inhibiting the enzymatic degradation of glucagon like peptide-1 and glucose-dependent insulinotropic peptide. The anti inflammatory effect of DPP4 inhibitors was proved by preclinical and clinical studies of type 2 diabetes and coronary artery disease. Preclinical data using DPP4 inhibitors-based therapies in studies of nonobese diabetic mice demonstrated additional effects, including immunomodulation, preserving beta-cell mass, promoting beta-cell regeneration and reversing newly diagnosed diabetes. Thus, these data show that DPP4 inhibitors may be effective for type 1 diabetes mellitus. However, their potential clinical benefits for type 1 diabetes remain to be evaluated. This paper will provide an overview of the progress of the anti inflammatory and immunomodulatory effects of DPP4 inhibitors in treating both type 1 and type 2 diabetes. PMID- 25034245 TI - Psychosocial influences on glycemic control in women with pre-existing diabetes preparing for pregnancy. AB - OBJECTIVE: The purpose of this study was to identify psychosocial factors associated with glycemic control in a sample of adult women with type 1 or type 2 diabetes mellitus preparing for pregnancy. METHODS: This was a cross-sectional study. Participants comprised a subsample (n=38) of a larger study investigating predictors of prepregnancy care uptake in women with pre-existing diabetes. Participants were recruited from the diabetes and pregnancy clinics at 2 major hospitals and completed self-report questionnaires on personality, coping style, social support and knowledge of diabetes and pregnancy. The main outcome was glycemic control using glycated hemoglobin (A1C) as the outcome of interest. RESULTS: The sample was divided into good (n=20) vs. poor (n=18) glycemic control based on their A1C at entry to the study. Univariate tests indicated no differences between the 2 groups on any of the variables except that the good control group were better educated. Hierarchical multiple regression analysis revealed that problem-focused coping and higher education remained significantly associated with better glycemic control when controlling for potential confounds. CONCLUSIONS: Providing women with enhanced prepregnancy diabetes education with a particular emphasis on problem-solving and coping skills may enable them to take more proactive approaches to challenges they face in managing their diabetes. That in turn can improve glycemic control at the critical period. PMID- 25034246 TI - Understanding the relationships between the physical environment and physical activity in older adults: a systematic review of qualitative studies. AB - BACKGROUND: While physical activity (PA) provides many physical, social, and mental health benefits for older adults, they are the least physically active age group. Ecological models highlight the importance of the physical environment in promoting PA. However, results of previous quantitative research revealed inconsistencies in environmental correlates of older adults' PA that may be explained by methodological issues. Qualitative studies can inform and complement quantitative research on environment-PA relationships by providing insight into how and why the environment influences participants' PA behaviors. The current study aimed to provide a systematic review of qualitative studies exploring the potential impact of the physical environment on older adults' PA behaviors. METHODS: A systematic search was conducted in databases of various disciplines, including: health, architecture and urban planning, transportation, and interdisciplinary databases. From 3,047 articles identified in the physical activity, initial search, 31 articles published from 1996 to 2012 met all inclusion criteria. An inductive content analysis was performed on the extracted findings to identify emerging environmental elements related to older adults' PA. The identified environmental elements were then grouped by study methodologies [indoor interviews (individual or focus groups) vs spatial methods (photo-voice, observations, walk-along interviews)]. RESULTS: This review provides detailed information about environmental factors that potentially influence older adults' PA behaviors. These factors were categorized into five themes: pedestrian infrastructure, safety, access to amenities, aesthetics, and environmental conditions. Environmental factors especially relevant to older adults (i.e., access to facilities, green open spaces and rest areas) tended to emerge more frequently in studies that combined interviews with spatial qualitative methods. CONCLUSIONS: Findings showed that qualitative research can provide in-depth information on environmental elements that influence older adults' PA. Future qualitative studies on the physical environment and older adults' PA would benefit from combining interviews with more spatially-oriented methods. Multidisciplinary mixed-methods studies are recommended to establish quantitative relationships complemented with in-depth qualitative information. PMID- 25034247 TI - Effect of Psychosocial Skills Training on Functional Remission of Patients With Schizophrenia. AB - This study was conducted as a two-group pretest-posttest design to determine the effect of psychosocial skills training on functional remission levels of patients with schizophrenia. A total of 100 patients were divided into the training group (n = 50) and the control group (n = 50). The data were collected using a Personal Information Form and Functional Remission of General Schizophrenia (FROGS) scale. The 13-session training program was given in the form of face-to-face group training and 45- to 60-min sessions twice a week. Training was completed by five groups. Every group comprised of 9 to 12 individuals on average. The training group had higher scores significantly on functional remission levels compared with the control group after psychosocial skills training (p < .001). Psychosocial skills training has become considerably effective in increasing the functional remission levels of patients with schizophrenia. PMID- 25034248 TI - Multi-method assessments of sleep over the transition to college and the associations with depression and anxiety symptoms. AB - A growing body of research has demonstrated links between sleep problems and symptoms of depression and anxiety in community and clinical samples of adolescents and young adults. Scant longitudinal research, however, has examined reciprocal associations over socio-contextual shifts such as the transition to college. Using multiple methods of assessment (e.g., actigraphy, subjective report), the current study assessed whether sleep quantity, quality or variability changed over the transition to college and investigated the potential cross-lagged relationships between adolescents' sleep and symptoms of anxiety and depression. The participants (N = 82; 24% male) were studied at three time points over approximately 1 year: spring of their senior year of high school (T1), fall of their first year of college (T2), and spring of their first year of college (T3). Sleep minutes, sleep efficiency, wake time variability and anxiety increased over the transition to college. Subjective reports of sleep problems decreased. Cross-lagged panel models indicated significant relationships between subjective sleep quality and anxiety symptoms over time where subjective sleep problems at T1 were associated with anxiety at T2, and anxiety at T2 was associated with subjective sleep problems at T3. In contrast, greater depressive symptoms at T1 preceded increases in subjective sleep problems, sleep latency and sleep start time variability at T2. Importantly, there were concurrent associations between symptoms of anxiety or depression at T2 and sleep efficiency, sleep start time variability, and subjective sleep problems. These findings suggest that, overall, sleep quantity and quality improved over the transition to college, although the overall amounts of sleep were still below developmental recommendations. However, for some youth, the first semester of college may be a sensitive period for both sleep problems and symptoms of anxiety. In contrast, depressive symptoms were stable across time but were associated with worsening sleep problems in the first semester of college. Implications for future prevention and intervention programs should include strategies to help youth cope effectively with adjustment like increased sleep variability and symptoms of anxiety associated with the transition to college. PMID- 25034249 TI - Demographic marginalization, social integration, and adolescents' educational success. AB - Links between schools' demographic composition and students' achievement have been a major policy interest for decades. Using a racially/ethnically diverse sample from the National Longitudinal Study of Adolescent Health (N = 6,302; 54% females; 53% White, 21% African American, 15% Latino, 8% Asian American, 2% other race/ethnicity), we examined the associations between demographic marginalization, students' later social integration (loneliness at school, school attachment), and educational performance and attainment. Adolescents who were socioeconomically marginalized at school [i.e., having <15% same-socioeconomic status (SES) peers] had lower cumulative grade point averages across high school and lower educational attainment. A similar disadvantage was observed among students who were both socioeconomically and racially/ethnically marginalized at school (i.e., having <15% same-SES peers and <15% same-racial/ethnic peers). Indirect effects were also observed, such that demographic marginalization was linked to poorer school attachment, and poorer school attachment, in turn, was related to poorer academic performance. These results highlight the educational barriers associated with demographic marginalization and suggest potential targets for future intervention efforts. PMID- 25034250 TI - Diclofenac potassium powder for oral solution: a review of its use in patients with acute migraine. AB - Diclofenac potassium powder for oral solution (Voltfast((r)), Catafast((r)), Cambia((r)); hereafter referred to as diclofenac potassium powder) is a non steroidal anti-inflammatory drug (NSAID), and is indicated for the acute treatment of migraine. This article reviews the pharmacological properties of diclofenac potassium powder and its efficacy and tolerability in patients with acute migraine. Diclofenac potassium powder was clinically efficacious and generally well tolerated in placebo-controlled trials in patients with this indication; it was more effective than diclofenac potassium tablets with regard to the primary endpoint of 2-h pain relief as well as in several important secondary endpoints, such as time to onset of analgesic action. The oral powder for-solution formulation of diclofenac potassium is a useful option in the acute treatment of migraine with or without aura. PMID- 25034251 TI - Structural effects of PrP polymorphisms on intra- and interspecies prion transmission. AB - Understanding the molecular parameters governing prion propagation is crucial for controlling these lethal, proteinaceous, and infectious neurodegenerative diseases. To explore the effects of prion protein (PrP) sequence and structural variations on intra- and interspecies transmission, we integrated studies in deer, a species naturally susceptible to chronic wasting disease (CWD), a burgeoning, contagious epidemic of uncertain origin and zoonotic potential, with structural and transgenic (Tg) mouse modeling and cell-free prion amplification. CWD properties were faithfully maintained in deer following passage through Tg mice expressing cognate PrP, and the influences of naturally occurring PrP polymorphisms on CWD susceptibility were accurately reproduced in Tg mice or cell free systems. Although Tg mice also recapitulated susceptibility of deer to sheep prions, polymorphisms that provided protection against CWD had distinct and varied influences. Whereas substitutions at residues 95 and 96 in the unstructured region affected CWD propagation, their protective effects were overridden during replication of sheep prions in Tg mice and, in the case of residue 96, deer. The inhibitory effects on sheep prions of glutamate at residue 226 in elk PrP, compared with glutamine in deer PrP, and the protective effects of the phenylalanine for serine substitution at the adjacent residue 225, coincided with structural rearrangements in the globular domain affecting interaction between alpha-helix 3 and the loop between beta2 and alpha-helix 2. These structure-function analyses are consistent with previous structural investigations and confirm a role for plasticity of this tertiary structural epitope in the control of PrP conversion and strain propagation. PMID- 25034252 TI - Roles of coactosin-like protein (CLP) and 5-lipoxygenase-activating protein (FLAP) in cellular leukotriene biosynthesis. AB - 5-Lipoxygenase (5LO) is a key enzyme in leukotriene (LT) biosynthesis. Two accessory proteins, coactosin-like protein (CLP) and 5-lipoxygenase-activating protein (FLAP), can support 5LO activity. To study the roles of CLP and FLAP, we knocked down these proteins in the human monocytic cell line Mono Mac 6 (MM6). Expression of CLP increased MM6 cellular 5LO activity for all stimuli tested. CLP is not absolutely crucial, however; some 5LO activity remained in all incubations of CLP knockdown cells. FLAP knockdown had minor effects in the presence of exogenous arachidonic acid, but led to prominent reductions in 5LO product formation from endogenous substrate. Similar effects were observed after CLP and FLAP knockdown in human primary macrophages as well. In addition, FLAP knockdown reduced conversion of leukotriene A4 to leukotriene C4 (LTC4), suggesting a role for the activity of LTC4 synthase. After stimulation of MM6 cells by phorbol myristate acetate and ionophore A23187, a perinuclear ring pattern was observed for 5LO. This redistribution from cytosolic to perinuclear was clearly compromised in both CLP- and FLAP-deficient cells. In addition, association of CLP with the nucleus was almost absent after 5LO knockdown, and was clearly reduced in FLAP knockdown cells. Coimmunoprecipitation experiments indicated that 5LO-CLP complex formation in MM6 cells was increased by stimulation with ionophore, and that this complex was formed to the same extent in FLAP knockdown cells. A possible interpretation of our findings is that on cell stimulation, formation of the 5LO-CLP complex augments the translocation from cytosol to nucleus, whereas FLAP stabilizes association of this complex with the perinuclear membrane. PMID- 25034253 TI - Encapsidated hepatitis B virus reverse transcriptase is poised on an ordered RNA lattice. AB - Assembly of a hepatitis B virus (HBV) virion begins with the formation of an RNA filled core composed of a symmetrical capsid (built of core protein), viral pregenomic RNA, and viral reverse transcriptase. To generate the circular dsDNA genome of HBV, reverse transcription requires multiple template switches within the confines of the capsid. To date, most anti-HBV therapeutics target this reverse transcription process. The detailed molecular mechanisms of this crucial process are poorly understood because of the lack of structural information. We hypothesized that capsid, RNA, and viral reverse transcriptase would need a precise geometric organization to accomplish reverse transcription. Here we present the asymmetric structure of authentic RNA-filled cores, determined to 14.5-A resolution from cryo-EM data. Capsid and RNA are concentric. On the interior of the RNA, we see a distinct donut-like density, assigned to viral reverse transcriptase, which pins the viral pregenomic RNA to the capsid inner surface. The observation of a unique ordered structure inside the core suggests that assembly and the first steps of reverse transcription follow a single, determinate pathway and strongly suggests that all subsequent steps in DNA synthesis do as well. PMID- 25034254 TI - Identification of Helicobacter pylori infection in symptomatic patients in Surabaya, Indonesia, using five diagnostic tests. AB - SUMMARY The prevalence of Helicobacter pylori infection in Indonesia is controversial. We examined the H. pylori infection rate in 78 patients in a hospital in Surabaya using five different tests, including culture, histology, immunohistochemistry, rapid urease test, and urine antibody test. Furthermore, we analysed virulence factors in H. pylori strains from Indonesia. The H. pylori infection rate was only 11.5% in all patients studied, and 2.3% of Javanese patients and 18.0% of Chinese patients were infected (P = 0.01). Although severe gastritis was not observed, activity and inflammation were significantly higher in patients positive for H. pylori than in patients negative for H. pylori. Among genotypes identified from five isolated strains, cagA was found in four; two were vacA s1m1. All cagA-positive strains were oipA 'on' and iceA1 positive. We confirmed both a low H. pylori infection rate and a low prevalence of precancerous lesions in dyspeptic patients in a Surabaya hospital, which may contribute to the low incidence of gastric cancer in Indonesia. PMID- 25034255 TI - Antioxidant and alpha-amylase inhibitory activities of extract and isolates from Zygogynum pancheri subsp. arrhantum. AB - One new sesquiterpenoid (5R(*),8R(*),9R(*),10R(*))-cinnamolide (8), and seven known compounds, 5-hydroxy-7-methoxyflavonone (1), 8-hydroxy-3-(4'-hydroxyphenyl) 6,7-(2",2"-dimethylchromene)-tetralone (2), 8-hydroxy-3-(3',4'-dihydroxyphenyl) 6,7-(2",2"-dimethylchromene)-tetralone (3), 1beta-E-O-p-methoxycinnamoyl bemadienolide (4), 1beta-O-(E-cinnamoyl)-6alpha-hydroxy-9-epi-polygodial (5), 1beta-O-(E-cinnamoyl)-6alpha-hydroxypolygodial (6), and 1beta-O-E cinnamoylpolygodial (7) were isolated from the ethyl acetate extract of barks of Zygogynum pancheri subsp. arrhantum (Winteraceae). The structures of these molecules were assigned predominantly based on spectral data. The structure of compound 8 was confirmed by X-ray crystallographic analysis. Compounds 2 and 3 exhibited significant antioxidant activity, whereas compounds 1 and 4-7 showed significant alpha-amylase inhibitory activity. PMID- 25034256 TI - A systematic assessment of the current capacity to act in nutrition in West Africa: cross-country similarities and differences. AB - BACKGROUND: Although it is widely accepted that lack of capacity is one of the barriers to scaling up nutrition in West Africa, there is a paucity of information about what capacities exist and the capacities that need to be developed to accelerate progress toward improved nutrition outcomes in the region. OBJECTIVE: To systematically assess the current capacity to act in nutrition in the West Africa region and explore cross-country similarities and differences. DESIGN: Data were collected from 13 West African countries through interviews with government officials, key development partners, tertiary-level training institutions, and health professional schools. The assessment was based on a conceptual framework of four interdependent levels (tools; skills; staff and infrastructure; and structures, systems and roles). In each of the surveyed countries, we assessed capacity assets and gaps at individual, organizational, and systemic levels. RESULTS: Important similarities and differences in capacity assets and gaps emerged across all the surveyed countries. There was strong momentum to improve nutrition in nearly all the surveyed countries. Most of the countries had a set of policies on nutrition in place and had set up multisectoral, multi-stakeholder platforms to coordinate nutrition activities, although much remained to be done to improve the effectiveness of these platforms. Many initiatives aimed to reduce undernutrition were ongoing in the region, but there did not seem to be clear coordination between them. Insufficient financial resources to implement nutrition activities were a major problem in all countries. The bulk of financial allocations for nutrition was provided by development partners, even though some countries, such as Niger, Nigeria, and Senegal, had a national budget line for nutrition. Sporadic stock outs of nutrition supplies were reported in most of the countries as a result of a weak logistic and supply chain system. They also had a critical shortage of skilled nutrition professionals. There was limited supervision of nutrition activities, especially at lower levels. Nigeria and Ghana emerged as the countries with the greatest capacities to support the expansion of a nutrition workforce, although a significant proportion of their trained nutritionists were not employed in the nutrition sector. None of the countries had in place a unified nutrition information system that could guide decision-making processes across the different sectors. CONCLUSIONS: There is an urgent need for a shift toward wider reforms for nutrition capacity development in the West Africa region. Addressing these unmet needs is a critical first step toward improved capacity for action in nutrition in the region. PMID- 25034257 TI - A rare cause of arthropathy: An ochronotic patient with black joints. AB - INTRODUCTION: Alkaptonuria is an autosomal recessive disorder of metabolism. The pathogenesis of alkaptonuria includes chronic inflammation, degeneration, and eventually osteoarthritis. Ochronotic arthropathy is a rare condition found in patients with alkaptonuria. PRESENTATION OF CASE: A 60-year-old female presented for evaluation after a 10-year history of low back pain, right hip pain, and bilateral knee pain. A cementless right total hip and a cemented left knee replacement were performed. Intraoperatively, the joint surfaces, neighboring ligaments, and tendons were black with pieces of black cartilage tissue. Histological sections of bone and soft tissue demonstrated classic findings of ochronosis, including multiple pigmented areas, reactive giant cells, and a thickened, inflamed synovium. DISCUSSION: The management of ochronotic arthropathy in alkaptonuria patients is usually conservative, but replacement surgery is offered for severely affected hip and knee joints. A few reports of the surgical treatment of ochronotic arthropathy have been published. This report describes a case of ochronotic hip and knee arthritis treated with total hip and knee arthroplasties. CONCLUSION: Joint replacement has excellent outcomes in a patient with significant degenerative arthropathy due to ochronosis. PMID- 25034258 TI - Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. AB - Patients with germline mutation of succinate dehydrogenase (SDH) subunit genes are prone to develop paraganglioma, gastrointestinal stromal tumor, and rarely renal cell carcinoma (RCC). However, SDH-deficient RCC is not yet widely recognized. We identified such tumors by distinctive morphology and confirmed absence of immunohistochemical staining for SDHB. Immunohistochemical features were evaluated using a panel of antibodies to renal tumor antigens. Targeted next generation sequencing was performed on DNA extracted from paraffin-embedded tissue. Eleven tumors were identified from 10 patients, 22-72 years of age (median 40). Two patients had paragangliomas, 1 bilateral SDH-deficient RCC, and 1 contralateral oncocytoma. Grossly, tumors were tan or red-brown, 2-20 cm in diameter (median 4.25 cm). Fuhrman grade was 2 (n=10) or 3 (n=1). Stage was pT1a pT2b. One patient developed widespread metastases 16 years after nephrectomy and died of disease 6 years later. All tumors were composed of uniform eosinophilic cells containing vacuoles or flocculent cytoplasmic inclusions. Architecture was primarily solid; entrapped renal tubules and intratumoral mast cells were common. By immunohistochemistry, tumor cells were negative for SDHB (11/11) and rarely SDHA (1/11). Labeling was uniformly positive for PAX8 and kidney-specific cadherin and absent for KIT, RCC, and carbonic anhydrase IX. Staining for broad spectrum epithelial markers was often negative or focal (positive staining for AE1/AE3 in 4/10, CAM5.2 3/7, CK7 1/11, EMA 10/10). By sequencing, SDHB mutation and loss of the second allele were present in 5/6 tumors; the SDHA-deficient tumor showed no SDHB abnormality. SDH-deficient RCC is a unique neoplasm that is capable of progression, often harboring SDHB mutation. A monomorphic oncocytic renal tumor with solid architecture, cytoplasmic inclusions of flocculent material, and intratumoral mast cells should prompt evaluation of SDH status, as it may have implications for screening the patient and relatives. Negative immunohistochemistry for KIT and heterogeneous labeling for epithelial antigens are other supportive features. PMID- 25034259 TI - Determination of the ruminant origin of bone particles using fluorescence in situ hybridization (FISH). AB - Molecular biology techniques such as PCR constitute powerful tools for the determination of the taxonomic origin of bones. DNA degradation and contamination by exogenous DNA, however, jeopardise bone identification. Despite the vast array of techniques used to decontaminate bone fragments, the isolation and determination of bone DNA content are still problematic. Within the framework of the eradication of transmissible spongiform encephalopathies (including BSE, commonly known as "mad cow disease"), a fluorescence in situ hybridization (FISH) protocol was developed. Results from the described study showed that this method can be applied directly to bones without a demineralisation step and that it allows the identification of bovine and ruminant bones even after severe processing. The results also showed that the method is independent of exogenous contamination and that it is therefore entirely appropriate for this application. PMID- 25034260 TI - Simulated disparity and peripheral blur interact during binocular fusion. AB - We have developed a low-cost, practical gaze-contingent display in which natural images are presented to the observer with dioptric blur and stereoscopic disparity that are dependent on the three-dimensional structure of natural scenes. Our system simulates a distribution of retinal blur and depth similar to that experienced in real-world viewing conditions by emmetropic observers. We implemented the system using light-field photographs taken with a plenoptic camera which supports digital refocusing anywhere in the images. We coupled this capability with an eye-tracking system and stereoscopic rendering. With this display, we examine how the time course of binocular fusion depends on depth cues from blur and stereoscopic disparity in naturalistic images. Our results show that disparity and peripheral blur interact to modify eye-movement behavior and facilitate binocular fusion, and the greatest benefit was gained by observers who struggled most to achieve fusion. Even though plenoptic images do not replicate an individual's aberrations, the results demonstrate that a naturalistic distribution of depth-dependent blur may improve 3-D virtual reality, and that interruptions of this pattern (e.g., with intraocular lenses) which flatten the distribution of retinal blur may adversely affect binocular fusion. PMID- 25034261 TI - Determinants of the direction illusion: motion speed and dichoptic presentation interact to reveal systematic individual differences in sign. AB - When two fields of dots with different directions of movement are presented in tandem, the perceived direction of one is biased by the presence of the other. Although this ''direction illusion'' typically involves repulsion, with an exaggeration of the perceived angular difference in direction between the dot fields, attraction effects, where the perceived difference is reduced, have also been found under certain presentation conditions. Earlier literature has been inconsistent, and there is debate surrounding the nature of the interactions that facilitate the direction illusion, as well as whether they occur at a local or global stage of the motion processing hierarchy. Here we measured the operating characteristics of the direction illusion by parametrically varying inducer contrast and coherence while examining the effects of stimulus speed and dichoptic presentation. It was found that the magnitude and sign of the direction illusion differed substantially from earlier research. Furthermore, there appeared to be significant interindividual variability, with dichoptic presentation producing an attractive rather than repulsive direction illusion in some participants. PMID- 25034262 TI - Epigenetics in immune development and in allergic and autoimmune diseases. AB - Epigenetic mechanisms such as DNA methylation, histone modification, and micro RNA signaling regulate the activity of the genome. Virtually all aspects of immunity involve some level of epigenetic regulation, whether it be host defense or in mediating tolerance. These processes are critically important in mediating dynamic responses to the environment over the life course of the individual, yet we are only just beginning to understand how dysregulation in these pathways may play a role in immune disease. Here, we give a brief chronological overview of epigenetic processes during immune development in health and disease. PMID- 25034265 TI - Base rate of performance invalidity among non-clinical undergraduate research participants. AB - Neuropsychological research frequently uses non-clinical undergraduate participants to evaluate neuropsychological tests. However, a recent study by An and colleagues (2012, Archives of Clinical Neuropsychology, 27, 849-857) called into question that the extent to which the interpretation of these participants' performance on neuropsychological tests is valid. This study found that in a sample of 36 participants, 55.6% exhibited performance invalidity at an initial session and 30.8% exhibited performance invalidity at a follow-up session. The current study attempted to replicate these findings in a larger, more representative sample using a more rigorous methodology. Archival data from 133 non-clinical undergraduate research participants were analyzed. Participants were classified as performance invalid if they failed any one PVT. In the current sample, only 2.26% of participants exhibited performance invalidity. Thus, concerns regarding insufficient effort and performance invalidity when using undergraduate research participants appear to be overstated. PMID- 25034266 TI - Embedded validity indicators on CNS vital signs in youth with neurological diagnoses. AB - Computerized screening measures can provide valuable information on cognition. However, determining the validity of obtained data is critical for interpretation. The purpose of this study was to examine the embedded validity indicators on the CNS Vital Signs battery in a sample of youth with neurological diagnoses. The sample included 275 children and adolescents (mean = 13.9, SD = 3.0) with neurological disorders. Six out of seven subtests and six of the nine domain scores on CNS Vital Signs had fewer than 5% of the sample flagged as invalid on the embedded indicators. However, the Shifting Attention Test and its derived domain scores had higher rates of being flagged. Patients with one or more flagged scores (18% of sample) were younger and had lower intellectual abilities, psychomotor speed, verbal memory, and performance on other validity tests. Compared to stand-alone validity tests, CNS Vital Signs embedded validity indicators had low sensitivity. More research is needed with the embedded indicators in youth. PMID- 25034267 TI - Diagnostic performance of urinary metanephrines for the postmortem diagnosis of hypothermia. AB - The purpose of this study was to assess the diagnostic potential of urinary metanephrines and 3-methoxytyramine compared to urinary catecholamine determination in diagnosing antemortem cold exposure and fatal hypothermia. 83 cases of fatal hypothermia and 144 control cases were included in this study. Catecholamines (adrenaline, noradrenaline and dopamine), metanephrines (metanephrine, normetanephrine) and 3-methoxytyramine were measured in urine collected during autopsy. All tested analytes were significantly higher in hypothermia cases compared to control subjects and displayed a generally satisfying discriminative value, thus indicating urinary catecholamines and their metabolites as reliable markers of cold-related stress and hypothermia related deaths. Metanephrine and adrenaline had the best discriminative value between hypothermia and control cases compared to other tested analytes, though with different sensitivity and specificity. These can therefore be considered the most suitable markers of cold-related stress. PMID- 25034268 TI - High-directivity emissions with flexible beam numbers and beam directions using gradient-refractive-index fractal metamaterial. AB - A three-dimensional (3D) highly-directive emission system is proposed to enable beam shaping and beam steering capabilities in wideband frequencies. It is composed of an omnidirectional source antenna and several 3D gradient-refractive index (GRIN) lenses. To engineer a broadband impedance match, the design method for these 3D lenses is established under the scenario of free-space excitation by using a planar printed monopole. For realizations and demonstrations, a kind of GRIN metamaterial is proposed, which is constructed by non-uniform fractal geometries. Due to the non-resonant and deep-subwavelength features of the fractal elements, the resulting 3D GRIN metamaterial lenses have extra wide bandwidth (3 to 7.5 GHz), and are capable of manipulating electromagnetic wavefronts accurately, advancing the state of the art of available GRIN lenses. The proposal for the versatile highly-directive emissions has been confirmed by simulations and measurements, showing that not only the number of beams can be arbitrarily tailored but also the beam directions can be steerable. The proposal opens a new way to control broadband highly-directive emissions with pre-designed directions, promising great potentials in modern wireless communication systems. PMID- 25034269 TI - LOTUS suppresses axon growth inhibition by blocking interaction between Nogo receptor-1 and all four types of its ligand. AB - Axon growth inhibitors such as Nogo proteins, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and B lymphocyte stimulator (BLyS) commonly bind to Nogo receptor-1 (NgR1), leading to enormous restriction of functional recovery after damage to the adult central nervous system. Recently, we found that lateral olfactory tract usher substance (LOTUS) antagonizes NgR1-mediated Nogo signaling. However, whether LOTUS exerts antagonism of NgR1 when bound by the other three ligands has not been determined. Overexpression of LOTUS together with NgR1 in COS7 cells blocked the binding of MAG, OMgp, and BLyS to NgR1. In cultured dorsal root ganglion neurons in which endogenous LOTUS is only weakly expressed, overexpression of LOTUS suppressed growth cone collapse and neurite outgrowth inhibition induced by these three NgR1 ligands. LOTUS suppressed NgR1 ligand-induced growth cone collapse in cultured olfactory bulb neurons, which endogenously express LOTUS. Growth cone collapse was induced by NgR1 ligands in lotus-deficient mice. These data suggest that LOTUS functions as a potent endogenous antagonist for NgR1 when bound by all four known NgR1 ligands, raising the possibility that LOTUS may protect neurons from NgR1-mediated axonal growth inhibition and thereby may be useful for promoting neuronal regeneration as a potent inhibitor of NgR1. PMID- 25034270 TI - Leukoencephalopathy, cerebral calcifications and cysts: a family study. AB - We present a clinical, neuro-radiological and genetic study on a family with members suffering from an autosomal dominantly inherited syndrome characterised by epilepsy, cerebral calcifications and cysts, bone abnormalities; progressive neuro-cognitive deterioration and paranasal sinusitis. This syndrome shares several features with leukoencephalopathy with calcifications and cysts also called Labrune syndrome and the condition of cerebroretinal microangiopathy with calcifications and cysts (CRMCC; Coats plus syndrome). Genetic studies in this family did not reveal mutations in the CTC1 gene defected in CRMCC. We interpret our results as those supporting recent findings that despite clinical similarities, late-onset Labrune and Coats plus syndrome might be distinct entities. This family may have Labrune syndrome or a yet unclassified entity; exploration of similar cases could help classifying this one, and related conditions. PMID- 25034271 TI - C9orf72 expansion as a possible genetic cause of Huntington disease phenocopy syndrome. AB - Huntington disease (HD), the most common inherited cause of chorea, is an autosomal dominant disorder, caused by an expanded trinucleotide CAG repeat (>39) in the HTT gene on chromosome 4p16.3. Among patients diagnosed as HD solely on clinical grounds, a certain number was negative on genetic testing for HD. Therefore, HD-like disorders comprised a number of genetic causes of chorea, that may be indistinguishable from HD (e.g. HD phenocopy syndrome). Recent data suggested that the C9orf72 expansion may be the most common genetic cause of HD phenocopy presentations. In continuation with this observation, we analyzed a small cohort of 39 patients with HD phenocopy syndrome and detected the C9orf72 expansion in one female patient (2.6%) with two-year lasting mild generalized chorea and severe oro-bucco-lingual dyskinesia, who complained on forgetfullness (neuropsychological testing revealed dysexecutive syndrome with preserved episodic memory and recognition), unexplainable fears and increased appetite. Our results confirmed a possible role of the C9orf72 expansion in the genetic background of HD phenocopy syndrome. PMID- 25034272 TI - Early-onset optic neuropathy as initial clinical presentation in SPG7. PMID- 25034273 TI - Narcolepsy: environment, genes and treatment. PMID- 25034274 TI - Gadolinium enhancement patterns of tumefactive demyelinating lesions: correlations with brain biopsy findings and pathophysiology. AB - Tumefactive demyelinating lesions (TDLs) can mimic brain tumors on radiological images. TDLs are often referred to as tumefactive multiple sclerosis (TMS), but the heterogeneous nature and monophasic course of TDLs do not fulfill clinical and magnetic resonance imaging (MRI) criteria for multiple sclerosis. Redefining TDLs, TMS and other inflammatory brain lesions is essential for the accurate clinical diagnosis of extensive demyelinating brain lesions. We retrospectively analyzed MRI from nine TDL cases that underwent brain biopsy. Patterns of gadolinium enhancement on MRI were categorized as homogenous, inhomogeneous, patchy and diffuse, open ring or irregular rim, and were compared with pathological hallmarks including demyelination, central necrosis, macrophage infiltration, angiogenesis and perivascular lymphocytic cuffing. All cases had coexistence of demyelinating features and axonal loss. Open-ring and irregular rim patterns of gadolinium enhancement were associated with macrophage infiltrations and angiogenesis at the inflammatory border. An inhomogeneous pattern of gadolinium enhancement was associated with perivascular lymphocytic cuffing. Central necrosis was seen in cases of severe multiple sclerosis and hemorrhagic leukoencephalopathy. These results suggest that the radiological features of TDLs may be related to different pathological processes, and indicate that MRI may be useful in understanding their pathophysiology. Further investigation is needed to determine the precise disease entity of these inflammatory demyelinating brain lesions. PMID- 25034275 TI - Predictors for and impact of high peritonitis rate in Taiwanese continuous ambulatory peritoneal dialysis patients. AB - AIM: The influence of high peritonitis rate (HPR) on clinical outcomes of continuous ambulatory peritoneal dialysis (CAPD) patients has been far less studied in the Chinese population than in those of the USA, Australia and Europe. Furthermore, concerning the peritonitis risk, most studies primarily examined the risk of developing the first peritonitis episode, rather than a HPR. METHODS: A single-center, retrospective, observational study was carried out over 10 years in Taiwan. A total of 124 patients with at least one peritonitis episode were the study subjects. The Cox proportional hazard model was used to assess the impact of HPR on clinical outcomes. Multivariate logistic regression was conducted to determine the independent factors associated with a HPR. RESULTS: In the multivariate Cox regression model, HPR was still a significant predictor for technique failure, patient mortality and dropout from peritoneal dialysis (PD). Factors independently associated with a HPR were peritonitis occurrence during the first year after the start of CAPD and the first peritonitis infected with streptococcus species. CONCLUSION: Peritonitis during the first year after PD commencement and the first peritonitis infected by streptococcus species were significantly associated with an increased risk of a HPR. Our data also indicate that HPR was correlated with technique failure, patient mortality and dropout from PD, thus highlighting the need and role of future studies to reduce this complication. PMID- 25034277 TI - [Rehabilitation of multiple injured patients in Germany: Clinic locations, structural and equipment attributes]. AB - BACKGROUND: In recent years, there has been an ongoing improvement in the treatment and structural aspects of acute trauma care. Because of the definition of rehabilitation as a post-acute part of the treatment of traumatic injuries, especially in multiple injured patients, there is need to improve the interaction and cooperation between acute care hospitals and rehabilitation clinics. This article gives a survey of the current state of rehabilitation in Germany. MATERIALS AND METHODS: Based on a directory of rehabilitation clinics and an internet search, all rehabilitation clinics were identified and included in the analysis for clinic location, structural and equipment attributes. RESULTS: In total 551 rehabilitation clinics with expertise in the treatment of traumatic and orthopedic injuries were identified. In detail, broad differences between the federal states could be observed. The number of rehabilitation clinics per state ranged from 1 to 136 and the number of beds from 70 to 18040. The average catchment area covered by a rehabilitation clinic is 648 km(2) (range 149-2106 km(2)) with an average of 1584 patients per clinic per year. Of the clinics 68% can treat patients with methicillin-resistant Staphylococcus aureus (MRSA) infections and 62.1% are able to deal with patients who need renal dialyses. Almost all clinics provide an x-ray facility (96.4%) while computed tomography (CT) and magnetic resonance imaging (MRI) are available in 52.6% and 50.3%, respectively. CONCLUSION: The number of rehabilitation clinics available seems to be adequate for all patients with traumatic injuries but there are enormous differences between the federal states. Because rehabilitation is important for the outcome of multiple injured patients, a further improvement of the quality and integration into the regional trauma network seem to be necessary. PMID- 25034276 TI - Human plasma enhances the expression of Staphylococcal microbial surface components recognizing adhesive matrix molecules promoting biofilm formation and increases antimicrobial tolerance In Vitro. AB - BACKGROUND: Microbial biofilms have been associated with the development of chronic human infections and represent a clinical challenge given their increased antimicrobial tolerance. Staphylococcus aureus is a major human pathogen causing a diverse range of diseases, of which biofilms are often involved. Staphylococcal attachment and the formation of biofilms have been shown to be facilitated by host factors that accumulate on surfaces. To better understand how host factors enhance staphylococcal biofilm formation, we evaluated the effect of whole human plasma on biofilm formation in clinical isolates of S. aureus and the expression of seven microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) known to be involved in biofilm formation by quantitative real-time PCR. We also evaluated whether plasma augmented changes in S. aureus biofilm morphology and antimicrobial resistance. RESULTS: Exposure of clinical isolates of S. aureus to human plasma (10%) within media, and to a lesser extent when coated onto plates, significantly enhanced biofilm formation in all of the clinical isolates tested. Compared to biofilms grown under non-supplemented conditions, plasma-augmented biofilms displayed significant changes in both the biofilm phenotype and cell morphology as determined by confocal scanning laser microscopy (CLSM) and scanning electron microscopy (SEM), respectively. Exposure of bacteria to plasma resulted in a significant fold-increase in MSCRAMM expression in both a time and isolate-dependent manner. Additionally, plasma augmented biofilms displayed an increased tolerance to vancomycin compared to biofilms grown in non-supplemented media. CONCLUSIONS: Collectively, these studies support previous findings demonstrating a role for host factors in biofilm formation and provide further insight into how plasma, a preferred growth medium for staphylococcal biofilm formation enhances as well as augments other intrinsic properties of S. aureus biofilms. Consequently, these findings indicate that incorporation of host factors may be necessary to better replicate in vivo conditions and for the best utility of a clinical biofilm assay to evaluate the process of biofilm formation and treatments. PMID- 25034278 TI - [Special prosthesis implant with partial femoral replacement. Operation after periprosthetic femoral fracture and ipsilateral long-stem knee prosthesis and fixed-angle osteosynthesis]. AB - The development of modular prostheses is becoming increasingly important in revision surgery due to the rising need of arthroplasty in knee and hip joints. The demand for suitable prostheses is high because of the desire for a higher mobility and a good postoperative functionality, whereby preliminary experience with megaprostheses using modular implant systems in orthopedic oncology have already been obtained. Considering the clinical outcome of our 58-year-old patient (obesity III, BMI 58) and the third revision operation after two periprosthetic fractures, a megaprosthesis was implanted (Mega C-system, co. Link, Hamburg). We aimed both at good clinical functionality and good stability of the knee joint. After the implant, a good functional result was observed at the beginning; however, there were some indices for prosthesis loosening. During the fourth revision we implanted a total femoral replacement. Postoperatively, a good clinical outcome after intensive physiotherapy was observed. Nevertheless, the use of megaprostheses has to be judged cautiously because of a lack of long term results. In addition, it should not be used as a standard implant in periprosthetic joint surgery because of the risk of aseptic loosening during its course. PMID- 25034279 TI - User evaluations of design complexity: the impact of visual perceptions for effective online health communication. AB - OBJECTIVE: This paper highlights the influential role of design complexity for users' first impressions of health websites. METHOD: An experimental design was utilized to investigate whether a website's level of design complexity impacts user evaluations. An online questionnaire measured the hypothesized impact of design complexity on predictors of message effectiveness. RESULTS: Findings reveal that increased design complexity was positively associated with higher levels of perceived design esthetics, attitude toward the website, perceived message comprehensibility, perceived ease of use, perceived usefulness, perceived message quality, perceived informativeness, and perceived visual informativeness. CONCLUSION: This research gives further evidence that design complexity should be considered an influential variable for health communicators to effectively reach their audiences, as it embodies the critical first step for message evaluation via electronic platforms. PMID- 25034281 TI - Bone marrow stem cell therapy for liver disease. AB - Liver disease is a rising cause of mortality and morbidity, and treatment options remain limited. Liver transplantation is curative but limited by donor organ availability, operative risk and long-term complications. The contribution of bone marrow (BM)-derived stem cells to tissue regeneration has been recognised and there is considerable interest in the potential benefits of BM stem cells in patients with liver disease. In chronic liver disease, deposition of fibrous scar tissue inhibits hepatocyte proliferation and leads to portal hypertension. Although initial reports had suggested transdifferentiation of stem cells into hepatocytes, the beneficial effects of BM stem cells are more likely derived from the ability to breakdown scar tissue and stimulate hepatocyte proliferation. Studies in animal models have yielded promising results, although the exact mechanisms and cell type responsible have yet to be determined. Small-scale clinical studies have quickly followed and, although primarily designed to examine safety and feasibility of this approach, have reported improvements in liver function in treated patients. Well-designed, controlled studies are required to fully determine the benefits of BM stem cell therapy. PMID- 25034282 TI - Future perspective: immunomodulatory therapy for autoimmune hepatitis. AB - In the last two decades, more and more light has been shed on the immunologic pathogenesis of autoimmune liver diseases, notably autoimmune hepatitis (AIH). An immunologic dysbalance with proinflammatory immune responses dominating over hepatic tolerance seems to be part of AIH pathogenesis. In detail, an impairment of regulatory T cells (Treg) is suspected. If this holds true and reduced Treg numbers or their function are pathogenic for AIH, this offers the option of cellular or immunomodulatory therapy. However, the exact immunological role of Treg in AIH still needs to be clarified before cellular therapy is promising for patients. PMID- 25034283 TI - The inflammasome in liver injury and non-alcoholic fatty liver disease. AB - The liver possesses a strong inflammatory response, as seen experimentally and clinically with liver inflammation due to toxic and metabolic stress, sepsis and ischemia. Initiation of this inflammatory response requires the interaction of two types of extracellular signals which collectively upregulate and activate a cytosolic molecular complex termed the inflammasome. Signal 1 is via activation of pattern recognition receptors, and signal 2 is delivered by diverse stimuli including particulates and adenosine triphosphate. The common end result of inflammasome activation is the activation of the protease caspase-1 with release of active interleukin-1beta. The inflammasome is important in a wide range of conditions including alcoholic and non-alcoholic steatohepatitis. Kupffer cells are known to be important, but the consequences of inflammasome activation in other hepatic immune cells have not been well characterized. The inflammasome pathway is also known to be required for a full fibrotic response, as demonstrated by reduced lung, skin and liver fibrosis in inflammasome-deficient mice. Identification of the inflammasome machinery has opened up novel therapeutic avenues by the use of antagonists for Toll-like receptors as well as the adenosine triphosphate receptor P2X7, and the interleukin-1 receptor. There is now great interest in how inflammasome pathways are regulated. The initial challenge is to understand how an acute inflammatory response is sustained. This is a significant issue as the known stimuli result in an acute response that is self-limited to under 24 h. This suggests that there are significant regulators which allow sustained inflammasome activation in conditions such as non-alcoholic steatohepatitis and alcoholic hepatitis. PMID- 25034284 TI - Purinergic signaling in liver disease. AB - Adenosine triphosphate (ATP) is essential for the myriad of metabolic processes upon which life is based and is known widely as the universal energy currency unit of intracellular biologic reactions. ATP, adenosine diphosphate, adenosine, as well as other purines and pyrimidines also serve as ubiquitous extracellular mediators which function through the activation of specific receptors (viz. P2 receptors for nucleotides and purinergic P1 receptors for adenosine). Extracellular nucleotides are rapidly converted to nucleosides, such as adenosine, by highly regulated plasma membrane ectonucleotidases that modulate many of the normal biological and metabolic processes in the liver - such as gluconeogenesis and insulin signaling. Under inflammatory conditions, as with ischemia reperfusion, sepsis or metabolic stress, ATP and other nucleotides can also act as 'damage-associated molecular patterns' causing inflammasome activation in innate immune cells and endothelium resulting in tissue damage. The phosphohydrolysis of ATP by ectonucleotidases, such as those of the CD39/ENTPD family, results in the generation of immune suppressive adenosine, which in turn markedly limits inflammatory processes. Experimental studies by others and our group have implicated purinergic signaling in experimental models of hepatic ischemia reperfusion and inflammation, transplant rejection, hepatic regeneration, steatohepatitis, fibrosis and cancer, amongst others. Expression of ectonucleotidases on sinusoidal endothelial, stellate or immune cells allows for homeostatic integration and linking of the control of vascular inflammatory and immune cell reactions in the liver. CD39 expression also identifies hepatic myeloid dendritic cells and efficiently distinguishes T-regulatory-type cells from other resting or activated T cells. Our evolving data strongly indicate that CD39 serves as a key 'molecular switch' and is an integral component of the suppressive machinery of myeloid, dendritic and T cells. Increased understanding of mechanisms of extracellular ATP scavenging and specifically conversion to nucleosides by ectonucleotidases of the CD39 family have also led to novel insights into the exquisite balance of nucleotide P2-receptor and adenosinergic P1-receptor signaling in inflammatory and hepatic diseases. Further, CD39 and other ectonucleotidases exhibit genetic polymorphisms in humans which alter levels of expression/function and are associated with predisposition to inflammatory and immune diseases, diabetes and vascular calcification, amongst other problems. Development of therapeutic strategies targeting purinergic signaling and ectonucleotidases offers promise for the management of disordered inflammation and aberrant immune reactivity. PMID- 25034285 TI - The HCV life cycle: in vitro tissue culture systems and therapeutic targets. AB - Hepatitis C virus (HCV) is a highly variable plus-strand RNA virus of the family Flaviviridae. Viral strains are grouped into six epidemiologically relevant genotypes that differ from each other by more than 30% at the nucleotide level. The variability of HCV allows immune evasion and facilitates persistence. It is also a substantial challenge for the development of specific antiviral therapies effective across all HCV genotypes and for prevention of drug resistance. Novel HCV cell culture models were instrumental for identification and profiling of therapeutic strategies. Concurrently, these models revealed numerous host factors critical for HCV propagation, some of which have emerged as targets for antiviral therapy. It is generally assumed that the use of host factors is conserved among HCV isolates and genotypes. Additionally, the barrier to viral resistance is thought to be high when interfering with host factors. Therefore, current drug development includes both targeting of viral factors but also of host factors essential for virus replication. In fact, some of these host-targeting agents, for instance inhibitors of cyclophilin A, have advanced to late stage clinical trials. Here, we highlight currently available cell culture systems for HCV, review the most prominent host-targeting strategies against hepatitis C and critically discuss opportunities and risks associated with host-targeting antiviral strategies. PMID- 25034286 TI - Viral hepatitis and liver transplantation: pathogenesis, prevention and therapy of recurrent disease. AB - Cirrhosis secondary to hepatitis C virus infection is the leading cause of liver transplantation in most countries. Hepatitis C has an accelerated course after transplantation, and for this reason graft and patient survival are decreased in comparison with other indications of liver transplantation. The development of direct-acting antivirals has been a major step in the management of hepatitis C and in a few years from now the infection will be eradicated with the combination of oral drugs with a good safety profile. This will likely allow prevention of hepatitis C recurrence in most cases. Meanwhile, management of hepatitis C virus infection still relies on the combination of interferon, ribavirin and the first generation protease inhibitors telaprevir and boceprevir. PMID- 25034287 TI - The pathogenesis of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. The multikinase inhibitor sorafenib still remains the only approved agent for advanced HCC. In most cases, HCC develops based on advanced liver cirrhosis, whereas the underlying risk factors can be identified in the vast majority of patients. METHODS: Here, we summarise and review the pathomechanisms in dependence of the underlying disease, gene signatures and frequent mutations in HCC. RESULTS: Worldwide, HCC is most commonly caused by viral hepatitis B and C. It is less frequently associated with chronic exposure to toxins or hereditary liver diseases. Non-alcoholic fatty liver disease is an emerging risk factor with increasing prevalence nowadays. Emerging innovative technologies including whole-genome or -exome analyses have been applied for molecular and prognostic classifications as well as therapeutic implications. Mutations leading to activation of the Wnt pathway and inactivation of p53 were most frequently identified in HCC. CONCLUSIONS: Recent advances have significantly improved our understanding of the molecular pathogenesis of HCC and its complex genetic landscape. The emerging data will open the door towards novel and more effective targeted and personalized therapies in this devastating disease. PMID- 25034288 TI - Treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia. Several studies have shown that HCC is the main cause of death in patients with cirrhosis. A better knowledge of the natural history of the tumor and the development of staging systems has allowed to refine the prognosis of the patients. The Barcelona Clinic Liver Cancer system (BCLC) has become the preferred staging system since it takes into account the tumor characteristics, the degree of liver impairment and the physical performance. It has been endorsed by several scientific associations and research consortia as it does not just define prognosis, but, more interestingly, it links staging with prognosis assessment and treatment recommendation. Curative therapies such as resection, transplantation and ablation can improve survival in patients diagnosed at an early HCC stage and may offer a long-term cure with overall survival that may exceed 70% at 5 years. Patients with intermediate stage HCC benefit from chemoembolization and proper selection of candidates permits a 50% survival at 3 4 years. Finally, patients diagnosed at an advanced stage benefit from sorafenib, an oral available, multikinase inhibitor with antiangiogenic and antiproliferative effects. Current research efforts are aimed at further refining prognosis prediction through molecular profiling and enhanced clinical characterization. At the same time, better knowledge of the molecular mechanisms of cancer should result in a further improvement of the current life expectancy of patients. PMID- 25034289 TI - Molecular pathogenesis of cholangiocarcinoma. AB - It has become increasingly apparent of late that inflammation plays an integral role in a spectrum of malignancies including cholangiocarcinoma (CCA). Primary sclerosing cholangitis with chronic inflammation is the most common risk factor for CCA in the Western world. Recent work has highlighted that inflammatory pathways are essential in carcinogenesis and tissue invasion and migration. Inflammation advances carcinogenesis by induction of DNA damage, evasion of apoptosis, promotion of cell proliferation, and neoangiogenesis. CCA is characterized by the presence of a desmoplastic stroma consisting of cancer associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating lymphocytes. This rich inflammatory milieu is vital to the cancer ecosystem, and targeting its components represents an attractive therapeutic option. PMID- 25034290 TI - Update on the management of cholangiocarcinoma. AB - Cholangiocarcinoma (CC) is a rare cancer arising from the epithelium of the biliary tree, anywhere from the small peripheral hepatic ducts to the distal common bile duct. Classification systems for CC typically group tumours by anatomical location into intrahepatic, hilar or extrahepatic subtypes. Surgical resection or liver transplantation remains the only curative therapy for CC, but up to 80% of patients present with advanced, irresectable disease. Unresectable CC remains resistant to many chemotherapeutic agents, although gemcitabine, particularly in combination with other agents, has been shown to improve overall survival. Ongoing investigation of biological agents has also yielded some promising results. Several novel interventional and endoscopic techniques for the diagnosis and management of non-operable CC have been developed: initial results show improvements in symptoms and progression-free survival, but further randomised studies are required to establish their role in the management of CC. PMID- 25034291 TI - Adipocyte cell death, fatty liver disease and associated metabolic disorders. AB - Obesity has reached epidemic proportions in the U.S.A. and many other parts of the world. Obesity increases the risk of a number of adverse health conditions including type 2 diabetes, insulin resistance, dyslipidemia, hypertension, and hepatic steatosis. Adipocyte hypertrophy occurs during weight gain and is associated with recruitment of immune cells, mainly macrophages, into the adipose tissue (AT). These cells typically surround a dying or dead adipocyte with the formation of crown-like structures that are present in experimental models of obesity as well as obese humans. The immune infiltration of AT results in increased production of various adipokines, cytokines, and chemokines that play a crucial role in the development of insulin resistance and hepatic steatosis. The pathogenic mechanisms resulting in AT macrophage recruitment are under intense investigation and remain incompletely understood. Recent evidence suggests that various programmed cell death pathways are activated in stressed hypertrophied adipocytes and may result in cell death. These events appear to occur at early stages and be important in triggering the metabolic dysregulation associated with obesity. PMID- 25034292 TI - Non-alcoholic fatty liver disease: diagnosis and investigation. AB - Given the worldwide increase in obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD is associated with increased hepatic and extrahepatic morbidity and mortality, mainly related to non-alcoholic steatohepatitis with fibrosis. An early diagnosis in the high-risk population with features of insulin resistance and a proper identification of those patients with progressive liver disease are needed. Practicing physicians dealing with NAFLD should be aware of and should carefully evaluate the extended spectrum of NAFLD-related extrahepatic diseases, which significantly affects liver- and non-liver-related prognosis. This clinical practice-oriented article reviews the diagnostic methods and staging strategies for NAFLD and proposes an investigational algorithm for a global evaluation of NAFLD patients. PMID- 25034293 TI - Treatment of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of chronic liver disease in developed countries. Treatment depends on the stage of disease, and non-invasive methods for risk stratification are urgently needed. Lifestyle modification (aimed at weight loss and increasing physical activity) and management of the features of metabolic syndrome are vital for all patients with NAFLD. Metformin is the first-line therapy for diabetic patients with NAFLD and also reduces the risk of hepatocellular carcinoma. Clinicians should have a low threshold for introducing a statin for the management of dyslipidaemia. Antihypertensive agents that target the renin-angiotensin system should be first line in NAFLD for the management of hypertension. For patients with progressive disease, liver-directed pharmacotherapy with vitamin E should be considered. Non alcoholic steatohepatitis cirrhosis is an increasingly common indication for liver transplantation. PMID- 25034294 TI - IgG4-associated cholangitis. AB - IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease (IgG4-RD), a systemic fibroinflammatory disorder with a wide variety of clinical presentations and organ manifestations. IgG4-RD predominantly affects the hepatobiliary tract (IAC) and pancreas (autoimmune pancreatitis) and mimics hepatobiliary, pancreatic and other malignancies. Patients typically are 60-80 years old and 80-85% are male. They often present with painless obstructive jaundice and organ swelling that can be mistaken for pancreatic or bile duct cancer, as well as primary or secondary sclerosing cholangitis. An accurate diagnostic marker is lacking and extensive surgery for presumed malignant hepatobiliary or pancreatic disease leads to the diagnosis of IgG4-RD in 1 of 3 patients. Early effective immunosuppressive treatment is often missed. The pathogenesis of IgG4-RD has been enigmatic. We recently identified dominant IgG4+ B-cell receptor clones in blood and tissue of patients with IAC, but not in healthy or disease controls, and hypothesized that specific B-cell responses are pivotal to the pathogenesis of IAC and IgG4-RD. Analysis of our Amsterdam cohort and blinded extramural validation of the Oxford cohort of patients with IgG4-RD disclosed a remarkable association with 'blue collar work'. Thus, long-term exposure to solvents and other organic agents might predispose to IgG4-RD. PMID- 25034295 TI - Coagulopathy in liver diseases: complication or therapy? AB - Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagulation to a parallel reduction of both pro- and anticoagulant factors. Cirrhosis is therefore no longer considered a hypocoagulable state but rather a more unstable hemostatic balance with a lower threshold for tipping toward thrombosis or bleeding. Tendency to bleeding in cirrhosis is due to the reduction in the synthesis of procoagulants and a low platelet count as well as hyperfibrinolysis. Variceal hemorrhage is a frequent bleeding complication in decompensated cirrhosis. However, the possible contribution of coagulopathy as a precipitant or an aggravating factor is poorly documented and further data are required to clarify its real contributing role. Moreover, apart from the gastrointestinal tract, the occurrence of spontaneous and procedure-related bleeding elsewhere in the body, whilst not uncommon, is less than would be expected. By contrast, a large-scale population-based study has shown the propensity towards venous thrombosis in patients with liver diseases. Portal vein thrombosis (PVT) is a critical but frequent event occurring in up to 40% of patients with liver cirrhosis. PVT causes deterioration of the clinical course, the complications of portal hypertension and an increase in post-transplant mortality. The pathogenesis of PVT includes both local alterations, like blood flow reduction and endothelial activation, and systemic derangement. Systemic prohemostatic alterations include high von Willebrand factor, low ADAMTS-13, low levels of anticoagulants (antithrombin, proteins C and S) and increases in procoagulants like factor VIII. Low-molecular-weight heparin such as enoxaparin has proven to be safe and effective in both the treatment and prevention of PVT. In addition, patients in prophylaxis with enoxaparin showed a lower rate of decompensation and a better survival without bleeding complications. In such patients, circulating bacterial DNA, endotoxemia and markers of inflammation were attenuated compared to controls. These results therefore suggest a possible connection between enoxaparin, decrease of endotoxemia and reduction of portal hypertension. The approach to the coagulopathy in patients with liver diseases is changing: while the main goal for clinicians so far has been to reduce the risk of bleeding, the results of these new studies highlight the importance of preventing or treating thrombophilic disorders like PVT to avoid microcirculatory damage and eventually liver decompensation. PMID- 25034296 TI - Pathogenesis of primary biliary cirrhosis and its fatigue. AB - Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterised by a breakdown of immune tolerance to mitochondrial and nuclear antigens, causing injury to the biliary epithelial cells (BEC) lining the small intrahepatic bile ducts. This leads to bile duct injury and the retention of hydrophobic bile acids which cause further BEC injury leading to a self sustaining cycle of bile duct injury. Initially the BEC respond to injury via a homeostatic response including through proliferation. Ultimately they become senescent; an active process with accompanying release of inflammatory cytokines ('the senescent secretome') which contributes to the process of interface hepatitis which is a feature of high-risk and treatment-unresponsive disease. This model for pathogenesis of PBC has implications for potential therapy approaches in targeting both the 'upstream' immune injury and 'downstream' BEC response to the immune injury. Fatigue is the commonest reported symptom in PBC and has a negative impact on patients' perceived quality of life, often through social isolation. It is unrelated to the severity of liver disease and appears unresponsive to current therapies, including ursodeoxycholic acid and transplantation. Fatigue in PBC is complex, with numerous associated peripheral and CNS features. Initially, cholestasis causes degenerative CNS change affecting areas of the brain regulating autonomic dysfunction and sleep, and these changes lead directly to some manifestations of fatigue and the associated cognitive impairment. In addition to this, the anti-mitochondrial antibody has direct muscle level metabolic effects leading to over-utilisation of anaerobic metabolism. Autonomic dysfunction contributes to the impact of this metabolic change by limiting the capacity of the muscle to respond through increased proton/lactate efflux from cells and outflow from tissues. The model has a number of implications for potential therapy approaches. PMID- 25034297 TI - Evidence-based treatment of primary biliary cirrhosis. AB - The natural history of primary biliary cirrhosis (PBC) has improved greatly during the past two decades because of its diagnosis at earlier stages and the widespread use of ursodeoxycholic acid as first-line treatment. As a result, far fewer patients require liver transplantation and patients diagnosed with early stage disease appear to have a normal life expectancy. The evidence-based treatment of PBC is reviewed here. The challenge of designing and executing high quality clinical trials as well as lessons from past clinical trials are discussed. The rationales for the use of budesonide and new investigational therapies (PPAR and FXR agonists) as well as their therapeutic potential in light of recent available data are also reviewed. An algorithm of the management of PBC patients responding or not to ursodeoxycholic acid is proposed. PMID- 25034298 TI - Therapeutic role of bile acids and nuclear receptor agonists in fibrosing cholangiopathies. AB - Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g., obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3-4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC. PMID- 25034299 TI - Advances in pathogenesis and management of pruritus in cholestasis. AB - Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, MU-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the MU-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis. PMID- 25034302 TI - Cor a 14: missing link in the molecular diagnosis of hazelnut allergy? AB - BACKGROUND: Hazelnut allergy shows distinct clinical patterns that can be predicted through component-resolved diagnosis. However, identification of sensitization profiles remains incomplete. METHODS: Sera of 75 patients allergic to hazelnuts, 14 infants with atopic dermatitis (AD) sensitized to hazelnuts, 15 hazelnut-tolerant individuals with specific IgE (sIgE) to hazelnuts and 15 healthy control individuals were tested for sIgE reactivity to rCor a 1.04, rCor a 8, nCor a 9, nCor a 11, rCor a 14, rBet v 1, rBet v 2 and cross-reactive carbohydrate determinants (CCDs). RESULTS: Sensitization to Cor a 14 was observed in 18 out of 20 preschool children, 8 out of 10 school-aged children and 2 out of 7 adults with generalized reactions and in 3 out of 14 infants with AD. Only 2 out of 38 patients with an oral allergy syndrome (OAS) were sensitized to Cor a 14. No sensitization to Cor a 14 was observed in the group of hazelnut-tolerant and healthy control individuals. Sensitization to Cor a 1.04 was seen in 36 out of 38 OAS patients and in 14 out of 37 patients with generalized reactions. However, only 3 patients with generalized reactions were monosensitized to Cor a 1.04. Sensitization to Cor a 9 was observed in 26 out of 37 patients with generalized reactions and in 4 out of 14 infants with AD. Sensitization to Cor a 11, Cor a 8, rBet v 2 and CCDs was rare. CONCLUSIONS: Sensitization to Cor a 14 can have early onset and shows age-related variations. Together with Cor a 9, Cor a 14 enables us to correctly identify almost 90% of children with generalized reactions to hazelnut. PMID- 25034303 TI - Oral care may reduce pneumonia in the tube-fed elderly: a preliminary study. AB - Pneumonia is one of the most important diseases in terms of mortality in the elderly. In particular, bedridden patients who are forbidden oral ingestion during enteral nutrition may have a poor outcome resulting from a respiratory infection. Oral hygiene can play a positive role in preventing aspiration pneumonia in the elderly. The aim of this study was to investigate the effectiveness of oral hygiene for bedridden and tube-fed patients at an increased risk of pneumonia. This retrospective study was conducted from July 2011 to June 2013 on a long-term-care hospital unit. The oral care protocol (OCP) intervention commenced in July 2012, during the study period. The subjects of this study were 63 elderly patients with a mean age of 81.7 years. Thirty-one patients were enrolled in the OCP intervention group, and the mean observation length was 130.4 days; the mean observation length for the 32 patients in the control group was 128.4 days. The incidence of pneumonia and the numbers of days with a recorded fever, antibiotics administration, blood tests, and radiological examinations were reduced from 1.20 to 0.45, 24.57 to 17.48, 25.52 to 10.12, 10.91 to 6.54, and 6.33 to 3.09 %, respectively. These reductions were significantly less in the OCP intervention group. In conclusion, the results of the present study suggest that daily oral care for tube-fed patients who do not receive nutrition by mouth reduced the incidence of pneumonia. In addition to patients consuming food by mouth, all tube-fed patients require dedicated oral care to maintain healthy oral conditions. PMID- 25034304 TI - Inhibition of stress induced premature senescence in presenilin-1 mutated cells with water soluble Coenzyme Q10. AB - A water-soluble formulation of CoQ10 (WS-CoQ10) was shown to stabilize mitochondria and prevent oxidative stress-induced neuronal death. Presenilin-1 (PS-1)-mutated Alzheimer's Disease (AD) fibroblasts (PSAF) were used for studying the effects of PS-1 mutation. PS-1 mutation correlated to increased reactive oxygen species (ROS) production and stress induced premature senescence (SIPS) in PSAF; WS-CoQ10 treatment decreased ROS generation, increased population doublings, and postponed SIPS. Treated PSAF had higher PCNA expression, and lower levels of MnSOD, p21, p16Ink4A, and Rb. WS-CoQ10 caused the resumption of autophagy in PSAF. Thus, WS-CoQ10 as inhibitor of SIPS and ameliorator of autophagy could be an effective prophylactic/therapeutic agent for AD. PMID- 25034305 TI - Mesenchymal stem cells and hypoxia: where are we? AB - Multipotent mesenchymal stromal cells (MSCs) are involved in the organization and maintenance of tissue integrity. MSCs have also attracted attention as a promising tool for cell therapy and regenerative medicine. However, their usage is limited due to cell impairment induced by an extremely harsh microenvironment during transplantation ex vivo. The microenvironment of MSCs in tissue depots is characterized by rather low oxygen consumption, demonstrating that MSCs might be quite resistant to oxygen limitation. However, accumulated data revealed that the response of MSCs to hypoxic conditions is rather controversial, demonstrating both damaging and ameliorating effects. Here, we make an attempt to summarize recent knowledge on the survival of MSCs under low oxygen conditions of varying duration and severity and to elucidate the mechanisms of MSC resistance/sensitivity to hypoxic impact. PMID- 25034307 TI - Middle East respiratory syndrome: what clinicians need to know. AB - A severe viral illness caused by a newly discovered coronavirus was first reported in the Middle East in 2012. The virus has since been named the Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV cases have been reported in several countries around the world in travelers from the Middle East. The illness has a high mortality rate. Limited human-to-human transmission has occurred including transmission to health care workers. The source of the virus remains unclear, but camels are a possible source. Two unrelated imported cases of MERS-CoV have been reported in the United States. Neither a vaccine nor effective therapy against the virus is available. International cooperation and information sharing will be key to understanding and ending the MERS-CoV outbreak. PMID- 25034306 TI - High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects. AB - Repurposing of FDA-approved drugs with effects on mitochondrial function might shorten the critical path to mitochondrial disease drug development. We improved a biosensor-based assay of mitochondrial O2 consumption, and identified mitofunctional defects in cell models of LHON and FXTAS. Using this platform, we screened a 1600-compound library of clinically used drugs. The assay identified drugs known to affect mitochondrial function, such as metformin and decoquinate. We also identified several drugs not previously known to affect mitochondrial respiration including acarbose, metaraminol, gallamine triethiodide, and acamprosate. These previously unknown 'mitoactives' represent novel links to targets for mitochondrial regulation and potentially therapy, for mitochondrial disease. PMID- 25034308 TI - Sedentary behavior, cardiorespiratory fitness, physical activity, and cardiometabolic risk in men: the cooper center longitudinal study. AB - OBJECTIVE: To examine the association between sedentary behavior and cardiometabolic risk, while taking into account cardiorespiratory fitness (fitness) and physical activity. PARTICIPANTS AND METHODS: We examined the association of sedentary behavior, physical activity, and fitness (exposure variables) to cardiometabolic biomarkers and metabolic syndrome (outcome measures) among a historic cohort (January 2, 1981, through October 16, 2012) of men. First, we estimated the association (cross-sectionally and longitudinally) of sedentary behavior along with physical activity and fitness to lipids and lipoproteins, glucose, blood pressure, and markers of adiposity, including body mass index, waist circumference, and body fat percentage. We then prospectively examined the effects of baseline sedentary time on the incidence of metabolic syndrome, while adjusting for physical activity, fitness, and other covariates in multivariate models. RESULTS: Multivariate analysis of baseline data revealed that in comparison with the reference group (<=9 h/wk of sedentary time), more sedentary behavior was significantly associated with a higher triglyceride level, a higher triglycerides-high-density lipoprotein cholesterol ratio, and a higher body mass index, waist circumference, and body fat percentage (P<.05 for trend), after adjusting for physical activity and covariates. When adjusting for fitness and covariates, prolonged sedentary time was only associated with a higher triglyceride-high-density lipoprotein cholesterol ratio (P=.02 for trend). Sedentary time was not associated with the incidence of metabolic syndrome in multivariate models. Longitudinal analyses revealed that a 1-metabolic equivalent increase in fitness was significantly (P<.05) associated with almost all biomarkers when adjusting for sedentary behavior, with little moderation observed. CONCLUSION: The association between prolonged sedentary time and cardiometabolic biomarkers is markedly less pronounced when taking fitness into account. Further exploration of the effects of sedentary behavior on cardiometabolic risk is warranted in cohorts with available fitness data. Furthermore, our findings underscore the need to encourage achieving higher fitness levels through meeting physical activity guidelines to decrease disease risk factors. PMID- 25034309 TI - Salvage of a post-traumatic arthritic wrist using the scaphoid as an osteochondral graft. AB - The authors describe a case of post-traumatic wrist arthritis with an osteochondral defect in the scaphoid fossa of the radius. The patient was treated with proximal row carpectomy, radial styloidectomy and reconstruction of the defect using the proximal half of the scaphoid as an autologous osteochondral graft. Pain relief was achieved while wrist motion and strength were improved. The carpal bones are a source of osteochondral grafts and can be used to expand the indications of motion-preserving wrist salvage procedures. PMID- 25034310 TI - The ameliorative effect of propolis against methoxychlor induced ovarian toxicity in rat. AB - A study was designed to evaluate ameliorative effect of propolis against methoxychlor (MXC) induced ovarian toxicity in rat. The organochlorine pesticide (MXC) is a known endocrine disruptor with estrogenic, anti-estrogenic, and anti androgenic properties. To investigate whether chronic exposure to MXC could cause ovarian dysfunction, two groups of Sprague-Dawley adult female rats were exposed to MXC alone in a dose of 200mg/kg, twice/weekly, orally or MXC dose as previous plus propolis in a dose of 200mg/l/day, in drinking water for 10 months. Another two groups of rat were given corn oil (control) or propolis. Multiple reproductive parameters, ovarian weight, serum hormone levels, ovarian oxidative status and ovarian morphology were examined. In MXC-exposed group, there is a significant decrease in body and ovarian weight vs. control. MXC decreases serum estradiol and progesterone levels. A significant increase in the levels of lipid peroxidation was obtained while a significant decrease of the total antioxidant was recorded. Ovarian histopathology showed primary, secondary and vesicular follicles displaying an atretic morphology. Increase in the ovarian surface epithelium height accompanied with vacuolated, pyknotic oocytes were obtained. The previous toxic effects were neutralized by the administration of propolis in MXC+propolis group. The present results suggest that propolis may be effective in decreasing of MXC-induced ovarian toxicity in rat. PMID- 25034311 TI - Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. AB - This report summarizes a 5-year phase 1/2 allogeneic islet transplantation clinical trial conducted at the University of Illinois at Chicago (UIC). Ten patients were enrolled in this single center, open label, and prospective trial in which patients received 1-3 transplants. The first four subjects underwent islet transplantation with the Edmonton immunosuppressive regimen and the remaining six subjects received the UIC immunosuppressive protocol (Edmonton plus etanercept and exenatide). All 10 patients achieved insulin independence after 1 3 transplants. At 5 years of follow-up, 6 of the initial 10 patients were free of exogenous insulin. During the follow-up period, 7 of the 10 patients maintained positive C-peptide levels and a composite hypoglycemic score of 0. Most patients maintained HbA1c levels <6.0 % (42.1 mmol/mol) and a significantly improved beta score. In conclusion, this study demonstrated long-term islet graft function without using T cell depleting induction, with an encouraging outcome that includes 60 % of patients remaining insulin independent after 5 years of initial transplantation. PMID- 25034312 TI - Efficacy and safety of the pterional keyhole approach for the treatment of anterior circulation aneurysms. AB - Keyhole surgery is partly replacing the standard pterional approach in patients undergoing surgery to treat aneurysms of the anterior circulation. We describe the pterional keyhole approach for the clipping of anterior circulation aneurysms and discuss the efficacy and safety of our keyhole craniotomy procedure. We treated 103 patients with 111 intracranial aneurysms by surgical clipping via the pterional keyhole approach and retrospectively compared the characteristics and clinical outcomes of the keyhole procedure and the standard pterional approach. We also compared the surgical results of the keyhole approach when the operator was an experienced neurosurgeon or a less experienced neurosurgeon guided by an experienced colleague. All keyhole operations were carried out successfully without enlargement of the craniotomy or a change to a different approach. The outcomes of the keyhole and the standard pterional approach in patients with subarachnoid hemorrhage were not significantly different. Favorable outcomes were obtained in patients with unruptured aneurysms treated by either experienced or less experienced surgeons. The pterional keyhole approach offers the same surgical possibilities as conventional pterional approaches for the treatment of anterior circulation aneurysms. It is safe and simple and yields favorable outcomes even if the operators are less experienced neurosurgeons. Careful patient selection and sufficient opening of the sylvian fissure are the key points for good outcomes and the prevention of intraoperative complications. PMID- 25034314 TI - The impact of puberty and social anxiety on amygdala activation to faces in adolescence. AB - Adolescence is associated with the onset of puberty, shifts in social and emotional behavior and an increased vulnerability to social anxiety disorder. These transitions coincide with changes in amygdala response to social and affective stimuli. Utilizing an emotional face-matching task, we examined amygdala response to peer-aged neutral and fearful faces in relation to puberty and social anxiety in a sample of 60 adolescent females between the ages of 8 and 15 years. We observed amygdala activation in response to both neutral and fearful faces compared to the control condition but did not observe differential amygdala activation between fearful and neutral faces. Right amygdala activity in response to neutral faces was negatively correlated with puberty and positively correlated with social anxiety, and these effects were statistically independent. Puberty and social anxiety did not relate to amygdala activation in response to fearful faces. These findings suggest that emotional differentiation between fearful and neutral faces may arise during later pubertal development and may result from decreasing sensitivity to neutral faces rather than increasing sensitivity to threatening faces. Furthermore, these findings highlight the importance of considering individual differences in social anxiety when examining the neural response to social stimuli in adolescents. PMID- 25034315 TI - Effect of vitamin D3 supplementation on serum 25(OH)D, lipids and markers of insulin resistance in obese adolescents: a prospective, randomized, placebo controlled pilot trial. AB - BACKGROUND/AIMS: To determine the effect of vitamin D3 supplementation on 25 hydroxyvitamin D [25(OH)D], lipid profile and markers of insulin resistance in obese adolescents. METHODS: In this double-blind, randomized, placebo-controlled trial, 58 obese adolescents (n = 58; 12-18 years of age) received either vitamin D3 (2,000 IU/day) or placebo for 12 weeks. Total 25(OH)D, fasting plasma glucose, insulin and lipid profile were measured at baseline and following supplementation. RESULTS: The trial was completed by 44/58 enrolled participants. At the end of the 12 weeks, total serum 25(OH)D concentrations increased to a modest degree (median 6 ng/ml) in the vitamin D-supplemented group (p < 0.001). Supplementation showed no detectable changes in fasting plasma glucose, insulin, homeostatic model of assessment index (HOMA-IR), lipids and highly sensitive C reactive protein. CONCLUSIONS: 12 weeks of vitamin D3 supplementation in obese adolescents with 2,000 IU once daily resulted in a modest increase in 25(OH)D concentration in obese adolescents, but did not affect the lipid profile and markers of insulin resistance and inflammation. Further studies with higher doses of vitamin D3 and/or longer duration of supplementation are needed to understand if vitamin D3 supplementation can impact lipid profiles and markers of insulin resistance and inflammation in obese children. PMID- 25034316 TI - Surgical training of anastomotic technique using Thiel cadavers. PMID- 25034317 TI - Adaptive-weighted bilateral filtering and other pre-processing techniques for optical coherence tomography. AB - This paper presents novel pre-processing image enhancement algorithms for retinal optical coherence tomography (OCT). These images contain a large amount of speckle causing them to be grainy and of very low contrast. To make these images valuable for clinical interpretation, we propose a novel method to remove speckle, while preserving useful information contained in each retinal layer. The process starts with multi-scale despeckling based on a dual-tree complex wavelet transform (DT-CWT). We further enhance the OCT image through a smoothing process that uses a novel adaptive-weighted bilateral filter (AWBF). This offers the desirable property of preserving texture within the OCT image layers. The enhanced OCT image is then segmented to extract inner retinal layers that contain useful information for eye research. Our layer segmentation technique is also performed in the DT-CWT domain. Finally we describe an OCT/fundus image registration algorithm which is helpful when two modalities are used together for diagnosis and for information fusion. PMID- 25034318 TI - The unprecedented catalytic activity of alkanolamine CO2 scrubbers in the cycloaddition of CO2 and oxiranes: a DFT endorsed study. AB - A novel application of alkanolamines, widely employed as CO2 scrubbers in catalyzing the insertion of CO2 into epoxides generating cyclic carbonates in excellent yield and selectivity via the synergistic activity of hydroxyl and amine groups, is unravelled along with computational studies. PMID- 25034319 TI - Observation of an intrinsic bandgap and Landau level renormalization in graphene/boron-nitride heterostructures. AB - Van der Waals heterostructures formed by assembling different two-dimensional atomic crystals into stacks can lead to many new phenomena and device functionalities. In particular, graphene/boron-nitride heterostructures have emerged as a very promising system for band engineering of graphene. However, the intrinsic value and origin of the bandgap in such heterostructures remain unresolved. Here we report the observation of an intrinsic bandgap in epitaxial graphene/boron-nitride heterostructures with zero crystallographic alignment angle. Magneto-optical spectroscopy provides a direct probe of the Landau level transitions in this system and reveals a bandgap of ~38 meV (440 K). Moreover, the Landau level transitions are characterized by effective Fermi velocities with a critical dependence on specific transitions and magnetic field. These findings highlight the important role of many-body interactions in determining the fundamental properties of graphene heterostructures. PMID- 25034320 TI - Rivaroxaban for the treatment of venous thromboembolism. A "real-life" perspective in 103 patients. AB - INTRODUCTION: Randomized clinical trials have demonstrated non-inferiority of rivaroxaban compared with vitamin K antagonists (VKAs) in the treatment of venous thromboembolism (VTE). Our objective was to analyze in real life, tolerance, recurrence, bleeding and adverse events of rivaroxaban in patients with acute symptomatic VTE. MATERIAL AND METHODS: Open follow-up study of a cohort of patients aged 18 and over diagnosed with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) treated with rivaroxaban from December 2011 to January 2014. RESULTS: The total number of patients treated with rivaroxaban was 103. The mean age was 58+/-17 years. The most frequent co-morbidities were: hypertension (30.0%), dyslipidemia (23.3%) and respiratory disease (25.2%). The type of thromboembolic event treated was: DVT (64.1%), PE (18.4%), DVT+PE (17.5%). Of the rivaroxaban-treated patients, 30% did so from the initial anticoagulant therapy and the other 70% in long-term or extended anticoagulant therapy. The median time of treatment with rivaroxaban was 6 months [corrected]. There was one recurrence and no deaths occurred. Six patients had bleeding, one of which was severe. CONCLUSIONS: Rivaroxaban provides a therapeutic alternative in a group of patients with VTE with advantages over VKAs, because of the convenience in dosing, lack of requirements for periodic monitoring and limited interaction with other drugs. PMID- 25034321 TI - Increased risk of venous thromboembolism in patients with dermatomyositis/polymyositis: a nationwide cohort study. AB - OBJECTIVES: The number of previous studies on the risk of venous thromboembolism (VTE) in patients with dermatomyositis/polymyositis (DM/PM) is limited. Therefore, we conducted a nationwide retrospective cohort study to investigate the effects of DM/PM on the risk of VTE. METHODS: We identified patients with newly diagnosed DM/PM in Taiwan between 2000 and 2010 using the National Health Insurance Research Database (NHIRD) and the Catastrophic Illness Patient Database. Each DM/PM patient was frequency-matched to 4 control patients according to age, sex, and index year. All of the patients were observed from the index date until the occurrence of a VTE event, censor, or until December 31, 2010. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of VTE in the DM/PM and comparison cohorts using the Cox proportional hazards regression model. RESULTS: We followed up with the 2031 DM/PM patients (67.8% women, mean age of 46.1 y) and 8124 control patients for 9987 and 48 081 person years, respectively. The DM/PM patients exhibited an 11.1-fold increased risk of VTE compared with that of the non-DM/PM comparison cohort after adjusting for age, sex, and comorbidities (95% CI=5.21-23.6). The older patients with DM/PM exhibited a multiplicative increased risk of VTE development compared with that of the control patients (adjusted HR=26.8, 95% CI=8.55-84.2), and the DM/PM patients with any comorbidity showed an additive risk of developing VTE (adjusted HR=33.3, 95% CI=11.2-99.4). CONCLUSION: The risk of VTE is significantly higher in DM/PM patients than in non-DM/PM patients. PMID- 25034322 TI - D-dimer level predicts in-hospital mortality in patients with infective endocarditis: a prospective single-centre study. AB - BACKGROUND: Increased circulating D-dimer levels have been correlated with adverse outcomes in various clinical conditions. To our knowledge, the association of on-admission D-dimer and in-hospital mortality in infective endocarditis (IE) has not been investigated. We hypothesized that increased on admission D-dimer levels would correlate with adverse outcomes when prospectively studied in patients with IE. METHODS: In this prospective study, a total of 157 consecutive patients with the definite IE diagnosis met the inclusion criteria and underwent testing for on-admission D-dimer and CRP assays. The outcome measure was in-hospital death from any cause. RESULTS: In-hospital mortality occurred in 40 (26%) patients. Increased levels of plasma D-dimer (5.1 +/- 1.7 vs 1.9 +/- 0.8, p<0.001), CRP [45(13-98) vs 12(5-28), p<0.001] were found in dead patients compared with those survived. In addition to S. aureus infection, increased leukocyte count, end-stage renal disease, LVEF<50%, vegetation size of >10mm, perivalvular abscess, on-admission D-dimer (HR: 1.32; 95% CI: 1.24-1.40; p<0.001) and CRP (HR: 1.18; 95% CI: 1.09-1.36; p=0.001) levels were significantly associated with in-hospital mortality. Furthermore, the sensitivity and specificity of D-dimer >= 4.2mg/L in predicting in-hospital death in IE were 86% and 85%, respectively. Moreover, the sensitivity and specificity of CRP levels >= 13.6 mg/L were 72% and 69%, respectively. CONCLUSION: Our findings suggest that on-admission D-dimer level may be a simple, available and valuable biomarker that allows us to identify high-risk IE patients for in-hospital mortality. D-dimer >= 4.2mg/L, CRP >= 13.6 mg/L were independently associated with IE related in hospital death. PMID- 25034323 TI - Does dabigatran interfere with intraablation heparinization? PMID- 25034324 TI - Associated changes in the transcription levels of IL-17A and tight junction associated genes in the duodenal mucosa of rhesus macaques repeatedly exposed to simian/human immunodeficiency virus. AB - BACKGROUND: Mucosal barrier dysfunction might play a key role in HIV/AIDS, yet the early effects of HIV-1 on intestinal mucosal barrier, especially tight junctions (TJ) have not been well addressed. AIMS: To investigate the effects of acute HIV-1 infection on the expression of intestinal IL-17A and TJ-associated genes using an NHP-AIDS model. METHODS: TaqMan probe real-time RT-PCR methods were established and claudin-1, claudin-3, occludin and zonula occluden-1 (ZO-1) mRNA levels in the duodenal biopsies of rhesus macaques collected before and after rectal exposures to SHIV-SF162P4 were examined and compared with that of IL 17A, IL-6, TGF-beta, RORgammat, T-bet, Foxp-3 and GATA-3. RESULTS: The mRNA levels of TJ-associated genes were statistically significantly reduced soon after viral exposures and the mRNA levels of claudin-1, occludin and ZO-1 in viral positive tissues (from Group I) were lower than that in viral negative tissues (from Group II) after viral exposure. IL-17A mRNA levels were also decreased and positively correlated with the mRNA levels of the TJ-associated genes after viral exposure or infection, although the levels of IL-6, TGF-beta and RORgammat mRNA showed no statistical difference. The levels of GATA-3 mRNA in tissues collected before viral exposure were statistically different between Group I and Group II animals. The balance between T-bet and GATA-3 mRNA levels in Group II was markedly altered and statistically significantly different from that in Group I. CONCLUSIONS: Acute SHIV, and by extension HIV infection could affect the expression of TJ-associated genes, probably through IL-17A and other immune alterations. PMID- 25034325 TI - Safety of physical examination alone for managing well-appearing neonates >= 35 weeks' gestation at risk for early-onset sepsis. AB - OBJECTIVE: The published data to support recommendations for prevention and management of well-appearing at-risk newborns (WAARNs) for early-onset sepsis (EOS) are limited. METHODS: Retrospective cohort study comparing two different strategies for managing WAARNs (>= 35 weeks' gestation) during a 6-year period (Period 1, from 2005 to 2007; Period 2, from 2009 to 2011). WAARNs were defined as healthy-appearing neonates evaluated because of risk factors for EOS. Laboratory evaluation plus simplified physical examination (Period 1) was compared with physical examination alone (PEA, Period 2). The use of antibiotics, the length of stay, the timeliness of diagnosis and the risk of falling ill immediately after hospital discharge in both periods were also compared. RESULTS: WAARNs receiving empirical antibiotics were 14/500 (Period 1) and 3/500 (Period 2, p = 0.01). Median length of stay was 4 (Period 1) and 3 days (Period 2, p = 0.04). Symptoms of EOS were earlier than laboratory evaluation results in 42/44 neonates. Severe disease was diagnosed within 6 h of life in all neonates. No WAARNs presented with EOS following hospital discharge. CONCLUSIONS: WAARNs managed through PEA received less unnecessary antibiotics and had a shorter length of stay. They had no increased risk of severe complications or increased risk of becoming ill following hospital discharge. PMID- 25034326 TI - Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231 human breast cancer cell lines. AB - BACKGROUND: Development of tumour resistance to chemotherapeutic drugs and concerns over their toxic effects has led to the increased use of medicinal herbs or natural products by cancer patients. Strobilanthes crispus is a traditional remedy for many ailments including cancer. Its purported anticancer effects have led to the commercialization of the plant leaves as medicinal herbal tea, although the scientific basis for its use has not been established. We previously reported that a bioactive subfraction of Strobilanthes crispus leaves (SCS) exhibit potent cytotoxic activity against human breast cancer cell lines. The current study investigates the effect of this subfraction on cell death activities induced by the antiestrogen drug, tamoxifen, in estrogen receptor responsive and nonresponsive breast cancer cells. METHODS: Cytotoxic activity of SCS and tamoxifen in MCF-7 and MDA-MB-231 human breast cancer cells was determined using lactate dehydrogenase release assay and synergism was evaluated using the CalcuSyn software. Apoptosis was quantified by flow cytometry following Annexin V and propidium iodide staining. Cells were also stained with JC-1 dye to determine changes in the mitochondrial membrane potential. Fluorescence imaging using FAM-FLICA assay detects caspase-8 and caspase-9 activities. DNA damage in the non-malignant breast epithelial cell line, MCF-10A, was evaluated using Comet assay. RESULTS: The combined SCS and tamoxifen treatment displayed strong synergistic inhibition of MCF-7 and MDA-MB-231 cell growth at low doses of the antiestrogen. SCS further promoted the tamoxifen-induced apoptosis that was associated with modulation of mitochondrial membrane potential and activation of caspase-8 and caspase-9, suggesting the involvement of intrinsic and extrinsic signaling pathways. Interestingly, the non-malignant MCF-10A cells displayed no cytotoxicity or DNA damage when treated with either SCS or SCS-tamoxifen combination. CONCLUSIONS: The combined use of SCS and lower tamoxifen dose could potentially reduce the side effects/toxicity of the drug. However, further studies are needed to determine the effectiveness and safety of the combination treatment in vivo. PMID- 25034327 TI - A modified nomogram for ramp treadmill testing using the Veterans Specific Activity Questionnaire. AB - Studies performed over the past 2 decades have supported the recommendation that the exercise test protocol be individualized and that a targeted duration of 8 to 12 minutes is optimal. However, this is not always implemented clinically because of the complication of having to choose a specific ramp to match a patient. We present a simple nomogram based on a questionnaire to choose 1 of 4 possible ramp protocols that provide individualized ramp rates for subjects undergoing clinical exercise testing. PMID- 25034328 TI - Pentatricopeptide repeat motifs in the processing enzyme PRORP1 in Arabidopsis thaliana play a crucial role in recognition of nucleotide bases at TpsiC loop in precursor tRNAs. AB - Proteinaceous RNase P (PRORP1) in Arabidopsis thaliana is an endoribonuclease that catalyzes hydrolysis to remove the 5'-leader sequence of precursor tRNAs (pre-tRNAs). PRORP1 is composed of pentatricopeptide repeat (PPR) motifs, a central linker region, and a metal nuclease domain, the NYN domain. The PPR motifs are single-stranded RNA-binding motifs that recognize bases in a modular fashion. To obtain insight into the mechanism by which the PPR motifs in PRORP1 recognize a target sequence in catalysis, N-terminal successive deletion mutants were overproduced in Escherichia coli, and the resulting proteins were characterized in terms of enzymatic activity using chloroplast pre-tRNA(Phe) as a substrate. Although Delta89, in which all PPR motifs are present, retained the pre-tRNA cleavage activity, Delta129 devoid of the first PPR motif (PPR1) had significantly reduced cleavage activity. Likewise, deletions of the second (PPR2) or third PPR (PPR3) motif abolished the cleavage activity, suggesting that PPR motifs play a crucial role in catalysis. A proposed recognition code for PPR motifs predicted that PPR2-PPR5 in PRORP1 recognize C, A/U, A, and U, respectively, whose sequence is in good agreement with C56-A57-A58-A59 in the TpsiC loop in pre-tRNA(Phe). Mutational analyses of nucleotide residues in the TpsiC loop as well as nucleotide-specifying residues (NSRs) in PPR motifs further suggested that PPR2 and PPR3 in PRORP1 favorably recognize nucleotide bases C56 and A57 at the TpsiC loop in pre-tRNA(Phe), respectively. This prediction and previous biochemical data were combined to construct a fitting model of tRNA onto PRORP1, showing that the mechanism by which PRORP1 recognizes pre-tRNAs appears to be distinct from that by bacterial RNase P. PMID- 25034329 TI - Live-cell topology assessment of URG7, MRP6102 and SP-C using glycosylatable green fluorescent protein in mammalian cells. AB - Experimental tools to determine membrane topology of a protein are rather limited in higher eukaryotic organisms. Here, we report the use of glycosylatable GFP (gGFP) as a sensitive and versatile membrane topology reporter in mammalian cells. gGFP selectively loses its fluorescence upon N-linked glycosylation in the ER lumen. Thus, positive fluorescence signal assigns location of gGFP to the cytosol whereas no fluorescence signal and a glycosylated status of gGFP map the location of gGFP to the ER lumen. By using mammalian gGFP, the membrane topology of disease-associated membrane proteins, URG7, MRP6102, SP-C(Val) and SP-C(Leu) was confirmed. URG7 is partially targeted to the ER, and inserted in Cin form. MRP6102 and SP-C(Leu/Val) are inserted into the membrane in Cout form. A minor population of untargeted SP-C is removed by proteasome dependent quality control system. PMID- 25034330 TI - A prospective study to evaluate the efficacy of Cistiquer in improving lower urinary tract symptoms in females with urethral syndrome. AB - AIM: The aim of the study was to compare Cistiquer, a new phytotherapeutic product developed for chronic bladder inflammatory diseases, and intra-vesical administration of gentamicin plus betametasone, in females with urethral syndrome. METHODS: Between september 2013 and may 2014, 60 women with urethral syndrome and trigonitis were incuded in this study. Patients were randomly assigned to treatment with intra-vesical administration of betametasone 8 mg plus gentamicin 80 mg (group A), and oral administration of Cistiquer (group B) for 7 weeks. Before and after the therapeutic protocol, symptoms were assessed by three days voiding diary, the overactive bladder questionnaire short form and a ten points visual analogic scale adopted to assess the micturition discomfort. Histologic findings were assessed by the examination of specimens obtained by cold bladder biopsies of the bladder trigone at baseline in all the subjects. RESULTS: The two groups had significant and comparable symptoms improvement. However, the score obtained from the visual analogic scale decreased significantly only in the group submitted to oral therapy. Furthermore, in the group treated with endovesical approach, higher drop out rate and higher incidence of urinary infection were observed. CONCLUSION: Patients with urethral syndrome and trigonitis improved symptoms either with oral therapy with Cistiquer and with intra-vesical administration of gentamicin plus betametasone. However, treatment adherence resulted higher for patients treated by oral therapy and rate of adverse events resulted higher for those submitted to endovesical treatment. PMID- 25034331 TI - Comparing the validity of the self reporting questionnaire and the Afghan symptom checklist: dysphoria, aggression, and gender in transcultural assessment of mental health. AB - BACKGROUND: The relative performance of local and international assessment instruments is subject to ongoing discussion in transcultural research on mental health and psychosocial support. We examined the construct and external validity of two instruments, one developed for use in Afghanistan, the other developed by the World Health Organization for use in resource-poor settings. METHODS: We used data collected on 1003 Afghan adults (500 men, 503 women) randomly sampled at three sites in Afghanistan. We compared the 22-item Afghan Symptom Checklist (ASCL), a culturally-grounded assessment of psychosocial wellbeing, with Pashto and Dari versions of the 20-item Self-Reporting Questionnaire (SRQ-20). We derived subscales using exploratory and confirmatory factor analyses (EFA and CFA) and tested total and subscale scores for external validity with respect to lifetime trauma and household wealth using block model regressions. RESULTS: EFA suggested a three-factor structure for SRQ-20--somatic complaints, negative affect, and emotional numbing--and a two-factor structure for ASCL--jigar khun (dysphoria) and aggression. Both factor models were supported by CFA in separate subsamples. Women had higher scores for each of the five subscales than men (p < 0.001), and larger bivariate associations with trauma (rs .24 to .29, and .10 to .19, women and men respectively) and household wealth (rs -.27 to -.39, and .05 to -.22, respectively). The three SRQ-20 subscales and the ASCL jigar khun subscale were equally associated with variance in trauma exposures. However, interactions between gender and jigar khun suggested that, relative to SRQ-20, the jigar khun subscale was more strongly associated with household wealth for women; similarly, gender interactions with aggression indicated that the aggression subscale was more strongly associated with trauma and wealth. CONCLUSIONS: Two central elements of Afghan conceptualizations of mental distress -aggression and the syndrome jigar khun--were captured by the ASCL and not by the SRQ-20. The appropriateness of the culturally-grounded instrument was more salient for women, indicating that the validity of instruments may be gender differentiated. Transcultural validation processes for tools measuring mental distress need to explicitly take gender into account. Culturally relevant measures are worth developing for long-term psychosocial programming. PMID- 25034332 TI - Role of mitochondrial permeability transition pore and mitochondrial ATP sensitive potassium channels in the protective effects of ischemic preconditioning in isolated hearts from fed and fasted rats. AB - The aim of the present study was to assess whether the protective effects of ischemic preconditioning (PC) are associated with activation of the mitochondrial ATP-sensitive potassium channels (mitoKATP) and if there is any relationship between the activity of these channels and the mitochondrial permeability transition pore (MPTP) opening in ischemic-reperfused rat hearts under different nutritional conditions. Langendorff-perfused hearts of fed and 24-h fasted rats were exposed to 25 min of no-flow global ischemia plus 30 min of reperfusion. Fasting accelerated functional recovery and attenuated MPTP opening. The mitoKATP blocker, 5-hydroxydecanoic (HD), did not influence functional recovery and MPTP opening induced by ischemia-reperfusion in the fed hearts but partially reversed the beneficial effects of fasting. PC and the mitoKATP opener, diazoxide (DZ), improved functional recovery, preserved cell viability, and inhibited MPTP opening in both fed and fasted hearts. The protection elicited by PC and DZ on contractile recovery and MPTP opening was reversed by HD, which did not affect cell viability. Altogether, these results argue for a role of mitoKATP and its impact on preservation mitochondrial inner membrane permeability as a relevant factor in the improvement of contractile function in the ischemic-reperfused rat heart. They also suggest that the functional protection elicited by PC may be related to this mechanism. PMID- 25034333 TI - Levels of polybrominated diphenyl ethers in settled house dust from urban dwellings with resident preschool-aged children in Nanjing, China. AB - We investigated the levels and possible determinants of polybrominated diphenyl ethers (PBDEs) in the settled house-dust (SHD) of urban dwellings with resident preschool-aged children in Nanjing, China. The possible neurodevelopmental effects of house-dust PBDEs were also explored. SHD was collected from 216 urban houses. Levels of 8 PBDEs were measured by gas chromatography-negative chemical ionization mass spectrometry. The Child Behavior Checklist and the Gesell Development Inventory were used to evaluate the child's development. BDE47, BDE99, BDE153, BDE18, and BDE209 were detected in the SHD of >90 % of houses, of which BDE209 predominated. Most PBDEs were found at significantly greater levels in indoor than in outdoor dust (P < 0.05). Levels of BDE28 and BDE154 in houses with solid-wood floors were significantly greater than those in houses with plywood floors (P < 0.05). BDE154 levels in houses with wallpaper were significantly greater than those without wallpaper (P < 0.05). Greater BDE47 concentrations were found in houses with less natural ventilation time (linear trend P < 0.05). After dichotomization at the geometric mean concentration, BDE209 and total BDEs showed significant risks for depressed behavior problems and lower personal social developmental quotients (DQs); BDE99 and BDE153 indicated a risk for lower personal social DQs. In conclusion, PBDEs (especially BDE209) are ubiquitous in urban SHD in Nanjing residences. Natural ventilation and floor materials potentially influence PBDE levels in SHD. The potential adverse effect of postnatal exposure to PBDEs on the behavior and neurodevelopment of preschool-age children requires follow-up in larger studies. PMID- 25034334 TI - Oribatid mite communities on lichens in heavily contaminated post-smelting dumps. AB - In this study, we examined oribatid fauna of strongly contaminated post-smelting dumps (southern Poland) that exist in the substrate and are associated with the most frequent lichen, Cladonia rei. Due to artificial origin of the substrate and the extremely high contamination with heavy metals, the studied dumps are unique in Europe in terms of unfavourable life conditions. In total, 2,936 specimens of Oribatida, representing 50 oribatid species, were sampled on 10 dumps and a reference site. Thalli of C. rei act as an island for soil oribatid mites on extremely contaminated post-smelting dumps. Both abundance and species richness of oribatid fauna collected from C. rei thalli were significantly greater than those recorded in the dump's substrate. The pool of oribatid species that was able to persist in extremely high doses of heavy metals was comparatively broad. However, only one species, Tectocepheus velatus, was able to achieve high abundances on all dumps. Three different responses of species (tolerant, sensitive, and indifferent) to heavy-metal contamination were recognised. Redundancy analysis indicated that highly increased levels of heavy metals, as well as K content, C/N ratio, and pH value, were the main factors that influence the composition and distribution of species. The concentrations of heavy metals (both essential elements (zinc) as well as xenobiotics (lead, cadmium) in T. velatus from the most contaminated dumps were not increased compared with those observed in moderately contaminated soils. PMID- 25034335 TI - Composite hyoid bone graft interposition for the treatment of laryngotracheal stenosis. AB - INTRODUCTION: Chronic laryngotracheal stenosis (LTS) remains a challenging problem for otolaryngologists. A composite hyoid bone interposition graft has the potential to be an ideal graft because the head and neck surgeon can obtain the graft in the same operative field with good vascular supply from the muscle pedicle. METHODS: A composite hyoid interposition graft was used to provide structural support for the reconstructed lumen of the larynx or trachea in 2 cases of LTS. RESULTS: Two patients underwent successful decannulation with acceptable laryngeal function over a long-term observation period. CONCLUSION: This technique allows vascularized stable graft survival with minimal donor site morbidity. Furthermore, it can be performed for thyroid, cricoid, and tracheal stenosis without fear of damage to the recurrent laryngeal nerves. PMID- 25034336 TI - Stocking density and Piscirickettsia salmonis infection effect on Patagonian blennie (Eleginops maclovinus, Cuvier 1830) skeletal muscle intermediate metabolism. AB - The need to expand aquaculture production has led to other fish to be considered as potential species for culture, such as the sub-Antarctic notothenioid Eleginops maclovinus (Valenciennes, 1830). The aim of this study was to determine the cumulative effect of density and pathogen infection by protein extract of Piscirickettsia salmonis on skeletal muscle metabolism. In a first experiment, specimens were submitted to three different stocking densities: (1) 3.1 kg m(-3), (2) 15 kg m(-3) and (3) 60 kg m(-3), for a period of 10 days. In a second experiment, metabolic changes caused by an infection of P. salmonis protein extract (a single injection of 0.5 MUL P. salmonis protein extract g body weight( 1) was inoculated in the fish) and its combined effect with stocking density was assessed during a period of 10 days. This study concludes that stress caused by high stocking density led to the reorganization of some metabolic routes to fulfill skeletal muscle energy needs. Furthermore, infection response by pathogen P. salmonis differed when stocking density increased, suggesting an increase of energy needs with density in skeletal muscle of infected fish. PMID- 25034338 TI - A simple model of group selection that cannot be analyzed with inclusive fitness. AB - A widespread claim in evolutionary theory is that every group selection model can be recast in terms of inclusive fitness. Although there are interesting classes of group selection models for which this is possible, we show that it is not true in general. With a simple set of group selection models, we show two distinct limitations that prevent recasting in terms of inclusive fitness. The first is a limitation across models. We show that if inclusive fitness is to always give the correct prediction, the definition of relatedness needs to change, continuously, along with changes in the parameters of the model. This results in infinitely many different definitions of relatedness - one for every parameter value - which strips relatedness of its meaning. The second limitation is across time. We show that one can find the trajectory for the group selection model by solving a partial differential equation, and that it is mathematically impossible to do this using inclusive fitness. PMID- 25034337 TI - Simulations suggest pharmacological methods for rescuing long-term potentiation. AB - Congenital cognitive dysfunctions are frequently due to deficits in molecular pathways that underlie the induction or maintenance of synaptic plasticity. For example, Rubinstein-Taybi syndrome (RTS) is due to a mutation in cbp, encoding the histone acetyltransferase CREB-binding protein (CBP). CBP is a transcriptional co-activator for CREB, and induction of CREB-dependent transcription plays a key role in long-term memory (LTM). In animal models of RTS, mutations of cbp impair LTM and late-phase long-term potentiation (LTP). As a step toward exploring plausible intervention strategies to rescue the deficits in LTP, we extended our previous model of LTP induction to describe histone acetylation and simulated LTP impairment due to cbp mutation. Plausible drug effects were simulated by model parameter changes, and many increased LTP. However no parameter variation consistent with a effect of a known drug class fully restored LTP. Thus we examined paired parameter variations consistent with effects of known drugs. A pair that simulated the effects of a phosphodiesterase inhibitor (slowing cAMP degradation) concurrent with a deacetylase inhibitor (prolonging histone acetylation) restored normal LTP. Importantly these paired parameter changes did not alter basal synaptic weight. A pair that simulated the effects of a phosphodiesterase inhibitor and an acetyltransferase activator was similarly effective. For both pairs strong additive synergism was present. The effect of the combination was greater than the summed effect of the separate parameter changes. These results suggest that promoting histone acetylation while simultaneously slowing the degradation of cAMP may constitute a promising strategy for restoring deficits in LTP that may be associated with learning deficits in RTS. More generally these results illustrate how the strategy of combining modeling and empirical studies may provide insights into the design of effective therapies for improving long-term synaptic plasticity and learning associated with cognitive disorders. PMID- 25034339 TI - How to not get stuck-negative feedback due to crowding maintains flexibility in ant foraging. AB - Ant foraging is an important model system in the study of adaptive complex systems. Many ants use trail pheromones to recruit nestmates to resources. Differential recruitment depending on resource quality coupled with positive feedback allows ant colonies to make rapid and accurate collective decisions about how best to allocate their work-force. However, ant colonies can become trapped in sub-optimal foraging decisions if recruitment to a poor resource becomes too strong before a better resource is discovered. Genetic algorithms and Ant Colony Optimisation heuristics can also suffer from being trapped in such local optima. Recently, two negative feedback effects were described, in which an increase in crowding (crowding negative feedback-CNF) or trail pheromones (pheromone negative feedback-PNF) caused a decrease in subsequent pheromone deposition. Using agent based simulations with realistic parameters I test whether these negative feedback effects can prevent simulated ant colonies from becoming trapped in sub-optimal foraging decisions. Colonies are presented with two food sources of different qualities, and these qualities switch part way through the experiment. When either no negative feedback effects are implemented or only PNF is implemented colonies are completely unable to refocus their foraging effort to the high quality feeder. However, when CNF alone is implemented at a realistic level 97% of colonies successfully refocus their foraging effort. This ability to refocus colony foraging efforts is due to the strong reduction of pheromone deposition caused by CNF. This suggests that CNF is an important behaviour enabling ant colonies to maintain foraging flexibility. However, CNF comes at a slight cost to colonies when making their initial foraging decision. PMID- 25034340 TI - Adolescent physical activity and inactivity: a prospective study of risk of benign breast disease in young women. AB - In previous investigations of adolescent activity recalled in adulthood, modest reductions in risk of benign breast disease (BBD) and premenopausal breast cancer were seen with moderate-strenuous activity during high school. We therefore investigated physical activity, walking, and recreational inactivity (watching TV videos, playing computer-videogames) reported by adolescent girls in relation to their subsequent risk for BBD as young women. The Growing Up Today Study includes 9,039 females, 9-15 years at study initiation (1996), who completed questionnaires annually through 2001, then in 2003, 2005, 2007, 2010 and 2013. Annual surveys (1996-2001) obtained data on physical and sedentary activities during the past year. Beginning in 2005, women (>=18 years) reported whether they had ever been diagnosed with BBD confirmed by breast biopsy (n = 133 cases, to 11/01/2013). Logistic regression (adjusted for baseline adiposity and age; additional factors in multivariable-adjusted models) estimated associations between adolescent activities (moderate-vigorous, walking, METS, inactivity) and biopsy-confirmed BBD in young women. Girls who walked the most had significantly lower risk of BBD (multivariable-adjusted OR = 0.61, >=30 vs <=15 min/day; p = .049). We observed no evidence that inactivity (>=3 vs <2 h/day OR = 1.02, p = .92) or METS (top vs bottom tertile OR = 1.19, p = .42) were associated with BBD. Accounting for factors including family history, childhood adiposity, and other activities and inactivities, adolescent girls who walked the most were at lower risk for BBD. We found no evidence that high moderate-vigorous activity might reduce risk, nor did we observe any association with inactivity. Continued follow up will re-evaluate these findings as more BBD cases, and ultimately breast cancer, are diagnosed. PMID- 25034341 TI - Stimulus-to-matching-stimulus interval influences N1, P2, and P3b in an equiprobable Go/NoGo task. AB - Previous research has shown that as the stimulus-to-matching-stimulus interval (including the target-to-target interval, TTI, and nontarget-to-nontarget interval, NNI) increases, the amplitude of the P300 ERP component increases systematically. Here, we extended previous P300 research and explored TTI and NNI effects on the various ERP components elicited in an auditory equiprobable Go/NoGo task. We also examined whether a similar mechanism was underpinning interval effects in early ERP components (e.g., N1). Thirty participants completed a specially-designed variable-ISI equiprobable task whilst their EEG activity was recorded. Component amplitudes were extracted using temporal PCA with unrestricted Varimax rotation. As expected, N1, P2, and P3b amplitudes increased as TTI and NNI increased, however, Processing Negativity (PN) and Slow Wave (SW) did not show the same systematic change with interval increments. To determine the origin of interval effects in sequential processing, a multiple regression analysis was conducted on each ERP component including stimulus type, interval, and all preceding components as predictors. These analyses showed that matching-stimulus interval predicted N1, P3b, and weakly predicted P2, but not PN or SW; SW was determined by P3b only. These results suggest that N1, P3b, and to some extent, P2, are affected by a similar temporal mechanism. However, the dissimilar pattern of results obtained for sequential ERP components indicates that matching-stimulus intervals are not affecting all aspects of stimulus processing. This argues against a global mechanism, such as a pathway-specific refractory effect, and suggests that stimulus processing is occurring in parallel pathways, some of which are not affected by temporal manipulations of matching stimulus interval. PMID- 25034342 TI - Administration of a selective beta2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease. AB - Currently, there are no available approaches to cure or slow down the progression of Alzheimer's disease (AD), which is characterized by the accumulation of extracellular amyloid-beta (Abeta) deposits and intraneuronal tangles that comprised hyperphosphorylated tau. The beta2 adrenergic receptors (beta2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to AD; however, these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent beta-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here, we show that administration of ICI 118,551 (ICI), a selective beta2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased Abeta levels and Abeta plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic inhibition of beta2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between beta2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of beta blockers on AD. PMID- 25034343 TI - Weighted brain networks in disease: centrality and entropy in human immunodeficiency virus and aging. AB - Graph theory models can produce simple, biologically informative metrics of the topology of resting-state functional connectivity (FC) networks. However, typical graph theory approaches model FC relationships between regions (nodes) as unweighted edges, complicating their interpretability in studies of disease or aging. We extended existing techniques and constructed fully connected weighted graphs for groups of age-matched human immunodeficiency virus (HIV) positive (n = 67) and HIV negative (n = 77) individuals. We compared test-retest reliability of weighted versus unweighted metrics in an independent study of healthy individuals (n = 22) and found weighted measures to be more stable. We quantified 2 measures of node centrality (closeness centrality and eigenvector centrality) to capture the relative importance of individual nodes. We also quantified 1 measure of graph entropy (diversity) to measure the variability in connection strength (edge weights) at each node. HIV was primarily associated with differences in measures of centrality, and age was primarily associated with differences in diversity. HIV and age were associated with divergent measures when evaluated at the whole graph level, within individual functional networks, and at the level of individual nodes. Graph models may allow us to distinguish previously indistinguishable effects related to HIV and age on FC. PMID- 25034344 TI - Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease. AB - A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer's disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2(PP2A), or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-beta protein. Dietary supplementation with EHT for 6-12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD. PMID- 25034346 TI - Structure and sequence based analysis of alpha-amylase evolution. AB - alpha-Amylases hydrolyze alpha- 1,4-glycosidic bonds during assimilation of biological macromolecules. The amino acid sequences of these enzymes in thousands of diverse organisms are known and the 3D structures of several proteins have been solved. The 3D structure analysis of these universal enzymes from diverse organisms has been studied by the generation of phylogenetic trees and structure based sequence analysis to generate a metric for the degree of conservation that is responsible for individual speciation. Greater similarities are observed between reference NCBI tree and structure based phylogenetic tree compared to sequence based phylogenetic tree indicating that structures truly represent the functional aspects of proteins than from the sequence information alone. We report differences in the profile specific conserved and insertion/deletion regions, factors responsible for the Ca(2+) and Cl(-) ion binding and the disulfide connectivity pattern that discriminate the enzymes over evolution. PMID- 25034345 TI - Correlates of smoking susceptibility among adolescents in a peri-urban area of Nepal: a population-based cross-sectional study in the Jhaukhel-Duwakot Health Demographic Surveillance Site. AB - BACKGROUND: Susceptibility to smoking is defined as an absence of firm commitment not to smoke in the future or when offered a cigarette by best friends. Susceptibility begins in adolescence and is the first step in the transition to becoming an established smoker. Many scholars have hypothesized and studied whether psychosocial risk factors play a crucial role in preventing adolescent susceptibility to smoking or discourage susceptible adolescents from becoming established smokers. Our study examined sociodemographic and family and childhood environmental factors associated with smoking susceptibility among adolescents in a peri-urban area of Nepal. DESIGN: We conducted a population-based cross sectional study during October-November 2011 in the Jhaukhel-Duwakot Health Demographic Surveillance Site (JD-HDSS) located in a peri-urban area near Kathmandu, the capital city of Nepal, where tobacco products are easily available. Trained local enumerators conducted face-to-face interviews with 352 respondents aged 14-16. We used stepwise logistic regression to assess sociodemographic and family and childhood environmental factors associated with smoking susceptibility. RESULTS: The percentage of smoking susceptibility among respondents was 49.70% (95% CI: 44.49; 54.93). Multivariable analysis demonstrated that smoking susceptibility was associated with smoking by exposure of adolescents to pro-tobacco advertisements (AOR [adjusted odds ratio] =2.49; 95% CI: 1.46-4.24), the teacher (2.45; 1.28-4.68), adolescents attending concerts/picnics (2.14; 1.13-4.04), and smoking by other family members/relatives (1.76; 1.05-2.95). CONCLUSIONS: Smoking susceptible adolescents are prevalent in the JD-HDSS, a peri-urban community of Nepal. Several family and childhood environmental factors increased susceptibility to smoking among Nepalese non smoking adolescents. Therefore, intervention efforts need to be focused on family and childhood environmental factors with emphasis on impact of role models smoking, refusal skills in social gatherings, and discussing harmful effects of smoking with family members and during gatherings with friends. PMID- 25034347 TI - Counter-advertising may reduce parent's susceptibility to front-of-package promotions on unhealthy foods. AB - OBJECTIVE: Assess the effect of counter-advertisements on parents' appraisals of unhealthy foods featuring front-of-package promotions (FOPPs). DESIGN: A 2 * 2 * 5 between-subjects Web-based experiment. Parents were randomly shown an advertisement (counter-advertisement challenging FOPP/control advertisement) and then a pair of food products from the same category: an unhealthy product featuring an FOPP (nutrient content claim/sports celebrity endorsement) and a healthier control product with no FOPP. SETTING: Australia. PARTICIPANTS: A total of 1,269 Australian-based parents of children aged 5-12 years recruited from an online panel. MAIN OUTCOME MEASURES: Parents nominated which product they would prefer to buy and which they thought was healthier, then rated the unhealthy product and FOPP on various characteristics. ANALYSIS: Differences between advertisement conditions were assessed using logistic regression (product choice tasks) and analysis of variance tests (ratings of unhealthy product and FOPP). RESULTS: Compared with parents who saw a control advertisement, parents who saw a counter-advertisement perceived unhealthy products featuring FOPPs as less healthy, expressed weaker intentions for buying such products, and were more likely to read the nutrition facts panel before nominating choices (all P < .001). CONCLUSIONS AND IMPLICATIONS: Counter-advertising may help reduce the misleading influence of unhealthy food marketing and improve the accuracy of parents' evaluations of how nutritious promoted food products are. PMID- 25034348 TI - Tracer kinetic model selection for dynamic contrast-enhanced magnetic resonance imaging of locally advanced cervical cancer. AB - BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a unique capability to probe tumour microvasculature. Different analysis of the acquired data will possibly lead to different conclusions. Therefore, the objective of this study was to investigate under which conditions the Tofts (TM), extended Tofts (ETM), compartmental tissue uptake model (C-TU) and 2-compartment exchange model (2CXM) were the optimal tracer kinetic models (TKMs) for the analysis of DCE-MRI in patients with cervical cancer. MATERIAL AND METHODS: Ten patients with locally advanced cervical cancer (FIGO: IIA/IIB/IIIB/IVA - 1/5/3/1) underwent DCE-MRI prior to radiotherapy. From the two-parameter TM it was possible to extract the forward volume transfer constant (K(trans)) and the extracellular-extravascular volume fraction (ve). From the three-parameter ETM, additionally the plasma volume fraction (vp) could be extracted. From the three parameter C-TU it was possible to extract information about the blood flow (Fp), permeability-surface area product (PS) and vp. Finally, the four-parameter 2CXM extended the C-TU to include ve. For each voxel, corrected Akaike information criterion (AICc) values were calculated, taking into account both the goodness-of fit and the number of model parameters. The optimal model was defined as the model with the lowest AICc. RESULTS: All four TKMs were the optimal model in different contiguous regions of the cervical tumours. For the 24 999 analysed voxels, the TM was optimal in 17.0%, the ETM was optimal in 2.2%, the C-TU in 23.4% and the 2CXM was optimal in 57.3%. Throughout the tumour, a high correlation was found between K(trans)(TM) and Fp(2CXM), rho = 0.91. CONCLUSION: The 2CXM was most often optimal in describing the contrast agent enhancement of pre-treatment cervical cancers, although this model broke down in a subset of the tumour voxels where overfitting resulted in non-physiological parameter estimates. Due to the possible overfitting of the 2CXM, the C-TU was found more robust and when 2CXM was excluded from comparison the C-TU was the preferred model. PMID- 25034349 TI - Capture rate and representativity of The National Prostate Cancer Register of Sweden. AB - BACKGROUND: Capture rate and representativity of quality registers need to be assessed in order to ensure that register data are generalizable. MATERIAL AND METHODS: In 1998-2009, 103 047 men had been diagnosed with prostate cancer and registered in the Swedish Cancer Register to which registration is mandated by law and of these men, 100 849 men (98%) had also been registered in The National Prostate Cancer Register (NPCR) of Sweden. We compared demographics, cancer treatment, comorbidity, and mortality in men in NPCR, with those who had only been registered in the Cancer Register, by use of data from the Cause of Death Register, the In-Patient Register and the Prescribed Drug Register. In addition, we identified 1929 men who had prostate cancer as underlying cause of death in the Cause of Death Register who had neither been registered in the Cancer Register nor in NPCR. RESULTS: Compared to men in NPCR, men only registered in the Cancer Register were slightly older, median age 72 versus 71 years, and a lower proportion underwent radical prostatectomy, 15% versus 27%. Ten year prostate cancer mortality was 23% (95% CI 20-25) for men in the Cancer Register only and 24% (95% CI 24-25) in NPCR, while mortality from competing causes was 28% (95% CI 26-31) and 30% (95% CI 30-30), respectively. Men identified with prostate cancer by a death certificate were old and had high comorbidity. CONCLUSION: The capture rate of NPCR is very high and there are only modest differences in demographics, cancer treatment, comorbidity, and mortality between the small proportion of men only registered in the Cancer Register and men registered in NPCR, indicating that information in NPCR can be generalized to all men with prostate cancer in Sweden. PMID- 25034350 TI - Long-term functional and radiological pulmonary changes after radiation therapy for breast cancer. AB - BACKGROUND: We assessed late functional and radiological pulmonary changes in breast cancer patients after a median of 11 years following radiotherapy (RT). MATERIAL AND METHODS: Seventy women who received adjuvant loco-regional RT for breast cancer during November 1994-May 1998 accepted to participate in this follow-up study. Pulmonary function tests (PFTs) (n = 56) were compared to pre-RT examinations and diagnostic computer tomography (CT) of the lungs (n = 70) were performed and compared to four months post-RT examinations. RESULT: The median matched vital capacity (VC), forced expiratory volume in one second (FEV1), and total lung capacity (TLC) were reduced 15%, 9%, and 7%, respectively, at the long term follow-up (p < 0.001). We could not, however, detect a correlation between ipsilateral V20 and VC-changes. Diffusion capacity (DLCO) appeared to improve compared with the pre-RT baseline level probably due to transient chemotherapy induced toxicity. The median-matched percentage of the predicted DLCO 11 years after RT was, however, only 86%, indicating a chronic therapy-induced reduction also of this metric. According to the Arriagada classification, ipsilateral V20 and long-term CT-changes showed a significant correlation (rs: 0. 57; p < 0.001) in a small subset of the women. CONCLUSION: A chronic clinically significant reduction of PFTs compared to pre-RT values and CT-changes four months after RT were still detectable after a median follow-up of 11 years. There was a statistical correlation between V20 and abnormalities on CT but no statistical correlation between V20 and VC-changes. PMID- 25034351 TI - Commissioners defend policies on surgery referrals amid accusations of rationing. PMID- 25034352 TI - A new symmetrical tetramer oligostilbenoid containing tetrahydrofuran ring from the stem bark of Dryobalanops lanceolata. AB - A new tetramer oligostilbenoid possessing tetrahydrofuran ring, malaysianol C (1), was isolated from the acetone extract of the stem bark of Dryobalanops lanceolata, together with four known oligostilbenoids nepalensinol E (2), epsilon viniferin (3), laevifonol (4), and ampelopsin F (5). The structures of isolated compounds were elucidated on the basis of spectral evidence. The antibacterial activity of the isolated compounds was evaluated using resazurin microtitre-plate assay, whereas the cytotoxic activity was tested using MTT assay. The plausible biogenetic routes of the isolated compounds are also discussed. PMID- 25034353 TI - Scaly erythematous perineal dermatitis in twins. PMID- 25034354 TI - Temporal and regional variations in sporadic Creutzfeldt-Jakob disease in Japan, 2001-2010. AB - The objective of this study was to examine temporal and regional variations of sporadic Creutzfeldt-Jakob disease (sCJD) in a retrospective study using Japanese national surveillance data from 2001 to 2010. We calculated the incidence of sCJD by age and sex, derived the standardized incidence in each of the 47 prefectures, and performed spatial disease clustering analysis. The average annual incidence of sCJD was 1.026 per million in men (637 patients) and 1.132 per million in women (733 patients), a significant sex difference after adjustment for age (P = 0.001). The ratios of familial CJD to sCJD apparently increased between 2001-2005 and 2006-2010, possibly as a result of the nationwide introduction of genetic testing after 2006. Based on the data of 2006-2010, certain geographical clusters of sCJD were identified. The incidence of sCJD was higher in several specific prefectures compared to the national average. Thus, sCJD appears to have regional variations, suggesting the existence of genetic or region-specific factors affecting the incidence of the disease. PMID- 25034355 TI - Comparison osteopontin vs AFP for the diagnosis of HCC: a meta-analysis. AB - BACKGROUNDS: Osteopontin (OPN) has been reported as one of the most promising markers for hepatocellular carcinoma (HCC). The goal of this meta-analysis was to evaluate the clinical value of the plasma OPN versus alpha-fetoprotein (AFP) in the diagnosis of HCC. METHODS: A comprehensive literature search of PubMed, Foreign Medical Journal Service, Chinese Science Journals Database, and Google Scholar was conducted on articles published before 1st October 2013. The sensitivity, specificity, and other measures of accuracy of OPN in the diagnosis of HCC were pooled using random effects models. The methodological quality of each study was assessed by QUADAS (quality assessment for studies of diagnostic accuracy). Statistical analysis was performed by employing Meta-Disc 1.4 and Stata, version 12. Summary receiver operating characteristic curves were used to summarize overall test performance. RESULTS: Seven studies were included in our meta-analysis. The summary estimates for OPN and AFP in the diagnosis of HCC in these studies as follows: sensitivity, 0.86 (0.79-0.91) vs 0.66 (0.53-0.76), specificity, 0.86 (0.69-0.94) vs 0.95 (0.87-0.98), positive likelihood ratio (PLR), 6.10 (2.43-15.32) vs 13.25 (4.69-37.49), negative likelihood ratio (NLR), 0.16 (0.09-0.28) vs 0.36 (0.26-0.51), diagnostic odds ratio (DOR), 38.52 (8.99 165.08) vs 36.75 (11.04-122.32), and the area under the curve (AUC), 0.92 vs 0.87. CONCLUSION: Our study demonstrates that OPN has a comparable accuracy to AFP for the diagnosis of HCC, while the value of OPN in combination with AFP for HCC detection deserves further investigation. PMID- 25034356 TI - Impact of IL28B on the treatment decision in naive and experienced patients with genotype 1 and 4 chronic hepatitis C in real-life clinical practice: a prospective multicenter cohort. AB - BACKGROUND: The impact of the IL28B genotype on the real-life treatment decisions for patients infected with the hepatitis C virus (HCV) is unknown. OBJECTIVE: To prospectively analyze the impact of IL28B genotype in HCV genotype 1 (G1)- or 4 (G4)-infected patients using buccal epithelial cell samples in real-life clinical practices. PATIENTS AND METHODS: From October 2011 to March 2013, 1007 CHC patients were included among 127 French clinical centers. RESULTS: The IL28B CC, CT, and TT genotype distribution was 252 (25%), 576 (57%), and 177 (18%), respectively. The treatment decisions were recorded and matched with the initial intentions for 433 patients. Multivariate analysis on intention to start treatment showed that patients with HCV G4 were less likely to be intended to be treated than HCV G1 patients (odds ratio [OR]=0.43 [95% CI 0.19-0.97], P=0.04); similarly HIV-HCV coinfected patients were less likely to be intended to be treated than HCV monoinfected patients (OR=0.20 [0.09-0.41], P<.0001); conversely, F3-F4 patients were more likely to be intended to be treated than F0 F2 patients (OR=2.24 [1.29-3.89], P=0.004). Multivariate analysis on final decision to treat showed that Patients with F3-F4 were more likely to be treated than others (OR=2.06 [1.26-3.38], P=0.004). Conversely, although P-values are not significant, patients recruited in public hospitals tended to be less treated (OR=0.65 [0.40-1.04], P=0.069), similarly to HIV-HCV coinfected patients (OR=0.55 [0.28-1.11], P=0.095). CONCLUSION: Our study showed that the IL28B genotype is used for the management of HCV-infected patients. In the context of future treatments, IL28B genotyping may remain useful if it can be used to develop individualized treatment strategies, identifying patients who can be successfully treated with shorter, simpler, or cheaper regimens. PMID- 25034357 TI - Hyperactive piggyBac transposons for sustained and robust liver-targeted gene therapy. AB - The development of robust nonviral vectors could facilitate clinical gene therapy applications and may overcome some of the immune complications of viral vectors. Nevertheless, most nonviral gene deliver approaches typically yield only transient and/or low gene expression. To address these caveats, we have explored piggyBac transposons to correct hemophilia B by liver-directed factor IX (FIX) gene therapy in hemophilic mice. To achieve this, we combined the use of: (i) a hyperactive codon-optimized piggyBac transposase, (ii) a computationally enhanced liver-specific promoter, (iii) a hyperfunctional codon-optimized FIX transgene (FIX R338L Padua), and (iv) a modification of the transposon terminal repeats. This combination strategy resulted in a robust 400-fold improvement in vector performance in hepatocytes, yielding stable supraphysiologic human FIX activity (>1 year). Liver-specific expression resulted in the induction of FIX-specific immune tolerance. Remarkably, only very low transposon/transposase doses were required to cure the bleeding diathesis. Similarly, PB transposons could be used to express supraphysiologic factor VIII levels using low transposon/transposase doses. PB transposition did not induce tumors in a sensitive hepatocellular carcinoma-prone mouse model. These results underscore the potency and relative safety of the latest generation PB transposons, which constitutes a versatile platform for stable and robust secretion of therapeutic proteins. PMID- 25034358 TI - Influenza vaccination of pregnant women: attitudes and behaviors of Oregon physician prenatal care providers. AB - In spite of increased risk of influenza complications during pregnancy, only half of US pregnant women get influenza vaccination. We surveyed physician prenatal care providers in Oregon to assess their knowledge and behaviors regarding vaccination of pregnant women. From September through November 2011, a state-wide survey was mailed to a simple random sample (n = 1,114) of Oregon obstetricians and family physicians. The response rate was 44.5 %. Of 496 survey respondents, 187 (37.7 %) had provided prenatal care within the last 12 months. Of these, 88.5 % reported that they routinely recommended influenza vaccine to healthy pregnant patients. No significant differences in vaccine recommendation were found by specialty, practice location, number of providers in their practice, physician gender or years in practice. In multivariable regression analysis, routinely recommending influenza vaccine was significantly associated with younger physician age [adjusted odds ratio (AOR) 2.01, 95 % confidence interval (CI) 1.29 3.13] and greater number of pregnant patients seen per week (AOR 1.95, 95 % CI 1.25-3.06). Among rural physicians, fewer obstetricians (90.3 %) than family physicians (98.5 %) had vaccine-appropriate storage units (p = 0.001). Most physician prenatal care providers understand the importance of influenza vaccination during pregnancy. To increase influenza vaccine coverage among pregnant women, it will be necessary to identify and address patient barriers to receiving influenza vaccination during pregnancy. PMID- 25034359 TI - The role of atypical antipsychotics for treatment of Tourette's syndrome: an overview. AB - Tourette's syndrome (TS) is a neuropsychiatric disorder of childhood onset characterized by multiple motor and phonic tics that fluctuate over time. Tic symptoms often improve by late adolescence, but some children and adults with TS may experience significant tic-related morbidity, including social and family problems, academic difficulties, and pain. When more conservative interventions are not successful, and when certain psychiatric co-morbidities further complicate the clinical profile, treating TS with an atypical antipsychotic medication may be a reasonable second-tier approach. However, the evidence supporting efficacy and safety of the atypical antipsychotics for treatment of tics is still very limited. The objective of this paper is to provide an updated overview of the role of atypical antipsychotics for treatment of TS, with evidence-based guidance on their use. Evidence for efficacy of different typical and atypical antipsychotics for treatment of tics was examined by conducting a systematic, keyword-related search of 'atypical antipsychotics' and 'Tourette's syndrome' in PubMed (National Library of Medicine, Washington, DC, USA). Four recent treatment consensus publications were also reviewed. This review focused on literature published from 2000 to 2013 and on available randomized controlled trials in TS. Evidence supporting the use of atypical antipsychotics for treatment of TS is limited. There are few randomized medication treatment trials in TS (i.e. risperidone, aripiprazole, ziprasidone), which employed varying methodologies, thereby restricting meaningful comparisons among studies. Future collaborations among clinical sites with TS expertise employing high-quality study design may better elucidate the role of atypical antipsychotics for treatment of TS. PMID- 25034360 TI - Etanercept: a review of its use in autoimmune inflammatory diseases. AB - With its approval more than 15 years ago, subcutaneous etanercept (Enbrel((r))) was the first biological disease-modifying antirheumatic drug (bDMARD) and the first tumour necrosis factor inhibitor to be approved for use in rheumatic diseases. Etanercept remains an important cost-effective treatment option in adult patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or plaque psoriasis, and in paediatric patients with juvenile idiopathic arthritis or plaque psoriasis. In all of these populations, etanercept (with or without methotrexate) effectively reduced signs and symptoms, disease activity and disability, and improved health-related quality of life, with these benefits sustained during long-term treatment. The safety profile of etanercept during short- and long-term treatment was consistent with the approved product labelling, with adverse events being of a predictable and manageable nature. The introduction of etanercept and other bDMARDs as therapeutic options for patients with autoimmune rheumatic diseases and spondyloarthropathies revolutionized disease management and these agents continue to have a central role in treatment strategies. This article reviews the extensive clinical experience with etanercept in these patient populations. PMID- 25034361 TI - Edoxaban: an update on the new oral direct factor Xa inhibitor. AB - Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options. PMID- 25034362 TI - omega-Alkynyl lipid surrogates for polyunsaturated fatty acids: free radical and enzymatic oxidations. AB - Lipid and lipid metabolite profiling are important parameters in understanding the pathogenesis of many diseases. Alkynylated polyunsaturated fatty acids are potentially useful probes for tracking the fate of fatty acid metabolites. The nonenzymatic and enzymatic oxidations of omega-alkynyl linoleic acid and omega alkynyl arachidonic acid were compared to that of linoleic and arachidonic acid. There was no detectable difference in the primary products of nonenzymatic oxidation, which comprised cis,trans-hydroxy fatty acids. Similar hydroxy fatty acid products were formed when omega-alkynyl linoleic acid and omega-alkynyl arachidonic acid were reacted with lipoxygenase enzymes that introduce oxygen at different positions in the carbon chains. The rates of oxidation of omega alkynylated fatty acids were reduced compared to those of the natural fatty acids. Cyclooxygenase-1 and -2 did not oxidize alkynyl linoleic but efficiently oxidized alkynyl arachidonic acid. The products were identified as alkynyl 11 hydroxy-eicosatetraenoic acid, alkynyl 11-hydroxy-8,9-epoxy-eicosatrienoic acid, and alkynyl prostaglandins. This deviation from the metabolic profile of arachidonic acid may limit the utility of alkynyl arachidonic acid in the tracking of cyclooxygenase-based lipid oxidation. The formation of alkynyl 11 hydroxy-8,9-epoxy-eicosatrienoic acid compared to alkynyl prostaglandins suggests that the omega-alkyne group causes a conformational change in the fatty acid bound to the enzyme, which reduces the efficiency of cyclization of dioxalanyl intermediates to endoperoxide intermediates. Overall, omega-alkynyl linoleic acid and omega-alkynyl arachidonic acid appear to be metabolically competent surrogates for tracking the fate of polyunsaturated fatty acids when looking at models involving autoxidation and oxidation by lipoxygenases. PMID- 25034363 TI - The effect of immune microenvironment on the progression and prognosis of colorectal cancer. AB - Cancer cells may escape from host immune responses through active suppression of the immune response, but the detailed mechanisms in colorectal cancer remain to be elucidated. In this study, 108 colorectal tumor samples and their peritumoral tissues were collected for immunohistochemistry of infiltrating lymphocytes. Th1 and Tregs cells were determined by the positive expression of T-bet and FOXP3 proteins, respectively. The Tr1 cells were identified by CD49b and LAG-3 protein expression. IL-17-positive cells were identified by IL-17 expression. Results showed that the percentage of T-bet-positive cells was significantly decreased, while the percentages of IL-17-, FOXP3-, CD49b-, and LAG-3-positive cells were significantly increased in tumor tissues compared to that in peritumoral tissues. The ratio of IL-17-, FOXP3-, CD49b-, and LAG3-positive cells to T-bet-positive cells was significantly higher in tumor tissues than in peritumoral tissues. The percentage of infiltrating IL-17-positive cells in tumor tissues was negatively associated with lymph metastasis, invasion, and TNM stage. The percentage of CD49b- and LAG-3-positive cells was positively associated with differentiation, lymph metastasis, invasion, TNM, and Duke stage of colorectal cancer. The percentage of positive Th17 and Tr1 cells is a marker for poor prognosis in patients with CRC. In conclusion, decreased composition of regulative Th1 cells and increased composition of FOXP(+) Tregs-, CD49b(+)/LAG-3(+) Tr1-, and IL-17 positive cells in tumor tissues may be associated with the progression of colorectal cancer. The high percentage of IL-17- and Tr1-positive cells in tumor tissues is a predictive marker for poor prognosis of colorectal cancer. PMID- 25034364 TI - Analysis of V600E BRAF and D816V KIT mutations in systemic mastocytosis. AB - Most patients with systemic mastocytosis (SM) carry a D816 V KIT mutation causing a ligand-independent activation of the receptor. Down-stream of KIT is several components known to be mutated in different malignancies. RAF is among the most frequently mutated kinases, where BRAF V600E mutation occurs in most hairy cell leukemias (HCL) and half of malignant melanomas. We investigated BRAF mutations in 36 subjects with different forms of SM, but could not detect BRAF mutation in any of the cases, not even in the mast cell lineage of a patient with V600E BRAF positive HCL. Thus, although BRAF is commonly mutated it appears not to be present in SM. PMID- 25034365 TI - M2-polarized macrophages contribute to the decreased sensitivity of EGFR-TKIs treatment in patients with advanced lung adenocarcinoma. AB - Previous study has revealed that tumor-associated macrophages (TAMs) correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC). In the present study, we further determined that M2-TAMs, but not M1-TAMs, are related to the treatment response to EGFR-TKIs in advanced NSCLC and may be an independent predictor of survival. Eighty-eight advanced lung adenocarcinoma patients treated with a second-line EGFR-TKI were involved in this study. M2-TAMs counts but not M1-TAMs were significantly higher in patients with progressive disease than in those without (P < 0.001). A trend also remained in patients with known EGFR status (n = 61) and those with mutant EGFR (n = 49). High M2-TAMs counts were shown to be significantly related to poor progression-free survival (PFS) and overall survival (OS) in all patients, or subsets of patients with known EGFR status or patients with EGFR mutation (all P < 0.05). Multivariate Cox analyses showed that high M2-TAMs counts and EGFR mutations were both independent factors associated with PFS and OS (P < 0.05). Overall, we revealed that M2- but not M1-TAMs are related to the response of EGFR-TKIs treatment irrespective of EGFR mutation and can independently predict survival in advanced lung adenocarcinoma treated with a second-line EGFR-TKI. PMID- 25034366 TI - Matrix metalloproteinase-8 promoter gene polymorphisms in Mexican women with ovarian cancer. AB - Increased levels of matrix metalloproteinase-8 (MMP-8) have been associated with tumor grade and stage in ovarian cancer. Also, it has been reported that higher concentrations of this enzyme in fluid from malignant ovarian cysts compared with benign ovarian cysts. However, no genetic analysis has been conducted yet to assess the contribution of MMP-8 polymorphisms in ovarian cancer. Thus, this study was performed to investigate the frequencies of MMP-8 genotypes in Mexican women with ovarian cancer. MMP-8 promoter genotypes were examined in 35 malignant ovarian tumors, 51 benign tumors, and 37 normal ovary tissues. Two single nucleotide polymorphisms were selected and characterized using polymerase chain reaction-restriction fragment length polymorphism analysis. The chi-square test was used to calculate statistical significance. Haplotype analysis was performed using the SNPstats web tool. Of the two polymorphisms, only the MMP-8 -799 T/T genotype was significantly associated with an increased risk of ovarian cancer (OR 3.78, 95 % CI 1.18-12.13). The Kaplan-Meier analysis for this polymorphism showed that patients with the T/T genetic variant had a tendency toward significant worse overall survival compared with patients with the C/C + C/T genotypes. Haplotype analysis revealed no significant differences in haplotype distribution between benign ovarian tumors, malignant ovarian cancer, and controls. This study suggests that MMP-8 promoter gene polymorphism -799 T/T is significantly associated with an increased risk of ovarian cancer in Mexican women. PMID- 25034367 TI - Second-harmonic response of multilayer nanocomposites of silver-decorated nanoparticles and silica. AB - We perform a detailed characterisation of the second-order nonlinear optical response of nanocomposites consisting of alternating layers of silver-decorated silica glass nanoparticles and pure silica glass. The samples are fabricated using aerosol techniques and electron-beam dielectric coating, resulting in a bulk-like material with symmetry-breaking induced by the porosity of the alternating layers. The second-order nonlinear response increases with the number of layers. Further, by determining the components of the second-order susceptibility tensor of the samples, we show that the structural properties of the samples are well maintained as the sample thickness is increased. Our results form an important baseline for any further optimization of these types of structures, which can be fabricated using very straightforward methods. PMID- 25034368 TI - The reality of waste management in primary health care units in Brazil. AB - A large number of users are serviced in primary health care units in Brazil, both in health facilities and in households. These services generate waste that must be managed safely, but there is no legislation that regulates this type of waste management in Brazil. The objective of this study was to analyse the production and management of waste in primary health care. A direct observation was performed of the stages in the handling and weighing of waste generated in primary health care units in the municipality of Goiania (Brazil). The units generated infectious, chemical, and common waste, as well as sharp objects. The generation of waste ranged between 0.027 and 0.075 kg user-day. The generated waste was classified mostly as common and recyclable. Flaws were observed in the management of all types of waste. The critical point is segregation. Only 34.1% of the waste disposed of as infectious actually belonged to this group, the rest was ordinary waste. Flaws at this stage increase the volume of infectious waste, the occupational and environmental risks, and associated costs. Intervention to change this reality is needed and it requires the careful preparation of a waste management plan, corroborating structural changes to the implementation of this plan, and professional training and public policies to guide waste management in primary care, especially those generated in households. PMID- 25034369 TI - A novel albumin-based tissue scaffold for autogenic tissue engineering applications. AB - Tissue scaffolds provide a framework for living tissue regeneration. However, traditional tissue scaffolds are exogenous, composed of metals, ceramics, polymers, and animal tissues, and have a defined biocompatibility and application. This study presents a new method for obtaining a tissue scaffold from blood albumin, the major protein in mammalian blood. Human, bovine, and porcine albumin was polymerised into albumin polymers by microbial transglutaminase and was then cast by freeze-drying-based moulding to form albumin tissue scaffolds. Scanning electron microscopy and material testing analyses revealed that the albumin tissue scaffold possesses an extremely porous structure, moderate mechanical strength, and resilience. Using a culture of human mesenchymal stem cells (MSCs) as a model, we showed that MSCs can be seeded and grown in the albumin tissue scaffold. Furthermore, the albumin tissue scaffold can support the long-term osteogenic differentiation of MSCs. These results show that the albumin tissue scaffold exhibits favourable material properties and good compatibility with cells. We propose that this novel tissue scaffold can satisfy essential needs in tissue engineering as a general-purpose substrate. The use of this scaffold could lead to the development of new methods of artificial fabrication of autogenic tissue substitutes. PMID- 25034370 TI - Digital pathology and image analysis in tissue biomarker research. AB - Digital pathology and the adoption of image analysis have grown rapidly in the last few years. This is largely due to the implementation of whole slide scanning, advances in software and computer processing capacity and the increasing importance of tissue-based research for biomarker discovery and stratified medicine. This review sets out the key application areas for digital pathology and image analysis, with a particular focus on research and biomarker discovery. A variety of image analysis applications are reviewed including nuclear morphometry and tissue architecture analysis, but with emphasis on immunohistochemistry and fluorescence analysis of tissue biomarkers. Digital pathology and image analysis have important roles across the drug/companion diagnostic development pipeline including biobanking, molecular pathology, tissue microarray analysis, molecular profiling of tissue and these important developments are reviewed. Underpinning all of these important developments is the need for high quality tissue samples and the impact of pre-analytical variables on tissue research is discussed. This requirement is combined with practical advice on setting up and running a digital pathology laboratory. Finally, we discuss the need to integrate digital image analysis data with epidemiological, clinical and genomic data in order to fully understand the relationship between genotype and phenotype and to drive discovery and the delivery of personalized medicine. PMID- 25034371 TI - Regulation of coronaviral poly(A) tail length during infection is not coronavirus species- or host cell-specific. AB - It has been demonstrated that the length of the poly(A) tail in the bovine coronavirus (BCoV), which belongs to genus betacoronaviruses, is regulated throughout infection in human rectal tumor-18 (HRT-18) cells, and the length of the poly(A) tail is associated with the efficiency of virus translation. Here, we examined whether the regulation of viral poly(A) tail length is cell-type independent and whether it is a common feature of coronaviruses to assess the significance of the regulation. By ligating head-to-tail viral RNA positive strands and sequencing, we found that (1) the regulation pattern of coronaviral poly(A) tail length in BCoV-infected hamster kidney-21 (BHK-21) cells was similar to that in BCoV-infected HRT-18 cells and (2) the poly(A) tail length of wild type avian infectious bronchitis virus (IBV) virulent strain IBV-TW1, which is in the genus gammacoronaviruses, varied throughout infection in primary chicken embryo kidney (CEK) cells and in the tracheas of 1-day-old chicks. Interestingly, the poly(A) tail length variation was similarly found in the avirulent IBV strain H120 in CEK cells, although the overall poly(A) tail length was shorter for this virus. The results suggest that the regulation of coronaviral poly(A) tail length during infection may be a common feature among coronaviruses and can occur in a noncancerous cell line (BHK-21 cells), primary cell culture (CEK cells), and living system (chickens), further reinforcing the biological significance of this regulation during coronavirus infection. PMID- 25034373 TI - Procalcitonin as a prognostic marker for sepsis: a prospective observational study. AB - BACKGROUND: Procalcitonin is useful for the diagnosis of sepsis but its prognostic value regarding mortality is unclear. This prospective observational study was designed to study the prognostic value of procalcitonin in prediction of 28 day mortality in patients of sepsis. Fifty-four consecutive patients of sepsis, severe sepsis and septic shock defined using the 2001 Consensus Conference SCCM/ESICM/ACCP/ATS/SIS criteria from medical Intensive Care Unit (ICU) of a tertiary care center in New Delhi, India were enrolled from July 2011 to June 2013. Procalcitonin (PCT), C-reactive protein (CRP) measurements were recorded on day 1, day 7 and day 28 of follow up. RESULTS: Procalcitonin value was a better predictor of all-cause short-term mortality than C-reactive protein. Those patients with Procalcitonin levels <7 ng/ml showed higher cumulative survival than those with level [greater than or equal to]7 ng/ml (69.1% vs. 39.5%, p = 0.02). No such effect was observed in relation to C-reactive protein. Procalcitonin levels [greater than or equal to]7 ng/ml predicted mortality with a hazard ratio of 2.6(1.1-6.3). CONCLUSIONS: A Procalcitonin value [greater than or equal to]7 ng/ml obtained at the time of admission to the ICU is a predictor of short-term mortality and thus may allow the identification of those septic patients at increased mortality risk, and help improve their treatment. PMID- 25034374 TI - A comparison of the demographic and clinical characteristics of laboratory confirmed influenza B Yamagata and Victoria lineage infection. AB - BACKGROUND: The evolution of influenza viruses is characterized by the co circulation of two antigenically and genetically distinct lineages B/Victoria/2/87-like viruses (Victoria) and B/Yamagata/16/88-like viruses (Yamagata). To date, there is not much data associating lineages variation with demographic and clinical data. OBJECTIVES: We compared the demographic and clinical characteristics of patients with laboratory-confirmed influenza B Victoria or Yamagata lineage infection. STUDY DESIGN: We retrospectively analyzed data from 6811 patients aged from <1 through 99 years with influenza like-illness who consulted the sentinel site or sentinel hospital in the seasons 2010/2011, 2011/2012 and 2012/2013. There were 662 patients positive for influenza B virus by multiplex real-time RT-PCR. Six hundred thirty-seven (96.8%) were successfully subtyped for Victoria or Yamagata lineage infection. The available demographic and clinical data was compared. RESULTS: Patients with the Victoria lineage were significantly younger compared to patients infected with the Yamagata lineage. The Victoria lineage was the predominant strain in the 15-34 age groups in patients consulting at primary care level and in hospitalized patients. In the youngest age group (0-4 years) approximately half of the confirmed influenza B cases belonged to the Victoria (55%) and the rest to the Yamagata lineage (45%). Aside from age, there was no statistically significant difference found in gender distribution, vaccination history, clinical presentation or risk factors for severe influenza infection in hospitalized patients after adjustment for the age. CONCLUSIONS: The frequency of influenza B Victoria and Yamagata infection is age dependent with no significant differences detected in clinical presentation comparing both lineages. PMID- 25034375 TI - Multicenter clinical performance evaluation of BD VeritorTM system for rapid detection of respiratory syncytial virus. AB - BACKGROUND: BD VeritorTM System for Rapid Detection of Respiratory Syncytial Virus (RSV) is a new-generation lateral flow immunochromatographic assay for objective detection of RSV in respiratory specimens from children. OBJECTIVE: To evaluate the performance of BD VeritorTM System for Rapid Detection of RSV in respiratory specimens collected from pediatric patients. STUDY DESIGN: A prospective, multicenter clinical trial was undertaken at five study sites representing geographically diverse regions of the U.S. to assess the performance of the BD VeritorTM System for Rapid Detection of RSV in comparison to R-mix shell vial culture and ProFlu+ reverse transcription-PCR assay (Gen Probe/Prodesse). RESULTS: 440 nasopharyngeal washes/aspirates (NPW/A) and 706 nasopharyngeal swab (NPS) specimens from U.S. subjects<20 years of age were collected and tested using the BD VeritorTM System and compared with shell vial culture and real-time RT-PCR results. Analysis of the data indicates the overall sensitivity and specificity for BD VeritorTM System for all sample types combined was 90% and 97.0% versus shell vial culture and 75.5% and 98.7% versus RT-PCR respectively. CONCLUSION: Overall, the BD VeritorTM System for the Rapid Detection of RSV performed well when compared to both viral cell culture and RT PCR in children. PMID- 25034376 TI - Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment: (questionable) classification of diabetic patients based on combination of specific glucose-lowering drugs. Reply to Holden SE, Bannister CA, Currie CJ [letter]. PMID- 25034377 TI - Cerebrospinal fluid levels of Alzheimer's disease biomarkers in middle-aged patients with type 1 diabetes. AB - AIMS/HYPOTHESIS: Type 1 diabetes is associated with moderate cognitive decline and cerebral alterations and may lead to an increased risk of dementia, including Alzheimer's disease. This study aimed to investigate the levels of risk markers for Alzheimer's disease in middle-aged patients with type 1 diabetes and controls, and their potential associations with cognitive and cerebral measures. METHODS: Levels of beta-amyloid (Abeta) 42, Tau, phosphorylated Tau (pTau), the soluble form of low-density lipoprotein receptor-related protein 1 (sLRP1) and macrophage colony-stimulating factor (MCSF) were quantified by ELISA in serum and cerebrospinal fluid (CSF) collected from 37 patients with type 1 diabetes and 15 controls. Associations between biomarkers and determinants of cognitive function and white matter integrity were assessed using hierarchical regression analysis controlling for age, HbA1c and estimated intelligence quotient (IQ). RESULTS: CSF levels of pTau, Abeta42 and LRP1 were higher in patients with type 1 diabetes than in controls (all p < 0.05). There was a trend towards increased Tau levels in patients with type 1 diabetes (p = 0.056), while CSF levels of MCSF were similar between patients with type 1 diabetes and controls. Regression analysis showed that elevated CSF sLRP1 levels were associated with better attention (beta = 0.518; p = 0.002) and a better speed of information-processing (beta = 0.368; p = 0.034), as well as increased integrity of the white matter of the right inferior fronto-occipital tract (beta = 0.395; p = 0.022). Furthermore, elevated Tau levels were associated with decreased integrity of the white matter of right inferior fronto-occipital tract (beta = -0.584; p = 0.002). CONCLUSIONS/INTERPRETATION: CSF levels of biomarkers for Alzheimer's disease are altered in patients with type 1 diabetes compared with controls, but the observed profile does not match the profile characterising pre-Alzheimer's disease patients. PMID- 25034378 TI - Syringomyelia in an older patient. AB - We describe the case of an 80-year-old man who presented with lower limb upper motor neurone weakness and spinothalamic tract sensory deficit secondary to previously undiagnosed syringomyelia. The case highlights the need for methodical history, examination and investigation in elderly patients to achieve diagnostic accuracy. PMID- 25034379 TI - Chronic food protein-induced enterocolitis syndrome caused by cow's milk proteins passed through breast milk. AB - We describe 2 cases of food protein-induced enterocolitis syndrome (FPIES) caused by cow's milk (CM) passed through breast milk. The onset in both cases was characterized by chronic symptoms (regurgitation, colic, diarrhea, failure to thrive); in one patient, two acute episodes due to the direct consumption of CM formula by the infant were also reported. The diagnosis of FPIES through breast milk can be easily overlooked, especially in milder cases. We also discuss some important issues concerning the general management of the disease. In conclusion, (1) the diagnosis of chronic FPIES should be taken into account even in exclusively breast-fed infants who present suggestive symptoms such as persistent regurgitation, small amounts of vomiting, lethargy, failure to thrive, dehydration, diarrhea (sometimes bloody) and abdominal distention. A 2-week maternal elimination diet should be considered even in apparently mild cases. (2) CM seems to be the most frequently reported culprit food. (3) In those cases in which acute FPIES is elicited by the direct consumption of the culprit food in breast-fed infants, maternal diet may be unrestricted. PMID- 25034380 TI - Should technical aptitude evaluation become part of resident selection for surgical residency? PMID- 25034381 TI - Camera navigation and cannulation: validity evidence for new educational tasks to complement the Fundamentals of Laparoscopic Surgery program. AB - BACKGROUND: Experts identified camera navigation and cannulation as important skills that are not assessed by the Fundamentals of Laparoscopic Surgery (FLS) hands-on examination. The purpose of this study was to create metrics for and evaluate the validity for two new tasks: camera navigation (N) and cannulation (C), and to explore the potential value of adding these tasks to the FLS program. METHODS: Participants were assessed by two raters during performance of N and C in addition to the five standard FLS tasks. They also completed a questionnaire regarding the educational value of the new tasks. Validity evidence was assessed by comparing performance between Novice (PGY 1 and 2) and Experienced (PGY 3 and higher) participants, and by correlating new task scores with standard FLS scores. The ability to predict level of training using scores was evaluated by regression analysis. RESULTS: Sixty subjects participated from five North American centers. Inter-rater reliabilities for both tasks were 0.99. Novice and Experienced participants scored 74 +/- 17.8 versus 85 +/- 8.3 (p < 0.01) and 21 +/- 17.3 versus 39 +/- 20.1 (p < 0.01) on N and C tasks, respectively. Correlations with total FLS scores for N and C were 0.39 and 0.53, respectively. Prediction of training level using the combination of all seven tasks was 52.6 % (R (2) = 0.526, p < 0.01), adding an additional 2.2 % to the five FLS tasks. Of 55 participants with laparoscopic experience, 51 % reported N to be similar in difficulty to reality. Of 28 participants who perform intraoperative cholangiograms, 43 % found C to be more difficult than reality. Most (70 %) participants thought the new tasks added value to FLS. CONCLUSIONS: This study provides preliminary validity evidence for the metrics of these new tasks. The value of adding these tasks to the FLS manual skills assessment is marginal in terms of predicting level of training. PMID- 25034382 TI - Timing of esophageal stent placement and outcomes in patients with esophageal perforation: a single-center experience. AB - BACKGROUND: Endoscopic treatment for esophageal perforation with stenting is an alternative to surgery. There is no data on the impact of timing of esophageal stent placement and outcomes in patients with esophageal perforation. OBJECTIVE: To determine the significance of timing of esophageal stent placement on short term (30-day complications) and long-term clinical outcomes of patients with esophageal perforation. METHODS: Patients with esophageal perforations who underwent endoscopic treatment with stenting from 2007 to 2012 at the Cleveland Clinic were included for the study. Main outcomes measurements were impact of time to esophageal stent placement on 30-day complications and long-term outcomes. RESULTS: A total of 20 patients (males 40 % and females 60 %) were included. Mean age was 72.5 +/- 10 years. The most common etiology for perforation was iatrogenic after endoscopy procedure in 10 (50 %) patients. The stent was in place for a median of 24.6 days in our cohort. Eight patients (40 %) had stent placement within 24 h, while the remaining 12 patients (60 %) had stent placement after 24 h. The mortality rate due to perforation related causes was 10 % (2/20) in our study. The 30-day complication rate was 10 %; 1 with stent migration and the other with chest pain. The 30-day readmission rates excluding patients who died during the initial hospitalization were 10 %. On long-term follow-up, 30 % complication rates were encountered; 3 (15 %) stent migrations, 2 (10 %) patients presented with hematemesis, and 1 (5 %) with chest pain. The timing of stent placement (within 24 h or later) did not impact the risk of complications (Odds Ratio [OR] 1.13, 95 % confidence interval 0.1-8.9, P = 0.91). CONCLUSIONS: Endoscopic stent placement is safe and effective for treating esophageal perforations. However, the timing of stent placement on outcomes remains unclear. PMID- 25034384 TI - Expression of neurotrophic factors and their receptors in the carotid body of spontaneously hypertensive rats. AB - The carotid body (CB) is a small neural crest-derived structure that senses oxygen levels in blood and monitors ventilation. The spontaneously hypertensive rat (SHR) is considered a good experimental model for primary hypertension and is extensively used to study cardiovascular diseases. The hypertensive CB shows structural plasticity and could enlarge without vasodilation. Our immunohistochemical studies revealed the presence of nuclear Ki-67 protein in the sustentacular cells, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and their corresponding receptors p75(NTR), TrkA, TrkB and TrC in the majority of glomus cells and also in a subset of sustentacular cells. In addition, virtually all glomus cells expressed glial cell line-derived neurotrophic factor and its specific receptor GFRalpha1. The present study demonstrates that in glomus cells of hypertensive animals there is enhanced expression of components of the neurotrophin signaling system compared to normotensive rats. Our results suggest that the elevated production of neurotrophic factors in SHRs could explain CB and sympathetic hyperactivity leading to hypertension. PMID- 25034383 TI - Vertical distribution of major sulfate-reducing bacteria in a shallow eutrophic meromictic lake. AB - The vertical distribution of sulfate-reducing bacteria was investigated in a shallow, eutrophic, meromictic lake, Lake Harutori, located in a residential area of Kushiro, Japan. A steep chemocline, characterized by gradients of oxygen, sulfide and salinity, was found at a depth of 3.5-4.0 m. The sulfide concentration at the bottom of the lake was high (up to a concentration of 10.7 mM). Clone libraries were constructed using the aprA gene, which encodes adenosine-5'-phosphosulfate reductase subunit A, in order to monitor sulfate reducing bacteria. In the aprA clone libraries, the most abundant sequences were those from the Desulfosarcina-Desulfococcus (DSS) group. A primer set for a DSS group-specific 16S rRNA gene was used to construct another clone library, analysis of which revealed that the uncultured group of sulfate-reducing bacteria, SEEP SRB-1, accounted for nearly half of the obtained sequences. Quantification of the major bacterial groups by catalyzed reporter deposition fluorescence in situ hybridization demonstrated that the DSS group accounted for 3.2-4.8% of the total bacterial community below the chemocline. The results suggested that the DSS group was one of the major groups of sulfate-reducing bacteria and that these presumably metabolically versatile bacteria might play an important role in sulfur cycling in Lake Harutori. PMID- 25034385 TI - Negative regulation of glucose metabolism in human myotubes by supraphysiological doses of 17beta-estradiol or testosterone. AB - OBJECTIVE: Exposure of skeletal muscle to high levels of testosterone or estrogen induces insulin resistance, but evidence regarding the direct role of either sex hormone on metabolism is limited. Therefore, the aim of this study was to investigate the direct effect of acute sex hormone exposure on glucose metabolism in skeletal muscle. MATERIALS/METHODS: Differentiated human skeletal myotubes were exposed to either 17beta-estradiol or testosterone and metabolic characteristics were assessed. Glucose incorporation into glycogen, glucose oxidation, palmitate oxidation, and phosphorylation of key signaling proteins were determined. RESULTS: Treatment of myotubes with either 17beta-estradiol or testosterone decreased glucose incorporation into glycogen. Exposure of myotubes to 17beta-estradiol reduced glucose oxidation under basal and insulin-stimulated conditions. However, testosterone treatment enhanced basal palmitate oxidation and prevented insulin action on glucose and palmitate oxidation. Acute stimulation of myotubes with testosterone reduced phosphorylation of S6K1 and p38 MAPK. Exposure of myotubes to either 17beta-estradiol or testosterone augmented phosphorylation GSK3beta(Ser9) and PKCdelta(Thr505), two negative regulators of glycogen synthesis. Treatment of myotubes with a PKC specific inhibitor (GFX) restored the effect of either sex hormone on glycogen synthesis. PKCdelta silencing restored glucose incorporation into glycogen to baseline in response to 17beta-estradiol, but not testosterone treatment. CONCLUSION: An acute exposure to supraphysiological doses of either 17beta-estradiol or testosterone regulates glucose metabolism, possibly via PKC signaling pathways. Furthermore, testosterone treatment elicits additional alterations in serine/threonine kinase signaling, including the ribosomal protein S6K1 and p38 MAPK. PMID- 25034386 TI - Advanced glycation end products in the skin are enhanced in COPD. AB - BACKGROUND: Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity. METHODS: 202 mild-to-very-severe COPD patients and 83 old (40-75 years) and 110 young (18-40 years) healthy smokers and never-smokers were included. AGEs were measured by skin autofluorescence (SAF). Demographic variables, smoking habits, co morbidities and lung function values were obtained. RESULTS: COPD patients (FEV1=55% predicted) had significantly higher SAF values than old and young healthy controls: 2.5 vs. 1.8 and 1.2 (arbitrary units, p<0.05). No differences in SAF values were found between GOLD stages I-IV (2.4, 2.3, 2.5, 2.5 respectively). Lower function (FEV1/FVC, MEF50/FVC, RV/TLC) and higher number of packyears were significantly associated with SAF (p<0.05). CONCLUSIONS: SAF is increased in mild-to-very severe COPD patients compared with healthy controls. Interestingly, SAF was not associated with disease severity as values were comparable between different GOLD stages (stage I-IV) of COPD. This may suggest that AGEs play a role in the induction phase of COPD in susceptible smokers. Future studies should further investigate the mechanisms underlying AGEs formation and accumulation in COPD. PMID- 25034387 TI - Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. AB - Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. OBJECTIVE: The objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. METHODS AND RESULTS: Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 +/- 6.4 years and a body mass index of 30.7 +/- 4.9 kg/m2) were recruited into this double-blind, cross-over study using sitagliptin (100mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P=0.006), interleukin (IL)-6 (24.7%, P=0.04), IL-18 (7.3%, P=0.004), secreted phospholipase-A2 (sPLA2) (12.9%, P=0.04), soluble intercellular adhesion molecule-1 (5.3%, P=0.002), and E selectin (5.9%, P=0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r=0.41, P=0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. CONCLUSIONS: Treatment with sitagliptin for 6 weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities. PMID- 25034388 TI - A case of non-cirrhotic portal hypertension associated with anti-retroviral therapy in a Japanese patient with human immunodeficiency virus infection. AB - The diagnosis of non-cirrhotic portal hypertension (NCPH), a rare but potentially life-threatening complication in human immunodeficiency virus (HIV)-positive individuals, often occurs only after the emergence of fatal manifestations such as bleeding of esophageal varices. We herein report a female Japanese HIV patient who developed NCPH approximately 4 years after discontinuation of 65 months of didanosine (ddI) administration. The patient presented with severe ascites, bloody bowel discharge, extreme abdominal swelling, and symptoms of portal hypertension but no sign of liver cirrhosis. Examination revealed esophageal varices, oozing-like bleeding from a wide part of the colon, significant atrophy of the right lobe of the liver, and arterio-portal shunting and recanalization from the left medial segment branch of the portal vein to a paraumbilical vein, but no visible obstruction of the main trunk of the portal vein. Treatment for esophageal varices consisted of coagulation therapy with argon plasma after enforcement by endoscopic sclerotherapy and oral administration of beta-blockers for elevated portal blood pressure. The patient has not experienced gastrointestinal bleeding in the approximately 5 years since the diagnosis of NCPH. Reviewing this case suggests the importance of suspecting NCPH in HIV patients with liver dysfunction of unknown etiology with a history of ddI and other purine analogs use, as well as the importance of controlling portal hypertension and esophageal varices in the treatment of NCPH. PMID- 25034389 TI - Endovascular stroke therapy. AB - BACKGROUND: Following the development of intravenous thrombolysis as a successful treatment for ischaemic stroke, advances in neurointerventional radiology have facilitated endovascular approaches to treatment. This article reviews the available endovascular therapeutic options and their evidence-base. SUMMARY: Initial studies demonstrated that endovascular treatment of ischaemic stroke with intra-arterial thrombolysis and/or the use of clot-retrieval, thrombus aspiration and stent-retriever devices produced early recanalisation and reperfusion and improved neurological outcome. More recent randomised trials, however, have failed to show translation of recanalisation into successful clinical outcome with 'time to treatment' proving crucial. In this rapidly evolving field, combined therapy incorporating intravenous and intra-arterial thrombolysis in combination with endovascular clot-retrieval has been developed and further studies are expected to yield better evidence to guide the optimal treatment of acute cerebral ischaemia. PMID- 25034390 TI - Severe acute kidney injury and multiple myeloma: evaluation of kidney and patient prognostic factors. AB - BACKGROUND: Patients with multiple myeloma (MM) manifesting acute kidney injury (AKI) and who later recover renal function and independence from renal replacement therapy (RRT) are considered to have a better outcome. The aim of this work was to study the factors associated with renal function recovery (independence of hemodialysis) and longer survival in these patients. METHODS: A retrospective single center study including patients with a diagnosis of MM and severe AKI, defined as stage 3 of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria: 3.0 times baseline increase in serum creatinine (sCr) or increase in sCr to >=4.0mg/dL or initiation of RRT, was conducted. Data was registry-based and collected between January 2000 and December 2011. We examined demographic and laboratorial data, presenting clinical features, precipitating factors, need for RRT and chemotherapy. Death was considered the primary endpoint. RESULTS: Lower serum beta2-microglobulin was the only independent factor associated with recovery of renal function and independence of RRT (OR 0.95, 95% CI: 0.91-0.99, P=0.02). The median survival after AKI was 10.7+/ 12.1months. The factors associated with longer survival were independence of RRT (HR 2.21; 95% CI: 1.08-4.49; P=0.02), lower CRP (HR 1.07; 95% CI: 1.03-1.12; P=0.001) and younger age (HR 1.03; 95% CI: 1.01-1.06; P=0.005). CONCLUSIONS: Our study suggests that MM patients with lower serum beta2-microglobulin have a higher likelihood of recovering renal function after severe AKI. Independence of RRT, lower CRP and younger age are associated with longer survival. PMID- 25034393 TI - Rotational propulsion enabled by inertia. AB - The fluid mechanics of small-scale locomotion has recently attracted considerable attention, due to its importance in cell motility and the design of artificial micro-swimmers for biomedical applications. Most studies on the topic consider the ideal limit of zero Reynolds number. In this paper, we investigate a simple propulsion mechanism --an up-down asymmetric dumbbell rotating about its axis of symmetry-- unable to propel in the absence of inertia in a Newtonian fluid. Inertial forces lead to continuous propulsion for all finite values of the Reynolds number. We study computationally its propulsive characteristics as well as analytically in the small-Reynolds-number limit. We also derive the optimal dumbbell geometry. The direction of propulsion enabled by inertia is opposite to that induced by viscoelasticity. PMID- 25034394 TI - Self-ordering of small-diameter metal nanoparticles by dewetting on hexagonal mesh templates. AB - Arrays of small-diameter nanoparticles with high spatial order are useful for chemical and biological sensors, data storage, synthesis of nanowires and nanotubes, and many other applications. We show that self-ordered metal nanoparticle arrays can be formed by dewetting of thin films on hexagonal mesh substrates made of anodic aluminum oxide (AAO). Upon heating, the metal (Fe) film dewets onto the interstitial sites (i.e., the node points) between pores on the top surface of the AAO. We investigated the particle morphology and dynamics of dewetting using a combination of atomic force microscopy (AFM), grazing-incidence small-angle X-ray scattering (GISAXS), and numerical simulations. Templated metal particles are more monodisperse and have higher local order than those formed by the same dewetting process on flat, nonporous alumina. The degree of order depends on the initial film thickness, and for the optimal thickness tested (nominally 2 nm), we achieved uniform coverage and high order of the particles, comparable to that of the AAO template itself. Computational modeling of dewetting on templates with various pore order and size shows that the order of AAO pores is primarily influential in determining particle position and spacing, while the variance in pore size is less impactful. Potential uses of these ordered nanoparticle arrays on porous materials include plasmonic sensors and spatially controlled catalysts. PMID- 25034395 TI - Role of surgery in multi-modality treatment for carcinomatous pleuritis in patients with non-small cell lung cancer. AB - OBJECTIVE: To evaluate the role of surgery in the treatment of the patients with non-small cell lung cancer with pleural dissemination. METHODS: The clinical records of 25 patients (mean age 69 years) diagnosed with carcinomatous pleuritis during a thoracotomy by pathological examination and followed by surgery between 1994 and 2012 were reviewed. The treatment modality, including surgery, the clinicopathologic characteristics and 5-year survival were analyzed. RESULTS: There were 16 adenocarcinomas, 6 squamous cell carcinomas and 3 large cell carcinomas. Surgery included resection of the main tumor by partial resection in 10 cases, segmentectomy in 2 cases, lobar resection in 12 cases and bilobectomy in 1 case. Intrathoracic irrigation was performed in 20 cases. The pathological N status was N0/N1/N2/Nx: 10/6/7/2. Fifteen patients received adjuvant therapy. The overall 5-year survival rate was 22.2 %. The 5-year survival rates of the N0, N1 and N2 groups were 36.0, 16.7 and 14.3 %, respectively (p = 0.0068). Nine patients lived more than 3 years including 5 in N0, 3 in N1 and 1 in N2. CONCLUSIONS: Surgery should not be excluded from the multi-modality treatment of patients with carcinomatous pleuritis because there are some patients who could benefit from surgery especially if they are in N0 status. PMID- 25034396 TI - Renal function is associated with bone mineral density and arterial stiffness in healthy postmenopausal women. AB - BACKGROUND/AIMS: This study aimed to investigate the effect of renal function on bone mineral density (BMD) and arterial stiffness in postmenopausal women. METHODS: This is a retrospective cross-sectional study. We studied 252 postmenopausal women who visited a health promotion center for a medical checkup. The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault (CG) formula and the modification of diet in renal disease (MDRD) formula. Areal BMD measurements were performed using dual-energy X-ray absorptiometry, and arterial stiffness was measured using the brachial-ankle pulse wave velocity (baPWV). RESULTS: The eGFR according to the CG formula was significantly correlated with age, BMI, follicle-stimulating hormone, thyroid stimulating hormone, high-density lipoprotein cholesterol, baPWV, and BMD at the lumbar spine, femoral neck, and total hip sites. However, the eGFR according to the MDRD formula was significantly correlated with age and baPWV but not with BMD at the lumbar spine, femoral neck, and total hip sites. Decreased renal function (eGFR <60 ml/min/1.73 m(2) according to the CG formula) was independently associated with decreased BMD at the femoral neck site and with increased baPWV (>1,500 cm/s) after adjusting for confounding variables. CONCLUSION: Postmenopausal women with decreased renal function are more likely to have a decreased BMD and greater arterial stiffness. PMID- 25034397 TI - [Another story of sevelamer]. PMID- 25034399 TI - Whole exome sequencing in short stature: finding needles in the haystack. PMID- 25034398 TI - Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib. AB - BACKGROUND: Chronic infection with Hepatitis B virus (HBV) is the major risk factor of Hepatocellular Carcinoma (HCC). This study is to explore the mechanism of sorafenib resistance and find an effective strategy to sensitize HBV associated HCC to sorafenib. METHODS: Cytotoxicity to sorafenib was evaluated in HBV-positive/negative HCC cell lines. Expression of miR-193b and myeloid cell leukemia-1 (Mcl-1) protein were assessed by Q-PCR, in situ hybridization and western blot, immunohistochemistry, respectively. A luciferase reporter of Mcl-1 3'-UTR was used for validation as a target of miR-193b. Cell apoptosis was measured by flow cytometry, caspase-3 activity assay and DAPI staining. RESULT: The IC50 to sorafenib was significantly higher in HBV-positive HCC cells than those without HBV infection. Significant downregulation of miR-193b and a higher level of Mcl-1 were observed in HBV-positive HCC cells and tissues. The activity of Mcl-1 3'-UTR reporter was inhibited by co-transfection with miR-193b mimic. Restoring the expression of miR-193b sensitized HBV-associated HCC cells to sorafenib treatment and facilitated sorafenib-induced apoptosis. CONCLUSIONS: Modulation of miRNAs expression might be a potential way to enhance response to sorafenib in HBV-associated HCC. PMID- 25034400 TI - The ascending aortic elasticity feature in normotensive subjects: evaluation with coronary CT angiography. AB - To evaluate the ascending aortic elasticity feature, 118 normotensive subjects who underwent coronary computed tomography angiography (CCTA) were enrolled. Two groups of parameters assessing elasticity were calculated based on the measurements of volume and area of ascending aorta. Multivariate analysis revealed that some factors including age, systolic BP, diastolic BP, heart rate, smoking status and hyperlipidemia independently related to decreased aortic elasticity. Both measuring methods are applicable for evaluation of aortic elasticity. As the prevalence of CCTA, it is meaningful that CCTA can provide not only the structural details of ascending aorta but also functional information of the vessel elasticity. PMID- 25034401 TI - Diastolic function assessed by cardiac MRI using longitudinal left ventricular fractional shortening. AB - INTRODUCTION: Diastolic dysfunction contributes significantly to diastolic heart failure. We examined the use of cardiac magnetic resonance imaging (CMR) using midwall longitudinal fractional shortening (MLFS) in the evaluation of transthoracic echocardiogram (TTE)-evidenced diastolic dysfunction. METHODS: A total of 80 patients with CMR within 6 months of TTE and normal ejection fraction were identified. MLFS was calculated as percentage change in distance from the anterior mitral leaflet base to the apical endocardium in systole and diastole. RESULTS: MLFS of grade II/III [0.14 (0.12-0.16)] was significantly lower than that of grade 0/I [0.20 (0.19-0.21)], P=.001. MLFS detected age-related changes with grade 0 [0.22 (0.21-0.23)] significantly lower than grade I [0.18 (0.16 0.20)], P=.001. CONCLUSION: TTE-evidenced diastolic dysfunction can be reliably identified by CMR using MLFS. PMID- 25034402 TI - Hepatocellular adenoma showing high uptake of (18)F-fluorodeoxyglucose (FDG) via an increased expression of glucose transporter 2 (GLUT-2). AB - Hepatocellular adenoma (HCA) is a benign liver neoplasm composed of hepatocytes. We experienced HCA demonstrating a high uptake of (18)F-fluorodeoxyglucose (FDG) on positron emission tomography-computed tomography, mimicking a malignant tumor. The mechanism underlying the uptake of FDG has not been identified. Here, we discuss that an enhancement of glucose metabolism via an increased expression of glucose transporter 2 may have a role in the high uptake of FDG shown by HCAs. PMID- 25034403 TI - Sinus rhythm heart rate estimation in high noise environments by application of a priori RR interval statistics. AB - Most existing heart beat detection algorithms serially process peaks, which can be either noise or true beats. Serial processing can result in inaccurate detections in the context of high noise. The proposed method relies on the relative regularity of sinus rhythm RR interval changes to select the best sequences of peaks in a 5-10 s long segment of cardiac data. The best sequences with a current data segment are subjected to a trending analysis, to determine whether their associated RR intervals fit within a pattern of prior best segments. The RR regularity scores and the results of the trending analysis are combined into a single sequence score and the final sequence for a segment is chosen from the best sequences based on this overall score. The current heart rate estimate is updated with the final sequence's RR interval by an adaptive filter that weights the overall score. Twenty-four hour RR interval records for 54 normal individuals were parsed into 10-s segments and corrupted with spurious 'noise' peaks, which resulted in a revised RR interval series that included a number of false RR intervals. The algorithm was run on these corrupted RR interval series. The percentages of mean heart rate values within 5 beats min(-1) of the true value were 95%, 88% and 77% for 10, 20 and 30 added noise spikes, respectively. The percentages of mean heart rate values within 10 beats min(-1) of the true value were 98%, 96% and 91% for 10, 20 and 30 added noise spikes, respectively. Accuracy was higher for data segments characterized by relatively low RR interval variability. The proposed algorithm shows promise for estimating average heart rate for sinus rhythm in high noise environments. PMID- 25034404 TI - Decreased bile-acid synthesis in livers of hepatocyte-conditional NADPH cytochrome P450 reductase-null mice results in increased bile acids in serum. AB - NADPH-cytochrome P450 reductase (Cpr) is essential for the function of microsomal cytochrome P450 monooxygenases (P450), including those P450s involved in bile acid (BA) synthesis. Mice with hepatocyte-specific deletion of NADPH-cytochrome P450 reductase (H-Cpr-null) have been engineered to understand the in vivo function of hepatic P450s in the metabolism of xenobiotics and endogenous compounds. However, the impact of hepatic Cpr on BA homeostasis is not clear. The present study revealed that H-Cpr-null mice had a 60% decrease in total BA concentration in liver, whereas the total BA concentration in serum was almost doubled. The decreased level of cholic acid (CA) in both serum and livers of H Cpr-null mice is likely due to diminished enzyme activity of Cyp8b1 that is essential for CA biosynthesis. Feedback mechanisms responsible for the reduced liver BA concentrations and/or increased serum BA concentrations in H-Cpr-null mice included the following: 1) enhanced alternative BA synthesis pathway, as evidenced by the fact that classic BA synthesis is diminished but chenodeoxycholic acid still increases in both serum and livers of H-Cpr-null mice; 2) inhibition of farnesoid X receptor activation, which increased the mRNA of Cyp7a1 and 8b1; 3) induction of intestinal BA transporters to facilitate BA absorption from the intestine to the circulation; 4) induction of hepatic multidrug resistance-associated protein transporters to increase BA efflux from the liver to blood; and 5) increased generation of secondary BAs. In summary, the present study reveals an important contribution of the alternative BA synthesis pathway and BA transporters in regulating BA concentrations in H-Cpr-null mice. PMID- 25034405 TI - The alpha7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys. AB - Previous studies in Parkinsonian rats and monkeys have shown that beta2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce l-Dopa-induced dyskinesias (LIDs), a serious complication of l-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of alpha7 nAChRs in LIDs, we tested the effect of the potent, selective alpha7 agonist ABT-107 [5-(6 [(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole]. MPTP (1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with l Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT 107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the beta2 agonist ABT-894 [(3 (5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, alpha7 and beta2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either alpha7 or beta2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease. PMID- 25034406 TI - HLA-DRB1*15:01 allele protects from asthma susceptibility. PMID- 25034407 TI - Synthesis of rhodamine-labelled dieckol: its unique intracellular localization and potent anti-inflammatory activity. AB - Rhodamine-labelled dieckol (1) synthesized through a click reaction was found to be localized in the endoplasmic reticulum (ER) of RAW 264.7 cells. Anti inflammatory activity of compound was considerably greater than that of dieckol itself. PMID- 25034408 TI - Revealing the micromechanisms behind semi-solid metal deformation with time resolved X-ray tomography. AB - The behaviour of granular solid-liquid mixtures is key when deforming a wide range of materials from cornstarch slurries to soils, rock and magma flows. Here we demonstrate that treating semi-solid alloys as a granular fluid is critical to understanding flow behaviour and defect formation during casting. Using synchrotron X-ray tomography, we directly measure the discrete grain response during uniaxial compression. We show that the stress-strain response at 64-93% solid is due to the shear-induced dilation of discrete rearranging grains. This leads to the counter-intuitive result that, in unfed samples, compression can open internal pores and draw the free surface into the liquid, resulting in cracking. A soil mechanics approach shows that, irrespective of initial solid fraction, the solid packing density moves towards a constant value during deformation, consistent with the existence of a critical state in mushy alloys analogous to soils. PMID- 25034409 TI - Effectiveness of the tailored Evidence Based Practice training program for Filipino physical therapists: a randomized controlled trial. AB - BACKGROUND: This study evaluated the effectiveness of the contextualized EBP training program for Filipino physical therapists in terms of knowledge, skills, attitudes and behavior. METHODS: A randomized controlled trial was designed to assess the effectiveness of the EBP training program. Fifty four physical therapists were randomly allocated to the EBP group (intervention) and waitlist (control) group. The EBP group had a one day face-to-face training with an online support, whilst the control was waitlisted. There were three measurement points which were pre, post, and three months post intervention for knowledge, skills and attitudes. Activity diaries were used to measure behavior. The diaries were collected after three months. Data analysis was by intention to treat in EBP domains of knowledge, skills and attitudes. RESULTS: Fifty-four physical therapists were included in the study. Fifty two (52) completed the post training assessment and 26 completed the 3 months post training assessment for EBP knowledge, skills and attitudes. There were significant improvements in these domains in the EBP group from pre to post training and over a period of three months (p < 0.05) compared with the waitlist control group. Thirty seven (37) physical therapists completed their activity diaries over three months. Behavior significantly improved in the EBP group in terms of EBP behaviors (formulating PICO, searching, appraising and applying the evidence) when faced with both new/unique and usual case scenarios (p < 0.05). More physical therapists in the waitlist control group significantly performed non-EBP behaviors (asking doctors and reading textbooks) when faced with new/unique cases compared with the EBP group (p < 0.05). No differences were noted between groups regarding non-EBP behaviors (asking colleagues and doctors and reading textbooks) particularly when faced with usual cases. CONCLUSION: The contextually designed EBP training program for Filipino physical therapists was effective in improving knowledge, skills and attitudes to EBP from pre to post training. Improvements were also observed at three months post training in knowledge, skills, attitudes and behavior to EBP. This model of training can be modified as needed based on the needs of the local context. Findings need to be interpreted with caution due to study limitations. CURRENT CONTROLLED TRIALS: ISRCTN74485061 (Registration date: February 9, 2011). PMID- 25034410 TI - Laparoscopic sleeve gastrectomy for morbid obesity: 5-year results. AB - BACKGROUND: Data concerning the long-term efficacy of laparoscopic sleeve gastrectomy in the treatment of morbid obesity remain scarce. In this retrospective, the authors present 5-year follow-up of 30 patients having undergone laparoscopic sleeve gastrectomy. METHODS: Since 2004, 30 patients underwent laparoscopic sleeve gastrectomy and completed 5 years of follow-up. Five patients were subsequently subjected to laparoscopic Roux-en-Y gastric bypass and were excluded from further analysis. The remaining 25 patients comprised the study population. RESULTS: Mean excess weight loss was 65.2 +/- 6.1%, 64.7 +/- 5.6%, 62 +/- 4.9%, 58.2 +/- 5.5%, and 56.4 +/- 5.8% for the first 5 years, respectively. There were no deaths, nor any major morbidity. Remission of comorbidities was observed in 40% to 80.9% of cases. CONCLUSIONS: Laparoscopic sleeve gastrectomy is a safe and effective means of treatment of morbid obesity both in the short and in the long term. More research is needed to better predict which patient will benefit most from this operation. PMID- 25034411 TI - The impact of an acute care surgery team on general surgery residency. AB - BACKGROUND: Acute care surgical teams (ACSTs) have limited data in residency. We sought to determine the impact of an ACST on the depth and breadth of general surgery resident training. METHODS: One year prior to and after implementation of an ACST, Accreditation Council for Graduate Medical Education case logs spanning multiple postgraduate year levels were compared for numbers, case types, and complexity. RESULTS: We identified 6,009 cases, including 2,783 after ACST implementation. ACSTs accounted for 752 cases (27%), with 39.2% performed laparoscopically. ACST cases included biliary (19.4%), skin/soft tissue (10%), hernia (9.8%), and appendix (6.5%). Second-year residents performed a lower percentage of laparoscopic cases after the creation of the ACST (20.4% vs 26.3%; P = .003), while chief residents performed a higher percentage (42.1 vs 37.4; P = .04). Case numbers and complexity following ACST development were unchanged within all year groups (P > .1). CONCLUSION: ACST in a residency program does not sacrifice resident case complexity, diversity, or volume. PMID- 25034412 TI - Modulatory roles of glycolytic enzymes in cell death. AB - Cancer cells depend on an altered energy metabolism characterized by increased rates of both glycolysis and glutaminolysis. Accordingly, corresponding key metabolic enzymes are overexpressed or hyperactivated. As a result, this newly acquired metabolic profile determines most other cancer hallmarks including resistance to cell death. Recent findings highlighted metabolic enzymes as direct modulators of cell death pathways. Conversely, key mediators of cell death mechanisms are emerging as new binding partners of glycolytic actors; moreover, there is evidence that metabolic regulators re-localize to specific subcellular compartments or organelles to modulate various types of cell demise. The final outcome is the resistance against cell death programs. Current findings give a new meaning to metabolic pathways and allow understanding how they affect cancer specific pathological alterations. Furthermore, they shed light on potentially targetable functions of metabolic actors to restore susceptibility of cancer cells to death. Here, we discuss an emerging interplay between cell metabolism and cell death, focusing on interactions that may offer new options of targeted therapies in cancer treatment involving more specifically hexokinases and glyceraldehyde-3-phosphate dehydrogenase. PMID- 25034413 TI - Epstein-Barr virus (EBV)-encoded dUTPase and chronic restraint induce impaired learning and memory and sickness responses. AB - Most adult humans have been infected with Epstein-Barr virus (EBV) and carry the latent virus. The EBV genome codes for several proteins that form an early antigen complex important for viral replication; one of these proteins is deoxyuridine triphosphate nucleotidohydrolase (dUTPase). The EBV-encoded dUTPase can induce sickness responses in mice. Because stress can increase latent virus reactivation, we hypothesized that chronic restraint would exacerbate sickness behaviors elicited by EBV-encoded dUTPase. Male Swiss-Webster mice were injected daily for 15 days with either saline or EBV-encoded dUTPase. Additionally, half of the mice from each condition were either restrained for 3h daily or left undisturbed. Restraint stress impaired learning and memory in the passive avoidance chamber; impaired learning and memory was due to EBV-encoded dUTPase injected into restrained mice. EBV-encoded dUTPase induced sickness responses and restraint stress interacts with EBV-encoded dUTPase to exacerbate the sickness response. These data support a role for EBV-encoded dUTPase and restraint stress in altering the pathophysiology of EBV independent of viral replication. PMID- 25034414 TI - A review of self-report medication side effect questionnaires for mental health patients. AB - Side effects of psychotropic medications are important determinants of adherence to treatment. Discussion between the patient and clinician facilitated through the use of a side effect self-report questionnaire (SRQ) could lead to improved communications and treatment adherence. The aim of this review was to 1) identify all currently available side effect SRQs used in the assessment of mental health patients' subjective experiences, 2) evaluate the characteristics of the studies and 3) assess the psychometric properties of each of the questionnaires. Eight electronic databases were searched for peer-reviewed published articles. Six side effect SRQs were identified. Two independent reviewers assessed the quality of the study designs and psychometric properties of the identified SRQs. All questionnaires consisted of closed questions relating to antipsychotic side effects and completion times ranged from 5 to 20 min. Five questionnaires had undergone some form of psychometric testing, ranging from basic to comprehensive. There is a need in everyday clinical practice for a side effect communication tool applicable to all psychotropic medications, which allows the patient to express their subjective beliefs about their medications. This could provide an important contribution to the working relationship between patients and clinicians leading to informed decision-making and improved adherence. PMID- 25034416 TI - Free Choice and Patient Best Interests. AB - In medical practice, the doctrine of informed consent is generally understood to have priority over the medical practitioner's duty of care to her patient. A common consequentialist argument for the prioritisation of informed consent above the duty of care involves the claim that respect for a patient's free choice is the best way of protecting that patient's best interests; since the patient has a special expertise over her values and preferences regarding non-medical goods she is ideally placed to make a decision that will protect her interests. In this paper I argue against two consequentialist justifications for a blanket prioritisation of informed consent over the duty of care by considering cases in which patients have imperfect access to their overall best interests. Furthermore, I argue that there are cases where the mere presentation of choice under the doctrine of informed consent is detrimental to patient best interests. I end the paper by considering more nuanced approaches to resolving the conflict between informed consent and the duty of care and consider the option of permitting patients to waive informed consent. PMID- 25034415 TI - An exploration of Early Childhood Education students' knowledge and preparation to facilitate physical activity for preschoolers: a cross-sectional study. AB - BACKGROUND: Early childhood educators play an important role in influencing preschoolers' physical activity levels. The current study sought to explore Early Childhood Education (ECE) students' physical activity-related knowledge and educational experience during their formal training in Ontario. METHODS: A total of 1,113 ECE students from 20 Ontario Colleges completed the study survey (online or on paper), which examined students' physical activity course content; awareness of physical activity guidelines; understanding of health-related benefits of physical activity; self-efficacy to facilitate physical activity for preschoolers; self-reported physical activity levels; as well as physical activity-related resource needs. Descriptive statistics and independent samples t tests were used to analyze the quantitative findings. RESULTS: Survey results identified that 72.1% of ECE students had not completed any physical activity/physical education specific courses, while only 28.7% were familiar with, and 2.0% accurately reported, the Canadian Physical Activity Guidelines for the Early Years. Only 10.5% of ECE students reported personal physical activity behaviors consistent with national recommendations for adults (150 minutes/week). ECE students' mean overall task self-efficacy to facilitate physical activity was 7.37 (SD = 1.64). Self-efficacy was significantly higher (p < .05) when students had taken one or more courses devoted to physical activity/physical education, as well as when students engaged in sufficient physical activity to meet the national guidelines for adults (p < .05). CONCLUSIONS: The results indicate that the current ECE college curriculum represents an excellent opportunity to provide future childcare providers with enriched physical activity-related training and support, such as physical activity guidelines, workshops, and new ideas for activities. Emphasizing the health benefits of physical activity for adults might be important in light of ECE students' low self-reported physical activity levels. PMID- 25034417 TI - Cytoprotective and anti-inflammatory effects of PAL31 overexpression in glial cells. AB - BACKGROUND: Acute spinal cord injury (SCI) leads to a series of reactive changes and causes severe neurological deficits. A pronounced inflammation contributes to secondary pathology after SCI. Astroglia respond to SCI by proliferating, migrating, and altering phenotype. The impact of reactive gliosis on the pathogenesis of SCI is not fully understood. Our previous study has identified an inflammatory modulating protein, proliferation related acidic leucine-rich protein (PAL31) which is upregulated in the microglia/macrophage of injured cords. Because PAL31 participates in cell cycle progression and reactive astroglia often appears in the injured cord, we aim to examine whether PAL31 is involved in glial modulation after injury. RESULTS: Enhanced PAL31 expression was shown not only in microglia/macrophages but also in spinal astroglia after SCI. Cell culture study reveal that overexpression of PAL31 in mixed glial cells or in C6 astroglia significantly reduced LPS/IFNgamma stimulation. Further, enhanced PAL31 expression in C6 astroglia protected cells from H2O2 toxicity; however, this did not affect its proliferative activity. The inhibiting effect of PAL31 on LPS/IFNgamma stimulation was observed in glia or C6 after co-culture with neuronal cells. The results demonstrated that the overexpressed PAL31 in glial cells protected neuronal damages through inhibiting NF-kB signaling and iNOS. CONCLUSIONS: Our data suggest that PAL31upregulation might be beneficial after spinal cord injury. Reactive gliosis might become a good target for future therapeutic interventions. PMID- 25034418 TI - Editorial commentary: failing our patients by suboptimally treating influenza infections. PMID- 25034420 TI - Reply to Nguyen et al. PMID- 25034419 TI - Use of influenza antiviral agents by ambulatory care clinicians during the 2012 2013 influenza season. AB - BACKGROUND: Early antiviral treatment (<=2 days since illness onset) of influenza reduces the probability of influenza-associated complications. Early empiric antiviral treatment is recommended for those with suspected influenza at higher risk for influenza complications regardless of their illness severity. We describe antiviral receipt among outpatients with acute respiratory illness (ARI) and antibiotic receipt among patients with influenza. METHODS: We analyzed data from 5 sites in the US Influenza Vaccine Effectiveness Network Study during the 2012-2013 influenza season. Subjects were outpatients aged >=6 months with ARI defined by cough of <=7 days' duration; all were tested for influenza by polymerase chain reaction (PCR). Medical history and prescription information were collected by medical and pharmacy records. Four sites collected prescribing data on 3 common antibiotics (amoxicillin-clavulanate, amoxicillin, and azithromycin). RESULTS: Of 6766 enrolled ARI patients, 509 (7.5%) received an antiviral prescription. Overall, 2366 (35%) had PCR-confirmed influenza; 355 (15%) of those received an antiviral prescription. Among 1021 ARI patients at high risk for influenza complications (eg, aged <2 years or >=65 years or with >=1 chronic medical condition) presenting to care <=2 days from symptom onset, 195 (19%) were prescribed an antiviral medication. Among participants with PCR confirmed influenza and antibiotic data, 540 of 1825 (30%) were prescribed 1 of 3 antibiotics; 297 of 1825 (16%) were prescribed antiviral medications. CONCLUSIONS: Antiviral treatment was prescribed infrequently among outpatients with influenza for whom therapy would be most beneficial; in contrast, antibiotic prescribing was more frequent. Continued efforts to educate clinicians on appropriate antibiotic and antiviral use are essential to improve healthcare quality. PMID- 25034421 TI - Impact of 13-valent pneumococcal conjugate vaccination in invasive pneumococcal disease incidence and mortality. AB - BACKGROUND: The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) at the population level is unclear. We explored PCV13's effect in reducing invasive pneumococcal disease (IPD)-related morbidity and mortality, and whether serotype specific changes were attributable to vaccination or expected as a part of natural, cyclical variations. METHODS: This was a Danish nationwide population based cohort study based on the linkage of laboratory surveillance data and the Danish Civil Registration System. Changes in IPD incidence and mortality during baseline (2000-2007), 7-valent pneumococcal conjugate vaccine (PCV7) (2008-2010), and PCV13 (2011-2013) periods were estimated. Predicted incidences of serotypes were estimated controlling for cyclical trends from historical patterns observed during the past 20 years. RESULTS: We observed a 21% reduction (95% confidence interval [CI], 17%-25%) in IPD incidence in the total population after PCV13's introduction, and a 71% reduction (95% CI, 62%-79%) in children aged <2 years, considered as the vaccine effectiveness. We estimated a 28% reduction (95% CI, 18%-37%) in IPD-related 30-day mortality, from 3.4 deaths (95% CI, 3.2-3.6) per 100 000 population in the pre-PCV period to 2.4 (95% CI, 2.2-2.7) in the PCV13 period. The decline in mortality was observed across all age groups but was mainly related to mortality reductions in the nonvaccinated population. For serotypes 1 and 3, there were no significant changes in incidence beyond what would be expected from natural cyclical patterns. Serotype 19A significantly increased following PCV7's introduction, but the incidence declined toward baseline in 2012. CONCLUSIONS: PCV13 has brought greater benefits than we had expected in our setting. We observed a further decline on IPD incidence shortly after the shift from PCV7 to PCV13 in the national immunization program. This decline was accompanied by a substantial population-level decline in pneumococcal related mortality of nearly 30% among nonvaccinated persons. PMID- 25034422 TI - Pooled specimens for HIV RNA monitoring: cheaper, but is it reliable? PMID- 25034423 TI - Reply to Krause et al. PMID- 25034424 TI - Tempered enthusiasm for fecal transplantation? PMID- 25034425 TI - Bedbugs and vector-borne diseases. PMID- 25034427 TI - HIV quality report cards: impact of case-mix adjustment and statistical methods. AB - BACKGROUND: There will be increasing pressure to publicly report and rank the performance of healthcare systems on human immunodeficiency virus (HIV) quality measures. To inform discussion of public reporting, we evaluated the influence of case-mix adjustment when ranking individual care systems on the viral control quality measure. METHODS: We used data from the Veterans Health Administration (VHA) HIV Clinical Case Registry and administrative databases to estimate case mix adjusted viral control for 91 local systems caring for 12 368 patients. We compared results using 2 adjustment methods, the observed-to-expected estimator and the risk-standardized ratio. RESULTS: Overall, 10 913 patients (88.2%) achieved viral control (viral load <=400 copies/mL). Prior to case-mix adjustment, system-level viral control ranged from 51% to 100%. Seventeen (19%) systems were labeled as low outliers (performance significantly below the overall mean) and 11 (12%) as high outliers. Adjustment for case mix (patient demographics, comorbidity, CD4 nadir, time on therapy, and income from VHA administrative databases) reduced the number of low outliers by approximately one third, but results differed by method. The adjustment model had moderate discrimination (c statistic = 0.66), suggesting potential for unadjusted risk when using administrative data to measure case mix. CONCLUSIONS: Case-mix adjustment affects rankings of care systems on the viral control quality measure. Given the sensitivity of rankings to selection of case-mix adjustment methods-and potential for unadjusted risk when using variables limited to current administrative databases-the HIV care community should explore optimal methods for case-mix adjustment before moving forward with public reporting. PMID- 25034426 TI - Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppression-associated conditions. AB - BACKGROUND: An increased incidence of alveolar echinococcosis (AE) in patients with immunosuppression (IS) has been observed; our aim was to study this association and its characteristics. METHODS: Fifty AE cases with IS-associated conditions (ISCs) before or at AE diagnosis were collected from the French AE registry (1982-2012, 509 cases). There were 30 cancers, 9 malignant hematological disorders, 14 chronic inflammatory diseases, 5 transplants, and 1 case of AIDS; 9 patients had >=2 ISCs. Characteristics of the 42 IS/AE cases and the 187 non IS/AE cases diagnosed during the period 2002-2012 were statistically compared. RESULTS: There was a significant increase in IS/AE cases over time. Risk factors did not differ between IS/AE and non-IS/AE patients. However, AE was more frequently an incidental finding (78% vs 42%) and was diagnosed at earlier stages (41% vs 23%) in IS/AE than in non-IS/AE patients. Serology was more often negative (14% vs 1%) and treatment efficacy was better (51% regression after 1 year treatment vs 27%) in IS/AE patients. All IS/AE patients but 7 took IS drugs; 7 received biotherapeutic agents. When not concomitant, AE occurred in IS patients within a 48-month median time period. Atypical presentation and abscess , hemangioma-, and metastasis-like images delayed AE diagnosis in 50% of IS/AE patients, resulting in inappropriate treatment. Liver images obtained for 15 patients 1-5 years before diagnosis showed no AE lesions. Albendazole efficacy was good, but 19 of 48 treated patients experienced side effects. CONCLUSIONS: Patients with immunosuppression are at increased risk for occurrence, delayed diagnosis, and progression of AE. PMID- 25034428 TI - Making sense of cephalosporin and amoxicillin/clavulanate susceptibility testing for uropathogens. PMID- 25034429 TI - Difficulties in emotion regulation are associated with panic symptom severity following a quit attempt among cannabis dependent veterans. AB - BACKGROUND AND OBJECTIVES: Prior research suggests that difficulties in emotion regulation are associated with elevations in panic symptoms. The present study aimed to extend this work by prospectively examining the relation between difficulties in emotion regulation and panic symptoms over the course of a self guided cannabis cessation attempt. DESIGN AND METHOD: One hundred and four cannabis-dependent military veterans participated in the study. Difficulties in emotion regulation and panic symptoms were assessed at baseline and at each week during a four-week cessation attempt for a total of five time-points. RESULTS: Fewer difficulties in emotion regulation were associated with a greater reduction in panic symptoms during the self-guided cannabis cessation period. RESULTS remained significant after statistically adjusting for mean substance use (i.e., cannabis, alcohol, and tobacco) during the study period. CONCLUSIONS: RESULTS are discussed in terms of integrating adaptive emotion regulation skills training into existing evidence-based treatments for cannabis dependence. PMID- 25034430 TI - Screening and selection of synthetic peptides for a novel and optimized endotoxin detection method. AB - The current validated endotoxin detection methods, in spite of being highly sensitive, present several drawbacks in terms of reproducibility, handling and cost. Therefore novel approaches are being carried out in the scientific community to overcome these difficulties. Remarkable efforts are focused on the development of endotoxin-specific biosensors. The key feature of these solutions relies on the proper definition of the capture protocol, especially of the bio receptor or ligand. The aim of the presented work is the screening and selection of a synthetic peptide specifically designed for LPS detection, as well as the optimization of a procedure for its immobilization onto gold substrates for further application to biosensors. PMID- 25034431 TI - Hydrothermal treatment of oleaginous yeast for the recovery of free fatty acids for use in advanced biofuel production. AB - Microbial oils hold great potential as a suitable feedstock for the renewable production of biofuels. Specifically, the use of oleaginous yeasts offers several advantages related to cultivation and quality of lipid products. However, one of the major bottlenecks for large-scale production of yeast oils is found in the lipid extraction process. This work investigated the hydrothermal treatment of oleaginous yeast for hydrolysis and lipid extraction resulting in fatty acids used for biofuel production. The oleaginous yeast, Cryptococcus curvatus, was grown in 5 L bioreactors and the biomass slurry with 53+/-4% lipid content (dry weight basis) was treated at 280 degrees C for 1h with an initial pressure of 500 psi in batch stainless steel reactors. The hydrolysis product was separated and each of the resulting streams was further characterized. The hexane soluble fraction contained fatty acids from the hydrolysis of yeast triacylglycerides, and was low in nitrogen and minerals and could be directly integrated as feedstock into pyrolysis processing to produce biofuels. The proposed hydrothermal treatment addresses some current technological bottlenecks associated with traditional methodologies such as dewatering, oil extraction and co-product utilization. It also enhances the feasibility of using microbial biomass for production of renewable fuels and chemicals. PMID- 25034432 TI - One-step synthesis of 2-keto-3-deoxy-d-gluconate by biocatalytic dehydration of d gluconate. AB - 2-Keto-3-deoxy-sugar acids are key intermediates of central metabolism and integral constituents of bacterial (lipo)polysaccharides and cell wall components and are therefore continuously and highly demanded in related research fields. The stereospecific chemical synthesis of chiral 2-keto-deoxy-sugar acids involves a multitude of reaction steps, while in metabolic pathways only few conversions lead to the same 2-keto-3-deoxy sugar acids from easily available carbohydrate precursors. Here we present a straightforward and highly economic one-step biocatalytic synthesis procedure of 2-keto-3-deoxy-d-gluconate (KDG) from d gluconate using recombinant gluconate dehydratase (GAD) from the hyperthermophilic crenarchaeon Thermoproteus tenax. This method is highly advantageous to KDG production schemes described so far for several reasons: (i) the d-gluconate is completely converted to stereochemically pure D-KDG without side-product formation, (ii) the final KDG yield is approximately 90%, (iii) the newly developed quantitative and qualitative LC-MS analysis method enabled the simultaneous detection of d-gluconate and KDG and (iv) the T. tenax GAD as biocatalyst can be provided by a simple and rapid procedure involving only two precipitation steps. The described utilization of dehydratases for 2-keto-3-deoxy sugar acid syntheses represents a highly resource-efficient one-step preparation and offers potential short synthetic routes toward a broad range of 2-keto-3 deoxy sugar acids and their derivatives. PMID- 25034433 TI - In vivo biodistribution and oxygenation potential of a new generation of oxygen carrier. AB - Natural giant extracellular hemoglobins (Hbs) from polychaete annelids are currently actively investigated as promising oxygen carriers. Their powerful oxygenating ability and their safety have been demonstrated in preclinical studies, motivating their development for therapeutic and industrial applications. HEMARINA-M101 (M101) is derived from the marine invertebrate Arenicola marina. It is formulated as a manufactured product designated HEMOXYCarrier((r)) (HEMARINA SA, France). The aim of the present study was to unveil the fate of M101 after a single intravenous (i.v.) injection in mice. For this purpose, M101 was tagged with a far-red fluorescent dye. Repeated non invasive fluorescent imaging revealed a rapid diffusion of M101 in the whole body of animals, reaching all the examined organs such as brain, liver, lungs and ovaries. Functional M101 was circulating in bloodstream for several hours, without inducing any obvious side-effects. Last, a single i.v. injection of M101 in mice bearing human-derived subcutaneous tumors demonstrated the ability of this Hb to reduce hypoxia in poorly vascularized tissues, thus supporting the biological relevance of M101 oxygen release to vertebrate tissues. Altogether, these results further encourage the development of M101 as an oxygen carrying therapeutic. PMID- 25034434 TI - Rational design of a glycosynthase by the crystal structure of beta-galactosidase from Bacillus circulans (BgaC) and its use for the synthesis of N acetyllactosamine type 1 glycan structures. AB - The crystal structure of beta-galactosidase from Bacillus circulans (BgaC) was determined at 1.8A resolution. The overall structure of BgaC consists of three distinct domains, which are the catalytic domain with a TIM-barrel structure and two all-beta domains (ABDs). The main-chain fold and steric configurations of the acidic and aromatic residues at the active site were very similar to those of Streptococcus pneumoniae beta(1,3)-galactosidase BgaC in complex with galactose. The structure of BgaC was used for the rational design of a glycosynthase. BgaC belongs to the glycoside hydrolase family 35. The essential nucleophilic amino acid residue has been identified as glutamic acid at position 233 by site directed mutagenesis. Construction of the active site mutant BgaC-Glu233Gly gave rise to a galactosynthase transferring the sugar moiety from alpha-d galactopyranosyl fluoride (alphaGalF) to different beta-linked N acetylglucosamine acceptor substrates in good yield (40-90%) with a remarkably stable product formation. Enzymatic syntheses with BgaC-Glu233Gly afforded the stereo- and regioselective synthesis of beta1-3-linked key galactosides like galacto-N-biose or lacto-N-biose. PMID- 25034435 TI - Optimization of a peptide nucleic acid fluorescence in situ hybridization (PNA FISH) method for the detection of bacteria and disclosure of a formamide effect. AB - Despite the fact that fluorescence in situ hybridization (FISH) is a well established technique to identify microorganisms, there is a lack of understanding concerning the interaction of the different factors affecting the obtained fluorescence. In here, we used flow cytometry to study the influence of three essential factors in hybridization - temperature, time and formamide concentration - in an effort to optimize the performance of a Peptide Nucleic Acid (PNA) probe targeting bacteria (EUB338). The PNA-FISH optimization was performed with bacteria representing different families employing response surface methodology. Surprisingly, the optimum concentration of formamide varied according to the bacterium tested. While hybridization on the bacteria possessing the thickest peptidoglycan was more successful at nearly 50% (v/v) formamide, hybridization on all other microorganisms appeared to improve with much lower formamide concentrations. Gram staining and transmission electron microscopy allowed us to confirm that the overall effect of formamide concentration on the fluorescence intensity is a balance between a harmful effect on the bacterial cell envelope, affecting cellular integrity, and the beneficial denaturant effect in the hybridization process. We also conclude that microorganisms belonging to different families will require different hybridization parameters for the same FISH probe, meaning that an optimum universal PNA-FISH procedure is non-existent for these situations. PMID- 25034436 TI - The role of A-kinase anchoring protein 95-like protein in annealing of tRNALys3 to HIV-1 RNA. AB - BACKGROUND: RNA helicase A (RHA), a DExH box protein, promotes annealing of tRNALys3, a primer for reverse transcription, to HIV-1 RNA and assembles into virus particles. A-kinase anchoring protein 95-like protein (HAP95) is a binding partner of RHA. The role of HAP95 in the annealing of tRNALys3 was examined in this study. RESULTS: HAP95 associates with the reverse transcriptase region of Pol protein of HIV-1. Decreasing endogenous HAP95 in HIV-1-producing 293T cells by siRNA reduces the amount of tRNALys3 annealed on viral RNA. This defect was further deteriorated by knockdown of RHA in the same cells, suggesting a cooperative effect between these two proteins. Biochemical assay in vitro using purified GST-tagged HAP95 shows that HAP95 may inhibit the activity of RHA. CONCLUSION: The results support a hypothesis that HAP95 may transiently block RHA's activity to protect the annealed tRNALys3 on viral RNA in the cells from removing by RHA during the packaging of RHA into virus particles, thus facilitating the annealing of tRNALys3 to HIV-1 RNA. PMID- 25034437 TI - Widespread vascular inflammation in a patient with antineutrophil cytoplasmic antibody-associated vasculitis as detected by positron emission tomography. PMID- 25034440 TI - Breast cancer in adolescent and young adult women. AB - Breast cancer is one of the most frequently diagnosed malignancy among adolescent and young adult (AYA) women, accounting for approximately 14% of all AYA cancer diagnoses and 7% of all breast cancer. Breast cancer in AYA women is believed to represent a more biologically aggressive disease, but aside from commonly known hereditary predispositions, little is still known about the underlying molecular genetic causes. This review examines the current trends of breast cancer in AYA women as they relate to clinical, social, genetic, and molecular pathologic characteristics. We highlight existing trends, treatment and imaging approaches, and health burdens as they relate to breast cancer in AYA women and provide a discussion on ways to help improve the overall management of this breast cancer cohort. PMID- 25034439 TI - Inflammatory breast cancer management in the national comprehensive cancer network: the disease, recurrence pattern, and outcome. AB - BACKGROUND: Inflammatory breast cancer (IBC) is an uncommon clinicopathologic entity characterized by rapid progression and aggressive behavior. We used the National Comprehensive Cancer Network (NCCN) Outcomes Database to characterize recurrence patterns and outcomes. METHODS: Patients with newly diagnosed IBC treated between 1999 and 2009 at 12 NCCN institutions were identified, and baseline characteristics were obtained. Patients had multimodality therapy if they received 2 of 3 treatments: surgery, perioperative (neoadjuvant or adjuvant) chemotherapy, or perioperative radiation. The first site of recurrence/metastatic diagnosis was identified. Overall survival was calculated on the basis of stage at diagnosis and receipt of multimodality therapy. RESULTS: We identified 673 patients, of whom 195 (29%) had metastatic disease at presentation. Median follow up was 29 months. Of patients in stage III, 82% received > 1 treatment modality. Among 203 patients in stage III with recurrence, the most frequent sites of first recurrence were bone (28%), central nervous system (CNS), lung, and liver (all 21%). Human epidermal growth factor receptor 2 positive and triple negative subtypes had higher rates of CNS recurrence (P = .001). Median survival was 66 months (95% confidence interval [CI], 54-107) for stage III and 26 months (95% CI, 22-33) for stage IV. Among 82% of patients in stage III receiving multimodality therapy, the median survival was 107 months (95% CI, 71 to not reached). CONCLUSIONS: This large, retrospective, multi-institutional study confirms the aggressive clinical features, unique recurrence patterns, and adverse prognosis of IBC. The high rate of CNS recurrence among high-risk subtypes, despite the inflammatory nature of the breast cancer, suggests that new strategies are needed for earlier detection or prevention of brain metastases to improve long-term prognosis. PMID- 25034438 TI - Reproductive factors and subtypes of breast cancer defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2: a register based study from Korea. AB - BACKGROUND: The relationship between reproductive breast risk factors and breast cancer survival in patients with different breast cancer subtypes is not well known. METHODS: We examined a large-sized, retrospective study of 23,882 subjects from the Korean Breast Cancer Registry. The breast cancer subtype was determined by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Information regarding reproductive factors, including breastfeeding, age at first birth (AFB), and parity, was gathered. Multivariate Cox regression analysis was used to estimate the association among breast cancer subtypes, such as luminal A, luminal B, Her 2/neu overexpressing, and triple negative breast cancer (TNBC), and breast cancer survival as dependent variables and adjusting for age and stage. RESULTS: High parity (>= 5) increased the recurrence risk of luminal A and B breast cancer (hazard ratio [HR], 1.95; 95% confidence interval [CI], 0.96-3.97; P = .0055 and HR, 1.12; 95% CI, 0.42-3.02, respectively; P = .0073) in breast cancer-specific survival (BCSS), but 1 to 3 child births decreased the recurrence risk of luminal A breast cancer (HR, 0.56; 95% CI, 0.34-0.91; P = .0055) and luminal B breast cancer (HR, 0.32; 95% CI, 0.17-0.61; P = .0073) in BCSS. Early AFB (< 20 years) increased the recurrence risk of luminal A breast cancers (HR, 1.61; 95% CI, 0.62 4.26; P = .039) in BCSS and of TNBC (HR, 1.31; 95% CI, 0.78-2.21; P = .0006) in overall survival. Her-2/neu overexpressing breast cancer had no correlation with parity and AFB in breast cancer survival. CONCLUSIONS: High parity (>= 5) and early AFB (< 20 years) were correlated with worse clinical outcomes in patients with luminal breast cancer, but not with other subtyped breast cancers. PMID- 25034441 TI - Human epidermal growth factor receptor 2-positive breast cancer: heat shock protein 90 overexpression, Ki67 proliferative index, and topoisomerase II-alpha co-amplification as predictors of pathologic complete response to neoadjuvant chemotherapy with trastuzumab and docetaxel. AB - BACKGROUND: The combination of trastuzumab and chemotherapy is currently considered the standard of care for patients with locally advanced/operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The potential correlation between the pathologic complete response (pCR) and the overexpression of heat shock protein 90 (Hsp90), Ki67, and the amplification of topoisomerase II alpha (TOPO2A) was investigated in a series of patients who received neoadjuvant treatment. METHODS: HER2-amplified patients who received neoadjuvant trastuzumab docetaxel were gathered. Baseline and postsurgical Hsp90 immunoscore, Ki67 proliferation index, and TOPO2A amplification were determined together with classic clinical-pathologic predictors and correlated with pCR and imaging data. RESULTS: A total of 24 patients were evaluated for response; pCR, clinical, and radiologic response were found in 4 patients (16.7%; 95% confidence interval [CI], 1.7-31.5), 9 patients (37.5%; 95% CI, 18.1-56.8), and 6 patients (25.0%; 95% CI, 7.6-42.3) patients, respectively. pCR was significantly higher in premenopausal (60.0% vs. 5.3%, P = .02) and negative hormonal receptor patients (50.0% vs. 5.6%, P = .03). A trend for patients with high Ki67 and TOPO2A/HER2 co amplification was found (21.1% vs. none, P = .54; 50.0% vs. 12%, P = .16). pCR was significantly higher in patients with Hsp90 score 3+, in comparison with score 2+ and score 1+ (50.0% vs. 14.3% vs. none, P = .05). After treatment, a statistically significant lower Ki67 staining (30.0% vs. 17.5%, P = .005) and a trend for the decreased expression of high (score 3+) and moderate (score 2+) Hsp90 immunostaining (McNemar P = .25, Wilcoxon-Mann-Whitney P = .08) were found. CONCLUSIONS: Although underpowered, our data suggest that patients with HER2 positive breast cancer overexpressing Hsp90 should be investigated as a "newer" molecular subtype with a significantly higher chance of pCR when receiving anti Her2 agents. PMID- 25034442 TI - Accelerated reepithelialization by triterpenes: proof of concept in the healing of surgical skin lesions. AB - The acceleration of wound healing is a major surgical concern. A triterpene extract from birch bark (Betulae cortex) experimentally enhances keratinocyte differentiation in vitro and accelerates wound healing ex vivo. We conducted an open, blind-evaluated, controlled, prospective, randomized (1:1) phase II clinical trial in patients requiring split-thickness skin graft transplantation at two university hospitals in Germany. Donor sites on the upper legs were covered with a moist silicone-coated dressing. Oleogel-S10 ointment containing 10% birch bark extract was randomly applied to the distal or proximal half of the wound, with the other half serving as an intraindividual control, for 14 days after the skin graft surgery. The primary efficacy variable was faster reepithelialization as determined from macrophotographs by independent, blinded experts. Twenty-four patients were randomized and completed the trial. After the 14-day test period, the planned interim analysis revealed a highly significant (p < 0.0001) superiority of Oleogel-S10 in the primary efficacy variable and the trial was terminated early due to ethical concerns. The treatment side was also better reepithelialized and more similar to normal skin after 3 months. In conclusion, Oleogel-S10 significantly accelerated reepithelialization at split thickness skin graft donor sites. Treatment with Oleogel-S10 was safe and well tolerated. PMID- 25034443 TI - Emotion effects during reading: Influence of an emotion target word on eye movements and processing. AB - Recently, Scott, O'Donnell and Sereno reported that words of high valence and arousal are processed with greater ease than neutral words during sentence reading. However, this study unsystematically intermixed emotion (label a state of mind, e.g., terrified or happy) and emotion-laden words (refer to a concept that is associated with an emotional state, e.g., debt or marriage). We compared the eye-movement record while participants read sentences that contained a neutral target word (e.g., chair) or an emotion word (no emotion-laden words were included). Readers were able to process both positive (e.g., happy) and negative emotion words (e.g., distressed) faster than neutral words. This was true across a wide range of early (e.g., first fixation durations) and late (e.g., total times on the post-target region) measures. Additional analyses revealed that State Trait Anxiety Inventory scores interacted with the emotion effect and that the emotion effect was not due to arousal alone. PMID- 25034444 TI - Carbamazepine poisoning treated by multiple extracorporeal treatments. AB - CONTEXT: Hemoperfusion (HP) or dialysis is occasionally used following carbamazepine (CBZ) toxicity but it remains unclear which is the most efficient modality. We describe a case of severe CBZ intoxication treated with different extracorporeal modalities during which CBZ toxicokinetics were compared. CASE DETAILS: A 58-year-old man was transferred to our facility 24 hours after ingesting over 14 g of sustained-release CBZ. Because of worsening neurological condition requiring mechanical ventilation and CBZ levels reaching 47.6 MUg/mL, he underwent three intermittent hemodialysis (IHD), two continuous veno-venous hemofiltration (CVVH), and one IHD with HP (IHD-HP). IHD and CVVH removed 1.73 g of carbamazepine over 43 hours. Mean apparent half-life was 8.8 hours during IHD 49.1 hours during CVVH, and 5.1 hours during IHD-HP, while measured endogenous half-life after extracorporeal therapies was 81.4 hours. Mean CBZ clearances were 106.2 mL/min during IHD and 21.2 mL/ min during CVVH. His neurological status improved during extracorporeal elimination, and he was discharged without sequela after 16 days. Treatments were well tolerated aside from thrombocytopenia during IHDHP. DISCUSSION: All extracorporeal treatments facilitated CBZ elimination, although CVVH was significantly less efficient than IHD and IHD-HP. IHD-HP may be better than IHD alone but must be weighed against its risks. IHD appears sufficient to eliminate CBZ and may need to be repeated or prolonged according to the clinical context if CBZ absorption is delayed. PMID- 25034445 TI - Genetics of regular exercise and sedentary behaviors. AB - Studies on the determinants of physical activity have traditionally focused on social factors and environmental barriers, but recent research has shown the additional importance of biological factors, including genetic variation. Here we review the major tenets of this research to arrive at three major conclusions: First, individual differences in physical activity traits are significantly influenced by genetic factors, but genetic contribution varies strongly over age, with heritability of leisure time exercise behavior ranging from 27% to 84% and heritability of sedentary behaviors ranging from 9% to 48%. Second, candidate gene approaches based on animal or human QTLs or on biological relevance (e.g., dopaminergic or cannabinoid activity in the brain, or exercise performance influencing muscle physiology) have not yet yielded the necessary evidence to specify the genetic mechanisms underlying the heritability of physical activity traits. Third, there is significant genetic modulation of the beneficial effects of daily physical activity patterns on strength and endurance improvements and on health-related parameters like body mass index. Further increases in our understanding of the genetic determinants of sedentary and exercise behaviors as well as the genetic modulation of their effects on fitness and health will be key to meaningful future intervention on these behaviors. PMID- 25034446 TI - Do twins differ from single-born children on rates of behavioral difficulty in early childhood? A study of sibling relationship risk factors. AB - The hypothesis that twinning raises risk for behavioral difficulties in childhood is persistent, yet there is limited and inconsistent empirical evidence. Simple mean comparison without control for confounders provides data on prevalence rates but cannot provide knowledge about risk or etiology. To assess the effect of twin relationship on behavior, comparison of patterns of association with single-born siblings may be informative. Analyses of data from an Australian sample of twins and single-born children (N = 305, mean age 4 years 9 months, and a follow-up 12 months later) were undertaken. The outcome measure was the Strengths and Difficulties Questionnaire. Predictor and control measures were obtained from parent report on the sibling/co-twin relationship behavior, family demographics, and obstetric history. We assessed difference between twins and single-born children in two respects: (a) mean behavioral difficulties, and (b) patterns of association between sibling relationship and behavioral difficulties, controlling for confounders. Results showed no differences in mean levels of behavioral difficulties between twins and single-born siblings identifying the importance of statistical control for family and obstetric adversity. Differences in patterns of association were found; for twin children, conflict in their co-twin relationship predicted externalizing behaviors, while for single-born children conflict predicted internalizing behaviors. The findings of mean differences between twin and single-born children in social background, but not in behavioral difficulties, underscore the necessity of statistical control to identify risk associated with twinning compared with risk associated with family and obstetric background factors. PMID- 25034451 TI - A structural approach to understanding the interactions between colour, water holding capacity and tenderness. AB - The colour, water-holding capacity (WHC) and tenderness of meat are primary determinants of visual and sensory appeal. Although there are many factors which influence these quality traits, the end-results of their influence is often through key changes to the structure of muscle proteins and their spatial arrangement. Water acts as a plasticiser of muscle proteins and water is lost from the myofibrillar lattice structure as a result of protein denaturation and consequent reductions in the muscle fibre volume with increasing cooking temperature. Changes in the myofilament lattice arrangement also impact the light scattering properties and the perceived paleness of the meat. Causes of variation in the quality traits of raw meat do not generally correspond to variations in cooked meat and the differences observed between the raw muscle and cooked or further processed meat are discussed. The review will also identify the gaps in our knowledge and where further investigation would beneficial. PMID- 25034452 TI - Inclusion of red meat in healthful dietary patterns. AB - Dietary patterns are an important concept in dietary recommendations. The Western pattern is most commonly defined as a diet characterized by high intakes of refined grains, sugar and red meat, and has been shown to be associated with increased risks for certain types of cancer, coronary heart disease, diabetes, and obesity. However, isolating the independent effects of individual foods on health outcomes is central to helping individuals choose foods to build healthier dietary patterns to which they can adhere. Red meat is a popular source of high quality protein and provides a variety of essential nutrients that improve overall diet quality. It is also a source of saturated fatty acids, which observational evidence suggests are associated with heart disease, although recent data challenge this. Several studies have shown that lean red meat can be successfully included in recommended heart-healthy dietary patterns without detriment to blood lipids. Furthermore, increased dietary protein has been shown to promote healthy body weight and composition, in part by increasing satiety, and to improve vitality and stamina. PMID- 25034453 TI - Active and intelligent packaging systems for a modern society. AB - Active and intelligent packaging systems are continuously evolving in response to growing challenges from a modern society. This article reviews: (1) the different categories of active and intelligent packaging concepts and currently available commercial applications, (2) latest packaging research trends and innovations, and (3) the growth perspectives of the active and intelligent packaging market. Active packaging aiming at extending shelf life or improving safety while maintaining quality is progressing towards the incorporation of natural active agents into more sustainable packaging materials. Intelligent packaging systems which monitor the condition of the packed food or its environment are progressing towards more cost-effective, convenient and integrated systems to provide innovative packaging solutions. Market growth is expected for active packaging with leading shares for moisture absorbers, oxygen scavengers, microwave susceptors and antimicrobial packaging. The market for intelligent packaging is also promising with strong gains for time-temperature indicator labels and advancements in the integration of intelligent concepts into packaging materials. PMID- 25034454 TI - Treatment of acute lung injury by targeting MG53-mediated cell membrane repair. AB - Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischaemia reperfusion and overventilation-induced injury to the lung when compared with wild-type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases. PMID- 25034455 TI - Is abnormal non-high-density lipoprotein cholesterol a gender-specific predictor for metabolic syndrome in patients with schizophrenia taking second-generation antipsychotics? AB - Evidence supports an association between metabolic syndrome (MetS) and schizophrenia. However, specific risk factors for MetS and gender differences in patients with schizophrenia taking second-generation antipsychotics (SGAs) have not been well explored. A cross-sectional cohort of 329 Han Chinese patients was recruited in a psychiatric hospital in central Taiwan. Using the definitions of the International Diabetes Federation for Chinese, the prevalence of MetS was 23.7% (men: 25.7%; women: 21.2%). Logistic regression analyses showed that patients with a BMI >= 24 and an abnormal non-high-density lipoprotein cholesterol (non-HDL-C) were significantly (p < 0.001) more likely to develop MetS. A BMI >= 24 was a significant risk factor in men (OR: 6.092, p < 0.001) and women (OR: 5.886, p < 0.001). An abnormal non-HDL-C was a significant specific risk factor for men with MetS (OR: 4.127, p < 0.001), but not for women. This study supports a greater prevalence of MetS in patients with schizophrenia taking SGAs than in the general population. Abnormal BMI and non-HDL-C were significantly associated with developing MetS, and an abnormal non-HDL-C was a specific risk factor for men. Future development of specific interventions and regular monitoring for MetS is imperative for early identification and prevention. PMID- 25034456 TI - Psychometric and EEG changes after carotid endarterectomy. AB - The influence of carotid stenosis and its surgical treatment on brain function is still poorly defined. We therefore performed a study to assess psychometric and quantified EEG findings after carotid endarterectomy (CEA). Sixty-nine non demented patients (aged 72 +/- 7 years) with severe carotid stenosis (>= 70%) eligible for CEA were studied. Forty patients (group A) had unilateral stenosis, and 29 patients (group B) had bilateral stenosis. Before and 5 months after CEA all the patients were evaluated by the Trail Making Test A, the Symbol Digit Test, and spectral EEG analysis. At baseline, compared to group A, group B patients performed slowly the Trail Making Test A (Z: 1.45 +/- 1.4 vs. 0.76 +/- 1.3; p < 0.05), but not the Symbol Digit Test (Z: 0.83 +/- 1.38 vs. 0.64 +/- 1.26; p = 0.59). Altogether, the patients with at least one abnormal psychometric test were 29% (group A: 26%; group B: 33%, p = 0.56). The EEG did not differ significantly between patients of group A compared to group B. After CEA, psychometric tests improved (mean Z score from 0.73 +/- 1.12 to 0.45 +/- 1.15, p < 0.05). The improvement was similar in group A and B. The EEG mean dominant frequency improved only in group B patients and it was related to the improvement in psychometric tests (r = 0.43, p = 0.05). Low psychometric performance was detectable in about 1/ 3 of non-demented patients with severe carotid stenosis. CEA improved mental performance and, in patients with severe bilateral stenosis, accelerated the EEG frequency. PMID- 25034457 TI - Serum levels of AgRP protein in patients with schizophrenia on clozapine monotherapy. AB - AIM: Agouti-related peptide (AgRP) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism, thus leading to weight gain. The aim of the study was to find out if AgRP level in subjects with schizophrenia on clozapine monotherapy is higher compared with healthy controls. METHODOLOGY: We determined fasting serum AgRP levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition analysis. RESULTS: There was no difference for AgRP levels between patients taking clozapine and control group (15.00+/-8.65 vs. 15.33+/-6.82 pg/mL, p =0.37). We found negative correlations between AgRP levels and total body fat (r =-0.34 and 0.48 in the whole study group and clozapine group, respectively) and positive correlations with lean body mass (r =0.38 and 0.49 in the whole study group and clozapine group, respectively), body water (r =0.34 and 0.49 in the whole study group and clozapine group, respectively) and basal metabolic rate (r =0.42 both in the clozapine and control groups). There were no correlations with age, height, weight, body mass index, fat mass index, abdominal, waist or hip circumferences, waist-hip ratio, blood pressure, total cholesterol, HDL, LDL, triglycerides, uric acid, glucose, insulin, clozapine dose or treatment duration, duration of treatment with antipsychotics and markers for insulin resistance. CONCLUSION: We cannot conclude that treatment with clozapine is associated with increased level of AgRP. We did not find previously described differences in AgRP levels between obese and non-obese subjects or associations between AgRP and various metabolic parameters. PMID- 25034459 TI - Molybdenum catalyzed ammonia borane dehydrogenation: oxidation state specific mechanisms. AB - Though numerous catalysts for the dehydrogenation of ammonia borane (AB) are known, those that release >2 equiv of H2 are uncommon. Herein, we report the synthesis of Mo complexes supported by a para-terphenyl diphosphine ligand, 1, displaying metal-arene interactions. Both a Mo(0) N2 complex, 5, and a Mo(II) bis(acetonitrile) complex, 4, exhibit high levels of AB dehydrogenation, releasing over 2.0 equiv of H2. The reaction rate, extent of dehydrogenation, and reaction mechanism vary as a function of the precatalyst oxidation state. Several Mo hydrides (Mo(II)(H)2, [Mo(II)(H)](+), and [Mo(IV)(H)3](+)) relevant to AB chemistry were characterized. PMID- 25034458 TI - Can lactate serve as an energy substrate for axons in good times and in bad, in sickness and in health? AB - In the mammalian white matter, glycogen-derived lactate from astrocytes plays a critical role in supporting axon function using the astrocyte-neuron lactate transfer shuttle (ANLTS) system with specialized monocarboxylate transporters (MCTs). A rapid breakdown of glycogen to lactate during increased neuronal activity or low glucose conditions becomes essential to maintain axon function. Therefore astrocytes actively regulate their glycogen stores with respect to ambient glucose levels such that high ambient glucose upregulates glycogen and low levels of glucose depletes glycogen stores. Although lactate fully supports axon function in the absence of glucose and becomes a preferred energy metabolite when axons discharge at high frequency, it fails to benefit axon function during an ischemic episode in white matter. Emerging evidence implies a similar lactate transport system between oligodendrocytes and the axons they myelinate, suggesting another metabolic coupling pathway in white matter. Therefore the conditions that activate this lactate shuttle system and the signaling mechanisms that mediate activation of this system are of great interest. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish how white matter components metabolically cooperate and that lactate may be the universal metabolite to sustain CNS function. PMID- 25034460 TI - Evaluation and analysis of plasma soluble adhesion molecules in patients with coronary ectasia and atherosclerotic coronary artery disease. AB - BACKGROUND AND AIMS: The pathogenesis of coronary artery ectasia (CE) is poorly understood. An underlying inflammatory process is suspected; current therapy aims to prevent thrombotic events. Presently, there is no evidence to support an anti inflammatory approach for CE patients. We undertook this study to determine the presence and levels of adhesion molecules as well as other inflammation-related markers and evaluate their invasive angiography findings to compare between patients with CE or atherosclerotic coronary artery disease (CAD). METHODS: We included 23 patients with CE alone and 23 patients with CAD alone reported by diagnostic angiography. The two groups were paired according to gender and age. Clinical variables, angiographic findings (STEMI, NSTEMI, previous coronary stenting and previous CABG), serum VCAM, ICAM, C-reactive protein (CRP), IL-6 and adiponectin were compared between groups. RESULTS: In patients with CE, median for serum VCAM was 1700 ng/mL with a range from 900-4050 and for serum ICAM was 550 ng/mL (370-1530); in contrast to the obstructive lesions group where we found a median for VCAM of 1150 ng/mL (650-2000) and for ICAM of 370 ng/mL (150-480). Both measurements achieved statistical significance with a p value = 0.0001. There was no important variation between patients measured at different times from diagnosis. CONCLUSION: Plasma soluble adhesion molecules in CE are elevated in comparison to CAD. The presence of high levels of these molecules, along with not uncommon multivessel and extensive coronary affection suggest the participation of subclinical inflammation, which may have an important role in the development of CE. PMID- 25034461 TI - Oral contraceptive use, parity, and constitutional characteristics in soft tissue sarcoma: a Swedish population-based case-control study 1988-2009. AB - PURPOSE: The study was designed to investigate the influence of surrogate factors associated with sex (SH) and growth hormones (GH) on the risk of developing soft tissue sarcomas (STS). BACKGROUND AND METHODS: The etiology of soft tissue sarcoma is largely unknown. We have studied the effect of hormone related factors on STS in the Swedish population between 1988 and 2009 using a population-based matched case-control design. RESULTS: Our study is the largest on this topic to date, including 634 cases in a primary matched analysis and 855 cases in an unmatched sensitivity analysis. We identified protective effects connected to constitutional characteristics, hormonal and reproductive factors. Being shorter than your peers at age 11 was associated with an odds ratio (OR) of 0.51 (0.36 0.74). Having used oral contraceptives (OC), OR 0.75 (0.49-1.15), and high parity, OR 0.16 (0.04-0.63), comparing three or more children to two or less, also appeared to reduce the risk of STS. The risk was further reduced with the duration of OC use (p = 0.01), comparing use for 11 years or more to use for 3 years or less yielded an OR of 0.10 (0.02-0.41). No effect was observed for ever having had perimenopausal hormone therapy OR 1.02 (0.70-1.47). The effect of BMI varied significantly with subtype (p = 0.03) and tumor location (p < 0.001). CONCLUSIONS: We observed surrogates of SH, GH, and insulin-like growth factor 1 to be associated with STS development. These findings are important as they may connect STSs to the group of hormone-dependent tumors, potentially revealing common treatment and prevention targets. PMID- 25034462 TI - Trends in incidence, mortality, and survival for kidney cancer in Canada, 1986 2007. AB - PURPOSE: Kidney cancer is one of the fastest rising cancers worldwide. We aimed to examine the trends in incidence, mortality, and survival for this cancer in Canada. METHODS: Incidence data for kidney cancer for 1986-2010 were from the Canadian Cancer Registry and the National Cancer Incidence Reporting System. These data were only available up to 2007 for the province of Quebec and consequently for the same year nationally, for Canada. Mortality data for 1986 2009 were from the Canadian Vital Statistics Death Database. Changes in age standardized rates were analyzed by Joinpoint regression. Incidence rates were projected to 2025 using a Nordpred age-period-cohort model. Five-year relative survival ratios (RSR) were analyzed for 2004-2008 and earlier periods. RESULTS: Between 1986 and 2007, the age-standardized incidence rate (ASIR) per 100,000 rose from 13.4 to 17.9 in males and 7.7 to 10.3 in females. Annual increases in ASIR were greatest for age groups <65 years (males) and >=65 years (females). The ASIRs increased significantly over time in both sexes for renal cell carcinoma (RCC) but not for other kidney cancer types. RCC rates are projected to increase until at least 2025. Mortality rates decreased only slightly in each sex since 1986 (0.4%/year in males; 0.8%/year in females). The 5-year RSR for kidney cancer was 68% but differed largely by morphology and age, and has increased slightly over time. CONCLUSIONS: The incidence rate of kidney cancer in Canada has risen since at least 1986, led largely by RCC. Increasing detection of incidental tumors, and growing obesity and hypertension rates are possible factors associated with this increase. Greater prevention of modifiable risk factors for kidney cancer is needed. PMID- 25034463 TI - 5-HT6 Receptor Recruitment of mTOR Modulates Seizure Activity in Epilepsy. AB - Approximately 30% of epilepsy cases are refractory to current pharmacological treatments. Thus, novel therapeutic approaches that prevent or reverse the molecular and cellular mechanisms of epilepsy are required. 5-HT6 receptor (HTR6) blockade can modulate multiple neurotransmitter systems, and HTR6 may be a potential therapeutic treatment for neurological diseases, including epilepsy. Here, we investigated the role of HTR6 in epilepsy. We detected HTR6 expression both in human epileptic tissues and the pilocarpine rat model by western blotting. We observed behavioral changes after administration of pilocarpine in rats pretreated with a selective HTR6 antagonist, SB-399885, and recorded the electrophysiological index in the pilocarpine rat model pre- or posttreated with SB-399885 by electroencephalogram (EEG) and whole-cell clamp. We measured the activity of mammalian target of rapamycin (mTOR) in the pilocarpine rat model pretreated with the mTOR-specific inhibitor, rapamycin, and SB-399885 using western blotting. We found that HTR6 expression was upregulated in both human tissues and the pilocarpine rat model, and that SB-399885 could suppress epileptic seizures and mTOR activity in epileptic seizures. These results suggest that HTR6 plays an important role in modulating seizure activity and that the blockade of the HTR6/mTOR pathway could be a potential therapeutic target for epilepsy treatment. PMID- 25034464 TI - Impact of temperature, feeding preference and vaccination on Schmallenberg virus transmission in Scotland. AB - First identified in 2011, Schmallenberg virus (SBV) is principally transmitted by Culicoides midges and affects ruminants. Clinical presentation is typified by foetal abnormalities, but despite very high infection rates, relatively few animals present with clinical signs. In this paper we further develop a previously published stochastic mathematical model of SBV spread to investigate the optimal deployment of a vaccine for SBV in Scotland, a country that has experienced only sporadic and isolated cases of SBV. We consider the use of the vaccine under different temperatures and explore the effects of a vector preference for feeding on cattle. We demonstrate that vaccine impact is optimised by targeting it at the high risk areas in the south of Scotland, or vaccinating only cattle. At higher than average temperatures, and hence increased transmission potential, the relative impact of vaccination is considerably enhanced. Vaccine impact is also enhanced if vectors feed preferentially on cattle. These findings are of considerable importance when planning control strategies for SBV and also have important implications for management of other arboviruses such as Bluetongue virus. Environmental determinants and feeding preferences should be researched further to inform development of effective control strategies. PMID- 25034465 TI - Lipid profile components and subclinical cerebrovascular disease in the northern Manhattan study. AB - BACKGROUND: Subclinical cerebrovascular disease has been associated with multiple adverse events related to aging, including stroke and dementia. The modifiable risk factors for subclinical cerebrovascular disease beyond hypertension have not been well characterized. Our objective was to examine the association between baseline, and changes over time, in lipid profile components and subclinical cerebrovascular disease on magnetic resonance imaging (MRI). METHODS: Fasting plasma lipids were collected on participants in the Northern Manhattan Study, a prospective cohort study examining risk factors for cardiovascular disease in a multiethnic elderly urban-dwelling population. A subsample of the cohort underwent brain MRI between 2003 and 2008 (a median of 6.2 years, range = 0-14, after enrollment), when repeat fasting lipids were obtained. We used lipid profile components at the time of initial enrollment (n = 1,256 with lipids available) as categorical variables, as well as change in clinical categories over the two measures (n = 1,029). The main outcome measures were (1) total white matter hyperintensity volume (WMHV) using linear regression and (2) silent brain infarcts (SBI) using logistic regression. RESULTS: None of the plasma lipid profile components at the time of enrollment were associated with WMHV. The association between baseline lipids and WMHV was, however, modified by apolipoprotein E (apoE) status (chi(2) with 2 degrees of freedom, p = 0.03), such that among apoE4 carriers those with total cholesterol (TC) >=200 mg/dl had a trend towards smaller WMHV than those with TC <200 mg/dl (difference in logWMHV 0.19, p = 0.07), while there was no difference among apoE3 carriers. When examining the association between WMHV and change in lipid profile components we noted an association with change in high-density lipoprotein cholesterol (HDL-C, >50 mg/dl for women, >40 mg/dl for men) and TC. A transition from low-risk HDL-C (>50 mg/dl for women, >40 mg/dl for men) at baseline to high-risk HDL-C at the time of MRI (vs. starting and remaining low risk) was associated with greater WMHV (difference in logWMHV 0.34, p value 0.03). We noted a similar association with transitioning to a TC >=200 mg/dl at the time of MRI (difference in logWMHV 0.25, p value 0.006). There were no associations with baseline or change in lipid profile components with SBI. CONCLUSIONS: The association of plasma lipid profile components with greater WMHV may depend on apoE genotype and worsening HDL and TC risk levels over time. PMID- 25034466 TI - Real-world observations with prasugrel compared to clopidogrel in acute coronary syndrome patients treated with percutaneous coronary intervention in the United States. AB - OBJECTIVES: To compare 30 and 90 day real-world acute myocardial infarction (AMI) and bleeding related rehospitalization rates in acute coronary syndrome (ACS) patients receiving percutaneous coronary intervention (PCI; ACS-PCI) treated with clopidogrel or prasugrel. RESEARCH DESIGN AND METHODS: Using the Premier hospital database, ACS-PCI patients receiving a drug-eluting (DES) or bare-metal (BMS) stent and clopidogrel or prasugrel from July 2009 to June 2011 were analyzed. Patients were included based on the prasugrel US prescribing information (USPI), excluding patients with a history of transient ischemic attack/stroke and patients >=75 years without diabetes or prior MI. The primary endpoint was 30 day adjusted AMI rehospitalization rate. Secondary endpoints included 90 day AMI and 30 and 90 day bleeding-related rehospitalization rates. Treatment comparisons were adjusted using propensity score stratification. RESULTS: At the index event, prasugrel patients (N = 9404) differed from clopidogrel patients (N = 74,163) by having a lower risk of comorbid conditions associated with bleeding, being more likely younger and male, having ST-elevation MI and receiving a DES. For clopidogrel and prasugrel, respectively, the observed AMI-related rehospitalization rates were 4.7% and 3.9% at 30 days (p < 0.0001) and 6.3% and 5.1% at 90 days (p < 0.0001). After adjustment, prasugrel was associated with ~10% lower odds of AMI-related rehospitalization (30 days: OR = 0.892 [95% CI: 0.798, 0.998]; 90 days, OR = 0.901 [95% CI: 0.817, 0.994]). Adjusted bleeding related rehospitalization rates were similar to each other (OR = 1.035 at 30 days [95% CI: 0.765, 1.399]; OR = 0.922 at 90 days [95% CI: 0.725, 1.172]). STUDY LIMITATIONS: Treatment adherence was not assessed. Bleeding events not resulting in a hospitalization (e.g. office, outpatient, or emergency room visits), deaths outside the hospital, or readmissions to a hospital outside of the Premier alliance were not captured in the database. CONCLUSIONS: The different patient characteristics between prasugrel- and clopidogrel-treated patients suggest physicians are more selective in choosing patients for prasugrel than recommended in the prasugrel USPI. However, after adjustment for these differences, 30 and 90 day AMI rehospitalization rates were lower for prasugrel-treated patients compared to clopidogrel-treated patients, with no difference in adjusted bleeding related rehospitalization rates. PMID- 25034467 TI - Wireless control and selection of forces and torques--towards wireless engines. AB - Powering and manipulating translational and rotational motions of objects wirelessly, and controlling several objects independently is of significant importance in numerous fields such as robotics, medicine, biology, fluid dynamics, optics. We propose a method based on coupled LC resonators, to control objects selectively by steering the frequency of an external magnetic field. This concept does not need any magnetic materials and it brings a rich variety of features concerning forces and torques. We theoretically and experimentally show that the forces can be enhanced by the interaction of resonators and that both direction and magnitude of forces can be controlled by the frequency of the applied external magnetic field. Moreover, we demonstrate interesting rotational effects, such as bi-directionally controllable torques, controllable stable orientations, and spinning, which leads to a wirelessly powered motor. PMID- 25034468 TI - Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates from Korea and analysis of the correlation between the mutations and pyrazinamidase activity. AB - To investigate the effect of natural pyrazinamidase (PncA) mutations on protein function, we analyzed expression and PncA activity of eight pncA point mutants identified in nineteen pyrazinamide-resistant Mycobacterium tuberculosis clinical isolates. Among them, two mutants (Y99D and T135P) showed high expression level and solubility comparable to those of the wild-type PncA protein, two (K48E and G97D) displayed low expression level and solubility, and four (C14R, H51P, W68S, and A146V) were insoluble. Interestingly, when possible structural effects of these mutations were predicted by the CUPSAT program based on the proposed three dimensional structure of M. tuberculosis PncA, only two highly soluble mutant proteins (Y99D and T135P) were predicted to be stabilizing and have favorable torsion angles. However, the others exhibiting either low solubility or precipitation were foreseen to be destabilizing and/or have unfavorable torsion angles, suggesting that the alterations could interfere with proper protein folding, thereby decreasing or depleting protein solubility. A PncA activity assay demonstrated that two mutants (G97D and T135P) showed virtually no activity, but two other mutants (K48E and Y99D) exhibited wild-type activity, indicating that the PncA residues (Cys14, His51, Trp68, Gly97, Thr135, and Ala146) may be important for PncA activity and/or proper protein folding. PMID- 25034471 TI - Density related effects on lifetime fecundity of Heterakis gallinarum in chickens. AB - BACKGROUND: Density related effects, both inverse density- and density-dependent, contribute to regulating population dynamics of parasites. We investigated whether density related effects are directly controlling lifetime fecundity of Heterakis gallinarum. METHODS: Daily total numbers of H. gallinarum eggs in faeces samples (N = 1365) from chickens (N = 39) were quantified starting from 3 weeks (wk) post-infection (p.i.). The birds were necropsied 8 wk p.i., and intensity and demographic characteristics of infrapopulations were determined. Density related effects on cumulative egg excretion (CEE), lifetime fecundity and worm length were investigated with a segmented regression analysis. RESULTS: For CEE, lifetime fecundity and female worm length, we determined highly similar parasite intensity thresholds (52-54 worms), which separated infrapopulations for influences of inverse density- and density dependence. CEE increased as parasite intensity increased up to an intensity of 52 worms. After this threshold, the relationship followed more of a horizontal line indicating impaired worm fecundity at higher parasite intensities. Lifetime fecundity was enhanced linearly in infrapopulations with up to 54 worms, but thereafter decreased gradually with increasing infrapopulation size. Female worm length increased linearly with elevating parasite intensity up to a threshold of 54 worms and thereafter declined with a rate of -0.014 mm for each additional worm. Lifetime fecundity and female worm length did not significantly differ between infrapopulations below and above the thresholds (P > 0.05). Lifetime fecundity was positively associated with the percentage of male worms (r = 0.44; P < 0.001), but negatively with absolute deviation from the theoretically expected sex-ratio in the infrapopulations (r = -0.56; P = 0.005). These relationships were stronger in infrapopulations below the threshold (r = 0.51 and -0.61, respectively), and were not significantly different from zero in the infrapopulations above the threshold (P > 0.05). CONCLUSIONS: Egg production of H. gallinarum is regulated by the effects of both inverse density- and density dependent mechanisms, which result in similar average lifetime fecundity below or above intensity thresholds. In infrapopulations below the intensity thresholds, inverse density dependence effects on lifetime fecundity appear to result partly from sex-ratio fluctuations and impaired mating success of the nematode. PMID- 25034472 TI - Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). AB - A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years. PMID- 25034473 TI - Intracranially recorded ictal direct current shifts may precede high frequency oscillations in human epilepsy. AB - OBJECTIVE: We assessed the temporal-spatial characteristics of ictal direct current (DC) shifts (or infraslow activity) and high frequency oscillations (HFOs) in 16 patients with intractable focal epilepsy. METHODS: The underlying etiology consisted of cortical dysplasia, glioma, hippocampal sclerosis, and low grade neuroepithelial tumor in nine, four, two, and one patients, respectively. The median number of analyzed seizure events was 8.0 per patient (range: 2-10). Chronic electrocorticographic recording was performed with (1) a band-pass filter of 0.016-600Hz (or 0.016-300Hz) and a sampling rate of 2000Hz (or 1000Hz). RESULTS: Ictal DC shifts and a sustained form of ictal HFOs were observed in 75.0% and 50.0% of the patients, and 71.3% and 46.3% of the analyzed seizures. Visual assessment revealed that the onset of ictal DC shifts preceded that of ictal HFOs with statistical significance in 5/7 patients. The spatial extent of ictal DC shifts or HFOs was smaller than that of the conventionally defined seizure onset zone in 9/12 patients. CONCLUSION: Both ictal DC shifts and HFOs might represent the core of tissue generating seizures. SIGNIFICANCE: The early occurrence of ictal DC shifts warrants further studies to determine the role of glia (possibly mediating ictal DC shifts) in seizure generation. PMID- 25034474 TI - What startle can tell us about the brainstem controlling finger movements. PMID- 25034475 TI - Weight-for-age distribution and case-mix adjusted outcomes of 14,307 paediatric intensive care admissions. AB - AIMS: To determine whether the paediatric intensive care (PIC) population weight distribution differs from the UK reference population and whether weight-for-age at admission is an independent risk factor for mortality. METHODS: Admission weight-for-age standard deviation scores (SDS) were calculated for all PIC admissions (March 2003-December 2011) to Great Ormond Street Hospital: this is the number of standard deviations (SD) between a child's weight and the UK mean weight-for-age. Categorised into nine SDS groups, standardised mortality ratios (SMR) and logistic regression were used to assess the relationship between weight for-age at admission and risk-adjusted mortality. RESULTS: Out of 12,458 admissions, mean weight-for-age was 1.04 SD below the UK reference population mean (p < 0.0001). Based on 942 deaths, risk-adjusted mortality was lowest in those with mild-to-moderately raised weight-for-age (SDS 0.5-2.5) and highest in children with extreme under- or overweight (SDS < -3.5 and SDS > +3.5). Logistic regression indicated that age, gender, ethnicity and weight-for-age are independent risk factors for mortality. South Asian and 'other' ethnicities had significantly increased risk of death compared to children of white and black ethnic origin. CONCLUSION: The PIC population mean weight-for-age is significantly lower than the UK reference mean. The extremes of weight-for-age are over-represented, especially underweight. Weight-for-age at admission is an independent risk factor for mortality. A U-shaped association between weight and risk-adjusted mortality exists, with the lowest risk of death in children who are mild-to-moderately overweight. Future studies should determine the impact of malnutrition on risk-adjusted mortality and investigate the aetiology of risk disparities with ethnicity. PMID- 25034476 TI - Optic nerve sheath diameter on computed tomography is correlated with simultaneously measured intracranial pressure in patients with severe traumatic brain injury. AB - PURPOSE: Assess the relationship between optic nerve sheath diameter (ONSD) measured on bedside portable computed tomography (CT) scans and simultaneously measured intracranial pressure (ICP) in patients with severe traumatic brain injury. METHODS: Retrospective cohort study of 57 patients admitted between 2009 and 2013. Linear and logistic regression were used to model the correlation and discrimination between ONSD and ICP or intracranial hypertension, respectively. RESULTS: The cohort had a mean age of 40 years (SD 16) and a median admission Glasgow coma score of 7 (IQR 4-10). The between-rater agreement by intraclass coefficient was 0.89 (95 % CI 0.83-0.93, P < 0.001). The mean ONSD was 6.7 mm (SD 0.75) and the mean ICP during CT was 21.3 mmHg (SD 8.4). Using linear regression, there was a strong correlation between ICP and ONSD (r = 0.74, P < 0.001). ONSD had an area under the curve to discriminate elevated ICP (>=20 mmHg vs. <20 mmHg) of 0.83 (95 % CI 0.73-0.94). Using a cutoff of 6.0 mm, ONSD had a sensitivity of 97 %, specificity of 42 %, positive predictive value of 67 %, and a negative predictive value of 92 %. Comparing linear regression models, ONSD was a much stronger predictor of ICP (R(2) of 0.56) compared to other CT features (R(2) of 0.21). CONCLUSIONS: Simultaneous measurement of ONSD on CT and ICP were strongly correlated and ONSD was discriminative for intracranial hypertension. ONSD was much more predictive of ICP than other CT features. There was excellent agreement between raters in measuring ONSD. PMID- 25034477 TI - Extubation to facilitate mother-baby bonding in refractory acute respiratory distress syndrome. PMID- 25034478 TI - Controversies in colorectal cancer screening. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide and a good candidate for screening programmes. However, there is controversy concerning which of the available screening tests should be used. SUMMARY: There is general agreement that screening for CRC in the asymptomatic population should begin at the age of 50. Several different screening methods are available which can be separated into those that mainly detect cancers: faecal occult blood tests [guaiac (FOBT) and immunochemical (FIT)], genetic stool tests, blood tests and the M2-pyruvate kinase (M2-PK) test. Methods that detect cancers and polyps are colonoscopy, sigmoidoscopy, CT-colonography (CT-C) and colon capsule endoscopy. The only tests for which a reduction in CRC mortality compared to no screening have been proven in randomized trials are FOBT and sigmoidoscopy. Several trials suggest that FIT are superior to FOBT in terms of detection rates of cancers and advanced adenomas and possibly compliance. There is indirect evidence suggesting efficacy of colonoscopy as a screening test. The role of CT-C is controversial. There is data suggesting a good sensitivity for neoplasia >9 mm with a lower sensitivity for smaller neoplasia. However, radiation exposure is considered a major limitation in some countries. Unresolved questions include the lesion cut off for referral to colonoscopy and work-up of extracolonic findings. For other methods, like genetic stool testing using newer markers, blood tests, capsule endoscopy and M2-PK, there is currently insufficient data on screening of the asymptomatic population. Key Messages: Colorectal screening is recommended and should be performed in the form of an organized programme. If detection of early stage cancers is the aim of a screening programme, FIT seem to be superior to FOBT. If detection and removal of adenomas is the aim of a screening programme, endoscopic methods seem to be good alternatives. Sigmoidoscopy is easier to perform but will likely only have an effect on distal cancers. Colonoscopy is more invasive but enables inspection of the whole colon. The role of CT-C, capsule endoscopy, genetic stool tests, blood tests and M2-PK is currently unknown. PMID- 25034480 TI - Molecular virology of hepatitis B virus and targets for antiviral intervention. AB - The members of the viral family Hepadnaviridae comprise one of the smallest enveloped DNA viruses and cause acute and chronic infections in mammals and birds, leading to large virus and antigen loads in the blood. They have a restricted host range and depend on differentiated hepatocytes for replication. Hepatitis B virus (HBV) is the prototype of the Hepadnaviridae. HBV can persist in infected hepatocytes and has evolved elaborate strategies to evade the immune system. HBV replicates like HIV (family of Retroviridae) via reverse transcription. Drugs licensed for inhibition of HIV reverse transcriptase lower the viral load of chronic HBV patients, but they do not cure the infection. HBV genomes are archived in the nucleus of hepatocytes as episomal DNA before reverse transcription. In contrast, the RNA genome of HIV first needs reverse transcription before proviral integration within the host genome. Wild-type HBV remains relatively stable in chronic HBV patients during the immunotolerant state, but is able to evolve mutants rapidly upon selective pressure due to therapy or immune reactions. Current therapies for chronic hepatitis B are far from optimal. To extend therapeutic options, further studies on HBV and its interaction with the host are urgently needed. PMID- 25034481 TI - Genotypes and genetic variability of hepatitis B virus. AB - Sequence heterogeneity is a feature of hepatitis B virus (HBV), the prototype member of the family Hepadnaviridae. Based on an intergroup divergence of greater than 7.5% across the complete genome, HBV has been classified phylogenetically into 9 genotypes, A-I, with a putative 10th genotype 'J', isolated from a single individual. With between approximately 4 and 8% intergroup nucleotide divergence across the complete genome and good bootstrap support, genotypes A-D, F, H, and I are classified further into subgenotypes. There is a broad and highly statistically significant correlation between serological subtypes and genotypes, and in some cases, serological subtypes can be used to differentiate subgenotypes. The genotypes, and certain subgenotypes, have distinct geographical distributions and are important in both the clinical manifestation of infection and response to antiviral therapy. HBV genotypes/subgenotypes and genetic variability of HBV are useful in epidemiological and transmission studies, tracing human migrations, and in predicting the risk for the development of severe liver disease and response to antiviral therapy. Moreover, knowledge of the genotype/subgenotype is important in implementing preventative strategies. Thus, it is crucial that new strains are correctly assigned to their respective genotype/subgenotype and consistent, unambiguous, and generally accepted nomenclature is utilized. PMID- 25034482 TI - Inhibitors of hepatitis B virus attachment and entry. AB - Inhibition of virus entry has become a major concept in the development of new antiviral drugs. Entry inhibitors can either neutralize activities of viral surface proteins or target essential host factors such as (co)receptors. Due to its distinct tissue tropism and the highly specific viral and cellular factors involved in its entry, hepatitis B virus (HBV) is an ideal candidate for entry inhibition. Hepatitis B immunoglobulins neutralize infection by binding to the S domain of HBV surface proteins and are used to prevent reinfection of the graft after liver transplantation. Novel S or preS-specific monoclonal antibodies are currently in development. The identification of sodium-taurocholate cotransporting polypeptide (NTCP) as a bona fide receptor has revealed a suitable target for HBV entry inhibition. NTCP receptor function is blocked by a variety of different agents including Myrcludex B, a synthetic N-acylated preS1-derived lipopeptide that inhibits HBV entry in vitro and in vivo with high efficacy. Current antiviral treatment for chronic HBV-infected patients focuses on the inhibition of the viral polymerase via nucleos(t)ide analogues (NA). Entry inhibitors in combination with NAs could block reinfection and shield naive hepatocytes that emerge from natural liver turnover, opening up new therapeutic options. PMID- 25034483 TI - Host factor-targeted hepatitis B virus therapies. AB - In this review we will focus on host factors known to impact hepatitis B virus (HBV) replication as current or potential targets for therapeutic intervention. Some immunotherapeutic strategies will be discussed because they have the potential to activate interferon-mediated clearance of HBV, but attention will also be paid to host machinery and proteins that silence covalently closed circular DNA, destabilize viral RNA, or disrupt entry and trafficking of HBV virions. Many of these are in the early stages of development, but may represent novel avenues to reduce HBV burden when combined with nucleos(t)ide analogues. PMID- 25034484 TI - Interferon therapy of chronic hepatitis B. AB - Chronic hepatitis B (CHB) results from the inability of the host's immune system to control viral replication. Interferon-alpha (IFN-alpha) therapy can convert CHB into inactive hepatitis B virus (HBV) infection in 20-30% of the treated patients. In spite of the low response rate, IFN-alpha therapy has the advantage of having a limited duration and being effective even after therapy, as demonstrated by a much higher incidence of HBsAg clearance in responders to IFN alpha than in naturally occurring inactive HBsAg carriers. IFN-alpha has multiple antiviral, antiproliferative, and immunomodulatory activities and targets: cellular genes (IFN-stimulated genes) activating different pathways of antiviral defense in infected and noninfected cells, HBV replication blocking the RNA containing core particle formation and accelerating their decay, degrading pregenomic RNA, and modulating the nuclear viral minichromosome (covalently closed circular DNA) activity by targeting its epigenetic regulation and both innate and adaptive immune response. The interference of viral heterogeneity and genetic polymorphisms of the host on IFN-alpha susceptibility is under investigation. Only a better understanding of the complex interplay between the different activities of IFN-alpha would warrant the amelioration of current therapeutic strategies and the design of new therapeutic approaches. The study of on-treatment dynamics of HBV infection by means of combined quantitative monitoring of serum HBV DNA and HBsAg warrant tailoring treatment at the single patient level and can help to make treatment more cost-effective by using the different combinations of currently available antivirals, including IFN, more appropriately. Integrated molecular and clinical knowledge in a systems medicine fashion is mandatory to further improve antiviral therapy in CHB. PMID- 25034485 TI - Antiviral therapy of chronic hepatitis B. AB - Since the licensing of lamivudine in 1999, the treatment of chronic hepatitis B has been revolutionized by the introduction of oral nucleoside and nucleotide analogues (NAs), which act as inhibitors of the HBV polymerase. The effectiveness of the first of these substances was limited by incomplete response and resistance development in many patients, but today, highly potent substances are available that make a reliable and durable suppression of HBV replication, a reduction of necroinflammatory activity in the liver, and even a reversion of liver fibrosis achievable for almost all patients. Beyond that, NA treatment can prevent the development of hepatocellular carcinoma in many patients. HBeAg seroconversion appears in approximately 50% of all HBeAg-positive patients during NA treatment. However, the ideal treatment endpoint, the serologic loss of HBsAg, remains a rare event almost exclusively achievable for HBeAg-positive patients. After cessation of the treatment, HBV replication tends to relapse in most patients, which is why the duration of NA treatment is indefinite. Future treatment strategies should aim at tailoring individual NA treatment regimens to increase HBs loss rates and optimize treatment duration. PMID- 25034486 TI - Therapy of acute and fulminant hepatitis B. AB - Although new hepatitis B virus (HBV) infections are decreasing due to improving vaccination coverage, patients without vaccination coverage can still suffer from manifestation of acute hepatitis B with jaundice and (although rarely) liver failure. No treatment is indicated for mild acute hepatitis B; however, antiviral therapy should be initiated for patients showing signs of significant liver impairment as exemplified by deterioration of prothrombin time to an equivalent of 1.5 or 50% of the 'Quick test'. For fulminant hepatitis, there is no complete agreement on whether antiviral treatment would alter the course, but it should still be started, as it would reduce the risk of reinfection in case there is a need for liver transplantation. Patients in danger of progression towards acute liver failure should be referred to transplant centers as early as possible. PMID- 25034487 TI - Therapy of occult hepatitis B virus infection and prevention of reactivation. AB - Occult hepatitis B virus infection (OBI) is highly prevalent worldwide. In some cases, it is a consequence of infection with variant viruses mutated in the S gene and producing a surface antigen not recognized by diagnostic kits. In most cases, OBI is due to a strong inhibition of hepatitis B virus (HBV) activities exerted by host defense mechanisms. OBI may reactivate in patients undergoing immunosuppressive therapy and/or chemotherapy with the possibility of a consequent development of acute hepatitis that may lead to hepatic failure. Hematological malignancies and therapeutic schedules including rituximab are the conditions most frequently associated with OBI reactivation. However, this event may occur in a large number of additional clinical and therapeutic settings. Identification of patients prone to undergo reactivation is of great importance for promptly starting a proper antiviral therapy that may stop the HBV reactivation and prevent its clinical sequelae. PMID- 25034488 TI - Prevention of hepatitis B virus reinfection in liver transplant recipients. AB - Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates such as entecavir or tenofovir could suppress hepatitis B virus (HBV) replication, improve liver function, delay or obviate the need for liver transplantation in some patients, and reduce the risk of HBV recurrence. The combination of long-term antiviral and low-dose hepatitis B immune globulin (HBIG) can effectively prevent HBV recurrence in more than 90% of transplant recipients. Some form of HBV prophylaxis needs be continued indefinitely after transplantation. However, in patients with a low risk of HBV recurrence (i.e. HBV DNA levels undetectable before transplantation), it is possible to discontinue HBIG and maintain long-term antiviral therapy. A more cautious approach to prophylaxis regimen is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e. HIV or HDV coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those with a risk of noncompliance to antiviral therapy. PMID- 25034489 TI - Reduction of infectivity in chronic hepatitis B virus carriers among healthcare providers and pregnant women by antiviral therapy. AB - The main purpose of therapy for infectious diseases is restoration or protection of the patient's health, but suppression or elimination of infectious agents is also important. In two well-defined situations, reduction of potential infectivity may be the main reason for therapy in hepatitis B virus (HBV) carriers who do not suffer from significant disease: (1) healthcare providers who perform exposure-prone procedures to prevent transmission of HBV to individuals, and (2) pregnant women in the third trimester to prevent transmission to the fetus. This article describes the necessity to recognize highly viremic HBV infected individuals in these situations, the methods to estimate the risk of transmission, and the therapeutic possibilities to prevent transmission. With today's methods of monitoring HBV DNA, it is possible to reliably estimate the risk of transmission. The drugs entecavir or tenofovir are able to suppress infectivity of HBV carriers to levels acceptable for healthcare providers performing exposure-prone procedures. According to the CDC, 'chronic HBV infection in itself should not preclude the practice or study of medicine, surgery, dentistry, or allied health professions.' Treatment of pregnant women with very high levels of HBV DNA prevents the transmission to the fetus and further if the newborn receives immediate active/passive immunization against HBV. PMID- 25034490 TI - Effect of antiretroviral HIV therapy on hepatitis B virus replication and pathogenicity. AB - Coinfections with hepatitis B virus (HBV) and HIV are very frequent. Although HBV is a DNA virus, it replicates via reverse transcription like HIV. Structural similarities between the enzymatic pocket of the HBV DNA polymerase and HIV-1 reverse transcriptase are the basis that certain drugs inhibit both enzymes and thus the replication of both viruses. HBV components increase the pathogenic action of HIV and vice versa directly by certain proteins like HBsAg in the case of HBV and HIV-encoded Tat and Vpr and by disturbing the cytokine balance in affected cells. Antiretroviral therapy is highly beneficial for HIV/HBV coinfected patients, but carries the risk of drug-induced resistance development and hepatotoxicity. Even with restoration of the immune capacity, signs of hepatic inflammation may develop even after 10 years of treatment. PMID- 25034491 TI - Mechanisms of hepatitis B virus resistance development. AB - Hepatitis B virus (HBV) resistance to nucleos(t)ide analogue (NA) therapy is essentially structure specific, with each NA falling within three main structural groups. Resistance to each of these is characterized by specific mutations in the reverse transcriptase domains of the HBV polymerase, and may be associated with compensatory mutations which can increase replication. HBV polymerase is considered to have a traditional 'right-handed' structural conformation, and each of the resistance mutations is predicted to cause a specific structural change of the polymerase, thereby preventing incorporation of NA into replicating DNA. The selection of resistance occurs at different rates for each NA, and is affected by the high mutational rate of HBV and the ability of the drug to suppress viral replication. Some mutations or combinations of mutations may be associated with multidrug resistance, limiting treatment options. In contrast to most other viruses, resistance in HBV is confounded by the overlapping surface gene, the major NA-resistant mutations also altering the surface proteins in most cases, potentially altering virus secretion and neutralization, which may pose a public health threat in the future. PMID- 25034492 TI - Selected phenotypic assays used to evaluate antiviral resistance and viral fitness of hepatitis B virus and its variants. AB - Currently available antiviral therapies specifically target viral replication by blocking reverse transcription with orally given nucleos(t)ide analogues and are able to specifically suppress viral replication. The unique replication strategy of hepatitis B virus (HBV), however, allows long-term persistence of the viral genome within infected hepatocytes in spite of successful therapy. Thus, antiviral therapy needs to be continued for years. Therapy can result either in the emergence and selection of antiviral-resistant variants or the relapse of viral replication after the termination of antiviral therapy. Resistance is a major problem for 4 of the 5 approved HBV nucleos(t)ide analogues, but it is not the only reason for therapy failure. An accurate phenotypic in vitro assay for resistance allows the identification of a viral variant selected in vivo during antiviral therapy and helps to find therapeutic alternatives. Furthermore, these assays can be used to measure viral fitness and pathogenicity in vitro. With the help of these assays, the prediction of emerging viral variants with drug resistance or increased pathogenic potential can be realized. Phenotypic resistance tests for HBV are not trivial because the virus cannot be readily grown in cell culture. This review focuses on currently available phenotypic assays to evaluate antiviral resistance of HBV and fitness of viral variants in general. PMID- 25034493 TI - Hepatitis B virus drug resistance tools: one sequence, two predictions. AB - Drug resistance testing, genotype analysis, and the determination of immune and vaccine escape variants support personalized antiviral treatment for hepatitis B patients. As phenotypic drug resistance testing for hepatitis B virus (HBV) is especially labor-intensive, due to the lack of simple cell culture systems, genotypic methods play a very pronounced role. The genetic structure of HBV allows the simultaneous analysis of two different genes by examination of a single region in the genome of HBV. Nevertheless, the overlapping open reading frames of the hepatitis B surface antigen (HBsAg) and the reverse transcriptase (RT) have to be interpreted separately. In diagnostic procedures, standard Sanger type sequencing (mostly performed as a dye-dideoxynucleotide terminator system) is still the most commonly used method. This allows using established techniques for interpreting those types of genetic information. Besides reviewing the foundation of drug resistance interpretation for HBV, different interpretation systems, either commercially available (TRUGENE, Abbott, ViroScore) or free to use (geno2pheno[HBV], HIV-GRADE HBV tool), are compared in this article. PMID- 25034495 TI - Marked serum procalcitonin level in response to isolated anaphylactic shock. AB - The objective of this study was to present a case report that highlights the limitation of serum procalcitonin levels greater than 10 ng/mL as being almost exclusively secondary to septic shock. Data source was a medical intensive care unit patient at the University of Louisville. Anaphylactic shock may cause elevations of serum procalcitonin to levels greater than 10 ng/mL. PMID- 25034496 TI - Could the survival and outcome benefit of adrenaline also be dependent upon the presence of gasping upon arrival of emergency rescuers? AB - A recent systematic review and meta-analysis of randomized controlled trials of adrenaline use during resuscitation of out-of-hospital cardiac arrest found no benefit of adrenaline in survival to discharge or neurological outcomes. It did, however, find an advantage of standard dose adrenaline (SDA) over placebo and high dose adrenaline over SDA in overall survival to admission and return of spontaneous circulation (ROSC), which was also consistent with previous reviews. As a result, the question that remains is "Why is there no difference in the rate of survival to discharge when there are increased rates of ROSC and survival to admission in patients who receive adrenaline?" It was suggested that the lack of efficacy and effectiveness of adrenaline may be confounded by the quality of cardiopulmonary resuscitation (CPR) during cardiac arrest, which has been demonstrated in animal models. CPR quality was not measured or reported in the included randomized controlled trials. However, the survival and outcome benefit of adrenaline may also depend upon the presence of witnessed gasping and/or gasping upon arrival of emergency rescuers, which is a critical factor not accounted for in the analyses of the cited animal studies that allowed gasping but showed the survival and neurological outcome benefits of adrenaline use. Moreover, without the aid of gasping, very few rescuers can provide high-quality CPR. Also, age and the absence of gasping observed by bystanders and/or upon arrival of emergency- rescuers may be important factors in the determination of whether vasopressin instead of adrenaline should be used first. PMID- 25034494 TI - The pgip family in soybean and three other legume species: evidence for a birth and-death model of evolution. AB - BACKGROUND: Polygalacturonase-inhibiting proteins (PGIPs) are leucine-rich repeat (LRR) plant cell wall glycoproteins involved in plant immunity. They are typically encoded by gene families with a small number of gene copies whose evolutionary origin has been poorly investigated. Here we report the complete characterization of the full complement of the pgip family in soybean (Glycine max [L.] Merr.) and the characterization of the genomic region surrounding the pgip family in four legume species. RESULTS: BAC clone and genome sequence analyses showed that the soybean genome contains two pgip loci. Each locus is composed of three clustered genes that are induced following infection with the fungal pathogen Sclerotinia sclerotiorum (Lib.) de Bary, and remnant sequences of pgip genes. The analyzed homeologous soybean genomic regions (about 126 Kb) that include the pgip loci are strongly conserved and this conservation extends also to the genomes of the legume species Phaseolus vulgaris L., Medicago truncatula Gaertn. and Cicer arietinum L., each containing a single pgip locus. Maximum likelihood-based gene trees suggest that the genes within the pgip clusters have independently undergone tandem duplication in each species. CONCLUSIONS: The paleopolyploid soybean genome contains two pgip loci comprised in large and highly conserved duplicated regions, which are also conserved in bean, M. truncatula and C. arietinum. The genomic features of these legume pgip families suggest that the forces driving the evolution of pgip genes follow the birth-and death model, similar to that proposed for the evolution of resistance (R) genes of NBS-LRR-type. PMID- 25034497 TI - The spontaneous pneumopyopericardium simultaneously masquerading as acute myocardial infarction and surgical abdomen: a case report. AB - Pneumopyopericardium is a rare disease, presenting clinically as a spectrum of acute myocardial infarction or severe surgical abdomen, which includes various symptoms and changes in cardiac enzymes and electrocardiogram. Here, we report a case of pneumopyopericardium in a 61-year-old male farmer in China. An early diagnosis of pneumopyopericardium was difficult due to his acute myocardial infarction- and severe surgical abdomen-like symptoms and signs. The electrocardiogram, esophagogram, and chest computed tomographic scan commonly revealed pericardial fluid and air and excluded a gastrointestinal perforation in late stage of severe inflammation. Despite therapy with antibiotics and pericardial open surgical drainage, his severe inflammation was not well controlled, partly due to the pericardial cavity drainage obstruction induced by pericardial adhesion. The present case indicated the importance of early diagnosis and treatment of pneumopyopericardium. PMID- 25034498 TI - Increased risk of idiopathic nephrotic syndrome in children with atopic dermatitis. AB - BACKGROUND: Clinical and immunological studies have consistently shown a relationship between atopic diathesis and idiopathic nephrotic syndrome (INS). However, no large population cohort study has yet to demonstrate the nature of the relationship between these disorders. METHODS: Claims data from a random selection of children representing half of the insured population in Taiwan were examined. During the period from 1998 to 2007, we identified 192,295 children aged <18 years with newly diagnosed atopic dermatitis (AD) and 769,169 frequency matched controls. Incidence of INS and hazard ratios (HRs) were calculated. RESULTS: The AD cohort had a 2-fold higher overall incidence of INS than the non AD cohort [7.20 vs. 3.60 per 100,000 person-years, respectively; 95 % confidence interval (CI) 1.50-2.66]. The HR for INS increased with age and was higher among females. The HR for INS was also higher in AD children with more medical visits per year, ranging from 0.94 for those having <=3 visits to 38.6 for those having >6 visits (trend test P < 0.0001). In particular, the risk of INS clearly increased during the initial 5 years after AD onset. CONCLUSIONS: Children with AD have a greater incidence and risk of developing INS and this risk increases with AD severity. PMID- 25034499 TI - Serum suPAR levels help differentiate steroid resistance from steroid-sensitive nephrotic syndrome in children. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) has been regarded as a permeability factor in proteinuria, though its role in primary nephrotic syndrome remains to be elucidated further. METHODS: Plasma samples and clinical information from 176 children with primary nephrotic syndrome were collected and concentrations of suPAR were measured. We evaluated the correlation between suPAR concentrations and clinical features, and the value of the plasma suPAR level in predicting steroid-resistant nephrotic syndrome (SRNS). RESULTS: There is a significant difference in plasma suPAR concentration between SRNS and steroid-sensitive nephrotic syndrome (SSNS) groups (3,744.1 +/- 2,226.0 vs. 2,153.5 +/- 1,167.0, p < 0.05). The area under the curve (AUC) was 0.80, with p < 0.001 for the receiver operating characteristic (ROC) curve analysis using suPAR to predict SRNS. The suspicious range for predicting SRNS was estimated to be 1,907.0 pg/ml to 3,043.5 pg/ml (chi(2) = 14.775, p = 0.001). CONCLUSIONS: From ROC curve analysis, we demonstrated the significance of the suPAR level in predicting SRNS with a high specificity but low sensitivity. However, the clinical value of suPAR to predict steroid resistance and guide therapy remains to be investigated further. PMID- 25034500 TI - Fungal beta-trefoil trypsin inhibitors cnispin and cospin demonstrate the plasticity of the beta-trefoil fold. AB - The recently identified fungal protease inhibitors cnispin, from Clitocybe nebularis, and cospin, from Coprinopsis cinerea, are both beta-trefoil proteins highly specific for trypsin. The reactive site residue of cospin, Arg27, is located on the beta2-beta3 loop. We show here, that the reactive site residue in cnispin is Lys127, located on the beta11-beta12 loop. Cnispin is a substrate-like inhibitor and the beta11-beta12 loop is yet another beta-trefoil fold loop recruited for serine protease inhibition. By site-directed mutagenesis of the P1 residues in the beta2-beta3 and beta11-beta12 loops in cospin and cnispin, protease inhibitors with different specificities for trypsin and chymotrypsin inhibition have been engineered. Double headed inhibitors of trypsin or trypsin and chymotrypsin were prepared by introducing a second specific site residue into the beta2-beta3 loop in cnispin and into the beta11-beta12 loop in cospin. These results show that beta-trefoil protease inhibitors from mushrooms exhibit broad plasticity of loop utilization in protease inhibition. PMID- 25034501 TI - The utility of the combination of the corrosion cast method and post mortem MSCT scans. AB - A careful post-mortem investigation is needed to determine the cause of death of patients bearing coronary stents and to describe complications of stent implantation. The main purpose of this study was to combine post mortem methods of CT angiography and corrosion cast preparation for the visualization of coronary stenoses, coronary stents, instent restenosis, and stent occlusion. Injection-corrosion method was combined with post-mortem MSCT angiography to characterize the pathomorphological changes after stent implantation in 6 male cadaver hearts. Multi-slice computed tomography was employed to visualize the coronary artery system. For image post processing, multiplanar reconstructions, maximal intensity projections and three dimensional reconstructions were used. This study was assessing the feasibility of post mortem MSCT for intracoronary stent evaluation. We described a method for characterization of the coronary side branch stenosis caused by stent implantation. Post mortem CT imaging proved to be a feasible and highly reproducible technique for the characterization of pathological changes in the coronary system. PMID- 25034502 TI - Polyphenol-rich blackcurrant extract prevents inflammation in diet-induced obese mice. AB - Obesity is closely associated with chronic, low-grade inflammation. We investigated if polyphenol-rich blackcurrant extract (BCE) can prevent inflammation in vivo. Male C57BL/6J mice were fed a modified AIN-93M control diet containing high fat/high cholesterol (16% fat, 0.25% cholesterol by weight) or the control diet supplemented with 0.1% BCE (wt/wt) for 12 weeks. In BCE-fed mice, the percentage of body weight and adipocyte size of the epididymal fat were significantly lower than those of control mice. There were fewer crown-like structures (CLS) with concomitant decreases in F4/80, cluster of differentiation 68 and inhibitor of nuclear factor kappaB kinase epsilon (IKKepsilon) mRNA in the epididymal adipose of BCE-fed mice. F4/80 and IKKepsilon mRNA levels were positively correlated with CLS number. In the skeletal muscle of mice fed with BCE, mRNA expression of genes involved in energy expenditure and mitochondrial biogenesis, including PPARalpha, PPARdelta, UCP-2, UCP-3 and mitochondrial transcription factor A, were significantly increased. When splenocytes from BCE fed mice were stimulated by lipopolysaccharides, tumor necrosis factor alpha and interleukin-1beta mRNA were significantly lower than control splenocytes. Together, the results suggest that BCE supplementation decreases obesity-induced inflammation in adipose tissue and splenocytes, at least in part, by modulating energy metabolism in skeletal muscle. PMID- 25034503 TI - Allyl isothiocyanate ameliorates insulin resistance through the regulation of mitochondrial function. AB - Mitochondrial dysfunction is associated with the pathophysiology of insulin resistance. Allylisothiocyanate (AITC) is found in many cruciferous vegetables and has been reported to possess anticancer activity. However, the effect of AITC on insulin resistance and mitochondrial function has not yet been investigated. Here, we show that AITC increased glucose uptake in insulin-resistant C2C12 myotubes and augmented glucose transporter 4 (GLUT4) translocation in L6-GLUT4myc cells. AITC recovered the impaired insulin signaling evoked by free fatty acid exposure and increased mitochondrial membrane potential and mitochondrial DNA content. AITC also elevated the rate of oxygen consumption in C2C12 cells. Furthermore, mice that were fed a high-fat diet with AITC for 10 weeks had reduced diet-induced obesity and hepatic steatosis. AITC also inhibited the hyperglycemia and hyperinsulinemia induced by the consumption of a high-fat diet. Glucose and insulin tolerance tests indicated that AITC improved both glucose tolerance and insulin sensitivity. In addition, AITC inhibited hepatic gluconeogenesis and ameliorated high fat diet-induced mitochondrial dysfunction. Collectively, these data suggest that the protective effect of AITC on insulin resistance is partly mediated through the modulation of mitochondrial dysfunction. PMID- 25034504 TI - The role of glottal surface adhesion on vocal folds biomechanics. AB - The airway surface liquid (ASL) is a very thin mucus layer and covers the vocal fold (VF) surface. Adhesion mediated by the ASL occurs during phonation as the VFs separate after collision. Such adhesion is hypothesized to determine voice quality and health. However, biomechanical insights into the adhesive processes during VF oscillation are lacking. Here, a computational study is reported on self-sustained VF vibration involving contact and adhesion. The VF structural model and the glottal airflow are considered fully three-dimensional. The mechanical behavior of the ASL is described through a constitutive traction separation law where mucosal cohesive strength, cohesive energy, and rupture length enter. Cohesive energy values considered are bound below by the cohesive energy of water at standard temperature and pressure. Cohesive strength values considered are bound above by prior reported data on the adhesive strength of mucosal surface of rat small intestine. This model introduces a mechanical length scale into the analysis. The sensitivity of various aspects of VF dynamics such as flow-declination rate, VF separation under adhesive condition, and formation of multiple local fluid bridges is determined in relation to specific ASL adhesive properties. It is found that for the ASL considered here, the characteristics of the VF separation process are of debond type. Instabilities lead to the breakup of the bond area into several smaller bond patches. Such finding is consistent with in vivo observations. PMID- 25034505 TI - Direct growth of patterned graphene on SiO2 substrates without the use of catalysts or lithography. AB - We demonstrate a one-step fabrication of patterned graphene on SiO2 substrates through a process free from catalysts, transfer, and lithography. By simply placing a shadow mask during the plasma enhanced chemical vapor deposition (PECVD) of graphene, an arbitrary shape of graphene can be obtained on SiO2 substrate. The formation of graphene underneath the shadow mask was effectively prevented by the low-temperature, catalyst-free process. Growth conditions were optimized to form polycrystalline graphene on SiO2 substrates and the crystalline structure was characterized by Raman spectroscopy and transmission electron microscopy (TEM). Patterned graphene on SiO2 functions as a field-effect device by itself. Our method is compatible with present device processing techniques, and should be highly desirable for the proliferation of graphene applications. PMID- 25034506 TI - Transdural indocyanine green video-angiography of vascular malformations. AB - BACKGROUND: The role of indocyanine green video-angiography (ICG-VA) in the surgical resection of vascular malformations has been largely described; conversely, the utility of ICG-VA before dural opening (transdural ICG-VA) in this situation remains unclear. The aim of this study is to present the application of transdural ICG-VA in a consecutive series of patients in order to explore the potential provided by a transdural visualisation of vascular malformations. METHOD: We retrospectively analysed the application of intra operative ICG-VA before dural opening in 15 consecutive patients who underwent surgical resection of vascular malformations. The cases included 12 cerebral arterio-venous malformations (AVMs), 2 cerebral dural arterio-venous fistulas (dAVFs) and 1 spinal arterio-venous fistula (AVF). RESULTS: ICG-VA before dural opening allowed the visualisation of the site and extension of the malformation in 13 out of 15 cases, whilst arterial feeders and venous drainages were identified in 9 out of 15 cases. In two patients with dAVF, the point of fistula could be transdurally identified through ICG-VA. In 14% of cases, the size of bone flap designed on neuronavigation data was then modified according to transdural ICG-VA findings. CONCLUSIONS: Transdural ICG-VA proved an efficient tool that allows optimising the exposure of the malformation, performing a safe dural opening and identifying dural vascular connections of the lesion. PMID- 25034507 TI - Aneurysms of the anterior and posterior cerebral circulation: comparison of the morphometric features. AB - BACKGROUND: Intracranial aneurysms (IAs) located in the posterior circulation are considered to have higher annual bleed rates than those in the anterior circulation. The aim of the study was to compare the morphometric factors differentiating between IAs located in the anterior and posterior cerebral circulation. METHODS: A total number of 254 IAs diagnosed between 2009 and 2012 were retrospectively analyzed. All patients qualified for diagnostic, three dimensional rotational angiography. IAs were assigned to either the anterior or posterior cerebral circulation subsets for the analysis. Means were compared with a t-test. The univariate and stepwise logistic regression analyses were used to determine the predictors of morphometric differences between the groups. For the defined predictors, ROC (receiver-operating characteristic) curves and interactive dot diagrams were calculated with the cutoff values of the morphometric factors. RESULTS: The number of anterior cerebral circulation IAs was 179 (70.5 %); 141 (55.5 %) aneurysms were ruptured. Significant differences between anterior and posterior circulation IAs were found for: the parent artery size (5.08 +/- 1.8 mm vs. 3.95 +/- 1.5 mm; p < 0.05), size ratio (2.22 +/- 0.9 vs. 3.19 +/- 1.8; p < 0.045) and aspect ratio (AR) (1.91 +/- 0.8 vs. 2.75 +/- 1.8; p = 0.02). Predicting factors differentiating anterior and posterior circulation IAs were: the AR (OR = 2.20; 95 % CI 1.80-270; Is 270 correct or should it be 2.70 and parent artery size (OR = 0.44; 95 % CI 0.38-0.54). The cutoff point in the ROC curve was 2.185 for the AR and 4.89 mm for parent artery size. CONCLUSIONS: Aspect ratio and parent artery size were found to be predictive morphometric factors in differentiating between anterior and posterior cerebral IAs. PMID- 25034508 TI - Endovascular armamentarium for wide-necked intracranial aneurysms: comparison of modern embolization techniques. PMID- 25034509 TI - Vaginal misoprostol versus a rectal nonsteroidal anti-inflammatory drug to reduce pain during Pipelle endometrial biopsies: a prospective, randomized, placebo controlled trial. AB - BACKGROUND: To evaluate and compare the efficacy of vaginal misoprostol and a rectal nonsteroidal anti-inflammatory drug (NSAID) on pain relief during Pipelle endometrial biopsies in a placebo-controlled randomized study. METHODS: One hundred and fifty-one women who had an indication for a Pipelle endometrial biopsy were randomized into three groups as follows: group 1, vaginal misoprostol; group 2, rectal NSAID, and group 3, control. After the procedure, the women were asked to record their pain severity on a visual analog scale. The secondary outcome of the study was patient acceptability, and vasovagal symptoms and analgesic requirements after the procedure were also recorded. RESULTS: There were no statistically significant differences in the demographic characteristics of the patients. The primary study outcome was the comparison of the median visual analog scale pain scores of groups 1 and 2 versus group 3 (controls); no statistically significant differences were found (p = 0.502). In addition, the patient acceptability (Likert scale), vasovagal symptoms and analgesic requirements after the procedure were similar among the groups (p = 0.204, 1 and 0.546, respectively). CONCLUSION: Our study did not demonstrate a reduction in pain relief during Pipelle endometrial biopsies for patients receiving vaginal misoprostol or a rectal NSAID when compared to patients receiving placebo treatment. PMID- 25034510 TI - 'It's those first few weeks': Women's views about breastfeeding support in an Australian outer metropolitan region. AB - OBJECTIVE: To examine factors that influence the establishment and continuation of breastfeeding among women living in a southern region of Victoria. METHOD: Sequential mixed methods design including paper-based survey and focus group enquiry. FINDING: Women who had breastfed their infants (n=170) reported reliance on midwives, lactation consultants and maternal and child health nurses for breastfeeding advice and support in the immediate and medium postnatal periods. Women who chose a private hospital appeared to receive less immediate postnatal support than those in a public hospital. Access to individual guidance from midwives and MCH nurses was regarded as critical to overcoming breastfeeding difficulties, in the face of the alternative suggested by people to 'give up'. They described themes of: 'Women's experience of nurses/midwives', 'Expectations versus reality', 'Not giving up despite difficulties', and 'Breastfeeding support'. Sources of lay support were not universal. CONCLUSION: The duration of breastfeeding might be extended by early problem resolution. To enhance breastfeeding participation, further examination of the extent and timeliness of service provision by health service providers is necessary. PMID- 25034511 TI - Doublecortin is a highly valuable endogenous marker of adult neurogenesis in canaries. Commentary on Vellema M et al. (2014): Evaluating the predictive value of doublecortin as a marker for adult neurogenesis in canaries (Serinus canaria) . J Comparative Neurol 522:1299-1315. PMID- 25034512 TI - Estradiol treatment decreases cell proliferation in the neurogenic zones of adult female zebrafish (Danio rerio) brain. AB - While estrogens are known to play a crucial role in the neurogenesis of the mammalian and avian brain, their role in teleost adult proliferation pattern is not yet fully understood. The present study aimed to determine the estrogen effects in adult brain proliferation zones, using zebrafish, as a model organism. Indeed, teleost fish brain provides a unique adult neurogenesis model, based on its extensive proliferation, contrasting the restricted adult telencephalic neurogenesis observed in birds and mammals. To determine the effect of estrogens, 17-beta estradiol was administrated for 7 days in adult female zebrafish, followed by bromodeoxyuridine (BrdU)-immunohistochemistry and double immunofluorescence. Stereological analyses of the BrdU-positive cells within the neurogenic zones, showed region-specific decreases of actively proliferating cells in the estrogen-treated animals, compared to matched controls. Interestingly, the most prominent estradiol effects were found in the number of cycling cells of the ventral nucleus of ventral telencephalic area (Vv) and cerebellar areas. Significant decreases were also determined in the dorso-lateral telencephalic, preoptic and dorsal hypothalamic areas. In contrast, medial dorsal telencephalic, caudal (Hc) and ventral (Hv) hypothalamic areas were unaffected by estrogen treatment. The majority of the BrdU-labeled cells were found to co express PCNA proliferating marker in Hc, Hv and Vv. Additionally, a population of proliferating cells co-expressed the early neuronal marker TOAD in all areas studied. These results provide significant evidence on the 17-beta estradiol impact on adult neurogenesis, down-regulating the fast-cycling and post-mitotic cells within the female zebrafish brain neurogenetic zones. PMID- 25034513 TI - Sex differences in behavior and pro-inflammatory cytokine mRNA expression following stressor exposure and re-exposure. AB - Stressful events promote a wide range of neurotransmitter and neuroendocrine changes, which likely serve in an adaptive capacity. However, with repeated stressor exposure, behavioral disturbances, such as anxiety and depression, may develop. Moreover, re-exposure to a stressor for some time following an initial aversive experience may instigate especially pronounced neurochemical variations that favor the emergence of depression and anxiety. These outcomes may stem from any number of neurobiological changes, but increasing attention has focused on the potential contribution of inflammatory factors, such as cytokines. Given the distinct differences in stressor responsiveness that have been reported between males and females, alongside a much higher rate of mood disorders in females, we sought to examine whether repeated exposure to stressors would differentially influence elevated plus-maze behavior in male and female CD-1 mice, and whether such changes would be paralleled by variations of pro-inflammatory mRNA cytokine expression within the prefrontal cortex (PFC) and the hippocampus. In males, the sensitization of interleukin (IL)-1beta was evident in both brain regions in those mice that had initially been stressed and then 6 weeks later re-exposed to a stressor exhibiting higher IL-1beta expression than did mice stressed on only a single occasion. Females demonstrated higher baseline expression of cytokine expression within the hippocampus, but neither a single exposure nor re-exposure stressor treatment produced significant cytokine elevations. In the PFC an acute stressor treatment increased IL-1R expression, but otherwise had little effect. In a plus-maze test, stressed male mice displayed markedly reduced latencies to the open arms that was evident in a test 6 weeks later irrespective of whether mice were re-exposed to a stressor, whereas in females this outcome was less evident. These studies are consistent with the perspective that female mice are relatively resilient toward stressor-induced cytokine elevations even though in humans females are generally more prone to developing mood disturbances. PMID- 25034514 TI - Preclinical pathways to treatment in infants with positional cranial deformity. AB - Positional plagiocephaly in infants is frequent. As well as positioning, physiotherapy, and osteopathy, helmet therapy is an effective treatment option. The outcome also depends on the timely initiation of treatment. We investigated the preclinical pathways to treatment. Parents of 218 affected children were interviewed. Data were collected regarding detection and the treatments used prior to the first craniofacial consultation at the study clinic in Germany. Descriptive and statistical analyses were performed. For 78.4% of the children, the cranial deformities were first detected at <=4 months of age. One hundred and twenty-two children received helmet therapy. Parents consulted the paediatrician with a mean latency of 0.4 months; 3.3 months passed until the first craniofacial consultation. Approximately 90% were treated with repositioning and 75.2% received additional physiotherapy or osteopathy prior to presentation. Children treated with physiotherapy/osteopathy presented significantly later (P=0.023). The time lapse to craniofacial consultation was not significantly different between children with and without later helmet therapy. We identified a relevant delay between the detection of positional cranial deformity and consultation with a craniofacial specialist. For affected children, this may potentially compromise the outcome of helmet therapy. Early referral to a specialist and if necessary the simultaneous application of different treatments should be preferred. PMID- 25034515 TI - Effect of interval from induction of puberty to initiation of a timed AI protocol on pregnancy rate in Nellore heifers. AB - Prepubertal Bos indicus heifers (n = 774) were submitted to an E2/P4-based timed artificial insemination (TAI) protocol at three different intervals after induction of their pubertal ovulation by insertion of an intravaginal progesterone (P4) device for 12 days. Heifers were randomly assigned to start the TAI protocol at 10 (group 10; n = 253), 12 (group 12; n = 265), or 14 (group 14; n = 256) days after the P4 device was removed. The TAI protocol consisted of the following: insertion of intravaginal device containing P4 (Controlled internal drug release [CIDR]; previously used twice for 9 days each) + estradiol benzoate (2 mg) on Day 0, CIDR withdrawal + estradiol cypionate (0.5 mg) and PGF2alpha (12.5 mg) on Day 9, and TAI on Day 11. A subgroup of heifers (n = 472) was evaluated by ultrasound on Days 9 and 11 to evaluate the ovaries and to determine P4 concentrations on Day 9. On Day 9, more (P < 0.05) CLs were present, and follicular diameter was smaller (P < 0.05) for group 10 than for groups 12 and 14 (38.4%, 29.3%, and 23.3% with CL and 9.4 +/- 0.1, 9.9 +/- 0.1, and 9.8 +/- 0.1 mm diameter, respectively), but P4 concentrations did not differ (P > 0.1) between treatments (2.4 +/- 0.06 ng/mL). Follicular diameter at TAI (11.08 +/- 0.09 mm) and ovulation rate (88.4%) did not differ between treatments (P > 0.1). However, conception and pregnancy rates for all heifers were greater (P < 0.05) in group 12 (50.4% and 45.5%, respectively) than in group 10 (38.2% and 33.7%, respectively), with group 14 intermediate to other treatments (45.6% and 40.6%, respectively). The final pregnancy rate did not differ between treatments (80.9%). In conclusion, a 12-day interval from the end of the puberty induction protocol to the start of the TAI protocol resulted in greater conception and pregnancy rates in prepubertal Nellore heifers. PMID- 25034516 TI - Seminal plasma proteins of adult boars and correlations with sperm parameters. AB - The present study was conducted to identify the major seminal plasma protein profile of boars and its associations with semen criteria. Semen samples were collected from 12 adult boars and subjected to evaluation of sperm parameters (motility, morphology, vitality, and percent of cells with intact acrosome). Seminal plasma was obtained by centrifugation, analyzed by two-dimensional SDS PAGE, and proteins identified by mass spectrometry (electrospray ionization quadrupole time-of-flight). We tested regression models using spot intensities related to the same proteins as independent variables and semen parameters as dependent variables (P <= 0.05). One hundred twelve spots were identified in the boar seminal plasma gels, equivalent to 39 different proteins. Spermadhesin porcine seminal protein (PSP)-I and PSP-II, as well as spermadhesins AQN-1, AQN-3 and AWN-1 represented 45.2 +/- 8% of the total intensity of all spots. Other proteins expressed in the boar seminal plasma included albumin, complement proteins (complement factor H precursor, complement C3 precursor and adipsin/complement factor D), immunoglobulins (IgG heavy chain precursor, IgG delta heavy chain membrane bound form, IgG gamma-chain, Ig lambda chain V-C region PLC3, and CH4 and secreted domains of swine IgM), IgG-binding proteins, epididymal-specific lipocalin 5, epididymal secretory protein E1 precursor, epididymal secretory glutathione peroxidase precursor, transferrin, lactotransferrin and fibronectin type 1 (FN1). On the basis of the regression analysis, the percentage of sperm with midpiece defects was related to the amount of CH4 and secreted domains of swine IgM and FN1 (r2 = 0.58, P = 0.006), IgG binding protein (r2 = 0.41, P = 0.024), complement factor H precursor (r2 = 0.61, P = 0.014) and lactadherin (r2 = 0.45, P = 0.033). The percentage of sperm with tail defects was also related to CH4 and secreted domains of swine IgM and FN1 (r2 = 0.40, P = 0.034), IgG-binding protein (r2 = 0.35, P = 0.043) and lactadherin (r2 = 0.74, P = 0.001). Sperm motility, in turn, had association with the intensities of spots identified as lactadherin (r2 = 0.48, P = 0.027). In conclusion, we presently describe the major proteome of boar seminal plasma and significant associations between specific seminal plasma proteins and semen parameters. Such relationships will serve as the basis for determination of molecular markers of sperm function in the swine species. PMID- 25034517 TI - Wheelchair interventions, services and provision for disabled children: a mixed method systematic review and conceptual framework. AB - BACKGROUND: Wheelchairs for disabled children (<= 18 years) can provide health, developmental and social benefits. World Health Organisation and United Kingdom Government reports demonstrate the need for improved access to wheelchairs both locally and internationally. The use of health economics within this field is lacking. Provision of wheelchairs based on cost-effectiveness evidence is not currently possible. We conducted the first systematic review in this field to incorporate evidence of effectiveness, service user perspectives, policy intentions and cost-effectiveness in order to develop a conceptual framework to inform future research and service development. METHODS: We used an adapted EPPI Centre mixed-method systematic review design with narrative summary, thematic and narrative synthesis. 11 databases were searched. Studies were appraised for quality using one of seven appropriate tools. A conceptual framework was developed from synthesised evidence. RESULTS: 22 studies and 14 policies/guidelines were included. Powered wheelchairs appear to offer benefits in reduced need for caregiver assistance; improved communicative, personal-social and cognitive development; and improved mobility function and independent movement. From 14 months of age children can learn some degree of powered wheelchair driving competence. However, effectiveness evidence was limited and low quality. Children and parents placed emphasis on improving social skill and independence. Participation in wider society and development of meaningful relationships were key desired outcomes. Policy intentions and aspirations are in line with the perspectives of children and parents, although translation of policy recommendations into practice is lacking. CONCLUSIONS: There is a distinct lack of high quality effectiveness and economic evidence in this field. Social and health needs should be seen as equally important when assessing the mobility needs of disabled children. Disabled children and parents placed highest priority on independence and psychosocial outcomes of wheelchair interventions. Translation of policy and guidelines into practice is lacking and more effective implementation strategies are required to improve services and outcomes. Future research should focus on outcome measure development, developing economic evaluation tools and incorporating these into high quality studies to address known research gaps. The novel conceptual framework maps current gaps in evidence and outlines areas for development. PMID- 25034518 TI - Evolution of increased phenotypic diversity enhances population performance by reducing sexual harassment in damselflies. AB - The effect of evolutionary changes in traits and phenotypic/genetic diversity on ecological dynamics has received much theoretical attention; however, the mechanisms and ecological consequences are usually unknown. Female-limited colour polymorphism in damselflies is a counter-adaptation to male mating harassment, and thus, is expected to alter population dynamics through relaxing sexual conflict. Here we show the side effect of the evolution of female morph diversity on population performance (for example, population productivity and sustainability) in damselflies. Our theoretical model incorporating key features of the sexual interaction predicts that the evolution of increased phenotypic diversity will reduce overall fitness costs to females from sexual conflict, which in turn will increase productivity, density and stability of a population. Field data and mesocosm experiments support these model predictions. Our study suggests that increased phenotypic diversity can enhance population performance that can potentially reduce extinction rates and thereby influence macroevolutionary processes. PMID- 25034519 TI - Impacts of different types of insoles on postural stability in older adults. AB - The objective of this study was to examine the effects of different types of insoles on postural stability in older adults. Four types of commercially available insoles were selected including the cupped insoles, textured insoles, rigid insoles, and soft insoles. The experiment included a static stance session and a walking session. In the static stance session, the participants stood upright on a force platform as still as possible, with feet together, arms by the side and looking straight ahead. The mean velocity of center-of-pressure time series obtained from the force platform was used to assess static postural stability. In the walking session, the participants walked on a treadmill at their self-selected comfortable speed for 4.5 min in each insole condition. Dynamic postural stability was assessed using the margin of stability. It was found that static postural stability was not affected by insoles, but cupped insoles improved dynamic postural stability, and rigid insole was associated with better dynamic postural stability compared to soft insoles. These findings can aid in better understanding the insole design features associated with improved postural stability in older adults. PMID- 25034521 TI - Medical error and systems of signaling: conceptual and linguistic definition. AB - In recent years the issue of patient safety has been the subject of detailed investigations, particularly as a result of the increasing attention from the patients and the public on the problem of medical error. The purpose of this work is firstly to define the classification of medical errors, which are distinguished between two perspectives: those that are personal, and those that are caused by the system. Furthermore we will briefly review some of the main methods used by healthcare organizations to identify and analyze errors. During this discussion it has been determined that, in order to constitute a practical, coordinated and shared action to counteract the error, it is necessary to promote an analysis that considers all elements (human, technological and organizational) that contribute to the occurrence of a critical event. Therefore, it is essential to create a culture of constructive confrontation that encourages an open and non punitive debate about the causes that led to error. In conclusion we have thus underlined that in health it is essential to affirm a system discussion that considers the error as a learning source, and as a result of the interaction between the individual and the organization. In this way, one should encourage a non-guilt bearing discussion on evident errors and on those which are not immediately identifiable, in order to create the conditions that recognize and corrects the error even before it produces negative consequences. PMID- 25034520 TI - Hypoadiponectinemia, cardiometabolic comorbidities and left ventricular hypertrophy. AB - This study was designed to evaluate the prevalence of cardiometabolic comorbidities and the changes in left ventricular geometry and function in 135 subjects subgrouped according to low or normal total adiponectin plasma (ADPN) levels. Left ventricular (LV) internal diameter/height, total LV mass (LVM) and LVM index (LVMI), relative wall thickness (RWT), LV ejection fraction by echocardiography and diastolic parameters by pulsed-wave Doppler were calculated. Body mass index (BMI) (p < 0.0001), waist-to-hip ratio (p < 0.03), triglycerides (p < 0,001), prevalence of obesity (p < 0.005), visceral obesity (p < 0.003), left ventricular hypertrophy (LVH) (p < 0.001), metabolic syndrome (p < 0.0003) and coronary artery disease (CAD) (p < 0.003) were significantly increased and high-density lipoprotein-cholesterol (p < 0.001) was significantly reduced in hypo-ADPN than normal-ADPN subjects. LVM, LVMI, interventricular septum thickness and RWT were significantly (p < 0.0001) higher and left ventricular ejection fraction was significantly (p < 0.0002) lower in hypo-ADPN than normal-ADPN patients. LVMI correlated directly with BMI (p < 0.001), mean blood pressure (p < 0.001), metabolic syndrome (MetS) (p < 0.001) and inversely with ADPN (p < 0.0001). The prevalence of LVH (p < 0.001) and CAD (p < 0.01) was higher in subjects with normal-ADPN and MetS, while the presence of MetS did not change this finding in hypo ADPN group. Both models of regression analysis indicated that ADPN and BMI resulted independently associated with LVMI. In conclusion, our data seem to indicate that hypoadiponectinemia might be associated with an increased prevalence both of clinical comorbidities and increased LVMI. In this subset of subjects, ADPN and BMI, more than MetS, are able to explain cardiac damage. Accordingly, ADPN might become a new target in the management of cardiometabolic risk. PMID- 25034522 TI - Bayesian approach to guide termination of retrospective retesting after detection of a systematic quality control failure. AB - BACKGROUND: When a systematic error is detected in the analytical process, ideally, one seeks to retest only patient samples between the onset of the error and the time the error was detected. In practice, the onset of error is often unknown, and patient samples are retrospectively retested back to the last acceptable QC sample. This can be wasteful of reagents and operator time. METHODS: An alternative approach that is based on the expected number of spurious results is described to determine when retrospective retesting should terminate. Assuming each patient sample was independently measured by an analytical process with an underlying Gaussian distribution, a Bayesian model that takes into account the difference between the original and retest result of each patient sample was developed. RESULTS: We are able to significantly reduce the number of samples retested, while ensuring that the average number of spurious results observed under the proposed retesting procedure was similar to or only marginally higher than the baseline number of spurious results when the assay was in control. CONCLUSION: Patient samples measured after the systematic error have high probabilities of being retested under the proposed retesting procedure. PMID- 25034523 TI - Barrett's oesophagus patients with low-grade dysplasia can be accurately risk stratified after histological review by an expert pathology panel. AB - OBJECTIVE: Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett's Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD. DESIGN: We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC. RESULTS: 293 LGD patients (76% men; mean 63 years+/-11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16-72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively. CONCLUSIONS: Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification. PMID- 25034524 TI - Oncogenicity of LHX4 in colorectal cancer through Wnt/beta-catenin/TCF4 cascade. AB - The LHX genes play an important role in a number of developmental processes. Potential roles of LHXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the function role of LHXs in the human colorectal cancer (CRC). The gene expression changes of LHXs in CRC tissues compared with noncancerous colorectal tissues was detected using real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. And we identified the gene LHX4 that were significantly upregulated in CRC by QRT-PCR analysis and immunohistochemistry. Furthermore, we discovered that LHX4 promoted cancer cell proliferation in vitro, and LHX4 expression correlated with elevated beta-catenin levels in CRC and beta-catenin function was required for LHX4's oncogenic effects. Mechanistically, LHX4 facilitate TCF4 to bind to beta-catenin and form a stable LHX4/TCF4/beta-catenin complex and transactive its downstream target gene. LHX4 mutations that disrupt the LHX4-beta-catenin interaction partially prevent its function in tumor cells. All in all, LHX4 is a commonly activated tumor promoter that activate Wnt/beta catenin signaling in cancer cells of CRC. PMID- 25034525 TI - Prognostic significance of cyclooxygenase-2 protein in pancreatic cancer: a meta analysis. AB - We conducted a meta-analysis of relevant cohort studies to investigate the relationships between cyclooxygenase-2 (COX-2) protein and the prognosis of pancreatic cancer. The following electronic databases were searched without language restrictions: MEDLINE (1966~2013), the Library Database (Issue 12, 2013), EMBASE (1980~2013), CINAHL (1982~2013), Web of Science (1945~2013), and the Chinese Biomedical Database (CBM) (1982~2013). Meta-analysis was performed using the STATA statistical software. Six cohort studies with a total of 712 pancreatic cancer patients were involved in this meta-analysis. Our findings showed that COX-2-positive patients were significantly associated with a shorter overall survival (OS) than COX-2-negative patients (hazard ratio (HR) = 1.48, 95 % confidence interval (95%CI) = 1.12~1.85, P < 0.001). A subgroup analysis by ethnicity also revealed that pancreatic cancer patients with an abnormal COX-2 expression exhibited a worse OS than COX-2-negative patients among both Asians and Caucasians (Asians: HR = 1.40, 95%CI = -0.09~2.89, P = 0.066; Caucasians: HR = 1.49, 95%CI = 1.11~1.87, P < 0.001, respectively). Our findings provide empirical evidence that abnormal COX-2 expression may be strongly correlated with poor prognosis for patients with pancreatic cancer. Thus, COX-2 protein may be a useful biomarker for pancreatic cancer. PMID- 25034526 TI - Lung cancer risk in relation to TP53 codon 47 and codon 72 polymorphism in Bangladeshi population. AB - The objective of this study was to determine whether p53 codon 47 and codon 72 polymorphisms are associated with increased risk of lung cancer in Bangladeshi population. We carried out a case-control study and examined the genotype distribution Pro47Ser and Arg72Pro single-nucleotide polymorphisms along with tobacco smoking in the predisposition of lung cancer by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The study included 106 lung cancer patients and 116 control subjects from Bangladesh. Lung cancer risk was estimated as odds ratio (OR) and 95 % confidence interval (CI) using conditional logistic regression models adjusting for age, sex, and smoking. No significant association was found between Pro47Ser SNP and lung cancer. The frequencies of p53 codon 72 polymorphisms (Arg/Arg, Arg/Pro, and Pro/Pro) in lung cancer were 25.5, 37.7, and 36.8 %, respectively; frequencies in the controls were 53.4, 30.2, and 16.4 %, respectively (p < 0.01). The Arg/Pro and Pro/Pro genotype were significantly associated with increased risk of lung cancer (OR = 2.51, 95 % CI = 1.38-4.82 and OR = 4.62, 95 % CI = 2.31-9.52, respectively) compared with the Arg/Arg genotype. The combined frequency of Arg/pro and Pro/Pro genotype was also found to be associated with elevated risk of lung cancer (OR = 3.36, 95 % CI = 1.90-5.94, p < 0.01). However, no significant relationship was found between age, sex, and histological subtypes of lung cancer with p53 codon 72 genotype distributions. When classified by smoking status, the effects of Arg72Pro polymorphism on lung cancer risk was only found to be significant (chi (2) = 33.94, p = 0.00000004) in case of heavy smokers (40 packs per year or more). We conclude that not Pro47Ser SNP but Arg72Pro SNP is involved in susceptibility to developing lung cancer, at least in Bangladeshi population. PMID- 25034527 TI - Interaction of PTPRO and TLR4 signaling in hepatocellular carcinoma. AB - Protein tyrosine phosphatase receptor type O (PTPRO) has been identified as a tumor suppressor in a number of cancers including hepatocellular carcinoma (HCC). Toll-like receptor 4 (TLR4) plays diverse roles in HCC tumorigenesis and progression. The association between PTPRO and TLR4 signaling in HCC remains largely unknown. We aimed to clarify the interaction between PTPRO and TLR4 in HCC. Surprisingly, we found reduced and positive-related expression of TLR4 and PTPRO in 84 human HCC specimens. Increased TLR4 expression and activity was found in PTPRO-overexpressed HCC cells stimulated with lipopolysaccharide (LPS). The feedback regulation of PTPRO and TLR4 was dependent on nuclear factor-kappaB (NF kappaB) activation, as suggested by NF-kappaB inhibition and luciferase reporter assay. Our study suggests that the effect of PTPRO on TLR4 signaling is dependent on NF-kappaB pathway, suggesting an interesting PTPRO/TLR4/NF-kappaB signaling feedback loop in HCC carcinogenesis and progression. PMID- 25034528 TI - Upregulation of SYF2 in esophageal squamous cell carcinoma promotes tumor cell proliferation and predicts poor prognosis. AB - SYF2, also known as CCNDBP1-interactor or p29, is reported in pre-mRNA splicing and cell cycle progression. However, the role of SYF2 in esophageal squamous cell carcinoma (ESCC) development remains elusive. In the present study, Western blot and immunohistochemistry assays demonstrated that SYF2 was overexpressed in ESCC tumor tissues and cell lines. In addition, immunohistochemistry analysis revealed that SYF2 expression was positively correlated with tumor grade and predicted poor prognosis of ESCC. In vitro studies using serum starvation-refeeding experiment and SYF2-siRNA transfection assay demonstrated that SYF2 expression promoted proliferation of ESCC cells, while SYF2 knockdown led to decreased cell growth rate and colony formation resulted from growth arrest of cell cycle at G0/G1 phase. Furthermore, our results indicated that SYF2 can down-regulate the sensitivity of ESCC cells for cisplatin. Our findings for the first time supported that SYF2 might play an important role in the regulation of ESCC proliferation and would provide a novel therapeutic strategy against human ESCC. PMID- 25034529 TI - MicroRNA-142-3p, a novel target of tumor suppressor menin, inhibits osteosarcoma cell proliferation by down-regulation of FASN. AB - Menin, encoded by MEN1 gene, has been viewed as a tumor suppressor in several types of tumors, such as insulinoma, parathyroid tumor, and adrenocortical and lung carcinoma. However, its expression and molecular regulation mechanism in osteosarcoma has not been elucidated. Here, our results show menin expression is significantly down-regulated in osteosarcoma tissues, compared with adjacent normal tissues. Besides, we report that MicroRNA-142-3p as a novel target of menin. Up-regulation of MicroRNA-142-3p by menin overexpression inhibits cell proliferation in U2OS and MG63 cells. At the molecular level, MicroRNA-142-3p inhibits the protein expression of FASN through binding to its 3'-untranslated region. Therefore, we elucidate a novel regulation pathway in osteosarcoma cells and suggest a potential therapeutic approach for the tumor therapy. PMID- 25034530 TI - X protein mutations in hepatitis B virus DNA predict postoperative survival in hepatocellular carcinoma. AB - Hepatitis B virus (HBV) DNA is prone to mutations because of the proofreading deficiencies of HBV polymerase. The postoperative prognostic value of HBV mutations in HBV X protein (HBx) gene was assessed in HBV associated hepatocellular carcinoma (HCC) patients. The HBx gene was amplified and sequenced, the HBV mutations was identified according to NCBI database ( http://www.ncbi.nlm.nih.gov/genome/5536 ). The relationship between the HBV mutations and HCC survival was compared. Survival curves were generated using the Kaplan-Meier method, and comparisons between the curves were made using the log rank test. Multivariate survival analysis was performed using a Cox proportional hazards model. After adjusting for clinical characteristics, the following eight mutational sites were identified as statistically significant independent predictors of HCC survival: 1383, 1461, 1485, 1544, 1613, 1653, 1719, and 1753. In addition, the following four mutational sites were identified for their association with survival at a border-line significance level: 1527, 1637, 1674, and 1762/1764. A total of 12 mutations in HBx gene region were identified as independent predictors of postoperative survival in HCC patients. The analysis of HBV DNA mutations may help identify patient subgroups with poor prognosis and may help refine therapeutic decisions regarding HCC patients. PMID- 25034531 TI - Expression and clinical significance of CRABP1 and CRABP2 in non-small cell lung cancer. AB - The impairment of retinoic acid (RA)-dependent signaling is a frequent event during carcinogenesis. Cellular retinoic acid-binding proteins (CRABP1 and CRABP2) are important modulators of RA activity. Up to date, the role of these proteins in cancer progression remains poorly investigated. Here, we studied for the first time the simultaneous messenger RNA (mRNA) and protein expression of CRABPs in non-small cell lung cancer (NSCLC) samples. CRABP1 and CRABP2 mRNA levels were elevated in 42 and 56 % of NSCLC samples, respectively. Decrease of CRABP2 mRNA expression was significantly associated with the presence of lymph node metastases. Protein expression of CRABP1 and CRABP2 was detected in 50 and 56 % of tumor samples, respectively. We also found a positive correlation between CRABP1 and CRABP2 expression. Taken together, we demonstrated significant changes in CRABP expression in NSCLC samples. Importantly, the presented data provide the first evidence of potential involvement of CRABP2 in lung cancer metastasis. PMID- 25034532 TI - Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells. AB - Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. PMID- 25034533 TI - Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs. AB - As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-beta-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs=1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species. PMID- 25034534 TI - Tools to support evidence-informed public health decision making. AB - BACKGROUND: Public health professionals are increasingly expected to engage in evidence-informed decision making to inform practice and policy decisions. Evidence-informed decision making involves the use of research evidence along with expertise, existing public health resources, knowledge about community health issues, the local context and community, and the political climate. The National Collaborating Centre for Methods and Tools has identified a seven step process for evidence-informed decision making. Tools have been developed to support public health professionals as they work through each of these steps. This paper provides an overview of tools used in three Canadian public health departments involved in a study to develop capacity for evidence-informed decision making. METHODS: As part of a knowledge translation and exchange intervention, a Knowledge Broker worked with public health professionals to identify and apply tools for use with each of the steps of evidence-informed decision making. The Knowledge Broker maintained a reflective journal and interviews were conducted with a purposive sample of decision makers and public health professionals. This paper presents qualitative analysis of the perceived usefulness and usability of the tools. RESULTS: Tools were used in the health departments to assist in: question identification and clarification; searching for the best available research evidence; assessing the research evidence for quality through critical appraisal; deciphering the 'actionable message(s)' from the research evidence; tailoring messages to the local context to ensure their relevance and suitability; deciding whether and planning how to implement research evidence in the local context; and evaluating the effectiveness of implementation efforts. Decision makers provided descriptions of how the tools were used within the health departments and made suggestions for improvement. Overall, the tools were perceived as valuable for advancing and sustaining evidence-informed decision making. CONCLUSION: Tools are available to support the process of evidence-informed decision making among public health professionals. The usability and usefulness of these tools for advancing and sustaining evidence informed decision making are discussed, including recommendations for the tools' application in other public health settings beyond this study. Knowledge and awareness of these tools may assist other health professionals in their efforts to implement evidence-informed practice. PMID- 25034535 TI - Localisation of the Notch family in the human endometrium of fertile and infertile women. AB - To investigate the spatial and temporal immunolocalisation and staining intensity of the Notch signalling family in endometrium of fertile and infertile women, endometrial biopsies were collected by curettage from 25 fertile women across the menstrual cycle and 10 infertile women in the mid secretory phase of menstrual cycle. Immunohisotchemistry was completed for NOTCH1, -2, -3, -4, cleaved Notch, DLL1, -3, -4, JAGGED1, -2, HES and NUMB and immunostaining intensity measured in both the endometrial glandular and luminal epithelium. NOTCH1 and the ligands DLL1 and JAGGED1 were key proteins displaying increased staining intensity during the receptive phase of the menstrual cycle and dysregulated in infertile endometrium. Conversely, NUMB a negative regulator of Notch signalling was decreased in the mid secretory phase of the menstrual cycle in fertile women and increased with infertility. PMID- 25034536 TI - A neural microcircuit for cognitive conflict detection and signaling. AB - During human response conflict - competition between multiple conflicting actions when a mistake could be made - a specific pattern of brain electrical activity occurs over the medial frontal cortex (MFC), characterized by modulations of ongoing theta-band (~6Hz) oscillations and synchronization with task-relevant brain regions. Despite the replicable and robust findings linking MFC theta to conflict processing, the significance of MFC theta for how neural microcircuits actually detect conflict and broadcast that signal is unknown. A neural MFC microcircuit model is proposed for processing conflict and generating theta oscillations. The model makes several novel predictions for the causes and consequences of MFC theta and conflict processing, and may be relevant for understanding the neural implementations of related cognitive processes. PMID- 25034537 TI - Contraception counselling of female soldiers in primary healthcare facilities. AB - BACKGROUND: Effectiveness of barrier and oral contraceptive pills is dependent on daily adherence and consistency that cannot always be guaranteed by military lifestyle. Long-acting reversible contraceptive (LARC) methods could provide a good alternative to guarantee effective contraception in unpredictable scenarios, and recent studies have suggested they could provide wider non-contraceptive benefits. LARC has been proven to be more cost effective than the combined oral contraceptive pill. The National Institute of Health and Care Excellence (NICE) has released guidelines on contraception provision to ensure all women receive the contraception method that is most appropriate to the individual. METHOD: A retrospective audit of 105 sets of primary healthcare notes of serving female soldiers was assessed to establish contraceptive choices and whether appropriate information had been provided within the last year of their last consultation. RESULTS: 100% had seen a healthcare provider capable of providing contraceptive advice in the last year. 69% documented as using some form of non-surgical contraception versus 58% quoted as national usage. 21% were using some form of LARC versus 8% national usage. 66% of eligible women had not had LARC discussed with them, and of these 50% did not have any contraceptive usage documented. Among other consultations, 41% had had a medical within the year period, of which over half had no documented contraceptive status. CONCLUSIONS: As military healthcare providers, we have more exposure to our patients than NHS equivalents and this small study suggests there is an increased demand for contraception. Contraceptive choice counselling should be a mandatory part of routine initial medicals. If the situation demands a medical for any other reason, a documented contraception status should form an important part of the risk assessment process. PMID- 25034538 TI - Chirality-switchable circularly polarized luminescence in solution based on the solvent-dependent helix inversion of poly(quinoxaline-2,3-diyl)s. AB - Poly(quinoxaline-2,3-diyl)s containing (S)-2-methylbutoxy side chains were found to exhibit blue circularly polarized luminescence (CPL). The handedness of the CPL could be switched by a solvent-dependent helix inversion of the polymer backbone between chloroform (M-helical structure) and 1,1,1-trichloroethane (P helical structure). PMID- 25034539 TI - Moxifloxacin modulates inflammation during murine pneumonia. AB - BACKGROUND: Moxifloxacin is a synthetic antibacterial agent belonging to the fluoroquinolone family. The antimicrobial activity of quinolones against Gram positive and Gram-negative bacteria is based on their ability to inhibit topoisomerases. Quinolones are described to have immunomodulatory features in addition to their antimicrobial activities. It was the goal of this study to examine whether a short term treatment with moxifloxacin modulates the inflammation during a subsequently induced bacterial infection in an animal model. METHODS: Mice were treated with moxifloxacin or saline for two consecutive days and were subsequently intranasally infected with viable or heat-inactivated bacterial pathogens (Streptococcus pneumoniae, Pseudomonas aeruginosa) for 6 and 24 hours. Measurements of cytokines in the lungs and plasma were performed. Alveolar cells were determined in bronchoalveolar lavage fluits. RESULTS: The inflammation was increased after the inoculation of viable bacteria compared to inactivated bacteria. Numbers of total immune cells and neutrophils and concentrations of inflammatory mediators (e.g. KC, IL-1beta, IL-17A) were significantly reduced in lungs of moxifloxacin-treated mice infected with inactivated and viable bacterial pathogens as compared to infected control mice. Plasma concentrations of inflammatory mediators were significantly reduced in moxifloxacin-treated mice. Immunohistochemistry showed a stronger infiltrate of TNF-alpha-expressing cells into lungs of saline-treated mice infected with viable P. aeruginosa as compared to moxifloxacin-treated mice. CONCLUSIONS: These data show that in this pneumonia model moxifloxacin has anti-inflammatory properties beyond its antibacterial activity. PMID- 25034540 TI - "Knotless" laparoscopic extraperitoneal adenomectomy. AB - INTRODUCTION: Laparoscopic adenomectomy is a feasible and effective surgical procedure. We have progressively simplified the procedure using barbed sutures and a technique we call "knotless" laparoscopic adenomectomy. We present a prospective, multicenter, descriptive study that reflects the efficacy and safety of this technique in an actual, reproducible clinical practice situation. METHODS: A total of 26 patients with benign prostatic hyperplasia of considerable size (>80cc) underwent "knotless" laparoscopic adenomectomy. This is an extraperitoneal laparoscopic technique with 4 trocars based on the controlled and hemostatic enucleation of the adenoma using ultrasonic scalpels, precise urethral sectioning under direct vision assisted by a urethral plug, trigonization using barbed suture covering the posterior wall of the fascia, capsulorrhaphy with barbed suture and extraction of the morcellated adenoma through the umbilical incision. RESULTS: The median patient age was 69 (54-83)years, the mean prostate volume was 127 (89-245)cc, the mean operative time was 136 (90-315)min, the mean estimated bleeding volume was 200 (120-500)cc and the hospital stay was 3 (2 6)days. All patients experienced improved function in terms of uroflowmetry and International Prostate Symptom Score and quality of life questionnaires. There were complications in 6 patients, 5 of which were minor. CONCLUSIONS: "Knotless" laparoscopic adenomectomy is a procedure with low complexity that combines the advantages of open surgery (lasting functional results and complete extraction of the adenoma) with laparoscopic procedures (reduced bleeding and need for transfusions, shorter hospital stays and reduced morbidity and complications related to the abdominal wall). The use of ultrasonic scalpels and barbed sutures simplifies the procedure and enables a safe and hemostatic technique. PMID- 25034541 TI - Treatment-seeking for selected reproductive health problems: behaviours of unmarried female adolescents in two low-performing areas of Bangladesh. AB - PURPOSE: The reproductive health needs of unmarried adolescents in Bangladesh are largely unmet. This study aimed to explore treatment-seeking behaviour of unmarried female adolescents for selected reproductive health (RH) concerns in two low-performing areas of Bangladesh. METHODS: As part of a large community based-project, a cross-sectional survey was conducted from November 2006 to March 2007. From each of two select study areas, 800 unmarried female adolescents aged 12-19 years were selected for participation by simple random sampling through household listing and were recruited into the study. Trained interviewers administered a structured questionnaire to participating female adolescents. Descriptive and bivariate analytic methods were used compare RH conditions and healthcare seeking behaviour of adolescents across urban and rural settings. RESULTS: Approximately 50% of the sample reported experiencing menstrual problems in the last year. The predominant problems reported by participants included: lower abdominal pain, back pain, irregular menstruation, and excessive bleeding during menstruation. Irrespective of study area, only 40% of the female adolescents with menstrual problems sought treatment from qualified physicians. Otherwise, utilization of healthcare facilities and care providers for reported problems varied significantly by rural and urban areas. Higher proportions of adolescents in the urban setting (15%) also reported recent symptoms of sexually transmitted infections (STIs), compared to those in the rural setting (9%; p<0.001). Across sites, however, self-treatment was the most commonly reported method of care for those who experienced any symptoms of STI. CONCLUSIONS: In general, treatment-seeking behaviours by unmarried female adolescents was low for menstrual problems. A vast majority of unmarried female adolescents practiced self-care for symptoms of STIs while only small proportions sought treatment from qualified physicians. These findings emphasize the need for offering relevant information on RH issues and introducing confidential adolescent-friendly reproductive healthcare facilities to enable unmarried female adolescents access to RH services when necessary. PMID- 25034542 TI - Exercise and glucose control. AB - The prevalence of type 2 diabetes mellitus (T2DM) has increased dramatically in the United States over the past 20 years. The American Diabetes Association recommends regular exercise and maintenance of healthy body weight as important in prevention of T2DM, and exercise is also a cornerstone of treatment regimens for persons already diagnosed with T2DM. T2DM most commonly develops via progressive insulin resistance, a state that has been shown to be caused through several pathways, three of which are discussed in this review. First, the accumulation of lipid intermediates in skeletal muscle under conditions of sustained energy surplus can impair insulin signaling downstream of insulin binding to its receptor. Second, several inflammatory mediators have been shown to negatively affect insulin signaling and gene expression of glucose transporters. Third, oxidative stress induces insulin resistance by creating an environment that interferes with insulin signaling in several ways. Exercise can improve insulin sensitivity by opposing each of these three mechanisms of insulin resistance, as well as providing an avenue for muscle glucose uptake that bypasses insulin, and as such, has the capacity to serve as an important preventative measure. Furthermore, in persons with T2DM, the capacity of muscle contraction to stimulate glucose uptake in a manner that is independent of insulin establishes exercise as a powerful "medicine" in its treatment. Exercise, therefore, serves an important role in prevention and treatment of T2DM. PMID- 25034543 TI - Elite cross-country skiers do not reach their running VO2max during roller ski skating. AB - AIM: Cross-country skiers' VO2max is often measured during treadmill running. However, VO2max during treadmill skiing with the diagonal stride technique is higher, whereas it is lower during double poling, another classical style technique. How these values compare to VO2max during ski skating in elite cross country skiers is not known. Therefore, this study compared VO2max during treadmill uphill running and treadmill roller ski skating. METHODS: Twenty-two males (21+/-2 years, 182+/-6 cm, 77+/-7 kg, VO2max running; 72.4+/-4.4 mL.kg 1.min-1) elite cross-country skiers and biathlon athletes underwent testing in both running and roller ski skating before (May) and at the end (October) of the preseason training. RESULTS: From May to October VO2max increased during running (3.1+/-4.5%, P=0.003, Effect size; ES=0.44, small) but not during roller ski skating (1.8+/-5.6%, P=0.13, ES=0.24, small). In May the subjects' VO2max during running was 1.7+/-4.7% higher compared to during roller ski skating (P=0.08, ES=0.24, small) while in October this difference was 3.0+/-5.0 % (P<0.001, ES=0.49, small). CONCLUSION: Elite cross-country skiers do not elicit higher VO2max during roller ski skating than during running and this relationship does not change during the pre-season training period. PMID- 25034544 TI - Strength field tests performance are correlated with isokinetic strength of shoulder rotator muscles in female handball players. AB - BACKGROUND: The aim of this study was to analyze the relationship between the isokinetic shoulder strength of the athletes and their performance on strength field tests. Data on the balance and functional strength ratios of the internal and external rotator muscles of shoulders of handball players was also investigated. METHODS: Twenty-seven female athletes (23+/-3.4 years, 71+/-10.6 kg and 173.3+/-7.1 cm) underwent an isokinetic assessment of the strength of the shoulder rotator muscles. Athletes also performed the following strength field tests: bench press test, lying bench barbell row test, handgrip test, and medicine ball throwing. RESULTS: The bench press test results and the lying bench barbell row test results were significantly correlated with the concentric internal and external rotator peak torques at 1.05 rad.s-1 and 5.23 rad.s-1, with total work at 1.05 rad.s-1 and with average power at 5.23 rad.s-1 (r=0.51 to 0.81). CONCLUSION: We suggested the use of field test to infer about internal and external rotator muscular strength, but not to infer about isokinetic muscular strength ratios. These findings could be useful to coaches and trainers. PMID- 25034545 TI - Does the junior IAAF athletic world championship represent a springboard for the success in the throwing events? A retrospective study. AB - AIM: The aim of the present study was to analyze how many finalists of the IAAF World Junior Championships (WJC) in the throwing events were present in the senior IAAF ranking at the end of 2012. METHODS: The results of the 8 male and the 8 female finalists of all throwing events of the last 5 editions of the WJC from the 2002 edition were gathered. We analyzed how many athletes were missing from the IAAF ranking in 2012. For those athletes that did not drop out we monitored their progression in performance comparing their WJC and their 2012 performance. Moreover, we evaluated if the relative age effects (RAE) influenced drop out rate. RESULTS: Drop out rate was 58% in 2002, 59% in 2004, 39% in 2006, and 28% in 2008 and in 2010. The female javelin throwers showed the highest drop out rate (100%) in 2002, while the female hammer throwers showed the lowest drop out rate (0%) in 2008. Performance decreased for all male shot putters, discus and hammer throwers (P<0.001). For females and for male javelin throwers, performance increased (P<0.001). RAEs showed no significant influence on drop out rate CONCLUSION: Even if 8 of the finalists won a medal at the Olympic Games or at the World Championships, it is still not clear if participation at the WJC is a prerequisite to success at a senior level, given the elevated drop out rate observed in the present study. PMID- 25034546 TI - The relationship between an athlete's maximal aerobic speed determined in a laboratory and their final speed reached during a field test (UNCa Test). AB - AIM: The main purpose of this study was to apply a field test to predict the maximal aerobic speed (MAS) of an athlete using the same protocol done in a laboratory. METHODS: Fourteen male subjects volunteered to participate in this study and were evaluated on four separate occasions. First, an anthropometric evaluation was carried out. Secondly, an aerobic test was done on the treadmill with a gass analyzer to measure the maximum oxygen consumption (VO2max) and to calculate the MAS. Third, Unca test was evaluated again to confirm the reliability of the test. Finally, the participants were evaluated on field using the National University of Catamarca test (UNCa test). RESULTS: The MAS reached on a treadmill 15.6+/-1.0 km.h-1 was significantly higher than that found during the field test 13,6 +/- 1,1 km.h-1 (P=0.0001). However the relationship between the treadmill and the field test were highly correlated in all variables: speed: r=0.83, distance covered r= 0,81, test duration r=0.83. CONCLUSION: If MAS found on a treadmill is considered to be "the gold-standard" to validate MAS on field, it can be said that the UNCa test underestimates speed. PMID- 25034547 TI - Effects of a very short-term preseason training procedure on the fitness of soccer players. AB - AIM: The aim of the study was to examine the effect of a very short-term training program on the immediate and late changes in the fitness level of young soccer players during the pre-season period. METHODS: Twenty-four young (17-18 years) soccer players were randomly assigned to either an interval (9 to 5 X 1000 m) or continuous (9000 to 5000 m) training group, matched for total running distance. While the number of intervals or total distance was reduced every day, speed was increased in each session throughout the five days of both training programs. Each group performed 20 m shuttle run, 10 m sprint, 5 X 10 m run, 250 m run and vertical jump test, before (pre), immediately after (post) and 10 days after (late) completion of five successive training days during the preseason period for the upcoming soccer season. RESULTS: There was a significant increase in aerobic capacity both immediately post-training and in the late test, in both training groups. We found a significantly greater reduced performance in the 250 m run immediately following training in the interval compared to the continuous training group. In addition, there was a decrease in vertical jump that was significantly greater in the interval compared to the continuous training group, both immediately post-training and in the late test. CONCLUSION: Very short interval or continuous preseason training programs induce significant improvement in aerobic fitness but lead to stagnation or deterioration in anaerobic performance. Considering the opposing effects of both training modes (positive on the aerobic power but negative on the anaerobic performance), coaches should make their choices based on the relevant conditions at hand. PMID- 25034548 TI - Effects of a concurrent physical exercise program on aerobic power and body composition in adults. AB - AIM: This study aimed to observe the effects of a concurrent physical training program (CPTP) on aerobic power and body composition in adults. METHODS: The final sample was composed of 71 non-athletic men, randomized into 2 groups: experimental group (EG, N.=42, 45+/-8.46 years) and control group (CG, N.=29, 47+/-8.34 years). Body composition was assessed by Dual Energy X-ray Absorptiometry (DEXA) and aerobic power by maximal oxygen uptake (VO2max), obtained in the Cooper 12-minute run test. CPTP consisted of running training in the Fatmax intensity zone and strength training (squats and bench presses); three 40-minute sessions a week for 24 weeks. Descriptive and inferential analysis (intra-group: t-test and inter-group: 2x2 ANOVA and Sheffe post-hoc) was applied, and the Shapiro-Wilk test was used to test sample normality. The significance level was set at 5% for all tests. RESULTS: A significant alteration was found in intra-group comparison for the EG, with respect to fat percentage (D=-1.13 kg; P<0.001), lean mass (D=0.29 kg; P=0.030) and VO2max (D=1.18 mL/kg/min; P<0.001). CONCLUSION: It can be inferred that CPTP caused an increase in aerobic power, evidenced in VO2max and enhanced body composition, with an increase in LM and reduction in F%. PMID- 25034549 TI - Return to sport following amputation. AB - Amputation in athletes has a substantial impact on lifestyle and sporting activity, as well as self-perception and quality of life. The impact of limb loss on athletic ability will vary depending on the cause of amputation and the anatomical location of the amputation. The use of sporting activity for rehabilitation of amputees was first introduced in 1944 at Stoke Mandeville Hospital. The first international paralympic games were founded in 1960. Following these events the opportunity to participate in sport following limb loss has increased significantly. Sport participation has been aided by the development of sporting prostheses, however multiple factors will determine the exact prosthesis used. These include the nature of the sporting activity as well as the level of the amputation. The biomechanics involved in walking and running are altered following the loss of a limb or part thereof. This can cause subsequent degenerative changes within the remaining joints on the amputated limb as well as the contralateral limb. Factors affecting return to sporting activity are multivariate and inter-related, including patient factors, surgical factors, nature and level of the sporting activity and prosthetic factors. The authors review current literature, detail predictive factors of return to sport and the physical and psychosocial impact on patients following limb amputation. PMID- 25034550 TI - Groin pain and soccer players: male versus female occurrence. AB - AIM: Groin pain is common in soccer players. Comparison of results from different studies, especially between genders, is difficult as studies use different definitions and data collection procedures. Therefore we conducted a study of both male and female soccer players enabling direct gender comparison. METHODS: The study enrolled 479 male soccer players aged 25 years (17-43) (mean with range) and 144 female soccer players aged 23 years (16-47), who answered a mailed questionnaire that included specific questions on groin pain and sports history. Data are presented as proportions (%) or as mean with 95% confidence intervals (95% CI). RESULTS: Groin pain was experienced by 55% of male soccer players and 28% of female soccer players, resulting in an odds ratio (OR) of 2.9 (95% CI 1.9, 4.5). Groin pain occurred more often in the preseason, than during the rest of the season in both male and female players (both P<0.001). Playing position in the team or playing league did not seem to influence the risk of suffering groin pain. CONCLUSION: In soccer players, male gender and preseasonal training appear to be risk factors for developing groin pain. PMID- 25034551 TI - Risk and consequences of osteoarthritis after a professional football career: a systematic review of the recent literature. AB - BACKGROUND: The aim of the present study was to assess whether previous injury is a risk determinant for knee and ankle osteoarthritis (OA) in former professional football players and to explore OA-related activity and work limitations. METHODS: To retrieve the relevant recent literature, the Medline, Embase and Sportdiscus databases were systematically searched for studies published from January 2000 to May 2012. Included studies must be primary studies that are written in English, Dutch, French or German and involve former professional football players; injury had to be studied as an independent variable; and knee/ankle OA, work participation or limited activities had to be described as an outcome. The data from included studies were extracted using a standardised extraction form, and the methodological quality was assessed. RESULTS: No studies were retrieved about injury as a risk determinant for knee/ankle OA in former professional football players. Four studies about OA-related activity and work limitations were included (three of high and one of moderate methodological quality). Up to 17% of former professional football players with knee/ankle OA reported suffering from joint pain and discomfort during activities such as squatting, walking and climbing stairs. Former professional football players with knee/ankle OA reported that their conditions were very painful, chronically painful and affected their daily lives, while 28% reported work-related limitations. CONCLUSION: Knee and ankle OA in former professional football players causes joint pain and discomfort that has negative consequences for daily life and work activities. An OA health examination programs should be developed to empower the sustainable health and functioning of professional football players. PMID- 25034552 TI - Magnetic resonance imaging and dual energy X-ray absorptiometry of the lumbar spine in professional wrestlers and untrained men. AB - The aim of this study was to examine the relation between bone marrow adipose tissue (BMAT) and bone mineral density (BMD) of lumbar spine in male professional wrestlers and healthy untrained men. A total of 14 wrestlers (22.9+/-3.4 years) and 11 controls (24.4+/-1.6 years) were studied cross-sectionally. Body composition and BMD were measured by dual-energy X-ray absorptiometry. Magnetic resonance imaging of the lumbar spine was examined in a sagittal T1-weighted (T1 w) spin-echo (SE) sequence. The averaged bone marrow signal intensity (SI) of L2 L4 was related to the signal of an adjacent nondegenerative disk. Mean SI of T1-w SE in wrestlers was lower than controls (P=0.001), indicating L2-L4 BMAT in wrestlers was lower compared to controls. L2-L4 BMD in wrestlers was higher than controls (P<0.001). In the total subject population, L2-L4 BMD was inversely correlated with mean SI of T1-w SE (r=-0.62, P=0.001). This association remained strong after adjusting for body mass and whole lean mass, but became weaker after adjusting for whole body or trunk fat percentage. The inverse relationship between BMAT and BMD was confirmed in this relatively small subject sample with narrow age range, which implies that exercise training is an important determinant of this association. PMID- 25034553 TI - Analysis of the performance of women with fibromyalgia in the six-minute walk test and its relation with health and quality of life. AB - Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain that causes a significant reduction in functional capacity, affecting thus health and quality of life (QOL). AIM: The aim of the present study was to evaluate the performance of FM patients in the 6-Minute Walk Test (6MWT) and its relation with health and QOL. METHODS: Thirty-six FM patients (all women), differentiated by degree of severity of disease, and 14 healthy women were evaluated. Distance walked in the 6MWT, cardiorespiratory responses, heart rate responses, kinematic parameters of gait, the results of the Fibromyalgia Impact Questionnaire (FIQ), and the results of the Short-Form Healthy Survey (SF 36) were analyzed. RESULTS: Women with FM covered a shorter distance in the 6MWT, had a lower cardiorespiratory response, and had lower spatio-temporal parameters of gait than healthy women. No correlation was found in FM patients between the total FIQ score and the distance walked in the 6MWT. CONCLUSION: The analysis of performance parameters in the 6MWT may be an element of clinical relevance in FM patients. PMID- 25034554 TI - Physical activity, body mass index and mental health in Chinese adolescents: a population based study. AB - AIM: The aim of the present study was to examine the association between physical activity, BMI level and mental health among Chinese adolescents. METHODS: Three thousand ninety-six adolescents aged 11 to 13 were analyzed from 6 middle schools of Xuzhou. Physical activity level was measured using self-designed questionnaires. BMI was calculated according to the results of these students' physical examinations. Anxiety symptoms were assessed by using the Screen for Child Anxiety Related Emotional Disorder, depression via the Children's Depression Inventory. Data were analyzed using chi-square test and logistic regression. RESULTS: Adolescents' self-reported rate of insufficient physical activity was 58.1%. The overweight and obesity rates were 18.4%, 16.0%. The point prevalence rates on anxiety and depression were 15.2%, 11.5%. Insufficient physical activity was positively associated with anxiety and depression (OR [95%CI]: 1.31 [1.06-1.63]; 1.33 [1.04-1.70]). Obesity was positively associated with depression (OR [95%CI]: 1.48 [1.10-2.00]). IS-OB was positively associated with anxiety and depressive (OR [95%CI]: 1.71 [1.19-2.45]; 1.99 [1.33-2.97]). CONCLUSION: Physical inactivity and overweight/obesity were negatively association with mental health of adolescents, respectively. Meanwhile, to explore the combined effects of physical inactivity and obesity would increase the risk of anxiety and depression in adolescents. PMID- 25034555 TI - Epidemiologic study of young soccer player's injuries in U12 to U20. AB - AIM: The aim of this study was an epidemiological report of the injuries to young soccer players from pretraining centres (12 to 15 years: U12-U15) and training centres (16 to 20 years: U16-U20). METHOD: Over 3 years, 618 injuries were analysed, concerning an average of 137 players per season (66 and 71 players in U12-U15 and U16-U20, respectively). The injuries were diagnosed by a physician. Numerous injury-related information were documented: player, player's age category, date of the injury, site of the injury, injured side, type of injury, circumstances: training vs. match and contact vs non-contact, number of days of play missed, severity, and player's position. RESULTS: The injury rate was higher in matches than in training sessions. Non-contact injuries accounted for 77.0% of the injuries for U12-U15 and 65.6% for U16-U20. The injuries were mainly to the thigh and hip in pretraining players (23.3% and 19.0%, respectively), and to the thigh and ankle in training players (32.1% and 20.3%, respectively). Contact injuries occurred more frequently during matches, presumably because of the higher intensity of play. The analysis of match injuries by position indicated that for U12-U15, during the matches, lateral defenders were injured most often: 30.4%. For U16-U20, axial midfielders and axial defenders were most subject to injuries during the matches (26.6% and 23.1%, respectively). CONCLUSION: These results may help to improve the programming of training. Between the first and third seasons of this study, a decrease in injuries during both matches and training sessions: from 174 to 107 (decrease of 38.5%). PMID- 25034556 TI - The influence of music on exercise in a group of sedentary elderly women: an important tool to help the elderly to stay active. AB - AIM: The aim of this study was to verify how listening to instrumental asynchronous music, with tempo of 90 bpm, can affect the aerobic physical performance in elderly women engaged in a continuous and constant exercising, predominantly aerobic, consisting of walking routines. METHODS: Twenty women (N.=20, age=75.8+/-4.2 years) volunteered to the study and underwent a six-week period of physical exercising. All women were previously sedentary, as they had not trained systematically within the last 5 years. The experimental group (Eg=10) performed all the exercise sessions and tests listening to music. The control group (Cg=10) performed the same program without listening to music. Total distances covered, heart rates before and after the tests and the rates of perceived exertion (RPE) were measured. RESULTS: Significant differences between groups (P<0.01) were found in RPE. No statistically significant differences were observed in total distances covered and heart rates, although there was an increase of 9.83% in the total distance covered by the Eg compared to the Cg, in accordance with other previous researches. CONCLUSION: The results are in line with those reported by other authors in different populations and ages, confirming that music may be considered an important tool in supporting elderly people involved in physical exercising. PMID- 25034557 TI - Physical fitness and volume of leisure time physical activity relate with low stress and high mental resources in young men. AB - AIM: There is limited evidence available regarding the relationship between physical fitness, especially muscular fitness, and the mental well-being among young healthy men. Therefore, the aim of the present study was to investigate the impact of measured cardiovascular and muscle fitness and self reported leisure time physical activity (LTPA) on outcomes of stress and mental resources in Finnish young men. METHODS: In a cross-sectional study, 831 men (mean age 25 y) underwent cardiovascular and muscle fitness test and completed LTPA and Occupational Stress Questionnaires (OSQ). For analysis, the subjects were divided to LTPA, CVF and MFI tertiles. RESULTS: The group with low LTPA reported 6% and 13% more stress (ANCOVA using age, body mass index, smoking and alcohol use as covariates, P<0.05 in both) and 6% and 12% (P<0.05 in both) less mental resources than the moderate and high LTPA groups, respectively. The group having low cardiovascular fitness experienced 8% and 9% (P<0.001 in both) more stress and 7% and 7% (P<0.05 in both) less mental resources than moderate and high cardiovascular fitness groups. The low muscle fitness index (MFI) group reported 7% (P<0.01) less mental resources than those with moderate MFI and 8% (P<0.001) more stress and 8% (P<0.001) less mental resources than those with high MFI. CONCLUSION: Both good aerobic and muscular fitness together with high LTPA are associated with low stress and high mental resources. PMID- 25034558 TI - Detection of prostate cancer with multiparametric MRI (mpMRI): effect of dedicated reader education on accuracy and confidence of index and anterior cancer diagnosis. AB - PURPOSE: To evaluate the impact of dedicated reader education on accuracy/confidence of peripheral zone index cancer and anterior prostate cancer (PCa) diagnosis with mpMRI; secondary aim was to assess the ability of readers to differentiate low-grade cancer (Gleason 6 or below) from high-grade cancer (Gleason 7+). MATERIALS AND METHODS: Five blinded radiology fellows evaluated 31 total prostate mpMRIs in this IRB-approved, HIPAA-compliant, retrospective study for index lesion detection, confidence in lesion diagnosis (1-5 scale), and Gleason grade (Gleason 6 or lower vs. Gleason 7+). Following a dedicated education program, readers reinterpreted cases after a memory extinction period, blinded to initial reads. Reference standard was established combining whole mount histopathology with mpMRI findings by a board-certified radiologist with 5 years of prostate mpMRI experience. RESULTS: Index cancer detection: pre education accuracy 74.2%; post-education accuracy 87.7% (p = 0.003). Confidence in index lesion diagnosis: pre-education 4.22 +/- 1.04; post-education 3.75 +/- 1.41 (p = 0.0004). Anterior PCa detection: pre-education accuracy 54.3%; post education accuracy 94.3% (p = 0.001). Confidence in anterior PCa diagnosis: pre education 3.22 +/- 1.54; post-education 4.29 +/- 0.83 (p = 0.0003). Gleason score accuracy: pre-education 54.8%; post-education 73.5% (p = 0.0005). CONCLUSIONS: A dedicated reader education program on PCa detection with mpMRI was associated with a statistically significant increase in diagnostic accuracy of index cancer and anterior cancer detection as well as Gleason grade identification as compared to pre-education values. This was also associated with a significant increase in reader diagnostic confidence. This suggests that substantial interobserver variability in mpMRI interpretation can potentially be reduced with a focus on education and that this can occur over a fellowship training year. PMID- 25034559 TI - Impacts of peroxisome proliferator-activated receptor-gamma activation on cigarette smoke-induced exacerbated response to bacteria. AB - Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)gamma activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARgamma may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection. PMID- 25034560 TI - Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with chronic inflammation but the pathological mechanisms are largely unknown. Our study aimed to simultaneously profile a broad range of cytokines in the supernatant of pulmonary endarterectomy (PEA) surgical material, as well as prospectively in patients with CTEPH to investigate whether circulating cytokines are associated with haemodynamic and physical characteristics of CTEPH patients. Herein, we show that PEA specimens revealed a significant upregulation of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-gamma-induced protein-10 (IP)-10, macrophage inflammatory protein (MIP)1alpha and RANTES compared to lung tissue from healthy controls. In prospectively collected serum, levels of IL-6, IL-8, IP 10, monokine induced by interferon-gamma (MIG) and MIP1alpha were significantly elevated in CTEPH patients compared to age- and sex-matched healthy controls. In serum of idiopathic pulmonary arterial hypertension (IPAH) patients, only IP-10 and MIG were significantly increased. In CTEPH but not in IPAH, IP-10 was negatively correlated with cardiac index, 6-min walking distance and carbon monoxide diffusion capacity. In vitro, IP-10 significantly increased migration of freshly isolated adventitial fibroblasts. Our study is the first to show that IP 10 secretion is associated with poor pulmonary haemodynamics and physical capacity in CTEPH and might be involved in the pathological mechanism of PEA tissue formation. PMID- 25034561 TI - CD14/Toll-like receptors interact with bacteria and regulatory T-cells in the development of childhood asthma. PMID- 25034562 TI - Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. AB - Sarcoidosis is characterised by non-caseating granulomas that secrete pro inflammatory cytokines, including interleukin (IL)-12, IL-23, and tumour necrosis factor (TNF)-alpha. Ustekinumab and golimumab are monoclonal antibodies that specifically inhibit IL-12/IL-23 and TNF-alpha, respectively. Patients with chronic pulmonary sarcoidosis (lung group) and/or skin sarcoidosis (skin group) received either 180 mg ustekinumab at week 0 followed by 90 mg every 8 weeks, 200 mg golimumab at week 0 followed by 100 mg every 4 weeks, or placebo. Patients underwent corticosteroid tapering between weeks 16 and 28. The primary end-point was week 16 change in percentage predicted forced vital capacity (DeltaFVC % pred) in the lung group. Major secondary end-points were: week 28 for DeltaFVC % pred, 6-min walking distance, St George's Respiratory Questionnaire (lung group), and Skin Physician Global Assessment response (skin group). At week 16, no significant differences were observed in DeltaFVC % pred with ustekinumab (-0.15, p = 0.13) or golimumab (1.15, p = 0.54) compared with placebo (2.02). At week 28, there were no significant improvements in the major secondary end-points, although a nonsignificant numerically greater Skin Physician Global Assessment response was observed following golimumab treatment (53%) when compared with the placebo (30%). Serious adverse events were similar in all treatment groups. Although treatment was well tolerated, neither ustekinumab nor golimumab demonstrated efficacy in pulmonary sarcoidosis. However, trends towards improvement were observed with golimumab in some dermatological end-points. PMID- 25034564 TI - Pyrosequencing reveals transient cystic fibrosis lung microbiome changes with intravenous antibiotics. AB - Chronic airway infection in adults with cystic fibrosis (CF) is polymicrobial and the impact of intravenous antibiotics on the bacterial community composition is poorly understood. We employed culture-independent molecular techniques to explore the early effects of i.v. antibiotics on the CF airway microbiome. DNA was extracted from sputum samples collected from adult subjects with CF at three time-points (before starting treatment, and at day 3 and day 8-10 of i.v. antibiotics) during treatment of an infective pulmonary exacerbation. Microbial community profiles were derived through analysis of bacterial-derived 16S ribosomal RNA by pyrosequencing and changes over time were compared. 59 sputum samples were collected during 24 pulmonary exacerbations from 23 subjects. Between treatment onset and day 3 there was a significant reduction in the relative abundance of Pseudomonas and increased microbial diversity. By day 8-10, bacterial community composition was similar to pre-treatment. Changes in community composition did not predict improvements in lung function. The relative abundance of Pseudomonas falls rapidly in subjects with CF receiving i.v. antibiotic treatment for a pulmonary exacerbation and is accompanied by an increase in overall microbial diversity. However, this effect is not maintained beyond the first week of treatment. PMID- 25034563 TI - The PROactive innovative conceptual framework on physical activity. AB - Although physical activity is considered an important therapeutic target in chronic obstructive pulmonary disease (COPD), what "physical activity" means to COPD patients and how their perspective is best measured is poorly understood. We designed a conceptual framework, guiding the development and content validation of two patient reported outcome (PRO) instruments on physical activity (PROactive PRO instruments). 116 patients from four European countries with diverse demographics and COPD phenotypes participated in three consecutive qualitative studies (63% male, age mean+/-sd 66+/-9 years, 35% Global Initiative for Chronic Obstructive Lung Disease stage III-IV). 23 interviews and eight focus groups (n = 54) identified the main themes and candidate items of the framework. 39 cognitive debriefings allowed the clarity of the items and instructions to be optimised. Three themes emerged, i.e. impact of COPD on amount of physical activity, symptoms experienced during physical activity, and adaptations made to facilitate physical activity. The themes were similar irrespective of country, demographic or disease characteristics. Iterative rounds of appraisal and refinement of candidate items resulted in 30 items with a daily recall period and 34 items with a 7-day recall period. For the first time, our approach provides comprehensive insight on physical activity from the COPD patients' perspective. The PROactive PRO instruments' content validity represents the pivotal basis for empirically based item reduction and validation. PMID- 25034565 TI - Does a single Pseudomonas aeruginosa isolation predict COPD mortality? PMID- 25034566 TI - Mortality risk prediction in COPD by a prognostic biomarker panel. AB - Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death. We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low. In the derivation cohort (n = 142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8-5.1) for one high biomarker, 4.8 (95% CI 2.4-9.5) for two biomarkers and 9.6 (95% CI 3.3-28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n = 243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1-3.3), 3.1 (95% CI 1.8-5.4) and 5.4 (95% CI 2.5-11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7-92.4%) and 45.9% (95% CI 13.9-75.7%) at 3 and 5 years, respectively. Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD. PMID- 25034567 TI - Development and validation of the RAND Asthma Control Measure. AB - Patient-based measures for asthma control are important in assessing the worldwide impact of this highly prevalent chronic illness. We sought to refine an asthma symptom scale that RAND had previously developed to shorten it and validate it further, as well as reflect updated international expert definitions of asthma control. We conducted rigorous psychometric testing of new and adapted self-administered survey items in a sample of 2032 adults with asthma. The reliability and preliminary validity of the resulting measure, henceforth referred to as the RAND Asthma Control Measure (RAND-ACM), matched or exceeded that of the original RAND measure and others in the literature. RAND-ACM scores for worse asthma control were significantly associated with worse asthma-related quality of life, increased asthma-related healthcare use, Hispanic ethnicity and lower educational level. Evidence for internal consistency was strong with a Cronbach's alpha of 0.84. We also found adequate concordance between the RAND-ACM and the Global Initiative for Asthma categories of "uncontrolled", "partly controlled" and "controlled" asthma. The RAND-ACM, a five-item self-reported asthma control survey measure, performs well in a large ethnically-diverse sample of US adults with asthma and provides a cost-free alternative to other asthma control measures currently available. PMID- 25034568 TI - Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role? AB - Recently, a locus centred on rs9273349 in the HLA-DQ region emerged from genome wide association studies of adult-onset asthma. We aimed to further investigate the role of human leukocyte antigen (HLA) class II in adult-onset asthma and a possible interaction with occupational exposures. We imputed classical HLA-II alleles from 7579 single-nucleotide polymorphisms in 6025 subjects (1202 with adult-onset asthma) from European cohorts: ECRHS, SAPALDIA, EGEA and B58C, and from surveys of bakers and agricultural workers. Based on an asthma-specific job exposure matrix, 2629 subjects had ever been exposed to high molecular weight (HMW) allergens. We explored associations between 23 common HLA-II alleles and adult-onset asthma, and tested for gene-environment interaction with occupational exposure to HMW allergens. Interaction was also tested for rs9273349. Marginal associations of classical HLA-II alleles and adult-onset asthma were not statistically significant. Interaction was detected between the DPB1*03:01 allele and exposure to HMW allergens (p = 0.009), in particular to latex (p = 0.01). In the unexposed group, the DPB1*03:01 allele was associated with adult-onset asthma (OR 0.67, 95%CI 0.53-0.86). HMW allergen exposures did not modify the association of rs9273349 with adult-onset asthma. Common classical HLA-II alleles were not marginally associated with adult-onset asthma. The association of latex exposure and adult-onset asthma may be modified by DPB1*03:01. PMID- 25034569 TI - Co-exposure to refractory ceramic fibres and asbestos and risk of pleural mesothelioma. AB - The aim of this study was to investigate the hypothesis of an increased risk of pleural mesothelioma due to co-exposure to asbestos and refractory ceramic fibres (RCF) compared to asbestos exposure alone. Males were selected from a French case control study conducted in 1987-1993 and from the French National Mesothelioma Surveillance Program in 1998-2006. Two population controls were frequency matched to each case by year of birth. Complete job histories were collected and occupational asbestos and RCF exposures were assessed using job exposure matrices. The dose-response relationships for asbestos exposure were estimated from an unconditional logistic regression model in subjects exposed to asbestos only (group 1) and subjects exposed to both asbestos and RCF (group 2). A total of 988 cases and 1125 controls ever-exposed to asbestos were included. A dose response relationship was observed in both groups but it was stronger in group 2. In comparison with subjects exposed at the minimum value of the cumulative index of exposure, the odds ratio was 2.6 (95% CI 1.9-3.4) for subjects exposed to 75 fibres . mL(-1) . year(-1) in group 1 increasing to 12.4 (95% CI 4.6-33.7) in group 2. Our results suggest that the pleural carcinogenic effect of occupational asbestos exposure may be modified by additional exposure to RCF. PMID- 25034570 TI - Small airway dysfunction is associated with poorer asthma control. PMID- 25034571 TI - Lung cancer in never-smokers: a case-control study in a radon-prone area (Galicia, Spain). AB - The aim of the study was to assess the effect of residential radon exposure on the risk of lung cancer in never-smokers and to ascertain if environmental tobacco smoke modifies the effect of residential radon. We designed a multicentre hospital-based case-control study in a radon-prone area (Galicia, Spain). All participants were never-smokers. Cases had an anatomopathologically confirmed primary lung cancer and controls were recruited from individuals undergoing minor, non-oncological surgery. Residential radon was measured using alpha track detectors. We included 521 individuals, 192 cases and 329 controls, 21% were males. We observed an odds ratio of 2.42 (95% CI 1.45-4.06) for individuals exposed to >=200 Bq.m(-3) compared with those exposed to <100 Bq.m(-3). Environmental tobacco smoke exposure at home increased lung cancer risk in individuals with radon exposure>200 Bq.m(-3). Individuals exposed to environmental tobacco smoke and to radon concentrations>200 Bq.m(-3) had higher lung cancer risk than those exposed to lower radon concentrations and exposed to environmental tobacco smoke. Residential radon increases lung cancer risk in never-smokers. An association between residential radon exposure and environmental tobacco smoke on the risk of lung cancer might exist. PMID- 25034572 TI - Identification of treatment goals in paediatric pulmonary arterial hypertension. AB - To be able to design goal-oriented treatment strategies in paediatric pulmonary arterial hypertension (PAH), we aimed to identify treatment goals by investigating the prognostic value of treatment-induced changes in noninvasive predictors of transplant-free survival. 66 consecutive, treatment-naive paediatric PAH patients in the Dutch National Network for Paediatric Pulmonary Hypertension who started taking PAH-targeted drugs between January 2000 and April 2013 underwent prospective, standardised follow-up. Clinical, biochemical and echocardiographic measures were longitudinally collected at treatment initiation and follow-up, and their respective predictive values for transplant-free survival were assessed. Furthermore, the predictive values of treatment-induced changes were assessed. From the identified set of baseline predictors, the variables World Health Organization functional class (WHO-FC), N-terminal pro brain natriuretic peptide (NT-proBNP) and tricuspid annular plane systolic excursion (TAPSE) were identified as follow-up predictors in which treatment induced changes were associated with survival. Patients in whom these variables improved after treatment showed better survival (p<0.002). Therefore, WHO-FC, NT proBNP and TAPSE are not only predictors of transplant-free survival in paediatric PAH but can also be used as treatment goals, as treatment-induced improvements in these variables are associated with improved survival. The identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH. PMID- 25034573 TI - Reproductive function assessment after surgery plus chemotherapy for germ cell ovarian tumors (MOGCT): novel clues deriving from the field of fertility preservation. AB - Germ cell ovarian tumors (malignant ovarian germ cell tumors - MOGCT) affect young women and are treated by surgery plus chemotherapy. It is well known that cytotoxic treatment may accelerate depletion of the primordial follicle pool leading to impaired fertility and premature menopause. Aim of this study is to identify patient candidates for fertility preservation strategies. We report our experience in preservation of fertility for four patients affected by MOGCT, referred to San Raffaele Hospital Oncofertility Unit. All patients received fertility sparing surgery plus platinum-based chemotherapy. Two patients were affected by mixed germ cell tumors and two by disgerminomas. After 24 months from the end of treatment, serum AMH levels have been measured. We report lower serum anti-Mullerian hormone (AMH) levels in our patients than in healthy general population as serum AMH levels were under the 25th age-specific percentiles. Fertility preservation, in terms of oocytes cryopreservation, was offered to those two patients with serum AMH levels predictive of significantly poor ovarian reserve (1st and 2nd patients). Using the gonadotropin releasing hormone (GnRH) antagonist protocol for ovarian stimulation, we obtained two and six oocytes, respectively. Therefore, serum AMH, as a marker of ovarian function, can improve the identification of patients that need to be referred to fertility preservation strategies. PMID- 25034574 TI - No association between body size and frequency of sexual intercourse among oral contraceptive users. AB - PURPOSE: This study aimed to describe the frequency of sexual intercourse and whether body size was associated with weekly sexual intercourse among a diverse group of women using oral contraceptives. METHODS: This longitudinal prospective cohort study recruited participants (n = 185) from several clinics in Charlotte, NC. Body mass index (BMI) and waist-to-hip ratio (WHR) were used as measures of body size and sexual intercourse frequency was determined from self-reported information provided on daily diaries. Mean monthly frequencies of sexual intercourse were calculated and linear mixed models were used to assess if means remained constant over time. Generalized estimating equations were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Mean monthly frequency of sexual intercourse was similar for women classified as normal or underweight or obese by BMI during each month of data collection but was highest for women classified as overweight. After adjustment, obesity-sexual intercourse associations were attenuated (BMI >=30 vs. <25.0: OR = 0.78; 95% CI, 0.43-1.42 and WHR >= 0.85 vs. <0.85: OR = 1.11; 95% CI, 0.62-2.01). CONCLUSIONS: This study found no association between BMI or WHR and weekly sexual intercourse. However, more research is warranted given the importance of this possible relationship for future studies of fertility, contraceptive effectiveness, and sexual health. PMID- 25034575 TI - Cytochrome c end-capped mesoporous silica nanoparticles as redox-responsive drug delivery vehicles for liver tumor-targeted triplex therapy in vitro and in vivo. AB - To develop carriers for efficient anti-cancer drug delivery with reduced side effects, a biocompatible and redox-responsive nanocontainer based on mesoporous silica nanoparticles (MSNs) for tumor-targeted triplex therapy was reported in this study. The nanocontainer was fabricated by immobilizing cytochrome c (CytC) onto the MSNs as sealing agent via intermediate linkers of disulfide bonds for redox-responsive intracellular drug delivery. AS1411 aptamer was further tailored onto MSNs for cell/tumor targeting. The successful construction of redox- responsive MSNs was confirmed by BET/BJH analysis, transmission electron microscopy, Fourier transform infrared spectroscopy, fluorescence spectroscopy and thermogravimetric analysis (TGA), respectively. Detailed investigations demonstrated that anticancer drug of doxorubicin (DOX) loaded nanocontainer could be triggered by reductant (e.g. glutathione) within cellular microenvironment and release DOX to induce tumor cell apoptosis in vitro. More importantly, the nanocontainer displayed great potential for tumor targeting and achieved triplex therapy effects on the tumor inhibition in vivo through the loading DOX, gatekeeper of CytC and AS1411 aptamer, which were reflected by the change of tumor size, TUNEL staining and HE staining assays. PMID- 25034576 TI - An in vitro skin penetration model for compromised skin: estimating penetration of polyethylene glycol [14C]-PEG-7 phosphate. AB - BACKGROUND/AIMS: Establishing dermal penetration rates is important to better understand the safety of topically applied materials, especially for premature infant skin with compromised skin barrier function. Skin prematurity involves thinner stratum corneum and underdeveloped epidermis/dermis resulting in decreased barrier function, higher transepidermal water loss and greater chemical penetration, when compared to healthy full-term neonate/adult skin. METHODS: We developed an in vitro skin penetration model using human ex vivo skin to estimate penetration for premature/compromised skin barrier conditions by tape stripping. Skin barrier deficiency was characterized by transepidermal water loss. Baby wipe lotion containing 5 mg/cm(2) [(14)C]-PEG-7 phosphate was applied 5 times to human skin samples of intact, moderately or highly compromised skin barrier and once at 25 mg/cm(2) over 24 h. RESULTS: Overall penetration of [(14)C]-PEG-7 phosphate was low (<5%) even for highly compromised skin. The absorption rate was higher (p < 0.001) for compromised skin versus intact skin. No significant difference was seen between moderately and highly compromised skin by repeated dosing. Under single-dose conditions, penetration through highly compromised skin was significantly higher compared to intact skin (p = 0.001). CONCLUSION: Our model demonstrates that even under highly compromised skin conditions, penetration of [(14)C]-PEG-7 phosphate is low (<5%) and only 4-6 times higher compared to mature/intact skin and does not approach 100%. Penetration was unaffected by single or multiple dosing conditions. PMID- 25034577 TI - [Trends of thoracic surgery and mission of thoracic surgery branch of Chinese Medical Doctor Association]. PMID- 25034578 TI - [Current status analysis of development of thoracic surgery in China]. PMID- 25034579 TI - [Non-small cell lung cancer lung metastasis? Or the second (and more) of primary lung cancer -- key concepts influencing treatment strategies]. PMID- 25034580 TI - [Uniportal VATS: a sublimation of micro-invasive lung cancer resection]. AB - Micro-invasive thoracic surgery, especially represented by video-assisted thoracic surgery (VATS), has become the mainstream of lung cancer resection. Traditional multi-portal VATS techniques, including four-port, three-port, and two-port VATS, have been widely used to perform nearly all kinds of lung cancer resections. However, how to make lung cancer resection less invasive is always the subject that all thoracic surgeons never stop pursuing. Compared with multi portal VATS, uniportal VATS causes less postoperative pain and paresthesia because only one small incision is made and one intercoastal space is involved. In recent years, good clinical results have been obtained from uniportal VATS in lung cancer resections. In this paper, we'd like to present a brief summary about the progresses made in the application of uniportal VATS in lung cancer resection. Uniportal VATS is a sublimation of micro-invasive lung cancer resection. PMID- 25034581 TI - [Discussion and summary on operation treatment of small lung nodules]. PMID- 25034582 TI - [Influencing factor of postoperation fast-track recovery and in hospital cost after lobctomy for lung cancer]. AB - BACKGROUND: It is unknown that the postoperation fast-track recovery and in hospital cost of the lobectomy in lung cancer, we explored the influencing factor of postoperative fast-track recovery and in hospital cost after undergoing lobectomy for lung cancer. METHODS: We retrospectively reviewed the medical records of all patients (n=176) who underwent lobectomy for lung cancer between January 2010 and November 2011 by a thoracic surgeon. RESULTS: The hospital costs of video-assisted thoracic surgery (VATS) lobectomy (47,308.21 Y) is significantly higher than open lobectomy (45,664.31 Y)(P=0.007). The hospital costs of body mass index (BMI) >= 24 kg/m2 (51,186.99 Y) is significantly higher than BMI < 24 kg/m2 (41,701.64 Y)(P=0.032). The hospital stay of VATS lobectomy (5.70 d) is significantly less than open lobectomy (7.10 d)(P<0.001). CONCLUSIONS: These findings indicate that preoperative pulmonary rehabilitation and VATS lobectomy is contributed to fast-track recovery for patients who undergo lobectomy, but increase the hospital costs. PMID- 25034584 TI - [Fibro-bronchoscopic cryosurgery for unresectable endobronchial tumors]. AB - BACKGROUND: Patients with tracheobronchial tumor are too frail for curative surgical treatment, and the original sites are unsuitable for radical resection. They always suffered from dyspnea, hymoptosis, obstructive pneumonia, and fever. Airway obstruction has a strong bad impact on the quality of life, and is the main cause of respiratory failure and death. An effective method of palliative is very important. We choose fibro-bronchoscopic cryosurgery for destruction of endobronchial tumors and analyze the outcomes. METHODS: Clinical records of 126 cases who under went endobronchoscopic cryosurgery were reviewed retrospectively from August 2004 to February 2014. Techniques and survival outcomes were analyzed. The precise position and length of the cryosurgery was evaluated through three dimension chest computed tomography (CT) and reconstruction of trachea and bronchus. Local infiltration and general intravenous anesthesia are two options before surgical procedure. Endobronchial tumor was removed by combining two methods of "Cryo-Resecion" and "Cryo-Melt". Bronchoscopic examination was rechecked 2 weeks later to evaluate if it is necessary to redo the endobronchoscopic cryosurgery. RESULTS: The symptoms of cough, short of breath, and hemoptysis were alleviated to different extend. The rate of dramatically improved and partial improved were 65.1% and 77.0% respectively. The mortality is 0.79%. Postoperative Complications included 2 cases of airway bleeding, 4 cases of bronchial stenosis, 2 cases of trachea burning injury, 2 cases of tracheomalacia, and 3 cases of atrium fibrillation. The median survival is 14 months, 1-, 2-, 3-yr survival rates were 58.6%, 24.2%, and 12.2% respectively, based on Kaplan-Meier estimates. CONCLUSIONS: Endobronchial cryosurgery is an easy and effective minimally invasive choice for controlling and releasing the airway obstructive symptoms resulting from the trachea or bronchial tumors. Besides, the problem of difficult endotracheal intubation could be resolved after removing the tracheal tumor with the benefit of cryotreatment. Some patients could get the chance for further treatment or radical resection. Therefore, the patients' quality of life could be improved and the lifetime could be prolonged. PMID- 25034583 TI - [Clinical experience of the treatment of solitary pulmonary nodules with Da Vinci surgical system]. AB - BACKGROUND: A solitary pulmonary nodule (SPN) is defined as a round intraparenchimal lung lesion less than 3 cm in size, not associated with atelectasis or adenopathy. The aim of this study is to learn clinical experience of the treatment of SPN with Da Vinci Surgical System. METHODS: A total of 9 patients with solitary pulmonary nodules (SPN) less than 3 cm in diameter was treated with Da Vinci Surgical System (Intuitive Surgical, California) in thoracic surgery department from General Hospital of Shenyang Militrary Region from November 2011 to March 2014. This group of patients included 3 males and 6 females, and the mean age was 51+/-9.9 yr (range: 41-74 yr). Most of the patients were no obvious clinical symptoms (7 cases were found by physical examination, others were with cough and expectoration). Their median medical history was 12 mo (range: 4 d-3 yr). All the lesions of patients were peripheral pulmonary nodules and the mean diameter of those was (1.4+/-0.6) cm(range: 0.8-2.8 cm). Wedge shaped resection or lobectomy was performed depending on the result of rapid pathology and systemic lymph node dissection was done for malignant leision. We used general anesthesis with double lumens trachea cannula. We set the patients in lateral decubitus position with jackknife. The patient cart enter from top of the patient. The position of trocars would be set according to the position of lesion. A 12 mm incision was positioned at the 8th intercostal space in the posterior axillary line as vision port, and two 8 mm incisions were positioned at the 5th intercostal space between the anterior axillary line and midclavicular line, and the 8th infrascapular line as robotic instrument ports about 10 cm apart from the vision port. One additional auxiliary small incision for instrument without retracting ribs was set at the 7th intercostal space in the middle axillary line. RESULTS: There were 4 benign leisions and 5 malignancies identified. Wedge-shaped resection was performed for 4 patients, lobectomy with systemic lymph node dissection for 3 patients (including 2 right middle lobectomies and 1 left upper lobectomy) and wedge-shaped resection with systemic lymph node dissection for 2 patients of poor lung function. All of the 9 cases were completed with total robotic procedure without conversion. The pathological results included 3 inflammatory pseudotumors, 1 hamartoma, 5 adenocarcinomas. All of the 29 patients were hospital discharged smoothly. The patients were followed up for 0.1-18.5 mo (median 11 mo) without recurrence or metastasis. CONCLUSIONS: The SPN patients should be given active surgical treatments to improve the diagnose rate as well as the cure rate of early non-small cell lung cancer. Since da Vinci Surgical System is a safe and minimally invasive treatment for SPN, it has higher value to the diagnosis and treatment of SPN. PMID- 25034585 TI - [Pulmonary benign metastasizing leiomyoma: a clinicopathological study of 5 cases]. AB - Pulmonary benign metastasizing leiomyoma (PBML) is a rare and often to be misdiagnosed disease. In this study, we want to investigate the diseased of the clinicopathological characteristics, diagnosis, treatment and prognosis. The retrospective analysis were performed on the clinicopathological data of 5 patients with PBML. All 5 cases were female, mean age 46.8 years old, and were found with single nodule. One case was found with left kidney metastasis. Surgical procedures includes: VATS biopsy (3 cases), resection of superior lobe of left lung (1 case), resection of superior lobe of right lung and wedge resection of middle and inferior lobe of right lung (1 case). The residual nodules in lung were stable in all cases with followup 3-48 mo. PBML is dominated occurring in females with history of uterine leiomyoma, preferential to metastasize to lung, and surgery is the primary therapy. Since it is hormone dependent, hormonal therapy may be suggested in these patients. PMID- 25034586 TI - [Thin-walled cystic lung cancer: an analysis of 24 cases and review of literatures]. AB - BACKGROUND: Lung cancer presenting as cystic lesions was first described by Anderson and Pierce in 1954. Lung cancer presenting as cysts is a rare entity in clinical practice. Differential diagnosis is difficult in the benign-like cyst. This study investigated the clinical characteristics, diagnosis and treatment of lung cancer presenting as cysts. METHODS: We conducted a retrospective analysis of the clinical records of 24 patients who underwent surgery for a primary lung cancer presenting as cysts in our department between 2007 and 2013. We defined a 'Thin-walled cyst' as a cavitary lesion with a wall thickness of 4 mm or less along at least 75% of the circumference of the lesion. The whole group underwent post-operative follow-up. RESULTS: The incidence of cystic lung cancer was 0.49% (24/4,897) of surgical cases. The subjects' age ranged from 19 to 77 yr with a median age of 56.5 yr. Ten cases presented with respiratory symptoms while 14 showed abnormal shadows on a chest CT without symptoms. Histological analysis showed that 18 cases were of adenocarcinoma, three of squamous cell carcinoma, one of small cell carcinoma, one of adenosquamous carcinoma and one of large cell carcinoma. Three patients were dead, and the remaining 21 patients are alive and disease free at the end of follow-up. CONCLUSIONS: Cystic lung cancer should be kept in mind during the differential diagnosis of focal benign cyst. Cystic lung cancer could achieve a good outcome if early diagnose can be obtained. PMID- 25034587 TI - [A comparative study of Da Vinci robot system with video-assisted thoracoscopy in the surgical treatment of mediastinal lesions]. AB - BACKGROUND: In recent years, Da Vinci robot system applied in the treatment of intrathoracic surgery mediastinal diseases become more mature. The aim of this study is to summarize the clinical data about mediastinal lesions of General Hospital of Shenyang Military Region in the past 4 years, then to analyze the treatment effect and promising applications of da Vinci robot system in the surgical treatment of mediastinal lesions. METHODS: 203 cases of mediastinal lesions were collected from General Hospital of Shenyang Military Region between 2010 and 2013. These patients were divided into two groups da Vinci and video assisted thoracoscopic surgery (VATS) according to the selection of the treatments. The time in surgery, intraoperative blood loss, postoperative drainage amount within three days after surgery, the period of bearing drainage tubes, hospital stays and hospitalization expense were then compared. RESULTS: All patients were successfully operated, the postoperative recovery is good and there is no perioperative death. The different of the time in surgery between two groups is Robots group 82 (20-320) min and thoracoscopic group 89 (35-360) min (P>0.05). The intraoperative blood loss between two groups is robot group 10 (1 100) mL and thoracoscopic group 50 (3-1,500) mL. The postoperative drainage amount within three days after surgery between two groups is robot group 215 (0 2,220) mL and thoracoscopic group 350 (50-1,810) mL. The period of bearing drainage tubes after surgery between two groups is robot group 3 (0-10) d and thoracoscopic group: 5 (1-18) d. The difference of hospital stays between two groups is robot group 7 (2-15) d and thoracoscopic group 9 (2-50) d. The hospitalization expense between two groups is robot group (18,983.6+/-4,461.2) RMB and thoracoscopic group (9,351.9+/-2,076.3) RMB (All P<0.001). CONCLUSIONS: The da Vinci robot system is safe and efficient in the treatment of mediastinal lesions compared with video-assisted thoracoscopic approach, even though its expense is higher. PMID- 25034588 TI - [A method for introducing mutations into large vectors]. AB - BACKGROUND AND OBJECTIVE: In vitro site-directed mutagenesis is a routine technique in molecular biology labs. However, although there are numbers of related methods available, most of these methods are not suitable for introducing mutations into large vectors. METHODS: In this report, we describe a method which is highly effective for this purpose. Our method is based on the other site directed method we recently reported. The basic protocol of our method is as follows: (1) Synthesize a pair of vector primers based on the sequences around the region to be mutated, each containing a suitable type IIs endonuclease restriction site; meanwhile, synthesize a pair of short complementary oligonucleotides which forms a mutagenic fragment after annealing; (2) Synthesize a pair of bridge primers which can specifically bind to a site in the vector sequence, each containing a suitable type IIs endonuclease restriction site; (3) Perform PCR reactions using these Vector primers and Bridge primers; (4) Digest the PCR products with the corresponding type IIs restriction enzyme; (5) Ligate the digested fragment with the mutagenic fragment to make the desired mutant. RESULTS: Using this protocol, we have introduced mutations into a vector larger than 9 kb. The results shows that the mutation rates are more that 90%. CONCLUSIONS: Our method provides a useful tool for performing site-directed mutagenesis experiment in large vector. PMID- 25034589 TI - [Advances in the molecular mechanisms and prognostic significance of EMT in non small cell lung cancer]. AB - Epithelial to mesenchymal transition (EMT) has an important role in the development of embryo, as well as that in the metastasis of non-small cell lung cancer (NSCLC). Recent researches have demonstrated that both morphological and phenotypic conversions emerge in cells undergoing EMT. As most of relevant studies were on other cancers, it is essential to uncover whether it is the similar mechanisms accounting for EMT in NSCLC. With the progress of the studies, EMT-related basic researches are gradually applied to predicting the prognosis of NSCLC. The aim of this article was to discuss the mechanisms related to EMT emerging in NSCLC. PMID- 25034590 TI - [Treatment progress for EGFR wild-type advanced non-small cell lung cancer]. AB - Lung cancer is the leading cause of death from cancer in the world. The treatment remains one of the most challenging tasks in the medical world. The discovery and development of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) have had a major impact in the treatment of non small cell lung cancer (NSCLC). But the efficacy of EGFR-TKI in EGFR wild-type patients is limited, and the limited EGFR mutation incidence also prompts researchers to study what is the best treatment choice for patients with NSCLC who are negative for EGFR mutations. This review will discuss the research status in treatment choice for EGFR wild-type NSCLC. PMID- 25034591 TI - Laparoscopic ventral rectopexy in an elderly population with external rectal prolapse: clinical and anal manometric results. AB - AIM: We report the clinical and anal manometric results of elderly patients treated with laparoscopic ventral rectopexy (LVR) for full-thickness rectal prolapse. METHOD: From March 2009 to June 2012, patients were consecutively included. A modified laparoscopic Orr-Loygue procedure with posterior mobilisation was used. The patients were evaluated preoperatively, 2 months postoperatively and after 1 year. We registered Wexner incontinence scores and laxative uses by a questionnaire and performed simple anal manometry. RESULTS: A total of 46 patients underwent operation, all women. The median age was 83 years (range 34-99), median prolapse size was 8 cm (range 2-15), and 30 % had previous prolapse surgery. The median operative time was 135 min (range 90-215), and the median length of stay was 2 days (range 1-14). The 30-day morbidity rate was 15 %, and there were two (4 %) deaths within 30 days. There was a significant reduction in incontinence scores after 2 months and 1 year. The anal resting pressures improved from 10 cm H(2)O slightly to 16 cm H(2)O after 2 months, significantly, and still significant after 1 year at 13 cm H(2)O. There were no changes in the use of laxatives. The median follow-up time was 1.5 years (range 0.5-3), and there were two prolapse recurrences (4 %) in this period. CONCLUSIONS: Laparoscopic ventral rectopexy with posterior mobilisation seems to be effective and relatively well tolerated, although not without mortality in elderly debilitated patients. It improves incontinence. With increased life-year expectance, these patients may benefit from a lower risk of recurrence compared with perineal procedures. PMID- 25034592 TI - Attachment and quality of life in patients with inflammatory bowel disease. AB - PURPOSE: Inflammatory bowel diseases (IBD) are chronic disorders affecting psychological well-being, quality of life (QOL), social interactions, and close interpersonal relationships of patients affected. The attachment theory provides a theoretical framework to evaluate the quality of close interpersonal relationships in the context of chronic disorders. The aims of this study were to compare the attachment dimensions between IBD patients and healthy controls and to evaluate the impact of these dimensions on QOL in IBD patients. METHODS: One hundred three consecutive IBD outpatients (70 with Crohn's disease and 33 with ulcerative colitis) were recruited in the IBD Unit of the University of Bologna. They were clinically evaluated and filled out the questionnaire Short Form health survey-36 (SF-36), assessing QOL, and the attachment style questionnaire (ASQ), assessing attachment dimensions. One hundred three matched healthy subjects filled out the same questionnaires and represented the control group. RESULTS: IBD patients exhibited worst scores in the QOL measures (both physical and mental health) and in the attachment dimensions Relationships as secondary and Preoccupation with relationships. In IBD, the significant predictors of physical health were disease activity and disease type, while the significant predictors of mental health were disease activity and type, surgery, and the attachment dimensions Confidence and Preoccupation with relationships. CONCLUSIONS: Compared to controls, in IBD patients, the close interpersonal relationships are characterized by attachment insecurity that, in turn, is a significant predictor of QOL. These findings suggest plausible insights for psychological interventions in IBD patients with deterioration in QOL. PMID- 25034593 TI - The impact of surgical specialisation on survival following elective colon cancer surgery. AB - PURPOSE: Reorganisation of cancer services in the UK and across Europe has led to elective surgery for colon cancer being increasingly, but not exclusively, delivered by specialist colorectal surgeons. This study examines survival after elective colon cancer surgery performed by specialist compared to non-specialist surgeons. METHOD: Patients undergoing elective surgery for colon cancer in 16 hospitals between 2001 and 2004 were identified from a prospectively maintained regional audit database. Post-operative mortality (<30 days) and 5-year relative survival in those receiving surgery under the care of a specialist or non specialist surgeon were compared. RESULTS: A total of 1,856 patients were included, of which, 1,367 (73.7%) were treated by a specialist and 489 (26.4%) by a non-specialist surgeon. Those treated by a specialist were more likely to be deprived, undergo surgery in a high volume unit and have higher lymph node yields than those treated by a non-specialist. Post-operative mortality was lower (4.5 versus 7.0%; P = 0.032) and 5-year relative survival was higher (72.2 versus 65.6%; P = 0.012) among those treated by a specialist surgeon. In multivariate analysis, surgery by non-specialists was independently associated with increased post-operative mortality (adjusted odds ratio (OR) 1.69; P < 0.001) and poorer 5 year relative survival (adjusted relative excess risk (RER) 1.17; P = 0.045). After exclusion of post-operative deaths, there was no difference in long-term survival (adjusted RER 1.08; P = 0.505). CONCLUSION: Five-year relative survival after elective colon cancer surgery was higher among those treated by specialist colorectal surgeons due to increased post-operative mortality among those treated by non-specialists. PMID- 25034595 TI - Computer-aided image analysis algorithm to enhance in vivo diagnosis of plaque erosion by intravascular optical coherence tomography. AB - BACKGROUND: Recent reports show that plaque erosion can be diagnosed in vivo using optical coherence tomography in patients with acute coronary syndrome. However, quantitative optical coherence tomographic image criteria for computer aided diagnosis of plaque erosion have not been established. METHODS AND RESULTS: A total of 42 patients with acute coronary syndrome caused by plaque erosion were included. Plaque erosion was identified according to the previously established optical coherence tomography criteria. Both optical properties and morphological features of the focal-eroded region as well as erosion-adjacent region were analyzed using a custom-designed computer algorithm. Noneroded fibrous plaques remote from the erosion site within the same vessel were used as controls. Eroded plaques have significantly lower surface intensity (P<0.001), lower region of interest intensity (P<0.001), lower surface normalized SD (P<0.001), lower region of interest normalized SD (P<0.001), higher optical attenuation (P<0.001), larger tissue protrusion area (P<0.001), and greater surface roughness (P<0.001) when compared with control plaques. Erosion-adjacent regions also have lower region of interest normalized SD (P=0.008), higher attenuation (P<0.001), and greater surface roughness (P=0.005). Using a logistic regression model built on the quantitative features, plaque erosion can be accurately classified against intact fibrous plaques. There was low inter- and intraobserver variability associated with the algorithm-assisted quantitative assessment. CONCLUSIONS: Plaque erosion has distinctive optical properties and morphological features when compared with noneroded fibrous plaques. Quantitative image analysis may enhance diagnostic accuracy for plaque erosion in vivo. PMID- 25034594 TI - Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis. AB - Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coli with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and translocation of E. coli across epithelia and control colonic biopsy specimens, which was more striking in Crohn's disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases. PMID- 25034596 TI - Relationship between visual acuity and retinal structures measured by spectral domain optical coherence tomography in patients with open-angle glaucoma. AB - PURPOSE: We assessed the relationship between retinal structures measured by spectral-domain optical coherence tomography (SD-OCT) and visual acuity in open angle glaucoma (OAG) patients. METHODS: In this cross-sectional observational study, 186 eyes from 186 OAG patients were included. The participants underwent RTVue OCT for measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macular ganglion cell complex (mGCC) thickness. The correlations between best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) parameters were evaluated using Pearson's partial correlation test and regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to obtain a cutoff value for OCT parameters in detecting decreased visual acuity (BCVA < 0.7). RESULTS: Among RNFL parameters, average RNFL thickness (r = -0.447, P < 0.001) showed the highest correlation with BCVA, followed by superior hemisphere (r = -0.440, P <0.001), and TU1 (67.5 degrees -90 degrees , r = -0.427, P < 0.001), TU2 (45 degrees -67.5 degrees , r = -0.408, P < 0.001), and TL1 (90 degrees -112.5 degrees , r = -0.40, P < 0.001) sectors. When logMAR BCVA was plotted against average RNFL/ganglion cell complex (GCC) thickness, second-order polynomial models fit better than the linear model. The areas under the receiver operating characteristic curves (AUROCs) of the average RNFL/GCC thickness were 0.910 (95% confidence interval [CI], 0.856-0.965) and 0.874 (95% CI, 0.795-0.953), respectively. CONCLUSIONS: The relationship between BCVA and SD-OCT parameters were curvilinear, and significant correlations were noted only in eyes with severe glaucoma. The global average cpRNFL thickness showed the highest correlation with BCVA rather than TU1, TL1 sectors, or GCC parameters. Considering the wide variability of structure-visual acuity relationship in glaucoma patients, the clinicians should take other variables into account to predict the visual acuity in advanced glaucoma patients. PMID- 25034597 TI - Photic injury to cultured RPE varies among individual cells in proportion to their endogenous lipofuscin content as modulated by their melanosome content. AB - PURPOSE: We determined whether photic stress differentially impairs organelle motility of RPE lipofuscin and melanin granules, whether lethal photic stress kills cells in proportion to lipofuscin abundance, and whether killing is modulated by melanosome content. METHODS: Motility of endogenous lipofuscin and melanosome granules within the same human RPE cells in primary culture was quantified by real-time imaging during sublethal blue light irradiation. Cell death during lethal irradiation was quantified by dynamic imaging of the onset of nuclear propidium iodide fluorescence. Analyzed were individual cells containing different amounts of autofluorescent lipofuscin, or similar amounts of lipofuscin and a varying content of phagocytized porcine melanosomes, or phagocytized black latex beads (control for light absorbance). RESULTS: Lipofuscin granules and melanosomes showed motility slowing with mild irradiation, but slowing was greater for lipofuscin. On lethal irradiation, cell death was earlier in cells with higher lipofuscin content, but delayed by the copresence of melanosomes. Delayed death did not occur with black beads, suggesting that melanosome protection was due to properties of the biological granule, not simple screening. CONCLUSIONS: Greater organelle motility slowing of the more photoreactive lipofuscin granule compared to melanosomes suggests that lipofuscin mediates mild photic injury within RPE cells. With lethal light stress endogenous lipofuscin mediates killing, but the effect is cell autonomous and modulated by coincident melanosome content. Developing methods to quantify the frequency of individual cells with combined high lipofuscin and low melanosome content may have value for predicting the photic stress susceptibility of the RPE monolayer in situ. PMID- 25034599 TI - Aniseikonia and Foveal Microstructure after Retinal Detachment Surgery. AB - Purpose:To quantify aniseikonia after successful surgical repair of rhegmatogenous retinal detachment (RD), and to investigate the relationship between the severity of postoperative aniseikonia and retinal microstructures as well as clinical parameters. Methods:The study included 106 eyes of 106 patients, without any history of ocular disease/surgery and less than 2 diopters of anisometropia, who had undergone successful retinal reattachment surgery. Aniseikonia was measured with New Aniseikonia Test and foveal microstructure was assessed with the spectral-domain optical coherence tomography at 6 months postoperatively. Results:Twenty-eight of 106 patients (26%) had micropsia, 17 patients (16%) had macropsia, and 61 patients (58%) had no aniseikonia. The mean absolute value of aniseikonia was 2.3 +/- 2.9% (range; -12.5% - +12.0%). Of 57 eyes with macula-on RD, 3 had micropsia and 12 had macropsia. Of 49 eyes with macula-off RD, 25 had micropsia and 5 had macropsia. Eyes with micropsia mostly exhibited persistent or transient cystoid macular edema, subretinal fluid, hyperreflective or disruption of IS/OS line, while most of the eyes with macropsia presented epiretinal membrane. Stepwise multiple regression analysis revealed that postoperative best-corrected visual acuity and the area of RD were significantly relevant to the mean absolute value of aniseikonia. Conclusions:These results suggested that about half of patients with successful repair of RD had aniseikonia. Eyes with macula-off RD tended to show micropsia, while those with macula-on RD mostly presented macropsia. Micropsia and macropsia were primarily caused by respective specific abnormal structures at the foveal region. PMID- 25034598 TI - Bis(zinc-dipicolylamine), Zn-DPA, a new marker for apoptosis. AB - PURPOSE: To characterize the labeling of apoptotic cells with a molecular probe of bis(zinc(II)-dipicolylamine) (Zn-DPA) conjugated with a fluorescent reporter in a rat model of retinal ganglion cell (RGC) degeneration induced by N-methyl-D aspartate (NMDA). METHODS: Adult Wistar rats were given unilateral intravitreal injections of 3 MUL 40 mM neutralized NMDA and euthanized at 1, 2, 4, 24, and 48 hours. One hour before euthanasia, 3 MUL Zn-DPA conjugated with fluorescein (Zn DPA 480) was intravitreally injected. Prelabeling of RGC with retrograde fluorogold (FG), TUNEL, and immunohistochemistry with III beta-tubulin and vimentin were performed. RESULTS: Fluorescence labeling of Zn-DPA 480 was observed in the retinas from 1 hour up to 24 hours after NMDA injection, whereas the labeling was reduced at 48 hours postinjection. At both 4 and 24 hours postinjection, most Zn-DPA 480-positive cells in the RGC layer were labeled by FG and III beta-tubulin. The number of TUNEL-positive cells increased from 4 to 24 hours. At 24 hours, 95.7% of Zn-DPA 480-positive cells were TUNEL positive, whereas 95.1% of TUNEL-positive cells were Zn-DPA 480 positive. The numbers of Zn DPA 480-positive cells at 1 and 2 hours after NMDA injection were significantly higher than TUNEL. CONCLUSIONS: Our findings demonstrate that intravitreal injection of fluorescent Zn-DPA 480 labels retinal neurons undergoing apoptosis and that recognition of exposed phosphatidylserine appears earlier than detection of DNA fragmentation, indicating the potential of Zn-DPA as an imaging probe for tracking degenerating retinal neurons. PMID- 25034600 TI - Topical administration of lacritin is a novel therapy for aqueous-deficient dry eye disease. AB - PURPOSE: Lacritin is a tear glycoprotein with prosecretory, prosurvival, and mitogenic properties. We examined lacritin levels in the tears of Sjogren's syndrome (SS) patients and explored the therapeutic potential of topical lacritin for the treatment of keratoconjunctivitis sicca. METHODS: Tears from healthy controls (n = 14) and SS patients (n = 15) were assayed for lacritin using a C terminal antibody. In a paired-eye study, autoimmune regulator (Aire) knockout (KO) mice (n = 7) were treated three times daily for 21 days with 10 MUL of 4 MUM lacritin (left eye) or vehicle (PBS) control (right eye). Tear secretion and ocular surface integrity were assessed at baseline and after treatment. Immunohistochemical staining of CD4+ T cells, cytokeratin-10 (K10), and cytokeratin-12 (K12) expression in the cornea and CD4+ T cell infiltration in the lacrimal glands were assessed. RESULTS: Lacritin monomer (421.8 +/- 65.3 ng [SS] vs. 655.8 +/- 118.9 ng [controls]; P = 0.05) and C-terminal fragment protein (125 +/- 34.1 ng [SS] vs. 399.5 +/- 84.3 ng [controls]; P = 0.008) per 100 MUL of tear eluate were significantly lower in SS patients. In Aire KO mice treated with lacritin, tear secretion increased by 46% (13.0 +/- 3.5 mm vs. 8.9 +/- 2.9 mm; P = 0.01) and lissamine green staining score significantly decreased relative to baseline (-0.417 +/- 0.06 vs. 0.125 +/- 0.07; P = 0.02). Expression of K10 but not K12 in the cornea was significantly decreased in lacritin-treated eyes. Focal CD4+ T cell infiltration of the lacrimal glands was significantly reduced on the lacritin-treated side versus the untreated side. CONCLUSIONS: Lacritin is significantly reduced in the tears of SS patients. Topically administered lacritin has therapeutic potential for the treatment of aqueous-deficient dry eye disease. PMID- 25034601 TI - Changes in rod and cone-driven oscillatory potentials in the aging human retina. AB - PURPOSE: We recorded oscillatory potentials (OPs) to document how age impacts on rod- and cone-driven inner retina function. METHODS: Dark- and light-adapted electroretinogram (ERG) luminance-response functions were recorded in healthy human subjects aged 20 to 39, 40 to 59, and 60 to 82 years. Raw ERG traces (0.1 300 Hz) were filtered (75-300 Hz) to measure OPs trough-to-peak in the time amplitude domain. Morlet wavelet transform (MWT) allowed documenting OPs time amplitude-frequency distribution from raw traces. RESULTS: Under dark adaptation, both methods revealed reduced OP amplitudes and prolonged implicit times by 40 years of age. The MWT identified a high-frequency band as the main oscillator, which frequency (150-155 Hz) was unaffected by age. Under light adaptation, most OP peaks were delayed by 40 years of age. Peak-trough measures yielded inconsistent results in relation to luminance. Contrastingly, MWT distinguished two frequency bands at all luminances: high frequency (135 +/- 6 Hz) time locked to the onset of early OPs and low frequency (82 +/- 7 Hz), giving rise to early and late OPs. By 60 years, there was a consistent power reduction specific to the low-frequency band. CONCLUSIONS: Age-related OP changes precede those seen with a (photoreceptoral) and b-waves (postphotoreceptoral). In addition, MWT allows quantifying distinct low- and high-frequency oscillators in the human retina, which complement traditional OP analysis methods. The identification of an age independent OP marker (light-adapted high frequency band) opens a new dimension for the screening of retinal degenerations and their impact on inner retina function. PMID- 25034603 TI - The effects of different culture media on human corneal endothelial cells. AB - PURPOSE: To investigate the most appropriate media condition for the proliferation and functional maintenance of human corneal endothelial cells (HCECs). METHODS: We cultured HCECs in traditional media (medium A or D) and in stem cell media (medium E or N). The morphology of the cells was evaluated by inverted microscopy. Collagen, type VIII, alpha 2 and sodium-potassium adenosine triphosphatase (Na(+)-K(+) ATPase) expression were analyzed as differentiation markers. Octamer-binding transcription factor 3/4, glial fibrillary acidic protein, nestin and beta-catenin expression were evaluated as stem cell associated proteins. The cell proliferation rate was evaluated with a cell counting kit-8 assay. Wound healing assays were also performed. The transendothelial electrical potential difference (TEPD) value was used to estimate the endothelial cell permeability in vitro. RESULTS: The proliferation and morphology analyses demonstrated that there were significant differences between the media. The expression of differentiation markers and stem cell associated proteins was different between the media. Medium D resulted in higher proliferation rates compared with the other media, while still maintaining the differentiation potential and surface marker expression profile characteristic of HCECs. Compared with other media, TEPD was higher in medium N. CONCLUSIONS: Culture medium D was superior to the other media with regard to the expression of stem cell-associated proteins, proliferation, and cell migration. However, medium N was more appropriate than the other three media with regard to maintaining the proper cell shape and function. PMID- 25034602 TI - Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium. AB - PURPOSE: Lipofuscin (LF) accumulation within RPE cells is considered pathogenic in AMD. To test whether LF contributes to RPE cell loss in aging and to provide a cellular basis for fundus autofluorescence (AF) we created maps of human RPE cell number and histologic AF. METHODS: Retinal pigment epithelium-Bruch's membrane flat mounts were prepared from 20 donor eyes (10 <= 51 and 10 > 80 years; postmortem: <=4.2 hours; no retinal pathologies), preserving foveal position. Phalloidin-binding RPE cytoskeleton and LF-AF (488-nm excitation) were imaged at up to 90 predefined positions. Maps were assembled from 83,330 cells in 1470 locations. From Voronoi regions representing each cell, the number of neighbors, cell area, and total AF intensity normalized to an AF standard was determined. RESULTS: Highly variable between individuals, RPE-AF increases significantly with age. A perifoveal ring of high AF mirrors rod photoreceptor topography and fundus AF. Retinal pigment epithelium cell density peaks at the fovea, independent of age, yet no net RPE cell loss is detectable. The RPE monolayer undergoes considerable lifelong re-modeling. The relationship of cell size and AF, a surrogate for LF concentration, is orderly and linear in both groups. Autofluorescence topography differs distinctly from the topography of age-related rod loss. CONCLUSIONS: Digital maps of quantitative AF, cell density, and packing geometry provide metrics for cellular-resolution clinical imaging and model systems. The uncoupling of RPE LF content, cell number, and photoreceptor topography in aging challenges LF's role in AMD. PMID- 25034604 TI - Vascular dysfunction in ocular blood flow regulation: impact of reactive oxygen species in an experimental setup. AB - PURPOSE: Glaucoma is associated with an altered blood flow and increased levels of reactive oxygen species (ROS). Reactive oxygen species can have opposing influences on the tone of a vessel; depending on the condition and type of the vessel, ROS can induce vasodilation or vasoconstriction. In the present study, we investigated the impact of ROS on the tone of rat ophthalmic arteries under various conditions and present data on the underlying mechanisms. METHODS: Freshly dissected rat ophthalmic arteries were pressurized in a perfusion setup to 80 mm Hg, at which a stable myogenic tone was observed. After various pretreatments (e.g., removal of endothelium, partial depolarization to -41 mV, blocking of the Na(+)/Ca(2+)-exchanger (NCX) in reverse mode by KB-R7943, or blocking of the Na(+)/K(+)-ATPase by ouabain), the vessels were exposed to ROS. Vessel diameter was continuously recorded and values before and after treatment compared. RESULTS: Stable myogenic tone of vessels with and without endothelium was established at a pressure of 80 mm Hg. At the physiological resting membrane potential, ROS exposure led to a significant vasodilatation, which was significantly reduced by pretreatment with ouabain. After depolarization to -41 mV, ROS exposure led to vasoconstriction. Blocking the NCX in reverse mode using KB-R7943 completely abolished this ROS-induced vasoconstriction. CONCLUSIONS: At resting potential, ROS provoke dilation; however, in precontracted vessels they act synergistically and induce further vasoconstriction. In diseases involving altered blood flow through altered vascular tone (e.g., vasospasms), ROS may influence blood flow and may thereby contribute indirectly to further disease progression. PMID- 25034605 TI - Wnt modulators in the aqueous humor are associated with outer retinal damage severity in patients with neovascular age-related macular degeneration. AB - PURPOSE: To investigate the associations of the Wnt modulators Wnt inhibitory factor 1 (WIF-1) and Dickkopf 3 (DKK-3) in the aqueous humor with neovascular age related macular degeneration (nAMD) and to determine their clinical implications. METHODS: Seventy-four nAMD patients initially treated with an intravitreal injection of ranibizumab (IVR) and 74 age- and sex-matched controls were studied. Aqueous humor WIF-1 and DKK-3 levels were measured by Western blotting and an ELISA before and 1 month after two consecutive IVRs (pre- and post-IVR). Visual acuity assessments and spectral domain optical coherence tomography were performed pre- and post-IVR. RESULTS: Western blotting showed increased WIF-1 and DKK-3 in 12 nAMD patients compared with 12 controls. The ELISA analysis demonstrated elevated WIF-1 (pre) and DKK-3 (pre) in 62 patients compared with 62 controls (54.7 vs. 23.0 and 114.3 vs. 93.0 ng/mL, respectively). In multivariate analyses, high WIF-1 (pre) levels were associated with increased disruption in the photoreceptor junction's inner and outer segments (IS/OS) (pre and post) and high WIF-1 (post) levels. Interestingly, WIF-1 (pre) levels were significantly higher in type 3 neovascularization (NV) patients than in type 1 or 2 NV (90.5 +/ 36.7 vs. 48.3 +/- 22.5 and 41.3 +/- 28.8 ng/mL, respectively). However, choroidal thickness was not correlated with WIF-1 levels. CONCLUSIONS: We report, for the first time, the possibility of phenotypic, anatomic, and ocular proteomic correlations, demonstrating correlated WIF-1 and DKK-3 upregulation in nAMD patients' aqueous humor. Secreted WIF-1, reflecting the degree of retinal structure damage, may be a new biomarker for the retina's healthy and disease states. PMID- 25034606 TI - TSG-6 protects corneal endothelium from transcorneal cryoinjury in rabbits. AB - PURPOSE: To investigate the effect of an anti-inflammatory protein, TNF-alpha stimulated gene/protein (TSG)-6 and an antiapoptotic protein, stanniocalcin (STC) 1 on corneal endothelium in rabbits with transcorneal cryoinjury. METHODS: Transcorneal freezing (-80 degrees C) was applied to rabbit corneas for 30 seconds. Immediately post injury, either TSG-6 (10 MUg/100 MUL), STC-1 (10 MUg/100 MUL), or the same volume of balanced salt solution (BSS) was injected into the anterior chamber. Each eye was examined for corneal opacity, corneal thickness, endothelial cell density, and endothelial hexagonality every 2 to 6 hours for 48 hours post injury. The concentrations of myeloperoxidase (MPO) and IL-1beta were measured in the aqueous humor every 6 hours. At 48 hours post injury, each cornea was assayed for TNF-alpha, IL-1beta, IL-6, and MPO, and histologically evaluated with alizarin red-trypan blue staining, hematoxylin eosin staining, and immunostaining for neutrophils. RESULTS: Tumor necrosis factor-alpha stimulated gene/protein-6 significantly decreased the development of corneal opacity and edema after cryoinjury compared with STC-1 or BSS. The corneal endothelial cell density and hexagonality were markedly preserved by TSG 6. The mRNA levels of TNF-alpha, IL-1beta, and IL-6 in the cornea and the protein levels of MPO and IL-1beta in the aqueous humor and cornea were significantly lower in TSG-6-treated eyes than BSS-treated controls. Similarly, the expression of fibroblast growth factor-2 was reduced by TSG-6 treatment. Histologic evaluation demonstrated that neutrophil infiltration of the cornea was decreased in TSG-6-treated eyes. CONCLUSIONS: Tumor necrosis factor-alpha stimulated gene/protein-6 protected corneal endothelial cells from transcorneal cryoinjury through suppression of inflammation. PMID- 25034607 TI - A mouse model for studying cone photoreceptor pathologies. AB - PURPOSE: Due to the low abundance of cone photoreceptors in the mouse retina and the scarcity of alternative animal models, little is known about mechanisms of cone degeneration. Nrl knockout mice develop exclusively the cone-type of photoreceptors. However, the cone photoreceptor layer in Nrl(-/-) mice displays an irregular morphology with severe rosette formation. Retinas of Rpe65(-/-);Nrl( /-) mice have no rosettes due to the lack of 11-cis-retinal, but also are not functional. To develop a model with a functional all-cone retina that is morphologically well structured, we generated R91W;Nrl(-/-) double-mutant mice, which express a hypomorphic Rpe65 allele (R91W). METHODS: The following analyses were used to characterize the R91W;Nrl(-/-)mice: morphology by light and electron microscopy, protein distribution by immunofluorescence, cone function by electroretinography and optomotor response, RNA levels by RT-PCR, and chromophore levels by HPLC. Cone degeneration was assessed in R91W;Nrl(-/-) mice treated with MNU, and in triple R91W;Nrl(-/-);Cpfl1 and quadruple R91W;Nrl(-/-);Cpfl1;rd10 mutant mice. RESULTS: The all-cone retina of R91W;Nrl(-/-) mice is functional and relatively stable with only very slow age-related degeneration. Using triple and quadruple mutant mice, or a chemical treatment, we demonstrated that cone degeneration could be induced and analyzed in these mice. CONCLUSIONS: The reduced levels of visual chromophore prevented rosette formation and sustained function in the R91W;Nrl(-/-) retina. Thus, the R91W;Nrl(-/-) mouse allows study of the etiology of diseases related to cone degeneration in a "morphologically intact" and functional all-cone photoreceptor retina. PMID- 25034609 TI - Intrauterine diagnosis and pathology of fetal choroid plexus carcinoma--a case study. AB - This is a case report of a 39-year-old pregnant woman whose fetus was found to have a large hydrocephalus on routine prenatal ultrasound at the 29th gestational week. A 56 mm * 73 mm mass was detected in the fetal brain arising from the brainstem and invading the third cerebral ventricle. On the subsequent fetal cranial MRI, T2-weighted image the tumor measured 55 mm * 50 mm * 48 mm and had a non-homogeneous consistency and irregular contours. Elective cesarean section was performed during gestational week 32, delivering a male fetus with a cranial circumference of 46 cm (normal circumference, 30 cm) and a birth weight of 2920 g. The infant expired 4h following delivery. Autopsy revealed a carcinoma of the choroid plexus. Our case, like others, suggests that MRI is more accurate than prenatal ultrasound in prenatal brain tumor diagnosis. More precise morphological detail is provided by MRI, which improves surgical planning and survival. PMID- 25034608 TI - Structural dynamic analysis of apo and ATP-bound IRAK4 kinase. AB - Interleukin-1 receptor-associated kinases (IRAKs) are Ser/Thr protein kinases that play an important role as signaling mediators in the signal transduction facilitated by the Toll-like receptor (TLR) and interleukin-1 receptor families. Among IRAK family members, IRAK4 is one of the drug targets for diseases related to the TLR and IL-1R signaling pathways. Experimental evidence suggests that the IRAK4 kinase domain is phosphorylated in its activation loop at T342, T345, and S346 in the fully activated state. However, the molecular interactions of subdomains within the active and inactive IRAK4 kinase domain are poorly understood. Hence, we employed a long-range molecular dynamics (MD) simulation to compare apo IRAK4 kinase domains (phosphorylated and unphosphorylated) and ATP bound phosphorylated IRAK4 kinase domains. The MD results strongly suggested that lobe uncoupling occurs in apo unphosphorylated IRAK4 kinase via the disruption of the R334/T345 and R310/T345 interaction. In addition, apo unphosphorylated trajectory result in high mobility, particularly in the N lobe, activation segment, helix alphaG, and its adjoining loops. The Asp-Phe-Gly (DFG) and His-Arg Asp (HRD) conserved kinase motif analysis showed the importance of these motifs in IRAK4 kinase activation. This study provides important information on the structural dynamics of IRAK4 kinase, which will aid in inhibitor development. PMID- 25034610 TI - Of shifting economies and making ends meet: the changing role of the accompagnant at the Fann Psychiatric Clinic in Dakar, Senegal. AB - Since 1972, inpatients at the Fann Psychiatric Clinic have been required to have a family member or close friend--an accompagnant--stay with them for the duration of their hospitalization. In recent years, however, the role of the accompagnant has seen a dramatic transformation. This article considers the emergence of a new kind of accompagnant at Fann: the for-hire accompagnant mercenaire, who is unrelated to the patient and not employed by the clinic. Against the backdrop of Senegal's neoliberal turn and in light of the growing prominence of the biomedical approach at Fann, the author shows how the idealized accompagnant model of family caretaking has given way to this new form of commodified care. At the same time, however, the author argues that accompagnants mercenaires regularly draw upon and establish new sets of moral codes, obligations, debts, and expectations in their day-to-day interactions with patients, family members, and staff alike. By way of a careful ethnographic examination of the evolution of the accompagnant role at Fann, this article brings into focus a complex and multidimensional picture of the shifting economies--moral and political, as well as therapeutic--within the present-day clinic. PMID- 25034611 TI - Effortful versus automatic emotional processing in schizophrenia: Insights from a face-vignette task. AB - Adaptive emotional responding relies on dual automatic and effortful processing streams. Dual-stream models of schizophrenia (SCZ) posit a selective deficit in neural circuits that govern goal-directed, effortful processes versus reactive, automatic processes. This imbalance suggests that when patients are confronted with competing automatic and effortful emotional response cues, they will exhibit diminished effortful responding and intact, possibly elevated, automatic responding compared to controls. This prediction was evaluated using a modified version of the face-vignette task (FVT). Participants viewed emotional faces (automatic response cue) paired with vignettes (effortful response cue) that signalled a different emotion category and were instructed to discriminate the manifest emotion. Patients made less vignette and more face responses than controls. However, the relationship between group and FVT responding was moderated by IQ and reading comprehension ability. These results replicate and extend previous research and provide tentative support for abnormal conflict resolution between automatic and effortful emotional processing predicted by dual stream models of SCZ. PMID- 25034612 TI - A systematic review of the impact of patient and public involvement on service users, researchers and communities. AB - OBJECTIVE: Patient and public involvement (PPI) in research has expanded nationally and internationally over the last decade, and recently there has been significant attention given to understanding its impact on research. Less attention has been given to the impact of PPI on the people involved, yet it has been shown that the success of PPI in research can be reliant on the processes of engagement between these individuals and communities. This paper therefore critically explores the impact of PPI on service users, researchers and communities involved in health and social care research. DATA SOURCES: Searches were undertaken from 1995 to April 2012 in the electronic databases MEDLINE, EMBASE, PsycINFO, Cochrane library, CINAHL, HMIC and HELMIS. Searches were undertaken for grey literature using the databases InvoNet and NHS Evidence. STUDY SELECTION: Studies were included if they included the impact of PPI on individual service users, researchers or communities under research. Studies were excluded if they were in a foreign language (unless they were deemed critical to the systematic review) or were in children and adolescent services. STUDY APPRAISAL: Data were extracted using a narrative synthesis, and quality was assessed using the Critical Appraisal Skills Programme. MAIN RESULTS: Service users reported feeling empowered and valued, gaining confidence and life skills. Researchers developed a greater understanding and insight into their research area, gaining respect and a good rapport with the community. The community involved in research became more aware and knowledgeable about their condition. However, lack of preparation and training led some service users to feel unable to contribute to the research, while other service users and communities reported feeling overburdened with the work involved. Researchers reported difficulties in incorporating PPI in meaningful ways due to lack of money and time. CONCLUSION: This is the first international systematic review to focus on the impact of PPI on the people involved in the process. The beneficial and challenging impacts reported highlight the importance of optimising the context and processes of involvement, so creating the potential for PPI to impact positively on the research itself. PMID- 25034613 TI - Tabletop imaging of structural evolutions in chemical reactions demonstrated for the acetylene cation. AB - The introduction of femto-chemistry has made it a primary goal to follow the nuclear and electronic evolution of a molecule in time and space as it undergoes a chemical reaction. Using Coulomb Explosion Imaging, we have shot the first high resolution molecular movie of a to and fro isomerization process in the acetylene cation. So far, this kind of phenomenon could only be observed using vacuum ultraviolet light from a free-electron laser. Here we show that 266 nm ultrashort laser pulses are capable of initiating rich dynamics through multiphoton ionization. With our generally applicable tabletop approach that can be used for other small organic molecules, we have investigated two basic chemical reactions simultaneously: proton migration and C=C bond breaking, triggered by multiphoton ionization. The experimental results are in excellent agreement with the timescales and relaxation pathways predicted by new and quantitative ab initio trajectory simulations. PMID- 25034614 TI - Asphodosides A-E, anti-MRSA metabolites from Asphodelus microcarpus. AB - Bioassay guided fractionation of the ethanolic extract of Asphodelus microcarpus Salzm. et Viv. (Xanthorrhoeaceae or Asphodelaceae) resulted in isolation of five compounds identified as asphodosides A-E (1-5). Compounds 2-4 showed activity against methicillin resistant Staphylococcus aureus (MRSA) with IC50 values of 1.62, 7.0 and 9.0MUg/mL, respectively. They also exhibited activity against Staphylococcus aureus (non-MRSA) with IC50 values of 1.0, 3.4 and 2.2MUg/mL, respectively. The structure elucidation of isolated metabolites was carried out using spectroscopic data (1D and 2D NMR), optical rotation and both experimental and calculated electronic circular dichroism (ECD). PMID- 25034615 TI - Volatile compounds in cryptic species of the Aneura pinguis complex and Aneura maxima (Marchantiophyta, Metzgeriidae). AB - Aneura pinguis is one of the liverwort species complexes that consist of several cryptic species. Ten samples collected from different regions in Poland are in the focus of our research. Eight of the A. pinguis complex belonging to four cryptic species (A, B, C, E) and two samples of closely related species Aneura maxima were tested for the composition of volatile compounds. The HS-SPME technique coupled to GC/FID and GC/MS analysis has been applied. The fiber coated with DVB/CAR/PDMS has been used. The results of the present study, revealed the qualitative and quantitative differences in the composition of the volatile compounds between the studied species. Mainly they are from the group of sesquiterpenoids, oxygenated sesquiterpenoids and aliphatic hydrocarbons. The statistical methods (CA and PCA) showed that detected volatile compounds allow to distinguish cryptic species of A. pinguis. All examined cryptic species of the A. pinguis complex differ from A. maxima. Species A and E of A. pinguis, in CA and PCA, form separate clusters remote from two remaining cryptic species of A. pinguis (B and C) and A. maxima. Relationship between the cryptic species appeared from the chemical studies are in accordance with that revealed on the basis of DNA sequences. PMID- 25034616 TI - Experiences of patients undergoing anti-VEGF treatment for neovascular age related macular degeneration: a systematic review. AB - Current therapy to slow disease progression in patients with neovascular age related macular degeneration (AMD) often entails intra-vitreal injection of an anti-vascular endothelial growth factor (VEGF) agent, that begins with a three month loading phase of four weekly injections followed by regular monthly visits with clinician-determined re-treatment. The effects of AMD on quality of life and visual function have been extensively reported in the literature, however, less is known about the burden imposed on patients by the arduous and often indefinite treatment schedule which habitually follows a diagnosis of wet AMD. To date, no systematic review has been conducted of research investigating patients' experiences of anti-VEGF treatment for AMD. A systematic search of the Embase, Medline, PsycINFO and PubMed electronic databases was undertaken to identify all studies between January 2004 and December 2013, published in the English language and involving human participants. A hand-search of an additional four journals was conducted. Ten articles were identified for inclusion in this review. A critical appraisal was undertaken using the Critical Appraisal Skills Programme Qualitative Research Checklist and the results synthesised to form a narrative review. Few studies to date have investigated patients' experiences of treatment for AMD. These studies have focused primarily on patients' experiences of the injection procedure with respect to pain and anxiety. Anticipated discomfort is often greater than actual discomfort experienced during intra-vitreal injection. However, different stages of the treatment procedure produce varying levels of patient discomfort. No one method of anaesthesia has consistently been shown to be more effective in reducing discomfort associated with treatment. Common reasons underlying patient apprehension surrounding treatment include the thought of having an injection, fear of losing eyesight and fear of the unknown. Whilst these studies have not been without their methodological limitations, they provide a platform for further exploration of the patient experience. PMID- 25034617 TI - Bio-specific and bio-orthogonal chemistries to switch-off the quencher of a FRET based fluorescent probe: application to living-cell biothiol imaging. AB - We report the first molecular system that is responsive to both a bio-specific and a bio-orthogonal stimulus. This dual activation process was applied to the design of a biothiol-specific FRET-based fluorescent probe that could be turned on via an original concept of quencher bleaching. PMID- 25034618 TI - Pharmacokinetic comparison of amlodipine adipate/valsartan fixed-dose combination with amlodipine besylate/valsartan fixed-dose combination in healthy volunteers. AB - The aim of this study was to compare pharmacokinetic characteristics of fixed dose combination (FDC) of two different salt form of amlodipine, amlodipine adipate/valsartan and amlodipine besylate/ valsartan, in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two treatment, two-way crossover study with a 14-day wash-out period was conducted. Plasma samples were collected for up to 144 hours for amlodipine and 24 hours for valsartan. Plasma concentrations of amlodipine and valsartan were analyzed using a validated ultra-performance liquid chromatography tandem mass-spectrometry. A non-compartmental method was used to calculate pharmacokinetic parameters. Vital signs and adverse events were monitored and physical examinations, laboratory tests, and electrocardiograms were conducted to evaluate safety. 44 subjects completed the study. The 90% CIs for the geometric mean ratio of Cmax and the AUC0-t were 93.5 - 100.4% and 93.2 - 98.3% for amlodipine, and 92.1 - 121.3% and 94.1 - 115.2% for valsartan, respectively. 17 adverse events occurred in 15 subjects during the study; 5 and 7 adverse drug reactions from the 5 and 6 subjects were considered to probably be related to the test and reference treatments respectively. All adverse drug reactions were in line with those known for the reference drug. All subjects recovered fully with no sequelae. A FDC of amlodipine adipate/valsartan and amlodipine besylate/valsartan combination tablets met the regulatory criteria for bioequivalence. In addition, no significant difference was observed in the safety assessments between two treatments. Thus, the newly developed FDC of amlodipine adipate/valsartan seems to be interchangeable with amlodipine besylate valsartan combination. PMID- 25034619 TI - Investigation of the relationship between a starting dose in first-in-human studies and no observed adverse effect level in nonclinical studies. AB - OBJECTIVE: A starting dose in first-in-human (FIH) studies has been determined carefully to guarantee the safety of participants in the study but sometimes it seems to be too conservative. The objective of the present study is to investigate a reasonable safety factor to enable effective drug development without serious safety problems in study participants. METHODS: No-observed adverse-effect levels (NOAELs) in nonclinical studies, starting doses in FIH studies, and approved doses in Japan were reviewed by documents disclosed by health authorities, and the relationships among each parameter were analyzed retrospectively. RESULTS: The present study suggested that the starting doses in the past FIH studies had been determined very prudently, and revealed that there were significant differences between the starting dose and approved dose. CONCLUSION: It would be possible to develop new drugs effectively without serious safety risks if a reasonable safety factor had been applied to determine a starting dose in FIH studies. PMID- 25034620 TI - Estimation of hyper-parameters for a hierarchical model of combined cortical and extra-brain current sources in the MEG inverse problem. AB - One of the major obstacles in estimating cortical currents from MEG signals is the disturbance caused by magnetic artifacts derived from extra-cortical current sources such as heartbeats and eye movements. To remove the effect of such extra brain sources, we improved the hybrid hierarchical variational Bayesian method (hyVBED) proposed by Fujiwara et al. (NeuroImage, 2009). hyVBED simultaneously estimates cortical and extra-brain source currents by placing dipoles on cortical surfaces as well as extra-brain sources. This method requires EOG data for an EOG forward model that describes the relationship between eye dipoles and electric potentials. In contrast, our improved approach requires no EOG and less a priori knowledge about the current variance of extra-brain sources. We propose a new method, "extra-dipole," that optimally selects hyper-parameter values regarding current variances of the cortical surface and extra-brain source dipoles. With the selected parameter values, the cortical and extra-brain dipole currents were accurately estimated from the simulated MEG data. The performance of this method was demonstrated to be better than conventional approaches, such as principal component analysis and independent component analysis, which use only statistical properties of MEG signals. Furthermore, we applied our proposed method to measured MEG data during covert pursuit of a smoothly moving target and confirmed its effectiveness. PMID- 25034621 TI - Left atrial functional reservoir: predictive value for outcome of catheter ablation in paroxysmal atrial fibrillation. AB - Left arial (LA) function, defined according to conduit, reservoir and booster functions, is closely linked to left ventricular (LV) mechanics, particularly during diastole. Right ventricular pacing (RVP) is thought to impair LA diastolic restoring forces through alteration of ventricular activation. The aim of this study was to determine whether the LA functional reservoir estimated as the change in mean LA ejection fraction (EF) immediately after RVP, and for the second and for the third beats after RVP, predicts clinical outcome in patients with paroxysmal atrial fibrillation (AF) who have undergone catheter ablation (CA). Data from 155 patients with paroxysmal AF (56.0 +/- 10.6 years, M:F = 114:41) were analyzed. All patients underwent LA angiography during RVP. LA EFs were measured at the immediate first (LA EF(1)), second (LA EF(2)) and third beats (LA EF(3)) after RVP, using a right anterior oblique 30 degrees view. During follow-up, AF recurred in 35 patients (22.6 %). Mean LA EF(1) was 37.9 +/- .8 % in the AF recurrence group and 48.0 +/- 8.6 % in the non-recurrence group (P < 0.001). Mean LA EF(2) and LA EF(3) were also lower in the AF recurrence group than in the non-recurrence group (P < 0.001, respectively). Mean percent changes from LA EF(2) to LA EF(3) were -0.4 +/- 3.4 in the AF recurrence group and 5.2 +/ 4.9 in the non-recurrence group (P = 0.041). The change in mean EF from LA EF(1) to LA EF(3) in the non-recurrence group was significantly greater than in the recurrence group (P = 0.001). Cox regression analysis showed that predictors of AF recurrence were LA EF(2), LA EF(3) and accompanied obstructive sleep apnea (OSA) (P < 0.001, respectively). Decreased functional LA reservoir (LA EF after RVP) and OSA are significantly related to recurrence of AF following CA in patients with paroxysmal AF. PMID- 25034622 TI - Determination of inulin-type fructooligosaccharides in edible plants by high performance liquid chromatography with charged aerosol detector. AB - Fructooligosaccharides (FOS), which are regarded as functional ingredients, are commonly classified as dietary fibers in many countries. However, few analytical methods for separation and analysis of individual FOS in plants, crops, and food products have been developed. In this study, a simple, rapid, and sensitive high performance liquid chromatography with charged aerosol detector (HPLC-CAD) method was developed for simultaneous determination of 11 inulin-type FOS with degree of polymerization (DP) 3-13 in different samples. The separation was performed on a Waters XBridge Amide column (4.6 * 250 mm i.d., 3.5 MUm) with gradient elution. All calibration curves for investigated analytes showed good linear regression (R(2) > 0.9962). Their limits of detection (LOD) and quantification (LOQ) were in the ranges 0.4-0.6 MUg/mL and 1.4-2.3 MUg/mL, respectively. The recoveries ranged from 94.0% to 114.4%. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to qualitative analysis of FOS in different samples. The developed method was successfully applied to analysis of 11 FOS in different samples of plants from Compositae, Campanulaceae, and Rubiaceae families. The developed HPLC-CAD nethod with microwave-assisted extraction can be used for quantitative analysis of FOS and is helpful for quality control of plants containing FOS. PMID- 25034623 TI - A highly efficient hybrid GaAs solar cell based on colloidal-quantum-dot sensitization. AB - This paper presents a hybrid design, featuring a traditional GaAs-based solar cell combined with various colloidal quantum dots. This hybrid design effectively boosts photon harvesting at long wavelengths while enhancing the collection of photogenerated carriers in the ultraviolet region. The merits of using highly efficient semiconductor solar cells and colloidal quantum dots were seamlessly combined to increase overall power conversion efficiency. Several photovoltaic parameters, including short-circuit current density, open circuit voltage, and external quantum efficiency, were measured and analyzed to investigate the performance of this hybrid device. Offering antireflective features at long wavelengths and luminescent downshifting for high-energy photons, the quantum dots effectively enhanced overall power conversion efficiency by as high as 24.65% compared with traditional GaAs-based devices. The evolution of weighted reflectance as a function of the dilution factor of QDs was investigated. Further analysis of the quantum efficiency response showed that the luminescent downshifting effect can be as much as 6.6% of the entire enhancement of photogenerated current. PMID- 25034624 TI - Utility of [18 F]FLT-PET to assess treatment response in trastuzumab-resistant and trastuzumab-sensitive HER2-overexpressing human breast cancer xenografts. AB - PURPOSE: The objective of this study was to evaluate 3'-deoxy-3'-[(18) F]fluorothymidine ([(18) F]FLT) positron emission tomography (PET) as an early marker of trastuzumab response in HER2-overexpressing xenografts. PROCEDURES: Tumor-to-muscle ratios were compared between both trastuzumab-sensitive and trastuzumab-resistant cohorts prior to and after one and two treatments. RESULTS: A significant difference (P = 0.03) was observed between treated and control trastuzumab-sensitive xenografts after one treatment, which preceded between group differences in tumor volume. Reduced Ki67 (P = 0.02) and thymidine kinase 1 (TK1) (P = 0.35) immunoreactivity was observed in the treated xenografts. No significant differences in volume, tumor-to-muscle ratio, or immunoreactivity were observed between treated and control trastuzumab-resistant cohorts. A significant difference (P = 0.02) in tumor-to-muscle ratio was observed between trastuzumab-sensitive and trastuzumab-resistant cohorts after two treatments; however, tumor volumes were also different (P = 0.04). Ki67 (P = 0.04) and TK1 (P = 0.24) immunoreactivity was ~50 % less in trastuzumab-sensitive xenografts. CONCLUSIONS: [(18) F]FLT-PET provided early response assessment in trastuzumab sensitive xenografts but only differentiated between trastuzumab-resistant and trastuzumab-sensitive xenografts concurrent with differences in tumor size. PMID- 25034625 TI - Phase II study of pemetrexed and erlotinib in pretreated nonsquamous, non-small cell lung cancer patients without an EGFR mutation. AB - BACKGROUND: Preclinical data indicated that the combination of erlotinib and pemetrexed is synergistic when erlotinib is administered after pemetrexed. PATIENTS AND METHODS: This was a phase II study of pemetrexed and erlotinib in patients with pretreated advanced non-squamous non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR). Chemotherapy consisted of pemetrexed (500 mg/m(2)) on day 1 and erlotinib (150 mg/body) on days 2-15 every 3 weeks. The protocol treatment was repeated until disease progression or intolerable toxicities occurred. RESULTS: Seventeen patients were enrolled between January 2010 and January 2013, and 15 patients were evaluable for both safety and efficacy. The study was terminated due to slow patient accrual. There was 1 complete response. There was a partial response in 3 patients, stable disease in 4 and progressive disease in 7. The response rate was 27% and disease control rate was 53%. The median progression-free survival and overall survival were 2.5 months and 6.7 months, respectively. CONCLUSIONS: Statistical interpretation could not been made due to the early termination of the study. Further studies are needed to clarify the efficacy of this regimen in NSCLC patients without EGFR mutation (UMIN-CTR No. 0000024531). PMID- 25034626 TI - Regular change in spontaneous preparative behaviour on intra-abdominal pressure and breathing during dynamic lifting. AB - PURPOSE: Intra-abdominal pressure (IAP) and breathing behaviour are important preparative pre-lifting actions for functional stability during lifting. This study aimed to examine spontaneous changes in the peak rate of IAP development (Rate-IAP), peak IAP (Peak-IAP), the time of Rate- and Peak-IAP occurrence and respiratory volume in response to dynamic load lifting. METHODS: Eleven healthy men performed quick dynamic deadlifting using 30, 45, 60 and 75% of the isometric maximal lifting effort (iMLE). IAP was measured using an intrarectal pressure transducer. The spontaneous respiratory volume was calculated from air flow data using pneumotachography. The lifting motion onset was determined from the hip joint motion using an electrogoniometer. RESULTS: From 30 to 75% of the iMLE, Rate-IAP occurred early from 2 +/- 28 to -179 +/- 16 ms (P < 0.01), whereas Peak IAP occurred late from 165 +/- 31 to 82 +/- 23 ms (P = 0.12) relative to the lifting motion onset. Rate-IAP increased from 224 +/- 47 to 507 +/- 69 mmHg/s (P < 0.01), whereas Peak-IAP increased from 37 +/- 8 to 90 +/- 11 mmHg (P < 0.01) at 30-75% of the iMLE. Rate-IAP strongly correlated with Peak-IAP at each lifting load (r = 0.94-0.97). Relative to the resting tidal volume, the inspiratory volume during pre-lifting significantly increased above 60% of the iMLE, whereas expiratory volume significantly decreased at all lifting loads. CONCLUSIONS: Preparative pre-lifting behaviours alter IAP and breathing and are co-ordinated by the lifting load magnitude. These behaviours appear to be functionally important for dynamic lifting. PMID- 25034627 TI - Altered neuromuscular control of leg stiffness following soccer-specific exercise. AB - PURPOSE: To examine changes to neuromuscular control of leg stiffness following 42 min of soccer-specific exercise. METHODS: Ten youth soccer players, aged 15.8 +/- 0.4 years, stature 1.73 +/- 0.06 m and mass 59.8 +/- 9.7 kg, hopped on a force plate at a self-selected frequency before and after simulated soccer exercise performed on a non-motorised treadmill. During hopping, muscle activity was measured using surface electromyography from four lower limb muscles and analysed to determine feedforward- and feedback-mediated activity, as well as co contraction. RESULTS: There was a small, non-significant change in stiffness following exercise (26.6 +/- 10.6 vs. 24.0 +/- 7.0 kN m(-1), p > 0.05, ES = 0.25), with half the group increasing and half decreasing their stiffness. Changes in stiffness were significantly related to changes in centre of mass (CoM) displacement (r = 0.90, p < 0.01, extremely large correlation) but not changes in peak ground reaction force (r = 0.58, p > 0.05, large correlation). A number of significant relationships were observed between changes in stiffness and CoM displacement with changes in feedforward, feedback and eccentric muscle activity of the soleus and vastus lateralis muscles following exercise (r = 0.64 0.98, p < 0.05, large-extremely large correlations), but not with changes in co contraction (r = 0.11-0.55, p > 0.05, small-large correlations). CONCLUSIONS: Following soccer-specific exercise individual changes in feedforward- and reflex mediated activity of the soleus and vastus lateralis, and not co-contraction around the knee and ankle, modulate changes in CoM displacement and leg stiffness. PMID- 25034628 TI - Prognostic impact of moderate or severe mitral regurgitation (MR) irrespective of concomitant comorbidities: a retrospective matched cohort study. AB - OBJECTIVE: We sought to objectively quantify the independent impact of significant mitral regurgitation (MR) on prognosis in patients with multiple comorbidities and ascertain the extent to which median survival is affected by increasing comorbidities. METHODS: This was a retrospective matched cohort study using a clinical-echocardiography reporting database linked to a clinical and administrative database in an Australian tertiary hospital. We identified our study cohort (patients with significant MR) and control cohort (without MR) on transthoracic echocardiographies performed between 2005 and 2010. The main outcome measures were mortality and heart failure rehospitalisation. A Cox proportional hazards model was used to adjust for clinical covariates and the 'win ratio' methodology was utilised to estimate the impact of MR on main outcomes. RESULTS: A total of 218 matched patients with and without significant MR were followed-up for 1 year. Significant MR was associated with an adjusted HR for mortality of 1.83 (95% CI 1.28 to 2.62, p<0.001). The win ratio for death and death or heart failure readmission was 0.57 (95% CI 0.40 to 0.78, p=0.0002) and 0.53 (95% CI 0.39 to 0.71, p<0.0001), respectively. Significant MR with left ventricular (LV) systolic dysfunction and age between 75 and 85 years were associated with a substantial reduction in median survival by 2.3 years. Significant MR with LV systolic dysfunction, age beyond 85 and advance comorbidities were associated with a lesser reduction in median survival by 0.2 years. CONCLUSIONS: Significant MR in patients with multiple comorbidities leads to increase in death and heart failure rehospitalisation with reduced estimated median survival. However, its impact diminishes with increasing comorbidities. PMID- 25034629 TI - The safety of intravitreal bevacizumab monotherapy in adult ophthalmic conditions: systematic review. AB - OBJECTIVES: To assess the safety of intravitreal bevacizumab (IVB) as a monotherapy and to evaluate the relationship between quality of treatment and adverse events. DATA SOURCES: Cochrane Library, Ovid MEDLINE, MEDLINE in-process, Ovid EMBASE and Toxicology Literature Online (TOXLINE) from January 2009 to May 2012. Studies included in an earlier systematic review were also assessed for inclusion. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Randomised controlled trials (RCTs), controlled trials or observational studies including >=10 participants reporting adverse events data following IVB monotherapy as a primary treatment in patients (aged 18 years or more) with any eye condition were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Study selection was undertaken independently by a minimum of two reviewers using pre-defined criteria. Data abstraction and quality assessment were performed by one reviewer, and then checked by a second reviewer. Study quality was assessed for only RCTs in accordance to the Cochrane Risk of Bias Tool. Additional items relating to safety data were also assessed. Results were tabulated or meta-analysed as appropriate. RESULTS: 22 RCTs and 67 observational studies were included. Only two RCTs reported valid safety data. Rates of serious adverse events following treatment were low. There was insufficient data to explore the relationship between the incidence of adverse events and quality of IVB injection. LIMITATIONS: A majority of relevant existing studies were characterised by small sample sizes, unclear diagnostic criteria and reporting of safety outcomes. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Available evidence demonstrates low rates of serious local and systemic adverse events following treatment. However, the role of IVB quality in the incidence of adverse events remains unclear. Robust evidence is needed to examine the relationship between the incidence of adverse events and variables such as injection techniques, pre-existing risk factors (eg, immunosuppression, cross-contamination) and quality of IVB treatment. PMID- 25034630 TI - Pre-existing hyperlipidaemia increased the risk of new-onset anxiety disorders after traumatic brain injury: a 14-year population-based study. AB - OBJECTIVES: Anxiety disorders (ADs) are common after traumatic brain injury (TBI). However, the risk factors of new-onset ADs remain unclear. This study was aimed at evaluating the incidence and risk factors for new-onset ADs, including pre-existing hyperlipidaemia and three major comorbidities (diabetes mellitus, hypertension and cardiovascular disease), in patients with TBI. SETTING: A matched cohort study was conducted using the Taiwan Longitudinal Health Insurance Database between January 1997 and December 2010. PARTICIPANTS: A total of 3822 participants (1274 patients with TBI with hyperlipidaemia and 2548 age-matched and gender-matched patients with TBI without hyperlipidaemia). OUTCOME MEASURES: The incidence and HRs for the development of new-onset ADs after TBI were compared between the two groups. RESULTS: The overall incidence rate of new-onset ADs for patients with TBI with hyperlipidaemia is 142.03/10 000 person-years (PYs). Patients with TBI with hyperlipidaemia have a 1.60-fold incidence rate ratio (p<0.0001) and increased HR of ADs (1.58, 95% CI 1.24 to 2.02) compared with those without hyperlipidaemia. The incidence rates of ADs for males and females with hyperlipidaemia, respectively, were 142.12 and 292.32/10 000 PYs, which were higher than those without hyperlipidaemia (93.03 and 171.68/10 000 PYs, respectively). Stratified by age group, hyperlipidaemia is a risk factor of ADs for patients with TBI aged 65 years or younger. CONCLUSIONS: Pre-existing hyperlipidaemia is an independent predictor of new-onset ADs in patients with TBI, even when controlling for other demographic and clinical variables. Female patients with pre-existing hyperlipidaemia had significantly higher risk of new onset ADs than males, especially between the ages of 35 and 65 years. PMID- 25034631 TI - 'You feel you've been bad, not ill': Sick doctors' experiences of interactions with the General Medical Council. AB - OBJECTIVE: To explore the views of sick doctors on their experiences with the General Medical Council (GMC) and their perception of the impact of GMC involvement on return to work. DESIGN: Qualitative study. SETTING UK PARTICIPANTS: Doctors who had been away from work for at least 6 months with physical or mental health problems, drug or alcohol problems, GMC involvement or any combination of these, were eligible for inclusion into the study. Eligible doctors were recruited in conjunction with the Royal Medical Benevolent Fund, the GMC and the Practitioner Health Programme. These organisations approached 77 doctors; 19 participated. Each doctor completed an in-depth semistructured interview. We used a constant comparison method to identify and agree on the coding of data and the identification of central themes. RESULTS: 18 of the 19 participants had a mental health, addiction or substance misuse problem. 14 of the 19 had interacted with the GMC. 4 main themes were identified: perceptions of the GMC as a whole; perceptions of GMC processes; perceived health impacts and suggested improvements. Participants described the GMC processes they experienced as necessary, and some elements as supportive. However, many described contact with the GMC as daunting, confusing and anxiety provoking. Some were unclear about the role of the GMC and felt that GMC communication was unhelpful, particularly the language used in correspondence. Improvements suggested by participants included having separate pathways for doctors with purely health issues, less use of legalistic language, and a more personal approach with for example individualised undertakings or conditions. CONCLUSIONS: While participants recognised the need for a regulator, the processes employed by the GMC and the communication style used were often distressing, confusing and perceived to have impacted negatively on their mental health and ability to return to work. PMID- 25034632 TI - A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol. AB - INTRODUCTION: Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. METHODS AND ANALYSIS: The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05956042. PMID- 25034633 TI - Complete mitochondrial genome sequences from five Eimeria species (Apicomplexa; Coccidia; Eimeriidae) infecting domestic turkeys. AB - BACKGROUND: Clinical and subclinical coccidiosis is cosmopolitan and inflicts significant losses to the poultry industry globally. Seven named Eimeria species are responsible for coccidiosis in turkeys: Eimeria dispersa; Eimeria meleagrimitis; Eimeria gallopavonis; Eimeria meleagridis; Eimeria adenoeides; Eimeria innocua; and, Eimeria subrotunda. Although attempts have been made to characterize these parasites molecularly at the nuclear 18S rDNA and ITS loci, the maternally-derived and mitotically replicating mitochondrial genome may be more suited for species level molecular work; however, only limited sequence data are available for Eimeria spp. infecting turkeys. The purpose of this study was to sequence and annotate the complete mitochondrial genomes from 5 Eimeria species that commonly infect the domestic turkey (Meleagris gallopavo). METHODS: Six single-oocyst derived cultures of five Eimeria species infecting turkeys were PCR-amplified and sequenced completely prior to detailed annotation. Resulting sequences were aligned and used in phylogenetic analyses (BI, ML, and MP) that included complete mitochondrial genomes from 16 Eimeria species or concatenated CDS sequences from each genome. RESULTS: Complete mitochondrial genome sequences were obtained for Eimeria adenoeides Guelph, 6211 bp; Eimeria dispersa Briston, 6238 bp; Eimeria meleagridis USAR97-01, 6212 bp; Eimeria meleagrimitis USMN08-01, 6165 bp; Eimeria gallopavonis Weybridge, 6215 bp; and Eimeria gallopavonis USKS06 01, 6215 bp). The order, orientation and CDS lengths of the three protein coding genes (COI, COIII and CytB) as well as rDNA fragments encoding ribosomal large and small subunit rRNA were conserved among all sequences. Pairwise sequence identities between species ranged from 88.1% to 98.2%; sequence variability was concentrated within CDS or between rDNA fragments (where indels were common). No phylogenetic reconstruction supported monophyly of Eimeria species infecting turkeys; Eimeria dispersa may have arisen via host switching from another avian host. Phylogenetic analyses suggest E. necatrix and E. tenella are related distantly to other Eimeria of chickens. CONCLUSIONS: Mitochondrial genomes of Eimeria species sequenced to date are highly conserved with regard to gene content and structure. Nonetheless, complete mitochondrial genome sequences and, particularly the three CDS, possess sufficient sequence variability for differentiating Eimeria species of poultry. The mitochondrial genome sequences are highly suited for molecular diagnostics and phylogenetics of coccidia and, potentially, genetic markers for molecular epidemiology. PMID- 25034634 TI - Purification and properties of recombinant exopolyphosphatase PPN1 and effects of its overexpression on polyphosphate in Saccharomyces cerevisiae. AB - Inorganic polyphosphate performs many regulatory functions in living cells. The yeast exopolyphosphatase PPN1 is an enzyme with multiple cellular localization and probably variable functions. The Saccharomyces cerevisiae strain with overexpressed PPN1 was constructed for large-scale production of the enzyme and for studying the effect of overproduction on polyphosphate metabolism. The DeltaPPN1 strain was transformed by the vector containing this gene under a strong constitutive promoter of glycerol aldehyde-triphosphate dehydrogenase of S. cerevisiae. Exopolyphosphatase activity in the transformant increased 28- and 11-fold compared to the DeltaPPN1 and parent strains, respectively. The content of acid-soluble polyphosphate decreased ~6-fold and the content of acid-insoluble polyphosphate decreased ~2.5-fold in the cells of the transformant compared to the DeltaPPN1 strain. The recombinant enzyme was purified. The substrate specificity, cation requirement, and inhibition by heparin were found to be similar to native PPN1. The molecular mass of a subunit (~33 kD) and the amino acid sequence of the recombinant enzyme were the same as in mature PPN1. The recombinant enzyme was localized mainly in the cytoplasm (40%) and vacuoles (20%). The overproducer strain had no growths defects under phosphate deficiency or phosphate excess. In contrast to the parent strains accumulating polyphosphate, the transformant accumulated orthophosphate under phosphate surplus. PMID- 25034635 TI - Telomere-mediated chromosomal truncation in Aspergillus oryzae. AB - We truncated the short arm of chromosome 3 to delete the aflatoxin biosynthesis gene homolog cluster using telomeric repeats in Aspergillus oryzae. The predicted deletion was confirmed by Southern blot analyses. This telomere-mediated chromosomal truncation method enables the development of an artificial chromosome in A. oryzae. PMID- 25034636 TI - Smoking status and prevalence of upper gastrointestinal disorders. AB - BACKGROUND: Lifestyle and environmental factors affecting upper gastrointestinal (GI) disorders are different in developing countries than those in developed nations. OBJECTIVE: This study aimed to examine the association between smoking status and upper GI disorders among a large group of the Iranian adult population. METHODS: This cross-sectional study was conducted among 1,933 adult men in Isfahan, Iran. Smoking status was assessed by a self-administered questionnaire. Required information on GI health was collected through the use of the validated ROME III questionnaire. Individuals who reported having heartburn sometimes, often, or always in the last 3 months were considered as having epidemiologic gastroesophageal reflux disease (GERD), and those who reported having heartburn often or always were considered as having clinical GERD. Subjects who reported having functional dyspepsia (FD) symptoms (based on the ROME III criteria) sometimes, often, or always in the last 3 months were considered as having epidemiologic FD, and those who reported having these disorders often or always were considered as having clinical FD. RESULTS: Smoking was prevalent among 7.8% of the study population. FD and GERD was prevalent among 12.6% (n = 244) and 22.3% (n = 432), respectively. Smoking was not associated with GERD by either the epidemiologic or clinical definition. Although the association between smoking and FD (epidemiologic definition) was not statistically significant, smokers had an 83% higher risk of suffering from clinical FD compared with nonsmokers after taking potential confounders into account [odds ratio (OR) = 1.83, 95% CI: 1.12-3.00; p = 0.01]. Smokers had a 57% higher risk for epidemiologic postprandial fullness (OR = 1.57, 95% CI: 1.05 2.33; p = 0.02) and a 92% higher risk for clinical epigastric pain compared with nonsmokers (OR = 1.92, 95% CI: 1.02-3.62; p = 0.04). We found no significant association between smoking and severity of upper GI disorders. CONCLUSION: This large population-based study indicated that smoking was not associated with GERD and epidemiologic FD. However, smoking was significantly associated with clinical FD, postprandial fullness, and epigastric pain. PMID- 25034637 TI - Twelve myths about shared decision making. AB - OBJECTIVE: As shared decision makes increasing headway in healthcare policy, it is under more scrutiny. We sought to identify and dispel the most prevalent myths about shared decision making. METHODS: In 20 years in the shared decision making field one of the author has repeatedly heard mention of the same barriers to scaling up shared decision making across the healthcare spectrum. We conducted a selective literature review relating to shared decision making to further investigate these commonly perceived barriers and to seek evidence supporting their existence or not. RESULTS: Beliefs about barriers to scaling up shared decision making represent a wide range of historical, cultural, financial and scientific concerns. We found little evidence to support twelve of the most common beliefs about barriers to scaling up shared decision making, and indeed found evidence to the contrary. CONCLUSION: Our selective review of the literature suggests that twelve of the most commonly perceived barriers to scaling up shared decision making across the healthcare spectrum should be termed myths as they can be dispelled by evidence. PRACTICE IMPLICATIONS: Our review confirms that the current debate about shared decision making must not deter policy makers and clinicians from pursuing its scaling up across the healthcare continuum. PMID- 25034638 TI - A Balint-inspired reflective forum in oncology for medical residents: main themes during seven years. AB - OBJECTIVE: Reflection groups for clinicians, often called Balint groups, are a way of refining professional competence in health care. This study presents a model for reflective practice in a group setting and describes the kinds of troublesome cases that medical residents are concerned about. METHODS: From 2005 to 2012 a Balint-inspired reflective forum has been a part of the academic seminar program for physicians in training in a Department of Oncology at a Swedish university. The present study is focused on all 63 cases presented in the forum. RESULTS: The cases were categorized into three kinds of challenges: Communication challenges in the patient-physician relationship, Communication challenges in organizational matters, and Communication challenges with close relatives of the patient. CONCLUSION: The study tells us something about the vulnerability of being a medical resident and the identified challenges have bearings on medical education curricula as well as on how the training of junior physicians is organized. PRACTICE IMPLICATIONS: The cases are contextual and multifaceted, and a forum of this kind might therefore be regarded as a potential way to develop professional competence and to refine communication in clinical practice. A structured evaluation of the forum would be valuable. PMID- 25034639 TI - Soft wearable contact lens sensor for continuous intraocular pressure monitoring. AB - Intraocular pressure (IOP) is a primary indicator of glaucoma, but measurements from a single visit to the clinic miss the peak IOP that may occur at night during sleep. A soft chipless contact lens sensor that allows the IOP to be monitored throughout the day and at night is developed in this study. A resonance circuit composed of a thin film capacitor coupled with a sensing coil that can sense corneal curvature deformation is designed, fabricated and embedded into a soft contact lens. The resonance frequency of the sensor is designed to vary with the lens curvature as it changes with the IOP. The frequency responses and the ability of the sensor to track IOP cycles were tested using a silicone rubber model eye. The results showed that the sensor has excellent linearity with a frequency response of ~8 kHz/mmHg, and the sensor can accurately track fluctuating IOP. These results showed that the chipless contact lens sensor can potentially be used to monitor IOP to improve diagnosis accuracy and treatment of glaucoma. PMID- 25034642 TI - Effects of dietary salt restriction on renal progression and interstitial fibrosis in adriamycin nephrosis. AB - BACKGROUND/AIMS: Although high salt intake is thought to accelerate renal progression in proteinuric kidney disease, it is not known whether strict dietary salt restriction could delay renal inflammation and interstitial fibrosis. Here, we sought to answer this question in a rat model of adriamycin-induced nephrotic syndrome. METHODS: Adriamycin was administered via the femoral vein in a single bolus (7.5 mg/kg), and the rats were put on a sodium-deficient rodent diet. Rats with intact kidneys were studied for 5 weeks (experiment 1), and uninephrectomized rats were studied for 6 weeks (experiment 2). RESULTS: In experiment 1, restricting salt intake improved renal tubulointerstitial histopathology in adriamycin-treated rats. Immunohistochemical and immunoblot results additionally showed that restricting dietary salt lowered adriamycin induced expression of osteopontin, collagen III, and fibronectin. In experiment 2, salt restriction improved adriamycin-induced azotemia, although it did not affect proteinuria or blood pressure. Dietary salt restriction also reduced adriamycin-induced infiltration of ED1-positive cells and the upregulated expression of osteopontin and alpha-SMA. Masson's trichrome and Sirius red staining revealed that salt restriction slowed Adriamycin-induced progression of renal interstitial fibrosis. Finally, qPCR revealed that adriamycin-induced expression of TNF-alpha, IkappaB-alpha, gp91(phox), p47(phox), and p67(phox) mRNA was blocked by salt restriction. CONCLUSION: Our findings demonstrate that strict dietary salt restriction delays the progress of renal inflammation and fibrosis in proteinuric kidney disease, most likely via relieving the reactive oxygen species-mediated NF-kappaB activation. PMID- 25034643 TI - Identification and independent validation of a stable yield and thousand grain weight QTL on chromosome 6A of hexaploid wheat (Triticum aestivum L.). AB - BACKGROUND: Grain yield in wheat is a polygenic trait that is influenced by environmental and genetic interactions at all stages of the plant's growth. Yield is usually broken down into three components; number of spikes per area, grain number per spike, and grain weight (TGW). In polyploid wheat, studies have identified quantitative trait loci (QTL) which affect TGW, yet few have been validated and fine-mapped using independent germplasm, thereby having limited impact in breeding. RESULTS: In this study we identified a major QTL for TGW, yield and green canopy duration on wheat chromosome 6A of the Spark x Rialto population, across 12 North European environments. Using independent germplasm in the form of BC2 and BC4 near isogenic lines (NILs), we validated the three QTL effects across environments. In four of the five experiments the Rialto 6A introgression gave significant improvements in yield (5.5%) and TGW (5.1%), with morphometric measurements showing that the increased grain weight was a result of wider grains. The extended green canopy duration associated with the high yielding/TGW Rialto allele was comprised of two independent effects; earlier flowering and delayed final maturity, and was expressed stably across the five environments. The wheat homologue (TaGW2) of a rice gene associated with increased TGW and grain width was mapped within the QTL interval. However, no polymorphisms were identified in the coding sequence between the parents. CONCLUSION: The discovery and validation through near-isogenic lines of robust QTL which affect yield, green canopy duration, thousand grain weight, and grain width on chromosome 6A of hexaploid wheat provide an important first step to advance our understanding of the genetic mechanisms regulating the complex processes governing grain size and yield in polyploid wheat. PMID- 25034644 TI - On the mechanical properties of tooth enamel under spherical indentation. AB - The mechanical properties of tooth enamel generally exhibit large variations, which reflect its structural and material complexity. Some key properties were evaluated under localized contact, simulating actual functioning conditions. Prominent cusps of extracted human molar teeth were polished down ~0.7 mm below the cusp tip and indented by tungsten carbide balls. The internal damage was assessed after unloading from longitudinal or transverse sections. The ultimate tensile stress (UTS) was determined using a novel bilayer specimen. The damage is characterized by penny-like radial cracks driven by hoop stresses and cylindrical cracks driven along protein-rich interrod materials by shear stresses. Shallow cone cracks typical of homogeneous materials which may cause rapid tooth wear under repeat contact are thus avoided. The mean stress vs. indentation strain curve is highly nonlinear, attributable to plastic shearing of protein between and within enamel rods. This curve is also affected by damage, especially radial cracks, the onset of which depends on ball radius. Several material properties were extracted from the tests, including shear strain at the onset of ring cracks gamma(F) (=0.14), UTS (=119 MPa), toughness K(C) (=0.94 MPa m(1/2)), a crack propagation law and a constitutive response determined by trial and error with the aid of a finite-element analysis. These quantities, which are only slightly sensitive to anatomical location within the enamel region tested, facilitate a quantitative assessment of crown failure. Causes for variations in published UTS and K(C) values are discussed. PMID- 25034645 TI - A novel design of injectable porous hydrogels with in situ pore formation. AB - The use of injectable porous hydrogels is of great interest in biomedical applications due to their excellent permeability and ease of integration into sites of surgical intervention. By implementing a method that enables the formation in situ of pores with controllable porosity and pore size, it is possible to synthesize bioactive hydrogels that are tailor-made for specific biomedical applications. An emulsion-templating technique was used to encapsulate oil droplets, which are subsequently leached out of the hydrogel to create the porous structure. Pore size and porosity were manipulated by changing oil-to water ratios and the surfactant concentrations. Highly swellable porous hydrogels were obtained with control over mechanical strength and diffusive properties. The relationship between porosity, pore size, and the hydrogel's physical and mechanical characteristics was analyzed, and the potential of this material as a protein drug delivery system was demonstrated. PMID- 25034646 TI - Recent advances on the development of magnesium alloys for biodegradable implants. AB - In recent years, much progress has been made on the development of biodegradable magnesium alloys as "smart" implants in cardiovascular and orthopedic applications. Mg-based alloys as biodegradable implants have outstanding advantages over Fe-based and Zn-based ones. However, the extensive applications of Mg-based alloys are still inhibited mainly by their high degradation rates and consequent loss in mechanical integrity. Consequently, extensive studies have been conducted to develop Mg-based alloys with superior mechanical and corrosion performance. This review focuses on the following topics: (i) the design criteria of biodegradable materials; (ii) alloy development strategy; (iii) in vitro performances of currently developed Mg-based alloys; and (iv) in vivo performances of currently developed Mg-based implants, especially Mg-based alloys under clinical trials. PMID- 25034647 TI - Design of two-channel filter bank using nature inspired optimization based fractional derivative constraints. AB - In this article, a novel approach for 2-channel linear phase quadrature mirror filter (QMF) bank design based on a hybrid of gradient based optimization and optimization of fractional derivative constraints is introduced. For the purpose of this work, recently proposed nature inspired optimization techniques such as cuckoo search (CS), modified cuckoo search (MCS) and wind driven optimization (WDO) are explored for the design of QMF bank. 2-Channel QMF is also designed with particle swarm optimization (PSO) and artificial bee colony (ABC) nature inspired optimization techniques. The design problem is formulated in frequency domain as sum of L2 norm of error in passband, stopband and transition band at quadrature frequency. The contribution of this work is the novel hybrid combination of gradient based optimization (Lagrange multiplier method) and nature inspired optimization (CS, MCS, WDO, PSO and ABC) and its usage for optimizing the design problem. Performance of the proposed method is evaluated by passband error (phip), stopband error (phis), transition band error (phit), peak reconstruction error (PRE), stopband attenuation (As) and computational time. The design examples illustrate the ingenuity of the proposed method. Results are also compared with the other existing algorithms, and it was found that the proposed method gives best result in terms of peak reconstruction error and transition band error while it is comparable in terms of passband and stopband error. Results show that the proposed method is successful for both lower and higher order 2-channel QMF bank design. A comparative study of various nature inspired optimization techniques is also presented, and the study singles out CS as a best QMF optimization technique. PMID- 25034648 TI - Improved stabilization method for networked control systems with variable transmission delays and packet dropout. AB - This paper investigates the problem of stability analysis and stabilization for networked control systems with the network-induced delay and data dropout. In order to obtain less conservative results, a novel augmented Lyapunov-Krasovskii functional is introduced and new free-weighting matrices are employed to make some extra degrees of freedom in the sufficient stabilizability condition. The gain of the memoryless state-feedback controller is computed by solving a set of linear matrix inequalities (LMIs). Illustrative examples are given to verify the applicability and outperformance of the proposed method compared to the existing approaches in the literature. PMID- 25034649 TI - Adaptive control of nonlinear uncertain active suspension systems with prescribed performance. AB - This paper proposes adaptive control designs for vehicle active suspension systems with unknown nonlinear dynamics (e.g., nonlinear spring and piece-wise linear damper dynamics). An adaptive control is first proposed to stabilize the vertical vehicle displacement and thus to improve the ride comfort and to guarantee other suspension requirements (e.g., road holding and suspension space limitation) concerning the vehicle safety and mechanical constraints. An augmented neural network is developed to online compensate for the unknown nonlinearities, and a novel adaptive law is developed to estimate both NN weights and uncertain model parameters (e.g., sprung mass), where the parameter estimation error is used as a leakage term superimposed on the classical adaptations. To further improve the control performance and simplify the parameter tuning, a prescribed performance function (PPF) characterizing the error convergence rate, maximum overshoot and steady-state error is used to propose another adaptive control. The stability for the closed-loop system is proved and particular performance requirements are analyzed. Simulations are included to illustrate the effectiveness of the proposed control schemes. PMID- 25034650 TI - A metal-dielectric-graphene sandwich for surface enhanced Raman spectroscopy. AB - The Raman intensity of Rhodamine B (RhB) is enhanced by inserting a thin high kappa dielectric layer which reduces the surface plasmon damping at the gold graphene interface. The results indicate that the Raman intensity increases sharply by plasmonic resonance enhancement while maintaining efficient fluorescence quenching with optimized dielectric layer thickness. PMID- 25034651 TI - [Pediatric general practitioners and tertiary care structures for pain therapy. A qualitative study on the need for networking]. AB - BACKGROUND: Despite the urgency of the problem of chronic pediatric pain and the importance of early interventions, many children experience intermittent episodes of pain over a long period of time. One aim of this study was to investigate the need of structured diagnostic tools and therapies of chronic pediatric pain in pediatric general practices. Another aim was to describe the aims, services and challenges of a network between pediatric practices and a tertiary pediatric pain centre, from the perspective of general pediatric practitioners. MATERIAL AND METHODS: A qualitative research design was selected and 20 general pediatric practitioners were interviewed using a semistructured interview guide. Interviews were analyzed by use of qualitative content analysis according to Mayring. RESULTS: Generally, the idea of a network between pediatric practices and the German Pediatric Pain Centre was rated positively by pediatric general practitioners. From the results of the analysis three categories were identified: (i) expectations from the network (ii) desire for cooperation in the network and (iii) recommendations for improved patient care. CONCLUSION: A network with a centre for tertiary care was preferred by the general pediatric practitioners. To optimize the care of children with chronic pain further education for general pediatric practitioners as well as structured diagnostic tools and therapies of frequent pediatric chronic pain diseases are warranted. PMID- 25034652 TI - [Attachment style and cytokine levels in patients with fibromyalgia. A prospective longitudinal study]. AB - BACKGROUND AND OBJECTIVES: The association between attachment style and subjective pain is controversially discussed and the influence of attachment styles on cytokine levels in chronic pain has received little attention in research. In this prospective longitudinal clinical study, we evaluated the relationship between cytokines, attachment style and subjective pain intensity as well as pain-related functioning in patients with fibromyalgia (FM) who underwent a 4-week multidisciplinary pain therapy. MATERIALS AND METHODS: The attachment style was determined in 43 patients with FM using the relationship questionnaire (RQ-2) and subjective pain with the German version of the West Haven-Yale multidimensional pain inventory. Serum levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) and the anti inflammatory cytokines IL-4 and IL-10 were assessed before and after treatment and additionally once only in 18 healthy controls (Bio-Plex system). RESULTS: Patients with FM syndrome were significantly more often insecurely attached than healthy controls (p = 0.001). Serum levels of TNF-alpha (p = 0.001) and IL-10 (p = 0.039) were significantly higher in FM patients compared to controls. Attachment was unrelated to IL-4, IL-8, and IL-10 levels. Insecurely attached FM patients had significantly higher levels of TNF-alpha (p = 0.002). than securely attached patients. Insecurely and securely attached patients did not differ in subjective levels of pain severity, activity or functional interference. Cytokine levels were not correlated with subjective levels of pain severity or functional interference. Multidisciplinary pain therapy significantly reduced cytokine levels, pain severity, anxiety and depression independent of attachment style. PMID- 25034653 TI - Deregulated expression of annexin-A2 and galectin-3 is associated with metastasis in gastric cancer patients. AB - Gastric cancer (GC) is the second highest cause of cancer mortality worldwide. However, nowadays, most of the studies aiming to understand the gastric carcinogenesis analyzed tumors of individuals from Asian population and, thus, may not reflect the distinct biological and clinical behaviors among GC processes. Since several membrane proteins have been implicated in carcinogenesis, we aimed to evaluate ANXA2 and GAL3 role in gastric tumors and GC cell lines of individuals from northern Brazil. The cellular localization of ANXA2 and GAL3 in the GC cell lines was evaluated by immunofluorescence. Gene expression was evaluated by real-time reverse-transcription PCR and protein expression by Western blot in gastric adenocarcinomas and non-neoplastic gastric samples, as well as in GC cell lines. ANXA2 and GAL3 were presented as dots in the plasma membrane and cytoplasm in ACP02 and ACP03 cell lines. ANXA2 mRNA expression was up-regulated in 32.14 % of gastric tumors compared to non neoplastic tissues. ANXA2 up-regulation was associated with the metastasis process in vivo and with cell line invasive behavior. GAL3 protein expression was at least 1.5-fold reduced in 50 % of gastric tumors. The reduced GAL3 expression was associated with the presence of distant metastasis and with a higher invasive phenotype in vitro. Our study shows that ANXA2 and GAL3 deregulated expression was associated with an invasive phenotype in GC cell lines and may contribute to metastasis in GC patients. Therefore, these proteins may have potential prognostic relevance for GC of individuals from northern Brazil. PMID- 25034654 TI - Activated Notch1 expression is associated with angiogenesis in cutaneous melanoma. AB - An early event in melanocytic tumor growth is the upregulation of Notch signaling. When an active form of Notch1 is overexpressed in primary human melanocytes, it increases cell growth, survival and invasive properties, promoting melanoma progression. Recent evidence suggested that tumor initiation and growth are driven by a subset of tumor-initiating cells termed cancer stem cells. Notch1 plays a predominant role in the maintenance of melanoblasts, including melanocyte stem cells, by preventing initiation of apoptosis. Moreover, the importance of Notch1 in the regulation of tumor angiogenesis is supported by growing evidence in various cancers. Nestin has been widely used as a marker for melanocyte stem cells as well as an angiogenic marker to evaluate neovascularity of endothelial cells in tumors. To gain an insight into the impact of Notch1 activation on the maintenance of melanocyte stem cells and angiogenesis in melanoma, the expression levels of activated Notch1 and nestin were analyzed by immunohistochemistry in 114 primary cutaneous melanomas and 35 lymph node metastases. Activated Notch1 and nestin expression was also evaluated in four dysplastic melanocytic nevi. This study provides evidence that activated Notch1 is overexpressed in cutaneous melanoma, in tumor cells as well as in microvessel endothelium, and that it can promote tumor angiogenesis. Indeed, the overexpression of activated Notch1 in both tumor and vascular endothelial cells was significantly associated with microvascular density in melanoma samples. Thus, activated Notch1 inhibitors may provide a therapeutic strategy in the treatment of melanoma by blocking tumor-associated vascularization. PMID- 25034655 TI - Chemoprevention of esophageal adenocarcinoma in a rat model by ursodeoxycholic acid. AB - Reflux of bile acid into the esophagus induces esophagitis, inflammation stimulated hyperplasia, metaplasia such as Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC). Caudal-type homeobox 2 (Cdx2) via nuclear factor (NF)-kappaB induced by bile acid is an important factor in the development of BE and EAC. In colorectal cancer, experimental data suggest a chemopreventive effect of ursodeoxycholic acid (UDCA). We hypothesized that UDCA may protect against the esophageal inflammation-metaplasia-carcinoma sequence by decreasing the overall proportion of the toxic bile acids. Wistar male rats that underwent a duodenoesophageal reflux procedure were divided into two groups. One group was given commercial chow (control group), and the other was given experimental chow containing UDCA (UDCA group). The animals were killed at 40 weeks after surgery, and their bile and esophagus were examined. In the UDCA group, the esophagitis was milder and the incidence of BE was significantly lower (p < 0.05) than in the control group, and EAC was not observed (p < 0.05). In analysis of the compartment of bile acid, UDCA was markedly increased in the UDCA group compared with the control group (32.7 +/- 11.4 vs. 0.82 +/- 0.33 mmol/L, p < 0.05) and cholic acid was decreased (32.7 +/- 4.05 vs. 60.9 +/- 8.26 mmol/L, p < 0.05). Expression intensity of Cdx2 and NF-kappaB was greater in the control group than in the UDCA group (p < 0.05). UDCA may be a chemopreventive agent against EAC by varying the bile acid composition. PMID- 25034656 TI - The level of patient-reported outcome reporting in randomised controlled trials of brain tumour patients: a systematic review. AB - BACKGROUND: To determine the net clinical benefit of a new treatment strategy, information on both survival and patient-reported outcomes (PROs) is required. However, to make an adequately informed decision, PRO evidence should be of sufficiently high quality. OBJECTIVE: To investigate the methodological quality of PRO reporting in randomised controlled trials (RCTs) in patients with brain tumours, and to assess the proportion of studies that should impact clinical decision-making. METHODS: We conducted a systematic literature search in several databases covering January 2004 to March 2012. We selected relevant RCTs and retrieved the following data: (1) basic trial demographics and PRO characteristics, (2) quality of PRO reporting and (3) risk of bias. Studies that should impact clinical decision-making based on their methodological robustness were analysed systematically. RESULTS: We identified 14 RCTs, representing over 3000 glioma patients. Only two RCTs (14%) satisfied sufficiently many key methodological criteria to provide high-quality PRO evidence, and should therefore impact clinical decision-making. Important methodological limitations in other studies were lack of reporting of the extent (43%) and reasons (86%) of missing data and statistical approaches to handle this (71%). PRO results were not interpreted in 79% of the studies and clinical significance was not discussed in 86%. Studies with high-quality PRO evidence generally showed lower risk of bias. CONCLUSIONS: Investigators involved in brain tumour research should pay special attention to methodological challenges identified in current work. The level of PRO reporting should continue to improve in order to facilitate a critical appraisal of study results. PMID- 25034657 TI - Application of Short Tandem Repeat markers in diagnosis of chromosomal aneuploidies and forensic DNA investigation in Pakistan. AB - PURPOSE: Short Tandem Repeat (STR) genetic markers hold great potential in forensic investigations, molecular diagnostics and molecular genetics research. AmpFlSTR(r) IdentifilerTM PCR amplification kit is a multiplex system for co amplification of 15 STR markers used worldwide in forensic investigations. This study attempts to assess forensic validity of these STRs in Pakistani population and to investigate its applicability in quick and simultaneous diagnosis and tracing parental source of common chromosomal aneuploidies. METHODOLOGY: Samples from 554 healthy Pakistani individuals from 5 different ethnicities were analyzed for forensic parameters using Identifiler STRs and 74 patients' samples with different aneuploidies were evaluated for diagnostic strengths of these markers. RESULTS: All STRs hold sufficient forensic applicability in Pakistani population with paternity index between 1.5 and 3.5, polymorphic information content from 0.63 to 0.87 and discrimination power >=0.9 (except TPOX locus). Variation from Hardy-Weinberg equilibrium was observed at some loci reflecting selective breeding and intermarriages trend in Pakistan. Among aneuploidic samples, all trisomies were precisely detectable while aneuploidies involving sex chromosomes or missing chromosomes were not clearly detectable using Identifiler STRs. Parental origin of aneuploidy was traceable in 92.54% patients. CONCLUSION: The studied STR markers are valuable tools for forensic application in Pakistan and utilizable for quick and simultaneous identification of some common trisomic conditions. Adding more sex chromosome specific STR markers can immensely increase the diagnostic and forensic potential of this system. PMID- 25034658 TI - Validating a rapid, real-time, PCR-based direct mutation detection assay for preimplantation genetic diagnosis. AB - Although co-amplification of polymorphic microsatellite markers is the current gold standard for preimplantation genetic diagnosis (PGD) of single-gene disorders (SGD), this approach can be hampered by the lack of availability of informative markers. We recently (2011) devised a novel in-house assay for PGD of aromatic L-amino acid decarboxylase deficiency, based on an amplification refractory mutation system and quantitative PCR (ARMS-qPCR). The objective of the present study was to verify ARMS-qPCR in a cohort of 20 PGD cycles with a diverse group of SGDs (15 couples at risk for 10 SGDs). Day-3 cleavage-stage embryos were subjected to biopsy and genotyping, followed by fresh embryo transfer (FET). The diagnostic rate was 82.9%; unaffected live births were achieved in 9 of 20 FET cycles (45%), with only one false negative (among 54 transferred embryos). Overall, the ARMS-qPCR had frequent allele-dropout (ADO), rendering it inappropriate as the sole diagnostic method (despite a favorable live-birth rate). Regardless, it has the potential to complement the current gold-standard methodology, especially when trophectoderm biopsy becomes a preferred option and genotyping needs to be timely enough to enable FET. PMID- 25034659 TI - Myoclonus dystonia syndrome: a novel epsilon-sarcoglycan gene mutation with variable clinical symptoms. PMID- 25034660 TI - Sex-specific association between X-linked Toll-like receptor 7 with the outcomes of hepatitis C virus infection. AB - Toll-like receptor 7 (TLR7) senses hepatitis C virus (HCV) infection and drives the host specific innate and adaptive immune response. The aim of this study was to estimate the distributions of TLR7 single nucleotide polymorphisms (SNPs), including rs179019 and rs3853839, as well as the effect of TLR7 gene variants on TLR7 mRNA expression and cytokine production in response to TLR7 agonist in vitro. TLR7 SNP genotyping was performed among a Chinese sample population of 418 patients with persistent HCV infection, 317 patients with HCV spontaneous clearance, and 989 healthy controls. TLR7 mRNA expression and TLR7-specific IFN alpha and IL-6 secretion in peripheral blood mononuclear cells, derived from 60 healthy individuals in vitro, were then quantified. We identified the association of TLR7 rs3853839C allele, haplotype CC and haplotype AC (rs179019/rs3853839) with protection against HCV persistence in Chinese females (OR=0.49, 95% CI=0.29 0.81, P=0.01 for rs3853839 GC; OR=0.29, 95% CI=0.11-0.75, P=0.01 for rs3853839 CC; OR=0.51, 95% CI=0.38-0.77, P<0.01 for haplotype CC; OR=0.29, 95% CI=0.10 0.88, P=0.03 for haplotype AC). In addition, the rs3853839 CC genotype among female carriers had significantly low TLR7 mRNA expression (P=0.006 for GG vs. CC, P=0.021 for GC vs. CC), along with decreased IFN-alpha (P=0.002 for GG vs. CC, P=0.021 for GC vs. CC) and increased antiviral IL-6 production (P=0.002 for GG vs. CC, P=0.030 for GC vs. CC), after treatment with Imiquimod in vitro. The cytokine profile among rs3853839 CC genotype female carriers may indicate a pronounced protective effect against persistent HCV infection. The functional polymorphism of TLR7 rs3853839C allele was found to be sex-specific and associated with protection against HCV persistence among Chinese females, which may be due to specific IFN-alpha and IL-6 secretion profiles. PMID- 25034661 TI - Whole transcriptome RNA-seq analysis: tumorigenesis and metastasis of melanoma. AB - Melanoma is the most malignant cutaneous cancer and causes over 9000 deaths annually. Because fatality rates from malignant melanoma (MM) increase dramatically upon metastasis, we investigated tumorigenesis and metastasis of MM in transcriptome analyses of three distinct cell lines that correspond with the stages of MM pathogenesis: the normal stage (HEMn-LP), the onset of MM (A375), and the metastasis stage (A2058). Using next-generation sequencing (NGS) technology, we detected asymmetrical expression of genes among the three cell lines, notably on chromosomes 9, 11, 12, and 14, suggesting their involvement in tumorigenesis and metastasis of MM. These genes were clustered into 41 categories based on their expression patterns, and their biological functions were analyzed using Ingenuity Pathway Analysis. In the top cancer-associated category, HIF1A, IL8, TERT, ONECUT1, and FOXA1 directly interacted with either transcription factors or cytokines that are known to be involved in the tumorigenesis or metastasis of other malignant tumors. The present data suggest that cytokine regulatory pathways in macrophages predominate over other pathways during the pathogenesis of MM. This study provides new targets for the downstream mechanistic studies of the tumorigenesis and metastasis of MM and demonstrates a new strategy for studies of the progression of other malignant cancers. PMID- 25034662 TI - Phylogenetic analysis and evolutionary studies of plant carotenoid cleavage dioxygenase gene. AB - The oxidative breakdown of carotenoid evidences the formation of apocarotenoids through carotenoid cleavage dioxygenases (CCDs). Numerous CCDs and apocarotenoids have been identified and characterized in plants. Using available sequence data, a study was performed to investigate the phylogenetic relationship among CCD genes and to statistically estimate the sequence conservation and functional divergence. In total, 77 genes were identified from 39 species belonging to 21 families. Our result of phylogenetic analysis indicated the existence of well conserved subfamilies. Moreover, comparative genomic analysis showed that the gene structures of the CCDs were highly conserved across some different lineage species. Through functional divergence analysis, a substantial divergence was found between CCD subfamilies. In addition, examination of the site-specific profile revealed the critical amino acid residues accounting for functional divergence. This study mainly focused on the evolution of CCD genes and their functional divergence which may deliver an initial step for further experimental verifications. PMID- 25034663 TI - Psychiatric boarding incidence, duration, and associated factors in United States emergency departments. AB - INTRODUCTION: Boarding, especially among psychiatric patients, has been characterized as a significant cause of ED crowding, but no quantitative analysis has described boarding nationally. This study determines the incidence, duration, and factors associated with ED boarding in the United States. METHODS: 2008 National Hospital Ambulatory Medical Care Survey ED data were stratified by visit type (psychiatric vs. non-psychiatric), boarding status, and patient and hospital characteristics. Boarding was defined as a visit with an ED length of stay >6 hours, and boarding time as ED length of stay minus 6 hours. Pearson's chi-square tests describe hospital and patient characteristics stratified by boarding status. Multilevel multivariable logistic and linear regressions determine associations with boarding and boarding time. RESULTS: While 11% of all ED patients boarded, 21.5% of all psychiatric ED patients boarded. Boarding was also more prolonged for psychiatric ED patients. Controlling for confounders, odds of boarding for psychiatric patients were 4.78 (2.63-8.66) times higher than non psychiatric, and psychiatric patients boarded 2.78 (1.91-3.64) hours longer than non-psychiatric. DISCUSSION: US EDs experienced high proportions and durations of boarding with psychiatric patients disproportionately affected. Additional research concerning mental health care services and legislation may be required to address ED psychiatric patient boarding. PMID- 25034664 TI - A profile of women at the highest risk of maternal death in Pakistan. AB - Traditionally, health interventions implemented in Pakistan have been designed to increase the supply of maternal health services, but have not focused on reaching the poorest women or on providing high-quality services. Demand-side barriers to the utilization of health services are substantial in Pakistan, as are supply side constraints to the provision of quality health care. This study uses data from the Pakistan Demographic and Health Survey 2006-07 to develop a profile of the poorest women in Pakistan in order to understand demand-side barriers to accessing maternal health care. The study shows stark differences in human capital, material and demographic resources between the poorest women and other women. It illustrates how these differences translate into low levels of service utilization among the poorest women. The purpose of the study is to stimulate a discussion of both the difficulty and the importance of reaching the poorest women with high-quality maternal health interventions. The findings from several pilot projects in Pakistan suggest that the poorest women can be reached at disproportionately higher rates than non-poor women through targeted, community based, interventions. There is little demonstrable evidence, however, that high quality care has been provided through these interventions. Evidence-based approaches, which have the potential to overcome financial and sociocultural barriers to service utilization, should be scaled up as soon as possible. However, measures should be taken to ensure that the quality of care provided through these interventions is adequate and able to lead to significant reductions in mortality. PMID- 25034665 TI - Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. AB - Catalytic asymmetric 1,3-dipolar cycloadditions of azomethine ylides have turned out to be one of the most efficient methods for the preparation of enantioenriched pyrrolidines. The past decade has witnessed the development of a bunch of well-defined catalytic systems capable of affording excellent diastereo and enantioselectivities. Recently, a great effort has been focused on expanding the scope of the cycloaddition with regard to both reaction partners. In this review, we will discuss important advances that have been reported in this area since 2011. PMID- 25034666 TI - Latent homology and convergent regulatory evolution underlies the repeated emergence of yeasts. AB - Convergent evolution is common throughout the tree of life, but the molecular mechanisms causing similar phenotypes to appear repeatedly are obscure. Yeasts have arisen in multiple fungal clades, but the genetic causes and consequences of their evolutionary origins are unknown. Here we show that the potential to develop yeast forms arose early in fungal evolution and became dominant independently in multiple clades, most likely via parallel diversification of Zn cluster transcription factors, a fungal-specific family involved in regulating yeast-filamentous switches. Our results imply that convergent evolution can happen by the repeated deployment of a conserved genetic toolkit for the same function in distinct clades via regulatory evolution. We suggest that this mechanism might be a common source of evolutionary convergence even at large time scales. PMID- 25034668 TI - Erratum to: Albiglutide Does Not Prolong QTc Interval in Healthy Subjects: A Thorough ECG Study. PMID- 25034667 TI - CLA supplementation and aerobic exercise lower blood triacylglycerol, but have no effect on peak oxygen uptake or cardiorespiratory fatigue thresholds. AB - This study examined the effects of 6 weeks of conjugated linoleic acid (CLA) supplementation and moderate aerobic exercise on peak oxygen uptake (VO2 peak), the gas exchange threshold (GET), the respiratory compensation point (RCP), and serum concentrations of cholesterol, triacylglycerol, and glucose in humans. Thirty-four untrained to moderately trained men (mean +/- SD; age = 21.5 +/- 2.8 years; mass = 77.2 +/- 9.5 kg) completed this double-blind, placebo controlled study and were randomly assigned to either a CLA (Clarinol A-80; n = 18) or placebo (PLA; sunflower oil; n = 16) group. Prior to and following 6 weeks of aerobic training (50% VO2 peak for 30 min, twice per week) and supplementation (5.63 g of total CLA isomers [of which 2.67 g was c9, t11 and 2.67 g was t10, c12] or 7.35 g high oleic sunflower oil per day), each participant completed an incremental cycle ergometer test to exhaustion to determine their [Formula: see text] peak, GET, and RCP and fasted blood draws were performed to measure serum concentrations of cholesterol, triacylglycerol, and glucose. Serum triacylglycerol concentrations were lower (p < 0.05) in the CLA than the PLA group. For VO2 peak and glucose, there were group * time interactions (p < 0.05), however, post hoc statistical tests did not reveal any differences (p > 0.05) between the CLA and PLA groups. GET and RCP increased (p < 0.05) from pre- to post-training for both the CLA and PLA groups. Overall, these data suggested that CLA and aerobic exercise may have synergistic, blood triacylglycerol lowering effects, although CLA may be ineffective for enhancing aerobic exercise performance in conjunction with a 6-week aerobic exercise training program in college-age men. PMID- 25034669 TI - Genetic and antigenic characterization of a newly emerging porcine circovirus type 2b mutant first isolated in cases of vaccine failure in Korea. AB - This study describes the genetic and antigenic characterization of a newly emerging porcine circovirus type 2b (PCV2b) mutant first isolated in cases of vaccine failure in Korea. The full genome of the PCV2b isolates (SNUVR130689 and SNUVR140004) is 1,767 base pairs (bp) in length. The size of ORF1 is 945 bp, encoding a protein of 314 amino acids (aa), and the size of ORF2 is 705 bp, encoding a protein of 234 aa, which is 1 aa longer than that of the common PCV2 (233 aa). Korean PCV2b mutant strains had higher levels of nucleotide sequence identity to other PCV2b mutant strains (99.7-99.8 %) than to reference PCV2a (94.5-95.0 %) and PCV2b (95.5-96.1 %) strains. There was no difference in antigenic reactivity among PCV2a, PCV2b and PCV2b mutant strains to the polyclonal and monoclonal PCV2a antibodies. PCV2b mutant strains have distinct genetic characteristics but similar antigenic reactivity when compared to common PCV2a and 2b strains. PMID- 25034670 TI - Molecular characterisation of novel mitoviruses associated with Sclerotinia sclerotiorum. AB - Seven putative mitoviral genomes, representing four species from three Sclerotinia sclerotiorum isolates, were fully sequenced. The genome lengths ranged from 2438 to 2815 nucleotides. The RNA-dependent RNA polymerase (RdRp) of one genome shared high amino acid (aa) sequence identity (98.5 %) with the previously described Sclerotinia sclerotiorum mitovirus 2 (SsMV2/NZ1) and was provisionally assigned the name SsMV2/14563. The RdRps of three of the genomes with closest aa sequence identity of 78.8-79.3 % to Sclerotinia sclerotiorum mitovirus 1 (SsMV1/KL1) were provisionally considered to represent a new species, and the corresponding virus was named Sclerotinia sclerotiorum mitovirus 5 (SsMV5/11691, SsMV5/14563 and SsMV5/Lu471). The remaining two novel genomes, for which the viruses were provisionally named Sclerotinia sclerotiorum mitovirus 6 (SsMV6/14563 and SsMV6/Lu471) and Sclerotinia sclerotiorum mitovirus 7 (SsMV7/Lu471), showed closest aa sequence identities to Sclerotinia sclerotiorum mitovirus 3 (SsMV3/NZ1; 57.5-57.8 %) and Cryphonectria cubensis mitovirus 1a (CcMV1a; 32 %), respectively. The RdRp proteins of all seven genomes contained the conserved aa sequence motifs (I-IV) previously reported for mitoviruses, and their 5' and 3' untranslated regions (UTRs) have the potential to fold into stem loop secondary structures. PMID- 25034671 TI - Can appropriate diagnosis and treatment of childhood asthma reduce excessive antibiotic usage? AB - INTRODUCTION: This study compared the frequency of antibiotic usage and the number of asthma episodes before and after the diagnosis and treatment of pediatric asthma patients who were followed up by specialists. SUBJECTS AND METHODS: Included in this study were 334 patients (211 males and 123 females) of 2-16 years of age who were diagnosed with asthma and followed up for at least 1 year in our clinic. The frequency of antibiotic usage and the number of asthma episodes in the year prior to diagnosis and treatment were compared to these same variables after 1 year of follow-up by specialists. RESULTS: The median age was 84 months (range: 24-192) and 212 (63%) children were at school or in day care centers. Atopy and a family history of asthma were present in 200 (60%) of the patients, and 137 (41%) reported that at least one member of their household smoked. Antibiotics were used a median number of 7 times [interquartile range (IQR) = 6] in the year before the asthma diagnosis, and 2 times (IQR = 3) during the year after treatment (p < 0.001). The mean number of asthma episodes before diagnosis, i.e. 4 (IQR = 8) was reduced to 0 (IQR = 2) in the year after treatment when the patients were followed up by specialists (p < 0.001). CONCLUSION: This study shows that appropriate diagnosis and treatment of childhood asthma significantly reduce the frequency of antibiotic usage and the number of asthmatic episodes. PMID- 25034672 TI - AHVLA invites tenders for TB testing and other veterinary services. PMID- 25034674 TI - Ability to use antibiotics preventively must be maintained, says BVA. PMID- 25034675 TI - Research into TB vaccination 'will not be hindered by lack of resources'. PMID- 25034677 TI - FAO identifies top 10 foodborne parasites. PMID- 25034678 TI - Cases of ASF confirmed in Latvia. PMID- 25034679 TI - Construction of avian diseases laboratory gets underway at Pirbright. PMID- 25034680 TI - Innovation centre to help make fish an even bigger business in Scotland. PMID- 25034681 TI - One Health in action: the work of the HAIRS group. AB - The Human Animal Infections and Risk Surveillance (HAIRS) group is a collaboration between a number of human and animal health organisations within the UK government. The group aims to provide a 'joined-up' response to emerging diseases that threaten the health of people or animals. Here, Dilys Morgan, who chairs the group, discusses its work, highlighting its response to Schmallenberg virus, and shows how a One Health approach can improve government responses to potential crises. PMID- 25034682 TI - An alternative to surgical desexing in ferrets. PMID- 25034683 TI - Non-stun slaughter. PMID- 25034684 TI - Confirmation of LA-MRSA in pigs in the UK. PMID- 25034685 TI - Confirmation of myxomatosis in a European brown hare in Great Britain. PMID- 25034687 TI - Construction of mate pair full-length cDNAs libraries and characterization of transcriptional start sites and termination sites. AB - To identify and characterize transcript structures ranging from transcriptional start sites (TSSs) to poly(A)-addition sites (PASs), we constructed and analyzed human TSS/PAS mate pair full-length cDNA libraries from 14 tissue types and four cell lines. The collected information enabled us to define TSS cluster (TSC) and PAS cluster (PAC) relationships for a total of 8530/9400 RefSeq genes, as well as 4251/5618 of their putative alternative promoters/terminators and 4619/4605 intervening transcripts, respectively. Analyses of the putative alternative TSCs and alternative PACs revealed that their selection appeared to be mostly independent, with rare exceptions. In those exceptional cases, pairs of transcript units rarely overlapped one another and were occasionally separated by Rad21/CTCF. We also identified a total of 172 similar cases in which TSCs and PACs spanned adjacent but distinct genes. In these cases, different transcripts may utilize different functional units of a particular gene or of adjacent genes. This approach was also useful for identifying fusion gene transcripts in cancerous cells. Furthermore, we could construct cDNA libraries in which 3'-end mate pairs were distributed randomly over the transcripts. These libraries were useful for assembling the internal structure of previously uncharacterized alternative promoter products, as well as intervening transcripts. PMID- 25034688 TI - Road rules for traffic on DNA-systematic analysis of transcriptional roadblocking in vivo. AB - Genomic DNA is bound by many proteins that could potentially impede elongation of RNA polymerase (RNAP), but the factors determining the magnitude of transcriptional roadblocking in vivo are poorly understood. Through systematic experiments and modeling, we analyse how roadblocking by the lac repressor (LacI) in Escherichia coli cells is controlled by promoter firing rate, the concentration and affinity of the roadblocker protein, the transcription-coupled repair protein Mfd, and promoter-roadblock spacing. Increased readthrough of the roadblock at higher RNAP fluxes requires active dislodgement of LacI by multiple RNAPs. However, this RNAP cooperation effect occurs only for strong promoters because roadblock-paused RNAP is quickly terminated by Mfd. The results are most consistent with a single RNAP also sometimes dislodging LacI, though we cannot exclude the possibility that a single RNAP reads through by waiting for spontaneous LacI dissociation. Reducing the occupancy of the roadblock site by increasing the LacI off-rate (weakening the operator) increased dislodgement strongly, giving a stronger effect on readthrough than decreasing the LacI on rate (decreasing LacI concentration). Thus, protein binding kinetics can be tuned to maintain site occupation while reducing detrimental roadblocking. PMID- 25034689 TI - Inducible, tightly regulated and growth condition-independent transcription factor in Saccharomyces cerevisiae. AB - The precise control of gene expression is essential in basic biological research as well as in biotechnological applications. Most regulated systems available in yeast enable only the overexpression of the target gene, excluding the possibility of intermediate or weak expression. Moreover, these systems are frequently toxic or depend on growth conditions. We constructed a heterologous transcription factor that overcomes these limitations. Our system is a fusion of the bacterial LexA DNA-binding protein, the human estrogen receptor (ER) and an activation domain (AD). The activity of this chimera, called LexA-ER-AD, is tightly regulated by the hormone beta-estradiol. The selection of the AD proved to be crucial to avoid toxic effects and to define the range of activity that can be precisely tuned with beta-estradiol. As our system is based on a heterologous DNA-binding domain, induction in different metabolic contexts is possible. Additionally, by controlling the number of LexA-binding sites in the target promoter, one can scale the expression levels up or down. Overall, our LexA-ER-AD system is a valuable tool to precisely control gene expression in different experimental contexts without toxic side effects. PMID- 25034690 TI - Nuclear dynamics of topoisomerase IIbeta reflects its catalytic activity that is regulated by binding of RNA to the C-terminal domain. AB - DNA topoisomerase II (topo II) changes DNA topology by cleavage/re-ligation cycle(s) and thus contributes to various nuclear DNA transactions. It is largely unknown how the enzyme is controlled in a nuclear context. Several studies have suggested that its C-terminal domain (CTD), which is dispensable for basal relaxation activity, has some regulatory influence. In this work, we examined the impact of nuclear localization on regulation of activity in nuclei. Specifically, human cells were transfected with wild-type and mutant topo IIbeta tagged with EGFP. Activity attenuation experiments and nuclear localization data reveal that the endogenous activity of topo IIbeta is correlated with its subnuclear distribution. The enzyme shuttles between an active form in the nucleoplasm and a quiescent form in the nucleolus in a dynamic equilibrium. Mechanistically, the process involves a tethering event with RNA. Isolated RNA inhibits the catalytic activity of topo IIbeta in vitro through the interaction with a specific 50 residue region of the CTD (termed the CRD). Taken together, these results suggest that both the subnuclear distribution and activity regulation of topo IIbeta are mediated by the interplay between cellular RNA and the CRD. PMID- 25034691 TI - A multicopy sRNA of Listeria monocytogenes regulates expression of the virulence adhesin LapB. AB - The multicopy sRNA LhrC of the intracellular pathogen Listeria monocytogenes has been shown to be induced under infection-relevant conditions, but its physiological role and mechanism of action is not understood. In an attempt to pinpoint the exact terms of LhrC expression, cell envelope stress could be defined as a specific inducer of LhrC. In this process, the two-component system LisRK was shown to be indispensable for expression of all five copies of LhrC. lapB mRNA, encoding a cell wall associated protein that was recently identified as an important virulence factor, was disclosed to be directly bound by LhrC leading to an impediment of its translation. Although LhrC binds to Hfq, it does not require the RNA chaperone for stability or lapB mRNA interaction. The mechanism of LhrC-lapB mRNA binding was shown to involve three redundant CU-rich sites and a structural rearrangement in the sRNA. This study represents an extensive depiction of a so far uncharacterized multicopy sRNA and reveals interesting new aspects concerning its regulation, virulence association and mechanism of target binding. PMID- 25034692 TI - ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells. AB - Embryonic stem (ES) cells are in a dynamic equilibrium of distinct functional states, characterized by the heterogeneous expression of critical pluripotency factors and regulated by a spectrum of reversible histone modifications. Maintenance of this equilibrium is a hallmark of pluripotency. Here we find that the ADP-ribosyltransferases Parp1 and Parp7 play a critical role in safeguarding this state by occupying key pluripotency genes, notably Nanog, Pou5f1, Sox2, Stella, Tet1 and Zfp42, thereby protecting them from progressive epigenetic repression. In the absence of either Parp1 or Parp7, or upon inhibition of the ADP-ribosylating activity, ES cells exhibit a decrease in ground state pluripotency as they cannot maintain the typical heterogeneity characteristic of the metastable state. As a consequence, they display a higher propensity to differentiate. These findings place Parp1 and Parp7 at the genetic-epigenetic interface of pluripotency networks, fine-tuning the transcriptional heterogeneity and thereby determining the developmental plasticity of ES cells. PMID- 25034693 TI - SpliceNet: recovering splicing isoform-specific differential gene networks from RNA-Seq data of normal and diseased samples. AB - Conventionally, overall gene expressions from microarrays are used to infer gene networks, but it is challenging to account splicing isoforms. High-throughput RNA Sequencing has made splice variant profiling practical. However, its true merit in quantifying splicing isoforms and isoform-specific exon expressions is not well explored in inferring gene networks. This study demonstrates SpliceNet, a method to infer isoform-specific co-expression networks from exon-level RNA-Seq data, using large dimensional trace. It goes beyond differentially expressed genes and infers splicing isoform network changes between normal and diseased samples. It eases the sample size bottleneck; evaluations on simulated data and lung cancer-specific ERBB2 and MAPK signaling pathways, with varying number of samples, evince the merit in handling high exon to sample size ratio datasets. Inferred network rewiring of well established Bcl-x and EGFR centered networks from lung adenocarcinoma expression data is in good agreement with literature. Gene level evaluations demonstrate a substantial performance of SpliceNet over canonical correlation analysis, a method that is currently applied to exon level RNA-Seq data. SpliceNet can also be applied to exon array data. SpliceNet is distributed as an R package available at http://www.jjwanglab.org/SpliceNet. PMID- 25034694 TI - In vivo co-localization of enzymes on RNA scaffolds increases metabolic production in a geometrically dependent manner. AB - Co-localization of biochemical processes plays a key role in the directional control of metabolic fluxes toward specific products in cells. Here, we employ in vivo scaffolds made of RNA that can bind engineered proteins fused to specific RNA binding domains. This allows proteins to be co-localized on RNA scaffolds inside living Escherichia coli. We assembled a library of eight aptamers and corresponding RNA binding domains fused to partial fragments of fluorescent proteins. New scaffold designs could co-localize split green fluorescent protein fragments to produce activity as measured by cell-based fluorescence. The scaffolds consisted of either single bivalent RNAs or RNAs designed to polymerize in one or two dimensions. The new scaffolds were used to increase metabolic output from a two-enzyme pentadecane production pathway that contains a fatty aldehyde intermediate, as well as three and four enzymes in the succinate production pathway. Pentadecane synthesis depended on the geometry of enzymes on the scaffold, as determined through systematic reorientation of the acyl-ACP reductase fusion by rotation via addition of base pairs to its cognate RNA aptamer. Together, these data suggest that intra-cellular scaffolding of enzymatic reactions may enhance the direct channeling of a variety of substrates. PMID- 25034695 TI - Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer. AB - The mechanism for generating double minutes chromosomes (dmin) and homogeneously staining regions (hsr) in cancer is still poorly understood. Through an integrated approach combining next-generation sequencing, single nucleotide polymorphism array, fluorescent in situ hybridization and polymerase chain reaction-based techniques, we inferred the fine structure of MYC-containing dmin/hsr amplicons harboring sequences from several different chromosomes in seven tumor cell lines, and characterized an unprecedented number of hsr insertion sites. Local chromosome shattering involving a single-step catastrophic event (chromothripsis) was recently proposed to explain clustered chromosomal rearrangements and genomic amplifications in cancer. Our bioinformatics analyses based on the listed criteria to define chromothripsis led us to exclude it as the driving force underlying amplicon genesis in our samples. Instead, the finding of coexisting heterogeneous amplicons, differing in their complexity and chromosome content, in cell lines derived from the same tumor indicated the occurrence of a multi-step evolutionary process in the genesis of dmin/hsr. Our integrated approach allowed us to gather a complete view of the complex chromosome rearrangements occurring within MYC amplicons, suggesting that more than one model may be invoked to explain the origin of dmin/hsr in cancer. Finally, we identified PVT1 as a target of fusion events, confirming its role as breakpoint hotspot in MYC amplification. PMID- 25034696 TI - Molecular mechanisms of master regulator VqsM mediating quorum-sensing and antibiotic resistance in Pseudomonas aeruginosa. AB - The Pseudomonas aeruginosa quorum-sensing (QS) systems contribute to bacterial homeostasis and pathogenicity. Although the AraC-family transcription factor VqsM has been characterized to control the production of virulence factors and QS signaling molecules, its detailed regulatory mechanisms still remain elusive. Here, we report that VqsM directly binds to the lasI promoter region, and thus regulates its expression. To identify additional targets of VqsM in P. aeruginosa PAO1, we performed chromatin immunoprecipitation (ChIP) followed by high throughput DNA sequencing (ChIP-seq) and detected 48 enriched loci harboring VqsM binding peaks in the P. aeruginosa genome. The direct regulation of these genes by VqsM has been confirmed by electrophoretic mobility shift assays and quantitative real-time polymerase chain reactions. A VqsM-binding motif was identified by using the MEME suite and verified by footprint assays in vitro. In addition, VqsM directly bound to the promoter regions of the antibiotic resistance regulator NfxB and the master type III secretion system (T3SS) regulator ExsA. Notably, the vqsM mutant displayed more resistance to two types of antibiotics and promoted bacterial survival in a mouse model, compared to wild type PAO1. Collectively, this work provides new cues to better understand the detailed regulatory networks of QS systems, T3SS, and antibiotic resistance. PMID- 25034697 TI - Estimation of the RNU2 macrosatellite mutation rate by BRCA1 mutation tracing. AB - Large tandem repeat sequences have been poorly investigated as severe technical limitations and their frequent absence from the genome reference hinder their analysis. Extensive allelotyping of this class of variation has not been possible until now and their mutational dynamics are still poorly known. In order to estimate the mutation rate of a macrosatellite, we analysed in detail the RNU2 locus, which displays at least 50 different alleles containing 5-82 copies of a 6.1 kb repeat unit. Mining data from the 1000 Genomes Project allowed us to precisely estimate copy numbers of the RNU2 repeat unit using read depth of coverage. This further revealed significantly different mean values in various recent modern human populations, favoring a scenario of fast evolution of this locus. Its proximity to a disease gene with numerous founder mutations, BRCA1, within the same linkage disequilibrium block, offered the unique opportunity to trace RNU2 arrays over a large timescale. Analysis of the transmission of RNU2 arrays associated with one 'private' mutation in an extended kindred and four founder mutations in multiple kindreds gave an estimation by maximum likelihood of 5 * 10(-3) mutations per generation, which is close to that of microsatellites. PMID- 25034698 TI - Spacing requirements for Class I transcription activation in bacteria are set by promoter elements. AB - The Escherichia coli cAMP receptor protein (CRP) activates transcription initiation at many promoters by binding upstream of core promoter elements and interacting with the C-terminal domain of the RNA polymerase alpha subunit. Previous studies have shown stringent spacing is required for transcription activation by CRP. Here we report that this stringency can be altered by the nature of different promoter elements at target promoters. Several series of CRP dependent promoters were constructed with CRP moved to different upstream locations, and their activities were measured. The results show that (i) a full UP element, located immediately downstream of the DNA site for CRP, relaxes the spacing requirements for activation and increases the recruitment of RNAP and open complex formation; (ii) the distal UP subsite plays the key role in this relaxation; (iii) modification of the extended -10 element also affects the spacing requirements for CRP-dependent activation. From these results, we conclude that the spacing requirements for CRP-dependent transcription activation vary according to the sequence of different promoter elements, and our results are important for understanding the organization of promoters in many different bacteria which are controlled by transcription factors that use activatory mechanisms similar to CRP. PMID- 25034699 TI - Characteristics affecting oral anticoagulant therapy choice among patients with non-valvular atrial fibrillation: a retrospective claims analysis. AB - BACKGROUND: Dabigatran is one of the three newer oral anticoagulants (OACs) recently approved in the United States for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. The objective of this study was to identify patient, healthcare provider, and health plan factors associated with dabigatran versus warfarin use among NVAF patients. METHODS: Administrative claims data from patients with >= 2 NVAF medical claims in the HealthCore Integrated Research Database between 10/1/2009 and 10/31/2011 were analyzed. During the study intake period (10/1/2010 - 10/31/2011), dabigatran patients had >= 2 dabigatran prescriptions, warfarin patients had >= 2 warfarin and no dabigatran prescriptions, and the first oral anticoagulant (OAC) prescription date was the index date. Continuous enrollment for 12 months preceding ("pre-index") and >= 6 months following the index date was required. Patients without pre-index warfarin use were assigned to the 'OAC-naive' subgroup. Separate analyses were performed for 'all-patient' and 'OAC-naive' cohorts. Multivariable logistic regression (LR) identified factors associated with dabigatran versus warfarin use. RESULTS: Of 20,320 patients (3,019 dabigatran and 17,301 warfarin) who met study criteria, 27% of dabigatran and 13% of warfarin patients were OAC-naive. Among all patients, dabigatran patients were younger (mean 67 versus 73 years, p < 0.001), predominantly male (71% versus 61%, p < 0.001), and more frequently had a cardiologist prescriber (51% versus 30%, p < 0.001) than warfarin patients. Warfarin patients had higher pre-index Elixhauser Comorbidity Index (mean: 4.3 versus 4.0, p < 0.001) and higher ATRIA bleeding risk score (mean: 3.0 versus 2.3, p < 0.001). LR results were generally consistent between all- and OAC-naive patients. Among OAC-naive patients, strongest factors associated with dabigatran use were prescriber specialty (OR = 3.59, 95% CI 2.68-4.81 for cardiologist; OR = 2.22, 95% CI 1.65-2.97 for other specialist), health plan type (OR = 1.47 95% CI 1.10-1.96 for preferred provider organization), and prior ischemic stroke (OR = 1.42, 95% CI 1.06-1.90). Older age decreased the probability of dabigatran use. CONCLUSIONS: Beside patient characteristics, cardiology specialty of the prescribing physician and health plan type were the strongest factors associated with dabigatran use. PMID- 25034700 TI - The association between obesity and blood pressure in Thai public school children. AB - BACKGROUND: The prevalence of obesity has substantially increased in the past 3 decades in both developed and developing countries and may lead to an increase in high blood pressure (BP) at an early age. This study aimed to determine the prevalence of obesity and its association with blood pressure among primary school children in central Thailand. METHODS: A cross-sectional study was conducted in two public schools in Bangkok in 2012. A total of 693 students (317 boys and 376 girls) aged 8-12 years participated voluntarily. Anthropometric measurements of weight, height, waist circumference (WC) and BP were collected. Fasting venous blood samples were obtained for biochemical analysis of fasting plasma glucose (FPG) and lipid parameters. Child nutritional status was defined by body mass index (BMI) for age based on the 2000 Center for Diseases Control and Prevention growth charts. The cutoff for abdominal obesity was WC at the 75 percentile or greater. Hypertension was defined according to the 2004 Pediatrics US blood pressure reference. Multinomial logistic regression was used to examine the relationship between high BP and obesity after controlling for other covariates. RESULTS: The prevalence of obese children was 30.6% for boys and 12.8% for girls (mean prevalence 20.9%). Pre-hypertension (Pre-HT) was 5.7% and 2.7% for boys and girls and hypertension (HT) was 4.7% for boys and 3.2% for girls, respectively. Children with pre-HT and HT had significantly higher body weight, height, WC, BMI, SBP, DBP, TG, and TC/HDL-C levels but lower HDL-C levels than those children with normotension. After controlling for age, sex, glucose and lipid parameters, child obesity was significantly associated with pre-HT and HT (odds rations (ORs) = 9.00, 95% CI: 3.20-25.31 for pre-HT and ORs = 10.60, 95% CI: 3.75-30.00 for HT). So also was WC (abdominal obesity) when considered alone (ORs = 6.20, 95% CI: 2.60-14.81 for pre-HT and ORs = 13.73, 95% CI: 4.85-38.83 for HT) (p-value < 0.001). CONCLUSIONS: Obesity among school children was positively associated with higher BP. Prevention of childhood obesity should be strengthened to prevent the risk of early high BP including cardiovascular risk factors. PMID- 25034701 TI - Beta-blockers in heart failure with preserved ejection fraction: a meta-analysis. AB - Beta-blockers are established drugs in heart failure with reduced ejection fraction, but their role in heart failure with preserved ejection fraction (HFpEF) is not established. Hence, we undertook a meta-analysis to evaluate the efficacy of beta-blockers on mortality and morbidity in HFpEF patients. A systematic search using PubMed, Embase, Scopus and Cochrane databases was performed to identify all relevant studies on beta-blockers and HFpEF. A random effects model was performed to assess the role of beta-blockers on all-cause mortality and HF hospitalization. Overall 15 observational studies and two randomized control trial involving a total of 27,099 patients were included in the analysis. In the observational studies, beta-blocker therapy was associated with lower all-cause mortality [RR 0.81 (0.72-0.90), p < 0.001], but not HF hospitalization [RR 0.79 (0.57-1.10), p < 0.001]. However, in the two RCTs, the use of beta-blocker was not associated with all-cause mortality [RR 0.94 (0.67 1.32), p = 0.72] or HF hospitalization [0.90 (0.54-1.49), p = 0.68]. The results were consistent by geographic region (USA vs. rest of world) and ejection fraction subgroups. Subgroup analysis revealed that the beneficial survival effect of beta-blocker was limited to studies with mean age <75 years. Observational studies showed a significant benefit from the use of beta-blockers for all-cause mortality, but not for HF hospitalization. Beta-blockers in the two RCTs were not associated with significant reduction in all-cause mortality or HF hospitalization; however, both the trials were not adequately powered and had high loss to follow-up rates. Further large sampled well-conducted randomized trials are warranted to confirm the effects of beta-blockers on mortality and hospitalization. PMID- 25034702 TI - Tegumentary leishmaniasis: a diagnostic approach considering aspects of the cytological examination. AB - OBJECTIVE: To elaborate figures that highlight the microscopic appearance of amastigote forms of the genus Leishmania and other structures subject to confusion during the routine of the direct examination of tegumentary leishmaniasis (TL). STUDY DESIGN: We reviewed imprint and scraping slides previously prepared from patients with a definite diagnosis. Smear examinations were performed with an immersion objective (*1,000) selecting structures of interest for photodocumentation and elaboration of the illustrations. RESULTS: We elaborated two 13 * 17 cm figures containing photomicrographs of amastigote forms with typical and atypical morphology of Leishmania parasites and other microorganisms, mainly fungi in the yeast-like phase and bacteria which could be confused with amastigote forms during the direct examination. CONCLUSIONS: The production of material like we show here is important and should be encouraged because of the need for constant training of professionals working in the area of TL diagnosis. PMID- 25034703 TI - Brain invasion assessability in meningiomas is related to meningioma size and grade, and can be improved by extensive sampling of the surgically removed meningioma specimen. AB - AIMS: Despite the important prognostic value of brain invasion in meningiomas, little attention has been paid to its massessment, and the parameters associated with brain invasion assessability (identification of brain tissue in the surgical specimen) are not well characterized. The aim of our study was to determine the parameters that are associated with brain invasion assessability and brain invasion in meningiomas. MATERIAL AND METHODS: By binary logistic regression analysis, we studied the association of various clinical and pathologic parameters with brain invasion assessabilitym and brain invasion in 294 meningiomas: 149 unselected consecutive meningiomas with extensive sampling, diagnosed in 2009 and 2010, collected prospectively, and 145 meningiomas diagnosed in 1999 and 2000 when little attention was paid to brain invasion assessment. RESULTS: Meningioma grade, size and number of tissue blocks were independent predictors of brain invasion assessability. Brain tissue was identified in 78 of 233 (33%) benign, 33 of 51 (65%) atypical, and 10 of 10 (100%) malignant meningiomas. In univariate analysis, group (prospective vs.retrospective), type (recurrent vs. primary), cleavability, meningioma grade and mitotic count were predictors of brain invasion, while only meningioma grade, and group retained predictive value in multivariate analysis. Brain invasion, when assessable, was identified in 22 of 78 (28%) benign, 21 of 33 (64%) atypical, and 10 of 10 (100%) malignant meningiomas. CONCLUSIONS: Brain invasion assessability is related to meningioma grade and size and can be improved by extensive sampling of meningioma surgical. PMID- 25034704 TI - Pleomorphic xanthoastrocytoma: report of two cases with unconventional clinical presentations. AB - AIMS: Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm with a relative circumscribed architecture that typically arises superficially in the cerebral hemispheres of teenagers and young adults. Our aim is to highlight unconventional clinical presentations of this distinct neoplasm. MATERIALS AND METHODS: We report two cases of PXA with unconventional clinical features, including clinical, pathologic, and immunohistochemical features. RESULTS: The first case developed in the left frontal lobe of a 20-year-old female with neurofibromatosis type 1 (NF1). Focal anaplastic features were present. The neoplastic cells were immunoreactive for GFAP, S-100 protein and focally for synaptophysin, with a MIB-1/Ki-67 proliferative labelling index of 16%. The second case developed in a 39-year-old female as a suprasellar neoplasm. The neoplastic cells expressed GFAP, S-100 protein and focally CD34. The adenohypophysis was positive for synaptophysin and pituicytes for TTF1. Molecular studies were negative for BRAF (V600E) mutation in both cases. CONCLUSION: PXA is a distinct circumscribed neoplasm that may present in unexpected locations or clinical backgrounds. Neuropathologists must be aware of these unconventional presentations in order to provide a precise diagnosis leading to appropriate treatment. PMID- 25034705 TI - Midterm outcome of implantable left ventricular assist devices as a bridge to transplantation: Single-center experience in Japan. AB - BACKGROUND: Two implantable continuous-flow left ventricular assist devices (LVADs), DuraHeart (Terumo Heart, Ann Arbor, MI, USA) and EVAHEART (Sun Medical, Nagano, Japan), were approved in Japan in April 2011. We analyzed the midterm outcome of patients implanted with these implantable LVADs at the University of Tokyo Hospital. METHODS AND RESULTS: A total of 31 patients who underwent implantation of LVADs (10 DuraHeart, 21 EVAHEART) as a bridge to transplantation at our institution between April 2011 and August 2013 were retrospectively reviewed. All patients were followed up through December 2013. Seven patients underwent conversions from NIPRO paracorporeal LVAD (Nipro, Osaka, Japan) to an implantable LVAD. The mean observation period was 483+/-239 days (41.0 patient years). Eight patients were transplanted and one patient showed functional recovery with subsequent LVAD explantation. Four patients died due to cerebrovascular accident, empyema, or device malfunction due to pump thrombosis after cerebral bleeding. Kaplan-Meier analysis revealed 6-, 12-, and 24-month survival rates of 93%, 86%, and 86%, respectively. The rates of freedom from cerebrovascular accidents and device-related infections at 1 year after LVAD implantation were 65% and 36%, respectively. Twenty-nine patients were discharged home after LVAD implantation. During the period of this study, there were 59 readmissions (53 urgent, 6 elective) among 22 patients (76%). The overall and urgent readmission rates were 1.66 and 1.49 per patient year, respectively. The common reason for readmission was device-related infection (31%), followed by cerebrovascular accidents (17%). The total out-of-hospital time after the primary discharge was 90%. CONCLUSIONS: Our midterm survival rate after LVAD implantation is satisfactory. However, patients undergoing LVAD support were often readmitted with adverse events. PMID- 25034706 TI - The effects of metabolic syndrome and its components on arterial stiffness in relation to gender. AB - OBJECTIVES: The influence of gender-dependent metabolic risk factors on arterial stiffness has not been fully determined. This study was performed to investigate the relationship between components of metabolic syndrome and brachial-ankle pulse wave velocity (baPWV) according to gender. METHODS: A total of 537 subjects (54.4+/-7.5 years and 70.6% men) who underwent baPWV measurement during routine check-ups were analyzed. RESULTS: BaPWV was 1363+/-229cm/s in men and 1387+/ 269cm/s in women (p=0.313). The prevalence of metabolic syndrome was not different according to gender (23% in men versus 27% in women, p=0.335). In multiple linear regression analyses, after adjustment for age, baPWV was significantly associated with systolic and diastolic blood pressures, fasting glucose, and triglyceride in both genders. Waist circumference was associated with baPWV in women but not in men. High-density lipoprotein levels were not associated with baPWV in either gender. Subjects with metabolic syndrome had a higher baPWV than those without metabolic syndrome for women aged <55 years, but not for all men and women aged >=55 years. As the number of the components of metabolic syndrome increased, baPWV increased proportionally in both genders. However, this correlation was more strong in women than that in men (beta=0.408 versus beta=0.146 after adjustment for age). CONCLUSION: In middle-aged Koreans, women showed stronger associations between each component of metabolic syndrome and baPWV than men. The association of each component of metabolic syndrome to arterial stiffness may differ between men and women. PMID- 25034707 TI - The significance of pulmonary arterial hypertension pre- and post-transfemoral aortic valve implantation for severe aortic stenosis. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become the treatment of choice for the symptomatic patients with aortic stenosis (AS) and high surgical risk. Pulmonary hypertension (PHTN) has been shown to be associated with worse early and late outcomes after aortic valve surgery. Data regarding the effect of TAVI on PHTN are limited. METHODS AND RESULTS: We evaluated the characteristics and outcome of the patients with various degrees of systolic PHTN referred for TAVI. PHTN was defined as systolic pulmonary arterial pressure (SPAP) >=50mmHg as assessed by echocardiography. The patients with SPAP decrease after TAVI to below 50mmHg were compared to the patients with persistent PHTN following TAVI. Of the 122 patients included in the present study, 49 (40%) patients had elevated SPAP prior to TAVI. This group of patients presented with smaller aortic valve areas, greater degrees of mitral or tricuspid regurgitation, lower left ventricular ejection fraction, and more prevalent chronic obstructive pulmonary disease (COPD) (all p<0.05). Following TAVI, 57% of the patients with prior PHTN experienced a reduction in SPAP to below 50mmHg. Multivariable analysis identified COPD to be the most powerful predictor for PHTN presence post TAVI (hazard ratio 3.9, 95% confidence interval 1.5-9.9, p=0.005). Post-TAVI PHTN (SPAP >=50mmHg) was associated with a 3.4-fold, independent, 2-year mortality risk (p=0.04). CONCLUSIONS: Our data suggest that TAVI is associated with a significant reduction in pulmonary pressure in more than half of the patients with preprocedural PHTN. COPD identifies the patients with persistent PHTN after TAVI. Post-TAVI PHTN is associated with markedly worse outcome. PMID- 25034708 TI - What are the factors associated with physical activity (PA) participation in community dwelling adults with dementia? A systematic review of PA correlates. AB - PA shows promise as a modifiable lifestyle intervention to benefit pathological symptoms of dementia. However, little is known about the factors associated with participation in PA in community dwelling adults with dementia. A systematic review was undertaken to identify PA correlates. Two independent reviewers searched major electronic databases and extracted data on studies reporting quantitative correlates of PA participation in community dwelling adults with dementia. PA correlates were analyzed using the summary code approach within the socio-ecological model. Out of a potential of 118 articles, 12 met the eligibility criteria encompassing 752 participants. We conducted secondary analysis on nine data sets. Increased energy intake, resting metabolic rate, fat free mass, gait speed, global motor function, overall health related quality of life (HRQOL), physical HRQOL, higher levels of social functioning and reduced apathy were positively associated with PA. Taking >= four medications, dizziness, lower activities of daily living (ADL) function, a history of falls, less waking hours in the day, more autonomic problems and delirium were negatively associated with PA. Increasing age and lower global cognition were not consistently associated with PA participation. It is surprising that increasing age and lower global cognition do not appear to influence PA participation. All significant correlates should be confirmed in prospective studies with particular focus on the relationship of PA and gait speed, ADL function, falls history and dietary intake and the progression of frailty and nursing home admission as a priority. PMID- 25034709 TI - Sodium tanshinone IIA sulfonate prolongs the survival of skin allografts by inhibiting inflammatory cell infiltration and T cell proliferation. AB - Acute rejection is a major problem for allograft transplantation in the clinic. Classic immunosuppressive drug therapy is accompanied by a variety of side effects. Therefore, safe and effective immunosuppressive drugs remain in demand. In this study, the effect of sodium tanshinone IIA sulfonate (STS) on prolonging the allogeneic skin graft survival was determined using a rat skin transplantation model. Rat recipients were divided into four groups that received different treatments: physiological saline, STS, CsA, or STS+CsA. The results indicated that the administration of STS alone, CsA alone or combined STS and CsA all significantly promoted skin allograft survival as demonstrated by a longer mean survival time (MST) compared with the control group. This effect was due to the reductions in the infiltration of inflammatory cells into allograft and the percentages of CD4+ T cells and CD8+ T cells in the peripheral blood of rat recipients. The injection of STS could also downregulate the expression of RANTES, IP-10 as well as IL-2, IFN-gamma and TNF-alpha in allograft tissue. STS markedly inhibited the proliferation of mouse spleen T lymphocytes stimulated by mitogen and alloantigen in vitro. Taken together, these results suggest that STS is a widely applicable drug with few complications that may serve as a new therapeutic alternative for allograft rejection or even other Th1 cell-dominated immune diseases. PMID- 25034711 TI - Neurovascular coupling in pregnancy and the risk of preeclampsia. AB - BACKGROUND AND PURPOSE: This study investigated whether a short testing of neurovascular coupling during midterm pregnancy could identify women at risk for subsequent preeclampsia. METHODS: Transcranial Doppler sonography of the posterior cerebral artery during a brief visual stimulation was analyzed in 68 women at midterm pregnancy, the primary clinical end point was preeclampsia. RESULTS: Women with bilateral notching of the uterine arteries showed an exaggerated visually evoked blood flow increase and longer time-to-peak. Neurovascular coupling was not significantly associated with the occurrence of preeclampsia. CONCLUSIONS: Neurovascular coupling was altered in women with impaired uteroplacentar vasoregulation but not a significant predictor of preeclampsia. PMID- 25034710 TI - Dynamics of BMP signaling in limb bud mesenchyme and polydactyly. AB - Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis. PMID- 25034712 TI - Response to Letter Regarding Article, "Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients During Head-of-Bed Manipulation". PMID- 25034713 TI - High prevalence of atrial fibrillation among patients with ischemic stroke. AB - BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is a common cause of devastating but potentially preventable stroke. Estimates of the prevalence of AF among patients with stroke vary considerably because of difficulties in detection of intermittent, silent AF. Better recognition of AF in this patient group may help to identify and offer protection to individuals at risk. Our aim was to determine the nationwide prevalence of AF among patients with ischemic stroke, as well as their use of oral anticoagulation. METHODS: Cross-sectional study of unselected patients in cross-linked nationwide Swedish health registers. All 94 083 patients with a diagnosis of ischemic stroke in the nationwide stroke register Riks-Stroke between 2005 and 2010 were studied. Information about previously diagnosed AF, and comorbidity, was obtained from the nationwide Patient Register and cross referenced with the national Drug Register containing data on all dispensed pharmacological prescriptions in Sweden. RESULTS: Combination of data from Riks Stroke and from the Patient Register showed that 31 428 (33.4%) patients with ischemic stroke had previously known, or newly diagnosed, AF. Of those, only 16.2% had received warfarin in a pharmacy within 6 months before stroke onset. After hospital discharge, only 35.0% of the survivors received warfarin within the first 3 months after discharge. The likelihood for underlying AF was strongly correlated to the CHA2DS2-VASC score, which is a point based scheme for assessment of stroke risk in AF but which also predicts likelihood of AF. In this scheme points are given for age, previous stroke or transient ischemic attack, hypertension, heart failure, diabetes, vascular disease and female sex. CONCLUSIONS: Access to nationwide register data shows that AF is more common among patients with ischemic stroke than those previously reported. Few patients with stroke and AF had anticoagulant treatment before the event, and few got it after the event. CHA2DS2-VASc could be a useful monitoring tool to intensify efforts to diagnose AF among patients with cryptogenic stroke. PMID- 25034714 TI - Three-dimensional carotid ultrasound plaque texture predicts vascular events. AB - BACKGROUND AND PURPOSE: Carotid ultrasound atherosclerosis measurements, including those of the arterial wall and plaque, provide a way to monitor patients at risk of vascular events. Our objective was to examine carotid ultrasound plaque texture measurements and the change in carotid plaque texture during 1 year in patients at risk of events and to compare these with measurements of plaque volume and other risk factors as predictors of vascular events. METHODS: We evaluated 298 patients with carotid atherosclerosis using 3 dimensional (3D) ultrasound at baseline and after 1 year and measured carotid plaque volume and 376 measures of plaque texture. Patients were followed up to 5 years (median [range], 3.12 [0.77-4.66]) for myocardial infarction, transient ischemic attack, and stroke. Sparse Cox regression was used to select the most predictive plaque texture measurements in independent training sets using a 10 fold cross-validation, repeated 5*, to ensure unbiased results. RESULTS: Receiver operator curves and Kaplan-Meier analysis showed that changes in texture and total plaque volume combined provided the best predictor of vascular events. In multivariate Cox regression, changes in plaque texture (median hazard ratio, 1.4; P<0.001) and total plaque volume (median hazard ratio, 1.5 per 100 mm(3); P<0.001) were both significant predictors, whereas the Framingham risk score was not. CONCLUSIONS: Changes in both plaque texture and volume are strongly predictive of vascular events. In high-risk patients, 3D ultrasound plaque measurements should be considered for vascular event risk prediction. PMID- 25034715 TI - Abuse and subclinical cardiovascular disease among midlife women: the study of women's health across the nation. AB - BACKGROUND AND PURPOSE: Some evidence suggests that abuse may be related to cardiovascular disease (CVD) risk among women. However, this relation has largely been addressed using self-reported measures of CVD. We tested whether a history of abuse was related to subclinical CVD among midlife women without clinical CVD. METHODS: The Study of Women's Health Across the Nation (SWAN) is a longitudinal cohort study of women transitioning through the menopause. One thousand four hundred two white, black, Hispanic, and Chinese SWAN participants completed measures of childhood and adult physical and sexual abuse, underwent a blood draw, completed physical measures, and underwent a carotid artery ultrasound at SWAN study visit 12. Associations between abuse and intima media thickness and plaque were tested in linear and multinomial logistic regression models controlling for age, site, race/ethnicity, financial strain, education, body mass index, lipids, blood pressure, measures of insulin resistance, smoking, alcohol use, physical activity, and medication use. RESULTS: Findings indicated that a history of childhood sexual abuse was associated with higher intima media thickness controlling for standard CVD risk factors and other confounders (beta=0.022; SE=0.010; P<0.05; adjusted mean childhood sexual abuse: 0.800 mm versus no childhood sexual abuse: 0.782 mm). CONCLUSIONS: Childhood sexual abuse was associated with higher intima media thickness controlling for CVD risk factors and other confounders. These findings indicate the importance of considering the potential impact of early-life stressors on women's later cardiovascular health. PMID- 25034716 TI - Lacunar strokes in patients with diabetes mellitus: risk factors, infarct location, and prognosis: the secondary prevention of small subcortical strokes study. AB - BACKGROUND AND PURPOSE: Diabetes mellitus is an independent risk factor for lacunar strokes. Few data are available regarding patient features, infarct location, and recurrent vascular events for patients with diabetes mellitus with lacunar stroke. METHODS: We compared features at study entry and prognosis during 3.6 years of follow-up of patients with diabetes mellitus versus patients without diabetes mellitus with recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes (SPS3) randomized trial. RESULTS: Among the 3020 participants, the prevalence of diabetes mellitus was 37% with a mean duration of 11 years. Diabetes mellitus was independently associated with slightly younger age (63 versus 64 years; P<0.001), Hispanic ethnicity (36% versus 28%; P<0.0001), ischemic heart disease (11% versus 6%; P=0.002), and peripheral vascular disease (5% versus 2%; P<0.001). Patients with diabetes mellitus more frequently had intracranial stenosis >=50% (P<0.001), infarcts involving the brain stem or cerebellum (P<0.001), and more extensive white matter abnormalities (P<0.001). Patients with diabetes mellitus were almost twice as likely to have a recurrent stroke (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.3), recurrent ischemic stroke (HR, 1.8; 95% CI, 1.4-2.4), disabling/fatal stroke (HR, 1.8; 95% CI, 1.2-2.9), myocardial infarction (HR, 1.7; 95% CI, 1.0-2.8), and death (HR, 2.1 95% CI, 1.6-2.8) compared with patients without diabetes mellitus. CONCLUSIONS: Patients with diabetes mellitus with lacunar stroke have a distinctive clinical profile that includes double the prevalence of systemic and intracranial atherosclerosis, preferential involvement of the posterior circulation, and a poor prognosis for recurrent stroke and death. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306. PMID- 25034717 TI - Letter by Aries et al Regarding Article, "Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients During Head-of-Bed Manipulation". PMID- 25034718 TI - Evidence for stroke family caregiver and dyad interventions: a statement for healthcare professionals from the American Heart Association and American Stroke Association. AB - Stroke is a leading cause of severe, long-term disability. Most stroke survivors are cared for in the home by a family caregiver. Caregiver stress is a leading cause of stroke survivor institutionalization, which results in significant costs to the healthcare system. Stroke family caregiver and dyad intervention studies have reported a variety of outcomes. A critical analysis of 17 caregiver intervention studies and 15 caregiver/stroke survivor dyad intervention studies was conducted to provide evidence-based recommendations for the implementation and future design of stroke family caregiver and dyad interventions. PMID- 25034719 TI - Iterative method for atrioventricular optimization of cardiac resynchronization therapy: is beauty only in the eye of the beholder? PMID- 25034720 TI - Author reply: To PMID 24068445. PMID- 25034721 TI - [A study on the hepatitis B virus vaccination rates in hepatitis C-infected patients in a Primary Care centre]. PMID- 25034722 TI - [Familial combined hyperlipidemia: consensus document]. AB - Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease. It is transmitted in an autosomal dominant manner, although there is not a unique gene involved. The diagnosis is performed using clinical criteria, and variability in lipid phenotype and family history of hyperlipidemia are necessaries. Frequently, the disorder is associated with type2 diabetes mellitus, arterial hypertension and central obesity. Patients with FCH are considered as high cardiovascular risk and the lipid target is an LDL cholesterol <100mg/dL, and <70mg/dL if cardiovascular disease or type 2 diabetes are present. Patients with FCH require lipid lowering treatment using potent statins and sometimes, combined lipid-lowering treatment. Identification and management of other cardiovascular risk factors as type 2 diabetes and hypertension are fundamental to reduce cardiovascular disease burden. This document gives recommendations for the diagnosis and global treatment of patients with FCH directed to specialists and general practitioners. PMID- 25034723 TI - Quantitative detection of the human cervical cancer oncogene for monitoring the minimal residual disease in acute leukemia. AB - The human cervical cancer oncogene (HCCR) has been shown to be over-expressed in some solid tumors, and its function is involved in negative regulation of p53 tumor suppressor gene. However, the roles of HCCR in leukemia remain unclear. The present study is to investigate whether the expression levels of HCCR mRNA are associated with clinical prognosis in patients with acute leukemia (AL) and to explore the potential use as a biomarker for monitoring minimal residual disease (MRD) in AL. The mRNA levels of HCCR1 and HCCR2 were quantified by real-time reverse transcription polymerase chain reaction in bone marrow samples from 80 adult de novo AL patients and 20 normal healthy donors. The expressions of HCCR1 and HCCR2 were significantly higher in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) than those in healthy donors (P < 0.01), but there was no significant difference between AML and ALL (P > 0.05). Besides white blood cell count, we did not find any significant correlation between HCCR expression and clinical characteristics, such as age, sex, CD34 antigen expression, and response to chemotherapy. HCCR was monitored in 12 cases during remission and/or relapse. Significant reductions of both HCCR1 and HCCR2 mRNA levels were observed in patients who had achieved complete remission after chemotherapy but not in patients with non-responsive. However, an increased HCCR expression was detected in these patients who relapsed. Our findings suggest that HCCR gene is over-expressed in AL patients and may be as a useful biomarker for monitoring MRD in AL. PMID- 25034724 TI - Dexmedetomidine reduces the risk of delirium, agitation and confusion in critically Ill patients: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: Delirium frequently is observed in critically ill patients in the intensive care unit (ICU) and is associated strongly with a poor outcome. Dexmedetomidine seems to reduce time to extubation and ICU stay without detrimental effects on mortality. The objective of the authors' study was to evaluate the effect of this drug on delirium, agitation, and confusion in the ICU setting. DESIGN: Meta-analysis of all the randomized clinical trials ever performed on dexmedetomidine versus any comparator in the ICU setting. SETTING: Intensive care units. PARTICIPANTS: Critically ill patients. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Pertinent studies were independently searched in BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials. Primary endpoint was the rate of delirium, including the adverse events, agitation and confusion. The 13 included manuscripts (14 trials) randomized 3,029 patients. Overall analysis showed that the use of dexmedetomidine was associated with significant reductions in the incidence of delirium, agitation and confusion (298/1,565 [19%] in the dexmedetomidine group v 337/1,464 [23%] in the control group, RR = 0.68 [0.49 to 0.96], p = 0.03). Results were confirmed in subanalyses performed on patients undergoing noninvasive ventilation (1/53 [2%] in the dexmedetomidine group v 7/49 [14%] in the control group, RR=0.18 [0.03 to 1.01], p = 0.05), receiving midazolam as a comparator (268/1,164 [23%] in the dexmedetomidine group v 277/1,025 [27%] in the control group, RR = 0.68 [0.47 to 1.00], p = 0.05) and in general ICU setting patients (204/688 [30%] in the dexmedetomidine group v 204/560 [36%] in the control group, RR = 0.68 [0.45 to 0.81], p < 0.01). CONCLUSIONS: This meta-analysis of randomized controlled studies suggests that dexmedetomidine could help to reduce delirium in critically ill patients. PMID- 25034725 TI - Genetic structure of wild boar (Sus scrofa) populations from East Asia based on microsatellite loci analyses. AB - BACKGROUND: Wild boar, Sus scrofa, is an extant wild ancestor of the domestic pig as an agro-economically important mammal. Wild boar has a worldwide distribution with its geographic origin in Southeast Asia, but genetic diversity and genetic structure of wild boar in East Asia are poorly understood. To characterize the pattern and amount of genetic variation and population structure of wild boar in East Asia, we genotyped and analyzed microsatellite loci for a total of 238 wild boar specimens from ten locations across six countries in East and Southeast Asia. RESULTS: Our data indicated that wild boar populations in East Asia are genetically diverse and structured, showing a significant correlation of genetic distance with geographic distance and implying a low level of gene flow at a regional scale. Bayesian-based clustering analysis was indicative of seven inferred genetic clusters in which wild boars in East Asia are geographically structured. The level of genetic diversity was relatively high in wild boars from Southeast Asia, compared with those from Northeast Asia. This gradient pattern of genetic diversity is consistent with an assumed ancestral population of wild boar in Southeast Asia. Genetic evidences from a relationship tree and structure analysis suggest that wild boar in Jeju Island, South Korea have a distinct genetic background from those in mainland Korea. CONCLUSIONS: Our results reveal a diverse pattern of genetic diversity and the existence of genetic differentiation among wild boar populations inhabiting East Asia. This study highlights the potential contribution of genetic variation of wild boar to the high genetic diversity of local domestic pigs during domestication in East Asia. PMID- 25034726 TI - To tell or not to tell: disclosure to children and family amongst Thai women living with HIV/AIDS. AB - HIV disclosure is a complex phenomenon. The choice of disclosure or non disclosure is a reflection of how each HIV-positive person experiences and deals with HIV/AIDS in their everyday life. In this study, we qualitatively explore the experiences of disclosing HIV status to family members and children among HIV positive women living in Thailand. Due to fear of stigma and discrimination, the women decided to tell only a few people, usually their significant others including parents and children. Although most women received good support from their family members, some were rejected and discriminated against by their family members. This stems from lack of knowledge about HIV/AIDS among family members. Women found disclosure to their children a difficult decision to make. Only some women told their children about their HIV status. They wished to protect their children from emotional burden. This protection also appeared in their attempts to prepare their children for dealing with HIV/AIDS. Support from family members played a major role in the lives of HIV-positive women. Although disclosure has been promoted as a means of ending stigma and discrimination, our data suggested that disclosure may not be positive for some women. This has implications for health promotion in HIV health care. Healthcare providers need to appreciate the ramifications of promoting disclosure to HIV-positive women who are mothers. PMID- 25034727 TI - Phylogeny and character evolution of the fern genus Tectaria (Tectariaceae) in the Old World inferred from chloroplast DNA sequences. AB - In this study we provide a phylogeny for the pantropical fern genus Tectaria, with emphasis on the Old World species, based on sequences of five plastid regions (atpB, ndhF plus ndhF-trnL, rbcL, rps16-matK plus matK, and trnL-F). Maximum parsimony, maximum likelihood, and Bayesian inference are used to analyze 115 individuals, representing ca. 56 species of Tectaria s.l. and 36 species of ten related genera. The results strongly support the monophyly of Tectaria in a broad sense, in which Ctenitopsis, Hemigramma, Heterogonium, Psomiocarpa, Quercifilix, Stenosemia, and Tectaridium should be submerged. Such broadly circumscribed Tectaria is supported by the arising pattern of veinlets and the base chromosome number (x=40). Four primary clades are well resolved within Tectaria, one from the Neotropic (T. trifoliata clade) and three from the Old World (T. subtriphylla clade, Ctenitopsis clade, and T. crenata clade). Tectaria crenata clade is the largest one including six subclades. Of the genera previously recognized as tectarioid ferns, Ctenitis, Lastreopsis, and Pleocnemia, are confirmed to be members in Dryopteridaceae; while Pteridrys and Triplophyllum are supported in Tectariaceae. To infer morphological evolution, 13 commonly used characters are optimized on the resulting phylogenetic trees and in result, are all homoplastic in Tectaria. PMID- 25034728 TI - The corbiculate bees arose from New World oil-collecting bees: implications for the origin of pollen baskets. AB - The economically most important group of bees is the "corbiculates", or pollen basket bees, some 890 species of honeybees (Apis), bumblebees (Bombus), stingless bees (Meliponini), and orchid bees (Euglossini). Molecular studies have indicated that the corbiculates are closest to the New World genera Centris, with 230 species, and Epicharis, with 35, albeit without resolving the precise relationships. Instead of concave baskets, these bees have hairy hind legs on which they transport pollen mixed with floral oil, collected with setae on the anterior and middle legs. We sampled two-thirds of all Epicharis, a third of all Centris, and representatives of the four lineages of corbiculates for four nuclear gene regions, obtaining a well-supported phylogeny that has the corbiculate bees nested inside the Centris/Epicharis clade. Fossil-calibrated molecular clocks, combined with a biogeographic reconstruction incorporating insights from the fossil record, indicate that the corbiculate clade arose in the New World and diverged from Centris 84 (72-95)mya. The ancestral state preceding corbiculae thus was a hairy hind leg, perhaps adapted for oil transport as in Epicharis and Centris bees. Its replacement by glabrous, concave baskets represents a key innovation, allowing efficient transport of plant resins and large pollen/nectar loads and freeing the corbiculate clade from dependence on oil-offering flowers. The transformation could have involved a novel function of Ubx, the gene known to change hairy into smooth pollen baskets in Apis and Bombus. PMID- 25034730 TI - Pertussis vaccine uptake during pregnancy: we need to do better in the U.S. PMID- 25034729 TI - Addressing cancer control needs of African-born immigrants in the US: a systematic literature review. AB - Compared to non-Hispanic Whites, African immigrants have worse cancer outcomes. However, there is little research about cancer behaviors and/or interventions in this growing population as they are generally grouped with populations from America or the Caribbean. This systematic review examines cancer-related studies that included African-born participants. We searched PsycINFO, Ovid Medline, Pubmed, CINHAL, and Web of Science for articles focusing on any type of cancer that included African-born immigrant participants. Twenty articles met study inclusion criteria; only two were interventions. Most articles focused on one type of cancer (n=11) (e.g., breast cancer) and were conducted in disease-free populations (n=15). Studies included African participants mostly from Nigeria (n=8) and Somalia (n=6). However, many papers (n=7) did not specify nationality or had small percentages (<5%) of African immigrants (n=5). Studies found lower screening rates in African immigrants compared to other subpopulations (e.g. US born). Awareness of screening practices was limited. Higher acculturation levels were associated with higher screening rates. Barriers to screening included access (e.g. insurance), pragmatic (e.g. transportation), and psychosocial barriers (e.g. shame). Interventions to improve cancer outcomes in African immigrants are needed. Research that includes larger samples with diverse African subgroups including cancer survivors is necessary to inform future directions. PMID- 25034731 TI - Significant disparity in base and sugar damage in DNA resulting from neutron and electron irradiation. AB - In this study, a comparison of the effects of neutron and electron irradiation of aqueous DNA solutions was investigated to characterize potential neutron signatures in DNA damage induction. Ionizing radiation generates numerous lesions in DNA, including base and sugar lesions, lesions involving base-sugar combinations (e.g. 8,5'-cyclopurine-2'-deoxynucleosides) and DNA-protein cross links, as well as single- and double-strand breaks and clustered damage. The characteristics of damage depend on the linear energy transfer (LET) of the incident radiation. Here we investigated DNA damage using aqueous DNA solutions in 10 mmol/l phosphate buffer from 0-80 Gy by low-LET electrons (10 Gy/min) and the specific high-LET (~0.16 Gy/h) neutrons formed by spontaneous (252)Cf decay fissions. 8-hydroxy-2'-deoxyguanosine (8-OH-dG), (5'R)-8,5'-cyclo-2' deoxyadenosine (R-cdA) and (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA) were quantified using liquid chromatography-isotope-dilution tandem mass spectrometry to demonstrate a linear dose dependence for induction of 8-OH-dG by both types of radiation, although neutron irradiation was ~50% less effective at a given dose compared with electron irradiation. Electron irradiation resulted in an exponential increase in S-cdA and R-cdA with dose, whereas neutron irradiation induced substantially less damage and the amount of damage increased only gradually with dose. Addition of 30 mmol/l 2-amino-2-(hydroxymethyl)-1,3 propanediol (TRIS), a free radical scavenger, to the DNA solution before irradiation reduced lesion induction to background levels for both types of radiation. These results provide insight into the mechanisms of DNA damage by high-LET (252)Cf decay neutrons and low-LET electrons, leading to enhanced understanding of the potential biological effects of these types of irradiation. PMID- 25034732 TI - Geometric accuracy of 3D coordinates of the Leksell stereotactic skull frame in 1.5 Tesla- and 3.0 Tesla-magnetic resonance imaging: a comparison of three different fixation screw materials. AB - We assessed the geometric distortion of 1.5-Tesla (T) and 3.0-T magnetic resonance (MR) images with the Leksell skull frame system using three types of cranial quick fixation screws (QFSs) of different materials-aluminum, aluminum with tungsten tip, and titanium-for skull frame fixation. Two kinds of acrylic phantoms were placed on a Leksell skull frame using the three types of screws, and were scanned with computed tomography (CT), 1.5-T MR imaging and 3.0-T MR imaging. The 3D coordinates for both strengths of MR imaging were compared with those for CT. The deviations of the measured coordinates at selected points (x = 50, 100 and 150; y = 50, 100 and 150) were indicated on different axial planes (z = 50, 75, 100, 125 and 150). The errors of coordinates with QFSs of aluminum, tungsten-tipped aluminum, and titanium were <1.0, 1.0 and 2.0 mm in the entire treatable area, respectively, with 1.5 T. In the 3.0-T field, the errors with aluminum QFSs were <1.0 mm only around the center, while the errors with tungsten tipped aluminum and titanium were >2.0 mm in most positions. The geometric accuracy of the Leksell skull frame system with 1.5-T MR imaging was high and valid for clinical use. However, the geometric errors with 3.0-T MR imaging were larger than those of 1.5-T MR imaging and were acceptable only with aluminum QFSs, and then only around the central region. PMID- 25034733 TI - Protective effect of inhalation of hydrogen gas on radiation-induced dermatitis and skin injury in rats. AB - The effect of inhalation of hydrogen-containing gas (1.3% hydrogen + 20.8% oxygen + 77.9% nitrogen) (HCG) on radiation-induced dermatitis and on the healing of healing-impaired skin wounds in rats was examined using a rat model of radiation induced skin injury. An X-ray dose of 20 Gy was irradiated onto the lower part of the back through two holes in a lead shield. Irradiation was performed before or after inhalation of HCG for 2 h. Inhalation of HCG significantly reduced the severity of radiodermatitis and accelerated healing-impaired wound repair. Staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and 8-hydroxy-2(')-deoxyguanosine (8-OHdG) showed that the proportion of apoptotic keratinocytes and the level of staining in the X irradiated skin of rats that pre-inhaled HCG were significantly lower than that of rats which did not pre-inhale HCG. Cutaneous full-thickness wounds were then created in the X-irradiated area to examine the time-course of wound healing. X irradiation significantly increased the time required for wound healing, but the inhalation of HCG prior to the irradiation significantly decreased the delay in wound healing compared with the control and post-inhalation of HCG groups. Therefore, radiation-induced skin injury can potentially be alleviated by the pre inhalation of HCG. PMID- 25034734 TI - Cultural factors related to adherence to imatinib in CML: a Mexican perspective. AB - INTRODUCTION: The advent of imatinib as a therapeutic option of chronic myeloid leukemia (CML) has transformed this previously highly resistant disease into one that is susceptible to management with oral drugs that now offer high long-term survival rates. However, achieving an adequate adherence to treatment regimes is of critical importance. The characteristics of treatment compliance in Mexican patients have not been determined. METHODS: We evaluated 38 CML patients, members of the Glivec((r)) International Patient Assistance Program (GIPAP). A bimonthly simplified medication adherence questionnaire was applied and the adherence rate was calculated by direct tablet counting. RESULTS: Two groups, one of local patients and another of out-of-town patients, were studied using an 85% adherence rate as a cut-off. The overall adherence rate was 85.9%. Fifteen patients were considered non-adherent (39.5%). The group of out-of-town patients presented a higher adherence rate of 92.8% in contrast with 76.3% in the local population (P = 0.021). The probability of achieving a complete cytogenetic response at some point of evolution after 8 years of follow-up was 93% in the adherent group vs. 58% in the group with an adherence rate <85% (P = 0.008). In patients with imatinib failure, the adherence rate was 75.8% compared to 95.5% (P = 0.008) in the optimal response group. CONCLUSIONS: In Mexican patients with CML, non adherence to treatment is a cause of the failure to achieve remission or the subsequent loss of a complete cytogenetic and major molecular response. PMID- 25034735 TI - [Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation: the 2013 Chinese edition]. PMID- 25034736 TI - [Liver cirrhosis and choice of surgical modalities in patients with hepatocellular carcinoma]. PMID- 25034737 TI - [A clinicopathological and prognostic study of rare pathological subtype cases of hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the clinicopathological features and prognosis of clear cell carcinoma (CCC), giant cell carcinoma (GCC) and sarcomatoid carcinoma (SC), the 3 rare cellular morphological subtypes of hepatocellular carcinoma (HCC). METHODS: The clinic data of 78 rare pathological subtype HCC cases, which were diagnosed by postoperative pathological examination during October 1998 and June 2013 was analyzed retrospectively. CCC group involved 43 patients (33 male and 10 female), with a median age of 56 years (ranging from 25 to 80 years). GCC group involved 19 patients (16 male and 3 female), with a median age of 59 years (ranging from 38 to 66 years). SC group involved 16 patients (14 male and 2 female), with a median age of 57 years (ranging from 46 to 70 years). Characteristic differences were analyzed by chi(2) test and Fisher exact test. Survival analysis was estimated by Kaplan-Meier method. Cox proportional hazards model was used in survival multivariate analysis. RESULTS: The proportion of multiple lesions in CCC group (4.7%) was significantly lower than those in GCC group (21%) or SC group (25%) (P = 0.034). The histologic grade of CCC group was the best, whereas SC group was the worst (P = 0.000). The survival analysis revealed that median survival time and the 1-, 3-, 5-year survival rates for the 3 groups are CCC group (45 months, 92%, 65%, 45%) > GCC group (13 months, 55%, 30%, 0) > SC group (8 months, 31%, 0, 0), respectively (chi(2) = 4.473 to 26.981, P < 0.05, between each 2 groups). Two cases in CCC group underwent abdominal metastasectomy 18 and 32 months after hepatectomy, and they still achieved long term survival time. The histologic grade of tumor cell and the TNM staging were 2 independent unfavorable prognostic factors (regression coefficient: 4.038 and 1.354, P < 0.05). CONCLUSION: CCC is a rare low degree malignancy pathological subtype of HCC and may achieve a relatively optimistic prognosis. However, the GCC, especially SC are 2 rare high degree malignancy pathological subtypes of HCC with highly aggressive and poor prognosis. PMID- 25034738 TI - [A prospective randomized controlled trial of pancreatic duct stent internal versus external drainage with pancreaticojejunostomy for the early curative effect after pancreaticoduodenectomy]. AB - OBJECTIVE: To investigate the effect of pancreatic duct stent internal versus external drainage with pancreaticojejunostomy on the early curative effect after pancreaticoduodenectomy (PD). METHODS: The study was a prospective controlled trial. A total of 219 patients undergoing PD from January 2010 to March 2013 were randomly divided into external drainage group (n = 110) and internal drainage group (n = 109). The pancreatic duct stent was put in the jejunum during the operation in the internal drainage group, while that in the external drainage group was placed outside the body through the jejunum and abdominal wall. The intra-operative blood loss, operative duration, post-operative hospital stay, mortality rate, and the morbidity of pancreatic fistula as well as other complications were compared between the two groups. RESULTS: Compared with internal drainage group, pancreatic duct stent external drainage obviously reduced the morbidity of pancreatic fistula (13.6% vs. 22.6%), delayed gastric emptying (10.0% vs. 27.5%), abdominal infection (6.4% vs. 19.3%), intestinal obstruction (8.2% vs. 20.2%) along with the overall complications (24.5% vs. 41.3%) after PD (chi(2) = 5.735 8 to 11.047 7, P < 0.05), and shortened the healing duration of pancreatic fistula ((11.5 +/- 2.9) d vs. (20.1 +/- 5.7) d, t = 5.07, P < 0.01), while there was no significant difference in the intra operative blood loss, operative duration, post-operative hospital stay and mortality rate, etc between the two groups (P > 0.05). CONCLUSIONS: Pancreatic duct stent external drainage can effectively reduce the morbidity of pancreatic fistula and the overall complications after PD, which is safe and feasible. The method is worthy of popularization and application clinically. PMID- 25034739 TI - [Clinical and pathological characteristics in acute complicated appendicitis]. AB - OBJECTIVE: To find out the clinical and pathological characteristics in acute complicated appendicitis. METHODS: A retrospective clinical analysis was made on 742 cases of acute appendicitis from January 2003 to December 2012. All cases underwent appendectomy. Patients were allocated to the acute complicated appendicitis (ACA) group and the acute uncomplicated appendicitis group based on pathological reports. The chi2 test was used to check for differences between proportions. Multivariate analysis was made through the Logistic regression. RESULTS: Of 742 patients, 533 were allocated to the ACA group, including acute suppurative appendicitis 306 patients, acute gangrenous appendicitis 100 patients, appendicitis with perforation 59 patients, appendicitis with abscess formation 6 patients and appendicitis with tumor 5 patients. Statistical result shows that the patients of ACA group usually had higher total WBC count, local or diffuse muscle guarding, intraluminal stercolith or periappendiceal fluid. Logistic regression also indicated that ACA were mathematically related to high level white blood cell count (>20 * 109/L, OR = 2.717, 95%CI: 1.834-4.027, P < 0.05), local or diffuse muscle guarding (OR = 1.649, 95%CI: 1.047-2.597, P < 0.05), intraluminal stercolith (OR = 2.939, 95%CI: 1.607-5.377, P < 0.05) and periappendiceal fluid (OR = 3.273, 95%CI: 1.424-7.525, P < 0.05). CONCLUSIONS: Patients with high level WBC count, local or diffuse muscle guarding, intraluminal stercolith or periappendiceal fluid are likely suffering from acute complicated appendicitis. Appendectomy must be considered as first-line therapy other than conservative antibiotic therapy under these situations. PMID- 25034740 TI - [Comparison of perioperative outcome after endovascular repair between symptomatic and asymptomatic abdominal aortic aneurysm]. AB - OBJECTIVE: To compare the perioperative outcome after endovascular repair (EVAR) of symptomatic abdominal aneurysms (S-AAAs) and elective non-symptomatic AAAs (E AAAs). METHODS: From January 2008 to February 2013, a total of 230 non-ruptured AAA patients treated by EVAR met the inclusion criteria. S-AAAs were present in 43 (18.7%) patients, 40 patients were male, 3 patients were female, aged (69 +/- 10) years and E-AAAs in 187 (81.3%) patients, 162 of which were male, the other 25 patients were female, aged (71 +/- 9) years. Patients were followed up at 1 month after EVAR. The primary outcome of the study was perioperative mortality, secondary outcome included procedural data and major perioperative adverse events. RESULTS: At baseline, there were no differences in age, gender, American Society of Anesthesiologists classification score, and basic diseases. S-AAA patients had larger aneurysms on average (6.00 (1.97) cm vs. 5.10 (1.7) cm, Z = 2.51, P = 0.01). S-AAA patients had shorter preoperative hospitalization (5.00 (5.0) days vs. 7.00 (4.0) days, Z = 1.86, P = 0.02). No differences in the perioperative mortality, respectively, 0 and 1.1% (P = 0.66). Technical success and clinical success were all 100% and the other procedure data was similar (P > 0.05). The occurrence of major adverse events, including mortality, within the 30 day after EVAR were similar between S-AAA and E-AAA patients (0 vs. 2.1%, P = 0.43). CONCLUSIONS: There is no difference in perioperative outcome between S-AAA and elective E-AAA patients treated by EVAR. More study is needed to compare the middle and long-outcome between S-AAAs and E-AAAs after EVAR. PMID- 25034741 TI - [High risk factors of the third level of lymphatic metastasis in breast cancer patients received radical/modified mastectomy: an analysis of 746 cases]. AB - OBJECTIVE: To study the high risk factors of the third level of lymphatic metastasis in breast cancer patients to guide clinical practice. METHODS: The clinical data of 746 breast cancer patients (all female, aged from 33 to 80 years with a median of 46 years) received radical or modified mastectomy between 2001 and 2011 was analyzed retrospectively. Eleven individual variables were selected to investigate high risk factors of the third level of lymphatic metastasis in different conditions. RESULTS: Axillary nodes metastasis status (OR = 4.541, 95%CI:3.569-5.776), tumor site (OR = 1.437, 95%CI:1.029-2.007), external nodes involved (OR = 3.809, 95%CI:1.683-8.618) and estrogen receptor (OR = 0.740, 95%CI:0.569-0.964) were high risk factors of the third level of lymphatic metastasis. Further analysis found that it is prone to happen a metastasis, especially when the tumor with a size over 5 cm and located at the lateral quadrant. Negative estrogen receptor was a risk factor of the third level lymphatic metastasis along with the tumor stage. CONCLUSION: For preoperative tumor biopsy shows Negative estrogen receptor of tumor stage T3 and over stage T3 when considering suspicious lymph node metastasis or external tissues metastasis intraoperatively should take in account into third level axillary lymph node dissection actively. PMID- 25034742 TI - [Abnormal growth of spine in patients with adolescent idiopathic thoracic scoliosis]. AB - OBJECTIVE: To investigate if the growth patterns of the spine and pelvis are consistent in adolescent idiopathic scoliosis (AIS) patients with single thoracic curves. METHODS: Forty-eight thoracic adolescent idiopathic scoliosis (T-AIS) female patients and 48 healthy age-matched adolescents were recruited consecutively between December 2011 and October 2012. Radiographic parameters including height of spine (HOS), length of spine (LOS), height of thoracic spine (HOT), length of thoracic spine (LOT), height of pelvis (HOP), width of pelvis (WOP) and width of thorax (WOT) were measured on the long-cassette posteroanterior standing radiographs. In addition, ratios including HOS/HOP, LOS/HOP, HOT/HOP, LOT/HOP, LOS/LOT, WOT/WOP were also calculated. Independent t test was performed to compare the radiographic parameters and ratios between the two groups. RESULTS: Compared to the age-matched healthy adolescents, T-AIS patients had a significantly higher LOS and LOT (t = -2.364 and -1.495, P = 0.020 and 0.043) and smaller HOS and HOT (t = 2.060 and 3.359, P = 0.042 and 0.001). Yet, all of HOP, WOP and WOT showed no significant difference between T-AIS patients and healthy adolescents. Similarly, LOS/HOP and LOT/HOP were significantly higher in T-AIS patients as may be expected with an average LOS/HOP of 2.26 +/- 0.14 in normal controls.In addition, LOS/LOT in normal controls had a trend of increase with age which was different from the stable LOS/LOT in T-AIS patients, indicating an increased growth of thoracic vertebra compared to lumbar vertebra. CONCLUSIONS: Compared to the age-matched healthy adolescents, T-AIS patients have an abnormal growth characteristics with longer spine. The growth of pelvis and thorax show no significant differences between T-AIS patients and healthy adolescents. PMID- 25034743 TI - [Changhai fulcrum bending radiographic technique to assess curve flexibility in patients with adolescent idiopathic scoliosis]. AB - OBJECTIVE: To evaluate the role and value of Changhai fulcrum bending radiograph(CH-FBR) in curve flexibility assessment of adolescent idiopathic scoliosis(AIS) patients. METHODS: Thirty-seven AIS patients treated between June 2012 and August 2013 were enrolled, including 31 female and 6 male patients whose age ranged from 10 to 19 years, averaged of 15.0 years. The assessment of radiographs included preoperative standing posterior-anterior radiograph, supine side-bending radiograph, traditional fulcrum bending radiograph, Changhai fulcrum bending radiograph and postoperative standing posterior-anterior radiograph. Postoperatively, radiographs were assessed at one week. The CH-FBR was performed at the lowest height and the optimized height which means the weight on the fulcrum touch the maximum. All measurements of angle were made with use of the Cobb method. The flexibility of the curve as well as the correction rate and fulcrum bending correction index (FBCI) were calculated for all patients. The maximum height of CH-FBR, basic weight and maximum weight were measured for all AIS. Paired t-tests were used to assess differences between preoperative and postoperative curves within group samples. The Pearson correlation coefficients were calculated using bivariate analysis between CH-FBR flexibility rate and correction rate, the maximum height of CH-FBR and maximum weight, the height changes of CH-FBR and weight changes. RESULTS: A total of 46 curves were involved in this study, including 28 thoracic and 18 thoracolumbar/lumbar curves. Preoperatively, the mean Cobb angle of the 46 structural curves was 47 degrees +/- 11 degrees . Postoperatively, the mean Cobb angle was 11 degrees +/- 5 degrees . Cobb's angle in supine side-bending(t = 7.2, P = 0.001), traditional fulcrum bending (t = 7.1, P = 0.001) and lowest height of Changhai fulcrum bending (t = 6.5, P = 0.001) were significantly different from the postoperative Cobb angle; Cobb's angle in traditional FBR (t = 11.0, P = 0.001) and lowest height of Changhai fulcrum bending (t = 13.6, P = 0.001) were significantly different from the optimized height CH-FBR Cobb angle. There was no significant difference found between traditional FBR Cobb angle and lowest height CH-FBR Cobb angle (t = 2.0, P = 0.051), optimized height CH-FBR Cobb angle and postoperative Cobb angle (t = 0.9, P = 0.36), lowest height CH-FBR Cobb angle and traditional FBR Cobb angle(t = 2.0, P = 0.051). The maximum height of CH-FBR, basic weight and maximum weight were (29.6 +/- 1.4)cm,(20 +/- 6)kg, and (40 +/- 6) kg. Preoperatively, the mean Cobb angle of the 28 structural curves(main thoracic curves) was 46 degrees +/- 11 degrees . Postoperatively, the mean Cobb angle was 12 degrees +/- 6 degrees . Preoperatively, the mean Cobb angle of the 18 structural curves(thoracolumbar/lumbar curves) was 49 degrees +/- 12 degrees . Postoperatively, the mean Cobb angle was 10 degrees +/- 5 degrees . The results were same in 28 structural curves, 18 structural curves as well as 46 curves. Correlation analysis of 46 curves indicated that the maximum height of CH-FBR positively correlated with maximum weight (r = 0.69, r(2) = 0.47, P = 0.001), the height changes of CH-FBR positively correlated with weight changes on CH-FBR (r = 0.62, r(2) = 0.38, P = 0.001). CONCLUSIONS: CH-FBR is a more reliable and effective method than traditional FBR and supine side-bending for curve flexibility evaluation in AIS patients. Moreover, compared to the traditional FBR and side-bending radiograph, the flexibility suggested by the optimized height CH FBR more closely approximates the postoperative result made by pedicle screws fixation and fusion. PMID- 25034744 TI - [Treatment of patellofemoral osteoarthritis with patello-femoral joint arthroplasty]. AB - OBJECTIVE: To study the outcome and surgical technique of patello-femoral joint arthroplasty (PFJ) for osteoarthritis of the knee. METHODS: From January 2010 to June 2012, 17 patients (24 knees) with patello-femoral compartmental osteoarthritis treated by PFJ were reviewed retrospectively. There were 2 male patients (4 knees) and 15 female patients (15 knees), with an average age of (64 +/- 9) years (52-77 years) . The mean body mass index was (24 +/- 3) kg/m2 (18.0 30.1 kg/m2) . Patients were asked to return for follow-up examinations at 3, 6 months and at every year after PFJ. The range of motion (ROM), visual analogue scale(VAS), Hospital for Special Surgery score (HSS score) , Feller patella score, quadriceps muscle strength were evaluated before and after PFJ. The paired sample t-test and one-way analysis of variance (ANOVA) with replicate measures were used to determine whether there were statistically significant differences between the mean data. RESULTS: All of the patients were followed up for 18-47 months, with a mean time of (29 +/- 10) months, 75.0% patients were satisfied with the outcome of this surgical procedure 1 year postoperative, and 87.5% were satisfied 2 years postoperative. HSS score was increased from 61 +/- 11 to 90 +/- 6 at the final follow-up (t = 12.24, P = 0.000). VAS score was reduced from 6.7 +/- 1.0 to 2.4 +/- 1.0 (t = 15.84, P = 0.000). The mean post-operative ROM of the knees was 126 degrees +/- 7 degrees (t = 3.25, P = 0.003). Feller patella scores were 18.0 +/- 3.2 before operation, and 18.5 +/- 4.5, 19.7 +/- 3.4, 24.0 +/- 3.8, 26.0 +/- 3.3, 26.6 +/- 2.5 at 3, 6, 12, 24 months after operation, final follow-up, respectively. Quadriceps muscle strength were 3.9 +/- 0.5 before operation, and 3.7 +/- 0.5, 3.9 +/- 0.5, 4.2 +/- 0.5, 4.3 +/- 0.5, 4.3 +/- 0.5 at 3, 6, 12, 24 months after operation, final follow-up, respectively. Repeated measures ANOVA found significant time effects for Feller patella scores (F = 38.97, P = 0.000) and quadriceps muscle (F = 6.89, P = 0.000). Feller patella scores and quadriceps muscle strength were low at 3, 6 months after operation, with no significant differences compared with pre-operation data (P > 0.05). The improvements of Feller patella scores and quadriceps muscle strength after 6 months were of significant difference compared with pre-operation and postoperative 6 months data (t = 5.65-10.65 and t = 2.18-2.73, P < 0.05) . Three knee reported continuing pains with quadriceps muscle strength less than 4 level. CONCLUSIONS: PFJ is an effective method for patello-femoral compartmental osteoarthritis with less trauma. The early term outcome of PFJ is encouraging. Quadriceps muscle strength should be enhanced. PMID- 25034745 TI - [Effects of recombinant human erythropoietin on angiogenesis in chronic ischemic porcine myocardium]. AB - OBJECTIVE: To investigate the effect and mechanism of recombinant human erythropoietin (rhEPO) on angiogenesis in chronic ischemic porcine myocardium. METHODS: A ameroid constrictor was placed around the proximal circumflex branch of the left coronary artery in 12 Bama miniatures' swine artery by thoracoscopy. Electrocardiogram and coronary angiography were used to confirm the establishment of myocardial ischemia. The animals were divided into rhEPO treatment group (n = 6) and negative control group (n = 6). Treatment group received subcutaneous injection of rhEPO at 1, 3, 7, 14, 21 days, control group received saline. The expression of vascular endothelial growth factor (VEGF) in serum was assessed by ELISA. Ultrasonography and coronary angiography were assessed 28 days after therapy. Western blot was used to detect the expression of VEGF, phosphorylated protein kinase B (p-Akt) and phosphorylated extracellular signal regulated kinases (p-Erk). The degree of angiogenesis was assessed by immunohistochemical analysis. RESULTS: Serum VEGF rose significantly in both control and treatment groups, peaking at 3 days and then returning to the near-baseline level at 28 days, but the two groups showed no significant difference at each time point (P > 0.05). Echocardiographic measurements showed that the left ventricular systolic function of animals in treatment group increase significantly after rhEPO therapy. the expression levels of VEGF, p-Akt and p-Erk had markedly increased, which resulted in a 2.5-fold increased of VEGF, 1.1-fold increased of p-Akt, 1.5 fold increased of p-Erk (t = 37.721, 10.907, 12.957, all P = 0.000). there were significant increase in capillary density and arteriole density in the two groups ((944 +/- 98) %/mm2 vs. (569 +/- 102) %/mm2, (73 +/- 13) %/mm2 vs. (45 +/- 10) %/mm2, t = 4.214, 2.869, P = 0.016, 0.023). CONCLUSIONS: rhEPO can promote angiogenesis and arteriogenesis and improve the left ventricular systolic function in porcine model of chronic myocardial ischemia. The potential mechanism is to up-regulated the expression of p-Akt and p-Erk. PMID- 25034746 TI - [Comparison of total disc replacement versus fusion for lumbar degenerative disc disease: a Meta-analysis of randomized controlled trials]. AB - OBJECTIVE: To compare the related clinical outcomes of total disc replacement (TDR) versus fusion in management of lumbar degenerative disc disease (LDDD)and provide available basis for choice of surgical procedure. METHODS: Computer systematically researched PubMed,EMBase, COCHRANE Library, CBMWin, CNKI, VIP databases for randomized controlled trials comparing TDR and fusion for LDDD. Data were searched until October 2013. The available statistical data was extracted after methodological assessment. The statistical soft RevMan 5.1 was used to analyze the results. RESULTS: Total 1 658 cases of patients in 6 studies were conducted, including 543 cases of fusion and 1 115 cases of TDR. The results of Meta-analysis showed that TDR was superior to fusion in term of visual analogue scale (VAS) (OR = -3.33, 95%CI:-5.94--0.71, P = 0.01) , Oswestry disability index (ODI) (OR = -5.21, 95%CI:-7.51--2.92, P = 0.00) , complication (OR = 0.45, 95%CI:0.21-0.95, P = 0.04) . There were no statistically difference regarding operating time, blood loss and reoperation (P > 0.05). However, there was no difference in term of complication in two-year and five-year sub-analysis. CONCLUSION: Regardless TDR may be more effective comparable to lumbar fusion at the immediate postoperative time, vigorous evidence is still requisite to certify the result in long-term follow-up. PMID- 25034747 TI - [Clinical effectiveness and safety of combined therapy with alpha-blocker and an anticholinergic drug for bladder outlet obstruction with overactive bladder: a Meta-analysis of outcomes]. AB - OBJECTIVE: To compare the clinical effectiveness and safety of alpha-blocker alone and combined tamsulosin with an anticholinergic drug for bladder outlet obstruction (BOO) with overactive bladder (OAB). METHODS: Literature search was performed using PubMed, EMBASE, Ovid, Wanfang, and CNKI from inception to October 2013 for comparative studies assessing alpha-blocker alone and combined alpha blocker with an anticholinergic drug for BOO+OAB. Data were extracted and evaluated by two reviewers independently according to the Cochrane Handbook for systematic reviews. Meta-analyses were conducted using RevMan 5.2. RESULTS: A total of 7 studies involving 3 458 patients were included for the analysis. The values of total IPSS and storage IPSS reduced significantly after treatment in combination group (RR = -0.23, 95%CI: -0.44--0.02, P = 0.03; RR = -0.69, 95%CI: 0.88--0.51, P < 0.01). There were no significant differences between the two groups in voiding IPSS and Qmax (P = 0.86 and 0.89). The incidences of dry mouth (OR = 2.53), constipation (OR = 3.74), dizziness (OR = 0.73), and urinary retention (OR = 0.26) were higher in combination group than in alpha-blocker alone group (P < 0.05). But most adverse events were mild in degree. CONCLUSION: Alpha-blocker combined with an anticholinergic drug in the treatment of BOO+OAB was better than that of alpha-blocker alone, and was safe and well tolerated. PMID- 25034748 TI - Acute respiratory distress syndrome in a patient with primary myelofibrosis after ruxolitinib treatment discontinuation. AB - Ruxolitinib is a Janus kinase (JAK) inhibitor used for the treatment of myelofibrosis with demonstrated efficacy for the alleviation of disease-related symptoms and splenomegaly. Anemia and thrombocytopenia are the main secondary effects. However, there are case reports of rare but serious adverse events following drug withdrawal. We present a case of a 76-year-old man diagnosed with primary myelofibrosis who presented with constitutional symptoms and symptomatic splenomegaly. Ruxolitinib was started (15 mg twice daily) and his disease-related symptoms disappeared. Six weeks later, he developed grade 4 thrombocytopenia and grade 3 anemia. Ruxolitinib was stopped and corticosteroid treatment (prednisone 1 mg/kg/day) was started to avoid a cytokine-rebound reaction. The patient then developed fever, chills, a biological inflammatory syndrome, and an acute respiratory disease syndrome. Full workup excluded an infection and we concluded that ruxolitinib withdrawal syndrome was the likely cause. Continued treatment with corticosteroids, as well as oxygen supply and continuous positive airway pressure, allowed an alleviation of his symptoms. This case report describes acute respiratory distress syndrome as another potential complication of ruxolitinib withdrawal syndrome. PMID- 25034749 TI - Primary central nervous system lymphoma in an immunocompetent 12-year-old boy. PMID- 25034750 TI - Imaging 3.0: a resident's perspective. PMID- 25034751 TI - An ecology of prestige in New York City: examining the relationships among population density, socio-economic status, group identity, and residential canopy cover. AB - Several social theories have been proposed to explain the uneven distribution of vegetation in urban residential areas: population density, social stratification, luxury effect, and ecology of prestige. We evaluate these theories using a combination of demographic and socio-economic predictors of vegetative cover on all residential lands in New York City. We use diverse data sources including the City's property database, time-series demographic and socio-economic data from the US Census, and land cover data from the University of Vermont's Spatial Analysis Lab (SAL). These data are analyzed using a multi-model inferential, spatial econometrics approach. We also examine the distribution of vegetation within distinct market categories using Claritas' Potential Rating Index for Zipcode Markets (PRIZMTM) database. These categories can be disaggregated, corresponding to the four social theories. We compare the econometric and categorical results for validation. Models associated with ecology of prestige theory are more effective for predicting the distribution of vegetation. This suggests that private, residential patterns of vegetation, reflecting the consumption of environmentally relevant goods and services, are associated with different lifestyles and lifestages. Further, our spatial and temporal analyses suggest that there are significant spatial and temporal dependencies that have theoretical and methodological implications for understanding urban ecological systems. These findings may have policy implications. Decision makers may need to consider how to most effectively reach different social groups in terms of messages and messengers in order to advance land management practices and achieve urban sustainability. PMID- 25034752 TI - Communicating about smoke from wildland fire: challenges and opportunities for managers. AB - Wildland fire and associated management efforts are dominant topics in natural resource fields. Smoke from fires can be a nuisance and pose serious health risks and aggravate pre-existing health conditions. When it results in reduced visibility near roadways, smoke can also pose hazardous driving conditions and reduce the scenic value of vistas. Communicating about smoke, whether in the preparation phases before a planned burn or during a wildfire event, can enable those at risk to make informed decisions to minimize their exposure to smoke or choose alternate activities that mitigate smoke completely. To date, very little research has been completed on the social aspects of smoke, such as communication or public perceptions. Here, we present findings from an exploratory study that examined challenges and opportunities related to communication (within agencies or to the public) for management of smoke from wildland fires. Interviews were conducted in California, Oregon, Montana, and South Carolina among a purposive sample of individuals, who are involved in fire or smoke management. Findings indicate that smoke poses several challenges to management agencies. Findings also provide insight into potential strategies to address such challenges by improving communication in both inter- and intra-agency situations as well as with members of the public. In particular, prioritizing fire and smoke-related communication within agencies, allocating agency resources specifically for training in communication and outreach endeavors, taking advantage of existing resources including informal social networks among the public, and building long term relationships both between agencies and with the public were viewed as effective. PMID- 25034753 TI - Informal institutional responses to government interventions: lessons from Madhupur National Park, Bangladesh. AB - Madhupur National Park is renowned for severe resource ownership conflicts between ethnic communities and government authorities in Bangladesh. In this study, we applied the Institutional Analysis and Development framework to identify: (i) past and present informal institutional structures within the ethnic Garo community for land resource management; (ii) the origin of the land ownership dispute; (iii) interaction mechanisms between formal and informal institutions; and (iv) change in land management authority and informal governance structures. We identify that the informal institutions of the traditional community have undergone radical change due to government interventions with implications for the regulation of land use, informal institutional functions, and joint-decision-making. Importantly, the government's persistent denial of the role of existing informal institutions is widening the gap between government and community actors, and driving land ownership conflicts in a cyclic way with associated natural resource degradation. PMID- 25034754 TI - Public acceptance of wildland fire and fuel management: panel responses in seven locations. AB - Wildland fire affects both public and private resources throughout the United States. A century of fire suppression has contributed to changing ecological conditions and accumulated fuel loads. Managers have used a variety of approaches to address these conditions and reduce the likelihood of wildland fires that may result in adverse ecological impacts and threaten communities. Public acceptance is a critical component of developing and implementing successful management programs. This study examines the factors that influence citizen support for agency fuel reduction treatments over time-particularly prescribed fire and mechanical vegetation removal. This paper presents findings from a longitudinal study examining resident beliefs and attitudes regarding fire management and fuels treatments in seven states: Arizona, Colorado, Oregon, Utah, Michigan, Minnesota, and Wisconsin. The study was implemented in two phases over a 6-year period using mail surveys to residents of communities adjacent to federal lands in each location. Questions replicated measures from the original project as well as some new items to allow a more in-depth analysis of key concepts. The study design enables comparisons over time as well as between locations. We also assess the factors that influence acceptance of both prescribed fire and mechanical vegetation removal. Findings demonstrate a relative stability of attitudes toward fuels management approaches over time and suggest that this acceptance is strongly influenced by confidence in resource managers and beliefs that the treatments would result in positive outcomes. PMID- 25034756 TI - Quaternized chitosan oligomers as novel elicitors inducing protection against B. cinerea in Arabidopsis. AB - Chitosan oligomers prepared from enzyme hydrolysis of chitosan have for many years been recognized as potent elicitors of plant innate immunity, but their efficacy is limited by the degree of polymerization and the degree of acetylation. In this study, we presented a new type of chitosan oligomers (COS), with the name of quaternized chitosan oligomers (QCOS) that were prepared by reacting COS with glycidyltrimethylammonium chloride and overcome these problems. First, QCOS clearly induced hydrogen peroxide accumulation and callose deposition in Arabidopsis seedlings. Second, we found that PAD3 expression was significantly upregulated more than 5-fold by QCOS as compared to COS. Further, PAD3 expression activated by QCOS was required for inducing Arabidopsis resistance to the necrotrophic fungus Botrytis cinerea, independent of salicylic acid signaling. These results demonstrate that quaternized modifications of COS possess better elicitor properties than the original COS and that QCOS stimulate plant protection against B. cinerea attack in Arabidopsis. Importantly, our work provides a novel and valuable strategy for enhancing elicitor activities of other types of oligosaccharides for plant innate immunity. PMID- 25034755 TI - The spectrum of biopsy-proven kidney diseases in elderly Chinese patients. AB - BACKGROUND: Studies on biopsy-proven renal disease in the elderly (age >=65 years) are extremely limited in China. The aim of this study was to examine the spectrum of renal diseases and their clinical presentations in elderly patients undergoing renal biopsy. METHODS: All native renal biopsies (n = 851) performed in patients aged >=65 years from January 2003 to December 2012 were retrospectively analyzed. The results were compared with a control group of 28 574 patients aged 18-64 years undergoing renal biopsy over the same period. RESULTS: These 851 patients included 549 males and 302 females. Primary glomerular diseases (53.94%) occurred more frequently than secondary glomerular diseases (36.49%). The clinical manifestations were nephrotic syndrome (NS) in 29.49% of the patients, chronic renal failure in 24.68%, proteinuria and hematuria in 13.28%, proteinuria in 10.93%, acute kidney injury (AKI) in 10.81% and AKI and NS in 8.93%. Membranous nephropathy (MN) was the most frequent diagnosis (28.79%), followed by diabetic nephropathy (DN, 9.75%), IgA nephropathy (IgAN, 9.64%) and vasculitis (6.82%). When compared with the control group, the results showed that MN (P < 0.0001), DN (P < 0.0001), vasculitis (P < 0.0001) and amyloidosis (P < 0.0001) occurred more frequently and IgAN (P < 0.0001), lupus nephritis (P < 0.0001) and minimal change disease (P < 0.0001) occurred less frequently in the elderly. CONCLUSION: This study is the first and largest renal biopsy series to analyze patients aged >=65 years in China, and the results obtained from this study may increase the knowledge of renal diseases in elderly patients. PMID- 25034757 TI - Do assorted approaches aid in estimation of uronic acids? Case studies on Tinospora sinensis polysaccharides. AB - Polysaccharides containing uronic acids are of immense biological significance. Colorimetric methods using different chromogens have been explored for uronic acid estimation in polysaccharides but these methods counter numerous difficulties, when neutral sugars are present in substantial amount. The uronic acid content of cold water-soluble polysaccharide (CWSP) and hot water-soluble polysaccharide (HWSP) isolated from Tinospora sinensis, widely known for marked therapeutic significance has been studied. The uronic acid was quantitatively estimated by spectrophotometric methods using carbazole, 3-phenylphenol and 3,5 dimethylphenol (DMP) vis-a-vis gas-liquid chromatography (GLC) analysis. Galacturonic acid in CWSP and HWSP was estimated as 1.41% and 1.20% respectively. The findings bring to light, the efficacy of chromogens and also reveal to what extent, they could be relied upon. The results also indicated higher specificity and selectivity of DMP over carbazole and 3-phenylphenol. However, GLC analysis despite time consuming remains the finest method for precise estimation of uronic acids. Further, GLC analysis of alditol acetates indicated the monosugar composition of L-rhamnose, L-arabinose, D-mannose, D-galactose and D-glucose in molar ratio 0.178, 0.259, 0.140, 1.045 and 98.377 in CWSP and L-rhamnose, L arabinose, D-xylose, D-mannose, D-galactose and D-glucose in molar ratio 0.608, 0.628, 0.978, 0.227, 0.111 and 97.448 in HWSP respectively. PMID- 25034758 TI - Functional crosstalk between the adenosine transporter CNT3 and purinergic receptors in the biliary epithelia. AB - BACKGROUND & AIMS: Both hepatocytes and cholangiocytes release ATP into the bile, where it acts as a potent autocrine/paracrine stimulus that activates biliary secretory mechanisms. ATP is known to be metabolized into multiple breakdown products, ultimately yielding adenosine. However, the elements implicated in the adenosine-dependent purinergic regulation of cholangiocytes are not known. METHODS: Normal rat cholangiocytes (NRCs) were used to study the expression of adenosine receptors and transporters and their functional interactions at the apical and basolateral membrane domains of polarized cholangiocytes. RESULTS: We found that: (1) cholangiocytes exclusively express two concentrative nucleoside transporters (CNT) known to be efficient adenosine carriers: CNT3, located at the apical membrane, and CNT2, located at apical and basolateral membrane domains; (2) in both domains, NRCs also express the high affinity adenosine receptor A2A, which modulated the activity of apical CNT3 in a domain-specific manner; (3) the regulation exerted by A2A on CNT3 was dependent upon the cAMP/PKA/ERK/CREB axis, intracellular trafficking mechanisms and AMPK phosphorylation; (4) secretin increased the activity of the apically-located CNT3, and promoted additional basolateral CNT3-related activity; and (5) extracellular ATP (a precursor of adenosine) was able to exert an inhibitory effect on the apical activity of both CNT3 and CNT2. CONCLUSIONS: This study uncovered the functional expression of nucleoside transporters in cholangiocytes and provides evidence for direct crosstalks between adenosine transporters and receptors for adenosine and its natural extracellular precursor, ATP. Our data anticipate the possibility of adenosine playing a major role in the physiopathology of the biliary epithelia. PMID- 25034759 TI - A longitudinal study on the relationship between duration of untreated psychosis and executive function in early-onset first-episode psychosis. AB - BACKGROUND: The relationship between duration of untreated psychosis (DUP) and executive function (EF) in patients with first-episode psychosis (FEP) is controversial. We aim to assess the influence of DUP on changes in EF over a 2 year period in subjects with early-onset FEP (first psychotic symptom before age 18) and less than 6 months of positive symptoms. METHODS: A total of 66 subjects were included in the study (19 females [28.8%], mean age 16.2 +/- 1.6 years). The influence of DUP on changes in EF over the 2-year follow-up (expressed as a composite score of 5 cognitive abilities: attention, working memory, cognitive flexibility, response inhibition, and problem solving) was estimated using a multivariate linear regression model after removing the effect of intelligence quotient and controlling for age, gender, diagnosis, premorbid adjustment, severity of positive and negative symptoms at baseline, global functioning at baseline, and mean daily antipsychotic dosage during follow-up. RESULTS: Mean DUP was 65.0 +/- 6.9 days (95% confidence interval [CI], 51.2, 78.8). Median DUP was 47.5 days (range 2-180 days). Negative symptoms at baseline was the only variable significantly associated with EF at baseline (10.9% of explained variance [e.v. 10.9%], p=0.007). Only shorter DUP (e.v. 8.7%, p=0.013) and greater severity of baseline negative symptoms (e.v. 10.0%, p=0.008) were significantly associated with greater improvement in EF. CONCLUSIONS: In early-onset FEP, shorter DUP was associated with greater improvement in EF over a 2-year follow-up period. PMID- 25034761 TI - Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia - An observational 9-year follow-up study. AB - BACKGROUND: The association between the course of cognition and long-term antipsychotic medication in schizophrenia remains unclear. We analysed the association between cumulative lifetime antipsychotic medication dose and change of verbal learning and memory during a 9-year follow-up. METHOD: Forty schizophrenia subjects and 73 controls from the Northern Finland Birth Cohort 1966 were assessed by California Verbal Learning Test (CVLT) at the ages of 34 and 43 years. Data on the lifetime antipsychotic doses in chlorpromazine equivalents were collected. The association between antipsychotic dose-years and baseline performance and change in CVLT was analysed, controlling for baseline performance, gender, age of onset and severity of illness. RESULTS: Higher antipsychotic dose-years by baseline were significantly associated with poorer baseline performance in several dimensions of verbal learning and memory, and with a larger decrease in short-delay free recall during the follow-up (p=0.031). Higher antipsychotic dose-years during the follow-up were associated with a larger decrease of immediate free recall of trials 1-5 during the follow-up (p=0.039). Compared to controls, decline was greater in some CVLT variables among those using high-doses, but not among those using low-doses. CONCLUSION: This is the first report of an association between cumulative lifetime antipsychotic use and change in cognition in a long-term naturalistic follow-up. The use of high doses of antipsychotics may be associated with a decrease in verbal learning and memory in schizophrenia years after illness onset. The results do not support the view that antipsychotics in general prevent cognitive decline or promote cognitive recovery in schizophrenia. PMID- 25034762 TI - Psychosis risk screening: a systematic review. AB - Despite the wealth of evidence linking duration of untreated psychosis to critical illness outcomes, most clinicians do not utilize any formal evaluation tools to identify attenuated or emerging psychotic symptoms. Given the costs associated with training and administration, interview-based assessments such as the Structured Interview for Psychosis Risk Syndromes (SIPS) are not likely to be widely adopted for clinical use. The ability to identify high-risk individuals through low-cost, brief methods is essential to the success of scalable prevention efforts. The aim of this article is to present a comprehensive review of the use of self-report forms as psychosis risk "screeners." A literature search revealed 34 investigations in which authors used a self-report questionnaire as a first-step screener in a clinical high-risk assessment protocol. Information about each screener, including reported psychometric data, is presented within the review. Psychosis risk screeners have been used in diverse samples with the goals of validating assessments, screening populations for clinical referral, recruiting samples of interest for research participation, and estimating symptom prevalence and severity. Screeners focusing on attenuated psychotic experiences appear to measure a reliable construct with variable prevalence in help-seeking and general population samples. Administration of screeners to help-seeking populations can identify enriched samples with substantially elevated likelihood of meeting CHR criteria and transitioning to psychosis over time. More research is needed, however, to establish reliable norms and screening thresholds, as score elevations indicating a likely high-risk respondent appear to be unreliable across populations and settings. PMID- 25034763 TI - A naturalistic longitudinal study of at-risk mental state with a 2.4 year follow up at a specialized clinic setting in Japan. AB - OBJECTIVE: The notion of at-risk mental state (ARMS) is valuable for identifying individuals in a putative prodromal state of psychosis and for reducing conversion risk by pharmacological and psychological interventions. However, further systematic study is required because 1) diagnostic reliability in various clinical settings is not yet established; 2) predictive ability is insufficient; 3) optimal interventions in diversified populations are elusive; and 4) little evidence from non-Western regions exists. METHODS: A naturalistic longitudinal study was conducted at a specialized clinic for early psychosis at a university hospital in Sendai, Japan. Individuals with ARMS (n=106) were recruited and followed up with case-by-case treatment. RESULTS: Two-thirds of the participants were psychiatrist referrals, and 83 were followed up for at-least 1 year (mean follow-up=2.4 years). Fourteen developed psychosis and the estimated (by Kaplan Meier) cumulative transition rate was 11.1% at 12, 15.4% at 24, and 17.5% at 30 months. At the end-point, about 30% of the 83 followed-up participants including 11 converters received antipsychotic medication. Compared to non-converters, converters showed more severe attenuated psychotic symptoms, including ego boundary disturbance, formal thought disorder, and emotional disturbance. CONCLUSIONS: The present study replicated previous major Western longitudinal studies, in terms of clinical characteristics, psychosis transition rate, and antipsychotic prescription rate. Our results emphasize the importance of phenomenological assessment of ARMS and intensive care in a clinical setting. PMID- 25034760 TI - Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. AB - Autoimmunity, gastrointestinal (GI) disorders and schizophrenia have been associated with one another for a long time. This paper reviews these connections and provides a context by which multiple risk factors for schizophrenia may be related. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease. Exposure to wheat gluten and bovine milk casein also contribute to non-celiac food sensitivities in susceptible individuals. Co-morbid GI inflammation accompanies humoral immunity to food antigens, occurs early during the course of schizophrenia and appears to be independent from antipsychotic-generated motility effects. This inflammation impacts endothelial barrier permeability and can precipitate translocation of gut bacteria into systemic circulation. Infection by the neurotropic gut pathogen, Toxoplasma gondii, will elicit an inflammatory GI environment. Such processes trigger innate immunity, including activation of complement C1q, which also functions at synapses in the brain. The emerging field of microbiome research lies at the center of these interactions with evidence that the abundance and diversity of resident gut microbiota contribute to digestion, inflammation, gut permeability and behavior. Dietary modifications of core bacterial compositions may explain inefficient gluten digestion and how immigrant status in certain situations is a risk factor for schizophrenia. Gut microbiome research in schizophrenia is in its infancy, but data in related fields suggest disease associated altered phylogenetic compositions. In summary, this review surveys associative and experimental data linking autoimmunity, GI activity and schizophrenia, and proposes that understanding of disrupted biological pathways outside of the brain can lend valuable information regarding pathogeneses of complex, polygenic brain disorders. PMID- 25034764 TI - Patients with schizophrenia demonstrate reduced cortical sensitivity to auditory oddball regularities. AB - BACKGROUND: Individuals with schizophrenia demonstrate deficits in context processing. These deficits can be characterized by examining the influence of auditory context on ERP responses to rare target tones. Previous studies demonstrate that target ERP deficits in schizophrenia depend on the number of non targets that precede the target ERP. Our goal was to extend these findings by examining whether patients with schizophrenia demonstrate a reduced sensitivity to subtle differences in the auditory context preceding rare target stimuli, as quantified by Itti and Baldi's Bayesian prediction error model. METHODS: Cortical responses to auditory oddball tones were measured within 59 individuals with schizophrenia (SZ) and 59 controls (HC). Individual trial amplitudes were estimated by conducting group ICA on the EEG time series and analyzing the reconstructed individual temporal sources. We quantified the auditory context of target tones using the Bayesian prediction error model and determined whether ERP amplitudes to tones were sensitive to this measure of context, or the number of preceding non-targets directly, within HC and SZ. RESULTS: Individuals with schizophrenia show a significant reduction in ERP response amplitudes to targets approximately 244-412 ms following target onsets. Individual amplitudes within this window showed significantly greater sensitivity to the modeled prediction error within the controls than in individuals with schizophrenia. These differences approached significance when examining differences in amplitudes as a function of the number of preceding non-targets. CONCLUSIONS: These findings further clarify differences in HC and SZ with regard to their attentional and perceptual sensitivity to subtle environmental regularities. PMID- 25034765 TI - Early versus delayed surgery for acute cholecystitis as an applied treatment strategy when assessed in a population-based cohort. AB - BACKGROUND: The aims of this study were to describe the surgical management of acute cholecystitis (AC) in a well-defined population-based patient cohort, in particular adherence to and outcome of the early open/laparoscopic cholecystectomy (EC/ELC) strategy. METHODS: The medical records of all patients residing in Stockholm County who were treated for AC during 2003 and 2008 were reviewed according to a standardized protocol. RESULTS: In 2003, 799 patients were admitted 850 times for AC, and the respective figures for 2008 were 833 and 919. The number of patients who underwent EC/ELC increased from 42.9% in 2003 to 47.4% in 2008. In multivariate regression analysis adjusting for age, gender, severity of cholecystitis, maximal CRP and maximal WBC, EC/ELC was associated with shorter operation time but higher perioperative blood loss when compared to delayed open/laparoscopic cholecystectomy (DC/DLC). The odds ratio for completing the procedure laparoscopically was significantly higher in DC/DLC when adjusting for the same covariates. There were no significant differences in peri- or postoperative complications between the groups. CONCLUSION: Strategies should be implemented in order to secure a more evidence-based approach to the surgical treatment of AC. PMID- 25034766 TI - MicroRNA expression profiles related to early stage murine concanavalin A-induced hepatitis. AB - BACKGROUND: Fulminant hepatitis is a severe liver disease characterized by massive hepatocyte necrosis and clinical signs of liver failure. This study explores the expression profile of microRNAs, which are regulators of a number of pathophysiological processes, during the early stage of concanavalin A (Con A) induced hepatitis. METHODS: Balb/c mice were given ConA injections to induce fulminant hepatitis. miRNA expression profiling in liver tissues was carried out by microarray analysis. The differentially expressed miRNAs were subjected to time sequence profile analysis, gene-miRNA regulatory network analysis, and gene ontology-miRNA regulatory network analysis. RESULTS: Eleven miRNAs among multiClass were found to be significantly differentially expressed between liver tissue in early stage fulminant hepatitis and normal control liver tissue. Mmu miR-133a was the most differentially expressed with the strongest regulatory ability, regulating 47 mRNAs. Mmu-miR-10a was the most highly expressed in the microRNA-GO-Network and also exerted a strong regulatory ability. The expression profiles of miR-133a and miR-10a were verified by RT-PCR. CONCLUSIONS: These results show that, in the early stage, ConA-induced fulminant hepatitis induces a distinct miRNA expression profile. This differential miRNA expression profile may provide pathogenic clues and potential diagnostic and prognostic markers in acute and severe liver disease. PMID- 25034767 TI - Overexpression of miR-19b impairs cardiac development in zebrafish by targeting ctnnb1. AB - BACKGROUND: MicroRNAs are broadly accepted as crucial regulators of cardiovascular development, and dysregulation of their expression has been linked to cardiac disease. MicroRNA cluster miR-17-92 has been implicated in cardiac development and function, yet its defined mechanisms of action in this context are uncertain. Here, we focused on miR-19b, a key component of the miR-17-92 cluster proven to induce cardiomyocyte proliferation in vitro. We aimed to identify the biological significance of miR-19b in cardiac development and its underlying molecular mechanism of action in vivo. METHODS: We micro-injected zebrafish embryos with different concentrations (0, 2, 4 and 8 MUm) of miR-19b mimics or a negative control, and assessed the embryo malformation rate, mortality rate, hatching rate and heart abnormalities at 72 hours post fertilization (72 hpf). RESULTS: We found that overexpression of miR-19b impacted left-right symmetry and cardiac development of zebrafish embryos, characterized by pericardial edema, slower heart rate and cardiac looping defects in a dose dependent manner. Moreover, several important signaling molecules in the Wnt signaling pathway were abnormally expressed, suggesting that overexpression of miR-19b induces the inhibition of the Wnt signaling pathway by directly targeting ctnnb1. Interestingly, the deformed cardiac phenotype was partially rescued by treatment with the GSK3beta inhibitor lithium chloride. CONCLUSION: Our findings suggest that miR-19b regulates laterality development and heart looping in zebrafish embryos by targeting ctnnb1. PMID- 25034768 TI - The effect of the physiological rest position of the mandible on cerebral blood flow and physical balance: an observational study. AB - AIMS: There has been much published evidence that balance can improve by changing the mandible's position relative to the maxilla as it comes together with the teeth (or oral device) as the endpoint. To help with the complexity of this topic, a definitions table* (in Appendix) has been included at the end of the manuscript for reference as needed. The aim of the current study is to evaluate whether the physiologic rest position of the jaw* (oral device overtop of the teeth as endpoint where the muscles of mastication are optimized) can have an effect on cerebral blood flow and physical balance using measurable data relative to the person's natural, or habitual bite (teeth as endpoint) in both healthy and diseased volunteers. METHODOLOGY: Seven healthy male professional football athletes and two females with multiple sclerosis were included in this observational study, which tested the subjects in both jaw positions. Cerebral blood flow was measured non-invasively by ultrasound over the temporal region of the skull using mean flow velocity (MFV)* and pulsatility index (PI)* of the right and left middle cerebral arteries while the subject clenched the teeth together in both jaw positions. The MFV is the average speed of the blood flow in a given region of a blood vessel. The PI measures cerebral intravascular resistance. Physiologic balance of the whole body was also tested while the subjects were in both jaw positions using the y-excursion balance test* and by videotape. RESULTS: (i) Cerebral blood flow. On the natural teeth, the MFV dropped from baseline to clenching position (mean drop -2.6+/-7.7 cm/second, whereas, the MFV was slightly enhanced with the physiologic rest position (PRP) [mean enhancement is 0.82+/-3.7 cm/second (P=0.07)]. At baseline on natural teeth, the PI dropped slightly from baseline to clenching (mean drop 0.015+/ 0.19). Whereas with PRP, the PI dropped by mean of 0.059+/-0.072 (P=0.15). (ii) Balance. The mean balance measurement while using the PRP was 119.54+/-12.56 cm (P=0.001), whereas the mean balance measurement on natural teeth was 110.72+/ 9.47 cm. Balance improved subjectively in both MS patients on videotape. CONCLUSION: The physiologic rest position of the mandible might have an effect on balance by showing a trend (demonstrating a tendency) in enhancing cerebral blood flow as measured by transcranial Doppler. Further studies are needed to confirm this study's finding. PMID- 25034770 TI - [Not Available]. PMID- 25034769 TI - What makes a marker a good marker?. Commentary on Balthazart J and Ball G (2014): Doublecortin is a highly valuable endogenous marker of adult neurogenesis in canaries. Brain Behav Evol 84:1-4. PMID- 25034771 TI - [Not Available]. PMID- 25034772 TI - Transorbital sonography in acute optic neuritis: a case-control study. AB - BACKGROUND AND PURPOSE: Acute unilateral optic neuritis is associated with a thickening of the retrobulbar portion of the optic nerve as revealed by transorbital sonography, but no comparison has been made between nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis versus healthy controls. We evaluated optic nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis and healthy controls and compared optic nerve sheath diameter and optic nerve diameter with visual-evoked potentials in patients. MATERIALS AND METHODS: A case-control study was performed in 2 centers. Twenty-one consecutive patients with onset of visual loss during the prior 10 days and established acute noncompressive unilateral optic neuritis were compared with 21 healthy controls, matched for sex and age (+/-5 years). Two experienced vascular sonographers performed the study by using B-mode transorbital sonography. Visual-evoked potentials were performed on the same day as the transorbital sonography and were evaluated by an expert neurophysiologist. Sonographers and the neurophysiologist were blinded to the status of the patient or control and to clinical information, including the side of the affected eye. RESULTS: The median optic nerve sheath diameter was thicker on the affected side (6.3 mm; interquartile range, 5.9-7.2 mm) compared with the nonaffected side (5.5 mm; interquartile range, 5.1-6.2 mm; P < .0001) and controls (5.2 mm; interquartile range, 4.8-5.5 mm; P < .0001). The median optic nerve diameter was 3.0 mm (range, 2.8-3.1 mm) on the affected side and 2.9 mm (range, 2.8-3.1 mm) on the nonaffected side (P = not significant.). Both sides were thicker than those in controls (2.7 mm; interquartile range, 2.5-2.8 mm; P = .001 and .009). No correlation was found between optic nerve sheath diameter and optic nerve diameter and amplitude and latency of visual-evoked potentials in patients with optic neuritis. CONCLUSIONS: Transorbital sonography is a promising tool to support the clinical diagnosis of acute optic neuritis. Further studies are needed to define its specific role in the diagnosis and follow-up of optic neuritis. PMID- 25034773 TI - Social media and the neuroradiologist: a brief introduction. PMID- 25034774 TI - Forced arterial suction thrombectomy with the penumbra reperfusion catheter in acute basilar artery occlusion: a retrospective comparison study in 2 Korean university hospitals. AB - BACKGROUND AND PURPOSE: A performance of forced arterial suction thrombectomy was not reported for the treatment of acute basilar artery occlusion. This study compared revascularization performance between intra-arterial fibrinolytic treatment and forced arterial suction thrombectomy with a Penumbra reperfusion catheter in patients with acute basilar artery occlusion. MATERIALS AND METHODS: Fifty-seven patients with acute basilar artery occlusion were treated with intra arterial fibrinolysis (n = 25) or forced arterial suction thrombectomy (n = 32). Baseline characteristics, successful revascularization rate, and clinical outcomes were compared between the groups. RESULTS: Baseline characteristics, the frequency of patients receiving intravenous recombinant tissue plasminogen activator, and mean time interval between symptom onset and femoral puncture did not differ between groups. The forced arterial suction thrombectomy group had a shorter procedure duration (75.5 minutes versus 113.3 minutes, P = .016) and higher successful revascularization rate (88% versus 60%, P = .017) than the fibrinolysis group. Fair outcome, indicated by a modified Rankin Scale 0-3, at 3 months was achieved in 34% of patients undergoing forced arterial suction thrombectomy and 8% of patients undergoing fibrinolysis (P = .019), and the mortality rate was significantly higher in the fibrinolysis group (25% versus 68%, P = .001). Multiple logistic regression analysis identified the forced arterial suction thrombectomy method as an independent predictor of fair outcome with adjustment for age, sex, initial NIHSS score, and the use of intravenous recombinant tissue plasminogen activator (odds ratio, 7.768; 95% CI, 1.246 48.416; P = .028). CONCLUSIONS: In acute basilar artery occlusion, forced arterial suction thrombectomy demonstrated a higher revascularization rate and improved clinical outcome compared with traditional intra-arterial fibrinolysis. Further clinical trials with the newer Penumbra catheter are warranted. PMID- 25034775 TI - Social media and research visibility. PMID- 25034776 TI - Memory part 1: overview. PMID- 25034777 TI - Whole-brain adaptive 70-kVp perfusion imaging with variable and extended sampling improves quality and consistency while reducing dose. AB - BACKGROUND AND PURPOSE: Despite common use of CTP to assess cerebral hemodynamics in the setting of ischemia, concerns over radiation exposure remain. Our aim was to evaluate the efficacy of an adaptive 70-kVp (peak) whole-brain CTP protocol with variable sampling intervals and extended duration against an established fixed-sampling, limited-period protocol at 80 kVp. MATERIALS AND METHODS: A retrospective analysis of 37 patients with stroke scanned with conventional (n = 17) and variant-protocol (n = 20) whole-brain CTP was performed. We compared radiation dose, parametric map quality, and consistency of full-contrast circulation capture between a modified 70-kVp protocol, with 20 whole-brain passes at variable sampling intervals over an extended sampling period, and a conventional 80-kVp CTP examination with 24 passes at fixed-sampling intervals and a more limited scanning window. Mann-Whitney U test analysis was used to compare both protocols. RESULTS: The 70-kVp CTP scan provided superior image quality at a 45% lower CT dose index volume and 13% lower dose-length product/effective dose compared with the conventional 80-kVp scan. With respect to the consistency of contrast-passage capture, 95% of the adaptive, extended protocol continued through the venous return to baseline, compared with only 47% by using the conventional limited-length protocol. Rapid sampling during the critical arterial arrival and washout period was accomplished in nearly 95% with both the variable and fixed-sampling-interval protocols. CONCLUSIONS: Seventy kilovolt (peak) CTP with variable and extended sampling produces improved image quality at lower radiation doses with greater consistency of full contrast passage capture. PMID- 25034778 TI - Diagnostic accuracy of screening MR imaging using unenhanced axial CISS and coronal T2WI for detection of small internal auditory canal lesions. AB - BACKGROUND AND PURPOSE: While enhanced T1WI is considered the "gold standard" for detection of internal auditory canal pathology, unenhanced fluid-sensitive sequences have shown high sensitivity for lesion identification. Our purpose was to evaluate the diagnostic accuracy of an unenhanced MR imaging protocol using axial CISS and coronal T2WI for detection of small (10 mm or less) internal auditory canal lesions. MATERIALS AND METHODS: Twenty-three patients with small internal auditory canal lesions and 13 patients without lesions who had undergone MR imaging using the screening protocol and confirmatory gadolinium-enhanced thin section T1WI were identified. Two blinded neuroradiologists retrospectively evaluated all examinations using 1) only axial CISS, 2) only coronal T2WI, and 3) axial and coronal sequences together. Accuracy, specificity, sensitivity, and interobserver agreement were assessed. RESULTS: Median maximum lesion dimension was 4 mm (range, 2-10 mm). Accuracy, specificity, and sensitivity for axial CISS alone were 0.94, 0.96, and 0.91 for observer 1 and 0.94, 0.92, and 1.00 for observer 2. The data for the coronal T2WI sequence only were 0.94, 0.96, and 0.91 for observer 1, and 0.99, 1.00, and 0.96 for observer 2. Using axial and coronal sequences, the data were 0.97, 0.96, and 1.00 for observer 1, and 0.99, 0.98, and 1.00 for observer 2. kappa coefficients were 0.84 for the axial sequence only, 0.90 for coronal only, and 0.91 for axial and coronal both. CONCLUSIONS: Screening noncontrast MR imaging using a combination of axial CISS and coronal T2WI sequences can detect small internal auditory canal lesions with 100% sensitivity and excellent interobserver agreement. PMID- 25034779 TI - Radiation dose reduction in CT-guided spine biopsies does not reduce diagnostic yield. AB - BACKGROUND AND PURPOSE: CT-guided biopsy is the most commonly used method to obtain tissue for diagnosis in suspected cases of malignancy involving the spine. The purpose of this study was to demonstrate that a low-dose CT-guided spine biopsy protocol is as effective in tissue sampling as a regular-dose protocol, without adversely affecting procedural time or complication rates. MATERIALS AND METHODS: We retrospectively reviewed all patients who underwent CT-guided spine procedures at our institution between May 2010 and October 2013. Biopsy duration, total number of scans, total volume CT dose index, total dose-length product, and diagnostic tissue yield of low-dose and regular-dose groups were compared. RESULTS: Sixty-four patients were included, of whom 31 underwent low-dose and 33 regular-dose spine biopsies. There was a statistically significant difference in total volume CT dose index and total dose-length product between the low-dose and regular-dose groups (P < .0001). There was no significant difference in the total number of scans obtained (P = .3385), duration of procedure (P = .149), or diagnostic tissue yield (P = .6017). CONCLUSIONS: Use of a low-dose CT-guided spine biopsy protocol is a practical alternative to regular-dose approaches, maintaining overall quality and efficiency at reduced ionizing radiation dose. PMID- 25034780 TI - Optimized angiographic CT using intravenous contrast injection: a noninvasive imaging option for the follow-up of coiled aneurysms? AB - BACKGROUND AND PURPOSE: Because recanalization of coiled cerebral aneurysms is reported to occur, follow-up imaging is mandatory, ideally noninvasively. Our study aimed to evaluate the accuracy of an optimized angiographic CT by using intravenous contrast material injection in the assessment of coiled cerebral aneurysms, compared with MR angiography and digital subtraction angiography, the criterion standard. MATERIALS AND METHODS: We included 69 patients with 76 coiled cerebral aneurysms. In each patient, we performed an angiographic CT with intravenous contrast material injection with a dual rotational acquisition, a time-of-flight MR angiography, and a DSA. The angiographic CT with intravenous contrast material injection data was postprocessed by using newly implemented reconstructions modes and a dual-volume technique. An aneurysm occlusion rate was assessed in angiographic CT with intravenous contrast material injection and MRA; remnants were measured and correlated with DSA, respectively. RESULTS: Twenty eight remnants were revealed by DSA with a mean size of 3.1 * 3.1 mm. Angiographic CT with intravenous contrast material injection demonstrated a sensitivity of 93% and a specificity of 96% in remnant detection. MRA showed almost identical accuracy (sensitivity of 93%, specificity of 100%). Assessment of remnant size by angiographic CT with intravenous contrast material injection and by MRA revealed a high significant correlation with DSA, respectively (P < .001). CONCLUSIONS: Optimized angiographic CT with intravenous contrast material injection and MRA demonstrated accuracy comparable with that of DSA in the follow up of coiled aneurysms, respectively. The assessment of remnant size showed a high correlation with DSA for both techniques. Due to the lack of radiation exposure, MRA seems to be the preferred technique. However, angiographic CT with intravenous contrast material injection can be considered a reliable, noninvasive alternative in patients with MR imaging contraindications or in cases of compromising artifacts due to metal implants (ie, clips). PMID- 25034781 TI - CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition. AB - The CD300 receptor family members are a group of molecules that modulate a variety of immune cell processes. We show that mouse CD300b (CLM7/LMIR5), expressed on myeloid cells, recognizes outer membrane-exposed phosphatidylserine (PS) and does not, as previously reported, directly recognize TIM1 or TIM4. CD300b accumulates in phagocytic cups along with F-actin at apoptotic cell contacts, thereby facilitating their engulfment. The CD300b-mediated activation signal is conveyed through CD300b association with the adaptor molecule DAP12, and requires a functional DAP12 ITAM motif. Binding of apoptotic cells promotes the activation of the PI3K-Akt kinase pathway in macrophages, while silencing of CD300b expression diminishes PI3K-Akt kinase activation and impairs efferocytosis. Collectively, our data show that CD300b recognizes PS as a ligand, and regulates the phagocytosis of apoptotic cells via the DAP12 signaling pathway. PMID- 25034782 TI - Interleukin-17 enhances immunosuppression by mesenchymal stem cells. AB - IL-17 is one of the most potent and most actively investigated proinflammatory cytokines. In this study, we examined the effect of IL-17 on mesenchymal stem cells (MSCs) under the influence of inflammatory cytokines. Ironically, IL-17 dramatically enhanced the immunosuppressive effect of MSCs induced by IFNgamma and TNFalpha, revealing a novel role of IL-17 in immunosuppression. Interestingly, we found that this action of IL-17 was dependent on the promoted expression of a key immune suppressive molecule, inducible nitric oxide synthase (iNOS), in MSCs. In a concanavalin A (ConA)-induced hepatitis mouse model, we found that IL-17 also enhanced the in vivo immunosuppressive effect of MSCs in an iNOS-dependent manner. Moreover, this promoting effect of IL-17 was found to be exerted through enhancing mRNA stability by modulating the protein level of ARE/poly(U)-binding/degradation factor 1 (AUF1), a well-known factor that promotes mRNA decay. In auf1(-/-) MSCs, IFNgamma and TNFalpha could induce maximal immunosuppressive effect, both in vitro and in vivo, without the need for IL-17. Thus, our studies demonstrated that in the presence of MSCs, IL-17 promotes immunosuppression. PMID- 25034783 TI - p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells. AB - The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-kappaB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34(+) progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a pro-survival function of the NF-kappaB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA. PMID- 25034784 TI - Inhibition of autophagy, lysosome and VCP function impairs stress granule assembly. AB - Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein (VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation. This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here, we describe that inhibition of autophagy, lysosomes and VCP causes defective SG formation after induction. Silencing the VCP co-factors UFD1L and PLAA, which degrade defective ribosomal products (DRIPs) and 60S ribosomes, also impaired SG assembly. Intriguingly, DRIPs and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome or VCP function. Our results suggest that deregulated autophagy, lysosomal or VCP activities, which occur in several neurodegenerative (VCP-associated) diseases, may alter SG morphology and composition. PMID- 25034785 TI - Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer. AB - Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC. PMID- 25034787 TI - Scientific authorship and intellectual involvement in the research: should they coincide? AB - An update of the widely acknowledged recommendations on how to handle authorship in research, issued by the International Committee of Medical Journal Editors (ICMJE), was issued in August, 2013. While the revised recommendations contain several clarifications compared to earlier versions, one arguably important aspect is still not addressed: the relationship between authorship and intellectual involvement in research. In this paper, it is argued that the ICMJE authorship criteria are flawed in this respect: they do not explicitly require of authors of scientific papers that they do research. It is further suggested that unless academic authorship clearly reflects to what extent individual researchers have been intellectually involved in the research and to what extent they have merely contributed with research-related work, they will, in many cases, be misleading about research merits. PMID- 25034786 TI - Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway. AB - Clioquinol is an anti-microbial drug, and it was recently found to induce cancer cell death. In the present study, clioquinol was found to trigger autophagy by inducing LC3 lipidation and autophagosome formation which was abolished by an autophagy inhibitor 3-methyladenine. Further study showed clioquinol displayed no effects on PI3KC3 or Beclin 1 expression but downregulated the expression and the enzymatic activity of mammalian target of Rapamycin (mTOR), a critical modulator of autophagy. Moreover, clioquinol inhibited the catalytic activity of the mTOR complex 1, thus suppressing phosphorylation of P70S6K and 4E-BP1, two major proteins associated with autophagy in the mTORC1 signaling pathway. Clioquinol induced leukemia and myeloma cell apoptosis, however, addition of autophagy inhibitor 3-methyladenine attenuated this kind of cell death. Therefore, this study demonstrated that clioquinol induces autophagy in associated with apoptosis in leukemia and myeloma cells by disrupting mTOR signaling pathway. PMID- 25034788 TI - Reconstruction of pediatric brachial plexus injuries with nerve grafts and nerve transfers. AB - PURPOSE: To review the demographics and injury patterns in consecutive pediatric patients with traumatic brachial plexus injury presenting to a single center over a 16-year period and to review the outcomes of nerve grafting and nerve transfers for reconstruction of shoulder abduction and elbow flexion in these patients. METHODS: Forty-five pediatric patients presented for treatment of traumatic Brachial plexus injury from 1996 to 2012. Subgroup analysis of patients who had nerve grafting or nerve transfers for restoration of shoulder abduction and elbow flexion was carried out to compare outcomes of Medical Research Council (MRC) motor grading. RESULTS: The mean age of patients was 13.8 years (range, 3-17 y). Panplexal injuries (62%) and upper plexus injuries (16%) were particularly common. There was a very high proportion of preganglionic injuries (91%). Six of the 10 of patients who underwent intraplexal nerve grafting only for restoration of shoulder abduction achieved grade 3 or better power compared with 42% (5/12) of patients who had nerve transfers. When contralateral C7 was used as a donor for nerve transfer in restoration of shoulder abduction, 1 of the 5 patients achieved grade 3 or better shoulder abduction. All 4 patients who had nerve grafts for restoration of elbow flexion achieved grade 3 or better power, compared with 11 of 12 patients who had nerve transfers. There was no statistical difference in outcome (MRC grade 3 or 4) between patients who had nerve grafts and those who had nerve transfers. CONCLUSIONS: This study shows that nerve grafts can result in similar outcomes (MRC grading) to nerve transfers for restoration of shoulder abduction and elbow flexion in traumatic pediatric BPI. The findings of this study do not support the use of contralateral C7 as a donor for nerve transfer in reconstruction of shoulder abduction in this age group. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25034790 TI - Commentary: incorporating patient-reported outcomes in periodontal clinical trials. AB - The authors review patient-reported outcome (PRO) metrics for dentistry, and in particular, periodontics. The PRO commentary for periodontics includes a review of split-mouth, randomized, controlled clinical trial results that specifically tracked pain at different sites over time after intervention and provided guidelines for peak pain time points and evidence for referred pain assessment when studying soft tissue augmentation procedures. Both the questions that are asked of patients and the timing of those questions are important study design considerations. The authors suggest PRO methodology for periodontal clinical trials that can be used to identify information important to patients and clinicians. PMID- 25034791 TI - Pressure effect on stabilities of self-interstitials in HCP-zirconium. AB - The self-interstitial atoms (SIAs) mediate the evolution of micro-structures which is crucial in understanding the instabilities of hexagonal close packed (HCP) structures. Taking zirconium as a prototype, we investigate the pressure effect on the stabilities of SIAs using first-principles calculations based on density-functional theory. We found that the pressure greatly affects the stability of the SIAs. The SIAs in basal planes are more stable under pressure. The SIA configuration of the lowest formation energy changes from basal octahedral (BO) to octahedral (O) at a pressure of 21 GPa. The lowest formation enthalpy configuration switches from BO to S (split-dumbbell) at the pressure of 30 GPa. The formation volumes of SIAs decrease monotonically in response to an increase in pressure. Our results reveal that it is important to take pressure effects into account when predicting the micro-structural evolution of HCP structures. PMID- 25034792 TI - Recent advances in animal models of diabetic nephropathy. AB - Diabetic nephropathy (DN) is the single most common cause of end-stage kidney disease. Therefore, it is imperative that novel therapies are developed. Progress has been hindered, however, by the lack of robust animal models. In the current review we describe recent advances in the field, including the impact of background strain, hypertension and transcriptomic profiling. While the C57BL/6J strain is relatively resistant to DN, the FVB strain appears more susceptible and Ove26 and db/db mice on this background may be useful in modelling types 1 and 2 DN, respectively. Black and tan, brachyury (BTBR) mice deficient for the leptin receptor (ob/ob) develop many of the pathological features of human DN and, remarkably, treatment with exogenous leptin ameliorates hyperglycaemia, albuminuria and glomerulosclerosis. Hypertension plays a key role in the progression of human DN and exacerbates nephropathy in diabetic rodents. Endothelial nitric oxide synthase deficiency (eNOS(-/-)) results in moderate hypertension and the development of nodular glomerulosclerosis and hyaline arteriosclerosis in streptozotocin-induced diabetic C57BL/6J mice. In Cyp1a1mRen2 rats, renin-dependent hypertension synergises with streptozotocin-induced hyperglycaemia to produce a 500-fold increase in albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. Renal transcriptional profiling suggests that many of the gene expression changes observed in human DN are replicated in eNOS( /-) mice and Cyp1a1mRen2 rats. Despite these advances, no model faithfully recapitulates all the features of human DN and further refinements are required. In the interim, it is likely that researchers may use publically available transcriptomic data to select the most appropriate model to study their molecule or pathway of interest. PMID- 25034793 TI - Evolution and impact of drive-line infection in a large cohort of continuous-flow ventricular assist device recipients. AB - BACKGROUND: Drive-line infections (DLIs) frequently complicate ventricular assist device (VAD) support. We sought to describe the detailed effects of DLIs over time in patients with continuous-flow VADs, including the onset, risk factors, organisms involved, association with invasive infections, and outcomes. METHODS: We reviewed data for patients with HeartMate II VADs (HMII) who were implanted at the Cleveland Clinic from October 2004 to September 2011 and followed through December 2011. DLIs were defined according to published criteria. RESULTS: DLIs developed in 45 of 194 HMII VADs over a median period of 232 days (range 22 to 883 days). Hazard for DLI was 2.0%/month, but transiently peaked at 11%/month at 7.5 months after implant. Pseudomonas aeruginosa accounted for 31%, 42% and 55% of initial, final and deep DLIs, respectively. Of the 40 superficial DLIs, 13 (32.5%) became deep. DLI-associated bacteremia and hospitalization occurred in 14 of 45 (31%) and 30 of 45 (67%), respectively. All patients received antibiotics (median 171 days), but only 3 of 44 (6.8%) developed an antibiotic complication. DLIs increased the risk for death while on VAD support (HR 2.20, 95% CI 1.20 to 4.05; p = 0.01). Six and 12 months after DLI, mortality was 9.8% and 31%, but the competing event of transplantation occurred successfully in 20% and 28%, respectively. CONCLUSIONS: Most DLIs begin superficially with peak hazard at 7.5 months after implant. Depth of infection and infecting organism may evolve over months on support, with Pseudomonas becoming more prominent. Although effectively managed for prolonged periods, DLIs are associated with reduced survival on VAD support. Earlier transplantation is the most successful approach to treatment. PMID- 25034789 TI - Interobserver variability in the treatment of little finger metacarpal neck fractures. AB - PURPOSE: To address the null hypothesis that surgeons shown radiographs of little finger metacarpal neck fractures with measured fracture angulation would recommend surgery as often as surgeons shown unmarked radiographs. METHODS: Members of the Science of Variation Group, an international collaboration of fully trained orthopedic and trauma surgeons, were asked to review 20 little finger metacarpal neck fracture cases, which included a vignette and 3 high quality radiographs. Members were then randomized to review radiographs with or without measured fracture angulation on the lateral view and select operative or nonoperative management. RESULTS: Surgeons shown radiographs with measured angulation were more likely to recommend surgery, and there was less variability among these surgeons, particularly for fractures with less angular deformity. CONCLUSIONS: Measured fracture angulation has a small but significant influence on treatment recommendations for little finger metacarpal neck fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 25034794 TI - Transplantation of SIRT1-engineered aged mesenchymal stem cells improves cardiac function in a rat myocardial infarction model. AB - BACKGROUND: Previous studies have demonstrated that biological aging has a negative influence on the therapeutic effects of mesenchymal stem cells (MSCs) based therapy. Using a rat myocardial infarction (MI) model, we tested the hypothesis that silent mating type information regulation 2 homolog 1 (SIRT1) may ameliorate the phenotype and improve the function of aged MSCs and thus enhance the efficacy of aged MSCs-based therapy. METHODS: Sixty female rats underwent left anterior descending coronary artery ligation and were randomly assigned to receiving: intramyocardial injection of cell culture medium (DMEM group); SIRT1 overexpression vector-treated aged MSCs (SIRT1-aged MSCs group) obtained from aged male SD rats or empty vector-treated aged MSCs (vector-aged MSCs group). Another 20 sham-operated rats that underwent open-chest surgery without coronary ligation or any other intervention served as controls. RESULTS: SIRT1-aged MSC group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level. CONCLUSIONS: Up regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI as it relates to the amelioration of senescent phenotype and hence improved biological function of aged MSCs. PMID- 25034795 TI - Factors determining post-operative readmissions after left ventricular assist device implantation. AB - BACKGROUND: In the current era of extensive healthcare reform, there has been a heightened focus on the frequency and cause for readmissions within 30 days of discharge given that readmissions are not reimbursed by most providers. The aim of our study was to determine the frequency, etiology and patterns of 30-day readmissions among recipients of continuous-flow left ventricular assist devices (LVADs) at our institution as well to determine whether there were any significant predictors of readmission. METHODS: From March 2006 through June 2013, 150 patients underwent implantation of a continuous-flow LVAD at our institution. Patients were stratified into two groups based on their 30-day readmission status. A total of 12 patients died before discharge and were excluded from our analysis. Causes for 30-day readmissions and duration of hospital stay for the readmissions were recorded. Numerous pre-operative variables and post-operative complications were compared using 2-sided t-tests and chi-square tests between patients who were and were not readmitted within 30 days of their discharge after their LVAD implant. RESULTS: The 30-day readmission rate was 26.1% (36 of 138), with approximately 70% of post-operative readmissions occurring within 10 days of the patient's initial hospital discharge. Recurrent heart failure (12 of 36, 33.3%) and gastrointestinal bleeding (8 of 36, 22.2%) were the most common causes for 30-day readmission. The median length of stay (LOS) for readmission was 11.7 days. Thirty-day readmission did not affect short- or long-term survival. On univariate analysis, post-operative gastrointestinal bleeding (GIB) was a significant risk factor for 30-day readmissions (HR 1.4, 95% CI 0.19 to 0.99, p = 0.05), and overall length of stay was a significant factor in reducing 30-day readmission rates (HR 0.91, 95% CI 0.85 to 0.99, p = 0.02). CONCLUSIONS: Our experience indicates that 30-day readmission rates after LVAD implantation remain relatively high, with most occurring within 10 days of discharge. Recurrent heart failure and GIB were the most common causes of post operative rehospitalization. In addition, GIB during the index hospitalization was a significant predictor of 30-day readmission. PMID- 25034797 TI - Lipid profiling and corresponding biodiesel quality of Mortierella isabellina using different drying and extraction methods. AB - Four lipid extraction methods (Bligh & Dyer, hexane & isopropanol, dichloromethane & methanol, and hexane) were evaluated to extract lipid from freeze- and oven-dried fungus Mortierella isabellina ATCC42613. The highest lipid yield (41.8%) was obtained from Bligh & Dyer extraction on the oven-dried fungal biomass with a methanol:chloroform:water ratio of 2:1:0.8. Other lipid extraction methods on both freeze- and oven-dried samples had lipid yields ranging from 20.7% to 35.9%. Non-polar lipid was the main lipid class (more than 90% of total lipid) in M. isabellina. Regarding fatty acid profile, there was no significant difference on fatty acid concentration between different drying and extraction methods. Estimation of biodiesel fuel properties using correlative models further demonstrated that the fungal biodiesel is a good alternative to fossil diesel. PMID- 25034796 TI - Contribution of daily and seasonal biorhythms to obesity in humans. AB - While the significance of obesity as a serious health problem is well recognized, little is known about whether and how biometerological factors and biorhythms causally contribute to obesity. Obesity is often associated with altered seasonal and daily rhythmicity in food intake, metabolism and adipose tissue function. Environmental stimuli affect both seasonal and daily rhythms, and the latter are under additional control of internal molecular oscillators, or body clocks. Modifications of clock genes in animals and changes to normal daily rhythms in humans (as in shift work and sleep deprivation) result in metabolic dysregulation that favours weight gain. Here, we briefly review the potential links between biorhythms and obesity in humans. PMID- 25034798 TI - Treatment of childhood tuberculosis: caregivers' practices and perceptions in Cape Town, South Africa. AB - BACKGROUND: A child's caregiver is key to the successful drug delivery and outcome of tuberculosis (TB) treatment. Understanding caregivers' practices and perceptions is important in the management of childhood TB. OBJECTIVE: To investigate caregivers' practices and perceptions regarding TB treatment of children. METHODS: A prospective, questionnaire-based study at Red Cross War Memorial Children's Hospital, Cape Town, South Africa of caregivers of children receiving TB treatment. During the children's follow-up visits at 1 (M1), 3 (M3) and 6 (M6) months after initiation of TB treatment, caregivers were interviewed face-to-face. RESULTS: Caregivers of 253 children being treated for TB were interviewed and 434 surveys were completed between May 2011 and April 2013. 168 (39%) questionnaires were completed at M1, 165 (39%) at M3 and 94 (22%) at M6. Median age of children was 41 months (IQR 20-81). TB drugs were generally obtained from clinics most commonly visited 1-3 times a week. Only 86/162 (53%) and 109/155 (70%) children had been weighed at the clinic at M1 and M3, respectively. Drugs were most commonly administered after meals (69%). Two-thirds of interviewees crushed, dissolved or mixed the tablets with beverages or food. Most (88%) respondents reported easy drug administration. Few adverse drug reactions were reported. In 54/427 (13%) of surveys, concomitant antiretroviral treatment was given, most commonly before TB medication. CONCLUSION: Administration of TB drugs was regarded as easy, but differed substantially from recommended practice. Children were not weighed so that dosage could be adjusted, most caregivers crushed, dissolved or mixed the tablets with beverages or food, and administered medication after meals, all potentially contributing to sub therapeutic drug levels. PMID- 25034799 TI - Low birthweight or rapid catch-up growth: which is more associated with cardiovascular disease and its risk factors in later life? A systematic review and cryptanalysis. AB - BACKGROUND: The effects of birthweight (the Barker hypothesis) and growth trajectory in early life on the incidence of cardiovascular disease (CVD) and its risk factors in later life have been investigated in a number of studies. OBJECTIVE: To undertake a systematic review and cryptanalysis of the association of low birthweight (LBW) and the postnatal growth trajectory with CVD and its risk factors. METHODS: English-language publications in PubMed, ISI Web of Science and Scopus were searched. Initially, two independent reviewers identified relevant papers in several steps and the quality of papers was then determined by a validated quality-appraisal checklist. RESULTS: By applying maximum sensitivity, 7259 paper were identified, 382 of which were duplicates and 1273 were considered to be relevant to the topic. Then, after title and abstract review, 628 irrelevant papers were excluded; 26 papers were added after reference checking. Then, 250 other papers were deleted after full text review. Finally, 39 relevant papers remained and were entered into the systematic review. Overall, 79.6% of all CVD risk factors reported in primary studies of the rapid catch-up growth hypothesis were statistically significant, whereas the corresponding figure was 58.5% for the effects of LBW (Barker hypothesis). CONCLUSIONS: This systematic review highlights the importance of low birthweight in increasing the risk of CVD and its risk factors in later life. The results support rapid postnatal catch-up growth of LBW neonates as a more important factor than LBW alone in CVD and its risk factors. PMID- 25034800 TI - Water solubilization capacity of pharmaceutical microemulsions based on Peceol(r), lecithin and ethanol. AB - Biocompatible microemulsions composed of Peceol((r)), lecithin, ethanol and water developed for encapsulation of hydrophilic drugs were investigated. The binary mixture Peceol((r))/ethanol was studied first. It was shown that the addition of ethanol to pure Peceol((r)) has a significant fluidifying and disordering effect on the Peceol((r)) supramolecular structure with an enhancement in water solubilization. The water solubilization capacity was improved by adding lecithin as a third component. It was then demonstrated that the ethanol/lecithin weight ratio played an important role in determining the optimal composition in term of water solubilization efficiency, a necessary property for a nutraceutical or pharmaceutical application. The optimal ethanol/lecithin weight ratio in the Peceol((r)) rich region was found to be 40/60. Combination different techniques such as SAXS, fluorimetry, rheology and conductivity, we analyzed the water uptake within the microemulsion taking into account the partitioning of ethanol between polar and apolar domains. This ethanol distribution quantified along a water dilution line has a major effect on microemulsion properties. PMID- 25034801 TI - A false positive case of cardiac troponin I identified with CK-MB reflex testing. PMID- 25034802 TI - Impact of short-term mechanical circulatory support with extracorporeal devices on postoperative outcomes after emergency heart transplantation: data from a multi-institutional Spanish cohort. AB - OBJECTIVES: We sought to investigate the potential impact of preoperative short term mechanical circulatory support (MCS) with extracorporeal devices on postoperative outcomes after emergency heart transplantation (HT). METHODS: We conducted an observational study of 669 patients who underwent emergency HT in 15 Spanish hospitals between 2000 and 2009. Postoperative outcomes of patients bridged to HT on short-term MCS (n=101) were compared with those of the rest of the cohort (n=568). Short-term MCS included veno-arterial extracorporeal membrane oxygenators (VA-ECMOs, n=23), and both pulsatile-flow (n=53) and continuous-flow (n=25) extracorporeal ventricular assist devices (VADs). No patient underwent HT on intracorporeal VADs. RESULTS: Preoperative short-term MCS was independently associated with increased in-hospital postoperative mortality (adjusted odds ratio 1.75, 95% CI 1.05-2.91) and overall post-transplant mortality (adjusted hazard-ratio 1.60, 95% CI 1.15-2.23). Rates of major surgical bleeding, cardiac reoperation, postoperative infection and primary graft failure were also significantly higher among MCS patients. Causes of death and survival after hospital discharge were similar in MCS and non-MCS candidates. Increased risk of post-transplant mortality affected patients bridged on pulsatile-flow extracorporeal VADs (adjusted hazard-ratio 2.21, 95% CI 1.48-3.30) and continuous flow extracorporeal VADs (adjusted hazard-ratio 2.24, 95% CI 1.20-4.19), but not those bridged on VA-ECMO (adjusted hazard-ratio 0.51, 95% CI 0.21-1.25). CONCLUSIONS: Patients bridged to emergency HT on short-term MCS are exposed to an increased risk of postoperative complications and mortality. In our series, preoperative bridging with VA-ECMO resulted in comparable post-transplant outcomes to those of patients transplanted on conventional support. PMID- 25034803 TI - Persistent aortic insufficiency secondary to Impella device implantation. PMID- 25034804 TI - Evidence of pleiotropy by statins: leukocyte Rho kinase (ROCK) activity and pretreated statin before percutaneous coronary interventions are clinical vascular outcome predictors. PMID- 25034805 TI - Intake of green tea inhibited increase of salivary chromogranin A after mental task stress loads. AB - BACKGROUND: Green tea has become renowned for its health benefits. In this study, we investigated the anti-stress effect of two kinds of green tea against a mental stress task load. METHODS: Warm water, ordinary green tea (Sagara), and shaded white tea, which contains more amino acid components than Sagara, were used as test samples in a randomized cross-over design study. Eighteen students (nine male and nine female) participated in three experimental trials on different days at intervals of seven days. Saliva was collected before beverage intake and after performing the mental stress load tasks. Concentration of chromogranin A (CgA) in the saliva was used as an index of autonomic nervous system activity. RESULTS: CgA level increased after the mental tasks, but intake of green tea inhibited this increase; the anti-stress effect was even greater after consumption of shaded white tea. Intake of shaded white tea also lowered Total Mood Disturbance (TMD) score on the Profile of Mood States (POMS); subjects in this condition tended to perform more calculations in the arithmetic task than those in the warm water treatment condition. CONCLUSIONS: Salivary CgA concentration levels increased after mental stress load tasks, but ingestion of green tea inhibited this increase. This anti-stress effect was larger after the consumption of shaded white tea than after Sagara. Shaded white tea intake also lowered TMD score (POMS) and tended to improve performance on an arithmetic task compared to warm water, suggesting that shaded white tea might also improve mood during and after mental stress load. PMID- 25034806 TI - Protective effect of veratric acid on lipopolysaccharide-induced acute lung injury in mice. AB - Veratric acid, a simple benzoic acid derived from plants and fruits, has been reported to exhibit antibacterial, anti-inflammatory and other important therapeutic activities. The aim of this study was to detect the effects of veratric acid on LPS-induced acute lung injury and to investigate the effects of veratric acid on NF-kappaB signaling pathway. Male BALB/c mice were pretreated with dexamethasone or veratric acid 1h before intranasal instillation of LPS. 7h after LPS administration, the myeloperoxidase in lung tissues, lung wet/dry weight ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The effects of veratric acid on pro-inflammatory cytokines and signal pathways were analyzed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The results showed that veratric acid inhibited LPS-induced TNF alpha, IL-6 and IL-1beta production in a dose dependent manner. It was also observed that veratric acid attenuated lung histopathologic changes. The wet/dry weight ratio of lungs and the number of total cells, neutrophils, macrophages in the BALF were all decreased. Furthermore, veratric acid inhibited the phosphorylation of NF-kappaB p65 and IkappaB. These results indicate that veratric acid inhibits NF-kappaB signaling pathways to attenuate inflammatory injury induced by LPS. Veratric acid may be a potential therapeutic reagent for acute lung injury treatment. PMID- 25034807 TI - Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer's disease. AB - We previously reported that melanocortins induce neuroprotection in experimental acute and chronic neurodegenerative conditions, including Alzheimer's disease (AD) of mild severity. Here we investigated whether melanocortins afford neuroprotection and counteract cognitive decline in AD with a medium level of severity by using 24 week-old (at the start of the study) APPSwe transgenic mice (Tg2576). Saline-treated (days 1-50) control Tg2576 mice showed an impairment in spatial learning and memory, associated (at day 50, end of the study) with hippocampus at low levels of the synaptic activity-dependent gene Zif268, relevant brain changes such as cerebral cortex/hippocampus increased level of beta-amyloid (Abeta) deposit, and neuronal loss, in comparison with wild-type animals. Treatment of Tg2576 mice (once daily at days 1-50) with a nanomolar dose of the melanocortin analog [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP alpha-MSH) reduced cerebral cortex/hippocampus level of Abeta deposit, decreased neuronal loss, increased hippocampus Zif268 expression and improved cognitive functions, relative to saline-treated Tg2576 mice. Pharmacological blockade of melanocortin MC4 receptors with the MC4 receptor antagonist HS024 prevented all favorable effects of NDP-alpha-MSH. Our data indicate that MC4 receptor stimulating melanocortins are able to counteract cognitive decline in experimental AD of medium severity through induction of neuroprotection and improvement of synaptic transmission. After further studies, these agents could gain a role as disease modifying therapeutics for AD. PMID- 25034808 TI - Evidence for tachykinin NK3 receptors-triggered peptide YY release from isolated guinea-pig distal colon. AB - The anorectic gut hormone, peptide YY (PYY), is released from colonic mucosal endocrine cells, but little is known about the role for tachykinin NK3 receptor in the control of PYY release from the colonic mucosa. We investigated the functional role for NK3 receptors in the control of PYY release from isolated guinea-pig distal colon, and the role for NK3 receptors-triggered PYY release in the control of colonic motility. Isolated colonic preparations were mounted in organ baths for measurement of PYY release and mechanical activity. The release of PYY from these preparations was determined by enzyme immunoassays. The NK3 receptor agonist senktide produced a tetrodotoxin/atropine-sensitive sustained increase in the release of PYY from the colonic preparations. Basal PYY release was transiently inhibited by the NK3 receptor antagonist SB222200. The neuropeptide Y1 receptor antagonist BIBO3304 produced a leftward shift of the concentration-response curves for senktide-evoked neurogenic contraction, but neither the neuropeptide Y2 receptor antagonist BIIE0246 nor the neuropeptide Y5 receptor antagonist CGP71683 affected the senktide concentration-response curves. NK3 receptors appear to play an important role in the control of PYY release from colonic mucosa, and NK3 receptor-triggered PYY release can exert Y1 receptor mediated inhibition of tachykinergic neuromuscular transmission. This indicates a pathophysiological role for the NK3 receptor-triggered PYY release in the control of colonic motility. PMID- 25034809 TI - Involvement of 5-HT2 receptors in the expression of withdrawal diarrhea in morphine-dependent mice. AB - The withdrawal syndrome after the cessation of MU-opioid receptor agonists remains an obstacle in the clinical treatment of pain. We recently showed that peripheral opioid receptors play a significant role in the withdrawal signs in morphine-dependent mice. Therefore, the present study was designed to investigate the underlying mechanism of morphine-induced withdrawal symptoms, especially the peripheral oriented body-weight loss that accompanied diarrhea, in mice. Withdrawal signs were precipitated by the injection of naloxone 1 day after the slow-release emulsion administration of morphine. Withdrawal body-weight loss and diarrhea precipitated by naloxone in morphine-dependent mice were significantly suppressed by ritanserin (a 5-HT2 receptor antagonist), olanzapine (5-HT2/D2 receptor antagonist) and fullerene (a free radical scavenger), whereas neither ondansetron (a 5-HT3 receptor antagonist) nor atropine (a muscarine receptor antagonist) significantly suppressed naloxone-precipitated diarrhea. 5-HT3 receptors (but not 5-HT2-receptors) are known to play a significant role in 5-HT induced diarrhea. Therefore, we also examined the effects of ritanserin and fullerene on 5-HT-induced diarrhea in morphine-dependent mice. Ritaserin significantly suppressed 5-HT-induced diarrhea in morphine-dependent mice, but not saline-treated mice. These results suggest that peripheral 5-HT2-receptor function could be altered in morphine-dependent mice, and the blockade of 5-HT2 receptor or free radical scavengers may be useful for the treatment of opioid withdrawal diarrhea. PMID- 25034810 TI - Cellular mechanism underlying hydrogen sulfide induced mouse tracheal smooth muscle relaxation: role of BKCa. AB - Recent studies have suggested that hydrogen sulfide (H2S), an important endogenous signaling gaseous molecule, participates in relaxation of smooth muscle. Nevertheless, the mechanism of this relaxation effect on respiratory system is still unclear. The present study aims to investigate the physiological function as well as cellular mechanism of H2S in tracheal smooth muscle. Application of the H2S donor, sodium hydrosulphide (NaHS) and the precursor of H2S, l-cysteine (l-Cys) induced mouse tracheal smooth muscle (TSM) relaxation in an epithelium-independent manner. The relaxation of TSM induced by NaHS was abrogated by iberiotoxin (IbTX), the large conductance calcium activated potassium channel (BKCa) blocker. In primary cultured mouse TSM cells, NaHS remarkably increased potassium outward currents in whole-cell patch clamp, hyperpolarized TSM cells and inhibited the calcium influx. All of these effects were significantly blocked by IbTX. Consistent with the results in vitro, administration of NaHS in vivo also reduced airway hyperresponsiveness in Ovalbumin (OVA)-challenged asthmatic mice. Our present study indicates that NaHS can induce mouse TSM relaxation by activating BKCa. These observations reveal the physiological function of H2S in airway, which provides a promising pharmacological target for the treatment of asthma and other respiratory diseases associated with over-contraction of TSM. PMID- 25034811 TI - Functional and pharmacological characterization of volume-regulated anion channels in human normal and cystic fibrosis bronchial and nasal epithelial cells. AB - Volume-regulated anion channels (VRACs) are widely present in various cell types and have important functions ranging from regulatory volume decrease to control of cell proliferation and apoptosis. Here we aimed to compare the biophysical features and pharmacological profiles of VRAC currents in healthy and cystic fibrosis (CF) respiratory epithelial cells in order to characterize these currents both functionally and pharmacologically. Whole-cell electrophysiology was used to characterize the VRAC current in normal (16HBE14o-; HBE) and CF cell lines (CFBE14o-; CFBE), as well as in native human nasal epithelial cells. Application of hypotonic solution produced current responses of similar sizes in both HBE and CFBE cells. Biophysical properties of VRACs, such as instantaneous activation and deactivation upon voltage step, some inactivation at potentials positive to 40 mV and outwardly-rectifying I-V curves, were indistinguishable in both cell types. Extensive pharmacological analysis of the currents revealed a similar pharmacological profile in response to three blockers--NPPB, DCPIB and DIDS. Native primary human nasal epithelial cells from both healthy and CF volunteers also showed typical VRAC responses of comparable sizes. VRACs in these cells were more sensitive to external solution hypotonicity compared to HBE and CFBE cells. In all cell types studied robust VRAC currents could be induced at constant cell volume by G-protein activation with GTPgammaS infusion. This study provides the first extensive comparative functional and pharmacological analysis of VRAC currents in normal and CF airway epithelial cells and shows that VRACs are unimpaired molecularly or functionally in CF. PMID- 25034812 TI - Neuroprotective effects of carboxymethylated chitosan on hydrogen peroxide induced apoptosis in Schwann cells. AB - The protective and promotion effects of Carboxymethylated chitosan (CMCS) on peripheral nerve and cultured Schwann cells (SCs) have been demonstrated, but few studies discussed the protective roles of CMCS on SCs apoptosis. We explored the anti-apoptotic activities of CMCS in SCs to enhance cells survival in this present study. Rat SCs were isolated and cultured in vitro, hydrogen peroxide (H2O2) was used to establish the apoptosis models of SCs. Cells proliferative activity was assessed by CCK-8 assay. The apoptosis of SCs was detected by flow cytometry (FCM) analysis. Superoxide dismutase (SOD) and malondialdehyde (MDA) activities were detected by the corresponding assay kit. The nuclear appearance of apoptotic SCs was observed by nuclear staining with Hoechst 33342. The real time PCR was performed to detect the levels of Bcl-2, Bax, Caspase-3 and -9 mRNA. Detection of caspase-3 and -9 was fulfilled by using Western blot analysis. FCM assay and Hoechst33342 staining results indicated that CMCS could protect SCs from apoptosis with dose and time-dependent manner. SOD and MDA analysis results indicated that CMCS could promote SOD activity and reduce the MDA levels in H2O2 induced SCs. The decreased caspase-3, -9 and Bax activities and increased Bcl-2 activity were observed in CMCS treated SCs. The present study indicates CMCS has the neuroprotective effect on peripheral nerves and inhibit SCs apoptosis. PMID- 25034813 TI - Determinants of disability after proximal interphalangeal joint sprain or dislocation. AB - BACKGROUND: Sprain or dislocation of the proximal interphalangeal joint may be a useful example of the counterintuitive aspects of recovery as the prognosis is excellent, but protectiveness in response to discomfort often hinders the stretching exercises that are a key component of the recovery process. OBJECTIVE: The aim of this study was to investigate the relationship between disability and pain self-efficacy in this context. METHODS: A total of 82 patients (54 men and 28 women) were enrolled in this prospective study. Finger motion was measured, and the patients completed measures of upper limb-specific disability (the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire), symptoms of depression (Patient Health Questionnaire-9), effective coping strategies in response to pain (the Pain Self-Efficacy Questionnaire), and a pain scale at enrollment. RESULTS: Patients were enrolled a mean of 48 days after injury. The final multivariable model accounting for greater disability included lower self-efficacy, greater symptoms of depression, and gender (women have more disability). Lower self-efficacy was also the strongest predictor of pain intensity and finger stiffness. CONCLUSIONS: Effective coping strategies such as self-efficacy facilitate recovery (less disability, pain, and stiffness) after proximal interphalangeal joint sprain/dislocation. LEVEL OF EVIDENCE: Prognostic level I. PMID- 25034815 TI - Significance of diaphragmatic resections and thoracic chemoperfusion on outcomes of peritoneal surface disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - BACKGROUND: Diaphragmatic resection (DR) during CRS/HIPEC exposes the thoracic cavity to direct contamination from the peritoneal cavity. The effect of thoracic chemoperfusion in combination with HIPEC in these patients is unknown. METHODS: A prospective database of 1,077 procedures was analyzed. Type of malignancy, thoracic perfusion, resection status, comorbidities, morbidity, mortality, and overall survival were reviewed. RESULTS: DR was a component of 102 CRS/HIPEC procedures performed for 57 (55.9 %) appendiceal and 22 (21.6 %) colon primary lesions. DR was associated with higher volume of disease as evidenced by more organ resections (3.7 vs. 2.8, p < 0.001) and increased rates of incomplete cytoreduction (67 vs. 52 %, p = 0.004). Patients with and without DR had similar 30-day major morbidity (23.5 vs. 16.8 %, p = 0.1) and worse 90-day mortality (12.8 % vs. 6.12 %, p = 0.03), respectively. Multivariate analysis showed DR (p = 0.01) and diabetes (p = 0.005) to be associated with worse mortality. Nineteen (20 %) DR patients underwent synchronous abdominal and thoracic chemoperfusion. Intrathoracic recurrence following DR with thoracic perfusion was 17 % (3/18) vs. 2.3 % (2/85) without perfusion (p = 0.04). Median survival following complete cytoreduction was similar for patients with low-grade appendiceal (LGA) (not reached with DR and 175 months without DR, p = 0.17) and colorectal cancer (23 months with and 31 months without DR, p = 0.76). CONCLUSIONS: Diaphragmatic resection during CRS/HIPEC is an independent predictor of surgical mortality. Intrapleural perfusion was associated with more thoracic recurrence; however, complete cytoreduction with or without DR can achieve similar survival for patients with LGA and colorectal primary lesions. DR should be performed only if careful inspection deems all peritoneal disease resectable. PMID- 25034816 TI - Risk factors for recurrence of papillary thyroid carcinoma with clinically node positive lateral neck. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) with clinically node-positive lateral neck is more likely to recur after surgery than node-negative PTC. The present study investigated the risk factors for recurrence in PTC patients with clinically node-positive lateral neck. MATERIALS AND METHODS: This study involved 136 patients with pathologically confirmed PTC and a clinically lymph node (LN) positive lateral neck but no initial distant metastasis who underwent total thyroidectomy with therapeutic central and lateral neck dissection. Clinicopathologic characteristics, intraoperative findings, postoperative thyroglobulin (Tg) levels, and post-treatment recurrences were examined. Univariate and multivariate analyses were performed to identify factors associated with recurrence-free survival (RFS). RESULTS: During a median follow up of 62 months (range 33-90 months), 27 (19.9 %) patients had locoregional or distant recurrences. Univariate analyses showed that primary tumor size (p = 0.049), recurrent laryngeal nerve invasion (p = 0.035), the maximal size of metastatic LN foci (>=1.5 cm; p = 0.012), extranodal extension (p = 0.025), total LN ratio (>=0.26; p = 0.008), American Thyroid Association (ATA) risk categories (p < 0.001), and stimulated serum Tg level (>=4.4; p < 0.001) at the time of radioactive iodine ablation therapy just after thyroidectomy were significant predictors of RFS. Multivariate analyses showed that the maximal size of metastatic foci (p = 0.037), ATA risk categories (p < 0.001), and stimulated Tg level (p < 0.001) were independent predictors of RFS. CONCLUSIONS: Maximal size of metastatic foci, ATA risk categories, and stimulated serum Tg levels are predictive of recurrence after surgery. Careful follow-up of patients with these risk factors is therefore recommended. PMID- 25034814 TI - The mitochondrial and chloroplast genomes of the haptophyte Chrysochromulina tobin contain unique repeat structures and gene profiles. AB - BACKGROUND: Haptophytes are widely and abundantly distributed in both marine and freshwater ecosystems. Few genomic analyses of representatives within this taxon have been reported, despite their early evolutionary origins and their prominent role in global carbon fixation. RESULTS: The complete mitochondrial and chloroplast genome sequences of the haptophyte Chrysochromulina tobin (Prymnesiales) provide insight into the architecture and gene content of haptophyte organellar genomes. The mitochondrial genome (~34 kb) encodes 21 protein coding genes and contains a complex, 9 kb tandem repeat region. Similar to other haptophytes and rhodophytes, but not cryptophytes or stramenopiles, the mitochondrial genome has lost the nad7, nad9 and nad11 genes. The ~105 kb chloroplast genome encodes 112 protein coding genes, including ycf39 which has strong structural homology to NADP-binding nitrate transcriptional regulators; a divergent 'CheY-like' two-component response regulator (ycf55) and Tic/Toc (ycf60 and ycf80) membrane transporters. Notably, a zinc finger domain has been identified in the rpl36 ribosomal protein gene of all chloroplasts sequenced to date with the exception of haptophytes and cryptophytes--algae that have gained (via lateral gene transfer) an alternative rpl36 lacking the zinc finger motif. The two C. tobin chloroplast ribosomal RNA operon spacer regions differ in tRNA content. Additionally, each ribosomal operon contains multiple single nucleotide polymorphisms (SNPs)--a pattern observed in rhodophytes and cryptophytes, but few stramenopiles. Analysis of small (<200 bp) chloroplast encoded tandem and inverted repeats in C. tobin and 78 other algal chloroplast genomes show that repeat type, size and location are correlated with gene identity and taxonomic clade. CONCLUSION: The Chrysochromulina tobin organellar genomes provide new insight into organellar function and evolution. These are the first organellar genomes to be determined for the prymnesiales, a taxon that is present in both oceanic and freshwater systems and represents major primary photosynthetic producers and contributors to global ecosystem stability. PMID- 25034817 TI - Surgical treatment of borderline and malignant phyllodes tumors: the effect of the extent of resection and tumor characteristics on patient outcome. AB - INTRODUCTION: Malignant phyllodes tumors are rare fibroepithelial breast neoplasms. Appropriate surgical management remains a subject of debate. The purpose of our study was to define optimal surgical treatment and to identify factors associated with outcome. METHODS: After confirmatory pathology review, we identified 67 patients with borderline (n = 15) and malignant (n = 52) phyllodes tumors treated at our institution between 1971 and 2008. We used Cox proportional hazards models to evaluate associations between treatment, patient and tumor characteristics, and disease-free (DFS) and cancer-specific survival (CSS). RESULTS: Median patient age was 47 years. For 32 patients, definitive surgical treatment was wide local excision (WLE): 27 with margins >=1 cm and 5 with margins <1 cm. Thirty-five underwent mastectomy. Two patients received radiotherapy after WLE and two after mastectomy with microscopically positive margins. After 10 years median follow-up, 16 patients (24 %) recurred locally (8 postmastectomy and 8 after WLE). Treatment type and margin extent did not impact local recurrence. Fifteen patients (22 %) developed distant disease. Overall 5 year DFS was 67.9 % and CSS 80.1 %. Tumor size >5 cm, mitotic rate >=10/10 HPF, stromal overgrowth and cellularity (all p < 0.05) predicted DFS, whereas CSS was associated with the latter three variables. CSS was diminished for mastectomy patients who were significantly more likely to harbor tumors with adverse features. CONCLUSIONS: With long-term follow-up, extent of surgical resection did not affect DFS for patients with borderline and malignant phyllodes tumors. Tumor features, most notably stromal overgrowth, were predictive of recurrence and survival, suggesting these high-risk patients may benefit from additional therapeutic strategies. PMID- 25034818 TI - Localizing high-risk lesions for excisional breast biopsy: a comparison between radioactive seed localization and wire localization. AB - BACKGROUND: Improved resolution and utilization of screening breast imaging has increased identification of nonpalpable high-risk lesions (HRL) and subsequent excisional breast biopsies (EBBs). Wire localization (WL), used most commonly for EBBs, may have shortcomings, including wire displacement, patient discomfort, limitations with incision planning and scheduling logistics. Radioactive seed localization (RSL) may overcome these drawbacks. The purpose of this study was to compare WL and RSL for EBBs for HRLs. METHODS: All single-site EBBs for HRL performed by four breast surgeons were retrospectively reviewed over two consecutive 1-year periods. Patients with cancer on percutaneous core biopsy (CB) were excluded. Clinicopathologic information, operative time, targeted lesion retrieval rate, and upstage rate were collected. RESULTS: A total of 324 EBBs for HRL were performed: 196 using WL and 128 using RSL. CB pathology was atypical hyperplasia in 56 % of WLs and 62 % of RSLs. The remaining pathologies were radial scar, papilloma, atypical papilloma or lobular carcinoma in situ. Mean age was 54 years. OR time was 27 +/- 8 min for WL and 27 +/- 7 min for RSL (p = 0.9). Upstage rate was 6 and 5 % for WLs and RSLs, respectively (p = 0.5). Targeted lesions were retrieved in 98 % of WL and 99 % of RSL (p = 0.5). SV was 37.2 +/- 32.8 cm(3) and 25.7 +/- 22.3 cm(3) for WL and RSL, respectively (p = 0.001). CONCLUSIONS: RSL is comparable to WL for EBB of HRLs with similar OR times and upstage rates. SV is significantly decreased with RSL and may translate into improved cosmetic outcomes without sacrificing the diagnostic accuracy of the EBB. PMID- 25034819 TI - Use of hydrogel breast biopsy tissue markers reduces the need for wire localization. AB - BACKGROUND: The purpose of this study was to determine whether breast biopsy tissue markers composed of an ultrasound-visible hydrogel reduced the need for preoperative wire localization (WL) in patients undergoing a partial mastectomy. METHODS: A single-surgeon, single-institution, retrospective chart review was performed on 691 consecutive female patients, with mean age 67 years (range 36-98 years), from 2009 to 2012 undergoing partial mastectomies after percutaneous biopsies by stereotactic or ultrasound guidance. RESULTS: Overall, the use of WL was more frequent in patients who had standard (other) markers placed during biopsy as opposed to those with hydrogel markers (HydroMARK). For stereotactic biopsy, 75.8 % of patients with a standard marker required WL versus 17.1 % with HydroMARK and for ultrasound biopsy, 22.6 % standard versus 4.3 % HydroMARK (p < .0001, p < .0001). In some cases where hydrogel markers were used, WL was used for "bracketing" because of the presence of microcalcifications. In cases where standard markers were used, WL was not used because of either IOUS visibility of residual lesion or marker visibility. Specimen volume and re-excision rate were comparable between patients with hydrogel and standard markers, showing no significant differences (p = .1673, p = .1813 respectively). CONCLUSIONS: Hydrogel biopsy tissue markers optimize the surgeon's ability to perform a partial mastectomy without the use of WL. HydroMARK was as effective as a standard marker in terms of partial mastectomy specimen volume and re-excision rate. This yields potential for cost savings, increased efficacy in operating room and radiology scheduling, and patient comfort and convenience. PMID- 25034820 TI - Screening for psychological distress in surgical breast cancer patients. AB - BACKGROUND: This pilot study assessed the levels of patient emotional distress and impact on clinic throughput time. METHODS: From April through August 2012, 149 breast cancer patients at the Penn State Hershey Breast Center were screened with the emotions thermometer (ET), a patient-rated visual 0-10 scale that measures distress, anxiety, depression, anger, burden, and need for help. Also, patients indicated their most pressing cancer-related concerns. Clinic visit time was computed and compared with a control group. RESULTS: Using a previously validated cut point >=4 for any thermometer, we found emotional difficulty in the following proportions: distress 22 %, anxiety 28 %, depression 18 %, anger 14 %, burden 16 %, and need for help 10 %; 35 % scored above the cut point on at least 1 thermometer. We found higher levels of distress in all domains associated with younger age at diagnosis. More extensive surgery (bilateral mastectomy vs unilateral mastectomy vs. lumpectomy) was correlated with higher levels of psychosocial distress. Most often cited concerns, experienced by >20 %, included eating/weight, worry about cancer, sleep problems, fatigue, anxiety, and pain. Mean clinic visit time for evaluable patients screened using the ET (n = 109) was 43.9 min (SD 18.6), compared with 42.6 min (SD 16.2) for the control group (n = 50). CONCLUSIONS: Utilizing the ET, more than one-third of women screened met criteria for psychological distress. Younger age at diagnosis and more extensive surgery were risk factors. The ET is a simple validated screening tool that identifies patients in need of further psychological evaluation without impacting clinic throughput time. PMID- 25034821 TI - Paravertebral blocks in patients undergoing mastectomy with or without immediate reconstruction provides improved pain control and decreased postoperative nausea and vomiting. AB - BACKGROUND: Mastectomy is associated with postoperative nausea and pain. We evaluated whether paravertebral block (PVB) use altered opioid use, antiemetic use, and length of stay in patients undergoing mastectomy. METHODS: We performed a retrospective cohort analysis of all patients who underwent mastectomy with or without PVB from 2008 to 2010. Patient demographics, operative procedure, intraoperative medications, postoperative opioid and antiemetic use, and length of stay were reviewed. Statistical analysis included univariable and multivariable analysis. RESULTS: A total of 605 patients were identified, of whom 526 patients were evaluable. A total of 294 patients underwent mastectomy without PVB (132 bilateral), and 232 patients underwent mastectomy with PVB (148 bilateral). Immediate reconstruction was performed in 203 (39 %) patients. Need for any postoperative antiemetic was less frequent in the PVB group (39 vs. 57 %, p < 0.0001). Day of surgery opioid use was lower in the PVB group than the non PVB group (mean +/- SD 40.1 +/- 15.2 vs. 47.6 +/- 17.7 morphine equivalents, p < 0.0001). Decreased opioid use was seen in unilateral mastectomy without reconstruction and bilateral mastectomy with and without immediate reconstruction. The proportion of patients discharged within 36 h of surgery was significantly higher in the PVB group (55 vs. 42 %, p = 0.0031). On multivariable analysis controlling for year of surgery, patient age and surgeon, PVB use affected antiemetic use and opioid use but not hospital length of stay. CONCLUSIONS: PVB results in decreased opioid use and decreased need for postoperative antiemetic medication in patients undergoing mastectomy. The greatest benefit is seen in patients undergoing bilateral mastectomy with immediate breast reconstruction. PMID- 25034822 TI - Prospective validation and assessment of cardiovascular and offspring risk models for pregnant women with congenital heart disease. AB - OBJECTIVES: Adequate prepregnancy prediction of maternal cardiovascular and offspring risk is important for counselling and management of pregnancy in women with congenital heart disease (CHD). Therefore we performed a study to identify the optimal assessment strategy for estimating the risk of pregnancy in women with CHD. METHODS: In this prospective study, we determined the outcomes of 213 pregnancies in 203 women with CHD. The ZAHARA I (Zwangerschap bij Aangeboren HARtAfwijkingen I) and CARPREG (CARdiac disease in PREGnancy) risk scores were calculated for each pregnancy, as was the total number of cardiovascular (TPc) or offspring risk predictors (TPo) from these and other studies combined. Pregnancies were also classified according to the modified WHO classification of maternal cardiovascular risk and according to disease complexity (DC). RESULTS: Maternal cardiovascular events occurred during 22 pregnancies (10.3%). Offspring events occurred during 77 pregnancies in 81 children (37.3%). Cardiovascular and offspring event rates increased with higher risk scores, higher TPc or TPo, higher WHO class and greater DC. The highest area under the curve (AUC) for maternal cardiovascular risk was achieved by the WHO class (AUC: 0.77, p<0.0001). AUC for the ZAHARA I risk score was 0.71 (p=0.001), and for the CARPREG risk score 0.57 (p=0.32). All models performed insufficiently in predicting offspring events (AUC<=0.6). CONCLUSIONS: The WHO classification is the best available risk assessment model for estimating cardiovascular risk in pregnant women with CHD. None of the offspring prediction models perform adequately in our cohort. PMID- 25034824 TI - Resolution of carbon metabolism and sulfur-oxidation pathways of Metallosphaera cuprina Ar-4 via comparative proteomics. AB - Metallosphaera cuprina is able to grow either heterotrophically on organics or autotrophically on CO2 with reduced sulfur compounds as electron donor. These traits endowed the species desirable for application in biomining. In order to obtain a global overview of physiological adaptations on the proteome level, proteomes of cytoplasmic and membrane fractions from cells grown autotrophically on CO2 plus sulfur or heterotrophically on yeast extract were compared. 169 proteins were found to change their abundance depending on growth condition. The proteins with increased abundance under autotrophic growth displayed candidate enzymes/proteins of M. cuprina for fixing CO2 through the previously identified 3 hydroxypropionate/4-hydroxybutyrate cycle and for oxidizing elemental sulfur as energy source. The main enzymes/proteins involved in semi- and non phosphorylating Entner-Doudoroff (ED) pathway and TCA cycle were less abundant under autotrophic growth. Also some transporter proteins and proteins of amino acid metabolism changed their abundances, suggesting pivotal roles for growth under the respective conditions. BIOLOGICAL SIGNIFICANCE: The described work is of great significance: For general microbiology: How do extremophile organisms use their unique metabolic capabilities in adapting to autotrophic and hetetrotrophic growth conditions? Which are important enzymes involved in the metabolic adaptation and which enzyme candidate should be investigated in more detail with microbiological/biochemical approaches? For applied microbiology: Which are the key enzymes and reaction pathways for sulfur oxidation and autotrophic growth? This knowledge should accelerate future design of improved bioleaching processes in biomining industries or bioremediation. PMID- 25034823 TI - Genetic disruption of the core circadian clock impairs hippocampus-dependent memory. AB - Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1-/- mice, which are arrhythmic under constant conditions, were examined for hippocampus dependent memory, LTP at the Schaffer-collateral synapse, and signal transduction activity in the hippocampus. Bmal1-/- mice exhibit impaired contextual fear and spatial memory. Furthermore, LTP in hippocampal slices from Bmal1-/- mice is also significantly decreased relative to that from wild-type mice. Activation of Erk1,2 MAP kinase (MAPK) during training for contextual fear memory and diurnal oscillation of MAPK activity and cAMP in the hippocampus is also lost in Bmal1-/- mice, suggesting that the memory defects are due to reduction of the memory consolidation pathway in the hippocampus. We conclude that critical signaling events in the hippocampus required for memory depend on BMAL1. PMID- 25034825 TI - A prospective 10-year follow-up polygraphic study of patients treated with a mandibular protruding device. AB - PURPOSE: This 10-year follow-up prospective study aimed to evaluate the effects of treatment with a mandibular protruding device (MPD) on respiratory parameters and subjective symptoms in patients with obstructive sleep apnea (OSA) or snoring. METHODS: Seventy-seven consecutive patients diagnosed with OSA or snoring were treated with an MPD. At baseline and the 10-year follow-up, a polygraphic examination and questionnaires on sleep quality were administrated and weight, and neck size was measured. RESULTS: At the 10-year follow-up, we examined 64 of the 77 patients and recorded their current treatment (45 MPD, 9 continuous positive airway pressure (CPAP), and 10 no treatment). For MPD patients, 89 % reported MPD use every night and 9 % several nights a week. Compared to baseline, MPD users with OSA had a significantly decreased oxygen desaturation index (ODI) (p = 0.006) and increased lowest arterial oxygen saturation, SaO2 nadir (p = 0.007) after 10 years. MPD treatment was successful for 70 % of OSA patients, yet 89 % subjectively considered themselves cured, indicating overestimation of the treatment effect. OSA patients who responded to treatment maintained baseline weight and neck size, while these increased for non responders. Of the baseline snorers still using an MPD, 93 % maintained an ODI value of <5. All CPAP users had an ODI value of <5. Both OSA and snorers using an MPD had significantly fewer self- and relative reports of snoring, apnea, daytime tiredness, and poor night sleep quality (p < 0.001). CONCLUSIONS: MPD treatment is well tolerated and effective in a long-term, 10-year perspective. Weight gain may jeopardize MPD effects. Both patients and relatives reported significantly less snoring and fewer periods of apnea. PMID- 25034826 TI - Endogenous salicylic acid accumulation is required for chilling tolerance in cucumber (Cucumis sativus L.) seedlings. AB - Salicylic acid (SA) is an important plant hormone, and its exogenous application can induce tolerance to multiple environmental stresses in plants. In this study, we examine the potential involvement of endogenous SA in response to chilling in cucumber (Cucumis sativus L.) seedlings. A low temperature of 8 degrees C induces a moderate increase in endogenous SA levels. Chilling stimulates the enzymatic activities and the expression of genes for phenylalanine ammonia-lyase (PAL) and benzoic acid-2-hydroxylase rather than isochorismate synthase. This indicates that the PAL enzymatic pathway contributes to chilling-induced SA production. Cucumber seedlings pretreated with SA biosynthesis inhibitors accumulate less endogenous SA and suffer more from chilling damage. The expression of cold-responsive genes is also repressed by SA inhibitors. The reduction in stress tolerance and in gene expression can be restored by the exogenous application of SA, confirming the critical roles of SA in chilling responses in cucumber seedlings. Furthermore, the inhibition of SA biosynthesis under chilling stress results in a prolonged and enhanced hydrogen peroxide (H2O2) accumulation. The application of exogenous SA and the chemical scavenger of H2O2 reduces the excess H2O2 and alleviates chilling injury. In contrast, the protective effects of SA are negated by foliar spraying with high concentrations of H2O2 and an inhibitor of the antioxidant enzyme. These results suggest that endogenous SA is required in response to chilling stress in cucumber seedlings, by modulating the expression of cold-responsive genes and the precise induction of cellular H2O2 levels. PMID- 25034827 TI - Ethylene is differentially regulated during sugar beet germination and affects early root growth in a dose-dependent manner. AB - MAIN CONCLUSION: By integrating molecular, biochemical, and physiological data, ethylene biosynthesis in sugar beet was shown to be differentially regulated, affecting root elongation in a concentration-dependent manner. There is a close relation between ethylene production and seedling growth of sugar beet (Beta vulgaris L.), yet the exact function of ethylene during this early developmental stage is still unclear. While ethylene is mostly considered to be a root growth inhibitor, we found that external 1-aminocyclopropane-1-carboxylic acid (ACC) regulates root growth in sugar beet in a concentration-dependent manner: low concentrations stimulate root growth while high concentrations inhibit root growth. These results reveal that ethylene action during root elongation is strongly concentration dependent. Furthermore our detailed study of ethylene biosynthesis kinetics revealed a very strict gene regulation pattern of ACC synthase (ACS) and ACC oxidase (ACO), in which ACS is the rate liming step during sugar beet seedling development. PMID- 25034828 TI - Dynamic strain-mediated coupling of a single diamond spin to a mechanical resonator. AB - The development of hybrid quantum systems is central to the advancement of emerging quantum technologies, including quantum information science and quantum assisted sensing. The recent demonstration of high-quality single-crystal diamond resonators has led to significant interest in a hybrid system consisting of nitrogen-vacancy centre spins that interact with the resonant phonon modes of a macroscopic mechanical resonator through crystal strain. However, the nitrogen vacancy spin-strain interaction has not been well characterized. Here, we demonstrate dynamic, strain-mediated coupling of the mechanical motion of a diamond cantilever to the spin of an embedded nitrogen-vacancy centre. Via quantum control of the spin, we quantitatively characterize the axial and transverse strain sensitivities of the nitrogen-vacancy ground-state spin. The nitrogen-vacancy centre is an atomic scale sensor and we demonstrate spin-based strain imaging with a strain sensitivity of 3 * 10(-6) strain Hz(-1/2). Finally, we show how this spin-resonator system could enable coherent spin-phonon interactions in the quantum regime. PMID- 25034829 TI - The impact of romance novels on women's sexual and reproductive health. PMID- 25034830 TI - Primary perivascular epithelioid cell tumor of the liver: new case report and literature review. AB - Perivascular epithelioid cell tumors (PEComas) encompass a group of rare mesenchymal neoplasms, which typically have a perivascular location with dual melanocytic and muscular differentiation. They are found in a variety of localizations, though lesions in the liver are exceedingly rare. Because of their rarity, the clinical, radiological and histological features of these tumors have yet to be established. This is why, it seems appropriate to report the observation of this rare hepatic tumor with a literary review including others published cases, assessing through it, clinicopathologic and radiologic features of all reported cases as well as their follow-up whenever possible. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1967094999126169. PMID- 25034831 TI - Does flexible tunnel drilling affect the femoral tunnel angle measurement after anterior cruciate ligament reconstruction? AB - PURPOSE: To quantify the mean difference in femoral tunnel angle (FTA) as measured on knee radiographs between rigid and flexible tunnel drilling after anatomic anterior cruciate ligament (ACL) reconstruction. METHODS: Fifty consecutive patients that underwent primary anatomic ACL reconstruction with a single femoral tunnel drilled with a flexible reamer were included in this study. The control group was comprised of 50 patients all of who underwent primary anatomic ACL reconstruction with a single femoral tunnel drilled with a rigid reamer. All femoral tunnels were drilled through a medial portal to ensure anatomic tunnel placement. The FTA was determined from post-operative anterior-to posterior (AP) radiographs by two independent observers. A 5 degrees difference between the two mean FTA was considered clinically significant. RESULTS: The average FTA, when drilled with a rigid reamer, was 42.0 degrees +/- 7.2 degrees . Drilling with a flexible reamer resulted in a mean FTA of 44.7 degrees +/- 7.0 degrees . The mean difference of 2.7 degrees was not statistically significant. The intraclass correlation coefficient for inter-tester reliability was 0.895. CONCLUSIONS: The FTA can be reliably determined from post-operative AP radiographs and provides a useful and reproducible metric for characterizing femoral tunnel position after both rigid and flexible femoral tunnel drilling. This has implications for post-operative evaluation and preoperative treatment planning for ACL revision surgery. LEVEL OF EVIDENCE: IV. PMID- 25034832 TI - Oxymatrine lightened the inflammatory response of LPS-induced mastitis in mice through affecting NF-kappaB and MAPKs signaling pathways. AB - Mastitis, an inflammatory reaction of the mammary gland, is recognized as one of the most costly diseases in dairy cattle. Oxymatrine, one of the alkaloids extracted from Chinese herb Sophora flavescens Ait, has been reported to have many biological activities, such as anti-inflammatory, anti-virus, and anti hepatic fibrosis properties. The aim of this study was to investigate the protective effect and the anti-inflammatory mechanism of oxymatrine on lipopolysaccharide (LPS)-induced mastitis in mice. The mouse mastitis was induced by 10 MUg of LPS for 24 h. Oxymatrine was intraperitoneally administered with the dose of 30, 60, and 120 mg/kg 1 h before and 12 h after LPS induction. The results showed that oxymatrine significantly attenuated the damage of the mammary gland induced by LPS. Oxymatrine inhibited the phosphorylation of NF-kappaB p65 and IkappaB in NF-kappaB signal pathway and reduced the phosphorylation of p38, ERK, and JNK in mitogen-activated protein kinase (MAPKs) signal pathway. The results showed that oxymatrine had a protective effect on LPS-induced mastitis, and the anti-inflammatory mechanism of oxymatrine was related to the inhibition of NF-kappaB and MAPKs signal pathways. PMID- 25034833 TI - The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma. AB - Immunological T cells and associated cytokines have been shown to be involved in the pathogenesis of multiple myeloma (MM). However, the abnormal immune imbalance of T lymphocyte subsets on MM remains unknown. We investigate the proportions of T helper 1 (Th1)/Th2/Th17/T regulatory (Treg) cells in peripheral blood mononuclear cells (PBMCs) by flow cytometry (FCM), and serum levels of relevant cytokines in MM patients and controls were detected by enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) expression of T-bet, STAT6, RORgammat, and Foxp3 was measured by real-time quantitative polymerase chain reaction (PCR). The CD4+ Th1 and CD4+ Th17 cells in patients with MM were significantly higher than those in health controls as well as the expression of T bet and RORgammat mRNA. Furthermore, serum levels of interferon gamma (IFN gamma), IL-6, and IL-17A in MM group were greatly increased and significantly associated with each other. Significant differences on Th cells, cytokines, and transcription factors were observed on MM patients. The imbalance of T lymphocyte subsets was thought to contribute to the pathogenesis and underlying mechanisms of MM. PMID- 25034834 TI - Higher orthostatic heart rate predicts mortality: The Irish Longitudinal Study on Ageing (TILDA). AB - BACKGROUND: Orthostatic hemodynamic signals may predict adverse outcomes in elders. AIMS: To study the association between orthostatic hemodynamics and incident mortality in The Irish Longitudinal Study on Ageing (TILDA). METHODS: Wave 1 subjects underwent an active stand with non-invasive beat-to-beat blood pressure monitoring. We compared wave 1 active stands, dead vs alive in wave 2. RESULTS: Compared to the 4,415 participants who had not died, the 53 who had died had a higher baseline heart rate [HR mean of 69 vs 65 beats per minute (bpm)] and a higher mean orthostatic HR, especially between 30 and 60 s post-stand (mean of 79 vs 73 bpm). After adjusting for age, sex, baseline HR, mini-mental state examination score and cardiovascular comorbidities and medications, the mean HR between 30 and 60 s post-stand independently predicted mortality (baseline HR did not). DISCUSSION: Higher early orthostatic HR may be an independent risk marker. Further validation is required. PMID- 25034835 TI - Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. PMID- 25034836 TI - The role of endoscopy in the management of variceal hemorrhage. PMID- 25034837 TI - Evaluating the "weekend effect" on patient outcomes in upper GI bleeding. PMID- 25034838 TI - Resolution of walled-off pancreatic necrosis by EUS-guided drainage when using a fully covered through-the-scope self-expandable metal stent in a single procedure (with video). AB - BACKGROUND: Walled-off pancreatic necrosis (WOPN) is effectively managed with percutaneous and endoscopic techniques such as direct endoscopic necrosectomy. However, they require repeat interventions and lengthy hospital stays. OBJECTIVE: To evaluate a new platform to manage WOPNs by using a large-bore, through-the scope, fully covered, self-expandable metal stent (FCSEMS) to overcome the need for repeat interventions and extended hospital stays. DESIGN: Retrospective, single-center study. SETTING: Academic tertiary care center. PATIENTS: Five consecutive patients with symptomatic WOPN underwent EUS-guided drainage of WOPN by using a large-bore FCSEMSs. INTERVENTIONS: EUS-guided transgastric drainage of WOPN by using a large-bore FCSEMS. Cross-sectional imaging was repeated at 6- to 8-week intervals. The FCSEMS was removed after WOPN resolution. MAIN OUTCOME MEASUREMENTS: Clinical success, number of repeat interventions, and length of hospital stay. RESULTS: Five patients (mean age 60 years) with WOPN (mean diameter, 12.3 cm; range 9.8-14.3 cm) underwent drainage with the described technique. Technical and clinical success was achieved in 100% of patients. Direct endoscopic necrosectomy was not required in any patient. The median number of endoscopic procedures was 1. The median length of hospital stay was 1 day. There were no adverse events. LIMITATIONS: Small, retrospective study. CONCLUSIONS: The described novel platform facilitates resolution of WOPN with a single procedure, avoiding the need for repeat interventions and lengthy hospital stays. PMID- 25034839 TI - Single-session circumferential EMR and metal stent placement for the treatment of long-segment Barrett's esophagus with high-grade intraepithelial neoplasia. PMID- 25034840 TI - Closure of a chronic tracheoesophageal fistula by use of a cardiac septal occluder. PMID- 25034841 TI - A case of endoscopic enucleation of a large upper GI submucosal tumor originating from the muscularis propria. PMID- 25034842 TI - Endoscopic full-thickness resection for GI stromal tumors. PMID- 25034843 TI - Successful management of biliary stones in the hepatic duct after a Whipple procedure by using an EUS-guided antegrade approach and temporary metal stent placement. PMID- 25034844 TI - Response. PMID- 25034845 TI - Treatment of patients with new diagnosis of achalasia: laparoscopic Heller's myotomy may be more effective than pneumatic dilation. PMID- 25034846 TI - Primary pancreatic leiomyosarcoma: a rare diagnosis obtained by EUS-FNA cytology. PMID- 25034847 TI - Endoscopic suturing closure of large mucosal defects after endoscopic submucosal dissection: is the technique, at all times, feasible and effective? PMID- 25034848 TI - Response. PMID- 25034849 TI - EUS-FNA versus ERCP-based tissue sampling: can intraductal aspiration improve ERCP diagnostic accuracy in suspected malignant biliary obstruction? PMID- 25034850 TI - Response. PMID- 25034851 TI - ASGE's assessment of competency in endoscopy evaluation tools for colonoscopy and EGD. PMID- 25034852 TI - Response. PMID- 25034853 TI - Preservation of the arterial vascularisation after hepatic artery pseudoaneurysm following orthotopic liver transplantation: long-term results. AB - BACKGROUND: Hepatic artery pseudoaneurysm (HAP) is a serious complication of orthotopic liver transplantation (OLT). The aim of this study was to determine risk factors for HAP and the best management of this complication. MATERIAL AND METHODS: Between 1990 and 2005, 787 OLT were performed at our center. Patients who developed HAP were identified from our prospective database and risk factors of HAP were identified. Management of HAP was analyzed retrospectively. RESULTS: There were 16 OLT (2.5%) complicated by HAP [median delay =13 days; range: 4-100 days]. Presentation was massive bleeding with shock (n=13), pain (n=2), or transient gastrointestinal bleeding (n=1). Bacteriological culture of HAP wall or ascites fluid was positive in 13 (81%) patients. Bilio-enteric anastomosis and biliary leak were identified as risk factors for HAP (p=0.011 and 0.002, respectively), whereas indication for OLT, surgical technique (full-graft OLT versus other techniques), and re-LT were not. Mortality rate after HAP rupture was 53% (7/13), but no deaths occurred in the 3 patients treated before rupture. Treatment included: excision and immediate revascularization [n=7; early mortality =2 (28%), long-term graft survival =4 (57%)], hepatic artery ligation [n=5; early mortality =3 (80%);, long-term graft survival with good liver function =0], and endovascular treatment [n=2; early mortality =0, long-term survival with good liver function =2]. CONCLUSIONS: HAP post-OLT carries a high mortality rate when detected after rupture, but recognition before rupture usually allows a successful outcome. Reconstruction with bilio-enteric anastomosis and postoperative biliary leak increase the risk for HAP. In these settings, CT with contrast injection should be performed to screen for HAP when there is any suspicion. Graft revascularization should be attempted whenever possible. PMID- 25034855 TI - Utility of fluorodeoxyglucose positron emission tomography/computed tomography in patients with fever of unknown origin diagnosed as lymphoma. AB - OBJECTIVE: To assess the efficacy of fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET)/computed tomography (CT) in the diagnosis of patients with fever of unknown origin (FUO), who were finally diagnosed as lymphoma. SUBJECTS AND METHODS: A retrospective study was performed in the First Affiliated Hospital, School of Medicine of Zhejiang University, China, from March 2009 to March 2012. The PET/CT images of consecutive patients with FUO were analyzed. Within 1 week of PET/CT scanning, additional histological tests were also performed if clinically needed. RESULTS: A total of 73 consecutive patients were included. Of these, 34 (47%) had a PET/CT finding suggestive of the presence of lymphoma and 29 (85%) had a diagnosis of confirmed lymphoma; 39 (53%) had a PET/CT result revealing the absence of lymphoma and 4 (10%) were diagnosed by biopsy as having lymphoma, . The most frequent lymphoma diagnosis was peripheral T cell lymphoma (n = 16; 55%), followed by diffuse large B cell lymphoma (n = 9; 31%). The accuracy of PET/CT was 88%. CONCLUSION: In this study, PET/CT had high diagnostic accuracy in patients with FUO resulting from lymphoma, which indicated that PET/CT scanning was a valuable diagnostic tool for these groups of patients with FUO. PMID- 25034854 TI - [Epidemiological study of nasopharyngeal carriers of Streptococcus pneumoniae in children in Murcia region]. AB - BACKGROUND AND OBJECTIVES: Streptococcus pneumoniae is a human pathogen that requires prior nasopharyngeal colonization to cause disease. An epidemiological study was conducted on nasopharyngeal carriers of pneumococci in healthy children in Murcia after the introduction of the VCN7, and immediately before the marketing of new vaccines, with the aim of determining the influence of vaccination in our geographic area, and other factors in relation to the state of being a carrier, and the different circulating serotypes. METHODS: A multicentre study was conducted in in 60 primary care health centres in summer 2009 and winter of 2010. A nasopharyngeal swab was collected, and an epidemiological study was carried out on 1562 children aged 1 and 4 years. Of the 1562 nasopharyngeal samples, pneumococci were found in 489 of them, with 343 of them able to be serotyped (70.2%). RESULTS: The prevalence of carriers was 31.3%. Of the patients included, 61.7% (964/1562) had received at least one dose of VCN7. Only 12.8% of the identified serotypes were vaccine serotypes. The independent protective factors against colonization were; Summer time in all age groups, previous vaccination in all the children (OR: 0.75; 95%CI: 0.56-0.93]; P=.01, and in 1 year-olds (OR: 0.6; 95%CI: 0.42-0.84; P=.002), and had taken antibiotics in the last month in the total cohort [OR: 0.69; 95%CI: 0.50-0.96). On the other hand, attendance at school or day-care centre (OR: 1.85; 95%CI: 1.27-2.18; P=.001), number of siblings (OR: 1.3; 95%CI: 1.01-1.91), and passive tobacco smoke exposure (OR: 1.33; 95%CI: 1.02-1.73), were colonization risk factors. The serotypes 6A, 19A, 23B, 15A/B, 11A, 14, 23A/F, 3 y 19F were the most prevalent. CONCLUSIONS: A low proportion of SV was found, with 14, 23F and 19F are persisting. A high prevalence of serotypes 6A and 19A was found. Summer time, vaccination, and the prior administration of antibiotics proved to be protective against colonization, whereas schooling, smoking, and siblings contributed to it. PMID- 25034857 TI - Methicillin resistance in Staphylococcus isolates: the "mec alphabet" with specific consideration of mecC, a mec homolog associated with zoonotic S. aureus lineages. AB - Livestock-associated (LA) methicillin-resistant Staphylococcus aureus (MRSA) have globally emerged during the past decade. In Europe, this was particularly due to the occurrence of LA-MRSA strains associated with the clonal complex (CC) 398 as defined by multilocus sequence typing. However, more recently animal-adapted clonal lineages of S. aureus showing phenotypic methicillin resistance have been identified such as CC130, CC599, CC59, CC1943 and CC425. These newly emerging LA MRSA CCs/STs caused infections in animals and zoonoses in humans. In contrast to other S. aureus clonal lineages, the methicillin resistance of the latter CCs/STs is based on a mecA gene homolog, designated mecC, which is part of a distinct SCCmec type (SCCmec XI). Including mecB found in Macrococcus caseolyticus, henceforth, the "mec alphabet" comprises three major gene types with several allotypes. As known for mecA, the gene homolog mecC is also not restricted to S. aureus, but found in several staphylococcal species including S. sciuri, S. stepanovicii and S. xylosus (mecC1 allotype). First investigations showed a wide geographical distribution of mecC-MRSA in Europe and a broad diversity of host species including livestock, companion and wildlife animals. In particular, wild rodents and insectivores might serve as reservoir for staphylococci harboring mecC. Economic burden may be caused by mastitis of dairy cattle. Livestock animals may likely serve as source for human infections with mecC-MRSA; reported cases comprise skin and soft tissue infections, osteomyelitis and bacteremia. Due to the divergent molecular nature of mecC-MRSA, its diagnostics is hampered by difficulties to verify the methicillin resistance using phenotypic as well as DNA based procedures, which could have negative consequences for therapy of mecC-MRSA caused infections. PMID- 25034858 TI - LA-MRSA CC398 differ from classical community acquired-MRSA and hospital acquired MRSA lineages: functional analysis of infection and colonization processes. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) of the clonal complex (CC) 398 became primarily known as colonizers of livestock animals. In the past few years, they have been increasingly introduced into hospitals with subsequent emergence of human infections. However, the (re )adaptation to the human host is only incompletely understood. This study aimed to assess virulence properties of LA-MRSA CC398 by functional modeling of infection and colonization processes. A selection of 15 human LA-MRSA CC398 isolates and 11 pig-colonizing isolates were characterized regarding their virulence capacities and compared with human isolates of hospital-acquired (HA) MRSA (CC5, CC22 and CC45) and community-associated (CA)-MRSA (CC8, CC30 and CC80) clonal lineages. Our investigations demonstrated that LA-MRSA CC398 adhered less efficient to human cells and human/bovine plasma fibronectin than CA-MRSA and HA MRSA isolates. In contrast, the LA-MRSA CC398 isolates revealed a high cytotoxic potential comparable to certain CA-MRSA. Comparing the most prevalent LA-MRSA CC398 spa types (t011, t034, t108), isolates associated with spa t108 showed an increased adhesive and invasive potential paired with an increased ability to evade phagocytosis. The results underline both the pathogenic potential of LA MRSA in general and the heterogeneity within the CC398 clade regarding the virulence characteristics of CC398 subpopulations. Assuming an ongoing (re )adaptation to the human host combined with a huge reservoir of LA-MRSA CC398 in livestock and constant zoonotic transmission, the LA-MRSA CC398 lineage has the potential to pose a serious threat to human health. PMID- 25034859 TI - Perinatal depression: an update and overview. AB - Over the last 3 years there have been notable developments in the screening and treatment of perinatal depression. Most importantly, the DSM-V has made only minor changes in the diagnostic criteria for perinatal depression as compared to the DSM-IV; "perinatal," as opposed to "postpartum," is a specifier for depression with a requirement that the depression onset occurs during pregnancy or the first 4 weeks postpartum. Advances in the treatment of perinatal depression have been made over the last 3 years, including both prevention and acute interventions. Additional support has emerged confirming the primary risk factors for perinatal depression: a personal or family history, low SES and poor interpersonal support. There is general agreement that universal screening be conducted for all perinatal women, by both the woman's obstetrician and the baby's pediatrician. PMID- 25034856 TI - Phylogenetic measures of biodiversity and neo- and paleo-endemism in Australian Acacia. AB - Understanding spatial patterns of biodiversity is critical for conservation planning, particularly given rapid habitat loss and human-induced climatic change. Diversity and endemism are typically assessed by comparing species ranges across regions. However, investigation of patterns of species diversity alone misses out on the full richness of patterns that can be inferred using a phylogenetic approach. Here, using Australian Acacia as an example, we show that the application of phylogenetic methods, particularly two new measures, relative phylogenetic diversity and relative phylogenetic endemism, greatly enhances our knowledge of biodiversity across both space and time. We found that areas of high species richness and species endemism are not necessarily areas of high phylogenetic diversity or phylogenetic endemism. We propose a new method called categorical analysis of neo- and paleo-endemism (CANAPE) that allows, for the first time, a clear, quantitative distinction between centres of neo- and paleo endemism, useful to the conservation decision-making process. PMID- 25034860 TI - Tunable photonic crystals with partial bandgaps from blue phase colloidal crystals and dielectric-doped blue phases. AB - Blue phase colloidal crystals and dielectric nanoparticle/polymer doped blue phases are demonstrated to combine multiple components with different symmetries in one photonic material, creating a photonic crystal with variable and micro controllable photonic band structure. In this composite photonic material, one contribution to the band structure is determined by the 3D periodic birefringent orientational profile of the blue phases, whereas the second contribution emerges from the regular array of the colloidal particles or from the dielectric/nanoparticle-doped defect network. Using the planewave expansion method, optical photonic bands of the blue phase I and II colloidal crystals and related nanoparticle/polymer doped blue phases are calculated, and then compared to blue phases with no particles and to face-centred-cubic and body-centred-cubic colloidal crystals in isotropic background. We find opening of local band gaps at particular points of Brillouin zone for blue phase colloidal crystals, where there were none in blue phases without particles or dopants. Particle size and filling fraction of the blue phase defect network are demonstrated as parameters that can directly tune the optical bands and local band gaps. In the blue phase I colloidal crystal with an additionally doped defect network, interestingly, we find an indirect total band gap (with the exception of one point) at the entire edge of SC irreducible zone. Finally, this work demonstrates the role of combining multiple - by symmetry - differently organised components in one photonic crystal material, which offers a novel approach towards tunable soft matter photonic materials. PMID- 25034863 TI - Melanoma: immune checkpoint blockade story gets better. PMID- 25034862 TI - Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. AB - BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged >=18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. FUNDING: Merck Sharp and Dohme. PMID- 25034864 TI - High-resolution ultrasound of rotator cuff and biceps reflection pulley in non elite junior tennis players: anatomical study. AB - BACKGROUND: Tennis is believed to be potentially harmful for the shoulder, therefore the purpose of this study is to evaluate the anatomy of the rotator cuff and the coraco-humeral ligament (CHL) in a-symptomatic non-elite junior tennis players with high-resolution ultrasound (US). METHODS: From August 2009 to September 2010 n = 90 a-symptomatic non-elite junior tennis players (mean age +/- standard deviation: 15 +/- 3) and a control group of age- and sex- matched subjects were included. Shoulder assessment with a customized standardized protocol was performed. Body mass index, dominant arm, years of practice, weekly hours of training, racket weight, grip (Eastern, Western and semi-Western), kind of strings were recorded. RESULTS: Abnormalities were found at ultrasound in 14/90 (15%) players. Two players had supraspinatus tendinosis, two had subacromial impingement and ten had subacromial bursitis. CHL thickness resulted comparable in the dominant and non-dominant arms (11.3 +/- 4.4 mm vs. 13 +/- 4.2, p > 0.05). Multivariate analysis demonstrated that no association was present among CHL thickness and the variables evaluated. In the control group, abnormalities were found at ultrasound in 6/60 (10%) subjects (sub-acromial bursitis). No statistically significant differences between players and control group were found (p = 0.71). CONCLUSION: In a-symptomatic non-elite junior tennis players only minor shoulder abnormalities were found. PMID- 25034865 TI - Development, validation, and application of a novel 7-day Caco-2 cell culture system. AB - INTRODUCTION: Monolayers of Caco-2 cells have been widely accepted as one of the well-established in vitro models to predict intestinal drug permeability and absorption in humans. However, the procedure for culturing the traditional 21-day Caco-2 model is labor intensive and time consuming, which limits its wide application in drug development. The objective of the present study was to develop a rapid Caco-2 model with a 7-day cell culture process. METHODS: A few modifications of the BIOCOAT(r) HTS Caco-2 Assay System were introduced including changing the cell seeding density, the composition of cell culture media, and the interval to change media. The monolayer structure was visualized through confocal microscopy. The transepithelial electrical resistance (TEER), apparent permeability coefficients (Papp), and functional activity of P-glycoprotein (P gp) were determined and compared with the 21-day model. Moreover, pharmacokinetic studies were performed in animal models to evaluate the absolute bioavailability of oral doses (Foral) of different compounds. RESULTS: Our newly developed 7-day Caco-2 model displayed comparable cellular morphology and integrity with the traditional 21-day model. No significant difference in paracellular and transcellular permeability was observed between the two systems. The efflux ratios of transporting digoxin, the prototypical substrate of P-gp in 21- and 7 day systems were 16.04 and 24.92, respectively. When the P-gp inhibitor verapamil was present, the efflux ratios of 21- and 7-day systems were 1.37 and 0.86, respectively, suggesting the comparability of the P-gp functional activity in both systems. Furthermore, pharmacokinetic studies of several compounds performed in animal models revealed that the absolute bioavailability of oral doses in vivo was well correlated with the Caco-2 permeability in vitro. DISCUSSION: The novel system provides a rapid and economical option for assessing the drug permeability, and is applicable to the studies of intestinal drug absorption. PMID- 25034866 TI - Comparison of porcine circovirus type 2 (PCV2)-associated lesions produced by co infection between two genotypes of PCV2 and two genotypes of porcine reproductive and respiratory syndrome virus. AB - The objective of this study was to compare the virulence and pathogenicity of a combination of concurrent infections of two genotypes of porcine circovirus type 2 (PCV2) and two genotypes of porcine reproductive and respiratory syndrome virus (PRRSV) in terms of PCV2 viraemia, and PCV2-associated lesions and antigens in co infected pigs. Pigs with PCV2a (or 2b)/type 1 (or type 2) PRRSV had significantly (P<0.05) higher mean clinical respiratory scores and lower average daily weight gain compared with pigs with PCV2a (or 2b). Co-infection induced significantly lower levels of anti-PCV2 and anti-PRRSV IgG antibodies than infection with one genotype alone, regardless of the genotype of the two viruses. Pigs with PCV2a (or 2b)/type 2 PRRSV had significantly (P<0.05) higher levels of PCV2 viraemia, more severe PCV2-associated lesions, and more PCV2 DNA within the lesions compared with pigs with PCV2a (or 2b)/type 1 PRRSV. However, there was no significant difference in these parameters in pigs with PCV2a/type 2 PRRSV or PCV2b/type 2 PRRSV. The results of this study demonstrate significant differences in the virulence and pathogenicity of type 1 and type 2 PRRSV but no significant differences in the virulence and pathogenicity of PCV2a and PCV2b with respect to the production of PCV2-associated lesions. PMID- 25034867 TI - Detection of diverse novel astroviruses from small mammals in China. AB - Astroviruses infect humans and many animal species and cause gastroenteritis. To extensively understand the distribution and genetic diversity of astrovirus in small mammals, we tested 968 anal swabs from 39 animal species, most of which were bats and rodents. We detected diverse astroviruses in 10 bat species, including known bat astroviruses and a large number of novel viruses. Meanwhile, novel groups of astroviruses were identified in three wild rodent species and a remarkably high genetic diversity of astrovirus was revealed in Eothenomys cachinus. We detected astroviruses in captive-bred porcupines and a nearly full length genome sequence was determined for one strain. Phylogenetic analysis of the complete ORF2 sequence suggested that this strain may share a common ancestor with porcine astrovirus type 2. Moreover, to our knowledge, this study reports the first discovery of astroviruses in shrews and pikas. Our results provide new insights for understanding these small mammals as natural reservoirs of astroviruses. PMID- 25034869 TI - Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment. AB - The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication. PMID- 25034868 TI - Maternity leave duration and full-time/part-time work status are associated with US mothers' ability to meet breastfeeding intentions. AB - BACKGROUND: Breastfeeding provides numerous health benefits for infants and mothers; however, many infants are not breastfed as long as recommended or desired by mothers. Maternal employment is frequently cited as a barrier to breastfeeding. OBJECTIVE: This study aimed to assess whether maternity leave duration and return status (full-time [FT], part-time [PT]) were associated with not meeting a mother's intention to breastfeed at least 3 months. METHODS: We used data from the Infant Feeding Practices Study II, a cohort study. Analyses were limited to women employed prenatally who intended to breastfeed 3 months or longer (n = 1172). Multivariable logistic regression was used to assess the relationship between maternity leave duration and return-to-work status (< 6 weeks/FT, < 6 weeks/PT, 6 weeks-3 months/FT, 6 weeks-3 months/PT, not working by 3 months) and meeting a mother's intention to breastfeed at least 3 months. RESULTS: Overall, 28.8% of mothers did not meet their intention to breastfeed at least 3 months. Odds of not meeting intention to breastfeed at least 3 months were higher among mothers who returned to work FT before 3 months (< 6 weeks/FT: adjusted odds ratio = 2.25, 95% confidence interval, 1.23-4.12; 6 weeks-3 months/FT: adjusted odds ratio = 1.82, 95% confidence interval, 1.30-2.56), compared with mothers not working at 3 months. CONCLUSION: Returning to work full time before 3 months may reduce a mother's ability to meet her intention to breastfeed at least 3 months. Employer support for flexible work scheduling may help more women achieve their breastfeeding goals. PMID- 25034870 TI - Estimating the incidence of adverse events in Portuguese hospitals: a contribution to improving quality and patient safety. AB - BACKGROUND: Several review studies have shown that 3.4% to 16.6% of patients in acute care hospitals experience one or more adverse events. Adverse events (AEs) in hospitals constitute a significant problem with serious consequences and a challenge for public health. The occurrence of AEs in Portuguese hospitals has not yet been systematically studied. The main purpose of this study is to estimate the incidence, impact and preventability of adverse events in Portuguese hospitals. It is also our aim to examine the feasibility of applying to Portuguese acute hospitals the methodology of detecting AEs through record review, previously used in other countries. METHODS: This work is based on a retrospective cohort study and was carried out at three acute care hospitals in the Administrative Region of Lisbon. The identification of AEs and their impact was done using a two-stage structured retrospective medical records review based on the use of 18 screening criteria. A random sample of 1,669 medical records (representative of 47,783 hospital admissions) for the year 2009 was analyzed. RESULTS: The main results found in this study were an incidence rate of 11.1% AEs, of which around 53.2% were considered preventable. The majority of AEs were associated with surgical procedures (27%), drug errors (18.3%) and hospital acquired infections (12.2%). Most AEs (61%) resulted in minimal or no physical impairment or disability, and 10.8% were associated with death. In 58.6% of the AEs' cases, the length of stay was prolonged on average 10.7 days. Additional direct costs amounted to ?470,380.00. CONCLUSION: The magnitude of these results was critical, reinforcing the need of more detailed studies in this area. The knowledge of the incidence and nature of AEs that occur in hospitals should be seen as a first step towards the improvement of quality and safety in health care. PMID- 25034872 TI - Radiation dose to rectum in high-dose-rate brachytherapy with a single implant and two fractions for prostate cancer, and its prediction by prostate volume. AB - We aimed to clarify the differences between the estimated rectal dose (ERD) and the first measured dose (FMD) and second measured dose (SMD) to the rectum during high-dose-rate (HDR) brachytherapy, and to predict FMD from the prostate volume (PV) or the rectal dose-volume parameters (RDVPs). ERD, FMD, and SMD were assessed with a rectal dosimeter during HDR brachytherapy of 18 Gy given in two fractions to 110 patients (48 hormone recipients, 62 hormone-naive patients) with prostate cancer. The correlations between FMD and PV, and between FMD and RDVP (D 2ml-D 5ml) were investigated. ERD (mean +/- SD) was 219 +/- 44 cGy, FMD was 255 +/- 52 cGy, and SMD was 298 +/- 63 cGy, which differed significantly (p < 0.001). The correlation coefficients between ERD and FMD, and between FMD and SMD, were 0.82 and 0.78, respectively. SMD was equivalent to 118 +/- 16 % FMD. The measured doses were significantly greater in the hormone recipients than in the hormone naive patients (p < 0.001). The increase in FMD correlated with the increases in PV and in RDVPs. The correlation coefficients between PV and FMD in all of the patients, in the hormone recipients, and in the hormone-naive patients were 0.61, 0.64, and 0.64, respectively, whereas that between RDVPs and FMD was <0.53. In conclusion, the dose to the rectum increased with time and was correlated with the increases in PV and RDVPs. The correlation coefficient between FMD and PV was greater than that between FMD and RDVPs. PMID- 25034871 TI - Digenean-gastropod host associations inform on aspects of specific immunity in snails. AB - Gastropod immunology is informed importantly by the study of the frequent encounters snails endure with digeneans (digenetic trematodes). One of the hallmarks of gastropod-digenean associations is their specificity: any particular digenean parasite species is transmitted by a limited subset of snail taxa. We discuss the nature of this specificity, including its immunological basis. We then review studies of the model gastropod Biomphalaria glabrata indicating that the baseline responses of snails to digeneans can be elevated in a specific manner. Studies incorporating molecular and functional approaches are then highlighted, and are further suggestive of the capacity for specific gastropod immune responses. These studies have led to the compatibility polymorphism hypothesis: the interactions between diversified fibrinogen-related proteins (FREPs) and diverse carbohydrate-decorated polymorphic parasite antigens determine recognition and trigger specific immunity. Complex glycan structures are also likely to play a role in the host specificity typifying snail-digenean interactions. We conclude by noting the dynamic and consequential interactions between snails and digeneans can be considered as drivers of diversification of digenean parasites and in the development and maintenance of specific immunity in gastropods. PMID- 25034873 TI - Efficacy and safety of sofosbuvir-based therapy for the treatment of chronic hepatitis C in treatment-naive and treatment-experienced patients. AB - Sofosbuvir, a hepatitis C virus (HCV) NS5B polymerase inhibitor, is a new direct acting antiviral for chronic HCV infection. This systematic review and proportional meta-analysis examined the efficacy and safety of sofosbuvir-based therapy for chronic HCV infection in treatment-naive and -experienced patients. Medline, Cochrane Database of Systematic Reviews, EMBASE and Web of Science databases were searched. Clinical trials examining sofosbuvir plus ribavirin (RBV) and pegylated interferon-alpha (peg-IFN) or sofosbuvir plus RBV among adults with chronic HCV infection were included. Data were extracted on virological responses including sustained virological response at post-treatment Week 12 (SVR12), relapse, treatment discontinuation due to an adverse event (AE), virological breakthrough during treatment, and AEs. One trial and 13 treatment arms/cohorts from seven studies met the criteria for analysis in treatment-naive patients who were treated with sofosbuvir, RBV and peg-IFN; the SVR12 was 89% (95% CI 85-92%), relapse was 5% and the serious adverse event (SAE) rate was 4%. Six treatment arms/cohorts met the criteria for analysis in treatment-naive patients who were treated with sofosbuvir and RBV; the SVR12 was 72% (95% CI 60 81%), relapse was 27% and the SAE rate was 3%. Three treatment arms/cohorts met the criteria for analysis in treatment-experienced patients who were treated with sofosbuvir and RBV; the SVR12 was 51% (95% CI 27-75%), relapse was 46% and the SAE rate was 4%. In conclusion, sofosbuvir-based treatment is effective and safe in treating chronic HCV infection, although the SVR12 of its combination with RBV, especially in treatment-experienced patients, requires improvement. PMID- 25034874 TI - Association of Catechol-O-Methyltransferase and monoamine oxidase B gene polymorphisms with motor complications in parkinson's disease in a Chinese population. AB - BACKGROUND: Catechol-O-Methyltransferase (COMT) and Monoamine oxidase B (MAO-B) are the main enzymes that metabolize dopamine in the brain. The polymorphisms of the COMT gene and MAO-B gene are associated with high, intermediate and low levels of activity. This may influence the prevalence of motor complications in Parkinson's Disease (PD). METHODS: The study enrolled 1087 Chinese PD patients throughout the country. Sanger dideoxynucleotide chain termination methods were used for COMT and MAO-B genotyping. The researchers compared the association between presence of motor complications and COMT and MAO-B gene polymorphisms, both separately and in combination. RESULTS: Comparison of the allele frequencies revealed that COMT (GG) was significantly more common among PD patients who exhibited wearing-off compared to PD patients without wearing-off (P < 0.05). A statistically higher frequency of the MAO-B (AG) genotype in PD patients with dyskinesias was found (P < 0.05). Although these differences were not significant after Bonferroni's correction. The combined haplotype of the MAO-B and COMT showed no increase (p < 0.05) in the risk of wearing-off and dyskinesias. CONCLUSIONS: Our findings suggest that polymorphisms in COMT and MAO-B may increase the risk of wearing-off and dyskinesias. COMT (GG) genotype may be the risk factor of wearing-off. While MAO-B (AG) genotype may be the risk factor of dyskinesias. PMID- 25034876 TI - Serum albumin as a stable predictor of prognosis during initial treatment in patients with diffuse large B cell lymphoma. PMID- 25034877 TI - Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound. AB - A study that combines microneedles (MNs) and sonophoresis pre-treatment was explored to determine their combined effects on percutaneous delivery of lidocaine from a polymeric hydrogel formulation. Varying ratios of carboxymethylcellulose and gelatine (NaCMC/gel ranges 1:1.60-1:2.66) loaded with lidocaine were prepared and characterized for zeta potential and particle size. Additionally, variations in the formulation drying techniques were explored during the formulation stage. Ex vivo permeation studies using Franz diffusion cells measured lidocaine permeation through porcine skin after pre-treatment with stainless steel MNs and 20 kHz sonophoresis for 5-and 10-min durations. A stable formulation was related to a lower gelatine mass ratio because of smaller mean particle sizes and high zeta potential. Lidocaine permeability in skin revealed some increases in permeability from combined MN and ultrasound pre-treatment studies. Furthermore, up to 4.8-fold increase in the combined application was observed compared with separate pre-treatments after 30 min. Sonophoresis pre treatment alone showed insignificant enhancement in lidocaine permeation during the initial 2 h period. MN application increased permeability at a time of 0.5 h for up to ~17 fold with an average up to 4 fold. The time required to reach therapeutic levels of lidocaine was decreased to less than 7 min. Overall, the attempted approach promises to be a viable alternative to conventional lidocaine delivery methods involving painful injections by hypodermic needles. The mass transfer effects were fairly enhanced and the lowest amount of lidocaine in skin was 99.7% of the delivered amount at a time of 3 h for lidocaine NaCMC/GEL 1:2.66 after low-frequency sonophoresis and MN treatment. PMID- 25034878 TI - Three-dimensional modeling of ovarian cancer. AB - New models for epithelial ovarian cancer initiation and metastasis are required to obtain a mechanistic understanding of the disease and to develop new therapeutics. Modeling ovarian cancer however is challenging as a result of the genetic heterogeneity of the malignancy, the diverse pathology, the limited availability of human tissue for research, the atypical mechanisms of metastasis, and because the origin is unclear. Insights into the origin of high-grade serous ovarian carcinomas and mechanisms of metastasis have resulted in the generation of novel three-dimensional (3D) culture models that better approximate the behavior of the tumor cells in vivo than prior two-dimensional models. The 3D models aim to recapitulate the tumor microenvironment, which has a critical role in the pathogenesis of ovarian cancer. Ultimately, findings using models that accurately reflect human ovarian cancer biology are likely to translate into improved clinical outcomes. In this review we discuss the design of new 3D culture models of ovarian cancer primarily using human cells, key studies in which these models have been applied, current limitations, and future applications. PMID- 25034879 TI - The associations between yogurt consumption, diet quality, and metabolic profiles in children in the USA. AB - PURPOSE: Recent studies have shown that yogurt consumption was associated with better diet quality and a healthier metabolic profile in adults. However, such associations have not been investigated in children. The present study examined the associations in children using data from a nationally representative survey. METHODS: Data from 5,124 children aged 2-18 years, who participated in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2006 in the USA were analyzed. The frequency of yogurt consumption over 12 months was determined using a validated food frequency questionnaire. Diet quality was assessed by the Healthy Eating Index 2005 (HEI-2005) using one 24-HR dietary recall, and metabolic profiles were obtained from the NHANES laboratory data. RESULTS: It was found that only 33.1 % of children consumed yogurt at least once per week (frequent consumers). Adjusting for covariates, frequent consumers had better diet quality than infrequent consumers, as indicated by a higher HEI-2005 total score (P = 0.04). Frequent yogurt consumption was associated with a lower fasting insulin level (P < 0.001), a lower homeostatic model assessment of insulin resistance (P < 0.001), and a higher quantitative insulin sensitivity check index (P = 0.03). However, yogurt consumption was not associated with body weight, fasting glucose, serum lipid profiles, C-reactive protein, and blood pressures (all P > 0.05). CONCLUSIONS: These results suggest that frequent yogurt consumption may contribute to improved diet quality and a healthier insulin profile in children. Future longitudinal studies and clinical trials in children are warranted to explore the health benefits of yogurt consumption. PMID- 25034880 TI - Dietary glycaemic load associated with cognitive performance in elderly subjects. AB - PURPOSE: Ageing is associated with loss of cognitive function and an increased risk of dementia which is expected to place growing demands on health and long term care providers. Among multiple causative factors, evidence suggests that cognitive impairment in older subjects may be influenced by diet. The objective of this study was to examine the association between dietary patterns, dietary glycaemic load (GL) and cognition in older Irish adults. METHODS: Community dwelling subjects (n 208; 94 males and 114 females; aged 64-93 years) were analysed. Dietary intake was assessed using a validated semi-quantitative food frequency questionnaire. Cognitive capacity was tested using the Mini-Mental State Examination (MMSE). The data were clustered to derive patterns of dietary intake. Multivariable-adjusted logistic and Poisson regression models were used to examine the relationship between dietary GL and MMSE score. RESULTS: Elderly subjects consuming 'prudent' dietary patterns (high in fruit, vegetables, fish, low-fat dairy and salad dressings and low in red meat and white bread) had higher MMSE scores (better cognitive function) than those consuming 'Western' dietary pattern (high in red meat and white bread and low in fruit and vegetables; P < 0.05). Logistic and Poisson regression analyses both indicated that the MMSE score was inversely associated with the GL of the diet (P < 0.05) even after adjusting for age, gender, diabetes, hypertension, healthy food diversity, nutritional status, residential property price, cardiovascular medications and energy intake. CONCLUSION: In this community-dwelling elderly Irish cohort, consumption of a high glycaemic diet is associated with poorer cognitive performance as assessed by the MMSE. PMID- 25034881 TI - Patient reported allergies are a risk factor for poor outcomes in total hip and knee arthroplasty. AB - We evaluated 459 patients undergoing THA or TKA who completed preoperative and postoperative WOMAC and/or SF36 surveys. Medical comorbidities and reported allergies were also recorded. Evaluation of surveys was compared for patients with or without 4 or more reported allergies using statistical methods. Patients with 4 or more reported allergies had less improvement on SF36 Physical Component Score (?PCS=4.2) than those with 0-3 allergies (?PCS=10.0, P=0.0002). Regression analysis showed that this change was independent of self-reported comorbidities. Patients reporting 4 or more allergies also had less improvement in WOMAC function (?F=21.4) than those with 0-3 allergies (?F = 27.2, P=0.036). Similar nonsignificant trends occurred in SF36 mental and WOMAC pain and stiffness scores. PMID- 25034882 TI - Letter to the editor concerning the article: "Total knee arthroplasty after lower extremity amputation: a review of 13 cases". PMID- 25034883 TI - Total hip arthroplasty after acetabular fracture: incidence of complications, reoperation rates and functional outcomes: evidence today. AB - The outcome of THA following acetabular fracture was analyzed on 654 patients with a systematic review approach. An uncemented acetabular and femoral component was used in 80.1% and 59.8% of the cases respectively. The median Harris hip score was 88 points. In the early THA group, Kaplan-Meier survivorship analysis with any loosening, osteolysis or revision as the end point revealed that the 10 year cup survival was 81% whereas in the late THA group was 76% (P=0.287). The 10 year survival was 95% for the early stems and 85% for the late ones (P=0.001). Due to their complexity these fractures should be managed in highly specializing units where the expertise of arthroplasty and trauma reconstruction is available. PMID- 25034884 TI - Patellar clunk syndrome after total knee arthroplasty; risk factors and functional outcomes of arthroscopic treatment. AB - This study reports the incidence, risk factors, and functional outcomes of the largest reported series of patients treated arthroscopically for patella clunk syndrome (PCS). All patients treated arthroscopically for PCS were identified. Patients were matched with controls by sex and date of surgery. Follow-up was conducted using SF-12 and WOMAC questionnaires. Operative notes and preoperative and postoperative radiographs were reviewed. Seventy-five knees in 68 patients were treated arthroscopically for PCS. Average follow-up was 4.2 years. Functional scores demonstrated no statistical difference. PCS patients had a significantly more valgus preoperative alignment, greater change in posterior femoral offset and smaller patellar component size. PCS is a relatively common complication following TKA. Arthroscopy yields functional results comparable to controls. Radiographic and technical factors are associated with PCS. PMID- 25034885 TI - Melanotic progonoma: an unusual pathology for an infantile midline scalp mass. PMID- 25034886 TI - Tumor-specific oncolytic adenoviruses expressing granulocyte macrophage colony stimulating factor or anti-CTLA4 antibody for the treatment of cancers. AB - The purpose of this study was to examine the tumor specificity, cytotoxicity and the antitumor activity of two conditionally replicating oncolytic adenoviruses, SKL001 and SKL002, which expressed granulocyte macrophage colony-stimulating factor (GM-CSF) or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA4) antibody, respectively, and determine their antitumor efficacy in A549 lung tumor model, B16F10 mouse melanoma tumor model and CMT-64 mouse small lung carcinoma tumor model. Virus yield and cytotoxicity were used to determine tumor specificity and virus replication-mediated cytotoxicity of SKL001 and SKL002 in a panel of human tumor cell lines and primary cells in vitro. Two subcutaneous (s.c.) tumor nexograft tumor models were used to assess their antitumor activity. Under the control of the E2F promoter, the expression of E1a genes appeared only in tumor cells, whereas the wild-type Ad5 expressed its E1a genes in both tumor cells and normal cells. GM-CSF and anti-CTLA4 production were significantly higher in tumor cells than normal cells. SKL001 and SKL002 replicated in Rb defective cell lines as efficiently as wild-type adenovirus but produced 100-fold less virus in normal human cells. SKL001 and SKL002 was up to 1000-fold more cytotoxic in Rb pathway-defective human tumor cells in comparison with normal human cells. Antitumor activity of SKL001 and SKL002 following intravenous administration was shown in a human lung A549 s.c. xenograft tumor model and mouse B16F10 melanoma tumor model when compared with phosphate-buffered saline treatment. In immune-competent mice, the addition of GM-CSF produced a stronger antitumor activity and induced a higher number of mature dendritic cells and macrophages, whereas additive antitumor activity was observed in the group when SKL001 and SKL002 were combined. In vitro and in vivo studies showed the selective replication, cytotoxicity, gene production and antitumor efficacy of SKL001 and SKL002 in human tumor model, suggesting a potential utility of this oncolytic agent for the treatment of human cancer. Further studies are warranted to show the role of human GM-CSF and anti-CTLA4 antibody in the antitumor efficacy of these two oncolytic viruses. PMID- 25034887 TI - Enhancement of electroporation facilitated immunogene therapy via T-reg depletion. AB - Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25 depleting antibodies (PC61). The combinational treatment effectively depleted T regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival. PMID- 25034888 TI - Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-kappaB. AB - Growing evidence links tumor progression with chronic inflammatory processes and dysregulated activity of various immune cells. In this study, we demonstrate that various types of macrophages internalize microvesicles, called exosomes, secreted by breast cancer and non-cancerous cell lines. Although both types of exosomes targeted macrophages, only cancer-derived exosomes stimulated NF-kappaB activation in macrophages resulting in secretion of pro-inflammatory cytokines such as IL-6, TNFalpha, GCSF, and CCL2. In vivo mouse experiments confirmed that intravenously injected exosomes are efficiently internalized by macrophages in the lung and brain, which correlated with upregulation of inflammatory cytokines. In mice bearing xenografted human breast cancers, tumor-derived exosomes were internalized by macrophages in axillary lymph nodes thereby triggering expression of IL-6. Genetic ablation of Toll-like receptor 2 (TLR2) or MyD88, a critical signaling adaptor in the NF-kappaB pathway, completely abolished the effect of tumor-derived exosomes. In contrast, inhibition of TLR4 or endosomal TLRs (TLR3/7/8/9) failed to abrogate NF-kappaB activation by exosomes. We further found that palmitoylated proteins present on the surface of tumor-secreted exosomes contributed to NF-kappaB activation. Thus, our results highlight a novel mechanism used by breast cancer cells to induce pro-inflammatory activity of distant macrophages through circulating exosomal vesicles secreted during cancer progression. PMID- 25034889 TI - The association between the ratio of monocytes:lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life. AB - BACKGROUND: Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV. METHODS: We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious. RESULTS: Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%). CONCLUSION: Elevated ML ratio at three- to four months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease. PMID- 25034890 TI - P53 related apoptosis in kidneys in CO2 pneumoperitoneum rat model: an immunohistochemical study. AB - Laparoscopic surgery techniques have been increasingly preferred to classic laparotomy by surgeons since 1987. However, this method may have some side effects on different intraabdominal organs including kidneys. The aim of this study is to evaluate the effects of different pressures of CO2 on p53 related apoptosis in kidneys. Totally 24 male rats were divided into four equal groups. CO2 is insufflated into rats' intraabdominal cavity in two different pressures of 10 and 20 mmHg during 1 h. However, in sham group, only cannula was inserted, but no gas was insufflated. After 1 h, 30 min reperfusion was applied. At last, the kidneys were excised and p53 expression and apoptosis were evaluated immunohistochemically. All the data revealed that the number of apoptotic cell in kidney' tubular cells significantly increases in proportion to CO2 pressure level. On the other hand, p53 expression was detected only in the highest pressure. Because the low CO2 pressured group' rats had no p53 expression in kidneys, we suggest that this method can be safely used for abdominal surgery. At the same time, increasing in the number of apoptotic cells parallel to pressure also suggest that CO2 pressure level and application time are very important parameters during CO2 pneumoperitoneum. PMID- 25034891 TI - Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells. AB - Mitofusin 2 (Mfn2) is a dynamin-like protein anchored in the outer mitochondrial membrane that plays a crucial role in ensuring optimal mitochondrial morphological homeostasis. It has been shown that reduced expression of Mfn2 is associated with insulin resistance, but the mechanism is still unclear. We investigated whether Mfn2 deficiency leads to impaired insulin sensitivity via elevated oxidative stress. L6 skeletal muscle cells were treated with palmitate and Mfn2 expression was repressed by transfection with antisense Mfn2. Levels of antioxidant enzymes, reactive oxygen species (ROS), the phosphorylation of c-Jun N-terminal Kinase (JNK) and nuclear factor-kappaB (NF-kappaB) and the mitochondrial membrane potential (Deltapsim) were measured. The results showed palmitate-induced insulin resistance of skeletal muscle cells was accompanied by Mfn2 repression. Meanwhile, the cells had decreased Deltapsim and activity of antioxidant enzymes which could increase production of ROS, phosphorylation of JNK and NF-kappaB. When Mfn2 was up-regulated in palmitate-treated cells, oxidative stress and insulin resistance was alleviated. Furthermore, knock-down of Mfn2 in control cells enhanced oxidative stress. Mfn2 deficiency led to increased superoxide concentration and activation of JNK as well as NF-kappaB associated with insulin signaling. In conclusion, Mfn2 is a potent repressor for oxidative stress and regulation of Mfn2 expression may prove to be a potential method to circumvent insulin resistance. PMID- 25034892 TI - Molecular characterization, tissue expression profile and SNP analysis of the porcine NR1H4 gene. AB - Nuclear Receptor subfamily 1, group H, member 4 (NR1H4) is a receptor for bile acids and has an important role in regulating energy metabolism in liver, muscle and adipose tissues in humans and animals. In this study, we cloned the full coding region of NR1H4 gene from porcine Longissimus dorsi by Rapid amplification of cDNA end (RACE). Results indicated that the open reading frame of NR1H4 covered 1461 bp encoding 486 amino acid residues and the deduced amino acid sequence was 91-94 % identical to that of Homo sapiens, Bos taurus, Macaca mulatta, Gorilla gorilla, and Ovis aries. Bioinformatic analysis indicated that NR1H4 contained 31 phosphorylation sites with 14 serine, 6 threonine and 11 tyrosine. One single nucleotide polymorphism (SNP) was detected by PCR-RFLP in 3' untranslated region of exon 9 (NR1H4) and the allele frequency analysis showed that A allele frequency was low among 396 pigs from five breeds. The NR1H4 mRNA expression pattern showed that NR1H4 gene was expressed highly in live and Longissimus dorsi. This work provided an important experimental basis for further research on mechanism of lipid metabolism and fat deposition in pigs. PMID- 25034893 TI - Modulation of cysteine-rich protein 2 expression in vascular injury and atherosclerosis. AB - Vascular smooth muscle cells (VSMCs) of the arterial wall normally display a differentiated and contractile phenotype. In response to arterial injury, VSMCs switch to a synthetic phenotype, contributing to vascular remodeling. Cysteine rich protein 2 (CRP2) is a cytoskeletal protein expressed in VSMCs and blunts VSMC migration in part by sequestering the scaffolding protein p130Cas at focal adhesions. CRP2 deficiency in mice increases neointima formation following arterial injury. The goal of this study was to use Csrp2 promoter-lacZ transgenic mice to analyze CRP2 expression during VSMC phenotypic modulation. In a neointima formation model after carotid artery cessation of blood flow, lacZ reporter activity and smooth muscle (SM) alpha-actin expression in the media were rapidly downregulated 4 days after carotid ligation. Fourteen days after ligation, there was a high level expression of both Csrp2 promoter activity and SM alpha-actin protein expression in neointimal cells. In atherosclerosis prone mice fed an atherogenic diet, Csrp2 promoter activity was detected within complex atherosclerotic lesions. Interestingly, Csrp2 promoter activity was also present in the fibrous caps of complicated atherosclerotic lesions, indicating that CRP2 might contribute to plaque stability. These findings support the concept that CRP2 contributes to the phenotypic modulation of VSMCs during vascular disease. Modulating transcription to increase CRP2 expression during vascular injury might attenuate vascular remodeling. In addition, increased CRP2 expression at the fibrous caps of advanced lesions might also serve to protect atherosclerotic plaques from rupture. PMID- 25034894 TI - Associations of platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphisms with circulating PAF-AH levels and risk of coronary heart disease or blood stasis syndrome in the Chinese Han population. AB - The circulating level of platelet-activating factor acetylhydrolase (PAF-AH) is a novel biomarker to predict the presence of coronary heart disease. PAF-AH gene polymorphisms may be responsible for the variance of circulating PAF-AH levels in individuals. However, the association of PAF-AH gene polymorphisms with circulating PAF-AH levels and the susceptibility to coronary heart disease (CHD) remains unsolved. Blood stasis syndrome (BSS) of CHD is the most common type of TCM syndromes, and a previous study discovered its relationship with the elevated circulating PAF-AH levels. However, the association of gene polymorphisms and CHD with BSS is unclear at present. In this study, four polymorphisms (R92H, I198T, A379V, V279F) of the PAF-AH gene were genotyped in 570 CHD patients, of which 299 had BSS. In addition, 317 unaffected individuals from the same hospitals served as controls. Plasma PAF-AH levels were measured in 155 controls and 271 CHD patients selected randomly, including 139 CHD patients with BSS. In the Chinese Han population, plasma PAF-AH levels in CHD patients with BSS or without BSS were significantly higher (12.9 +/- 6.5 and 11.1 +/- 5.0 MUM, respectively) than in controls (9.3 +/- 5.2 MUM); this difference still remained significant after adjustment for traditional risk factors or the inflammatory factors. The R92H polymorphism was highly related to the plasma PAF-AH levels and the risk of CHD, especially among patients with BSS, even with the adjustment for the effects of traditional factors. The I198T polymorphism was highly associated with risk of CHD with BSS, but was associated with neither the risk of CHD with no BSS nor with elevated plasma PAF-AH levels. PMID- 25034895 TI - Is nucleus accumbens atrophy correlated with cognitive symptoms of Parkinson's disease? PMID- 25034896 TI - Reply: is nucleus accumbens atrophy correlated with cognitive symptoms of Parkinson's disease? PMID- 25034898 TI - Concordance of risk behavior reporting within HCV serodiscordant injecting partnerships of young injection drug users in San Francisco, CA. AB - INTRODUCTION: Young injection drug users (IDU, under age 30) often inject with other IDU, creating an environment for risk of blood-borne disease transmission through sharing of needles and drug preparation equipment. Epidemiologic studies rely on self reported injection behavior data for measures of transmission risk, therefore we sought to quantify the degree of concordance of reported injecting risk behaviors between injecting dyads. METHODS: From May, 2006 through 2013 we enrolled 72 injecting dyads in San Francisco, California, who were hepatitis C virus (HCV) RNA discordant. Each partnership was followed prospectively for up to six months. Monthly interviews from each partner were date-matched and responses to relationship characteristics and risk behavior questions were compared. Concordance of reporting was estimated with the concordance correlation coefficient for longitudinal data (CCC) and the prevalence adjusted bias adjusted kappa (PABAK). RESULTS: Participants had a median age of 26 (IQR: 23, 28) years and median years injecting of 7.0 (IQR: 3.0, 10.6). Thirty-eight percent of the injecting dyads were also sexual partners. Concordance levels were highest for partnership characteristics, such as length of acquaintance, number of days cohabitating, and sexual intercourse in the past month (CCC=0.95; 0.82, and 0.90, respectively). Shared injection risk behaviors such as injecting with the HCV+ partner's previously used syringe and using contaminated injection preparation equipment had slight to fair agreement (CCC=0.22; 0.23; PABAK=0.43, 0.36, respectively). CONCLUSIONS: Concordance levels ranged from low to high. Potential sources of measurement error for low agreement items include recall and social desirability biases and question interpretation. PMID- 25034897 TI - The modern pre-levodopa era of Parkinson's disease: insights into motor complications from sub-Saharan Africa. AB - During the past decade, a number of large drug trials suggested that the initiation of levodopa therapy should be delayed to reduce the risk of motor complications in patients with Parkinson's disease. However, the relative contribution of the cumulative exposure to levodopa and of disease progression to the pathophysiology of motor fluctuations and dyskinesias is still poorly understood. In this 4-year multicentre study, we investigated a large cohort of patients with Parkinson's disease in a sub-Saharan African country (Ghana), where access to medication is limited and the initiation of levodopa therapy often occurs many years after onset. The primary objective was to investigate whether the occurrence of motor complications is primarily related to the duration of levodopa therapy or to disease-related factors. Study design included a cross sectional case-control analysis of data collected between December 2008 and November 2012, and a prospective study of patients followed-up for at least 6 months after the initiation of levodopa therapy. Ninety-one patients fulfilled criteria for clinical diagnosis of idiopathic Parkinson's disease (58 males, mean age at onset 60.6 +/- 11.3 years). Demographic data were compared to those of 2282 consecutive Italian patients recruited during the same period, whereas nested matched subgroups were used to compare clinical variables. Demographic features, frequency and severity of motor and non-motor symptoms were comparable between the two populations, with the only exception of more frequent tremor dominant presentation in Ghana. At baseline, the proportion of Ghanaian patients with motor fluctuations and dyskinesias was 56% and 14%, respectively. Although levodopa therapy was introduced later in Ghana (mean disease duration 4.2 +/- 2.8 versus 2.4 +/- 2.1 years, P < 0.001), disease duration at the occurrence of motor fluctuations and dyskinesias was similar in the two populations. In multivariate analysis, disease duration and levodopa daily dose (mg/kg of body weight) were associated with motor complications, while the disease duration at the initiation of levodopa was not. Prospective follow-up for a mean of 2.6 +/- 1.3 years of a subgroup of 21 patients who were drug-naive at baseline [median disease duration 4.5 (interquartile range, 2.3-5) years] revealed that the median time to development of motor fluctuations and dyskinesias after initiation of levodopa therapy was 6 months. We conclude that motor fluctuations and dyskinesias are not associated with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified. PMID- 25034899 TI - Pain management perceptions among prescription opioid dependent individuals. AB - BACKGROUND: Nearly two-thirds of prescription opioid dependent individuals report chronic pain conditions as both an initial and current motivation for prescription opioid use. However, to date, limited information exists regarding perceptions of the adequacy of pain management and pain management behaviors among prescription opioid dependent individuals with a history of treatment for chronic pain. METHODS: The current study examined perceptions of the medical management of chronic pain among community-recruited individuals (N=39) who met DSM-IV-TR criteria for current prescription opioid dependence and reported a history of treatment for chronic pain. Prescription opioid dependence, symptoms of depression, and pain management perceptions were assessed using the Structured Clinical Interview for DSM disorders, Beck Depression Inventory, and the Pain Management Questionnaire, respectively. RESULTS: Reports of insufficient pain management were common (46.2%), as was utilization of emergency room services for pain management (56.4%). Nearly half reported a physician as their initial source (46.2%) and pain management as their primary initial reason for prescription opioid use (53.8%), whereas 35.9% reported pain relief as their primary reason for current prescription opioid use. Symptoms of depression were common (51.3%), as was comorbid abuse of other substances and history of treatment for substance abuse. CONCLUSIONS: Results highlight the complicated clinical presentation and prevalent perception of the under-treatment of pain among this population. Findings underscore the importance of interdisciplinary approaches to managing the complex presentation of chronic pain patients with comorbid prescription opioid dependence. Implications for future research are discussed. PMID- 25034900 TI - Decreasing sensitivity of clinical alcohol screening with the AUDIT-C after repeated negative screens in VA clinics. AB - BACKGROUND: Routine screening for unhealthy alcohol use is widely recommended in primary care settings. However, the validity of repeat screening among patients who have previously screened negative remains unknown. This study aims to evaluate the performance of a clinical alcohol screen compared to a confidential comparison alcohol screen among patients with previous negative alcohol screens. METHODS: This study included four nested samples of Veteran Health Administration (VA) outpatients with at least one (N=18,493) and up to four (N=714) prior negative annual clinical AUDIT-C screens who completed the AUDIT-C the following year, both in a VA clinic (clinical screen) and on a confidential mailed survey (comparison screen). AUDIT-C screens were categorized as either negative (0-3 points men; 0-2 women) or positive (>=4 men; >=3 women). For each sample, the performance of the clinical screen was compared to the comparison screen, the reference measure for unhealthy alcohol use. RESULTS: The sensitivity of clinical screens decreased as the number of prior negative screens in a sample increased (40.0-17.4%) for patients with 1-4 negative screens. The positive predictive value also decreased as the number of prior negative screens in a sample increased (67.7-33.3%) while specificity was consistently high for all samples (>=97.8%). CONCLUSIONS: Repeat clinical alcohol screens became progressively less sensitive for identifying unhealthy alcohol use among patients who repeatedly screened negative over several years. Alternative approaches for assessing unhealthy alcohol use may be needed for these patients. PMID- 25034901 TI - Long-range PCR in next-generation sequencing: comparison of six enzymes and evaluation on the MiSeq sequencer. AB - Long-range PCR remains a flexible, fast, efficient and cost-effective choice for sequencing candidate genomic regions in a small number of samples, especially when combined with next-generation sequencing (NGS) platforms. Several long-range DNA polymerases are advertised as being able to amplify up to 15 kb or longer genomic DNA. However, their real-world performance characteristics and their suitability for NGS remain unclear. We evaluated six long-range DNA polymerases (Invitrogen SequalPrep, Invitrogen AccuPrime, TaKaRa PrimeSTAR GXL, TaKaRa LA Taq Hot Start, KAPA Long Range HotStart and QIAGEN LongRange PCR Polymerase) to amplify three amplicons, with sizes of 12.9 kb, 9.7 kb, and 5.8 kb, respectively. Subsequently, we used the PrimeSTAR enzyme to amplify entire BRCA1 (83.2 kb) and BRCA2 (84.2 kb) genes from nine subjects and sequenced them on an Illumina MiSeq sequencer. We found that the TaKaRa PrimeSTAR GXL DNA polymerase can amplify almost all amplicons with different sizes and Tm values under identical PCR conditions. Other enzymes require alteration of PCR conditions to obtain optimal performance. From the MiSeq run, we identified multiple intronic and exonic single-nucleotide variations (SNVs), including one mutation (c.5946delT in BRCA2) in a positive control. Our study provided useful results for sequencing research focused on large genomic regions. PMID- 25034902 TI - Relevance of microRNA in metabolic diseases. AB - Metabolic syndrome is a complex metabolic condition caused by abnormal adipose deposition and function, dyslipidemia and hyperglycemia, which affects >47 million American adults and ~1 million children. Individuals with the metabolic syndrome have essentially twice the risk for developing cardiovascular disease (CVD) and Type 2 diabetes mellitus (T2D), compared to those without the syndrome. In the search for improved and novel therapeutic strategies, microRNAs (miRNA) have been shown to be interesting targets due to their regulatory role on gene networks controlling different crucial aspects of metabolism, including lipid and glucose homeostasis. More recently, the discovery of circulating miRNAs suggest that miRNAs may be involved in facilitating metabolic crosstalk between organs as well as serving as novel biomarkers of diseases, including T2D and atherosclerosis. These findings highlight the importance of miRNAs for regulating pathways that underlie metabolic diseases, and their potential as therapeutic targets for the development of novel treatments. PMID- 25034903 TI - Treatment results of endosaccular coil embolization of asymptomatic unruptured intracranial aneurysms in elderly patients. AB - BACKGROUND AND PURPOSE: We report the results of endosaccular coil embolization of asymptomatic unruptured intracranial aneurysms (UIAs) in elderly patients (>=65 years). MATERIALS: There were 375 elderly patients with 400 asymptomatic UIAs. Patients were divided into two groups: group A included patients aged 65-74 years and group B patients aged >=75 years. RESULTS: Endovascular procedures were completed in 97.8% of patients. Immediate anatomical outcomes showed complete occlusion in 53.7%, residual neck in 18.9%, and residual aneurysm in 27.4%. Anatomical follow-ups (mean 36.3+/-28.1 months) were unchanged in 55.7%, improved in 22.6%, minor recurrence in 11.5%, and major recurrence in 10.2%. Procedure related complications occurred in 31 patients (8.3%). 15 patients had ischemic and 10 hemorrhagic complications. Retreatments were performed in 16 patients (4.3%). Among 366 patients technically completed, 363 (99.2%) showed a favorable clinical outcome (modified Rankin Scale (mRS) score <1) at 30 days. The remaining three patients showed a worsening of mRS >0 at 30 days. The latest clinical follow-up outcomes showed: mRS score 0 in 362 patients; mRS score 1 in one; mRS score 3 in one; mRS score 4 in one; and mRS score 5 in one patient. Permanent morbidity and mortality rates were 1.1% and 0%, respectively. There were no statistically significant differences in gender, comorbidities, aneurysm size, neck width, dome-to-neck ratio, immediate anatomical outcomes, anatomical follow up outcomes, or procedure related complications between the groups. CONCLUSIONS: Endosaccular coil embolization is safe and feasible for elderly patients with asymptomatic UIAs. Old age itself should not be a contraindication. PMID- 25034904 TI - The position of a standard optical computer mouse affects cardiorespiratory responses during the operation of a computer under time constraints. AB - OBJECTIVES: This study investigated the association between task-induced stress and fatigue by examining the cardiovascular responses of subjects using different mouse positions while operating a computer under time constraints. MATERIAL AND METHODS: The study was participated by 16 young, healthy men and examined the use of optical mouse devices affixed to laptop computers. Two mouse positions were investigated: (1) the distal position (DP), in which the subjects place their forearms on the desk accompanied by the abduction and flexion of their shoulder joints, and (2) the proximal position (PP), in which the subjects place only their wrists on the desk without using an armrest. The subjects continued each task for 16 min. We assessed differences in several characteristics according to mouse position, including expired gas values, autonomic nerve activities (based on cardiorespiratory responses), operating efficiencies (based on word counts), and fatigue levels (based on the visual analog scale - VAS). RESULTS: Oxygen consumption (VO(2)), the ratio of inspiration time to respiration time (T(i)/T(total)), respiratory rate (RR), minute ventilation (VE), and the ratio of expiration to inspiration (Te/T(i)) were significantly lower when the participants were performing the task in the DP than those obtained in the PP. Tidal volume (VT), carbon dioxide output rates (VCO(2)/VE), and oxygen extraction fractions (VO(2)/VE) were significantly higher for the DP than they were for the PP. No significant difference in VAS was observed between the positions; however, as the task progressed, autonomic nerve activities were lower and operating efficiencies were significantly higher for the DP than they were for the PP. CONCLUSIONS: Our results suggest that the DP has fewer effects on cardiorespiratory functions, causes lower levels of sympathetic nerve activity and mental stress, and produces a higher total workload than the PP. This suggests that the DP is preferable to the PP when operating a computer. PMID- 25034905 TI - Global review of studies on traffic police with special focus on environmental health effects. AB - Since occupation is a major determinant of health, traffic police personnel face multiple occupational hazards. They are continuously exposed to vehicular emissions and work in a noisy and polluted environment. The objective of the present review is to explore the impact of occupational health hazards on the health of traffic police personnel. Published research papers on traffic police reporting occupational health issues were accessed and reviewed. Attempts were made to access papers that reported negative associations in order to present a balanced review. The majority of the studies have reported a decrease in the lung function and increased respiratory morbidity. The research on the cytogenetic abnormalities or genotoxic effect of vehicular emissions arising due to long-term exposure to benzene and other polyaromatic hydrocarbons has provided conflicting results, since more or less equal numbers of studies have given evidence for and against the causal association. There is a vast accumulation of epidemiological evidence on the casual association between vehicular pollution and its carcinogenic effect. Multiple studies have concluded that traffic police are highly stressed. A number of occupational factors have been attributed to stress among traffic police. Occupational health studies help us to understand the effects of vehicular pollution and its adverse influence on workers. They also provide opportunity for defined exposures measurements and precise risk assessment. The findings from these studies are easily generalizable and can help us understand the impact of air pollution on the general population. PMID- 25034906 TI - Job satisfaction of occupational physicians in commercial and other delivery settings: a comparative and explorative study. AB - OBJECTIVES: Commercialization of occupational health services (OHS) and transition to a supplier market which started in 1995, has affected work and working conditions of occupational physicians (OPs) profoundly. OPs have lost influence on the organization of their work and managers took over control. This study explores the impact of commercialization on job satisfaction of occupational physicians. MATERIAL AND METHODS: Data were collected through a questionnaire completed by 797 OPs, members of the Netherlands Association of Occupational Medicine (response: 45%). A range of work satisfiers and dissatisfiers measures was included that, according to the Social Action Approach, could explain the variation in job satisfaction. Stepwise multivariate regression analyses were performed to explore to what extent the differences in job satisfaction can be attributed to the characteristics of the setting, biographical variables, satisfiers and dissatisfiers. RESULTS: Occupational physicians in commercial settings had the lowest average score as regards job satisfaction (6.7) contrasting sharply with their colleagues in private practices (8.7) and in non-commercial settings (7.9). The variation in job satisfaction between delivery settings could largely be attributed to satisfiers and dissatisfiers. Biographical characteristics (age, gender) had no effect. The data suggested that not commercialization as such, but the ability of commercial OHS providers to integrate professional values was the crucial factor to bring about job satisfaction. CONCLUSIONS: The challenge for commercial OHS providers is to preserve the professional zeal in OPs by integrating professional values in their organization in order to improve the quality of the services and the attractiveness of the profession. PMID- 25034907 TI - Temperamental correlates of trauma symptoms in firemen, policemen and soldiers. AB - OBJECTIVES: The main goal of the research was to assess temperamental determinants of trauma symptoms in firemen, policemen and soldiers. The temperament traits which were considered were those postulated by the Regulative Theory of Temperament (briskness, perseveration, sensory sensitivity, emotional reactivity, endurance and activity). MATERIAL AND METHODS: A cross-sectional study was run on non-clinical samples. The participants were 417 men, White Caucasian only: 284 firemen (aged 21-55), 58 policemen (aged 22-45), and 75 soldiers (aged 21-42). Temperament was assessed using the Formal Characteristics of Behavior - Temperament Inventory. Intensity of trauma symptoms was assessed with the PTSD-Factorial Version Inventory, a quantitative measure of trauma related symptoms. The respondents were examined in their place of work. The study included only men reporting at least 1 traumatic event during the year before the trauma diagnosis. RESULTS: Emotional reactivity had a significant positive effect on the intensity of trauma symptoms only in the group of firemen. Emotional reactivity accounted for 16% of the variance of trauma intensity symptoms in this occupational group. Negative significant effect on trauma symptoms was found for briskness only in the soldiers group (briskness explained 20% trauma intensity variance in this group). CONCLUSIONS: Emotional reactivity was conducive to the increased trauma symptoms intensity in firemen, whereas briskness tended to reduce symptoms intensity only in the group of soldiers. PMID- 25034908 TI - Photosensitized mefloquine induces ROS-mediated DNA damage and apoptosis in keratinocytes under ambient UVB and sunlight exposure. AB - The present study illustrates the photosensitizing behavior of mefloquine (MQ) in human skin keratinocytes under ambient doses of UVB and sunlight exposure. Photochemically, MQ generated reactive oxygen species superoxide radical, hydroxyl radical, and singlet oxygen through type I and type II photodynamic reactions, respectively, which caused photooxidative damage to DNA and formed localized DNA lesions cyclobutane pyrimidine dimers. Photosensitized MQ reduced the viability of keratinocytes to 25 %. Significant level of intracellular reactive oxygen species (ROS) generation was estimated through fluorescence probe DCF-H2. Increased apoptotic cells were evident through AO/EB staining and phosphatidyl serine translocation in cell membrane. Single-stranded DNA damage was marked through single-cell gel electrophoresis. Mitochondrial membrane depolarization and lysosomal destabilization were evident. Upregulation of Bax and p21 and downregulation of Bcl-2 genes and corresponding protein levels supported apoptotic cell death of keratinocyte cells. Cyclobutane pyrimidine dimers (CPDs) were confirmed through immunofluorescence. In addition, hallmarks of apoptosis and G2/M phase cell cycle arrest were confirmed through flow cytometry analysis. Our findings suggest that MQ may damage DNA and produce DNA lesions which may induce differential biological responses in the skin on brief exposure to UVB and sunlight. PMID- 25034909 TI - [MUV researcher of the month]. PMID- 25034910 TI - Mitochondrial quality control and age-associated arterial stiffening. AB - Stiffening of large elastic arteries with age increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. We investigated the role of mitochondrial quality control (QC, i.e., mitophagy and biogenesis) in arterial stiffening with aging. In C57BL6 mice, aging was associated with impaired aortic expression of mitochondrial QC mediators, greater activation of the mitochondrial redox/stress sensor p66shc, elevated superoxide production and increased arterial stiffness-as indicated by ~25% higher aortic pulse wave velocity (aPWV). In old mice, supplementation with trehalose, a nutraceutical reported to enhance mitophagy, normalized mitochondrial QC markers, p66shc activation and superoxide production, and reduced aPWV and aortic collagen I (a structural protein that confers stiffness). In vitro experiments suggested that mitochondrial QC processes were enhanced in the aortas from old trehalose-treated mice, and in aortic rings studied ex vivo, both aging and treatment with the mitochondrial stressor rotenone were associated with increases in p66shc activation and intrinsic mechanical stiffness, whereas co-incubation with trehalose prevented these effects. Taken together, these findings suggest that mitochondrial stress/dysfunction as a result of impaired mitochondrial QC contributes to large elastic artery stiffening with age. Enhancing mitochondrial QC with agents such as trehalose may be a novel strategy for reducing age-associated arterial stiffness and CVD. PMID- 25034911 TI - Phase angle as bioelectrical marker to identify elderly patients at risk of sarcopenia. AB - Several markers have been associated with sarcopenia in the elderly, including bioelectrical indices. Phase angle (PhA) is an impedance parameter and it has been suggested as an indicator of cellular death. Thus, the relationship between PhA and muscle mass and strength was investigated in 207 consecutively elderly participants (mean age 76.2+/-6.7years) admitted for multidimensional geriatric evaluation. Muscle strength by grip strength using a hand-held dynamometer and muscle mass was measured by bioimpedentiometer. PhA was calculated directly with its arctangent (resistance/reactance*180 degrees /pi). Linear relationship among muscular mass and strength and with clinical and biochemical parameters, including PhA at uni- and multivariate analysis were performed. Linear regression analysis demonstrated that lower level of PhA is associated with reduction in grip strength (y=3.16+0.08x; r=0.49; p<0.001), and even more, with muscle mass (y=3.04+0.25x; r=0.60; p<0001). Multivariate analysis confirms these relationships (grip strength beta=0.245, p=0.031; muscular mass beta=0.623, p<0.01). Thus, PhA is inversely related to muscle mass and strength in elderly subjects and it may be considered a good bioelectrical marker to identify elderly patients at risk of sarcopenia. PMID- 25034913 TI - Afghanistan's health system: moving forward in challenging circumstances 2002 2013. PMID- 25034914 TI - Towards gender equality in health in Afghanistan. AB - The Afghanistan gender inequality index shows that 70% loss in development is due to the limited participation of women in the workforce, low education and poor women's health outcomes. However, since the fall of the Taliban regime in 2002, gender inequalities in health have improved. This paper will review factors that led to these improvements. The review draws upon information from various sources, including formative and applied research, surveys and existing information systems. The review showed gender differentials in morbidity, mortality and accessing and utilising health services. Health professionals have expressed inadequate medical knowledge and interpersonal skills to address sensitive issues, such as domestic, physical and sexual violence. Discussing sexuality and its impact on health remains taboo both within and outside of the medical profession. Strict cultural norms restrict a woman's autonomy to seek health care, choose a marriage partner and have control over her body, indicating a need to increase awareness about how harmful social practices adversely affect health. The policy review showed that the Ministry of Public Health has made a commitment to reducing gender inequity in health and developed a two-pronged action plan to improve health providers' skills in handling gender-sensitive issues and mass media campaigns to change social norms. PMID- 25034915 TI - Stiff by stress: operant LV diastolic stiffness assessed with pre-load stress echocardiography. PMID- 25034916 TI - CMR-guided targeting of gaps after initial pulmonary vein isolation. PMID- 25034917 TI - Mapping myocarditis: still searching for the north star. PMID- 25034918 TI - The sins of the fathers (and mothers) and the 2013 guidelines. PMID- 25034919 TI - Cardiovascular imaging utilization: boom or bust? PMID- 25034920 TI - Defining the natural history of uremic cardiomyopathy in chronic kidney disease: the role of cardiovascular magnetic resonance. AB - Chronic kidney disease (CKD) is an under-recognized, highly prevalent cardiovascular (CV) risk factor affecting 1 in 7 adults. Large epidemiological studies have clearly established a graded association between the severity of CKD and CV event rates. Although patients with end-stage renal disease who are undergoing dialysis are at greatest CV risk, the disease process is evident in the early stages of CKD with glomerular filtration rates as high as 75 ml/min/1.73 m(2). Indeed, these patients are at least 6 times more likely to die of CV disease than to reach end-stage CKD. Thus, the major impact of CKD on the population and the healthcare budget is not that of providing renal replacement therapy but the cost of death and disability from premature CV disease. Although end-stage CKD is characterized by a clustering of conventional atherosclerotic risk factors, it has little association with CV event rates. This is reflected in disproportionate levels of sudden cardiac death, heart failure, and stroke, rather than myocardial infarction. Thus it appears that nonatherosclerotic processes, including left ventricular hypertrophy and fibrosis, account for most of the excess CV risk. Over the past decade, the use of cardiac magnetic resonance in CKD has brought about an improved understanding of the adverse CV changes collectively known as uremic cardiomyopathy. The unique ability of cardiac magnetic resonance to provide a comprehensive noninvasive examination of cardiac structure and function, arterial function, myocardial tissue characterization (T1 mapping and inversion recovery imaging), and myocardial metabolic function (spectroscopy) is ideally suited to characterize the phenotype of CV disease in CKD and to provide insight into the mechanisms leading to uremic cardiomyopathy. Concerns relating to an association between gadolinium contrast agents and nephrogenic systemic fibrosis in dialysis recipients have led to the use of lower doses and lower-risk gadolinium agents that appear to minimize this risk. PMID- 25034921 TI - Screening and risk stratification of coronary artery disease in end-stage renal disease. AB - End-stage renal disease (ESRD) is a growing global health problem with major health and economic implications. Cardiovascular complication is the major cause of morbidity and mortality in this population. Clustering of traditional atherosclerotic risk factors, such as diabetes, systemic inflammation, and altered mineral metabolism, contributes to enhanced systemic atherosclerosis in patients with ESRD. Prevalence of obstructive coronary artery disease (CAD) on coronary angiography exceeds 50% in this population. Despite having extensive CAD and vascular disease, patients with ESRD often do not present with classic symptoms because of impaired exercise capacity and diabetes. Furthermore, clinical trial data are exceedingly lacking in this population, resulting in considerable clinical equipoise regarding the optimal approach to the identification and subsequent management of CAD in these patients. Traditional clinical screening tools, including conventional risk prediction models, are significantly limited in their predictive accuracy for cardiovascular events in patients with ESRD. Noninvasive cardiac stress imaging modalities, such as nuclear perfusion and echocardiography, have been shown to improve the traditional clinical model in identifying the presence of CAD. Furthermore, they add incremental prognostic information to angiographic data. Novel imaging techniques and biomarker assays hold significant promise in further improving the ability to identify and risk-stratify for CAD. This review focuses on the current understanding of the clinical risk profile of asymptomatic patients with ESRD with an emphasis on the strengths and limitations of various noninvasive cardiovascular imaging modalities, including the role of novel methods in refining risk prediction. In addition, issues and challenges pertaining to the optimal timing of initial risk assessment ("screening") and possible repeat screening ("surveillance") are addressed. We also summarize the current data on the approach to the patient with ESRD being evaluated for transplantation in the context of recent guidelines and position statements by various professional societies. PMID- 25034922 TI - Atherosclerotic versus nonatherosclerotic evaluation: the Yin and Yang of cardiovascular imaging in advanced chronic kidney disease. PMID- 25034923 TI - CMR in assessment of cardiac masses: primary benign tumors. PMID- 25034924 TI - 3D real-time TEE during pulmonary vein isolation in atrial fibrillation. PMID- 25034925 TI - Fatigue crack growth under pulsatile pressure and plaque rupture. PMID- 25034926 TI - Complexity of assessment and management of Tako-Tsubo cardiomyopathy. PMID- 25034927 TI - Reply: complexity of assessment and management of Tako-Tsubo cardiomyopathy. PMID- 25034928 TI - What truly causes the adverse outcome in Tako-Tsubo cardiomyopathy? PMID- 25034929 TI - Reply: what truly causes the adverse outcome in tako-tsubo cardiomyopathy? PMID- 25034930 TI - An unfolding view of imaging: when perception becomes unreal! PMID- 25034931 TI - Current and future role of neoadjuvant therapy for breast cancer. AB - Neoadjuvant systemic chemotherapy is a possible therapeutic approach for the treatment of locally advanced operable, primarily non-operable or inflammatory breast cancer. Neoadjuvant systemic chemotherapy is an option for breast cancer patients who would require adjuvant chemotherapy otherwise based on clinical and histological examination and imaging. The use of neoadjuvant systemic therapy in operable breast cancer is currently increasing because of its advantages that include higher rates of breast conserving surgery and the possibility of measuring early in-vivo response to systemic treatment. The timing of axillary sentinel lymph node diagnosis (i.e. before or after neoadjuvant chemotherapy) is critical in that it may influence the likelihood of axillary preservation. It is not yet clear if neoadjuvant therapy might improve outcomes in certain subgroups of breast cancer patients. Neoadjuvant treatment modalities require a close collaboration between oncology professionals, including surgeons, gynecologists, medical oncologists, radiation oncologists, radiologists and pathologists. The most important parameter for treatment success and improved overall survival is the achievement of a pathologic complete response (pCR), although the role of pCR in patients with luminal A like tumours might be less informative. Identification of patient subgroups with high pCR rates may allow less invasive surgical or radiological interventions. Patients not achieving a pCR may be candidates for postoperative clinical trials exploring novel systemic treatments. PMID- 25034933 TI - Position shifts and volume changes of pelvic and para-aortic nodes during IMRT for patients with cervical cancer. AB - BACKGROUND AND PURPOSE: To evaluate volume changes and position shifts and their contribution to treatment margins of pelvic and para-aortic lymph nodes during Intensity Modulated Radiation Therapy (IMRT) for advanced cervical cancer. MATERIALS AND METHODS: Seventeen patients with visible nodes on MR images underwent T2-weighted MR scans before and weekly during the course of IMRT. Thirty-nine pelvic and para-aortic nodes were delineated on all scans. Margins accommodating for volume and position changes were taken from the boundaries of the nodal volumes in the six main directions. RESULTS: Nodal volume regression from the pre-treatment situation to week 4 was 58% on average (range: 11.7% increase to 100% decrease). Nodal volumes partly increased between the pre treatment scans and the scans in weeks 1-3, but in week 4 all nodes except one had regressed. Around the nodal volumes manually derived ITV margins accounting for volume changes and position shifts of 7.0, 4.0, 7.0, 8.0, 7.0 and 9.0mm to the medial, lateral, anterior, posterior, superior and inferior directions were needed to cover 95% of all nodes. CONCLUSIONS: We used weekly MR scans to derive inhomogeneous margins that accommodate for nodal volume and position changes during treatment. These margins should be taken into consideration when planning external beam radiotherapy (EBRT) boosts, especially for highly conformal boosting techniques. PMID- 25034932 TI - Quality of life among a population-based cohort of older patients with breast cancer. AB - BACKGROUND: Growing numbers of older women receive adjuvant breast cancer therapies, but little is known about the long-term effects of current therapies upon health-related quality of life outside of clinical trials. METHODS: A population-based cohort of postmenopausal women with incident breast cancer aged sixty-five and older was identified from Medicare claims from four states and followed over five years. General health-related quality of life (HRQOL) was assessed using the Medical Outcomes Study SF-12 Health Survey, and breast cancer related HRQOL was assessed using the breast cancer subscale of the functional assessment of cancer therapy (FACT-B BCS). The association of HRQOL with sociodemographic variables, comorbidity, and breast cancer variables (stage, treatments, and treatment sequelae) was examined in longitudinal models. RESULTS: Among the 3083 older breast cancer survivors, general HRQOL as measured by SF-12 mental and physical component scores was similar to norms for non-cancer populations, and remained stable throughout follow-up. Breast cancer treatments, including surgery and radiation, adjuvant hormonal therapy, and cytotoxic chemotherapy were not associated with worsened general health scores. A similar pattern was seen for breast cancer-related HRQOL scores, except that chemotherapy was associated with slightly worse scores. Lymphedema occurred in 17% of the cohort, and was strongly associated with all measures of HRQOL. Reductions in general HRQOL with lymphedema development were larger than those with an age increase of 10 years. CONCLUSIONS: There is little association of breast cancer treatment with HRQOL in older breast cancer patients followed for up to five years, but the development of lymphedema is associated with substantial reductions in HRQOL. PMID- 25034934 TI - FTY720 attenuates hypoxia-reoxygenation-induced apoptosis in cardiomyocytes. AB - FTY720, sphingosine 1 phosphate (S1P) receptor agonist, is a potent immunosuppressive agent. Numerous studies have documented a relationship between S1P and cardioprotection. We therefore hypothesized that a S1P analogue FTY720 would attenuate hypoxia/reoxygenation (H/R) induced cadiomyocyte apoptosis. H9C2 cardiomyocytes were employed to establish an in vitro model of H/R. Cells were treated or not with different doses of FTY720. Cell viability was measured by flow cytometry and TUNEL staining. Western blot was used to analyze downstream signaling pathway. We observed that FTY720 inhibits the expression of cleaved caspase-3 and activates both AKT and ERK1/2 pathways. AKT pathway can be blocked by MEK kinase inhibitor PD98059. ERK1/2 pathway can be blocked by the phosphoinositide-3 kinase inhibitor wortmannin. AKT and ERK1/2 activation can also be inhibited by S1P1/3 receptor antagonist VPC23019, Gi antagonist PTX. The protein levels of TNF-alpha and IL1beta were upregulated during hypoxia/reoxygenation and were attenuated by FTY720. We conclude that FTY720, via its cargo of S1P, can protect cardiomyocytes against hypoxia/reoxygenation injury. This effect is achieved by inhibiting caspase-3 expression, inflammatory cytokine levels and activating AKT and ERK1/2 signaling pathways. The prosurvival signal activation is dependent on S1P1, 3 subtype receptors and Gi protein. PMID- 25034935 TI - [Epidural anaesthesia: Simulated intravascular test dose with S(+) ketamine, lidocaine and adrenaline. A prospective, randomized, double blind and placebo controlled study]. AB - OBJECTIVE: The use of a test dose in epidural anaesthesia is a safety recommendation. However specificity and sensitivity of the drugs used with this indication have been not conclusive. The main objective of this study was to compare the effectiveness and the adverse effects of a simulated intravascular test dose of adrenaline, lidocaine and S(+)-ketamine. MATERIAL AND METHODS: A prospective, randomized, double blinded, placebo controlled study was designed. ASA I patients scheduled for elective surgery were included. These were randomized to the following study groups: S(+)-ketamine 0.5 mg.kg-1 (S+K group), 5% lidocaine 1.5 mg.kg-1 (L5% group), adrenaline 15MUg (ADR group), and physiological saline 3 ml (SF group; control group). An evaluation was made during the first 15 minutes after the study drug was administered. Variables including heart rate (HR) systolic and diastolic blood pressure (sBP and dBP), mean arterial pressure (MAP), and SpO2 were recorded at 0 min (baseline) and at 2, 5, 8, 10 and 15 minutes after drug injection. An increase of at least 20 beats per minute (bpm) in relation to the baseline measurement was considered a positive result, as was an increase sBP >15 mmHg. The clinical effects described as related to iv injection of the study drugs recorded were: sedation-hypnosis, dizziness, nystagmus, metallic taste perception, perioral or facial paresthesias, tinnitus, as well as any other effect the patients mentioned. Sensitivity and specificity were calculated as was the percent increase in the parameters in order to see if these were clinically useful. RESULTS: A total of 80 patients, 20 per group, were included. The sBP, dBP, and MAP were significantly raised at the 2, 5, 8 and 10 minutes measurements in the S(+)K group compared to the rest of the groups (P<.05), as well as HR in the 2, 5, 8, 10 and 15 minute measurements in the S(+)K compared to the rest of the groups (P<.05). Sensitivity and specificity were high, and significant in the S(+)K group from minute 2 to minute 8 compared with the placebo group, as well as percentage points differences in the same interval. There were significant differences in the incidence of sedation-hypnosis, nystagmus and dizziness, which were more frequent in the S(+)K group. There were no differences in the incidence of metallic taste, perioral and facial paresthesias or tinnitus. The effects in the S(+)K group always occurred before minute 5 after drug injection. CONCLUSION: Both lidocaine an adrenaline at the scheduled doses showed low sensitivity and specificity as a simulated iv epidural test dose. S(+)-ketamine could be a feasible marker after accidental iv injection during epidural anaesthesia or analgesia. PMID- 25034936 TI - [Giant cervical mass. An anesthetic challenge]. PMID- 25034937 TI - [McArdle disease or glycogen storage disease type v: Should it affect anaesthetic management?]. AB - McArdle disease is a metabolic myopathy that can may lead to severe perioperative problems. A case is reported of a woman with a history of McArdle disease, who was scheduled for a mastectomy. An understanding of the physiology and pathology, and the application of appropriate preventive measures can avoid complications. A overview of the complications and the management are described. PMID- 25034938 TI - [Iliac aneurysm rupture during preconditioning with levosimendan for coronary artery graft, it was levosimendan the most influencing factor?]. PMID- 25034939 TI - Identification of collaborative driver pathways in breast cancer. AB - BACKGROUND: An important challenge in cancer biology is to computationally screen mutations in cancer cells, separating those that might drive cancer initiation and progression, from the much larger number of bystanders. Since mutations are large in number and diverse in type, the frequency of any particular mutation pattern across a set of samples is low. This makes statistical distinctions and reproducibility across different populations difficult to establish. RESULTS: In this paper we develop a novel method that promises to partially ameliorate these problems. The basic idea is although mutations are highly heterogeneous and vary from one sample to another, the processes that are disrupted when cells undergo transformation tend to be invariant across a population for a particular cancer or cancer subtype. Specifically, we focus on finding mutated pathway-groups that are invariant across samples of breast cancer subtypes. The identification of informative pathway-groups consists of two steps. The first is identification of pathways significantly enriched in genes containing non-synonymous mutations; the second uses pathways so identified to find groups that are functionally related in the largest number of samples. An application to 4 subtypes of breast cancer identified pathway-groups that can highly explicate a particular subtype and rich in processes associated with transformation. CONCLUSIONS: In contrast to previous methods that identify pathways across a set of samples without any further validation, we show that mutated pathway-groups can be found in each breast cancer subtype and that such groups are invariant across the majority of samples. The algorithm is available at http://www.visantnet.org/misi/MUDPAC.zip. PMID- 25034940 TI - Medical pluralism predicts non-ART use among parents in need of ART: a community survey in KwaZulu-Natal, South Africa. AB - Despite documented common use of traditional healers and efforts to scale up antiretroviral treatment (ART) in sub-Saharan Africa, evidence on whether medical pluralism predicts ART use is inconclusive and restricted to clinic settings. This study quantitatively assesses whether medical pluralism predicts ART use among parents in need of ART in South Africa. 2,477 parents or primary caregivers of children were interviewed in HIV-endemic communities of KwaZulu-Natal. Analysis used multiple logistic regression on a subsample of 435 respondents in need of ART, who reported either medical pluralism (24.6 %) or exclusive public healthcare use (75.4 %). Of 435 parents needing ART, 60.7 % reported ART use. Medical pluralism emerged as a persistent negative predictor of ART utilization among those needing it (AOR [95 % CI] = .556 [.344 - .899], p = .017). Use of traditional healthcare services by those who need ART may act as a barrier to treatment access. Effective intersectoral collaboration at community level is urgently needed. PMID- 25034941 TI - Testicular development of male mice offsprings exposed to acrylamide and alcohol during the gestation and lactation period. AB - Acrylamide (Ac) in the foods and alcohol (Al) in the drinks are unavoidable. Several previous studies demonstrated that these substances which are taken into the body via diet may cause adverse effects in the cells. However, there is no study about how Ac and Al may affect the male reproductive system of the offspring when consumed by the mother during pregnancy and lactation. For this purpose, sexual development in male mice was evaluated after intake of 14 mg/kg Ac and 2 g/kg Al from gestation day 6 to postnatal day (PND) 21. The weight of the offspring was reduced at birth and PND 21 for those exposed to Ac and/or Al. The gonadosomatic index of male offsprings was reduced except for the Ac-treated lactation group. Both substances induced multinuclear giant cells, degenerative cells, atrophic tubules, and maturation-arrested tubules, while decreased Leydig, Sertoli, and spermatogenic cell numbers. Lipid peroxidation level and superoxide dismutase enzyme activity increased in both Al-treated and Ac and Al-treated groups. There was only reduction in the catalase activity during the gestation and lactation periods. These findings suggest that consumption of Ac together with Al may induce impairments on testicular spermatogenesis in male offsprings. PMID- 25034942 TI - Evaluation of the reproductive toxicity of naproxen sodium and meloxicam in male rats. AB - Nonsteroidal anti-inflammatory drugs that are cyclooxygenase (COX) enzyme inhibitors have generally been used in short-term pain management and also to treat inflammation chronically. It is known that COX enzyme and prostaglandins play important roles in the regulation of reproductive functions in females. However, there are relatively few studies for the male reproductive system, and the results of these studies are contradictory. In this study, sperm count and motility, COX-1, COX-2, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and prostaglandin F2alpha (PGF2alpha) levels in testis tissue, plasma follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, and histopathological examination of testis tissue were evaluated after naproxen sodium and meloxicam administration in male rats. Also, testis superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) levels were measured to investigate the oxidation status. According to our results, sperm count and motility were significantly decreased in treatment groups. Plasma hormone levels did not show any statistical differences between the groups. COX-1, PGE2, and PGF2alpha levels were significantly decreased, while the decreases in COX-2 and PGE1 levels did not show any significance statistically. Testis SOD, catalase, GPx, and GSH levels were decreased significantly. According to the results of histopathological examination, damage in seminiferous tubules, where spermatogenesis developed, was observed. In conclusion, naproxen sodium and meloxicam decreased the sperm count and motility and also induced the damage of seminiferous tubules as a direct effect without affecting plasma hormone levels in our study. The mechanism of the reproductive toxicity induced by these agents may be based on the inhibition of prostaglandin synthesis and the induction of oxidative stress can be emphasized as a secondary factor. PMID- 25034943 TI - A cohort study using pulmonary function tests and x-ray examination in toner handling workers: cross-sectional and longitudinal analyses from 2003 to 2008. AB - OBJECTIVES: This study uses pulmonary function tests and chest x-ray examinations to examine the relationship between toner-handling work and its health effects. METHODS: The subjects were 1504 male workers in a Japanese toner and photocopier manufacturing company, in the age range from 19 to 50 years in 2003. Personal exposure measurements, pulmonary function tests, chest x-ray examinations, biomarker measurements, and a questionnaire about respiratory symptoms were conducted. The present study reports the results of pulmonary function tests and chest x-ray examinations conducted in the subjects, which includes a cross sectional study on the toner handling and non-handling workers and a longitudinal study from 2003 to 2008. RESULTS: Few significant findings were suspected to be caused by toner exposure found in pulmonary function indices in both the cross sectional and longitudinal studies. Any obvious fibrotic findings in chest x-ray findings related to the toner exposure could not be found out. CONCLUSION: No evidence of adverse effects on pulmonary function indices and chest x-rays was present in the toner-handling workers as compared to the nonspecifically exposed workers. Although the toner exposure concentration is quite low in the current well-controlled working environment, even among the toner-handling workers, we would like to continue this study in the future to verify the toner exposure health effects. PMID- 25034944 TI - Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells. AB - Down's syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug. PMID- 25034945 TI - Identification of novel biomarker candidates for the immunohistochemical diagnosis of cholangiocellular carcinoma. AB - The aim of this study was the identification of novel biomarker candidates for the diagnosis of cholangiocellular carcinoma (CCC) and its immunohistochemical differentiation from benign liver and bile duct cells. CCC is a primary cancer that arises from the epithelial cells of bile ducts and is characterized by high mortality rates due to its late clinical presentation and limited treatment options. Tumorous tissue and adjacent non-tumorous liver tissue from eight CCC patients were analyzed by means of two-dimensional differential in-gel electrophoresis and mass-spectrometry-based label-free proteomics. After data analysis and statistical evaluation of the proteins found to be differentially regulated between the two experimental groups (fold change >= 1.5; p value <= 0.05), 14 candidate proteins were chosen for determination of the cell-type specific expression profile via immunohistochemistry in a cohort of 14 patients. This confirmed the significant up-regulation of serpin H1, 14-3-3 protein sigma, and stress-induced phosphoprotein 1 in tumorous cholangiocytes relative to normal hepatocytes and non-tumorous cholangiocytes, whereas some proteins were detectable specifically in hepatocytes. Because stress-induced phosphoprotein 1 exhibited both sensitivity and specificity of 100%, an immunohistochemical verification examining tissue sections of 60 CCC patients was performed. This resulted in a specificity of 98% and a sensitivity of 64%. We therefore conclude that this protein should be considered as a potential diagnostic biomarker for CCC in an immunohistochemical application, possibly in combination with other candidates from this study in the form of a biomarker panel. This could improve the differential diagnosis of CCC and benign bile duct diseases, as well as metastatic malignancies in the liver. PMID- 25034946 TI - Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. AB - BACKGROUND: Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. METHODS: In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. RESULTS: In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma. CONCLUSIONS: These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis. PMID- 25034947 TI - An autism case history to review the systematic analysis of large-scale data to refine the diagnosis and treatment of neuropsychiatric disorders. AB - Analysis of large-scale systems of biomedical data provides a perspective on neuropsychiatric disease that may be otherwise elusive. Described here is an analysis of three large-scale systems of data from autism spectrum disorder (ASD) and of ASD research as an exemplar of what might be achieved from study of such data. First is the biomedical literature that highlights the fact that there are two very successful but quite separate research communities and findings pertaining to genetics and the molecular biology of ASD. There are those studies positing ASD causes that are related to immunological dysregulation and those related to disorders of synaptic function and neuronal connectivity. Second is the emerging use of electronic health record systems and other large clinical databases that allow the data acquired during the course of care to be used to identify distinct subpopulations, clinical trajectories, and pathophysiological substructures of ASD. These systems reveal subsets of patients with distinct clinical trajectories, some of which are immunologically related and others which follow pathologies conventionally thought of as neurological. The third is genome wide genomic and transcriptomic analyses which show molecular pathways that overlap neurological and immunological mechanisms. The convergence of these three large-scale data perspectives illustrates the scientific leverage that large scale data analyses can provide in guiding researchers in an approach to the diagnosis of neuropsychiatric disease that is inclusive and comprehensive. PMID- 25034948 TI - Motor Improvement and Emotional Stabilization in Patients With Tourette Syndrome After Deep Brain Stimulation of the Ventral Anterior and Ventrolateral Motor Part of the Thalamus. AB - BACKGROUND: Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS. METHODS: In this prospective open label trial, eight patients (three female, five male) 19-56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset. RESULTS: Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome. CONCLUSIONS: Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS. PMID- 25034949 TI - Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets. AB - BACKGROUND: MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs. METHODS: Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11.2 CNVs. We also performed a gene-set enrichment analysis of the predicted miRNA target genes. RESULTS: The schizophrenia group was enriched for the proportion of individuals with a rare CNV overlapping a miRNA (3.29-fold increase over comparison subjects, p < .0001). The presence of a rare CNV overlapping a miRNA remained a significant predictor of schizophrenia case status (p = .0072) in a multivariate logistic regression model correcting for total CNV size. In contrast, comparable analyses correcting for CNV size showed no enrichment of rare CNVs overlapping protein-coding genes. A gene-set enrichment analysis indicated that predicted target genes of recurrent CNV-overlapped miRNAs in schizophrenia may be functionally enriched for neurodevelopmental processes, including axonogenesis and neuron projection development. Predicted gene targets driving these results included CAPRIN1, NEDD4, NTRK2, PAK2, RHOA, and SYNGAP1. CONCLUSIONS: These data are the first to demonstrate a genome-wide role for CNVs overlapping miRNAs in the genetic risk for schizophrenia. The results provide support for an expanded multihit model of causation, with potential implications for miRNA-based therapeutics. PMID- 25034950 TI - Daily stressors, past depression, and metabolic responses to high-fat meals: a novel path to obesity. AB - BACKGROUND: Depression and stress promote obesity. This study addressed the impact of daily stressors and a history of major depressive disorder (MDD) on obesity-related metabolic responses to high-fat meals. METHODS: This double blind, randomized, crossover study included serial assessments of resting energy expenditure (REE), fat and carbohydrate oxidation, triglycerides, cortisol, insulin, and glucose before and after two high-fat meals. During two separate 9.5 hour admissions, 58 healthy women (38 breast cancer survivors and 20 demographically similar control subjects), mean age 53.1 years, received either a high saturated fat meal or a high oleic sunflower oil meal. Prior day stressors were assessed by the Daily Inventory of Stressful Events. RESULTS: Greater numbers of stressors were associated with lower postmeal REE (p = .008), lower fat oxidation (p = .04), and higher insulin (p = .01), with nonsignificant effects for cortisol and glucose. Women with prior MDD had higher cortisol (p = .008) and higher fat oxidation (p = .004), without significant effects for REE, insulin, and glucose. Women with a depression history who also had more stressors had a higher peak triglyceride response than other participants (p = .01). The only difference between meals was higher postprandial glucose following sunflower oil compared with saturated fat (p = .03). CONCLUSIONS: The cumulative 6-hour difference between one prior day stressor and no stressors translates into 435 kJ, a difference that could add almost 11 pounds per year. These findings illustrate how stress and depression alter metabolic responses to high-fat meals in ways that promote obesity. PMID- 25034951 TI - Reply to: Serum zinc and the risk of depression in men: observations from a 20 year follow-up study. PMID- 25034952 TI - Serum zinc and the risk of depression in men: observations from a 20-year follow up study. PMID- 25034953 TI - The relationship between quality of life and spirituality, religiousness, and personal beliefs of medical students. AB - OBJECTIVE: This study investigated the effects of spirituality, religiousness, and personal beliefs on the quality of life (QOL) of medical students affiliated with a religious faith and those without affiliation. METHODS: Using a cross sectional design, 275 medical students (78 % response rate) in their fourth and fifth year of study completed the WHOQOL-BREF quality of life instrument and the WHOQOL-SRPB module for spirituality, religiousness, and personal beliefs. RESULTS: For religious students, a larger range of characteristics of existential beliefs were positively related to quality of life. For all students, hope and optimism and meaning of life predicted higher scores on psychological. CONCLUSIONS: For religious and nonreligious medical students, reduced meaning in life and hope were the strongest indicators of psychological distress. Interventions to improve the mental well-being of medical students may be more effective if aimed at teaching students how to find meaning and purpose in their lives and how to foster an enduring sense of hope and optimism. PMID- 25034954 TI - Medfest: the effect of a national medical film festival on attendees' attitudes to psychiatry and psychiatrists and medical students' attitudes to a career in psychiatry. AB - OBJECTIVE: The authors proposed that a national film festival organized by psychiatrists could change attendees' views toward psychiatry and psychiatrists positively and increase the numbers of medical students considering psychiatry as a career. METHODS: Medfest held events at nine UK universities in 2011. The program consisted of short films (The Family Doctor, Shadowscan, Beards & Bow Ties) and panelist discussions. Data were gathered using an anonymous "before and after" questionnaire. RESULTS: A total of 450 attendees across all sites returned 377 feedback forms (84 % response rate). Views of psychiatry and psychiatrists changed for the better for 42 % (98 % of those who answered the question) and 40 % (96 % of those who answered the question) of all respondents, respectively. Respondents' views were significantly more likely to change for the better than for the worse toward both psychiatry (p < 0.001) and psychiatrists (p < 0.001). Post-event, 46 % of the 232 medical students that attended were more likely to consider a career in psychiatry (48 % of those who answered the question). CONCLUSIONS: A multicenter film festival organized by psychiatrists was associated with more positive attitudes to psychiatry and psychiatrists and an increase in students considering psychiatry as a career. The festival is now an annual event, continuing to expand. PMID- 25034955 TI - Efficacy of burnout interventions in the medical education pipeline. AB - OBJECTIVE: Little is known about the efficacy of current interventions to mitigate burnout among medical students and residents, despite its association with mood disorders, absenteeism, low job satisfaction, and medical errors. This review summarizes the efficacy data of burnout interventions and how each modality is used. METHOD: OVID-SP Medline, Google Scholar and PsychINFO were searched for combinations of medical subject headings (MeSH) terms: premedical students, medical students, internships, intern, medical graduate, clinical clerkship, and residents in combination with a keyword group of burnout, professional burnout, suicide, attempted suicide, and prevention. Studies with data on the efficacy from burnout prevention programs were included for review. RESULTS: Nineteen studies were selected for inclusion in this review. Eleven different types of interventions and combinations of interventions were used. There were six studies on the impact of the 2003 duty-hour restrictions by the Accreditation Council for Graduate Medical Education on burnout. Other approaches included self-development groups, conversion to a pass-fail grading system and training in mindfulness, communication, and stress management. Half of the intervention approaches had at least one study demonstrating benefit in reducing burnout. Self-development groups, the Respiratory One Method for relaxation, and conversion to a pass-fail grading system appear to reduce burnout. The burnout data on mindfulness training and the 2003 resident duty-hour restrictions are mixed. There were no studies available on burnout among premedical students or suicide prevention among medical students or residents. CONCLUSIONS: There is a growing body of evidence-based interventions to mitigate burnout which can be used in the development of future programs. More research is needed to identify and intervene against burnout earlier in the medical education pipeline, including at the undergraduate level. PMID- 25034956 TI - The Korean version of the Lasater Clinical Judgment Rubric: a validation study. AB - BACKGROUND: The scarcity of reliable and valid evaluation tools targeting nursing students' learning outcomes including clinical judgment was identified as one of the barriers in advancing nursing knowledge and skills. However, few studies have assessed the validity and reliability of these tools. OBJECTIVES: Therefore, this study aimed to validate the Korean language version of the Lasater Clinical Judgment Rubric (LCJR), a clinical judgment tool currently used in nursing simulation research and English speaking nursing societies. DESIGN, SETTINGS, PARTICIPANTS: This was an observational study in which a cross-sectional designed survey was used to validate the Korean version of the LCJR (K-LCJR) in three universities in Seoul, South Korea with one hundred fifty two senior nursing students. METHODS: All participants completed the established simulation coursework as well as the regular clinical rotation on pediatric nursing along with their assigned team. Students evaluated their clinical judgment from their simulation performance using the K-LCJR after completing a simulation session using high-fidelity simulators and standardized patients (SP). Audio-video enhancing equipment for the student's individual and group reflection was used. RESULTS: Item analysis of K-LCJR results showed a Cronbach's alpha coefficient of between .897 and .909 and the overall internal consistency reliability coefficient was .910. In the confirmatory factor analysis, the four-factor K-LCJR composed by noticing, interpreting, responding, and reflecting was confirmed with a very good model fit to data, which demonstrated good construct validity. CONCLUSIONS: The K-LCJR is a reliable and valid instrument for measuring clinical judgment in nursing students in Korea. PMID- 25034957 TI - Usefulness of lung ultrasound in the diagnosis of community-acquired pneumonia in children. AB - BACKGROUND: Pneumonia is a life-threatening disease in children. With the current lack of universal diagnostic criteria, the diagnosis is usually made on clinical manifestations and findings from chest radiographs. Ultrasonography has recently been applied to the detection of pulmonary diseases. However, few data have been published showing its effectiveness in detecting pneumonia in children. The objective of this study was to determine the power of lung ultrasonography (LUS) for the diagnosis of pneumonia in children. METHODS: This retrospective study was carried out by reviewing medical records. Patients admitted to a pediatric ward with a diagnosis of pneumonia from June 1, 2010 to December 31, 2012 were enrolled in this study. Personal information, laboratory data, characteristics on LUS scan, and the results of chest radiography and LUS were collected. We compared the detection rate of pneumonia by chest radiography and LUS. LUS scans were followed up in 23 patients during the progression of their disease. RESULTS: A total of 163 patients was enrolled. Chest radiography was able to detect pneumonia in 152 patients, whereas LUS detected pneumonia in 159 patients. In LUS, the positive rates of the comet-tail sign, air bronchograms, fluid bronchograms, vascular pattern within the consolidation, and pleural effusion were 50.9%, 93.7%, 20.1%, and 28.9%, respectively. During follow up, the average size of the pneumonia patch in 23 patients decreased from 10.9 +/- 8.7 cm(2) to 5.5 +/- 8.2 cm(2), and finally to 2 +/- 1.9 cm(2) on Day 1, Days 3-5 and Days 7 14, respectively. CONCLUSION: LUS is a sensitive diagnostic tool with which to identify pneumonia in children. It is also useful in following up the progress of pneumonia. We suggest that LUS is a complementary tool to chest radiography in the diagnosis of pneumonia in children and that the follow up of pneumonia by LUS can reduce the exposure of children to ionizing radiation. PMID- 25034958 TI - Moderating effects of brooding and co-rumination on the relationship between stress and depressive symptoms in early adolescence: a multi-wave study. AB - The current study investigated brooding and co-rumination as moderators of the relationship between interpersonal and noninterpersonal stress and depressive symptom trajectories. The sample consisted of 368 early adolescents ages 9 to 15 (M = 11.72, 63 % female) who completed self-report measures of brooding, co rumination, stress, and depressive symptoms at baseline with follow-up assessments of stress and depressive symptoms at 3, 8, and 12 months post baseline. Data were analyzed using multi-level modeling. Results showed that the association between interpersonal stress and depressive symptoms was stronger for adolescents high on brooding, compared to adolescents low on brooding. Sex moderated a co-rumination * stress interaction, with girls high on co-rumination and boys low on co-rumination reporting the highest levels of depressive symptoms when faced with interpersonal stress across the 1-year study period. These findings shed light on pathways to depressive symptoms in early adolescence and suggest that adolescent boys and girls may differ in these pathways. PMID- 25034959 TI - A new description of scapulothoracic motion during arm movements in healthy subjects. AB - The participation of scapula motion in arm movement is clinically well known and recent three dimensional (3D) analyses using kinematic techniques have confirmed its importance. Scapular motion relative to the thorax has a theoretical maximum of 6 degrees of freedom (DoF), resulting from rotations at both clavicular joints (3 rotational DoF each). However, most recent kinematic studies have only analysed the 3D rotations of the scapula relative to the thorax. In the present study, the 3D translations of the barycentre of the scapula were considered in order to complete the description of movement at the shoulder complex. Eight healthy subjects performed arm elevation in the sagittal and frontal planes, simulated activities of daily living (hair combing and back washing) and maximum voluntary scapula movement (forward and backward rolling). Measurements were recorded using a 6 DoF electromagnetic device and the acromial method of analysis was used. The results showed that 3D scapular rotations and translation of its barycentre were functionally consistent for all tasks. A principal component analysis (PCA) yielded three factors, explaining 97.6% of the variance. The first two factors (protraction and shrug, according to clinical descriptions) combined rotations and translations, consistent with the hypothesis that the scapula rolls over the curved thoracic surface. The third factor related to lateral-medial rotation, thus representing rotation in the plane tangential to the thorax. The PCA suggested that scapular motion can be described using these 3 DoF. This should be studied in a larger group of individuals, including patients with pathological conditions. PMID- 25034960 TI - Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. AB - Because the efficacy of donor lymphocyte infusion (DLI) for acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) remains uncertain, especially in the Asian population, a nationwide registry study was retrospectively performed by the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation to identify the factors affecting the patient survival after DLI. Among 143 adult AML patients who received DLI for the treatment of first hematological relapse after HSCT, the overall survival rates at 1 year, 2 years, and 5 years were 32% +/- 4%, 17% +/- 3%, and 7% +/- 3%, respectively. Complete remission (CR) at the time of DLI, which was obtained in 8% of the patients, was the strongest predictive factor for survival after DLI. Therefore, long-term survival after DLI was achieved almost exclusively in patients who successfully achieved a CR before DLI, indicating the limited efficacy of DLI in a minority of patients. PMID- 25034961 TI - Does the hematopoietic cell transplantation specific comorbidity index (HCT-CI) predict transplantation outcomes? A prospective multicenter validation study of the Kanto Study Group for Cell Therapy. AB - Recent advances in allogeneic hematopoietic stem cell transplantation have led to increasing use of this modality in older patients who tend to have been more heavily pretreated and have more comorbidities. Thus, the evaluation of comorbidity is of increasing importance to more precisely assess the benefits and risks of the transplantation procedure. Researchers from Seattle developed the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which was associated with the risk of mortality in several retrospective studies. However, its clinical utility has not been extensively documented in prospective studies. The aim of the present study was to evaluate the utility of the HCT-CI prospectively in a multicenter setting. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years were 59% and 20%, respectively (n = 243). We found that the HCT-CI in its original scale failed to predict OS and NRM in this set of patients. Thus, we applied a flexible HCT-CI risk scoring system (restratifying scores from 0 to 3 to indicate low risk, and scores of 4 or higher as high-risk). The flexible HCT-CI was found to predict 2-year NRM and OS better than the original HCT-CI (NRM: P = .01, OS: P = .003). In subgroup analysis, we evaluated the usefulness of the original HCT-CI for patients excluding those who received cord blood transplantation (n = 186). Both 2-year OS and 2-year NRM were not significantly different according to the original HCT-CI (P = .304, P = .996), but with the flexible HCT-CI, there were significant differences in 2-year OS and 2-year NRM (P = .005 and P = .005, respectively). Multivariate analysis identified age >50, performance status (PS) <90, donor type (HLA mismatched/unrelated donor), and the flexible HCT-CI >=4 as significant predictors for worse OS at 2 years. However, the flexible HCT-CI did not remain a significant predictor for NRM at 2 years in multivariate analysis, whereas age, PS, and donor type did. The HCT-CI did not consistently predict both NRM and OS, but it still can be a useful tool in combination with other factors, such as PS and age. Furthermore, the HCT-CI, although potentially useful for capturing pretransplantation comorbidity and risk assessment, may need further validation before its adoption for routine clinical use. PMID- 25034962 TI - Neurotrauma burden in a tropical urban conurbation level I trauma centre. AB - BACKGROUND: Neurotrauma is a preventable public health problem whose quantum is said to be increasing in Third-World countries. This evaluation was performed to collate data which is needed to guide in designing, implementing, and evaluating public health prevention programmes with respect to neurotrauma. METHODS: A single institution prospective study was carried out. Data was collected at the surgical emergency (SE) room over a year period (1st October 2012-30th September 2013). These included patients' demographics, cause of injury, region of the body involved, Glasgow coma scale score, and outcome. The patients were further divided into patients with traumatic brain (TBI) and spine injury (TSI). Analysis of the variables was by simple proportion, percentages, Chi-square and analysis of variance was used to determine the differences between group means. A probability (p) of less than 0.05 was considered statistically significant. RESULTS: A total of 2149 neurotrauma cases (38.8%) out of a total of 5541 surgical trauma cases were seen within the study period at our SE unit. Of the neurotrauma cases, 1621 were males, giving a male:female ratio of 3.1:1. The mean age was 31 years (median 30 years). The most common age group was 20-29 (29.6%) and 30-39 years (29.6%). Assault was the cause of neurotrauma in 903 patients (42%), closely followed by road traffic injury in 744 patients (34.6%). Brain and spine injury separately occurred in 93.2% and 5.3% of cases, respectively. Five hundred patients (23.3%) were resuscitated and referred to other centres due to lack of bed space. Forty (1.9%) patients were dead on arrival, while twenty-six (1.2%) died while on treatment at the emergency room. CONCLUSION: Neurotrauma is one of the most common form of trauma at our surgical emergency. Assault and road traffic injury (RTI) were the most common cause of TBI and TSI respectively, with RTI being the most common cause of moderate and severe TBI. The incidence and aetiology of TBI varies according to age and gender. PMID- 25034963 TI - Protein imprinting in polyacrylamide-based gels. AB - Protein imprinting in hydrogels is a method to produce materials capable of selective recognition and capture of a target protein. Here we report on the imprinting of fluorescently-labeled maltose binding protein (MBP) in acrylamide (AAm)/N-isopropylacrylamide (NIPAm) hydrogels. The targeting efficiency and selectivity of protein recognition is usually characterized by the imprinting factor, which in the simplest case is the ratio of protein uptake in an imprinted film divided by the uptake by the corresponding non-imprinted film. Our objective in this work is to study the dynamics of protein binding and elution in imprinted and non-imprinted films to elucidate the processes that control protein recognition. Protein elution from imprinted and non-imprinted films suggests that imprinting results in sites with a distribution of binding energies, and that only a relatively small fraction of these sites exhibit strong binding. PMID- 25034964 TI - Inhibition of islet amyloid polypeptide fibril formation by selenium-containing phycocyanin and prevention of beta cell apoptosis. AB - Human islet amyloid polypeptide (hIAPP) fibril is the major constituent of amyloid deposits in pancreatic islets of type 2 diabetes. Misfolding and hIAPP fibril formation are thought to be important in the pathogenesis of diabetes. Studies have showed that selenium-containing phycocyanin (Se-PC) inhibited the fibrillation of hIAPP to form nanoscale particles, which is mainly by interfering with the combination between hIAPP. Small nanoscale oligomers tended to grow into larger nanoparticles and the size of nanoparticles increased with the incubation time. By interfering with the fibrillation of hIAPP and altering the structure, Se-PC alleviated hIAPP-induced cell apoptosis. Meantime, generation of ROS produced during the fibrillation process was inhibited, which was proposed to be the main factor for the hIAPP-cytotoxicity in beta cells. Taken together, Se-PC inhibited hIAPP fibrillation, thus suppressed the formation of ROS to show protective effect on hIAPP mediated cell apoptosis. Our studies provide useful information for our understanding of the interaction mechanisms of Se-PC on hIAPP structure and protective mechanisms on hIAPP cytotoxicity, presenting useful candidate for anti-diabetes drug development. PMID- 25034965 TI - Fluorescent polymeric aggregates for selective response to sarin surrogates. AB - By combining the sensitivity of fluorescent units with the response of "smart" polymers to environmental changes, we propose a new approach for chemical detection applications. The system proved to be sensitive to 12 ppb of diethyl chlorophosphate (DCP), a Sarin surrogate, and to discriminate between the interfering molecules. PMID- 25034966 TI - Digital colloids: reconfigurable clusters as high information density elements. AB - Through the design and manipulation of discrete, nanoscale systems capable of encoding massive amounts of information, the basic components of computation are open to reinvention. These components will enable tagging, memory storage, and sensing in unusual environments - elementary functions crucial for soft robotics and "wet computing". Here we show how reconfigurable clusters made of N colloidal particles bound flexibly to a central colloidal sphere have the capacity to store an amount of information that increases as O(N ln(N)). Using Brownian dynamics simulations, we predict dynamical regimes that allow for information to be written, saved, and erased. We experimentally assemble an N = 4 reconfigurable cluster from chemically synthesized colloidal building blocks, and monitor its equilibrium dynamics. We observe state switching in agreement with simulations. This cluster can store one bit of information, and represents the simplest digital colloid. PMID- 25034968 TI - Completeness assessment of type II active pharmaceutical ingredient drug master files under generic drug user fee amendment: review metrics and common incomplete items. AB - Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA's "Available for Reference List". The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs. PMID- 25034969 TI - Mechanism of Hbgamma-35-induced an increase in the activation of the human immune system by endotoxins. AB - Endotoxins (LPS) are highly potent immune stimulatory molecules and are mainly known for triggering Gram-negative sepsis. However, besides their toxic effects, this stimulatory function may be advantageous, for example when used as an adjuvant during vaccination. Thus, there is always a narrow range between the useful wake-up of the immune system and its overwhelming reaction, which can lead to diseases like sepsis. This raises the question of which conformational properties are responsible for making the LPS aggregates more or less potent. As described previously, the size, type and form of LPS aggregates play a major role in their immune stimulatory activity. In this study we investigate the role of these parameters. On the one hand, we use a peptide (Pep19-2.5; Aspidasept) that causes a change of the LPS aggregate structure into a less toxic state; on the other hand, we use a potent immune stimulating peptide (Hbgamma-35), leading to higher toxicity. We have found opposing effects on LPS aggregate conformations allowing a better understanding of the processes of immune stimulation. PMID- 25034970 TI - Clinically assisted hydration and the Liverpool Care Pathway: Catholic ethics and clinical evidence. AB - The Liverpool Care Pathway for the Dying Patient (LCP), a framework introduced for providing comfortable care at the last stage of life, has recently become highly contentious. Among the most serious allegations levelled against it, has been that the LCP may be used as a covert form of euthanasia by withdrawal of clinically assisted hydration (CAH). This concern has been raised, in particular by a number of Catholic medical professionals, who have asserted that the LCP is incompatible with Catholic ethics. This paper examines the key Catholic ethical principles relevant to treatment and care towards the end of life (the sanctity/inviolability of life principle, the distinction between ordinary and extraordinary means). Relevant current clinical evidence regarding CAH in relation to terminal thirst, dehydration, prolongation of life and possible negative impacts on the dying is also scrutinised. It is argued that for some patients at the very end of life it may be permissible and even desirable to withhold or withdraw it. Thus, as administration of CAH may become extraordinary, forgoing it in some situations is fully compatible with Catholic ethics. The article therefore concludes that the stance of the LCP in respect of provision of CAH is fully in alignment with Catholic teaching. PMID- 25034971 TI - Oncolytic viruses as platform for multimodal cancer therapeutics: a promising land. PMID- 25034972 TI - Effects of fondaparinux on pulmonary embolism following hemiarthroplasty for femoral neck fracture: a retrospective observational study using the Japanese Diagnosis Procedure Combination database. AB - BACKGROUND: Pulmonary embolism (PE) is recognized as an important complication in patients undergoing hip fracture surgery. However, clinical evidence demonstrating the effectiveness of pharmacological thromboprophylaxis, including fondaparinux, is limited because the occurrence of postoperative PE after hemiarthroplasty is very low. The goal of this study was to analyze the effect of fondaparinux in reducing PE following hemiarthroplasty for femoral neck fracture using large-scale retrospective data. METHODS: Employing data from the Japanese Diagnosis Procedure Combination database from July 1 to December 31 between 2007 and 2010, we retrospectively identified 22,776 patients who underwent hemiarthroplasty for femoral neck fracture; we included those who received mechanical prophylaxis alone (n = 17,984) and those who received both mechanical prophylaxis and pharmacological prophylaxis with fondaparinux (n = 4,792). Logistic regression analysis was performed to compare the occurrence of postoperative PE with adjustment for sex, age, comorbidities, and type and duration of anesthesia. RESULTS: The mean age of the patients was 79.5 +/- 9.4 years. Overall, postoperative PE occurred in 189 (0.83%) patients. The rate of postoperative PE in the fondaparinux group (0.61%) was lower than in the control group (0.89%), although the difference was not significant in the univariate analysis (odds ratio [OR] 0.68; p = 0.055). In the multivariate analysis, the fondaparinux group showed a significantly lower rate of postoperative PE than the group receiving mechanical prophylaxis alone (OR 0.67; p = 0.047). General anesthesia and a longer duration of anesthesia were significant risk factors for postoperative PE. CONCLUSIONS: Fondaparinux combined with mechanical prophylaxis is more effective in preventing postoperative PE following hemiarthroplasty for femoral neck fracture than mechanical prophylaxis alone. PMID- 25034973 TI - p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS uncoupling in obesity. AB - BACKGROUND: Endothelial nitric oxide synthase (eNOS)-uncoupling links obesity associated insulin resistance and type-II diabetes to the increased incidence of cardiovascular disease. Studies have indicated that increased arginase is involved in eNOS-uncoupling through competing with the substrate L-arginine. Given that arginase-II (Arg-II) exerts some of its biological functions through crosstalk with signal transduction pathways, and that p38 mitogen-activated protein kinase (p38mapk) is involved in eNOS-uncoupling, we investigated here whether p38mapk is involved in Arg-II-mediated eNOS-uncoupling in a high fat diet (HFD)-induced obesity mouse model. METHODS: Obesity was induced in wild type (WT) and Arg-II-deficient (Arg-II(-/-)) mice on C57BL/6 J background by high-fat diet (HFD, 55% fat) for 14 weeks starting from age of 7 weeks. The entire aortas were isolated and subjected to 1) immunoblotting analysis of the protein level of eNOS, Arg-II and p38mapk activation; 2) arginase activity assay; 3) endothelium dependent and independent vasomotor responses; 4) en face staining of superoxide anion and NO production with Dihydroethidium and 4,5-Diaminofluorescein Diacetate, respectively, to assess eNOS-uncoupling. To evaluate the role of p38mapk, isolated aortas were treated with p38mapk inhibitor SB203580 (10 MUmol/L, 1 h) prior to the analysis. In addition, the role of p38mapk in Arg-II induced eNOS-uncoupling was investigated in cultured human endothelial cells overexpressing Arg-II in the absence or presence of shRNA against p38mapk. RESULTS: HFD enhanced Arg-II expression/activity and p38mapk activity, which was associated with eNOS-uncoupling as revealed by decreased NO and enhanced L-NAME inhibitable superoxide in aortas of WT obese mice. In accordance, WT obese mice revealed decreased endothelium-dependent relaxations to acetylcholine despite of higher eNOS protein level, whereas Arg-II(-/-) obese mice were protected from HFD induced eNOS-uncoupling and endothelial dysfunction, which was associated with reduced p38mapk activation in aortas of the Arg-II(-/-) obese mice. Moreover, overexpression of Arg-II in human endothelial cells caused eNOS-uncoupling and augmented p38mapk activation. The Arg-II-induced eNOS-uncoupling was prevented by silencing p38mapk. Furthermore, pharmacological inhibition of p38mapk recouples eNOS in isolated aortas from WT obese mice. CONCLUSIONS: Taking together, we demonstrate here for the first time that Arg-II causes eNOS-uncoupling through activation of p38 mapk in HFD-induced obesity. PMID- 25034974 TI - Nanoscale metal-organic frameworks as highly sensitive luminescent sensors for Fe2+ in aqueous solution and living cells. AB - We report the exploration of fluorescent nanoscale metal-organic frameworks (nMOF 253s) for highly selective and sensitive detection of Fe(2+) ions in aqueous solution. Moreover, nMOF-253 of 50 nm is successfully applied in fluorescent bioimaging and intracellular Fe(2+) sensing in HeLa cells. PMID- 25034975 TI - Gonadal development in fish. AB - Vertebrate reproduction depends on the function of 2 distinct gametes, sperm and eggs, which develop in 2 different organs, the testis and the ovary. Testes and ovaries are composed of germ cells, supporting cells and interstitial cells. In this review, we describe the origin and the fate of these cell lineages and how they interact with each other to form sexually dimorphic reproductive organs in medaka. We delineate how the temporally different association and establishment of these lineages contribute to a variety of seemingly different sex differentiation processes among teleost fish. Thus, teleosts represent an intriguing group in which to study the fundamental processes of gonadal development through comparing conserved and unique mechanisms. PMID- 25034976 TI - Strategies for multigene expression in eukaryotic cells. AB - Multigene delivery systems for heterologous multiprotein expression in mammalian cells are a key technology in contemporary biological research. Multiprotein expression is essential for a variety of applications, including multiparameter analysis of living cells in vitro, changing the fate of stem cells, or production of multiprotein complexes for structural biology. Depending on the application, these expression systems have to fulfill different requirements. For some applications, homogenous expression in all cells with defined stoichiometry is necessary, whereas other applications need long term expression or require that the proteins are not modified at the N- and C-terminus. Here we summarize available multiprotein expression systems and discuss their advantages and disadvantages. PMID- 25034977 TI - Phase I clinical trial of pegylated liposomal mitoxantrone plm60-s: pharmacokinetics, toxicity and preliminary efficacy. AB - PURPOSE: Plm60-s is a pegylated liposomal mitoxantrone formulation, in which mitoxantrone was loaded into small unilamellar vesicles (~60 nm) made from solid lipid membrane. This two-arm, dose-escalating phase I study was designed to determine safety and pharmacokinetics of plm60-s, and to compare with those of conventional mitoxantrone injection (c-MI). METHODS: Patients received an intravenous infusion of plm60-s at 6, 10, 12, 14, 16 and 18 mg/m(2) every 4 weeks. Three or 6 patients were in each group of dose level. If more than one third patients of a group experienced dose-limiting toxicity, dose climbing will stop. The control group of 3 patients received c-MI at 10 mg/m(2) every 28 days. Samples for pharmacokinetic studies were collected. The analysis of the safety and tolerability was done according to the record and laboratory examination, etc. RESULTS: Twenty patients were enrolled. One grade 3 leukocytopenia occurred in plm60-s groups. Plm60-s was safer than c-MI at the same dose of 10 mg/m(2). Two complete responses and one partial response occurred in plm60-s group. In plasma, plm60-s exhibited sustained release of the content, resulting in the reduced peak concentrations and enhanced AUC of released MIT. Total mitoxantrone was linearly cleared, and mitoxantrone was predominantly in the liposomal encapsulation form. Repeated administration of plm60-s did not affect the clearance kinetics. CONCLUSIONS: At a dose of up to 18 mg/m(2), plm60-s could be well tolerated and potential efficacy could be observed. The pharmacokinetic profile of plm60-s was remarkably altered. Further investigations are in progression. PMID- 25034978 TI - A phase II study of amrubicin and carboplatin for previously untreated patients with extensive-disease small cell lung cancer. AB - BACKGROUND: Amrubicin is active in the treatment of extensive-disease small cell lung cancer (ED-SCLC), and carboplatin is an analogue of cisplatin with less non hematological toxicity. PURPOSE: The purpose of this study was to determine the efficacy and toxicity of amrubicin and carboplatin combination chemotherapy for previously untreated patients with ED-SCLC. PATIENTS AND METHODS: Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0-1, age <=75, and adequate hematological, hepatic and renal function. Based on the phase I study, the patients received amrubicin 35 mg/m(2) i.v. infusion on days 1, 2, and 3, and carboplatin AUC 5 i.v. infusion on day 1. Four cycles of chemotherapy were repeated every 3 weeks. RESULTS: Thirty-five patients were enrolled, and 34 patients were eligible and assessable for response, toxicity, and survival. Patients' characteristics were as follows: male/female = 26/8; performance status 0/1 = 4/30; median age (range) = 64 (41-75); stage IV = 34. Evaluation of responses was 6 complete response, 21 partial response, and 7 stable disease (response rate 79.4 %, 95 % CI 63.6-88.5 %). Grade 3 and 4 leukopenia, neutropenia, and thrombocytopenia occurred in 59, 82, and 26 %, respectively. There were no treatment-related deaths or pneumonitis. Three patients experienced hypotension as an amrubicin infusion reaction. The median progression-free survival time was 6.5 months. The median overall survival time and 1-, 2-, and 3 year survival rates were 15.6 months, and 63, 28, and 7 %, respectively. CONCLUSIONS: Amrubicin and carboplatin were effective and tolerable as chemotherapy for previously untreated patients with ED-SCLC. Further investigation of amrubicin and carboplatin is warranted. PMID- 25034979 TI - How precise is computer-navigated gap assessment in TKA? AB - BACKGROUND: Methods to improve gap balancing in total knee arthroplasty (TKA) include the development of calibrated distractors and various devices to determine the distances of the gaps. However, few studies have validated the accuracy or precision of computer navigation to determine these measurements, especially gaps created after bone cuts have been made; doing so would be important, because optimal surgical technique relies on appropriate gap spacing. QUESTIONS/PURPOSES: We investigated the ability of a new image-free computer navigation surface registration protocol to measure gap distances in TKA. METHODS: Eight embalmed cadaveric specimens of the lower extremity were used. A surface registration software protocol defined the most distal and posterior surface points of the femoral condyles and the navigation system measured the distance of the most distal femoral condyle point to the surface of the tibia after tibial resection. The tibial resection was perpendicular to the mechanical axis and was cut with a 7 degrees posterior slope. The navigation system measured gaps spaced by modular spacing blocks at 5 degrees intervals from full extension to 120 degrees of flexion. Repeatability assessed repeated measures by one surgeon. Reproducibility was assessed by performing the same measurements after complete reregistration of the computer protocol to the cadaver bones. RESULTS: The gaps measured by the computer were statistically the same as those assessed with the use of blocks with a maximum measurement error of 1 mm. Reregistration did introduce error into the measurement. The gaps changed with position of knee flexion, and there was gradual and significant stretching of the gaps with repeated measurements. CONCLUSIONS: Preliminary testing shows that computer navigation can reproduce static measurements reliably and with equal accuracy as spacer blocks. We have not demonstrated that this could be applied in a dynamic setting. CLINICAL RELEVANCE: This computer navigation system has sufficient precision to warrant investigation in the clinical setting for measuring gaps created during the surgical procedure. PMID- 25034981 TI - What are the economic consequences of unplanned readmissions after TKA? AB - BACKGROUND: In 2009, the Center for Medicare & Medicaid Services (CMS) began penalizing hospitals with high rates of 30-day readmissions after hospitalizations for certain conditions. This policy will expand to include TKA in 2015. QUESTIONS/PURPOSES: What are the median profits and contribution margins of: (1) Medicare-reimbursed TKA, (2) 30-day TKA readmission, and (3) entire episode of care for readmitted TKA patients within 30 days compared to nonreadmitted patients? (4) Under new CMS guidelines, what financial penalty will the authors' institution face if its arthroplasty readmission rate exceeds the national average? METHODS: A retrospective review of 3218 primary TKAs performed during 2 years at a large urban academic hospital network was conducted using administrative and financial data. RESULTS: The median profit and contribution margins, respectively, were as follows: TKA episode, USD 5209 and USD 11,726; 30 day readmission, USD 608 and USD 3814; TKA visit with readmission, USD 2855 and USD 13,901; TKA visit without readmission, USD 5300 and USD 11,652. Readmission penalties could reach USD 6.21 million per year for the authors' institution. DISCUSSION: If our results are generalizable, unplanned TKA readmissions lead to diminished total profit. Although associated with a positive contribution margin, this is likely to be a short-term phenomenon as the new CMS policy will result in readmissions coming at a steep cost to referral centers. PMID- 25034982 TI - Analysis of volatile organic compounds in rats with dopaminergic lesion: Possible application for early detection of Parkinson's disease. AB - Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron depletion. Early detection of PD may help in selecting the appropriate treatment. Biomarkers of PD have been suggested, however none of these is currently in clinical use. The aim of this study was to identify volatile organic compounds (VOCs) as early biomarkers of PD. Our hypothesis was that during PD progression, specific VOCs are generated that are linked to the biochemical pathways characterizing PD. These VOCs can be detected by GC-MS combined with solid-phase microextraction (SPME) technique. Three groups of rats were studied: DA-lesioned rats injected with 6-hydroxydopamine (HDA; 250MUg/rat n=11); control rats injected with saline (n=9), and control rats injected with DSP-4 (n=8), a specific noradrenergic neuron toxin. Blood and striatal tissue homogenate were analyzed. In the blood, 1 octen-3-ol and 2-ethylhexanol were found at significantly higher concentrations in HDA versus sham rats. In the striatal homogenate 1-octen-3-ol and other four compounds were found at significantly lower concentrations in HDA versus sham rats. 1-Octen-3-ol is a cytotoxic compound. These results may lead to the development of an early diagnostic test for PD based on profiling of VOCs in body fluids. PMID- 25034980 TI - Do genetic susceptibility, Toll-like receptors, and pathogen-associated molecular patterns modulate the effects of wear? AB - BACKGROUND: Overwhelming evidence supports the concept that wear particles are the primary initiator of aseptic loosening of orthopaedic implants. It is likely, however, that other factors modulate the biologic response to wear particles. This review focuses on three potential other factors: genetic susceptibility, Toll-like receptors (TLRs), and bacterial pathogen-associated molecular patterns (PAMPs). WHERE ARE WE NOW?: Considerable evidence is emerging that both genetic susceptibility and TLR activation are important factors that modulate the biologic response to wear particles, but it remains controversial whether bacterial PAMPs also do so. WHERE DO WE NEED TO GO?: Detailed understanding of the roles of these other factors may lead to identification of novel therapeutic targets for patients with aseptic loosening. HOW DO WE GET THERE?: Highest priority should be given to polymorphism replication studies with large numbers of patients and studies to replicate the reported correlation between bacterial biofilms and the severity of aseptic loosening. PMID- 25034983 TI - Re: Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. PMID- 25034984 TI - Re: Prognostic significance of venous tumour thrombus consistency in patients with renal cell carcinoma (RCC). PMID- 25034985 TI - Re: Comparing radiation exposure between ablative therapies for small renal masses. PMID- 25034986 TI - Re: Comparative analysis of vascular bulldog clamps used in robot-assisted partial nephrectomy. PMID- 25034988 TI - Re: Comparison of radical cystectomy with conservative treatment in geriatric (>=80) patients with muscle-invasive bladder cancer. PMID- 25034989 TI - Re: Radical prostatectomy or watchful waiting on early prostate cancer. PMID- 25034990 TI - Re: Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate specific antigen doubling time. PMID- 25034991 TI - Re: Clinical performance of serum isoform (-2)proPSA (p2PSA) and its derivatives, namely %p2PSA and PHI (Prostate Health Index) in men younger than 60 years of age: results from a multicentric European study. PMID- 25034992 TI - Re: Screening for prostate cancer with the prostate-specific antigen test: a review of current evidence. PMID- 25034993 TI - Re: The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease. PMID- 25034994 TI - Re: MR imaging of prostate cancer in radiation oncology: what radiologists need to know. PMID- 25034995 TI - Re: Primary retroperitoneal lymph node dissection in low-stage testicular germ cell tumors: a detailed pathologic study with clinical outcome analysis with special emphasis on patients who did not receive adjuvant therapy. PMID- 25034996 TI - Re: Active surveillance: does serial prostate biopsy increase histological inflammation? PMID- 25034997 TI - Re: Prostate specific antigen enhances the innate defence of prostatic epithelium against Escherichia coli infection. PMID- 25034998 TI - Re: Surgical site infections following ambulatory surgery procedures. PMID- 25034999 TI - Re: Comparative effectiveness of skin antiseptic agents in reducing surgical site infections: a report from the Washington State Surgical Care and Outcomes Assessment Program. PMID- 25035000 TI - Re: Financial impact of surgical site infections on hospitals: the hospital management perspective. PMID- 25035001 TI - Re: Overtreatment of presumed urinary tract infection in older women presenting to the emergency department. PMID- 25035002 TI - Re: Stone disease in living-related renal donors: long-term outcomes for transplant donors and recipients. PMID- 25035003 TI - Re: Age-dependent association between Dickkopf-1 and calcium-containing urolithiasis. PMID- 25035004 TI - Re: Deep lateral transurethral incisions for recurrent bladder neck contracture: promising 5-year experience using a standardized approach. PMID- 25035005 TI - Re: Artificial urinary sphincter revision: the role of ultrasound. PMID- 25035006 TI - Re: Safety of the "drain and retain" option for defunctionalized urologic prosthetic balloons and reservoirs during artificial urinary sphincter and inflatable penile prosthesis revision surgery: 5-year experience. PMID- 25035007 TI - Re: External validation of a substratification of the American Association for the Surgery of Trauma renal injury scale for grade 4 injuries. PMID- 25035008 TI - Re: Pyocystis after urinary diversion for incontinence-is a concomitant cystectomy necessary? PMID- 25035009 TI - Re: Impact of graft position on failure of single-stage bulbar urethroplasties with buccal mucosa graft. PMID- 25035010 TI - Re: The management of secondary pelvi-ureteric junction obstruction--a comparison of pyeloplasty and endopyelotomy. PMID- 25035011 TI - Re: Unfavorable outcomes of laparoscopic pyeloplasty using barbed sutures: a multi-center experience. PMID- 25035012 TI - Re: I COUGH: reducing postoperative pulmonary complications with a multidisciplinary patient care program. PMID- 25035013 TI - Re: Smoking and the risk of mortality and vascular and respiratory events in patients undergoing major surgery. PMID- 25035014 TI - Re: The role of phosphodiesterases in bladder pathophysiology. PMID- 25035015 TI - Re: a systematic review of surgical techniques used in the treatment of female urethral stricture. PMID- 25035016 TI - Re: TVT-O for the treatment of pure urodynamic stress incontinence: efficacy, adverse effects, and prognostic factors at 5-year follow-up. PMID- 25035017 TI - Re: Anticholinergic drug use, serum anticholinergic activity, and adverse drug events among older people: a population-based study. PMID- 25035018 TI - Re: Prevalence of commonly prescribed medications potentially contributing to urinary symptoms in a cohort of older patients seeking care for incontinence. PMID- 25035019 TI - Re: Use of the SF-36 quality of life scale to assess the effect of pelvic floor muscle exercise on aging males who received transurethral prostate surgery. PMID- 25035020 TI - Re: The effect of benign lower urinary tract symptoms on subsequent prostate cancer testing and diagnosis. PMID- 25035021 TI - Re: Development of a quality of life scale specific for patients with benign prostatic hyperplasia. PMID- 25035022 TI - Re: The decline in living kidney donation in the United States: random variation or cause for concern? PMID- 25035023 TI - Re: Early rehospitalization after kidney transplantation: assessing preventability and prognosis. PMID- 25035024 TI - Re: Comparative Patient-Centered Outcomes (Health State and Adverse Sexual Symptoms) between Adjuvant Brachytherapy versus No Adjuvant Brachytherapy in Early Stage Endometrial Cancer. PMID- 25035027 TI - Re: Clitoral size and location in relation to sexual function using pelvic MRI. PMID- 25035028 TI - Re: the effect of vaginal pelvic organ prolapse surgery on sexual function. PMID- 25035030 TI - Re: Impact of fresh versus cryopreserved testicular sperm upon intracytoplasmic sperm injection pregnancy outcomes in men with azoospermia due to spermatogenic dysfunction: a meta-analysis. PMID- 25035031 TI - Re: Microdissection testicular sperm extraction and salvage hormonal treatment in patients with postchemotherapy azoospermia. PMID- 25035032 TI - Re: Comparison of sperm retrieval and intracytoplasmic sperm injection outcome in patients with and without Klinefelter syndrome. PMID- 25035033 TI - Re: Microsurgical vasoepididymostomy is an effective treatment for azoospermic patients with epididymal obstruction and prior failure to achieve pregnancy by sperm retrieval with intracytoplasmic sperm injection. PMID- 25035034 TI - Re: Vasectomy reversal outcomes among patients with vasal obstructive intervals greater than 10 years. PMID- 25035036 TI - Re: Failed pyeloplasty in children: revisiting the unknown. PMID- 25035037 TI - Re: Examining long-term outcomes of bladder exstrophy: a 20-year follow-up. PMID- 25035038 TI - Re: Gender-related fetal development of the internal urethral sphincter. PMID- 25035039 TI - Re: The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. PMID- 25035040 TI - Re: Dietary sources of N-nitroso compounds and bladder cancer risk: findings from the Los Angeles Bladder Cancer Study. PMID- 25035041 TI - Re: Carvedilol efficiently protects kidneys without affecting the antitumor efficacy of cisplatin in mice. PMID- 25035042 TI - Re: Persistence of 1,25D-induced hypercalciuria in alendronate treated genetic hypercalciuric stone-forming rats fed a low calcium diet. PMID- 25035043 TI - Re: Effect of melatonin on chronic bladder-ischaemia-associated changes in rat bladder function. PMID- 25035044 TI - Re: Chronic administration of anticholinergics in rats induces a shift from muscarinic to purinergic transmission in the bladder wall. PMID- 25035047 TI - The role of rapid thromboelastography in trauma. AB - Evaluation of: Hampton DA, Lee TH, Diggs BJ, McCully SP, Schreiber MA. A predictive model of early mortality in trauma patients. Am. J. Surg. 207(5), 642 647 (2014). In their prospective multi-centred observational study, Hampton et al. tested the ability of rapid thromboelastography (r-TEG) to predict mortality in trauma patients. A total of 795 patients were assessed. The authors analysed both patient demographic and physiological measures. Validation of variables that significantly related to mortality was subsequently undertaken. Ly30 (a measurement of the degree of clot lysis over 30 min) was observed to be a predictor of 24-h mortality in trauma (odds ratio 3.7 p = 0.03). This was incorporated with haemoglobin level, international normalized ratio, Glasgow Coma Score and the presence of penetrating injury to form their five-variable mortality prediction model. Hampton et al. conclude that the correlation between r-TEG measurements and trauma mortality makes it a useful tool in mortality prediction. The report highlights the importance of using this point-of-care coagulation assessment machine in mortality prediction for trauma patients. PMID- 25035048 TI - Central venous pressure after coronary artery bypass surgery: does it predict postoperative mortality or renal failure? AB - OBJECTIVE: Although hemodynamic monitoring is often performed after coronary artery bypass grafting (CABG), the role of monitoring postoperative central venous pressure (CVP) measurement as a predictor of clinical outcomes is unknown. As such, this study tests the hypothesis that postoperative CVP is predictive of operative mortality or renal failure. METHODS: This is an observational cohort study of detailed clinical data from 2390 randomly selected patients undergoing high-risk CABG or CABG/valve at 55 hospitals participating in the Society of Thoracic Surgeons' National Cardiac Surgery Database 2004-2005. Eligible patients underwent elective/urgent CABG with an ejection fraction less than 40% or elective/urgent CABG at 65 years or older with diabetes or a glomerular filtration rate less than 60 mL/min per 1.73 m2. The exposure of interest is CVP monitoring in the intensive care unit after adult cardiac surgery. The primary outcome measure was correlation between postoperative CVP and inhospital/30-day mortality and renal failure, assessed as a continuous variable, both unadjusted and after adjusting for important clinical factors using logistic regression modeling. RESULTS: Mean age was 72 years, 54% of patients had diabetes mellitus, 49% were urgent procedures, and mean cardiopulmonary bypass time was 105 minutes. Patients' CVP 6 hours postoperation was strongly associated with inhospital and 30-day mortality: odds ratio (OR) of 1.5 (95% confidence interval [CI], 1.23 1.87) for every 5-mm Hg increase in CVP; P<.0001. This association remained significant after risk adjustment: adjusted OR of 1.44 (95% CI, 1.10-1.89); P<.01. A model adjusting for cardiac index also revealed increased incidence of mortality or renal failure: adjusted OR of 1.5 (95% CI, 1.28-1.86) for every 5-mm Hg increase in CVP; P<.0001. CONCLUSIONS: Patients' CVP at 6 hours after CABG surgery was highly predictive of operative mortality or renal failure, independent of cardiac index and other important clinical variables. Future studies will need to assess whether interventions guided by postoperative CVP can improve patient outcomes. PMID- 25035049 TI - Chlorhexidine gluconate-impregnated central-line dressings and necrosis in complicated skin disorder patients. AB - Although chlorhexidine gluconate (CHG) disks have been shown to help reduce the incidence of central line-associated blood stream infections, their use can result in local skin necrosis. The effects of CHG disks on patients with complex skin pathology have not been studied. We report 6 cases of dermal necrosis associated with Biopatch (Ethicon Inc, Somerville, NJ) CHG disks in adults with complex skin pathology including those with Stevens-Johnson syndrome, toxic epidermal necrolysis syndrome, graft-versus-host disease, burns, and anasarca. All patients had a CHG disk placed at a central venous catheter insertion site. Age range was from 21 to 84 years. Discovery of the reaction ranged from 4 to 14 days after disk placement. Resultant skin erosions required 2 to 10 weeks to reepithelialize. Complicated skin disorder patients represent a rare subset of the critically ill who appear prone to CHG disk necrosis. Continuous contact of CHG under occlusive dressings is speculated to predispose Stevens-Johnson syndrome, toxic epidermal necrolysis syndrome, graft-versus-host disease, and burn patients to local chemical injury secondary to loss of the epithelial tissue barrier, decreased cohesion of the epidermal-dermal junction, and increased tissue permeability. In these patients, the risk of placing the CHG disk may present more risk than using alternative antimicrobial dressings. PMID- 25035050 TI - Serial explant culture provides novel insights into the potential location and phenotype of corneal endothelial progenitor cells. AB - The routine cultivation of human corneal endothelial cells, with the view to treating patients with endothelial dysfunction, remains a challenging task. While progress in this field has been buoyed by the proposed existence of progenitor cells for the corneal endothelium at the corneal limbus, strategies for exploiting this concept remain unclear. In the course of evaluating methods for growing corneal endothelial cells, we have noted a case where remarkable growth was achieved using a serial explant culture technique. Over the course of 7 months, a single explant of corneal endothelium, acquired from cadaveric human tissue, was sequentially seeded into 7 culture plates and on each occasion produced a confluent cell monolayer. Sample cultures were confirmed as endothelial in origin by positive staining for glypican-4. On each occasion, small cells, closest to the tissue explant, developed into a highly compact layer with an almost homogenous structure. This layer was resistant to removal with trypsin and produced continuous cell outgrowth during multiple culture periods. The small cells gave rise to larger cells with phase-bright cell boundaries and prominent immunostaining for both nestin and telomerase. Nestin and telomerase were also strongly expressed in small cells immediately adjacent to the wound site, following transfer of the explant to another culture plate. These findings are consistent with the theory that progenitor cells for the corneal endothelium reside within the limbus and provide new insights into expected expression patterns for nestin and telomerase within the differentiation pathway. PMID- 25035051 TI - Rapid determination of trace dicyandiamide in mussels from Zhejiang coast by ultra-fast liquid chromatography-tandem mass spectrometry with isotope internal standard dilution technique. AB - In this study, a rapid and accurate ultra-fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS) method coupled with the isotope internal standard dilution technique was established and validated to determine trace dicyandiamide (DCD) in mussels. The sample was extracted by acetonitrile, and chromatographic separations were performed on an Acquity UPLC BEH Amide column by using water-acetonitrile (9:91, v/v) as the mobile phase within 3 min. DCD was determined by using DCD-(15)N4 as an internal standard. The results showed that the recoveries were between 96.2 and 103 % with relative standard deviations (RSDs) in the range of 0.6-6.0 %. The limit of quantification (LOQ) was 0.05 MUg/kg. This method can be applied to the routine analysis for the rapid and sensitive determination of trace DCD in mussels. Overall, the data reiterate the importance of investigating the presence of DCD in marine biological samples, which can act as food quality controls for human health. PMID- 25035053 TI - Cell cycle stage specific application of municipal landfill leachates to assess the genotoxicity in root meristem cells of barley (Hordeum vulgare). AB - Municipal solid wastes (MSW) are unavoidable sources of environmental pollution. Improper disposal of municipal waste results in the leaching of toxic metals and organic chemicals, which can contaminate the surface and ground water leading to serious health hazard. In this study, the toxic effects of the leachate prepared from municipal solid waste samples were examined in root meristem cells of barley (Hordeum vulgare L.) at various stages of cell cycle, i.e., G1, S, and G2. Seeds of barley were exposed to 2.5, 5, and 10 % of leachates in soil and aqueous media in 48 h at different cell cycle stages. The physicochemical data of the present study revealed that municipal solid waste leachate contains high amount of heavy metals, which significantly affected growth and physiological activities of barley. Significant inhibition in hypocotyl length, germination, and mitotic index were observed at all concentration of leachate treatment. Induction of chromosomal aberrations (CA's) and micronuclei (MN) formation were also observed with different concentrations of leachate treatment at 7, 17, and 27 h of presoaking durations, which falls in G1, S, and G2 phase of the cell cycle, respectively. Also, exposure of leachate at S phase of the cell cycle had significant effects in barley through chromosomal aberration and micronuclei formation. PMID- 25035052 TI - Risks of large-scale use of systemic insecticides to ecosystem functioning and services. AB - Large-scale use of the persistent and potent neonicotinoid and fipronil insecticides has raised concerns about risks to ecosystem functions provided by a wide range of species and environments affected by these insecticides. The concept of ecosystem services is widely used in decision making in the context of valuing the service potentials, benefits, and use values that well-functioning ecosystems provide to humans and the biosphere and, as an endpoint (value to be protected), in ecological risk assessment of chemicals. Neonicotinoid insecticides are frequently detected in soil and water and are also found in air, as dust particles during sowing of crops and aerosols during spraying. These environmental media provide essential resources to support biodiversity, but are known to be threatened by long-term or repeated contamination by neonicotinoids and fipronil. We review the state of knowledge regarding the potential impacts of these insecticides on ecosystem functioning and services provided by terrestrial and aquatic ecosystems including soil and freshwater functions, fisheries, biological pest control, and pollination services. Empirical studies examining the specific impacts of neonicotinoids and fipronil to ecosystem services have focused largely on the negative impacts to beneficial insect species (honeybees) and the impact on pollination service of food crops. However, here we document broader evidence of the effects on ecosystem functions regulating soil and water quality, pest control, pollination, ecosystem resilience, and community diversity. In particular, microbes, invertebrates, and fish play critical roles as decomposers, pollinators, consumers, and predators, which collectively maintain healthy communities and ecosystem integrity. Several examples in this review demonstrate evidence of the negative impacts of systemic insecticides on decomposition, nutrient cycling, soil respiration, and invertebrate populations valued by humans. Invertebrates, particularly earthworms that are important for soil processes, wild and domestic insect pollinators which are important for plant and crop production, and several freshwater taxa which are involved in aquatic nutrient cycling, were all found to be highly susceptible to lethal and sublethal effects of neonicotinoids and/or fipronil at environmentally relevant concentrations. By contrast, most microbes and fish do not appear to be as sensitive under normal exposure scenarios, though the effects on fish may be important in certain realms such as combined fish-rice farming systems and through food chain effects. We highlight the economic and cultural concerns around agriculture and aquaculture production and the role these insecticides may have in threatening food security. Overall, we recommend improved sustainable agricultural practices that restrict systemic insecticide use to maintain and support several ecosystem services that humans fundamentally depend on. PMID- 25035054 TI - Anaerobic treatability of liquid residue from wet oxidation of sewage sludge. AB - Wet Oxidation (WO) of sewage sludge is a chemical oxidation of sludge at high temperatures and pressures by means of an oxygen-containing gas. The liquid stream originated by WO is easily biodegradable, and therefore, the recirculation to the biological Waste Water Treatment Plant (WWTP) may be a feasible solution. However, the WO effluent has a residual organic and nitrogen content so that its treatment may be required when the receiving WWTP has no surplus treatment capacity left. The aim of this research was the assessment of the anaerobic treatability of the WO liquid residue, in order to reduce the organic load to be recirculated to the WWTP, simultaneously promoting energy recovery. For this purpose, the liquid residue obtained during full scale WO tests on two different types of sludge was submitted to anaerobic digestion in a continuous flow pilot reactor (V = 5 L). Furthermore, batch tests were carried out in order to evaluate possible inhibition factors. Experimental results showed that, after the start up/acclimation period (~130 days), Chemical Oxygen Demand (COD) removal efficiency was stably around 60% for about 120 days, despite the change in operating conditions. In the last phase of the experimental activity, COD removal reached 70% under the following treatment conditions: Hydraulic Retention Time (HRT) = 20 days, Volumetric Organic Loading Rate (VOLR) = 0.868 kg COD/m(3)/day, Organic Loading Rate per Volatile Suspended Solids (OLRvss) = 0.078 kg COD/kg VSS/day, temperature (T) = 36.5 degrees C, pH = 8. Energy balance calculation demonstrated anaerobic treatment sustainability. PMID- 25035055 TI - Atmospheric mercury pollution around a chlor-alkali plant in Flix (NE Spain): an integrated analysis. AB - An integrated analysis approach has been applied to a mercury (Hg) case study on a chlor-alkali plant located in the Ebro River basin, close to the town of Flix (NE Spain). The study focused on atmospheric Hg and its incorporation in soils and lichens close to a mercury cell chlor-alkali plant (CAP), which has been operating since the end of the 19th century. Atmospheric Hg present in the area was characterized by means of seven total gaseous mercury (TGM) surveys carried out from 2007 to 2012. Surveys were carried out by car, walking, and at fixed locations, and covered an area of some 12 km(2) (including the CAP area, the village in which workers live, Flix town, and the Sebes Wildlife Reserve). Finally, an atmospheric Hg dispersion model was developed with ISC-AERMOD software validated by a lichen survey of the area. The results for the atmospheric compartment seem to indicate that the Flix area currently has the highest levels of Hg pollution in Spain on the basis of the extremely high average concentrations in the vicinity of the CAP (229 ng m(-3)). Moreover, the Hg(0) plume affects Flix town center to some extent, with values well above the international thresholds for residential areas. Wet and dry Hg deposition reached its highest values on the banks of the Ebro River, and this contributes to increased soil contamination (range 44-12,900 ng g(-1), average 775 ng g(-1)). A good fit was obtained between anomalous areas indicated by lichens and the dispersion model for 1 year. PMID- 25035056 TI - Isolation and characterization of a Pseudomonas aeruginosa from a virgin Brazilian Amazon region with potential to degrade atrazine. AB - The use of pesticides to increase agricultural production can result in the contamination of the environment, causing changes in the genetic structure of organisms and in the loss of biodiversity. This practice is also inducing changes in the rainforest ecosystem. In this work, a Pseudomonas aeruginosa isolated from a preservation soil area of the Brazilian Amazon Forest, without usage of any pesticide, was evaluated for its potential to degrade atrazine. This isolate presented all responsible genes (atzA, atzB, atzC, atzD, atzE, and atzF) for atrazine mineralization and demonstrated capacity to use atrazine as a nitrogen source, having achieved a reduction of 44 % of the initial concentration of atrazine after 24 h. These results confirm gene dispersion and/or a possible contamination of the area with the herbicide, which reinforces global concern of the increase and intensive use of pesticides worldwide. PMID- 25035057 TI - Formation potentials of bromate and brominated disinfection by-products in bromide-containing water by ozonation. AB - The ozonation involved in drinking water treatment raises issues of water quality security when the raw water contains bromide (Br(-)). Br(-) ions may be converted to bromate (BrO3 (-)) during ozonation and some brominated disinfection by products (Br-DBPs) in the following chlorination. In this study, the effects of ozone (O3) dosage, contact time, pH, and Br(-) and ammonia (NH3-N) concentrations on the formation of BrO3 (-) and Br-DBPs have been investigated. The results show that decreasing the initial Br(-) concentration is an effective means of controlling the formation of BrO3 (-). When the concentration of Br(-) was lower than 100 MUg/L, by keeping the ratio of O3 dosage to dissolved organic carbon (DOC) concentration at less than 1, BrO3 (-) production was effectively suppressed. The concentration of BrO3 (-) steadily increased with increasing O3 dosage at high Br(-) concentration (>900 MUg/L). Additionally, a longer ozonation time increased the concentrations of BrO3 (-) and total organic bromine (TOBr), while it had less impact on the formation potentials of brominated trihalomethanes (Br-THMFP) and haloacetic acids (Br-HAAFP). Higher pH value and the presence of ammonia may lead to an increase in the formation potential of BrO3 (-) and Br-DBPs. PMID- 25035058 TI - Upregulated expression of SSTR1 is involved in neuronal apoptosis and is coupled to the reduction of bcl-2 following intracerebral hemorrhage in adult rats. AB - Somatostatins are peptide hormones that regulate diverse cellular processes, such as neurotransmission, cell proliferation, apoptosis, and endocrine signaling as well as inhibiting the release of many hormones and other secretory proteins. SSTR1 is a member of the superfamily of somatostatin receptors possessing seven transmembrane segments. Aberrant expression of SSTR1 has been implicated in several human diseases, including pseudotumor cerebri, and oncogenic osteomalacia. In this study, we investigated a potential role of SSTR1 in the regulation of neuronal apoptosis in the course of intracerebral hemorrhage (ICH). A rat ICH model in the caudate putamen was established and subjected to behavioral tests. Western blot and immunohistochemistry indicated a remarkable up regulation of SSTR1 expression surrounding the hematoma after ICH. Double-labeled immunofluorescence showed that SSTR1 was mostly co-localized with neurons, and was rarely distributed in activated astrocytes and microglia. Additionally, SSTR1 co-localized with active-caspase-3 and bcl-2 around the hematoma. The expression of active-caspase-3 was parallel with that of SSTR1 in a time-dependent manner. In addition, SSTR1 knockdown specifically resulted in reduced neuronal apoptosis in PC12 cells. All our findings suggested that up-regulated SSTR1 contributed to neuronal apoptosis after ICH, which was accompanied with reduced expression of bcl-2. PMID- 25035059 TI - Protective effects of Andrographis paniculata extract and pure andrographolide against chronic stress-triggered pathologies in rats. AB - This study was designed to experimentally verify the possibility that Andrographis paniculata could be another medicinal herb potentially useful for prevention of diverse spectrums of pathologies commonly associated with chronic unavoidable environmental stress, and whether andrographolide could as well be its quantitatively major bioactive secondary metabolite. Preventive effects of 21 daily oral 50, 100 and 200 mg/kg doses of a therapeutically used extract of the plant (AP) and 30 and 60 mg/kg/day of pure andrographolide were compared in rats subjected to 1-h daily unavoidable foot-shocks. A pharmaceutically well standardized Withania somnifera (WS) root extract was used as a reference herbal anti-stress agent in all experiments. Effects of the treatments on stress-induced alterations in body weight, gastric ulcer, adrenal and spleen weights, and depressive state and sexual behavior in male rats were quantified. Other parameters quantified were plasma cortisol levels, and expressions of the cytokines TNF-alpha, IL-10 and IL-1beta in blood and brain. All observed stress induced pathological changes were less pronounced or completely prevented by both AP and pure andrographolide. Even the lowest tested doses of AP (50 mg/kg/day) or of andrographolide (30 mg/kg/day) suppressed almost maximally the blood IL-1beta and IL-10 as well as brain TNF-alpha and IL-10 expressions induced by chronic stress. Qualitatively, the observed activity profiles of both of them were similar to those of WS dose tested. These results reveal that both AP and andrographolide are pharmacologically polyvalent anti-stress agents, and that biological processes regulating corticosterone and cytokine homeostasis are involved in their modes of actions. PMID- 25035060 TI - Increased fibrosis and progression to heart failure in MRL mice following ischemia/reperfusion injury. AB - The cardiac regenerative capacity of MRL/MpJ mouse remains a controversy. Although the MRL mouse has been reported to exhibit minimal scarring and subsequent cardiac regeneration after cryoinjury of the right ventricle, multiple studies have been unable to replicate this cardiac regenerative capacity after both cryogenic and coronary ligation cardiac injury. Therefore, we evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice compared to C57 mice, in response to a clinically relevant left ventricular (LV) coronary ligation. Male MRL/MpJ+/+ and C57BL/6 mice underwent left coronary artery ligation followed by reperfusion. Cardiac function was evaluated by echocardiography [LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV mass, wall thickness] at 24 hours post-ischemia and weekly for 13 weeks thereafter. Hearts were also analyzed histologically for individual cardiomyocyte hypertrophy and cardiac fibrosis. Our results show that contrary to prior reports of cardiac regenerations, MRL mice progress to heart failure more rapidly following I/R injury as marked by a significant decrease in LVEF, increase in LVEDV, LV mass, individual myocyte size, and fibrosis in the post-ischemic myocardium. Therefore, we conclude that MRL mice do not exhibit regeneration of the LV or enhanced functional improvement in response to coronary ligation. However, unlike prior studies, we matched initial infarct size in MRL and C57 mice, used high frequency echocardiography, and histological analysis to reach this conclusion. The prospect of cardiac regeneration after ischemia in MRL mice seems to have attenuated interest, given the multiple negative studies and the promise of stem cell cardiac regeneration. However, our novel observation that MRL may possess an impaired compensated hypertrophy response makes the MRL mouse strain an interesting model in the study of cardiac hypertrophy. PMID- 25035061 TI - Staurosporine from the endophytic Streptomyces sp. strain CNS-42 acts as a potential biocontrol agent and growth elicitor in cucumber. AB - Chinese medicinal plants and their surrounding rhizospheric soil serve as promising sources of actinobacteria. A total of 180 actinobacteria strains were isolated from the rhizosphere soil, leaves, stems, and roots of nine selected plants and have been identified as potential biocontrol agents against Fusarium oxysporum f. sp. cucumerinum. An endophytic strain CNS-42 isolated from Alisma orientale showed the largest zone of inhibition demonstrating a potent effect against F. oxysporum f. sp. cucumerinum and a broad antimicrobial activity against bacteria, yeasts, and other pathogenic fungi. The in vivo biocontrol assays showed that the disease severity index was significantly reduced (P < 0.05), and plant shoot fresh weight and height increased greatly (P < 0.05) in plantlets treated with strain CNS-42 compared to the negative control. This isolate was identified as Streptomyces sp. based on cultural, physiological, morphological characteristics, and 16S rRNA gene analysis. Further bioassay guided isolation and purification revealed that staurosporine was responsible for its antifungal and plant growth promoting activities and the latter property of staurosporine is reported for the first time. The in vivo assay was further performed and indicated that staurosporine showed good growth promoting effect on the plant shoot biomass of cucumber. This is the first critical evidence identifying CNS-42 as a biocontrol agent for the soil borne pathogen, F. oxysporum f. sp. cucumerinum. PMID- 25035062 TI - Use of chronic disease management algorithms in Australian community pharmacies. AB - BACKGROUND: In Australia, standardized chronic disease management algorithms are available for medical practitioners, nursing practitioners and nurses through a range of sources including prescribing software, manuals and through government and not-for-profit non-government organizations. There is currently no standardized algorithm for pharmacist intervention in the management of chronic diseases.. AIM: To investigate if a collaborative community pharmacists and doctors' model of care in chronic disease management could improve patients' outcomes through ongoing monitoring of disease biochemical markers, robust self management skills and better medication adherence. DESIGN: This project was a pilot pragmatic study, measuring the effect of the intervention by comparing the baseline and the end of the study patient health outcomes, to support future definitive studies. Algorithms for selected chronic conditions were designed, based on the World Health Organisation STEPSTM process and Central Australia Rural Practitioners' Association Standard Treatment Manual. They were evaluated in community pharmacies in 8 inland Australian small towns, mostly having only one pharmacy in order to avoid competition issues. The algorithms were reviewed by Murrumbidgee Medicare Local Ltd, New South Wales, Australia, Quality use of Medicines committee. They constitute a pharmacist-driven, doctor/pharmacist collaboration primary care model. The Pharmacy owners volunteered to take part in the study and patients were purposefully recruited by in-store invitation. RESULTS: Six out of 9 sites' pharmacists (67%) were fully capable of delivering the algorithm (each site had 3 pharmacists), one site (11%) with 2 pharmacists, found it too difficult and withdrew from the study, and 2 sites (22%, with one pharmacist at each site) stated that they were personally capable of delivering the algorithm but unable to do so due to workflow demands. CONCLUSION: This primary care model can form the basis of workable collaboration between doctors and pharmacists ensuring continuity of care for patients. It has potential for rural and remote areas of Australia where this continuity of care may be problematic. PMID- 25035063 TI - The strength of weak connections in the macaque cortico-cortical network. AB - Examination of the cortico-cortical network of mammals has unraveled key topological features and their role in the function of the healthy and diseased brain. Recent findings from social and biological networks pinpoint the significant role of weak connections in network coherence and mediation of information from segregated parts of the network. In the current study, inspired by such findings and proposed architectures pertaining to social networks, we examine the structure of weak connections in the macaque cortico-cortical network by employing a tract-tracing dataset. We demonstrate that the cortico-cortical connections as a whole, as well as connections between segregated communities of brain areas, comply with the architecture suggested by the so-called strength-of weak-ties hypothesis. However, we find that the wiring of these connections is not optimal with respect to the aforementioned architecture. This configuration is not attributable to a trade-off with factors known to constrain brain wiring, i.e., wiring cost and efficiency. Lastly, weak connections, but not strong ones, appear important for network cohesion. Our findings relate a topological property to the strength of cortico-cortical connections, highlight the prominent role of weak connections in the cortico-cortical structural network and pinpoint their potential functional significance. These findings suggest that certain neuroimaging studies, despite methodological challenges, should explicitly take them into account and not treat them as negligible. PMID- 25035064 TI - Long thoracic nerve injury in breast cancer patients treated with axillary lymph node dissection. AB - PURPOSE: The objectives of this study were to electromyographically (EMG) describe and analyze factors associated with long thoracic nerve injuries in breast cancer patients after axillary lymph node dissection. METHODS: This was a prospective longitudinal observational study. Two hundred sixty-four women with primary invasive breast cancer were included between 2008 and 2011. All of them were treated by axillary lymph node dissection. Patients were evaluated at 1, 6, and 12 months following surgery. The presence of winged scapula was systematically tested at each follow-up and an EMG performed whenever it was observed. Affected and unaffected groups were compared for demographic, tumour, and treatment variables. Student t test, Mann-Whitney U test, chi-squared or Fisher test were computed as appropriate. RESULTS: Among the 36 (13.6%) winged scapula observed, the EMG confirmed long thoracic nerve injury in 30 (11.3%) of them, 27 were partial axonotmesis and three were severe axonotmesis. At 12 months, the EMG showed that injury persisted in six (2.27%) patients. Patients with long thoracic nerve injury had a lower body mass index than unaffected patients (26.2 vs. 28.2, p = 0.045). Age, tumour stage, type of breast surgery, nodes excised, surgical complications, previous chemotherapy and previous hormonotherapy were not factors associated with winged scapula. CONCLUSIONS: A lower body mass index was the only factor associated to long thoracic nerve injury. In most of the patients, the EMG showed partial axonotmesis. At 12 months, 2.27% of studied patients remained with an unsolved long thoracic nerve injury. PMID- 25035065 TI - Appendiceal adhesion to synthetic mesh after laparoscopic sacrocolpopexy: a case report. AB - Minimally invasive alternatives to abdominal sacrocolpopexy have been shown to be equivalent with low overall complication rates. A small number of direct mesh related gastrointestinal complications have been reported in the literature. Sacrocolpopexy with mesh retroperitonealization is recommended to minimize bowel adhesions. A 53-year-old nulligravid woman presented with persistent right lower quadrant pain 1 year after laparoscopic sacrocolpopexy. The polypropylene mesh used during the case was retroperitonealized. Computed tomography (CT) prior to surgical exploration revealed no obvious pathology. On diagnostic laparoscopy, appendiceal adhesion to mesh requiring an appendectomy was observed. The patient's symptoms resolved after surgical intervention. Appendiceal adhesion to surgical mesh leading to chronic discomfort is a potential complication of intraperitoneal synthetic mesh placement. Our case emphasizes that bowel adhesions may occur even after proper mesh retroperitonealization. Appendiceal adhesion to the surgical site is a potential complication of retroperitonealized synthetic mesh placement at the time of sacrocolpopexy. PMID- 25035066 TI - Aberrant expression of p-Smad3 in oral carcinogenesis. AB - OBJECTIVE: Smads are the keys of transforming growth factor beta (TGFbeta) signaling cascade and play a crucial role in many cancers. Once TGFbeta receptors are activated, Smad2 and Smad3 are phosphorylated and form complexes with Smad4. These complexes translocate from the cytoplasm to the nucleus where they regulate the target genes. The subcellular localization of phosphorylated Smad3 (p-Smad3) in oral carcinogenesis has never been reported. This study investigated the subcellular distribution of p-Smad3 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL) with and without dysplasia. MATERIALS AND METHODS: Expression of p-Smad3 was immunohistochemically examined in 150 samples including OSCC, OL with and without dysplasia, and normal mucosa (NM). Cytoplasmic and nuclear positive cells were counted separately. The results were present as the frequency of positive cases. RESULTS: Cytoplasmic and/or nuclear staining for p Smad3 was detected. The frequency of cytoplasmic expression in OL with dysplasia was significantly higher than that in NM. The numbers of cytoplasmic expression and cytoplasmic plus nuclear expression in OSCC were significantly higher than those in NM and OL with and without dysplasia. CONCLUSIONS: The overexpression of cytoplasmic p-Smad3 in OL with dysplasia and in OSCC suggests that p-Smad3 is in the nonfunctional state. Thus, the growth inhibitory effect of p-Smad3 is diminished during oral carcinogenesis. The cytoplasmic plus nuclear staining of p Smad3 was aberrant in OSCC. CLINICAL RELEVANCE: The cytoplasmic staining of p Smad3 may serve as a marker for oral premalignant lesions whereas the cytoplasmic plus nuclear staining of p-Smad3 may serve as a marker for OSCC. PMID- 25035067 TI - Color alteration, hydrogen peroxide diffusion, and cytotoxicity caused by in office bleaching protocols. AB - OBJECTIVES: This study evaluated the color alteration, cytotoxicity, and hydrogen peroxide (HP) diffusion associated with different in-office bleaching protocols. MATERIALS AND METHODS: Bovine enamel/dentin disks were subjected to three bleaching sessions with 35 % HP (three 15-min applications), 35 % HP (one 45-min application), or 20 % HP (one 45-min application). The control group was not bleached. Before bleaching, the disks were adapted to artificial pulp chambers positioned in compartments containing 1 ml of acetate buffer or medium, so that the dentin remained in contact with these substances. Immediately after bleaching, the HP that diffused through the disks was stabilized by acetate buffer and was quantified (two-way repeated measures ANOVA/Fisher's protected least significant difference (PLSD) test; alpha = 5 %). Cells of mouse dental papilla cell-23 (MDPC-23) were incubated in this culture media for 1 h, followed by analysis of cellular metabolism (methyl tetrazolium assay) (one-way ANOVA/Tukey test; alpha = 5 %) and morphology (scanning electron microscopy). The specimen color alteration (DeltaE) was analyzed by reflection spectrophotometry (two-way repeated measures ANOVA/Fisher's PLSD test; alpha = 5 %). RESULTS: All protocols showed equal effectiveness at the end of the treatment. HP diffusion was significantly higher in the groups bleached with 35 % HP. Reapplication of 35 % HP resulted in increased diffusion only in the first session; however, the decrease in cell metabolism was similar for all studied protocols. CONCLUSION: Despite greater peroxide diffusion in the groups treated with 35 % HP, all protocols showed the same effectiveness and were cytotoxic to MDPC-23 cells. CLINICAL RELEVANCE: Bleaching protocols using high HP concentrations should be avoided because they exert aggressive actions on odontoblast-like cells. PMID- 25035068 TI - The archaic chaperone-usher pathways may depend on donor strand exchange for intersubunit interactions. AB - Subunit-subunit interactions of the classical and alternate chaperone-usher (CU) systems have been shown to proceed through a donor strand exchange (DSE) mechanism. However, it is not known whether DSE is required for intersubunit interactions in the archaic CU system. We have previously shown that the Myxococcus xanthus Mcu system, a member of the archaic CU family that functions in spore coat formation, is likely to use the principle of donor strand complementation to medicate chaperone-subunit interactions analogous to the classical CU pathway. Here we describe the results of studies on Mcu subunit subunit interactions. We constructed a series of N-terminal-deleted, single amino acid-mutated and donor strand-complemented Mcu subunits, and characterized their abilities to participate in subunit-subunit interactions. It appears that certain residues in both the N and C termini of McuA, a subunit of the Mcu system, play a critical role in intersubunit interactions and these interactions may involve the general principle of DSE of the classical and alternate CU systems. In addition, the specificity of the M. xanthus CU system for Mcu subunits over other spore coat proteins is demonstrated. PMID- 25035069 TI - Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler. AB - AIM: To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps((r))/Rotahaler((r))) and a multi dose dry powder inhaler (Diskus((r))) in healthy volunteers. METHODS: An open label, randomised, repeat-dose, cross-over, adaptive design study (n = 36 in each part) evaluated SFC 50/250 MUg and SFC 50/100 MUg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration time curve over the dosing interval [AUC0-tau] and maximum plasma concentration [Cmax]. RESULTS: SFC 50/250 MUg Rotacaps/Rotahaler (S) showed 1.2-1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 MUg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8-1.25) for salmeterol (AUC0 tau and Cmax) and FP (AUC0-tau). Following SFC 50/100 MUg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2-1.4 fold higher in terms of FP (AUC0-tau and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. CONCLUSIONS: SFC 50/250 MUg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 MUg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 MUg requires further evaluation. PMID- 25035070 TI - Characterization and evaluation of 5-fluorouracil-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification technique. AB - The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU loaded SLNs can potentially be utilized in an anticancer drug delivery system. PMID- 25035072 TI - An STM study of molecular exchange processes in organic thin film growth. AB - The growth of a fullerene derivative (PCBM) on top of a layer of a tetrathiafulvalene (TTF) derivative previously deposited on Au(111) has been studied by scanning tunneling microscopy (STM). The results show that the preferential interaction with the gold substrate induces the exchange of PCBM molecules with the exTTF monolayer, expelling exTTF molecules to the outer surface. This exchange process is forbidden when the thickness of the exTTF layer increases above the monolayer, and the larger surface energy of PCBM leads to the growth of 3D islands. PMID- 25035071 TI - Preparation and characterization of fenofibrate-loaded nanostructured lipid carriers for oral bioavailability enhancement. AB - The aim of this study is to investigate the potential of nanostructured lipid carriers (NLCs) in improving the oral bioavailability of a lipid lowering agent, fenofibrate (FEN). FEN-loaded NLCs (FEN-NLCs) were prepared by hot homogenization followed by an ultrasonication method using Compritol 888 ATO as a solid lipid, Labrafil M 1944CS as a liquid lipid, and soya lecithin and Tween 80 as emulsifiers. NLCs were characterized in terms of particle size and zeta potential, surface morphology, encapsulation efficiency, and physical state properties. Bioavailability studies were carried out in rats by oral administration of FEN-NLC. NLCs exhibited a spherical shape with a small particle size (84.9 +/- 4.9 nm). The drug entrapment efficiency was 99% with a loading capacity of 9.93 +/- 0.01% (w/w). Biphasic drug release manner with a burst release initially, followed by prolonged release was depicted for in vitro drug release studies. After oral administration of the FEN-NLC, drug concentration in plasma and AUCt-infinity was fourfold higher, respectively, compared to the free FEN suspension. According to these results, FEN-NLC could be a potential delivery system for improvement of loading capacity and control of drug release, thus prolonging drug action time in the body and enhancing the bioavailability. PMID- 25035073 TI - Delay in the administration of all-trans retinoic acid and its effects on early mortality in acute promyelocytic leukemia: final results of a multicentric study in the United States. AB - Early death (ED) occurs in 10-30% of patients with acute promyelocytic leukemia (APL). Is all-trans retinoic acid (ATRA) promptly given and does it decrease overall early mortality? ATRA was administered within 24h of morphological suspicion in only 44% of the 120 consecutive patients treated in the four collaborating centers. Absence of disseminated intravascular coagulation (p=0.012) and admission to a non-university-affiliated hospital (p=0.032) were independent predictors of ATRA delay. ED occurred in 17% of patients, and was independently correlated only with ICU admission (p=0.002). Our results do not demonstrate that prompt (versus delayed) ATRA administration decreases overall early death. PMID- 25035074 TI - Glutathione S-transferase and MRP1 form an integrated system involved in the storage and transport of dinitrosyl-dithiolato iron complexes in cells. AB - Nitrogen monoxide (NO) is vital for many essential biological processes as a messenger and effector molecule. The physiological importance of NO is the result of its high affinity for iron in the active sites of proteins such as guanylate cyclase. Indeed, NO possesses a rich coordination chemistry with iron and the formation of dinitrosyl-dithiolato iron complexes (DNICs) is well documented. In mammals, NO generated by cytotoxic activated macrophages has been reported to play a role as a cytotoxic effector against tumor cells by binding and releasing intracellular iron. Studies from our laboratory have shown that two proteins traditionally involved in drug resistance, namely multidrug-resistance protein 1 and glutathione S-transferase, play critical roles in intracellular NO transport and storage through their interaction with DNICs (R.N. Watts et al., Proc. Natl. Acad. Sci. USA 103:7670-7675, 2006; H. Lok et al., J. Biol. Chem. 287:607-618, 2012). Notably, DNICs are present at high concentrations in cells and are biologically available. These complexes have a markedly longer half-life than free NO, making them an ideal "common currency" for this messenger molecule. Considering the many critical roles NO plays in health and disease, a better understanding of its intracellular trafficking mechanisms will be vital for the development of new therapeutics. PMID- 25035075 TI - SG2NA recruits DJ-1 and Akt into the mitochondria and membrane to protect cells from oxidative damage. AB - SG2NA is a WD-40 repeat protein with multiple protein-protein interaction domains of unknown functions. We demonstrate that it associates with the antioxidant protein DJ-1 and the survival kinase Akt. The C-terminal WD-40 repeat domain of SG2NA is required for its interaction with Akt, while DJ-1 binds it further upstream. No interaction between DJ-1 and Akt occurs in the absence of SG2NA. SG2NA, DJ-1, and Akt colocalize in mitochondria and plasma membrane. Their association is enhanced by increasing levels of reactive oxygen species up to a threshold level but falters thereafter with further increase in oxidants. Mutants of DJ-1 found in patients with familial parkinsonism are not recruited by SG2NA, suggesting its role in neuroprotection. Cells depleted of SG2NA are susceptible, while those overexpressing it are resistant to apoptosis induced by oxidative stress. Our study thus unravels a novel pathway of recruitment of Akt and DJ-1 that provides protection against oxidative stress, especially in neurons. PMID- 25035076 TI - A1M, an extravascular tissue cleaning and housekeeping protein. AB - Alpha-1-microglobulin (A1M) is a small protein found intra- and extracellularly in all tissues of vertebrates. The protein was discovered 40 years ago and its physiological role remained unknown for a long time. A series of recent publications have demonstrated that A1M is a vital part of tissue housekeeping. A strongly electronegative free thiol group forms the structural basis of heme binding, reductase, and radical-trapping properties. A rapid flow of liver produced A1M through blood and extravascular compartments ensures clearing of biological fluids from heme and free radicals and repair of oxidative lesions. After binding, both the radicals and the A1M are electroneutral and therefore do not present any further oxidative stress to tissues. The biological cleaning cycle is completed by glomerular filtration, renal degradation, and urinary excretion of A1M heavily modified by covalently linked radicals and heme groups. Based on its role as a tissue housekeeping cleaning factor, A1M constitutes a potential therapeutic drug candidate in treatment or prophylaxis of diseases or conditions that are associated with pathological oxidative stress elements. PMID- 25035077 TI - Intracellular oxidation of hydroethidine: compartmentalization and cytotoxicity of oxidation products. AB - Hydroethidine (HE) is a blue fluorescent dye that is intracellularly converted into red-emitting products on two-electron oxidation. One of these products, namely 2-hydroxyethidium, is formed as the result of HE superoxide anion-specific oxidation, and so HE is widely used for the detection of superoxide in cells and tissues. In our experiments we exploited three cell lines of different origin: K562 (human leukemia cells), A431 (human epidermoid carcinoma cells), and SCE2304 (human mesenchymal stem cells derived from endometrium). Using fluorescent microscopy and flow cytometry analysis, we showed that HE intracellular oxidation products accumulate mostly in the cell mitochondria. This accumulation provokes gradual depolarization of mitochondrial membrane, affects oxygen consumption rate in HE-treated cells, and causes cellular apoptosis in the case of high HE concentrations and/or long cell incubations with HE, as well as a high rate of HE oxidation in cells exposed to some stimuli. PMID- 25035078 TI - Hippocampal GLP-1 receptors influence food intake, meal size, and effort-based responding for food through volume transmission. AB - Glucagon-like peptide-1 (GLP-1) is produced in the small intestines and in nucleus tractus solitarius (NTS) neurons. Activation of central GLP-1 receptors (GLP-1Rs) reduces feeding and body weight. The neural circuits mediating these effects are only partially understood. Here we investigate the inhibition of food intake and motivated responding for food in rats following GLP-1R activation in the ventral hippocampal formation (HPFv), a region only recently highlighted in food intake control. Increased HPFv GLP-1R activity following exendin-4 administration potently reduced food intake (both chow and Western diet) and body weight, whereas HPFv GLP-1R blockade increased food intake. These hypophagic effects were based on reduced meal size, and likely do not involve nausea as HPFv exendin-4 did not induce a conditioned flavor avoidance. HPFv GLP-1R activation also reduced effort-based responding for food under an operant progressive ratio reinforcement schedule, but did not affect food conditioned place preference expression. To investigate possible routes of HPFv GLP-1 signaling, immunohistochemical analysis revealed the absence of GLP-1 axon terminals in the HPFv, suggesting volume transmission as a mechanism of action. Consistent with this, the presence of active GLP-1 was detected in both the cerebrospinal fluid (CSF) and the HPFv. The source of CSF GLP-1 may be NTS GLP-1-producing neurons, as, (1) ~30% of NTS GLP-1 neurons colocalized with the retrograde tracer fluorogold (FG) following lateral ventricle FG injection, and (2) GLP-1 immunoreactive axon terminals were observed adjacent to the ventricular ependymal layer. Collectively these findings illuminate novel neuronal and behavioral mechanisms mediating food intake reduction by GLP-1. PMID- 25035079 TI - Amylin modulates the mesolimbic dopamine system to control energy balance. AB - Amylin acts in the CNS to reduce feeding and body weight. Recently, the ventral tegmental area (VTA), a mesolimbic nucleus important for food intake and reward, was identified as a site-of-action mediating the anorectic effects of amylin. However, the long-term physiological relevance and mechanisms mediating the intake-suppressive effects of VTA amylin receptor (AmyR) activation are unknown. Data show that the core component of the AmyR, the calcitonin receptor (CTR), is expressed on VTA dopamine (DA) neurons and that activation of VTA AmyRs reduces phasic DA in the nucleus accumbens core (NAcC). Suppression in NAcC DA mediates VTA amylin-induced hypophagia, as combined NAcC D1/D2 receptor agonists block the intake-suppressive effects of VTA AmyR activation. Knockdown of VTA CTR via adeno associated virus short hairpin RNA resulted in hyperphagia and exacerbated body weight gain in rats maintained on high-fat diet. Collectively, these findings show that VTA AmyR signaling controls energy balance by modulating mesolimbic DA signaling. PMID- 25035080 TI - 'Can you look me in the face?' Short-term SSRI administration reverts avoidant ocular face exploration in subjects at risk for psychopathology. AB - Anxiety and depression are associated with altered ocular exploration of facial stimuli, which could have a role in the misinterpretation of ambiguous emotional stimuli. However, it is unknown whether a similar pattern is seen in individuals at risk for psychopathology and whether this can be modified by pharmacological interventions used in these disorders. In Study 1, eye gaze movement during face discrimination was compared in volunteers with high vs low neuroticism scores on the Eysenck Personality Questionnaire. Facial stimuli either displayed a neutral, happy, or fearful expression. In Study 2, volunteers with high neuroticism were randomized in a double-blind design to receive the selective serotonin reuptake inhibitor citalopram (20 mg) or placebo for 7 days. On the last day of treatment, eye gaze movement during face presentation and the recognition of different emotional expressions was assessed. In Study 1, highly neurotic volunteers showed reduced eye gaze towards the eyes vs mouth region of the face compared with low neurotic volunteers. In Study 2, citalopram increased gaze maintenance over the face stimuli compared with placebo and enhanced recognition of positive vs negative facial expressions. Longer ocular exploration of happy faces correlated positively with recognition of positive emotions. Individuals at risk for psychopathology presented an avoidant pattern of ocular exploration of faces. Short-term SSRI administration reversed this bias before any mood or anxiety changes. This treatment effect may improve the capacity to scan social stimuli and contribute to the remediation of clinical symptoms related to interpersonal difficulties. PMID- 25035081 TI - Mineralocorticoid receptor stimulation improves cognitive function and decreases cortisol secretion in depressed patients and healthy individuals. AB - Memory and executive function are often impaired in patients with major depression, while cortisol secretion is increased. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory, executive function, and cortisol inhibition. Here, we investigated whether MR stimulation with fludrocortisone (1) improves memory and executive function and (2) decreases cortisol secretion in depressed patients and healthy individuals. Twenty-four depressed patients without medication and 24 age-, sex-, and education-matched healthy participants received fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured verbal memory, visuospatial memory, executive function, psychomotor speed, and salivary cortisol secretion during cognitive testing between 1400 and 1700 hours. For verbal memory and executive function, we found better performance after fludrocortisone compared with placebo across groups. No treatment effect on other cognitive domains emerged. Depressed patients performed worse than healthy individuals in psychomotor speed and executive function. No group effect or group * treatment interaction emerged on other cognitive domains. Fludrocortisone decreased cortisol secretion across groups and there was a significant correlation between cortisol inhibition and verbal memory performance. Our data suggest a crucial role of MR in verbal memory and executive function and demonstrate the possibility to improve cognition in depressed patients and healthy individuals through MR stimulation. PMID- 25035082 TI - XRCC5 as a risk gene for alcohol dependence: evidence from a genome-wide gene-set based analysis and follow-up studies in Drosophila and humans. AB - Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence. PMID- 25035083 TI - Sensitive periods in affective development: nonlinear maturation of fear learning. AB - At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development. PMID- 25035084 TI - GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self administering rats. AB - Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse. PMID- 25035085 TI - Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus. AB - Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms. PMID- 25035087 TI - Antioxidant therapy for patients with chronic pancreatitis: A systematic review and meta-analysis. AB - BACKGROUND & AIMS: Chronic pancreatitis is a progressive, inflammatory disease of pancreas characterized by significant abdominal pain, malabsorption, and diabetes mellitus. Antioxidant therapy has been proposed as an effective treatment for painful chronic pancreatitis. We performed a meta-analysis of trials in which antioxidant therapy was compared with placebo in chronic pancreatitis. METHODS: We searched six databases to identify relevant trials. Results are expressed as risk ratio (RR) or standardized mean difference (SMD) with accompanying 95% confidence intervals (CI). The meta-analysis was performed with the fixed-effects model or random-effects model according to heterogeneity. RESULTS: Eight studies including 573 patients met the inclusion criteria. A meta-analysis of these studies revealed that the intervention of antioxidants was associated with a significant increase in patients with pain relief (RR, 2.15; 95% CI, 1.72-2.69; P < 0.00001), and a significant decrease in patients' need for analgesics (RR, 0.56; 95% CI, 0.40-0.78; P = 0.0006). For pain score, antioxidants improved pain tolerance in chronic pancreatitis patients (SMD: -0.41; 95% CI: -0.83 to -0.10; P = 0.0005). Additionally, antioxidants may cause some adverse reactions (RR, 4.22; 95% CI: 2.17-8.20; P < 0.0001). CONCLUSIONS: Based on current evidence, oxidative stress may play an important role in the pathophysiology of chronic pancreatitis, and administration of antioxidants to patients with painful chronic pancreatitis is effective in relieving pain. Antioxidant supplements may be advocated as one medical therapy for chronic pancreatitis patients with low antioxidant capacity in their blood. PMID- 25035086 TI - Differential roles of alpha6beta2* and alpha4beta2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice. AB - Mesolimbic alpha6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various alpha6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of alpha6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of alpha6beta2* nAChRs and genetic deletion of the alpha6 or alpha4 subunits in mice. We found that alpha6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WT littermates but that alpha4 KO failed to show nicotine preference, suggesting that alpha6alpha4beta2*-nAChRs are involved. Furthermore, alpha6beta2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective alpha6beta2* alpha-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, alpha6 KO failed to condition to cocaine, but cocaine CPP in the alpha4 KO was preserved. Intriguingly, alpha-conotoxin MII [H9A; L15A], blocked cocaine conditioning in alpha4 KO mice, implicating alpha6beta2* nAChRs in cocaine reward. Importantly, these effects did not generalize as alpha6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the alpha6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic alpha6beta2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential. PMID- 25035088 TI - Autism spectrum disorder: FRAXE mutation, a rare etiology. AB - Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication, restricted interests and repetitive behaviors. Fragile X E is associated with X-linked non-specific mild intellectual disability (ID) and with behavioral problems. Most of the known genetic causes of ASD are also causes of ID, implying that these two identities share common genetic bases. We present a child with an ASD with a normal range of intelligence quotient, that later evolved to compulsive behavior. FRAXE locus analysis by polymerase chain reaction revealed a complete mutation of the FMR 2 gene. This report stresses the importance of clinicians being aware of the association between a full mutation of FMR2 and ASD associated with compulsive behavior despite normal intellectual level. PMID- 25035089 TI - Increasing Access to an ASD Imitation Intervention Via a Telehealth Parent Training Program. AB - Systematic research focused on developing and improving strategies for the dissemination and implementation of effective ASD services is essential. An innovative and promising area of research is the use of telehealth programs to train parents of children with ASD in intervention techniques. A hybrid telehealth program, combining self-directed internet-based instruction with remote coaching, was created to introduce parents of children with ASD to an imitation intervention. A single-subject multiple-baseline design study evaluated the effect of the program on changes in parent and child behavior. Parents improved in their use of the intervention techniques and their children demonstrated concurrent increases in spontaneous imitation skills. Parents also indicated that the intervention and telehealth service delivery model were acceptable, useable, and effective. Results suggest that this hybrid telehealth program has the potential to increase access to ASD services. PMID- 25035090 TI - Brief report: High and low level initiations of joint attention, and response to joint attention: differential relationships with language and imitation. AB - Frequency of high-level (showing/pointing) and low-level (coordinated gaze shifts) behaviors on the Early Social Communication Scales are often used as a measure of joint attention initiations (IJA). This study examined the degree to which these skills and response to joint attention (RJA; e.g. gaze following) were differentially related to measures of language and imitation in 53 children with autism spectrum disorder between the ages of 22 and 93 months. High-level and low-level IJA were not associated with each other, and only high-level IJA was associated with RJA, and language and imitation measures. High-level IJA and RJA were unique predictors of imitation, while RJA was a unique predictor of language. Findings indicate that IJA involves distinct skills, with high-level behaviors more closely related to social-communication skills. PMID- 25035091 TI - The use of contrast-enhanced magnetic resonance imaging to diagnose cesarean scar pregnancies. AB - OBJECTIVE: To evaluate whether contrast-enhanced magnetic resonance imaging (MRI) could be used as a routine method for diagnosing cesarean scar pregnancy (CSP). METHODS: A retrospective study was performed, with review and analysis of medical records, ultrasonography results, MRI results, and clinical outcomes of 44 women with CSP admitted to Beijing Chaoyang Hospital, Beijing, China, between May 2010 and November 2013. The women initially underwent ultrasonography followed approximately 5 days later by contrast-enhanced MRI. RESULTS: CSP was accurately diagnosed in 42 cases (95.5%) using contrast-enhanced MRI compared with 39 cases (88.6%) using ultrasonography (P<0.05). Two cases with a heterogeneous signal intensity pattern using MRI were initially misdiagnosed as a uterine leiomyoma and a trophoblastic tumor. No contrast agent-related complications occurred. The typical findings of a gestational sac embedded in the anterior lower part of the uterus in the sagittal T2-weighted views were identified in all the patients. All patients recovered well without experiencing major morbidity after treatment. CONCLUSION: Contrast-enhanced MRI could be used as a reliable adjunct and initial imaging modality for diagnosing CSP in select cases. The imaging features of contrast-enhanced MRI may result in a more accurate diagnosis before specific treatment for CSP. PMID- 25035092 TI - Psychiatric evaluation of women who were assisted at a university referral center in Campinas, Brazil, following an experience of sexual violence. AB - OBJECTIVE: To present the sociodemographic characteristics and psychiatric symptoms of women who have been raped. METHODS: Between 2006 and 2010, a retrospective study was conducted of 468 women who underwent psychiatric evaluation at a university referral center in Brazil after an experience of sexual violence. RESULTS: The women had a mean age of 24.1 years; were predominantly white, unmarried, childless, and employed; had 9-11 years of education; and had a religion. Rape was the first sexual intercourse for 124 (26.8%) of 462 for whom data were available; 53 (13.6%) of 389 had a personal history of sexual violence and 29 (8.0%) of 361 had a family history. No psychiatric symptoms were reported in 146 (32.9%) of 444 women, mild/short-term symptoms were reported in 107 (24.1%), and a psychiatric diagnosis was made for 191 (43.0%). Psychiatric comorbidity was seen in 59 (12.6%) women, and 174 (38.0%) received pharmacologic treatment. All follow-up consultations were attended by 215 (45.9%) of 468 women; 166 (35.5%) attended some, and 87 (18.6%) attended only one during the 6-month follow-up period. CONCLUSION: The frequency and severity of psychiatric symptoms and mental disorders among women who have been raped highlights the importance of mental health monitoring. PMID- 25035093 TI - Correlates of completing routine vaccination among children in Mysore, India. AB - BACKGROUND: More than half of the over 18 million incompletely vaccinated children worldwide in 2011 lived in India (32%), Nigeria (14%) and Indonesia (7%). Overall immunization coverage in India was 61% in 2009. Few studies have explored the role of parental attitudes in children's vaccination. OBJECTIVES: To explore the correlates of completion of routine vaccination among children in Mysore City, India. METHODS: A two-stage probability sample of 800 girls aged 11 15 years was selected from 12 schools in Mysore to take home questionnaires to be completed by their parents. The questionnaire elicited information on socio demographic characteristics, attitudes and practices relevant to vaccination. Bivariate and multivariable logistic regression analyses were performed to identify factors independently associated with completion of routine vaccination. RESULTS: Of the 797 (99.6%) parents who completed questionnaires, 29.9% reported completing all routine vaccinations for their children. Parents who had obtained optional vaccinations for their children (adjusted odds ratio [AOR]: 4.56; 95% confidence interval [CI]: 3.09-6.74), who believed in vaccines' effectiveness (2.50; 1.19-5.28) and who asked doctors or nurses about vaccination (2.07; 1.10 3.90) were significantly more likely to report complete vaccination, after controlling for all other factors. Belief that the disease was more protective than vaccination was independently associated with lower likelihood of vaccination series completion (0.71; 0.52-0.96). No other attitudinal or socio demographic factors were associated with vaccine completion. CONCLUSION: Interest and belief in vaccine effectiveness are important facilitators motivating parents to obtain full vaccination for their children in India. PMID- 25035094 TI - Structured clinical follow-up for CKD stage 5 may safely postpone dialysis. AB - BACKGROUND AND OBJECTIVES: The optimal timing of dialysis initiation is still unclear. We aimed to ascertain whether a strict clinical follow-up can postpone need for dialysis in chronic kidney disease (CKD) stage 5 patients. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We reviewed records of all consecutive adult patients attending our conservative CKD stage 5 outpatient clinic from 2001 to 2010. Chronicity was defined as two consecutive estimated glomerular filtration rate (eGFR) measurements below 15 ml/min/1.73 m(2). Characteristics of subjects, including comorbidities, were assessed at baseline; blood pressure and serum markers of uremia were assessed both at first and last visit. GFR was estimated by the 4-variable Modification of Diet in Renal Disease (MDRD) formula. RESULTS: In the 312 patients analyzed baseline eGFR was 9.7 +/- 2.7 ml/min, which declined by 1.93 +/- 4.56 ml/min after 15.6 +/- 18.2 months. Age was inversely related to eGFR decline (r -0.27, p = 0.000). During conservative follow-up 55 subjects (18%) died. In comparison with those eventually entering dialysis, deceased subjects were older and had a longer follow-up with no CKD progression. Multivariate analysis identified age, proteinuria and lower baseline K values as the only independent determinants of death. One hundred ninety-four subjects (66%) started dialysis with an average eGFR of 6.1 +/- 1.9 ml/min. During 35.8 +/ 24.7 months of dialysis follow-up, 84 patients died. Multivariate analysis identified age as the main determinant of death (hazard ratio [HR] for every year 1.07, 95% confidence interval [CI] 1.04-1.11, p 0.000). Patients starting dialysis with eGFR below the median, e.g. <5.7 ml/min, showed a better survival (HR for mortality 0.52, 95% CI 0.30-0.89, p 0.016) than the other group. CONCLUSIONS: A well-organized nephrological outpatient clinic for conservative follow-up of CKD stage five patients can delay dialysis entry as long as 1 year. Starting dialysis with eGFR lower than 6 ml/min does not confer any increased risk of death in selected early-referral patients. PMID- 25035095 TI - Gender effect on quality of life in hemodialysis patients: response to Einollahi and Motalebi. PMID- 25035096 TI - Routine piloting in systematic reviews--a modified approach? AB - BACKGROUND: A continuous growth in the publication of research papers means that there is an expanding volume of data available to the systematic reviewer. Sometimes, researchers can become overwhelmed by the sheer volume of data being processed, leading to inefficient data extraction. This paper seeks to address this problem by proposing a modification to the current systematic review methodology. PROPOSED METHOD: This paper details the routine piloting of a systematic review all the way through to evidence-synthesis stage using data from a sample of included papers. RESULTS AND DISCUSSION: The result of piloting a sample of papers through to evidence-synthesis stage is to produce a 'mini systematic review'. Insights from such a pilot review may be used to modify the criteria in the data extraction form. It is proposed that this approach will ensure that in the full review the most useful and relevant information is extracted from all the papers in one phase without needing to re-visit the individual papers at a later stage. CONCLUSIONS: Routine piloting in systematic reviews has been developed in response to advances in information technology and the subsequent increase in rapid access to clinical papers and data. It is proposed that the routine piloting of large systematic reviews will enable themes and meaning in the data to become apparent early in the review process. This, in turn, will facilitate the efficient extraction of data from all the papers in the full review. It is proposed that this approach will result in increased validity of the review, with potential benefits for increasing efficiency. PMID- 25035097 TI - Lactobacillus rhamnosus GG suspected infection in a newborn with intrauterine growth restriction. AB - A disseminated Lactobacillus rhamnosus GG ATCC 53103 infection was suspected in a 6 day-old newborn with intrauterine growth restriction (IUGR) symptoms, treated empirically with antibiotics and given L. rhamnosus GG with the aim of preventing antibiotic-associated gastrointestinal complications. The level of C-reactive protein on day 5 compared with day 2 was increased in spite of negative urine and cerebrospinal fluid cultures. The blood sampled on day 6 was found to be positive for lactobacilli, and the isolate was pre-identified as L. rhamnosus or Lactobacillus casei on day 11. The strain identity was then verified as L. rhamnosus GG through PCR and 16S rRNA sequencing. Genotyping with the rep-PCR and AFLP methods confirmed the 100% genetic similarity for both the strain isolated from patient blood and the probiotic product. The newborn became touch-sensitive, cried a lot, had worsening laboratory test results, and increased inflammation parameters, but no fever was observed. After a further 9 days of antibiotic therapy, blood cultures became negative, and laboratory tests improved on day 25. The patient was discharged from the hospital after 27 days. IUGR with a possible link to L. rhamnosus GG bacteraemia might be a new potential risk group, beside patients with organ failure, immunocompromised status and dysfunctional gut barrier mechanisms, for which safe use of probiotics needs careful attention. Universally accepted or improved guidelines for the safer administration of probiotics in risk groups are urgently needed. This report should not discourage the use of probiotics, but should highlight the need for their careful use in IUGR patients. PMID- 25035098 TI - Spinal cord infarction in giant cell arteritis associated with scalp necrosis. AB - Spinal cord infarction is extremely rare in patients with giant cell arteritis (GCA). There are only four case reports in the literature. We describe a 65-year old man who presented with sudden paraplegia and back pain of 4-days duration with sensory loss below the umbilicus and bilateral scalp necrosis. Magnetic resonance imaging finding was consistent with dorsal spinal cord infarction. Biopsy of the temporal artery confirmed the diagnosis of GCA. The patient was treated with high dose of corticosteroids, which resulted in healing of the scalp ulcerations in 3 weeks, but the paraplegia was irreversible. To our knowledge, this is the first report of spinal cord infarction and simultaneous occurrence of bilateral scalp necrosis in a histopathologically proven GCA. Although literature about spinal cord involvement in GCA is very limited, cord infarction is associated with high mortality and therapeutic challenges since little is understood regarding the pathogenesis that leads to infarction. PMID- 25035099 TI - Cognition in patients with newly diagnosed brain metastasis: profiles and implications. AB - Cognitive impairment is a common symptom in patients with brain metastasis, and significant cognitive dysfunction is prevalent in a majority of patients who are still able to engage in basic self-care activities. In the current study, the neurocognitive performance of 32 patients with brain metastasis and 32 demographically-matched controls was examined using a battery of standardized neuropsychological tests, with the goal of comprehensively examining the cognitive functioning of newly diagnosed brain metastasis patients. The cognition of all patients was assessed within 1 week of beginning treatment for brain metastasis. Results indicated impairments in verbal memory, attention, executive functioning, and language in relation to healthy controls. Performance in relation to appropriate normative groups was also examined. Overall, cognitive deficits were prevalent and memory was the most common impairment. Given that cognitive dysfunction was present in this cohort of patients with largely minimal functional impairment, these results have implications for patients, caregivers and health care providers treating patients with brain metastasis. PMID- 25035100 TI - TERT promoter mutations and BRAF mutations are rare in sporadic, and TERT promoter mutations are absent in NF1-related malignant peripheral nerve sheath tumors. AB - Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT promoter mutations) occur frequently in tumors of neuroectodermal origin such as melanoma and glioma. Many of these tumors are of neuroectodermal or ectomesenchymal origin which is suggestive of TERT promoter mutations playing a role in the development of malignant peripheral nerve sheath tumors (MPNSTs). In melanoma a correlation has been suggested between the occurrence of TERT promoter mutations and v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutations. We investigated TERT promoter and BRAF mutation frequency in respectively 94 and 86 consecutive MPNST cases from our institute. TERT promoter mutation analysis on DNA from formalin-fixed, paraffin-embedded specimens was performed by SNaPshot analysis. Sequence analysis of BRAF was performed by bidirectional DNA sequencing. We identified TERT C228T or C250T promoter mutations in 10 % (9/94) and BRAF V600E mutations in 3 % (3/86) of MPNSTs. All TERT promoter- and BRAF mutations occurred in NF1 unrelated tumors. One co-occurrence of a TERT promoter- and a BRAF mutation was observed. In comparison with other neuroectodermal derived malignant neoplasms, TERT promoter mutations occur at relatively low frequency in MPNSTs. The observation of TERT promotor and BRAF mutations in sporadic MPNSTs and the absence of TERT promotor and rarity of BRAF mutations in NF1 related tumors may imply an alternative genetic route of tumor progression in both patient groups. PMID- 25035101 TI - Effect of fasting in the digestive system: histological study of the small intestine in house sparrows. AB - In birds and mammals the metabolic response to fasting has been studied and can be characterized by three consecutive phases reflecting metabolic and physiological adjustments. An effective way to minimize energy expenditure during food scarcity is to decrease the mass of the organs. As the digestive system is metabolically expensive to maintain, the small intestine and the liver are the most affected organs. We evaluated the effects of phase III starvation on the mass of the different organs and histological parameters on house sparrows, a small non-migrant bird. In a short period of time (34 h) we observed a larger reduction in the digestive organ mass when compared to the mass of the body and non-alimentary tissues. Furthermore, the intestinal mass was proportionally more reduced than its length and nominal surface area. A reduction on the intestinal mucosal layer also resulted in a shortening of villus (length and thickness) and crypt depth. Moreover, the morphology of the enterocytes changed from cylindrical to cubical, suggesting that the surface exposed to the lumen was conserved. This may indicate an adaptive response to the moment of refeeding. The nominal surface area/body mass remained constant in both groups and several histological parameters were reduced, suggesting that starving induces the atrophy of the small intestine. However, the goblet cells were conserved after fasting indicating a protective tendency. PMID- 25035102 TI - Perspectives on cognitive conflict control. PMID- 25035103 TI - Enhancement and reduction of associative retroactive cue interference by training in multiple contexts. AB - Retroactive cue interference refers to situations in which a target cue X is paired with an outcome in phase 1 and a nontarget cue Z is paired with the same outcome in phase 2, with less subsequent responding to X being seen as a result of the phase 2 training. Two conditioned suppression experiments with rats were conducted to determine whether retroactive cue interference is similarly modulated by a manipulation that influences retroactive outcome interference (e.g., extinction). Both experiments used an ABC renewal-like design in which phase 1 training, phase 2 training, and testing each occurred in different contexts. Experiment 1 found that training the target association in multiple contexts without altering the number of training trials during phase 1 decreased retroactive cue interference (i.e., increased responding consistent with the target association). Experiment 2 found that training the interfering association in multiple contexts without altering the number of interference trials during phase 2 increased retroactive cue interference (i.e., decreased responding consistent with the target association). The possibility of similar mechanisms underlying cue interference and outcome interference is discussed. PMID- 25035104 TI - Purification and characterization of a chymosin from Rhizopus microsporus var. rhizopodiformis. AB - Purification and characterization of a chymosin from Rhizopus microsporus var. rhizopodiformis were investigated in the present study. A newly isolated R. microsporus var. rhizopodiformis F518 produced a high level of milk-clotting activity (1,001 SU/mL). A chymosin from the fungus was purified 3.66-fold with a recovery yield of 33.2 %. The enzyme appeared as a single protein band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with a molecular mass of 37.0 kDa. It was optimally active at 60 degrees C and was stable up to 40 degrees C. The purified enzyme was an acid protease with an optimum pH of 5.2 and retained 80 % of residual activity within pH 2.0-8.0. The inhibition of 96 and 100 % by pepstatin A at 0.01 and 0.02 mM, respectively, revealed that the enzyme is an aspartic protease. Thus, high milk-clotting activity of the chymosin with good stability will strengthen the potential use of the chymosin as a substitute for calf rennet in cheese manufacturing. PMID- 25035105 TI - Neutral serine protease from Penicillium italicum. Purification, biochemical characterization, and use for antioxidative peptide preparation from Scorpaena notata muscle. AB - In the present study, purification and properties of an extracellular neutral serine protease from the fungus Penicillium italicum and its potential application as an antioxidant peptides producer are reported. The protease was purified to homogeneity using ammonium sulfate precipitation, Sephacryl S-200 gel filtration, diethylaminoethanol (DEAE)-Sepharose ion exchange chromatography, and TSK-HPLC gel filtration with a 10.2-fold increase in specific activity and 25.8 % recovery. The purified enzyme appeared as single protein band with a molecular mass of 24 kDa in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE). The optimum pH and temperature for the proteolytic activity were pH 7.0 and 50 degrees C, respectively. The enzyme was stable in the pH range of 6.0 9.0. The protease was activated by divalent cations such as Ca(2+) and Mg(2+). Complete inhibition of the purified enzyme by phenylmethylsulfonyl fluoride confirmed that the protease was of serine-type. The purified enzyme revealed high stability and relatively broad specificity. Scorpaena notata muscle protein hydrolysates prepared using purified serine protease (protease from P. italicum (Prot-Pen)) showed good in vitro antioxidative activities. The antioxidant activities of Scorpaena muscle protein hydrolyzed by Prot-Pen (SMPH-PP) were evaluated using various antioxidant assays: 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, reducing power, ferrous chelating activity, and DNA nicking assay. SMPH-PP showed varying degrees of antioxidant activity and almost the same strongest protection against hydroxyl radical induced DNA breakage. PMID- 25035106 TI - Analysis of genetic diversity of certain species of Piper using RAPD-based molecular markers. AB - The utility of RAPD markers in assessing genetic diversity and phenetic relationships of six different species of Piper from Northeast India was investigated. Polymerase chain reaction (PCR) with four arbitrary 10-mer oligonucleotide primers applied to the six species produced a total of 195 marker bands, of which, 159 were polymorphic. On average, six RAPD fragments were amplified per reaction. In the UPGMA phenetic dendrogram based on Jaccard's coefficient, the different accessions of Piper showed a high level of genetic variation. This study may be useful in identifying diverse genetic stocks of Piper, which may then be conserved on a priority basis. PMID- 25035107 TI - Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes. AB - The present study aimed to evaluate the association of alcohol dependence and alcohol dependence-related phenotypes with platelet monoamine oxidase type B (MAO B) activity, Val108/158Met of catechol-o-methyltransferase (COMT), variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene, VNTR in the 3'-untranslated region of dopamine transporter (DAT) gene, 1021C/T of dopamine beta-hydroxylase (DBH) and MAO-B intron 13 polymorphisms. The study included 1270 Caucasian men and women of Croatian origin: 690 patients with alcohol dependence and 580 healthy controls. Patients with alcohol dependence were subdivided according to the presence or absence of withdrawal symptoms, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, suicidal behavior, lifetime suicide attempt and early/late onset of alcohol abuse. The results, corrected for multiple testing, revealed increased platelet MAO-B activity in patients with alcohol dependence, subdivided into those with or without alcohol-related liver diseases, compared to control subjects (P<0.001). In addition, we found an increased frequency of the COMT Met/Met genotype among suicidal (P=0.002) and patients who attempted suicide (P<0.001) and an increased frequency of COMT Val/Val genotype in patients with an early onset of alcohol dependence (P=0.004). This study provides data from a sample of ethnically homogeneous unrelated Caucasian subjects for future meta analyses and suggests that the increased platelet MAO-B activity might be used as independent peripheral indicator of alcohol dependence, while COMT Val108/158Met polymorphism is associated with increased suicidality and early onset of alcohol dependence. PMID- 25035108 TI - Ordered water within the collapsed globules of an amyloidogenic intrinsically disordered protein. AB - Intrinsically disordered proteins (IDPs) confront the traditional sequence structure-function paradigm and are associated with important functions and amyloid disorders. Water molecules residing in the vicinity of the polypeptide chain play potentially important roles in directing the course of binding-induced folding and amyloid aggregation of IDP. Here we characterized the nature of water molecules entrapped within the collapsed globules of an amyloidogenic IDP, namely, kappa-casein. These globules can undergo further compaction in the presence of an anionic detergent that is capable of diminishing the intrachain repulsion from the positively charged glutamine/asparagine-rich amyloidogenic N terminal domain comprising 100 residues. Using time-resolved fluorescence spectroscopy, we estimated the longer component of the solvation time to be ~1.4 ns, which is 3 orders of magnitude slower than that in bulk water and more than an order of magnitude slower than the "biological water" present at the protein surface. Profoundly restrained water within the collapsed IDP globules resembles the ordered water cluster found under nanoconfinement. We suggest that the association of these globules would result in the release of ordered water molecules into the bulk milieu causing an entropic gain that would eventually drive the formation of the key (obligatory) oligomeric intermediates on the pathway to amyloids via nucleation-dependent polymerization. PMID- 25035109 TI - Heme oxygenase-1 upregulation modulates tone and fibroelastic properties of internal anal sphincter. AB - A compromise in the internal anal sphincter (IAS) tone and fibroelastic properties (FEP) plays an important role in rectoanal incontinence. Herein, we examined the effects of heme oxygenase (HO)-1 upregulation on these IAS characteristics in young rats. We determined the effect of HO-1 upregulator hemin on HO-1 mRNA and protein expressions and on basal IAS tone and its FEP before and after HO-1 inhibitor tin protoporphyrin IX. For FEP, we determined the kinetics of the IAS smooth muscle responses, by the velocities of relaxation, and recovery of the IAS tone following 0 Ca(2+) and electrical field stimulation. To characterize the underlying signal transduction for these changes, we determined the effects of hemin on RhoA-associated kinase (RhoA)/Rho kinase (ROCK) II, myosin-binding subunit of myosin light chain phosphatase 1, fibronectin, and elastin expression levels. Hemin increased HO-1 mRNA and protein similar to the increases in the basal tone, and in the FEP of the IAS. Underlying mechanisms in the IAS characteristics are associated with increases in the genetic and translational expressions of RhoA/ROCKII, and elastin. Fibronectin expression levels on the other hand were found to be decreased following HO-1 upregulation. The results of our study show that the hemin/HO-1 system regulates the tone and FEP of IAS. The hemin/HO-1 system thus provides a potential target for the development of new interventions aimed at treatment of gastrointestinal motility disorders, specifically the age-related IAS dysfunction. PMID- 25035111 TI - Differential cell growth/apoptosis behavior of 13-hydroxyoctadecadienoic acid enantiomers in a colorectal cancer cell line. AB - Cyclooxygenases (COXs) and lipoxygenases (LOXs) are important enzymes that metabolize arachidonic and linoleic acids. Various metabolites generated by the arachidonic acid cascade regulate cell proliferation, apoptosis, differentiation, and senescence. Hydroxyoctadecadienoic acids (HODEs) are synthesized from linoleic acid, giving two enantiomeric forms for each metabolite. The aim was to investigate the effect of 13-HODE enantiomers on nondifferentiated Caco-2 cell growth/apoptosis. Our results indicate that 13(S)-HODE decreases cell growth and DNA synthesis of nondifferentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS). Moreover, 13(S)-HODE showed an apoptotic effect that was reduced in the presence of a specific peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonist. In addition, we observed that 13(S)-HODE but not 13(R) HODE is a ligand to PPARgamma, confirming the implication of this nuclear receptor in 13(S)-HODE actions. In contrast, 13(R)-HODE increases cell growth and DNA synthesis in the absence of FBS. 13(R)-HODE interaction with BLT receptors activates ERK and CREB signaling pathways, as well as PGE2 synthesis. These results suggest that the proliferative effect of 13(R)-HODE could be due, at least in part, to COX pathway activation. Thus both enantiomers use different receptors and have contrary effects. We also found these differential effects of 9-HODE enantiomers on cell growth/apoptosis. Therefore, the balance between (R) HODEs and (S)-HODEs in the intestinal epithelium could be important to its cell growth/apoptosis homeostasis. PMID- 25035110 TI - Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis. AB - Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene (PTHrP(Deltaacinar)) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrP(Deltaacinar) exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-kappaB activity; these effects were attenuated in PTHrP(Deltaacinar) cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrP(Deltaacinar) mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP (7-34). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs. PMID- 25035112 TI - PPARalpha-dependent exacerbation of experimental colitis by the hypolipidemic drug fenofibrate. AB - Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor alpha (PPARalpha) agonists and have been used for several decades as hypolipidemic agents in the clinic. However, contradictory observations exist on the role of fibrates in host response to acute inflammation, with unclear mechanisms. The role of PPARalpha in colitis was assessed using fenofibrate and Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid, and Salmonella Typhi. Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Messenger RNAs of PPARalpha target genes and genes involved in inflammation were determined by qunatitative PCR analysis. Fenofibrate treatment exacerbated inflammation and tissue injury in acute colitis, and this was dependent on PPARalpha activation. Lipidomics analysis revealed that bioactive sphingolipids, including sphingomyelins (SM) and ceramides, were significantly increased in the colitis group compared with the control group; this was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce the markedly increased expression of mRNA encoding TNFalpha found in the acute colitis model, while it decreased hydrolysis and increased synthesis of SM, upregulated RIPK3-dependent necrosis, and elevated mitochondrial fatty acid beta oxidation, which were possibly related to the exacerbated colitis. PMID- 25035114 TI - Assessment of paediatric inpatient care during a multifaceted quality improvement intervention in Kenyan district hospitals--use of prospectively collected case record data. AB - BACKGROUND: In assessing quality of care in developing countries, retrospectively collected data are usually used given their availability. Retrospective data however suffer from such biases as recall bias and non-response bias. Comparing results obtained using prospectively and retrospectively collected data will help validate the use of the easily available retrospective data in assessing quality of care in past and future studies. METHODS: Prospective and retrospective datasets were obtained from a cluster randomized trial of a multifaceted intervention aimed at improving paediatric inpatient care conducted in eight rural Kenyan district hospitals by improving management of children admitted with pneumonia, malaria and diarrhea and/or dehydration. Four hospitals received a full intervention and four a partial intervention. Data were collected through 3 two weeks surveys conducted at baseline, after 6 and 18 months. Retrospective data was sampled from paediatric medical records of patients discharged in the preceding six months of the survey while prospective data was collected from patients discharged during the two week period of each survey. Risk Differences during post-intervention period of 16 quality of care indicators were analyzed separately for prospective and retrospective datasets and later plotted side by side for comparison. RESULTS: For the prospective data there was strong evidence of an intervention effect for 8 of the indicators and weaker evidence of an effect for one indicator, with magnitude of effect sizes varying from 23% to 60% difference. For the retrospective data, 10 process (these include the 8 indicators found to be statistically significant in prospective data analysis) indicators had statistically significant differences with magnitude of effects varying from 10% to 42%. The bar-graph comparing results from the prospective and retrospective datasets showed similarity in terms of magnitude of effects and statistical significance for all except two indicators. CONCLUSION: Multifaceted interventions can help improve adoption of clinical guidelines and hence improve the quality of care. The similar inference reached after analyses based on prospective assessment of case management is a useful finding as it supports the utility of work based on examination of retrospectively assembled case records allowing longer time periods to be studied while constraining costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42996612. Trial registration date: 20/11/2008. PMID- 25035115 TI - Are pushing and pulling work-related risk factors for upper extremity symptoms? A systematic review of observational studies. AB - Systematically review observational studies concerning the question whether workers that perform pushing/pulling activities have an increased risk for upper extremity symptoms as compared to workers that perform no pushing/pulling activities. A search in MEDLINE via PubMed and EMBASE was performed with work related search terms combined with push/pushing/pull/pulling. Studies had to examine exposure to pushing/pulling in relation to upper extremity symptoms. Two authors performed the literature selection and assessment of the risk of bias in the studies independently. A best evidence synthesis was used to draw conclusions in terms of strong, moderate or conflicting/insufficient evidence. The search resulted in 4764 studies. Seven studies were included, with three of them of low risk of bias, in total including 8279 participants. A positive significant relationship with upper extremity symptoms was observed in all four prospective cohort studies with effect sizes varying between 1.5 and 4.9. Two out of the three remaining studies also reported a positive association with upper extremity symptoms. In addition, significant positive associations with neck/shoulder symptoms were found in two prospective cohort studies with effect sizes of 1.5 and 1.6, and with shoulder symptoms in one of two cross-sectional studies with an effect size of 2.1. There is strong evidence that pushing/pulling is related to upper extremity symptoms, specifically for shoulder symptoms. There is insufficient or conflicting evidence that pushing/pulling is related to (combinations of) upper arm, elbow, forearm, wrist or hand symptoms. PMID- 25035113 TI - Genetic inhibition of protein kinase Cepsilon attenuates necrosis in experimental pancreatitis. AB - Understanding the regulation of death pathways, necrosis and apoptosis, in pancreatitis is important for developing therapies directed to the molecular pathogenesis of the disease. Protein kinase Cepsilon (PKCepsilon) has been previously shown to regulate inflammatory responses and zymogen activation in pancreatitis. Furthermore, we demonstrated that ethanol specifically activated PKCepsilon in pancreatic acinar cells and that PKCepsilon mediated the sensitizing effects of ethanol on inflammatory response in pancreatitis. Here we investigated the role of PKCepsilon in the regulation of death pathways in pancreatitis. We found that genetic deletion of PKCepsilon resulted in decreased necrosis and severity in the in vivo cerulein-induced pancreatitis and that inhibition of PKCepsilon protected the acinar cells from CCK-8 hyperstimulation induced necrosis and ATP reduction. These findings were associated with upregulation of mitochondrial Bak and Bcl-2/Bcl-xL, proapoptotic and prosurvival members in the Bcl-2 family, respectively, as well as increased mitochondrial cytochrome c release, caspase activation, and apoptosis in pancreatitis in PKCepsilon knockout mice. We further confirmed that cerulein pancreatitis induced a dramatic mitochondrial translocation of PKCepsilon, suggesting that PKCepsilon regulated necrosis in pancreatitis via mechanisms involving mitochondria. Finally, we showed that PKCepsilon deletion downregulated inhibitors of apoptosis proteins, c-IAP2, survivin, and c-FLIPs while promoting cleavage/inactivation of receptor-interacting protein kinase (RIP). Taken together, our findings provide evidence that PKCepsilon activation during pancreatitis promotes necrosis through mechanisms involving mitochondrial proapoptotic and prosurvival Bcl-2 family proteins and upregulation of nonmitochondrial pathways that inhibit caspase activation and RIP cleavage/inactivation. Thus PKCepsilon is a potential target for prevention and/or treatment of acute pancreatitis. PMID- 25035116 TI - Dampness, bacterial and fungal components in dust in primary schools and respiratory health in schoolchildren across Europe. AB - BACKGROUND: Respiratory health effects of damp housing are well recognised, but less is known about the effect of dampness and water damage in schools. The HITEA study previously reported a higher prevalence of respiratory symptoms in pupils from moisture damaged schools, but the role of specific microbial exposures remained unclear. OBJECTIVES: To study associations between school dampness, levels of fungal and bacterial markers, respiratory symptoms and lung function in children. METHODS: Primary schools in Spain, the Netherlands and Finland were selected on the basis of the observed presence (n=15) or absence (n=10) of moisture, dampness and/or mould. Settled dust was repeatedly sampled in 232 classrooms and levels of 14 different microbial markers and groups of microbes were determined. Parental reports of respiratory symptoms were available from 3843 children aged 6-12 years, of whom 2736 provided acceptable forced spirometry testing. Country-specific associations between exposure and respiratory health were evaluated by multilevel mixed-effects logistic and linear regression models and combined using random-effects meta-analysis. RESULTS: The prevalence of respiratory symptoms was higher in moisture damaged schools, being more pronounced in Finnish pupils. Effects on lung function were not apparent. Levels of microbial markers were generally higher in moisture damaged schools, varied by season and were lower in Finnish schools. Wheeze tended to be inversely associated with microbial levels. All other respiratory symptoms were not consistently associated with microbial marker levels. CONCLUSIONS: Health effects of moisture and microbial exposures may vary between countries, but this requires further study. PMID- 25035117 TI - Neurodegenerative disease: the next occupational disease epidemic? PMID- 25035118 TI - Republished: Safety checklist compliance and a false sense of safety: new directions for research. PMID- 25035119 TI - Republished: Fibrosing organising pneumonia. AB - Organising pneumonia (otherwise referred to as bronchiolitis obliterans organising pneumonia) is characterised histologically by plugs of granulation tissue, which are present predominantly within small airways, alveolar ducts and peri-bronchiolar alveoli. This pattern is not specific for any disorder or cause, but is one type of inflammatory response to pulmonary injury, which may be seen in a wide variety of clinical conditions. Typically, organising pneumonia responds very well to corticosteroid treatment; however, a small percentage of patients appear to develop progressive fibrosis. PMID- 25035120 TI - Patient choice and narrative ethics. PMID- 25035121 TI - Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial. AB - There is a great concern about the safety of THC-based drugs in older people (>=65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol((r)), a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72+/-5 years) randomly received a single oral dose of 3mg, 5mg, or 6.5mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5mg than with 3mg (p=0.048), 5mg (p=0.034) and placebo (p=0.013). There was a wide inter individual variability in plasma concentrations of THC. Subjects for whom the Cmax fell within the sampling period (over 2h), Cmax was 1.42-4.57ng/mL and Tmax was 67-92min. The AUC0-2h (n=11) was 1.67-3.51ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC. PMID- 25035122 TI - The effect of vision on knee biomechanics during functional activities - A systematic review. AB - OBJECTIVES: The objective of this study was to assess the effect of occluded vision on lower limb kinematics and kinetics of the knee joint during functional tasks including drop landing (single or double leg), squatting (single or double leg), stepping down, cutting movement and hopping in healthy individuals, or individuals who had an ACL reconstruction or deficiency with no vision impairments. DESIGN: A systematic review was conducted. METHODS: A systematic review was conducted and electronic databases were searched between March 2012 and April 2013 for eligible papers. Methodological quality of each study was assessed using the Downs and Black revised checklist. RESULTS: Six studies met the eligibility criteria and a wide variation in methodological approaches was reported. This small evidence base indicated equivocal evidence about the effect of vision on knee biomechanics in individuals with healthy and compromised somatosensory function post an ACL reconstruction or injury. CONCLUSIONS: Clinicians should consider innovative, individualised ACL rehabilitation strategies when prescribing exercises which involve visual occlusion. Further research to increase the relatively small evidence base for the effect of vision on knee biomechanics is warranted. PMID- 25035123 TI - What doesn't kill me...: Adversity-related experiences are vital in the development of superior Olympic performance. AB - OBJECTIVES: Recent research suggests that experiencing some adversity can have beneficial outcomes for human growth and development. The purpose of this paper was to explore the adversities that the world's best athletes encounter and the perceived role that these experiences play in their psychological and performance development. DESIGN: A qualitative design was employed because detailed information of rich quality was required to better understand adversity-related experiences in the world's best athletes. METHODS: Semi-structured interviews were conducted with 10 Olympic gold medalists from a variety of sports. Inductive thematic analysis was used to analyze the data. RESULTS: The findings indicate that the participants encountered a range of sport- and non-sport adversities that they considered were essential for winning their gold medals, including repeated non-selection, significant sporting failure, serious injury, political unrest, and the death of a family member. The participants described the role that these experiences played in their psychological and performance development, specifically focusing on their resultant trauma, motivation, and learning. CONCLUSIONS: Adversity-related experiences were deemed to be vital in the psychological and performance development of Olympic champions. In the future, researchers should conduct more in-depth comparative studies of Olympic athletes' adversity- and growth-related experiences, and draw on existing and alternative theoretical explanations of the growth-performance relationship. For professional practitioners, adversity-related experiences offer potential developmental opportunities if they are carefully and purposely harnessed. PMID- 25035124 TI - Targeting cancer-derived adenosine: new therapeutic approaches. AB - CD73 generation of immunosuppressive adenosine within the hypoxic tumor microenvironment causes dysregulation of immune cell infiltrates, resulting in tumor progression, metastases, and poor disease outcomes. Therapies targeted toward the adenosinergic pathway, such as antibodies targeting CD73 and CD39, have proven efficacy in mouse tumor models; however, humanized versions are only in preliminary development. In contrast, A(2A) adenosine receptor antagonists have progressed to late-stage clinical trials in Parkinson disease, yet evidence of their role in oncology is limited. This review will compare the merits and challenges of these therapeutic approaches, identifying tumor indications and combinations that may be fruitful as they progress to the clinic. SIGNIFICANCE: High concentrations of immunosuppressive adenosine have been reported in cancers, and adenosine is implicated in the growth of tumors. This brief review delineates the current treatment strategies and tumor subtypes that will benefit from targeting adenosinergic pathways, alone or in combination with contemporary approaches to cancer treatment. PMID- 25035125 TI - Respiratory microbiota: addressing clinical questions, informing clinical practice. AB - Over the last decade, technological advances have revolutionised efforts to understand the role played by microbes in airways disease. With the application of ever more sophisticated techniques, the literature has become increasingly inaccessible to the non-specialist reader, potentially hampering the translation of these gains into improvements in patient care. In this article, we set out the key principles underpinning microbiota research in respiratory contexts and provide practical guidance on how best such studies can be designed, executed and interpreted. We examine how an understanding of the respiratory microbiota both challenges fundamental assumptions and provides novel clinical insights into lung disease, and we set out a number of important targets for ongoing research. PMID- 25035126 TI - A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO). AB - RATIONALE: Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. OBJECTIVES: To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. MEASUREMENTS AND METHODS: This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5-<30/h and Epworth Sleepiness Scale (ESS) score >=9 underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. MAIN RESULTS: 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a L20,000/quality-adjusted life year (QALY) threshold. SP2 was the most cost effective up to L39,800/QALY. CONCLUSIONS: Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective. Of those trialled, the semi-bespoke MAD is an appropriate first choice. TRIAL REGISTRATION NUMBER: ISRCTN02309506. PMID- 25035127 TI - Sputum-to-serum hydrogen sulfide ratio in COPD. AB - OBJECTIVES: Hydrogen sulfide (H2S) is a gas produced by respiratory cells including smooth muscle cells and may play a role as a cellular gasotransmitter. We evaluated whether H2S levels in serum or sputum could represent a new biomarker of COPD in a cross-sectional study. METHODS: H2S levels in sputum and serum samples were measured using a sulfide-sensitive electrode in 64 patients with stable COPD (S-COPD), 29 COPD subjects during acute exacerbation (AE-COPD), 14 healthy smokers and 21 healthy non-smokers. RESULTS: Sputum H2S levels in AE COPD subjects were higher than those in S-COPD, healthy smoking and non-smoking subjects (p<0.001), but serum H2S levels in AE-COPD were lower than those in S COPD (p<0.001). Thus, the sputum-to-serum ratio of H2S (H2S ratio) in AE-COPD subjects were higher than those in stable COPD, healthy smoking and non-smoking subjects (p<0.001). In 14 COPD subjects whose H2S ratios were measured during and after an exacerbation, the mean ratio was increased during exacerbation (p<0.05). H2S ratio was positively correlated with St. George's Respiratory Questionnaire score, sputum neutrophils and IL-6 and IL-8 levels in sputum and serum (p<0.01) but inversely correlated with sputum macrophages (%), FEV1%predicted and FEV1/FVC (p<0.01). The cut-off level of H2S ratio to indicate an exacerbation was >=0.44 (sensitivity of 93.1% and specificity of 84.5%). CONCLUSIONS: The ratio of sputum to-serum levels of H2S may provide a useful marker of COPD indicative of obstructive neutrophilic inflammation and of potential ongoing exacerbation. PMID- 25035130 TI - Ca2+ in the cleft: fast and fluorescent. PMID- 25035131 TI - Is the therapeutic window for mitochondrial ROS half-open or half-closed? Mixing mitophagic metaphors. PMID- 25035132 TI - Hippo in the path to heart repair. PMID- 25035133 TI - Renal denervation for the treatment of cardiovascular high risk-hypertension or beyond? AB - Hypertension imposes a major burden of morbidity and mortality and is associated with sympathetic nervous system overactivity. Renal sympathetic denervation has been shown to reduce office blood pressure, ambulatory blood pressure, and sympathetic activity in patients with resistant hypertension. Therefore, the procedure has attracted a lot of attention. Beyond blood pressure, renal denervation has been shown to improve glucose tolerance, microalbuminuria, and arrhythmias in several experimental models and, in admittedly, often uncontrolled clinical studies. It has been demonstrated to reduce myocardial hypertrophy in a blood pressure-independent and blood pressure-dependent way. The first studies on heart failure with preserved and reduced ejection fraction are ongoing. Renal sympathetic denervation holds promise for future indications in hypertension and related comorbidities and consequences, such as metabolic disease, renal failure, and heart failure. Published data in a placebo-control blinded study, however, are needed. The aim of this review is to provide a critical and comprehensive overview of heretofore generated data on renal denervation in experimental models, in human hypertension, and on early developments in new indications, which should indicate the way to powered and performed, controlled clinical studies appropriately. PMID- 25035134 TI - Scaling in neurotrauma: how do we apply animal experiments to people? AB - Scaling is an essential component for translating the clinical outcomes of a neurotrauma model to the human equivalent. This article reviews the principles of biomechanical scaling for traumatic brain injuries, and a number of different approaches to scaling the dose (inputs) and response (outputs) of an animal model to humans are highlighted. A particular focus on blast injury scaling is given as an ongoing area of research, and discussion on the implications of scaling on the current blast TBI literature is provided. The risk of using neurotrauma models without considering an appropriate scaling method is that injuries may be induced with non-realistic loading conditions, and the injury mechanisms produced in the laboratory may not be consistent with those in the clinical setting. PMID- 25035135 TI - Bleomycin-induced gammaH2AX foci map preferentially to replicating domains in CHO9 interphase nuclei. AB - Exposure to DNA damaging agents triggers phosphorylation of histone variant H2AX (generating gammaH2AX) in large chromatin regions flanking DNA lesions, allowing their immunodetection as nuclear foci. Even though a predominance of gammaH2AX foci in euchromatin has been postulated, foci positioning when DNA insult occurs in replicating eu- or heterochromatin regions has not been extensively explored. Labeling of interphase nuclei with 5-ethynyl-2'-deoxyuridine (EdU) pulses has revealed that DNA replication is temporarily and spatially regulated: euchromatin replicates in early S (ES) and heterochromatin along mid and late S (MS/LS) phases. In order to map DNA damage with respect to replicating domains, the distribution of gammaH2AX foci induced by the radiomimetic agent bleomycin was analyzed in CHO9 interphase nuclei by delineating euchromatic (H3K4me3+) and replicating (EdU+) regions. Quantification of overlapping pixels and 3D inter object overlap in binary masks revealed colocalization between gammaH2AX foci and EdU + domains both in ES and MS/LS nuclei, indicating that primary damage distribution is modulated by DNA synthesis. Further, we verified that EdU incorporation by itself did not influence BLEO-induced gammaH2AX nuclear patterns. Our results also revealed a repeated localization of gammaH2AX foci in replicating/nonreplicating interfaces which could reflect short-range chromatin migration following DNA insult. PMID- 25035136 TI - Relationship between chronological and bone ages and pubertal stage of breasts with bone biomarkers and bone mineral density in adolescents. AB - OBJECTIVE: To study bone mineral density (BMD) in adolescent females according to five groups of chronological age (CA), bone age (BA), and breast development stage (B), and to correlate these parameters with plasma bone biomarkers (BB). METHODS: This was a cross-sectional study performed in 101 healthy adolescent females between 10 and 20 years old. The study variables were: weight, height, body mass index (BMI), CA, B, BA, calcium intake, BMD, and BB. Osteocalcin (OC), bone alkaline phosphatase (BAP), and C-terminal telopeptide (S-CTx) were evaluated for BB. BMD was measured using dual energy X-ray absorptiometry (DXA). RESULTS: BMD in lumbar spine, proximal femur, and total body increased with age, and the respective observed averages were: in CA1 (10 years old), 0.631, 0.692, 0.798 g/cm(2); in CA2 (11 to 12 years old), 0.698, 0.763, 0.840 g/cm(2); in CA3 (13 to 14 years old), 0.865, 0.889, 0.972 g/cm(2); in CA4 (15 to 16 years old), 0.902, 0.922, 1.013 g/cm(2); and in CA5 (17 to 19 years old), 0.944, 0.929, 1.35 g/cm(2). These results showed significant differences between 13 and 14 years of age (CA3) or when girls reached the B3 stage (0.709, 0.832, 0.867 g/cm(2)). The highest median concentrations of BB were between 10 and 12 years of age when adolescents were in the B2-B3 (p<0.001). Median BB concentrations decreased in advanced BA and B. CONCLUSIONS: BB concentrations were positively correlated with the peak height velocity and negatively correlated with BMD in the study sites. Increased BMD and BB concentrations were observed in B3. PMID- 25035137 TI - Comment on Tadrous et al.: comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis. PMID- 25035138 TI - Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis-reply to Pazianas and Abrahamsen. PMID- 25035139 TI - beta-Arrestin 2 mediates the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells. AB - Recent evidence has suggested that microglial activation plays an important role in the pathogenesis of depression. Activated microglia can secrete various pro inflammatory cytokines, which may contribute to the development and maintenance of depression. Thus, inhibition of microglial activation may have a therapeutic benefit in the treatment of depression. In the present study, we found that fluoxetine significantly inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin- 6 (IL-6) and nitric oxide (NO) and reduced the phosphorylation of transforming growth factor-beta-activated kinase 1 (TAK1) and nuclear factor-kappa B (NF-kappaB) p65 nuclear translocation in microglia. We further found that fluoxetine increased the expression of beta arrestin 2 and enhanced the association of beta-arrestin 2 with TAK1-binding protein 1 (TAB1) and disrupted TAK1-TAB1 interaction. Moreover, beta-arrestin 2 knock-down abolished the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells. Collectively, our findings suggest that beta-arrestin 2 is necessary for the anti-inflammatory effects of fluoxetine and offers novel drug targets in the convergent fluoxetine/beta arrestin 2 and inflammatory pathways for treating microglial inflammatory neuropathologies like depression. PMID- 25035140 TI - Posterior reversible encephalopathy syndrome in acute intermittent porphyria. AB - BACKGROUND: Acute intermittent porphyria is an inherited disease that is rarely diagnosed in prepubertal children. It can affect the autonomic, peripheral, and central nervous system. Posterior reversible encephalopathy syndrome is a clinicoradiological entity characterized by headache, seizures, altered consciousness, and visual disorder associated with potentially reversible neuroradiological abnormalities predominantly in the parieto-occipital lobes. We report a child with acute intermittent porphyria who presented with radiological manifestations suggestive of posterior reversible encephalopathy syndrome. PATIENT: A 9-year-old girl underwent an appendectomy after developing abdominal pain. She subsequently developed bilateral visual disturbance, confusion, seizures, hypertension, tachycardia, nausea, vomiting, constipation, dark tea colored urine, and recurrent abdominal pain. RESULTS: Initial brain magnetic resonance imaging revealed hyperintense gyriform lesions on T2-weighted images and hypointense to isointense lesions on T1-weighted images in both parieto occipital lobes with mild enhancement. The diagnosis of acute intermittent porphyria was confirmed by increased urinary excretion of porphyrin precursors. Her clinical signs gradually improved after intravenous high-dose glucose treatment and symptomatic therapies. A repeat magnetic resonance imaging confirmed complete resolution of the parieto-occipital lesions, suggesting with posterior reversible encephalopathy syndrome. CONCLUSIONS: The association of abdominal pain, mental status changes, and autonomic dysfunction should arouse the suspicion of acute intermittent porphyria. Acute intermittent porphyria can be associated with posterior reversible encephalopathy syndrome. PMID- 25035141 TI - Clinically mild encephalitis/encephalopathy with a reversible splenial lesion caused by human parvovirus b19 infection: a case of two brothers with hereditary spherocytosis. PMID- 25035142 TI - CIDP: mimics and chameleons. AB - The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is usually straightforward, but atypical presentations can represent a significant diagnostic challenge. This review highlights the clinical and electrophysiological 'red flags' that should make one consider an alternative diagnosis. PMID- 25035144 TI - Triple jeopardy for Hodgkin lymphoma survivors? AB - In this issue of Blood, van Eggermond et al demonstrate that Hodgkin lymphoma survivors who develop a second malignancy have increased risk of developing yet a third malignancy. PMID- 25035143 TI - Comparing indices of diet quality with chronic disease mortality risk in postmenopausal women in the Women's Health Initiative Observational Study: evidence to inform national dietary guidance. AB - Poor diet quality is thought to be a leading risk factor for years of life lost. We examined how scores on 4 commonly used diet quality indices-the Healthy Eating Index 2010 (HEI), the Alternative Healthy Eating Index 2010 (AHEI), the Alternate Mediterranean Diet (aMED), and the Dietary Approaches to Stop Hypertension (DASH) are related to the risks of death from all causes, cardiovascular disease (CVD), and cancer among postmenopausal women. Our prospective cohort study included 63,805 participants in the Women's Health Initiative Observational Study (from 1993-2010) who completed a food frequency questionnaire at enrollment. Cox proportional hazards models were fit using person-years as the underlying time metric. We estimated multivariate hazard ratios and 95% confidence intervals for death associated with increasing quintiles of diet quality index scores. During 12.9 years of follow-up, 5,692 deaths occurred, including 1,483 from CVD and 2,384 from cancer. Across indices and after adjustment for multiple covariates, having better diet quality (as assessed by HEI, AHEI, aMED, and DASH scores) was associated with statistically significant 18%-26% lower all-cause and CVD mortality risk. Higher HEI, aMED, and DASH (but not AHEI) scores were associated with a statistically significant 20%-23% lower risk of cancer death. These results suggest that postmenopausal women consuming a diet in line with a priori diet quality indices have a lower risk of death from chronic disease. PMID- 25035145 TI - Targeted diphtheria toxin to treat BPDCN. AB - In this issue of Blood, Frankel et al describe a novel treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) using an engineered version of diphtheria toxin that is targeted to malignant cells via a fusion with interleukin (IL)3 (see panel A). PMID- 25035146 TI - Pearson syndrome in a Diamond-Blackfan anemia cohort. AB - In this issue of Blood, Gagne et al describe a cohort of 362 patients clinically classified as having Diamond-Blackfan anemia (DBA), in which 175 (48%) were found to have mutations and deletions in ribosomal protein genes or GATA1, and 8 of the remaining patients (2.2% overall) had mitochondrial gene deletions consistent with Pearson marrow-pancreas syndrome (PS). The authors propose that all patients with presumptive DBA should be tested for mitochondrial DNA (mtDNA) deletion during their initial genetic evaluation. PMID- 25035147 TI - FVIII stabilization: VWF D'D3 will do. AB - In this issue of Blood, Yee et al1 have demonstrated that expression or infusion of a truncated von Willebrand factor (VWF) fragment containing the factor VIII (FVIII)-binding D'D3 region of VWF is sufficient to stabilize endogenous FVIII levels in VWF-deficient mice. In the absence of the carrier function of VWF, FVIII is susceptible to rapid proteolysis and clearance resulting in markedly reduced plasma levels of FVIII that contribute to a bleeding diathesis. PMID- 25035150 TI - Long noncoding RNAs in patients with acute myocardial infarction. AB - RATIONALE: Long noncoding RNAs (lncRNAs) constitute a novel class of noncoding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia. OBJECTIVE: To measure lncRNAs in patients with myocardial infarction (MI). METHODS AND RESULTS: We enrolled 414 patients with acute MI treated by primary percutaneous coronary intervention. Blood samples were harvested at the time of reperfusion. Expression levels of 5 lncRNAs were measured in peripheral blood cells by quantitative polymerase chain reaction: hypoxia inducible factor 1A antisense RNA 2, cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL), potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1), myocardial infarction associated transcript, and metastasis-associated lung adenocarcinoma transcript 1. Levels of hypoxia inducible factor 1A antisense RNA 2, KCNQ1OT1, and metastasis-associated lung adenocarcinoma transcript 1 were higher in patients with MI than in healthy volunteers (P<0.01), and levels of ANRIL were lower in patients with MI (P=0.003). Patients with ST-segment-elevation MI had lower levels of ANRIL (P<0.001), KCNQ1OT1 (P<0.001), myocardial infarction-associated transcript (P<0.001), and metastasis-associated lung adenocarcinoma transcript 1 (P=0.005) when compared with patients with non-ST-segment-elevation MI. Levels of ANRIL were associated with age, diabetes mellitus, and hypertension. Patients presenting within 3 hours of chest pain onset had elevated levels of hypoxia inducible factor 1A antisense RNA 2 when compared with patients presenting later on. ANRIL, KCNQ1OT1, myocardial infarction-associated transcript, and metastasis associated lung adenocarcinoma transcript 1 were significant univariable predictors of left ventricular dysfunction as assessed by an ejection fraction <=40% at 4-month follow-up. In multivariable and reclassification analyses, ANRIL and KCNQ1OT1 improved the prediction of left ventricular dysfunction by a model, including demographic features, clinical parameters, and cardiac biomarkers. CONCLUSIONS: Levels of lncRNAs in blood cells are regulated after MI and may help in prediction of outcome. This motivates further investigation of the role of lncRNAs after MI. PMID- 25035151 TI - Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. AB - RATIONALE: Autosomal-dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and increased risk for coronary vascular disease. ADH is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin 9. A number of patients, however, suffer from familial hypercholesterolemia 4 (FH4), defined as ADH in absence of mutations in these genes and thereafter use the abbreviation FH4. OBJECTIVE: To identify a fourth locus associated with ADH. METHODS AND RESULTS: Parametric linkage analysis combined with exome sequencing in a FH4 family resulted in the identification of the variant p.Glu97Asp in signal transducing adaptor family member 1 (STAP1), encoding signal transducing adaptor family member 1. Sanger sequencing of STAP1 in 400 additional unrelated FH4 probands identified a second p.Glu97Asp carrier and 3 additional missense variants, p.Leu69Ser, p.Ile71Thr, and p.Asp207Asn. STAP1 carriers (n=40) showed significantly higher plasma total cholesterol and low-density lipoprotein cholesterol levels compared with nonaffected relatives (n=91). CONCLUSIONS: We mapped a novel ADH locus at 4p13 and identified 4 variants in STAP1 that associate with ADH. PMID- 25035152 TI - Epigenetics and arterial hypertension: the challenge of emerging evidence. AB - Epigenetic phenomena include DNA methylation, post-translational histone modifications, and noncoding RNAs, as major marks. Although similar to genetic features of DNA for their heritability, epigenetic mechanisms differ for their potential reversibility by environmental and nutritional factors, which make them potentially crucial for their role in complex and multifactorial diseases. The function of these mechanisms is indeed gaining interest in relation to arterial hypertension (AH) with emerging evidence from cell culture and animal models as well as human studies showing that epigenetic modifications have major functions within pathways related to AH. Among epigenetic marks, the role of DNA methylation is mostly highlighted given the primary role of this epigenetic feature in mammalian cells. A lower global methylation was observed in DNA of peripheral blood mononuclear cells of hypertensive patients. Moreover, DNA hydroxymethylation appears modifiable by salt intake in a Dahl salt-sensitive rat model. The specific function of DNA methylation in regulating the expression of AH-related genes at promoter site was described for hydroxysteroid (11-beta) dehydrogenase 2 (HSD11B2), somatic angiotensin converting enzyme (sACE), Na+/K+/2Cl- cotransporter 1 (NKCC1), angiotensinogen (AGT), alpha-adducin (ADD1), and for other crucial genes in endocrine hypertension. Post-translational histone methylation at different histone 3 lysine residues was also observed to control the expression of genes related to AH as lysine-specific demethylase-1(LSD1), HSD11B2, and epithelial sodium channel subunit alpha (SCNN1A). Noncoding RNAs including several microRNAs influence genes involved in steroidogenesis and the renin-angiotensin-aldosterone pathway. In the present review, the current knowledge on the relationship between the main epigenetic marks and AH will be presented, considering the challenge of epigenetic patterns being modifiable by environmental factors that may lead toward novel implications in AH preventive and therapeutic strategies. PMID- 25035153 TI - Prostate health index vs percent free prostate-specific antigen for prostate cancer detection in men with "gray" prostate-specific antigen levels at first biopsy: systematic review and meta-analysis. AB - The most promising approach to improve the specificity of prostate-specific antigen (PSA) test relies on the measurement of different molecular isoforms of PSA in serum. Currently, in men with a total PSA (tPSA) level between 2 and 10 ng/mL, measurement of %fPSA (free to total PSA ratio *100) is used as reflex testing to better distinguish between malignant and benign prostate disease. Recently, Beckman Coulter developed the prostate health index (PHI) and several studies suggested that this test may improve the diagnostic ability of %fPSA.We performed a meta-analysis to evaluate the usefulness of PHI compared with %fPSA in the detection of prostate cancer (PCa) at first biopsy in men with tPSA "gray" levels of 2-10 ng/mL. Data on sensitivity and specificity were extracted from 8 eligible studies. Only observational studies comparing the diagnostic ability of PHI and %fPSA in tPSA range of 2-10 ng/mL were included. A total of 8 studies involving 2969 patients with a tPSA range of 2-10 ng/mL undergoing first biopsy were included in this meta-analysis. Biopsy-confirmed PCa was detected in 1287 (43.3%) men. Selected studies determined both PHI and %fPSA as a reflex test. The areas under curve (AUCs) of PHI and %fPSA were 0.74 (95% confidence interval [CI], 0.70-0.77) and 0.63 (95% CI, 0.58-0.67), respectively. Meta-regression analysis confirmed the superiority of PHI which showed, compared with %fPSA, a relative diagnostic odds ratio of 2.81 (95% CI, 2.19-3.6; P < 0.0001). In conclusion, PHI instead of %fPSA as a reflex test in men with tPSA "gray" levels is a better predictor of positive first biopsy and can offer a reduction in unnecessary biopsies. PMID- 25035154 TI - Widespread white matter degeneration preceding the onset of dementia. AB - BACKGROUND: Brain atrophy in subjects with mild cognitive impairment (MCI) introduces partial volume effects, limiting the sensitivity of diffusion tensor imaging to white matter microstructural degeneration. Appropriate correction isolates microstructural effects in MCI that might be precursors of Alzheimer's disease (AD). METHODS: Forty-eight participants (18 MCI, 15 AD, and 15 healthy controls) had magnetic resonance imaging scans and clinical evaluations at baseline and follow-up after 36 months. Ten MCI subjects were diagnosed with AD at follow-up and eight remained MCI. Free-water (FW) corrected measures on the white matter skeleton were compared between groups. RESULTS: FW corrected radial diffusivity, but not uncorrected radial diffusivity, was increased across the brain of the converted group compared with the nonconverted group (P < .05). The extent of increases was similar to that found comparing AD with controls. CONCLUSION: Partial volume elimination reveals microstructural alterations preceding dementia. These alterations may prove to be an effective and feasible early biomarker of AD. PMID- 25035155 TI - Trajectories of Alzheimer disease-related cognitive measures in a longitudinal sample. AB - BACKGROUND: The delineation of the relative temporal trajectories of specific cognitive measures associated with Alzheimer's disease (AD) is important for evaluating preclinical markers and monitoring disease progression. METHODS: We characterized the temporal trajectories of measures of verbal episodic memory, short-term visual memory, and mental status using data from 895 participants in the Baltimore Longitudinal Study of Aging. RESULTS: The California Verbal Learning Test (CVLT) immediate recall was the first measure to decline, followed by CVLT delayed recall. However, further along the disease progression scale, CVLT delayed recall and visual memory changed more rapidly than CVLT immediate recall. CONCLUSIONS: Our findings reconcile reports of early changes in immediate recall with greater reliance on delayed recall performance in clinical settings. Moreover, the utility of cognitive markers in evaluating AD progression depends on the stage of cognitive decline, suggesting that optimal endpoints in therapeutic trials may vary across different stages of the disease process. PMID- 25035156 TI - Association between family history of malignant neoplasm with colorectal adenomatous polyp in 40s aged relative person. AB - PURPOSE: We assessed the association between a family history of malignancy and risk of colorectal adenoma among individuals aged 40-49 years. METHODS: The study population consisted of subjects, aged in their 40s, who underwent colonoscopy. Their family histories of cancer were collected with a self-administered questionnaire. A logistic regression model was used to assess the association between a family history of cancer and the risk of colorectal polyp. RESULTS: In total, 2275 participants were included in the study. Univariate analysis showed that old age, male sex, current cigarette smoking, BMI>25 kg/m(2), and a family history of colorectal cancer (CRC) were risk factors for the development of sporadic colorectal adenomatous polyps in these patients. A multivariate analysis showed that a family history of CRC or kidney cancer was associated with adenoma development. A family history of CRC was also a risk factor for advanced and multiple adenoma. CONCLUSIONS: This study shows that a family history of CRC is a risk factor for advanced and multiple colorectal adenoma in people in their 40s. These results support earlier screening for colorectal neoplasms in individuals with a family history of CRC. PMID- 25035157 TI - Increased risk of breast cancer in women with false-positive test: the role of misclassification. AB - INTRODUCTION: Studies have shown that women with a false-positive result from mammography screening have an excess risk for breast cancer compared with women who only have negative results. We aimed to assess the excess risk of cancer after a false-positive result excluding cases of misclassification, i.e. women who were actually false-negatives instead of false-positives. METHOD: We used data from the Copenhagen Mammography Screening Programme, Denmark. The study population was the 295 women, out of 4743 recalled women from a total of 58,003 participants, with a false-positive test during the screening period 1991-2005 and who later developed breast cancer. Cancers that developed in the same location as the finding that initially caused the recall was studied in-depth in order to establish whether there had been misclassification. RESULTS: Seventy-two cases were found to be misclassified. When the women with misclassified tests had been excluded, there was an excess risk of breast cancer of 27% (RR=1.27, 95% confidence interval (CI), 1.11-1.46) among the women with a false-positive test compared to women with only negative tests. Women with a false-positive test determined at assessment had an excess risk of 27%, while false-positives determined at surgery had an excess risk of 30%. CONCLUSIONS: The results indicate that the increased risk is not explained only by misclassification. The excess risk remains for false-positives determined at assessment as well as at surgery, which favours some biological susceptibility. Further research into the true excess risk of false positives is warranted. PMID- 25035158 TI - The MitraClip experience and future percutaneous mitral valve therapies. AB - Mitral regurgitation is the most common valve abnormality worldwide and its prevalence is expected to increase in the future due to aging of the population. Percutaneous mitral valve repair therapies may offer an opportunity to treat severe MR in the elderly or other high-risk groups who would otherwise be ineligible for surgery. The MitraClip system uses edge-to-edge coaptation of the mitral leaflets to create a double-orifice valve and reduce MR. It has been performed in over 10 000 patients to date, and as experience has improved, procedural times have shortened from over 200 minutes to less than 100 minutes, with increasing numbers of patients being left with <= grade 2+ MR. This review will focus on the literature available on MitraClip and other novel percutaneous techniques that are being developed for the treatment of severe MR. PMID- 25035159 TI - Aortopulmonary window: a rare untreated adult case. PMID- 25035160 TI - Assessment of fatigue using the Multidimensional Fatigue Inventory in patients with major depressive disorder. AB - OBJECTIVES: There are problems with the fatigue measures currently used in depressed patients. The Multidimensional Fatigue Inventory (MFI-20) covering general fatigue, physical fatigue, mental fatigue, reduced activity and reduced motivation has been widely used in patients with cancer and chronic fatigue syndrome. To address the multidimensional nature of fatigue, we examined the validity and reliability of a Chinese version of the MFI-20 in major depressive disorder (MDD). METHODS: Data were derived from a randomized controlled trial of acupuncture in 137 patients with partially remitted MDD. The test-retest reliability, internal consistency, construct and concurrent validity and sensitivity to change of the MFI-20 were analyzed. RESULTS: The MFI-20 was found to have good internal consistency (Cronbach's alpha=0.89) and 1-week test-retest reliability (Pearson correlation of the total score=0.73). Factor analysis showed 5 factors, but the factor structure was different from that in medical conditions. The 2 most prominent factors, explaining 46% of the total variance, were both associated with physical and mental energy but different in directions. There were adequate concurrent validity and sensitivity to change as evidenced by the significant correlations between the MFI-20 scores and depressive and anxiety symptoms, general health and quality of life. CONCLUSION: The Chinese MFI-20 is a valid and reliable instrument for the assessment of fatigue in MDD patients with residual symptoms. The construct of fatigue in MDD seems to be different from that in medical conditions. Further studies are needed to examine the MFI-20 in MDD patients from other cultures. PMID- 25035161 TI - Is impulsivity in remitted bipolar disorder a stable trait? A meta-analytic review. AB - OBJECTIVE: To review scores on measures of impulsivity in remitted bipolar disorder. DATA SOURCE: We used keywords "impulsivity and bipolar" and "impulsivity and mania" to narrow down our search on Medline, EMBASE and Psychinfo to include those studies that had reported impulsivity scores using validated and reliable assessment measures in remitted bipolar disorder (both I and II). We searched all English language studies from 1990 to October 2012. STUDY SELECTION: Nineteen reports met the inclusion criteria and were reviewed by two abstractors independently. DATA ABSTRACTION: We generated weighted mean differences (WMDs) from pooled data using RevManager 5.0 from Cochrane analysis. RESULTS: The Barratt Impulsivity Scale (BIS) 11 was the instrument most commonly used. Nineteen studies met the inclusion criteria, of which 2 were excluded due to incomplete data. A WMD of 12.8 was observed for BIS 11 total scores, 4.3 on the motor component, 4.1 on the cognitive and 7.6 on the non-planning components of the BIS 11 respectively. CONCLUSION: Impulsivity is significantly higher in remitted bipolar patients than normal controls. Non-planning impulsivity is a key domain affected in bipolar disorder, which may represent a stable trait. PMID- 25035162 TI - Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL. PMID- 25035163 TI - Viral lower respiratory tract infections and preterm infants' healthcare utilisation. AB - The aim of this study was to determine whether respiratory syncytial virus (RSV) and other viral lower respiratory tract infections (LRTI) in prematurely born infants were associated with similar effects on healthcare utilisation and related cost of care in the second compared to the first year after birth. Thirteen infants who had RSV LRTIs (RSV), 21 who had other viral LRTIs (other viral) and 25 had no viral LRTIs (no LRTI) were prospectively followed. Nasopharyngeal aspirates were collected whenever an infant had an LRTI regardless of whether it was in the hospital or in the community. Healthcare utilisation and the health-related cost of care were determined. Only the RSV group compared to the no LRTI group had higher overall respiratory costs in both year 1 (mean, L3,917 versus L24; p < 0.041) and year 2 (mean, L1,164 versus L61; p = 0.012). Only the RSV group required respiratory admissions; the RSV admission rate in year 2 was 3.4 % (number needed to treat 59). CONCLUSION: RSV LRTIs are associated with increased healthcare utilisation and cost of care in the first and second year; nevertheless, if prophylaxis is to be cost-effective in the second year, a high risk group needs to be identified. PMID- 25035164 TI - Reply to "No evidence to support a priming strategy with FFP in infants". PMID- 25035165 TI - Transmission of ESBL/AmpC-producing Escherichia coli from broiler chicken farms to surrounding areas. AB - Although previous studies have demonstrated high carriage of ESBL/AmpC-producing Escherichia coli in livestock, especially in broiler chickens, data on emission sources of these bacteria into the environment are still rare. Therefore, this study was designed to systematically investigate the occurrence of ESBL/AmpC producing E. coli in slurry, air (inside animal houses), ambient air (outside animal houses) and on soil surfaces in the areas surrounding of seven ESBL/AmpC positive broiler chicken fattening farms, including investigation of the possible spread of these bacteria via the faecal route and/or exhaust air into the environment. Seven German broiler fattening farms were each investigated at three points in time (3-36 h after restocking, 14-18 and 26-35 days after housing) during one fattening period. The occurrence of ESBL/AmpC genes in the investigated samples was confirmed by PCR, detecting blaCTX-M, blaSHV, blaTEM and blaCMY-genes, and, if necessary, by sequencing and/or the disc diffusion method. The results showed a wide spread of ESBL/AmpC-producing E. coli in broiler farms, as well as emissions into the surroundings. 12 out of 14 (86%) slurry samples were positive for ESBL/AmpC-producing E. coli. Additionally, 28.8% (n=23/80) of boot swabs taken from various surfaces in the areas surrounding of the farms as well as 7.5% (n=3/40) of the exhaust air samples turned out to be positive for these microorganisms. Moreover, a small proportion of air samples from inside the barns were ESBL/AmpC-positive. By comparing selected isolates using pulsed field gel electrophoresis, we proved that faecal and airborne transfer of ESBL/AmpC producing microorganisms from broiler fattening farms to the surrounding areas is possible. Two isolates from farm G2 (slurry and boot swab 50 m downwind), two isolates from farm G3 (slurry and individual animal swab) as well as two isolates from farm G6 (air sample in the barn and air sample 50 m downwind) showed 100% similarity in PFGE analysis. PMID- 25035166 TI - Seeking empowerment to comfort patients in severe pain: a grounded theory study of the nurse's perspective. AB - BACKGROUND: Hospital patients experience significant pain, which can delay healing and increase the risk of developing chronic pain. Nurses are affected by patients' ongoing pain and may cope with consequent anxiety and helplessness by distancing themselves from such patients. Understanding nurses' responses to patients in severe pain will inform strategies to support their coping, their patients and, ultimately, their retention in the nursing workforce. OBJECTIVES: The aim of the study was to develop a substantive theory explaining the hospital nurse's perspective of caring for patients in severe pain. DESIGN: The study used grounded theory method. SETTINGS: Data were collected on four acute care wards in a 610 bed Australian hospital. PARTICIPANTS: The sample included 33 nurse participants and 11 patient participants. Selection criteria for nurse participants were those who worked in the four study wards, cared for patients who experienced severe pain, and consented to be included. Selection criteria for patient participants were those who self-reported pain at intensity of seven or more on a scale of 0-10, were aged 18 years or older, could speak and read English, and consented to be included. METHODS: Theoretical sampling directed the collection of data using semi-structured interviews with nurses and participant observation, including structured observations of nurses who cared for patients in pain. Data were analysed using constant comparison method. RESULTS: Nurse participants encountered a basic psychosocial problem of feelings of disempowerment when their patients experienced persisting severe pain. In response, they used a basic psychosocial process of seeking empowerment to provide comfort in order to resolve distress and exhaustion associated with disempowerment. This coping process comprised three stages: building connections; finding alternative ways to comfort; and quelling emotional turmoil. CONCLUSIONS: The substantive theory proposed a link between the stress of nurses' disempowerment and a coping response that provides direction to support nurses' practice. Strategies indicated include enhanced communication protocols, access to advanced practice nurses, use of nonpharmacological comfort measures, utilization of ward-based pain resource nurses, and unit-specific pain management education. Further research to verify and extend the substantive theory to other settings and nursing populations is warranted. PMID- 25035167 TI - SSC(high)CD11b(high)Ly-6C(high)Ly-6G(low) myeloid cells curtail CD4 T cell response by inducible nitric oxide synthase in murine hepatitis. AB - Myeloid-derived suppressor cells (MDSCs) play an important role in maintaining immune tolerance in response to tumors and inflammatory diseases. Several liver MDSCs have been described in hepatitis in humans and mouse models. Although all the murine MDSCs are CD11b(+)Gr-1(+), their true phenotype and mechanism of suppression remain elusive. This study revealed that SSC(high)CD11b(high)Ly 6C(high)Ly-6G(low) monocytic cells but not the other liver-infiltrating, CD11b(+)Gr-1(+) subsets could suppress CD4 T cell responses. Their suppressive activity was remarkably effective even at a ratio of 1:50 when co-cultured with CD4 T cells. Mechanistically, the suppression was dependent on nitric oxide production by inducible nitric oxide synthase (iNOS). Furthermore, the suppressive function by these liver MDSCs was found to require direct contact with activated CD4 T cells. Adoptive transfer experiments demonstrate that these liver MDSCs can dramatically ameliorate concanavalin A (Con A)-induced fulminant hepatitis in mice. Finally, MDSC-mediated suppression in vivo was dependent on iNOS expression. Altogether, SSC(high)CD11b(high)Ly-6C(high)Ly-6G(low) cells represent authentic MDSCs in the inflammatory liver and may function to minimize collateral damage caused by an overzealous CD4 T cell response following hepatitis infection. PMID- 25035168 TI - Soy isoflavones administered to rats from weaning until sexual maturity affect ovarian follicle development by inducing apoptosis. AB - Twenty-one-day-old female Wistar rats were treated daily with orally administered soy isoflavones (SIFs) at concentrations of 50, 100, or 200 mg/kg body weight from weaning until sexual maturity (3 mo.), and ovarian follicle development was evaluated. At the end of the treatment period, the ultrastructure of the ovarian granulosa cells was examined by transmission electron microscopy. The apoptotic cell death of ovarian granulosa cells was detected using TUNEL staining. The mRNA expression levels of caspase-3, caspase-8, caspase-9, Bcl2, Bax, and Fas were determined by real-time quantitative PCR. The protein expression levels of caspase-3, Bcl2, Bax, and Fas were determined by western blotting. Our data showed that exposure to SIFs resulted in morphological changes consistent with ovarian granulosa cell apoptosis. The percentage of TUNEL-positive granulosa cells was increased. The mRNA expression levels of the apoptosis-related genes caspase-3, caspase-8, caspase-9, Bax, and Fas increased significantly. The protein levels of Bax, Fas, and cleaved caspase-3 were also increased. These results indicate that the exposure of rats to modest doses of SIFs from weaning until sexual maturity can affect ovarian follicle development by inducing apoptosis. The mechanism of SIF-induced alterations in ovarian follicle development may involve the activation of Fas-mediated and Bcl2/Bax-mediated apoptotic signaling pathways. PMID- 25035169 TI - Exposure assessment of Malondialdehyde, 4-Hydroxy-2-(E)-Nonenal and 4-Hydroxy-2 (E)-Hexenal through specific foods available in Belgium. AB - Malondialdehyde (MDA), 4-Hydroxy-2-(E)-Nonenal (HNE) and 4-Hydroxy-2-(E)-Hexenal (HHE) are reactive aldehydes found in foods and are formed due to decomposition of polyunsaturated fatty acid hydroperoxides. In the present study, sixteen food categories were analyzed for the aforementioned aldehydes and in combination with consumption data obtained from a national representative sample of the Belgian population, a quantitative exposure assessment was performed. MDA was detected above the detection limit in 84% of the analyzed samples while HNE and HHE in 63% and 16% of the samples respectively. Consumption of dry nuts, fried snacks, French fries and cured minced meat products were found to contribute the most to the intake of MDA and HNE. Intake of HHE from the foods analyzed was found not to be significant. An evaluation of any potential risk related to the intake of the studied aldehydes through the studied foods was performed by applying the threshold of toxicological concern concept. No risk to human health could be identified related to the consumption of these foods for the vast majority of the consumers, with the only exception of a small proportion (3.8%) of those who consume cured and minced raw meat, that could be at risk. PMID- 25035170 TI - Identification and validation of TGFBI as a promising prognosis marker of clear cell renal cell carcinoma. AB - OBJECTIVE: To identify prognostic biomarkers in clear cell renal cell carcinoma (ccRCC) using a proteomic approach. MATERIAL AND METHODS: We performed a comparative proteomic profiling of ccRCC and normal renal tissues from 9 different human specimens. We assessed differential protein expression by iTRAQ (isobaric tagging reagent for absolute quantify) labeling with regard to tumor aggressiveness according to the stage, size, grade, and necrosis (SSIGN) score and confirmed our results using Western blot (9 patients) and immunohistochemistry (135 patients) analysis. RESULTS: After proteomic analysis, 928 constitutive proteins were identified. Among these proteins, 346 had a modified expression in tumor compared with that of normal tissue. Pathway and integrated analyses indicated the presence of an up-regulation of the pentose phosphate pathway in aggressive tumors. In total, 14 proteins were excreted and could potentially become biomarkers. Overexpression of transforming growth factor, beta-induced (TGFBI) in ccRCC was confirmed using Western blot and immunohistochemistry analysis. A significant association was found between the presence of TGFBI expression with tumor category T3-4 (P<0.0001), Fuhrman grades III and IV (P<0.0001), tumor size>4cm (P<0.0001), presence of tumor necrosis (P<0.0001), nodal involvement (n = 0.009), metastasis (P = 0.012), SSIGN score>=5 (P<0.0001), cancer progression (P<0.0001), and cancer-specific death (P<0.0001). Cancer-specific survival was significantly better for patients with no cytoplasmic TGFBI expression (1-, 3-, 5-y cancer-specific survival of 94.7%, 87.8%, and 73.4% vs. 92.9%, 71.2%, and 49.8%, respectively; P<0.0001). CONCLUSION: We identified 346 proteins involved in renal carcinogenesis and confirmed the presence of a metabolic shift in aggressive tumors. TGFBI was overexpressed in tumors with high SSIGN scores and was significantly associated with oncologic outcomes. PMID- 25035171 TI - Emotion dysregulation as a mediator between childhood emotional abuse and current depression in a low-income African-American sample. AB - Abuse and neglect in childhood are well-established risk factors for later psychopathology. Past research has suggested that childhood emotional abuse may be particularly harmful to psychological development. The current cross-sectional study employed multiple regression techniques to assess the effects of childhood trauma on adulthood depression and emotion dysregulation in a large sample of mostly low-income African Americans recruited in an urban hospital. Bootstrap analyses were used to test emotion dysregulation as a potential mediator between emotional abuse in childhood and current depression. Childhood emotional abuse significantly predicted depressive symptoms even when accounting for all other childhood trauma types, and we found support for a complementary mediation of this relationship by emotion dysregulation. Our findings highlight the importance of emotion dysregulation and childhood emotional abuse in relation to adult depression. Moving forward, clinicians should consider the particular importance of emotional abuse in the development of depression, and future research should seek to identify mechanisms through which emotional abuse increases risk for depression and emotion dysregulation. PMID- 25035172 TI - Responding to abuse: Children's experiences of child protection in a central district, Uganda. AB - Part of a comprehensive response to violence against children involves child protection systems, but there are few data available on such systems in low income countries. This study describes the characteristics and help seeking behavior of children referred to local child protection services and the quality of the first-line response in one district in Uganda. Participants included 3,706 children from 42 primary schools who participated in a baseline survey on violence as part of the Good Schools Study (NCT01678846, clinicaltrial.gov). Children who disclosed violence were referred according to predefined criteria based on the type, severity, and timeframe of their experiences. Children were followed up to 4 months after the study ended. First-line responses by receiving agencies were classified into 3 categories: plan for action only, some action taken, and no plan and no action taken. Appropriateness of responses was based on which agency responded, timeliness of the response, quality of the documentation, and final status of the case. From the baseline survey, 529 children (14%) were referred. Girls were more likely to be referred and to meet the criteria for a serious case (9% girls, 4% boys). In total, 104 referrals (20%) had some kind of concrete action taken, but only 20 (3.8%) cases met all criteria for having received an adequate response. Nearly half (43%) of referred children had ever sought help by disclosing their experiences of violence prior to the baseline survey. In our study areas, the first-line response to children's reports of abuse was poor even though some referral structures are in place. PMID- 25035173 TI - The influence of differential response on decision-making in child protective service agencies. AB - Differential response (DR) profoundly changes the decision pathways of public child welfare systems, yet little is known about how DR shapes the experiences of children whose reports receive an investigation rather than an alternate response. Using data from the National Child Abuse and Neglect Data System (NCANDS), this study examined the relationship between DR implementation and decision outcomes in neglect cases, as measured by investigation, substantiation, and removal rates in 297 U.S. counties. Multivariate regression models included county-level measures of child poverty and proportions of African American children. Path analyses were also conducted to identify mediating effects of prior decision points and moderating effects of DR on poverty and race's influence on decision outcomes. Results indicate that compared to non-DR counties, those implementing DR have significantly lower investigation and substantiation rates within county populations but higher substantiation rates among investigated cases. Regression models showed significant reductions in removal rates associated with DR implementation, but these effects became insignificant in path models that accounted for mediation effects of previous decision points. Findings also suggest that DR implementation may reduce the positive association between child poverty rates and investigation rates, but additional studies with larger samples are needed to confirm this moderation effect. Two methods of calculating decision outcomes, population- and decision based enumeration, were used, and policy and research implications of each are discussed. This study demonstrates that despite their inherit complexity, large administrative datasets such as NCANDS can be used to assess the impact of wide scale system change across jurisdictions. PMID- 25035175 TI - Return to play after lateral meniscectomy compared with medial meniscectomy in elite professional soccer players. AB - BACKGROUND: Meniscectomy is frequently performed in elite soccer athletes to allow return to a high level of performance as early as possible. Although lateral meniscectomy is known to have more serious long-term sequelae than medial meniscectomy, little is known about the effect of lateral meniscectomy on the time to return to play during the early recovery phase in professional soccer players. HYPOTHESIS: Lateral meniscectomy results in longer times to return to preinjury level of competition and a higher incidence of adverse outcomes compared with medial meniscectomy in elite professional soccer players. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A single-surgeon database containing the injury history and operative details of elite soccer athletes from 2005 to 2009 was used to identify players who had undergone an isolated partial lateral or medial meniscectomy. The time to return to preinjury level of competition, the incidence of adverse events during early recovery, and the need for further arthroscopy were recorded. Time to return to play was analyzed by using the Kaplan-Meier method. A multivariate analysis was used to control for age, location of meniscectomy, percentage of meniscus excised, and type of tear. RESULTS: Ninety soccer players were identified, of which 42 had a lateral meniscectomy and 48 had a medial meniscectomy. The median time to return to play, to the nearest week, was longer in the lateral group than the medial group (7 vs 5; P < .001). At all time points after surgery, the cumulative probability of returning to play was 5.99 times greater (95% confidence interval, 3.34-10.74; P < .001) after medial meniscectomy. More lateral meniscectomy cases experienced adverse events related to pain/swelling-29 (69%) vs 4 (8%) (P < .001)-and required a second arthroscopy: 3 (7%) vs 0 (P = .098). CONCLUSION: The time to return to preinjury level of competition is significantly longer after lateral than medial meniscectomy in elite professional soccer athletes. Lateral meniscectomy has a higher incidence of adverse events in the early recovery period, including pain/swelling and the need for further arthroscopy. It is also associated with a significantly lower rate of return to play. These findings form the basis of an important discussion that must be had with player and club before a lateral meniscectomy is performed in elite soccer athletes. PMID- 25035174 TI - Osteochondral allograft transplant to the medial femoral condyle using a medial or lateral femoral condyle allograft: is there a difference in graft sources? AB - BACKGROUND: Osteochondral allograft (OCA) transplantation is an effective treatment for defects in the medial femoral condyle (MFC), but the procedure is limited by a shortage of grafts. Lateral femoral condyles (LFCs) differ in geometry from MFCs but may be a suitable graft source. The difference between articular surface locations of the knee can be evaluated with micro-computed tomography imaging and 3-dimensional image analysis. HYPOTHESIS: LFC OCAs inserted into MFC lesions can provide a cartilage surface match comparable with those provided by MFC allografts. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty MFCs and 10 LFCs were divided into 3 groups: 10 MFC recipients (MFCr), 10 MFC donors (MFCd), and 10 LFC donors (LFCd). A 20-mm defect was created in the weightbearing portion of the MFCr. Two grafts, 1 MFCd and 1 LFCd, were implanted sequentially into each MFCr. Micro-computed tomography (MUCT) images of the MFCr were acquired and analyzed to compare the topography of the original recipient site with the MFCd- and LFCd-repaired sites. Three-dimensional transformations were defined to register the defect site in the 3 scans of each MFCr. Vertical deviations from each voxel of the graft cartilage surface, relative to the intact recipient cartilage surface, were calculated and assessed as root mean square deviation and percentage graft area that was proud, sunk, and within the "acceptable" distance (+/-1.00 mm). The effect of repair (with MFC vs with LFC) on each of the surface match parameters is presented as mean +/- SD and was assessed by t test: height deviation over area (root mean square, mm), graft area acceptable (%), area unacceptably proud (%), area unacceptably sunk (%), step-off height over circumference (root mean square, mm), graft circumference acceptable (%), circumference unacceptably proud (%), and circumference unacceptably sunk (%). Percentage data were arcsin transformed before statistical testing. An alpha level of 0.05 was used to conclude if variations were statistically significant. RESULTS: MFCr defects were filled with both orthotopic MFCd and nonorthotopic LFCd. Registered MUCT images of the MFCr illustrate the cartilage surface contour in the sagittal and coronal planes, in the original intact condyle, as well as after OCA repairs. Specimen-specific surface color maps for the MFCr after implant of the MFCd and after implant of LFCd were generally similar, with some deviation near the edges. On average, the MFCr site exhibited a typical contour, and the MFCd and LFCd were slightly elevated. Both types of OCA-MFCd and LFCd-matched well, showing overall height deviations of 0.63 mm for area and 0.47 mm for step-off, with no significant difference between MFCd and LFCd (P = .92 and .57, respectively) and acceptable deviation based on area (87.6% overall) and step-off (96.7% overall), with no significant difference between MFCd and LFCd (P = .87 and .22, respectively). A small portion of the implant was proud (12.1% of area and 2.6% of circumference step-off height), with no significant difference between MFCd and LFCd (P = .26 and .27, respectively). A very small portion of the implant area and edge was sunk (0.3% of area and 0.6% of circumference), with no significant difference between MFCd and LFCd (P = .29 and .86, respectively). CONCLUSION/CLINICAL RELEVANCE: The achievement of excellent OCA surface match with an MFCd or LFCd graft into the common MFCr site suggests that nonorthotopic LFC OCAs are acceptable graft options for MFC defects. PMID- 25035176 TI - Optimizing the crowding strategy: sugar-based ionic micelles in the dilute-to condensed regime. AB - In the present study, we explore the effect of concentration on micelles made by different gangliosides, which are ionic biological glycolipids bearing multisugar headgroups with huge steric hindrance. Moreover, strong preferential interactions exist among like-conformer headgroups that can keep the ganglioside micelles in a trapped configuration. We extend the well-known ionic-amphiphiles paradigm, where local condensation and micelle crowding are matched by forming larger aggregates at increasing concentration. In fact, we force the balance between interparticle and intraparticle interactions while allowing for like conformers to modulate rebalancing. In the vast experimental framework, obtained by Small Angle X-ray scattering (SAXS) experiments, a theoretical model, accounting for a collective conformational transition of the bulky headgroups, is developed and successfully tested. It allows us to shed some light on the nature and coupling of the intermolecular forces involved in the interactions among glycolipid micelles. Energy minimization leads to complex behavior of the aggregation number on increasing concentration, fully consistent with the experimental landscape. From a biological perspective, this result could be reflected in the properties of ganglioside-enriched rafts on cell membranes, with a nonlinear structural response to approaching bodies such as charged proteins. PMID- 25035177 TI - Brain functional connectivity and the pathophysiology of schizophrenia. AB - In the last decade there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neuronal responses are associated with synchronized oscillatory activity in various frequency ranges suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia. Consequently, disturbances in neural synchronization may represent the functional relationship of disordered connectivity of cortical networks underlying the characteristic fragmentation of mind and behavior in schizophrenia. In recent studies the synchronization of oscillatory activity in the experience of characteristic symptoms such as auditory verbal hallucinations and thought blocks have been studied in patients with schizophrenia. Studies involving analysis of EEG activity obtained from individuals in resting state (in cage Faraday, isolated from external influences and with eyes closed). In patients with schizophrenia and persistent auditory verbal hallucinations (AVHs) observed a temporary increase in the synchronization phase of alpha and high theta oscillations of the electroencephalogram (EEG) compared with those of healthy controls and patients without AVHs . This functional hyper-connection manifested in time windows corresponding to experience AVHs, as noted by the patients during the recording of EEG and observed in speech related cortical areas. In another study an interaction of theta and gamma oscillations engages in the production and experience of AVHs. The results showed increased phase coupling between theta and gamma EEG rhythms in the left temporal cortex during AVHs experiences. A more recent study, approaches the thought blocking experience in terms of functional brain connectivity. Thought blocks (TBs) are characterized by regular interruptions of the flow of thought. Outward signs are abrupt and repeated interruptions in the flow of conversation or actions while subjective experience is that of a total and uncontrollable emptying of the mind. In the very limited bibliography regarding TB, the phenomenon is thought to be conceptualized as a disturbance of consciousness that can be attributed to stoppages of continuous information processing due to an increase in the volume of information to be processed. In an attempt to investigate potential expression of the phenomenon on the functional properties of electroencephalographic (EEG) activity, an EEG study was contacted in schizophrenic patients with persisting auditory verbal hallucinations (AVHs) who additionally exhibited TBs. Phase synchronization analyses performed on EEG segments during the experience of TBs showed that synchrony values exhibited a long-range common mode of coupling (grouped behavior) among the left temporal area and the remaining central and frontal brain areas. These common synchrony fluctuation schemes were observed for 0.5 to 2 s and were detected in a 4-s window following the estimated initiation of the phenomenon. The observation was frequency specific and detected in the broad alpha band region (6-12 Hz). The introduction of synchrony entropy (SE) analysis applied on the cumulative synchrony distribution showed that TB states were characterized by an explicit preference of the system to be functioned at low values of synchrony, while the synchrony values are broadly distributed during the recovery state. The results indicate that during TB states, the phase locking of several brain areas were converged uniformly in a narrow band of low synchrony values and in a distinct time window, impeding thus the ability of the system to recruit and to process information during this time window. The results of this study seem to have greater importance on neuronal correlation of consciousness. The brain is a highly distributed system in which numerous operations are executed in parallel and that lacks a single coordinating center. This raises the question of how the computations occurring simultaneously in spatially segregated processing areas are coordinated and bound together to give rise to coherent percepts and actions. One of the coordinating mechanisms appears to be the synchronization of neuronal activity by phase locking of self-generated network oscillations. This led to the hypothesis that the cerebral cortex might exploit the option to synchronize the discharges of neurons with millisecond ' theoretical formulations of the binding by-synchrony hypothesis were proposed earlier by Milner (1974), but the Singer lab in the 1990s was the first to obtain experimental evidence supporting the potential role of synchrony as a relational code. The results concerning the functional connectivity of the brain during TBs further support the hypothesis of phase synchronization as a key mechanism for neuronal assemblies underlying mental representations in the human brain. PMID- 25035178 TI - [Psychological burden of patients diagnosed with obstructive sleep apnea]. AB - Obstructive sleep apnea syndrome (OSAS) is characterized by repeated episodes of upper airway obstruction during sleep, which leads to the presence of excessive daytime drowsiness. Regarding the psychological comorbidity in patients diagnosed with OSAS, previous studies focused mainly on depressive and secondarily on anxiety symptoms. Due to the lack of research data regarding the prevalence of anxiety and depressive symptoms as well as of alexithymic characteristics in patients with OSAS in Greece, the aim of the study was to record the above symptomatology in a sample of Greek OSAS patients and to investigate its relation to the respiratory parameter (Apnea-Hypopnea Index, AHI) of polysomnography. The study was conducted in a certified sleep laboratory. Thirty five randomly selected patients who attended the laboratory with symptoms of daytime drowsiness, fatigue, disrupted sleep and snoring, were examined for anxiety, depression and alexithymia using the Spielberger Trait Anxiety Inventory (STAI), the Beck Depression Inventory (BDI) and the Toronto Alexithymia Scale (TAS-20), respectively, 24 hours prior to being submitted to polysomnography. All 35 patients met the inclusion criteria of the study (age<=75 years, no other chronic diseases and no history of major psychiatric disorders). Six patients did not meet the diagnostic criteria for OSAS and were thus used as the control group of the study. A high prevalence of anxiety (41.4%) and depressive (55.2%) symptoms and of alexithymic characteristics (41.4%) was observed in OSAS patients. Although the control group showed a higher prevalence of anxiety (66.7%) and depressive (83.3%) symptoms, there were no differences between the two groups (STAI: t=-0.927, p=0.360, BDI: t=-1.537, p=0.134, TAS-20: t=0.196, p=0.846). With regard to severity, no differences were observed between control, mild, moderate and severe OSAS subgroups (STAI: F=0.583, p=0.660, BDI: F=0.829, p=0.488, TAS-20: F=0.987, p=0.412). Females scored higher on the BDI and on the STAI compared to males (STAI: t=-2.38, p=0.039, BDI: t=-3.59, p=0.01). Finally, no correlation was observed between psychometric scores and AHI (Pearson correlation p>0.05). The study confirms the high prevalence of anxiety and depressive symptoms which has been found in previous studies. Furthermore, we found a high prevalence of alexithymic characteristics, a factor that has not been investigated previously and which is positively correlated with anxiety symptoms. The coexistence of alexithymic characteristics may further complicate the clinical manifestations of OSAS due to the fact that patients with alexithymia typically have difficulty in indentifying and describing their underlying psychological symptomatology and, moreover, tend to exhibit more, and often atypical, physical symptoms. In conclusion, the study supports the presence of a high degree of psychological burden in patients diagnosed with OSAS, regardless of the severity of their symptoms, as determined by the AHI. This comorbidity should be taken into consideration during the clinical assessment of OSAS and for the treatment planning. PMID- 25035179 TI - [Attempted suicide during the financial crisis in Athens]. AB - Suicidal behavior is considered as the result of complex cognitive and emotional processes and it is a timeless, global and multifactorial phenomenon. Periods of financial crises in the past, such as the Great Depression in the USA in 1929 and the economic crises of Asia, Russia and Argentina in the late 1990s, have been associated with impairment of mental health of the economically affected. Unemployment, job insecurity, debts, poverty and social exclusion seems to lead to higher incidence of anxiety and depressive symptoms and increased suicidality. Alcohol and substance use and the reduction of the state budget for health services reinforce the negative effects of the economic recession on mental health. The financial crisis which currently affects many European countries began in 2008 and its impact on the mental health of European citizens is in progress. Greece is probably the most affected country by the European financial crisis. The aim of this study is to investigate the potential impact of the crisis' consequences on the attempted suicide rates in the Athens population and the differentiation of suicide attempters on social, demographic and clinical psychopathological parameters during the crisis. A retrospective study was conducted. The semi-structured records of 165 attempters who were hospitalized in the Internal Medicine Clinics of the "Sotiria" General Hospital in Athens, after attempted suicide in the years 2007 and 2011, before and during the financial crisis respectively, were studied. Among suicide attempters 95(57.6%) were suffering from mental disorders. Most often diagnoses were these of mood disorders (n=60, 63.2%). Demographic data, current psychiatric disorder, previous suicide attempt and severity of psychopathology at the time of suicide attempt were recorded for each patient. Furthermore, the severity of each suicide attempt was estimated. Suicide attempts were 70 in 2007, before the financial crisis (mean age 36.9 years, 71% women) and 95 in 2011, during the financial crisis (mean age 41.0 years, women 65%). There is an increase of suicide attempts by 35.71%. There were no statistically significant differences between the two periods regarding the gender and age of attempters. There was a statistically significant increase of unemployed (p=0.004), as well as of married/widowed/divorced (p=0.02) suicide attempters during the crisis. There was not statistically significant difference in the severity of suicide attempts before and during the economic crisis or the severity of psychopathology of the attempters. The financial crisis is probably associated with upward trend in attempted suicide of the Athens population. Most affected are those who are unemployed, married, widowed, divorced. Suicide prevention programs are essential for the accurate and timely identification and the immediate and effective management of this special high risk group of attempters during the financial crisis. PMID- 25035180 TI - [Comparative study of the operation of two day's Hospitals in Athens]. AB - The present paper describes the preparation for the commencement of services by the University Mental Health Research Institute (UMHRI) Day Hospital and Eginition Day Hospital whose operation (in 1977) signifies the beginning of the Psychiatric Reform in our country. The two units' functional characteristics and the type of offered services are mentioned. Psychotherapeutic, biological and sociotherapeutic approaches are practiced on a daily basis within a framework of Therapeutic Community services. Moreover, relations, similarities and differences among the two day hospitals are pointed out. Special mention is given to the problems and difficulties that these two units faced upon their commencement, which took place at different time periods, set 32 years apart. The lack of legislative framework with regards to the operation of Day Hospitals, the bureaucratic obstacles and the skepticism towards the new treatment approach of patients, were the basic obstacles that had to be overcome in order for the first Day Hospital to become operational in 1977. Licensing and funding were the main obstacles that the creation of UMHRI's Day Hospital faced, although these two units had already been established. Emphasis was placed on the staff's training, which mainly consisted of young professionals and at the social environment's and all those services' (health-care, community etc) attitude, in the specific catchment area (6th Mental Health Sector). The study of patients' characteristics hospitalized in Eginition's Day Hospital throughout its first year of operation (1977-1978) and of patients hospitalized at UMHRI's Day Hospital, also at its first year of operation (2009-2010), showed, among other things, that in both cases, the number of hospitalized male patients is larger than the number of female patients. This constitutes an exception compared to other countries, whereby female patients outnumber male patients in Day Hospitals. Especially at UMHRI's Day Hospital, the number of men is twice the number of women and three times the number of women in the subgroup of patients with schizophrenia. In addition, at Eginition Day Hospital, the men- women ratio is 3:2 in the total number of hospitalized patients and 2:1 in the schizophrenia subgroup. The comparison between the hospitalized patients in Eginition Day Etaospital and UMHRI. Day Hospital brought out the following differences: inpatients at UMHRI's day Hospital were more often older, (x2= 29.52, p=0.0001), unemployed (x2=14.65, p=0.0001) and used public means of transportation more rarely (x2=7.38, p=0.005). No other differences were found in the rest of the sociodemographic variables such as education, marital status, insurance agency, living conditions, traveling time to the day Hospital, referral source, diagnosis of schizophrenia, past hospitalizations. To conclude, it is worth mentioning that the Day Hospital is in a position to treat patients with active psychotic symptomatology, preventing thus their hospitalization on a 24 hour basis. PMID- 25035181 TI - [Attitudes and perceptions of staff and resident-patients in residential units in Thessaly]. AB - With the implementation of the psychiatric reform in Greece, the care of chronically mentally ill persons has been transferred into sheltered housing in the community (nursing homes, hostels, sheltered apartments), for the psychosocial rehabilitation of the patients, aiming at the deinstutionalization and their social reintegration. The scope of the present study was to record and analyze the attitudes and perceptions of both staff members and resident-patients of the 17 residential units (5 nursing homes, 4 hostels and 8 sheltered apartments) of "Psychargos" Project in Thessaly, as well as to check the hypothesis of "neo" institutionalization for the units under investigation. Data were collected onsite (field study) from 157 staff members and 88 resident patients, by structuring and using original questionnaires as well as the Global Assessment Scale (GAS). The independent variables for the staff members (sex, age, education, profession, legal form of the residential unit, previous professional experience in mental health services) as well as for the resident patients (sex, age, GAS score, legal form of the residential unit, residence time in the unit, and previously in other psychiatric institutions) were correlated to dependent variables in order to assess possible statistical relationships (x2). The statistical significance test p-value was set at 0.05. Data statistical processing was carried out using SPSS 16.0. The hypothesis of "neo" institutionalization for these residential units was checked in a 34-month follow up period. Regarding the staff, a positive attitude towards the institution of residential care structures itself was recorded. Nevertheless, a negative opinion regarding the prospect of resident patients recovery, and even skepticism as to the acceptability of these persons by the local community, were expressed. Surely, it is positive that a remarkable percentage of the staff members are willing, even though under certain conditions, to provide foster care to resident patients. On their part, the resident-patients maintain good relationships with staff and fellow residents, and feel content with their residence itself and the services provided. However, most of them (especially the most functional and with milder symptoms) express their desire for more autonomy, with regard to the degree of supervision received by the staff, their contact with the local community, the perspective of receiving foster care, the perspective of return in their natural family as well as of autonomous living. Ultimately however, the survey results give rise to pessimism with respect to an intermediate transitional character of the residential units, since only a few resident patients moved during the follow-up period (34 months) towards reduced supervision housing and none to the community. However, the functionality of a non-insignificant part of the resident-patients could be employed for leaving "neo"-institutionalized housing and living, and finally their social reintegration. PMID- 25035182 TI - [Psychiatrist-Psychotherapist: thoughts and suggestions]. AB - A basic training in psychotherapy is a necessary requirement for the speciality of psychiatry. Nevertheless, any thorough training in psychotherapy in Greece lacks planning and a credible certification system. Tauraining is carried out by different psychotherapeutic societies of varying prestige, through a number of programs. There have been very few attempts until now to map this field. The Section of Psychotherapy of the Hellenic Psychiatric Association (HPA) has tried to document the characteristics of the psychiatrists practicing psychotherapy. The study aimed at all of the trainee and trained psychiatrists, members of HPA. 210 questionnaires were filled in by members of HPA in 2000 and 2009-2011. Most of them were returned by post to the Section of Psychotherapy, while some were filled in during the 21rst HPA congress. With regard to psychotherapeutic training 151 (72%) reported some kind of psychoanalytic training, 90 (42.8%) cognitive, 85 (40.5%) systemic and 38 (18%) other (interpersonal, drama therapy, existentialist, cognitive-analytic, hypnosis, group therapy of another kind, orgonotherapy, vegetotherapy, Eye Movement Desensitization Reprocessing). The average duration of the training in years was 5.26 (+/-3.7) for the psychoanalytic one, 2.73 (+/-1.6) for the cognitive, 3.83 (+/-2.1) for the systemic and 3.08 (+/-2.5) for the psychiatrists with a different type of training. Interestingly, many of the participants reported more than one types of psychotherapeutic training. Another important finding is the fact that the range of training varies from a single seminar to many years, something which underlines the considerable divergence with regard to what is considered psychotherapeutic training. Several questions arise from the above findings: A first one is if a psychiatrist should, during his/her training, also be trained in psychotherapy and what kind of training this should be. A second question is if being a trained psychiatrist entails the capacity to practice psychotherapy and to be called a psychotherapist. Should the title of psychotherapist be a general one or should a specific theoretical-clinical approach be mentioned in the title (psychoanalyst, cognitive-behavioral, systemic, etc.). One more question is which institution is appropriate for the certification of a psychotherapist: a state authority or another, possibly private, institution such as scientific societies or Non-Governmental Organizations? A final question is where professionals from different fields certified as psychotherapists could converge and how their differences could be specified. The mapping and study of the field of psychotherapy within HPA can create the basis for a fruitful discussion on the issue of the psychiatrists' training and certification in psychotherapy, thus outlining a number of questions and dilemmas. PMID- 25035183 TI - [Behavioral disorders and substance abuse in adolescents with mental retardation]. AB - The percentage of people with mental retardation in the general population is estimated at about 2.3%, with adolescence (15-20 years) constituting the development period during which a peak in rates of mental retardation is observed. The increased prevalence of adolescence may be explained from the fact that the specified requirements of the school initially, and society later, inevitably lead to comparative evaluation of the teen with mental retardation in relation to peers, thus making mental retardation more apparent. Adolescents with mental retardation face a number of physical and psychological needs which are not often distinguishable and as a consequence undergo the deterioration of their already burdened quality of life. In particular, mental health problems occur 3 to 4 times more often in adolescents with mental retardation compared with adolescents of the general population. This review presents the most recent epidemiological findings regarding the correlation between behavioral disorders, substance use and the possible comorbidity in adolescents with intellectual disability, both at community level and residential care level. Epidemiological data indicate that behavioral disorders are among the most common types of psychopathology in mentally retarded adolescents with the severity and symptoms varying depending on the personal characteristics of each adolescent. Regarding substance use, the available data show that the rates of substance use (alcohol, smoking, illicit drugs) are lower in this specific population group but the differences over the last years tend to be eliminated. Finally, according to the few surveys that were examined referring to the comorbidity of behavioral disorders and substance use in adolescents with intellectual disability, the results were contradictory. Specifically, while behavioral disorders continued to be one of the most common types of psychopathology, the related substances disorders indicated lower rates compared to normal intelligence adolescents with behavioral disorders. Risk factors that increase the chances of developing either simple or more complicated types of psychopathology in adolescents with mental retardation have been found to be based on individual, family and social levels. On the other hand, the individual characteristics of adolescents (intellectual level, attention capacity, understandable linguistic expression, overall progress until adolescence), the existence of a supportive family environment and the presence of social support and awareness through the creation of special counseling, education and medical services, are the most important protective factors which contribute to the prevention of several forms of psychopathology in adolescents with mental retardation. For the writing of the literature review, the following electronic databases were used: PubMed, Scopus, Psycinfo, Cochrane Library, Web of Science and Google Scholar. The key words used were: Intellectual Disability, Behavioral disorders, Adolescents, Mental Retardation, Learning disabilities, Developmental Disabilities, Disruptive behaviour disorders, Conduct disorder, Substance Abuse, Substance Misuse, Oppositional defiant disorder, Alcohol and illicit drug use, Smoking Use, Young people, Teenagers, Youths. PMID- 25035184 TI - Prophylactic mastectomy of contralateral breast only marginally improves survival, study shows. PMID- 25035186 TI - The influences of partner accuracy and partner memory ability on social false memories. AB - In this study, we examined whether increasing the proportion of false information suggested by a confederate would influence the magnitude of socially introduced false memories in the social contagion paradigm Roediger, Meade, & Bergman (Psychonomic Bulletin & Review 8:365-371, 2001). One participant and one confederate collaboratively recalled items from previously studied household scenes. During collaboration, the confederate interjected 0 %, 33 %, 66 %, or 100 % false items. On subsequent individual-recall tests across three experiments, participants were just as likely to incorporate misleading suggestions from a partner who was mostly accurate (33 % incorrect) as they were from a partner who was not at all accurate (100 % incorrect). Even when participants witnessed firsthand that their partner had a very poor memory on a related memory task, they were still as likely to incorporate the confederate's entirely misleading suggestions on subsequent recall and recognition tests (Exp. 2). Only when participants witnessed firsthand that their partner had a very poor memory on a practice test of the experimental task itself were they able to reduce false memory, and this reduction occurred selectively on a subsequent individual recognition test (Exp. 3). These data demonstrate that participants do not always consider their partners' memory ability when working on collaborative memory tasks. PMID- 25035185 TI - Evidence for joint moment asymmetry in healthy populations during gait. AB - The purpose of this study was to determine the presence and prevalence of asymmetry in lower extremity joint moments within and across healthy populations during overground walking. Bilateral gait data from several studies performed at two institutions were pooled from 182 healthy, pain-free subjects. Four distinct populations were identified based on age, activity level and body mass index. Mean peak external joint moments were calculated from three to six trials of level overground walking at self-selected speed for each subject. Right and left limb moments were reclassified as "greater" or "lesser" moment for each subject to prevent obscuring absolute asymmetry due to averaging over positive and negative asymmetries across subjects. A clinically relevant asymmetry measure was calculated from the peak joint moments with an initial chosen cutoff value of 10%. Confidence intervals for the proportion of subjects with greater than 10% asymmetry between limbs were estimated based on the binomial distribution. We found a high amount of asymmetry between the limbs in healthy populations. More than half of our overall population exceeded 10% asymmetry in peak hip and knee flexion and adduction moments. Group medians exceeded 10% asymmetry for all variables in all populations. This may have important implications on gait evaluations, particularly clinical evaluations or research studies where asymmetry is used as an outcome. Additional research is necessary to determine acceptable levels of joint moment asymmetry during gait and to determine whether asymmetrical joint moments influence the development of symptomatic pathology or success of lower extremity rehabilitation. PMID- 25035187 TI - Not enough familiarity for fluency: definitional encoding increases familiarity but does not lead to fluency attribution in associative recognition. AB - Five experiments were conducted to test whether encoding manipulations thought to encourage unitization would affect fluency attribution in associative recognition memory. Experiments 1a and 1b, which utilized a speeded recognition memory test, demonstrated that definitional encoding increased reliance on familiarity during the recognition memory test. Experiments 2a, 2b, and 3, however, replicated previous research that had shown that fluency is unlikely to be attributed as evidence of previous occurrence in associative recognition (Westerman, Journal of Experimental Psychology: Learning, Memory, and Cognition 27:723-732, 2001). The results put limits on the degree to which fluency can influence recognition memory judgments, even in cases of enhanced familiarity, and are consistent with previous work suggesting that participants have preexperimental expectations about fluency that are difficult to change (e.g., Miller, Lloyd, & Westerman, Journal of Memory and Language 58:1080-1094, 2008), as well as with work suggesting that fluency has less of an influence on recognition memory decisions that are conceptual in nature (Parks, Journal of Experimental Psychology: Learning, Memory, and Cognition 39:1280-1286, 2013). PMID- 25035188 TI - Combination of omega-3 Fatty acids, lithium, and aripiprazole reduces oxidative stress in brain of mice with mania. AB - Manic episode in bipolar disorder (BD) was evaluated in the present study with supplementation of omega-3 fatty acids in combination with aripiprazole and lithium on methylphenidate (MPD)-induced manic mice model. Administration of MPD 5 mg/kg bw intraperitoneally (i.p.) caused increase in oxidative stress in mice brain. To retract this effect, supplementation of omega-3 fatty acids 1.5 ml/kg (p.o.), aripiprazole 1.5 mg/kg bw (i.p.), and lithium 50 mg/kg bw (p.o) were given to mice. Omega-3 fatty acids alone and in combination with aripiprazole- and lithium-treated groups significantly reduced the levels of superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation products (thiobarbituric acid reactive substances) in the brain. MPD treatment significantly decreased the reduced glutathione (GSH) level and glutathione peroxidase (GPx) activity, and they were restored by supplementation of omega-3 fatty acids with aripiprazole and lithium. There is no remarkable difference in the effect of creatine kinase (CK) activity between MPD-induced manic model and the treatment groups. Therefore, our results demonstrate that oxidative stress imbalance and mild insignificant CK alterations induced by administration of MPD can be restored back to normal physiological levels through omega-3 fatty acids combined with lithium and aripiprazole that attributes to effective prevention against mania in adult male Swiss albino mice. PMID- 25035189 TI - Cadmium-induced injury and the ameliorative effects of selenium on chicken splenic lymphocytes: mechanisms of oxidative stress and apoptosis. AB - Cadmium (Cd) is an important environmental pollutant present in soil, water, air, and food. Selenium (Se) can antagonize some metal element toxicity including Cd. To investigate the cytotoxicity of Cd and the protective effects of Se on bird immunocytes in vitro, chicken splenic lymphocytes with CdCl2 (10(-6) mol/L), Na2SeO3 (10(-7) mol/L), and the mixture (10(-7) mol/L Na2SeO3 and 10(-6) mol/L CdCI2) were incubated for 12, 24, 36, and 48 h, respectively. A high level of malondialdehyde (MDA) and reactive oxygen species (ROS) productions were observed in Cd treatment group; the activities of catalase (CAT), glutathione peroxidise (GSH-Px), superoxide dismutase (SOD), and the mitochondrial inner transmembrane potential (DeltaPsim) were significantly lower in Cd treatment group than those in controls (P < 0.05 or P < 0.01). In contrast, Se significantly improved the activities of antioxidant enzymes and reduced MDA and ROS levels compared to Cd treatment alone group, although not restored to the levels of control group. The population of apoptosis cells demonstrated that Cd induces the apoptosis of chicken splenic lymphocytes; in addition, increased mRNA level of Bak, p53, caspase-3, caspase-9, and cytochrome c (Cyt c) and decreased Bcl-2, Bcl-xl, and CaM were observed in Cd treatment group. Se ameliorated DeltaPsim and [Ca(2+)]i for mitochondria function restoring, and Se was able to modulate the expression of relative genes. In conclusion, concurrent treatment with Se reduced the Cd induced morphological changes and oxidative stress, ion disorder, and apoptosis, suggesting that the toxic effects of Cd on the chicken splenic lymphocytes were partly meliorated by Se. PMID- 25035190 TI - Copper as ancillary diagnostic tool in preoperative evaluation of possible papillary thyroid carcinoma in patients with benign thyroid disease. AB - Preoperative diagnosis of papillary thyroid carcinoma (PTC) comprises numerous diagnostic procedures which are mostly applicable in tertiary institutions. Normal thyroid function depends on the presence of many trace elements and copper (Cu) and zinc (Zn) are some of those. The study is based on retrospective review of 118 patients with preoperatively diagnosed benign thyroid disease (BTD) and 12 with PTC, who underwent thyroid surgery at the Center for Endocrine Surgery Clinical Center of Serbia, Belgrade, between 2010 and 2012. The objective was to evaluate concentrations of Cu and Zn in serum as possible prediction markers for PTC in patients who underwent surgery for preoperatively diagnosed BTD. Concentrations of Cu and Zn ions in serum were measured using atomic absorption spectrophotometer. Data were analyzed using methods of descriptive statistics, Anova and t-test (p < 0.05 was considered statistically significant). Definitive pathohistological findings revealed PTC in 23 (19.5%) and papillary microcarcinoma-mPTC in 13 (11.0%) of BTD patients. The concentrations of Cu ions in serum of PTC patients as well as in serum of patients with mPTC were significantly higher than in serum of BTD patients (p < 0.05). The concentrations of Zn ions and Cu/Zn ratio in serum of PTC and mPTC patients were not significantly higher than in serum of BTD patients. The concentration of Cu ions in serum of patients before thyroid surgery can be useful, easy available, and a low-cost tool in prediction of preoperatively undiagnosed PTC in patients with BTD. PMID- 25035191 TI - Assessment of the iodine status of the Wa national boarding school students in Southwest China. AB - Iodine deficiency disorder (IDD) has been recognized as a major public health problem worldwide and has serious detrimental effects on the growth and development of the children. Therefore, monitoring the iodine status of the school-aged children is of great importance. We randomly recruited 159 boarding school students (aged from 6 to 14) from 10 primary schools in Lincang County, Yunnan Province. The dietary iodine level of the students was measured by the new mixed meal method and chemical analysis. Fifty-seven daily water samples and 32 salt samples were collected from the same surveyed area to determine the iodine content using the sulfate cerium catalytic spectrophotometric method and the hyposulphite quantitative titration method, respectively. The iodine level of each water sample was ranged from 0.611 to 1.473 MUg/L. The median and the mean value of the iodine content in water were 0.972 and 0.979 +/- 0.189 MUg/L. The average iodine intake of each age group was higher that the recommended nutrient intakes (RNI) but lower than the tolerable upper intake level (UL). The median and the mean value of the iodine content in salt were 25.53 and 25.62 +/- 1.70 mg/kg. Taken together, the present study investigated the iodine intake status of Wa school-aged children through examination of their dietary iodine intake, the environment, and the salt iodine status. Results showed that the status of the iodine uptake of the Wa children were higher than the RNI, but lower than the UL. PMID- 25035192 TI - Relationships between blood Mg2+ and energy metabolites/enzymes after acute exhaustive swimming exercise in rats. AB - Magnesium (Mg) plays a central role in neuronal activity, cardiac excitability, neuromuscular transmission, muscular contraction, vasomotor tone, and blood pressure, all of which are significantly related to physical performance. To date, the available data about detection of blood total Mg (tMg; free-ionized, protein-bound, and anion-complex forms) are inconsistent, and there is limited information on blood free-ionized Mg (Mg(2+)) in relation to physical exercise. The aim of this study was to determine the biochemical changes related to energy metabolism after acute exhaustive swimming exercise (AESE) in rats in an attempt to correlate the role of blood Mg(2+) with metabolites/enzymes related to energy production. After AESE, blood Mg(2+), tMg, K(+), partial pressure of carbon dioxide, lactate, total protein (T-PRO), high-density lipoprotein (HDL), creatinine (CRE), blood urea nitrogen (BUN), uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alanine phosphatase (ALP), lactate dehydrogenase (LDH), and creatinine kinase (CK) were significantly increased, whereas pH, partial pressure of oxygen, oxygen saturation, the Mg(2+)/tMg and Ca(2+)/Mg(2+) ratios, HCO3 (-), glucose, triglyceride (TG), and low-density lipoprotein (LDL) were significantly decreased. During AESE, lactate, T-PRO, albumin, AST, ALP, LDH, CK, CRE, BUN, and UA showed significant positive correlations with changes in blood Mg(2+), while glucose, TG, and LDL correlated to Mg(2+) in a negative manner. In conclusion, AESE induced increases in both blood Mg(2+) and tMg, accompanied by changes in blood metabolites and enzymes related to energy metabolism due to increased metabolic demands and mechanical damages. PMID- 25035193 TI - Perceived quality of interprofessional interactions between physicians and nurses in oncology outpatient clinics. AB - PURPOSE: To evaluate the perceived quality of interactions between nurses and physicians in oncology outpatient clinics. METHODS: A cross-sectional, observational survey involving 250 physicians and nurses was conducted at oncology outpatient clinics at two regional cancer centres in the province of Ontario, Canada. Eligible participants were identified by administrators and invited to complete a one-time survey questionnaire. Quality of interactions was assessed using a seven-item survey of relational coordination, which measures two factors of interaction: supportive relationships and quality communication. Descriptive analyses and multivariate analyses of variance (MANOVA) were conducted to assess potential differences between the two study sites and the two professional groups. RESULTS: Overall, nurses and physicians at both study sites rated their interactions highly (mean = 4.32 and 4.51 out of 5 for supportive relationships and quality communication, respectively). No difference in either factor was reported between physicians and nurses at either study site, but the two study sites differed significantly in both factors [F(2, 245) = 7.54, p < 0.001]. CONCLUSIONS: Overall, oncology nurses and oncologists at outpatient clinics rated their levels of interprofessional interaction highly. Contextual factors may have contributed to the high interaction scores and different ratings between the two cancer centres. The finding that nurses and physicians reported similar levels of perceived interactions suggests that relationships in these outpatient cancer clinics are highly collaborative and collegial. PMID- 25035194 TI - The Red Journal's top downloads of 2013. PMID- 25035195 TI - Attitudes toward blinding of peer review and perceptions of efficacy within a small biomedical specialty. AB - PURPOSE: Peer reviewers' knowledge of author identity may influence review content, quality, and recommendations. Therefore, the International Journal of Radiation Oncology, Biology, Physics ("Red Journal") implemented double-blinded peer review in 2011. Given the relatively small size of the specialty and the high frequency of preliminary abstract presentations, we sought to evaluate attitudes, the efficacy of blinding, and the potential impact on the disposition of submissions. METHODS AND MATERIALS: In May through August 2012, all Red Journal reviewers and 1 author per manuscript completed questionnaires regarding demographics, attitudes, and perceptions of success of blinding. We also evaluated correlates of the outcomes of peer review. RESULTS: Questionnaires were received from 408 authors and 519 reviewers (100%). The majority of respondents favored double blinding; 6% of authors and 13% of reviewers disagreed that double blinding should continue in the Red Journal. In all, 50% of the reviewers did not suspect the identity of the author of the paper that they reviewed; 19% of reviewers believed that they could identify the author(s), and 31% suspected that they could. Similarly, 23% believed that they knew the institution(s) from which the paper originated, and 34% suspected that they did. Among those who at least suspected author identity, 42% indicated that prior presentations served as a clue, and 57% indicated that literature referenced did so. Of those who at least suspected origin and provided details (n=133), 13% were entirely incorrect. Rejection was more common in 2012 than 2011, and submissions from last authors with higher H-indices (>21) were more likely to survive initial review, without evidence of interactions between submission year and author gender or H-index. CONCLUSIONS: In a relatively small specialty in which preliminary research presentations are common and occur in a limited number of venues, reviewers are often familiar with research findings and suspect author identity even when manuscript review is blinded. Nevertheless, blinding appears to be effective in many cases, and support for continuing blinding was strong. PMID- 25035196 TI - Oncology scan--the role of personalized medicine in gynecologic cancers. PMID- 25035197 TI - Design and implementation of bundled payment systems for cancer care and radiation therapy. PMID- 25035198 TI - Getting the next version of payment policy "right" on the road toward accountable cancer care. PMID- 25035199 TI - Randomized trial of hyperfractionation versus conventional fractionation in T2 squamous cell carcinoma of the vocal cord (RTOG 9512). AB - PURPOSE: To compare hyperfractionation versus standard fractionation for T2N0 vocal cord carcinoma in a randomized controlled trial. METHODS AND MATERIALS: Patients with T2 vocal cord cancer were stratified by substage (T2a vs T2b) and randomly assigned to receive either hyperfractionation (HFX) to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The trial was designed to detect a 55% reduction in the local failure hazard rate with 80% statistical power. RESULTS: Between April 1996 and July 2003, a total of 250 patients were enrolled. Of 239 patients analyzable for outcomes, 94% were male, 83% had a Karnofsky performance status of 90-100, and 62% had T2a tumor. Median follow-up for all surviving patients was 7.9 years (range, 0.6-13.1 years). The 5-year local control (LC) rate was 8 points higher but not statistically significant (P=.14 for HFX [78%] vs SFX [70%]), corresponding to a 30% hazard rate reduction. The 5-year disease free survival (DFS) was 49% versus 40% (P=.13) and overall survival (OS) was 72% versus 63% (P=.29). HFX was associated with higher rates of acute skin, mucosal, and laryngeal toxicity. Grade 3-4 late effects were similar with a 5-year cumulative incidence of 8.5% (3.4%-13.6%) after SFX and 8.5% (3.4%-13.5%) after HFX. CONCLUSIONS: The 5-year local control was modestly higher with HFX compared to SFX for T2 glottic carcinoma, but the difference was not statistically significant. These results are consistent with prior studies of hyperfractionation showing a benefit in local control. Substaging by T2a versus T2b carries prognostic value for DFS and OS. For cost and convenience reasons other altered fractionation schedules have been adopted in routine practice. PMID- 25035200 TI - Effects of voice rehabilitation after radiation therapy for laryngeal cancer: a randomized controlled study. AB - BACKGROUND: Patients treated with radiation therapy for laryngeal cancer often experience voice problems. The aim of this randomized controlled trial was to assess the efficacy of voice rehabilitation for laryngeal cancer patients after having undergone radiation therapy and to investigate whether differences between different tumor localizations with regard to rehabilitation outcomes exist. METHODS AND MATERIALS: Sixty-nine male patients irradiated for laryngeal cancer participated. Voice recordings and self-assessments of communicative dysfunction were performed 1 and 6 months after radiation therapy. Thirty-three patients were randomized to structured voice rehabilitation with a speech-language pathologist and 36 to a control group. Furthermore, comparisons with 23 healthy control individuals were made. Acoustic analyses were performed for all patients, including the healthy control individuals. The Swedish version of the Self Evaluation of Communication Experiences after Laryngeal Cancer and self-ratings of voice function were used to assess vocal and communicative function. RESULTS: The patients who received vocal rehabilitation experienced improved self-rated vocal function after rehabilitation. Patients with supraglottic tumors who received voice rehabilitation had statistically significant improvements in voice quality and self-rated vocal function, whereas the control group did not. CONCLUSION: Voice rehabilitation for male patients with laryngeal cancer is efficacious regarding patient-reported outcome measurements. The patients experienced better voice function after rehabilitation. Patients with supraglottic tumors also showed an improvement in terms of acoustic voice outcomes. Rehabilitation with a speech-language pathologist is recommended for laryngeal cancer patients after radiation therapy, particularly for patients with supraglottic tumors. PMID- 25035201 TI - Economic analyses in squamous cell carcinoma of the head and neck: a review of the literature from a clinical perspective. AB - The purpose of this review was to describe cost-effectiveness and cost analysis studies across treatment modalities for squamous cell carcinoma of the head and neck (SCCHN), while placing their results in context of the current clinical practice. We performed a literature search in PubMed for English-language studies addressing economic analyses of treatment modalities for SCCHN published from January 2000 to March 2013. We also performed an additional search for related studies published by the National Institute for Health and Clinical Excellence in the United Kingdom. Identified articles were classified into 3 clinical approaches (organ preservation, radiation therapy modalities, and chemotherapy regimens) and into 2 types of economic studies (cost analysis and cost effectiveness/cost-utility studies). All cost estimates were normalized to US dollars, year 2013 values. Our search yielded 23 articles: 13 related to organ preservation approaches, 5 to radiation therapy modalities, and 5 to chemotherapy regimens. In general, studies analyzed different questions and modalities, making it difficult to reach a conclusion. Even when restricted to comparisons of modalities within the same clinical approach, studies often yielded conflicting findings. The heterogeneity across economic studies of SCCHN should be carefully understood in light of the modeling assumptions and limitations of each study and placed in context with relevant settings of clinical practices and study perspectives. Furthermore, the scarcity of comparative effectiveness and quality of-life data poses unique challenges for conducting economic analyses for a resource-intensive disease, such as SCCHN, that requires a multimodal care. Future research is needed to better understand how to compare the costs and cost effectiveness of different modalities for SCCHN. PMID- 25035202 TI - Postmastectomy radiation therapy for inflammatory breast cancer: is more better? PMID- 25035203 TI - Pattern of ipsilateral breast tumor recurrence after breast-conserving therapy. AB - PURPOSE: To analyze the incidence and prognostic factors of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) in a large, population-based, single-center study with long-term follow-up. METHODS AND MATERIALS: We analyzed 3595 cases in which BCT was performed in 3824 women with stage I or II breast cancer. The incidence of IBTR was analyzed over time and was based on IBTR as first event. RESULTS: The 15-year local relapse-free survival was 90.9%. The hazard estimates for IBTR showed a time course with 2 peaks, the first at approximately 5 years and the second, twice as high, at 12 years. Stratifying subjects by age and margin status showed that, for women <=40 years old with negative margins, adjuvant systemic therapy led to a 5-fold reduced risk of recurrence compared to none, and the presence of lymph vascular space invasion (LVSI) had a 3-fold increased risk compared to its absence. For women >40 years old, the presence of LVSI (hazard ratio [HR] 2.5) and the presence of lobular carcinoma in situ in the lumpectomy specimen (HR 2.3) were the only 2 risk factors. CONCLUSIONS: We demonstrated a pattern in risk of IBTR over time, with 2 peaks, first at approximately 5 years and a second, much higher peak at approximately 12 years, especially for women <=40 years old. For women <=40 years old with tumor-free resection margins, we noted that the absence of adjuvant systemic therapy and the presence of LVSI were independent prognostic factors of IBTR. For women >40 years old, the presence of LVSI and the presence of lobular carcinoma in situ were independent risk factors. PMID- 25035204 TI - Intraoperative radiation therapy in early breast cancer using a linear accelerator outside of the operative suite: an "image-guided" approach. AB - PURPOSE: To present local control, complications, and cosmetic outcomes of intraoperative radiation therapy (IORT) for early breast cancer, as well as technical aspects related to the use of a nondedicated linear accelerator. METHODS AND MATERIALS: This prospective trial began in May of 2004. Eligibility criteria were biopsy-proven breast-infiltrating ductal carcinoma, age >40 years, tumor <3 cm, and cN0. Exclusion criteria were in situ or lobular types, multicentricity, skin invasion, any contraindication for surgery and/or radiation therapy, sentinel lymph node involvement, metastasis, or another malignancy. Patients underwent classic quadrantectomy with intraoperative sentinel lymph node and margins evaluation. If both free, the patient was transferred from operative suite to linear accelerator room, and IORT was delivered (21 Gy). Primary endpoint: local recurrence (LR); secondary endpoints: toxicities and aesthetics. Quality assurance involved using a customized shield for chest wall protection, applying procedures to minimize infection caused by patient transportation, and using portal films to check collimator-shield alignment. RESULTS: A total of 152 patients were included, with at least 1 year follow-up. Median age (range) was 58.3 (40-85.4) years, and median follow-up time was 50.7 (12-110.5) months. The likelihood of 5-year local recurrence was 3.7%. There were 3 deaths, 2 of which were cancer related. The Kaplan-Meier 5-year actuarial estimates of overall, disease-free, and local recurrence-free survivals were 97.8%, 92.5%, and 96.3%, respectively. The overall incidences of acute and late toxicities were 12.5% and 29.6%, respectively. Excellent, good, fair, and bad cosmetic results were observed in 76.9%, 15.8%, 4.3%, and 2.8% of patients, respectively. Most treatments were performed with a 5-cm collimator, and in 39.8% of the patients the electron-beam energy used was >=12 MeV. All patients underwent portal film evaluation, and the shielding was repositioned in 39.9% of cases. No infection or anesthesia complications were observed. CONCLUSIONS: Local control with IORT was adequate, with low complication rates and good cosmetic outcomes. More than one third of patients benefited from the "image-guidance" approach, and almost 40% benefited from the option of higher electron beam energies. PMID- 25035205 TI - Random forests to predict rectal toxicity following prostate cancer radiation therapy. AB - PURPOSE: To propose a random forest normal tissue complication probability (RF NTCP) model to predict late rectal toxicity following prostate cancer radiation therapy, and to compare its performance to that of classic NTCP models. METHODS AND MATERIALS: Clinical data and dose-volume histograms (DVH) were collected from 261 patients who received 3-dimensional conformal radiation therapy for prostate cancer with at least 5 years of follow-up. The series was split 1000 times into training and validation cohorts. A RF was trained to predict the risk of 5-year overall rectal toxicity and bleeding. Parameters of the Lyman-Kutcher-Burman (LKB) model were identified and a logistic regression model was fit. The performance of all the models was assessed by computing the area under the receiving operating characteristic curve (AUC). RESULTS: The 5-year grade >=2 overall rectal toxicity and grade >=1 and grade >=2 rectal bleeding rates were 16%, 25%, and 10%, respectively. Predictive capabilities were obtained using the RF-NTCP model for all 3 toxicity endpoints, including both the training and validation cohorts. The age and use of anticoagulants were found to be predictors of rectal bleeding. The AUC for RF-NTCP ranged from 0.66 to 0.76, depending on the toxicity endpoint. The AUC values for the LKB-NTCP were statistically significantly inferior, ranging from 0.62 to 0.69. CONCLUSIONS: The RF-NTCP model may be a useful new tool in predicting late rectal toxicity, including variables other than DVH, and thus appears as a strong competitor to classic NTCP models. PMID- 25035206 TI - Risk prediction models of locoregional failure after radical cystectomy for urothelial carcinoma: external validation in a cohort of korean patients. AB - PURPOSE: To evaluate the predictive accuracy and general applicability of the locoregional failure model in a different cohort of patients treated with radical cystectomy. METHODS AND MATERIALS: A total of 398 patients were included in the analysis. Death and isolated distant metastasis were considered competing events, and patients without any events were censored at the time of last follow-up. The model included the 3 variables pT classification, the number of lymph nodes identified, and margin status, as follows: low risk (<=pT2), intermediate risk (>=pT3 with >=10 nodes removed and negative margins), and high risk (>=pT3 with <10 nodes removed or positive margins). RESULTS: The bootstrap-corrected concordance index of the model 5 years after radical cystectomy was 66.2%. When the risk stratification was applied to the validation cohort, the 5-year locoregional failure estimates were 8.3%, 21.2%, and 46.3% for the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of locoregional failure differed significantly between the low-risk and intermediate-risk groups (subhazard ratio [SHR], 2.63; 95% confidence interval [CI], 1.35-5.11; P<.001) and between the low-risk and high-risk groups (SHR, 4.28; 95% CI, 2.17-8.45; P<.001). Although decision curves were appropriately affected by the incidence of the competing risk, decisions about the value of the models are not likely to be affected because the model remains of value over a wide range of threshold probabilities. CONCLUSIONS: The model is not completely accurate, but it demonstrates a modest level of discrimination, adequate calibration, and meaningful net benefit gain for prediction of locoregional failure after radical cystectomy. PMID- 25035207 TI - Genomic prostate cancer classifier predicts biochemical failure and metastases in patients after postoperative radiation therapy. AB - PURPOSE: To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP). METHODS AND MATERIALS: Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms. RESULTS: The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA <=0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups. CONCLUSION: The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision making for treatment of high-risk prostate cancer. PMID- 25035208 TI - Role of FDG-PET in the implementation of involved-node radiation therapy for Hodgkin lymphoma patients. AB - PURPOSE: This study examines the role of (18)F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) in the implementation of involved-node radiation therapy (INRT) in patients treated for clinical stages (CS) I/II supradiaphragmatic Hodgkin lymphoma (HL). METHODS AND MATERIAL: Patients with untreated CS I/II HL enrolled in the randomized EORTC/LYSA/FIL Intergroup H10 trial and participating in a real-time prospective quality assurance program were prospectively included in this study. Data were electronically obtained from 18 French cancer centers. All patients underwent APET-computed tomography (PET-CT) and a post-chemotherapy planning CT scanning. The pre-chemotherapy gross tumor volume (GTV) and the postchemotherapy clinical target volume (CTV) were first delineated on CT only by the radiation oncologist. The planning PET was then co registered, and the delineated volumes were jointly analyzed by the radiation oncologist and the nuclear medicine physician. Lymph nodes undetected on CT but FDG-avid were recorded, and the previously determined GTV and CTV were modified according to FDG-PET results. RESULTS: From March 2007 to February 2010, 135 patients were included in the study. PET-CT identified at least 1 additional FDG avid lymph node in 95 of 135 patients (70.4%; 95% confidence interval [CI]: 61.9% 77.9%) and 1 additional lymph node area in 55 of 135 patients (40.7%; 95% CI: 32.4%-49.5%). The mean increases in the GTV and CTV were 8.8% and 7.1%, respectively. The systematic addition of PET to CT led to a CTV increase in 60% of the patients. CONCLUSIONS: Pre-chemotherapy FDG-PET leads to significantly better INRT delineation without necessarily increasing radiation volumes. PMID- 25035209 TI - Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. AB - PURPOSE/OBJECTIVE(S): Primary low-grade gliomas are common brain tumors of childhood, many of which require radiation therapy (RT) as definitive treatment. Increased conformality of RT could decrease the incidence and severity of late effects. We report our experience with 32 pediatric patients treated with proton RT. METHODS AND MATERIALS: Thirty-two pediatric patients with low-grade gliomas of the brain or spinal cord were treated with proton RT from 1995 to 2007. Sixteen patients received at least 1 regimen of chemotherapy before definitive RT. The median radiation dose was 52.2 GyRBE (48.6-54 GyRBE). RESULTS: The median age at treatment was 11.0 years (range, 2.7-21.5 years), with a median follow-up time of 7.6 years (range, 3.2-18.2 years). The 6-year and 8-year rates of progression-free survival were 89.7% and 82.8%, respectively, with an 8-year overall survival of 100%. For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (P=.80), with a median neurocognitive testing interval of 4.5 years (range, 1.2-8.1 years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (<7 years) and those with significant dose to the left temporal lobe/hippocampus. The incidence of endocrinopathy correlated with a mean dose of >=40 GyRBE to the hypothalamus, pituitary, or optic chiasm. Stabilization or improvement of visual acuity was achieved in 83.3% of patients at risk for radiation-induced injury to the optic pathways. CONCLUSIONS: This report of late effects in children with low-grade gliomas after proton RT is encouraging. Proton RT appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis. PMID- 25035210 TI - Whole lung irradiation for adults with pulmonary metastases from Ewing sarcoma. AB - PURPOSE: To evaluate feasibility and patterns of failure in adult patients with Ewing sarcoma (ES) treated with whole lung irradiation (WLI) for pulmonary metastases. METHODS AND MATERIALS: Retrospective review of all ES patients treated at age 18 or older with 12-15 Gy WLI for pulmonary metastases at a single institution between 1990 and 2014. Twenty-six patients met the study criteria. RESULTS: The median age at WLI was 23 years (range, 18-40). The median follow-up time of the surviving patients was 3.8 years (range, 1.0-9.6). The 3-year cumulative incidence of pulmonary relapse (PR) was 55%, with a 3-year cumulative incidence of PR as the site of first relapse of 42%. The 3-year event-free survival (EFS) and overall survival (OS) were 38 and 45%, respectively. Patients with exclusively pulmonary metastases had better outcomes than did those with extrapulmonary metastases: the 3-year PR was 45% in those with exclusively lung metastases versus 76% in those with extrapulmonary metastases (P=.01); the 3-year EFS was 49% versus 14% (P=.003); and the 3-year OS was 61% versus 13% (P=.009). Smoking status was a significant prognostic factor for EFS: the 3-year EFS was 61% in nonsmokers versus 11% in smokers (P=.04). Two patients experienced herpes zoster in the radiation field 6 and 12 weeks after radiation. No patients experienced pneumonitis or cardiac toxicity, and no significant acute or late sequelae were observed among the survivors. CONCLUSION: WLI in adult patients with ES and lung metastases is well tolerated and is associated with freedom from PR of 45% at 3 years. Given its acceptable toxicity and potential therapeutic effect, WLI for pulmonary metastases in ES should be considered for adults, as it is in pediatric patients. All patients should be advised to quit smoking before receiving WLI. PMID- 25035211 TI - Interrater reliability of the categorization of late radiographic changes after lung stereotactic body radiation therapy. AB - PURPOSE: Radiographic changes after lung stereotactic body radiation therapy (SBRT) have been categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis; (B), scar-like fibrosis (C), and no evidence of increased density (D). The purpose of this study was to assess the interrater reliability of this categorization system in patients with early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Seventy-seven patients were included in this study, all treated with SBRT for early-stage (T1/2) NSCLC at a single institution, with a minimum follow-up of 6 months. Six experienced clinicians familiar with post-SBRT radiographic changes scored the serial posttreatment CT images independently in a blinded fashion. The proportion of patients categorized as A, B, C, or D at each interval was determined. Krippendorff's alpha (KA), Multirater kappa (M-kappa), and Gwet's AC1 (AC1) scores were used to establish interrater reliability. A leave-one-out analysis was performed to demonstrate the variability among raters. Interrater agreement of the first and last 20 patients scored was calculated to explore whether a training effect existed. RESULTS: The number of ratings ranged from 450 at 6 months to 84 at 48 months of follow-up. The proportion of patients in each category was as follows: A, 45%; B, 16%; C, 13%; and D, 26%. KA and M-kappa ranged from 0.17 to 0.34. AC1 measure range was 0.22 to 0.48. KA increased from 0.24 to 0.36 at 12 months with training. The percent agreement for pattern A peaked at 12 month with a 54% chance of having >50% raters in agreement and decreased over time, whereas that for patterns B and C increased over time to a maximum of 20% and 22%, respectively. CONCLUSION: This post-SBRT radiographic change categorization system has modest interrater agreement, and there is a suggestion of a training effect. Patterns of fibrosis evolve after SBRT and alternative categorization systems should be evaluated. PMID- 25035212 TI - Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. AB - PURPOSE: Radiation therapy (RT) can both suppress and stimulate the immune system. We sought to investigate the mechanisms underlying radiation-induced lymphopenia and its associations with patient outcomes in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Subjects consisted of 711 patients who had received definitive RT for NSCLC. A lymphocyte nadir was calculated as the minimum lymphocyte value measured during definitive RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman correlation coefficients. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and compared with log rank test results. Multivariate regressions were conducted with linear and Cox regression analyses. All variables were analyzed as continuous if possible. RESULTS: Larger GTVs were correlated with lower lymphocyte nadirs regardless of concurrent chemotherapy receipt (with concurrent: r = -0.26, P<.0001; without: r = -0.48, P<.0001). Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V5-V10: P<.0001) that incrementally decreased and became nonsignificant at higher doses (lung V60-V70: P>.05). Of note, no significant associations were detected between GTV and lung DVH parameters with total leukocyte, neutrophil, or monocyte nadirs during RT or with lymphocyte count prior to RT. Multivariate analysis revealed larger GTV (P<.0001), receipt of concurrent chemotherapy (P<.0001), twice-daily radiation fractionation (P=.02), and stage III disease (P=.05) to be associated with lower lymphocyte nadirs. On univariate analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] = 0.51 per 10(3) lymphocytes/MUL, P=.01) and EFS (HR = 0.46 per 10(3) lymphocytes/MUL, P<.0001). These differences held on multivariate analyses, controlling for common disease and treatment characteristics including GTV. CONCLUSIONS: Lower lymphocyte nadirs during definitive RT were associated with larger GTVs and worse patient outcomes. PMID- 25035213 TI - Use of single- versus multiple-fraction palliative radiation therapy for bone metastases: population-based analysis of 16,898 courses in a Canadian province. AB - PURPOSE: There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population based, publicly funded health care system. METHODS AND MATERIALS: All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. RESULTS: A total of 16,898 courses of RT were delivered to 8601 patients. SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group (P<.001; most commonly in prostate cancer), worse prognosis (P<.001), increasing physician experience (P<.001), site of metastases (P<.001; least for spine metastases), and area of training (P<.001; most commonly for oncologists trained in the United Kingdom). There was wide variation in the prescription of SFRT across 5 regional cancer centers, ranging from 25.5% to 73.4%, which persisted after controlling for other, potentially confounding factors (P<.001). CONCLUSIONS: The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life. PMID- 25035214 TI - Patterns of care among patients receiving radiation therapy for bone metastases at a large academic institution. AB - PURPOSE: This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution. METHODS AND MATERIALS: Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed. RESULTS: We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patients (83%) were prescribed <=10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days. CONCLUSIONS: These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, single-fraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival. PMID- 25035216 TI - Human papillomavirus (HPV) infection in squamous cell carcinomas arising from the oropharynx: detection of HPV DNA and p16 immunohistochemistry as diagnostic and prognostic indicators--a pilot study. AB - PURPOSE: Human papillomavirus (HPV) 16 infection is associated with oropharyngeal carcinogenesis and is likely the cause of the reported increase in disease incidence. We evaluated the prevalence of HPV infection and the reliability of different diagnostic tools using primary tumor samples from a cohort of 50 patients. METHODS AND MATERIALS: Formalin-fixed paraffin-embedded (FFPE) tumor samples were collected from all 50 consecutive primary oropharyngeal SCC patients who were enrolled in the study; fresh tumor samples were available in 22 cases. NucliSENS EasyQ HPVv1 was used for RNA, and Digene Hybrid Capture-2(HC2) was used for DNA detection. p16 Expression was evaluated by immunohistochemistry in FPPE specimens. RESULTS: Based on the DNA detection assay on FFPE samples, the frequency of high-risk HPV infection was 32%. The agreement rate between HPV RNA and HPV DNA detection in fresh samples was 100%. The agreement rate between p16 immunohistochemistry (IHC) and the detection of HPV DNA in the FFPE samples was fair but not excellent (kappa = 0.618). HPV DNA detection was highly significant, as measured by disease-specific survival and determined using a Wilcoxon test (P=.001). p16 IHC also exhibited a prognostic value but with a lower statistical significance (P=.0475). The detection of HPV DNA, but not p16 IHC, was also significantly correlated with locoregional control (P=.0461). CONCLUSION: Diagnostic methods based on the detection of HPV nucleic acids appear to be more reliable and objective because they do not require reading by a trained histopathologist. Furthermore, the detection of HPV DNA exhibits an improved correlation with survival, and therefore appears definitely more reliable than p16 IHC for routine use in clinical practice. PMID- 25035215 TI - Targeting nucleophosmin 1 represents a rational strategy for radiation sensitization. AB - PURPOSE: To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization. METHODS AND MATERIALS: Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, gammaH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107 mediated radiosensitization was assessed in NSCLC cell lines and xenografts. RESULTS: Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with gammaH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts. CONCLUSIONS: These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity. PMID- 25035217 TI - Dose escalated liver stereotactic body radiation therapy at the mean respiratory position. AB - PURPOSE: The dosimetric impact of dose probability based planning target volume (PTV) margins for liver cancer patients receiving stereotactic body radiation therapy (SBRT) was compared with standard PTV based on the internal target volume (ITV). Plan robustness was evaluated by accumulating the treatment dose to ensure delivery of the intended plan. METHODS AND MATERIALS: Twenty patients planned on exhale CT for 27 to 50 Gy in 6 fractions using an ITV-based PTV and treated free breathing were retrospectively evaluated. Isotoxic, dose escalated plans were created on midposition computed tomography (CT), representing the mean breathing position, using a dose probability PTV. The delivered doses were accumulated using biomechanical deformable registration of the daily cone beam CT based on liver targeting at the exhale or mean breathing position, for the exhale and midposition CT plans, respectively. RESULTS: The dose probability PTVs were on average 38% smaller than the ITV-based PTV, enabling an average +/- standard deviation increase in the planned dose to 95% of the PTV of 4.0 +/- 2.8 Gy (9 +/- 5%) on the midposition CT (P<.01). For both plans, the delivered minimum gross tumor volume (GTV) doses were greater than the planned nominal prescribed dose in all 20 patients and greater than the planned dose to 95% of the PTV in 18 (90%) patients. Nine patients (45%) had 1 or more GTVs with a delivered minimum dose more than 5 Gy higher with the midposition CT plan using dose probability PTV, compared with the delivered dose with the exhale CT plan using ITV-based PTV. CONCLUSIONS: For isotoxic liver SBRT planned and delivered at the mean respiratory, reduced dose probability PTV enables a mean escalation of 4 Gy (9%) in 6 fractions over ITV-based PTV. This may potentially improve local control without increasing the risk of tumor underdosing. PMID- 25035218 TI - Time-adjusted internal target volume: a novel approach focusing on heterogeneity of tumor motion based on 4-dimensional computed tomography imaging for radiation therapy planning of lung cancer. AB - PURPOSE: To consider nonuniform tumor motion within the internal target volume (ITV) by defining time-adjusted ITV (TTV), a volume designed to include heterogeneity of tumor existence on the basis of 4-dimensional computed tomography (4D-CT). METHODS AND MATERIALS: We evaluated 30 lung cancer patients. Breath-hold CT (BH-CT) and free-breathing 4D-CT scans were acquired for each patient. The tumors were manually delineated using a lung CT window setting (window, 1600 HU; level, -300 HU). Tumor in BH-CT images was defined as gross tumor volume (GTV), and the sum of tumors in 4D-CT images was defined as ITV-4D. The TTV images were generated from the 4D-CT datasets, and the tumor existence probability within ITV-4D was calculated. We calculated the TTV80 value, which is the percentage of the volume with a tumor existence probability that exceeded 80% on ITV-4D. Several factors that affected the TTV80 value, such as the ITV-4D/GTV ratio or tumor centroid deviation, were evaluated. RESULTS: Time-adjusted ITV images were acquired for all patients, and tumor respiratory motion heterogeneity was visualized. The median (range) ITV-4D/GTV ratio and median tumor centroid deviation were 1.6 (1.0-4.1) and 6.3 mm (0.1-30.3 mm), respectively. The median TTV80 value was 43.3% (2.9-98.7%). Strong correlations were observed between the TTV80 value and the ITV-4D/GTV ratio (R=-0.71) and tumor centroid deviation (R= 0.72). The TTV images revealed the tumor motion pattern features within ITV. CONCLUSIONS: The TTV images reflected nonuniform tumor motion, and they revealed the tumor motion pattern features, suggesting that the TTV concept may facilitate various aspects of radiation therapy planning of lung cancer while incorporating respiratory motion in the future. PMID- 25035219 TI - SSO-ASTRO consensus guidelines for breast-conserving surgery with whole-breast radiation: in regard to Moran et al. PMID- 25035220 TI - In regard to Moran et al. PMID- 25035221 TI - In reply to Dixon and Thomas. PMID- 25035222 TI - Stereotactic ablative radiation therapy for centrally located recurrences of non small cell lung cancer: in regard to Chang et al. PMID- 25035223 TI - In reply to Oskan. PMID- 25035224 TI - In reply to Lo et al. PMID- 25035225 TI - Stereotactic ablative therapy and the central chest: in regard to Oskan. PMID- 25035230 TI - Novel antibacterial orthodontic cement containing quaternary ammonium monomer dimethylaminododecyl methacrylate. AB - OBJECTIVES: Demineralized lesions in tooth enamel around orthodontic brackets are caused by acids from cariogenic biofilm. This study aimed to develop a novel antibacterial orthodontic cement by incorporating a quaternary ammonium monomer dimethylaminododecyl methacrylate (DMADDM) into a commercial orthodontic cement, and to investigate the effects on microcosm biofilm response and enamel bond strength. METHODS: DMADDM, a recently-synthetized antibacterial monomer, was incorporated into orthodontic cement at 0%, 1.5%, 3% and 5% mass fractions. Bond strength of brackets to enamel was measured. A microcosm biofilm model was used to measure metabolic activity, lactic acid production, and colony-forming units (CFU) on orthodontic cements. RESULTS: Shear bond strength was not reduced at 3% DAMDDM (p > 0.1), but was slightly reduced at 5% DMADDM, compared to 0% DMADDM. Biofilm viability was substantially inhibited when in contact with orthodontic cement containing 3% DMADDM. Biofilm metabolic activity, lactic acid production, and CFU were much lower on orthodontic cement containing DMADDM than control cement (p < 0.05). CONCLUSIONS: Therefore, the novel antibacterial orthodontic cement containing 3% DMADDM inhibited oral biofilms without compromising the enamel bond strength, and is promising to reduce or eliminate demineralization in enamel around orthodontic brackets. PMID- 25035233 TI - Alpha-plane based automatic general type-2 fuzzy clustering based on simulated annealing meta-heuristic algorithm for analyzing gene expression data. AB - This paper considers microarray gene expression data clustering using a novel two stage meta-heuristic algorithm based on the concept of alpha-planes in general type-2 fuzzy sets. The main aim of this research is to present a powerful data clustering approach capable of dealing with highly uncertain environments. In this regard, first, a new objective function using alpha-planes for general type 2 fuzzy c-means clustering algorithm is represented. Then, based on the philosophy of the meta-heuristic optimization framework 'Simulated Annealing', a two stage optimization algorithm is proposed. The first stage of the proposed approach is devoted to the annealing process accompanied by its proposed perturbation mechanisms. After termination of the first stage, its output is inserted to the second stage where it is checked with other possible local optima through a heuristic algorithm. The output of this stage is then re-entered to the first stage until no better solution is obtained. The proposed approach has been evaluated using several synthesized datasets and three microarray gene expression datasets. Extensive experiments demonstrate the capabilities of the proposed approach compared with some of the state-of-the-art techniques in the literature. PMID- 25035231 TI - Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4. AB - Sphingosine 1-phosphate (S1P) has been implicated in anti-atherogenic properties of high-density lipoproteins. However, the roles and signaling of S1P in macrophages, the main contributor to atherosclerosis, have not been well studied. Furthermore, pro-inflammatory M1 and anti-inflammatory M2 macrophage phenotypes may influence the development of atherosclerosis. Therefore, we investigated the effects of S1P on macrophage phenotypes, especially on M2 polarization and its signaling in relation to the anti-atherogenic properties of S1P. It was found that S1P induced anti-inflammatory M2 polarization via IL-4 secretion and its signaling, and induced IL-4Ralpha and IL-2Rgamma. In addition, down-stream signalings, such as, stat-6 phosphorylation, SOCS1 induction, and SOCS3 suppression were also observed in macrophages in response to S1P. Furthermore, S1P-induced ERK activation, and the inhibitions of p38 MAPK and JNK were found to be key signals for IL-4 induction. Moreover, the anti-atherogenic effect of S1P in HDL was confirmed by the observation that oxidized LDL-induced lipid accumulation was attenuated in S1P-treated M2 macrophages. Furthermore, the atheroprotective effect of S1P was demonstrated by its anti-apoptotic effect on S1P-treated macrophages. The present study shows that S1P-induced M2 polarization of macrophages could be mediated via IL-4 signaling, and suggests that M2 polarization by S1P is responsible for the anti-atherogenic and atheroprotective properties of high-density lipoproteins in vivo. PMID- 25035232 TI - Decoding the EGFR mutation-induced drug resistance in lung cancer treatment by local surface geometric properties. AB - Epidermal growth factor receptor (EGFR) mutation-induced drug resistance leads to a limited efficacy of tyrosine kinase inhibitors during lung cancer treatments. In this study, we explore the correlations between the local surface geometric properties of EGFR mutants and the progression-free survival (PFS). The geometric properties include local surface changes (four types) of the EGFR mutants compared with the wild-type EGFR, and the convex degrees of these local surfaces. Our analysis results show that the Spearman's rank correlation coefficients between the PFS and three types of local surface properties are all greater than 0.6 with small P-values, implying a high significance. Moreover, the number of atoms with solid angles in the ranges of [0.71, 1], [0.61, 1] or [0.5, 1], indicating the convex degree of a local EGFR surface, also shows a strong correlation with the PFS. Overall, these characteristics can be efficiently applied to the prediction of drug resistance in lung cancer treatments, and easily extended to other cancer treatments. PMID- 25035234 TI - Comparison of hydrodynamically closed isotachophoresis-capillary zone electrophoresis with hydrodynamically open capillary zone electrophoresis hyphenated with tandem mass spectrometry in drug analysis: pheniramine, its metabolite and phenylephrine in human urine. AB - The advanced two dimensional isotachophoresis (ITP)-capillary zone electrophoresis (CZE) hyphenated with tandem mass spectrometry (MS/MS, here triple quadrupole, QqQ) was developed in this work to demonstrate analytical potentialities of this approach in the analysis of drugs in multicomponent ionic matrices. Pheniramine (PHM), phenylephrine (PHE), paracetamol (PCM) and their potential metabolic products were taken for the analysis by the ITP-CZE-ESI-QqQ technique working in hydrodynamically closed CE separation system and then a comparison with the conventional (hydrodynamically open) CZE-ESI-QqQ technique was made. The ITP-CZE-ESI-QqQ method was favorable in terms of obtainable selectivity (due to highly effective heart-cut analysis), concentration limits of detection (LOD at pgmL(-1) levels due to enhanced sample load capacity and ITP preconcentration), sample handling (on-line sample pretreatment, i.e. clean-up, preconcentration, preseparation), and, by that, possibilities for future automation and miniaturization. On the other hand, this experimental arrangement, in contrast to the CZE-ESI-QqQ arrangement supported by an electroosmotic flow, is principally limited to the analysis of uniformly (i.e. positively or negatively) charged analytes in one run without any possibilities to analyze neutral compounds (here, PCM and neutral or acidic metabolites of the drugs had to be excluded from the analysis). Hence, these general characteristics should be considered when choosing a proper analytical CE-MS approach for a given biomedical application. Here, the analytical potential of the ITP-CZE-ESI-QqQ method was demonstrated showing the real time profiles of excreted targeted drugs and metabolite (PHM, PHE, M-PHM) in human urine after the administration of one dose of Theraflu((r)) to the volunteers. PMID- 25035235 TI - Development and validation of a liquid chromatographic method for the stability study of a pharmaceutical formulation containing voriconazole using cellulose tris(4-chloro-3-methylphenylcarbamate) as chiral selector and polar organic mobile phases. AB - The ophthalmic solution of voriconazole, i.e. (2R,3S)-2-(2,4-difluorophenyl)-3-(5 fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, made from an injection formulation which also contains sulfobutylether-beta-cyclodextrin sodium salt as an excipient (Vfend), is used for the treatment of fungal keratitis. A liquid chromatographic (LC) method using polar organic mobile phase and cellulose tris(4 chloro-3-methylphenylcarbamate) coated on silica as chiral stationary phase was successfully developed to evaluate the chiral stability of the ophthalmic solution. The percentage of methanol (MeOH) in the mobile phase containing acetonitrile (ACN) as the main solvent significantly influenced the retention and resolution of voriconazole and its enantiomer ((2S,3R)-2-(2,4-difluorophenyl)-3 (5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol). The optimized mobile phase consisted of ACN/MeOH/diethylamine/trifluoroacetic acid (80/20/0.1/0.1; v/v/v/v). The method was found to be selective not only regarding the enantiomer of voriconazole but also regarding the specified impurities described in the monograph from the European Pharmacopoeia. The LC method was then fully validated applying the strategy based on total measurement error and accuracy profiles. Under the selected conditions, the determination of 0.1% of voriconazole enantiomer could be performed. Finally, a stability study of the ophthalmic solution was conducted using the validated LC method. PMID- 25035236 TI - Quantitative structure-retention relationship modeling of gas chromatographic retention times based on thermodynamic data. AB - Thermodynamic parameters of DeltaH(T0), DeltaS(T0), and DeltaCP for 156 compounds comprising alkanes, alkyl halides and alcohols were determined for a 5% phenyl 95% methyl stationary phase. The determination of thermodynamic parameters relies on a Nelder-Mead simplex optimization to rapidly obtain the parameters. Two methodologies of external and leave one out cross validations were applied to assess the robustness of the estimations of thermodynamic parameters. The largest absolute errors in predicted retention time across all temperature ramps and all compounds were 1.5 and 0.3s for external and internal sets, respectively. The possibility of an in silico extension of the thermodynamic library was tested using a quantitative structure-retention relationship (QSRR) methodology. The estimated thermodynamic parameters were utilized to develop QSRR models. Individual partial least squares (PLS) models were developed for each of the three classes of the molecules. R(2) values for the test sets of all models across all temperature ramps were larger than 0.99 and the average of relative errors in retention time predictions of the test sets for alkanes, alcohols, and alkyl halides were 1.8%, 2.4%, and 2.5%, respectively. PMID- 25035237 TI - Insights into chiral recognition mechanism in supercritical fluid chromatography III. Non-halogenated polysaccharide stationary phases. AB - The majority of published enantiomeric separations by supercritical fluid chromatography (SFC) utilize chiral stationary phases (CSP) based on chemically derivatized amylose or cellulose, coated or immobilized on silica. There is a large diversity among these polysaccharide-type CSP enhancing the scope of chiral separation applications. But on the other hand, identifying the appropriate support for a given separation problem is rather difficult. Hence, this study aims to provide insights on the difference and similarity among the non halogenated polysaccharide CSP in terms of retention and selectivity at a molecular level. Firstly, the potential of the clones provided by different manufacturers is evaluated with carbon dioxide - methanol mobile phases. Then different aspects of the chiral recognition mechanism contributing to the separations on 16 different columns of five distinct chiral selectors will be explored based on a large amount of experimental data acquired with the help of modelling and chemometric techniques. We report the influence of the ligand bonded to the polysaccharide on the non-enantio-specific interactions between the solute and the CSP, comparing phenylcarbamate to 3,5-dimethylphenylcarbamate, and 4-methylphenylester to 3,5-dimethylphenylcarbamate. In addition, we evaluate the impact of the silica treatment on the quality of the separation. The phases are characterized in terms of their retention characteristics assessed by the solvation parameter model and separation capabilities assessed by discriminant analysis. PMID- 25035238 TI - Interaction evaluation of bacteria and protoplasts with single-stranded deoxyribonucleic acid library based on capillary electrophoresis. AB - For whole-cell aptamers selection, cells surface situation has great impact on single-stranded (ssDNA) binding and aptamers selection. In this work, both Lactobacillus acidophilus and Escherichia coli as well as their protoplasts were as cells targets, their interaction with ssDNA library were evaluated based on capillary zone electrophoresis (CZE) and affinity capillary electrophoresis (ACE) with UV and LIF detection. Our results demonstrated that protoplasts without cells wall had apparently stronger interaction with ssDNA library than bacteria, the protoplasts-ssDNA complex could be observed clearly with CZE-LIF. Furthermore, E. coli pretreated by four organic solvents (methanol, ethanol, formaldehyde and glutaraldehyde) showed binding difference with ssDNA library, which could be identified with ACE-UV. Binding constants indicated the interaction of E. coli with ssDNA library were in the order of E. coli protoplasts>methanol (ethanol) treated E. coli>formaldehyde (glutaraldehyde) treated E. coli~E. coli. Above results suggest that cells surface situation determines their binding affinity with ssDNA, which should be considered in whole cell aptamers selection and aptamers further application. Capillary electrophoresis is a preferable technique for interaction evaluation of composite targets binding with ssDNA library. PMID- 25035240 TI - Labware, Lab Supplies, and Microplates. PMID- 25035241 TI - Corticosteroids for asthma may suppress growth in children in first year of treatment, researchers say. PMID- 25035242 TI - Effect of transport on blood selenium and glutathione status in feeder lambs. AB - Stress from transport may be linked to increased generation of reactive oxygen species, the removal of which requires reduced glutathione and selenium. The aim of this experiment was to examine the effect of transport on glutathione and Se status of feeder lambs. Recently weaned lambs (n = 40) were blocked by gender and BW on d 0 of the experiment and randomly assigned to 2 treatment groups: group 1, no transport and full access to feed and water (control), and group 2, 8-h road transport followed by another 16 h of feed deprivation (transport). After 24 h, both treatment groups were treated the same. All lambs were weighed, and blood samples were collected at 0, 8, 24, and 72 h and analyzed for whole-blood (WB) and serum Se concentrations, serum NEFA concentrations, and erythrocyte concentrations of glutathione. Transport of feeder lambs for 8 h followed by another 16 h of feed deprivation transiently (significant at 24 h but no longer different at 72 h) decreased BW and erythrocyte glutathione concentrations and increased serum NEFA and blood Se concentrations compared with control lambs. Our results suggest that 8 h of transport followed by another 16 h of feed deprivation results in fatty acid and Se mobilization from tissue stores with a coincident decrease in erythrocyte glutathione concentrations. PMID- 25035243 TI - Habituating to handling: factors affecting preorbital gland opening in red deer calves. AB - The preorbital gland plays not only an olfactory role in cervids but also a visual one. Opening this gland is an easy way for the calf to communicate with the mother, indicating hunger/satiety, stress, pain, fear, or excitement. This information can be also useful for farm operators to assess how fast the calves habituate to handling routines and to detect those calves that do not habituate and may suffer chronic stress in the future. Thirty-one calves were subjected to 2 consecutive experiments to clarify if observing preorbital gland opening is related to habituation to handling in red deer calves (Cervus elaphus). Calves were born in 3 different paddocks, handled as newborns (Exp. 1), and then subjected to the same routine handling but with different periodicity: every 1, 2, or 3 wk (Exp. 2). In Exp. 1, preorbital gland opening was recorded in newborns during an initial handling (including weighing, ear tagging, and sex determination). Preorbital gland opening occurred in 93% of calves during this procedure and was not affected by sex, time since birth, or birth weight. Experiment 2 consisted of measuring preorbital opening during the same routine handling (weighing, blood sampling, and rump touching to assess body condition) when calves were 1, 3, and 5 mo old. Binary logistic regression showed that gland opening was associated with habituation to handling, since at 1 and 3 mo the probability of opening the gland decreased with the number of handlings that a calf experienced before (P = 0.008 and P = 0.028, respectively). However, there were no further changes in preorbital gland opening rate in the 5-mo-old calves (P = 0.182). The significant influence of the number of previous handlings on the probability of opening the preorbital gland was confirmed through generalized linear model with repeated measures (P = 0.007). Preorbital gland opening decreased along the phases of the study. Nevertheless, we found a significant trend in individuals to keep similar opening patterns (intraclass correlation coefficient = 0.807, P < 0.001), which suggests that the more stressed individuals can be detected with this method. Therefore, we conclude that preorbital gland opening during routine handlings is related to the number of previous handlings, and thus it can be used as an indicator of lack of habituation to handling in farmed cervids. PMID- 25035244 TI - Optimization of novel spectral estimator for fractionated electrogram analysis is helpful to discern atrial fibrillation type. AB - INTRODUCTION: Paroxysmal versus persistent atrial fibrillation (AF) can be distinguished based on differences in the spectral parameters of fractionated atrial electrograms. Maximization of these differences would improve characterization of the arrhythmogenic substrate. A novel spectral estimator (NSE) has been shown previously to provide greater distinction in AF spectral parameters as compared with the Fourier transform estimator. Herein, it is described how the differences in NSE spectral parameters can be further improved. METHOD: In 10 persistent and 9 paroxysmal AF patients undergoing electrophysiologic study, fractionated electrograms were acquired from the distal bipolar ablation electrode. A total of 204 electrograms were recorded from the pulmonary vein (PV) antra and from the anterior and posterior left atrial free wall. The following spectral parameters were measured: the dominant frequency (DF), which reflects local activation rate, the DF amplitude (DA), and the mean spectral profile (MP), which represents background electrical activity. To optimize differences in parameters between paroxysmal versus persistent AF patients, the NSE was varied by selectively removing subharmonics, using a threshold. The threshold was altered in steps to determine the optimal subharmonics removal. RESULTS: At the optimal threshold level, mean differences in persistent versus paroxysmal AF spectral parameters were: DeltaDA=+0.371 mV, DeltaDF=+0.737 Hz, and DeltaMP=-0.096 mV. When subharmonics were not removed, the differences were substantially less: DeltaDA=+0.301 mV, DeltaDF=+0.699 Hz, and DeltaMP=-0.063 mV. CONCLUSIONS: NSE optimization produces greater spectral parameter difference between persistent versus paroxysmal AF data. Quantifying spectral parameter differences can be assistive in characterizing the arrhythmogenic substrate. PMID- 25035245 TI - Preface. Fourth Mammalian Embryo Genomics Meeting. PMID- 25035246 TI - Efficacy of atomoxetine in adults with attention deficit hyperactivity disorder: an integrated analysis of the complete database of multicenter placebo-controlled trials. AB - Persistence of attention deficit hyperactivity disorder (ADHD) into adulthood can be disabling or lead to substantial impairment. Several clinical trials of atomoxetine (ATX) in adults with ADHD have been reported following the National Institute for Health and Clinical Excellence (NICE) guidelines issued in 2008. We performed an integrated analysis of all Eli Lilly-sponsored, randomized, double blind, placebo-controlled studies of ATX in adults with ADHD completed as of May 2012. Individual patient data were pooled from six short-term (10-16 week) studies (1961 patients) and three longer-term (six-month) studies (1413 patients). In the short-term analysis, ATX patients achieved a significantly greater mean reduction in ADHD symptoms than placebo patients (-12.2 vs -8.1; Conners' Adult ADHD Rating Scale-Investigator-Rated: Screening Version (CAARS Inv: SV); p<0.001). In the longer-term analysis, respective improvements after six months were -13.2 vs -9.7 (p<0.001). Response rates at study endpoints for ATX vs placebo, based on CAARS-Inv: SV improvement >= 30% and Clinical Global Impressions of ADHD-Severity (CGI-ADHD-S) <= 3 were 34.8% vs 22.3% in the short term and 43.4% vs 28.0% after six months, and CAARS-Inv: SV improvements >= 40% were 41.3% vs 25.3% in the short-term and 44.0% vs 31.4% after six months (all p<0.001). Overall, ATX had a clinically significant effect in adults with ADHD, with reductions in core symptoms and clinically meaningful responder rates. PMID- 25035247 TI - Diagnosis and management of heritable thrombophilias. PMID- 25035248 TI - Epirubicin combined with oxaliplatin and 5-day continuous infusion of 5 fluorouracil as a first-line treatment for metastatic gastric cancer: treatment outcomes and analysis of prognostic factors. AB - PURPOSE: In order to confirm the efficacy, tolerability, and baseline prognostic factors of an epirubicin (EPR)-containing triplet regimen, the EOF5 regimen, in patients with metastatic gastric cancer (MGC), we conducted the phase II trial and retrospective analysis. METHODS: MGC patients received the EOF5 regimen (EPR 50 mg/m(2) and oxaliplatin (OX) 130 mg/m(2) on day 1 followed by continuous infusion of 5-fluorouracil (5-FU) 375-425 mg/m(2)/days for 5 days every 3 weeks). Log-rank tests were used for univariate analysis of time to progression (TTP) and overall survival rate (OS), and stepwise Cox proportional hazards regression modeling was performed to generate a prognostic index. RESULTS: A total of 158 patients received the EOF5 regimen. Of the 150 evaluable patients, complete remission, partial remission, and stable disease were observed in 5 (3.3%), 70 (46.7%), and 58 patients (38.7%), respectively. The median TTP and OS were 6.0 (95% CI 5.4-6.6) and 12.6 months (95% CI 8.2-16.9), respectively. Grade 3-4 neutropenia (44.0%), thrombocytopenia (25.3%), and anemia (6.7%) were recorded. A prognostic index that included liver and lung metastasis, ascites/pleural effusion, and baseline serum CA19-9 was used to categorize the patients into three groups: good risk (0 risk factors), moderate risk (1 or 2 risk factors), and poor risk (3 or 4 risk factors). The median OS for these groups was 30.4, 12.4, and 5.6 months, respectively (P < 0.001). CONCLUSIONS: EOF5 is an effective regimen and a suitable alternative for the first-line treatment of MGC. According to the prognostic index used in our study, patients with no risk factors have a better OS when treated with EOF5 than those with one or more risk factors. PMID- 25035249 TI - Moderate precision of prognostic scoring systems in a consecutive, prospective cohort of 544 patients with metastatic spinal cord compression. AB - PURPOSE: Improved survival among cancer patients and diverse conclusions from recent studies make it relevant to reassess the performance of the Tokuhashi Revised score and the Tomita score. The aim of this study was to validate and compare these two scoring systems in a recent and unselected cohort of patients with metastatic spinal cord compression (MSCC). METHODS: In 2011, we conducted a prospective cohort study of 544 patients who were consecutively admitted with MSCC to one treatment facility. Patients estimated survival were assessed with the Tokuhashi Revised score and the Tomita score and compared to the observed survival. We assessed how precise the scoring systems predicted survival with McNemar's test. The prognostic value was illustrated with Kaplan-Meier curves, and the individual prognostic components were analyzed with Cox regression analysis. RESULTS: The mean age was 65 years (range 20-95), and 57 % of the patients were men. The majority of tumors were lung (23 %), prostate (21 %), and breast tumors (18 %). The overall precision of predicted survival was 58.7 % for the Tokuhashi Revised score and 52.9 % for the Tomita score. The observed survival in each of the scoring groups categorized by the scoring systems was statistically significantly different (p < 0.0001). CONCLUSIONS: The Tokuhashi Revised score and the Tomita score are useful in categorizing patients into prognostic groups, and the individual components have important prognostic values. The Tokuhashi Revised score was most precise in predicting survival. However, due to the relatively low precision, we suggest that a modification of both scoring systems is necessary. PMID- 25035250 TI - The MoCA and MMSE as screeners for cognitive impairment in a heart failure population: a study with comprehensive neuropsychological testing. AB - OBJECTIVE: To examine the ability of the Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to detect cognitive impairment in persons with heart failure (HF). BACKGROUND: Although the MMSE and MoCA are commonly used screeners in HF, no research team has validated their performance against neuropsychological testing. METHODS: Participants were 106 patients with HF (49.1% male, 68.13 +/- 9.82 years) who completed the MoCA, MMSE, and a full neuropsychological battery. Sensitivity and specificity were examined. Discriminant function analyses tested whether the screeners correctly detected cognitive impairment. RESULTS: A MoCA score <25 and MMSE score of <28 yielded optimal sensitivity/specificity (.64/.66 and .70/.66, respectively). The MoCA correctly classified 65% of patients, Wilk's lambda = .91, chi(2)(1) = 9.89, p < .01, and the MMSE correctly classified 68%, Wilk's lambda = .87, chi(2)(1) = 14.26, p < .001. CONCLUSIONS: In HF, both the MoCA and MMSE are useful in identifying the majority of patients with and without cognitive impairment. Both tests misclassified approximately one-third of patients, so continued monitoring and evaluation of patients is needed in conjunction with screening. PMID- 25035251 TI - [Minimally invasive dynamic hip screw technique: Shorter surgical time with similar post-surgical results compared to conventional DHS technique. A retrospective cohort study]. AB - AIM: The treatment of intertrochanteric fractures using a minimally invasive dynamic hip screw (MIDHS) technique has been reported to provide better results than the conventional technique (CDHS). The present study aims to determine whether there are any differences in terms of transfusion needs, morbidity, length of hospital stay, and economical costs, based on a study of two retrospective cohorts. MATERIAL AND METHOD: Cohorts study of 80 patients with intertrochanteric femoral fractures (31-A1 and 31-A2.1) who underwent DHS procedure from July 2005 to September 2007; 40 of them were treated using the traditional technique (CDHS), and the other 40 using the minimally invasive technique (MIDHS). RESULTS: No differences were found in terms of blood loss, transfusion requirements or morbidity. Mean hospital stay for MIDHS group was 1.3 days lower, reducing the costs regarding the CDHS group by ?306.3, but this difference was not statistically significant (P=.3). The time required to perform the surgery was shorter for the MIDHS group: 49.3 versus 78.8minutes (p=0.0001). DISCUSSION: Contrary to previous studies published, the present study did not show any advantage for the MIDHS technique, except for a shorter surgical time to perform the procedure. We consider that the MIDHS could help in improving operating room productivity and efficiency. PMID- 25035252 TI - Battlefield medicine: paradigm shift for pharmaceuticals manufacturing. PMID- 25035253 TI - The changing role of quality assurance in the pharmaceutical industry. AB - ICH Q10. Pharmaceutical Quality System emphasizes that senior management is responsible for the quality system. Thus, it is not the quality assurance organization that has the primary responsibility for the quality system. With this shift of responsibilities, what can quality assurance do to help senior management fulfill their responsibility? How can quality assurance be more proactive, add more value? What new skills does quality assurance need to have in order to perform its new role? This article attempts to answer these questions. PMID- 25035254 TI - The Evolution of quality by design (QbD) for biologics. AB - In recent years, regulators have recognized the need for more controls in drug manufacturing processes. Quality by design is a science- and risk-based approach to drug product development and several pilot programs are ongoing to evaluate enhanced drug development strategies. This article provides a commentary on a recent regulatory publication on the subject of design space verification. PMID- 25035255 TI - Justification for the use of aseptic filling for sterile injectable products. AB - This review article will provide general guidance to product development scientists for the justification for the use of aseptic filling for sterile injectable products in the place of terminal sterilization using moist heat. The discussion is centered on the position of U.S. and European regulatory agencies on aseptic processing versus terminal sterilization, and regulatory actions-that is, 483 observations, warning letters, and product recalls-associated with a lack of sterility assurance of aseptically filled injectable products. Also discussed are the sterility assurance levels achieved using terminal sterilization and aseptic processing, sterilization processes used for terminal sterilization, compatibility of different product, product packaging and delivery systems with terminal sterilization, physicochemical stability of product during a terminal sterilization process, and storage during the product shelf life. The author believes that a better understanding of the options surrounding terminal sterilization will result in fewer products being aseptically filled. PMID- 25035256 TI - Formulation design and characterization of an elementary osmotic pump tablet of flurbiprofen. AB - Elementary osmotic pumps are well known for delivering moderately soluble drugs at a zero-order rate. The objective of the present study was to develop elementary osmotic pump tablets containing Flurbiprofen using an inclusion complex. Formation of complex was confirmed by Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy. A 3(2) factorial design was applied systematically; the amount of osmotic agent (X1) and size of delivery orifice (X2) were selected as independent variables. Batches were prepared by the direct compression method and evaluated for percent cumulative drug release (%CDR) at 9 h as dependent variables. The amount of osmotic agent and size of the delivery orifice had a significant effect on %CDR. The results of multiple linear regression analysis revealed that elementary osmotic pump tablets should be prepared using an optimum concentration of osmotic agent and size of delivery orifice to achieve a zero-order drug release. Contour plots as well as response surface plots were constructed to show the effects of X1 and X2 on %CDR. A model was validated for accurate prediction of %CDR by performing checkpoint analysis. The computer optimization process, contour plots, and response surface plots were predicted at the concentration of independent variables X1 and X2 (78.38 mg and 0.99 mm, respectively), for maximized response. The drug release from the developed formulation was found to be independent of pH and agitational intensity. The above optimized batch was also evaluated by different pharmacokinetic models like zero-order, first-order, Higuchi, Korsmeyer Peppas, and Hixson Crowell models. Stability study of the optimized batch was conducted at accelerated conditions for 6 months, and was found stable. This study strongly indicates application of osmotic tablets of Flurbiprofen for the treatment of rheumatoid arthritis, as well as osteoarthritis. LAY ABSTRACT: The aim of this study was to develop an elementary osmotic pump tablet of Flurbiprofen and to deliver the drug at a zero-order rate. Elementary osmotic pumps are well known for delivering moderately soluble drugs at a zero-order rate. Elementary osmotic pump tablets containing an inclusion complex of Flurbiprofen was prepared by the direct compression method. The amount of osmotic agent and size of delivery orifice were selected as independent variables. Percent cumulative drug release at 9 h was evaluated for all batches, and it was found that amount of osmotic agent and size of delivery orifice had a significant effect on percent cumulative drug release. The drug release from the developed formulation was found to be independent of pH and agitational intensity. It was also observed that the optimized formulation followed zero-order kinetics and was stable for 6 months at accelerated conditions. PMID- 25035257 TI - Human factors studies for injectable combination products: from planning to reporting. AB - Interest in human factors usability testing has seen a sharp increase from manufacturers bringing new injectable pharmaceutical combination products to market and from regulators reviewing and approving submissions. This paper highlights the special regulatory considerations in the planning, execution, and reporting of human factor usability studies for injectable combination products. The paper describes recent human factors examples that capture and convey important sponsor learning for drug/device combination products. Special emphasis is placed on the recent focus across U.S. Food and Drug Administration centers, offices, and divisions in issuing new draft guidance outlining expectations in the execution and reporting of usability testing. Insight is provided into how the new guidance has been put into practice in the development and review of injectable combination products, and some of the unwritten recommendations/expectations that have been gleaned from these regulatory interactions are identified. The paper also describes future areas of opportunity for regulatory guidance based on reflections from over two dozen recent combination product human factor studies covering from early design development and testing through to the reporting of human factors results in the final submission. LAY ABSTRACT: Human factors is the study of the interaction of people and technology to ensure the safety and effectiveness of that interaction and to improve human/device compatibility, including the user interface, instructions, and training programs to avoid use error. The enhanced focus on human factors usability assessments for injectable combination products is an acknowledgement by regulators and industry that the device mechanics are typically quite reliable and that device risk hazards are likely due to device usability. Use errors can occur when the device is not being used as intended or the design features are less than optimal. Human factors testing, analysis, and validation helps to identify and eliminate use errors by informing appropriate mitigation strategies to ensure the device design provides the optimum use of injectable drug/device combination products. PMID- 25035258 TI - Classification of glass particles in parenteral product vials by visual, microscopic, and spectroscopic methods. AB - Glass vials have been used as primary containers for parenteral drugs including biopharmaceuticals. Different types of glass-related particles, although in low occurrence rate, may be adventitiously introduced in these parenterals. Proper classification and investigations of these glass-related particles may help to understand their formation, improve process control, reduce glass-related particles, and deliver safe parenteral drugs to patients. In this article, we introduced a classification scheme, and identification procedures and methods, for the glass-related particles. We propose to classify them as glass chip, glass lamella/flake, and silica gel. Eight characteristics for each glass particle type have been identified and described for the visual inspection method. The limitations of the visual method and the need to correlate visual results with forensic analysis are discussed. Using representative examples from each type of glass particle, this study summarized their forensic differentiations based on microscopic methods of optical microscopy, scanning electron microscopy, micro flow imaging, and spectroscopic methods of dnergy-dispersive spectroscopy and Fourier transform infrared spectroscopy. The mechanisms of glass particle formation are listed as references for drug development scientists to investigate the root causes and improve process control on visible glass particles in parenteral vials. LAY ABSTRACT: Glass vials have been used as primary containers for parenteral drugs including biopharmaceuticals. Different types of glass related particles, although in low occurrence rate, may be adventitiously introduced in these parenterals. Proper classification and investigations of these glass-related particles may help to understand their formation, improve process control, reduce glass-related particles, and deliver safe parenteral drugs to patients. In this article, we introduced a classification scheme, and identification procedures and methods, for the glass-related particles. We propose to classify them as glass chip, glass lamella/flake, and silica gel. Using representative examples from each type of glass particle, this study summarized their forensic differentiations based on microscopic and spectroscopic methods. The mechanisms of glass particle formation are listed as references for drug development scientists to investigate the root causes and improve process control on visible glass particles in parenteral vials. PMID- 25035259 TI - A quick test to monitor the delamination propensity of glass containers. AB - Glass delamination has developed as a quality problem for primary packaging containers over the last years. Beside other factors the container production process can contribute to this phenomenon, and it seems mandatory to steer and control the critical parameters. With the Schott Delamination Quicktest, a rapid test method is developed that provides a rough measure for the container-related properties that affect delamination risk in a simple and reliable manner and in a relatively short time span. The application of this testing method minimizes the risk of unexpected corrosion behavior and can be used as a release criterion for the running production. LAY ABSTRACT: If pharmaceutical products do not match properly with the glass containers used, the creation of delaminated glass flakes can occur. This process is slow and time-dependent and mostly visible after month or years. With the Schott Delamination Quicktest a rapid method is developed that provides a fast measure for a rough indication of a higher risk for a delamination behavior. The application of the test gives quick evidence and can be used as a release criterion. PMID- 25035260 TI - Advantages of single-use technology for vaccine fill-finish operations. AB - The biopharmaceutical industry continues to face enormous pressure to accelerate time to market, improve productivity and efficiency, and reduce costs. Vaccine manufacturers face additional challenges, including small batch sizes, varied product portfolios, pandemic outbreaks that require rapid responses and highly potent ingredients that place large demands on cleaning processes. Given these pressures, single-use fill-finish assemblies can represent an attractive option for vaccine manufacturing facilities. This article describes the implementation of a single-use fill-finish system at a large vaccine manufacturer. The new assembly enabled flexibility while reducing set-up time, capital investment, cross-contamination risk, and cleaning requirements. LAY ABSTRACT: Overall the biopharmaceutical industry is constantly being challenged to bring new products more quickly and efficiently to market while keeping costs as low as possible. One specific segment of this industry is the companies that manufacture vaccines. Vaccines present unique challenges because they tend to be made in smaller amounts for a larger number of individual products. The products can also be very potent, which can require special handling methods. Another challenge is the potential outbreak of a disease that may affect a large area or a large part of the population and would require immediate action. Single-use assemblies for filling the product into its final container are an attractive option for vaccine manufacturing facilities. This article describes the implementation of a single use filling system at a large vaccine manufacturer. The new assembly was flexible enough to meet the demands of the manufacturer while allowing quick and efficient implementation with low upfront investment. PMID- 25035261 TI - "Thinking about numbers is not my idea of fun": need for cognition mediates age differences in numeracy performance. AB - BACKGROUND: Numeracy refers to people's ability to use numbers. Low numeracy has been associated with difficulties in understanding risk-benefit information and making health decisions. Older adults tend to perform worse than younger adults on measures of numeracy, but some theories of aging suggest that older adults may lack motivation for such tasks. We therefore test whether age differences in numeracy performance are mediated by a reduced motivation to think hard about complex problems-as measured by need for cognition. METHOD: We recruited an age diverse convenience sample of 306 UK adults. They completed measures of numeracy and need for cognition. They self-reported their educational attainment and other demographics. RESULTS: Older age was related to lower numeracy and lower need for cognition. The negative relationship between age and numeracy was mediated by need for cognition. These findings held after we controlled for educational attainment and other demographic factors. DISCUSSION: Older adults may show lower numeracy performance due to lack of motivation. We discuss strategies for improving people's motivation to complete numeracy measures and other numerical tasks. PMID- 25035262 TI - Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe D-Leu-Phe-D-Leu-Phe-OH. AB - While stimulation of formyl peptide receptors (FPRs) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-D-Leu-Phe-D Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1 MUM. In addition to finding a potent antagonist, the structure-activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist. PMID- 25035264 TI - Ammonia-assisted semicarbonization: a simple method to introduce micropores without damaging a 3D mesoporous carbon nanonetwork structure. AB - A simple and effective way to introduce micropores into skeleton of carbon aerogel (CA) without damaging its unique 3D mesoporous nanonetwork has been successfully developed by NH3-assisted semicarbonization. During the NH3-assisted semicarbonization process, nitrogen functional groups with high thermo decomposable ability like pyrrolic/pyridine and pyridinic can be introduced into the semicarbonized aerogel framework by substituting oxygen functional groups with low thermo-decomposable ability like C?O quinone-type groups and then escape from the resultant CA framework during the subsequent carbonization, thus forming abundant micropores inside carbon framework under the circumstance of keeping wonderful stability of mesoporous nanonetwork structure. Compared with the traditional CA without NH3 assistance during semicarbonization, the as-prepared novel CA represents a much higher surface area (1100 vs 620 m(2) g(-1)) and a compatible mesopore structure. Meanwhile, such a NH3 treatment confers many useful nitrogen functional groups on the nanonetwork framework. The novel CA is then used as electrode material of supercapacitors and shows a much higher capacitance and comparable high capacitance retention as compared with the traditional CA. PMID- 25035263 TI - Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis. AB - P450 enzymes (P450s) are well known for their ability to oxidize unactivated CH bonds with high regio- and stereoselectivity. Hence, there is emerging interest in exploiting P450s as potential biocatalysts. Although bacterial P450s typically show higher activity than their mammalian counterparts, they tend to be more substrate selective. Most drug-metabolizing P450s on the other hand, display remarkable substrate promiscuity, yet product prediction remains challenging. Protein engineering is one established strategy to overcome these issues. A less explored, yet promising alternative involves substrate engineering. This review discusses the use of small molecules for controlling the substrate specificity and product selectivity of P450s. The focus is on two approaches, one taking advantage of non-covalent decoy molecules, and the other involving covalent substrate modifications. PMID- 25035265 TI - A comparison study of KOOS-PS and KOOS function and sport scores. AB - BACKGROUND: The KOOS-PS represents a shortened version of the Knee Injury and Osteoarthritis Outcome Score (KOOS) Function and Sport scales. Previous investigations have not evaluated the KOOS-PS against performance measures or self-report measures composed of items that assess a broad spectrum of ability levels. OBJECTIVE: The purpose of this study was to compare the construct validity of the KOOS Function and Sport subscales with a shorter version of the measure (KOOS-PS). METHODS: Using a cross-sectional, observational design, consecutive consenting patients diagnosed with knee osteoarthritis were recruited at an assessment center visit to determine need for conservative or surgical management. Participants completed the Lower Extremity Functional Scale (LEFS), KOOS, Timed "Up & Go" Test, and Six-Minute Walk Test. A single function-sport score (KOOS FunSportsum) and the KOOS-PS were abstracted from the KOOS. Pearson correlation coefficients were compared between the reference standards' scores (performance measures and LEFS) and KOOS scores. KOOS-PSraw scores were compared with KOOS-PSRasch scores. RESULTS: Three hundred seventy-seven patients with a mean age of 64.4 years (SD=10.5) participated. The correlation between performance reference standard and KOOS-PSRasch scores was significantly lower than with KOOS FunSportsum scores (mean difference in r=.08 [95% confidence interval=.03, .11], z=4.45, P1<.001). A similar finding was observed with the LEFS comparison. LIMITATIONS: The study sample did not consist of many patients with mild or severe functional status limitations. CONCLUSIONS: For patients with knee osteoarthritis, the KOOS-PS appears too restricted in item content to provide a comprehensive estimate of lower extremity functional status level relative to the KOOS Function and Sport subscales. Pursuit of a computer-adapted test may be a productive direction for future inquiry. PMID- 25035266 TI - Use of the theoretical domains framework to develop an intervention to improve physical therapist management of the risk of falls after discharge. AB - BACKGROUND AND PURPOSE: Older adults have an increased risk of falls after discharge from the hospital. Guidelines to manage this risk of falls are well documented but are not commonly implemented. The aim of this case report is to describe the novel approach of using the Theoretical Domains Framework (TDF) to develop an intervention to change the clinical behavior of physical therapists. CASE DESCRIPTION: This project had 4 phases: identifying the evidence-practice gap, identifying barriers and enablers that needed to be addressed, identifying behavior change techniques to overcome the barriers, and determining outcome measures for evaluating behavior change. OUTCOMES: The evidence-practice gap was represented by the outcome that few patients who had undergone surgery for hip fracture were recognized as having a risk of falls or had a documented referral to a community agency for follow-up regarding the prevention of falls. Project aims aligned with best practice guidelines were established; 12 of the 14 TDF domains were considered to be relevant to behaviors in the project, and 6 behavior change strategies were implemented. Primary outcome measures included the proportion of patients who had documentation of the risk of falls and were referred for a comprehensive assessment of the risk of falls after discharge from the hospital. DISCUSSION: A systematic approach involving the TDF was useful for designing a multifaceted intervention to improve physical therapist management of the risk of falls after discharge of patients from an acute care setting in South Australia, Australia. This framework enabled the identification of targeted intervention strategies that were likely to influence health care professional behavior. Early case note audit results indicated that positive changes were being made to reduce the evidence-practice gap. PMID- 25035268 TI - Introduction to the GRADE approach for guideline development: considerations for physical therapist practice. AB - BACKGROUND: Practice guidelines (guidelines) have an increasing role in health care delivery and are being published more frequently. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is an approach for guideline development. The GRADE approach has been adopted by multiple national and international organizations producing guidelines related to physical therapist care. OBJECTIVE: The purpose of this article is to introduce physical therapists to the GRADE approach for guideline development. RESULTS: GRADE provides a consistent approach for guideline development and transparency in the communication of how the guidelines were developed and how the recommendations were reached, leading to informed choices by patients, clinicians, and policy makers in health care. GRADE leads to a clear distinction between the strength of the evidence and the recommendation. Both the direction (for or against) and the strength (weak or strong) of the recommendation are considered. For determining the strength of the recommendation, GRADE takes into account the quality of evidence, the balance of benefit and harm, uncertainty about or variability in patients' values and preferences, and uncertainty about whether the intervention is a wise use of resources. LIMITATIONS: The GRADE approach has been used primarily with interventions and clinical questions and less often with questions related to diagnosis and prognosis. CONCLUSIONS: The frequency of publication of guidelines is increasing. To make informed choices in the health care system, physical therapists should understand how guidelines are developed. The GRADE approach has been adopted by national and international organizations that produce guidelines relevant to physical therapist practice. Understanding the GRADE approach will enable physical therapists to make informed clinical choices. PMID- 25035267 TI - Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation. AB - Pain is a primary symptom driving patients to seek physical therapy, and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain; however, stress is rarely addressed in pain rehabilitation. A physiologic stress response may be evoked by fear or perceived threat to safety, status, or well being and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol also may facilitate the consolidation of fear-based memories for future survival and avoidance of danger. Although short-term stress may be adaptive, maladaptive responses (eg, magnification, rumination, helplessness) to pain or non-pain related stressors may intensify cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain. Stress may be unavoidable in life, and challenges are inherent to success; however, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg, catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may exacerbate cortisol secretion and facilitate the consolidation of fear-based memories of pain or non-pain-related stressors; however, coping, cognitive reappraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non-pain-related stressors, physical therapists should consider screening for non-pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life. PMID- 25035269 TI - The use of a knowledge translation program to increase use of standardized outcome measures in an outpatient pediatric physical therapy clinic: administrative case report. AB - BACKGROUND AND PURPOSE: Pediatric physical therapists face many challenges related to the application of research evidence to clinical practice. A multicomponent knowledge translation (KT) program may be an effective strategy to support practice change. The purpose of this case report is to describe the use of a KT program to improve the knowledge and frequency of use of standardized outcome measures by pediatric physical therapists practicing in an outpatient clinic. CASE DESCRIPTION: This program occurred at a pediatric outpatient facility with 1 primary clinic and 3 additional satellite clinics, and a total of 17 physical therapists. The initial underlying problem was inconsistency across staff recommendations for frequency and duration of physical therapist services. Formal and informal discussion with the department administrator and staff identified a need for increased use of standardized outcome measures to inform these decisions. The KT program to address this need spanned 6 months and included identification of barriers, the use of a knowledge broker, multiple workshop and practice sessions, online and hard-copy resources, and ongoing evaluation of the KT program with dissemination of results to staff. Outcome measures included pre- and post-knowledge assessment and self-report surveys and chart review data on use of outcome measures. OUTCOMES: Participants (N=17) gained knowledge and increased the frequency of use of standardized outcome measures based on data from self-report surveys, a knowledge assessment, and chart reviews. DISCUSSION: Administrators and others interested in supporting practice change in physical therapy may consider implementing a systematic KT program that includes a knowledge broker, ongoing engagement with staff, and a variety of accessible resources. PMID- 25035270 TI - Association of preeclampsia with podocyte turnover. AB - BACKGROUND AND OBJECTIVES: Preeclampsia is characterized by hypertension and proteinuria, and increased shedding of podocytes into the urine is a common finding. This finding raises the question of whether preeclamptic nephropathy involves podocyte damage. This study examined podocyte-related changes in a unique sample of renal tissues obtained from women who died of preeclampsia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients with preeclampsia who died in The Netherlands since 1990 and had available autopsy tissue were identified using a nationwide database of the Dutch Pathology Registry (PALGA). This resulted in a cohort of 11 women who died from preeclampsia. Three control groups were also identified during the same time period, and consisted of normotensive women who died during pregnancy (n=25), and nonpregnant controls either with (n=14) or without (n=13) chronic hypertension. Glomerular lesions, including podocyte numbers, podocyte proliferation, and parietal cell activation, were measured. RESULTS: Patients with preeclampsia had prominent characteristic glomerular lesions. The results showed that the number of podocytes per glomerulus did not differ significantly between the patients with preeclampsia and the control groups. However, preeclampsia was associated with a significant increase in intraglomerular cell proliferation (7.3% [SD 9.4] of the glomeruli of patients with preeclampsia had Ki-67-positive cells versus 1.6% [SD 3.3] of the glomeruli of hypertensive controls and 1.1% [SD 1.3] of nonpregnant controls; P=0.004) and activated parietal epithelial cells on a podocyte location (34% [SD 13.1] of the glomeruli of patients with preeclampsia versus 18.0% [SD 15.3] of pregnant controls, 11.9% [SD 13.2] of hypertensive controls, and 10.8% [SD 13.4] of nonpregnant controls; P=0.01). CONCLUSIONS: These findings suggest that the recently described mechanisms of podocyte replacement play a role in preeclampsia. These results provide key new insights into the pathogenesis of preeclamptic nephropathy, and they open new possibilities for developing therapeutic modalities. PMID- 25035271 TI - The role of the podocyte in preeclampsia. PMID- 25035272 TI - Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. AB - BACKGROUND: The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A2 receptor (PLA2R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months. Patients were prospectively followed, and outcome was ascertained up to 5 years after completion of immunosuppressive therapy. Serum samples were collected before and after completion of therapy. PLA2R antibodies were determined retrospectively in stored samples using ELISA. RESULTS: In total, 48 patients (37 men) were included. The median age was 55 years (range, 34-75), and the median serum creatinine level was 1.60 mg/dl (range, 0.98-3.37 mg/dl). Twenty-two patients received MMF and 26 received CP. At baseline, PLA2R-abs were present in 34 patients (71%). Baseline characteristics and outcome did not significantly differ between patients negative or positive for PLA2R-ab. In PLA2R-ab-positive patients, treatment resulted in a rapid decrease of antibodies: median anti-PLA2R ab, 428 U/ml (range, 41-16,260 U/ml) at baseline and 24 U/ml (range, 0-505 U/ml) after 2 months. The PLA2R-ab levels at baseline did not predict initial response, but antibody status at end of therapy predicted long-term outcome: After 5 years, 14 of 24 (58%) antibody-negative patients were in persistent remission compared with 0 of 9 (0%) antibody-positive patients (P=0.003). CONCLUSIONS: These data suggest that in PLA2R-ab-positive patients, measuring PLA2R-abs at the end of therapy predicts the subsequent course. PMID- 25035274 TI - Antiphospholipase A2 receptor autoantibody guided diagnosis and treatment of membranous nephropathy: a new personalized medical approach. PMID- 25035273 TI - Nephrotoxic effects of common and emerging drugs of abuse. AB - The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCA-associated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves. PMID- 25035275 TI - Patient-centered care: an opportunity to accomplish the "Three Aims" of the National Quality Strategy in the Medicare ESRD program. AB - In light of mounting federal government debt and levels of Medicare spending that are widely viewed as unsustainable, commentators have called for a transformation of the United States health care system to deliver better care at lower costs. This article presents the priorities of the Coalition for Supportive Care of Kidney Patients for how clinicians might achieve this transformation for patients with advanced CKD and their families. The authors suspect that much of the high intensity, high-cost care currently delivered to patients with advanced kidney disease may be unwanted and that the "Three Aims" put forth by the National Quality Strategy of better care for the individual, better health for populations, and reduced health care costs may be within reach for patients with CKD and ESRD. This work describes the coalition's vision for a more patient centered approach to the care of patients with kidney disease and argues for more concerted efforts to align their treatments with their goals, values, and preferences. Key priorities to achieve this vision include using improved prognostic models and decision science to help patients, their families, and their providers better understand what to expect in the future; engaging patients and their families in shared decision-making before the initiation of dialysis and during the course of dialysis treatment; and tailoring treatment strategies throughout the continuum of their care to address what matters most to individual patients. PMID- 25035276 TI - The Italian validation of the Salford-Scott Nursing Values Questionnaire. AB - BACKGROUND: To properly direct nursing training and to improve the professional practice to become more effective, it is important to understand students' values. Literature review has shown that there have been changes in students' values in the last 20 years. In contemporary students, a general decrease in altruism has been observed, but also a larger appreciation for honesty toward patients has been declared. The analyzed literature did not find validated tools available in Italian that explore personal and professional values of nursing students. DESIGN OF THE STUDY: This study was an Italian linguistic and cultural adaptation of a research tool. PURPOSE: The authors aimed to validate, for the Italian context, the Salford-Scott Nursing Values Questionnaire, enhanced by Johnson to explore the nursing profession's values. METHODS: The Beaton Model was used as well as Valmi's. These models require five phases, with the goal of producing a pre-final version of the instrument for it to then be administered to a sample of the target and expert population. ETHICAL CONSIDERATIONS: The study was approved by the Council of the Nursing Degree University course of the Modena and Reggio Emilia University, Reggio Emilia site, and the identity of the subjects was protected at every moment of the testing. RESULTS: Face validation was achieved since the clarity percentile for each item was 100%. Content validity was also reached, measured from the content validity index and the scale validity index. The study has confirmed the reliability of the instrument's internal consistence with a value of Cronbach's alpha on 0.95 of total of items. The reliability of the test-retest confirms the stability of the instrument in time (r = 0.908; p = 0.01). CONCLUSION: The study concludes that the instrument is ready to be administered to the target population, a sample group of nursing students. PMID- 25035277 TI - Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. PMID- 25035278 TI - Reply to the letter to the editor 'clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK positive NSCLC' by Ou et al. PMID- 25035279 TI - Delay of left ventricular longitudinal expansion with diastolic dysfunction: impact on load dependence of e' and longitudinal strain rate. AB - The effect of diastolic dysfunction (DD) on the timing of left ventricular (LV) diastolic longitudinal and circumferential expansion and their load dependence is not known. This study evaluated the timing of the peak early diastolic LV inflow velocity (E), mitral annular velocity (e'), and longitudinal and circumferential global strain rates (SRE) in 161 patients in sinus rhythm. The intraventricular pressure difference (IVPD) from the left atrium to the LV apex was obtained using color M-mode Doppler data to integrate the Euler equation. The diastolic function was graded according to the guidelines. In normals (N = 57), E, e', longitudinal SRE, and circumferential SRE occurred nearly simultaneously during the IVPD. With DD (N = 104), e' and longitudinal SRE were delayed occurring after the IVPD (e': 18 +/- 23 msec, longitudinal SRE: 13 +/- 21 msec from the IVPD), whereas circumferential SRE (-8 +/- 28 msec) and E (-2 +/- 13 msec) were not delayed. The normal dependence of e' and longitudinal SRE on IVPD was reduced in DD; while the relation of circumferential SRE and E to IVPD were unchanged in DD. Thus, normally, the LV expands symmetrically during early diastole and both longitudinal and circumferential expansions are related to the IVPD. With DD, early diastolic longitudinal LV expansion is delayed, occurring after the IVPD and LV filling, resulting in their relative independence from the IVPD. In contrast, with DD, circumferential SRE and mitral inflow are not delayed and their normal relation to the IVPD is unchanged. PMID- 25035280 TI - Why do parents litigate and what does it do for the family? PMID- 25035281 TI - Untreated head and neck surgical disease in Sierra Leone: a cross-sectional, countrywide survey. AB - OBJECTIVES: Demonstrate how the Surgeons OverSeas Assessment of Surgical Need (SOSAS) can be used to determine the burden of head and neck (H&N) surgical disease in developing countries and identify reasons for untreated disease. STUDY DESIGN: Cluster randomized, cross-sectional, countrywide survey. SETTING: Sierra Leone. SUBJECTS AND METHODS: The survey was administered to 75 of 9671 enumeration areas in Sierra Leone between January 9 and February 3, 2012, with 25 households in each cluster randomly selected for the survey. A household representative and 2 randomly selected household members were interviewed. Need for surgical care was based on participants' responses to whether they had an H&N condition that they believed needed surgical care. RESULTS: Of 1875 households, data were analyzed for 1843 (98%), with 3645 total respondents. Seven hundred and one H&N surgical conditions were reported as occurring during the lifetime of the 3645 respondents (19.2%).The current prevalence of H&N conditions in need of a surgical consultation was 11.8%. No money (60.1%) was the most common reason respondents reported for not receiving medical care. A bivariate analysis demonstrated that age, village type, education, and type of condition may be predictors for seeking health care and/or receiving surgical care. CONCLUSIONS: These results show limited access for patients to be evaluated for a potential H&N surgical condition in Sierra Leone. The true incidence of untreated surgical disease is unknown as most respondents were not evaluated by a surgeon. This survey could be used in other countries as health care professionals assess surgical needs throughout the world. PMID- 25035282 TI - Patient eligibility and trial design for the salvage therapy of advanced urothelial carcinoma. PMID- 25035283 TI - Current practices in the management of adverse events associated with targeted therapies for advanced renal cell carcinoma: a national survey of oncologists. AB - BACKGROUND: Oncologists treating patients with targeted therapies encounter adverse events (AEs) that pose management challenges, lead to dosing inconsistencies, and impact patient quality of life. Oncologists' practices and attitudes in the management of targeted therapy-related AEs in patients with renal cell carcinoma (RCC) are poorly understood. We sought to identify unmet needs associated with AE management and understand oncologists' treatment optimization strategies. METHODS: A 24-item online survey was administered in August 2012 to 119 US oncologists treating patients with advanced RCC. The survey solicited responses regarding demographics, practice settings, AE management practice patterns and beliefs, treatment barriers, and patient education. RESULTS: Respondents indicated that between 25% and 50% of patients require dose modification/discontinuation because of AEs. The greatest barrier to optimizing treatment for RCC is the unpredictability of patient responses to treatment (43%). Most respondents (78%) discuss AE management with patients, but only a minority of them proactively reach out to patients (46%). Most practitioners (70%) refer patients to nononcology specialists when faced with unfamiliar AEs, although finding interested physicians (43%) and time constraints (40%) were the most commonly cited barriers to consulting with other specialties. CONCLUSION: Results suggest that many patients require dose modification/discontinuation because of AEs and that nononcologists are a frequently utilized resource to manage these events. There is a need for predictive drug toxicity markers to establish counseling and prevention, along with opportunities for increased education on supportive care techniques to maintain health-related quality of life and consistent dosing. PMID- 25035284 TI - Cynomolgus monkey as a surrogate for human aldehyde oxidase metabolism of the EGFR inhibitor BIBX1382. AB - BIBX1382 was an epidermal growth factor receptor inhibitor under clinical investigation for treatment of cancer. This candidate possessed an attractive preclinical absorption, distribution, metabolism, and excretion profile, yet failed in clinical studies due in part to poor oral exposure, resulting from extensive metabolism by aldehyde oxidase (AO). In vitro metabolism studies were performed in liver cytosol and cryopreserved hepatocytes from multiple species. In addition, a pharmacokinetic study was performed in cynomolgus monkey for comparison with the reported human pharmacokinetics of BIBX1382. Estimated hepatic clearance of BIBX1382 in rhesus (42 ml/min per kg) and cynomolgus monkey (43 ml/min per kg) liver cytosol was comparable to human (>=93% of liver blood flow). Metabolite identification after incubation of BIBX1382 in liver cytosol fortified with the AO inhibitor raloxifene confirmed that AO is involved in the formation of the predominant metabolite (BIBU1476, M1) in cynomolgus monkey. After intravenous and oral administration of BIBX1382 to cynomolgus monkeys, high plasma clearance (118 ml/min per kg) and low oral exposure (C(max) = 12.7 nM and 6% oral bioavailability) was observed, with the exposure of M1 exceeding BIBX1382 after oral dosing. This pharmacokinetic profile compared favorably with the human clinical data of BIBX1382 (plasma clearance 25-55 ml/min per kg and 5% oral bioavailability). Thus, it appears that cynomolgus monkey represents a suitable surrogate for the observed human AO metabolism of BIBX1382. To circumvent clinical failures due to uncharacterized metabolism by AO, in vitro studies in the appropriate subcellular fraction, followed by pharmacokinetic and toxicokinetic studies in the appropriately characterized surrogate species should be conducted for substrates of AO. PMID- 25035285 TI - Minister admits to "dysfunctional" NHS care for child and adolescent mental health. PMID- 25035286 TI - Safety lapses are common in US labs that handle deadly pathogens, experts tell Congress. PMID- 25035287 TI - Rural health and higher tobacco taxes are key priorities in India's 2014-15 budget. PMID- 25035288 TI - Australia sees large fall in smoking after introduction of standardised packs. PMID- 25035289 TI - Genome of brown tide virus (AaV), the little giant of the Megaviridae, elucidates NCLDV genome expansion and host-virus coevolution. AB - Aureococcus anophagefferens causes economically and ecologically destructive "brown tides" in the United States, China and South Africa. Here we report the 370,920bp genomic sequence of AaV, a virus capable of infecting and lysing A. anophagefferens. AaV is a member of the nucleocytoplasmic large DNA virus (NCLDV) group, harboring 377 putative coding sequences and 8 tRNAs. Despite being an algal virus, AaV shows no phylogenetic affinity to the Phycodnaviridae family, to which most algae-infecting viruses belong. Core gene phylogenies, shared gene content and genome-wide similarities suggest AaV is the smallest member of the emerging clade "Megaviridae". The genomic architecture of AaV demonstrates that the ancestral virus had an even smaller genome, which expanded through gene duplication and assimilation of genes from diverse sources including the host itself - some of which probably modulate important host processes. AaV also harbors a number of genes exclusive to phycodnaviruses - reinforcing the hypothesis that Phycodna- and Mimiviridae share a common ancestor. PMID- 25035290 TI - Extremely rare presentation of Frantz's tumour: synchronous localisation in the pancreatic head and tail. AB - INTRODUCTION: Solid pseudopapillary tumour of the pancreas is a rare lesion with low malignant potential occurring predominantly in young women. This is a report of an extremely rare occurrence of synchronous presentation of pseudopapillary tumour in the pancreatic head and tail of a 16-year-old female patient. CASE PRESENTATION: The patient presented with a three-month intermittent upper abdominal pain and swelling. Computed tomography scan showed two separate masses, involving the pancreatic head and tail. The patient underwent surgery, where successful tumour enucleation of both tumours was performed. Histological report confirmed solid pseudopapillary tumour of the pancreas with the low malignant potential. CONCLUSION: To the best of our knowledge, this is the first report of synchronous presentation of pseudopapillary tumour of the pancreas. PMID- 25035291 TI - Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. AB - BACKGROUND: Treatment options for recurrent glioblastoma are scarce, with second line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma. METHODS: The BELOB trial was an open label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (>=18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929). FINDINGS: Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment. INTERPRETATION: The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment. FUNDING: Roche Nederland and KWF Kankerbestrijding. PMID- 25035293 TI - Renewing interest in targeting angiogenesis in glioblastoma. PMID- 25035292 TI - Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. AB - BACKGROUND: The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. METHODS: In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age >=18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3 4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. FINDINGS: 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0.94, 95% CI 0.82-1.06; p=0.30). IDFS (HR 0.93, 95% CI 0.82-1.05; p=0.22), overall survival (0.93, 0.81-1.08; p=0.37), and distant recurrences (0.93, 0.81-1.07; p=0.29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0.78, 95% CI 0.63-0.96; p=0.020) and at any time during follow-up (0.81, 0.68-0.97; p=0.022). The effects of zoledronic acid on DFS were not affected by oestrogen receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0.77, 95% CI 0.63-0.96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1.03, 95% CI 0.89-1.20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1.7%, 95% CI 1.0-2.4). INTERPRETATION: These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. FUNDING: Novartis Global and NIHR Cancer Research Network. PMID- 25035294 TI - S100A4 regulates the Src-tyrosine kinase dependent differentiation of Th17 cells in rheumatoid arthritis. AB - OBJECTIVES: To evaluate the role of S100A4, a calcium-binding regulator of nonmuscle myosin assembly, for T-cell responses in rheumatoid arthritis. METHODS: Arthritis was induced in the methylated bovine serum albumin (mBSA)-immunized mice lacking the entire S100A4 protein (S100A4KO) and in wild-type counterparts treated with short hairpin ribonucleic acid (shRNA)-lentiviral constructs targeting S100A4 (S100A4-shRNA). The severity of arthritis was evaluated morphologically. T-cell subsets were characterized by the expression of master transcription factors, and functionally by proliferation activity and cytokine production. The activity of the Scr-kinases Fyn and Lck was assessed by the autophosphorylation of C-terminal thyrosine and by the phosphorylation of the CD5 cytodomain. The interaction between S100A4 and the CD5 cytodomain was analysed by nuclear magnetic resonance spectrophotometry. RESULTS: S100A4-deficient mice (S100A4KO and S100A4-shRNA) had significantly alleviated morphological signs of arthritis and joint damage. Leukocyte infiltrates in the arthritic joints of S100A4-deficient mice accumulated Foxp3(+) Treg cells, while the number of RORgammat(+) and (pTyr705)STAT3(+) cells was reduced. S100A4-deficient mice had a limited formation of Th17-cells with low retinoic acid orphan receptor gamma t (RORgammat) mRNA and IL17 production in T-cell cultures. S100A4-deficient mice had a low expression and activity of T-cell receptor (TCR) inhibitor CD5 and low (pTyr705)STAT3 (signal transducer and activator of transcription 3), which led to increased (pTyr352)ZAP-70 (theta-chain associated protein kinase of 70kDa), lymphocyte proliferation and production of IL2. In vitro experiments showed that S100A4 directly binds Lck and Fyn and reciprocally regulates their kinase activity towards the CD5 cytodomain. Spectrometry demonstrates an interaction between the CD5 cytodomain and EF2-binding sites of S100A4. CONCLUSION: The present study demonstrates that S100A4 plays an important part in the pathogenesis of arthritis. It controls CD5-dependent differentiation of Th17 cells by regulating the activity of the Src-family kinases Lck and Fyn. PMID- 25035295 TI - Probing the shRNA characteristics that hinder Dicer recognition and consequently allow Ago-mediated processing and AgoshRNA activity. AB - Recent evidence indicates the presence of alternative pathways for microRNA (miRNA) and short hairpin (shRNA) processing. Specifically, some of these molecules are refractory to Dicer-mediated processing, which allows alternative processing routes via the Ago2 endonuclease. The resulting RNA molecules differ in size and sequence and will thus trigger the silencing of different target RNAs. It is, therefore, important to understand these processing routes in mechanistic detail such that one can design exclusive RNA reagents for a specific processing route. The exact sh/miRNA properties that determine this routing toward Dicer or Ago2 are incompletely understood. The size of the base-paired stem seems an important determinant, but other RNA elements may contribute as well. In this study, we document the importance of a weak G-U or U-G base pair at the top of the hairpin stem. PMID- 25035296 TI - Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1. AB - MicroRNAs (miRNAs) play critical roles in a variety of biological processes through widespread effects on protein synthesis. Upon association with the miRNA induced silencing complex (miRISC), miRNAs repress target mRNA translation and accelerate mRNA decay. Degradation of the mRNA is initiated by shortening of the poly(A) tail by the CCR4-NOT deadenylase complex followed by the removal of the 5' cap structure and exonucleolytic decay of the mRNA. Here, we report a direct interaction between the large scaffolding subunit of CCR4-NOT, CNOT1, with the translational repressor and decapping activator protein, DDX6. DDX6 binds to a conserved CNOT1 subdomain in a manner resembling the interaction of the translation initiation factor eIF4A with eIF4G. Importantly, mutations that disrupt the DDX6-CNOT1 interaction impair miRISC-mediated gene silencing in human cells. Thus, CNOT1 facilitates recruitment of DDX6 to miRNA-targeted mRNAs, placing DDX6 as a downstream effector in the miRNA silencing pathway. PMID- 25035297 TI - Pat1 contributes to the RNA binding activity of the Lsm1-7-Pat1 complex. AB - A major mRNA decay pathway in eukaryotes is initiated by deadenylation followed by decapping of the oligoadenylated mRNAs and subsequent 5'-to-3' exonucleolytic degradation of the capless mRNA. In this pathway, decapping is a rate-limiting step that requires the hetero-octameric Lsm1-7-Pat1 complex to occur at normal rates in vivo. This complex is made up of the seven Sm-like proteins, Lsm1 through Lsm7, and the Pat1 protein. It binds RNA and has a unique binding preference for oligoadenylated RNAs over polyadenylated RNAs. Such binding ability is crucial for its mRNA decay function in vivo. In order to determine the contribution of Pat1 to the function of the Lsm1-7-Pat1 complex, we compared the RNA binding properties of the Lsm1-7 complex purified from pat1Delta cells and purified Pat1 fragments with that of the wild-type Lsm1-7-Pat1 complex. Our studies revealed that both the Lsm1-7 complex and purified Pat1 fragments have very low RNA binding activity and are impaired in the ability to recognize the oligo(A) tail on the RNA. However, reconstitution of the Lsm1-7-Pat1 complex from these components restored these abilities. We also observed that Pat1 directly contacts RNA in the context of the Lsm1-7-Pat1 complex. These studies suggest that the unique RNA binding properties and the mRNA decay function of the Lsm1-7 Pat1 complex involve cooperation of residues from both Pat1 and the Lsm1-7 ring. Finally our studies also revealed that the middle domain of Pat1 is essential for the interaction of Pat1 with the Lsm1-7 complex in vivo. PMID- 25035298 TI - The effects of carbamazepine on prefrontal activation in manic youth with bipolar disorder. AB - This preliminary study investigated the neurofunctional effects of carbamazepine extended release (XR) treatment in 11 manic youth with bipolar disorder during performance of a sustained attention task, the Continuous Performance Task - Identical Pairs version (CPT-IP), during functional magnetic resonance imaging (fMRI). All patients underwent baseline fMRI, and 10 patients were scanned again at endpoint. Nine demographically matched healthy youth, who were scanned once, served as controls. Carbamazepine-XR treatment was associated with normalization of activation in right Brodmann area 10 (BA). These results suggest that carbamazepine-XR treatment may correct prefrontal dysfunction in adolescent mania. PMID- 25035300 TI - Lewy body compared with Alzheimer dementia is associated with decreased functional connectivity in resting state networks. AB - Resting state functional magnetic resonance imaging (fMRI) was used to measure whole brain functional connectivity within specific networks hypothesised to be more affected in dementia with Lewy bodies (DLB) (a disease characterised by prominent attentional deficits, spontaneous motor features of parkinsonism and depression) than in Alzheimer's disease (AD) and controls. This study involved 68 subjects (15 DLB, 13 AD and 40 controls) who were scanned using resting state BOLD (blood-oxygen-level-dependent) fMRI on a 3T MRI scanner. Functional connectivity was measured using a model-free independent component analysis approach that consisted of temporally concatenating the resting state fMRI data of all study subjects and investigating group differences using a back reconstruction procedure. Resting state functional connectivity was affected in the default mode, salience, executive and basal ganglia networks in DLB subjects compared with AD and controls. Functional connectivity was lower in DLB compared with AD and controls in these networks, except for the basal ganglia network, where connectivity was greater in DLB. No resting state networks showed less connectivity in AD compared with DLB or controls. Our results suggest that functional connectivity of resting state networks can identify differences between DLB and AD subjects that may help to explain why DLB subjects have more frequent attentional deficits, parkinsonian symptoms, and depression than those with AD. PMID- 25035301 TI - The role of substrate strain in the mechanism of the carbon-carbon lyases. AB - The carbon-carbon lyases, tryptophan indole lyase (TIL) and tyrosine phenol-lyase (TPL) are bacterial enzymes which catalyze the reversible elimination of indole and phenol from l-tryptophan and l-tyrosine, respectively. These PLP-dependent enzymes show high sequence homology (~40% identity) and both form homotetrameric structures. Steady state kinetic studies with both enzymes show that an active site base is essential for activity, and alpha-deuterated substrates exhibit modest primary isotope effects on kcat and kcat/Km, suggesting that substrate deprotonation is partially rate-limiting. Pre-steady state kinetics with TPL and TIL show rapid formation of external aldimine intermediates, followed by deprotonation to give quinonoid intermediates absorbing at about 500nm. In the presence of phenol and indole analogues, 4-hydroxypyridine and benzimidazole, the quinonoid intermediates of TPL and TIL decay to aminoacrylate intermediates, with lambdamax at about 340nm. Surprisingly, there are significant kinetic isotope effects on both formation and subsequent decay of the quinonoid intermediates when alpha-deuterated substrates are used. The crystal structure of TPL with a bound competitive inhibitor, 4-hydroxyphenylpropionate, identified several essential catalytic residues: Tyr-71, Thr-124, Arg-381, and Phe-448. The active sites of TIL and TPL are highly conserved with the exceptions of these residues: Arg-381(TPL)/Ile-396 (TIL); Thr-124 (TPL)/Asp-137 (TIL), and Phe-448 (TPL)/His 463 (TIL). Mutagenesis of these residues results in dramatic decreases in catalytic activity without changing substrate specificity. The conserved tyrosine, Tyr-71 (TPL)/Tyr-74 (TIL) is essential for elimination activity with both enzymes, and likely plays a role as a proton donor to the leaving group. Mutation of Arg-381 and Thr-124 of TPL to alanine results in very low but measurable catalytic activity. Crystallography of Y71F and F448H TPL with 3 fluoro-l-tyrosine bound demonstrated that there are two quinonoid structures, relaxed and tense. In the relaxed structure, the substrate aromatic ring is in plane with the Cbeta-Cgamma bond, but in the tense structure, the substrate aromatic ring is about 20 degrees out of plane with the Cbeta-Cgamma bond. In the tense structure, hydrogen bonds are formed between the substrate OH and the guanidinium of Arg-381 and the OH of Thr-124, and the phenyl rings of Phe-448 and 449 provide steric strain. Based on the effects of mutagenesis, the substrate strain is estimated to contribute about 10(8) to TPL catalysis. Thus, the mechanisms of TPL and TIL require both substrate strain and acid/base catalysis, and substrate strain is probably responsible for the very high substrate specificity of TPL and TIL. PMID- 25035299 TI - Clarifying the neural basis for incentive salience of tobacco cues in smokers. AB - In functional magnetic resonance imaging (fMRI) studies, smoking cues have been found to elicit increases in brain activity in regions associated with processing rewarding and emotional stimuli. However, most smoking cue studies to date have reported effects relative to neutral control stimuli with no incentive properties, making it unclear whether the observed activation pertains to value in general or the value of cigarettes in particular. The current fMRI study sought to clarify the neural activity reflecting tobacco-specific incentive value versus domain-general incentive value by examining smoking cues, neutral cues, and a third set of cues, monetary cues, which served as an active control condition. Participants were 42 male daily smokers. Compared to neutral cues, significantly greater activation was found in the left ventral striatum in response to tobacco and money cues. Monetary cues also elicited significantly increased activation in the right inferior frontal gyrus and cuneus compared to the other two cue types. Overall, the results suggest that the salience of monetary cues was the highest and, as a result, might have reduced the incentive salience of tobacco cues. PMID- 25035303 TI - Crystallization kinetics of colloidal model suspensions: recent achievements and new perspectives. AB - Colloidal model systems allow studying crystallization kinetics under fairly ideal conditions, with rather well-characterized pair interactions and minimized external influences. In complementary approaches experiment, analytic theory and simulation have been employed to study colloidal solidification in great detail. These studies were based on advanced optical methods, careful system characterization and sophisticated numerical methods. Over the last decade, both the effects of the type, strength and range of the pair-interaction between the colloidal particles and those of the colloid-specific polydispersity have been addressed in a quantitative way. Key parameters of crystallization have been derived and compared to those of metal systems. These systematic investigations significantly contributed to an enhanced understanding of the crystallization processes in general. Further, new fundamental questions have arisen and (partially) been solved over the last decade: including, for example, a two-step nucleation mechanism in homogeneous nucleation, choice of the crystallization pathway, or the subtle interplay of boundary conditions in heterogeneous nucleation. On the other hand, via the application of both gradients and external fields the competition between different nucleation and growth modes can be controlled and the resulting microstructure be influenced. The present review attempts to cover the interesting developments that have occurred since the turn of the millennium and to identify important novel trends, with particular focus on experimental aspects. PMID- 25035302 TI - Acyl transfer mechanisms of tissue transglutaminase. AB - Tissue transglutaminase (TG2) is a calcium-dependent enzyme that catalyses several acyl transfer reactions. The most biologically relevant of these involve protein-bound Gln residues as an acyl-donor substrate, and either water or a primary amine as an acyl-acceptor substrate. The former leads to deamidation of Gln to Glu, whereas the latter leads to transamidation, typically resulting in protein cross-linking when the amine substrate is a protein-bound Lys residue. In this review, we present an overview of over fifty years of mechanistic studies that have led to our current understanding of TG2-mediated hydrolysis and transamidation. PMID- 25035310 TI - Recognition and treatment of depressive symptoms in Parkinson's disease: the NPF dataset. AB - Depression is a major determinant of Health Related Quality of Life in PD, but there is limited data on physician recognition of depression and treatment efficacy. We used data obtained from the QII dataset of the National Parkinson's Foundation database to determine whether there was an association between depressive symptoms and utilization of antidepressants and/or mental health services (MHS) in a large cohort of PD patients. We found that prevalence of depressive symptoms remained high in the PD population despite improved physician recognition and treatment initiation. PMID- 25035311 TI - Impulsive and compulsive behaviors in Parkinson Study Group (PSG) centers performing deep brain stimulation surgery. AB - BACKGROUND: Impulse control disorders (ICDs), dopamine dysregulation syndrome (DDS), and dopamine agonist withdrawal syndrome (DAWS) have been reported commonly in Parkinson's disease (PD) populations. The treatment approaches may be widely variable and there is not much information on these syndromes in the setting of deep brain stimulation (DBS). OBJECTIVE: To evaluate (1) ICDs, DAWS and DDS pre- and post DBS in PD and (2) to investigate pre-DBS treatment strategies regarding these behaviors among Parkinson Study Group (PSG) centers. METHODS: Forty-eight PSG centers were surveyed on ICDs, DAWS and DDS, as well as on potential relationships to DBS and treatment approaches. RESULTS: Sixty-seven percent of PSG centers reported that they served a population of over 500 PD patients per year, and 94% of centers performed DBS surgery. Most centers (92%) reported screening for ICDs, DAWS and DDS. Of the centers screening for these symptoms, 13% reported always employing a formal battery of pre-operative tests, 46% of sites inconsistently used a formal battery, while 23% of sites reported never using a formal battery to screen for these symptoms. The estimated numbers of centers observing ICDs, DAWS and DDS pre-operatively in individuals with PD were 71%, 69%, and 69%, respectively. PSG DBS centers observing at least one case of a new de novo occurrence of an ICD, DAWS or DDS after DBS surgery were 67%, 65% and 65%, respectively. CONCLUSIONS: The results suggest that addiction-like syndromes and withdrawal syndromes are prevalent in expert PSG centers performing DBS. Most centers reported screening for these issues without the use of a formal battery, and there were a large number of centers reporting ICDs, DAWS and DDS post-DBS. A single treatment strategy did not emerge. PMID- 25035312 TI - How to use: amplitude-integrated EEG (aEEG). AB - Amplitude-integrated electroencephalography (aEEG) is a method for continuous monitoring of brain activity that is increasingly used in the neonatal intensive care unit. In its simplest form, aEEG is a processed single-channel electroencephalogram that is filtered and time-compressed. Current evidence demonstrates that aEEG is useful to monitor cerebral background activity, diagnose and treat seizures and predict neurodevelopmental outcomes for preterm and term infants. This review aims to explain the fundamentals behind aEEG and its clinical applications. PMID- 25035309 TI - Non-cardiovascular effects associated with statins. AB - Statins form the pharmacologic cornerstone of the primary and secondary prevention of atherosclerotic cardiovascular disease. In addition to beneficial cardiovascular effects, statins seem to have multiple non-cardiovascular effects. Although early concerns about statin induced hepatotoxicity and cancer have subsided owing to reassuring evidence, two of the most common concerns that clinicians have are myopathy and diabetes. Randomized controlled trials suggest that statins are associated with a modest increase in the risk of myositis but not the risk of myalgia. Severe myopathy (rhabdomyolysis) is rare and often linked to a statin regimen that is no longer recommended (simvastatin 80 mg). Randomized controlled trials and meta-analyses suggest an increase in the risk of diabetes with statins, particularly with higher intensity regimens in people with two or more components of the metabolic syndrome. Other non-cardiovascular effects covered in this review are contrast induced nephropathy, cognition, cataracts, erectile dysfunction, and venous thromboembolism. Currently, systematic reviews and clinical practice guidelines indicate that the cardiovascular benefits of statins generally outweigh non-cardiovascular harms in patients above a certain threshold of cardiovascular risk. Literature is also accumulating on the potential non-cardiovascular benefits of statins, which could lead to novel applications of this class of drug in the future. PMID- 25035313 TI - Whistles and wheezes: don't miss diseases. AB - Upper airway obstruction (UAO) in infants and children has a broad spectrum of presentations including benign self-resolving conditions, from mild croup, to critical life-threatening conditions which, though uncommon now, require prompt recognition and effective multidisciplinary collaborative management to achieve a good outcome. The aim of this article is to highlight the diagnostic and management difficulties in acute UAO in paediatric patients and encourage a problem-solving approach. PMID- 25035314 TI - Fifteen-minute consultation: investigation and management of childhood epistaxis. AB - Recurrent epistaxis is very common in children, and the majority of cases are self-limiting with simple first aid measures. However, recurrent episodes are a source of distress and anxiety for child and parent alike, and commonly result in hospital referral. We present a structured approach highlighting initial assessment, examination and management including when to refer to ear, nose and throat (ENT) surgery. PMID- 25035315 TI - Scalp conditions. PMID- 25035316 TI - Forced limb-use enhances brain plasticity through the cAMP/PKA/CREB signal transduction pathway after stroke in adult rats. AB - PURPOSE: The mechanism underlying forced limb-use -induced structural plasticity remains to be studied. We examined whether the cyclic adenosine monophosphate (cAMP)-mediated signal transduction pathway was involved in brain plasticity and promoted behavioral recovery induced by forced limb-use after stroke. METHODS: Adult rats were divided into a sham group, an ischemia group, an ischemia group with forced limb-use, and an ischemia group with forced limb-use and infusion of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89). Forced limb use began on post-stroke day 7. Biotinylated dextran amine (BDA) was injected into the sensorimotor cortex on post-stroke day 14. Behavioral recovery was evaluated on post-stroke days 29 to 32, and the levels of cAMP, PKA C-alpha, phosphorylated CREB (pCREB), synaptophysin, PSD-95, BDA, and BrdU/NeuN were measured. RESULTS: The number of midline-crossing axons and the expression levels of synaptophysin and PSD-95 were increased after forced limb-use. Forced limb-use enhanced the survival of the newborn neurons and increased the levels of cAMP, PKA C-alpha and pCREB. These were significantly suppressed by H89. Behavioral performance improved with forced limb-use and was reversed with H89. CONCLUSIONS: Enhanced structural plasticity and the behavioral recovery promoted by post stroke forced limb-use are suggested to be mediated through the cAMP/PKA/CREB signal transduction pathway. PMID- 25035317 TI - Genome Sequence of Borrelia garinii Strain SZ, Isolated in China. AB - We announce the genome sequence of Borrelia garinii strain SZ, isolated from Dermacentor ticks collected in northeastern China. B. garinii strain SZ carries numerous plasmids, both 10 circular and 9 linear plasmids. The 902,487-bp linear chromosome (28.2% GC content) contains 820 open reading frames, 33 tRNAs, and 4 complete rRNAs. The plasmid cp32-10 contains one clustered regularly interspaced short palindromic repeat (CRISPR) with four repeats. PMID- 25035318 TI - Genome Sequence of Lactobacillus delbrueckii subsp. lactis CNRZ327, a Dairy Bacterium with Anti-Inflammatory Properties. AB - Lactobacillus delbrueckii subsp. lactis CNRZ327 is a dairy bacterium with anti inflammatory properties both in vitro and in vivo. Here, we report the genome sequence of this bacterium, which appears to contain no less than 215 insertion sequence (IS) elements, an exceptionally high number regarding the small genome size of the strain. PMID- 25035319 TI - Draft Genome Sequence of Enterococcus hirae Strain INF E1 Isolated from Cultured Milk. AB - Here, we present the draft genome of Enterococcus hirae INF E1, found as a contaminant in cultured milk and studied for its ability to metabolize milk fat globule membrane glycoconjugates. PMID- 25035320 TI - Genome Sequences of the Oxytetracycline Production Strain Streptomyces rimosus R6 500 and Two Mutants with Chromosomal Rearrangements. AB - The genome sequence of Streptomyces rimosus R6-500, an industrially improved strain which produces high titers of the important antibiotic oxytetracycline, is reported, as well as the genome sequences of two derivatives arising due to the genetic instability of the strain. PMID- 25035321 TI - Curtobacterium sp. Genome Sequencing Underlines Plant Growth Promotion-Related Traits. AB - Endophytic bacteria are microorganisms residing in plant tissues without causing disease symptoms. Here, we provide the high-quality genome sequence of Curtobacterium sp. strain S6, isolated from grapevine plant. The genome assembly contains 2,759,404 bp in 13 contigs and 2,456 predicted genes. PMID- 25035322 TI - Genome Sequence of Bacillus thuringiensis subsp. kurstaki Strain HD-1. AB - We report here the complete genome sequence of Bacillus thuringiensis subsp. kurstaki strain HD-1, which serves as the primary U.S. reference standard for all commercial insecticidal formulations of B. thuringiensis manufactured around the world. PMID- 25035323 TI - Draft Genome Sequence of Streptomyces iranensis. AB - Streptomyces iranensis HM 35 has been shown to exhibit 72.7% DNA-DNA similarity to the important drug rapamycin (sirolimus)-producing Streptomyces rapamycinicus NRRL5491. Here, we report the genome sequence of HM 35, which represents a partially overlapping repertoire of secondary metabolite gene clusters with S. rapamycinicus, including the gene cluster for rapamycin biosynthesis. PMID- 25035324 TI - Draft Genome Sequencing of Vibrio cholerae O1 El Tor Isolates Collected in the Russian Federation from Imported Cholera Cases. AB - We report the draft genome sequencing of five Vibrio cholerae O1 El Tor clinical isolates collected in the Russian Federation from imported cholera cases in 2006, 2010, and 2012. In the initial phylogenetic analysis, one isolate clustered with the Haiti/Nepal-4 group. PMID- 25035325 TI - Strain Kaplan of Pseudorabies Virus Genome Sequenced by PacBio Single-Molecule Real-Time Sequencing Technology. AB - Pseudorabies virus (PRV) is a neurotropic herpesvirus that causes Aujeszky's disease in pigs. PRV strains are widely used as transsynaptic tracers for mapping neural circuits. We present here the complete and fully annotated genome sequence of strain Kaplan of PRV, determined by Pacific Biosciences RSII long-read sequencing technology. PMID- 25035326 TI - Whole-Genome Sequencing of an Isoniazid-Resistant Clinical Isolate of Mycobacterium tuberculosis Strain MtURU-002 from Uruguay. AB - The incidence of tuberculosis in Uruguay has been effectively reduced to <30 per 100,000 population, although an increase in nonrisk populations in the last few years is evident. Here, we present the genome sequence of Mycobacterium tuberculosis strain MtURU-002 isolated from a patient showing bilateral pulmonary tuberculosis that was resistant to isoniazid. PMID- 25035327 TI - Characterization of a genogroup I sapovirus isolated from chimpanzees in the republic of congo. AB - Sapoviruses, which are members of the Caliciviridae family, are small nonenveloped viruses known to infect a large spectrum of mammalian hosts. We report here the first complete genome sequences of two genogroup I sapoviruses isolated from fecal samples from chimpanzees living in the Tchimpounga sanctuary, Republic of Congo. PMID- 25035328 TI - Genome Sequence of Pseudomonas chlororaphis Strain PA23. AB - Pseudomonas chlororaphis strain PA23 is a plant-beneficial bacterium that is able to suppress disease caused by the fungal pathogen Sclerotinia sclerotiorum through a process known as biological control. Here we present a 7.1-Mb assembly of the PA23 genome. PMID- 25035329 TI - Draft Genome Sequences of Respiratory and Urinary Tract Isolates of Acinetobacter baumannii from the Same Patient. AB - Acinetobacter baumannii is a frequent hospital-acquired human pathogen. This report describes the draft genome sequences of two distinct A. baumannii clinical isolates from the same patient. A comparison of the genomes revealed differences in antibiotic resistance and will enable the determination of genomic differences responsible for virulence at each body site. PMID- 25035330 TI - Whole-Genome Sequence of Brucella canis Strain SVA13, Isolated from an Infected Dog. AB - An outbreak of canine brucellosis in Sweden was confirmed by the National Veterinary Institute (SVA) in August 2013. The whole genome of the causative agent was sequenced, assembled, and analyzed. PMID- 25035331 TI - Whole Genome Sequence of Polyresistant Mycobacterium tuberculosis CWCFVRF PRTB 19 Sputum Isolate from Chennai, India, Closely Clustering with East African Indian 5 Genogroup. AB - We announce the draft genome sequence of a polyresistant Mycobacterium tuberculosis strain (CWCFVRF PRTB 19) isolated from the sputum of a clinically suspected tuberculosis patient, and it closely clusters to the East African Indian 5 (EAI5) lineage. PMID- 25035332 TI - Draft Genome Sequence of Deinococcus sp. Strain RL Isolated from Sediments of a Hot Water Spring. AB - Deinococcus sp. strain RL, a moderately thermophilic bacterium, was isolated from sediments of a hot water spring in Manikaran, India. Here, we report the draft genome (2.79 Mbp) of this strain, which contains 62 contigs and 2,614 coding DNA sequences, with an average G+C content of 69.4%. PMID- 25035333 TI - Genome Sequence of "Candidatus Arthromitus" sp. Strain SFB-Mouse-NL, a Commensal Bacterium with a Key Role in Postnatal Maturation of Gut Immune Functions. AB - "Candidatus Arthromitus" sp. strain SFB-mouse-NL (SFB, segmented filamentous bacteria) is a commensal bacterium necessary for inducing the postnatal maturation of homeostatic innate and adaptive immune responses in the mouse gut. Here, we report the genome sequence of this bacterium, which sets it apart from earlier sequenced mouse SFB isolates. PMID- 25035334 TI - Draft Genome Sequences of the Alga-Degrading Bacteria Aeromonas hydrophila Strain AD9 and Pseudomonas pseudoalcaligenes Strain AD6. AB - Aeromonas hydrophila AD9 and Pseudomonas pseudoalcaligenes AD6 have been linked to algal cell degradation. Here we report the draft genomes of A. hydrophila AD9 and P. pseudoalcaligenes AD6 for the investigation of causative agents for algal cell degradation. PMID- 25035335 TI - Genome Sequence of Pseudomonas mandelii PD30. AB - The genome sequence of Pseudomonas mandelii PD30 is reported in this announcement. The genes for the reduction of nitrate to dinitrogen were identified in the genome assembly and subsequently used in gene expression research. PMID- 25035336 TI - Draft Genome Sequence of a New Shigella flexneri Subserotype, 4S BJ10610. AB - Shigella flexneri is of great concern in the prevalence of shigellosis and resistance to many antibiotics in developing countries. Here, we report the draft genome sequence of a new S. flexneri subserotype, 4S BJ10610, isolated from the stool specimens of a patient in Beijing, China. PMID- 25035337 TI - Draft Genome Sequence of the Endosymbiont "Candidatus Ruthia magnifica" UCD-CM (Phylum Proteobacteria). AB - Here, we present the draft genome of the endosymbiont "Candidatus Ruthia magnifica" UCD-CM, a member of the phylum Proteobacteria, found from the gills of a deep-sea giant clam, Calyptogena magnifica. The assembly consists of 1,160,249 bp contained in 18 contigs. PMID- 25035338 TI - Ergonomic practices in Hong Kong. PMID- 25035339 TI - The application of participatory ergonomics in a healthcare setting in Hong Kong. AB - BACKGROUND: Work-related musculoskeletal disorders (WRMDs) are recognized as a major source of significant pain and disability in the healthcare sector. However, they are preventable if appropriate surveillance and intervention programs are implemented. OBJECTIVE: The purpose of this paper is to describe the holistic ergonomic approach that was used to address the multifactorial problems encountered by healthcare workers in their daily work. METHODS: Using participatory ergonomics, healthcare workers in this study teamed up with management and staff with expertise in ergonomic analysis, design, and implementation of remedies. Selected participatory ergonomic intervention programs targeted at an organizational level are elaborated. Interventions included pre-work stretching, workplace surveillance at a psychiatric department, on-site ergonomic teaching for community nurses, and display screen equipment consultancy. DISCUSSIONS: Changes in workplace design, equipment re-arrangement, awareness of proper posture, and adoption of good work practices all play important roles in reducing musculoskeletal disorders among healthcare workers. Prompt occupational medicine and rehabilitation services were also provided to complement the work disability prevention process. The impact of the various intervention programs on staff health, costs and productivity of the organization are simultaneously discussed. PMID- 25035340 TI - Effectiveness of computerized risk assessment system on enhancing workers' occupational health and attitudes towards occupational health. AB - BACKGROUND: Efforts have been paid to lower the health risks associated with use of computers at the workplace. Computerized risk assessment systems are available in the market for adoption by companies. OBJECTIVES: The Display Screen Equipment Risk Assessment and Management System was designed for conducting risk assessment and providing intelligent-driven solutions for DSE-related occupational health problems. This report summarizes two consecutive research work conducted on evaluating its effect in reducing body discomfort and mental fatigue, and enhancing sedentary workers' occupational health. METHODS: Convenience sampling was adopted to recruit participants (111 participants for Study 1 and 75 participants for Study 2 who were randomly assigned to an immediate or a delayed intervention group. The intervention was using DSE RAM System to perform a risk assessment followed by an immediate modification of participant's workstation based on the recommendations generated by the System. Face to face interview was conducted and participants completed three sets of questionnaires right before the assessment and two weeks after the intervention. RESULTS: The results of Study 1 revealed that the DSE RAM System was effective for alleviating the discomfort and fatigue levels by rectifying the workstation-worker match. These mismatches were identified to be the heights of monitor, keyboard and chair with the workers. The results of Study 2 indicate that the System was specific for promoting participants to take more frequent rest breaks (OR: 3.65) and pay more attention to occupational safety and health information (OR: 3.90). In particular, the take frequent rest breaks behavior was found to predict decrease in discomfort in the eyes and mental fatigue (lack of energy). Nevertheless, there was no strong evidence on the use of the System can lead to immediate attitudinal changes towards occupational health and safety. CONCLUSION: The findings support the notion that workers' participation and integration of ergonomics into the management are important for successful implementation of occupational health programs. Together with educational and skill training sessions on occupational health at the workplace, the DSE RAM System offers a venue for implementing participatory ergonomics at the workplace. PMID- 25035341 TI - Impaired fibrous repair: a possible contributor to atherosclerotic plaque vulnerability in patients with type II diabetes. AB - OBJECTIVE: Diabetes mellitus (DM) type II is increasing rapidly worldwide. Patients with DM II have a greater atherosclerotic burden and higher risk of developing cardiovascular complications. Inflammation has been proposed as the main cause for the high risk of atherosclerotic disease in DM II. In this study, we compared markers of inflammation and fibrous repair in plaques from subjects with and without DM II. APPROACH AND RESULTS: Carotid endarterectomy specimens were obtained from 63 patients with and 131 without DM. Plaque structure, connective tissue proteins, inflammatory cells, and markers were analyzed by immunohistochemistry, ELISA, Mesoscale, and Luminex technology. Carotid plaques from diabetics had lower levels of extracellular matrix proteins, elastin, and collagen, which are critical for plaque stability. Plaques from diabetics had reduced levels of platelet-derived growth factor and matrix metalloproteinase-2, both important for tissue repair. No differences were observed in inflammatory markers in plaques from diabetic and nondiabetic patients. CONCLUSION: This study suggests that atherosclerotic plaques in subjects with DM II are more prone to rupture because of impaired repair responses rather than to increased vascular inflammation. Although this study did not have a mechanistic design, our findings suggest that targeting impaired repair responses in carotid plaques may help to increase our understanding of atherosclerotic plaque development and vulnerability in patients with DM II. PMID- 25035342 TI - Links between ectopic fat and vascular disease in humans. AB - The average of overweight individual can have differential fat depots in target organs or specific compartments of the body. This ectopic fat distribution may be more of a predictive factor for cardiovascular risk than obesity. Abdominal visceral obesity, a representative ectopic fat, is robustly associated with insulin resistance and cardiovascular risk. Fat depots in the liver and muscle tissue cause adverse cardiometabolic risk by affecting glucose and lipid metabolism. Pericardial fat and perivascular fat affect coronary atherosclerosis, cardiac function, and hemodynamics. Fat around the neck is associated with systemic vascular resistance. Fat around the kidney may increase blood pressure and induce albuminuria. Fat accumulation in or around the pancreas alters glucose metabolism, conferring cardiovascular risk. Ectopic fat may act as an active endocrine and paracrine organ that releases various bioactive mediators that influence insulin resistance, glucose and lipid metabolism, coagulation, and inflammation, which all contribute to cardiovascular risk. Because both obese and apparently lean individuals can have ectopic fat, regional fat distribution may play an important role in the development of cardiovascular diseases in both nonobese and obese people. PMID- 25035343 TI - Polymorphisms in catechol-O-methyltransferase modify treatment effects of aspirin on risk of cardiovascular disease. AB - OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. APPROACH AND RESULTS: We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4*10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05 3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83 2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar. CONCLUSIONS: Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required. PMID- 25035344 TI - Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. AB - OBJECTIVE: Recent genome-wide association studies revealed that a genetic variant in the loci corresponding to histone deacetylase 9 (HDAC9) is associated with large vessel stroke. HDAC9 expression was upregulated in human atherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear. APPROACH AND RESULTS: In this study, we show that systemic and bone marrow cell deletion of HDAC9 decreased atherosclerosis in LDLr(-/-) (low density lipoprotein receptor) mice with minimal effect on plasma lipid concentrations. HDAC9 deletion resulted upregulation of lipid homeostatic genes, downregulation of inflammatory genes, and polarization toward an M2 phenotype via increased accumulation of total acetylated H3 and H3K9 at the promoters of ABCA1 (ATP-binding cassette transporter), ABCG1, and PPAR-gamma (peroxisome proliferator-activated receptor) in macrophages. CONCLUSIONS: We conclude that macrophage HDAC9 upregulation is atherogenic via suppression of cholesterol efflux and generation of alternatively activated macrophages in atherosclerosis. PMID- 25035346 TI - Epidemiology and public health policy of tobacco use and cardiovascular disorders in low- and middle-income countries. AB - All forms of tobacco lead to an increased risk of cardiovascular disorders. During the past few decades, the number of people who consume tobacco has increased worldwide because of an overall increase in the global population. It is estimated that close to 80% of the >1.3 billion people who smoke tobacco in the world are in low- and middle-income countries. Smokeless forms of tobacco are also widely consumed in low- and middle-income countries, including chewable and snuffed forms. Lack of targeted and effective strategies to control tobacco consumption contributes to a large burden of cardiovascular disorders in low- and middle-income countries, where cardiovascular disorders have become the leading cause of morbidity and mortality. In this review, we evaluate the epidemiology of tobacco use in low- and middle-income countries and assess the public health policies needed to control tobacco use in such regions for the prevention of cardiovascular disorders and other tobacco-related morbidities and mortality. PMID- 25035345 TI - Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism. AB - OBJECTIVE: Interindividual variation in pathways affecting cellular cholesterol metabolism can influence levels of plasma cholesterol, a well-established risk factor for cardiovascular disease. Inherent variation among immortalized lymphoblastoid cell lines from different donors can be leveraged to discover novel genes that modulate cellular cholesterol metabolism. The objective of this study was to identify novel genes that regulate cholesterol metabolism by testing for evidence of correlated gene expression with cellular levels of 3-hydroxy-3 methylglutaryl-CoA reductase (HMGCR) mRNA, a marker for cellular cholesterol homeostasis, in a large panel of lymphoblastoid cell lines. APPROACH AND RESULTS: Expression array profiling was performed on 480 lymphoblastoid cell lines established from participants of the Cholesterol and Pharmacogenetics (CAP) statin clinical trial, and transcripts were tested for evidence of correlated expression with HMGCR as a marker of intracellular cholesterol homeostasis. Of these, transmembrane protein 55b (TMEM55B) showed the strongest correlation (r=0.29; P=4.0E-08) of all genes not previously implicated in cholesterol metabolism and was found to be sterol regulated. TMEM55B knockdown in human hepatoma cell lines promoted the decay rate of the low-density lipoprotein receptor, reduced cell surface low-density lipoprotein receptor protein, impaired low-density lipoprotein uptake, and reduced intracellular cholesterol. CONCLUSIONS: Here, we report identification of TMEM55B as a novel regulator of cellular cholesterol metabolism through the combination of gene expression profiling and functional studies. The findings highlight the value of an integrated genomic approach for identifying genes that influence cholesterol homeostasis. PMID- 25035347 TI - Solid pseudopapillary tumors of the pancreas. Case report and review of the literature. AB - Solid pseudopapillary tumors (SPTs) are classified among the rare malignant tumors but they usually appear as slowly growing and low-grade malignancy and also occur in children and adolescents. They are mostly detected incidentally, but may occasionally present with sudden pain or symptoms of compression of adjacent structures. We report the case of a 15-year-old girl having an SPT of the exocrine pancreas presenting with an upper abdominal mass following a slight trauma at the dancing school. Imaging investigation showed a fairly heterogeneous density consistent with an SPT arising from the body and the tail of the pancreas, adherent to the splenic vein. The patient underwent complete enucleation. The aim of this paper is to report and discuss this recent experience and also review the literature focusing some questions still debated on this intriguing topic. KEY WORDS: Children, Neoplasm, Pancreas, Solid pseudopapillary tumors. PMID- 25035348 TI - Historical development of mesenteric anatomy provides a universally applicable anatomic paradigm for complete/total mesocolic excision. AB - Although total mesorectal excision has now become the 'gold standard' for the surgical management of rectal cancer, this is not so for colon cancer. Recent data, provided by Hohenberger and West et al. and others, have demonstrated excellent oncological outcomes when mesenterectomy is extensive (as is implicit in the concept of a 'high tie') and the mesenteric package not violated. Such studies highlight the importance of understanding the basics of the mesenteric organ (including the small intestinal mesentery, mesocolon, mesosigmoid and mesorectum) and of abiding to principles of planar surgery. In this review, we first offer classic descriptions of the mesocolon and then detail contemporary thinking. In so doing, we provide an anatomical basis for safe and effective complete mesocolic excision (CME) in the management of colon cancer. Finally we list opportunities associated with the new anatomical paradigm, demonstrating benefits across multiple disciplines. Perhaps most importantly, we feel that a crystallized view of mesenteric anatomy will overcome factors that have hindered the general uptake of CME. PMID- 25035349 TI - How do I look? PMID- 25035350 TI - Treatment of pemphigus: an Indian perspective. PMID- 25035351 TI - A new occlusive patch test system comparable to IQ and Finn chambers. AB - BACKGROUND: A good patch test system should have good adhesion and contact, and minimal leakage; Finn and IQ patch test system have these properties but are expensive. AIMS: To develop a new cost-effective occlusive patch test system that had good contact with the skin and was non-irritant. METHODS: The system (designated Chamber X) was fabricated using a semi-permeable tape and a flexible virgin plastic chamber. Chamber X was developed by (i) selecting adhesive tape based on its non irritancy and adhesive potential (ii) testing plastic chamber material for its skin irritancy (iii) testing the assembled system against Finn, IQ and locally available chambers for irritancy, contact, leakage and occlusivity. RESULTS: Chamber X showed better occlusion than IQ, Finn and locally available chambers and was comparable to, (P > 0.05) IQ and Finn in terms of irritancy, contact and leakage. CONCLUSIONS: The results demonstrate that the Chamber X offers a cost effective patch test system comparable to IQ and Finn chambers in terms of safety, adhesion, leakage and occlusivity. PMID- 25035352 TI - Factors affecting the duration of phase I of dexamethasone - cyclophosphamide pulse therapy. AB - BACKGROUND: The introduction of dexamethasone-cyclophosphamide pulse (DCP) therapy for the pemphigus group of disorders by Pasricha has revolutionized the therapy for pemphigus. There are very few studies regarding factors affecting duration of phase I of the DCP. AIMS: Our purpose was to study the relationship between various factors and duration of the phase I. METHODS: A retrospective study of 98 patients of pemphigus on Dexamethasone Pulse therapy was conducted. Patients were classified according to duration of Phase 1 as those with phase I less than 6 months and those more than 6 months and analyzed for variable factors affecting duration of phase I. RESULTS: Disease severity in pemphigus significantly prolonged the duration of phase I of DCP. Longer duration was also observed in patients on concurrent oral steroid therapy (both statistically significant). CONCLUSION: The findings from our study help us to address patient expectations and apprehensions regarding duration of therapy. A detailed understanding of the various patient and disease related factors responsible for affecting Phase I duration will help in better management of the patient, and the disease. PMID- 25035353 TI - Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus. AB - BACKGROUND: Rituximab, a monoclonal anti-CD20 antibody, has been used with encouraging results in pemphigus. We describe herein refractory cases of pemphigus vulgaris (n = 23) and pemphigus foliaceus (n = 1) treated with rituximab in addition to steroids and immunosuppressants. AIMS: To assess the response to treatment, the duration of clinical remission, serology of the response and adverse effects of rituximab in pemphigus patients. METHODS: We recorded observations of 24 patients with pemphigus having either refractory disease in spite of high dose of steroids and immunosuppressants, corticosteroid dependent disease, strong contraindications to corticosteroids, or severe disease. The patients were treated with infusions of one injection per week for three consecutive weeks of 375 mg of rituximab per m 2 of body-surface area. One similar infusion was repeated after 3 months of 3 rd dose. We observed the clinical outcome after 6 months of 3 rd dose of rituximab and looked for complete healing of cutaneous and mucosal lesions (complete remission). OBSERVATIONS: After follow-up of 7-24 months, five patients showed only partial improvement while 19 of 24 patients had a complete remission 3 months after rituximab. Of these 19 patients, 12 patients achieved complete remission and are off all systemic therapy, and the rest are continuing with no or low dose of steroids with immunosuppressants. Two patients relapsed after initial improvement; one was given moderate dose of oral steroids and immunosuppressant and the other was given repeat single dose of rituximab to control relapse. CONCLUSION: Rituximab is able to induce a prolonged clinical remission in pemphigus after a single course of four infusions. The high cost and limited knowledge of long term adverse effects are limitations to the use of this biologic agent. PMID- 25035354 TI - Clinical features of primary cicatricial alopecia in Chinese patients. AB - BACKGROUND: There have been few reports on primary cicatricial alopecias (PCR) especially from Asia (PCA). AIMS: To study the clinical, pathological and dermoscopic characteristics of PCA among Chinese patients. METHODS: A retrospective analysis of the clinical data of 59 patients with PCA was conducted and the dermoscopic, pathological, treatment and prognosis characteristics analyzed. Fisher's Chi-square exact test, Kruskal-Wallis and Spearman rank correlation test were performed. RESULTS: The ratio of neutrophilic to lymphocytic cicatricial alopecias was about 1.3:1 in this group. The most frequent disorder was folliculitis decalvans. Follicular openings were absent on dermoscopy in all cases except alopecia mucinosa. Patulous follicular openings were characterisitc of alopecia mucinosa. After treatment, an increase in short vellus hairs was the earliest feature, while telangiectasia, epidermal scale, follicular hyperkeratosis, pustules and hair diameter diversity gradually decreased or even disappeared. Improvement in the areas of hair loss after treatment was seen more often in discoid lupus erythematosus, folliculitis decalvans and dissecting cellulitis than in patients with classic pseudopelade of Brocq. Nine patients (13.6%) relapsed after cessation of therapy. Female patients needed longer treatment times. Long duration, large areas of hair loss and shorter treatment courses were the major factors in relapses. CONCLUSIONS: Dermatoscopy provides a rapid, practical and useful aid for the diagnosis of PCA and also to assess disease activity. Patulous follicular openings are a specific dermoscopic sign of alopecia mucinosa. Lichen planopilaris is less common in China than in the West. PMID- 25035355 TI - Comparison of acquired bilateral nevus of Ota-like macules in men and women. AB - BACKGROUND: The clinical and histopathological characteristics of acquired bilateral nevus of Ota-like macules in men are poorly documented due to its rarity. AIMS: To compare the clinical and histopathological characteristics of acquired bilateral nevus of Ota-like macules in men with the condition in women. METHODS: We studied 11 men and 62 women, all with a clinical diagnosis of acquired bilateral nevus of Ota-like macules. Biopsies were taken from 5 men and 10 women and their clinical and histopathological features were compared. RESULTS: The most frequently affected site in men was the forehead [8 (73%) out of 11 patients]. Lesions on the forehead were more common in men than women (P = 0.001). In contrast to women, there was no apparent tendency of the lesions to become more blue with age in men. Concurrent melasma was observed in 14 (23%) out of 62 women, but not in men. Extra-facial acquired dermal melanocytosis was noted in 2 (18%) out of 11 men and in none of the 62 women. CONCLUSION: Significant differences were noted between men and women in the appearance of concurrent pigmentary lesions and the distribution of lesions. Extra-facial acquired dermal melanocytosis was noted in men. PMID- 25035356 TI - Lyme disease in Haryana, India. AB - Lyme disease is a multiorgan animal-borne disease caused by the spirochete Borrelia burgdorferi. This case series highlights its presence in Haryana, a nonendemic zone. The first case was a 27-year-old housewife who presented with an annular erythematous patch with a central papule following an insect bite on the left upper arm. The second case was a 32-year-old farmer who gave a history of insect bite on the right arm followed by the development of an erythematous patch with a central blister. The third case, a 17-year-old boy presented with a history of tick bite over right thigh and a typical bull's eye lesion with central ulceration. These cases were managed with oral doxycycline 100 mg twice daily for 14 days. The fourth case was a 7-year-old boy with typical erythema migrans on the right check and neck while the fifth case, a 30-year-old housewife, presented with an erythematous patch with a central papule on the right buttock. These patients were treated with oral amoxycillin 25 mg/kg, thrice daily for 14 days. All patients showed IgM antibodies to B. burgdorferi. Treatment led to clearance of lesions in all the patients. Lyme borreliosis was diagnosed in these patients based on the history of established exposure to tick bites, presence of classic signs and symptoms, serology and the response to treatment. PMID- 25035357 TI - Trichosporon inkin and Trichosporon mucoides as unusual causes of white piedra of scalp hair. AB - White piedra of scalp hair is considered a rare entity. We report three cases of this disorder all of whom presented with nodules on the hair. Potassium hydroxide preparations of the hair revealed clustered arthrospores and mature, easily detachable nodules. Cultures grew Trichosporon inkin in 2 patients and Trichosporon mucoides in one patient. Both these fungi are unusual causes of white piedra. PMID- 25035358 TI - Paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus) with unusual manifestations and without detectable autoantibodies. AB - We describe a patient with paraneoplastic autoimmune multiorgan syndrome (PAMS) secondary to a lymphoblastic T- cell lymphoma who presented with a lichenoid dermatitis and vitiligo, later developing bronchiolitis obliterans and autoimmune hepatitis. Notably, he had no detectable autoantibodies. The development of vitiligo and autoimmune hepatic involvement probably indicate a role for cytotoxic T- cell lymphocytes in the pathogenesis of this syndrome. PMID- 25035359 TI - Cutaneous Paecilomyces lilacinus infections in immunocompromised and immunocompetent patients. AB - Paecilomyces is a genus of saprophytic fungus that has been associated, in rare instances, with human disease. We report two cases in which Paecilomyces lilacinus was isolated from cutaneous and subcutaneous lesions in an immunocompromised and an immunocompetent host. The first case was a subcutaneous infection due to P. lilacinus in a patient with a renal transplant and diabetes mellitus. The second case was an immunocompetent young woman who developed a cutaneous infection, with no identified predisposing factors. A biopsy from each patient provided an initial diagnosis of fungal elements in the tissues under examination and multiple positive fungal cultures were obtained from the tissue biopsy samples. Both microscopic and macroscopic examinations of the biopsy revealed the presence of P. lilacinus. Each of the two cases was successfully treated with oral ketoconazole (200 mg/day) and itraconazole. We also review previously reported cases in which the clinical history and response to therapy were noted. PMID- 25035360 TI - Pediatric tuberous xanthomas. PMID- 25035361 TI - Narrow-band ultraviolet B home phototherapy in vitiligo. PMID- 25035362 TI - Changing trends in leprosy among patients attending a tertiary care institution. PMID- 25035363 TI - Seroprevalence of syphilis and biologically false positive cases in a tertiary care center. PMID- 25035364 TI - Isospora induced diarrhea in a pemphigus vulgaris patient. PMID- 25035365 TI - Isolated oral mucosal leishmaniasis. PMID- 25035366 TI - Progressive symmetric erythrokeratoderma with dermatophytosis. PMID- 25035367 TI - Multiple morphological presentations of skin tuberculosis in a patient. PMID- 25035368 TI - Severely disfiguring multiple familial trichoepitheliomas with basal cell carcinoma. PMID- 25035369 TI - Panniculitis-polyarthritis-pancreatitis syndrome. PMID- 25035370 TI - EMPACT syndrome. PMID- 25035371 TI - Muir-Torre syndrome. PMID- 25035372 TI - Adult T cell leukemia-lymphoma. PMID- 25035373 TI - Persistent skin donor site erythema: a simple physiological phenomenon. PMID- 25035374 TI - Bullous pemphigoid induced by topical PUVASOL. PMID- 25035375 TI - Bullous pemphigoid in a female with hypogonadotrophic hypogonadism. PMID- 25035376 TI - Primary mucinous carcinoma of skin with psammoma bodies. PMID- 25035377 TI - Primary melanoma in rare locations: clinical and dermatoscopic features. PMID- 25035378 TI - Dermoscopy in tungiasis. PMID- 25035379 TI - Calcipotriol and adapalene therapy for disseminated superficial actinic porokeratosis. PMID- 25035380 TI - Multiple reactive keratoacanthomas in a patient with hypertrophic lichen planus treated with cyclosporine: successful treatment with acitretin. PMID- 25035381 TI - Hidradenitis suppurativa treated with carbon dioxide laser followed by split skin thickness graft. PMID- 25035382 TI - Electrochemotherapy for a locally advanced basal cell carcinoma on the forehead. PMID- 25035383 TI - The molecular fingerprint of human papillomavirus infection and its effect on the Langerhans cell population in squamous cell carcinomas of the genital skin. AB - BACKGROUND: Information is scarce about the presence of molecular alterations related to human papillomavirus (HPV) infection in squamous cell carcinomas of the genital skin and about the effect of this infection in the number of Langerhans cells present in these tumors. AIMS: To determine the presence of HPV in genital skin squamous cell carcinomas and to see the relationship between HPV infection and changes in the expression of Ki-67 antigen (Ki-67), p53 protein (p53), retinoblastoma protein (pRb) and E-cadherin and to alterations in Langerhans cell density, if any. METHODS: A descriptive, comparative, retrospective and cross-sectional study was performed with all the cases diagnosed as squamous cell carcinomas of the genital skin at the Dermatopathology Service from 2001 to 2011. The diagnosis was verified by histopathological examination. The presence of HPV was examined using chromogenic in situ hybridization, and protein expression was studied via immunohistochemical analysis. RESULTS: The 34 cases studied were verified as squamous cell carcinomas and 44.1% were HPV positive. The degree of expression of pRb was 17.50% +/-14.11% (mean +/- SD) in HPV-positive cases and 29.74% +/-20.38% in HPV-negative cases (P = 0.0236). The degree of expression of Ki-67 was 47.67% +/-30.64% in HPV-positive cases and 29.87% +/-15.95% in HPV-negative cases (P = 0.0273). CONCLUSION: HPV infection was related to lower pRb expression and higher Ki-67 expression in comparison with HPV negative samples. We could not find a relationship between HPV infection and the degree of expression of p53 and E-cadherin or with Langerhans cell density. PMID- 25035384 TI - Borderline tuberculoid leprosy with scrofuloderma: an uncommon association. PMID- 25035385 TI - Zoster ophthalmicus with dissemination in a six year old immunocompetent child. PMID- 25035388 TI - Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. PMID- 25035389 TI - The increasing urgency for standards in basic biologic research. AB - Research advances build upon the validity and reproducibility of previously published data and findings. Yet irreproducibility in basic biologic and preclinical research is pervasive in both academic and commercial settings. Lack of reproducibility has led to invalidated research breakthroughs, retracted articles, and aborted clinical trials. Concerns and requirements for transparent, reproducible, and translatable research are accelerated by the rapid growth of "post-publication peer review," open access publishing, and data sharing that facilitate the identification of irreproducible data/studies; they are magnified by the explosion of high-throughput technologies, genomics, and other data intensive disciplines. Collectively, these changes and challenges are decreasing the effectiveness of traditional research quality mechanisms and are contributing to unacceptable-and unsustainable-levels of irreproducibility. The global oncology and basic biologic research communities can no longer tolerate or afford widespread irreproducible research. This article discusses (i) how irreproducibility in preclinical research can ultimately be traced to an absence of a unifying life science standards framework, and (ii) makes an urgent case for the expanded development and use of consensus-based standards to both enhance reproducibility and drive innovations in cancer research. PMID- 25035390 TI - Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor. AB - ERBB3/HER3 expression and signaling are upregulated in mutant BRAF melanoma as an adaptive, prosurvival response to FDA-approved RAF inhibitors. Because compensatory ERBB3 signaling counteracts the effects of RAF inhibitors, cotargeting ERBB3 may increase the efficacy of RAF inhibitors in mutant BRAF models of melanoma. Here, we corroborate this concept by showing that the ERBB3 function-blocking monoclonal antibody huHER3-8 can inhibit neuregulin-1 activation of ERBB3 and downstream signaling in RAF-inhibited melanoma cells. Targeting mutant BRAF in combination with huHER3-8 decreased cell proliferation and increased cell death in vitro, and decreased tumor burden in vivo, compared with targeting either mutant BRAF or ERBB3 alone. Furthermore, the likelihood of a durable tumor response in vivo was increased when huHER3-8 was combined with RAF inhibitor PLX4720. Together, these results offer a preclinical proof of concept for the application of ERBB3-neutralizing antibodies to enhance the efficacy of RAF inhibitors in melanoma to delay or prevent tumor regrowth. As ERBB3 is often upregulated in response to other kinase-targeted therapeutics, these findings may have implications for other cancers as well. PMID- 25035392 TI - Role of the neural niche in brain metastatic cancer. AB - Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer. PMID- 25035393 TI - Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC. AB - Somatic mutations in FGFR2 are present in 4% to 5% of patients diagnosed with non small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLCs, and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma, although mouse models of FGFR-driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade 3/4 adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting. PMID- 25035394 TI - miR149 functions as a tumor suppressor by controlling breast epithelial cell migration and invasion. AB - Deregulated molecular signaling pathways are responsible for the altered adhesive, migratory, and invasive properties of cancer cells. The different breast cancer subtypes are characterized by the expression of distinct miRNAs, short non-coding RNAs that posttranscriptionally modulate the expression of entire gene networks. Profiling studies have revealed downregulation of miR149 in basal breast cancer. Here, we show that miR149 expression severely impairs cell spreading, migration, and invasion of basal-like breast cancer cells. We identify signaling molecules, including the small GTPases Rap1a and Rap1b, downstream of integrin receptors as miR149 targets, providing an explanation for the defective Src and Rac activation during cell adhesion and spreading upon miR149 expression. Suppression of cell spreading by miR149 could be rescued, at least in part, by expression of constitutively active Rac. Finally, we demonstrate that increased miR149 levels block lung colonization in vivo. On the basis of our findings, we propose that miR149 downregulation in basal breast cancer facilitates the metastatic dissemination of tumor cells by supporting aberrant Rac activation. Cancer Res; 74(18); 5256-65. (c)2014 AACR. PMID- 25035395 TI - Epigenetic targeting of ovarian cancer stem cells. AB - Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer. PMID- 25035396 TI - Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance. AB - Isocitrate dehydrogenase 1 (IDH1) mutations occur in most lower grade glioma and not only drive gliomagenesis but are also associated with longer patient survival and improved response to temozolomide. To investigate the possible causative relationship between these events, we introduced wild-type (WT) or mutant IDH1 into immortalized, untransformed human astrocytes, then monitored transformation status and temozolomide response. Temozolomide-sensitive parental cells exhibited DNA damage (gamma-H2AX foci) and a prolonged G2 cell-cycle arrest beginning three days after temozolomide (100 MUmol/L, 3 hours) exposure and persisting for more than four days. The same cells transformed by expression of mutant IDH1 exhibited a comparable degree of DNA damage and cell-cycle arrest, but both events resolved significantly faster in association with increased, rather than decreased, clonogenic survival. The increases in DNA damage processing, cell-cycle progression, and clonogenicity were unique to cells transformed by mutant IDH1, and were not noted in cells transformed by WT IDH1 or an oncogenic form (V12H) of Ras. Similarly, these effects were not noted following introduction of mutant IDH1 into Ras-transformed cells or established glioma cells. They were, however, associated with increased homologous recombination (HR) and could be reversed by the genetic or pharmacologic suppression of the HR DNA repair protein RAD51. These results show that mutant IDH1 drives a unique set of transformative events that indirectly enhance HR and facilitate repair of temozolomide-induced DNA damage and temozolomide resistance. The results also suggest that inhibitors of HR may be a viable means to enhance temozolomide response in IDH1-mutant glioma. PMID- 25035397 TI - Osteopontin shapes immunosuppression in the metastatic niche. AB - The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1(-/-) mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor- and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the monocytic subset was the predominant source of OPN. In Spp1(-/-) mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in Spp1(-/-) mice were less suppressive than their wild-type counterparts due to lower expression of arginase-1, IL6, and phospho-Stat3. Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1(-/ ) mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche. PMID- 25035398 TI - Preventing pertussis. PMID- 25035399 TI - lrgpr: interactive linear mixed model analysis of genome-wide association studies with composite hypothesis testing and regression diagnostics in R. AB - The linear mixed model is the state-of-the-art method to account for the confounding effects of kinship and population structure in genome-wide association studies (GWAS). Current implementations test the effect of one or more genetic markers while including prespecified covariates such as sex. Here we develop an efficient implementation of the linear mixed model that allows composite hypothesis tests to consider genotype interactions with variables such as other genotypes, environment, sex or ancestry. Our R package, lrgpr, allows interactive model fitting and examination of regression diagnostics to facilitate exploratory data analysis in the context of the linear mixed model. By leveraging parallel and out-of-core computing for datasets too large to fit in main memory, lrgpr is applicable to large GWAS datasets and next-generation sequencing data. AVAILABILITY AND IMPLEMENTATION: lrgpr is an R package available from lrgpr.r forge.r-project.org. PMID- 25035400 TI - The boron efflux transporter ROTTEN EAR is required for maize inflorescence development and fertility. AB - Although boron has a relatively low natural abundance, it is an essential plant micronutrient. Boron deficiencies cause major crop losses in several areas of the world, affecting reproduction and yield in diverse plant species. Despite the importance of boron in crop productivity, surprisingly little is known about its effects on developing reproductive organs. We isolated a maize (Zea mays) mutant, called rotten ear (rte), that shows distinct defects in vegetative and reproductive development, eventually causing widespread sterility in its inflorescences, the tassel and the ear. Positional cloning revealed that rte encodes a membrane-localized boron efflux transporter, co-orthologous to the Arabidopsis thaliana BOR1 protein. Depending on the availability of boron in the soil, rte plants show a wide range of phenotypic defects that can be fully rescued by supplementing the soil with exogenous boric acid, indicating that rte is crucial for boron transport into aerial tissues. rte is expressed in cells surrounding the xylem in both vegetative and reproductive tissues and is required for meristem activity and organ development. We show that low boron supply to the inflorescences results in widespread defects in cell and cell wall integrity, highlighting the structural importance of boron in the formation of fully fertile reproductive organs. PMID- 25035402 TI - Paired-end analysis of transcription start sites in Arabidopsis reveals plant specific promoter signatures. AB - Understanding plant gene promoter architecture has long been a challenge due to the lack of relevant large-scale data sets and analysis methods. Here, we present a publicly available, large-scale transcription start site (TSS) data set in plants using a high-resolution method for analysis of 5' ends of mRNA transcripts. Our data set is produced using the paired-end analysis of transcription start sites (PEAT) protocol, providing millions of TSS locations from wild-type Columbia-0 Arabidopsis thaliana whole root samples. Using this data set, we grouped TSS reads into "TSS tag clusters" and categorized clusters into three spatial initiation patterns: narrow peak, broad with peak, and weak peak. We then designed a machine learning model that predicts the presence of TSS tag clusters with outstanding sensitivity and specificity for all three initiation patterns. We used this model to analyze the transcription factor binding site content of promoters exhibiting these initiation patterns. In contrast to the canonical notions of TATA-containing and more broad "TATA-less" promoters, the model shows that, in plants, the vast majority of transcription start sites are TATA free and are defined by a large compendium of known DNA sequence binding elements. We present results on the usage of these elements and provide our Plant PEAT Peaks (3PEAT) model that predicts the presence of TSSs directly from sequence. PMID- 25035401 TI - The cysteine protease CEP1, a key executor involved in tapetal programmed cell death, regulates pollen development in Arabidopsis. AB - Tapetal programmed cell death (PCD) is a prerequisite for pollen grain development in angiosperms, and cysteine proteases are the most ubiquitous hydrolases involved in plant PCD. We identified a papain-like cysteine protease, CEP1, which is involved in tapetal PCD and pollen development in Arabidopsis thaliana. CEP1 is expressed specifically in the tapetum from stages 5 to 11 of anther development. The CEP1 protein first appears as a proenzyme in precursor protease vesicles and is then transported to the vacuole and transformed into the mature enzyme before rupture of the vacuole. cep1 mutants exhibited aborted tapetal PCD and decreased pollen fertility with abnormal pollen exine. A transcriptomic analysis revealed that 872 genes showed significantly altered expression in the cep1 mutants, and most of them are important for tapetal cell wall organization, tapetal secretory structure formation, and pollen development. CEP1 overexpression caused premature tapetal PCD and pollen infertility. ELISA and quantitative RT-PCR analyses confirmed that the CEP1 expression level showed a strong relationship to the degree of tapetal PCD and pollen fertility. Our results reveal that CEP1 is a crucial executor during tapetal PCD and that proper CEP1 expression is necessary for timely degeneration of tapetal cells and functional pollen formation. PMID- 25035403 TI - DELLAs function as coactivators of GAI-ASSOCIATED FACTOR1 in regulation of gibberellin homeostasis and signaling in Arabidopsis. AB - Gibberellins (GAs) are essential regulators of plant development, and DELLAs are negative regulators of GA signaling. The mechanism of GA-dependent transcription has been explained by DELLA-mediated titration of transcriptional activators and their release through the degradation of DELLAs in response to GA. However, the effect of GA on genome-wide expression is predominantly repression, suggesting the existence of unknown mechanisms of GA function. In this study, we identified an Arabidopsis thaliana DELLA binding transcription factor, GAI-ASSOCIATED FACTOR1 (GAF1). GAF1 shows high homology to INDETERMINATE DOMAIN1 (IDD1)/ENHYDROUS. GA responsiveness was decreased in the double mutant gaf1 idd1, whereas it was enhanced in a GAF1 overexpressor. GAF1 binds to genes that are subject to GA feedback regulation. Furthermore, we found that GAF1 interacts with the corepressor TOPLESS RELATED (TPR) and that DELLAs and TPR act as coactivators and a corepressor of GAF1, respectively. GA converts the GAF1 complex from transcriptional activator to repressor via the degradation of DELLAs. These results indicate that DELLAs turn on or off two sets of GA-regulated genes via dual functions, namely titration and coactivation, providing a mechanism for the integrative regulation of plant growth and GA homeostasis. PMID- 25035404 TI - Direct phosphorylation and activation of a mitogen-activated protein kinase by a calcium-dependent protein kinase in rice. AB - The mitogen-activated protein kinase (MAPK) is a pivotal point of convergence for many signaling pathways in eukaryotes. In the classical MAPK cascade, a signal is transmitted via sequential phosphorylation and activation of MAPK kinase kinase, MAPK kinase (MKK), and MAPK. The activation of MAPK is dependent on dual phosphorylation of a TXY motif by an MKK, which is considered the sole kinase to phosphorylate and activate MAPK. Here, we report a novel regulatory mechanism of MAPK phosphorylation and activation besides the canonical MAPK cascade. A rice (Oryza sativa) calcium-dependent protein kinase (CDPK), CPK18, was identified as an upstream kinase of MAPK (MPK5) in vitro and in vivo. Curiously, CPK18 was shown to phosphorylate and activate MPK5 without affecting the phosphorylation of its TXY motif. Instead, CPK18 was found to predominantly phosphorylate two Thr residues (Thr-14 and Thr-32) that are widely conserved in MAPKs from land plants. Further analyses reveal that the newly identified CPK18-MPK5 pathway represses defense gene expression and negatively regulates rice blast resistance. Our results suggest that land plants have evolved an MKK-independent phosphorylation pathway that directly connects calcium signaling to the MAPK machinery. PMID- 25035406 TI - Transport of boron by the tassel-less1 aquaporin is critical for vegetative and reproductive development in maize. AB - The element boron (B) is an essential plant micronutrient, and B deficiency results in significant crop losses worldwide. The maize (Zea mays) tassel-less1 (tls1) mutant has defects in vegetative and inflorescence development, comparable to the effects of B deficiency. Positional cloning revealed that tls1 encodes a protein in the aquaporin family co-orthologous to known B channel proteins in other species. Transport assays show that the TLS1 protein facilitates the movement of B and water into Xenopus laevis oocytes. B content is reduced in tls1 mutants, and application of B rescues the mutant phenotype, indicating that the TLS1 protein facilitates the movement of B in planta. B is required to cross-link the pectic polysaccharide rhamnogalacturonan II (RG-II) in the cell wall, and the percentage of RG-II dimers is reduced in tls1 inflorescences, indicating that the defects may result from altered cell wall properties. Plants heterozygous for both tls1 and rotten ear (rte), the proposed B efflux transporter, exhibit a dosage-dependent defect in inflorescence development under B-limited conditions, indicating that both TLS1 and RTE function in the same biological processes. Together, our data provide evidence that TLS1 is a B transport facilitator in maize, highlighting the importance of B homeostasis in meristem function. PMID- 25035407 TI - Nanodomains of cytochrome b6f and photosystem II complexes in spinach grana thylakoid membranes. AB - The cytochrome b6f (cytb6f) complex plays a central role in photosynthesis, coupling electron transport between photosystem II (PSII) and photosystem I to the generation of a transmembrane proton gradient used for the biosynthesis of ATP. Photosynthesis relies on rapid shuttling of electrons by plastoquinone (PQ) molecules between PSII and cytb6f complexes in the lipid phase of the thylakoid membrane. Thus, the relative membrane location of these complexes is crucial, yet remains unknown. Here, we exploit the selective binding of the electron transfer protein plastocyanin (Pc) to the lumenal membrane surface of the cytb6f complex using a Pc-functionalized atomic force microscope (AFM) probe to identify the position of cytb6f complexes in grana thylakoid membranes from spinach (Spinacia oleracea). This affinity-mapping AFM method directly correlates membrane surface topography with Pc-cytb6f interactions, allowing us to construct a map of the grana thylakoid membrane that reveals nanodomains of colocalized PSII and cytb6f complexes. We suggest that the close proximity between PSII and cytb6f complexes integrates solar energy conversion and electron transfer by fostering short-range diffusion of PQ in the protein-crowded thylakoid membrane, thereby optimizing photosynthetic efficiency. PMID- 25035409 TI - A mixture of Bose and Fermi superfluids. AB - Superconductivity and superfluidity of fermionic and bosonic systems are remarkable many-body quantum phenomena. In liquid helium and dilute gases, Bose and Fermi superfluidity has been observed separately, but producing a mixture in which both the fermionic and the bosonic components are superfluid is challenging. Here we report on the observation of such a mixture with dilute gases of two lithium isotopes, lithium-6 and lithium-7. We probe the collective dynamics of this system by exciting center-of-mass oscillations that exhibit extremely low damping below a certain critical velocity. Using high-precision spectroscopy of these modes, we observe coherent energy exchange and measure the coupling between the two superfluids. Our observations can be captured theoretically using a sum-rule approach that we interpret in terms of two coupled oscillators. PMID- 25035408 TI - Polyploid evolution of the Brassicaceae during the Cenozoic era. AB - The Brassicaceae (Cruciferae) family, owing to its remarkable species, genetic, and physiological diversity as well as its significant economic potential, has become a model for polyploidy and evolutionary studies. Utilizing extensive transcriptome pyrosequencing of diverse taxa, we established a resolved phylogeny of a subset of crucifer species. We elucidated the frequency, age, and phylogenetic position of polyploidy and lineage separation events that have marked the evolutionary history of the Brassicaceae. Besides the well-known ancient alpha (47 million years ago [Mya]) and beta (124 Mya) paleopolyploidy events, several species were shown to have undergone a further more recent (~7 to 12 Mya) round of genome multiplication. We identified eight whole-genome duplications corresponding to at least five independent neo/mesopolyploidy events. Although the Brassicaceae family evolved from other eudicots at the beginning of the Cenozoic era of the Earth (60 Mya), major diversification occurred only during the Neogene period (0 to 23 Mya). Remarkably, the widespread species divergence, major polyploidy, and lineage separation events during Brassicaceae evolution are clustered in time around epoch transitions characterized by prolonged unstable climatic conditions. The synchronized diversification of Brassicaceae species suggests that polyploid events may have conferred higher adaptability and increased tolerance toward the drastically changing global environment, thus facilitating species radiation. PMID- 25035410 TI - Biotechnology. Regulating gene drives. PMID- 25035411 TI - Cell reprogramming. Histone chaperone ASF1A is required for maintenance of pluripotency and cellular reprogramming. AB - Unfertilized oocytes have the intrinsic capacity to remodel sperm and the nuclei of somatic cells. The discoveries that cells can change their phenotype from differentiated to embryonic state using oocytes or specific transcription factors have been recognized as two major breakthroughs in the biomedical field. Here, we show that ASF1A, a histone-remodeling chaperone specifically enriched in the metaphase II human oocyte, is necessary for reprogramming of human adult dermal fibroblasts (hADFs) into undifferentiated induced pluripotent stem cell. We also show that overexpression of just ASF1A and OCT4 in hADFs exposed to the oocyte specific paracrine growth factor GDF9 can reprogram hADFs into pluripotent cells. Our Report underscores the importance of studying the unfertilized MII oocyte as a means to understand the molecular pathways governing somatic cell reprogramming. PMID- 25035413 TI - Reply to Lobo Filho et al. PMID- 25035414 TI - Major geographical variations in elective coronary revascularization by stents or surgery in England. AB - OBJECTIVES: Revascularization in stable coronary artery disease (CAD) can be achieved through percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) depending on the anatomical pattern of CAD, comorbidities and patient preference. Recent studies in the USA, Canada and Australia show marked local variation in the PCI/CABG ratio that is unexplained by patient related factors. This current study assesses the geographical variation in elective coronary revascularization interventions across England and discusses its appropriateness. METHODS: The rates and actual procedure numbers of total CABG, total PCIs and elective PCIs were collated for each of 151 primary care trusts (PCTs). The 'elective PCI/total CABG ratio' was taken as an indicator of elective coronary revascularization practices. The Index of Multiple Deprivation (IMD) for PCTs was taken as a marker of deprivation. RESULTS: In 2010/2011, the degree of variation in elective PCI/total CABG ratios across 151 PCTs in England was >13-fold (min = 0.36, max = 4.74, median = 1.19, interquartile range = 0.98, 1.73). The ratio was not correlated to the IMD 2010 rank of the PCTs (Spearman's rho = 0.08, P = 0.36) and was not explained by the volume of interventions performed. CONCLUSIONS: Despite clear evidence-based guidelines for intervention, marked geographical variation in elective coronary revascularization practices also exists in England. This variation is unexplained by procedure volume or deprivation, suggesting the contribution of unwarranted influences which may include practitioner preference. To reduce this level of unwarranted variation, we suggest that all interventions should be underpinned by internationally recognized guidelines or approved by a multidisciplinary team approach (The Heart Team). PMID- 25035412 TI - Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe. AB - OBJECTIVES: To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. METHODS: All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One third of more than 400 contacted centres completed the survey correctly. RESULTS: The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26 degrees C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near infrared spectroscopy associated with bilateral radial pressure measurement. CONCLUSIONS: These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approaches. PMID- 25035415 TI - Favourable mid-term outcome after heart transplantation for late Fontan failure. AB - OBJECTIVES: Fontan failure (FF) represents a growing and challenging indication for paediatric orthotopic heart transplantation (OHT). The aim of this study was to identify predictors of the best mid-term outcome in OHT after FF. METHODS: Twenty-year multi-institutional retrospective analysis on OHT for FF. RESULTS: Between 1991 and 2011, 61 patients, mean age 15.0 +/- 9.7 years, underwent OHT for failing atriopulmonary connection (17 patients = 27.8%) or total cavopulmonary connection (44 patients = 72.2%). Modality of FF included arrhythmia (14.8%), complex obstructions in the Fontan circuit (16.4%), protein losing enteropathy (PLE) (22.9%), impaired ventricular function (31.1%) or a combination of the above (14.8%). The mean time interval between Fontan completion and OHT was 10.7 +/- 6.6 years. Early FF occurred in 18%, requiring OHT 0.8 +/- 0.5 years after Fontan. The hospital mortality rate was 18.3%, mainly secondary to infection (36.4%) and graft failure (27.3%). The mean follow-up was 66.8 +/- 54.2 months. The overall Kaplan-Meier survival estimate was 81.9 +/- 1.8% at 1 year, 73 +/- 2.7% at 5 years and 56.8 +/- 4.3% at 10 years. The Kaplan Meier 5-year survival estimate was 82.3 +/- 5.9% in late FF and 32.7 +/- 15.0% in early FF (P = 0.0007). Late FF with poor ventricular function exhibited a 91.5 +/ 5.8% 5-year OHT survival. PLE was cured in 77.7% of hospital survivors, but the 5-year Kaplan-Meier survival estimate in PLE was 46.3 +/- 14.4 vs 84.3 +/- 5.5% in non-PLE (P = 0.0147). Cox proportional hazards identified early FF (P = 0.0005), complex Fontan pathway obstruction (P = 0.0043) and PLE (P = 0.0033) as independent predictors of 5-year mortality. CONCLUSIONS: OHT is an excellent surgical option for late FF with impaired ventricular function. Protein dispersion improves with OHT, but PLE negatively affects the mid-term OHT outcome, mainly for early infective complications. PMID- 25035416 TI - A novel composite coronary bypass graft strategy using the saphenous vein bridge: could the venous valves induce worse patency results? PMID- 25035417 TI - Multiple FLC haplotypes defined by independent cis-regulatory variation underpin life history diversity in Arabidopsis thaliana. AB - Relating molecular variation to phenotypic diversity is a central goal in evolutionary biology. In Arabidopsis thaliana, FLOWERING LOCUS C (FLC) is a major determinant of variation in vernalization--the acceleration of flowering by prolonged cold. Here, through analysis of 1307 A. thaliana accessions, we identify five predominant FLC haplotypes defined by noncoding sequence variation. Genetic and transgenic experiments show that they are functionally distinct, varying in FLC expression level and rate of epigenetic silencing. Allelic heterogeneity at this single locus accounts for a large proportion of natural variation in vernalization that contributes to adaptation of A. thaliana. PMID- 25035418 TI - High-throughput functional testing of ENCODE segmentation predictions. AB - The histone modification state of genomic regions is hypothesized to reflect the regulatory activity of the underlying genomic DNA. Based on this hypothesis, the ENCODE Project Consortium measured the status of multiple histone modifications across the genome in several cell types and used these data to segment the genome into regions with different predicted regulatory activities. We measured the cis regulatory activity of more than 2000 of these predictions in the K562 leukemia cell line. We tested genomic segments predicted to be Enhancers, Weak Enhancers, or Repressed elements in K562 cells, along with other sequences predicted to be Enhancers specific to the H1 human embryonic stem cell line (H1-hESC). Both Enhancer and Weak Enhancer sequences in K562 cells were more active than negative controls, although surprisingly, Weak Enhancer segmentations drove expression higher than did Enhancer segmentations. Lower levels of the covalent histone modifications H3K36me3 and H3K27ac, thought to mark active enhancers and transcribed gene bodies, associate with higher expression and partly explain the higher activity of Weak Enhancers over Enhancer predictions. While DNase I hypersensitivity (HS) is a good predictor of active sequences in our assay, transcription factor (TF) binding models need to be included in order to accurately identify highly expressed sequences. Overall, our results show that a significant fraction (-26%) of the ENCODE enhancer predictions have regulatory activity, suggesting that histone modification states can reflect the cis regulatory activity of sequences in the genome, but that specific sequence preferences, such as TF-binding sites, are the causal determinants of cis regulatory activity. PMID- 25035420 TI - Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians. AB - The electrocardiogram has several advantages in detecting cardiac arrhythmia-it is readily available, noninvasive and cost-efficient. Recent genome-wide association studies have identified single-nucleotide polymorphisms that are associated with electrocardiogram measures. We performed a genome-wide association study using Korea Association Resource data for the discovery phase (Phase 1, n = 6805) and two consecutive replication studies in Japanese populations (Phase 2, n = 2285; Phase 3, n = 5010) for QRS duration and PR interval. Three novel loci were identified: rs2483280 (PRDM16 locus) and rs335206 (PRDM6 locus) were associated with QRS duration, and rs17026156 (SLC8A1 locus) correlated with PR interval. PRDM16 was recently identified as a causative gene of left ventricular non-compaction and dilated cardiomyopathy in 1p36 deletion syndrome, which is characterized by heart failure, arrhythmia and sudden cardiac death. Thus, our finding that a PRDM16 SNP is linked to QRS duration strongly implicates PRDM16 in cardiac function. In addition, C allele of rs17026156 increases PR interval (beta +/- SE, 2.39 +/- 0.40 ms) and exists far more frequently in East Asians (0.46) than in Europeans and Africans (0.05 and 0.08, respectively). PMID- 25035419 TI - Phosphorodiamidate morpholino oligomers suppress mutant huntingtin expression and attenuate neurotoxicity. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Disease pathogenesis derives, at least in part, from the long polyglutamine tract encoded by mutant HTT. Therefore, considerable effort has been dedicated to the development of therapeutic strategies that significantly reduce the expression of the mutant HTT protein. Antisense oligonucleotides (ASOs) targeted to the CAG repeat region of HTT transcripts have been of particular interest due to their potential capacity to discriminate between normal and mutant HTT transcripts. Here, we focus on phosphorodiamidate morpholino oligomers (PMOs), ASOs that are especially stable, highly soluble and non-toxic. We designed three PMOs to selectively target expanded CAG repeat tracts (CTG22, CTG25 and CTG28), and two PMOs to selectively target sequences flanking the HTT CAG repeat (HTTex1a and HTTex1b). In HD patient derived fibroblasts with expanded alleles containing 44, 77 or 109 CAG repeats, HTTex1a and HTTex1b were effective in suppressing the expression of mutant and non-mutant transcripts. CTGn PMOs also suppressed HTT expression, with the extent of suppression and the specificity for mutant transcripts dependent on the length of the targeted CAG repeat and on the CTG repeat length and concentration of the PMO. PMO CTG25 reduced HTT-induced cytotoxicity in vitro and suppressed mutant HTT expression in vivo in the N171-82Q transgenic mouse model. Finally, CTG28 reduced mutant HTT expression and improved the phenotype of Hdh(Q7/Q150) knock-in HD mice. These data demonstrate the potential of PMOs as an approach to suppressing the expression of mutant HTT. PMID- 25035421 TI - New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. AB - Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knockin mice (here Braf(Q241R/+)) expressing the Braf Q241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf(Q241R/+) mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf(Q241R/+) embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knockin mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf(Q241R/+) embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new Braf knockin mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome. PMID- 25035422 TI - Lhx1 maintains synchrony among circadian oscillator neurons of the SCN. AB - The robustness and limited plasticity of the master circadian clock in the suprachiasmatic nucleus (SCN) is attributed to strong intercellular communication among its constituent neurons. However, factors that specify this characteristic feature of the SCN are unknown. Here, we identified Lhx1 as a regulator of SCN coupling. A phase-shifting light pulse causes acute reduction in Lhx1 expression and of its target genes that participate in SCN coupling. Mice lacking Lhx1 in the SCN have intact circadian oscillators, but reduced levels of coupling factors. Consequently, the mice rapidly phase shift under a jet lag paradigm and their behavior rhythms gradually deteriorate under constant condition. Ex vivo recordings of the SCN from these mice showed rapid desynchronization of unit oscillators. Therefore, by regulating expression of genes mediating intercellular communication, Lhx1 imparts synchrony among SCN neurons and ensures consolidated rhythms of activity and rest that is resistant to photic noise. PMID- 25035424 TI - The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy. AB - The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart. PMID- 25035423 TI - Concerning RNA-guided gene drives for the alteration of wild populations. AB - Gene drives may be capable of addressing ecological problems by altering entire populations of wild organisms, but their use has remained largely theoretical due to technical constraints. Here we consider the potential for RNA-guided gene drives based on the CRISPR nuclease Cas9 to serve as a general method for spreading altered traits through wild populations over many generations. We detail likely capabilities, discuss limitations, and provide novel precautionary strategies to control the spread of gene drives and reverse genomic changes. The ability to edit populations of sexual species would offer substantial benefits to humanity and the environment. For example, RNA-guided gene drives could potentially prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species. However, the possibility of unwanted ecological effects and near-certainty of spread across political borders demand careful assessment of each potential application. We call for thoughtful, inclusive, and well-informed public discussions to explore the responsible use of this currently theoretical technology. PMID- 25035425 TI - Lipase maturation factor 1 (lmf1) is induced by endoplasmic reticulum stress through activating transcription factor 6alpha (Atf6alpha) signaling. AB - Lipase maturation factor 1 (Lmf1) is a critical determinant of plasma lipid metabolism, as demonstrated by severe hypertriglyceridemia associated with its mutations in mice and human subjects. Lmf1 is a chaperone localized to the endoplasmic reticulum (ER) and required for the post-translational maturation and activation of several vascular lipases. Despite its importance in plasma lipid homeostasis, the regulation of Lmf1 remains unexplored. We report here that Lmf1 expression is induced by ER stress in various cell lines and in tunicamycin (TM) injected mice. Using genetic deficiencies in mouse embryonic fibroblasts and mouse liver, we identified the Atf6alpha arm of the unfolded protein response as being responsible for the up-regulation of Lmf1 in ER stress. Experiments with luciferase reporter constructs indicated that ER stress activates the Lmf1 promoter through a GC-rich DNA sequence 264 bp upstream of the transcriptional start site. We demonstrated that Atf6alpha is sufficient to induce the Lmf1 promoter in the absence of ER stress, and this effect is mediated by the TM responsive cis-regulatory element. Conversely, Atf6alpha deficiency induced by genetic ablation or a dominant-negative form of Atf6alpha abolished TM stimulation of the Lmf1 promoter. In conclusion, our results indicate that Lmf1 is an unfolded protein response target gene, and Atf6alpha signaling is sufficient and necessary for activation of the Lmf1 promoter. Importantly, the induction of Lmf1 by ER stress appears to be a general phenomenon not restricted to lipase-expressing cells, which suggests a lipase-independent cellular role for this protein in ER homeostasis. PMID- 25035426 TI - Requirements for pseudosubstrate arginine residues during autoinhibition and phosphatidylinositol 3,4,5-(PO4)3-dependent activation of atypical PKC. AB - Atypical PKC (aPKC) isoforms are activated by the phosphatidylinositol 3-kinase product phosphatidylinositol 3,4,5-(PO4)3 (PIP3). How PIP3 activates aPKC is unknown. Although Akt activation involves PIP3 binding to basic residues in the Akt pleckstrin homology domain, aPKCs lack this domain. Here we examined the role of basic arginine residues common to aPKC pseudosubstrate sequences. Replacement of all five (or certain) arginine residues in the pseudosubstrate sequence of PKC iota by site-directed mutagenesis led to constitutive activation and unresponsiveness to PIP3 in vitro or insulin in vivo. However, with the addition of the exogenous arginine-containing pseudosubstrate tridecapeptide to inhibit this constitutively active PKC-iota, PIP3-activating effects were restored. A similar restoration of responsiveness to PIP3 was seen when exogenous pseudosubstrate was used to inhibit mouse liver PKC-lambda/zeta maximally activated by insulin or ceramide and a truncated, constitutively active PKC-zeta mutant lacking all regulatory domain elements and containing "activating" glutamate residues at loop and autophosphorylation sites (Delta1-247/T410E/T560E PKC-zeta). NMR studies suggest that PIP3 binds directly to the pseudosubstrate. The ability of PIP3 to counteract the inhibitory effects of the exogenous pseudosubstrate suggests that basic residues in the pseudosubstrate sequence are required for maintaining aPKCs in an inactive state and are targeted by PIP3 for displacement from the substrate-binding site during kinase activation. PMID- 25035427 TI - Identification of the docking site between a type III secretion system ATPase and a chaperone for effector cargo. AB - A number of Gram-negative pathogens utilize type III secretion systems (T3SSs) to inject bacterial effector proteins into the host. An important component of T3SSs is a conserved ATPase that captures chaperone-effector complexes and energizes their dissociation to facilitate effector translocation. To date, there has been limited work characterizing the chaperone-T3SS ATPase interaction despite it being a fundamental aspect of T3SS function. In this study, we present the 2.1 A resolution crystal structure of the Salmonella enterica SPI-2-encoded ATPase, SsaN. Our structure revealed a local and functionally important novel feature in helix 10 that we used to define the interaction domain relevant to chaperone binding. We modeled the interaction between the multicargo chaperone, SrcA, and SsaN and validated this model using mutagenesis to identify the residues on both the chaperone and ATPase that mediate the interaction. Finally, we quantified the benefit of this molecular interaction on bacterial fitness in vivo using chromosomal exchange of wild-type ssaN with mutants that retain ATPase activity but no longer capture the chaperone. Our findings provide insight into chaperone recognition by T3SS ATPases and demonstrate the importance of the chaperone-T3SS ATPase interaction for the pathogenesis of Salmonella. PMID- 25035428 TI - Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs. AB - The transient receptor potential vanilloid 1 (TRPV1) ion channel is a polymodal protein that responds to various stimuli, including capsaicin (the pungent compound found in chili peppers), extracellular acid, and basic intracellular pH, temperatures close to 42 degrees C, and several lipids. Lysophosphatidic acid (LPA), an endogenous lipid widely associated with neuropathic pain, is an agonist of the TRPV1 channel found in primary afferent nociceptors and is activated by other noxious stimuli. Agonists or antagonists of lipid and other chemical natures are known to possess specific structural requirements for producing functional effects on their targets. To better understand how LPA and other lipid analogs might interact and affect the function of TRPV1, we set out to determine the structural features of these lipids that result in the activation of TRPV1. By changing the acyl chain length, saturation, and headgroup of these LPA analogs, we established strict requirements for activation of TRPV1. Among the natural LPA analogs, we found that only LPA 18:1, alkylglycerophosphate 18:1, and cyclic phosphatidic acid 18:1, all with a monounsaturated C18 hydrocarbon chain activate TRPV1, whereas polyunsaturated and saturated analogs do not. Thus, TRPV1 shows a more restricted ligand specificity compared with LPA G-protein-coupled receptors. We synthesized fatty alcohol phosphates and thiophosphates and found that many of them with a single double bond in position Delta9, 10, or 11 and Delta9 cyclopropyl group can activate TRPV1 with efficacy similar to capsaicin. Finally, we developed a pharmacophore and proposed a mechanistic model for how these lipids could induce a conformational change that activates TRPV1. PMID- 25035429 TI - Giant virus Megavirus chilensis encodes the biosynthetic pathway for uncommon acetamido sugars. AB - Giant viruses mimicking microbes, by the sizes of their particles and the heavily glycosylated fibrils surrounding their capsids, infect Acanthamoeba sp., which are ubiquitous unicellular eukaryotes. The glycans on fibrils are produced by virally encoded enzymes, organized in gene clusters. Like Mimivirus, Megavirus glycans are mainly composed of virally synthesized N-acetylglucosamine (GlcNAc). They also contain N-acetylrhamnosamine (RhaNAc), a rare sugar; the enzymes involved in its synthesis are encoded by a gene cluster specific to Megavirus close relatives. We combined activity assays on two enzymes of the pathway with mass spectrometry and NMR studies to characterize their specificities. Mg534 is a 4,6-dehydratase 5-epimerase; its three-dimensional structure suggests that it belongs to a third subfamily of inverting dehydratases. Mg535, next in the pathway, is a bifunctional 3-epimerase 4-reductase. The sequential activity of the two enzymes leads to the formation of UDP-l-RhaNAc. This study is another example of giant viruses performing their glycan synthesis using enzymes different from their cellular counterparts, raising again the question of the origin of these pathways. PMID- 25035430 TI - Innexin AGAP001476 is critical for mediating anti-Plasmodium responses in Anopheles mosquitoes. AB - The Toll and IMD pathways are known to be induced upon Plasmodium berghei and Plasmodium falciparum infection, respectively. It is unclear how Plasmodium or other pathogens in the blood meal and their invasion of the midgut epithelium would trigger the innate immune responses in immune cells, in particular hemocytes. Gap junctions, which can mediate both cell-to-cell and cell-to extracellular communication, may participate in this signal transduction. This study examined whether innexins, gap junction proteins in insects, are involved in anti-Plasmodium responses in Anopheles gambiae. Inhibitor studies using carbenoxolone indicated that blocking innexons resulted in an increase in Plasmodium oocyst number and infection prevalence. This was accompanied by a decline in TEP1 levels in carbenoxolone-treated mosquitoes. Innexin AGAP001476 mRNA levels in midguts were induced during Plasmodium infection and a knockdown of AGAP001476, but not AGAP006241, caused an induction in oocyst number. Silencing AGAP001476 caused a concurrent increase in vitellogenin levels, a TEP1 inhibitor, in addition to a reduced level of TEP1-LRIM1-APL1C complex in hemolymph. Both vitellogenin and TEP1 are regulated by Cactus under the Toll pathway. Simultaneous knockdown of cactus and AGAP001476 failed to reverse the near refractoriness induced by the knockdown of cactus, suggesting that the AGAP001476-mediated anti-Plasmodium response is Cactus-dependent. These data demonstrate a critical role for innexin AGAP001476 in mediating innate immune responses against Plasmodium through Toll pathway in mosquitoes. PMID- 25035432 TI - An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression. AB - STUDY QUESTION: Is the decreased natural killer (NK) cell cytolytic activity in the peritoneal fluid (PF) of endometriosis patients due to primary cytokine activity? SUMMARY ANSWER: An increased level of interleukin-6 (IL-6) in the PF of patients with endometriosis suppresses NK cell cytolytic activity by down regulating cytolytic granule components, such as granzyme B and perforin, through the modulation of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) expression. WHAT IS ALREADY KNOWN: Endometriosis is known to be related to a defect in NK cell cytolytic activity. Additionally, the levels of inflammatory cytokines are elevated in the PF of women with endometriosis. STUDY DESIGN, SIZE, DURATION: The effects of PF on the differentiation and functional activity of NK cells were investigated in patients with or without endometriosis, and cytokines that reduce NK cell cytolytic activity in endometriosis patients were examined. The study included women who underwent laparoscopic examination for the diagnosis of endometriosis from August 2012 to July 2013 (33 women with, and 15 women without, endometriosis). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women of reproductive age (20-40 years old) who underwent laparoscopic examination for endometriosis were included. Cytokines present in the PF were identified by enzyme-linked immunosorbent assay. The cytolytic activity of NK cells in the PF was also analyzed using a calcein-acetoxy methyl ester (AM) release assay. MAIN RESULTS AND THE ROLE OF CHANCE: PF from patients with endometriosis suppressed the differentiation and cytotoxicity of NK cells compared with PF from controls (P < 0.05). Increased levels of IL-6 were also found in the PF of patients with endometriosis (P < 0.01), and IL-6 levels were negatively correlated with the cytolytic activity of NK cells (rs = -0.558, P = 0.03). Furthermore, IL-6 reduced the cytolytic activity of NK cells, concomitantly with the down-regulation of granzyme B and perforin (P < 0.05), by modulating SHP-2. Importantly, the addition of anti-IL-6 to the PF of endometriosis patients restored the activity of NK cells (P < 0.01), suggesting that IL-6 plays a crucial role in the reduction of NK cell activity in the PF of patients with endometriosis. LIMITATIONS, REASONS FOR CAUTION: PF contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the differentiation and activity of NK cells. WIDER IMPLICATIONS OF THE FINDINGS: Our results imply that the suppression of IL-6 using an anti-IL-6 antibody or soluble IL-6 receptor could rescue the impairment of NK cell activity in patients with endometriosis. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the KRIBB Creative Research Program (KCS3051312); the STP project (DTM0111221) of the Ministry of Knowledge & Economy and the Basic Science Research Program (RBM0271312) of the National Research Foundation of Korea (NRF) from the Ministry of Education, Science & Technology. There are no conflicts of interest. PMID- 25035431 TI - FUN26 (function unknown now 26) protein from saccharomyces cerevisiae is a broad selectivity, high affinity, nucleoside and nucleobase transporter. AB - Equilibrative nucleoside transporters (ENTs) are polytopic integral membrane proteins that transport nucleosides and, to a lesser extent, nucleobases across cell membranes. ENTs modulate efficacy for a range of human therapeutics and function in a diffusion-controlled bidirectional manner. A detailed understanding of ENT function at the molecular level has remained elusive. FUN26 (function unknown now 26) is a putative ENT homolog from S. cerevisiae that is expressed in vacuole membranes. In the present system, proteoliposome studies of purified FUN26 demonstrate robust nucleoside and nucleobase uptake into the luminal volume for a broad range of substrates. This transport activity is sensitive to nucleoside modifications in the C(2')- and C(5')-positions on the ribose sugar and is not stimulated by a membrane pH differential. [(3)H]Adenine nucleobase transport efficiency is increased ~4-fold relative to nucleosides tested with no observed [(3)H]adenosine or [(3)H]UTP transport. FUN26 mutational studies identified residues that disrupt (G463A or G216A) or modulate (F249I or L390A) transporter function. These results demonstrate that FUN26 has a unique substrate transport profile relative to known ENT family members and that a purified ENT can be reconstituted in proteoliposomes for functional characterization in a defined system. PMID- 25035433 TI - Quality control of training and performance in embryo transfer: time to broadcast LC CUSUM and CUSUM tests. PMID- 25035434 TI - Indices of methylation in sperm DNA from fertile men differ between distinct geographical regions. AB - STUDY QUESTION: Which are the main determinants, if any, of sperm DNA methylation levels? SUMMARY ANSWER: Geographical region resulted associated with the sperm methylation status assessed on genome-wide repetitive sequences. WHAT IS KNOWN ALREADY: DNA methylation level, assessed on repetitive sequences from peripheral blood lymphocyte, can vary with age, gender, alcohol consumption and white blood cell counts. STUDY DESIGN, SIZE, DURATION: A cross-sectional study. Individual data were collected from 269 young healthy men of proven fertility living in three geographical regions: Inuits from Greenland, Caucasians from Warsaw (Poland) and Kharkiv (Ukraine). Semen samples were collected between May 2002 and February 2004 and aliquots were immediately frozen. PARTICIPANTS/MATERIALS, SETTING, METHODS: We estimated sperm DNA global methylation level (DGML) in two ways. First DNA methylation in repetitive DNA sequences (LINE-1, Satalpha and Alu) was quantified by PCR pyrosequencing after bisulfite conversion and second by flow cytometry (FCM) using fluorescently labeled monoclonal antibodies anti-5 methylcytosine. We analyzed whether personal characteristics and habits, body mass index, semen quality parameters, sperm chromatin integrity, biomarkers of accessory gland function and the plasma concentration of reproductive hormones were associated with sperm DNA methylation levels in men. Associations were evaluated by analysis of variance and linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The geographical location emerged as the main determinant when using the methylation level in repetitive sequences. FCM DGML results were not associated with those from repetitive sequence analysis. No other consistent associations between methylation markers and the assessed variables were identified across countries. LIMITATIONS, REASONS FOR CAUTION: The methods used are only surrogates of the actual sperm methylome and the methylation levels at individual specific loci were not explored. WIDER IMPLICATIONS OF THE FINDINGS: Sperm DGML is relatively independent from semen quality parameters and is a new candidate biomarker for epidemiological studies of the impact of environmental contaminants on male fertility. STUDY FUNDING/COMPETING INTERESTS: The study is part of the project CLEAR (Climate change, Environmental contaminants and Reproductive health) supported by the European Commission 7th framework program, contract no: FP7-ENV-2008-1-226217. No competing interest is declared. PMID- 25035435 TI - Association of inflammation markers with menstrual symptom severity and premenstrual syndrome in young women. AB - STUDY QUESTION: Are markers of chronic inflammation associated with menstrual symptom severity and premenstrual syndrome (PMS)? SUMMARY ANSWER: Serum levels of inflammatory markers, including interleukin (IL)-2, IL-4, IL-10, IL-12 and interferon (IFN)-gamma were positively associated with menstrual symptom severity and/or PMS in young women. WHAT IS KNOWN ALREADY: Chronic inflammation has been implicated in the etiology of depression and other disorders that share common features with PMS, but whether inflammation contributes to menstrual symptom severity and PMS is unknown. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 277 women aged 18-30 years, conducted in 2006-2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants provided information on menstrual symptoms, lifestyle, diet, anthropometry and other factors by questionnaire and/or direct measurement, and a mid-luteal phase fasting blood sample was taken between 7 a.m. and 12 p.m. Total, physical and affective menstrual symptom scores were calculated for all participants, of whom 13% (n = 37) met criteria for moderate to-severe PMS and 24% (n = 67) met PMS control criteria. Inflammatory factors assayed in serum included IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL 12p70, IL-13, tumor necrosis factor-alpha, granulocyte macrophage colony stimulating factor, IFN-gamma and C-reactive protein. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age, smoking status and BMI, total menstrual symptom score was positively associated with levels of IL-2 (percentage difference in women at the 75th percentile of total symptom score versus at the 25th percentile = 24.7%; P = 0.04), IL-4 (21.5%; P = 0.04), IL-10 (28.0%; P < 0.01) and IL-12 (42.0%; P = 0.02) in analyses including all participants. Affective menstrual symptom score was linearly related to levels of IL-2 (percentage difference at 75th percentile versus 25th percentile = 31.0%; P = 0.02), while physical/behavioral symptom score was linearly related to levels of IL-4 (19.1%; P = 0.03) and IL-12 (33.2%; P = 0.03). Additionally, mean levels of several factors were significantly higher in women meeting PMS criteria compared with women meeting control criteria, including IL-4 (92% higher in cases versus controls; P = 0.01); IL-10 (87%; P = 0.03); IL-12 (170%; P = 0.04) and IFN-gamma (158%; P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Our study has several limitations. While a single blood sample may not perfectly capture long-term levels of inflammation, ample data suggest that levels of cytokines are stable over time. Although we did not base our assessment of PMS on prospective symptom diaries, we used validated criteria to define PMS cases and controls, and excluded women with evidence of comorbid mood disorders. Furthermore, because of the cross-sectional design of the study, the temporal relation of inflammatory factors and menstrual symptoms is unclear. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is among the first studies to suggest that inflammatory factors may be elevated in women experiencing menstrual symptoms and PMS. Additional studies are needed to determine whether inflammation plays an etiologic role in PMS. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Departments of Public Health and Nutrition and by a Faculty Research Grant, University of Massachusetts Amherst. No conflicts declared. TRIAL REGISTRATION NUMBER: N/A. PMID- 25035436 TI - Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk. AB - STUDY QUESTION: Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? SUMMARY ANSWER: Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. WHAT IS KNOWN ALREADY: Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. STUDY DESIGN, SIZE, DURATION: This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 ug/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with logVF and IAUC. ccIMT was not related to logVF. The relationships between e':a' or aPWV and insulin resistance were only partly attenuated by adjusting for logVF. There was no significant relationship between aPWV or e':a' and either testosterone or adiponectin. LIMITATIONS, REASONS FOR CAUTION: The study recruited young women meeting the Rotterdam criteria for PCOS diagnosis; hence our findings may not be generalizable to older patients or those meeting other definitions of the syndrome. Biochemical hyperandrogenism was based solely on measurement of total testosterone. Cases and controls were not matched in advance for age and BMI, although the influence of these variables on the cardiovascular outcome measures was adjusted for. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that central arterial stiffness and diastolic dysfunction are not increased in young women with PCOS, whereas they are associated with both insulin resistance and central obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. STUDY FUNDING/COMPETING INTERESTS: This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare. PMID- 25035437 TI - IVF culture media: past, present and future. AB - BACKGROUND: The advances in the world of IVF during the last decades have been rapid and impressive and culture media play a major role in this success. Until the 1980s fertility centers made their media in house. Nowadays, there are numerous commercially available culture media that contain various components including nutrients, vitamins and growth factors. This review goes through the past, present and future of IVF culture media and explores their composition and quality assessment. METHODS: A computerized search was performed in PubMed regarding IVF culture media including results from 1929 until March 2014. Information was gathered from the websites of companies who market culture media, advertising material, instructions for use and certificates of analysis. The regulation regarding IVF media mainly in the European Union (EU) but also in non European countries was explored. RESULTS: The keyword 'IVF culture media' gave 923 results in PubMed and 'embryo culture media' 12 068 results dating from 1912 until March 2014, depicting the increased scientific activity in this field. The commercialization of IVF culture media has increased the standards bringing a great variety of options into clinical practice. However, it has led to reduced transparency and comparisons of brand names that do not facilitate the scientific dialogue. Furthermore, there is some evidence suggesting that suboptimal culture conditions could cause long-term reprogramming in the embryo as the periconception period is particularly susceptible to epigenetic alterations. IVF media are now classified as class III medical devices and only CE (Conformite Europeene)-marked media should be used in the EU. CONCLUSION: The CE marking of IVF culture media is a significant development in the field. However, the quality and efficiency of culture media should be monitored closely. Well-designed randomized controlled trials, large epidemiological studies and full transparency should be the next steps. Reliable, standardized models assessing multiple end points and post-implantation development should replace the mouse embryo assay. Structured long-term follow-up of children conceived by assisted reproduction technologies and traceability are of paramount importance. PMID- 25035438 TI - Clinical outcomes following selection of human preimplantation embryos with time lapse monitoring: a systematic review. PMID- 25035439 TI - Thoracic epidural anaesthesia for awake thoracic surgery in severely dyspnoeic patients excluded from general anaesthesia. AB - OBJECTIVES: General anaesthesia (GA) carries high risks of ventilator dependency with increased morbidity and mortality in patients with severe respiratory disease. It also presents an ethical dilemma if surgery remains the only treatment option for patients with advanced terminal chronic respiratory disease. Thoracic epidural anaesthesia for awake thoracic surgery (TEATS) in high-risk patients with dyspnoea at rest could avoid ventilator dependency and speed up recovery even in patients with severe dyspnoea. This retrospective observational study analysed indications, management and outcome of patients contraindicated to GA undergoing awake thoracic surgery with thoracic epidural anaesthesia. METHODS: From 716 patients requiring thoracic surgery, nine were contraindicated to GA. Eight patients [American Society of Anesthesiologists (ASA) 4] had a maximum grade four of the modified Medical Research Council dyspnea scale (MMRC). Two patients (ASA 3, grade 1 MMRC and ASA 4, grade 4 MMRC) refused GA. RESULTS: Patients (female : male ratio 1.25 : 1, age 19-76 years) had the following chronic respiratory diseases: pulmonary fibrosis (n = 2), pulmonary metastases (n = 3), chronic obstructive pulmonary disease (n = 1), alveolitis (n = 1) and myopathy (n = 2). Surgical indications were: thoracotomy (n = 6) for pleurectomy to treat recurring pneumothorax (n = 3), pleurostomy (n = 1), emphysema surgery (n = 1), lung biopsy (n = 1) and thoracoscopy (n = 3) for pleural/lung biopsy (n = 2), pneumothorax (n = 1). Lidocaine 20 mg/ml or ropivacaine 7.5 mg/ml was titrated to achieve an anaesthesia level T2-T12. No patient required GA [time of surgery: 46-128 min, mean = 76 min, standard deviation (SD) = 23 min]. Seven patients had light sedation with TCI propofol, remifentanyl or both and remained responsive. Fifty percent of patients received phenylephrine or ephedrine to maintain arterial pressure. Two patients went into hypercapnia, which was reversed with assisted mask ventilation. One patient suffered acute respiratory distress 7 days postoperatively and died of intestinal bleeding on Day 25. There were no postoperative complications in other patients. Excluding Patient 9 always remaining in a medical intensive care unit (ICU), the mean postoperative ICU stay in thoracic surgery was 4.4 days (SD 5.2). Hospital discharge was between 5 and 40 days after surgery. CONCLUSIONS: TEATS with/without sedation was an alternative to GA for thoracotomy/thoracoscopy in severely dyspnoeic patients (MMRC grade 4, ASA 4) without postoperative sequelae. PMID- 25035440 TI - Role of psychotherapy in managing a case of generalised aggressive periodontitis. AB - Generalised aggressive periodontitis is characterised by "generalized interproximal attachment loss affecting at least three permanent teeth other than first molars and incisors." The management of generalised aggressive periodontitis is challenging as it involves an interdisciplinary approach. When the patient presents himself late to the clinician, the tooth and bone loss can be up to 60%. Natural teeth and alveolar bone contribute to the contour and aesthetics of the face. Loss of teeth in younger age may lead to attitude, behaviour changes and may cause psychological depression and withdrawal from society. The main distinguishing feature of this case report is the psychological counselling provided along with periodontal and prosthetic treatment. PMID- 25035441 TI - Lower urinary tract symptoms: thinking beyond the urinary tract. AB - We present a case of a 54-year-old man with progressive lower urinary tract symptoms over 12 months. Physical examination, urinalysis, serum biochemistry and ultrasound of the renal tract were all unremarkable. Flexible cystoscopy was normal. Urodynamic assessment revealed an overactive bladder of unknown aetiology. The patient went on to have an MRI of the lumbosacral spine which showed a spinal cord tumour of the conus medullaris. The patient underwent a laminectomy and resection of the tumour. Histology showed myxopapillary ependymoma of the spinal cord. This case highlights the need to consider the full spectrum of causes, urological and non-urological, in assessing a patient with voiding dysfunction. PMID- 25035442 TI - Ortner's syndrome: a case report and review of the literature. AB - We present a case of a 67-year-old man who was an active smoker, with a clinical history of ischaemic cardiopathy, hypertension, who presented to the emergency room with hoarseness of voice of 2 weeks duration. No other neurological or cardiorespiratory symptoms were found. Physical examination revealed an aortic regurgitation murmur with radial pulse difference between the upper limbs and femoral pulse difference on lower limbs. Laryngoscopy examination revealed a left vocal cord paralysis in the paramedian position, without signs of malignancy. Thoracoabdominal CT angiography was performed to rule out an aortic dissection. CT revealed a dissection in the descending thoracic aortic arch and abdominal aorta. Cardiovascular surgery was consulted and decided to place endoprosthesis at the thoracic and abdominal aortic area. Hoarseness eventually resolved during the following weeks. Ortner's syndrome is described as hoarseness of voice caused by compression of the left recurrent laryngeal nerve of cardiovascular origin. PMID- 25035443 TI - Confirmed viral meningitis with normal CSF findings. AB - An 18-year-old woman presented with a progressively worsening headache, photophobia feverishness and vomiting. Three weeks previously she had returned to the UK from a trip to Peru. At presentation, she had clinical signs of meningism. On admission, blood tests showed a mild lymphopenia, with a normal C reactive protein and white cell count. Chest X-ray and CT of the head were normal. Cerebrospinal fluid (CSF) microscopy was normal. CSF protein and glucose were in the normal range. MRI of the head and cerebral angiography were also normal. Subsequent molecular testing of CSF detected enterovirus RNA by reverse transcriptase PCR. The patient's clinical syndrome correlated with her virological diagnosis and no other cause of her symptoms was found. Her symptoms were self-limiting and improved with supportive management. This case illustrates an important example of viral central nervous system infection presenting clinically as meningitis but with normal CSF microscopy. PMID- 25035444 TI - Andrew's bridge system: an aesthetic and functional option for rehabilitation of compromised maxillary anterior dentition. AB - Summary A patient with several missing teeth in the anterior aesthetic region along with severe ridge defect poses a greater challenge for prosthodontic rehabilitation. In such cases treatment using fixed partial denture (FPD) may not be feasible because of the extent of edentulous span and the periodontal conditions of the abutment teeth. To present a case of multiple missing maxillary anterior teeth with class III ridge defect rehabilitated using FPD-removable partial denture. A 38-year-old female patient was successfully rehabilitated using Andrew's bridge system in the maxillary anterior region. The fixed removable Andrew's bridge system provides a good prognosis if diagnosed and planned meticulously. PMID- 25035445 TI - Hepatogastric fistula: a rare complication of pyogenic liver abscess. AB - Hepatogastric fistula is very rare. We report a case of hepatogastric fistula as a complication of pyogenic liver abscess. A 40-year-old man presented with upper abdominal pain and high-grade fever of 2 weeks. Evaluation revealed multiple liver abscesses. On an empirical diagnosis of pyogenic liver abscess, he was treated with antibiotics. During hospital stay he developed intermittent large quantity bilious vomiting. Gastroduodenoscopy and contrast-enhanced CT of the abdomen showed rupture of left lobe liver abscess into the stomach. As expectant management failed to resolve the abscess, endoscopic retrograde papillotomy and stenting of common bile duct was performed. After endoscopic stenting, symptoms subsided. Imaging repeated after 2 weeks of endoscopic stenting showed resolving abscess. He was discharged and is doing well on regular follow-ups. We conclude that hepatogastric fistula can be managed by endoscopic stenting as bile flow through the stent hastens resolution and healing of the fistula. PMID- 25035446 TI - Successful treatment of calciphylaxis by a multidisciplinary approach. AB - A 48-year-old woman performing peritoneal dialysis for end-stage renal disease presented with a painful leg ulcer. The investigation revealed an elevated parathyroid hormone level and the histological examination of the biopsy tissue from the ulcer revealed medial calcification of the arterioles, consistent with calciphylaxis. The patient developed additional ulcers in the lower limbs and treatment with antibiotics, cinacalcet, sevelamer, sodium thiosulfate, low calcium dialysate and hyperbaric oxygen therapy was instituted. The patient had a favourable outcome and after 9 months the ulcers had healed and the parathyroid hormone level reached the normal range. Calciphylaxis is a rare and life threatening disorder associated with a mortality of 60-80%. Its pathogenesis is not fully understood hence there is no consensus in the treatment of this pathology. PMID- 25035447 TI - Mediastinal widening and miliary chest radiograph pattern in a middle aged man: could it be sarcoidosis? AB - A diagnosis of sarcoidosis is based on suggestive radiographic pattern, presence of non-caseating granulomas and negative fungal and acid-fast bacilli (AFB) cultures. Sarcoidosis usually presents with hilar and/or mediastinal lymphadenopathy and distinct parenchymal radiographic patterns, such as fine nodular, reticulonodular or acinar opacities and rarely focal nodules or masses. A diffuse miliary pattern occurs in less than 1% of cases and can be identical to patterns seen in tuberculosis, fungal infections, histiocytosis and miliary metastases. Here the authors report the case of a 48-year-old man who presented with mediastinal widening and miliary pattern on chest radiograph, initially erroneously treated for tuberculosis. Transbronchial biopsies, bronchoalveolar lavage (BAL) and serological tests were compatible with sarcoidosis, while BAL cultures were negative for fungi and AFB growth. The patient finally demonstrated clinical and radiological remission under corticosteroids. Clinicians should consider sarcoidosis in the differential diagnosis when bilateral miliary-type lesions are revealed on chest X-ray. PMID- 25035449 TI - Decidualised fallopian tube endometriotic implant causing spontaneous haemoperitoneum in a twin pregnancy. AB - Spontaneous haemoperitoneum in pregnancy (SHiP) is a rare but serious condition associated with an adverse pregnancy outcome. We present a case of previable twin pregnancy presenting with SHiP secondary to endometriosis, necessitating an emergency laparotomy and hysterotomy as a life-saving measure to achieve haemostasis. At laparotomy there was massive haemoperitoneum with active bleeding from the left fallopian tube and a left salpingectomy was performed. Histological examination showed haemorrhagic foci of endometriosis on the fallopian tube exhibiting florid stromal decidual change. We wish to raise awareness of this uncommon but potentially life-threatening condition requiring early recognition and prompt recourse to surgical intervention to minimise the morbidity and mortality. PMID- 25035450 TI - Cytomegalovirus pouchitis in a patient with Crohn's disease. AB - Colectomy with ileoanal pouch formation is usually contraindicated in patients with Crohn's disease (CD) due to the risk of recurrent disease and pouch failure. We report the case of a patient, initially thought to have ulcerative colitis (UC), who underwent such surgery but subsequently developed perianal CD. She presented with diarrhoea and weight loss. Inflammatory markers were raised. Pouchoscopy revealed deep ulcers within the pouch. The main differential diagnoses were idiopathic pouchitis and recurrent CD. However, immunohistochemical staining demonstrated positivity for cytomegalovirus (CMV). Stool frequency, C reactive protein and albumin normalised within 48 h of starting oral valgancyclovir. At 15 weeks, pouch appearances were improved, no histological evidence of CMV was found and baseline pouch function had returned. This case highlights that CD can present many years after surgery for apparent UC. Also, CMV pouchitis should be considered as a differential cause of pouchitis especially as it is treatable with antiviral therapy. PMID- 25035451 TI - ACE inhibitors: upper respiratory symptoms. AB - Cough and angioedema are well-known adverse reactions of ACE inhibitors. However, other adverse effects of upper airways such as postnasal drainage, rhinitis and nasal blockage, are less frequently recognised. These might share the same pathophysiological mechanism: bradykinin accumulation. We present two patients with ACE inhibitor-induced upper respiratory symptoms that improved after the discontinuation of ACE-inhibitors and substitution with angiotensin II receptor blockers. The incidence of these adverse events is not accurately known, since these are not required to be reported, but it is estimated to be low. This presents challenges to the physician and demonstrates the importance of keeping it as a differential diagnosis. Most physicians are aware of ACE inhibitor induced cough but not of ACE inhibitor-induced nasal blockage, rhinitis or postnasal drainage. Identifying these can avoid unnecessary diagnostic tests and inappropriate treatment. PMID- 25035452 TI - Hantavirus: an infectious cause of acute kidney injury in the UK. AB - We present a case of an undifferentiated febrile illness in a 59-year-old man from East Yorkshire. He was initially treated for leptospirosis due to the fact that he had farm exposure and the findings of acute kidney injury (AKI), thrombocytopenia and a raised alanine transferase (ALT) on his initial blood results. Serology tests later proved him to have had another rodent-borne illness: hantavirus. An investigation by Public Health England (formerly known as Health Protection Agency) (PHE) went on to prove the presence of the same serotype of hantavirus in rats caught on the patient's property. After an initial deterioration, the patient made a relatively uneventful recovery and all his blood tests returned to normal levels. PMID- 25035453 TI - From prednisone to pylori: a case of Helicobacter pylori-induced chronic immune thrombocytopenia. AB - A 54-year-old woman was seen by her primary care internist for a general health maintenance visit. Her major chronic illness was immune thrombocytopenic purpura (ITP) for which she had been treated with prednisone therapy for the past 15 years. Recent review of possible aetiologies of her chronic thrombocytopenia revealed infection with Helicobacter pylori. Successful eradication resulted in complete resolution of her thrombocytopenia within 2 months. She was weaned from steroid therapy and at 1-year follow-up, her platelet counts remained in the normal range. This case report summarises what is known about the association of H. pylori infection and ITP. PMID- 25035455 TI - Love, sex, and aging. PMID- 25035462 TI - Science advocacy, defined. PMID- 25035464 TI - Lab safety. Alarm over biosafety blunders. PMID- 25035465 TI - Research grants. A radical change in peer review. PMID- 25035454 TI - Disentangling the disabling process: insights from the precipitating events project. AB - Among older persons, disability in activities of daily living is common and highly morbid. The Precipitating Events Project (PEP Study), an ongoing longitudinal study of 754 initially nondisabled, community-living persons, aged 70 or older, was designed to further elucidate the epidemiology of disability, with the goal of informing the development of effective interventions to maintain and restore independent function. Over the past 16 years, participants have completed comprehensive, home-based assessments at 18-month intervals and have been interviewed monthly to reassess their functional status and ascertain intervening events, other health care utilization, and deaths. Findings from the PEP Study have demonstrated that the disabling process for many older persons is characterized by multiple and possibly interrelated disability episodes, even over relatively short periods of time, and that disability often results when an intervening event is superimposed upon a vulnerable host. Given the frequency of assessments, long duration of follow-up, and recent linkage to Medicare data, the PEP Study will continue to be an outstanding platform for disability research in older persons. In addition, as the number of decedents accrues, the PEP Study will increasingly become a valuable resource for investigating symptoms, function, and health care utilization at the end of life. PMID- 25035466 TI - Biomedicine. Proteins and a pregnancy woe. PMID- 25035467 TI - Neuroscience. Researchers aim for an electrical memory prosthesis. PMID- 25035468 TI - Agriculture. Harvest of genome data for wheat growers. PMID- 25035469 TI - The elusive heart fix. PMID- 25035470 TI - Top heart lab comes under fire. PMID- 25035471 TI - Statistics. The future lies in uncertainty. PMID- 25035472 TI - Cell biology. Mind the midzone. PMID- 25035473 TI - Ultrafast dynamics. Charge transfer goes the distance. PMID- 25035474 TI - Translational medicine. Improving cardiac rhythm with a biological pacemaker. PMID- 25035475 TI - Chemistry. Creating antioxidants by oxidation catalysis. PMID- 25035477 TI - Physics. Quantum systems under control. PMID- 25035476 TI - Cell biology. One, two, three, cytoplasmic dynein is go! PMID- 25035478 TI - Funding transdisciplinary research. NIH Roadmap/Common Fund at 10 years. PMID- 25035479 TI - Retrospective. Walter Gehring (1939-2014). PMID- 25035480 TI - Partnering with Cuba: weather extremes. PMID- 25035481 TI - Partnering with Cuba: earthquake hazards. PMID- 25035482 TI - Delisted whales good news for pipeline. PMID- 25035483 TI - Outside the tower. A night at the museum. PMID- 25035484 TI - Slicing the wheat genome. Introduction. PMID- 25035485 TI - Imaging charge transfer in iodomethane upon x-ray photoabsorption. AB - Studies of charge transfer are often hampered by difficulties in determining the charge localization at a given time. Here, we used ultrashort x-ray free-electron laser pulses to image charge rearrangement dynamics within gas-phase iodomethane molecules during dissociation induced by a synchronized near-infrared (NIR) laser pulse. Inner-shell photoionization creates positive charge, which is initially localized on the iodine atom. We map the electron transfer between the methyl and iodine fragments as a function of their interatomic separation set by the NIR-x ray delay. We observe signatures of electron transfer for distances up to 20 angstroms and show that a realistic estimate of its effective spatial range can be obtained from a classical over-the-barrier model. The presented technique is applicable for spatiotemporal imaging of charge transfer dynamics in a wide range of molecular systems. PMID- 25035486 TI - High-turnover hypoiodite catalysis for asymmetric synthesis of tocopherols. AB - The diverse biological activities of tocopherols and their analogs have inspired considerable interest in the development of routes for their efficient asymmetric synthesis. Here, we report that chiral ammonium hypoiodite salts catalyze highly chemo- and enantioselective oxidative cyclization of gamma-(2 hydroxyphenyl)ketones to 2-acyl chromans bearing a quaternary stereocenter, which serve as productive synthetic intermediates for tocopherols. Raman spectroscopic analysis of a solution of tetrabutylammonium iodide and tert-butyl hydroperoxide revealed the in situ generation of the hypoiodite salt as an unstable catalytic active species and triiodide salt as a stable inert species. A high-performance catalytic oxidation system (turnover number of ~200) has been achieved through reversible equilibration between hypoiodite and triiodide in the presence of potassium carbonate base. We anticipate that these findings will open further prospects for the development of high-turnover redox organocatalysis. PMID- 25035487 TI - A hole-conductor-free, fully printable mesoscopic perovskite solar cell with high stability. AB - We fabricated a perovskite solar cell that uses a double layer of mesoporous TiO2 and ZrO2 as a scaffold infiltrated with perovskite and does not require a hole conducting layer. The perovskite was produced by drop-casting a solution of PbI2, methylammonium (MA) iodide, and 5-ammoniumvaleric acid (5-AVA) iodide through a porous carbon film. The 5-AVA templating created mixed-cation perovskite (5 AVA)x(MA)1- xPbI3 crystals with lower defect concentration and better pore filling as well as more complete contact with the TiO2 scaffold, resulting in a longer exciton lifetime and a higher quantum yield for photoinduced charge separation as compared to MAPbI3. The cell achieved a certified power conversion efficiency of 12.8% and was stable for >1000 hours in ambient air under full sunlight. PMID- 25035488 TI - Dielectric gradient metasurface optical elements. AB - Gradient metasurfaces are two-dimensional optical elements capable of manipulating light by imparting local, space-variant phase changes on an incident electromagnetic wave. These surfaces have thus far been constructed from nanometallic optical antennas, and high diffraction efficiencies have been limited to operation in reflection mode. We describe the experimental realization and operation of dielectric gradient metasurface optical elements capable of also achieving high efficiencies in transmission mode in the visible spectrum. Ultrathin gratings, lenses, and axicons have been realized by patterning a 100 nanometer-thick Si layer into a dense arrangement of Si nanobeam antennas. The use of semiconductors can broaden the general applicability of gradient metasurfaces, as they offer facile integration with electronics and can be realized by mature semiconductor fabrication technologies. PMID- 25035489 TI - Electro-optical frequency division and stable microwave synthesis. AB - Optical frequency division by using frequency combs has revolutionized time keeping and the generation of stable microwave signals. We demonstrate optical frequency division and microwave generation by using a tunable electrical oscillator to create dual combs through phase modulation of two optical signals that have a stable difference frequency. Phase-locked control of the electrical oscillator by means of optical frequency division produces stable microwaves. Our approach transposes the oscillator and frequency reference of a conventional microwave frequency synthesizer. In this way, the oscillator experiences large phase noise reduction relative to the frequency reference. The electro-optical approach additionally relaxes the need for highly linear photodetection of the comb mode spacing. As well as simplicity, the technique is also tunable and scalable to higher division ratios. PMID- 25035490 TI - Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans. AB - The phosphatidylinositol 3-kinase (PI3K) pathway regulates many cellular functions, but its roles in the nervous system are still poorly understood. We found that a newly discovered insulin receptor isoform, DAF-2c, is translocated from the cell body to the synaptic region of the chemosensory neuron in Caenorhabditis elegans by a conditioning stimulus that induces taste avoidance learning. This translocation is essential for learning and is dependent on the mitogen-activated protein kinase-regulated interaction of CASY-1 (the calsyntenin ortholog) and kinesin-1. The PI3K pathway is required downstream of the receptor. Light-regulated activation of PI3K in the synaptic region, but not in other parts of the cell, switched taste-attractive behavior to taste avoidance, mimicking the effect of conditioning. Thus, synaptic PI3K is crucial for the behavioral switch caused by learning. PMID- 25035491 TI - Oceanic mass transport by mesoscale eddies. AB - Oceanic transports of heat, salt, fresh water, dissolved CO2, and other tracers regulate global climate change and the distribution of natural marine resources. The time-mean ocean circulation transports fluid as a conveyor belt, but fluid parcels can also be trapped and transported discretely by migrating mesoscale eddies. By combining available satellite altimetry and Argo profiling float data, we showed that the eddy-induced zonal mass transport can reach a total meridionally integrated value of up to 30 to 40 sverdrups (Sv) (1 Sv = 10(6) cubic meters per second), and it occurs mainly in subtropical regions, where the background flows are weak. This transport is comparable in magnitude to that of the large-scale wind- and thermohaline-driven circulation. PMID- 25035492 TI - Leverage points for improving global food security and the environment. AB - Achieving sustainable global food security is one of humanity's contemporary challenges. Here we present an analysis identifying key "global leverage points" that offer the best opportunities to improve both global food security and environmental sustainability. We find that a relatively small set of places and actions could provide enough new calories to meet the basic needs for more than 3 billion people, address many environmental impacts with global consequences, and focus food waste reduction on the commodities with the greatest impact on food security. These leverage points in the global food system can help guide how nongovernmental organizations, foundations, governments, citizens' groups, and businesses prioritize actions. PMID- 25035493 TI - Human tRNA synthetase catalytic nulls with diverse functions. AB - Genetic efficiency in higher organisms depends on mechanisms to create multiple functions from single genes. To investigate this question for an enzyme family, we chose aminoacyl tRNA synthetases (AARSs). They are exceptional in their progressive and accretive proliferation of noncatalytic domains as the Tree of Life is ascended. Here we report discovery of a large number of natural catalytic nulls (CNs) for each human AARS. Splicing events retain noncatalytic domains while ablating the catalytic domain to create CNs with diverse functions. Each synthetase is converted into several new signaling proteins with biological activities "orthogonal" to that of the catalytic parent. We suggest that splice variants with nonenzymatic functions may be more general, as evidenced by recent findings of other catalytically inactive splice-variant enzymes. PMID- 25035494 TI - Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes. AB - Cytoplasmic dynein is a molecular motor that transports a large variety of cargoes (e.g., organelles, messenger RNAs, and viruses) along microtubules over long intracellular distances. The dynactin protein complex is important for dynein activity in vivo, but its precise role has been unclear. Here, we found that purified mammalian dynein did not move processively on microtubules in vitro. However, when dynein formed a complex with dynactin and one of four different cargo-specific adapter proteins, the motor became ultraprocessive, moving for distances similar to those of native cargoes in living cells. Thus, we propose that dynein is largely inactive in the cytoplasm and that a variety of adapter proteins activate processive motility by linking dynactin to dynein only when the motor is bound to its proper cargo. PMID- 25035495 TI - Tell the negative committee to shut up. PMID- 25035496 TI - Organogenesis in a dish: modeling development and disease using organoid technologies. AB - Classical experiments performed half a century ago demonstrated the immense self organizing capacity of vertebrate cells. Even after complete dissociation, cells can reaggregate and reconstruct the original architecture of an organ. More recently, this outstanding feature was used to rebuild organ parts or even complete organs from tissue or embryonic stem cells. Such stem cell-derived three dimensional cultures are called organoids. Because organoids can be grown from human stem cells and from patient-derived induced pluripotent stem cells, they have the potential to model human development and disease. Furthermore, they have potential for drug testing and even future organ replacement strategies. Here, we summarize this rapidly evolving field and outline the potential of organoid technology for future biomedical research. PMID- 25035497 TI - Structural and functional partitioning of bread wheat chromosome 3B. AB - We produced a reference sequence of the 1-gigabase chromosome 3B of hexaploid bread wheat. By sequencing 8452 bacterial artificial chromosomes in pools, we assembled a sequence of 774 megabases carrying 5326 protein-coding genes, 1938 pseudogenes, and 85% of transposable elements. The distribution of structural and functional features along the chromosome revealed partitioning correlated with meiotic recombination. Comparative analyses indicated high wheat-specific inter- and intrachromosomal gene duplication activities that are potential sources of variability for adaption. In addition to providing a better understanding of the organization, function, and evolution of a large and polyploid genome, the availability of a high-quality sequence anchored to genetic maps will accelerate the identification of genes underlying important agronomic traits. PMID- 25035498 TI - Genome interplay in the grain transcriptome of hexaploid bread wheat. AB - Allohexaploid bread wheat (Triticum aestivum L.) provides approximately 20% of calories consumed by humans. Lack of genome sequence for the three homeologous and highly similar bread wheat genomes (A, B, and D) has impeded expression analysis of the grain transcriptome. We used previously unknown genome information to analyze the cell type-specific expression of homeologous genes in the developing wheat grain and identified distinct co-expression clusters reflecting the spatiotemporal progression during endosperm development. We observed no global but cell type- and stage-dependent genome dominance, organization of the wheat genome into transcriptionally active chromosomal regions, and asymmetric expression in gene families related to baking quality. Our findings give insight into the transcriptional dynamics and genome interplay among individual grain cell types in a polyploid cereal genome. PMID- 25035499 TI - Ancient hybridizations among the ancestral genomes of bread wheat. AB - The allohexaploid bread wheat genome consists of three closely related subgenomes (A, B, and D), but a clear understanding of their phylogenetic history has been lacking. We used genome assemblies of bread wheat and five diploid relatives to analyze genome-wide samples of gene trees, as well as to estimate evolutionary relatedness and divergence times. We show that the A and B genomes diverged from a common ancestor ~7 million years ago and that these genomes gave rise to the D genome through homoploid hybrid speciation 1 to 2 million years later. Our findings imply that the present-day bread wheat genome is a product of multiple rounds of hybrid speciation (homoploid and polyploid) and lay the foundation for a new framework for understanding the wheat genome as a multilevel phylogenetic mosaic. PMID- 25035501 TI - eComment. Haemolysis in cardiac surgery: a well-known problem with no solution. PMID- 25035500 TI - A chromosome-based draft sequence of the hexaploid bread wheat (Triticum aestivum) genome. AB - An ordered draft sequence of the 17-gigabase hexaploid bread wheat (Triticum aestivum) genome has been produced by sequencing isolated chromosome arms. We have annotated 124,201 gene loci distributed nearly evenly across the homeologous chromosomes and subgenomes. Comparative gene analysis of wheat subgenomes and extant diploid and tetraploid wheat relatives showed that high sequence similarity and structural conservation are retained, with limited gene loss, after polyploidization. However, across the genomes there was evidence of dynamic gene gain, loss, and duplication since the divergence of the wheat lineages. A high degree of transcriptional autonomy and no global dominance was found for the subgenomes. These insights into the genome biology of a polyploid crop provide a springboard for faster gene isolation, rapid genetic marker development, and precise breeding to meet the needs of increasing food demand worldwide. PMID- 25035502 TI - eComment re: Atrial apoptosis and fibrosis adversely affect atrial conduit, reservoir and contractile functions. PMID- 25035503 TI - eReply to: atrial apoptosis and fibrosis adversely affect atrial conduit, reservoir and contractile functions. PMID- 25035504 TI - eComment re: the role of patient's profile and allogeneic blood transfusion in development of post-cardiac surgery infections: a retrospective study. PMID- 25035505 TI - eComment. Similar surgical strategy is required for both typical and atypical carcinoid tumours. PMID- 25035506 TI - eComment. Drug-eluting stents versus angioplasty with or without bare metal stents in infra-inguinal arterial diseas. PMID- 25035507 TI - eComment. The thoracic configuration of patients with left ventricular assist devices likely determines whether cardiopulmonary resuscitation using sternal compressions is both safe and effective. PMID- 25035508 TI - eComment. Should intestinal malperfusion be addressed before the Type A dissection repair? PMID- 25035509 TI - eComment. Right cervical aortic arch and aberrant left subclavian artery. PMID- 25035510 TI - Photo quiz: An unexpected colonoscopic finding in a 13-year-old boy. PMID- 25035516 TI - CD8+ T cells maintain suppression of simian immunodeficiency virus in the central nervous system. AB - Human immunodeficiency virus (HIV) accesses the brain early in infection and can lead to neurocognitive disorders. The brain can also serve as a viral reservoir, but how virus is controlled in the brain is unknown. To examine this, CD8 depleting monoclonal antibody was injected into the cerebrospinal fluid of rhesus monkeys with chronic simian immunodeficiency virus (SIV) infection. This treatment led to the rapid increase of SIV in the brain. Virus in the brain is maintained by active suppression from the host immune system. This dynamic interaction can be manipulated in efforts to control and eradicate virus from the brain and other reservoirs. PMID- 25035517 TI - The surface rhamnopolysaccharide epa of Enterococcus faecalis is a key determinant of intestinal colonization. AB - Enterococcus faecalis is a commensal bacterium of the human intestine and a major opportunistic pathogen in immunocompromised and elderly patients. The pathogenesis of E. faecalis infection relies in part on its capacity to colonize the gut. Following disruption of intestinal homeostasis, E. faecalis can overgrow, cross the intestinal barrier, and enter the lymph and bloodstream. To identify and characterize E. faecalis genes that are key to intestinal colonization, our strategy consisted in screening mutants for the following phenotypes related to intestinal lifestyle: antibiotic resistance, overgrowth, and competition against microbiota. From the identified colonization genes, epaX encodes a glycosyltransferase located in a variable region of the enterococcal polysaccharide antigen (epa) locus. We demonstrated that EpaX acts on sugar composition, promoting resistance to bile salts and cell wall integrity. Given that EpaX is enriched in hospital-adapted isolates, this study points to the importance of the epa variability as a key determinant for enterococcal intestinal colonization. PMID- 25035518 TI - High-accuracy mapping of protein binding stability on nucleosomal DNA using a single-molecule method. PMID- 25035519 TI - Population income and longitudinal trends in living kidney donation in the United States. AB - Living kidney donation is declining in the United States. We examined longitudinal trends in living donation as a function of median household income and donor relation to assess the effect of financial barriers on donation in a changing economic environment. The zip code-level median household income of all 71,882 living donors was determined by linkage to the 2000 US Census. Longitudinal changes in the rate of donation were determined in income quintiles between 1999 and 2004, when donations were increasing, and between 2005 and 2010, when donations were declining. Rates were adjusted for population differences in age, sex, race, and ESRD rate using multilevel linear regression models. Between 1999 and 2004, the rate of growth in living donation per million population was directly related to income, increasing progressively from the lowest to highest income quintile, with annualized changes of 0.55 (95% confidence interval [95% CI], 0.14 to 1.05) for Q1 and 1.77 (95% CI, 0.66 to 2.77) for Q5 (P<0.05). Between 2005 and 2010, donation declined in Q1, Q2, and Q3; was stable in Q4; and continued to grow in Q5. Longitudinal changes varied by donor relationship, and the association of income with longitudinal changes also varied by donor relationship. In conclusion, changes in living donation in the past decade varied by median household income, resulting in increased disparities in donation between low- and high-income populations. These findings may inform public policies to support living donation during periods of economic volatility. PMID- 25035520 TI - Modeling Social Ties and Household Mobility. AB - Underlying the aggregate phenomena of persistent problems such as urban sprawl and spatial socio-economic disparity is the individual choice of where to live. This study develops an agent-based model to simulate social and economic influences on neighborhood choice. With Danville, Illinois as an empirical context, a pattern-oriented approach is employed to examine the role of social ties in shaping intra-urban household mobility. In the model, household agents decide whether and where to relocate within the community based upon factors such as neighborhood attractiveness, affordability, and the density of a household's social network in the prospective block group. Social network and neighborhood choices are encoded with logit utility functions. The relative influence of factors affecting the formation of social ties in the simulated social network, such as geographic proximity, similarity of income, race, and presence of children, are adjusted using parameter variation to create alternative model settings. Simulated migration patterns resulting from different network and neighborhood choice coefficients are compared with observed migration patterns over a two-year period. Based upon 1000 simulation experiments, a regression of homeowner migration error (the difference between simulated and observed migration) relative to the parameter settings revealed components of social network choice such as income, race, and probability of local ties to be significant in matching observed migration patterns. A non-linear effect of simulated social networks on household mobility and thus migration error was exhibited in this study. PMID- 25035521 TI - Group testing in heterogeneous populations by using halving algorithms. AB - Group (pooled) testing is often used to reduce the total number of tests that are needed to screen a large number of individuals for an infectious disease or some other binary characteristic. Traditionally, research in group testing has assumed that each individual is independent with the same risk of positivity. More recently, there has been a growing set of literature generalizing previous work in group testing to include heterogeneous populations so that each individual has a different risk of positivity. We investigate the effect of acknowledging population heterogeneity on a commonly used group testing procedure which is known as 'halving'. For this procedure, positive groups are successively split into two equal-sized halves until all groups test negatively or until individual testing occurs. We show that heterogeneity does not affect the mean number of tests when individuals are randomly assigned to subgroups. However, when individuals are assigned to subgroups on the basis of their risk probabilities, we show that our proposed procedures reduce the number of tests by taking advantage of the heterogeneity. This is illustrated by using chlamydia and gonorrhoea screening data from the state of Nebraska. PMID- 25035522 TI - Do Moral Communities Play a Role in Criminal Sentencing? Evidence From Pennsylvania. AB - Religion and social control have been a sociological concern since Durkheim and Weber, and the relationship between religion and punishment has long been the subject of speculation. However, surprisingly little empirical research exists on the role of religion or religious context in criminal justice, and almost no research on the role of religious context on actual sentencing practices. We conceptualize the potential relationships between religious context and sentencing severity by drawing from the focal concerns and court community perspectives in the sentencing literature and moral communities theory developed by Rodney Stark. We suspect that Christian moral communities might shape notions of perceived blameworthiness for court community actors. Such moral communities might also affect notions of community protection - affecting perceptions of dangerousness, or perhaps rehabilitation, and might influence practical constraints/consequences (e.g., local political ramifications of harsh or lenient sentences). We examine these questions using a set of hierarchical models using sentencing data from Pennsylvania county courts and data on the religious composition of Pennsylvania counties from the Associated Religion Data Archives. We find that county Christian religious homogeneity increases the likelihood of incarceration. In addition, Christian homogeneity as well as the prevalence of civically engaged denominations in a county condition the effects of important legally relevant determinants of incarceration. Furthermore, we find evidence that Christian homogeneity activates the effect of local Republican electoral dominance on incarceration. We argue that Christian homogeneity effects sentencing practices primarily through local political processes that shape the election of judges and prosecutors. PMID- 25035523 TI - Racial and Ethnic Disparities in Structural Disadvantage and Crime: White, Black, and Hispanic Comparisons. AB - OBJECTIVES: The objective of this study is to advance knowledge on racial/ethnic disparities in violence and the structural sources of those disparities. We do so by extending scarce and limited research exploring the relationship between race/ethnic gaps in disadvantage and differences in violent crime across groups. METHODS: Using census place-level data from California and New York, we construct White, Black, and Hispanic "gap" measures that take as a given the existence of disparities across race/ethnic groups in structural disadvantage and crime and subsequently utilize seemingly unrelated regression models to assess the extent to which gaps in disadvantage are predictive of gaps in homicide and index violence. RESULTS: Our results suggest that (1) there is considerable heterogeneity in the size of White-Black, White-Hispanic, and Black-Hispanic gaps in structural disadvantage and crime and (2) that race/ethnic disparities in structural disadvantage, particularly poverty and female headship, are positively associated with race/ethnic gaps in homicide and index violence. CONCLUSION: In light of recent scholarship on the racial invariance hypothesis and on the relationship between structural inequality and crime, the current study demonstrates that disparities in disadvantage, particularly family structure and poverty, are important in driving racial and ethnic disparities in crime. PMID- 25035524 TI - COMBINING PREVALENCE AND MORTALITY RISK RATES: THE CASE OF CIGARETTE SMOKING. AB - Cigarette smoking is a particularly pernicious behavior because of its high prevalence and mortality risk. We use the powerful methodology of life tables with covariates and employ the National Health Interview Survey-Multiple Cause of Death file to illuminate the interrelations of smoking with other risk factors, and with the combined influences of smoking prevalence and population size on smoking-attributable mortality. We find that the smoking-mortality gap is only modestly affected by other risk factors and excess deaths due to smoking among U.S. adults in the year 2000 were as great as 340,000. Better knowledge of the prevalence and mortality risk associated with cigarette smoking statuses enhances the future health and longevity prospects of the U.S. population. PMID- 25035525 TI - Math Schemata and the Origins of Number Representations. AB - The contrast Rips et al. draw between "bottom-up" and "top-down" approaches to understanding the origin of the capacity for representing natural number is a false dichotomy. Its plausibility depends upon the sketchiness of the authors' own proposal. At least some of the proposals they characterize as bottom-up are worked-out versions of the very top-down position they advocate. Finally, they deny that the structures that these putative bottom-up proposals consider to be sources of natural number are even precursors of concepts of natural number. This denial depends upon an idiosyncratic, and mistaken, idea of what a precursor is. PMID- 25035526 TI - Family Contexts and Schooling Disruption among Orphans in Post-Genocide Rwanda. AB - This study examines the relationship between orphan status and schooling disruption in post-genocide Rwanda. The results indicate that while non-orphans have more favorable schooling outcomes in two-parent than in single-parent families, the reverse is true among Rwandan orphans. In single-mother households, paternal orphans, i.e. orphans with only a living mother, have better outcomes than their orphan and non-orphan counterparts. In contrast, paternal orphans have worse outcomes than other children in two-parent households, especially in households headed by males. Maternal orphans are more likely to experience schooling disruptions than non-orphans regardless of family structure. The maternal-orphan disadvantage is nevertheless greater in female-headed than in male-headed households. As expected, non-related orphans are more disadvantaged than orphans related to their household heads. However, non-related orphans have a greater disadvantage in two-parent than in single-parent households. The results also suggest that within households, the provision of childcare to children below schooling age is an impediment to orphan's schooling. These impediments are, however, greater for double-orphans than paternal or maternal orphans. PMID- 25035527 TI - System Justification, Mental Health, and Behavior Among Disadvantaged Mothers and Their Children. AB - Integrating social psychological research with work in child development, this study explored relationships between system justification (Jost & Banaji, 1994), maternal mental health and child externalizing behavior among low-income immigrants and racial/ethnic minorities. Dominican, Mexican and African-American families (N = 239) were assessed when children were 14-, 24- and 36-months old. SEM was used to explore longitudinal relationships between maternal system justification and mental health and associations with child behavior. Earlier mental health was negatively related to later system justification and system justification was negatively related to children's externalizing behavior. Implications for system justification theory, child development and immigration are discussed. PMID- 25035528 TI - Central Composite Design for Validation of HPTLC Method for Simultaneous Estimation of Olmesartan Medoxomil, Amlodipine Besylate and Hydrochlorothiazide in Tablets. AB - High performance thin layer chromatographic method for simultaneous estimation of olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide was developed and validated as per ICH guidelines. Moreover, robustness testing was performed applying a central composite design with k factor having 2(k) factorial runs, 2k axial experiments and two center points. High performance thin layer chromatographic separation was performed on aluminium plates precoated with silica gel 60F254 and toluene:chloroform:methanol:acetonitrile:formic acid (2:7:1.8:0.8:0.2% v/v) as optimized mobile phase. The detection wavelength for simultaneous estimation of three drugs was 232nm. The Rf values for olmesartan medoxomil, amlodipine besylate and hydrochlorthiazide were 0.78, 0.20 and 0.45, respectively. Percent recoveries in terms of accuracy for the marketed formulation was found to be 101.3-104.4, 100.7-104 and 101.5-103.9 for, olmesartan medoxomil, amlodipine besylate and hydrochlorthiazide, respectively. The pooled %relative standard deviation values for repeatability studies and intermediate precision studies was found to be less than 2% for olmesartan medoxomil, amlodipine besylate and hydrochlorthiazide, respectively. All the three factors evaluated in the robustness testing by central composite design were found to have an insignificant effect on the retention factor. However, methanol content in total mobile phase as a factor appeared to have significant effect on robustness, compared to band size and developing distance and hence it is important to be carefully controlled. In summary, a novel, simple, accurate and reproducible high performance thin layer chromatographic method was developed, which would be of use in quality control of these tablets. PMID- 25035530 TI - Development and Validation of Stability-indicating RP-HPLC Method for Estimation of Pamabrom in Tablets. AB - The present study depicts the development of a validated RP-HPLC method for the determination of the pamabrom in presence of degradation products or other pharmaceutical excipients. Stress study was performed on pamabrom and it was found that it degrade sufficiently in acidic, alkali and oxidative condition but less degradation was found in thermal and photolytic condition. The separation was carried out on Enable G 120 A(0) (250*4.6 mm, 5 MU) column having particle size 5 MU using methanol: water (75:25 v/v) with pH 4.0 adjusted with ortho phosphoric acid as mobile phase at flow rate of 1 ml/min. The wavelength of the detection was 280nm. A retention time (Rt) nearly 3.9 min was observed. The calibration curve for pamabrom was linear (r (2) = 0.9997) from range of 10-60 MUg/ml with limit of detection and limit of quantification of 1.41 MUg/ml and 4.28 MUg/ml, respectively. Analytical validation parameter such as selectivity, specificity, linearity, accuracy and precision were evaluated and relative standard deviation value for all the key parameters were less than 2.0%. The recovery of the drug after standard addition was found to be 101.35%. Thus, the developed RP-HPLC method was found to be suitable for the determination of pamabrom in bulk as well as stability samples of tablets containing various excipients. PMID- 25035529 TI - Evaluation of the Leishmanicidal Activity of Rutaceae and Lauraceae Ethanol Extracts on Golden Syrian Hamster (Mesocricetus auratus) Peritoneal Macrophages. AB - Traditional medicine has provided a number of therapeutic solutions for the control of infectious agents, cancers, and other diseases. After screening a wide variety of Colombian plant extracts, we have identified promising antileishmanial activity in ethanol extracts from Ocotea macrophylla (Lauraceae) and Zanthoxyllum monophyllum (Rutaceae). In this study, we evaluated the in vitro activity of two ethanol extracts, one from Ocotea macrophylla and the other from Zanthoxyllum monophyllum and one alkaloid fraction of ethanol extract of Zanthoxyllum monophyllum, on peritoneal macrophages isolated from golden Syrian hamsters (Mesocricetus auratus) infected with Leishmania panamensis and Leishmania major promastigotes. All of the extracts studied displayed promising (>=2) selectivity indices (S/I), the most significant of which were for ethanol extract of Zanthoxyllum monophyllum against Leishmania panamensis (S/I=12) and alkaloid fraction of ethanol extract of Zanthoxyllum monophyllum against Leishmania major (S/I=11). These results support the use of ethanol extracts and alkaloid fractions isolated from Ocotea macrophylla and Zanthoxyllum monophyllum, respectively; as therapeutic options for cutaneous leishmaniasis. PMID- 25035531 TI - Does Curcumin or Pindolol Potentiate Fluoxetine's Antidepressant Effect by a Pharmacokinetic or Pharmacodynamic Interaction? AB - This study was designed to study potentiation of fluoxetine's antidepressant effect by curcumin or pindolol. Twenty eight groups of mice (n=8) were used in three sets of experiments. In the first set, 9 groups were subjected to the forced swimming test after being treated intraperitoneally with three vehicles, fluoxetine (5 and 20 mg/kg), curcumin (20 mg/kg), pindolol (32 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). One hour after the test, serum and brain fluoxetine and norfluoxetine levels were measured in mice receiving fluoxetine (5 and 20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). In the second set, the test was done after pretreatment with p-chlorophenylalanine. In the third set, the locomotor activity was measured. The immobility duration was significantly decreased in fluoxetine (20 mg/kg), curcumin (20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. These decreases were reversed with p chlorophenylalanine. Fluoxetine and norfluoxetine levels were significantly higher in fluoxetine (20 mg/kg) group with no differences in fluoxetine (5 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. Moreover, drugs failed to alter the locomotor activity indicating absence of central stimulation. In conclusion, curcumin, more than pindolol enhanced the antidepressant effect of a subeffective dose of fluoxetine in mice without increasing its serum or brain levels excluding any pharmacokinetic interaction. Reversal of this potentiation with p-chlorophenylalanine suggests a pharmacodynamic interaction through involvement of presynaptic 5-HT1A receptors. PMID- 25035532 TI - Measurement of adult antimicrobial drug use in tertiary care hospital using defined daily dose and days of therapy. AB - Widespread overuse and inappropriate use of antimicrobial drugs continues to fuel an increase in antimicrobial resistance and leads to consequent treatment complications and increased healthcare costs. In the present study we aimed to describe antimicrobial drug consumption and predictors and to identify potential targets for antimicrobial stewardship. This was a prospective observational study conducted at adult medicine wards of tertiary care teaching hospital over the period of five months. Antimicrobial drug consumption was measured using days of therapy per 1000 patient days and defined daily dose per 1000 patient days. Additionally, predictors of multiple antimicrobial prescribing were also analyzed. Seven hundred thirty patients were screened and 550 enrolled, receiving 1,512 courses of antimicrobial therapy, mainly intravenously (66%). Most frequently prescribed agents were artesunate (13%), ceftriaxone (11%) and metronidazole (10.5%). Overall consumption was 1,533 days of therapy per 1000 patient days and was mainly attributed to antibiotics (98.3%) for empirical therapy (50%). Median days of antimicrobial drugs prescribing were 3 (inter quartile range 2-5). Most commonly consumed antimicrobials were ceftriaxone (31%, 248.8 g) and artesunate (26%, 29 g). Antimicrobials contributed to 72.5% expense of the total incurred. Multivariate analysis reveals that younger patients (>=45 years) (odds ratio: 1.59, 95% CI 1.14-2.21) were more likely and absence of comorbidities (odds ratio: 0.58, 95% CI 0.42-0.79) and shorter hospital stay (>=6 days)(odds ratio: 0.44, 95% CI 0.32-0.60) were associated with less likelihood of prescribing multiple antimicrobial drugs. Estimating antimicrobial drugs use by defined daily dose method will remain open to criticism because the prescribed dosage is not often in agreement with the "usual" daily dose, which depends on location of and susceptibility of pathogenic organisms and metabolic status of the patient. PMID- 25035533 TI - In vivo Evaluation of Self Emulsifying Drug Delivery System for Oral Delivery of Nevirapine. AB - Nevirapine is a highly lipophilic and water insoluble non-nucleoside reverse transcriptase inhibitor used for the treatment of HIV-1 infection. Lymphoid tissue constitutes the major reservoir of HIV virus and infected cells in HIV infected patients. Self-emulsifying drug delivery system, using long chain triglycerides, is a popular carrier of drugs due to their ability to transport lipophilic drugs into the lymphatic circulation. However, HIV/AIDS patients experience a variety of functional and anatomical abnormalities in gastrointestinal tract that result in diarrhoea and nutrient malabsorption. Medium chain triglycerides are readily absorbed from the small bowel under conditions in which the absorption of long chain triglycerides is impaired. Therefore, nevirapine self-emulsifying drug delivery system containing medium chain fatty acid, caprylic acid and a solubilizer, Soluphor((r)) P (2 pyrrolidone) was developed and found to be superior to the marketed conventional suspension with respect to in vitro diffusion and ex vivo intestinal permeability. This self-emulsifying drug delivery system has now been further investigated for in vivo absorption in an animal model. The contribution of caprylic acid and Soluphor((r)) P on in vivo absorption of nevirapine was also studied in the present study. The bioavailability of nevirapine from self emulsifying drug delivery system, after oral administration, was 2.69 times higher than that of the marketed suspension. The improved bioavailability could be due to absorption of nevirapine via both portal and intestinal lymphatic routes. The study indicates that medium chain or structured triglycerides can be a better option to develop self-emulsifying drug delivery system for lipophilic and extensively metabolised drugs like nevirapine for patients with AIDS associated malabsorption. PMID- 25035534 TI - RP-HPLC and UV Spectrophotometric Methods for Estimation of Pirfenidone in Pharmaceutical Formulations. AB - High-performance liquid chromatographic and UV spectrophotometric methods were developed and validated for the quantitative determination of pirfenidone, a novel antifibrotic agent used in idiopathic pulmonary fibrosis. Chromatography was carried out by isocratic technique on a reversed-phase C18 Zorbax Eclipse plus column with mobile phase consisting of acetonitrile:water (35:65 %v/v) at flow rate of 0.7 ml/min. The UV spectrophotometric determinations were performed at 317 nm using methanol as a solvent. The proposed methods were validated according to International Conference on Harmonization ICH Q2 (R1) guidelines. The linearity range for pirfenidone was 0.2-5.0 and 3-25 MUg/ml for HPLC and UV method, respectively. Both the methods were accurate and precise with recoveries in the range of 98 and 102 % and relative standard deviation <2 %. The developed methods were successfully applied for determination of pirfenidone in tablets. PMID- 25035535 TI - Bactericidal Effect of Selected Antidiarrhoeal Medicinal Plants on Intracellular Heat-Stable Enterotoxin-Producing Escherichia coli. AB - Diarrhoeal diseases due to enterotoxigenic Escherichia coli continue to be a cause of global concern. Medicinal plants have been gaining popularity as promising antidiarrhoeal agents. In the present study, four antidiarrhoeal plants, viz. Aegle marmelos, Cyperus rotundus, Psidium guajava and Zingiber officinale were screened against a heat-stable toxin-producing enterotoxigenic E. coli strain. Decoctions of these plants were studied for their effect on intracellular killing of the bacterial strain using murine monocytic cell line, J774. [(3)H] thymidine release assay was used to evaluate the apoptotic/necrotic effect. All plants at concentrations <1% enhanced intracellular killing of the bacteria by J774 cells. However, at higher concentrations, the decoctions induced apoptosis in J774 cells. The study demonstrates that these plants could control diarrhoea caused by heat-stable toxin-producing enterotoxigenic E. coli through their immunomodulatory effect. PMID- 25035536 TI - Antinociceptive activity of aqueous and alcohol extract of evodia rutaecarpa. AB - Water, methanol and ethanol extracts of Evodia rutaecarpa were tested for antinociceptive activity, which were correlated with the contents of evodiamine, rutaecarpine and evodine. Determination of contents was achieved by chromatographic techniques. Extracts were evaluated for antinociceptive activities using hot-plate test; acetic acid-induced writhing test and formalin test. All three extracts of Evodia rutaecarpa showed antinociceptive activities but the ethanol extract exhibited better effect. The better antinociceptive activity appeared to be related to higher contents of evodiamine, rutaecarpine and evodine in ethanol extract of Evodia rutaecarpa. PMID- 25035537 TI - Posological Considerations of Ocimum sanctum (Tulasi) as per Ayurvedic Science and Pharmaceutical Sciences. AB - A study in 2010 reported that administration of 2 g of O. sanctum leaves for 30 days to laboratory male albino rabbits showed adverse effect on sperm count and male hormones. The dose and duration at which this testing was reported was commented upon as being high. It is learnt that basis this publication a few European regulators have imposed restrictions on usage of O. sanctum. Recognizing the need for evaluation, a review has been made of the posological considerations related to decision on dose of a drug in pharmaceuticals (drug development stages) and in Ayurvedic science as part of history of use and current usage. Specifically, we report the dose range as per documented tradition, marketed products containing O. sanctum as an ingredient and current clinical practice. Greater consultation is suggested before deciding the studies on Ayurvedic herbs. Regulatory action of banning use of O. sanctum needs a review and may need to be replaced with an advisory. PMID- 25035538 TI - Nomogram for computing the value of similarity factor. AB - The objective of present work was to construct nomogram for obtaining a value of similarity factor (f2) by employing the values of number of observations (n) and sum of squared difference of percentage drug dissolved between reference (R) and test (T) products . The steps for rearrangement of equation of similarity factor are presented. The values of f2 were selected in the range of 45 to 100 for 4 to 12 observations (n) for computing the values of Linear regression analysis was performed between number of observations and . Perfect correlation was observed in each case. Nomogram was constructed and later it was validated by using drug dissolution data from literature and our laboratory. The use of nomogram is recommended during research and development work to investigate effect of formulation or process variables. The nomogram can also be used during change in manufacturing site or change in equipment. It is concluded that the steps for calculation of f2 can be truncated in the middle (i.e. at the step of calculation of factor and a decision of similarity/dissimilarity can be taken employing the nomogram. PMID- 25035539 TI - Investigation of Phytochemical and Antioxidant Properties of Methanol Extract and Fractions of Ballota limbata (Lamiaceae). AB - Ballota limbata (Lamiaceae) has been used for its antispasmodic, antiulcer, diuretic, vermifuge and sedative effects in folk medicine. However, little is known about how does it work to produce these therapeutic actions. Present research investigated phytochemical components and antioxidant properties of methanol extract and different fractions of Ballota limbata. In this study, phytochemical investigation was done by performing different chemical tests. Here, antioxidant property of the extract and fractions was investigated by using 1,1-diphenyl-2-picryl hydrazyl radical scavenging activity, total antioxidant activity by the phosphomolybdenum method, linoleic acid peroxidation, ferric thiocyanate analysis and ferric-reducing antioxidant power. Methanol extract and fractions showed presence of numerous chemical principles including alkaloids, cardiac glycosides, tannins and flavonoids. The ethyl acetate fraction exhibited higher scavenging activity compared to the other fractions under investigation. This fraction displayed 84.16+/-1.02% 1,1-diphenyl-2-picryl hydrazyl radical inhibition at a dose of 60 MUg/ml. IC50 for 1,1-diphenyl-2-picryl hydrazylradical scavenging activity was 13.53+/-0.22 MUg/ml, relative to the standard, butylatedhydroxytoluene, having IC50 of 12.33+/-0.88 MUg/ml. Thus, Ballota limbata showed significant antioxidant activity, which may contribute in the mechanism of above pharmacological actions. PMID- 25035540 TI - Antimycobacterial and Antibacterial Activity of Allium sativum Bulbs. AB - Tuberculosis is one of the major public health problems faced globally. Resistance of Mycobacterium tuberculosis to antitubercular agents has called for an urgent need to investigate newer drugs to combat tuberculosis. Garlic (Allium sativum) is an edible plant which has generated a lot of curiosity throughout human history as a medicinal plant. Garlic contains sulfur compounds like allicin, ajoene, allylmethyltrisulfide, diallyltrisulfide, diallyldisulphide and others which exhibit various biological properties like antimicrobial, anticancer, antioxidant, immunomodulatory, antiinflammatory, hypoglycemic, and cardiovascular effects. According to various traditional systems of medicine, garlic is one of the established remedies for tuberculosis. The objective of the current study was to investigate in vitro antimycobacterial activity as well as anti-bacterial activity of various extracts rich in specific phytoconstituents from garlic. Preparation of garlic extracts was done based on the chemistry of the constituents and their stability. The estimation of in vitro antimycobacterial activity of different garlic extracts was done using Resazurin microtire plate assay technique whereas activity of garlic oil was evaluated by colony count method. The antibacterial activity of extracts and oil was estimated by zone of inhibition method. Extracts of garlic rich in allicin and ajoene showed appreciable antimycobacterial activity as compared to standard drugs. Garlic oil demonstrated significant antibacterial activity, particularly against methicillin-resistant Staphylococcus aureus. PMID- 25035541 TI - Effect of Red Clover on CYP Expression: An Investigation of Herb-Drug Interaction at Molecular Level. AB - Hormone replacement therapy and selective estrogen receptor modulator are the most common therapy for women going through menopause. These therapies though popular fail to relieve withdrawal symptoms such as hot flashes, fatigue, leg cramps and nausea. This scenario necessitates to herbal preparations as alternative which may lead to simultaneous intake of herbal preparations, containing flavonoids, as well as Selective estrogen receptor modulator hence creating a phenomenon of herb drug interaction. Here we investigate the effect of red clover on steady state mRNA levels of rat cytochrome P 450 enzymes. Further, red clover's effect on cytochrome P 450's expression has been investigated when co-administered with tamoxifen and raloxifene. Exposure to red clover resulted in significant down regulation of all the cytochrome P 450 isoform mRNA except cytochrome P 450 2C13 and cytochrome P 450 3A2. When red clover is given in combination with tamoxifen or raloxifene altered level of cytochrome P 450 enzyme mRNA is observed. Present results suggest that herbal medical preparations such red clover has potential for herb drug interaction. PMID- 25035542 TI - Schizophrenia and Other Psychotic Disorders in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5: Clinical Implications of Revisions from DSM-IV. PMID- 25035543 TI - A review of web based interventions for managing tobacco use. AB - Web based interventions (WBIs) have been developed for various health conditions. These include interventions for various psychoactive substance use disorders including tobacco and alcohol. Tobacco use has remained the single largest preventable cause of global mortality and morbidity for many years. It is responsible for around 6 million deaths annually world-wide. Ironically, most of the tobacco users reside in resource poor low and middle-income countries. The article reviews the existing literature on WBIs for management of tobacco use. The literature search was performed using MedLine, PubMed, PsycINFO, Embase and Cochrane Review for relevant English language articles published from 1998 up to 2013. There is limited support for effectiveness of WBIs for managing tobacco use among adolescents. Although most of the trials among adults found WBIs to be more effective at short term follow-up (a few days to weeks), the benefits failed to extend beyond 3 months in most of the studies. All but one interventions studied in a randomized controlled trial is for smoking forms. PMID- 25035544 TI - A Study on First Intake Assessments of In-patient Referrals to Psychiatric Rehabilitation Services. AB - BACKGROUND: Psychiatric rehabilitation is an important component in mental health services. The rehabilitation needs of patients with mental illness have been highlighted in various studies. The studies on in-patient referrals to rehabilitation services however are sparse. This study describes the clinical and demographic details and the reasons for referrals to rehabilitation services during the in-patients stay. MATERIALS AND METHODS: A semi-structured pro forma was used for the assessment of in-patients referred for the psychiatric rehabilitation services. The pro forma included socio-demographic details such as background, family resources, illness related details such as symptom status, risk assessment, medication details. The total number of referrals for a period of 5 months was collected and coded. RESULTS: The total number of referrals for a period of 5 months was 216 and there were 197 forms available for the study. The mean age of the sample was 31.48 +/- 10.46 years. Vocational rehabilitation was the commonest reason for referral to the in-patient services. Severe mental disorders were the most common diagnosis of patients refereed to the services. CONCLUSIONS: Patients with severe mental illness were most often referred to the in-patient services. This indicates that we need include to rehabilitation in the management plan at the earliest. Vocational rehabilitation is the most common reason for referrals and there is a need to develop services to cater to these needs. PMID- 25035545 TI - Perfectionism, emotion regulation and their relationship to negative affect in patients with social phobia. AB - CONTEXT: Research on the perfectionism and emotion regulation strategies in anxiety disorders has gained increased attention. These have an important implication for formulation of therapies. AIMS: We examined perfectionism, emotion regulation were examined in 30 patients with social phobia (SP) and 30 community participants. SETTINGS AND DESIGN: A cross-sectional design using a clinical and a community control sample was adopted in this exploratory study. MATERIALS AND METHODS: Participants were assessed on The Mini-International Neuropsychiatric Interview, Frost's-Multidimensional Perfectionism Scale, Ruminative Response Scale of the response style questionnaire, cognitive emotion regulation questionnaire, Social Interaction Anxiety Scale and the Beck's Depression Inventory. STATISTICAL ANALYSIS: Data was analyzed using independents samples t-test and Pearson's Product moment correlations and step-wise linear regression. RESULTS: Individuals with SP had higher perfectionism (mean = 100.30, SD = +/-17.73, t = 7.29, P < 0.001), rumination (mean = 61.47, SD = +/-11.96, t = 6.71, P < 0.001) and lower levels of positive reappraisal (mean = 11.53, SD = +/ 3.85, t = 4.90, P < 0.001). Perfectionism was correlated with social anxiety (r = 0.44, P < 0.05) and rumination (r = 0.43, P < 0.05), but not with depression. Rumination was positively correlated with both social anxiety (r = 0.513, P < 0.01) and depression (r = 0.485, P < 0.01). Positive reappraisal was negatively correlated with depression (r = -0.396, P < 0.05) and anxiety (r = -0.335, P < 0.05). Acceptance was found to be significantly correlated only to the reflective pondering subscale of rumination. Parental criticism was a significant predictor of social anxiety (F = 11.11, P < 0.01) and brooding predicted depression (F = 10.49, P < 0.01). CONCLUSIONS: This study highlights the role of perfectionism as a maintaining factor in SP and the importance of adaptive forms of emotion regulation that need to be addressed in psychological interventions. PMID- 25035546 TI - Depression and stigma in medical students at a private medical college. AB - OBJECTIVES: This study aimed to assess prevalence rate of depression and perceptions regarding stigma associated with depression amongst medical students. MATERIALS AND METHODS: A cross-sectional survey was conducted amongst 331 undergraduate medical students at a private medical college in Gujarat. Data was collected, which comprised of socio-demographic details, Patient Health Questionnaire (PHQ-9), and a 22-item semi-structured questionnaire to assess personal, perceived, and help-seeking stigma. Univariate analysis and chi-square tests were used to test for association between variables. RESULTS: Overall prevalence of depression was found to be 64%. Highest level of depression was seen in first year. Moderate to severe depression was found in 26.6% students. 73.3% students felt that having depression would negatively affect their education, and 52.3% saw depression as a sign of personal weakness. Females more strongly believed that students would not want to work with a depressed student (50.9% v/s 36.2%) and that if depressed, they would be unable to complete medical college responsibilities (61.9% v/s 44.1%). With increasing academic year, there was increase in stigma about disclosing depression to friends (P = 0.0082) and increase in stigma about working with a depressed student (P = 0.0067). Depressed students felt more strongly than non-depressed students on 10 items of the stigma questionnaire. CONCLUSIONS: High stigma exists among students about the causation of depression, and there exists an environment in which students discriminate fellow colleagues based on the presence of depression. This raises need for increasing awareness and support from peers and faculty. PMID- 25035547 TI - Cognitive Deficits in HIV Infected Children. AB - BACKGROUND AND OBJECTIVES: Children infected with HIV are at risk for significant neurological and neuropsychological problems. This study is aimed at identifying cognitive deficits in HIV-infected children and to compare them with equal number of normal controls. MATERIALS AND METHODS: Twenty children with HIV infection who are currently on antiretroviral therapy were recruited. They were assessed for their intelligence using Malin's Intelligence Scale for Indian Children and also evaluated for their cognitive abilities with a comprehensive neuropsychological battery. They were matched with equal number of normal controls. RESULTS: HIV infected children have shown substantial impairments in the domains of attention, language, verbal learning and memory, visuomotor functions, fine motor performance, and executive functions. CONCLUSION: HIV-infected children have average intelligence, but they performed poorly on several neuropsychological measures. PMID- 25035548 TI - Social networking sites: an adjunctive treatment modality for psychological problems. AB - BACKGROUND: Social networking is seen as a way to enhance social support and feeling of well-being. The present work explores the potentials of social networking sites as an adjunctive treatment modality for initiating treatment contact as well as for managing psychological problems. MATERIALS AND METHODS: Interview schedule, Facebook intensity questionnaire were administered on 28 subjects with a combination of 18 males and 10 females. They were taken from the in-patient and out-patient psychiatry setting of the hospital. RESULTS: Facebook was the most popular sites and used to seek emotional support on the basis of the frequent updates of emotional content that users put in their profile; reconciliations, escape from the problems or to manage the loneliness; getting information about illness and its treatment and interaction with experts and also manifested as problematic use. CONCLUSIONS: It has implications for developing social networking based adjunctive treatment modality for psychological problems. PMID- 25035549 TI - Knowledge and Attitude of Patients with Psychiatric Disorders and their Relatives Toward Electroconvulsive Therapy. AB - OBJECTIVE: Knowledge and attitude regarding electroconvulsive therapy (ECT) is one of the important parameters for acceptance of ECT as a safe and effective treatment option. Several factors shape the knowledge and attitude of general people such as previous experience of ECT, sources of their information about ECT and prevailing myths about ECT. The present study attempted to examine the knowledge and attitude concerning ECT among patients with psychiatric disorders and their relatives. MATERIALS AND METHODS: Knowledge and attitudes regarding ECT were assessed using the Bengali version of the ECT knowledge and attitude questionnaires, between 100 clinically stable patients with mental illnesses and their healthy relatives. RESULTS: Majority of the patients and relatives were unaware of the basic facts about ECT. Relatives were somewhat better informed and more positive about ECT than patients, but the differences between the two groups were not significant. Previous experience of ECT did not have any major impact in knowledge and attitude in both patients and relative groups. Patients obtained information, mostly from media (44%), doctors (23%), and from personal experiences (13%). On the other hand, relatives obtained information almost equally from media (26%), doctors (27%), and experience of friends or relatives (28%). No significant difference was observed in knowledge and attitude in patients who had obtained their facts from doctors (n=23) and from other sources (n=77). Among relatives, those who had obtained their information from doctors (n=27) were better informed than those who had obtained so from other sources (n=73). CONCLUSIONS: Since patients and relatives have poor knowledge and negative attitude toward ECT, medical professionals should impart proper information about ECT to patients and relatives to increase the acceptability of this treatment. PMID- 25035550 TI - Co-morbidity in Bipolar Disorder: A Retrospective Study. AB - BACKGROUND: Bipolar disorder is a relatively common, long-term, and disabling psychiatric illness that is associated with high levels of functional impairment, morbidity, mortality, and an increased risk of suicide. Psychiatric co-morbidity in bipolar disorder ranges from 57.3% to 74.3%, whereas medical co-morbidity varies from 2.7-70%. Indian scenario in this aspect is not clear. MATERIALS AND METHODS: The objective was to ascertain the prevalence of physical and psychiatric co-morbidities in patients attending a tertiary care center over a period of 1 year and its relationship with socio-demographic and clinical variables. One hundred and twenty-five case record files were included in the review. OPCRIT software was used for re-establishing the diagnosis of bipolar disorder, which yielded 120 cases. A semi-structured pro-forma, specifically designed for the study, was used to collect the socio-demographic and clinical details. RESULTS: Co-morbid psychiatric disorders were found in 52 (43.3%) of the sample, whereas co-morbid physical illness was present in 77 (64.2%) patients. The most common psychiatric disorder associated was substance use disorder (27.5%), whereas co-morbid cardiovascular disorder was the most frequent physical diagnosis in the sample (20%). DISCUSSION: The prevalence of co-morbid psychiatric disorders in bipolar patients was lower than that reported in western literature. It could be related to retrospective nature of study or reflect true lower prevalence rates. Also, certain disorders such as eating disorders were absent in our sample, and migraine diagnosis was very infrequent. PMID- 25035551 TI - Mu-wave Activity in Schizophrenia: Evidence of a Dysfunctional Mirror Neuron System from an Indian Study. AB - BACKGROUND: The 'mirror-neuron system' is thought to play an important role in automatic decoding of biological motions and interpretation of socially adaptive environmental stimuli. Accordingly, a dysfunction in this system in schizophrenia has been hypothesised to mediate the psychotic manifestations. MATERIALS AND METHODS: As a part of an ongoing study, we evaluated the mirror neuron system using 'EEG mu-wave (8-13 Hz) suppression' paradigm in 15 drug naive/drug free patients and compared the working to 15 age, sex and education matched controls. We also correlated the psychopathology scores on PANSS with the mu wave suppression in the schizophrenia patients, at baseline. We used high (192 channel) resolution EEG to record the mu rhythm while the subjects watched alternating sequences of a socially-relevant biological motion and white visual noise on a custom made video-clip. RESULTS: We found a significant difference in the degree of mu wave suppression between the two groups. We also found that the degree of mu suppression over right sensorimotor cortex at presentation correlated significantly and negatively with thought disorder in the patient group, and had a strong linear relationship. CONCLUSION: This study replicates past findings regarding a dysfunctional mirror neuron system in schizophrenia patients, and also emphasizes the role of rMNS in schizophrenic thought disorders. PMID- 25035552 TI - Changes in distressing behavior perceived by family of persons with schizophrenia at home - 25 years later. AB - BACKGROUND: Schizophrenia disorders as well as their symptoms cause distress to the family members or caregivers, which may cause poor quality of life. However, there have been advances in management, which could possibly alter this family distress. AIMS: To determine if there was any change in the perception of distressful symptoms of schizophrenia, by the family members, now, 25 years after the initial studies in the same centre. MATERIALS AND METHODS: Fifty-six consecutive and consenting new cases diagnosed as schizophrenia were administered the Scale for Assessment of Family Distress to identify the amount of distress caused by each of the symptoms reported. These findings were then compared with those reported by 50 patients, 25 years earlier. RESULTS: Symptoms like does not do work and earn, does not sleep, and does not do household tasks were reported as the commonest distressing symptoms in both the samples, however, in the 1988 sample, negative symptoms like, slow in doing things, social withdrawal and has few leisure interests, were the commonest, in the present sample behavioral symptoms like beats and assaults others, threatens, is abusive and talks nonsense were the commonest distressing symptoms. CONCLUSIONS: The relatives of patients with schizophrenia suffer from considerable amount of distress and burden. There are some changes in the type of behaviours considered distressful in the current period. Assessing family distress is helpful in providing support to caregivers of persons with schizophrenia. PMID- 25035553 TI - Attitudes towards antipsychotics among patients with schizophrenia on first- or second-generation medications. AB - BACKGROUND: Given the paucity of research in this area, this study attempted to assess attitudes toward antipsychotic medications and its correlates among patients with schizophrenia, either on first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs) medications. MATERIALS AND METHODS: Structured assessments of attitudes to antipsychotics, psychopathology, insight and side-effects were carried out in 120 patients with DSM-IV schizophrenia; 89 of these were on SGAs and 31 on FGAs. RESULTS: Patients had predominantly positive attitudes toward antipsychotics. Severity of side-effects was the principal correlate of attitudes, explaining 19.5% of the variance, followed by greater insight (4.2% of the variance). Other factors such as younger age, male gender, employment, higher family income, urban residence and lower symptom severity explained only a negligible proportion of the variance (0.2%) in attitudes. Patients on SGAs had more positive views of their medications than those on FGAs. They felt more normal on their medications, believed that their thoughts were clearer on medications, felt that good things about their medications outweighed the bad and believed that their medications helped them from falling ill again. In addition, they did not feel as tired and sluggish on their medications and did not believe that medications were unnatural or controlled their bodies. CONCLUSIONS: Positive attitudes toward antipsychotics were common among patients with schizophrenia. Attitudes were principally determined by severity of side-effects and insight levels. Patients on SGAs had better attitudes, possibly because of less severe side-effects and greater insight among them. The importance of exploring patients' attitudes toward their antipsychotics is highlighted by this study. PMID- 25035554 TI - Attitudes toward Medication and Reasons for Non-Compliance in Patients with Schizophrenia. AB - BACKGROUND: Non-compliance for the medication is an important area of concern in schizophrenia as it contributes to relapse and re-hospitalization of the patients. One of the ways to improve the drug compliance is to know crucial factors responsible for poor drug compliance and hence that proper strategies may be planned to improve patient's drug compliance. AIM: The aim of the following study is to find out the attitudes of patients toward medication and reasons for drug non-compliance in schizophrenia and its association with clinical and socio demographic variables. MATERIALS AND METHODS: The study was conducted on follow up patients with schizophrenia for the duration of 5 months. Their socio demographic details were noted and illness related variables were evaluated using Positive and Negative Syndrome scale (PANSS). Patient's attitudes toward medication and the reasons for treatment non-compliance were assessed using the standardized tools, which consist of Drug Attitude Inventory-10 scale and Rating of Medication Influences scale respectively. RESULTS: Nearly 41.9% of our study sample were non-compliant to medication. A significant association has been found between non-compliance and younger age group, unemployment, early age of onset, high positive PANSS score and poorer insight into the illness. The significant reasons for non-compliance in our study were Denial of illness, financial burden, less access to treatment facilities, Side-effects of the medication, Feeling that the medication was unnecessary and Substance abuse. CONCLUSIONS: Findings suggest that there is a need to provide adequate information about mental illness and medications prescribed, to enhance medication compliance and to develop community mental health care facilities. PMID- 25035555 TI - Asynchronous telepsychiatry in maharashtra, India: study of feasibility and referral pattern. AB - CONTEXT: There is a paucity of published telepsychiatry results in India. AIMS: This study was conducted to assess the feasibility of asynchronous telepsychiatry and to study the referral patterns. SETTINGS AND DESIGN: This study was conducted in the telemedicine unit of a tertiary care center and design was retrospective analysis of 94 cases, which were diagnosed and treated by telepsychiatry. MATERIALS AND METHODS: All 94 patients who were referred between January 2007 and August 2013 for telepsychiatry consultations were retrospectively analyzed to assess the referral pattern and feasibility. STATISTICAL ANALYSIS USED: Comparisons between demographic parameters and psychiatric diagnosis was done using Chi-square test. RESULTS: In 89 out of 94 (95%) patients it was possible to make a definitive diagnosis and recommend appropriate treatment only on the basis of data received from the primary care physician by telepsychiatry. This indicates the feasibility of telepsychiatry. The most common problems for which referrals were made included schizophrenia and other psychotic disorders, mood disorders and substance related disorders. CONCLUSIONS: This study demonstrates the feasibility of Asynchronous telepsychiatry. Additional Indian studies should be conducted to build the evidence base for the best use of asynchronous telepsychiatry. PMID- 25035556 TI - Psychiatric morbidity and quality of life in vitiligo patients. AB - BACKGROUND: Vitiligo has underlying mental illness but mostly not diagnosed and never used psychiatric medication. Hence, the problem persists affecting mostly the individual's quality of life. AIM: Assessing the quality of life, level of depression, and self-esteem of patients with vitiligo and give psychiatric medication for underlying mental illness. MATERIALS AND METHODS: The study conducted at Owaisi Hospital Research Centre, Hyderabad. The patients registered for dermatologist consultation were also registered for consultation with psychiatrist to rule out any mental illness after detailed evaluation using standardized scales. RESULTS: Patients suffering with vitiligo had depression and low self-esteem; their quality of life was disturbed. CONCLUSION: The findings provide the role of Mental Health Professionals involved in the field of dermatology for the patients suffering with vitiligo. PMID- 25035557 TI - The relationships between self-efficacy, internet addiction and shame. AB - BACKGROUND: Internet addiction (IAD) is one of the most diffuse mental disorders among adolescents. AIMS: The aim of our study was to evaluate the relationships between shame, self-efficacy and Internet addiction. MATERIALS AND METHODS: We recruited a total of 670 college students (males = 164, 24.5%; females = 506, 75.5%). The subjects were aged between 18 and 36 years (M = 20.93, SD = 2.52; males: M = 21.43, SD = 2.95; females: M = 20.76, SD = 2.35). We administered the following instruments: Experience of Shame Scale; Perceived Social Self-Efficacy Scale - Adult Version; Perceived Self-Efficacy in Handling Negative Emotions Scales; Internet Addiction Test. STATISTICS ANALYSIS: We applied multivariate analyses of variance (MANOVA), Pearson's correlation indices and linear regression analysis. RESULTS AND CONCLUSION: We found a significant inter relation between Internet addiction and shame. Shame could be a good predictor of Internet addiction. PMID- 25035558 TI - Job stress, satisfaction, and coping strategies among medical interns in a South Indian tertiary hospital. AB - BACKGROUND: It has previously been demonstrated that there is a significant drop in all domains of quality of life among interns during internship. AIMS: A modified version of the health consultant's job stress and satisfaction questionnaire (HCJSSQ) was used to assess and quantify aspects of internship that were perceived as stressful and satisfying. Methods used to cope with work place stress were explored. SETTINGS AND DESIGN: A prospective cohort study was undertaken among 93 medical interns doing a rotating internship at the Christian Medical College and Hospital, a tertiary-care hospital in southern India. MATERIALS AND METHODS: After completion of 6 months of internship, the modified version of the HCJSSQ was administered to all participants. STATISTICAL ANALYSIS: The data were entered into Statistical Package for the Social Sciences (SPSS) Version 9 by double data entry technique. Percentages of interns reporting high levels of stress, satisfaction were calculated. RESULTS: While 63.4% of interns reported high levels of satisfaction, 45.2% of the interns experienced high levels of stress, 17.6% coped with work stress by using alcohol and nicotine, and 37% coped through unhealthy eating habits. CONCLUSION: More people found internship satisfying than stressful. However, a high proportion found it stressful, and many reported unhealthy coping mechanisms. PMID- 25035559 TI - Role of psychosocial care on ICU trauma. AB - CONTEXT: Patients treated in intensive care units (ICU) though receive the best medical attention are found to suffer from trauma typically attributed to the ICU environment. Biopsychosocial approach in ICUs is found to minimize ICU trauma. AIMS: This study investigates the role of psychosocial care on patients in ICU after coronary artery bypass graft (CABG). SETTINGS AND DESIGN: The study included 250 post-operative CABG patients from five corporate hospitals. The combination of between subject and correlation design was used. MATERIALS AND METHODS: The ICU psychosocial care scale (ICUPCS) and ICU trauma scale (ICUTS) were used to measure the psychosocial care and trauma. STATISTICAL ANALYSIS: ANOVA and simple and multiple regression were applied. RESULTS: Hospitals significantly differed in psychosocial care provided in ICUs. Higher the psychosocial care in ICU, lower was the ICU trauma experienced and vice versa. Psychosocial care was a significant major predictor of ICU trauma. CONCLUSIONS: The study suggests emphasis on psychosocial aspects in ICU care for optimizing prognosis. PMID- 25035560 TI - Brief dynamic psychotherapy in a case of obsessive compulsive disorder. AB - A 57 years old married, retired official of Indian Railway service presented with two months complaints of recurrent fears of circulation of a duplicate CD of one of his presentations in an international conference, recurrent thoughts that the years of winning medals during his tenure in Indian Railways service were misrepresented in the records as early years. He recognized these fears as irrational, intrusive causing irritability and extreme anxiety, as he felt an urge to go and check the records, and feared it would cause humiliation. A diagnosis of obsessive compulsive disorder predominantly obsessions were made. Patient refused medication and a keen interest to receive insight. Patient had strong ego functions, stable heterosexual partnership, was open to interpretations and therapeutic contract of ten sessions of David Malan's school of brief dynamic therapy was initiated. Unconscious therapeutic alliance dominated over resistance. Displacement, isolation of affect and undoing were the neurotic defenses interpreted by the therapist. Therapeutic focus was relief of obsessions occurred by 9(th) session and therapy was successfully terminated. PMID- 25035561 TI - Dream work in grief therapy. AB - Working with dreams is useful with grief and loss clients who present with dreams. Adlerian dream analysis is one-way of exploring dreams. It incorporates the life-style of the client. This case report demonstrates how Adlerian dream analysis was used with a client. Progress was noted in improved life-style once the client began to talk about her dream. PMID- 25035562 TI - Secondary enuresis associated with chorea in a nigerian girl. AB - Enuresis is a distressing psycho-social disorder. It is often a neglected disorder, and its effect on the psychosocial development of a child is often overlooked, especially in those of low socio-economic status. Its exact pathophysiology is not completely understood, but it has been related to the effect of dopamine in the basal ganglia. However, its association with pediatric autoimmune neuropsychiatric disorder associated with streptococci infection is well-established. But, the case of an 11-year-old Nigerian girl diagnosed with Sydenham's chorea and had secondary enuresis is reported. PMID- 25035563 TI - Doing Psychiatry Right: A Case of Severe Avoidant Personality Disorder with Obsessive-compulsive Personality Disorder, Obsessive Compulsive Disorder, Intermittent Explosive Disorder and Sexual Paraphilias. AB - Over dependence on pharmacotherapy in psychiatry, known as biological imperialism, is a world-wide phenomenon. Some authors have opined that the inadequate and ineffective utilization of psychotherapeutic interventions and only dependence on pharmacotherapy amounts to institutional malpractice. Here is an example of such a case. A young male mainly received multiple psychotropic medicines, including clozapine (and also a failed psychotherapy) over a period of 4 years, without any benefit. His global assessment of function score remained at 30. However, with proper diagnosis and effectively conducted psychotherapy a significant improvement in Global assessment of functioning score of 70 was achieved, over a period of 11/2 years. PMID- 25035564 TI - Situational psychogenic anejaculation: a case study. AB - Anejaculation is an uncommon clinical entity that may result from a variety of causes, both organic and psychological. Psychogenic anejaculation is influenced by relationship, behavioral, and psychological factors. We present a clinical case of situational anejaculation, which was managed with a combination of techniques that addressed these factors including changes in masturbatory technique, improved marital communication and quality, and reduction of anxiety using cognitive behavioral techniques. It is suggested that the standard techniques of sex therapy be modified and tailored to manage the specific problems of the individual patient. PMID- 25035565 TI - Functional convergence spasm. AB - Convergence spasm (CS) means intermittent episodes of convergence, miosis and accommodation with disconjugate gaze mimicking abducens palsy. The organic causes range from metabolic to host of neurological and ophthalmic diseases that we describe. It was first described as a presentation of psychogenic disorders by von Graefe as early as in 1856. Nonetheless, patients exhibiting this sign are often subjected to plethora of unnecessary, sophisticated and invasive diagnostic procedures. Such functional cases were treated with either cycloplegic/placebo eye drop or amytal abreaction. Though epidemiological studies suggest that conversion disorder is equally prevalent in industrialized nations and developing countries, a few cases of functional CS are reported from West including Asia, that to, decade(s) before and none from India, to the best of our knowledge. We illustrate a case of functional CS with photograph after consent from patient and its successful treatment. PMID- 25035566 TI - Ketamine dependence in an anesthesiologist: an occupational hazard? AB - Substance abuse among medical professionals is a cause for concern. Certain psychotropic substances such as ketamine are at easy dispense to anesthesiologists increasing the likelihood of misuse and dependence and raise several issues including safety of patients. We discuss a case demonstrating ketamine dependence in an anesthesiologist from India. The reported psychotropic effects of ketamine ranged from dissociation and depersonalization to psychotic experiences. There was also development of significant tolerance to ketamine without prominent physical withdrawal symptoms and cyclical use of very high doses was observed. Issues related to management of health professionals are also discussed. PMID- 25035567 TI - Cerebellar Stroke-manifesting as Mania. AB - Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID- 25035568 TI - Persistent hiccups (singultus) as the presenting symptom of lateral medullary syndrome. AB - Lateral medullary syndrome (LMS) is a constellation of varied neurologic manifestations seen in cerebrovascular accidents. The posterolateral part of the medulla oblongata of the brain stem and cerebellum receiving arterial blood supply from the posterior inferior cerebellar artery are the areas commonly affected. We present a case of a middle aged gentleman referred to our hospital for persistent intractable hiccups as presenting symptom of LMS. He presented to our emergency room with persistent hiccups and left sided cerebellar signs. The patient had significant past history of alcohol and tobacco (smoking) dependence since 30 years apart from being a hypertensive. PMID- 25035569 TI - Unilateral Galactorrhea Associated with Low-dose Escitalopram. AB - Galactorrhea is a rare adverse effect of selective serotonin reuptake inhibitor treatment. We report a 27-year-old woman who developed unilateral breast engorgement with galactorrhea 18 days after initiation of escitalopram (10 mg/day). The symptom remitted 7 days after withdrawal of escitalopram and did not subsequently recur during maintenance therapy with agomelatine (25 mg/day). PMID- 25035570 TI - Serum Lithium Levels: Ideal Time for Sample Collection! Are We Doing it Right? AB - Lithium has been the gold standard drug for bipolar disorders. The efficacy of lithium is dose-dependent and reliably correlates with that of serum lithium levels (trough levels). Trough levels are best measured when tested just before the next dose. In clinical practice, when lithium was administered in divided doses, trough levels were measured at 12 h after the last dose. Does this practice of 12 h lithium estimation apply to once a day (OD) administration of lithium also? This study was undertaken to test this hypothesis. Serum lithium levels were measured at 12 and 24 h post the last dose in 48 patients taking an OD dosing of sustained preparations of lithium. The mean and (standard deviation) of serum lithium levels at 12 h (0.82 [0.29]) and at 24 h (0.60 [0.20]) were calculated. The serum lithium level at 12 h was 1.3 times higher than that of the 24 h levels (actual trough levels). Thus, it seems appropriate to estimate the serum lithium levels (trough levels) at 24 h post the last dose in patients taking lithium as an OD dosage, which may prevent patient maintained on a lower than required dose of lithium. PMID- 25035571 TI - Evaluation of clinical guidelines in psychiatry. PMID- 25035572 TI - Lomotil dependence. PMID- 25035573 TI - Time Matters!: When is the Right Time to Estimate Serum Valproic Acid Levels? PMID- 25035574 TI - Sleep Behaviors and Parent Functioning in Young Children With Type 1 Diabetes. AB - This study evaluates sleep characteristics among young children with type 1 diabetes and associations with parent sleep and emotional functioning and diabetes care. Study participants included twenty-four parents of young children with type 1 diabetes (ages 2-5) enrolled in a pilot study of a randomized controlled trial. Child sleep characteristics were within normal limits. However, increased child bedtime resistance and behavioral insomnia were related to greater parent stress, anxiety, and depression and use of an intensive insulin regimen. Type 1 diabetes management may impact child and parent sleep as well as parent emotional functioning. Implications for practice are presented. PMID- 25035575 TI - A Guide for Health Professionals Working with Aboriginal Peoples: Health Issues Affecting Aboriginal Peoples. PMID- 25035576 TI - Proliferative and non-proliferative lesions of the rat and mouse soft tissue, skeletal muscle and mesothelium. AB - The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the soft tissues including skeletal muscle as well as the mesothelium of rats and mice. The standardized nomenclature of lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions in soft tissues, skeletal muscle and mesothelium in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. (DOI: 10.1293/tox.26.1S; J Toxicol Pathol 2013; 26: 1S-26S). PMID- 25035578 TI - A survey of reservoir hosts in two foci of cutaneous leishmaniasis in Kerman province, southeast of Iran. AB - In the Old World, cutaneous leishmaniasis (CL) is zoonoses and natural vertebrate hosts of CL parasites are mammals. This study was carried out on natural infection rates of Leishmania parasites in reservoir hosts in one new focus of zoonotic cutaneous leishmaniasis (ZCL) and in suspected reservoir in an old focus of ACL in Iran. The sampling of rodents using Sherman traps was carried out and PCR technique was used for detection and identification of Leishmania species in Bahreman district, Kerman province, southeast of Iran. In addition, the smears were taken from suspicious lesions in stray dogs in the city of Kerman, the center of Kerman province. Simultaneously, pieces of lesion (1 * 1*1 cm) were taken for further histopathological examination. Overall, 25 rodents were collected and identified, including Meriones libycus and Rhombomys opimus. Amastigotes were observed in 33 % of the R. opimus by microscopic examination and indentified as Leishmania major by PCR technique. Four suspicious dogs out of 391 stray dogs showed no Leishmania species. To the best of our knowledge, this is the first isolation and identification of L. major from R. opimus in Kerman province, where ZCL has been present in recent years. Therefore, R. opimus is considered as the main animal reservoir host in Bahreman ZCL focus. In ACL focus such as the city of Kerman, dogs had no role in CL infection as reservoir host. PMID- 25035577 TI - Proliferative and non-proliferative lesions of the rat and mouse integument. AB - The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the societies of toxicological pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP). Its aim is to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory rodents. A widely accepted international harmonization of nomenclature in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and will provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. The purpose of this publication is to provide a standardized nomenclature for classifying microscopical lesions observed in the integument of laboratory rats and mice. Example colour images are provided for most lesions. The standardized nomenclature presented in this document and additional colour images are also available electronically at http://www.goreni.org. The nomenclature presented herein is based on histopathology databases from government, academia, and industrial laboratories throughout the world, and covers lesions that develop spontaneously as well as those induced by exposure to various test materials. (DOI: 10.1293/tox.26.27S; J Toxicol Pathol 2013; 26: 27S 57S). PMID- 25035579 TI - High prevalence of pfcrt K76T and mdr1 N86Y mutations in Sonitpur district of Assam, India. AB - Present study reports the prevalence and distribution of pfcrt K76T and mdr1 N86Y mutations in malaria endemic areas of Sonitpur district of Assam. Out of 163 individuals tested for malaria, 67 (SPR = 41.1 %) were detected positive for malaria infection using rapid detection kit in the field and PCR assay in the laboratory. Nested PCR-RFLP assay was used to amplify pfcrt K76T and mdr1 N86Y genes flanking the K76T and N86Y mutations. P. falciparum was most abundant (91.04 %) among the three Plasmodium species reported and its prevalence was significantly higher as compared to P. vivax and P. malariae (chi(2) = 150.76; p <= 0.0001; df = 2). Malaria was equally distributed among all the age groups and both the sexes. Hemoglobin contents in severe anaemic patients had a significant linear decreasing trend among patients with the increase in age (chi(2) = 4.33; p = 0.03), whereas non severe anaemic patients exhibited significant linear increasing trend among the patients with the increase in age (chi(2) = 18.38; p <= 0.0001). Pfcrt K76T mutation was recorded in 44 (72.13 %) isolates, whereas mdr1 N86Y mutation could be detected in 28 (41.79 %) isolates only. Only 32.7 % of the samples had both pfcrt K76T and mdr N86Y mutations. Number of pfcrt K76T mutant isolates was significantly higher than the wild type. However no significant difference was observed among the number of isolates with mdr1 N86Y mutant and wild isolates. PMID- 25035580 TI - Emergence of a new focus of visceral leishmaniasis due to Leishmania infantum in Golestan Province, north-eastern of Iran. AB - Over the last decade, a few cases of visceral leishmaniasis (VL) have been reported in some districts of the province of Golestan, in north-eastern Iran. The aim of the present study was to investigate the prevalence of Leishmania infantum infection among humans and domestic dogs by using direct agglutination test (DAT) and PCR assays in the eastern zone of the province. Between 2011 and 2012, blood samples were randomly collected from 450 humans and 50 domestic dogs, in the eastern zone of Golestan Province including 7 villages from Marave-tappeh district where new cases of human VL had been recorded there. Each of these samples was tested for anti-Leishmania antibodies, in DAT, and for L. infantum kinetoplast DNA on whole blood, in PCR-based assays. A total of 450 human samples, 6 (1.33 %) were found seropositive and 13 (2.8 %) was found PCR positive. Of the 50 dog samples, 16 (32 %) were found seropositive and 15 (30 %) were PCR-positive. All PCR-positive dogs were found seropositive except one as well as 6 (46.2 %) PCR-positive humans were also found seropositive. Moreover, the species of L. infantum was detected in all PCR-positive samples. The high prevalence of VL in the study areas offer it has emerged as an endemic focus in the province. Further investigations on the vectors, reservoirs and human population are recommended. PMID- 25035581 TI - Partial sequencing of Bm86 gene for studying the phylogeny of an Indian isolate of Rhipicephalus (Boophilus) microplus tick. AB - Tick gut glycoprotein, designated as Bm86, found on the luminal surface of the plasma membrane of gut epithelial cells of Boophilus microplus, which is a concealed antigen, has been used as vaccine candidate molecule for immunization against ticks. To better understand the molecular diversity of Bm86 gene in ticks, a portion of the cDNA was sequenced from an Indian isolate of B. microplus. Comparison of nucleotide sequence revealed that Indian isolate had 97 % homology (18 polymorphisms) with that of the Australian isolate and 96 % homology (20 polymorphisms) with that of the Cuban vaccine strain. Further, the Indian isolate differed from the Cuban vaccine isolate at 7 amino acid loci, including 5 substitutions (at residues 88, 94, 175, 176 and 177) and 2 deletions (at 183 and 184). However, protein prediction studies did not show any difference in the putative antigenic epitopes of the protein expressed. PMID- 25035582 TI - A survey on intestinal parasites of golden hamster (Mesocricetus auratus) in the northeast of Iran. AB - The aims of this study were to provide baseline knowledge about gastrointestinal parasites in golden hamster (Mesocricetus auratus) that inhabit the Mashhad area, and to analyze possible independent variable from October 2011-August 2012. To determine the prevalence of intestinal parasites in golden hamster, faecal samples were tested specifically for nematode eggs, protozoan oocysts and sporocysts utilizing a combined sedimentation-flotation technique. In addition, all fecal samples were examined to detect oocysts of Cryptosporidium spp. using modified Ziehl-Neelsen staining. Of 100 golden hamsters, 52 % were females and 48 % males. Of all examined fecal samples of golden hamsters, 44 % (95 % CI: 34.3 53.7 %) were found to harbor at least one parasite species. The following parasites were detected (with their respective prevalence): undetermined Trichurata (42 %, 95 % CI: 29.5-48.5 %), Syphacia spp. (4.3 %, 95 % CI: 1-7.3 %). Cryptosporidium and protozoan oocysts were not found in these animals. There was no significant difference (p > 0.05) between age, sex, litter, breeding place, breeding style and anthelminthic treatment with individual helminth infection in faecal examination. This is the first record of the gastrointestinal parasites of golden hamster in Iran. Considering that hamster and other rodents are pets in many homes, the likelihood of cross-infections, particularly involving children and mainly due to unhygienic habits, should be determined. PMID- 25035583 TI - Oxidative stress in the gill tissues of goldfishes (Carassius auratus) parasitized by Dactylogyrus spp. AB - The aim of this study was to investigate the status of oxidative stress in the gill tissues of goldfishes (Carassius auratus) parasitized by Dactylogyrus spp. We therefore compared the concentrations of malondialdehyde (MDA) and total thiol groups in the gill tissues of parasitized and non- parasitized goldfishes. 15 goldfishes parasitized by Dactylogyrus spp. along with 15 non-parasitized goldfishes were selected for the study. A significant increase in MDA concentration (P < 0.01) and a significant decrease in total thiol groups in the parasitized group, were observed when compared to the non- parasitized group. This is the first study which evaluates the effect of Dactylogyrus spp. on the oxidative stress status of goldfish. The results of the present study revealed that parasitized goldfishes showed more severe oxidative stress and lipid peroxidation than non- parasitized fishes and enhanced lipid peroxidation may be linked to gill damage in goldfishes parasitized by Dactylogyrus spp. PMID- 25035584 TI - First report on the record of parasitic infection in the Moray eel (Thyrsoidea macrura) along the Parangipettai coastal waters (Southeast coast of India). AB - An isopod belongs to the family Cirolanidae namely Anopsilana sp. was recorded from Parangipettai coastal waters during February and March, 2011. This is the first report and first record of occurrence of parasite in the Moray eel from this region. In the present study, totally 110 specimens of Moray eel (Thyrsoidea macrura) were examined for parasites and discussed about parasitic infection. PMID- 25035585 TI - Monogeneans (Platyhelminthes) from marine fishes of Tongyeong, Korea. AB - Monogeneans (Platyhelminthes) mostly parasitize on fins, skin and gills of fishes. In Korea, the study on monogeneans is limited, although, fishes are frequently encountered with severe infection of monogeneans. Hence, some of ranched and wild fishes were collected from Tongyeong marine living resources research and conservation center, southern part of Korea to screen and understand the infection of monogeneans. All three fish hosts were found with the infection of monogeneans including five species from four different families. They are: (1) Anoplodiscus spari Yamaguti (Publ Seto Mar Biol Lab Kyoto Univ 7:53-88, 1958) (Anoplodiscidae) from the fins and body surface of blackhead seabream Acanthopagrus schlegelii schlegelii (Bleeker); (2) A. tai Ogawa (Fish Pathol 29:5 10, 1994) from the fins of red seabream Pagrus major (Temminck and Schlegel); (3) Benedenia sekii Yamaguti (Studies on the helminth fauna of Japan. Part 19. Fourteen new ectoparasitic trematodes of fishes. Published by the author, Kyoto, 1937), Meserve (Rep Allan Hancock Paci Exped (1932-1937) 2:31-89, 1938) (Capsalidae) from the body surface of P. major; (4) Choricotyle elongata Goto (J Coll Sci Imp Univ Tokyo 8:1-273, 1894) (Diclidophoridae) from the gills of P. major; (5) Udonella fugu Freeman and Ogawa (Int J Parasitol 40:255-264, 2010) (Udonellidae) hyperparasitized on the body of parasitic copepod Pseudocaligus fugu (Yamaguti 1936) (Caligidae) infecting the wild grass puffer Takifugu niphobles (Jordan and Snyder). Capsalids are commonly reported in Korea, except B. sekii, however, other reported genera are uncommon. Hence, all reported monogeneans are considered as a first record from Korea. PMID- 25035586 TI - Coenurus gaigeri cyst in the thigh of a goat and its successful management. AB - A 11 month old female goat was presented to Polyclinic, IVRI with the history of swelling in the left hind leg on the inner aspect of thigh and inguinal region. Physical and radiological examination revealed a large fluctuating fluid filled bladder with distinct dimension. The cyst was successfully removed along with its membrane and parasitological examination revealed it as a Coenurus gaigeri, the intermediate stage of T. multiceps gaigeri. The animal recovered completely by 10th postoperative day without any complications. This is being described in detail as under. PMID- 25035587 TI - Comparison of two methods of Marshallagia marshalli donor sheep production. AB - Marshallagia marshalli is found in the abomasums of sheep, goats and wild ruminants in tropical and sub tropical climates. In Iran among different species of Ostertagiinae that can infect sheep, M. marshalli is currently the major cause of parasitic gastroenteritis in ruminant. Having a donor animal is essential for various studies. In the present study we compared the efficacy of two different method of M. marshalli donor sheep production. In the first method, M. marshalli donor sheep was produced by transplanting of adult forms of this worm into abomasum of a lamb (6 months of age) through a surgically established cannula. In the second method, 5,000 infective larvae (L3) from the female M. marshalli culture were given to a worm-free lamb of 6 months age through a stomach tube. After 3 days of transplanting, few eggs of M. marshalli appeared in the cannulated lamb's faeces. The number of eggs per gram of faeces (EPG) increased in the following days. The average number of EPG reached up to 23.5 +/- 11.26 per day in 2 months. In larval infected lamb by day 21 post infection the eggs were appeared in faeces. The average number of EPG reached up 53.5 +/- 42.5 per day in 2 months. In comparison between cannulation and larval infected, the number of eggs laid by worms transplanted in cannulated lamb was less than that of larval infected lamb. However, the abomasal cannulation method seems more preferable due to some advantages such as defined number of worms transplanted into abomasums, rapid access to the eggs and their culture. PMID- 25035588 TI - Kalicephalus sp. in a captive Russell's viper: a case report. AB - The occurrence of Kalicephalus sp. of hookworms in a Russell's viper snake maintained in Chennai snake park trust, Chennai is reported. These worms were found in the stomach and intestine. They were cylindrical, thread like and had an elongate body. Anterior end was obliquely truncated with bivalvular buccal capsule. Short, thick and muscularised oesophagus ending in a rounded bulb was observed. In males, a well developed trilobed bursa was observed and the spicules were short and equal. Typical strongyle type eggs were found in the uterus of female worms as well as in the intestinal contents. PMID- 25035589 TI - Prevalence of a protozoan parasite Cristigera sp. (Ciliophora:Ciliatea) from edible oysters (Mollusca:Bivalvia) of Sundarbans, West Bengal, India. AB - The coastal region of West Bengal is bestowed with a wide range of natural forest and aquatic resources. The estuarine complex is a culmination of the interaction of land, sea and freshwater. It offers diverse specialised habitats such as mangroves, non vegetated mudflats, inter tidal zones and reclaimed areas. Such areas are home to a number of terrestrial, freshwater and marine communities. Edible oyster resources in these regions are Crassostrea gryphoides and Saccostrea cucullata, which are the keystone species found in the intertidal zone and can tolerate huge variation of salinity. These are used as food by local people and marketed to earn cash. The population of this species has been declined due to parasitic infection and pollution. There are many protozoan parasites which infect these oysters causing diseases. During survey period, a protozoan parasite of the genus Cristigera have been observed only from the edible oyster Crassostrea gryphoides collected from Kaikhali and Frasergunj among three selected sites namely Kaikhali, Frasergunj and Digha of West Bengal mainly during monsoon and post-monsoon season. Considering such rare and specific prevalence of Cristigera sp, it may be considered as potential bio-indicator. PMID- 25035590 TI - Development of enzyme linked immunosorbent assay (ELISA) for the detection of root-knot nematode Meloidogyne incognita. AB - Root-knot nematodes (Meloidogyne incognita) are obligate, sedentary plant endoparasites that are extremely polyphagous in nature and cause severe economic losses in agriculture. Hence, it is essential to control the parasite at an early stage. For any control strategy to be effective, an early and accurate diagnosis is of paramount importance. Immunoassays have the inherent advantages of sensitivity and specificity; have the potential to identify and quantify these plant-parasitic nematodes. Hence, in the present studies, enzyme-linked immunosorbent assay (ELISA) has been developed for the detection of M.incognita antigens. First an indirect ELISA was developed for detection and titration of anti-M.incognita antibodies. Results indicated as high as 320 K titre of the antisera. Finally competitive inhibition ELISA was developed employing these anti M.incognita antibodies for detection of M.incognita antigens. Sensitivity of ELISA was 10 fg. Competitive inhibition ELISA developed in the present studies has the potential of being used as an easy, rapid, specific and sensitive diagnostic tool for the detection of M.incognita infection. PMID- 25035591 TI - Seasonal changes in the population of Menacanthus cornutus (Phthiraptera: Amblycera). AB - The chicken body louse, Menacanthus cornutus (Menoponidae s.l.) completes its whole life cycle on the body of Gallus gallus domesticus. The louse exploits the microclimate developed by host skin temperature and feather cover. The weekly visual examination has demonstrated the pronounced response on the population fluctuation of M. cornutus to the seasonal changes in the environment despite all favourable condition on the body of homothermic host. The experiments commences from April 2008. The peak index was obtained in the month of August followed by drastically decline in succeeding 5 months. Lice index begins building up slowly from the months of February and March. The correlation between mean monthly lice indices with temperature and photoperiod were analyses as strong positive. The moderate positive correlation was found with relative humidity and it remained insignificant with rainfall. PMID- 25035592 TI - Evaluation of two Iranian domestic ovine breeds for their pathological findings to gastrointestinal infection of Haemonchus contortus. AB - The generally warm, moist environmental conditions in the Northwestern Iran are ideal for survival and growth of the egg and larval stages of Haemonchus contortus and other gastrointestinal nematodes (GIN) of sheep and goats.A total of 2,421 animals were slaughtered and examined from July 2010 to July 2011 in Urmia abattoir. In case of sheep, 225 out of 2,421 were positive and prevalence of H. contortus infestation was 9.3 %. Sex wise prevalence of H. contortus in sheep was 33.08 % (76/229) in male and 66.22 % (149/225) in female. The females indicated significantly (P < 0.05) higher prevalence (66.22 %) as compared to males (33.08 %). The highest prevalence was recorded in the spring (April) and the lowest was in summer (July), respectively. On microscopic examination, infiltration of mononuclear cells and eosinophils in gastric glands, periglandular hyperemia and hemorrhage, mucous gland hyperplasia, connective tissue proliferation and necrosis was observed. Also, in mixed abomasal infection with Haemonchus and Ostertagia species, mucosal hyperplasia and increased mucous glands and sometimes cystic glands were seen. Statistical analysis using SPSS software, and Chi-square test, demonstrated a non-significant difference between ages and abomasal PH values of infected and healthy sheep (P < 0.05). But the difference between sexes, seasons and abomasal lesions was significant (P > 0.05). PMID- 25035593 TI - Occurrence of parasitic copepods in Carangid fishes from Parangipettai, Southeast coast of India. AB - In the present study, 68 fishes were infested out of 544 specimens examined from six different species of Carangid fishes which were collected from Parangipettai coastal waters. Eight species of parasitic copepods were found on gill filaments, body surface and nasal capsule regions. The maximum prevalence was recorded in Carangoides malabaricus (22.5 %) and minimum was noticed in (2.4 %) Selaroides leptolepis. The intensity of infection ranged from 1 to 1.2. Thus, considerable variation in the respiratory area was observed owing to the attachment of parasites in the infected fishes. Caligus sp. and C. epidemicus parasites were attached to body surface and only one Sphyriid sp. parasites were found in nasal capsule region. It is very difficult to estimate the actual harm to fish caused by the presence of parasites; if this is uneasy in cultured fish, it is almost impossible in feral fish populations. It should also be emphasized that the presence of a parasite does not necessarily imply manifestation of a disease. In aquaculture, some parasites are able to reproduce rapidly and heavily infect a large proportion of fish which may lead to diseases with significant economic consequences. PMID- 25035594 TI - Occurrence and histopathology of Przhevalskiana silenus larvae infestation in sheep of Jammu, India. AB - Warble fly infestation is primarily a myiasis of cattle and goat. However, a nondescript sheep from an endemic region was observed with nodules under subcutaneous tissue. So, this paper reports infestation of a sheep with Przhevalskiana silenus larvae in Jammu region of North India. The myiasis was confirmed with parasite morphology and specific histopathological changes observed in cutaneous myiasis. PMID- 25035595 TI - A new record of parasitic isopod for the Indian fauna (Mothocya karobran Bruce, 1986) from Strongylura strongylura in the Pazhayar region, Southeast coast of India. AB - Cymothoid isopods are permanent ectoparasites of fish. In the present study Strongylura strongylura captured in gillnets from the inshore waters of Pazhayar from January to March-12. Among the 122 Belonidae fishes examined, 16 specimens were parasitized by isopods belonging to the species Mothocya karobran, a new record of this cymothoid isopod for the first time from India. Lowest prevalence occurred in January (10.5 %) and the highest in February (15.9 %). The infected fishes usually carried one cymothoid per branchial cavity. 12 parasites were found in the left branchial cavity and 4 parasites in the right. The non ovigerous female (18.5-24.7 mm) and female ovigerous (20.8-27.4 mm) in total length. PMID- 25035596 TI - Occurrence of heavy copepod infestation on Hemiramphus lutkei and double parasitisms on Hemiramphus far with copepod (Lernaeenicus hemiramphi) and isopod (Mothocya plagulophora). AB - In the present study about, 66 copepod parasites of Lernaeenicus hemiramphi of two Hemiramphus sp., H. far (17 copepod) and H. lutkei (49 copepod), and an isopod (Mothocya plagulophora) on the gill chamber were observed. H. lutkei was added as a new host for L. hemiramphi. The copepod infestation was almost on the ventral side of the hosts. PMID- 25035597 TI - A new report on the occurrence of clinico-histopathological diagnostic criteria for Spinodiplotriaena. AB - Parasitic diseases of wild birds follows its companion volume, infectious diseases of wild birds, both of which complement the third edition of infectious diseases of wild mammals and second edition of parasitic diseases of wild mammals. In October 2012, a mature black male mynah with lack of balance and ataxia was brought into the birds department of educational hospital in veterinary medicine faculty of Tehran University. Because of no cure in clinical signs after several days of empirical therapy euthanasia and clinical pathology studies were performed. There was no microscopic pathological lesions in brain, bone marrow, heart, lung, liver and the microscopic results were as following; bone marrow: hemophagocytosis reactive macrophages, liver: infiltration of inflammatory cells (hepatitis) and hemosiderin-laden macrophages. Lung: hemosiderin-laden macrophages and spleen findings: infiltration of inflammatory cells, heterophils with phagocytic bacteria. In abdominal cavity two male and one female parasite was detect. Three parasites were cleared with lactophenol and investigated under the light microscopy and important morphological parts of them measured. Also these parasites in serum containing send to the department of parasitology. Based on all collecting data, Spinodiplotriaena (three parasites each by the length of 2/5, 1/7 and 1/5 cm were found) were diagnosed. Report of this case in important because of first report of this infection in a black mynah in Iran. PMID- 25035598 TI - Infestation of parasitic barnacle Sacculina spp. in commercial marine crabs. AB - Commercial crab species infected of rhizocephalan cirripedes are reported from the coast of Parangipettai. Sacculina spp. were collected from brachyuran hosts Portunus sanquinolentus, Portunus hastatoides, Chaybdis feriatus, Charybdis variegate, Charybdis natator, Charybdis miles, Charybdis lucifera, Charybdis hoplites, Charybdis hellerii, Charybdis granulate, Charybdis amboinensis and Thalamita coeruleipes respectively. PMID- 25035599 TI - Effect of supreme 15 CS against Meloidogyne incognita on tomato. AB - Pot and laboratory experiments were conducted to study the efficacy of supreme 15 CS in varying doses for management of root- knot nematode, M. incognita in tomato. The results indicated that supreme 15 CS containing alkali metal N-(n propyl) Dithiocarbamate proved to be more effective in improving plant growth characters and reducing root-knot index and final nematode population. Among the doses tested, higher dose of 0.5 % (w/w) was more effective than lower doses. PMID- 25035600 TI - Prana and electrons in health and beyond. PMID- 25035601 TI - In search of yoga: Research trends in a western medical database. AB - CONTEXT: The promotion of yoga practice as a preventative and treatment therapy for health outcomes in the western hemisphere is increasing rapidly. As the commercial success of yoga burgeons in popular culture, it is important to investigate the trends of yoga as a therapeutic intervention in academic literature. The free-access search engine, PubMed is a preeminent resource to identify health-related research articles published for academics, health practitioners and others. AIMS: To report the recent yoga-related publications in the western healthcare context with particular interest in the subject and type of yoga titles. MATERIALS AND METHODS: A bibliometric analysis to describe the annual trends in publication on PubMed from January 1950 to December 2012. RESULTS: The number of yoga-related titles included in the PubMed database is limited until a marked increase 2000 and steady surge since 2007. Bibliometric analysis indicates that more than 200 new titles are added per annum since 2011. Systematic reviews and yoga trials are increasing exponentially, indicating a potential increase in the quality of evidence. Titles including pain management, stress or anxiety, depression and cancer conditions are highly correlated with yoga and healthcare research. CONCLUSIONS: The prevalence of yoga research in western healthcare is increasing. The marked increase in volume indicates the need for more systematic analysis of the literature in terms of quality and results. PMID- 25035602 TI - Referral to yoga therapists in rural primary health care: A survey of general practitioners in rural and regional New South Wales, Australia. AB - BACKGROUND: Yoga is an increasingly accepted complementary treatment modality for referral in Australian general practice, yet this practitioner group has largely escaped research attention in Australia. Complementary medicine use is highest in rural and regional areas, where a number of primary health care challenges are also more pronounced. Despite the significant role of complementary therapists in rural and regional Australia, and the increasing acceptance of yoga therapy in general practice, there has been little exploration of the interface between yoga therapists and conventional primary health care practitioners in this area. MATERIALS AND METHODS: A 27-item questionnaire was sent to all 1486 general practitioners (GPs) currently practising in rural and regional Divisions of General Practice in New South Wales, Australia. RESULTS: Completed questionnaires were returned by 585 GPs, with 49 returned as 'no longer at this address' (response rate 40.7%). One-in-eight GPs (12.1%) advised their patients of specific yoga therapies and protocols, and 7.2% advised specific meditation techniques. Three-quarters of GPs (76.6%) referred to a yoga therapist at least a few times per year, with 12.5% of GPs referring at least once per week. GPs being in a remote location (OR = 10.95; CI: 1.55, 77.31), being female (OR = 1.85; 95% CI: 1.16, 2.94), GPs graduating from an Australian medical school (OR = 4.52; 95% CI: 2.61, 7.80), perceiving lack of other treatment options (OR = 3.29; 95% CI: 1.61, 6.74), GPs reporting good or very good knowledge of yoga therapies (OR = 18.2; 95% CI: 9.19, 36.19), and GPs using CAM for their own personal health (OR = 4.53; 95% CI: 2.60, 7.87) were all independently predictive of increased referral to yoga therapists amongst the rural GPs in this study. CONCLUSIONS: There is a significant interface between yoga therapists in Australian rural and regional general practice. There is generally high support for yoga therapies among Australian GPs, with low levels of opposition to the incorporation of these therapies in patient care. There is a need for increased research into yoga therapies practice, policy and regulation in these areas. PMID- 25035603 TI - Impact of yoga on biochemical profile of asthmatics: A randomized controlled study. AB - BACKGROUND: Asthma is a chronic inflammatory disorder of the airways. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing at night or in the early morning. Most of the studies have reported, as the effects of yoga on bronchial asthma, significant improvements in pulmonary functions, quality of life, and decrease in medication use, but none of the studies has attempted to show the effect of yoga on biochemical changes. OBJECTIVE: To evaluate the effect of yoga on biochemical profile of asthmatics. MATERIALS AND METHODS: In the present study, 276 patients of mild to moderate asthma (FEV 1> 60%) aged between 12 to 60 years were recruited from the Department of Pulmonary Medicine, King George's Medical University, U.P., Lucknow, India. They were randomly divided into two groups: Yoga group (with standard medical treatment and yogic intervention) and control group as standard medical treatment (without yogic intervention). At completion of 6 months of the study period, 35 subjects were dropped out, so out of 276 subjects, only 241 subjects completed the whole study (121 subjects from yoga group and 120 subjects from control group). Biochemical assessment was carried out at baseline and after 6 months of the study period. RESULTS: In yoga group, there was significant improvement found in the proportion of hemoglobin and antioxidant superoxide dismutase in comparison to control group and significant decrease was found in total leukocyte count (TLC) and differential leukocytes count in comparison to control group. There was no significant change found in TLC, polymorphs, and monocytes in between group comparison. CONCLUSIONS: Yoga group got significantly better improvement in biochemical variables than control group. Result shows that yoga can be practiced as adjuvant therapy with standard inhalation therapy for better outcome of asthma. PMID- 25035604 TI - Decoding the integrated approach to yoga therapy: Qualitative evidence based conceptual framework. AB - AIM: The aim of this study was to define, decode, and append to the conceptual frame-work of the integrated approach to yoga therapy (IAYT). MATERIALS AND METHODS: Four stakeholders who followed two in-patients with depression over a period of 2 weeks in the residential center Arogyadhama (of Swami Vivekananda Yoga Anusandana Samsthana, Bangalore, India) were interviewed before the start of the IAYT treatment and prior to discharge of the patient. The patients were also interviewed pre and post and were observed once during their session. The data from the audio recordings from eight in-depth interviews were transcribed manually and qualitative analysis was conducted. RESULTS: The conceptual frame work of IAYT depicts that patient related factors ("co-operation of patient", "patients awareness of his/her condition"), therapist related factors ("ability to guide", "the assistance to the patients", "explanation of the exercises") and treatment related factors ("combination of psychiatric or Ayurvedic medication with yoga", "counseling during the IAYT treatment", duration of treatment), play an integrated role in reaching the "aim of IAYT" and experiencing "improvements and changes". CONCLUSION: The IAYT is a holistic program and the ability of the patient to cooperate with and integrate the available factors (therapist related and treatment related) could enable best results. PMID- 25035605 TI - Can yoga practices benefit health by improving organism regulation? Evidence from electrodermal measures of acupuncture meridians. AB - OBJECTIVES: To document and explain Yoga's effects on acupuncture meridian energies. To understand mechanisms behind Yoga's efficacy by testing links between yoga and traditional Chinese medicine. MATERIALS AND METHODS: THE STUDY COMPARED TWO GROUPS OF YOGA PRACTITIONERS: Novice and experienced. Novices consisted of 33 volunteers from a Swami Vivekananda Yoga Anusandhana Samsthana (S VYASA) yoga instructor training module and the experienced practitioners were 20 resident SVYASA students. The intervention was 3 weeks of a yoga training program, new for the novices, but the lifestyle of the experienced group, who were therefore assessed only once. Novices were assessed on day 2 and 23 of their program at SVYASA's Yoga Medicine Hospital, making their data a pre-post, self-as control, prospective study. Main outcome measures were mean acumeridian energy levels assessed by AcuGraph3 measures of electrodermal resistance at acupoints; additionally, gender differences, standard deviations (SDs) of all measures, and comparison of post and experienced group data. RESULTS: Averaged energy levels significantly improved in all 24 meridians (maximum P = 0.032, 4-P < 0.01, and 19 P < 0.001). Females improved more than males (P < 0.05), both ending at similar levels to experienced practitioners, whose SDs were lower than novices on 19/24 meridians (mean F = 3.715, P = 0.0022), and 4/5 average variables. CONCLUSIONS: AcuGraph3 electrodermal measures contain substantial information, P << 0.00001. Yoga-lifestyle practice can increase and balance acumeridian energies; long-term practice decreases group SD's. These three suggest reasons why yoga practice impacts health: One, increased prana levels are important; two and three, improved physiological regulation is the key. Further studies relating traditional Indian and Chinese medical systems are needed. PMID- 25035606 TI - Effect of yoga training and detraining on respiratory muscle strength in pre pubertal children: A randomized trial. AB - OBJECTIVE: To evaluate the effect of yoga on forced vital capacity (FVC), forced expiratory volume in I(st) second (FEV1), peak expiratory flow rate (PEFR), FEVI/FVC ratio, and pulmonary pressures [maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP) at the end of 3 months yoga training and the detraining effect on the above parameters in 7-9-years-old school going children. MATERIALS AND METHODS: A total of 100 participants were recruited from a school in Bangalore. After baseline assessments, the participants were randomly allocated to either yoga or physical activity group. Intervention was given for 3 months, and measures of pulmonary function and pulmonary pressures were determined immediately post-intervention and at 3-months follow-up. RESULTS: Although significant increase was observed in FVC, FEV1, PEFR, FEV1/FVC, MIP, and MEP at post-intervention, there were no significant differences between the two study groups after adjusting for height and age post training . However, MIP increased significantly in both the groups post-intervention, but the yoga group performed significantly higher than the PE group. The effects of training did not fade off even after 3 months of detraining. In fact, the FVC and FEV1 continued to increase significantly. A trend of decrease was observed in PEFR, MIP, and MEP. However, the values did not regress to the baseline value. CONCLUSIONS: This study suggests that practice of yoga for a short duration (3 months) of time can significantly improve respiratory muscle strength in pediatric population. PMID- 25035607 TI - Changes in pain intensity and health related quality of life with Iyengar yoga in nonspecific chronic low back pain: A randomized controlled study. AB - BACKGROUND: Nonspecific chronic low back (nCLBP) pain is prevalent among adult population and often leads to functional limitations, psychological symptoms, lower quality of life (QOL), and higher healthcare costs. The purpose of this study was to determine the efficacy of Iyengar yoga therapy on pain intensity and health related quality of life (HRQOL) with nCLBP. AIM OF THE STUDY: To compare the effect of Iyengar yoga therapy and conventional exercise therapy on pain intensity and HRQOL in nonspecific chronic low back pain. MATERIALS AND METHODS: Experimental study with random sampling technique. SUBJECTS/INTERVENTION: Sixty subjects who fulfilled the selection criteria were randomly assigned to Iyengar yoga (yoga group, n = 30) and control group (exercise group, n = 30). Participants completed low back pain evaluation form and HRQOL-4 questionnaire before their intervention and again 4 weeks and 6 month later. Yoga group underwent 29 yogic postures training and exercise group had undergone general exercise program for 4 weeks. STATISTICS: Repeated measures analysis of variance (ANOVA) was used to analyze group differences over time, while controlling for baseline differences. RESULTS: Patients in both groups experienced significant reduction in pain and improvement in HRQOL. In visual analogue scale (VAS) yoga group showed reduction of 72.81% (P = 0.001) as compared to exercise group 42.50% (P = 0.001). In HRQOL, yoga group showed reduction of 86.99% (P = 0.001) as compared to exercise group 67.66% (P = 0.001). CONCLUSION: These results suggest that Iyengar yoga provides better improvement in pain reduction and improvement in HRQOL in nonspecific chronic back pain than general exercise. PMID- 25035608 TI - Effect of yoga on the Myofascial Pain Syndrome of neck. AB - Myofascial Pain Syndrome (MPS) refers to pain attributed to muscle and its surrounding fascia, which is associated with "myofascial trigger points" (MTrPs). MTrPs in the trapezius has been proposed as the main cause of temporal and cervicogenic headache and neck pain. Literature shows that the prevalence of various musculoskeletal disorders (MSD) among physiotherapists is high. Yoga has traditionally been used to treat MSDs in various populations. But there is scarcity of literature which explains the effects of yoga on reducing MPS of the neck in terms of various physical parameters and subjective responses. Therefore, a pilot study was done among eight physiotherapists with minimum six months of experience. A structured yoga protocol was designed and implemented for five days in a week for four weeks. The outcome variables were Disability of Arm, Shoulder and Hands (DASH) score, Neck Disability Index (NDI), Visual Analogue Scale (VAS), Pressure Pain Threshold (PPT) for Trigger Points, Cervical Range of Motion (CROM) - active & passive, grip and pinch strengths. The variables were compared before and after the intervention. Finally, the result revealed that all the variables (DASH: P<0.00, NDI: P<0.00, VAS: P<0.00, PPT: Left: P<0.00, PPT: Right: P<0.00, Grip strength: left: P<0.00, Grip strength: right: P<0.01, Key pinch: left: P<0.01, Key pinch: right: P<0.01, Palmar pinch: left: P<0.01, Palmar pinch: right: P<0.00, Tip pinch: left: P<0.01, Tip pinch: Right: P<0.01) improved significantly after intervention. PMID- 25035609 TI - Differential effects of uninostril and alternate nostril pranayamas on cardiovascular parameters and reaction time. AB - BACKGROUND: Recent studies have reported the differential physiological and psychological effects of yogic uninostril breathing (UNB) and alternate nostril breathing (ANB) techniques. This study aims to determine differential effects of these techniques on reaction time (RT), heart rate (HR), and blood pressure (BP). MATERIALS AND METHODS: Twenty yoga-trained subjects came to the lab on six different days and RT, HR, and BP were recorded randomly before and after nine rounds of right UNB (surya nadi [SN]), left UNB (chandra nadi [CN]), right initiated ANB (surya bhedana [SB]), left initiated ANB (chandra bhedana [CB]), nadi shuddhi (NS), and normal breathing (NB). RESULTS: Overall comparison of ? % changes showed statistically significant differences between groups for all parameters. There was an overall reduction in HR- and BP-based parameters following CB, CN, and NS with concurrent increases following SB and SN. The differential effects of right nostril initiated (SB and SN) and left nostril initiated (CB, CN, and NS) UNB and ANB techniques were clearly evidenced. Changes following NB were insignificant in all respects. The overall comparison of ? % changes for RT showed statistically significant differences between groups that were significantly lowered following both SB and SN. DISCUSSION AND CONCLUSION: Our study provides evidence of sympathomimetic effects of right nostril initiated pranayamas with sympatholytic/parasympathomimetic effect following left nostril initiated pranayamas. We suggest that the main effect of UNB and ANB techniques is determined by the nostril used for inspiration rather than that used for expiration. We conclude that right and left yogic UNB and ANB techniques have differential physiological effects that are in tune with the traditional swara yoga concept that air flow through right nostril (SN and pingala swara) is activatory in nature, whereas the flow through left nostril (CN and ida swara) is relaxatory. PMID- 25035610 TI - Barriers in the path of yoga practice: An online survey. AB - CONTEXT: Clinical benefits of yoga have been well explored, but factors contributing to adherence to regular yoga practice are not well studied. AIMS: To study the factors influencing adherence to yoga practices on those participants who have completed 1-month Yoga Instructors' course from a yoga university. SETTINGS AND DESIGN: Online survey was conducted on participants who had finished 1-month Yoga Instructors' course at a yoga university. MATERIALS AND METHODS: Online survey was conducted using Survey Monkey web portal with response rate of 42.5%. A total of 1355 participants were approached. Demographic items and a checklist of 21 items on a 5-point likert scale were prepared based on traditional yoga texts. A few items to assess modern lifestyle barriers were also included. STATISTICAL ANALYSIS: One-sample proportion test with chi square statistics was used for analysis. RESULTS: Irregularity in lifestyle, family commitments, and occupational commitments are perceived as significant strong barriers. Dullness, excessive talking, strictly adhering to rules, laziness, physical and mental overexertion, fickleness and wandering of mind, unsteadiness of mind, procrastination, and oversleeping are considered as significant barriers of moderate nature. CONCLUSIONS: Modern lifestyle is the major challenge for yoga practitioners to adhere to regular practice of yoga. To address this, attention is required in strengthening the lifestyle management and the spiritual dimension of yoga practice as the spiritual component seems to be side-tracked. PMID- 25035611 TI - Effect of 11 months of yoga training on cardiorespiratory responses during the actual practice of Surya Namaskar. AB - BACKGROUND: Surya Namaskar (SN), a popular traditional Indian yogic practice, includes practicing 12 physical postures with alternate forward and backward bending movement of the body along with deep breathing maneuvers. The practice of SN has become popular among yoga practitioners and other fitness conscious people. The long-term effect of practicing SN and other yogic practices on cardiorespiratory responses during SN are lacking. AIM: The present study was conducted to study the effect of yogic training on various cardiorespiratory responses during the SN practice in yoga trainees after a time interval of 3, 6, and 11 months. MATERIALS AND METHODS: The present study was conducted on 9 healthy male Army soldiers who underwent training in various yoga postures including SN, meditation, and pranayama for 1 h daily for 11 months. First, second, and third phase of the study was conducted in the laboratory after completion of 3, 6, and 11 months of the yoga training. The participants performed SN along with other yogic practices in the laboratory as per their daily practice schedule. The cardiorespiratory responses of the volunteers were recorded during actual practice of SN. STATISTICAL ANALYSIS: One-way repeated measure ANOVA followed by Tukey HSD. RESULTS: Oxygen consumption and heart rate during actual practice of SN was 0.794 +/- 0.252, 0.738 +/- 0.229, and 0.560 +/- 0.165 L/min and 92.1 +/- 11.6, 97.9 +/- 7.3 and 87.4 +/- 9.2 beats/min respectively at 1(st) , 2(nd) , and 3(rd) phase of yoga training. Minute ventilation and tidal volume also reduced from 19.9 +/- 4.65 to 17.8 +/- 4.41 L/min and 1.091 +/- 0.021 to 0.952 L/breath from 1(st) phase to 3(rd) phase of yoga training. However, respiratory parameters like breathing rate (fR) did not show any reduction across the three phases. CONCLUSION: The results of the present study indicated that yogic training caused conditioning of cardiorespiratory parameters except fR, which did not reduce across three phases of training. PMID- 25035612 TI - Effect of repetitive yogic squats with specific hand position (Thoppukaranam) on selective attention and psychological states. AB - CONTEXT: Research on the effect of Thoppukaranam is limited despite it being practiced as a form of worship to the elephant-headed deity Lord Ganapati and punishment in schools. AIMS: The purpose of this study was to examine the effect of Thoppukaranam on selective attention and psychological states in a sample of young adults. SETTINGS AND DESIGNS: A randomized self-as-control within subjects design was employed. Thirty undergraduate students (4 females and 26 males) from a residential Yoga University in Southern India were recruited for this study (group mean age +/- standard deviation, 20.17 +/- 2.92). MATERIALS AND METHODS: The d2 test, State Anxiety Inventory-Short Form and State Mindful Attention Awareness Scale (SMAAS) were used to measure cognitive performance and psychological states. Assessments were made in three sessions: Baseline, control (squats), and experimental (Thoppukaranam) on 3 separate days. STATISTICAL ANALYSIS USED: Data were analyzed using one-way repeated measures analyses of variance between three sessions, that is, baseline, squat, and Thoppukaranam. RESULTS: There was a significant improvement in all measures of the d2 test of attention (TN, E, TN-E, E%, and concentration performance) and state mindfulness after Thoppukaranam. Further state anxiety reduced significantly after the experimental session. CONCLUSIONS: These findings indicate Thoppukaranam results in enhancement of cognitive functioning and psychological states. PMID- 25035613 TI - Does yoga exercise therapy affect oxidative stress parameters in end-stage renal disease patients undergoing hemodialysis? PMID- 25035614 TI - A commentary on Nemati (2013): "The effect of pranayama on test anxiety and test performance". PMID- 25035616 TI - Toward building evidence for yoga. PMID- 25035617 TI - Comparative immediate effect of different yoga asanas on heart rate and blood pressure in healthy young volunteers. AB - INTRODUCTION: This study planned to compare immediate cardiovascular effects of different yoga asanas in healthy young volunteers. MATERIALS AND METHODS: Heart rate (HR), systolic pressure (SP), and diastolic pressure (DP), blood pressure (BP), were recorded using the non invasive blood pressure (NIBP) apparatus in 22 healthy young subjects, before and after the performance of Dhanurasana (DA), Vakrasana (VA) (both sides), Janusirasasana (JSA) (both sides), Matsyasana and Shavasana for 30 s. HR and BP were further recorded during supine recovery at 2, 4, 6, 8, and 10 min. A repeated measure of ANOVA was used for statistical analysis. RESULTS: There were significant changes in HR and BP both immediately after the Asanas as well as during the recovery period. Overall comparisons of ?% changes immediately after the performance of the Asanas revealed significant differences with regard to HR that increased significantly after DA. In the recovery phase, there were significant intergroup differences from 2 min onward in both SP and DP. The decrease of SP after VA (right side) (VA-R) was significantly greater than Shavasana (4(th), 6(th), and 8(th) min) and JSA (left side) (JSA-L) at 6(th) and 8(th) min. DP decreased significantly after performing JSA-L compared to VA-R at the 6(th) and 8(th) min. DISCUSSION: The cardiovascular changes immediately after the Asanas and during the recovery phase reveal inherent differences between the selected postures. The rise of HR in DA may be attributed to increased sympathetic response due to the relative difficulty of the posture as well as abdominal compression occurring in it. The effect of supine relaxation is more pronounced after the performance of the Asanas as compared to mere relaxation in Shavasana. This may be attributed to a normalization and resultant homeostatic effect occurring due to a greater, healthier de-activation of the autonomic nervous system occurring towing to the presence of prior activation. There were also subtle differences between the right sided and left sided performance of VA and JSA that may be occurring due to the different internal structures being either compressed or relaxed on either side. CONCLUSION: Our study provides initial evidence of differential cardiovascular effects of Asanas and subtle differences between right and left sided performance. Further, cardiovascular recovery is greater after the performance of the Asanas as compared to shavasan; thus, implying a better response when effort precedes relaxation. PMID- 25035618 TI - Effect of trataka on cognitive functions in the elderly. AB - BACKGROUND: Trataka, a type of yoga practice is considered to improve cognitive functions. The aim of this study was to test the effect of trataka on cognitive functions of the elderly. MATERIALS AND METHODS: Elderly subjects were recruited based on inclusion and exclusion criteria (n = 60) and randomly divided using randomized block design into two groups: Trataka and wait list control group. Trataka (a visual cleansing technique) was given for a period of 1 month (26 days). The subjects in both groups were assessed on day 1 (pre- and postintervention in trataka group and after quiet sitting in control group) and on day 30 on Digit Span Test, Six Letter Cancellation Test (SLCT), and Trail Making Test-B (TMT-B). RESULTS: Friedman's test and Wilcoxon signed-rank test showed that at the 2(nd) follow-up there was significant improvement in digit span scores (z = -3.35, P < 0.01) in the trataka group. SLCT scores (t = 5.08, P < 0.01) and TMT-B scores (t = -4.26, P < 0.01) improved immediately after the practice of trataka (when baseline compared to first follow-up). At 1 month follow-up, trataka group showed significantly better performance in the SLCT test compared to baseline (t = -3.93, P < 0.01) and TMT-B scores (t = 7.09, P < 0.01). Repeated measure analysis of variance (RM ANOVA) results also reiterated that there was significant interaction effect at the end of 1 month of trataka intervention as compared to control group on TMT-B and SLCT scores. CONCLUSIONS: The results of this study establish that Trataka can be used as a technique to enhance cognition in the elderly. PMID- 25035619 TI - Effect of Bhramari pranayama and OM chanting on pulmonary function in healthy individuals: A prospective randomized control trial. AB - BACKGROUND/AIM: Yoga is an ancient Indian science as well as the way of life. Pranayama is a part of yoga, which improves pulmonary function in combination of many pranayama, but the aim of our study is to evaluate the effect of only Bhramari pranayama and OM chanting on pulmonary function in healthy individuals. MATERIALS AND METHODS: A total of 82 subjects were randomized into the study group (SG) (n = 41) and control group (CG) (n = 41). Baseline assessment was performed before intervention for both groups. SG practiced Bhramari pranayama and OM chanting for the duration of 10 min (5 min for each practice)/day for the period of 6 days/week for 2 weeks and CG did not practice so. After intervention post-assessment was performed for SG (n = 40) and CG (n = 39). Statistical analysis was performed by Independent samples t-test and Student's paired t-test with the use of Statistical Package for the Social Sciences version 16 (2007, USA). RESULTS: The result showed a significant improvement in peak expiratory flow (PEF), forced expiratory flow (FEF)25% and maximal voluntary ventilation (MVV) along with a significant reduction in weight in SG compared with CG in independent samples t-test. Significant improvement in slow vital capacity (SVC), forced expired volume in 1 s (FEV1) along with PEF, FEF25% and MVV; Significant reduction in weight and body mass index were observed in SG unlike in CG in Student's paired t-test. No significant changes were found in forced vital capacity, FEV1 /SVC and FEF50% , between and within the group analysis of SG and CG. CONCLUSION: Bhramari pranayama and OM chanting are effective in improving pulmonary function in healthy individuals. PMID- 25035620 TI - Effect of yogic colon cleansing (Laghu Sankhaprakshalana Kriya) on pain, spinal flexibility, disability and state anxiety in chronic low back pain. AB - BACKGROUND: Studies have shown that Integrated Yoga reduces pain, disability, anxiety and depression and increases spinal flexibility and quality-of-life in chronic low back pain (CLBP) patients. OBJECTIVE: The objective of this study was to compare the effect of two yoga practices namely laghu shankha prakshalana (LSP) kriya, a yogic colon cleansing technique and back pain specific asanas (Back pain special technique [BST]) on pain, disability, spinal flexibility and state anxiety in patients with CLBP. MATERIALS AND METHODS: In this randomized control (self as control) study, 40 in-patients (25 were males, 15 were females) between 25 and 70 years (44.05 +/- 13.27) with CLBP were randomly assigned to receive LSP or BST sessions. The measurements were taken immediately before and after each session of either of the practices (30 min) in the same participant. Randomization was used to decide the day of the session (3(rd) or 5(th) day after admission) to ensure random distribution of the hang over effect of the two practices. Statistical analysis was performed using the repeated measures analysis of variance. RESULTS: Significant group * time interaction (P < 0.001) was observed in 11 point numerical rating scale, spinal flexibility (on Leighton type Goniometer) and (straight leg raise test in both legs), Oswestry Disability Index, State Anxiety (XI component of Spieldberger's state and trait anxiety inventory. There was significantly (P < 0.001, between groups) better reduction in LSP than BST group on all variables. No adverse effects were reported by any participant. CONCLUSION: Clearing the bowel by yoga based colon cleansing technique (LSP) is safe and offers immediate analgesic effect with reduced disability, anxiety and improved spinal flexibility in patients with CLBP. PMID- 25035621 TI - Implicit measure for yoga research: Yoga implicit association test. AB - CONTEXT: The implicit association test (IAT), a new tool for yoga research is presented. Implicit measures could be used in those situations where (1) The construct is difficult to self-report, (2) there is a threat of social desirability. Clinically, we can assess cognitive dissonance by evaluating incongruence between implicit and explicit measures. Explicit preferences are self-reported. Implicit preferences are what we inherently believe, often without our conscious awareness. AIMS: The primary objective of this study is to provide a bird's eye view of the field, implicit cognition, with emphasis on the IAT and the secondary objective is to illustrate through an example of our study to develop an implicit tool to assess implicit preference toward yoga. SETTINGS AND DESIGN: A total of 5 independent samples of total 69 students undergoing short and long-term yoga courses in a Yoga University were assessed for their implicit and explicit preferences towards yoga. MATERIALS AND METHODS: The yoga-IAT (Y IAT), explicit self-rating scale was administered through computers using the Inquisit program by Millisecond Software. Experimental and scoring materials are provided. RESULTS: A moderate preference toward yoga was detected, with a lower implicit-explicit congruence, reflecting possible confound of social desirability in the self-report of preference toward yoga. CONCLUSIONS: Implicit measures may be used in the yoga field to assess constructs, which are difficult to self report or may have social desirability threat. Y-IAT may be used to evaluate implicit preference toward yoga. PMID- 25035622 TI - Effect of Yoga on migraine: A comprehensive study using clinical profile and cardiac autonomic functions. AB - CONTEXT AND AIMS: Migraine is an episodic disabling headache requiring long-term management. Migraine management through Yoga therapy would reduce the medication cost with positive health benefits. Yoga has shown to improve the quality of life, reduce the episode of headache and medication. The aim of the present study was to evaluate the efficacy of Yoga as an adjuvant therapy in migraine patients by assessing clinical outcome and autonomic functions tests. SUBJECTS AND METHODS: Migraine patients were randomly given either conventional care (n = 30) or Yoga with conventional care (n = 30). Yoga group received Yoga practice session for 5 days a week for 6 weeks along with conventional care. Clinical assessment (frequency, intensity of headache and headache impact) and autonomic function test were done at baseline and at the end of the intervention. RESULTS: Yoga with conventional care and convention care groups showed significant improvement in clinical variables, but it was better with Yoga therapy. Improvement in the vagal tone along with reduced sympathetic activity was observed in patients with migraine receiving Yoga as adjuvant therapy. CONCLUSIONS: Intervention showed significant clinical improvement in both groups. Headache frequency and intensity were reduced more in Yoga with conventional care than the conventional care group alone. Furthermore, Yoga therapy enhanced the vagal tone and decreased the sympathetic drive, hence improving the cardiac autonomic balance. Thus, Yoga therapy can be effectively incorporated as an adjuvant therapy in migraine patients. PMID- 25035623 TI - Hatha yoga on body balance. AB - BACKGROUND: A good body balance requires a proper function of vestibular, visual, and somatosensory systems which can be reach with exercise practice and/or yoga. AIM: To determine the effects of a 5-month hatha yoga training program on body balance in young adults. MATERIALS AND METHODS: This study used a controlled, nonrandomized design, where the experimental group underwent a 5-month training program and were then compared with the control group that had a sedentary lifestyle. A convenience sample of 34 out of 40 men aged 25-55 years old (34.0 +/ 0.9) were deemed eligible for this study. They were randomly divided into two groups: Experimental and control groups. Subjects in the experimental group were engaged in 60 min sessions of hatha yoga three times a week for 5 months. We evaluated postural control by measuring the limit of stability and velocity of oscillation (VOS) in three conditions of the balance rehabilitation unit (BRU) and through field procedures (four position, plane, flamingo, hopscotch, and dynamic test). RESULTS: We observed differences (P < 0.05) in postintervention scores between the groups regardless of BRU parameters and field procedures (except for flamingo) even after adjusting for preintervention scores, suggesting that these changes were induced by hatha yoga training. The partial eta squared on BRU parameters ranged from 0.78 (VOS1)-0.97 (COP2), and from 0.00 (flamingo) 0.94 (four position) for the field procedures. CONCLUSIONS: Our results provide substantial evidence that postural control in healthy young adults can be improved through practicing hatha yoga. PMID- 25035624 TI - Effect of Bhramari Pranayama on response inhibition: Evidence from the stop signal task. AB - CONTEXT: Response inhibition is a key executive control processes. An inability to inhibit inappropriate actions has been linked to a large range of neurologic and neuropsychiatric disorders. AIMS: Examine the effect of Bhramari Pranayama (Bhpr) on response inhibition in healthy individuals. SETTINGS AND DESIGN: Thirty one male students age ranged from 19-31 years from a residential Yoga University, Bengaluru, India were recruited for this study. We used a randomized self as control within-subjects design. Participants were counterbalanced randomly into two different experimental conditions (Bhpr and deep breathing (DB)). MATERIALS AND METHODS: Response inhibition has been measured using a standard tool Stop Signal Task (SST). Each session lasted for 50 min with 10 min for the experimental conditions, preceded and followed by 20 min of assessment. The primary outcome measure was stop signal reaction time (SSRT), an estimate of the subject's capacity for inhibiting prepotent motor responses. Additional measures of interest were the probability of responding on stop signal trials, P (r | s) and mean RT to go stimuli. RESULTS: The mean probability of responding on stop signal trials (P (r | s)) during Bhpr and DB are close to 50%, indicating reliable SSRT. Paired sample t-tests showed a significant decrease (P = 0.024) in SSRT after Bhpr session, while the DB group did not show any significant change. Further, t-tests show that the go RT increased significantly after Bhpr (P = 0.007) and no other changes/differences were observed. CONCLUSIONS: Bhpr enhanced response inhibition and cognitive control in nonclinical participants. PMID- 25035625 TI - Self-reported measures of mindfulness in meditators and non-meditators: A cross sectional study. AB - CONTEXT: Mindfulness forms an important component of meditation practice and has been increasingly popular around the world. There has been growing interest in studying the mindful component of various meditation techniques. One of the various forms of mindfulness is the practice of a unique technique called cyclic mediation (CM). We aimed at ascertaining the level of mindfulness in experienced practitioners of CM using a Mindfulness Attention Awareness Scale (MAAS). MATERIALS AND METHODS: MAAS was administered anonymously in a classroom setup and two of the project coordinators were present to supervise the administration and to assist the participants where necessary. We executed a cross sectional design. One hundred and thirty-three (n = 133) healthy male volunteers (66 meditators and 67 non-meditators) with ages ranging from 25 to 35 years participated in the study. Meditators had a minimum 3 years experience of meditation. RESULTS: Data were analyzed using IBM SPSS 20. The data were checked for normality and an independent samples t-test was employed to compare the means of both the groups. MAAS scores were significantly higher in meditators as compared with the non meditators (P < 0.001). We found a positive correlation (r = 0.620) between the years of meditation practice and the levels of trait mindfulness. CONCLUSIONS: CM can lead to development of higher levels of mindfulness and may have the ability to positively impact mental states and attention, thereby offering the potential for prevention of clinical levels of psychopathology and improving overall psychological well-being in healthy individuals. PMID- 25035626 TI - Levels of immune cells in transcendental meditation practitioners. AB - CONTEXT: Relationships between mind and body have gradually become accepted. Yogic practices cause modulation of the immune system. Transcendental meditation (TM) is a specific form of mantra meditation. We reported previously different plasma levels of catecholamines and pituitary hormones in TM practitioners comparing with a control group, and patterns of the daytime secretion of these hormones different from those normally described. AIMS: The aim of the following study is to evaluate the immune system in these meditation practitioners, by determining leukocytes and lymphocytes subsets. METHODS: TM group consisted of 19 subjects who regularly practice either TM or the more advanced Sidhi-TM technique. A control group consisted of 16 healthy subjects who had not previously used any relaxation technique. Total leukocytes, granulocytes, lymphocytes and monocytes were counted by an automated quantitative hematology analyzer, whereas lymphocytes subsets were determined by flow cytometry. Samples were taken from each subject at 0900 h after an overnight fast. RESULTS: The results indicated that the TM group had higher values than the control group in CD3+CD4-CD8+ lymphocytes (P < 0.05), B lymphocytes (P < 0.01) and natural killer cells (P < 0.01), whereas CD3+CD4+CD8- lymphocytes showed low levels in meditation practitioners (P < 0.001). No significant differences were observed in total leukocytes, granulocytes, monocytes, total lymphocytes or CD3+ lymphocytes comparing both groups. CONCLUSIONS: The technique of meditation studied seems to have a significant effect on immune cells, manifesting in the different circulating levels of lymphocyte subsets analyzed. The significant effect of TM on the neuroendocrine axis and its relationship with the immune system may partly explain our results. PMID- 25035627 TI - Do side-effects/injuries from yoga practice result in discontinued use? Results of a national survey. AB - CONTEXT: Yoga-related injuries are of increasing concern as the use of yoga continues to rise. AIMS: The aim of the following study is to examine whether a national sample of yoga practitioners would report discontinued use of yoga due to injury from the practice, assess what injuries resulted in discontinued use, determine what injuries were most common and identify injuries requiring medical attention. METHODS: Secondary data analysis of a nationally representative sample of adults in the United States (n = 23,393). RESULTS: Less than 1% of individuals who had ever practiced yoga (n = 2230) reported an injury from yoga that led to discontinued use. Of those reporting injury, less than one-third (n = 4) reported seeking medical attention. The most common side-effect was back pain. Approximately, half of those reporting back pain sought medical attention. CONCLUSIONS: Injury due to yoga is an infrequent barrier to continued practice and severe injury due to yoga is rare. PMID- 25035628 TI - Pulmonary functions in yogic and sedentary population. AB - BACKGROUND: The Pulmonary Function Tests are important for measuring the fitness of an individual from a physiological point of view. Lung function parameters tend to have a relationship with lifestyle such as regular yoga, an ancient system of Indian Philosophy. Yoga is probably the best lifestyle ever devised in the history of mankind. Hence the present analytical study was undertaken to assess the effects of yoga on respiratory system when compared with sedentary subjects. OBJECTIVE: To compare the pulmonary function test among the yogic and sedentary groups. MATERIALS AND METHODS: The present study was conducted on 50 subjects practicing yoga and 50 sedentary subjects in the age group of 20-40 years. They were assessed for pulmonary function test in which sedentary group acted as controls. The tests which were recorded as per standard procedure using Medspiror as determinants of pulmonary function were FVC, FEV1, FEV3, PEFR and FVC/FEV1 ratio. RESULTS: Pulmonary Functions were compared between the yoga practitioners and sedentary group. Yoga exercise significantly increased chest wall expansion as observed by higher values of pulmonary functions compared with sedentary controls. The study group were having higher mean of percentage value of FVC 109.1 +/- 18.2%, FEV1 of 116.3 +/- 15.9%, FEV3 of 105.7 +/- 14.9 %, PEFR of 109.2 +/- 21.3% and FEV1/FVC ratio of 111.3 +/- 6.9% as compared to sedentary group. CONCLUSIONS: Regular Yoga practice increases the vital capacity, timed vital capacity, maximum voluntary ventilation, breath holding time and maximal inspiratory and expiratory pressures. PMID- 25035629 TI - Role of integrated approach of yoga therapy in a failed post-total knee replacement of bilateral knees. AB - OA Knee is the most common arthritis. Knee replacement Surgeries are being done increasingly in the present times. This has led to the violation of the standard indications and when knees are replaced ignoring other co - musculoskeletal conditions it results in the surgery failing early. This is about a patient who encountered a failed TKR due to improper selection as patient had bilateral OA Hip that was ignored in the initial stages. To overcome the problem she was advised bilateral hip replacement which would leave her with four replacements in the lower limb. She refused surgery and was told there are no alternative treatment options. This patient underwent a 3 week integrated course of IAYT at our center and she made a remarkable recovery. IAYT is a good non-surgical treatment that can be affective both before and after knee replacement and it should be considered as the first choice of treatment before surgery. PMID- 25035630 TI - Response to prana and electrons in health and beyond. PMID- 25035631 TI - Decoding the integrated approach to yoga therapy. PMID- 25035632 TI - Predicting perfect drug candidates: Molecular docking 2.0. PMID- 25035633 TI - Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. AB - Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID- 25035634 TI - Management of diabetes mellitus type-2 in the geriatric population: Current perspectives. AB - The prevalence of diabetes mellitus (DM) has increased exponentially throughout the world and there is rapid increase in elderly diabetics. DM is associated with increased mortality and considerable morbidity including stroke, heart disease, and diminished quality of life in the elderly. However, the unique features of geriatric diabetes have not been given due a prominence in medical literature. Hypoglycemia remains the biggest complicating factor and needs to be avoided in the elderly. Most people in the geriatric age group have some degree of renal insufficiency and medications need to be adjusted wisely with changing renal profile. Because safer and more effective pharmacological therapy is available, an individual approach to DM in the elderly is essential. PMID- 25035635 TI - In silico designing and molecular docking of a potent analog against Staphylococcus aureus porphobilinogen synthase. AB - BACKGROUND: The emergence of multidrug-resistant strains of Staphylococcus aureus, there is an urgent need for the development of new antimicrobials which are narrow and pathogen specific. AIM: In this context, the present study is aimed to have a control on the staphylococcal infections by targeting the unique and essential enzyme; porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of delta-aminolevulinic acid, an essential step in the tetrapyrrole biosynthesis. Hence developing therapeutics targeting PBGS will be the promising choice to control and manage the staphylococcal infections. 4,5 dioxovalerate (DV) is known to inhibit PBGS. MATERIALS AND METHODS: In view of this, in this study, novel dioxovalerate derivatives (DVDs) molecules were designed so as to inhibit PBGS, a potential target of S. aureus and their inhibitory activity was predicted using molecular docking studies by molecular operating environment. The 3D model of PBGS was constructed using Chlorobium vibrioform (Protein Data Bank 1W1Z) as a template by homology modeling method. RESULTS: The built structure was close to the crystal structure with Z score - 8.97. Molecular docking of DVDs into the S. aureus PBGS active site revealed that they are showing strong interaction forming H-bonds with the active sites of K248 and R217. The ligand-receptor complex of DVD13 showed a best docking score of - 14.4555 kcal/mol among DV and all its analogs while the substrate showed docking score of - 13.0392 kcal/mol showing interactions with S199, K217 indicating that DVD13 can influence structural variations on the enzyme and thereby inhibiting the enzyme. CONCLUSION: The substrate analog DVD13 is showing significant interactions with active site of PBGS and it may be used as a potent inhibitor to control S. aureus infections. PMID- 25035636 TI - Evaluation of a classical unani pharmacopeial formulation safoof-e-muhazzil in hyperlipidemia: A randomized, standard controlled clinical study. AB - AIM OF THE STUDY: The aim of the following study is to evaluate the efficacy and tolerability of a compound Unani formulation in hyperlipidemia on clinical and biochemical parameters. MATERIALS AND METHODS: A total of 90 patients with total cholesterol level of 220 mg/dl and above were included. In Group 'A' thirty patients with total cholesterol 243.5 +/- 5.294 mg/dl received Unani formulation safoof-e-muhazzil (SM) in its classical powder form 5 g twice daily orally, in Group 'B' thirty patients with total cholesterol 234 +/- 3.822 mg/dl received the SM but in compressed tablet form in the same dosage and in Group 'C' 30 patients with total cholesterol 242.7 +/- 5.563 mg/dl received atorvastatin 10 mg as a standard control. Follow-up was carried out on second, fourth and 6th week and patients were evaluated on clinical as well as biochemical parameters. RESULTS: Group A before treatment had mean total cholesterol of 243.5 +/- 5.294 mg/dl which decreased significantly after treatment to 225.6 +/- 5.953 mg/dl (P < 0.001) with a percentage change of 7.35%. Group B had mean total cholesterol of 234 +/- 3.822 mg/dl which was significantly reduced to 212.67 +/- 3.94 mg/dl (P < 0.001) post-treatment with a percentage change of 9.11%. Control Group C having mean total cholesterol of 242.7 +/- 5.563 mg/dl before treatment was significantly decreased to 178.73 +/- 4.669 mg/dl (P < 0.001) post-treatment with a percentage change of 26.3%. Group A had significant relief 20.72% (P < 0.001) in fatigue, 16.09% (P > 0.5) relief in palpitation and 26.17% (P < 0.001) relief in dyspnea post-treatment. Group B fatigue decreased significantly by 18.14% (P < 0.01), palpitation by 22.91% (P < 0.01) and dyspnea by 20.46% (P < 0.01). In Group C a non-significant increase of 2.2% was observed in fatigue post treatment, palpitation decreased by 10.22% non-significantly and dyspnea decreased significantly by 17.64% (P < 0.001). Results indicate that the test drug safely and effectively ameliorates the clinical condition of patients with hyperlipidemia while decreasing cholesterol level as well. PMID- 25035637 TI - Formulation and evaluation of sustained release matrix tablet of rabeprazole using wet granulation technique. AB - INTRODUCTION: Rabeprazole, a member of substituted benzimidazoles, inhibits the final step in gastric acid secretions. This drug claims to cause fastest acid separation (due to higher pKa), and more rapidly converts to the active species to aid gastric mucin synthesis. The most significant pharmacological action of Rabeprazole is dose dependent suppression of gastric acid secretion; without anticholinergic or H2-blocking action. It completely abolishes the hydrochloric acid secretion as it is powerful inhibitor of gastric acid. Rabeprazole is acid labile and hence commonly formulated as an enteric coated tablet. The absorption of rabeprazole occurs rapidly as soon as tablet leaves the stomach. AIM: In the present study an attempt was made to formulate and evaluate Rabeprazole sustained release matrix tablet using wet granulation technique incorporating various polymers like HPMC-E15, Carbopol934, and sodium carboxymethyl cellulose (CMC). MATERIALS AND METHODS: The Formulated tablets were evaluated for different physicochemical properties like rheological properties, weight variation, thickness, hardness, % friability, in vitro release studies and drug content. RESULTS: Studies revealed that all the physicochemical parameters comply with the official standards. The in vitro release studies exhibits the release up to 90%, over a prolonged period of time which confirms the extended release profile of formulation, having better bioavailability as well as decreased dosing frequency with reduced doses. CONCLUSION: The sustained release matrix tablets of rabiprazole shown better bioavailability, efficacy and potency, when compared with official standards. PMID- 25035638 TI - Reduction in mortality and teratogenicity following simultaneous administration of folic acid and vitamin E with antiepileptic, antihypertensive and anti allergic drugs. AB - AIM: The present study was designed to evaluate the teratogenic effects on breeding pattern in mice following administration of lamotrigine (LT) and levetiracetam (LV) and its combination with anti-hypertensive and anti-allergic drugs. Moreover, possibility of decrease in teratogenic effect was also evaluated upon simultaneous administration of these combinations with folic acid or vitamin E. MATERIALS AND METHODS: The study was carried out on mature female mice housed in polycarbonate breeding cages. Drugs were administered continuously till the birth of neonates and pups were examined for any teratogenic potential of drugs. RESULTS: The results of the study reveals that teratogenic effects of lamotrigine, methyldopa and loratadine (LTMLO) combination were seems to be reduced upon simultaneous administration with folic acid, while addition of vitamin E was found to be more effective in reducing the mortality rate of levetiracetam, methyldopa and loratadine combination. CONCLUSION: Teratogenic effects of LTMLO combination were better prevented by folic acid. However, further studies on large number of animals and humans are required before reaching to definite conclusion. PMID- 25035639 TI - Pandemic influenza A (H1N1) vaccination among libyan health care personnel: A cross-sectional retrospective study. AB - CONTEXT: Vaccination rate among health-care personnel's (HCPs) are not promising notwithstanding the World Health Organization campaigns over three decades resulting in compromising patient safety. The H1N1 virus, which caused a world wide pandemic earlier has now transformed into a seasonal flu virus. AIMS: The aim of this study was to analyze the incidence of 2009-10 pandemic influenza A (H1N1) vaccination among Libyan HCPs in four hospitals of Al-Zawia, Libya. MATERIALS AND METHODS: A questionnaire, which listed eight sections of parameters distributed among 310 HCPs to assess the vaccination rate and resulting adverse effects. STATISTICAL ANALYSIS: The data were analyzed using descriptive statistics, Pearson's chi(2)-test and Student's t-test where appropriate. RESULTS: The overall pandemic A (H1N1) vaccination among all HCPs was only 107 (39.9%) out of 268 respondents. The distribution of respondents based on physicians, other staff and sex were found significant (P < 0.05). The common barriers of H1N1 vaccination being lack of awareness fear of adverse effects, allergies and religious beliefs. The major adverse effect observed was erythema in 95.56% of physicians and 87.1% in other staff. About 2% of HCPs have reported arthralgia. No significant differences existed between the responses of general variables and adverse effects. The glycoprotein 120 and squalene were found responsible for the reported adverse effects. 37 (82.22%) vaccinated medical HCPs have advised their patients to get vaccinated. CONCLUSIONS: Due to recurrence of H1N1 influenza in recent times, vaccination campaigns should be promoted immediately to address the knowledge gap of HCPs for intervention by regulatory and health organizations in Libya. The health belief model could be applied to improve vaccination among HCPs. PMID- 25035640 TI - Anti-nuclear antibodies positive serum from systemic lupus erythematosus patients promotes cardiovascular manifestations and the presence of human antibody in the brain. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by the presence of anti-nuclear antibodies (ANAs) in the serum of patients. These antibodies may cross over into the brain resulting in the development of neuropsychiatric symptoms and result in abnormal pathology in other organs such as the heart and kidneys. OBJECTIVE: The objective of this study was to determine if SLE pathology could be detected in the hearts and brains of rats injected with positive human ANA serum. MATERIALS AND METHODS: Lewis rats (n = 31) were selected for this study due to documented research already performed with this strain in the investigation of serum sickness, encephalitis and autoimmune related carditis. Rats were injected once a week with either ANA positive or negative control serum or saline. Hearts were examined for initial signs of heart disease including the presence of lipid deposits, vegetation, increased ventricular thickness and a change in heart weight. Brains were examined for the presence of human antibody and necrotic lesions. Animals were observed for outward signs of neuropathy as well. Blood samples were taken in order to determine final circulating concentrations of IgG and monitor histamine levels. RESULTS: Animals injected with ANA were significantly higher for lipid deposits in the heart and an increased ventricular thickness was noted. One animal even displayed Libman-Sacks endocarditis. Brains were positive for the presence of human IgG and diffuse internal lesions occurred in 80% of the ANA positive serum injected animals examined. Blood histamine levels were not significantly different, but actually lower than controls by the end of the experiment. CONCLUSION: Since human antibodies were detected in the brain, further studies will have to identify which antibody cross reactions are occurring within the brain, examine cell infiltration as well as characterize the antibodies associated with more destructive consequences such as lesion formation. PMID- 25035641 TI - An in vivo and in vitro investigation of the effect of Aloe vera gel ethanolic extract using animal model with diabetic foot ulcer. AB - AIM: To examine the preventive effect of Aloe vera gel ethanolic extract using diabetic foot ulcer (DFUs) protocol in Wistar rats. MATERIALS AND METHODS: Male Wistar rats were divided into untreated control (Group I), untreated DFUs (Group II), DFUs treated with A. vera gel ethanolic extract (Group III), DFUs treated with topical A. vera gel (Group IV), DFUs treated with A. vera gel ethanolic extract and topical A. vera gel (Group V). The rats in the treatment groups were daily administered the A. vera gel and ethanolic extract for 9 days. Fasting blood glucose levels and percentage of wound ulcer contraction were measured on day 3, 6, and 9. STATISTICAL ANALYSIS USED: The results are expressed as a mean +/- Standard Error Mean (SEM). Data were analyzed using one-way analysis of variance (ANOVA) after Newman-Keuls test. P < 0.05 were considered statistically significant in all cases. RESULTS: Oral administration of A. vera gel ethanolic extract at a dose of 300 mg/kg body weight per day to diabetic rats for a period of 9 days resulted in a significant reduction in fasting blood glucose and a significant improvement in plasma insulin. Topical application of A. vera gel at a dose 30 mg/kg body weight per day to streptozotocin (STZ)-induced diabetic rats for a period of 9 days resulted in no change in blood glucose and plasma insulin. Oral administration as well as topical application of A. vera gel ethanolic extract and gel significantly reduced the blood glucose, improved the plasma insulin, and significantly increased DNA and glycosaminoglycans (GAGs) to improve the wound ulcer healing as well as the breaking strength on day 9. CONCLUSIONS: Present findings provide a scientific rationale for the use of A. vera gel ethanolic extract, and showed that the gel attenuated the diabetic foot wound in rats. PMID- 25035642 TI - Marker based standardization of polyherbal formulation (SJT-DI-02) by high performance thin layer chromatography method. AB - BACKGROUND: Preparation of highly standardized herbal products with respect to chemical composition and biological activity is considered to be a valuable approach in this field. SJT-DI-02 polyherbal formulation was successfully developed at our institute and filed for patent at Mumbai patent office. OBJECTIVE: The present work was marker based standardization of patented, novel and efficacious polyherbal formulation namely SJT-DI-02 for the treatment of diabetes. The SJT-DI-02 was comprised of dried extracts of rhizomes of Acorus calamus, leaves of Aegle marmelose, fruits of Benincasa hispida, roots of Chlorophytum arendinaceum, seeds of Eugenia jambolana, leaves of Ocimum sanctum, pericarp of Punica granatum, seeds of Tamarindus indica. Selected plants were collected, dried and extracted with suitable solvents. The formulation was prepared by mixing different fractions of extracts. MATERIALS AND METHODS: For successful and best standardization, first of all selection and procurement was carried out. Selection is done on the basis of therapeutic efficacy and amount of the marker present in the particular plant part. At the time of procurement side by side phytochemical screening and estimation of phytoconstituents was carried out. After completion of preliminary screening using characterized markers, we tried to develop best TLC systems using selected solvent composition. Finally well-developed TLC systems were applied in HPTLC. In the present study polyherbal formulation was standardized by using different four markers. TLC Densitometric methods were developed using HPTLC for the quantification of these marker compounds. Solvent systems were optimized to achieve best resolution of the marker compounds from other components of the sample extract. The identity of the bands in the sample extracts were confirmed by comparing the Rf and the absorption spectra by overlaying their UV absorption spectra with those of their respective standards. The purity of the bands due to marker compounds in the sample extracts were confirmed by overlaying the absorption spectra recorded at start, middle and end position of the band in the sample tracks. After conforming all these things fingerprints were developed for all three formulations which will be act as authentification and quality control tool. RESULTS: % w/w of asarones is 3.61, % w/w of marmelosin is 4.60, % w/w of gallic acid is 10.80 and % w/w of lupeol is 4.13. The method was validated in terms of linearity, precision, repeatability, limit of detection, limit of quantification and accuracy. In well-developed mobile phase system linearity was found to be in the range of 0.983-0.995, % recovery was found to be in the range of 97.48-99.63, % RSD for intraday and interday was found to be 0.13- 0.70 and 0.32 -1.41 and LOD and LOQ was found to be in the range of 0.15- 0.61 and 0.45 -1.83 microgram per ml. CONCLUSION: Thus High performance thin layer chromatography (HPTLC) methods were developed and validated in terms of linearity, precision, repeatability, limit of detection, limit of quantification and accuracy. The methods were rapid, sensitive, reproducible and economical. It does not suffer any positive or negative interference due to common other component present in the formulation and would also serve as a tool for authentication of herbal products containing marmelosin, gallic acid, lupeol and asarones. Thus this work provides standardized and therapeutically active polyherbal formulations for the different ailments. PMID- 25035643 TI - Laparoscopic approach for hepatocellular carcinoma: where is the limit? PMID- 25035644 TI - The unique phenotypes of adenocarcinoma of the esophagogastric junction in China. PMID- 25035645 TI - Adenocarcinoma of esophagogastric junction: controversial classification, surgical management, and clinicopathology. PMID- 25035646 TI - Comments to young surgeons concerning laparoscopic spleen-preserving D2 lymph node dissection for advanced gastric cancer on the upper body. AB - Qualified radical gastrectomy with lymph node dissection is very important to the prognosis of patients with gastric cancer. Now D2 lymph node dissection is standard procedure for gastric cancer surgery, and spleen hilar lymph node dissection is mandatory for gastric cancer in upper body. Because the anatomy of vessels in this area is very complicated, D2 lymph node dissection is technical challenging not only for open gastrectomy but also for laparoscopic one. Adapting a new technique is important to all surgeons, but we surgeons should always consider a patient's safety as the most important factor during surgery and that efforts should be based on scientific rationale with oncologic principles. I hope that the recent report by Huang et al. about laparoscopic spleen preserving hilar lymph node dissection would be helpful to young surgeons who will perform laparoscpic total gastrectomy for gastric cancer. PMID- 25035647 TI - Laparoscopic resection for hepatocellular carcinoma: eastern and western experiences. PMID- 25035648 TI - Lymph node metastasis and lymphadenectomy of resectable adenocarcinoma of the esophagogastric junction. AB - Based on Siewert classification, adenocarcinomas of the esophagogastric junction (AEGs) have different behaviors of perigastric-mediastinal nodal metastasis. Siewert type I AEGs have higher incidence of mediastinal nodal metastasis than those of type II or III, especially at middle-upper mediastinum. With regard to the necessity of mediastinal lymphadenectomy, theoretically, transthoracic esophagogastrectomy with complete mediastinal lymphadenectomy is suggested for Siewert type I AEGs, while transhiatal total gastrectomy with lower mediastinal and D2 perigastric lymphadenectomy is a standard surgery for type II-III AEGs. Nevertheless, the mediastinal nodal metastasis is an independent factor of poor prognosis for any type of AEG. PMID- 25035649 TI - Laparoscopic liver resection: western versus eastern experience. PMID- 25035650 TI - Laparoscopic resection for hepatocellular carcinoma: comparison between Middle Eastern and Western experience. PMID- 25035651 TI - Clinical analysis of intracranial germinoma's craniospinal irradiation using helical tomotherapy. AB - OBJECTIVE: To evaluate the short-term clinical outcomes of intracranial germinoma patients treated with craniospinal irradiation (CSI) using helical tomotherapy (HT) system in our center. METHODS: Twenty-three patients who were treated with CSI in our center from January 2008 to July 2012 were collected, with an average age of 20. All of the patients' CSI used the HT system. The total doses were 27 36 Gy/15-20 F (1.5-2 Gy per fraction), and total local doses were 46-60 Gy/30-50 F (5 fractions per week). All female patients for CSI were treated with left right parallel-opposed field irradiation to protect their ovarian functions. Median follow-up time was 30.9 months (range, 5-67 months). The SPSS19.0 software was used, and the overall survival (OS) was calculated using the Kaplan-Meier method. RESULTS: Among 17 patients with assessable tumors, 9 cases (52.9%) were CR, 7 cases (41.2%) were PR, and 1 case (5.9%) was SD. Hematological toxicity was the severest side-effect occurred in the procedure of CSI. The level 1-4 acute leukopenia were 8.7%, 30.4%, 34.8% and 21.7% and the level 1-4 acute thrombopenia were 8.7%, 30.4%, 21.7% and 8.7%, respectively. CONCLUSIONS: For primary intracranial germinomas, HT can be used to implement CSI for simplifying radiotherapy procedures, improving radiotherapy accuracy, enhancing protection of peripheral organs at risk (ORA) and guaranteeing therapeutic effects. With the acceptable acute and long-term toxicity, CSI using HT in intracranial germinoma patients can be a safe and alternative mode. PMID- 25035652 TI - A systemic review of glutathione S-transferase P1 Ile105Val polymorphism and colorectal cancer risk. AB - OBJECTIVES: To investigate the correlation between glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and colorectal cancer (CRC) risk. METHODS: Studies were identified to investigate the association between GSTP1 Ile105Val polymorphism and CRC risk. Systematic computerized searches of the PubMed, Chinese National Knowledge Infrastructure, WANFANG and SinoMed were performed. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were used to measure GSTP1 Ile105Val polymorphisms and CRC risk. RESULTS: A total of 23 retrospective studies were included in the meta-analysis. During all studies including 6,981 cases and 8,977 controls, sample sizes ranged from 146 to 2,144. Overall, the pooled results revealed that Ile105Val polymorphism was not associated with CRC risk and confused results were found in subgroup analyses. Further meta-analyses were conducted after excluding low-quality studies. GSTP1 Ile105Val is associated with increased risk of CRC limited in studies with matched control. There was no significant heterogeneity in all genetic comparisons, but heterogeneity existed in subgroup analyses of heterozygous and dominant comparisons. The meta-regression analyses indicated that matched controls were the significant factor influencing between-study heterogeneity in all possible influential factors including published year, ethnicity, source of control, sample size, Hardy-Weinberg equilibrium (HWE) in control and matched controls. Sensitivity analysis revealed the pooled ORs were not changed before and after removal of each single study in all genetic comparisons, indicating the robustness of the results. CONCLUSIONS: GSTP1 Ile105Val might be associated with increased risk of CRC. However, more high-quality case-control studies should be performed to confirm the authenticity of our conclusion. PMID- 25035653 TI - Erythropoiesis-stimulating agents in the management of cancer patients with anemia: a meta-analysis. AB - BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are widely used in the management of anemia in cancer patients. Despite their apparent effectiveness, recent studies have suggested that ESAs could result in serious adverse events and even higher mortality. The aim of the current study was to evaluate the benefits and risks of ESAs in the management of cancer patients with anemia using a meta-analysis. METHODS: The initial literature search covered Medline, PubMed, Embase, and the Cochrane Center Register of Controlled Trials, and identified 1,569 articles. The final meta-analysis included eight randomized controlled trials (n=2,387) in cancer patients with <11 g/dL hemoglobin (Hb) at the baseline and target Hb (for stopping ESA treatment) at no more than 13 g/dL. The assessment measures included Hb response, blood transfusion rate and adverse events that included venous thromboemblism (VTE), hypertension, and on-study mortality. The results are expressed as pooled odds ratio (OR). Publication bias was assessed using funnel plot analysis. RESULTS: ESAs significantly increased the Hb concentration [OR 7.85, 95% confidence interval (CI): 5.85 to 10.53, P<0.001] and reduced the red blood cell (RBC) transfusion rate (OR 0.52, 95% CI: 0.42 to 0.65, P<0.001). ESAs did not increase the accumulated adverse events (OR 0.95, P=0.82), or the on-study mortality (OR 1.09, P=0.47). CONCLUSIONS: ESAs are not associated with increased frequency of severe adverse events in anemic cancer patients when the target Hb value is no more than 13 g/dL. PMID- 25035654 TI - Internal compared with external drainage of pancreatic duct during pancreaticoduodenectomy: a retrospective study. AB - OBJECTIVE: To compare internal with external drainage of the pancreatic duct during pancreaticoduodenectomy with regard to the incidence of postoperative pancreatic fistula (POPF) and other complications. METHODS: We retrospectively analyzed 316 patients who underwent pancreaticoduodenectomy with a placed drainage tube (external, n=128; internal, n=188) in the pancreatic duct from 1 January 1999 to 31 December 2011 in Tianjin Third Central Hospital of China. The incidence of POPF and some other complications were compared. RESULTS: There was no difference in the incidence rates of POPF between those given an internal or external drainage tube (P=0.788), but POPF was more severe in the former (P=0.014). Intraperitoneal bleeding rate was also higher in the patients with internal drainage (P=0.040), but operative time and postoperative hospitalization were longer in those with external drainage (P=0.002 and P=0.007, respectively). There was no difference between the groups with regard to the incidence rates of gastrointestinal bleeding, delayed gastric emptying, pulmonary infection, or incision infection and in-hospital mortality. CONCLUSIONS: External drainage of the pancreatic duct during pancreaticoduodenectomy can decrease the severity of POPF, but operative time and postoperative hospitalization will be extended. PMID- 25035655 TI - Characteristics and trends in incidence of childhood cancer in Beijing, China, 2000-2009. AB - OBJECTIVE: To investigate the characteristics and incidence trends of childhood cancer in Beijing, China, from 2000 to 2009. METHODS: A total of 1,274 cases with childhood cancer in Beijing from 2000 to 2009 were included in the study. All rates were age-standardized using the direct method to the world standard population and expressed per million person-years. Incidence trends were characterized by calculating annual percent change (APC) using Joinpoint Regression Program. RESULTS: The crude incidence rate was 106.47 per million [age standardized rate (ASR) 113.34] between 2000 and 2009 in Beijing with the most common diagnoses, leukemia (N=505, 39.64%, ASR 45.20), followed by central nervous system (CNS) tumors (N=228, 17.90%, ASR 19.28) and lymphoma (N=91, 7.14%, ASR 6.97). The incidence for all childhood cancers combined has increased during the study period, with an APC of 5.84% [95% confidence interval (95% CI): 1.0 10.9] after adjusted by world population. The ASR of all combined cancers in boys showed a slight, but no significant increase, with an APC of 5.33% (95% CI: -0.6 11.6); for girls, the trends increased significantly, with an APC of 6.54% (95% CI: 1.5-11.8). CONCLUSIONS: The incidence rate of childhood cancer in Beijing was higher than the average level of China and lower than that of western countries. The incidence trends of childhood cancer, especially leukemia among girls showed a significantly increase from 2000 to 2009. While among boys, no substantially change was seen during the observed time period. Some sex-specific trends by subcategories and trends of major cancers in different age groups by cancer site merit further investigation. PMID- 25035656 TI - Report of China's innovation increase and research growth in radiation oncology. AB - AIMS: To investigate the research status of radiation oncology in China through survey of literature in international radiation oncology journals and retrospectively compare the outputs of radiation oncology articles of the three major regions of China-Mainland (ML), Taiwan (TW) and Hong Kong (HK). METHODS: Radiation oncology journals were selected from "oncology" and "radiology, nuclear & medical image" category from Science Citation Index Expand (SCIE). Articles from the ML, TW and HK were retrieved from MEDLINE. The number of total articles, clinical trials, case reports, impact factors (IF), institutions and articles published in each journals were conducted for quantity and quality comparisons. RESULTS: A total 818 articles from 13 radiation oncology journals were searched, of which 427 are from ML, 259 from TW, and 132 from HK. Ninety-seven clinical trials and 5 case reports are reported in China. Accumulated IF of articles from ML (1,417.11) was much higher than that of TW (1,003.093) and HK (544.711), while the average IF of articles from ML is the lowest. CONCLUSIONS: The total number of articles from China especially ML increased significantly in the last decade. The number of articles published from the ML has exceeded those from TW and HK. However, the quality of articles from TW and HK is better than that from ML. PMID- 25035657 TI - "Wrapping the gastroduodenal artery stump" during pancreatoduodenectomy reduced the stump hemorrhage incidence after operation. AB - OBJECTIVE: After pancreaticoduodenectomy (PD), the postoperative gastroduodenal artery stump (GDAS) hemorrhage is one of the most serious complications. The purpose of this study is to determine whether wrapping the GDAS during PD could decrease the postoperative GDAS hemorrhage incidence. METHODS: A retrospective review involving 280 patients who underwent PD from 2005 to 2012 was performed. Wrapping the GDAS during PD was defined as "Wrapping the GDAS using the teres hepatis ligamentum during PD". A total of 140 patients accepted the "wrapping" procedure (wrapping group). The other 140 patients didn't apply the procedure (non-wrapping group). Age, sex, preoperative data, estimated intraoperative blood loss, postoperative complications, pathologic parameters and hospitalization time were compared between two groups. RESULTS: There were no significant differences in patient characteristics between two groups. After wrapping, the incidence of postoperative GDAS bleeding decreased significantly (1/140 vs. 9/140, P=0.01). The rates of the other complications (such as intra-abdominal infection pancreatic fistula, billiary fistula, gastrointestinal bleeding, et al.) showed no significant differences. CONCLUSIONS: Wrapping the GDAS during PD significantly reduced the postoperative GDAS hemorrhage incidence. And the "wrapping" had no obvious influence on other complications. PMID- 25035658 TI - Risk factors of intra-abdominal bacterial infection after liver transplantation in patients with hepatocellular carcinoma. AB - OBJECTIVE: To explore the risk factors of intra-abdominal bacterial infection (IAI) after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). METHODS: A series of 82 HCC patients who received LT surgeries in our department between March 2004 and April 2010 was recruited in this study. Then we collected and analyzed the clinical data retrospectively. Statistical analysis system (SPSS) software was adopted to perform statistical analysis. Chi-square test, t-test and Wilcoxon rank sum test were used to analyze the clinical data and compute the significance of the incidences of early-stage IAI after LT for HCC patients. Binary logistic regression was performed to screen out the risk factors, and multiple logistic regression analyses were performed to compute the independent risk factors. RESULTS: A series of 13 patients (13/82, 15.9%) had postoperative IAI. The independent risk factors of postoperative intra-abdominal bacterial infections after LT for HCC patients were preoperative anemia [Hemoglobin (HGB) <90 g/L] and postoperative abdominal hemorrhage (72 hours >400 mL), with the odds ratios at 8.121 (95% CI, 1.417 to 46.550, P=0.019) and 5.911 (95% CI, 1.112 to 31.432, P=0.037). CONCLUSIONS: Postoperative IAI after LT in patients with HCC was a common complication. Preoperative moderate to severe anemia, as well as postoperative intra-abdominal hemorrhage more than 400 mL within the first 72 hours might independently indicate high risk of IAI for these patients. PMID- 25035659 TI - Association between hsa-miR-34b/c rs4938723 T > C promoter polymorphism and cancer risk: a meta-analysis based on 6,036 cases and 6,204 controls. AB - OBJECTIVE: Emerging evidence shows that microRNAs (miRNAs) function as tumor suppressors or oncogenes in human carcinogenesis. A single nucleotide polymorphism (SNP) located in the pri-miRNA promoter may affect the processing and expression of mature miRNA. However, previous studies showed conflicting results regarding the association of hsa-miR-34b/c rs4938723 T > C promoter polymorphism with cancer. Therefore, we conducted a meta-analysis to determine the association of polymorphism with cancer risk. METHODS: A computerized search of PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) for publications on hsa-miR-34b/c rs4938723 T > C promoter polymorphism and cancer risk was performed and the genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Test of heterogeneity, cumulative meta-analysis, sensitivity analysis and assessment of bias were performed in our meta-analysis by STATA software 12.0. RESULTS: There was no significant association between hsa-miR 34b/c rs4938723 polymorphism and overall cancer risk in the comparison models. Moreover, subgroup analysis revealed that the variant CT (OR =1.19, 95% CI: 1.03 1.37) and CC/CT (OR =1.18, 95% CI: 1.03-2.35) genotypes were associated with an increased risk of hepatocellular carcinoma (HCC) compared with wild-type TT genotype. However, a decreased risk of colorectal cancer (CRC) was found in the genetic model of CC/TT (OR =0.66, 95% CI: 0.47-0.92) and CC/CTTT (OR =0.67, 95% CI: 0.49-0.93). CONCLUSIONS: The results suggest that hsa-miR-34b/c rs4938723 polymorphism may play an opposite role in different types of cancer based on current studies, which is the main origin of heterogeneity in this meta-analysis. Further large-scale studies and functional studies between this polymorphism and cancer risk are warranted. PMID- 25035660 TI - Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer. AB - AIM: This study explored the correlation between the expression of excision repair cross-complementation group 1 (ERCC1) and the prognosis of gastric cancer patients. METHODS: From January 2005 to December 2008, 605 patients who underwent radical surgery in The First Affiliated Hospital of Nanjing Medical University were enrolled. We conducted the follow-up every 6 months and its contents included a comprehensive medical history, tumor markers and abdominal ultrasound or CT and other imaging findings. Deadline was April 30, 2013 and follow-up time between 51 to 91 months. Survival time is calculated from the date of diagnosis to death or last follow-up date. Immunohistochemistry (IHC) was used to assess the expression of ERCC1 in resected samples. The relationship between ERCC1 expression and survival of patients was investigated. The comparison of count data were analyzed by Chi-square test. Median survival time (MST) and the 5-year survival rate were calculated by life table analysis. The Kaplan-Meier curves were used for survival analysis. RESULTS: ERCC1 expression was positive in 412 patients (68.1%). There is no significant difference between ERCC1-positive group and ERCC1-negative group in terms of the MST and 5-year survival rate (P=0.455). The MST and 5-year survival rate have no significant difference (P=0.162) between group with chemotherapy and group with no chemotherapy in patients with ERCC1 positive expression. However, the MST and 5-year survival rate in patients with ERCC1-negative expression benefited more from with chemotherapy (P=0.019). The ERCC1-positive patients survived longer than those ERCC1-negative patients (P=0.183) in subgroup with no adjuvant chemotherapy. In the subgroup analysis, ERCC1 expression had no significant relationship with overall survival in patients with stage II or III gastric cancer (P>0.05). CONCLUSIONS: ERCC1 might be a good prognostic factor for the patients of gastric cancer after radical resection. Patients with ERCC1-negative expression could benefit more from adjuvant chemotherapy. PMID- 25035661 TI - Diagnosis and management of acute complications in patients with colon cancer: bleeding, obstruction, and perforation. AB - Among the colorectal cancers, the incidence of colon cancer has obviously increased. As a result, the actual incidence of colon cancer has exceeded that of rectal cancer, which dramatically changed the long-existing epidemiological profile. The acute complications of colon cancer include bleeding, obstruction, and perforation, which were among the common acute abdominal surgical conditions. The rapid and accurate diagnosis of these acute complications was very important, and laparoscopic techniques can be applied in abdominal surgery for management of the complications. PMID- 25035662 TI - Severe acute pancreatitis due to tamoxifen-induced hypertriglyceridemia with diabetes mellitus. AB - The side effects of tamoxifen are generally mild, including the effect on lipoprotein metabolism. However, there are few cases of severe tamoxifen induced hypertriglyceridemia. Hypertriglyceridemia is a marked risk factor for acute pancreatitis and approximately 2% to 5% of cases of acute pancreatitis are related to drugs. We report on tamoxifen-induced hypertriglyceridemia and acute pancreatitis in a 40 years old woman with type 2 diabetes mellitus occurred by dexamethasone. She was treated with insulin infusion and fenofibrate, and goserelin acetate was started instead of tamoxifen after discharge from the hospital. Also, probable pathogenic hypotheses about the correlation between tamoxifen and dexamethasone induced type 2 diabetes mellitus on severe acute pancreatitis are provided. Clinicians should take care of risks of severe acute pancreatitis on using tamoxifen, especially for patients with dexamethasone induced diabetes mellitus. These individuals should undergo pre-post tamoxifen lipid screening and careful history taking of drugs, including dexamethasone. PMID- 25035663 TI - Synchronous primary cancers of trachea and esophagus and ventricular tachycardia. AB - The incidence of multiple primary cancers involving trachea is rare. We present a case of synchronous double primary cancer of trachea and esophagus in a 70-year old woman, with a special symptom of ventricular tachycardia and no history of smoking and alcohol drinking. Biopsies from multiple foci demonstrated the patient had primary small cell cancer of trachea and squamous cell carcinoma in situ of esophagus. The patient was successfully treated with four cycles of chemotherapy consisting of etoposide and carboplatin (EC) followed by thoracic radiotherapy (60 Gy in 30 fractions, in 6 weeks), and was evaluated to have complete response of tumor. To our knowledge, there is no synchronous cancer of trachea and esophagus has been reported in English literature, and our experience showed sequential EC chemotherapy and radiotherapy provided an effective treatment to control both cancers. PMID- 25035664 TI - Primary malignant melanoma of uterine cervix: a suggestion of new scheme of treatment combination. AB - Historically, the lack of melanocytes in the vaginal and cervical mucus membranes has deterred the findings of primary melanomas. Mainly due to its rarity, difficulty to diagnose, and poor prognosis, there has been no absolute agreement on comprehensive treatment so far. In this case report, we present a case of a 46 year-old woman with primary malignant melanoma of uterine cervix. She underwent neo-adjuvant chemotherapy initially followed by a radical hysterectomy. After adjuvant concurrent chemo-radiation, the patient has been followed up for 24 months. So far, she has not shown any symptoms or signs of recurrence. Further studies with more cases based on variable combinations of treatment regimen have been on the way. PMID- 25035665 TI - Synchronous breast cancer and breast lymphoma: two case reports and literature review. AB - Synchronous breast cancer and breast lymphoma are rare. It is of high rate of misdiagnosis in clinical practice. Here we present two cases with this presentation. They are both middle-aged women, with stage I invasive ductal carcinoma of the breast. One patient happened to have primary breast lymphoma (PBL); the other was secondary breast lymphoma (SBL). Their pathology and immunohistochemistry (IHC) findings supported the diagnosis of multiple primary carcinoma. Both patients had a surgery. Then they both received CHOP regime chemotherapy and subsequent endocrine therapy. PMID- 25035666 TI - Screening Offenders: The Exploration of a Youth Level of Service/Case Management Inventory: (YLS/CMI) Brief Screener. AB - Although structured assessments have helped standardize juvenile court processes by systematically measuring risk for recidivism, it has been argued that some assessments lack the ability to perform as a brief screener. This study explored the potential for the original 42-item Youth Level of Service/Case Management Inventory (YLS/CMI) risk assessment to perform as a brief screener for a sample of first-time juvenile offenders in a mid-western, industrialized county. Results indicated that the original and shortened version of the YLS/CMI significantly predicted two-year recidivism for male and female offenders. Implications for situationally targeted forms of risk assessment are discussed. PMID- 25035667 TI - Recommendations for the Treatment of Invasive Fungal Infections in Hematological Malignancies: A Critical Review of Evidence and Turkish Expert Opinion (TEO-1). AB - The introduction of novel antifungal agents for the treatment of invasive fungal disease in hematological malignancies and also changing treatment strategies have had a great impact in managing affected patients. The medical literature includes some important clinical studies that are being used as evidence for guidelines. The problem with these studies and the guidelines is that they are not very easy to interpret, they include controversial issues, and they are not easy to apply to every patient or country. This paper was designed to critically show the main problems associated with these approaches and provide important information that will help Turkish doctors to adopt them in daily clinical practice. PMID- 25035668 TI - sEPCR Levels in Chronic Myeloproliferative Diseases and Their Association with Thromboembolic Events: A Case-Control Study. AB - OBJECTIVE: Venous, arterial, and microcirculatory events are frequently encountered in the clinical course of essential thrombocytosis and polycythemia vera. We aimed to investigate the levels of soluble endothelial protein C receptor (sEPCR) in myeloproliferative diseases to see whether there was a difference between the patients with and without history of thromboembolism. MATERIALS AND METHODS: The study included patients with polycythemia vera (n=12), patients with essential thrombocytosis (n=13), and controls (n=29). In all groups, we measured proteins C and S, antithrombin and sEPCR levels, and plasma concentrations of thrombin-antithrombin complex, prothrombin fragments 1+2, and D dimer. RESULTS: Comparing the patients with and without history of thromboembolic attack, statistically significant differences were not observed in terms of sEPCR, D-dimer, thrombin-antithrombin complex, prothrombin fragments 1+2, and hematocrit levels (p=0.318, 0.722, 0.743, 0.324, and 0.065, respectively). CONCLUSION: Significant increase in the parameters that reflect activation of coagulation, such as sEPCR, thrombin-antithrombin complex, prothrombin fragments 1+2, and D-dimer, reflects the presence of a basal condition that leads to a tendency toward thrombosis development in ET and PV when compared to healthy controls. PMID- 25035669 TI - Prognostic Significance of the Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) GeneExpression in Egyptian Patients with AcuteMyeloid Leukemia. AB - OBJECTIVE: Aberrant activation of transcription factor genes is the most frequent target of genetic alteration in lymphoid malignancies. The lymphoblastic leukemia derived sequence 1 (LYL1) gene, which encodes a basic helix-loop helix, was first identified with human T-cell acute leukemia. Recent studies suggest its involvement in myeloid malignancies. We aimed to study the expression percent of oncogene LYL1 in primary and secondary high-risk myeloid leukemia and the impact on prognostic significance in those patients. MATERIALS AND METHODS: Using quantitative real-time polymerase chain reaction for detection of LYL1 oncogenes, our study was carried out on 39 myeloid leukemia patients including de novo cases, myelodysplastic syndrome (MDS) with transformation, and chronic myelogenous leukemia (CML) in accelerated and blast crisis, in addition to 10 healthy individuals as the reference control. RESULTS: LYL1 expression was increased at least 2 times compared to the controls. The highest expression of this transcription factor was observed in the MDS cases transformed to acute leukemia at 7.3+/-3.1, p=0.0011. LYL1 expression was found in 68.2%, 75%, and 77.8% of cases of acute myeloid leukemia, CML crisis, and MDS, respectively. Significant correlation of LYL1 overexpression with some subtypes of French American-British classification was found. There was, for the first time, significant correlation between the blood count at diagnosis and LYL1 expression (p=0.023, 0.002, and 0.031 for white blood cells, hemoglobin, and platelets, respectively). The rate of complete remission was lower with very high levels of LYL1 expression and the risk of relapse increased with higher levels of LYL1 expression, suggesting an unfavorable prognosis for cases with enhanced expression. CONCLUSION: Overexpression of LYL1 is highly associated with acute myeloid leukemia and shows more expression in MDS with unfavorable prognosis in response to induction chemotherapy. These observations could signal a promising tool for a therapeutic target to basic helix-loop helix protein related to transcription factors, which may improve patient outcome in acute myeloid leukemia, MDS, and CML in blast crisis. PMID- 25035670 TI - Local Renin-Angiotensin system in normal hematopoietic and multiple myeloma related progenitor cells. AB - OBJECTIVE: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells. MATERIALS AND METHODS: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis. RESULTS: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89). CONCLUSION: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols. PMID- 25035671 TI - Wilms tumor 1 gene mutations in patients with cytogenetically normal acute myeloid leukemia. AB - OBJECTIVE: This study aimed to assess the prognostic impact of Wilms tumor 1 (WT1) mutations in cytogenetically normal acute myeloid leukemia (CN-AML) among Egyptian patients. MATERIALS AND METHODS: Exons 1, 2, 3, 7, 8, and 9 of WT1 were screened for mutations in samples from 82 CN-AML patients out of 203 newly diagnosed AML patients, of age ranging from 21 to 74 years, using high-resolution capillary electrophoresis. RESULTS: Eleven patients out of 82 (13.41%) harbored WT1 mutations. Mutations were detected in exon 7 (n=7), exon 9 (n=2), exon 8 (n=1), and exon 3 (n=1), but not in exons 1 or 2. There was no statistically significant difference between the WT1 mutants and wild types as regards age, sex, French-American-British subtypes, and the prevalence of success of induction remission therapy (p=0.966; 28.6% vs. 29.3%). Patients with WT1 mutations had overall survival lower than patients with the wild type (HR=1.38; 95% CI 4.79 6.86; p=0.004). CONCLUSION: CN-AML patients with WT1 mutations have poor clinical outcome. We recommend molecular testing for WT1 mutations in patients with CN-AML at diagnosis in order to improve risk stratification of those patients. PMID- 25035672 TI - Assessment of cytokine expression profile in acute myeloid leukemia patients before and after chemotherapy. AB - OBJECTIVE: One of the major goals of cancer treatment is the monitoring of chemotherapeutic protocols. Quantitative and comparative cytokine expression profiling could be reliable to be used for biomarkers in deadly and fast-growing cancers such as acute myeloid leukemia (AML). The present study aims to assess and further validate cytokines with probable effects on proliferation and maturation of blood cells in AML. MATERIALS AND METHODS: Gene expression levels of IL-1beta, IL-10, IL-8, TNF-alpha, and IFN-gamma were analyzed before and after chemotherapy and after granulocyte colony-stimulating factor (G-CSF) therapy in 46 AML patients by an in-house quantitative comparative RT-PCR method. RESULTS: Our findings indicated that although the gene expression level of TNF-alpha was almost constant in all 3 samples, IL-1beta, IL-8, and IL-10 expression levels showed a decrease after chemotherapy and an increase after G-CSF therapy. On the other hand, the expression level of IFN-gamma had a different pattern with an increase after chemotherapy and a decrease after G-CSF therapy. CONCLUSION: Taken together, the results of this study are in support of the idea that the analyzed cytokines could be useful biomarkers for AML treatment monitoring. However, further molecular epidemiological investigations are suggested to elaborate more cancer monitoring biomarkers. PMID- 25035673 TI - Investigation of epstein-barr virus and parvovirus b19 DNA in allogeneic stem cell transplant patients. AB - OBJECTIVE: We aimed to investigate posttransplant Epstein-Barr virus (EBV) and parvovirus B19 DNA in allogeneic stem cell transplant patients between 2009 and 2010. MATERIALS AND METHODS: Forty-five adult patients in whom allogeneic stem cell transplantation was performed between April 2009 and November 2010 in the Erciyes University Faculty of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, were included in the study. EBV and parvovirus B19 DNA positivity was investigated by using real-time polymerase chain reaction technique in 135 plasma samples obtained after transplantation at between 1 and 6 months. Pretransplant serological markers of EBV and parvovirus B19 were provided from patient files. RESULTS: In 32 (71.1%) of the patients, EBV antibodies in the pretransplantation period were as follows: anti-EBNA-1 IgG (+), VCA IgM (-), and VCA IgG (+). In 2 patients (4.45%), these antibodies were as follows: anti-EBNA-1 IgG (+), VCA IgM (-), and VCA IgG (-). In 1 patient (2.2%), they were as follows: anti-EBNA-1 IgG (-), VCA IgM (-), and VCA IgG (+). EBV serological markers were negative in 2 (2.2%) out of 45 patients before transplantation. There was low DNA positivity (<600 copies/mL) in 4 patients (8.9%), and VCA IgM was negative and VCA IgG was positive in these same 4 patients. In spite of low viral load, there were no symptoms related to EBV, and posttransplant lymphoproliferative disorder (PTLD) did not occur. While in 44 (99.7%) of 45 patients parvovirus B19 IgM was negative and IgG was positive, parvovirus B19 IgM was positive and IgG was negative in 1 (2.3%) patient. Parvovirus B19 DNA was not identified in any of the samples obtained from these 45 patients. CONCLUSION: In this study, EBV and parvovirus B19 DNA were investigated in allogeneic stem cell transplant patients. None of the patients developed PTLD and parvovirus B19 DNA positivity was not detected. However, this issue needs to be further evaluated in prospective, multicenter studies with larger series of patients. PMID- 25035674 TI - Determination of rate and causes of wastage of blood and blood products in Iranian hospitals. AB - OBJECTIVE: The purpose of this study was to determine the rate and causes of wastage of blood and blood products (packed red cells, plasma, platelets, and cryoprecipitate) in Qazvin hospitals. MATERIALS AND METHODS: The study was conducted in all hospitals in Qazvin, including 5 teaching hospitals, 2 social welfare hospitals, 3 private hospitals, 1 charity hospital, and 1 military hospital. This descriptive study was based on available data from hospital blood banks in the province of Qazvin. The research instrument was a 2-part questionnaire. The first part was related to demographic characteristics of hospitals and the second part elicited information about blood and blood component wastage. The collected data were then analyzed using descriptive statistic methods and SPSS 11.5. RESULTS: Blood wastage may occur for a number of reasons, including time expiry, wasted imports, blood medically or surgically ordered but not used, stock time expired, hemolysis, or miscellaneous reasons. Data indicated that approximately 77.9% of wasted pack cell units were wasted for the reason of time expiry. Pack cell wastage in hospitals is reported to range from 1.93% to 30.7%. Wastage at all hospitals averaged 9.8% among 30.913 issued blood products. Overall blood and blood product (packed red cells, plasma, platelets, and cryoprecipitate) wastage was 3048 units and average total wastage per participant hospital for all blood groups was 254 units per year. CONCLUSION: Blood transfusion is an essential part of patient care. The blood transfusion system has made significant advancements in areas such as donor management, storage of blood, cross-matching, rational use of blood, and distribution. In order to improve the standards of blood banks and the blood transfusion services in Iran, comprehensive standards have been formulated to ensure better quality control in collection, storage, testing, and distribution of blood and its components for the identified major factors affecting blood product wastage. PMID- 25035675 TI - The functional significance of the rho/rho-kinase pathway in human erythrocytes. AB - OBJECTIVE: Erythrocyte deformability, which can be influenced by various intracellular signaling mechanisms, such as nitric oxide, cAMP, cGMP, and protein kinases, is the most important physiological factor providing the blood flow in microcirculation. However, the functional significance of the Rho/Rho-kinase pathway, which contributes cell shape changes and the reorganization of the actin cytoskeleton, has yet to be explored in erythrocytes. Therefore, we examined the influence of several activators and inhibitors of Rho/Rho-kinase signaling on human erythrocyte deformability. MATERIALS AND METHODS: RhoA and ROCK-2 proteins were studied by western blotting. Influences of 2 Rho-kinase inhibitors, fasudil and Y-27632 (both 10-7 to 10-4 M), on erythrocyte deformability was determined by ektacytometer at various shear stresses (0-30 Pa) in the presence or absence of a known Rho activator, lysophosphatidic acid (LPA, 10-5 to 5x10-5 M, 1-15 min). RESULTS: LPA incubation reduced deformability with concomitant RhoA-GTP inhibition. Y-27632 and fasudil also decreased deformability, but had no effect on LPA-induced reduction of deformability. Rho inhibitor C3 had no effect on RhoA activation. Reduction in RhoA activation was induced by sub-hemolytic mechanical stress. CONCLUSION: Our findings may indicate that the Rho/Rho-kinase pathway could contribute to the regulation of deformability of human erythrocytes. PMID- 25035676 TI - Gelatinous marrow transformation: a series of 11 cases from a tertiary care centre in South India. AB - Gelatinous marrow transformation (GMT) or serous atrophy of bone marrow (BM) is a rare disease characterised by focal marrow hypoplasia, fat atrophy, and accumulation of extracellular mucopolysaccharides abundant in hyaluronic acid. This study reviews 11 cases of GMT from South India. Clinical and haematological parameters, BM aspirate, and biopsies of all patients diagnosed with GMT over a period of 7 years were studied. GMT was diagnosed in BM biopsy based on characteristic morphological appearance and was confirmed by alcian blue positive staining pattern at pH levels of 2.5 and 0.5. Eleven patients were diagnosed with GMT. All were males within the age range of 15 to 50 years. The underlying clinical diagnosis was human immunodeficiency virus positivity in 5 cases, 2 with coexistent disseminated tuberculosis, 1 with cryptococcal meningitis, and 1 with oral candidiasis; disseminated tuberculosis in 1 case; pyrexia of unknown origin in 2 cases; Hodgkin's lymphoma in 1 case; acute lymphoblastic lymphoma with maintenance chemotherapy in 1 case; and alcoholic pancreatitis in 1 case. BM aspirates showed gelatinous metachromatic seromucinous material in 3 cases. BM biopsies were hypocellular in 7 and normocellular in 4 cases and showed focal GMT in 5 and diffuse GMT in 6 cases. Reactive changes were seen in 4 cases and haemophagocytosis in addition to GMT in 1 case. GMT is a relatively uncommon condition and an indicator of severe illness. It should be differentiated from myelonecrosis, amyloidosis, and marrow oedema. A high index of suspicion is required to diagnose this condition. PMID- 25035677 TI - Use of mesenchymal cells to modulate immune suppression and immune reconstruction in a patient with aplastic anemia complicated by invasive sino-orbital aspergillosis. AB - Cultured human bone marrow mesenchymal cells (MSCs) have immunomodulatory and tissue regenerative properties. This report summarizes the result of post transplant treatment with MSCs of a 26-year-old patient with aplastic anemia complicated by invasive sino-orbital aspergillosis. The patient was treated with MSCs to benefit from the dual effects of MSCs in immune reconstitution: suppression against alloreactive T cells and facilitation of the re-engraftment process. The patient did not develop acute or chronic graft-versus-host disease. The aspergillus infection healed completely. The engraftment failure was also ended without any complications. During his last visit in his fourth year after transplantation, the patient was in hematological remission. Human bone marrow derived MSCs seem to have an important role in preventing or overcoming immunological complications in patients who undergo stem cell transplantation. PMID- 25035678 TI - A case associated with comorbidities among cerebral infarction, idiopathic thrombocytopenic purpura, and triple x syndrome. AB - A 46-year-old female presented to the emergency room due to the chief complaint of left-sided weakness. By imaging study, she was diagnosed with cerebral infarction. Thrombolytic and antiplatelet agents were not considered due to the "golden hour" for treatment having passed and a low platelet count. The peripheral blood smear, bone marrow biopsy, and aspirate findings were consistent with immune thrombocytopenic purpura. The chromosome analysis revealed the 47,XXX karyotype. To the best of our knowledge, this is the first case report associated with the comorbidities of cerebral infarction, idiopathic thrombocytopenic purpura, and triple X syndrome. PMID- 25035679 TI - Primary adrenal lymphoma. AB - Primary non-Hodgkin's lymphoma of the adrenal gland is rare. We report the case of a 56-year-old patient suffering from B symptoms. The CT scan showed a bilateral adrenal mass without any lymph nodes. Scan-guided biopsies led to the diagnosis of diffuse large B-cell lymphoma. The medullar biopsy eliminated a secondary lymphoma. The patient was treated by immunochemotherapy with a complete response before autologous stem cell transplantation. PMID- 25035680 TI - Bone and bone marrow involvement in sarcoidosis. PMID- 25035681 TI - The treatment of acquired hemophilia with combination therapy of immunosuppressives and immunoadsorption. PMID- 25035682 TI - The Role of Radiotherapy Among the Therapeutic Options for Castleman's Disease. PMID- 25035683 TI - The relationship between hematological findings and coronary artery aneurysm in kawasaki disease. PMID- 25035684 TI - An unusual cause of thigh swelling: extramedullary myeloid tumor. PMID- 25035685 TI - Isolated breast relapse mimicking breast cancer in elderly patient with acute lymphoblastic leukemia. PMID- 25035686 TI - Bilateral primary adrenal non-hodgkin lymphoma. PMID- 25035687 TI - A Case of Cutaneous Diffuse Large B-cell Lymphoma. PMID- 25035688 TI - Lysosomal vesicles, giant granules, and erythrophagocytosis in chediak-higashi syndrome. PMID- 25035689 TI - Bone marrow involvement of rhabdomyosarcoma from unknown origin. PMID- 25035690 TI - Aleukemic leukemia cutis: an unusual rash in a child. PMID- 25035692 TI - Integrating care for people with mental illness: the Care Programme Approach in England and its implications for long-term conditions management. AB - INTRODUCTION: This policy paper considers what the long-term conditions policies in England and other countries could learn from the experience of the Care Programme Approach (CPA). The CPA was introduced in England in April 1991 as the statutory framework for people requiring support in the community for more severe and enduring mental health problems. The CPA approach is an example of a long standing 'care co-ordination' model that seeks to develop individualised care plans and then attempt to integrate care for patients from a range of providers. POLICY DESCRIPTION: The CPA experience is highly relevant to both the English and international debates on the future of long-term conditions management where the agenda has focused on developing co-ordinated care planning and delivery between health and social care; to prioritise upstream interventions that promote health and wellbeing; and to provide for a more personalised service. CONCLUSION: This review of the CPA experience suggests that there is the potential for better care integration for those patients with multiple or complex needs where a strategy of personalised care planning and pro-active care co-ordination is provided. However, such models will not reach their full potential unless a number of preconditions are met including: clear eligibility criteria; standardised measures of service quality; a mix of governance and incentives to hold providers accountable for such quality; and genuine patient involvement in their own care plans. IMPLICATIONS: Investment and professional support to the role of the care co-ordinator is particularly crucial. Care co-ordinators require the requisite skills and competencies to act as a care professional to the patient as well as to have the power to exert authority among other care professionals to ensure multidisciplinary care plans are implemented successfully. Attention to inter professional practice, culture, leadership and organisational development can also help crowd-in behaviours that promote integrated care. PMID- 25035693 TI - MEASUREMENT OF AMPLITUDE AND DELAY OF STIMULUS FREQUENCY OTOACOUSTIC EMISSIONS. AB - Although stimulus frequency otoacoustic emissions (SFOAEs) have been used as a non-invasive measure of cochlear mechanics, clinical and experimental application of SFOAEs has been limited by difficulties in accurately deriving quantitative information from sound pressure measured in the ear canal. In this study, a novel signal processing method for multicomponent analysis (MCA) was used to measure the amplitude and delay of the SFOAE. This report shows the delay-frequency distribution of the SFOAE measured from the human ear. A low level acoustical suppressor near the probe tone significantly suppressed the SFOAE, strongly indicating that the SFOAE was generated at characteristic frequency locations. Information derived from this method may reveal more details of cochlear mechanics in the human ear. PMID- 25035691 TI - Dermal wound transcriptomic responses to Infection with Pseudomonas aeruginosa versus Klebsiella pneumoniae in a rabbit ear wound model. AB - BACKGROUND: Bacterial infections of wounds impair healing and worsen scarring. We hypothesized that transcriptome analysis of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) would indicate host-responses associated with the worse healing of P.a.- than K.p.-infected wounds. METHODS: Wounds created on post-operative day (POD) 0 were infected during the inflammatory phase of healing on POD3 and were harvested on POD4 for microarray and transcriptome analysis. Other wounds received topical antibiotic after infection for 24 hours to promote biofilm development, and were harvested on POD6 or POD12. RESULTS: Wounds infected for 24 hours, relative to uninfected wounds, elevated transcripts of immune-response functions characteristic of infiltrating leukocytes. But P.a.-infected wounds elevated many more transcripts and to higher levels than K.p.-infected wounds. Coincidently, suppressed transcripts of both wounds enriched into stress-response pathways, including EIF2 signaling; however, this was more extensive for P.a.-infected wounds, including many-fold more transcripts enriching in the 'cell death' annotation, suggesting resident cutaneous cell toxicity in response to a more damaging P.a. inflammatory milieu. The POD6 wounds were colonized with biofilm but expressed magnitudes fewer immune response transcripts with no stress-response enrichments. However, elevated transcripts of P.a.-infected wounds were inferred to be regulated by type I interferons, similar to a network unique to P.a.-infected wounds on POD4. On POD12, transcripts that were more elevated in K.p.-infected wounds suggested healing, while transcripts more elevated in P.a.-infected wounds indicated inflammation. CONCLUSIONS: An extensive inflammatory response of wounds was evident from upregulated transcripts 24 hours after infection with either bacterium, but the response was more intense for P.a.- than K.p.-infected wounds. Coincidently, more extensive down-regulated transcripts of P.a.-infected wounds indicated a stronger "integrated stress response" to the inflammatory milieu that tipped more toward cutaneous cell death. Unique to P.a.-infected wounds on POD4 and POD6 were networks inferred to be regulated by interferons, which may result from intracellular replication of P.a. These data point to specific downregulated transcripts of cells resident to the wound as well as upregulated transcripts characteristic of infiltrating leukocytes that could be useful markers of poorly healing wounds and indicators of wound-specific treatments for improving outcomes. PMID- 25035694 TI - Nutcracker Syndrome Accompanying Pelvic Congestion Syndrome; Color Doppler Sonography and Multislice CT Findings: A Case Report. AB - Nutcracker syndrome (NCS) is a rare pathology, caused by compression of the left renal vein (LRV) between the abdominal aorta (AA) and the superior mesenteric artery (SMA), due to reduction of the angle between AA and SMA. This leads to LRV varices, left gonadal vein varices and therefore, the pelvic congestion syndrome. For this reason, coexistence of NCS and pelvic congestion syndrome has been described. It manifests by hematuria, proteinuria, and nonspecific pelvic pain secondary to pelvic congestion, dyspareunia and persistent genital arousal. We report a 27-year-old woman who experienced hematuria and left flank pain. The diagnosis of NCS accompanied by pelvic congestion syndrome was missed initially, but later on the diagnosis was made by color Doppler ultrasound, abdominal computed tomography (CT) and CT angiography that were later performed. She refused interventional and surgical treatments, and was lost to follow up. PMID- 25035695 TI - CT and MR Imaging Characteristics of Intravestibular and Cerebellopontine Angle Lipoma. AB - Intracranial lipoma is an uncommon entity. A rare type of tumor in the internal auditory canal (IAC) and the cerebellopontine angle (CPA) is lipoma. There are a few case reports in the literature related to intravestibular lipoma. Herein, we report a case of lipomas within the cerebellopontine angle and vestibule of the inner ear in a patient with tinnitus and dizziness. The patient was evaluated with a 1.5 T magnetic resonance imaging (MRI) system. MRI and CT showed the masses in the left CPA and the left IAC. These lesions were hyperintense on both T1- and T2 weighted images and showed no enhancement after gadolinium administration. Conservative management was suggested. Histopathological diagnosis is rarely necessary with the widespread use of magnetic resonance imaging. Considering significant morbidity during resection, conservative follow up is the best approach for CPA and IAC lipoma. PMID- 25035696 TI - The Effect of Inversion Time on the Relationship Between Iron Oxide Nanoparticles Concentration and Signal Intensity in T1-Weighted MR Images. AB - BACKGROUND: Magnetic nanoparticles have been widely applied in recent years for biomedical applications. Signal intensity (SI) of magnetic resonance (MR) images depends on the concentration of nanoparticles. It is important to find the minimum concentration of iron oxide nanoparticles that produces maximum SI and determines the minimum injection dose for clinical studies. OBJECTIVES: This study was performed to determine the relationship between the iron oxide nanoparticle concentration and SI using inversion recovery (IR) sequence in T1 weighted MR images. MATERIALS AND METHODS: Different concentrations of carboxydextran-coated iron oxide nanoparticles 20 nm in size were prepared. In vitro MR imaging was performed with inversion times (TI) of 100-400 ms (interval of 20 ms) and IR Turbo-FLASH (Turbo fast low angle shot) pulse sequence using a 1.5 T MRI system. Then the SI produced by each concentration of nanoparticles was measured and the minimum nanoparticle concentration that led to the maximum SI was determined. Coil non-uniformity was also considered for measuring the accurate SI of each image. RESULTS: The results indicate that SI depended on the concentration of nanoparticles and TI. In addition, SI increased by increasing the TIs ranging from 200 to 400 ms for all studied concentrations. The linear relationship between the nanoparticle concentrations and SI that gave a square correlation coefficient (R(2)) equal to 0.99 was seen up to 76.83 umol Fe/L in 400 ms for long TI and 239.16 umol Fe/L in 200 ms for short TI. CONCLUSIONS: TI is an important parameter to consider in the relationship between SI and nanoparticle concentrations. An increase in TI leads to a decrease in the range of linearity. PMID- 25035697 TI - The role of bone subtraction computed tomographic angiography in determining intracranial aneurysms in non-traumatic subarachnoid hemorrhage. AB - BACKGROUND: The presence of blood in the subarachnoid space is an acute pathology with a serious risk of death and complications. The most common etiology (approximately 80%) is intracranial aneurysm. OBJECTIVES: The aim of this study was to assess the role of bone subtracted computed tomographic angiography (BSCTA), a novel and noninvasive method for determining and characterizing intracranial aneurysms. PATIENTS AND METHODS: Sixty consecutive patients with clinically suspected non-traumatic subarachnoid hemorrhage (SAH) were considered to enter the study. The subtraction quality was inadequate in ten patients; thus, they were excluded, leaving 50 patients (84.4%) in the study. Bone subtracted and non-subtracted 3D images were obtained from the BSCTA raw data sets. All images obtained by digital subtraction angiography (DSA), BSCTA, and computed tomographic angiography (CTA) were evaluated for the presence or absence of an aneurysm and the location, minimal sac diameter, and neck size ratio of the aneurysm. DSA was considered as the gold standard during the evaluation of the data. RESULTS: Of the 50 patients who participated in this study, 11 had no aneurysms as determined by both CTA and DSA. Examination of the remaining 39 patients revealed the presence of 51 aneurysms. While 3D-CTA could not detect six aneurysms that were located in the base of the skull, 3D-BSCTA easily detected them. Moreover, five aneurysms were only partially detected by 3D-CTA. According to this data, the sensitivity of 3D-BSCTA and 3D-CTA was calculated as 98% and 86.3%, respectively; the specificity was calculated as 100% and 90.9%, respectively, per aneurysm; and the sensitivity of 100% for 3D-BSCTA and 98% for 3D-CTA was achieved by using combined images with multi-planar reconstruction (MPR) and maximum intensity projection (MIP). BSCTA detected and characterized the aneurysms as well as DSA, and BSCTA and DSA gave concordant results in detecting aneurysms. CONCLUSIONS: BSCTA is easily accessible, less time consuming, and most importantly, a non-invasive technique for detecting intracranial aneurysms. It is also suitable for patients who have been referred to emergency services. Therefore, it can be used in emergency conditions and as a first-line diagnostic method in patients with non-traumatic SAH. PMID- 25035698 TI - Ultrasound as a screening tool for performing caudal epidural injections. AB - BACKGROUND: The caudal approach to the epidural space has been used for decades to treat low back pain caused by lumbosacral root compression. The use of fluoroscopy during epidural steroid injection is the preferred method for placing the needle more accurately in the sacral hiatus, but it carries the risk of radiation hazard. OBJECTIVES: The aim of the study was to assess the anatomical structure of the sacral hiatus and the feasibility of caudal epidural injections under ultrasound guidance. PATIENTS AND METHODS: Two hundred and forty patients (male = 100, female = 140) with low back pain and sciatica who were candidates for caudal epidural injection were enrolled into this study. Ultrasound images of the sacral hiatus and bilateral cornua were obtained by a real-time linear array ultrasound transducer. The distance between bilateral cornua and the anterior and posterior wall of the sacrum were measured at the base (sacral hiatus). Under the guide of ultrasonography, we defined the injection successful if turbulence of medication fluid was observed in the sacral canal, but correct placement of the needle and injectant was confirmed on fluoroscopic view as the gold standard technique. RESULTS: The epidurogram showed that the injection was successful in 230 of the 240 patients (95.8%). In eight patients, the injection was not in the correct place in the sacral canal. The sacral hiatus could not be identified by ultrasound images in only two patients who had a closed sacral hiatus identified by fluoroscopy. The mean distance of the sacral hiatus was 4.7 +/- 1.7 mm and the mean distance between bilateral cornua was 18.0 +/- 2.8 mm. The mean duration of the procedure was 10.8 +/- 6.8 minutes. No major complication was observed in the next month. CONCLUSIONS: In conclusion, ultrasound could be used as a safe, fast and reliable modality to observe the anatomic variation of the sacral hiatus and to perform caudal epidural injections. PMID- 25035699 TI - A rare cause of chronic cough: intrathoracic gossypiboma. AB - Intrathoracic gossypiboma, a retained surgical sponge in the thoracic cavity, is a rare but serious complication of thoracic surgeries. A 70-year-old man presented with an eight-month history of cough. He had undergone coronary artery bypass surgery eight years ago. The posteroanterior chest X-ray revealed a well marginated homogeneous opacity at the left hemithorax with striped appearance in the center. Thoracic CT revealed a pleural-based mass at the left lower lobe with a hyperdense rim. After the diagnosis of gossypiboma, it was removed surgically. Although rare after thoracic surgery, gossypibomas need to be considered in the differential diagnosis in case of respiratory symptoms. PMID- 25035700 TI - Comparison of brain white matter hyperintensities in methamphetamine and methadone dependent patients and healthy controls. AB - BACKGROUND: Previous studies have proven the development of white matter hyperintensities (WMH) in methamphetamine and opioid users. Opiates and methamphetamines (MA) are the most common addictive agents in Iran. The adverse effects of drugs on the CNS is of concern to specialists and researchers, and given that the neurotoxicity associated with methamphetamine is greater than opioids, it is hypothesized that the severity of WMH in patients with methamphetamine dependence is more than opioid drug-dependent individuals. OBJECTIVES: To our knowledge, this is the first research comparing the effect of methamphetamine and methadone (M) on the brain. PATIENTS AND METHODS: In a historical cohort study, we compared WMH in the brain MRI of 50 methamphetamine dependent patients, 50 methadone-dependent patients and 50 healthy volunteers who were matched for age, sex and dominant hand. RESULTS: WMH was detected in 18 methamphetamine users, in 12 methadone users and in seven controls (P = 0.038). The site of brain lesions in MA users was mostly in the frontal lobe in 17 cases, in M users in the frontal lobe in 12 cases and in the control group, it was in the parietal lobe in four cases (P=0.001). The frontal lobes were the predominant locations of WMH in MA and M groups (P = 0.001). The frequency of brain lesions was mostly in the deep WM in 18 cases in MA users, in 12 cases in M users and in two cases in the control group (P=0.007). Hyper-signal foci of deep WM in the MA group were grade I (punctuate) in 12 cases, grade II (beginning confluence) in five cases and grade III (large confluent) in four cases. In the M group, there were six cases in grade I, three cases in grade II and one case in grade III. In the control group, there were three grade I cases, two grade II cases, and no grade III cases. Except for periventricular WMH (P = 0.13), there were statistical significant differences in the deep WMH (P = 0.007) and subcortex WMH (P = 0.01) between the three groups. The history of using other drugs and the duration of MA and M consumption were similar. The prevalence of brain lesions was generally higher in both drug user groups compared with the healthy controls. Increased WMH in the MA group was higher than the M group. CONCLUSIONS: A greater number of blood flow defects and ischemic lesions in the brain of MA users compared to opiate users may explain the prevalence of psychiatric disorders in these patients. PMID- 25035701 TI - Dynamic comparison of segmentary scapulohumeral rhythm between athletes with and without impingement syndrome. AB - BACKGROUND: Patients who have shoulder pain usually have compensatory or contributory deviation of shoulder motion during arm elevation. In the traditional scapulohumeral rhythm, the share of the acromioclavicular (AC) and the sternoclavicular (SC) joint movements and also the role of AC internal rotation angle are unknown. OBJECTIVES: The main purpose of this study was to measure and compare the segmentary scapulohumeral rhythm (SSHR) during scapular arm elevation at a steady rotational speed in athletes with and without impingement syndrome. PATIENTS AND METHODS: Using a speedometer, the maximum speed of arm elevation was measured in 21 men in each of the involved and uninvolved groups. Using fluoroscopy on the dominant side, SSHR during scapular arm elevation at a rotational speed equal to 1/30 of maximum speed was compared between the two groups. The ratio of glenohumeral (GH) elevation angle to AC rotation angle in the scapular plane was considered as SSHR. RESULTS: The maximum speed of arm elevation between the two groups was significantly different (P < 0.001). The rhythm of the involved group significantly exceeded the rhythm of the uninvolved group in a part of the first quarter range of the arm elevation. SSHR during arm elevation in the uninvolved group did not change significantly (P = 0.845); however, it decreased significantly in the involved group (P = 0.024). CONCLUSIONS: Speed differences between the two groups were probably due to the pain in some ranges of arm elevation. SSHR in the involved group probably changed in order to compensate downward rotation of the scapula in the resting position. Study of the AC upward rotation range can be misleading; therefore, the study of scapulohumeral rhythm is recommended. PMID- 25035702 TI - The role of choice-lock catheter and trocar technique in percutaneous ablation of symptomatic renal cysts. AB - BACKGROUND: The most common benign lesions of the kidney are simple cysts. They are acquired lesions and mostly affect the elderly population. OBJECTIVES: To describe the usage of choice-lock catheter and trocar technique in percutaneous renal cyst treatment and determining long-term outcomes. PATIENTS AND METHODS: This retrospective study was carried out between February 2000 and July 2011. Eighty-eight cysts all of which were Bosniak type-1 cysts were selected in 75 patients. The treatment indications were flank pain, hydronephrosis and hypertension. The choice-lock catheter was used for 84 cysts with the trocar technique. Ninety-five percent ethanol was used as the sclerosing agent. Maximum volume of the injected ethanol was 175 ml. The mean follow-up time after the treatment procedure was 23 months. Sixty-four cysts were located in the cortical and 24 cysts were located at the parapelvic region. RESULTS: Fifty-seven cysts had complete regression, while 31 cysts regressed partially. After the procedure, pain was relieved in 44 (82%) patients and the pain alleviated in four (8%). Normotension was obtained in five (62.5%) of the eight hypertensive patients and no hydronephrosis was detected in nine patients. There were no relationship between the localization and the regression rate. No major complications occurred. CONCLUSIONS: Percutaneous ethanol sclerotheraphy in simple cysts is a safe, cost-effective and minimally invasive method. We consider that this technique may be an alternative solution in the percutaneous cyst treatment. PMID- 25035703 TI - Primitive neuroectodermal tumor with kidney involvement: a case report. AB - Primitive neuroectodermal tumor (PNET) is usually an aggressive, rapidly progressing and metastasizing tumor. Occurrence of this type of tumor in the kidney is considered as unusual and few cases have been reported so far. We present a metastatic PNET arising probably from the kidney in a 17-year-old female patient with local invasion and metastasis to the stomach. PNET should be considered as a differential diagnosis of a large heterogeneous soft tissue mass in the abdomen, especially in those with widely local invasion and metastases. PMID- 25035704 TI - Primary pancreatic leiomyosarcoma. AB - Primary pancreatic leiomyosarcomas are rare malignant neoplasms with an aggressive course and a large size. A 56-year-old woman presented with an 8-year history of abdominal pain. Multislice computed tomography revealed a large heterogeneous mass with necrotic, calcified and macroscopic fatty areas. The tumor was excised. Histopathological evaluation revealed leiomyosarcoma of the pancreas. If a patient has a large size mass with a cystic-necrotic component, pancreatic leiomyosarcoma should be considered in the differential diagnosis list after excluding other common differential diagnoses. PMID- 25035705 TI - New mutation of pelizaeus--merzbacher-like disease; a report from iran. AB - Pelizaeus--Merzbacher-like disease (PMLD) is a hypomyelinating leukoencephalopathy disorder with a genetically heterogeneous pattern. Mutations in the GJA12/GJC2 gene cause one form of autosomal recessive Pelizaeus- Merzbacher-like disease. Here, we report a new mutation in a -10-month-old girl with nystagmus, psychomotor delay, hypotonicity, head nodding and dysmyelination from healthy second cousin parents. The genetic study showed a homozygote deletion as c902-918del in the exone 2. According to our study and recent reports from other Middle East countries, we suggest GJA12 gene mutations are common in this area, but we didnot find any previous report about this new mutation (c902 918Del). PMID- 25035706 TI - Iatrogenic Superficial External Pudendal Artery Pseudoaneurysm: Treatment with Doppler US-Guided Compression. AB - Pseudoaneurysms rarely occur as a serious complication following incomplete hemostasis of an arterial puncture site. As a result of the increase in diagnostic and therapeutic angiography, the frequency of iatrogenic pseudoaneurysm has increased as well. Iatrogenic pseudoaneurysms associated with angiographic catheterization occur most commonly in the common femoral artery. Here we report a case of iatrogenic superficial external pudendal artery (SEPA) pseudoaneurysm following cardiac catheterization, which was diagnosed with Doppler ultrasound (US) and multidetector computed tomographic angiography (MDCTA) before Doppler US-guided compression therapy. To the best of our knowledge, iatrogenic SEPA pseudoaneurysm, which is an unusual vessel location for pseudoaneurysm occurrence, has not been reported in the literature. In patients in whom anticoagulant-thrombolytic therapy or therapeutic catheterization with larger sized sheath is planned, determination of the precise localization of arterial puncture site is important for the prevention of iatrogenic pseudoaneurysm development. Arterial puncture guided with Doppler US might reduce complications. When suspected, MDCTA is useful in the diagnosis and demonstration of iatrogenic pseudoaneurysms. Treatment of US-guided compression should be the first choice for iatrogenic pseudoaneurysms. Interventional radiologists and cardiologists should have enough experience about the catheterization complications and their treatment in order to decrease the morbidity and mortality related to the intervention. PMID- 25035707 TI - Unusual presentation of chronic eosinophilic pneumonia with "reversed halo sign": a case report. AB - The reversed halo sign (RHS) may sometimes be seen in patients with cryptogenic organizing pneumonia (COP), but is rarely associated with other diseases. Herein, we present a case of a 21-year-old woman with chronic eosinophilic pneumonia, with high resolution computed tomography (HRCT) finding of RHS. This is an unusual and rare presentation of chronic eosinophilic pneumonia. PMID- 25035708 TI - Virologic outcomes of second-line antiretroviral therapy in Eastern European country of Georgia. AB - BACKGROUND: Data on the effectiveness of second-line antiretroviral therapy (ART) in resource-limited countries of Eastern Europe is limited. Objective of this study was to evaluate virological outcomes of second-line ART in Georgia. METHODS: We conducted retrospective analysis using routinely available program data. Study included adult HIV-infected patients with confirmed HIV drug resistance, who were switched to second-line ART from August 2005 to December 2010. Patients were followed until July 1, 2011. Primary outcome was achievement of viral suppression. Demographic, clinical, laboratory and adherence data were abstracted from medical and program records. Adherence was expressed as percentage based on medication refill data, and was calculated as days supply of medications dispensed divided by days between prescription fills. Predictors of primary outcome were assessed in modified Poisson regression analysis. RESULTS: A total of 84 patients were included in the study. Among them 71.4% were men and 62% had history of IDU. All patients were receiving non-nucleoside reverse transcriptase based regimen as initial ART. The mean 6-month adherence prior to virologic failure was 75%, with 31% of patients showing 100% adherence. All patients were switched to protease inhibitor based regimens. Patients were followed for median 27 months. Over this period 9 (10.7%) patients died. Among 80 patients remaining alive at least 6 month after ART regimen switch, 72 (90%) patients ever reached undetectable viral load. The mean first 6-month adherence on second-line treatment was 81%, with 47.5% of patients showing 100% adherence. The proportion of patients achieving viral suppression after 6, 12, 24 and 36 months of second-line ART did not vary significantly ranging from 79 to 83%. Percentage of IDUs achieving viral suppression ranged from 75% and 83%. Factors associated with failure to achieve viral suppression at 6-months of second-line ART were: adherence <80% (Risk ratio [RR] 5.09, 95% CI: 1.89-13.70) and viral load >100,000 at the time of treatment failure (RR 3.39, 95% CI: 1.46-7.89). CONCLUSIONS: The study demonstrated favourable virological outcomes of the second line ART in Georgia. Majority of patients, including IDUs, achieved sustained virological response over 36 month period. The findings highlight the need of improving adherence. PMID- 25035709 TI - The prevalence of transmitted HIV drug resistance among MSM in Anhui province, China. AB - BACKGROUND: To optimize treatment regimens, we assessed human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) among men who have sex with men (MSM) in Anhui province, China. METHODS: A total of 139 MSM who were newly diagnosed and antiretroviral treatment-naive were enrolled in Anhui in 2011. A partial pol fragment was amplified and sequenced, and HIV subtypes were determined by phylogenetic analyses. Surveillance/transmitted drug resistance mutations (SDRMs) were identified according to the 2009 World Health Organization (WHO) list. RESULTS: A total of 133 (95.7%) samples were successfully amplified and sequenced. Based on phylogenetic analyses of the pol fragment, CRF01_AE accounted for 55.6% (74/133) of the infections, followed by CRF07_BC with 32.3% (43/133), B with 5.3% (7/133), and unique recombinant forms with 6.8% (9/133). A total of 3.0% (4/133) of the subjects were found to harbor HIV variants with SDRMs, including 1.5% with NRTI related mutations and 1.5% with NNRTI-related mutations. PI-related mutations were absent. The SDRMs included L210W (1.5%), Y181C (0.8%), and G190A (0.8%). CONCLUSIONS: In Anhui, CRF01_AE strains contributed to most of the HIV infections among MSM, and the prevalence of TDR was relatively low in this population. Further studies should be performed to evaluate the trend of TDR among MSM in Anhui and to inform first-line antiretroviral treatment. PMID- 25035710 TI - Acid-Catalyzed Conversion of Furfuryl Alcohol to Ethyl Levulinate in Liquid Ethanol. AB - Reaction pathways for the acid-catalyzed conversion of furfuryl alcohol (FAL) to ethyl levulinate (EL) in ethanol were investigated using liquid chromatography mass spectrometry (LC-MS), 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and ab initio high-level quantum chemical (G4MP2) calculations. Our combined studies show that the production of EL at high yields from FAL is not accompanied by stoichiometric production of diethyl either (DEE), indicating that ethoxymethyl furan (EMF) is not an intermediate in the major reaction pathway. Several intermediates were observed using an LC-MS system, and three of these intermediates were isolated and subjected to reaction conditions. The structures of two intermediates were elucidated using 1D and 2D NMR techniques. One of these intermediates is EMF, which forms EL and DEE in a secondary reaction pathway. The second intermediate identified is 4,5,5-triethoxypentan-2-one, which is analogous to one of the intermediates observed in the conversion of FAL to LA in water (i.e. 4,5,5-trihydroxypentan-2-one). Furthermore, conversion of this intermediate to EL again involves the formation of DEE, indicating that it is also part of a secondary pathway. The primary pathway for production of EL involves solvent assisted transfer of a water molecule from the partially detached protonated hydroxyl group of FAL to a ring carbon, followed by intra-molecular hydrogen shift, where the apparent reaction barrier for the hydrogen shift is relatively smaller in ethanol (21.1 kcal/mol) than that in water (26.6 kcal/mol). PMID- 25035711 TI - trans-10,cis-12 CLA promotes osteoblastogenesis via SMAD mediated mechanism in bone marrow mesenchymal stem cells. AB - The inverse relationship between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells has been linked to overall bone mass. It has previously been reported that conjugated linoleic acid (CLA) inhibits adipogenesis via a peroxisome-proliferator activated receptor-gamma (PPARgamma) mediated mechanism, while it increases osteoblastogenesis via a PPARgamma independent mechanism in mesenchymal stem cells. This suggests potential implication of CLA on improving bone mass. Thus the purpose of this study was to determine involvement of CLA on regulation of osteoblastogenesis in murine mesenchymal stem cells by focusing on the Mothers against decapentaplegic (MAD) related family of molecules 8 (SMAD8), one of key regulators of osteoblastogenesis. The trans-10,cis-12 CLA, but not the cis-9,trans-11, significantly increased osteoblastogenesis via SMAD8, and inhibited adipogenesis independent of SMAD8, while inhibiting factors regulating osteoclastogenesis in this model. These suggest that CLA may help improve osteoblastogenesis via a SMAD8 mediated mechanism. PMID- 25035712 TI - Intelligent approach for analysis of respiratory signals and oxygen saturation in the sleep apnea/hypopnea syndrome. AB - This work deals with the development of an intelligent approach for clinical decision making in the diagnosis of the Sleep Apnea/Hypopnea Syndrome, SAHS, from the analysis of respiratory signals and oxygen saturation in arterial blood, SaO2. In order to accomplish the task the proposed approach makes use of different artificial intelligence techniques and reasoning processes being able to deal with imprecise data. These reasoning processes are based on fuzzy logic and on temporal analysis of the information. The developed approach also takes into account the possibility of artifacts in the monitored signals. Detection and characterization of signal artifacts allows detection of false positives. Identification of relevant diagnostic patterns and temporal correlation of events is performed through the implementation of temporal constraints. PMID- 25035713 TI - Assessing the adherence to and the therapeutic effectiveness of hypolipidemic agents in a population of patients in Brazil: a retrospective cohort study. AB - OBJECTIVE: to evaluate the relation between patient adherence and therapeutic effectiveness of hypolipidemic agents in clinical practice. METHODS: A retrospective cohort study of 417 patients using hypolipidemic drugs (simvastatin, atorvastatin) between 2003 and 2010 was performed. The population studied consists of patients assisted by the Public Health Service in the far west region of the State of Santa Catarina, Brazil. The Medication Possession Ratio obtained from pharmacy refill data was used to measure patient adherence. Therapeutic effectiveness was evaluated based on the difference obtained in the serum levels of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides, before and after taking the drug, in an average time of 8.3 months. RESULTS: Following the treatment with hypolipidemic agents, it has been observed a reduction of 14.3% for total cholesterol, 19.6% for LDL-cholesterol, and 14.4% for triglycerides. HDL-cholesterol increased by an 8.0% average. The major changes in lipid profile were promoted by atorvastatin 20 mg daily. The medication adherence rate decreased over the monitoring period. Adherence rates below 60% were associated with therapeutic failure, while rates equal to 80% or higher were associated with the best response to the lipid-lowering drugs. CONCLUSION: Adherence to hypolipidemic agents is higher at the beginning of the treatment, but it decreases over time, affecting the achievement of therapeutic goals. PMID- 25035714 TI - High prescription of antimicrobials in a rural district hospital in India. AB - BACKGROUND: The World Health Organization (WHO) recommends surveillance of antibiotic use as part of the strategy to fight against antimicrobial resistance. However, there is little information about the antibiotic consumption in developing countries, especially in rural areas. OBJECTIVE: The objective of this study was to describe the antimicrobial consumption in a rural hospital in India. METHODS: The study was performed in a district hospital situated in Anantapur, Andhra Pradesh. In accordance with WHO recommendations, we used the defined daily dose (DDD) methodology to measure the antibiotic use during one year (from 1st August 2011 to 1st August 2012). The antibiotic use was measured using DDDs/100 admissions and DDDs/100 patient-days for inpatients, and DDDs/100 visits for outpatients. RESULTS: During the study period, there were 15,735 admissions and 250,611 outpatient visits. Antibiotics were prescribed for 86% of inpatients and 12.5% of outpatients. Outpatient prescriptions accounted for 2/3 of the overall antibiotic consumption. For inpatients, the total antibiotic use was 222 DDDs/ 100 patient-days, 693 DDDs/ 100 admissions and the mean number of antibiotics prescribed was 1.8. For outpatients, the total antibiotic use was 86 DDDs/ 100 outpatient visits and the mean number of antibiotics prescribed was 1.2. The most common antibiotics prescribed were aminopenicillins and 3rd generation cephalosporins for inpatients, and tetracyclines and quinolones for outpatients. In a sample of patients with diarrhoea or upper respiratory tract infections (URTI), the proportion of patients who received antibiotics was 84% (95% confidence interval [CI], 67-93) and 52% (95% CI, 43-62), respectively. CONCLUSION: In this rural setting, the use of antimicrobials was extremely high, even in conditions with a predominantly viral aetiology such as diarrhoea or URTI. PMID- 25035715 TI - Course experiences, satisfaction and career intent of final year pre-registration Australian pharmacy students. AB - BACKGROUND: In Australia, the profession of pharmacy has undergone many changes to adapt to the needs of the community. In recent years, concerns have been raised with evidence emerging of workforce saturation in traditional pharmacy practice sectors. It is not known how current final year pharmacy students' perceive the different pharmacy career paths in this changing environment. Hence investigating students' current experiences with their pharmacy course, interaction with the profession and developing an understanding of their career intentions would be an important step, as these students would make up a large proportion of future pharmacy workforce. OBJECTIVE: The objective of this study was thus to investigate final year students' career perspectives and the reasons for choosing pharmacy, satisfaction with this choice of pharmacy as a tertiary course and a possible future career, factors affecting satisfaction and intention of future career paths. METHODS: A quantitative cross sectional survey of final year students from 3 Australian universities followed by a qualitative semi structured interview of a convenience sample of final year students from the University of Sydney. RESULTS: 'Interest in health and medicine' was the most important reason for choosing pharmacy (n=238). The majority of students were 'somewhat satisfied' with the choice of pharmacy (35.7%) as a course and possible future career. Positive associations were found between satisfaction and reasons for joining pharmacy such as 'felt pharmacy is a good profession' (p=0.003) while negative associations included 'joined pharmacy as a gateway to medicine or dentistry' (p=0.001). Quantitate and qualitative results showed the most frequent perception of community pharmacy was 'changing' while hospital and pharmaceutical industry was described as 'competitive' and 'research' respectively. The highest career intention was community followed by hospital pharmacy. CONCLUSION: Complex factors including university experiences are involved in shaping students' satisfaction and perception of career. This may relate to challenges in the community pharmacy sector, job opportunities in hospital and limited understanding of the pharmaceutical industry. The results offer insight for the profession in terms of entry into various roles and also to pharmacy educators for their roles in shaping curricula and placement experiences that attract future graduates to defined career pathways in pharmacy. PMID- 25035716 TI - PERSYVE - Design and validation of a questionnaire about adverse effects of antihypertensive drugs. AB - OBJECTIVE: The aim of this study was to design and validate a questionnaire to measure perceived symptoms associated with antihypertensive drugs (PERSYVE). METHODS: THE PERSYVE DEVELOPMENT AND VALIDATION INCLUDED FOUR STAGES: 1) item development (bibliographic review and questionnaire elaboration); 2) face and content validation; 3) field testing (pre-test); and 4) test-retest validation, assessment of internal consistency (Cronbach's alpha) and reproducibility over time (intraclass correlation coefficient and Cohen's kappa coefficient). RESULTS: PERSYVE IS DIVIDED INTO SIX SECTIONS ACCORDING TO RESULTS OBTAINED FROM THE LITERATURE REVIEW: (1) drug adherence, (2) perceived symptoms and how they affect quality of life (five-point Likert scale), (3) communication with health professionals, (4) perception of symptoms as adverse reactions, (5) influence on therapy compliance, and (6) adoption of non-pharmacological methods for blood pressure control. Content and face validation of the questionnaire led to some vocabulary changes and the introduction of section 2.1. Field-testing (n=26) revealed high comprehensibility of the questions. The Cronbach's alpha, calculated for section 2 (five-point Likert scale) was 0.850. PERSYVE was reproducible (n=167): kappa values presented fair to substantial reproducibility and, in section 2, ICC values resulted in good to excellent reproducibility. CONCLUSION: Results showed that PERSYVE is a well-structured, objective, patient friendly, valid and reliable questionnaire. PERSYVE can be a very useful instrument in hypertensive patients' monitoring and in the screening of adverse effects. PMID- 25035717 TI - Maternal outcomes of magnesium sulphate and diazepam use in women with severe pre eclampsia and eclampsia in Ethiopia. AB - BACKGROUND: Preferred anticonvulsant used to treat and prevent fits in eclampsia currently is magnesium sulphate. Clinical monitoring of tendon reflexes, respiration rate and measuring hourly urine output should be done to ensures safe administration of magnesium sulphate. OBJECTIVE: This study was conducted to evaluate maternal outcomes of magnesium sulphate and diazepam use in the management of severe pre-eclampsia and eclampsia in Jimma University Specialized Hospital. METHODS: A retrospective hospital based cross-sectional comparative study was conducted using data collection format. Data was collected from the hospital delivery care register and patient chart records of all pregnant women who presented with the diagnosis of severe pre-eclampsia and eclampsia in two years and three months period from January, 2010 to April, 2012. Data analysis was done by SPSS version 16.0. A P-value of <0.05 was considered statistically significant in all tests. RESULTS: A total of 357 patient charts, 217 from magnesium sulphate and 140 from diazepam treated pregnant women group, were reviewed and analyzed. Three pregnant women from the magnesium sulphate treated group and eleven pregnant women from diazepam treated group had at least one convulsion after taking the drug. Greater proportion of patients in the magnesium sulphate treated group had less than four days postpartum stay as compared to the diazepam treated patients (82.3% versus 66.2%). Seizure occurrence, duration of postpartum hospital stays and birth outcome had a statistically significant association with the type of anticonvulsant used. CONCLUSIONS: Magnesium sulphate is more effective than diazepam in the management of severe pre-eclamptic and eclamptic pregnant women in terms of seizure prevention, shortening postpartum hospital stay and reducing maternal morbidities. PMID- 25035718 TI - A cross-sectional study of applied bioethical reasoning in pharmacy students and preceptors. AB - OBJECTIVE: To compare ethical principles most often utilized by pharmacy students and preceptors to determine plan of action for an ethical dilemma and to determine if ethical principles utilized are the same for individuals in the postconventional range. METHOD: A two part survey was administered to a convenience sample of pharmacy students and preceptors. The first part was comprised of an original measure, the Pharmacy Ethical Dilemmas Survey (PEDS), that was developed to assess participants' action choices on healthcare-related ethical dilemmas and which moral rule or ethical principle was most influential in their decision. The second part was comprised of the Defining Issues Test. RESULTS: Patient autonomy and non-maleficience were the primary bioethical principles applied by students but pharmacists applied non-maleficience, patient autonomy, and also pharmacist autonomy. For all scenarios, students were more likely to rely on the principle of beneficence, while preceptors were more likely to rely on the pharmacist's right to autonomy. In the analysis of application of bioethical principles by higher and lower principled reasoning individuals, only in the assisted suicide scenario did the two groups agree on the primary principle applied with both groups relying predominantly on patient autonomy. CONCLUSION: Students and preceptors utilize different bioethical principles to support how they would handle each ethical dilemma but P-scores do not play a role in determining which bioethical principles were used to justify their action choices. PMID- 25035719 TI - Influenza vaccination in patients with diabetes: disparities in prevalence between African Americans and Whites. AB - BACKGROUND: Patients with diabetes who contract influenza are at higher risk of complications, such as hospitalization and death. Patients with diabetes are three times more likely to die from influenza complications than those without diabetes. Racial disparities among patients with diabetes in preventive health services have not been extensively studied. OBJECTIVE: To compare influenza vaccination rates among African Americans and Whites patients with diabetes and investigate factors that might have an impact on racial disparities in the receipt of influenza vaccinations. METHODS: A secondary data analysis of 47,283 (unweighted) patients with diabetes from the 2011 Behavioral Risk Factor Surveillance System survey (BRFSS) (15,902,478 weighted) was performed. The survey respondents were asked whether they received an influenza vaccination in the last twelve months. We used logistic regression to estimate the odds of receiving the influenza vaccine based on race. RESULTS: The results indicated a significantly lower proportion of African Americans respondents (50%) reported receiving the influenza vaccination in the last year when compared with Whites respondents (61%). Age, gender, education, health care coverage, health care cost, and employment status were found to significantly modify the effect of race on receiving the influenza vaccination. CONCLUSIONS: This study found a significant racial disparity in influenza vaccination rates in adults with diabetes with higher rates in Whites compared to African Americans individuals. The public health policies that target diabetes patients in general and specifically African Americans in the 65+ age group, women, and homemakers, may be necessary to diminish the racial disparity in influenza vaccination rates between African Americans and Whites diabetics. PMID- 25035720 TI - Anti-hypertensive medicines prescribing for medical outpatients in a premier teaching hospital in Nigeria: a probable shift of paradigm. AB - BACKGROUND: Previous studies of anti-hypertensive medicines utilization pattern in Nigeria showed that Angiotensin converting enzyme inhibitors (ACEIs) were often the least prescribed. However, the appropriate use of ACEIs in the black population achieves good blood pressure control and provides additional long term cardio- and renovascular protection benefits. OBJECTIVE: To assess the current utilization pattern of antihypertensive medicines with specific emphasis on identifying possible shift in the frequency of use of ACEIs. METHODS: A prospective cross-sectional assessment of the current utilization pattern of anti hypertensive medicines was conducted among 300 randomly selected cohort at a 900 bed premier Teaching Hospital located in Ibadan, Southwestern Nigeria. The current utilization pattern was compared with the results of a study conducted at the same site and published 10 years ago. RESULTS: Of the 300 random cohorts, a majority (79%) were females (237) with mean age 58.7 years (SD=2.81 years. Stage 2 hypertension was the most frequent diagnosis (54.3%). The utilization of ACEIs and long acting CCB (amlodipine) significantly increased from 8.6% and 21% (Ten years ago) to 29.93% and 36.68% respectively (p < 0.0001). The use of thiazide diuretic and methyldopa declined significantly from 39.4% and 23.3% (Ten years ago) to 16.12% and 9.7% respectively (p < 0.0001). Adverse drug reactions due to ACEIs were documented in 1.5% (3), while laboratory monitoring of serum potassium, urea and creatinine was conducted in only 37% (111) of cohort. Potentially harmful drug-drug interactions were identified in 25% (75) of cohorts, and the most frequent were ACEIs + NSAIDs (53.3%), ACEIs + amiloride / hydrochlorothiazide (22.6%). CONCLUSIONS: Anti-hypertensive medicines utilization has significantly shifted towards the increased use of ACEIs and long acting dihydropyridine CCBs. The use of thiazides and methyldopa has declined significantly. Physicians appeared more cognizant of the long term cardio- and renovascular benefits inherent in using ACEIs in a high cardiovascular risk group such as black hypertensive. PMID- 25035721 TI - Pharmacists implementing transitions of care in inpatient, ambulatory and community practice settings. AB - OBJECTIVE: To introduce pharmacists to the process, challenges, and opportunities of creating transitions of care (TOC) models in the inpatient, ambulatory, and community practice settings. METHODS: TOC literature and resources were obtained through searching PubMed, Ovid, and GoogleScholar. The pharmacist clinicians, who are the authors in this manuscript are reporting their experiences in the development, implementation of, and practice within the TOC models. RESULTS: Pharmacists are an essential part of the multidisciplinary team and play a key role in providing care to patients as they move between health care settings or from a health care setting to home. Pharmacists can participate in many aspects of the inpatient, ambulatory care, and community pharmacy practice settings to implement and ensure optimal TOC processes. This article describes establishing the pharmacist's TOC role and practicing within multiple health care settings. In these models, pharmacists focus on medication reconciliation, discharge counseling, and optimization of medications [corrected]. CONCLUSION: Optimizing the TOC process, reducing medication errors, and preventing adverse events are important focus areas in the current health care system, as emphasized by The Joint Commission and other health care organizations. Pharmacists have the unique opportunity and skillset to develop and participate in TOC processes that will enhance medication safety and improve patient care. PMID- 25035722 TI - Continuous hemodynamic monitoring in acute stroke: an exploratory analysis. AB - INTRODUCTION: Non-invasive, continuous hemodynamic monitoring is entering the clinical arena. The primary objective of this study was to test the feasibility of such monitoring in a pilot sample of Emergency Department (ED) stroke patients. Secondary objectives included analysis of hemodynamic variability and correlation of continuous blood pressure measurements with standard measurements. METHODS: This study was a secondary analysis of 7 stroke patients from a prospectively collected data set of patients that received 2 hours of hemodynamic monitoring in the ED. Stroke patients were included if hemorrhagic or ischemic stroke was confirmed by neuroimaging, and symptom onset was within 24 hours. They were excluded for the presence of a stroke mimic or transient ischemic attack. Monitoring was performed using the Nexfin device (Edwards Lifesciences, Irvine CA). RESULTS: The mean age of the cohort was 71 +/- 17 years, 43% were male, and the mean National Institute of Health Stroke Scale (NIHSS) was 6.9 +/- 5.5. Two patients had hemorrhagic stroke. We obtained 42,456 hemodynamic data points, including beat-to-beat blood pressure measurements with variability of 18 mmHg and cardiac indices ranging from 1.8 to 3.6 l/min/m2. The correlation coefficient between continuous blood pressure measurements with the Nexfin device and standard ED readings was 0.83. CONCLUSION: This exploratory investigation revealed that continuous, noninvasive monitoring in the ED is feasible in acute stroke. Further research is currently underway to determine how such monitoring may impact outcomes in stroke or replace the need for invasive monitoring. PMID- 25035723 TI - Arm weakness and deformity. PMID- 25035724 TI - Man with altered mentation after trauma. PMID- 25035726 TI - Giant hydronephrosis. PMID- 25035725 TI - Man with abdominal distension. PMID- 25035727 TI - Chemosis from trauma. PMID- 25035728 TI - "Whirl sign" of primary small bowel volvulus. PMID- 25035729 TI - Incidental finding in a headache patient: intracranial lipoma. PMID- 25035730 TI - Ear drainage after trauma. PMID- 25035731 TI - Thoracic outlet syndrome with secondary Paget Schroetter Syndrome: a rare case of effort-induced thrombosis of the upper extremity. PMID- 25035732 TI - A purple ulcer. PMID- 25035733 TI - Handlebar trauma causing small bowel hernia with jejunal perforation. PMID- 25035734 TI - Asystolic cardiac arrest from near drowning managed with therapeutic hypothermia. PMID- 25035735 TI - Pediatric patient with a rash. AB - A 2 year old fully immunized male with no personal history of chicken pox presented to the emergency department with a chief complaint of a rash for one week after returning from a hiking trip in a remote island in Canada. After initially being diagnosed with contact dermatitis, a diagnosis of herpes zoster was made by confirmatory viral polymerase chain reaction testing. The purpose of this case report is to examine the literature for the incidence and etiology of shingles in children without a prior history of a primary varicella rash outbreak. PMID- 25035736 TI - A case of rivaroxaban associated intracranial hemorrhage. AB - Rivaroxaban is a newer anticoagulant initially approved by the Food and Drug Administration to treat nonvalvular atrial fibrillation. Rivaroxaban has several characteristics that are more favorable than warfarin. One of the characteristics is decreased risk of hemorrhage. We report one of the first case reports of severe intracranial hemorrhage associated with rivaroxaban in an elderly patient with decreased renal function. We aim to alert emergency medicine providers regarding the likelihood of encountering these patient as newer anticoagulants rise in popularity. PMID- 25035737 TI - Paralytic shellfish poisoning: a case series. AB - We describe a case series of seven patients presenting to an emergency department with symptoms of paralytic shellfish poisoning. They developed varying degrees of nausea, vomiting, diarrhea, weakness, ataxia and paresthesias after eating mussels harvested from a beach near their resort. Four patients were admitted to the hospital, one due to increasing respiratory failure requiring endotracheal intubation and the remainder for respiratory monitoring. All patients made a full recovery, most within 24 hours. The ability to recognize and identify paralytic shellfish poisoning and manage its complications are important to providers of emergency medicine. PMID- 25035738 TI - Bilateral hydronephrosis and cystitis resulting from chronic ketamine abuse. AB - Ketamine associated urinary dysfunction has become increasingly more common worldwide. Point-of-care ultrasound (POCUS) is an established modality for diagnosing hydronephrosis in the emergency department. We describe a case of a young male ketamine abuser with severe urinary urgency and frequency in which POCUS performed by the emergency physician demonstrated bilateral hydronephrosis and a focally thickened irregular shaped bladder. Emergency physicians should consider using POCUS evaluate for hydronephrosis and bladder changes in ketamine abusers with lower urinary tract symptoms. The mainstay of treatment is discontinuing ketamine abuse. PMID- 25035739 TI - Intestinal obstruction caused by phytobezoars. PMID- 25035740 TI - Facial firework injury: a case series. AB - Fireworks are used to celebrate a variety of religious, patriotic, and cultural holidays and events around the world. Fireworks are common in the United States, with the most popular holiday for their use being national Independence Day, also known as July Fourth. The use of fireworks within the context of celebrations and holidays presents the ideal environment for accidents that lead to severe and dangerous injuries. Injuries to the face from explosions present a challenging problem in terms of restoring ideal ocular, oral, and facial function. Despite the well documented prevalence of firework use and injury, there is a relatively large deficit in the literature in terms of firework injury that involves the face. We present a unique case series that includes 4 adult male patients all with severe firework injuries to the face that presented at an urban level 1 trauma center. These four patients had an average age of 26.7 years old and presented within 5 hours of each other starting on July Fourth. Two patients died from their injuries and two patients underwent reconstructive surgical management, one of which had two follow up surgeries. We explore in detail their presentation, management, and subsequent outcomes as an attempt to add to the very limited data in the field of facial firework blast injury. In addition, the coincidence of their presentation within the same 5 hours brings into question the availability of the fireworks involved, and the possibility of similar injuries related to this type of firework in the future. PMID- 25035741 TI - Ocular ultrasound identifies early orbital cellulitis. PMID- 25035742 TI - Acute mesenteric venous thrombosis with a vaginal contraceptive ring. AB - Mesenteric venous thrombosis is a rare cause of abdominal pain, which if left untreated may result in bowel infarction, peritonitis and death. The majority of patients with this illness have a recognizable, predisposing prothrombotic condition. Oral contraceptives have been identified as a predisposing factor for mesenteric venous thrombosis in reproductive-aged women. In the last fifteen years new methods of hormonal birth control have been introduced, including a transdermal patch and an intravaginal ring. In this report, we describe a case of mesenteric venous thrombosis in a young woman caused by a vaginal contraceptive ring. PMID- 25035743 TI - Emergency medicine clerkship directors: current workforce. AB - INTRODUCTION: The emergency medicine clerkship director serves an important role in the education of medical students. The authors sought to update the demographic and academic profile of the emergency medicine clerkship director. METHODS: We developed and implemented a comprehensive questionnaire, and used it to survey all emergency medicine clerkship directors at United States allopathic medical schools accredited by the Liaison Committee on Medical Education. We analyzed and interpreted data using descriptive statistics. RESULTS: One hundred seven of 133 (80.4%) emergency medicine clerkship directors completed the survey. Clerkship Director's mean age was 39.7 years (SD-7.2), they were more commonly male 68.2%, of Caucasian racial backgrounds and at the instructor or assistant professor (71.3%) level. The mean number of years of experience as clerkship director was 5.5 (SD-4.5). The mean amount of protected time for clerkship administration reported by respondents was 7.3 hours weekly (SD-5.1), with the majority (53.8%) reporting 6 or more hours of protected time per week. However, 32.7% of emergency medicine clerkship directors reported not having any protected time for clerkship administration. Most clerkship directors (91.6%) held additional teaching responsibilities beyond their clerkship and many were involved in educational research (49.5%). The majority (79.8%), reported being somewhat or very satisfied with their job as clerkship director. CONCLUSION: Most clerkship directors were junior faculty at the instructor or assistant professor rank and were involved with a variety of educational endeavors beyond the clerkship. PMID- 25035744 TI - Effect of prior cardiopulmonary resuscitation knowledge on compression performance by hospital providers. AB - INTRODUCTION: The purpose of this study was to determine cardiopulmonary resuscitation (CPR) knowledge of hospital providers and whether knowledge affects performance of effective compressions during a simulated cardiac arrest. METHODS: This cross-sectional study evaluated the CPR knowledge and performance of medical students and ED personnel with current CPR certification. We collected data regarding compression rate, hand placement, depth, and recoil via a questionnaire to determine knowledge, and then we assessed performance using 60 seconds of compressions on a simulation mannequin. RESULTS: Data from 200 enrollments were analyzed by evaluators blinded to subject knowledge. Regarding knowledge, 94% of participants correctly identified parameters for rate, 58% for hand placement, 74% for depth, and 94% for recoil. Participants identifying an effective rate of >=100 performed compressions at a significantly higher rate than participants identifying <100 (MU=117 vs. 94, p<0.001). Participants identifying correct hand placement performed significantly more compressions adherent to guidelines than those identifying incorrect placement (MU=86% vs. 72%, p<0.01). No significant differences were found in depth or recoil performance based on knowledge of guidelines. CONCLUSION: Knowledge of guidelines was variable; however, CPR knowledge significantly impacted certain aspects of performance, namely rate and hand placement, whereas depth and recoil were not affected. Depth of compressions was poor regardless of prior knowledge, and knowledge did not correlate with recoil performance. Overall performance was suboptimal and additional training may be needed to ensure consistent, effective performance and therefore better outcomes after cardiopulmonary arrest. PMID- 25035745 TI - Assessing knowledge base on geriatric competencies for emergency medicine residents. AB - INTRODUCTION: Emergency care of older adults requires specialized knowledge of their unique physiology, atypical presentations, and care transitions. Older adults often require distinctive assessment, treatment and disposition. Emergency medicine (EM) residents should develop expertise and efficiency in geriatric care. Older adults represent over 25% of most emergency department (ED) volumes. Yet many EM residencies lack curricula or assessment tools for competent geriatric care. Fully educating residents in emergency geriatric care can demand large amounts of limited conference time. The Geriatric Emergency Medicine Competencies (GEMC) are high-impact geriatric topics developed to help residencies efficiently and effectively meet this training demand. This study examines if a 2-hour didactic intervention can significantly improve resident knowledge in 7 key domains as identified by the GEMC across multiple programs. METHODS: A validated 29-question didactic test was administered at six EM residencies before and after a GEMC-focused lecture delivered in summer and fall of 2009. We analyzed scores as individual questions and in defined topic domains using a paired student t test. RESULTS: A total of 301 exams were administered; 86 to PGY1, 88 to PGY2, 86 to PGY3, and 41 to PGY4 residents. The testing of didactic knowledge before and after the GEMC educational intervention had high internal reliability (87.9%). The intervention significantly improved scores in all 7 GEMC domains (improvement 13.5% to 34.6%; p<0.001). For all questions, the improvement was 23% (37.8% pre, 60.8% post; P<0.001) Graded increase in geriatric knowledge occurred by PGY year with the greatest improvement post intervention seen at the PGY 3 level (PGY1 19.1% versus PGY3 27.1%). CONCLUSION: A brief GEMC intervention had a significant impact on EM resident knowledge of critical geriatric topics. Lectures based on the GEMC can be a high-yield tool to enhance resident knowledge of geriatric emergency care. Formal GEMC curriculum should be considered in training EM residents for the demands of an aging population. PMID- 25035746 TI - Improving community understanding of medical research: audience response technology for community consultation for exception to informed consent. AB - INTRODUCTION: The Department of Health and Human Services and Food and Drug Administration described guidelines for exception from informed consent (EFIC) research. These guidelines require community consultation (CC) events, which allow members of the community to understand the study, provide feedback and give advice. A real-time gauge of audience understanding would allow the speaker to modify the discussion. The objective of the study is to describe the use of audience response survey (ARS) technology in EFIC CCs. METHODS: As part of the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), 13 CC events were conducted. We prepared a PowerPointTM presentation with 4 embedded ARS questions,according to specific IRB guidelines to ensure that the pertinent information would reach our targeted audience. During 6 CCs, an ARS was used to gauge audience comprehension. Participants completed paper surveys regarding their opinion of the study following each CC. RESULTS: The ARS was used with minimal explanation and only one ARS was lost. Greater than 80% of the participants correctly answered 3 of the 4 ARS questions with 61% correctly answering the question regarding EFIC. A total of 105 participants answered the paper survey; 80-90% of the responses to the paper survey were either strongly agree or agree. The average scores on the paper survey in the ARS sites compared to the non-ARS sites were significantly more positive. CONCLUSION: The use of an audience response system during the community consultation aspects of EFIC is feasible and provides a real-time assessment of audience comprehension of the study and EFIC process. It may improve the community's opinion and support of the study. PMID- 25035747 TI - Analysis of the evaluative components on the Standard Letter of Recommendation (SLOR) in Emergency Medicine. AB - INTRODUCTION: The standard letter of recommendation in emergency medicine (SLOR) was developed to standardize the evaluation of applicants, improve inter-rater reliability, and discourage grade inflation. The primary objective of this study was to describe the distribution of categorical variables on the SLOR in order to characterize scoring tendencies of writers. METHODS: We performed a retrospective review of all SLORs written on behalf of applicants to the three Emergency Medicine residency programs in the University of Arizona Health Network (i.e. the University Campus program, the South Campus program and the Emergency Medicine/Pediatrics combined program) in 2012. All "Qualifications for Emergency Medicine" and "Global Assessment" variables were analyzed. RESULTS: 1457 SLORs were reviewed, representing 26.7% of the total number of Electronic Residency Application Service applicants for the academic year. Letter writers were most likely to use the highest/most desirable category on "Qualifications for EM" variables (50.7%) and to use the second highest category on "Global Assessments" (43.8%). For 4-point scale variables, 91% of all responses were in one of the top two ratings. For 3-point scale variables, 94.6% were in one of the top two ratings. Overall, the lowest/least desirable ratings were used less than 2% of the time. CONCLUSIONS: SLOR letter writers do not use the full spectrum of categories for each variable proportionately. Despite the attempt to discourage grade inflation, nearly all variable responses on the SLOR are in the top two categories. Writers use the lowest categories less than 2% of the time. Program Directors should consider tendencies of SLOR writers when reviewing SLORs of potential applicants to their programs. PMID- 25035748 TI - Deliberate apprenticeship in the Pediatric Emergency Department improves experience for third-year students. AB - INTRODUCTION: The Pediatric Emergency Department (PED) provides medical students with learning in a high-volume, fast-paced environment; characteristics that can be stressful for new students. Shadowing can improve transitioning, yet this alone does not facilitate students' development of independent medical care competencies. This study evaluates if third-year medical students' deliberate apprenticeship with senior residents increases students' comfort and patient exposure in the PED. METHODS: This study took place over the 2011-2012 academic year, and study participants were all third-year medical students during their pediatric clerkship rotation. This was a prospective educational intervention assigning students to randomized control blocks of deliberate apprenticeship (DA) intervention or control. DA students were paired with a senior resident who oriented and worked with the student, while control students were unpaired. All students completed a 20-question structured survey at shift end, which included questions about their perception of the learning environment, comfort with, and number of patient care responsibilities performed. We used independent Mann Whitney and t-tests to compare experiences between the groups. Statistical significance was defined as p<0.05. We used the constant comparative method to qualitatively analyze students' comments. RESULTS: Response rate was 85% (145/169). Students also rated on 5-point Likert-scale their level of comfort with defined aspects of working in the PED. DA students (n=76) were significantly more comfortable obtaining histories (4.2 versus 3.8) and formulating differential diagnoses (3.9 versus 3.4). DA students also performed more physical exams (2.9 versus 2.4). We categorized themes from the qualitative analysis of the students' comments about their PED experience. The titles for these themes are as follows: PED provides a good learning experience; uncertainty about the medical student's role in the PED; third-year medical students compete with other learners for teaching attention; opportunities provided to medical students for inclusion in patient care; personal knowledge deficits limit the ability to participate in the PED; PED pace affects learning opportunities. CONCLUSION: DA constitutes a feasible approach to the clinical learning environment that increases students' patient care experiences and may ease transitioning for undergraduate medical students to new clinical environments. PMID- 25035749 TI - Unrecognized hypoxia and respiratory depression in emergency department patients sedated for psychomotor agitation: pilot study. AB - INTRODUCTION: The incidence of respiratory depression in patients who are chemically sedated in the emergency department (ED) is not well understood. As the drugs used for chemical restraint are respiratory depressants, improving respiratory monitoring practice in the ED may be warranted. The objective of this study is to describe the incidence of respiratory depression in patients chemically sedated for violent behavior and psychomotor agitation in the ED. METHODS: Adult patients who met eligibility criteria with psychomotor agitation and violent behavior who were chemically sedated were eligible. SpO2 and ETCO2 (end-tidal CO2) was recorded and saved every 5 seconds. Demographic data, history of drug or alcohol abuse, medical and psychiatric history, HR and BP every 5 minutes, any physician intervention for hypoxia or respiratory depression, or adverse events were also recorded. We defined respiratory depression as an ETCO2 of >=50 mmHg, a change of 10% above or below baseline, or a loss of waveform for >=15 seconds. Hypoxia was defined as a SpO2 of <=93% for >=15 seconds. RESULTS: We enrolled 59 patients, and excluded 9 because of >=35% data loss. Twenty-eight (28/50) patients developed respiratory depression at least once during their chemical restraint (56%, 95% CI 42-69%); the median number of events was 2 (range 1-6). Twenty-one (21/50) patients had at least one hypoxic event during their chemical restraint (42%, 95% CI 29-55%); the median number of events was 2 (range 1-5). Nineteen (19/21) (90%, 95% CI 71-97%) of the patients that developed hypoxia had a corresponding ETCO2 change. Fifteen (15/19) (79%, 95% CI 56-91%) patients who became hypoxic met criteria for respiratory depression before the onset of hypoxia. The sensitivity of ETCO2 to predict the onset of a hypoxic event was 90.48% (95% CI: 68-98%) and specificity 69% (95% CI: 49-84%). Five patients received respiratory interventions from the healthcare team to improve respiration [Airway repositioning: (2), Verbal stimulation: (3)]. Thirty-seven patients had a history of concurrent drug or alcohol abuse and 24 had a concurrent psychiatric history. None of these patients had a major adverse event. CONCLUSION: About half of the patients in this study exhibited respiratory depression. Many of these patients went on to have a hypoxic event, and most of the incidences of hypoxia were preceded by respiratory depression. Few of these events were recognized by their treating physicians. PMID- 25035750 TI - Characteristics of United States emergency departments that routinely perform alcohol risk screening and counseling for patients presenting with drinking related complaints. AB - INTRODUCTION: Emergency department (ED) screening and counseling for alcohol misuse have been shown to reduce at-risk drinking. However, barriers to more widespread adoption of this service remain unclear. METHODS: We performed a secondary analysis of a nationwide survey of 277 EDs to determine the proportion of EDs that routinely perform alcohol screening and counseling among patients presenting with alcohol-related complaints and to identify potential institutional barriers and facilitators to routine screening and counseling. The survey was randomly mailed to 350 EDs sampled from the 2007 National Emergency Department Inventory (NEDI), with 80% of ED medical directors responding after receiving the mailing or follow-up fax/email. The survey asked about a variety of preventive services and ED directors' opinions regarding perceived barriers to offering preventive services in their EDs. RESULTS: Overall, only 27% of all EDs and 22% of Level I/II trauma center EDs reported routinely screening and counseling patients presenting with drinking-related complaints. Rates of routine screening and counseling were similar across geographic areas, crowding status, and urban-rural status. EDs that performed routine screening and counseling often offered other preventive services, such as tobacco cessation (P<0.01) and primary care linkage (P=0.01). EDs with directors who expressed concern about increased financial costs to the ED, inadequate follow-up, and diversion of nurse/physician time all had lower rates of screening and counseling and also more frequently reported lacking the perceived capacity to perform routine counseling and screening. Among EDs that did not routinely perform alcohol screening and counseling, more crowded than non-crowded (P<0.01) and more metro than rural (P<0.01) EDs reported lacking the capacity to perform routine screening and counseling. The capacity to perform routine screening also decreased as ED visit volume increased (P=0.04). CONCLUSION: To increase routine alcohol screening and counseling for patients presenting with alcohol-related complaints, ED directors' perceived barriers related to an ED's capacity to perform screening, such as limited financial and staff resources, should be addressed, as should directors' concerns regarding the implementation of preventive health services in EDs. Uniform reimbursement methods should be used to increase ED compensation for performing this important and effective service. PMID- 25035751 TI - Application of a proactive risk analysis to emergency department sickle cell care. AB - INTRODUCTION: Patients with sickle cell disease (SCD) often seek care in emergency departments (EDs) for severe pain. However, there is evidence that they experience inaccurate assessment, suboptimal care, and inadequate follow-up referrals. The aim of this project was to 1) explore the feasibility of applying a failure modes, effects and criticality analysis (FMECA) in two EDs examining four processes of care (triage, analgesic management, high risk/high users, and referrals made) for patients with SCD, and 2) report the failures of these care processes in each ED. METHODS: A FMECA was conducted of ED SCD patient care at two hospitals. A multidisciplinary group examined each step of four processes. Providers identified failures in each step, and then characterized the frequency, impact, and safeguards, resulting in risk categorization. RESULTS: Many "high risk" failures existed in both institutions, including a lack of recognition of high-risk or high-user patients and a lack of emphasis on psychosocial referrals. Specific to SCD analgesic management, one setting inconsistently used existing analgesic policies, while the other setting did not have such policies. CONCLUSION: FMECA facilitated the identification of failures of ED SCD care and has guided quality improvement activities. Interventions can focus on improvements in these specific areas targeting improvements in the delivery and organization of ED SCD care. Improvements should correspond with the forthcoming National Heart, Lung and Blood-sponsored guidelines for treatment of patients with sickle cell disease. PMID- 25035752 TI - Adherence to head computed tomography guidelines for mild traumatic brain injury. AB - INTRODUCTION: Traumatic brain injury (TBI) is a significant health concern. While 70-90% of TBI cases are considered mild, decision-making regarding imaging can be difficult. This survey aimed to assess whether clinicians' decision-making was consistent with the most recent American College of Emergency Physicians (ACEP) clinical recommendations regarding indications for a non-contrast head computed tomography (CT) in patients with mild TBI. METHODS: We surveyed 2 academic emergency medicine departments. Six realistic clinical vignettes were created. The survey software randomly varied 2 factors: age (30, 59, or 61 years old) and presence or absence of visible trauma above the clavicles. A single important question was asked: "Would you perform a non-contrast head CT on this patient?" RESULTS: Physician decision-making was consistent with the guidelines in only 62.8% of total vignettes. By age group (30, 59, and 61), decision-making was consistent with the guidelines in 66.7%, 47.4%, and 72.7% of cases, respectively. This was a statistically-significant difference when comparing the 59- and 61 year-old age groups. In the setting of presence/absence of trauma above the clavicles, respondents were consistent with the guidelines in 57.1% of cases. Decision-making consistent with the guidelines was significantly better in the absence of trauma above the clavicles. CONCLUSION: Respondents poorly differentiated the "older" patients from one another, suggesting that respondents either inappropriately apply the guidelines or are unaware of the recommendations in this setting. No particular cause for inconsistency could be determined, and respondents similarly under-scanned and over-scanned in incorrect vignettes. Improved dissemination of the ACEP clinical policy and recommendations is a potential solution to this problem. PMID- 25035753 TI - Yield and clinical predictors of thoracic spine injury from chest computed tomography for blunt trauma. AB - INTRODUCTION: Cost and radiation risk have prompted intense examination of trauma patient imaging. A proposed decision instrument (DI) for the use of chest computed tomography (CT), (CCT) in blunt trauma patients includes thoracic spine (TS) tenderness, altered mental status (AMS) and distracting painful injury (DPI) as potential predictor variables. TS CT is a separate, costly study whose value is currently ill-defined. The objective of this study is to determine test characteristics of these predictor variables alone, and in combination, to derive a TS injury DI. METHODS: Prospective cohort study of blunt trauma patients age > 14 in a Level I Trauma Center who had either CCT or TS CT. RESULTS: Of 1,798 blunt trauma patients, 1,174 (65.3%) had CCT, and 46 (2.6%) had a TS CT at physician discretion. CCT identified 58 TS injuries in 1,220 patients (4.8%). For 1,032 patients without AMS, 18/35 had TS tenderness, for sensitivity of 51.4%, specificity 84.7%, positive (PPV) and negative predictive values (NPV) of 10.5% and 98.0%. Positive likelihood ratio (+LR) was 3.35, with negative (-LR) 0.57. Among the 58 TS injuries, 23 had AMS for sensitivity of 39.7%, with other test characteristics of 85.8%, 12.2%, 96.6%, with +LR 2.79 and -LR 0.70. Thirty-eight of 58 had DPI, for sensitivity 65.5%, with other test characteristics 65.7%, 8.7%, and 97.4%, with +LR 1.91 and -LR 0.52. Combining 3 predictor variables into a proposed DI found 56/58 injuries for test characteristics of 96.6% (95% CI 88.1 99.6%), 49.1% (46.1-52.0%), 8.6% (6.6-11.1%) and 99.7% (CI 98.7-100%), with +LR 1.90 (1.76-2.04) and -LR 0.07 (0.02-0.28). If validated, the DI would exclude 572/1,220 CCT patients from separate TS CT (46.9%, CI 44.1-49.7%), and 141/511 (27.6%, CI 23.8-31.7%) patients who actually had TS CT in our cohort. Medicare payment at our center for sagittal reconstructions of TS CT is $280 for professional plus technical charges ($3,312 per study). The DI, if validated, would save $39,000-$160,000 in TS imaging payments. CONCLUSION: TS CT is low yield and costly. Patients who are alert, have no TS tenderness and no DPI have a very low likelihood of TS injury (NPV 99.7% 95% CI lower limit 98.7%) with LR=0.07, 95% CI upper limit 0.28). Avoiding TS CT may save considerable charges and payments. PMID- 25035754 TI - Comparison of three prehospital cervical spine protocols for missed injuries. AB - INTRODUCTION: We wanted to compare 3 existing emergency medical services (EMS) immobilization protocols: the Prehospital Trauma Life Support (PHTLS, mechanism based); the Domeier protocol (parallels the National Emergency X-Radiography Utilization Study [NEXUS] criteria); and the Hankins' criteria (immobilization for patients <12 or >65 years, those with altered consciousness, focal neurologic deficit, distracting injury, or midline or paraspinal tenderness).To determine the proportion of patients who would require cervical immobilization per protocol and the number of missed cervical spine injuries, had each protocol been followed with 100% compliance. METHODS: This was a cross-sectional study of patients >=18 years transported by EMS post-traumatic mechanism to an inner city emergency department. Demographic and clinical/historical data obtained by physicians were recorded prior to radiologic imaging. Medical record review ascertained cervical spine injuries. Both physicians and EMS were blinded to the objective of the study. RESULTS: Of 498 participants, 58% were male and mean age was 48 years. The following participants would have required cervical spine immobilization based on the respective protocol: PHTLS, 95.4% (95% CI: 93.1-96.9%); Domeier, 68.7% (95% CI: 64.5-72.6%); Hankins, 81.5% (95% CI: 77.9-84.7%). There were 18 cervical spine injuries: 12 vertebral fractures, 2 subluxations/dislocations and 4 spinal cord injuries. Compliance with each of the 3 protocols would have led to appropriate cervical spine immobilization of all injured patients. In practice, 2 injuries were missed when the PHTLS criteria were mis-applied. CONCLUSION: Although physician-determined presence of cervical spine immobilization criteria cannot be generalized to the findings obtained by EMS personnel, our findings suggest that the mechanism-based PHTLS criteria may result in unnecessary cervical spine immobilization without apparent benefit to injured patients. PHTLS criteria may also be more difficult to implement due to the subjective interpretation of the severity of the mechanism, leading to non-compliance and missed injury. PMID- 25035755 TI - Successful conviction of intoxicated drivers at a level I trauma center. AB - INTRODUCTION: Conviction rates for drivers driving under the influence (DUI) and in motor vehicle collisions (MVC) presenting to trauma centers are based primarily on data from the 1990s. Our goal was to identify DUI conviction rates of intoxicated drivers in MVCs presenting to a trauma center and to identify factors associated with the failure to obtain a DUI conviction. METHODS: Retrospective study of adults (>18 years) presenting to a trauma center emergency department (ED) in 2007. Eligible subjects were drivers involved in a MVC with an ED blood alcohol level (BAL) >= 80mg/dL. Subjects were matched to their Department of Motor Vehicle (DMV) records to identify DUI convictions from the collision, the legal blood alcohol concentration (BAC), and arresting officer's impression of the driver's sobriety. We entered potential variables predictive of failure to obtain a DUI conviction into a regression model. RESULTS: The 241 included subjects had a mean age of 34.1 +/- 12.8 years, and 185 (77%) were male. Successful DUI convictions occurred in 142/241 (58.9%, 95% CI 52.4, 65.2%) subjects. In a regression model, Injury Severity Score > 15 (odds ratio = 2.70 (95% CI 1.06, 6.85)) and a lower ED BAL from 80 to 200mg/dL (odds ratio = 5.03 (95% CI 1.69, 14.9) were independently associated with a failure to obtain a DUI conviction. CONCLUSION: Slightly more than half of drivers who present to an ED after a MVC receive a DUI conviction. The most severely injured subjects and those with lower BALs are least likely to be convicted of a DUI. PMID- 25035756 TI - Analysis of medication errors in simulated pediatric resuscitation by residents. AB - INTRODUCTION: The objective of our study was to estimate the incidence of prescribing medication errors specifically made by a trainee and identify factors associated with these errors during the simulated resuscitation of a critically ill child. METHODS: The results of the simulated resuscitation are described. We analyzed data from the simulated resuscitation for the occurrence of a prescribing medication error. We compared univariate analysis of each variable to medication error rate and performed a separate multiple logistic regression analysis on the significant univariate variables to assess the association between the selected variables. RESULTS: We reviewed 49 simulated resuscitations. The final medication error rate for the simulation was 26.5% (95% CI 13.7% - 39.3%). On univariate analysis, statistically significant findings for decreased prescribing medication error rates included senior residents in charge, presence of a pharmacist, sleeping greater than 8 hours prior to the simulation, and a visual analog scale score showing more confidence in caring for critically ill children. Multiple logistic regression analysis using the above significant variables showed only the presence of a pharmacist to remain significantly associated with decreased medication error, odds ratio of 0.09 (95% CI 0.01 - 0.64). CONCLUSION: Our results indicate that the presence of a clinical pharmacist during the resuscitation of a critically ill child reduces the medication errors made by resident physician trainees. PMID- 25035757 TI - Clinical management of skin and soft tissue infections in the U.S. Emergency Departments. AB - INTRODUCTION: Community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) has emerged as the most common cause of skin and soft-tissue infections (SSTI) in the United States. A nearly three-fold increase in SSTI visit rates had been documented in the nation's emergency departments (ED). The objective of this study was to determine characteristics associated with ED performance of incision and drainage (I+D) and use of adjuvant antibiotics in the management of skin and soft tissue infections (SSTI). METHODS: Cross-sectional study of the National Hospital Ambulatory Medical Care Survey, a nationally representative database of ED visits from 2007-09. Demographics, rates of I+D, and adjuvant antibiotic therapy were described. We used multivariable regression to identify factors independently associated with use of I+D and adjuvant antibiotics. RESULTS: An estimated 6.8 million (95% CI: 5.9-7.8) ED visits for SSTI were derived from 1,806 sampled visits; 17% were for children <18 years of age and most visits were in the South (49%). I+D was performed in 27% (95% CI 24-31) of visits, and was less common in subjects <18 years compared to adults 19-49 years (p<0.001), and more common in the South. Antibiotics were prescribed for 85% of SSTI; there was no relationship to performance of I+D (p=0.72). MRSA-active agents were more frequently prescribed after I+D compared to non-drained lesions (70% versus 56%, p<0.001). After multivariable adjustment, I+D was associated with presentation in the South (OR 2.36; 95% CI 1.52-3.65 compared with Northeast), followed by West (OR 2.13; 1.31-3.45), and Midwest (OR 1.96; 1.96-3.22). CONCLUSION: Clinical management of most SSTIs in the U.S. involves adjuvant antibiotics, regardless of I+D. Although not necessarily indicated, CA-MRSA effective therapy is being used for drained SSTI. PMID- 25035758 TI - Expansion of U.S. emergency medical service routing for stroke care: 2000-2010. AB - INTRODUCTION: Organized stroke systems of care include preferential emergency medical services (EMS) routing to deliver suspected stroke patients to designated hospitals. To characterize the growth and implementation of EMS routing of stroke nationwide, we describe the proportion of stroke hospitalizations in the United States (U.S.) occurring within regions having adopted these protocols. METHODS: We collected data on ischemic stroke using International Classification of Diseases-9 (ICD-9) coding from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) database from the years 2000-2010. The NIS contains all discharge data from 1,051 hospitals located in 45 states, approximating a 20% stratified sample. We obtained data on EMS systems of care from a review of archives, reports, and interviews with state emergency medical services (EMS) officials. A county or state was considered to be in transition if the protocol was adopted in the calendar year, with establishment in the year following transition. RESULTS: Nationwide, stroke hospitalizations remained constant over the course of the study period: 583,000 in 2000 and 573,000 in 2010. From 2000-2003 there were no states or counties participating in the NIS with EMS systems of care. The proportion of U.S. stroke hospitalizations occurring in jurisdictions with established EMS regional systems of acute stroke care increased steadily from 2004 to 2010 (1%, 13%, 28%, 30%, 30%, 34%, 49%). In 2010, 278,538 stroke hospitalizations, 49% of all U.S. stroke hospitalizations, occurred in areas with established EMS routing, with an additional 18,979 (3%) patients in regions undergoing a transition to EMS routing. CONCLUSION: In 2010, a majority of stroke patients in the U.S. were hospitalized in states with established or transitioning to organized stroke systems of care. This milestone coverage of half the U.S. population is a major advance in systematic stroke care and emphasizes the need for novel approaches to further extend access to stroke center care to all patients. PMID- 25035759 TI - Emergency physician awareness of prehospital procedures and medications. AB - INTRODUCTION: Maintaining patient safety during transition from prehospital to emergency department (ED) care depends on effective handoff communication between providers. We sought to determine emergency physicians' (EP) knowledge of the care provided by paramedics in terms of both procedures and medications, and whether the use of a verbal report improved physician accuracy. METHODS: We conducted a 2-phase observational survey of a convenience sample of EPs in an urban, academic ED. In this large ED paramedics have no direct contact with physicians for non-critical patients, giving their report instead to the triage nurse. In Phase 1, paramedics gave verbal report to the triage nurse only. In Phase 2, a research assistant (RA) stationed in triage listened to this report and then repeated it back verbatim to the EPs caring for the patient. The RA then queried the EPs 90 minutes later regarding their patients' prehospital procedures and medications. We compared the accuracy of these 2 reporting methods. RESULTS: There were 163 surveys completed in Phase 1 and 116 in Phase 2. The oral report had no effect on EP awareness that the patient had been brought in by ambulance (86% in Phase 1 and 85% in Phase 2.) The oral report did improve EP awareness of prehospital procedures, from 16% in Phase 1 to 45% in Phase 2, OR=4.28 (2.5-7.5). EPs were able to correctly identify all oral medications in 18% of Phase 1 cases and 47% of Phase 2 cases, and all IV medications in 42% of Phase 1 cases and 50% of Phase 2 cases. The verbal report led to a mild improvement in physician awareness of oral medications given, OR=4.0 (1.09-14.5), and no improvement in physician awareness of IV medications given, OR=1.33 (0.15-11.35). Using a composite score of procedures plus oral plus IV medications, physicians had all three categories correct in 15% of Phase 1 and 39% of Phase 2 cases (p<0.0001). CONCLUSION: EPs in our ED were unaware of many prehospital procedures and medications regardless of the method used to provide this information. The addition of a verbal hand-off report resulted in a modest improvement in overall accuracy. PMID- 25035760 TI - Multidimensional attitudes of emergency medicine residents toward older adults. AB - INTRODUCTION: The demands of our rapidly expanding older population strain many emergency departments (EDs), and older patients experience disproportionately high adverse health outcomes. Trainee attitude is key in improving care for older adults. There is negligible knowledge of baseline emergency medicine (EM) resident attitudes regarding elder patients. Awareness of baseline attitudes can serve to better structure training for improved care of older adults. The objective of the study is to identify baseline EM resident attitudes toward older adults using a validated attitude scale and multidimensional analysis. METHODS: Six EM residencies participated in a voluntary anonymous survey delivered in summer and fall 2009. We used factor analysis using the principal components method and Varimax rotation, to analyze attitude interdependence, translating the 21 survey questions into 6 independent dimensions. We adapted this survey from a validated instrument by the addition of 7 EM-specific questions to measures attitudes relevant to emergency care of elders and the training of EM residents in the geriatric competencies. Scoring was performed on a 5-point Likert scale. We compared factor scores using student t and ANOVA. RESULTS: 173 EM residents participated showing an overall positive attitude toward older adults, with a factor score of 3.79 (3.0 being a neutral score). Attitudes trended to more negative in successive post-graduate year (PGY) levels. CONCLUSION: EM residents demonstrate an overall positive attitude towards the care of older adults. We noted a longitudinal hardening of attitude in social values, which are more negative in successive PGY-year levels. PMID- 25035761 TI - Impact of the balance billing ban on California emergency providers. AB - INTRODUCTION: The objective of this study was to examine reimbursement trends for emergency provider professional services following the balance billing ban in California. METHODS: We conducted a blinded web-based survey to collect claims data from emergency providers and billing companies. Members of the California Chapter of the American College of Emergency Physicians (California ACEP) reimbursement committee were invited to participate in the survey. We used a convenience sample of claims to determine payment rates before and after the balance billing ban. RESULTS: We examined a total of 55,243 claims to determine the percentage of charges paid before and after the balance billing ban took effect on October 15, 2008. The overall reduction in percentage of charges paid was 13% in the first year and 19% in the second year following the balance billing ban. The average percentage of charges paid by health plans decreased from 91% to 86% from 2008 to 2010. Payments by risk-bearing organizations decreased from 72% to 46% of charges during the same time frame. CONCLUSION: Payment rates by subcontracted risk-bearing organizations for non-contracted emergency department professional services declined significantly following the balanced billing ban whereas payment rates by health plans remained relatively stable. PMID- 25035762 TI - Outlaw motorcycle gangs: aspects of the one-percenter culture for emergency department personnel to consider. AB - Outlaw motorcycle gangs (OMGs) are an iconic element of the criminal landscape in the United States, the country of their origin. Members of OMGs may present to the emergency department (ED) as a result of motor vehicle accidents or interpersonal violence. When one member of an OMG is injured, other members and associates are likely to arrive in the ED to support the injured member. The extant literature for ED personnel lacks an overview of the culture of OMGs, a culture that promotes the display of unique symbols and that holds certain paraphernalia as integral to an outlaw biker's identity and pride. The objective of this manuscript is to discuss various aspects of the culture of OMGs so that ED personnel may better understand the mentality of the outlaw biker. Knowledge of their symbols, values, and hierarchy can be crucial to maintaining order in the ED when an injured outlaw biker presents to the ED. We used standard search engines to obtain reports from law enforcement agencies and studies in academic journals on OMGs. We present the observations of 1 author who has conducted ethnographic research on outlaw bikers since the 1980s. PMID- 25035763 TI - Availability of insurance linkage programs in U.S. Emergency departments. AB - INTRODUCTION: As millions of uninsured citizens who use emergency department (ED) services are now eligible for health insurance under the Affordable Care Act, the ED is ideally situated to facilitate linkage to insurance. Forty percent of U.S. EDs report having an insurance linkage program. This is the first national study to examine the characteristics of EDs that offer or do not offer these programs. METHODS: This was a secondary analysis of data from the National Survey for Preventive Health Services in U.S. EDs conducted in 2008-09. We compared EDs with and without insurance programs across demographic and operational factors using univariate analysis. We then tested our hypotheses using multivariable logistic regression. We also further examined program capacity and priority among the sub group of EDs with no insurance linkage program. RESULTS: After adjustment, ED insurance linkage programs were more likely to be located in the West (RR= 2.06, 95% CI = 1.33 - 2.72). The proportion of uninsured patients in an ED, teaching hospital status, and public ownership status were not associated with insurance linkage availability. EDs with linkage programs also offer more preventive services (RR = 1.87, 95% CI = 1.37-2.35) and have greater social worker availability (RR = 1.71, 95% CI = 1.12-2.33) than those who do not. Four of five EDs with a patient mix of >=25% uninsured and no insurance linkage program reported that they could not offer a program with existing staff and funding. CONCLUSION: Availability of insurance linkage programs in the ED is not associated with the proportion of uninsured patients served by an ED. Policy or hospital-based interventions to increase insurance linkage should first target the 27% of EDs with high rates of uninsured patients that lack adequate program capacity. Further research on barriers to implementation and cost effectiveness may help to facilitate increased adoption of insurance linkage programs. PMID- 25035764 TI - Novel ultrasound guidance system for real-time central venous cannulation: safety and efficacy. AB - INTRODUCTION: Real-time ultrasound guidance is considered to be the standard of care for central venous access for non-emergent central lines. However, adoption has been slow, in part because of the technical challenges and time required to become proficient. The AxoTrack((r)) system (Soma Access Systems, Greenville, SC) is a novel ultrasound guidance system recently cleared for human use by the United States Food and Drug Administration (FDA). METHODS: After FDA clearance, the AxoTrack((r)) system was released to three hospitals in the United States. Physicians and nurse practitioners who work in the intensive care unit or emergency department and who place central venous catheters were trained to use the AxoTrack((r)) system. De-identified data about central lines placed in living patients with the AxoTrack((r)) system was prospectively gathered at each of the three hospitals for quality assurance purposes. After institutional review board approval, we consolidated the data for the first five months of use for retrospective review. RESULTS: The AxoTrack((r)) system was used by 22 different health care providers in 50 consecutive patients undergoing central venous cannulation (CVC) from September 2012 to February 2013. All patients had successful CVC with the guidance of the AxoTrack((r)) system. All but one patient (98%) had successful cannulation on the first site attempted. There were no reported complications, including pneumothorax, hemothorax, arterial puncture or arterial cannulation. CONCLUSION: The AxoTrack((r)) system was a safe and effective means of CVC that was used by a variety of health care practitioners. PMID- 25035765 TI - Typed versus voice recognition for data entry in electronic health records: emergency physician time use and interruptions. AB - INTRODUCTION: Use of electronic health record (EHR) systems can place a considerable data entry burden upon the emergency department (ED) physician. Voice recognition data entry has been proposed as one mechanism to mitigate some of this burden; however, no reports are available specifically comparing emergency physician (EP) time use or number of interruptions between typed and voice recognition data entry-based EHRs. We designed this study to compare physician time use and interruptions between an EHR system using typed data entry versus an EHR with voice recognition. METHODS: We collected prospective observational data at 2 academic teaching hospital EDs, one using an EHR with typed data entry and the other with voice recognition capabilities. Independent raters observed EP activities during regular shifts. Tasks each physician performed were noted and logged in 30 second intervals. We compared time allocated to charting, direct patient care, and change in tasks leading to interruptions between sites. RESULTS: We logged 4,140 minutes of observation for this study. We detected no statistically significant differences in the time spent by EPs charting (29.4% typed; 27.5% voice) or the time allocated to direct patient care (30.7%; 30.8%). Significantly more interruptions per hour were seen with typed data entry versus voice recognition data entry (5.33 vs. 3.47; p=0.0165). CONCLUSION: The use of a voice recognition data entry system versus typed data entry did not appear to alter the amount of time physicians spend charting or performing direct patient care in an ED setting. However, we did observe a lower number of workflow interruptions with the voice recognition data entry EHR. Additional research is needed to further evaluate the data entry burden in the ED and examine alternative mechanisms for chart entry as EHR systems continue to evolve. PMID- 25035766 TI - Evaluation of Karl Storz CMAC TipTM device versus traditional airway suction in a cadaver model. AB - INTRODUCTION: We compared the efficacy of Karl Storz CMAC TipTM with inline suction to CMAC with traditional suction device in cadaveric models simulating difficult airways, using media mimicking pulmonary edema and vomit. METHODS: This was a prospective, cohort study in which we invited emergency medicine faculty and residents to participate. Each participant intubated 2 cadavers (one with simulated pulmonary edema and one with simulated vomit), using CMAC with inline suction and CMAC with traditional suction. Thirty emergency medicine providers performed 4 total intubations each in a crossover trial comparing the CMAC with inline suction and CMAC with traditional suction. Two intubations were performed with simulated vomit and two with simulated pulmonary edema. The primary outcome was time to successful intubation; and the secondary outcome was proportion of successful intubation. RESULTS: The median time to successful intubation using the CMAC with inline suction versus traditional suction in the pulmonary edema group was 29s and 30s respectively (p=0.54). In the vomit simulation, the median time to successful intubation was 40s using the CMAC with inline suction and 41s using the CMAC with traditional suction (p=0.70). There were no significant differences in time to successful intubation between the 2 devices. Similarly, the proportions of successful intubation were also not statistically significant between the 2 devices. The proportions of successful intubations using the inline suction were 96.7% and 73.3%, for the pulmonary edema and vomit groups, respectively. Additionally using the handheld suction device, the proportions for the pulmonary edema and vomit group were 100% and 66.7%, respectively. CONCLUSION: CMAC with inline suction was no different than CMAC with traditional suction and was associated with no statistically significant differences in median time to intubation or proportion of successful intubations. PMID- 25035767 TI - Epidemiology of nursemaid's elbow. AB - INTRODUCTION: To provide an epidemiological description of radial head subluxation, also known as nursemaid's elbow, from a database of emergency department visits. METHODS: We conducted a retrospective medical record review of patients 6 years of age and younger, who presented to the ED between January 1, 2005, and December 31, 2012, and were diagnosed with nursemaid's elbow. Inclusion criteria consisted of chart information, including date, unique account number, medical record number, weight, age, sex, and arm affected. Exclusion criteria included any charts with missing or incomplete data. RESULTS: There were 1,228 charts that met inclusion criteria. The majority of patients were female (60%). The mean age was 28.6 months (+/-12.6). The left arm was affected 60% of the time. Most of the included patients were over the 75(th) percentile for weight and more than one quarter were over the 95(th) percentile in each gender. CONCLUSION: The average age of children presenting with nursemaid's elbow was 28.6 months. Females were affected more than males, and the left arm was predominately affected. Most patients were above the 75(th) percentile for weight and more than one quarter were over the 95(th) percentile for weight. PMID- 25035768 TI - Wordsmithing in medical toxicology: a primer on portmanteaus. PMID- 25035769 TI - The law of unintended consequences: illicit for licit narcotic substitution. PMID- 25035770 TI - Simulation for professionals who care for bariatric patients: some unanswered questions. PMID- 25035771 TI - Laparoscopy-assisted versus open gastrectomy with D2 lymph node dissection for advanced gastric cancer: a meta-analysis. AB - A raising number of surgeons have chosen laparoscopy-assisted gastrectomy (LAG) as an alternative to open gastrectomy (OG) with D2 lymph node dissection for treatment of advanced gastric cancer (ADG). But no meta-analysis has been performed to evaluate the value of LAG versus OG with regard to safety and efficacy for treatment of ADG. A comprehensive literature research was performed in PubMed, Web of Science and Embase to identify studies that compared LAG and OG with D2 lymph node dissection for treatment of ADG. Data of interest were checked and subjected to meta-analysis with RevMan 5.1 software. 11 studies with 1904 patients (982 in LAG and 922 in OG) were enrolled. Pooled risk ratios (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI) were appropriately derived from random-effects models or fixed-effects models. Compared with OG, LAG was associated with less blood loss (WMD = -144.47; P < 0.05), shorter time of first flatus time (WMD = -0.91; P < 0.05) and postoperative hospital stay (WMD = -3.27; P < 0.05), and lower morbidity (RR = 0.70; P < 0.05), but longer operation time (WMD = 41.78; P < 0.05). No significant differences were noted in terms of harvested lymph nodes (WMD = 1.85; P = 0.09), pathological N stage (chi(2) 3.97; P = 0.26), tumor size (WMD = -0.05; P = 0.81), mortality (RR 0.82; P = 0.76), cancer recurrence rate (RR 0.77; P = 0.18) and 3-year overall survival rate (RR 1.09; P = 0.18). Compared with OG, LAG with D2 lymph node dissection for ADG had the advantages of minimal invasion, faster recovery, and fewer complications, and it could achieve the same degree of radicality, harvested lymph nodes, short-term and long-term prognosis as OG, though the operation time was slightly longer. PMID- 25035772 TI - Acaroid mite allergens from the filters of air-conditioning system in China. AB - Accumulation of acaroid mites in the filters of air-conditioners is harmful to human health. It is important to clarify the allergen components of mites from the filters of local air-conditioning system. The present study was to detect the allergen types in the filters of air-conditioners and assesse their allergenicity by asthmatic models. Sixty aliquots of dust samples were collected from air conditioning filters in civil houses in Wuhu area. Total protein was extracted from the dust samples using PBS and quantified by Bradford method. Allergens I and II were also detected by Western blot using primary antibody (anti-Der f1/2, Der p1/Der f2/Der p2, respectively). Ten aliquots of the positive samples were randomly selected for homogenization and sensitized the mice for developing asthmatic animal models. Total serum IgE level and IFN-gamma, IL-4 and IL-5 in the bronchoalveolar lavage fluid (BALF). The allergenicity of the extraction was assessed using pathological sections developed from the mouse pulmonary tissues. The concentration of extract from the 60 samples was ranged from 4.37 MUg/ml to 30.76 MUg/ml. After analyzing with Western blot, 31 of 60 samples were positive for 4 allergens of acaroid mites, and yet 16 were negative. The levels of total IgE from serum IL-4 and IL-5 from the BALF in the experimental group were apparently higher than that of negative control and PBS group (P < 0.01), but there were no statistical difference compared to OVA group (P > 0.05). However,the IFN-gamma level in BALF was lower compared with the negative control and PBS group (P < 0.05) but with the OVA group (P > 0.05). The pathological changes were evidently emerged in pulmonary tissues, which were similar to those of OVA group, compared with the PBS ground and negative controls. The air conditioner filters in human dwellings of Wuhu area potentially contain the major group allergen 1 and 2 from D. farinae and D. pteronyssinus, which may be associated with seasonal prevalence of allergic disorders in this area. PMID- 25035773 TI - Tumor suppressor TSLC1 inhibits growth, proliferation, invasiveness and angiogenesis in nude mice xenografted tumor of Eca109 cells. AB - Tumor suppressor in lung cancer 1 (TSLC1) is a novel tumor suppressor gene whose inactivation is implicated in the occurrence, invasion, metastasis and prognosis of esophageal cancer. TSLC1 was studied by comparing the tumor formation of TSLC1 transfectant and control cells in nude mice. Compared with blank group and mock group, tumor size and infiltrating range of transfected group was less, differentiation of tumor tissue was slightly better, and differences of tumor angiogenesis was worse. There was no obvious difference between blank group and mock group. We have shown TSLC1 gene inhibited the growth proliferation, infiltration and angiogenesis of Eca109 cells. PMID- 25035774 TI - Relationship of PCNA, C-erbB2 and CD44s expression with tumor grade and stage in urothelial carcinomas of the bladder. AB - In the present study, the intention was to reveal the relationship of histological grade and stage with c-erbB2, CD44s, and PCNA immunoreactivity in bladder urothelial carcinomas (UC). In our study, we evaluated 46 items of transurethral resection material of patients submitted by YYU Faculty of Medicine, Main Department of Pathology, with a mass revealed in their bladder after clinical and radiological studies at our laboratories and who were diagnosed with urothelial carcinomas. PCNA, c-erbB2, and CD44s were applied in an immunohistochemical manner comprised from nine low-malignant potential papillary urothelial neoplasia, 23 low-grade papillary urothelial carcinoma, and 14 high grade papillary urothelial carcinoma. Immunostaining was scored according to the percentage of positive cells. The immunohistochemical study demonstrated that the c-erbB2 and PCNA staining ratio increased when an increase occurred in stage and grade. The CD44s staining ratio decreased. C-erbB2, PCNA, and CD44s appear to be a useful marker in the assessment of the prognosis and treatment options in urothelial carcinomas. PMID- 25035775 TI - Expressional analysis of p16 and cytokeratin19 protein in the genesis of oral squamous cell carcinoma patients. AB - p16 is a cell cycle inhibitor that is frequently inactivated in various types of tumours. In spite of p16 importance and its association with clinical behaviour in the genesis of Oral Squamous Cell Carcinoma (OSCC) is not understood fully. The aim of study was to examine the impact of p16 and CK19 in the development and progression of tumour with other clinical behaviours. In the present study, expression profiles of p16 and Cytokeratin19 (CK19) protein were analysed through immunohistochemistry using anti-p16 and anti-CK19 antibody. Expressions pattern of p16 and CK19 were noticed 40% and 58% in the OSCC respectively. Whereas expressions pattern were different in control cases for both markers as p16 (70%) and CK19 (20%). There was progressive loss of p16 expression from oral inflammatory lesion to OSCC and this differences were statically significant (p<0.05). The positivity of p16 were observed in gender where its expression pattern did not reach statistical significance (p>0.05). Expression pattern of CK19 were observed and its expression increased according to the grade and stage of cancer. Furthermore, CK19 expression was seen to be significantly higher in male in the age group >=50 years (p<0.05). This finding shows that p16 and CK19 may have potential as a prognostic marker in human OSCC and important molecular event in pathogenesis of oral carcinoma. PMID- 25035776 TI - Zinc dependent endopeptidases of matrix metalloproteinases-9 expressions is associated with tumor metastases of oral squamous cell carcinoma in Chinese population: a meta-analysis. AB - Matrix metalloproteinase-9 (MMP-9) is an important member of zinc dependent endopeptidases family and is considered to be involved in the invasion and metastasis of cancer cells. Many studies were published to assess the prognostic role of MMP-9 expression in patients with oral squamous cell Carcinoma, but the findings from those studies were inconsistent in Chinese population. We searched eligible studies in Pubmed, Embase, and Web of Science databases. Six studies with a total of 556 patients were finally included into the meta-analysis. The pooled odds ratios (OR) with the corresponding 95% confidence interval (95% CIs) for positive rate of MMP-9 were calculated by using meta-analysis. Overall, MMP-9 positive expression was associated with tumor metastases in patients with oral squamous cell Carcinoma (fixed-effects OR 4.24, 95% CI 2.25-7.99, P < 0.001; random-effects OR 4.35, 95% CI 2.31-8.21, P < 0.001). Our results indicated that MMP-9 expression is associated with tumor metastases in patients with oral squamous cell carcinoma, and patients with higher MMP-9 expression have less tumor metastases. PMID- 25035777 TI - Meta-analysis of GSTT1 null genotype and preterm delivery risk. AB - Glutathione S-transferase T1 (GSTT1) null genotype has been indicated to be correlated with preterm delivery (PTD) susceptibility, but study results were still debatable. Thus, a meta-analysis was conducted. PubMed, EMBASE, and CNKI were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the random-effects model or fixed effects model. Nine case-control studies with a total of 2526 cases and 4565 controls were eligible. The null genotype of GSTT1 was associated with a significantly increased risk of PTD when compared with present genotype (OR = 1.18; 95% CI 1.05-1.33; I(2) = 33). In the subgroup analysis according to ethnicity, significantly increased PTD risk was observed in Asians (OR = 1.20; 95% CI 1.01-1.33; I(2) = 0%) but not in Caucasians (OR = 1.32; 95% CI 0.89-1.97; I(2) = 77). This meta-analysis suggested that GSTT1 null genotype may be associated with the risk of PTD. PMID- 25035778 TI - Red and processed meat consumption and the risk of lung cancer: a dose-response meta-analysis of 33 published studies. AB - This meta-analysis was to summarize the published studies about the association between red/processed meat consumption and the risk of lung cancer. 5 databases were systematically reviewed, and random-effect model was used to pool the study results and to assess dose-response relationships. Results shown that six cohort studies and twenty eight case-control studies were included in this meat analysis. The pooled Risk Radios (RR) for total red meat and processed meat were 1.44 (95% CI, 1.29-1.61) and 1.23 (95% CI, 1.10-1.37), respectively. Dose response analysis revealed that for every increment of 120 grams red meat per day the risk of lung cancer increases 35% and for every increment of 50 grams red meat per day the risk of lung cancer increases 20%. The present dose-response meta-analysis suggested that both red and processed meat consumption showed a positive effect on lung cancer risk. PMID- 25035779 TI - Investigation of granulomatous prostatitis incidence following intravesical BCG therapy. AB - In the present manuscript, we studied the incidence of granulomatous prostatitis in the prostatectomy specimen of the patients who underwent transurethral resection of the prostate (TURP) after superficial bladder cancer treatment with intravesical Bacillus Calmette-Guerin (BCG) and were diagnosed with benign prostate hyperplasia (BPH). The clinical data and histopathological specimen records of 472 patients who underwent TUR-P due to BPH diagnosis, obtained over a period of 6 years in the urology department of Private Konya Hospital, Konya, Turkey, were studied retrospectively. The cases were divided into two groups as (Group I) who did not undergo any treatment and as (Group II) who underwent BCG treatment. The frequency and the clinical course of the cases with granulomatous prostatitis were studied histopathologically. There were in total 472 patients who underwent TUR-P. Out of the 459 patients who did not undergo BCG treatment (Group I), the histopathological specimen records of 262 (57%) was BPH, of 197 (43%) BPH + chronic prostatitis. Of the second group, 13 cases underwent intravesical BCG treatment before surgical intervention due to superficial bladder CA diagnosis. In this group 4 of the cases were diagnosed as (30%) BPH, 9 as (70%) chronic prostatitis + BPH. 6 out of the 9 chronic prostatitis cases were chronic prostatitis, 2 caseous granulomatous prostatitis, 1 non-caseous granulomatous prostatitis. Granulomatous prostatitis cases should require no specific therapy. CONCLUSION: In patients with obstruction complaints following intravesical BCG treatment, granulomatous prostatitis should also be considered and treatment plans should be made accordingly. PMID- 25035780 TI - Abdominal wall-lifting versus CO2 pneumoperitoneum in laparoscopy: a review and meta-analysis. AB - The aim of this study is to compare the operative parameters and outcomes of conventional CO2-pneumoperitoneum (PP) versus gasless abdominal wall-lifting (AWL) for laparoscopic surgery. The literature databases of PubMed, Google Scholar and Cochrane Library were searched for randomized controlled trials (RCTs) that had compared the CO2-PP approach with that of gasless AWL for laparoscopic surgery and which had been published between 1995 and 2012. Data for the operative parameters (i.e. surgery duration, intraoperative heart rate (HR), perioperative complications, and postoperative duration of hospital stay and time to activity) and outcomes (postoperative shoulder pain, nausea/vomiting (PONV), partial pressure of CO2 in the blood (PaCO2), blood pH, and serum levels of the inflammatory cytokine interleukin (IL)-6) were extracted from the identified RCTs. RevMan software, version 5.2, was used for data synthesis and statistical analysis. Nineteen RCTs were selected for the meta-analysis, involving a total of 791 patients who had undergone laparoscopic operations with CO2-PP (n = 399) or gasless AWL (n = 392). Sub-group analysis indicated that the patients who underwent gasless AWL had significantly shorter postoperative time to activity (weighted mean difference (WMD) = -0.23 d, 95% confidence interval (CI): -0.37 to -0.09; P = 0.001), lower incidence of PONV (odds ratio (OR) = 0.24, 95% CI: 0.10 to 0.57; P = 0.001) and lower postoperative PaCO2 level (WMD = -3.09 mmHg, 95% CI: -4.66 to -1.53; P = 0.0001), compared to the patients who underwent CO2-PP. However, the CO2-PP method was associated with a significantly shorter surgery duration than the gasless AWL method (WMD = 8.61, 95% CI: 3.19 to 14.03; P = 0.002). There were no significant advantages detected for either approach with respect to the intraoperative HR, the perioperative complication rate, or the postoperative parameters of duration of hospital stay, shoulder pain, blood pH, or serum IL-6 level. We concluded form present study that the gasless AWL method has the features of shorter time, lower postoperative PaCO2, and lower PONV incidence while the CO2-PP method for laparoscopy requires shorter surgical time. PMID- 25035781 TI - Effect of Tai-chi exercise on lower limb muscle strength, bone mineral density and balance function of elderly women. AB - To study the effect of Tai-chi exercise on lower limb muscle strength, bone mineral density and balance function of elderly female, 105 urban elderly women, who do insufficient exercise in daily life, are selected as the subject and randomly divided into an observation group (Tai Chi Group), a control group I (Dance Group) and a control group II (Walking Group). Each group is consists of 35 women. Among them, the women in the observation group do Tai-chi exercise once a day, while the women in the control group I dance once a day and in the control group II stick to brisk walking once a day. All women in the three groups do the above said exercises for 40 minutes and the exercise intensity is controlled to be medium. At the time of selection and after 4, 8 and 12 months upon their exercises, respectively detect and compare the lower limb skeletal muscle mass, lower limb muscle strength, bone mineral density and balance function of the subject. RESULTS: At the time of selection, the general information of the subjects in the three groups show no significant difference (P > 0.05); however, after 4 months' exercise, most of the study indexes in the control group I and group II are improved significantly (P < 0.05), while most of the study indexes in the observation group show no significant difference (P > 0.05) in comparison with those at the time of selection and their general improvement effect is slightly lower than that in the control group; after 8 months, relevant study indexes of the subjects in the three groups are significantly improved (P < 0.05) in comparison with those at the time of selection, especially, the effect in the observation group is more obvious and is better than that of the control group II (P < 0.05). 12 months later, the effect of the observation group is improved significantly from day to day when comparing to theose in the control group I and group II (P < 0.05 or P < 0.01). CONCLUSION: Compared with the senile dance and walking exercises, the short-term Tai-chi exercise effect is not obvious, however, once the exercise period is extended, that is, continuous exercise for 8 months or even above 12 months, the advantage of Tai Chi is more and more significant. The study suggests that as a fitness measure, Tai Chi is more suitable for long-term exercise and its short-term effect is not obvious. PMID- 25035782 TI - Anxiety levels among Turkish public transportation drivers: a relation to restless legs syndrome? AB - The aim of this study was to estimate the prevalence of individuals who are at high risk for state and trait anxiety as well as to investigate the relationship of anxiety levels of urban transportation drivers from Istanbul, Turkey with restless legs syndrome (RLS). The data was gathered between April 2013 and June 2013 by the use of a questionnaire prepared for the purpose of this study, completed anonymously. Restless leg syndrome and anxiety level were evaluated in the group; data obtained was analyzed using the SPSS version 16. Chi-square, correlation and student-t tests were used. Restless leg syndrome symptoms were determined by a self-assessment questionnaire, including the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria, to determine RLS symptoms and Spielberger State-Trait Anxiety Inventory (STAI) to determine anxiety levels of the participants. In the present study, the four RLS criteria were reported in 31.2%. STAI-state and STAI-trait scores were 40.82 +/- 9.55 and 42.99 +/- 8.54 respectively. The state and trait anxiety mean scores were different among participants with RLS in this study (p < 0.05). It was found a significant difference between tobacco usage and state anxiety (p < 0.05). There were a significant difference between RLS and age, number of cigarettes daily consumed and employment time (p < 0.05). The state and trait anxiety scores were found high among bus drivers with RLS in this study. PMID- 25035783 TI - Comparison of different surgical approaches of functional endoscopic sinus surgery on patients with chronic rhinosinusitis. AB - Chronic rhinosinusitis (CRS) is not a life-threatening disorder but may have a great impact on the patients. This study intended to evaluate the impact of functional endoscopic sinus surgery (FESS), and compare the effect and quality of life (QOL) after two different surgical approaches on patients with CRS. Sixty patients of CRS were analyzed before and after FESS. The extent of disease was evaluated by the Lund-Mackay scoring system using computed tomography (CT) and endoscopy. Subjective patient QOL scores were assessed by SF-36 questionnaire and symptom scores were recorded using the SNOT-20 questionnaire. Forty patients of multiunit CRS were randomly allocated to two groups in order to be taken radical FESS (RFESS) and conservative FESS (CFESS), respectively. The Lund-Mackay score and degree of preoperative polyps did not differ statistically between the two groups. In the 1 months follow-up settings, such domains as role physical, mental health, role emotional and general health of SF-36, and total of the SNOT-20 items scores and the most important 5-item scores of SNOT-20 all began to get better markedly (P<0.05); in the 6-12 months follow-up settings, the indices of QOL and symptoms status entirely improved from the baseline, and CFESS scope surgery is no significantly difference with RFESS in improving the QOL and symptoms of patients. The results of this study suggesting that nasal polyps have a significant negative impact on the patients with CRS. FESS is a reliable and effective method for improving a patient's QOL and symptoms after 6 months of surgery, regardless of approaches. PMID- 25035784 TI - Serum paraoxonase, TAS, TOS and ceruloplasmin in brucellosis. AB - It is possible that brucellosis may be related to increase free radical production and antioxidant depletion. Thus, in the present study we aimed to evaluate the oxidative status in patient with brucellosis and healthy controls. METHODS: This study includes the patients with brucellosis diagnosed by clinical findings and positive agglutination titer. The paraoxonase, ceruloplasmin, total antioxidant capacity and total oxidant status values were measured from the samples taken. The oxidative stress index value was calculated through the total antioxidant capacity and total oxidant status values. RESULTS: A total number of 93 people, 40 women (43%) and 53 men (57%) were included to the study. The levels of ceruloplasmin were found higher in patients when compared to the control group (p < 0.001). The total antioxidant capacity level was found significantly higher in the patients group when compared to the control group (p < 0.001). The oxidative stress index value was significantly lower in the patients group when compared to the control group (p < 0.001). The paraoxonase-1 level was not different in control and patient groups (p = 0.077). CONCLUSIONS: Brucellosis is an infection that is frequently seen in Mediterranean countries. This infection breaks the oxidant and antioxidant balance. In this disease, oxidant-antioxidant system indicators such as ceruloplasmin, total antioxidant capacity, total oxidant status and oxidative stress index can be used for showing the role of the brucella infection and for the monitoring of the treatment results. PMID- 25035785 TI - Evaluation of therelationship between epicardial adipose tissue and myocardial performance (Tei) index. AB - AIM: Epicardial adipose tissue (EAT) is a tissue around the heart with visceral adipose properties. It can affect the structure and functions of the myocardium and coronary arteries through inflammatory markers and regulators. The myocardial performance (Tei) index is a parameter capable of globally assessing systolic and diastolic heart functions. This study investigated the relation between EAT thickness and the Tei index. METHODS: The study population was selected from patients without structural heart disease. EAT thickness was measured with two dimensional imaging in parasternal long axis view and from the anterior face of the right ventricle. Tei index measurement was calculated with tissue Doppler echocardiography from the mitral lateral annulus. The relation between the Tei index and EAT was assessed using multivariate linear regression analysis. RESULTS: Forty-three patients (36 female, 7 male; mean age 50.2 +/- 10.6 years) were included in the study. Mean Tei index was 0.39 +/- 0.09, and mean EAT thickness 4.7 +/- 2.4 mm. A significant correlation was determined between tissue Doppler Tei index and EAT thickness at correlation analysis (r = 0.522, P < 0.001). EAT thickness was independently correlated with Tei index at multivariate linear regression analysis (Beta = 0.443, t = 3.522, P = 0.001). CONCLUSION: EAT thickness is independently correlation with Tei index. Increased EAT thickness may therefore be a predictor of left ventricular dysfunction. PMID- 25035786 TI - Left renal atrophy. AB - BACKGROUND: We tried to understand whether or not there is a higher risk of left renal atrophy in human being. METHODS: All patients applying to the Hematology Service with any underlying complaint were studied. RESULTS: The study included 2,417 cases (1,248 females). The mean ages were 47.3 versus 50.7 years in females and males, respectively (p<0.000). There were 33 cases (1.3%) with the left renal atrophy against five cases (0.2%) with the right (p<0.001). The left renal atrophy cases have splenomegaly (SM) in 51.5%, thalassemia minors (TMs) in 30.3%, sickle cell diseases (SCDs) in 27.2%, myeloproliferative disorders in 18.1%, chronic lymphocytic leukemia in 6.0%, cirrhosis in 6.0%, solid organ malignancies in 6.0%, chronic obstructive pulmonary disease in 3.0%, multiple myeloma in 3.0%, and Waldenstrom's macroglobulinemia in 3.0%. Similarly, the right renal atrophy cases have SM in 20.0%, TMs in 40.0%, and SCDs in 20.0%. CONCLUSION: Left renal atrophy may be significantly higher than the right side in human being. Aortic pressure induced flow disorders in the left renal vein, structural anomalies of the left renal vein, and possibly the higher arterial pressure of the left kidney due to the shorter distance to the heart as an underlying cause of atherosclerosis may be some of the possible causes. Due to the stronger arterial wall protecting itself from compression and high prevalences of SM and left varicocele in population, SM induced flow disorders of the left renal vein may be the most common cause. PMID- 25035787 TI - Sinus floor augmentation using miniscrew and in situ hardening biomaterial: method and case report. AB - Sinus floor augmentation in case of severe pneumatization is a challenge for surgical management. We present a low invasive endoscopically assisted technique facilitating the stabilization of augmentation material in the subantral space. The technique consists of (1) trepanation of the lateral sinus wall with tunnelling of the sinus membrane and creation of the subantral space, (2) subantroscopically assisted insertion of a mini screw, (3) precise stepwise placement of in situ hardening graft material with antroscopic control. Based on a case example, details of the procedure are presented. The technique provides a minimally invasive treatment for difficult and instable augmentation sites. PMID- 25035788 TI - A giant primary retroperitoneal mature cystic teratoma in right adrenal region in a 39-year-old female. AB - We report an unusual case of a giant primary retroperitoneal mature cystic teratoma in right adrenal region in a 39-year-old Chinese female. The patient has complained of dizziness and a high blood pressure approximately 170/110 mmHg for half one year. A plain helical and enhanced CT scan showed a huge tumor with a mixing density in recessus hepatorenalis. This tumor had calcification and fat, as well as a mild enhancement in part of the tumor. The patient was successfully treated with a right surgical resection of the mass. Although the primary retroperitoneal mature cystic teratomas in right adrenal regions are extremely rare, we should pay attention to it and close follow up is indispensable on account of the incidence of malignant transformation is approximately 3-6%. PMID- 25035789 TI - Adult congenital intestinal malrotation accompanied by midgut volvulus: report of eight cases. AB - Congenital midgut malrotation is a complex gastrointestinal anomaly, which could easily lead to midgut volvulus and gastrointestinal obstruction. Large studies on congenital midgut malrotation in adults are rarely investigated. The current study aimed to explore the clinical profile and diagnostic modalities of congenital midgut malrotation in Chinese adult patients. Clinical and radiological data of eight adult patients with intestinal malrotation were retrospectively analyzed and related literatures were simultaneously reviewed. Mean age of patients was 41.25 years range, 14 to 63 years. Abdominal radiography and computerized tomography (CT) were conducted for all studied patients prior to surgery, and the diagnosis of congenital midgut malrotation was confirmed during surgery. All patients underwent volvulus reduction, Ladd's band loosening, and stage I appendectomy. In addition, three patients received additional extensive intestinal adhesion loosening, and one patient received resection of bowel up to 50 cm. All patients recovered well after surgery, and no recurrence and adhesive intestinal obstruction were reported. All three patients with malnutrition prior to surgery had gained significant weight. Thus, we consider that adult congenital intestinal malrotation accompanied with midgut volvulus should be treated with surgery as soon as possible. Preoperative colour ultrasonography and CT are helpful for definitive diagnosis. PMID- 25035790 TI - A novel case report of sickle cell disease-associated immunoglobulin A nephropathy: the diagnostic value of erythrocyte dysmorphism evaluation. AB - Sickle cell disease is a severe disease with a genetic pattern; it may cause anemia, vaso-occlusive phenomena, and multiorgan injury. It may damage any renal compartment, thereby causing tubular abnormalities, papillary necrosis, or glomerulopathies such as focal and segmental glomerulosclerosis and membranoproliferative pattern. The clinical consequences are hematuria and proteinuria. Hematuria associated with SCD is characteristically isomorphic (non glomerular). This case report describes a novel case of a patient with sickle cell disease who presented with proteinuria and microscopic dysmorphic (glomerular) hematuria. A renal biopsy revealed immunoglobulin A nephropathy. Despite the fact that immunoglobulin A nephropathy is the most commonly diagnosed glomerulonephritis worldwide, an association between this entity and sickle cell disease has not yet been reported, probably because all cases of hematuria in patients with sickle cell disease have been regarded as secondary to sickle cell disease. Thus, new approaches are necessary to differentiate these conditions, such as evaluation of urinary erythrocyte dysmorphism, even more so because these two entities have different therapeutic options, morbidity, and mortality rates. PMID- 25035791 TI - Hydroxyethyl starch effects on tissue perfusion and oxygenation in patients undergoing liver surgery. PMID- 25035792 TI - MR PROSTATE SEGMENTATION VIA DISTRIBUTED DISCRIMINATIVE DICTIONARY (DDD) LEARNING. AB - Segmenting prostate from MR images is important yet challenging. Due to non Gaussian distribution of prostate appearances in MR images, the popular active appearance model (AAM) has its limited performance. Although the newly developed sparse dictionary learning method[1, 2] can model the image appearance in a non parametric fashion, the learned dictionaries still lack the discriminative power between prostate and non-prostate tissues, which is critical for accurate prostate segmentation. In this paper, we propose to integrate deformable model with a novel learning scheme, namely the Distributed Discriminative Dictionary (DDD) learning, which can capture image appearance in a non-parametric and discriminative fashion. In particular, three strategies are designed to boost the tissue discriminative power of DDD. First, minimum Redundancy Maximum Relevance (mRMR) feature selection is performed to constrain the dictionary learning in a discriminative feature space. Second, linear discriminant analysis (LDA) is employed to assemble residuals from different dictionaries for optimal separation between prostate and non-prostate tissues. Third, instead of learning the global dictionaries, we learn a set of local dictionaries for the local regions (each with small appearance variations) along prostate boundary, thus achieving better tissue differentiation locally. In the application stage, DDDs will provide the appearance cues to robustly drive the deformable model onto the prostate boundary. Experiments on 50 MR prostate images show that our method can yield a Dice Ratio of 88% compared to the manual segmentations, and have 7% improvement over the conventional AAM. PMID- 25035793 TI - Capillary damage in the area postrema by venom of the northern black-tailed rattlesnake (Crotalus molossus molossus). AB - The Northern black-tailed rattlesnake (Crotalus molossus molossus) venom is mainly hemotoxic, hemorrhagic, and neurotoxic. Its effects in the central nervous system are unknown and only poorly described for all Viperidae species in general. This is why we are interested in describe the damage induced by C. m. molossus venom in rat brain, particularly in the area postrema capillaries. Four C. m. molossus venom doses were tested (0.02, 0.05, 0.10 and 0.20mg/kg) injected intramuscularly at the lower limb, incubated by 24 hours and the brains were harvested. Area postrema coronal sections were stained with Haematoxylin and Eosin, and examined to observe the venom effect in quantity of capillaries and porphology. Starting from the 0.10mg/kg treatment we observed lysed extravasated erythrocytes and also capillary breakdown, as a consequence of hemorrhages appearance. The number of capillaries decreased significantly in response to the venom dose increment. Hemorrhages could be caused by the metalloproteinase activity on the basal membrane and the apoptosis generated by L-amino acid oxidases. Hemolysis could be caused by phospholipase A2 hemotoxic effect. We conclude that C. m. molossus crude venom produces hemolysis, capillary breakdown, hemorrhages, and the reduction in number of capillaries in the area postrema. PMID- 25035794 TI - Peptides with in vitro anti-tumor activity from the venom of the Eastern green mamba, Dendroaspis angusticeps (Elapidae). AB - Two structurally related (48.6% amino acid sequence identity) peptides with cytotoxic activity against human non-small cell lung adenocarcinoma A549 cells were purified from the venom of the Eastern green mamba Dendroaspis angusticeps using reversed phase HPLC. The peptides were identified as members of the three finger superfamily of snake toxins by mass fingerprinting of tryptic digests. The more potent peptide (LC50 against A549 cells = 56+/-4ug/ml) was identical to the previously described toxin C13S1C1 and the less active peptide (LC50 against A549 cells = 106+/-5ug/ml) was identical to toxin F-VIII. Toxin C13S1C1 was also cytotoxic against breast adenocarcinoma MDA-MB-231 cells (LC50 = 62+/-2ug/ml) and colorectal adenocarcinoma HT-29 cells (LC50 = 110+/-4ug/ml). Although the peptide was appreciably less hemolytic activity against human erythrocytes (LC50 >600ug/ml), it was cytotoxic to human umbilical vein endothelial HUVEC cells (57+/-3ug/ml) indicating no differential activity against cell lines derived from neoplastic tissues. Toxin F-VIII was not cytotoxic to MDA-MB-231, HT-29 cells, and HUVEC cells at concentrations up to 300ug/ml and was not hemolytic at concentrations up to 1mg/ml. Neither peptide inhibited growth of reference strains of Escherichia coli or Staphylococcus aureus (MIC values >200MUg/ml). PMID- 25035795 TI - Does inter-vertebral range of motion increase after spinal manipulation? A prospective cohort study. AB - BACKGROUND: Spinal manipulation for nonspecific neck pain is thought to work in part by improving inter-vertebral range of motion (IV-RoM), but it is difficult to measure this or determine whether it is related to clinical outcomes. OBJECTIVES: This study undertook to determine whether cervical spine flexion and extension IV-RoM increases after a course of spinal manipulation, to explore relationships between any IV-RoM increases and clinical outcomes and to compare palpation with objective measurement in the detection of hypo-mobile segments. METHOD: Thirty patients with nonspecific neck pain and 30 healthy controls matched for age and gender received quantitative fluoroscopy (QF) screenings to measure flexion and extension IV-RoM (C1-C6) at baseline and 4-week follow-up between September 2012-13. Patients received up to 12 neck manipulations and completed NRS, NDI and Euroqol 5D-5L at baseline, plus PGIC and satisfaction questionnaires at follow-up. IV-RoM accuracy, repeatability and hypo-mobility cut offs were determined. Minimal detectable changes (MDC) over 4 weeks were calculated from controls. Patients and control IV-RoMs were compared at baseline as well as changes in patients over 4 weeks. Correlations between outcomes and the number of manipulations received and the agreement (Kappa) between palpated and QF-detected of hypo-mobile segments were calculated. RESULTS: QF had high accuracy (worst RMS error 0.5o) and repeatability (highest SEM 1.1o, lowest ICC 0.90) for IV-RoM measurement. Hypo-mobility cut offs ranged from 0.8o to 3.5o. No outcome was significantly correlated with increased IV-RoM above MDC and there was no significant difference between the number of hypo-mobile segments in patients and controls at baseline or significant increases in IV-RoMs in patients. However, there was a modest and significant correlation between the number of manipulations received and the number of levels and directions whose IV RoM increased beyond MDC (Rho=0.39, p=0.043). There was also no agreement between palpation and QF in identifying hypo-mobile segments (Kappa 0.04-0.06). CONCLUSIONS: This study found no differences in cervical sagittal IV-RoM between patients with non-specific neck pain and matched controls. There was a modest dose-response relationship between the number of manipulations given and number of levels increasing IV-RoM - providing evidence that neck manipulation has a mechanical effect at segmental levels. However, patient-reported outcomes were not related to this. PMID- 25035796 TI - Domestication of the neotropical tree Chrysophyllum cainito from a geographically limited yet genetically diverse gene pool in Panama. AB - Species in the early stages of domestication, in which wild and cultivated forms co-occur, provide important opportunities to develop and test hypotheses about the origins of crop species. Chrysophyllum cainito (Sapotaceae), the star apple or caimito, is a semidomesticated tree widely cultivated for its edible fruits; it is known to be native to the neotropics, but its precise geographic origins have not been firmly established. Here, we report results of microsatellite marker analyses supporting the hypothesis that the center of domestication for caimito was the Isthmus of Panama, a region in which few crop species are believed to have originated, despite its importance as a crossroads for the dispersal of domesticated plants between North and South America. Our data suggest that caimito was domesticated in a geographically restricted area while incorporating a diverse gene pool. These results refute the generally accepted Antillean origin of caimito, as well as alternative hypotheses that the species was domesticated independently in the two areas or over a broad geographic range including both. Human-mediated dispersal from Panama to the north and east was accompanied by strong reductions in both genotypic and phenotypic diversity. Within Panama, cultivated and wild trees show little neutral genetic divergence, in contrast to striking phenotypic differentiation in fruit and seed traits. In addition to providing a rare example of data that support the hypothesis of a narrow geographic origin on the Isthmus of Panama for a now widespread cultivated plant species, this study is one of the first investigations of the origins of an edible species of the large pantropical family Sapotaceae. PMID- 25035797 TI - Differing impact of a major biogeographic barrier on genetic structure in two large kangaroos from the monsoon tropics of Northern Australia. AB - Tropical savannas cover 20-30% of the world's land surface and exhibit high levels of regional endemism, but the evolutionary histories of their biota remain poorly studied. The most extensive and unmodified tropical savannas occur in Northern Australia, and recent studies suggest this region supports high levels of previously undetected genetic diversity. To examine the importance of barriers to gene flow and the environmental history of Northern Australia in influencing patterns of diversity, we investigated the phylogeography of two closely related, large, vagile macropodid marsupials, the antilopine wallaroo (Macropus antilopinus; n = 78), and the common wallaroo (Macropus robustus; n = 21). Both species are widespread across the tropical savannas of Australia except across the Carpentarian Barrier (CB) where there is a break in the distribution of M. antilopinus. We determined sequence variation in the hypervariable Domain I of the mitochondrial DNA control region and genotyped individuals at 12 polymorphic microsatellite loci to assess the historical and contemporary influence of the CB on these species. Surprisingly, we detected only limited differentiation between the disjunct Northern Territory and QueenslandM. antilopinus populations. In contrast, the continuously distributedM. robustus was highly divergent across the CB. Although unexpected, these contrasting responses appear related to minor differences in species biology. Our results suggest that vicariance may not explain well the phylogeographic patterns in Australia's dynamic monsoonal environments. This is because Quaternary environmental changes in this region have been complex, and diverse individual species' biologies have resulted in less predictable and idiosyncratic responses. PMID- 25035798 TI - Length of intervals between epidemics: evaluating the influence of maternal transfer of immunity. AB - The length of intervals between epidemic outbreaks of infectious diseases is critical in epidemiology. In several species of marine mammals and birds, it is pivotal to also consider the life history of the species of concern, as the contact rate between individuals can have a seasonal flux, for example, due to aggregations during the breeding season. Recently, particular interest has been given to the role of the dynamics of immunity in determining the intervals between epidemics in wild animal populations. One potentially powerful, but often neglected, process in this context is the maternal transfer of immunity. Here, we explore theoretically how the transfer of maternal antibodies can delay the recurrence of epidemics using Phocine Distemper in harbor seals as an example of a system in which epidemic outbreaks are followed by pathogen extinction. We show that the presence of temporarily protected newborns can significantly increase the predicted interval between epidemics, and this effect is strongly dependent on the degree of synchrony in the breeding season. Furthermore, we found that stochasticity in the onset of epidemics in combination with maternally acquired immunity increases the predicted intervals between epidemics even more. These effects arise because newborns with maternal antibodies temporarily boost population level immunity above the threshold of herd immunity, particularly when breeding is synchronous. Overall, our results show that maternal antibodies can have a profound influence on the dynamics of wildlife epidemics, notably in gregarious species such as many marine mammals and seabirds. PMID- 25035799 TI - An Ixodes minor and Borrelia carolinensis enzootic cycle involving a critically endangered Mojave Desert rodent. AB - Microtus californicus scirpensis is an endangered, isolated subspecies of California vole. It requires water pools and riparian bulrush (Schoenoplectus americanus) and occupies some of the rarest habitat of any North American mammal. The minimally vegetated, extremely arid desert surrounding the pools is essentially uninhabitable for Ixodes species ticks. We describe an enzootic cycle of Borrelia carolinensis in Ixodes minor ticks at a site 3500 km distant from the region in which I. minor is known to occur in Tecopa Host Springs, Inyo County, eastern Mojave Desert, California. Voles were live-trapped, and ticks and blood samples queried by PCR and DNA sequencing for identification and determination of the presence of Borrelia spp. Between 2011-2013, we found 21 Ixodes minor ticks (prevalence 4-8%) on Amargosa voles and Reithrodontomys megalotis. DNA sequencing of 16S rRNA from ticks yielded 99% identity to I. minor. There was 92% identity with I. minor in the calreticulin gene fragment. Three ticks (23.1%), 15 (24%) voles, three (27%) house mice, and one (7%) harvest mice were PCR positive for Borrelia spp. Sequencing of the 5S-23S intergenic spacer region and flagellin gene assigned Amargosa vole Borrelia strains to B. carolinensis. Ixodes minor, first described in 1902 from a single Guatemalan record, reportedly occurs only in the southeast American on small mammals and birds. The source of this tick in the Mojave Desert and time scale for introduction is not known but likely via migratory birds. Borrelia strains in the Amargosa ecosystem most closely resemble B. carolinensis. B. carolinensis occurs in a rodent-I. minor enzootic cycle in the southeast U.S. although its epidemiological significance for people or rodents is unknown. The presence of a tick and Borrelia spp. only known from southeast U.S. in this extremely isolated habitat on the other side of the continent is of serious concern because it suggests that the animals in the ecosystem could be vulnerable to further incursions of pathogens and parasites. PMID- 25035800 TI - Exploring the effects of spatial autocorrelation when identifying key drivers of wildlife crop-raiding. AB - Few universal trends in spatial patterns of wildlife crop-raiding have been found. Variations in wildlife ecology and movements, and human spatial use have been identified as causes of this apparent unpredictability. However, varying spatial patterns of spatial autocorrelation (SA) in human-wildlife conflict (HWC) data could also contribute. We explicitly explore the effects of SA on wildlife crop-raiding data in order to facilitate the design of future HWC studies. We conducted a comparative survey of raided and nonraided fields to determine key drivers of crop-raiding. Data were subsampled at different spatial scales to select independent raiding data points. The model derived from all data was fitted to subsample data sets. Model parameters from these models were compared to determine the effect of SA. Most methods used to account for SA in data attempt to correct for the change in P-values; yet, by subsampling data at broader spatial scales, we identified changes in regression estimates. We consequently advocate reporting both model parameters across a range of spatial scales to help biological interpretation. Patterns of SA vary spatially in our crop-raiding data. Spatial distribution of fields should therefore be considered when choosing the spatial scale for analyses of HWC studies. Robust key drivers of elephant crop-raiding included raiding history of a field and distance of field to a main elephant pathway. Understanding spatial patterns and determining reliable socio-ecological drivers of wildlife crop-raiding is paramount for designing mitigation and land-use planning strategies to reduce HWC. Spatial patterns of HWC are complex, determined by multiple factors acting at more than one scale; therefore, studies need to be designed with an understanding of the effects of SA. Our methods are accessible to a variety of practitioners to assess the effects of SA, thereby improving the reliability of conservation management actions. PMID- 25035801 TI - Local adaptations to frost in marginal and central populations of the dominant forest tree Fagus sylvatica L. as affected by temperature and extreme drought in common garden experiments. AB - Local adaptations to environmental conditions are of high ecological importance as they determine distribution ranges and likely affect species responses to climate change. Increased environmental stress (warming, extreme drought) due to climate change in combination with decreased genetic mixing due to isolation may lead to stronger local adaptations of geographically marginal than central populations. We experimentally observed local adaptations of three marginal and four central populations of Fagus sylvaticaL., the dominant native forest tree, to frost over winter and in spring (late frost). We determined frost hardiness of buds and roots by the relative electrolyte leakage in two common garden experiments. The experiment at the cold site included a continuous warming treatment; the experiment at the warm site included a preceding summer drought manipulation. In both experiments, we found evidence for local adaptation to frost, with stronger signs of local adaptation in marginal populations. Winter frost killed many of the potted individuals at the cold site, with higher survival in the warming treatment and in those populations originating from colder environments. However, we found no difference in winter frost tolerance of buds among populations, implying that bud survival was not the main cue for mortality. Bud late frost tolerance in April differed between populations at the warm site, mainly because of phenological differences in bud break. Increased spring frost tolerance of plants which had experienced drought stress in the preceding summer could also be explained by shifts in phenology. Stronger local adaptations to climate in geographically marginal than central populations imply the potential for adaptation to climate at range edges. In times of climate change, however, it needs to be tested whether locally adapted populations at range margins can successfully adapt further to changing conditions. PMID- 25035802 TI - Influence of drainage divides versus arid corridors on genetic structure and demography of a widespread freshwater turtle, Emydura macquarii krefftii, from Australia. AB - The influence of Pleistocene climatic cycles on Southern Hemisphere biotas is not yet well understood. Australia's eastern coastal margin provides an ideal setting for examining the relative influence of landscape development, sea level fluctuation, and cyclic climatic aridity on the evolution of freshwater biodiversity. We examined the impact of climatic oscillations and physical biogeographic barriers on the evolutionary history of the wide-ranging Krefft's river turtle (Emydura macquarii krefftii), using range-wide sampling (649 individuals representing 18 locations across 11 drainages) and analysis of mitochondrial sequences (~1.3-kb control region and ND4) and nuclear microsatellites (12 polymorphic loci). A range of phylogeographic (haplotype networks, molecular dating), demographic (neutrality tests, mismatch distributions), and population genetic analyses (pairwise F ST, analysis of molecular variance, Bayesian clustering analysis) were implemented to differentiate between competing demographic (local persistence vs. range expansion) and biogeographic (arid corridor vs. drainage divide) scenarios. Genetic data reveal population genetic structure in Krefft's river turtles primarily reflects isolation across drainage divides. Striking north-south regional divergence (2.2% ND4 p-distance; c. 4.73 Ma, 95% higher posterior density (HPD) 2.08-8.16 Ma) was consistent with long-term isolation across a major drainage divide, not an adjacent arid corridor. Ancient divergence among regional lineages implies persistence of northern Krefft's populations despite the recurrent phases of severe local aridity, but with very low contemporary genetic diversity. Stable demography and high levels of genetic diversity are inferred for southern populations, where aridity was less extreme. Range-wide genetic structure in Krefft's river turtles reflects contemporary and historical drainage architecture, although regional differences in the extent of Plio Pleistocene climatic aridity may be reflected in current levels of genetic diversity. PMID- 25035803 TI - Relating microbial community structure to functioning in forest soil organic carbon transformation and turnover. AB - Forest soils store vast amounts of terrestrial carbon, but we are still limited in mechanistic understanding on how soil organic carbon (SOC) stabilization or turnover is controlled by biotic and abiotic factors in forest ecosystems. We used phospholipid fatty acids (PLFAs) as biomarker to study soil microbial community structure and measured activities of five extracellular enzymes involved in the degradation of cellulose (i.e., beta-1,4-glucosidase and cellobiohydrolase), chitin (i.e., beta-1,4-N-acetylglucosaminidase), and lignin (i.e., phenol oxidase and peroxidase) as indicators of soil microbial functioning in carbon transformation or turnover across varying biotic and abiotic conditions in a typical temperate forest ecosystem in central China. Redundancy analysis (RDA) was performed to determine the interrelationship between individual PFLAs and biotic and abiotic site factors as well as the linkage between soil microbial structure and function. Path analysis was further conducted to examine the controls of site factors on soil microbial community structure and the regulatory pathway of changes in SOC relating to microbial community structure and function. We found that soil microbial community structure is strongly influenced by water, temperature, SOC, fine root mass, clay content, and C/N ratio in soils and that the relative abundance of Gram-negative bacteria, saprophytic fungi, and actinomycetes explained most of the variations in the specific activities of soil enzymes involved in SOC transformation or turnover. The abundance of soil bacterial communities is strongly linked with the extracellular enzymes involved in carbon transformation, whereas the abundance of saprophytic fungi is associated with activities of extracellular enzymes driving carbon oxidation. Findings in this study demonstrate the complex interactions and linkage among plant traits, microenvironment, and soil physiochemical properties in affecting SOC via microbial regulations. PMID- 25035804 TI - Habitat-specific differences in plasticity of foliar delta (13)C in temperate steppe grasses. AB - A decrease in foliar delta (13)C with increasing precipitation is a common tendency in steppe plants. However, the rate of decrease has been reported to differ between different species or populations. We here hypothesized that plant populations in the same habitat of temperate steppes may not differ in foliar delta (13)C response patterns to precipitation, but could differ in the levels of plasticity of foliar delta (13)C across different habitats. In order to test this hypothesis, we conducted controlled watering experiments in northeast China at five sites along a west-east transect at latitude 44 degrees N, which show substantial interannual fluctuations and intra-annual changes in precipitation among them. In 2001, watering treatment (six levels, three replicates) was assigned to 18 plots at each site. The responses of foliar delta (13)C to precipitation (i.e., the sum of watering and rainfall) were determined in populations of several grass species that were common across all sites. Although similar linear regression slopes were observed for populations of different species growing at the same site, significantly different slopes were obtained for populations of the same species growing at different sites. Further, the slope of the line progressively decreased from Site I to Site V for all species in this study. These results suggest habitat-specific differences in plasticity of foliar delta (13)C in temperate steppe grasses. This indicates that species' delta (13)C response to precipitation is conservative at the same site due to their long-term acclimation, but the mechanism responsible behind this needs further investigations. PMID- 25035805 TI - Temperature thresholds of physically dormant seeds and plant functional response to fire: variation among species and relative impact of climate change. AB - Variation in dormancy thresholds among species is rarely studied but may provide a basis to better understand the mechanisms controlling population persistence. Incorporating dormancy-breaking temperature thresholds into existing trait frameworks could improve predictions regarding seed bank persistence, and subsequently species resilience in response to fire, climate change and anthropogenic management. A key ecological strategy for many species from fire prone ecosystems is the possession of a long-lived seed bank, ensuring recovery after fire. Physical dormancy is dominant in these ecosystems and maintaining this dormancy is directly linked to seed bank persistence. We identified a suite of seed-related factors relevant to maintaining populations in fire-prone regions for 14 co-occurring physically dormant species. We measured variation in initial levels of dormancy and then applied experimental heating treatments, based on current seasonal temperatures and those occurring during fires, to seeds of all study species. Additionally, higher seasonal temperature treatments were applied to assess response of seeds to temperatures projected under future climate scenarios. Levels of germination response and mortality were determined to assess how tightly germination response was bound to either fire or seasonal cues. Six species were found to have dormancy cues bound to temperatures that only occur during fires (80 degrees C and above) and were grouped as having obligate pyrogenic dormancy release. The remaining species, classified as having facultative pyrogenic dormancy, had lower temperature dormancy thresholds and committed at least 30% of seeds to germinate after summer-temperature treatments. Evidence from this study supports including dormancy-breaking temperature thresholds as an attribute for identifying functional types. High temperature thresholds for breaking dormancy, found in our obligate pyrogenic group, appear to be a fire-adapted trait, while we predict that species in the facultative group are most at risk to increased seed bank decay resulting from elevated soil temperatures under projected climate change. PMID- 25035806 TI - Ecology and evolution. PMID- 25035807 TI - Unraveling macrophage contributions to bone repair. AB - Macrophages have reemerged to prominence with widened understanding of their pleiotropic contributions to many biologies and pathologies. This includes clear advances in revealing their importance in wound healing. Here we have focused on the current state of knowledge with respect to bone repair, which has received relatively little scientific attention compared with its soft-tissue counterparts. Our detailed characterization of resident tissue macrophages residing in bone-lining tissues (osteomacs), including their pro-anabolic function, exposed a more prominent role for these cells in bone biology than previously anticipated. Recent studies have confirmed the importance of macrophages in early inflammatory processes that establish the healing cascade after bone fracture. Emerging data support that macrophage influence extends into both anabolic and catabolic phases of repair, suggesting that these cells have prolonged and diverse functions during fracture healing. More research is needed to clarify macrophage phase-specific contributions, temporospatial subpopulation variance and macrophage specific-molecular mediators. There is also clear motivation for determining whether macrophage alterations underlie compromised fracture healing. Overall, there is strong justification to pursue strategies targeting macrophages and/or their products for improving normal bone healing and overcoming failed repair. PMID- 25035808 TI - Decoding the dynamics of cellular metabolism and the action of 3-bromopyruvate and 2-deoxyglucose using pulsed stable isotope-resolved metabolomics. AB - BACKGROUND: Cellular metabolism is highly dynamic and continuously adjusts to the physiological program of the cell. The regulation of metabolism appears at all biological levels: (post-) transcriptional, (post-) translational, and allosteric. This regulatory information is expressed in the metabolome, but in a complex manner. To decode such complex information, new methods are needed in order to facilitate dynamic metabolic characterization at high resolution. RESULTS: Here, we describe pulsed stable isotope-resolved metabolomics (pSIRM) as a tool for the dynamic metabolic characterization of cellular metabolism. We have adapted gas chromatography-coupled mass spectrometric methods for metabolomic profiling and stable isotope-resolved metabolomics. In addition, we have improved robustness and reproducibility and implemented a strategy for the absolute quantification of metabolites. CONCLUSIONS: By way of examples, we have applied this methodology to characterize central carbon metabolism of a panel of cancer cell lines and to determine the mode of metabolic inhibition of glycolytic inhibitors in times ranging from minutes to hours. Using pSIRM, we observed that 2-deoxyglucose is a metabolic inhibitor, but does not directly act on the glycolytic cascade. PMID- 25035809 TI - Factors influencing adherence to the food by prescription program among adult HIV positive patients in Addis Ababa, Ethiopia: a facility-based, cross-sectional study. AB - BACKGROUND: One way of addressing malnutrition among HIV/AIDS patients is through the Food by Prescription program (FBP) and many studies have explained the treatment outcomes after therapeutic food supplementation, though available evidences on adherence levels and factors associated with these sorts of programs are limited. The findings of this study would therefore contribute to the existing knowledge on adherence to Ready-to-Use Therapeutic/Supplementary Food (RUF) in Ethiopia. METHODS: A facility-based, cross-sectional study supplemented with qualitative methods was conducted among 630 adult HIV + patients. Their level of adherence to RUF was measured using the Morisky 8-item Medication Adherence Scale (MMAS-8). The total score on the MMAS-8 ranges from 0 to 8, with scores of <6, 6 to <8, and 8 reflecting low, medium, and high adherence, respectively. Patients who had a low or a moderate rate of adherence were considered non-adherent. RESULTS: The level of adherence was found to be 36.3% with a 95.0% response rate. With the exception of the educational status, other socio-demographic variables had no significant effect on adherence. Those who knew the benefits of the FBP program were 1.78 times more likely to adhere to the therapy than the referent groups. On the other hand, patients who were not informed on the duration of the treatment, those prescribed with more than 2 sachets/day and had been taking RUF for more than 4 month were less likely to adhere. The main reasons for non-adherence were not liking the way the food tasted and missing follow-up appointments. Stigma and sharing and selling food were the other reasons, as deduced from the focus group discussion (FGD) findings. CONCLUSION: The observed level of adherence to the FBP program among respondents enrolled in the intervention program was low. The major factors identified with a low adherence were a low level of education, poor knowledge on the benefits of RUF, the longer duration of the program, consuming more than two prescribed sachets of RUF per day, and not being informed about the duration of the treatment. Therefore, counseling patients on the program's benefits, including the treatment plans, would likely contribute to improved adherence. PMID- 25035810 TI - Missed opportunities in the diagnosis and management of protein energy malnutrition among children under 5 years in Wakiso district, Uganda. AB - Protein energy malnutrition (PEM) is one of the leading causes of death among children below 5 years in Uganda. It develops after acute childhood illnesses despite children having received treatment from health facilities. This study assessed knowledge and practices of health workers in the diagnosis and management of PEM, which was used to establish missed opportunities to prevent severe acute malnutrition (SAM) in its management. This was a cross sectional descriptive study that used questionnaires and observation of health workers at Health Center IV (HCIV) in Wakiso district, Uganda. The clinical nutrition diagnosis of the children was then obtained. There were 44 health workers that assessed 225 children. Most of the health workers 32 (72.7%) had education in PEM management and over 60% of them knew the forms of PEM, clinical signs of kwashiorkor and marasmus and the factors that predispose to PEM. Health workers did not weigh 56 (24.9%) of the children, 193 (86%) children had no height taken and only 32 (14.2%) had mid upper arm circumference measured. The weight for height of 223 (99.2%) and weight for age of 109 (93%) children was not calculated. Only 38 (16.89%) were examined for edema and 40 (17.78%) for muscle wasting. Health workers diagnosed only 21 (9%) children with malnutrition, while researchers found 94 (31.9%) with malnutrition. Children who missed opportunity to have malnutrition diagnosed at the health facility were 73 (32.9%). The knowledge of health workers on PEM is adequate, but their practice is inadequate. There is missed opportunity to diagnose and manage PEM among children who present with acute illnesses at the health centers, hence missed opportunity to prevent SAM. PMID- 25035811 TI - Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the Cerebellum. AB - BACKGROUND: Fetal alcohol spectrum disorder (FASD) is associated with deficits in cerebellar function that can persist through adolescence. Previous studies demonstrated striking inhibition of insulin and insulin-like growth factor (IGF) signaling in ethanol-exposed cerebella. OBJECTIVES: We sought to determine if FASD-induced impairments in motor function were associated with deficits in insulin/IGF signaling in juvenile cerebella. Given the growing evidence that insulin/IGF pathways cross-talk with Notch and Wnt to promote brain development and maturation; we also examined the integrity of canonical Wnt and Notch signaling networks in the brain following chronic prenatal ethanol exposure. METHODS: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 24% ethanol by caloric content from gestation day 6 through delivery. Pups were subjected to rotarod testing on postnatal days (P) 15-16 and sacrificed on P30. Cerebella were used for molecular and biochemical analysis of insulin/IGF-1, canonical Wnt, and Notch signaling mechanisms. RESULTS: Prenatal ethanol exposures impaired rotarod performance, inhibited signaling through insulin and IGF-1 receptors, IRS-1, and Akt, increased activation of GSK-3beta, and broadly suppressed genes mediating the canonical Wnt and Notch networks. CONCLUSIONS: Abnormalities in cerebellar function following chronic prenatal ethanol exposure are associated with inhibition of insulin/IGF, canonical Wnt, and Notch networks that cross-talk via GSK-3beta. Effective therapeutic measures for FASD may require multi-pronged support of interrelated signaling networks that regulate brain development. PMID- 25035812 TI - Bronchoalveolar Lavage Fluid Utilized Ex Vivo to Validate In Vivo Findings: Inhibition of Gap Junction Activity in Lung Tumor Promotion is Toll-Like Receptor 4-Dependent. AB - TLR4 protects against lung tumor promotion and pulmonary inflammation in mice. Connexin 43 (Cx43), a gap junction gene, was increased in Tlr4 wildtype compared to Tlr4-mutant mice in response to promotion, which suggests gap junctional intercellular communication (GJIC) may be compromised. We hypothesized that the early tumor microenvironment, represented by Bronchoalveolar Lavage Fluid (BALF) from Butylated hydroxytoluene (BHT; promoter)-treated mice, would produce TLR4 dependent changes in pulmonary epithelium, including dysregulation of GJIC in the Tlr4-mutant (BALB Lps-d ) compared to the Tlr4-sufficient (BALB; wildtype) mice. BHT (4 weekly doses) was injected ip followed by BALF collection at 24 h. BALF total protein and total macrophages were significantly elevated in BHT-treated BALB Lps-d over BALB mice, similar to previous findings. BALF was then utilized in an ex vivo manner to treat C10 cells, a murine alveolar type II cell line, followed by the scrape-load dye transfer assay (GJIC), Cx43 immunostaining, and quantitative RT-PCR (Mcp-1, monocyte chemotactic protein 1). GJIC was markedly reduced in C10 cells treated with BHT-treated BALB Lps-d BALF for 4 and 24 h compared to BALB and control BALF from the respective mice (p < 0.05). Mcp-1, a chemokine, was also significantly increased in the BHT-treated BALB Lps-d BALF compared to the BALB mice, and Cx43 protein expression in the cell membrane altered. These novel findings suggest signaling from the BALF milieu is involved in GJIC dysregulation associated with promotion and links gap junctions to pulmonary TLR4 protection in a novel ex vivo model that could assist in future potential tumor promoter screening. PMID- 25035813 TI - A Potential Biomarker for Acute Kidney Injury in Preterm Infants from Metabolic Profiling. AB - BACKGROUND: Currently used biomarkers for acute kidney injury (AKI), namely Ngal, SCr, and BUN, are inadequate for timely detection of AKI in preterm infants. METHODS: Nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was conducted on urines from 20 preterm infants to determine if novel metabolic biomarkers could be identified for early detection of AKI. Urines were collected from every patient each day for the first 14 days of life. NMR spectra were measured for all urines and metabolic profiling analysis conducted. RESULTS: One metabolite, carnitine, increased significantly in urines of three extremely low birth weight (ELBW) infants starting on day five of life. The three affected infants either received prolonged antibiotic treatment, extended treatment with indomethacin, or both. One ELBW patient who received both treatments and reached the highest urinary carnitine level died on day 10 of life due to localized gut perforation complicated by suspected AKI. CONCLUSIONS: It was concluded that carnitine increased in the three neonates in part due to antibiotic- and/or indomethacin-induced AKI. It is hypothesized that combined antibiotic and indomethacin treatment promoted AKI resulting in reduced proximal renal tubule reabsorption of carnitine and that beta-lactam antibiotics blocked renal carnitine uptake by human organic cation transporter, hOCTN2. PMID- 25035814 TI - Sterilization of Silver Nanoparticles Using Standard Gamma Irradiation Procedure Affects Particle Integrity and Biocompatibility. AB - Silver nanoparticles are commonly used in a variety of commercial and medical products. Here we investigate the effects of standard sterilization methods, including heat/steam (autoclave) and gamma-irradiation on the structural integrity and biocompatibility of citrate-stabilized silver nanoparticles with nominal sizes of 20, 40, 60 and 80 nm. Particle size, shape and in vitro biocompatibility were studied pre- and post-sterilization. Sterilization by gamma irradiation at dose levels commonly used in medical device industry (15, 25 and 50 kGy) resulted in dramatic changes in particle size and morphology, as monitored by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Exposing the particles to a chemical producer of hydroxyl radicals (N hydroxy-2-pyridinethione) allowed us to duplicate the sterilization-based changes in size and morphology, implying a free radical mechanism of action. Compared to untreated controls, we also observed a three- to five-fold increase in tendency of sterilized silver nanoparticles to cause platelet aggregation, a sensitive in vitro indicator of thrombogenicity. PMID- 25035816 TI - Transcriptional Regulation of the Group IIA Secretory Phospholipase A2 Gene by C/EBPdelta in Rat liver and its Relationship to Hepatic Gluconeogenesis during Sepsis. AB - BACKGROUND: The present study was undertaken to test hypothesis that altered transcription of secretory Phospholipase A2 (sPLA2) gene in rat liver is regulated by CCAAT/enhancer binding protein delta (C/EBPdelta), and to assess its relationship to hepatic gluconeogenesis during the progression of sepsis. METHODS: Sepsis was induced by Cecal Ligation and Puncture (CLP). Experiments were divided into three groups, control, early sepsis (9 h after CLP), and late sepsis (18 h after CLP). RESULTS: DNA mobility and super shift assays reveal that C/EBP complexes in the liver consisted of at least three isoforms: C/EBPalpha, C/EBPbeta, and C/EBPdelta; and various C/EBP isoforms were capable of interacting with each other. Hepatocyte transfection experiments demonstrate that under normal conditions, binding of C/EBPdelta to sPLA2 gene enhanced sPLA2 promoter activity and the binding resulted in an increase in hepatic gluconeogenesis. Under pathological conditions such as sepsis, binding of C/EBPdelta to sPLA2 promoter increased during early and late phases of sepsis, and the increases in C/EBPdelta binding correlated with increases in sPLA2 mRNA abundance and sPLA2 protein levels. Under otherwise the identical experimental conditions, hepatic gluconeogenesis was reduced during early and late phases of sepsis and the sepsis induced reductions in liver gluconeogenesis were aggravated by binding of C/EBPdelta to sPLA2 gene. CONCLUSIONS: These results link C/EBPdelta binding to altered sPLA2 promoter, and to hepatic gluconeogenesis under normal and pathological conditions. It is suggested that C/EBPdelta-sPLA2- hepatic gluconeogenesis may function as a signalling axis affecting glucose homeostasis during the progression of sepsis. PMID- 25035815 TI - CSF and Brain Indices of Insulin Resistance, Oxidative Stress and Neuro Inflammation in Early versus Late Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by progressive impairments in cognitive and behavioral functions with deficits in learning, memory and executive reasoning. Growing evidence points toward brain insulin and insulin-like growth factor (IGF) resistance-mediated metabolic derangements as critical etiologic factors in AD. This suggests that indices of insulin/IGF resistance and their consequences, i.e. oxidative stress, neuro-inflammation, and reduced neuronal plasticity, should be included in biomarker panels for AD. Herein, we examine a range of metabolic, inflammatory, stress, and neuronal plasticity related proteins in early AD, late AD, and aged control postmortem brain, postmortem ventricular fluid (VF), and clinical cerebrospinal fluid (CSF) samples. In AD brain, VF, and CSF samples the trends with respect to alterations in metabolic, neurotrophin, and stress indices were similar, but for pro-inflammatory cytokines, the patterns were discordant. With the greater severities of dementia and neurodegeneration, the differences from control were more pronounced for late AD (VF and brain) than early or moderate AD (brain, VF and CSF). The findings suggest that the inclusion of metabolic, neurotrophin, stress biomarkers in AbetaPP-Abeta+pTau CSF-based panels could provide more information about the status and progression of neurodegeneration, as well as aid in predicting progression from early- to late-stage AD. Furthermore, standardized multi targeted molecular assays of neurodegeneration could help streamline postmortem diagnoses, including assessments of AD severity and pathology. PMID- 25035817 TI - Exercise awareness and barriers after spinal cord injury. AB - Exercise is an essential element in managing several of the non-communicable diseases after spinal cord injury (SCI). Awareness of the importance of prescribing a customized exercise program that meets the goals of persons with SCI should be highly considered in the rehabilitation community. The barriers of implementing specific exercise program as well as the factors that may mask the outcomes of regular exercise regimen need to be continuously addressed as a part of patients' rehabilitation care. The focus of this editorial is to encourage the medical community to consider routine physical activity as one of the necessary vital signs that needs to be routinely checked in patients with SCI. Providing education tips, nutritional counseling and engaging in recreational programs may provide motivational route to the community of SCI. This may result in reinforcing active lifestyle in survivors with SCI as well as to reduce the impact of chronic life threatening medical disorders. PMID- 25035818 TI - Anterior knee pain after a total knee arthroplasty: What can cause this pain? AB - Total Knee Arthroplasty has been shown to be a successful procedure for treating patients with osteoarthritis, and yet approximately 5%-10% of patients experience residual pain, especially in the anterior part of the knee. Many theories have been proposed to explain the etiology of this anterior knee pain (AKP) but, despite improvements having been made, AKP remains a problem. AKP can be described as retropatellar or peripatellar pain, which limits patients in their everyday lives. Patients suffering from AKP experience difficulty in standing up from a chair, walking up and down stairs and riding a bicycle. The question asked was: "How can a 'perfectly' placed total knee arthroplasty (TKA) still be painful: what can cause this pain?". To prevent AKP after TKA it is important to first identify the different anatomical structures that can cause this pain. Greater attention to and understanding of AKP should lead to significant pain relief and greater overall patient satisfaction after TKA. This article is a review of what pain is, how nerve signalling works and what is thought to cause Anterior Knee Pain after a Total Knee Arthroplasty. PMID- 25035819 TI - Cartilage repair techniques of the talus: An update. AB - Symptomatic chondral or osteochondral defects of the talus reduce the quality of life of many patients. Although their pathomechanism is well understood, it is well known that different aetiologic factors play a role in their origin. Additionally, it is well recognised that the talar articular cartilage strongly differs from that in the knee. Despite this fact, many recommendations for the management of talar cartilage defects are based on approaches that were developed for the knee. Conservative treatment seems to work best in paediatric and adolescent patients with osteochondritis dissecans. However, depending on the size of the lesions, surgical approaches are necessary to treat many of these defects. Bone marrow stimulation techniques may achieve good results in small lesions. Large lesions may be treated by open procedures such as osteochondral autograft transfer or allograft transplantation. Autologous chondrocyte transplantation, as a restorative procedure, is well investigated in the knee and has been applied in the talus with increasing popularity and promising results but the evidence to date is poor. The goals of the current article are to summarise the different options for treating chondral and osteochondral defects of the talus and review the available literature. PMID- 25035820 TI - Dual mobility cups in total hip arthroplasty. AB - Total hip arthroplasty (THA) is considered one of the most successful surgical procedures in orthopaedics. With the increase in the number of THAs performed in the world in the next decades, reducing or preventing medical and mechanical complications such as post-operative THA instability will be of paramount importance, particularly in an emerging health care environment based on quality control and patient outcome. Dual mobility acetabular component (also known as unconstrained tripolar implant) was introduced in France at the end of the 1970s as an alternative to standard sockets, to reduce the risk of THA dislocation in patients undergoing primary THA in France. Dual mobility cups have recently gained wider attention in the United States as an alternative option in the prevention and treatment of instability in both primary and revision THA and offer the benefit of increased stability without compromising clinical outcomes and implant longevity. In this article, we review the use of dual mobility cup in total hip arthroplasty in terms of its history, biomechanics, outcomes and complications based on more than 20 years of medical literature. PMID- 25035821 TI - New oral pharmacotherapeutic agents for venous thromboprophylaxis after total hip arthroplasty. AB - Patients undergoing total hip arthroplasty (THA) are at high risk for developing venous thromboembolism and, therefore, require short term prophylaxis with antithrombotic agents. Recently, target specific oral anticoagulants (TSOA) including the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have been approved for THA thrombopropylaxis in various countries. The TSOAs provide a rapid acting, oral alternative to parenteral agents including low-molecular weight heparins (LMWH) and fondaparinux; and compared to warfarin, they do not require routine laboratory monitoring and possess much fewer drug-drug interactions. Based on phase III clinical studies, TSOAs have established themselves as an effective and safe option for thromboprophylaxis after THA compared to LMWH, particularly enoxaparin, but require additional evaluation in specific populations such as the renally impaired or elderly. The ability to monitor and reverse these TSOAs in the case of bleeding complications or suspected sub- or supra-therapeutic anticoagulation is of importance, but remains investigational. This review will focus on the drug-specific characteristics, efficacy, safety, and economic impact of the TSOAs for thromboprophylaxis following THA, as well as the aspects of therapeutic monitoring and anticoagulation reversal in the event of bleeding complications or a need for urgent reversal. PMID- 25035823 TI - Can periprosthetic hip joint infections be successfully managed by debridement and prosthesis retention? AB - To evaluate the current literature about how successfully periprosthetic hip joint infections can be managed by debridement and prosthesis retention. A literature search was performed through PubMed until September 2013. Search terms were "DAIR (debridement, antibiotics, irrigation, and retention)" alone and in combination with "hip" as well as "hip infection + prosthesis retention". A total of 11 studies reporting on 292 cases could be identified. Five different treatment modalities have been described with varying success rates (debridement 21% infection eradication rate; debridement + lavage-75% infection eradication rate; debridement, lavage, with change of modular prosthesis components-70.4% infection eradication rate; debridement, lavage, change of modular prosthesis components + vacuum-assisted closure-92.8% infection eradication rate; acetabular cup removal + spacer head onto retained stem-89.6% infection eradication rate). With regard to the postoperative antibiotic therapy, no general consensus could be drawn from the available data. Debridement, antibiotic therapy, irrigation, and prosthesis retention is an acceptable solution in the management of early and acute hematogenous periprosthetic hip joint infections. The current literature does not allow for generalization of conclusions with regard to the best treatment modality. A large, multi-center study is required for identification of the optimal treatment of these infections. PMID- 25035822 TI - Management of femoral neck fractures in the young patient: A critical analysis review. AB - Femoral neck fractures account for nearly half of all hip fractures with the vast majority occurring in elderly patients after simple falls. Currently there may be sufficient evidence to support the routine use of hip replacement surgery for low demand elderly patients in all but non-displaced and valgus impacted femoral neck fractures. However, for the physiologically young patients, preservation of the natural hip anatomy and mechanics is a priority in management because of their high functional demands. The biomechanical challenges of femoral neck fixation and the vulnerability of the femoral head blood supply lead to a high incidence of non-union and osteonecrosis of the femoral head after internal fixation of displaced femoral neck fractures. Anatomic reduction and stable internal fixation are essentials in achieving the goals of treatment in this young patient population. Furthermore, other management variables such as surgical timing, the role of capsulotomy and the choice of implant for fixation remain controversial. This review will focus both on the demographics and injury profile of young patients with femoral neck fractures and the current evidence behind the surgical management of these injuries as well as their major secondary complications. PMID- 25035824 TI - Perioperative pain control after total knee arthroplasty: An evidence based review of the role of peripheral nerve blocks. AB - Over the last decades, the number of total knee arthroplasty procedures performed in the United States has been increasing dramatically. This very successful intervention, however, is associated with significant postoperative pain, and adequate postoperative analgesia is mandatory in order to allow for successful rehabilitation and recovery. The use of regional anesthesia and peripheral nerve blocks has facilitated and improved this goal. Many different approaches and techniques for peripheral nerve blockades, either landmark or, more recently, ultrasound guided have been described over the last decades. This includes but is not restricted to techniques discussed in this review. The introduction of ultrasound has improved many approaches to peripheral nerves either in success rate and/or time to block. Moreover, ultrasound has enhanced the safety of peripheral nerve blocks due to immediate needle visualization and as consequence needle guidance during the block. In contrast to patient controlled analgesia using opioids, patients with a regional anesthetic technique suffer from fewer adverse events and show higher patient satisfaction; this is important as hospital rankings and advertisement have become more common worldwide and many patients use these factors in order to choose a certain institution for a specific procedure. This review provides a short overview of currently used regional anesthetic and analgesic techniques focusing on related implications, considerations and outcomes. PMID- 25035825 TI - Treatment of meniscal tears: An evidence based approach. AB - Treatment options for meniscal tears fall into three broad categories; non operative, meniscectomy or meniscal repair. Selecting the most appropriate treatment for a given patient involves both patient factors (e.g., age, co morbidities and compliance) and tear characteristics (e.g., location of tear/age/reducibility of tear). There is evidence suggesting that degenerative tears in older patients without mechanical symptoms can be effectively treated non-operatively with a structured physical therapy programme as a first line. Even if these patients later require meniscectomy they will still achieve similar functional outcomes than if they had initially been treated surgically. Partial meniscectomy is suitable for symptomatic tears not amenable to repair, and can still preserve meniscal function especially when the peripheral meniscal rim is intact. Meniscal repair shows 80% success at 2 years and is more suitable in younger patients with reducible tears that are peripheral (e.g., nearer the capsular attachment) and horizontal or longitudinal in nature. However, careful patient selection and repair technique is required with good compliance to post operative rehabilitation, which often consists of bracing and non-weight bearing for 4-6 wk. PMID- 25035826 TI - Osteoporosis and obesity: Role of Wnt pathway in human and murine models. AB - Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research. Although the onset of these two diseases can occur in a different way, recent studies have shown that obesity and osteoporosis share common genetic and environmental factors. Despite being a risk factor for health, obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading, exerted by high body mass, on bone formation. However, contrasting studies have not achieved a clear consensus, suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or, even worse, could be rather detrimental to bone. On the other hand, it is hitherto better established that, since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor, molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa. Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation, which are peroxisome proliferators activated receptor-gamma and Wnts, respectively. In particular, we will focus on the role of both canonical and non-canonical Wnt signalling, involved in mesenchymal cell fate regulation. Moreover, at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis, although it is well known its role on bone metabolism. In addition, the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause. Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity, we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years. PMID- 25035827 TI - Bone anabolics in osteoporosis: Actuality and perspectives. AB - Vertebral and nonvertebral fractures prevention is the main goal for osteoporosis therapy by inhibiting bone resorption and/or stimulating bone formation. Antiresorptive drugs decrease the activation frequency, thereby determining a secondary decrease in bone formation rate and a low bone turnover. Bisphosphonates are today's mainstay among antiresorptive treatment of osteoporosis. Also, oral selective estrogen receptor modulators and recently denosumab have a negative effect on bone turnover. Agents active on bone formation are considered a better perspective in the treatment of severe osteoporosis. Recombinant-human parathyroid hormone (PTH) has showed to increase bone formation and significantly decrease vertebral fractures in severe patients, but with a modest effect on nonvertebral fractures. The study of Wnt signaling pathway, that induces prevalently an osteoblastic activity, opens large possibilities to antagonists of Wnt-inhibitors, such as sclerostin antibodies and dickkopf-1 antagonists, with potential effects not only on trabecular bone but also on cortical bone. PMID- 25035828 TI - Reverse polarity shoulder replacement: Current concepts and review of literature. AB - Shoulder replacement in cuff tear arthropathy (CTA) is an unsolved challenge. CTA poses a soft tissue deficiency in an arthritic glenohumeral joint which the anatomical total shoulder replacement and hemiarthroplasty cannot reliably provide stability, range of movement, function or satisfactory long term outcome. In the past two decades since the introduction of the reverse shoulder replacement, the prosthesis has evolved and has shown promising results. It is a partially constraint joint by virtue of its design features. The reversal of the concavity and convexity of the joint to the proximal humerus and the glenoid, respectively, also shifts and improves its center of rotation onto the osseous surface of the glenoid with less exposure to shear stress. It is a successful pain relieving procedure, offering good outcome in patients with irreparable massive rotator cuff tear with or without osteoarthritis. Consequently, this has led to wider use and expansion of its indication to include more complex elective and trauma cases. Whereas originally used in the more elderly patients, there is increasingly more demand in the younger patients. It is important to have good quality long term data to support these increasing indications. Therefore, we review the literature on the concepts of reverse shoulder replacement and the contemporary evidence. PMID- 25035829 TI - Scoring system for prediction of metastatic spine tumor prognosis. AB - Assessing the prognosis before treatment for metastatic spine tumor is extremely important in therapy selection. Therefore, we review some prognostic scoring systems and their outcomes. Articles with combinations of two keywords among "metastatic spine tumor" and "prognosis", "score", "scoring system", "predicting", or "life expectancy" were searched for in PubMed. As a result, 236 articles were extracted. Those referring to representative scoring systems about predicting the survival of patients with metastatic spine tumors were used. The significance and limits of these scoring systems, and the future perspectives were described. Tokuhashi score, Tomita score, Baur score, Linden score, Rades score, and Katagiri score were introduced. They are all scoring systems prepared by combining factors that affect prognosis. The primary site of cancer and visceral metastasis were common factors in all of these scoring systems. Other factors selected to influence the prognosis varied. They were useful to roughly predict the survival period, such as, "more than one year or not" or "more than six months or not". In particular, they were utilized for decision-making about operative indications and avoidance of excessive medical treatment. Because the function depended on the survival period in the patients with metastatic spine tumor, it was also utilized in assessing functional prognosis. However, no scoring system had more than 90% consistency between the predicted and actual survival periods. Future perspectives should adopt more oncological viewpoints with adjustment of the process of treatment for metastatic spine tumor. PMID- 25035830 TI - Imaging of multiple myeloma: Current concepts. AB - Medical imaging is of crucial importance for diagnosis and initial staging as well as for differentiation of multiple myeloma (MM) from other monoclonal plasma cell diseases. Conventional radiography represents the reference standard for diagnosis of MM due to its wide availability and low costs despite its known limitations such as low sensitivity, limited specificity and its inability to detect extraosseous lesions. Besides conventional radiography, newer cross sectional imaging modalities such as whole-body low-dose computed tomography (CT), whole-body magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT are available for the diagnosis of osseous and extraosseous manifestations of MM. Whole-body low-dose CT is used increasingly, replacing conventional radiography at selected centers, due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions. The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI and (18)F-FDG PET/CT. According to current evidence, MRI is the most sensitive method for initial staging while (18)F-FDG PET/CT allows monitoring of treatment of MM. There is an evolving role for assessment of treatment response using newer MR imaging techniques. Future studies are needed to further define the exact role of the different imaging modalities for individual risk stratification and therapy monitoring. PMID- 25035831 TI - Perioperative management of the patient with rheumatoid arthritis. AB - A multidisciplinary approach is required to care for patients with rheumatoid arthritis (RA) in the perioperative period. In preparation for surgery, patients must have a cardiovascular risk assessment performed due to the high risk of heart disease in patients with RA. Treatment of RA is with immunomodulatory medications, which present unique challenges for the perioperative period. Currently, there is no consensus on how to manage disease modifying antirheumatic drug (DMARD) therapy in the perioperative setting. Much of the data to guide therapy is based on retrospective cohort data. Choices regarding DMARDs require an individualized approach with collaboration between surgeons and rheumatologists. Consensus regarding biologic therapy is to hold the therapy in the perioperative period with the length of time dictated by the half-life of the medication. Special attention is required at the time of surgery for potential need for stress dose steroids. Further, there must be close communication with anesthesiologists in terms of airway management particularly in light of the risk for cervical spine disease. There are no consensus guidelines regarding the requirement for cervical spine radiographs prior to surgery. However, history and exam alone cannot be relied upon to identify cervical spine disease. Patients with RA who undergo joint replacement arthroplasty are at higher risk for infection and dislocation compared to patients with osteoarthritis, necessitating particular vigilance in postoperative follow up. This review summarizes available evidence regarding perioperative management of patients with RA. PMID- 25035833 TI - Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship? AB - Life expectancy in patients with rheumatoid arthritis (RA) is reduced compared to the general population owing to an increase in cardiovascular diseases (CVD) not fully explained by traditional cardiovascular risk factors. In recent years, interest has been focused on the alterations in lipid metabolism in relation to chronic inflammation as one of the possible mechanisms involved in the pathogenesis of atherosclerosis of RA patients. Research regarding this issue has revealed quantitative alterations in lipoproteins during the acute-phase reaction, and has also demonstrated structural alterations in these lipoproteins which affect their functional abilities. Although many alterations in lipid metabolism have been described in this regard, these structural changes associated with inflammation are particularly important in high-density lipoproteins as they affect their cardioprotective functions. In this respect, excessive oxidation in low-density lipoprotein (LDL) and increased lipoprotein(a) with a predominance of smaller apolipoprotein(a) isoforms has also been reported. This article will discuss proinflammatory high-density lipoproteins (piHDL), oxidized LDL and lipoprotein(a). Elevated concentrations of these lipoproteins with marked pro-atherogenic properties have been observed in RA patients, which could help to explain the increased cardiovascular risk of these patients. PMID- 25035832 TI - Advances in the treatment of cervical rheumatoid: Less surgery and less morbidity. AB - Rheumatoid arthritis is a chronic systemic inflammatory disease that often affects the cervical spine. While it was initially thought that cervical involvement was innocuous, natural history studies have substantiated the progressive nature of untreated disease. Over the past 50 years, there has been further elucidation in the pathophysiology of the disease, as well as significant advancements in medical and surgical therapy. The introduction of disease modifying drugs and biologic agents has reduced the amount of patients with advanced stages of the disease needing surgery. Advancement in instrumentation techniques has improved patient outcomes and fusion rates. The introduction of endoscopic approaches for ventral decompression may further lower surgical morbidity. In this review, we give a brief overview of the pertinent positives of the disease. A discussion of historical techniques and the evolution of surgical therapy into the modern era is provided. With improved medical therapies and less invasive approaches, we will likely continue to see less advanced cases of disease and less surgical morbidity. Nonetheless, a thorough understanding of the disease is crucial, as its systemic involvement and need for continued medical therapy have tremendous impact on overall complications and outcomes even in patients being seen for standard degenerative disease with comorbid rheumatoid. PMID- 25035834 TI - Rheumatoid arthritis: Nuclear Medicine state-of-the-art imaging. AB - Rheumatoid arthritis (RA) is an autoimmune disease, which is associated with systemic and chronic inflammation of the joints, resulting in synovitis and pannus formation. For several decades, the assessment of RA has been limited to conventional radiography, assisting in the diagnosis and monitoring of disease. Nevertheless, conventional radiography has poor sensitivity in the detection of the inflammatory process that happens in the initial stages of RA. In the past years, new drugs that significantly decrease the progression of RA have allowed a more efficient treatment. Nuclear Medicine provides functional assessment of physiological processes and therefore has significant potential for timely diagnosis and adequate follow-up of RA. Several single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals have been developed and applied in this field. The use of hybrid imaging, which permits computed tomography (CT) and nuclear medicine data to be acquired and fused, has increased even more the diagnostic accuracy of Nuclear Medicine by providing anatomical localization in SPECT/CT and PET/CT studies. More recently, fusion of PET with magnetic resonance imaging (PET/MRI) was introduced in some centers and demonstrated great potential. In this article, we will review studies that have been published using Nuclear Medicine for RA and examine key topics in the area. PMID- 25035835 TI - Adipokines: Biomarkers for osteoarthritis? AB - Osteoarthritis (OA) is one of the most common degenerative joint diseases in aging population. Obesity is an important risk factor for initiation and progression of OA. It is accepted that excess body weight may lead to cartilage degeneration by increasing the mechanical forces across weight-bearing joints. However, emerging data suggest that additional metabolic factors released mainly by white adipose tissue may also be responsible for the high prevalence of OA among obese people. Adipocyte-derived molecules ''adipokines'' have prompt much interest in OA pathophysiological research over the past decade since they play an important role in cartilage and bone homeostasis. Therefore, the aim of this review is to summarize the current knowledge on the role of adipokines including leptin, adiponectin, visfatin and resistin in OA and their potential to be used as biomarkers for earlier diagnosis, classifying disease severity, monitoring disease progression, and testing pharmacological interventions for OA. In OA patients, leptin, visfatin and resistin showed increased production whereas adiponectin showed decreased production. Leptin and adiponectin are far more studied than visfatin and resistin. Importantly, altered adipokine levels also contribute to a wide range of diseases. Further experiments are still crucial for understanding the relationship between adipokines and OA. PMID- 25035836 TI - Beyond the joint: Subclinical atherosclerosis in rheumatoid arthritis. AB - Rheumatoid arthritis is a chronic autoimmune inflammatory disease associated with increased cardiovascular risk and higher mortality in respect to general population. Beyond joint disease, inflammation is the major determinant of accelerated atherosclerosis observed in rheumatoid arthritis. We review the relationship between inflammation, atherosclerosis and cardiovascular risk in rheumatoid arthritis, focusing on the assessment of subclinical atherosclerosis by functional and morphological methods. These tools include flow mediated dilatation, carotid intima-media thickness, ankle/brachial index, coronary calcium content, pulse wave analysis and serum biomarker of subclinical atherosclerosis. PMID- 25035837 TI - Perioperative outcomes and type of anesthesia in hip surgical patients: An evidence based review. AB - Over the last decades the demand for hip surgery, be it elective or in a traumatic setting, has greatly increased and is projected to expand even further. Concurrent with demographic changes the affected population is burdened by an increase in average comorbidity and serious complications. It has been suggested that the choice of anesthesia not only affects the surgery setting but also the perioperative outcome as a whole. Therefore different approaches and anesthetic techniques have been developed to offer individual anesthetic and analgesic care to hip surgery patients. Recent studies on comparative effectiveness utilizing population based data have given us a novel insight on anesthetic practice and outcome, showing favorable results in the usage of regional vs general anesthesia. In this review we aim to give an overview of anesthetic techniques in use for hip surgery and their impact on perioperative outcome. While there still remains a scarcity of data investigating perioperative outcomes and anesthesia, most studies concur on a positive outcome in overall mortality, thromboembolic events, blood loss and transfusion requirements when comparing regional to general anesthesia. Much of the currently available evidence suggests that a comprehensive medical approach with emphasis on regional anesthesia can prove beneficial to patients and the health care system. PMID- 25035838 TI - Superior labrum anterior to posterior lesions of the shoulder: Diagnosis and arthroscopic management. AB - After the improvement in arthroscopic shoulder surgery, superior labrum anterior to posterior (SLAP) tears are increasingly recognized and treated in persons with excessive overhead activities like throwers. Several potential mechanisms for the pathophysiology of superior labral tears have been proposed. The diagnosis of this condition can be possible by history, physical examination and magnetic resonance imaging combination. The treatment of type 1 SLAP tears in many cases especially in older patients is non-operative but some cases need arthroscopic intervention. The arthroscopic management of type 2 lesions in older patients can be biceps tenodesis, but young and active patients like throwers will need an arthroscopic repair. The results of arthroscopic repair in older patients are not encouraging. The purpose of this study is to perform an overview of the diagnosis of the SLAP tears and to help decision making for the surgical management. PMID- 25035840 TI - Identification and preoperative optimization of risk factors to prevent periprosthetic joint infection. AB - Despite significant improvements over the past several decades in diagnosis, treatment and prevention of periprosthetic joint infection (PJI), it still remains a major challenge following total joint arthroplasty. Given the devastating nature and accelerated incidence of PJI, prevention is the most important strategy to deal with this challenging problem and should start from identifying risk factors. Understanding and well-organized optimization of these risk factors in individuals before elective arthroplasty are essential to the ultimate success in reducing the incidence of PJI. Even though some risk factors such as demographic characteristics are seldom changeable, they allow more accurate expectation regarding individual risks of PJI and thus, make proper counseling for shared preoperative decision-making possible. Others that increase the risk of PJI, but are potentially modifiable should be optimized prior to elective arthroplasty. Although remarkable advances have been achieved in past decades, many questions regarding standardized practice to prevent this catastrophic complication remain unanswered. The current study provide a comprehensive knowledge regarding risk factors based on general principles to control surgical site infection by the review of current literature and also share own practice at our institution to provide practical and better understandings. PMID- 25035839 TI - Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. AB - Osteoarthritis (OA) is a complex "whole joint" disease pursued by inflammatory mediators, rather than purely a process of "wear and tear". Besides cartilage degradation, synovitis, subchondral bone remodeling, degeneration of ligaments and menisci, and hypertrophy of the joint capsule take parts in the pathogenesis. Pain is the hallmark symptom of OA, but the extent to which structural pathology in OA contributes to the pain experience is still not well known. For the knee OA, intraarticular (IA) injection (corticosteroids, viscosupplements, blood derived products) is preferred as the last nonoperative modality, if the other conservative treatment modalities are ineffective. IA corticosteroid injections provide short term reduction in OA pain and can be considered as an adjunct to core treatment for the relief of moderate to severe pain in people with OA. IA hyaluronic acid (HA) injections might have efficacy and might provide pain reduction in mild OA of knee up to 24 wk. But for HA injections, the cost effectiveness is an important concern that patients must be informed about the efficacy of these preparations. Although more high-quality evidence is needed, recent studies indicate that IA platelet rich plasma injections are promising for relieving pain, improving knee function and quality of life, especially in younger patients, and in mild OA cases. The current literature and our experience indicate that IA injections are safe and have positive effects for patient satisfaction. But, there is no data that any of the IA injections will cause osteophytes to regress or cartilage and meniscus to regenerate in patients with substantial and irreversible bone and cartilage damage. PMID- 25035841 TI - Primary total elbow arthroplasty in complex fractures of the distal humerus. AB - AIM: To evaluate short- to medium term outcome of total elbow arthroplasty (TEA) in complex fractures of the distal humerus. METHODS: A consecutive series of 24 complex distal humerus fractures operated with TEA in the period 2006-2012 was evaluated with the Mayo Elbow Performance score (MEPS), plain radiographs, complications and overall satisfaction. The indications for surgery were 1: AO type B3 or C3 or Sheffield type 3 fracture and age above 65 or 2: fracture and severe rheumatoid arthritis. Mean follow-up time was 21 mo. RESULTS: Twenty patients were followed up. Four patients, of which 3 had died, were lost to follow up. According to the AO classification there were 17 C3, 1 B2 and 2 A2 fractures. Mean follow-up was 21 months (range 4-54). Mean MEPS was 94 (range 65 100). Mean flexion was 114 degrees (range 80-140). According to MEPS there were 15 excellent, 4 good and 1 fair result. Patient satisfaction: 8 excellent, 10 good, 2 fair and 1 poor. There were two revisions due to infection treated successfully with revision and three months of antibiotics. In two patients the locking split had loosened. One was referred to re-insertion and one chose yearly controls. Two patients had persistent dysaesthesia of their 5th finger, but were able to discriminate between sharp and blunt. CONCLUSION: Our study suggests that TEA in complex fractures of the distal humerus in elderly patients can result in acceptable short- to medium term outcome. PMID- 25035842 TI - Partial anterior cruciate ligament tears treated with intraligamentary plasma rich in growth factors. AB - AIM: To evaluate the effect of the application of plasma rich in growth factors (PRGF)-Endoret to the remaining intact bundle in partial anterior cruciate ligament (ACL) tears. METHODS: A retrospective review of the rate of return to play in football players treated with the application of PRGF-Endoret in the remaining intact bundle in partial ACL injuries that underwent surgery for knee instability. Patients with knee instability requiring revision surgery for remnant ACL were selected. PRGF was applied in the wider part of posterolateral bundle and the time it took patients to return to their full sporting activities at the same level before the injury was evaluated. RESULTS: A total of 19 patients were reviewed. Three had a Tegner activity level of 10 and the remaining 16 level 9. The time between the injury and the time of surgery was 5.78 wk (SD 1.57). In total, 81.75% (16/19) returned to the same pre-injury level of sport activity (Tegner 9-10). 17 males and 2 females were treated. The rate of associated injury was 68.42% meniscal lesions and 26.31% cartilage lesions. The KT-1000 values were normalized in all operated cases. One patient was not able to return to sport due to the extent of their cartilage lesions. The 15 patients with Tegner activity level 9 returned to play at an average of 16.20 wk (SD 1.44) while the 3 patients with Tegner activity level 10 did so in 12.33 wk (SD 1.11). CONCLUSION: With one remaining intact bundle the application of PRGF-Endoret in instability cases due to partial ACL tear showed high return to sport rates at pre- injury level in professional football players. PMID- 25035843 TI - Treatment of distal femur fractures in a regional Australian hospital. AB - AIM: To review our outcomes and compare the results of the Less Invasive Stabilization System (LISS) to other implants for distal femur fracture management at a regional Australian hospital. METHODS: The LISS is a novel implant for the management of distal femur fractures. It is, however, technically demanding and treatment results have not yet been assessed outside tertiary centres. Twenty-seven patients with 28 distal femur fractures who had been managed surgically at the Mackay Base Hospital from January 2004 to December 2010 were retrospectively enrolled and assessed clinically and radiologically. Outcomes were union, pain, Lysholm score, knee range of motion, and complication rates. RESULTS: Twenty fractures were managed with the LISS and eight fractures were managed with alternative implants. Analysis of the surgical techniques revealed that 11 fractures managed with the LISS were performed according to the recommended principles (LISS-R) and 9 were not (LISS-N). Union occurred in 67.9% of fractures overall: 9/11 (82%) in the LISS-R group vs 5/9 (56%) in the LISS-N group and 5/8 (62.5%) in the alternative implant group. There was no statistically significant difference between pain, Lysholm score, and complication rates between the groups. However, there was a trend towards the LISS-R group having superior outcomes which were clinically significant. There was a statistically significant greater range of median knee flexion in the LISS R group with compared to the LISS-N group (P = 0.0143) and compared with the alternative implant group (P = 0.0454). CONCLUSION: The trends towards the benefits of the LISS procedure when correctly applied would suggest that not only should the LISS procedure be performed for distal femur fractures, but the correct principle of insertion is important in improving the patient's outcome. PMID- 25035844 TI - Ten years of hip fractures in Italy: For the first time a decreasing trend in elderly women. AB - AIM: To evaluate the hospitalization rate of femoral neck fractures in the elderly Italian population over ten years. METHODS: We analyzed national hospitalizations records collected at central level by the Ministry of Health from 2000 to 2009. Age- and sex-specific rates of fractures occurred at femoral neck in people >= 65 years old. We performed a sub-analysis over a three-year period (2007-2009), presenting data per five-year age groups, in order to evaluate the incidence of the hip fracture in the oldest population. RESULTS: We estimated a total of 839008 hospitalizations due to femoral neck fractures between 2000 and 2009 in people >= 65, with an overall increase of 29.8% over 10 years. The incidence per 10000 inhabitants remarkably increased in people >= 75, passing from 158.5 to 166.8 (+5.2%) and from 72.6 to 77.5 (+6.8%) over the ten year period in women and men, respectively. The oldest age group (people > 85 years old) accounted for more than 42% of total hospital admissions in 2009 (n = 39000), despite representing only 2.5% of the Italian population. Particularly, women aged > 85 accounted for 30.8% of total fractures, although they represented just 1.8% of the general population. The results of this analysis indicate that the incidence of hip fractures progressively increased from 2000 to 2009, but a reduction can be observed for the first time in women <= 75 (-7.9% between 2004 and 2009). CONCLUSION: Incidence of hip fractures in Italy are continuously increasing, although women aged 65-74 years old started showing a decreasing trend. PMID- 25035845 TI - Top 20 cited Spine Journal articles, 1990-2009. AB - AIM: To determine the most cited articles and most published authors in Spine Journal from 1990-2009. METHODS: Spine Journal, established in 1976, is affiliated with 12 spine societies and a leader in spine research articles. Citation analysis is a method to determine the impact of a journal and its articles on academia and clinical practice. Using the Institute for Scientific Information Web of Knowledge, we determined the most cited articles in Spine Journal between1990-2009. The characteristics and type of article were recorded. Next, we evaluated the most published authors during the same time period and calculated the number of citations for each author. The number of first authorships for each of these authors was also determined along with the number of citations for those articles. RESULTS: The top 20 cited articles range from 491 to 267 total citations. The top 20 published authors had between 41 and 135 articles. Seventeen of the top 20 articles were clinical studies. The range of citations per lead authorship ratio was 36 to 724 with one author having no lead authorships. Low back pain was the most common theme encountered in the top cited articles. The first-ranked article was not a spine-specific topic rather it was regarding general physical and mental health status survey update review. CONCLUSION: Spine Journal and its authors have a clear impact on the scientific community based on this review of the top articles and authors in the last 20 years. PMID- 25035846 TI - Delayed presentation of a loose body in undisplaced paediatric talar neck fracture. AB - Fractures of the talus are rare in children. A high index of suspicion is needed to avoid missing such an injury, which is not an uncommon occurrence especially with undisplaced fractures. We present an unusual case of an undisplaced talar neck fracture in a five-year-old child leading to a delayed presentation of a symptomatic osteochondral loose body in the ankle joint. To our knowledge there are no reports in the literature of osteochondral loose bodies occurring in conjunction with an associated undisplaced talar neck fracture in either children or adults. The loose body was removed using anterior ankle arthroscopy. The child had an uneventful post operative recovery and regained full range of movement and function of his ankle joint and was discharged at one year follow-up. We aim to highlight the need to have a low threshold to further evaluate symptomatic children after fracture healing of an undisplaced talar neck fracture for a possible associated loose body in the ankle joint. PMID- 25035847 TI - pH of soul: how does acid-base balance affect our cognition? AB - Respiratory Alkalosis due to changes in sympathetic hyperarousal during pathological emotional states can change our cognitive abilities. This occurs through the effects of Alkalosis upon cerebral vasoconstriction and the amount of ionized calcium in the serum. The effects on our cognition and "sense of self " could be considerable. PMID- 25035849 TI - Chemical composition and in vitro antioxidant and antibacterial activity of Heracleum transcaucasicum and Heracleum anisactis roots essential oil. AB - INTRODUCTION: In vitro antioxidant and antibacterial activity and volatile compositions of two Heracleum species (Apiaceae) including Heracleum transcaucasicum and Heracleum anisactis roots Essential Oil (EO) were investigated. METHODS: The volatile compositions of EOs were analyzed by GC/Mass spectroscopy. To detect the antioxidant activity of essential oils TLC bioautography and DPPH radical scavenging assay by spectrophotometry was performed. Additionally, the antibacterial activity of two essential oils were studied and compared against four pathogenic bacteria by agar disc diffusion method and MIC values of the EOs were determined using the broth dilution method. RESULTS: Myristicin was the dominant component in both EOs. It was identified as 96.87% and 95.15% of the essential oil composition of H. transcaucasicum and H. anisactis roots, respectively. The TLC-bioautography showed antioxidant spots in both EOs and IC50 of H. anisactis and H. transcaucasicum EO was found to be 54 MUg * ml (-1) and 77 MUg * ml (-1), respectively. Regarding the antimicrobial assay, H. anisactis EO exhibited weak to moderate antibacterial activity against gram-positive bacteria and also Escherichia coli, whereas the essential oil from H. transcaucasicum was inactive. CONCLUSION: Based on the results from this study, both tested EOs mainly consist of myristicin. Despite the presence of myristicin with known antibacterial property, the EO from H. transcacausicum showed no antibacterial activity. Thus it is supposed that the biological activity of plants is remarkably linked to the extracts' chemical profile and intercomponents' synergistic or antagonistic effect could play a crucial role in bioactivity of EOs and other plant extracts. PMID- 25035848 TI - Targeting tumor microenvironment: crossing tumor interstitial fluid by multifunctional nanomedicines. AB - INTRODUCTION: The genesis of cancer appears to be a complex matter, which is not simply based upon few genetic abnormalities/alteration. In fact, irregular microvasculature and aberrant interstitium of solid tumors impose significant pathophysiologic barrier functions against cancer treatment modalities, hence novel strategies should holistically target bioelements of tumor microenvironment (TME). In this study, we provide some overview and insights on TME and important strategies used to control the impacts of such pathophysiologic barriers. METHODS: We reviewed all relevant literature for the impacts of tumor interstitium and microvasculature within the TME as well as the significance of the implemented strategies. RESULTS: While tumorigenesis initiation seems to be in close relation with an emergence of hypoxia and alterations in epigenetic/genetic materials, large panoplies of molecular events emerge as intricate networks during oncogenesis to form unique lenient TME in favor of tumor progression. Within such irregular interstitium, immune system displays defective surveillance functionalities against malignant cells. Solid tumors show multifacial traits with coadaptation and self-regulation potentials, which bestow profound resistance against the currently used conventional chemotherapy and immunotherapy agents that target solely one face of the disease. CONCLUSION: The cancerous cells attain unique abilities to form its permissive microenvironment, wherein (a) extracellular pH is dysregulated towards acidification, (b) extracellular matrix (ECM) is deformed, (c) stromal cells are cooperative with cancer cells, (d) immune system mechanisms are defective, (e) non-integrated irregular microvasculature with pores (120-1200 nm) are formed, and (h) interstitial fluid pressure is high. All these phenomena are against cancer treatment modalities. As a result, to control such abnormal pathophysiologic traits, novel cancer therapy strategies need to be devised using multifunctional nanomedicines and theranostics. PMID- 25035850 TI - The effect of single dose of thymoquinone, the main constituents of Nigella sativa, in guinea pig model of asthma. AB - INTRODUCTION: In previous studies, the relaxant and antihistaminic effects of thymoquinone, the main constituents of Nigella sativa, have been demonstrated on guinea pig tracheal chains. In the present study, the prophylactic effect of (IP) single dose of thymoquinone on tracheal responsiveness and lung inflammation of guinea pig model of asthma was examined. METHODS: Thirty guinea pigs were randomly divided to 3 groups; control (C), sensitized (S) and pretreated group with (TQ); 3 mg/kg, IP (S+TQ). Tracheal responsiveness to methacholine and ovalbumin (OA), total and differential cell count in bronchoalveolar lavage, lung pathological changes and blood Interleukin 4(IL-4) and Interferon gamma (IFNgamma) level in three groups were measured. RESULTS: Increased tracheal responsiveness to methacholine and OA, lung lavage fluid white blood cell (WBC) and eosinophil count, IL-4 and IFN-gamma levels and pathological changes were seen in sensitized group in comparison to control group (p<0.001 to p<0.05). Decreased tracheal responsiveness to methacholine and OA, pathological changes and bronchoalveolar lavage eosinophil were observed in S+TQ group compared to S group (p<0.001 to p<0.05). However, tracheal responsiveness to methacholine and OA, contractility, bronchoalveolar lavage WBC and eosinophil and most of pathological changes in S+TQ group were significantly higher than those in controls (p<0.01 to p<0.05). CONCLUSION: These results showed the preventive effect of single dose of thymoquinone on guinea pig model of asthma. PMID- 25035851 TI - Effects of probiotic yogurt consumption on inflammatory biomarkers in patients with type 2 diabetes. AB - INTRODUCTION: The role of inflammatory cytokines in diabetes and its complications has been shown in some studies. The purpose of this study was to compare the effect of probiotic and conventional yogurt on inflammatory markers in patients with type 2 diabetes. METHODS: Forty-four patients with type 2 diabetes were participated in this randomized, double-blind controlled clinical trial and assigned to two intervention and control groups. The subjects in the intervention group consumed 300 g/d probiotic yogurt and subjects in the control group consumed 300 g/d conventional yogurt for 8 weeks. Anthropometric indices, dietary intakes, and serum levels of glucose, HbA1c, IL-6, TNF-alpha and hs-CRP were evaluated at the beginning and end of the intervention. RESULTS: For anthropometric indices and dietary intakes, no significant differences were seen within and between groups post intervention (p> 0.05). The consumption of probiotic yogurt caused significant decrease in HbA1c and TNF-alpha levels (p= 0.032 and p= 0.040, respectively) in the intervention group. CONCLUSION: It is suggested that probiotic yogurt may be used as an alternative prevention approach and treatment method to control diabetic complications. PMID- 25035852 TI - Numerical Simulation of the blood flow behavior in the circle of Willis. AB - INTRODUCTION: This paper represents the numerical simulation of blood flow in the circle of Willis (CoW). Circle of Willis is responsible for the oxygenated blood distribution into the cerebral mass. To investigate the blood behavior, two Newtonian and non-Newtonian viscosity models were considered and the results were compared under steady state conditions. METHODS: Methodologically, the arterial geometry was obtained using 3D magnetic resonance angiography (MRA) data. The blood flow through the cerebral vasculature was considered to be steady and laminar, and the Galerkin's finite element method was applied to solve the systems of non-linear Navier-Stokes equations. RESULTS: Flow patterns including flow rates and shear rates were obtained through the simulation. The minimal magnitude of shear rates was much greater than 100 s(-1) through the larger arteries; thus, the non-Newtonian blood viscosity tended to approach the constant limit of infinite shear viscosity through the CoW. So, in larger arteries the non Newtonian nature of blood was less dominant and it would be treated as a Newtonian fluid. The only exception was the anterior communicating artery (ACoA) in which the blood flow showed different behavior for the Newtonian and non Newtonian cases. Conclusion By comparing the results it was concluded that the Newtonian viscosity assumption of blood flow through the healthy, complete circle of Willis under the normal and steady conditions would be acceptably accurate. PMID- 25035853 TI - Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent. AB - INTRODUCTION: Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. METHODS: In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. RESULTS: The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. CONCLUSION: This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians. PMID- 25035854 TI - Antioxidant activity of Syzygium cumini leaf gall extracts. AB - INTRODUCTION: Free radicals are implicated in several metabolic diseases and the medicinal properties of plants have been explored for their potent antioxidant activities to counteract metabolic disorders. This research highlights the chemical composition and antioxidant potential of leaf gall extracts (aqueous and methanol) of Syzygium cumini (S. cumini), which have been extensively used in traditional medications to treat various metabolic diseases. METHODS: The antioxidant activities of leaf gall extracts were examined using diphenylpicrylhydrazyl (DPPH), nitric oxide scavenging, hydroxyl scavenging and ferric reducing power (FRAP) methods. RESULTS: In all the methods, the methanolic extract showed higher antioxidant potential than the standard ascorbic acid. The presence of phenolics, flavonoids, phytosterols, terpenoids, and reducing sugars was identified in both the extracts. When compared, the methanol extract had the highest total phenolic and flavonoid contents at 474+/-2.2 mg of GAE/g d.w and 668+/-1.4 mg of QUE/g d.w, respectively. The significant high antioxidant activity can be positively correlated to the high content of total polyphenols/flavonoids of the methanol extract. CONCLUSION: The present study confirms the folklore use of S. cumini leaves gall extracts as a natural antioxidant and justifies its ethnobotanical use. Further, the result of antioxidant properties encourages the use of S. cumini leaf gall extracts for medicinal health, functional food and nutraceuticals applications. PMID- 25035855 TI - Distribution of HPV Genotypes and Involvement of Risk Factors in Cervical Lesions and Invasive Cervical Cancer: A Study in an Indian Population. AB - Human papilloma virus (HPV) is considered as the main sexually transmitted etiological agent for the cause and progression of preneoplastic cervical lesions to cervical cancer. This study is discussing the prevalence of HPV and its genotypes in cervical lesions and invasive cervical cancer tissues and their association with various risk factors in women from Varanasi and its adjoining areas in India. A total of 122 cervical biopsy samples were collected from SS Hospital and Indian Railways Cancer Institute and Research Centre, Varanasi and were screened for HPV infection by PCR using primers from L1 consensus region of the viral genome. HPV positive samples were genotyped by type-specific PCR and sequencing. The association of different risk factors with HPV infection in various grades of cervical lesion was evaluated by chi-square test. A total of 10 different HPV genotypes were observed in women with cervicitis, CIN, invasive squamous cell cervical carcinoma and adenocarcinoma. Increased frequency of HPV infection with increasing lesion grade (p=0.002) was observed. HPV16 being the predominant type was found significantly associated with severity of the disease (p=0.03). Various socio- demographic factors other than HPV including high parity (p<0.0001), rural residential area (p<0.0001), elder age (p<0.0001), low socio economic status (p<0.0001) and women in postmenopausal group (p<0.0001) were also observed to be associated with cervical cancer.These findings show HPV as a direct cause of cervical cancer suggesting urgent need of screening programs and HPV vaccination in women with low socio-economic status and those residing in rural areas. PMID- 25035856 TI - Human fibroblast switches to anaerobic metabolic pathway in response to serum starvation: a mimic of warburg effect. AB - Fibroblasts could be considered as connective tissue cells that are morphologically heterogeneous with diverse functions depending on their location and activity. These cells play critical role in health and disease such as cancer and wound by Production of collagen, fibronectin, cytokines and growth factors. Absence of insulin and other growth factors in serum deprivation condition and similarity of this condition to the environment of tumor cells and ulcer made us to investigate anaerobic glycolysis in these cells. To this end, we cultured fibroblasts isolated from fresh human newborn foreskin in serum free medium for 16, 24, 48 and 72 hrs and measured glucose consumption, lactate secretion and intracellular LDH in these cells. The results showed despite the lack of insulin, the 16hr serum starved fibroblasts consumed glucose similar to non-starved fibroblasts control. Moreover, in this condition these cells secreted higher levels of lactate and exhibited higher levels of intracellular LDH in comparison to non-starved fibroblasts control. Thus it could be concluded that in serum starvation condition, the newborn human dermal fibroblasts may change the metabolic strategy to Warburg effect. This finding opens a new perspective to further understanding the basic mechanisms involved in communication between tumor cells and fibroblasts. PMID- 25035857 TI - Effect of zinc-deficient diet on oral tissues and periodontal indices in rats. AB - Zinc (Zn) as a nutritional factor affects the health of the oral tissues. This study was done for the evaluation of the effects of zinc deficiency on the oral tissues of rats. The study was carried out on 14 male Wistar rats, cessation of lactation on the 24(th) day after birth. The rats were randomly divided into two groups. Zinc deficient (ZD) diet was used for one group and another group was fed with a zinc-containing (ZC) diet. The alterations of the oral tissues in both groups were evaluated clinically after four weeks. Also the gingival index and periodontal pocket depth were recorded. The measurement of serum zinc level was done by atomic absorption spectrophotometry. The microscopic slides of oral tissue specimen were evaluated quantitatively. The serum zinc level of the ZD rats was lower than the ZC group (p< 0.001). According clinical findings, the gingival index was lower in ZC rat (p=0.001), but there was no significant difference regarding the periodontal pocket depth between two groups (p=0.07). Aphthous ulcer was observed in ZD rats on the floor of the mouth. There was no significant difference regarding the epithelial and keratin thickening between two groups. This study indicated that oral and periodontal health was better in ZC rats than in ZD rats. Aphthous lesions were more prominent in ZD rats. This study confirmed that zinc deficiency may endanger oral and periodo ntal structures. PMID- 25035858 TI - Fetal Vegf Genotype is More Important for Abortion Risk than Mother Genotype. AB - VEGF gene has been reported to be related with many diseases and recurrent pregnancy loss in various studies. Concerning the role of VEGF polymorphisms in pregnancy losses, generally mothers genotypes have been analyzed. To evaluate the association between VEGF A +405G/C (rs2010963), -460T/C (rs833061), +936C/T (rs3025039) and - 2578A/C (rs699947) polymorphisms and spontaneous abortion, we studied the genotypes of spontaneously aborted fetuses, their mothers and healthy controls. 23 spontaneously aborted fetal materials, 22 mothers who had these abortions and 86 healthy controls were included in this study. rs2010963, rs833061, rs3025039 and rs699947 polymorphisms were analyzed by Real Time PCR technique after genomic DNA isolation from all subjects. The frequencies of VEGF A rs2010963 GG genotype and rs2010963 G allele were higher in fetuses compared both with mothers and healthy controls. VEGF A rs3025039 TT genotype and rs3025039 T allele frequencies were higher in fetuses comparing with mothers. VEGF A rs833061 CT and TT genotypes frequencies were higher in fetuses comparing with mothers. We ascertained that VEGF A rs2010963, rs833061 and rs3025039 are the risk factors for spontaneous abortion in fetal genotypes comparing with their mothers and healthy controls. PMID- 25035859 TI - UBE2Q1, as a Down Regulated Gene in Pediatric Acute Lymphoblastic Leukemia. AB - Ubiquitin - proteasome system (UPS), the major protein degradation pathway in the cells, typically degrades short - lived and damaged proteins and regulates growth and stress responses. This pathway is altered in various cancers, including Acute Lymphoblastic Leukemia (ALL). ALL begins with a change in bone marrow cells and is the most common type of leukemia in children under 15 years. UBE2Q1 as a new characterized gene of E2 enzyme family is located on chromosome 1 and reported to be altered in some malignancies. In this study, we aimed to explore the expression pattern of UBE2Q1 gene in children with ALL. For this purpose, a series of RT - PCR and quantitative RT - PCR were performed on a collection of 20 bone marrow samples of ALL patients and the same number of whole blood samples of age - matched normal subjects. Gel electrophoresis of RT - PCR products revealed the expression of UBE2Q1 mRNA in most of the normal (90%) and about half of the leukemic (45%) samples. QRT - PCR data indicated that only 1 patient out of 20 (5%) showed up regulation of the gene (> 2 folds). In 4 patients (20%), the expression of UBE2Q1 mRNA was equivocal (from 1/2 to 2) and in 15 cases (75%), the gene was down regulated (> 1/2) when compared to the normal samples. In conclusion, down regulation of UBE2Q1 in the majority of the leukemic samples suggests its potential implication in the pathogenesis of ALL. UBE2Q1 can be considered as a molecular marker and a candidate targeting to treat ALL in the future. PMID- 25035860 TI - Total Phenolic and Flavonoid Contents of Aqueous Extract of Stinging Nettle and In Vitro Antiproliferative Effect on Hela and BT-474 Cell Lines. AB - Phenolic compounds including flavonoids and phenolic acids are plants secondary metabolites. Due to their ability to act as antioxidant agents, there is a growing interest to use those components in traditional medicine for cancer prevention or treatment. The aim of this study was to measure the amounts of total phenolics and flavonoids as well as anti-proliferative effect of aqueous extract of Stinging nettle on BT-474 and Hela cell lines. The amounts of phenolics content and total flavonoids were determined by folin ciocalteu and aluminium chloride methods, respectively. The free radical scavenging activity was measured by using diphenyl - picrylhydrazyl (DPPH). The reducing power of the extract was measured in the presence of potassium hexacyanoferrate and its antiproliferative activity was assessed on BT-474 and Hela cell lines using MTT assay. Total phenolic content was 322.941+/- 11.811 mg gallic acid/g extract. Total flavonoid content was 133.916+/-12.006 mg Catechin/g. The IC50 of DPPH radical was 1.2 mg/ ml and the reducing power was 218.9+/- 15.582 MUg ascorbic acid/ g. Cell viability of BT-474 cells decreased to less than half of the control (no added extract) at the presence of 3 mg/ ml extract while no significant changes were detected for Hela cells at similar conditions. There was no significant difference in the percentage of surviving cells between consecutive days (day 1, 2 and 3) for both BT-474 and Hela cells (P>0.05). Although the relatively high amount of phenolic and flavonoid contents of the aqueous extract make this plant a promising candidate for diseases treatment; however, there is not a direct relationship between the amounts of these antioxidant components and the efficiency in in vitro cancer treatment. PMID- 25035861 TI - Effect of shiga toxin and its subunits on cytokine induction in different cell lines. AB - Shiga toxins (Stxs) are bacterial virulence factors produced by Shigella dysenteriae serotype 1 and Escherichia coli strains. Stxs are critical factors for the development of diseases such as severe bloody diarrhea and hemolytic uremic syndrome. Additionally, Stxs trigger the secretion of pro- inflammatory cytokines and chemokines, particularly in monocytes or macrophages. The inflammatory cytokines result in the modulation of the immune system, local inflammations and enhancement of cytotoxicity. In this study, stimulation of the pro- inflammatory cytokines IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha was assessed by recombinant Stx (rStx) and its subunits (rStxA and rStxB). Cytokines expression at mRNA level was investigated by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method in HeLa cells and THP1 monocyte/ macrophage cell lines. After incubation with rStx and its recombinant subunits, the expression of IL-1alpha, IL- 6 and IL- 8 mRNAs was strongly induced in HeLa cells. In HeLa cells, low expression of IL-1alpha mRNA was shown by rStxB induction. Furthermore, the expression of IL-1alpha and IL-1beta mRNAs in undifferentiated THP1 cells was only induced by rStx. In differentiated THP1 cells, rStx and its recombinant subunits elicited the expression of IL-1alpha, IL-1beta, IL-8 and IL- 6 mRNAs. On the other hand, expression of TNF-alpha mRNA was only induced by rStx. Based on the data, the profile of cytokine induction in response to the rStx, and its subunits differs depending on the cell types. PMID- 25035862 TI - Tissue culture study of the medicinal plant leek (allium ampeloprasum L). AB - Persian shallot, also called leek (Allium ampeloprasum), is a monocotyledon plant of the lily family (Liliaceae). It belongs to the genus Allium, has a characteristic taste and morphological features, making it to be considered as one of the popular herbal medicine. This research was conducted with the purpose of obtaining optimal conditions for tissue culture of Persian shallot and comparing its active ingredient production in vitro versus in vivo. In this study, the auxin 2, 4-D and benzyl aminopurine- 6 (BAP) hormones, each at two concentrations (0.5 and 0.1 mg/ L) and Kin at 0.5 mg/ L were used in the format of a randomized complete block design in three replications. Results showed that the best culture media for callus formation for leaf and seed explants were the MS cultures with the hormonal compositions (0.5 mg/ L of 2, 4- D, 0.1 mg/ L of BAP) and (0.5 mg/ L of Kin and 0.1 mg/ L of 2, 4- D). Identification of the chemical composition of the essential oils, extracted either from leek callus or leaf was carried out using GC mass analysis. Twenty one compounds were detected in the GC mass spectra, seven of which constitutv about 51.5% of the total amount of compounds present in the essential oils were identified. Our data demonstrate that the leek essential oil constituents as well as callus formation can be affected by culture medium condition. PMID- 25035863 TI - Screening of Different Organs of Rats for HCA2 Receptor mRNA. AB - Interest in hydroxy - carboxylic acid 2 (HCA2) receptor has been raised since it is the target of antidyslipidemic drug nicotinic acid. The present study aimed to evaluate the presence of mRNA of this receptor in different organs of laboratory rat. Twenty two different organs of rats including mesenteric fat, epididymis (head, body and tail), testis, ovary, xiphoid process, liver, adrenal gland, femoral head, proximal epiphyseal and metaphyseal bone marrow of femur, esophagus, glandular stomach, forestomach, intestines, colons, heart, spleen, kidney, trachea, lung, skeletal muscle (quadriceps), cerebrum and cerebellum were removed and examined for HCA2 mRNA by RT- PCR method. The mRNA for HCA2 receptor was detected in all analyzed tissues. In conclusion, the different organs of rat express HCA2 receptor mRNA which makes a proper animal model for future studies on the physiological and pharmacological roles of this receptor in vivo. PMID- 25035865 TI - Fast and Accurate Calculation of Protein Depth by Euclidean Distance Transform. AB - The depth of each atom/residue in a protein structure is a key attribution that has been widely used in protein structure modeling and function annotation. However, the accurate calculation of depth is time consuming. Here, we propose to use the Euclidean distance transform (EDT) to calculate the depth, which conveniently converts the protein structure to a 3D gray-scale image with each pixel labeling the minimum distance of the pixel to the surface of the molecule (i.e. the depth). We tested the proposed EDT method on a set of 261 non-redundant protein structures. The data show that the EDT method is 2.6 times faster than the widely used method by Chakravarty and Varadarajan. The depth value by EDT method is also highly accurate, which is almost identical to the depth calculated by exhaustive search (Pearson's correlation coefficient~1). We believe the EDT based depth calculation program can be used as an efficient tool to assist the studies of protein fold recognition and structure-based function annotation. PMID- 25035866 TI - New surgical technique for ventral penile curvature without circumcision. AB - OBJECTIVES: To describe and report on our variant of penile corporoplasty, the 'double-breasted' corporoplasty, with penoscrotal and infrapubic access not requiring circumcision. The medicolegal aspects of treatment are also discussed. PATIENTS AND METHODS: Between February 1995 and October 2012, double-breasted corporoplasty was performed in 93 patients with congenital ventral penile curvature. Preoperative assessment comprised RigiScan monitoring, prostaglandin E1 injection with photographic documentation and measurement of penile angulation, administration of the International Index of Erectile Function-5 (IIEF-5) questionnaire, and biothesiometry up until 5 years ago when it was substituted with the Genito Sensory Analyser for testing sensitivity. Dorsal infrapubic access was used in the patients with ventral curvature. After preparation and incision of Colles' fascia, the penis is degloved and double breasted corporoplasty is performed at the site established at preoperative assessment. The tunica albuginea is prepared, an incision is made, and the cavernous tissue is isolated from the albuginea to obtain two flaps that are then overlaid and sutured asymmetrically with interrupted 2-0 polyglactin 910 (Vicryl(r)) sutures. After the free edge of the albuginea is sutured with a running polyglactin 910 suture, a non-absorbable monofilament and uncoated suture made of polypropylene (Premicron(r)) suture is placed at the point of maximum traction. RESULTS: Complete correction of penile curvature was achieved in 96% of patients; recurrence occurred in 4%. No major complications were reported, nor were there neurovascular lesions or change in erectile function. Palpable subcutaneous irregularities at the site of the corporoplasty, without functional or aesthetic impairment, were reported by 35% of patients. There was no change in the appearance of the penis as circumcision was not performed and the residual scar was barely noticeable as it was hidden in the infrapubic fold. The corporoplasty technique can adequately restore the patient's psychophysical integrity, making it, from a medicolegal perspective, one of the most reliable procedures in the surgical repair of penile curvature. CONCLUSIONS: This original technique is associated with low morbidity, a low recurrence rate and excellent aesthetic results. The results show that it is safe and effective. When indicated for the surgical treatment of penile curvature, the choice of the technique satisfies the criteria of diligence and prudence for the surgeon's conduct. PMID- 25035867 TI - Janet Davison Rowley, M.D. (1925-2013). PMID- 25035864 TI - Organomatics and organometrics: Novel platforms for long-term whole-organ culture. AB - Organ culture systems are instrumental as experimental whole-organ models of physiology and disease, as well as preservation modalities facilitating organ replacement therapies such as transplantation. Nevertheless, a coordinated system of machine perfusion components and integrated regulatory control has yet to be fully developed to achieve long-term maintenance of organ function ex vivo. Here we outline current strategies for organ culture, or organomatics, and how these systems can be regulated by means of computational algorithms, or organometrics, to achieve the organ culture platforms anticipated in modern-day biomedicine. PMID- 25035868 TI - Calcineurin inhibitors suppress the high-temperature stress sensitivity of the yeast ubiquitin ligase Rsp5 mutant: a new method of screening for calcineurin inhibitors. AB - The ubiquitin/proteasome system plays significant and important roles in the regulation of metabolism of various proteins. The dysfunction of this system is involved in several diseases, for example, cancer, neurogenic diseases and chronic inflammation. Therefore, the compounds, which regulate the ubiquitin/proteasome system, might be candidates for the development use as clinical drugs. The Saccharomyces cerevisiae mutant (rsp5(A401E)) has a single amino acid change, Ala401Glu, in the RSP5 gene, which encodes an essential E3 ubiquitin ligase, is hypersensitive to high-temperature stress. Here, we found that the immunosuppressants FK506 and cyclosporin A, both known as calcineurin inhibitors, complemented the high-temperature stress-induced growth defect of rsp5(A401E) strain. The defect of calcineurin pathway by disrupting the CNB1 and CRZ1 gene also partially complemented the high-temperature stress sensitivity of rsp5(A401E) cells. Thus, these results suggest that inhibition of the calcineurin pathway confers the tolerance to high-temperature stress on rsp5(A401E) cells. Furthermore, some diterpenoid compounds, which restore the growth of rsp5(A401E) cells, showed the activities of calcineurin inhibition and protein phosphatase 2C activation. These results indicate that calcineurin inhibitors suppress the high temperature stress sensitivity of rsp5(A401E) cells and that analysis of their physiological function is effective for the screening of calcineurin inhibitors in yeast cells. PMID- 25035869 TI - Regulation of Saccharomyces cerevisiae MEF1 by Hda1p affects salt resistance of bdf1Delta mutant. AB - Bromodomain factor 1 (Bdf1p) is a transcriptional regulator. The absence of Bdf1p causes salt sensitivity with abnormal nucleus and mitochondrial dysfunction. In this study, we reported that the salt sensitivity, mitochondrial dysfunction, and nuclear instability of bdf1Delta mutant were suppressed by HDA1 deletion or MEF1 overexpression. Hda1p overexpression inhibited the relieving effects of low-copy overexpression of MEF1. Further analysis showed that Bdf1p regulated HDA1 transcription positively by binding to its promoter at -201 to +6 bp, whereas Hda1p modulated MEF1 expression negatively by binding to its promoter at -201 to +6 bp. These results suggested that Bdf1p likely regulated MEF1 expression negatively by regulating HDA1 positively. Mitochondrial proteomics analysis showed that the expression levels of six mitochondrial proteins were significantly changed by MEF1 overexpression. Among the six genes, over expression of PDB1, ILV5, or ATP2 partially recovered the salt stress sensitivity of bdf1Delta. However, none of these mitochondrial proteins could recover mitochondrial respiration indicating that the individual functional proteins could not replace Mef1p activity. It indicated that positive regulation of MEF1 was important in recovering the salt sensitivity of bdf1Delta mutant. PMID- 25035870 TI - Three Agt1 transporters from brewer's yeasts exhibit different temperature dependencies for maltose transport over the range of brewery temperatures (0-20 degrees C). AB - Zero-trans rates of maltose transport by brewer's yeasts exert strong control over fermentation rates and are strongly temperature-dependent over the temperature range (20-0 degrees C) of brewery fermentations. Three alpha glucoside transporters, ScAgt1(A60) (a Saccharomyces cerevisiae version of Agt1 from an ale strain), ScAgt1-A548V (a variant of ScAgt1(A60) with a single amino acid change in a transmembrane domain), and SbAgt1 (a Saccharomyces (eu)bayanus version from a lager strain), were compared. When expressed in the same laboratory yeast, grown at 24 degrees C and assayed at 0, 10, and 20 degrees C, SbAgt1 had the lowest absolute maltose uptake activity at 20 degrees C but smallest temperature dependence, ScAgt1-A548V had the highest activity but greatest temperature dependence, and ScAgt1(A60) had intermediate properties. ScAgt1(A60) exhibited higher absolute rates and smaller temperature dependencies when expressed in laboratory rather than brewer's strains. Absolute rates closely reflected the amounts of GFP-tagged ScAgt1(A60) transporter in each host's plasma membrane. Growth at 15 degrees C instead of 24 degrees C decreased the absolute activities of strains expressing ScAgt1(A60) by two- to threefold. Evidently, the kinetic characteristics of at least ScAgt1(A60) depended on the nature of the host plasma membrane. However, no consistent correlation was observed between transport activities and fatty acid or ergosterol compositions. PMID- 25035871 TI - Chest X-ray quiz. A left basal intercostal catheter has been inserted. PMID- 25035872 TI - Aspirin still overprescribed for stroke prevention in atrial fibrillation. PMID- 25035873 TI - Septic shock in infective endocarditis. PMID- 25035874 TI - Innovation in atrial fibrillation therapy. PMID- 25035875 TI - The carcinogenicity of outdoor air pollution. PMID- 25035876 TI - Comments from Dr. Jerker Ronnberg, Mary Rudner, Thomas Lunner. PMID- 25035877 TI - Comment from Dr. Arthur Wingfield. PMID- 25035878 TI - [Routine HIV screening in emergency departments is cost-effective but requires motivation from the medical staff]. PMID- 25035879 TI - [Gene therapy in HIV infection: proof-of-concept in 12 patients]. PMID- 25035880 TI - Professor Schreiber - a pioneer in TRH research. PMID- 25035881 TI - Interdisciplinary research: Break out. PMID- 25035882 TI - Do you "like" my photo? Facebook use maintains eating disorder risk. AB - OBJECTIVE: Social media sites, such as Facebook, merge two factors that influence risk for eating disorders:media and peers. Previous work has identified cross sectional and temporal associations between Facebook use and disordered eating. This study sought to replicate and extend these findings using an experimental design. METHOD: In Study 1, 960 women completed self-report surveys regarding Facebook use and disordered eating. In Study 2, 84 women were randomly assigned to use Facebook or to use an alternate internet site for 20 min. RESULTS: More frequent Facebook use was associated with greater disordered eating in a cross sectional survey. Facebook use was associated with the maintenance of weight/shape concerns and state anxiety compared to an alternate internet activity. DISCUSSION: Facebook use may contribute to disordered eating by maintaining risk for eating pathology. As such, targeting Facebook use may be helpful in intervention and prevention programs. PMID- 25035883 TI - [Nonmotor signs of Parkinson's disease]. AB - The article reviews the literature on some nonmotor symptoms. Sections of the paper are devoted to depression, anxiety, apathy, cognitive dysfunction, psychotic signs, sleep disorders, pain, olfactory disorders. PMID- 25035884 TI - Unwavering dedication. Dr Grace Lau Yuk-fung and Dr Paul Wong Kin-shing--their endeavour for better medical service in Cambodia. PMID- 25035885 TI - [Antipsychotic drugs and their influence on the carbohydrate metabolism in patients with schizophrenia-spectrum disorders]. AB - The effect of antipsychotic drugs, typical and atypical neuroleptics, is described in the following sections of this paper: antipsychotic drugs and carbohydrate metabolism, prevention and risk factors, pharmacoepidemiology, treatment. It is concluded that neuroleptic treatment increases the risk of metabolic impairment. Mechanisms of this effect are not clear so far. Ethnicity, sex, age and features of the therapy may play a role. Clozapine, olanzapine, ziprasidone, sertindole and some typical neuroleptics are risk factors as well. Common glucose-reducing drugs as well as prevention of metabolic impairment and special behavioral training,including the control over the level of glycemia, are used in treatment of diabetes mellitus induced by neuroleptics. PMID- 25035886 TI - Reminiscence: artefacts from the Hong Kong Museum of Medical Sciences. Plombage treatment for pulmonary tuberculosis in Hong Kong. PMID- 25035887 TI - [Current conceptions about astrocyte reactivity in schizophrenia]. AB - Literature data of the last two decades are summarized. Based on the classic conceptions about structure and functions of astrocytes, the authors review further development of research concerning the role of astroglia in schizophrenia in the following aspects: astrocyte reactivity, ultrastructural astrocyte pathology, markers of gliosis and astrocyte activation in schizophrenia, effect of neuroleptics on astrocytes. In conclusion, the authors emphasize that current studies confirm the absence of astrogliosis in the brain of schizophrenic patients. At the same time, there is evidence of the active involvement of these cells in the pathological process. It is suggested that the astrocyte activation is associated with immune changes in schizophrenia. PMID- 25035888 TI - [Sleep disorders in epilepsy]. AB - The review of the literature on sleep disorders in epilepsy over the last two decades is presented. Paroxysmal phenomena of epileptic origin, nonepileptic paroxysms, antiepileptic drugs, polypragmasia and comorbid depression may affect sleep in epilepsy.Shortening of sleep time may cause seizures, hallucinations and depression because sleep plays an important role in the regulation of excitatory and inhibitory processes in the brain both in healthy people and in patients with epilepsy. According to the literature data, drugs (short treatment courses of hypnotics) or nonpharmacological methods should be used for treatment insomnia inpatients with epilepsy. PMID- 25035889 TI - Reply to Legates et al.: Negligible role of arctic cloud albedo changes in observed darkening. PMID- 25035890 TI - Reply to Murrell et al.: Noise matters. PMID- 25035891 TI - [Biodegradable polymers in medicine (main research directions and perspectives]. PMID- 25035892 TI - [Role of endothelium dysfunction in microcirculatory disorders by periodontal disease]. AB - This review presents the advanced data about the role endothelial dysfunction in the pathogenesis of inflammatory periodontal diseases. This article describes the mechanisms of endothelial cell damage. Special attention is paid to the role of endothelial dysfunction in the pathogenesis of local microcirculatory changes at inflammatory periodontal diseases. The modern notions of systemic endothelial dysfunction at periodontal tissues inflammation as a risk factor for several diseases. PMID- 25035893 TI - [Anesthesia and sedation by admixture of xenon-oxygen in dentistry. Part I]. AB - The modern out-patient dental treatment which is performed under combined anesthesia with of xenon-oxygen inhalations provides comfortable conditions for the doctor and the patient, effective anesthesia and safe level of the sedation controlled by dentist. PMID- 25035894 TI - [In memorial of outstanding soviet dentist and scientist V.Yu.Kurlyandskij (on the occasion of 105th anniversary]. PMID- 25035895 TI - Top-paid execs at publicly traded healthcare industry companies. Ranked by total compensation for 2013 as reported to the U.S. Securities and Exchange Commission. PMID- 25035896 TI - [Comorbidity profile of the Russian Northern fleet flying personnel disqualified for health reasons]. AB - Analysis of 202 medical histories of the Northern fleet naval pilots suggested the necessity to introduce the criteria of comorbidity number and formulation. It has been found that psychosomatic diseases (up to 60% of the cases) with the pathogenesis engendered by stress factor remain the leading cause for medical disqualification of Northern fleet naval pilots. The authors recommend changing over the nosologic diagnostics to physiological to optimize the aeromedical certification process. Probabilistic modeling of chronic pathology pathogenesis may be viewed as a foundation stone for programming as part of the pilots' anti risk rehabilitation technology. PMID- 25035897 TI - [Results of statistical analysis of the dynamics of ionizing radiation dose fields in the service module of the International Space Station in 2000-2012]. AB - The on-going 24th solar cycle (SC) is distinguished from the previous ones by low activity. On the contrary, levels of proton fluxes from galactic cosmic rays (GCR) are high, which increases the proton flow striking the Earth's radiation belts (ERB). Therefore, at present the absorbed dose from ERB protons should be calculated with consideration of the tangible increase of protons intensity built into the model descriptions based on experimental measurements during the minimum between cycles 19 and 20, and the cycle 21 maximum. The absorbed dose from GCR and ERB protons copies galactic protons dynamics, while the ERB electrons dose copies SC dynamics. The major factors that determine the absorbed dose value are SC phase, ISS orbital altitude and shielding of the dosimeter readings of which are used in analysis. The paper presents the results of dynamic analysis of absorbed doses measured by a variety of dosimeters, namely, R-16 (2 ionization chambers), DB8-1, DB8-2, DB8-3, DB8-4 as a function of ISS orbit altitude and SC phase. The existence of annual variation in the absorbed dose dynamics has been confirmed; several additional variations with the periods of 17 and 52 months have been detected. Modulation of absorbed dose variations by the SC and GCR amplitudes has been demonstrated. PMID- 25035898 TI - [Russian oxygen generation system "Elektron-VM": hydrogen content in electrolytically produced oxygen for breathing by International Space Station crews]. AB - The article presents the particulars of hydrogen content in electrolysis oxygen produced aboard the ISS Russian segment by oxygen generator "Elektron-VM" (SGK) for crew breathing. Hydrogen content was estimated as in the course of SGK operation in the ISS RS, so during the ground life tests. According to the investigation of hydrogen sources, the primary path of H2 appearance in oxygen is its diffusion through the porous diaphragm separating the electrolytic-cell cathode and anode chambers. Effectiveness of hydrogen oxidation in the SGK reheating unit was evaluated. PMID- 25035900 TI - [Human resources in the space activities (summary of the discussions at the XLVIIIth scientific readings in memory of K.E. Tsiolkovsky)]. PMID- 25035899 TI - [Modern instruments for electrocardiogram monitoring with wearable electrodes]. PMID- 25035901 TI - [on the results of the 61st International Congress of Aviation and Space Medicine]. PMID- 25035902 TI - [On commemoration of the 50th anniversary of the State Scientific Center of Russian Federation--Institute of Biomedical Problems of the Russian Academy of Sciences]. PMID- 25035903 TI - Ambulatory surgery-center procedures by state. Number of procedures per 100,000 population performed at Medicare-certified ASCs in 2012. PMID- 25035904 TI - Under-reporting of notifiable infectious disease hospitalizations: significant improvements in the Irish context. AB - Notification of infectious disease is essential for prompt public health action and epidemiological analysis. The aim of this study was to compare national hospitalization data to national notification data in order to assess if there was significant under-reporting of hospitalized notifiable infectious diseases in recent years in Ireland. All in-patient discharges from public hospitals in the Republic of Ireland from 2006 to 2011 with a principal diagnosis of a notifiable disease were compared with national notification data. It was found that only a potential 1.8% of extra notifications could have arisen due to these hospitalization events and would represent a tenfold reduction on a previous estimate of under-reporting in the Irish context. Viral meningitis, viral encephalitis, bacterial meningitis not otherwise specified and malaria were the most common diseases for which there were more hospitalizations than notifications reported. The results of this study support the conclusion that the reduction in under-reporting can mainly be accounted for by the introduction of laboratories as notifiers in conjunction with the roll out of the Computerized Infectious Disease Reporting system (CIDR). However, for the diseases highlighted, the notification data underestimates the true burden of disease and this has implications for understanding the epidemiology of these diseases. PMID- 25035905 TI - EPR line shifts and line shape changes due to Heisenberg spin exchange and dipole dipole interactions of nitroxide free radicals in liquids: 9. An alternative method to separate the effects of the two interactions employing 15N and 14N. AB - A method to separate the effects of Heisenberg spin exchange (HSE) and dipole dipole (DD) interactions on EPR spectra of nitroxide spin probes in solution by employing (15)N and (14)N nitroxide spin probes in parallel experiments is developed theoretically and tested experimentally. Comprehensive EPR measurements are reported of 4-oxo-2,2,6,6-tetramethylpiperidine-d16;1-(15)N-1-oxyl (perdeuterated (15)N Tempone; 15pDT), in 70 wt % aqueous glycerol as functions of concentration and temperature. The method, termed the relative broadening constant method (RBCM), is demonstrated by using the present results together with those in the literature that employed perdeuterated (14)N Tempone (14pDT) under identical conditions. In principle, the separation of DD and HSE is dependent on the model of diffusion and molecular-kinetic parameters; however, within present day experimental uncertainties, the RBCM method turns out to be insensitive to the model. The earlier methods to separate DD and HSE by measuring the dispersion component introduced by the two interactions shows general agreement with the RBCM; however, there are discrepancies larger than estimated uncertainties due to random errors. Thus, further support is found for Salikhov's recent theory of the effects of DD and HSE on EPR spectra (Appl. Magn. Reson. 2010, 38, 237); however, detailed confirmation is still lacking. The RBCM affords a possible approach to separate HSE and DD in spectra complicated by slow motion and/or overlap with other resonance lines, allowing the method to be used in situations more complicated than low-viscosity simple liquids. PMID- 25035906 TI - The Adolescent Community Reinforcement Approach (A-CRA) as a model paradigm for the management of adolescents with substance use disorders and co-occurring psychiatric disorders. AB - BACKGROUND: Integrated treatment for youth with substance use disorders (SUDs) and co-occurring psychiatric disorders is recommended; however, there are few studies that have evaluated integrated treatment approaches. METHODS: This paper includes a brief review of cognitive-behavioral and family therapies, since they have been demonstrated to be effective treatments for the disorders that commonly co-occur with substance use. It also describes how an integrated treatment paradigm has been implemented using one Empirically Supported Treatment, the Adolescent Community Reinforcement Approach (A-CRA). RESULTS: There is existing research that supports the use of several A-CRA procedures to treat substance use and commonly co-occurring psychiatric disorders. CONCLUSIONS: In the absence of further research, it is reasonable in the interim to train clinicians in treatments that incorporate components that have been found to be effective for both substance use and commonly co-occurring psychiatric disorders. These treatments can then be adapted as needed based on an individual youth's set of problems. Further research is needed to test treatments for various combinations of SUDs and psychiatric disorders (i.e., depression, trauma-related problems, conduct disorder/behavior problems, and attention-deficit/hyperactivity disorder [ADHD]). PMID- 25035908 TI - Vocational identity, positive affect, and career thoughts in a group of young adult central nervous system cancer survivors. AB - The aims of this study were as follows: (a) to compare levels of career thoughts and vocational identity between young adult childhood central nervous system (CNS) cancer survivors and noncancer peers and (b) to investigate the contribution of vocational identity and affect on career thoughts among cancer survivors. Participants included 45 young adult CNS cancer survivors and a comparison sample of 60 college students. Participants completed Career Thoughts Inventory, My Vocational Situation, and the Positive and Negative Affect Schedule. Multivariate analysis of variance and multiple regression analysis were used to analyze the data in this study. CNS cancer survivors had a higher level of decision-making confusion than the college students. Multiple regression analysis indicated that vocational identity and positive affect significantly predicted the career thoughts of CNS survivors. The differences in decision making confusion suggest that young adult CNS survivors would benefit from interventions that focus on providing knowledge of how to make decisions, while increasing vocational identity and positive affect for this specific population could also be beneficial. PMID- 25035907 TI - Notch signaling pathway activation in normal and hyperglycemic rats differs in the stem cells of visceral and subcutaneous adipose tissue. AB - The precise mechanisms underlying the differential function and cardiometabolic risk of white adipose tissue (WAT) remain unclear. Visceral adipose tissue (VWAT) and subcutaneous adipose tissue (SCWAT) have different metabolic functions that seem to be ascribed to their different intrinsic expansion capacities. Here we have hypothesized that the WAT characteristics are determined by the resident adipose-derived stem cells (ASCs) found in the different WAT depots. Therefore, our objective has been to investigate adipogenesis in anatomically distinct fat depots. ASCs from five different WAT depots were characterized in both healthy lean and diabetic obese rats, showing significant differences in expression of some of genes governing the stemness and the earlier adipogenic differentiation steps. Notch-target genes [Hes (hairy and enhancer of split) and Hey (hairy/enhancer of split related with YRPW motif) families] were upregulated in ASCs derived from visceral depots. Upon adipogenic differentiation, adipocyte cell markers were downregulated in ASCs from VWAT in comparison to ASCs from SCWAT, revealing a lower adipogenic capacity in ASCs of visceral origin than in those of SCWAT in accordance with the differential activation of Notch signaling. Notch upregulation by its activator phenethyl isothiocyanate attenuated the adipogenic differentiation of ASCs from SCWAT whereas Notch inhibition by N-[N (3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) increased the adipogenic differentiation of ASCs from visceral origin. In conclusion, the differential activation of Notch in ASCs is the origin of the different intrinsic WAT expansion capacities that contribute to the regional variations in WAT homeostasis and to its associated cardiometabolic risk. PMID- 25035909 TI - Validation of the Comprehensive ICF Core Set for Stroke by exploring the patient's perspective on functioning in everyday life: a qualitative study. AB - International Classification of Functioning, Disability and Health (ICF) core sets are short procedures to record and provide information on health. However, further validation is needed. The aim of this study was to validate the Comprehensive ICF Core Set for stroke by exploring the patient's living at home and receiving outpatient rehabilitation perspective on functioning in everyday life. Qualitative interviews of 22 patients with previous stroke in Finland were analyzed using the content analysis method: functional concepts that described the participants' perspective on functioning in everyday life were extracted from the interview transcripts and linked to ICF categories using ICF linking rules. Extracted functional concepts from 372 meaning units were linked to 115 of the 166 categories included in the Comprehensive ICF Core Set for stroke and to six additional ICF categories. Thirty-eight concepts could not be linked to the ICF categories. Sixty-eight percent of the second-level ICF categories in the Comprehensive ICF Core Set for stroke were validated. In total, 28 of 36 categories added to the Comprehensive ICF Core Set for stroke from the Core Sets for patients with neurological conditions in the acute and early postacute phases were not confirmed in this sample of individuals with stroke living in their homes. PMID- 25035910 TI - Participants' evaluation of a brief intervention for pain-related work disability. AB - The aim of the study was to describe participants' evaluation of a light cognitive-behavioral therapy-based intervention for pain-related work disability. The sample (n=33) participated in a 6-week program and had the following features: mean age was 41 years; 67% men; 54.5% back injury; 48.5% unskilled; and mean time lost from work was 16.6 months (range 2-161 months). A program evaluation form was completed. The program was reportedly helpful for improving pain self-management, activity levels, and work resumption. However, over 25% of the sample requested more time be spent on sleep strategies, relaxation, and anger and flare-ups management. It 'did not solve the pain problem'. Despite making gains in pain management, many participants continued to experience pain and desired to sleep better, relax more, and be distress and pain free. This ongoing suffering may be under recognized in a system that focuses on return-to work before full recovery. PMID- 25035911 TI - Evaluation of stem injection for managing giant reed (Arundo donax). AB - Giant reed is an emergent aquatic plant that may be weedy in riparian habitats. Two herbicides approved for controlling giant reed in the US are glyphosate (N (phosphonomethyl) glycine) and imazapyr (2-[4,5-dihydro-4-methyl-4-(1 methylethyl)-5-oxo-1H-imidazol-2-yl]-3-pyridinecarboxylic acid). Foliar applications of these herbicides may be restricted in some areas, such as those, which are within the range of threatened or endangered species. We conducted two field experiments at sites in northern and central California. The first experiment evaluated the effects of three aquatic herbicides (glyphosate, imazapyr, and triclopyr [(3,5,6-trichloro-2-pyridinyl)oxy]acetic acid) injected into all of the stems within a giant reed (5 mL stem(-1)). In this experiment, leaf chlorophyll content, the proportion of living stems, and the number of new stems produced during the year after treatment declined (>80%) following injection of either full strength glyphosate or imazapyr. The effects of injecting full strength triclopyr were considerably less. In a second experiment, different proportions (0, 10%, 25%, or 100%) of the stems within a plant were injected with full strength glyphosate. Results indicated that it was necessary to inject all of the stems within a clump to achieve the greatest reduction in the plant growth characteristics measured. These results imply that giant reed may be successfully controlled by injecting full strength glyphosate (5 mL stem( 1)) into all of the stems within a clump. While labor intensive and thus potentially more costly this method, offers a new method for managing giant reed in sensitive sites where foliar spray applications may be restricted. PMID- 25035912 TI - Variability of Corylus avellana, L. CorA and profilin pollen allergens expression. AB - Corylus avellana is the source of inhalant allergies induced by hazel pollen as well as food allergies induced after ingestion of hazelnuts. In this study, real time PCR approach was used to analyse expression of hazel pollen allergens on the molecular level. Relative quantity of hazelnut allergens Corylus avellana, L. CorA and Corylus avellana, L. pollen profiling in samples from different Ukraine areas were determining and comparing. Differences among the levels of both analysed allergen transcripts were found for hazel CorA and profillin. In both cases, the expression within the urbanized growth conditions was higher when compared to the sample from village area. The average expression for CorA was 0.84 times higher than for profilin and the results are very variable depending on the place of growth. Expression levels here were within the range of 2.957 up to the 52.936. Profilin expression was the highest in the sample from the polluted place of growth-cement plant area with the value of 52 times higher when compared to the sample from the village area. In this study, comparison of expression levels of hazel CorA and profiling pollen allergens was performed for the first time. Real-time PCR assay developed in this study proved the sensitivity for detection of the changes of the hazel pollen allergens expression levels and could benefit labs by fast and reproducible detection method of these allergens. PMID- 25035913 TI - Enantioselective effects of herbicide imazapyr on Arabidopsis thaliana. AB - The enantioselective toxicity of chiral herbicides in the environment is of increasing concern. To investigate the enantioselective effects of the chiral herbicide imazapyr on target organisms, we exposed Arabidopsis thaliana to imazapyr enantiomers and racemate. The results show that imazapyr was enantioselectively toxic to A. thaliana. The total chlorophyll content in A. thaliana was affected more by (+)-imazapyr than (+/-)-imazapyr and (-)-imazapyr. Concentrations of proline and malondialdehyde reflected a toxic effect in the order of (+)-imazapyr > (+/-)-imazapyr > (-)-imazapyr at every concentration. Acetolactate synthase (ALS) activity was inhibited more by (+)-imazapyr than (+/ )-imazapyr or (-)-imazapyr. At 100 mg L(-1) of imazapyr, ALS activity was 78%, 43%, and 19% with (-)-, (+/-)-, and (+)-imazapyr, respectively. The results suggest the significant enantioselective toxicity of imazapyr in A. thaliana for greater toxicity with (+)-imazapyr than (+/-)-imazapyr and (-)-imazapyr, which suggests that (+)-imazapyr has more herbicidal effect. PMID- 25035914 TI - Use of molecular and in silico bioinformatic tools to investigate pesticide binding to insect (Lepidoptera) phenoloxidases (PO): insights to toxicological aspects. AB - In the present work, the promising bioinformatic tools, based on structure affinity analysis, allowed to screen several pesticides supposed to bind to the insect immune Phenoloxidases (PO). First, the binding of aminoparathion, a reference compound, to the PO was structurally (3D) validated in accordance with previous reports. Second, using the same docking conditions, a range of pesticides was checked for their binding ability to the crystal 3D structure (PDB 3HSS) of the insect Manduca sexta (Lepidoptera) PO. The obtained data showed that many of the tested pesticides were able to bind, in silico, to M. sexta PO. The combination of in vitro (chemical and biochemical) and in silico (automated docking) approaches was found advantageous to elucidate the behavior of phenolic pesticides as substrate-analogues when binding to the active site of insect POs. Our findings emphasize new ecotoxicological aspects of pesticide residues in the agro-chemical and environmental circles. PMID- 25035915 TI - Co-metabolic transformation of the neonicotinoid insecticide imidacloprid by the new soil isolate Pseudoxanthomonas indica CGMCC 6648. AB - A new imidacloprid (IMI) degrading bacterium Z-9 (deposited number CGMCC 6648) was isolated and identified as Pseudoxanthomonas indica by 16S rRNA gene analysis. Two metabolites were identified as olefin and 5-hydroxy IMI by liquid chromatography-mass spectrometry and nuclear magnetic resonance analysis. P. indica CGMCC 6648 degraded 70.1% of IMI (1.22 mmol L(-1)) and formed 0.93 mmol L( 1) 5-hydroxy IMI and 0.05 mmol L(-1) olefin IMI in 6 days and in the presence of 100 mmol L(-1) glucose. The half-life of IMI degradation was 3.6 days. P. indica CGMCC 6648 transforms IMI via a co-metabolism mechanism and different carbohydrates have significant effects on 5-hydroxy IMI formation, whereas different organic acids have substantial effects on olefin IMI production. Lactose is the best co-substrate for IMI degradation and 5-hydroxy IMI formation with 0.77 mmol L(-1) degraded and 0.67 mmol L(-1) formed in 48 h, respectively. Pyruvate is the best co-substrate for olefin IMI formation with 0.17 mmol L(-1) produced in 96 h for all carbon sources tested. Pyruvate significantly stimulates the conversion of 5-hydroxy IMI to olefin IMI, whereas glucose slightly inhibits this reaction. P. indica CGMCC 6648 rapidly degrades IMI and forms olefin IMI, which may enhance its potential for biodegradation of IMI and increase its insecticidal activity, which can decrease the IMI dosage required. PMID- 25035916 TI - Determination of 28 pesticides applied on two tomato cultivars with a different surface/weight ratio of the berries, using a multiresidue GC-MS/MS method. AB - The behavior of 28 pesticides on two tomato cultivars with a different surface/weight (S/W) ratio of the berries (S/W, Birikino vs. Tombola) was studied, in order to provide appropriate indications about their persistence on crops reaching the pre-harvest interval (PHI). Quantitative analysis was performed using a GC MS/MS method. Birikino cv. (BIR) was a "cherry type tomato" with a double S/W ratio compared with Tombola cv. (TOM). The results showed a different pesticide behavior. Azoxystrobin, Boscalid, Bupirimate, Difenoconazole, Etofenprox, Iprodione, Mepanipyrim, Myclobutanil, Tebuconazole, Zoxamide, Metalaxyl M, Pyrimethanil, Tetraconazole, Benalaxyl, Cyprodinil, Fenamidone, Famoxadone and Fludioxonil immediately after treatments showed residues on BIR higher than TOM, and this behavior is consistent with its greater exposed surface. BIR showed higher decay rates of these pesticides during the whole trial, nevertheless residue averages remained higher than TOM reaching the time of harvest. Residues at the PHI were all below their Maximum Residue Levels (MRLs), but data indicated that they could exceed their legal limits especially if the above-mentioned active ingredients were employed more than once per crop cycle on cherry type tomatoes. As regards to Chlorpyrifos, Chlorpyrifos methyl, Triadimenol, Pyridaben and Tebufenpyrad, no different residual behavior related to S/W ratio of the cultivars was observed. Even in this case, residues at the PHI were all below MRLs. As for Cyfluthrin, Deltamethrin, Lambda cyhalothrin, Etoxazole and Cyproconazole, residues were lower than the limit of quantitation (LOQ) of the analytical method just after the treatment, according to their low doses of employment. PMID- 25035917 TI - Thermal treatment for pathogen inactivation as a risk mitigation strategy for safe recycling of organic waste in agriculture. AB - Thermal treatment at temperatures between 46.0 degrees C and 55.0 degrees C was evaluated as a method for sanitization of organic waste, a temperature interval less commonly investigated but important in connection with biological treatment processes. Samples of dairy cow feces inoculated with Salmonella Senftenberg W775, Enterococcus faecalis, bacteriophage phiX174, and porcine parvovirus (PPV) were thermally treated using block thermostats at set temperatures in order to determine time-temperature regimes to achieve sufficient bacterial and viral reduction, and to model the inactivation rate. Pasteurization at 70 degrees C in saline solution was used as a comparison in terms of bacterial and viral reduction and was proven to be effective in rapidly reducing all organisms with the exception of PPV (decimal reduction time of 1.2 h). The results presented here can be used to construct time-temperature regimes in terms of bacterial inactivation, with D-values ranging from 0.37 h at 55 degrees C to 22.5 h at 46.0 degrees C and 0.45 h at 55.0 degrees C to 14.5 h at 47.5 degrees C for Salmonella Senftenberg W775 and Enterococcus faecalis, respectively and for relevant enteric viruses based on the phiX174 phage with decimal reduction times ranging from 1.5 h at 55 degrees C to 16.5 h at 46 degrees C. Hence, the study implies that considerably lower treatment temperatures than 70 degrees C can be used to reach a sufficient inactivation of bacterial pathogens and potential process indicator organisms such as the phiX174 phage and raises the question whether PPV is a valuable process indicator organism considering its extreme thermotolerance. PMID- 25035918 TI - Mercury in certain boletus mushrooms from Poland and Belarus. AB - This paper reports the results of the study of Hg contents of four species of Boletus mushroom (Boletus reticulatus Schaeff. 1763, B. pinophilus Pilat & Dermek 1973, B. impolitus Fr. 1838 and B. luridus Schaeff. 1774) and the surface soils (0-10 cm layer, ~100 g) samples beneath the mushrooms from ten forested areas in Poland and Belarus by cold-vapour atomic absorption spectroscopy. The ability of the species to bioconcentrate Hg was calculated (as the BCF) while Hg intakes from consumption of these mushroom species were also estimated. The median Hg content of the caps of the species varied between 0.38 and 4.7 mg kg(-1) dm; in stipes between 0.13 and 2.5 mg kg(-1) dm and in the mean Hg contents of soils varied from 0.020 +/- 0.01 mg kg(-1) dm to 0.17 +/- 0.10 mg kg(-1) dm which is considered as "background" Hg level. The median Hg content of caps of B. reticulatus and B. pinophilus were up to 4.7 and 3.6 mg kg(-1) dm, respectively, and they very efficiently bioaccumulate Hg with median BCF values of up to 130 for caps and 58 for stipes. The caps and stipes of these mushrooms if eaten will expose consumer to elevated dose of total Hg estimated at 1.4 mg for caps of Boletus reticulatus from the Kacze Legi site, which is a nature reserve area. Nevertheless, the occasional consumption of the valued B. reticulatus and B. pinophilus mushrooms maybe safe. PMID- 25035919 TI - Measuring and modeling nitrous oxide and methane emissions from beef cattle feedlot manure management: First assessments under Brazilian condition. AB - Intensive beef production has increased during recent decades in Brazil and may substantially increase both methane (CH(4)) and nitrous oxide (N(2)O) emissions from manure management. However, the quantification of these gases and methods for extrapolating them are scarce in Brazil. A case study examines CH(4) and N(2)O emissions from one typical beef cattle feedlot manure management continuum in Brazil and the applicability of Manure-DNDC model in predicting these emissions for better understand fluxes and mitigation options. Measurements track CH(4) and N(2)O emissions from manure excreted in one housing floor holding 21 animals for 78 days, stockpiled for 73 days and field spread (360 kg N ha(-1)). We found total emissions (CH(4) + N(2)O) of 0.19 +/- 0.10 kg CO(2)eq per kg of animal live weight gain; mostly coming from field application (73%), followed housing (25%) and storage (2%). The Manure-DNDC simulations were generally within the statistical deviation ranges of the field data, differing in -28% in total emission. Large uncertainties in measurements showed the model was more accurate estimating the magnitude of gases emissions than replicate results at daily basis. Modeled results suggested increasing the frequency of manure removal from housing, splitting the field application and adopting no-tillage system is the most efficient management for reducing emissions from manure (up to about 75%). Since this work consists in the first assessment under Brazilian conditions, more and continuous field measurements are required for decreasing uncertainties and improving model validations. However, this paper reports promising results and scientific perceptions for the design of further integrated work on farm-scale measurements and Manure-DNDC model development for Brazilian conditions. PMID- 25035920 TI - Nanoplasmonic biosensing for soft matter adsorption: kinetics of lipid vesicle attachment and shape deformation. AB - An indirect nanoplasmonic sensing platform is reported for investigating the kinetics of attachment and shape deformation associated with lipid vesicle adsorption onto a titanium oxide-coated substrate. The localized surface plasmon resonance (LSPR) originates from embedded gold nanodisks and is highly sensitive to the local lipid environment. To interpret the corresponding results, we have extended treatments of diffusion-limited adsorption kinetics and adsorbate related LSPR physics, identified the expected scaling laws for the LSPR-tracked kinetics measured at different lipid concentrations and/or nanometer-scale vesicle sizes in the case when vesicle deformation is negligible, and scrutinized experimental deviations accordingly. After adsorption, the smallest 58 nm diameter vesicles were found to maintain shape on the time scale of adsorption at high lipid concentrations in solution, and shape deformation became more appreciable at lower lipid concentrations. Higher saturation coverage was observed with increasing lipid concentration, which is attributed to the difference in relative time scales of vesicle attachment and deformation. For larger vesicles between 80 and 160 nm diameter, deviations associated with their shape deformation and correlations with the location of gold nanodisks became more apparent at moderate and high coverages. Taken together, the results obtained support that the quantitative measurement capabilities of nanoplasmonic biosensing should be considered for applications demanding highly surface sensitive characterization of soft matter adsorption and related phenomena at liquid-solid interfaces. PMID- 25035921 TI - Pyrazolopyrimidines establish MurC as a vulnerable target in Pseudomonas aeruginosa and Escherichia coli. AB - The bacterial peptidoglycan biosynthesis pathway provides multiple targets for antibacterials, as proven by the clinical success of beta-lactam and glycopeptide classes of antibiotics. The Mur ligases play an essential role in the biosynthesis of the peptidoglycan building block, N-acetyl-muramic acid pentapeptide. MurC, the first of four Mur ligases, ligates l-alanine to UDP-N acetylmuramic acid, initiating the synthesis of pentapeptide precursor. Therefore, inhibiting the MurC enzyme should result in bacterial cell death. Herein, we report a novel class of pyrazolopyrimidines with subnanomolar potency against both Escherichia coli and Pseudomonas aeruginosa MurC enzymes, which demonstrates a concomitant bactericidal activity against efflux-deficient strains. Radio-labeled precursor incorporation showed these compounds selectively inhibited peptidoglycan biosynthesis, and genetic studies confirmed the target of pyrazolopyrimidines to be MurC. In the presence of permeability enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar MIC against the wild-type bacteria, thereby, indicating permeability and efflux as major challenges for this chemical series. Our studies provide biochemical and genetic evidence to support the essentiality of MurC and serve to validate the attractiveness of target for antibacterial discovery. PMID- 25035922 TI - Molecular functionalization of graphite surfaces: basal plane versus step edge electrochemical activity. AB - The chemical functionalization of carbon surfaces has myriad applications, from tailored sensors to electrocatalysts. Here, the adsorption and electrochemistry of anthraquinone-2,6-disulfonate (AQDS) is studied on highly oriented pyrolytic graphite (HOPG) as a model sp(2) surface. A major focus is to elucidate whether adsorbed electroactive AQDS can be used as a marker of step edges, which have generally been regarded as the main electroactive sites on graphite electrode surfaces. First, the macroscopic electrochemistry of AQDS is studied on a range of surfaces differing in step edge density by more than 2 orders of magnitude, complemented with ex situ tapping mode atomic force microscopy (AFM) data. These measurements show that step edges have little effect on the extent of adsorbed electroactive AQDS. Second, a new fast scan cyclic voltammetry protocol carried out with scanning electrochemical cell microscopy (SECCM) enables the evolution of AQDS adsorption to be followed locally on a rapid time scale. Subsequent AFM imaging of the areas probed by SECCM allows a direct correlation of the electroactive adsorption coverage and the actual step edge density of the entire working area. The amount of adsorbed electroactive AQDS and the electron transfer kinetics are independent of the step edge coverage. Last, SECCM reactive patterning is carried out with complementary AFM measurements to probe the diffusional electroactivity of AQDS. There is essentially uniform and high activity across the basal surface of HOPG. This work provides new methodology to monitor adsorption processes at surfaces and shows unambiguously that there is no correlation between the step edge density of graphite surfaces and the observed coverage of electroactive AQDS. The electroactivity is dominated by the basal surface, and studies that have used AQDS as a marker of steps need to be revised. PMID- 25035923 TI - Resveratrol is not compatible with a Fura-2-based assay for measuring intracellular Ca2+ signaling. AB - Fura-2 is a commonly used fluorescent Ca(2+) dye that allows an accurate determination of cytosolic Ca(2+) levels by measuring the emission obtained at 510 nm after alternating excitation at 340 nm and 380 nm (F340/F380 ratio). Previous studies, based on Fura-2 measurements, claimed that resveratrol, a polyphenol implicated in human health, triggered an acute rise in cytosolic [Ca(2+)]. In this report, we show that the spectral properties of resveratrol are not compatible with the fluorescent properties of Fura-2. Resveratrol displays a strong absorption of light at a wavelength of 340 nm and a strong emission at 510 nm upon excitation at 340 nm (F340). As a consequence, the F340 values, but not the F380 values, are increased when incubating cells with resveratrol. Consequently the F340/F380 ratio values acutely increase upon addition of resveratrol, independently of changes in cytosolic [Ca(2+)]. Yet, we show that pretreating cells with resveratrol does not affect the F340/F380 ratios of Fura 2, provided that resveratrol is washed away before fluorescence measurement. These results indicate that Fura-2 is not suitable for assessing acute effects of resveratrol on Ca(2+) signaling but that long-time effects can be assessed, provided that the resveratrol is carefully removed by appropriate wash steps. PMID- 25035924 TI - Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells. AB - The invariant chain (CD74) mediates targeting of the MHCII complex to endosomal compartments, where CD74 undergoes degradation allowing MHCII to acquire peptides. We demonstrated recently that intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalyzed by Signal-peptide peptidase-like 2a (SPPL2a) and that this process is indispensable for development and function of B lymphocytes in mice. In SPPL2a(-/-) mice, homeostasis of these cells is disturbed by the accumulation of the unprocessed CD74 NTF. So far, evidence for this essential role of SPPL2a is restricted to mice. Nevertheless, inhibition of SPPL2a has been suggested as novel approach to target B cells for treating autoimmunity. Here, we characterize human B cell lines with a homozygous microdeletion on chromosome 15. We demonstrate that this deletion disrupts the SPPL2a genomic locus and leads to loss of SPPL2a transcript. Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a( /-) mice. By this means, we present evidence that the role of SPPL2a in CD74 proteolysis is conserved in human B cells and provide support for modulation of SPPL2a activity as a therapeutic concept. PMID- 25035925 TI - Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor alpha. AB - Interleukin (IL)-10 is a prototypical anti-inflammatory cytokine that has been shown to attenuate atherosclerosis development. In addition to its anti inflammatory properties, the anti-atherogenic effect of IL-10 has recently also been suggested to reflect a complex effect of IL-10 on lipid metabolism in macrophages. In the present study we examined the effects of IL-10 on cholesterol efflux mechanism in lipid-loaded THP-1 macrophages. Our main findings were: (i) IL-10 significantly enhanced cholesterol efflux induced by fetal-calf serum, high density lipoprotein (HDL)2 and apolipoprotein A-1. (ii) The IL-10-mediated effects on cholesterol efflux were accompanied by an increased IL-10-mediated expression of the ATP-binding cassette transporters ABCA1 and ABCG1, that was further enhanced when the cells were co-activated with the liver X receptor (LXR)alpha agonist (22R)-hydroxycholesterol. (iii) The effect of LXRalpha activation on the IL-10-mediated effects on the ATP-binding cassette transporters seems to include enhancing effects on the IL-10 receptor 1 (IL10R1) expression and interaction with STAT-3 signaling. (iv) These enhancing effects on ABCA1 and ABCG1 was not seen when the cells were stimulated with the IL-10 family members IL-22 and IL-24. This study suggests that the anti-atherogenic properties of IL 10 may include enhancing effects on cholesterol efflux mechanism that involves cross-talk with LXRalpha activation. PMID- 25035926 TI - Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy. AB - Little is known about role of PDE4 in the development and progression of diabetic nephropathy. Here, we investigated the effect of roflumilast, a selective PDE 4 inhibitor in type 1 diabetic nephropathy. Diabetes was induced in male Sprague Dawley rats using streptozotocin (55 mg/kg). Diabetic rats showed elevated plasma glucose, blood urea nitrogen, creatinine and decrease in plasma albumin confirming signs of nephropathy. Roflumilast at 2 and 3mg/kg normalized these alterations. Roflumilast also suppressed oxidative stress and deposition of an extracellular matrix protein such as fibronectin and collagen in kidney of diabetic rats. TUNEL assay revealed apoptosis in diabetic kidney than control and that roflumilast prevents this effect. We show that kidney of diabetic rats displayed a state of p-AMPK and SIRT1 deficiency and that roflumilast, interestingly, was able to restore their levels. Further, roflumilast prevented an increase in HO-1 and loss in the FoxO1 expression in diabetes. However, it did not improve the reduced NRF2 levels in diabetes. This is the first report to show that, like resveratrol and other SIRT1 activators, roflumilast also mimics calorie restriction effects through activation of AMPK/SIRT1 and protects against diabetic nephropathy. This study unveils the unexplored potential of roflumilast which can be used in treatment of metabolic disorders. PMID- 25035927 TI - Naturally-occurring tetrahydro-beta-carboline alkaloids derived from tryptophan are oxidized to bioactive beta-carboline alkaloids by heme peroxidases. AB - beta-Carbolines are indole alkaloids that occur in plants, foods, and endogenously in mammals and humans, and which exhibit potent biological, psychopharmacological and toxicological activities. They form from naturally occurring tetrahydro-beta-carboline alkaloids arising from tryptophan by still unknown way and mechanism. Results in this research show that heme peroxidases catalyzed the oxidation of tetrahydro-beta-carbolines (i.e. 1,2,3,4-tetrahydro beta-carboline-3-carboxylic acid and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3 carboxylic acid) into aromatic beta-carbolines (i.e. norharman and harman, respectively). This oxidation followed a typical catalytic cycle of peroxidases through redox intermediates I, II, and ferric enzyme. Both, plant peroxidases (horseradish peroxidase, HRP) and mammalian peroxidases (myeloperoxidase, MPO and lactoperoxidase, LPO) catalyzed the oxidation in an efficient manner as determined by kinetic parameters (VMAX and KM). Oxidation of tetrahydro-beta carbolines was inhibited by peroxidase inhibitors such as sodium azide, ascorbic acid, hydroxylamine and excess of H2O2. The formation of aromatic beta-carbolines by heme peroxidases can help to explain the presence and activity of these compounds in biological systems. PMID- 25035928 TI - Overexpression of TGF-beta1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells. AB - Transforming growth factor-beta (TGF-beta) superfamily proteins play a critical role in proliferation, differentiation, and other functions of mesenchymal stem cells (MSCs). During chondrogenic differentiation of MSCs, TGF-beta up-regulates chondrogenic gene expression by enhancing the expression of the transcription factor SRY (sex-determining region Y)-box9 (Sox9). In this study, we investigated the effect of continuous TGF-beta1 overexpression in human synovium-derived MSCs (hSD-MSCs) on immunophenotype, differentiation potential, and proliferation rate. hSD-MSCs were transduced with recombinant retroviruses (rRV) encoding TGF-beta1. The results revealed that continuous overexpression of TGF-beta1 did not affect their phenotype as evidenced by flow cytometry and reverse transcriptase PCR (RT PCR). In addition, continuous TGF-beta1 overexpression strongly enhanced cell proliferation of hSD-MSCs compared to the control groups. Also, induction of chondrogenesis was more effective in rRV-TGFB-transduced hSD-MSCs as shown by RT PCR for chondrogenic markers, toluidine blue staining and glycosaminoglycan (GAG)/DNA ratio. Our data suggest that overexpression of TGF-beta1 positively enhances the proliferation and chondrogenic potential of hSD-MSCs. PMID- 25035929 TI - PKCdelta regulates hepatic triglyceride accumulation and insulin signaling in Lepr(db/db) mice. AB - PKCdelta has been linked to key pathophysiological features of non-alcoholic fatty liver disease (NAFLD). Yet, our knowledge of PKCdelta's role in NAFLD development and progression in obese models is limited. PKCdelta(-/ )/Lepr(db)(/)(db) mice were generated to evaluate key pathophysiological features of NAFLD in mice. Hepatic histology, oxidative stress, apoptosis, gene expression, insulin signaling, and serum parameters were analyzed in Lepr(db)(/)(db) and PKCdelta(-/-)/Lepr(db)(/)(db) mice. The absence of PKCdelta did not abrogate the development of obesity in Lepr(db)(/)(db) mice. In contrast, serum triglyceride levels and epididymal white adipose tissue weight normalized to body weight were reduced in PKCdelta(-/-)/Lepr(db)(/)(db) mice compared Lepr(db)(/)(db) mice. Analysis of insulin signaling in mice revealed that hepatic Akt and GSK3beta phosphorylation were strongly stimulated by insulin in PKCdelta( /-)/Lepr(db)(/)(db) compared Lepr(db)(/)(db) mice. PKCdelta may be involved in the development of obesity-associated NAFLD by regulating hepatic lipid metabolism and insulin signaling. PMID- 25035930 TI - The role of wogonin in controlling SOCS3 expression in neuronal cells. AB - The mechanism underlying the wogonin-mediated increase in the expression of suppressor of cytokine signaling 3 (SOCS3) is unclear. Promoter deletion assay results revealed that wogonin-induced SOCS3 expression is dependent on the AP-1 consensus sequences and two STAT responsive elements (TTACAAGAA and TTCCAGGAA) in the 5'-flanking region of the SOCS3 gene in SH-SY5Y cells. Wogonin-induced SOCS3 expression was blocked by inhibitors of PI3K, Akt, Raf, p38, JNK, MEK, and STAT3, respectively. However, JAK2 inhibitors did not inhibit wogonin-induced SOCS3 expression. These results indicate that SOCS3-inducing effect of wogonin is caused by the activation of PI3K-mediated MAPK signaling pathways (Akt, ERK1/2, p38, and JNK), and the subsequent activation of AP-1 consensus sequences and STAT responsive elements in SH-SY5Y cells. PMID- 25035931 TI - Effects of dimethyl sulfoxide on lipid membrane electroporation. AB - Pores can be generated in lipid membranes by the application of an external electric field or by the addition of particular chemicals such as dimethyl sulfoxide (DMSO). Molecular dynamics (MD) has been shown to be a useful tool for unveiling many aspects of pore formation in lipid membranes in both situations. By means of MD simulations, we address the formation of electropores in cholesterol-containing lipid bilayers under the influence of DMSO. We show how a combination of physical and chemical mechanisms leads to more favorable conditions for generating membrane pores and, in particular, how the addition of DMSO to the medium significantly reduces the minimum electric field required to electroporate a lipid membrane. The strong alteration of membrane transversal properties and the energetic stabilization of the hydrophobic pore stage by DMSO provide the physicochemical mechanisms that explain this effect. PMID- 25035932 TI - Modular, multi-input transcriptional logic gating with orthogonal LacI/GalR family chimeras. AB - In prokaryotes, the construction of synthetic, multi-input promoters is constrained by the number of transcription factors that can simultaneously regulate a single promoter. This fundamental engineering constraint is an obstacle to synthetic biologists because it limits the computational capacity of engineered gene circuits. Here, we demonstrate that complex multi-input transcriptional logic gating can be achieved through the use of ligand-inducible chimeric transcription factors assembled from the LacI/GalR family. These modular chimeras each contain a ligand-binding domain and a DNA-binding domain, both of which are chosen from a library of possibilities. When two or more chimeras have the same DNA-binding domain, they independently and simultaneously regulate any promoter containing the appropriate operator site. In this manner, simple transcriptional AND gating is possible through the combination of two chimeras, and multiple-input AND gating is possible with the simultaneous use of three or even four chimeras. Furthermore, we demonstrate that orthogonal DNA-binding domains and their cognate operators allow the coexpression of multiple, orthogonal AND gates. Altogether, this work provides synthetic biologists with novel, ligand-inducible logic gates and greatly expands the possibilities for engineering complex synthetic gene circuits. PMID- 25035934 TI - Operational modelling to guide implementation and scale-up of diagnostic tests within the health system: exploring opportunities for parasitic disease diagnostics based on example application for tuberculosis. AB - Research and innovation in the diagnosis of infectious and parasitic diseases has led to the development of several promising diagnostic tools, for example in malaria there is extensive literature concerning the use of rapid diagnostic tests. This means policymakers in many low and middle income countries need to make difficult decisions about which of the recommended tools and approaches to implement and scale-up. The test characteristics (e.g. sensitivity and specificity) of the tools alone are not a sufficient basis on which to make these decisions as policymakers need to also consider the best combination of tools, whether the new tools should complement or replace existing diagnostics and who should be tested. Diagnostic strategies need dovetailing to different epidemiology and structural resource constraints (e.g. existing diagnostic pathways, human resources and laboratory capacity). We propose operational modelling to assist with these complex decisions. Projections of patient, health system and cost impacts are essential and operational modelling of the relevant elements of the health system could provide these projections and support rational decisions. We demonstrate how the technique of operational modelling applied in the developing world to support decisions on diagnostics for tuberculosis, could in a parallel way, provide useful insights to support implementation of appropriate diagnostic innovations for parasitic diseases. PMID- 25035933 TI - The role of homeobox genes in retinal development and disease. AB - Homeobox genes are an evolutionarily conserved class of transcription factors that are critical for development of many organ systems, including the brain and eye. During retinogenesis, homeodomain-containing transcription factors, which are encoded by homeobox genes, play essential roles in the regionalization and patterning of the optic neuroepithelium, specification of retinal progenitors and differentiation of all seven of the retinal cell classes that derive from a common progenitor. Homeodomain transcription factors control retinal cell fate by regulating the expression of target genes required for retinal progenitor cell fate decisions and for terminal differentiation of specific retinal cell types. The essential role of homeobox genes during retinal development is demonstrated by the number of human eye diseases, including colobomas and anophthalmia, which are attributed to homeobox gene mutations. In the following review, we highlight the role of homeodomain transcription factors during retinogenesis and regulation of their gene targets. Understanding the complexities of vertebrate retina development will enhance our ability to drive differentiation of specific retinal cell types towards novel cell-based replacement therapies for retinal degenerative diseases. PMID- 25035935 TI - Determination of Tinopal CBS-X in rice papers and rice noodles using HPLC with fluorescence detection and LC-MS/MS. AB - To date there have been no reports of methods to determine Tinopal CBS-X. We developed a rapid and simple method to determine the Tinopal CBS-X content in rice noodles and rice papers using HPLC equipped with fluorescence detection. Heating the rice noodles and rice papers to 80 degrees C after adding 75% methanol solution induced the release of Tinopal CBS-X from processed rice products. Tinopal CBS-X was separated using an isocratic mobile phase comprising 50% acetonitrile/water containing 0.4% tetrabutyl ammonium hydrogen sulphate at pH 8.0. The samples suspected to be positive by HPLC analysis were then confirmed by LC-MS/MS analysis. This study also investigated the Tinopal CBS-X content of three rice noodle products and two rice papers. The limits of quantification for rice papers and rice noodles were 1.58 and 1.51 ug kg(-1), respectively, and their correlation curves showed good linearity with r(2) >= 0.9997 and >= 0.9998, respectively. Moreover, rice papers had recoveries of 70.3-83.3% with precision ranging from 5.0% to 7.9%, whereas rice noodles had slightly lower recoveries of 63.4-78.7% and precisions of 8.5-11.5%. Only one rice noodle product contained Tinopal CBS-X, at around 2.1 mg kg(-1), whereas it was not detected in four other samples. Consequently, Tinopal CBS-X from rice noodles and rice papers can be successfully detected using the developed pre-treatment and ion-pairing HPLC system coupled with fluorescence detection. PMID- 25035936 TI - Particle Swarm Optimization for inverse modeling of solute transport in fractured gneiss aquifer. AB - Particle Swarm Optimization (PSO) has received considerable attention as a global optimization technique from scientists of different disciplines around the world. In this article, we illustrate how to use PSO for inverse modeling of a coupled flow and transport groundwater model (MODFLOW2005-MT3DMS) in a fractured gneiss aquifer. In particular, the hydroPSO R package is used as optimization engine, because it has been specifically designed to calibrate environmental, hydrological and hydrogeological models. In addition, hydroPSO implements the latest Standard Particle Swarm Optimization algorithm (SPSO-2011), with an adaptive random topology and rotational invariance constituting the main advancements over previous PSO versions. A tracer test conducted in the experimental field at TU Bergakademie Freiberg (Germany) is used as case study. A double-porosity approach is used to simulate the solute transport in the fractured Gneiss aquifer. Tracer concentrations obtained with hydroPSO were in good agreement with its corresponding observations, as measured by a high value of the coefficient of determination and a low sum of squared residuals. Several graphical outputs automatically generated by hydroPSO provided useful insights to assess the quality of the calibration results. It was found that hydroPSO required a small number of model runs to reach the region of the global optimum, and it proved to be both an effective and efficient optimization technique to calibrate the movement of solute transport over time in a fractured aquifer. In addition, the parallel feature of hydroPSO allowed to reduce the total computation time used in the inverse modeling process up to an eighth of the total time required without using that feature. This work provides a first attempt to demonstrate the capability and versatility of hydroPSO to work as an optimizer of a coupled flow and transport model for contaminant migration. PMID- 25035937 TI - Zeta potential of polyelectrolyte multilayers using the spinning disk method. AB - Zeta potentials of surfaces bearing stable mono- or multilayers of polyelectrolyte were determined using the spinning disk method recently described by Sides et al. (Langmuir 2004, 20, 11493-11498). In this technique, the streaming potential difference between two electrodes, one at the disk surface, is quantitatively related to zeta potential. Variables such as rotation speed, electrolyte concentration, and electrode distance from the disk surface were explored and used to validate the recently-described theory, which emphasizes minimal contribution to net potential from surface conductivity. Layer-by-layer oscillations in sign and magnitude of the zeta potential were observed, in accord with prior work using electrophoretic mobility of multilayer-coated particles and other streaming potential measurements. The open geometry and the excellent mass transport of the spinning disk allowed in-situ observation of surface charge switching during the addition of a layer. As with all zeta potentials, especially those recorded at soft interfaces, translating results to quantitative densities of fixed surface charge is a challenge. PMID- 25035938 TI - Combined myomectomy and uterine artery embolization. AB - Objective: To evaluate the safety and efficacy of uterine artery embolization combined with endoscopic myomectomy. MATERIAL AND METHODS: We conducted a retrospective chart review of patients (n = 125) who underwent myomectomy concurrent with embolization within one month. We assessed two groups: 1) uterine artery embolization followed by hysteroscopic myomectomy and 2) uterine artery embolization followed by laparoscopic myomectomy. RESULTS: Following the combination procedures, 72% of the surveyed women reported symptom improvement. With the combined procedures, 92.5% of patients experienced reduction in myoma diameter and 87.5% of patients had decreased uterine size after an average of 4.70 months post subsequent procedure. The amount of decrease in the uterine volume (p = 0.39) and fibroid size (p = 0.23) were not significant between the two endoscopic myomectomy groups. CONCLUSIONS: Combining myomectomy with uterine artery embolization is a safe and effective procedure in treating symptoms and reducing myoma and uterine volumes. PMID- 25035939 TI - Aglycosylated full-length IgG antibodies: steps toward next-generation immunotherapeutics. AB - Albeit the removal of Asn297 glycans of IgG perturbs the overall conformation and flexibility of the IgG CH2 domain, resulting in the loss of Fc-ligand interactions and therapeutically critical immune effector functions, aglycosylated full-length IgG antibodies are nearly identical to the glycosylated counterparts in terms of antigen binding, stability at physiological or low temperature conditions, pharmacokinetics, and biodistribution. To bypass the drawbacks of glycosylated antibodies that include glycan heterogeneity and requirement of high capital investment for biomanufacturing, aglycosylated antibodies have been developed and several are under clinical trials. Comprehensive cellular and bioprocess engineering has enabled to produce highly complex aglycosylated IgGs in a simple bacterial cultivation with comparable production level as that of mammalian cells. Moreover, extensive engineering of aglycosylated Fc has converted the aglycosylated IgG antibodies into a new class of effector functional human immunotherapeutics. PMID- 25035940 TI - Towards real-time monitoring of therapeutic protein quality in mammalian cell processes. AB - Protein biopharmaceuticals are mainly produced in mammalian cells which can perform human-like post-translational modifications crucial to protein function. Subject to high variability, these critical quality attributes should be monitored and controlled during the manufacturing process. However, the large time requirements for analysis have been a bottleneck. Recent advances towards automated and high-throughput techniques, combined with multivariate data analysis, are increasingly providing relevant process knowledge in near real time. New or re-designed analytical tools suited for monitoring product quality are starting to fit in this landscape. Moreover, omics technologies are expanding our understanding of how intracellular mechanisms and the extracellular milieu influence protein quality and quantity, reshaping the adoption of Process Analytical Technology (PAT) and Quality by Design (QbD) in the biopharmaceutical industry. PMID- 25035941 TI - The microbial cell-functional unit for energy dependent multistep biocatalysis. AB - Whole-cell biocatalysis has emerged as an important tool for the synthesis of value-added fine and bulk chemicals as well as pharmaceuticals. Especially, the rapid development of recombinant DNA technologies resulted in a shift from the exploitation of natural enzymes and pathways to the design of recombinant cell factories comprising heterologous enzymes and/or synthetic, orthologous pathways for the synthesis of industrially relevant compounds. This review discusses recent developments and concepts applied in the frame of multistep whole-cell biocatalysis along with representative examples. PMID- 25035942 TI - Enhancing extracellular lipolytic enzyme production in an arctic bacterium, Psychrobacter sp. ArcL13, by using statistical optimization and fed-batch fermentation. AB - A strain isolated from seawater samples in the Chuckchi Sea and exhibiting extracellular lipolytic activity was identified using 16S rRNA gene sequence analysis as Psychrobacter sp. ArcL13. The lipolytic enzyme exhibited cold-active properties and high hydrolytic activity toward p-nitrophenyl caprylate (C8), p nitrophenyl decanoate (C10), and sunflower oil. Statistical optimization of the medium components was performed to enhance the production of cold-active extracellular lipolytic activity. Glucose, yeast extract (YE), and NaCl were selected as the main efficient nutrient sources. Fed-batch fermentation using optimized medium with concentrated YE as the main feeding material showed a maximum lipolytic activity of 10.7 U/mL, which was a 21-fold increase in production over unoptimized flask culture conditions. The information obtained in the present study could prove applicable to the production of cold-active lipase on a large scale. PMID- 25035943 TI - Preferential adherence to antiretroviral therapy over tuberculosis treatment: a qualitative study of drug-resistant TB/HIV co-infected patients in South Africa. AB - Adherence to antiretroviral therapy (ART) and second-line antituberculosis medications is essential to achieve successful outcomes among individuals co infected with HIV and multi or extensively drug-resistant TB (M/XDR-TB). In 2012 2013, we designed a qualitative study to explore barriers to adherence in KwaZulu Natal, South Africa. We conducted six focus groups comprising 23 adults receiving treatment for either MDR-TB (n = 2) or XDR-TB (n = 21); 17 were on concurrent ART. Participants expressed a preference for ART over M/XDR-TB treatment as a result of greater tolerability, lower pill burden and a commitment to ART. Treatment outcomes and the social morbidity associated with M/XDR-TB, characterised by public notification, stigma and social isolation, were perceived to be worse than with HIV. Poor communication, low patient involvement and provider supervision of treatment exacerbated participants' negative experiences with TB care. To improve adherence, it is critical that new regimens for drug resistant TB be developed with better efficacy, lower pill burden and fewer adverse effects. For the first time, such improved regimens are on the horizon. In parallel and equally important is the implementation of a cohesive approach that promotes patient involvement, empowerment and treatment literacy for HIV and for TB. PMID- 25035944 TI - Futility sustains memory T cells. AB - Memory T cells display a distinct metabolic profile compared to effector T cells. In this issue of Immunity, O'Sullivan et al. (2014) report that memory T cells activate a "futile cycle" of de novo fatty-acid synthesis and concurrent fatty acid oxidation to generate ATP for cell survival. PMID- 25035945 TI - Regulatory T cells: exosomes deliver tolerance. AB - T regulatory (Treg) cells enforce peripheral tolerance through regulation of diverse immune responses in a context-specific manner. Okoye et al. show one way that Treg cells suppress Th1 cell responses is through nonautonomous gene silencing mediated by microRNA-containing exosomes. PMID- 25035946 TI - Bipotent or Oligopotent? A macrophage and DC progenitor revisited. AB - Macrophage and dendritic cell (DC) progenitors (MDPs) produce macrophages and DCs but not other hematopoietic lineages. In this issue of Immunity, Sathe et al. (2014) show that isolated MDP populations hardly contain such bipotent progenitors at clonal levels, arguing against the existence of MDPs. PMID- 25035947 TI - Memory T cells officially join the stem cell club. AB - In this issue of Immunity, Graef et al. (2014) demonstrate self-renewal and multipotency of a single CD62L(+) memory T cell across serial adoptive transfers and infection-driven re-expansions, providing evidence of true stemness within the T cell memory compartment. PMID- 25035948 TI - Tfr cells and IgA join forces to diversify the microbiota. AB - How diversity of the microbiota is generated and maintained is an open question. In this issue of Immunity, Kawamoto et al. show that T follicular regulatory cells foster microbiota diversity via the regulation of IgA selection. PMID- 25035949 TI - Macrophages have a grip on the gut. AB - We host a world inside, and every day, new evidence reveals how relevant our microbiota is for daily living. In the most recent issue of Cell, Muller and colleagues demonstrate that microbiota commensals also influence colon peristalsis via a direct effect of muscolaris externae macrophages (Muller et al., 2014). PMID- 25035950 TI - Macrophage activation and polarization: nomenclature and experimental guidelines. AB - Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature. PMID- 25035951 TI - Origin and functions of tissue macrophages. AB - Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease. Recently, it has become evident that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6c(hi) monocytes patrol the extravascular space in resting organs, and Ly6c(lo) nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation. PMID- 25035952 TI - Macrophages, immunity, and metabolic disease. AB - Chronic, low-grade adipose tissue inflammation is a key etiological mechanism linking the increasing incidence of type 2 diabetes (T2D) and obesity. It is well recognized that the immune system and metabolism are highly integrated, and macrophages, in particular, have been identified as critical effector cells in the initiation of inflammation and insulin resistance. Recent advances have been made in the understanding of macrophage recruitment and retention to adipose tissue and the participation of other immune cell populations in the regulation of this inflammatory process. Here we discuss the pathophysiological link between macrophages, obesity, and insulin resistance, highlighting the dynamic immune cell regulation of adipose tissue inflammation. We also describe the mechanisms by which inflammation causes insulin resistance and the new therapeutic targets that have emerged. PMID- 25035953 TI - Tumor-associated macrophages: from mechanisms to therapy. AB - The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate that these macrophages generally play a protumoral role. In the primary tumor, macrophages can stimulate angiogenesis and enhance tumor cell invasion, motility, and intravasation. During monocytes and/or metastasis, macrophages prime the premetastatic site and promote tumor cell extravasation, survival, and persistent growth. Macrophages are also immunosuppressive, preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immunotherapy. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment. PMID- 25035954 TI - MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. AB - Foxp3(+) T regulatory (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely. Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of intercellular regulation. Here, we demonstrate that non cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T-cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg-cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg-cell-mediated suppression mediated by miRNA-containing exosomes. PMID- 25035955 TI - Lymphoid tissue and plasmacytoid dendritic cells and macrophages do not share a common macrophage-dendritic cell-restricted progenitor. AB - The relationship between dendritic cells (DCs) and macrophages is often debated. Here we ask whether steady-state, lymphoid-tissue-resident conventional DCs (cDCs), plasmacytoid DCs (pDCs), and macrophages share a common macrophage-DC restricted precursor (MDP). Using new clonal culture assays combined with adoptive transfer, we found that MDP fractions isolated by previous strategies are dominated by precursors of macrophages and monocytes, include some multipotent precursors of other hematopoietic lineages, but contain few precursors of resident cDCs and pDCs and no detectable common precursors restricted to these DC types and macrophages. Overall we find no evidence for a common restricted MDP leading to both macrophages and FL-dependent, resident cDCs and pDCs. PMID- 25035956 TI - Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8(+) central memory T cells. AB - Maintenance of immunological memory has been proposed to rely on stem-cell-like lymphocytes. However, data supporting this hypothesis are focused on the developmental potential of lymphocyte populations and are thus insufficient to establish the functional hallmarks of stemness. Here, we investigated self renewal capacity and multipotency of individual memory lymphocytes by in vivo fate mapping of CD8(+) T cells and their descendants across three generations of serial single-cell adoptive transfer and infection-driven re-expansion. We found that immune responses derived from single naive T (Tn) cells, single primary, and single secondary central memory T (Tcm) cells reached similar size and phenotypic diversity, were subjected to comparable stochastic variation, and could ultimately reconstitute immunocompetence against an otherwise lethal infection with the bacterial pathogen Listeria monocytogenes. These observations establish that adult tissue stem cells reside within the CD62L(+) Tcm cell compartment and highlight the promising therapeutic potential of this immune cell subset. PMID- 25035958 TI - Lacosamide-induced rash. AB - Cutaneous eruptions and hypersensitivity represent frequently reported side effects of anti-seizure medications. However, these side-effects have rarely been previously reported for lacosamide, a newer-generation anti-seizure medication with a novel mechanism of action. Here, we report a case of diffuse skin eruption in a patient with history of epilepsy soon after initiation of lacosamide. The rash resolved after discontinuation of lacosamide and use of antihistamines and steroids. We also review the information on drug hypersensitivity syndrome. PMID- 25035957 TI - Epitope-specific regulation of memory programming by differential duration of antigen presentation to influenza-specific CD8(+) T cells. AB - Memory CD8(+) T cells are programmed during the primary response for robust secondary responsiveness. Here we show that CD8(+) T cells responding to different epitopes of influenza virus received qualitatively different signals during the primary response that altered their secondary responsiveness. Nucleoprotein (NP)-specific CD8(+) T cells encountered antigen on CD40-licensed, CD70-expressing, CD103(-)CD11b(hi) dendritic cells (DCs) at later times in the primary response. As a consequence, they maintained CD25 expression and responded to interleukin-2 (IL-2) and CD27, which together programmed their robust secondary proliferative capacity and interferon-gamma (IFN-gamma)-producing ability. In contrast, polymerase (PA)-specific CD8(+) T cells did not encounter antigen-bearing, CD40-activated DCs at later times in the primary response, did not receive CD27 and CD25 signals, and were not programmed to become memory CD8(+) T cells with strong proliferative and cytokine-producing ability. As a result, CD8(+) T cells responding to abundant antigens, like NP, dominated the secondary response. PMID- 25035959 TI - 20-(s)-ginsenoside Rg3 induces apoptotic cell death in human leukemic U937 and HL 60 cells through PI3K/Akt pathways. AB - Leukemia is currently one of the most deadly diseases. Ginseng has been used in Asian countries for the treatment and prevention of various diseases, including leukemia, but the molecular mechanism of its antileukemia activity has not been well defined. The aim of this study was to explore the effect of 20-(s) ginsenoside Rg3 on apoptosis in human leukemic U937 and HL-60 cells and the underlying mechanism. We found that 20-(s)-ginsenoside Rg3 reduced cell viability and induced apoptosis in U937 and HL-60 cells. The induction of apoptosis was accompanied by the downregulation of PI3K/Akt family proteins. Moreover, we observed that 20-(s)-ginsenoside Rg3 treatment resulted in activation of caspase 3 and caspase-9. Taken together, our findings suggest for the first time that 20 (s)-ginsenoside Rg3 can promote apoptosis in U937 and HL-60 cells, at least partly through the downregulation of PI3K/Akt family proteins. Moreover, the triggering of caspase-3 and caspase-9 activation mediated apoptotic induction. All these findings collectively demonstrate that the natural compound 20-(s) ginsenoside Rg3 effectively induces apoptosis in human leukemic cells, which suggests that this compound may play a role in future therapies for leukemia. PMID- 25035960 TI - Nimotuzumab suppresses epithelial-mesenchymal transition and enhances apoptosis in low-dose UV-C treated salivary adenoid cystic carcinoma cell lines in vitro. AB - Salivary adenoid cystic carcinoma (SACC), which is one of the most common malignant tumors of the salivary glands, is associated with a poor long-term outcome. There are currently few therapeutic options for patients with SACC. Recent studies have shown the potential of the application of ultraviolet-C (UV C) irradiation for the treatment of human cancer. In the present study, we investigated the effects of UV-C in the SACC cell lines SACC-83 and SACC-LM. High dose UV-C (200 J/m) induced apoptosis and inhibited colony formation significantly. However, low-dose UV-C (10 J/m), which had little effect on apoptosis and colony formation, increased the ability of migration in SACC cells accompanied by a decrease in E-cadherin and an increase in vimentin, suggesting the occurrence of epithelial-mesenchymal transition (EMT). Low-dose UV-C (10 J/m) also resulted in upregulation of the phosphorylated forms of epidermal growth factor receptor (EGFR) and Akt (p-EGFR and p-Akt, respectively). Pretreatment with Nimotuzumab, an anti-EGFR monoclonal antibody, reversed the EMT as well as upregulation of p-EGFR/p-Akt induced by UV-C. Moreover, Nimotuzumab enhanced UV-C induced apoptosis and inhibition of colony formation. Our results indicate that EMT exerts a protective effect against apoptosis induced by low-dose UV-C. Thus, the combined application of Nimotuzumab and low-dose UV-C in vitro has an advantageous antitumor effect in SACC compared with the application of UV-C alone. PMID- 25035961 TI - PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway. AB - Although preclinical work with rapalogs suggests potential in the treatment of gastric cancer, they have been less successful clinically. In this study, we report the impact of the investigational drug PP242, a potent and selective small molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis. The antiproliferative effect of PP242 was assessed using the Cell Counting Kit-8 assay. The migration and invasion potential were analyzed using wound-healing and transwell assays, respectively. The Matrigel capillary tube formation assay was performed to mimic in-vivo angiogenesis. Immunoblotting and immunofluorescence were used to observe protein levels and distribution of actin fibers. Finally, p mammalian target of rapamycin (mTOR) expression was detected on gastric cancer tissues using immunohistochemistry. First, PP242 potently inhibited cell proliferation in gastric cancer cell lines and in human endothelial cells in vitro at the IC50 ranged from 50 to 500 nmol/l. Then, an inhibitory effect of PP242 on metastasis was observed in gastric cancer cell AGS, along with the cytoskeletal rearrangements and suppression of the phosphorylation of PI3K downstream factors including AKT, mTOR, and P70S6K. Furthermore, PP242 was found to decrease the tube formation and migration of human umbilical vein endothelial cells. Using immunohistochemistry, we found that p-mTOR staining was observed in 41.8% (82/196) of gastric cancer tissues and correlated with depth of mural invasion, lymph node metastasis, tumor node metastasis stage, and vascular invasion. These results show that PP242 suppresses cell proliferation and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway, which might be an effective novel therapeutic candidate against gastric cancer in the future. PMID- 25035962 TI - Nitric oxide donors reduce the invasion ability of ovarian cancer cells in vitro. AB - The most important factors involved in tumor metastasis and angiogenesis are metalloproteinases (MMPs), vascular endothelial growth factor, and multifunctional transforming growth factor beta1. These factors are responsible for extracellular matrix degradation, induction of vascular permeability, and enhancement of tumor cells' invasion and metastasis. Elevated expression and secretion of the above-mentioned factors are correlated with the higher aggressiveness of tumors and low patient survival for example, patients with ovarian cancer. Therefore, regulation of the expression, secretion, and activity of these factors is still considered a potent target for therapeutic intervention in cancer patients. Nitric oxide (NO) donors belong to the class of agents with multivalent targeted activities in cancer cells and are considered potential anticancer therapeutics. Our studies have shown that NO donors such as spermine/NO and diethylenetriamine/NO decrease the secretion of vascular endothelial growth factor-A from the OVCAR-3 ovarian cancer cell line, but not from the SK-OV-3 ovarian cancer cell line. The release of MMP-2 from both cell lines was reduced in a soluble guanylate cyclase-dependent manner by spermine/NO and diethylenetriamine/NO. Nevertheless, MMP-2 activity was only affected in SK OV-3 cells. Both NO donors reduced the transmigration of the ovarian cancer cell lines. We did not observe any significant effect of spermine/NO and diethylenetriamine/NO on mRNA expression of the tested aggressiveness factors. In conclusion, our data indicated that NO donors reduced the metastatic potential of ovarian cancer cells, but its impact is rather low and requires high concentrations of donors. Moreover, both the tested cell lines differed in the susceptibility to NO donors. PMID- 25035963 TI - Effect of mitochondrial metabolism-interfering agents on cancer cell mitochondrial function and radio/chemosensitivity. AB - Abnormal mitochondrial function is common in cancer cells and activates metabolic pathways suppressed in normal tissues. Experimental and clinical studies suggest that mitochondria might serve as targets for novel anticancer therapies. We investigated whether mitochondrial metabolism-interfering agents (MMIAs) available currently in clinical practice affect cancer cell mitochondrial metabolism and synergize with chemotherapy and radiotherapy. Two cancer cell lines A549 (lung cancer) and DU145 (prostate cancer) were treated with a variety of MMIAs (metformin, nimodipine, memantine, oxytetracycline, amiodarone, and sodium azide) and their response was assessed using a resazurin reduction method and confocal microscopy. Focusing on amiodarone and metformin, we investigated their potential sensitizing effect on cancer cells when treated with ionizing radiation, cisplatin, and docetaxel. Resazurin reduction was increased by metformin and decreased by amiodarone at nontoxic concentrations. Amiodarone induced mitochondrial swelling, whereas metformin exerted no apparent effect on their morphology. Amiodarone and metformin exerted a weak radiosensitization effect on A549, whereas a synergetic activity with cisplatin and docetaxel was evident in both cell lines. It can be concluded that amiodarone and metformin, being well-established drugs in clinical practice, constitute two potential drugs for further experimental and clinical evaluation as cancer cell sensitizers to chemotherapy and radiotherapy. PMID- 25035964 TI - Clinical phenotypes in sarcoidosis. AB - PURPOSE OF REVIEW: To describe the methods for derivation of clinical phenotypes in general and how they should be applied in sarcoidosis, taking into account the dimensions of the disease. The results from the small number of studies in this area are summarized. RECENT FINDINGS: Clinical phenotypes are determined by diverse ways. In sarcoidosis, some studies defined clinical phenotypes based on severity of disease and outcome after treatment of variable duration. A second approach to characterize clinical phenotypes is by using analytic or multivariate techniques. This approach considers several domains of disease and does not make assumptions a priori, with the hypothesis being developed after the results. A small study used factorial analysis for this purpose. Some well defined clinical phenotypes are described and future directions for research are given. SUMMARY: Clinical phenotypes, by examining relationships between several domains in sarcoidosis, are likely to better delineate the underlying processes and pathways. Larger studies with appropriate methods should be performed to better delineate clinical phenotypes in sarcoidosis. PMID- 25035965 TI - Hierarchical Adaptive Means (HAM) clustering for hardware-efficient, unsupervised and real-time spike sorting. AB - This work presents a novel unsupervised algorithm for real-time adaptive clustering of neural spike data (spike sorting). The proposed Hierarchical Adaptive Means (HAM) clustering method combines centroid-based clustering with hierarchical cluster connectivity to classify incoming spikes using groups of clusters. It is described how the proposed method can adaptively track the incoming spike data without requiring any past history, iteration or training and autonomously determines the number of spike classes. Its performance (classification accuracy) has been tested using multiple datasets (both simulated and recorded) achieving a near-identical accuracy compared to k-means (using 10 iterations and provided with the number of spike classes). Also, its robustness in applying to different feature extraction methods has been demonstrated by achieving classification accuracies above 80% across multiple datasets. Last but crucially, its low complexity, that has been quantified through both memory and computation requirements makes this method hugely attractive for future hardware implementation. PMID- 25035966 TI - Hydrogen bonding directed self-assembly of small-molecule amphiphiles in water. AB - Compounds comprising one or two quadruply hydrogen bonding units, 2-ureido-4[1H] pyrimidinone (UPy) and tris(tetraethylene glycol monomethyl ether) moieties, were reported to form highly stable hydrogen-bonded assemblies in water. Compound 1, containing one UPy, assembles into vesicles, and compound 2, containing two UPy units, forms micelles. The aggregates disassemble reversibly when the solution pH is raised to 9.0 or above. The results demonstrate the utility of hydrogen bonding to direct the self-assembly of small-molecule building blocks in aqueous media. PMID- 25035967 TI - Synthesis and application of resorufin beta-D-glucuronide, a low-cost chromogenic substrate for detecting Escherichia coli in drinking water. AB - The development of low-cost tests for Escherichia coli is hampered by the expense and limited choice of enzyme substrates. Most chromogenic substrates are required in costly amounts, while fluorogenic substrates require an additional apparatus (e.g., an ultraviolet lamp) to be detected. Herein, we propose an alternative chromogenic substrate, resorufin beta-d-glucuronide (REG), which is exceptionally sensitive and may be employed in very small amounts. We show that REG can be produced similarly to other simple glucuronides and should therefore be no more expensive. The compound is used by both healthy and injured E. coli, resulting in a pronounced color change from orange to a bright pink. Because the released dye (resorufin) has a high extinction coefficient, substantially lower amounts are needed than for commercially available substrates. The potential of this substrate is demonstrated by a presence/absence test requiring just 0.1 mg of REG/100 mL of water sample, one hundredth of the quantity needed for common chromogenic substrates, with an estimated bulk cost of <=0.1 U.S. cents/test. REG shows promise as a chromogenic substrate for E. coli detection and should be considered in the development of new water tests, especially for low-income settings. PMID- 25035969 TI - On the relationship between pedestrian gap acceptance and time to arrival estimates. AB - The identification of safe gaps between passing cars when crossing a street is a task most of us accomplish successfully on a daily basis. Objectively, how safe a specific gap is, is mainly dependent on how long it would take the approaching vehicle to arrive (time to arrival; TTA). Common sense might suggest that TTA is the basis for pedestrians' gap selection. However, it has been shown repeatedly that vehicle approach speed has a substantial influence on the size of chosen gaps. At higher speeds, pedestrians tend to accept smaller time gaps, i.e. they initiate riskier crossings. Some researchers have gone so far as to suggest that pedestrians rely more on physical distance of a vehicle in their crossing decisions than TTA. Yet, at the same time, there is evidence that TTA estimates themselves are influenced by object approach speed. It is suspected that pedestrians are more apt to base their decisions on systematically distorted TTA estimates, rather than physical distance. The goal of the two experiments described in this article was to explore the relationship between gap acceptance and TTA estimation. Participants were presented with video clips of approaching vehicles, and were either required to indicate a crossing decision, or to estimate TTA. Results show the typical effects of speed (smaller gaps at higher speed, lower TTA estimate at lower speed) and age (larger gaps for older participants). However, when using subjective time gap size (the TTA estimate) instead of objective time gap size to predict gap acceptance, the effect of speed either disappeared (Experiment I) or decreased substantially (Experiment II). The results indicate that systematic differences in TTA estimates can be a reasonable explanation for the effect of speed on gap acceptance. PMID- 25035968 TI - Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer. AB - INTRODUCTION: The integration of diagnostic testing for the presence of a molecular target is of interest to predict successful targeted radionuclide therapy (TRNT). This so-called 'theranostic' approach aims to improve personalized treatment based on the molecular characteristics of cancer cells. Moreover, it offers new insights in predicting adverse effects and provides appropriate tools to monitor therapy responses. Recent findings using nanobodies emphasize their potential as theranostic tools in cancer treatment. Nanobodies are recombinant, small antigen-binding fragments that are derived from camelid heavy-chain-only antibodies. AREAS COVERED: We review the current status of theranostic approaches in TRNT, with a focus on antibodies, peptides, scaffold proteins and emerging nanobodies. In recent years, nanobodies have been evaluated intensively for molecular imaging. In addition, novel data on TRNT using radiolabeled nanobodies for carcinomas and multiple myeloma highlight their promising opportunities in cancer treatment. EXPERT OPINION: We trust that radiolabeled nanobodies will have a future potential as theranostic tools in cancer therapy, both for diagnosis as well as for TRNT. PMID- 25035970 TI - Development of a variable speed limit strategy to reduce secondary collision risks during inclement weathers. AB - Inclement weather reduces traveler's sight distance and increases vehicle's stopping distance. Once a collision occurred during inclement weather and resulted in a slow traffic, approaching vehicles may not have adequate time to make emergency responses to the hazardous traffic, resulting in increased potentials of secondary collisions. The primary objective of this study is to develop a control strategy of variable speed limits (VSL) to reduce the risks of secondary collisions during inclement weathers. By analyzing the occurrence condition of secondary collision, the VSL strategy is proposed to dynamically adjust the speed limits according to the current traffic and weather conditions. A car-following model is modified to simulate the vehicle maneuvers with the VSL control. Two surrogate safety measures, based on the time-to-collision notion, are used to evaluate the control effects of VSL. Five weather scenarios are evaluated in simulation. The results show that the VSL strategy effectively reduces the risks of secondary collisions in various weather types. The time exposed time-to-collision (TET) is reduced by 41.45%-50.74%, and the time integrated time-to-collision (TIT) is reduced by 38.19%-41.19%. The safety effects are compared to those with a previous VSL strategy. The results show that in most cases our strategy outperforms the previous one. We also evaluate how driver's compliance to speed limit affects the effectiveness of VSL control. PMID- 25035971 TI - Chromophores in photoproteins of a glowing squid and mollusk. AB - Bioluminescence is a chemical reaction process for light emission in vivo. An organic substance is normally oxidized in the protein to obtain the energy required for the light emission. Determination of the structure of the substance is one of the most important parts of bioluminescent research. Photoproteins of a flying squid and a mollusk contain chromophores that are formed by connecting an apo-protein and dehydrocoelenterazine. The chromophore has a chemical structure that can emit light in a photoprotein. The structural analysis of the chromophores in the photoproteins is described. PMID- 25035972 TI - The hierarchic network of metal-response transcription factors in Escherichia coli. AB - Enterobacteria such as Escherichia coli are able to survive under various environments within host animals by changes of the expression pattern of its genome. The selective expression of genes in its genome takes place by controlling the promoter recognition properties of RNA polymerase by protein protein interplays with transcription factors. In this review, I describe the regulatory network formed by the metal-sensing transcription factors in E. coli. Comprehensive analyses identify the set of regulation targets for a total of 13 metal-response transcription factors, indicating that nine species of transcription factors are local regulators while four species of transcription factors are global regulators. The signal transduction pathways for these metal response regulons show not only the complex cross-talks but also the hierarchic multi-regulatory network. This regulatory network seems to play a role for E. coli survival to colonize in a large intestine within host animals. PMID- 25035973 TI - Toward continuous LC-MS analysis: surface modification of magnetic microparticles with TiO2 for phosphate adsorption. AB - Continuous liquid chromatography-mass spectrometry (LC-MS) analysis was successfully demonstrated by using magnetic TiO2/Fe3O4 microparticles at the desalination interface. The particles could be prepared easily even on a practical scale at sufficient quality for efficient phosphate adsorption. Not only phosphate but several biomolecules were adsorbed onto the particles in a non specific manner. Such samples could still be detected effectively in MS because the removal of phosphate derived from the LC eluent enhanced sample ionization and resulted in a significant reduction of phosphate cluster ions. PMID- 25035974 TI - A new compound from the mushroom Tricholoma flavovirens. AB - A novel compound (1) and a known one (2) were isolated from the fruiting bodies of Tricholoma flavovirens. Their structures were determined by the interpretation of spectroscopic data. Both compounds showed inhibition effects on the growth of hypocotyl of lettuce with significant differences. In addition, compound 1 showed a promotion effect on the growth of root with significant differences and 2 had the similar tendency to promote the growth. PMID- 25035975 TI - Efficiency of 2.45 and 5.80 GHz microwave irradiation for a hydrolysis reaction by thermostable beta-Glucosidase HT1. AB - Microwave irradiation at different frequencies gave unique results for the hydrolyses of glycosyl bonds by beta-Glucosidase HT1. With the observed relative complex permittivity data for the reaction buffer, 2.45 GHz microwave radiation affected both waters and ions, while 5.80 GHz only affected waters. We, here, propose that would be one of the unique "microwave nonthermal effects". PMID- 25035976 TI - Enantiospecific synthesis and filed evaluation of four stereoisomers of 10,14 dimethyloctadec-1-ene, a sex pheromone component secreted by female moths of the apple leafminer. AB - All four stereoisomers of 10,14-dimethyloctadec-1-ene, a sex pheromone component of the apple leafminer (Lyonetia prunifoliella: Lepidoptera), were synthesized starting from (R)- and (S)-propylene oxide by applying stereospecific inversion of chiral secondary tosylates as a key step. Field evaluation showed that male moths of the Japanese population were selectively attracted by the (10S,14S) isomer and that the activity was not inhibited by the enantiomer. PMID- 25035977 TI - Facile synthesis of the cyclohexane fragment of enacloxins, a series of antibiotics isolated from Frateuria sp. W-315. AB - An efficient and good yield synthesis of the cyclohexane moiety of enacyloxins, a series of antibiotics isolated from Frateuria sp. W-315, was achieved from d quinic acid using a successive Barton-McCombie deoxygenation. PMID- 25035978 TI - Structural alteration of cell surface heparan sulfate through the stimulation of the signaling pathway for heparan sulfate 6-O-sulfotransferase-1 in mouse fibroblast cells. AB - Heparan sulfate (HS) is a randomly sulfated polysaccharide that is present on the cell surface and in the extracellular matrix. The sulfated structures of HS were synthesized by multiple HS sulfotransferases, thereby regulating various activities such as growth factor signaling, cell differentiation, and tumor metastasis. Therefore, if the sulfated structures of HS could be artificially controlled, those manipulations would help to understand the various functions depending on HS. However, little knowledge is currently available to realize the mechanisms controlling the expression of such enzymes. In this study, we found that the ratio of 6-O-sulfated disaccharides increased at 3 h after adrenaline stimulation in mouse fibroblast cells. Furthermore, adrenaline-induced up regulation of HS 6-O-sulfotransferase-1 (6-OST-1) was controlled by Src-ERK1/2 signaling pathway. Finally, inhibiting the signaling pathways for 6-OST-1 intentionally suppressed the adrenaline-induced structural alteration of HS. These observations provide fundamental insights into the understanding of structural alterations in HS by extracellular cues. PMID- 25035979 TI - Molecular cloning and characterization of pathogenesis-related protein family 10 gene from spinach (SoPR10). AB - PR10 genes encode small, intracellular proteins that respond to biotic and abiotic stresses. In this study, a cDNA clone (designated as SoPR10, GenBank Accession No. KC142174) encoding a PR10 protein from spinach (Spinacia oleracea L.) was isolated and characterized. SoPR10 encoded a 161-amino acid polypeptide with a predicted molecular mass of 19.76 kDa and a pI of 4.61. Real-time quantitative analysis indicated that SoPR10 was constitutively expressed in root and shoot. The abundance of SoPR10 in salt-resistant cultivar (Chaoji) was generally greater than in salt-sensitive cultivar (Daye) under 160 mM L(-1) NO3( ) treatment for 0.5, 3, and 6 h. The expression of SoPR10 was also induced by other abiotic stresses including polyethylene glycol, NaCl, salicylic acid, and H2O2. Our results indicated that SoPR10 might play important roles under nitrate stress and other abiotic stresses. PMID- 25035980 TI - Calcitonin gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor beta1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells. AB - Transforming growth factor (TGF) beta1-induced plasminogen activator inhibitor (PAI)-1 is one of factors associated with the development of hepatic fibrosis. Calcitonin gene-related peptide (CGRP) shows hepatoprotective effect during hepatic injuries, including fibrosis. However, the effects of CGRP on PAI-1 expression induced by TGFbeta1 are unknown. In this study, we investigated the effect of CGRP on TGFbeta1-induced PAI-1 expression and its regulatory mechanisms in HepG2 cells. CGRP inhibited TGFbeta1-induced PAI-1 expression. H89, a protein kinase A inhibitor, abolished the inhibition of TGFbeta1-induced PAI-1 expression by CGRP. TGFbeta1 activated mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase, c-jun NH2-terminal kinase, and p38, and this activation was abolished by CGRP. These results show that the CGRP-induced cAMP/PKA activation suppresses activation of MAPK induced by TGFbeta1, leading to decreased PAI-1 expression in HepG2 cells. PMID- 25035981 TI - De novo assembly and analysis of Cassia obtusifolia seed transcriptome to identify genes involved in the biosynthesis of active metabolites. AB - A cDNA library generated from seeds of Cassia obtusifolia was sequenced using Illumina/Solexa platform. More than 12,968,231 high quality reads were generated, and have been deposited in NCBI SRA (SRR 1012912). A total of 40,102 unigenes (>200 bp) were obtained with an average sequence length of 681 bp by de novo assembly. About 34,089 (85%) unique sequences were annotated and 8694 of the unique sequences were assigned to specific metabolic pathways by the Kyoto Encyclopedia of Genes and Genomes. Among them, 131 unigenes, which are involved in the biosynthesis and (or) regulation of anthraquinone, carotenoid, flavonoid, and lipid, the 4 best known active metabolites, were identified from cDNA library. In addition, three lipid transfer proteins were obtained, which may contribute to the lipid molecules transporting between biological membranes. Meanwhile, 30 cytochrome P450, 12 SAM-dependent methyltransferases, and 12 UDP glucosyltransferase unigenes were identified, which could also be responsible for the biosynthesis of active metabolites. PMID- 25035982 TI - Glycogen synthase kinase-3 is involved in regulation of ribosome biogenesis in yeast. AB - Secretory defects cause transcriptional repression of both ribosomal proteins and ribosomal RNA genes in Saccharomyces cerevisiae. Rrs1, a trans-acting factor that participates in ribosome biogenesis, is involved in the signaling pathway induced by secretory defects. Here, we found that Rrs1 interacts with two homologs of the glycogen synthase kinase-3 (GSK-3), Rim11, and Mrk1. Rrs1 possesses a repetitive consensus amino acid sequence for phosphorylation by GSK-3, and mutation of this sequence abolished the interaction of Rrs1 with Rim11 and Mrk1. Although this mutation did not affect vegetative cell growth or secretory response, disruption of all four genes encoding GSK-3 homologs, especially Mck1, diminished the transcriptional repression of ribosomal protein genes in response to secretory defects. Among the four GSK-3 kinases, Mck1 appears to be the primary mediator of this response, while the other GSK-3 kinases contribute redundantly. PMID- 25035983 TI - Purification and characterization of a novel O-methyltransferase from Flammulina velutipes. AB - An enzyme catalyzing the methylation of phenolic hydroxyl groups in polyphenols was identified from mycelial cultures of edible mushrooms to synthesize O methylated polyphenols. Enzyme activity was measured to assess whether methyl groups were introduced into (-)-epigallocatechin-3-O-gallate (EGCG) using SAM as a methyl donor, and (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3"Me), (-) epigallocatechin-3-O-(4-O-methyl)-gallate (EGCG4"Me), and (-)-epigallocatechin-3 O-(3,5-O-dimethyl)-gallate (EGCG3",5"diMe) peaks were detected using crude enzyme preparations from mycelial cultures of Flammulina velutipes. The enzyme was purified using chromatographic and two-dimensional electrophoresis. The purified enzyme was subsequently analyzed on the basis of the partial amino acid sequence using LC-MS/MS. Partial amino acid sequencing identified the 17 and 12 amino acid sequences, VLEVGTLGGYSTTWLAR and TGGIIIVDNVVR. In database searches, these sequences showed high identity with O-methyltransferases from other mushroom species and completely matched 11 of 17 and 9 of 12 amino acids from five other mushroom O-methyltransferases. PMID- 25035984 TI - High-efficiency nuclear transformation of the oleaginous marine Nannochloropsis species using PCR product. AB - Nannochloropsis are model species for investigating biofuel production by algae. To develop them into an integrated photons-to-fuel production platform, high efficiency transformation methods are necessary. Here, we obtained the beta tubulin promoter regions of all recognized species of genus Nannochloropsis, and successfully transformed all five marine species by electroporation. In addition, the PCR amplified double stranded DNA fragments (PCR fragments) based transformation system was established in these Nannochloropsis species, which showed much higher transformation efficiency (10.7-61.2 * 10(-6), 1.5-13-fold) than that of linearized plasmid based transformation. The cotransformation of N. salina using a circular plasmid containing a non-selectable GUS gene and a PCR fragment containing only a selection marker cassette was also achieved and found to be very efficient (over 50%). This simple and highly efficient transformation protocol reported in our study provided a useful tool for gene functional analysis and genetic engineering of the oleaginous Nannochloropsis species. PMID- 25035985 TI - Enzymatic fragmentation of carbohydrate moieties of radish arabinogalactan protein and elucidation of the structures. AB - We investigated the structures of L-arabino-galactooligosaccharides released from the sugar moieties of a radish arabinogalactan-protein (AGP) by the action of exo beta-(1->3)-galactanase. We detected a series of neutral beta-(1 -> 6)-linked galactooligosaccharides forming branches of one to up to at least 19 consecutive Gal groups, together with corresponding acidic derivatives terminating in 4-O methyl-glucuronic acid (4-Me-GlcA) at the non-reducing end. Some oligosaccharide chains of degree of polymerization (dp) higher than 3 for neutral, and 4 for acidic oligomers were modified with L-Araf residues. The acidic tetrasaccharide 4 Me-beta-GlcA-(1 -> 6)[alpha-L-Araf-(1 -> 3)]-beta-Gal-(1 -> 6)-Gal was detected as an abundant L-Araf-containing oligosaccharide among these neutral and acidic oligomers. A pentasaccharide containing an additional L-Araf group attached to the L-Ara in the tetrasaccharide through an alpha-(1 -> 5)-linkage was also found. We observed L-arabino-galactooligosaccharides substituted with single or disaccharide L-Araf units at different Gal residues along these neutral and acidic beta-(1 -> 6)-galactooligosaccharide chains, indicating that these side chains are highly variable in length and substituted variously with L-Araf residues. PMID- 25035986 TI - A high-throughput screen for inhibitors of the prolyl isomerase, Pin1, identifies a seaweed polyphenol that reduces adipose cell differentiation. AB - The peptidyl prolyl cis/trans isomerase Pin1 enhances the uptake of triglycerides and the differentiation of fibroblasts into adipose cells in response to insulin stimulation. Pin1 downregulation could be a potential approach to prevent and treat obesity-related disorders. In order to identify an inhibitor of Pin1 that exhibited minimal cytotoxicity, we established a high-throughput screen for Pin1 inhibitors and used this method to identify an inhibitor from 1,056 crude fractions of two natural product libraries. The candidate, a phlorotannin called 974-B, was isolated from the seaweed, Ecklonia kurome. 974-B inhibited the differentiation of mouse embryonic fibroblasts and 3T3-L1 cells into adipose cells without inducing cytotoxicity. We discovered the Pin1 inhibitor, 974-B, from the seaweed, E. kurome, and showed that it blocks the differentiation of fibroblasts into adipose cells, suggesting that 974-B could be a lead drug candidate for obesity-related disorders. PMID- 25035987 TI - Further validation of unsaturated long-chain fatty acids as inhibitors for oxidized low-density lipoprotein binding to CD36 via assays with synthetic CD36 peptide-cross-linked plates. AB - We recently obtained evidence that unsaturated long-chain fatty acids (LCFAs) (e.g. oleic acid) inhibit binding of oxidized low-density lipoproteins (oxLDLs) to CD36. In the present study, we validated this prediction by examining inhibition by unsaturated LCFAs of Alexa-fluor-labeled oxLDL binding to multiwell plates onto which a synthetic CD36 peptide is covalently immobilized via thiol maleimide coupling. PMID- 25035988 TI - Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 beta cells. AB - Chronic hyperglycemia has deleterious effects on pancreatic beta-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 beta cells, and whether hyperoxia (35% O2) can reverse glucotoxicity-induced inhibition of insulin secretion. CHG (33.3 mm, 96 h) reduced insulin secretion, and down-regulated insulin and pancreatic duodenal homeobox factor 1 gene expression. CHG also increased intracellular pimonidazole-protein adducts, a marker for hypoxia. CHG also enhanced hypoxia-inducible factor 1alpha (HIF-1alpha) protein expression and its DNA-binding activity, which was accompanied by a decrease in mRNA expression of glucose transporter 2 (GLUT2), glucokinase and uncoupling protein-2 and an increase in mRNA expression of GLUT1 and pyruvate dehydrogenase kinase 1. Hyperoxia restored the decrease in insulin secretion and the gene expression except for GLUT2, and suppressed intracellular hypoxia and HIF-1alpha activation. These results suggest that glucotoxicity may cause beta-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced beta-cell dysfunction and improve insulin secretion. PMID- 25035989 TI - Identification and evaluation of anti-inflammatory compounds from Kaempferia parviflora. AB - The rhizome of Kaempferia parviflora has been used in traditional Thai medicine. In this study, we identified and compared specific compounds from the hexane extract of K. parviflora with those from other Zingiberaceous plants by using gas chromatography-mass spectrometry. We identified 5,7-dimethoxyflavone (DMF), 5 hydroxy-3,7,3',4'-tetramethoxyflavone (TMF), estimated 3,5,7-trimethoxyflavone, 5 hydroxy-7,4'-dimethoxyflavone, 3,5,7,4'-tetramethoxyflavone, and investigated their anti-inflammatory effects in rat basophilic leukemia (RBL-2H3) cells stimulated with an IgE antigen or a calcium ionophore. We found that DMF and TMF more potently inhibited antigen-induced degranulation than did nobiletin, a well known anti-inflammatory agent. In addition, compared to RBL-2H3 cells stimulated with a calcium ionophore, those treated with DMF and TMF showed more marked inhibition of the degranulation and the production and mRNA expression of inflammatory mediators. These results suggest that DMF and TMF inhibit an early step in the high-affinity IgE receptor signaling cascade rather than intracellular calcium release and protein kinase C activation. PMID- 25035990 TI - 1-Kestose consumption during pregnancy and lactation increases the levels of IgA in the milk of lactating mice. AB - To examine the effect of dietary supplementation with 1-kestose on the IgA levels in milk, BALB/c mice were fed diets with or without 5% 1-kestose during pregnancy and lactation. The total and specific IgA levels in the milk were measured at 7 and 14 days after delivery. A two-way ANOVA with repeated measures resulted in a significant effect of 1-kestose-supplementation on total IgA concentrations (p < 0.05) and the level of anti-Bacteroides IgA (p < 0.05). A significant positive correlation was found between the mean count of Bacteroides spp. in maternal feces and the total IgA concentration in maternal milk (r = 0.55, p < 0.05), suggesting a potential link between the gut and mammary gland immune system. In conclusion, this study demonstrated the effects of dietary prebiotics on milk IgA production. PMID- 25035991 TI - Supplementation of Vitis thunbergii root extract alleviated high-fat diet-induced obesity in C57BL/6J mice. AB - Vitis thunbergii root, widely used as folk medicine in Taiwan, has been found to contain polyphenolic compounds and resveratrol derivatives, which have been implicated in the prevention and treatment of obesity. Thus, we hypothesized it might show beneficial effects against obesity. C57BL/6JNarl mice fed with a high fat diet for 14 weeks increased body weight and epididymal fat pad weight, and accompanied by fatty liver, hyperglycemia, hyperinsulinemia, insulin resistance, hyperleptinemia, hypercholesterolemia, hyper-LDL-cholesterol, and high level of serum GPT, GOT, creatinine, and BUN. Supplementation of VTE in the last 7 weeks remarkably decreased body weight and epididymal fat pad weight, implying a potential anti-obesity effect. Mechanistic study showed that VTE supplementation increased energy expenditure-related CPT1 mRNA expression and AMPK phosphorylation, and decreased lipogenesis-related SREBP-1 expression in liver. In conclusion, Vitis thunbergii roots could alleviate high fat diet-induced obesity and its related complications by enhancing hepatic fatty acid oxidation and inhibitng lipogenesis. PMID- 25035992 TI - Extraction of arbutin and its comparative content in branches, leaves, stems, and fruits of Japanese pear Pyrus pyrifolia cv. Kousui. AB - Arbutin is a tyrosinase inhibitor and is extensively used as a human skin whitening agent. This study investigated the optimum conditions for extracting arbutin by ultrasonic homogenization from discarded branches pruned from Japanese pear (Pyrus pyrifolia cv. Kousui) trees. The arbutin content was measured in the branches and also in the leaves, stems, fruit peel, and fruit flesh. PMID- 25035993 TI - Contributions of tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase to the conversion of D-tryptophan to nicotinamide analyzed by using tryptophan 2,3 dioxygenase-knockout mice. AB - We investigated the contribution percentage of tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) to the conversion of D-tryptophan to nicotinamide in TDO-knockout mice. The calculated percentage conversions indicated that TDO and IDO oxidized 70 and 30%, respectively, of the dietary L tryptophan. These results indicate that both TDO and IDO biosynthesize nicotinamide from D-tryptophan and L-tryptophan in mice. PMID- 25035994 TI - Bio-functional pickles that reduce blood pressure of rats. AB - Addition of gamma-aminobutyric acid (GABA) and angiotensin converting enzyme (ACE)-inhibitory peptides to the pickles was studied in order to develop a new type of pickles that reduce blood pressure. Based on the outcome of these studies, a new type of fermentation bed composed of rice bran and white miso has been successfully developed. The advantage of such pickles is that they not only contain both GABA and ACE-inhibitory peptides, but also that their taste and flavor are excellent, with colors close to the original ones. The new type of pickles could temporarily reduce blood pressure in two types of rats, spontaneously hypertensive rats and NaCl-sensitive model rats. Thus, the newly developed pickles appear to be beneficial for pickle business. PMID- 25035995 TI - Phylogenetic relationship of Paenibacillus species based on putative replication origin regions and analysis of an yheCD-like sequence found in this region. AB - To determine the phylogenetic relationship among Paenibacillus species, putative replication origin regions were compared. In the rsmG-gyrA region, gene arrangements in Paenibacillus species were identical to those of Bacillus species, with the exception of an open reading frame (orf14) positioned between gyrB and gyrA, which was observed only in Paenibacillus species. The orf14 product was homologous to the endospore-associated proteins YheC and YheD of Bacillus subtilis. Phylogenetic analysis based on the YheCD proteins suggested that Orf14 could be categorized into the YheC group. In the Paenibacillus genome, DnaA box clusters were found in rpmH-dnaA and dnaA-dnaN intergenic regions, known as box regions C and R, respectively; this localization was similar to that observed in B. halodurans. A phylogenetic tree based on the nucleotide sequences of the whole replication origin regions suggested that P. popilliae, P. thiaminolyticus, and P. dendritiformis are closely related species. PMID- 25035996 TI - Cell motility and biofilm formation in Bacillus subtilis are affected by the ribosomal proteins, S11 and S21. AB - Bacillus subtilis differentiates into various cellular states in response to environmental changes. It exists in two states during the exponential growth phase: motile cells and connected chains of sessile cells. Here, we identified new regulators of cell motility and chaining, the ribosomal proteins S21 (rpsU) and S11 (rpsK). Their mutants showed impaired cell motility (observed in a laboratory strain) and robust biofilm formation (observed in an undomesticated strain). The two major operons for biofilm formation, tapA-sipW-tasA and epsA-O, were strongly expressed in the rpsU mutant, whereas the flagellin-encoding hag gene and other SigD-dependent motility regulons were not. Genetic analysis revealed that the mutation of remA, the transcriptional activator of the eps operon, is epistatic to that of rpsU, whereas the mutation of antagonistic regulators of SinR is not. Our studies demonstrate that S11 and S21 participate in the regulation of bistability via the RemA/RemB pathway. PMID- 25035997 TI - Pyrosequencing-based analysis of bacterial community and metabolites profiles in Korean traditional seafood fermentation: a flatfish-fermented seafood. AB - Bacterial community and metabolites were analyzed in a flatfish jeotgal, a Korean fermented seafood. Inverse relationship of pH and 16S rRNA gene copy number was identified during fermentation. Lactobacillus was the predominant bacterial genus. Increase of Firmicutes was a common characteristic shared by other fermented seafood. Fructose, glucose, and maltose were the major metabolites. PMID- 25035998 TI - Isolation of diploid baker's yeast capable of strongly activating immune cells and analyses of the cell wall structure. AB - Diploid baker's yeast capable of strongly activating a mouse macrophage was constructed based on haploid mutant AQ-37 obtained previously. The obtained strain BQ-55 activated also human immune cells. To clarify a factor for the activation, the cell wall structure, especially the beta-glucan structure, was analyzed, suggesting that the length of branching, beta-1,6-glucan, may be one of the factors. PMID- 25036000 TI - A novel dinuclear ruthenium(II)-copper(II) complex-based luminescent probe for hydrogen sulfide. AB - A novel dinuclear ruthenium(II)-copper(II) complex, [Ru(bpy)2(phen-cyc)Cu](PF6)4 (bpy: 2,2'-bipyridine; cyc: 1,4,7,10-tetraazacyclododecane; phen: 1,10 phenanthroline), has been designed and synthesized by conjugating a ruthenium(II) complex with a cyclen-Cu(2+) complex. This has almost no luminescence due to the efficient quenching by Cu(2+) of the luminescence of the ruthenium(II) complex. In aqueous media, the reaction of [Ru(bpy)2(phen-cyc)Cu](PF6)4 with hydrogen sulfide results in the release of the Cu(2+) from the azamacrocyclic ring, accompanied by a ~130-fold increase in the luminescence intensity at 605 nm with a 159 nm Stokes shift. The dose-dependent luminescence enhancement shows a good linearity in a concentration range of 2.0 to 20 MUM, with a detection limit of 21.6 nM for hydrogen sulfide. In addition, the luminescence response of [Ru(bpy)2(phen-cyc)Cu](PF6)4 to hydrogen sulfide is very rapid and widely available in the pH range of 3.0-9.5. It also has excellent selectivity so it can distinguish hydrogen sulfide with no interference by other anions and amino acids. On the basis of these features, a rapid, highly selective and sensitive luminescence method for the detection of hydrogen sulfide under physiological conditions was established, using [Ru(bpy)2(phen-cyc)Cu](PF6)4 as a probe. PMID- 25035999 TI - Cardiac applications of optogenetics. AB - In complex multicellular systems, such as the brain or the heart, the ability to selectively perturb and observe the response of individual components at the cellular level and with millisecond resolution in time, is essential for mechanistic understanding of function. Optogenetics uses genetic encoding of light sensitivity (by the expression of microbial opsins) to provide such capabilities for manipulation, recording, and control by light with cell specificity and high spatiotemporal resolution. As an optical approach, it is inherently scalable for remote and parallel interrogation of biological function at the tissue level; with implantable miniaturized devices, the technique is uniquely suitable for in vivo tracking of function, as illustrated by numerous applications in the brain. Its expansion into the cardiac area has been slow. Here, using examples from published research and original data, we focus on optogenetics applications to cardiac electrophysiology, specifically dealing with the ability to manipulate membrane voltage by light with implications for cardiac pacing, cardioversion, cell communication, and arrhythmia research, in general. We discuss gene and cell delivery methods of inscribing light sensitivity in cardiac tissue, functionality of the light-sensitive ion channels within different types of cardiac cells, utility in probing electrical coupling between different cell types, approaches and design solutions to all-optical electrophysiology by the combination of optogenetic sensors and actuators, and specific challenges in moving towards in vivo cardiac optogenetics. PMID- 25036002 TI - Refining the audiological assessment in children using narrow-band CE-Chirp evoked auditory steady state responses. AB - OBJECTIVE: To demonstrate the feasibility and reliability of simultaneous binaural recording of auditory steady-state responses (ASSR) in young children using narrow-band CE-Chirps as stimuli. DESIGN: Prospective cohort study comparing ASSR thresholds to four frequency stimuli (0.5, 1, 2, and 4 kHz), with click-evoked auditory brainstem responses (ABR) and behavioral response audiometry. STUDY SAMPLE: Thirty-two young children (mean age 7.4 +/- 5.2 months) referred for auditory assessment were evaluated. RESULTS: The mean duration for ABR recordings was 13.3 +/- 7.2 min versus 22.9 +/- 15.8 min for ASSR (p < 0.01). ASSR (means of 2 and 4 kHz thresholds) were highly correlated with ABR thresholds (R2 = 0.935, p < 0.001), though significantly different (3 +/- 10.7 dB, p = 0.02). ASSR (means of 0.5, 1, 2, and 4 kHz thresholds) were highly correlated with mean behavioral response audiometry thresholds (R2 = 0.968, p < 0.001). ASSRs were highly and significantly correlated with behavioral response audiometry at 0.5, 1, 2, and 4 kHz (R2 = 0.845, 0.907, 0.929, and 0.859 respectively, p < 0.001). 87.5% and 90.7% ASSR thresholds were within a +/- 10 dB range around their corresponding ABR and mean behavioral response audiometry thresholds. CONCLUSIONS: Narrow-band CE-Chirps allow a fast and reliable assessment of auditory thresholds in children, especially in the low-frequency range, by comparison with other stimuli. PMID- 25036001 TI - Structure-based rational design to enhance the solubility and thermostability of a bacterial laccase Lac15. AB - Bacterial laccases are ideal alternatives of fungal laccases for specific industrial applications due to specific characteristics such as alkalescence dependence and high chloride tolerance. However, some bacterial laccases presented as inclusion bodies when expressing in Escherichia coli and showed thermal instability. In this study, rational design was employed to enhance the solubility and the thermostablity of the bacterial laccase Lac15-His6 based on the crystal structure obtained previously. After deletion of His-tag and residues323-332, the obtained Lac15D was completely expressed in soluble form even at a higher temperature of 28 degrees C, compared to only 50% of Lac15-His6 expressed solubly at 16 degrees C. It showed a two-time higher activity at temperatures lower than 35 degrees C and a half-life increasing from 72 min to 150 min at 45 degrees C. When used in chromogenic reactions, Lac15D showed constant activity toward dye precursors and their combinations under alkaline conditions, demonstrating its application potential in hair coloring biotechnology. PMID- 25036003 TI - Variability in temperature-related mortality projections under climate change. AB - BACKGROUND: Most studies that have assessed impacts on mortality of future temperature increases have relied on a small number of simulations and have not addressed the variability and sources of uncertainty in their mortality projections. OBJECTIVES: We assessed the variability of temperature projections and dependent future mortality distributions, using a large panel of temperature simulations based on different climate models and emission scenarios. METHODS: We used historical data from 1990 through 2007 for Montreal, Quebec, Canada, and Poisson regression models to estimate relative risks (RR) for daily nonaccidental mortality in association with three different daily temperature metrics (mean, minimum, and maximum temperature) during June through August. To estimate future numbers of deaths attributable to ambient temperatures and the uncertainty of the estimates, we used 32 different simulations of daily temperatures for June-August 2020-2037 derived from three global climate models (GCMs) and a Canadian regional climate model with three sets of RRs (one based on the observed historical data, and two on bootstrap samples that generated the 95% CI of the attributable number (AN) of deaths). We then used analysis of covariance to evaluate the influence of the simulation, the projected year, and the sets of RRs used to derive the attributable numbers of deaths. RESULTS: We found that < 1% of the variability in the distributions of simulated temperature for June-August of 2020-2037 was explained by differences among the simulations. Estimated ANs for 2020-2037 ranged from 34 to 174 per summer (i.e., June-August). Most of the variability in mortality projections (38%) was related to the temperature-mortality RR used to estimate the ANs. CONCLUSIONS: The choice of the RR estimate for the association between temperature and mortality may be important to reduce uncertainty in mortality projections. PMID- 25036004 TI - Expression of prtA from Photorhabdus luminescens in Bacillus thuringiensis enhances mortality in lepidopteran larvae by sub-cutaneous but not oral infection. AB - The prtA gene from Photorhabdus luminescens encodes the virulence factor Protease A. When P. luminescens is injected into the hemocoel of insects by entomopathogenic nematodes, PrtA is a key component of pathogenicity thought to help degrade the immune system. The prtA gene was cloned and introduced on a plasmid into Bacillus thuringiensis. PrtA was shown to be actively expressed in vitro by cleavage of a specific Dabcyl-Edans heptapeptide substrate. There was no difference in the speed or level of mortality when spores and delta-endotoxins crystals of the transformed strain were fed to larvae of Pieris brassicae, as compared to the wild-type strain. When vegetative cells were injected into the hemocoel of larvae of Galleriamellonella, however, there was a significant increase in the rate and level of mortality over the wild type. The yield of B. thuringiensis per cadaver was a hundred-fold greater in the PrtA-secreting strain. The increased pathogenicity from intrahemocoelic infection may have been due to a greater ability to overcome the immune response of G. mellonella while other factors such as resident gut bacteria may have negated this advantage after oral dosage. PMID- 25036005 TI - Geometrical spin frustration in Pr5Ni2Si3 composed of triangular crystal lattices. AB - We have studied the transport, magnetic and thermal properties of Pr5Ni2Si3 with complex triangular lattices under various magnetic fields. The ferromagnetic transitions in the basal plane were observed at T(C1) = 52 K and T(C2) = 65 K. A decrease in magnetization below 30 K and the reduced paramagnetic Curie temperature thetaP are indicative of the development of antiferromagnetic correlation. These features are well understood by the frustration effect of the magnetic moments of Pr ions which constitute the triangular structural unit. The frustration caused the rapid rise of electrical resistivity below 30 K and an enormous entropy in low-temperature regions. The antiferromagnetic correlation acting between the frustrated Pr ions never causes any long-range order down to 0.6 K. PMID- 25036006 TI - Shisa3 is associated with prolonged survival through promoting beta-catenin degradation in lung cancer. AB - RATIONALE: Despite advances in treatment and prognosis of non-small cell lung cancer (NSCLC), patient outcomes are still unsatisfactory. OBJECTIVES: To reduce the morbidity and mortality of patients with NSCLC, a more comprehensive understanding of mechanisms involved in cancer progression is urgently needed. METHODS: By comparison of gene expression profiles in the cell line pair with differential invasion ability, CL1-0 and CL1-5, we found that Shisa3 was highly expressed in the low invasive cells. The effect of Shisa3 on invasion, migration, proliferation, apoptosis, epithelial-mesenchymal transition, and anchorage independent growth activities in vitro and on tumor growth and metastasis in mice models were examined. The underlying mechanism of Shisa3 was explored by microarray and pathway analysis. Finally, the correlation of Shisa3 expression and clinical outcome was also calculated. MEASUREMENTS AND MAIN RESULTS: We identified Shisa3 as a novel tumor suppressor, which induces beta-catenin degradation resulting in suppression of tumorigenesis and invasion in vitro. Shisa3 decreased the tumor growth in mice with subcutaneous implantation and reduced the number of metastatic nodules in mice with tail vein injection and orthotopic implantation. Shisa3 performs the tumor suppression activity through WNT signaling predicted by microarray analysis. Our data found that Shisa3 accelerates beta-catenin degradation and was positively associated with overall survival and progression-free survival of NSCLC. CONCLUSIONS: Our results reveal that Shisa3 acts as a tumor suppressor by acceleration of beta-catenin degradation and provide new insight for cancer prognosis and therapy. PMID- 25036007 TI - Boiling at a different degree: an investigation of trait and state anger in remitted bipolar I disorder. AB - BACKGROUND: Elevated anger is a prominent clinical feature of bipolar disorder (BD). However, it is unclear whether this feature is characterized by elevated trait anger (i.e., how much anger one experiences in general) and/or state anger (i.e., how much anger one experiences when provoked), how stable anger elevations are (i.e., whether they appear during remission), and whether they have prognostic significance. METHODS: The present study assessed trait anger as well as state anger during a neutral baseline and a validated laboratory anger provocation among adults with remitted bipolar I disorder (BD; n=27) and healthy controls (CTL; n=29). To examine prognostic significance, we assessed manic and depressive symptom severity one year later in a subsample of BD participants (n=18). RESULTS: Results revealed greater trait anger as well as state anger experience at baseline for the BD compared to the CTL group. No group differences emerged in anger during the provocation. Anger did not predict symptom severity, but greater positive emotion during the provocation predicted mania (but not depression) symptom severity. LIMITATIONS: We utilized a relatively high functioning sample of remitted BD patients. Future studies should include BD patients with current mood episodes and more diverse functioning, to ensure generalizability of our results. CONCLUSIONS: These findings suggest that BD is characterized by elevated trait and baseline state anger, but not greater responding to anger provocation. Persistently elevated anger may represent a marker of BD, and context-inappropriate positive emotion experience during anger provocation may constitute a vulnerability factor for mania severity. PMID- 25036008 TI - An fMRI study of emotional face processing in adolescent major depression. AB - BACKGROUND: Major depressive disorder (MDD) often begins during adolescence when the brain is still maturing. To better understand the neurobiological underpinnings of MDD early in development, this study examined brain function in response to emotional faces in adolescents with MDD and healthy (HC) adolescents using functional magnetic resonance imaging (fMRI). METHOD: Thirty-two unmedicated adolescents with MDD and 23 healthy age- and gender-matched controls completed an fMRI task viewing happy and fearful faces. Fronto-limbic regions of interest (ROI; bilateral amygdala, insula, subgenual and rostral anterior cingulate cortices) and whole-brain analyses were conducted to examine between group differences in brain function. RESULTS: ROI analyses revealed that patients had greater bilateral amygdala activity than HC in response to viewing fearful versus happy faces, which remained significant when controlling for comorbid anxiety. Whole-brain analyses revealed that adolescents with MDD had lower activation compared to HC in a right hemisphere cluster comprised of the insula, superior/middle temporal gyrus, and Heschl's gyrus when viewing fearful faces. Brain activity in the subgenual anterior cingulate cortex was inversely correlated with depression severity. LIMITATIONS: Limitations include a cross sectional design with a modest sample size and use of a limited range of emotional stimuli. CONCLUSIONS: Results replicate previous studies that suggest emotion processing in adolescent MDD is associated with abnormalities within fronto-limbic brain regions. Findings implicate elevated amygdalar arousal to negative stimuli in adolescents with depression and provide new evidence for a deficit in functioning of the saliency network, which may be a future target for early intervention and MDD treatment. PMID- 25036009 TI - Openness predicts cognitive functioning in bipolar disorder. AB - OBJECTIVES: Openness to experience (O) is a well-established personality factor and is associated with cognitive performance. Little is known about the personality-cognitive relationship in bipolar disorder, an illness with significant variability in mood. Cognitive evaluation is essential in psychopathology assessment as it may reflect underlying disease processes and psychosocial functional capacity. Screening using a proxy personality variable may identify those in need of comprehensive cognitive testing. We hypothesized that O and measures of cognition would associate in both the Bipolar Disorder (BD) and healthy control (HC) samples, whereas neuroticism and extraversion would correlate with cognition only in the BD sample. METHODS: Data from a longitudinal study of BD were used to study the association between personality factors and cognitive measures of attention, executive functioning, memory and fine motor skills. Regression analyses were used to determine the variables that account for the association between personality and cognition. RESULTS: Aspects of O explained significant cognitive variance (~5%) in both groups; this persisted when demographic variables (including BD versus HC status) were considered. Neuroticism and extraversion did not consistently correlate with cognitive performance in either group. LIMITATIONS: There were more females in the HC group who were slightly younger compared to the BD group. We lack direct measures of positive affect, and there is a reliance on a single measure of personality. CONCLUSIONS: BD Individuals scoring low on self-reported Openness are potential candidates for more comprehensive cognitive assessments (which represent a limited resource). PMID- 25036010 TI - Childhood trauma associates with clinical features of bipolar disorder in a sample of Chinese patients. AB - OBJECTIVES: Childhood trauma is a major public health problem which has a long term consequence, a few studies have examined the relationship between childhood trauma and clinical features of bipolar disorder, most in western culture, with no such studies done in Chinese culture. METHODS: The CTQ-SF was administered to 132 Chinese patients with DSM-IV bipolar disorder. Participants also completed the Childhood Experience of Care and Abuse Questionnaire (CECA.Q), the Impact of Events Scale-Revised (IES-R), and the State-Trait Anxiety Inventory (STAI). The CTQ-SF cut-off scores for exposure were used to calculate the prevalence of trauma. The relationship between childhood trauma and clinical features of bipolar disorder were examined. RESULTS: The internal consistency of CTQ-SF was good (Cronbach's alpha=0.826) and four week test-retest reliability was high (r=0.755). 61.4% of this sample reported physical neglect (PN) in childhood, followed by emotional neglect (EN, 49.6%), sexual abuse (SA, 40.5%), emotional abuse (EA, 26.0%) and physical abuse (PA,13.1%). Significant negative correlations existed between age of onset and EA and EN score (r=-0.178~-0.183, p<0.05). Significant positive correlations were observed between EA, CTQ-SF total score and intrusion and hyper-arousal scores of IES-R (r=0.223~0.309, p<0.05). Similarly, significant positive correlations were found between EN, PN, CTQ-SF total and STAI score (r=0.222~0.425, p<0.05). LIMITATIONS: Data on childhood trauma were derived from a retrospective self-report questionnaire without independent corroboration. A number of potential patients (more severe or chronic patients) was excluded because they were either refused to participate or inappropriate to participate in research. CONCLUSIONS: Significant number of subjects in patients with BD reported experience of childhood abuse and neglect. Exposure to childhood trauma is associated with age of onset of illness, co morbid PTSD and anxiety symptoms. To study the pathogenesis of childhood trauma on bipolar disorder and explanation the interaction between childhood trauma and susceptibility genes are proposed. PMID- 25036011 TI - Getting "just deserts" or seeing the "silver lining": the relation between judgments of immanent and ultimate justice. AB - People can perceive misfortunes as caused by previous bad deeds (immanent justice reasoning) or resulting in ultimate compensation (ultimate justice reasoning). Across two studies, we investigated the relation between these types of justice reasoning and identified the processes (perceptions of deservingness) that underlie them for both others (Study 1) and the self (Study 2). Study 1 demonstrated that observers engaged in more ultimate (vs. immanent) justice reasoning for a "good" victim and greater immanent (vs. ultimate) justice reasoning for a "bad" victim. In Study 2, participants' construals of their bad breaks varied as a function of their self-worth, with greater ultimate (immanent) justice reasoning for participants with higher (lower) self-esteem. Across both studies, perceived deservingness of bad breaks or perceived deservingness of ultimate compensation mediated immanent and ultimate justice reasoning respectively. PMID- 25036013 TI - The influence of gender equality policies on gender inequalities in health in Europe. AB - Few studies have addressed the effect of gender policies on women's health and gender inequalities in health. This study aims to analyse the relationship between the orientation of public gender equality policies and gender inequalities in health in European countries, and whether this relationship is mediated by gender equality at country level or by other individual social determinants of health. A multilevel cross-sectional study was performed using individual-level data extracted from the European Social Survey 2010. The study sample consisted of 23,782 men and 28,655 women from 26 European countries. The dependent variable was self-perceived health. Individual independent variables were gender, age, immigrant status, educational level, partner status and employment status. The main contextual independent variable was a modification of Korpi's typology of family policy models (Dual-earner, Traditional-Central, Traditional-Southern, Market-oriented and Contradictory). Other contextual variables were the Gender Empowerment Measure (GEM), to measure country-level gender equality, and the Gross Domestic Product (GDP). For each country and country typology the prevalence of fair/poor health by gender was calculated and prevalence ratios (PR, women compared to men) and 95% confidence intervals (CI) were computed. Multilevel robust Poisson regression models were fitted. Women had poorer self-perceived health than men in countries with traditional family policies (PR = 1.13, 95%CI: 1.07-1.21 in Traditional-Central and PR = 1.27, 95%CI: 1.19-1.35 in Traditional-Southern) and in Contradictory countries (PR = 1.08, 95%CI: 1.05-1.11). In multilevel models, only gender inequalities in Traditional-Southern countries were significantly higher than those in Dual earner countries. Gender inequalities in self-perceived health were higher, women reporting worse self-perceived health than men, in countries with family policies that were less oriented to gender equality (especially in the Traditional Southern country-group). This was partially explained by gender inequalities in the individual social determinants of health but not by GEM or GDP. PMID- 25036014 TI - Exploring socio-cultural factors that mediate, facilitate, & constrain the health and empowerment of refugee youth. AB - Studies on youth health and well-being are predominantly quantitative and expert driven with less attention given to how youth understand what it means to be healthy themselves and the role of socio-cultural factors in shaping this. Knowledge on the perceptions and experiences of refugee youth is particularly lacking and notable given their unique stressors related to migratory, settlement and integration experiences. We contribute a better understanding of how refugee youth themselves define and contextualize health, with particular emphasis given to socio-cultural factors that enable or constrain health promotion efforts and individual health agency. This research was undertaken at a downtown drop-in centre in Hamilton, Ontario, Canada that provided settlement and integration services to newcomer youth. We employ a grounded theory approach and draw upon participant observation, focus groups and in-depth interviews. Twenty-six youth (age 18-25 years), representing 12 different countries of origin participated. The youth defined health very broadly touching upon many typical determinants of health (e.g. education, income, etc.). Yet factors of most importance (as demonstrated by the frequency and urgency in which they were discussed by youth) included a sense of belonging, positive self-identity, emotional well-being, and sense of agency or self-determination. We conceptualize these as "mediating" factors given the youth argued they enabled or constrained their ability to cope with adversities related to other health determinant categories. The youth also discussed what we interpret as "facilitators" that encourage mediating factors to manifest positively (e.g. informal, non-biomedical settings and programs that nurture trust, break down access barriers, and promote a sense of community amongst peers, mentors, and health professionals). When creating health promotion strategies for refugee youth (and perhaps youth more generally) it is important to understand the factors that may mediate the magnitude of effects from various risks/stressors, in addition to those which facilitate health agency. PMID- 25036012 TI - Computational investigation of locked nucleic acid (LNA) nucleotides in the active sites of DNA polymerases by molecular docking simulations. AB - Aptamers constitute a potential class of therapeutic molecules typically selected from a large pool of oligonucleotides against a specific target. With a scope of developing unique shorter aptamers with very high biostability and affinity, locked nucleic acid (LNA) nucleotides have been investigated as a substrate for various polymerases. Various reports showed that some thermophilic B-family DNA polymerases, particularly KOD and Phusion DNA polymerases, accepted LNA nucleoside 5'-triphosphates as substrates. In this study, we investigated the docking of LNA nucleotides in the active sites of RB69 and KOD DNA polymerases by molecular docking simulations. The study revealed that the incoming LNA-TTP is bound in the active site of the RB69 and KOD DNA polymerases in a manner similar to that seen in the case of dTTP, and with LNA structure, there is no other option than the locked C3'-endo conformation which in fact helps better orienting within the active site. PMID- 25036016 TI - The alteration of 18F-FDG uptake in bone marrow after treatment with interleukin 11. AB - Diffuse increased F-FDG in the bone marrow can be seen with colony-stimulating factors. Here, we reported a case of idiopathic cytopenia of undetermined significance treated with interleukin 11. After administration of interleukin 11, both diffuse and focally increased FDG activity in the bone marrow were noted. The focal activity was histologically proven as hyperplastic bone marrow. PMID- 25036018 TI - Unusual uptake of radioiodine in the small bowel in a patient with thyroid cancer and bowel malrotation. AB - Whole-body radioiodide scan is an essential procedure in the evaluation of radioiodine-avid metastatic foci in patients with differentiated thyroid carcinoma. Normal physiologic distribution of the radiotracer includes the stomach and colon, but the small intestine is not often seen. Gastrointestinal anatomic variants may be associated with atypical activity on I scan. We report here a case of intestinal malrotation with associated I uptake in the small intestine. Careful correlation of planar imaging with SPECT/CT revealed the likely malrotation as well as small bowel uptake superimposed over normal colonic uptake. This finding was occult on prior I scan. PMID- 25036020 TI - Tips for a physician in getting the right job, part XV: selected interview points. AB - The interview is usually a major determinant on whether or not a physician job applicant is hired. This article addresses a number of fine points for the interview not previously emphasized in this series of articles. For example, the job candidate needs to be careful that the questions he/she asks are not negative and show respect and sensitivity to the interviewer. Some types of questions should not generally be asked. One technique to get at information is to use neutral open-ended questions. The importance of personal observations is emphasized. However, if the interview does not seem to be going well, the candidate may want to directly address that. The spouse should also ask appropriate questions regarding the community and not reveal information on certain subjects such as how many other offers the job hunter has and any reservations they have regarding the job or the area. PMID- 25036015 TI - Use of 18F-FDG PET/CT imaging for evaluation of patients with primary splenic lymphoma. AB - Primary splenic lymphoma (PSL) is a rare disease, and its management differs from other splenic malignancies. The purpose of the present study was to evaluate the role of 18F-FDG PET/CT in patients with PSL. METHODS: We retrospectively evaluated the data of 17 patients with PSL (median age, 46 years; range, 3-64) who had undergone 50 18F-FDG PET/CT studies. Of the 50 PET/CTs, 15 were done for primary diagnosis/staging and 35 were done for restaging. PET/CT images were evaluated both qualitatively and quantitatively [maximum standardized uptake value (SUVmax)]. Combination of clinical/imaging follow-up and/or histopathologic diagnosis was taken as reference standard. RESULTS: Of the total 50 F-FDG PET/CT studies, 27 studies (54%) were positive and 23 (46%) were negative for disease. PET/CT was true positive in 25 studies, true negative in 22 studies, false positive in 2 studies, and false negative in 1 study. Overall, per study-based sensitivity was 96.2%, specificity was 91.7%, and accuracy was 94%. In those studies performed for diagnosis/staging (15/50), PET/CT was true positive in all 15, with an accuracy of 100%. In those studies performed for restaging (35/50), sensitivity was 90.9%, specificity was 91.7%, and accuracy was 91.4%. No significant difference was seen in the accuracy of PET/CT between staging and restaging groups (P=0.601). On 18F-FDG PET/CT, splenic involvement was seen in 24 studies, lymph nodal involvement in 5 studies, liver involvement in 3 studies, and bone marrow involvement in 1 study. More than one site of disease was seen in 9 PET/CT studies. On semiquantitative analysis, the overall mean splenic lesion SUVmax was 6.9+/-7.9 (median, 4.6; range, 1.3-29). The mean value of ratio of SUVmax of splenic lesions and SUVliver was 4.4+/-5.5 (median, 2.4; range, 0.9 24.2). On comparison of areas under the curve, the mean value of ratio of SUVmax of splenic lesions and SUVliver was found to be superior to SUVmax alone for this differentiation of involvement from normal spleen (P=0.018). CONCLUSION: 18F-FDG PET/CT seems useful in patients with primary splenic lymphoma and shows high diagnostic accuracy. PMID- 25036017 TI - Unexpectedly expected fetal thyroid function on posttreated radioiodine (131I) SPECT/CT of a patient with differentiated thyroid cancer. AB - We present a 25-year-old woman who has a diagnosis of differentiated thyroid cancer, a 2.5-cm papillary carcinoma in the right lobe, and presence of minimal extrathyroid invasion. 131I ablation and/or treatment of 150 mCi was given orally 3 months after total thyroidectomy. A fetus with radioiodine uptake in the fetal thyroid was unsuspectedly detected by SPECT/CT after 131I treatment. PMID- 25036019 TI - The effect of radioactive iodine treatment on 14C urea breath test results in patients with hyperthyroidism. AB - PURPOSE: Radioactive Iodine therapy (RAIT) plays a major role in the treatment of hyperthyroidism. In addition to the thyroid gland, significant amounts of radioactive iodine are maintained in the stomach. The aim of this study was to determine if RAIT has any effect on Helicobacter pylori infection, based on the C urea breath test (UBT). MATERIALS AND METHODS: The study included 85 patients with hyperthyroidism scheduled to undergo RAIT and 69 hyperthyroid subjects in whom methimazole treatment was planned. All subjects had pretreatment-positive UBT results, and the test was repeated on the first and third months after RAIT and methimazole treatment. RESULTS: After a mean RAIT dose of 15 mCi (range, 10 20 mCi), UBT became negative in 13 (15.3%) of 85 patients on the first month and 18 (21.2%) of 85 patients on the third month. All subjects treated with methimazole remained UBT positive on the first and third months of methimazole treatment (100%). Reduction in the number of UBT-positive patients on both the first and the third months after RAIT was statistically significant (P < 0.001). Distribution of hyperthyroidism etiologies and thyroid autoantibody levels in subjects with UBT that became negative and in subjects with UBT that remained positive were similar in the RAIT group (P > 0.05). Urea breath test negativity rates did not differ according to the radioiodine dose. CONCLUSIONS: Our findings indirectly showed that RAIT might have an antimicrobial effect on H. pylori. Clinical applications of this beneficial effect of RAIT on H. pylori should be further evaluated. PMID- 25036021 TI - Prostate-specific antigen and prostate-specific antigen velocity as threshold indicators in 11C-acetate PET/CTAC scanning for prostate cancer recurrence. AB - PURPOSE: The aim of this study was to identify which patient characteristics are associated with the highest likelihood of positive findings on 11C-acetate PET/computed tomography attenuation correction (CTAC) (PET/CTAC) scan when imaging for recurrent prostate cancer. METHODS: From 2007 to 2011, 250 11C acetate PET/CTAC scans were performed at a single institution on patients with prostate cancer recurrence after surgery, brachytherapy, or external beam radiation. Of these patients, 120 met our inclusion criteria. Logistic regression analysis was used to examine the relationship between predictability of positive findings and patients' characteristics, such as prostate-specific antigen (PSA) level at the time of scan, PSA kinetics, Gleason score, staging, and type of treatment before scan. RESULTS: In total, 68.3% of the 120 11C-acetate PET/CTAC scans were positive. The percentage of positive scans and PSA at the time of scanning and PSA velocity (PSAV) had positive correlations. The putative sensitivity and specificity were 86.6% and 65.8%, respectively, when a PSA level greater than 1.24 ng/mL was used as the threshold for scanning. The putative sensitivity and specificity were 74% and 75%, respectively, when a PSAV level greater than 1.32 ng/mL/y was used as the threshold. No significant associations were found between scan positivity and age, PSA doubling time, Gleason score, staging, or type of treatment before scanning. CONCLUSIONS: This retrospective study suggests that threshold models of PSA greater than 1.24 ng/mL or PSAV greater than 1.32 ng/mL per year are independent predictors of positive findings in 11C-acetate PET/CTAC imaging of recurrent prostate cancer. PMID- 25036022 TI - 11C-MET PET/CT and advanced MRI in the evaluation of tumor recurrence in high grade gliomas. AB - OBJECTIVES: The purpose of this study was to evaluate the performance of l [methyl-()11C]methionine (11C-MET) PET/CT and MRI (with the inclusion of advanced imaging techniques, namely, MR spectroscopy and MR perfusion) in the assessment of tumor recurrence in high-grade gliomas. PATIENTS AND METHODS: Twenty-nine patients with high-grade gliomas who underwent surgical resection, external beam radiation therapy, and standard regimens of chemotherapy were subjected to MRI (conventional, MR perfusion, and MR spectroscopy) and 11C-MET PET/CT scans. A definitive diagnosis was made based on histopathology and/or long-term clinical and radiological follow-up. Several indices were obtained for lesion characterization, namely, SUVmean, SUVmax, and mean lesion-to-normal tissue on PET/CT, as well as relative cerebral blood volume and choline-to-creatine ratio on MRI. RESULTS: Histological examination revealed viable tumor cells in 19 cases, whereas the remaining 10 were deemed to be negative based on histology (3 cases) or long-term follow-up (7 cases). All the quantitative indices mentioned previously tended to be higher in patients with tumor recurrence/residual. The sensitivity, specificity, and accuracy of 11C-MET PET/CT in identifying tumor recurrence/residual were 94.7%, 80%, and 89.6%, respectively, whereas that of MRI were 84.2%, 90%, and 86.2%, respectively. CONCLUSIONS: Both 11C-MET PET/CT and MRI (with the inclusion of advanced MRI techniques) demonstrated a high diagnostic performance in the identification of tumor residual/recurrence in high grade gliomas posttherapy. Although 11C-MET PET/CT seemed to be more sensitive, whereas advanced MRI seemed more specific, there was no statistically significant difference in the diagnostic performance of either modality in the present study. Further studies with a larger group of patients are warranted. PMID- 25036023 TI - An overview of managing stuttering in Japan. AB - PURPOSE: The purpose of this article is to describe the rapid development of speech-language pathology in Japan since governmental licensing started in 1997 and to summarize the current trends in assessing and treating stuttering for preschoolers, school-age children, adolescents, and adults. METHOD: The authors review relevant information about the current assessment and treatment services for people who stutter in Japan and discuss the issues and challenges faced by speech-language pathologists in managing stuttering. CONCLUSION: It is predicted that as expertise in stuttering grows in Japan, the role of stuttering specialists in allied health, school districts, and research will increase. PMID- 25036024 TI - Guest-induced supramolecular chirality in a ditopic azoprobe-cyclodextrin complex in water. AB - We report a novel supramolecular chirality induced by the twisted structural change of two ditopic azoprobes (15C5-Azo-dpa) inside the chiral cavity of gamma cyclodextrin (gamma-CyD) due to multi-point recognition of guest ions by 15C5-Azo dpa molecules in water. PMID- 25036026 TI - A microfluidic device to sort capsules by deformability: a numerical study. AB - Guided by extensive numerical simulations, we propose a microfluidic device that can sort elastic capsules by their deformability. The device consists of a duct embedded with a semi-cylindrical obstacle, and a diffuser which further enhances the sorting capability. We demonstrate that the device can operate reasonably well under changes in the initial position of the capsule. The efficiency of the device remains essentially unaltered under small changes of the obstacle shape (from semi-circular to semi-elliptic cross-section). Confinement along the direction perpendicular to the plane of the device increases its efficiency. This work is the first numerical study of cell sorting by a realistic microfluidic device. PMID- 25036025 TI - Behavioral and cardiorespiratory responses to bilateral microinjections of oxytocin into the central nucleus of amygdala of Wistar rats, an experimental model of compulsion. AB - INTRODUCTION: The central nucleus of amygdala plays an important role mediating fear and anxiety responses. It is known that oxytocin microinjections into the central nucleus of amygdala induce hypergrooming, an experimental model of compulsive behavior. We evaluated the behavioral and cardiorespiratory responses of conscious rats microinjected with oxytocin into the central nucleus of amygdala. METHODS: Male Wistar rats were implanted with guide cannulae into the central nucleus of amygdala and microinjected with oxytocin (0.5 ug, 1 ug) or saline. After 24 h, rats had a catheter implanted into the femoral artery for pulsatile arterial pressure measurement. The pulsatile arterial pressure was recorded at baseline conditions and data used for cardiovascular variability and baroreflex sensitivity analysis. Respiratory and behavioral parameters were assessed during this data collection session. RESULTS: Microinjections of oxytocin (0.5 ug) into the central nucleus of amygdala produced hypergrooming behavior but did not change cardiorespiratory parameters. However, hypergrooming evoked by microinjections of oxytocin (1 ug) into the central nucleus of amygdala was accompanied by increase in arterial pressure, heart rate and ventilation and augmented the power of low and high (respiratory-related) frequency bands of the systolic arterial pressure spectrum. No changes were observed in power of the low and high frequency bands of the pulse interval spectrum. Baroreflex sensitivity was found lower after oxytocin microinjections, demonstrating that the oxytocin induced pressor response may involve an inhibition of baroreflex pathways and a consequent facilitation of sympathetic outflow to the cardiovascular system. CONCLUSIONS: The microinjection of oxytocin (1 ug) into the central nucleus of amygdala not only induces hypergrooming but also changes cardiorespiratory parameters. Moreover, specific oxytocin receptor antagonism attenuated hypergrooming but did not affect pressor, tachycardic and ventilatory responses to oxytocin, suggesting the involvement of distinct neural pathways. PMID- 25036027 TI - Calcium dependence of eugenol tolerance and toxicity in Saccharomyces cerevisiae. AB - Eugenol is a plant-derived phenolic compound which has recognised therapeutical potential as an antifungal agent. However little is known of either its fungicidal activity or the mechanisms employed by fungi to tolerate eugenol toxicity. A better exploitation of eugenol as a therapeutic agent will therefore depend on addressing this knowledge gap. Eugenol initiates increases in cytosolic Ca2+ in Saccharomyces cerevisiae which is partly dependent on the plasma membrane calcium channel, Cch1p. However, it is unclear whether a toxic cytosolic Ca2+elevation mediates the fungicidal activity of eugenol. In the present study, no significant difference in yeast survival was observed following transient eugenol treatment in the presence or absence of extracellular Ca2+. Furthermore, using yeast expressing apoaequorin to report cytosolic Ca2+ and a range of eugenol derivatives, antifungal activity did not appear to be coupled to Ca2+ influx or cytosolic Ca2+ elevation. Taken together, these results suggest that eugenol toxicity is not dependent on a toxic influx of Ca2+. In contrast, careful control of extracellular Ca2+ (using EGTA or BAPTA) revealed that tolerance of yeast to eugenol depended on Ca2+ influx via Cch1p. These findings expose significant differences between the antifungal activity of eugenol and that of azoles, amiodarone and carvacrol. This study highlights the potential to use eugenol in combination with other antifungal agents that exhibit differing modes of action as antifungal agents to combat drug resistant infections. PMID- 25036028 TI - Phylogeny and evolution of pharmacophagy in tiger moths (Lepidoptera: Erebidae: Arctiinae). AB - The focus of this study was to reconstruct a phylogenetic hypothesis for the moth subfamily Arctiinae (tiger moths, woolly bears) to investigate the evolution of larval and adult pharmacophagy of pyrrolizidine alkaloids (PAs) and the pathway to PA chemical specialization in Arctiinae. Pharmacophagy, collection of chemicals for non-nutritive purposes, is well documented in many species, including the model species Utetheisa ornatrix L. A total of 86 exemplar ingroup species representing tiger moth tribes and subtribes (68 genera) and nine outgroup species were selected. Ingroup species included the most species-rich generic groups to represent the diversity of host-plant associations and pharmacophagous behaviors found throughout Arctiinae. Up to nine genetic markers were sequenced: one mitochondrial (COI barcode region), one nuclear rRNA (D2 region, 28S rRNA), and seven nuclear protein-coding gene fragments: elongation factor 1-alpha protein, wingless, ribosomal protein subunit S5, carbamoylphosphate synthase domain regions, glyceraldehyde-3-phosphate dehydrogenase, isocitrate dehydrogenase and cytosolic malate dehydrogenase. A total of 6984 bp was obtained for most species. These data were analyzed using model-based phylogenetic methods: maximum likelihood (ML) and Bayesian inference (BI). Ancestral pharmacophagous behaviors and obligate PA associations were reconstructed using the resulting Bayes topology and Reconstructing Ancestral States in Phylogenies (RASP) software. Our results corroborate earlier studies on the evolution of adult pharmacophagous behaviors, suggesting that this behavior arose multiple times and is concentrated in the phaegopterine-euchromiine ctenuchine clade (PEC). Our results suggest that PA specialization may have arisen early in the phylogeny of the subfamily and that facultative larval pharmacophagous behaviors are the derived condition. PMID- 25036029 TI - Identification of the multi-resistance gene cfr in Escherichia coli isolates of animal origin. AB - Previous study indicated that the multi-resistance gene cfr was mainly found in gram-positive bacteria, such as Staphylococcus and Enterococcus, and was sporadically detected in Escherichia coli. Little is known about the prevalence and transmission mechanism of cfr in E. coli. In this study, the presence of cfr in E. coli isolates collected during 2010-2012 from food-producing animals in Guangdong Province of China was investigated, and the cfr-positive E. coli isolates were characterized by PFGE, plasmid profiling, and genetic environment analysis. Of the 839 E. coli isolates, 10 isolates from pig were cfr positive. All the cfr-positive isolates presented a multi-resistance phenotype and were genetically divergent as determined by PFGE. In 8 out of the 10 strains, the cfr gene was located on plasmids of ~30 kb. Restriction digestion of the plasmids with EcoRI and sequence hybridization with a cfr-specific probe revealed that the cfr-harboring fragments ranged from 6 to 23 kb and a ~18 kb cfr-carrying fragment was common for the plasmids that were ~30 kb. Four different genetic environments of cfr were detected, in which cfr is flanked by two identical copies of IS26, which may loop out the intervening sequence through homologous recombination. Among the 8 plasmids of ~30 kb, 7 plasmids shared the same genetic environment. These results demonstrate plasmid-carried cfr in E. coli and suggest that transposition and homologous recombination mediated by IS26 might have played a rule in the transfer of the cfr gene in E. coli. PMID- 25036030 TI - Association between toll-like receptor 4 expression and neural stem cell proliferation in the hippocampus following traumatic brain injury in mice. AB - Whether or how neural stem cells (NSCs) respond to toll-like receptor 4 (TLR4) in an inflammatory environment caused by traumatic brain injury (TBI) has not been understood. In the present study, association between TLR4 expression and NSCs proliferation in the hippocampus was investigated in a mouse model of TBI using controlled cortical impact (CCI). Hippocampal proliferating cells were labeled with the thymidine analog 5-bromo-2-deoxyuridine (BrdU). In order to identify NSCs, the proliferating cells were further co-labeled with BrdU/sex determination region of Y chromosome related high mobility group box gene 2 (SOX2). Morphological observation on the expression of BrdU, SOX2, and TLR4 in the hippocampus was performed by inmmunofluorescence (IF). Relative quantification of TLR4 expression at the protein and mRNA level was performed using Western blotting and real-time polymerase chain reaction (PCR). It was observed that BrdU+/SOX2+cells accounted for 95.80%+/-7.91% among BrdU+ cells; several BrdU+ cells and SOX2+ cells in the hippocampus were also TLR4-positive post injury, and that BrdU+ cell numbers, together with TLR4 expression at either protein or mRNA level, increased significantly in TBI mice over 1, 3, 7, 14, and 21 days survivals and changed in a similar temporal pattern with a peak at 3 day post injury. These results indicate that hippocampal proliferating cells (suggestive of NSCs) expressed TLR4, and that there was a potential association between increased expression of TLR4 and the proliferation of NSCs post TBI. It is concluded that hippocampal TLR4 may play a potential role in endogenous neurogenesis after TBI. PMID- 25036032 TI - Novel and functional DNA sequence variants within the GATA6 gene promoter in ventricular septal defects. AB - Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes and underlying molecular mechanisms for isolated CHD remain largely unknown. Studies have demonstrated that GATA transcription factor 6 (GATA6) plays an essential role in the heart development. Mutations in GATA6 gene have been associated with diverse types of CHD. As GATA6 functions in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the CHD development. In the present study, GATA6 gene promoter was genetically and functionally analyzed in large groups of patients with ventricular septal defect (VSD) (n=359) and ethnic-matched healthy controls (n=365). In total, 11 DSVs, including four SNPs, were identified in VSD patients and controls. Two novel and heterozygous DSVs, g.22169190A>T and g.22169311C>G, were identified in two VSD patients, but in none of controls. In cultured cardiomyocytes, the activities of the GATA6 gene promoter were significantly reduced by the DSVs g.22169190A>T and g.22169311C>G. Therefore, our findings suggested that the DSVs within the GATA6 gene promoter identified in VSD patients may change GATA6 levels, contributing to the VSD development as a risk factor. PMID- 25036031 TI - Transforming growth factor-beta1 (TGF-beta1) induces mouse precartilaginous stem cell proliferation through TGF-beta receptor II (TGFRII)-Akt-beta-catenin signaling. AB - Precartilaginous stem cells (PSCs) could self-renew or differentiate into chondrocytes to promote bone growth. In the current study, we aim to understand the role of transforming growth factor-beta1 (TGF-beta1) in precartilaginous stem cell (PSC) proliferation, and to study the underlying mechanisms. We successfully purified and primary-cultured PSCs from the neonate mice' perichondrial mesenchyme, and their phenotype was confirmed by the PSC marker fibroblast growth factor receptor-3 (FGFR-3) overexpression. We found that TGF-beta1 induced Akt glycogen synthase kinase-3beta (GSK3beta) phosphorylation and beta-catenin nuclear translocation in the mouse PSCs, which was almost blocked by TGF-beta receptor-II (TGFRII) shRNA knockdown. Further, perifosine and MK-2206, two Akt specific inhibitors, suppressed TGF-beta1-induced GSK3beta phosphorylation and beta-catenin nuclear translocation. Akt inhibitors, as well as beta-catenin shRNA knockdown largely inhibited TGF-beta1-stimulated cyclin D1/c-myc gene transcription and mouse PSC proliferation. Based on these results, we suggest that TGF-beta1 induces Akt activation to promote beta-catenin nuclear accumulation, which then regulates cyclin D1/c-myc gene transcription to eventually promote mouse PSC proliferation. PMID- 25036033 TI - Role of EZH2 polymorphisms in esophageal squamous cell carcinoma risk in Han Chinese population. AB - Gene single nucleotide polymorphisms play a critical role in the development of esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the associations between EZH2 gene polymorphisms and ESCC risk. We undertook a case-control study to analyze three EZH2 polymorphisms (148505302C>T, 2110+6A>C and 626-394T>C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 476 patients with ESCC and 492 control participants, and performed EZH2 genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in 148505302C>T and 2110+6A>C. However, 626-394T>C genotype was at increased risk of ESCCs (p=0.006; odds ratio (OR)=1.131, CI 95%: 1.034-1.236). Moreover, 626-394C/C genotype ESCCs were more significantly common in patients with tumor size of >5 cm than T allele ESCC and in cases of poor differentiation and lower advanced pathological stage. In conclusion, polymorphism in 626-394T>C was observed to be associated with susceptibility of ESCC. Nevertheless, further investigation with a larger sample size is needed to support our results. PMID- 25036034 TI - Carnosic acid inhibits the epithelial-mesenchymal transition in B16F10 melanoma cells: a possible mechanism for the inhibition of cell migration. AB - Carnosic acid is a natural benzenediol abietane diterpene found in rosemary and exhibits anti-inflammatory, antioxidant, and anti-carcinogenic activities. In this study, we evaluated the effects of carnosic acid on the metastatic characteristics of B16F10 melanoma cells. When B16F10 cells were cultured in an in vitro Transwell system, carnosic acid inhibited cell migration in a dose dependent manner. Carnosic acid suppressed the adhesion of B16F10 cells, as well as the secretion of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, urokinase plasminogen activator (uPA), and vascular cell adhesion molecule (VCAM)-1. Interestingly, secretion of TIMP-2 increased significantly in B16F10 cells treated with 10 MUmol/L carnosic acid. Additionally, carnosic acid suppressed the mesenchymal markers snail, slug, vimentin, and N-cadherin and induced epithelial marker E-cadherin. Furthermore, carnosic acid suppressed phosphorylation of Src, FAK, and AKT. These results indicate that inhibition of the epithelial-mesenchymal transition may be important for the carnosic acid-induced inhibition of B16F10 cell migration. PMID- 25036035 TI - Inbreeding in Mimulus guttatus reduces visitation by bumble bee pollinators. AB - Inbreeding in plants typically reduces individual fitness but may also alter ecological interactions. This study examined the effect of inbreeding in the mixed-mating annual Mimulus guttatus on visitation by pollinators (Bombus impatiens) in greenhouse experiments. Previous studies of M. guttatus have shown that inbreeding reduced corolla size, flower number, and pollen quantity and quality. Using controlled crosses, we produced inbred and outbred families from three different M. guttatus populations. We recorded the plant genotypes that bees visited and the number of flowers probed per visit. In our first experiment, bees were 31% more likely to visit outbred plants than those selfed for one generation and 43% more likely to visit outbred plants than those selfed for two generations. Inbreeding had only a small effect on the number of flowers probed once bees arrived at a genotype. These differences were explained partially by differences in mean floral display and mean flower size, but even when these variables were controlled statistically, the effect of inbreeding remained large and significant. In a second experiment we quantified pollen viability from inbred and self plants. Bees were 37-54% more likely to visit outbred plants, depending on the population, even when controlling for floral display size. Pollen viability proved to be as important as floral display in predicting pollinator visitation in one population, but the overall explanatory power of a multiple regression model was weak. Our data suggested that bees use cues in addition to display size, flower size, and pollen reward quality in their discrimination of inbred plants. Discrimination against inbred plants could have effects on plant fitness and thereby reinforce selection for outcrossing. Inbreeding in plant populations could also reduce resource quality for pollinators, potentially resulting in negative effects on pollinator populations. PMID- 25036036 TI - 1H/31P polarization transfer at 9.4 Tesla for improved specificity of detecting phosphomonoesters and phosphodiesters in breast tumor models. AB - PURPOSE: To assess the ability of a polarization transfer (PT) magnetic resonance spectroscopy (MRS) technique to improve the detection of the individual phospholipid metabolites phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC), and glycerophosphoethanolamine (GPE) in vivo in breast tumor xenografts. MATERIALS AND METHODS: The adiabatic version of refocused insensitive nuclei enhanced by polarization transfer (BINEPT) MRS was tested at 9.4 Tesla in phantoms and animal models. BINEPT and pulse-acquire (PA) 31P MRS was acquired consecutively from the same orthotopic MCF-7 (n = 10) and MDA-MB-231 (n = 10) breast tumor xenografts. After in vivo MRS measurements, animals were euthanized, tumors were extracted and high resolution (HR)-MRS was performed. Signal to noise ratios (SNRs) and metabolite ratios were compared for BINEPT and PA MRS, and were also measured and compared with that from HR-MRS. RESULTS: BINEPT exclusively detected metabolites with 1H-31P coupling such as PC, PE, GPC, and GPE, thereby creating a significantly improved, flat baseline because overlapping resonances from immobile and partly mobile phospholipids were removed without loss of sensitivity. GPE and GPC were more accurately detected by BINEPT in vivo, which enabled a reliable quantification of metabolite ratios such as PE/GPE and PC/GPC, which are important markers of tumor aggressiveness and treatment response. CONCLUSION: BINEPT is advantageous over PA for detecting and quantifying the individual phospholipid metabolites PC, PE, GPC, and GPE in vivo at high magnetic field strength. As BINEPT can be used clinically, alterations in these phospholipid metabolites can be assessed in vivo for cancer diagnosis and treatment monitoring. PMID- 25036037 TI - Reported high salt intake is associated with increased prevalence of abdominal aortic aneurysm and larger aortic diameter in older men. AB - BACKGROUND: Salt intake has been implicated in the pathogenesis of abdominal aortic aneurysm (AAA) through studies in rodent models but not previously studied in humans. The aim of this study was to examine the association between reported addition of salt to food and the prevalence of AAA. METHODS: A risk factor questionnaire which contained a question about salt intake was included as part of a population screening study for AAA in 11742 older men. AAA presence was assessed by abdominal ultrasound imaging using a reproducible protocol. RESULTS: The prevalence of AAA was 6.9, 8.5 and 8.6% in men who reported adding salt to food never, sometimes and always, respectively, p = 0.005. Addition of salt to food sometimes (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.03-1.44) or always (OR: 1.23, 95% CI 1.04-1.47) was independently associated with AAA after adjustment for other risk factors including age, waist-hip ratio, blood pressure, history of hypertension, high cholesterol, angina, diabetes, myocardial infarction and stroke. Salt intake was also independently associated with aortic diameter (beta 0.023, p = 0.012). In men with no prior history of hypertension, high cholesterol, angina, myocardial infarction or stroke (n = 4185), the association between addition of salt to food sometimes (OR: 1.41, 95% CI 0.96 2.08) or always (OR: 1.52, 95% CI 1.04-2.22) and AAA remained evident. CONCLUSION: Reported salt intake is associated with AAA in older men. Additional studies are needed to determine whether reducing salt intake would protect against AAA. PMID- 25036038 TI - KIF20A regulates porcine oocyte maturation and early embryo development. AB - KIF20A (Kinesin-like family member 20A), also called mitotic kinesin-like proteins 2 (MKLP2), is a mammalian mitotic kinesin-like motor protein of the Kinesin superfamily proteins (KIFs), which was originally involved in Golgi apparatus dynamics and thought to essential for cell cycle regulation during successful cytokinesis. In the present study, we investigated whether KIF20A has roles on porcine oocyte meiotic maturation and subsequent early embryo development. By immunofluorescence staining, KIF20A was found to exhibit a dynamic localization pattern during meiosis. KIF20A was restricted to centromeres after germinal vesicle breakdown (GVBD), transferred to the midbody at telophase I (TI), and again associated with centromeres at metaphase II (MII). Inhibition of endogenous KIF20A via a specific inhibitor, Paprotrain, resulted in failure of polar body extrusion. Further cell cycle analysis showed that the percentage of oocytes that arrested at early metaphase I (MI) stage increased after KIF20A activity inhibition; however, the proportion of oocytes at anaphase/telophase I (ATI) and MII stages decreased significantly. Our results also showed that KIF20A inhibition did not affect spindle morphology. In addition, KIF20A was localized at the nucleus of early embryos, and KIF20A inhibition resulted in failure of early parthenogenetic embryo development. These results demonstrated that KIF20A is critical for porcine oocyte meiotic maturation and subsequent early embryo development. PMID- 25036039 TI - Quantitative analysis of long-form aromatase mRNA in the male and female rat brain. AB - In vitro studies show that estrogens acutely modulate synaptic function in both sexes. These acute effects may be mediated in vivo by estrogens synthesized within the brain, which could fluctuate more rapidly than circulating estrogens. For this to be the case, brain regions that respond acutely to estrogens should be capable of synthesizing them. To investigate this question, we used quantitative real-time PCR to measure expression of mRNA for the estrogen synthesizing enzyme, aromatase, in different brain regions of male and female rats. Importantly, because brain aromatase exists in two forms, a long form with aromatase activity and a short form with unknown function, we targeted a sequence found exclusively in long-form aromatase. With this approach, we found highest expression of aromatase mRNA in the amygdala followed closely by the bed nucleus of the stria terminalis (BNST) and preoptic area (POA); we found moderate levels of aromatase mRNA in the dorsal hippocampus and cingulate cortex; and aromatase mRNA was detectable in brainstem and cerebellum, but levels were very low. In the amygdala, gonadal/hormonal status regulated aromatase expression in both sexes; in the BNST and POA, castration of males down-regulated aromatase, whereas there was no effect of estradiol in ovariectomized females. In the dorsal hippocampus and cingulate cortex, there were no differences in aromatase levels between males and females or effects of gonadal/hormonal status. These findings demonstrate that long-form aromatase is expressed in brain regions that respond acutely to estrogens, such as the dorsal hippocampus, and that gonadal/hormonal regulation of aromatase differs among different brain regions. PMID- 25036041 TI - Evaluation of the in vitro cytogenotoxicity profile of antipsychotic drug haloperidol using human peripheral blood lymphocytes. AB - Haloperidol (HLP) is a potent antipsychotic drug that is commonly used for the treatments of schizophrenia and bipolar disorders but has a tendency to cause adverse effects. In the present study, the cyto/genotoxic potential of clinically relevant concentrations of HLP was evaluated in human peripheral blood lymphocytes (HPBLs) as sensitive biomarkers of exposure. HLP was administered as HLP hydrochloride in the final concentrations of 5, 10 and 20 ng/ml for 4 and 24 h period. Cytotoxicity was determined using differential staining of HPBLs with acridine orange and ethidium bromide while chromosomal aberrations, micronucleus and comet assays were applied to estimate the chromosomal and DNA damage after the treatment. The results of the present study indicate that HLP is capable of inducing cyto/genotoxicity in tested cells. Present study has also confirmed the need for further cytogenetic research and regular patient monitoring to minimize the risk of any possible adverse events. PMID- 25036040 TI - Integrating genomics and proteomics data to predict drug effects using binary linear programming. AB - The Library of Integrated Network-Based Cellular Signatures (LINCS) project aims to create a network-based understanding of biology by cataloging changes in gene expression and signal transduction that occur when cells are exposed to a variety of perturbations. It is helpful for understanding cell pathways and facilitating drug discovery. Here, we developed a novel approach to infer cell-specific pathways and identify a compound's effects using gene expression and phosphoproteomics data under treatments with different compounds. Gene expression data were employed to infer potential targets of compounds and create a generic pathway map. Binary linear programming (BLP) was then developed to optimize the generic pathway topology based on the mid-stage signaling response of phosphorylation. To demonstrate effectiveness of this approach, we built a generic pathway map for the MCF7 breast cancer cell line and inferred the cell specific pathways by BLP. The first group of 11 compounds was utilized to optimize the generic pathways, and then 4 compounds were used to identify effects based on the inferred cell-specific pathways. Cross-validation indicated that the cell-specific pathways reliably predicted a compound's effects. Finally, we applied BLP to re-optimize the cell-specific pathways to predict the effects of 4 compounds (trichostatin A, MS-275, staurosporine, and digoxigenin) according to compound-induced topological alterations. Trichostatin A and MS-275 (both HDAC inhibitors) inhibited the downstream pathway of HDAC1 and caused cell growth arrest via activation of p53 and p21; the effects of digoxigenin were totally opposite. Staurosporine blocked the cell cycle via p53 and p21, but also promoted cell growth via activated HDAC1 and its downstream pathway. Our approach was also applied to the PC3 prostate cancer cell line, and the cross-validation analysis showed very good accuracy in predicting effects of 4 compounds. In summary, our computational model can be used to elucidate potential mechanisms of a compound's efficacy. PMID- 25036042 TI - A meta-analysis approach for characterizing pan-cancer mechanisms of drug sensitivity in cell lines. AB - Understanding the heterogeneous drug response of cancer patients is essential to precision oncology. Pioneering genomic analyses of individual cancer subtypes have begun to identify key determinants of resistance, including up-regulation of multi-drug resistance (MDR) genes and mutational alterations of drug targets. However, these alterations are sufficient to explain only a minority of the population, and additional mechanisms of drug resistance or sensitivity are required to explain the remaining spectrum of patient responses to ultimately achieve the goal of precision oncology. We hypothesized that a pan-cancer analysis of in vitro drug sensitivities across numerous cancer lineages will improve the detection of statistical associations and yield more robust and, importantly, recurrent determinants of response. In this study, we developed a statistical framework based on the meta-analysis of expression profiles to identify pan-cancer markers and mechanisms of drug response. Using the Cancer Cell Line Encyclopaedia (CCLE), a large panel of several hundred cancer cell lines from numerous distinct lineages, we characterized both known and novel mechanisms of response to cytotoxic drugs including inhibitors of Topoisomerase 1 (TOP1; Topotecan, Irinotecan) and targeted therapies including inhibitors of histone deacetylases (HDAC; Panobinostat) and MAP/ERK kinases (MEK; PD-0325901, AZD6244). Notably, our analysis implicated reduced replication and transcriptional rates, as well as deficiency in DNA damage repair genes in resistance to TOP1 inhibitors. The constitutive activation of several signaling pathways including the interferon/STAT-1 pathway was implicated in resistance to the pan-HDAC inhibitor. Finally, a number of dysregulations upstream of MEK were identified as compensatory mechanisms of resistance to the MEK inhibitors. In comparison to alternative pan-cancer analysis strategies, our approach can better elucidate relevant drug response mechanisms. Moreover, the compendium of putative markers and mechanisms identified through our analysis can serve as a foundation for future studies into these drugs. PMID- 25036043 TI - The role of Iex-1 in the pathogenesis of venous neointimal hyperplasia associated with hemodialysis arteriovenous fistula. AB - Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage renal disease worldwide and the majority requires hemodialysis. In the present study, the role of the intermediate early response gene X-1 (IEX-1), also known as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. In Iex-1-/- mice and wild type (WT) controls, chronic kidney disease was induced and an AVF placed 28 days later by connecting the carotid artery to jugular vein. The outflow vein was removed three days following the creation of the AVF and gene expression analysis demonstrated a significant decrease in vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant protein-1 (Mcp-1) gene expression in Iex-1-/- mice when compared to WT mice (P<0.05). At 28 days after AVF placement, histomorphometric and immune histochemical analyses of the outflow vein demonstrated a significant decrease in neointimal hyperplasia with an increase in average lumen vessel area associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of Iex 1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In aggregate, these results indicate that the absence of IEX-1 gene results in reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of nanoparticles coated with calcitriol reduced Iex-1 and VNH. PMID- 25036044 TI - Enhanced vitreous imaging in healthy eyes using swept source optical coherence tomography. AB - PURPOSE: To describe enhanced vitreous imaging for visualization of anatomic features and microstructures within the posterior vitreous and vitreoretinal interface in healthy eyes using swept-source optical coherence tomography (SS OCT). The study hypothesis was that long-wavelength, high-speed, volumetric SS OCT with software registration motion correction and vitreous window display or high-dynamic-range (HDR) display improves detection sensitivity of posterior vitreous and vitreoretinal features compared to standard OCT logarithmic scale display. DESIGN: Observational prospective cross-sectional study. METHODS: Multiple wide-field three-dimensional SS-OCT scans (500*500A-scans over 12*12 mm2) were obtained using a prototype instrument in 22 eyes of 22 healthy volunteers. A registration motion-correction algorithm was applied to compensate motion and generate a single volumetric dataset. Each volumetric dataset was displayed in three forms: (1) standard logarithmic scale display, enhanced vitreous imaging using (2) vitreous window display and (3) HDR display. Each dataset was reviewed independently by three readers to identify features of the posterior vitreous and vitreoretinal interface. Detection sensitivities for these features were measured for each display method. RESULTS: Features observed included the bursa premacularis (BPM), area of Martegiani, Cloquet's/BPM septum, Bergmeister papilla, posterior cortical vitreous (hyaloid) detachment, papillomacular hyaloid detachment, hyaloid attachment to retinal vessel(s), and granular opacities within vitreous cortex, Cloquet's canal, and BPM. The detection sensitivity for these features was 75.0% (95%CI: 67.8%-81.1%) using standard logarithmic scale display, 80.6% (95%CI: 73.8%-86.0%) using HDR display, and 91.9% (95%CI: 86.6%-95.2%) using vitreous window display. CONCLUSIONS: SS-OCT provides non-invasive, volumetric and measurable in vivo visualization of the anatomic microstructural features of the posterior vitreous and vitreoretinal interface. The vitreous window display provides the highest sensitivity for posterior vitreous and vitreoretinal interface analysis when compared to HDR and standard OCT logarithmic scale display. Enhanced vitreous imaging with SS-OCT may help assess the natural history and treatment response in vitreoretinal interface diseases. PMID- 25036045 TI - Cost-effectiveness of computed tomographic angiography in screening for aneurysm in spontaneous subarachnoid hemorrhage. PMID- 25036046 TI - Faecal carriage of extended-spectrum beta-lactamase (ESBL)-producing enterobacteria in liver disease patients from two hospitals in Egypt and France: a comparative epidemiological study. AB - This study aimed to assess and compare the epidemiology of faecal carriage of extended spectrum beta-lactamase-producing enterobacteria (ESBL-E) in Hepatology departments of two hospitals specializing in liver diseases, Theodor Bilharz Research Institute (TBRI) in Cairo (Egypt) and Beaujon Hospital (Bj) in Clichy (France). CTX-M groups were identified by PCR, and TEM and SHV derivatives with the check-point system. Phylogenetic groups of E. coli were determined by multiplex PCR, and clone ST131 by PCR of gene pabB. Prevalence of ESBL-E was 77.6% (45/58) in TBRI and 6.5% (13/199) in Bj (P < 10-7). Previous hospitalization was more common (P = 0.003) in Bj patients (93%) than in TBRI patients (45%) suggesting high prevalence of ESBL-E in the Egyptian community. The presence of E. coli B2 ST131 among ESBL-E faecal E. coli in Egypt confirms its pervasiveness in the community and raises concern regarding this highly virulent and resistant clone. PMID- 25036047 TI - Incidence of pneumococcal and varicella disease in HIV-infected children and adolescents in the United Kingdom and Ireland, 1996-2011. AB - BACKGROUND: To define the burden of hospitalization due to 2 vaccine-preventable infections, invasive pneumococcal disease (IPD) and varicella zoster (VZ), among HIV-infected children in the UK and Ireland. METHODS: Analysis of hospitalizations of HIV-infected children <18 years receiving pediatric care and reported to the Collaborative HIV Paediatric Study (CHIPS) between 1996 and 2011. RESULTS: Admissions for IPD and VZ combined accounted for ~5% of all hospital admissions for HIV-infected children each year. When compared with background rates for healthy children, the admission rate ratio for HIV-infected children on combination antiretroviral therapy (cART) was 16.7, 14.8 and 126.7 for IPD, varicella and herpes zoster, respectively, and 156.7, 86.1 and 470, respectively, for HIV-infected children not on cART. Those admitted with IPD or VZ were more likely to have Centers for Disease Control stage B/C at presentation with HIV than those without such admissions (36.8% for IPD, 29.7% for VZ and 22.1% for no IPD or VZ, P = 0.006), and were more likely to subsequently commence cART (94.7%, 91.3% and 80.2% respectively, P = 0.004). CONCLUSIONS: There is a clear increased risk of admission with IPD or VZ in HIV-infected compared with uninfected children, magnified in those who have not yet commenced cART. It is anticipated that the introduction of new guidelines will result in improved vaccine uptake and thereby reduce the burden of IPD and VZ disease. Subsequent evaluation will assess the impact of these guidelines. PMID- 25036048 TI - The safety and immunogenicity of two hepatitis B vaccine formulations (thiomersal free and thiomersal-containing) in healthy vietnamese infants: a phase III, prospective, single-blinded, randomized, controlled trial. AB - BACKGROUND: To evaluate the safety and immunogenicity of the thiomersal-free (TF) and thiomersal-containing (TC) formulations of Hepavax-Gene in healthy Vietnamese neonates. METHODS: A single-blind, randomized, controlled study in Ho Chi Minh City, Vietnam. Healthy infants, born after a normal gestational period (37-42 weeks) to hepatitis B surface antigen-negative mothers, participated in the study. Subjects were randomly allocated in a 1:1 ratio to receive either Hepavax Gene TC or Hepavax-Gene TF using a standard 0-1-6-month administration schedule. Postvaccination blood samples were taken at months 1, 6 and 7. Parents/legal guardians recorded solicited local and systemic adverse events up to 4 weeks after each vaccination. RESULTS: Very high proportions of subjects were seroprotected. Seroprotection rates at 1, 6 and 7 months were all above 95% using a 10 IU/L cutoff, and were mostly above 90% using a 100 IU/L cutoff. Seroprotection rates between the 2 formulations were equivalent within a 5% margin for either cutoff titer both after 6 and 7 months. There were no significant differences in the number of adverse events reported between the 2 formulations. Safety results were in line with previous reports for Hepavax-Gene. Both formulations of Hepavax-Gene were well tolerated. There were no local adverse events reported in the TF group. No serious adverse events were reported during the study. CONCLUSIONS: The thiomersal-free formulation of Hepavax-Gene was noninferior to the thiomersal-containing formulation of Hepavax-Gene in terms of immunogenicity. There was evidence that the thiomersal-free vaccine was associated with fewer local adverse events. PMID- 25036049 TI - Febrile young infants with altered urinalysis at low risk for invasive bacterial infection. a Spanish Pediatric Emergency Research Network's Study. AB - BACKGROUND: Urinary tract infection (UTI) is the most common serious bacterial infection (SBI) in infants younger than 90 days of age. Many physicians admit infants younger than 90 days old because of their greater risk of developing invasive bacterial infections (IBIs), secondary to UTI. The primary objective of this study was to design a prediction model to identify febrile infants younger than 90 days old with an altered urinalysis who were at low risk for IBI and suitable for outpatient management METHODS: : Prospective multicenter study included 19 hospitals that are members of the Spanish Pediatric Emergency Research Group of the Spanish Society of Pediatric Emergencies. Febrile infants younger than 90 days old with altered urinalysis were included. RESULTS: A total of 766 (22.5%) infants with altered urine dipstick were analyzed. Fifty (6.5%) of them developed IBI, 39 (78.0%) secondary to UTI. Patients were at low risk for IBI if they were well appearing at arrival to the emergency department, were older than 21 days and had procalcitonin and C-reactive protein (CRP) blood values lower than 0.5 ng/mL and 20 mg/L, respectively. These factors were used to create a prediction model for IBI secondary to UTI, with a sensitivity of 100% (95% CI: 89.3-100) and a negative predictive value of 100% (95% CI: 97.5-100). CONCLUSIONS: We have derived a highly accurate prediction model for IBI in febrile infants with altered urinalysis. Given these results, outpatient management might be suitable for 1 of each 4 infants diagnosed, with a considerable improvement in resource utilization. PMID- 25036050 TI - Rationale for the development of speckled hyperpigmentation in the areas of psoriatic plaques after treatment with biologic agents. PMID- 25036051 TI - Talaporfin sodium-mediated photodynamic therapy alone and in combination with pulsed dye laser on cutaneous vasculature. PMID- 25036052 TI - Genomic profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology. AB - The host immune response has a critical role not only in protection from human leishmaniasis but also in promoting disease severity. Although candidate gene approaches in mouse models of leishmaniasis have been extremely informative, a global understanding of the immune pathways active in lesions from human patients is lacking. To address this issue, genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls was carried out. A signature of the L. braziliensis skin lesion was defined, which includes over 2,000 differentially regulated genes. Pathway-level analysis of this transcriptional response revealed key biological pathways present in cutaneous lesions, generating a testable 'metapathway' model of immunopathology and providing new insights for treatment of human leishmaniasis. PMID- 25036054 TI - Influence of physico-chemical material characteristics on staphylococcal biofilm formation--a qualitative and quantitative in vitro analysis of five different calcium phosphate bone grafts. AB - Various compositions of synthetic calcium phosphates (CaP) have been proposed and their use has considerably increased over the past decades. Besides differences in physico-chemical properties, resorption and osseointegration, artificial CaP bone graft might differ in their resistance against biofilm formation. We investigated standardised cylinders of 5 different CaP bone grafts (cyclOS, chronOS (both beta-TCP (tricalcium phosphate)), dicalcium phosphate (DCP), calcium-deficient hydroxyapatite (CDHA) and alpha-TCP). Various physico-chemical characterisations e.g., geometrical density, porosity, and specific surface area were investigated. Biofilm formation was carried out in tryptic soy broth (TSB) and human serum (SE) using Staphylococcus aureus (ATCC 29213) and S. epidermidis RP62A (ATCC 35984). The amount of biofilm was analysed by an established protocol using sonication and microcalorimetry. Physico-chemical characterisation showed marked differences concerning macro- and micropore size, specific surface area and porosity accessible to bacteria between the 5 scaffolds. Biofilm formation was found on all scaffolds and was comparable for alpha-TCP, chronOS, CDHA and DCP at corresponding time points when the scaffolds were incubated with the same germ and/or growth media, but much lower for cyclOS. This is peculiar because cyclOS had an intermediate porosity, mean pore size, specific surface area, and porosity accessible to bacteria. Our results suggest that biofilm formation is not influenced by a single physico-chemical parameter alone but is a multi-step process influenced by several factors in parallel. Transfer from in vitro data to clinical situations is difficult; thus, advocating the use of cyclOS scaffolds over the four other CaP bone grafts in clinical situations with a high risk of infection cannot be clearly supported based on our data. PMID- 25036055 TI - mTOR inhibition, AKT proteins and chronic kidney disease. PMID- 25036053 TI - Fibrin-genipin adhesive hydrogel for annulus fibrosus repair: performance evaluation with large animal organ culture, in situ biomechanics, and in vivo degradation tests. AB - Annulus fibrosus (AF) defects from annular tears, herniation, and discectomy procedures are associated with painful conditions and accelerated intervertebral disc (IVD) degeneration. Currently, no effective treatments exist to repair AF damage, restore IVD biomechanics and promote tissue regeneration. An injectable fibrin-genipin adhesive hydrogel (Fib-Gen) was evaluated for its performance repairing large AF defects in a bovine caudal IVD model using ex vivo organ culture and biomechanical testing of motion segments, and for its in vivo longevity and biocompatibility in a rat model by subcutaneous implantation. Fib Gen sealed AF defects, prevented IVD height loss, and remained well-integrated with native AF tissue following approximately 14,000 cycles of compression in 6 day organ culture experiments. Fib-Gen repair also retained high viability of native AF cells near the repair site, reduced nitric oxide released to the media, and showed evidence of AF cell migration into the gel. Biomechanically, Fib-Gen fully restored compressive stiffness to intact levels validating organ culture findings. However, only partial restoration of tensile and torsional stiffness was obtained, suggesting opportunities to enhance this formulation. Subcutaneous implantation results, when compared with the literature, suggested Fib-Gen exhibited similar biocompatibility behaviour to fibrin alone but degraded much more slowly. We conclude that injectable Fib-Gen successfully sealed large AF defects, promoted functional restoration with improved motion segment biomechanics, and served as a biocompatible adhesive biomaterial that had greatly enhanced in vivo longevity compared to fibrin. Fib-Gen offers promise for AF repairs that may prevent painful conditions and accelerated degeneration of the IVD, and warrants further material development and evaluation. PMID- 25036056 TI - Renal function, nephrogenic systemic fibrosis and other adverse reactions associated with gadolinium-based contrast media. AB - Nephrogenic systemic fibrosis is a fibrosing disorder that affects patients with impaired renal function and is associated with the administration of gadolinium based contrast media used in MRI. Despite being in a group of drugs that were considered safe, report about this potentially serious adverse reaction was a turning point in the administration guidelines of these contrast media. There has been an attempt to establish safety parameters to identify patients with risk factors of renal failure. The close pharmacovigilance and strict observation of current regulations, with special attention being paid to the value of glomerular filtration, have reduced the published cases involving the use of gadolinium based contrast media. In a meeting between radiologists and nephrologists we reviewed the most relevant aspects currently and recommendations for its prevention. PMID- 25036057 TI - Treatment of hyponatremia induced by the syndrome of Inappropriate antidiuretic hormone secretion: a multidisciplinary spanish algorithm. AB - INTRODUCTION: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent cause of hyponatremia in a hospital setting. However, detailed protocols and algorithms for its management are lacking. Our objective was to develop 2 consensus algorithms for the therapy of hyponatremia due to SIADH in hospitalized patients. MATERIAL AND METHODS: A multidisciplinary group made up of 2 endocrinologists, 2 nephrologists, 2 internists, and one hospital pharmacist held meetings over the period of a year. The group worked under the auspices of the European Hyponatremia Network and the corresponding Spanish medical societies. Therapeutic proposals were based on widely-accepted recommendations, expert opinion and consensus guidelines, as well as on the authors' personal experience. RESULTS: Two algorithms were developed. Algorithm 1 addresses acute correction of hyponatremia posing as a medical emergency, and is applicable to both severe euvolemic and hypovolemic hyponatremia. The mainstay of this algorithm is the iv use of 3% hypertonic saline solution. Specific infusion rates are proposed, as are steps to avoid or reverse overcorrection of serum sodium levels. Algorithm 2 is directed to the therapy of SIADH-induced mild or moderate, non-acute hyponatremia. It addresses when and how to use fluid restriction, solute, furosemide, and tolvaptan to achieve eunatremia in patients with SIADH. CONCLUSIONS: Two complementary strategies were elaborated to treat SIADH-induced hyponatremia in an attempt to increase awareness of its importance, simplify its therapy, and improve prognosis. PMID- 25036059 TI - Cost analysis and sociocultural profile of kidney patients. Impact of the treatment method. AB - BACKGROUND: The cost analysis of chronic kidney disease based on individual data for treatment methods and components has not been published in Spain. OBJECTIVES: a) To study the health costs of a year of treatment with haemodialysis (HD), deceased donor renal transplantation (RTx), renal-pancreas transplantation (RPTx), and S4 and S5 advanced chronic kidney disease (ACKD) b) Assess the potential relationship between sociocultural diversity, costs and treatment method. METHODS: Observational study of: 1) 81 patients with ACKD (53 S4 and 28 S5) 2) 162 with more than 3 months on HD and 3) 173 with a Tx for more than 6 months (140 RTx and 33 RPTx). The costs were assessed in five categories: 1) HD sessions, 2) drug intake, 3) hospitalisation, 4) outpatient care and 5) transportation. We carried out a survey with socio-demographic parameters. RESULTS: The financial impact of HD was ?47,714±18,360 (mean±SD), that of Tx ?13,988±9970, and that of ACKD ?9654±9412. The cost of HD was the highest in all financial items. The costs were similar between RTx and RPTx. In ACKD, the greater the renal deterioration, the greater the cost is (S4 ?7846±8901 versus S5 ?13,300±9820, P<.01). Tx patients had the best sociocultural status, while HD patients had the worst profile. We did not find differences in costs between the three sociocultural groups. CONCLUSIONS: HD has the greatest financial impact in all items, five times higher than the ACKD patient cost and three times than the Tx patient cost. Optimising early prevention and Tx, if appropriate, must be priority strategies. This analysis invites us to think about whether sociocultural status can have an influence on opportunities for Tx. PMID- 25036058 TI - Predictive factors for kidney damage in febrile urinary tract infection. Usefulness of procalcitonin. AB - OBJECTIVE: To establish the utility of procalcitonin (PCT) and other clinical and analytical parameters as markers of acute and permanent renal damage in children after a first febrile urinary tract infection (UTI). METHODS: Retrospective multicentre study. Statistical study: descriptive, receiver operating characteristic (ROC) curves and multiple logistic regression. RESULTS: 219 patients, aged between 1 week and 14 years (68% under 1 year). The mean PCT values were significantly higher in patients with acute pyelonephritis with respect to normal acute DMSA (4.8 vs 1.44; p=0.0001), without achieving that signification for late affected DMSA (6.5 vs 5.05; p=0.6). The area under the ROC curve for PCT was 0.64 (CI 95% 0.55-0.72) for acute renal damage, and 0.62 (CI 95% 0.44-0.80) for permanent damage, with optimum statistical cut-off values of 0.85 and 1.17ng/ml. Multivariate analysis for acute renal damage only found correlation with PCT (Odds Ratio [OR] 1.2 (CI 95% 1.06-1.4, p=0.005), and hours of fever (OR for less than 6 hours of fever 0.4 (CI 95% 0.2-1.02, p=0.05). In patients with renal scarring, PCT showed an OR 1.0 (CI 95% 0.9-1.1, p=0.6). CONCLUSIONS: PCT and the duration of fever were the only parameters statistically associated with early renal damage. PCT and renal scarring did not reach statistical significance. PMID- 25036060 TI - During the pre-dialysis stage of chronic kidney disease, which treatment is associated with better survival in dialysis? AB - INTRODUCTION: Specialised care of patients in advanced stages of chronic kidney disease (CKD) is associated with better survival in dialysis, but it is not known which treatments specifically favour this outcome. OBJECTIVES: To analyse normal treatment in advanced stages of CKD and establish which treatments are associated with better survival in dialysis as well as their relationship with causes of death. MATERIAL AND METHOD: Cohort, prospective observational study of 591 patients who started dialysis (491 haemodialysis and 100 peritoneal dialysis), who had previously been monitored in the CKD clinic. The treatments analysed were: antihypertensive treatments, statins, antiplatelet drugs, xanthine oxidase inhibitors, correction of metabolic acidosis, treatment with (calcium or non calcium) phosphate binders, vitamin D (calcitriol or paricalcitol), erythropoietin and the availability of an internal arteriovenous fistula (IAVF). The independent association of each of these treatments with mortality in dialysis was analysed using Cox regression models adjusted for age, sex, pre dialysis monitoring time, renal function at the start of dialysis, comorbidity, serum albumin and C-reactive protein, and with stratification of the type of dialysis. RESULTS: With a median follow-up period of 28 months, the total number of patients who died was 191 (32%). In the multivariate models, we observed that, in addition to age, the comorbidity index, serum albumin, pre-dialysis treatment with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor blockers, correction of acidosis with sodium bicarbonate and IAVF at the start of haemodialysis were significantly associated with better survival in dialysis. We did not observe differences in causes of death between the different treatments analysed. CONCLUSION: These results suggest a potential delayed benefit of some treatments in pre-dialysis stages on the outcome of dialysis. Furthermore, beginning dialysis without an IAVF, resulting in the need for intravenous catheters, worsens prognosis in these patients. PMID- 25036061 TI - Fluid therapy and iatrogenic hyponatraemia risk in children hospitalised with acute gastroenteritis: prospective study. AB - OBJECTIVE: The purpose of this study is to analyse whether the use of hypotonic fluids increases the risk of iatrogenic hyponatraemia in children hospitalised with acute gastroenteritis (AGE). PATIENTS AND METHODS: Prospective study carried out on 205 patients with ages ranging from 1 to 28 months and admitted with a diagnosis of mild or moderate dehydration due to AGE and treated with intravenous hypotonic fluids in a paediatric department in Madrid (Spain). The degree of dehydration at presentation was estimated using standard clinical measures. 198 children received 0.3 % glucosaline solution and in 7 patients, with baseline hypernatraemia, 0.2 % gluco-hyposaline solution was administered. We analysed the results according to whether children were hyponatraemic, normonatraemic or hypernatraemic at presentation. The blood and urine samples were analysed and the concentration of sodium and fractional sodium excretion (EFNa) before and after intervention were considered as outcome measures. RESULTS: The 205 patients included in the study were distributed in 3 groups according to the baseline natraemia results. In 37 cases we detected hyponatraemia (18.04%), in 133 cases isonatraemia (64.87%) and in 35 children hypernatraemia (17.07%). After administering hypotonic fluids we detected a significant difference between initial and final natraemia in all groups; in the group with hyponatraemia, sodium increased and in the groups with iso and hypernatraemia, sodium slightly decreased. A significant correlation between the EFNa and the evolution of natraemia was found. No cases of hyponatraemia post-infusion were seen and there was no correlation between free water administered and natraemia evolution. CONCLUSIONS: RESULTS show that the use of hypotonic fluids does not increase the risk of hospital acquired hyponatraemia in hospitalised children with normal renal function. Our children with gastroenteritis did not develop hyponatraemia even though they were all treated with hypotonic intravenous solutions. PMID- 25036062 TI - Soy protein and genistein improves renal antioxidant status in experimental nephrotic syndrome. AB - BACKGROUND AND OBJECTIVES: Nephrotic syndrome is a chronic disease especially common in the childhood and adolescence. Reactive oxygen species (ROS) and free radicals have significant role in the pathogenesis of nephrotic syndrome. The aim of this study was to evaluate the effect of soy protein and genistein (main isoflavone of soybean) on renal antioxidant status of nephrotic rats. METHODS: This study was done for 8 weeks on 40 adult male Sprague-Dawley rats divided into four groups of 10 rats each. Study groups included: 1-Control, 2-Nephrotic syndrome, 3-Nephrotic syndrome+soy protein diet and 4-Nephrotic syndrome+soy protein diet+genistein. Urine protein and urine creatinine were measured. After homogenization of kidney, total antioxidant capacities (TAC), activities of catalase enzyme, the concentration of malondialdehydes (MDA) and carbolynated proteins were determined spectrophotometrically. Pathological examination was done on kidneys with light microscope. Cell viability was evaluated with MTT assay on WEHI-164 fibro sarcoma cell line. The MMP2 enzyme activity was evaluated in different concentrations of genistein. RESULTS: Total antioxidant capacity was significantly increased in soy genistein. Catalase activity was significantly increased in soy and soy genistein groups. Protein carbonyl and MDA were significantly lower in soy and soy genistein groups. The scores of pathological examination showed significant improvement in soy and soy genistein groups. Genistein decreased the proliferation of the WEHI-164 fibrosarcoma cell line. CONCLUSION: It seems that soy protein decreases kidney damages in nephrotic syndrome. Adding genistein to soy protein causes improvements in antioxidant status of kidney tissue. Genistein decreases proliferation of cell. PMID- 25036063 TI - Evolution of antibody titre against the M-type phospholipase A2 receptor and clinical response in idiopathic membranous nephropathy patients treated with tacrolimus. AB - INTRODUCTION AND OBJECTIVES: The level of circulating antibodies against M-type phospolipase A2 receptor has been reported as having a significant correlation with clinical activity in idiopathic membranous nephropathy. However, the usefulness of monitoring antibody titre as a predictor of clinical response following the onset of treatment has not been formally analysed. The predictive value of the evolution of anti-PLA2R antibody titre on the clinical response of idiopathic membranous nephropathy patients treated with tacrolimus is analysed in the following study. PATIENTS AND METHOD: 36 patients with nephrotic syndrome secondary to idiopathic membranous nephropathy with immunosuppressive treatment indication criteria were treated with tacrolimus in monotherapy. The level of anti-PLA2R antibodies was determined before treatment and at 3, 6, 9 and 12 months after the onset of treatment. The study analysed the predictive value of the reduction in antibody titre and the relative and absolute reduction in antibody titre at 3 and 6 months over the period until remission and on the probability of remission at 6, 9 and 12 months. RESULTS: The relative reduction in the anti-PLA2R antibody titre was significantly greater in those patients with remission and it preceded the clinical response. No association was observed between the antibody titre prior to treatment and the mean response time or the response at 12 months. Reduction in antibody titre is significantly associated with the time until signs of remission. Relative reduction in anti-PLA2R antibody titre at 3 months had a high sensitivity and specificity to predict the response at 6 and 9 months, but not at 12 months; however the relative reduction in the antibody titre at 6 months had a high sensitivity and specificity for predicting the response at 12 months. CONCLUSION: In patients with IMN associated with anti PLA2R antibodies, the monitoring of antibody titre following the onset of treatment is useful for estimating the time period until remission and predicting the probability of remission at 12 months. PMID- 25036065 TI - Defining protein-energy wasting syndrome in chronic kidney disease: prevalence and clinical implications. AB - The presence of malnutrition in chronic kidney disease (CKD) is well-known. The discovery in the last 15 years of pathophysiological mechanisms that lead to this process, such as anorexia, the increase of protein catabolism and inflammation, has created the need for a new name by the International Society of Renal Nutrition and Metabolism (ISRNM): protein-energy wasting syndrome (PEW). This document's objectives are to propose the use of the term "desgaste proteico energetico" (DPE) as a more accurate translation of the English term and to update the pathogenic mechanisms involved that are inherent to DPE (PEW). We simultaneously review the latest epidemiological evidence that highlight the relevance of malnutrition and its impact both on mortality and morbidity in CKD. Finally, we point out the need to redefine DPE (PEW) diagnostic criteria so that they are applicable to the Spanish population with CKD. We do not think that the criteria established by the ISRNM can be extrapolated to different populations, as is the case, for example, with interracial anthropometric differences. PMID- 25036066 TI - Hypersensitivity reactions to synthetic haemodialysis membranes. AB - Undergoing a haemodialysis (HD) session poses a certain risk of hypersensitivity adverse reactions as large quantities of blood are in contact with various synthetic materials. Hypersensitivity reactions to ethylene oxide and non biocompatible membranes, such as cuprophane, have been described in HD. Cases of hypersensitivity with biocompatible membranes, such as polysulfone, and even polysulfone-polyvinylpyrrolidone, have also been reported. In this article we describe six cases of mostly early-stage hypersensitivity reactions to HD occurring in our department, characterised by malaise, desaturation, bronchospasm and arterial hypotension, with good response to the session’s temporary suspension and with reappearance in subsequent sessions that used a synthetic dialyser. No hypersensitivity reactions reappeared in successive observations when the sessions were carried out using a cellulose membrane. PMID- 25036067 TI - Increase of ischaemic colitis incidence in haemodialysis. PMID- 25036064 TI - Hidden sources of phosphorus: presence of phosphorus-containing additives in processed foods. AB - INTRODUCTION AND OBJECTIVES: An increased consumption of processed foods that include phosphorus-containing additives has led us to propose the following working hypothesis: using phosphate-rich additives that can be easily absorbed in processed foods involves a significant increase in phosphorus in the diet, which may be considered as hidden phosphorus since it is not registered in the food composition tables. MATERIALS AND METHOD: The quantity of phosphorus contained in 118 processed products was determined by spectrophotometry and the results were contrasted with the food composition tables of the Higher Education Centre of Nutrition and Diet, those of Morandeira and those of the BEDCA (Spanish Food Composition Database) Network. RESULTS: Food processing frequently involves the use of phosphoric additives. The products whose label contains these additives have higher phosphorus content and higher phosphorus-protein ratio. We observed a discrepancy with the food composition tables in terms of the amount of phosphorus determined in a sizeable proportion of the products. The phosphorus content of prepared refrigerated foods hardly appears in the tables. CONCLUSIONS: Product labels provide little information on phosphorus content. We observed a discrepancy in phosphorus content in certain foods with respect to the food composition tables. We should educate our patients on reviewing the additives on the labels and on the limitation of processed foods. There must be health policy actions to deal with the problem: companies should analyse the phosphorus content of their products, display the correct information on their labels and incorporate it into the food composition tables. Incentives could be established to prepare food with a low phosphorus content and alternatives to phosphorus containing additives. PMID- 25036068 TI - Comment on "Kaposi's sarcoma in the early post-transplant period in a kidney transplant recipient". PMID- 25036069 TI - Home haemodialysis: a right and a duty. PMID- 25036070 TI - Influence of glucose solutions on the development of hyperglycaemia in peritoneal dialysis. Behaviour of glycated haemoglobin and the lipid profile. PMID- 25036071 TI - Results 5 years after living donor renal transplantation without calcineurin inhibitors. PMID- 25036072 TI - Hepatitis C virus infection, interferon alpha and lupus; a curious combination. PMID- 25036073 TI - Baclofen neurotoxicity in a patient with end-stage chronic renal failure. PMID- 25036074 TI - Achromobacter xylosoxidans in two haemodialysis patients. PMID- 25036075 TI - Methylmalonic acidemia with homocystinuria. A very rare cause of kidney failure in the neonatal period. PMID- 25036076 TI - An uncommon cause of linfadenopathy in a kidney transplant patient: cat-scratch disease. PMID- 25036077 TI - Extreme hypocalcaemia and hyperparathyroidism following denosumab. Is this drug safe in chronic kidney disease? PMID- 25036078 TI - Sustained release of recombinant surface antigen 2 (rSAG2) from poly(lactide-co glycolide) microparticles extends protective cell-mediated immunity against Toxoplasma gondii in mice. AB - SUMMARY Current development efforts of subunit vaccines against Toxoplasma gondii, the aetiological agent of toxoplasmosis, have been focused mainly on tachyzoite surface antigens (SAGs) such as SAG2, due to their attachment roles in the process of host-cell invasion. In the present study, we aimed to produce poly(lactide-co-glycolide) (PLG) microparticles (MPs) containing recombinant SAG2 (rSAG2) to induce improved immunity against T. gondii. The resulting PLG encapsulated rSAG2 (PLG-rSAG2) MPs, 2.14-3.63 MUm in diameter, showed 74-80% entrapment efficiency and gradually released antigenic rSAG2 protein (88.3% of the total protein load) for a long 33-day period. Peritoneal immunization with PLG-rSAG2 MPs in BALB/c mice resulted in not only sustained (10 weeks) lymphocyte proliferation and IFN-gamma production but also an improved protective capacity (87%) against a lethal subcutaneous challenge of 1*104 live tachyzoites of T. gondii (RH strain). In conclusion, the sustained release of rSAG2 protein from PLG-rSAG2 MPs extends Th1 cell-mediated immunity (lymphocyte proliferation and IFN-gamma production) and induces improved protection against T. gondii tachyzoite infection in mice. PMID- 25036079 TI - Going up? PMID- 25036086 TI - Simulation is all about you: it is not about the technology. PMID- 25036083 TI - Direct care registered nurses' and nursing leaders' review of the clinical competencies needed for the successful nurse of the future: a gap analysis. AB - Direct care nurses and nurse leaders were surveyed on their perceptions of the appropriateness, importance, and use in daily practice of 10 clinical nursing competencies needed for nurses to be successful in the future. Competencies needed in the 21st century are not based entirely on task-driven motor skills because comprehensive knowledge is essential to care for complex patients. Differences identified between direct care nurses, leaders, and educational levels provide educational opportunities for both groups. PMID- 25036082 TI - Graduate nurse internship program: a formalized orientation program. AB - The graduate nurse internship program was developed on the basis of Watson's Human Caring Theory. In this article, the author discusses how an orientation program was formalized into an internship program and how the theory was applied. PMID- 25036085 TI - "But no one ever told me!": ensuring learning and transfer. PMID- 25036081 TI - TERN Residency Program: transitioning the experienced registered nurse. AB - One pediatric hospital addressed the challenges of registered nurses (RNs) transitioning to new roles by developing a year-long residency for experienced RNs, whether newly hired or transitioning to another role within the hospital. The evidence-based program's goal is for the participant to demonstrate effective decision-making skills, applying principles into his or her practice at the point of care. Objectives of the program are measured using pre/post tool and through the use of reflective journaling. The article provides a framework to develop an experienced RN residency program that supports transition from competent to proficient in a new work environment. PMID- 25036080 TI - Improving client and nurse satisfaction through the utilization of bedside report. AB - Bedside reporting improves client safety and trust and facilitates nursing teamwork and accountability; however, many nurses do not consider it best practice when caring for their clients. A literature review was conducted to determine whether bedside report is an essential shift handover process that promotes both client and nursing satisfaction. Implications for nurses in professional development are discussed, and strategies for developing and implementing bedside report using Lewin's theory of planned change are provided. PMID- 25036084 TI - Maintaining competency for float nursing staff. AB - Orienting staff to multiple areas is challenging, as is maintaining multiple competencies, which might be used infrequently. Creating a strategy to regularly assess needed competencies to maintain a highly skilled pool of nurses, prepared to float to multiple areas, is critical to supporting flexible staffing. A plan for how to achieve this complex analysis is described and can be translated to other complex environments. PMID- 25036087 TI - Return on investment for professional organization membership. PMID- 25036088 TI - Ask an expert. PMID- 25036091 TI - High dietary lipid level is associated with persistent hyperglycaemia and downregulation of muscle Akt-mTOR pathway in Senegalese sole (Solea senegalensis). AB - High levels of dietary lipids are incorporated in feeds for most teleost fish to promote growth and reduce nitrogen waste. However, in Senegalese sole (Solea senegalensis) previous studies revealed that increasing the level of dietary lipids above 8% negatively affect growth and nutrient utilization regardless of dietary protein content. It has been shown that glucose regulation and metabolism can be impaired by high dietary fat intake in mammals, but information in teleost fish is scarce. The aim of this study was to assess the possible effect of dietary lipids on glucose metabolism in Senegalese sole with special emphasis on the regulation of proteins involved in the muscle insulin-signalling pathway. Senegalese sole juveniles (29 g) were fed two isonitrogenous diets (53% dry matter) for 88 days. These two diets were one with a high lipid level (~17%, HL) and a moderate starch content (~14%, LC), and the other being devoid of fish oil (4% lipid, LL) and with high starch content (~23%, HC). Surprisingly, feeding Senegalese sole the HL/LC diet resulted in prolonged hyperglycaemia, while fish fed on LL/HC diet restored basal glycaemia 2 h after feeding. The hyperglycaemic phenotype was associated with greater glucose-6-phosphatase activity (a key enzyme of hepatic glucose production) and lower citrate synthase activity in the liver, with significantly higher liver glycogen content. Sole fed on HL/LC diet also had significantly lower hexokinase activity in muscle, although hexokinase activity was low with both dietary treatments. The HL/LC diet was associated with significant reductions in muscle AKT, p70 ribosomal S6-K1 Kinase (S6K-1) and ribosomal protein S6 (S6) 2 h after feeding, suggesting down regulation of the AKT-mTOR nutrient signalling pathway in these fish. The results of this study show for the first time that high level of dietary lipids strongly affects glucose metabolism in Senegalese sole. PMID- 25036090 TI - P-glycoprotein mediated efflux limits the transport of the novel anti-Parkinson's disease candidate drug FLZ across the physiological and PD pathological in vitro BBB models. AB - FLZ, a novel anti-Parkinson's disease (PD) candidate drug, has shown poor blood brain barrier (BBB) penetration based on the pharmacokinetic study using rat brain. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two important transporters obstructing substrates entry into the CNS as well as in relation to PD neuropathology. However, it is unclear whether P-gp and BCRP are involved in low BBB permeability of FLZ and what the differences of FLZ brain penetration are between normal and Parkinson's conditions. For this purpose, in vitro BBB models mimicking physiological and PD pathological-related BBB properties were constructed by C6 astroglial cells co-cultured with primary normal or PD rat cerebral microvessel endothelial cells (rCMECs) and in vitro permeability experiments of FLZ were carried out. High transepithelial electrical resistance (TEER) and low permeability for sodium fluorescein (NaF) confirmed the BBB functionality of the two models. Significantly greater expressions of P-gp and BCRP were detected in PD rCMECs associated with the lower in vitro BBB permeability of FLZ in pathological BBB model compared with physiological model. In transport studies only P-gp blocker effectively inhibited the efflux of FLZ, which was consistent with the in vivo permeability data. This result was also confirmed by ATPase assays, suggesting FLZ is a substrate for P-gp but not BCRP. The present study first established in vitro BBB models reproducing PD-related changes of BBB functions in vivo and demonstrated that poor brain penetration of FLZ and low BBB permeability were due to the P-gp transport. PMID- 25036092 TI - CXCL12/stromal-cell-derived factor-1 effectively replaces endothelial progenitor cells to induce vascularized ectopic bone. AB - Bone defect healing is highly dependent on the simultaneous stimulation of osteogenesis and vascularization. In bone regenerative strategies, combined seeding of multipotent stromal cells (MSCs) and endothelial progenitor cells (EPCs) proves their mutual stimulatory effects. Here, we investigated whether stromal-cell-derived factor-1alpha (SDF-1alpha) stimulates vascularization by EPCs and whether SDF-1alpha could replace seeded cells in ectopic bone formation. Late EPCs of goat origin were characterized for their endothelial phenotype and showed to be responsive to SDF-1alpha in in vitro migration assays. Subsequently, subcutaneous implantation of Matrigel plugs that contained both EPCs and SDF 1alpha showed more tubule formation than constructs containing either EPCs or SDF 1alpha. Addition of either EPCs or SDF-1alpha to MSC-based constructs showed even more elaborate vascular networks after 1 week in vivo, with SDF-1alpha/MSC-laden groups showing more prominent interconnected networks than EPC/MSC-laden groups. The presence of abundant mouse-specific CD31/PECAM expression in these constructs confirmed ingrowth of murine vessels and discriminated between angiogenesis and vessel networks formed by seeded goat cells. Importantly, implantation of EPC/MSC or SDF-1alpha/MSC constructs resulted in indistinguishable ectopic bone formation. In both groups, bone onset was apparent at week 3 of implantation. Taken together, we demonstrated that SDF-1alpha stimulated the migration of EPCs in vitro and vascularization in vivo. Further, SDF-1alpha addition was as effective as EPCs in inducing the formation of vascularized ectopic bone based on MSC-seeded constructs, suggesting a cell-replacement role for SDF-1alpha. These results hold promise for the design of larger centimeter-scale, cell-free vascular bone grafts. PMID- 25036093 TI - Environmental health research recommendations from the Inter-Environmental Health Sciences Core Center Working Group on unconventional natural gas drilling operations. AB - BACKGROUND: Unconventional natural gas drilling operations (UNGDO) (which include hydraulic fracturing and horizontal drilling) supply an energy source that is potentially cleaner than liquid or solid fossil fuels and may provide a route to energy independence. However, significant concerns have arisen due to the lack of research on the public health impact of UNGDO. OBJECTIVES: Environmental Health Sciences Core Centers (EHSCCs), funded by the National Institute of Environmental Health Sciences (NIEHS), formed a working group to review the literature on the potential public health impact of UNGDO and to make recommendations for needed research. DISCUSSION: The Inter-EHSCC Working Group concluded that a potential for water and air pollution exists that might endanger public health, and that the social fabric of communities could be impacted by the rapid emergence of drilling operations. The working group recommends research to inform how potential risks could be mitigated. CONCLUSIONS: Research on exposure and health outcomes related to UNGDO is urgently needed, and community engagement is essential in the design of such studies. PMID- 25036094 TI - Are normal decision-makers sensitive to changes in value contrast under uncertainty? Evidence from the Iowa Gambling Task. AB - The Iowa Gambling Task (IGT) developed by Bechara et al. in 1994 is used to diagnose patients with Ventromedial Medial Prefrontal Cortex (VMPFC) lesions, and it has become a landmark in research on decision making. According to Bechara et al., the manipulation of progressive increments of monetary value can normalize the performance of patients with VMPFC lesions; thus, they developed a computerized version of the IGT. However, the empirical results showed that patients' performances did not improve as a result of this manipulation, which suggested that patients with VMPFC lesions performed myopically for future consequences. Using the original version of the IGT, some IGT studies have demonstrated that increments of monetary value significantly influence the performance of normal subjects in the IGT. However, other research has resulted in inconsistent findings. In this study, we used the computerized IGT (1X-IGT) and manipulated the value contrast of progressive increments (i.e., by designing the 10X-IGT, which contained 10 times of progressive increment) to investigate the influence of value contrast on the performance of normal subjects. The resulting empirical observations indicated that the value contrast (1X- vs. 10X IGT) of the progressive increment had no effect on the performance of normal subjects. This study also provides a discussion of the issue of value in IGT related studies. Moreover, we found the "prominent deck B phenomenon" in both versions of the IGT, which indicated that the normal subjects were guided mostly by the gain-loss frequency, rather than by the monetary value contrast. In sum, the behavioral performance of normal subjects demonstrated a low correlation with changes in monetary value, even in the 10X-IGT. PMID- 25036095 TI - Beyond apoptosis in lupus. AB - PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is characterized by autoantibodies directed against nuclear autoantigens normally concealed from immune recognition in healthy individuals. Here, we summarize recently identified mechanisms of abnormal cell death leading to exposure and aberrant processing of nucleoprotein self antigens, and discuss their role in the SLE pathogenesis. RECENT FINDINGS: During the past few years, the unveiling of several new forms of cell death has expanded our understanding beyond the simple view of 'apoptotic' versus 'necrotic' cell death. SLE patients show abnormalities in cell death at several levels, including increased rates of apoptosis, necrosis, and autophagy, as well as reduced clearance of dying cells. These abnormalities lead to an increased autoantigen burden and antigen modifications, such as nucleic acid oxidation that increases the inflammatory properties of self antigens. Recent investigations have highlighted the role of opsonins in determining the immunogenic versus tolerogenic characteristics of self antigens. SUMMARY: Dysregulation of different forms of programmed cell death contributes to increased exposure, availability, and immunogenic characteristics of intracellular self antigens, which all participate in development of lupus autoimmunity. As our understanding of abnormalities of cell death in SLE advances, potential therapeutic opportunities await human implementation. PMID- 25036096 TI - Oxidative stress induced age dependent meibomian gland dysfunction in Cu, Zn superoxide dismutase-1 (Sod1) knockout mice. AB - PURPOSE: The purpose of our study was to investigate alterations in the meibomian gland (MG) in Cu, Zn-Superoxide Dismutase-1 knockout (Sod1-/-) mouse. METHODS: Tear function tests [Break up time (BUT) and cotton thread] and ocular vital staining test were performed on Sod1-/- male mice (n = 24) aged 10 and 50 weeks, and age and sex matched wild-type (+/+) mice (n = 25). Tear and serum samples were collected at sacrifice for inflammatory cytokine assays. MG specimens underwent Hematoxylin and Eosin staining, Mallory staining for fibrosis, Oil Red O lipid staining, TUNEL staining, immunohistochemistry stainings for 4HNE, 8-OHdG and CD45. Transmission electron microscopic examination (TEM) was also performed. RESULTS: Corneal vital staining scores in the Sod1-/- mice were significantly higher compared with the wild type mice throughout the follow-up. Tear and serum IL-6 and TNF-alpha levels also showed significant elevations in the 10 to 50 week Sod1-/- mice. Oil Red O staining showed an accumulation of large lipid droplets in the Sod1-/- mice at 50 weeks. Immunohistochemistry revealed both increased TUNEL and oxidative stress marker stainings of the MG acinar epithelium in the Sod1-/- mice compared to the wild type mice. Immunohistochemistry staining for CD45 showed increasing inflammatory cell infiltrates from 10 to 50 weeks in the Sod1-/- mice compared to the wild type mice. TEM revealed prominent mitochondrial changes in 50 week Sod1-/- mice. CONCLUSIONS: Our results suggest that reactive oxygen species might play a vital role in the pathogensis of meibomian gland dysfunction. The Sod1-/- mouse appears to be a promising model for the study of reactive oxygen species associated MG alterations. PMID- 25036097 TI - The EAR motif controls the early flowering and senescence phenotype mediated by over-expression of SlERF36 and is partly responsible for changes in stomatal density and photosynthesis. AB - The EAR motif is a small seven amino acid motif associated with active repression of several target genes. We had previously identified SlERF36 as an EAR motif containing gene from tomato and shown that its over-expression results in early flowering and senescence and a 25-35% reduction of stomatal density, photosynthesis and stomatal conductance in transgenic tobacco. In order to understand the role of the EAR motif in governing the phenotypes, we have expressed the full-length SlERF36 and a truncated form, lacking the EAR motif under the CaMV35S promoter, in transgenic Arabidopsis. Plants over-expressing the full-length SlERF36 show prominent early flowering under long day as well as short day conditions. The early flowering leads to an earlier onset of senescence in these transgenic plants which in turn reduces vegetative growth, affecting rosette, flower and silique sizes. Stomatal number is reduced by 38-39% while photosynthesis and stomatal conductance decrease by about 30-40%. Transgenic plants over-expressing the truncated version of SlERF36 (lacking the C-terminal EAR motif), show phenotypes largely matching the control with normal flowering and senescence indicating that the early flowering and senescence is governed by the EAR motif. On the other hand, photosynthetic rates and stomatal number were also reduced in plants expressing SlERF36DeltaEAR although to a lesser degree compared to the full- length version indicating that these are partly controlled by the EAR motif. These studies show that the major phenotypic changes in plant growth caused by over-expression of SlERF36 are actually mediated by the EAR motif. PMID- 25036098 TI - Specific interaction with cardiolipin triggers functional activation of Dynamin Related Protein 1. AB - Dynamin-Related Protein 1 (Drp1), a large GTPase of the dynamin superfamily, is required for mitochondrial fission in healthy and apoptotic cells. Drp1 activation is a complex process that involves translocation from the cytosol to the mitochondrial outer membrane (MOM) and assembly into rings/spirals at the MOM, leading to membrane constriction/division. Similar to dynamins, Drp1 contains GTPase (G), bundle signaling element (BSE) and stalk domains. However, instead of the lipid-interacting Pleckstrin Homology (PH) domain present in the dynamins, Drp1 contains the so-called B insert or variable domain that has been suggested to play an important role in Drp1 regulation. Different proteins have been implicated in Drp1 recruitment to the MOM, although how MOM-localized Drp1 acquires its fully functional status remains poorly understood. We found that Drp1 can interact with pure lipid bilayers enriched in the mitochondrion-specific phospholipid cardiolipin (CL). Building on our previous study, we now explore the specificity and functional consequences of this interaction. We show that a four lysine module located within the B insert of Drp1 interacts preferentially with CL over other anionic lipids. This interaction dramatically enhances Drp1 oligomerization and assembly-stimulated GTP hydrolysis. Our results add significantly to a growing body of evidence indicating that CL is an important regulator of many essential mitochondrial functions. PMID- 25036099 TI - The biomechanical function of periodontal ligament fibres in orthodontic tooth movement. AB - Orthodontic tooth movement occurs as a result of resorption and formation of the alveolar bone due to an applied load, but the stimulus responsible for triggering orthodontic tooth movement remains the subject of debate. It has been suggested that the periodontal ligament (PDL) plays a key role. However, the mechanical function of the PDL in orthodontic tooth movement is not well understood as most mechanical models of the PDL to date have ignored the fibrous structure of the PDL. In this study we use finite element (FE) analysis to investigate the strains in the alveolar bone due to occlusal and orthodontic loads when PDL is modelled as a fibrous structure as compared to modelling PDL as a layer of solid material. The results show that the tension-only nature of the fibres essentially suspends the tooth in the tooth socket and their inclusion in FE models makes a significant difference to both the magnitude and distribution of strains produced in the surrounding bone. The results indicate that the PDL fibres have a very important role in load transfer between the teeth and alveolar bone and should be considered in FE studies investigating the biomechanics of orthodontic tooth movement. PMID- 25036100 TI - Epidemiology of Functional abdominal bloating and its impact on health related quality of life: male-female stratified propensity score analysis in a population based survey in mainland China. AB - BACKGROUND: The epidemiology of Functional abdominal bloating (FAB) and its impact on health-related quality of life (HRQoL) in Chinese people remains unclear. METHODS: Randomised, stratified, multi-stage sampling methodology was used to select a representative sample of the general population from five cities in China (n = 16,078). All respondents completed the modified Rome II questionnaire; 20% were asked to complete the 36-item Short Form (SF-36). The associated factors of FAB were analyzed. The effects of FAB on HRQoL were estimated with gender stratification using propensity score techniques in 20% subsample. RESULTS: Overall, 643 individuals (4.00%) had FAB and it was more prevalent in males than in females (4.87% vs. 3.04%, P<0.001). For males, self reported history of dyspepsia was most strongly associated with FAB (OR = 2.78; 95% CI: 1.59, 4.72). However, the most strongly associated factor was self reported health status for females (moderate health vs. good health: OR = 2.06, 95% CI: 1.07, 3.96. P = 0.030; poor health vs. good health: OR = 5.71, 95% CI: 2.06, 15.09). Concerning HRQoL, FAB was found to be related to two domains: role limitation due to physical problems (P = 0.030) and bodily pain (P<0.001) in females. While, in males, there were significant differences in multiple domains between those with and without FAB. CONCLUSION: The prevalence of FAB in China was lower than previous reports. Males who had ever been diagnosed with dyspepsia and females who were in a poor self-reported health status were correlated with a higher prevalence of FAB. FAB affected only physical health in females, but impaired both physical and mental health in males. PMID- 25036101 TI - Identification of SH3 domain proteins interacting with the cytoplasmic tail of the a disintegrin and metalloprotease 10 (ADAM10). AB - The a disintegrin and metalloproteases (ADAMs) play a pivotal role in the control of development, adhesion, migration, inflammation and cancer. Although numerous substrates of ADAM10 have been identified, the regulation of its surface expression and proteolytic activity is still poorly defined. One current hypothesis is that both processes are in part modulated by protein-protein interactions mediated by the intracellular portion of the protease. For related proteases, especially proline-rich regions serving as docking sites for Src homology domain 3 (SH3) domain-containing proteins proved to be important for mediating regulatory interactions. In order to identify ADAM10-binding SH3 domain proteins, we screened the All SH3 Domain Phager library comprising 305 human SH3 domains using a GST fusion protein with the intracellular region of human ADAM10 as a bait for selection. Of a total of 291 analyzed phage clones, we found 38 SH3 domains that were precipitated with the ADAM10-derived fusion protein but not with GST. We verified the binding to the cytosolic portion of ADAM10 for several candidates by co-immunoprecipitation and/or pull down analyses. Intriguingly, several of the identified proteins have been implicated in regulating surface appearance and/or proteolytic activity of related ADAMs. Thus, it seems likely that they also play a role in ADAM10 biology. PMID- 25036102 TI - Obesity and associated lifestyle in a large sample of multi-morbid German primary care attendees. AB - BACKGROUND: Obesity and the accompanying increased morbidity and mortality risk is highly prevalent among older adults. As obese elderly might benefit from intentional weight reduction, it is necessary to determine associated and potentially modifiable factors on senior obesity. This cross-sectional study focuses on multi-morbid patients which make up the majority in primary care. It reports on the prevalence of senior obesity and its associations with lifestyle behaviors. METHODS: A total of 3,189 non-demented, multi-morbid participants aged 65-85 years were recruited in primary care within the German MultiCare-study. Physical activity, smoking, alcohol consumption and quantity and quality of nutritional intake were classified as relevant lifestyle factors. Body Mass Index (BMI, general obesity) and waist circumference (WC, abdominal obesity) were used as outcome measures and regression analyses were conducted. RESULTS: About one third of all patients were classified as obese according to BMI. The prevalence of abdominal obesity was 73.5%. Adjusted for socio-demographic variables and objective and subjective disease burden, participants with low physical activity had a 1.6 kg/m2 higher BMI as well as a higher WC (4.9 cm, p<0.001). Current smoking and high alcohol consumption were associated with a lower BMI and WC. In multivariate logistic regression, using elevated WC and BMI as categorical outcomes, the same pattern in lifestyle factors was observed. Only for WC, not current but former smoking was associated with a higher probability for elevated WC. Dietary intake in quantity and quality was not associated with BMI or WC in either model. CONCLUSIONS: Further research is needed to clarify if the huge prevalence discrepancy between BMI and WC also reflects a difference in obesity related morbidity and mortality. Yet, age-specific thresholds for the BMI are needed likewise. Encouraging and promoting physical activity in older adults might a starting point for weight reduction efforts. PMID- 25036104 TI - Multilayered optic disc hemorrhages in adolescents. AB - PURPOSE: To describe the clinical characteristics of multilayered optic disc hemorrhages, which are defined as subretinal, superficial retinal, and subhyaloid or vitreous hemorrhages in adolescents. METHODS: Case records of adolescents with acute multilayered optic disc hemorrhages were identified and evaluated retrospectively from 1994 to 2012. The appearance of the hemorrhages including the size, location, extension, and disc anatomy was recorded. Fluorescein angiography, visual field examination, and spectral-domain optical coherence tomography were performed in select cases. RESULTS: Nine boys and 7 girls were included, with a mean age of 15.0 +/- 2.6 years. No precipitating factor, such as involuntary Valsalva maneuver, was identified in the majority of patients (93.75%). All eyes were myopic with an average refraction of -4.64 +/- 1.88 diopters. Fifteen (93.75%) of the affected optic discs were crowded and tilted with small cups. Peripapillary subretinal hemorrhages were all crescent in shape and located at the nasal disc. Eight (50%) eyes had marked subretinal blood extension exceeding 1 disc diameter away from the disc edge. Superficial flame hemorrhages were predominantly located in the superotemporal part of the disc. Spectral-domain optical coherence tomography of the disc showed vitreopapillary traction and obvious subretinal hemorrhage with increased thickness. All multilayered optic disc hemorrhages resolved spontaneously. CONCLUSIONS: Multilayered optic disc hemorrhages in adolescents more commonly affect myopic eyes with crowded and tilted discs. The visual outcome is excellent. PMID- 25036103 TI - 7-Ketocholesterol-induced inflammation signals mostly through the TLR4 receptor both in vitro and in vivo. AB - The cholesterol oxide 7-ketocholesterol (7KCh) has been implicated in numerous age-related diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer and age-related macular degeneration. It is formed by the autooxidation of cholesterol and especially cholesterol-fatty acid esters found in lipoprotein deposits. This molecule causes complex and potent inflammatory responses in vitro and in vivo. It is suspected of causing chronic inflammation in tissues exposed to oxidized lipoprotein deposits. In this study we have examined the inflammatory pathways activated by 7KCh both in cultured ARPE19 cells and in vivo using 7KCh-containing implants inserted into the anterior chamber of the rat eye. Our results indicate that 7KCh-induced inflammation is mediated mostly though the TLR4 receptor with some cross-activation of EGFR related pathways. The majority of the cytokine inductions seem to signal via the TRIF/TRAM side of the TLR4 receptor. The MyD88/TIRAP side only significantly effects IL-1beta inductions. The 7KCh-induced inflammation also seems to involve a robust ER stress response. However, this response does not seem to involve a calcium efflux-mediated UPR. Instead the ER stress response seems to be mediated by yet identified kinases activated through the TLR4 receptor. Some of the kinases identified are the RSKs which seem to mediate the cytokine inductions and the cell death pathway but do not seem to be involved in the ER stress response. PMID- 25036105 TI - Effect of general anesthesia and muscle relaxants on keratometry measurements using a handheld keratometer. AB - PURPOSE: Keratometry measurements are often obtained under general anesthesia in the supine position in difficult patients and pediatric procedures. This study investigates the effect of general anesthesia and muscle relaxants on keratometry readings using a handheld keratometer. METHODS: Fifty patients (with no history of intraocular surgery or corneal pathology) undergoing general anesthesia were prospectively enrolled. Keratometry readings were obtained using the Nidek KM-500 handheld keratometer (Nidek, Inc., Fremont, CA). in three settings: when the patient was awake in the upright and supine positions, and after general anesthesia. Readings were averaged in each eye and compared among the three settings; patients were also subgrouped by whether muscle relaxants were administered at induction. Intraclass correlation coefficients were calculated and Bland-Altman analysis was performed. RESULTS: Keratometry readings were comparable between the upright and supine positions before anesthesia in all groups. In the muscle relaxant group, keratometry readings were flatter after anesthesia and this was statistically significant for right eyes (P = .02), but not for left eyes (P = .16). In the group with no muscle relaxant, no significant differences were noted. Intraclass correlation coefficients of the differences were high (>= 0.97) for all eyes in both groups and Bland-Altman plots showed most of the differences to be within the limits of agreement. CONCLUSIONS: Keratometry readings using the handheld keratometer obtained under general anesthesia were as reliable as readings obtained in the awake state, regardless of posture; administration of muscle relaxants at induction may produce flatter keratometry readings. PMID- 25036106 TI - Spreading information in a network of interacting neighbours. AB - Dispersed individuals can coordinate the onset of life history events, like reproduction or migration, on a large (population) spatial scale. However, the mechanism of this synchronisation has not yet been identified. In many species signals produced by one individual stimulate signalling activity of immediate neighbours. I propose that such local focuses of signalling could transform into waves propagating in space. This hypothesis predicts that signalling self organizes into bursts, because neighbours tend to enter activity and refractory periods together. Temporal characteristics of such pulses should be more similar in locations proximate to one another than in distant ones. Finally, denser populations should produce relatively more complex wave patterns, since the number of propagating waves is proportional to the number of individuals. These predictions were tested in an analysis of time series of numbers of territorial songs in chaffinches, Fringilla coelebs, and the results supported the hypothesis. Time series of singing activity had memory of their past states: they were autoregressive processes with spectra in which low frequency oscillations predominated. The degree of similarity in two synchronously sampled time series, measured as a Euclidean distance between their spectra, decreased with the increasing physical distance of sampling spots and the number of signalling males. It is concluded that networks of interacting neighbours may integrate populations synchronising life cycles of dispersed individuals. PMID- 25036107 TI - Limbic encephalitis with anti-GAD antibodies and Thomsen myotonia: a casual or causal association? AB - The association between hereditary myotonic disorders and epilepsy is seldom described in the literature. To date, few reports have dealt with dystrophic myotonias, whereas a single case demonstrating an association between sporadic congenital myotonia and epilepsy was recently reported in a patient carrying a de novo mutation of the CLCN1 gene. Additional evidence for a role of CLCN1 in the pathogenesis of epilepsy is derived from large-scale exome analysis of ion channel variants and expression studies. Here, we describe the first case of association between familial Thomsen myotonia and epilepsy. All the affected members of a two-generation family presented myotonia and disclosed a pathogenic mutation in CLCN1. In addition, one individual experienced epileptic seizures due to limbic encephalitis (LE) with anti-GAD antibodies. The occurrence of the two diseases in this patient could be a chance association, however, CLCN1 mutation, as a susceptibility factor for epilepsy through dysfunction of GABAA inhibitory signalling, cannot be ruled out as a possible influence. PMID- 25036108 TI - Improving functional capacity in heart failure: the need for a multifaceted approach. AB - PURPOSE OF REVIEW: Functional capacity is a broad term that describes a person's ability to perform the daily activities that require physical exertion. Patients diagnosed with heart failure, regardless of cause, demonstrate a compromised functional capacity. The ability to perform aerobic activities is a central, but not complete, determinant of functional capacity. Muscular strength and endurance are other important elements of functional capacity. It is well established that patients with heart failure demonstrate attenuated muscular strength and endurance as a consequence of their disease process. Typically, a heart failure patient's ability to perform daily activities that are either aerobic or resistive in nature is compromised and contributes to the decline in functional capacity. RECENT FINDINGS: There is an abundance of literature demonstrating that exercise training improves aerobic capacity and muscular strength and endurance in those with heart failure. These training benefits translate to an improvement in functional capacity and an enhanced ability to perform activities of daily living. There are several approaches to exercise training in the heart failure population, each of which has implications for the degree to which functional capacity can be improved. SUMMARY: This review summarizes the current body of literature related to exercise training as a means of optimizing functional capacity in patients with heart failure. PMID- 25036110 TI - Thermal decomposition of propargyl alcohol: single pulse shock tube experimental and ab initio theoretical study. AB - Thermal decomposition of propargyl alcohol (C3H3OH), a molecule of interest in interstellar chemistry and combustion, was investigated using a single pulse shock tube in the temperature ranging from 953 to 1262 K. The products identified include acetylene, propyne, vinylacetylene, propynal, propenal, and benzene. The experimentally observed overall rate constant for thermal decomposition of propargyl alcohol was found to be k = 10((10.17 +/- 0.36)) exp(-(39.70 +/- 1.83)/RT) s(-1). Ab initio theoretical calculations were carried out to understand the potential energy surfaces involved in the primary and secondary steps of propargyl alcohol thermal decomposition. Transition state theory was used to predict the rate constants, which were then used and refined in a kinetic simulation of the product profile. The first step in the decomposition is C-O bond dissociation, leading to the formation of two important radicals in combustion, OH and propargyl. This has been used to study the reverse OH + propargyl radical reaction, about which there appears to be no prior work. Depending on the site of attack, this reaction leads to propargyl alcohol or propenal, one of the major products at temperatures below 1200 K. A detailed mechanism has been derived to explain all the observed products. PMID- 25036109 TI - Gene expression in peripheral immune cells following cardioembolic stroke is sexually dimorphic. AB - AIMS: Epidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells. METHODS AND RESULTS: Blood samples from patients with cardioembolic stroke were obtained at <=3 hours (prior to treatment), 5 hours and 24 hours (after treatment) after stroke onset (n = 23; 69 samples) and compared with vascular risk factor controls without symptomatic vascular diseases (n = 23, 23 samples) (ANCOVA, false discovery rate p<=0.05, |fold change| >=1.2). mRNA levels were measured on whole genome Affymetrix microarrays. There were more up-regulated than down-regulated genes in both sexes, and females had more differentially expressed genes than males following cardioembolic stroke. Female gene expression was associated with cell death and survival, cell-cell signaling and inflammation. Male gene expression was associated with cellular assembly, organization and compromise. Immune response pathways were over represented at <=3, 5 and 24 h after stroke in female subjects but only at 24 h in males. Neutrophil-specific genes were differentially expressed at 3, 5 and 24 h in females but only at 5 h and 24 h in males. CONCLUSIONS: There are sexually dimorphic immune cell expression profiles following cardioembolic stroke. Future studies are needed to confirm the findings using qRT-PCR in an independent cohort, to determine how they relate to risk and outcome, and to compare to other causes of ischemic stroke. PMID- 25036111 TI - Systematic molecular dynamics, MM-PBSA, and ab initio approaches to the saquinavir resistance mechanism in HIV-1 PR due to 11 double and multiple mutations. AB - Mutations in the human immunodeficiency virus (HIV) enable virus replication even when appropriate antiretroviral therapy is followed, thus leading to the emergence of drug resistance. In a previous work, we systematically examined seven single mutations that are associated with saquinavir (SQV) resistance in HIV-1 protease (Tzoupis, H.; Leonis, G.; Mavromoustakos, T.; Papadopoulos, M. G. J. Chem. Theory Comput. 2013, 9, 1754-1764). Herein, we extend our analysis, which includes seven double (G48V-V82A, L10I-G48V, G48V-L90M, I84V-L90M, L10I V82A, L10I-L63P, A71V-G73S) and four multiple (L10I-L63P-A71V, L10I-G48V-V82A, G73S-I84V-L90M, L10I-L63P-A71V-G73S-I84V-L90M) SQV-HIV-1 PR mutant complexes, in an attempt to generalize our findings and formulate the main elements of the SQV resistance mechanism in the protease. On the basis of molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and ab initio computational approaches, we identified specific features that constitute the HIV 1 PR mechanism of resistance at the molecular level: the low flexibility of SQV in the binding cavity and the preservation of hydrogen bonding (HB) and van der Waals interactions between SQV and several active-site (Gly27/27', Asp29/29'/30/30', especially Asp25/25') and flap (Ile50/50', Gly48/48') residues of the protease contribute significantly to efficient binding. The total enthalpy loss in all mutants is mostly due to the loss in enthalpy of the active-site region. Furthermore, it was observed that mutation accumulation may induce stabilization to SQV and to the flaps through enhanced HB interactions that lead to improved inhibition (e.g., accumulation of mutations in complexes containing L10I, G48V, L63P, I84V, or L90M single mutations). It was also concluded that permanent flap closure is obtained independently of mutations and SQV binding is mostly driven by van der Waals, nonpolar, and exchange-energy contributions. Importantly, it was indicated that the optimal positioning of SQV and the structure of the binding cavity are tightly coupled, since small changes in geometry may affect the binding energy greatly. The results of our theoretical approaches are in agreement with experimental evidence and provide a reliable description of SQV resistance in HIV-1 PR. PMID- 25036112 TI - Origination and immigration drive latitudinal gradients in marine functional diversity. AB - Global patterns in the functional attributes of organisms are critical to understanding biodiversity trends and predicting biotic responses to environmental change. In the first global marine analysis, we find a strong decrease in functional richness, but a strong increase in functional evenness, with increasing latitude using intertidal-to-outer-shelf bivalves as a model system (N = 5571 species). These patterns appear to be driven by the interplay between variation in origination rates among functional groups, and latitudinal patterns in origination and range expansion, as documented by the rich fossil record of the group. The data suggest that (i) accumulation of taxa in spatial bins and functional categories has not impeded continued diversification in the tropics, and (ii) extinctions will influence ecosystem function differentially across latitudes. PMID- 25036113 TI - Detection of methicillin-resistant Staphylococcus aureus carrying the mecC gene in human samples in Slovenia. AB - SUMMARY Following the recognition of a mecC MRSA isolate from a patient hospitalized in the northeastern region of Slovenia, a national collection of 395 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates from 2006 to 2013 was screened. An additional six mecC MRSA strains were found and characterized as spa types t843, t9397 and t10009, and multilocus sequence type ST130. The low oxacillin minimum inhibitory concentrations and absence of the mecA gene make recognition of these MRSA strains problematical for diagnostic laboratories. In such strains the presence of mecC should be determined. PMID- 25036114 TI - Pueraria mirifica leaves, an alternative potential isoflavonoid source. AB - We investigated the major leaf isoflavonoid contents of Pueraria mirifica from three different cultivars (PM-III, PM-IV, and PM-V) using reverse RP-HPLC analysis. The proportions and net levels of puerarin, daidzin, genistin, and daidzein in P. mirifica leaves were found to depend on the plant cultivar and to correlate with cultivation temperature and rainfall amount. The crude leaf extracts were tested using the Yeast Estrogen Screen (YES) assay with both human estrogen receptors (hERalpha and hERbeta). Their estrogenic activity was higher when determined by the YES system containing hERbeta than that with hERalpha and was also higher when the Deltasnq2 than the wildtype yeast was employed. The results open the possibility of selecting and cultivating certain P. mirifica cultivars at a farm scale to produce a sufficient supply of leaf material to act as a starting source for the commercial scale extraction of these major isoflavonoids. PMID- 25036115 TI - Measurement of endo-alpha-mannosidase activity using a fluorescently labeled oligosaccharide derivative. AB - Endo-alpha-mannosidase, a GH99-family glycoside hydrolase, cleaves alpha mannoside linkages with glucose residues. This enzyme is proposed to play a critical role in N-glycan processing for deglucosylation. To measure endo-alpha mannosidase activity, we synthesized a fluorescently labeled tetrasaccharide derivative (Glcalpha1-3Manalpha1-2Manalpha1-2Manalpha1-O-C3H6-NH-Dansyl) in a stereocontrolled manner. The tetrasaccharide skeleton was prepared by step-wise coupling using mannose donors 4 and 7. The 1,2-cis alpha-glycosidic linkage on the non-reducing end of the glucose residue was constructed by inversion of the stereochemistry of the C-2 hydroxyl group in the alpha-mannose residue. Finally, the dansyl group was introduced at the reducing end via an aminopropyl linker. This probe successfully measured endo-alpha-mannosidase activity. PMID- 25036116 TI - Structural determination of elicitors in Sogatella furcifera (Horvath) that induce Japonica rice plant varieties (Oryza sativa L.) to produce an ovicidal substance against S. furcifera eggs. AB - Certain Japonica rice plant varieties (Oryza sativa L.) show resistance to the eggs of the white backed planthopper (Sogatella furcifera Horvath) by the formation of watery lesions and production of benzyl benzoate, an active ovicidal compound. Benzyl benzoate results in high ovicidal activity of S. furcifera eggs and reduces egg hatchability. The production of benzyl benzoate by the rice plants is only induced by an unknown elicitor(s) from the female S. furcifera. Therefore, we tried to isolate and identify these elicitors. An active 80% MeOH extract of S. furcifera was separated on a reverse-phase ODS MPLC, and the elicitor(s) was eluted in 100% MeOH and 100% EtOH fractions. Further separation of the active 100% MeOH fraction using a HPLC led to the isolation of four active compounds. The structures of each compound were determined by using NMR, LC-MS, and GC-MS spectra. The compounds were 1,2-dilinoleoyl-sn-glycero-3 phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1-palmitoyl-2 oleoyl-X-glycero-3-phosphoethanolamine, and 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine. PMID- 25036117 TI - Desmodianone H and uncinanone B, potential tyrosinase inhibitors obtained from Lespedeza maximowiczii by using bioactivity-guided isolation. AB - A new bioactive compound, namely desmodianone H(1), and another known compound uncinanone B(2) were first isolated using bioactivity-guided isolation from the leaves of Lespedeza maximowiczii and structures were elucidated by comprehensive analysis of their nuclear magnetic resonance and mass spectrometry data. Compounds 1 and 2 exhibited strong inhibitory effects on mushroom tyrosinase activity. PMID- 25036118 TI - Proteomic analysis of Physcomitrella patens treated with 12-oxo-phytodienoic acid, an important oxylipin in plants. AB - 12-Oxo-phytodienoic acid (OPDA) is biosynthesized in the octadecanoid pathway and is considered to be a signaling molecule in plants. In Physcomitrella patens, OPDA is induced by bacterial infection and mechanical stress and is known to suppress growth; however, the functional mechanism of OPDA signaling remains elusive. In this study, we performed a proteomic analysis of P. patens treated with OPDA and found that the expression of 82 proteins was significantly altered, with approximately 80% of these proteins being downregulated by OPDA. The identified proteins were mainly categorized as being involved in photosynthesis, metabolism, and protein synthesis, and most of the proteins that were upregulated by OPDA are involved in light-dependent reactions, suggesting that OPDA regulates a function in chloroplasts. Additionally, OPDA induced the expression of an allene oxide cyclase (PpAOC1) in the octadecanoid pathway, demonstrating positive feedback regulation by OPDA in P. patens. PMID- 25036119 TI - Multiple solvent, N-methyl-2-pyrrolidone, acts as a novel adjuvant for enhancing cutaneous immune responses. AB - N-methyl-2-pyrrolidone (NMP) is known for its multi-solvent properties. However, its biological, especially immunological significance still remains to be elucidated. In this study, we show for the first time that NMP stimulates the skin immune system by activating epidermal Langerhans cells (LCs). In contrast with the placebo tape, when the NMP-containing adhesive tape was applied on murine skin, LCs were stimulated immediately. Activated LCs not only exhibited enhanced expression of major histocompatibility complex class II and morphological changes, including the loss of dendrites, but also migrated effectively to draining lymph nodes. In addition, application of the tyrosine related protein-2 peptide, which is the cytotoxic T lymphocyte (CTL) epitope against B16 melanoma, in combination with the NMP tape, resulted in explosive expansion of specific CTLs in mouse spleens. Taken together, these results demonstrate a novel role of NMP as an adjuvant in percutaneous peptide immunization. PMID- 25036120 TI - Brassinosteroid-related transcription factor BIL1/BZR1 increases plant resistance to insect feeding. AB - The plant steroid hormones brassinosteroids (BRs) play important roles in plant growth and responses to stresses. The up-regulation of pathogen resistance by BR signaling has been analyzed, but the relationship between BR and insect herbivores remains largely unclear. BIL1/BZR1 is a BR master transcription factor known to be involved in the regulation of plant development through work conducted on a gain of function mutation. Here, we analyzed the function of BIL1/BZR1 in response to insect feeding and demonstrated that resistance against thrip feeding was increased in the bil1-1D/bzr1-1D mutant compared to wild-type. We generated Lotus japonicus transgenic plants that over-express the Arabidopsis bil1/bzr1 mutant, Lj-bil1/bzr1-OX. The Lj-bil1/bzr1-OX plants showed increased resistance to thrip feeding. The expression levels of the jasmoninc acid (JA) inducible VSP genes were increased in both Arabidopsis bil1-1D/bzr1-1D mutants and L. japonicus Lj-bil1/bzr1-OX plants. The resistance to thrip feeding caused by the BIL1/BZR1 gene may involve JA signaling. PMID- 25036121 TI - Vacuolar transporter Avt4 is involved in excretion of basic amino acids from the vacuoles of Saccharomyces cerevisiae. AB - Basic amino acids (lysine, histidine and arginine) accumulated in Saccharomyces cerevisiae vacuoles should be mobilized to cytosolic nitrogen metabolism under starvation. We found that the decrease of vacuolar basic amino acids in response to nitrogen starvation was impaired by the deletion of AVT4 gene encoding a vacuolar transporter. In addition, overexpression of AVT4 reduced the accumulation of basic amino acids in vacuoles under nutrient-rich condition. In contrast to AVT4, the deletion and overexpression of AVT3, which encodes the closest homologue of Avt4p, did not affect the contents of vacuolar basic amino acids. Consistent with these, arginine uptake into vacuolar membrane vesicles was decreased by Avt4p-, but not by Avt3p-overproduction, whereas various neutral amino acids were excreted from vacuolar membrane vesicles in a manner dependent on either Avt4p or Avt3p. These results suggest that Avt4p is a vacuolar amino acid exporter involving in the recycling of basic amino acids. PMID- 25036122 TI - Attenuation of migration properties of CD4+ T cells from aged mice correlates with decrease in chemokine receptor expression, response to retinoic acid, and RALDH expression compared to young mice. AB - Aging results in attenuation of abilities to mount appropriate immune responses. The influence of aging on CD4(+) T cell migration ability toward chemokines was investigated with young and aged mice. We found functional decline in migration ability toward CCL19 and also decreased CCR7 expression level in antigen stimulated CD4(+) T cells from aged mice compared with those from young mice. Upon addition of retinoic acid (RA), CD4(+) T cells from aged mice showed decreased CCR9 expression level compared to young mice and the migration ability of CD4(+) T cells from aged mice toward CCL25 was attenuated compared to young mice. We also observed that the expression of RALDH2 mRNA was decreased in mesenteric lymph node dendritic cells from aged mice compared to those from young mice. These results demonstrate that attenuated migration abilities of CD4(+) T cells were observed in aged mice, which correlated with decreased chemokine receptor expression. Furthermore, the reduced production and response to RA by aging may be one of the causes of such attenuated migration abilities in the intestinal immune system. PMID- 25036123 TI - Detection of choline and phosphatidic acid (PA) catalyzed by phospholipase D (PLD) using MALDI-QIT-TOF/MS with 9-aminoacridine matrix. AB - Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), the most abundant phospholipids of plasma membrane, resulting in the production of choline and phosphatidic acid (PA). Choline is a precursor of the neurotransmitter acetylcholine, whereas PA functions as an intracellular lipid mediator of diverse biological functions. For assessing PLD activity in vitro, PLD-derived choline has been often analyzed with radioactive or non-radioactive methods. In this study, we have developed a new method for detecting choline and PA with MALDI-QIT-TOF/MS by using 9-aminoacridine as a matrix. The standard calibration curves showed that choline and PA could be detected with linearity over the range from 0.05 and 1 pmol, respectively. Importantly, this method enables the concomitant detection of choline and PA as a reaction product of PC hydrolysis by PLD2 proteins. Thus, our simple and direct method would be useful to characterize the enzymatic properties of PLD, thereby providing insight into mechanisms of PLD activation. PMID- 25036124 TI - Crystal structure of alpha-amylase from Oryza sativa: molecular insights into enzyme activity and thermostability. AB - AmyI-1 is an alpha-amylase from Oryza sativa (rice) and plays a crucial role in degrading starch in various tissues and at various growth stages. This enzyme is a glycoprotein with an N-glycosylated carbohydrate chain, a unique characteristic among plant alpha-amylases. In this study, we report the first crystal structure of AmyI-1 at 2.2-A resolution. The structure consists of a typical (beta/alpha)8 barrel, which is well-conserved among most alpha-amylases in the glycoside hydrolase family-13. Structural superimposition indicated small variations in the catalytic domain and carbohydrate-binding sites between AmyI-1 and barley alpha amylases. By contrast, regions around the N-linked glycosylation sites displayed lower conservation of amino acid residues, including Asn-263, Asn-265, Thr-307, Asn-342, Pro-373, and Ala-374 in AmyI-1, which are not conserved in barley alpha amylases, suggesting that these residues may contribute to the construction of the structure of glycosylated AmyI-1. These results increase the depths of our understanding of the biological functions of AmyI-1. PMID- 25036125 TI - Detection of mutations by fill-in ligation reaction with enzyme-linked immunosorbent assay for rapid medical diagnosis. AB - Several approaches for parallel genotyping have been developed with increasingly available information on DNA variation. However, these methods require either complex laboratory procedures or expensive instrumentation. None of these procedures is readily performed in local clinical laboratories. In this study, we developed a flexible genotyping method involving fill-in ligation reaction with enzyme-linked immunosorbent assay successfully applied to detect important single nucleotide polymorphisms (SNPs) for EGFR c.2573T > G (L858R), EGFR c.2582T > A (L861Q), and EGFR c.2155G > T (G719C). This assay exhibited excellent specificity, with a sensitivity as low as 0.5%. Eight out of 62 clinical samples were identified as heterozygotes for the SNP site of L858R, whereas only two samples were identified as heterozygotes by direct sequencing. The developed method enabled accurate identification of SNP in a simple and cost-effective manner adapted to routine analysis. PMID- 25036126 TI - A protocol for in vitro production of microtubers in Chinese yam (Dioscorea opposita). AB - Chinese yam (Dioscorea opposita) is an important tuberous crop owing to its dual use as a food as well as a medicine. Tissue culture techniques allow the rapid multiplication of virus-free plant materials. The use of microtubers offers an attractive alternative to in vitro-grown plantlets for the micropropagation and exchange of healthy Chinese yam materials. A protocol for the in vitro production of Chinese yam microtubers was developed in this study. Though we tested both one step and two-step procedures, only the two-step procedure showed favorable results for tuberization. Media with 60 g L(-1) sucrose yielded the highest microtuber index. We demonstrate that table sugar was an efficient and economical alternative to analytical grade sucrose for microtuber production. Using an orthogonal experimental design, we determined the optimal growth regulator combination for microtuber induction and development. The microtubers obtained from our protocol sprouted readily both in vitro and in soil. PMID- 25036127 TI - Regulation of tissue factor pathway inhibitor-2 (TFPI-2) expression by lysine specific demethylase 1 and 2 (LSD1 and LSD2). AB - Tissue factor pathway inhibitor-2 (TFPI-2) is a major inhibitor of extracellular matrix degradation. Decreases in TFPI-2 contribute to malignant tumor cell production, and TFPI-2 is a presumed tumor suppressor. TFPI-2 gene transcription is regulated by two epigenetic mechanisms: DNA methylation of the promoter and K4 methylation of histone 3 (H3). Lysine-specific demethylase 1 (LSD1) and LSD2 demethylate H3K4me2/1. LSD1 has been implicated in TFPI-2 regulation through both epigenetic mechanisms, but the involvement of LSD2 remains unknown. We prepared a monoclonal anti-LSD2 antibody that clearly distinguishes LSD2 from LSD1. Knockdown of LSD1 or LSD2 by siRNAs increased TFPI-2 protein and mRNA. Simultaneous knockdown of both LSD1 and LSD2 showed additive effects. Bisulfite sequencing revealed that CpG sites in the TFPI-2 promoter region were unmethylated. These results indicate that LSD2 also contributes to TFPI-2 regulation through histone modification, and that further studies of the involvement of LSD2 in tumor malignancy are warranted. PMID- 25036128 TI - Effects of low molecular weight soybean peptide on mRNA and protein expression levels of differentiation markers in normal human epidermal keratinocytes. AB - Low molecular weight soybean peptide (LSP) was applied to normal human epidermal keratinocytes, and the results showed a significant increase in the gene expression levels of involucrin, transglutaminase, and profilaggrin. Filaggrin protein levels were also significantly higher. It is possible that LSP has an epidermal cell differentiation-promoting effect and may be able to regulate metabolism of the epidermis. PMID- 25036129 TI - Biochemical analyses of ppGpp effect on adenylosuccinate synthetases, key enzymes in purine biosynthesis in rice. AB - The ppGpp-signaling system functions in plant chloroplasts. In bacteria, a negative effect of ppGpp on adenylosuccinate synthetase (AdSS) has been suggested. Our biochemical analysis also revealed rice AdSS homologs are apparently sensitive to ppGpp. However, further investigation clarified that this phenomenon is cancelled by the high substrate affinity to the enzymes, leading to a limited effect of ppGpp on adenylosuccinate synthesis. PMID- 25036130 TI - A simple and rapid method for visualization of male meiotic chromosomes in Arabidopsis thaliana. AB - Meiotic chromosomes are of basic interest to the geneticist and cell biologist who study their behavior. A rapid and highly repeatable method for visualization of meiotic chromosomes is useful. Here we describe a fast staining protocol for Arabidopsis male meiotic chromosomes. Meiocytes were squashed into a labeling buffer, the chromosome morphology could be analyzed using fluorescence without any additional treatment. PMID- 25036131 TI - Antioxidative activity, moisture retention, film formation, and viscosity stability of Auricularia fuscosuccinea, white strain water extract. AB - This study showed that both water extracts (WAF-W) and ethanol extracts (EAF-W) of Auricularia fuscosuccinea (Montagne) Farlow, white strain (AF-W) demonstrated significantly stronger antioxidative effects than did commercially available Tremella fuciformis sporocarp extracts (WSK; with the exception of EAF-W in terms of superoxide radical scavenging activity levels). The moisture retention capacity of WAF-W is as potent as that of sodium hyaluronate (SHA), but less than that of WSK. No corrugation or fissures were observed in WAF-W film; only the SHA and WSK films demonstrated such effects in low-moisture conditions. The WAF-W solution also exhibited stable viscosity at high temperatures, indicating that the WAF-W film was more stable compared with the SHA and WSK films. WAF-W induced no adverse effects when a hen's egg test was performed on the chorioallantoic membrane (CAM). This study demonstrated that WAF-W exhibits excellent potential as a topical material for skin moisturizing and anti-aging effects. PMID- 25036132 TI - Cyanidin-3-glucoside suppresses Th2 cytokines and GATA-3 transcription factor in EL-4 T cells. AB - Allergic disease is dominated by Th2 immune responses. Interleukin (IL)-4 and IL 13, representative Th2 cytokines, play pivotal roles in the pathogenic activation of the Th2 immune response. In this study, we found that cyanidin-3-glucoside chloride (C3G), an anthocyanin suppressed IL-4 and IL-13 produced in activated EL 4 T cells but not Th1 cytokines including IL-2, interferon-gamma, or IL-12. IL-4 and IL-13 mRNA levels and luciferase activation in cells transiently transfected with IL-4 and IL-13 promoter reporter plasmids were significantly inhibited by C3G, suggesting that suppression might be, at least in part, regulated at the transcriptional level. Data from western blot and reverse transcription polymerase chain reaction analyses of transcription factors involved in cytokine expression suggested that expression of GATA-3, but not T-bet, was downregulated in the nucleus by C3G. Taken together, our data indicate that C3G may has potential as an anti-allergic agent suppressing Th2 activation by downregulating Th2 cytokines and the GATA3 transcription factor in allergies. PMID- 25036133 TI - Effects of laver extracts on adhesion, invasion, and migration in SK-Hep1 human hepatoma cancer cells. AB - The laver (Porphyra tenera), red seaweed, has been reported to have anticancer activity, but little is known about its molecular mechanisms of action. The objective of this study was to determine the effects of laver extract on cancer cell proliferation, invasion, and metastasis in SK-Hep1 cells using migration and invasion assays. We also investigated the relationship of MMP-2/-9 and TIMP-1/-2 expression at both the protein and gene level in SK-Hep1 human hepatoma carcinoma cells after laver extract treatment. Laver extract inhibited cancer cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, laver extract showed 19.6 and 27.2% inhibition of cancer cell at 200 and 400 MUg/mL, respectively, compared to the control. The mRNA levels of both MMP-2 and MMP-9 were down-regulated by laver extract treatment in a dose-dependent manner. Laver extract, at 400 MUg/mL, was inhibited by MMP-2 and MMP-9 expressions by 70.1 and 77.0%, respectively. An inverse relationship in the mRNA contents of MMP 2/-9 and TIMP-1/-2 expressions in SK-Hep1 cells was found by laver extract treatment. Our results demonstrate antimetastatic properties of laver extract in inhibiting the adhesion, invasion, and migration of SK-Hep1 human hepatoma cancer cells. PMID- 25036134 TI - Hesperetin glucuronides induce adipocyte differentiation via activation and expression of peroxisome proliferator-activated receptor-gamma. AB - In previous reports, hesperidin, a flavonoid glucoside from citrus fruit, is hydrolyzed to hesperetin, an aglycone of hesperidin, and converted to the hesperetin glucuronides (H7-OG and H3'-OG) in vivo and depresses blood glucose levels. But there are no reports on the activity of hesperetin glucuronides. To determine the activity of hesperetin glucuronides, H7-OG and H3'-OG were synthesized and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist activity was observed at 250 MUM. These glucuronides accelerated the differentiation of 3T3-L1 cells into adipocytes at 10 MUM. Furthermore, H7-OG showed additive effects in reporter gene assays and caused noncompetitive reactions in time-resolved fluorescence resonance energy transfer assays with a thiazolidinedione derivative. Our results indicated that hesperetin glucuronides activated PPARgamma, accelerated adipocyte differentiation. PMID- 25036135 TI - Ascorbic acid deficiency decreases hepatic cytochrome P-450, especially CYP2B1/2B2, and simultaneously induces heme oxygenase-1 gene expression in scurvy prone ODS rats. AB - The mechanisms underlying the decrease in hepatic cytochrome P-450 (CYP) content in ascorbic acid deficiency was investigated in scurvy-prone ODS rats. First, male ODS rats were fed a diet containing sufficient ascorbic acid (control) or a diet without ascorbic acid (deficient) for 18 days, with or without the intraperitoneal injection of phenobarbital. Ascorbic acid deficiency decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial cytochrome oxidase (COX) complex IV subunit I protein, and simultaneously increased heme oxygenase-1 protein in microsomes and mitochondria. Next, heme oxygenase-1 inducers, that is lipopolysaccharide and hemin, were administered to phenobaribital-treated ODS rats fed sufficient ascorbic acid. The administration of these inducers decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial COX complex IV subunit I protein. These results suggested that the stimulation of hepatic heme oxygenase-1 expression by ascorbic acid deficiency caused the decrease in CYP content in liver. PMID- 25036136 TI - Thiol modification by bioactivated polyphenols and its potential role in skin inflammation. AB - In the present study, we evaluated the modifying behavior of simple phenolic compounds on the sulfhydryl groups of glutathione and proteins. The catechol-type polyphenols, including protocatechuic acid, but neither the monophenols nor O methylated catechol, can modify the sulfhydryl groups in a phenol oxidase dependent manner. The possible involvement of polyphenol bioactivation in the enhancement of skin inflammation was also suggested. PMID- 25036137 TI - Re-feeding rats a high-sucrose diet after 3 days of starvation enhances histone H3 acetylation in transcribed region and expression of jejunal GLUT5 gene. AB - Fasting for 3 days leads to reduction in the expression of GLUT5 and SGLT1 genes in jejunum. Re-feeding a high-sucrose diet in fasted rats enhanced mRNA levels and histone H3 acetylation on transcribed region of GLUT5 gene within 24 h, but not in SGLT1. Responsiveness of jejunal GLUT5 gene is associated with changes in histone H3 acetylation on transcribed region. PMID- 25036138 TI - Production of Bacillus subtilis-fermented red alga Porphyra dentata suspension with fibrinolytic and immune-enhancing activities. AB - The fermented marine alga Porphyra dentata suspension was tested for its fibrinolytic and immune-enhancing activities. An isolated Bacillus subtilis N2 strain was selected for its fibrinolytic activity on fibrin plates. After investigating the effects of biomass amounts of P. dentata powder in water, various additives including sugars, nitrogen-containing substances, lipids and minerals, and cultural conditions of temperature and agitation in flask, the highest fibrinolytic activity in the cultural filtrate was obtained by cultivating N2 strain in 3% (w/v) P. dentata powder suspension containing 1% peanut oil at 37 degrees C, 150 rpm for 48 h. A fermentor system was further established using the same medium with controlled pH value of 7.0 at 37 degrees C, 150 rpm, 2.0 vvm for 48 h for the best fibrinolytic activity. The fermented product also showed its immune-enhancing activity by increasing cell proliferation and stimulating the secretion of IL-1beta, IL-6, and TNF-alpha in J774.1 cells. PMID- 25036139 TI - Salmonella typhimurium with gamma-radiation induced H2AX phosphorylation and apoptosis in melanoma. AB - To investigate the combinatorial effects using Salmonella and gamma-radiation, the Salmonella typhimurium infection in combination with gamma-radiation was investigated on melanoma. We showed that ROS expression and H2AX phosphorylation increased during stress by gamma-radiation irrespective of Salmonella infection, inducing apoptosis by caspase-3 and bcl2 in tumor cells. In addition, tumor growth was suppressed by this combinatory therapy suggesting candidates for radiation therapy against melanoma. PMID- 25036140 TI - Efficient screening of environmental isolates for Saccharomyces cerevisiae strains that are suitable for brewing. AB - We developed an efficient screening method for Saccharomyces cerevisiae strains from environmental isolates. MultiPlex PCR was performed targeting four brewing S. cerevisiae genes (SSU1, AWA1, BIO6, and FLO1). At least three genes among the four were amplified from all S. cerevisiae strains. The use of this method allowed us to successfully obtain S. cerevisiae strains. PMID- 25036141 TI - Improvement of the transformation efficiency of Sacchaaromyces cerevisiae by altering carbon sources in pre-culture. AB - We show here that the transformation efficiency of Saccharomyces cerevisiae is improved by altering carbon sources in media for pre-culturing cells prior to the transformation reactions. The transformation efficiency was increased up to sixfold by combination with existing transformation protocols. This method is widely applicable for yeast research since efficient transformation can be performed easily without changing any of the other procedures in the transformation. PMID- 25036142 TI - Characterization and genetic analyses of a carbazole-degrading gram-positive marine isolate, Janibacter sp. strain OC11. AB - Strain OC11 was isolated from seawater sampled at the coast of Chiba, Japan, in artificial seawater medium with carbazole (CAR) as the sole carbon source. Its 16S ribosomal RNA gene sequence suggested that strain OC11 belongs to the genus Janibacter. The CAR-degradation genes (car genes) of strain OC11 were PCR amplified, using degenerate primers designed based on the car gene sequences of other CAR-degrading bacteria. Complete nucleotide sequences encoding six complete open reading frames were determined, and the first known ferredoxin reductase gene (carAd) was found from a CAR-degrading bacterium isolated from the marine environment. An experiment using a mutant strain suggested that the car genes of strain OC11 are functional in CAR degradation. Southern hybridization indicated that strain OC11 had one car gene cluster in vivo. RT-PCR revealed that transcription of carOC11 constitutes an operon. PMID- 25036143 TI - Atypical mismatch negativity in response to emotional voices in people with autism spectrum conditions. AB - Autism Spectrum Conditions (ASC) are characterized by heterogeneous impairments of social reciprocity and sensory processing. Voices, similar to faces, convey socially relevant information. Whether voice processing is selectively impaired remains undetermined. This study involved recording mismatch negativity (MMN) while presenting emotionally spoken syllables dada and acoustically matched nonvocal sounds to 20 subjects with ASC and 20 healthy matched controls. The people with ASC exhibited no MMN response to emotional syllables and reduced MMN to nonvocal sounds, indicating general impairments of affective voice and acoustic discrimination. Weaker angry MMN amplitudes were associated with more autistic traits. Receiver operator characteristic analysis revealed that angry MMN amplitudes yielded a value of 0.88 (p<.001). The results suggest that people with ASC may process emotional voices in an atypical fashion already at the automatic stage. This processing abnormality can facilitate diagnosing ASC and enable social deficits in people with ASC to be predicted. PMID- 25036144 TI - The CRAFFT cut-points and DSM-5 criteria for alcohol and other drugs: a reevaluation and reexamination. AB - BACKGROUND: The CRAFFT, previously validated against DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnostic criteria, is the most widely used screening instrument for alcohol and other substance misuse in adolescents. The present secondary analysis study sought to compare the CRAFFT with the new DSM-5 diagnostic criteria in order to assess the CRAFFT's psychometric properties and determine the optimal cut-point for identifying adolescents in need of further assessment. METHODS: Participants were primary care patients aged 12-17 (N = 525) who were recruited while waiting for a medical appointment in an urban federally qualified health center in Baltimore, Maryland, USA. Participants were administered the CRAFFT and the Composite International Diagnostic Interview, second edition, modified to include the new DSM-5 craving item. The authors examined the performance of the CRAFFT in identifying any problem use (defined as 1 or more DSM-5 criteria) and any DSM-5 substance use disorder (2 or more DSM-5 criteria) for alcohol or drugs other than tobacco. The authors examined sensitivity, specificity, and receiver operating characteristic areas under the curve (AUC) to determine the optimal CRAFFT cut-point(s) for predicting any problem use and any DSM-5 substance use disorder (SUD). RESULTS: Examining the CRAFFT as a continuous measure, AUC values were 0.93 for problem use or higher and 0.97 for DSM-5 SUD. Consistent with previously recommended cut points for the CRAFFT, the cut-point of 2 performed optimally for identifying adolescents both exhibiting problem use of alcohol or drugs and meeting DSM-5 SUD criteria for alcohol or other drugs. CONCLUSIONS: Despite changes in the DSM substance use diagnostic criteria, the CRAFFT continues to demonstrate excellent sensitivity and specificity at its established cut-point of 2. Additional studies examining the CRAFFT in light of the new DSM-5 diagnostic criteria with more diverse populations are warranted. PMID- 25036145 TI - Preparation of triple-negative breast cancer vaccine through electrofusion with day-3 dendritic cells. AB - Dendritic cells (DCs) are professional antigen-presenting cells (APCs) in human immune system. DC-based tumor vaccine has met with some success in specific malignancies, inclusive of breast cancer. In this study, we electrofused MDA-MB 231 breast cancer cell line with day-3 DCs derived from peripheral blood monocytes, and explored the biological characteristics of fusion vaccine and its anti-tumor effects in vitro. Day-3 mature DCs were generated from day-2 immature DCs by adding cocktails composed of TNF-alpha, IL-1beta, IL-6 and PEG2. Day-3 mature DCs were identified and electofused with breast cancer cells to generate fusion vaccine. Phenotype of fusion cells were identified by fluorescence microscope and flow cytometer. The fusion vaccine was evaluated for T cell proliferation, secretion of IL-12 and IFN-gamma, and induction of tumor-specific CTL response. Despite differences in morphology, day-3 and day-7 DC expressed similar surface markers. The secretion of IL-12 and IFN-gamma in fusion vaccine group was much higher than that in the control group. Compared with control group, DC-tumor fusion vaccine could better stimulate the proliferation of allogeneic T lymphocytes and kill more breast cancer cells (MDA-MB-231) in vitro. Day-3 DCs had the same function as the day-7 DCs, but with a shorter culture period. Our findings suggested that day-3 DCs fused with whole apoptotic breast cancer cells could elicit effective specific antitumor T cell responses in vitro and may be developed into a prospective candidate for adoptivet immunotherapy. PMID- 25036146 TI - Comparisons between detection threshold and loudness perception for individual cochlear implant channels. AB - OBJECTIVE: The objective of this study was to examine how the level of current required for cochlear implant listeners to detect single-channel electrical pulse trains relates to loudness perception on the same channel. The working hypothesis was that channels with relatively high thresholds, when measured with a focused current pattern, interface poorly to the auditory nerve. For such channels, a smaller dynamic range between perceptual threshold and the most comfortable loudness would result, in part, from a greater sensitivity to changes in electrical field spread compared to low-threshold channels. The narrower range of comfortable listening levels may have important implications for speech perception. DESIGN: Data were collected from eight, adult cochlear implant listeners implanted with the HiRes90k cochlear implant (Advanced Bionics Corp.). The partial tripolar (pTP) electrode configuration, consisting of one intracochlear active electrode, two flanking electrodes carrying a fraction (sigma) of the return current, and an extracochlear ground, was used for stimulation. Single-channel detection thresholds and most comfortable listening levels were acquired using the most focused pTP configuration possible (sigma >= 0.8) to identify three channels for further testing-those with the highest, median, and lowest thresholds-for each subject. Threshold, equal-loudness contours (at 50% of the monopolar dynamic range), and loudness growth functions were measured for each of these three test channels using various pTP fractions. RESULTS: For all test channels, thresholds increased as the electrode configuration became more focused. The rate of increase with the focusing parameter sigma was greatest for the high-threshold channel compared to the median- and low-threshold channels. The 50% equal-loudness contours exhibited similar rates of increase in level across test channels and subjects. Additionally, test channels with the highest thresholds had the narrowest dynamic ranges (for sigma >= 0.5) and steepest growth of loudness functions for all electrode configurations. CONCLUSIONS: Together with previous studies using focused stimulation, the results suggest that auditory responses to electrical stimuli at both threshold and suprathreshold current levels are not uniform across the electrode array of individual cochlear implant listeners. Specifically, the steeper growth of loudness and thus smaller dynamic ranges observed for high-threshold channels are consistent with a degraded electrode neuron interface, which could stem from lower numbers of functioning auditory neurons or a relatively large distance between the neurons and electrodes. These findings may have potential implications for how stimulation levels are set during the clinical mapping procedure, particularly for speech-processing strategies that use focused electrical fields. PMID- 25036147 TI - The effects of within- and between-group competition on trust and trustworthiness among acquaintances. AB - Several studies have indicated that between-group competition is a key stimulator of trust and trustworthiness. Another important but neglected type of competition may also affect trust and trustworthiness: within-group competition, especially competition among acquaintances. The present study investigated the effects of both within- and between-group competition on trust and trustworthiness, which were measured using an investment game played by acquaintances. We found that, compared to the participants' performance in the non-competition condition, when individuals were motivated to compete with their in-group members or the other groups for financial rewards, they demonstrated more trust. When individuals were motivated to compete with their in-group members, they exhibited lower trustworthiness than in non-competition and between-group competition. In addition, within-group competition decreased the trustor's payoff while both within- and between- group competition increased the trustee's payoff. Finally, we found that males trusted their group members more than females. PMID- 25036150 TI - Variation in the bioactive compound content at three ripening stages of strawberry fruit. AB - During the harvest season of two consecutive years, five strawberry cultivars ('Arosa', 'Elsanta', 'Marmolada', 'Miss' and 'Raurica'), grown in the continental part of the Republic of Croatia, were examined. Strawberry fruits quality was evaluated by individual phenol compounds, individual anthocyanins and fruit color. Fruits were harvested in three different periods. Analyzed strawberry cultivars show very good average values of the studied phenolic acids and flavonoids with predominant caffeic acid and epicatechin content in all researched strawberry cultivars. Considering the content of individual anthocyanins, pelargonidin 3-glucoside is predominant in strawberry extract followed by cyanidin-3-glucoside and pelargonidin 3-rutinoside. The correlation between individual anthocyanin content and chromaticity parameters was detected in all strawberry cultivars, additionally correlation coefficients and statistical significance were much lower. The results show a positive association between cultivar and harvest time on strawberry pulp color, with each of the color variables, a, b, a/b ratio, C, L and h degrees values. PMID- 25036148 TI - Tubular overexpression of gremlin induces renal damage susceptibility in mice. AB - A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-beta. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2 to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-beta and alphaSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression. PMID- 25036149 TI - Atypical McMurry cross-coupling reactions leading to a new series of potent antiproliferative compounds bearing the key [ferrocenyl-ene-phenol] motif. AB - In the course of the preparation of a series of ferrocenyl derivatives of diethylstilbestrol (DES), in which one of the 4-hydroxyphenyl moieties was replaced by a ferrocenyl group, the McMurry reaction of chloropropionylferrocene with a number of mono-aryl ketones unexpectedly yielded the hydroxylated ferrocenyl DES derivatives, 5a-c, in poor yields (10%-16%). These compounds showed high activity on the hormone-independent breast cancer cell line MDA-MB 231 with IC50 values ranging from 0.14 to 0.36 uM. Surprisingly, non-hydroxylated ferrocenyl DES, 4, showed only an IC50 value of 1.14 uM, illustrating the importance of the hydroxyethyl function in this promising new series. For comparison, McMurry reactions of the shorter chain analogue chloroacetylferrocene were carried out to see the difference in behaviour with mono-aryl ketones versus a diaryl ketone. The effect of changing the length of the alkyl chain adjacent to the phenolic substituent of the hydroxylated ferrocenyl DES was studied, a mechanistic rationale to account for the unexpected products is proposed, and the antiproliferative activities of all of these compounds on MDA-MB-231 cells lines were measured and compared. X-ray crystal structures of cross-coupled products and of pinacol-pinacolone rearrangements are reported. PMID- 25036151 TI - Preparation and biological properties of ring-substituted naphthalene-1 carboxanilides. AB - In this study, a series of twenty-two ring-substituted naphthalene-1 carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized carboxanilides was performed against Mycobacterium avium subsp. paratuberculosis. N-(2-Methoxyphenyl)naphthalene-1-carboxamide, N-(3-methoxy phenyl)naphthalene-1-carboxamide, N-(3-methylphenyl)naphthalene-1-carboxamide, N (4-methylphenyl)naphthalene-1-carboxamide and N-(3-fluorophenyl)naphthalene-1 carboxamide showed against M. avium subsp. paratuberculosis two-fold higher activity than rifampicin and three-fold higher activity than ciprofloxacin. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The testing of biological activity of the compounds was completed with the study of photosynthetic electron transport (PET) inhibition in isolated spinach (Spinacia oleracea L.) chloroplasts. The PET-inhibiting activity expressed by IC50 value of the most active compound N-[4-(trifluoromethyl)phenyl]naphthalene-1-carboxamide was 59 MUmol/L. The structure-activity relationships are discussed. PMID- 25036152 TI - Preparation of crosslinked amphiphilic silver nanogel as thin film corrosion protective layer for steel. AB - Monodisperse silver nanoparticles were synthesized by a new developed method via reaction of AgNO3 and oleic acid with the addition of a trace amount of Fe3+ ions. Emulsion polymerization at room temperature was employed to prepare a core shell silver nanoparticle with controllable particle size. N,N' methylenebisacrylamide (MBA) and potassium peroxydisulfate (KPS) were used as a crosslinker, and as redox initiator system, respectively for crosslinking polymerization. The structure and morphology of the silver nanogels were characterized by Fourier transform infrared spectroscopy (FTIR), transmission and scanning electron microscopy (TEM and SEM). The effectiveness of the synthesized compounds as corrosion inhibitors for steel in 1 M HCl was investigated by various electrochemical techniques such as potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). Monolayers of silver nanoparticle were self-assembled on the fresh active surface of the steel electrode and have been tested as a corrosion inhibitor for steel in 1 M HCl solution. The results of polarization measurements showed that nanogel particles act as a mixed type inhibitor. PMID- 25036153 TI - Qualitative and quantitative analysis of Rhizoma Smilacis glabrae by ultra high performance liquid chromatography coupled with LTQ OrbitrapXL hybrid mass spectrometry. AB - Rhizoma Smilacis glabrae, a traditional Chinese medicine (TCM) as well as a functional food, has been commonly used for detoxification treatments, relieving dampness and as a diuretic. In order to quickly define the chemical profiles and control the quality of Smilacis glabrae, ultra high performance liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap mass spectrometry (UHPLC-ESI/LTQ-Orbitrap-MS) was applied for simultaneous identification and quantification of its bioactive constituents. A total of 56 compounds, including six new compounds, were identified or tentatively deduced on the basis of their retention behaviors, mass spectra, or by comparison with reference substances and literature data. The identified compounds belonged to flavonoids, phenolic acids and phenylpropanoid glycosides. In addition, an optimized UHPLC-ESI/LTQ-Orbitrap-MS method was established for quantitative determination of six marker compounds from five batches. The validation of the method, including linearity, sensitivity (LOQ), precision, repeatability and spike recoveries, was carried out and demonstrated to be satisfied the requirements of quantitative analysis. The results suggested that the established method would be a powerful and reliable analytical tool for the characterization of multi-constituent in complex chemical system and quality control of TCM. PMID- 25036154 TI - Dynamic changes of flavonoids contents in the different parts of rhizome of Belamcanda chinensis during the thermal drying process. AB - The dried rhizome of Belamcanda. chinensis (L.) DC. is an important traditional Chinese medicine. Previous chemical and pharmacological investigations indicated that flavonoids may be responsible for the bioactivity of the herb. In this paper, the effects on the contents of twelve flavonoids in the three subunit parts of the rhizome of B. chinensis during the thermal drying process under treatment temperatures ranging from 40 degrees C to 120 degrees C at 10 degrees C intervals were investigated. The results showed that the content of most of the individual flavonoids except that of tectorigenin in the fresh eldest parts of the rhizome that originate directly from the seedling was higher than those of the other junior parts. The change trends of flavonoids contents were similar for three subunit parts of the rhizome during the drying process under the same treatment temperature. Most of the individual flavonoid contents in the rhizome increased in the early stages of the drying processes and decreased as the process was prolonged. The durations required to reaching the points of the maximal amounts of flavonoids revealed a significant negative correlation with the temperature. The variation of the content of mangiferin, iristectorigenin A, irigenin, irilone and dichotomitin was positively correlated with irisflorentin that is the chemical marker used for the quality control of this herb. Taking into account of the production effectiveness and flavonoid yields, the appropriate drying temperature for this herb was suggested to be 100 degrees C. PMID- 25036155 TI - The effect of mini-PEG-based spacer length on binding and pharmacokinetic properties of a 68Ga-labeled NOTA-conjugated antagonistic analog of bombesin. AB - The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7 triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethyleneglycol (PEG2) spacer (NOTA-PEG2-RM26) and labeled with 68Ga can be used for imaging of GRPR expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of natGa-NOTA-PEGn-RM26 (n = 2, 3, 4, 6) were 3.1 +/- 0.2, 3.9 +/- 0.3, 5.4 +/- 0.4 and 5.8 +/- 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however 68Ga-NOTA-PEG3-RM26 showed lower liver uptake. Biodistribution of 68Ga-NOTA-PEG3-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 +/- 0.6%ID/g and 2.8 +/- 0.4%ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/blood of 44 +/- 12 and 42 +/- 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of 68Ga-NOTA-PEG3-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared. PMID- 25036156 TI - Copper-catalyzed trifluoromethylthiolation of aryl halides with diverse directing groups. AB - The expansion of cross-coupling components in Cu-catalyzed C-X bond forming reactions have received much attention recently. A novel Cu-catalyzed trifluoromethylthiolation of aryl bromides and iodides with the assistance of versatile directing groups such as pyridyl, methyl ester, amide, imine and oxime was reported. CuBr was used as the catalyst, and 1,10-phenanthroline as the ligand. By changing the solvent from acetonitrile to DMF, the coupling process could even take place at room temperature. PMID- 25036157 TI - Optimization of intracellular product release from Neisseria denitrificans using microfluidizer. AB - Disruption of Neisseria denitrificans cells by microfluidizer was optimized using a factorial experiments design. The pH, pretreatment time, cell concentration, NaCl, ethylenediamine tetraacetic acid (EDTA) and Triton X-100 concentrations showed significant impact on disruption process and the process was optimized using central composite design and response surface methodology (RSM). Investigation revealed optimum conditions: 90 min pretreatment at pH 9.0 containing 110 g L(-1) cells (dry cell weight), 50 mM NaCl, 10 mM EDTA, and 0.2% Triton X-100. At optimized conditions, the disruption rate increased twofold, up to 5.62 +/- 0.27 * 10(-3) MPa(-a); meanwhile, yield of intracellular content was increased by 26%, with 1 g of cells resulting in 113.2 +/- 8.2 mg proteins, 12.1 +/- 0.7 mg nucleic acids, 21.0 +/- 1.2 mg polysaccharides, 0.99 +/- 0.08 kU glucose-6-phosphate dehydrogenase (G6PD), and 10,100 +/- 110 kU restriction endonuclease NdeI endonuclease. Particle size distribution analysis revealed nearly twofold larger cell lysate particles with diameter of 120 nm. For optimal release of intracellular content, 9200 J/g of energy was needed (95% confidence), yielding 6900 J/g energy savings. Model equations generated from RSM on cell disruption of N. denitrificans were found adequate to determine significant factors and its interaction. The results showed that optimized combination of known pretreatment and disruption methods could considerably improve cell disruption efficiency. PMID- 25036158 TI - Efficient whole-cell biocatalyst for acetoin production with NAD+ regeneration system through homologous co-expression of 2,3-butanediol dehydrogenase and NADH oxidase in engineered Bacillus subtilis. AB - Acetoin (3-hydroxy-2-butanone), an extensively-used food spice and bio-based platform chemical, is usually produced by chemical synthesis methods. With increasingly requirement of food security and environmental protection, bio fermentation of acetoin by microorganisms has a great promising market. However, through metabolic engineering strategies, the mixed acid-butanediol fermentation metabolizes a certain portion of substrate to the by-products of organic acids such as lactic acid and acetic acid, which causes energy cost and increases the difficulty of product purification in downstream processes. In this work, due to the high efficiency of enzymatic reaction and excellent selectivity, a strategy for efficiently converting 2,3-butandiol to acetoin using whole-cell biocatalyst by engineered Bacillus subtilis is proposed. In this process, NAD+ plays a significant role on 2,3-butanediol and acetoin distribution, so the NADH oxidase and 2,3-butanediol dehydrogenase both from B. subtilis are co-expressed in B. subtilis 168 to construct an NAD+ regeneration system, which forces dramatic decrease of the intracellular NADH concentration (1.6 fold) and NADH/NAD+ ratio (2.2 fold). By optimization of the enzymatic reaction and applying repeated batch conversion, the whole-cell biocatalyst efficiently produced 91.8 g/L acetoin with a productivity of 2.30 g/(L.h), which was the highest record ever reported by biocatalysis. This work indicated that manipulation of the intracellular cofactor levels was more effective than the strategy of enhancing enzyme activity, and the bioprocess for NAD+ regeneration may also be a useful way for improving the productivity of NAD+-dependent chemistry-based products. PMID- 25036159 TI - Effects of beraprost sodium on renal function and inflammatory factors of rats with diabetic nephropathy. AB - Beraprost sodium (BPS) is a prostaglandin analogue. We investigated its effects on rats with diabetic nephropathy. There were 20 rats each in the normal control group (NC), the diabetic nephropathy group (DN), and the BPS treatment group. The rats in DN and BPS groups were given a high-fat diet combined with low-dose streptozotocin intraperitoneal injections. The rats in the BPS group were given daily 0.6 mg/kg intraperitoneal injections of this drug. After 8 weeks, blood glucose, 24-h UAlb, Cr, BUN, hs-CRP, and IL-6 levels increased significantly in the DN group compared with the NC group; however, the body mass was significantly reduced in the DN group compared with the NC group. Blood glucose, urine output, 24-h UAlb, Cr, hs-CRP, and IL-6 levels were significantly lower in the BPS group than in the DN group; the body mass was significantly greater in the DN group. Therefore, we concluded that BPS can improve renal function and protect the kidneys of DN rats by reducing oxidative stress and generation of inflammatory cytokines; it also decreases urinary protein excretion of rats with diabetic nephropathy. PMID- 25036160 TI - Case report. Johanson-Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation. AB - Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disorder resulting from loss-of-function mutations in the UBR1 gene. JBS can be easily recognized by its unique clinical presentation (including exocrine pancreatic insufficiency, hypoplasia/aplasia of the alae nasi, congenital scalp defects, sensorineural hearing loss, growth retardation, psychomotor retardation, and anal and genitourinary anomalies). The objective of this study is to report on the first familial case of gender-discordant twins presenting JBS and a novel mutation in the UBR1 gene. We also review literature describing molecularly confirmed cases of JBS. The female twin developed refractory severe diarrhea after the second month of life and died at the age of 3 months. The male twin also developed diarrhea and failure to thrive after the 3 month of life but improved when nutrition support and pancreatic enzyme replacement was started, and he has survived into adolescence. Both patients presented typical clinical features of JBS. A homozygous nonsense mutation (c.3682C>T; p.Q1228X) in UBR1 was confirmed. Severe presentation of JBS usually involves deleterious (nonsense, frameshift, or splice-site) mutations in the UBR1 gene that are thought to completely abolish the expression of a functional protein product, as in this familial case; however, milder presentation of JBS has occasionally been observed with missense mutations in at least 1 of the 2 copies of UBR1, in which there may be residual activity of the product of this gene. Early diagnosis and adequate treatment are crucial for a favorable outcome. PMID- 25036161 TI - New support vector machine-based method for microRNA target prediction. AB - MicroRNA (miRNA) plays important roles in cell differentiation, proliferation, growth, mobility, and apoptosis. An accurate list of precise target genes is necessary in order to fully understand the importance of miRNAs in animal development and disease. Several computational methods have been proposed for miRNA target-gene identification. However, these methods still have limitations with respect to their sensitivity and accuracy. Thus, we developed a new miRNA target-prediction method based on the support vector machine (SVM) model. The model supplies information of two binding sites (primary and secondary) for a radial basis function kernel as a similarity measure for SVM features. The information is categorized based on structural, thermodynamic, and sequence conservation. Using high-confidence datasets selected from public miRNA target databases, we obtained a human miRNA target SVM classifier model with high performance and provided an efficient tool for human miRNA target gene identification. Experiments have shown that our method is a reliable tool for miRNA target-gene prediction, and a successful application of an SVM classifier. Compared with other methods, the method proposed here improves the sensitivity and accuracy of miRNA prediction. Its performance can be further improved by providing more training examples. PMID- 25036162 TI - Analysis of geographic and pairwise distances among sheep populations. AB - This study investigated geographic and pairwise distances among seven Chinese local and four introduced sheep populations via analysis of 26 microsatellite DNA markers. Genetic polymorphism was rich, and the following was discovered: 348 alleles in total were detected, the average allele number was 13.38, the polymorphism information content (PIC) of loci ranged from 0.717 to 0.788, the number of effective alleles ranged from 7.046 to 7.489, and the observed heterozygosity ranged from 0.700 to 0.768 for the practical sample, and from 0.712 to 0.794 for expected heterozygosity. The Wright's F-statistic of subpopulations within the total (FST) was 0.128, the genetic differentiation coefficient (GST) was 0.115, and the average gene flow (Nm) was 1.703. The phylogenetic trees based on the neighbor-joining method by Nei's genetic distance (DA) and Nei's standard genetic distance (DS) were similar. Sheep populations clustered into group 1 (Ta, M, L, H, O, G, and Q breeds) and group 2 (PD, WS, B, and T breeds). These results will have an important value applied and directive significance for sheep breeding in the future. PMID- 25036163 TI - MicroRNA-200 family members are weakly expressed in the neurosensory epithelia of the developing zebrafish (Danio rerio) inner ear. AB - MicroRNA-200 family members are expressed in the developing mouse inner ear and in zebrafish (Danio rerio) olfactory epithelia, taste buds, and neuromasts, and have also been shown to be associated with differentiation of olfactory and taste buds. However, the role of the miR-200 family in the inner ear of zebrafish had not been studied. We investigated the expression and function of the miR-200 family in the zebrafish inner ear via in situ hybridization and loss-of-function methods. Expression of the miR-200 family was weak and dispersed throughout the developing zebrafish inner ear. After knockdown of miR-200 family members in the developing inner ear, no significant differences in development were observed compared to the controls. Otic vesicles, otoliths, and semicircular canals appeared normal. Compared with less differentiated olfactory filaments in olfactory epithelia, the development of hair cells and statoacoustic ganglion neurons were normal. The kinocilia and stereocilia of hair cells, the innervation of hair cells, and the formation of ribbon synapses were also unaffected. Overall, we conclude that the miR-200 family has a negligible role in the development of zebrafish inner ear; the functions of the miR- 200 family may be organ-specific. PMID- 25036164 TI - Water buffalo genome characterization by the Illumina BovineHD BeadChip. AB - To define the best strategies for genomic association studies and genomic selection, it is necessary to determine the extent of linkage disequilibrium (LD) and the genetic structure of the study population. The current study evaluated the transference of genomic information contained in the Illumina BovineHD BeadChip from cattle to buffaloes, and assessed the extent of the LD in buffaloes. Of the 688,593 bovine single nucleotide polymorphism (SNP) that were successfully genotyped from the 384 buffalo samples, only 16,580 markers were polymorphic, and had minor allele frequencies greater than 0.05. A total of 16,580 polymorphic SNPs were identified, which were uniformly distributed throughout the autosomes, because the density and mean distance between markers were similar for all autosomes. The average minor allele frequency for the 16,580 SNPs was 0.23. The overall mean LD for pairs of adjacent markers was 0.29 and 0.71, when measured as for r2 and |D'|, respectively. The 16,580 polymorphic SNPs were matched to Bos taurus chromosome in the current bovine genome assembly (Btau 4.2), and could be utilized in association studies. In conclusion, the Illumina BovineHD BeadChip contains approximately 16,580 polymorphic markers for the water buffalo, which are broadly distributed across the genome. These data could be used in genomic association and genomic selection studies; however, it might be necessary to develop a panel with specific SNP markers for water buffaloes. PMID- 25036165 TI - Relationships between methods of variety adaptability and stability in sugarcane. AB - The identification and recommendation of superior genotypes is crucial for the growth of industrial crops, and sugarcane breeding performs a vital role by developing more productive cultivars. The study of genotype x environment interaction has been an essential tool in this process. Thereby, the purpose of this study was to investigate the relationship between methods of adaptability and stability in sugarcane. Data were collected from trials using a randomized block design with three repetitions and 15 clones of sugarcane in nine environments in the State of Minas Gerais, Brazil. Methodologies based on analysis of variance, linear regression, multivariate analysis, nonparametric statistics, and mixed model were used. The methods of Lin and Binns, Annicchiarico, and harmonic mean of relative performance of genotypic values (MHPRVG) were similar in their classification of genotypes. The additive main effect and multiplicative interactions (AMMI) and Wricke methods tended to select the most stable genotypes; however, genotypes were less productive, coinciding with the stability parameter of Eberhart and Russell. The MHPRVG method is preferred over the methods of Lin and Binns and Annicchiarico because it includes the concepts of productivity, adaptability, and stability, and it provide direct genetic values of individuals. The use of the MHPRVG and Eberhart and Russell methods is recommended because the combination of these methods is complementary and leads to greater accuracy in the identification of genotypes of sugarcane for different environments. PMID- 25036166 TI - Genetic diversity and structure of natural Dactylis glomerata L. populations revealed by morphological and microsatellite-based (SSR/ISSR) markers. AB - Dactylis glomerata L. is an important forage species in the Mediterranean region, and in other regions with a similar climate. Genetic material from 3 locations in north, central, and south Greece was studied, using morphological traits, SSR, and ISSR molecular markers. Morphological analysis revealed differences among the geographic locations studied for all morphological traits, except the number of reproductive tillers. Moreover, the highest phenotypic variation was observed on the accessions from south, while the lowest was observed on the accessions from the north. Although the results of the molecular marker analysis are indicative, a high level of genetic diversity at the species level was revealed by ISSRs (GST=0.291) and SSRs (FST=0.186). Analysis of molecular variance showed that a high level of genetic diversity existed for ISSRs and SSRs within populations (62 and 83%, respectively), rather than among populations (38 and 17%, respectively). Cluster analysis divided the 3 populations in 2 groups, with the population originating from the island of Crete forming 1 group, while the populations from north Greece (Taxiarchis) and central Greece (Pertouli) were clustered in a 2nd group. In general, the results indicate that SSRs are more informative compared to ISSRs about the genetic variation within a population, whereas the ISSRs were more informative about the genetic diversity among populations However, a similar trend in diversity (genotypic and phenotypic) was observed in the morphological traits and microsatellite-based (SSR/ISSR) markers at the locations studied. PMID- 25036167 TI - High resolution computed tomography and classification of children with interstitial lung diseases. AB - High resolution computed tomography (HRCT) was used to classify children with interstitial lung diseases (ILD). Sixty children with ILD underwent HRCT in supine position under free-respiratory conditions during scanning. Children under 5 years old were sedated with chloral hydrate and the scanning scope was from the lung apex to the diaphragm. In children older than 5 years old, scans were obtained at three levels: aortic arch, tracheal carina, and 1 cm above the right diaphragm. Five infectious patients were followed up. Two experienced radiologists read the films blindly to observe the type and distribution of ground-glass opacities and bronchovascular bundle abnormalities. Bronchovascular bundles were thick in 49 patients, and were thick and stiff in 27 patients. Of the 41 infectious patients, 39 showed thickened bronchovascular bundles, and 26 showed thick and stiff bronchovascular bundles. Of the 19 non-infectious patients, bronchovascular bundles were thickened in 10 patients, and were thick and stiff in 1 patient. Forty-one patients showed lobular ground-glass opacity (32 infectious, 9 non-infectious). Twenty-seven patients showed both bronchovascular bundle abnormality and lobular ground-glass opacity (20 infectious, 7 non-infectious). Eighteen patients showed patchy or mosaic ground glass opacity (16 infectious, 2 non-infectious). There were 4 cases of bronchiectasis. HRCT is the first non-invasive diagnostic method for children with ILD, and its different manifestations can be classified. In early manifestation, bronchovascular bundles were abnormal and complicated with lobular ground-glass opacity. Patchy ground-glass opacity was the most common manifestation, and appeared to be difficult to disappear. Bronchiectasis indicated that the disease is irretrievable. PMID- 25036168 TI - Correlation and interventional embolization therapy of posterior intercostal arteries-induced hemoptysis. AB - The incidence of posterior intercostal arteries-induced hemoptysis, its correlation with primary diseases, and the value of interventional embolization therapy were investigated. Clinical data, multislice spiral computed tomography (MSCT), digital subtraction angiography (DSA), and other imaging data of 143 cases of hemoptysis were retrospectively analyzed. After the offending vessels were subjected to interventional embolization therapy, patients were followed-up for observations of clinical efficacies and complications. Thirty-one patients (21.7%) showed 65 branches of posterior intercostal arteries as the non-bronchial systemic arteries involved in hemoptysis; pleural thickening was evident in 25 (80.6%) cases. Posterior intercostal arteries-induced hemoptysis was observed in 16 of the 27 (59.3%) patients with pulmonary tuberculosis, and in 9 of the 10 (90.0%) patients with pulmonary tuberculosis and pulmonary damage. Posterior intercostal arteries-induced hemoptysis was correlated to pleural thickening (P<0.05), which differed significantly among different underlying diseases (P<0.05). Twenty-eight cases of 58 branches of posterior intercostal arteries were found to be involved in hemoptysis by preoperative chest CT angiogram (CTA); the intraoperative matching rates were 90.3% (28/31) and 89.2% (58/65), respectively. Thirty-one patients received transcatheter arterial embolization (TAE), of which 29 (93.5%) showed immediate hemostasis; 1 case had surgical treatment for ineffectuality, and 2 cases showed recurrence without serious complications. The posterior intercostal arteries were commonly involved in hemoptysis, and were closely associated with pleural thickening and pulmonary tuberculosis, especially when accompanied by pulmonary damage. Complete TAE could improve the treatment effect of hemoptysis and preoperative chest CTA was helpful for interventional embolization therapy. PMID- 25036169 TI - Correlation of serum high-sensitivity C-reactive protein and interleukin-6 in patients with acute coronary syndrome. AB - Serum high-sensitivity C-reactive protein (hs-CRP) is a sensitive indicator of inflammation, which is closely related with the progress of plaque formation. Interleukin-6 (IL-6) is one of the inflammatory markers of local coronary plaque and the peripheral blood cycle, promoting the occurrence of atherosclerosis development and plaque rupture. In this study, the correlation of hs-CRP and IL-6 was investigated in patients with acute coronary syndrome (ACS). Sixty cases of ACS, including 33 cases of acute myocardial infarction (AMI) and 27 cases of unstable angina pectoris (UAP), 45 cases of stable angina pectoris (SAP), and 45 healthy people (HG) were enrolled in study. The serum hs-CRP and serum IL-6 levels were tested by the immune turbidimetric method and enzyme-linked immunosorbent assay (ELISA), respectively. The differences among groups and their correlations were evaluated. Results showed that the serum hs-CRP and IL-6 concentrations of the AMI and UAP groups were significantly higher than those of the SAP and HG groups, respectively (P<0.01), and those of the AMI group were significantly higher than those of the UAP group (P<0.05). The serum hs-CRP and IL-6 levels of the ACS group were positively correlated (r=0.836). The serum hs CRP and IL-6 levels could be used to determine the stability of plaque, and have some relevance in the ACS process, showing great value in judgments of ACS prognosis. PMID- 25036170 TI - Accuracy of low-field MRI on meniscal tears. AB - This study aimed to verify the accuracy of low-field-intensity magnetic resonance imaging (MRI) in diagnosing meniscus tears. A total of 171 patients were examined through low-field-intensity MRI to detect meniscus injuries. These patients were then diagnosed through arthroscopy. Examination results were recorded and compared. The accuracy of the diagnosis for internal and external meniscus tears through low-field-intensity MRI was 95.91% and 95.91%, respectively, the sensitivities were 95.60% and 96.47%, respectively, and the specificities were 96.25% and 95.35%, respectively. Low-field-intensity MRI is an accurate and cost effective method for diagnosing meniscus tears. PMID- 25036171 TI - Screening and prevention of neonatal glucose 6-phosphate dehydrogenase deficiency in Guangzhou, China. AB - We aimed to summarize the results of screening protocol and prevention of neonatal glucose 6-phosphate dehydrogenase (G6PD) deficiency during a 22-year long period to provide a basis of reference for the screening of this disease. About 1,705,569 newborn subjects in Guangzhou City were screened for this deficiency. Specimens were collected according to the conventional method of specimen acquisition for "newborn dried bloodspot screening", preserved, and inspected. The specimens were studied with fluorescent spot test and quantitative fluorescence assay. Diagnosis was performed using the modified NBTG6PD/6PGD ratio method. Bloodspot filter paper specimens were sent to the laboratory within 24 h via EMS Express, and the G6PD test was performed on the same day. The G6PD deficiency-positive rate was 4.2% in the samples screened using the fluorescent spot test, while it was 5% in case of the quantitative fluorescence assay. Neonatal screening for G6PD deficiency for 11,437 cases (6117 boys and 5320 girls) showed positive results in 481 cases. About 420 cases (318 boys and 102 girls) of G6PD deficiency were confirmed with the modified Duchenne NBT ratio method. The total detection rate was 3.7:5.2% for boys and 1.9% for girls. Quantitative fluorescence assay improved the sensitivity and detection rate. Accelerating the speed of sample delivery by using Internet network systems and ensuring online availability of screening results can aid the screening and diagnosis of this deficiency within 1 week of birth. PMID- 25036172 TI - Intra-aortic balloon pump treatment for patients with acute anterior wall myocardial infarction after reperfusion therapy. AB - We evaluated the effects of an intra-aortic balloon pump on hemodynamics, brain natriuretic peptide concentration and cardiac function of patients with acute myocardial infarction, after reperfusion therapy. Sixty-three patients with acute anterior wall ST-elevation myocardial infarction who underwent primary percutaneous coronary intervention were given an intra-aortic balloon pump (32 cases) or not (control group, 31 cases). The mean pulmonary arterial pressure, pulmonary capillary wedge pressure and cardiac index were measured with a Swan Ganz catheter. The brain natriuretic peptide concentration was detected by immunochemiluminometric assay. Left ventricular end-diastolic diameter and left ventricular ejection fraction were measured by echocardiography. No difference in baseline was observed between the two groups on day 1 in the hospital. On day 5, mean pulmonary artery pressure and pulmonary capillary wedge pressure of patients with the intra-aortic balloon pump were significantly lower, and cardiac index of was higher than that of the controls, whereas no differences in left ventricular end-diastolic diameter or left ventricular ejection fraction were observed between the two groups. On days 5 and 90, the brain natriuretic peptide concentration of the intra-aortic balloon pump patients was lower than that of the controls. On day 90, left ventricular end-diastolic diameter was smaller in the intra-aortic balloon pump patients, but no difference in left ventricular ejection fraction was observed between the two groups. The intra-aortic balloon pump improved the hemodynamic index and cardiac function and decreased brain natriuretic peptide concentration in patients with acute anterior wall ST elevation myocardial infarction. PMID- 25036173 TI - Differential expression of resistance to powdery mildew at the early stage of development in wheat line N0308. AB - Powdery mildew, caused by Blumeria graminis f. sp tritici (Bgt) is one of the devastating diseases of wheat and causes yield losses in temperate wheat growing regions. A wheat line, N0308 with resistance to powdery mildew was used in this study. A suppression subtractive hybridization cDNA library was constructed from the wheat leaves inoculated by Bgt at the two-leaf stage. The differentially expressed genes in response to Bgt infection in wheat were identified, and a total of 175 positive clones from the library were sequenced, and 90 expressed sequence tags (ESTs) were subjected to clustering, BLAST alignment, functional annotation, and classification into different categories. By comparing the EST sequences among the SSH-cDNA libraries, we analyzed gene expression patterns of 7 ESTs associated with the resistance reaction of powdery mildew by using semi quantitative reverse transcription-polymerase chain reaction. The expression of 5 genes (sulfatase, pathogenesis-related protein 17, betacarbonic anhydrase 2, thioredoxin h-like protein, and coronatine-insensitive) transcripts was induced, and the transcript levels of these genes were the highest at 72 h after Bgt infection, while those of 2 genes (violaxanthin de-epoxidase and gag-pol polyprotein) were the highest level at 12 and 18 h post-infection, respectively. These findings suggest that these genes are induced at an early stage of infection and are transcriptionally activated for the host defense response. PMID- 25036174 TI - Case report. Familial balanced translocation leading to an offspring with phenotypic manifestations of 9p syndrome. AB - We report two similarly affected cousins (children of monozygotic twin sisters) with phenotypic features consistent with 9p deletion syndrome, including dysmorphic craniofacial features (trigonocephaly, midface hypoplasia, upward slanting palpebral fissures and long philtrum), intellectual disability and disorders of sex development. Initial cytogenetic examination showed normal karyotypes in the probands and their respective parents, though multiplex ligation probe amplification revealed a 1q terminal duplication and a 9p terminal deletion in both affected children. Further analysis by fluorescence in situ hybridization, identified a familial balanced cryptic translocation t(1;9)(q44;p23) in the mothers, showing the importance of the association of molecular cytogenetic techniques in clinical genetics, given the implications for the care of patients and for genetic counseling. PMID- 25036175 TI - Drynaria total flavonoids decrease cathepsin K expression in ovariectomized rats. AB - This study investigated the effects of Drynaria total flavonoids on cathepsin K serum concentrations and gene expression, biomechanics and bone mineral density (BMD) of the tibial shaft in ovariectomized rat models of osteoporosis, and mechanism in the prevention and cure of osteoporosis. Seventy-two female Sprague Dawley rats were divided into six groups. The rats in each group were subjected to gastric lavage after the model was established. The tibial shaft of the right hindlimb was obtained to measure the BMD. Serum cathepsin K concentrations were determined. The cathepsin K mRNA expression was also determined using fluorescent quantitative polymerase chain reaction. The three-point bending method was performed to measure the maximum bending load of the tibial shaft. The total flavonoid and normal groups had significant differences in serum cathepsin K concentrations compared with that in the estrogen group (P<0.05). The total flavonoid and sham-operated groups also showed significant differences in cathepsin K mRNA expression compared with that in the normal group (P<0.01). The maximum bending load of the rats in the total flavonoid group was significantly different from that in the estrogen group (P<0.05) and the sham-operated and normal groups (P<0.01). The high-dose total flavonoid group elicited a better effect on BMD than that by the medium- and low-dose groups (P<0.05). Thus, Drynaria total flavonoids inhibited the serum cathepsin K concentration and increased the maximum bending load of the tibial shaft in ovariectomized rats. PMID- 25036176 TI - Huwe1 as a therapeutic target for neural injury. AB - The ubiquitin-proteasome system (UPS) regulates many cellular processes, including protein stability, cell cycle control, DNA repair, transcription, signal transduction, and protein trafficking. In fact, UPS plays a key role in various stress conditions such as ischemia, glutamate toxicity, Alzheimer's disease, and Parkinson's disease. Huwe1, a homologous to E6-AP carboxy terminus (HECT) domain ubiquitin ligase, is now being regarded as a vital protein involved in neural stem cell differentiation, adult neurogenesis, and the DNA damage response pathway. In response to DNA damage, Huwe1 may have a dual function in arresting DNA replication and in ending checkpoint signaling. The proliferation and differentiation of neural stem cells regulated by Huwe1-mediated Notch signaling could also play an important role in neural protection following neural injury. Considering Huwe1 is required for neural precursor survival and the regulation of the DNA damage response pathway, there is growing evidence and considerable hope that Huwe1 might be a therapeutic target for neural injury. PMID- 25036177 TI - Identification and analysis of a 5-bp indel of a porcine BMP7 gene promoter. AB - Bone morphological protein7 (BMP7), a member of the transforming growth factor beta (TGF-beta) family, was first identified because of its ability to induce ectopic chondro-osteogenesis in vivo. It also plays a crucial role in the growth, development, and physiological functioning of the reproductive system. Among intra-ovarian growth factors, many studies have shown that BMP7 plays a pivotal role in regulating the early phases of follicular growth. We detected a 5-bp insertion-deletion at 602 bp upstream from the transcription start site of the BMP7 gene promoter among 258 pigs of 3 breeds. Along with 2 homoduplex DNAs, another 4 previously unknown bands (named A, B, C, and D) were detected by non denaturing polyacrylamide gel electrophoresis. By DNA sequencing, we found that PCR products from heterozygotes contained 2 homoduplexes and 4 heteroduplexes. Genetic polymorphism analysis revealed 3 genotypes (AA, AB, and BB) at this site; the distribution of these genotypes followed Hardy-Weinberg equilibrium. A was the dominant allele (0.715), and AA was the dominant genotype (0.500). The polymorphism information content value was calculated to be 0.325, the expected heterozygosity was 0.407, and effective number of alleles was 1.688, indicating an intermediate degree of polymorphism and good potential for selection and breeding. Highly significant differences were found between different breeds and distributions of genotypes. Based on correlation analysis, the 5-bp indel site does not significantly affect porcine reproductive traits (total number of births, number of piglets born alive, litter birth weight, and litter weight at 21 days; P>0.05), which was consistent with the results of genetic variation analysis. PMID- 25036178 TI - Molecular cloning and expression of the male sterility-related CtYABBY1 gene in flowering Chinese cabbage (Brassica campestris L. ssp chinensis var. parachinensis). AB - Expression of the YABBY gene family in the abaxial surface of lateral plant organs determines abaxial destiny of cells, enhances growth and expansion of lateral organs, and plays an important role in polar establishment of lateral organs. However, the YABBY gene has not been studied in male sterility and fertility restoration. We homologously cloned the CtYABBY1 gene of male-sterile TC1 in Brassica campestris L. ssp chinensis var. parachinensis; its expression was analyzed by real-time PCR. A 937-bp sequence was cloned from TC1 and named CtYABBY1. The ORF of this gene has 702 bp, contains a "C2C2 zinc finger" motif at the N-terminal end, and a "YABBY" structural domain at the C-terminal end. This gene had the highest homology with DBC43-3-2 gene in B. campetris ssp pekinensis. Expression of CtYABBY1 gene has a wide range of functions. It is involved in growth and development of lateral organs, such as leaves and flowers, enhancing expansion of the area and volume of young organs. CtYABBY1 is a gene that promotes thermo-sensitive fertility restoration. At room temperature, expression level of this gene was found to be lower in the stamens of sterile flowers. After treating TC1 at a low temperature of 2 degrees -6 degrees C for 20 days, expression of this gene was upregulated in the stamen of fertile flowers. We conclude that male sterility in TC1 is negatively regulated by this gene, which facilitates transition from male sterility to fertility. PMID- 25036179 TI - Structural and phylogenetic analysis of Pto-type disease resistance gene candidates in Hevea brasiliensis. AB - The tomato Pto gene encodes a serine/threonine kinase (STK) whose molecular characterization has provided valuable insights into the disease resistance mechanism of tomato. Therefore, Pto is considered as a promising candidate for engineering broad-spectrum pathogen resistance in this crop. In this study, a pair of degenerate primers based on conserved subdomains of plant STKs similar to the tomato Pto protein was used to amplify similar sequences in a hevea cultivar (Hevea brasiliensis Muell. Arg). A fragment of ~550 bp was amplified, cloned, and sequenced. The sequence analysis of several clones revealed 12 distinct sequences highly similar to STKs. Based on their significant similarity with the tomato Pto protein (BLASTX E value<3e-53), seven sequences were classified as Pto resistance gene candidates (Pto-RGCs). Multiple sequence alignment of the hevea Pto-RGC products revealed that these sequences contain several conserved subdomains present in most STKs, as well as several conserved residues that are crucial for Pto function. Moreover, phylogenetic analysis showed that the hevea Pto-RGCs clustered with Pto, suggesting a common evolutionary origin with this resistance gene. The Pto-RGCs isolated in this study represent a valuable sequence resource that could assist in the development of disease resistance in hevea. PMID- 25036180 TI - Biolistic transformation of wheat using the HMW-GS 1Dx5 gene without selectable markers. AB - Genetic manipulation using linear DNA was applied to the common wheat variety Xindong No. 26 via particle bombardment with the aim to improve bread-making quality of flour. Initially, 2 biolistic parameters, helium pressure and target distance, were optimized using plasmid pAHC25. We transformed wheat immature embryo scutella with the linear 1Dx5 gene without selectable markers. The highest transient beta-glucuronidase expression was obtained when scuttles were bombarded at 1100 psi with a 9-cm target distance. Using the optimized parameters, the transformation of the common wheat variety Xindong No. 26 was carried out using the linear 1Dx5. Three transgenic plants were identified from 1003 transgenic plants, yielding a transformation frequency of 0.4%. A sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis confirmed that the 1Dx5 gene was expressed in 4 T1 seeds of the transgenic plants. These experiments indicate the possibility of obtaining marker-free transgenic wheat plants via particle bombardment using the minimal gene cassettes with the particle bombardment parameters. PMID- 25036181 TI - A meta-analysis of mortality in end-stage renal disease patients receiving implantable cardioverter defibrillators (ICDs). AB - Data on the effectiveness of implantable implantable cardioverter defibrillators (ICDs) with respect to reducing mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) are lacking. The purpose of this meta analysis was to compare the mortality of patients with ESRD who have received and not received an ICD. A search was conducted on January 31, 2013 of Medline, Cochrane, EMBASE, and Google Scholar. Studies were selected for inclusion based on the following criteria. 1) Randomized controlled trial. 2) ESRD patients with heart failure. 3) Device therapy (ICD, CRT-defibrillator [CRT-D]) used to treat heart failure. 4) Primary outcome is survival analysis. 5) Retrospective study if survival analysis was performed. The primary outcome was overall survival (OS), and the secondary outcome was 2-year survival. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, and a chi2-based test of homogeneity was performed. Three studies were included in the analysis. The combined OR for OS was 2.245 (95% CI 1.871 to 2.685, P<0.001), indicating that patients with an ICD had a significantly higher OS than those without an ICD. The combined OR for 2-year survival was 2.312 (95% CI 1.921 to 2.784, P<0.001), indicating that patients with an ICD had a significantly higher 2-year survival rate than those without an ICD. The use of ICD in patients with ESRD is associated with an increase in the OS and the 2-year survival rate. PMID- 25036183 TI - Palbociclib, a selective inhibitor of cyclin-dependent kinase4/6, blocks HIV-1 reverse transcription through the control of sterile alpha motif and HD domain containing protein-1 (SAMHD1) activity. AB - BACKGROUND: Sterile alpha motif and HD domain-containing protein-1 (SAMHD1) inhibits HIV-1 reverse transcription by decreasing the pool of intracellular deoxynucleotides. SAMHD1 is controlled by cyclin-dependent kinase (CDK)-mediated phosphorylation. However, the exact mechanism of SAMHD1 regulation in primary cells is unclear. We explore the effect of palbociclib, a CDK6 inhibitor, in HIV 1 replication. METHODS: Human primary monocytes were differentiated into macrophages with monocyte-colony stimulating factor and CD4 T lymphocytes stimulated with phytohaemagglutinin (PHA)/interleukin-2. Cells were treated with palbociclib and then infected with a Green fluorescent protein-expressing HIV-1 or R5 HIV-1 BaL. Viral DNA was measured by quantitative PCR and infection assessed by flow cytometry. Deoxynucleotide triphosphate (dNTP) content was determined using a polymerase-based method. RESULTS: Pan-CDK inhibitors AT7519, roscovitine and purvalanol A reduced SAMHD1 phosphorylation. HIV-1 replication was blocked by AT7519 (66.4 +/- 3.8%; n = 4), roscovitine (47.3 +/- 3.9%; n = 4) and purvalanol A (55.7 +/- 15.7%; n = 4) at subtoxic concentrations. Palbociclib, a potent and selective CDK6 inhibitor, blocked SAMHD1 phosphorylation, intracellular dNTP levels, HIV-1 reverse transcription and HIV-1 replication in primary macrophages and CD4 T lymphocytes. Notably, treatment of macrophages with palbociclib led to reduced CDK2 activation, measured as the phosphorylation of the T-loop at the Thr160. The antiviral effect was lost when SAMHD1 was degraded by Vpx, providing further evidence for a role of SAMHD1 in mediating the antiretroviral effect. CONCLUSIONS: Our results indicate that SAMHD1-mediated HIV 1 restriction is controlled by CDK as previously suggested but point to a preferential role for CDK2 and CDK6 as mediators of SAMHD1 activation. Our study provides a new signaling pathway susceptible for the development of new therapeutic approaches against HIV-1 infection. PMID- 25036182 TI - Socio-economic factors of bacillary dysentery based on spatial correlation analysis in Guangxi Province, China. AB - BACKGROUND: In the past decade, bacillary dysentery was still a big public health problem in China, especially in Guangxi Province, where thousands of severe diarrhea cases occur every year. METHODS: Reported bacillary dysentery cases in Guangxi Province were obtained from local Centers for Diseases Prevention and Control. The 14 socio-economic indexes were selected as potential explanatory variables for the study. The spatial correlation analysis was used to explore the associations between the selected factors and bacillary dysentery incidence at county level, which was based on the software of ArcGIS10.2 and GeoDA 0.9.5i. RESULTS: The proportion of primary industry, the proportion of younger than 5 year-old children in total population, the number of hospitals per thousand persons and the rates of bacillary dysentery incidence show statistically significant positive correlation. But the proportion of secondary industry, per capital GDP, per capital government revenue, rural population proportion, popularization rate of tap water in rural area, access rate to the sanitation toilets in rural, number of beds in hospitals per thousand persons, medical and technical personnel per thousand persons and the rate of bacillary dysentery incidence show statistically significant negative correlation. The socio-economic factors can be divided into four aspects, including economic development, health development, medical development and human own condition. The four aspects were not isolated from each other, but interacted with each other. PMID- 25036184 TI - Limited clinical benefit of minority K103N and Y181C-variant detection in addition to routine genotypic resistance testing in antiretroviral therapy-naive patients. AB - OBJECTIVE: The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. DESIGN: We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naive patients in whom no NNRTI resistance mutations were detected by routine resistance testing. METHODS: Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. RESULTS: Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. CONCLUSION: As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered. PMID- 25036185 TI - Vagus nerve stimulation attenuates cerebral ischemia and reperfusion injury via endogenous cholinergic pathway in rat. AB - Inflammation and apoptosis play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that vagus nerve stimulation (VNS) following focal cerebral ischemia and reperfusion (I/R) may be neuroprotective by limiting infarct size. However, the underlying molecular mechanisms remain unclear. In this study, we investigated whether the protective effects of VNS in acute cerebral I/R injury were associated with anti inflammatory and anti-apoptotic processes. Male Sprague-Dawley (SD) rats underwent VNS at 30 min after focal cerebral I/R surgery. Twenty-four h after reperfusion, neurological deficit scores, infarct volume, and neuronal apoptosis were evaluated. In addition, the levels of pro-inflammatory cytokines were detected using enzyme-linked immune sorbent assay (ELISA), and immunofluorescence staining for the endogenous "cholinergic anti-inflammatory pathway" was also performed. The protein expression of a7 nicotinic acetylcholine receptor (a7nAchR), phosphorylated Akt (p-Akt), and cleaved caspase 3 in ischemic penumbra were determined with Western blot analysis. I/R rats treated with VNS (I/R+VNS) had significantly better neurological deficit scores, reduced cerebral infarct volume, and decreased number of TdT mediated dUTP nick end labeling (TUNEL) positive cells. Furthermore, in the ischemic penumbra of the I/R+VNS group, the levels of pro-inflammatory cytokines and cleaved caspase 3 protein were significantly decreased, and the levels of a7nAchR and phosphorylated Akt were significantly increased relative to the I/R alone group. These results indicate that VNS is neuroprotective in acute cerebral I/R injury by suppressing inflammation and apoptosis via activation of cholinergic and a7nAchR/Akt pathways. PMID- 25036186 TI - ERBB4 promoter polymorphism is associated with poor distant disease-free survival in high-risk early breast cancer. AB - A number of genetic variants have been linked to increased risk of breast cancer. Little is, however, known about the prognostic significance of hereditary factors. Here, we investigated the frequency and prognostic significance of two ERBB4 promoter region variants, -782G>T (rs62626348) and -815A>T (rs62626347), in a cohort of 1010 breast cancer patients. The frequency of nine previously described somatic ERBB4 kinase domain mutations was also analyzed. Clinical material used in the study consisted of samples from the phase III, adjuvant, FinHer breast cancer trial involving 1010 women. Tumor DNA samples were genotyped for ERBB4 variants and somatic mutations using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Paraffin-embedded tumor sections from all patients were immunohistochemically stained for ErbB4 expression. Association of ERBB4 genotype to distant disease-free survival (DDFS) was assessed using Kaplan-Meier and Cox regression analyses. Genotyping was successful for 91-93% of the 1010 samples. Frequencies observed for the ERBB4 variants were 2.5% and 1.3% for -782G>T and -815A>T, respectively. Variant 815A>T was significantly associated with poor survival (HR = 2.86 [95% CI 1.15 6.67], P = 0.017). In contrast, variant -782G>T was associated with well differentiated cancer (P = 0.019). Two (0.2%) ERBB4 kinase domain mutations were found, both of which have previously been shown to be functional and promote cancer cell growth in vitro. These data present the germ-line ERBB4 variant 815A>T as a novel prognostic marker in high-risk early breast cancer and indicate the presence of rare but potentially oncogenic somatic ERBB4 mutations in breast cancer. PMID- 25036187 TI - Hand-held and integrated single-cell pipettes. AB - Successful single-cell isolation is a primary step for subsequent chemical and biological analyses of single cells. Conventional single-cell isolation methods often encounter operational complexity, limited efficiency, deterioration of cell viability, incompetence in the isolation of a single-cell into nanoliter liquid, and/or inability to select single adherent cells with specific phenotypes. Here, we develop a hand-held single-cell pipet (hSCP) that is rapid, operationally simple, highly efficient, and inexpensive for unbiased isolation of single viable suspended cells directly from submicroliter cell suspensions into nanoliter droplets without the assistance of any additional equipment. An integrated SCP (iSCP) has also been developed for selective isolation of single suspended and adherent cells according to the fluorescence imaging and morphological features. The isolated single cells can be conveniently transferred into standard 96-/384 well plates, Petri dishes, or vials for cloning, PCR, and other single-cell biochemical assays. PMID- 25036188 TI - Expanding the logic of bacterial promoters using engineered overlapping operators for global regulators. AB - The understanding of how the architecture of cis-regulatory elements at bacterial promoters determines their final output is of central interest in modern biology. In this work, we attempt to gain insight into this process by analyzing complex promoter architectures in the model organism Escherichia coli. By focusing on the relationship between different TFs at the genomic scale in terms of their binding site arrangement and their effect on the target promoters, we found no strong constraint limiting the combinatorial assembly of TF pairs in E. coli. More strikingly, overlapping binding sites were found equally associated with both equivalent (both TFs have the same effect on the promoter) and opposite (one TF activates while the other repress the promoter) effects on gene expression. With this information on hand, we set an in silico approach to design overlapping sites for three global regulators (GRs) of E. coli, specifically CRP, Fis, and IHF. Using random sequence assembly and an evolutionary algorithm, we were able to identify potential overlapping operators for all TF pairs. In order to validate our prediction, we constructed two lac promoter variants containing overlapping sites for CRP and IHF designed in silico. By assaying the synthetic promoters using a GFP reporter system, we demonstrated that these variants were functional and activated by CRP and IHF in vivo. Taken together, presented results add new information on the mechanisms of signal integration in bacterial promoters and provide new strategies for the engineering of synthetic regulatory circuits in bacteria. PMID- 25036189 TI - The importance of coagulation factors binding to adenovirus: historical perspectives and implications for gene delivery. AB - INTRODUCTION: The interaction of human adenovirus (HAdV) serotype 5 (HAdV-5) with the blood coagulation factor X (FX) results in a high liver transduction after AdV intravascular administration, causing toxicity and limiting AdV delivery to the target tissue. However, FX also protects adenoviral vectors from neutralization by the complement system and natural antibodies, potentially benefiting adenoviral gene delivery, as neutralization results in the reduction of HAdV-5 binding to host cells. AREAS COVERED: This review gives an overview on the use of adenoviruses as gene transfer vehicles and their impact in gene therapy. The structure of coagulation factors and their interactions with HAdV are described, highlighting their influence on the AdV biodistribution profile. The implications of this interaction in immunity and its potential influence on the use of adenoviral vectors in gene therapy applications are discussed. EXPERT OPINION: The protective role of FX brings under discussion how beneficial abolishment of FX binding would be for HAdV-5 liver detargeting. The dispensability of FX for liver transduction in immunocompromised mice suggests the involvement of other blood factors or receptors in enhancing HAdV-5 liver transduction. Better understanding of the interactions that take place in the bloodstream is essential to generate safe and efficient adenoviral vectors. PMID- 25036190 TI - What is the gold standard for comprehensive interinstitutional communication of perioperative information for thyroid cancer patients? A comparison of existing electronic health records with the current American Thyroid Association recommendations. AB - BACKGROUND: Appropriate management of well-differentiated thyroid cancer requires treating clinicians to have access to critical elements of the patient's presentation, surgical management, postoperative course, and pathologic assessment. Electronic health records (EHRs) provide an effective method for the storage and transmission of patient information, although most commercially available EHRs are not intended to be disease-specific. In addition, there are significant challenges for the sharing of relevant clinical information when providers involved in the care of a patient with thyroid cancer are not connected by a common EHR. In 2012, the American Thyroid Association (ATA) defined the critical elements for optimal interclinician communication in a position paper entitled, "The Essential Elements of Interdisciplinary Communication of Perioperative Information for Patients Undergoing Thyroid Cancer Surgery." SUMMARY: We present a field-by-field comparison of the ATA's essential elements as applied to three contemporary electronic reporting systems: the Thyroid Surgery e-Form from Memorial Sloan-Kettering Cancer Center (MSKCC), the Alberta WebSMR from the University of Calgary, and the Thyroid Cancer Care Collaborative (TCCC). The MSKCC e-form fulfills 21 of 32 intraoperative fields and includes an additional 14 fields not specifically mentioned in the ATA's report. The Alberta WebSMR fulfills 45 of 82 preoperative and intraoperative fields outlined by the ATA and includes 13 additional fields. The TCCC fulfills 117 of 120 fields outlined by the ATA and includes 23 additional fields. CONCLUSIONS: Effective management of thyroid cancer is a highly collaborative, multidisciplinary effort. The patient information that factors into clinical decisions about thyroid cancer is complex. For these reasons, EHRs are particularly favorable for the management of patients with thyroid cancer. The MSKCC Thyroid Surgery e-Form, the Alberta WebSMR, and the TCCC each meet all of the general recommendations for effective reporting of the specific domains that they cover in the management of thyroid cancer, as recommended by the ATA. However, the TCCC format is the most comprehensive. The TCCC is a new Web-based disease-specific database to enhance communication of patient information between clinicians in a Health Insurance Portability and Accountability Act (HIPAA)-compliant manner. We believe the easy to-use TCCC format will enhance clinician communication while providing portability of thyroid cancer information for patients. PMID- 25036191 TI - Isolating fungal pathogens from a dynamic disease outbreak in a native plant population to establish plant-pathogen bioassays for the ecological model plant Nicotiana attenuata. AB - The wild tobacco species Nicotiana attenuata has been intensively used as a model plant to study its interaction with insect herbivores and pollinators in nature, however very little is known about its native pathogen community. We describe a fungal disease outbreak in a native N. attenuata population comprising 873 plants growing in an area of about 1500 m2. The population was divided into 14 subpopulations and disease symptom development in the subpopulations was monitored for 16 days, revealing a waxing and waning of visible disease symptoms with some diseased plants recovering fully. Native fungal N. attenuata pathogens were isolated from diseased plants, characterized genetically, chemotaxonomically and morphologically, revealing several isolates of the ascomycete genera Fusarium and Alternaria, that differed in the type and strength of the disease symptoms they caused in bioassays on either detached leaves or intact soil-grown plants. These isolates and the bioassays will empower the study of N. attenuata-pathogen interactions in a realistic ecological context. PMID- 25036193 TI - Respiratory bronchiolitis with fibrosis-interstitial lung disease: a new form of smoking-induced interstitial lung disease. PMID- 25036194 TI - Improvement in social function and health-related quality of life after shunt surgery for idiopathic normal-pressure hydrocephalus. AB - OBJECTIVES: To investigate the impact of shunt surgery on the activity, participation, autonomy, and health-related quality of life (HRQOL) of patients with idiopathic normal-pressure hydrocephalus (iNPH) as well as the effect on caregiver burden. METHODS: Thirty-seven patients (median age 70 years, range 50 89 years) with iNPH were evaluated before and 6 months after surgery. Symptoms and signs were assessed by the iNPH scale, activities of daily living (ADL) with the Functional Independence Measure (FIM) and Assessment of Motor and Process Skills (AMPS), autonomy and participation with Impact on Participation and Autonomy (IPA), and caregiver burden with the Caregiver Burden Scale (CBS). HRQOL was evaluated with the EQ-5D (EuroQol Group-5 Dimension health survey). RESULTS: Twenty-four patients (65%) improved clinically (iNPH scale score) and 31 (86%) improved their HRQOL after surgery, almost to the same level as found in the normal population. The patients became more independent in physical and cognitive activities, and participation and autonomy improved. The caregiver burden was decreased among caregivers to male patients but remained unchanged on the overall group level. CONCLUSIONS: After shunt surgery, patients with iNPH showed improvement in most aspects of social life, they became more independent, and their quality of life returned to nearly normal. PMID- 25036192 TI - A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR. AB - Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08+/-0.13 * 10(6), 1.08+/-0.11 * 10(5), 1.03+/-0.10 * 10(4), 1.02+/-0.09 * 10(3), 1.04+/-0.10 * 10(2) and 10.0+/-1.5 copies/MUl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a f). PMID- 25036195 TI - Association between silent embolic cerebral infarction and continuous increase of P2Y12 reaction units after neurovascular stenting. AB - OBJECTIVES: Endovascular procedures are one of the important treatment options for steno-occlusive arteries in ischemic stroke patients. However, embolic complications after such procedures are always a concern. The authors investigated the association between serial change of residual platelet reactivity and silent embolic cerebral infarction (SECI) after endovascular treatment. METHODS: Ischemic stroke patients undergoing stenting of intra- or extracranial arteries were recruited prospectively. Residual platelet reactivity, represented by aspirin reaction units (ARUs) and P2Y12 reaction units (PRUs), was measured serially (6 hours before, immediately after, and 24 hours after the procedure). A loading dosage of aspirin (500 mg) and/or clopidogrel (300 mg) was given 24 hours before the procedure to patients naive to antiplatelet agents, whereas the usual dosage (aspirin 100 mg and clopidogrel 75 mg) was continued for patients who had previously been taking these agents for more than a week. Diffusion-weighted MRI was performed before and 24 hours after the procedure to detect new SECIs. Clinical characteristics, baseline ARU and PRU values, and the change in ARU and PRU values after stenting were compared between patients with and without SECIs. RESULTS: Among 69 consecutive patients who underwent neurovascular stent insertion, 41 patients (59.4%) had poststenting SECIs. The lesion was located only at the vascular territory of the stented vessel in 21 patients (51.2%), outside the stented vessel territory in 8 patients (19.5%), and both inside and outside in 12 patients (29.3%). The occurrence of SECIs was not associated with the baseline ARU or PRU value, but was associated with PRU increase after stenting (36 +/- 73 vs -12 +/- 59, p = 0.007), deployment of a longer stent (31.1 +/- 16.5 mm vs 21.8 +/- 9.9 mm, p = 0.01), and stent insertion in extracranial arteries (78.1% vs 45.2%, p = 0.008). Stent length (OR 1.066, p = 0.01) and PRU change (OR 1.009, p = 0.04) were independently associated with the occurrence of SECI. CONCLUSIONS: Residual platelet reactivity after dual antiplatelet treatment measured before stenting did not predict poststenting SECI. However, the longer stent and the serial increase of PRU values after stenting were related to SECI. Continuous increase of platelet activation after endovascular procedure may be important in poststent cerebral infarction. PMID- 25036196 TI - Closed-loop electrochemical feedback system for DBS. PMID- 25036197 TI - Idiopathic intracranial hypertension presenting solely as CSF rhinorrhea. PMID- 25036198 TI - Edwin Smith papyrus case 8. PMID- 25036199 TI - Risk factors for postoperative CSF leakage after elective craniotomy and the efficacy of fleece-bound tissue sealing against dural suturing alone: a randomized controlled trial. AB - OBJECT: Cerebrospinal fluid leakage is an immanent risk of cranial surgery with dural opening. Recognizing the risk factors for this complication and improving the technique of dural closure may reduce the associated morbidity and its surgical burden. The aim of this paper was to investigate whether the addition of TachoSil on top of the dural suture reduces postoperative CSF leakage compared with dural suturing alone and to assess the frequency and risk factors for dural leakage and potentially related complications after elective craniotomy. METHODS: The authors conducted a prospective, randomized, double-blinded single-center trial in patients undergoing elective craniotomy with dural opening. They compared their standard dural closure by running suture alone (with the use of a dural patch if needed) to the same closure with the addition of TachoSil on top of the suture. The primary end point was the incidence of CSF leakage, defined as CSF collection or any open CSF fistula within 30 days. Secondary end points were the incidence of infection, surgical revision, and length of stay in the intensive care unit (ICU) or intermediate care (IMC) unit. The site of craniotomy, a history of diabetes mellitus, a diagnosis of meningioma, the intraoperative need of a suturable dural substitute, and blood parameters were assessed as potential risk factors for CSF leakage. RESULTS: The authors enrolled 241 patients, of whom 229 were included in the analysis. Cerebrospinal fluid leakage, mostly self-limiting subgaleal collections, occurred in 13.5% of patients. Invasive treatment was performed in 8 patients (3.5%) (subgaleal puncture in 6, lumbar drainage in 1, and surgical revision in 1 patient). Diabetes mellitus, a higher preoperative level of C-reactive protein (CRP), and the intraoperative need for a dural patch were positively associated with the occurrence of the primary end point (p = 0.014, 0.01, and 0.049, respectively). Cerebrospinal fluid leakage (9.7% vs 17.2%, OR 0.53 [95% CI 0.23-1.15], p = 0.108) and infection (OR 0.18 [95% CI 0.01-1.18], p = 0.077) occurred less frequently in the study group than in the control group. TachoSil significantly reduced the probability of staying in the IMC unit for 1 day or longer (OR 0.53 [95% CI 0.27-0.99], p = 0.048). Postoperative epidural hematoma and empyema occurred in the control group but not in the study group. CONCLUSIONS: Dural leakage after elective craniotomy/durotomy occurs more frequently in association with diabetes mellitus, elevated preoperative CRP levels, and the intraoperative need of a dural patch. This randomized controlled trial showed no statistically significant reduction of postoperative CSF leakage and surgical site infections upon addition of TachoSil on the dural suture, but there was a significant reduction in the length of stay in the IMC unit. Dural augmentation with TachoSil was safe and not related to adverse events. Clinical trial registration no. NCT00999999 ( http://www.ClinicalTrials.gov ). PMID- 25036200 TI - Comparison of techniques for ventriculoperitoneal shunting in 523 patients with subarachnoid hemorrhage. AB - OBJECTIVE: It is common practice to use a new contralateral bur hole for ventriculoperitoneal shunt (VPS) placement in subarachnoid hemorrhage (SAH) patients with an existing ventriculostomy. At Thomas Jefferson University and Jefferson Hospital for Neuroscience, the authors have primarily used the ventriculostomy site for the VPS. The purpose of this study was to compare the safety of the 2 techniques in patients with SAH. METHODS: The rates of VPS related hemorrhage, infection, and proximal revision were compared between the 2 techniques in 523 patients undergoing VPS placement (same site in 464 and contralateral site in 59 patients). RESULTS: The rate of new VPS-related hemorrhage was significantly higher in the contralateral-site group (1.7%) than in the same-site group (0%; p = 0.006). The rate of VPS infection did not differ between the 2 groups (6.4% for same site vs 5.1% for contralateral site; p = 0.7). In multivariate analysis, higher Hunt and Hess grades (p = 0.05) and open versus endovascular treatment (p = 0.04) predicted shunt infection, but the VPS technique was not a predictive factor (p = 0.9). The rate of proximal shunt revision was 6% in the same-site group versus 8.5% in the contralateralsite group (p = 0.4). In multivariate analysis, open surgery was the only factor predicting proximal VPS revision (p = 0.05). CONCLUSIONS: The results of this study suggest that the use of the ventriculostomy site for VPS placement may be feasible and safe and may not add morbidity (infection or need for revision) compared with the use of a fresh contralateral site. This rapid and simple technique also was associated with a lower risk of shunt-related hemorrhage. While both techniques appear to be feasible and safe, a definitive answer to the question of which technique is superior awaits a higher level of medical evidence. PMID- 25036201 TI - The efficacy of erythropoietin in treating experimental traumatic brain injury: a systematic review of controlled trials in animal models. AB - OBJECT: Erythropoietin (EPO) shows promise as a neuroprotective agent in animal models of traumatic brain injury (TBI). However, clinical trials of the efficacy of EPO treatment in patients with TBI yield conflicting results. The authors conducted a systematic review and meta-analysis to assess the effect of EPO in experimental animal models of TBI, the goal being to inform the design of future clinical trials. METHODS: The authors identified eligible studies by searching PubMed, Web of Science, MEDLINE, Embase, and Google Scholar in October 2013. Data were pooled using the random-effects model, and results were reported in terms of standardized mean difference. Statistical heterogeneity was examined using both I(2) and chi-square tests, and the presence of small study effects was investigated with funnel plots and Egger tests. In-depth analyses were performed for lesion volume and neurobehavioral outcome, and the studies' methodological quality was also evaluated. RESULTS: Of a total of 290 studies, 13 found an effect of EPO on lesion volume and neurobehavioral outcome. Overall, the methodological quality of the studies was poor, and there was evidence of statistical heterogeneity among the publications as well as small-study effects. However, in-depth analyses showed statistically significant findings in favor of a beneficial effect of EPO after TBI. CONCLUSIONS: Despite limitations of this systematic review that may have influenced the findings, the authors conclude that EPO might be beneficial in treating experimental TBI in terms of reducing lesion volume and improving neurobehavioral outcome. However, this review also indicates that more well-designed and well-reported animal studies are needed. PMID- 25036202 TI - Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy. AB - OBJECT: The authors assessed the risk factors and outcomes associated with blood brain barrier (BBB) disruption in patients with severe, nonpenetrating, traumatic brain injury (TBI) requiring decompressive craniectomy. METHODS: At 2 major neurotrauma centers in Western Australia, a retrospective cohort study was conducted among 97 adult neurotrauma patients who required an external ventricular drain (EVD) and decompressive craniectomy during 2004-2012. Glasgow Outcome Scale scores were used to assess neurological outcomes. Logistic regression was used to identify factors associated with BBB disruption, defined by a ratio of total CSF protein concentrations to total plasma protein concentration > 0.007 in the earliest CSF specimen collected after TBI. RESULTS: Of the 252 patients who required decompressive craniectomy, 97 (39%) required an EVD to control intracranial pressure, and biochemical evidence of BBB disruption was observed in 43 (44%). Presence of disruption was associated with more severe TBI (median predicted risk for unfavorable outcome 75% vs 63%, respectively; p = 0.001) and with worse outcomes at 6, 12, and 18 months than was absence of BBB disruption (72% vs 37% unfavorable outcomes, respectively; p = 0.015). The only risk factor significantly associated with increased risk for BBB disruption was presence of nonevacuated intracerebral hematoma (> 1 cm diameter) (OR 3.03, 95% CI 1.23-7.50; p = 0.016). Although BBB disruption was associated with more severe TBI and worse long-term outcomes, when combined with the prognostic information contained in the Corticosteroid Randomization after Significant Head Injury (CRASH) prognostic model, it did not seem to add significant prognostic value (area under the receiver operating characteristic curve 0.855 vs 0.864, respectively; p = 0.453). CONCLUSIONS: Biochemical evidence of BBB disruption after severe nonpenetrating TBI was common, especially among patients with large intracerebral hematomas. Disruption of the BBB was associated with more severe TBI and worse long-term outcomes, but when combined with the prognostic information contained in the CRASH prognostic model, this information did not add significant prognostic value. PMID- 25036203 TI - Spinal cerebrospinal fluid leak as the cause of chronic subdural hematomas in nongeriatric patients. AB - OBJECT: The etiology of chronic subdural hematoma (CSDH) in nongeriatric patients (<= 60 years old) often remains unclear. The primary objective of this study was to identify spinal CSF leaks in young patients, after formulating the hypothesis that spinal CSF leaks are causally related to CSDH. METHODS: All consecutive patients 60 years of age or younger who underwent operations for CSDH between September 2009 and April 2011 at Bern University Hospital were included in this prospective cohort study. The patient workup included an extended search for a spinal CSF leak using a systematic algorithm: MRI of the spinal axis with or without intrathecal contrast application, myelography/fluoroscopy, and postmyelography CT. Spinal pathologies were classified according to direct proof of CSF outflow from the intrathecal to the extrathecal space, presence of extrathecal fluid accumulation, presence of spinal meningeal cysts, or no pathological findings. The primary outcome was proof of a CSF leak. RESULTS: Twenty-seven patients, with a mean age of 49.6 +/- 9.2 years, underwent operations for CSDH. Hematomas were unilateral in 20 patients and bilateral in 7 patients. In 7 (25.9%) of 27 patients, spinal CSF leakage was proven, in 9 patients (33.3%) spinal meningeal cysts in the cervicothoracic region were found, and 3 patients (11.1%) had spinal cysts in the sacral region. The remaining 8 patients (29.6%) showed no pathological findings. CONCLUSIONS: The direct proof of spinal CSF leakage in 25.9% of patients suggests that spinal CSF leaks may be a frequent cause of nongeriatric CSDH. PMID- 25036204 TI - Frameless neuronavigation based only on 3D digital subtraction angiography using surface-based facial registration. AB - OBJECT: Cerebrovascular lesions can have complicated abnormal anatomy that is not completely characterized by CT or MR angiography. Although 3D rotational angiography provides superior spatial and temporal resolution, catheter angiograms are not easily registered to the patient, limiting the use of these images as a source for neuronavigation. However, 3D digital subtraction angiography (DSA) contains not only vascular anatomy but also facial surface anatomy data. The authors report a novel technique to register 3D DSA images by using only the surface anatomy contained within the data set without having to fuse the DSA image set to other imaging modalities or use fiducial markers. METHODS: A cadaver model was first created to assess the accuracy of neuronavigation based on 3D DSA images registered by facial surface anatomy. A 3D DSA scan was obtained of a formalin-fixed cadaver head, with acquisitions of mask and contrast runs. The right common carotid artery was injected prior to the contrast run with a 45% contrast solution diluted with water-soluble red liquid latex. One week later, the head was registered to a neuronavigation system loaded with the 3D DSA images acquired earlier using facial surface anatomy. A right pterional craniotomy was performed and 10 different vascular landmarks were identified and measured for accuracy using the neuronavigation system. Neuronavigation based only on 3D DSA was then used to guide an open clipping procedure for a patient who presented with a ruptured distal lenticulostriate aneurysm. RESULTS: The accuracy of the measurements for the cadaver model was 0.71 +/- 0.25 mm (mean +/- SE), which is superior to the 1.8-5 mm reported for neuronavigation. The 3D DSA-based navigation-assisted surgery for the distal lenticulostriate aneurysm aided in localization, resulting in a small craniotomy and minimal brain dissection. CONCLUSIONS: This is the first example of frameless neuronavigation based on 3D catheter angiography registered by only the surface anatomy data contained within the 3D DSA image set. This is an easily applied technique that is beneficial for accurately locating vascular pathological entities and reducing the dissection burden of vascular lesions. PMID- 25036205 TI - A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma. AB - OBJECT: Robust methodology that allows objective, automated, and observer independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability. METHODS: Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations. RESULTS: There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors' novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (kappa = 0.96) when compared with 2D (kappa = 0.54) or 1D (kappa = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94). CONCLUSIONS: Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors. PMID- 25036206 TI - Perianeurysmal edema as a predictive sign of aneurysmal rupture. AB - Subarachnoid hemorrhage following intracranial aneurysmal rupture is a major cause of morbidity and mortality. Several factors may affect the probability of rupture, such as tobacco and alcohol use; size, shape, and location of the aneurysm; presence of intraluminal thrombus; and even the sex of the patient. However, few data correlate such findings with the timing of aneurysmal rupture. The authors report 2 cases of middle-age women with headache and MRI findings of incidental aneurysms. Magnetic resonance imaging showed evidence of surrounding parenchymal edema, and in one case there was a clear increase in edema during follow-up, suggesting a progressive inflammatory process that culminated with rupture. These findings raise the possibility that bleb formation and an enlargement of a cerebral aneurysm might be associated with an inflammatory reaction of the aneurysm wall resulting in perianeurysmal edema and subsequent aneurysmal rupture. There may be a temporal link between higher degree of edema and higher risk for rupture, including risk for immediate rupture. PMID- 25036207 TI - Suprajugular extension of the retrosigmoid approach. PMID- 25036208 TI - Effect of local application of transforming growth factor-beta at the nerve repair site following chronic axotomy and denervation on the expression of regeneration-associated genes. Laboratory investigation. AB - OBJECTIVES: Although peripheral nerves can regenerate after traumatic injury, functional recovery is often suboptimal, especially after injuries to large nerve trunks such as the sciatic nerve or brachial plexus. Current research with animal models suggests that the lack of functional recovery resides in the lack of sufficient mature axons reaching their targets due to the loss of neurotrophic support by Schwann cells in the distal stump of injured nerves. This study was designed to investigate the effect of one-time application of transforming growth factor-beta (TGF-beta) at the repair site of chronically injured nerve. METHODS: The authors used the rat tibial nerve injury and repair model to investigate the effects of application of physiological concentrations of TGF-beta plus forskolin or forskolin alone in vivo at the repair site on gene and protein expression and axon regeneration at 6 weeks after nerve repair. They used gene expression profiling and immunohistochemical analysis of indicative activated proteins in Schwann cells to evaluate the effects of treatments on the delayed repair. They also quantified the regenerated axons distal to the repair site by microscopy of paraffin sections. RESULTS: Both treatment with forskolin only and treatment with TGF-beta plus forskolin resulted in increased numbers of axons regenerated compared with saline-only control. There was robust activation and proliferation of both Schwann cells and macrophages reminiscent of the processes during Wallerian degeneration. The treatment also induced upregulation of genes implicated in cellular activation and growth as detected by gene array. CONCLUSIONS: Addition of TGF-beta plus forskolin to the repair after chronic nerve injury improved axonal regeneration, probably via upregulation of required genes, expression of growth-associated protein, and reactivation of Schwann cells and macrophages. Further studies are required to better understand the mechanism of the positive effect of TGF-beta treatment on old nerve injuries. PMID- 25036209 TI - A Picea abies linkage map based on SNP markers identifies QTLs for four aspects of resistance to Heterobasidion parviporum infection. AB - A consensus linkage map of Picea abies, an economically important conifer, was constructed based on the segregation of 686 SNP markers in a F1 progeny population consisting of 247 individuals. The total length of 1889.2 cM covered 96.5% of the estimated genome length and comprised 12 large linkage groups, corresponding to the number of haploid P. abies chromosomes. The sizes of the groups (from 5.9 to 9.9% of the total map length) correlated well with previous estimates of chromosome sizes (from 5.8 to 10.8% of total genome size). Any locus in the genome has a 97% probability to be within 10 cM from a mapped marker, which makes the map suited for QTL mapping. Infecting the progeny trees with the root rot pathogen Heterobasidion parviporum allowed for mapping of four different resistance traits: lesion length at the inoculation site, fungal spread within the sapwood, exclusion of the pathogen from the host after initial infection, and ability to prevent the infection from establishing at all. These four traits were associated with two, four, four and three QTL regions respectively of which none overlapped between the traits. Each QTL explained between 4.6 and 10.1% of the respective traits phenotypic variation. Although the QTL regions contain many more genes than the ones represented by the SNP markers, at least four markers within the confidence intervals originated from genes with known function in conifer defence; a leucoanthocyanidine reductase, which has previously been shown to upregulate during H. parviporum infection, and three intermediates of the lignification process; a hydroxycinnamoyl CoA shikimate/quinate hydroxycinnamoyltransferase, a 4-coumarate CoA ligase, and a R2R3-MYB transcription factor. PMID- 25036211 TI - Generation of 3D nanopatterns with smooth surfaces. AB - Ga implantation into Si and reactive ion etching has been previously identified as candidate techniques for the generation of 3D nanopatterns. However, the structures manufactured using these techniques exhibited impedingly high surface roughness. In this work, we investigate the source of roughness and introduce a new patterning process to solve this issue. The novel patterning process introduces an additional layer absorbing the implanted Ga, thus preventing the clustering of the implanted Ga observed with uncoated Si substrates. This process enables 3D nanopatterning with sub-100 nm lateral resolution in conjunction with smooth height transitions and surface roughness down to 4 nm root mean square. Such patterns are ideally suited for optical applications and enable the manufacturing of nanoimprint lithography templates for low-profile Fresnel lenses. PMID- 25036210 TI - Bayesian pathway analysis of cancer microarray data. AB - High Throughput Biological Data (HTBD) requires detailed analysis methods and from a life science perspective, these analysis results make most sense when interpreted within the context of biological pathways. Bayesian Networks (BNs) capture both linear and nonlinear interactions and handle stochastic events in a probabilistic framework accounting for noise making them viable candidates for HTBD analysis. We have recently proposed an approach, called Bayesian Pathway Analysis (BPA), for analyzing HTBD using BNs in which known biological pathways are modeled as BNs and pathways that best explain the given HTBD are found. BPA uses the fold change information to obtain an input matrix to score each pathway modeled as a BN. Scoring is achieved using the Bayesian-Dirichlet Equivalent method and significance is assessed by randomization via bootstrapping of the columns of the input matrix. In this study, we improve on the BPA system by optimizing the steps involved in "Data Preprocessing and Discretization", "Scoring", "Significance Assessment", and "Software and Web Application". We tested the improved system on synthetic data sets and achieved over 98% accuracy in identifying the active pathways. The overall approach was applied on real cancer microarray data sets in order to investigate the pathways that are commonly active in different cancer types. We compared our findings on the real data sets with a relevant approach called the Signaling Pathway Impact Analysis (SPIA). PMID- 25036212 TI - Assessment of microcirculation dynamics during cutaneous wound healing phases in vivo using optical microangiography. AB - Cutaneous wound healing consists of multiple overlapping phases starting with blood coagulation following incision of blood vessels. We utilized label-free optical coherence tomography and optical microangiography (OMAG) to noninvasively monitor healing process and dynamics of microcirculation system in a mouse ear pinna wound model. Mouse ear pinna is composed of two layers of skin separated by a layer of cartilage and because its total thickness is around 500 MUm, it can be utilized as an ideal model for optical imaging techniques. These skin layers are identical to human skin structure except for sweat ducts and glands. Microcirculatory system responds to the wound injury by recruiting collateral vessels to supply blood flow to hypoxic region. During the inflammatory phase, lymphatic vessels play an important role in the immune response of the tissue and clearing waste from interstitial fluid. In the final phase of wound healing, tissue maturation, and remodeling, the wound area is fully closed while blood vessels mature to support the tissue cells. We show that using OMAG technology allows noninvasive and label-free monitoring and imaging each phase of wound healing that can be used to replace invasive tissue sample histology and immunochemistry technologies. PMID- 25036213 TI - Molecular imaging of human tumor cells that naturally overexpress type 2 cannabinoid receptors using a quinolone-based near-infrared fluorescent probe. AB - Cannabinoid CB2 receptors (CB2R) hold promise as therapeutic targets for treating diverse diseases, such as cancers, neurodegenerative diseases, pain, inflammation, osteoporosis, psychiatric disorders, addiction, and immune disorders. However, the fundamental role of CB2R in the regulation of diseases remains unclear, largely due to a lack of reliable imaging tools for the receptors. The goal of this study was to develop a CB2R-targeted molecular imaging probe and evaluate the specificity of the probe using human tumor cells that naturally overexpress CB2R. To synthesize the CB2R-targeted probe (NIR760 Q), a conjugable CB2R ligand based on the quinolone structure was first prepared, followed by bioconjugation with a near-infrared (NIR) fluorescent dye, NIR760. In vitro fluorescence imaging and competitive binding studies showed higher uptake of NIR760-Q than free NIR760 dye in Jurkat human acute T-lymphoblastic leukemia cells. In addition, the high uptake of NIR760-Q was significantly inhibited by the blocking agent, 4-quinolone-3-carboxamide, indicating specific binding of NIR760-Q to the target receptors. These results indicate that the NIR760-Q has potential in diagnostic imaging of CB2R positive cancers and elucidating the role of CB2R in the regulation of disease progression. PMID- 25036214 TI - Near-infrared imaging of demineralization under sealants. AB - Previous studies have shown that near-infrared (NIR) reflectance and transillumination imaging can be used to acquire high contrast images of early caries lesions and composite restorative materials. The aim of the study was to determine the optimum NIR wavelengths for imaging demineralized areas under dental sealants. Fifteen natural human premolars and molars with occlusal lesions were used in this in vitro study. Images before and after application of sealants were acquired using NIR reflectance and NIR transillumination at wavelengths of 1300, 1460, and 1500 to 1700 nm. Images were also acquired using polarization sensitive optical coherence tomography (OCT) for comparison. The highest contrast for NIR reflectance was at 1460 nm and 1500 to 1700 nm. These NIR wavelengths are coincident with higher water absorption. The clear Delton sealant investigated was not visible in either copolarization or cross-polarization OCT images. The wavelength region between 1500 and 1700 nm yielded the highest contrast of lesions under sealants for NIR reflectance measurements. PMID- 25036215 TI - In vivo measurement of tissue oxygenation by time-resolved luminescence spectroscopy: advantageous properties of dichlorotris(1, 10-phenanthroline) ruthenium(II) hydrate. AB - Measuring tissue oxygenation in vivo is of interest in fundamental biological as well as medical applications. One minimally invasive approach to assess the oxygen partial pressure in tissue (pO2) is to measure the oxygen-dependent luminescence lifetime of molecular probes. The relation between tissue pO2 and the probes' luminescence lifetime is governed by the Stern-Volmer equation. Unfortunately, virtually all oxygen-sensitive probes based on this principle induce some degree of phototoxicity. For that reason, we studied the oxygen sensitivity and phototoxicity of dichlorotris(1, 10-phenanthroline)-ruthenium(II) hydrate [Ru(Phen)] using a dedicated optical fiber-based, time-resolved spectrometer in the chicken embryo chorioallantoic membrane. We demonstrated that, after intravenous injection, Ru(Phen)'s luminescence lifetime presents an easily detectable pO2 dependence at a low drug dose (1 mg/kg) and low fluence (120 mJ/cm2 at 470 nm). The phototoxic threshold was found to be at 10 J/cm2 with the same wavelength and drug dose, i.e., about two orders of magnitude larger than the fluence necessary to perform a pO2 measurement. Finally, an illustrative application of this pO2 measurement approach in a hypoxic tumor environment is presented. PMID- 25036216 TI - Evaluation of various mental task combinations for near-infrared spectroscopy based brain-computer interfaces. AB - A number of recent studies have demonstrated that near-infrared spectroscopy (NIRS) is a promisingneuroimaging modality for brain-computer interfaces (BCIs). So far, most NIRS-based BCI studies have focusedon enhancing the accuracy of the classification of different mental tasks. In the present study, we evaluated theperformances of a variety of mental task combinations in order to determine the mental task pairs that are bestsuited for customized NIRS-based BCIs. To this end, we recorded event-related hemodynamic responses whileseven participants performed eight different mental tasks. Classification accuracies were then estimated for allpossible pairs of the eight mental tasks (8C2 = 28). Based on this analysis, mental task combinations with relatively high classification accuracies frequently included the following three mental tasks: "mental multiplication," "mental rotation," and "right-hand motor imagery." Specifically, mental task combinations consisting of two of these three mental tasks showed the highest mean classification accuracies. It is expected that our results will be a useful reference to reduce the time needed for preliminary tests when discovering individual-specific mental task combinations. PMID- 25036217 TI - Adsorption of glucose, cellobiose, and cellotetraose onto cellulose model surfaces. AB - Reliable simulation of molecular adsorption onto cellulose surfaces is essential for the design of new cellulose nanocomposite materials. However, the applicability of classical force field methods to such systems remains relatively unexplored. In this study, we present the adsorption of glucose, cellobiose, and cellotetraose on model surfaces of crystalline cellulose Ialpha and Ibeta. The adsorption of the two large carbohydrates was simulated with the GLYCAM06 force field. To validate this approach, quantum theoretical calculations for the adsorption of glucose were performed: Equilibrium geometries were studied with density functional theory (DFT) and dispersion-corrected DFT, whereas the adsorption energies were calculated with two standard density functional approximations and five dispersion-containing DFT approaches. We find that GLYCAM06 gives a good account of geometries and, in most cases, accurate adsorption energies when compared to dispersion-corrected DFT energies. Adsorption onto the (100) surface of cellulose Ialpha is, in general, stronger than onto the (100) surface of cellulose Ibeta. Contrary to intuition, the adsorption energy is not directly correlated with the number of hydrogen bonds; rather, it is dominated by dispersion interactions. Especially for bigger adsorbates, a neglect of these interactions leads to a dramatic underestimation of adsorption energies. PMID- 25036218 TI - Clinical and radiographic analysis of an artificial cervical disc: 7-year follow up from the Prestige prospective randomized controlled clinical trial: Clinical article. AB - OBJECT: The authors assess the long-term safety and efficacy of cervical disc replacement with the Prestige Cervical Disc in a prospective, randomized, multicenter trial at 7 years of follow-up. METHODS: At 31 investigational sites, 541 patients with single-level cervical disc disease with radiculopathy were randomized to 1 of 2 treatment groups: 276 investigational group patients underwent anterior cervical discectomy and arthroplasty with the Prestige disc, and 265 control group patients underwent anterior cervical discectomy and fusion. Clinical outcomes included Neck Disability Index, the 36-Item Short-Form Health Survey, and neck and arm pain scores. Radiographs were assessed for angle of motion and fusion. Clinical and radiographic outcomes were evaluated preoperatively, intraoperatively, and at 1.5, 3, 6, 12, 24, 36, 60, and 84 months. RESULTS: Of the 541 patients treated, 395 patients (73%; 212 investigational and 183 control patients) completed 7 years of clinical follow up. Significant improvements achieved by 1.5 months in both groups were sustained at 7 years. In the investigational group, mean Neck Disability Index improvements from preoperative scores were 38.2 and 37.5 at 60 and 84 months, respectively. In the control group, the corresponding means were 33.8 and 31.9. The differences between the investigational and control groups at the 60-month and 84-month periods were significant (p = 0.014 and 0.002, respectively). The overall rates of maintenance or improvement in neurological status in the investigational group were significantly higher: 92.2% and 88.2% at 60 months and 84 months, respectively, compared with 85.7% and 79.7% in the control group (p = 0.017 and 0.011, respectively). At 84 months, the percentage of working patients in the investigational group was 73.9%, and in the control group, 73.1%. Postoperatively, the implant effectively maintained average angular motion of 6.67 degrees at 60 months and 6.75 degrees at 84 months. Cumulative rates for surgery at the index level were lower (p < 0.001) in the investigational group (11 [4.8%] of 276) when compared with the control group (29 [13.7%] of 265) (based on life-table method), and there were statistical differences between the investigational and control groups with specific regard to the rate of subsequent revision and supplemental fixation surgical procedures. Rates for additional surgical procedures that involved adjacent levels were lower in the investigational group than in the control group (11 [4.6%] of 276 vs. 24 [11.9%] of 265, respectively). CONCLUSIONS: Cervical disc arthroplasty has the potential for preserving motion at the operated level while providing biomechanical stability and global neck mobility and may result in a reduction in adjacent segment degeneration. The Prestige Cervical Disc maintains improved clinical outcomes and segmental motion after implantation at 7-year follow-up. Clinical trial registration no. NCT00642876 ( ClinicalTrials.gov ). PMID- 25036219 TI - Results of the AANS membership survey of adult spinal deformity knowledge: impact of training, practice experience, and assessment of potential areas for improved education: Clinical article. AB - OBJECT: Adult spinal deformity (ASD) surgery is increasing in the spinal neurosurgeon's practice. METHODS: A survey of neurosurgeon AANS membership assessed the deformity knowledge base and impact of current training, education, and practice experience to identify opportunities for improved education. Eleven questions developed and agreed upon by experienced spinal deformity surgeons tested ASD knowledge and were subgrouped into 5 categories: (1) radiology/spinopelvic alignment, (2) health-related quality of life, (3) surgical indications, (4) operative technique, and (5) clinical evaluation. Chi-square analysis was used to compare differences based on participant demographic characteristics (years of practice, spinal surgery fellowship training, percentage of practice comprising spinal surgery). RESULTS: Responses were received from 1456 neurosurgeons. Of these respondents, 57% had practiced less than 10 years, 20% had completed a spine fellowship, and 32% devoted more than 75% of their practice to spine. The overall correct answer percentage was 42%. Radiology/spinal pelvic alignment questions had the lowest percentage of correct answers (38%), while clinical evaluation and surgical indications questions had the highest percentage (44%). More than 10 years in practice, completion of a spine fellowship, and more than 75% spine practice were associated with greater overall percentage correct (p < 0.001). More than 10 years in practice was significantly associated with increased percentage of correct answers in 4 of 5 categories. Spine fellowship and more than 75% spine practice were significantly associated with increased percentage correct in all categories. Interestingly, the highest error was seen in risk for postoperative coronal imbalance, with a very low rate of correct responses (15%) and not significantly improved with fellowship (18%, p = 0.08). CONCLUSIONS: The results of this survey suggest that ASD knowledge could be improved in neurosurgery. Knowledge may be augmented with neurosurgical experience, spinal surgery fellowships, and spinal specialization. Neurosurgical education should particularly focus on radiology/spinal pelvic alignment, especially pelvic obliquity and coronal imbalance and operative techniques for ASD. PMID- 25036220 TI - Thoracic discectomy by posterior pedicle-sparing, transfacet approach with real time intraoperative ultrasonography: Clinical article. AB - OBJECT: Symptomatic thoracic disc herniations (TDHs) are relatively uncommon, and the technical challenges of resecting the offending disc are formidable due to the location of spinal cord that has relatively poor perfusion characteristics within a narrow canal. The majority of disc herniations are long-standing calcified discs that can be adherent to the ventral dura. Real-time intraoperative ultrasound (RIOUS) visualization of the spinal cord during the retraction and resection of the disc greatly enhances the safety and efficacy of disc resection. The authors have adopted the posterior laminectomy with pedicle sparing transfacet approach with real-time ultrasound guidance in their practice, and they present the clinical outcome in their patients to illustrate the safety profile of this technique. METHODS: Sixteen consecutive patients undergoing operative management of TDHs were identified from the authors' database. All patients underwent microdiscectomy through a posterior transfacet pedicle-sparing approach under RIOUS. Outcomes and complications were retrospectively assessed in this patient series. Clinical records and pre- and postoperative imaging studies were scrutinized to assess levels and types of disc herniation, blood loss, surgical time, pre- and postoperative Nurick grades, Japanese Orthopaedic Association (JOA) scores, and complications. RESULTS: All patients had single level symptomatic TDHs. The patients presented with symptoms including thoracic myelopathy, axial back pain, urinary symptoms, and thoracic radiculopathy. Thoracic disc herniations involved levels T2-3 to T12-L1. Discs were classified as central or paracentral, and as calcified or noncalcified. All discs were successfully removed with no incidence of neural injury or CSF leak. The mean estimated blood loss was 523 ml, and the mean surgical time was 159 minutes. Nurick grades improved on average from 3.3 to 1.6. The mean JOA scores improved from 5.7 to 8.3 out of 11. The mean Hirabayashi recovery rate of the JOA score was 57%. All patients reported improvement in symptoms compared with preoperative status except for 1 patient with an American Spinal Injury Association Grade A spinal cord injury prior to surgery. The average duration of follow-up was 10.5 months. One patient developed postoperative wound infection that required additional operative debridement and revision of hardware. CONCLUSIONS: Thoracic discectomy via a posterior pedicle-sparing transfacet approach is an adequate method of managing herniations at any thoracic level. The safety of the operation is significantly enhanced by the use of realtime intraoperative ultrasonography. PMID- 25036221 TI - Occipital condyle to cervical spine screw and rod fixation. PMID- 25036222 TI - The emotional and attentional impact of exposure to one's own body in bulimia nervosa: a physiological view. AB - BACKGROUND: Body dissatisfaction is the most relevant body image disturbance in bulimia nervosa (BN). Research has shown that viewing one's own body evokes negative thoughts and emotions in individuals with BN. However, the psychophysiological mechanisms involved in this negative reaction have not yet been clearly established. Our aim was to examine the emotional and attentional processes that are activated when patients with BN view their own bodies. METHOD: We examined the effects of viewing a video of one's own body on the physiological (eye-blink startle, cardiac defense, and skin conductance) and subjective (pleasure, arousal, and control ratings) responses elicited by a burst of 110 dB white noise of 500 ms duration. The participants were 30 women with BN and 30 healthy control women. The experimental task consisted of two consecutive and counterbalanced presentations of the auditory stimulus preceded, alternatively, by a video of the participant's own body versus no such video. RESULTS: The results showed that, when viewing their own bodies, women with BN experienced (a) greater inhibition of the startle reflex, (b) greater cardiac acceleration in the first component of the defense reaction, (c) greater skin conductance response, and (d) less subjective pleasure and control combined with greater arousal, compared with the control participants. CONCLUSION: Our findings suggest that, for women with BN, peripheral-physiological responses to self-images are dominated by attentional processes, which provoke an immobility reaction caused by a dysfunctional negative response to their own body. PMID- 25036223 TI - Chronic aerobic exercise associated to dietary modification improve endothelial function and eNOS expression in high fat fed hamsters. AB - Obesity is epidemic in the western world and central adipose tissue deposition points to increased cardiovascular morbidity and mortality, independently of any association between obesity and other cardiovascular risk factors. Physical exercise has been used as non-pharmacological treatment to significantly reverse/attenuate obesity comorbidities. In this study we have investigated effects of exercise and/or dietary modification on microcirculatory function, body composition, serum glucose, iNOS and eNOS expression on 120 male hamsters treated for 12 weeks with high fat chow (HF, n = 30) starting on the 21st day of birth. From week 12 to 20, animals were randomly separated in HF (no treatment change), return to standard chow (HFSC, n = 30), high fat chow associated to an aerobic exercise training program (AET) (HFEX, n = 30) and return to standard chow+AET (HFSCEX, n = 30). Microvascular reactivity in response to acetylcholine and sodium nitroprusside and macromolecular permeability increase induced by 30 minutes ischemia followed by reperfusion were assessed on the cheek pouch preparation. Total body fat and aorta eNOS and iNOS expression by immunoblotting assay were evaluated on the experimental day. Compared to HFSC and HFSCEX groups, HF and HFEX ones presented increased visceral fat [(mean+/-SEM) (HF)4.9+/-1.5 g and (HFEX)4.7+/-0.9 g vs. (HFSC)*3.0+/-0.7 g and (HFSCEX)*1.9+/-0.4 g/100 g BW]; impaired endothelial-dependent vasodilatation [Ach 10(-8) M (HF)87.9+/-2.7%; (HFSC)*116.7+/-5.9%; (HFEX)*109.1+/-4.6%; (HFSCEX)*105+/-2.8%; Ach10(-6) M (HF)95.3+/-3.1%; (HFSC)*126+/-6.2%; (HFEX)*122.5+/-2.8%; (HFSCEX)*118.1+/-4.3% and Ach10(-4) M (HF)109.5+/-4.8%; (HFSC)*149.6+/-6.6%; (HFEX)*143.5+/-5.4% and (HFSCEX)*139.4+/-5.2%], macromolecular permeability increase after ischemia/reperfusion [(HF)40.5+/-4.2; (HFSC)*19.0+/-1.6; (HFEX)*18.6+/-2.1 and (HFSCEX)* 21.5+/-3.7 leaks/cm2), decreased eNOS expression, increased leptin and glycaemic levels. Endothelial-independent microvascular reactivity was similar between groups, suggesting that only endothelial damage had occurred. Our results indicate that an aerobic routine and/or dietary modification may cause significant improvements to high fat fed animals, diminishing visceral depots, increasing eNOS expression and reducing microcirculatory dysfunction. PMID- 25036225 TI - Remarkable pressure responses of metal-organic frameworks: proton transfer and linker coiling in zinc alkyl gates. AB - Metal-organic frameworks demonstrate a wide variety of behavior in their response to pressure, which can be classified in a rather limited list of categories, including anomalous elastic behavior (e.g., negative linear compressibility, NLC), transitions between crystalline phases, and amorphization. Very few of these mechanisms involve bond rearrangement. Here, we report two novel piezo mechanical responses of metal-organic frameworks, observed under moderate pressure in two materials of the zinc alkyl gate (ZAG) family. Both materials exhibit NLC at high pressure, due to a structural transition involving a reversible proton transfer between an included water molecule and the linker's phosphonate group. In addition, the 6-carbon alkyl chain of ZAG-6 exhibits a coiling transition under pressure. These phenomena are revealed by combining high pressure single-crystal X-ray crystallography and quantum mechanical calculations. They represent novel pressure responses for metal-organic frameworks, and pressure-induced proton transfer is a very rare phenomenon in materials in general. PMID- 25036224 TI - Molecular comparisons of full length metapneumovirus (MPV) genomes, including newly determined French AMPV-C and -D isolates, further supports possible subclassification within the MPV Genus. AB - Four avian metapneumovirus (AMPV) subgroups (A-D) have been reported previously based on genetic and antigenic differences. However, until now full length sequences of the only known isolates of European subgroup C and subgroup D viruses (duck and turkey origin, respectively) have been unavailable. These full length sequences were determined and compared with other full length AMPV and human metapneumoviruses (HMPV) sequences reported previously, using phylogenetics, comparisons of nucleic and amino acid sequences and study of codon usage bias. Results confirmed that subgroup C viruses were more closely related to HMPV than they were to the other AMPV subgroups in the study. This was consistent with previous findings using partial genome sequences. Closer relationships between AMPV-A, B and D were also evident throughout the majority of results. Three metapneumovirus "clusters" HMPV, AMPV-C and AMPV-A, B and D were further supported by codon bias and phylogenetics. The data presented here together with those of previous studies describing antigenic relationships also between AMPV-A, B and D and between AMPV-C and HMPV may call for a subclassification of metapneumoviruses similar to that used for avian paramyxoviruses, grouping AMPV-A, B and D as type I metapneumoviruses and AMPV-C and HMPV as type II. PMID- 25036226 TI - A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania. AB - BACKGROUND: Evidence synthesis methods enabling direct and indirect comparisons over the entire set of relevant clinical data produce quantitative point estimates for the treatments contrasts between competing interventions, and provide a hierarchical rank ordering between them. We aimed to provide evidence based guidance on the efficacy and all-cause discontinuation of antimanic treatments. METHOD: We conducted a network meta-analysis within a Bayesian framework. We searched all standard literature databases without language restrictions up to 15 January 2014 to identify reports of short-term, randomized, blinded trials of putative antimanic drugs as monotherapy for adults with bipolar I mania. RESULTS: Altogether, 14256 manic patients randomized to one of 18 active treatments or placebo provided 95 direct comparisons on 128 data points. For the primary outcome, standardized mean difference as Hedges' g (standardized mean difference; SMD), the hierarchies indicated by surface under the cumulative ranking (SUCRA) probabilities were in agreement with the point estimates for all antimanic drugs identified as effective. For the 12 effective antimanic drugs on clinical use, SMDs against placebo ranged from 0.32 to 0.66 without superiority of one over another, except for risperidone v. aripiprazole and valproate. Aripiprazole, olanzapine, quetiapine, risperidone, and valproate had less all cause discontinuation rates than placebo. Sensitivity analysis by drug class indicated similar efficacy profiles for haloperidol, second-generation antipsychotics, and mood stabilizers. CONCLUSIONS: Hierarchical rank ordering by comparative efficacy and risk of all-cause discontinuations should help to guide antimanic treatment choices by clinicians, healthcare policy makers, and guideline developers. PMID- 25036227 TI - Ultrasonographic assessment of pes anserinus tendon and pes anserinus tendinitis bursitis syndrome in patients with knee osteoarthritis. AB - OBJECTIVE: The aim of this study was to assess the ultrasonographic (US) findings of pes anserinus tendon and bursa in patients with knee osteoarthritis (OA) with or without clinical pes anserinus tendinitis bursitis syndrome (PATBS). METHODS: A total of 157 female patients with the diagnosis of knee OA on both knees (314 knees), and 30 age, and body mass index- matched healthy female controls without knee pain (60 knees), were included in the study. PATBS was clinically diagnosed. US evaluation parameters were the measurement of the thickness of pes anserinus tendon insertion region (PA) and examination of the morphologic intratendinous PA tissue characteristics and pes anserinus bursitis (PAB). Radiographic knee osteoarthritis graded I-IV according to Kellgren and Lawrence (KL) for each knee was recorded. Pain and functional status were assessed by the Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: There were 183 PATBS (58.3%) clinical diagnoses among the 314 knees with OA. The mean thickness of PA in the patients with knee OA graded 1,2,3,4 with/without PATBS was significantly greater than the controls (p = 0.001). The mean thickness of PA in knees with OA KL graded 3 and 4 with/without PATBS, was greater than knees with OA KL graded 1 and 2 with/without PATBS (p < 0,05) (except knee OA KL graded 2 with PATBS versus knee OA KL graded 4 without PATBS).The knee OA KL graded 1,2,3,4 with PATBS had significantly more PAB and less loss of normal fibrillar echotexture of PA compared to controls and knees with OA KL graded 1,2,3,4 without PATBS (p < 0.05). The VAS scores of knees with OA KL graded 3, 4 with PATBS were significantly greater than those of knees with OA KL graded 3,4 without PATBS (p < 0.05). PA thickness was significantly associated with the KL grade (r: 0.336, p:0.001) and PATBS (r: 0.371, p < 0.001). CONCLUSION: It is concluded that the mean thickness of PA in knees with OA with/without PATBS was significantly greater than the controls. The mean thickness of PA in knees with OA, KL graded 3 and 4 with/without PATBS, was greater than in knees with OA KL graded 1 and 2 with/without PATBS. The knee OA with PATBS had significantly more PAB, less loss of normal fibrillar echotexture of PA, and higher VAS scores compared to the knees with OA without PATBS. US can serve as a useful diagnostic tool for detection of PATBS in knee OA. PMID- 25036228 TI - Epidemiology of nontraumatic osteonecrosis of the femoral head in Japan. AB - OBJECTIVES: To elucidate the epidemiology of nontraumatic osteonecrosis of the femoral head (ONFH), and to estimate the annual incidence rate in Japan. METHODS: We examined, over the course of 3 years, personal records and radiographic images from the national registry of documents used for the study of nontraumatic ONFH in patients in Aichi Prefecture, Japan (population: 7.4 million). Those patients not meeting the diagnostic criteria according to the Japanese Investigation Committee for nontraumatic ONFH were excluded from this study. RESULTS: A total of 285 out of the 327 patients who applied for the national registration of nontraumatic ONFH during the 3-year study met the diagnostic criteria for personal records, radiographic images, and magnetic resonance images. Forty-two patients (12.8%) were not considered to have nontraumatic ONFH. The mean age of patients was 50.4 years, and the male-female ratio was 2.1:1. Nontraumatic ONFH was steroid-induced in 135 cases (47.4%), alcohol-associated in 87 cases (30.5%), steroid-induced and alcohol- associated in 14 cases (4.9%), and idiopathic in 49 cases (17.2%). CONCLUSIONS: The age-adjusted annual incidence of nontraumatic ONFH in Aichi Prefecture was estimated at 138.5 patients.Thus the annual incidence rate in Japan (population 128 million) was 1.91/100,000. PMID- 25036229 TI - Clinicopathologic characteristics of IgG4-related retroperitoneal fibrosis among patients initially diagnosed as having idiopathic retroperitoneal fibrosis. AB - Abstract Objective. The purpose of our study was to determine the number of IgG4 related retroperitoneal fibrosis (RPF) cases that were initially diagnosed as idiopathic RPF and to investigate clinical characteristics of IgG4-related RPF. Methods. We retrospectively reviewed the medical records of 41 RPF patients who were treated at our tertiary care medical center in South Korea between January 2000 and January 2013. We identified cases of 19 patients in which a diagnosis was made based on percutaneous biopsy or surgery and selected these cases for further analysis. Immunostaining for IgG4 and histopathologic examinations were performed for pathology specimens. Results. In the 19 RPF patients, more than 30 IgG4-positive plasma cells per specimen were identified in 9 cases with dense lymphoplasmacytic infiltrates, storiform fibrosis, or obliterative phlebitis (IgG4-related RPF group). The recurrence rate of IgG4-related RPF was significantly higher than that of idiopathic RPF (67% vs. 10%, p = 0.015). Initial and cumulative steroid dosages were not different between the two groups. Conclusions. We found that 47% of the patients initially diagnosed with idiopathic RPF showed IgG4-related RPF evidence according to the pathology and IgG4-related RPF patients showed higher recurrence rate than idiopathic RPF patients. We suggest that maintenance immunosuppressive therapy is required in IgG4-related RPF patients. PMID- 25036230 TI - (18)F-fluorodeoxy glucose and (18)F fluoride PET for detection of inflammation focus in periprosthetic hip joint infection cases. PMID- 25036231 TI - Autoantibodies against interferon-gamma reduce the frequency of pulmonary fibrosis and concentration of C-reactive protein in patients with primary Sjogren's syndrome. PMID- 25036233 TI - Usefulness of tacrolimus for refractory adult-onset still's disease: Report of six cases. AB - Six patients with refractory adult-onset Still's disease (AOSD) were treated with tacrolimus (TAC). Patient 1 was pregnant, for whom high-dose corticosteroid (CS) monotherapy did not achieve clinical remission, whereas TAC concomitant with CS was successful, and her baby had no apparent abnormalities. Patient 2 had hemophagocytic syndrome (HPS), for whom high-dose CS monotherapy did not achieve clinical remission, whereas TAC improved HPS, and a complete clinical remission was achieved with concomitant administration of TAC and methotrexate (MTX) with CS. Cases 3-5 could not have reduced CS doses due to repeated recurrences and other disease-modifying antirheumatic drugs, including MTX, Cyclosporine A, and tumor necrosis factor alpha inhibitors, did not control disease activity. TAC administration allowed for reduced CS doses. Case 6 experienced adverse effects, and TAC was discontinued due to elevated serum creatinine and potassium levels. TAC was useful for five of six patients, which suggests it as an option for refractory AOSD. PMID- 25036232 TI - Efficacy and safety of abatacept in routine care of patients with rheumatoid arthritis: Orencia((r)) as Biological Intensive Treatment for RA (ORBIT) study. AB - OBJECTIVE: To investigate the efficacy and safety of abatacept for treating patients with rheumatoid arthritis (RA) in routine clinical practice. METHODS: We performed a retrospective study of 137 RA patients who were treated with abatacept for 24 weeks between October 2010 and June 2011 at four rheumatology centers in Japan. Outcomes were compared between biologic-naive and biologic experienced patients. Disease activity was assessed using the Simplified Disease Activity Index (SDAI) and the 28-joint Disease Activity Score based on the erythrocyte sedimentation rate (DAS28-ESR). RESULTS: The retention rate of abatacept at 24 weeks was 79.6%. SDAI (from 24.6 +/- 12.5 to 12.9 +/- 11.6) and DAS28-ESR (from 5.2 +/- 1.4 to 3.9 +/- 1.4) decreased significantly from baseline to Week 24 (both P < 0.001). Remission/low disease activity were achieved in 2.2%/11.2% (SDAI) and in 5.3%/2.3% (DAS28-ESR). The change in SDAI and the remission/low disease activity rates at Week 24 was greater in biologic-naive patients than in biologic-experienced patients. Structural remission (van der Heijde-modified total Sharp score <= 0.5) was achieved by 63.4% of patients. CONCLUSIONS: The present results confirm that abatacept is effective in routine clinical practice and support its use as the first-line biologic agent in patients. PMID- 25036234 TI - Erythematosus plaques with macrophage infiltration as an initial manifestation of macrophage activation syndrome in a patient with systemic lupus erythematosus. AB - The diagnosis of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) may be challenging as it can mimic the clinical features of the underlying disease or be confused with an infectious complication. In this report, a Japanese woman in her forties had diverse clinical features of MAS at initial presentation of SLE, where erythematosus plaques with histiocytic infiltrates focally surrounding degenerated collagen might be the earliest indicator of MAS. PMID- 25036235 TI - Relationship of complement activation route with clinical manifestations in Japanese patients with systemic lupus erythematosus: a retrospective observational study. AB - OBJECTIVES: To assess the relationship between the complement activation route and clinical manifestations in systemic lupus erythematosus (SLE). METHODS: Patients with SLE in whom complement activation occurred were divided into two groups: those in whom the complement system was mainly activated through the classical pathway (low serum C3 and C4 levels; CP group); and those in whom the complement system was solely activated through the alternative pathway (low serum C3 with normal C4 levels; AP group). Clinical manifestations were compared between the groups. RESULTS: The CP group had higher frequencies of arthritis, serositis, and nephritis, and a higher prevalence of anti-DNA antibodies compared to the AP group (arthritis: 50.0% vs. 13.0%, p = 0.0014; serositis: 37.5% vs. 13.0%, p = 0.0257; nephritis: 63.6% vs. 21.7%, p = 0.0003; anti-DNA antibodies: 73.9% vs. 30.4%, p = 0.0001). In contrast, the AP group had a higher frequency of anti-phospholipid (anti-PL) antibodies and a higher prevalence of antiphospholipid syndrome (APS) (anti-PL antibodies: 70.6% vs. 37.3%, p = 0.0136; APS: 39.1% vs. 5.7%, p < 0.0001). CONCLUSIONS: Our results suggest that a different complement system mechanism may act in the pathogenesis of APS in patients with SLE. PMID- 25036236 TI - [Hereditary predisposition to cancers of the digestive tract, breast, gynecological and gonadal: focus on the Peutz-Jeghers]. AB - Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease due to mutations in the tumor suppressor gene STK11. PJS is characterized by periorificial hyperpigmented macules (lentiginosis) and hamartomatous polyposis. Polyps can be located anywhere in the gastrointestinal tract, but are preferably observed in the small bowel (70-90%), the colon (50%) and the stomach (25%). They tend to be cancerous in a particular sequence hamartoma-dysplasia-cancer. The diagnosis is often made in the first or second decade following the appearance of lentigines or upon the occurrence of complications due to polyps (obstruction, intussusception, occult bleeding responsible for anemia). Furthermore PJS is associated with a significant increase in cancer risk (relative risk of 89% over the life according to the most recent series). Digestive cancers are the more frequent with cumulative incidences of 55% for gastro-intestinal cancer (39% for colorectal cancer, 13% for small bowel cancer and between 11 and 36% for pancreatic cancer, respectively). There is also an increased risk of non digestive cancers. In particular the risk of breast cancer is similar to that of patients carrying deleterious BRCA1 or BRCA2 mutations (cumulative incidence of 45%). Gynecological and gonadal tumors are frequent as well and can be more (adenoma malignum) or less aggressive (ovarian sex cord tumors with annular tubules and testicular tumors with calcified Sertoli cells). Finally the frequency of lung cancer is moderately increased. Recommendations for screening and management based on retrospective series in the literature have led to various strategies. The aim of this paper is to summarize the clinical and molecular diagnostic criteria of PJS as well as recommendations on screening strategies, management and monitoring. PMID- 25036238 TI - Environmentally persistent free radicals (EPFRs). 3. Free versus bound hydroxyl radicals in EPFR aqueous solutions. AB - Additional experimental evidence is presented for in vitro generation of hydroxyl radicals because of redox cycling of environmentally persistent free radicals (EPFRs) produced after adsorption of 2-monochlorophenol at 230 degrees C (2-MCP 230) on copper oxide supported by silica, 5% Cu(II)O/silica (3.9% Cu). A chemical spin trapping agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), in conjunction with electron paramagnetic resonance (EPR) spectroscopy was employed. Experiments in spiked O(17) water have shown that ~15% of hydroxyl radicals formed as a result of redox cycling. This amount of hydroxyl radicals arises from an exogenous Fenton reaction and may stay either partially trapped on the surface of particulate matter (physisorbed or chemisorbed) or transferred into solution as free OH. Computational work confirms the highly stable nature of the DMPO-OH adduct, as an intermediate produced by interaction of DMPO with physisorbed/chemisorbed OH (at the interface of solid catalyst/solution). All reaction pathways have been supported by ab initio calculations. PMID- 25036239 TI - Commentary for Clancy, P et al., ARBs and ERK activation: new insights on human atherosclerosis. PMID- 25036241 TI - Detecting gas molecules via atomic magnetization. AB - Adsorptions of gas molecules were found to alter the directions and magnitudes of magnetic moments of transition metal (Co, Fe) atoms adsorbed on graphene. Using first-principles calculations, we demonstrated that magnetism of surface atoms can be used to identify the kind of existing gas molecules via spin-reorientation and/or demagnetizations caused by the reconfigurations of 3d electron energy levels of Co and Fe. We suggest for the first time that magnetic properties of transition metal-embedded nanostructures can be used in highly selective gas sensing applications. PMID- 25036240 TI - Cationic peptides neutralize Ox-LDL, prevent its uptake by macrophages, and attenuate inflammatory response. AB - OBJECTIVE: Apolipoprotein A1 (ApoA1) and apolipoprotein E (ApoE) mimetic peptides have attracted attention due to their ability to reduce atherosclerosis and exhibit antioxidant, anti-inflammatory, and hypolipidemic properties. In this study, we tested whether three distinct and unrelated cationic peptides would inhibit the oxidation of lipoproteins and whether they would counteract and neutralize the negatively charged modified lipoproteins, inhibit their uptake and inflammation by macrophages. METHODS AND RESULTS: 5F-mimetic peptide of ApoA1, LL27 derived from the anti-microbial peptide hCAP, and a human glycodelin derived peptide were commercially synthesized. We noted that these three distinct cationic lysine-rich peptides, two of which were unrelated to any known apolipoproteins, inhibited copper-mediated oxidation of lipoproteins and reduced lipid peroxides in a lysine dependent manner. The peptides also retarded the electrophoretic mobility of previously oxidized LDL and acetylated LDL by virtue of their net positive charge. Pre-incubation of peptides with modified lipoproteins reduced the uptake of the latter by macrophages, thus preventing the formation of foam cells. The cationic peptides inhibited oxidized LDL (Ox-LDL) induced inflammatory response both in vitro and in vivo. CONCLUSION: Based on these results, we suggest that in addition to the well known mimetic peptides, other suitable cationic peptides may be of use for controlling Ox-LDL mediated inflammation and atherosclerotic progression. PMID- 25036242 TI - Diagnosis and management of functional constipation: a common pediatric problem. AB - : Constipation may be functional, anatomic, neurologic, obstructive, endocrine, metabolic, or medicinal. This article will review the common presentation of functional constipation, diagnostic criteria, treatment, and management guidelines in pediatric primary care. Implications for nurse practitioners and directions for future research will be discussed. PMID- 25036243 TI - 2014 national conference for nurse practitioners: success in Chicago. PMID- 25036244 TI - Diagnosis and management of acetabular dysplasia in the primary care setting. PMID- 25036245 TI - Adult acne: overview and case study. PMID- 25036246 TI - Maximizing reimbursement: what nurse practitioners need to know. PMID- 25036247 TI - Antibiotic-resistant pathogens: a future at risk. PMID- 25036250 TI - Recognizing pediatric sleep apnea. AB - Obstructive sleep apnea is a common condition in childhood and has a significant impact on health, learning, academic performance, and quality of life. The purpose of this article is to review the epidemiology, etiology, risk factors, clinical presentation, diagnostic procedures, and treatment of obstructive sleep apnea. PMID- 25036251 TI - Transradial vascular access: a growing trend. AB - The transradial route for coronary angiography is a growing trend in the United States. Nurse practitioners (NPs) are an essential part of the preprocedural assessment and management of patients. This article will outline the benefits and risks of transradial access as well as methods for NPs to assess arterial hand circulation. PMID- 25036254 TI - Calcium sensing receptor activation by calcimimetic R-568 in human amniotic fluid mesenchymal stem cells: correlation with osteogenic differentiation. AB - Human amniotic fluid mesenchymal stem cells (hAFMSCs) are promising for therapeutic applications in bone damage. Calcium sensing receptor (CaSR), a G protein-coupled receptor, plays a physiological role in the regulation of bone metabolism. Thus, the bone CaSR could be targeted by calcimimetic agonists, which may be potentially helpful in treating bone diseases. The aim of our study was to characterize CaSR expression in hAFMSCs and to assess the activity of calcimimetic R-568 during in vitro osteogenesis. Using western blotting, immunofluorescence, and flow cytometry, we consistently observed constitutive CaSR in osteo-differentiating hAFMSCs. Notably, both R-568 and calcium significantly enhanced hAFMSC osteogenic differentiation after exposure to osteogenic medium. To provide further evidence of the involvement of CaSR in osteogenesis, we correlated its expression with that of established osteogenic markers, that is, alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteopontin (OPN), and novel, not yet completely defined regulators of osteogenesis. Among these are beta-catenin and Slug, which are mediators of Wnt signaling, and nuclear factor of activated T cells c1 (NFATc1), which plays a critical role in calcium/calcineurin signaling. Taken together, our results demonstrate that CaSR is expressed in hAFMSCs, positively correlates with osteogenic markers, and is activated by R-568. Notably, downregulation of CaSR by RNA interference supports the conclusion that CaSR activation plays a central role in hAFMSC osteogenesis. Thus, this study provides significant information on the mechanisms of hAFMSC osteogenesis, which could provide additional molecular basis for the use of calcimimetics in bone regenerative medicine. PMID- 25036259 TI - Molecular metal catalysts on supports: organometallic chemistry meets surface science. AB - Recent advances in the synthesis and characterization of small, essentially molecular metal complexes and metal clusters on support surfaces have brought new insights to catalysis and point the way to systematic catalyst design. We summarize recent work unraveling effects of key design variables of site-isolated catalysts: the metal, metal nuclearity, support, and other ligands on the metals, also considering catalysts with separate, complementary functions on supports. The catalysts were synthesized with the goal of structural simplicity and uniformity to facilitate incisive characterization. Thus, they are essentially molecular species bonded to porous supports chosen for their high degree of uniformity; the supports are crystalline aluminosilicates (zeolites) and MgO. The catalytic species are synthesized in reactions of organometallic precursors with the support surfaces; the precursors include M(L)2(acetylacetonate)1-2, with M = Ru, Rh, Ir, or Au and the ligands L = C2H4, CO, or CH3. Os3(CO)12 and Ir4(CO)12 are used as precursors of supported metal clusters, and some such catalysts are made by ship-in-a-bottle syntheses to trap the clusters in zeolite cages. The simplicity and uniformity of the supported catalysts facilitate precise structure determinations, even in reactive atmospheres and during catalysis. The methods of characterizing catalysts in reactive atmospheres include infrared (IR), extended X-ray absorption fine structure (EXAFS), X-ray absorption near edge structure (XANES), and nuclear magnetic resonance (NMR) spectroscopies, and complementary methods include density functional theory and atomic-resolution aberration corrected scanning transmission electron microscopy for imaging of individual metal atoms. IR, NMR, XANES, and microscopy data demonstrate the high degrees of uniformity of well-prepared supported species. The characterizations determine the compositions of surface metal complexes and clusters, including the ligands and the metal-support bonding and structure, which identify the supports as ligands with electron-donor properties that influence reactivity and catalysis. Each of the catalyst design variables has been varied independently, illustrated by mononuclear and tetranuclear iridium on zeolite HY and on MgO and by isostructural rhodium and iridium (diethylene or dicarbonyl) complexes on these supports. The data provide examples resolving the roles of the catalyst design variables and place the catalysis science on a firm foundation of organometallic chemistry linked with surface science. Supported molecular catalysts offer the advantages of characterization in the absence of solvents and with surface science methods that do not require ultrahigh vacuum. Families of supported metal complexes have been made by replacement of ligands with others from the gas phase. Spectroscopically identified catalytic reaction intermediates help to elucidate catalyst performance and guide design. The methods are illustrated for supported complexes and clusters of rhodium, iridium, osmium, and gold used to catalyze reactions of small molecules that facilitate identification of the ligands present during catalysis: alkene dimerization and hydrogenation, H-D exchange in the reaction of H2 with D2, and CO oxidation. The approach is illustrated with the discovery of a highly active and selective MgO-supported rhodium carbonyl dimer catalyst for hydrogenation of 1,3-butadiene to give butenes. PMID- 25036253 TI - Non-canonical roles for Yorkie and Drosophila Inhibitor of Apoptosis 1 in epithelial tube size control. AB - Precise control of epithelial tube size is critical for organ function, yet the molecular mechanisms remain poorly understood. Here, we examine the roles of cell growth and a highly conserved organ growth regulatory pathway in controlling the dimensions of the Drosophila tracheal (airway) system, a well-characterized system for investigating epithelial tube morphogenesis. We find that tracheal tube-size is regulated in unexpected ways by the transcription factor Yorkie (Yki, homolog of mammalian YAP and TAZ) and the Salvador/Warts/Hippo (SWH) kinase pathway. Yki activity typically promotes cell division, inhibits apoptosis, and can promote cell growth. However, reducing Yki activity in developing embryos increases rather than decreases the length of the major tracheal tubes, the dorsal trunks (DTs). Similarly, reduction of Hippo pathway activity, which antagonizes Yki, shortens tracheal DTs. yki mutations do not alter DT cell volume or cell number, indicating that Yki and the Hippo pathway regulate cell shape and apical surface area, but not volume. Yki does not appear to act through known tracheal pathways of apical extracellular matrix, septate junctions (SJs), basolateral or tubular polarity. Instead, the Hippo pathway and Yki appear to act downstream or in parallel to SJs because a double mutant combination of an upstream Hippo pathway activator, kibra, and the SJ component sinu have the short tracheal phenotype of a kibra mutant. We demonstrate that the critical target of Yki in tube size control is Drosophila Inhibitor of Apoptosis 1 (DIAP1), which in turn antagonizes the Drosophila effector caspase, Ice. Strikingly, there is no change in tracheal cell number in DIAP1 or Ice mutants, thus epithelial tube size regulation defines new non-apoptotic roles for Yki, DIAP1 and Ice. PMID- 25036260 TI - Impact of implementing ISO 9001:2008 standard on the Spanish Renal Research Network biobank sample transfer process. AB - BACKGROUND: Biobank certification ISO 9001:2008 aims to improve the management of processes performed. This has two objectives: customer satisfaction and continuous improvement. This paper presents the impact of certification ISO 9001:2008 on the sample transfer process in a Spanish biobank specialising in kidney patient samples. The biobank experienced a large increase in the number of samples between 2009 (12,582 vials) and 2010 (37,042 vials). METHODS: The biobank of the Spanish Renal Research Network (REDinREN), located at the University of Alcalá, has implemented ISO standard 9001:2008 for the effective management of human material given to research centres. Using surveys, we analysed two periods in the “sample transfer” process. During the first period between 1-10-12 and 26-11-12 (8 weeks), minimal changes were made to correct isolated errors. In the second period, between 7-01-13 and 18-02-13 (6 weeks), we carried out general corrective actions. RESULTS: The identification of problems and implementation of corrective actions for certification allowed: a 70% reduction in the process execution time, a significant increase (200%) in the number of samples processed and a 25% improvement in the process. The increase in the number of samples processed was directly related to process improvement. CONCLUSION: The certification of ISO standard 9001:2008, obtained in July 2013, allowed an improvement of the REDinREN biobank processes to be achieved, which increased quality and customer satisfaction. PMID- 25036261 TI - Heparin-induced thrombocytopenia in haemodialysis treated with argatroban. AB - We present the case of a patient diagnosed with likely immune heparin-induced thrombocytopenia (HIT II) based on clinical criteria and a positive ELISA test, in which emergency treatment was crucial, given the seriousness of the process. The discontinuation of heparin and administration of argatroban resolved inefficiency of dialysis resulting from repeated coagulation of the circuit and catheter, allowing peritoneal dialysis without further setbacks. We consider decision-making to be a priority before certifying diagnostic confidence. PMID- 25036262 TI - Cardiovascular mortality: how can it be prevented? AB - The first step in the prevention and treatment of many chronic diseases such as cardiovascular diseases is to follow a healthy diet. Several epidemiological studies have observed that following a traditional Mediterranean diet reduces overall and cardiovascular mortality, as well as the incidence of chronic diseases such as cardiovascular diseases, cancer and neurodegenerative diseases. However, up to now, only one study has analysed the effects of the Mediterranean diet on the primary prevention of cardiovascular disease, the PREDIMED (PREvención con DIeta MEDiterránea) study. This trial included 7447 high vascular risk individuals who were randomly divided into three dietary intervention groups: Mediterranean diet supplemented with extra-virgin olive oil, Mediterranean diet supplemented with nuts, and a control diet (low in all types of fat). Analyses of intermediate markers demonstrated beneficial effects of the Mediterranean diet on blood pressure, lipid profile, lipoprotein particles, oxidative stress and inflammation markers and carotid atherosclerosis. However, the most important finding was the 30% reduction in the relative risk of major cardiovascular complications (heart attack, stroke and cardiovascular mortality) in both Mediterranean diet groups compared to those who followed a low-fat diet. The results of the PREDIMED trial demonstrate that a high unsaturated fat, antioxidant and anti-inflammatory diet plan such as the Mediterranean diet is a useful tool in reducing overall mortality and in preventing cardiovascular disease. PMID- 25036263 TI - Impact of the 5008 monitor software update on total convective volume. AB - INTRODUCTION: On-line haemodiafiltration (OL-HDF) is based on the controlled administration of large volumes of replacement ultrapure dialysate to the extracorporeal blood circuit of dialysis. It is currently the most effective technique for eliminating small and large uraemic toxins. Recent studies have observed a direct association between a decrease in mortality and the received convective volume. The latest Fresenius 5008 (5008 CorDiax) monitor software update enables the automation of the replacement volume without requiring total protein and haematocrit values, with the aim of maximising convection. OBJECTIVE: The study’s objective was to evaluate the recent version of the 5008 monitor software, compared to the previous version, on the impact on total convective volume. MATERIAL AND METHOD: We included 63 patients (44 males and 19 females), with a mean age of 65.2 ± 15 years, on OL-HDF. Each patient was analysed in 6 sessions; 3 with the 5008 monitor and 3 with the 5008 CorDiax monitor. The replacement volume, total convective volume and dialysis parameters were determined in each session. RESULTS: No significant differences were observed in blood, venous or transmembrane pressure, nor was there an increase in the number of alarms or coagulation of lines or dialysers. A significant increase of replacement fluid volume, from 27.2 to 31.2 L/session, was observed using the CorDiax software. Total convective volume increased from 29.5 to 33.3 L/session, representing an effective convective volume increase from 26 % to 29.6 % of total filtered blood. CONCLUSION: The 5008 dialysis monitor software update has meant a 13 % increase of total convective volume and a 3.5 % increase of total filtered blood. PMID- 25036264 TI - Recommendations for vaccination against pneumococcus in kidney patients in Spain. AB - Invasive pneumococcal disease (IPD) is a serious problem in some risk groups: patients with stage 4 and 5 chronic kidney disease, stage 3 CKD undergoing immunosuppressive treatment, nephrotic syndrome or diabetes. These individuals are more susceptible to infections and more prone to suffering more severe and worsening symptoms. Vaccination is one of the strategies for preventing IPD, although vaccination coverage in this group at present is lower than desired. Currently, there are two vaccinations for adults. The polysaccharide vaccine (PPSV23), used for decades in patients over the age of 2, includes most serotypes (23), but it does not generate immune memory, causing the immune tolerance phenomenon and it does not act on nasopharyngeal colonisation. The conjugate vaccine (VNC13) can be used from infancy until adulthood (advice in patients over 18 years old received approval from the European Medicines Agency in July 2013) and generates a more powerful immune response than PPSV23 against the majority of the 13 serotypes that it includes. The 16 scientific societies most directly associated with the groups at risk of IPD have discussed and drafted a series of vaccination recommendations based on scientific evidence related to pneumococcal vaccination in adults with underlying conditions and pathologies, which are the subject of the document “ CONSENSUS: Pneumococcal vaccination in adults with underlying pathology”. This text sets out the vaccination recommendations for the chronic kidney disease population. PMID- 25036265 TI - Moxonidine modulates cytokine signalling and effects on cardiac cell viability. AB - Regression of left ventricular hypertrophy and improved cardiac function in SHR by the centrally acting imidazoline I1-receptor agonist, moxonidine, are associated with differential actions on circulating and cardiac cytokines. Herein, we investigated cell-type specific I1-receptor (also known as nischarin) signalling and the mechanisms through which moxonidine may interfere with cytokines to affect cardiac cell viability. Studies were performed on neonatal rat cardiomyocytes and fibroblasts incubated with interleukin (IL)-1beta (5 ng/ml), tumor necrosis factor (TNF)-alpha (10 ng/ml), and moxonidine (10(-7) and 10(-5) M), separately and in combination, for 15 min, and 24 and 48 h for the measurement of MAPKs (ERK1/2, JNK, and p38) and Akt activation and inducible NOS (iNOS) expression, by Western blotting, and cardiac cell viability/proliferation and apoptosis by flow cytometry, MTT assay, and Live/Dead assay. Participation of imidazoline I1-receptors and the signalling proteins in the detected effects was identified using imidazoline I1-receptor antagonist and signalling protein inhibitors. The results show that IL-1beta, and to a lower extent, TNF-alpha, causes cell death and that moxonidine protects against starvation- as well as IL 1beta -induced mortality, mainly by maintaining membrane integrity, and in part, by improving mitochondrial activity. The protection involves activation of Akt, ERK1/2, p38, JNK, and iNOS. In contrast, moxonidine stimulates basal and IL-1beta induced fibroblast mortality by mechanisms that include inhibition of JNK and iNOS. Thus, apart from their actions on the central nervous system, imidazoline I1-receptors are directly involved in cardiac cell growth and death, and may play an important role in cardiovascular diseases associated with inflammation. PMID- 25036266 TI - Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle. AB - Taste-sensing type 2 receptors (TAS2Rs) have been implicated in extraoral functions. Airway smooth muscle expresses TAS2Rs and is strongly relaxed by TAS2R agonists. We hypothesised that TAS2R agonists might affect vascular smooth muscle as well. Moreover, the general pharmacological profile of TAS2R agonists, which are used to investigate the functions of TAS2R's, are undefined. The aim of this study was to pharmacologically characterise the effects of five prototype TAS2R agonists in vascular smooth muscle. Responses to the TAS2R agonists were investigated in guinea-pig aorta and taenia coli, mouse aorta (wild-type and caveolin-1-/- mice) and human pulmonary arteries. Chloroquine, denatonium, dextromethorphan, noscapine and quinine, agonists for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, induced strong endothelium-independent relaxations (responses between 82 96% of maximal relaxations) in phenylephrine pre-contracted guinea-pig aorta that persisted in the presence of L-type Ca2+ and KCa1.1-channel blockers. Experiments in guinea-pig taenia coli revealed that denatonium and quinine also inhibited relaxations to phenylephrine, indicating antagonism of alpha-adrenoceptors. Only chloroquine and noscapine mediated relaxations when the guinea pig aorta was pre contracted by U-46619 or PGF2alpha. Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1-/- mice. Chloroquine and noscapine mediated relaxations of human pulmonary arteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the alpha1A adrenoceptor. Notwithstanding whether TAS2Rs are involved or not, TAS2R agonists have profound effects on vascular smooth muscle. Chloroquine and noscapine are of special interest as their effects cannot be accounted for by conventional pathways. PMID- 25036267 TI - Implementing Adolescent Screening, Brief Intervention, and Referral to Treatment (SBIRT) Education in a Pediatric Residency Curriculum. AB - BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care for adolescents as well as adults. In an effort to promote universal SBIRT, the Substance Abuse and Mental Health Services Administration awarded funding to residency programs to develop and implement SBIRT education and training. Our project focused on creating scientifically based, developmentally appropriate strategies and teaching materials for the adolescent age range. This paper describes curriculum development and implementation and presents evaluation data. METHODS: Pediatric and child psychiatry residents were trained. The training consisted of 4 activities: (1) case-based teaching modules, (2) role-play of motivational interviewing and brief interventions, (3) mock interviews with trained adolescents, and (4) supervised "hands-on" screening and brief interventions. Main outcome measures included trainee satisfaction, and SBIRT knowledge, perceived self-efficacy, and self- and observer report of use of the SBIRT algorithm. RESULTS: Among 150 total participants completing the SBIRT training modules, nearly all (92.3%) were satisfied/very satisfied with the training modules. Knowledge accuracy immediately post training was high, but declined significantly by the end of the first residency year, with little change across subsequent years of residency. Confidence ratings also declined over time. Use of the SBIRT algorithm during the Adolescent Medicine rotation was high according to trainee self- and faculty observer report. CONCLUSIONS: We found evidence of training satisfaction, increased confidence in talking to adolescents about substance use, and widespread use of recommended practices immediately following training. Use of a highly structured algorithm to guide practice, and simple, highly structured brief interventions was a successful training approach, as residents self-reported accurate use of the SBIRT algorithm immediately after training. Knowledge and self-confidence declined over time. It is possible that "booster" sessions and ongoing opportunities to review materials could help residents retain knowledge and skills. PMID- 25036268 TI - Transcatheter aortic valve implantation through distal axillary artery: novel option for vascular access. AB - AIMS: We describe an alternative access approach for patients undergoing transcatheter aortic valve implantation (TAVI) using surgical cut down of the distal axillary artery, in cases wherein transfemoral access is not feasible. METHODS: From January 2012 to July 2013, 61 patients (59% men; mean age 81 +/- 8 years) underwent TAVI at our institution. The mean logistic EuroSCORE and EuroSCORE II were 36 +/- 24 and 14 +/- 10, respectively. We assessed device success, 30-day safety and clinical efficacy using VARC II criteria. RESULTS: TAVI was performed with the CoreValve Revalving System (CRS) (Medtronic Inc., Minneapolis, Minnesota, USA) in all cases, using transfemoral approach in 57 patients and distal trans-axillary route in four patients. A device was successfully implanted in 94%, without any major intraprocedural complications. One case of acute kidney disease, four cases of minor vascular complication and two cases of life-threatening bleeding occurred after the procedure for pericardial bleeding requiring pericardiocentesis. Permanent pacemaker was implanted in 26% of patients. There was no instance of in-hospital mortality, while two deaths (3%) occurred in the first 30 days. The total procedure time (skin-to-skin) was longer in the trans-axillary group secondary to surgical management of access site (P = 0.027), whereas revalving and fluoroscopy time were similar (P = 0.95 and P = 0.83, respectively). CONCLUSION: The location and anatomical relations of the distal axillary artery make it a safer, reproducible and operator friendly access option for TAVI. PMID- 25036269 TI - Selection of potential predictors of worsening heart failure: rational and design of the SELENE HF study. AB - BACKGROUND: Heart failure is a leading cause of hospitalization and a significant medical burden in our society. Implantable medical devices are nowadays established therapies in heart failure patients that not only provide cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillators (ICDs) therapy but are also able to continuously and remotely monitor diagnostic information of various physiologic parameters. The value of combining individual diagnostic variables to predict worsening of heart failure is still largely unclear but could eventually become a valuable tool towards a better heart failure management. METHODS: SELENE HF (Selection of potential predictors of worsening Heart Failure) is an observational, multicentre study designed to prospectively collect follow-up and home monitoring data trends from a population of individuals with ICDs with or without resynchronization therapy (CRT-D), to document heart failure hospitalizations and deaths and to correlate these events with Home Monitoring data in order to identify the combination with the greatest sensitivity and specificity in predicting heart failure events.The purpose of this study is to describe the design of the study focusing on the Heart Failure Predicting model and statistical approach that will be used to analyse the data. CONCLUSION: The results of the SELENE HF study could help to select and define potential predictors of worsening heart failure in patients with remotely monitored ICD or CRT-D devices. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01836510. PMID- 25036270 TI - Refractory hyperaldosteronism in heart failure is associated with plasma renin activity and angiotensinogen polymorphism. AB - AIMS: Refractory hyperaldosteronism is frequently observed in heart failure patients on up-to-date treatment, and holds prognostic value. Our aim was to identify which factors, either genetic or nongenetic, are associated with refractory hyperaldosteronism. METHODS: We enrolled 109 consecutive patients with left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) 32 +/- 10%; 86% males; age 65 +/- 13 years (mean +/- standard deviation)] on optimized adrenergic and renin-angiotensin-aldosterone system (RAAS) antagonism, undergoing clinical and neuroendocrine characterization, and genotyping for six polymorphisms in key RAAS-regulating genes [angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE-240A>T and I/D), angiotensin II type I receptor (AGTR1 1166A>C), aldosterone synthase (CYP11B2-344C>T) and renin (REN rs7539596)]. RESULTS: Patients with refractory hyperaldosteronism (n = 41, 38%, with plasma concentration >180 ng/l, URL, median 283 ng/l, interquartile range 218-433), when compared with those without (106 ng/l, 74-144; P < 0.001), were not different either for treatment or LVEF, while presented with different AGT M235T genotype distribution (P = 0.047). After adjustment for several humoral, instrumental, functional and therapeutical variables, only plasma renin activity (PRA) (P < 0.001) and potassium (P = 0.027) were independently associated with refractory hyperaldosteronism. Among polymorphisms, only AGT M235T (P = 0.038) was associated with refractory hyperaldosteronism, after adjustment for nongenetic variables. CONCLUSIONS: In conclusion, refractory hyperaldosteronism in heart failure may be influenced by AGT M235T polymorphism, among RAAS candidate genes, and by PRA, which may represent, respectively, a constitutive (genotype dependent) and a nongenetic (phenotype-dependent) trigger for aldosterone elevation. PMID- 25036271 TI - Restrictive cardiomyopathy and pseudoxanthoma elasticum skin lesions. AB - : We report a rare case of a patient with AL amyloidosis and pseudoxanthoma elasticum skin lesions. An association between these two diseases has been previously described as amyloid elastosis in only six cases, but cardiac findings were not fully elucidated. The peculiarity of our case is that a severe cardiac involvement influenced the prognosis negatively. Furthermore, the electron microscopic examination did not show all the peculiar histopathological findings of amyloid elastosis, precluding a final diagnosis of this disease. PMID- 25036272 TI - Mechanical interference between a closure device and the rigid stent of mitral bioprosthesis: a mechanism for closure device late dislodgement. AB - : We report here the mechanical interference between mitral bioprostheses and devices currently adopted for percutaneous paravalvular leak closure as a possible cause for late dislodgement and embolization of successfully implanted and apparently stable closure devices.The images included in this study demonstrate that the topographical relationship of the target leak with the bioprosthetic valve posts may be a major obstacle for device stability after percutaneous paravalvular leak closure procedures. PMID- 25036273 TI - Dynamic dialysis: an efficient technique for large-volume sample desalting. AB - Dialysis is a well-known technique for laboratory separation. However, its efficiency is commonly restricted by the dialyzer volume and its passive diffusion manner. In addition, the sample is likely to be precipitated and inactive during a long dialysis process. To overcome these drawbacks, a dynamic dialysis method was described and evaluated. The dynamic dialysis was performed by two peristaltic pumps working in reverse directions, in order to drive countercurrent parallel flow of sample and buffer, respectively. The efficiency and capacity of this dynamic dialysis method was evaluated by recording and statistically comparing the variation of conductance from retentate under different conditions. The dynamic method was proven to be effective in dialyzing a large-volume sample, and its efficiency changes proportionally to the flow rate of sample. To sum up, circulating the sample and the buffer creates the highest possible concentration gradient to significantly improve dialysis capacity and shorten dialysis time. PMID- 25036274 TI - The smart aerial release machine, a universal system for applying the sterile insect technique. AB - BACKGROUND: Beyond insecticides, alternative methods to control insect pests for agriculture and vectors of diseases are needed. Management strategies involving the mass-release of living control agents have been developed, including genetic control with sterile insects and biological control with parasitoids, for which aerial release of insects is often required. Aerial release in genetic control programmes often involves the use of chilled sterile insects, which can improve dispersal, survival and competitiveness of sterile males. Currently available means of aerially releasing chilled fruit flies are however insufficiently precise to ensure homogeneous distribution at low release rates and no device is available for tsetse. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the smart aerial release machine, a new design by the Mubarqui Company, based on the use of vibrating conveyors. The machine is controlled through Bluetooth by a tablet with Android Operating System including a completely automatic guidance and navigation system (MaxNav software). The tablet is also connected to an online relational database facilitating the preparation of flight schedules and automatic storage of flight reports. The new machine was compared with a conveyor release machine in Mexico using two fruit flies species (Anastrepha ludens and Ceratitis capitata) and we obtained better dispersal homogeneity (% of positive traps, p<0.001) for both species and better recapture rates for Anastrepha ludens (p<0.001), especially at low release densities (<1500 per ha). We also demonstrated that the machine can replace paper boxes for aerial release of tsetse in Senegal. CONCLUSIONS/SIGNIFICANCE: This technology limits damages to insects and allows a large range of release rates from 10 flies/km2 for tsetse flies up to 600,000 flies/km2 for fruit flies. The potential of this machine to release other species like mosquitoes is discussed. Plans and operating of the machine are provided to allow its use worldwide. PMID- 25036275 TI - Visible-light photocatalyzed cross-linking of diacetylene ligands by quantum dots to improve their aqueous colloidal stability. AB - Ligand cross-linking is known to improve the colloidal stability of nanoparticles, particularly in aqueous solutions. However, most cross-linking is performed chemically, in which it is difficult to limit interparticle cross linking, unless performed at low concentrations. Photochemical cross-linking is a promising approach but usually requires ultraviolet (UV) light to initiate. Using such high-energy photons can be harmful to systems in which the ligand nanoparticle bond is fairly weak, as is the case for the commonly used semiconductor quantum dots (QDs). Here, we introduce a novel approach to cross link thiolated ligands on QDs by utilizing the photocatalytic activity of QDs upon absorbing visible light. We show that using visible light leads to better ligand cross-linking by avoiding the problem of ligand dissociation that occurs upon UV light exposure. Once cross-linked, the ligands significantly enhance the colloidal stability of those same QDs that facilitated cross-linking. PMID- 25036276 TI - Socio-cultural and economic valuation of ecosystem services provided by Mediterranean mountain agroecosystems. AB - The aim of this work was to elucidate the socio-cultural and economic value of a number of ecosystem services delivered by mountain agroecosystems (mostly grazing systems) in Euro-Mediterranean regions. We combined deliberative (focus groups) and survey-based stated-preference methods (choice modelling) to, first, identify the perceptions of farmers and other citizens on the most important ecosystem services and, second, to value these in economic terms according to the willingness to pay of the local (residents of the study area) and general (region where the study area is located) populations. Cultural services (particularly the aesthetic and recreational values of the landscape), supporting services (biodiversity maintenance) and some regulating services (particularly fire risk prevention) were clearly recognized by both farmers and citizens, with different degrees of importance according to their particular interests and objectives. The prevention of forest fires (~50% of total willingness to pay) was valued by the general population as a key ecosystem service delivered by these agroecosystems, followed by the production of specific quality products linked to the territory (~20%), biodiversity (~20%) and cultural landscapes (~10%). The value given by local residents to the last two ecosystem services differed considerably (~10 and 25% for biodiversity and cultural landscape, respectively). The Total Economic Value of mountain agroecosystems was ~120 ? person(-1) year(-1), three times the current level of support of agro-environmental policies. By targeting and quantifying the environmental objectives of the European agri-environmental policy and compensating farmers for the public goods they deliver, the so-called "green" subsidies may become true Payments for Ecosystems Services. PMID- 25036278 TI - CANDLE syndrome: a recently described autoinflammatory syndrome. AB - CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) is a recently described autoinflammatory syndrome characterized by early onset, recurrent fever, skin lesions, and multisystemic inflammatory manifestations. Most of the patients have been shown to have mutation in PSMB8 gene. Herein, we report a 2-year-old patient with young onset recurrent fever, atypical facies, widespread skin lesions, generalized lymphadenopathy, hepatosplenomegaly, joint contractures, hypertrglyceridemia, lipodystrophy, and autoimmune hemolytic anemia. Clinical features together with the skin biopsy findings were consistent with the CANDLE syndrome. The pathogenesis and treatment of this syndrome have not been fully understood. Increased awareness of this recently described syndrome may lead to recognition of new cases and better understanding of its pathogenesis which in turn may help for development of an effective treatment. PMID- 25036277 TI - Gallstones in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. AB - PURPOSE: To determine risk factors for the development of gallstones and the prevalence of related cholecystectomy in children following hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: A retrospective chart review of 1343 patients aged below 18 years old who survived at least 1 year after HCT from 1969 to 2011 was performed. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with gallstones. RESULTS: Gallstones developed in 91 patients, a median of 3.5 (range, 0.1 to 30.9) years after HCT at 16.3 (range, 0.8 to 44.2) years of age, with a 40-year cumulative incidence of 11%. At initial diagnosis, 61 (67%) patients were symptomatic and 30 (23%) had incidental gallstones. Risk factors associated with gallstones included autologous transplant (HR=2.7, P=0.02), unrelated donor (HR=2.0, P=0.05), grade 3 to 4 acute graft-versus-host disease (GVHD) (HR=2.2, P=0.03), chronic GVHD (HR=2.0, P=0.05), second transplant (HR=2.3, P=0.03), diabetes (HR=2.2, P=0.05), and estrogen therapy (HR=1.8, P=0.03). Fifty-six patients underwent cholecystectomy. The prevalence of cholecystectomy among 853 surviving patients was 5.2%. CONCLUSIONS: Childhood HCT patients have an increased risk of developing gallstones. PMID- 25036279 TI - Phospholipid polymer-based antibody immobilization for cell rolling surfaces in stem cell purification system. AB - We previously developed an antibody-conjugated cell rolling column that successfully separates stem cell subpopulations depending on the cell surface marker density, but a large amount of the injected cells were retained in the column because of non-specific interactions. In this study, an amphiphilic copolymer, poly[2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (nBMA)-co-N-vinyl formamide (NVf)], with phospholipid polar side groups was designed as a novel antibody-immobilizing modifier. The formamide groups in NVf units were converted to active maleimide groups. A plastic flow microfluidic chamber was coated with the copolymers, and a reduced anti-CD90 antibody was immobilized. The adipose tissue-derived stem cells isolated from the rat were injected into the flow chamber, and their rolling behavior was observed under a microscope with a high-speed camera. Non-specific cell adhesion was reduced strongly by means of this immobilization method because of the MPC unit, resulting in a high percentage of rolling cells. These results demonstrate that a surface coated with phospholipid polar groups can be used in an effective stem cell separation system based on the cell rolling process. PMID- 25036280 TI - Editorial comment: technology bridges the gap. PMID- 25036282 TI - Fabrication of nitrogen-modified annealed nanodiamond with improved catalytic activity. AB - Annealed ultradispersed nanodiamond (ADD) with sp(2) curved concentric graphitic shells is an interesting hybrid material consisting of the remarkable surface properties of graphene-based nanomaterials and the intrinsic properties of a diamond core. In this case, based on its specific properties and surface oxygen functional groups, nitrogen-modified ADD powders have been tunably synthesized via three different preparation methods in a calcination treatment process. The detailed formation and dynamic behaviors of the nitrogen species on the modified ADD during the preparation process are revealed by elemental analysis, X-ray photoelectron spectroscopy (XPS) and temperature-programmed desorption. Moreover, we study the catalytic performance on the metal-free nitrogen-modified ADD catalysts by means of selective oxidation of benzylic alcohols as a probe reaction. The results indicate that the modified ADD catalysts exhibit a higher catalytic activity than pristine ADD. By correlating XPS data with catalytic measurements, we conclude that the pyridinic nitrogen species plays a pivotal role in the catalytic reaction. Our work provides valuable information on the design of modified carbon materials with more excellent properties. PMID- 25036283 TI - Spinal ultrasound versus palpation for epidural catheter insertion in labour: A randomised controlled trial. AB - BACKGROUND: Ultrasound imaging of the spine is thought to reduce failed and traumatic neuraxial procedures. Most of the evidence supporting this assumption has been produced in the context of an expert sonographer performing the ultrasound assessment, and it remains unknown whether this technique is useful when used by multiple individual operators. OBJECTIVE: To invesstigate the impact of preprocedural spinal ultrasound on the ease of insertion of labour epidurals by a group of trainees. We hypothesised that the ultrasound-assisted technique would improve the ease of insertion when compared with the conventional palpation technique. DESIGN: A randomised controlled trial. SETTING: Academic hospital in Toronto, Canada. PARTICIPANTS AND INTERVENTION: A group of 17 second-year anaesthesia residents and five anaesthesia fellows underwent a training programme in ultrasound assessment of the spine. Parturients with easily palpable lumbar spines were randomised to either ultrasound or palpation group. Residents and fellows performed both the assessment (ultrasound or palpation) and the epidural procedure. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: ease of insertion of epidural catheter composed of the time taken to insert the epidural catheter, number of interspace levels attempted and number of needle passes. SECONDARY OUTCOMES: total procedural time (assessment and insertion); first pass success rate; number of attempts required to thread the epidural catheter; failure of epidural analgesia; and patient satisfaction. RESULTS: We analysed 128 epidural catheter insertions (residents 84, fellows 44). There was no difference in median (interquartile range, IQR) epidural insertion time between the ultrasound and palpation groups [174 (120 to 241) versus 180 (130 to 322.5) s, respectively; P = 0.14]. The number of interspace levels attempted and needle passes were also similar in both groups. The total procedural time was longer in the ultrasound group. CONCLUSION: The use of preprocedural spinal ultrasound by a cohort of anaesthesia trainees did not improve the ease of insertion of labour epidural catheters in patients with easily palpable lumbar spines, as compared with the traditional palpation technique based on anatomical landmarks. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00996905. PMID- 25036284 TI - Mutations in the B30.2 domain of pyrin and the risk of ankylosing spondylitis in the Chinese Han population: a case-control study. AB - Ankylosing spondylitis (AS) and familial Mediterranean fever (FMF) are a common autoimmune disease and a classic autoinflammatory disease, respectively. Mediterranean fever (MEFV) encodes the pyrin protein and is the causal disease gene in FMF. This protein is an important regulator of innate immunity and may play a key role in the development of AS. To identify the mutations in the B30.2 domain of pyrin and to uncover the relationships between these mutations and AS risk in the Chinese Han population, we extracted genomic DNA from the peripheral blood of 200 AS patients and 200 matched controls and performed polymerase chain reactions (PCRs) and direct sequencing on those samples. Statistical analysis indicated that only Met694Val (rs61752717) in the B30.2 domain of pyrin could affect the risk of AS (P = 0.042; odds ratio [OR] = 5.103; 95% confidence interval [CI] = 1.111-23.437 for the model of Met (M) vs. Val (V), P = 0.040; OR = 5.211; 95% CI = 1.127-24.091 for the model of MM vs. MV+VV). Moreover, M694V is significantly associated with a higher level of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in AS patients. Our results are the first to suggest that the M694V allele of the pyrin was associated with AS risk in the Chinese Han population and that this mutation may be associated with the inflammatory response in the development of AS. PMID- 25036285 TI - Gold-plated magnetic polymers for highly specific enrichment and label-free detection of blood biomarkers under physiological conditions. AB - A mass-based label-free detection of blood biomarkers under physiological conditions is realised using gold-plated magnetic polymer microspheres covered with self-assembled monolayers of polyethylene glycol alkanethiolates that effectively prevent heavy nonspecific binding of serum proteins. PMID- 25036286 TI - Beyond the standard model of Ginzburg-Landau theory: multiband superconductors. AB - The recently discovered multiband superconductors have created a new class of novel superconductors. In these materials multiple superconducting gaps arise due to the formation of Cooper pairs on different sheets of the Fermi surfaces. An important feature of these superconductors is the interband couplings, which not only change the individual gap properties, but also create new collective modes. Here we investigate the effect of the interband couplings in the Ginzburg-Landau theory. We produce a general tau((2n + 1)/2) expansion (tau = 1 - T/Tc) and show that this expansion has unexpected behaviour for n ? 2. This point emphasises the weaker validity of the GL theory for lower temperatures and gives credence to the existence of hidden criticality near the critical temperature of the uncoupled subdominant band. We apply this theory to a range of material parameters fitted to experimental measurements and find that for some cases the theory performs very well at all temperatures, but for other materials the range of applicability can be very limited. PMID- 25036287 TI - Antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1 tosylpyrazole. A Celecoxib structural analog in models of pathological pain. AB - Pain is the most common complaint in the medical field and the identification of novel compounds that can effectively treat painful states without causing side effects remains a major challenge in biomedical research. The aim of the present study is to investigate the antinociceptive effect of 3-(4-fluorophenyl)-5 trifluoromethyl-1H-1-tosylpyrazole (FTosPz) in models of pathological pain in mice and compare these effects with those produced by Celecoxib. FTosPz (100-500 MUmol/kg) or Celecoxib (26-260 MUmol/kg) was administrated orally. The administration of either FTosPz or Celecoxib reduced the hyperalgesia but not the edema or leukocyte infiltration that was caused by Complete Freund's Adjuvant (CFA), used as an arthritis model. Oral administration of both FTosPz and Celecoxib also attenuated the postoperative hyperalgesia as well as the hyperalgesia caused by partial sciatic nerve ligation, used as a neuropathic pain model. FTosPz and Celecoxib produced antinociceptive effects without altering the locomotor activity of animals. Furthermore, FTosPz neither altered AST/ALT enzyme activity nor the urea/creatinine levels. Still, the FTosPz did not alter the COX 1 and COX-2 enzyme activities. Thus, FTosPz is an interesting prototype for the development of novel analgesic drugs. PMID- 25036288 TI - Pathways for virus assembly around nucleic acids. AB - Understanding the pathways by which viral capsid proteins assemble around their genomes could identify key intermediates as potential drug targets. In this work, we use computer simulations to characterize assembly over a wide range of capsid protein-protein interaction strengths and solution ionic strengths. We find that assembly pathways can be categorized into two classes, in which intermediates are either predominantly ordered or disordered. Our results suggest that estimating the protein-protein and the protein-genome binding affinities may be sufficient to predict which pathway occurs. Furthermore, the calculated phase diagrams suggest that knowledge of the dominant assembly pathway and its relationship to control parameters could identify optimal strategies to thwart or redirect assembly to block infection. Finally, analysis of simulation trajectories suggests that the two classes of assembly pathways can be distinguished in single molecule fluorescence correlation spectroscopy or bulk time-resolved small-angle X-ray scattering experiments. PMID- 25036290 TI - CYP2C19 polymorphisms account for inter-individual variability of drug metabolism in cynomolgus macaques. AB - CYP2C19 (formerly known as CYP2C75), highly homologous to human CYP2C19, has been identified in cynomolgus and rhesus macaques, non-human primate species widely used in drug metabolism studies. CYP2C19 is predominantly expressed in liver and encodes a functional drug-metabolizing enzyme. Genetic variants in human CYP2C genes account for the inter-individual variability in drug metabolism; however, genetic variants have not been investigated in macaque CYP2C19. In the present study, re-sequencing of CYP2C19 in 78 cynomolgus and 36 rhesus macaques identified 34 non-synonymous variants. Among these, 6 were located in substrate recognition sites, the domains important for protein function. Eighteen and 6 variants were unique to cynomolgus and rhesus macaques, respectively. Four variants were characterized by site-directed mutagenesis and metabolic assays, and 3 variants (p.Phe100Asn, p.Ala103Val, and p.Ile112Leu) showed substantially reduced activity as compared with wild type in flurbiprofen 4'-hydroxylation, omeprazole 5-hydroxylation, and R-/S-warfarin 7-hydroxylation. These variants, co segregating in the animals analyzed, influenced metabolic activities because the homozygotes and/or heterozygotes showed significantly reduced catalytic activities in liver toward flurbiprofen 4'-hydroxylation and omeprazole 5 hydroxylation as compared with wild type. Kinetic analysis for R-warfarin 7 hydroxylation and docking simulation indicated that CYP2C19 Ala103Val would change the function and conformation of this enzyme. Ala103Val variation diminished homotropic cooperativity of CYP2C19 with R-warfarin yielding low metabolic capacity. These results indicated that the interindividual variability of CYP2C-dependent drug metabolism is at least partly accounted for by CYP2C19 variants in cynomolgus macaques. PMID- 25036289 TI - Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. AB - Immunoglobulin G (IgG) is a central mediator of host defense due to its ability to recognize and eliminate pathogens. The recognition and effector responses are encoded on distinct regions of IgGs. The diversity of the antigen recognition Fab domains accounts for IgG's ability to bind with high specificity to essentially any antigen. Recent studies have indicated that the Fc effector domain also displays considerable heterogeneity, accounting for its complex effector functions of inflammation, modulation, and immune suppression. Therapeutic anti tumor antibodies, for example, require the pro-inflammatory properties of the IgG Fc to eliminate tumor cells, while the anti-inflammatory activity of intravenous IgG requires specific Fc glycans for activity. In particular, the anti inflammatory activity of intravenous IgG is ascribed to a small population of IgGs in which the Asn297-linked complex N-glycans attached to each Fc CH2 domain include terminal alpha2,6-linked sialic acids. We used chemoenzymatic glycoengineering to prepare fully disialylated IgG Fc and solved its crystal structure. Comparison of the structures of asialylated Fc, sialylated Fc, and F241A Fc, a mutant that displays increased glycan sialylation, suggests that increased conformational flexibility of the CH2 domain is associated with the switch from pro-inflammatory to anti-inflammatory activity of the Fc. PMID- 25036292 TI - Vertical ionization energies of free radicals and electron detachment energies of their anions: a comparison of direct and indirect methods versus experiment. AB - The performance of several direct and indirect computational strategies for the calculation of the first ionization energies (IEs) of free radicals and adiabatic detachment energies of their anions has been tested using experimental data as references. The outer valence Green's function and the partial third-order approximations, which are based on electron propagator theory, have been identified as the most accurate. They were in turn used to estimate the IEs of a large set of free radicals for which these data have not been previously reported. The calculated data also have been used to assess the possible oxidation of nucleosides by these radicals, as well as the potential, antioxidant protection effects of phenol, catechol, ascorbic acid, and Trolox in their neutral and deprotonated forms, via electron transfer. PMID- 25036291 TI - Factors associated with four or more antenatal care visits and its decline among pregnant women in Tanzania between 1999 and 2010. AB - In Tanzania, the coverage of four or more antenatal care (ANC 4) visits among pregnant women has declined over time. We conducted an exploratory analysis to identify factors associated with utilization of ANC 4 and ANC 4 decline among pregnant women over time. We used data from 8035 women who delivered within two years preceding Tanzania Demographic and Health Surveys conducted in 1999, 2004/05 and 2010. Multivariate logistic regression models were used to examine the association between all potential factors and utilization of ANC 4; and decline in ANC 4 over time. Factors positively associated with ANC 4 utilization were higher quality of services, testing and counseling for HIV during ANC, receiving two or more doses of SP (Sulphadoxine Pyrimethamine)/Fansidar for preventing malaria during ANC and higher educational status of the woman. Negatively associated factors were residing in a zone other than Eastern zone, never married woman, reported long distance to health facility, first ANC visit after four months of pregnancy and woman's desire to avoid pregnancy. The factors significantly associated with decline in utilization of ANC 4 were: geographic zone and age of the woman at delivery. Strategies to increase ANC 4 utilization should focus on improvement in quality of care, geographic accessibility, early ANC initiation, and services that allow women to avoid pregnancy. The interconnected nature of the Tanzanian Health System is reflected in ANC 4 decline over time where introduction of new programs might have had unintended effects on existing programs. An in-depth assessment of the recent policy change towards Focused Antenatal Care and its implementation across different geographic zones, including its effect on the perception and understanding among women and performance and counseling by health providers can help explain the decline in ANC 4. PMID- 25036294 TI - Encoding methods for B1(+) mapping in parallel transmit systems at ultra high field. AB - Parallel radiofrequency (RF) transmission, either in the form of RF shimming or pulse design, has been proposed as a solution to the B1(+) inhomogeneity problem in ultra high field magnetic resonance imaging. As a prerequisite, accurate B1(+) maps from each of the available transmit channels are required. In this work, four different encoding methods for B1(+) mapping, namely 1-channel-on, all channels-on-except-1, all-channels-on-1-inverted and Fourier phase encoding, were evaluated using dual refocusing acquisition mode (DREAM) at 9.4 T. Fourier phase encoding was demonstrated in both phantom and in vivo to be the least susceptible to artefacts caused by destructive RF interference at 9.4 T. Unlike the other two interferometric encoding schemes, Fourier phase encoding showed negligible dependency on the initial RF phase setting and therefore no prior B1(+) knowledge is required. Fourier phase encoding also provides a flexible way to increase the number of measurements to increase SNR, and to allow further reduction of artefacts by weighted decoding. These advantages of Fourier phase encoding suggest that it is a good choice for B1(+) mapping in parallel transmit systems at ultra high field. PMID- 25036293 TI - Ultrashort echo time (UTE) imaging using gradient pre-equalization and compressed sensing. AB - Ultrashort echo time (UTE) imaging is a well-known technique used in medical MRI, however, the implementation of the sequence remains non-trivial. This paper introduces UTE for non-medical applications and outlines a method for the implementation of UTE to enable accurate slice selection and short acquisition times. Slice selection in UTE requires fast, accurate switching of the gradient and r.f. pulses. Here a gradient "pre-equalization" technique is used to optimize the gradient switching and achieve an effective echo time of 10MUs. In order to minimize the echo time, k-space is sampled radially. A compressed sensing approach is used to minimize the total acquisition time. Using the corrections for slice selection and acquisition along with novel image reconstruction techniques, UTE is shown to be a viable method to study samples of cork and rubber with a shorter signal lifetime than can typically be measured. Further, the compressed sensing image reconstruction algorithm is shown to provide accurate images of the samples with as little as 12.5% of the full k-space data set, potentially permitting real time imaging of short T2(*) materials. PMID- 25036295 TI - Anomalous behavior of control pulses in presence of noise with singular autocorrelation. AB - We report on the anomalous behavior of control pulses for spins under spin-spin relaxation and subject to classical noise with a singular autocorrelation function. This behavior is not detected for noise with analytic autocorrelation functions. The effect is manifest in the different scaling behavior of the deviation of a real pulse to the ideal, instantaneous one. While a standard pulse displays scaling ?taup(1), a first-order refocusing pulse normally shows scaling ?taup(2). But in presence of cusps in the noise autocorrelation the scaling ?taup(3/2) occurs. Cusps in the autocorrelation are characteristic for fast fluctuations in the noise with a spectral density of Lorentzian shape. We prove that the anomalous exponent cannot be avoided; it represents a fundamental limit. On the one hand, this redefines the strategies one has to adopt to design refocusing pulses. On the other hand, the anomalous exponent, if found in experiment, provides important information on the noise properties. PMID- 25036296 TI - Visualizing skin effects in conductors with MRI: (7)Li MRI experiments and calculations. AB - While experiments on metals have been performed since the early days of NMR (and DNP), the use of bulk metal is normally avoided. Instead, often powders have been used in combination with low fields, so that skin depth effects could be neglected. Another complicating factor of acquiring NMR spectra or MRI images of bulk metal is the strong signal dependence on the orientation between the sample and the radio frequency (rf) coil, leading to non-intuitive image distortions and inaccurate quantification. Such factors are particularly important for NMR and MRI of batteries and other electrochemical devices. Here, we show results from a systematic study combining rf field calculations with experimental MRI of (7)Li metal to visualize skin depth effects directly and to analyze the rf field orientation effect on MRI of bulk metal. It is shown that a certain degree of selectivity can be achieved for particular faces of the metal, simply based on the orientation of the sample. By combining rf field calculations with bulk magnetic susceptibility calculations accurate NMR spectra can be obtained from first principles. Such analyses will become valuable in many applications involving battery systems, but also metals, in general. PMID- 25036297 TI - Efficient synthesis of polysubstituted olefins using stable palladium nanocatalyst: applications in synthesis of tamoxifen and isocombretastatin A4. AB - A phosphine-free stable palladium nanocatalyst was used for an efficient synthesis of polysubstituted olefins from N-tosylhydrazones and aryl iodides. This methodology was successfully utilized in the synthesis of biologically important tamoxifen and isocombretastatin A4. The nanocatalyst was easily recovered and reused without any apparent loss in size and catalytic activity. PMID- 25036299 TI - Microbiota meet big data. PMID- 25036298 TI - Prenatal cocaine exposure differentially affects stress responses in girls and boys: associations with future substance use. AB - Prenatal cocaine exposure may affect developing stress response systems in youth, potentially creating risk for substance use in adolescence. Further, pathways from prenatal risk to future substance use may differ for girls versus boys. The present longitudinal study examined multiple biobehavioral measures, including heart rate, blood pressure, emotion, and salivary cortisol and salivary alpha amylase (sAA), in response to a stressor in 193 low-income 14- to 17-year-olds, half of whom were prenatally cocaine exposed (PCE). Youth's lifetime substance use was assessed with self-report, interview, and urine toxicology/breathalyzer at Time 1 and at Time 2 (6-12 months later). PCE * Gender interactions were found predicting anxiety, anger, and sadness responses to the stressor, with PCE girls showing heightened responses as compared to PCE boys on these indicators. Stress Response * Gender interactions were found predicting Time 2 substance use in youth (controlling for Time 1 use) for sAA and sadness; for girls, heightened sadness responses predicted substance use, but for boys, dampened sAA responses predicted substance use. Findings suggest distinct biobehavioral stress response risk profiles for boys and girls, with heightened arousal for girls and blunted arousal for boys associated with prenatal risk and future substance use outcomes. PMID- 25036308 TI - Allostery: A GPCR's back door. PMID- 25036309 TI - Natural products: Sponge symbionts play defense. PMID- 25036314 TI - Numerical magnitude processing deficits in children with mathematical difficulties are independent of intelligence. AB - Developmental dyscalculia (DD) is thought to arise from difficulties in the ability to process numerical magnitudes. Most research relied on IQ-discrepancy based definitions of DD and only included individuals with normal IQ, yet little is known about the role of intelligence in the association between numerical magnitude processing and mathematical difficulties (MD). The present study examined numerical magnitude processing in matched groups of 7- to 8-year-olds (n=42) who had either discrepant MD (poor math scores, average IQ), nondiscrepant MD (poor math scores, below-average IQ) or no MD. Both groups of children with MD showed similar impairments in numerical magnitudes processing compared to controls, suggesting that the association between numerical magnitude processing deficits and MD is independent of intelligence. PMID- 25036315 TI - Decreasing excessive functional communication responses while treating destructive behavior using response restriction. AB - Functional communication training (FCT) is an established treatment for destructive behavior that missucceeds in about 37% of cases when the reinforcement schedule for the functional communication response (FCR) is thinned using multiples schedules (mult FCT; Hagopian, Boelter, & Jarmolowicz, 2011). In this investigation, we evaluated the use of response restriction FCT (RR FCT) in a cohort of patients with poorly differentiated responding of the FCR during mult FCT. Results showed that (a) RR FCT maintained high rates of correct FCRs during the reinforcement component of RR FCT without increasing destructive behavior; (b) children displayed highly discriminated FCRs when an FCR card and a control card were simultaneously available during the reinforcement component of RR FCT; and (c) near-zero rates of destructive behavior were observed during the last five sessions of the terminal reinforcement schedule. Results are discussed relative to differences between mult FCT and RR FCT and successive and simultaneous discriminations. PMID- 25036317 TI - A low cost, customizable turbidostat for use in synthetic circuit characterization. AB - Engineered biological circuits are often disturbed by a variety of environmental factors. In batch culture, where the majority of synthetic circuit characterization occurs, environmental conditions vary as the culture matures. Turbidostats are powerful characterization tools that provide static culture environments; however, they are often expensive, especially when purchased in custom configurations, and are difficult to design and construct in a lab. Here, we present a low cost, open source multiplexed turbidostat that can be manufactured and used with minimal experience in electrical or software engineering. We demonstrate the utility of this system to profile synthetic circuit behavior in S. cerevisiae. We also demonstrate the flexibility of the design by showing that a fluorometer can be easily integrated. PMID- 25036316 TI - Joint association of nicotinic acetylcholine receptor variants with abdominal obesity in American Indians: the Strong Heart Family Study. AB - Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se. PMID- 25036318 TI - Understanding the safety and tolerability of facial filling therapeutics. AB - INTRODUCTION: Aesthetic medicine represents an emerging field for many specialties. Nowadays, a plethora of approaches are available to rejuvenate the human body and face, the latter being a frequent target for the placement of filling substances to correct wrinkles and volume loss. Nevertheless, based on the many products on the market, treating clinicians must pay specific attention to the properties of the respective materials, their associated side effects and any specific handling requirements to prevent potential short- and long-term adverse events. AREAS COVERED: Types of filling materials, including biodegradable and non-biodegradable products, related complications, their conservative and invasive treatment options, as well as prevention strategies are described in this review. EXPERT OPINION: A profound knowledge of the facial anatomy as well as extensive experience with the various filling techniques and suitable materials for the respective areas remains crucial to prevent adverse events associated with filling procedures to the human face. Since side effects such as malar edema and foreign body granuloma do affect patients physically and psychologically to a significant extent and their successful treatment still remains challenging, further in depth studies on the tolerability of many filling materials utilized are required. PMID- 25036319 TI - The effect of caffeic acid phenethyl ester on isoproterenol-induced myocardial injury in hypertensive rats. AB - OBJECTIVE: The aim of this study is to investigate the effects of caffeic acid phenethyl ester (CAPE) on isoproterenol (ISO)-induced myocardial injury in hypertensive rats. METHODS: Rats were divided into 4 groups (n=29): Control group (n=8), L-NNA (NG-Nitro-L-arginine) group (n=8), L-NNA+ISO (L-NNA+isoproterenol) group (n=7) and L-NNA+ISO+CAPE (L-NNA+ISO + caffeic acid phenethyl ester) group (n=6). ISO (150 mg/kg/day) was given intraperitoneally (i.p.) once a day for 2 consecutive days (at the 12th and 13th days of L-NNA treatment). NG-Nitro-L arginine (L-NNA) was given orally (25 mg/kg/day) in drinking water for 14 days. CAPE (10 MUmol/kg/day) was given (i.p.) for 7 days after the first week. Systolic blood pressure (SBP) was evaluated by the tail-cuff method and biochemical analysis were performed using an autoanalyzer and a spectrophotometer. RESULTS: SBP in all L-NNA-treated groups was found to be increased at seventh day. AST and LDH levels in LNNA+ISO group were significantly increased compared to control (AST: 125+/-5 vs. 105+/-2; LDH: 861+/-154 vs. 571+/-46 U/L respectively) (p<0.05). Also, ISO caused to extensive necrosis and mononuclear cell infiltration in hypertensive rat myocardium. CAPE application reversed the enhanced AST and LDH levels as well as the extensive necrosis and the mononuclear cell infiltration in LNNA+ISO+CAPE group compared LNNA+ISO. CONCLUSION: According to our findings, it might be suggested that CAPE may be a favorable agent to protect the hypertensive myocardium from the injury induced by isoproterenol via mechanisms such as the induction of the antioxidant enzymes and the inhibition of lipid peroxidation. PMID- 25036320 TI - The time interval between the onset of tricuspid E wave and annular Ea wave (TE Ea) can predict right atrial pressure in patients with heart failure. AB - OBJECTIVE: There is conflicting data regarding the tricuspid annular velocities and their relation to right ventricular filling pressures. We aimed to assess if the time interval between the onset of tricuspid E wave and annular Ea wave has any correlation with right sided filling pressure in patients with heart failure. METHODS: Thirty heart failure patients (left ventricular ejection fraction<=35%) were enrolled. Echocardiography was performed to obtain tricuspid inflow and tissue Doppler annular velocities just before a standard right heart catheterization. The right atrial pressure was obtained from right heart catheterization. The E/Ea [the ratio of peak velocity of early tricuspid inflow wave (E) to peak velocity of early diastolic wave of the lateral tricuspid annulus (Ea)] and the time intervals between the beginning of R wave of electrocardiogram and onset of E (TE) as well as between the beginning of R wave and onset of Et (TEa) were measured, TE-Ea was calculated as TE-TEa. RESULTS: The mean right atrial pressure (RAP) was 8.8 (SD=4.7) mm Hg. The mean TE-Ea was + 8.61 milliseconds. There was no significant correlation between RAP and E/Ea (r=0.08, p>0.05) but the correlation between TE-Ea and RAP was significant (r=0.5, p=0.01). CONCLUSION: According to our results and in contrary to some prior studies, we showed for the first time that right side TE-Ea stands as a better surrogate of right atrial pressure than E/Ea in heart failure patients. This finding needs more accurate studies and could present TE-Ea as a feasible tool to look into hemodynamics of heart failure patients. PMID- 25036321 TI - Acute effect of primary percutaneous coronary intervention on left ventricular dyssynchrony in ST-segment elevation myocardial infarction. AB - OBJECTIVE: The aim of this study was to prospectively evaluate the effect of percutaneous coronary intervention in the acute period on left ventricular dyssynchrony in ST-segment elevation myocardial infarction patients by using Tissue Synchronization Imaging. METHODS: Forty-four ST-segment elevation myocardial infarction (MI) patients (29 male, 15 female), who were admitted within the first 12 hours of chest pain symptoms, were enrolled in the study. According to the localization of MI, the patients were divided into groups as anterior MI (n=26) and inferior MI (n=18). All echocardiography measurements were taken just before percutaneous coronary intervention (PCI) and following PCI at a mean of 3-6 days. They were assessed according to the time to reach the peak systolic velocity, which was calculated by the tissue synchronization imaging method from four pairs of non-apical alternate segments. The difference between the duration to reach the peak systolic velocity in alternate segments was regarded as left ventricle dyssynchrony and the results were compared. RESULTS: In the anterior MI group, basal anterior (p<0.01), mid-anterior segment (p<0.01) and basal septal segment (p<0.01); in the inferior MI group, the basal septal segment (p=0.02), mid-septal segment (p=0.02), and basal and mid-inferior segment (p<0.01) values were significantly lower in the post-PCI measurements when compared to the measurements taken prior to PCI. In both groups, the intraventricular dyssynchrony indices of the basal anterior-basal inferior (p<0.01), mid-anterior-mid-inferior (p<0.01) segments were found to be significantly lower in the post-PCI period when compared to the pre-PCI period. CONCLUSION: It was found that percutaneous coronary intervention in patients with ST-elevation significantly decreases the degree of LV dyssynchrony in the acute period. PMID- 25036322 TI - The relationship between C-reactive protein and the lapse of time since the onset of the symptoms after acute myocardial infarction: an prospective-observational study. AB - OBJECTIVE: It is important to know the elapsed symptom-to-door (StD) time between the emergence of ST-elevation myocardial infarction (STEMI) symptoms and admission to the hospital in terms of the selection of appropriate treatment and prognosis. In this study, we aimed to assess the relationship between serum C reactive protein (CRP) and StD time after STEMI. METHODS: 436 of the patients admitted to our center with STEMI between August 2012-February 2013 (338 male, mean age, 63.9+/-12.8) were included in this prospective-observational cohort study. Blood samples were obtained from laboratory results of the first reference period. Patients were divided into four groups according to the duration of StD time [0-1. hour; group 1 (G1), 1-3. hour; group 2 (G2), 3-6. hour; group 3 (G3), 6-12. hour; group 4 (G4)]. Statistical analysis was performed via chi-squre test, ANOVA test, Pearson's correlation analysis and receiver operator charecteristic (ROC) analysis. RESULTS: As the time progressed, an increase in CRP levels was observed. The difference among the means of the G1-G3 (p=0.002), G1-G4 (p<0.001), G2-G4 (p<0.001) and G3-G4 (p<0.001) groups was found to be statistically significant. There was a good correlation between the StD time and CRP levels (r=0.676). ROC analysis of the predictive value of CRP for the third hour was determined as 0.78 mg/dL, respectively (AUC was 0.824; 95% C.I. was 0.785-0.859; 73.9% sensitivity, 78.1% specificity). CONCLUSION: According to serum CRP levels after STEMI at hospital admission, StD time can be estimated. PMID- 25036323 TI - Cardio-ankle vascular index may be an important marker of silent neuronal injury after percutaneous coronary angiography and intervention: a prospective observational study on diagnostic accuracy. AB - OBJECTIVE: The relationship between silent neuronal injury (SNI) and arterial stiffness assessed by cardio-ankle vascular index (CAVI) has not been evaluated in patients treated with coronary angiography and intervention due to acute coronary syndrome (ACS). The aim of this study is to evaluate the value of CAVI in prediction of SNI after percutaneous coronary angiography and intervention in patients presented with ACS. METHODS: Eighty-three consecutive patients presented with ACS, who underwent percutaneous coronary angiography and intervention, were included in this prospective observational study on diagnostic accuracy. Neuron specific enolase (NSE) was studied before and 18 hour after the coronary angiography and intervention. CAVI was measured by VaSera-1000 instrument. Clinical and echocardiographic characteristics were analyzed and independent predictors of SNI were evaluated. Chi-square, Student t-test, Mann-Whithney U test, correlation analysis and logistic regression analysis was used for statistical analysis. RESULTS: NSE levels significantly increased after cardiac catheterization (9.82+/-3.22 mg/dL vs. 13.15+/-8.55 mg/dL, p<0.001). CAVI (OR=2.992, 95% CI: 1.494-5.713, p=0.002), left ventricular ejection fraction (LVEF) (OR=0.911, 95% CI: 0.843-0.983, p=0.017) and undergoing percutaneous coronary intervention (OR=4.430, 95% CI: 1.034-18.97, p=0.045) were the independent predictors of SNI in logistic regression analysis. The cut-off value to show SNI for CAVI was 10.45 (sensitivity=71.8%, specificity=91.5%) in receiver operator charecteristic (ROC) curve analysis. The area under curve was 0.832 (95% CI=0.746-0.918, p<0.001). CONCLUSION: Besides undergoing PCI and having LVEF, measurement of CAVI may be a useful tool for predicting the development of SNI after percutaneous coronary angiography and intervention in patients with ACS. PMID- 25036324 TI - Association between restless leg syndrom and slow coronary flow. AB - OBJECTIVE: Restless legs syndrome (RLS) is a common sleep disorder in which patients feel unpleasent leg sensations and urge to move the legs during rest, especially at night, and symptoms are improved by leg movement. Prior studies analyzing the associations between cardiovascular disease and restless legs syndrome has shown controversial results. The goal of the study was to estimate the relationship between restless legs syndrome and slow coronary flow (SCF). METHODS: The present study was cross-sectional and observational and consists of 176 individuals who underwent coronary angiography and had angiographically normal coronary arteries of varying coronary flow rates. The study included 86 patients with isolated SCF and 90 control participants with normal coronary flow (NCF). RLS was assessed the day after the coronry flow was evaluated, using a self-administered questionnaire based on the International Restless Legs Study Group criteria. The following question was asked: "Do you have unpleasant leg sensations (like crawling, paraesthesia, or pain) combined with motor restlessness and an urge to move?" The possible responses were as follows: no, less than once/month, 2-4 times/month, 5-14 times/month, and 15 or more times per month. Those who answered that they had these feelings were asked the following two more questions: 1) "Do these symptoms occur only at rest and does moving improve them?" and 2) "Are these symptoms worsen in the evening/at night compared with the morning?" RLS is considered to be probable if the participant has answered "yes" for all three of the above questions, and has a frequency of >=5 times/month. Student's t-test, Mann-Whitney U test, multiple logistic regression analysis were used for statistical analysis. RESULTS: The prevalence of restless legs syndrome was 48 (27%) and increased significantly with age. Patients with SCF have more likely had RLS than the control group (p<0.001). The age-adjusted prevalence odds of SCF were 3.11 times higher (95% CI: 1.54-6.29; P<0.001) among patients with RLS symptoms. Significant associations between RLS and SCF did not materially change after further adjustment for other potential covariates, such as sex, BMI, BMI squared, smoking. CONCLUSION: Our study concluded that there is a strong link between SCF and RLS. PMID- 25036325 TI - Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic cardiomyopathy. AB - OBJECTIVE: Homeodomain Only Protein X (HOPX) is an unusual homeodomain protein which regulates Serum Response Factor (SRF) dependent gene expression. Due to the regulatory role of HOPX on SRF activity and the regulatory role of SRF on cardiac hypertrophy, we aimed to investigate the relationship between HOPX gene variations and hypertrophic cardiomyopathy (HCM). METHODS: In this study, designed as a case-control study, we analyzed coding and flanking non-coding regions of the HOPX gene through 67 patients with HCM and 31 healty subjects. Certain regions of the gene were investigated by Single Stranded Conformation Polymorphism (SSCP) and Restriction Fragment Length Polymorphism (RFLP). Statistical analyses of genotypes and their relationship with clinical parameters were performed by chi-square, Kruskal-Wallis and the Fisher's exact test. RESULTS: In 5' Untranslated Region (UTR) and intronic region of the HOPX gene, we found a C>T substitution and an 8-bp insertion/deletion (In/Del) polymorphism, respectively. These two polymorphisms seemed to constitute an haplotype. While the frequency of homozygous genotypes of In/Del and C/T polymorphisms were found significantly lower in the patients with syncope (p=0.014 and p=0.017, respectively), frequency of their heterozygous genotypes were found significantly higher in the patients with syncope (p=0.048 and p=0.030, respectively). CONCLUSION: Though there was not found any mutation in coding sequence of HOPX gene, two non-coding polymorphisms were found related to syncope in HCM patients. While homozygous status of these polymorphisms was found to be protective against the syncope, their heterozygous status seemed to be a risk factor for syncope in HCM patients. Our results suggest that HOPX may contribute to pathogenesis or manifestation of HCM as a modifier gene. PMID- 25036326 TI - Results of radiofrequency ablation in children with tachycardia-induced cardiomyopathy. AB - OBJECTIVE: Tachycardia-induced cardiomyopathy (TIC) is a rare but potentially curable cause of dilated cardiomyopathy. Data on radiofrequency ablation (RFA) for TIC is limited. The aim of this study is to present our experience with RFA in children with TIC, retrospectively. METHODS: The medical records of patients with TIC and those underwent RFA between 2000-2011 were systematically reviewed. Demographics and echocardiographic features were recorded. Tachycardia-induced cardiomyopathy is defined as dilatation of the heart chambers or heart failure with chronic or very frequent cardiac arrhythmia. Diagnosis was confirmed with normalization of functions after sinus rhythm has been achieved. RESULTS: A total of 12 patients with a mean age of 6.3+/-4.1 years (in utero-11.5 years) at diagnosis were enrolled in the study consisting of 7 patients with permanent junctional reciprocating tachycardia and 5 patients with focal atrial tachycardia. The mean pre-RFA left ventricular end-diastolic diameter and left ventricular ejection fraction (LVEF) values were 49.1+/-9.6 mm (32-66) and 40.8+/ 13.4% (23-57%), respectively. One month after RFA, the mean LVEF value was 62+/ 4.9% (52-69), with only 2 out of 12 patients' LVEF values were still lower than 58%. Tachycardia recurrence was observed in 4 patients, 3 of which had successful repeated RFA procedure. Overall, cure for arrhythmia was achieved in 11 patients (92%), while reversal of heart failure achieved in all patients. In 1 patient permanent complete AV block was developed after the procedure. CONCLUSION: Treatment of tachycardia with RFA, particularly in patients with arrhythmia refractory to medical therapy, is a feasible and effective treatment option regardless of age. PMID- 25036327 TI - Obesity is still a risk factor in coronary artery bypass surgery. AB - OBJECTIVE: Even with the improvements in surgical techniques and perioperative care, obesity is still a risk factor for occurrence of adverse events following cardiac surgery. In this observational, retrospective study, we aimed to document the effects of obesity on surgical outcomes in patients undergoing coronary artery bypass surgery and find out the effects of improvements in cardiac surgery. METHODS: Between January 2011 and March 2013, isolated coronary artery bypass surgery was performed on 790 patients. The body mass index values of the patients were calculated and patients were divided into two groups; below 30 were classified as non-obese group whereas above 30 were classified as obese group. The odds ratio was obtained by using univariate analysis in order to document the effects of obesity on outcomes. RESULTS: There were 548 (69.3%) patients in non obese group, whereas 242 (30.7%) patients in obese group. The cardiopulmonary bypass (80.47+/-23.58 vs. 80.89+/-28.46, p=0.449) and aortic clamp times (54.13+/ 16.60 vs. 54.19+/-19.85, p=0.511) and number of bypass grafts (3.09+/-1.02 vs. 2.96+/-1.00, p=0.11) were comparable between the groups. The mean number of fresh frozen plasma used was higher in obese patients (1.37+/-1.75 vs. 1.48+/-4.63, p=0.02). Intubation time was higher in obese patients (10.57+/-6.87 vs. 12.71+/ 35.31, p=0.014). Total amount of postoperative drainage was higher in non-obese patients (766.77+/-472.27 vs. 648.72+/-371.39, p<0.001). The superficial infection/mediastenitis (0.4% vs. 2.5%, p=0.012), dehiscence (0.2% vs. 3.7%, p<0.001) and postoperative renal failure rates (4.7% vs. 8.7%, p=0.031) were higher in obese patients. The incidence of atrial fibrillation was lower in obese patients (19.7% vs. 12.8%, p=0.019). The mortality (0.5% vs. 1.7%, p=0.210) and postoperative stroke rates (1.1% vs. 0.8%, p=1.000) were similar in both groups. CONCLUSION: We documented that obesity is still a risk factor for occurrence of postoperative adverse events. We believe that improved perioperative care together with meticulous regimens can improve postoperative outcomes in patients undergoing coronary artery bypass surgery. PMID- 25036328 TI - The rules of the game: properties of a database of expository language samples. AB - PURPOSE: The authors created a database of expository oral language samples with the aims of describing the nature of students' expository discourse and providing benchmark data for typically developing preteen and teenage students. METHOD: Using a favorite game or sport protocol, language samples were collected from 235 typically developing students in Grades 5, 6, 7, and 9. Twelve language measures were summarized from this database and analyses were completed to test for differences across ages and topics. To determine whether distinct dimensions of oral language could be captured with language measures from these expository samples, a factor analysis was completed. RESULTS: Modest differences were observed in language measures across ages and topics. The language measures were effectively classified into four distinct dimensions: syntactic complexity, expository content, discourse difficulties, and lexical diversity. CONCLUSION: Analysis of expository data provides a functional and curriculum-based assessment that has the potential to allow clinicians to document multiple dimensions of children's expressive language skills. Further development and testing of the database will establish the feasibility of using it to compare individual students' expository discourse skills to those of their typically developing peers. PMID- 25036329 TI - Lewis acid triggered reactivity of a Lewis base stabilized scandium-terminal imido complex: C-H bond activation, cycloaddition, and dehydrofluorination. AB - A stable scandium-terminal imido complex is activated by borane to form an unsaturated terminal imido complex by removing the coordinated Lewis base, 4 (dimethylamino)pyridine, from the metal center. The ensuing terminal imido intermediate can exist as a THF adduct and/or undergo cycloaddition reaction with an internal alkyne, C-H activation of a terminal alkene, and dehydrofluorination of fluoro-substituted benzenes or alkanes at room temperature. DFT investigations further highlight the ease of C-H activation for terminal alkene and fluoroarene. They also shed light on the mechanistic aspects of these two reactions. PMID- 25036330 TI - Integrated GNSS attitude determination and positioning for direct geo referencing. AB - Direct geo-referencing is an efficient methodology for the fast acquisition of 3D spatial data. It requires the fusion of spatial data acquisition sensors with navigation sensors, such as Global Navigation Satellite System (GNSS) receivers. In this contribution, we consider an integrated GNSS navigation system to provide estimates of the position and attitude (orientation) of a 3D laser scanner. The proposed multi-sensor system (MSS) consists of multiple GNSS antennas rigidly mounted on the frame of a rotating laser scanner and a reference GNSS station with known coordinates. Precise GNSS navigation requires the resolution of the carrier phase ambiguities. The proposed method uses the multivariate constrained integer least-squares (MC-LAMBDA) method for the estimation of rotating frame ambiguities and attitude angles. MC-LAMBDA makes use of the known antenna geometry to strengthen the underlying attitude model and, hence, to enhance the reliability of rotating frame ambiguity resolution and attitude determination. The reliable estimation of rotating frame ambiguities is consequently utilized to enhance the relative positioning of the rotating frame with respect to the reference station. This integrated (array-aided) method improves ambiguity resolution, as well as positioning accuracy between the rotating frame and the reference station. Numerical analyses of GNSS data from a real-data campaign confirm the improved performance of the proposed method over the existing method. In particular, the integrated method yields reliable ambiguity resolution and reduces position standard deviation by a factor of about 0:8, matching the theoretical gain of ? 3/4 for two antennas on the rotating frame and a single antenna at the reference station. PMID- 25036331 TI - An acetone microsensor with a ring oscillator circuit fabricated using the commercial 0.18 MUm CMOS process. AB - This study investigates the fabrication and characterization of an acetone microsensor with a ring oscillator circuit using the commercial 0.18 MUm complementary metal oxide semiconductor (CMOS) process. The acetone microsensor contains a sensitive material, interdigitated electrodes and a polysilicon heater. The sensitive material is alpha-Fe2O3 synthesized by the hydrothermal method. The sensor requires a post-process to remove the sacrificial oxide layer between the interdigitated electrodes and to coat the alpha-Fe2O3 on the electrodes. When the sensitive material adsorbs acetone vapor, the sensor produces a change in capacitance. The ring oscillator circuit converts the capacitance of the sensor into the oscillation frequency output. The experimental results show that the output frequency of the acetone sensor changes from 128 to 100 MHz as the acetone concentration increases 1 to 70 ppm. PMID- 25036332 TI - SVAS3: Strain Vector Aided Sensorization of Soft Structures. AB - Soft material structures exhibit high deformability and conformability which can be useful for many engineering applications such as robots adapting to unstructured and dynamic environments. However, the fact that they have almost infinite degrees of freedom challenges conventional sensory systems and sensorization approaches due to the difficulties in adapting to soft structure deformations. In this paper, we address this challenge by proposing a novel method which designs flexible sensor morphologies to sense soft material deformations by using a functional material called conductive thermoplastic elastomer (CTPE). This model-based design method, called Strain Vector Aided Sensorization of Soft Structures (SVAS3), provides a simulation platform which analyzes soft body deformations and automatically finds suitable locations for CTPE-based strain gauge sensors to gather strain information which best characterizes the deformation. Our chosen sensor material CTPE exhibits a set of unique behaviors in terms of strain length electrical conductivity, elasticity, and shape adaptability, allowing us to flexibly design sensor morphology that can best capture strain distributions in a given soft structure. We evaluate the performance of our approach by both simulated and real-world experiments and discuss the potential and limitations. PMID- 25036333 TI - Design, experiments and simulation of voltage transformers on the basis of a differential input D-dot sensor. AB - Currently available traditional electromagnetic voltage sensors fail to meet the measurement requirements of the smart grid, because of low accuracy in the static and dynamic ranges and the occurrence of ferromagnetic resonance attributed to overvoltage and output short circuit. This work develops a new non-contact high bandwidth voltage measurement system for power equipment. This system aims at the miniaturization and non-contact measurement of the smart grid. After traditional D-dot voltage probe analysis, an improved method is proposed. For the sensor to work in a self-integrating pattern, the differential input pattern is adopted for circuit design, and grounding is removed. To prove the structure design, circuit component parameters, and insulation characteristics, Ansoft Maxwell software is used for the simulation. Moreover, the new probe was tested on a 10 kV high voltage test platform for steady-state error and transient behavior. Experimental results ascertain that the root mean square values of measured voltage are precise and that the phase error is small. The D-dot voltage sensor not only meets the requirement of high accuracy but also exhibits satisfactory transient response. This sensor can meet the intelligence, miniaturization, and convenience requirements of the smart grid. PMID- 25036334 TI - Classification of EEG signals using a multiple kernel learning support vector machine. AB - In this study, a multiple kernel learning support vector machine algorithm is proposed for the identification of EEG signals including mental and cognitive tasks, which is a key component in EEG-based brain computer interface (BCI) systems. The presented BCI approach included three stages: (1) a pre-processing step was performed to improve the general signal quality of the EEG; (2) the features were chosen, including wavelet packet entropy and Granger causality, respectively; (3) a multiple kernel learning support vector machine (MKL-SVM) based on a gradient descent optimization algorithm was investigated to classify EEG signals, in which the kernel was defined as a linear combination of polynomial kernels and radial basis function kernels. Experimental results showed that the proposed method provided better classification performance compared with the SVM based on a single kernel. For mental tasks, the average accuracies for 2 class, 3-class, 4-class, and 5-class classifications were 99.20%, 81.25%, 76.76%, and 75.25% respectively. Comparing stroke patients with healthy controls using the proposed algorithm, we achieved the average classification accuracies of 89.24% and 80.33% for 0-back and 1-back tasks respectively. Our results indicate that the proposed approach is promising for implementing human-computer interaction (HCI), especially for mental task classification and identifying suitable brain impairment candidates. PMID- 25036335 TI - Measuring perinatal health equity and migration indicators for international comparisons. AB - An international research collaboration answered, "Can equity in perinatal health for migrant women be measured for comparison across countries?" In nine countries, perinatal databases were assessed for the availability of equity indicators. Equity data were also sought from women and health records. Optimal sources of data differed depending on the migrant perinatal health equity indicator. Health and migration data, required to capture equity, were often not reported in the same location. Migration indicators other than country of birth were underreported. Perinatal health equity can be measured for international comparisons, although a standardized protocol is required to capture all indicators. PMID- 25036336 TI - Xylanase and laccase based enzymatic kraft pulp bleaching reduces adsorbable organic halogen (AOX) in bleach effluents: a pilot scale study. AB - In present study, xylanase and laccase were produced in a cost-effective manner up to 10 kg substrate level and evaluated in elemental chlorine free bleaching of Eucalyptus kraft pulp. Compared to the pulp pre-bleached with xylanase (15%) or laccase (25%) individually, the ClO2 savings were higher with sequential treatment of xylanase followed by laccase (35%) at laboratory scale. The sequential enzyme treatment when applied at pilot scale (50 kg pulp), resulted in improved pulp properties (50% reduced post color number, 15.71% increased tear index) and reduced AOX levels (34%) in bleach effluents. The decreased AOX level in effluents will help to meet AOX discharge limits, while improved pulp properties will be value addition to the paper. PMID- 25036338 TI - Self-controlled fabrication of single-crystalline silicon nanobeams using conventional micromachining. AB - This paper reports on a low-cost top-down approach to the nano-precision fabrication of nanobeams on single-crystalline silicon using only conventional micromachining technology. The fabrication technique takes advantage of the crystalline structure of silicon for controllable feature size reduction of nanobeams with atomically smooth surfaces and sharp edges. Applying a deliberate rotational misalignment in a 2 MUm resolution standard lithography process, followed by anisotropic wet etching of the silicon, nanobeams with well uniform widths as small as ~85 nm are fabricated on thin SOI substrates. As a proof of concept for the incorporation of such nanobeams within electromechancial structures, we successfully demonstrate thermally actuated resonators that show very high frequencies (close to 50 MHz). PMID- 25036337 TI - Microbial characteristics and nitrogen removal of simultaneous partial nitrification, anammox and denitrification (SNAD) process treating low C/N ratio sewage. AB - Simultaneous partial nitrification, anammox and denitrification (SNAD) process was successfully realized for treating low C/N ratio sewage, nitrogen and COD removal achieved to 3.26 kg m(-3) d(-1), 81%, respectively. The nitrogen removal performance, microbial community and distribution of the functional microorganisms were investigated. Results suggested that the presence of COD performed activity inhibition on both aerobic ammonia-oxidizing bacteria (AerAOB) and anaerobic ammonia-oxidizing bacteria (AnAOB), and led to the number decreasing of both AerAOB and AnAOB. Even though COD presence resulted in the biodiversity increasing of AerAOB and decreasing of AnAOB, the dominant species were always Nitrosomonas and Candidatus brocadia during the whole experiment. Clone-sequencing of 16S rRNA results suggested the emergence of five different denitrifying species, which then led to a higher nitrogen removal. Results in this study demonstrated that the applied start-up strategy was feasible for SNAD process treating low C/N ratio sewage. PMID- 25036339 TI - Purification and recombinant expression of major peanut allergen Ara h 1. AB - Reaction to peanut, as one of the major food allergens, has become an increasingly common life-threatening disorder. Although peanut allergens have been extensively identified, Ara h 1 is still too expensive to be applied in food safety or clinical utility. In this study, the purification, expression, and immunological analyses of Ara h 1 are investigated. It was shown that a high purity (>95%) of Ara h 1 could be prepared by either purification or expression. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and mass spectroscopy were used to identify the Ara h 1, and it was found that natural Ara h 1 (nAra h 1) and expressed Ara h 1 (rAra h 1) have the same properties, including amino acid sequence. In particular, rAra h 1 reacted positively with anti-nAra h 1 serum, showing their similar immunological property. Thus, by either purification or expression, Ara h 1 could be prepared with low cost, as performed in the present work. SDS-PAGE, mag trix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS), and immunological analysis confirmed that both forms of Ara h 1 had the same properties. PMID- 25036340 TI - Each of the eight simian hemorrhagic fever virus minor structural proteins is functionally important. AB - The simian hemorrhagic fever virus (SHFV) genome differs from those of other members of the family Arterivirus in encoding two adjacent sets of four minor structural protein open reading frames (ORFs). A stable, full-length, infectious SHFV-LVR cDNA clone was constructed. Virus produced from this clone had replication characteristics similar to those of the parental virus. A subgenomic mRNA was identified for the SHFV ORF previously identified as 2b. As an initial means of analyzing the functional relevance of each of the SHFV minor structural proteins, a set of mutant infectious clones was generated, each with the start codon of one minor structural protein ORF mutated. Different phenotypes were observed for each ortholog of the pairs of minor glycoproteins and all of the eight minor structural proteins were required for the production of infectious extracellular virus indicating that the duplicated sets of SHFV minor structural proteins are not functionally redundant. PMID- 25036341 TI - Predictive markers in bladder cancer: do we have molecular markers ready for clinical use? AB - Bladder cancer (BC) is a heterogeneous disease. Approximately 75% of patients present with non-muscle-invasive BC (NMIBC), which has a high recurrence rate and a low but unpredictable progression rate. Conversely, patients with muscle invasive BC (MIBC) are at high risk for progression and cancer-specific mortality, but, again, disease behavior is unpredictable. To date, risk assessment for tumor recurrence and progression is based on clinico-pathological factors only. A risk assessment calculator that is based on several such parameters is available for NMIBC, but it has been reported to have potential flaws. In the last two decades, great effort has been made to evaluate the prognostic and predictive role of several molecular markers in MIBC and, even more so, in NMIBC, where the need for more precise risk stratification is urgently needed. This review addresses current evidence for the role of several molecular markers easily assessable by immunohistochemical techniques in prognosticating/predicting the outcome of NMIBC and MIBC. To date, because of divergent results among the many studies, no molecular marker has yet entered routine clinical practice; however, some of them (e.g., p53, pRb, p21, and survivin) have proved their predictive value in studies that included a homogeneous patient population on standardized treatment, and, therefore, are probably ready for clinical validation on a larger scale. Even more interesting is the possibility of constructing multimarker panels that could be used in routine clinical practice, as all these markers can easily be evaluated by immunohistochemistry on routine surgical pathology specimens. The molecular markers described herein hold promise for becoming widely available and cost effective tools for reliable risk assessment, which would represent a great advancement in counseling patients, in selecting them for neoadjuvant and adjuvant treatments, and in determining their eligibility for clinical trials. PMID- 25036342 TI - The physiologist Ewald Hering (1834-1918): curriculum vitae. PMID- 25036343 TI - Nested polymerase chain reaction amplification and sequencing analysis of the light-chain and heavy-chain variable regions in the influenza A H1N1 virus hemagglutinin monoclonal antibody gene. AB - The nested polymerase chain reaction (PCR) method was used for the amplification of the influenza A H1N1 virus hemagglutinin monoclonal antibody light-chain and heavy-chain genes. Sequence analysis of the obtained genes was then used to identify common cloning methods of the mouse immunoglobulin-kappa (Igkappa) light chain and heavy-chain variable gene regions. Twenty-two pairs of amplification primers for the mouse Igkappa light-chain and heavy-chain variable gene regions were designed, and 6 mouse anti-human H1N1 influenza virus hemagglutinin monoclonal antibody light-chain and heavy-chain variable gene regions were cloned and sequenced. Comparative analysis was conducted between our results and the mouse Ig sequences published in the National Center of Biotechnology Information (NCBI). The nested PCR method effectively avoided cloning the pseudogenes of the monoclonal antibody, and the amino acid sequence obtained was consistent with the characteristics of the mouse Ig variable region. A general method of cloning the mouse Ig light-chain and heavy-chain variable gene regions was established, which provides a basis for further cloning of mouse monoclonal antibody variable gene regions. This study also provides data for further studies of H1N1 influenza virus hemagglutinin antibody binding sites. PMID- 25036344 TI - Isolation and expression analysis of the soybean GmPic gene. AB - The differential screening method was used to isolate the soy photoperiodic response-related genes and to further elucidate the molecular mechanisms of the soybean photoperiodic response. The light-sensitive species Zhong Dou 24 was used to receive long-time sunshine, short-time sunshine, and natural sunshine treatment. The cDNA-amplified fragment length polymorphism technique was used to screen the differentially expressed cDNA fragments. The rapid amplification of cDNA end technique was used to isolate the gene. Semi-quantitative reverse transcription polymerase chain reaction analysis was used to analyze the gene expression patterns in different light cycles. The gene had a total length of 983 bp, contained a complete open reading frame that encoded 248 amino acids, and shared homology with the mitochondrial phosphate transporter protein. The expression pattern analysis results showed that this gene was expressed in the early stages of soybean growth and development. The short-time sunshine inhibited its expression, whereas the long-time sunshine enhanced its expression. The differential screening method was used to isolate the soybean mitochondrial phosphate transporter gene. The gene may be used as a negative regulatory factor that is involved in the photoperiodic response of soybean. PMID- 25036345 TI - Evaluation of mutagenic, teratogenic, and immunomodulatory effects of Annona nutans hydromethanolic fraction on pregnant mice. AB - Plants such as Annona nutans used in folk medicine have a large number of biologically active compounds with pharmacological and/or toxic potential. Moreover, pregnant women use these plants indiscriminately, mainly in the form of teas, without being aware of the harm that they could cause to the health of the embryo/fetus. Therefore, it is necessary to analyze the potential toxic effects of medicinal plants during gestation. The present study aimed to evaluate the effects of A. nutans hydromethanolic fraction leaves (ANHMF) on mutagenic and immunomodulatory activity, reproductive performance, and embryo-fetal development in pregnant female mice. The animals (N=50 female and 25 male) were divided into 5 groups: Control, Pre-treatment, Organogenesis, Gestational, and Pre+Gestational. The results indicate that ANHMF mainly contains flavonoid and other phenolic derivatives. It was found that it does not exhibit any mutagenic or immunomodulatory activity, and it does not cause embryo-fetal toxicity. Based on the protocols used in the present studies, our analyses confirm that it is safe to use ANHMF during pregnancy. PMID- 25036346 TI - Analysis of diversity and relationships among orchardgrass (Dactylis glomerata L.) accessions using start codon-targeted markers. AB - Orchardgrass, or cocksfoot, is an important perennial forage grass worldwide. The comprehensive understanding of orchardgrass accessions will benefit germplasm collection and breeding progress, and it will enhance efforts to improve forage yield and quality. Therefore, 24 novel, simple, polymorphic, and reliable start codon-targeted (SCoT) markers were used to analyze the diversity and genetic relationships among 95 orchardgrass accessions. In total, 273 polymorphic bands were detected with an average of 11.4 bands per primer. The average polymorphic rate for the species was 83.4%, suggesting a high discriminating ability of the SCoT technique for orchardgrass. The molecular variance analysis revealed that 69.13 and 30.87% of variation resided within and among groups, respectively, demonstrating that the orchardgrass germplasms had a higher level of genetic diversity within groups than among geographical regions and distributions. The distinct geographical divergence of orchardgrass was revealed between North America and Oceania. The unweighted pair-group method with arithmetic mean dendrogram revealed a separation of 7 main clusters between 95 accessions according to the geographical origin. Furthermore, each cluster was divided into subgroups mainly according to the origin of its state. The genetic divergence of orchardgrass might be influenced by the ecogeographical conditions, climatic types, breeding systems and gene flow with variations in cultures, bird migration, and breeder selection. These results could facilitate orchardgrass germplasm collection, management, and breeding worldwide. PMID- 25036347 TI - Absolute quantification of free tumor cells in the peripheral blood of gastric cancer patients. AB - Gastric cancer remains the third most common cancer in the world. Metastatic disease is a major cause of death in about half of the patients; therefore, early diagnosis is crucial for successful outcome. This study applied a sensitive method for the detection of circulating tumor cells using specific tumor markers for early detection. A total of 80 blood samples from 40 patients and 40 age matched healthy controls were collected for the study. Circulating mRNA levels of two tumor markers, tumor endothelial marker 8 (TEM-8) and carcinoembryogenic antigen (CEA) were evaluated using absolute quantitative real-time PCR assay in the Stratagene Mx-3000P real-time PCR system. GAPDH was used to normalize the data. TEM-8 and CEA were detected in patients' blood more than in controls, 22/40 vs 9/40, P=0.005, and 30/40 vs 11/40, P=0.008, respectively. The mRNA level of these markers in patients was significantly higher in comparison to normal controls (P=0.018, 0.01). This panel showed an overall sensitivity of 64% and specificity of 73%. Statistical analysis for demographic variants did not show any significant differences. Both markers were detected more frequently and in significantly higher levels in blood samples of patients compared to samples from normal individuals. Copy number of CEA and TEM-8 mRNA, as detected by real-time quantitative PCR, appears to be a promising marker to evaluate the risk of tumor spread. PMID- 25036348 TI - Growth and viability of Liaoning Cashmere goat hair follicles during the annual hair follicle cycle. AB - Here, we studied hair follicle development of Liaoning Cashmere goats. Every month for 1 year, skin samples were collected from five 1.5-year-old female goats, and made into paraffin sections. A number of parameters were measured of primary and secondary hair follicles via microscopic observation including follicle depth, hair bulb width, dermis and epidermis thickness, changes in follicle activity, and histology. The results showed the presence of three phases in the annual hair cycle: anagen, catagen, and telogen. Primary and secondary hair follicle depth varied across the months; however, no significant difference was obtained between adjacent months (P>0.05). Primary hair follicles had a bigger hair bulb width compared to secondary hair follicles; however, this difference declined during hair follicle developed in anagen. As hair follicle growth slowed, the hair bulb broadened, and hair root depth became shallower. During the entire hair cycle, hair follicle depth and dermis thickness were positively correlated; however, this relationship was not significant (P>0.05) for primary and secondary hair follicle density and the ratio of secondary hair follicle density and primary hair follicle density (S/P ratio). In addition, new and old primary hair follicles coexisted with secondary hair follicles. Finally, secondary hair follicles had a higher activity rate compared to primary hair follicle in adult Liaoning Cashmere goats in certain months. PMID- 25036350 TI - In vivo osteogenic activity of bone marrow stromal stem cells transfected with Ad GFP-hBMP-2. AB - The aim of this study was to investigate the expression of bone morphogenetic protein-2 (BMP-2) in bone marrow stromal stem cells (BMSCs) and the in vivo and in vitro osteogenic activity of BMSCs transfected with the adenovirus plasmid, Ad GFP-hBMP-2. The Ad-GFP-hBMP-2 plasmid was packaged and transfected into rabbit BMSCs to determine the transfection rate. The alkaline phosphatase (ALP) activities of Ad-GFP-hBMP-2-transfected BMSCs (experimental group) and untransfected BMSCs (control group) were detected. In situ hybridization of type I collagen and Western blot were used to determine the BMP-2 gene and protein expressions. The transfected and untransfected BMSCs were respectively inoculated into nude mice to observe in vivo osteogenesis. The decalcified bovine cancellous bone scaffold was respectively combined with transfected and untransfected BMSCs and implanted into ulnar defects in rabbits to repair the bone. The adenovirus titer was 1.2x10(10) pfu/mL. Green fluorescent protein expression appeared 48 h after transfection with the adenovirus plasmid, and the transfection rate was 71.1%. The ALP activity was higher in the experimental group than the control group at each time point after transfection. The gene and protein expressions of BMP-2 were higher in the experimental group than the control group. The positive rates of in vivo osteogenesis in the experimental and control groups were 90% and 40%, respectively. The bone defect repair effects differed markedly between the two groups. The BMP-2 gene can be highly expressed in BMSCs to successfully induce osteogenic differentiation. BMSCs can be used as seed cells for bone tissue engineering. PMID- 25036349 TI - Microbial community and performance of slaughterhouse wastewater treatment filters. AB - The performance of anaerobic filter bioreactors (AFs) is influenced by the composition of the substrate, support medium, and the microbial species present in the sludge. In this study, the efficiency of a slaughterhouse effluent treatment using three AFs containing different support media was tested, and the microbial diversity was investigated by amplified ribosomal DNA restriction analysis and 16S rRNA gene sequencing. The physicochemical analysis of the AF systems tested suggested their feasibility, with rates of chemical oxygen demand removal of 72+/-8% in hydraulic retention times of 1 day. Analysis of pH, alkalinity, volatile acidity, total solids, total volatile solids, total Kjeldahl nitrogen, and the microbial community structures indicated high similarity among the three AFs. The composition of prokaryotic communities showed a prevalence of Proteobacteria (27.3%) and Bacteroidetes (18.4%) of the Bacteria domain and Methanomicrobiales (36.4%) and Methanosarcinales (35.3%) of the Archaea domain. Despite the high similarity of the microbial communities among the AFs, the reactor containing pieces of clay brick as a support medium presented the highest richness and diversity of bacterial and archaeal operational taxonomic units. PMID- 25036351 TI - Influence of the c.1517G>C genetic variant in the XRCC1 gene on pancreatic cancer susceptibility in a Chinese population. AB - We investigated the influence of the c.1517G>C genetic variant in the X-ray repair complementing group 1 gene (XRCC1) on pancreatic cancer (PC) susceptibility in Chinese patients. A total of 390 PC patients and 392 controls were enrolled in this case-control study. The genotypes of c.1517G>C genetic variants were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Our findings suggested that the allele and genotype frequencies in PC patients were significantly different from those in cancer-free controls. The CC genotype was associated with an increased risk of PC compared to the wild-type GG genotype (odds ratio=2.43, 95% confidence interval 1.43-4.13, X2=11.19, P=0.001). The C allele may contribute to the development of PC (C vs G, odds ratio=1.32, 95% confidence interval 1.06-1.64, X2=6.25, P=0.012). Results from this study indicate that the c.1517G>C genetic variant of the XRCC1 gene is significantly associated with PC susceptibility in the Chinese population. PMID- 25036352 TI - Association between IRF5 polymorphisms and autoimmune diseases: a meta-analysis. AB - In this study, we investigated the association between 5 interferon regulatory factor-5 (IRF5) single nucleotide polymorphisms (SNPs) and autoimmune diseases using the Medline citation index. Twenty-eight studies with 74 comparisons, including 16 rheumatoid arthritis (RA), 43 systemic lupus erythematous (SLE), 2 juvenile idiopathic arthritis (JIA), 6 multiple sclerosis (MS), and 5 systemic sclerosis (SSc) studies, were examined in the meta-analysis. The SNP rs2004640 was significantly associated with SLE, MS, and SSc, but not with JIA [odds ratio (OR)=1.06, 95% confidence interval (CI)=0.90-1.24, P=0.48] or RA (OR=1.03, 95%CI=0.95-1.11, P=0.44). A significant association was observed between rs2280714 and SLE, MS, and SSc, but not RA (OR=1.01, 95%CI=0.94-1.09, P=0.80). Rs10954213 was associated with the pathogenesis of SLE, RA, MS, and SSc. rs2070197 and the exon 6 insertion were significantly associated with SLE. Haplotypes containing rs2004640T and rs2280714T were significantly associated with an increased risk of SLE, but not with RA. This meta-analysis certified that IRF5 polymorphisms confer susceptibility to SLE, MS, and SSc. To further confirm the correlations between polymorphisms of IRF5 and autoimmune disease susceptibility, studies involving a larger number of patients worldwide are necessary. PMID- 25036353 TI - Comparison of methods to isolate DNA from Caesalpinia ferrea. AB - Molecular markers are important for characterizing the genetic diversity of plants and can provide the basis for strategies to protect and conserve endangered populations. However, numerous molecular techniques are used, requiring an evaluation of fast and efficient methods to extract DNA. Since molecular studies of Caesalpinia ferrea are rare, it is important to develop and/or adapt a DNA extraction protocol that produces quality DNA samples to enable the design of strategies for the conservation of this threatened species. This study aimed to compare five methods for DNA extraction and to determine the most efficient protocol for C. ferrea. Sufficient genomic DNA was obtained from the leaves of C. ferrea using all the tested protocols to perform techniques involving molecular markers. Two protocols based on the detergent cetyl trimethyl ammonium bromide, as well as a commercial kit, yielded high concentrations of pure DNA. However, when polymerase chain reaction amplifications were performed, DNA was only successfully amplified from extractions performed with the commercial kit, which produced sufficient genomic DNA of good quality from the leaves of C. ferrea to perform techniques involving molecular markers. PMID- 25036354 TI - Oligonucleotide microarray analysis reveals dysregulation of energy-related metabolism in insulin-sensitive tissues of type 2 diabetes patients. AB - Impaired insulin action within skeletal muscle, adipose tissue, and the liver is an important characteristic of type 2 diabetes (T2D). In order to identify common underlying defects in insulin-sensitive tissues that may be involved in the pathogenesis of T2D, the gene expression profiles of skeletal muscle, visceral adipose tissue, and liver from autopsy donors with or without T2D were examined using oligonucleotide microarrays and quantitative reverse transcriptase-PCR. Compared with controls, 691 genes were commonly dysregulated in these three insulin-sensitive tissues of humans with T2D. These co-expressed genes were enriched within the mitochondrion, with suggested involvement in energy metabolic processes such as glycolysis and gluconeogenesis, fatty acid beta oxidative, tricarboxylic acid cycle, and electron transport. Genes related to energy metabolism were mostly downregulated in diabetic skeletal muscle and visceral adipose tissue, while they were upregulated in the diabetic liver. This observed dysregulation in energy-related metabolism may be the underlying factor leading to the molecular mechanisms responsible for the insulin resistance of patients with T2D. PMID- 25036355 TI - Bioinformatic analysis and characteristics of glycoprotein C encoded by the newly identified UL44 gene of duck plague virus. AB - Glycoprotein C is one of the duck plague virus (DPV) glycoproteins and is encoded by the DPV UL44 gene. DPV glycoprotein C (DPV-gC) comprises 431 amino acids with a putative molecular mass of 47.35 kDa. Sequence analysis indicated that the protein possesses typical characteristics of type-I membrane glycoproteins, containing an N-terminal signal sequence, an external domain, a C-terminal membrane anchor region, and a short cytoplasmic domain. Comparisons of 22 alphaherpesvirus-gC protein sequences revealed eight conservative Cys-residue sites, which may play a crucial role in the biological functions and structural stabilization of the DPV-gC protein. Estimates of potential antigenic epitopes and secondary structure identified four B cell dominant epitopes, which are located at amino acids 68-71, 87-91, 369-352, and 372-374. A model for the structure of DPV-gC was derived by associating its predicted secondary and three dimensional structures. In conclusion, these results will provide a basis for further functional studies of DPV-gC, establishing novel clinical diagnoses of DPV, and in the development of a new DPV vaccine. PMID- 25036356 TI - Effect of mitochondrial ATP-sensitive potassium channel opening on the translocation of protein kinase C epsilon in adult rat ventricular myocytes. AB - This study aimed to investigate the effects of mitochondrial ATP-sensitive potassium (MitoKATP) channel opening on the translocation of protein kinase C epsilon (PKCepsilon). In addition, we aimed to determine the relationship between PKCepsilon translocation and the production of reactive oxygen species (ROS). PKCepsilon protein expression in cultured adult rat ventricular myocytes was investigated by immunofluorescence and Western blotting. Diazoxide (DZ), a selective MitoKATP channel activator, caused a significant translocation to myofibrillar-like structures in cultured adult rat ventricular myocytes. N-2 Mercaptopropionylglycine, a free radical scavenger, could partially inhibit the translocation of PKCepsilon induced by DZ. By contrast, chelerythrine, a selective PKC inhibitor, could completely block the translocation of PKCepsilon induced by DZ. The opening of MitoKATP channels might activate and cause PKCepsilon to translocate into myofibrillar-like structures. PKCepsilon activation occurred downstream of the MitoKATP channel, possibly as a result of ROS production that occurred after the MitoKATP channels opened. PMID- 25036357 TI - Anesthesia treatment in cases of infant epiglottis cyst emergency extirpation operations. AB - Congenital epiglottic cyst is a rare embryonic disease. As a congenital laryngeal mucocele, its clinical manifestations include repeated sudden dyspneic respiration and even suffocation accompanied by laryngeal stridor after birth. During food intake, bucking and vomiting is a key feature. Delay in diagnosis and treatment of the disease affects growth and the development of neonatorum leading to suffocation and death. This study was designed to investigate the safety of anesthesia in infants with congenital epiglottic cyst during operation to reduce the occurrence of its complications. The treatment of operations on 12 infants with congenital epiglottic cysts were retrospectively analyzed. Twelve cases of infants with epiglottic cysts received emergency enucleation. Owing to adequate preanesthetic preparation, cystectomies were successfully performed with microwave cauterization under suspension laryngoscopy. None of the 12 patients showed apparent suffocation during anesthesia, the surgical results were good, and after 6 months to 1 year of follow-up, the disease had not recurred. Because of the acute onset of the disease and its severe symptoms and complications, attention should be paid to improve preoperative preparation. Careful selection of proper anesthesia is the key to achieving a successful operation. PMID- 25036358 TI - Comparative application of direct sequencing, PCR-RFLP, and cytogenetic markers in the genetic characterization of Pimelodus (Siluriformes: Pimelodidae) species: possible implications for fish conservation. AB - Pimelodus (Pimelodidae) is a genus comprising a group of South American species with complex taxonomic relationships. Cytogenetics, polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and sequencing data of mitochondrial genes were analyzed to characterize 4 Pimelodus species: P. fur, P. heraldoi, P. maculatus, and Pimelodus sp. All populations presented 2n=56 chromosomes and distinct karyotypic formulae. The heterochromatin distribution pattern and the number and location of 5S and 18S rDNA sites are discussed. The application of PCR-RFLP markers and sequencing of mitochondrial DNA genes provided species-specific haplotypes, which allowed us to differentiate the species studied. The mitochondrial gene sequences presented nucleotide mutations in the restriction sites and throughout the sequences, and they were mostly related to synonymous substitutions in the coded proteins; however, they did not affect the protein and its function. Comparing the data obtained using these 3 methodologies, the existence of a species complex in P. maculatus along the basins studied might be inferred, showing that cytogenetics is an important tool in studies focusing on the conservation or management of both natural and captive populations of these fishes. PMID- 25036359 TI - Analysis of age of onset, pre-existing infections, and features of magnetic resonance imaging results in patients with acute myelitis. AB - The clinical features and potential risk factors of acute myelitis (AM) were investigated. The medical records of patients with AM admitted to our department between January 2004 and December 2011 were collected and retrospectively analyzed. The diagnosis of AM was in line with the diagnostic criteria of the Transverse Myelitus Consortium Working Group. The age of onset, clinical, and imaging features of these patients were analyzed. A total of 64 patients satisfying the inclusion criteria were enrolled in the study, including 39 males and 25 females. The patients ranged in age from 1 to 80 years, with a mean age of 34 years. Twenty-three patients had symptoms of pre-existing infections. The correlation between spinal cord lesions and spinal lesions was statistically significant (P<0.05). Cervical spinal cord inflammation was the most common. Prodromal infections were more commonly observed in thoracic spinal cord myelitis than in cervical spinal cord myelitis (P<0.05). AM appears to be more likely to occur in male minors. Lesions of the spinal column were partially implicated with the occurrence of myelitis, which suggests that such lesions might be a predisposing factor. Compared to AM of the cervical cord, pre-existing infections appear to be of greater significance for the occurrence of myelitis of the thoracic cord. PMID- 25036360 TI - Food Fortification and Supplement Use-Are There Health Implications? AB - Dietary supplements are a multi-billion dollar industry in the U.S., and their use is increasing exponentially. Additionally, many foods and beverages are increasingly being fortified with single or multiple vitamins and minerals. Consequently, nutrient intakes are exceeding the safe limits established by the Institute of Medicine. In this paper, we examine the benefits and drawbacks of vitamin and mineral supplements and increasing consumption of fortified foods (in addition to dietary intake) in the U.S. POPULATION: The pros and cons are illustrated using population estimates of folic acid, calcium, and vitamin D intake, highlighting concerns related to overconsumption of nutrients that should be addressed by regulatory agencies. PMID- 25036361 TI - Sumoylation of human argonaute 2 at lysine-402 regulates its stability. AB - Gene silencing by small RNAs has emerged as a powerful post-transcriptional regulator of gene expression, however processes underlying regulation of the small RNA pathway in vivo are still largely elusive. Here, we identified sumoylation as a novel post-translational modification acting on Ago2, the main effector of small RNA-mediated gene silencing. We demonstrate that Ago2 can be modified by SUMO1 and SUMO2/3 and identified Lys402 as the major Ago2 sumoylation site in vivo. Ago2 physically interacts with the SUMO E2 conjugating enzyme Ubc9 and the E3 ligase RanBP2 facilitates Ago2 sumoylation in vitro. Mutation of Lys402 enhances the stability of Ago2 protein and impairment of cellular sumoylation by siRNA- or shRNA-mediated extinction of Ubc9 or in Ubc9 knockout mouse tissues results in increased steady-state levels and enhanced stability of Ago2. Similarly, knockdown of RanBP2 or of the SAE2 E1 enzyme enhances Ago2 protein levels. Lys402 is located in the L2g1 loop linking the PAZ and PIWI domains of Ago2, in the immediate vicinity of Tyr393 which can be phosphorylated, implying that the L2g1 linker represents an easily accessible hot spot for post translational modifications. Altogether, our results show that sumoylation of Ago2 at Lys402 negatively regulates its stability, thereby establishing a first link between SUMO and the small RNA machinery. PMID- 25036362 TI - Maresin biosynthesis and identification of maresin 2, a new anti-inflammatory and pro-resolving mediator from human macrophages. AB - Maresins are a new family of anti-inflammatory and pro-resolving lipid mediators biosynthesized from docosahexaenoic acid (DHA) by macrophages. Here we identified a novel pro-resolving product, 13R,14S-dihydroxy-docosahexaenoic acid (13R,14S diHDHA), produced by human macrophages. PCR mapping of 12-lipoxygenase (12-LOX) mRNA sequence in human macrophages and platelet showed that they are identical. This human 12-LOX mRNA and enzyme are expressed in monocyte-derived cell lineage, and enzyme expression levels increase with maturation to macrophages or dendritic cells. Recombinant human 12-LOX gave essentially equivalent catalytic efficiency (kcat/KM) with arachidonic acid (AA) and DHA as substrates. Lipid mediator metabololipidomics demonstrated that human macrophages produce a novel bioactive product 13,14-dihydroxy-docosahexaenoic acid in addition to maresin-1, 7R,14S dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (MaR1). Co-incubations with human recombinant 12-LOX and soluble epoxide hydrolase (sEH) demonstrated that biosynthesis of 13,14-dihydroxy-docosahexaenoic acid (13,14-diHDHA) involves the 13S,14S-epoxy-maresin intermediate produced from DHA by 12-LOX, followed by conversion via soluble epoxide hydrolase (sEH). This new 13,14-diHDHA displayed potent anti-inflammatory and pro-resolving actions, and at 1 ng reduced neutrophil infiltration in mouse peritonitis by ~40% and at 10 pM enhanced human macrophage phagocytosis of zymosan by ~90%. However, MaR1 proved more potent than the 13R,14S-diHDHA at enhancing efferocytosis with human macrophages. Taken together, the present findings demonstrate that macrophages produced a novel bioactive product identified in the maresin metabolome as 13R,14S-dihydroxy docosahexaenoic acid, from DHA via conversion by human 12-LOX followed by sEH. Given its potent bioactions, we coined 13R,14S-diHDHA maresin 2 (MaR2). PMID- 25036363 TI - Susceptibility to COPD: differential proteomic profiling after acute smoking. AB - Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as "susceptible individuals". Here we perform unbiased analyses of proteomic profiles to assess how "susceptible individuals" differ from age matched "non-susceptible individuals" in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD. PMID- 25036364 TI - Surfactant protein D inhibits HIV-1 infection of target cells via interference with gp120-CD4 interaction and modulates pro-inflammatory cytokine production. AB - Surfactant Protein SP-D, a member of the collectin family, is a pattern recognition protein, secreted by mucosal epithelial cells and has an important role in innate immunity against various pathogens. In this study, we confirm that native human SP-D and a recombinant fragment of human SP-D (rhSP-D) bind to gp120 of HIV-1 and significantly inhibit viral replication in vitro in a calcium and dose-dependent manner. We show, for the first time, that SP-D and rhSP-D act as potent inhibitors of HIV-1 entry in to target cells and block the interaction between CD4 and gp120 in a dose-dependent manner. The rhSP-D-mediated inhibition of viral replication was examined using three clinical isolates of HIV-1 and three target cells: Jurkat T cells, U937 monocytic cells and PBMCs. HIV-1 induced cytokine storm in the three target cells was significantly suppressed by rhSP-D. Phosphorylation of key kinases p38, Erk1/2 and AKT, which contribute to HIV-1 induced immune activation, was significantly reduced in vitro in the presence of rhSP-D. Notably, anti-HIV-1 activity of rhSP-D was retained in the presence of biological fluids such as cervico-vaginal lavage and seminal plasma. Our study illustrates the multi-faceted role of human SP-D against HIV-1 and potential of rhSP-D for immunotherapy to inhibit viral entry and immune activation in acute HIV infection. PMID- 25036365 TI - Bridging the mechanical and the human mind: spontaneous mimicry of a physically present android. AB - The spontaneous mimicry of others' emotional facial expressions constitutes a rudimentary form of empathy and facilitates social understanding. Here, we show that human participants spontaneously match facial expressions of an android physically present in the room with them. This mimicry occurs even though these participants find the android unsettling and are fully aware that it lacks intentionality. Interestingly, a video of that same android elicits weaker mimicry reactions, occurring only in participants who find the android "humanlike." These findings suggest that spontaneous mimicry depends on the salience of humanlike features highlighted by face-to-face contact, emphasizing the role of presence in human-robot interaction. Further, the findings suggest that mimicry of androids can dissociate from knowledge of artificiality and experienced emotional unease. These findings have implications for theoretical debates about the mechanisms of imitation. They also inform creation of future robots that effectively build rapport and engagement with their human users. PMID- 25036367 TI - Spray assembled, cross-linked polyelectrolyte multilayer membranes for salt removal. AB - The present study reports the synthesis of spray-coated cross-linked polyelectrolyte multilayer membranes. Membrane cross-linking was performed using alkyne-azide "click" chemistry, where alkyne and azide functional groups were used to modify the poly(acrylic acid) (PAA) and the poly(allylamine) hydrochloride (PAH) polyelectrolytes. The results demonstrate that deposition at lower ionic strength produced smoother and denser membrane structures. Pore size analysis using neutral poly(ethylene glycol) revealed a decrease in the membrane pore size as the degree of cross-linking was increased, resulting in the membrane rejecting divalent CaCl2 at levels of up to 80%, and 50% rejection of monovalent NaCl. When poly(sodium-4-styrenesulfonate) (PSS) was combined with small amounts of cross-linkable PAA, significant flux increases were observed in the multilayer membranes with no observable reduction in ion rejection. PMID- 25036366 TI - Personality and suicide risk: the impact of economic crisis in Japan. AB - BACKGROUND: The interactive effect of personal factors and social factors upon suicide risk is unclear. We conducted prospective cohort study to investigate whether the impact of the economic crisis in 1997-1998 upon suicide risk differed according to Neuroticism and Psychoticism personality traits. METHODS: The Miyagi Cohort Study in Japan with a follow-up for 19 years from 1990 to 2008 has 29,432 subjects aged 40-64 years at baseline who completed a questionnaire about various health habits and the Japanese version of the Eysenck Personality Questionnaire - Revised Short Form in 1990. RESULTS: The suicide mortality rate increased from 4.6 per 100,000 person-years before 1998 to 27.8 after 1998. Although both Neuroticism and Psychoticism were significantly associated with an increased risk of mortality during the whole period from 1990 to 2008, the impact of the economic crisis upon suicide risk differed between the Neuroticism and Psychoticism personality traits. Compared with the lowest category, the hazard ratios (HRs) for the highest Neuroticism increased from 0.66 before 1998 to 2.45 after 1998. On the other hand, the HRs for the highest Psychoticism decreased from 7.85 before 1998 to 2.05 after 1998. CONCLUSIONS: The impact of the 1997 1998 economic crisis upon suicide risk differed according to personality. Suicide risk increased among these with higher Neuroticism after the economic crisis, but this was not the case for other personality subscales. PMID- 25036368 TI - Distribution patterns in the native vascular flora of Iceland. AB - The aim of our study was to reveal biogeographical patterns in the native vascular flora of Iceland and to define ecological factors responsible for these patterns. We analysed dataset of more than 500,000 records containing information on the occurrence of vascular plants. Analysis of ecological factors included climatic (derived from WORLDCLIM data), topographic (calculated from digital elevation model) and geological (bedrock characteristics) variables. Spherical k means clustering and principal component analysis were used to detect biogeographical patterns and to study the factors responsible for them. We defined 10 biotic elements exhibiting different biogeographical patterns. We showed that climatic (temperature-related) and topographic variables were the most important factors contributing to the spatial patterns within the Icelandic vascular flora and that these patterns are almost completely independent of edaphic factors (bedrock type). Our study is the first one to analyse the biogeographical differentiation of the native vascular flora of Iceland. PMID- 25036369 TI - Reconstitution of peptidoglycan cross-linking leads to improved fluorescent probes of cell wall synthesis. AB - The peptidoglycan precursor, Lipid II, produced in the model Gram-positive bacterium Bacillus subtilis differs from Lipid II found in Gram-negative bacteria such as Escherichia coli by a single amidation on the peptide side chain. How this difference affects the cross-linking activity of penicillin-binding proteins (PBPs) that assemble peptidoglycan in cells has not been investigated because B. subtilis Lipid II was not previously available. Here we report the synthesis of B. subtilis Lipid II and its use by purified B. subtilis PBP1 and E. coli PBP1A. While enzymes from both organisms assembled B. subtilis Lipid II into glycan strands, only the B. subtilis enzyme cross-linked the strands. Furthermore, B. subtilis PBP1 catalyzed the exchange of both D-amino acids and D-amino carboxamides into nascent peptidoglycan, but the E. coli enzyme only exchanged D amino acids. We exploited these observations to design a fluorescent D-amino carboxamide probe to label B. subtilis PG in vivo and found that this probe labels the cell wall dramatically better than existing reagents. PMID- 25036372 TI - Intravenous lidocaine decreases tumor necrosis factor alpha expression both locally and systemically in pigs undergoing lung resection surgery. AB - BACKGROUND: Lung resection surgery is associated with an inflammatory reaction. The use of 1-lung ventilation (OLV) seems to increase the likelihood of this reaction. Different prophylactic and therapeutic measures have been investigated to prevent lung injury secondary to OLV. Lidocaine, a commonly used local anesthetic drug, has antiinflammatory activity. Our main goal in this study was to investigate the effect of IV lidocaine on tumor necrosis factor alpha (TNF alpha) lung expression during lung resection surgery with OLV. METHODS: Eighteen pigs underwent left caudal lobectomy. The animals were divided into 3 groups: control, lidocaine, and sham. All animals received general anesthesia. In addition, animals in the lidocaine group received a continuous IV infusion of lidocaine during surgery (1.5 mg/kg/h). Animals in the sham group only underwent thoracotomy. Samples of bronchoalveolar lavage (BAL) fluid and plasma were collected before initiation of OLV, at the end of OLV, at the end of surgery, and 24 hours after surgery. Lung biopsy specimens were collected from the left caudal lobe (baseline) before surgery and from the mediastinal lobe and the left cranial lobe 24 hours after surgery. Samples were flash-frozen and stored to measure levels of the following inflammatory markers: interleukin (IL) 1beta, IL-2, IL 10, TNF-alpha, nuclear factor kappaB, monocyte chemoattractant protein-1, inducible nitric oxide synthase, and endothelial nitric oxide synthase. Markers of apoptosis (caspase 3, caspase 9, Bad, Bax, and Bcl-2) were also measured. In addition, levels of metalloproteinases and nitric oxide metabolites were determined in BAL fluid and in plasma samples. A nonparametric test was used to examine statistical significance. RESULTS: OLV caused lung damage with increased TNF-alpha expression in BAL, plasma, and lung samples. Other inflammatory (IL 1beta, nuclear factor kappaB, monocyte chemoattractant protein-1) and apoptosis (caspase 3, caspase 9, and BAX) markers were also increased. With the use of IV lidocaine there was a significant decrease in the levels of TNF-alpha in the same samples compared with the control group. Lidocaine administration also reduced the inflammatory and apoptotic changes observed in the control group. Hemodynamic values, blood gas values, and airway pressure were similar in all groups. CONCLUSIONS: Our results suggest that lidocaine can prevent OLV-induced lung injury through reduced expression of proinflammatory cytokines and lung apoptosis. Administration of lidocaine may help to prevent lung injury during lung surgery with OLV. PMID- 25036370 TI - Production of the Escherichia coli common pilus by uropathogenic E. coli is associated with adherence to HeLa and HTB-4 cells and invasion of mouse bladder urothelium. AB - Uropathogenic Escherichia coli (UPEC) strains cause urinary tract infections and employ type 1 and P pili in colonization of the bladder and kidney, respectively. Most intestinal and extra-intestinal E. coli strains produce a pilus called E. coli common pilus (ECP) involved in cell adherence and biofilm formation. However, the contribution of ECP to the interaction of UPEC with uroepithelial cells remains to be elucidated. Here, we report that prototypic UPEC strains CFT073 and F11 mutated in the major pilin structural gene ecpA are significantly deficient in adherence to cultured HeLa (cervix) and HTB-4 (bladder) epithelial cells in vitro as compared to their parental strains. Complementation of the ecpA mutant restored adherence to wild-type levels. UPEC strains produce ECP upon growth in Luria-Bertani broth or DMEM tissue culture medium preferentially at 26 degrees C, during incubation with cultured epithelial cells in vitro at 37 degrees C, and upon colonization of mouse bladder urothelium ex vivo. ECP was demonstrated on and inside exfoliated bladder epithelial cells present in the urine of urinary tract infection patients. The ability of the CFT073 ecpA mutant to invade the mouse tissue was significantly reduced. The presence of ECP correlated with the architecture of the biofilms produced by UPEC strains on inert surfaces. These data suggest that ECP can potentially be produced in the bladder environment and contribute to the adhesive and invasive capabilities of UPEC during its interaction with the host bladder. We propose that along with other known adhesins, ECP plays a synergistic role in the multi-step infection of the urinary tract. PMID- 25036373 TI - The relationship between serum progesterone concentration and anesthetic and analgesic requirements: a prospective observational study of parturients undergoing cesarean delivery. AB - BACKGROUND: In clinical practice, pregnant women have lower anesthetic requirements for general anesthesia than nonpregnant women. Although the hormonal changes such as progesterone associated with pregnancy may affect the minimum alveolar concentration of volatile anesthetics, the relationship between the anesthetic or analgesic requirements and progesterone level in full-term women has not been studied. In this study, we attempted to identify relationships between anesthetic or analgesic requirements and maternal serum concentrations of progesterone. METHODS: We studied 100 parturients >36 weeks' gestation who were scheduled for planned cesarean delivery under general anesthesia. Venous blood was collected to measure the maternal progesterone concentration. Anesthesia was induced with 4 to 5 mg/kg thiopental and 0.8 mg/kg rocuronium. During anesthetic maintenance, sevoflurane 0.5% to 2.0% and nitrous oxide 50% in oxygen were titrated based on arterial blood pressure, heart rate, and bispectral index value. Vital signs, bispectral index, end-tidal sevoflurane concentration, and sevoflurane consumption per hour were recorded. Visual analog scale pain scores and cumulative analgesic consumption were recorded at 2, 24, and 48 hours postoperatively. RESULTS: The mean serum progesterone concentration was 128.2 +/- 83.0 ng/mL. There was a significant negative correlation between sevoflurane consumption per hour and serum progesterone concentration (Pearson correlation r = -0.26; 95% confidence interval, -0.44 to -0.05, P = 0.01). Cumulative analgesic consumption at postoperative hours 2 (r = -0.20, P = 0.05), 24 (r = -0.25, P = 0.02), and 48 (r = -0.28, P = 0.01) were correlated inversely with serum progesterone concentration. Women with high progesterone levels (higher than the median value) had lower sevoflurane consumption per hour (P = 0.02) and 48-hour postoperative cumulative analgesic consumption (P = 0.02) than women with low (below the median value) levels. CONCLUSIONS: The decreased anesthetic and analgesic requirements of near full-term parturients might partially depend on serum progesterone concentration. PMID- 25036371 TI - Spinal cord injury causes chronic liver pathology in rats. AB - Traumatic spinal cord injury (SCI) causes major disruption to peripheral organ innervation and regulation. Relatively little work has investigated these post SCI systemic changes, however, despite considerable evidence that multiple organ system dysfunction contributes to chronic impairments in health. Because metabolic dysfunction is common after SCI and the liver is a pivotal site for metabolic homeostasis, we sought to determine if liver pathology occurs as a result of SCI in a rat spinal contusion model. Histologic evidence showed excess lipid accumulation in the liver for at least 21 days post-injury after cervical or midthoracic SCI. Lipidomic analysis revealed an acute increase in hepatic ceramides as well as chronically elevated lactosylceramide. Post-SCI hepatic changes also included increased proinflammatory gene expression, including interleukin (IL)-1alpha, IL-1beta, chemokine ligand-2, and tumor necrosis factor alpha mRNA. These were coincident with increased CD68+ macrophages in the liver through 21 days post-injury. Serum alanine transaminase, used clinically to detect liver damage, was significantly increased at 21 days post-injury, suggesting that early metabolic and inflammatory damage preceded overt liver pathology. Surprisingly, liver inflammation was even detected after lumbar SCI. Collectively, these results suggest that SCI produces chronic liver injury with symptoms strikingly similar to those of nonalcoholic steatohepatitis (fatty liver disease). These clinically significant hepatic changes after SCI are known to contribute to systemic inflammation, cardiovascular disease, and metabolic syndrome, all of which are more prevalent in persons with SCI. Targeting acute and prolonged hepatic pathology may improve recovery and reduce long-term complications after SCI. PMID- 25036374 TI - Trending and accuracy of noninvasive hemoglobin monitoring in pediatric perioperative patients. AB - BACKGROUND: Rainbow Pulse CO-Oximetry technology (Masimo Corporation, Irvine, CA) provides continuous and noninvasive measurement of arterial hemoglobin concentration (SpHb). We assessed the trending and accuracy of SpHb by this innovative monitoring compared with Hb concentration obtained with conventional laboratory techniques (Hb) in children undergoing surgical procedures with potential for substantial blood loss. METHODS: Hb concentrations were recorded from Pulse CO-Oximetry and a conventional hematology analyzer. Regression analysis and 4-quadrant plot were used to evaluate the trending for changes in SpHb and Hb measurements (DeltaSpHb and DeltaHb). Bias, precision, and limits of agreement of SpHb and of in vivo adjusted SpHb (SpHb - first bias to HB) compared with Hb were calculated. RESULTS: One hundred fifty-eight SpHb-Hb data pairs and 105 delta pairs (DeltaSpHb and DeltaHb) from 46 patients aged 2 months to 17 years with Hb ranging from 16.7 to 7.9 g/dL were collected. To evaluate trending, the delta pairs (DeltaSpHb and DeltaHb) were plotted, which revealed a positive correlation (DeltaSpHb = 0.022 + 0.76DeltaHb) with correlation coefficient r = 0.76, 95% CI [confidence interval] = 0.57-0.86. The bias and precision of SpHb to Hb and in vivo adjusted SpHb were 0.4 +/- 1.3 g/dL and 0.1 +/- 1.2 g/dL, respectively; the limits of agreement were -2.0 to 3.2 g/dL before in vivo adjustment and -2.4 to 2.2 g/dL after in vivo adjustment (P value = 0.04). The mean percent bias (from the reference Hb concentration) decreased from 4.1% +/- 11.9% to 0.7% +/- 11.3% (P value = 0.01). No drift in bias over time was observed during the study procedure. Of patient demographic and physiological factors tested for correlation with the SpHb, only perfusion index at sensor site showed a weak correlation. CONCLUSIONS: The accuracy of SpHb in children with normal Hb and mild anemia is similar to that previously reported in adults and is independent of patient demographic and physiological states except for a weak correlation with perfusion index. The trending of SpHb and Hb in children with normal Hb and mild anemia showed a positive correlation. Further studies are necessary in children with moderate and severe anemia. PMID- 25036375 TI - Hydroxyethyl starch and acute kidney injury in orthotopic liver transplantation: a single-center retrospective review. AB - BACKGROUND: Acute kidney injury (AKI) is a frequent complication of orthotopic liver transplantation (OLT). Hepatic failure pathophysiology and intraoperative events contribute to AKI after OLT. Colloids are routinely used to maintain intravascular volume during OLT. Recent evidence has implicated 6% hydroxyethyl starch (HES) (130/0.4) with AKI in critically ill patients. METHODS: We performed a retrospective cross-sectional analysis of electronic anesthesia records, surgical dictations, and perioperative laboratory results. Postoperative AKI incidence was determined by RIFLE (Risk Injury Failure Loss End-Stage) criteria. AKI was staged into Risk, Injury, and Failure based on change in serum creatinine from preoperative baseline to peak level by postoperative day 7. Uni- and multivariate analysis was used to evaluate the association between type of intraoperative colloid administered and AKI. RESULTS: One hundred seventy-four adult patients underwent OLT and had complete records for review. Of these, 50 received only 5% albumin, 25 received both 5% albumin and HES, and 99 received only HES. Albumin-only, albumin and HES, and HES-only groups were otherwise homogeneous based on patient characteristics and intraoperative variables. There was a statistically significant linear-by-linear association between type of colloid(s) administered and AKI (Rifle Criteria-Injury Stage). Patients administered HES were 3 times more likely to develop AKI within 7 days after OLT compared with albumin (adjusted odds ratio 2.94, 95% confidence interval, 1.13 7.7, P = 0.027). The linear trend between colloidal use (5% albumin only versus albumin/HES versus HES only, ranked ordering) and "injury" was statistically significant (P = 0.048). A propensity-matched analysis also showed a significant difference in the incidence of AKI between the patients receiving albumin compared with HES (P = 0.044). CONCLUSIONS: Patients receiving 6% HES (130/0.4) likely had an increased odds of AKI compared with patients receiving 5% albumin during OLT. These retrospective findings are consistent with recent clinical trials that found an association between 6% HES (130/0.4) and renal injury in critically ill patients. PMID- 25036376 TI - [Association between methylene-tetrahydrofolate reductase gene polymorphisms and chronic myeloid leukemia]. AB - Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolism. Few studies were reported about its relationship with chronic myeloid leukemia (CML). We conducted a case-control study analyzing the prevalence of the polymorphisms MTHFR C677T and MTHFR A1298C in Algerians CML patients. Using TaqMan((r)) allelic discrimination assay, we investigate MTHFR C677T and A1298C polymorphism distribution in 90 cases of CML and 100 healthy subjects. The frequencies of 677T alleles and genotypes 677TT and 677CT were significantly higher in cases than in control (P = 1E-6; OR = 6.77 [4.22-10.86]) and (P = 1E-6; OR = 10.38 [4.56-23.6]) respectively. Also, the frequencies of 1298C alleles and genotypes 1298CC and 1298AC were higher in cases (P = 9 E-6; OR = 2.65 [1.71 4.10]) and (P = 0.008; OR = 2.22 [1.21-4.06]) respectively. We report also the higher significance of the haplotype 677T/1298A and 677T/1298C in cases (P = 0.007; OR = 2.57 [1.26-5.24]) and (P = 5 E-6, OR = 6.91 [2.7646-17.2899]) respectively. Our results demonstrate that 677T and 1298C alleles are both associated with an increased risk of CML in Algeria. PMID- 25036377 TI - L1 retrotransposons and somatic mosaicism in the brain. AB - Long interspersed element 1 (LINE-1 or L1) retrotransposons have generated one third of the human genome, and their ongoing mobility is a source of inter- and intraindividual genetic diversity. Although retrotransposition in metazoans has long been considered a germline phenomenon, recent experiments using cultured cells, animal models, and human tissues have revealed extensive L1 mobilization in rodent and human neurons, as well as mobile element activity in the Drosophila brain. In this review, we evaluate the available evidence for L1 retrotransposition in the brain and discuss mechanisms that may regulate neuronal retrotransposition in vivo. We compare experimental strategies used to map de novo somatic retrotransposition events and present the optimal criteria to identify a somatic L1 insertion. Finally, we discuss the unresolved impact of L1 mediated somatic mosaicism upon normal neurobiology, as well as its potential to drive neurological disease. PMID- 25036378 TI - Vanadate influence on metabolism of sugar phosphates in fungus Phycomyces blakesleeanus. AB - The biological and chemical basis of vanadium action in fungi is relatively poorly understood. In the present study, we investigate the influence of vanadate (V5+) on phosphate metabolism of Phycomyces blakesleeanus. Addition of V5+ caused increase of sugar phosphates signal intensities in 31P NMR spectra in vivo. HPLC analysis of mycelial phosphate extracts demonstrated increased concentrations of glucose 6 phosphate, fructose 6 phosphate, fructose 1, 6 phosphate and glucose 1 phosphate after V5+ treatment. Influence of V5+ on the levels of fructose 2, 6 phosphate, glucosamine 6 phosphate and glucose 1, 6 phosphate (HPLC), and polyphosphates, UDPG and ATP (31P NMR) was also established. Increase of sugar phosphates content was not observed after addition of vanadyl (V4+), indicating that only vanadate influences its metabolism. Obtained results from in vivo experiments indicate catalytic/inhibitory vanadate action on enzymes involved in reactions of glycolysis and glycogenesis i.e., phosphoglucomutase, phosphofructokinase and glycogen phosphorylase in filamentous fungi. PMID- 25036380 TI - Waste to energy operability enhancement under waste uncertainty via oxygen enrichment. AB - Waste to energy (WTE) performance is evaluated by maximization of electrical energy production and throughput, while maintaining low operational costs and complying with emission limits. Uncertainty in the quantities, composition and heating values of received wastes, pose severe operability problems and impair performance and emissions. The present work demonstrates and quantifies the possibility of improving WTE efficiency under feedstock uncertainty via oxygen enrichment of the combustion air. Acting essentially as a nitrogen depletion mechanism, oxygen enrichment has reverse effects compared to excess air (EA); synergistic use provides extended capabilities for performance improvement, without impairing final emissions, while satisfying capacity constraints. Increased oxygen enrichment is required at higher EA to maintain temperature. Lower charging rates of rich wastes (plastics, paper, etc.) or diminishing heating values, require higher oxygen enrichment or lower EA. The opposite holds for lower charging rates of poor wastes (biodegradables, biosludge, inerts, etc.) or rising heating values. The results establish the possibility of nominal designs to respond to feedstock variations and may be useful for low range excess air operation (low cost) or adiabatic operation (high EA, combustor temperature controlled by large fluegas volumes). The vector formulation facilitates digital coding for applications featuring multiple waste mixture variability. A 700000 tpa WTE facility in Athens, now under public-private-partnership contract tender is investigated. PMID- 25036379 TI - West Nile virus-induced cell adhesion molecules on human brain microvascular endothelial cells regulate leukocyte adhesion and modulate permeability of the in vitro blood-brain barrier model. AB - Characterizing the mechanisms by which West Nile virus (WNV) causes blood-brain barrier (BBB) disruption, leukocyte infiltration into the brain and neuroinflammation is important to understand the pathogenesis of WNV encephalitis. Here, we examined the role of endothelial cell adhesion molecules (CAMs) in mediating the adhesion and transendothelial migration of leukocytes across human brain microvascular endothelial cells (HBMVE). Infection with WNV (NY99 strain) significantly induced ICAM-1, VCAM-1, and E-selectin in human endothelial cells and infected mice brain, although the levels of their ligands on leukocytes (VLA-4, LFA-1and MAC-1) did not alter. The permeability of the in vitro BBB model increased dramatically following the transmigration of monocytes and lymphocytes across the models infected with WNV, which was reversed in the presence of a cocktail of blocking antibodies against ICAM-1, VCAM-1, and E selectin. Further, WNV infection of HBMVE significantly increased leukocyte adhesion to the HBMVE monolayer and transmigration across the infected BBB model. The blockade of these CAMs reduced the adhesion and transmigration of leukocytes across the infected BBB model. Further, comparison of infection with highly neuroinvasive NY99 and non-lethal (Eg101) strain of WNV demonstrated similar level of virus replication and fold-increase of CAMs in HBMVE cells suggesting that the non-neuropathogenic response of Eg101 is not because of its inability to infect HBMVE cells. Collectively, these results suggest that increased expression of specific CAMs is a pathological event associated with WNV infection and may contribute to leukocyte infiltration and BBB disruption in vivo. Our data further implicate that strategies to block CAMs to reduce BBB disruption may limit neuroinflammation and virus-CNS entry via 'Trojan horse' route, and improve WNV disease outcome. PMID- 25036381 TI - Multi-level three-dimensional Mg-Al layered double hydroxide hierarchical microstructures with enhanced basic catalytic property. AB - Novel three-dimensional (3D) rosette-like carbonate-type Mg-Al layered double hydroxide (MgAl-LDH) hierarchical microstructures were fabricated successfully by a surfactant-assisted coprecipitation method in the presence of hexamethylenetetramine as precipitant, and the morphology-dependent basic catalytic property was exploited. The morphologies of MgAl-LDH aggregates were diversified depending on the synthesis parameters including the type of precipitant, concentration of sodium stearate surfactant, and hydrothermal aging time. Specifically, the morphology of MgAl-LDH particles could change progressively from platelet-like aggregates to rosette-like microspheres with the increasing concentration of sodium stearate. A possible formation mechanism for special 3D flower-like MgAl-LDH microstructures was proposed based on the synergistic effect of precipitant with surfactant. Moreover, the resulting activated rosette-like MgAl-LDH, which was prepared through calcination rehydration process, showed a higher catalytic activity in the transesterification of tributyrin with methanol, compared with that derived from the conventional platelet-like MgAl-LDH precursor, which was attributed to its higher specific basicity originating from multi-level hierarchical superstructure offering an advantage in contact with more exposed base sites. PMID- 25036383 TI - Interrogation of multidrug resistance (MDR1) P-glycoprotein (ABCB1) expression in human pancreatic carcinoma cells: correlation of 99mTc-Sestamibi uptake with western blot analysis. AB - Histopathological studies indicate that ~63% of pancreatic tumors express multidrug resistance (MDR1) P-glycoprotein (Pgp) and its polymorphic variants. However, Pgp expression detected at the mRNA or protein level does not always correlate with functional transport activity. Because Pgp transport activity is affected by specific mutations and the phosphorylation state of the protein, altered or less active forms of Pgp may also be detected by PCR or immunohistochemistry, which do not accurately reflect the status of tumor cell resistance. To interrogate the status of the functional expression of MDR1 Pgp in MiaPaCa-2 and PANC-1 cells, cellular transport studies using Tc-Sestamibi were performed and correlated with western blot analysis. Biochemical transport assays in human pancreatic carcinoma MiaPaCa-2 and PANC-1 cells, human epidermal carcinoma drug-sensitive KB-3-1 cells, and human breast carcinoma MCF-7 cells (negative controls), and human epidermal carcinoma drug-resistant KB-8-5 cells, human breast carcinoma stably transfected with Pgp MCF-7/MDR1Pgp cells, and liver carcinoma HepG2 cells (positive controls) were performed. Protein levels were determined using a monoclonal antibody C219. Tc-Sestamibi demonstrates accumulation in human pancreatic carcinoma MiaPaCa-2 and PANC-1 cells. Uptake profiles are not affected by treatment with LY335979, a Pgp inhibitor, and correlate with western blot analysis. These cellular transport studies indicate an absence of Pgp at a functional level in MiaPaCa-2 and PANC-1 cells. Because major pancreatic tumors originate from the pancreatic duct and Tc-Sestamibi undergoes a dominant hepatobiliary mode of excretion, it would not be a sensitive probe for imaging pancreatic adenocarcinomas. Following interrogation of the functional status of Pgp in other pancreatic carcinoma cells, chemotherapeutic drugs that are also MDR1 substrates could offer alternative therapeutics for treating pancreatic adenocarcinomas. PMID- 25036382 TI - Coaxial electrospray of liquid core-hydrogel shell microcapsules for encapsulation and miniaturized 3D culture of pluripotent stem cells. AB - A novel coaxial electrospray technology is developed to generate microcapsules with a hydrogel shell of alginate and an aqueous liquid core of living cells using two aqueous fluids in one step. Approximately 50 murine embryonic stem (ES) cells encapsulated in the core with high viability (92.3 +/- 2.9%) can proliferate to form a single ES cell aggregate of 128.9 +/- 17.4 MUm in each microcapsule within 7 days. Quantitative analyses of gene and protein expression indicate that ES cells cultured in the miniaturized 3D liquid core of the core shell microcapsules have significantly higher pluripotency on average than the cells cultured on the 2D substrate or in the conventional 3D alginate hydrogel microbeads without a core-shell architecture. The higher pluripotency is further suggested by their significantly higher capability of differentiation into beating cardiomyocytes and higher expression of cardiomyocyte specific gene markers on average after directed differentiation under the same conditions. Considering its wide availability, easiness to set up and operate, reusability, and high production rate, the novel coaxial electrospray technology together with the microcapsule system is of importance for mass production of ES cells with high pluripotency to facilitate translation of the emerging pluripotent stem cell based regenerative medicine into the clinic. PMID- 25036384 TI - Commissioning of a new SeHCAT detector and comparison with an uncollimated gamma camera. AB - Measurements of SeHCAT (tauroselcholic [75selenium] acid) retention have been used to diagnose bile acid malabsorption for a number of years. In current UK practice the vast majority of centres calculate uptake using an uncollimated gamma camera. Because of ever-increasing demands on gamma camera time, a new 'probe' detector was designed, assembled and commissioned. To validate the system, nine patients were scanned at day 0 and day 7 with both the new probe detector and an uncollimated gamma camera. Commissioning results were largely in line with expectations. Spatial resolution (full-width 95% of maximum) at 1 m was 36.6 cm, the background count rate was 24.7 cps and sensitivity at 1 m was 720.8 cps/MBq. The patient comparison study showed a mean absolute difference in retention measurements of 0.8% between the probe and uncollimated gamma camera, and SD of +/- 1.8%. The study demonstrated that it is possible to create a simple, reproducible SeHCAT measurement system using a commercially available scintillation detector. Retention results from the probe closely agreed with those from the uncollimated gamma camera. PMID- 25036385 TI - Mesenchymal stem cells deliver exogenous miRNAs to neural cells and induce their differentiation and glutamate transporter expression. AB - MicroRNAs (miRNAs) are potential therapeutic targets in a variety of pathological conditions in the brain; however, their clinical application is hampered by lack of efficient delivery modes. Mesenchymal stromal stem cells (MSCs) migrate to sites of injury and inflammation and exert therapeutic effects in various neurological disorders. Here, we examined the ability of MSCs to deliver exogenous miRNA mimics and pre-miRNAs to human neural progenitor cells (NPCs) and astrocytes and characterized the functional impact of this delivery. We found that MSCs efficiently delivered fluorescent-labeled miR-124 and miR-145 mimics to cocultured NPCs and astrocytes. We further demonstrated the delivery of the miRNAs using novel reporter plasmids that contain a sequence complementary to miR 124 or miR-145 downstream of luciferase or mCherry. Binding of the specific miRNAs to these sequences results in decreased luciferase activity or mCherry fluorescence and therefore enable analysis of miRNA delivery in living cells. The delivered exogenous miR-124 significantly decreased the expression of the target gene Sox9 by targeting its 3'-UTR, and increased the neuronal differentiation of the NPCs. In addition, the delivered miR-124 increased the expression of the glutamate transporters, EAAT1 in NPCs and EAAT2 in both NPCs and astrocytes. Similar results were obtained with MSCs transfected with pre-miR-124. The miRNA delivery was mediated by MSC-derived exosomes and was cell contact independent. These results suggest that MSCs can functionally deliver exogenous miRNAs to neural cells and provide an efficient route of therapeutic miRNA delivery to the brain in pathological conditions with clinical implications for regenerative medicine. PMID- 25036387 TI - Organometallic macromolecules with piano stool coordination repeating units: chain configuration and stimulated solution behaviour. AB - Theoretical calculations illustrate that organometallic macromolecules with piano stool coordination repeating units (Fe-acyl complex) adopt linear chain configuration with a P-Fe-C backbone surrounded by aromatic groups. The macromolecules show molecular weight-dependent and temperature stimulated solution behaviour in DMSO. PMID- 25036386 TI - Effect of low-frequency rTMS on aphasia in stroke patients: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Small clinical trials have reported that low-frequency repetitive transcranial magnetic stimulation (rTMS) might improve language recovery in patients with aphasia after stroke. However, no systematic reviews or meta analyses studies have investigated the effect of rTMS on aphasia. The objective of this study was to perform a meta-analysis of studies that explored the effects of low-frequency rTMS on aphasia in stroke patients. METHODS: We searched PubMed, CENTRAL, Embase, CINAHL, ScienceDirect, and Journals@Ovid for randomized controlled trials published between January 1965 and October 2013 using the keywords "aphasia OR language disorders OR anomia OR linguistic disorders AND repetitive transcranial magnetic stimulation OR rTMS". We used fixed- and random effects models to estimate the standardized mean difference (SMD) and a 95% CI for the language outcomes. RESULTS: Seven eligible studies involving 160 stroke patients were identified in this meta-analysis. A significant effect size of 1.26 was found for the language outcome severity of impairment (95% CI = 0.80 to 1.71) without heterogeneity (I2 = 0%, P = 0.44). Further analyses demonstrated prominent effects for the naming subtest (SMD = 0.52, 95% CI = 0.18 to 0.87), repetition (SMD = 0.54, 95% CI = 0.16 to 0.92), writing (SMD = 0.70, 95% CI = 0.19 to 1.22), and comprehension (the Token test: SMD = 0.58, 95% CI = 0.07 to 1.09) without heterogeneity (I2 = 0%). The SMD of AAT and BDAE comprehension subtests was 0.32 (95% CI = -0.08 to 0.72) with moderate heterogeneity (I2 = 32%,P = 0.22). The effect size did not change significantly even when any one trial was eliminated. None of the patients from the 7 included articles reported adverse effects from rTMS. CONCLUSIONS: Low-frequency rTMS with a 90% resting motor threshold that targets the triangular part of the right inferior frontal gyrus (IFG) has a positive effect on language recovery in patients with aphasia following stroke. Further well-designed studies with larger populations are required to ascertain the long-term effects of rTMS in aphasia treatment. PMID- 25036389 TI - Do we know the optimal management of a torn anterior cruciate ligament of the knee? PMID- 25036388 TI - Characterization of MORE AXILLARY GROWTH genes in Populus. AB - BACKGROUND: Strigolactones are a new class of plant hormones that play a key role in regulating shoot branching. Studies of branching mutants in Arabidopsis, pea, rice and petunia have identified several key genes involved in strigolactone biosynthesis or signaling pathway. In the model plant Arabidopsis, MORE AXILLARY GROWTH1 (MAX1), MAX2, MAX3 and MAX4 are four founding members of strigolactone pathway genes. However, little is known about the strigolactone pathway genes in the woody perennial plants. METHODOLOGY/PRINCIPAL FINDING: Here we report the identification of MAX homologues in the woody model plant Populus trichocarpa. We identified the sequence homologues for each MAX protein in P. trichocarpa. Gene expression analysis revealed that Populus MAX paralogous genes are differentially expressed across various tissues and organs. Furthermore, we showed that Populus MAX genes could complement or partially complement the shoot branching phenotypes of the corresponding Arabidopsis max mutants. CONCLUSION/SIGNIFICANCE: This study provides genetic evidence that strigolactone pathway genes are likely conserved in the woody perennial plants and lays a foundation for further characterization of strigolactone pathway and its functions in the woody perennial plants. PMID- 25036390 TI - [Distal locking techniques without fluoroscopy in intramedullar nailing]. AB - OBJECTIVES: In this study, we present three distal locking techniques and two checking methods in intramedullar nailing. PATIENTS AND METHODS: Between January 1999 and December 2011, we performed distal locking with locked intramedullary nails on 501 femoral bone fractures using bone alignment and aspiration technique without fluoroscopy and 578 tibial bone fractures using medial malleolus alignment, bone alignment and aspiration technique without fluoroscopy at Antalya Training and Research Hospital. RESULTS: With the combination of these three locking techniques and two checking methods, locking was successful in all cases except one. In the latter case, the nail remained anteriorly, as the distal screws were not fully compliant with the surgical technique. CONCLUSION: Distal locking can be achieved in a short time using one or combining two or more techniques and methods without fluoroscopy. PMID- 25036391 TI - An investigation of consistency between posterior condylar axis +3 degree external rotation line and clinical transepicondylar axis line techniques in primary total knee arthroplasty. AB - OBJECTIVES: This study aims to investigate discrepancy between posterior condylar axis (PCA)+3 degree external rotation (ER) line and clinical transepicondylar axis (cTEA) line and consistency between the both techniques in primary total knee arthroplasty. PATIENTS AND METHODS: Thirty-six knees [Bilateral knees were operated simultaneously in 12 patients (50%)] in 24 patients [3 men (12.5%), 21 women (87.5%); average age 67 (59-80 age)] were included in the study. During surgery, PCA+3 degrees ER line and cTEA line were drawn on the distal femoral cutting surface by electrocautery pencil following distal femoral cut. The both lines on distal femur were recorded by digital camera and relationship between lines was ascertained in reference to PCA+3 degrees ER line [parallel, internal rotation (IR), ER]. Statistical analysis was performed by the McNamara chi square test and Kappa (kappa) value. RESULTS: Assessment of the images revealed that cTEA line in comparison to PCA+3 degrees ER line was parallel in 22 knees (61.2%), but not parallel in 14 knees (38.8%) [IR in 10 knees (71.5%), ER in 4 knees (28.5%)]. There was a significant difference (McNamara chi square=12.7+/-1; p<0.001) and poor consistency (kappa=0.00055) between both lines and techniques, respectively. CONCLUSION: For determination of femoral component rotation in surgery setting, different results between cTEA and PCA+3 degrees ER techniques possibly may due to disadvantages of techniques and anatomic variation of distal femur. Thus, using both techniques to check each other's results seems unsafe. PMID- 25036392 TI - The accuracy of two different extra-medullary tibial cutting guides for posterior tibial slope in total knee arthroplasty. AB - OBJECTIVES: This study aims to evaluate the effectiveness of two different external tibial cutting guides with and without a spike anchoring to the intercondylar eminentia to achieve a desired posterior tibial slope. PATIENTS AND METHODS: Between January 2008 and December 2011, 120 posterior cruciate ligament protecting total knee arthroplasty (TKA) surgeries of 83 patients in which two different external tibial cutting guides used were included. Fifty-nine knees were included into the spiked and 61 knees were included into the spikeless cutting guide group. Posterior tibial slope angles were measured using the postoperative X-rays. RESULTS: There was no significant difference between two groups in terms of age, sex, and body mass indexes (p<0.05). While the mean postoperative slope angle was 2.66 degrees +/-2.001 degrees (range 0 degrees -7 degrees ) in spiked group, it was 2.46 degrees +/-2.277 degrees (range 0 degrees -7 degrees ) in spikeless group. Both systems had identical accuracy, indicating a low rate. The comparison of variances of two groups showed that both cutting guides had similar precision (p=0.234). There was no effect of body mass index on the results in both groups. CONCLUSION: Although different extra-medullary tibial cutting guides with and without a spike can reproducibly impart a desired posterior tibial slope in TKA, we concluded that a spiked guide was considered user-friendly. PMID- 25036393 TI - [Are orthopedic surgeons more aware of medical treatment of osteoporotic fractures in the last decade?]. AB - OBJECTIVES: This study aims to whether orthopedic and traumatology specialists are more aware of medical treatment of osteoporotic fractures in the last decade. PATIENTS AND METHODS: Between January 2002 and December 2011, 844 patients (560 females, 284 males; mean age: 78 years; range 60 to 94 years) who suffered from surgical fractures due to low-energy trauma and received no osteoporotic treatment previously without a diagnosis of secondary osteoporosis were included in the study. The rate of initiation of osteoporotic treatment for surgical fractures due to low-trauma energy was investigated. RESULTS: Treatment initiation varied significantly according to the years (p=0.009), while there was no significant difference in the treatment initiation according to the diagnosis (p=0.735). In 2005 and 2008 years, a two-fold increase was seen in the initiation of medical treatment of osteoporotic fractures. Over the years, increased awareness of diagnosis and treatment of osteoporotic fractures was replaced with a decline. CONCLUSION: Orthopedic surgeons are more aware of medical treatment of osteoporotic fractures in the last decade, but this is temporary. PMID- 25036394 TI - The effect of early weight-bearing on comminuted calcaneal fractures treated with locking plates. AB - OBJECTIVES: This study aims to evaluate the possible effects of early weight bearing on clinical and radiological outcomes of comminuted calcaneal fractures treated with locking plates. PATIENTS AND METHODS: This retrospective study included 15 patients (12 males, 3 females; mean age 40.1 years; range 18 to 55 years) with comminuted calcaneal fractures between October 2010 and April 2012. Standard lateral extensile approach was carried out for surgical exposure. A corticocancellous allograft was used to fill the defect following the reduction and fixation of posterior facet. Titanium locking plates and screws were used to maintain reduction. The patients were encouraged for a limited weight-bearing at six weeks postoperatively, if tolerated. All patients were able to full weight bear at 12 weeks postoperatively. Clinical and radiological assessments were performed using the American Orthopaedic Foot and Ankle Society (AOFAS) and Maryland scores. RESULTS: The mean follow-up was 19 months (range, 12 to 27 months). The AOFAS and Maryland scores were 89 and 88.46 points, respectively. The Bohler's angle showed 0.3 degrees loss from early post-surgery to the last visit. Among the workers, all returned to work but one with Sanders type IV fracture and all retired patients returned to their daily activities. The functional status of the patient with Sanders type IV fracture was poor according to the AOFAS and Maryland criteria. CONCLUSION: Based on radiographic and clinical assessment, there was no unfavorable effect of early weight-bearing after calcaneal fracture surgery. Therefore, these results suggest that sufficient stability can be achieved by locking plates in comminuted calcaneal fractures, when early weight-bearing is recommended, even. PMID- 25036395 TI - Does surgically fixation of pubic fracture increase the stability of the operated posterior pelvis? AB - OBJECTIVES: This study aims to investigate whether surgical treatment of pubic rami fractures increases the stability of the posterior pelvis. PATIENTS AND METHODS: A finite element pelvic model with improved geometric and material characteristics was analyzed. By imitating a standing position, a type I Denis sacrum fracture and a unilateral pubis fracture, we measured the differences in tension and displacement. The posterior injury was treated with a direct plate synthesis or transsacral plate synthesis, while the pubis fracture was left without fixation or fixed with either a retrograde pubic screw or plate synthesis. RESULTS: The operative fixation of pubic rami fractures decreased the movement in the fracture gap not only at the site of the pubis fracture, but also at the site of the fixed sacrum fracture. The plate synthesis provided greater stability of the anterior fracture than the retrograde screw. The tensions in the implants were below the allowed values. CONCLUSION: We concluded that surgically fixation of pubic fracture increases the stability of the operated posterior pelvis. PMID- 25036396 TI - Collagen membrane wrapping around methotrexate-containing calcium-phosphate cement reduces the side effects on soft tissue healing. AB - OBJECTIVES: This study aims to evaluate whether the collagen membrane (membrane) wrapping around the methotrexate (MTX)-containing calcium-phosphate cement (CPC) reduces the side effects on soft tissue healing. MATERIAL AND METHODS: In 36 rats, femoral bone defects were created and treated in six groups which were CPC only, CPC and membrane wrapping around, CPC containing 2% MTX, CPC containing 2% MTX and membrane wrapping around, CPC containing 5% MTX, CPC containing 5% MTX and membrane wrapping around. RESULTS: Histological examinations revealed a statistically significantly improved healing in the connective tissue samples of the CPC containing 5% MTX group wrapped around by membrane compared to those without membrane (p=0.04). However, this was not seen in other groups. CONCLUSION: Membrane wrapping around the CPC containing MTX reduces the side effect of MTX on cellular proliferation at its highest concentration, particularly. Membrane wrapping may allow administration of higher doses of an anti-neoplastic drug which can be more effective. PMID- 25036397 TI - Does hyaluronic acid decrease the apoptotic effect of bupivacaine? AB - OBJECTIVES: In this study, we aimed to study the anti-apoptotic effects of hyaluronic acid on the apoptotic effects of bupivacaine in cultured rat chondrocytes in a time and dose-dependent manner. MATERIAL AND METHODS: The rat chondrocytes were treated with 7.69 uM, 76.9 uM, and 384.5 uM bupivacaine and 50 ug/ml hyaluronic acid concentrations for six, 24, and 48 hours. At the end of the treatment period, cells were stained with mixture of acridine orange and ethidium bromide. Apoptosis was evaluated using a fluorescence microscope. RESULTS: A significant protective effect of hyaluronic acid on chondrocytes against bupivacaine exposure at 7.69 uM and 76.9 uM concentrations, particularly was observed. There was also a significant protective effect in the exposure time at six and 24 hours for 7.69 uM and 76.9 uM bupivacaine doses. CONCLUSION: Our study results show that hyaluronic acid against chondrotoxicity of bupivacaine may have a protective effect in a time and dose-dependent manner. PMID- 25036398 TI - [An unusual management of advanced gonarthrosis: total knee arthroplasty with posterior approach]. AB - In this article, we present a 68 year-old female case admitted with complaints of a painful knee and walking difficulty with simultaneous advanced gonarthrosis and a huge osteochondroma in posterior distal femur which was adjacent to the vessel and nerve structures, who was treated with a single incision via posterior approach for tumor excision and arthroplasty. Simultaneous tumor excision and arthroplasty application were scheduled and the knee joint was reached via posterior popliteal approach. Hinged knee prosthesis was applied through the same incision following tumor excision. Two-stage surgical procedures can be an option for coexisting bone tumor and arthrosis. Arthroplasty can be performed following tumor excision. In our case, we managed two distinct different problems in a single session with a single approach. To the best of our knowledge, this is the first knee arthroplasty case performed with posterior approach. PMID- 25036399 TI - Minimally invasive hollow trephine technique is recommended for revision of broken uncemented and extensively porous-coated monolithic femoral stems: a review of three cases. AB - Revisions of fractured, uncemented and extensively porous-coated femoral stems are challenging. In this article, we report three cases of revision surgeries for broken, cementless, and extensively porous-coated femoral stems with Solution stems (DePuy, Warsaw, Indiana). In all cases, minimally invasive endofemoral revision was successfully performed without femoral osteotomy or cortical fenestration. Removal of distal broken femoral stem was performed with hollow trephine technique under fluoroscopy. For revision arthroplasty of the femoral component, Solution stems of larger diameter were used. Endofemoral approach reduces duration of surgery and the amount of blood and bone loss. Minimally invasive technique for broken and uncemented femoral stem is recommended. PMID- 25036400 TI - [Arthroscopic excision of elastofibroma dorsi at scapulothoracic joint: a surgical technique]. AB - Elastofibroma dorsi is a rare soft tissue pseudotumor which is located at the anteroinferior aspect of the scapula. In this article, we report a 19-year-old female case who had arthroscopic marginal excision of elastofibroma dorsi at the scapulothoracic joint without recurrences during follow-up. The arthroscopic marginal excision of the elastofibroma dorsi may have good clinical results in selected cases. PMID- 25036401 TI - [A giant hydatid cyst localized in pelvis and thigh]. AB - A hydatid cyst is a parasitic disease which is caused by a cestode named Echinococcus and often located in the liver. Localization in the bone and soft tissue is rarely seen. In this article, we present a 64-year-old male case with a hydatid cyst located in the soft tissue of the left anterolateral aspect of the thigh. The hydatid cyst starting from the gluteal region proximally into the pelvis, the femoral head and the hip joint leading to the spread of secondary protrusio acetabuli and extending distally to the popliteal region formed a massive lesion. In addition to medical treatment followed by repeated surgeries, the patient with relapses is still under surgical follow-up and medical treatment. PMID- 25036402 TI - Decreased expression and prognostic role of cytoplasmic BRSK1 in human breast carcinoma: correlation with Jab1 stability and PI3K/Akt pathway. AB - OBJECTIVE: Jun activation domain-binding protein 1 (Jab1) was overexpressed in breast cancer, which was involved in degradation of the cyclin-dependent kinase inhibitor p27(Kip1). The objective of this study was to examine the effect of brain specific kinase 1 (BRSK1) expression on Jab1 over-expression and related signaling pathway in breast cancer. METHODS: Immunohistochemical analysis was performed in 95 human breast carcinoma samples and the data were correlated with clinicopathologic features. Furthermore, Western blot analysis was performed for BRSK1 and Jab1 in breast carcinoma samples and cell lines to evaluate their protein levels and molecular interaction. RESULTS: We found that the cytoplasmic BRSK1 expression was inversely associated with Jab1 expression (P<0.01) and correlated significantly with histologic grade (P=0.006), however nuclear BRSK1 expression couldn't obtain similar results. Kaplan-Meier analysis revealed that survival curves of low versus high expressers of cytoplasmic BRSK1 and Jab1 showed a highly significant separation in breast cancer (P<0.01). While in vitro, following release of breast cancer cell lines from serum starvation, the expression of Jab1, phosphor-Akt (p-Akt) was up-regulated, whereas BRSK1 and p27(Kip1) were decreased. Treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 could diminish Jab1 expression but increase BRSK1 expression. In addition, we employed siRNA technique to knock down Jab1 and/or BRSK1 expression and observed their effects on MDA-MB-231 cell growth. CONCLUSIONS: BRSK1 is a novel tumor suppressor in breast cancer which inversely correlated with Jab1 expression, may involve in the restoring Jab1-induced suppression of p27(Kip1) and may regulate cell cycle through the PI3K/Akt pathway. PMID- 25036403 TI - Annexin A3 plays a role in cytoplasmic calcium oscillation by extracellular calcium in the human promyelocytic leukemia HL-60 cells differentiated by phorbol 12-myristate-13-acetate. AB - The roles of annexin A3 (ANXA3) in macrophages are not fully understood. In contrast to C5a, we have demonstrated that C-terminal ribosomal protein S19 (RP S19)-tagged S-tagged C5a (S-tagged C5a/RP S19) raises an alternative cytoplasmic calcium oscillation by extracellular calcium during macrophage migration into apoptotic cells. We here differentiated human promyelocytic leukemia HL-60 cells bearing with either control sense RNA and shRNA for ANXA3 mRNA or a vector cDNA with or without ANXA3 cDNA into macrophage-like cells by phorbol-12-myristate-13 acetate and found that a fluorescence ratio (340 nm/380 nm) upon the S-tagged C5a/RP S19-induced alternative cytoplasmic calcium oscillation by extracellular calcium was an equilateral association with a dose of ANXA3. Moreover, the ANXA3 dependent modification was partially reflected upon the S-tagged C5a-induced classical cytoplasmic calcium oscillation by both intracellular calcium and extracellular calcium. ANXA3 seems to extend the C5aR-mediated cytoplasmic calcium oscillation by extracellular calcium at least in the HL-60 macrophage like cells. PMID- 25036404 TI - The impact of TP53 and RAS mutations on cerebellar glioblastomas. AB - Cerebellar glioblastoma (cGBM) is a rare, inadequately characterized disease, without detailed information on its molecular basis. This is the first report analyzing both TP53 and RAS alterations in cGBM. TP53 mutations were detected in more than half of the samples from our cohort, mainly in hotspot codons. There were no activating mutations in hotspot codons 12/13 and 61 of KRAS and HRAS genes in cGBM samples but we detected alterations in other parts of exons 2 and 3 of these genes, including premature induction of STOP codon. This mutation was present in 3 out of 5 patients. High incidence of RAS mutations, as well as significantly longer survival of cGBM patients compared to those with supratentorial GBM suggest that cGBM may have different mechanisms of occurrence. Our results suggest that inactivation of TP53 and RAS may play an important role in the progression of cerebellar GBM. PMID- 25036405 TI - Characteristic, polymorphism and expression distribution of LCAT gene in a Mongolian gerbil model for hyperlipidemia. AB - This study aims to evaluate the genetic basis and activity of lecithin cholesterol acyltransferase (LCAT) in a novel Mongolian gerbil model for hyperlipidemia. Gerbils may be susceptible to high fat and cholesterol (HF/HC) diets, which can rapidly lead to the development of hyperlipidemia. Approximately 10-30% of gerbils that are over 8months old and fed controlled diets spontaneously develop hyperlipidemia. Using the HF/HC diet model, we detected triglycerides (TG), total cholesterol (TC), HDL (high density lipoprotein)-C, LDL (low density lipoprotein)-C and LCAT in both old (>8months) and young gerbils. The TC and HDL-C levels were two times higher in old gerbils compared with young gerbils (P<0.01). However, in the old group the LCAT activity fell slightly compared with the normal lipidemia group. It is reasonable to hypothesize that this may be associated with single nucleotide polymorphisms of the LCAT gene. We cloned this gene to investigate the sensitivity of the gerbil to the HF/HC diet and spontaneous hyperlipidemia. The entire LCAT gene was cloned by splicing sequences of RACE (rapid amplification of cDNA ends) and nest-PCR products (AN: KC533867.1). The results showed that the 3683base pair gene consists of six exons and five introns. The LCAT protein consists of 444 amino acid (AA) residues, which are analogous to the human LCAT gene, and includes 24 signal peptide AA and 420 mature protein AA. Expression of LCAT was detected in the kidney, spleen and adrenal tissue, apart from the liver, by immunohistochemistry. The abundance of the protein was greater in the older group compared with the control group. Polymorphisms were analyzed by PCR-SSCP (PCR-single-strand conformation polymorphism) but none were found in 444 animals of the ZCLA closed population (a Chinese cultured laboratory gerbil population). PMID- 25036406 TI - Mid-term follow-up of the TVT-Secur midurethral sling for primary stress incontinence. AB - OBJECTIVE: The TVT-Secur was introduced in 2006 as a less invasive alternative to retropubic and transobturator suburethral slings. This retrospective cohort study evaluated objective and subjective results in a series of 158 consecutive patients as well as complications and the reoperation rate after TVT-Secur procedure. STUDY DESIGN: Between November 2006 and June 2010 a total of 158 patients underwent a TVT-Secur procedure at a single institution. All patients underwent preoperative urodynamic testing. All patients were invited for follow up including physical examination, urodynamic studies and subjective evaluation. RESULTS: A total of 96 patients (61%) were available for follow-up with a mean follow-up of 29.8 months (range 5-50, median 30). At follow-up, eight (8%) of 96 patients had reoperations for stress incontinence. There were no reoperations for bleeding/hematoma, tape erosions or obstructed micturition and there were no tape erosions or exposures. 29 patients (30%) had a negative cough stress test and 44 patients (46%) subjectively considered themselves "cured". Nine of 43 patients (21%) without urgency symptoms preoperatively developed de novo urgency; 24 of 35 patients (69%) with preoperative urgency complaints were free of urgency symptoms. CONCLUSION: At 2.4 years, the TVT-Secur appears to have a low adverse events profile but inferior results compared with traditional midurethral slings. PMID- 25036407 TI - Exploring the scope of practice and training of obstetricians and gynaecologists in England, Italy and Belgium: a qualitative study. AB - INTRODUCTION: This study explores the scope of practice of Obstetrics and Gynaecology specialists in Italy, Belgium and England, in light of the growth of professional and patient mobility within the EU which has raised concerns about a lack of standardisation of medical speciality practice and training. METHODS: Semi-structured qualitative interviews were conducted with 29 obstetricians and gynaecologists from England, Belgium and Italy, exploring training and scope of practice, following a common topic guide. Interviews were recorded, transcribed and coded following a common coding framework in the language of the country concerned. Completed coding frames, written summaries and key quotes were then translated into English and were cross-analysed among the researchers to identify emerging themes and comparative findings. RESULTS: Although medical and specialty qualifications in each country are mutually recognised, there were great differences in training regimes, with different emphases on theory versus practice and recognition of different subspecialties. However all countries shared concerns about the impact of the European Working Time Directive on trainees' skills development. Reflecting differences in models of care, the scope of practice of OBGYN varied among countries, with pronounced differences between the public and private sector within countries. Technological advances and the growth of co-morbidities resulting from ageing populations have created new opportunities and greater links with other specialties. In turn new ethical concerns around abortion and fertility have also arisen, with stark cultural differences between the countries. CONCLUSION: Variations exist in the training and scope of practice of OBGYN specialists among these three countries, which could have significant implications for the expectations of patients seeking care and specialists practising in other EU countries. Changes within the specialty and advances in technology are creating new opportunities and challenges, although these may widen existing differences. Harmonisation of the training and scope of practice of OBGYN within Europe remains a distant goal. Further research on the scope of practice of medical professionals would better inform future policies on professional mobility. PMID- 25036408 TI - Comparison of serum anti-Mullerian hormone levels in normal weight and overweight obese adolescent patients with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate serum concentration of anti-Mullerian hormone (AMH) in adolescent patients with polycystic ovary syndrome (PCOS) with respect to body mass index (BMI), and to investigate the relationship with clinical, metabolic and hormonal parameters. STUDY DESIGN: Fifty-eight adolescent girls (29 normal weight and 29 overweight-obese) diagnosed with PCOS and 28 apparently healthy girls (controls) were enrolled in the study. BMI was calculated in all cases. Serum AMH, hormonal and metabolic parameters were compared between patients with PCOS (normal weight and overweight-obese) and controls. RESULTS: Serum AMH did not differ between patients with PCOS and controls (p=0.283), and no correlation was found between BMI and AMH. A significant positive correlation was found between 2-h plasma glucose on 75-g oral glucose tolerance test and AMH (R=0.364, p=0.005). HOMA-IR index and insulin were significantly higher in overweight-obese patients with PCOS than in controls, but no significant difference was found between controls and normal-weight patients with PCOS. CONCLUSIONS: AMH was not found to be a reliable predictor for the presence of PCOS, and serum AMH did not differ between obese and non-obese adolescent patients with PCOS. PMID- 25036409 TI - Facile deposition of YSZ-inverse photonic glass films. AB - An alternative all-colloidal and single-step deposition method of yttrium stabilized zirconia (YSZ)-infiltrated polymeric photonic glass films is presented. Heterocoagulation of oppositely charged polystyrene (PS) microspheres and YSZ nanocrystals in aqueous dispersions created PS/YSZ core-shell spheres. These composite particles were deposited on glass substrates by a simple drop coating process. Heterocoagulation impaired self-assembly of the particles, resulting in a disordered structure. Burn-out of the polymer yielded a random array of YSZ shells. The effect of the filling fraction of YSZ between these shells was explored. YSZ-inverse photonic glass films with a thickness below 40 MUm achieved 70% reflectance of the incident radiation over a broad wavelength range between 0.4 and 2.2 MUm. The YSZ structures demonstrated structural stability up to 1000 degrees C and maintained high reflectance up to 1200 degrees C for several hours, thus enabling applications as broadband reflectors at elevated temperatures. PMID- 25036410 TI - Detailed evaluation of the aspartate aminotransferase/platelet ratio index and enhanced liver fibrosis tests in assessing hepatic fibrosis. PMID- 25036411 TI - Fecal microbiota transplantation for treatment of Clostridium difficile infection. PMID- 25036412 TI - Comparative analyses of universal extraction buffers for assay of stress related biochemical and physiological parameters. AB - Comparative efficiency of three extraction solutions, including the universal sodium phosphate buffer (USPB), the Tris-HCl buffer (UTHB), and the specific buffers, were compared for assays of soluble protein, free proline, superoxide radical (O2?-), hydrogen peroxide (H2O2), and the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POD), ascorbate peroxidase (APX), glutathione peroxidase (GPX), and glutathione reductase (GR) in Populus deltoide. Significant differences for protein extraction were detected via sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and two dimensional electrophoresis (2-DE). Between the two universal extraction buffers, the USPB showed higher efficiency for extraction of soluble protein, CAT, GR, O2? , GPX, SOD, and free proline, while the UTHB had higher efficiency for extraction of APX, POD, and H2O2. When compared with the specific buffers, the USPB showed higher extraction efficiency for measurement of soluble protein, CAT, GR, and O2? , parallel extraction efficiency for GPX, SOD, free proline, and H2O2, and lower extraction efficiency for APX and POD, whereas the UTHB had higher extraction efficiency for measurement of POD and H2O2. Further comparisons proved that 100 mM USPB buffer showed the highest extraction efficiencies. These results indicated that USPB would be suitable and efficient for extraction of soluble protein, CAT, GR, GPX, SOD, H2O2, O2?-, and free proline. PMID- 25036413 TI - Hybrid fixation with sublaminar polyester bands in the treatment of neuromuscular scoliosis: a comparative analysis. AB - BACKGROUND: Segmental spinal instrumentation with Luque wire fixation has been the standard treatment of neuromuscular scoliosis for >30 years. More recently, pedicle screw constructs have become the most widely utilized method of posterior spinal fixation; however, they are associated with complications such as implant malposition. We report the use of polyester bands and clamps utilized with pedicle screws in a hybrid fixation construct in the treatment of neuromuscular scoliosis. METHODS: A retrospective review was conducted of 115 pediatric spinal deformity cases between 2008 and 2010 at a single center performed by a single surgeon. Intraoperative and postoperative complications were recorded. Radiographs were reviewed preoperatively and at the latest follow-up. A systematic review of the literature was conducted. Data from case series reporting outcomes of sublaminar wires and all-pedicle screw constructs in the treatment of neuromuscular scoliosis were compared with outcomes of the present study. RESULTS: Twenty-nine patients with neuromuscular scoliosis who underwent segmental spinal instrumentation with a hybrid construct including sublaminar bands and pedicle screws were included. There was an average follow-up of 29 months (range, 12 to 40 mo). The average postoperative correction of coronal balance was 69% (range, 24 to 71 degrees). Sagittal balance was corrected to within 2 cm of the C7 plumbline in 97% of patients. The loss of coronal and sagittal correction at latest follow-up was 0% and 2%, respectively. There were 2 intraoperative clamp failures of the 398 implants (0.5%). There were 2 major (6.9%) and 7 minor (24%) complications in 7 patients (24% overall). These results compared favorably to previous case series of sublaminar wire and all-pedicle screw fixation techniques. CONCLUSIONS: The polyester band technique is an excellent adjunct in the correction of spinal deformity in patients with neuromuscular scoliosis. Sublaminar bands utilized in a hybrid construct appear to be safe, can achieve corrections equivalent to all-pedicle screw constructs, and may decrease the potential complications associated with every level transpedicular fixation in the patient with a highly dysmorphic and osteoporotic spine. LEVEL OF EVIDENCE: Level IV: cohort study. PMID- 25036414 TI - Radiographic diagnosis of occult distal fibular avulsion fracture in children with acute lateral ankle sprain. AB - BACKGROUND: Skeletally immature children with ankle sprain are presumed to have distal fibula fracture than ligamentous injury. The purpose of this study is to determine the incidence of associated occult avulsion fracture in children with lateral ankle sprain and the efficacy of identifying fractures using anterior talofibular ligament view. METHODS: Patients who were diagnosed with distal fibular fracture in the initial ankle anteroposterior, lateral, and mortise were excluded and 78 patients (below 16 y of age) who had been initially diagnosed as ankle sprain were included. The initial and 4 weeks' follow-up ankle series and additional anterior talofibular ligament view suggested by Haraguchi were evaluated. RESULTS: Twenty patients were diagnosed with occult distal fibular avulsion fracture. Ten patients were diagnosed in anterior talofibular ligament view and others were diagnosed in the follow-up radiography. Displacement was highest on the anterior talofibular ligament view. CONCLUSIONS: This study found 20 (26%) of 78 ankle sprain show occult avulsion fracture in the anterior talofibular ligament view or follow-up radiography. The anterior talofibular ligament view is an appropriate radiologic view for the diagnosis of distal fibular avulsion fracture. LEVEL OF EVIDENCE: Level IV--diagnostic study. PMID- 25036415 TI - Secondary ossification centers in the development of the medial malleolus. AB - BACKGROUND: Accessory ossicles of the medial malleolus have been reported, however, these have not been linked to a pattern of development and are considered anomalies. Here, we describe a pattern of ossification of the medial malleolus in children including a secondary ossification center. METHODS: Twenty anteroposterior (AP) and mortise x-rays of each sex and age from 4 to 12 were randomly selected from skeletally immature patients identified at our institution. X-rays were excluded if there was a cast or splint, fracture, hardware, or obvious tibial deformity. Each x-ray was evaluated and categorized to a 4-part stage of development. These stages were then applied to randomly selected AP hip to ankle films from the same age groups. RESULTS: Four distinct stages of medial malleolus ossification were identified on ankle x-rays. Stage 1 consists of the widening of the epiphysis that did not reach the medial border of the metaphysis. In stage 2, the epiphysis had widened medially to the level of the metaphysis, however, had not extended distally to the level of the dome of the talus. In stage 3, the proximal portion of the medial malleolus has ossified distal to the dome of the talus with ossification centers at this level identified. Stage 4 consisted of a completely fused ossification center extending distally to a mature medial malleolus. The stages were reconfirmed on AP standing hip to ankle to have a similar distribution, secondary ossification centers were more common in females aged 6 to -9 and males aged 8 to 11 years. CONCLUSIONS: The medial malleolus develops in predictable stages which may involve a secondary ossification center in the final stages of development. These findings were initially described on AP and mortise views, then confirmed on AP hip to ankle radiographs were evaluated to exclude potentially confounding ankle pain. These secondary ossification centers were seen at similar ages on both ankle and hip to ankle x-rays. LEVEL OF EVIDENCE: Level III. PMID- 25036416 TI - Elbow dislocation with an associated lateral condyle fracture of the humerus: a rare occurrence in the pediatric population. AB - BACKGROUND: In the pediatric population, reports of a concomitant lateral condyle fracture (LCF) of the humerus and an elbow dislocation are rare. METHODS: From 2007 to 2013, we identified a group of 12 children who presented to our institution with a concomitant LCF and an elbow dislocation. This subset of fractures (group 1), all of which were managed surgically, is the subject of the present report. Their outcome was compared with that of all LCFs that were treated surgically at our institution during the study period (group 2, n=179). The length of surgery, recovery of range of motion (ROM), lateral spur formation, and the presence or absence of neurological or vascular complications, pin-tract infection, loss of fixation, and avascular necrosis or nonunion of the lateral condyle were used to describe the outcome of the fracture. RESULTS: A concomitant elbow dislocation and LCF of the humerus was observed in 12 patients with a mean age of 5.5 years (range, 2 to 8), and a mean follow-up of 51 weeks. A posteromedial dislocation of the elbow was observed in most patients. The recovery of ROM appeared to be slower for patients with an associated elbow dislocation, but a full recovery of ROM was obtained in the long term. Lateral spur formation was seen in all fractures in group 1 and only in 72% of fractures in group 2 (P=0.02). A satisfactory outcome was observed in 92% of fractures in group 1 and in 88% of fractures in group 2 (P=0.58). CONCLUSIONS: Concomitant LCF of the humerus and an elbow dislocation are rare. Satisfactory outcomes can be expected when prompt reduction of the elbow dislocation and timely anatomic reduction and fixation of the fracture is obtained. A delayed recovery of elbow motion is common among this population, but a full recovery of ROM can be expected in the long term. LEVEL OF EVIDENCE: Level II-retrospective. PMID- 25036417 TI - Does preoperative orientation and education alleviate anxiety in posterior spinal fusion patients? A prospective, randomized study. AB - BACKGROUND: A prospective, randomized study examined the effect of interventional preoperative education and orientation for scoliosis surgery (PEOSS) on anxiety levels of patients undergoing posterior spinal fusion (PSF). Secondary outcomes analyzed were caregiver anxiety, length of stay, morphine equivalent usage, and patient/caregiver satisfaction. METHODS: Patients undergoing PSF were randomly distributed into a control group (N=39) or interventional group (N=26). All subjects and caregivers completed the State (current)-Trait (typical) Anxiety Inventory (STAI) at different intervals: preoperative appointment, preoperative holding area, postoperative orthopaedic unit, and discharge. At discharge, patients and caregivers completed a satisfaction survey. RESULTS: Significantly higher state anxiety scores were found compared with baseline at all time intervals in both the control group and PEOSS group. The PEOSS group had higher state anxiety scores than the control group at the postoperative interval (P=0.024). There were no significant differences in the caregiver state anxiety scores between the groups at any time interval. Trait anxiety scores for both groups remained stable over time, establishing that the measurement tool accurately reflected baseline anxiety. No significant differences were found in length of stay or morphine equivalent use. Patient satisfaction scores were higher in the PEOSS group than in the control group (P=0.0005). CONCLUSIONS: PSF was associated with increased anxiety at all time intervals in adolescents in both groups. In the PEOSS group, PSF was associated with increased anxiety in the immediate postoperative period. Despite the increase in anxiety, patient satisfaction was higher in the intervention group. It is likely that patients need age-appropriate information and educational strategies to minimize anxiety during PSF. Further work is underway to study and develop more effective interventional strategies. LEVEL OF EVIDENCE: Level I study. PMID- 25036419 TI - How Zulu-speaking youth with physical and visual disabilities understand love and relationships in constructing their sexual identities. AB - Popular socio-medical discourses surrounding the sexuality of disabled people have tended to subjugate young people with disabilities as de-gendered and asexual. As a result, very little attention has been given to how young people with disabilities in the African context construct their sexual identities. Based on findings from a participatory research study conducted amongst Zulu-speaking youth with physical and visual disabilities in KwaZulu-Natal, this paper argues that young people with disabilities are similar to other non-disabled youth in the way they construct their sexual identities. Using a post-structural framework, it outlines how the young participants construct discursive truths surrounding disability, culture and gender through their discussions of love and relationships. In this context, it is argued that the sexual identities' of young people with physical and visual disabilities actually emerges within the intersectionality of identity discourses. PMID- 25036418 TI - His bundle activates faster than ventricular myocardium during prolonged ventricular fibrillation. AB - BACKGROUND: The Purkinje fiber system has recently been implicated as an important driver of the rapid activation rate during long duration ventricular fibrillation (VF>2 minutes). The goal of this study is to determine whether this activity propagates to or occurs in the proximal specialized conduction system during VF as well. METHODS AND RESULTS: An 8*8 array with 300 um spaced electrodes was placed over the His bundles of isolated, perfused rabbit hearts (n = 12). Ventricular myocardial (VM) and His activations were differentiated by calculating Laplacian recordings from unipolar signals. Activation rates of the VM and His bundle were compared and the His bundle conduction velocity was measured during perfused VF followed by 8 minutes of unperfused VF. During perfused VF the average VM activation rate of 11.04 activations/sec was significantly higher than the His bundle activation rate of 6.88 activations/sec (p<0.05). However from 3-8 minutes of unperfused VF the His system activation rate (6.16, 5.53, 5.14, 5.22, 6.00, and 4.62 activations/sec significantly faster than the rate of the VM (4.67, 3.63, 2.94, 2.24, 3.45, and 2.31 activations/sec) (p<0.05). The conduction velocity of the His system immediately decreased to 94% of the sinus rate during perfused VF then gradually decreased to 67% of sinus rhythm conduction at 8 minutes of unperfused VF. CONCLUSION: During prolonged VF the activation rate of the His bundle is faster than that of the VM. This suggests that the proximal conduction system, like the distal Purkinje system, may be an important driver during long duration VF and may be a target for interventional therapy. PMID- 25036420 TI - Antecedents, consequences and interventions for workplace bullying. AB - PURPOSE OF REVIEW: The issue of workplace bullying has become an area of research interest in the last 3 decades. Much of the extant literature is published in the business management journals. This is problematic as the targets of workplace bullying may need psychiatric treatment; as a discipline, therefore psychiatrists may benefit from a deeper understanding of the nature of workplace bullying and its sequelae. RECENT FINDINGS: There is still no agreed upon definition, although most definitions include similar criteria. Managers and human resources personnel frequently have difficulty identifying and effectively managing workplace bullying. The consequences for the targets of bullying can be severe; they may need psychiatric treatment and it can have a lifelong impact. There is a paucity of research into effective prevention and intervention programs. Preventive measures that focus on the whole workplace culture or on targets alone have mixed results. Workplace policies and procedures may lessen the prevalence and incidence of bullying, but often competing interests of senior management, human resources personnel, supervisors and workers may mitigate any antibullying interventions. SUMMARY: Although psychiatrists are likely to treat the targets of bullying, bullying has yet to attract much attention as a research topic in psychiatry. Although the consequences of bullying can be severe for both targets and workplaces, prevention strategies are hampered by competing interests. PMID- 25036422 TI - On-surface Ullmann coupling: the influence of kinetic reaction parameters on the morphology and quality of covalent networks. AB - On-surface Ullmann coupling is a versatile and appropriate approach for the bottom-up fabrication of covalent organic nanostructures. In two-dimensional networks, however, the kinetically controlled and irreversible coupling leads to high defect densities and a lack of long-range order. To derive general guidelines for optimizing reaction parameters, the structural quality of 2D porous covalent networks was evaluated for different preparation protocols. For this purpose, polymerization of an iodine- and bromine-functionalized precursor was studied on Au(111) by scanning tunneling microscopy under ultrahigh vacuum conditions. By taking advantage of the vastly different temperature thresholds for C-Br and C-I cleavage, two different polymerization routes were compared - hierarchical and direct polymerization. The structural quality of the covalent networks was evaluated for different reaction parameters, such as surface temperatures, heating rates, and deposition rates by statistical analysis of STM data. Experimental results are compared to Monte Carlo simulations. PMID- 25036423 TI - Persistent behavioral and neurochemical sensitization to an acute injection of methamphetamine following unpredictable stress. AB - Prior research in humans and animals suggest that exposure to chronic stress alters the response to drugs of abuse, increasing vulnerability to drug addiction. Chronic unpredictable stress (CUS) has been shown to augment the increase of dopamine in the striatum when challenged with high doses of methamphetamine immediately following stress exposure, however it is not known whether this neurochemical stress-sensitization continues after the cessation of the stressors or if behavioral sensitization is also present. Therefore, the current study examined the immediate and delayed effects of CUS on methamphetamine-induced behaviors and striatal dopamine levels. Male rats were exposed to 10 days of CUS and then tested in either an open field box to assess locomotion or underwent in vivo microdialysis to measure striatal dopamine levels immediately following CUS or after a 1-2 week delay. All rats exposed to CUS showed a potentiated locomotor response immediately following an acute injection of 7.5mg/kg methamphetamine compared to non-stressed control rats. Both groups of CUS rats also showed augmented dopamine release and rectal temperatures following methamphetamine with prolonged increases in the CUS rats tested after a delay. These results suggest that CUS increases the sensitivity of a rat to a single injection of methamphetamine and that the increased sensitivity persists for up to 2 weeks following the last stressor. PMID- 25036421 TI - Psychiatric aspects of bariatric surgery. AB - PURPOSE OF REVIEW: Bariatric surgery has been consistently shown to be effective in long-term marked weight loss and in bringing significant improvement to medical comorbidities such as metabolic syndrome. Empirical data suggest a high prevalence of psychiatric disorders among bariatric surgery candidates. In this review, we focus on the studies published recently with a high impact on our understanding of the role of psychiatry in bariatric surgery. RECENT FINDINGS: This article reviews the specific psychopathologies before surgery, changes in psychopathologies after surgery, suicide risk related to bariatric surgery, factors associated with weight loss, and recommendations for presurgical and postsurgical assessment and management. Research indicates a decrease in certain psychiatric symptoms after weight loss with bariatric surgery. However, the risk of suicide and unsuccessful weight loss in some bariatric surgery patients make monitoring following surgery as important as careful assessment and management before surgery. Specific considerations for youth and older populations and future potential research foci are discussed. SUMMARY: Recent publications suggest new directions for psychiatric evaluation and interventions for bariatric surgery patients. Future research on outcomes of specific populations, effectiveness of psychopharmacotherapy, and underlying pathophysiology are warranted for the advancement of treating bariatric surgery patients. PMID- 25036424 TI - Donepezil and the alpha-7 agonist PHA 568487, but not risperidone, ameliorate spatial memory deficits in a subchronic MK-801 mouse model of cognitive impairment in schizophrenia. AB - Cognitive impairment associated with schizophrenia (CIAS) is an important etiological feature of this disorder with implications for symptom severity and quality of life. Acute N-methyl-d-aspartate receptor (NMDAR) blockade using MK 801, a non-competitive antagonist to NMDARs, is assumed to produce temporary cognitive impairments in mice similar to those seen in schizophrenia patients. Less is known, however, about the effects of subchronic MK-801 administration on cognition. In the current study, twenty-eight male C57/BL6 mice received a daily dose of MK-801 (0.1mg/kg, i.p.) for seven days. Spatial memory was assessed using an object location task prior to MK-801 administration as well as at multiple time points after the treatment. Subchronic treatment with MK-801 caused lasting memory deficits, which were ameliorated by acute doses of an acetylcholinesterase inhibitor (donepezil) and an alpha-7 nicotinic agonist (PHA 568487), but were unaffected by acute administration of the atypical antipsychotic risperidone. Subchronic administration of MK-801 may lend this pharmaceutical model increased face validity, while its resemblance to prodromal schizophrenia makes it suitable for screening new CIAS treatments. PMID- 25036426 TI - Copy number deletion burden is associated with cognitive, structural, and resting state network differences in patients with schizophrenia. AB - Total burden of copy number deletions has been implicated in schizophrenia risk and has been associated with reduced cognitive functioning. The current study aims to replicate the cognitive findings and investigate regional grey and white matter volumes. Moreover, it will explore resting-state networks for correlations between functional connectivity and total deletion burden. All imaging differences will be investigated for correlations with cognitive differences. Seventy-eight patients with chronic schizophrenia, who formed a subset of a large genome-wide association study (GWAS), were assessed for intelligence, 34 had structural magnetic resonance imaging, 33 had resting-state functional magnetic resonance imaging, and 32 had diffusion tensor imaging (DTI). Total deletion burden was negatively associated with IQ performance and positively associated with regional volumes in the striatum bilaterally and in the right superior temporal gyrus and white-matter in the corpus callosum. Correlations were identified between deletion burden and both hyper and hypoconnectivity within the default-mode network and hypoconnectivity within the cognitive control network. The functional connectivity correlations with deletion burden were also correlated with the IQ differences identified. Total deletion burden affects regional volumes and resting-state functional connectivity in key brain networks in patients with schizophrenia. Moreover, effects of deletions on cognitive functioning in may be due to inefficiency of key brain networks as identified by dysconnectivity in resting-state networks. PMID- 25036427 TI - Sex differences in adolescent methylphenidate sensitization: effects on glial cell-derived neurotrophic factor and brain-derived neurotrophic factor. AB - This study analyzed sex differences in methylphenidate (MPH) sensitization and corresponding changes in glial cell-derived neurotrophic factor (GDNF) and brain derived neurotprhic factor protein (BDNF) in adolescent male and female rats. After habituation to a locomotor arena, animals were sensitized to MPH (5mg/kg) or saline from postnatal day (P) 33-49, tested every second day. On P50, one group of animals were injected with saline and behavior assessed for conditioned hyperactivity. Brain tissue was harvested on P51 and analyzed for GDNF protein. A second group of animals was also sensitized to MPH from P33 to 49, and expression of behavioral sensitization was analyzed on a challenge given at P60, and BDNF protein analyzed at P61. Females demonstrated more robust sensitization to MPH than males, but only females given MPH during sensitization demonstrated conditioned hyperactivity. Interestingly, MPH resulted in a significant increase in striatal and accumbal GDNF with no sex differences revealed. Results of the challenge revealed that females sensitized and challenged with MPH demonstrated increased activity compared to all other groups. Regarding BDNF, only males given MPH demonstrated an increase in dorsal striatum, whereas MPH increased accumbal BDNF with no sex differences revealed. A hierarchical regression analysis revealed that behavioral sensitization and the conditioned hyperactivity test were reliable predictors of striatal and accumbal GDNF, whereas sensitization and activity on the challenge were reliable predictors of accumbal BDNF, but had no relationship to striatal BDNF. These data have implications for the role of MPH in addiction and dopamine system plasticity. PMID- 25036428 TI - Chronic social stress does not affect behavioural habituation in male CD1 mice. AB - Various protocols to induce chronic stress in rodents are being used to determine the effects and underlying mechanisms of prolonged stress experience. Recently, a novel chronic social stress (CSS) protocol has been developed for mice where social instability in adolescence and early adulthood is induced. This protocol has been shown to cause an increase in HPA-axis activity and acute avoidance behaviour in the elevated plus maze. The aim of the present study was to investigate the effect of this CSS protocol on habituation to an initially novel environment in CD1 mice, since it has been shown that initially high avoidance behaviour in mice can still be followed by rapid habituation, pointing towards an adaptive response. One group of male mice, the CSS group, was exposed to the CSS protocol for 7 weeks and we compared their behavioural and physiological responses with male mice that were housed in a stable social group, the SH group. The results reveal a decrease in body weight gain and fur condition, changes in adrenal weight and decreased GR mRNA expression in the CA1 and the dentate gyrus of the hippocampus in chronically stressed CD1 animals. Irrespective of such evidence for a significantly stressful effect of the protocol, CD 1 mice, after termination of the stress procedure, revealed habituation profiles that matched those of control animals. We conclude that the physiological and central-nervous effects caused by a CSS procedure as used in this experiment fall within the coping capacities of CD1 mice at the behavioural level. PMID- 25036430 TI - The application of cure models in the presence of competing risks: a tool for improved risk communication in population-based cancer patient survival. AB - Quantifying cancer patient survival from the perspective of cure is clinically relevant. However, most cure models estimate cure assuming no competing causes of death. We use a relative survival framework to demonstrate how flexible parametric cure models can be used in combination with competing-risks theory to incorporate noncancer deaths. Under a model that incorporates statistical cure, we present the probabilities that cancer patients (1) have died from their cancer, (2) have died from other causes, (3) will eventually die from their cancer, or (4) will eventually die from other causes, all as a function of time since diagnosis. We further demonstrate how conditional probabilities can be used to update the prognosis among survivors (eg, at 1 or 5 years after diagnosis) by summarizing the proportion of patients who will not die from their cancer. The proposed method is applied to Swedish population-based data for persons diagnosed with melanoma, colon cancer, or acute myeloid leukemia between 1973 and 2007. PMID- 25036431 TI - Weight histories and mortality among finnish adults: the role of duration and peak body mass index. AB - BACKGROUND: Many studies use information on weight histories to examine the association between body weight and mortality. A recent paper in Epidemiology (2013;25:707-710) developed a typology of the most common weight-history specifications. METHODS: We use data from a sample of Finnish adults to explore the associations of body weight and mortality, using existing specifications and also peak body mass index (BMI), a new specification. RESULTS: We confirm earlier findings that longer time in a high BMI state is predictive of mortality. Peak BMI (the highest BMI attained in life or available in the data) is also positively associated with mortality. CONCLUSIONS: The specifications of duration in a high BMI state and peak BMI are both valuable for understanding the relationship between lifetime weight dynamics and mortality. The collection of information on peak body weight may be useful when collection of more detailed weight histories is not feasible. PMID- 25036433 TI - Long-term exposure to crystalline silica and risk of heart disease mortality. AB - BACKGROUND: The association between crystalline silica exposure and risk of heart disease mortality remains less clear. METHODS: We investigated a cohort of 42,572 Chinese workers who were potentially exposed to crystalline silica and followed from 1960 to 2003. Cumulative silica exposure was estimated by linking a job exposure matrix to each person's work history. Low-level silica exposure was defined as never having held a job with an exposure higher than 0.1 mg/m. We estimated hazard ratios (HRs) in exposure-response analyses using Cox proportional hazards model. RESULTS: We identified 2846 deaths from heart disease during an average of 35 years follow-up. Positive exposure-response trends were observed for cumulative silica exposure associated with mortality from total heart disease (HRs for increasing quartiles of cumulative silica exposure compared with the unexposed group = 0.89, 1.09, 1.32, 2.10; P for linear trend < 0.001) and pulmonary heart disease (0.92, 1.39, 2.47, 5.46; P for linear trend < 0.001). These positive trends remained among workers with both high- and low level silica exposure. There was also a positive trend for ischemic heart disease among workers with low-level exposure, with quartile HRs of 1.04, 1.13, 1.52, and 1.60 (P for linear trend < 0.001). CONCLUSION: Low-level crystalline silica exposure was associated with increased mortality from heart disease, including pulmonary heart disease and ischemic heart disease, whereas high-level exposure mainly increased mortality from pulmonary heart disease. Current permissible exposure limits for crystalline silica in many countries may be insufficient to protect people from deaths due to heart disease. PMID- 25036432 TI - Air pollution during pregnancy and childhood cognitive and psychomotor development: six European birth cohorts. AB - BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 MUm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 MUg/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable. PMID- 25036434 TI - Traffic-related air pollution in relation to cognitive function in older adults. AB - BACKGROUND: Few epidemiologic studies have investigated associations of air pollution with cognition in older adults, and none has specifically compared associations across particle sources. We investigated whether exposure to particulate air pollution, characterized by size and source, was associated with cognitive function and decline in cognitive function. METHODS: We included participants of the Whitehall II cohort who were residents of greater London and who attended the medical examination in study wave 2007-2009 (n = 2867). Annual average concentrations of particulate matter (PM) (PM10 and PM2.5 from all sources and from traffic exhaust) were modeled at resolution of 20 * 20 m for 2003-2009. We investigated the relationship between exposure to particles and a cognitive battery composed of tests of reasoning, memory, and phonemic and semantic fluency. We also investigated exposure in relation to decline in these tests over 5 years. RESULTS: Mean age of participants was 66 (standard deviation = 6) years. All particle metrics were associated with lower scores in reasoning and memory measured in the 2007-2009 wave but not with lower verbal fluency. Higher PM2.5 of 1.1 MUg/m (lag 4) was associated with a 0.03 (95% confidence interval = -0.06 to 0.002) 5-year decline in standardized memory score and a 0.04 (-0.07 to -0.01) decline when restricted to participants remaining in London between study waves. CONCLUSIONS: This study provides support for an association between particulate air pollution and some measures of cognitive function, as well as decline over time in cognition; however, it does not support the hypothesis that traffic-related particles are more strongly associated with cognitive function than particles from all sources. PMID- 25036436 TI - Hydrogen bonding tunes the early stage of hydrogen-atom abstracting reaction. AB - The spontaneous and collision-assisted hydrogen-atom abstracting reaction (HA) dynamics of triplet benzil are investigated through the combination of transient absorption spectroscopy with TD-DFT calculations. HA dynamics exhibit a remarkable dependence on the hydrogen donor properties. The effects of the triplet-state hydrogen bonding on the reaction dynamics are illustrated. In particular, it is experimentally observed that strengthened triplet-state hydrogen bonding could accelerate the HA, whereas weakened triplet-state hydrogen bonding would postpone the HA. The triplet-state hydrogen bonding has great influences on the early stage of the HA reaction, while the bond dissociation energy of the hydrogen donors determines the subsequent reaction pathways. Protic solvents could sustain longer lifetimes of the excited-state intermediate formed after HA than non-protic solvents by 10 MUs. This investigation provides insights into the HA dynamics and guidance to improve the product efficiency of photochemical reactions. PMID- 25036435 TI - Flexibility of PCNA-protein interface accommodates differential binding partners. AB - The expanding roles of PCNA in functional assembly of DNA replication and repair complexes motivated investigation of the structural and dynamic properties guiding specificity of PCNA-protein interactions. A series of biochemical and computational analyses were combined to evaluate the PIP Box recognition features impacting complex formation. The results indicate subtle differences in topological and molecular descriptors distinguishing both affinity and stoichiometry of binding among PCNA-peptide complexes through cooperative effects. These features were validated using peptide mimics of p85alpha and Akt, two previously unreported PCNA binding partners. This study characterizes for the first time a reverse PIP Box interaction with PCNA. Small molecule ligand binding at the PIP Box interaction site confirmed the adaptive nature of the protein in dictating overall shape and implicates allosterism in transmitting biological effects. PMID- 25036425 TI - Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. AB - Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy. PMID- 25036437 TI - A primer on the use of cluster analysis or factor analysis to assess co occurrence of risk behaviors. AB - OBJECTIVE: The aim of this paper is to provide a guideline to a universal understanding of the analysis of co-occurrence of risk behaviors. The use of cluster analysis and factor analysis was clarified. METHOD: A theoretical introduction to cluster analysis and factor analysis and examples from literature were provided. A representative sample (N=4395) of the Dutch population, aged 16 40 and participating from fall 2005 to spring 2006, was used to illustrate the use of both techniques in assessing the co-occurrence of risk behaviors. RESULTS: Whereas cluster analysis techniques serve to focus on particular clusters of individuals showing the same behavioral pattern, factor analysis techniques are used to assess possible groups of interrelated health-risk behaviors that can be explained by an unknown common source. Choice between the techniques partly depends on the research question and the aim of the research, and has different implications for inferences and policy. CONCLUSION: By integrating theory and results from an illustrative example, a guideline has been provided that contributes towards a systematic approach in the assessment of co-occurrence of risk behaviors. Following this guideline, a better comparison between outcomes from various studies is expected, leading to improved effectiveness of multiple behavior change interventions. PMID- 25036438 TI - Reproduction cost reduces demographic stochasticity and enhances inter-individual compatibility. AB - A population's survival depends on its ability to adapt to constraints impinging upon it. As such, adaptation is at the heart of an increasing number of theoretical models. In this paper, we propose a bottom-up evolutionary model to explore the relationship between individual evolutionary dynamics and population level survival. To do so, we extend a well-established model of gene network evolution by introducing a cost for reproduction. As a result population sizes fluctuate and populations can even go extinct. We find that if a population survives a small and critical number of generations, it will reach a quasi stationary state which ensures long-term survival. In a constant environment, individual adaptation occurs in response to changes in a populations genetic composition. We show that genetic compatibility increases over generations as a by-product of selection for robustness, thus preventing extinction. We also demonstrate that the number of reproductive opportunities per individual, initial population size, and mutation rates all influence population survival. Finally, mixing different populations reveals that individual properties of gene networks co-evolve with the genetic composition of the population in order to maximize an individuals reproductive success. PMID- 25036439 TI - Three level signal transduction cascades lead to reliably timed switches. AB - Signaling cascades proliferate signals received on the cell membrane to the nucleus. While noise filtering, ultra-sensitive switches, and signal amplification have all been shown to be features of such signaling cascades, it is not understood why cascades typically show three or four layers. Using singular perturbation theory, Michaelis-Menten type equations are derived for open enzymatic systems. Cascading these equations we demonstrate that the output signal as a function of time becomes sigmoidal with the addition of more layers. Furthermore, it is shown that the activation time will speed up to a point, after which more layers become superfluous. It is shown that three layers create a reliable sigmoidal response progress curve from a wide variety of time-dependent signaling inputs arriving at the cell membrane, suggesting the evolutionary benefit of the observed cascades. PMID- 25036440 TI - A model for population dynamics of the mimetic butterfly Papilio polytes in the Sakishima Islands, Japan. AB - We present a mathematical model for population dynamics of the mimetic swallowtail butterfly Papilio polytes in the Sakishima Islands, Japan. The model includes four major variables, that is, population densities of three kinds of butterflies (two female forms f. cyrus, f. polytes and the unpalatable butterfly Pachliopta aristolochiae) and their predator. It is well-known that the non-mimic f. cyrus resembles and attracts the male most, and the mimic f. polytes mimics the model butterfly P. aristolochiae. Based on experimental evidence, we assume that two forms f. cyrus and f. polytes interact under intraspecific competition for resources including the male, and the growth rate of f. cyrus is higher than that of f. polytes. We further assume that both the benefit of mimicry for the mimic f. polytes and the cost for the model are dependent on their relative frequencies, i.e. the motality of the mimic by predation decreases with increase in frequency of the model, while the motality of the model increases as the frequency of the mimic increases. Taking the density-dependent effect through carrying capacity into account, we set up a model system consisting of three ordinary differential equations (ODEs), analyze it mathematically and provide computer simulations that confirm the analytical results. Our results reproduce field records on population dynamics of P. polytes in the Miyako-jima Island. They also explain the positive dependence of the relative abundance (RA) of the mimic on the advantage index (AI) of the mimicry in the Sakishima Islands defined in Section 2. PMID- 25036441 TI - A belief-based evolutionarily stable strategy. AB - As an equilibrium refinement of the Nash equilibrium, evolutionarily stable strategy (ESS) is a key concept in evolutionary game theory and has attracted growing interest. An ESS can be either a pure strategy or a mixed strategy. Even though the randomness is allowed in mixed strategy, the selection probability of pure strategy in a mixed strategy may fluctuate due to the impact of many factors. The fluctuation can lead to more uncertainty. In this paper, such uncertainty involved in mixed strategy has been further taken into consideration: a belief strategy is proposed in terms of Dempster-Shafer evidence theory. Furthermore, based on the proposed belief strategy, a belief-based ESS has been developed. The belief strategy and belief-based ESS can reduce to the mixed strategy and mixed ESS, which provide more realistic and powerful tools to describe interactions among agents. PMID- 25036442 TI - Evidence for the participation of Ca(2+)-activated chloride channels in formalin induced acute and chronic nociception. AB - In this study we determined the role of Ca(2+)-activated chloride channels (CaCC) in acute and chronic nociceptive responses elicited by 1% formalin. Formalin injection produced a typical pattern of flinching behavior for about 1h. Moreover, it produced secondary allodynia and hyperalgesia in the ipsilateral and contralateral paws for at least 6 days. Local peripheral and intrathecal pre treatment (-10 min) with the non-selective and selective CaCC blockers niflumic acid and CaCCinh-A01, respectively, prevented formalin-induced flinching behavior mainly during phase 2 of the formalin test. Furthermore, niflumic acid and CaCCinh-A01 also prevented in a dose-dependent manner the long-lasting evoked secondary mechanical allodynia and hyperalgesia in the ipsilateral and contralateral paws. Moreover, local peripheral and intrathecal post-treatment (on day 6) with both CaCC blockers decreased the established formalin-induced secondary mechanical allodynia and hyperalgesia behavior in both paws. CaCC anoctamin-1 and bestrophin-1 were detected in the dorsal root ganglia. Formalin injection increased anoctamin-1, but not bestrophin-1 protein levels at 6 days. Intrathecal injection of the CaCC inhibitor CaCCinh-A01 prevented formalin induced anoctamin-1 increase. Data suggest that peripheral and spinal CaCC, and particularly anoctamin-1, participates in the acute nociception induced by formalin as well as in the development and maintenance of secondary mechanical allodynia and hyperalgesia. Thus, CaCC activity contributes to neuronal excitability in the process of nociception induced by formalin. PMID- 25036443 TI - A preorganized hydrogen bond network and its effect on anion stability. AB - Rigid tricyclic locked in all axial 1,3,5-cyclohexanetriol derivatives with 0-3 trifluoromethyl groups were synthesized and photoelectron spectra of their conjugate bases and chloride anion clusters are reported along with density functional computations. The resulting vertical and adiabatic detachment energies span 4.07-5.50 eV (VDE) and 3.75-5.00 (ADE) for the former ions and 5.60-6.23 eV (VDE) and 5.36-6.00 eV (ADE) for the latter species. These results provide measures of the anion stabilization due to the hydrogen bond network and inductive effects. The latter mechanism is found to be transmitted through space via hydrogen bonds, and the presence of three ring skeleton oxygen atoms and up to three trifluoromethyl groups enhance the ADEs by 1.61-2.88 eV for the conjugate bases and 1.01-1.60 eV for the chloride anion clusters. Computations indicate that the most favorable structures of the latter complexes have two hydrogen bonds to the chloride anion and one bifurcated interaction between the remote OH substituent and the two hydroxyl groups that directly bind to Cl(-). PMID- 25036444 TI - [Treat to target in Systemic Lupus Erythematosus]. PMID- 25036445 TI - Expression of VEGF-A, HIF-1 A, CD34 and Ki67 in clear cell renal cell carcinomas and their relationship with conventional prognostic markers. AB - Clear cell renal carcinoma is the most frequent type of renal carcinoma. Recently, attention has been focused in the expression of angiogenic factors by these tumors, which would justify in part their capacity to grow, invade and disseminate, stating a worse evolution of those patients with an unfavorable angiogenic profile. 83 samples of nephrectomy with a diagnosis of clear cell renal cell carcinoma were studied. Clinical and pathological data were collected. Tumors were studied to assess immunohistochemical expression of the following markers: VEGF-A, HIF-1alpha, CD34 and Ki67. Results indicated a direct linear relationship between expressions of these four markers. Besides, the expression of HIF-1alpha was directly related to Furhman grade, invasion of the renal vein and tumor stage. Likewise, tumor proliferation index, assessed with Ki67, was directly related to the presence of necrosis, capsular invasion and advanced tumor stage. Regarding the expression of CD34, vascular density was inversely related to tumor necrosis and overall survival. These findings are controversial compared with the available literature. Then, a research scenery would be open, where the importance of generating prospective and more standardized studies are highlighted to determine the role of these angiogenic factors in tumor evolution and prognostic evaluation of these tumors. PMID- 25036446 TI - [Complications of conventional and laparoscopic gastric bypass. Prospective and comparative study]. AB - BACKGROUND: Roux-en-y gastric bypass for the management of morbid obesity is currently the safest and more efficient treatment option. the laparoscopic era has shown its benefits in this type of surgery, so some authors advocate its implementation in a practical systematic way. all of which has lead in recent years to the unavoidable change in the surgical approach. OBJECTIVES: To evaluate and compare the complications of laparoscopic gastric bypass and the conventional one in patients with morbid obesity. Application site: self-administration national university hospital. DESIGN: Comparative, prospective no randomized study. POPULATION: Between 2002 and 2011, 420 morbidly obese patients received surgical treatment for the obesity either open (167) or laparoscopic (253) surgery RESULTS: Early postoperative complication rate was 4% in the lbg and 34% in the cbg (p < 05, 95%ci 22-38), mostly represented by seromas (25%) and wall abscesses (5.4%). the percentage of late postoperative complications was 2.8% in the lbg group and 9.6% in the cbg (p=0.004, 95%ci 1.4-12.2), the most frequent being incisional hernias (7.18%). CONCLUSIONS: According to our experience and consulted literature, laparoscopic gastric bypass is a safe, reproducible and with a lower rate of both early and late complications than cbg, and so we consider and offer lbg as the ideal technique for the treatment of patients with morbid obesity. PMID- 25036447 TI - [Human milk in hospitalized premature neonates and nutritional evolution]. AB - BACKGROUND: Preterm infants require special considerations than term infants to obtain adequate growth. OBJECTIVE: The aim was to evaluate human milk (HM) in low birth weight premature newborn (LBW-PN) and very low birth weight (VLBW-PN) during hospitalization, maternal factors, and the relationship with nutritional parameters. MATERIAL AND METHODS: 87 LBW-PN and 82 VLBW-PN), admitted in a public hospital in Cordoba, Argentina, were included. Anthropometry, food and biochemical parameters, and child and maternal history were registered. HM contribution was calculated. Anthropometric and biochemical values, days of hospitalization and maternal factors by HM intake were analyzed. RESULTS: Only 36,36% of VLBW-PN and 31,02% of LBW-PN had more than 20% of their diet with HM. The hemoglobin concentration at discharge was higher in VLBW-PN group with more HM (p=0,01). There was a statistically significant association between HM amount and height at discharge in the PN with less than 20% of their diet with HM. A high prevalence of cesarean delivery was observed, related to lower HM. CONCLUSIONS: HM contributes to hemoglobin stabilization. Cesarean delivery may be associated with lower contribution of HM to newborn infants. PMID- 25036448 TI - [Safety of beta-agonists in asthma]. AB - Beta 2 agonist bronchodilators (beta2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The beta2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting beta2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting beta2 agonists (LABAs) The long-acting bronchodilators beta2A (Long acting beta2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy. PMID- 25036449 TI - [Pancoast tumor. A clinical case]. AB - We described a patient who was diagnosed with a Pancoast tumor in the Neumologico Benefico Juridico Hospital. This neoplastic non metastatic disease more frequently affects the brachial plexus. Therefore, a differential diagnosis of the painful shoulder was carried out and the patient was admitted in our center with the probable Pancoast tumor diagnosis. Subsequently, its study continued and the clinical suspicion was confirmed by a computerized tomography and a magnetic resonance, to be also confirmed later on with an anatomopathological study. PMID- 25036450 TI - [Lung eosinophilic syndrome: clinical presentation and cases report]. AB - INTRODUCTION: Pulmonary eosinophilia syndrome is characterized by a group of diseases that present clinical-radiological conditions, pulmonary eosinophilia or peripheral lung parenchyma in its evolution. We described the clinical and radiological presentation. METHODS: Retrospective descriptive analysis of medical records of 7 patients between 2007 and 2010. RESULTS: The highest numbers of cases were observed in women, with peripheral eosinophilia with values between 550 and 10,000 cells/mm3. The more frequent signs and symptoms were cough, dyspnea, fever and wheezing. The more prevalent radiological findings were alveolar interstitial and alveolar pattern. At CT scan, the most frequent pattern was ground glass. The main diagnoses made were acute and chronic eosinophilic pneumonia in equal proportions, both with response to steroids. CONCLUSIONS: The pulmonary eosinophilia syndrome shares common features with clinical and radiological entities most prevalent, particularly community-adquired pneumonia. PMID- 25036451 TI - [Development and consolidation of General Student Welfare Direction at National University of Cordoba: institutional actions directed to integrated student health. Decades of 1960-1970]. AB - Starting from historical records attempts to identify the events which made possible the creation and regulation of Welfare Student Department. A Decade of 60 and 70 was fruitful for starting and development of first institutional politics designed to attend the health and welfare of students. In that way, the actions of Welfare Student Direction and Vocational Guidance focus their objective to bring on welfare, permanence, development of university student. It stand out the accent put it on the integral health exam of students, the concern about the empty in his cultural training, the possibility of make it easier vocational support and the execution of health insurance. PMID- 25036452 TI - Azo-sulforhodamine dyes: a novel class of broad spectrum dark quenchers. AB - A rapid access to a novel class of water-soluble dark quencher dyes was achieved using an azo-coupling reaction between a fluorescent primary arylamine derived from a sulforhodamine 101 scaffold and a tertiary aniline equipped with different bioconjugatable groups. The thus obtained nonfluorescent azo-sulforhodamine hybrids display a broad quenching range spanning the visible to NIR regions. This was demonstrated through the preparation and enzymatic activation of FRET-based fluorogenic substrates of urokinase. PMID- 25036453 TI - Implementation of the surgical safety checklist in Switzerland and perceptions of its benefits: cross-sectional survey. AB - OBJECTIVES: To examine the implementation of the Surgical Safety Checklist (SSC) among surgeons and anaesthetists working in Swiss hospitals and clinics and their perceptions of the SSC. METHODS: Cross-sectional survey at the 97th Annual Meeting of the Swiss Society of Surgery, Switzerland, 2010. Opinions of the SSC were assessed with a 6-item questionnaire. RESULTS: 152 respondents answered the questionnaire (participation rate 35.1%). 64.7% respondents acknowledged having a checklist in their hospital or their clinic. Median implementation year was 2009. More than 8 out of 10 respondents reported their team applied the Sign In and the Time Out very often or quasi systematically, whereas almost half of respondents acknowledged the Sign Out was applied never or rarely. The majority of respondents agreed that the checklist improves safety and team communication, and helps to develop a safety culture. However, they were less supportive about the opinion that the checklist facilitates teamwork and eliminates social hierarchy between caregivers. CONCLUSIONS: This survey indicates that the SSC has been largely implemented in many Swiss hospitals and clinics. Both surgeons and anaesthetists perceived the SSC as a valuable tool in improving intraoperative patient safety and communication among health care professionals, with lesser importance in facilitating teamwork (and eliminating hierarchical categories). PMID- 25036455 TI - Comparative spectroscopic and DFT calculations of binary and ternary complexes derived from 4-allyl-1-(2-hydroxybenzoyl) thiosemicarbazide (L1) and 2,2' dipyridyl. AB - Five metal complexes derived the reactions of 4-allyl-1-(2-hydroxybenzoyl) thiosemicarbazide (L(1)) with MX2 (M=Co(2+), Cu(2+) and Zn(2+) ions; X=Cl(-) in case of Co(2+) and Cu(2+) ions and Cl(-) and Ac(-) in case of Zn(2+) ion) in EtOH were synthesized and characterized. The results suggested that the binary and ternary complexes have the general formulae, [Cu(L(1)-2H)(EtOH)], [Co(L(1) 2H)(H2O)2]?H2O and [Zn(L(1)-2H) (H2O)1/2]?1/2EtOH, [Cu2(dipy)(L(1) 2H)(OH)2(H2O)], [Co(dipy)(L(1)-2H)]?4H2O and [Zn(dipy)(L(1)-2H)]. The binary and ternary complexes were characterized by elemental analyses, molar conductivities, spectral (IR, UV-vis; (1)H NMR, mass), thermal (TGA, DTG) and magnetic moments measurements. The mode of chelation is suggested using spectral data. The existence of OH group in the ternary complexes is confirmed from the results of IR, mass and (1)H NMR spectra. All the geometries of the ligands and the complexes are confirmed using DFT method from DMOL(3). The biological activity for the L(1) and two metal complexes were tested against DNA. PMID- 25036456 TI - Temperature dependence of C-terminal carboxylic group IR absorptions in the amide I' region. AB - Studies of structural changes in peptides and proteins using IR spectroscopy often rely on subtle changes in the amide I' band as a function of temperature. However, these changes can be obscured by the overlap with other absorptions, namely the side-chain and terminal carboxylic groups. The former were the subject of our previous report (Anderson et al., 2014). In this paper we investigate the IR spectra of the asymmetric stretch of alpha-carboxylic groups for amino acids representing all major types (Gly, Ala, Val, Leu, Ser, Thr, Asp, Glu, Lys, Asn, His, Trp, Pro) as well as the C-terminal groups of three dipeptides (Gly-Gly, Gly Ala, Ala-Gly) in D2O at neutral pH. Experimental temperature dependent IR spectra were analyzed by fitting of both symmetric and asymmetric pseudo-Voigt functions. Qualitatively the spectra exhibit shifts to higher frequency, loss in intensity and narrowing with increased temperature, similar to that observed previously for the side-chain carboxylic groups of Asp. The observed dependence of the band parameters (frequency, intensity, width and shape) on temperature is in all cases linear: simple linear regression is therefore used to describe the spectral changes. The spectral parameters vary between individual amino acids and show systematic differences between the free amino acids and dipeptides, particularly in the absolute peak frequencies, but the temperature variations are comparable. The relative variations between the dipeptide spectral parameters are most sensitive to the C-terminal amino acid, and follow the trends observed in the free amino acid spectra. General rules for modeling the alpha-carboxylic IR absorption bands in peptides and proteins as the function of temperature are proposed. PMID- 25036457 TI - Cancer-specific gene silencing through therapeutic siRNA delivery with B vitamin based nanoassembled low-molecular-weight hydrogelators. AB - This paper describes the synthesis, characterization, and in vitro and in vivo siRNA transfection ability of B vitamin-based cationic clickable bolaamphiphiles (VBs). Our VBs derived from vitamins B2, B3, B5, B6, and B7 formed nanoassembled low-molecular-weight hydrogelators (LMWGs, vitagels). The vitagels VB2, VB6, and VB7 (derived from vitamins B2, B6, and B7, respectively) facilitated delivery of small interfering RNAs (siRNA), efficiently silencing gene expression specifically into cancer cell lines; in addition, the LMWGs derived from vitamins B3, B5, and B6 were biocompatible. An ex vivo study in a mouse model revealed that the siRNA delivered by the vitagel VB7 was located primarily at the site of the tumor. The gene silencing efficiency of vascular endothelial growth factor siRNA delivered by vitagels was dependent on the nature of the vitamin headgroup, the N/P ratio, and, interestingly, the hydrogelation properties of the VBs. PMID- 25036458 TI - The risk of metabolic disorders in patients treated with asenapine or olanzapine: a study conducted on real-world data in Italy and Spain. AB - BACKGROUND: Atypical antipsychotics are the main treatment for a large number of psychiatric illnesses, with fewer extrapyramidal effects than conventional antipsychotics. However, it has been suggested that their use is associated with increased risk of dyslipidemia and type 2 diabetes mellitus. OBJECTIVE: The risk of metabolic adverse effects associated with asenapine was assessed in comparison with that associated with olanzapine using real-world data. METHODS: This study was a retrospective analysis based on data extracted from the Italian and Spanish Cegedim Strategic Data Longitudinal Patient-Data databases. Patients with asenapine or olanzapine prescriptions were retrieved from September 2010 to December 2012 using strict inclusion criteria to guarantee minimization of confounders. Patients with type 2 diabetes mellitus and dyslipidemia were identified by using ICD9 codes and by antidiabetic and dyslipidemic drug prescriptions. The presence or absence of the metabolic condition was compared before and after treatment, and between cohorts. RESULTS: The retrospective analysis showed a lower risk of developing type 2 diabetes with asenapine than with olanzapine (2.2 vs 3.5%, respectively; p value: 0.0002) and of developing dyslipidemia (2.8 vs 6.8%, respectively; p value: 0.0001). CONCLUSIONS: Asenapine is associated with a lower risk of metabolic adverse effects than olanzapine, demonstrating its improved safety profile. PMID- 25036459 TI - Complete blood count and retinal vessel calibers. AB - OBJECTIVE: The influence of hematological indices such as complete blood count on microcirculation is poorly understood. Retinal microvasculature can be directly visualized and vessel calibers are associated with a range of ocular and systemic diseases. We examined the association of complete blood count with retinal vessel calibers. METHODS: Cross-sectional population-based Blue Mountains Eye Study, n = 3009, aged 49+ years. Complete blood count was measured from fasting blood samples taken at baseline examination, 1992-4. Retinal arteriolar and venular calibers were measured from digitized retinal photographs using a validated semi automated computer program. RESULTS: All analyses adjusted for age, sex, systolic blood pressure, diabetes, smoking and fellow vessel caliber. Higher hematocrit, white cell count and platelet count were associated with narrower arteriolar caliber (p = 0.02, 0.03 and 0.001 respectively), while higher hemoglobin, hematocrit, red cell count, white cell count and platelet count were associated with wider venular caliber (p<0.0001 for all). Each quintile increase in hematocrit, white cell count and platelet count was associated with approximately 0.5 um narrower arteriolar caliber; whereas each quintile increase in all of the complete blood count components was associated with approximately 1-2 um wider venular caliber. CONCLUSIONS: These associations show that elevated levels of hematological indices can have adverse effects on the microcirculation. PMID- 25036460 TI - Characterization of a paramagnetic mononuclear nonheme iron-superoxo complex. AB - O2 bubbling into a THF solution of Fe(II)(BDPP) (1) at -80 degrees C generates a reversible bright yellow adduct 2. Characterization by resonance Raman and Mossbauer spectroscopy provides complementary insights into the nature of 2. The former shows a resonance-enhanced vibration at 1125 cm(-1), which can be assigned to the nu(O-O) of a bound superoxide, while the latter reveals the presence of a high-spin iron(III) center that is exchange-coupled to the superoxo ligand, like the Fe(III)-O2(-) pair found for the O2 adduct of 4-nitrocatechol-bound homoprotocatechuate 2,3-dioxygenase. Lastly, 2 oxidizes dihydroanthracene to anthracene, supporting the notion that Fe(III)-O2(-) species can carry out H atom abstraction from a C-H bond to initiate the 4-electron oxidation of substrates proposed for some nonheme iron enzymes. PMID- 25036461 TI - Current trends in pediatric cochlear implant candidate selection and postoperative follow-up. AB - PURPOSE: In this article, the authors describe current pediatric cochlear implant (CI) assessment and postoperative scheduling protocols in the United States. METHOD: A survey was conducted in 2 phases. RESULTS: Response rates were similar between Phase I (10%) and Phase II (13%). Across phases, nearly all respondents reported assessing speech perception both preoperatively and postoperatively. The most frequently used parent questionnaires were the Infant-Toddler Meaningful Auditory Integration Scale (Robbins, Renshaw, & Berry, 1991), the Meaningful Auditory Integration Scale (Robbins et al., 1991), and LittlEARS (Kuehn-Inacken, Weichboldt, Tsiakpini, Coninx, & D'Haese, 2003). The most commonly used speech perception measure for children <23 months of age was the Early Speech Perception Test-Low Verbal (ESP-LV; Moog & Geers, 1990). The most commonly used measures for children 24-35 months of age were the ESP-LV, the Northwestern University of Children's Perception of Speech (Elliot & Katz, 1980), and the Mr. Potato Head task (Robbins, 1993). For children >36 months of age, there was a wide variety of speech perception tests utilized. Patient follow-up visits were weekly or biweekly immediately following CI activation, then every 3 months for the remainder of the 1st year. After the 1st year, most children were seen semiannually. CONCLUSIONS: Although trends emerged, there is a lack of consistency in the selection of speech perception measures utilized across centers for children <36 months of age. The development of a working group to establish a standard minimum pediatric test battery (similar to the adult Minimum Speech Test Battery) would promote uniformity in clinical protocols used to assess children who receive CIs. PMID- 25036463 TI - Prevalence and genotyping of high risk human papillomavirus in cervical cancer samples from Punjab, Pakistan. AB - Cervical cancer is the third most common cause of cancer-related death in women worldwide. Infection with high-risk human papillomavirus (HPV) is established as the cause of cervical carcinoma, therefore, high risk HPV detection may have prognostic significance for the women who are at increased risk of disease progression. The paucity of data on the incidence of cervical cancer in Pakistan makes it difficult to determine disease burden. Even less information is available regarding the prevalent HPV strains in cervical specimens collected from this region. Cervical cancer is a neglected disease in Pakistan in terms of screening, prevention, and vaccination. Identification and accurate genotyping of the virus burden in cancer specimens is important to inform intervention policies for future management of HPV associated disease and to potentially stratify patients dependent on HPV status. In this study, detection and genotyping of HPV types 16 and 18 from 77 cervical specimens were carried out. Consensus primers GP5+/GP6+, which detect 44 genital HPV types, and type specific primers (TS16 and TS18) were used in conjunction with newly designed type specific primers. Using a combination of these methods of detection, a total of 94.81% (95% CI +/-4.95) of cervical lesions were positive for HPV. Single infections of HPV16 were detected in 24.68% (95% CI +/-9.63) of total samples and HPV18 was found in 25.97% (95% CI +/-9.79) samples. Interestingly, a high proportion of samples (40.26%, 95% CI +/ 10.95) was positive for both HPV16 and 18, indicating a higher incidence of co infection than previously reported for similar ethnic regions. The HPV genotype of 3.90% of HPV positive samples remained undetected, although these samples were positive with the GP5+/GP6+ primer set indicating infection with an HPV type other than 16 or 18. These data indicate that the overall incidence of high risk HPV infection in cervical cancer and intraepithelial neoplasia specimens in Punjab, Pakistan is in line with the worldwide prevalence, but that the incidence of HPV16 and 18 co-infections in our cohort is higher than that previously reported. PMID- 25036462 TI - Modified vaccinia virus ankara (MVA) as production platform for vaccines against influenza and other viral respiratory diseases. AB - Respiratory viruses infections caused by influenza viruses, human parainfluenza virus (hPIV), respiratory syncytial virus (RSV) and coronaviruses are an eminent threat for public health. Currently, there are no licensed vaccines available for hPIV, RSV and coronaviruses, and the available seasonal influenza vaccines have considerable limitations. With regard to pandemic preparedness, it is important that procedures are in place to respond rapidly and produce tailor made vaccines against these respiratory viruses on short notice. Moreover, especially for influenza there is great need for the development of a universal vaccine that induces broad protective immunity against influenza viruses of various subtypes. Modified Vaccinia Virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform. MVA can encode one or more foreign antigens and thus functions as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. However, there are some practical and regulatory issues that need to be addressed in order to develop MVA-based vaccines on short notice at the verge of a pandemic. In this review, we discuss promising novel influenza virus vaccine targets and the use of MVA for vaccine development against various respiratory viruses. PMID- 25036465 TI - Opening letter for twin-twin transfusion syndrome monograph. PMID- 25036464 TI - Identification of luteolin as enterovirus 71 and coxsackievirus A16 inhibitors through reporter viruses and cell viability-based screening. AB - Hand, foot and mouth disease (HFMD) is a common pediatric illness mainly caused by infection with enterovirus 71 (EV71) and coxsackievirus A16 (CA16). The frequent HFMD outbreaks have become a serious public health problem. Currently, no vaccine or antiviral drug for EV71/CA16 infections has been approved. In this study, a two-step screening platform consisting of reporter virus-based assays and cell viability-based assays was developed to identify potential inhibitors of EV71/CA16 infection. Two types of reporter viruses, a pseudovirus containing luciferase-encoding RNA replicons encapsidated by viral capsid proteins and a full-length reporter virus containing enhanced green fluorescent protein, were used for primary screening of 400 highly purified natural compounds. Thereafter, a cell viability-based secondary screen was performed for the identified hits to confirm their antiviral activities. Three compounds (luteolin, galangin, and quercetin) were identified, among which luteolin exhibited the most potent inhibition of viral infection. In the cell viability assay and plaque reduction assay, luteolin showed similar 50% effective concentration (EC50) values of about 10 MUM. Luteolin targeted the post-attachment stage of EV71 and CA16 infection by inhibiting viral RNA replication. This study suggests that luteolin may serve as a lead compound to develop potent anti-EV71 and CA16 drugs. PMID- 25036466 TI - A holistic antenatal model based on yoga, Ayurveda, and Vedic guidelines. AB - The prevalence of pregnancy complications are on the rise globally with severe consequences. According to the World Health Organization (WHO, 2009), every minute, at least one woman dies and 20 are affected by the complications related to pregnancy or childbirth. While the root cause of pregnancy complications is unclear, it likely has physical, psychological, social, and spiritual aspects. The Vedas are a rich source of antenatal health care guidelines in all these aspects. The primary objective of the authors was to compile the scriptural and scientific evidence for a holistic antenatal model of yoga with emphasis on sociocultural Indian practices. PMID- 25036467 TI - Economical and green synthesis of bagasse-derived fluorescent carbon dots for biomedical applications. AB - Carbon quantum dots (CDs) are promising nanomaterials in biomedical, photocatalytical and photoelectronic applications. However, determining how to explore an ideal precursor for a renewable carbon resource is still an interesting challenge. Here, for the first time, we report that renewable wastes of bagasse as a new precursor were prepared for fluorescent CDs by a hydrothermal carbonization (HTC) process. The characterization results show that such bagasse derived CDs are monodispersed, contain quasi spherical particles with a diameter of about 1.8 nm and exhibit favorable photoluminescence properties, super-high photostability and good dispersibility in water. Most importantly, bagasse derived CDs have good biocompatibility and can be easily and quickly internalized by living cancer cells; they can also be used for multicolour biolabeling and bioimaging in cancer cells. It is suggested that bagasse-derived CDs might have potential applications in biomedical and photoelectronic fields. PMID- 25036468 TI - Effect of calcium on strawberry fruit flavonoid pathway gene expression and anthocyanin accumulation. AB - Two diploid woodland strawberry (Fragaria vesca) inbred lines, Ruegen F7-4 (red fruit-bearing) and YW5AF7 (yellow fruit-bearing) were used to study the regulation of anthocyanin biosynthesis in fruit. Ruegen F7-4 fruit had similar total phenolics and anthocyanin contents to commercial octoploid (F. * ananassa) cultivar Seascape, while YW5AF7 exhibited relatively low total phenolics content and no anthocyanin accumulation. Foliar spray of CaCl2 boosted fruit total phenolics content, especially anthocyanins, by more than 20% in both Seascape and RF7-4. Expression levels of almost all the flavonoid pathway genes were comparable in Ruegen F7-4 and YW5AF7 green-stage fruit. However, at the turning and ripe stages, key anthocyanin structural genes, including flavanone 3 hydroxylase (F3H1), dihydroflavonol 4-reductase (DFR2), anthocyanidin synthase (ANS1), and UDP-glucosyltransferase (UGT1), were highly expressed in Ruegen F7-4 compared with YW5AF7 fruit. Calcium treatment further stimulated the expression of those genes in Ruegen F7-4 fruit. Anthocyanins isolated from petioles of YW5AF7 and Ruegen F-7 had the same HPLC-DAD profile, which differed from that of Ruegen F-7 fruit anthocyanins. All the anthocyanin structural genes except FvUGT1 were detected in petioles of YW5AF7 and Ruegen F-7. Taken together, these results indicate that the "yellow" gene in YW5AF7 is a fruit specific regulatory gene(s) for anthocyanin biosynthesis. Calcium can enhance accumulation of anthocyanins and total phenolics in fruit possibly via upregulation of anthocyanin structural genes. Our results also suggest that the anthocyanin biosynthesis machinery in petioles is different from that in fruit. PMID- 25036470 TI - Function Preservation After Conservative Resection and Radiotherapy for Soft tissue Sarcoma of the Distal Extremity: Utility and Application of the Toronto Extremity Salvage Score (TESS). AB - OBJECTIVE: To evaluate outcomes after conservative resection and radiotherapy (RT) for soft-tissue sarcoma (STS) of the distal extremity, with assessment of functional quality of life using the validated Toronto Extremity Salvage Score (TESS) questionnaire and Common Terminology Criteria for Adverse Events (CTCAE), v4.0. METHODS: Thirty-three patients with STS involving the hand/wrist (N=18) or foot/ankle (N=15) complex received adjuvant RT with conservative resection and were evaluated for local tumor control, survival, toxicities, and preservation of objective functional ability. Eight patients were treated with preoperative RT (median dose, 50.4 Gy) and 25 with postoperative RT (median dose, 61.8 Gy). Median follow-up was 11.5 years. Functional outcomes were measured using TESS; patients with amputations were excluded from the TESS analysis. Adverse events related to gait, limb edema, skin infection, wound complication, and wound dehiscence were assessed using the CTCAE. RESULTS: The 5- and 10-year local control rates were both 90%. The 10-year cause-specific, absolute, and distant metastasis-free survival rates were 97%, 87%, and 84%, respectively. Three patients had an amputation for reasons other than local recurrence or treatment complications and underwent amputation for patient preference. One third of the subjects (11/33 patients) were able to complete the TESS questionnaire; scores ranged from 88 to 100 (mean, 98.2). CTCAEv4 acute adverse events occurred in 2 cases: 1 patient had a grade 3 skin infection and 1 had a grade 2 wound complication of dehiscence. CONCLUSIONS: For management of distal extremity STS, the combination of adjuvant RT and conservative surgery achieves excellent local control and overall survival with few adverse events. In addition, through application of the TESS survey instrument, we have demonstrated that this treatment plan achieves robust functional preservation objectively and quantifiably. PMID- 25036469 TI - Fluctuations of an exposed pi-helix involved in lipoxygenase substrate recognition. AB - The second helix in lipoxygenases adapts to permit substrate access to the active site, but details of this process are varied and poorly understood. We therefore examined the dynamics of helix 2 in solutions of spin-labeled soybean lipoxygenase-1 and spin relaxation at 60 K of the spin-labels by catalytic iron. Helix 2 in soybean lipoxygenase structures is surface-exposed and contains one turn of pi-helix, centrally located. A site-directed spin-label scan of 18 of the 21 helix 2 residues, and electron paramagnetic resonance, showed that the pi helical segment became unusually mobile, on a nanosecond time scale, under conditions favoring substrate binding (pH 9 and lipid addition), while segments before and after had relatively unchanged dynamics. Backbone dynamics of residues in the pi-helical segment appeared to be correlated, at pH 9. Samples also were frozen to examine the polarity and proticity of the local environments, the effect of the local environment on intrinsic relaxation, and dipolar relaxation by two symmetries of catalytic iron. The average hyperfine tensor component, Azz, of four pi-helix residues decreased by 1.75 G, with an increase in pH from 7 to 9, while it remained unaffected for nearby buried residues. Power saturation data suggested the change in polarity specific to the pi-helix altered the intrinsic relaxation rates. Different symmetries of iron contributed to distance-dependent magnetic relaxation. We interpret these data to mean that a pi-helix in the second helix of plant lipoxygenases is highly dynamic and is the site where lipid chains penetrate to inner helices that outline the substrate pocket. PMID- 25036471 TI - Primary Cardiac Sarcoma: 25-Year Cleveland Clinic Experience. AB - BACKGROUND: Cardiac sarcomas are rare and have a poor prognosis. The median overall survival remains dismal and has been reported ranging from 6 months to a few years. Primary cardiac sarcoma is the most common malignant tumor comprising approximately 95% of all malignant tumors of the heart. METHODS: We conducted a retrospective chart review in a single institution of patients diagnosed between March 1988 and April 2013. A total of 42 patients were identified. The following variables were studied: age at diagnosis, year of diagnosis, sex, stage, site of tumor involvement, tumor histology, grade, treatment modality, type of chemotherapy, and survival outcome. The overall median follow-up time was 49.5 months. RESULTS: The most common histologic type was angiosarcoma. Overall estimated median survival (EMS) was 25 months. Tumors involving the left side of the heart and pericardium demonstrated better survival. Patients who received multimodality treatment (any combination of surgery, radiation therapy, and chemotherapy) had an EMS of 36.5 months compared with 14.1 months for patients treated with surgery, radiation therapy, or chemotherapy only (P=0.05). CONCLUSIONS: Cardiac sarcoma is a lethal tumor with an EMS of 25 months. The tumor histology could be a possible predictor of better survival. Although selection bias may have been present, multimodality therapy (surgery, radiation therapy, and chemotherapy) was associated with improved survival. PMID- 25036473 TI - Single-institution Experience of SBRT for Lung Metastases in Sarcoma Patients. AB - OBJECTIVES: Lung metastasectomy is regarded as the standard procedure for improving the prognosis of patients with metastatic sarcoma. Few reports are available in the literature describing the value of stereotactic body radiation therapy (SBRT) of lung metastases from primary sarcoma as an alternative to surgical treatment. We therefore sought to expand the evidence base for this modality. MATERIALS AND METHODS: Twenty-two patients with metastatic sarcoma to lung were treated by SBRT. The retrospective analysis of overall survival, toxicity, and local control of 53 treated lesions is presented in the study. Lung lesions were grouped into 2 categories for follow-up: <10 mm or >=10 mm diameter. RESULTS: Of 34 lesions <10 mm, 24 achieved complete response, 3 partial response, and 7 stable disease. The results of 18 lesions measuring >10 mm were as follows: 5 complete response, 5 progressive disease, and 8 stable disease. No progressive disease of all SBRT treated lesions was found at a median follow-up of 95 months (SD 32). Five-year overall survival of the entire group was 62% from the time of diagnosis and 50% from start of treatment. The treatment was well tolerated with minimal, mainly skin toxicity. CONCLUSION: SBRT is an effective tool that might be used as an alternative to operative treatment of lung metastases in sarcoma patients. PMID- 25036474 TI - Purification and characterization of polyphenol oxidase from waste potato peel by aqueous two-phase extraction. AB - Potato peel from food industrial waste is a good source of polyphenol oxidase (PPO). This work illustrates the application of an aqueous two-phase system (ATPS) for the extraction and purification of PPO from potato peel. ATPS was composed of polyethylene glycol (PEG) and potassium phosphate buffer. Effect of different process parameters, namely, PEG, potassium phosphate buffer, NaCl concentration, and pH of the system, on partition coefficient, purification factor, and yield of PPO enzyme were evaluated. Response surface methodology (RSM) was utilized as a statistical tool for the optimization of ATPS. Optimized experimental conditions were found to be PEG1500 17.62% (w/w), potassium phosphate buffer 15.11% (w/w), and NaCl 2.08 mM at pH 7. At optimized condition, maximum partition coefficient, purification factor, and yield were found to be 3.7, 4.5, and 77.8%, respectively. After partial purification of PPO from ATPS, further purification was done by gel chromatography where its purity was increased up to 12.6-fold. The purified PPO enzyme was characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by Km value 3.3 mM, and Vmax value 3333 U/mL, and enzyme stable ranges for temperature and pH of PPO were determined. These results revealed that ATPS would be an attractive option for obtaining purified PPO from waste potato peel. PMID- 25036472 TI - Ductal Carcinoma In Situ of the Breast: Evaluating the Role of Radiation Therapy in the Management and Attempts to Identify Low-risk Patients. AB - Ductal carcinoma in situ of the breast has rapidly increased in incidence over the past several decades secondary to an increased use of screening mammography. Local treatment options for women diagnosed with ductal carcinoma in situ include mastectomy or breast-conserving therapy. Although several randomized trials have confirmed a >50% reduction in the risk of local recurrence with the administration of radiation therapy (RT) compared with breast-conserving surgery alone, controversy persists regarding whether or not RT is needed in selected "low-risk" patients. Over the past two decades, two prospective single-arm studies and one randomized trial have been performed and confirm that the omission of RT after surgery is associated with higher rates of local recurrence even after selecting patients with optimal clinical and pathologic features. Importantly, these trials have failed to consistently and reproducibly identify a low-risk cohort of patients (based on clinical and pathologic features) that does not benefit from RT. As a result, adjuvant RT is still advocated in the majority of patients, even in low-risk cases. Future research is moving beyond traditional clinical and pathologic risk factors and instead focusing on approaches such as multigene assays and biomarkers with the hopes of identifying truly low-risk patients who may not require RT. However, recent studies confirm that even low risk patients identified from multigene assays have higher rates of local recurrence with local excision alone than would be expected with the addition of RT. PMID- 25036475 TI - Biosimilars: where we were and where we are. AB - Recent progress in biosimilars development is overviewed, with attention to the history of issues and processes leading to current regulations, and to scientific considerations, including progress on design and operational implementation issues that arise and are peculiar to biosimilars trial design and implementation. PMID- 25036476 TI - HSV-1 nucleocapsid egress mediated by UL31 in association with UL34 is impeded by cellular transmembrane protein 140. AB - During HSV-1 infection, the viral UL31 protein forms a complex with the UL34 protein at the cellular nuclear membrane, where both proteins play important roles in the envelopment of viral nucleocapsids and their egress into the cytoplasm. To characterize the mechanism of HSV-1 nucleocapsid egress, we screened host proteins to identify proteins that interacted with UL31 via yeast two-hybrid analysis. Transmembrane protein 140 (TMEM140), was identified and confirmed to bind to and co-localize with UL31 during viral infection. Further studies indicated that TMEM140 inhibits HSV-1 proliferation through selectively blocking viral nucleocapsid egress during the viral assembly process. The blockage function of TMEM140 is mediated by impeding the formation of the UL31 UL34 complex due to competitive binding to UL31. Collectively, these data suggest the essentiality of the UL31-UL34 interaction in the viral nucleocapsid egress process and provide a new anti-HSV-1 strategy in viral assembly process of nucleocapsid egress. PMID- 25036477 TI - Chemical ecology of insect-plant interactions: ecological significance of plant secondary metabolites. AB - Plants produce a diverse array of secondary metabolites as chemical barriers against herbivores. Many phytophagous insects are highly adapted to these allelochemicals and use such unique substances as the specific host-finding cues, defensive substances of their own, and even as sex pheromones or their precursors by selectively sensing, incorporating, and/or processing these phytochemicals. Insects also serve as pollinators often effectively guided by specific floral fragrances. This review demonstrates the ecological significance of such plant secondary metabolites in the highly diverse interactions between insects and plants. PMID- 25036478 TI - Exploration of polar lipid accumulation profiles in Euglena gracilis using LipidBlast, an MS/MS spectral library constructed in silico. AB - A rapid protocol for polar lipid profiling was applied to Euglena gracilis lipid metabolism by LipidBlast, an MS/MS spectral similarity search tool. The similarity search results suggested anoxia-induced polar lipid metabolism in Euglena characterized by the accumulation of differential lipid classes, carbon chain lengths, and unsaturated bond numbers. The informatics-supported MS spectral search provides an alternative option for global lipid profiling studies. PMID- 25036479 TI - Syntheses of all the stereoisomers of butanol type 1,7-seco-2,7'-cyclolignane. AB - All the stereoisomers of butanol type 1,7-seco-2,7'-cyclolignane were stereoselectively synthesized by employing (S)- and (R)-Evans' auxiliaries to construct the stereochemistry. (+)- and (-)-Kadangustin J and their diastereomers were also prepared. The optical purity of the synthesized butanol type 1,7-seco 2,7'-cyclolignane was more than 99%ee. PMID- 25036480 TI - Synthesis of biotinylated keratan sulfate repeating disaccharides. AB - We synthesized four types of keratan and keratan sulfate repeating disaccharides containing non-sulfate, Galbeta1-4GlcNAcbeta, and three types of sulfates, Gal6Sbeta1-4GlcNAcbeta, Galbeta1-4GlcNAc6Sbeta, and Gal6Sbeta1-4GlcNAc6Sbeta in an efficient and stereo-controlled manner. These disaccharides were conjugated with biotin via a hydrophilic linker at the reducing terminal. PMID- 25036481 TI - Stage-specific quercetin sulfation in the gut of Mythimna separata larvae (Lepidoptera: Noctuidae). AB - The metabolism of quercetin was investigated in Mythimna separata larvae. Quercetin 4'-O-sulfate was mainly identified in the frass when 6th instar larvae were fed artificial diets containing 1% quercetin. In the case of the 3rd instar larvae, a larger amount of quercetin was detected in the frass. M. separata larvae had different metabolic strategies for quercetin at different developmental stages. PMID- 25036482 TI - Effects of heparin and cholesterol sulfate on the activity and stability of human matrix metalloproteinase 7. AB - Sulfated glycosaminoglycans and sulfated lipids are involved in the biological functions of human matrix metalloproteinase 7 (MMP-7). In this study, the effects of heparin and cholesterol sulfate (CS) on the activity and stability of MMP-7 in the hydrolysis of a synthetic substrate, (7-methoxycoumarin-4-yl)acetyl-l-Pro-l Leu-Gly-l-Leu-[N(3)-(2,4-dinitrophenyl)-l-2,3-diaminopropionyl]-l-Ala-l-Arg-NH2, were examined. Heparin increased activity by decreasing Km, and the Km values for 0 and 50 MUM heparin were 57 +/- 8 and 19 +/- 5 MUM, respectively. CS decreased activity in a non-competitive inhibitory manner with a Ki value of 11 +/- 3 MUM. In thermal incubation at 50-70 degrees C, heparin increased relative activity (the ratio of kcat/Km of MMP-7 with incubation to that without it), while CS decreased relative activity. These results indicate that heparin increases the activity and stability of MMP-7, while CS decreases them. PMID- 25036483 TI - Fusion of an intact secretory protein permits a misfolded protein to exit from the endoplasmic reticulum in yeast. AB - Upon exit from the endoplasmic reticulum (ER), the nascent polypeptides of secretory proteins undergo sorting events. If properly folded, they are directly or indirectly recognized by the coat proteins of budding vesicles for forward transport, while unfolded or misfolded proteins are retained in the ER by a quality control mechanism. To gain insight into the interplay between ER export and ER quality control, we fused a secretory protein invertase to the C-terminus of mutated carboxypeptidase Y (CPY*), a model ER-associated degradation (ERAD) substrate in Saccharomyces cerevisiae. This substrate, designated CPY*-Inv, was largely exported from the ER, although it was fully recognized by the ERAD related lectin, Yos9, and hence degraded by the ERAD when it remained in the ER. CPY*-Inv relied primarily on the p24 complex, a putative ER export receptor for invertase, for escape from ERAD, suggesting that the ERAD and the ER export of soluble secretory proteins are competitive. PMID- 25036484 TI - Transient expression analysis revealed the importance of VTC2 expression level in light/dark regulation of ascorbate biosynthesis in Arabidopsis. AB - Ascorbate (AsA) is an important antioxidant and an enzyme cofactor involved in various metabolic pathways. In this study, we investigated the effects of estrogen (ES)-inducible transient expression of genes encoding enzymes involved in the d-mannose/l-galactose (d-Man/l-Gal) pathway for plant AsA biosynthesis on AsA levels under light and dark conditions. No significant difference was observed in AsA levels between Arabidopsis plants transiently expressing phosphomannose isomerase (PMI1), GDP-d-Man pyrophosphorylase (GMP/VTC1), GDP-Man 3',5'-epimerase (GME), and l-Gal 1-phosphate phosphatase (GPP/VTC4), but AsA levels in the plants transiently expressing GDP-l-Gal phosphorylase (GGP/VTC2) were 2.5-fold higher than those in control plants 7 d after ES treatment. The increase in AsA levels under continuous light conditions and the decrease in AsA levels under dark conditions were enhanced and suppressed, respectively, in the ES-treated plants. These results suggest that GGP/VTC2 acts as a rate-limiting step regulating AsA biosynthesis in response to light and dark conditions. PMID- 25036485 TI - Analysis of a putative auxin biosynthesis inhibitor, indole-3-oxoethylphosphonic acid, in Arabidopsis. AB - Previously we identified indole-3-acetic acid (IAA) biosynthesis inhibitors that act on the conversion of l-tryptophan to indole-3-pyruvic acid in the IAA biosynthesis of Arabidopsis. In the present study, we synthesized a new compound, indole-3-oxoethylphosphonic acid (IOEP), and found that IOEP had an inhibitory effect on IAA biosynthesis in Arabidopsis. The results suggest that IOEP is a novel inhibitor of auxin biosynthesis in Arabidopsis. PMID- 25036486 TI - Production of wild-type and mutant-type human DAP12 proteins by Bombyx mori nucleopolyhedrovirus vector. AB - A Japanese patient with Nasu-Hakola disease was found to have a serine-to asparagine (S39N) substitution in human DNAX-activation protein 12 (DAP12). To elucidate the functional abnormalities of mutant-type DAP12, we expressed wild type and mutant-type recombinant DAP12 protein with Bombyx mori nucleopolyhedrovirus (BmNPV) vector, and successfully purified the respective proteins from the hemolymph of recombinant BmNPV infected B. mori larvae. PMID- 25036487 TI - Stabilization of Moloney murine leukemia virus reverse transcriptase by site directed mutagenesis of surface residue Val433. AB - After thermal incubation at 48 degrees C for 10 min, single variants of Moloney murine leukemia virus reverse transcriptase, V433R and V433K in which a surface hydrophobic residue, Val433, was mutated, retained 55% of initial reverse transcription activity, while the wild-type enzyme retained 17%. After thermal incubation at 50 degrees C for 10 min, multiple variants D108R/E286R/V433R and D108R/E286R/V433R/D524A, in which Val433->Arg was combined with stabilizing mutations we identified previously, Asp108->Arg and Glu286->Arg, and RNase H activity-eliminating mutation Asp524->Ala, retained 70% of initial activity, exhibiting higher stability than V433R or V433K. PMID- 25036488 TI - Antibacterial and antioxidant activities and chemical compositions of volatile oils extracted from Schisandra chinensis Baill. seeds using simultaneous distillation extraction method, and comparison with Soxhlet and microwave assisted extraction. AB - The volatile oils were isolated from dried Schisandra chinensis Baill. seeds by Soxhlet extraction (SE), microwave-assisted extraction (MAE), and simultaneous distillation extraction (SDE), and fractions were identified by gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). The essential oils were assessed for their antioxidant and antibacterial activities. GC-MS results also revealed that the major ingredients in the oil extracted by SDE were terpenoids compounds such as ylangene (15.01%), alpha-phellandrene (8.23%), beta-himachalene (6.95%), and cuparene (6.74), and the oil extracts of MAE and SE mainly contained aromatics such as schizandrins, wuweizisu C, and gomisin A. HPLC analysis results confirmed that more schizandrin was obtained through extraction by MAE (996.64 MUg/g) and SE (722.13 MUg/g). SDE oil extract showed more significant antioxidant activity than MAE or SE oil. Only volatile oil from SDE showed good antibacterial activity against all tested strains. PMID- 25036489 TI - Initiation of protein association in tofu formation by metal ions. AB - Magnesium and calcium ions are important factors in making tofu. However, the molecular role of these ions remains unclear in tofu formation. We have previously shown that magnesium chloride concentration-dependent produced silken tofu-like (SP) and regular tofu-like (RP) precipitates, but was an inconsequential factor for the retention of tofu. We investigated in this present study, the effect of various metal chlorides on the metal chloride concentration dependent changes in tofu formation. These changes occurred in a similar manner to that of the magnesium ion, in which SP formation was followed by RP formation. It is interesting that the midpoint concentration for the formation of SP and RP represented a good correlation with the stability constant of EDTA. This correlation demonstrated the possibility that metal ions would interact with the carboxyl groups of soy proteins. We consider from these results that metal ions were the initiators of protein association in tofu formation. PMID- 25036490 TI - Regulation of the differentiation of osteoblasts and osteoclasts by a hot-water extract of adzuki beans (Vigna angularis). AB - Osteoporosis is a global public health problem thought to be caused by an imbalance in bone metabolism. We examined in this study the 40% ethanol fraction of HP-20 resin in combination with a hot-water adzuki extract (EtEx.40) for its effect on osteoblast and osteoclast differentiation. EtEx.40-treated murine preosteoblast MC3T3-E1 cells exhibited significantly elevated alkaline phosphatase activity and mineralization. EtEx.40 facilitated osteoblast differentiation by up-regulating such osteoblast differentiation-related molecules as runt-related transcription factor 2, distal-less homeobox 5, and osterix via p38 mitogen-activated protein kinase. EtEx.40 also suppressed the formation of large tartrate-resistant acid phosphatase-positive multinucleated cells in RAW264.7 cells that had been stimulated with the receptor activator of the nuclear factor kappaB ligand/macrophage colony-stimulating factor. EtEx.40 significantly inhibited NF-kappaB activation, thus reducing the expression of such downstream molecules as c-Fos and NFATc1. Our findings suggest that EtEx.40 could be used to maintain bone mass. PMID- 25036491 TI - Development of hypoallergenic galacto-oligosaccharides on the basis of allergen analysis. AB - Galacto-oligosaccharides (GOSs) are recognized as prebiotics beneficial to human health through their abilities to modulate gut microbiota. On the other hand, it has been reported that immediate allergic reactions are caused by a GOS product (Bc-GOS) produced by treating lactose with beta-galactosidase derived from Bacillus circulans. The objective of this study was to create a safer GOS product that is less likely to cause GOS-induced allergy (GOS-AL). First, we identified two derivatives of tetrasaccharide sugar chains in Bc-GOS as the factors responsible for GOS-AL by histamine release test (HRT) using blood samples obtained from two GOS-AL patients. Through our search for non-allergic GOS, we developed a new GOS product, SK-GOS, which was produced by catalyzing lactose with beta-galactosidase derived from Sporobolomyces singularis and Kluyveromyces lactis. We regard it as a hypoallergic and safe GOS product that does not cause GOS-AL. PMID- 25036492 TI - Formation by yeast of 2-furanmethanethiol and ethyl 2-mercaptopropionate aroma compounds in Japanese soy sauce. AB - Two aroma compounds of volatile thiols, 2-furanmethanethiol (2FM) and ethyl 2 mercaptopropionate (ET2MP), were formed in five types of Japanese soy sauce during fermentation by yeast. The concentrations of 2FM and ET2MP in the soy sauce samples increased during alcoholic fermentation. The concentrations of 2FM and ET2MP were higher in the soy sauce fermented by Zygosaccharomyces rouxii than in that fermented by Candida versatilis. The enantiomers of ET2MP were separated by gas chromatography in a capillary column. The average enantiomeric ratio of ET2MP in the soy sauce was approximately 1:1. 2FM was formed by yeast in a medium prepared from cysteine and furfural, and cysteine is considered the key precursor of 2FM by yeast in soy sauce. PMID- 25036493 TI - Characterization of the quality of imbibed soybean at an early stage of pre germination for the development of a new protein food item. AB - This was a pilot study carried out to develop a new protein food item from imbibed soybean before germination. It identified the significance of a short stage after imbibition and before germination, and that vitamin C production was activated in as little as 16 h from the start of imbibition, without any influence on the soy protein quality or sensory acceptability, while longer imbibition caused the imbibed soybean to activate its phytophysiological metabolism for germination. DNA microarray analysis indicated that the genes for carbohydrate metabolism were up-regulated prior to 16 h, and that the expression rates of genes responsible for environmental factors were down-regulated. Thereafter, the expression rates of the genes associated with lipid metabolism and secondary metabolite production were changed. This information should contribute to a better understanding of how to develop a new soy protein item in pre-germination before active physiological processes begin. PMID- 25036494 TI - Characterization of the key aroma compounds in pork soup stock by using an aroma extract dilution analysis. AB - The aroma extract dilution analysis of an extract prepared from pork stock and subsequent experiments led to the identification of 15 aroma-active compounds in the flavor dilution factor range of 64-2048. Omission experiments to select the most aroma-active compounds from the 15 odor compounds suggested acetol, octanoic acid, delta-decalactone, and decanoic acid as the main active compounds contributing to the aroma of pork stock. Aroma recombination, addition, and omission experiments of these four aroma compounds in taste-reconstituted pork stock showed that each compound had an individual aroma profile. A comparison of the overall aroma between this recombined mixture and pork stock showed strong similarity, suggesting that the key aroma compounds had been successfully identified. PMID- 25036495 TI - Insulin injection restored increased insulin receptor substrate (IRS)-2 protein during short-term protein restriction but did not affect reduced insulin-like growth factor (IGF)-I mRNA or increased triglyceride accumulation in the liver of rats. AB - Dietary protein restriction reduces insulin-like growth factor (IGF)-I synthesis and impairs growth. Moreover, insulin secretion is impaired and hepatic insulin signaling is activated presumably through upregulation of insulin receptor substrate (IRS)-2, which can stimulate lipogenesis thereby resulting in steatosis. In order to determine whether impaired insulin secretion is the primary cause of these changes, we injected insulin into protein-restricted rats and compensated for the reduction in insulin secretion for 1 and 7 d. Insulin infusion did not overcome the reduction in liver IGF-I mRNA nor the hepatic triglyceride accumulation. In contrast, it clearly suppressed the upregulation of hepatic IRS-2 on day 1, but not on day 7. Furthermore, insulin elimination increased IRS-2 in H4IIE-C3 cells. In summary, we found that reduced insulin secretion during protein restriction directly increased hepatic IRS-2 as a rapid response on day 1, while additional mechanisms contributed to the upregulation of IRS-2 on day 7. PMID- 25036496 TI - Effects of two sulfated triterpene saponins echinoside A and holothurin A on the inhibition of dietary fat absorption and obesity reduction. AB - Two similarly sulfated triterpene saponins from Pearsonothuria graeffei were prepared to investigate the anti-obesity effects of echinoside A (EA) and holothurin A (HA). The in vitro inhibitory activities of EA and HA toward pancreatic lipase were investigated, and two in vivo studies were performed: (i) Male Wistar rats were orally administered the lipid emulsion with or without a saponin (HA or EA). The serum's total triglyceride concentration was measured at various times. (ii) C57BL/6 mice were assigned to four groups, high fat (HF), EA (0.03%), HA (0.04%), and orlistat (0.01%), and the weight of adipose tissue and level of fatty acids excreted in the feces were determined. Both EA and HA repressed the pancreatic lipase activity and increased fatty acid excretion in the feces. Treatment with EA and HA significantly decreased the adipose tissue accumulation in mice. EA and HA manifested different inhibitory activities in vitro, but each of them dramatically inhibited lipid absorption in vivo and showed strong anti-obesity activity. PMID- 25036497 TI - Effects of various emulsification methods on the oxidation of methyl linoleate. AB - The effects of mechanical stress during emulsification on the oxidation of methyl linoleate were investigated by four methods (high-pressure homogenization, high speed stirring, ultrasonic homogenization, and membrane emulsification). The oxidation rates and induction periods were almost constant, regardless of the emulsification method, except for membrane emulsification, by which the induction period was prolonged when a cellulose acetate membrane was used. PMID- 25036498 TI - Metabolic engineering of Saccharomyces cerevisiae to improve succinic acid production based on metabolic profiling. AB - We performed metabolic engineering on the budding yeast Saccharomyces cerevisiae for enhanced production of succinic acid. Aerobic succinic acid production in S. cerevisiae was achieved by disrupting the SDH1 and SDH2 genes, which encode the catalytic subunits of succinic acid dehydrogenase. Increased succinic acid production was achieved by eliminating the ethanol biosynthesis pathways. Metabolic profiling analysis revealed that succinic acid accumulated intracellularly following disruption of the SDH1 and SDH2 genes, which suggests that enhancing the export of intracellular succinic acid outside of cells increases succinic acid production in S. cerevisiae. The mae1 gene encoding the Schizosaccharomyces pombe malic acid transporter was introduced into S. cerevisiae, and as a result, succinic acid production was successfully improved. Metabolic profiling analysis is useful in producing chemicals for metabolic engineering of microorganisms. PMID- 25036499 TI - Steam explosion treatment for ethanol production from branches pruned from pear trees by simultaneous saccharification and fermentation. AB - This study investigated the production of ethanol from unutilized branches pruned from pear trees by steam explosion pretreatment. Steam pressures of 25, 35, and 45 atm were applied for 5 min, followed by enzymatic saccharification of the extracted residues with cellulase (Cellic CTec2). High glucose recoveries, of 93.3, 99.7, and 87.1%, of the total sugar derived from the cellulose were obtained from water- and methanol-extracted residues after steam explosion at 25, 35, and 45 tm, respectively. These values corresponded to 34.9, 34.3, and 27.1 g of glucose per 100 g of dry steam-exploded branches. Simultaneous saccharification and fermentation experiments were done on water-extracted residues and water- and methanol-extracted residues by Kluyveromyces marxianus NBRC 1777. An overall highest theoretical ethanol yield of 76% of the total sugar derived from cellulose was achieved when 100 g/L of water- and methanol-washed residues from 35 atm-exploded pear branches was used as substrate. PMID- 25036500 TI - Targeted metabolomics for Aspergillus oryzae-mediated biotransformation of soybean isoflavones, showing variations in primary metabolites. AB - This study aimed to investigate the biotransformation of soybean isoflavones to hydroxyisoflavones, and the primary and secondary metabolite change during Aspergillus oryzae KACC40247-mediated fermentation by gas chromatography-time of flight-mass spectrometry and LC-MS with multivariate analysis. The mass spectrometric analysis revealed that acetylglycosides and glycosides decreased during the first 12 h of fermentation, while the aglycones increased up to that time point. This was followed by a decrease in aglycone levels due to the formation of hydroxyisoflavones. The hydroxyflavones, 8-hydroxydaidzein, hydroxygenistein, and hydroxyglycitein, resulting from the biotransformation of the corresponding aglycones, increased up to 24 h, and then subsequently decreased. During fermentation, the levels of monosaccharides, aspartic acid, pyroglutamic acid, gamma-aminobutyric acid, and organic acids gradually decreased, whereas the levels of threonine, serine, and glycine increased. Hydroxyisoflavone was more strongly correlated with antioxidant activity than the other metabolites. Our results suggest that biotransformation has the potential to improve the nutritional properties of soy-based food. PMID- 25036501 TI - Stable expression of a GFP-reporter gene in the red alga Cyanidioschyzon merolae. AB - The unicellular red alga Cyanidioschyzon merolae is used as a model organism to investigate the basic architecture of photosynthetic eukaryotes. We established a stable expression system for the green fluorescent protein fused with the phycocyanin-associated rod linker (APCC) protein in C. merolae, which was clearly localized on the plastid. This system should be useful in the genetic engineering of C. merolae. PMID- 25036503 TI - Small molecule ghrelin receptor inverse agonists and antagonists. AB - Ghrelin is an endogenous peptide hormone secreted primarily by the stomach and is involved in a number of physiological processes including growth hormone secretion, food intake, as well as energy and glucose homeostasis. The physiological actions of ghrelin are mediated through the growth hormone secretagogue receptor 1a (ghrelin receptor), a peptidic G-protein-coupled receptor. This target has attracted much interest, as agents that block ghrelin's actions on its receptor are anticipated to be pharmaceutical interventions for a number of diseases. This review provides an overview of ghrelin biology with a focus on metabolic diseases and summarizes recent medicinal chemistry programs aimed at delivering small molecule ghrelin receptor antagonists and inverse agonists to the clinic. PMID- 25036502 TI - Low concentrations of ethanol stimulate biofilm and pellicle formation in Pseudomonas aeruginosa. AB - Biofilms are communities of surface-attached microbial cells that resist environmental stresses. In this study, we found that low concentrations of ethanol increase biofilm formation in Pseudomonas aeruginosa PAO1 but not in a mutant of it lacking both Psl and Pel exopolysaccharides. Low concentrations of ethanol also increased pellicle formation at the air-liquid interface. PMID- 25036504 TI - Dynamic alterations of the tongue in obstructive sleep apnea-hypopnea syndrome during sleep: analysis using ultrafast MRI. AB - Patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) were evaluated using ultrafast magnetic resonance imaging (UMRI) while asleep and awake to analyze tongue changes. The upper airway of 21 OSAHS patients and 20 normal controls were examined during sleep using UMRI. A series of midline sagittal images of the upper airway were obtained to measure dynamic changes in tongue size and the distance from the tongue to the x-axis (an extended line from the anterior nasal spine to posterior nasal spine) and the y-axis (a perpendicular line from the center of the pituitary to the x-axis). The maximum and minimum sagittal diameters of the tongue were shorter in the OSAHS group than in the control group (P<0.01) while awake, whereas the difference between the maximum and minimum vertical diameters of the tongue and the upper and central part of tongue between the posterior border and the retropharyngeal wall were greater (P<0.05). During sleep, the maximum values and differences between the maximum and minimum tongue sizes in the OSAHS group were larger than in the control group (P<0.05), whereas the minimum values were lower than in the control group (P<0.01). Tongue size significantly differs between OSAHS patients and normal controls during sleep. The tongue tends to move downward during OSAHS, which may be attributed to increased upper airway resistance. PMID- 25036505 TI - Predicting bacterial essential genes using only sequence composition information. AB - Essential genes are those genes that are needed by organisms at any time and under any conditions. It is very important for us to identify essential genes from bacterial genomes because of their vital role in synthetic biology and biomedical practices. In this paper, we developed a support vector machine (SVM) based method to predict essential genes of bacterial genomes using only compositional features. These features are all derived from the primary sequences, i.e., nucleotide sequences and protein sequences. After training on the multiple samplings of the labeled (essential or not essential) features using a library for SVM, we obtained an average area under the ROC curve (AUC) of about 0.82 in a 5-fold cross-validation for Escherichia coli and about 0.74 for Mycoplasma pulmonis. We further evaluated the performance of the method proposed using the dataset consisting of 16 bacterial genomes, and an average AUC of 0.76 was achieved. Based on this training dataset, a model for essential gene prediction was established. Another two independent genomes, Shewanella oneidensis RW1 and Salmonella enterica serovar Typhimurium SL1344 were used to evalutate the model. Results showed that the AUC sores were 0.77 and 0.81, respectively. For the convenience of the vast majority of experimental scientists, a web server has been constructed, which is freely available at http://cefg.uestc.edu.cn:9999/egp. PMID- 25036506 TI - Birth of a healthy child by a woman with inherited Xq duplications who had experienced stillbirths. AB - A 23-year-old woman who had experienced repeated stillbirths, was found to carry an additional segment on the long arm of the X chromosome. Array comparative genomic hybridization (aCGH) confirmed the origin of the 2 duplications (about 17.11 Mb). Thus, her karyotype was 46, X, dup (X) (q13.2-q21.1), dup(X) (q21.32 q22.1). We demonstrate that aCGH is a useful complementary tool to cytogenetic analysis for accurately determining banding. To our knowledge, this is the first case with normal apparently phenotype who inherited 2 duplications on Xq. Notably, after 2 stillbirths, she bore a healthy, normal female infant via natural pregnancy. Thus, a carrier of this karyotype can birth a phenotypically normal child. PMID- 25036507 TI - Genetic diversity of central and peripheral populations of Toona ciliata var. pubescens, an endangered tree species endemic to China. AB - Our objective was to examine the genetic diversity of central and peripheral populations of Toona ciliata var. pubescens, to elucidate whether the central peripheral hypothesis applies to these populations. We analyzed 392 individuals from nine natural populations using eight pairs of polymorphic SSR primers. The results showed that the mean numbers of observed and expected alleles in peripheral populations were higher than in central populations. Common widespread and rare local (RL) alleles were observed in all populations. However, common local alleles were found in five populations and rare widespread alleles were only found in three. The total numbers of the four types of alleles were higher in peripheral than in central populations, and the quantity of the RL allele was obviously higher in the peripheral populations than in the central populations. Both the observed and expected heterozygosities were higher in peripheral populations compared with the central populations. The coefficient of gene differentiation of the peripheral populations was 0.3045, which was significantly higher than that of the central populations. The gene flow between central populations was greater than one, but less than one between peripheral populations. This indicates that frequent gene flow exists between central populations, while terrain and habitat fragmentation prevent gene flow between peripheral populations. A Mantel test indicated that there was no relationship between genetic and geographical distance of T. ciliata var. pubescens. PMID- 25036508 TI - Analysis of key genes and pathways involved in acute lung injury in a mouse model. AB - A mouse model of acute lung injury (ALI) was chosen in this study to explore the key genes and pathways involved in the process of ALI with microarray technology. Gene expression microarray data were downloaded from the Gene Expression Omnibus database. Mice from the experimental group were further divided into 6 subgroups, which received octadecenoate treatments for 1, 1.5, 3, 4, 18, and 24 h. Differentially co-expressed genes were screened to uncover the pathogenesis of ALI. Almost all of the differentially co-expressed genes were identified at two times: 1.5 and 3 h. Functional analysis revealed that several inflammation related pathways were significantly enriched. Ubiquitin-mediated proteolysis, hematopoietic cell lineage, and leukocyte transendothelial migration were enriched at 1.5 h. The B cell receptor signaling pathway, T cell receptor signaling pathway, natural killer cell-mediated cytotoxicity, Fc epsilon RI signaling pathway, and ubiquitin-mediated proteolysis were significantly enriched at 3 h. It could be inferred that ALI initiated at 1.5 h and lasted through 3 h. However, co-expression patterns were not found from 4 h onward. In conclusion, several key genes and pathways implicated in the development of ALI were found in this study using the mouse model, among which ubiquitin-mediated proteolysis appears to play an important role in the process. PMID- 25036509 TI - Repair of articular cartilage defects by tissue-engineered cartilage constructed with adipose-derived stem cells and acellular cartilaginous matrix in rabbits. AB - After injury, inflammation, or degeneration, articular cartilage has limited self repair ability. We aimed to explore the feasibility of repair of articular cartilage defects with tissue-engineered cartilage constructed by acellular cartilage matrices (ACMs) seeded with adipose-derived stem cells (ADSCs). The ADSCs were isolated from 3-month-old New Zealand albino rabbit by using collagenase and cultured and amplified in vitro. Fresh cartilage isolated from adult New Zealand albino rabbit were freeze-dried for 12 h and treated with Triton X-100, DNase, and RNase to obtain ACMs. ADSCs were seeded in the acellular cartilaginous matrix at 2x10(7)/mL, and cultured in chondrogenic differentiation medium for 2 weeks to construct tissue-engineered cartilage. Twenty-four New Zealand white rabbits were randomly divided into A, B, and C groups. Engineered cartilage was transplanted into cartilage defect position of rabbits in group A, group B obtained ACMs, and group C did not receive any transplants. The rabbits were sacrificed in week 12. The restored tissue was evaluated using macroscopy, histology, immunohistochemistry, and transmission electron microscopy (TEM). In the tissue-engineered cartilage group (group A), articular cartilage defects of the rabbits were filled with chondrocyte-like tissue with smooth surface. Immunohistochemistry showed type II-collagen expression and Alcian blue staining was positive. TEM showed chondrocytes in the recesses, with plenty of secretary matrix particles. In the scaffold group (group B), the defect was filled with fibrous tissue. No repaired tissue was found in the blank group (group C). Tissue engineered cartilage using ACM seeded with ADSCs can help repair articular cartilage defects in rabbits. PMID- 25036510 TI - Validation of two real-time PCRs targeting the PE-PGRS 20 gene and the region of difference 4 for the characterization of Mycobacterium bovis isolates. AB - This study aimed to develop and validate real-time PCR for the diagnosis of Mycobacterium bovis isolates. Two hundred and seventy-four M. bovis isolates and 156 M. tuberculosis isolates were tested. Both qPCRs amplified all of the 274 M. bovis samples, but none of the 156 M. tuberculosis samples. The qPCR for PE-PGRS 20 had 91% efficiency and a detection limit of 0.32 ng (sensitivity and specificity for qPCR "Mbovis.100" were 99.64 and 100%, respectively). The qPCR for RD4 had 100% efficiency, and a detection limit of 4 pg (diagnostic sensitivity and specificity were 100 and 100%. The qPCR tests were performed using 4 extraction sets, 3 qPCR kits, and with a range of equipment; yet, all combinations produced similar results in a diagnostic test, demonstrating the robustness of this method. The techniques proved to be efficient, robust, sensitive, and specific for the diagnosis of M. bovis. PMID- 25036511 TI - Effects of thrombin on the secondary cerebral injury of perihematomal tissues of rats after intracerebral hemorrhage. AB - This study aimed to investigate the effects of thrombin released in hematoma after intracerebral hemorrhage (ICH) on the cerebral injury of perihematomal tissues and to evaluate the protection effect of hirudin on the cerebral injury after ICH. We used the autologous uncoagulated blood injection method to prepare the ICH rat model, and all rats were randomly divided into a normal group, an ICH group, or a hirudin group. At different time points, rat heads were cut to harvest brain sections. Immunohistochemical staining, histochemical staining, and hematoxylin and eosin staining were conducted for CD34, microglia, and neutrocytes. CD34-positive microvessels were most abundant in brain tissues of the sham-operation group. At 12 h after ICH, CD34 expression reduced and reached the minimum level at 72 h (P<0.01). At 6 h after ICH, microglia expression was visible and reached a peak at 48 h (P<0.01). At 12 h after ICH, neutrocyte infiltration was visible and the number was greatest at 48 h (P<0.01). The early application of hirudin after ICH could significantly reduce microglia and neutrocyte expression and could significantly slow down the CD34 decrease trend (P<0.01). However, hirudin application in the edematization stage after ICH did not significantly increase CD34- positive microvessel abundance (P>0.05). A thrombin-mediated inflammatory reaction is involved in the cerebral injury after ICH, and the early application of hirudin has a protective effect. PMID- 25036513 TI - Developing selection criteria based on an ontogenetic path analysis approach to improve grain yield in barley. AB - We used correlation and path coefficient analysis based on an ontogenetic approach to develop selection criteria in barley (Hordeum vulgare L.) for an early production system in Ethiopia. A total of 100 genotypes using 10x10-simple lattices with two replications were used to perform the experiment at Ambo and Asasa. The combined analysis of the measured traits showed significant differences among genotypes for all traits. A positive correlation was observed between grain yield and spike/m2, kernel number/spike, and 1000-kernel weight. The path analysis showed that spike/m2, 1000-kernel weight, and kernel number per spike had significant positive direct effects on grain yield, which shows that these traits can be used as selection criteria to improve grain yield. The significant positive correlation of spike/ m2, 1000-kernel weight, and grain filling period and the positive direct effect on grain yield indicated the potential of these traits as indirect selection criteria to improve grain yield in the early production system in Ethiopia. This study also showed that the path coefficient analysis based on an ontogenetic model was efficient and produced results that can be interpreted clearly. PMID- 25036512 TI - Protective role of neuregulin-1 toward doxorubicin-induced myocardial toxicity. AB - The aim of this study was to investigate the role of the rat neuregulin-1 (NRG-1) protein in reducing doxorubicin (DOX)-induced myocardial toxicity and its underlying mechanism. The prokaryotic expression of the NRG-1 protein and the CCK8-determined activity of rat primary myocardial cells were evaluated under different DOX concentrations. Myocardial cells were divided into three groups: the control group, the 5 MUM DOX (DOX5) group, and the DOX5+NRG-1 group. Western blotting was used to determine the Na+-Ca2+ exchanger (NCX-1) and cardiac myosin light-chain kinase (cMLCK) protein expression levels and real-time quantitative polymerase chain reaction methods were used to determine the mRNA expression levels. The prokaryotic expression of NRG-1 in the DOX5 group produced toxicity in the rat myocardial cells, and cell activity was significantly restored with the addition of NRG-1. The protective effect of NRG-1 was limited at higher DOX concentrations (DOX10), and the degree of cellular activity restoration was positively correlated with NRG-1 concentration. The addition of NRG-1 to DOX5 intervention inhibited NCX-1 protein and mRNA expression, and increased cMLCK protein and mRNA expression. In conclusion, DOX-induced toxicity in rat myocardial cells could be protected by NRG-1, and the mechanism may be related to the role of NRG-1 in up-regulating the cMLCK expression level and down-regulating the NCX-1 expression level. PMID- 25036514 TI - Analysis of the linear epitope for Fc-binding on the mouse IgG Fc receptor (moFcgammaRI) by synthetic peptide. AB - To identify the linear epitope for Fc-binding to the mouse immunoglobulin G (IgG) Fc receptor (moFcgammaRI), peptides derived from the membrane-distal extracellular domain (EC2) of moFcgammaRI, corresponding to the homologous region of human FcgammaRI (huFcgammaRI) and huFcgammaRII, were synthesized. Using a dot blot assay, six peptides were tested. The results showed that the moRI3 peptide (CVFYRNGKSFQFS) could combine with mouse IgG efficiently. A competitive enzyme linked immunosorbent assay (ELISA) showed that the IC50 value of the moRI3 peptide was 38.03 mM. The moRI3 peptide could inhibit the combination of mouse IgG to the transfected COS 7 cells significantly with an IC50 value of 72.68 mM. The IgG-binding region of moFcgammaRI was also localized in the C'-E loop of the EC2 domain as predicted according to huFcgammaRI and huFcgammaRII. We predicted that the minimum effective IgG-binding region of moFcgammaRI may be the peptide 153SFQFSS158. The linear epitope for immunoglobulin-binding to mouse FcgammaR is also described. Thus, we generated a peptide that targets a fundamental aspect of ligand recognition by this receptor class. PMID- 25036515 TI - Genetic relatedness between Ardi, Black Bedouin and Damascus goat breeds. AB - The present study aimed to analyze genetic relatedness and differentiation of common native goat populations in some countries of the Middle East. The populations were Ardi, Black Bedouin, and Damascus goats in the Kingdom of Saudi Arabia, Jordan, and Syria, respectively. Domesticated goats of the Middle East are mostly related to common ancestors, but there is limited molecular genetic evidence. Four microsatellite DNA markers were genotyped in 89 individuals of the three populations using an automated genetic analyzer. Ardi, Black Bedouin, and Damascus goats exhibited high average allele number and expected heterozygosity of 8.25, 9, and 7.25, and 0.750, 0.804, and 0.779, respectively. F-statistics for population differentiation showed 6.0% of total genetic variation, whereas 94.0% as differentiation between individuals within all populations. The least varied within populations was Ardi goats, then Damascus goats and finally Black Bedouin goats. Furthermore, the Damascus goat population was more differentiated from Black Bedouin goats than from Ardi goats. On the other hand, there was strong evidence of admixture between the majority of Ardi and Black Bedouin goat individuals but little with those of Damascus goats. Genetic distance between Ardi and Black Bedouin goats was the shortest, whereas it was the longest between Ardi and Damascus goats. The phylogenetic tree clearly revealed the expected degree of differentiation in the three populations. From a genetic conservation point of view, it is recommended to maintain the biodiversity of these distinct populations in case genetic migration of genetic resources and genetic conservation are absent. PMID- 25036516 TI - Effect of superposition and masking between red blood cell autoantibodies and alloantibodies. AB - This study aimed to explore the law of superposition and masking between autoantibodies and alloantibodies, and to ensure the detection of alloantibodies and to improve the safety of warm autoimmune hemolytic anemia patients. Eight kinds of commercial IgG red blood cell antibody reagents were serially diluted, and 3 kinds of antibodies at dilutions showing a continuous gradual decline in agglutination strength with the corresponding antigen red blood cells were treated as the target antibodies. Anti-D and anti-M were treated as simulated autoantibodies, and anti-Fya was treated as a simulated alloantibody. Four concentrations, 4+, 3+, 2+ and 1+, of autoantibodies and three concentrations, 3+, 2+ and 1+, of alloantibodies were combined, and 12 kinds of hybrid antibodies were detected and evaluated by the anti-human globulin micro-column gel assay. When the simulated strong autoantibody (4+) was used, the alloantibodies (3+, 2+, 1+) had no effect on the final agglutination strength; when the strength of agglutination produced by the simulated autoantibody was less than 4+, and at the same time there were alloantibodies (3+, 2+, 1+), the differences in agglutination strength with a panel of RBCs could be clearly observed. Strong autoantibodies (4+) can exert a masking effect, leading to alloantibodies being undetected; autoantibodies less than 4+, will produce the superimposed effect with alloantibodies, resulting in differences in agglutination strength. PMID- 25036517 TI - IL-23 promotes osteoclastogenesis in osteoblast-osteoclast co-culture system. AB - The aim of this study was to determine the effect of IL-23 on the activity and proliferation of osteoclasts (OC) in co-culture with osteoblasts (OB). OB and OC were individually separated from the skull and femoral bone of a SD rat. OB-OC co culture with IL-23 added was designed as the experimental group, while the OB-OC co-culture without IL-23 was the control group. In the experimental group, five different concentrations of IL-23 were added, and the cells were then cultured for 24, 48 and 72 h. For each concentration at these three time points, cell proliferation, tartrate-resistant acid phosphatase (TRAP) activity and the lacunae in the bone slices were evaluated, compared with control group at the same time points. Compared to the control group, proliferation and TRAP activity of OC were significantly increased at 24, 48 and 72 h with addition of 0.5 to 10 ng/mL IL-23 (P<0.05). In addition, a dose- and time-dependent correlation between the effect of IL-23 and osteoclastogenesis was noticed though the comparison. Moreover, the area of lacunar resorption in each experimental group was significantly larger than in the control group (P<0.05). In conclusion, IL-23 promotes the proliferation, TRAP activity and bone resorption of OC in OB-OC co culture. PMID- 25036518 TI - Association between polymorphisms in ADAM33, CD14, and TLR4 with asthma in the Uygur population in China. AB - We evaluated the associations between single nucleotide polymorphisms (SNPs) and haplotypes of the genes encoding a disintegrin and metalloproteinase 33 (ADAM33), cluster of differentiation 14 (CD14), and Toll-like receptor 4 (TLR4) and the susceptibility of developing specific adult phenotypes of bronchial asthma in a Chinese Uygur population. Five SNPs of ADAM33 (T1, T2, and V4), 3 SNPs of CD14 ( 1359G/T, -1145G/A, and -159T/C), and 2 SNPs of TLR4 (-896A/G and -1196C/T) were genotyped in a Chinese Uygur sample of 126 adult asthmatic patients and 126 control subjects. Gene polymorphisms were detected by polymerase chain reaction restriction fragment length polymorphism analysis. The genotyping results were confirmed in a random subgroup of our samples using direct DNA sequencing. The allele frequencies of ADAM33 T1 (TC), T2 (AG), and V4 (GG) were significantly higher in patients than in controls (P<0.05). The genotypes T1 (TC+CC), T2 (AG+AA), and V4 (CG+GG) significantly increased the risk of asthma. After adjusting for confounding factors, these associations were stronger and remained significant. The T1 (TC) and V4 (GG) genotypes in the ADAM33 gene were associated with significantly decreased FEV1 levels in patients with asthma. The haplotype frequencies of Hap3 (CAC) and Hap4 (CAG) were significantly higher in patients than in controls (P<0.05). Our results suggest that polymorphisms T1, T2, and V4 in ADAM33 may contribute to the susceptibility to asthma. Specific haplotypes of ADAM33 may contribute to a higher susceptibility to asthma in the Chinese Uygur population. PMID- 25036519 TI - Construction and identification of pIRES2-LIF-NT-3 bicistronic eukaryotic expression vector. AB - We used a simple and efficient method to construct a bicistronic eukaryotic expression vector pIRES2-LIF-NT-3. The leukemia inhibitory factor (LIF) and neurotrophin-3 (NT-3) genes were obtained from the genomic DNA of human peripheral blood mononuclear cells by polymerase chain reaction. The LIF cDNA fragment was inserted into the multiple cloning sites of a vector containing internal ribosome entry site and enhanced green fluorescent protein (EGFP) (pIRES2-EGFP) to generate the bicistronic eukaryotic expression plasmid pIRES2 LIF-EGFP. Next, the NT-3 cDNA fragment was cloned into pIRES2-LIF-EGFP in place of EGFP to create the plasmid pIRES2-LIF-NT-3. pIRES2-LIF-NT-3 was transfected into HEK293 cells and reverse transcription-polymerase chain reaction and Western blotting were used to test the co-expression of double genes. LIF and NT-3 genes were cloned and the DNA was sequenced. Sequencing analysis revealed that LIF and NT-3 were consistent with the sequence recorded in GenBank. Restriction analysis indicated that the LIF and NT-3 genes were inserted correctly into the expression vector pIRES2-EGFP. Following transfection of pIRES2-LIF-NT-3 into HEK293 cells, the double gene was expressed at the mRNA and protein levels. The LIF and NT-3 coexpression plasmid is a novel expression system that will enable further study of the functions of the LIF and NT-3 genes. PMID- 25036520 TI - Construction and identification of pIRES2-VEGF165-NT-3 bicistronic eukaryotic expression vector. AB - We used a simple and efficient method to construct the bicistronic eukaryotic expression vector pIRES2-VEGF165-NT-3. The neurotrophin-3 (NT-3) gene was obtained from the genomic DNA of human peripheral blood mononuclear cells by polymerase chain reaction. The NT-3 cDNA fragment was cloned into the pIRES2 VEGF165-EGFP vector in place of enhanced green fluorescent protein (EGFP) to create the plasmid pIRES2-VEGF165-NT-3. Next, pIRES2-VEGF165-NT-3 was transfected into HEK293 cells, and reverse transcription-polymerase chain reaction and Western blotting were used to test co-expression of the double genes. The vascular endothelial growth factor 165 (VEGF165) and NT-3 genes were cloned; DNA sequencing analysis demonstrated that the VEGF165 and NT-3 sequences were the same as those recorded in GenBank. Restriction analysis indicated that the VEGF165 and NT-3 genes were correctly inserted into the expression vector pIRES2 EGFP. The double gene was expressed at both the mRNA and protein levels. The VEGF165 and NT-3 co-expression plasmid was successfully constructed, providing a novel expression system for further study of the functions of the VEGF165 and NT 3 genes. PMID- 25036521 TI - Opportunities and Challenges in Application of Forward Osmosis in Food Processing. AB - Food processing and preservation technologies must maintain the fresh-like characteristics of food while providing an acceptable and convenient shelf life as well as assuring safety and nutritional value. Besides, the consumers' demand for the highest quality convenience foods in terms of natural flavor and taste, free from additives and preservatives necessitated the development of a number of membrane-based non-thermal approaches to the concentration of liquid foods, of which forward osmosis has proven to be the most valuable one. A series of recent publications in scientific journals have demonstrated novel and diverse uses of this technology for food processing, desalination, pharmaceuticals as well as for power generation. Its novel features, which include the concentration of liquid foods at ambient temperature and pressure without significant fouling of membrane, made the technology commercially attractive. This review aims to identify the opportunities and challenges associated with this technology. At the same time, it presents a comprehensive account of recent advances in forward osmosis technology as related to the major issues of concern in its rapidly growing applications in food processing such as concentration of fruit and vegetable juices (grape, pineapple, red raspberry, orange, and tomato juice and red radish juice) and natural food colorants (anthocyanin and betalains extracts). Several vibrant and vital issues such as recent developments in the forward osmosis membrane and concentration polarization aspects have been also addressed. The asymmetric membrane used for forward osmosis poses newer challenges to account both external and internal concentration polarization leading to significant reduction in flux. The recent advances and developments in forward osmosis membrane processes, mechanism of water transport, characteristics of draw solution and membranes as well as applications of forward osmosis in food processing have been discussed. PMID- 25036522 TI - Sizing of metallic nanoparticles confined to a microfluidic film applying dark field particle tracking. AB - We present Brownian motion-based sizing of individual submicron and nanoparticles in liquid samples. The advantage of our approach is that particles can freely diffuse in a 10 MUm thin liquid film and are therefore always within the focal depth of a low numerical aperture objective. Particles are visualized with dark field microscopy, and the resulting diffraction-limited spots are tracked over a wide field of view of several hundred micrometers. Consequently, it is ascertained that long 2D trajectories are acquired, which leads to significantly increased particle sizing precision. The hydrodynamic diameters of metal particles with nominal sizes ranging from 70 to 200 nm in aqueous solution were determined by tracking for up to 2 min, and it was investigated if the diffusion characteristics were influenced by the proximity of substrates. This was not the case, and the estimated diameters were in good agreement with the values obtained by electron microscopy, thus validating the particle sizing principle. Furthermore, we measured a sample mixture to demonstrate the distinction of close particle sizes and performed the conjugation of a model protein (BSA) on the nanoparticle surface. An average increase in the radius of 9 nm was determined, which corresponds to the size of the BSA protein. PMID- 25036523 TI - Neural correlates of trauma-unrelated emotional processing in war veterans with PTSD. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is thought to be characterized by general heightened amygdala activation. However, this hypothesis is mainly based on specific studies presenting fear or trauma-related stimuli, hence, a thorough investigation of trauma-unrelated emotional processing in PTSD is needed. METHODS: In this study, 31 male medication-naive veterans with PTSD, 28 male control veterans (combat controls; CC) and 25 non-military men (healthy controls; HC) were included. Participants underwent functional MRI while trauma unrelated neutral, negative and positive emotional pictures were presented. In addition to the group analyses, PTSD patients with and without major depressive disorder (MDD) were compared. RESULTS: All groups showed an increased amygdala response to negative and positive contrasts, but amygdala activation did not differ between groups. However, a heightened dorsal anterior cingulate cortex (dACC) response for negative contrasts was observed in PTSD patients compared to HC. The medial superior frontal gyrus was deactivated in the negative contrast in HC, but not in veterans. PTSD+MDD patients showed decreased subgenual ACC (sgACC) activation to all pictures compared to PTSD-MDD. CONCLUSION: Our findings do not support the hypothesis that increased amygdala activation in PTSD generalizes to trauma-unrelated emotional processing. Instead, the increased dACC response found in PTSD patients implicates an attentional bias that extends to trauma-unrelated negative stimuli. Only HC showed decreased medial superior frontal gyrus activation. Finally, decreased sgACC activation was related to MDD status within the PTSD group. PMID- 25036524 TI - Serum vitamin D, vitamin D binding protein, and risk of colorectal cancer. AB - BACKGROUND: We previously reported a positive association between serum 25 hydroxyvitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to vitamin D binding protein (DBP), the primary 25(OH)D transport protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk. METHODS: In a nested case control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1?1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free, unbound circulating 25(OH)D. RESULTS: Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D:DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend = 0.87), although the interaction was not statistically significant (p for interaction = 0.24). CONCLUSION: Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non smokers. PMID- 25036525 TI - Insights into hydrate formation and stability of morphinanes from a combination of experimental and computational approaches. AB - Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl(-) counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group P212121. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of the different compounds exhibit only little structural variation. Anhydrous polymorphs were detected for all compounds except ethylmorphine (one anhydrate) and its hydrochloride salt (no anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential scanning and isothermal calorimetry were employed to estimate the heat of the hydrate <-> anhydrate phase transformations, indicating an enthalpic stabilization of the respective hydrate of 5.7 to 25.6 kJ mol(-1) relative to the most stable anhydrate. These results are in qualitative agreement with static 0 K lattice energy calculations for all systems except morphine hydrochloride, showing the need for further improvements in quantitative thermodynamic prediction of hydrates having water...water interactions. Thus, the combination of a variety of experimental techniques, covering temperature- and moisture dependent stability, and computational modeling allowed us to generate sufficient kinetic, thermodynamic and structural information to understand the principles of hydrate formation of the model compounds. This approach also led to the detection of several new crystal forms of the investigated morphinanes. PMID- 25036526 TI - Absence of BRCA/FMR1 correlations in women with ovarian cancers. AB - Previously reported findings in Austrian BRCA1/2 mutation carriers suggested a possible dependency of embryos with BRCA1/2 mutations on so-called low alleles of the fragile X mental retardation 1 (FMR1) gene, characterized by less than 26 CGG repeats (CGG(n<26)). The hypothesis arose from a study reporting highly statistically significant enrichment of low FMR1 alleles, significantly exceeding low allele prevalence in a general population, suggesting embryo lethality of BRCA1/2 mutations, "rescued" by presence of low FMR1 alleles. Such a dependency would also offer an explanation for the so-called "BRCA-paradox," characterized by BRCA1/2 deficient embryonic tissues being anti-proliferative (thereby potentially causing embryo-lethality) but proliferative in malignant tumors, including breast and ovarian cancers. Follow up investigations by other investigators, however, at most demonstrated trends towards enrichment but, mostly, no enrichment at all, raising questions about the original observation and hypothesis. We in this study, therefore, investigated CGGn of the FMR1 gene of 86 anonymized DNA samples from women with various forms of ovarian cancer, and were unable to demonstrate differences in prevalence of low FMR1 alleles either between positive and negative ovarian cancer patients for BRCA1/2 or between ovarian cancer patients and reported rates in non-cancer populations. This raises further questions about a suggested dependency between BRCA1/2 and FMR1, but also raises the possibility that investigated Austrian BRCA1/2 carrier populations differ from those in other countries. Either only selected BRCA1/2 mutations, therefore, interact with low FMR1 alleles or the Austrian data reflect only coincidental observations. PMID- 25036528 TI - Stereospecific ring-opening metathesis polymerization of norbornadienes employing tungsten oxo alkylidene initiators. AB - We report here the polymerization of several 7-isopropylidene-2,3-disubstituted norbornadienes, 7-oxa-2,3-dicarboalkoxynorbornadienes, and 11-oxa benzonorbornadienes with a single tungsten oxo alkylidene catalyst, W(O)(CH-t Bu)(OHMT)(Me2Pyr) (OHMT = 2,6-dimesitylphenoxide; Me2Pyr = 2,5-dimethylpyrrolide) to give cis, stereoregular polymers. The tacticities of the menthyl ester derivatives of two polymers were determined for two types. For poly(7 isopropylidene-2,3-dicarbomenthoxynorbornadiene) the structure was shown to be cis,isotactic, while for poly(7-oxa-2,3-dicarbomenthoxynorbornadiene) the structure was shown to be cis,syndiotactic. A bis-trifluoromethyl-7 isopropylidene norbornadiene was not polymerized stereoregularly with W(O)(CHCMe2Ph)(Me2Pyr)(OHMT) alone, but a cis, stereoregular polymer was formed in the presence of 1 equiv of B(C6F5)3. PMID- 25036527 TI - Characterization of the Caenorhabditis elegans HIM-6/BLM helicase: unwinding recombination intermediates. AB - Mutations in three human RecQ genes are implicated in heritable human syndromes. Mutations in BLM, a RecQ gene, cause Bloom syndrome (BS), which is characterized by short stature, cancer predisposition, and sensitivity to sunlight. BLM is a RecQ DNA helicase that, with interacting proteins, is able to dissolve various DNA structures including double Holliday junctions. A BLM ortholog, him-6, has been identified in Caenorhabditis elegans, but little is known about its enzymatic activities or its in vivo roles. By purifying recombinant HIM-6 and performing biochemical assays, we determined that the HIM-6 has DNA-dependent ATPase activity HIM-6 and helicase activity that proceeds in the 3'-5' direction and needs at least five 3' overhanging nucleotides. HIM-6 is also able to unwind DNA structures including D-loops and Holliday junctions. Worms with him-6 mutations were defective in recovering the cell cycle arrest after HU treatment. These activities strongly support in vivo roles for HIM-6 in processing recombination intermediates. PMID- 25036529 TI - An unsupervised text mining method for relation extraction from biomedical literature. AB - The wealth of interaction information provided in biomedical articles motivated the implementation of text mining approaches to automatically extract biomedical relations. This paper presents an unsupervised method based on pattern clustering and sentence parsing to deal with biomedical relation extraction. Pattern clustering algorithm is based on Polynomial Kernel method, which identifies interaction words from unlabeled data; these interaction words are then used in relation extraction between entity pairs. Dependency parsing and phrase structure parsing are combined for relation extraction. Based on the semi-supervised KNN algorithm, we extend the proposed unsupervised approach to a semi-supervised approach by combining pattern clustering, dependency parsing and phrase structure parsing rules. We evaluated the approaches on two different tasks: (1) Protein protein interactions extraction, and (2) Gene-suicide association extraction. The evaluation of task (1) on the benchmark dataset (AImed corpus) showed that our proposed unsupervised approach outperformed three supervised methods. The three supervised methods are rule based, SVM based, and Kernel based separately. The proposed semi-supervised approach is superior to the existing semi-supervised methods. The evaluation on gene-suicide association extraction on a smaller dataset from Genetic Association Database and a larger dataset from publicly available PubMed showed that the proposed unsupervised and semi-supervised methods achieved much higher F-scores than co-occurrence based method. PMID- 25036530 TI - Prevalence of depressive symptoms and associated factors in older adult public housing residents. AB - The purpose of this pilot study was to identify the prevalence of and risk factors associated with depressive symptoms among older adult residents of a public housing apartment. Self-reported depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CES-D) 8. A self-report questionnaire was used to collect data on risk factors of sociodemographic information, cardiovascular health history, and history of depression. Fifty eight of 171 residents responded, and 31% of residents met the CES-D 8 criterion for depression (total score >=7). Sequential multiple regression models identified age, loss of loved ones in the past year, and financial worries as significant predictors of CES-D 8 scores. These study results have implications for future studies of depressive symptoms in older adults, suggesting that grief and financial assistance programs may help reduce risks associated with depressive symptoms among community-dwelling older adults living in public housing. PMID- 25036531 TI - A multisite study of the relationships between blast exposures and symptom reporting in a post-deployment active duty military population with mild traumatic brain injury. AB - Explosive devices have been the most frequent cause of traumatic brain injury (TBI) among deployed contemporary U.S. service members. The purpose of this study was to examine the influence of previous cumulative blast exposures (that did or did not result in TBI) on later post-concussion and post-traumatic symptom reporting after sustaining a mild TBI (MTBI). Participants were 573 service members who sustained MTBI divided into four groups by number of blast exposures (1, 2, 3, and 4-10) and a nonblast control group. Post-concussion symptoms were measured using the Neurobehavioral Symptom Inventory (NSI) and post-traumatic stress disorder (PTSD) symptoms using the Post-traumatic Checklist-Civilian version (PCL-C). Results show groups significantly differed on total NSI scores (p<0.001), where symptom endorsement increased as number of reported blast exposures increased. Total NSI scores were significantly higher for the 3- and 4 10 blast groups compared with the 1- and 2-blast groups with effect sizes ranging from small to moderate (d=0.31 to 0.63). After controlling for PTSD symptoms using the PCL-C total score, NSI total score differences remained between the 4 10-blast group and the 1- and 2-blast groups, but were less pronounced (d=0.35 and d=0.24, respectively). Analyses of NSI subscale scores using PCL-C scores as a covariate revealed significant between-blast group differences on cognitive, sensory, and somatic, but not affective symptoms. Regression analyses revealed that cumulative blast exposures accounted for a small but significant amount of the variance in total NSI scores (4.8%; p=0.009) and total PCL-C scores (2.3%; p<0.001). Among service members exposed to blast, post-concussion symptom reporting increased as a function of cumulative blast exposures. Future research will need to determine the relationship between cumulative blast exposures, symptom reporting, and neuropathological changes. PMID- 25036532 TI - A nation-wide multicenter 10-year (1999-2008) retrospective clinical study of endocrine therapy for Chinese females with breast cancer. AB - Endocrine therapy (ET) is one of the main systemic treatments for patients with breast cancer. To our knowledge, few studies have addressed the performance of ET or relevant influencing factors in cancer treatment in China. By retrospectively analyzing the clinicopathological data on breast cancer collected from representative hospitals of 7 traditional areas in China in one random month from each year between year 1999 and 2008, we found that: 1) The rate of the use of hormone receptor (HR) testing was 83.8% (3529/4211), with the estrogen receptor positive (ER+) rate and/or the progesterone receptor-positive (PR+) rate being 67.9% (2395/3529), and the ER-PR rate being 32.1% (1134/3529). 2) Of the 1599 patients who had received ET, 999 patients (58.3%) were premenopausal while 600 (41.7%) were postmenopausal; 1598 patients received adjuvant hormonal therapy (AHT), whereas only 1 patient received palliative therapy. The medications mainly administered to patients were anti-estrogen agents (80.3% [1283/1598]), followed by AIs (15.5% [248/1598]). Of the 1598 patients receiving AHT, 1416 patients (88.6%) were positive for ER and/or PR, while 75 (4.7%) were negative for both and 108 patients (6.7%) had unknown HR status. The ratio of the use of endocrine therapy for breast cancer patients with ER+ and/or PR+ status was 60.0% (1416/2395). 3) Results from the logistic regression analysis revealed that geography, occupations, and history of chemotherapy and surgery were dependent factors affecting the application of ET in breast cancer treatment in China (P<0.001). In conclusion, the use of ET on Chinese women with breast cancer is increasingly and gradually accounted into the standardized process. Economic status, occupations, and history of chemotherapy and surgery were key factors affecting the application of ET. People residing in developed areas, engaging in mental labour, having history of chemotherapy and surgery are susceptible to accept ET. PMID- 25036534 TI - Neonatal hyperekplexia with homozygous p.R392H mutation in GLRA1. AB - Hyperekplexia is a rare neurogenetic disorder, frequently misdiagnosed in neonates with a risk of apnoea, asphyxia, and sudden infant death. We present video sequences of a male newborn, admitted on the second day of life to the neonatal intensive care unit, due to tonic-clonic movements. Following clinical and paraclinical investigations, a final diagnosis of hyperekplexia was made. Genetic analysis revealed a homozygous mutation in GLRA1 resulting in a R392H amino acid substitution and altered receptor dynamics, as indicated from previous work. The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam which is a strong clinical feature of GLRA1-mediated hyperekplexia. [Published with video sequences]. PMID- 25036533 TI - Liraglutide's safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: The prevalence of type 2 diabetes (T2D) in youth is increasing. Treatment options beyond metformin and insulin are needed. The safety, tolerability, pharmacokinetics, and pharmacodynamics of liraglutide once daily in youth (10-17 years old) with T2D were investigated in a randomized, double-blind, placebo-controlled trial. SUBJECTS AND METHODS: Youth treated with diet/exercise alone or with metformin and having a hemoglobin A1c (HbA1c) level of 6.5-11% were randomized to liraglutide (n=14) or placebo (n=7). Starting at 0.3 mg/day, doses were escalated weekly to 0.6, 0.9, 1.2, and 1.8 mg/day (or placebo equivalent) for 5 weeks. RESULTS: Nineteen participants completed the trial. Baseline characteristics were similar between groups, with mean (SD) values for age of 14.8 (2.2) years, weight of 113.2 (35.6) kg (range, 57-214 kg), diabetes duration of 1.7 (1.4) years, and HbA1c level of 8.1% (1.2%). No serious adverse events (AEs), including severe hypoglycemia, occurred. Transient gastrointestinal AEs were most common at lower liraglutide doses during dose escalation. No significant changes in safety and tolerability parameters occurred. There was no evidence of pancreatitis or lipase elevations above three times the upper normal limit; calcitonin levels remained within the normal range. For liraglutide 1.8 mg, mean half-life was 12 h, and clearance was 1.7 L/h. After 5 weeks, the decline in HbA1c level was greater with liraglutide versus placebo (-0.86 vs. 0.04%, P=0.0007), whereas mean body weight remained stable (-0.50 vs. -0.54 kg, P=0.9703). CONCLUSIONS: Liraglutide was well tolerated in youth with T2D, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults. PMID- 25036535 TI - Characterization of the reniform nematode genome by shotgun sequencing. AB - The reniform nematode (RN), a major agricultural pest particularly on cotton in the United States, is among the major plant-parasitic nematodes for which limited genomic information exists. In this study, over 380 Mb of sequence data were generated from pooled DNA of four adult female RNs and assembled into 67,317 contigs, including 25,904 (38.5%) predicted coding contigs and 41,413 (61.5%) noncoding contigs. Most of the characterized repeats were of low complexity (88.9%), and 0.9% of the contigs matched with 53.2% of GenBank ESTs. The most frequent Gene Ontology (GO) terms for molecular function and biological process were protein binding (32%) and embryonic development (20%). Further analysis showed that 741 (1.1%), 94 (0.1%), and 169 (0.25%) RN genomic contigs matched with 1328 (13.9%), 1480 (5.4%), and 1330 (7.4%) supercontigs of Meloidogyne incognita, Brugia malayi, and Pristionchus pacificus, respectively. Chromosome 5 of Caenorhabditis elegans had the highest number of hits to the RN contigs. Seven putative detoxification genes and three carbohydrate-active enzymes (CAZymes) involved in cell wall degradation were studied in more detail. Additionally, kinases, G protein-coupled receptors, and neuropeptides functioning in physiological, developmental, and regulatory processes were identified in the RN genome. PMID- 25036536 TI - Transamination governs nitrogen isotope heterogeneity of amino acids in rats. AB - The nitrogen isotope composition (delta15N) of different amino acids carries different dietary information. We hypothesized that transamination and de novo synthesis create three groups that largely explain their dietary information. Rats were fed with 15N-labeled amino acids. The redistribution of the dietary 15N labels among the muscular amino acids was analyzed. Subsequently, the labeling was changed and the nitrogen isotope turnover was analyzed. The amino acids had a common nitrogen half-life of ~20 d, but differed in delta15N. Nontransaminating and essential amino acids largely conserved the delta15N of the source and, hence, trace the origin in heterogeneous diets. Nonessential and nontransaminating amino acids showed a nitrogen isotope composition between their dietary composition and that of their de novo synthesis pool, likely indicating their fraction of de novo synthesis. The bulk of amino acids, which are transaminating, derived their N from a common N pool and hence their delta15N was similar. PMID- 25036537 TI - Synthesis, structures, and magnetic properties of end-to-end azide-bridged manganese(III) chains: elucidation of direct magnetostructural correlation. AB - The two one-dimensional chain compounds [Mn(L1)(N3)].H2O (1.H2O; H2L1 = 2,2' ((1E,1'E)-ethane-1,2-diylbis(azan-1-yl-1-ylidene))bis(phenylmethan-1-yl-1 ylidene)diphenol) and [Mn(L2)(N3)] (2; H2L2 = 2,2'-((1E,1'E)-2,2-dimethylpropane 1,3-diyl)bis(azan-1-yl-1-ylidene)-bis(phenylmethan-1-yl-1-ylidene)diphenol) bridged by single end-to-end azides were prepared via a self-assembly process. Each Mn(III) ion exhibits a characteristic Jahn-Teller elongation along the chain direction. For both compounds, antiferromagnetic interactions between Mn(III) spins within a chain are transmitted through the azide ligands, together with the apparent occurrence of spin canting at low temperatures. Remarkably, the coupling constants (J) for 1 and 2 exceed those reported for end-to-end azide-linked Mn(III) systems. A systematic magnetostructural relationship based on the torsion angle is established in terms of the torsion angle Mn-N(ax)...N(ax)-Mn (ax = axial) for the first time. PMID- 25036538 TI - Dialectical behaviour therapy-informed skills training for deliberate self-harm: a controlled trial with 3-month follow-up data. AB - Dialectical Behaviour Therapy (DBT) has been shown to be an effective treatment for deliberate self-harm (DSH) and emerging evidence suggests DBT skills training alone may be a useful adaptation of the treatment. DBT skills are presumed to reduce maladaptive efforts to regulate emotional distress, such as DSH, by teaching adaptive methods of emotion regulation. However, the impact of DBT skills training on DSH and emotion regulation remains unclear. This study examined the Living Through Distress (LTD) programme, a DBT-informed skills group provided in an inpatient setting. Eighty-two adults presenting with DSH or Borderline Personality Disorder (BPD) were offered places in LTD, in addition to their usual care. A further 21 clients on the waiting list for LTD were recruited as a treatment-as-usual (TAU) group. DSH, anxiety, depression, and emotion regulation were assessed at baseline and either post-intervention or 6 week follow-up. Greater reductions in the frequency of DSH and improvements in some aspects of emotion regulation were associated with completion of LTD, as compared with TAU. Improvements in DSH were maintained at 3 month follow-up. This suggests providing a brief intensive DBT-informed skills group may be a useful intervention for DSH. PMID- 25036539 TI - Sudden gains in two psychotherapies for posttraumatic stress disorder. AB - We examined sudden, large, and stable shifts in symptoms from one therapy session to the next in two treatments for posttraumatic stress disorder (PTSD). Shifts in a positive direction (sudden gains) have so far been more frequently analyzed than those in a negative direction (sudden losses). We analyzed data from 102 outpatients suffering from PTSD who received either a cognitive-behavioral or a Gestalt-based intervention. Sudden gains, at 22.5%, were more frequent than sudden losses (3.9% of patients). Participants who had experienced sudden gains had lower PTSD scores at posttreatment, but not at the 6-month follow-up. As sudden losses were so rare, they were not analyzed statistically. Sudden gains accounted for 52% of overall treatment gains or 26% of overall change in a positive direction. Among very successful patients, those with sudden gains were overrepresented, but in absolute terms, there were as many patients without sudden gains in this group. There was no connection between sudden gains and type of intervention or depressive symptoms. Sudden gains and sudden losses occurred in our sample of PTSD patients, but in the light of current results, their clinical importance seems to be limited. PMID- 25036540 TI - The mediational role of panic self-efficacy in cognitive behavioral therapy for panic disorder: a systematic review and meta-analysis. AB - Cognitive models of panic disorder (PD) with or without agoraphobia have stressed the role of catastrophic beliefs of bodily symptoms as a central mediating variable of the efficacy of cognitive behavioral therapy (CBT). Perceived ability to cope with or control panic attacks, panic self-efficacy, has also been proposed to play a key role in therapeutic change; however, this cognitive factor has received much less attention in research. The aim of the present review is to evaluate panic self-efficacy as a mediator of therapeutic outcome in CBT for PD using descriptive and meta-analytic procedures. We performed systematic literature searches, and included and evaluated 33 studies according to four criteria for establishing mediation. Twenty-eight studies, including nine randomized waitlist-controlled studies, showed strong support for CBT improving panic self-efficacy (criterion 1); ten showed an association between change in panic self-efficacy and change in outcome during therapy (criterion 2); three tested, and one established formal statistical mediation of panic self-efficacy (criterion 3); while four tested and three found change in panic self-efficacy occurring before the reduction of panic severity (criterion 4). Although none of the studies fulfilled all of the four criteria, results provide some support for panic self-efficacy as a mediator of outcome in CBT for PD, generally on par with catastrophic beliefs in the reviewed studies. PMID- 25036541 TI - Drastic nickel ion removal from aqueous solution by curcumin-capped Ag nanoparticles. AB - A completely green synthesis protocol has been adopted to obtain silver nanoaggregates capped by the natural compound (1E, 6E)-1,7-bis(4-hydroxy-3 methoxyphenyl)-1,6-heptadiene-3,5-diene), also known as curcumin. The synthesis has been monitored by infrared, Raman, visible and fluorescence spectroscopies. Characterization confirms that curcumin reduces and caps the nanoparticles, and such a procedure allows its solubility in water and drastically increases curcumin stability. Silver nanoparticles (AgNPs)/curcumin complex has been dispersed in a water solution containing a known nickel ion concentration. After three days, a grey precipitate is observed and nickel concentration in the solution is reduced by about 70%. PMID- 25036542 TI - Short-term refractive change and ocular parameter changes after cycloplegia. AB - PURPOSE: To explore short-term refractive and ocular parameter changes and their correlations after cycloplegia with tropicamide. METHODS: This study prospectively enrolled 114 right eyes of 114 participants (mean [+/-SD] age, 9.1 [+/-2.8] years). Spherical equivalent of refractive error (SER), axial length (AL), corneal curvature (CC), and anterior chamber depth (ACD) were measured before and after 30 minutes from instillation of 0.4% tropicamide. A partial optical coherence interferometry (Zeiss IOLMaster) was used for ocular parameter measurement. Refractive change and ocular parameter changes after cycloplegia and their correlations were evaluated. RESULTS: Spherical equivalent of refractive error, AL, and ACD all positively shifted significantly at 30 minutes after application of 0.4% tropicamide (p < 0.0001 for each parameter measured). After cycloplegia, 28 eyes (24.6%) had a hyperopic shift of more than 0.25 diopters (D), 3 eyes (2.6%) had a myopic shift of more than 0.25 D, and 83 eyes (72.8%) had their SER changes within -0.25 to 0.25 D. The mean, maximum, and minimum keratometric values all decreased (p = 0.005, 0.03, and 0.05, respectively), whereas corneal astigmatism did not change significantly. The changes in AL, ACD, or mean keratometric values contributed little to the refractive changes after cycloplegia by tropicamide (p > 0.05, pr <= 0.01 for all values). CONCLUSIONS: Spherical equivalent of refractive error, AL, and ACD all positively shifted after cycloplegia with tropicamide. Corneal curvature became flattened after cycloplegia with tropicamide, but the corneal astigmatism did not change significantly. Refractive changes did not correlate with changes in AL, ACD, or CC after cycloplegia with tropicamide. PMID- 25036543 TI - Meta-analysis of stratus OCT glaucoma diagnostic accuracy. AB - PURPOSE: To evaluate the diagnostic accuracy of glaucoma in different stages, different types of glaucoma, and different ethnic groups using Stratus optical coherence tomography (OCT). METHODS: We searched MEDLINE to identify available articles on diagnostic accuracy of glaucoma published between January 2004 and December 2011. A PubMed (National Center for Biotechnology Information) search using medical subject headings and keywords was executed using the following terms: "diagnostic accuracy" or "receiver operator characteristic" or "area under curve" or "AUC" and "Stratus OCT" and "glaucoma." The search was subsequently limited to publications in English. The area under a receiver operator characteristic (AUC) curve was used to measure the diagnostic performance. A random-effects model was used to estimate the pooled AUC value of the 17 parameters (average retinal nerve fiber layer thickness, temporal quadrant, superior quadrant, nasal quadrant, inferior quadrant, and 1 to 12 o'clock). Meta regression analysis was used to check the significance of some important factors: (1) glaucoma severity (five stages), (2) glaucoma types (four types), and (3) ethnicity (four categories). RESULTS: The orders of accuracy among those parameters were as follows: average > inferior > superior > 7 o'clock > 6 o'clock > 11 o'clock > 12 o'clock > 1 o'clock > 5 o'clock > nasal > temporal > 2 o'clock > 10 o'clock > 8 o'clock > 9 o'clock > 4 o'clock > 3 o'clock. After adjusting for the effects of age, glaucoma severity, glaucoma types, and ethnicity, the average retinal nerve fiber layer thickness provided highest accuracy compared with the other parameters of OCT. The diagnostic accuracy in Asian populations was significantly lower than that in whites and the other two ethnic types. CONCLUSIONS: Stratus OCT demonstrated good diagnostic capability in differentiating glaucomatous from normal eyes. However, we should be more cautious in applying this instrument in Asian groups in glaucoma management. PMID- 25036544 TI - Photodynamic therapy for choroidal hemangioma unresponsive to ranibizumab. AB - PURPOSE: To report a patient with circumscribed choroidal hemangioma with serous macular detachment successfully treated with photodynamic therapy (PDT) after being unresponsive to treatment with intravitreal ranibizumab. CASE REPORT: A 63 year-old Asian woman was incidentally found to have a circumscribed choroidal hemangioma without symptoms in the left eye during a routine health examination. Blurred vision of the left eye developed 3.5 years later, and a serous macular detachment was observed. Two consecutive intravitreal ranibizumab injections were administered, but the subretinal fluid (SRF) persisted and the vision did not improve. One PDT session was then given, and the SRF resolved completely within 1 month. The best-corrected visual acuity improved from 20/50 before treatment to 20/25 at 4 months after the PDT. The tumor thickness also decreased from 3.84 mm before treatment to 2.86 mm at 14 months after PDT. CONCLUSIONS: Circumscribed choroidal hemangioma with serous macular detachment may not respond to anti vascular endothelial growth factor agents. Photodynamic therapy may be an effective choice in such cases to remove SRF and improve vision. PMID- 25036545 TI - Proteus mirabilis and its role in dacryocystitis. AB - PURPOSE: Dacryocystitis is a common inflammation of the lacrimal sac, usually from an underlying bacterial infection. Most cases can be attributed to common ocular flora such as Staphylococcus aureus or Streptococcus pneumoniae; however, uncommon bacterial causes such as Proteus mirabilis can still occur. P. mirabilis is a gram-negative bacillus that is found abundantly in people who have undergone long-term catheterization and is uncommonly found in or around the eyes except in people who have undergone long-term catheterization. Proteus species can cause conjunctivitis, canaliculitis, and dacryocystitis and have the ability to manifest into preseptal cellulitis; therefore, timely recognition and treatment are important to prevent potential further complications. CASE REPORT: An 84-year old white man had several recurrences of acute dacryocystitis that had marginal improvement with empiric antibiotic treatment. Resultant culture of the ocular discharge revealed an uncommon bacterium, P. mirabilis. Successful dosing of oral antibiotics resolved the infection but ultimately the patient required an external dacryocystorhinostomy (DCR) procedure to maintain patency of the nasolacrimal lacrimal system and prevent recurrence. At 3 months after external DCR, the patient was symptom free with no recurrences. CONCLUSIONS: Dacryocystitis has a distinctive clinical presentation and is usually easily treated when appropriate oral antibiotics are directed at the underlying pathogen. In nonresponsive cases, culturing of the ocular discharge should be performed to identify the underlying pathogen. Cases of dacryocystitis caused by Proteus species are usually responsive to several standard antibiotics used orally in eye care; however, culturing and susceptibility testing can streamline the diagnostic and management sequence considerably in unclear or unresponsive cases. Typically, patients with dacryocystitis return to normal after appropriate treatment, but chronic recurrences and epiphora are potential sequelae. Patients should be educated that a DCR surgical procedure may be needed to prevent future recurrences in some cases. PMID- 25036546 TI - Uveal melanoma in the peripheral choroid masquerading as chronic uveitis. AB - PURPOSE: To describe a case of uveal melanoma in the peripheral choroid masquerading as chronic uveitis and to raise awareness about malignant masquerade syndromes. CASE REPORT: A 36-year-old Chinese woman presented from an outside ophthalmologist with a 6-month history of unilateral chronic uveitis unresponsive to medical therapy in the left eye. She was found to have a uveal melanoma in the retinal periphery and underwent successful enucleation of her left eye. The histopathological diagnosis confirmed the clinical diagnosis. CONCLUSIONS: When uveal melanoma presents in an atypical way, the diagnosis is more difficult. This case highlights the uncommon presentations of malignant melanoma of the choroid. It provides valuable information on how peripheral uveal melanoma can present with clinical signs consistent with an anterior uveitis. PMID- 25036547 TI - Tosufloxacin deposits in compromised corneas. AB - PURPOSE: To report the adverse effects of topical tosufloxacin in two patients with corneal deposits in compromised cornea. CASE REPORT: Tosufloxacin was administered topically to a 13-month-old girl after penetrating keratoplasty in the left eye. Three days posttransplantation, corneal precipitations appeared and thereafter continuously increased. An 80-year-old woman, who maintained postoperative multiple topical medications including tosufloxacin, presented dense white deposits in the left eye a month postoperation. In both cases, the deposits showed a granular pattern and were limited to areas of large epithelial defects. After discontinuation of tosufloxacin, the deposits slowly decreased and completely disappeared in a few weeks. In the former case, corneal re epithelialization was significantly disturbed and resulted in anterior stromal opacity, whereas visual acuity and visualization of the retina were severely interfered in the latter case. CONCLUSIONS: Tosufloxacin can precipitate especially on compromised corneal surfaces. Therefore, topical tosufloxacin should be avoided in patients who are at risk of losing corneal surface integrity. PMID- 25036548 TI - Cell viability and chondrogenic differentiation capability of human mesenchymal stem cells after iron labeling with iron sucrose. AB - For evaluation of cell therapy strategies using human mesenchymal stem cells (hMSCs), it is important to be able to trace transplanted cells and their distribution in tissues, for example, cartilage, over time. The aim of the study was to determine effects on cell viability, traceability, and chondrogenic differentiation of hMSCs after iron labeling with iron sucrose. hMSCs were collected (seven donors, 13-57 years) from patients undergoing spinal surgery. Two subsets of experiments were performed. (1) Iron labeling of hMSCs: 1 mg/mL of Venofer((r)) (iron sucrose) was added (16 h) to cultures. hMSCs were examined for uptake of iron sucrose (Prussian blue staining) and cell viability (flow cytometry). (2) Iron-labeled hMSCs (passage 4) (n=4, pellet mass), 200,000 cells/tube, were cultured (DMEM-HG) with 10 ng/mL TGFbeta and compared with controls (from each donor). The pellets were harvested at days 7, 14, and 28. Real-time PCR, IHC, and histology were used to evaluate SOX9, ACAN, C6S, and COL2A1 expression. Mean number of cells containing iron deposits was 98.1% and mean cell viability was 92.7% (no significant difference compared with unlabeled control cells). Pellets containing iron-labeled cells expressed COL2A1 on protein level (all time points), in similar levels as controls, and glycosaminoglycan accumulation was observed in iron-labeled pellets (day 14 or day 28). Results were supported by the expression of chondrogenic genes SOX9, ACAN, and COL2A1. The results in vitro indicate that iron sucrose can be used as a cell tracer for evaluation of cellular distribution in vivo after transplantation of MSCs and thus contribute with important knowledge when exploring new treatment strategies for degenerated cartilaginous tissues. PMID- 25036549 TI - DFA7, a new method to distinguish between intron-containing and intronless genes. AB - Intron-containing and intronless genes have different biological properties and statistical characteristics. Here we propose a new computational method to distinguish between intron-containing and intronless gene sequences. Seven feature parameters alpha, beta, gamma, lambda, theta, phi and sigma based on detrended fluctuation analysis (DFA) are fully used, and thus we can compute a 7 dimensional feature vector for any given gene sequence to be discriminated. Furthermore, support vector machine (SVM) classifier with Gaussian radial basis kernel function is performed on this feature space to classify the genes into intron-containing and intronless. We investigate the performance of the proposed method in comparison with other state-of-the-art algorithms on biological datasets. The experimental results show that our new method significantly improves the accuracy over those existing techniques. PMID- 25036550 TI - Effects of favorable alleles for water-soluble carbohydrates at grain filling on grain weight under drought and heat stresses in wheat. AB - Drought, heat and other abiotic stresses during grain filling can result in reductions in grain weight. Conserved water-soluble carbohydrates (WSC) at early grain filling play an important role in partial compensation of reduced carbon supply. A diverse population of 262 historical winter wheat accessions was used in the present study. There were significant correlations between 1000-grain weight (TGW) and four types of WSC, viz. (1) total WSC at the mid-grain filling stage (14 days after flowering) produced by leaves and non-leaf organs; (2) WSC contributed by current leaf assimilation during the mid-grain filling; (3) WSC in non-leaf organs at the mid-grain filling, excluding the current leaf assimilation; and (4) WSC used for respiration and remobilization during the mid grain filling. Association and favorable allele analyses of 209 genome-wide SSR markers and the four types of WSC were conducted using a mixed linear model. Seven novel favorable WSC alleles exhibited positive individual contributions to TGW, which were verified under 16 environments. Dosage effects of pyramided favorable WSC alleles and significantly linear correlations between the number of favorable WSC alleles and TGW were observed. Our results suggested that pyramiding more favorable WSC alleles was effective for improving both WSC and grain weight in future wheat breeding programs. PMID- 25036551 TI - Ionic liquid-phase synthesis of 1,5-disubstituted 1,2,3-triazoles. AB - A simplified ionic liquid-phase synthesis of 1,5-disubstituted 1,2,3-triazole was developed. Nineteen 1,5-disubstituted 1,2,3-triazoles were successfully obtained by merely washing the ionic liquid phase with ether, thus avoiding the need for intermediate purification. PMID- 25036552 TI - Self-assembly of random copolymers. AB - Self-assembly of random copolymers has attracted considerable attention recently. In this feature article, we highlight the use of random copolymers to prepare nanostructures with different morphologies and to prepare nanomaterials that are responsive to single or multiple stimuli. The synthesis of single-chain nanoparticles from random copolymers and their potential applications are also discussed in some detail. We aim to draw more attention to these easily accessible copolymers, which are likely to play an important role in translational polymer research. PMID- 25036553 TI - The hepatitis C cascade of care among HIV infected patients: a call to address ongoing barriers to care. AB - BACKGROUND: The aims were to investigate the hepatitis C (HCV) cascade of care among HIV-infected patients and to identify reasons for not referring for and not initiating HCV therapy after completion of HCV treatment staging. DESIGN AND METHODS: Retrospective cohort analysis of HIV-infected patients under care at the University of California, San Diego (UCSD). We identified patients screened for and diagnosed with active HCV infection. Logistic regression analyses were used to identify factors associated with lack of referral for HCV therapy. Electronic medical records were reviewed to ascertain reasons for not initiating HCV therapy. RESULTS: Between 2008 and 2012, 4725 HIV-infected patients received care at the UCSD Owen clinic. Most patients [4534 (96%)] were screened for HCV, 748 (16%) patients had reactive serum HCV antibodies but only 542 patients had active HCV infection. Lack of engagement in care was the most important predictor of non referral for HCV therapy [odds ratio (OR): 5.08, 95% confidence interval 3.24 6.97, p<0.00001]. Other significant predictors included unstable housing (OR: 2.26), AIDS (OR: 1.83), having a detectable HIV viral load (OR: 1.98) and being non-white (OR: 1.67). The most common reason (40%) for not initiating or deferring HCV therapy was the presence of ongoing barriers to care. CONCLUSIONS: Screening for HCV in HIV-infected patients linked to care is high but almost half of patients diagnosed with HCV are not referred for HCV therapy. Despite improvements in HCV therapy the benefits will not be realized unless effective measures for dealing with barriers to care are implemented. PMID- 25036554 TI - Nectar robbing positively influences the reproductive success of Tecomella undulata (Bignoniaceae). AB - The net consequence of nectar robbing on reproductive success of plants is usually negative and the positive effect is rarely produced. We evaluated the influence of nectar robbing on the behaviour of pollinators and the reproductive success of Tecomella undulata (Bignoniaceae) in a natural population. Experimental pollinations showed that the trees were strictly self-incompatible. The three types of floral colour morphs of the tree viz. red, orange and yellow, lacked compatibility barriers. The pollinators (Pycnonotus cafer and Pycnonotus leucotis) and the robber (Nectarinia asiatica) showed equal preference for all the morphs, as they visited each morph with nearly equal frequency and flower handling time. The sunbirds caused up to 60% nectar robbing, mostly (99%) by piercing through the corolla tube. Although nectar is replenished at regular intervals, insufficient amount of nectar compelled the pollinators to visit additional trees in bloom. Data of manual nectar robbing from the entire tree showed that the pollinators covered lower number of flowers per tree (5 flowers/tree) and more trees per bout (7 trees/bout) than the unrobbed ones (19 flowers/tree and 2 trees bout). The robbed trees set a significantly greater amount of fruits than the unrobbed trees. However, the number of seeds in a fruit did not differ significantly. The study shows that plant-pollinator-robber interaction may benefit the self-incompatible plant species under conditions that increases the visits of pollinators among the compatible conspecifics in a population. PMID- 25036555 TI - Matrix metalloproteinase-8 regulates transforming growth factor-beta1 levels in mouse tongue wounds and fibroblasts in vitro. AB - Matrix metalloproteinase-8 (MMP-8)-deficient mice (Mmp8-/-) exhibit delayed dermal wound healing, but also partly contradicting results have been reported. Using the Mmp8-/- mice we investigated the role of MMP-8 in acute wound healing of the mobile tongue, and analyzed the function of tongue fibroblasts in vitro. Interestingly, in the early phase the tongue wounds of Mmp8-/- mice healed faster than those of wild type (wt) mice resulting in significant difference in wound widths (P=0.001, 6-24h). The Mmp8-/- wounds showed no change in myeloperoxidase positive myeloid cell count, but the level of transforming growth factor (TGF) beta1 was significantly increased (P=0.007) compared to the wt tongues. Fibroblasts cultured from wt tongues expressed MMP-8 and TGF-beta1. However, higher TGF-beta1 levels were detected in Mmp8-/- fibroblasts, and MMP-8 treatment decreased phosphorylated Smad-2 levels and alpha-smooth muscle actin expression in these fibroblasts suggesting reduced TGF-beta1 signaling. Consistently, a degradation of recombinant TGF-beta1 by MMP-8 decreased its ability to activate the signaling cascade in fibroblasts. Moreover, collagen gels with Mmp8-/- fibroblasts reduced more in size. We conclude that MMP-8 regulates tongue wound contraction rate and TGF-beta1 levels. In vitro analyses suggest that MMP-8 may also play a role in regulating TGF-beta1 signaling of stromal fibroblasts. PMID- 25036556 TI - Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability. AB - Arginine deficiency in sepsis may impair nitric oxide (NO) production for local perfusion and add to the catabolic state. In contrast, excessive NO production has been related to global haemodynamic instability. Therefore, the aim of the present study was to investigate the dose-response effect of intravenous arginine supplementation in post-absorptive patients with septic shock on arginine-NO and protein metabolism and on global and regional haemodynamics. Eight critically ill patients with a diagnosis of septic shock participated in this short-term (8 h) dose-response study. L-Arginine-HCl was continuously infused [intravenously (IV)] in three stepwise-increasing doses (33, 66 and 99 MUmol.kg-1.h-1). Whole-body arginine-NO and protein metabolism were measured using stable isotope techniques, and baseline values were compared with healthy controls. Global and regional haemodynamic parameters were continuously recorded during the study. Upon infusion, plasma arginine increased from 48+/-7 to 189+/-23 MUmol.l-1 (means+/ S.D.; P<0.0001). This coincided with increased de novo arginine (P<0.0001) and increased NO production (P<0.05). Sepsis patients demonstrated elevated protein breakdown at baseline (P<0.001 compared with healthy controls), whereas protein breakdown and synthesis both decreased during arginine infusion (P<0.0001). Mean arterial and pulmonary pressure and gastric mucosal-arterial partial pressure of carbon dioxide difference (Pr-aCO2) gap did not alter during arginine infusion (P>0.05), whereas stroke volume (SV) increased (P<0.05) and arterial lactate decreased (P<0.05). In conclusion, a 4-fold increase in plasma arginine with intravenous arginine infusion in sepsis stimulates de novo arginine and NO production and reduces whole-body protein breakdown. These potential beneficial metabolic effects occurred without negative alterations in haemodynamic parameters, although improvement in regional perfusion could not be demonstrated in the eight patients with septic shock who were studied. PMID- 25036557 TI - Land-use suitability analysis for urban development in Beijing. AB - Land-use suitability analyses are of considerable use in the planning of mega cities. An Urban Development Land-use Suitability Mapping (UDLSM) approach has been constructed, based on opportunity and constraint criteria. Two Multi criteria Evaluation (MCE) methods, the Ideal Point Method (IPM) and Ordered Weighted Averaging (OWA), were used to generate the opportunity map. The protection map was obtained by means of constraint criteria, utilizing the Boolean union operator. A suitability map was then generated by overlaying the opportunity and protection maps. By applying the UDLSM approach to Beijing, its urban development land-use suitability was mapped, and a sensitivity analysis undertaken to examine the robustness of the proposed approach. Indirect validation was achieved by mutual comparisons of suitability maps resulting from the two MCE methods, where the overall agreement of 91% and kappa coefficient of 0.78 indicated that both methods provide very similar spatial land-use suitability distributions. The suitability level decreases from central Beijing to its periphery, and the area classed as suitable amounts to 28% of the total area. Leading attributes of each opportunity factor for suitability were revealed, with 2256 km(2), i.e. 70%, of existing development land being overlaid by suitable areas in Beijing. Conflicting parcels of land were identified by overlaying the resultant map with two previous development blueprints for Beijing. The paper includes several recommendations aimed at improving the long term urban development plans for Beijing. PMID- 25036558 TI - Enhanced sensitivity and stability of room-temperature NH3 sensors using core shell CeO2 nanoparticles@cross-linked PANI with p-n heterojunctions. AB - We report a room-temperature NH3 gas sensor with high response and great long term stability, including CeO2 NPs conformally coated by cross-linked PANI hydrogel. Such core-shell nanocomposites were prepared by in situ polymerization with different weight ratios of CeO2 NPs and aniline. At room temperature, the nanohybrids showed enhanced response (6.5 to 50 ppm of NH3), which could be attributed to p-n junctions formed by the intimate contact between these two materials. Moreover, the stability was discussed in terms of phytic acid working as a gelator, which helped the PANI sheath accommodate itself and enhance the mechanical strength and chemical stability of the sensors by avoiding "swelling effect" in high relative humidity. The sensors maintained its sensing characteristic (response of ca. 6.5 to 50 ppm of NH3) in 15 days. Herein, the obtained results could help to accelerate the development of ammonia gas sensor. PMID- 25036559 TI - Late-onset dysferlinopathy presented as "liver enzyme" abnormalities: a technical note. AB - Limb-girdle muscular dystrophy type 2B,a type of dysferlinopathy, is caused by mutations in the dysferlin gene (DYSE). It is characterized by predominant weakness and atrophy of muscles of the pelvic and shoulder girdles, massive elevation of serum CK concentration, slow progression, and onset usually within the second or third decade of life. We present a Chinese patient whose disease onset was at the age of 50 years with persistent elevation of transaminases for 3 years before weakness appeared. She had been considered as having liver disease for a long time and then polymyositis. Finally, biceps brachii biopsy revealed dystrophic morphology and depletion of dysferlin in immunohistochemistry. This case should remind readers that late-age onset of dysferlinopathy can be misdiagnosed as liver disease or polymyositis. PMID- 25036560 TI - Sonographic assessment of the carpal tunnel syndrome secondary to a tenosynovitis of the flexor digitorum superficialis in a patient with rheumatoid arthritis. PMID- 25036561 TI - Incidence of pulmonary hypertension in patients with systemic sclerosis and no pulmonary symptoms: is annual echocardiographic screening necessary? AB - BACKGROUND: Annual echocardiographic screening has been recommended for early detection of pulmonary hypertension (PHT) in systemic sclerosis (SSc) patient; however, the cost benefit for cases with no pulmonary symptoms is not well established. OBJECTIVES: The objective of this study was to determine the incidence and clinical predictors of echocardiographic diagnosis of PHT in "asymptomatic" SSc patients. METHODS: A historical cohort of adult SSc patients who underwent echocardiographic screening for PHT at least twice in Khon Kaen University, Thailand, during January 1, 2005, to December 31, 2011, was included. Pulmonary hypertension was defined by an estimate of right ventricular systolic pressure of greater than 40 mm Hg. RESULTS: A total of 143 medical records were reviewed (female-to-male ratio = 1.7:1). The majority had the diffuse subset (94 cases; 69.6%). Seventy-five (52.4%) were without pulmonary symptoms throughout the follow-up period. Of the 403.1 person-years under observation in the asymptomatic group, only 1 had pulmonary arterial hypertension confirmed by right sided heart catheterization. The incidence of PHT among such SSc patients was 0.2 per 100 person-years (95% confidence interval [CI], 0.006-0.01 per 100 person years). The disease duration at the time of PHT detection by echocardiography was 5.1 years. The declining functional class (FC) led to the higher incidence of PHT, with incidence of PHT in those who had declining FC I to FC II and FC I to FC III of 2.1 (95% CI, 0.4-6.0) and 4.2 (95% CI, 0.1-23.3), respectively. CONCLUSIONS: The incidence of echocardiography-diagnosed PHT among Thai with SSc, and no pulmonary symptoms was low. Annual echocardiography is less beneficial among such patients; repeated echocardiography should instead be performed on those with a declining FC. PMID- 25036562 TI - Nearly pain-free self-administration of subcutaneous methotrexate with an autoinjector: results of a phase 2 clinical trial in patients with rheumatoid arthritis who have functional limitations. AB - BACKGROUND: A methotrexate autoinjector (MTXAI) was developed for self administration of subcutaneous (SC) methotrexate by patients with rheumatoid arthritis (RA). The MTXAI circumvents the need for vials, needles, and syringes and may therefore improve dosing accuracy, handling risks, and patient adherence. OBJECTIVES: The objective of this study was to evaluate actual human use of the MTXAI in patients with RA and determine its reliability, robustness, safety, local tolerance, and ease of use. METHODS: In this phase 2, multicenter, open label, single-dose, single-arm, in-clinic US study, adults (N = 101) treated with methotrexate for 3 months or longer were trained to use the MTXAI and assigned to 10, 15, 20, or 25 mg methotrexate based on previous treatment and disease status. Patients completed training confirmation and ease-of-use questionnaires. Pain was evaluated immediately after self-administration and at follow-up with a 100-mm visual analog scale (0 = no pain, 100 = worst possible pain). RESULTS: At screening, 90.1% of patients had moderate to severe functional limitations (class II-IV). All patients successfully completed the study. All devices functioned correctly and as intended. The device was rated easy to use by 98%, and instructions clear and easy to follow by 100% of patients. On the visual analog scale, mean and median pain scores were 3.6/100 and 1.0/100 mm, respectively, immediately after self-administration, and were lower at follow-up. Most patients (92.3%) had no administration-site erythema; 7.7% had minimal erythema. CONCLUSIONS: The SC MTXAI was well tolerated and considered easy to use by patients with RA. Improving SC methotrexate delivery may increase patient tolerance of self-administration, possibly improving adherence. PMID- 25036563 TI - Pigmented villonodular synovitis developing in a patient with rheumatoid arthritis. AB - A 56-year-old man developed pigmented villonodular synovitis (PVNS) 3 years after he was diagnosed with rheumatoid arthritis (RA). He had been successfully treated with methotrexate, leflunomide, sulfadiazine, and intra-articular knee injection of etanercept (tumor necrosis factor alpha inhibitor) in 2010. He stopped all drugs for arthritis 1 year later for disease remission. He was readmitted for right knee pain and swelling in 2013, when the magnetic resonance imaging and arthroscopy of the right knee indicated PVNS. Following surgical resection, the patient was doing well after 1 year. This rare case is the first reported case in English-language literature of PVNS of the knee seen in RA patients and illustrates the importance of differential diagnosis of this condition with synovial cysts, which are commonly found in RA. PMID- 25036564 TI - Pain, physical functioning, and overeating in obese rheumatoid arthritis patients: do thoughts about pain and eating matter? AB - BACKGROUND: Obese rheumatoid arthritis (RA) patients have higher levels of pain, disability, and disease activity than do nonobese patients with RA. Patients' health-related thoughts about arthritis and weight may be important to consider in obese patients with RA who face the dual challenge of managing RA and weight. OBJECTIVES: The objective of this study was to examine the relationships of pain catastrophizing, self-efficacy (ie, confidence) for arthritis management and self efficacy for weight management to important outcomes in obese patients with RA. We expected that after controlling for demographic and medical variables, higher levels of pain catastrophizing and lower levels of confidence would account for significant and unique variance in pain, physical functioning, and overeating. METHODS: Participants had a diagnosis of RA and a body mass index of 28 kg/m or greater and completed self-report questionnaires assessing pain, physical functioning, overeating, pain catastrophizing, self-efficacy for arthritis management, self-efficacy for weight management, and a 6-minute walk test. RESULTS: Pain catastrophizing, self-efficacy for arthritis, and self-efficacy for weight management were significantly and uniquely related to RA-related outcomes. Pain catastrophizing was a significant independent predictor of pain severity (beta = 0.38); self-efficacy for arthritis was a significant independent predictor of self-report physical functioning (beta = -0.37) and the 6-minute walk performance (beta = 0.44), and self-efficacy for weight management was a significant independent predictor of overeating (beta = -0.58). CONCLUSIONS: Pain catastrophizing, self-efficacy for arthritis, and self-efficacy for weight management each contributed uniquely to relate to key outcomes in obese patients with RA. Clinicians should consider assessment of thought processes when assessing and intervening with patients who face dual health challenges; unique intervention approaches may be needed for addressing the challenges of arthritis and weight. PMID- 25036565 TI - Collagenous colitis in systemic sclerosis: an overlooked and treatable complication. AB - Collagenous colitis (CC) is an inflammatory bowel condition of unknown etiology. Systemic sclerosis (SSc) has been associated with CC in a few cases, but it is not clear whether CC could be considered an unusual manifestation of SSc or an independent condition. Here we present a case of SSc-associated CC and compare routine histology and immunofluorescence studies for allograft inflammatory factor 1 and caveolin 1 expression with other cases of CC and healthy controls. All CC biopsies showed characteristic sublaminal collagen accumulation and a decrease of caveolin 1 expression, this latter finding consistent with and common in any fibrotic reaction. In contrast, the expression of allograft inflammatory factor 1 was increased only in the SSc-CC specimen, suggesting a distinct pathogenesis. A literature review revealed 6 previously reported cases of SSc-CC with common clinical features. These observations suggest that CC should be suspected as a rare gastrointestinal complication of SSc and that clinicians should be aware of the possibility in SSc patients developing watery diarrhea. PMID- 25036566 TI - Toward development of a Tophus Impact Questionnaire: a qualitative study exploring the experience of people with tophaceous gout. AB - BACKGROUND: Although tophi are known to affect physical function, the impact of tophi on the lives of people with gout has not been explored in detail. OBJECTIVES: The aim of this qualitative study was to understand the experience of people living with tophaceous gout, as the first step to developing a patient reported Tophus Impact Questionnaire. METHODS: Twenty-five people with tophaceous gout (22 men; median age, 66 years; median gout disease duration, 26 years) participated in semistructured interviews that explored their experiences and perceptions of tophi. Interviews were recorded and transcribed. The transcripts were analyzed and coded to identify themes using content analysis. RESULTS: Three major interrelated themes arose from the interviews. The first theme was functional impact affecting body structures and functions (causing pain, restricted joint range of motion and deformity, and complications), and causing activity limitation and participation restriction (affecting day-to-day activities, leisure activities, employment participation, and family participation). The second theme was psychological impact including low self esteem, embarrassment, resignation, but also optimism. The third theme was the lack of impact in some participants. CONCLUSIONS: Gouty tophi can have an important impact on many aspects of the patient's life. In addition to the impact of tophi on physical function, tophi may also influence social and psychological functioning. Capturing these aspects of the patient experience will be important in the development of a patient-reported outcome measure of tophus burden. PMID- 25036567 TI - Multiple psychological factors are associated with poorer functioning in a sample of community-dwelling knee osteoarthritis patients. AB - BACKGROUND: Knee osteoarthritis (OA) is the most common type of arthritis and imposes a heavy burden on individual welfare among elderly people. There is preliminary evidence that psychological factors play a role in functional ability and pain in knee OA patients, particularly with respect to the surgery outcome. Less is known about psychological factors among community-dwelling patients with knee OA. OBJECTIVES: We aimed to determine which psychological factors are associated with pain and functional ability among community-dwelling knee OA patients using a comprehensive set of psychological questionnaires. METHODS: In the cross-sectional baseline setting of a prospective, randomized controlled intervention study, 111 patients aged from 35 to 75 years with clinical symptoms and radiographic grading of knee OA were included. They completed a comprehensive set of psychological questionnaires, including measures of resources and coping, fear and catastrophizing, and distress. RESULTS: In cross-sectional comparisons, pain self-efficacy, fear of movement, pain catastrophizing, and elevated anxiety were associated with pain and a poorer functional ability. In logistic regression analysis, independent association was seen between pain self-efficacy and poorer functioning. Knee OA patients also reported elevated levels of anxiety. CONCLUSIONS: The results reveal that both pain self-efficacy and negatively charged emotion and expectations toward pain are important factors when dealing with knee OA patients. Failure to consider these will probably contribute to prolonged disability and further pain. The results call for the routine assessment of multiple psychological factors in knee OA. PMID- 25036568 TI - Tuberculosis infection causing intestinal perforations in 2 patients with systemic lupus erythematosus. AB - Patients with systemic lupus erythematosus (SLE) have a higher incidence rate of tuberculosis and a more frequent extrapulmonary involvement than the general population. We present 2 SLE patients who developed gastrointestinal tuberculosis complicated with intestinal perforation, a rare but serious complication that could be confused with lupus-associated intestinal vasculitis. Opportunistic infections such as tuberculosis must be suspected in SLE patients with abdominal symptoms on immunosuppressive therapy because its early recognition could prevent catastrophic complications such as intestinal perforation and subsequent peritonitis. PMID- 25036569 TI - Immune complex-mediated autoimmunity in a patient With Smith-Magenis syndrome (del 17p11.2). AB - Smith-Magenis syndrome (SMS) is a sporadic congenital disorder involving multiple organ systems caused by chromosome 17p11.2 deletions. Smith-Magenis syndrome features craniofacial and skeletal anomalies, cognitive impairment, and neurobehavioral abnormalities. In addition, some SMS patients may exhibit hypogammaglobulinemia. We report the first case of SMS-associated autoimmunity in a woman who presented with adult onset of multiple autoimmune disorders, including systemic lupus erythematosus, antiphospholipid antibody syndrome, and autoimmune hepatitis. Molecular analysis using single-nucleotide polymorphism array confirmed a de novo 3.8-Mb deletion (breakpoints, chr17: 16,660,721 20,417,975), resulting in haploinsufficiency for TACI (transmembrane activator and CAML interactor). Our data are consistent with potential loss of function for the BAFF (B cell-activating factor) receptor TACI as a contributing factor to human autoimmune phenomena. PMID- 25036570 TI - Utilization of Leek (Allium ampeloprasum var. porrum) for inulinase production. AB - Inulinase production by Rhodotorula glutinis was carried out in this study, using leek (Allium ampeloprasum var. porrum) as an alternative carbon source due to its high inulin content and easy availability. Taguchi orthogonal array (OA) design of experiment (DOE) was used to optimize fermentation conditions. For this purpose, five influential factors (leek concentration, pH, incubation temperature, agitation speed, and fermentation time) related to inulinase production were selected at four convenient levels. The results showed that maximum inulinase activity was obtained as 30.89 U/mL, which was close to the predicted result (30.24 U/mL). To validate the obtained results, analysis of variance (ANOVA) was employed. Consequently, leek has a great potential as an effective and economical carbon source for inulinase production, and the use of Taguchi DOE enhanced enzyme activity about 2.87-fold when compared with the unoptimized condition. PMID- 25036571 TI - Nomogram Predicting Clinical Outcomes in Non-small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. AB - PURPOSE: The aim of this study was to develop a pragmatic nomogram for prediction of progressionfree survival (PFS) for the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 306 recurred or metastatic NSCLC patients with EGFR mutation, who received EGFR TKIs, were enrolled in this study. We developed the nomogram, using a Cox proportional hazard regression model for PFS. RESULTS: The median PFS was 11.2 months. Response rate to EGFR TKI was 71.9%. Multivariate Cox model identified disease status, performance status, chemotherapy line, response to EGFR TKI, and bone metastasis as independent prognostic factors, and the nomogram for PFS was developed, based on these covariates. The concordance index for a nomogram was 0.708, and the calibration was also good. CONCLUSION: We developed a nomogram, based on clinical characteristics, for prediction of the PFS to EGFR TKI in NSCLC patients with EGFR mutation. PMID- 25036572 TI - Efficacy and safety of everolimus in korean patients with metastatic renal cell carcinoma following treatment failure with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. AB - PURPOSE: The purpose of this study is to assess the efficacy and safety of everolimus in Korean patients with metastatic renal cell carcinoma (mRCC) for whom initial treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFr-TKI) has failed. MATERIALS AND METHODS: Eligible patients with mRCC (any histology) who had progressed on or were intolerant of VEGFr-TKI therapy received oral everolimus (10 mg dose once daily). Tumor response was reassessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: This study included 100 patientswith a median follow-up duration of 10.2 months, a median progression-free survival (PFS) of 4.2 months (95% confidence interval [CI], 3.4 to 5.0 months), and an overall survival of 10.1 months (95% CI, 6.9 to 13.3 months). The most common grade 3 or greater adverse events (AEs) overall were anemia (13%), pneumonitis (9%), hyperglycemia (8%), and stomatitis (6%). While the incidence of pneumonitis was similar (26 cases, 26%) to the reported incidence in Western patients, the Korean presentations were more severe: 10 patients permanently discontinued everolimus due to pneumonitis, including two deaths on treatment. Statistically significant relationships were established between biologic toxicities, hyperglycemia and anemia, and PFS (hyperglycemia vs. non-hyperglycemia: hazard ratio [HR], 0.61; p=0.055 and anemia vs. non-anemia: HR, 0.51; p=0.021). CONCLUSION: Everolimus was effective in Korean patients with mRCC who had failed initial VEGFr-TKI therapy. While everolimus was well tolerated in general and the AE incidence of this study was similar to those of previous reports, severe pneumonitis was common. Hyperglycemia and anemia showed significant correlation with PFS and thus may be potentially useful as prognostic indicators. PMID- 25036573 TI - Multicenter validation study of a prognostic index for portal vein tumor thrombosis in hepatocellular carcinoma. AB - PURPOSE: We previously reported on a staging system and prognostic index (PITH) for portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT) at a single institution. The aim of this study is to validate the PITH staging system using data from patients at other institutions and to compare it with other published staging systems. MATERIALS AND METHODS: A total of 994 HCC patients with PVTT who were treated with RT between 1998 and 2011 by the Korean Radiation Oncology Group were analyzed retrospectively. All patients were staged using the Cancer of the Liver Italian Program (CLIP), Japanese Integrated Staging (JIS), Okuda, and PITH staging systems, and survival data were analyzed. The likelihood ratio, Akaike information criteria (AIC), time-dependent receiver operating characteristics, and prediction error curve analysis were used to determine discriminatory ability for comparison of staging systems. RESULTS: The median survival was 9.2 months. Compared with the other staging systems, the PITH score gave the highest values for likelihood ratio and lowest AIC values, demonstrating that PITH may be a better prognostic model. Although the values were not significant and differences were not exceptional, the PITH score showed slightly better performance with respect to time-dependent area under curve and integrated Brier score of prediction error curve. CONCLUSION: The PITH staging system was validated in this multicenter retrospective study and showed better stratification ability in HCC patients with PVTT than other systems. PMID- 25036574 TI - Analysis of biologically equivalent dose of stereotactic body radiotherapy for primary and metastatic lung tumors. AB - PURPOSE: The purpose of this study was to determine the optimal biologically equivalent dose (BED) for stereotactic body radiotherapy (SBRT) by comparing local control rates in proportion to various total doses and fractionation schedules. MATERIALS AND METHODS: Thirty-four patients with early non-small-cell lung cancer and a single metastatic lung tumor were included in this study. Differences in local control rates were evaluated according to gender, primary tumor site, response, tumor size, and BED. For comparison of BEDs, the prescribed dose for SBRT was stratified according to three groups: high (BED > 146 Gy), medium to high (BED, 106 to 146 Gy), and low to medium (BED < 106 Gy). RESULTS: For all patients, the overall local control rate was 85.3% at two years after treatment. Five local recurrences were observed, and, notably, all of them were observed in the low to medium BED group. Significantly higher local control rates were observed for patients with a complete response than for those with a partial response or stable disease (p < 0.001). Twenty-six patients with a tumor size of < 3 cm showed no dose-response relationship in the low to medium, medium to high, and high BED groups, whereas eight patients with a tumor size of >= 3 cm showed a significant dose-response relationship. The observed 2-year local recurrence-free survival rates in patients with a tumor size of < 3 cm and in those with a tumor size of >= 3 cm were 96.2% and 50.0%, respectively, which were significantly different (p=0.007). CONCLUSION: BED > 100 Gy is required in order to achieve a > 85% local control rate regardless of tumor size. The optimal dose for small tumors of < 3 cm appears to be within a range below 150 Gy BED. Escalation of BED to high levels (> 150 Gy) may be required for patients with a tumor size larger than 3 cm. PMID- 25036575 TI - p27 Loss Is Associated with Poor Prognosis in Gastroenteropancreatic Neuroendocrine Tumors. AB - PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogeneous disease group originating from the neuroendocrine cells. Identification of prognostic markers, related to neuroendocrine tissue-selective tumorigenesis, is necessary to find therapeutic targets. MATERIALS AND METHODS: A total of 327 patients with GEP-NETs were included in this study; there were 49 gastric, 29 duodenal, 49 pancreatic, 12 hepatobiliary, 33 appendiceal, 5 proximal colon, and 150 distal colon cases. We performed immunostaining with the tissue microarray method for menin, p27, and p18. RESULTS: We observed negative staining for menin, p27, and p18 in 34%, 21%, and 56% of GEP-NETs, respectively. The loss of p27, but not menin, was positively correlated with the grade of Ki-67. Menin /p27-, menin-/p27+, menin+/p27-, and menin+/p27+ phenotype groups included 13%, 22%, 8%, and 57% of patients, respectively. A dichotomized comparison showed that menin- or p27- tumors were significantly associated with foregut and midgut localizations, high World Health Organization (WHO) grade, lymph node metastasis, and more advanced stage as compared to menin+/p27+ patients. Kaplan-Meier analysis for the overall survival showed that p27 loss was significantly associated with decreased survival. Multivariate analysis showed that p27 loss is an independent factor for poor overall survival. CONCLUSION: Our results revealed that the loss of p27 is associated with poor prognosis and the menin-p27 pathway is important in the tumorigenesis of GEP-NETs. PMID- 25036576 TI - Bladder and liver involvement of visceral larva migrans may mimic malignancy. AB - Visceral larva migrans (VLM) syndrome is a clinical manifestation of systemic organ involvement by Toxocara species. VLM with involvement of the bladder and liver is a rare finding. A 62-year-old woman presented with diffuse bladder wall thickening and multiple liver masses with peripheral eosinophilia and urinary symptoms. We considered malignancy or eosinophilic cystitis through clinical manifestations and imaging findings. However, no suspicious malignant lesions were observed on cystoscopy and liver mass biopsy revealed the presence of eosinophilic necrotizing granuloma without malignant cells. Anti-Toxocara antibodies were detected by western blotting and the patient was diagnosed with VLM syndrome. After taking prednisolone, urinary symptoms disappeared. On abdominal CT scan taken after three months, the size of multiple liver masses and bladder wall thickening had decreased. VLM syndrome should be suspected in patients with an atypical imaging pattern and peripheral eosinophilia. PMID- 25036577 TI - A new approach to the treatment of metastatic paraganglioma: sorafenib. AB - Paragangliomas are relatively rare chromaffin cell tumors which may be cured through resection. Patients with paragangliomas may develop metastatic diseases. There is no consensus regarding refractory chemotherapy for treatment of metastatic disease. In this report, we presented a case of a 43-year-old woman who was admitted to the hospital with a history of episodic headaches, diaphoresis, and weakness. Elevated plasma catecholamine levels and a right paraaortic mass were observed on computed tomography. The mass was excised, and a diagnosis of paraganglioma was confirmed. After 20 months of follow-up, local recurrence and metastases were detected in the thorax, abdomen, and skeletal system. Plasma and urinary catecholamine levels were high. Chemotherapy was administered, and no improvement was observed. Therefore, following this palliative conventional chemotherapy, sorafenib was administered for three months, and, finally, positron emission tomography showed that the patient's lesions had completely regressed. PMID- 25036578 TI - Pleural Metastasis as Initial Presentation of Occult Gastric Cardia Cancer: A Possible Role of PET-CT in Diagnosis. AB - We report on a case of malignant pleural effusion as initial metastatic presentation of occult gastric cardia cancer in a young woman. To the best of our knowledge, this is the first report of gastric adenocarcinoma metastasized to pleura as an initial presentation. Location of cardia and signet ring cell histology may contribute to the manifestation. Utilization of positron emission tomography-computed tomography was helpful for proper diagnosis. For patients with such distinct clinical presentations, it would be appropriate to consider gastric cancer as one of the possible primary sites. PMID- 25036579 TI - Trends in treatment. PMID- 25036580 TI - Prazosin in the treatment of PTSD. AB - Posttraumatic stress disorder (PTSD) often follows a chronic course, and the disorder is resistant to treatment with antidepressants and cognitive-behavioral therapy in a proportion of patients. Prazosin, an a1-adrenoceptor blocker, has shown some promise in treating chronic PTSD. A review of this literature was conducted via a search of MEDLINE and SUMMON, using keywords such as PTSD, prazosin, treatment, and resistance. At least 10 clinical studies of prazosin in the treatment of PTSD, including open-label and randomized controlled trials, have been published. All of these studies support the efficacy of prazosin either for treating nightmares and improving sleep or for reducing the severity of PTSD. Treatment of PTSD with prazosin is usually initiated at a dose of 1 mg, with monitoring for hypotension after the first dose. The dose is then gradually increased to maintenance levels of 2-6 mg at night. Studies of military patients with PTSD have used higher doses (e.g., 10-16 mg at night). Prazosin has also been studied in younger and older adults with PTSD and in patients with alcohol problems, in whom it was found to reduce cravings and stress responses. Prazosin offers some hope for treating resistant cases of PTSD in which recurrent nightmares are problematic, with a relatively rapid response within weeks. It is suggested that large-scale civilian trials of prazosin be done, as well as studies concerning the use of prazosin in acute PTSD and as a potential preventive agent. PMID- 25036581 TI - Shame, rumination, and self-compassion in men assessed for hypersexual disorder. AB - A number of studies have linked maladaptive shame to higher levels of hypersexual behavior and tendencies to ruminate. However, little research has examined factors that may attenuate the negative impact that shame and rumination may have on hypersexuality. Drawing on data collected from male patients (N=172) assessed for hypersexual disorder in a DSM-5 field trial, path analysis was used to explore relationships among shame, rumination, self-compassion, and hypersexual behavior. The findings from this study showed that self-compassion partially mediated the relationship between shame and rumination and hypersexual behavior. The implications of these results are discussed and directions for future research are offered. PMID- 25036582 TI - Behavioral activation: a strategy to enhance treatment response. AB - Behavioral activation is an empirically validated treatment for depression pioneered in 1973 by Ferster, based on B.F. Skinner's behavioral principles. After publication of Beck's work on cognitive therapy, the boundaries of behavioral and cognitive therapies were blurred and the two now overlap substantially. Behavioral activation is also used as a stand-alone treatment and can also be effective in conjunction with antidepressant medication. Case conceptualization in behavioral activation entails an assessment of the behaviors that the patient has stopped that produce pleasure or are of importance, as well as behaviors essential to self-care. Activity monitoring, which provides treatment targets and leads to the case conceptualization in behavioral activation, consists of using charts, forms, or other prompts to track the relationship between activities and other variables (e.g., mood, enjoyment). That technique is also used to target rumination, procrastination, and avoidance and may also be helpful for patients with psychosis. PMID- 25036583 TI - A performance improvement initiative for enhancing the care of patients with depression. AB - BACKGROUND: Depression is a common and potentially disabling condition, yet many patients remain undiagnosed, and many more fail to receive adequate treatment. To address this gap, clinicians must routinely evaluate patient care practices. The purpose of this study was to evaluate the effectiveness of a three-stage performance improvement (PI) continuing medical education (CME) initiative to strengthen evidence-based psychiatric practices for the screening and management of patients with depression. METHODS: A total of 492 physician participants voluntarily registered to complete a three-stage initiative consisting of self evaluation, improvement, and reevaluation. Participants were recruited through a series of faxes, e-mails, and direct-mail invitations. RESULTS: Approximately 20% (n=86) of the registrants completed the three-stage initiative. Completers provided chart data on 2,122 patients encountered before and 2,130 patients encountered after engaging in the PI CME activity. Large gains were made in the percentage of patients screened using standardized criteria to assess depression status, particularly the Patient Health Questionnaire-2 (PHQ-2) and the PHQ-9 (26% of 1,378 patients at Stage A vs.68% of 1,711 patients at Stage C; p<0.001). Physicians were also more likely to rescreen patients 4 to 8 weeks after initial screening (48% of 1,961 patients at Stage A vs. 75% of 2,028 patients at Stage C; p<0.001) and to assess patient adherence to antidepressants using standardized measures (10% of 1,909 patients at Stage A vs. 45% of 1,740 patients at Stage C; p<0.001). CONCLUSIONS: PI CME provides insight into and aids in improving evidence-based patient care in psychiatric practices. PMID- 25036584 TI - The package insert: who writes it and why, what are its implications, and how well does medical school explain it? AB - The package insert, which is jointly authored by the U.S. Food and Drug Administration and the manufacturer of the drug, is a summary of all of the preclinical and clinical data accumulated during the successful development of a new drug. Despite the role of the package insert in the safe practice of medicine, prescribers often minimize, overlook, or misunderstand its importance, suggesting a gap in their training. An anonymous, three-question survey was administered to third year medical students (N=34) from two medical schools to assess how well they had been educated about the evidence-based origin, purpose, and implications of the package insert. The results indicate a deficiency in their medical education, and the authors contrast the student responses with the facts. These results underscore the need to revise medical school curricula to provide future prescribers with more education about the importance of the package insert and the relationship between pharmaceutical companies, the U.S. Food and Drug Administration, and prescribers. PMID- 25036585 TI - What is medical about psychoanalysis--and what is psychoanalytic about medicine? AB - Despite the birth of psychoanalysis in neurology, modern psychoanalysis and modern medicine seem to have drifted apart. The author explores how and why this has taken place and what its effects may be. Yet the core principles of both medicine and psychoanalysis remain intertwined and vital to both, and the future holds the promise of new possibilities. As American medicine and American psychoanalysis both confront critical stages in their existence, both professions would be well advised to be mindful of their common foundations in science and the ethical, professional bond with the patient. PMID- 25036586 TI - Management and treatment of gamma butyrolactone withdrawal syndrome: a case report and review. AB - Gamma butyrolactone (GBL) is an increasingly popular drug of abuse that is readily available in most countries, and it is often purchased over the Internet. In addition to the acute hazards of intoxication and overdose, users who are dependent on GBL can also experience severe withdrawal reactions, including hallucinations, agitation, confusion, delusions, delirium, rhabdomyolysis, and seizures. Most of the existing literature suggests the use of a high-dose benzodiazepine as a first-line treatment for GBL withdrawal. However, several cases of resistance to benzodiazepines have been observed, which likely reflect some pharmacological differences between benzodiazepines and GBL. Specifically, the effects of benzodiazepines are primarily mediated by gamma-aminobutyric acid (GABA)-A receptors, while GBL and its analogues act mainly at GABA-B receptors, with possible additional effects via the ionotropic GABA-A receptors. In this regard, recent studies have found that GBL and its analogues possess a high affinity for a specific form of extrasynaptic GABA-A receptors that are strongly activated by barbiturates, such as phenobarbital, but that are insensitive to benzodiazepines. Taken together, these findings suggest that barbiturates could be evaluated as first-choice agents for the treatment of GBL/gamma hydroxybutyrate (GHB) withdrawal instead of benzodiazepines. In support of this view, we describe a clinical case of difficult to manage GBL withdrawal symptoms in a 42-year-old male. We also review the literature on treatment options for GBL/GHB withdrawal, including benzodiazepine-resistant withdrawal. PMID- 25036587 TI - Olanzapine-induced triglyceride and aminotransferase elevations without weight gain or hyperglycemia normalized after switching to aripiprazole. AB - Olanzapine induced a marked elevation in triglyceride and cholesterol levels and in liver transaminase enzymes after 12 weeks of treatment in a patient with schizophrenia. These changes were not seen in an earlier 10-week course of treatment with risperidone, and improved substantially 1 week after the patient stopped olanzapine and began treatment with aripiprazole. The patient did not exhibit weight gain or hyperglycemia with any of the medications. This case and a review of the literature suggest that olanzapine may have unique properties that affect hepatic enzyme pathways, independent of any effects on weight and glucose, that may lead to hyperlipidemia and transaminitis in some patients. PMID- 25036588 TI - The need to expand access to electroconvulsive therapy: a retrospective analysis of a new academic service. AB - BACKGROUND: Studies have long described the efficacy of electroconvulsive therapy (ECT); however, access to care continues to be an obstacle to treatment. Despite national trends resulting in declining availability of ECT, a new academic service was created to serve the needs of an area with limited resources. In this study, the characteristics and outcomes of patients receiving treatment during the first year of a new ECT program were assessed. The goals were to analyze treatment outcomes in this population and to identify associations between patient characteristics, treatment parameters, and clinical response. METHODS: Medical charts from the first 49 patients undergoing ECT between October 2010 and September 2011 were retrospectively reviewed. Patient characteristics, indications for ECT, and treatment parameters were compared with clinical improvement as defined by the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Of the 46 patients included in this study, the majority were female (63%), Caucasian (89%), and diagnosed with major depressive disorder (63%). The acute series duration ranged from 3 to 29 treatments (median of 13), with 50% (n=23) of patients achieving remission (MADRS<10) and 78% (n=36) achieving response (MADRS reduction > 50%) at the completion of the acute series. Positive outcomes were found to be associated with a history of medication-resistant conditions. CONCLUSIONS: ECT is a highly effective intervention for the treatment of depression and continues to be a sought-after therapy. Efficacy rates in the first year of this service were comparable to what has been reported in the general population and emphasize the need for the continued availability of ECT as a treatment option. PMID- 25036589 TI - The psychiatric facet of hyperhidrosis: demographics, disability, quality of life, and associated psychopathology. AB - We compared the sociodemographic and psychiatric features of treatment-seeking patients with (n=17) and without (n=29) primary hyperhidrosis (HYH) attending an outpatient dermatological clinic. Subjects were assessed with a structured clinical questionnaire, the Mini International Neuropsychiatric Interview, as well as the Screening for Abnormal Olfactory Experiences (to assess for symptoms of olfactory reference syndrome), the Obsessive-Compulsive Inventory-Revised, the Social Phobia Inventory, the Beck Depression and Anxiety Inventories, the Skindex 16 (a quality of life measure for patients with skin diseases), and the Sheehan Disability Scale. Patients with HYH were more frequently younger (p=0.003), unmarried (p=0.004), employed (p=0.019), more educated (p<0.0001), and better paid (p=0.001) than non-HYH patients. However, they also reported greater disabilities and impairments in work/school (p=0.05) and social life (p=0.014) domains, worse quality of life in emotional (p=0.003) and functioning (p>0.001) dimensions, and they had a greater frequency of comorbid social anxiety disorder (p=0.019). Conversely, non-HYH patients had greater severity of obsessive compulsive neutralization symptoms (repeating compulsions, counting, and having lucky/unlucky numbers) (p=0.034). In conclusion, patients with HYH are characterized by differential sociodemographic and psychopathological characteristics, with major disability, marked impairment in quality of life, and increased rates of social anxiety disorder. PMID- 25036590 TI - BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression? AB - Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies. PMID- 25036591 TI - Unveiling the silence: women's sexual health and experiences in Nepal. AB - Rising rates of HIV in Nepal signal an impending epidemic. In order to develop culturally appropriate and effective actions and programmes to reduce HIV transmission, it is necessary to understand attitudes, behaviours and norms surrounding sexual networking and safer-sex practices in Nepal. Nepali women are thought to be at increased risk of sexually transmitted infections (STIs) and HIV, sexual violence and exploitation and other sexual health disparities due to cultural scripts limiting access to education, ability to control sexual relationships and acceptability in discussing sex and sexual health. The present study comprises a series of interviews with 25 women living in Kathmandu (13 individual interviews and 2 focus-group discussions) about their knowledge and experiences related to sex and sexual health. Interviews were translated and transcribed and two independent coders conducted a thematic analysis. Overall, the women described sex as primarily a male domain. Sex and sexual health were viewed as taboo discussion topics and formal sex education was perceived as minimally available and far from comprehensive in its scope. This formative study can inform future interventions aimed at reducing the spread of STIs/HIV in Nepal and empowering women on issues of sexual health and well-being. PMID- 25036593 TI - Room temperature quantum emission from cubic silicon carbide nanoparticles. AB - The photoluminescence (PL) arising from silicon carbide nanoparticles has so far been associated with the quantum confinement effect or to radiative transitions between electronically active surface states. In this work we show that cubic phase silicon carbide nanoparticles with diameters in the range 45-500 nm can host other point defects responsible for photoinduced intrabandgap PL. We demonstrate that these nanoparticles exhibit single photon emission at room temperature with record saturation count rates of 7 * 10(6) counts/s. The realization of nonclassical emission from SiC nanoparticles extends their potential use from fluorescence biomarker beads to optically active quantum elements for next generation quantum sensing and nanophotonics. The single photon emission is related to single isolated SiC defects that give rise to states within the bandgap. PMID- 25036592 TI - Interaction of pathogens with host cholesterol metabolism. AB - PURPOSE OF REVIEW: Pathogens of different taxa, from prions to protozoa, target cellular cholesterol metabolism to advance their own development and to impair host immune responses, but also causing metabolic complications, for example, atherosclerosis. This review describes recent findings of how pathogens do it. RECENT FINDINGS: A common theme in interaction between pathogens and host cholesterol metabolism is pathogens targeting lipid rafts of the host plasma membrane. Many intracellular pathogens use rafts as an entry gate, taking advantage of the endocytic machinery and high abundance of outward-looking molecules that can be used as receptors. At the same time, disruption of the rafts' functional capacity, achieved by the pathogens through a number of various means, impairs the ability of the host to generate immune response, thus helping pathogen to thrive. Pathogens cannot synthesize cholesterol, and salvaging host cholesterol helps pathogens build advanced cholesterol-containing membranes and assembly platforms. Impact on cholesterol metabolism is not limited to the infected cells; proteins and microRNAs secreted by infected cells affect lipid metabolism systemically. SUMMARY: Given an essential role that host cholesterol metabolism plays in pathogen development, targeting this interaction may be a viable strategy to fight infections, as well as metabolic complications of the infections. PMID- 25036595 TI - Manipulating cardiovascular indices of challenge and threat using resource appraisals. AB - Challenge and threat reflect two distinct psychophysiological approaches to motivated performance situations. Challenge is related to superior performance in a range of tasks compared to threat, thus methods to promote challenge are valuable. In this paper we manipulate challenge and threat cardiovascular reactivity using only resource appraisals, without altering perceived task demands between challenge and threat conditions. Study 1 used a competitive throwing task and Study 2 used a physically demanding climbing task. In both studies challenge task instructions led to challenge cardiovascular reactivity and threat task instructions led to threat cardiovascular reactivity. In Study 1, participants who received challenge instructions performed better than participants who received threat instructions. In Study 2, attendance at the climbing task did not differ across groups. The findings have implications for stress management in terms of focusing on manipulating appraisals of upcoming tasks by promoting self-efficacy and perceived control and focusing on approach goals. Future research could more reliably assess the influence of similar task instructions on performance. PMID- 25036596 TI - Silica-surface reorganization during organotin grafting evidenced by 119Sn DNP SENS: a tandem reaction of gem-silanols and strained siloxane bridges. AB - Grafting reactive molecular complexes on dehydroxylated amorphous silica is a strategy to develop "single-site" heterogeneous catalysts. In general, only the reactivity of isolated silanols is invoked for silica dehydroxylated at 700 degrees C ([SiO(2-700)]), though ca. 10% of the surface silanols are in fact geminal Q2-silanols. Here we report the reaction of allyltributylstannane with [SiO(2-700)] and find that the geminal Q2-silanols react to form products that would formally arise from vicinal Q3-silanols that are not present on [SiO(2 700)], indicating that a surface rearrangement occurs. The reorganization of the silica surface is unique to silica dehydroxylated at 700 degrees C or above. The findings were identified using Dynamic Nuclear Polarization Surface Enhanced NMR Spectroscopy (DNP SENS) combined with DFT calculations. PMID- 25036594 TI - Oxaliplatin neurotoxicity involves peroxisome alterations. PPARgamma agonism as preventive pharmacological approach. AB - The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 uM for 48 h or 1 uM for 5 days) increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) antagonist G3335 (30 uM) induced a similar peroxisomal impairment suggesting a relationship between PPARgamma signaling and oxaliplatin neurotoxicity. The PPARgamma agonist rosiglitazone (10 uM) reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg(-1) per os) significantly reduced neuropathic pain evoked by noxious (Paw pressure test) and non-noxious (Cold plate test) stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role of peroxisomes in oxaliplatin-dependent nervous damage and suggest PPARgamma stimulation as a candidate to counteract oxaliplatin neurotoxicity. PMID- 25036597 TI - Preparation and characterization agar-based nanocomposite film reinforced by nanocrystalline cellulose. AB - Nanocrystalline cellulose (NCC) was prepared from microcrystalline cellulose (MCC) with particle size of 24.7 MUm using sulfuric acid hydrolysis technique. The obtained NCC revealed size of 0-100 nm, which the major part of them was about 30 nm. Then different contents (2.5, 5 and 10 wt%) of these NCC incorporated in agar film solution and the morphology, structure, and properties of the nanocomposite films were characterized by scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier transforms infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), mechanical, physical and optical testing. Results showed that the water vapor permeability (WVP) and water solubility (WS) of the agar-based nanocomposite films significantly (P<0.05) decreased about 13% and 21%, respectively, upon increasing the NCC content to 10%. Tensile strength (TS) and Young's modulus (YM) values of nanocomposite films significantly increased (P<=0.05) with addition of NCC, whereas the elongation percent (E%) decreased not significantly (P>0.05). In addition, swelling percentage, transparency and light transmission of the films were decreased by incorporating NCC into polymer matrix. PMID- 25036598 TI - Salicylic acid enhances antioxidant system in Brassica juncea grown under different levels of manganese. AB - The aim was to explore the responses of varied doses of manganese in mustard plants and also to test the proposition that salicylic acid induced up-regulation of antioxidant system which protect photosynthetic apparatus. Seeds were sown in pots and allowed to germinate under natural environmental conditions. At 10 days stage, soils in the pots were enriched with different levels (0, 3, 6, or 9 mM) of Mn for three days and allowed to grow till 30 day stage. At 31st day, foliage of plants was sprayed with 10 MUM of salicylic acid (SA) and then allowed to grow till 45 days. Then plants were harvested to assess various growth, leaf gas exchange traits and biochemical parameters. Mn-treated plants had diminished growth, water relations and photosynthetic attributes along with carbonic anhydrase activity whereas; the level of lipid peroxidation, electrolyte leakage, accumulation of H2O2 along with proline accumulation and antioxidant enzymes increased in a concentration dependent manner. Follow-up application of SA to the Mn-stressed plants improved growth, water relations and photosynthetic traits, accelerated the activity of antioxidant enzymes and also the accumulation of proline. SA mediated tolerance to Mn-stressed plants could have due to up regulation of antioxidant enzymes and proline accumulation. PMID- 25036599 TI - Response surface optimization of mucilage aqueous extraction from flixweed (Descurainia sophia) seeds. AB - The effects of four factors of pH (4-8), temperature (50-95 degrees C), weed-seed ratio (W/S, 15-45), and time (1-4 h) on the yield of mucilage extraction of Descurainia sophia seeds were investigated using response surface methodology-Box Behnken design (RSM-BBD). Results showed that a second-order model for the studied response was adequately fitted with a coefficient of determination of 98.7% (p<0.0001). The optimum conditions to achieve the highest yield (10.45%) were extraction time of 2.9 h, extraction temperature of 94.32 degrees C, pH of 7.55 and the W/S ratio of 44.2. The extracted mucilage at the optimal point effectively scavenged DPPH free radical, and more concentrations of this polysaccharide indicated potent antioxidant activity in a dose-dependent manner. PMID- 25036600 TI - Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers. AB - A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, DeltaDeltaGtheor, and docking studies elucidate these suggestions in more detail. PMID- 25036601 TI - Bioadhesive okra polymer based buccal patches as platform for controlled drug delivery. AB - In the present investigation, polysaccharide from the Okra fruits (Hibiscus esculentus) was extracted, characterized and explored for its mucoadhesive potential. Mucoadhesive films of okra polymer (OP) were prepared by solvent casting method based on 3(2) factorial design. For these studies, OP (2.0%, 2.5%, 3.0%, w/v) and glycerol (plasticizer) (0.25%, 0.50%, 0.75%, v/v) were taken as independent variables while tensile strength, mucoadhesive strength, contact angle, swelling index and residence time as dependent variables. The developed films were evaluated for their physicochemical, mechanical and electrical properties. The formulated films were found to be smooth, flexible, and displayed adequate mucoadhesive and tensile strength. Their near neutral pH and negative hemolytic studies indicated their non-irritability and biocompatible nature with biological tissues. The formulation comprising of 3% OP and 0.5% glycerol (F8) was found to exhibit optimum mechanical properties. Further, optimized film was loaded with zolmitriptan (model drug) to determine its drug release profiles. In vitro and ex vivo drug release studies demonstrated a controlled release of zolmitriptan over a period of 8h in simulated salivary fluid (SSF) pH 6.8, with the correlation coefficient values indicating its non-Fickian kinetics. Thus, OP can be used as a promising biomaterial for controlled drug delivery. PMID- 25036603 TI - Preparation of beta-D-glucan nanoparticles and its antifungal activity. AB - This work demonstrates the preparation of beta-D-glucan (isolated from the cell wall of Pythium aphanidermatum) nanoparticles through the addition of 2% (w/v) sodium hydroxide to beta-D-glucan solution with constant stirring at 90 degrees C. Addition of sodium tripolyphosphate (TPP) aids the stable formation of nanoparticles. Fourier transform infrared (FTIR) spectroscopy confirmed phosphoric groups of TPP linked with OH group of beta-D-glucan in the nanoparticles. The formation of nanoparticles was observed by the peak at 386 nm using UV-vis spectroscopy. The average size of nanoparticle as determined by Zetasizer was about 60 nm, while the zeta potential was negative. Scanning electron microscope image showed spherical, smooth and almost homogenous structure for nanoparticles with size ranging from 20 to 50 nm. Further analysis by TEM, indicated polydispersity with an average size of 20-30 nm. The XRD analysis confirmed the crystalline structure of beta-glucan nanoparticle. The prepared nanoparticles exhibited antifungal activity against P. aphanidermatum, a devastating fungus which affects major crop plants. PMID- 25036602 TI - Defluoridation of water using chitosan assisted ethylenediamine functionalized synthetic polymeric blends. AB - In this paper, a new kind of approach undertakes for the synthesis of novel chitosan (CS) blended with ethylenediamine (ED) functionalized synthetic polymers viz., acrylonitrile/divinylbenzene/vinylbenzyl chloride (CS@AN/DVB/VBC-ED) and styrene/divinylbenzene/vinylbenzyl chloride (CS@ST/DVB/VBC-ED) for defluoridation of water. Under batch mode, various influencing parameters like shaking time, pH, competitor ions and temperature were optimized. The fluoride removal was reasonably explained using Freundlich, Langmuir and D-R isotherms. The thermodynamic parameters viz., DeltaG degrees , DeltaH degrees and DeltaS degrees indicates the nature of the fluoride sorption with the sorbents. The FT IR, XRD and SEM with EDAX analysis were used to study the fluoride adsorption of CS@AN/DVB/VBC-ED and CS@ST/DVB/VBC-ED blends. The thermal stability of both the sorbents was tested using TGA/DSC analysis. Studies were also conducted to test the potential application of the prepared polymeric blends for fluoride removal from field water collected from the nearby fluoride endemic area. PMID- 25036604 TI - Preparation and characterization of octenylsuccinylated plantain starch. AB - Plantain starch was esterified with octenylsuccinic anhydride (OSA) at two concentrations (3 and 15% w/w) of OSA. The morphology, granule size distribution, pasting, gelatinization, swelling, and solubility of granules and structural features of the starch polymers were evaluated. Granules of the OSA-modified starches increased in size during cooking more than did the granules of the native starch, and the effect was greater at the higher OSA concentration. Pasting viscosities also increased, but gelatinization and pasting temperatures and enthalpy of gelatinization decreased in the OSA-modified starches. It was concluded that insertion of OS groups effected disorder in the granular structure. Solubility, weight average molar mass, Mw-, and z-average radius of gyration, RGz, of the amylopectin decreased as the OSA concentration increased, indicating a decrease in molecular size. PMID- 25036605 TI - Structure and antimicrobial mechanism of E-polylysine-chitosan conjugates through Maillard reaction. AB - The aim of the study was to testify the formation and antimicrobial activity of E polylysine-chitosan conjugate through Maillard reaction. The results of UV absorbance, browning index and fluorescence changes of Maillard reaction products (MRPs) between E-polylysine and chitosan indicated there existed Maillard reaction between E-polylysine and chitosan and the formation of their conjugate. The conjugate showed strong antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and beer yeast. Morphologies of E. coli and S. aureus treated with the conjugate were observed by transmission electron microscopy (TEM). The results revealed that the conjugate of E-polylysine and chitosan increased the permeability of the outer membrane (OM) and inner membrane (IM) and ultimately disrupted bacterial cell membranes, with the release of cellular cytoplasm. PMID- 25036606 TI - Improvement of reinforced concrete properties based on modified starch/polybutadiene nanocomposites. AB - A novel polymer-modified cement concrete with carboxymethyl starch (CMS) and 1,4 cis polybutadiene (PBD) system by mixing polymer dispersions or redispersible polymer powders with the fresh mixture have been examined. In this paper, the addition of CMS-PBD powders in an aqueous solution is studied. Polymeric molecules are supplied on a molecular scale, improving the approach of the relatively large cement grains by the polymers. The chemical and mechanical properties of CMS-PBD-modified cement concrete have been studied. The additions of very small amounts of CMS-PBD polymeric system results in an improvement of the durability and the adhesion strength of the cementitious materials, which makes them appropriate as repair materials. PMID- 25036607 TI - Caseins from bovine colostrum and milk strongly bind piscidin-1, an antimicrobial peptide from fish. AB - A model system of bovine colostrum and piscidin, a fish-derived antimicrobial peptide, was developed to study potential interactions of antimicrobial peptides in colostrum. We did not detect any antimicrobial activity of colostrum using the radial plate diffusion assay; in fact colostrum completely abrogated activity of added piscidin. This could not be explained by degradation of piscidin by colostrum, which was less than ten percent. We found that colostrum even protected piscidin against degradation by added proteases. We further observed that colostrum and milk rapidly quenched the fluorescence of fluorescein-piscidin but not that of fluorescein. This effect was not seen with BSA and the specific quenching of fluorescein-piscidin by colostrum was saturably inhibited with unlabeled piscidin. Size exclusion chromatography indicated that fluorescein piscidin bound to casein micelles with no apparent binding to IgG or whey proteins. Further, addition of pure caseins was able to quench fluorescence of fluorescein-piscidin and to inhibit the antimicrobial activity of piscidin. The interaction between caseins and piscidin could be dissociated by guanidine hydrochloride and recovered piscidin had antimicrobial activity against bacteria. Based on our results we propose that caseins could be carriers for antimicrobial peptides in colostrum and milk. PMID- 25036608 TI - A polysaccharide from Sanguisorbae radix induces caspase-dependent apoptosis in human leukemia HL-60 cells. AB - One polysaccharide (SRP) was purified from Sanguisorbae radix by DEAE-cellulose 52 anion-exchange and Sephacryl S-400 gel filtration chromatography. The aim of this study was to evaluate the anticancer efficacy of SRP on human leukemia HL-60 cells in vitro and unveil the underlying mechanisms. Our results showed that SRP was able to suppress the proliferation of HL-60 cells in a dose-dependent manner by the mechanism involved in the induction of apoptosis. The increase in SRP induced apoptosis was correlated with a rapid and sustained loss of mitochondrial transmembrane potential (DeltaPsim) and a release of cytochrome c from the mitochondria into the cytosol. Furthermore, Western blot and RT-PCR analysis revealed that the protein and mRNA levels of antiapoptotic Bcl-2 were downregulated, whereas those of pro-apoptotic Bax were upregulated. Besides, caspase-9 and caspase-3 were activated, while caspase-8 was intact. Additionally, the apoptotic cells by SRP were significantly inhibited by a caspase-3 inhibitor (z-DEVD-fmk) or a caspase-9 inhibitor (Z-LETD-FMK), demonstrating the important role of caspase-9 and -3 in the process. Taken together, these findings provided evidence that SRP induced the apoptosis of HL-60 cells through an intrinsic mitochondria-mediated signaling pathway and SRP may be a promising chemotherapeutic agent for treatment of leukemia. PMID- 25036609 TI - Ventromedial prefrontal cortex regulates depressive-like behavior and rapid eye movement sleep in the rat. AB - Major depressive disorder (MDD) is a debilitating disease with symptoms like persistent depressed mood and sleep disturbances. The prefrontal cortex (PFC) has been implicated as an important structure in the neural circuitry of MDD, with pronounced abnormalities in blood flow and metabolic activity in PFC subregions, including the subgenual cingulate cortex (sgACC, or Brodmann area 25). In addition, deep brain stimulation in the sgACC has recently been shown to alleviate treatment-resistant depression. Depressed patients also show characteristic changes in sleep: insomnia, increased rapid-eye-movement (REM) sleep and shortened REM sleep latency. We hypothesized that sleep changes and depressive behavior may be a consequence of the abnormal PFC activity in MDD. The rat ventromedial PFC (vmPFC, prelimbic and infralimbic cortices) is considered to be the homolog of the human sgACC, so we examined the effect of excitotic lesions in the vmPFC on sleep-wake and depressive behavior. We also made lesions in the adjacent dorsal region (dmPFC) to compare the effect of this similar but distinct mPFC region. We found that both dmPFC and vmPFC lesions led to increased REM sleep, but only vmPFC-lesioned animals displayed increased sleep fragmentation, shortened REM latency and increased immobility in the forced swim test. Anatomic tracing suggests that the mPFC projects to the pontine REM-off neurons that interact with REM-on neurons in the dorsal pons. These results support our hypothesis that neuronal loss in the rat vmPFC resembles several characteristics of MDD and may be a critical area for modulating both mood and sleep. PMID- 25036610 TI - Permanent suppression of cortical oscillations in mice after adolescent exposure to cannabinoids: receptor mechanisms. AB - Marijuana use in adolescence, but not adulthood, may permanently impair cognitive functioning and increase the risk of developing schizophrenia. Cortical oscillations are patterns of neural network activity implicated in cognitive processing, and are abnormal in patients with schizophrenia. We have recently reported that cortical oscillations are suppressed in adult mice that were treated with the cannabinoids WIN55,212-2 (WIN) or Delta(9)tetrahydrocannabinol (THC) in adolescence, but not adulthood. WIN and THC are cannabinoid-1 (CB1R) and CB2R agonists, and also have activity at non-cannabinoid receptor targets. However, as acute WIN and THC administration can suppress oscillations through CB1Rs, we hypothesize that a similar mechanism underlies the permanent suppression of oscillations by repeated cannabinoid exposure in adolescence. Here we test the prediction that cannabinoid exposure in adolescence permanently suppresses cortical oscillations by acting through CB1Rs, and that these suppressive effects can be antagonized by a CB1R antagonist. We treated adolescent mice with various cannabinoid compounds, and pharmacologically-evoked oscillations in local field potentials (LFPs) in vitro in adults. We find that WIN exposure for six days in early adolescence suppresses oscillations preferentially in adult medial prefrontal cortex (mPFC) via CB1Rs, and that a similar CB1R mechanism accounts for the suppressive effects of long-term (20 day) adolescent THC in adult somatosensory cortex (SCx). Unexpectedly, we also find that CB2Rs may be involved in the suppression of oscillations in both mPFC and SCx by long-term adolescent cannabinoid exposure, and that non-cannabinoid receptors may also contribute to oscillation suppression in adult mPFC. These findings represent a novel attempt to antagonize the effects of adolescent cannabinoid exposure on neural network activity, and reveal the contribution of non-CB1R targets to the suppression of cortical oscillations. PMID- 25036611 TI - PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption. AB - Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARalpha/gamma; 1.5 mg/kg) and fenofibrate (PPARalpha; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARalpha/gamma/beta; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co expression network analysis (WGCNA) revealed co-expression of treatment significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID- 25036613 TI - Chain interdigitation in DPPC bilayers induced by HgCl2: evidences from continuous wave and pulsed EPR. AB - Continuous-wave electron paramagnetic resonance (CW-EPR) spectroscopy and electron spin echo methods of pulsed EPR of phosphatidylcholine spin-labeled at different positions, n, in the sn-2 chain (n-PCSL, n=5, 7, 10, 12, 14, and 16) are used to study the interaction of inorganic mercury chloride HgCl2 with multilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC). For temperatures through the gel phase of DPPC multilayers, the CW-EPR spectra show that an increase of HgCl2 content in the dispersion medium slightly increases the rotational mobility of 5-PCSL and markedly restricts the motion of 16-PCSL. Mercury chloride at 100mM (HgCl2/lipid molar ratio=2:1) removes the gradient of increasing mobility along the chain found in DPPC bilayers in the gel phase. In contrast, HgCl2 does not influence the DPPC chain flexibility profile in the fluid phase. It also suppresses the pre-transition and moderately downshifts the main transition temperature of DPPC membranes. These findings indicate that HgCl2 affects the lipid chain packing of DPPC bilayers and are consistent with the induction of an interdigitated gel phase. Further, D2O-electron spin echo envelope modulation spectroscopy indicates that in the interdigitated phase a higher water permeation is favored at any chain position and the sigmoidal transmembrane water accessibility profile of DPPC bilayers is abolished. Accordingly, the positional dependence of (14)N-hyperfine splitting, 2Azz, shows that the typical hydrophobic barrier of DPPC is significantly altered in the interdigitated phase and all the segments of the lipid chains result to be in a more polar environment. PMID- 25036612 TI - Role of orexin/hypocretin in conditioned sucrose-seeking in female rats. AB - The orexin/hypocretin system has recently been implicated in reward-seeking, especially for highly salient food and drug rewards. Given that eating disorders affect women more than men, we reasoned that the orexin system may be strongly engaged in female rats, and during periods of food restriction as we recently reported in male rats. Therefore, the present study examined the involvement of the orexin system in operant responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed vs. food restricted female subjects. Female Sprague Dawley rats were trained to self administer sucrose pellets, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB 334867 (SB; 10-30 mg/kg) on fixed ratio (FR) sucrose self-administration, and on cue-induced reinstatement of extinguished sucrose-seeking. SB decreased sucrose self-administration in food-restricted but not in ad libitum-fed females. SB did not alter active lever responding during cue-induced reinstatement of sucrose-seeking in either feeding group. These results confirm our previous results in male rats that signaling at the OxR1 receptor is involved in the sucrose reinforcement and self-administration in food restricted subjects. However, the finding that SB is ineffective at attenuating cue-induced reinstatement in females, but was effective in food-restricted males, leads us to conclude that food seeking induced by conditioned stimuli engages the orexin system differentially in males and females. PMID- 25036614 TI - From thiol to sulfonic acid: modeling the oxidation pathway of protein thiols by hydrogen peroxide. AB - Hydrogen peroxide is a natural oxidant that can oxidize protein thiols (RSH) via sulfenic acid (RSOH) and sulfinic acid (RSO2H) to sulfonic acid (RSO3H). In this paper, we study the complete anionic and neutral oxidation pathway from thiol to sulfonic acid. Reaction barriers and reaction free energies for all three oxidation steps are computed, both for the isolated substrates and for the substrates in the presence of different model ligands (CH4, H2O, NH3) mimicking the enzymatic environment. We found for all three barriers that the anionic thiolate is more reactive than the neutral thiol. However, the assistance of the environment in the neutral pathway in a solvent-assisted proton-exchange (SAPE) mechanism can lower the reaction barrier noticeably. Polar ligands can decrease the reaction barriers, whereas apolar ligands do not influence the barrier heights. The same holds for the reaction energies: they decrease (become more negative) in the presence of polar ligands whereas apolar ligands do not have an influence. The consistently negative consecutive reaction energies for the oxidation in the anionic pathway when going from thiolate over sulfenic and sulfinic acid to sulfonic acid are in agreement with biological reversibility. PMID- 25036615 TI - Exposure to nitrosamines in thirdhand tobacco smoke increases cancer risk in non smokers. AB - In addition to passive inhalation, non-smokers, and especially children, are exposed to residual tobacco smoke gases and particles that are deposited to surfaces and dust, known as thirdhand smoke (THS). However, until now the potential cancer risks of this pathway of exposure have been highly uncertain and not considered in public health policy. In this study, we estimate for the first time the potential cancer risk by age group through non-dietary ingestion and dermal exposure to carcinogen N-nitrosamines and tobacco-specific nitrosamines (TSNAs) measured in house dust samples. Using a highly sensitive and selective analytical approach we have determined the presence of nicotine, eight N nitrosamines and five tobacco-specific nitrosamines in forty-six settled dust samples from homes occupied by both smokers and non-smokers. Using observations of house dust composition, we have estimated the cancer risk by applying the most recent official toxicological information. Calculated cancer risks through exposure to the observed levels of TSNAs at an early life stage (1 to 6years old) exceeded the upper-bound risk recommended by the USEPA in 77% of smokers' and 64% of non-smokers' homes. The maximum risk from exposure to all nitrosamines measured in a smoker occupied home was one excess cancer case per one thousand population exposed. The results presented here highlight the potentially severe long-term consequences of THS exposure, particularly to children, and give strong evidence of its potential health risk and, therefore, they should be considered when developing future environmental and health policies. PMID- 25036616 TI - Environmental fate and ecotoxicity of lanthanides: are they a uniform group beyond chemistry? AB - Lanthanides are a chemically uniform group of metals (La-Lu) that, together with yttrium (Y) and scandium (Sc), form the group of rare earth elements (REEs). Because of their many applications (e.g., agriculture, medicine, motor industry), their global production has increased exponentially in the last decades and their biogeochemical cycles are being disrupted by human uses (e.g., gadolinium anomalies in freshwater and tap water, REEs enrichment of soils as a consequence of agricultural practices). However, ecotoxicological effects and mechanism of action of these elements are still poorly understood. In particular, there is no consensus as to lanthanides showing a coherent and predictable pattern of (eco)toxicity in the same way as their atomic properties. For aquatic organisms, contradictory conclusions on this issue can be found in the bibliography. This review shows that the variable composition of culture media used in ecotoxicology, and the associated differences in lanthanide's speciation, are the most likely cause for such discrepancies. In particular, the formation of insoluble species in some highly complexing media likely leads to changes in the soluble concentration of lanthanide during some tests; with the potential for a generalized underestimation of their toxicity at the present state of knowledge. For terrestrial organisms, suitable studies to establish trends in lanthanides' toxicity are practically nonexistent; with most research focusing on the effects of REE mixtures. Molecular level studies to elucidate the mechanisms of action of lanthanides are essentially limited to La, pointing to the need for further research to identify common mechanisms of action or modes of action across lanthanides. Overall, agreement on the correct procedures to follow to obtain reliable and comparable data for individual lanthanide is the first action to take in order to arrive at a reliable risk assessment for this group of elements in both aquatic and terrestrial systems. PMID- 25036618 TI - Preorganized aryltriazole foldamers as effective transmembrane transporters for chloride anion. AB - Preorganized aryltriazole foldamers 1 and 2 were designed and synthesized. NMR studies and X-ray analysis demonstrate that 1 adopts a crescent conformation driven by a series of continuous hydrogen bonds at the periphery of the foldamer, whereas 2 displays a coil conformation. NMR titrations reveal that the affinities of fully preorganized foldamer 1 for halogen anions are much stronger that those of partially preorganized foldamer 2. Furthermore, it is found that such full preorganization makes 1 an effective transmembrane transporter for the chloride anion across a lipid bilayer. PMID- 25036617 TI - Longitudinal changes in total brain volume in schizophrenia: relation to symptom severity, cognition and antipsychotic medication. AB - Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999-2001 at the age of 33-35 years. A follow-up was conducted 9 years later during 2008-2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions. PMID- 25036619 TI - Acute and sub-lethal response to mercury in Arctic and boreal calanoid copepods. AB - Acute lethal toxicity, expressed as LC50 values, is a widely used parameter in risk assessment of chemicals, and has been proposed as a tool to assess differences in species sensitivities to chemicals between climatic regions. Arctic Calanus glacialis and boreal Calanus finmarchicus were exposed to mercury (Hg(2+)) under natural environmental conditions including sea temperatures of 2 degrees and 10 degrees C, respectively. Acute lethal toxicity (96 h LC50) and sub-lethal molecular response (GST expression; in this article gene expression is used as a synonym of gene transcription, although it is acknowledged that gene expression is also regulated, e.g., at translation and protein stability level) were studied. The acute lethal toxicity was monitored for 96 h using seven different Hg concentrations. The sub-lethal experiment was set up on the basis of nominal LC50 values for each species using concentrations equivalent to 50, 5 and 0.5% of their 96 h LC50 value. No significant differences were found in acute lethal toxicity between the two species. The sub-lethal molecular response revealed large differences both in response time and the fold induction of GST, where the Arctic species responded both faster and with higher mRNA levels of GST after 48 h exposure. Under the natural exposure conditions applied in the present study, the Arctic species C. glacialis may potentially be more susceptible to mercury exposure on the sub-lethal level. PMID- 25036620 TI - Histopathological and biochemical changes in goldfish kidney due to exposure to the herbicide Sencor may be related to induction of oxidative stress. AB - Molecular mechanisms of toxicity by the metribuzin-containing herbicide Sencor to living organisms, particularly fish, have not yet been extensively investigated. In the present work, we studied the effects of 96 h exposure to 7.14, 35.7, or 71.4 mg L(-1) of Sencor (corresponding to 5, 25, or 50 mg L(-1) of its herbicidal component metribuzin) on goldfish (Carassius auratus L.), examining the histology, levels of oxidative stress markers, and activities of antioxidant and related enzymes in kidney as well as hematological parameters and leukocyte profiles in blood. The treatment induced various histopathological changes in goldfish kidney, such as hypertrophy of intertubular hematopoietic tissue, small and multiple hemorrhages, glomerular shrinkage, a decrease in space between glomerulus and Bowman's capsule, degeneration and necrosis of the tubular epithelium. Sencor exposure also decreased activities of selected enzymes in kidney; activities of catalase decreased by 31-34%, glutathione peroxidase by 14 33%, glutathione reductase by 17-25%, and acetylcholinesterase by 31%. However, glucose-6-phosphate dehydrogenase and lactate dehydrogenase activities increased by 25-30% and 22% in kidney after treatment with 7.14 or 35.7 mg L(-1) and 71.4 mg L(-1) Sencor, respectively. Kidney levels of protein carbonyls increased by 177% after exposure to 35.7 mg L(-1) of Sencor indicating extensive damage to proteins. Lipid peroxide concentrations also increased by 25% after exposure to 7.14 mg L(-1) of Sencor, but levels were reduced by 42% in the 71.4 mg L(-1) exposure group. The data indicate that induction of oxidative stress is one of the mechanisms responsible for Sencor toxicity to fish. PMID- 25036621 TI - Environmental levels of the antidepressant venlafaxine impact the metabolic capacity of rainbow trout. AB - The antidepressant venlafaxine is detected at parts per billion levels in tertiary-treated municipal wastewater effluent. However, the impact of this serotonin-norepinephrine reuptake inhibitor (SNRI) on non-target aquatic animals is poorly understood. We tested the hypothesis that environmentally relevant levels of venlafaxine disrupt the highly conserved cortisol and glucose response to stress in rainbow trout (Oncorhynchus mykiss). Juvenile trout were exposed to venlafaxine (0, 0.2 and 1.0 MUg/L) in a static system with daily renewal for seven days. The fish were then subjected to an acute handling disturbance and sampled either prior to (0 h) or 1, 4 and 24h after stressor exposure. Venlafaxine exposure did not affect the handling disturbance-mediated transient elevation in plasma cortisol levels or target tissue glucocorticoid receptor expression. The drug exposure disrupted the interrenal steroidogenic capacity, including altered handling stressor-mediated changes in mRNA abundances of steroidogenic acute regulatory protein and cytochrome P450 side chain cleavage. The handling stressor-induced transient elevations in plasma glucose levels were significantly reduced in the venlafaxine-exposed fish. This was not accompanied by changes in liver glycogen content, glucose transporter 2 mRNA abundance or the glycolytic capacity, whereas the capacity for gluconeogenesis and amino acid catabolism were enhanced. Venlafaxine also brought about changes in the gill of trout, including enhanced lactate dehydrogenase activity and Na(+)-K(+) ATPase protein expression, while the Na(+)-K(+) ATPase enzyme activity was reduced. Collectively, our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts tissue metabolic capacities and may compromise the adaptive responses to an acute stressor in rainbow trout. PMID- 25036622 TI - Calorie restriction a Lamarck. AB - Epigenetic inheritance of resistance to exogenous nucleic acids via small interfering (si) RNA is well established in animal models. Rechavi et al. demonstrate epigenetic inheritance of a starvation-induced pattern of gene silencing caused by endogenous siRNAs and resulting in an increased longevity in the third generation progeny. Combined with recent findings in prokaryotes, these results suggest that Lamarckian-type inheritance of acquired traits is a major evolutionary phenomenon. PMID- 25036623 TI - GI motility: microbiota and macrophages join forces. AB - Gastrointestinal motility causes movement of food during digestion through contractions of the gut smooth muscle. The enteric nervous system regulates these events, and Muller et al. now find that its interaction with the immune system, in concert with gut microbiota, provides an additional layer of regulation to this complex task. PMID- 25036624 TI - A new twist on transcriptional bursting. AB - Transcriptional bursting has been observed across species and is one of the primary causes of variable gene expression in cells and tissue. In this issue, Chong et al. describe how DNA topology results in transcriptional bursting in E. coli. PMID- 25036625 TI - The contraction of time and space in remote chromosomal interactions. AB - Lucas et al. report the visualization of V(D)J recombination of the immunoglobulin heavy-chain gene (Igh) in living pro-B cells. Despite the huge distances separating V coding sequences from D-J sequences (~2 Mb), the authors document an astonishingly rapid rate of remote associations. The key to speed is contraction of the Igh chromosomal domain. These findings provide a foundation for understanding long-range regulatory interactions in a variety of developmental processes, including the patterning of vertebrate limbs. PMID- 25036626 TI - Microtubule self-organization via protein-RNA network crosstalk. AB - Microtubule plus-end tracking proteins are crucial for the regulation of microtubule dynamics. Preitner et al. report that one such protein, adenomatous polyposis coli (APC), also binds RNA and identify mRNAs encoding tubulin subunits within the brain APC-RNA interactome, suggesting a new mode of microtubule self regulation. PMID- 25036627 TI - gamma-Secretase: a horseshoe structure brings good luck. AB - The intramembrane protease gamma-secretase is a key player in signaling and Alzheimer's disease, but its structural features have remained obscure. A structure reported recently reveals a horseshoe-shaped arrangement of 19 transmembrane helices and an extracellular domain positioned for substrate recognition. This advance bodes well for a finer resolution before long. PMID- 25036628 TI - Conducting a microbiome study. AB - Human microbiome research is an actively developing area of inquiry, with ramifications for our lifestyles, our interactions with microbes, and how we treat disease. Advances depend on carefully executed, controlled, and reproducible studies. Here, we provide a Primer for researchers from diverse disciplines interested in conducting microbiome research. We discuss factors to be considered in the design, execution, and data analysis of microbiome studies. These recommendations should help researchers to enter and contribute to this rapidly developing field. PMID- 25036629 TI - Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. AB - The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2( /-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating beta-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PAPERCLIP: PMID- 25036630 TI - Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. AB - Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK: PMID- 25036631 TI - Mechanism of transcriptional bursting in bacteria. AB - Transcription of highly expressed genes has been shown to occur in stochastic bursts. But the origin of such ubiquitous phenomenon has not been understood. Here, we present the mechanism in bacteria. We developed a high-throughput, in vitro, single-molecule assay to follow transcription on individual DNA templates in real time. We showed that positive supercoiling buildup on a DNA segment by transcription slows down transcription elongation and eventually stops transcription initiation. Transcription can be resumed upon gyrase binding to the DNA segment. Furthermore, using single-cell mRNA counting fluorescence in situ hybridization (FISH), we found that duty cycles of transcriptional bursting depend on the intracellular gyrase concentration. Together, these findings prove that transcriptional bursting of highly expressed genes in bacteria is primarily caused by reversible gyrase dissociation from and rebinding to a DNA segment, changing the supercoiling level of the segment. PMID- 25036632 TI - Structural basis of hAT transposon end recognition by Hermes, an octameric DNA transposase from Musca domestica. AB - Hermes is a member of the hAT transposon superfamily that has active representatives, including McClintock's archetypal Ac mobile genetic element, in many eukaryotic species. The crystal structure of the Hermes transposase-DNA complex reveals that Hermes forms an octameric ring organized as a tetramer of dimers. Although isolated dimers are active in vitro for all the chemical steps of transposition, only octamers are active in vivo. The octamer can provide not only multiple specific DNA-binding domains to recognize repeated subterminal sequences within the transposon ends, which are important for activity, but also multiple nonspecific DNA binding surfaces for target capture. The unusual assembly explains the basis of bipartite DNA recognition at hAT transposon ends, provides a rationale for transposon end asymmetry, and suggests how the avidity provided by multiple sites of interaction could allow a transposase to locate its transposon ends amidst a sea of chromosomal DNA. PMID- 25036633 TI - APC is an RNA-binding protein, and its interactome provides a link to neural development and microtubule assembly. AB - Adenomatous polyposis coli (APC) is a microtubule plus-end scaffolding protein important in biology and disease. APC is implicated in RNA localization, although the mechanisms and functional significance remain unclear. We show APC is an RNA binding protein and identify an RNA interactome by HITS-CLIP. Targets were highly enriched for APC-related functions, including microtubule organization, cell motility, cancer, and neurologic disease. Among the targets is beta2B-tubulin, known to be required in human neuron and axon migration. We show beta2B-tubulin is synthesized in axons and localizes preferentially to dynamic microtubules in the growth cone periphery. APC binds the beta2B-tubulin 3' UTR; experiments interfering with this interaction reduced beta2B-tubulin mRNA axonal localization and expression, depleted dynamic microtubules and the growth cone periphery, and impaired neuron migration. These results identify APC as a platform binding functionally related protein and RNA networks, and suggest a self-organizing model for the microtubule to localize synthesis of its own subunits. PMID- 25036634 TI - Polo-like kinase 1 licenses CENP-A deposition at centromeres. AB - To ensure the stable transmission of the genome during vertebrate cell division, the mitotic spindle must attach to a single locus on each chromosome, termed the centromere. The fundamental requirement for faithful centromere inheritance is the controlled deposition of the centromere-specifying histone, CENP-A. However, the regulatory mechanisms that ensure the precise control of CENP-A deposition have proven elusive. Here, we identify polo-like kinase 1 (Plk1) as a centromere localized regulator required to initiate CENP-A deposition in human cells. We demonstrate that faithful CENP-A deposition requires integrated signals from Plk1 and cyclin-dependent kinase (CDK), with Plk1 promoting the localization of the key CENP-A deposition factor, the Mis18 complex, and CDK inhibiting Mis18 complex assembly. By bypassing these regulated steps, we uncoupled CENP-A deposition from cell-cycle progression, resulting in mitotic defects. Thus, CENP-A deposition is controlled by a two-step regulatory paradigm comprised of Plk1 and CDK that is crucial for genomic integrity. PMID- 25036635 TI - Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. AB - Although biosynthetic gene clusters (BGCs) have been discovered for hundreds of bacterial metabolites, our knowledge of their diversity remains limited. Here, we used a novel algorithm to systematically identify BGCs in the extensive extant microbial sequencing data. Network analysis of the predicted BGCs revealed large gene cluster families, the vast majority uncharacterized. We experimentally characterized the most prominent family, consisting of two subfamilies of hundreds of BGCs distributed throughout the Proteobacteria; their products are aryl polyenes, lipids with an aryl head group conjugated to a polyene tail. We identified a distant relationship to a third subfamily of aryl polyene BGCs, and together the three subfamilies represent the largest known family of biosynthetic gene clusters, with more than 1,000 members. Although these clusters are widely divergent in sequence, their small molecule products are remarkably conserved, indicating for the first time the important roles these compounds play in Gram negative cell biology. PMID- 25036636 TI - Cheese rind communities provide tractable systems for in situ and in vitro studies of microbial diversity. AB - Tractable microbial communities are needed to bridge the gap between observations of patterns of microbial diversity and mechanisms that can explain these patterns. We developed cheese rinds as model microbial communities by characterizing in situ patterns of diversity and by developing an in vitro system for community reconstruction. Sequencing of 137 different rind communities across 10 countries revealed 24 widely distributed and culturable genera of bacteria and fungi as dominant community members. Reproducible community types formed independent of geographic location of production. Intensive temporal sampling demonstrated that assembly of these communities is highly reproducible. Patterns of community composition and succession observed in situ can be recapitulated in a simple in vitro system. Widespread positive and negative interactions were identified between bacterial and fungal community members. Cheese rind microbial communities represent an experimentally tractable system for defining mechanisms that influence microbial community assembly and function. PMID- 25036637 TI - A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. AB - Chaperones are abundant cellular proteins that promote the folding and function of their substrate proteins (clients). In vivo, chaperones also associate with a large and diverse set of cofactors (cochaperones) that regulate their specificity and function. However, how these cochaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown. We combined mass spectrometry and quantitative high-throughput LUMIER assays to systematically characterize the chaperone-cochaperone-client interaction network in human cells. We uncover hundreds of chaperone clients, delineate their participation in specific cochaperone complexes, and establish a surprisingly distinct network of protein-protein interactions for cochaperones. As a salient example of the power of such analysis, we establish that NUDC family cochaperones specifically associate with structurally related but evolutionarily distinct beta propeller folds. We provide a framework for deciphering the proteostasis network and its regulation in development and disease and expand the use of chaperones as sensors for drug-target engagement. PMID- 25036639 TI - SnapShot: Necroptosis. AB - Regulated necrosis, termed necroptosis, is mediated by the kinase activity of RIPK1 and RIPK3. It has distinct cellular features that are different than apoptosis. Necroptosis can be triggered by extracellular stimuli known to activate inflammation and cell death and its intracellular signaling pathway involves necrosome formation and MLKL activation. Inhibition of necroptosis has been shown to mitigate pathology in numerous mouse models, providing potential strategies to treat human diseases. PMID- 25036638 TI - Systematic identification of barriers to human iPSC generation. AB - Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) holds enormous promise for regenerative medicine. To elucidate endogenous barriers limiting this process, we systematically dissected human cellular reprogramming by combining a genome-wide RNAi screen, innovative computational methods, extensive single-hit validation, and mechanistic investigation of relevant pathways and networks. We identify reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion. Specific a disintegrin and metalloproteinase (ADAM) proteins inhibit reprogramming, and the disintegrin domain of ADAM29 is necessary and sufficient for this function. Clathrin-mediated endocytosis can be targeted with small molecules and opposes reprogramming by positively regulating TGF-beta signaling. Genetic interaction studies of endocytosis or ubiquitination reveal that barrier pathways can act in linear, parallel, or feedforward loop architectures to antagonize reprogramming. These results provide a global view of barriers to human cellular reprogramming. PMID- 25036641 TI - Response of bacterial metabolic activity to riverine dissolved organic carbon and exogenous viruses in estuarine and coastal waters: implications for CO2 emission. AB - A cross-transplant experiment between estuarine water and seawater was conducted to examine the response of bacterial metabolic activity to riverine dissolved organic carbon (DOC) input under virus-rich and virus-free conditions, as well as to exogenous viruses. Riverine DOC input increased bacterial production significantly, but not bacterial respiration (BR) because of its high lability. The bioavailable riverine DOC influenced bulk bacterial respiration in two contrasting ways; it enhanced the bulk BR by stimulating bacterial growth, but simultaneously reduced the cell-specific BR due to its high lability. As a result, there was little stimulation of the bulk BR by riverine DOC. This might be partly responsible for lower CO2 degassing fluxes in estuaries receiving high sewage-DOC that is highly labile. Viruses restricted microbial decomposition of riverine DOC dramatically by repressing the growth of metabolically active bacteria. Bacterial carbon demand in the presence of viruses only accounted for 7 12% of that in the absence of viruses. Consequently, a large fraction of riverine DOC was likely transported offshore to the shelf. In addition, marine bacteria and estuarine bacteria responded distinctly to exogenous viruses. Marine viruses were able to infect estuarine bacteria, but not as efficiently as estuarine viruses, while estuarine viruses infected marine bacteria as efficiently as marine viruses. We speculate that the rapid changes in the viral community due to freshwater input destroyed the existing bacteria-virus relationship, which would change the bacterial community composition and affect the bacterial metabolic activity and carbon cycling in this estuary. PMID- 25036642 TI - Vibrational spectroscopy and density functional theory study of 3-[4,5-dimethyl-2 thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide. AB - In this work, the structural parameters of the title molecule (MTT) have been obtained at the B3LYP/6-311++G(**) level of theory. The two phenyl rings and the two heterocyclic rings are found in four different planes. The tetrazolium ring was connected with other three rings and their distances are also different in decrease order of 1.461 A (from tetrazolium ring to carbon connected phenyl)>1.445 A (from tetrazolium ring to nitrogen connected phenyl)>1.425 A (from tetrazolium ring to thiazolyl ring). Fourier transform infrared (FTIR) and Raman spectra of the compound were obtained experimentally. All FTIR and Raman bands of the compound obtained experimentally were assigned based on the modeling results obtained at the B3LYP/6-311++G(**) level. The calculated vibrational frequencies were in good agreement with the experimental values. In addition, the UV-Vis spectra were obtained experimentally and theoretically. Considering the effect of the PCM modelling error, the calculated absorbance peaks obtained at the B3LYP/6-311++G(**) level were also in good agreement with the experimental values. The HOMO-LUMO gap was predicted to be 1.83 eV at the B3LYP/6-311++G(**) level. PMID- 25036643 TI - The synthesis, characterization and optical properties of novel 2-acyl 6 arylindolizines. AB - A series of novel 2-acyl-6-aryl substituted indolizine derivatives was synthesized by a novel tandem reaction between 4-acyl-pyrrole-2-carbaldehyde derivatives and ethyl 4-bromo-3-arylbut-2-enoate under mild conditions. The compounds were characterized using IR, (1)H NMR (13)C NMR and HRMS. The crystal structure of 7a was determined using single crystal X-ray crystallography. The absorption results showed that compounds 7a-e presented their absorption maxima at ca. 270 nm, while compounds 7f and 7g with a larger conjugation system exhibited red-shifted absorption character (ca. 280 nm). Fluorescence spectra revealed that these compounds exhibited blue fluorescence (434-456 nm) in dilute solutions and showed quantum yields of fluorescence between 0.02 and 0.39 in dichloromethane. PMID- 25036644 TI - Tebipenem pivoxyl. Derivative spectroscopy study of stability of the first oral carbapenem. AB - A simple and selective derivative spectrophotometric method was developed for the quantitative determination of tebipenem and its pivoxyl ester in the presence of degradation products formed during degradation in aqueous solutions (hydrolysis, oxidation, phosphate buffer pH ~6.0) and in the solid state (photolysis, thermolysis in dry air and at an increased relative air humidity). The method was based on zero-crossing first-derivative spectrophotometry (lambda=341 nm for tebipenem pivoxyl and lambda=320 nm for tebipenem), which eliminated the overlapping caused by various degradation products. The selectivity of the method for determination of tebipenem pivoxyl and tepipenem during stability studies was an effect of lack of substituents containing pi-bond system chromophores in degradation products. It was also confirmed by comparison of the experimental spectra sample with the theoretical UV spectra and their first derivatives which were obtained by using the density functional theory with the B3LYP hybrid functional and 6-31G(d,p) basis set. The method were linear in the concentration range 16.70-220.0 MUg mL(-1) for tebipenem (lambda=320 nm; r=0.9989) and 10.70 160.0 MUg mL(-1) for tebipenem pivoxyl (lambda=341 nm, r=0.9990). The limits of detection and quantitation were 4.72 and 15.60 MUg mL(-1) for tebipenem and 2.54 and 8.40 MUg mL(-1) for tebipenem pivoxyl, respectively. The method had a good intra-day precision (RSD from 0.12% to 0.62%) and inter-day precision (RSD from 0.22% to 2.13%). The recovery of tebipenem and tebipenem pivoxyl ranged from 99.61% to 99.86% and from 99.38% to 99.87%, respectively. First-derivative spectrophotometry was used for a routine analysis of tebipenem and its ester as well as to monitor the conversion of tebipenem pivoxyl to tebipenem and to predict their degradation pathways. PMID- 25036645 TI - Synthesis of some metallophthalocyanines with dimethyl 5-(phenoxy)-isophthalate substituents and evaluation of their antioxidant-antibacterial activities. AB - The synthesis, characterization, spectral, antioxidant and antibacterial properties of dimethyl 5-(phenoxy)-isophthalate substituted Zinc, Cobalt, Copper, and Nickel phthalocyanines are reported. The novel compounds have been characterized by using electronic absorption, nuclear magnetic resonance spectroscopy, infrared, elemental analysis and mass spectrometry. The antioxidant and antibacterial activities of newly synthesized phthalocyanines and its starting material are tested. The DPPH free radical scavenging ability of phthalocyanine Co(II) and Zn(II) complexes on DPPH are 44.8% and 40.1% at 100 mg/L concentration, respectively. The phthalocyanine Co(II) and Cu(II) complexes show very strong ferrous ion chelating activity of 91.2% and 89.3% at concentration of 100 mg/L, respectively. Compound 3 displays strong reducing power like alpha-tocopherol. Antibacterial activities of phthalocyanine Co(II) and Amikacin (30 MUg/disk) against Micrococcus luteus (ATCC 9341) are 16 mm in diameter. PMID- 25036646 TI - On computational algorithms for real-valued continuous functions of several variables. AB - The subject of this paper is algorithms for computing superpositions of real valued continuous functions of several variables based on space-filling curves. The prototypes of these algorithms were based on Kolmogorov's dimension-reducing superpositions (Kolmogorov, 1957). Interest in these grew significantly with the discovery of Hecht-Nielsen that a version of Kolmogorov's formula has an interpretation as a feedforward neural network (Hecht-Nielse, 1987). These superpositions were constructed with devil's staircase-type functions to answer a question in functional complexity, rather than become computational algorithms, and their utility as an efficient computational tool turned out to be limited by the characteristics of space-filling curves that they determined. After discussing the link between the algorithms and these curves, this paper presents two algorithms for the case of two variables: one based on space-filling curves with worked out coding, and the Hilbert curve (Hilbert, 1891). PMID- 25036647 TI - Cell uptake and localization studies of squaramide based fluorescent probes. AB - Cell internalization is a major issue in drug design. Although squaramide-based compounds are receiving much attention because of their interesting bioactivity, cell uptake and trafficking within cells of this type of compounds are still unknown. In order to monitor the cell internalization process of cyclosquaramide compounds we have prepared two fluorescent probes by covalently linking a fluorescent dye (BODIPY derivative or fluorescein) to a noncytotoxic cyclosquaramide framework. These two probes (C2-BDP and C2-FITC) rapidly internalize across live cell membranes through endocytic receptor-mediated mechanisms. Due to its higher fluorescence and photochemical stability, C2-BDP is a superior dye than C2-FITC. C2-BDP remains sequestered in late endosomes allowing their fast and selective imaging in various live cell types. Cyclosquaramide-cell membrane interactions facilitate cell uptake and have been investigated by binding studies in solution as well as in live cells. Cyclosquaramide 1 (C2-BDP) can be used as a highly fluorescent probe for the rapid and selective imaging of late endosomes in live cells. PMID- 25036648 TI - Role of thyroid hormone receptor-alpha1 in endochondral ossification. PMID- 25036649 TI - Brainwork in the ovary: kisspeptin and BDNF signaling converge to ensure oocyte survival. PMID- 25036652 TI - Dynamically-driven enhancement of the catalytic machinery of the SARS 3C-like protease by the S284-T285-I286/A mutations on the extra domain. AB - Previously we revealed that the extra domain of SARS 3CLpro mediated the catalysis via different mechanisms. While the R298A mutation completely abolished the dimerization, thus resulting in the inactive catalytic machinery, N214A inactivated the enzyme by altering its dynamics without significantly perturbing its structure. Here we studied another mutant with S284-T285-I286 replaced by Ala (STI/A) with a 3.6-fold activity increase and slightly enhanced dimerization. We determined its crystal structure, which still adopts the dimeric structure almost identical to that of the wild-type (WT), except for slightly tighter packing between two extra-domains. We then conducted 100-ns molecular dynamics (MD) simulations for both STI/A and WT, the longest reported so far for 3CLpro. In the simulations, two STI/A extra domains become further tightly packed, leading to a significant volume reduction of the nano-channel formed by residues from both catalytic and extra domains. The enhanced packing appears to slightly increase the dynamic stability of the N-finger and the first helix residues, which subsequently triggers the redistribution of dynamics over residues directly contacting them. This ultimately enhances the dynamical stability of the residues constituting the catalytic dyad and substrate-binding pockets. Further correlation analysis reveals that a global network of the correlated motions exists in the protease, whose components include all residues identified so far to be critical for the dimerization and catalysis. Most strikingly, the N214A mutation globally decouples this network while the STI/A mutation alters the correlation pattern. Together with previous results, the present study establishes that besides the classic structural allostery, the dynamic allostery also operates in the SARS 3CLpro, which is surprisingly able to relay the perturbations on the extra domain onto the catalytic machinery to manifest opposite catalytic effects. Our results thus imply a promising avenue to design specific inhibitors for 3CL proteases by disrupting their dynamic correlation network. PMID- 25036653 TI - Mechanistic studies of ammonia borane dehydrogenation catalyzed by iron pincer complexes. AB - A series of iron bis(phosphinite) pincer complexes with the formula of [2,6 ((i)Pr2PO)2C6H3]Fe(PMe2R)2H (R = Me, 1; R = Ph, 2) or [2,6-((i)Pr2PO)2-4 (MeO)C6H2]Fe(PMe2Ph)2H (3) have been tested for catalytic dehydrogenation of ammonia borane (AB). At 60 degrees C, complexes 1-3 release 2.3-2.5 equiv of H2 per AB in 24 h. Among the three iron catalysts, 3 exhibits the highest activity in terms of both the rate and the extent of H2 release. The initial rate for the dehydrogenation of AB catalyzed by 3 is first order in 3 and zero order in AB. The kinetic isotope effect (KIE) observed for doubly labeled AB (k(NH3BH3)/k(ND3BD3) = 3.7) is the product of individual KIEs (k(NH3BH3)/k(ND3BH3) = 2.0 and k(NH3BH3)/k(NH3BD3) = 1.7), suggesting that B-H and N-H bonds are simultaneously broken during the rate-determining step. NMR studies support that the catalytically active species is an AB-bound iron complex formed by displacing trans PMe3 or PMe2Ph (relative to the hydride) by AB. Loss of NH3 from the AB-bound iron species as well as catalyst degradation contributes to the decreased rate of H2 release at the late stage of the dehydrogenation reaction. PMID- 25036654 TI - Effects of low-pass filtering on the perception of word-final plurality markers in children and adults with normal hearing. AB - PURPOSE: The purpose of this study was to evaluate the effect of low-pass filtering on the detection of word-final /s/ and /z/ for children and adults with normal hearing. METHOD: Stimuli were nouns from the University of Western Ontario Plurals Test (Glista & Scollie, 2012), low-pass filtered with 5 different cutoff frequencies: 8000 Hz, 5000 Hz, 4000 Hz, 3000 Hz, and 2000 Hz. Listeners were children (age range = 7-13 years) and adults with normal hearing. The task was a 2-alternative forced-choice task with a picture-pointing response. RESULTS: Performance was worse for lower than for higher low-pass filter cutoff frequencies, but the effect of low-pass filtering was similar for children and adults. Nearly all listeners achieved 100% correct performance when stimuli were low-pass filtered with cutoff frequencies of 8000 Hz or 5000 Hz. Performance remained well above chance even for the most severe filtering condition (2000 Hz). Restricting high-frequency audibility influenced performance for plural items to a greater extent than for singular items. CONCLUSION: The results indicate that children and adults with normal hearing can use acoustic information below the spectral range of frication noise typically associated with /s/ and /z/ to discriminate between singular and plural forms of nouns in the context of the University of Western Ontario Plurals Test. PMID- 25036656 TI - Out-of-pocket expenditures and the financial burden of healthcare among older adults: by nativity and length of residence in the United States. AB - Newly arrived older immigrants in the United States tend to be greatly affected by increasing out-of-pocket healthcare expenditures due to their limited insurance options. To examine such disparities in the out-of-pocket expenditures, this study analyzed the Medical Expenditure Panel Survey by immigrant status. Major findings of this study indicated that although recent immigrants had lower total healthcare expenditures, they spent much higher proportions of their annual income on out-of-pocket medical payments, compared with their US-born counterparts. Dramatically higher out-of-pocket burdens among recent immigrants represent a barrier to necessary healthcare, which needs to be addressed from both public health and economic perspectives. PMID- 25036657 TI - Familial idiopathic small-bowel and colonic varices in three siblings. AB - Idiopathic small-bowel and colonic varices are a rare source of bleeding from the gastrointestinal tract. To date there are only eight published case series of familial idiopathic small-bowel and colonic varices. We present a case series detailing three affected siblings who presented with significant lower gastrointestinal bleeding and had multiple varices on endoscopy and imaging. Though not confirmed, consanguinity in the parents suggests an autosomal recessive mode of inheritance. We summarize the literature to date and describe our institution's experience of endoscopy, diagnostic imaging, and treatment in these patients. PMID- 25036658 TI - Transcardiac tunneling technique for endoscopic submucosal dissection of gastric fundus tumors arising from the muscularis propria. AB - The promising endoscopic resection techniques for upper gastrointestinal submucosal tumors (SMTs) are challenged when performed in the gastric fundus. Here, we report on the development of a transcardiac endoscopic tunneling technique (TCTT) for the resection of tumors in this area. A total of 18 patients with gastric fundus SMTs arising from the muscularis propria on endoscopic ultrasound underwent TCTT. The procedure involved the excavation of a submucosal tunnel from the esophagus, through the cardia, to the gastric SMT for resection. The tunnel was closed by clips after retrieval of the tumor. The mean tumor size was 2.1 cm (range 0.8 - 5.0 cm). The mean procedure time was 75.1 minutes (range 40 - 100 minutes). Complete resection was achieved in all cases. Iatrogenic perforation occurred in one case. This and one other patient developed mild pneumoperitoneum on the day after the procedure; symptoms resolved under conservative management. No patient developed gastrointestinal leakage, delayed bleeding, or secondary infection. Therefore, in this pilot study, TCTT provided a definitive histological diagnosis as well as a feasible, safe, and easy therapeutic approach for gastric fundus SMTs arising from muscularis propria in the circular area within 8 cm below the cardia. PMID- 25036659 TI - How important are simulators for endoscopy training? PMID- 25036660 TI - Accuracy and concordance of endocytoscopic atypia for the diagnosis of gastric cancer. AB - BACKGROUND AND AIM: High-grade atypia demonstrated by endocytoscopy may be a key criterion for the diagnosis of gastric cancer. We therefore sought to verify whether endocytoscopic atypia can provide satisfactory levels of diagnostic accuracy and concordance among trainee and expert endoscopists. METHOD: A total of 100 lesions evaluated by endocytoscopy and histopathology were enrolled to create an endocytoscopic image catalog (44 early cancers, 10 low-grade adenomas, 46 non-neoplastic lesions). Four endoscopists (two trainees and two experts) independently reviewed the catalog images and evaluated each of them for the presence or absence of endocytoscopic atypia. High-grade endocytoscopic atypia, as a criterion for cancer diagnosis, was defined as the consistent observation of any of the following features: lumen absence, lumen fusion, and irregular nuclei showing the three typical features (heterogeneous shape, swelling, and disarrangement). RESULTS: High-grade endocytoscopic atypia was observed in 78 %, 18 %, and 4 % of cancers, adenomas, and non-neoplastic lesions, respectively. The sensitivity, specificity, accuracy, and positive and negative predictive values for cancer diagnosis by endocytoscopy were 78.4 %, 93.3 %, 87.3 %, 85.4 %, and 87.3 %, respectively. The concordance rate for the results of high-grade endocytoscopic atypia was good among the four endoscopists (kappa value 0.682). No significant difference in diagnostic accuracy or concordance was observed between trainee and expert endoscopists. CONCLUSION: Using the defined high-grade atypia as a diagnostic criterion of cancer, endocytoscopy provided a satisfactory level of accuracy and concordance for the diagnosis of early gastric cancer, regardless of endoscopic expertise. PMID- 25036661 TI - LIK1, a CERK1-interacting kinase, regulates plant immune responses in Arabidopsis. AB - Chitin, an integral component of the fungal cell wall, is one of the best-studied microbe-associated molecular patterns. Previous work identified a LysM receptor like kinase (LysM-RLK1/CERK1) as the primary chitin receptor in Arabidopsis. In order to identify proteins that interact with CERK1, we conducted a yeast two hybrid screen using the intracellular kinase domain of CERK1 as the bait. This screen identified 54 putative CERK1-interactors. Screening mutants defective in 43 of these interacting proteins identified only two, a calmodulin like protein (At3g10190) and a leucine-rich repeat receptor like kinase (At3g14840), which differed in their response to pathogen challenge. In the present work, we focused on characterizing the LRR-RLK gene where mutations altered responses to chitin elicitation. This LRR-RLK was named LysM RLK1-interacting kinase 1 (LIK1). The interaction between CERK1 and LIK1 was confirmed by co-immunoprecipitation using protoplasts and transgenic plants. In vitro experiments showed that LIK1 was directly phosphorylated by CERK1. In vivo phosphorylation assays showed that Col 0 wild-type plants have more phosphorylated LIK1 than cerk1 mutant plants, suggesting that LIK1 may be directly phosphorylated by CERK1. Lik1 mutant plants showed an enhanced response to both chitin and flagellin elicitors. In comparison to the wild-type plants, lik1 mutant plants were more resistant to the hemibiotrophic pathogen Pseudomonas syringae, but more susceptible to the necrotrophic pathogen Sclerotinia sclerotiorum. Consistent with the enhanced susceptibility to necrotrophs, lik1 mutants showed reduced expression of genes involved in jasmonic acid and ethylene signaling pathways. These data suggest that LIK1 directly interacts with CERK1 and regulates MAMP-triggered innate immunity. PMID- 25036662 TI - Spectroscopic, electrochemical DNA binding and in vivo anti-inflammatory studies on newly synthesized Schiff bases of 4-aminophenazone. AB - 4-Aminophenazone (Ap-1) Schiff bases i.e., 4-{(3,4,5-trimethoxybenzylidine) amino}phenazone (Ap-2), 4-{(2-chlorobenzylidine) amino}phenazone (Ap-3) and 4-{(4 chlorobenzylidine)amino} phenazone (Ap-4) were synthesized and characterized by different spectroscopic techniques. Interaction of these compounds with ds.DNA was investigated through UV-Visible spectroscopy, fluorescence spectroscopy and cyclic voltammetry at stomach (4.7) and blood (7.4) pH under 37 degrees C (human body temperature). Instrumental findings were further quantified both kinetically and thermodynamically. Results obtained through these techniques inferred intercalative mode of binding of all the compounds with DNA. The binding constant data, "Kb", and free energy change, DeltaG, indicated comparatively greater binding affinity and more spontaneity of binding of compounds with DNA at stomach pH (4.7), respectively. However, among these compounds, Ap-4 showed comparatively greater binding at both the pH. Formation of compound-DNA complex was further confirmed through the decrease in diffusion rates after the addition of DNA. The in vivo anti-inflammatory activity of the compounds was evaluated using the carrageenan-induced hind paw edema method. The results revealed that among all the compounds, Ap-4 showed greater percentage of edema inhibition compared to standard drug. PMID- 25036663 TI - Strengths-based nursing. AB - Strengths-based nursing (SBN) is an approach to care in which eight core values guide nursing action, thereby promoting empowerment, self-efficacy, and hope. In caring for patients and families, the nurse focuses on their inner and outer strengths-that is, on what patients and families do that best helps them deal with problems and minimize deficits. Across all levels of care, from the primary care of healthy patients to the critical care of patients who are unconscious, SBN reaffirms nursing's goals of promoting health, facilitating healing, and alleviating suffering by creating environments that work with and bolster patients' capacities for health and innate mechanisms of healing. In doing so, SBN complements medical care, provides a language that communicates nursing's contribution to patient and family health and healing, and empowers the patient and family to gain greater control over their health and healing. PMID- 25036664 TI - Sustaining pressure ulcer best practices in a high-volume cardiac care environment. AB - ?Narayana Hrudayalaya Cardiac Hospital (NHCH) in Bangalore, India (now known as the Narayana Institute of Cardiac Sciences), is one of the world's largest and busiest cardiac hospitals. In early 2009, NHCH experienced a sharp increase in the number of surgical procedures performed and a corresponding rise in hospital acquired pressure ulcers. The hospital sought to reduce pressure ulcer prevalence by implementing a portfolio of quality improvement strategies. Baseline data showed that, over the five-month observation period, an average of 6% of all adult and pediatric surgical patients experienced a pressure ulcer while recovering in the NHCH intensive therapy unit (ITU). Phase 1 implementation efforts, which began in January 2010, focused on four areas: raising awareness, increasing education, improving documentation and communication, and implementing various preventive practices. Phase 2 implementation efforts, which began the following month, focused on changing operating room practices. The primary outcome measure was the weekly percentage of ITU patients with pressure ulcers. By July 2010, that percentage was reduced to zero; as of April 1, 2014, the hospital has maintained this result. Elements that contributed significantly to the program's success and sustainability include strong leadership, nurse and physician involvement, an emphasis on personal responsibility, improved documentation and communication, ongoing training and support, and a portfolio of low-tech changes to core workflows and behaviors. Many of these elements are applicable to U.S. acute care environments. PMID- 25036665 TI - Enhancement of mechanical properties, microstructure, and antimicrobial activities of zein films cross-linked using succinic anhydride, eugenol, and citric Acid. AB - Zein constitutes about half of the endosperm proteins in corn. Recently, attempts have been made to utilize zein for food coatings and biodegradable materials, which require better physical properties, using chemical modification of zein. In this study, zein proteins were modified using citric acid, succinic anhydride, and eugenol as natural cross-linking agents in the wet state. The cross-linkers were added either separately or combined in increment concentrations (0.1, 0.2, 0.3, and 0.4%). The effects of those agents on the mechanical properties, microstructure, optical properties, infrared (IR) spectroscopy, and antibacterial activities of zein were investigated. The addition of cross-linking agents promoted changes in the arrangement of groups in zein film-forming particles. Regarding the film properties, incorporation of cross-linking agents into zein films prepared in ethanol resulted in two- to three-fold increases in tensile strength (TS) values. According to the Fourier-transform infrared (FTIR) spectra and Hunter parameters there were no remarkable changes in the structure and color of zein films. Transparency of zein films was decreased differentially according to the type and cross-linker concentration. The mechanical and optical properties of zein films were closely related to their microstructure. All cross-linked films showed remarkable antibacterial activities against Bacillus cereus ATCC 49064 and Salmonella enterica ATCC 25566. Food spoilage and pathogenic bacteria were affected in a film-dependent manner. Our experimental results show that even with partial cross-linking the mechanical properties and antipathogen activities of zein films were significantly improved, which would be useful for various industrial applications. PMID- 25036666 TI - Covariate effect on constancy assumption in noninferiority clinical trials. AB - Noninferiority (NI) clinical trials are getting a lot of attention of late due to their direct application in biosimilar studies. Because of the missing placebo arm, NI is an indirect approach to demonstrate efficacy of a test treatment. One of the key assumptions in the NI test is the constancy assumption, that is, that the effect of the reference treatment is the same in current NI trials as in historical superiority trials. However, if a covariate interacts with the treatment arms, then changes in distribution of this covariate will likely result in violation of constancy assumption. In this article, we propose four new NI methods and compare them with two existing methods to evaluate the change of background constancy assumption on the performance of these six methods. To achieve this goal, we study the impact of three elements-(1) strength of covariate, (2) degree of interaction between covariate and treatment, and (3) differences in distribution of the covariate between historical and current trials-on both the type I error rate and power using three different measures of association: difference, log relative risk, and log odds ratio. Based on this research, we recommend using a modified covariate-adjustment fixed margin method. PMID- 25036667 TI - Phosphorus in soil treatment systems: accumulation and mobility. AB - Septic tanks with subsequent soil treatment systems (STS) are a common treatment technique for domestic wastewater in rural areas. Phosphorus (P) leakage from such systems may pose a risk to water quality (especially if they are located relatively close to surface waters). In this study, six STS in Sweden (11-28 years old) were examined. Samples taken from the unsaturated subsoil beneath the distribution pipes were investigated by means of batch and column experiments, and accumulated phosphorus were characterized through X-ray absorption near edge structure (XANES) analysis. At all sites the wastewater had clearly influenced the soil. This was observed through decreased pH, increased amounts of oxalate extractable metals and at some sites altered P sorption properties. The amount of accumulated P in the STS were found to be between 0.32 and 0.87 kg m(-3), which in most cases was just a fraction of the estimated P load (<30%). Column studies revealed that high P concentrations (up to 6 mg L(-1)) were leached from the material when deionized water was applied. However, the response to deionized water varied between the sites. As evidenced by XANES analysis, aluminium phosphates or P adsorbed to aluminium (hydr)oxides, as well as organically bound P, were important sinks for P. Generally soils with a high content of oxalate extractable Al were also less vulnerable to P leakage. PMID- 25036668 TI - Anti-Inflammatory Spirostanol and Furostanol Saponins from Solanum macaonense. AB - Eight new spirostanol saponins, macaosides A-H (1-8), and 10 new furostanol saponins, macaosides I-R (9-18), together with six known spirostanol compounds (19-24) were isolated from Solanum macaonense. The structures of the new compounds were determined from their spectroscopic data, and the compounds were tested for in vitro antineutrophilic inflammatory activity. It was found that both immediate inflammation responses including superoxide anion generation and elastase release were significantly inhibited by treatment with compounds 20, 21, and 24 (superoxide anion generation: IC50 7.0, 7.6, 4.0 MUM; elastase release: IC50 3.7, 4.4, 1.0 MUM, respectively). However, compounds 1 and 4 exhibited effects on the inhibition of elastase release only, with IC50 values of 3.2 and 4.2 MUM, respectively, while 19 was active against superoxide anion generation only, with an IC50 value of 6.1 MUM. Accordingly, spirostanols may be promising lead compounds for further neutrophilic inflammatory disease studies. PMID- 25036669 TI - Genetic and biochemical analysis of the antibiotic biosynthetic gene clusters on the Streptomyces linear plasmid. AB - We extensively analyzed the giant linear plasmid pSLA2-L in Streptomyces rochei 7434AN4, a producer of two structurally unrelated polyketide antibiotics, lankacidin and lankamycin. It was found that amine oxidase LkcE oxidizes an acyclic amine to an imine, which is in turn converted to the 17-membered carbocyclic lankacidin. Heterologous expression and translational fusion experiments indicated the modular-iterative mixed polyketide biosynthesis of lankacidin. Concerning to lankamycin biosynthesis, starter unit biosynthesis and the post-PKS modification pathway were elucidated by feeding and gene inactivation experiments. It was shown that pSLA2-L contains many regulatory genes, which constitute the signaling molecule/receptor system for antibiotic production and morphological differentiation in this strain. Two signaling molecules, SRB1 and SRB2, that induce production of lankacidin and lankamycin were further isolated and their structures were elucidated. Each contains a 2,3 disubstituted butenolide skeleton, and the stereochemistry at C-1' position is crucial for inducing activity. PMID- 25036670 TI - Anti-proliferative activity of 6-O-acyl-D-allose against the human leukemia MOLT 4F cell line. AB - The anti-proliferative activities of the 6-O-acyl derivatives of D-allose against the human leukemia MOLT-4F cell line were examined. The activity of the 6-O dodecanoyl derivative (3) was approximately 30 times stronger than that of D allose. An evaluation of the derivatives of 3 that occurred in a furanose form revealed the pyranose forms of 3 to be important for the anti-proliferative activity. PMID- 25036671 TI - Characterization of chimeric and mutated isocitrate lyases of a mesophilic nitrogen-fixing bacterium, Azotobacter vinelandii, and a psychrophilic bacterium, Colwellia maris. AB - Chimeric enzymes between a cold-adapted isocitrate lyase (ICL) of a psychrophilic bacterium, Colwellia maris, (CmICL) and a mesophilic ICL of a nitrogen-fixing bacterium, Azotobacter vinelandii, (AvICL) were constructed by dividing the ICL genes into four regions of almost equal length and exchanging regions in various combinations. The chimeric ICL, which was replaced C-terminal region 4 of AvICL by the corresponding region of CmICL, showed much lower specific activity and lower optimum temperature and thermostability for activity than wild-type AvICL, indicating that region 4 is involved in its thermal properties. Furthermore, mutual substitution between the Met501 residue in region 4 of CmICL and the corresponding Ile504 residue of AvICL influenced the temperature dependence of their activities, suggesting that these amino acid residues are important to the respective mesophilic and cold-adapted properties of AvICL and CmICL. PMID- 25036672 TI - Purification and characterization of cocoonase from the silkworm Bombyx mori. AB - Cocoonase (CCN) which facilitates the degradation of a cocoon is recognized as a trypsin-like serine protease. In this study, CCN from the silkworm Bombyx mori was purified and comprehensively characterized. Its activity was maximal at about pH 9.8. It was stable above pH 3.4 at 4 degrees C and below 50 degrees C at pH 7.5. CuSO4, FeSO4, and ZnSO4 showed inhibitory effects on CCN, but other salts improved activity. Typical trypsin inhibitors inhibited CCN, but the relative inhibitory activities were much lower than those against bovine trypsin. An extract of cocoon shells inhibited trypsin, but it was only slightly inhibitory against CCN. There were significant differences in catalytic efficiencies and substrate specificities as between CCN and bovine trypsin. PMID- 25036673 TI - Akt induces down regulation of MUC5AC production in NCI-H292 human airway epithelial cells cultured on extracellular matrix. AB - MUC5AC mucin overproduction is a key feature of asthma as contributes to airway obstruction. The production of MUC5AC is regulated in part by signals from extracellular matrix via integrin pathways, but it remains largely unclear. We investigated the role of Akt, a typical signal transducer in the integrin pathway, in the regulation of MUC5AC production. When NCI-H292 human airway epithelial cells were cultured on laminin or Matrigel, we found that the activity of Akt was suppressed, as compared to control cells with upregulated MUC5AC production. In contrast, Akt was activated in cells cultured on type IV collagen with downregulated MUC5AC production. The Akt inhibitor induced upregulation of MUC5AC. In contrast, overexpression of active Akt induced downregulation of MUC5AC production. These results suggest that a signal from laminin or Matrigel induces upregulation of MUC5AC by suppressing Akt activity, whereas a signal from type IV collagen induces downregulation of MUC5AC, mediated by Akt activation. PMID- 25036674 TI - Characterization of a yam class IV chitinase produced by recombinant Pichia pastoris X-33. AB - A yam (Dioscorea opposita Thunb) class IV chitinase, whose genomic DNA was cloned by Mitsunaga et al. (2004), was produced by the recombinant Pichia pastoris X-33 in high yields such as 66 mg/L of culture medium. The chitinase was purified by column chromatography after Endoglycosidase H treatment and then characterized. It showed properties similar to the original chitinase E purified from the yam tuber reported by Arakane et al. (2000). This Pichia-produced chitinase also showed strong lytic activity against Fusarium oxysporum and Phytophthora nicotianae, wide pH and thermal stability, optimum activity at higher temperature such as 70 degrees C, and high substrate affinity, indicating that one can use this Pichia-produced yam chitinase as a bio-control agent. PMID- 25036675 TI - Tomato FRUITFULL homologs regulate fruit ripening via ethylene biosynthesis. AB - Certain MADS-box transcription factors play central roles in regulating fruit ripening. RIPENING INHIBITOR (RIN), a tomato MADS-domain protein, acts as a global regulator of ripening, affecting the climacteric rise of ethylene, pigmentation changes, and fruit softening. Previously, we showed that two MADS domain proteins, the FRUITFULL homologs FUL1 and FUL2, form complexes with RIN. Here, we characterized the FUL1/FUL2 loss-of-function phenotype in co-suppressed plants. The transgenic plants produced ripening-defective fruits accumulating little or no lycopene. Unlike a previous study on FUL1/FUL2 suppressed tomatoes, our transgenic fruits showed very low levels of ethylene production, and this was associated with suppression of the genes for 1-aminocyclopropane-1-carboxylic acid synthase, a rate-limiting enzyme in ethylene synthesis. FUL1/FUL2 suppression also caused the fruit to soften in a manner independent of ripening, possibly due to reduced cuticle thickness in the peel of the suppressed tomatoes. PMID- 25036676 TI - Unsaturated long-chain fatty acids inhibit the binding of oxidized low-density lipoproteins to a model CD36. AB - Transmembrane protein CD36 binds multiple ligands, including oxidized low-density lipoproteins (oxLDLs) and long-chain fatty acids (LCFAs). Our aim was to determine whether LCFAs compete with oxLDLs for binding to CD36. We addressed this issue by examining the inhibitory effect of LCFAs against the binding of Alexa-fluor-labeled oxLDLs (AFL-oxLDL) to a synthetic peptide representing the oxLDL-binding site on CD36 (3S-CD36150-168). All of the unsaturated LCFAs tested, inhibited the binding of AFL-oxLDL to 3S-CD36150-168, albeit to varying degrees. For instance, the concentrations required for 50% inhibition of binding for oleic, linoleic, and alpha-linolenic acids were 0.25, 0.97, and 1.2 mM, respectively. None of the saturated LCFAs tested (e.g. stearic acid) exhibited inhibitory effects. These results suggest that at least unsaturated LCFAs can compete with oxLDLs for binding to CD36. The study also provides information on the structural requirements of LCFAs for inhibition of oxLDLs-CD36 binding. PMID- 25036677 TI - Biochemistry of lipolytic enzymes secreted by Penicillium solitum and Cladosporium cladosporioides. AB - Two distinct extracellular lipases were obtained from Penicillium solitum 194A, isolated from domestic compost, and Cladosporium cladosporioides 194B, isolated from dairy wastewater. These alkaline enzymes had molecular masses of 42 and 30 kDa, respectively. The P. solitum 194A lipase differed in mass from previously reported enzyme, indicating that it is a novel lipase, and indicating that penicillia can secrete lipase isoenzymes. The C. cladosporioides lipase was more active on esters of medium-chain acids, whereas the P. solitum lipase was more active on longer chained substrates. The C. cladosporioides enzyme displayed higher thermal stability than the P. solitum lipase, preserving full activity up to 48 degrees C and showing a T50 (10 min) of 60 degrees C. Their different catalytic properties and good protein stability should make these enzymes suitable for biotechnological applications. Furthermore, the combined use of these two fungal strains may prove to be valuable in lipid-rich waste management. PMID- 25036678 TI - Induction of apoptosis by 2,3-dehydrosilybin via a caspase-dependent pathway in human HeLa cells. AB - The aim of this study was to investigate the mechanisms involved in the apoptosis of HeLa cells due to 2,3-dehydrosilybin (DHS) treatment. DHS treatment over 24 h significantly inhibited cell viability and induced apoptosis in a dose-dependent manner. It also triggered the cleavage of caspase-8, caspase-9, caspase-3, and PARP, and significantly increased caspase-3 activity in a dose-dependent manner. Moreover, it triggered the depolarization of the mitochondrial membrane potential (Deltapsim), the release of cytochrome c into the cytosol, the cleavage of Bid, and the downregulation of Bcl-2 in a dose-dependent manner. Furthermore, z-VAD fmk (a pan-caspase inhibitor) and z-IETD-fmk (a specific caspase-8 inhibitor) abolished the DHS-induced activation of the caspase-8, -9, and -3, cleavage of PARP, the depolarization of Deltapsim, the release of cytochrome c, the cleavage of Bid, and the downregulation of Bcl-2. Taken together, these results suggest that DHS-induced apoptosis is mediated by a caspase-dependent pathway in human HeLa cells. PMID- 25036679 TI - Characterization of a thermophilic 4-O-beta-D-mannosyl-D-glucose phosphorylase from Rhodothermus marinus. AB - 4-O-beta-D-Mannosyl-D-glucose phosphorylase (MGP), found in anaerobes, converts 4 O-beta-D-mannosyl-D-glucose (Man-Glc) to alpha-D-mannosyl phosphate and D glucose. It participates in mannan metabolism with cellobiose 2-epimerase (CE), which converts beta-1,4-mannobiose to Man-Glc. A putative MGP gene is present in the genome of the thermophilic aerobe Rhodothermus marinus (Rm) upstream of the gene encoding CE. Konjac glucomannan enhanced production by R. marinus of MGP, CE, and extracellular mannan endo-1,4-beta-mannosidase. Recombinant RmMGP catalyzed the phosphorolysis of Man-Glc through a sequential bi-bi mechanism involving ternary complex formation. Its molecular masses were 45 and 222 kDa under denaturing and nondenaturing conditions, respectively. Its pH and temperature optima were 6.5 and 75 degrees C, and it was stable between pH 5.5 8.3 and below 80 degrees C. In the reverse reaction, RmMGP had higher acceptor preferences for 6-deoxy-D-glucose and D-xylose than R. albus NE1 MGP. In contrast to R. albus NE1 MGP, RmMGP utilized methyl beta-D-glucoside and 1,5-anhydro-D glucitol as acceptor substrates. PMID- 25036680 TI - Quantitative analysis of CD3epsilon in a cloned canine lymphoma cell line by selected reaction monitoring assay. AB - We established a mass spectrometry-based quantitative method of assaying CD3epsilon, a component of the T-cell receptor complex. It revealed a CD3epsilon level of 1 mol per cell in a newly derived canine T-cell lymphoma cell line. Our results suggest that this method has sufficient sensitivity to quantify CD3epsilon levels in canine lymphoma cells reliably. PMID- 25036681 TI - Large-scale preparation of glycopeptides harboring the TF-antigen unit from royal jelly. AB - We have reported that new N-glycans carrying the TF-antigen occurred on a major royal jelly glycoprotein, and we have identified the glycosylation site to which the antigenic N-glycan is linked, but an appropriate procedure has not been established to prepare non-labeled immunoreactive glycopeptides in large amounts for functional analysis. In this study, we developed an effective method of preparing Asn-glycopeptide bearing TF-antigen. PMID- 25036682 TI - Theasaponin E1 as an effective ingredient for anti-angiogenesis and anti-obesity effects. AB - Theasaponin E1 (TSE1) has been suggested to have higher biological activity than other saponins present in tea seed. Saponins have recently been considered as a potential chemotherapeutic agent for treating cancer. We examined the anti angiogenic and anti-obesity properties of TSE1 contributing to anti-cancer efficacy. Treating with a 10 MUg/mL concentration of TSE1 completely inhibited tube formation in human umbilical vein endothelial cells (HUVECs). TSE1 showed toxicity toward cancer cells and inhibited in vivo growth of the tumor. The vascular endothelial growth factor (VEGF) receptor complex was suppressed, leading to the inhibition of protein kinase B (Akt) expression and down regulation of nuclear factor-kappa B (NF-kB) activation. The differentiating 3T3 L1 cells treated with TSE1 had decreased lipid droplet formation measured by Oil Red O staining. Reduced weight was measured in mice fed with a TSE1 plus high-fat diet. The results taken together, and particularly the NF-kB inhibition, suggest that TSE1 may have multi-target action for treating cancer as a novel chemotherapeutic agent. PMID- 25036683 TI - Potential of extracts from Saponaria officinalis and Calendula officinalis to modulate in vitro rumen fermentation with respect to their content in saponins. AB - Saponins have the potential to favorably modulate rumen fermentation, but there is generally a lack of the chemical structures associated with the described effects. The activity of extracts from Calendula officinalis and Saponaria officinalis in the rumen was evaluated in vitro. The S. officinalis root extract, reduced CH4 production by 8.5% and increased total VFA concentration by 25.2%. C. officinalis and S. officinalis root extracts and the S. officinalis aerial part extract decreased the acetate to propionate ratio from 8.6 to 17.4%, according to the extract. An HPLC-ELSD analysis indicated that the saponin content ranged from 43.6 to 57.6 mg/g of dry matter (DM) in the C. officinalis extracts and from 224.0 to 693.8 mg/g of DM in the S. officinalis extracts, expressed as the hederacoside C equivalent. Identification of the saponin compounds present in the extracts by HPLC-MS(n) suggested that the saponin profile modulated the biological activities, showing the importance of determining the structure of saponins when evaluating extracts. PMID- 25036684 TI - Phenolic compounds from leaves of Casimiroa edulis showed adipogenesis activity. AB - Casimiroa edulis is known as cochitzapotl, and it belongs to a species of tropical fruiting tree in the family Rutaceae, native to eastern Mexico and Central America south to Costa Rica. In this study, we isolated two furocoumarins and two polymethoxyflavones from leaves of C. edulis and evaluated the functions of glucose and lipid metabolism activity with 3T3-L1 adipocytes. We discovered that the addition of furocoumarins increased glucose uptake and lipid accumulation in 3T3-L1 adipocyte. These results suggest that furocoumarin compounds can be used as functional food-derived compounds, to regulate adipocyte functioning for the management of metabolic syndrome, which is associated with dysfunctions of glucose and lipid metabolism. PMID- 25036685 TI - Protection of free radical-induced cytotoxicity by 2-O-alpha-D-glucopyranosyl-L ascorbic acid in human dermal fibroblasts. AB - The stable ascorbic acid (AA) derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), exhibits vitamin C activity after enzymatic hydrolysis to AA. The biological activity of AA-2G per se has not been studied in detail, although AA 2G has been noted as a stable source for AA supply. The protective effect of AA 2G against the oxidative cell death of human dermal fibroblasts induced by incubating with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) for 24 h was investigated in this study. AA-2G showed a significant protective effect against the oxidative stress in a concentration-dependent manner. AA-2G did not exert a protective effect during the initial 12 h of incubation, but had a significant protective effect in the later part of the incubation period. Experiments using a alpha-glucosidase inhibitor and comparative experiments using a stereoisomer of AA-2G confirmed that AA-2G had a protective effect against AAPH-induced cytotoxicity without being converted to AA. Our results provide an insight into the efficacy of AA-2G as a biologically interesting antioxidant and suggest the practical use of AA-2G even before being converted into AA as a beneficial antioxidant. PMID- 25036686 TI - Comparison of bioavailability between beta-cryptoxanthin and beta-carotene and tissue distribution in its intact form in rats. AB - The bioavailability of two intact carotenoids in several tissues of beta cryptoxanthin- and beta-carotene-fed rats (20 mg/kg of diet) was investigated. Although metabolites of provitamin A are not included in our study, beta cryptoxanthin was found at higher concentrations in majority of the tissues. The results show that the bioavailability of intact beta-cryptoxanthin seemed to be higher than that of beta-carotene. PMID- 25036687 TI - Determination by UPLC-MS of four dammarane-type saponins from heat-processed Gynostemma pentaphyllum. AB - Heat-processed Gynostemma pentaphyllum and its main dammaran-type saponins, gypenoside L, gypenoside LI, damulin B, and damulin A, possess non-small cell lung carcinoma A549 cell inhibitory activity. We established in this study a method by ultra-high performance liquid chromatography with tandem mass spectrometry for determination of the saponins and also investigated their content change in heat-processed G. pentaphyllum. The main saponins increased with increasing heating temperature and time. Further investigation showed that they were produced from gypenoside XLVI and gypenoside LVI by undergoing hydrolysis during the heat treatment. PMID- 25036688 TI - Enzymatic production of three 6-deoxy-aldohexoses from L-rhamnose. AB - 6-Deoxy-L-glucose, 6-deoxy-L-altrose, and 6-deoxy-L-allose were produced from L rhamnose with an immobilized enzyme that was partially purified (IE) and an immobilized Escherichia coli recombinant treated with toluene (TT). 6-Deoxy-L psicose was produced from L-rhamnose by a combination of L-rhamnose isomerase (TT PsLRhI) and D-tagatose 3-epimerase (TT-PcDTE). The purified 6-deoxy-L-psicose was isomerized to 6-deoxy-L-altrose and 6-deoxy-L-allose with L-arabinose isomerase (TT-EaLAI) and L-ribose isomerase (TT-AcLRI), respectively, and then was epimerized to L-rhamnulose with immobilized D-tagatose 3-epimerase (IE-PcDTE). Following purification, L-rhamnulose was converted to 6-deoxy-L-glucose with D arabinose isomerase (TT-BpDAI). The equilibrium ratios of 6-deoxy-L-psicose:6 deoxy-L-altrose, 6-deoxy-L-psicose:6-deoxy-L-allose, and L-rhamnulose:6-deoxy-L glucose were 60:40, 40:60, and 27:73, respectively. The production yields of 6 deoxy-L-glucose, 6-deoxy-L-altrose, and 6-deoxy-L-allose from L-rhamnose were 5.4, 14.6, and 25.1%, respectively. These results indicate that the aldose isomerases used in this study acted on 6-deoxy aldohexoses. PMID- 25036689 TI - The putative stress sensor protein MtlA is required for conidia formation, cell wall stress tolerance, and cell wall integrity in Aspergillus nidulans. AB - The Mid2-like protein MtlA is a putative sensor of the cell wall integrity (CWI) signaling pathway in Aspergillus nidulans. An MtlA-EGFP fusion protein was localized at the cell surface and septa. The mtlA disruptant (?mtlA) showed radial colony growth similar to the wild-type (wt) strain, but showed reduced conidia formation. The ?mtlA mutant showed growth deficiency in the presence of inhibitors of cell wall synthesis. Moreover, mtlA disruption resulted in a reduction in the glucan and chitin content in the cell wall. These results suggest that MtlA plays a significant role in asexual sporulation, cell wall stress tolerance, and the maintenance of CWI in A. nidulans, but transcriptional upregulation of alpha-1,3-glucan synthase gene agsB induced by micafungin was observed in the ?mtlA strain as well as the wt strain. Thus, MtlA is not essential for activation of the downstream CWI signaling pathway components identified in previous studies of Saccharomyces cerevisiae. PMID- 25036690 TI - Isolation of oleaginous yeast (Rhodosporidium toruloides) mutants tolerant of sugarcane bagasse hydrolysate. AB - Rhodosporidium toruloides is a lipid-producing yeast, the growth of which is severely suppressed when hydrolysates of lignocellulosic biomass are used as carbon source. This is probably due to the toxic substances, such as organic acids, furans, and phenolic compounds produced during the preparation of the hydrolysates. In order to solve this problem, R. toruloides cultures were subjected to atmospheric room-temperature plasma mutagenesis, resulting in the isolation of mutants showing tolerance to sugarcane bagasse hydrolysate (SBH). Three mutant strains, M11, M13, and M18, were found to grow with producing lipids with SBH as carbon source. M11 in particular appeared to accumulate higher levels (up to 60% of dry cell weight) of intracellular lipids. Further, all three mutant strains showed tolerance of vanillin, furfural, and acetic acid, with different spectra, suggesting that different genetic determinants are involved in SBH tolerance. PMID- 25036691 TI - Lactate production as representative of the fermentation potential of Corynebacterium glutamicum 2262 in a one-step process. AB - The fermentative properties of thermo-sensitive strain Corynebacterium glutamicum 2262 were investigated in processes coupling aerobic cell growth and the anaerobic fermentation phase. In particular, the influence of two modes of fermentation on the production of lactate, the fermentation product model, was studied. In both processes, lactate was produced in significant amount, 27 g/L in batch culture, and up to 55.8 g/L in fed-batch culture, but the specific production rate in the fed-batch culture was four times lower than that in the batch culture. Compared to other investigated fermentation processes, our strategy resulted in the highest yield of lactic acid from biomass. Lactate production by C. glutamicum 2262 thus revealed the capability of the strain to produce various fermentation products from pyruvate. PMID- 25036692 TI - Production of P-aminobenzoic acid by metabolically engineered escherichia coli. AB - The production of chemical compounds from renewable resources is an important issue in building a sustainable society. In this study, Escherichia coli was metabolically engineered by introducing T7lac promoter-controlled aroF(fbr), pabA, pabB, and pabC genes into the chromosome to overproduce para-aminobenzoic acid (PABA) from glucose. Elevating the copy number of chromosomal PT7lac-pabA pabB distinctly increased the PABA titer, indicating that elevation of 4-amino-4 deoxychorismic acid synthesis is a significant factor in PABA production. The introduction of a counterpart derived from Corynebacterium efficiens, pabAB (ce), encoding a fused PabA and PabB protein, resulted in a considerable increase in the PABA titer. The introduction of more than two copies of PT7lac-pabAB (ce mod), a codon-optimized pabAB (ce), into the chromosome of a strain that simultaneously overexpressed aroF(fbr) and pabC resulted in 5.1 mM PABA from 55.6 mM glucose (yield 9.2%). The generated strain produced 35 mM (4.8 g L(-1)) PABA from 167 mM glucose (yield 21.0%) in fed-batch culture. PMID- 25036693 TI - A design for the control of apoptosis in genetically modified Saccharomyces cerevisiae. AB - We have engineered a system that holds potential for use as a safety switch in genetically modified yeasts. Human apoptotic factor BAX (no homolog in yeast), under the control of the FBP1 (gluconeogenesis enzyme) promoter, was conditionally expressed to induce yeast cell apoptosis after glucose depletion. Such systems might prove useful for the safe use of genetically modified organisms. PMID- 25036694 TI - Felbamate as an add-on therapy for refractory epilepsy. AB - BACKGROUND: This review is an update of a previously published review in The Cochrane Database of Systematic Reviews (Issue 1, 2011) on 'Felbamate as an add on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and its effects as an add-on therapy to standard drugs are assessed in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (24 July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), and PubMed (24 July 2013). This search was run for the original review on 20 May 2010. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomized placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or crossover design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: Three randomised controlled trials with a total of 153 participants were included. The first was a parallel design, the second had a two-period crossover design, and the third had a three-period crossover design. One study was at unclear risk of bias for random sequence generation and allocation concealment. And in the same study, there was no description of how to blind outcome assessment, performance blinding was for participants, might not be for doctors. Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. None of the three studies reported 50% or greater reduction in seizure frequency. Only one study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measure, we have found no reliable evidence to support the use of felbamate as an add-on therapy in patients with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.Since the last version of this review no new studies have been found. PMID- 25036695 TI - Recent Research in Antihypertensive Activity of Food Protein-derived Hydrolyzates and Peptides. AB - Year to year obesity prevalence, reduced physical activities, bad habits/or stressful lifestyle, and other environmental and physiological impacts lead to increase in diseases such as coronary heart disease, stroke, cancer, diabetes, and hypertension worldwide. Hypertension is considered as one of the most common serious chronic diseases; however, discovery of medications with high efficacy and without side effects for treatment of patients remains a challenge for scientists. Recent trends in functional foods have evidenced that food bioactive proteins play a major role in the concepts of illness and curing; therefore, nutritionists, biomedical scientists, and food scientists are working together to develop improved systems for the discovery of peptides with increased potency and therapeutic benefits. This review presents a recent research carried out to date for the purpose of isolation and identification of bioactive hydrolyzates and peptides with angiotensin I converting enzyme inhibitory activity and antihypertensive effect from animal, marine, microbial, and plant food proteins. Effects of food processing and hydrolyzation conditions as well as some other impacts on formation, activity, and stability of these hydrolyzates and peptides are also presented. PMID- 25036696 TI - Thermoresponse improvement of poly(N-isopropylacrylamide) hydrogels via formation of poly(sodium p-styrenesulfonate) nanophases. AB - The block copolymer networks composed of poly(N-isopropylacrylamide) (PNIPAM) and poly(sodium p-styrenesulfonate) were synthesized via sequential reversible addition-fragmentation chain transfer (RAFT) polymerization with alpha,omega didithiobenzoate-terminated poly(sodium p-styrenesulfonate) (PSSNa) as the macromolecular chain transfer agent. It was found that the block copolymer networks were microphase-separated as evidenced by means of transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS). In the block copolymer networks, spherical or cylindrical PSSNa microdomains were finely dispersed into continuous PNIPAM matrixes. In comparison with unmodified PNIPAM hydrogel, the nanostructured hydrogels displayed improved thermoresponsive properties. In addition, the swelling ratios of the PSSNa-modified PNIPAM hydrogels were significantly higher than that of plain PNIPAM hydrogel. The improvement of thermoresponse was attributable to the formation of the PSSNa nanophases, which promoted the transportation of water molecules in the cross-linked networks. PMID- 25036697 TI - Experimental and theoretical study of the silica particle interactions in the presence of multivalent rod-like ions. AB - The silica particle interactions in the presence of spermidine were systematically investigated both from experimental and theoretical points of view. The hydrodynamic radii and the corresponding polydispersity indices of the colloidal silica particles were determined by dynamic light scattering (DLS) as a function of spermidine concentration. Whereas the effective size of the silica particles increases with increasing spermidine concentration (pointing to the particle aggregation), the polydispersity index first increases reaches a maximum and then further decreases with the increasing spermidine concentration. From the mobility measurements it was concluded that the increase in spermidine concentration causes less negative values of zeta potential, meaning that the adsorption of spermidine leads to the less negative silica surface. Moreover, Monte Carlo (MC) simulations also confirmed that the addition of spermidine reduces the repulsion between silica particles. The MC concentration profiles of spermidine close to the charged silica particle are in a very good agreement with the results obtained by theory. An important motivation for our study is the effectiveness of multivalent ions to coagulate colloidal suspensions; e.g., the multivalent ions are exploited in the water purification process. PMID- 25036698 TI - Photoactivatable fluorescein derivatives caged with a (3-hydroxy-2 naphthalenyl)methyl group. AB - The (3-hydroxy-2-naphthalenyl)methyl (NQMP) group represents an efficient photocage for fluorescein-based dyes. Thus, irradiation of the 6-NQMP ether of 2' hydroxymethylfluorescein with low-intensity UVA light results in a 4-fold increase in emission intensity. Photoactivation of nonfluorescent NQMP-caged 3 allyloxyfluorescein produces a highly emissive fluorescein monoether. To facilitate conjugation of the caged dye to the substrate of interest via click chemistry, the allyloxy appendage was functionalized with an azide moiety. PMID- 25036700 TI - The cystine/glutamate antiporter: when too much of a good thing goes bad. AB - Glutamate excitotoxicity represents a major cellular component of ischemic brain injury. In this issue of the JCI, Soria and colleagues reveal that the cystine/glutamate exchanger is an important source of excitotoxic glutamate in response to ischemia induced by oxygen and glucose deprivation. As the exchanger is a primary determinant of both extracellular glutamate and intracellular glutathione, the findings from this study not only provide important insight into the mechanisms of brain ischemia but also demonstrate the complexity of the yin and yang of glutamate homeostasis and cellular redox balance. PMID- 25036699 TI - Clostridium difficile and the microbiota. AB - Clostridium difficile infection (CDI) is the leading health care-associated illness. Both human and animal models have demonstrated the importance of the gut microbiota's capability of providing colonization resistance against C. difficile. Risk factors for disease development include antibiotic use, which disrupts the gut microbiota, leading to the loss of colonization resistance and subsequent CDI. Identification of the specific microbes capable of restoring this function remains elusive. Future studies directed at how microbial communities influence the metabolic environment may help elucidate the role of the microbiota in disease development. These findings will improve current biotherapeutics for patients with CDI, particularly those with recurrent disease. PMID- 25036701 TI - A brain network response to sham surgery. AB - Evaluation of potential therapies for neurological disease has been challenging due to beneficial responses in patients receiving the sham/placebo treatment. Placebo effects are especially prominent in Parkinson's disease (PD), which has become a useful model for studying the neurobiology of placebo responses. In this issue of the JCI, Ko and colleagues identify a neural circuit associated with the placebo response in a PD patient cohort. The observed placebo effect-associated pattern involved metabolic activity increases that corresponded with long-term motor improvements after sham surgery. Presurgery activity in this network was inversely related to sham response, suggesting that this network has potential for identifying sham responders and thus reducing placebo-related variance in surgical trials. PMID- 25036702 TI - Wetting the whistle: neurotropic factor improves salivary function. AB - Xerostomia, or dry mouth, is a common side effect of head and neck radiotherapy, Sjogren syndrome, diabetes, old age, and numerous medications. In this issue of the JCI, Xiao and colleagues identified glial cell line-derived neurotrophic factor (GDNF) as a potential stimulus for salivary stem cell growth. Due to its ability to promote neuronal growth, differentiation, and survival, GDNF is currently being used in clinical trials as a treatment for Parkinson disease; therefore, the findings of Xiao and colleagues may initiate a potential treatment for the millions of patients who suffer from xerostomia each year. PMID- 25036703 TI - A "kiss" before conception: triggering ovulation with kisspeptin-54 may improve IVF. AB - A 30-year-old primigravid (G1P000) female with infertility secondary to her partner's oligospermia and her chronic anovulation presented 13 days after an oocyte retrieval for in vitro fertilization (IVF) with a positive home pregnancy test, abdominal distention, a 5-pound weight gain, nausea, shortness of breath, and reduced urinary frequency. Her IVF cycle included the usual cocktail for gonadotropin stimulation and was uncomplicated, except for excessively stimulated ovaries that led to a peak estradiol level of 6,000 pg/ml and the retrieval of 30 oocytes. Her past history was relevant only for anovulation due to polycystic ovarian syndrome (PCOS), though her preprocedure body mass index was normal at 21 kg/m2. Pelvic ultrasound revealed abundant ascites and enlarged ovaries, at 8 cm average diameter. Serum human chorionic gonadotropin (hCG) concentration was 200 mIU/ml; she was hemoconcentrated (hemoglobin 16 g/dl), with normal liver function and coagulation testing. An ultrasound guided, transvaginal paracentesis removed 4 liters of straw-colored fluid, resulting in significant short-term symptom relief. PMID- 25036704 TI - Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification? AB - A hallmark of type 2 diabetes is the reduction of pancreatic islet beta cell mass through induction of apoptosis and lack of regeneration. In most patients, beta cell dysfunction is associated with the presence of extracellular amyloid plaques adjacent to beta cells and intracellular toxic oligomers that are comprised of islet amyloid polypeptide (IAPP). In this issue of the JCI, three independent research groups reveal that a functional autophagy system normally prevents the accumulation of toxic IAPP oligomers in human IAPP-expressing murine models. Furthermore, mice expressing human IAPP but deficient for beta cell autophagy through genetic deletion of the autophagy initiator ATG7 developed beta cell apoptosis and overt diabetes. Together, these studies indicate that autophagy protects beta cells from the accumulation of toxic IAPP oligomers and suggest that enhancing autophagy may be a novel target for prevention of type 2 diabetes. PMID- 25036705 TI - Amyloidogenic peptide oligomer accumulation in autophagy-deficient beta cells induces diabetes. AB - Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with beta cell-specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP. In mice with beta cell specific expression of hIAPP, a deficiency in autophagy resulted in development of overt diabetes, which was not observed in mice expressing hIAPP alone or lacking autophagy alone. Furthermore, lack of autophagy in hIAPP-expressing animals resulted in hIAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of beta cells. Expression of hIAPP in purified monkey islet cells or a murine beta cell line resulted in pro-hIAPP dimer formation, while dimer formation was absent or reduced dramatically in cells expressing either nonamyloidogenic mIAPP or nonfibrillar mutant hIAPP. In autophagy-deficient cells, accumulation of pro-hIAPP dimers increased markedly, and pro-hIAPP trimers were detected in the detergent-insoluble fraction. Enhancement of autophagy improved the metabolic profile of hIAPP-expressing mice fed a high-fat diet. These results suggest that autophagy promotes clearance of amyloidogenic hIAPP, autophagy deficiency exacerbates pathogenesis of human T2D, and autophagy enhancers have therapeutic potential for islet amyloid accumulation associated human T2D. PMID- 25036706 TI - Human IAPP-induced pancreatic beta cell toxicity and its regulation by autophagy. AB - Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of beta cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS 1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of beta cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on beta cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in beta cell mass, which was due to limited beta cell proliferation and enhanced beta cell apoptosis. Importantly, expression of hIAPP in mice with a beta cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance beta cell dysfunction and progression of T2DM. PMID- 25036707 TI - Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. AB - During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death. PMID- 25036708 TI - Autophagy defends pancreatic beta cells from human islet amyloid polypeptide induced toxicity. AB - Type 2 diabetes (T2D) is characterized by a deficiency in beta cell mass, increased beta cell apoptosis, and extracellular accumulation of islet amyloid derived from islet amyloid polypeptide (IAPP), which beta cells coexpress with insulin. IAPP expression is increased in the context of insulin resistance, the major risk factor for developing T2D. Human IAPP is potentially toxic, especially as membrane-permeant oligomers, which have been observed to accumulate within beta cells of patients with T2D and rodents expressing human IAPP. Here, we determined that beta cell IAPP content is regulated by autophagy through p62 dependent lysosomal degradation. Induction of high levels of human IAPP in mouse beta cells resulted in accumulation of this amyloidogenic protein as relatively inert fibrils within cytosolic p62-positive inclusions, which temporarily averts formation of toxic oligomers. Mice hemizygous for transgenic expression of human IAPP did not develop diabetes; however, loss of beta cell-specific autophagy in these animals induced diabetes, which was attributable to accumulation of toxic human IAPP oligomers and loss of beta cell mass. In human IAPP-expressing mice that lack beta cell autophagy, increased oxidative damage and loss of an antioxidant-protective pathway appeared to contribute to increased beta cell apoptosis. These findings indicate that autophagy/lysosomal degradation defends beta cells against proteotoxicity induced by oligomerization-prone human IAPP. PMID- 25036709 TI - Deciphering the tete-a-tete between the microbiota and the immune system. AB - The past decade has witnessed an explosion in studies--both clinical and basic science--examining the relationship between the microbiota and human health, and it is now clear that the effects of commensal organisms are much broader than previously believed. Among the microbiota's major contributions to host physiology is regulation of the development and maintenance of the immune system. There are now a handful of examples of intestinal commensal bacteria with defined immunomodulatory properties, but our mechanistic understanding of how microbes influence the immune system is still in its infancy. Nevertheless, several themes have emerged that provide a framework for appreciating microbe-induced immunoregulation. In this Review, we discuss the current state of knowledge regarding the role of the intestinal microbiota in immunologic development, highlighting mechanistic principles that can guide future work. PMID- 25036710 TI - Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. AB - Cells isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation. Kinase inhibitors of ATM, the gene mutated in ataxia telangiectasia, can sensitize tumor cells to radiation therapy, but concern that inhibiting ATM in normal tissues will also increase normal tissue toxicity from radiation has limited their clinical application. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but the role of endothelial cell death in tumor response to radiation therapy remains controversial. Here, we developed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm to determine whether loss of Atm in endothelial cells sensitizes tumors and normal tissues to radiation. Although deletion of Atm in proliferating tumor endothelial cells enhanced the response of sarcomas to radiation, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. Blocking cell cycle progression reversed the effect of Atm loss on tumor endothelial cell radiosensitivity. These results indicate that endothelial cells must progress through the cell cycle in order to be radiosensitized by Atm deletion. PMID- 25036711 TI - Neurotrophic factor GDNF promotes survival of salivary stem cells. AB - Stem cell-based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin-CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line-derived neurotrophic factor (Gdnf) is highly expressed in Lin-CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation induced xerostomia. PMID- 25036712 TI - Network modulation following sham surgery in Parkinson's disease. AB - Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials. PMID- 25036713 TI - Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. AB - BACKGROUND: Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS: Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS: Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION: This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01667406. PMID- 25036714 TI - Radiation and ATM inhibition: the heart of the matter. AB - Numerous in vitro studies have shown that human cell lines lacking functional ATM are extremely radiosensitive. In this issue, Moding et al. demonstrate using a murine model of sarcoma that deletion of the Atm gene has much less of a radiosensitizing effect on normal cardiac endothelia than on rapidly proliferating tumor endothelia. This work confounds our assumptions about the generality of the role of ATM in radiation sensitivity and the potential use of ATM inhibitors as radiosensitizers. PMID- 25036715 TI - Political diversity will improve social psychological science. AB - Psychologists have demonstrated the value of diversity--particularly diversity of viewpoints--for enhancing creativity, discovery, and problem solving. But one key type of viewpoint diversity is lacking in academic psychology in general and social psychology in particular: political diversity. This article reviews the available evidence and finds support for four claims: (1) Academic psychology once had considerable political diversity, but has lost nearly all of it in the last 50 years. (2) This lack of political diversity can undermine the validity of social psychological science via mechanisms such as the embedding of liberal values into research questions and methods, steering researchers away from important but politically unpalatable research topics, and producing conclusions that mischaracterize liberals and conservatives alike. (3) Increased political diversity would improve social psychological science by reducing the impact of bias mechanisms such as confirmation bias, and by empowering dissenting minorities to improve the quality of the majority's thinking. (4) The underrepresentation of non-liberals in social psychology is most likely due to a combination of self-selection, hostile climate, and discrimination. We close with recommendations for increasing political diversity in social psychology. PMID- 25036716 TI - Structural evaluation of tandem hairpin pyrrole-imidazole polyamides recognizing human telomeres. AB - A polyamide containing N-methylpyrrole (Py) and N-methylimidazole (Im), designated PIPA, binds with high affinity and specificity to specific nucleotide sequences in the minor groove of double-helical DNA. Based on a recent report of the synthesis of PIPA for telomere visualization, the present paper focused on the size of the connecting part (hinge region) of two PIPA segments of the tandem hairpin PIPA, Dab(Im-Im-Py)-Py-Py-Py-Im-[Hinge]-Dab(Im-Im-Py)-Py-Py-Py-Im-betaAla NH(CH2)3N(CH3)-(CH2)3NH-[Dye]. The present paper also describes the characterization of binding by measuring the thermal melting temperature and surface plasmon resonance and by specific staining of telomeres (TTAGGG)n in human cells. Microheterogeneity was also investigated by high-resolution mass spectrometry. We found that the optimal compound as the hinge segment for telomere staining was [-NH(C2H4O)2(C2H4)CO-] with tetramethylrhodamine as the fluorescent dye. PMID- 25036717 TI - Legg-Calve-Perthes disease and the risk of ADHD, depression, and mortality. AB - BACKGROUND AND PURPOSE: Hyperactive behavior pattern (such as attention deficit hyperactivity disorder (ADHD)) is proposed to be present in individuals with Legg Calve-Perthes disease (LCPD). We investigated whether individuals with LCPD have a higher risk of ADHD, depression, and mortality. SUBJECTS AND METHODS: We identified 4,057 individuals with LCPD in Sweden during the period 1964-2011. 40,570 individuals without LCPD were randomly selected from the Swedish general population and matched by year of birth, sex, and region (control group). We used Cox proportional hazard regression to estimate the relative risks. RESULTS: Compared to the control group, individuals with LCPD had a raised hazard ratio (HR) of 1.5 (95% CI: 1.2-1.9) for ADHD. The risks were higher for female individuals (HR = 2.1, CI: 1.3-3.5) than for male individuals (HR = 1.4, CI: 1.1 1.8). Individuals with LCPD had a modestly higher hazard ratio for depression (HR = 1.3, CI: 1.1-1.5) than the control group. Furthermore, individuals with LCPD had a slightly higher mortality risk than the control group (HR = 1.2, CI: 1.0 1.4) INTERPRETATION: Individuals with LCPD have a higher risk of ADHD. Hyperactivity could expose the femoral head to higher mechanical stress and contribute to the etiology of LCPD. The higher risk of depression may be due to the burden of LCPD itself or could reflect neurobehavioral aspects of ADHD changing into depression later in life. Individuals with LCPD have a higher mortality risk, with higher risk of suicide and cardiovascular diseases. PMID- 25036718 TI - Risk of re-admission, reoperation, and mortality within 90 days of total hip and knee arthroplasty in fast-track departments in Denmark from 2005 to 2011. AB - PURPOSE: To compare the risks of re-admission, reoperation, and mortality within 90 days of surgery in orthopedic departments with well-documented fast-track arthroplasty programs with those in all other orthopedic departments in Denmark from 2005 to 2011. METHODS: We used the Danish hip and knee arthroplasty registers to identify patients with primary total hip arthroplasty or total knee arthroplasty. Information about re-admission, reoperation, and mortality within 90 days of surgery was obtained from administrative databases. The fast-track cohort consisted of 6 departments. The national comparison cohort consisted of all other orthopedic departments. Regression methods were used to calculate relative risk (RR) of adverse events, adjusting for age, sex, type of fixation, and comorbidity. Cohorts were divided into 3 time periods: 2005-2007, 2008-2009, and 2010-2011. RESULTS: 79,098 arthroplasties were included: 17,284 in the fast track cohort and 61,814 in the national cohort. Median length of stay (LOS) was less for the fast-track cohort in all 3 time periods (4, 3, and 3 days as opposed to 6, 4, and 3 days). RR of re-admission due to infection was higher in the fast track cohort in 2005-2007 (1.3, 95% CI: 1.1-1.6) than in the national cohort in the same time period. This was mainly due to urinary tract infections. RR of re admission due to a thromboembolic event was lower in the fast-track cohort in 2010-2011 (0.7, CI: 0.6-0.9) than in the national cohort in the same time period. No differences were seen in the risk of reoperation and mortality between the 2 cohorts during any time period. INTERPRETATION: The general reduction in LOS indicates that fast-track arthroplasty programs have been widely implemented in Denmark. At the same time, it appears that dedicated fast-track departments have been able to optimize the fast-track program further without any rise in re admission, reoperation, and mortality rates. PMID- 25036719 TI - What is the optimal alignment of the tibial and femoral components in knee arthroplasty? AB - BACKGROUND: Surgeon-dependent factors such as optimal implant alignment are thought to play a significant role in outcome following primary total knee arthroplasty (TKA). Exact definitions and references for optimal alignment are, however, still being debated. This overview of the literature describes different definitions of component alignment following primary TKA for (1) tibiofemoral alignment in the AP plane, (2) tibial and femoral component placement in the AP plane, (3) tibial and femoral component placement in the sagittal plane, and (4) rotational alignment of tibial and femoral components and their role in outcome and implant survival. METHODS: We performed a literature search for original and review articles on implant positioning following primary TKA. Definitions for coronal, sagittal, and rotational placement of femoral and tibial components were summarized and the influence of positioning on survival and functional outcome was considered. RESULTS: Many definitions exist when evaluating placement of femoral and tibial components. Implant alignment plays a role in both survival and functional outcome following primary TKA, as component malalignment can lead to increased failure rates, maltracking, and knee pain. INTERPRETATION: Based on currently available evidence, surgeons should aim for optimal alignment of tibial and femoral components when performing TKA. PMID- 25036720 TI - Thermal epiphysiodesis performed with radio frequency in a porcine model. AB - BACKGROUND AND PURPOSE: Current techniques for epiphysiodesis involve opening of cortical windows; use of staples, screws, and tension devices; and fusion with curettes or drills. Complications may have serious consequences. There is a need for a more reliable, precise, and less traumatic procedure that overcomes the known complications from existing techniques. We analyzed a new epiphysiodesis technique using radio-frequency ablation (RFA) in a porcine model. METHODS: Six 35-kg and two 25-kg immature pigs were used. 1 hind leg of each animal was randomly selected and the proximal tibia growth plate was ablated laterally and medially. The contralateral leg was used as a control. MR images were obtained immediately after the ablation and 12 weeks later for 6 animals, and 24 weeks later for the other 2 animals. CT was done for the 2 animals that were followed for 24 weeks for proof of bone bridges. RESULTS: Both tibias were equal in length initially. At the 12-week follow-up, there was an average leg length discrepancy of 3.9 mm (95% CI: 3.0-4.8), and at 24 weeks the difference was 8.4 mm and 7.5 mm. No damage to the adjacent tissue was found. Bone bridges and physeal closure were found after 24 weeks. The pigs showed no discomfort after the intervention. INTERPRETATION: We found RFA to be feasible for epiphysiodesis in a pig model. The method is minimally invasive and recovery may be quick compared to conventional methods. We recommend that the method should be tested in larger scale safety studies before clinical application. PMID- 25036721 TI - Medial tibial stress syndrome: a skeleton from medieval Rhodes demonstrates the appearance of the bone surface--a case report. PMID- 25036722 TI - Determinants of the activity and substrate recognition of breast cancer resistance protein (ABCG2). AB - The xenobiotic transporters are among the most important constituents of detoxification system in living organisms. Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of xenobiotics. To understand its role in chemotherapeutic and multidrug resistance, it is crucial to establish the determinants of its substrate specificity, which obviously is of high relevance for successful therapy of many diseases. This article summarizes the current knowledge about the substrate preferences of BCRP. We overview the factors which determine its activity, inhibition and substrate recognition, focusing on the structural features of the transporter. BCRP substrate specificity is quite low as it interacts with a spectrum of substances with only a few common features: hydrophobic and aromatic regions, possibly a flat conformation and the metal ion-, oxygen- and nitrogen-containing functionalities, most of which may be the donors/acceptors of H-bonds. Several amino acid residues and structural motifs are responsible for BCRP activity and substrate recognition. Thus, the active form of BCRP, at least a dimer or a larger oligomer is maintained by intramolecular disulfide bridge that involves Cys(603) residues. The GXXXG motif in transmembrane helix 1, Cys residues, Arg(482) and Lys(86) are responsible for maintaining the protein structure, which confers transport activity, and the His(457) or Arg(456) residues are directly involved in substrate binding. Arg(482) does not directly bind substrates, but electrostatically interacts with charged molecules, which initiates the conformational changes that transmit the signal from the transmembrane regions to the ABC domain. PMID- 25036723 TI - Sleep disturbances and health-related quality of life in adults with steady-state bronchiectasis. AB - BACKGROUND: Sleep disturbances are common in patients with chronic lung diseases, but little is known about the prevalence in patients with bronchiectasis. A cross sectional study was conducted to investigate the prevalence and determinants associated with sleep disturbances, and the correlation between sleep disturbances and quality of life (QoL) in adults with steady-state bronchiectasis. METHODS: One hundred and forty-four bronchiectasis patients and eighty healthy subjects were enrolled. Sleep disturbances, daytime sleepiness, and QoL were measured by utilizing the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and St. George Respiratory Questionnaire (SGRQ), respectively. Demographic, clinical indices, radiology, spirometry, bacteriology, anxiety and depression were also assessed. RESULTS: Adults with steady-state bronchiectasis had a higher prevalence of sleep disturbances (PSQI>5) (57% vs. 29%, P<0.001), but not daytime sleepiness (ESS>=10) (32% vs. 30%, P = 0.76), compared with healthy subjects. In the multivariate model, determinants associated with sleep disturbances in bronchiectasis patients included depression (OR, 10.09; 95% CI, 3.46-29.37; P<0.001), nocturnal cough (OR, 1.89; 95% CI, 1.13 3.18; P = 0.016), aging (OR, 1.04; 95% CI, 1.01-1.07; P = 0.009) and increased 24 hour sputum volume (OR, 2.01; 95% CI, 1.22-3.33; P = 0.006). Patients with sleep disturbances had more significantly impaired QoL affecting all domains than those without. Only 6.2% of patients reported using a sleep medication at least weekly. CONCLUSIONS: In adults with steady-state bronchiectasis, sleep disturbances are more common than in healthy subjects and are related to poorer QoL. Determinants associated with sleep disturbances include depression, aging, nighttime cough and increased sputum volume. Assessment and intervention of sleep disturbances are warranted and may improve QoL. PMID- 25036725 TI - Patterns of adherence to and compliance with the Portuguese smoke-free law in the leisure-hospitality sector. AB - BACKGROUND: In 2008, the Portuguese smoke-free law came into effect including partial bans in the leisure-hospitality (LH) sector. The objective of the study is to assess the prevalence of smoking control policies (total ban, smoking permission and designated smoking areas) adopted by the LH sector in Portugal. The levels of noncompliance with each policy are investigated as well as the main factors associated with smoking permission and noncompliance with the law. METHODS: Cross-sectional study conducted between January 2010 and May 2011. A random sample of venues was selected from the Portuguese LH sector database, proportionally stratified according to type, size and geographical area. All venues were assessed in loco by an observer. The independent effects of venues' characteristics on smoking permission and the level of noncompliance with the law were explored using logistic regression. RESULTS: Overall, 1.412 venues were included. Total ban policy was adopted by 75.9% of venues, while 8.4% had designated smoking areas. Smoking ban was more prevalent in restaurants (85.9%). Only 29.7% of discos/bars/pubs opted for complete ban. Full or partial smoking permission was higher in discos/bar/pubs (OR = 7.37; 95%CI 4.87 to 11.17). Noncompliance with the law was higher in venues allowing smoking and lower in places with complete ban (33.6% and 7.6% respectively, p<0.001). Discos/bars/pubs with full smoking permission had the highest level of noncompliance (OR = 3.31; 95%CI 1.40 to 7.83). CONCLUSIONS: Our findings show a high adherence to smoking ban policy by the Portuguese LH sector. Nonetheless, one quarter of the venues is fully or partially permissive towards smoking, with the discos/bars/pubs considerably contributing to this situation. Venues with smoking permission policies were less compliant with the legislation. The implementation of a comprehensive smoke-free law, without any exceptions, is essential to effectively protect people from the second hand smoke. PMID- 25036724 TI - The associations between two vital GSTs genetic polymorphisms and lung cancer risk in the Chinese population: evidence from 71 studies. AB - BACKGROUND: The genetic polymorphisms of glutathione S-transferase (GSTs) have been suspected to be related to the development of lung cancer while the current results are conflicting, especially in the Chinese population. METHODS: Data on genetic polymorphisms of glutathione S-transferase Mu 1 (GSTM1) from 68 studies, glutathione S-transferase theta 1 (GSTT1) from 17 studies and GSTM1-GSTT1 from 8 studies in the Chinese population were reanalyzed on their association with lung cancer risk. Odds ratios (OR) were pooled using forest plots. 9 subgroups were all or partly performed in the subgroup analyses. The Galbraith plot was used to identify the heterogeneous records. Potential publication biases were detected by Begg's and Egger's tests. RESULTS: 71 eligible studies were identified after screening of 1608 articles. The increased association between two vital GSTs genetic polymorphisms and lung cancer risk was detected by random-effects model based on a comparable heterogeneity. Subgroup analysis showed a significant relationship between squamous carcinoma (SC), adenocarcinoma (AC) or small cell lung carcinoma (SCLC) and GSTM1 null genotype, as well as SC or AC and GSTT1 null genotype. Additionally, smokers with GSTM1 null genotype had a higher lung cancer risk than non-smokers. Our cumulative meta-analysis demonstrated a stable and reliable result of the relationship between GSTM1 null genotype and lung cancer risk. After the possible heterogeneous articles were omitted, the adjusted risk of GSTs and lung cancer susceptibility increased (fixed-effects model: ORGSTM1 = 1.23, 95% CI: 1.19 to 1.27, P<0.001; ORGSTT1 = 1.18, 95% CI: 1.10 to 1.26, P<0.001; ORGSTM1-GSTT1 = 1.33, 95% CI: 1.10 to 1.61, P = 0.004). CONCLUSIONS: An increased risk of lung cancer with GSTM1 and GSTT1 null genotype, especially with dual null genotype, was found in the Chinese population. In addition, special histopathological classification of lung cancers and a wide range of gene environment and gene-gene interaction analysis should be taken into consideration in future studies. PMID- 25036726 TI - Persistent frequent subclinical seizures and memory impairment after clinical remission in smoldering limbic encephalitis. AB - AIM: To delineate a possible correlation between clinical course and EEG abnormalities in non-infectious "smoldering" limbic encephalitis. METHODS: Long term clinical data, including video-EEG monitoring records, were analysed in two patients. RESULTS: The two patients were positive for anti-voltage-gated potassium channel complex antibody and unspecified antineuronal antibody, respectively. The latter patient had small cell lung carcinoma. Both patients had memory impairment and clinical seizures. EEG showed frequent subclinical seizure patterns in the bilateral temporal regions. Subclinical seizure patterns and memory impairment persisted over one to two years after clinical seizure remission. Therapy (prednisolone and chemoradiation in the two patients, respectively) resulted in decreased occurrence of subclinical seizure patterns and memory improvement. CONCLUSIONS: EEG seizure patterns may persist years after clinical seizure remission in "smoldering" limbic encephalitis and lead to memory impairment. PMID- 25036727 TI - Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs. AB - The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness. PMID- 25036728 TI - Factors underlying the psychological and behavioral characteristics of Office of Strategic Services candidates: the assessment of men data revisited. AB - During World War II, the Office of Strategic Services (OSS), the forerunner of the Central Intelligence Agency, sought the assistance of clinical psychologists and psychiatrists to establish an assessment program for evaluating candidates for the OSS. The assessment team developed a novel and rigorous program to evaluate OSS candidates. It is described in Assessment of Men: Selection of Personnel for the Office of Strategic Services (OSS Assessment Staff, 1948). This study examines the sole remaining multivariate data matrix that includes all final ratings for a group of candidates (n = 133) assessed near the end of the assessment program. It applies the modern statistical methods of both exploratory and confirmatory factor analysis to this rich and highly unique data set. An exploratory factor analysis solution suggested 3 factors underlie the OSS assessment staff ratings. Confirmatory factor analysis results of multiple plausible substantive models reveal that a 3-factor model provides the best fit to these data. The 3 factors are emotional/interpersonal factors (social relations, emotional stability, security), intelligence processing (effective IQ, propaganda skills, observing and reporting), and agency/surgency (motivation, energy and initiative, leadership, physical ability). These factors are discussed in terms of their potential utility for personnel selection within the intelligence community. PMID- 25036729 TI - Fat-tailed fluctuations in the size of organizations: the role of social influence. AB - Organizational growth processes have consistently been shown to exhibit a fatter than-Gaussian growth-rate distribution in a variety of settings. Long periods of relatively small changes are interrupted by sudden changes in all size scales. This kind of extreme events can have important consequences for the development of biological and socio-economic systems. Existing models do not derive this aggregated pattern from agent actions at the micro level. We develop an agent based simulation model on a social network. We take our departure in a model by a Schwarzkopf et al. on a scale-free network. We reproduce the fat-tailed pattern out of internal dynamics alone, and also find that it is robust with respect to network topology. Thus, the social network and the local interactions are a prerequisite for generating the pattern, but not the network topology itself. We further extend the model with a parameter delta that weights the relative fraction of an individual's neighbours belonging to a given organization, representing a contextual aspect of social influence. In the lower limit of this parameter, the fraction is irrelevant and choice of organization is random. In the upper limit of the parameter, the largest fraction quickly dominates, leading to a winner-takes-all situation. We recover the real pattern as an intermediate case between these two extremes. PMID- 25036732 TI - High-pressure polymorph of phosphorus nitride imide HP4N7 representing a new framework topology. AB - A new polymorph of phosphorus nitride imide HP4N7 has been synthesized under high pressure/high-temperature conditions from P3N5 and NH4Cl at 6 GPa and temperatures between 800 and 1300 degrees C. Its crystal structure was elucidated using single-crystal X-ray diffraction data. beta-HP4N7 (space group C2/c, no. 15, Z = 4, a = 12.873(2) A, b = 4.6587(4) A, c = 8.3222(8) A, beta = 102.351(3) degrees , R1 = 0.0485, wR2 = 0.1083) crystallizes in a new framework structure type that is made up of all-side vertex-sharing PN4 tetrahedra. The topology of the network is represented by the point symbol (3(2).4(2).5(2).6(3).7)(3(4).4(4).5(4).6(3)), and it has not been identified in other compounds so far. Structural differences between the two polymorphs of HP4N7 as well as the topological relationship to the recently discovered high pressure polymorph beta-HPN2 are discussed. Additionally, FTIR and solid-state NMR spectroscopy are used to corroborate the results of the structure determination. PMID- 25036730 TI - Personality traits modulate emotional and physiological responses to stress. AB - An individual's susceptibility to psychological and physical disorders associated with chronic stress exposure, for example, cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease. This study examined the relationships between personality and acute responses to stress in 125 healthy adults, using hierarchical linear regression. We assessed personality traits using the Multidimensional Personality Questionnaire (MPQ-BF), and responses to acute stress (cortisol, heart rate, blood pressure, mood) using a standardized laboratory psychosocial stress task, the Trier Social Stress Test. Individuals with high Negative Emotionality exhibited greater emotional distress and lower blood pressure responses to the Trier Social Stress Test. Individuals with high agentic Positive Emotionality exhibited prolonged heart rate responses to stress, whereas those with high communal Positive Emotionality exhibited smaller cortisol and blood pressure responses. Separate personality traits differentially predicted emotional, cardiovascular, and cortisol responses to a psychosocial stressor in healthy volunteers. Future research investigating the association of personality with chronic stress-related disease may provide further clues to the relationship between acute stress reactivity and susceptibility to disease. PMID- 25036731 TI - Effects of stress and dietary tryptophan enhancement on craving for alcohol in binge and non-binge heavy drinkers. AB - Stress is known to play an important role in alcohol abuse, whereas binge drinking may increase individuals' susceptibility to the development of alcohol dependence. We set out to investigate whether binge drinkers (BDs) or non-BDs (NBDs) are at a greater risk of an increase in their desire for alcohol following experimental stress induction (modified Trier Social Stress Test; Experiment 1) and to explore the biological mechanisms underlying such an effect (Experiment 2). Preclinical evidence suggests that serotonin may mediate stress-induced reinstatement of alcohol intake. We therefore tested whether dietary tryptophan (TRP) enhancement would modulate stress-induced desire for alcohol and whether it would affect the two populations (BD/NBD) differently. In Experiment 1 (14 NBDs, 10 BDs; mean weekly alcohol intake 50.64 U), stress induction selectively increased strong desire for alcohol compared with the nonstressful condition in BDs. Throughout the experiment, BDs reported greater negative reinforcement type of craving than NBDs, but also a higher expectancy of alcohol-induced negative effects. In Experiment 2, 41 participants (22 NBDs, 19 BDs; mean alcohol intake 38.81 U) were given either the TRP-rich (TRP+; 9 BDs, 11 NBD) or the control (CTR; 10 BD, 11 NBD) diet before undergoing stress induction. In BDs, the TRP+ diet prevented the stress-induced increase in strong desire that was observed in individuals receiving the CTR diet. In NBDs, the TRP+ diet appeared to facilitate an increase in strong desire. These findings suggest that BDs may indeed be at a greater risk than NBDs of an increase in their craving for alcohol when stressed. Furthermore, whereas enhancement of 5-hydroxytryptamine function may moderate the impact of stress on craving in BDs, it seems to facilitate stress-induced craving in NBDs, suggesting that the serotonergic system may be differentially involved depending on individual binge drinking status. PMID- 25036733 TI - Determination of native capsular polysaccharide structures of Streptococcus pneumoniae serotypes 39, 42, and 47F and comparison to genetically or serologically related strains. AB - The diversity of capsular polysaccharides of the bacterial pathogen Streptococcus pneumoniae leads to at least 91 different serotypes. While the genetic loci for capsular biosynthesis have been characterized for all serotypes, the determination of resultant polysaccharide structures remains incomplete. Here, we report the chemical structures of the capsular polysaccharides of serotypes 39, 42, and 47F from the genetic cluster 4, and discuss the structures in the context of structures from serologically and genetically related serotypes. Antigenic determinants can be approximated in this manner. The structure of the serotype 39 capsular polysaccharide is [formula: see text] and has identical composition to the capsular polysaccharide 10A, but two different linkages. The serotype 42 structure [formula: see text] closely resembles the genetically related serotype 35A, which does not contain residue A. The structure of the serotype 47F capsular polysaccharide [formula: see text] is somewhat different from a recently determined structure from the same serogroup, while containing a structural motif that is reflected in serotype 35A and 42 capsular polysaccharide structures, thus explaining the cross-reactivity of serotype 47F with the typing serum 35a. PMID- 25036734 TI - Surface dynamics of poly(methyl methacrylate) films affected by the concentration of casting solutions. AB - The effect of the concentration of casting solutions on the surface dynamics of the corresponding spin-coated poly(methyl methacrylate) (PMMA) film was investigated by measuring the surface reorganization of fluorine tracer-labeled PMMA. The onset temperature of fluorinated PMMA chain end reorganization (T(onsetR)) was identified and is shown to depend on the PMMA concentration in the film-forming solution. It was found that the surface T(onsetR) and relaxation activation energy E(a) of the PMMA films prepared from 4.2 wt% PMMA cyclohexanone solution are 70 degrees C and 260 kJ mol(-1), respectively, which are higher than those of the PMMA films prepared from 0.8 wt% PMMA cyclohexanone solution (55 degrees C and 144 kJ mol(-1), respectively). The T(onsetR) and E(a) of PMMA films increased with increasing concentration of casting solutions within the range of 1.8 wt% to 4 wt%. The chain entanglement of PMMA chains is proposed to be the speculative origin for these observed depressed dynamics of poly(methyl methacrylate) chains on the films' surface prepared using casting solutions of various concentrations. PMID- 25036735 TI - Inhibition of DNA topoisomerase II selectively reduces the threat of tumorigenicity following induced pluripotent stem cell-based myocardial therapy. AB - The advent of induced pluripotent stem cell (iPSC) technology creates new opportunities for transplant-based therapeutic strategies. The potential for clinical translation is currently hindered by the risk of dysregulated cell growth. Pluripotent stem cells reprogrammed by three-factor (Sox2, Klf, and Oct4) and four-factor (Sox2, Klf, Oct4, and c-Myc) strategies result in the capacity for teratogenic growth from residual pluripotent progeny upon in vivo transplantation. However, these pluripotent stem cells also have a stage-specific hypersensitivity to DNA-damaging agents that may allow separation of lineage specific therapeutic subpopulation of cells. We aimed to demonstrate the selective effect of DNA topoisomerase II inhibitor, etoposide, in eliminating pluripotent cells in the early cardiac progenitor population thus decreasing the effect of teratoma formation. Immunodeficient murine hearts were infarcted and received implantation of a therapeutic dose of cardiac progenitors derived from partially differentiated iPSCs. Etoposide-treated cell implantation reduced mass formation in the intracardiac and extracardiac chest cavity compared with the same dose of iPSC-derived cardiac progenitors in the control untreated group. In vivo bioluminescence imaging confirmed the localization and engraftment of transplanted cells in the myocardium postinjection in both groups. Comparatively, the equivalent cell population without etoposide treatment demonstrated a greater incidence and size of teratoma formation. Hence, pretreatment with genotoxic etoposide significantly lowered the threat of teratogenicity by purging the contaminating pluripotent cells, establishing an adjunctive therapy to further harness the clinical value of iPSC-derived cardiac regeneration. PMID- 25036737 TI - Threaded macromolecules as a versatile framework for biomaterials. AB - Polyrotaxanes (PRXs) are a class of supramolecular threaded macromolecules, in which cyclic molecules are threaded onto the main- or side-chain of polymers. To date, various studies have been conducted on the synthesis of PRXs, and various combinations of cyclic molecules and polymers that can form a PRX have been discovered. Among these combinations, PRXs composed of cyclodextrins (CDs) and a linear polymer have attracted much attention and have been investigated by many researchers. Because of the non-covalently associated characteristic of PRXs, these supermolecules exhibit unique properties, such as the dynamic motion of the threaded cyclic molecules along a polymer axle and complete dissociation of the supramolecular structure, that are never observed in other synthetic polymers. These inherent properties of PRXs are of interest in the design of novel biomaterials, such as hydrogels, scaffolds in tissue engineering, drug delivery carriers, and polymer-drug conjugates. Thus, various studies have been conducted to utilize PRXs as a framework for biomaterials. In this review, we describe the recent progress in biomaterial application of PRXs such as drug delivery and gene delivery. PMID- 25036738 TI - MiR-204 promotes apoptosis in oxidative stress-induced rat Schwann cells by suppressing neuritin expression. AB - Neuritin (Nrn1) is a neurotrophin that plays an important role in nervous system plasticity and repair following nerve injury. MicroRNAs (miRNAs) are a type of small non-coding RNA that regulate nearly all aspects of nerve development and survival, including apoptosis. Here it was found that miR-204 negatively regulates Nrn1 protein expression through direct interaction with Nrn1 transcript. Moreover, miR-204 activates cleaved caspase-3, enhancing the sensitivity of RSC96 Schwann cells to H2O2-induced oxidative stress and apoptosis. Thus, miR-204 expressed at a low level may create a microenvironment suitable for the repair of injured nerves by relieving the inhibition of Nrn1 transcription and stimulating the anti-apoptotic function of Schwann cells. These results provide novel insights into the roles of miR-204 in nerve injury and repair. PMID- 25036739 TI - Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death. AB - Calmodulin (CaM) association with the cardiac muscle ryanodine receptor (RyR2) regulates excitation-contraction coupling. Defective CaM-RyR2 interaction is associated with heart failure. A novel CaM mutation (CaM(F90L)) was recently identified in a family with idiopathic ventricular fibrillation (IVF) and early onset sudden cardiac death. We report the first biochemical characterization of CaM(F90L). F90L confers a deleterious effect on protein stability. Ca(2+)-binding studies reveal reduced Ca(2+)-binding affinity and a loss of co-operativity. Moreover, CaM(F90L) displays reduced RyR2 interaction and defective modulation of [(3)H]ryanodine binding. Hence, dysregulation of RyR2-mediated Ca(2+) release via aberrant CaM(F90L)-RyR2 interaction is a potential mechanism that underlies familial IVF. PMID- 25036741 TI - Amine-capped Co nanoparticles for highly efficient dehydrogenation of ammonia borane. AB - Highly efficient heterogeneous catalysts are desired for the development of new energy storage materials. The rational choice and use of capping ligands are of significant importance for performance optimization of metal nanoparticle (NP) catalysts. By exploiting amine-rich polyethylenimine (PEI) and graphene oxide (GO) as a NP support, we demonstrate that as a capping ligand, PEI deposited on GO provides a novel pathway able to simultaneously control the morphology, spatial distribution, surface active sites of cobalt (Co) NPs, and remarkably enhances their catalytic properties for the hydrolytic dehydrogenation of ammonia borane (AB). Such a synergistic effect enables the synthesized PEI-GO/Co catalysts to reveal extremely high dehydrogenation activities under atmosphere condition. A total turnover frequency of 39.9 molH2 min(-1) molCo(-1) and an apparent activation energy of 28.2 kJ mol(-1) make the catalytic performance of these PEI-GO/Co catalysts comparable to those of noble metal-based catalysts, including bimetallic and multimetallic catalysts. PMID- 25036740 TI - Dynamic and multi-pharmacophore modeling for designing polo-box domain inhibitors. AB - The polo-like kinase 1 (Plk1) is a critical regulator of cell division that is overexpressed in many types of tumors. Thus, a strategy in the treatment of cancer has been to target the kinase activity (ATPase domain) or substrate binding domain (Polo-box Domain, PBD) of Plk1. However, only few synthetic small molecules have been identified that target the Plk1-PBD. Here, we have applied an integrative approach that combines pharmacophore modeling, molecular docking, virtual screening, and in vitro testing to discover novel Plk1-PBD inhibitors. Nine Plk1-PBD crystal structures were used to generate structure-based hypotheses. A common pharmacophore model (Hypo1) composed of five chemical features was selected from the 9 structure-based hypotheses and used for virtual screening of a drug-like database consisting of 159,757 compounds to identify novel Plk1-PBD inhibitors. The virtual screening technique revealed 9,327 compounds with a maximum fit value of 3 or greater, which were selected and subjected to molecular docking analyses. This approach yielded 93 compounds that made good interactions with critical residues within the Plk1-PBD active site. The testing of these 93 compounds in vitro for their ability to inhibit the Plk1 PBD, showed that many of these compounds had Plk1-PBD inhibitory activity and that compound Chemistry_28272 was the most potent Plk1-PBD inhibitor. Thus Chemistry_28272 and the other top compounds are novel Plk1-PBD inhibitors and could be used for the development of cancer therapeutics. PMID- 25036742 TI - Cervical conization for cervical intraepithelial neoplasia (CIN) 2 and 3 in HIV positive women: a case-control study. AB - OBJECTIVE: The purposes of the study were to investigate the outcomes of cervical conization for cervical intraepithelial neoplasia (CIN) 2 and 3 in HIV-positive women and age-matched HIV-negative controls and to determine whether positive margin, positive endocervical curettage, CD4 count, or viral load was associated with the persistence of CIN 2,3 or residual CIN 2,3 on the specimen from repeat excision procedure or hysterectomy. MATERIALS AND METHODS: HIV-positive women and HIV-negative controls with CIN 2,3 on cervical conization were enrolled in the study. Patients who underwent repeat conization or hysterectomy were identified, and the specimens were evaluated for residual CIN 2,3. CD4 count and viral load within 8 weeks of procedure were analyzed. RESULTS: A total of 44 patients and 44 age-matched controls were identified. Persistent CIN 2,3 was diagnosed in 28 HIV positive (63.6%) and 14 HIV-negative patients (31.8%; odds ratio [OR] = 4.7, 95% confidence interval [CI] = 1.9-11.5, p < .001). In HIV-positive women, a positive margin was associated with a higher persistence rate after cervical conization (OR = 5.3, 95% CI = 1.17-24.14, p = .03). In HIV-negative patients, positive endocervical curettage was associated with a higher persistence rate after conization (OR = 12, 95% CI = 2.24-64.23, p = .004). Of HIV-positive women, 75% had residual CIN 2,3 on the specimen from repeat procedure compared to 45.2% of controls (OR = 3.6, 95% CI = 1.3-10.6, p = .018). CD4 count or viral load was not associated with the rate of residual disease or persistence rate after cervical conization, but the lowest OR that the sample size allowed to assess with 90% power was 5.02. CONCLUSIONS: HIV-positive women have a higher rate of residual disease and higher persistence rate after conization for CIN 2,3 than age-matched HIV-negative controls. PMID- 25036743 TI - Responses to the McGill Pain Questionnaire predict neuropathic pain medication use in women in with vulvar lichen sclerosus. AB - OBJECTIVE: The goal of this study was to test the hypothesis that responses to the McGill Pain Questionnaire are predictive of adjunctive neuropathic pain medication use by women with lichen sclerosus (LS). MATERIALS AND METHODS: This is a retrospective chart review of 430 women with vulvar LS treated at a tertiary referral vulvar care clinic. Demographics, responses to the McGill Pain Questionnaire, and use of neuropathic pain medications were collected. Bivariate and multivariable logistic regression analyses were performed to identify factors significantly associated with use of neuropathic pain medications. RESULTS: Of the 430 subjects, 119 (27.7%) used neuropathic pain medications for vulvar pain. Factors significantly associated with use of these medications include lower body mass index (odds ratio [OR] = 0.96, p = .02), non-White race (OR = 2.97, p = .05), and total McGill Pain Questionnaire score (OR = 1.05, p < .001). CONCLUSIONS: Vulvar pain is a common presenting symptom in women with LS. Responses to the McGill Pain Questionnaire may be helpful in the long-term management of women with LS as a screen to identify those patients who might benefit from adjunctive neuropathic pain medication use. PMID- 25036744 TI - Regime shift in sandy beach microbial communities following Deepwater Horizon oil spill remediation efforts. AB - Sandy beaches support a wide variety of underappreciated biodiversity that is critical to coastal ecosystems. Prior to the 2010 Deepwater Horizon oil spill, the diversity and function of supratidal beach sediment microbial communities along Gulf of Mexico coastlines were not well understood. As such, it was unclear if microbial community compositional changes would occur following exposure to beached oil, if indigenous communities could biodegrade oil, or how cleanup efforts, such as sand washing and sediment redistribution, would impact microbial ecosystem resiliency. Transects perpendicular to the shoreline were sampled from public beaches on Grand Isle, Louisiana, and Dauphin Island, Alabama, over one year. Prior to oil coming onshore, elevated levels of bacteria associated with fecal contamination were detected (e.g., Enterobacteriales and Campylobacterales). Over time, significant shifts within major phyla were identified (e.g., Proteobacteria, Firmicutes, Actinobacteria) and fecal indicator groups were replaced by taxa affiliated with open-ocean and marine systems (e.g., Oceanospirillales, Rhodospirillales, and Rhodobacterales). These new bacterial groups included putative hydrocarbon degraders, similar to those identified near the oil plume offshore. Shifts in the microbial community composition strongly correlated to more poorly sorted sediment and grain size distributional changes. Natural oceanographic processes could not account for the disrupted sediment, especially from the backshore well above the maximum high-tide levels recorded at these sites. Sand washing and tilling occurred on both open beaches from August through at least December 2010, which were mechanisms that could replace fecal indicator groups with open-ocean groups. Consequently, remediation efforts meant to return beaches to pre-spill compositions caused a regime shift that may have added potential ecosystem function, like hydrocarbon degradation, to the sediment. Future research will need to assess the persistence and impact of the newly formed microbial communities to the overall sandy beach ecosystems. PMID- 25036745 TI - Partial purification and characterization of a novel histidine decarboxylase from Enterobacter aerogenes DL-1. AB - Histidine decarboxylase (HDC) from Enterobacter aerogenes DL-1 was purified in a three-step procedure involving ammonium sulfate precipitation, Sephadex G-100, and DEAE-Sepharose column chromatography. The partially purified enzyme showed a single protein band of 52.4 kD on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The optimum pH for HDC activity was 6.5, and the enzyme was stable between pH 4 and 8. Enterobacter aerogenes HDC had optimal activity at 40 degrees C and retained most of its activity between 4 and 50 degrees C. HDC activity was reduced in the presence of numerous tested compounds. Particularly with SDS, it significantly (p < 0.01) inhibited enzyme activity. Conversely, Ca(2+) and Mn(2+) showed prominent activation effects (p < 0.01) with activity increasing to 117.20% and 123.42%, respectively. The Lineweaver-Burk plot showed that K m and V max values of the enzyme for L-histidine were 0.21 mM and 71.39 umol/min, respectively. In comparison with most HDCs from other microorganisms and animals, HDC from E. aerogenes DL-1 displayed higher affinity and greater reaction velocity toward L-histidine. PMID- 25036746 TI - Managing 'resistance': is adherence a target for treatment? AB - PURPOSE OF REVIEW: Adherence to preventive measures and prescribed medications is the cornerstone of the successful management of hypertension. The role of adherence is particularly important when treatments are not providing the expected clinical results, for example, in patients with resistant hypertension. The goal of this article is to review the recent observations regarding drug adherence in resistant hypertension. RECENT FINDINGS: Today, the role of drug adherence as a potential cause of resistant hypertension is largely underestimated. Most studies suggest that a low adherence to the prescribed medications can affect up to 50% of patients with resistant hypertension.A good adherence to therapy is generally associated with an improved prognosis. Nonetheless, adherence should probably not be a target for treatment per se because data on adherence should always be interpreted in the view of clinical results. In our opinion, the availability of reliable data on drug adherence would be a major help for physicians to manage patients apparently resistant to therapy. SUMMARY: The actual development of new drugs for hypertension is slow. Thus, focusing on drug adherence to the drugs available is an important way to improve blood pressure control in the population. More emphasis should be put on measuring drug adherence in patients with resistant hypertension to avoid costly investigations and treatments. PMID- 25036747 TI - Targeting the immune system to treat hypertension: where are we? AB - PURPOSE OF REVIEW: Research over the past decade has significantly deepened our understanding of mechanisms that drive the development of hypertension. In particular, a novel paradigm of inflammation as a common mediator of cardiovascular and kidney disease has emerged. This review will summarize the role of the immune system in cardiovascular disease, explore some of the most promising new therapeutic directions and consider their potential as new treatments for hypertension. RECENT FINDINGS: Recent data continue to demonstrate that targeting the immune system can prevent hypertension in a variety of experimental models. Tempering the enthusiasm for a long-awaited new approach to treating hypertension is decades of clinical data, showing that classic immunosuppression regimens are associated with significant side-effects - including cardiovascular disease - that effectively preclude their use in the setting of chronic hypertension. New, more specific therapies are being developed that target cytokines including IL-17, IL-6 and TNFalpha. SUMMARY: Preclinical data convincingly demonstrate a key role for the immune system and specific cytokine mediators. Several biotherapeutics targeting these pathways are on the market and more are in development. Side-effects, however, continue to resemble those of classic immunosuppressants, highlighting the challenge of translating these research advances into new therapies for hypertension. VIDEO ABSTRACT: http://links.lww.com/CONH/A9. PMID- 25036748 TI - An AUG codon conserved for protein function rather than translational initiation: the story of the protein sElk1. AB - Elk1 belongs to the ternary complex (TCF) subfamily of the ETS-domain transcription factors. Several studies have implicated an important function for Elk1 in the CNS including synaptic plasticity and cell differentiation. Whilst studying ELK1 gene expression in rat brain a 54 aa N-terminally truncated isoform lacking the DBD was observed on immunoblots. A similar protein was also detected in NGF differentiated PC12 cells. It was proposed that this protein, referred to as sElk1, arose due to a de-novo initiation event at the second AUG codon on the Elk1 ORF. Transient over-expression of sElk1 potentiated neurite growth in the PC12 model and induced differentiation in the absence of NGF, leading to the proposition that it may have a specific function in the CNS. Here we report on the translational expression from the mouse and rat transcript and compare it with our earlier published work on human. Results demonstrate that the previously observed sElk1 protein is a non-specific band arising from the antibody employed. The tight conservation of the internal AUG reported to drive sElk1 expression is in fact coupled to Elk1 protein function, a result consistent with the Elk1-SRE crystal structure. It is also supported by the observed conservation of this methionine in the DBD of all ETS transcription factors independent of the N- or C terminal positioning of this domain. Reporter assays demonstrate that elements both within the 5'UTR and downstream of the AUGElk1 serve to limit 40S access to the AUGsElk1 codon. PMID- 25036749 TI - Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery. AB - One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology. PMID- 25036751 TI - Enantioselective, continuous (R)- and (S)-2-butanol synthesis: achieving high space-time yields with recombinant E. coli cells in a micro-aqueous, solvent-free reaction system. AB - The stereoselective production of (R)- or (S)-2-butanol is highly challenging. A potent synthesis strategy is the biocatalytic asymmetric reduction of 2-butanone applying alcohol dehydrogenases. However, due to a time-dependent racemisation process, high stereoselectivity is only obtained at incomplete conversion after short reaction times. Here, we present a solution to this problem: by using a continuous process, high biocatalytic selectivity can be achieved while racemisation is suppressed successfully. Furthermore, high conversion was achieved by applying recombinant, lyophilised E. coli cells hosting Lactobacillus brevis alcohol dehydrogenase in a micro-aqueous solvent-free continuous reaction system. The optimisation of residence time (tau) and 2-butanone concentration boosted both conversion (>99%) and enantiomeric excess (ee) of (R)-2-butanol (>96%). When a residence time of only tau=3.1 min was applied, productivity was extraordinary with a space-time yield of 2278+/-29g/(L*d), thus exceeding the highest values reported to date by a factor of more than eight. The use of E. coli cells overexpressing an ADH of complementary stereoselectivity yielded a synthesis strategy for (S)-2-butanol with an excellent ee (>98%). Although conversion was only moderate (up to 46%), excellent space-time yields of up to 461g/(L*d) were achieved. The investigated concept represents a synthesis strategy that can also be applied to other biocatalytic processes where racemisation poses a challenge. PMID- 25036752 TI - New examples of membrane protein expression and purification using the yeast based Pdr1-3 expression strategy. AB - Overexpression and purification of membrane proteins has been a bottleneck for their functional and structural study for a long time. Both homologous and heterologous expression of membrane proteins with suitable tags for purification presents unique challenges for cloning and expression. Saccharomyces cerevisiae is a potential host system with significant closeness to higher eukaryotes and provides opportunity for attempts to express membrane proteins. In the past, bakers yeast containing mutations within the transcriptional regulator Pdr1 has been used to overexpress various membrane proteins including for example the ABC transporters Pdr5 and Yor1, respectively. In this study we exploited this system and tried to express and purify 3 membrane proteins in yeast along with Pdr5 and Yor1 viz. Rsb1, Mdl1 and Drs2 by virtue of an N-terminal 14-histidine affinity tag. Out of these five, we could express all membrane proteins although at different levels. Satisfactory yields were obtained for three examples i.e. Pdr5, Yor1 and Drs2. Rsb1 expression was comparatively low and Mdl1 was rather unsatisfactory. Thus, we demonstrate here the application of this yeast based expression system that is suitable for cloning, expression and purification of a wide variety of membrane proteins. PMID- 25036750 TI - Accelerated neuronal differentiation toward motor neuron lineage from human embryonic stem cell line (H9). AB - Motor neurons loss plays a pivotal role in the pathoetiology of various debilitating diseases such as, but not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy. However, advancement in motor neuron replacement therapy has been significantly constrained by the difficulties in large-scale production at a cost-effective manner. Current methods to derive motor neuron heavily rely on biochemical stimulation, chemical biological screening, and complex physical cues. These existing methods are seriously challenged by extensive time requirements and poor yields. An innovative approach that overcomes prior hurdles and enhances the rate of successful motor neuron transplantation in patients is of critical demand. Iron, a trace element, is indispensable for the normal development and function of the central nervous system. Whether ferric ions promote neuronal differentiation and subsequently promote motor neuron lineage has never been considered. Here, we demonstrate that elevated iron concentration can drastically accelerate the differentiation of human embryonic stem cells (hESCs) toward motor neuron lineage potentially via a transferrin mediated pathway. HB9 expression in 500 nM iron treated hESCs is approximately twofold higher than the control. Moreover, iron treatment generated more matured and functional motor neuron-like cells that are ~1.5 times more sensitive to depolarization when compared to the control. Our methodology renders an expedited approach to harvest motor neuron-like cells for disease, traumatic injury regeneration, and drug screening. PMID- 25036753 TI - Ultrasonographic findings of type IIIa biliary atresia. AB - PURPOSE: To describe the ultrasonographic (US) findings of type IIIa biliary atresia. METHODS: We retrospectively reviewed a medical database of patients pathologically confirmed to have biliary atresia, Kasai type IIIa, between January 2002 and May 2013 (n=18). We evaluated US findings including the visible common bile duct (CBD), triangular cord thickness, gallbladder size and shape, and subcapsular flow on color Doppler US; laboratory data; and pathological hepatic fibrosis grades. We divided them into two groups-those with visible (group A) and invisible (group B) CBD on US-and compared all parameters between the two groups. RESULTS: CBD was visible on US in five cases (27.8%; group A) and invisible in 13 cases (72.2%; group B). US was performed at an earlier age in group A than in group B (median, 27 days vs. 60 days; P=0.027) with the maximal age of 51 days. A comparison of the US findings revealed that the triangular cord thickness was smaller (4.1 mm vs. 4.9 mm; P=0.004) and the gallbladder length was larger (20.0 mm vs. 11.7 mm; P=0.021) in group A. The gallbladder shape did not differ between the two groups, and the subcapsular flow was positive in all cases of both groups. There was no significant difference in the laboratory data between the two groups. Upon pathological analysis, group A showed low-grade and group B showed low- to high-grade hepatic fibrosis. CONCLUSION: When CBD is visible on US in patients diagnosed with type IIIa biliary atresia, other US features could have a false negative status. A subcapsular flow on the color Doppler US would be noted in the type IIIa biliary atresia patients. PMID- 25036754 TI - Interobserver agreement on the interpretation of automated whole breast ultrasonography. AB - PURPOSE: The purpose of this study was to prospectively evaluate the interobserver agreement on lesion characterization and the final assessment of automated whole breast ultrasonography (ABUS) images. METHODS: Between March and August 2012, 172 women underwent bilateral ABUS before biopsy guided by handheld ultrasonography (HHUS) and mammography. A total of 206 breast lesions were confirmed histopathologically by biopsy. Three-dimensional volume data from ABUS scans were analyzed by two radiologists without the knowledge of HHUS results or patient clinical information. The two readers described the type, shape, orientation, margin, echogenicity, posterior acoustic features, and categorization of the final assessment of detected breast lesions. Kappa statistics were used to analyze the described characteristics of the breast lesions detected by both of the two readers. RESULTS: Of the 206 histopathologically confirmed lesions, reader 1 detected 166 lesions and reader 2 detected 150 lesions. A total of 145 lesions were detected by both readers using ABUS images. There was substantial agreement on shape (kappa=0.707), and moderate agreement on type, margin, mass orientation, echogenicity, and posterior acoustic features (kappa=0.592, 0.438, 0.472, 0.524, and 0.541, respectively). Breast Imaging Reporting and Data System final assessment values yielded a kappa value of 0.3971 when category subdivisions 4A, 4B, and 4C were included. With respect to the C2, C3, C4, and C5 categories, the interobserver agreement was moderate (kappa=0.505). CONCLUSION: ABUS is a promising diagnostic tool with a good interobserver agreement, comparable to that of HHUS. PMID- 25036755 TI - Vacuum-assisted breast biopsy under ultrasonographic guidance: analysis of a 10 year experience. AB - PURPOSE: To determine the indications and the diagnostic accuracy of vacuum assisted breast biopsy (VABB) under ultrasonographic (US) guidance based on a 10 year period of clinical use. METHODS: This was a retrospective analysis of 2,920 breast lesions in 2,477 consecutive patients who underwent US-guided VABB between February 2002 and December 2011. The proportions of each indication for VABB were analyzed as well as the trend of its use over divided time periods. Histopathological diagnosis and the malignancy rate of the lesions with VABB were analyzed. A comparison of the pathological diagnosis of VABB and the gold standard diagnosis revealed the false negative rate, the underestimation rate, and the agreement rate. RESULTS: Palpable lesions (44.4%), low-suspicion lesions (15.7%), high-risk lesions (12.4%), and calcifications (10.3%) were the most common indications for US-guided VABB. The malignancy rate of lesions submitted to VABB was 5.4%. The false negative rate was only 0.1%, while the underestimation rate of high-risk lesions and ductal carcinoma in situ was 3.1% and 13.8%, respectively, with a 98.7% agreement rate. Among 1,512 therapeutic VABB cases, 84.9% showed no residual or recurrent lesions on long term follow-up US for more than a year. Complications occurred in 1% of the patients without need for surgical intervention. CONCLUSION: US-guided VABB is an accurate and safe method that can help decision-making in the diagnostic process and can be an alternative for excisional surgery in some therapeutic circumstances. PMID- 25036757 TI - Anionic derivatives of uracil: fragmentation and reactivity. AB - Uracil is an essential biomolecule for terrestrial life, yet its prebiotic formation mechanisms have proven elusive for decades. Meteorites have been shown to contain uracil and the interstellar abundance of aromatic species and nitrogen containing molecules is well established, providing support for uracil's presence in the interstellar medium (ISM). The ion chemistry of uracil may provide clues to its prebiotic synthesis and role in the origin of life. The fragmentation of biomolecules provides valuable insights into their formation. Previous research focused primarily on the fragmentation and reactivity of cations derived from uracil. In this study, we explore deprotonated uracil-5-carboxylic acid and its anionic fragments to elucidate novel reagents of uracil formation and to characterize the reactivity of uracil's anionic derivatives. The structures of these fragments are identified through theoretical calculations, further fragmentation, experimental acidity bracketing, and reactivity with several detected and potential interstellar species (SO2, OCS, CS2, NO, N2O, CO, NH3, O2, and C2H4). Fragmentation is achieved through collision induced dissociation (CID) in a commercial ion trap mass spectrometer, and all reaction rate constants are measured using a modification of this instrument. Experimental data are supported by theoretical calculations at the B3LYP/6-311++G(d,p) level of theory. Lastly, the astrochemical implications of the observed fragmentation and reaction processes are discussed. PMID- 25036756 TI - Fusion imaging of real-time ultrasonography with CT or MRI for hepatic intervention. AB - With the technical development of ultrasonography (US), electromagnetic tracking based fusion imaging of real-time US and computed tomography/magnetic resonance (CT/MR) images has been used for percutaneous hepatic intervention such as biopsy and radiofrequency ablation (RFA). Because of the fusion imaging technique, the fused CT or MR images show the same plane and move synchronously while performing real-time US. With this information, fusion imaging can enhance lesion detectability and reduce the false positive detection of focal hepatic lesions with poor sonographic conspicuity. Three-dimensional US can also be fused with realtime US for the percutaneous RFA of liver tumors requiring overlapping ablation. When fusion imaging is not sufficient for identifying small focal hepatic lesions, contrast-enhanced US can be added to fusion imaging. PMID- 25036758 TI - Risk factors for repetitive ileocolic resection in patients with Crohn's disease: results of an observational cohort study. AB - BACKGROUND: Surgical recurrence rates among patients with Crohn's disease with ileocolic resection (ICR) remain high, and factors predicting surgical recurrence remain controversial. We aimed to identify risk and protective factors for repetitive ICRs among patients with Crohn's disease in a large cohort of patients. METHODS: Data on 305 patients after first ICR were retrieved from our cross-sectional and prospective database (median follow-up: 15 yr [0-52 yr]). Data were compared between patients with 1 (ICR = 1, n = 225) or more than 1 (ICR >1, n = 80) resection. Clinical phenotypes were classified according to the Montreal Classification. Gender, family history of inflammatory bowel disease, smoking status, type of surgery, immunomodulator, and biological therapy before, parallel to and after first ICR were analyzed. RESULTS: The mean duration from diagnosis until first ICR did not differ significantly between the groups, being 5.93 +/- 7.65 years in the ICR = 1 group and 5.36 +/- 6.35 years in the ICR >1 group (P = 0.05). Mean time to second ICR was 6.7 +/- 5.74 years. In the multivariate logistic regression analysis, ileal disease location (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.02-5.78; P = 0.05) was a significant risk factor. A therapy with immunomodulators at time of or within 1 year after first ICR (OR, 0.23; 95% CI, 0.09-0.63; P < 0.01) was a protective factor. Neither smoking (OR, 1.16; 95% CI, 0.66-2.06) nor gender (male OR, 0.85; 95% CI, 0.51-1.42) or family history (OR, 1.68; 95% CI, 0.84-3.36) had a significant impact on surgical recurrence. CONCLUSIONS: Immunomodulators have a protective impact regarding surgical recurrence after ICR. In contrast, ileal disease location constitutes a significant risk factor for a second ICR. PMID- 25036760 TI - IL-12 and IL-18 induce interferon-gamma production and de novo CD2 expression in porcine gammadelta T cells. AB - gammadelta T cells are highly abundant in the blood and spleen of pigs but little is known about their functional differentiation. In this study the potential of the type-1 polarizing cytokines IL-12 and IL-18 in combination with IL-2 and Concanavalin A (ConA) to stimulate porcine gammadelta T cells was investigated. Stimulation of purified gammadelta T cells with ConA and IL-2 induced a strong proliferation of CD2(-) gammadelta T cells, whereas additional stimulation with IL-12 and IL-18 caused a stronger proliferation of CD2(+) gammadelta T cells. IFN gamma could only be detected in supernatants of gammadelta T-cell cultures supplemented with IL-12 and IL-18. Experiments with sorted CD2/SWC5-defined gammadelta T-cell subsets revealed that CD2(+)SWC5(-) gammadelta T cells are the main producers of IFN-gamma following stimulation with IL-2/IL-12/IL-18. Additional stimulation with ConA led to an upregulation of CD2 within the CD2(-) gammadelta T cell subsets, indicating a previously unnoticed plasticity of CD2 defined gammadelta T cell subsets. PMID- 25036761 TI - Characterization and expression analysis of an interferon-gamma2 induced chemokine receptor CXCR3 in common carp (Cyprinus carpio L.). AB - Chemokine and chemokine receptor signalling pairs play a crucial role in regulation of cell migration, morphogenesis, and cell activation. Expressed in mammals on activated T and NK cells, chemokine receptor CXCR3 binds interferon gamma inducible chemokines CXCL9-11 and CCL21. Here we sequenced the carp CXCR3 chemokine receptor and showed its relationship to CXCR3a receptors found in other teleosts. We found high expression of the CXCR3 gene in most of the organs and tissues of the immune system and in immune-related tissues such as gills and gut, corroborating a predominantly immune-related function. The very high expression in gill and gut moreover indicates a role for CXCR3 in cell recruitment during infection. High in vivo expression of CXCR3 at later stages of inflammation, as well as its in vitro sensitivity to IFN-gamma2 stimulation indicate that in carp, CXCR3 is involved in macrophage-mediated responses. Moreover, as expression of the CXCR3 and CXCb genes coincides in the focus of inflammation and as both the CXCb chemokines and the CXCR3 receptor are significantly up-regulated upon IFN gamma stimulation it is hypothesized that CXCb chemokines may be putative ligands for CXCR3. PMID- 25036759 TI - High-throughput sorting of the highest producing cell via a transiently protein anchored system. AB - Developing a high-throughput method for the effecient selection of the highest producing cell is very important for the production of recombinant protein drugs. Here, we developed a novel transiently protein-anchored system coupled with fluorescence activated cell sorting (FACS) for the efficient selection of the highest producing cell. A furin cleavage peptide (RAKR) was used to join a human anti-epithelial growth factor antibody (alphaEGFR Ab) and the extracellular transmembrane-cytosolic domains of the mouse B7-1 antigen (B7). The furin inhibitor can transiently switch secreted alphaEGFR Ab into a membrane-anchored form. After cell sorting, the level of membrane alphaEGFR Ab-RAKR-B7 is proportional to the amount of secreted alphaEGFR Ab in the medium. We further selected 23 alphaEGFR Ab expressing cells and demonstrated a high correlation (R2 = 0.9165) between the secretion level and surface expression levels of alphaEGFR Ab. These results suggested that the novel transiently protein-anchored system can easily and efficiently select the highest producing cells, reducing the cost for the production of biopharmaceuticals. PMID- 25036762 TI - Clitic pronouns reveal the time course of processing gender and number in a second language. AB - This study investigates grammatical gender and number processing marked on clitic pronouns in native Spanish speakers and in late English-Spanish bilinguals using ERPs. Spanish clitic pronouns were chosen as a critical grammatical structure which is absent in English, and which encodes both grammatical gender and number. Number, but not grammatical gender, is present in English, making this structure a prime one to investigate second language processing. Results reveal a P600 effect in native speakers for violations of both gender and number. Late but relatively proficient English-Spanish bilinguals show a P600 effect only for number violations occurring at the clitic pronoun, but not for gender violations. However a post-hoc analysis reveals that a subset of highly proficient late bilinguals does reveal sensitivity to violations of grammatical gender marked on clitic pronouns. Taken together these results suggest that native-like processing is possible for highly proficient late second language learners for grammatical features that are not present in the speakers' native language, even when those features are encoded on a grammatical morpheme which itself is absent in the speakers' native language. PMID- 25036763 TI - The quality of laboratory aspects of troponin testing in clinical practice guidelines and consensus documents needs to be improved. AB - OBJECTIVE: The European Federation of Laboratory Medicine (EFLM) and the Union of European Medical Specialists (UEMS) joint Working Group on guidelines recently proposed a checklist to help standardize the description of laboratory investigations in clinical practice guidelines (CPG). METHODS: Nine CPGs or consensus documents published from 2011 to 2013 describing the investigation of chest pain, diagnosis of acute coronary syndrome, or myocardial infarction were evaluated against the published checklist. RESULTS: Clinical use of troponin analysis are commonly dealt with but the publications present variable, vague and sometimes conflicting information regarding this laboratory test being very much relied on upon making a diagnosis of acute coronary syndrome. Most of the laboratory related checklist items are not considered or need to be updated e.g. suggested analytical quality goals are not applicable for the high sensitive assays and important interferences that may lead to false positive or negative diagnoses are commonly not mentioned. CONCLUSION: The current paper sums up important analytical and biological issues related to troponin assays and gives suggestions for analytical quality goals that could be included in CPG's. PMID- 25036764 TI - PCSK9 and lipid lowering drugs. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel circulating protein, which plays an important role in the regulation of cholesterol metabolism. Over the past decade, experimental and clinical studies have established that over- or poor expression of PCSK9 had a key impact not only on circulating PCSK9 and low density lipoprotein cholesterol (LDL-C) levels but also on cardiovascular risk and atherosclerotic process. Since the first discovery of PCSK9-related gene in 2003, factors that can influence circulating PCSK9 concentration are of great interest in a variety of medical fields, especially in pharmacology. In this review we focus on the impact of lipid-lowering drugs on circulating PCSK9 concentration and its clinical implications in order to optimal consideration for the current strategies with regard to cholesterol control. PMID- 25036765 TI - Safe azathioprine treatment in a pediatric ulcerative colitis patient with TPMT*16 by thiopurine metabolite monitoring. PMID- 25036766 TI - A data-driven approach to reverse engineering customer engagement models: towards functional constructs. AB - Online consumer behavior in general and online customer engagement with brands in particular, has become a major focus of research activity fuelled by the exponential increase of interactive functions of the internet and social media platforms and applications. Current research in this area is mostly hypothesis driven and much debate about the concept of Customer Engagement and its related constructs remains existent in the literature. In this paper, we aim to propose a novel methodology for reverse engineering a consumer behavior model for online customer engagement, based on a computational and data-driven perspective. This methodology could be generalized and prove useful for future research in the fields of consumer behaviors using questionnaire data or studies investigating other types of human behaviors. The method we propose contains five main stages; symbolic regression analysis, graph building, community detection, evaluation of results and finally, investigation of directed cycles and common feedback loops. The 'communities' of questionnaire items that emerge from our community detection method form possible 'functional constructs' inferred from data rather than assumed from literature and theory. Our results show consistent partitioning of questionnaire items into such 'functional constructs' suggesting the method proposed here could be adopted as a new data-driven way of human behavior modeling. PMID- 25036767 TI - Simultaneous and spectroscopic redox molecular imaging of multiple free radical intermediates using dynamic nuclear polarization-magnetic resonance imaging. AB - Redox reactions that generate free radical intermediates are essential to metabolic processes. However, their intermediates can produce reactive oxygen species, which may promote diseases related to oxidative stress. We report here the use of dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) to conduct redox molecular imaging. Using DNP-MRI, we obtained simultaneous images of free radical intermediates generated from the coenzyme Q10 (CoQ10), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) involved in the mitochondrial electron transport chain as well as the radicals derived from vitamins E and K1. Each of these free radicals was imaged in real time in a phantom comprising a mixture of free radicals localized in either lipophilic or aqueous environments. Changing the frequency of electron spin resonance (ESR) irradiation also allowed each of the radical species to be distinguished in the spectroscopic images. This study is the first to report the spectroscopic DNP-MRI imaging of free radical intermediates that are derived from endogenous species involved in metabolic processes. PMID- 25036768 TI - Mother-infant mutual eye gaze supports emotion regulation in infancy during the Still-Face paradigm. AB - This study was designed to examine the sequential relationship between mother infant synchrony and infant affect using multilevel modeling during the Still Face paradigm. We also examined self-regulatory behaviors that infants use during the Still-Face paradigm to modulate their affect, particularly during stressors where their mothers are not available to help them co-regulate. There were 84 mother-infant dyads, of healthy full term 4 month old infants. Second-by-second coding of infant self-regulation and infant affect was done, in addition to mother-infant mutual eye gaze. Using multilevel modeling, we found that infant affect became more positive when mutual gaze had occurred the previous second, suggesting that the experience of synchronicity was associated with observable shifts in affect. We also found a positive association between self-regulatory behaviors and increases in positive affect only during the Still-Face episode (episode 2). Our study provides support for the role of mother-infant synchronicity in emotion regulation as well as support for the role of self regulatory behaviors in emotion regulation that can have important implication for intervention. PMID- 25036769 TI - On combining image-based and ontological semantic dissimilarities for medical image retrieval applications. AB - Computer-assisted image retrieval applications can assist radiologists by identifying similar images in archives as a means to providing decision support. In the classical case, images are described using low-level features extracted from their contents, and an appropriate distance is used to find the best matches in the feature space. However, using low-level image features to fully capture the visual appearance of diseases is challenging and the semantic gap between these features and the high-level visual concepts in radiology may impair the system performance. To deal with this issue, the use of semantic terms to provide high-level descriptions of radiological image contents has recently been advocated. Nevertheless, most of the existing semantic image retrieval strategies are limited by two factors: they require manual annotation of the images using semantic terms and they ignore the intrinsic visual and semantic relationships between these annotations during the comparison of the images. Based on these considerations, we propose an image retrieval framework based on semantic features that relies on two main strategies: (1) automatic "soft" prediction of ontological terms that describe the image contents from multi-scale Riesz wavelets and (2) retrieval of similar images by evaluating the similarity between their annotations using a new term dissimilarity measure, which takes into account both image-based and ontological term relations. The combination of these strategies provides a means of accurately retrieving similar images in databases based on image annotations and can be considered as a potential solution to the semantic gap problem. We validated this approach in the context of the retrieval of liver lesions from computed tomographic (CT) images and annotated with semantic terms of the RadLex ontology. The relevance of the retrieval results was assessed using two protocols: evaluation relative to a dissimilarity reference standard defined for pairs of images on a 25-images dataset, and evaluation relative to the diagnoses of the retrieved images on a 72-images dataset. A normalized discounted cumulative gain (NDCG) score of more than 0.92 was obtained with the first protocol, while AUC scores of more than 0.77 were obtained with the second protocol. This automatical approach could provide real-time decision support to radiologists by showing them similar images with associated diagnoses and, where available, responses to therapies. PMID- 25036770 TI - Interprofessional learning and rural paramedic care. AB - INTRODUCTION: The traditional view of paramedic practice is one of provision of emergency care and transport within community or industrial settings. With greater integration of emergency services with the overall health system, this role is changing. Paramedics, especially in rural areas, are now working more closely with other professions in new and extended roles that incorporate non emergency community-based care, preventative medicine and social care. Workforce shortages, health service budget cuts, population size and the changing demographic profile of many rural and remote communities highlight the need for effective interaction between the health professions to respond to the health needs of these communities. The rural environment therefore provides an opportune setting in which to explore the evolving role of paramedics and their interaction with other healthcare professionals in ways that can improve health outcomes for patients and the community. This article presents a critical review of the literature in this area and identifies gaps in which further research is required to further interprofessional learning (IPL) for paramedics. METHODS: Search databases included MEDLINE, SCOPUS, CINAHL and the University of Tasmania (UTAS) electronic library. Specific journal searches included the Journal of Emergency Pre-Hospital Care (JEPHC) and the Journal of Interprofessional Care. Search terms for this literature review consisted of a combination of prefixes 'inter' and 'multi' with adjectives 'professional', 'disciplinary' and 'shared' and the nouns 'education', 'learning' and 'training'. These search terms were then used in combination with each of the terms 'rural' and 'remote' then with 'paramedic/s' and 'pre-hospital' in order to source reports of interprofessional activities in these areas. Each of these was also combined with the search term 'collaboration'. On completion of the initial search process, the reference lists of relevant articles were examined for reports of professional interactions and rural paramedic care. RESULTS: Three major concepts emerged from 24 articles: interprofessional education (IPE), multidisciplinary teamwork, and interprofessional learning. Six articles focused on IPE; nine concerned multidisciplinary teamwork and nine IPL. Examination of the reference lists of these articles revealed a further eight articles with the theme of IPL incorporating paramedics. Predominantly, IPL was associated with new roles for rural paramedics where collaborative practice incorporated community-based care rather than being focused on emergency treatment and transport to hospital. Only two articles reported on a measurable patient care outcome related to IPL. The majority of articles described programs or interventions without having directly examined the interactions and relationships between professions. CONCLUSIONS: Rural paramedics are involved with other healthcare professionals, often in new or expanded roles. Published journal articles that report on this interaction are largely descriptive in nature and few describe the dynamics of this interaction or the conditions under which interprofessional activity could yield potential benefit to health service delivery or patient outcomes. As an overarching construct, IPL may be used to frame further investigation of this interaction and may help shape the emerging role of paramedics in rural settings where population size and other factors limit the availability of health professionals. PMID- 25036771 TI - Detection of qnr, aac(6')-Ib-cr and qepA genes in Escherichia coli isolated from cooked meat products in Henan, China. AB - Antimicrobial resistance in Escherichia coli has increased in recent years in China. Antimicrobial resistant isolates and resistance genes of E. coli can be transferred to humans through the food chain and this presents a public health risk. However, few studies have investigated the prevalence of antimicrobial resistance-encoding genes in E. coli isolated from food samples in China. The aim of this study was to investigate the presence of quinolone resistance genes (QRGs) and extended-spectrum beta-lactamases (ESBLs) in E. coli isolated from cooked meat products in Henan, China. A total of 75 E. coli isolates (12.1%) were detected from 620 samples. High rates of resistance to the following drugs were observed: tetracycline (56.0%), trimethoprim/sulfamethoxazole (41.3%), streptomycin (29.3%), ampicillin (26.7%) and nalidixic acid (14.7%). Of the 75 isolates, QRGs were present in 10 isolates (13.3%), with qnr and aac(6')-Ib-cr detected alone or in combination in five (6.7%) and eight isolates (10.7%). The qnr genes detected in this study included qnrS (n=3) and qnrA (n=2). The qepA gene was absent among these isolates. Three types of beta-lactamase genes were identified in the five ESBL-producing E. coli isolates: blaCTX-M-1, blaCTX-M-9, and blaTEM-1. The qnrS gene was found to be co-transferred with blaCTX-M-1 and blaTEM-1 in one isolate. Our data suggest that cooked meat products may act as reservoirs for multi-resistant bacteria and facilitate the dissemination of antimicrobial resistance genes. PMID- 25036772 TI - The use of real-time PCR to study Penicillium chrysogenum growth kinetics on solid food at different water activities. AB - Fungal growth on solid foods can make them unfit for human consumption, but certain specialty foods require fungi to produce their characteristic properties. In either case, a reliable way of measuring biomass is needed to study how various factors (e.g. water activity) affect fungal growth rates on these substrates. Biochemical markers such as chitin, glucosamine or ergosterol have been used to estimate fungal growth, but they cannot distinguish between individual species in mixed culture. In this study, a real-time polymerase chain reaction (rt-PCR) protocol specific for a target fungal species was used to quantify its DNA while growing on solid food. The measured amount of DNA was then related to the biomass present using an experimentally determined DNA-to-biomass ratio. The highly sensitive rt-PCR biomass assay was found to have a wide range, able to quantify the target DNA within a six orders-of-magnitude difference. The method was used to monitor germination and growth of Penicillium chrysogenum spores on a model porous food (cooked wheat flour) at 25 degrees C and different water activities of 0.973, 0.936, and 0.843. No growth was observed at 0.843, but lag, exponential and stationary phases were identified in the growth curves for the higher water activities. The calculated specific growth rates (MU) during the exponential phase were almost identical, at 0.075/h and 0.076/h for aw=0.973 and 0.936, respectively. The specificity of the method was demonstrated by measuring the biomass of P. chrysogenum while growing together with Aspergillus niger on solid media at aw=0.973. PMID- 25036773 TI - Tracking hippo in the cancer jungle. AB - Signaling through the Hippo pathway controls major aspects of cell growth and proliferation. Focusing on the metabolic consequences of Hippo signaling, Mulvihill and colleagues in this issue of Chemistry & Biology employ a large scale, integrative approach and uncover downstream reorganization of cellular metabolism when the effector TAZ is upregulated, identifying new connections to lipid metabolism. PMID- 25036774 TI - Nonequivalent response to bromodomain-targeting BET inhibitors in oligodendrocyte cell fate decision. AB - The tandem bromodomains (BD1 and BD2) of the BET family proteins BRD2, BRD3, BRD4, and BRDT are structurally conserved but not functionally equivalent. In this issue of Chemistry & Biology, Gacias and colleagues report that a BD1 specific chemical inhibitor, Olinone, enhances oligodendrocyte differentiation, contrasting the reverse process triggered by broad BD1/BD2-targeting inhibitors, highlighting distinct roles of BD1 and BD2 in cell fate decision. PMID- 25036775 TI - Lighting up FGFR signaling. AB - In this issue of Chemistry & Biology, Kim and colleagues describe their work on optogenetic control of fibroblast growth factor receptor (FGFR) signaling. By engineering a chimeric receptor, the authors demonstrate that FGFR intracellular signaling can be controlled in space and time by blue light. PMID- 25036776 TI - Mechanism of action of compound-13: an alpha1-selective small molecule activator of AMPK. AB - AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of alpha1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of alpha2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in alpha2, containing the equivalent region from alpha1 thought to interact with AMP bound in site 3 of the gamma subunit. Consistent with our results in cell free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of alpha1 than of alpha2, beta1, or beta2. PMID- 25036777 TI - Structural, functional, and taxonomic diversity of three preQ1 riboswitch classes. AB - Previously, two riboswitch classes have been identified that sense and respond to the hypermodified nucleobase called prequeuosine1 (preQ1). The enormous expansion of available genomic DNA sequence data creates new opportunities to identify additional representatives of the known riboswitch classes and to discover novel classes. We conducted bioinformatics searches on microbial genomic DNA data sets to discover numerous additional examples belonging to the two previously known riboswitch classes for preQ1 (classes preQ1-I and preQ1-II), including some structural variants that further restrict ligand specificity. Additionally, we discovered a third preQ1-binding riboswitch class (preQ1-III) that is structurally distinct from previously known classes. These findings demonstrate that numerous organisms monitor the concentrations of this modified nucleobase by exploiting one or more riboswitch classes for this widespread compound. PMID- 25036778 TI - A cell-permeable inhibitor to trap Galphaq proteins in the empty pocket conformation. AB - In spite of the crucial role of heterotrimeric G proteins as molecular switches transmitting signals from G protein-coupled receptors, their selective manipulation with small molecule, cell-permeable inhibitors still remains an unmet challenge. Here, we report that the small molecule BIM-46187, previously classified as pan-G protein inhibitor, preferentially silences Galphaq signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps Galphaq in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule Galpha inhibitor to date. Our data show that Galpha proteins may be "frozen" pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence Galpha subclasses with cell-permeable inhibitors. PMID- 25036779 TI - Mechanistic study for immobilization of cysteine-labeled oligopeptides on UV activated surfaces. AB - In this study, we report immobilization of cysteine-labeled oligopeptides on UV activated surfaces decorated with N,N-dimethyl-n-octadecyl-3 aminopropyltrimethoxysilyl chloride (DMOAP). Our result shows that cysteine group, regardless of its position in the oligopeptide, is essential for successful immobilization of oligopeptide on the UV-activated surface. A possible reaction mechanism is nucleophilic addition of thiolates to surface aldehyde groups generated during UV activation. By using this technique, we are able to incorporate anchoring points into oligopeptides through cysteine residues. Furthermore, immobilized oligopeptides on the UV-activated surface is very stable even under harsh washing conditions. Finally, we show that an HPQ-containing oligopeptide can be immobilized on the UV-activated surface, but the final surface density and its ability to bind streptavidin are affected by the position of cysteine and HPQ. An oligopeptide with a cysteine at the N-terminus and a HPQ motif at the C-terminus gives the highest binding signal in the streptavidin binding assay. This result is potentially useful for the development of functional oligopeptide microarrays for detecting target protein molecules. PMID- 25036780 TI - The combined subtemporal-transfacial approach for the resection of juvenile nasopharyngeal angiofibromas with intracranial extension. AB - OBJECTIVE: Stage IVb juvenile nasopharyngeal angiofibromas (JNAs) are frequently regarded as unresectable because of their intracranial extension and cavernous sinus invasion. Although radiation has been described to control these tumors, it can leave the adolescent with long-lasting sequelae. Herein, we describe an alternative treatment strategy based on a combined subtemporal-transfacial surgical approach that permits the successful management of advanced stage JNAs by divorcing the intracranial vascular supply to these massive lesions. PATIENTS: Four male patients were identified with Andrew's Stage IVB JNAs. INTERVENTION: All patients were treated by surgical resection using a combined subtemporal transfacial surgical approach. MAIN OUTCOME MEASURES: Parameters assessed included tumor extent, number and types of surgical procedures, extent of resections, complications, and recurrence rate. RESULTS: Near-total tumor resections were achieved in all patients. No cerebrospinal fluid leak or cranial neuropathies were noted. All but one patient had local recurrences, and these could be managed with repetitive endoscopic debridement. No patient required adjuvant radiation treatment to control advanced disease. CONCLUSIONS: With the use of modern skull base surgical techniques, coordinated interdisciplinary care, and safe, near-total removal of the tumor mass, adolescent males with advanced JNAs may be spared the long-term morbidities associated with using radiation to treat these benign but aggressive lesions. PMID- 25036781 TI - Depression increases sympathetic activity and exacerbates myocardial remodeling after myocardial infarction: evidence from an animal experiment. AB - Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI. PMID- 25036782 TI - Identification of legal highs--ergot alkaloid patterns in two Argyreia nervosa products. AB - Nowadays psychoactive plants marketed as "legal highs" or "herbal highs" increase in popularity. One popular "legal high" are the seeds of the Hawaiian baby woodrose Argyreia nervosa (Synonym: Argyreia speciosa, Convolvolus speciosus). At present there exists no study on A. nervosa seeds or products, which are used by consumers. The quality of commercial available A. nervosa seeds or products is completely unknown. In the present study, a commercial available seed collection (five seeds labeled "flash of inspiration", FOI) was analyzed for ergot alkaloids together with an A. nervosa product (two preparations in capsule form, "druids fantasy", DF). For this purpose high performance liquid chromatography high resolution tandem mass spectrometry (HPLC-HRMS/MS) technique was employed. Besides the major ingredients such as lysergic acid amide (LSA) and ergometrine the well known A. nervosa compounds lysergol/elymoclavine/setoclavine, chanoclavine and the respective stereoisomers were detected in DF, while only LSA and ergometrine could be found in FOI. In addition, in DF lysergic acid was found, which has not been reported yet as ingredient of A. nervosa. In both products, DF as well as in FOI, LSA/LSA-isomers were dominant with 83-84% followed by ergometrine/ergometrinine with 10-17%. Therefore, LSA, followed by ergometrine/ergometrinine, could be confirmed to be the main ergot alkaloids present in A. nervosa seeds/products whereas the other ergot alkaloids seemed to be of minor importance (less than 6.1% in DF). The total ergot alkaloid amounts varied considerably between DF and FOI by a factor of 8.6 as well as the LSA concentration ranging from 3 MUg (lowest amount in one FOI seed) to approximately 34 MUg (highest amount in one DF capsule). Among the FOI seeds, the LSA concentration varied from approximately 3-15 MUg per seed. Thus, the quality/potency of seeds/preparations depends on the amount of ergot alkaloids and the intensity of an expected trip is totally unpredictable. PMID- 25036783 TI - 3-Naphthoylindazoles and 2-naphthoylbenzoimidazoles as novel chemical groups of synthetic cannabinoids: chemical structure elucidation, analytical characteristics and identification of the first representatives in smoke mixtures. AB - By means of gas chromatography with mass spectrometry detection (GC-MS), including high resolution mass spectrometry (GC-HRMS) together with ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of novel synthetic cannabinoids, namely, 1-(5-fluoropentyl)-1H-indazol-3-yl(naphthalen-1 yl)methanone, naphthalen-1-yl(1-pentyl-1H-benzo[d]imidazol-2-yl)methanone and 1 (5-fluoropentyl)-1H-benzo[d]imidazol-2-yl(naphthalen-1-yl)methanone was established. Analytical data obtained in the paper enable reliable identification of these compounds during qualitative analysis of seizures, including smoke mixtures. PMID- 25036786 TI - What is the best method to evaluate urine pH? A trial of three urinary pH measurement methods in a stone clinic. AB - BACKGROUND: Monitoring of urinary pH is an important part of the assessment of patients with urinary tract stones. It provides valuable information about the future stone risk of certain patients and further allows the effective tailoring of medical intervention. Accurate measurement is therefore essential in these patients. OBJECTIVE: The purpose of this study was to determine the most accurate method of measuring urinary pH in an outpatient setting. Materials, Methods, and Participants: Urine samples were collected from 200 patients attending stone clinics at The University Hospital of South Manchester. pH was measured by three commonly used methods: Siemens Clinitek Status pH meter, a hand-held pH meter, and litmus paper read visually. Results were compared with readings simultaneously obtained from a bench-top laboratory pH machine, which is the reference method for pH measurement. STATISTICAL ANALYSIS: The pH readings obtained were analyzed using the Bland-Altman plot. RESULTS AND LIMITATIONS: When compared with the reference method, the hand-held pH meter differed the least with a mean bias of 0.0073 and a maximum under-read of -0.2 pH units and maximum over-read of +0.2 pH units. The Siemens Clinitek pH meter differed most with a mean bias of -0.108, with a maximum over-read of +0.99 pH units and a maximum under-read of 0.78 pH units. The pH values obtained with the litmus paper gave similar results to that of the Clinitek pH meter with a mean bias of -0.069, with a maximum over-read of 0.96 and maximum under-read of 0.82 pH units. CONCLUSION: The hand-held pH device gave urinary pH readings that most closely and consistently matched those of the reference bench-top laboratory machine. This method of pH measurement should be considered in stone clinics in patients with pH-dependent stone risk. PMID- 25036787 TI - Design and synthesis of nonsteroidal progesterone receptor antagonists based on C,C'-diphenylcarborane scaffold as a hydrophobic pharmacophore. AB - The progesterone receptor (PR) plays important roles in multiple physiological processes, including female reproduction. Here, we report the synthesis of nonsteroidal PR antagonists containing a boron cluster as the hydrophobic core. We found that 1,7-diphenyl-meta-carborane was the preferred substructure among the three carborane isomers. Compound 39 was the most potent PR antagonist (IC50: 29 nM). Compound 41 also exhibited potent activity (IC50: 93 nM), and did not bind to androgen receptor, glucocorticoid receptor or mineralocorticoid receptor. These compounds may be useful for investigating potential clinical applications of PR modulators. PMID- 25036785 TI - Dlf1, a WRKY transcription factor, is involved in the control of flowering time and plant height in rice. AB - Flowering time and plant height are important agronomic traits for crop production. In this study, we characterized a semi-dwarf and late flowering (dlf1) mutation of rice that has pleiotropic effects on these traits. The dlf1 mutation was caused by a T-DNA insertion and the cloned Dlf1 gene was found to encode a WRKY transcription factor (OsWRKY11). The dlf1 mutant contains a T-DNA insertion at the promoter region, leading to enhanced accumulation of Dlf1 transcripts, resulting in a semidominant mutation. The dlf1 mutation suppressed the transcription of Ehd2/RID1/OsId1 and its downstream flowering-time genes including Hd1, Ehd1 and Hd3a under both long-day (LD) and short-day (SD) conditions. Knock-down of Dlf1 expression exhibited early flowering at LD condition related to the wild-type plants. Accumulation of Dlf1 mRNA was observed in most tissues, and two splicing forms of Dlf1 cDNAs were obtained (OsWRKY11.1 and OsWRKY11.2). These two proteins showed transactivation activity in yeast cells. Dlf1 protein was found to be localized in the nucleus. Enhanced expression of OsWRKY11.2 or its 5' truncated gene showed similar phenotypes to the dlf1 mutant, suggesting that it might function as a negative regulator. We conclude that Dlf1 acts as a transactivator to downregulate Ehd2/RID1/OsId1 in the signal transduction pathway of flowering and plays an important role in the regulation of plant height in rice. PMID- 25036788 TI - Photodynamic inactivation of bacteria and viruses using two monosubstituted zinc(II) phthalocyanines. AB - A zinc(II) phthalocyanine substituted with a triamino moiety and its tri-N methylated analogue have been prepared and characterized with various spectroscopic methods. Both compounds remain non-aggregated in N,N dimethylformamide and in water containing 0.05% Cremophor EL (v/v), and can generate singlet oxygen effectively. The photodynamic activities of these compounds have been examined against a range of bacterial strains, including the Gram-positive methicillin-sensitive Staphylococcus aureus ATCC 25923 and methicillin-resistant Staphylococcus aureus ATCC BAA-43, and the Gram-negative Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853. Both photosensitizers are highly cytotoxic, particularly for the two Gram-positive strains, for which as low as 5 nM of dye is required to induce a 4-log reduction of their viability. The tri-N-methylated derivative has also been shown to be able to effectively inhibit the growth of a series of clinical strains of Staphylococcus aureus and Escherichia coli, and biofilms of methicillin-resistant Staphylococcus aureus ATCC 67928 and ATCC 68507, and Staphylococcus epidermidis ATCC 35984. In addition, the photodynamic inactivation of a range of viruses using these two compounds has also been investigated. Both compounds are highly photocytotoxic against the enveloped viruses influenza A virus (H1N1) and herpes simplex virus type 1 (HSV1), but exhibit no significant cytotoxicity toward the non-enveloped viruses adenovirus type 3 (Ad3) and coxsackievirus (Cox B1). PMID- 25036789 TI - Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 MUM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity. PMID- 25036790 TI - Multi-dimensional target profiling of N,4-diaryl-1,3-thiazole-2-amines as potent inhibitors of eicosanoid metabolism. AB - Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2 amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4 phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2 ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 +/- 0.2 MUM (5-LO) and a residual activity of 9.1 +/- 1.1% at 10 MUM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases. PMID- 25036791 TI - Bioisosteric replacement of an acylureido moiety attached to an indolin-2-one scaffold with a malonamido or a 2/4-pyridinoylamido moiety produces a selectively potent Aurora-B inhibitor. AB - Bioisosteric replacement of acylureido moiety in 6-acylureido-3 pyrrolylmethylidene-2-oxoindoline derivatives resulted in a series of malonamido derivatives with indolin-2-one scaffold (11-14). Further conformational restrictions of the malonamido moiety led to 2-oxo-1,2-dihydropyridine (21-25) or a 4-oxo-1,4-dihydropyridine derivatives (31-36). 4-Oxo-1,4-dihydropyridine derivatives were more potent Aurora B inhibitors than their 2-oxo-1,2 dihydropyridine counterparts and demonstrated cytotoxicities against A549 and HepG2 cells in the submicromolar range. In A549 cells, 31h decreased phosphorylation of histone H3, triggered polyploidy, induced expression of pro apoptotic Fas and FasL with subsequent activation of caspase 8, resulting into apoptosis. In a Huh7-xenograft mouse model, 31h demonstrated potent in vivo efficacy with a daily dose of 5 mg/kg. PMID- 25036792 TI - Selenadiazole derivatives as potent thioredoxin reductase inhibitors that enhance the radiosensitivity of cancer cells. AB - Thioredoxin system is an attractive target to overcome radioresistance in cancer therapy. The redox enzyme thioredoxin reductase (TrxR) plays a vital role in restoring cellular thiol redox balance disrupted by radiation-induced reactive oxygens species (ROS) generation and oxidative damage. In this study, a series of 1,2,5-selenadiazoles have been synthesized and identified as highly effective inhibitors of TrxR to disrupt the intracellular redox balance, and thus significantly enhanced the sensitivity of cancer cells to X-ray. Upon irradiation, 1,2,5-selenadiazoles displayed a marked synergistic inhibitory effect on radioresistant A375 melanoma cell through enhancement of ROS overproduction, and subsequent induction of ROS-promoted apoptotic pathways, which triggered then mitochondrial dysfunction and caspase activation, finally resulted in augment of radiotherapeutic efficacy. Interestingly, we also found the interaction sites between 1,2,5-selenadiazole and the model peptide of TrxR, which can be confirmed by MALDI-ToF-MS. These results clearly demonstrate TrxR as a potential target for therapy of radioresistant cancers, and selenadiazole derivatives may be attractive radiosensitizing agent by targeting TrxR. PMID- 25036793 TI - Potentially bioactive organotin(IV) compounds: synthesis, characterization, in vitro bioactivities and interaction with SS-DNA. AB - Fourteen new organotin(IV) complexes with general formula R2SnL2 or R3SnL where R = CH3, C2H5, C4H9, C6H5, C6H11, CH2-C6H5, C(CH3)3, C8H17 and L = N-[(2 methoxyphenyl)]-4-oxo-4-[oxy]butanamide were synthesized and characterized by elemental analyses, FT-IR, NMR ((1)H, (13)C and (119)Sn), mass spectrometry and single crystal X-ray structural analysis. Crystallographic data for four triorganotin(IV) complexes (R3SnL, R = CH3, C2H5, C4H9, CH2-C6H5) showed the tin has approximate trigonal bipyramidal geometry with the R groups in the trigonal plane. The carboxylate groups of ligands L bridge adjacent tin atoms, resulting in polymeric chains. In case of the diorganotin(IV) derivatives a six-coordinate geometry at the tin atom is proposed from spectroscopic evidence. The Me-Sn-Me bond angle in complex 7 was determined from the (2)J[(119)Sn-(1)H] value as 166.3 degrees that falls in the range of six-coordinate geometry. The ligand and its complexes (1-14) were screened for their antimicrobial, antitumor, cytotoxic and antileishmanial activities and found to be biologically active. The ligand and its complexes bind to DNA via intercalative interactions resulting in hypochromism and minor bathochromic shifts as confirmed by UV-visible spectroscopy. Based on in vitro studies such as the potato disc method, the synthesized compounds were found to possess significant antitumor activity. Also, from cytotoxicity and DNA interaction studies, these compounds can also be used for the prevention and treatment of cancer. Gel electrophoresis assay was used to investigate the damage to double stranded super coiled plasmid pBR322 DNA by the synthesized compounds and compounds 1 and 7 were found to cause the maximum damage. All the synthesized compounds exhibit strong antileishmanial activity that was even higher than that of Amphotericin B, with significant cytotoxicity. This study, therefore, demonstrated the potential use of these compounds as source of novel agents for the treatment of leishmaniasis. PMID- 25036794 TI - Synthesis of novel chiral TBBt derivatives with hydroxyl moiety. Studies on inhibition of human protein kinase CK2alpha and cytotoxicity properties. AB - The efficient method for the synthesis of novel 4,5,6,7-tetrabromo-1H benzotriazole (TBBt) derivatives bearing a single stereogenic center has been developed. New compounds with a variety of substituents at the meta- and para position of the phenyl ring are reported. All of the presented compounds were obtained using classical synthetic methods, such as bromination of benzotriazole, and its subsequent alkylation by monotosylated arylpropane-1,3-diols, which in turn have been synthesized through reduction of the corresponding prochiral beta keto esters, and the selective monotosylation of the primary hydroxyl group. The influence of the new and previously reported N-hydroxyalkyl TBBt derivatives on the activity of human protein kinase CK2alpha catalytic subunit was examined. The most active were derivatives with N-hydroxyalkyl substituents (IC50 in 0.80-7.35 MUM range). A binding mode of (R)-1-(4,5,6,7-tetrabromo-2H-benzotriazol-2 yl)butan-3-ol 7b to hCK2alpha has been proposed based on in silico docking studies. Additionally, MTT-based cytotoxicity tests demonstrated high activities of novel 1-aryl-3-TBBt-propan-1-ol and 3-TBBt-propan-1,2-diol derivatives against human peripheral blood T lymphoblast (CCRF-CEM), and moderate anti-tumor activities against human breast adenocarcinoma (MCF7) cell lines. PMID- 25036795 TI - Indolinone-based acetylcholinesterase inhibitors: synthesis, biological activity and molecular modeling. AB - A series of indolinone-based compounds bearing benzylpyridinium moiety was designed as dual-binding inhibitors of acetylcholinesterase (AChE). The target compounds 3a-u were synthesized by condensation of oxindole and pyridin-4 carbalehyde, and subsequent N-benzylation. The anti-cholinesterase activity evaluation of synthesized compounds revealed that most of them had very potent inhibitory activity against AChE, superior to standard drug donepezil. Particularly, 2-chlorobenzyl derivative 3c was the most potent compound against AChE with IC50 value of 0.44 nM, being 32-fold more potent than donepezil. Also, most of compounds were more potent than standard drug donepezil against butyrylcholinesterase (BuChE). Docking study revealed that the hydrophobic aromatic part (indoline) of representative compound 3c binds to the PAS and the N benzylpyridinium residue binds to the CAS of AChE. PMID- 25036796 TI - Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors. AB - A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model. PMID- 25036797 TI - Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a]benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi. AB - A high-throughput (HTS) and high-content screening (HCS) campaign of a commercial library identified 2,3-dihydroimidazo[1,2-a]benzimidazole analogues as a novel class of anti-parasitic agents. A series of synthetic derivatives were evaluated for their in vitro anti-leishmanial and anti-trypanosomal activities against Leishmania donovani and Trypanosoma cruzi, which have been known as the causative parasites for visceral leishmaniasis and Chagas disease, respectively. In the case of Leishmania, the compounds were tested in both intracellular amastigote and extracellular promastigote assays. Compounds 4 and 24 showed promising anti leishmanial activity against intracellular L. donovani (3.05 and 5.29 MUM, respectively) and anti-trypanosomal activity against T. cruzi (1.10 and 2.10 MUM, respectively) without serious cytotoxicity toward THP-1 and U2OS cell lines. PMID- 25036798 TI - Oxidative bond formation and reductive bond cleavage at main group metal centers: reactivity of five-valence-electron MX2 radicals. AB - Monomeric five-valence-electron bis(boryl) complexes of gallium, indium, and thallium undergo oxidative M-C bond formation with 2,3-dimethylbutadiene, in a manner consistent with both the redox properties expected for M(II) species and with metal-centered radical character. The weaker nature of the M-C bond for the heavier two elements leads to the observation of reversibility in M-C bond formation (for indium) and to the isolation of products resulting from subsequent B-C reductive elimination (for both indium and thallium). PMID- 25036799 TI - Addressing patients' psychosocial concerns regarding hearing aids within audiology appointments for older adults. AB - PURPOSE: It has long been documented that patients may experience emotional reactions to a diagnosis of hearing impairment and recommendation of hearing aids. Because of this, patients may raise psychosocial concerns regarding their hearing rehabilitation during audiology appointments, particularly in relation to getting hearing aids. However, thus far there has been little systematic research exploring how patients' concerns about hearing aids are addressed by audiologists within appointments. METHOD: This study used conversation analysis to examine a corpus of 63 video-recorded initial audiology appointments with older adults with hearing impairment. RESULTS: The findings demonstrated that when patients expressed concerns regarding hearing aids, these concerns were typically psychosocial in nature and expressed in a way that carried a negative emotional stance. These types of turns thus invited an empathic response. However, patients' concerns were not typically addressed by audiologists during the appointment. As a consequence, patients persistently re-raised their concerns in subsequent turns, leading to expanded sequences of interaction during the management phase of the appointment. CONCLUSIONS: Older adults' psychosocial concerns regarding hearing aids may not always be sufficiently addressed within audiology appointments. A greater emphasis on emotionally focused communication within audiology could result in improved outcomes from hearing health care services. PMID- 25036800 TI - The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. AB - Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L PAM activity (inducing 2-4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM. PMID- 25036801 TI - The stimulation of PD-L1-specific cytotoxic T lymphocytes can both directly and indirectly enhance antileukemic immunity. PMID- 25036803 TI - [A picture is worth a thousand words! A movie tells the whole story!]. PMID- 25036802 TI - The prevalence of older couples with ADL limitations and factors associated with ADL help receipt. AB - Using the Andersen-Newman model, we investigated the prevalence of activities of daily living (ADLs) limitations in married couples, and couple characteristics associated with ADL help-receipt. In this sample of 3,235 couples age 65+ in the 2004 Health and Retirement Study, 74.3%, 22.1%, and 3.6% were couples in which neither partner, one partner, or both partners had limitations, respectively. Logistic regression results indicate that help-receipt was associated with certain health needs in the couple, but not with their predisposing characteristics or enabling resources. Social workers could target couples most in need of assistance by assessing both partners' health problems. PMID- 25036804 TI - [Ophthalmopathology]. PMID- 25036805 TI - [Morphological analysis of corneal refractive lenticules--is there a correlation with refractive results?]. AB - BACKGROUND: ReLEx(r)flex is a corneal refractive procedure performed by removing corneal lenticules with a femtosecond (fs) laser system. Using electron microscopy, tissue parameters of extracted lenticules were analysed for potential correlations to the refractive results. Furthermore, the effect of previous contact lens (CL) wear on refractive stability (regression) was tested. PATIENTS AND METHODS: 19 lenticules from 11 patients (age 24-56 years, 8 f, 3 m) were prepared for EM. The central areas of the samples were photographed and the distance between the collagen fibres and their diameters were digitally measured. ANOVA analysis was used to correlate postoperative refractional stability with time of preoperative CL use, fibre diameter and the coefficient of variation (CV) of fibre distance. RESULTS: 14 of 19 lenticules were from patients who had worn CL preoperatively. The cumulative duration of CL wear averaged around 31.2 +/- 35.5 thousand hours. Preoperative CL use significantly influenced the postoperative regression: the longer time patients had worn CL, the greater was the regression towards myopia (p = 0.01). Additionally, the morphological parameters collagen fibre diameter (p = 0.09) and CV of fibre distance (p = 0.07) had an impact on regression. CONCLUSIONS: Prolonged CL use and alterations in ultrastructural patterns affected the refractive stability after ReLExflex. Although the pathophysiological relationships between CL use, corneal morphological parameters, and refractive stability are still poorly understood, these findings could potentially be used as prognostic markers for postoperative refraction after ReLExflex. PMID- 25036806 TI - [Ophthalmopathology in everyday clinical routine]. AB - This article is intended to take up the cudgels on behalf of ophthalmopathology. To achieve this it is required to shed a light on ophthalmopathology in everyday clinical routine and to emphasise its relevance in today's world. Furthermore, it is intended to show how ophthalmopathology (unconsciously in part) has an impact on our actions. An ophthalmopathologist thinks differently, diagnoses differently and operates differently! Therefore ophthalmopathology should be a cornerstone not only in patient care but also in research and education. PMID- 25036807 TI - [Ophthalmic embryology and teratology--past and present]. PMID- 25036808 TI - [Routine investigation of foetal eyes--in what way and what for?]. AB - The investigation of foetal eyes not only allows for the observation of ocular development. It is supportive and sometimes even mandatory for the diagnosis of systemic and ocular syndromes. This review gives an overview about the investigation of foetal eyes, their assignment to developmental stages, challenges related to the investigation of foetal eyes, clinically relevant syndromes, and academic questions. The morphological development of the eye has been investigated since the 19th century and will not be covered in this article. The investigation of foetal eyes that have been collected during the routine paediatric autopsy, is complicated by artifacts. Artifacts are the result of autolysis, fixation, and mechanical manipulation. They have to be distinguished from genuine findings. Besides the search for findings such as coloboma or cataract, the morphological classification of the foetal eye is of importance. The anterior-posterior diameter allows for the diagnosis of microphthalmia. The case reports comprise Goldenhar's syndrome, MIDAS syndrome and others. In conclusion, the investigation of foetal eyes is often helpful and critical for paediatric diagnostics and should be performed with great care. PMID- 25036809 TI - [Obituary of Gunther Vormun (father of ruthenium plaques)]. PMID- 25036810 TI - [The use of botulinum toxin in ophthalmology]. PMID- 25036812 TI - Euphorbia diterpenes: isolation, structure, biological activity, and synthesis (2008-2012). PMID- 25036811 TI - Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs. AB - The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5), mechanical ventilation with dry oxygen dispensation, and Group II (n = 5), mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77). This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05). Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02). Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation. PMID- 25036813 TI - Optimization of storage and stability of camel liver glutathione S-transferase. AB - Glutathione S-transferases (GSTs) are multifunctional enzymes and play an important role in cellular detoxification. Besides this, GSTs act as cytosolic carrier proteins that bind hydrophobic compounds such as heme, bilirubin, steroids, and polycyclic hydrocarbons. GST has great importance in biotechnology, as it is a target for vaccine and drug development and biosensors development for xenobiotics. Moreover, the GST tag has been extensively used for protein expression and purification. Until now, biophysical properties of camel liver GST have not been characterized. In the present study we have purified camel (Camelus dromedarius) liver GST to homogeneity in a single step by affinity chromatography with 23.4-fold purification and 60.6% yield. Our results showed that maximal activity of GST was at pH 6.5 and it was stable in the pH range of 5 to 10. The optimum temperature was 55 degrees C and the Tm was 57 degrees C. The chemical chaperone glycerol (3.3 M) was able to protect GST activity and aggregation against thermal denaturation by stabilizing the protein structure at 50 and 57 degrees C, respectively. However, L-arginine (125 mM) did not protect GST against thermal stress. Far-ultraviolet circular dichroism (CD) spectra showed that glycerol protected the secondary structure of GST while L-arginine induced conformational changes under thermal stress. In conclusion, our studies on the GST stability suggest that glycerol works as a stabilizer and L-arginine acts as a destabilizer. PMID- 25036814 TI - Statin Use Mitigate the Benefit of Omega-3 Fatty Acids Supplementation-A Meta Regression of Randomized Trials. AB - During last 2 decades, multiple studies have evaluated omega-3 polyunsaturated fatty acids (omega-3 PUFA) supplementation for cardiovascular prevention. The benefit found in previous studies was not demonstrated in more contemporary trials. We aimed to investigate effect of study characteristics, particularly concomitant statin therapy on results of randomized controlled trials. We systematically searched electronic databases for randomized controlled trials evaluating omega-3 PUFA supplementation and reporting clinical outcomes. A meta analysis was performed using a random effect model, followed by a meta-regression of dose, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio, and duration of treatment and use of lipid-lowering/statin therapy in control group. Twenty three studies with 77,776 patients (38,910 PUFA; 38,866 controls) were included. PUFA had no effect on total mortality [risk ratio (RR) = 0.96; 95% confidence interval (CI), 0.92-1.01] and myocardial infarction (RR = 0.87; 95% CI, 0.73 1.02), but marginally reduced cardiovascular mortality (RR = 0.93; 95% CI, 0.87 0.98). Lower control group statin use (b = 0.222, P = 0.027) and higher DHA/EPA (b = -0.105, P = 0.033) ratio was associated with higher reduction in total mortality. Duration and dose had no effect. None of the variables except duration had significant effect on reduction in cardiovascular mortality by PUFA supplementation. There was evidence of publication bias. Statin use may mitigate, and higher DHA/EPA ratio is associated with the beneficial effect of PUFA supplementation. PMID- 25036815 TI - On the lower predictive bound approach for noninferiority clinical trials with binary data. AB - Clinical trials are mostly designed to provide data that allow direct inference of the underlying hypotheses. This, however, is not the case for noninferiority trials where placebo controls are absent due to ethical considerations, resulting in the need for indirect inference about the underlying hypotheses of the treatment effect of a new drug against a putative placebo control. In particular, the European Committee for Medicinal Products for Human Use (CHMP) guideline for noninferiority trials requires indirect confidence bounds for the "putative" effect of the new drug. To meet this requirement, we develop a new approach by which the lower predictive bound of a given confidence level is used to determine the noninferiority margin. For this approach, we provide methods for calculating the sample size and for making indirect statistical inference (i.e., p-values, confidence intervals, and point estimates) on the putative effect of the new test drug. For an actual trial example, we assess designs by the lower predictive bound approach as well as other approaches for determining noninferiority margins. PMID- 25036816 TI - Solid-phase organic synthesis of 2-tridecanyl-1,4-naphthoquinone and 2-tridecanyl 1,4-naphthodiol that form redox-active micelles and vesicles. AB - The solid-phase synthesis of new amphiphilic compounds is reported. It is based on a newly designed 1,4-naphthoquinone derivative that contains polar and nonpolar groups and self-assembles into micelles or vesicles in water depending on the concentration. They also display redox-active properties. PMID- 25036817 TI - Glycyrol suppresses collagen-induced arthritis by regulating autoimmune and inflammatory responses. AB - Glycyrol is a natural compound extracted from Glycyrrhiza uralensis, first reported by us to be a new immunosuppressant. Here, we demonstrate its beneficial effect in collagen-induced arthritis (CIA) in mice, a model for rheumatoid arthritis (RA) in man, and we document the underlying mechanisms. Peroral administration of glycyrol significantly reduced clinical scores, alleviated cartilage and bone erosion and reduced levels of serum inflammatory cytokines. Glycyrol also decreased delayed-type hypersensitivity, improved carbon clearance and reduced acetic acid-induced capillary permeability. Furthermore, glycyrol decreased NF-kappaB and NFAT transcriptional activities and inhibited IL-2 expression. The therapeutic effect of glycyrol was associated with down regulation of both autoimmune and inflammatory reactions. In addition, we demonstrated that glycyrol has minimal acute toxicity in mice. Therefore, we propose that glycyrol may hold promise for future treatment of RA. PMID- 25036818 TI - A Review of the Effect of Dietary Composition on Fasting Substrate Oxidation in Healthy and Overweight Subjects. AB - AIM: The purpose of this review was to assess existing evidence on the effects of chronic dietary macronutrient composition on substrate oxidation during a fasted state in healthy and overweight subjects. METHODS: A systematic review of studies was conducted across five databases. Studies were included if they were English language studies of human adults, >=19 years, used indirect calorimetry (ventilated hood technique), specified dietary macronutrient composition, and measured substrate oxidation. RESULTS: There was no evidence that variations of a typical, non-experimental diet influenced rate or ratio of substrate utilization, however there may be an upper and lower threshold for when macronutrient composition may directly alter preferences for fuel oxidation rates during a fasted state. CONCLUSION: This review indicates that macronutrient composition of a wide range of typical, non-experimental dietary fat and carbohydrate intakes has no effect on fasting substrate oxidation. This suggests that strict control of dietary intake prior to fasting indirect calorimetry measurements may be an unnecessary burden for study participants. Further research into the effects of long-term changes in isocaloric macronutrient shift is required. PMID- 25036819 TI - Lipid diffusion in alcoholic environment. AB - We have studied the effects of a high concentration of butanol and octanol on the phase behavior and on the lateral mobility of 1,2-palmitoyl-sn-glycero-3 phosphocholine (DPPC) by means of differential scanning calorimetry and pulsed gradient stimulated-echo (PGSTE) NMR spectroscopy. A lowering of the lipid transition from the gel to the liquid-crystalline state for the membrane-alcohol systems has been observed. NMR measurements reveal three distinct diffusions in the DPPC-alcohol systems, characterized by a high, intermediate, and slow diffusivity, ascribed to the water, the alcohol, and the lipid, respectively. The lipid diffusion process is promoted in the liquid phase while it is hindered in the interdigitated phase due to the presence of alcohols. Furthermore, in the interdigitated phase, lipid lateral diffusion coefficients show a slight temperature dependence. To the best of our knowledge, this is the first time that lateral diffusion coefficients on alcohol with so a long chain, and at low temperatures, are reported. By the Arrhenius plots of the temperature dependence of the diffusion coefficients, we have evaluated the apparent activation energy in both the liquid and in the interdigitated phase. The presence of alcohol increases this value in both phases. An explanation in terms of a free volume model that takes into account also for energy factors is proposed. PMID- 25036821 TI - Terpenoids from Tripterygium hypoglaucum and their inhibition of LPS-induced NO production. AB - One new (1) and three known (2-4) sesquiterpenes and four known diterpenes (5-8) were isolated from the root bark of Tripterygium hypoglaucum. Their structures were elucidated on the basis of extensive spectroscopic analyses (IR, ESI-MS, HR ESI-MS, 1D-NMR, and 2D-NMR). The inhibitory activity toward LPS-induced NO production of these terpenoids was evaluated, all the compounds showing inhibitory effects. PMID- 25036820 TI - Why fat is so preferable: from oral fat detection to inducing reward in the brain. AB - Potential mechanisms underlying the high palatability of fat can be assessed by reviewing animal studies on fat detection and brain patterns during reward behavior. Fatty acids are likely recognized by receptors on taste buds, with the signals transmitted to the brain through taste nerves. Ingested oil is broken down and absorbed in the gastrointestinal tract, which also sends signals to the brain through unknown mechanisms. Information from both sensory receptors and peripheral tissue is integrated by the brain, resulting in a strong appetite for fatty foods via a reward system. Understanding mechanisms of fat recognition will prove valuable in the development of strategies to manage the high palatability of foods. PMID- 25036822 TI - Phenolic components from the stem of Acanthopanax koreanum and their inhibitory effects on NF-kappa B. AB - Two novel phenolic glucosides (1-2), as well as seven known compounds (3-9), were isolated from the stem of Acanthopanax koreanum; their chemical structures were determined by chemical and spectroscopic methods and subsequently compared with previously reported data. Their inhibition of nuclear factor kappa B (NF-kappaB) was measured in human embryonic kidney (293T) cells by using an NF-kappaB luciferase assay. PMID- 25036823 TI - Construction and significance analysis of the MicroRNA expression profile of Hemerocallis fulva at low temperature. AB - MicroRNA (miRNA) identification was performed in Hemerocallis fulva by high throughput sequencing in combination with bioinformatics prediction. A total of 14,843,184 and 16,072,575 RNA sequences were explored under normal and low temperature conditions, respectively. There was a significant difference in RNAs species and quantity between the two samples. Of all the miRNAs, 26 were significantly upregulated and 30 were significantly downregulated, while nine were either significantly upregulated or downregulated under low-temperature stress. Twenty-one highly expressed miRNA families were screened in at least six species. The number of miRNA families was very similar between monocotyledons and dicotyledons, and only a few were more frequently found in monocotyledons. PMID- 25036824 TI - O2-dependent large electron flow functioned as an electron sink, replacing the steady-state electron flux in photosynthesis in the cyanobacterium Synechocystis sp. PCC 6803, but not in the cyanobacterium Synechococcus sp. PCC 7942. AB - To determine whether alternative electron flow (AEF) can replace the photosynthetic electron flow in cyanobacteria, we used an open O2-electrode system to monitor O2-exchange over a long period. In air-grown Synechocystis sp. PCC 6803 (S. 6803(WT)), the quantum yield of PSII, Y(II), held even after photosynthesis was suppressed by CO2 shortage. The S. 6803 mutant, deficient in flavodiiron (FLV) proteins 1 and 3, showed the same phenotype as S. 6803(WT). In contrast, Y(II) decreased in Synechococcus sp. PCC 7942 (S. 7942). These results suggest that AEF functioned as the Y(II) in S. 6803 and replaced the photosynthetic electron flux. In contrast, the activity of AEF in S. 7942 was lower. The affinity of AEF for O2 in S. 6803 did not correspond to those of FLVs in bacteria or terminal oxidases in respiration. AEF might be driven by photorespiration. PMID- 25036825 TI - Genetic approaches to generate hyper-producing strains of goadsporin: the relationships between productivity and gene duplication in secondary metabolite biosynthesis. AB - Improving the productivity of secondary metabolites is highly beneficial for the utilization of natural products. Here, we found that gene duplication of the goadsporin biosynthetic gene locus resulted in hyper-production. Goadsporin is a linear azole containing peptide that is biosynthesized via a ribosome-mediated pathway in Streptomyces sp. TP-A0584. Recombinant strains containing duplicated or triplicated goadsporin biosynthetic gene clusters produced 1.46- and 2.25-fold more goadsporin than the wild-type strain. In a surrogate host, Streptomyces lividans, chromosomal integration of one or two copies of the gene cluster led to 342.7 and 593.5 mg/L of goadsporin production. Expression of godI, a self resistance gene, and of godR, a pathway-specific transcriptional regulator, under a constitutive promoter gave 0.79- and 2.12-fold higher goadsporin production than the wild-type strain. Our experiments indicated that a proportional relationship exists between goadsporin production per culture volume and the copy number of the biosynthetic gene cluster. PMID- 25036826 TI - Cloning and transcriptional expression of mouse mannosyltransferase IV/V cDNA, which is involved in the synthesis of lipid-linked oligosaccharides. AB - We cloned the mouse mannosyltransferase IV/V gene (mALG11) from FM3A cells by a bioinformatic approach. The ORF contained 1476 bp encoding 492 amino acids. The cloned mALG11 complemented the growth defect of the Saccharomyces cerevisiae ALG11Delta mutant. In addition, we detected a variant cDNA by alternate splicing that had an additional four-nucleotide ATGC insertion at base 276 of the ORF. Consequently the variant cDNA encoded a truncated protein with 92 amino acids, lacking the glycosyltransferase group-1 domain. The variant cDNA occurs in many mouse strains according to EST database searches. Moreover, we detected it in FM3A cDNA, but we did not detect any such variants in the human EST database or in HeLa cDNA, although human ALG11 (hALG11) genomic DNA has the same sequence around the intron-exon boundaries as those of mALG11 genomic DNA. Hence, we concluded that there is different transcriptional control mechanism between mALG11 and hALG11. PMID- 25036827 TI - Structural analysis and characterization of new small serum proteins from the serum of a venomous snake (Gloydius blomhoffii). AB - Some snakes have several anti-toxic proteins in their sera that neutralize their own venom. Five new small serum proteins (SSPs) were isolated from Japanese mamushi (Gloydius blomhoffii) serum by gel-filtration and RP-HPLC, and their N Terminal sequences were determined. The amino acid sequences of the precursor proteins were deduced from the nucleotide sequences of cDNAs encoding them. Due to the sequence similarity to those of SSPs in habu snake (Protobothrops flavoviridis) serum (>75% identity), these proteins were designated mSSP-1 to mSSP-5 as the homologs of habu proteins. mSSP-1 was stable at 100 degrees C and in the pH range of 1-10, and inhibited the proteolytic activity of a certain snake venom metalloproteinase. The inhibitory activity was extinguished by modifying the amino groups of mSSP-1. mSSP-1 is the first prostate secretory protein of the 94 amino acid-family protein with a carbohydrate chain in the Asn37 residue. PMID- 25036829 TI - Characterization and expression pattern of a novel beta-defensin in common carp (Cyprinus carpio L.): implications for its role in mucosal immunity. AB - beta-defensins are a group of cysteine-rich cationic antimicrobial peptides that play antibacterial and antiviral roles in immune systems of vertebrates. Here, we report the cloning and identification of a beta-defensin 3 cDNA sequence from the common carp (Cyprinus carpio L.). Sequence alignment and phylogenetic analysis indicated that this beta-defensin 3 belonged to the BD-2 group of fish. Real-time PCR showed that the beta-defensin 3 mRNA was expressed in all the tissues of normal common carp that we examined and was highly expressed in the spleen and gills. When challenged with Vibrio anguillarum, the expression level of common carp beta-defensin 3 mRNA was quickly upregulated in various tissues. Our results indicate that the beta-defensin 3 showed markedly high constitutive expression in the gills, and significantly upregulated expression in the hindgut of the common carp after infection, suggesting it plays an important role in the innate and mucosal immunity of common carp. PMID- 25036828 TI - BPG3 is a novel chloroplast protein that involves the greening of leaves and related to brassinosteroid signaling. AB - Brassinosteroids are plant steroid hormones that regulate plant organs and chloroplast development. The detailed molecular mechanism for plant development by BR signaling is yet to be revealed, and many points regarding the relationship between BR signaling and chloroplast development remain unknown. We identify here the dominant mutant Brz-insensitive-pale green3-1D (bpg3-1D) from the Arabidopsis FOX lines that show reduced sensitivity to the chlorophyll accumulation promoted by the BR biosynthesis inhibitor, Brassinazole (Brz), in the light. BPG3 encodes a novel chloroplast protein that is evolutionally conserved in bacteria, algae, and higher plants. The expression of BPG3 was induced by light and Brz. The inhibition of electron transport in photosystem II of the chloroplasts was detected in bpg3-1D. These results suggest that BPG3 played an important role in regulating photosynthesis in the chloroplast under BR signaling. PMID- 25036830 TI - Identification of interacting proteins for calcium-dependent protein kinase 8 by a novel screening system based on bimolecular fluorescence complementation. AB - Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. We developed a novel assay system, based on the bimolecular fluorescence complementation (BiFC) technique in Escherichia coli, for detecting transient interactions such as those between kinases and their substrates. This system detected the interaction between OsMEK1 and its direct target OsMAP1. By contrast, BiFC fluorescence was not observed when OsMAP2 or OsMAP3, which are not substrates of OsMEK1, were used as prey proteins. We also screened for interacting proteins of calcium-dependent protein kinase 8 (OsCPK8), a regulator of plant immune responses, and identified three proteins as interacting molecules of OsCPK8. The interaction between OsCPK8 and two of these proteins (ARF-GEF and peptidyl prolyl isomerase) was confirmed in rice cells by means of BiFC technology. These results indicate that our new assay system has the potential to screen for protein kinase target molecules. PMID- 25036831 TI - A fungal prenyltransferase catalyzes the regular di-prenylation at positions 20 and 21 of paxilline. AB - A putative indole diterpene biosynthetic gene cluster composed of eight genes was identified in a genome database of Phomopsis amygdali, and from it, biosynthetic genes of fusicoccin A were cloned and characterized. The six genes showed significant similarities to pax genes, which are essential to paxilline biosynthesis in Penicillium paxilli. Recombinants of the three putative prenyltransferase genes in the cluster were overexpressed in Escherichia coli and characterized by means of in vitro experiments. AmyG is perhaps a GGDP synthase. AmyC and AmyD were confirmed to be prenyltransferases catalyzing the transfer of GGDP to IGP and a regular di-prenylation at positions 20 and 21 of paxilline, respectively. AmyD is the first know example of an enzyme with this function. The Km values for AmyD were calculated to be 7.6 +/- 0.5 MUM for paxilline and 17.9 +/- 1.7 MUM for DMAPP at a kcat of 0.12 +/- 0.003/s. PMID- 25036832 TI - Anti-aging and anti-microbial effects of melleolide on various types of yeast. AB - The chronological lifespan (CLS) of the budding yeast Saccharomyces cerevisiae is a model for the aging of post-mitotic cells in higher eukaryotes. In this study, we found that the sesquiterpene aryl ester melleolide expands the CLS of budding yeast. In contrast, melleolide compromised the CLS of the fission yeast Schizosaccharomyces pombe. This indicates that melleolide might have a potential anti-aging activity against some types of cell, and that it might be useful as a selective anti-fungal drug. PMID- 25036833 TI - Construction of collagen gel scaffolds for mechanical stress analysis. AB - We designed a cyclic compression system using readily available six-well culture plates to investigate the influence of mechanical stress on skin-like structures. The effects of cyclic mechanical stress on protein expression by cells were easily examined, and hence, this system should be useful for further analysis of skin responses to mechanical stress. PMID- 25036834 TI - Acyl-homoserine lactones suppresses IEC-6 cell proliferation and increase permeability of isolated rat colon. AB - We investigated to determine whether a variety of acyl-homoserine lactones (AHLs) influences epithelial cell proliferation and mucosal permeability. 3-Oxo-C12 homoserine lactone (HSL) and 3-oxo-C14-HSL significantly suppressed IEC-6 cell proliferation. A significant increase in mucosal permeability was observed in isolated rat colon tissue exposed to C12-HSL, 3-oxo-C12-HSL, and 3-oxo-C14-HSL. These data indicate that AHLs suppress epithelial proliferation and disrupt barrier function in intestinal mucosa. PMID- 25036835 TI - Synthesis and pharmacokinetic characterization of a pH-sensitive polyethylene glycol ginsenoside CK (PEG-CK) conjugate. AB - The ginsenosides in Panax ginseng have vast structural and pharmacological efficacies. We covalently conjugated polyethylene glycol on the surface of CK (PEG-CK) through an acid-labile ester-linkage that showed increased solubility of CK. HPLC analysis showed that the release of CK was enhanced at acidic pH 5, whereas it was dramatically decreased at physiological pH 7.4. This might enhance the efficacy of CK. PMID- 25036836 TI - Pressure effects on the chimeric 3-isopropylmalate dehydrogenases of the deep-sea piezophilic Shewanella benthica and the atmospheric pressure-adapted Shewanella oneidensis. AB - The chimeric 3-isopropylmalate dehydrogenase enzymes were constructed from the deep-sea piezophilic Shewanella benthica and the shallow water Shewanella oneidensis genes. The properties of the enzymatic activities under pressure conditions indicated that the central region, which contained the active center and the dimer forming domains, was shown to be the most important region for pressure tolerance in the deep-sea enzyme. PMID- 25036837 TI - Video-endoscopic comparison of swallowing waxy rice mochi and waxy wheat mochi: improvement of a traditional Japanese food that presents a choking hazard. AB - Mochi is highly cohesive and adhesive, and easy to choke on. Many of the fatal suffocation accidents with mochi occur in the elderly aged 65 years or older. These circumstances prompted us to investigate a special property of waxy wheat which is similar in texture to waxy rice, but is less cohesive and adhesive. We compared the differences in chewing and swallowing movements associated with eating waxy rice mochi and waxy wheat mochi between healthy adults and healthy elderly. Healthy elderly chewed mochi more and longer than healthy adults. Although there was no difference in the number of chewing cycles or total duration of chewing between the two types of mochi, waxy wheat mochi was easier to chew and left less pharyngeal residue. These findings lead us to suggest that waxy wheat mochi is promising as a food that is easy to swallow and difficult to choke on. PMID- 25036838 TI - Moderate food restriction suppresses the conversion of L-tryptophan to nicotinamide in weaning rats. AB - Calorie restriction leads to a change in the metabolism of nutrients. Nicotinamide is biosynthesized from L-tryptophan. We attempted to determine the effects of food restriction on the biosynthesis of nicotinamide from L tryptophan. Weaning male rats were fed a conventional chemically defined diet without preformed niacin for 63 d. However, the food intake was restricted to 80 and 65% of the intake of the ad libitum-fed control group of rats. The 24-h urine samples were periodically collected, and the urinary excretion of nicotinamide and its catabolites was measured. The conversion percentages were lower in both restricted groups than in the ad libitum-fed control group during the experimental period (control group, 1.37 +/- 0.24%; 80%-restricted group, 0.20 +/ 0.04%; 65%-restricted group, 0.15 +/- 0.02%; control vs. restricted groups, p < 0.01). Food restriction, even at mild level, suppressed the conversion of L tryptophan to nicotinamide when compared to the ad libitum-fed control group. PMID- 25036840 TI - Inhibitory effects of the kappa-casein macropeptide isolated from milk protein on the biofilm formation and virulence of Listeria monocytogenes. AB - We demonstrate the inhibitory effects of kappa-casein macropeptide (CMP) on the biofilm formation and virulence of Listeria monocytogenes Scott A. The inhibition of biofilm formation by CMP was initially investigated by using the protocol applied for the 96-well microtiter plate assay. Low concentrations of CMP (0.1, 0.2, 0.3, 0.4, and 0.5 mg/mL) that were tested resulted in a profound inhibitory effect on biofilm formation at a concentration of 0.4 mg/mL. CMP also significantly repressed the transcription of inlA (encoding internalin A) that was responsible for the initial adhesion and invasion event, and prolonged the survival of Caenorhabditis elegans infected by L. monocytogenes. Two-dimensional gel electrophoresis showed that newly identified proteins in the presence of CMP were involved in the stress response and metabolic processes that have important roles in developing listerial biofilms. Our results suggest that CMP from milk protein would be capable of eliminating biofilm formation and virulence by L. monocytogenes in the food industry. PMID- 25036839 TI - Attenuation by a Vigna nakashimae extract of nonalcoholic fatty liver disease in high-fat diet-fed mice. AB - A Vigna nakashimae (VN) extract has been shown to have antidiabetic and anti obesity effects. However, the mechanism underlying the effect of a VN extract on hepatic inflammation and endoplasmic reticulum (ER) stress remains unclear. In the present study, we investigated how a VN extract protects against the development of non-alcoholic fatty liver disease (NAFLD). A VN extract for 12 weeks reduced the body weight, serum metabolic parameters, cytokines, and hepatic steatosis in high-fat diet (HFD)-fed mice. A VN extract decreased HFD-induced hepatic acetyl CoA carboxylase and glucose transporter 4 expressions. In addition to the levels of high-mobility group box 1 and receptor for advanced glycation, the hepatic expression of ATF4 and caspase-3 was also reduced by a VN extract. Thus, these data indicate that a chronic VN extract prevented NAFLD through multiple mechanisms, including inflammation, ER stress, and apoptosis in the liver. PMID- 25036841 TI - Content of resveratrol and glycoside and its contribution to the antioxidative capacity of Polygonum cuspidatum (Itadori) harvested in Kochi. AB - We quantified trans-resveratrol in each part of fresh Polygonum cuspidatum harvested in Kochi Prefecture. A small amount of trans-resveratrol was detected in the edible stem parts, the content varying with seasonal, geographical, and environmental factors. We also examined the antioxidative activity of each part, suggesting that P. cuspidatum contained many more contributing antioxidants other than resveratrol. PMID- 25036842 TI - Effects of H2 and electrochemical reducing power on metabolite production by Clostridium acetobutylicum KCTC1037. AB - A conventional fermenter (CF), a single-cathode fermenter (SCF), and a double cathode fermenter (DCF) were employed to evaluate and compare the effects of H2 and electrochemical reducing power on metabolite production by Clostridium acetobutylicum KCTC1037. The source of the external reducing power for CF was H2, for the SCF was electrochemically reduced neutral red-modified graphite felt electrode (NR-GF), and for the DCF was electrochemically reduced combination of NR-GF and platinum plate electrodes (NR-GF/PtP). The metabolites produced from glucose or CO2 by strain KCTC1037 cultivated in the DCF were butyrate, ethanol, and butanol, but ethanol and butanol were not produced from glucose or CO2 by strain KCTC1037 cultivated in the CF and SCF. It is possible that electrochemically reduced NR-GF/PtP is a more effective source of internal and external reducing power than H2 or NR-GF for strain KCTC1037 to produce metabolites from glucose and CO2. This research might prove useful in developing fermentation technology to actualize direct bioalcohol production of fermentation bacteria from CO2. PMID- 25036843 TI - Analysis of a DNA region from low-copy-number plasmid pYAN-1 of Sphingobium yanoikuyae responsible for plasmid stability. AB - We identified and analyzed a DNA region that is required for the stable maintenance of plasmids in the genus Sphingomonas. This DNA fragment, a 244 bp, is localized in the upstream region of the repA gene of low-copy-number small plasmid pYAN-1 (4896 bp) of Sphingobium yanoikuyae. It has four inverted repeats and one direct repeat for possible secondary structures. We were able to stabilize not only another unstable plasmid, pYAN-2, in the genus Sphingomonas, but also the unstable plasmid pSC101 without par locus in Escherichia coli. The copy-number levels between the unstable plasmid and the parental plasmid were similar, and these results suggest that the stabilization of unstable plasmids by this DNA region of pYAN-1 was not due to an increase in plasmid copy number. We concluded that the stabilization of the plasmid was due to a plasmid partition mechanism encoded by a DNA fragment of pYAN-1. PMID- 25036844 TI - Biosurfactant-producing yeasts widely inhabit various vegetables and fruits. AB - The isolation of biosurfactant-producing yeasts from food materials was accomplished. By a combination of a new drop collapse method and thin-layer chromatography, 48 strains were selected as glycolipid biosurfactant producers from 347 strains, which were randomly isolated from various vegetables and fruits. Of the producers, 69% were obtained from vegetables of the Brassica family. Of the 48 producers, 15 strains gave relatively high yields of mannosylerythritol lipids (MELs), and were identified as Pseudozyma yeasts. These strains produced MELs from olive oil at yields ranging from 8.5 to 24.3 g/L. The best yield coefficient reached 0.49 g/g as to the carbon sources added. Accordingly, MEL producers were isolated at high efficiency from various vegetables and fruits, indicating that biosurfactant producers are widely present in foods. The present results should facilitate their application in the food and related industries. PMID- 25036845 TI - Construction and basic characterization of deletion mutants of the genes involved in chitin utilization by Serratia marcescens 2170. AB - In order to elucidate the roles of ChiP, ChiQ, and ChiX in chitin utilization by Serratia marcescens 2170, the construction of single-gene deletion mutants of the chiP, chiQ, and chiX genes was attempted by allelic exchange mutagenesis. DeltachiP formed smaller clearing zones and DeltachiX formed larger ones than wild-type 2170 on an agar plate containing colloidal chitin. DeltachiP grew slowly on the lower concentration of (GlcNAc)2, and there was essentially no growth on chitin oligosaccharides larger than (GlcNAc)3. The gene product of chiP was detected in the outer membrane fraction, consistently with the hypothesis that chiP encodes outer membrane chitoporin. Deletion of chiQ decreased and that of chiX increased the growth rates on chitin oligosaccharides. These observations strongly suggest that all three genes are involved in chitin utilization and that the deletion mutants obtained in this study might prove useful tools to clarify the details of the chitin utilization system of this bacterium. PMID- 25036846 TI - Identification and characterization of thermotolerant acetic acid bacteria strains isolated from coconut water vinegar in Sri Lanka. AB - From the pellicle formed on top of brewing coconut water vinegar in Sri Lanka, three Acetobacter strains (SL13E-2, SL13E-3, and SL13E-4) that grow at 42 degrees C and four Gluconobacter strains (SL13-5, SL13-6, SL13-7, and SL13-8) grow at 37 degrees C were identified as Acetobacter pasteurianus and Gluconobacter frateurii, respectively. Acetic acid production by the isolated Acetobacter strains was examined. All three strains gave 4% acetic acid from 6% initial ethanol at 37 degrees C, and 2.5% acetic acid from 4% initial ethanol at 40 degrees C. Compared with the two other strains, SL13E-4 showed both slower growth and slower acetic acid production. As well as the thermotolerant SKU1108 strain, the activities of the alcohol dehydrogenase and the aldehyde dehydrogenase of SL13E-2 and SL13E-4 were more stable than those of the mesophilic strain. The isolated strains were used to produce coconut water vinegar at higher temperatures than typically used for vinegar production. PMID- 25036847 TI - Sputtering deposition of P-type SnO films with SnO2 target in hydrogen-containing atmosphere. AB - In this work, we had investigated sputtering deposition of p-type SnO using the widely used and robust SnO2 target in a hydrogen-containing reducing atmosphere. The effects of the hydrogen-containing sputtering gas on structures, compositions, optical, and electrical properties of deposited SnOx films were studied. Results show that polycrystalline and SnO-dominant films could be readily obtained by carefully controlling the hydrogen gas ratio in the sputtering gas and the extent of reduction reaction. P-type conductivity was unambiguously observed for SnO-dominant films with traceable Sn components, exhibiting a p-type Hall mobility of up to ~3 cm(2) V(-1) s(-1). P-type SnO thin film transistors using such SnO-dominant films were also demonstrated. PMID- 25036848 TI - Synthesis and organic surface modification of luminescent, lanthanide-doped core/shell nanomaterials (LnF3@SiO2@NH2@organic acid) for potential bioapplications: spectroscopic, structural, and in vitro cytotoxicity evaluation. AB - A facile coprecipitation reaction between Ce(3+), Gd(3+), Tb(3+), and F(-) ions, in the presence of glycerine as a capping agent, led to the formation of ultrafine, nanocrystalline CeF3:Tb(3+) 5%, Gd(3+) 5% (LnF3). The as-prepared fluoride nanoparticles were successfully coated with an amine modified silica shell. Subsequently, the obtained LnF3@SiO2@NH2 nanostructures were conjugated with 4-ethoxybenzoic acid in order to prove the possibility of organic modification and obtain a new functional nanomaterial. All of the nanophosphors synthesized exhibited intense green luminescence under UV light irradiation. Based on TEM (transmission electron microscopy) measurements, the diameters of the cores (~12 nm) and core/shell particles (~50 nm) were determined. To evaluate the cytotoxic activity of the nanomaterials obtained, their effect on human erythrocytes was investigated. LnF3 nanoparticles were bound to the erythrocyte membrane, without inducing any cytotoxic effects. After coating with silica, the nanoparticles revealed significant cytotoxicity. However, further functionalization of the nanomaterial with -NH2 groups as well as conjugation with 4-ethoxybenzoic acid entailed a decrease in cytotoxicity of the core/shell nanoparticles. PMID- 25036849 TI - A diastereoselective synthesis of 5'-substituted-uridine derivatives. AB - A straightforward strategy for the synthesis of 5'-substituted-uridine derivatives is described. It relies on the introduction of various substituents at C-5' at the last step of the synthesis by regioselective nucleophilic opening of a unique epoxide that provides access to a small library of compounds. This epoxide results from the diastereoselective epoxidation, performed at a multigram scale, of a uridine-derived alkene. The configuration of the newly created 5' asymmetric center has been unambiguously assigned by X-ray diffraction analysis. PMID- 25036850 TI - Egg size effects across multiple life-history stages in the marine annelid Hydroides diramphus. AB - The optimal balance of reproductive effort between offspring size and number depends on the fitness of offspring size in a particular environment. The variable environments offspring experience, both among and within life-history stages, are likely to alter the offspring size/fitness relationship and favor different offspring sizes. Hence, the many environments experienced throughout complex life-histories present mothers with a significant challenge to optimally allocate their reproductive effort. In a marine annelid, we tested the relationship between egg size and performance across multiple life-history stages, including: fertilization, larval development, and post-metamorphosis survival and size in the field. We found evidence of conflicting effects of egg size on performance: larger eggs had higher fertilization under sperm-limited conditions, were slightly faster to develop pre-feeding, and were larger post metamorphosis; however, smaller eggs had higher fertilization when sperm was abundant, and faster planktonic development; and egg size did not affect post metamorphic survival. The results indicate that egg size effects are conflicting in H. diramphus depending on the environments within and among life-history stages. We suggest that offspring size in this species may be a compromise between the overall costs and benefits of egg sizes in each stage and that performance in any one stage is not maximized. PMID- 25036851 TI - But: do age and working memory influence conventional implicature processing? AB - Conventional implicatures are omnipresent in daily life communication but experimental research on this topic is sparse, especially research with children. The aim of this study was to investigate if eight- to twelve-year-old children spontaneously make the conventional implicature induced by but, so, and nevertheless in 'p but q' sentences. Additionally, the study aimed to shed light on the cognitive effort required for these inferences by measuring working memory (WM) capacity. Our results show that children do make these inferences to a certain extent, but are sensitive to the content of the arguments. We found a significant effect of sentence type, but did not observe any developmental effect, nor any effect of WM: a higher age or WM capacity does not result in more pragmatic inferences. PMID- 25036852 TI - Metal-catalyzed electroless etching of silicon in aerated HF/H2O vapor for facile fabrication of silicon nanostructures. AB - Inspired by metal corrosion in air, we demonstrate that metal-catalyzed electroless etching (MCEE) of silicon can be performed simply in aerated HF/H2O vapor for facile fabrication of three-dimensional silicon nanostructures such as silicon nanowires (SiNW) arrays. Compared to MCEE commonly performed in aqueous HF solution, the present pseudo gas phase etching offers exceptional simplicity, flexibility, environmental friendliness, and scalability for the fabrication of three-dimensional silicon nanostructures with considerable depths because of replacement of harsh oxidants such as H2O2 and AgNO3 by environmental-green and ubiquitous oxygen in air, minimum water consumption, and full utilization of HF. PMID- 25036853 TI - Half-metallicity in MnPSe3 exfoliated nanosheet with carrier doping. AB - Searching two-dimensional (2D) half-metallic crystals that are feasible in experiment is essential to develop next-generation nanospintronic devices. Here, a 2D exfoliated MnPSe3 nanosheet with novel magnetism is first proposed based on first-principles calculations. In particular, the evaluated low cleavage energy and high in-plane stiffness indicate that the free-standing MnPSe3 nanosheet can be exfoliated from its bulk structure in experiment. The MnPSe3 nanosheet is an antiferromagnetic semiconductor at its ground state, whereas both electron and hole doping induce its transition from antiferromagnetic semiconductor to ferromagnetic half-metal. Moreover, the spin-polarization directions of 2D half metallic MnPSe3 are opposite for electron and hole doping, which can be controlled by applying an external voltage gate. The Monte Carlo simulation based on the Ising model suggests the Curie temperature of the doped 2D MnPSe3 crystal is up to 206 K. These advantages render the 2D MnPSe3 crystal with great potentials for application in electric-field controlled spintronic devices. PMID- 25036855 TI - Predictors of severe self-reported disability in RA in a long-term follow-up study. AB - PURPOSE: Identify factors predictive for severe self-reported disability in patients with rheumatoid arthritis. METHODS: Patients (n = 1910) were sent a questionnaire 5-18 years after disease onset. Outcomes were the Health Assessment Questionnaire (HAQ), Rheumatoid Arthritis Outcome Score (RAOS) and physical activity. The tertile of patients most affected by the disease were compared to those less affected. Proposed predictive factors were function, pain, general health, radiographic joint damage, swollen/tender joints and disease activity measures at baseline. Age, gender and disease duration were controlled for in logistic regression analyses. RESULTS: Seventy-three percent (n = 1387) responded to the questionnaire, mean age 65 years (SD 15) and 70% were women. Worse scores in function, pain, general health and tender joints at baseline increased the risk of being in the most affected group, as measured by HAQ and RAOS 5-18 years after disease onset (p < 0.000). CONCLUSION: High levels of pain and worse reports of function at disease onset were risk factors for being in the most disabled tertile of patients after 5-18 years. Pain and function proved to be predictors of the outcome while some measures of inflammation were not. It is important to recognize these patients who may be in need of multidisciplinary treatments already at disease onset. IMPLICATIONS FOR REHABILITATION: Health care providers should be aware of the subgroup of patients with more severe symptoms of pain and impaired function at disease onset since they have an increased risk of being in the most disabled tertile of rheumatoid arthritis patients several years later. Health care providers should assess pain and function and act on high pain and impaired function already at disease onset as they proved to be predictors of patient-reported outcomes controlled for inflammatory parameters. These findings support European guidelines and research findings that patients with high pain and impaired function despite of well-managed inflammatory parameters should early in the disease course be referred to multidisciplinary treatment for supplementary regime. PMID- 25036854 TI - Ogilvie's syndrome after pediatric spinal deformity surgery: successful treatment with neostigmine. AB - Ogilvie's syndrome is a rare and potentially fatal disease that can easily be mistaken for postoperative ileus. Also known as acute colonic pseudo-obstruction, early recognition and diagnosis of the syndrome allows for treatment prior to bowel perforation and requisite abdominal surgery. The authors report a case of Ogilvie's syndrome following spinal deformity correction and tethered cord release in an adolescent who presented with acute abdominal distension, nausea, and vomiting on postoperative Day 0. The patient was initially diagnosed with adynamic ileus and treated conservatively with bowel rest, reduction in narcotic dosage, and a regimen of stool softeners, laxatives, and enemas. Despite this treatment, her clinical course failed to improve, and she demonstrated significant colonic distension radiographically. Intravenous neostigmine was administered as a bolus with a rapid and dramatic response. This case is the first reported instance of neostigmine use for Ogilvie's syndrome treatment following a pediatric neurosurgical operation. PMID- 25036856 TI - Quantitative MR and cognitive impairment in cryptogenic localisation-related epilepsy. AB - For patients with chronic cryptogenic localisation-related epilepsy (CLRE), conventional MRI does not provide measures to discern between patients with or without cognitive complaints. We investigated, in a preliminary study, whether it is possible to detect cerebral biomarkers of cognitive impairment in patients with CLRE using sensitive quantitative MRI techniques. Neuropsychological assessment and quantitative 3.0 T MRI, comprising T2 relaxometry, diffusion tensor imaging, and spectroscopic imaging, were applied to 35 patients with CLRE and 21 healthy controls. Analysis included the left and right hippocampi, and frontal and temporal lobes. Differences between the groups and correlations with cognitive and clinical characteristics were assessed. Patients with epilepsy scored significantly worse on cognitive tasks compared to healthy controls. Significantly larger CSF fractions in the hippocampi and left temporal lobe, a longer T2 relaxation time in the left hippocampus, and a significantly higher concentration of glutamate/glutamine in the left frontal lobe were observed in patients with epilepsy. Moreover, poor memory performance was significantly correlated with larger CSF fractions in the right hippocampus and left temporal lobe in patients. In the temporal lobe, an association between subtle changes in morphology (indicative of atrophy) and memory performance was found, consistent with previous literature. These results may help to explain the alterations in brain functioning in patients with epilepsy. PMID- 25036857 TI - Untold nutrition. AB - Nutrition is generally investigated, and findings interpreted, in reference to the activities of individual nutrients. Nutrient composition of foods, food labeling, food fortification, and nutrient recommendations are mostly founded on this assumption, a practice commonly known as reductionism. While such information on specifics is important and occasionally useful in practice, it ignores the coordinated, integrated and virtually symphonic nutrient activity (wholism) that occurs in vivo. With reductionism providing the framework, public confusion abounds and huge monetary and social costs are incurred. Two examples are briefly presented to illustrate, the long time misunderstandings (1) about saturated and total fat as causes of cancer and heart disease and (2) the emergence of the nutrient supplement industry. A new definition of the science of nutrition is urgently needed. PMID- 25036858 TI - Effect of statins in preventing contrast-induced nephropathy: an updated meta analysis. AB - OBJECTIVE: The effect of statins in preventing contrast-induced nephropathy (CIN) has been reported, with conflicting results. The aim of this study was to carry out an updated meta-analysis to determine whether pretreatment with statins can reduce the risk of CIN and adverse clinical events. MATERIALS AND METHODS: Systematic database searches of MEDLINE (1950 to December 2013), EMBASE (1966 to December 2013), and the Cochrane Central Register of Controlled Trials (Issue 12, December 2013) were performed. All randomized controlled trials assessing the efficacy of statins on CIN were included. RESULTS: Seventeen studies with 6323 patients were included. Pretreatment with statins before angiography significantly reduced the risk of CIN [relative risk 0.50; 95% confidence interval (CI) 0.35-0.71; P<0.001] and was associated with significantly lower postprocedural serum creatinine levels (weighted mean difference -0.05 mg/dl; 95% CI -0.09 to -0.02 mg/dl; P=0.005). Meanwhile, the use of statins resulted in trends of reduced risks of renal replacement therapy and all-cause death within 30 days (relative risk 0.44; 95% CI 0.18-1.08; P=0.07). Further analyses indicated that high-dose statins were more effective than low-dose statins in reducing the risk of CIN and that different types of statins showed similar effects in preventing CIN. CONCLUSION: Pretreatment with statins before angiography is effective in preventing CIN and may reduce the risk of adverse clinical events. However, the optimal dose and duration for statin pretreatment are still unknown. PMID- 25036859 TI - Relationship between methylenetetrahydrofolate reductase gene polymorphism and the coronary slow flow phenomenon. AB - OBJECTIVE: To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and the coronary slow flow phenomenon (CSFP), and to discover the involvement of genetic factors in CSFP. PARTICIPANTS AND METHODS: Seventy-five patients with normal angiographic coronary arteries were recruited between June 2012 and June 2013. MTHFR C677T genotypes were sequenced by pyrosequencing, whereas the concentration of homocysteine (Hcy) was determined using the enzymatic cycling assay. RESULTS: Compared with the controls, the CSFP patients had higher Hcy concentrations and higher male morbidity. The CSFP patients showed higher frequencies of MTHFR 677(TT+TC) genotypes and the 677T allele compared with the controls. Plasma Hcy levels and male morbidity were correlated positively with the average corrected TIMI frame count. Multiple linear regression and logistic regression analysis indicated that both Hcy and male sex were risk factors for CSFP. MTHFR C677T genotypes and the frequency distribution of 677T allele complied with Hardy-Weinberg equilibrium. CONCLUSION: CSFP was associated with a high level of plasma Hcy, and men were more vulnerable to CSFP. By regulating the plasma Hcy level, the MTHFR C677T gene polymorphism and folic acid level might be involved in the occurrence of CSFP. PMID- 25036860 TI - Insights into the denaturation of bovine serum albumin with a thermo-responsive ionic liquid. AB - Influence of bovine serum albumin on the phase transition behavior of the synthetic ionic liquid tetrabutylphosphonium styrenesulfonate ([P(4),(4),(4),(4)][SS]) together with the interactions between [P(4),(4),(4),(4)][SS] and bovine serum albumin (BSA) was investigated by differential scanning calorimetry (DSC), turbidity measurements, FT-IR, in combination with perturbation correlation moving window (PCMW) and two dimensional correlation spectroscopy (2DCOS). Our results reveal that the addition of BSA would increase the phase transition temperature but weaken the transition behavior of [P(4),(4),(4),(4)][SS] solution. DSC and turbidity data show us that the transition temperature of a ternary system with 20 wt% BSA added is 3 degrees C higher than that with 20% (w/v) [P(4),(4),(4),(4)][SS] solution. Interactions between [P(4),(4),(4),(4)][SS] and BSA together with the phase transition behavior of [P(4),(4),(4),(4)][SS] are responsible for the denaturation of BSA upon heating. PCMW determined the obvious distinctions in LCST of different chemical groups manifesting their various response sequences in the phase separation and denaturation upon heating. Finally, 2DCOS was employed to elucidate the sequential order of chemical group motions during heating. It is worth noting that the appearance of the isosbestic point in the C[double bond, length as m-dash]O groups of FTIR spectra indicates the direct transformation of the conformation of alpha-helix, random coil to beta-sheet and beta-turn without an intermediate transition state. Additionally, the phase separation process of ionic liquid is able to recover to the original state before heating while the denaturation of BSA is irreversible after a cooling process. PMID- 25036861 TI - Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. AB - BACKGROUND: Obese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats. METHODOLOGY: Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats. CONCLUSION: Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate. PMID- 25036862 TI - Prevalence and factors associated with herpes simplex virus type 2 infection in patients attending a Baltimore City emergency department. AB - OBJECTIVES: Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease, but there is limited data on its epidemiology among urban populations. The urban Emergency Department (ED) is a potential venue for surveillance as it predominantly serves an inner city minority population. We evaluate the seroprevalence and factors associated with HSV-2 infection among patients attending the Johns Hopkins Hospital Adult Emergency Department (JHH ED). METHODS: An identity unlinked-serosurvey was conducted between 6/2007 and 9/2007 in the JHH ED; sera were tested by the Focus HerpeSelect ELISA. Prevalence risk ratios (PRR) were used to determine factors associated with HSV-2 infection. RESULTS: Of 3,408 serum samples, 1,853 (54.4%) were seropositive for HSV-2. Females (adjPRR = 1.47, 95% CI 1.38-1.56), non-Hispanic blacks (adjPRR = 2.03, 95% CI 1.82-2.27), single (adjPRR = 1.15, 95% CI 1.07-1.25), divorced (adjPRR = 1.28, 95% CI 1.15-1.41), and unemployed patients (adjPRR = 1.13, 95% CI 1.05 1.21) had significantly higher rates of HSV-2 infection. Though certain zip codes had significantly higher seroprevalence of HSV-2, this effect was completely attenuated when controlling for age and gender. CONCLUSIONS: Seroprevalence of HSV-2 in the JHH ED was higher than U.S. national estimates; however, factors associated with HSV-2 infection were similar. The high seroprevalence of HSV-2 in this urban ED highlights the need for targeted testing and treatment. Cross sectional serosurveys in the urban ED may help to examine the epidemiology of HSV 2. PMID- 25036863 TI - Characterization and evolutionary implications of the triad Asp-Xxx-Glu in group II phosphopantetheinyl transferases. AB - Phosphopantetheinyl transferases (PPTases), which play an essential role in both primary and secondary metabolism, are magnesium binding enzymes. In this study, we characterized the magnesium binding residues of all known group II PPTases by biochemical and evolutionary analysis. Our results suggested that group II PPTases could be classified into two subgroups, two-magnesium-binding-residue PPTases containing the triad Asp-Xxx-Glu and three-magnesium-binding-residue PPTases containing the triad Asp-Glu-Glu. Mutations of two three-magnesium binding-residue-PPTases and one two-magnesium-binding-residue-PPTase indicate that the first and the third residues in the triads are essential to activities; the second residues in the triads are non-essential. Although variations of the second residues in the triad Asp-Xxx-Glu exist throughout the whole phylogenetic tree, the second residues are conserved in animals, plants, algae, and most prokaryotes, respectively. Evolutionary analysis suggests that: the animal group II PPTases may originate from one common ancestor; the plant two-magnesium binding-residue-PPTases may originate from one common ancestor; the plant three magnesium-binding-residue-PPTases may derive from horizontal gene transfer from prokaryotes. PMID- 25036864 TI - The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease. AB - Pompe disease is an inherited lysosomal storage disorder that results from a deficiency in acid alpha-glucosidase (GAA) activity due to mutations in the GAA gene. Pompe disease is characterized by accumulation of lysosomal glycogen primarily in heart and skeletal muscles, which leads to progressive muscle weakness. We have shown previously that the small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) binds and stabilizes wild-type as well as multiple mutant forms of GAA, and can lead to higher cellular levels of GAA. In this study, we examined the effect of AT2220 on mutant GAA, in vitro and in vivo, with a primary focus on the endoplasmic reticulum (ER)-retained P545L mutant form of human GAA (P545L GAA). AT2220 increased the specific activity of P545L GAA toward both natural (glycogen) and artificial substrates in vitro. Incubation with AT2220 also increased the ER export, lysosomal delivery, proteolytic processing, and stability of P545L GAA. In a new transgenic mouse model of Pompe disease that expresses human P545L on a Gaa knockout background (Tg/KO) and is characterized by reduced GAA activity and elevated glycogen levels in disease-relevant tissues, daily oral administration of AT2220 for 4 weeks resulted in significant and dose dependent increases in mature lysosomal GAA isoforms and GAA activity in heart and skeletal muscles. Importantly, oral administration of AT2220 also resulted in significant glycogen reduction in disease-relevant tissues. Compared to daily administration, less-frequent AT2220 administration, including repeated cycles of 4 or 5 days with AT2220 followed by 3 or 2 days without drug, respectively, resulted in even greater glycogen reductions. Collectively, these data indicate that AT2220 increases the specific activity, trafficking, and lysosomal stability of P545L GAA, leads to increased levels of mature GAA in lysosomes, and promotes glycogen reduction in situ. As such, AT2220 may warrant further evaluation as a treatment for Pompe disease. PMID- 25036865 TI - Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. AB - Bone marrow (BM)-derived mesenchymal stromal cells (MSCs), endowed with immunosuppressive and anti-inflammatory properties, represent a promising tool in immunoregulatory and regenerative cell therapy. Clarifying the interactions between MSCs and B-lymphocytes may be crucial for designing innovative MSC-based strategies in conditions in which B cells play a role, including systemic lupus erythematosus (SLE) and rejection of kidney transplantation. In this study, we show that, both in healthy subjects and in patients, in vitro B-cell proliferation, plasma-cell differentiation, and antibody production are inhibited by BM-derived MSCs when peripheral blood lymphocytes are stimulated with CpG, but not when sorted B cells are cultured with MSCs+CpG. Inhibition is restored in CpG+MSC cocultures when sorted T cells are added to sorted B cells, suggesting that this effect is mediated by T cells, with both CD4(+) and CD8(+) cells playing a role. Moreover, cell-cell contact between MSCs and T cells, but not between MSCs and B cells, is necessary to inhibit B-cell proliferation. Thus, the presence of functional T cells, as well as cell-cell contact between MSCs and T cells, are crucial for B-cell inhibition. This information can be relevant for implementing MSC-based therapeutic immune modulation in patients in whom T-cell function is impaired. PMID- 25036867 TI - A zirconium squarate metal-organic framework with modulator-dependent molecular sieving properties. AB - We report the first zirconium metal-organic framework based on squaric acid, representing the member with the smallest unit cell in the isoreticular UiO-66 family. Its molecular sieving properties are strongly influenced by the monocarboxylic acid modulator incorporated during synthesis. PMID- 25036866 TI - Stepwise threshold clustering: a new method for genotyping MHC loci using next generation sequencing technology. AB - Genes of the vertebrate major histocompatibility complex (MHC) are of great interest to biologists because of their important role in immunity and disease, and their extremely high levels of genetic diversity. Next generation sequencing (NGS) technologies are quickly becoming the method of choice for high-throughput genotyping of multi-locus templates like MHC in non-model organisms. Previous approaches to genotyping MHC genes using NGS technologies suffer from two problems:1) a "gray zone" where low frequency alleles and high frequency artifacts can be difficult to disentangle and 2) a similar sequence problem, where very similar alleles can be difficult to distinguish as two distinct alleles. Here were present a new method for genotyping MHC loci--Stepwise Threshold Clustering (STC)--that addresses these problems by taking full advantage of the increase in sequence data provided by NGS technologies. Unlike previous approaches for genotyping MHC with NGS data that attempt to classify individual sequences as alleles or artifacts, STC uses a quasi-Dirichlet clustering algorithm to cluster similar sequences at increasing levels of sequence similarity. By applying frequency and similarity based criteria to clusters rather than individual sequences, STC is able to successfully identify clusters of sequences that correspond to individual or similar alleles present in the genomes of individual samples. Furthermore, STC does not require duplicate runs of all samples, increasing the number of samples that can be genotyped in a given project. We show how the STC method works using a single sample library. We then apply STC to 295 threespine stickleback (Gasterosteus aculeatus) samples from four populations and show that neighboring populations differ significantly in MHC allele pools. We show that STC is a reliable, accurate, efficient, and flexible method for genotyping MHC that will be of use to biologists interested in a variety of downstream applications. PMID- 25036868 TI - Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats. AB - Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23-28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors. PMID- 25036869 TI - Decision-making impairments in breast cancer patients treated with tamoxifen. AB - The selective estrogen receptor modulator tamoxifen (TAM) is most commonly prescribed for patients with hormone-sensitive breast cancer. Although TAM can bind to estrogen receptors in the nervous system, it is unknown whether it acts as an estrogen agonist or antagonist in the human brain. Several studies have reported the negative effects of TAM on cognitive function; however, its effects on decision-making function have not been previously explored. The present study aimed to investigate the decision-making function under ambiguity and risk in breast cancer patients treated with TAM. Participants included breast cancer patients taking TAM (TAM, n=47) and breast cancer patients not taking TAM (non TAM, n=45) as well as their matched healthy controls (HC, n=50). All participants were given the Iowa Gambling Task (IGT) to assess their decision-making under conditions involving ambiguity, the Game of Dice Task (GDT) to assess their decision-making under conditions involving risk, and a battery of neuropsychological tests. Our results indicated that patients in the TAM group were significantly impaired as assessed by both the IGT and GDT and performed significantly worse on some aspects of various tasks involving memory and information processing. Furthermore, we found that decreased performance on verbal memory testing significantly correlated with IGT performance, and executive dysfunction was associated with poor GDT performance in breast cancer patients undergoing TAM treatment. This study demonstrates that breast cancer patients taking TAM have several decision-making impairments. These findings may support the idea that TAM resulting in cognitive changes plays an antagonistic role in the areas of the brain where estrogen receptors are present, including the prefrontal cortex, hippocampus and amygdala. PMID- 25036870 TI - A comparison of equivolume, equiosmolar solutions of hypertonic saline and mannitol for brain relaxation in patients undergoing elective intracranial tumor surgery: a randomized clinical trial. AB - BACKGROUND: Hyperosmolar solutions have been used in neurosurgery to modify brain bulk and prevent neurological deterioration. The purpose of the study was to compare the effects of equivolume, equiosmolar solutions of mannitol and hypertonic saline (HTS) on brain relaxation and postoperative complications in patients undergoing elective intracranial tumor surgery. METHODS: In this prospective, randomized study, patients with American Society of Anesthesiologists physical status I to III scheduled to undergo a craniotomy for intracranial tumors were enrolled. Patients received a 3.75 mL/kg intravenous infusion of either 3.2% HTS (group HTS, n=36) or 20% mannitol (group M, n=38). The surgeon assessed the condition of the brain using a 4-point scale after opening the dura. Recorded measures included duration of surgery, blood loss, urine output, volume and type of infused fluids, hemodynamic variables, electrolytes, glucose, creatinine, predefined postoperative complications, and length of intensive care unit and hospital stays. RESULTS: Brain relaxation conditions in group HTS (score 1/2/3/4, n=10/17/2/7) were better than those in group M (score 1/2/3/4, n=3/18/3/14, P=0.0281). Patients in group M had higher urine output, received more crystalloids during surgery, and displayed lower central venous pressure and lower natremia at the end of surgery than did patients in group HTS. No significant differences in postoperative complications or lengths of intensive care unit and hospital stays were observed between the groups. CONCLUSIONS: Our results suggest that HTS provides better brain relaxation than mannitol during elective intracranial tumor surgery. PMID- 25036872 TI - Management of asymptomatic cervical spinal stenosis in the setting of symptomatic tandem lumbar stenosis: a review. AB - INTRODUCTION: This article reviews the literature regarding tandem asymptomatic cervical stenosis in the setting of symptomatic lumbar stenosis. The presenting features of cervical spondylotic myelopathy are insidious and consistent with upper motor neuron loss. Often, asymptomatic cervical stenosis is encountered in the clinical setting during the workup of a symptomatic lumbar stenosis and degenerative disease. METHODS: A PubMed (1966 to July 2013) electronic database search was conducted for articles pertaining to the diagnosis of incidentally discovered cervical cord compression. Keywords and MESH terms were limited to asymptomatic cervical stenosis, asymptomatic cervical compression, asymptomatic spinal stenosis, asymptomatic cervical spondylosis, and asymptomatic cervical cord signal. The primary literature topics for manuscript inclusion were the development of symptomatic myelopathy from asymptomatic cord signal edema, as well as the presence of tandem stenosis as defined above by incidental cervical stenosis during the workup of lumbar degenerative disease. RESULTS: There were no previous systematic reviews, randomized trials, or prospective studies on the management of tandem cervical and thoracic stenosis. Five studies, all retrospective reviews containing relevant data were included in the review. Asymptomatic cervical stenosis encountered in the investigation of lumbar symptoms was had a 23% incidence. A risk of 5% per year of development of myelopathy previously reported. CONCLUSIONS: There is insufficient evidence in the literature to support the need for preemptive decompression for asymptomatic cervical cord compression with or without a correlative T2 hyperintense cord signal. Early diagnosis of radiculopathy or myelopathy in patients with cervical stenosis (i.e., through conversion of asymptomatic to symptomatic state) is important as each patient with in this clinical setting should be followed closely, as the literature shows the tendency for a clinical progression to eventual cervical myelopathy. PMID- 25036873 TI - Is progesteron receptor status really a prognostic factor for intracranial meningiomas? AB - OBJECTIVE: Presence of steroid hormone receptors in meningiomas is well-known, but their correlation with tumour behaviour is unclear. The purpose of this study was to assess the relation between steroid hormone receptor expression and tumour behaviour. METHODS: We retrospectively reviewed 48 patients undergoing surgery for intracranial meningioma between January 2002 and December 2004. We included World Health Organization (WHO) Grade I meningiomas in Group 1 and WHO Grades II and III in Group 2. Tumour grade, progesterone receptor (PR), oestrogen receptor (ER) expressions, MIB-1 Index and Mitotic Index were assessed. We sought the correlation between tumour grade and MIB-1, Mitotic Indices, and also PR expression. Furthermore, the correlation between PR expression and MIB-1 and Mitotic Indices was assessed in Group 1 and Group 2, separately. RESULTS: 26 patients were in Group 1 and 22 patients in Group 2. PR expression was determined in 56% of the tumours while there was no ER expression. PR expression was found to be higher in Group 1 compared to Group 2. The Mean MIB-1 Index and the Mean Mitotic Index were significantly higher in Group 2 compared to Group 1. However, when Groups 1 and 2 were assessed separately, PR expression does not appear to be correlated with MIB-1 and Mitotic Indices in benign and also in non-benign meningioma groups. CONCLUSION: Our findings suggest that tumour grade, but not PR expression, is correlated with meningioma behaviour. PMID- 25036874 TI - Reduced insulin clearance and lower insulin-degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein-restricted mice. AB - Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of insulin clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on insulin clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and insulinaemia, increased glucose tolerance and altered insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in insulin sensitivity through the phosphorylation of the insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in insulin dynamics could be attributed to reduced insulin secretion coupled with reduced insulin clearance and lower insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less insulin, but also remove and degrade less insulin. This phenomenon has the double benefit of sparing insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences. PMID- 25036875 TI - Protective role of probiotic lactic acid bacteria against dietary fumonisin B1 induced toxicity and DNA-fragmentation in sprague-dawley rats. AB - The genus Fusarium, especially F. verticillioides and F. proliferatum, has been found in several agricultural products worldwide, especially in maize. Regardless the occurrence of symptoms, the presence of Fusarium in maize constitutes an imminent risk due to its ability to produce fumonisins, mycotoxins with proven carcinogenic effect on rats, swine, and equines and already classified as possible carcinogens to humans. The toxicity of incremental levels of fumonisin B1 (FB1), that is, 50, 100, and 200 mg FB1/kg diet, and the role of Lactobacillus delbrueckii subsp. lactis DSM 20076 (LL) and Pediococcus acidilactici NNRL B-5627 (PA) supplementation in counteracting the FB1 effects in intoxicated rats were monitored over a period of 4 weeks. Effects on the feed intake and body weight gain were noticed. A significant (p <= 0.05) increase in the level of liver and kidney functions markers and DNA fragmentation was also noticed in rat groups T100 and T200. The lactic acid bacteria (LAB) supplementation could bring back the normal serum biochemical parameters in rats fed on fumonisin B1-contaminated diets (T50 and T100) compared to FB1-treated groups. In rats of high-dosage dietary groups supplemented with LAB (T200-LL and T200-PA), the supplementation reduced the serum activity levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatinine by 11.3, 11.9, 32, and 20%, respectively. DNA fragmentations were observed in the rat group treated with 200 mg FB1 after 3 weeks, while fragmentation was noticed in treated groups with 100 and 200 mg FB1 after 4 weeks. No DNA fragmentation was apparent in FB1-treated rats co-administered the LL or PA strain. These results suggest that in male rats consuming diets containing FB1, there is a time- and dose dependent increase in serum enzyme activities and DNA lesions. Moreover, Lb. delbrueckii subsp. lactis (LL) and P. acidilactici (PA) strains have a protective effect against antigenotoxicity and precancerous lesions. PMID- 25036871 TI - Rho GTPases modulate malignant transformation of tumor cells. AB - Rho GTPases are involved in the acquisition of all the hallmarks of cancer, which comprise 6 biological capabilities acquired during the development of human tumors. The hallmarks include proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis programs, as defined by Hanahan and Weinberg. (1) Controlling these hallmarks are genome instability and inflammation. Emerging hallmarks are reprogramming of energy metabolism and evading immune destruction. To give a different view to the readers, we will not be focusing on invasion, metastasis, or cytoskeletal remodeling, but we will review here how Rho GTPases contribute to other hallmarks of cancer with a special emphasis on malignant transformation. PMID- 25036876 TI - Prognostic impact of Bcl-2 depends on tumor histology and expression of MALAT-1 lncRNA in non-small-cell lung cancer. AB - INTRODUCTION: Apoptosis is a crucial pathway in tumor growth and metastatic development. Apoptotic proteins regulate the underlying molecular cascades and are thought to modulate the tumor response to chemotherapy and radiation. However, the prognostic value of the expression of apoptosis regulators in localized non-small-cell lung cancer (NSCLC) is still unclear. METHODS: We investigated the protein expression of apoptosis regulators Bcl-2, Bcl-xl, Mcl-1, and pp32/PHAPI, and the expression of the lncRNA MALAT-1 in tumor samples from 383 NSCLC patients (median age: 65.6 years; 77.5% male; paraffin-embedded tissue microarrays). For statistical analysis correlation tests, Log rank tests and Cox proportional hazard models were applied. RESULTS: Tumor histology was significantly associated with the expression of Bcl-2, Bcl-xl and Mcl-1 (all p < 0.001). Among the tested apoptotic markers only Bcl-2 demonstrated prognostic impact (hazard ratio = 0.64, p = 0.012). For NSCLC patients with non adenocarcinoma histology, Bcl-2 expression was associated with increased overall survival (p = 0.036). Besides tumor histology, prognostic impact of Bcl-2 was also found to depend on MALAT-1 lncRNA expression. Gene expression analysis of A549 adenocarcinoma cells with differential MALAT-1 lncRNA expression demonstrated an influence on the expression of Bcl-2 and its interacting proteins. CONCLUSIONS: Bcl-2 expression was specifically associated with superior prognosis in localized NSCLC. An interaction of Bcl-2 with MALAT-1 lncRNA expression was revealed, which merits further investigation for risk prediction in resectable NSCLC patients. PMID- 25036878 TI - Laser-assisted penetrating keratoplasty: 1-year results in patients using a laser welded anvil-profiled graft. AB - PURPOSE: To describe a new laser-assisted penetrating keratoplasty technique combining a femtosecond anvil-like trephination pattern with the laser welding procedure. DESIGN: Cohort prospective study with 1 year of follow-up (June 2011 through January 2013). METHODS: This study was performed at Misericordia e Dolce Public Hospital, Prato, Italy. Twenty-four eyes of 22 patients underwent penetrating keratoplasty: 4 had granular dystrophy, 12 had keratoconus in its final stages, 3 had post-herpetic leukoma, and 5 had corneal scars. A femtosecond laser was used to create anvil-profiled cuts in donor and recipient corneas. Diode laser welding was performed, supporting standard suturing. All patients were evaluated for corrected distance visual acuity, pachymetry, manifest astigmatism, and endothelial cell density after 1, 3, 6, and 12 months. RESULTS: Mean +/- standard deviation postoperative corrected visual acuity was 0.48 +/- 0.23 logarithm of the minimal angle of resolution (logMAR), 0.30 +/- 0.18 logMAR, 0.18 +/- 0.13 logMAR, and 0.13 +/- 0.16 logMAR at 1, 3, 6, and 12 months, respectively. At the same follow-up times, mean pachymetry was 537 +/- 57 MUm, 533 +/- 74 MUm, 528 +/- 72 MUm, and 529 +/- 58 MUm, respectively; and mean endothelial cell density was 1945 +/- 371 cells/mm(2), 1881 +/- 410 cells/mm(2), 1781 +/- 401 cells/mm(2), and 1730 +/- 376 cells/mm(2), respectively. Mean manifest and topographic postoperative astigmatism were: 3.6 +/- 2.5 diopters (D) and 4.65 +/- 2.57 D at 1 month, 2.93 +/- 2.34 D and 4.79 +/- 2.85 D at 3 months, 2.82 +/- 1.75 D and 3.44 +/- 2.28 D at 6 months, and 2.08 +/- 1.25 D and 2.73 +/- 2.01 D at 12 months, respectively. All surgical operations were successful and without intraoperative complications. CONCLUSIONS: The use of the anvil trephination profile was effective for performing laser-assisted penetrating keratoplasty. The large donor-recipient interface enables the laser welding procedure and good preservation of the recipient's endothelial cell pool. PMID- 25036877 TI - Systematic identification and characterization of RNA editing in prostate tumors. AB - RNA editing modifies the sequence of primary transcripts, potentially resulting in profound effects to RNA structure and protein-coding sequence. Recent analyses of RNA sequence data are beginning to provide insights into the distribution of RNA editing across the entire transcriptome, but there are few published matched whole genome and transcriptome sequence datasets, and designing accurate bioinformatics methodology has proven highly challenging. To further characterize the RNA editome, we analyzed 16 paired DNA-RNA sequence libraries from prostate tumor specimens, employing a comprehensive strategy to rescue low coverage sites and minimize false positives. We identified over a hundred thousand putative RNA editing events, a third of which were recurrent in two or more samples, and systematically characterized their type and distribution across the genome. Within genes the majority of events affect non-coding regions such as introns and untranslated regions (UTRs), but 546 genes had RNA editing events predicted to result in deleterious amino acid alterations. Finally, we report a potential association between RNA editing of microRNA binding sites within 3' UTRs and increased transcript expression. These results provide a systematic characterization of the landscape of RNA editing in low coverage sequence data from prostate tumor specimens. We demonstrate further evidence for RNA editing as an important regulatory mechanism and suggest that the RNA editome should be further studied in cancer. PMID- 25036879 TI - Granulomatous dacryoadenitis in regional enteritis (crohn disease). AB - PURPOSE: To evaluate the clinical and immunopathologic features of 2 patients with bilateral dacryoadenitis associated with regional enteritis. DESIGN: Retrospective, clinicopathologic study. METHODS: Clinical records, photographs, and imaging studies were reviewed and microscopic sections of lacrimal gland biopsy samples were critically re-evaluated. The microscopic slides were stained with hematoxylin and eosin, special stains for organisms, and a range of immunohistochemical biomarkers, including CD3, CD4, CD5, CD8, CD20, CD68, CD138, CD1a, and immunoglobulins Ig G, IgG4, and IgA. RESULTS: Both patients were young women with a well-established diagnosis of regional enteritis. Histopathologic examination of biopsy samples disclosed moderate intraparenchymal fibrosis and lymphoplasmacytic infiltrates without lymphoid follicles. Small to medium intraparenchymal, noncaseating granulomas lacking multinucleated giant cells and, in 1 patient, CD68-positive and CD1a-negative palisading granulomas in widened interlobular fibrous septa were detected. Vasculitis and IgG4 plasma cells were not observed. Additional immunohistochemical studies revealed that CD8 T lymphocytes (suppressor or cytotoxic subset) predominated over CD4-positive T lymphocytes (helper cells) surrounding the necrobiotic foci and were intermixed with the CD68-positive histiocytes in the absence of CD20 B lymphocytes. Special stains for organisms demonstrated negative results. CONCLUSIONS: Dacryoadenitis is the rarest form of ocular adnexal involvement in regional enteritis, which affects the orbit far more frequently than ulcerative colitis. It is a granulomatous process with the possibility of palisading necrobiotic foci. In contrast, ulcerative colitis causes an interstitial lymphocytic and nongranulomatous myositis. Sarcoidosis, Wegener granulomatosis, and pseudorheumatoid nodules must be ruled out. Treatment options entail a wide variety of agents with selection based on empirical considerations and tailored to the patient's symptoms. PMID- 25036880 TI - Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib. AB - PURPOSE: To determine the frequency of ocular adverse effects associated with vemurafenib (PLX4032) treatment for metastatic cutaneous melanoma. DESIGN: Retrospective review of the clinical study reports from the clinical pharmacology, phase 1, phase 2, and phase 3 trials of vemurafenib. METHODS: The vemurafenib clinical trials were a multicenter series involving adult patients with histologically confirmed, BRAF(V600) mutation-positive, unresectable, stage IIIC or IV melanoma. A total of 855 patients were enrolled in the trials: 568 patients were treated with vemurafenib and 287 patients were treated with dacarbazine. RESULTS: Among the 568 patients treated with vemurafenib, ocular adverse effects developed in 22% (95% confidence interval [CI], 18.5-25.6). The most common ocular diagnosis was uveitis (4.0%; 95% CI, 2.6-6.0), followed by conjunctivitis (2.8%; 95% CI, 1.6-4.5) and dry eyes (2.0%; 95% CI, 1.1-3.7). All were successfully managed while vemurafenib therapy was continued. CONCLUSIONS: Ocular adverse events and symptoms may be seen in more than one-fifth of patients being treated with vemurafenib. However, vemurafenib can be continued while the ocular symptoms are being managed. The pathogenesis of ocular symptoms in this patient population is unclear; additional studies are necessary. PMID- 25036881 TI - Tear exchangeable limbal rigid contact lens for ocular sequelae resulting from Stevens-Johnson syndrome or toxic epidermal necrolysis. AB - PURPOSE: To evaluate the therapeutic benefits of tear-exchangeable, limbal, rigid contact lenses (limbal CLs) in patients with Stevens-Johnson syndrome- or toxic epidermal necrolysis-associated ocular sequelae. DESIGN: Noncomparative, retrospective, interventional case series. METHODS: We enrolled 53 eyes of 42 patients (mean age, 51.8 +/- 13.9 years; mean follow-up, 25.7 +/- 15.7 months) with Stevens-Johnson syndrome- or toxic epidermal necrolysis-associated ocular sequelae and divided them into 3 groups according to the best-corrected visual acuity (BCVA) before limbal CL fitting: (1) BCVA worse than 20/2000 (11 eyes), (2) BCVA ranging from 20/200 to 20/2000 (31 eyes), and (3) BCVA of 20/200 or better (11 eyes). The BCVA and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score before fitting and after 3 months of limbal CL use were evaluated. The change in BCVA (in logarithm of the minimal angle of resolution [logMAR] units) and 25-item National Eye Institute Visual Function Questionnaire composite score change were compared among the 3 groups. RESULTS: Best-corrected visual acuity improved from 1.61 to 0.86 logMAR at 3 months after fitting CL use. Improvement in BCVA in groups 1, 2, and 3 was 0.95 logMAR, 0.82 logMAR, and 0.37 logMAR, respectively. The mean 25-item National Eye Institute Visual Function Questionnaire composite score for the 11 subscales improved from 37.6 +/- 16.0 to 58.4 +/- 17.4 (P = .000001). All 11 subscores, except that for driving ability, improved significantly. The general vision subscore improved most in group 3, yet the general health subscore improved most in group 1. No serious adverse events attributable to limbal CL use occurred. CONCLUSIONS: The tear-exchangeable limbal CL is safe and effective for the improvement of vision and quality of life in Stevens-Johnson syndrome or toxic epidermal necrolysis patients with severe ocular sequelae. PMID- 25036882 TI - Monitoring of 35 illegally added steroid compounds in foods and dietary supplements. AB - The adulteration of foods and dietary supplements with steroids has been well attested and has the potential to be dangerous owing to various possible side effects. Therefore, detecting the presence of steroids in various health food products has become increasingly important. The purpose of this study was to monitor illegally adulterated health food products by applying multiple reaction monitoring techniques to tandem liquid chromatography-mass spectrometry (LC MS/MS). Various food and supplement samples advertised for the treatment of arthritis, bone ache and joint pain were collected over a 4-year period (2010-13) from local and online Korean sources. The method was validated based on limits of quantification of 0.5-15.0 ng g(-1) and recoveries in spiked solid samples of 81 119%. Approximately 30% of the tested samples were identified as having been illicitly adulterated. Six compounds were observed overall, including dexamethasone (45.1%), cotrisone-21-aceteate and prednisone-21-acetate (16.2%), and betamethasone (14.4%), and found in some samples in high concentrations. PMID- 25036883 TI - Immunotherapy for ovarian cancer: recent advances and perspectives. AB - PURPOSE OF REVIEW: Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women, and prognosis for patients with recurrent or metastatic disease is extremely poor. Therefore, there is an enormous unmet need for the development of novel therapies in this indication. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies, such as immunotherapy to improve the outcomes for patients with advanced ovarian cancer. RECENT FINDINGS: We will discuss the rationale of immunotherapy and some of the mechanisms of immunogenicity in ovarian cancer. We will highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and will summarize the immune effects of selected chemotherapeutic agents, radiotherapy and recent results with combinatorial approaches in this disease setting. We will also discuss recent and potential future therapeutic interventions that might circumvent tumor-mediated immunosuppression. SUMMARY: Dramatic increase in the number of immunotherapy clinical trials was seen in the past decade with promising results in enhancing antitumor immune response and cancer vaccine efficacy. The future challenge for immunotherapy against ovarian cancer is to use a combinatorial approach to test rational, potentially synergistic immunotherapy combinations that can induce efficient antitumor immunity and prolong patients' survival. PMID- 25036885 TI - Comparative analysis of virus-specific small RNA profiles of three biologically distinct strains of Potato virus Y in infected potato (Solanum tuberosum) cv. Russet Burbank. AB - Deep sequencing technology has enabled the analysis of small RNA profiles of virus-infected plants and could provide insights into virus-host interactions. Potato virus Y is an economically important viral pathogen of potato worldwide. In this study, we investigated the nature and relative levels of virus-derived small interfering RNAs (vsiRNAs) in potato cv. Russet Burbank infected with three biologically distinct and economically important strains of PVY, the ordinary strain (PVY-O), tobacco veinal-necrotic strain (PVY-N) and tuber necrotic strain (PVY-NTN). The analysis showed an overall abundance of vsiRNAs of 20-24nt in PVY infected plants. Considerable differences were present in the distribution of vsiRNAs as well as total small RNAs. The 21nt class was the most prevalent in PVY infected plants irrespective of the virus strain, whereas in healthy potato plants, the 24nt class was the most dominant. vsiRNAs were derived from every position in the PVY genome, though certain hotspots were identified for each of the PVY strains. Among the three strains used, the population of vsiRNAs of different size classes was relatively different with PVY-NTN accumulating the highest level of vsiRNAs, while PVY-N infected plants had the least population of vsiRNAs. Unique vsiRNAs mapping to PVY genome in PVY-infected plants amounted to 3.13, 1.93 and 1.70% for NTN, N and O, respectively. There was a bias in the generation of vsiRNAs from the plus strand of the genome in comparison to the negative strand. The highest number of total vsiRNAs was from the cytoplasmic inclusion protein gene (CI) in PVY-O and PVY-NTN strains, whereas from PVY-N, the NIb gene produced maximum total vsiRNAs. These findings indicate that the three PVY strains interact differently in the same host genetic background and provided insights into virus-host interactions in an important food crop. PMID- 25036884 TI - Cavin-3 knockout mice show that cavin-3 is not essential for caveolae formation, for maintenance of body composition, or for glucose tolerance. AB - The cavins are a family of proteins associated with caveolae, cavin-1, -2 and -3 being widely expressed while cavin-4 is restricted to striated muscle. Deletion of cavin-1 results in phenotypes including metabolic changes consistent with adipocyte dysfunction, and caveolae are completely absent. Deletion of cavin-2 causes tissue-specific loss of caveolae. The consequences of cavin-3 deletion are less clear, as there are divergent data on the abundance of caveolae in cavin-3 null mice. Here we examine the consequences of cavin-3 deficiency in vivo by making cavin-3 knockout mice. We find that loss of cavin-3 has minimal or no effects on the levels of other caveolar proteins, does not appear to play a major role in formation of protein complexes important for caveolar morphogenesis, and has no significant effect on caveolae abundance. Cavin-3 null mice have the same body weight and fat mass as wild type animals at ages 8 through 30 weeks on both normal chow and high fat diets. Likewise, the two mouse strains exhibit identical glucose tolerance tests on both diets. Microarray analysis from adipose tissue shows that the changes in mRNA expression between cavin-3 null and wild type mouse are minimal. We conclude that cavin-3 is not absolutely required for making caveolae, and suggest that the mechanistic link between cavin-3 and metabolic regulation remains uncertain. PMID- 25036886 TI - Roles of HIV-1 capsid in viral replication and immune evasion. AB - The primary roles of the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein are to encapsidate and protect the viral RNA genome. It is becoming increasing apparent that HIV-1 CA is a multifunctional protein that acts early during infection to coordinate uncoating, reverse transcription, nuclear import of the pre-integration complex and integration of double stranded viral DNA into the host genome. Additionally, numerous recent studies indicate that CA is playing a crucial function in HIV-1 immune evasion. Here we summarize the current knowledge on HIV-1 CA and its interactions with the host cell to promote infection. The fact that CA engages in a number of different protein-protein interactions with the host makes it an interesting target for the development of new potent antiviral agents. PMID- 25036889 TI - Copper(II) complexes of bis(aryl-imino)acenaphthene ligands: synthesis, structure, DFT studies and evaluation in reverse ATRP of styrene. AB - Two new Ar-BIAN Cu(II) complexes (where Ar-BIAN = bis(aryl-imino)acenaphthene) of formulations [CuCl2(Mes-BIAN)] (1) (Mes = 2,4,6-Me3C6H2) and [CuCl2(Dipp-BIAN)] (2) (Dipp = 2,6-iPr2C6H3) were synthesised by direct reaction of CuCl2 suspended in dichloromethane with the respective ligands Mes-BIAN (L1) and Dipp-BIAN (L2), dissolved in dichloromethane, under an argon atmosphere. Attempts to obtain these compounds by solubilising CuCl2 in methanol and adding a dichloromethane solution of the corresponding ligand, under aerobic conditions, gave also compound 1, but, in the case of L2, the Cu(I) dimer [CuCl(Dipp-BIAN)]2 (3) was obtained instead of compound 2. The compounds were fully characterised by elemental analyses, MALDI TOF mass spectrometry, FT-IR, (1)H NMR and EPR spectroscopic techniques. The solid-state molecular structures of compounds 1-3 were determined by single crystal X-ray diffraction, showing the expected chelation of the Ar-BIAN ligands and two chloride ligands completing the coordination sphere of the Cu(II) centre. In the case of the complex 1, an intermediate coordination geometry around the Cu(II) centre, between square planar and tetrahedral, was revealed, while the complex 2 showed an almost square planar geometry. The structural differences and evaluation of energetic changes were rationalised by DFT calculations. Analysis of the electrochemical behaviour of complexes 1-3 was performed by cyclic voltammetry and the experimental redox potentials for Cu(II)/Cu(I) pairs have been compared with theoretical values calculated by DFT in the gas phase and in dichloromethane and methanol solutions. The complex 1 exhibited good activity in the reverse atom transfer radical polymerisation (ATRP) of styrene. PMID- 25036888 TI - Chaperoning proteins for destruction: diverse roles of Hsp70 chaperones and their co-chaperones in targeting misfolded proteins to the proteasome. AB - Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the Ub-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the Ub ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review, we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases. PMID- 25036890 TI - Applying incentive sensitization models to behavioral addiction. AB - The incentive sensitization theory is a promising model for understanding the mechanisms underlying drug addiction, and has received support in animal and human studies. So far the theory has not been applied to the case of behavioral addictions like Gambling Disorder, despite sharing clinical symptoms and underlying neurobiology. We examine the relevance of this theory for Gambling Disorder and point to predictions for future studies. The theory promises a significant contribution to the understanding of behavioral addiction and opens new avenues for treatment. PMID- 25036891 TI - Effects of mixing alcohol with caffeinated beverages on subjective intoxication: a systematic review and meta-analysis. AB - It has been suggested that mixing alcohol with energy drinks or other caffeinated beverages may alter the awareness of (or 'mask') intoxication. The proposed reduction in subjective intoxication may have serious consequences by increasing the likelihood of engaging in potentially dangerous activities while intoxicated. A literature search was conducted to collect all studies measuring subjective intoxication after administration of alcohol with energy drinks, or with other caffeinated alcoholic drinks compared with alcohol alone. The studies were critically reviewed and, where possible, included in a meta-analysis in order to determine whether masking exists after mixing alcohol with caffeinated beverages. Sixteen articles were identified, of which nine could be used for the meta analysis. When including the higher caffeine dose studies, the meta-analysis revealed no significant masking effect (p=0.404). Similarly, when including the lower caffeine dose studies, no significant masking effect was found (p=0.406). Despite the large range of caffeine doses (2.0-5.5 mg/kg resulting in absolute levels of 46-383 mg) and alcohol levels 0.29-1.068 g/kg (resulting in blood alcohol concentration (BAC) from 0.032 to 0.12%) investigated, caffeine had no effect on the judgement of subjective intoxication. PMID- 25036887 TI - New perspectives on oxidized genome damage and repair inhibition by pro-oxidant metals in neurological diseases. AB - The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region(s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases. PMID- 25036892 TI - Memory-related brain lateralisation in birds and humans. AB - Visual imprinting in chicks and song learning in songbirds are prominent model systems for the study of the neural mechanisms of memory. In both systems, neural lateralisation has been found to be involved in memory formation. Although many processes in the human brain are lateralised--spatial memory and musical processing involves mostly right hemisphere dominance, whilst language is mostly left hemisphere dominant--it is unclear what the function of lateralisation is. It might enhance brain capacity, make processing more efficient, or prevent occurrence of conflicting signals. In both avian paradigms we find memory-related lateralisation. We will discuss avian lateralisation findings and propose that birds provide a strong model for studying neural mechanisms of memory-related lateralisation. PMID- 25036893 TI - Effects of slag-based silicon fertilizer on rice growth and brown-spot resistance. AB - It is well documented that slag-based silicon fertilizers have beneficial effects on the growth and disease resistance of rice. However, their effects vary greatly with sources of slag and are closely related to availability of silicon (Si) in these materials. To date, few researches have been done to compare the differences in plant performance and disease resistance between different slag based silicon fertilizers applied at the same rate of plant-available Si. In the present study both steel and iron slags were chosen to investigate their effects on rice growth and disease resistance under greenhouse conditions. Both scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to examine the effects of slags on ultrastructural changes in leaves of rice naturally infected by Bipolaris oryaze, the causal agent of brown spot. The results showed that both slag-based Si fertilizers tested significantly increased rice growth and yield, but decreased brown spot incidence, with steel slag showing a stronger effect than iron slag. The results of SEM analysis showed that application of slags led to more pronounced cell silicification in rice leaves, more silica cells, and more pronounced and larger papilla as well. The results of TEM analysis showed that mesophyll cells of slag-untreated rice leaf were disorganized, with colonization of the fungus (Bipolaris oryzae), including chloroplast degradation and cell wall alterations. The application of slag maintained mesophyll cells relatively intact and increased the thickness of silicon layer. It can be concluded that applying slag-based fertilizer to Si deficient paddy soil is necessary for improving both rice productivity and brown spot resistance. The immobile silicon deposited in host cell walls and papillae sites is the first physical barrier for fungal penetration, while the soluble Si in the cytoplasm enhances physiological or induced resistance to fungal colonization. PMID- 25036894 TI - An assessment of the measurement equivalence of English and French versions of the Center for Epidemiologic Studies Depression (CES-D) Scale in systemic sclerosis. AB - OBJECTIVES: Center for Epidemiologic Studies Depression (CES-D) Scale scores in English- and French-speaking Canadian systemic sclerosis (SSc) patients are commonly pooled in analyses, but no studies have evaluated the metric equivalence of the English and French CES-D. The study objective was to examine the metric equivalence of the CES-D in English- and French-speaking SSc patients. METHODS: The CES-D was completed by 1007 English-speaking and 248 French-speaking patients from the Canadian Scleroderma Research Group Registry. Confirmatory factor analysis (CFA) was used to assess the factor structure in both samples. The Multiple-Indicator Multiple-Cause (MIMIC) model was utilized to assess differential item functioning (DIF). RESULTS: A two-factor model (Positive and Negative affect) showed excellent fit in both samples. Statistically significant, but small-magnitude, DIF was found for 3 of 20 CES-D items, including items 3 (Blues), 10 (Fearful), and 11 (Sleep). Prior to accounting for DIF, French speaking patients had 0.08 of a standard deviation (SD) lower latent scores for the Positive factor (95% confidence interval [CI]-0.25 to 0.08) and 0.09 SD higher scores (95% CI-0.07 to 0.24) for the Negative factor than English-speaking patients. After DIF correction, there was no change on the Positive factor and a non-significant increase of 0.04 SD on the Negative factor for French-speaking patients (difference = 0.13 SD, 95% CI-0.03 to 0.28). CONCLUSIONS: The English and French versions of the CES-D, despite minor DIF on several items, are substantively equivalent and can be used in studies that combine data from English- and French-speaking Canadian SSc patients. PMID- 25036895 TI - Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models. AB - Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. PMID- 25036896 TI - Relationship between the paraoxonase 1 gene glutamine 192 to arginine polymorphism and gestational diabetes mellitus in Saudi women. AB - OBJECTIVES: Gestational diabetes mellitus (GDM) is recognized as an imbalance between insulin resistance and insulin secretion, leading to maternal hyperglycemia. Previous studies in a Saudi population indicated a high frequency of Paraoxonase 1 glutamine 192 to arginine (PON1 Q192R) polymorphism, suggesting this polymorphism as an additional risk factor. The present study was designed to explore the possible association between the PON1 Q192R polymorphism and GDM in a Saudi population. METHODS: This case-control study was carried out in 500 pregnant women, including 200 GDM cases and 300 non-GDM women. Genotyping for PON1 Q192R (rs662) variants was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The results of the present study indicates that Q192R polymorphism was significantly associated with GDM in a Saudi population with the minor allele frequency (MAF) (p=0.0007). Q192R genotypes and alleles showed a strong association with GDM (p=0.009 and p=0.0007, respectively). CONCLUSION: In conclusion, these findings suggest that the PON1 Q192R polymorphism has high MAF in GDM in the studied Saudi population. PMID- 25036897 TI - Slow versus fast subcutaneous heparin injections for prevention of bruising and site-pain intensity. AB - BACKGROUND: Heparin is an anticoagulant medication that is normally injected subcutaneously. Subcutaneous administration of heparin may result in complications such as bruising, haematoma and pain at the injection site. One of the factors that may affect pain, haematoma and bruising is injection speed. OBJECTIVES: To assess the effects of the duration (speed) of subcutaneous heparin injection on pain, haematoma and bruising at the injection site in people admitted to hospitals or clinics who require treatment with unfractionated heparin or low molecular weight heparin. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched August 2013) and CENTRAL (2013, Issue 7). We searched MEDLINE, EMBASE, CINAHL and two Persian databases Iranmedex and SID (August 2013). SELECTION CRITERIA: We sought randomised controlled trials (RCTs) comparing the effects of different durations of subcutaneous injections of heparin on pain, bruising and haematoma at the injection site. DATA COLLECTION AND ANALYSIS: Two review authors, working independently, extracted data onto a structured form and assessed study quality. We used the criteria recommended by the Cochrane Handbook to assess the quality of included studies. The study outcomes were summarised using quantitative and qualitative methods. MAIN RESULTS: One RCT was identified which met the inclusion criteria, involving 50 participants with a mean age of 55.25 (+/- 12.37) years. In this trial it was not possible to blind the participants and care givers. The method of sequence generation and allocation concealment was not described. The overall quality of the evidence was moderate due to the single small included study. Each participant had two injections, one in the left side and one in right side of the abdomen. One of these was injected slowly (intervention) and the other was injected fast (control). The second injection was 12 hours after the first injection. The duration of fast injection was 10 seconds and the duration of slow injection was 30 seconds. The study reported a significantly lower pain intensity for slow versus fast injection. The mean pain intensity was 13.9 +/- 17.1 mm with the slow injection and 20.6 +/- 22.3 mm with the fast injection (P < 0.001). In addition the bruising sizes were smaller with slow injections compared to fast injections at 48 hours follow-up (mean bruising size 18.76 +/- 9.32 mm(2) with the slow injection and 109.2 +/- 468.66 mm(2) with the fast injection, P = 0.033) and 72 hours follow-up (mean bruising size 21.72 +/- 76.16 mm(2) with the slow injection and 110.12 +/- 472.86 mm(2) with the fast injection, P = 0.025). The incidence of haematoma was not measured as an outcome. AUTHORS' CONCLUSIONS: There is only limited evidence of any difference in pain intensity and bruising sizes following slow versus fast injections due to the inclusion of only one small unblinded trial. The single included study suggests that slow injection might have slightly lower pain intensity and bruising size at the heparin injection site, but the results should be considered with caution. Until more reliable evidence emerges, slow injection might be the preferred approach. PMID- 25036898 TI - An added dimension: GC atmospheric pressure chemical ionization FTICR MS and the Athabasca oil sands. AB - The Athabasca oil sands industry, an alternative source of petroleum, uses large quantities of water during processing of the oil sands. In keeping with Canadian environmental policy, the processed water cannot be released to natural waters and is thus retained on-site in large tailings ponds. There is an increasing need for further development of analytical methods for environmental monitoring. The following details the first example of the application of gas chromatography atmospheric pressure chemical ionization Fourier transform ion cyclotron resonance mass spectrometry (GC-APCI-FTICR MS) for the study of environmental samples from the Athabasca region of Canada. APCI offers the advantages of reduced fragmentation compared to other ionization methods and is also more amenable to compounds that are inaccessible by electrospray ionization. The combination of GC with ultrahigh resolution mass spectrometry can improve the characterization of complex mixtures where components cannot be resolved by GC alone. This, in turn, affords the ability to monitor extracted ion chromatograms for components of the same nominal mass and isomers in the complex mixtures. The proof of concept work described here is based upon the characterization of one oil sands process water sample and two groundwater samples in the area of oil sands activity. Using the new method, the Ox and OxS compound classes predominated, with OxS classes being particularly relevant to the oil sands industry. The potential to resolve retention times for individual components within the complex mixture, highlighting contributions from isomers, and to characterize retention time profiles for homologous series is shown, in addition to the ability to follow profiles of double bond equivalents and carbon number for a compound class as a function of retention time. The method is shown to be well-suited for environmental forensics. PMID- 25036899 TI - Control of phosphate homeostasis through gene regulation in crops. AB - Phosphorus (P) is an essential yet frequently deficient element in plants. Maintenance of phosphate (Pi) homeostasis is crucial for crop production. In comparison with the model plant Arabidopsis, crops face wider ranges and larger fluctuations in P supply from the soil environment, and thus develop more complicated strategies to improve Pi acquisition and utilization efficiency. Undergirding these strategies, there are numerous genes involved in alternative metabolism pathways that are regulated by complex Pi signaling networks. In this review, we intend to summarize the recent advances in crops on control of Pi homeostasis through gene regulation from Pi acquisition and mobilization within plants, as well as activation of rhizosphere P and P uptake through symbiotic associations. PMID- 25036900 TI - Acute diarrhea demanding hospitalization in rural India. PMID- 25036901 TI - Complex metastatic niches: already a target for therapy? AB - Metastatic spread is an inefficient process which requires generation of supportive microenvironments in which cancer cells can survive, proliferate and escape from immune attack. These niches are induced by systemic and locally produced factors and establish a tumor-supportive and immune suppressive environment which is molecularly and functionally different from the niche at the primary site. Tumor dormancy may result if the niche is not sufficiently supportive/protective. Co-evolution of cancer cells and the surrounding microenvironment creates a large number of such dynamic niches, and we are just beginning to elucidate the complexity of these interactions and their tissue specific differences. We will discuss exciting possibilities but also challenges which are immanent when trying to target these stromal responses for diagnosis and therapy. PMID- 25036902 TI - Psychiatric outcome of epilepsy surgery in patients with psychosis and temporal lobe drug-resistant epilepsy: a prospective case series. AB - OBJECTIVES: Temporal lobe resistant epilepsy has been associated with a high incidence of psychotic disorders; however, there are many controversies; while some patients get better after surgery from their psychiatric condition, others develop psychosis or de novo depression. The aim of this study was to determine the psychiatric and seizure outcome after epilepsy surgery in patients with a previous history of psychoses. METHODS: Surgical candidates with temporal lobe drug-resistant epilepsy and a positive history of psychosis diagnosed during the presurgical psychiatric assessment were included. A two-year prospective follow up was determined after surgery. The DSM-IV Structural Interview, GAF (global assessment of functionality, DSM-IV), Ictal Classification for psychoses, and Engel's classification were used. The Student t test and chi-square-Fisher tests were used. RESULTS: During 2000-2010, 89 patients were admitted to the epilepsy surgery program, 14 patients (15.7%) presented psychoses and were included in this series. After surgery, six patients (43%) did not develop any psychiatric complications, three patients (21%) with chronic interictal psychosis continued with no exacerbation, three patients (21%) developed acute and transient psychotic symptoms, and two patients (14%) developed de novo depression. Seizure outcome was Engel class I-II in 10 patients (71%). Total GAF scores were higher after surgery in patients found to be in Engel class I-II (p<0.05). CONCLUSIONS: Patients with comorbid psychosis and temporal lobe drug-resistant epilepsy may benefit from epilepsy surgery under close psychiatric supervision. PMID- 25036903 TI - Coexistence of genotypic and temperature-dependent sex determination in pejerrey Odontesthes bonariensis. AB - In this study, we examined whether a homolog of the master sex-determining gene amhy of Odontesthes hatcheri is present and plays any role in testis determination of pejerrey O. bonariensis, a species otherwise known for its strong temperature-dependent sex determination (TSD). Screening of wild and laboratory-reared pejerrey for amhy revealed a high, although not complete linkage with phenotypic sex. The sex ratio in an amhy+/-/amhy-/- full sibling progeny reared during the thermolabile period of sex determination at an intermediate temperature of 25 degrees C was 68.7% male:31.3% female; all amhy+/- fish developed as males whereas about 2/3 and 1/3 of the amhy-/- were female and male, respectively. Expression analyses revealed that amhy transcription began during embryo stage and decreased by the end of sex determination period. The autosomal amha was present in all individuals regardless of amhy genotype; its expression increased significantly from the end of the same period in the gonads of all amhy+/- but only in part of the amhy-/- animals. After histological gonadal differentiation, all gonads of amhy-/- animals with amha ISH signals were testes and those without it were ovaries. These results suggest that amhy is important for testicular differentiation in pejerrey, at least at intermediate temperatures. Thus, we hypothesize that amhy+/- animals differentiate as males by expression of either amhy alone or amhy and amha together whereas the amhy-/- probably rely solely on amha expression. These findings represent the first clear genomic evidence that genotypic and environmental sex determinants can coexist in species with marked TSD such as the pejerrey. The finding of amhy will make possible to monitor wild pejerrey populations for mismatches between genotypic and phenotypic sex and may prove instrumental for field studies addressing the effects of endocrine disruptors or abnormal temperatures on reproduction and the ecological relevance of TSD for this species. PMID- 25036904 TI - Simultaneous quantification of MTC-220 and its metabolites in beagle dog plasma by liquid chromatography-tandem mass spectrometry. AB - A sensitive LC-ESI-MS/MS method for simultaneous determination of MTC-220 and its metabolites (paclitaxel and MDA-linker) in dog plasma has been developed and validated. After addition of docetaxel (internal standard), plasma samples containing MTC-220, paclitaxel and MDA-linker were prepared based on a simple protein precipitation by adding two volumes of acetonitrile. The separation was performed on a ZorbaxSB-C18 column (3.5MUm, 2.1mm*100mm) at a flow rate of 0.2ml/min, using acetonitrile/water containing 0.1% formic acid (v/v) as mobile phase. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) by selected reaction monitoring (SRM). The MS/MS ion transit ions monitored were 1444.4->623.8 for MTC 220, 876.4->307.9 for paclitaxel, 631.2->531.2 for MDA-linker and 830.2->549.1 for the internal standard. Linear detection responses were obtained for MTC-220, paclitaxel and MDA-linker ranging from 10 to 5000, 5 to 2500 and 5 to 500ng/ml, respectively. The lower limits of quantitation (LLOQs) for MTC-220, paclitaxel and MDA-linker were 10, 5 and 5ng/ml, respectively. The intra-day and inter-day precisions (RSD, %) of the three analytes do not exceed 10.9% except for LLOQs (<=17.50), and the accuracy (RE, %) were within +/-17.5% for LLOQs and +/-12.6% for the others. The average recoveries of three compounds were greater than 85.0%. The analytes were proved to be stable during all sample storage, preparation and analytic procedures. The validated method was successfully applied to pharmacokinetic studies of MTC-220 and its metabolites in beagle dogs after intravenous infusion of MTC-220 at 2.5mg/kg. PMID- 25036905 TI - Heme oxygenase-1 gene promoter polymorphism is associated with the development of necrotizing acute pancreatitis. AB - OBJECTIVES: Acute pancreatitis is a severe and frequently life-threatening disease, which can lead to pancreatic necrosis, acute lung injury, systemic inflammatory response syndrome, and other complications. In this study, we hypothesized that the expression of heme oxygenase-1 determined by the number of guanidinium thiocyanate (GT) repeats can influence the occurrence of acute pancreatitis. METHODS: Patients with acute pancreatitis (n = 131) and age- and sex-matched healthy controls (n = 108) were studied. The polymerase chain reaction products were analyzed by ABI 3130 genetic analyzer and the exact size of the polymerase chain reaction products was determined by GeneMapper software. A short allele was defined as containing 27 GT repeats or fewer, whereas a long allele was more than 27 repeats. RESULTS: The subjects were categorized into 3 groups on the basis of the genotype results: 1 short and 1 long, 2 short, and 2 long alleles (L/L). Patients with necrotizing disease more frequently were carriers of LL genotype compared with those who had edematous acute pancreatitis. Furthermore, logistic regression analysis revealed that the presence of L/L allele type doubles the risk for developing pancreatic necrosis in patients with acute pancreatitis. CONCLUSIONS: The polymorphism of the GT repeats in the heme oxygenase-1 promoter region may be a risk factor for developing severe and necrotizing acute pancreatitis. PMID- 25036906 TI - Efficacy of capecitabine and temozolomide combination in well-differentiated neuroendocrine tumors: Jordan experience. AB - OBJECTIVES: Options for the treatment of well-differentiated neuroendocrine tumors (NETs) are limited. We evaluated the efficacy of capecitabine and temozolomide combination in patients from Jordan. METHODS: A retrospective review was conducted of 21 patients with metastatic well-differentiated NETs who failed somatostatin analogues and chemotherapy. Patients received capecitabine and temozolomide regimen every 28 days, and evaluation was done every 2 cycles. RESULTS: Twelve patients (57%) achieved partial response, and 5 (23%) achieved stable disease. Median progression-free survival was 16.5 months (range, 14.8-18 months). Of the 7 carcinoid tumors, 2 had partial response, and 2 had stable disease. There were no grade 4 toxicities or treatment-related deaths. CONCLUSIONS: Capecitabine and temozolomide regimen is an effective and well tolerated salvage option for well-differentiated NETs. PMID- 25036908 TI - Biphasic Alterations in Expression and Subcellular Localization of MUC1 in Pancreatic Ductal Carcinogenesis in Syrian Hamsters. AB - OBJECTIVES: The aim of the present study was to characterize molecular targets for the prevention/diagnosis of pancreatic cancer using a chemically induced hamster pancreatic carcinogenesis model, in which background injuries to the parenchyma, for example, chronic pancreatitis or acinar atrophy, are limited. METHODS: Gene expression profiles in atypical hyperplasias were first investigated using a microarray technique. Immunohistochemical analyses of early lesions and invasive ductal carcinoma (IDC) were then conducted for MUC1, of which mRNA levels were prominent among the up-regulated genes, in contrast with the coexpression of epithelial-mesenchymal transition (EMT)-related proteins. RESULTS: Immunohistochemistry for MUC1 cytoplasmic domain (MUC1-CD), which was not detected in normal-like pancreatic ducts, was positive in the apical surfaces of the epithelia of hyperplasias with and without atypia and IDC areas with distinct tubular patterns. In contrast, cytoplasmic/nuclear positivity for MUC1 CD was observed in the invasive front of IDCs. The coexpression of EMT-related proteins, such as slug and vimentin, with cytoplasmic/nuclear MUC1-CD was also detected. CONCLUSIONS: Alterations in the expression and subcellular localization of MUC1 represent a biphasic phenomenon, and the latter may be associated with EMT in pancreatic carcinogenesis in hamsters, which indicates that changes in MUC1 are important targets for pancreatic cancer prevention and chemotherapy. PMID- 25036907 TI - Improved human islet preparations using glucocorticoid and exendin-4. AB - OBJECTIVES: The effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture. METHODS: Methylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet cell transplantation. Islets were cultured for 24 hours with 3 different conditions (control, no additives; MP alone; and MP + EX). beta-Cell fractional viability, cellular composition, multiple cytokine/chemokine production, multiple phosphorylation proteins, and glucose-induced insulin secretion were evaluated. RESULTS: Viable beta-cell survival in MP and MP + EX group was significantly higher than in the control group. Exendin-4 prevented MP-induced reduction of insulin secretion. Methylprednisolone supplementation to the culture medium decreased cytokine and chemokine production. Moreover, extracellular signal-regulated kinase 1/2 phosphorylation was significantly increased by MP and MP + EX. CONCLUSIONS: Glucocorticoid supplementation into culture media significantly decreased the cytokine/chemokine production and increased the extracellular signal-regulated kinase 1/2 phosphorylation, resulting in the improvement of human beta-cell survival. In addition, EX maintained the insulin secretion suppressed by MP. The supplementation of MP and EX together could be a useful strategy to create suitable human islets for transplantation. PMID- 25036909 TI - Expression of Akt kinase-interacting protein 1, a scaffold protein of the PI3K/PDK1/Akt pathway, in pancreatic cancer. AB - OBJECTIVES: Akt kinase-interacting protein 1 (Aki1) has been reported to be a scaffold protein of the PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide dependent protein kinase)/Akt pathway and to interact with epidermal growth factor receptor signaling. Although Aki1 has been reported to be expressed in lung cancer, the significance of its expression in pancreatic cancer has not been clarified. METHODS: The expression of Aki1 and its associated proteins was assayed in pancreatic cancer cell lines, and its involvement in cell viability was examined by treatment with Aki1 small interfering RNA. We also assessed the immunohistochemical expression of Aki1 in tissue samples from 60 patients with pancreatic cancer. RESULTS: All of the pancreatic cancer cell lines expressed Aki1 and its associated proteins at various levels. Treatment with Aki1 small interfering RNA or PI3K inhibitor inhibited the viability of Panc1 cells. Silencing of Aki1 in Panc1 cells reduced the phosphorylation of Akt and increased the phosphorylation of cleaved PARP. The Aki1 was expressed in 25 (42%) of the 60 pancreatic cancers, but there was no correlation between Aki1 expression and clinicopathologic parameters. We observed a statistically significant correlation between Aki1 and p-Akt expression (P = 0.016). CONCLUSIONS: Inhibition of the Aki1-Akt axis may be a therapeutic target in some patients with pancreatic cancer. PMID- 25036910 TI - "High-risk stigmata" of the 2012 international consensus guidelines correlate with the malignant grade of branch duct intraductal papillary mucinous neoplasms of the pancreas. AB - OBJECTIVES: The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas stratified patients into 2 clinical categories, "high-risk stigmata" and "worrisome features," and recommended different therapeutic strategies for these groups. The aim of this study was to elucidate the significance of these categories in terms of predicting malignant IPMNs. METHODS: The medical records of 100 consecutive patients who underwent pancreatectomy for IPMNs were retrospectively reviewed. Seventy patients with branch duct IPMNs (BD-IPMNs) were stratified into 3 groups. The relationships between the number of predictive factors and histopathologic grade were investigated. RESULTS: The prevalence rates of malignant IPMN, invasive carcinoma, and lymph node metastasis in the high-risk group were 80%, 55%, and 20%, respectively, with these percentages significantly increasing in a stepwise manner according to the number of predictive factors. In contrast, there was no significant correlation between the number of worrisome features and grade of malignancy in patients stratified as having worrisome BD-IPMNs. CONCLUSIONS: The number of high-risk stigmata correlated significantly with the grade of malignancy of BD-IPMNs. The presence of at least 1 high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomy with lymphadenectomy. PMID- 25036911 TI - Rosiglitazone inhibits hepatic insulin resistance induced by chronic pancreatitis and IKK-beta/NF-kappaB expression in liver. AB - OBJECTIVES: This study aimed to investigate the influence of rosiglitazone on hepatic insulin resistance and the expressions of IkappaB kinase-beta (IKK beta)/nuclear factor-kappaB (NF-kappaB) in chronic pancreatitis (CP). METHODS: After CP was induced in rats, rosiglitazone and GW9662 were administered at the doses of 4 and 2 mg/kg per day for 4 weeks, respectively. Then, glucose and insulin tolerance tests were performed. Hepatocytes were isolated for the glucose release experiments. Determination of the IKK-beta, NF-kappaB, and Ser307p insulin receptor substrates-1 (Ser307p-IRS-1) expression in the liver was performed. RESULTS: The increased plasma glucose, reduced insulin sensitivity, and the capacity of insulin to suppress glucose release in hepatocytes were observed in CP rats. The IKK-beta, NF-kappaB, and Ser307p-IRS-1 expressions were significantly higher in the liver of CP rats than in sham-operated rats (P < 0.05). Rosiglitazone treatment significantly improved hepatic insulin sensitivity and inhibited the IKK-beta, NF-kappaB, and Ser307p-IRS-1 expressions in the liver (P < 0.05). Counteraction with peroxisome proliferator-activated receptor-gamma by GW9662 attenuated the aforementioned effects of rosiglitazone. CONCLUSIONS: Rosiglitazone attenuates hepatic insulin resistance induced by CP. The inhibition of hepatic IKK-beta and NF-kappaB expressions via peroxisome proliferator activated receptor-gamma may be involved in the therapeutic effect of rosiglitazone. PMID- 25036912 TI - Can the time course of systemic inflammatory response syndrome score predict future organ failure in acute pancreatitis? AB - OBJECTIVES: In patients with acute pancreatitis (AP), we aimed to precisely quantify the association between systemic inflammatory response syndrome score (SIRSS), an easily measured bedside tool, and various adverse outcomes of AP. METHODS: We prospectively identified patients admitted to Mayo Clinic on day 1 of AP. Patients with positive SIRSS (>=2) on day 1 were further followed up with daily measurement of SIRSS and organ failure status for 14 days or until discharge. Positive SIRSS on day 1, persistent SIRSS on day 3, and time course of SIRSS were correlated with development of organ failure. RESULTS: SIRSS and persistent SIRSS were associated with all the complications of AP with a high sensitivity and negative predictive value, ranging from 73.1% to 100.0%. Persistent SIRSS at day 3 added significantly higher specificity to this association (71.7%-80.0%). All patients who developed late-onset organ failure had the highest possible value of cumulative SIRSS. CONCLUSIONS: SIRSS of less than 2 on day 1 has a high negative predictive value for complications of AP. Eighty percent of the patients with persistent SIRSS on day 3 will develop at least 1 adverse outcome. A new variable "cumulative SIRSS" has the potential to reliably predict late-onset persistent organ failure. PMID- 25036913 TI - Prediction of malignancy with endoscopic ultrasonography in patients with branch duct-type intraductal papillary mucinous neoplasm. AB - OBJECTIVE: We evaluated the accuracy of a new endoscopic ultrasonography (EUS) scoring system to predict malignancy in branch duct-type intraductal papillary mucinous neoplasms (BD-IPMNs). METHODS: We performed a retrospective multicenter study of patients who underwent EUS within 3 months before surgery and were diagnosed as having BD-IPMNs by postoperative pathologies at 8 hospitals in Korea from August 2002 to December 2011. To predict the malignancy, we applied the EUS scoring system consisting of pancreatic cyst size, height of mural nodules, main duct dilatation, septal thickening, and patulous orifice. We evaluated the diagnostic accuracy of the new EUS scoring system and compared it with previous individual risk factors. RESULTS: Eighty-four patients (male-to-female ratio, 55:29; mean [SD] age, 64.7 [7.1] years) had 68 benign BD-IPMNs and 16 malignant intraductal papillary mucinous neoplasms. The EUS scoring system showed 75.0% sensitivity and 94.1% specificity at 7 points. This system (area under the curve, 0.939; 95% confidence interval, 0.884-0.994) resulted in a more accurate prediction than the previous known other factors including Sendai criteria, dilatation of ducts, size of the cyst, and presence of septal thickening and mural nodules. CONCLUSIONS: The EUS scoring system predicted BD-IPMN malignancy more accurately than the Sendai criteria and individual risk factors. PMID- 25036914 TI - Contemporary practice patterns associated with percutaneous nephrolithotomy among certifying urologists. AB - BACKGROUND AND PURPOSE: Percutaneous nephrolithotomy (PCNL) is the treatment of choice for patients with complex stone burdens. We performed a study to assess the effect of urologist-specific parameters on the use of PCNL-both the access component of the procedure as well as the stone removal. We also examined trends in PCNL utilization over time. METHODS: We analyzed self-reported 6-month case logs submitted to The American Board of Urology (ABU) for urologists who certified or recertified between 2004 and 2013. Surgeons performing PCNL were identified by Current Procedural Terminology coding. Urologist-specific data, including fellowship training, practice type, and practice population, were used to further stratify this cohort. Trends were examined over the study period. RESULTS: A total of 7278 urologists submitted case logs to the ABU between 2004 and 2013. The median ages of the initial certification group, first recertification group, and second recertification group were 36.0, 43.7, and 53 years, respectively. A greater proportion of newly certified urologists performed PCNL (53%) compared with urologists in the first (41%) and second (29%) recertification groups; initially certified urologists were also more likely to be high volume (>10) PCNL surgeons. Urologists with fellowship training were more likely to use PCNL (66%) and be high-volume surgeons (26.4%). PCNL utilization increased significantly during the study period, with 1330 procedures performed in 2004 and 2888 procedures performed in 2012 (117% increase). CONCLUSIONS: Younger and fellowship-trained urologists are the primary users of PCNL; the majority of senior urologists do not perform this operation. Overall, the use of PCNL and urologist-directed access has increased in the previous decade. PMID- 25036915 TI - Equivalent circuits of a self-assembled monolayer-based tunnel junction determined by impedance spectroscopy. AB - The electrical characteristics of molecular tunnel junctions are normally determined by DC methods. Using these methods it is difficult to discriminate the contribution of each component of the junctions, e.g., the molecule-electrode contacts, protective layer (if present), or the SAM, to the electrical characteristics of the junctions. Here we show that frequency-dependent AC measurements, impedance spectroscopy, make it possible to separate the contribution of each component from each other. We studied junctions that consist of self-assembled monolayers (SAMs) of n-alkanethiolates (S(CH2)(n-1)CH3 = SC(n) with n = 8, 10, 12, or 14) of the form Ag(TS)-SC(n)//GaO(x)/EGaIn (a protective thin (~0.7 nm) layer of GaO(x) forms spontaneously on the surface of EGaIn). The impedance data were fitted to an equivalent circuit consisting of a series resistor (R(S), which includes the SAM-electrode contact resistance), the capacitance of the SAM (C(SAM)), and the resistance of the SAM (R(SAM)). A plot of R(SAM) vs n(C) yielded a tunneling decay constant beta of 1.03 +/- 0.04 n(C)( 1), which is similar to values determined by DC methods. The value of C(SAM) is similar to previously reported values, and R(S) (2.9-3.6 * 10(-2) Omega.cm(2)) is dominated by the SAM-top contact resistance (and not by the conductive layer of GaO(x)) and independent of n(C). Using the values of R(SAM), we estimated the resistance per molecule r as a function of n(C), which are similar to values obtained by single molecule experiments. Thus, impedance measurements give detailed information regarding the electrical characteristics of the individual components of SAM-based junctions. PMID- 25036916 TI - Current and future therapies for herpes simplex virus infections: mechanism of action and drug resistance. AB - Forty years after the discovery of acyclovir (ACV), it remains the mainstay of therapy for herpes simplex virus (HSV) infections. Since then, other antiviral agents have also been added to the armamentarium for these infections but ACV remains the therapy of choice. As the efficacy of ACV is reassessed, however, it is apparent that a therapy with increased efficacy, reduced potential for resistance, and improved pharmacokinetics would improve clinical outcome, particularly in high risk patients. Inhibitors of viral targets other than the DNA polymerase, such as the helicase primase complex, are of particular interest and will be valuable as new therapeutic approaches are conceived. This review focuses on currently approved HSV therapies as well as new systemic therapies in development. PMID- 25036917 TI - An assessment of the (210)Po ingestion dose due to the consumption of agricultural, marine, fresh water and forest foodstuffs in Gudalore (India). AB - The activity concentration of (210)Po in cereals, pulses, food materials of animal origin, vegetables and spices collected from Gudalore (India) has been estimated by radiochemical method. The activity concentration of (210)Po in cereals is found to vary from 124 to 604 mBq kg(-1). Raw rice registered the highest mean activity 504 +/- 61 mBq kg(-1). In pulses (210)Po activity concentration varies from 42 to 320 mBq kg(-1) and the highest activity is found in black lentil with the average value of 172 +/- 38 mBq kg(-1). Leafy vegetables registered the highest (210)Po activity concentration (662-7336 mBq kg(-1)) and are followed by tuber vegetables (390-1269 mBq kg(-1)) and then by other vegetables (75-595 mBq kg(-1)). The higher concentration of (210)Po observed in leafy vegetables may be attributed to the dry deposition of (210)Po and other daughter products of (222)Rn on large leaf surfaces from the air. Among animal products fish of marine origin registered the highest (210)Po activity concentration 36,850-48,964 mBq kg(-1). The mean (210)Po activity concentration in coffee has been estimated as 7500 mBq kg(-1). The activity concentration of (210)Po in leaf and bark of tree Cinnamom zeylanicum, a popular spice, is found to vary from 3500 to 11,100 mBq kg(-1) and 1600-3400 mBq kg(-1). The consumption of marine and fresh water fish contribute 60.7% (506.1 MUSv y(-1)) to the total ingestion dose received. Cereals being consumed in a large scale, contribute 23.4% (194.9 MUSv y(-1)) of the total ingestion dose received. The contribution from spices and leafy vegetables consumed is 5.8% (48.1 MUSv y(-1)) and 6.5% (54.3 MUSv y(-1)), respectively. The remaining 3.6% (30.0 MUSv y(-1)) contribution to the total ingestion dose comes from other food materials and vegetables. PMID- 25036918 TI - Field analyses of (238)U and (226)Ra in two uranium mill tailings piles from Niger using portable HPGe detector. AB - The radioactivities of (238)U and (226)Ra in mill tailings from the U mines of COMINAK and SOMAIR in Niger were measured and quantified using a portable High Purity Germanium (HPGe) detector. The (238)U and (226)Ra activities were measured under field conditions on drilling cores with 600s measurements and without any sample preparation. Field results were compared with those obtained by Inductive Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) and emanometry techniques. This comparison indicates that gamma-ray absorption by such geological samples does not cause significant deviations. This work shows the feasibility of using portable HPGe detector in the field as a preliminary method to observe variations of radionuclides concentration with the aim of identifying samples of interest. The HPGe is particularly useful for samples with strong secular disequilibrium such as mill tailings. PMID- 25036919 TI - Delivery mechanism of (134)Cs and (137)Cs in seawater off the Sanriku Coast, Japan, following the Fukushima Dai-ichi NPP accident. AB - To assess the delivery mechanism of radiocesium emitted from the Fukushima Dai ichi Nuclear Power Plant (FDNPP), we examined vertical profiles of (134)Cs, (137)Cs, and (228)Ra concentrations and the (228)Ra/(226)Ra ratio in the water columns off the Sanriku Coast in the northwestern Pacific Ocean, in July 2012, along with their surface lateral variations in July 2009. Radiocesium concentrations exhibited maximum peaks (3-5 mBq/L for (134)Cs) at depths of 100 200 m, accompanied by high (228)Ra concentrations (0.6-0.8 mBq/L) in comparison with shallower depths (~0.4 mBq/L). Taking the circulation patterns of currents in the area into account, it was inferred that radioactive depositions were supplied to the (228)Ra-rich Tsugaru Warm Current Water (TWCW) in the offshore area of the Sanriku Coast following the FDNPP accident, and that after the spring of 2011, this water (~26.5sigmatheta) was covered by lower density surface water, which helped intrude its way to depths of 100-200 m. PMID- 25036920 TI - Relationship between the radiocesium interception potential and the transfer of radiocesium from soil to soybean cultivated in 2011 in Fukushima Prefecture, Japan. AB - The concentration of radiocesium ((134)Cs and (137)Cs) in agricultural fields around Fukushima Dai-ichi Nuclear Power Plant (FDNPP) was elevated after the accident in March 2011. Evaluation of soil properties that influence phytoavailability of radiocesium is important for optimal soil management to minimize radiocesium transfer to crops. In this study, soybean grain and soil samples (0-15 cm) were collected from 46 locations in Fukushima Prefecture in 2011, and (137)Cs concentrations were measured. (137)Cs concentration ranges were 11-329 Bq kg(-1)-dry in soybean grain samples, and 0.29-2.49 kBq kg(-1)-dry in soil samples. The radiocesium interception potential (RIP) values in the soil samples ranged from 0.30 to 8.61 mol kg(-1). RIP negatively correlated with total carbon content and oxalate-extractable Si and Al + 1/2 Fe in the soils, suggesting that soils rich in organic matter and poorly crystalline clays tended to have lower RIP in this region. The soil-to-plant transfer factor for (137)Cs, analyzed in relation with various soil characteristics, varied by two orders of magnitude and was significantly negatively correlated with RIP and exchangeable K concentration in soil. The results show that RIP is useful for evaluating the efficiency of radiocesium transfer from soil to plants in this region. PMID- 25036921 TI - The winter/summer ratio of airborne (210)Pb--a possible way to quantify the significance of long-range transport of natural radionuclides to the Arctic. PMID- 25036922 TI - Children's understanding of instructions presented in noise and reverberation. AB - PURPOSE: This study examined children's ability to follow audio-visual instructions presented in noise and reverberation. METHOD: Children (8-12 years of age) with normal hearing followed instructions in noise or noise plus reverberation. Performance was compared for a single talker (ST), multiple talkers speaking one at a time (MT), and multiple talkers with competing comments from other talkers (MTC). Working memory was assessed using measures of digit span. RESULTS: Performance was better for children in noise than for those in noise plus reverberation. In noise, performance for ST was better than for either MT or MTC, and performance for MT was better than for MTC. In noise plus reverberation, performance for ST and MT was better than for MTC, but there were no differences between ST and MT. Digit span did not account for significant variance in the task. CONCLUSIONS: Overall, children performed better in noise than in noise plus reverberation. However, differing patterns across conditions for the 2 environments suggested that the addition of reverberation may have affected performance in a way that was not apparent in noise alone. Continued research is needed to examine the differing effects of noise and reverberation on children's speech understanding. PMID- 25036924 TI - Exploring the functional soil-microbe interface and exoenzymes through soil metaexoproteomics. AB - Functionally important proteins at the interface of cell and soil are of potentially low abundance when compared with commonly recovered intracellular proteins. A novel approach was developed and used to extract the metaexoproteome, the subset of proteins found outside the cell, in the context of a soil enriched with the nitrogen-containing recalcitrant polymer chitin. The majority of proteins recovered was of bacterial origin and localized to the outer membrane or extracellular milieu. A wide variety of transporter proteins were identified, particularly those associated with amino-acid and phosphate uptake. The metaexoproteome extract retained chitinolytic activity and we were successful in detecting Nocardiopsis-like chitinases that correlated with the glycoside hydrolase family 18 (GH18) chi gene data and metataxonomic analysis. Nocardiopsis like chitinases appeared to be solely responsible for chitinolytic activity in soil. This is the first study to detect and sequence bacterial exoenzymes with proven activity in the soil enzyme pool. PMID- 25036923 TI - An in vitro culture model to study the dynamics of colonic microbiota in Syrian golden hamsters and their susceptibility to infection with Clostridium difficile. AB - Clostridium difficile infections (CDI) are caused by colonization and growth of toxigenic strains of C. difficile in individuals whose intestinal microbiota has been perturbed, in most cases following antimicrobial therapy. Determination of the protective commensal gut community members could inform the development of treatments for CDI. Here, we utilized the lethal enterocolitis model in Syrian golden hamsters to analyze the microbiota disruption and recovery along a 20-day period following a single dose of clindamycin on day 0, inducing in vivo susceptibility to C. difficile infection. To determine susceptibility in vitro, spores of strain VPI 10463 were cultured with and without soluble hamster fecal filtrates and growth was quantified by quantitative PCR and toxin immunoassay. Fecal microbial population changes over time were tracked by 16S ribosomal RNA gene analysis via V4 sequencing and the PhyloChip assay. C. difficile culture growth and toxin production were inhibited by the presence of fecal extracts from untreated hamsters but not extracts collected 5 days post-administration of clindamycin. In vitro inhibition was re-established by day 15, which correlated with resistance of animals to lethal challenge. A substantial fecal microbiota shift in hamsters treated with antibiotics was observed, marked by significant changes across multiple phyla including Bacteroidetes and Proteobacteria. An incomplete return towards the baseline microbiome occurred by day 15 correlating with the inhibition of C. difficile growth in vitro and in vivo. These data suggest that soluble factors produced by the gut microbiota may be responsible for the suppression of C. difficile growth and toxin production. PMID- 25036925 TI - Predominant pathogen competition and core microbiota divergence in chronic airway infection. AB - Chronic bacterial lung infections associated with non-cystic fibrosis bronchiectasis represent a substantial and growing health-care burden. Where Pseudomonas aeruginosa is the numerically dominant species within these infections, prognosis is significantly worse. However, in many individuals, Haemophilus influenzae predominates, a scenario associated with less severe disease. The mechanisms that determine which pathogen is most abundant are not known. We hypothesised that the distribution of H. influenzae and P. aeruginosa would be consistent with strong interspecific competition effects. Further, we hypothesised that where P. aeruginosa is predominant, it is associated with a distinct 'accessory microbiota' that reflects a significant interaction between this pathogen and the wider bacterial community. To test these hypotheses, we analysed 16S rRNA gene pyrosequencing data generated previously from 60 adult bronchiectasis patients, whose airway microbiota was dominated by either P. aeruginosa or H. influenzae. The relative abundances of the two dominant species in their respective groups were not significantly different, and when present in the opposite pathogen group the two species were found to be in very low abundance, if at all. These findings are consistent with strong competition effects, moving towards competitive exclusion. Ordination analysis indicated that the distribution of the core microbiota associated with each pathogen, readjusted after removal of the dominant species, was significantly divergent (analysis of similarity (ANOSIM), R=0.07, P=0.019). Taken together, these findings suggest that both interspecific competition and also direct and/or indirect interactions between the predominant species and the wider bacterial community may contribute to the predominance of P. aeruginosa in a subset of bronchiectasis lung infections. PMID- 25036930 TI - [Modern imaging of gouty arthritis]. PMID- 25036926 TI - Primate vaginal microbiomes exhibit species specificity without universal Lactobacillus dominance. AB - Bacterial communities colonizing the reproductive tracts of primates (including humans) impact the health, survival and fitness of the host, and thereby the evolution of the host species. Despite their importance, we currently have a poor understanding of primate microbiomes. The composition and structure of microbial communities vary considerably depending on the host and environmental factors. We conducted comparative analyses of the primate vaginal microbiome using pyrosequencing of the 16S rRNA genes of a phylogenetically broad range of primates to test for factors affecting the diversity of primate vaginal ecosystems. The nine primate species included: humans (Homo sapiens), yellow baboons (Papio cynocephalus), olive baboons (Papio anubis), lemurs (Propithecus diadema), howler monkeys (Alouatta pigra), red colobus (Piliocolobus rufomitratus), vervets (Chlorocebus aethiops), mangabeys (Cercocebus atys) and chimpanzees (Pan troglodytes). Our results indicated that all primates exhibited host-specific vaginal microbiota and that humans were distinct from other primates in both microbiome composition and diversity. In contrast to the gut microbiome, the vaginal microbiome showed limited congruence with host phylogeny, and neither captivity nor diet elicited substantial effects on the vaginal microbiomes of primates. Permutational multivariate analysis of variance and Wilcoxon tests revealed correlations among vaginal microbiota and host species specific socioecological factors, particularly related to sexuality, including: female promiscuity, baculum length, gestation time, mating group size and neonatal birth weight. The proportion of unclassified taxa observed in nonhuman primate samples increased with phylogenetic distance from humans, indicative of the existence of previously unrecognized microbial taxa. These findings contribute to our understanding of host-microbe variation and coevolution, microbial biogeography, and disease risk, and have important implications for the use of animal models in studies of human sexual and reproductive diseases. PMID- 25036933 TI - [The status of radiology in ambulatory specialty care according to S 116b SGB V]. PMID- 25036935 TI - Changing rates of adenocarcinoma of the lung. AB - Over the past several decades, adenocarcinoma of the lung has been increasing as a fraction of all lung cancer. Examination of the available evidence led the 2014 Report of the Surgeon General to conclude that the increases in the rates of adenocarcinoma among smokers in the U.S. were a result of changes in cigarette design and composition over the past 6 decades. While a causal link to design and composition changes as a whole is clear, the changes that have been implemented over the past several decades are not uniformly applied across all cigarette brands in the current market, raising questions about differences in risks among users of different cigarette brands. Recognition of the increased risks resulting from design and composition changes offers a corollary opportunity to reduce current disease risks by identifying and regulating the specific compositional and design changes that produced the increase in risk. PMID- 25036934 TI - Diabetic osteopenia by decreased beta-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. AB - In diabetics, methylglyoxal (MG), a glucose-derived metabolite, plays a noxious role by inducing oxidative stress, which causes and exacerbates a series of complications including low-turnover osteoporosis. In the present study, while MG treatment of mouse bone marrow stroma-derived ST2 cells rapidly suppressed the expression of osteotrophic Wnt-targeted genes, including that of osteoprotegerin (OPG, a decoy receptor of the receptor activator of NF-kappaB ligand (RANKL)), it significantly enhanced that of secreted Frizzled-related protein 4 (sFRP-4, a soluble inhibitor of Wnts). On the assumption that upregulated sFRP-4 is a trigger that downregulates Wnt-related genes, we sought out the molecular mechanism whereby oxidative stress enhanced the sFRP-4 gene. Sodium bisulfite sequencing revealed that the sFRP-4 gene was highly methylated around the sFRP-4 gene basic promoter region, but was not altered by MG treatment. Electrophoretic gel motility shift assay showed that two continuous CpG loci located five bases upstream of the TATA-box were, when methylated, a target of methyl CpG binding protein 2 (MeCP2) that was sequestered upon induction of 8-hydroxy-2 deoxyguanosine, a biomarker of oxidative damage to DNA. These in vitro data suggest that MG-derived oxidative stress (not CpG demethylation) epigenetically and rapidly derepress sFRP-4 gene expression. We speculate that under persistent oxidative stress, as in diabetes and during aging, osteopenia and ultimately low turnover osteoporosis become evident partly due to osteoblastic inactivation by suppressed Wnt signaling of mainly canonical pathways through the derepression of sFRP-4 gene expression. PMID- 25036936 TI - Exploring the perceptual biases associated with believing and disbelieving in paranormal phenomena. AB - Ninety-five participants (32 believers, 30 disbelievers and 33 neutral believers in the paranormal) participated in an experiment comprising one visual and one auditory block of trials. Each block included one ESP, two degraded stimuli and one random trial. Each trial included 8 screens or epochs of "random" noise. Participants entered a guess if they perceived a stimulus or changed their mind about stimulus identity, rated guesses for confidence and made notes during each trial. Believers and disbelievers did not differ in the number of guesses made, or in their ability to detect degraded stimuli. Believers displayed a trend toward making faster guesses for some conditions and significantly higher confidence and more misidentifications concerning guesses than disbelievers. Guesses, misidentifications and faster response latencies were generally more likely in the visual than auditory conditions. ESP performance was no different from chance. ESP performance did not differ between belief groups or sensory modalities. PMID- 25036937 TI - Optimization of beta-glucosidase production by Aspergillus terreus strain EMOO 6 4 using response surface methodology under solid-state fermentation. AB - Forty-two morphologically different fungal strains were isolated from different soil samples and agricultural wastes and screened for beta-glucosidase activity under solid-state fermentation. Eight species were chosen as the most active beta glucosidase producers and were subjected to primary morphological identification. beta-Glucosidase was highly produced by Aspergillus terreus, which showed the highest activity, and was subjected to full identification using scanning electron microscopy and molecular identification. Initial screening of different variables affecting beta-glucosidase production was performed using Plackett Burman design and the variables with statistically significant effects were identified. The optimal levels of the most significant variables with positive effect and the effect of their mutual interactions on beta-glucosidase production were determined using Box-Behnken design. Fifteen variables including temperature, pH, incubation time, inoculum size, moisture content, substrate concentration, NaNO3, KH2PO4, MgSO4 . 7H2O, KCl, CaCl2, yeast extract, FeSO4 . 7H2O, Tween 80, and (NH4)2SO4 were screened in 20 experimental runs. Among the 15 variables, NaNO3, KH2PO4 and Tween 80 were found as the most significant factors with positive effect on beta-glucosidase production. The Box-Behnken design was used for further optimization of these selected factors for better beta glucosidase production. The maximum beta-glucosidase production was 4457.162 U g( 1). PMID- 25036940 TI - Nonparametric tests for evaluation of biosimilarity in variability of follow-on biologics. AB - As more biologic products are going off patent protection, the development of follow-on biologic products (also known as biosimilars) has gained much attention from both the biotechnology industry and regulatory agencies. Unlike small molecules, the development of biologic products is not only more complicated but also sensitive to a small change in procedure/environment during the manufacturing process. In practice, biologics are expected to have much larger variation, which will potentially impact the product quality and potency. Thus, it is suggested that the assessment of biosimilarity between biologic products should take variability into consideration, in addition to average biosimilarity of endpoints of interest. In this article, we propose the use of nonparametric tests for evaluation of biosimilarity in variability between the follow-on biologic product and the reference product. Extensive simulations are conducted to compare the relative performance of the proposed methods with the adapted parametric F-test in terms of correctly concluding biosimilarity in variability. Under normality assumption, the proposed nonparametric tests are found to be comparably well with the adapted F-test. However, the proposed methods are more robust when the assumption is violated. PMID- 25036938 TI - Serotonin impairment in CSF of PD patients, without an apparent clinical counterpart. AB - In Parkinson's disease (PD), several studies have detected an impaired serotonin (5-HT) pathway, likely affecting both motor and non-motor domains. However, the precise impact of 5-HT impairment is far from established. Here, we have used a HPLC chromatographic method, in a homogenous cohort (n = 35) of non fluctuating, non dyskinetic PD patients, to assess the concentration of 5-HT and its metabolite 5-HIAA in peripheral cerebrospinal fluid (CSF) obtained from lumbar puncture (LP). LP was performed following three days of therapy withdrawal, in order to vanish the effects of prolonged released dopamine agonists (DA), and in absence of any serotonergic agent. The PD patient group showed a significantly reduced CSF level of both 5-HT and 5-HIAA compared to either age-matched control subjects (n = 18), or Alzheimer's disease patients (n = 20). However, no correlation emerged between 5-HT/5-HIAA concentrations and UPDRS-III (r = -0.12), disease duration (r = -0.1), age (r = -0.27) and MMSE (r = 0.11). Intriguingly, low CSF 5-HT levels did not differ for gender or for motor phenotype (in terms of non-tremor dominant subtype and tremor dominant subtype). Further, low CSF 5-HT levels did not correlate with the presence of depression, apathy or sleep disturbance. Our findings support the contention that 5-HT impairment is a cardinal feature of stable PD, probably representing a hallmark of diffuse Lewy bodies deposition in the brainstem. However, clinical relevance remains uncertain. Given these findings, an add-on therapy with serotonergic agents seems questionable in PD patients, or should be individually tailored, unless severe depression is present. PMID- 25036941 TI - Arsenic pollution of agricultural soils by concentrated animal feeding operations (CAFOs). AB - Animal wastes from concentrated animal feeding operations (CAFOs) can cause soil arsenic pollution due to the widespread use of organoarsenic feed additives. This study investigated the arsenic pollution of surface soils in a typical CAFO zone, in comparison with that of agricultural soils in the Pearl River Delta, China. The mean soil arsenic contents in the CAFO zone were elevated compared to those in the local background and agricultural soils of the Pearl River Delta region. Chemical speciation analysis showed that the soils in the CAFO zone were clearly contaminated by the organoarsenic feed additive, p-arsanilic acid (ASA). Transformation of ASA to inorganic arsenic (arsenite and arsenate) in the surface soils was also observed. Although the potential ecological risk posed by the arsenic in the surface soils was relatively low in the CAFO zone, continuous discharge of organoarsenic feed additives could cause accumulation of arsenic and thus deserves significant attention. PMID- 25036942 TI - Oxidative transformation of levofloxacin by delta-MnO2: products, pathways and toxicity assessment. AB - The characteristics of the oxidative transformation of the antibiotic levofloxacin (abbreviated as LEV) by manganese oxide were investigated. Up to 91% of LEV were removed with an equivalent of 200 units (abbreviated as equiv) of manganese oxide within a 35-day treatment period. A total of ten transformation products were identified, and five of them were newly reported. A tentative transformation pathway of LEV in the manganese oxide system involving oxidation and dealkylation was proposed. In addition, the variation in the genotoxicity and antibacterial activity along with the treatment by manganese oxide were traced using a SOS/umu assay and Escherichia coli growth inhibition assay, respectively. The results indicated that the genotoxicity significantly decreased in response to treatment with manganese oxide, while the antibacterial activity was not markedly affected until 160-equiv of delta-MnO2 were added. This study suggests that the oxidative degradation of LEV by manganese oxide can play an important role in the natural attenuation of LEV in sediment or soil matrices. The transformation reaction may be further optimized for removing quinolone antibiotics from wastewater or other environmental matrices to reduce the potential risk. PMID- 25036943 TI - Long-range atmospheric transport and the distribution of polycyclic aromatic hydrocarbons in Changbai Mountain. AB - The Changbai (also known as "Baekdu") Mountain, on the border between China and North Korea, is the highest mountain (2750 m) in northeastern China. Recently, this mountain region has experienced a dramatic increase in air pollution, not only because of increasing volumes of tourism-derived traffic but also because of the long-range transport of polluted westerly winds passing through major industrial and urban cities in the eastern region of China. To assess the relative importance of the two sources of pollution, 16 polycyclic aromatic hydrocarbons (PAHs) as model substances were determined in the mountain soil. A total of 32 soil samples were collected from different sides of the mountain at different latitudes between July and August of 2009. The ?PAH concentrations were within the range 38.5-190.1 ng g(-1) on the northern side, 117.7-443.6 ng g(-1) on the southern side, and 75.3-437.3 ng g(-1) on the western side. A progressive increase in the level of ?PAHs with latitude was observed on the southern and western sides that face the westerly wind with abundant precipitation. However, a similar concentration gradient was not observed on the northern side that receives less rain and is on the leeward direction of the wind. The high molecular-weight PAH compounds were predominant in the soils on the southern and western sides, while low-molecular-weight PAHs dominated the northern side soils. These findings show that the distribution of PAHs in the mountain soil is strongly influenced by the atmospheric long-range transport and cold trapping. PMID- 25036944 TI - Heterogeneous catalytic ozonation of dibutyl phthalate in aqueous solution in the presence of iron-loaded activated carbon. AB - Iron-loaded activated carbon was prepared and used as catalyst in heterogeneous catalytic ozonation of dibutyl phthalate (DBP). The catalytic activity of iron loaded activated carbon was investigated under various conditions and the mechanisms of DBP removal were deduced. Characterization of catalyst indicated that the iron loaded on activated carbon was mainly in the form of goethite, which reduced its surface area, pore volume and pore diameter. The presence of metals on activated carbon positively contributed to its catalytic activity in ozonation of DBP. Iron loading content of 15% and initial water pH of 8 achieved highest DBP removal among all the tried conditions. Catalyst dosage of 10 mg L( 1) led to approximately 25% of increase in DBP (initial concentration 2 mg L(-1)) removal in 60 min as compared with ozone alone, and when catalyst dosage increased to 100 mg L(-1), the DBP removal was further improved by 46%. Based on a comparison of reaction rates for direct and indirect transformation of DBP, the increased removal of DBP in this study likely occurred via transformation of ozone into hydroxyl radicals on the catalyst surface. PMID- 25036945 TI - Photoformation rate, steady-state concentration and lifetime of nitric oxide radical (NO.) in a eutrophic river in Higashi-Hiroshima, Japan. AB - Monthly measurements (January-December 2013) of the photoformation rate, steady state concentration and lifetime of nitric oxide radical (NO.) in the Kurose River in Higashi-Hiroshima City, Japan, were obtained. Each month, river water samples were collected at six different stations (upstream to downstream). NO. was quantified using 4, 5-diaminofluorescein-2 (DAF-2) as a probe and triazolofluorescein (DAF-2T) as a standard. Results show that NO. photoformation rate ranged from 0.01 to 35.4 (*10(-10) M s(-1)). The radical steady-state concentration in the river ranged from 0.02 to 68.5 (*10(-11) M). There was a strong correlation (r(2)=0.95) between NO. photoformation rate and the nitrite concentration in the river suggesting that this anion is a major NO. precursor. On average, 98% of the photoformed NO. came from river nitrite, and this was calculated using the photoformation rate constant {5.7*10(-5) M(NO.)s(-1) M(NO2( ))(-1)} of NO. from the anion concentration found in the study. The NO. lifetime ranged from 0.05 to 1.3 s in the river and remained fairly stable in the upstream and downstream samples. The .OH radical, which was quantified during the study, had a photoformation rate of 0.01-13.4 (*10(-10) M s(-1)) and a steady-state concentration of 0.04-119 (*10(-16) M) with a lifetime that ranged from 0.3 to 22.5 (*10(-6) s). .OH only accounted for ?0.0011% of the total NO. scavenged, showing that it was not a major sink for river NO.. PMID- 25036946 TI - Sorption of norfloxacin in soils: analytical method, kinetics and Freundlich isotherms. AB - Fluoroquinolones are potent antibacterial agents that are active against a wide range of pathogenic organisms and are widely used in veterinary medicine. Fluoroquinolones and their metabolites may reach the soil through animal excreta or manure and may contaminate water and soils. The degree of sorption of these antimicrobials to soils varies widely, as does the mobility of these drugs. In the present study, sorption of norfloxacin in four soils of the state of Sao Paulo was investigated with batch equilibrium experiments. A strong matrix effect on the chromatographic determination of norfloxacin was verified. Sorption kinetics were best fit by a pseudo second-order model (r>0.99), and sorption/desorption isotherms were well fit by the Freundlich model in log form (r>0.97). Norfloxacin showed high affinity for soil particles, with KF sorption values ranging from 643 to 2410 MUg(1-1/n)(cm(3))(1/n)g(-1) and KF desorption values ranging from 686 to 2468 MUg(1-1/n)(cm(3))(1/n)g(-1). The high desorption KF values indicate that norfloxacin is highly immobile in the evaluated soils. PMID- 25036947 TI - Unique influence of cholesterol on modifying the aggregation behavior of surfactant assemblies: investigation of photophysical and dynamical properties of 2,2'-bipyridine-3,3'-diol, BP(OH)2 in surfactant micelles, and surfactant/cholesterol forming vesicles. AB - The binding and rotational properties of an excited-state intramolecular proton transfer (ESIPT) fluorophore, 2,2'-bipyridine-3,3'-diol, BP(OH)2 has been investigated in alkyltrimethylammonium bromide containing (CnTAB, n = 12, 14, and 16) micelles and alkyltrimethylammonium bromide/cholesterol (CnTAB (n = 14 and 16)/cholesterol) forming vesicles using fluorescence-based spectroscopy techniques. The formation of thermodynamically stable unilamellar self-assemblies of alkyltrimethylammonium bromide/cholesterol are characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements. Individually, aqueous solutions of all these alkyltrimethylammonium bromide form micelles after certain surfactant concentration (critical micelle concentration, cmc) of surfactant, whereas cholesterol molecules are insoluble in water. But with the variation of the cholesterol-to-surfactant molar ratio (Q = [cholesterol]/[surfactant]), uniform distribution of vesicular aggregates in aqueous solution can be obtained. The micelle-to-vesicle transition of surfactant solution upon addition of cholesterol also influences the steady state emission profile, fluorescence lifetime, and rotational dynamics of BP(OH)2 molecule. The diketo tautomer of BP(OH)2 molecule gets stabilized as the concentration of surfactant increases in aqueous solution. Fluorescence lifetime and rotational time constant of the BP(OH)2 molecule are also influenced by the variation of alkyl chain length of surfactant molecule. The emission quantum yield (Phi) is also found to be sensitive with surfactant concentration, variation in chain length of surfactants, and it saturates after the cmc of surfactants. The rigid and restricted microenvironment of vesicle bilayer enhance the lifetime and also rotational relaxation of BP(OH)2 significantly. The rotational behavior of BP(OH)2 in surfactant/cholesterol self-assemblies is also explained by using analytical parameters related to time-resolved anisotropy following two-step process and wobbling in a cone models. PMID- 25036948 TI - A single amino acid polymorphism in the Drosophila melanogaster Dalpha1 (ALS) subunit enhances neonicotinoid efficacy at Dalpha1-chicken beta2 hybrid nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes. AB - Polymorphisms are sometimes observed in native insect nicotinic acetylcholine receptor (nAChR) subunits, which are important insecticide targets, yet little is known of their impact on insecticide actions. Here we investigated the effects of a polymorphism involving the substitution of histidine108 by leucine in the Drosophila melanogaster Dalpha1 subunit on the agonist actions of the neurotransmitter acetylcholine (ACh) and two commercial neonicotinoid insecticides (imidacloprid and clothianidin). There was no significant impact of the H108L substitution on either the ACh EC50, the concentration leading to a half maximal ACh response, or the maximum current amplitude in response at 10 MUM ACh, of the Dalpha1-chicken beta2 nAChR expressed in Xenopus laevis oocytes. However, the response amplitudes to imidacloprid and clothianidin were significantly enhanced, indicating a role of His108 in the selective interactions of Dalpha1 with these neonicotinoids. PMID- 25036949 TI - A region corresponding to second aspartate-rich motif in tryptophan isoprenylating enzyme, ComQ, serves as a substrate-binding site. AB - Posttranslational isoprenylation of a tryptophan residue identified from Bacillus quorum sensing pheromone, ComX pheromone, is unique and essential for the bioactivity. A modifying enzyme, ComQ, forms ComX pheromone from the ComX precursor and isoprenyl pyrophosphate and exhibits moderate similarity to isoprenyl pyrophosphate synthases. We investigated non-conserved region in ComQ, corresponding to isopentenyl pyrophosphate binding region of the synthases, using in vitro cell-free isoprenylation. These results suggested that the only conserved aspartic acid residue in the region of ComQ is critical for enzyme activity and responsible for ComX binding. Our findings should contribute to basic understanding of the mechanism of tryptophan isoprenylation. PMID- 25036950 TI - Live-cell imaging of HP1alpha throughout the cell cycle of mouse C3H10T1/2 cells and rhythmical flickering of heterochromatin dots in interphase. AB - Heterochromatin protein 1 alpha (HP1alpha) localizes to heterochromatin in interphase and shows dynamic molecular behavior in living cells. We previously reported that during mitosis, the majority of HP1alpha diffused into the cytoplasm but some remained in centromere heterochromatin. Here, we further characterize the molecular behavior of HP1alpha throughout the cell cycle. Time lapse imaging of DsRed-HP1alpha through two successive cell divisions indicated that interphase can be divided into four phases. HP1alpha forms heterochromatin dots in early G1, which are maintained without any apparent changes (Phase 1). However, the HP1alpha dots begin to diffuse into the nucleoplasm and start flickering with a rhythmical cycle (Phase 2). Then, the HP1alpha dots diffuse further towards the periphery of the nucleus (Phase 3), and uniformly diffuse throughout the entire nucleus (Phase 4). Rhythmical flickering of HP1alpha dots in the middle of interphase may be useful for following cell cycle progression in mouse living cells. PMID- 25036951 TI - Inserted rest period resensitizes MC3T3-E1 cells to fluid shear stress in a time dependent manner via F-actin-regulated mechanosensitive channel(s). AB - The underlying cellular mechanism of anabolic effect recovered by inserting rest is not fully understood. In this work, we studied the role of F-actin regulated mechanosensitive channel(s) re-activation in mechanosensitivity modulation in vitro. Results showed that steady fluid shear stress (sFSS) stimulation with 30 min rest period was more potential in increasing alkalinephosphatase (ALP) activity than 10 and 0-min rest periods, and insertion of 30 min, but not 0 or 10 min, recovered the [Ca(2+)]i transient and contribution of the mechanosensitive channel(s). During the rest period, F-actin experienced polymerization (0-10 min), followed by depolymerization (10-30 min); inhibition of F-actin polymerization/depolymerization significantly increased/decreased the [Ca(2+)]i transient, as well as the contribution of the mechanosensitive channel(s) in subsequent sFSS stimulation. Our results demonstrated that the long rest period between sFSS loadings recruited [Ca(2+)]i transient via F-actin depolymerization induced reactivation of mechanosensitive channel(s), suggesting that F-actin regulated cellular stiffness could account for the decreased anabolic response during continuous mechanical loading in bone cells. PMID- 25036952 TI - Purification and cDNA cloning of a lectin and a lectin-like protein from Apios americana Medikus tubers. AB - An Apios americana lectin (AAL) and a lectin-like protein (AALP) were purified from tubers by chromatography on Butyl-Cellulofine, ovomucoid-Cellulofine, and DEAE-Cellulofine columns. AAL showed strong hemagglutinating activity toward chicken and goose erythrocytes, but AALP showed no such activity toward any of the erythrocytes tested. The hemagglutinating activity of AAL was not inhibited by mono- or disaccharides, but was inhibited by glycoproteins, such as asialofetuin and ovomucoid, suggesting that AAL is an oligosaccharide-specific lectin. The cDNAs of AAL and AALP consist of 1,093 and 1,104 nucleotides and encode proteins of 302 and 274 amino acid residues, respectively. Both amino acid sequences showed high similarity to known legume lectins, and those of their amino acids involved in carbohydrate and metal binding were conserved. PMID- 25036953 TI - Over-expression of carbon monoxide dehydrogenase-I with an accessory protein co expression: a key enzyme for carbon dioxide reduction. AB - Carbon monoxide dehydrogenase-I (CODH-I) from the CO-utilizing bacterium Carboxydothermus hydrogenoformans are expected to be utilized as a part of reproducible carbon dioxide photoreduction system. However, the over-expression system for CODH-I remains to be constructed. CODH-I constitutes a hydrogenase/CODH gene cluster including a gene encoding a Ni-insertion accessory protein, CooC (cooC3). Through co-expression of CooC3, we found an over expression system with higher activity. The Rec-CODH-I with the co-expression exhibits 8060 U/mg which was approximately threefold than that without co expression (2270 U/mg). In addition, co-expression resulted in Ni(2+) content increase; the amount of Ni atoms of Rec-CODH-I was approximately thrice than that without co-expression. PMID- 25036954 TI - Evidence of positive selection at signal peptide region of interferon gamma. AB - Interferon gamma (IFNG) is a major cytokine and plays crucial roles in pathogen clearance. About the course of evolution of IFNG, it has been reported that IFNG is being subjected to adaptive selection, which is proved at the level of gene. Neighbor-joining method was used to reconstruct the phylogenetic tree of all IFNG protein-coding sequences. The pair-wise computation of Ka/Ks between every exon homologs, branch-specific model, and site-specific model of the likelihood method were performed to detect positive selection of IFNG. We reported, for the first time, that the signal peptide region of IFNG is under significant positive selection, evolving faster than other parts. We provide evidence at the level of individual exon and individual amino acid site that IFNG is under adaptive evolution, which establishes the basis for further researches about IFNG. PMID- 25036955 TI - Identification and functional analysis of peroxiredoxin isoforms in Euglena gracilis. AB - Euglena gracilis lacks catalase and contains ascorbate peroxidase (APX) which is localized exclusively in the cytosol. Other enzymes that scavenge reactive oxygen species (ROS) in Euglena have not yet been identified; therefore, ROS metabolism, especially in organelles, remains unclear in Euglena. The full-length cDNAs of four Euglena peroxiredoxins (EgPrxs) were isolated in this study. EgPrx1 and -4 were predicted to be localized in the cytosol, and EgPrx2 and -3 in plastids and mitochondria, respectively. The catalytic efficiencies of recombinant EgPrxs were similar to those of plant thiol-peroxidases, but were markedly lower than those of APX from Euglena. However, transcript levels of EgPrx1, -2, and -3 were markedly higher than those of APX. The growth rate of Euglena cells, in which the expression of EgPrx1 and -4 was suppressed by gene silencing, was markedly reduced under normal conditions, indicating physiological significance of Prx proteins. PMID- 25036956 TI - Increased microRNA-223 in Helicobacter pylori-associated gastric cancer contributed to cancer cell proliferation and migration. AB - Dysregulation of microRNA-223 (miR-223) was associated with gastric cancer (GC), in which Helicobacter pylori (H. pylori) played important roles. However, the mechanism of relationships between miR-223 and H. pylori-associated GC was largely undiscovered. Here, we found the overexpression of miR-223 was related with H. pylori positive infection in vivo and in vitro in GC by relative quantification of qRT-PCR. Upregulated miR-223 was responsible for the poorer prognosis of GC with H. pylori positive, also. The result indicated not only overexpression of miR-223 stimulated the proliferation by CCK-8 assays and colony formation of H. pylori associated GC cells, but also migration and invasion by scratch assay and transwell invasion assays in vitro. Above all, all our data declared H. pylori infection played an important role in developing GC according to overexpression of miR-223, which increased cancer cell proliferation and migration. PMID- 25036957 TI - Nocturnal phosphorylation of phosphoenolpyruvate carboxylase in the leaves of hygrophytic C3 monocots. AB - Phosphoenolpyruvate carboxylase (PEPC) undergoes activity regulation through reversible phosphorylation. The day/night phosphorylation of leaf PEPC in 27 C3 plant species was analyzed by immunoblotting. PEPC was phosphorylated in the daytime in 12 species, whereas it was phosphorylated at night in three species, rice, Monochoria vaginalis, and Sagittaria trifolia, all of which are hygrophytic monocots. Immunoblot analysis of isolated chloroplasts of M. vaginalis identified a PEPC protein inside the chloroplast in addition to cytosolic isozyme(s) as previously shown in genus Oryza. Using transgenic rice overexpressing the maize PEPC in the cytosol, we confirmed that the cytosolic PEPC underwent the nocturnal phosphorylation. These results suggest the interrelationship between the presence of chloroplastic PEPC and the nocturnal phosphorylation of cytosolic isozyme(s). PMID- 25036958 TI - Expression and functional analyses of Kruppel-like factor 3 in chicken adipose tissue. AB - Studies in mammalian species showed that Kruppel-like factor 3 (KLF3) regulated adipose tissue development. However, it was not reported in chicken. In the current study, we found that during the growth and development of abdominal fat tissue, chicken KLF3 (Gallus gallus KLF3, gKLF3) was consecutively expressed, and its transcripts were higher at 7 weeks of age and lower at 10 weeks of age in lean broilers than in fat broilers. In addition, gKLF3 overexpression suppressed chicken CCAAT/enhancer binding protein alpha (C/EBPalpha), fatty acid binding protein 4 (FABP4), fatty acid synthase (FASN), and lipoprotein lipase (LPL) promoter activities, but increased chicken peroxisome proliferator-activated receptor gamma (PPARgamma) promoter activity. Additionally, point mutagenesis analysis showed that the substitution of Asp by Gly within the Pro-Val-Asp-Leu Thr (PVDLT) motif of gKLF3 significantly reduced the ability of gKLF3 to regulate the promoter activities of FABP4, FASN, LPL, C/EBPalpha, and PPARgamma. PMID- 25036959 TI - Overexpression, purification, and characterization of Paenibacillus cell surface expressed chitinase ChiW with two catalytic domains. AB - Paenibacillus sp. strain FPU-7 produces several different chitinases and effectively hydrolyzes robust chitin. Among the P. FPU-7 chitinases, ChiW, a novel monomeric chitinase with a molecular mass of 150 kDa, is expressed as a cell surface molecule. Here, we report that active ChiW lacking the anchoring domains in the N-terminus was successfully overproduced in Escherichia coli and purified to homogeneity. The two catalytic domains at the C-terminal region were classified as typical glycoside hydrolase family 18 chitinases, whereas the N terminal region showed no sequence similarity to other known proteins. The vacuum ultraviolet circular dichroism spectrum of the enzyme strongly suggested the presence of a beta-stranded-rich structure in the N-terminus. Its biochemical properties were also characterized. Various insoluble chitins were hydrolyzed to N,N'-diacetyl-D-chitobiose as the final product. Based on amino acid sequence similarities and site-directed mutagenesis, Glu691 and Glu1177 in the two GH-18 domains were identified as catalytic residues. PMID- 25036960 TI - Pectin of Prunus domestica L. alters sulfated structure of cell-surface heparan sulfate in differentiated Caco-2 cells through stimulation of heparan sulfate 6-O endosulfatase-2. AB - Although previous reports have suggested that pectin induces morphological changes of the small intestine in vivo, the molecular mechanisms have not been elucidated. As heparan sulfate plays important roles in development of the small intestine, to verify the involvement of heparan sulfate (HS) in the pectin induced morphological changes of the small intestine, the effects of pectin from Prunus domestica L. on cell-surface HS were investigated using differentiated Caco-2 cells. Disaccharide compositional analysis revealed that sulfated structures of HS were markedly changed by pectin administration. Real-time RT-PCR showed that pectin upregulated human HS 6-O-endosulfatase-2 (HSulf-2) expression and markedly inhibited HSulf-1 expression. Furthermore, inhibition analysis suggested that pretreatment with fibronectin III1C fragment, RGD peptide, and ERK1/2 inhibitor suppressed pectin-induced HSulf-2 expression. These observations indicate that pectin induced the expression of HSulf-2 through the interaction with fibronectin, alpha5beta1 integrin, and ERK1/2, thereby regulating the sulfated structure of HS on differentiated Caco-2 cells. PMID- 25036961 TI - Neuronal cell-surface protein neurexin 1 interaction with multi-PDZ domain protein MUPP1. AB - Location of membrane proteins is often stabilized by PDZ domain-containing scaffolding proteins. Using the yeast two-hybrid screening, we found that neurexin 1 interacted with multi-PDZ domain protein 1 (MUPP1) through PDZ domain. Neurexin 2 and 3 also interacted with MUPP1. MUPP1 and neurexin 1 were co localized in cultured cells. These results suggest a novel mechanism for localizing neurexin 1 to synaptic sites. PMID- 25036962 TI - Mechanisms of induction of the stress-responsive transcription factors HsfA2 and DREB2A by 12-oxo-phytodienoic acid in Arabidopsis thaliana. AB - OPDA (12-oxo-phytodienoic acid) not only is an intermediate in jasmonic acid biosynthesis but also regulates gene expression, although mechanisms of OPDA induced signaling are largely unknown. Here, we measured transcriptional responses of the OPDA-responsive genes HsfA2 and DREB2A to the protein synthesis inhibitor cycloheximide and to the HSP90 inhibitor geldanamycin. The results suggest that HSP90 and other proteins suppress the expression. PMID- 25036963 TI - Inhibitor screening of lactate dehydrogenase C4 from black-lipped pika in the Western Sichuan Plateau. AB - Studies indicated that lactate dehydrogenase C4 (LDH-C4) was a good target protein for development of contraceptive drugs. Virtual screening and in vitro enzyme assay using pika LDH-C4 as target protein revealed NSC61610, NSC215718, and NSC345647 with Ki of 7.8, 27, and 41 MUM separately. This study might be helpful for development of pika contraceptive drugs. PMID- 25036964 TI - Administered chrysanthemum flower oil attenuates hyperuricemia: mechanism of action as revealed by DNA microarray analysis. AB - We applied Chrysanthemum flower oil (CFO) to a hyperuricemia model by feeding rats a hyperuricemia-inducing diet (HID) and investigated its effect on serum uric acid (SUA) levels and its mode of action. CFO is the oily fraction that contains polyphenols derived from chrysanthemum flowers. Oral administration of CFO to HID-fed rats significantly decreased their SUA levels. It also inhibited xanthine oxidase activities in the liver and increased urine uric acid levels. The effects of CFO on the renal gene expressions that accompanied the induction of hyperuricemia were comprehensively confirmed by DNA microarray analysis. The analysis showed up-regulation of those genes for uric acid excretion by CFO administration. These results suggest that CFO suppresses the increase in SUA levels via two mechanisms: suppression of uric acid production by inhibition of xanthine oxidase in the liver and acceleration of its excretion by up-regulation of uric acid transporter genes in the kidney. PMID- 25036965 TI - Presence of osteoinductive factors in bovine colostrum. AB - New approaches in the treatment of skeletal defects may benefit from the use of soluble biological factors. We previously standardized a derivative of bovine colostrum (SBCD), deprived of casein and fat and rich in cytokines. In the present study, we tested its possible use as an adjuvant in bone healing. SBCD contained factors involved in stromal cell stimulation and differentiation and induced cytokine production from stimulated mesenchymal stem cells (MSCs). In vitro, SBCD promoted proliferation, migration and, in association with osteogenic factors, osteogenic differentiation of osteoblastic and MSCs. In in vivo experiments of subcutaneous Matrigel injection in mice, SBCD plus hydroxyapatite, but not hydroxyapatite nor SBCD alone, induced recruitment of macrophages and stromal cells. After 60 days, plugs containing SBCD and hydroxyapatite were densely calcified and diffusely positive for osteocalcin, supporting the occurrence of an early osteogenic process. These results indicate that SBCD is a rich source of factors with osteoinductive properties. PMID- 25036966 TI - Bovine milk-derived alpha-lactalbumin inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sodium sulfate-treated mice. AB - Cyclooxygenase-2 is expressed early in colon carcinogenesis and plays crucial role in the progress of the disease. Recently, we found that alpha-lactalbumin had anti-inflammatory activity by inhibiting cyclooxygenase-2. In experiment 1, we investigated the effects of alpha-lactalbumin on the colon carcinogenesis initiated with azoxymethane (AOM) followed by promotion with dextran sodium sulfate (DSS) in mice. Dietary treatment with alpha-lactalbumin decreased fecal occult blood score at 3 days after DSS intake. alpha-Lactalbumin also decreased the colon tumor at week 9. In experiment 2, AOM-treated mice were sacrificed at 7 days after DSS intake. The plasma and colon prostaglandin E2 (PGE2) levels in AOM/DSS-treated mice were higher than those in the DSS-treated mice without initiation by AOM. alpha-Lactalbumin decreased PGE2 in both plasma and colon. These results suggest that alpha-lactalbumin effectively inhibited colon carcinogenesis, and the inhibition may be due to the decreased PGE2 by inhibiting cyclooxygenase-2 at cancer promotion stages. PMID- 25036967 TI - Heterologous production, purification, and immunodetection of Magnaporthe oryzae avirulence protein AVR-Pia. AB - The avirulence gene AVR-Pia of Magnaporthe oryzae, which induces a hypersensitive reaction in rice cultivars containing the resistance gene Pia, was expressed in Escherichia coli. AVR-Pia protein was collected as inclusion bodies, denatured, and refolded. Finally, recombinant AVR-Pia (rAVR-Pia) protein was purified by column chromatography. Infiltration of rAVR-Pia triggered cell browning in the leaves of rice cultivar Aichiasahi (Pia), with accumulation of H2O2 and induction of PR1a expression in rice. On the other hand, these reactions were not observed in Shin-2 (pia) leaves after the same treatment. This observation indicated that rAVR-Pia had the function of an avirulence protein. rAVR-Pia was used for immunization of a rabbit, and anti-AVR-Pia antiserum was prepared. The specificity of this antibody was appraised by detecting native AVR-Pia in the inoculated leaf sheath extract using Western blotting in combination with immunoprecipitation. Native AVR-Pia was successfully detected, and its molecular weight was estimated to be 7.4 kDa, indicating signal peptide cleavage. Additionally, secreted native AVR-Pia was quantified as 3.7 ng/g rice sheath. PMID- 25036968 TI - Improved ethanol production from cheese whey, whey powder, and sugar beet molasses by "Vitreoscilla hemoglobin expressing" Escherichia coli. AB - This work investigated the improvement of ethanol production by engineered ethanologenic Escherichia coli to express the hemoglobin from the bacterium Vitreoscilla (VHb). Ethanologenic E. coli strain FBR5 and FBR5 transformed with the VHb gene in two constructs (strains TS3 and TS4) were grown in cheese whey (CW) medium at small and large scales, at both high and low aeration, or with whey powder (WP) or sugar beet molasses hydrolysate (SBMH) media at large scale and low aeration. Culture pH, cell growth, VHb levels, and ethanol production were evaluated after 48 h. VHb expression in TS3 and TS4 enhanced their ethanol production in CW (21-419%), in WP (17-362%), or in SBMH (48-118%) media. This work extends the findings that "VHb technology" may be useful for improving the production of ethanol from waste and byproducts of various sources. PMID- 25036969 TI - Enhancement of (R)-1,3-butanediol production by engineered Escherichia coli using a bioreactor system with strict regulation of overall oxygen transfer coefficient and pH. AB - (R)-1,3-butanediol ((R)-1,3-BD) is an important substrate for the synthesis of industrial chemicals. Despite its large demand, a bioprocess for the efficient production of 1,3-BD from renewable resources has not been developed. We previously reported the construction of recombinant Escherichia coli that could efficiently produce (R)-1,3-BD from glucose. In this study, the fermentation conditions were optimized to further improve 1,3-BD production by the recombinant strain. A batch fermentation was performed with an optimized overall oxygen transfer coefficient (82.3 h(-1)) and pH (5.5); the 1,3-BD concentration reached 98.5 mM after 36 h with high-yield (0.444 mol (mol glucose)(-1)) and a high maximum production rate (3.63 mM h(-1)). In addition, a fed-batch fermentation enabled the recombinant strain to produce 174.8 mM 1,3-BD after 96 h cultivation with a yield of 0.372 mol (mol glucose)(-1), a maximum production rate of 3.90 mM h(-1), and a 98.6% enantiomeric excess (% ee) of (R)-1,3-BD. PMID- 25036970 TI - Asymmetric synthesis of tetrahydroisoquinolines by enzymatic Pictet-Spengler reaction. AB - Norcoclaurine synthase (NCS) catalyzes the stereoselective Pictet-Spengler reaction between dopamine and 4-hydroxyphenylacetaldehyde as the first step of benzylisoquinoline alkaloid synthesis in plants. Recent studies suggested that NCS shows relatively relaxed substrate specificity toward aldehydes, and thus, the enzyme can serve as a tool to synthesize unnatural, optically active tetrahydroisoquinolines. In this study, using an N-terminally truncated NCS from Coptis japonica expressed in Escherichia coli, we examined the aldehyde substrate specificity of the enzyme. Herein, we demonstrate the versatility of the enzyme by synthesizing 6,7-dihydroxy-1-phenethyl-1,2,3,4-tetrahydroisoquinoline and 6,7 dihydroxy-1-propyl-1,2,3,4-tetrahydroisoquinoline in molar yields of 86.0 and 99.6% and in enantiomer excess of 95.3 and 98.0%, respectively. The results revealed the enzyme is a promising catalyst that functions to stereoselectively produce various 1-substituted-1,2,3,4-tetrahydroisoquinolines. PMID- 25036971 TI - Construction of a novel secretion expression system guided by native signal peptide of PhoD in Zymomonas mobilis. AB - In the current study, three native signal peptides (SPs) from PhoC, PhoD, and ZMO0331were investigated and compared to construct novel secretion expression systems in Zymomonas mobilis. The secretion expression of target protein, alpha amylase from Bacillus amyloliquefaciens (BAA), guided by PhoD's SP resulted in more hydrolysis of starch than that by the other two SPs. Extracellular and intracellular alpha-amylase activities of the strain containing PhoD's SP were also higher than the other two strains containing PhoC or ZMO0331's SP. In addition, the evidence by alcohol dehydrogenase activity assay further confirmed that the starch hydrolysis was resulted from the secretion expression of BAA rather than the breakage of cells. Our results indicated that the SP of PhoD is able to serve as a promising candidate to assist secretion expression of heterogeneous genes in Z. mobilis. This will contribute to development of engineered Z. mobilis strains converting starch into ethanol. PMID- 25036972 TI - Forced expression of FLO11 confers pellicle-forming ability and furfural tolerance on Saccharomyces cerevisiae in ethanol production. AB - We constructed a plasmid that expresses FLO11 encoding a cell surface glycoprotein of Saccharomyces cerevisiae under the control of a constitutive promoter. This plasmid conferred pellicle-forming ability on the non-pellicle forming industrial strain of S. cerevisiae at the air-liquid interface of the glucose-containing liquid medium. The induced pellicle-forming cells exhibited tolerance to furfural, which is a key toxin in lignocellulosic hydrolysates, in ethanol production. PMID- 25036973 TI - Expression of a codon-optimized Aspergillus niger pectin methylesterase gene in the methylotrophic yeast Candida boidinii. AB - A codon-optimized Aspergillus niger pectin methylesterase (PME) gene was expressed in the methylotrophic yeast Canidia boidinii. The PME-producing strains showed better growth on pectin than the wild-type strains, suggesting that the PME-producing strains could efficiently utilize methyl ester moieties of pectin. On the other hand, overproduction of PME negatively affected the proliferation of C. boidinii on leaves of Arabidopsis thaliana. PMID- 25036974 TI - Purification and characterization of beta-mannanase from Reinekea sp. KIT-YO10 with transglycosylation activity. AB - Marine bacterium Reinekea sp. KIT-YO10 was isolated from the seashore of Kanazawa Port in Japan as a seaweed-degrading bacterium. Homology between KIT-YO10 16S rDNA and the 16S rDNA of Reinekea blandensis and Reinekea marinisedimentorum was 96.4 and 95.4%, respectively. Endo-1,4-beta-D-mannanase (beta-mannanase, EC 3.2.1.78) from Reinekea sp. KIT-YO10 was purified 29.4-fold to a 21% yield using anion exchange chromatography. The purified enzyme had a molecular mass of 44.3 kDa, as estimated by SDS-PAGE. Furthermore, the purified enzyme displayed high specificity for konjac glucomannan, with no secondary agarase and arginase activity detected. Hydrolysis of konjac glucomannan and locust bean gum yielded oligosaccharides, compatible with an endo mode of substrate depolymerization. The purified enzyme possessed transglycosylation activity when mannooligosaccharides (mannotriose or mannotetraose) were used as substrates. Optimal pH and temperature were determined to be 8.0 and 70 degrees C, respectively. It showed thermostability at temperatures from 20 to 50 degrees C and alkaline stability up to pH 10.0. The current enzyme was thermostable and thermophile compared to the beta-mannanase of other marine bacteria. PMID- 25036976 TI - Morphological analysis of disordered macroporous-mesoporous solids based on physical reconstruction by nanoscale tomography. AB - Solids with a hierarchically structured, disordered pore space, such as macroporous-mesoporous silica monoliths, are used as fixed beds in separation and catalysis. Targeted optimization of their functional properties requires a knowledge of the relation among their synthesis, morphology, and mass transport properties. However, an accurate and comprehensive morphological description has not been available for macroporous-mesoporous silica monoliths. Here we offer a solution to this problem based on the physical reconstruction of the hierarchically structured pore space by nanoscale tomography. Relying exclusively on image analysis, we deliver a concise, accurate, and model-free description of the void volume distribution and pore coordination inside the silica monolith. Structural features are connected to key transport properties (effective diffusion, hydrodynamic dispersion) of macropore and mesopore space. The presented approach is applicable to other fixed-bed formats of disordered macroporous-mesoporous solids, such as packings of mesoporous particles and organic-polymer monoliths. PMID- 25036977 TI - Ionic liquid-assisted synthesis of Pt nanoparticles onto exfoliated graphite nanoplatelets for fuel cells. AB - Exfoliated graphite nanoplatelets (GnP) has been investigated as an electrocatalyst support for fuel cell applications. GnP-supported Pt catalysts were synthesized by a microwave process in the presence of room temperature ionic liquids (RTILs). Thermal-oxidation resistance of GnP and GnP-supported Pt catalysts was studied by thermogravimetric analysis and compared with a variety of other carbon nanostructures: carbon black, graphite nanofiber, single- and multiwalled carbon nanotubes. GnP showed the best thermal-oxidative stability. The results obtained from X-ray diffraction, X-ray photoelectron spectroscopy, electrochemical testing, scanning and transmission electron microscopy showed that the RTIL synthesis method resulted in size reduction of Pt nanoparticle, improvement of Pt dispersion on GnP, and identification of the relationships between the mean size of Pt particles with increasing RTIL content. The interaction of Pt particles-GnP is stronger than that of a commercial Pt-CB, and the Pt/GnP catalysts prepared by this method have excellent electrocatalytic activity and stability for methanol oxidation. PMID- 25036978 TI - N-methylimidazole promotes the reaction of homophthalic anhydride with imines. AB - The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described. PMID- 25036979 TI - Synthesis and Diels-Alder reactions of a benzo[5]radialene derivative. AB - Apart from their exotic structure, radialenes have been employed as precursors of more complex polycyclic molecules. In this work we report the synthesis of the first compound having the benzo[5]radialene substructure, starting from simple materials. Such a compound proved to be a convenient diene in Diels-Alder reactions, for the preparation of highly functionalized fluorenes and benzo[b]fluorenes in a quimio- and stereocontrolled fashion. PMID- 25036980 TI - Chemically-modulated photoluminescence of graphene oxide for selective detection of neurotransmitter by "turn-on" response. AB - Designing artificial nanomaterials capable of selectively detecting targets without the use of expensive and fragile antibodies is of great interest in the applications of nanomedicine. Here, we show that the photoluminescence (PL) of graphene oxide (GO) was chemically modulated for the selective detection of a neurotransmitter without the use of antibodies. GO was functionalized with nitrotriacetic acid (NTA) on which four different metal ions were chelated (M-NTA GO), which led to its different PL responses to neurotransmitters. In particular, the Cu-NTA-GO hybrid was able to selectively detect norepinephrine at nanomolar concentrations in a simple manner via its "turn-on" PL. Moreover, it was successfully applied to the selective detection of norepinephrine secreted from living PC-12 cells. PMID- 25036981 TI - Ovarian cancer from an immune perspective. AB - Despite major advances in the treatment of ovarian cancer over the past two decades, it is still an incurable disease and requires the development of better treatment strategies. In recent years, we have developed a greater understanding of tumor immunology and the interactions between tumors and the immune system. This has led to the emergence of cancer immunotherapy as the fourth treatment modality in cancer. In this article, we address the principles of immunotherapy and different approaches that have been investigated over the past decade and discuss the future of immune therapy in ovarian cancer. PMID- 25036982 TI - In vivo effects of lattice radiation therapy on local and distant lung cancer: potential role of immunomodulation. AB - Radiation is a potent immune-modulator that elicits cell death upon tumor, stromal and angiogenic compartments of tumor microenvironment. Here, we test a novel approach of high-dose radiation delivery using three dimensional volume based lattice radiation therapy (LRT) to understand the impact of different volume irradiation in eliciting both local and metastatic/distant tumor control through modulation of tumor immune micro-environment. To study such effects of LRT, tumors were implanted in both hind legs of C57BL/6 mice using Lewis lung carcinoma 1 (LLC1) cells. Mice were divided into five groups: untreated; partial tumor volume groups included two 10% vertices, one 20% vertex and one 50% vertex of the total tumor volume; and 100% open-field irradiation. Tumors implanted in the left flank were irradiated with a single dose of 20 Gy while the tumors in the right flank were unirradiated. Tumor growth and regression as well as immune responses (such as Th1 and Th2; T-cell infiltration) were determined after radiation treatment. Results demonstrated that both 100% open-field irradiation and 20% volume irradiation (in two 10% volumes) resulted in significant growth delay in the irradiated tumor. Further, all types of radiation exposures, partial or 100% volume, demonstrated distal effectiveness, however, 20% volume irradiation (in two 10% volumes) and 50% tumor volume irradiation led to maximum growth delay. Mice treated with partial tumor volume radiation induced a robust IFN-gamma and Th1 response when compared to whole-tumor irradiation and down modulated Th2 functions. The presence of increased CD3+ cells and TRAIL in partially irradiated tumor volumes correlated well with tumor growth delay. Further, serum obtained from any of the LRT treated mice caused growth inhibition of endothelial cells when compared to serum obtained from either untreated or open-field irradiated groups. These results indicate that high-dose partial volume irradiation can cause an improved distant effect than the total tumor volume irradiation through activating the host immune system. PMID- 25036983 TI - Immunobiology of radiotherapy: new paradigms. PMID- 25036985 TI - Comfort and stability of wheelchair backrests according to the TAWC (tool for assessing wheelchair discomfort). AB - PURPOSE: The goal of this study was thus to determine if people with different types of wheelchair backrests on their personal wheelchairs reported different levels of comfort as measured by the Tool for Assessing Wheelchair disComfort (TAWC). METHODS: Participants were between 18 and 80 years of age and were manual wheelchair users. The TAWC was used to assess the participants' wheelchair seating discomfort levels with the wheelchair and seating systems. RESULTS: We surveyed 131 wheelchair users to assess the comfort of their backrests on their personal wheelchairs and found a trend suggesting that rigid backrests are were less comfortable as compared with sling backrests. This finding was statistically significant in a subgroup of participants with tetraplegia. CONCLUSIONS: Although many clinicians expect rigid backrests to be more comfortable because they may provide more support, the higher discomfort ratings among rigid backrest users with tetraplegia may be due to sub-optimal shape, fit, adjustment or user preferences. Implications for Rehabilitation Development of a measure for long term seating discomfort is needed. Design and development of better rigid backrests that are functional but provide adequate comfort are in need. PMID- 25036984 TI - Generation and characterization of a JAK2V617F-containing erythroleukemia cell line. AB - The JAK2V617F mutation is found in the majority of patients with myeloproliferative neoplasms (MPNs). Transgenic expression of the mutant gene causes MPN-like phenotypes in mice. We have produced JAK2V617F mice with p53 null background. Some of these mice developed acute erythroleukemia. From one of these mice, we derived a cell line designated J53Z1. J53Z1 cells were stained positive for surface markers CD71 and CD117 but negative for Sca-1, TER-119, CD11b, Gr-1, F4/80, CD11c, CD317, CD4, CD8a, CD3e, B220, CD19, CD41, CD42d, NK-1.1, and FceR1. Real time PCR analyses demonstrated expressions of erythropoietin receptor EpoR, GATA1, and GATA2 in these cells. J53Z1 cells grew rapidly in suspension culture containing fetal bovine serum with a doubling time of ~18 hours. When transplanted into C57Bl/6 mice, J53Z1 cells induced acute erythroleukemia with massive infiltration of tumor cells in the spleen and liver. J53Z1 cells were responsive to stimulation with erythropoietin and stem cell factor and were selectively inhibited by JAK2 inhibitors which induced apoptosis of the cells. Together, J53Z1 cells belong to the erythroid lineage, and they may be useful for studying the role of JAK2V617F in proliferation and differentiation of erythroid cells and for identifying potential therapeutic drugs targeting JAK2. PMID- 25036986 TI - Challenges of user-centred assistive technology provision in Australia: shopping without a prescription. AB - PURPOSE: People with disability have a right to assistive technology devices and services, to support their inclusion and participation in society. User-centred approaches aim to address consumer dissatisfaction and sub-optimal outcomes from assistive technology (AT) provision, but make assumptions of consumer literacy and empowerment. Policy discourses about consumer choice prompt careful reflection, and this paper aims to provide a critical perspective on user involvement in assistive technology provision. METHODS: User-centred approaches are considered, using literature to critically reflect on what user involvement means in AT provision. Challenges at the level of interactions between practitioners and consumers, and also the level of markets and policies are discussed, using examples from Australia. RESULTS: There is no unanimous conceptual framework for user-centred practice. Power imbalances and differing perspectives between practitioners and consumers make it difficult for consumers to feel empowered. Online access to information and international suppliers has not surmounted information asymmetries for consumers or lifted the regulation of publicly funded AT devices. CONCLUSIONS: Ensuring access and equity in the public provision of AT is challenging in an expanding market with diverse stakeholders. Consumers require personalised information and support to facilitate their involvement and choice in AT provision. Implications for Rehabilitation Variations in approaches informing AT provision practices have a profound impact on equity of access and outcomes for consumers. An internationalised and online market for AT devices is increasing the need for effective information provision strategies and services. Power imbalances between practitioners and consumers present barriers to the realisation of user-centred practice. PMID- 25036987 TI - Three's a crowd: 10q triplication secondary to a paternal 10q duplication. PMID- 25036988 TI - Full-dimensional quantum dynamics of vibrationally mediated photodissociation of NH3 and ND3 on coupled ab initio potential energy surfaces: absorption spectra and NH2(A(2)A1)/NH2(X(2)B1) branching ratios. AB - Vibrationally mediated photodissociation of NH3 and ND3 in the A band allows the exploration of the excited-state potential energy surface in regions that are not accessible from the ground vibrational state of these polyatomic systems. Using our recently developed coupled ab initio potential energy surfaces in a quasi diabatic representation, we report here a full-dimensional quantum characterization of the A <- X absorption spectra for vibrationally excited NH3 and ND3 and the corresponding nonadiabatic dissociation dynamics into the NH2(A(2)A1) + H and NH2(X(2)B1) + H channels. The predissociative resonances in the absorption spectra have been assigned with appropriate quantum numbers. The NH2(A(2)A1)/NH2(X(2)B1) branching ratio was found to be mildly sensitive to the initial vibrational excitation prior to photolysis. Implications for interpreting experimental data are discussed. PMID- 25036989 TI - In situ investigation of halide co-ion effects on SDS adsorption at air-water interfaces. AB - Co-ions are believed to have a negligible effect on surfactant adsorption, but we show here that they can significantly affect the surfactant adsorption at the air water interface. Sum frequency generation vibrational spectroscopy (SFG) was employed to examine the effects of three halides (Cl(-), Br(-) and I(-)) on the adsorption of an anionic surfactant, sodium dodecyl sulphate (SDS), at the air water interface. The SFG spectral features of both the interfacial water molecules and the C-H vibrations of the adsorbed surfactant alkyl chains were analysed to characterize the surfactant adsorption. We demonstrate and compare the effects of the three halides, as well as explain the unusual effect of Br(-), on the interfacial SDS and water molecules at the air/aqueous solution interface. It was observed that each of the three co-ions has a unique effect on the adsorption and conformation of the interfacial surfactant molecules at low halide concentrations of 10-50 mM, when the effect of halides on the interfacial water structure is believed to be negligible. This discovery implies that not only do they influence surfactant adsorption indirectly via the interfacial water network but also that there is an interaction occurring between these co-ions and the negatively charged head-groups at the interface via hydration by the interfacial water molecules. Even though this interaction/competition is likely to occur only between the surfactant head-groups and the halides, the surfactant hydrophobic tail was also observed to be influenced by the co-ions. These observed behavioural differences between the co-ions cannot be explained by the variation of charge densities. Therefore, further studies are required to determine the mode of action of halides influencing the adsorption of surfactant which gives Br(-) such a unique effect. PMID- 25036990 TI - Serum levels of monobenzylphthalate (MBzP) is related to carotid atherosclerosis in the elderly. AB - BACKGROUND AND OBJECTIVE: Background exposure to environmental contaminants has recently emerged as a new risk factor for cardiovascular disease in general and to atheroclerosis in particular. This cross-sectional study was performed to evaluate if serum concentrations of the phthalate metabolite monobenzylphthalate (MBzP) are related to atheroclerosis in the carotid arteries. METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1003 subjects all aged 70) the prevalence of overt plaques and echogenicity (gray-scale median, GSM) of carotid artery plaques were recorded by ultrasound in both of the carotid arteries. The intima-media thickness (IMT) and echogenicity (IM-GSM) of the intima-media complex were also measured. The phthalate metabolite MBzP was analyzed in serum by a liquid chromatograph/tandem mass spectrometer. RESULTS: The circulating level of the phthalate MBzP was related to intima-media thickness (IMT) when adjusting for gender, blood pressure, body mass index (BMI), waist circumference, HDL- and LDL-cholesterol, serum triglycerides, blood glucose and smoking (p=0.034). High levels of MBzP were also strongly associated with an echogenic IM-GSM and plaque GSM (p=0.0001 for both outcomes after adjustment) but not to plaque prevalence (p=0.42). CONCLUSION: The phthalate metabolite MBzP was strongly related to the echogenicity of intima-media and plaques and also to IMT, independently of traditional CV risk factors. This suggests a role for the phthalate MBzP in the development of atherosclerosis. PMID- 25036991 TI - Charge transfer (CT) mechanochromism: dramatic CT absorption change of crystalline pi-conjugated oligomers containing TCNQ upon mechanical grinding. AB - New pi-conjugated oligomers with high crystallinity were prepared from the simple solvothermal reaction of squaric acid and diaminopyrenes. The oligomers were bonded at the 1,3- and 1,6-positions of the pyrene units, oligo(sq-alt-1,3py) and oligo(sq-alt-1,6py), which greatly affected their planar configuration and resulting mechanochromic properties. Oligomers containing a charge transfer (CT) complex were selectively synthesized in one step. Upon mechanical grinding in the solid state, the color changed from orange to deep metallic green. PMID- 25036992 TI - Proteomics elucidates key molecules involved in exsheathment in vitro in Oesophagostomum dentatum. AB - We explored molecules involved in in vitro exsheathment of Oesophagostomum dentatum L3s using a proteomic-transcriptomic-bioinformatic approach. Analysis of L3s before, during and after exsheathment identified 11 proteins that were over expressed exclusively during exsheathment. These proteins (including key enzymes, heat shock, structural and nematode-specific proteins) were inferred to be involved in development, metabolism, structure, motility and/or host-parasite interactions. Some of these molecules represented homologues linked to entry into and exit from the dauer stage in the free-living nematode Caenorhabditis elegans. The approach established here provides a basis for investigations of ecdysis in other strongylid nematodes. PMID- 25036993 TI - Genome-wide identification of MAPKK and MAPKKK gene families in tomato and transcriptional profiling analysis during development and stress response. AB - Mitogen-activated protein kinase (MAPK) cascades have important functions in plant growth, development, and response to various stresses. The MAPKK and MAPKKK gene families in tomato have never been systematically analyzed. In this study, we performed a genome-wide analysis of the MAPKK and MAPKKK gene families in tomato and identified 5 MAPKK genes and 89 MAPKKK genes. Phylogenetic analyses of the MAPKK and MAPKKK gene families showed that all the MAPKK genes formed four groups (groups A, B, C, and D), whereas all the MAPKKK genes were classified into three subfamilies, namely, MEKK, RAF, and ZIK. Evolutionary analysis showed that whole genome or chromosomal segment duplications were the main factors responsible for the expansion of the MAPKK and MAPKKK gene families in tomato. Quantitative real-time RT-PCR analysis showed that the majority of MAPKK and MAPKKK genes were expressed in all tested organs with considerable differences in transcript levels indicating that they might be constitutively expressed. However, the expression level of most of these genes changed significantly under heat, cold, drought, salt, and Pseudomonas syringae treatment. Furthermore, their expression levels exhibited significant changes in response to salicylic acid and indole-3-acetic acid treatment, implying that these genes might have important roles in the plant hormone network. Our comparative analysis of the MAPKK and MAPKKK families would improve our understanding of the evolution and functional characterization of MAPK cascades in tomato. PMID- 25036994 TI - Coagulation-flocculation mechanisms in wastewater treatment plants through zeta potential measurements. AB - Based on the polyelectrolyte-contaminant physical and chemical interactions at the molecular level, this article analyzed and discussed the coagulation flocculation and chemical precipitation processes in order to improve their efficiency. Bench experiments indicate that water pH, polyelectrolyte (PE) dosing strategy and cationic polyelectrolyte addition are key parameters for the stability of metal-PE complexes. The coagulation-flocculation mechanism is proposed based on zeta potential (zeta) measurement as the criteria to define the electrostatic interaction between pollutants and coagulant-flocculant agents. Polyelectrolyte and wastewater dispersions are exposed to an electrophoretic effect to determine zeta. Finally, zeta potential values are compared at pH 9, suggesting the optimum coagulant dose at 162mg/L polydadmac and 67mg/L of flocculant, since a complete removal of TSS and turbidity is achieved. Based on the concentration of heavy metals (0.931mg/L Sn, 0.7mg/L Fe and 0.63mg/L Pb), treated water met the Mexican maximum permissible limits. In addition, the treated water has 45mg O2/L chemical oxygen demand (COD) and 45mg C/L total organic carbon (TOC). The coagulation-flocculation mechanism is proposed taking into account both: zeta potential (zeta)-pH measurement and chemical affinity, as the criteria to define the electrostatic and chemical interaction between pollutants and polyelectrolytes. PMID- 25036995 TI - Valorization of phosphogypsum waste as asphaltic bitumen modifier. AB - The accumulation of phosphogypsum waste from the fertilizer industries, which remain in regulated stacks occupying considerable land resources, is causing significant environment problems worldwide. In that sense, the scientific community is being pressured to find alternative ways for their disposal. In this research, we propose a novel application for phosphogypsum waste, as a modifier of bitumen for flexible road pavements. Viscous flow tests carried out on bitumen modified with a phosphogypsum waste and doped with sulfuric acid demonstrated an extraordinary increase in viscosity, at 60 degrees C, when compared to a counterpart sample which had been modified with gypsum, the main component of phosphogypsum. Similarly, a significant improvement in the viscoelastic response of the resulting material at high temperatures was also found. FTIR (Fourier transform infrared spectroscopy) scans provided evidences of the existence of chemical reactions involving phosphorus, as revealed by a new absorption band from 1060 to 1180cm(-1), related to COP vibrations. This result points at phosphorus contained in the phosphogypsum impurities to be the actual "modifying" substance. Furthermore, no COP band was observed in the absence of sulfuric acid, which seems to be the "promoting" agent of this type of bond. PMID- 25036996 TI - Photocatalytic degradation of 17alpha-ethinylestradiol (EE2) in the presence of TiO2-doped zeolite. AB - Current design limitations and ineffective remediation techniques in wastewater treatment plants have led to concerns about the prevalence of pharmaceutical and personal care products (PPCPs) in receiving waters. A novel photocatalyst, TiO2 doped low-silica X zeolite (TiO2-LSX), was used to study the degradation of the pharmaceutical compound, 17alpha-ethinylestradiol (EE2). The catalyst was synthesized and characterized using XRD, BET surface analysis, SEM-EDAX, and ICP OES. The effects of different UV light intensities, initial EE2 concentrations, and catalyst dosages on the EE2 removal efficiency were studied. A higher EE2 removal efficiency was attained with UV-TiO2-LSX when compared with UV-TiO2 or UV alone. The EE2 degradation process followed pseudo-first-order kinetics. A comprehensive empirical model was developed to describe the EE2 degradation kinetics under different conditions using multiple linear regression analysis. The EE2 degradation mechanism was proposed based on molecular calculations, identification of photoproducts using HPLC-MS/MS, and reactive species quenching experiments; the results showed that oxidative degradation pathways initiated by hydroxyl radicals were predominant. This novel TiO2-doped zeolite system provides a promising application for the UV disinfection process in wastewater treatment plants. PMID- 25036997 TI - Fabrication of magnetic porous Fe-Mn binary oxide nanowires with superior capability for removal of As(III) from water. AB - Magnetic porous Fe-Mn binary oxide nanowires were successfully fabricated to efficient removal of As(III) from water. The adsorption capacity of the porous nanowires for As(III) obviously increased with increasing of manganese oxide in the composite, accompanying decrease of the saturation magnetization of the adsorbents. Magnetic porous Fe-Mn binary oxide nanowires with an initial Fe:Mn molar ratio of 1:3 exhibited the highest absorption capacity for As(III) and enable magnetic separation from water. The maximal adsorption capacity value is 171mgg(-1) at pH 7.0. In the initial pH range from 3 to 9, 200MUgL(-1) of As(III) could be easily decreased to below 10MUgL(-1) by the magnetic porous Fe-Mn binary oxide nanowires (0.05gL(-1)) within 75min, and the corresponding residual As was completely oxidized to less toxic As(V). The coexisting chloride, nitrate and sulfate had no significant effect on arsenic removal, whereas, phosphate and humic acid reduced the removal of As(III) by competing with arsenic species for adsorption sites. The resulting magnetic porous Fe-Mn binary oxide nanowires could be a promising adsorbent for As(III) removal from water. PMID- 25036998 TI - Deposition of carbon nanotubes by a marine suspension feeder revealed by chemical and isotopic tracers. AB - Carbon nanotubes (CNTs) are one of the few truly novel nanomaterials and are being incorporated into a wide range of products, which will lead to environmental release and potential ecological impacts. We examined the toxicity of CNTs to marine mussels and the effect of mussels on CNT fate and transport by exposing mussels to 1, 2, or 3mg CNTsl(-1) for four weeks and measuring mussel clearance rate, shell growth, and CNT accumulation in tissues and deposition in biodeposits. We used metal impurities and carbon stable isotope ratios of the CNTs as tracers of CNT accumulation. Mussels decreased clearance rate of phytoplankton by 24% compared with control animals when exposed to CNTs. However, mussel growth rate was unaffected by CNT concentrations up to 3mgl(-1). Based on metal concentrations and carbon stable isotope values, mussels deposited most CNTs in biodeposits, which contained >110mg CNTsg(-1) dry weight, and accumulated about 1mg CNTsg(-1) dry weight of tissue. We conclude that extremely high concentrations of CNTs are needed to illicit a toxic response in mussels but the ability of mussels to concentrate and deposit CNTs in feces and pseudofeces may impact infaunal organisms living in and around mussel beds. PMID- 25036999 TI - A new insight into resource recovery of excess sewage sludge: feasibility of extracting mixed amino acids as an environment-friendly corrosion inhibitor for industrial pickling. AB - The work mainly presented a laboratory-scale investigation on an effective process to extract a value-added product from municipal excess sludge. The functional groups in the hydrolysate were characterized with Fourier transform infrared spectrum, and the contained amino acids were measured by means of an automatic amino acid analyzer. The corrosion-inhibition characteristics of the hydrolysate were determined with weight-loss measurement, electrochemical polarization and scanning electron microscopy. Results indicated that the hydrolysate contained 15 kinds of amino acid, and their adsorption on the surface could effectively inhibit the corrosion reaction of the steel from the acid medium. Polarization curves indicated that the obtained hydrolysate was a mixed type inhibitor, but mainly restricted metal dissolution on the anode. The adsorption accorded well with the Langmuir adsorption isotherm, involved an increase in entropy, and was a spontaneous, exothermic process. PMID- 25037000 TI - Selective recovery of palladium from waste printed circuit boards by a novel non acid process. AB - An environmental benign, non-acid process was successfully developed for selective recovery of palladium from waste printed circuit boards (PCBs). In the process, palladium was firstly enriched during copper recovery procedure and dissolved in a special solution made of CuSO4 and NaCl. The dissolved palladium was then extracted by diisoamyl sulfide (S201). It was found that 99.4% of Pd(II) could be extracted from the solution under the optimum conditions (10% S201, A/O ratio 5 and 2min extraction). In the whole extraction process, the influence of base metals was negligible due to the relatively weak nucleophilic substitution of S201 with base metal irons and the strong steric hindrance of S201 molecular. Around 99.5% of the extracted Pd(II) could be stripped from S201/dodecane with 0.1mol/L NH3 after a two-stage stripping at A/O ratio of 1. The total recovery percentage of palladium was 96.9% during the dissolution-extraction-stripping process. Therefore, this study established a benign and effective process for selective recovery of palladium from waste printed circuit boards. PMID- 25037001 TI - DNA electrochemical sensor for detection of PRSS1 point mutation based on restriction endonuclease technique. AB - To construct a restriction endonuclease based biosensor technology for PRSS1 genotyping. We designed a thiol-modified hairpin probe where the neck has EcoRI endonuclease recognition sites according to the PRSS1 gene c.410 C>T (p.T137 M) mutation and it was fixed on the gold electrode. Different charge generated by the binding of MB to phosphate groups of DNA before and after hybridization was used for distinguishing the different genotypes and quantity. This showed that the novel sensor can better distinguish the complementary sequence, single-base mismatches, and completely noncomplementary sequences, and the linear range for the logarithm was Y=-0.0242 X+0.1574, R=0.9912(Y=current, X=log target DNA concentration); the detection limit for DNA detection is estimated to be 50 fM. PMID- 25037002 TI - Long-term three-stage rehabilitation intervention alleviates spasticity of the elbows, fingers, and plantar flexors and improves activities of daily living in ischemic stroke patients: a randomized, controlled trial. AB - To investigate the effects of rehabilitation interventions on spasticity and activities of daily living (ADL) in ischemic stroke patients. A total of 165 ischemic stroke patients were recruited and assigned randomly to a control group (CG, n=82) or a therapeutic group (TG, n=83). Rehabilitation interventions were performed in the TG. The Modified Ashworth Scale was used to evaluate the severity of spasticity in the fingers, elbows, and plantar flexors, and the Modified Barthel Index (MBI) was used to measure ADL performance. Evaluations were performed at baseline (M0) and at the end of the first, third, and sixth months (M1, M3, M6) after enrollment. At M0, 20.8% (16/77) in the CG and 29.9% (23/77) in the TG developed spasticity, whereas at M6, the incidence of spasticity increased to 36.4% (28/77) in the TG and 42.9% (33/77) of patients in the CG. Fewer patients developed spasticity in the fingers, elbows, and ankles in the TG than CG, respectively. Both groups showed significant improvements in MBI scores (M6 vs. M0, P<0.01). MBI scores correlated negatively with the severity of spasticity in both groups at M6. Long-term standardized rehabilitation interventions alleviate spasticity and promote ADL with the presence of minor spasticity (Supplementary video, Supplemental digital content 1, http://links.lww.com/WNR/A291). PMID- 25037003 TI - Stress-induced enhancement of fear conditioning activates the amygdalar cholecystokinin system in a rat model of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD), a debilitating psychiatric disease characterized by invasive and persistent fear memories-induced stressful experience, is associated with numerous changes in neuroendocrine function. Here, we investigated whether PTSD-like symptoms are associated with changes in the cholecystokinin (CCK) system in the basolateral amygdala. We developed an animal model of PTSD using multiple foot shocks at 1.1 mA. The resulting conditioned fear response was severe (>80% freezing) and maintained for at least 28 days. The stress-associated neurotransmitters norepinephrine, dopamine, and corticotrophin releasing hormone were elevated at 1 day after foot shock. CCK immunoreactivity and extracellular concentration as well as the expression of CCK receptors (CCK1R, CCK2R) increased progressively for 28 days following foot shock. Taken together, these results suggest that stress-induced activation of the CCK system in the BLA, which may contribute toward the development of PTSD-like symptoms. PMID- 25037004 TI - The impact of perceived quality on online buying decisions: an event-related potentials perspective. AB - Consumer neuroscience can provide useful insights into the neural foundations of consumer decisions, such as perceived quality. One of the applications is to guide attribute configuration of products to fit consumers' expectations on the basis of individual preferences. In this study, we required 20 participants to decide whether to buy the product provided in the stimuli and to respond as soon as possible. According to their reports of expectations after the experiment, we subdivided the stimuli into two conditions. Condition 1 contained the stimuli that fit individual preferences, whereas Condition 2 contained the other stimuli. An essential component of event-related potentials (ERPs), the P300, was elicited in the two conditions and distributed over almost all parietal and occipital regions. Products in Condition 1 induced a higher P300 amplitude than those in Condition 2. The results show that evaluating product attributes is a cognitive process that modulates attention in the aforementioned regions. When participants evaluate the alternatives, categorical processing occurred on the basis of similarity judgment. The situation in Condition 1 produced a similarity overlap between the product and the expectation and resulted in a higher P300. Otherwise, there was no overlap, leading to a smaller P300. Hence, the P300 may be a useful neural endogenous indicator for measuring consumers' evaluations of products in marketing research. PMID- 25037005 TI - Binding of Abeta peptide creates lipid density depression in DMPC bilayer. AB - Using isobaric-isothermal replica exchange molecular dynamics and all-atom explicit water model we study the impact of Abeta monomer binding on the equilibrium properties of DMPC bilayer. We found that partial insertion of Abeta peptide into the bilayer reduces the density of lipids in the binding "footprint" and indents the bilayer thus creating a lipid density depression. Our simulations also reveal thinning of the bilayer and a decrease in the area per lipid in the proximity of Abeta. Although structural analysis of lipid hydrophobic core detects disordering in the orientations of lipid tails, it also shows surprisingly minor structural perturbations in the tail conformations. Finally, partial insertion of Abeta monomer does not enhance water permeation through the DMPC bilayer and even causes considerable dehydration of the lipid-water interface. Therefore, we conclude that Abeta monomer bound to the DMPC bilayer fails to perturb the bilayer structure in both leaflets. Limited scope of structural perturbations in the DMPC bilayer caused by Abeta monomer may constitute the molecular basis of its low cytotoxicity. PMID- 25037006 TI - The pore-lining regions in cytochrome c oxidases: A computational analysis of caveolin, cholesterol and transmembrane helix contributions to proton movement. AB - Cytochrome c oxidase (CcO) is the terminal enzyme in the electron transfer chain. CcO catalyzes a four electron reduction of O2 to water at a catalytic site formed by high-spin heme (a3) and copper atoms (CuB). While it is recognized that proton movement is coupled to oxygen reduction, the proton channel(s) have not been well defined. Using computational methods developed to study protein topology, membrane channels and 3D packing arrangements within transmembrane (TM) helix arrays, we find that subunit-1 (COX-1), subunit-2 (COX-2) and subunit-3 (COX-3) contribute 139, 46 and 25 residues, respectively, to channel formation between the mitochondrial matrix and intermembrane space. Nine of 12 TM helices in COX-1, both helices in COX-2 and 5 of the 6 TM helices in COX-3 are pore-lining regions (possible channel formers). Heme a3 and the CuB sites (as well as the CuA center of COX-2) are located within the channel that includes TM-6, TM-7, TM-10 and TM 11 of COX-1 and are associated with multiple cholesterol and caveolin-binding (CB) motifs. Sequence analysis identifies five CB motifs within COX-1, two within COX-2 and four within COX-3; each caveolin containing a pore-lining helix C terminal to a TM helix-turn-helix. Channel formation involves interaction between multiple pore-lining regions within protein subunits and/or dimers. PoreWalker analysis lends support to the D-channel model of proton translocation. Under physiological conditions, caveolins may introduce channel formers juxtaposed to those in COX-1, COX-2 and COX-3, which together with cholesterol may form channel(s) essential for proton translocation through the inner mitochondrial membrane. PMID- 25037007 TI - Group 3 LEA protein model peptides protect liposomes during desiccation. AB - We investigated whether a model peptide for group 3 LEA (G3LEA) proteins we developed in previous studies can protect liposomes from desiccation damage. Four different peptides were compared: 1) PvLEA-22, which consists of two tandem repeats of the 11-mer motif characteristic of LEA proteins from the African sleeping chironomid; 2) a peptide with amino acid composition identical to that of PvLEA-22, but with its sequence scrambled; 3) poly-l-glutamic acid; and 4) poly-l-lysine. Peptides 1) and 2) protected liposomes composed of 1-palmitoyl 2 oleoyl-sn-glycero-3-phosphatidylcholine (POPC) against fusion caused by desiccation, as revealed by particle size distribution measurements with dynamic light scattering. Indeed, liposomes maintain their pre-stress size distribution when these peptides are added at a peptide/POPC molar ratio of more than 0.5. Interestingly, peptide 1) achieved the comparable or higher retention of a fluorescent probe inside liposomes than did several native LEA proteins published previously. In contrast, the other peptides exhibited less protective effects. These results demonstrate that the synthetic peptide derived from the G3LEA protein sequence can suppress desiccation-induced liposome fusion. Fourier transform infrared (FT-IR) spectroscopic measurements were performed for the dried mixture of each peptide and liposome. Based on results for the gel-to liquid crystalline phase transition temperature of the liposome and the secondary structure of the peptide backbone, we discuss possible underlying mechanisms for the protection effect of the synthetic peptide on dried liposomes. PMID- 25037008 TI - Evolving trends in primary retinal detachment repair: microincisional vitrectomy and the role of OCT. AB - Retinal detachment repair continues to evolve toward less invasive techniques that can safely, efficiently, and consistently provide optimal outcomes. In fact, 53% of U.S. respondents to the American Society of Retinal Specialists 2013 Preferences and Trends Survey said they would perform a vitrectomy without scleral buckle to treat a retinal detachment with a superior tear, while 25% would perform pneumatic retinopexy, and 21% would use a scleral buckle with or without vitrectomy.11 Compared to in 2005, many more surgeons prefer vitrectomy only repair, whereas fewer prefer scleral buckle. Interestingly, preferences toward pneumatic retinopexy have slightly declined, which may reflect increased confidence in vitrectomy surgery to repair a detached retina safely and efficiently as an alternative. Even complex detachments can be treated in a minimally invasive fashion with the improvements in instrumentation, trocars, and oil infusion. While trends will likely continue toward minimal invasiveness, some form of scleral buckle, vitrectomy, and pneumatic retinopexy will all persist as treatment options. OCT advancements may allow for individualized discussions of visual prognosis and surgical decision making without the need for any invasive testing. PMID- 25037009 TI - Intravitreal bevacizumab and aflibercept for the treatment of exudative age related macular degeneration. AB - BACKGROUND AND OBJECTIVE: To compare treatment of exudative age-related macular degeneration (AMD) with bevacizumab versus aflibercept in terms of central retinal thickness (CRT) and best corrected visual acuity (BCVA). PATIENTS AND METHODS: A retrospective cohort study examining changes in CRT and BCVA over 12 months of follow-up in 111 patients treated with bevacizumab and 91 treated with aflibercept for exudative AMD. RESULTS: Treatment with bevacizumab and aflibercept reduced CRT from baseline to 12 months. Aflibercept significantly reduced the mean change from baseline CRT at 12 months compared to bevacizumab. However, mean CRT at 12 months was not significantly different after aflibercept versus bevacizumab (271.6 +/- 74.0 MUm vs 257.9 +/- 48.5 MUm). BCVA was significantly better at 6 months in the aflibercept group. At baseline, 18.5% of bevacizumab and 26.4% of aflibercept patients had BCVA better than 20/40. At 12 months, 34.8% of bevacizumab and 38.9% of aflibercept patients had BCVA better than 20/40. CONCLUSION: CRT decreased and BCVA improved after treatment with bevacizumab and aflibercept for exudative AMD. PMID- 25037010 TI - Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab. AB - BACKGROUND AND OBJECTIVE: Patients with neovascular age-related macular degeneration (AMD) require frequent follow-up and regular anti-VEGF injections for optimal outcomes. Although studies suggest that injection frequency is suboptimal in clinical practice, monitoring frequency in this setting is unclear. This study evaluates annual monitoring patterns between 2008 and 2011. PATIENTS AND METHODS: This retrospective claims analysis included newly diagnosed neovascular AMD patients with at least one intravitreal bevacizumab or ranibizumab injection (8,811 and 2,877 patients, respectively). Patient monitoring and treatment patterns were assessed at 12-month intervals. RESULTS: From 2008 to 2010, the mean number of injections increased. In the 2010 cohort, among bevacizumab- and ranibizumab-treated patients, respectively, less than 23% and less than 40% had at least 10 ophthalmologist visits, and less than 4% and less than 21% had at least 10 optical coherence tomography scans. CONCLUSION: Patients with neovascular AMD in clinical settings during 2008 to 2011 were monitored less frequently and received fewer anti-VEGF injections than patients in major clinical trials, which may affect outcomes. PMID- 25037011 TI - Ocriplasmin for treatment of stage 2 macular holes: early clinical results. AB - BACKGROUND AND OBJECTIVE: To review clinical and structural outcomes of ocriplasmin for treatment of stage 2 macular holes. PATIENTS AND METHODS: A retrospective review of the first patients with stage 2 macular holes to be treated with ocriplasmin at Massachusetts Eye and Ear Infirmary. All patients were imaged with spectral-domain optical coherence tomography (SD-OCT). RESULTS: Eight patients with stage 2 macular holes received a single injection of 125 MUg of ocriplasmin. One patient (12.5%) demonstrated macular hole closure. The posterior hyaloid separated from the macula in six eyes (75%). All seven holes that remained open showed enlargement in hole diameters (narrowest, apical, and basal) at 1 week and 1 month. All seven were successfully closed with surgery. Ellipsoid zone disruptions were observed by OCT in four eyes (50%) and persisted throughout follow-up (more than 6 months on average). CONCLUSION: In early clinical results, the authors found a lower macular hole closure rate with ocriplasmin than previously reported. Enlargement was observed in all holes that failed to close with ocriplasmin. The authors found ellipsoid zone disruptions that persisted through 6 months of follow-up after ocriplasmin injection. Further work is needed to investigate the cause for these ellipsoid zone changes. PMID- 25037012 TI - Topical lidocaine gel with and without subconjunctival lidocaine injection for intravitreal injection: a within-patient study. AB - BACKGROUND AND OBJECTIVE: To determine whether patients prefer topical anesthesia or subconjunctival anesthesia for intravitreal injection. PATIENTS AND METHODS: Consecutive patients receiving bilateral simultaneous injections of anti-vascular endothelial growth factor agents were asked to participate in this within patient, prospective, single-blinded, randomized, factorial study. Fifty-seven patients completed the study. Both eyes were treated with topical anesthesia. One eye was also injected with subconjunctival lidocaine. Anesthesia for the next treatment visit was based on patient preference at the conclusion of the study visit and at a 4-hour and 24-hour follow-up telephone call. Patients were allowed to change their anesthesia preference during the next three visits. The final endpoint for the study was anesthesia preference for ongoing intravitreal injections. RESULTS: Fifty patients (88%) preferred subconjunctival anesthesia and seven patients (12%) preferred topical anesthesia for ongoing treatments. (P = .0003) CONCLUSION: Given the choice, most patients prefer subconjunctival anesthesia to topical anesthesia for intravitreal injections. PMID- 25037013 TI - Precise montaging and metric quantification of retinal surface area from ultra widefield fundus photography and fluorescein angiography. AB - BACKGROUND AND OBJECTIVE: Accurate quantification of retinal surface area from ultra-widefield (UWF) images is challenging due to warping produced when the retina is projected onto a two-dimensional plane for analysis. By accounting for this, the authors sought to precisely montage and accurately quantify retinal surface area in square millimeters. PATIENTS AND METHODS: Montages were created using Optos 200Tx (Optos, Dunfermline, U.K.) images taken at different gaze angles. A transformation projected the images to their correct location on a three-dimensional model. Area was quantified with spherical trigonometry. Warping, precision, and accuracy were assessed. RESULTS: Uncorrected, posterior pixels represented up to 79% greater surface area than peripheral pixels. Assessing precision, a standard region was quantified across 10 montages of the same eye (RSD: 0.7%; mean: 408.97 mm(2); range: 405.34-413.87 mm(2)). Assessing accuracy, 50 patients' disc areas were quantified (mean: 2.21 mm(2); SE: 0.06 mm(2)), and the results fell within the normative range. CONCLUSION: By accounting for warping inherent in UWF images, precise montaging and accurate quantification of retinal surface area in square millimeters were achieved. PMID- 25037014 TI - A rare pattern of 360 degrees radiating choroidal folds associated with an orbital abscess. AB - A 78-year-old woman presented with periorbital swelling and visual loss in the right eye after a tooth extraction. Initial visual acuity was reduced to counting fingers in the right eye. No afferent pupillary defect was found on initial examination. Computed tomography revealed axial elongation due to increased orbital pressure caused by the orbital abscess. The authors present a case with a rare pattern of choroidal folds radiating 360 degrees from the optic disc. Initial optical coherence tomography revealed a markedly folded Bruch's membrane and retinal pigment epithelium, which disappeared completely 2 months after surgical drainage of the orbital abscess. Retinal images in this report can provide a better understanding of the pathogenesis of the choroidal folds. PMID- 25037015 TI - Efficacy of adalimumab for pediatric Vogt-Koyanagi-Harada syndrome. AB - Pediatric Vogt-Koyanagi-Harada syndrome (VKH) is rare, with limited cases of corticosteroid-sparing immunosuppression use reported. A 15-year-old Hispanic girl was referred for bilateral intraocular inflammation. Her initial best corrected visual acuity (BCVA) was 20/30 in the right eye and 20/200 in the left eye, with granulomatous keratic precipitates, anterior chamber and vitreous cell, optic disc edema, and nummular depigmented chorioretinal lesions on examination consistent with VKH after an unrevealing work-up. Inflammation was recurrent despite oral prednisone and methotrexate. Adalimumab, a TNF-alpha inhibitor, led to rapid resolution of inflammation, successful dose reduction of prednisone and methotrexate, and final BCVA of 20/25 in the right eye and 20/40 in the left at 26-month follow-up. PMID- 25037016 TI - 8 questions with Dr. Puliafito. PMID- 25037017 TI - Temperature-responsive polymeric micelles for optimizing drug targeting to solid tumors. AB - Targeting to solid tumors is the most challenging issue in the drug delivery field. To obtain the ideal pharmacodynamics of administrated drugs, drug carriers must suppress drug release and interactions with non-target tissues while circulating in the bloodstream, yet actively release the incorporated drug and interact with target cells after delivery to the tumor tissue. To handle this situation, stimuli-responsive drug carriers are extremely useful, because carriers change their physicochemical properties to control the drug release rate and interaction with cells in response to the surrounding environmental conditions or applied physical signals. The current review focuses on the strategy and availability of temperature-responsive (TR) polymeric micelles as a next-generation drug carrier. In particular, we discuss the unique properties of TR polymeric micelles, such as temperature-triggered drug release and intracellular uptake system. In addition, we explore the methodology for integrating other targeting systems into TR micelles to pursue the ideal pharmacodynamics in conjunction with thermal therapy as a future prospective of the TR system. PMID- 25037018 TI - Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles. AB - Polymeric micelles self-assembled from biodegradable amphiphilic block copolymers have been proven to be effective drug delivery carriers that reduce the toxicity and enhance the therapeutic efficacy of free drugs. Several reviews have been reported in the literature to discuss the importance of size/size distribution, stability and drug loading capacity of polymeric micelles for successful in vivo drug delivery. This review is focused on non-covalent and covalent interactions that are employed to enhance cargo loading capacity and in vivo stability, and to achieve nanosize with narrow size distribution. In particular, this review analyzes various non-covalent and covalent interactions and chemistry applied to introduce these interactions to the micellar drug delivery systems, as well as the effects of these interactions on micelle stability, drug loading capacity and release kinetics. Moreover, the factors that influence these interactions and the future research directions of polymeric micelles are discussed. PMID- 25037019 TI - A genetic fiber modification to achieve matrix-metalloprotease-activated infectivity of oncolytic adenovirus. AB - Selective tumor targeting of oncolytic adenovirus at the level of cell entry remains a major challenge to improve efficacy and safety. Matrix metalloproteases (MMPs) are overexpressed in a variety of tumors and in particular in pancreatic cancer. In the current work, we have exploited the expression of MMPs together with the penetration capabilities of a TAT-like peptide to engineer tumor selective adenoviruses. We have generated adenoviruses containing CAR-binding ablated fibers further modified with a C-terminus TAT-like peptide linked to a blocking domain by an MMP-cleavable sequence. This linker resulted in a MMP dependent cell transduction of the reporter MMP-activatable virus AdTATMMP and in efficient transduction of neoplastic cells and cancer-associated fibroblasts. Intravenous and intraductal administration of AdTATMMP into mice showed very low AdTATMMP activity in the normal pancreas, whereas increased transduction was observed in pancreatic tumors of transgenic Ela-myc mice. Intraductal administration of AdTATMMP into mice bearing orthotopic tumors led to a 25-fold increase in tumor targeting compared to the wild type fiber control. A replication competent adenovirus, Ad(RC)MMP, with the MMP-activatable fiber showed oncolytic efficacy and increased antitumor activity compared to Adwt in a pancreatic orthotopic model. Reduced local and distant metastases were observed in Ad(RC)MMP treated-mice. Moreover, no signs of pancreatic toxicity were detected. We conclude that MMP-activatable adenovirus may be beneficial for pancreatic cancer treatment. PMID- 25037021 TI - Design, crystal structures and magnetic properties of anionic salts containing fullerene C60 and indium(III) bromide phthalocyanine radical anions. AB - Two salts containing fullerene C60 and indium(III) bromide phthalocyanine (Pc) radical anions have been obtained as single crystals: (TBA(+))3(C60( )){In(III)(Br)(Pc)(-)}(Br(-)).C6H4Cl2 (1) and (TEA(+))2(C60(-)){In(III)(Br)(Pc)( )}.C6H4Cl2.C6H14 (2) where TBA(+) and TEA(+) are tetrabutyl- and tetraethylammonium cations, respectively. The presence of both radical anions is supported by spectra of 1 and 2 in the NIR and IR-ranges. The salts contain zigzag C60(-) chains with 10.136 and 10.383 A center-to-center (ctc) distances in 1 and a uniform ctc distance of 10.186 A in 2. In 1, the C60(-) radical anions are dimerized in the 180-140 K range to form singly bonded (C60(-))2 dimers, whereas they remain monomeric in 2. Effective packing of planar In(Br)(Pc)(-) and spherical C60(-) is attained by introducing fullerene spheres between the phenylene substituents of Pc allowing the formation of multiple van der Waals contacts between them. The effective magnetic moment of 1 at 300 K is 2.35MU(B), indicating a contribution of both C60(-) and In(Br)(Pc)(-) species having S = 1/2 spin state. There is strong antiferromagnetic coupling of spins between fullerenes in the chains and fullerenes and phthalocyanines in the monomeric phase of 1 with the Weiss temperature of -120 K in the 300-180 K range. The formation of diamagnetic (C60(-))2 dimers switches off magnetic coupling and magnetically isolates In(Br)(Pc)(-) (Weiss temperature is only -1 K in the 140-10 K range). Magnetic behavior of 2 is described by the Curie-Weiss law with weak ferromagnetic coupling of spins with Theta = +7.6 K in the 50-300 K range. Both salts manifest single Lorentzian EPR lines at room temperature with g = 1.9911 and a linewidth (DeltaH) of 25.4 mT (1) and g = 1.9956 and DeltaH = 7.5 mT (2) which can be attributed to both C60(-) and In(Br)(Pc)(-) species having strong exchange interaction. An asymmetric signal with the main component at g = 1.989 1.965 in the dimeric phase of 1 was attributed to the In(Br)(Pc)(-) radical anions. PMID- 25037020 TI - Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked. AB - Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically recognized pro-inflammatory effects, anti-inflammatory effects are also being described in recent years. Interestingly, these lipid mediators are involved in activation of pro-inflammatory signal transduction pathways such as the nuclear factor kappaB (NF-kappaB) pathway, which illustrates the intimate link between lipid signaling and transcription factor activation. The identification of the role of arachidonic acid metabolites in several inflammatory diseases led to a significant drug discovery effort around arachidonic acid metabolizing enzymes. However, to date success in this area has been limited. This might be attributed to the lack of selectivity of the developed inhibitors and to a lack of detailed understanding of the functional roles of arachidonic acid metabolites in inflammatory responses and cancer. This calls for a more detailed investigation of the activity of arachidonic acid metabolizing enzymes and development of more selective inhibitors. PMID- 25037022 TI - Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. AB - OBJECTIVES: The most frequent adverse events associated with valganciclovir treatment are hematological disturbances such as neutropenia. However, the consequences of neutropenia are unknown. We investigated the clinical impact of neutropenia during CMV preemptive therapy and its relationship with the length of antiviral therapy. METHODS: An observational, prospective cohort of 67 solid organ transplant recipients receiving CMV preemptive therapy was studied. RESULTS: Severe neutropenia occurred in 21.8% of the patients at a median of three weeks after initiating antiviral therapy. No association was observed between neutropenia and infection risk in these patients. Liver transplant recipients had 6.7 fold increased risk of neutropenia during CMV therapy compared to kidney transplant recipients (p = 0.012). Patients who developed severe neutropenia received antiviral therapy a median of six days longer than patient who did not (p = 0.457). CONCLUSIONS: Despite the frequency of neutropenia during CMV preemptive therapy, the incidence of infections is not increased. Adjusting the length of preemptive therapy during the episodes of viremia may be recommended, especially in patients with concurrent risk factors for neutropenia such as liver recipients. Further trials are warranted to confirm the safety of this approach. PMID- 25037023 TI - Dietary advanced glycation end products are associated with decline in memory in young elderly. AB - We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p=0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors). Since modifying the levels of AGEs in the diet may be relatively easy, these preliminary results suggest a simple strategy to diminish cognitive compromise in the elderly and warrant further investigation. PMID- 25037024 TI - Frozen adipose-derived mesenchymal stem cells maintain high capability to grow and differentiate. AB - In recent years, there has been a shift toward tissue-engineering strategies using stem cells for plastic and reconstructive surgical procedures. Therefore, it is important to develop safe and reproducible protocols for the extraction of adipose-derived stromal cells (ASCs) to allow cells to be stored in liquid nitrogen for future needs. The aspirated liposuction obtained from healthy donors were immediately processed after the suction using a protocol developed in our laboratory. The resulting stromal vascular fraction (SVF) was then characterized by the presence of adipose-derived stromal cells, at later stage frozen in liquid nitrogen. After that, cells were thawed and again characterized by adipose derived stromal cells, cellular survival, differentiation ability and Colony Forming Unit-Fibroblast like colonies (CFU-F). Extraction and freezing of cells contained in the stromal vascular fraction demonstrate that thawed cells maintain the full capability to grow and differentiate in culture. The advent of adipose derived stromal cells use in tissue engineering will assume a wide role in esthetic restoration in plastic surgery. It is thus important to develop clinically translatable protocols for the preparation and storage of adipose derived stromal cells. Our results show that adipose-derived stromal cells in serum free can easily be frozen and stored in liquid nitrogen with retention of 85% of cell viability and 180,890 cell/g yield plus normal proliferative capacity and differentiation potential compared with fresh controls. These observations set the basis for adipose-derived stromal cells banking. PMID- 25037025 TI - The treatment of paravertebral malignant mesenchymal tumor pain with cryoablation. AB - OBJECTIVE: The purpose of this study was to evaluate the feasibility, safety, and efficacy of cryoablation to treat pain from paravertebral malignant mesenchymal tumors. METHOD: Cryoablation was performed on 15 patients who suffer from unresectable painful paravertebral malignant mesenchymal tumors and whose pain was poorly controlled by conventional treatment methods. The sizes of the tumors varied from 3 to 20 cm. The patients' pain at baseline before the cryoablation and the pain they felt 1 day, 1 week, 1 month, and 3 months after the cryoablation were assessed respectively by the Brief Pain Inventory (BPI). RESULT: BPI scores are divided into two categories: the influence of pain and the severity of pain. Both results showed a decline after the cryoablation. The evaluation score of pain severity decreased significantly (P=0.001, P=0.031) on the observation of 1 day and 1 month after the cryoablation; that of pain influence decreased significantly (P=0.016, P=0.036) in the cases of 1 day and 1 week after cryoablation. Two patients (13.33%) had mild complications, but no serious complications occurred. CONCLUSION: Cryoablation is a low risk, well tolerated topical treatment for the pain of patients with unresectable paravertebral malignant mesenchymal tumor. PMID- 25037026 TI - Boar sperm cryosurvival is better after exposure to seminal plasma from selected fractions than to those from entire ejaculate. AB - Boar bulk ejaculates are now being collected instead of usual sperm-rich fractions (SRF) for artificial insemination purpose. The present study evaluated the influence of holding boar sperm samples before freezing surrounded in their own seminal plasma (SP), from either fractions/portions or the entire ejaculate, on post-thawing sperm quality and functionality. Ejaculates collected as bulk (BE) or as separate (first 10 mL of SRF [P1] and rest of SRF [P2]) from 10 boars were held 24h at 15-17 degrees C and then frozen. Some bulk ejaculate samples were frozen immediately after collections as Control. In addition, epididymal sperm samples from the same 10 boars were collected post-mortem and extended in SP from P1 (EP1), P2 (EP2) and post SRF (EP3), and also held 24h before freezing for a better understanding of the influence of SP on boar sperm cryopreservation. The sperm quality (motility, evaluated by CASA, and viability, evaluated by flow cytometry) and functionality (flow cytometry assessment of plasma membrane fluidity, mitochondrial membrane potential and intracellular generation of reactive oxygen species [ROS] in viable sperm) were evaluated at 30, 150 and 300 min post-thaw. Post-thawing sperm quality and functionality of P1 and P2 were similar but higher (p < 0.01) than BE samples. Control samples showed higher (p < 0.01) post-thaw sperm quality and functionality than BE samples. Post-thawing sperm quality and functionality of EP1 and EP2 were similar but higher (p < 0.05) than EP3. These results showed that boar sperm from BE are more cryosensitive than those from the SRF, particularly when held 24h before freezing, which would be attributable to the cryonegative effects exerted by the SP from post SRF. PMID- 25037027 TI - Exercise for intermittent claudication. AB - BACKGROUND: Exercise programmes are a relatively inexpensive, low-risk option compared with other more invasive therapies for leg pain on walking (intermittent claudication (IC)). This is an update of a review first published in 1998. OBJECTIVES: The prime objective of this review was to determine whether an exercise programme in people with intermittent claudication was effective in alleviating symptoms and increasing walking treadmill distances and walking times. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events and improving quality of life. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched September 2013) and CENTRAL (2013, Issue 8). SELECTION CRITERIA: Randomised controlled trials of an exercise regimen versus control or versus medical therapy in people with IC due to peripheral arterial disease. Any exercise programme or regimen used in the treatment of intermittent claudication was included, such as walking, skipping and running. Inclusion of trials was not affected by the duration, frequency or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain-free walking distance and maximum walking time or maximal walking distance), ankle brachial index (ABI), quality of life, morbidity or amputation; if none of these were reported the trial was not included in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: Eleven additional studies were included in this update making a total of 30 trials which met the inclusion criteria, involving a total of 1816 participants with stable leg pain. The follow up period ranged from two weeks to two years. The types of exercise varied from strength training to polestriding and upper or lower limb exercises; generally supervised sessions were at least twice a week. Most trials used a treadmill walking test for one of the outcome measures. Quality of the included trials was moderate, mainly due to an absence of relevant information. The majority of trials were small with 20 to 49 participants. Twenty trials compared exercise with usual care or placebo, the remainder of the trials compared exercise to medication (pentoxifylline, iloprost, antiplatelet agents and vitamin E) or pneumatic calf compression; people with various medical conditions or other pre existing limitations to their exercise capacity were generally excluded.Overall, when taking the first time point reported in each of the studies, exercise significantly improved maximal walking time when compared with usual care or placebo: mean difference (MD) 4.51 minutes (95% confidence interval (CI) 3.11 to 5.92) with an overall improvement in walking ability of approximately 50% to 200%. Walking distances were also significantly improved: pain-free walking distance MD 82.29 metres (95% CI 71.86 to 92.72) and maximum walking distance MD 108.99 metres (95% CI 38.20 to 179.78). Improvements were seen for up to two years, and subgroup analyses were performed at three, six and 12 months where possible. Exercise did not improve the ABI (MD 0.05, 95% CI 0.00 to 0.09). The effect of exercise, when compared with placebo or usual care, was inconclusive on mortality, amputation and peak exercise calf blood flow due to limited data. No data were given on non-fatal cardiovascular events.Quality of life measured using the Short Form (SF)-36 was reported at three and six months. At three months, physical function, vitality and role physical all significantly improved with exercise, however this was a limited finding as this measure was only reported in two trials. At six months five trials reported outcomes of a significantly improved physical summary score and mental summary score secondary to exercise. Only two trials reported improvements in other domains, physical function and general health.Evidence was generally limited for exercise compared with antiplatelet therapy, pentoxifylline, iloprost, vitamin E and pneumatic foot and calf compression due to small numbers of trials and participants. AUTHORS' CONCLUSIONS: Exercise programmes are of significant benefit compared with placebo or usual care in improving walking time and distance in people with leg pain from IC who were considered to be fit for exercise intervention. PMID- 25037028 TI - Trypanosoma brucei: meet the system. AB - African trypanosomes cause devastating diseases in humans and domestic animals. The parasites evolved early in the eukaryotic lineage and have numerous biochemical peculiarities that distinguish them from other systems. These include unconventional mechanisms for expressing nuclear and mitochondrial genes as well as unusual subcellular localizations for a variety of enzymes. Systems biology has arisen partly to allow contextualization of the massive datasets that describe individual chemical parts of biological systems. Here we describe recent efforts to collect and analyse data pertaining to all aspects of the trypanosome's biochemical physiology that go some way to describing the parasite as an integrated system. PMID- 25037029 TI - Subtype of mild cognitive impairment in elderly patients with essential tremor. AB - BACKGROUND AND AIMS: Several studies have demonstrated that patients with essential tremor (ET) may also have mild cognitive impairments (MCIs), and cross sectional and population-based studies have shown that ET is associated with prevalent dementia. Different presentations of MCI are suggested to be associated with different pathologies. For example, amnestic MCI may be associated with Alzheimer disease. Therefore, in this study, we explored whether the MCI subtype in patients with ET (MCI-ET+) is different from the MCI subtype in patients without ET attending a memory outpatient clinic (MCI-ET-). METHODS: Using a case control study design, cognitive status in MCI patients with ET and without ET was assessed by neuropsychological testing. Patients with MCI were stratified into groups: amnestic and nonamnestic MCI, or single-domain and multidomain MCI. RESULTS: Of the 93 patients in the ET+ group and the 169 in the ET- group, 45 (48.4%) and 94 (55.6%) patients had MCI, respectively. The frequency of MCI subtypes between the 2 groups was different, such that 25 (55.6%) patients had nonamnestic MCI in the ET+ group and 68 (72.3%) patients had amnestic MCI in ET- group (chi=10.195, P=0.001). Compared with the MCI-ET+ group, patients in the MCI ET- group showed more severe impairments in verbal and visuospatial memory functions. CONCLUSIONS: ET is associated with MCI, particularly the nonamnestic subtype. These results suggest that cognitive change in patients with ET may have a different pathogenesis from that of Alzheimer disease. PMID- 25037030 TI - Cognitive intervention in semantic dementia: maintaining words over time. AB - Patients with semantic dementia (SD) can improve their naming ability through cognitive intervention, with good retention 1 month later. Beyond this time, improvements often fade, yet no studies have investigated how to maintain performance. Nine SD patients completed a 2-month word training program and were then monitored over 6 months: firstly for 2 months without training, followed by a further 4 months, where additional training was provided to revise words, if required. All patients improved their naming immediately postintervention (P<0.001). After 2 months without practice, significant declines occurred in 4 patients. To sustain at least 80% of their postintervention performance 6 months later, 4 patients required minimal revision (<10 sessions over the period), 2 required regular weekly or biweekly revision sessions, with the remaining 3 patients requiring no revision sessions. During this period, group results indicated some decline in words that were initially known, but were not trained. Improvements in naming can be sustained in SD patients, with the support of less intense, but ongoing revision. Training words that are still known appears to help prolong memory of these words. PMID- 25037031 TI - BP variability and cognitive impairment: vascular risk factors for Alzheimer disease? PMID- 25037032 TI - A novel multi-amplification photoelectrochemical immunoassay based on copper(II) enhanced polythiophene sensitized graphitic carbon nitride nanosheet. AB - A new sandwich photoelectrochemical (PEC) sensing strategy was proposed for the first time based on the increasing photocurrent of water-soluble polythiophene sensitized g-C3N4 nanosheet (PT-Cl/g-C3N4) in the presence of copper(II) (Cu(2+)), which was doped on the surface of titanium dioxide as labels for multi amplification. Herein, the photoactive films of PT-Cl/g-C3N4 is employed as the photoactive antibody (Ab1) immobilization matrix for the subsequent sandwich-type antibody-antigen affinity interactions. Upon the presence of antigen (Ag), greatly enhanced photocurrent could be triggered in the PEC platform by the labels of second antibody (Ab2) of Cu(2+) doped titanium dioxide (Cu(2+)-TiO2). As a result of the multi-amplification in this Cu(2+)-TiO2 enhanced PT-Cl/g-C3N4 based PEC immunoassay, it possesses excellent analytical performance. The antigen could be detected from 0.01 pg mL(-1) to 100.0 ng mL(-1) with a detection limit of 5 fg mL(-1). This work opens up g-C3N4 nanosheet applied in PEC sensing. More importantly, the strategy of specific positive effect of Cu(2+) on the photocurrent of g-C3N4 opens an alternative horizon for PEC sensing. PMID- 25037033 TI - A randomized study to evaluate the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, haemophilus influenzae b, and meningococcal serogroup C combination vaccine administered to infants at 2, 4 and 12 months of age. AB - BACKGROUND: The immunogenicity and safety of the investigational diphtheria, tetanus, acellular pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae type b (Hib) and meningococcal serogroup C (MenC) heptavalent combination vaccine were compared with those of licensed control vaccines. METHODS: In this open, phase II, randomized study (NCT01090453), 480 infants from Germany, France and Canada received the heptavalent vaccine (Hepta group) or hexavalent and monovalent MenC control vaccines (HexaMenC group) co-administered with a 13 valent pneumococcal conjugate vaccine at 2, 4 and 12 months of age. Immunogenicity was measured 1 month after the second primary dose, and before and 1 month after the booster dose. Safety and reactogenicity were also evaluated. RESULTS: Non-inferiority of immune responses to MenC and Hib induced by 2-dose primary vaccination with the heptavalent vaccine versus control vaccines was demonstrated. In exploratory analyses, postprimary and postbooster functional antibody geometric mean titers against MenC tended to be lower (1119.5 vs. 3200.5; 2653.8 vs. 6028.4) and antibody geometric mean concentrations against Hib higher (1.594 vs. 0.671 MUg/mL; 17.678 vs. 13.737 MUg/mL) in the Hepta versus the HexaMenC group. The heptavalent and control vaccines were immunogenic to all other antigens, although immune responses to poliovirus were lower than expected in both groups. No differences in safety and reactogenicity profiles were detected between groups. CONCLUSIONS: The heptavalent vaccine induced non inferior MenC and Hib responses compared with control vaccines. Both vaccination regimens, when administered at 2, 4 and 12 months of age, had comparable safety profiles and were immunogenic to all antigens, with lower-than-expected responses to poliomyelitis. PMID- 25037034 TI - Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age. AB - INTRODUCTION: Annual seasonal influenza epidemics are particularly dangerous for the very young, the elderly and chronically ill individuals, in whom infection can cause severe morbidity, hospitalization and death. Existing, nonadjuvanted influenza vaccines exhibit a suboptimal immunogenicity and efficacy in immunologically naive subjects such as young children. METHODS: This phase II, randomized clinical trial was conducted to evaluate the antibody and cell mediated responses to a trivalent influenza vaccine administered without adjuvant (TIV) or adjuvanted with MF59 (ATIV) in previously nonvaccinated children less than 3 years of age. RESULTS: The MF59-adjuvanted vaccine was well tolerated, and induced higher titers of hemagglutination inhibition antibodies able to recognize strains different from the one used in the vaccine (heterovariant) than TIV. The presence of the adjuvant MF59 induced a larger expansion of vaccine-specific CD4 T cells. Interestingly, the adjuvant MF59 did not modify the cytokine profile of the elicited T cells, characterized by the production of IL-2 and TNF-alpha, and did not bias the response toward either Th1 or Th2. The advantage of ATIV over TIV was more pronounced for the virus strains that had not circulated in the years that preceded this study and for the heterovariant strains. CONCLUSION: These data highlight the relevant role played by the oil-in-water adjuvant MF59 in enhancing the immunogenicity of inactivated influenza vaccines in immunologically naive individuals. PMID- 25037035 TI - Factors associated with intrapartum transmission of group B Streptococcus. AB - BACKGROUND: Data regarding the minimum duration of intrapartum antibiotic prophylaxis (IAP) required for preventing group B Streptococcus (GBS) early-onset sepsis are conflicting. Understanding factors that influence neonatal colonization (NC) might help us understand factors associated with failure of prophylaxis. METHODS: This is a 14-month prospective cohort study conducted at a single tertiary care center with a screening-based strategy. Women were enrolled if they had >= 35 weeks' gestation and were GBS-positive at the vaginal site on admission. Their neonates were cultured from the throat and rectum at 24-48 h after birth. Colony growth was graded semiquantitatively (from 1+ to 4+). Uni- and multivariate logistic regression analyses were performed to evaluate risk factors for NC. RESULTS: There were 502 neonates, 458 of whom were exposed to IAP. All cases of NC were associated with a lack of IAP exposure (P < 0.01), intrapartum fever >= 37.5 degrees C (P < 0.01) and African ethnicity (P < 0.01). In the 458 IAP-exposed neonates, the rates of NC were low and did not vary significantly in the range of less than 1-12 h before delivery (score test for trend of odds, P = 0.13). The only independent factors associated with NC were intrapartum fever >= 37.5 degrees C and heavy maternal colonization (P < 0.01 and P = 0.03, respectively). CONCLUSIONS: Heavy maternal colonization, intrapartum fever, African ethnicity and lack of IAP exposure were associated with GBS transmission in neonates born to women who were tested positive on admission. Low rates of NC were found among IAP-exposed neonates irrespective of IAP duration. PMID- 25037036 TI - Mycobacterium phocaicum bacteremia: an emerging infection in pediatric hematology oncology patients. AB - Nontuberculous mycobacteria may cause central venous catheter-associated bacteremia. Between March 2011 and October 2013, 6 cases of Mycobacterium phocaicum bacteremia were found in the pediatric hematology-oncology department. All patients recovered. No positive blood culture was documented after removal of the central venous catheter. All 4 patients with pulsed field gel electrophoresis had the same pattern, different from the water sample, suggesting a common water source. PMID- 25037037 TI - Hand, foot and mouth disease caused by coxsackievirus A6, Beijing, 2013. AB - Specimens and clinical data were collected from 243 hand, foot and mouth disease patients in Beijing in 2013. In total, 130 stool specimens were genotyped for enterovirus. Hand, foot and mouth disease was mainly detected in suburban areas and at the edges of urban areas between May and August. Coxsackievirus (CV) A6 replaced enterovirus (EV) 71 and CVA16, becoming the main causative agent of hand, foot and mouth disease. CVA6 infection led to significantly reduced fever duration and glucose levels compared with EV71 infection. PMID- 25037038 TI - A study of cardiovascular miRNA biomarkers for Kawasaki disease. AB - We hypothesized that cardiovascular miRNAs might be diagnostic biomarkers for Kawasaki disease (KD). We identified dysregulated miRNAs in KD coronary arteries, and tested sera from KD patients and febrile controls for cardiovascular miRNAs using 2 methods. We did not identify cardiovascular miRNAs diagnostic for KD; our results may help guide future studies of potential miRNA biomarkers for KD. PMID- 25037039 TI - Interferon-gamma release assay sensitivity in children younger than 5 years is insufficient to replace the use of tuberculin skin test in western countries. AB - Tuberculin skin test, QuantiFERON-TB Gold In-Tube and T-SPOT.TB were performed in 338 children at risk for tuberculosis (TB), including 70 active TB cases. In children <5 years of age, QuantiFERON-TB Gold In-Tube sensitivity was 73.3% [95% confidence interval (CI): 57.5-89.1]; and T-SPOT.TB sensitivity was 59.3% (95% CI: 40.1-77.8); both were inferior to tuberculin skin test sensitivity (90.0%; 95% CI: 79.3-100). In children >= 5 years QuantiFERON-TB Gold In-Tube sensitivity was 92.5% (95% CI: 84.4-100); T-SPOT.TB sensitivity was 73.0% (95% CI: 58.6-87.3) ; and tuberculin skin test sensitivity was 97.5% (95% CI: 92.6-100).Test specificities were similar in all age groups. PMID- 25037040 TI - Real-time PCR identification of agents causing diarrhea in Rwandan children less than 5 years of age. AB - BACKGROUND: Knowledge about causes of acute diarrhea among children in developing countries is insufficient. Molecular methods might improve diagnostics of infectious gastroenteritis, but due to the high sensitivity, findings may be difficult to interpret. METHODS: Feces samples from Rwandan children 0.5-5.0 years of age, with diarrhea for <96 hours (patients, n = 544) or without diarrhea for 14 days (controls, n = 162), were analyzed by real-time polymerase chain reaction targeting 17 pathogens. RESULTS: At least 1 agent was detected in 94% of patients and in 79% of controls, with higher rates in sick children for rotavirus (42% vs. 2%, P < 0.0001) and enterotoxigenic Escherichia coli (ETEC)-estA (21% vs. 9%, P = 0.0006). Detection rates did not differ significantly for adenovirus (39% vs. 36%), ETEC-eltB (29% vs. 30%), Campylobacter (14% vs. 17%) or Shigella (13% vs. 10%), but for Shigella the threshold cycle (Ct) values were lower (pathogen loads were higher) in sick children than in controls. By multivariate analysis, including gender and age, detection of rotavirus (P < 0.0001), ETEC estA (P = 0.001), Shigella (P = 0.004) and norovirus genogroup II (P = 0.009) was associated with symptomatic infection, and a Ct value below a cutoff (in the range 28-29) improved identification of ETEC-estA, Shigella and norovirus genogroup II. CONCLUSION: Real-time polymerase chain reaction can detect essentially all diarrheagenic agents, and provides Ct values that improve identification of clinically relevant infections. PMID- 25037041 TI - Vitamin D insufficiency in HIV-infected pregnant women receiving antiretroviral therapy is not associated with morbidity, mortality or growth impairment in their uninfected infants in Botswana. AB - BACKGROUND: Low maternal 25(OH)D (vitamin D) values have been associated with higher mortality and impaired growth among HIV-exposed uninfected (HEU) infants of antiretroviral (ART)-naive women. These associations have not been studied among HEU infants of women receiving ART. METHODS: We performed a nested case control study in the Botswana Mma Bana Study, a study providing ART to women during pregnancy and breastfeeding. Median maternal vitamin D values, and the proportion with maternal vitamin D insufficiency, were compared between women whose HEU infants experienced morbidity/mortality during 24 months of follow-up and women with nonhospitalized HEU infants. Growth faltering was assessed for never hospitalized infants attending the 24-month-of-life visit. Multivariate logistic regression models determined associations between maternal vitamin D insufficiency and infant morbidity/mortality and growth faltering. RESULTS: Delivery plasma was available and vitamin D levels assayable from 119 (86%) of 139 cases and 233 (84%) of 278 controls, and did not differ significantly between cases and controls [median: 36.7 ng/mL, interquartile range (IQR): 29.1-44.7 vs. 37.1 ng/mL, IQR: 30.0-47.2, P = 0.32]. Vitamin D insufficiency (<32 ng/mL) was recorded among 112 (31.8%) of 352 women at delivery and occurred most frequently among women delivering in winter. Multivariate logistic regression models adjusted for maternal HIV disease progression did not show associations between maternal vitamin D insufficiency at delivery and child morbidity/mortality, or 24 month-of-life growth faltering. CONCLUSIONS: Vitamin D insufficiency was common among ART-treated pregnant women in Botswana, but was not associated with morbidity, mortality or growth impairment in their HIV-uninfected children. PMID- 25037042 TI - Genetic susceptibility to norovirus GII.3 and GII.4 infections in Chinese pediatric diarrheal disease. AB - BACKGROUND: Noroviruses (NoVs) are a leading cause of viral diarrhea in young children. Secretor status has been confirmed to be linked with Norwalk virus (NoV GI.1) infection but there is limited information about whether secretor genotypes are associated with pediatric NoV epidemic strains in vivo. METHODS: In this study, fecal specimens and serum samples were collected from 124 hospitalized children with acute diarrhea in Xi'an, China. TaqMan real-time reverse transcription polymerase chain reaction was used to detect NoVs in fecal samples, and NoV-positive samples were further verified using conventional reverse transcription polymerase chain reaction and sequenced. DNA was extracted from sera and TaqMan single-nucleotide polymorphism genotyping assay was applied to determine the FUT2 A385T polymorphism. RESULTS: Only NoV GII.3 and GII.4 genotypes were found in NoV-positive samples, and NoVs were detected in 25% (15/60), 40.5% (17/42) and 9.1% (2/22) of children with homozygous secretor genotype (Se 385 Se 385), heterozygous secretor genotype (Se 385 se 385) and homozygous weak secretor genotype (se 385 se 385), respectively. Children with secretor genotypes Se 385 Se 385 and Se 385 se 385 were significantly (P < 0.05) more susceptible to combined NoV GII.3 and GII.4 infections than children with weak secretor genotype se 385 se 385. CONCLUSIONS: These findings indicate that secretor positivity is significantly associated with GII.3 and GII.4 infections in Chinese pediatric diarrheal disease and the weak secretor phenotype does not completely protect children from GII.3 and GII.4 infections. PMID- 25037043 TI - Staphylococcal cassette chromosome mec elements in methicillin-resistant coagulase-negative staphylococci from a Brazilian neonatal care unit. AB - To characterize 46 methicillin-resistant coagulase-negative staphylococci from Brazilian neonates, we investigated their SCCmec type, susceptibility and clonality. Staphylococcus epidermidis and Staphylococcus haemolyticus were the prevalent species. SCCmec types III or IV were detected in 53.3% S. epidermidis, whereas 63.6% S. haemolyticus were nontypeable. Despite the diversity, specific clones carried specific SCCmec elements, highlighting that effective typing can help in epidemiological analysis. PMID- 25037044 TI - Trends of pneumococcal meningitis in children after introduction of the 13-valent pneumococcal conjugate vaccine in France. AB - BACKGROUND: Streptococcus pneumoniae remains an important cause of bacterial meningitis in children younger than 2 years. Here, we analyzed data from an active surveillance network established 12 years ago by the Pediatric Infectious Disease Group and the Pediatric Clinical and Therapeutical Association to analyze the impact of pneumococcal conjugate vaccine (PCV7 implemented in 2002 and PCV13 in 2010) on pneumococcal meningitis (PM). METHODS: Two hundred twenty-seven pediatric wards working with 168 microbiology departments throughout France were asked to report all cases of PM. RESULTS: From 2001 to 2012, among 4808 bacterial meningitis cases, 1406 cases of PM (29.2%) were reported. After PCV13 implementation, from 2009 to 2012, the number of cases significantly decreased by 27.4% (P = 0.041, Cuzick trend test). For children younger than 2 years, the decrease was 28.2% (P = 0.039, Cuzick trend test). In the same period, the decrease was 66.7% in cases due to 6 additional PCV13 types, and the number of cases due to nonvaccine types remained stable. In 2012, the non-PCV13 serotype represented 67.6% of cases and were mainly represented by 12F (15%), 24F (15%), 22F (7%) and 15B/C (7%). For 88.6% of cases, initial antibiotic treatment was vancomycin with a third-generation cephalosporin. Overall mortality was 10.6%, most deaths (86.4%) occurred before day 15. CONCLUSIONS: Two years after the PCV13 implementation, we found an impact on PM cases particularly for children younger than 2 years. PMID- 25037045 TI - Speech audiometry and Spanish-English bilinguals: challenges in clinical practice. AB - PURPOSE: The Spanish-English bilingual population has been on a steady rise in the United States and is projected to continue to grow. Speech audiometry, a key component of hearing care, must be customized for this linguistically unique and diverse population. METHOD: The tutorial summarizes recent findings concerning Spanish-English bilinguals' performance on English and Spanish speech audiometric tests in the context of the psychometric properties of the tests and the language and dialect profile of the individual (language status, history, stability, competency, and use). The tutorial also provides arguments for evaluating bilingual clients in Spanish, in English, or in both languages, which may serve as rationales in support of varied bilingual clinical practices. Last, the tutorial provides information regarding Spanish speech audiometry, including available tests, issues that clinicians may encounter when administering them, and dialectal consideration. CONCLUSIONS: It is a challenge as well as an opportunity for clinicians to expand service to the Spanish-English bilingual community. Understanding the characteristics of the individual and the test is essential for ensuring quality services to the bilingual client. PMID- 25037046 TI - Airborne pollutant characteristics in an urban, industrial and agricultural complex metroplex with high emission loading and ammonia concentration. AB - The size distribution of particulate mass and water-soluble ionic constituents and their gaseous precursors was investigated in a subtropical area, southern Taiwan. Field sampling and chemical analysis of particulate matter (PM) were conducted using a Micro Orifice Uniform Deposition Impactor (MOUDI) and a Nano MOUDI, and gaseous pollutants were determined by a denuder-filter pack system. PM size mass distribution, mass concentration and ionic species concentration were measured during the day and at night in the winter and summer. Average PM concentrations in the winter were as high as 132 +/- 42 MUg/m(3), and PM mass concentrations in the summer were as low as 38 +/- 19 MUg/m(3). Generally, PM concentration was 111 +/- 60 MUg/m(3) at night, which was 20% higher than that in the daytime. The size-segregated mass distribution of PM mass concentration was over 85% in the 0.1-3.2 MUm range. Ammonium, nitrate, and sulfate were the dominant water-soluble ionic species in PM, contributing 34%-48% of PM mass. High ammonia (12.9-49 MUg/m(3)) and SO2 (2.6-27 MUg/m(3)) were observed in the gas precursors. The molar ratio [Formula: see text] was 3.18 +/- 1.20 at PM1.0, which indicated that the PM was rich in ammonium. Therefore, the excess ammonium could neutralize nitrate to form ammonium nitrate, after the more stable ammonium sulfate and ammonium bisulfate formation. PMID- 25037047 TI - Thirteen years of air pollution hourly monitoring in a large city: potential sources, trends, cycles and effects of car-free days. AB - Thirteen air pollutant concentrations were measured hourly for 13 years (2000 2013) at an urban background site of a large city in the eastern Po Valley (Italy) and results were chemometrically analysed. The pollutant list includes CO, NO, NO2, NOx, O3, SO2, benzene, toluene, ethylbenzene, o-, m- and p-xylenes and PM10, all known or suspected of having adverse effects on human health. The hourly data were statistically processed to detect the long-term trends in relation to the changes in the emission scenarios occurred in the last decade. The most probable emission sources and atmospheric photochemical processes were investigated by analyzing the seasonal, weekly, diurnal cycles of pollutants and the lagged correlations amongst pollutants. The role of micro-meteorological factors upon the air quality was assessed by analyzing the relationships with key weather parameters, while the location of the potential sources was studied by matching atmospheric circulation and pollution data through bivariate polar plots and conditional probability functions. In addition, a new statistical procedure is presented and tested to analyze the periods when common mitigation measures were adopted in the city (e.g., the total stop of traffic and car-free days) and to evaluate their real effect upon the air quality. By providing direct information on the levels and trends of key pollutants, this study finally enables some general considerations about air pollution in an important hotspot of Southern Europe, the eastern Po Valley, where the levels of some key pollutants are still far from meeting the EC limit and target values. It may help policy-makers to take successful mitigation measures. PMID- 25037048 TI - Uncertainty in multi-media fate and transport models: a case study for TNT life cycle assessment. AB - Life cycle assessment (LCA) is an evaluation method used by decision-makers to help assess the relative environmental impacts of various industrial processes. Despite that many LCA methods remain sensitive to uncertain input data, which can reduce the utility of their results, uncertainty arising from constituent LCA models remains poorly understood. Here, we begin to address this problem by evaluating the extent to which parameter-value uncertainty affects the SimpleBox 2.0 fate and transport model, which serves as a backbone for many LCA ecotoxicological impact categories. Two Monte Carlo type sampling methods were used to evaluate dispersion in steady-state concentration values for three chemicals involved in grenade production: toluene, 2,4-dinitrotoluene (2,4-DNT), and 2,4,6-trinitrotoluene (TNT). Parameters were first sampled stochastically one at-a-time, then by randomly exploring a local patch of the parameter space. We confirmed that global temperatures contribute primarily to the overall variance of model results, which at most spanned approximately 8 decades in magnitude. These results are consistent with previous results obtained for the whole of the LCA method. LCA methods carry out calculations iteratively; a reduction in the error of a single component, such as the fate and transport model, may therefore improve its performance and utility as a decision-making aid. PMID- 25037049 TI - Multiple data sets and modelling choices in a comparative LCA of disposable beverage cups. AB - This study used multiple data sets and modelling choices in an environmental life cycle assessment (LCA) to compare typical disposable beverage cups made from polystyrene (PS), polylactic acid (PLA; bioplastic) and paper lined with bioplastic (biopaper). Incineration and recycling were considered as waste processing options, and for the PLA and biopaper cup also composting and anaerobic digestion. Multiple data sets and modelling choices were systematically used to calculate average results and the spread in results for each disposable cup in eleven impact categories. The LCA results of all combinations of data sets and modelling choices consistently identify three processes that dominate the environmental impact: (1) production of the cup's basic material (PS, PLA, biopaper), (2) cup manufacturing, and (3) waste processing. The large spread in results for impact categories strongly overlaps among the cups, however, and therefore does not allow a preference for one type of cup material. Comparison of the individual waste treatment options suggests some cautious preferences. The average waste treatment results indicate that recycling is the preferred option for PLA cups, followed by anaerobic digestion and incineration. Recycling is slightly preferred over incineration for the biopaper cups. There is no preferred waste treatment option for the PS cups. Taking into account the spread in waste treatment results for all cups, however, none of these preferences for waste processing options can be justified. The only exception is composting, which is least preferred for both PLA and biopaper cups. Our study illustrates that using multiple data sets and modelling choices can lead to considerable spread in LCA results. This makes comparing products more complex, but the outcomes more robust. PMID- 25037051 TI - (Post-)genomics approaches in fungal research. AB - To date, hundreds of fungal genomes have been sequenced and many more are in progress. This wealth of genomic information has provided new directions to study fungal biodiversity. However, to further dissect and understand the complicated biological mechanisms involved in fungal life styles, functional studies beyond genomes are required. Thanks to the developments of current -omics techniques, it is possible to produce large amounts of fungal functional data in a high throughput fashion (e.g. transcriptome, proteome, etc.). The increasing ease of creating -omics data has also created a major challenge for downstream data handling and analysis. Numerous databases, tools and software have been created to meet this challenge. Facing such a richness of techniques and information, hereby we provide a brief roadmap on current wet-lab and bioinformatics approaches to study functional genomics in fungi. PMID- 25037050 TI - Fecal metabolomics: assay performance and association with colorectal cancer. AB - Metabolomic analysis of feces may provide insights on colorectal cancer (CRC) if assay performance is satisfactory. In lyophilized feces from 48 CRC cases, 102 matched controls, and 48 masked quality control specimens, 1043 small molecules were detected with a commercial platform. Assay reproducibility was good for 527 metabolites [technical intraclass correlation coefficient (ICC) >0.7 in quality control specimens], but reproducibility in 6-month paired specimens was lower for the majority of metabolites (within-subject ICC <=0.5). In the CRC cases and controls, significant differences (false discovery rate <=0.10) were found for 41 of 1043 fecal metabolites. Direct cancer association was found with three fecal heme-related molecules [covariate-adjusted 90th versus 10th percentile odds ratio (OR) = 17-345], 18 peptides/amino acids (OR = 3-14), palmitoyl-sphingomyelin (OR = 14), mandelate (OR = 3) and p-hydroxy-benzaldehyde (OR = 4). Conversely, cancer association was inverse with acetaminophen metabolites (OR <0.1), tocopherols (OR = 0.3), sitostanol (OR = 0.2), 3-dehydrocarnitine (OR = 0.4), pterin (OR = 0.3), conjugated-linoleate-18-2N7 (OR = 0.2), N-2-furoyl-glycine (OR = 0.3) and p aminobenzoate (PABA, OR = 0.2). Correlations suggested an independent role for palmitoyl-sphingomyelin and a central role for PABA (which was stable over 6 months, within-subject ICC 0.67) modulated by p-hydroxy-benzaldehyde. Power calculations based on ICCs indicate that only 45% of metabolites with a true relative risk 5.0 would be found in prospectively collected, prediagnostic specimens from 500 cases and 500 controls. Thus, because fecal metabolites vary over time, very large studies will be needed to reliably detect associations of many metabolites that potentially contribute to CRC. PMID- 25037052 TI - Prediction of LV functional recovery by CMR in myocarditis: bright signals- bright answers? PMID- 25037053 TI - Cilia: traffic directors along the road of cortical development. AB - While the presence of a primary cilium on neural progenitors and on post-mitotic neurons was noted long ago, a primary cilium has been observed on migrating cortical interneurons only recently. As in fibroblasts, the cilium of interneurons controls the directionality of migration. It plays an important role in the reorientation of cortical interneurons toward the cortical plate. The morphogen Shh, which is expressed in the migratory pathway of interneurons, is one of the signals that control this reorientation. After a short description of the migratory pathways of cortical interneurons, we focus on cellular mechanisms that allow interneurons to reorient their trajectory during their long-distance migration. Then we examine the role of the primary cilium in cell migration and how ciliogenesis might be related to the migration cycle in interneurons. Finally, we review the molecular mechanisms at the basis of the sensory function of the primary cilium and examine how Shh signals could influence the migratory behavior of cortical interneurons. These novel data provide a cellular basis to further understanding cognitive deficits associated with human ciliopathies. PMID- 25037054 TI - Alleviation of moral disgust, shame, and guilt in posttraumatic stress reactions: an evaluation of comprehensive distancing. AB - Research suggests that moral disgust, shame, and guilt are present in posttraumatic psychopathology. However, it is unclear that these emotional states are responsive to empirically supported interventions for posttraumatic stress symptoms (PTSS). This study explored the relations among moral disgust, shame, guilt, and PTSS, and examined comprehensive distancing (CD) as a novel intervention for these emotional states in undergraduates with elevated PTSS. Participants were randomly assigned to use a CD or a cognitive challenge task in response to personalized scripts of a traumatic event. Both interventions were associated with decreases in disgust, moral disgust, shame, and guilt. Contrary to predictions, there were no significant differences between the exercises in the reduction of negative emotions. In addition, PTSS severity was correlated with trauma-related guilt as well as state guilt and shame, but not trait or state measures of disgust or moral disgust. This proof of concept project sets the stage for further research examining CD as an alternative or adjunctive intervention for posttraumatic stress reactions with strong features of moral disgust, shame, and guilt. PMID- 25037056 TI - Repeat coronary computed tomographic angiography in patients with a prior scan excluding significant stenosis. AB - BACKGROUND: ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 Appropriate Use Criteria for Cardiac Computed Tomography (AUC2010) does not incorporate prior coronary computed tomographic angiography (CCTA) results in the appropriateness of a CCTA examination. The purpose of this study was to explore the criteria for forgoing repeat CCTA among patients with clinical scenarios suggesting CCTA as appropriate after prior CCTA excluding coronary artery disease. METHODS AND RESULTS: Among patients from a single center (February 2006 to April 2013) who underwent appropriate CCTA based on AUC2010, consecutive 555 CCTAs, which had a prior CCTA excluding significant stenosis (>50% stenosis in diameter), were selected. The median time difference between the studies was 34.2 (Q1-Q3, 22.9 50.1) months. Significant stenosis was detected at the time of repeat scan (by CCTA or subsequent catheter angiography) in 13.3% (74 of 555). A multivariable logistic model (C-statistic, 0.74; bootstrapped overfitting bias, 0.8%) identified 3 predictors of significant stenosis: time difference between the studies >3 years (adjusted odds ratio, 2.1; 95% confidence interval, 1.2-3.5), diabetes mellitus (odds ratio, 2.4; 95% confidence interval,1.4-4.3), and 26% to 50% stenosis on the initial CCTA (odds ratio, 5.6; 95% confidence interval, 3.2 9.6). When these 3 factors were all absent (corresponding to 31.9% of the population), the probability of significant stenosis was 4.5% (95% confidence interval, 2.7-7.4%), whereas 17.1% of patients had significant stenosis among those with at least 1 positive variable. When coronary arteries were completely normal at the initial scan, the prevalence of significant stenosis was only 1.8% irrespective of other factors, and no patient underwent revascularization. CONCLUSIONS: Nondiabetic patients with a prior CCTA <3 years showing no or <=25% stenosis had a <5% prevalence of significant stenosis. The value of repeat CCTA in this group is likely small, especially when the prior CCTA demonstrated normal coronaries, even if the clinical scenario considered a CCTA appropriate. PMID- 25037057 TI - Protecting newborns from pertussis - the challenge of complete cocooning. AB - BACKGROUND: An increase of pertussis cases, especially in young infants and adolescents, has been noted in various countries. Whooping cough is most serious in neonates and young infants in whom it may cause serious complications such as cyanosis, apnoea, pneumonia, encephalopathy and death. To protect newborns and infants too young to be fully immunized, immunization of close contact persons has been proposed ("cocoon strategy") and implemented in several countries, including Switzerland in 2011. The goal of this study was to assess knowledge about pertussis among parents of newborns and acceptance, practicability and implementation of the recently recommended pertussis cocoon strategy in Switzerland. METHODS: We performed a cross sectional survey among all parents of newborns born between May and September 2012 and 2013 in Basel city and country. Regional statistical offices provided family addresses after approval by the ethical and data protection committees. A standardized questionnaire with detailed instructions was sent to all eligible families. For statistical analyses, independent proportions were compared by Pearson's chi-squared test. RESULTS: Of 3546 eligible parents, 884 (25%) participated. All three questions exploring pertussis knowledge were answered correctly by 37% of parents; 25% gave two correct answers, 22% gave one correct answer and in the remaining 16% no answer was correct. Pertussis immunization as part of cocooning was recommended to 20% and 37% of mothers and 14% and 32% of fathers in the 2012 and 2013 study cohorts, respectively. Principal advisors for cocooning were pediatricians (66%) followed by gynecologists/obstetricians (12%) and general practitioners (5%). When recommended, 64% of mothers and 59% of fathers accepted pertussis immunization. The majority of vaccinations were administered in the perinatal period and within 2 months of the child's birth. However, cocooning remained incomplete in 93% of families and in most families <50% of close contacts received pertussis vaccination. CONCLUSIONS: Implementation of cocooning for protecting newborns from pertussis is challenging and usually remains incomplete. Pertussis immunization rates among close contacts of newborns need to be improved. Ideally, all healthcare providers involved in family planning, pregnancy and child birth should recommend cocooning. Pertussis immunization of pregnant women is an additional measure for optimal protection of newborns and should be promoted. PMID- 25037055 TI - B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. AB - AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information. METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, chi(2) = 17.0; CRP, chi(2) = 10.5; BNP and CRP, chi(2) = 13.1). B-type natriuretic peptide improved the C statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS. CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers. PMID- 25037059 TI - Assessment of in vivo antimicrobial activity of the carbene silver(I) acetate derivative SBC3 using Galleria mellonella larvae. AB - The antimicrobial drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate (SBC3) was evaluated for its ability to function in vivo using larvae of Galleria mellonella. A SBC3 concentration of 25 MUg/ml inhibited the growth of Staphylococcus aureus by 71.2% and Candida albicans by 86.2% in vitro. Larvae inoculated with 20 MUl of SBC3 solution showed no ill effects up to a concentration of 250 MUg/ml but administration of 500 MUg/ml resulted in a 40% reduction in larval survival and administration of a dose of 1,000 MUg/ml resulted in total larval death at 24 h. Larvae inoculated with S. aureus or C. albicans and subsequently administered SBC3 showed increased survival. Administration of SBC3 to larvae did not boost the insect immune response as indicated by lack of an increase in the density of circulating haemocytes (immune cells). The abundance of a number of proteins involved in the insect immune response was reduced in larvae that received 20 MUl SBC3 solution of 100 MUg/ml. This is the first demonstration of the in vivo activity of SBC3 against S. aureus and C. albicans and demonstrates that SBC3 does not stimulate a non-specific immune response in larvae. PMID- 25037058 TI - Adiponectin expression and the cardioprotective role of the vitamin D receptor activator paricalcitol and the angiotensin converting enzyme inhibitor enalapril in ApoE-deficient mice. AB - BACKGROUND: Coronary heart disease (CHD) is the number one cause of death in the US. The adipokine adiponectin has been studied intensively for presenting and inversed association with almost every stage of CHD. For instance, the evaluation of molecules capable of enhancing endogenous adiponectin expression is well justified. In this study, we investigated the effect of the vitamin D receptor activator (VDRA) paricalcitol and the angiotensin-converting enzyme inhibitor (ACEI) enalapril on adiponectin expression, lipid profiles, adenosine monophosphate activated protein kinase (AMPK) expression, monocyte chemo attractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha),cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), antioxidant capacity, CuZn-superoxide dismutase (CuZn-SOD), Mn-SOD, NADPH p22phox subunits, inducible nitric oxidesynthase (iNOS), endothelial marker eNOS, and 81 atherosclerosis-related genes in ApoE-deficient mice. METHOD: Seven-week-old ApoE deficient mice were treated for 16 weeks as follows: Group 1, ApoE vehicle control (intraperitoneal [i.p.] 100 ul propylene glycol); Group 2, ApoE paricalcitol (200 ng i.p., 3/week); Group 3, ApoE-Enalapril (30 mg/kg daily); Group 4, ApoE-paricalcitol + enalapril (described dosing); and Group 5, wild-type control (C57BLV). RESULTS: All treated groups presented significant changes in circulating and cardiac adiponectin, cardiac cholesterol levels, AMPK, MCP-1, TNF alpha, COX-2, iNOS, eNOS, CuZn-SOD, Mn-SOD and p22phox. There were 15 genes that differed in their expression, 5 of which are involved in cardioprotection and antithrombotic mechanisms: Bcl2a1a, Col3a1, Spp1 (upregulated), Itga2, and Vwf (downregulated). CONCLUSION: Together, our data presented a novel role for VDRA and ACEI in reducing factors associated with CHD that may lead to the discovery of new therapeutic venues. PMID- 25037060 TI - Gadolinium promoted proliferation in mouse embryo fibroblast NIH3T3 cells through Rac and PI3K/Akt signaling pathways. AB - Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder disease developed in patients with underlying renal insufficiency following exposure to gadolinium based contrast agents (GBCAs). Previous studies have demonstrated that GdCl3 can promote NIH3T3 fibroblast cell proliferation, which provide a new clue to the role of GBCAs in the development of NSF. In the present study, we further clarify the molecular mechanism of Gd-promoted proliferation. The results showed that intervention with the Rac inhibitor NSC23766 abrogated Gd-promoted proliferation. The levels of active Rac1 significantly increased in Gd-treated cells detected by pull-down assays. In addition, the phosphorylation of Akt was significantly elevated in the treatment group, which was blocked by NSC23766. NSC23766 also reduced the migration of NIH3T3 cells enhanced by Gd. Moreover, the F-actin cytoskeleton was strengthened and the mitotic cell numbers was significantly increased after exposure to Gd. These results suggest that Rac and PI3K/Akt signaling pathways, as well as integrin-mediated signal pathway may play important roles in Gd-induced cell proliferation. In addition, under serum-free condition, Gd could decrease ROS accumulation and increase NIH3T3 cell survival. PMID- 25037062 TI - Wear rates of highly cross-linked polyethylene humeral liners subjected to alternating cycles of glenohumeral flexion and abduction. AB - BACKGROUND: Although short-term outcomes of reverse total shoulder arthroplasty have been promising, long-term success may be limited due to device-specific complications, including scapular notching. Scapular notching has been explained primarily as mechanical erosion; however, the generation of wear debris may lead to further biologic changes contributing to the severity of scapular notching. METHODS: A 12-station hip simulator was converted to a reverse total shoulder arthroplasty wear simulator subjecting conventional and highly cross-linked ultra high-molecular-weight polyethylene humeral liners to 5 million cycles of alternating abduction-adduction and flexion-extension loading profiles. RESULTS: Highly cross-linked polyethylene liners (36.5 +/- 10.0 mm(3)/million cycle) exhibited significantly lower volumetric wear rates compared with conventional polyethylene liners (83.6 +/- 20.6 mm(3)/million cycle; P < .001). The flexion extension loading profile exhibited significantly higher wear rates for conventional (P < .001) and highly cross-linked polyethylene (P < .001) compared with the abduction-adduction loading profile. Highly cross-linked wear particles had an equivalent circle diameter significantly smaller than wear particles from conventional polyethylene (P < .001). CONCLUSIONS: Highly cross-linked polyethylene liners significantly reduced polyethylene wear and subsequent particle generation. More favorable wear properties with the use of highly cross linked polyethylene may lead to increased device longevity and fewer complications but must be weighed against the effect of reduced mechanical properties. PMID- 25037063 TI - Preoperative opioid use and outcomes after reverse shoulder arthroplasty. AB - BACKGROUND: The potential adverse effect of preoperative opioid use on outcomes after reverse shoulder arthroplasty (RSA) has not been investigated. The purpose of this study was to evaluate outcomes after RSA in patients with a history of preoperative opioid use and compare them with a control group without a history of preoperative opioid use. METHODS: Sixty-eight RSAs performed for rotator cuff tear arthropathy (CTA) with a minimum of 2 years of follow-up were identified in a prospective shoulder arthroplasty registry. Thirty-two patients with a history of preoperative opioid use for shoulder pain were compared with a control group of 36 patients who did not use opioids preoperatively. Shoulder function scores and range of motion measurements were assessed preoperatively and at the final follow-up. RESULTS: No differences were noted between the 2 groups in age, gender, duration of follow-up, depression, smoking, chronic back pain, diabetes, heart disease, or body mass index. Preoperative opioid use was associated with significantly lower preoperative shoulder function scores. Both groups significantly improved on all shoulder function scores and for range of motion measurements from the preoperative to the final follow-up assessment; however, the nonopioid group had significantly better outcomes. The magnitude of change between the groups from preoperatively to the final follow-up was nearly identical. CONCLUSIONS: Improvements can be expected in patients with a history of preoperative opioid use; however, patients with preoperative opioid use have a lower preoperative baseline and should not expect to reach the same peak outcome scores after RSA as patients without a history of preoperative opioid use. PMID- 25037064 TI - Three-dimensional analysis of elbow soft tissue footprints and anatomy. AB - BACKGROUND: Tendinous and ligamentous injuries commonly occur in the elbow. This study characterized the location, surface areas, and origin and insertional footprints of major elbow capsuloligamentous and tendinous structures in relation to bony landmarks with the use of a precision 3-dimensional modeling system. METHODS: Nine unpaired cadaveric elbow specimens were dissected and mounted on a custom jig. Mapping of the medial collateral ligament (MCL), lateral ulnar collateral ligament (LUCL), triceps, biceps, brachialis, and capsular reflections was then performed with 3-dimensional digitizing technology. The location, surface areas, and footprints of the soft tissues were calculated. RESULTS: The MCL had a mean origin (humeral) footprint of 216 mm(2), insertional footprint of 154 mm(2), and surface area of 421 mm(2). The LUCL had a mean origin footprint of 136 mm(2), an insertional footprint of 142 mm(2), and a surface area of 532 mm(2). Of the tendons, the triceps maintained the largest insertional footprint, followed by the brachialis and the biceps (P < .001-.03). The MCL, LUCL, and biceps footprint locations were consistent, with little variability. The surface areas of the anterior (1251 mm(2)) and posterior (1147 mm(2)) capsular reflections were similar (P = .82), and the anterior capsule extended farther proximally. CONCLUSION: Restoring the normal anatomy of key elbow capsuloligamentous and tendinous structures is crucial for effective reconstruction after bony or soft tissue trauma. This study provides the upper extremity surgeon with information that may aid in restoring elbow biomechanics and preserving range of motion in these patients. PMID- 25037065 TI - Implementation of universal behavioral health screening in a university health setting. AB - Universal screening at university health centers can facilitate early identification and treatment of behavioral health problems common among college students. This article describes the (a) process of implementing behavioral health screening at a university health center and (b) results of universal screening for depression, suicidal ideation, alcohol misuse, tobacco use, and sleep problems. We discuss the decision points involved in screening, including what to screen for, whom to screen, how to implement the screening measure, and how to deal with patients who screen positive. During the Spring and Fall 2010 academic semesters, 4,126 screening questionnaires were completed by students (62% female) accessing a university health center. Each semester, 9-13% of students screened positive for depression, 2.5-3% for suicidal ideation, and 33 38% for alcohol misuse, while 10% wanted help with smoking cessation and 12-13% with sleep problems. The results suggest that behavioral health screening in a university health center can help identify students with behavioral health concerns to increase access to care. PMID- 25037066 TI - Body condition, energy balance and immune status of periparturient Murrah buffaloes (Bubalus bubalis) supplemented with inorganic chromium. AB - Periparturient Murrah buffaloes were used to determine whether body condition, energy balance and immune status are affected by inorganic Cr supplementation. Twenty-four Murrah buffaloes were blocked into four groups having six animals in each group and fed for 60 days pre-partum to 150 days post-partum. Feeding regimen was same in all the groups except that these were supplemented with 0.0, 0.5, 1.0 and 1.5 of Cr per kilogram of dry matter (DM) in the four respective groups. Buffaloes were weighed at fortnightly intervals. Blood samples were collected from the jugular vein at days -60, -30, -15, -7, 0, 7, 15, 30, 60, 90, 120 and 150 of experimental feeding for the estimation of non-esterified fatty acid (NEFA), beta-hydroxybutyric acid (BHBA), Cr level, lymphocyte proliferation, neutrophil phagocytic activity, plasma total immunoglobulin (TIg), immunoglobulin G (IgG) and cortisol levels. Results revealed that with approaching parturition, dry matter intake (DMI), immune response and plasma Cr level decreased (P < 0.05) gradually and minimum values were observed on the day of parturition in all groups. In contrast, body condition score (BCS), plasma NEFA and BHBA concentrations showed increasing (P < 0.05) trends towards calving and level decreased after calving. Dietary Cr supplementation did not have any effect on DMI and BCS, but immune response and plasma Cr concentration showed a positive correlation with dietary Cr supplementation. Buffaloes supplemented with 1.5 mg/kg Cr had significantly (P < 0.05) low plasma NEFA and BHBA concentrations. The results of present findings indicated that dietary inorganic Cr supplementation reduced lipid mobilization and improved immune response in periparturient buffaloes. PMID- 25037067 TI - Dietary manganese supplementation influences the expression of transporters involved in iron metabolism in chickens. AB - To investigate the effects of dietary manganese (Mn) supplementation on iron (Fe) metabolism, a total of 480 50-week-old hens were fed the basal diet (control, 24.35 mg Mn/kg) without Mn supplementation for 6 weeks to reduce Mn storage in the body. Hens were then randomly assigned to one of three treatments, which included the control and control added with 60 or 300 mg Mn/kg diet (M-Mn or H Mn). Duodenum, heart, liver, and tibia were collected in hens after 12-week feeding period. No significant differences were observed in egg production, feed/egg ratio, shell breaking strength, and shell thickness among different treatments. Compared with control or M-Mn, H-Mn decreased (P < 0.05) serum Fe concentration, while increased (P < 0.05) total Fe-binding capacity (TIBC). The Fe concentration decreased (P < 0.05) in duodenum, and tended to reduce (P < 0.10) in liver from control to M-Mn and to H-Mn; whereas, dietary Mn supplementation did not influence (P > 0.10) Fe concentration in the heart and tibia. In conjunction with reduced Fe retention, DMT1 mRNA expression decreased (P < 0.05) with dietary Mn concentration increasing in the duodenum and liver. Duodenal FPN1 mRNA level was higher (P < 0.05) in H-Mn group than that in control or M-Mn group, while hepatic FPN1 mRNA expression was lower (P < 0.05) in M-Mn or H-Mn group when compared with control. The results demonstrated that dietary Mn supplementation decreased Fe concentration in duodenum and liver of hens, which may be related to the alteration of DMT1 and FPN1 expression in these tissues. PMID- 25037068 TI - Assessing the potential for bias in direct observation of adult commuter cycling and helmet use. AB - OBJECTIVES: Bicycling and helmet surveillance, research, and programme evaluation depend on accurate measurement by direct observation, but it is unclear whether weather and other exogenous factors introduce bias into observed counts of cyclists and helmet use. METHODS: To address this issue, a time series was created of cyclists observed at two observation points in Washington, DC, at peak commuting times and locations between September 2012 and February 2013. Using multiple linear regression with Newey-West SEs to account for possible serial correlation, the association between various factors and cyclist counts and helmet use was investigated. RESULTS: The number of cyclists observed per 1 h session was significantly associated with predicted daily high temperature, chance of rain, and actual rain. Additionally, fewer cyclists were observed on Fridays. Helmet use was significantly lower during evening commutes than morning and also lower on Fridays. Helmet use was not associated with weather variables. Controlling for observable cyclists characteristics weakened the association between helmet use and the time of day and day of the week, but it did not eliminate that association. CONCLUSIONS: Direct observation to measure commuter cycling trends or evaluate interventions should control for weather and day of week. Measurement of helmet use is unlikely to be meaningfully biased by weather factors, but time of day and day of week should be taken into account. Failing to control for these factors could lead to significant bias in assessments of the level of, and trends in, commuter cycling and helmet use. PMID- 25037069 TI - Biosimilar drugs, myths and reality. PMID- 25037070 TI - The difference in antioxidant capacity of four alfalfa cultivars in response to Zn. AB - The aim of this study was to evaluate antioxidative responses in roots, stem and leaves of four alfalfa cultivars to different concentrations of zinc (Zn) (0, 300, 600 and 900 MUM) for 23 days. Among the four cultivars, Aohan displayed the highest Zn concentrations in tissues and the largest Zn amount in aerial parts. Zn stress induced the production of H2O2 and increased the content of free proline and activities of antioxidative enzymes in roots, stem and leaves of Aohan. Based on the above results, we concluded that Aohan is superior to other three cultivars for Zn phyto-remediation, which indicated that Aohan is a novel Zn accumulator and able to tolerate Zn-induced toxicity by activating the antioxidative defense system. PMID- 25037071 TI - Reply to correspondence on: Laparoscopic resection rectopexy versus laparoscopic ventral rectopexy for complete rectal prolapse by H. A. Formijne Jonkers et al. PMID- 25037072 TI - Ileal pouch fistulas after restorative proctocolectomy: management and outcomes. AB - BACKGROUND: Fistula between an ileal pouch and the vagina, anus, or perineum is an uncommon complication of ileal pouch-anal anastomosis and is a cause of considerable morbidity. Its optimal management has not been determined because of its low incidence. The aim of this study was to review the outcomes of patients who presented with symptomatic ileal pouch-associated fistulas after restorative proctocolectomy (RPC) and to present a diagnostic and treatment algorithm. METHODS: Retrospective review of patients treated for symptomatic ileal pouch associated fistulas after RPC from 1989 to 2011. RESULTS: Twenty-five patients (14 men, mean age 40 years) were presented with symptomatic ileal pouch associated fistulas. Median time to pouch fistula following RPC was 6.9 years (range 1 month-20 years). Fistulas were classified as pouch-anal (n = 12, 48 %), pouch-vaginal (n = 7, 28 %), complex (n = 4, 16 %), and pouch-perineal (n = 2, 8 %). Etiology included Crohn's disease (n = 15, 60 %), cryptoglandular (n = 6, 24 %), and anastomotic failure (n = 4, 16 %). Each patient underwent an average of 2.8 local procedures or repairs. Overall healing rate was 64 % at a median follow up of 29 (range 2-108) months. None of the complex fistulas were healed. Postoperative pelvic sepsis, fecal diversion, anti-tumor necrosis factor therapy, and fistula etiology did not significantly impact fistula healing. Three patients required pouch excision with end ileostomy. CONCLUSIONS: Operative treatment of pouch fistulas after RPC resulted in complete healing in 64 % of patients following a stepwise diagnostic and therapeutic approach. PMID- 25037074 TI - Invited comment on G. Bassotti and E. Battaglia: postoperative colonic motility after transverse loop colostomy: a further tassel in the mosaic. PMID- 25037073 TI - Circumferential resection margins of rectal tumours post-radiotherapy: how can MRI aid surgical planning? AB - BACKGROUND: Magnetic resonance imaging (MRI) is known to have high predictive accuracy for circumferential resection margin (CRM) involvement of pre-treatment rectal tumours. This study aims to assess predictive accuracy of MRI for CRM involvement in rectal cancers post-long-course chemoradiotherapy (CRT) and in particular to understand how this information can influence surgical planning. METHODS: Forty-seven rectal cancers treated with CRT followed by bowel resection in one hospital since 2005 were reviewed for clinical, radiological and pathological characteristics. Using a validated pro forma, a radiologist blinded to final histology and original MRI report predicted CRM status from post-CRT MRI images. Results were compared to histological CRM status of final specimen, and differential analysis by type of surgical operation was performed. RESULTS: Overall accuracy of MRI for CRM involvement post-CRT was 72 % with a negative predictive value of 92 %. Abdominoperineal excision (APE) post-CRT was associated with non-significantly higher rates of histologically involved CRM than anterior resection (AR; 41 vs. 21 %) as were mucinous adenocarcinomas when compared to non mucinous (56 vs. 21 %). Overall accuracy and positive predictive value were non significantly higher for cancer treated with a standard APE than AR, and negative predictive value was high for both groups. CONCLUSIONS: MRI post-CRT has high negative predictive value for CRM status. Such information is of particular clinical relevance in low rectal cancers treated with APE as it can indicate when a standard surgical approach is likely to be sufficient. PMID- 25037075 TI - Survival disparities in Australia: an analysis of patterns of care and comorbidities among indigenous and non-indigenous cancer patients. AB - BACKGROUND: Indigenous Australians have lower overall cancer survival which has not yet been fully explained. To address this knowledge deficit, we investigated the associations between comorbidities, cancer treatment and survival in Indigenous and non-Indigenous people in Queensland, Australia. METHODS: A cohort study of 956 Indigenous and 869 non-Indigenous patients diagnosed with cancer during 1998-2004, frequency-matched on age, sex, remoteness of residence and cancer type, and treated in Queensland public hospitals. Survival after cancer diagnosis, and effect of stage, treatment, and comorbidities on survival were examined using Cox proportional hazard models. RESULTS: Overall Indigenous people had more advanced cancer stage (p = 0.03), more comorbidities (p < 0.001), and received less cancer treatment (77% vs. 86%, p = 0.001). Among patients without comorbidities and social disadvantage, there was a lower uptake of treatment among Indigenous patients compared to non-Indigenous patients. For those who received treatment, time to commencement, duration and dose of treatment were comparable. Unadjusted cancer survival (HR = 1.30, 95% CI 1.15-1.48) and non cancer survival (HR = 2.39, 95% CI 1.57-3.63) were lower in the Indigenous relative to non-Indigenous patients over the follow-up period. When adjusted for clinical factors, there was no difference in cancer-specific survival between the groups (HR = 1.10, 95% CI 0.96-1.27). One-year survival was lower for Indigenous people for all-causes of death (adjusted HR = 1.33, 95% CI 1.12-1.83). CONCLUSION: In this study, Indigenous Australians received less cancer treatment, had more comorbidities and had more advanced cancer stage at diagnosis, factors which contribute to poorer cancer survival. Moreover, for patients with a more favourable distribution of such prognostic factors, Indigenous patients received less treatment overall relative to non-Indigenous patients. Personalised cancer care, which addresses the clinical, social and overall health requirements of Indigenous patients, may improve their cancer outcomes. PMID- 25037076 TI - Preresection transarterial chemoembolization for hepatocellular carcinoma: an experience with 23 patients. AB - PURPOSE: The routine use of transarterial chemoembolization (TACE) prior to resection for hepatocellular carcinoma (HCC) is not recommended, although its use in the transplant setting is gaining popularity. In the absence of other effective neoadjuvant or adjuvant treatment options, TACE may benefit selected patients. The aim was to evaluate the feasibility and outcomes of preoperative TACE for selected patients with HCC. METHODS: From November 2010 to October 2012, 23 patients of HCC were selected by a multidisciplinary team to undergo TACE prior to resection. RESULTS: TACE was successful in all patients with no intraprocedural complications. TACE reduced the mean maximum tumor diameter from 9.2 to 8.2 cm and increased the mean future liver remnant (FLR) from 37.7 % to 49.1 %. Nineteen resections were completed with negative margins, of which only three patients (15.8 %) had cirrhosis. Two patients (10.5 %) experienced postoperative bile leaks and six patients (31.5 %) developed postoperative liver failure, two (10.5 %) of which succumbed to grade C liver failure. From the date of surgery, the median follow up time was 17.1 months. Four patients (17 %) did not undergo curative resection due to disease progression in three patients and severe TACE toxicity in one patient. None of the resected patients developed disease recurrence and the overall survival was 21 months. CONCLUSION: Encouraging outcomes in terms of disease recurrence and overall survival need to be balanced with the risk of surgical drop out and perioperative complications when selecting patients for TACE prior to resection. PMID- 25037077 TI - Effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis. AB - SUMMARY: Osteoporosis is a major cause of mortality and morbidity worldwide. Decreased bone turnover markers and increased lumbar spine and total hip bone mineral density (BMD) in raloxifene-treated women add further support to the idea that raloxifene is an effective well-tolerated option for treating Kuwaiti postmenopausal osteoporosis, suitable for long-term use. INTRODUCTION/PURPOSE: Osteoporosis is currently a major cause of mortality, morbidity, and medical expense worldwide, and it is important to investigate therapies for the prevention and treatment of osteoporosis in postmenopausal women. This study was designed to detect the effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis. METHODS: Postmenopausal women who were free of severe or chronically disabling conditions, had their last menstrual period at least 2 years before the beginning of the study, had a T score for femoral neck or lumbar spine BMD measurements <=2.5, and were without fractures were included in this study. One hundred and seventy-six (176) women were included in this study and were divided into two groups; the first group (study) received raloxifene with calcium and vitamin D daily for 12 months, and the second group (control) received only calcium and vitamin D. BMD and bone metabolism markers were measured before and after treatment. RESULTS: One year after treatment, BMD of lumbar spine and total hip was significantly increased in study group (3.21 +/- 5.4 and 1.62 +/- 7.4, respectively) compared to controls (0.9 +/- 3.8 and -0.8 +/- 5.6, respectively); also, Ward's triangle and trochanter BMD was significantly increased in study group (4.84 +/- 9.3 and 1.78 +/- 8.5, respectively) compared to controls (1.53 +/- 6.6 and -1. 4 +/- 6.4, respectively). C-telopeptide was significantly decreased in study group (121 +/- 7.8) compared to control group (1,480 +/- 6.3); also, serum osteocalcin was significantly decreased in study group (14.5 +/- 8.3) compared to control group (43.8 +/- 1.3) 1 year after treatment. Occurrence of fractures during this study was significantly low in raloxifene group compared to controls (0 (0%) versus 3 (3.6%), respectively). CONCLUSIONS: Raloxifene appears to be an effective, well tolerated option for treating osteoporosis in Kuwaiti postmenopausal women, suitable for long-term use. PMID- 25037078 TI - Increased expression of Fe-chelatase leads to increased metabolic flux into heme and confers protection against photodynamically induced oxidative stress. AB - Fe-chelatase (FeCh, EC 4.99.1.1) inserts Fe(2+) into protoporphyrin IX (Proto IX) to form heme, which influences the flux through the tetrapyrrole biosynthetic pathway as well as fundamental cellular processes. In transgenic rice (Oryza sativa), the ectopic expression of Bradyrhizobium japonicum FeCh protein in cytosol results in a substantial increase of FeCh activity compared to wild-type (WT) rice and an increasing level of heme. Interestingly, the transgenic rice plants showed resistance to oxidative stress caused not only by the peroxidizing herbicide acifluorfen (AF) as indicated by a reduced formation of leaf necrosis, a lower conductivity, lower malondialdehyde and H2O2 contents as well as sustained Fv/Fm compared to WT plants, but also by norflurazon, paraquat, salt, and polyethylene glycol. Moreover, the transgenic plants responded to AF treatment with markedly increasing FeCh activity. The accompanying increases in heme content and heme oxygenase activity demonstrate that increased heme metabolism attenuates effects of oxidative stress caused by accumulating porphyrins. These findings suggest that increases in heme levels and porphyrin scavenging capacity support a detoxification mechanism serving against porphyrin induced oxidative stress. This study also implicates heme as possibly being a positive signal in plant stress responses. PMID- 25037079 TI - Geriatric pain competencies and knowledge assessment for nurses in long term care settings. AB - Pain in older adults is a prevalent problem that affects quality of life and challenges nurses, particularly those caring for older adults living in long term care settings. Despite the national priority of pain management, insufficient knowledge of nurses about geriatric pain is a documented barrier to effective geriatric pain management in all long term care settings. To address this knowledge gap, a website (GeriatricPain.org) was developed by the National Geriatric Pain Collaborative with a grant from the MayDay Fund to provide a single site for evidenced-based, easy-to-use, downloadable resources on pain management. This paper describes the development of the most recent addition to the website, a set of evidence-based core geriatric pain management competencies and a geriatric pain knowledge assessment, and discusses their potential uses in improving pain care for older adults. PMID- 25037080 TI - A pattern recognition approach to patients with a suspected myopathy. AB - Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. This review provides a diagnostic approach based predominantly on the clinical history and neurologic examination. Laboratory testing that can be used to confirm the suspected diagnosis based on this pattern recognition approach is also discussed. Careful consideration of the distribution of muscle weakness and attention to common patterns of involvement in the context of other aspects of the neurologic examination and laboratory evaluation should assist the clinician in making a timely and accurate diagnosis and can sometimes minimize the expense of further testing. PMID- 25037081 TI - Idiopathic inflammatory myopathies. AB - The idiopathic inflammatory myopathies (IIM) consist of rare heterogeneous autoimmune disorders that present with marked proximal and symmetric muscle weakness, except for distal and asymmetric weakness in inclusion body myositis. Despite many similarities, the IIM are fairly heterogeneous from the histopathologic and pathogenetic standpoints, and also show some clinical and treatment-response differences. The field has witnessed significant advances in our understanding of the pathophysiology and treatment of these rare disorders. This review focuses on dermatomyositis, polymyositis, and necrotizing myopathy, and examines current and promising therapies. PMID- 25037082 TI - Inclusion body myositis. AB - The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare disorders that share many similarities. In addition to sporadic inclusion body myositis (IBM), these include dermatomyositis, polymyositis, and autoimmune necrotizing myopathy. IBM is the most common IIM after age 50 years. Muscle histopathology shows endomysial inflammatory exudates surrounding and invading nonnecrotic muscle fibers often accompanied by rimmed vacuoles and protein deposits. It is likely that IBM is has a prominent degenerative component. This article reviews the evolution of knowledge in IBM, with emphasis on recent developments in the field, and discusses ongoing clinical trials. PMID- 25037084 TI - Duchenne and Becker muscular dystrophies. AB - The dystrophinopathies Duchenne and Becker muscular dystrophies (DMD and BMD) represent the most common inherited disorders of muscle. Improvements in cardiac care, attention to respiratory function, and judicious use of spinal correction surgery have led to increased survival in the DMD population. Meanwhile, advances in molecular therapeutics have led to promising therapies that are in or are entering clinical trials. An understanding of the dystrophinopathies, and recent advances in their molecular diagnosis and treatment, is of benefit to practicing neurologists. PMID- 25037083 TI - Toxic myopathies. AB - Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, because they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features, and possible underlying cellular mechanisms. PMID- 25037085 TI - Congenital myopathies and muscular dystrophies. AB - The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy. PMID- 25037087 TI - Facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease directed therapies to be effective for both FSHD types. PMID- 25037086 TI - Myotonic dystrophy. AB - Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. DM type 1 was first described over a century ago. More recently, a second form of the disease, DM type 2 was recognized, which results from repeat expansion in a different gene. Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. This article reviews the clinical presentation and pathophysiology of DM and discusses current management and future potential for developing targeted therapies. PMID- 25037088 TI - The limb-girdle muscular dystrophies. AB - A collection of more than 30 genetic muscle diseases that share certain key features, limb-girdle muscular dystrophies are characterized by progressive weakness and muscle atrophy of the hips, shoulders, and proximal extremity muscles with postnatal onset. This article discusses clinical, laboratory, and histologic features of the 6 most prevalent limb-girdle dystrophies. In this large group of disorders, certain distinctive features often can guide clinicians to a correct diagnosis. PMID- 25037090 TI - Metabolic and mitochondrial myopathies. AB - Metabolic and mitochondrial myopathies encompass a heterogeneous group of disorders that result in impaired energy production in skeletal muscle. Symptoms of premature muscle fatigue, sometimes leading to myalgia, rhabdomyolysis, and myoglobinuria, typically occur with exercise that would normally depend on the defective metabolic pathway. But in another group of these disorders, the dominant muscle symptom is weakness. This article reviews the clinical features, diagnosis, and management of these diseases with emphasis on the recent literature. PMID- 25037089 TI - Pompe disease: literature review and case series. AB - Pompe disease is a rare multi-systemic metabolic myopathy caused by autosomal recessive mutations in the acidic alpha glucosidase (GAA) gene. Significant progress had been made in the diagnosis and management of patients with Pompe disease. Here, we describe our experience with 12 patients with various forms of Pompe disease including 4 potentially pathogenic, novel GAA variants. We also review the recent the recent advances in the pathogenesis, diagnosis, and treatment of individuals with Pompe disease. PMID- 25037091 TI - Muscle channelopathies. AB - Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis and therapeutics. These disorders can cause lifetime disability and affect quality of life. There is no treatment of these disorders approved by the US Food and Drug Administration at this time. Recognition and treatment of symptoms might reduce morbidity and improve quality of life. This article summarizes the clinical manifestations, diagnostic studies, pathophysiology, and treatment options in nondystrophic myotonia, congenital myasthenic syndrome, and periodic paralyses. PMID- 25037093 TI - Myopathies. PMID- 25037092 TI - Distal myopathies. AB - In this article, distal myopathy syndromes are discussed. A discussion of the more traditional distal myopathies is followed by discussion of the myofibrillar myopathies. Other clinically and genetically distinctive distal myopathy syndromes usually based on single or smaller family cohorts are reviewed. Other neuromuscular disorders that are important to recognize are also considered, because they show prominent distal limb weakness. PMID- 25037094 TI - Ghrelin attenuates sepsis-associated acute lung injury oxidative stress in rats. AB - This study investigated the effect of ghrelin on oxidative stress in septic rat lung tissue. Male Sprague-Dawley rats were divided into sham-operation, sepsis, and ghrelin groups. Sepsis was induced by cecal ligation and puncture. Ghrelin was administered intraperitoneally at 3 and 15 h post-operation. Bronchoalveolar lavage was performed to collect alveolar macrophages (AMs). Inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) expression in alveolar macrophages and iNOS protein levels were measured by reverse transcription PCR (RT-PCR) and Western blot. Pulmonary pathology was analyzed and nitrotyrosine expression was examined by immunohistochemistry. Plasma superoxide dismutase (SOD) and lung wet/dry weight were measured. In the sepsis group, iNOS mRNA expression in AMs was 1.33 +/- 0.05, 1.44 +/- 0.08, and 1.57 +/- 0.11 at 6, 12, and 20 h post surgery, respectively, and were higher compared with the sham-operation group (p<0.05). No increase was observed at longer time points. iNOS mRNA expression in the sepsis group was lower compared with the ghrelin group (2.27 +/- 0.37) (p<0.05) at 20 h post-surgery. iNOS protein levels in the ghrelin group (0.87 +/- 0.03, p<0.05) were lower than in the sepsis group at 20 h. Ghrelin group pathological scores were lower than in the sepsis group (p<0.05). Plasma SOD was slightly non-significantly decreased in the ghrelin group. No difference was observed in lung wet/dry weight ratios between sepsis and ghrelin groups. iNOS mRNA expression in AMs was elevated between 6 and 20 h after cecal ligation and puncture (CLP), but did not progress. Ghrelin attenuated pulmonary iNOS protein expression and tended to increase plasma SOD activity. Ghrelin suppressed pulmonary nitrosative stress in septic rats, but did not improve lung wet/dry weight ratios. PMID- 25037095 TI - What happens to coroners' recommendations for improving public health and safety? Organisational responses under a mandatory response regime in Victoria, Australia. AB - BACKGROUND: Several countries of the British Commonwealth, including Australia and the United Kingdom, vest in coroners the power to issue recommendations for protecting public health and safety. Little is known about whether and how organisations that receive recommendations act on them. Concerns that recommendations are frequently ignored prompted the government of Victoria, Australia, to introduce a requirement in 2008 compelling organisations that receive recommendations to provide a written statement of action. METHODS: We conducted a prospective study of organisations that received recommendations from Victorian coroners over a 33-month period. Using an online survey, we asked representatives of "recipient organisations" what action (if any) their organisations took, and what factors influenced their decision. We also probed views of the quality of the recommendations and the mandatory response regime in general. Responses were analysed at the recommendation- and recipient organisation-level by calculating counts and proportions and using chi-square analyses to test for sub-group differences. RESULTS: Ninety of 153 recipient organisations surveyed responded (59% response rate); they received 164 recommendations (mean = 1.9; range, 1-7) from 74 cases. A total of 37% (60/164) of the recommendations were accepted and implemented, 27% (45/164) were rejected, and for 36% (59/164) the recommended action was "supplanted" (i.e., action had already been taken). In nearly half of rejected recommendations (18/45), recipient organisations indicated implementation was not logistically viable. In half of supplanted recommendations, an internal investigation had prompted the action. Three quarters (67/90) of recipient organisations believed the introduction of a mandatory response regime was a good idea, but fewer regarded the recommendations they received as appropriate (52/90) or likely to be effective in preventing death and injury (45/90). CONCLUSIONS: Only a third of coroners' recommendations were implemented by the organisations to which they were directed. In drawing policy lessons, it is important to separate recommendations that were rejected from those in which action had already been taken. Rejected recommendations raise questions about the quality of the recommendations, the reasonableness of the organisation's response, or both. Supplanted recommendations focus attention on the adequacy of consultation between coroners and affected organisations and the length of time it takes for recommendations to be issued. PMID- 25037096 TI - Fractional anisotropy asymmetry and the side of seizure origin for partial onset temporal lobe epilepsy. AB - This paper presents a fractional anisotropy asymmetry (FAA) method to detect the asymmetry of white matter (WM) integrity and its correlation with the side of seizure origin for partial onset temporal lobe epilepsy (TLE) using diffusion tensor image (DTI). In this study, FAA analysis is applied to 30 patients of partial TLE (15 left, 15 right) and 14 matched normal controls. Specifically, after registering all the images with the JHU-DTI-MNI template the average FA value of each FA skeleton section is calculated using the tract-based spatial statistics (TBSS) method. Then, FAA is calculated to quantify the WM diffusivity asymmetry of the corresponding region-pairs between the left and right hemispheres. Using FAA the regional asymmetry contributing significantly to the group differences of controls and left/right TLE, as well as the left and right TLE, is identified. As a comparison, the ROI-based average FA values for WM and corresponding FAAs are also calculated. TBSS-based analysis reflects the average of local maximal FA values along the white matter skeleton sections, and ROI based analysis shows the average of WM FA values within each anatomical region. The FAA statistical results indicated that the FA values of anatomical region pairs are asymmetric in the ipsilateral hemisphere with seizure origin against the contralateral hemisphere. Particularly, FAA values within the temporal lobe (superior, middle, and inferior temporal WM) are significantly different between the left and right TLE patients, consistently found from both analysis methods. The study suggests that FAA values can be potentially used to identify the seizures of origin of TLE and to help understand the relationship between fiber tracts with the side of seizure origin of TLE. PMID- 25037097 TI - Effects of mixtures of dissolved and particulate contaminants on phototrophic biofilms: new insights from a PICT approach combining toxicity tests with passive samplers and model substances. AB - Streams located in vineyard areas are particularly exposed to mixtures of dissolved and particulate contaminants such as metals and organic pesticides. In this context, phototrophic biofilms are increasingly used as indicators of river water contaminations through pollution-induced community tolerance (PICT) assessments based on short-term toxicity tests with individual or mixtures of toxicants. We conducted a laboratory experiment to evaluate the relative influence of the dissolved and particulate fractions on the effects of metals and pesticides on phototrophic biofilms in a context of contamination from a vineyard watershed. Three sets of artificial channels were supplied with (i) unfiltered water from a stream reference site, (ii) unfiltered water from a stream contaminated site, and (iii) filtered water (0.45 MUm) from the same contaminated site. Biofilm growth, diatom community structure, and dissolved toxicant concentrations differed slightly between channels supplied with unfiltered or filtered water from the contaminated site. However, PICT assessments with individual toxicants or mixtures of toxicants extracted from passive samplers suggested no significant difference in tolerance to metals and organic pesticides between phototrophic communities supplied with unfiltered or filtered contaminated water. Our results confirm the use of extracts from passive samplers as a promising approach in short-term toxicity tests to characterize impacts of contamination on aquatic communities. PMID- 25037098 TI - Alternation of antioxidative enzyme gene expression in rice seedlings exposed to methylene blue. AB - Hydroponic experiments were conducted with rice seedlings (Oryza sativa L. cv. ND1) exposed to methylene blue (MB) to investigate the accumulation of hydrogen peroxide (H2O2) and activities and gene expression of antioxidant enzymes. Results showed that a linear decrease in relative growth rate and water use efficiency was observed with rice seedlings with increasing MB concentrations. MB induced accumulation of H2O2 was evident in both roots and shoots. The activities of antioxidative enzymes were analyzed and found to be different at different MB treatment concentrations. The activities of enzymes related to the ascorbate glutathione cycle were more sensitive to MB treatments than other antioxidative enzymes. Transcript level, by real-time quantitative PCR, of antioxidative enzymes showed that the analyzed genes were differently expressed during different MB concentrations in both roots and shoots. The isoform analysis of superoxide dismutase (SOD) gene showed that the expressions of Cu/ZnSOD and MnSOD were relatively constant, where significant upregulation of FeSOD was observed with rice seedlings exposed to high MB concentrations. Furthermore, the expression of CAT, POD, and MDHAR genes responded biphasically to MB treatments by showing negligible changes at 1.56-15.63 MUM MB and significant induction at 31.36-62.52 MUM MB. The expression of GR, APX, and DHAR genes showed a remarkable induction to MB. Our results suggest that on transcription level, and in accordance with enzymatic responses, enzymes of GR, APX, and DHAR play central role in the H2O2 detoxification in rice seedlings under MB exposure. PMID- 25037099 TI - Composition of weathering crusts on sandstones from natural outcrops and architectonic elements in an urban environment. AB - This work presents mineralogical and chemical characteristics of weathering crusts developed on sandstones exposed to various air pollution conditions. The samples have been collected from sandstone tors in the Carpathian Foothill and from buildings in Krakow. It has been stated that these crusts differ in both fabric and composition. The sandstone black crust from tors is rich in organic matter and composed of amorphous silica. Sulphate incrustations accompanied by dust particles have been only sometimes observed. Beneath the black crust, a zone coloured by iron (oxyhydr)oxides occurs. The enrichment of the surface crust in silica and iron compounds protects the rock interior from atmospheric impact. The sandstones from architectonic details are also covered by a thin carbon-rich black crust, but they are visibly loosened. Numerous salts, mainly gypsum and halite, crystallise here, thus enhancing deterioration of the rock. Moreover, spherical particles originated from industrial emissions are much more common. Gypsum in natural outcrops, forms isolated and well-developed crystals, whilst these found on the architectonic details are finer and densely cover the surface. Such diversity reflects various concentrations of acid air pollutants in solutions. PMID- 25037100 TI - Study on biodegradation process of lignin by FTIR and DSC. AB - The biodegradation process of lignin by Penicillium simplicissimum was studied to reveal the lignin biodegradation mechanisms. The biodegradation products of lignin were detected using Fourier transform infrared spectroscopy (FTIR), UV-Vis spectrophotometer, different scanning calorimeter (DSC), and stereoscopic microscope. The analysis of FTIR spectrum showed the cleavage of various ether linkages (1,365 and 1,110 cm(-1)), oxidation, and demethylation (2,847 cm(-1)) by comparing the different peak values in the corresponding curve of each sample. Moreover, the differences (Tm and DeltaHm values) between the DSC curves indirectly verified the FTIR analysis of biodegradation process. In addition, the effects of adding hydrogen peroxide (H2O2) to lignin biodegradation process were analyzed, which indicated that H2O2 could accelerate the secretion of the MnP and LiP and improve the enzymes activity. What is more, lignin peroxidase and manganese peroxidase catalyzed the lignin degradation effectively only when H2O2 was presented. PMID- 25037101 TI - Methodological extensions of meta-analysis with excess relative risk estimates: application to risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy. AB - Although radiotherapy is recognized as an established risk factor for second malignant neoplasms (SMNs), the dose response of SMNs following radiotherapy has not been well characterized. In our previous meta-analysis of the risks of SMNs occurring among children who have received radiotherapy, the small number of eligible studies precluded a detailed evaluation. Therefore, to increase the number of eligible studies, we developed a method of calculating excess relative risk (ERR) per Gy estimates from studies for which the relative risk estimates for several dose categories were available. Comparing the calculated ERR with that described in several original papers validated the proposed method. This enabled us to increase the number of studies, which we used to conduct a meta analysis. The overall ERR per Gy estimate of radiotherapy over 26 relevant studies was 0.60 (95%CI: 0.30-1.20), which is smaller than the corresponding estimate for atomic bomb survivors exposed to radiation as young children (1.7; 95% CI: 1.1-2.5). A significant decrease in ERR per Gy with increase in age at exposure (0.85 times per annual increase) was observed in the meta-regression. Heterogeneity was suggested by Cochran's Q statistic (P < 0.001), which may be partly accounted for by age at exposure. PMID- 25037102 TI - Comparison study of tooth enamel ESR spectra of cows, goats and humans. AB - The ESR radiation dosimetric properties of tooth enamel samples from cows and goats were investigated and compared with those of human samples. Samples were prepared first mechanically, and then chemically. The study results showed that the native signals from cow and goat samples were weaker than those from human samples; the radiation sensitivities for cow and goat samples were very close to those of human tooth enamel samples. These results indicated that cow and goat teeth could be alternative materials for radiation dose estimation. PMID- 25037106 TI - A survey of dermatological diseases among older male adults of a Veterans Home in Southern Taiwan. AB - BACKGROUNDS: The dermatologic diseases of the dependent elderly require special attention. METHODS: This screening and treatment service of dermatological diseases was conducted in a Veterans Home in Southern Taiwan. RESULTS: A total of 337 male residents were screened with mean age 83 years (range 46-99). 271 (80.4 %) residents were in dependent status. Their skin diseases were recorded and the distribution pattern was compared with those in the other studies. Comparing by Chi-square test, scabies, bacterial infection, chronic ulcers, pruritus, and brown spots on the legs were present significantly in certain major systemic diseases, respectively. Higher prevalence of certain skin diseases was related to the severity of disability or major systemic diseases of the residents. Actinic keratosis and non-melanoma skin cancers were early detected and managed. CONCLUSIONS: The distribution patterns of skin diseases in a Veterans Home were unique. It provides the evidences on appropriate management and key nursing points for dependent elderly. PMID- 25037105 TI - Tuberculosis in children. AB - Many clinicians regard tuberculosis as an adult pulmonary disease, but tuberculosis (TB) is a major cause of disease, both pulmonary and extrapulmonary, and death in young children from TB-endemic countries, especially in areas affected by poverty, social disruption, and human immunodeficiency virus (HIV) infection. This article reviews the disease burden and the natural history of disease in children with TB. It also provides guidance regarding the diagnosis, treatment, and prevention of TB in children. PMID- 25037104 TI - Gene augmentation for adRP mutations in RHO. AB - Mutations in the gene for rhodopsin, RHO, cause autosomal dominant retinitis pigmentosa, a disease characterized by death of rod photoreceptor cells. At the end stage, when most rods are gone, cones die too, taking central vision with them. One goal of gene therapy, therefore, is to preserve central vision by promoting rod survival in the vicinity of the macula. Dominance in RHO mutations is associated with two phenomena: interference with the function of normal rhodopsin and intrinsic toxicity of the mutant protein. In the case of interference, increased production of the wild-type protein may be therapeutic, but in the case of toxicity, suppression of the mutant protein may also be needed. RHO augmentation has made use of advances in gene delivery to the retina using adeno-associated virus (AAV). Several strategies have been developed for suppression of rhodopsin expression, but because of the heterogeneity of RHO mutations they are not specific for the mutant allele: They suppress both mutant and wild-type RHO. Experiments in autosomal dominant retinitis pigmentosa (adRP) mouse models suggest that both RHO augmentation and supplementation plus suppression preserve the survival of rod cells. PMID- 25037107 TI - Brachial-ankle pulse wave velocity is a predictor of walking distance in community-dwelling adults. AB - Arterial stiffness represents the cumulative effects of cardiovascular risk factors, including aging, on the arterial wall, and has been found to be a surrogate marker of cardiovascular disease. However, it remains unknown whether baseline arterial stiffness is independently associated with improvement in functional abilities after exercise training. The subjects were 72 adults (9 men and 63 women) aged 67 +/- 7 years from a rural village. Before and at the end of a 12-week Nordic walking program, 6-min walk distance (6MWD) as functional abilities, metabolic characteristics, and the mean of the right and left brachial ankle pulse wave velocity (baPWV) as a marker of arterial stiffness were measured. Higher baseline mean baPWV levels correlated significantly with shorter baseline 6MWD (P < 0.001), and also with the follow-up 6MWD (P < 0.001) and change rate (P = 0.019) in 6MWD after the 12-week training program. Multivariate linear regression analysis was employed to evaluate the contribution of baseline mean baPWV for 6MWD parameters showing that baseline mean baPWV values were significantly and independently associated with follow-up 6MWD (beta = -0.523, P < 0.001) and change rate in 6MWD (beta = -0.399, P < 0.001) as well as baseline 6MWD (beta = -0.522, P < 0.001), but was not associated with change after the 12 week training program. Higher baPWV, a measurement of arterial stiffness, might be a predictor of functional abilities after exercise training, independent of confounding factors, in the general population. PMID- 25037108 TI - Physiologically clotted fibrin--preparation and characterization for tissue engineering and drug delivery applications. AB - Fibrin used for biomedical applications is prepared by mixing concentrated solutions of fibrinogen and thrombin in presence of cross-linking agents such as Factor XIII or glutaraldehyde. The main drawbacks associated with this procedure include cost, complexity and time required for fibrin preparation. Hence, present study deals with the characterization of physiologically clotted fibrin (PF) for bone tissue engineering and drug delivery applications. For this the physico chemical properties of PF were compared with those of the conventionally prepared fibrin (CF). Further MTT and haemolytic assays were performed for both PF and CF to compare their biocompatibility. The amount of alkaline phosphatase produced and calcium secreted by MG-63 cells in the presence of PF and CF were used to relate the osteogenic potency of PF with that of CF. Gallic acid, an anti-cancer drug was loaded within PF and CF and their role in drug delivery was compared. PMID- 25037109 TI - Case tracking and sharing system to foster consistent group standards of practice and improve radiologist experience in DBT. PMID- 25037110 TI - [Alagille's syndrome associated with proximal radio-ulnar synostosis: Clinical case and a literature review]. AB - Alagille's syndrome is an infrequent genetic condition with autosomal inheritance and variable expression. The complete form exhibits 5 clinical signs, chronic intrahepatic cholestasis, characteristic facies, cardiovascular anomalies, posterior embryotoxon, and vertebral defects. If only 3 or 4 of these are present the case is considered as an incomplete form. The association of Alagille's syndrome with radio-ulnar synostosis is extremely rare. There is only one case described in the indexed literature. A case is presented of Alagille's syndrome with bilateral proximal radioulnar synostosis. To the best of our knowledge this is the second reported case of this association. PMID- 25037111 TI - [The geometry of the keel determines the behaviour of the tibial tray against torsional forces in total knee replacement]. AB - The keel design of the tibial tray is essential for the transmission of the majority of the forces to the peripheral bone structures, which have better mechanical proprieties, thus reducing the risk of loosening. The aim of the present study was to compare the behaviour of different tibial tray designs submitted to torsional forces. Four different tibial components were modelled. The 3-D reconstruction was made using the Mimics software. The solid elements were generated by SolidWorks. The finite elements study was done by Unigraphics. A torsional force of 6 Nm. applied to the lateral aspects of each tibial tray was simulated. The GENUTECH(r) tibial tray, with peripheral trabecular bone support, showed a lower displacement and less transmitted tensions under torsional forces. The results suggest that a tibial tray with more peripheral support behaves mechanically better than the other studied designs. PMID- 25037112 TI - Impact of thin-cap fibroatheroma on predicting deteriorated coronary flow during interventional procedures in acute as well as stable coronary syndromes: insights from optical coherence tomography analysis. AB - The occurrence of deteriorated coronary flow associated with distal embolization during percutaneous coronary intervention results in impaired myocardial perfusion and worsens the clinical prognosis. This study aimed to examine the impact of optical coherence tomography (OCT)-determined coronary plaque morphology on the prediction of deteriorated coronary flow after stent implantation in acute as well as stable coronary syndromes (ACS and SAP, respectively). We studied 126 patients who underwent OCT during stenting for ACS (n = 44) and SAP (n = 82) with a de novo lesion. Angiographic deteriorated coronary flow was defined as the deterioration of TIMI flow grade after mechanical dilatation in the absence of a mechanical obstruction on angiograms. Patients could be divided into the deteriorated flow group (n = 21) and the reflow group (n = 105). Under these conditions, the presence of thin-cap fibroatheroma (TCFA) was more frequently observed in the deteriorated flow group than in the reflow group in both ACS and SAP. A multivariable logistic regression model revealed that TCFA was an independent predictor of deteriorated coronary flow (hazard ratio: 12.32; 95 % confidence interval: 3.02-50.31; p = 0.0005). These results demonstrate that TCFA detected by OCT could be a strong predictor of the occurrence of deteriorated coronary flow during stent implantation in ACS as well as SAP. PMID- 25037113 TI - Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome, but not overweight or obesity. AB - Background The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence. Aims and methods This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerstrom Nicotine Dependence Scale. Results PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder. Discussion PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS. PMID- 25037114 TI - Does form meet function in the coronavirus replicative organelle? AB - If we use the analogy of a virus as a living entity, then the replicative organelle is the part of the body where its metabolic and reproductive activities are concentrated. Recent studies have illuminated the intricately complex replicative organelles of coronaviruses, a group that includes the largest known RNA virus genomes. This review takes a virus-centric look at the coronavirus replication transcription complex organelle in the context of the wider world of positive sense RNA viruses, examining how the mechanisms of protein expression and function act to produce the factories that power the viral replication cycle. PMID- 25037115 TI - A genetic association study of single nucleotide polymorphisms in GNbeta3 and COMT in elderly patients with irritable bowel syndrome. AB - BACKGROUND: Several polymorphisms have been reported to be associated with irritable bowel syndrome (IBS), including C825T, the single nucleotide polymorphism (SNP), responsible for a truncated G protein beta3 subunit (GNbeta3), and the Vall158Met substitution in catechol-O-methyltransferase (COMT). We investigated the association between these mutations and the prevalence of IBS in 66 elderly Chinese patients. MATERIAL/METHODS: Sixty-six patients (over age 60 years) were diagnosed with IBS according to the Rome III criteria, and divided into 3 groups based on symptom presentation. The groups consisted of 7 patients with constipation, 46 patients with diarrhea, and 13 patients with both or neither symptoms. We enrolled 115 age-matched individuals without IBS as the control group. All patients were evaluated by using the Geriatric Depression Scale, disease progression was recorded, and GNbeta3 and COMT were genotyped by PCR. RESULTS: There was no significant difference in GNbeta3 C825T genotype distribution and allele frequency between the 2 groups. In contrast, compared with control subjects, COMT 158Met was significantly more prevalent in the IBS group (P=0.040) and significantly more prevalent in patients with diarrhea (P=0.029). 158Met was also more prevalent in those patients who had experienced symptoms for over 5 years (P=0.022). CONCLUSIONS: In elderly Chinese patients, the 158Met SNP in COMT is associated with IBS pathogenesis, but the GNbeta3-C825T SNP is not associated with IBS pathogenesis. PMID- 25037117 TI - Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma. AB - Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included. PMID- 25037116 TI - Predictive and prognostic value of circulating endothelial cells in non-small cell lung cancer patients treated with standard chemotherapy. AB - PURPOSE: Monitoring circulating endothelial cells (CECs) count reflects the tumor vasculature in cancer patients and might be a predictor of response to chemotherapy. We therefore investigated the clinical significance of changes in CECs count after three cycles of platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Peripheral blood samples were collected from 89 naive NSCLC patients at diagnosis and after chemotherapy. The CECs were quantified by an immuno-magnetic technique and fluorescent microscopy. After chemotherapy, patients were assessed according to the response evaluation criteria in solid tumors as partial response (PR), stable disease (SD) or progression disease (PD). RESULTS: Baseline CECs levels were significantly higher in PR patients (n = 62) than those in patients with SD/PD (n = 27) (p = 0.0007). Although there was no significant correlation between baseline CECs levels and progression-free survival (PFS) (p = 0.287), patients with high percentage change in CECs count after chemotherapy had significantly longer PFS than those with low percentage change (p = 0.048). Regarding treatment efficacy, CECs count significantly decreased after chemotherapy in comparison with CECs count at baseline in patients with PR (p < 0.0001). By contrast, CECs levels after chemotherapy were significantly higher than those at diagnosis in patients with PD (p = 0.002). Moreover, there was no significant change between pre- and post-treatment CECs amount in patients with SD (p = 0.681). CONCLUSIONS: Baseline CECs levels might be an early predictive biomarker for treatment efficacy in advanced NSCLC patients. Our results suggest the change in CECs count after chemotherapy as a prognostic factor for tumor response and PFS in NSCLC. PMID- 25037118 TI - Connoisseurship and drunkenness in Tokyo. AB - Although aggregate alcohol consumption in Japan is declining, national data overlook important anomalies and local trends. One is that young adults are drinking in greater volume and frequency than previously observed in the postwar era, while health concerns pertaining to alcohol consumption struggle for national recognition against largely uncritical views of intoxication. This article focuses on the connoisseurship of alcohol among Tokyo's young adults, particularly knowledge and breadth of sampled varieties, an emergent and growing pursuit that encourages drinking and structures drunkenness. Connoisseurship and drunkenness, the article argues, serve as means to assert expertise, sophistication and global competence - a form of cultural capital among young urbanites who increasingly find themselves on the economic and social margins, disconnected from the official institutions of Japanese society. Most of the data presented here were gathered over 14 months of ethnographic fieldwork in Tokyo (interviews, online survey and participant observation), supplemented by ongoing participation in online conversations on the popular social media website www.mixi.jp. Ethnographic attention reveals how alcohol consumption is discussed as a culturally meaningful pursuit illustrative of major societal shifts and challenges confronting Japan. PMID- 25037119 TI - Perceptions of genetic testing and genomic medicine among drug users. AB - BACKGROUND: Genetic testing will soon enter care for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), and for addiction. There is a paucity of data on how to disseminate genetic testing into healthcare for marginalized populations. We explored drug users' perceptions of genetic testing. METHODS: Six focus groups were conducted with 34 drug users recruited from syringe exchange programmes and an HIV clinic between May and June 2012. Individual interviews were conducted with participants reporting previous genetic testing. RESULTS: All participants expressed acceptance of genetic testing to improve care, but most had concerns regarding confidentiality and implications for law enforcement. Most expressed more comfort with genetic testing based on individual considerations rather than testing based on race/ethnicity. Participants expressed comfort with genetic testing in medical care rather than drug treatment settings and when specifically asked permission, with peer support, and given a clear rationale. CONCLUSION: Although participants understood the potential value of genetic testing, concerns regarding breaches in confidentiality and discrimination may reduce testing willingness. Safeguards against these risks, peer support, and testing in medical settings based on individual factors and with clear rationales provided may be critical in efforts to promote acceptance of genetic testing among drug users. PMID- 25037120 TI - Steroid treatment can inhibit nuclear localization of members of the NF-kappaB pathway in human disc cells stimulated with TNF-alpha. AB - Steroid applications are able to repress inflammatory activity in various conditions, including herniation of the nucleus pulposus (HNP), by inhibiting tumour necrosis factor (TNF)-alpha, but the effects of long-term use are unknown. Here, we investigated the effect of dexamethasone (DEXA) on TNF-alpha-stimulated intervertebral disc cells by monitoring the expression and localization of NF kappaB in the cytoplasm and nucleus. Cultured human intervertebral disc cells were left untreated or treated with only TNF-alpha, only DEXA, or with TNF-alpha and DEXA simultaneously. Cytoplasmic and nuclear proteins were extracted and Western blotted after 10 min, 1 or 2 h, to evaluate the expression of p50, p65, p52, and p100 (components of NF-kappaB). Immunofluorescence analysis was used to determine the subcellular localization of the proteins at 1 h. DEXA had limited effects on NF-kappaB expression in TNF-alpha-stimulated disc cells within the first 10 min. At 1 h, DEXA prevented the TNF-alpha-stimulated translocation of p50, p52, and p65. After 2 h, DEXA reduced the nuclear expression of p50, p65, and p52. Thus, DEXA resulted in delayed expression of NF-kappaB components and inhibited the translocation of p50, p52, and p65 to the nucleus, which would prevent expression of the corresponding genes. Therefore, following stimulation with TNF-alpha, transcriptional regulation of NF-kappaB in disc cells is mainly mediated via the classical pathway, but also to some extent via the alternative pathway. Hence, blockade of sub-acute inflammatory changes in HNP can be achieved by early injection of steroids, whereas long-term injection of a steroid may initiate NF-kappaB autophosphorylation. PMID- 25037121 TI - Review "Results of treatment of chronic osteomyelitis by gutter procedure and muscle flap transposition operation". PMID- 25037122 TI - Foundations of pediatrics: Lula Olga Lubchenco, MD (1915-2001); scientist, teacher, mentor/mother to many. PMID- 25037124 TI - Advances in the care of children with spina bifida. PMID- 25037125 TI - Update in pediatric imaging. PMID- 25037123 TI - Advances in pediatric pharmacology, therapeutics, and toxicology. AB - In the United States, passage of the FDASIA legislation made BPCA and PREA permanent, no longer requiring reauthorization every 5 years. This landmark legislation also stressed the importance of performing clinical trials in neonates when appropriate. In Europe the Pediatric Regulation, which went into effect in early 2007, also provides a framework for expanding pediatric clinical research. Although much work remains, as a result of greater regulatory guidance more pediatric data are reaching product labels. PMID- 25037126 TI - Conduction defects/cardiomyopathies. PMID- 25037127 TI - Advances in minimally invasive surgery in pediatric patients. AB - Surgery has changed dramatically over the last several decades. The emergence of MIS has allowed pediatric surgeons to manage critically ill neonates, children, and adolescents with improved outcomes in pain, postoperative course, cosmesis, and return to normal activity. Procedures that were once thought to be too difficult to attempt or even contraindicated in pediatric patients in many instances are now the standard of care. New and emerging techniques, such as single-incision laparoscopy, endoscopy-assisted surgery, robotic surgery, and techniques yet to be developed, all hold and reveal the potential for even further advancement in the management of these patients. The future of MIS in pediatrics is exciting; as long as our primary focus remains centered on developing techniques that limit morbidity and maximize positive outcomes for young patients and their families, the possibilities are both promising and infinite. PMID- 25037128 TI - A patient/family-centered strategic plan can drive significant improvement. AB - The use of a PFCSP, as a road map to operationalize the hospital's vision, has been a compelling paradigm to achieve significant QI results. The framework is simple yet directly aligns with the IOM domains of quality. It has inspired and helped actively engage hospital personnel in the work required to achieve the goals and vision of the hospital system. Five years after initiating this type of plan, activity is flourishing in each of the domains and midterm results are substantial. We think that the nature of this strategic plan has been an important aspect of our success to date. PMID- 25037129 TI - Hypothermia in hypoxic ischemic encephalopathy: a 5-year experience at Phoenix Children's Hospital Neuro NICU. AB - We found TH to be safe and effective in improving survival and neurodevelopmental outcomes following HIE in term children. Additionally, the use of a multidisciplinary team involved with these complex patients and the use of advanced monitoring techniques will likely assist in identifying second insults (ie, seizures), leading to more rapidly instituted treatments. Our study, however, had the limitation of including only retrospective data from patients in whom TH was provided. This makes it difficult to identify the specific sources for the improved outcomes and/or the presence of complications. PMID- 25037130 TI - Advances in the diagnosis and treatment of cystic fibrosis. AB - CF is a genetic, life-shortening, multisystem disease that is most commonly diagnosed through newborn screen performed in all 50 states in the United States. In the past, therapies for CF lung disease have primarily targeted the downstream effects of a dysfunctional CFTR protein. Newer CFTR modulator therapies, targeting the basic defect in CF, are available for a limited group of people with CF, and offer the hope of improved treatment options for many more people with CF in the near future. Best practice is directed by consensus clinical care guidelines from the CFF and is provided with a multidisciplinary approach by the team at the CF care center and the primary care office. PMID- 25037131 TI - Pediatrics in disasters: evaluation of a global training program. AB - The findings of this evaluation document partial success for the PEDS training program to achieve its 3 aims. It will take several years for the dissemination of this program to reach a critical mass of pediatricians and other physicians in many LMICs. Obtaining stronger support from MOHs and other governmental agencies is necessary to achieve this goal. Another additional approach would be to integrate the training into medical school and residency programs. PMID- 25037132 TI - Prevention and management of pediatric obesity: a multipronged, community-based agenda. PMID- 25037133 TI - Management of pediatric mild traumatic brain injury. AB - mTBI is a very common and underdiagnosed problem in the pediatric population. While most children who receive appropriate management recover uneventfully (80% 90%), referral to a concussion specialist is necessary for those with a complicated course. Fortunately, further improvements in identifying those children who have sustained an mTBI, coupled with strict adherence to the Return to Learn and Return to Play protocols, will ultimately lead to better long-term outcomes. PMID- 25037134 TI - Foodborne illnesses. PMID- 25037135 TI - Lead poisoning in children. AB - There is no safe lead level in children. Primary prevention is the most effective way to bring about the complete removal of lead from the environment and eliminate lead poisoning as a public health concern. The National Lead Information Center can be reached via the Internet at www.epa.gov/lead and www.hud.gov/lead, or via phone at 1-800-424-LEAD (5323). PMID- 25037136 TI - Atypical hemolytic uremic syndrome. PMID- 25037137 TI - Volume 61 of Advances in Pediatrics. Introduction. PMID- 25037138 TI - In memoriam: Lew Barness. PMID- 25037140 TI - Combined inhibition of BRAF and MEK in melanoma patients. PMID- 25037139 TI - Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600) mutated melanoma: a phase 1b study. AB - BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600) mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2.8 months (95% CI 2.6-3.4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13.7 months (95% CI 10.1-17.5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech. PMID- 25037141 TI - Response to: "preimplantation genetic diagnosis strategy combining blastocyst biopsy and array comparative genomic hybridization for parents carrying chromosomal translocation". PMID- 25037142 TI - Hospitals forecast a rise in emergency admissions, while commissioners forecast a fall. PMID- 25037143 TI - Nurse refuses "criminal" force feeding of Guantanamo detainees. PMID- 25037145 TI - Congenital coronary sinus aneurysm. PMID- 25037144 TI - Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors: analysis of patients beginning adjunctive treatment in a 52-week, open-label study. AB - BACKGROUND: This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). METHODS: Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1-4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impressions Severity (CGI-S). RESULTS: Forty-seven patients received bupropion plus aripiprazole and 245 received an SSRI/SNRI plus aripiprazole; 19 (40.4%) and 78 (31.8%), respectively, completed 52 weeks of treatment, and 46 and 242, respectively, received >=1 dose of study medication (safety sample). Median time to discontinuation (any reason) was 184.0 days. Overall, 97.8% of patients in the bupropion group and 93.8% in the SSRI/SNRI group experienced >=1 adverse event. The most common treatment-emergent adverse events were fatigue (26.1%) and somnolence (21.7%) with bupropion and fatigue (23.6%) and akathisia (23.6%) with an SSRI/SNRI. Mean change in body weight at week 52 (observed cases) was +3.1 kg for bupropion and +2.4 kg for an SSRI/SNRI. Treatment-emergent, potentially clinically relevant abnormalities in fasting glucose occurred in 8.3% of patients with bupropion and 17.4% with an SSRI/SNRI; for abnormalities in fasting total cholesterol, the incidence was 25.0% and 34.7%, respectively. Mean (SE) change from baseline in fasting glucose was 1.4 (1.9) mg/dL with bupropion and 2.7 (1.5) mg/dL with an SSRI/SNRI. Baseline MGH-SFI item scores indicated less severe impairment with bupropion versus an SSRI/SNRI; in both groups most MGH-SFI items exhibited improvement at week 52. Mean CGI-S improvement at week 52 (last observation carried forward) was -1.4 with bupropion and -1.5 with an SSRI/SNRI (efficacy sample). CONCLUSIONS: There were no unexpected AEs with long-term adjunctive aripiprazole therapy when added to either bupropion or SSRIs/SNRIs, and symptom improvement was similar between ADT groups. Sexual functioning in patients with MDD on antidepressants was also modestly improved after adding aripiprazole. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00095745 (November 9, 2004). PMID- 25037146 TI - Inappropriate antidiuretic hormone secretion due to squamous cell lung cancer. AB - The syndrome of inappropriate secretion of antidiuretic hormone is a disorder of impaired water excretion caused by the inability to suppress secretion of antidiuretic hormone. It has been commonly associated with small cell carcinoma. The association of this syndrome with squamous cell lung carcinoma has rarely been reported, with only 4 cases over the past two decades in the English literature. We describe the case of a 75-year-old Caucasian male who developed the syndrome after a right pneumonectomy for down-staged squamous cell lung cancer previously treated with neoadjuvant platinum-based chemotherapy and radiotherapy. PMID- 25037147 TI - Plain abdominal radiography: a powerful tool to prognosticate outcome in patients with zinc phosphide poisoning. AB - AIM: To evaluate the clinical features of zinc phosphide poisoning and to investigate whether outcome could be prognosticated based on abdominal radiography on presentation. MATERIALS AND METHODS: All zinc phosphide-poisoned patients who were referred to Loghman-Hakim Hospital between March 2011 and September 2013 were retrospectively reviewed. Data regarding patients' demographic characteristics, characteristics of the poisoning, abdominal radiography results, and patients' outcome were recorded. RESULTS: In 102 patients, the most common presenting signs/symptoms were nausea and vomiting (60%). Four patients died and another seven had developed complications during their hospitalization (metabolic acidosis, liver abnormalities, or acute renal failure). Nineteen patients had radio-opaque abdominal radiographs, nine of whom had died or developed complications (p = 0.001). Plain abdominal radiography had a sensitivity and specificity of 81% and 89% in predicting the patients' death or further development of complications. The positive and negative predictive values were 47% and 97%, respectively. CONCLUSION: Plain abdominal radiography is a very good tool for prognostication in patients with zinc phosphide poisoning. Immediate abdominal radiography can help stratify patients into high- or low-risk groups and determine treatment strategies. PMID- 25037148 TI - The role of embolization in reducing the complications of cryoablation in renal cell carcinoma. AB - AIM: To investigate whether embolization prior to cryoablation would decrease morbidity without negative effects on tissue pathology, renal function, or recurrence. MATERIAL AND METHODS: The electronic medical records of all patients undergoing cryoablation for renal cell carcinomas were reviewed for lesion size, pre-ablative renal function, post-ablative renal function, post-ablative complications, recurrence, and quality of biopsy specimen. Comparisons were made between patients who underwent cryoablation (the Cryo-Only group) and those who underwent cryoablation after same-day coil embolization of their lesion (the Cryo Embo group). Further comparison was made between the Cryo-Embo lesions and the subset of larger Cryo-Only lesions (>= 3 cm), which were expected to have a higher natural complication rate. RESULTS: A total of 21 lesions in 19 patients were treated by percutaneous cryoablation (17 Cryo-Only, four Cryo-Embo). Complications were seen in 83% of the large Cryo-Only lesions (average size 3.6 cm), whereas no complication was seen amongst Cryo-Embo lesions (average size 4 cm). Embolization significantly decreased complications between size-matched lesions (p = 0.048) without impacting renal function (p = 1), biopsy quality (p = 1), or recurrence (p = 1). CONCLUSION: Performance of trans-arterial embolization prior to cryoablation of large renal cell carcinomas significantly decreases complications, such as haemorrhage, without a discernible effect on biopsy quality, renal function, or recurrence rate. PMID- 25037149 TI - National audit of appropriate imaging. AB - AIMS: To audit the availability of imaging referral guidelines; vetting by radiologists of GP-initiated CT and MRI requests; and the achievement of appropriate imaging using retrospective assessment as a surrogate. MATERIALS AND METHODS: A web-based questionnaire was distributed to imaging departments in the UK seeking awareness of guideline availability; the percentage of consecutive general practitioner (GP)-requested computed tomography (CT) and magnetic resonance imaging (MRI) investigations that showed evidence of vetting; and the percentage of procedures where retrospective assessment showed the investigation to be appropriate according to imaging referral guidelines. RESULTS: Replies were received from 88 departments covering 1700 of 2700 (63%) consultant radiologists practising in the UK. Regarding the availability of guidelines, approximately a third of respondents were not aware of guidelines being available to all radiologists and radiographers. The 68% level of availability (58/88 departments) is well below the standard of 100%. In keeping with the target of 95%, vetting of CT requests was shown in 1815/1890 (96%) and MRI in 1181/1250 (95%). Appropriateness of CT examinations was shown in 1746/1870 (93%) and MRI in 1154/1215 (95%), well above the target of 90%. The most common reason for an inappropriate investigation for both MRI and CT was the inability to affect patient management. CONCLUSIONS: Although awareness of referral guidelines availability was limited at 68%, well below the 100% standard, the meticulous vetting of requests (shown in 95-96%) with the amendment or return of inappropriate requests (9-12%) enables a high level of appropriate imaging (93 95%) for GP-requested CT and MRI, thus making the best use of clinical radiology. PMID- 25037151 TI - Reduction of AMPK activity and altered MAPKs signalling in peripheral blood mononuclear cells in response to acute glucose ingestion following a short-term high fat diet in young healthy men. AB - BACKGROUND: Peripheral blood mononuclear cells (PBMCs) are known to respond to systematic changes in nutrient availability. The impact of a short-term high fat diet (HFD), with and without acute glucose ingestion, on the energy-sensing enzyme 5' AMP-activated protein kinase (AMPK) as well as mitochondrial oxidative phosphorylation (OXPHOS) proteins in PBMCs is currently unknown. METHODS: Nine healthy, lean young males participated in a 7 day HFD intervention, designed to induce transient glucose intolerance. The phosphorylation status and total protein content of AMPK and inflammatory mitogen-activated protein kinases (MAPKs), and total OXPHOS protein in PBMCs, along with circulating cytokines, were assessed in the fasted state and following an oral glucose tolerance test (OGTT) before and after the HFD. RESULTS: One week of HFD resulted in relative glucose intolerance. The HFD resulted in a reduction of AMPK phosphorylation under fasting basal conditions and following the OGTT (both P<0.05), while there were no differences in OXPHOS protein expression. Although the short-term HFD had no effect on basal phosphorylation of p38, JNK or ERK1/2, the activation of MAPKs signalling in response to glucose ingestion was attenuated post-HFD as compared to pre-HFD (P<0.05 for all). Circulating cytokines were not significantly affected by the HFD. CONCLUSIONS: We conclude that impaired glucose tolerance in response to 7 day HFD resulted in decreased AMPK activity and impaired glucose stimulated MAPK activation following glucose ingestion in vivo in PBMCs from young, lean subjects. Further studies are warranted to explore how dietary manipulations impact interplay between AMPK and inflammatory signalling, along with immune function, in PBMCs. PMID- 25037150 TI - Production and characterization of specific monoclonal antibodies binding the Plasmodium falciparum diagnostic biomarker, histidine-rich protein 2. AB - BACKGROUND: Early and accurate diagnosis of Plasmodium falciparum infection is important for providing appropriate treatment to patients with malaria. However, technical limitations of currently available diagnostic tests limit their use in control programs. One possible explanation for the vulnerability of current antibodies used in RDTs is their propensity to degrade at high ambient temperatures. Isolation of new antibodies with better thermal stability represents an appealing approach to improve the performance of RDTs. METHODS: In this study, phage display technology was deployed to isolate novel binders by screening a human naive scFv antibody library against recombinant Plasmodium falciparum histidine rich protein 2 (rPfHRP2). The isolated scFv clones were reformatted to whole IgG and the recombinant mAbs were produced in a mammalian CHO cell expression system. To verify the biological activity of these purified recombinant mAbs, range of functional assays were characterized. RESULTS: Two unique clones (D2 and F9) were isolated after five rounds of biopanning. The reformatted and expressed antibodies demonstrated high binding specificity to malaria recombinant PfHRP2 and native proteins. When 5 MUg/mL of mAbs applied, mAb C1-13 had the highest sensitivity, with an OD value of 1, the detection achieved 5 ng/mL of rPfHRP2, followed by mAbs D2 and F9 at 10 ng/mL and 100 ng/mL of rPfHRP2, respectively. Although the sensitivity of mAbs D2 and F9 was lower than the control, these recombinant human mAbs have shown better stability compared to mouse mAb C1-13 at various temperatures in DSC and blot assays. In view of epitope mapping, the predominant motif of rPfHRP2 recognized by mAb D2 was AHHAADAHHA, whereas mAb F9 was one amino acid shorter, resulting in AHHAADAHH. mAb F9 had the strongest binding affinity to rPfHRP2 protein, with a KD value of 4.27 * 10(-11) M, followed by control mAb C1-13 at 1.03 * 10(-10) M and mAb D2 at 3.05 * 10(-10) M. CONCLUSIONS: Overall, the performance of these mAbs showed comparability to currently available PfHRP2-specific mouse mAb C1-13. The stability of these novel binders indicate that they merit further work to evaluate their utility in the development of new generation point of care diagnosis of malaria. PMID- 25037152 TI - Antenatal depression and children's developmental outcomes: potential mechanisms and treatment options. AB - During the last decade there has been increased recognition of the prevalence of antenatal depression as well as an expansion in research examining the impact of maternal mood during pregnancy on offspring development. The aim of this review was to summarise the theoretical underpinnings and empirical evidence regarding the impact of antenatal depression on children's developmental outcomes. Biological mechanisms hypothesised to account for an association between antenatal depression and adverse offspring outcomes are first identified including the functioning of the prenatal Hypothalamic Pituitary Adrenal (HPA) axis and epigenetic processes. A systematic literature search is then conducted of studies examining the impact of antenatal depression on child development. In general, studies examining associations between antenatal depression and offspring temperament, cognitive and emotional outcomes reveal either no effect of the prenatal environment or small effects that often attenuate following adjustment for other antenatal and postnatal risk factors. In contrast, an independent effect of antenatal depression on children's conduct problems and antisocial behaviour is a well-replicated finding. There is emerging evidence that exposure to depression during pregnancy impacts negatively on offspring biology, although the findings are complex and require replication. Psychological and pharmacological treatments of antenatal depression are then reviewed, considering whether antidepressant medication exerts harmful effects on the foetus. We close by proposing that antenatal depression is an early marker of a developmental cascade to future mental health problems for both mothers and offspring. PMID- 25037154 TI - Spousal Caregiving for Partners With Dementia: A Deductive Literature Review Testing Calasanti's Gendered View of Care Work. AB - Spousal caregiving allows stressed couples to continue living in the community rather than seeking institutional solutions. Dr. Toni Calasanti has postulated that there are gender differences in the care work styles and coping strategies used by spousal caregivers dealing with dementia. While caregiving husbands tend to adopt task-oriented (masculine) approaches, caregiving wives are more likely to take an emotionally focused (feminine) orientation. These differences result in the need for varied interventions. Male caregivers tend toward a managerial approach, whereas female caregivers generally adopt a relational approach. This distinction was examined in the course of a literature review through the deductive process. It was determined that the core thesis of such a gender-based view of care work as a tiered entity threaded with masculinity/femininity remains quite plausible in contrast to models based on self-perceived gender identity of caregivers that require more exploration. Recommendations for future investigations are offered as new questions arise. PMID- 25037153 TI - Inpatient Rehabilitation Outcomes in a National Sample of Medicare Beneficiaries With Hip Fracture. AB - Effects of patient characteristics on rehabilitation outcomes (functional status at discharge, discharged home) were assessed in a retrospective study of Medicare beneficiaries admitted to Medicare-certified inpatient rehabilitation facilities (IRFs) following hospitalization for hip fracture in 2009 (N = 34,984). Hierarchical regression analysis showed significantly higher functional status at discharge (p < .0001) for patients with these characteristics: White or Asian, younger, female, lived alone, higher functional status at admission, fewer comorbidities, no tier comorbidities, and longer IRF length of stay (LOS). Likelihood of discharged home was higher for patients with these characteristics: Hispanic (1.49 [1.32, 1.68]), Asian (1.35 [1.04, 1.74]), or Black (1.28 [1.12, 1.47]); younger (0.96 [0.96, 0.96]); female (1.14 [1.08, 1.20]); lived with others (2.12 [2.01, 2.23]); higher functional status at admission (1.06 [1.06, 1.06]); fewer comorbidities, no tier comorbidities; and longer LOS (1.61 [1.56, 1.67]). Functional status at admission, tier comorbidities, and race/ethnicity contributed the most to variance in functional status at discharge. Living with others contributed the most to variance in discharged home. PMID- 25037155 TI - Effectiveness of tobacco control television advertisements with different types of emotional content on tobacco use in England, 2004-2010. AB - AIM: To examine the effects of tobacco control television advertisements with positive and negative emotional content on adult smoking prevalence and cigarette consumption. DESIGN: Analysis of monthly cross-sectional surveys using generalised additive models. SETTING: England. PARTICIPANTS: 60 000 adults aged 18 years or over living in England and interviewed in the Opinions and Lifestyle Survey from 2004 to 2010. MEASUREMENTS: Current smoking status, daily cigarette consumption, tobacco control gross rating points (GRPs-a measure of per capita advertising exposure), cigarette costliness, concurrent tobacco control policies, sociodemographic variables. RESULTS: After adjusting for cigarette costliness, other tobacco control policies and individual characteristics, we found that a 400-point increase in positive emotive GRPs was associated with 7% lower odds of smoking (odds ratio (OR) 0.93, 95% CI 0.87 to 0.98) 1 month later and a similar increase in negative emotive GRPs was significantly associated with 4% lower odds of smoking (OR 0.96, 95% CI 0.92 to 0.999) 2 months later. An increase in negative emotive GRPs from 0 to 400 was also associated with a significant 3.3% (95% CI 1.1 to 5.6) decrease in average cigarette consumption. There was no evidence that the association between positive emotive GRPs and the outcomes differed depending on the intensity of negative emotive GRPs (and vice versa). CONCLUSIONS: This is the first study to explore the effects of campaigns with different types of emotive content on adult smoking prevalence and consumption. It suggests that both types of campaign (positive and negative) are effective in reducing smoking prevalence, whereas consumption among smokers was only affected by campaigns evoking negative emotions. PMID- 25037156 TI - Theoretical impacts of a range of major tobacco retail outlet reduction interventions: modelling results in a country with a smoke-free nation goal. AB - OBJECTIVE: To inform endgame strategies in tobacco control, this study aimed to estimate the impact of interventions that markedly reduced availability of tobacco retail outlets. The setting was New Zealand, a developed nation where the government has a smoke-free nation goal in 2025. METHODS: Various legally mandated reductions in outlets that were phased in over 10 years were modelled. Geographic analyses using the road network were used to estimate the distance and time travelled from centres of small areas to the reduced number of tobacco outlets, and from there to calculate increased travel costs for each intervention. Age-specific price elasticities of demand were used to estimate future smoking prevalence. RESULTS: With a law that required a 95% reduction in outlets, the cost of a pack of 20 cigarettes (including travel costs) increased by 20% in rural areas and 10% elsewhere and yielded a smoking prevalence of 9.6% by 2025 (compared with 9.9% with no intervention). The intervention that permitted tobacco sales at only 50% of liquor stores resulted in the largest cost increase (~$60/pack in rural areas) and the lowest prevalence (9.1%) by 2025. Elimination of outlets within 2 km of schools produced a smoking prevalence of 9.3%. CONCLUSIONS: This modelling merges geographic, economic and epidemiological methodologies in a novel way, but the results should be interpreted cautiously and further research is desirable. Nevertheless, the results still suggest that tobacco outlet reduction interventions could modestly contribute to an endgame goal. PMID- 25037157 TI - Tumor surveillance by circulating microRNAs: a hypothesis. AB - A growing body of experimental evidence supports the diagnostic relevance of circulating microRNAs in various diseases including cancer. The biological relevance of circulating microRNAs is, however, largely unknown, particularly in healthy individuals. Here, we propose a hypothesis based on the relative abundance of microRNAs with predominant tumor suppressor activity in the blood of healthy individuals. According to our hypothesis, certain sets of circulating microRNAs might function as a tumor surveillance mechanism exerting continuous inhibition on tumor formation. The microRNA-mediated tumor surveillance might complement cancer immune surveillance. PMID- 25037160 TI - Hylomorphism and the metabolic closure conception of life. AB - This paper examines three exemplary theories of living organization with respect to their common feature of defining life in terms of metabolic closure: autopoiesis, (M, R) systems, and chemoton theory. Metabolic closure is broadly understood to denote the property of organized chemical systems that each component necessary for the maintenance of the system is produced from within the system itself, except for an input of energy. It is argued that two of the theories considered--autopoiesis and (M, R) systems--participate in a hylomorphist pattern of thinking which separates the "form" of the living system from its "matter." The analysis and critique of hylomorphism found in the work of the philosopher Gilbert Simondon is then applied to these two theories, and on the basis of this critique it is argued that the chemoton model offers a superior theory of minimal life which overcomes many of the problems associated with the other two. Throughout, the relationship between hylomorphism and the understanding of living things as machines is explored. The paper concludes by considering how hylomorphism as a background ontology for theories of life fundamentally influences the way life is defined. PMID- 25037159 TI - Population dynamics and growth rates of endosymbionts during Diaphorina citri (Hemiptera, Liviidae) ontogeny. AB - The infection density of symbionts is among the major parameters to understand their biological effects in host-endosymbionts interactions. Diaphorina citri harbors two bacteriome-associated bacterial endosymbionts (Candidatus Carsonella ruddii and Candidatus Profftella armatura), besides the intracellular reproductive parasite Wolbachia. In this study, the density dynamics of the three endosymbionts associated with the psyllid D. citri was investigated by real-time quantitative PCR (qPCR) at different developmental stages. Bacterial density was estimated by assessing the copy number of the 16S rRNA gene for Carsonella and Profftella, and of the ftsZ gene for Wolbachia. Analysis revealed a continuous growth of the symbionts during host development. Symbiont growth and rate curves were estimated by the Gompertz equation, which indicated a negative correlation between the degree of symbiont-host specialization and the time to achieve the maximum growth rate (t*). Carsonella densities were significantly lower than those of Profftella at all host developmental stages analyzed, even though they both displayed a similar trend. The growth rates of Wolbachia were similar to those of Carsonella, but Wolbachia was not as abundant. Adult males displayed higher symbiont densities than females. However, females showed a much more pronounced increase in symbiont density as they aged if compared to males, regardless of the incorporation of symbionts into female oocytes and egg laying. The increased density of endosymbionts in aged adults differs from the usual decrease observed during host aging in other insect-symbiont systems. PMID- 25037161 TI - Risk factors for and pre-medications to prevent cetuximab-induced infusion reactions in patients with squamous cell carcinoma of the head and neck. AB - OBJECTIVES: Cetuximab, a chimeric monoclonal antibody, is the only targeted therapy approved for squamous cell carcinoma of the head and neck (SCCHN). Infusion reactions (IRs) occur in 6-18% of patients pre-medicated with diphenhydramine. Evidence for clinical risk factors for IRs is limited and the benefit of additional pre-medication to prevent IRs is unclear. MATERIALS AND METHODS: A retrospective, single institution study of 243 SCCHN patients treated with cetuximab to evaluate potential risk factors for IRs and to assess the efficacy of additional pre-medications (nebulized albuterol and intravenous (IV) corticosteroids and/or H2-blockers) to decrease the risk of IR. RESULTS: IR (grades 1-4) and high grade (grades 3-4 only) IR occurred in 47 (19.3%) and 16 (6.6%) patients, respectively. Multivariate analysis identified Caucasian race (OR7.11, p=0.003), medication allergy (OR3.74, p=0.002), and blood eosinophils >3% (OR2.75, p=0.01) independently increased the risk of IR; Caucasian race (OR5.57, p=0.007) and medication allergy (OR4.10, p=0.0007) increased the risk of high grade IR. IR (grades 1-4) and high grade IR occurred in 31.8% and 22.7% pre medicated with diphenhydramine alone. Univariate analysis identified albuterol, famotidine, and corticosteroids decreased the risk of high grade IR. Furthermore, there was a significant difference between the possible combinations of the pre medications and the risk of high grade IR by Fisher Exact test (p=0.003) whereby the combination of albuterol, famotidine and corticosteroids was effective in preventing high grade IR. Thirty (64%) of the 47 patients who developed an IR were re-challenged and did not experience a recurrence of an IR. CONCLUSION: These data may be used to identify patients at higher risk for cetuximab-induced IR who may be advised to not receive cetuximab or who may benefit from additional pre-medications to decrease the risk of a high grade IR. PMID- 25037158 TI - Metabolic circuits in neural stem cells. AB - Metabolic activity indicative of cellular demand is emerging as a key player in cell fate decision. Numerous studies have demonstrated that diverse metabolic pathways have a critical role in the control of the proliferation, differentiation and quiescence of stem cells. The identification of neural stem/progenitor cells (NSPCs) and the characterization of their development and fate decision process have provided insight into the regenerative potential of the adult brain. As a result, the potential of NSPCs in cell replacement therapies for neurological diseases is rapidly growing. The aim of this review is to discuss the recent findings on the crosstalk among key regulators of NSPC development and the metabolic regulation crucial for the function and cell fate decisions of NSPCs. Fundamental understanding of the metabolic circuits in NSPCs may help to provide novel approaches for reactivating neurogenesis to treat degenerative brain conditions and cognitive decline. PMID- 25037162 TI - Assessment of the sensitivity and specificity of tissue-specific-based and anatomical-based optical biomarkers for rapid detection of human head and neck squamous cell carcinoma. AB - OBJECTIVES: We propose the use of morphological optical biomarkers for rapid detection of human head and neck squamous cell carcinoma (HNSCC) by leveraging the underlying tissue characteristics in aerodigestive tracts. MATERIALS AND METHODS: Diffuse reflectance spectra were obtained from malignant and contra lateral normal tissues of 57 patients undergoing panendoscopy and biopsy. Oxygen saturation, total hemoglobin concentration, and the reduced scattering coefficient were extracted. Differences in malignant and normal tissues were examined based on two different groupings: anatomical site and morphological tissue type. RESULTS AND CONCLUSIONS: Measurements were acquired from 252 sites, of which 51 were pathologically classified as SCC. Optical biomarkers exhibited statistical differences between malignant and normal samples. Contrast was enhanced when parsing tissues by morphological classification rather than anatomical subtype for unpaired comparisons. Corresponding linear discriminant models using multiple optical biomarkers showed improved predictive ability when accounting for morphological classification, particularly in node-positive lesions. The false-positive rate was retrospectively found to decrease by 34.2% in morphologically- vs. anatomically-derived predictive models. In glottic tissue, the surgeon exhibited a false-positive rate of 45.7% while the device showed a lower false-positive rate of 12.4%. Additionally, comparisons of optical parameters were made to further understand the physiology of tumor staging and potential causes of high surgeon false-positive rates. Optical spectroscopy is a user-friendly, non-invasive tool capable of providing quantitative information to discriminate malignant from normal head and neck tissues. Predictive models demonstrated promising results for real-time diagnostics. Furthermore, the strategy described appears to be well suited to reduce the clinical false positive rate. PMID- 25037163 TI - Characterization of a dual-active enzyme, DcpA, involved in cyclic diguanosine monophosphate turnover in Mycobacterium smegmatis. AB - We have reported previously that the long-term survival of Mycobacterium smegmatis is facilitated by a dual-active enzyme MSDGC-1 (renamed DcpA), which controls the cellular turnover of cyclic diguanosine monophosphate (c-di-GMP). Most mycobacterial species possess at least a single copy of a DcpA orthologue that is highly conserved in terms of sequence similarity and domain architecture. Here, we show that DcpA exists in monomeric and dimeric forms. The dimerization of DcpA is due to non-covalent interactions between two protomers that are arranged in a parallel orientation. The dimer shows both synthesis and hydrolysis activities, whereas the monomer shows only hydrolysis activity. In addition, we have shown that DcpA is associated with the cytoplasmic membrane and exhibits heterogeneous cellular localization with a predominance at the cell poles. Finally, we have also shown that DcpA is involved in the change in cell length and colony morphology of M. smegmatis. Taken together, our study provides additional evidence about the role of the bifunctional protein involved in c-di GMP signalling in M. smegmatis. PMID- 25037164 TI - Expression levels of transcription factors in Escherichia coli: growth phase- and growth condition-dependent variation of 90 regulators from six families. AB - The expression pattern of the genome in Escherichia coli is controlled by regulating the utilization of a limited number of RNA polymerases between a total of 4600 genes on its genome. The distribution pattern of RNA polymerase on the genome changes after two steps of protein-protein interaction with seven sigma subunits and about 300 transcription factors (TFs). Based on a systematic search for the regulation target promoters recognized by each TF, we propose two novel concepts: each TF regulates a number of target promoters; and each promoter is regulated by many TFs. In parallel, attempts have been made to determine the intracellular concentrations of all TFs using two systems: quantitative immunoblot analysis using TF-specific antibodies; and reporter assay of TF promoter activities. The direct measurement of TF protein level has so far been published for a set of 60 regulators with known functions. This study describes the determination of growth phase-dependent expression levels of 90 TFs using the reporter assay system. The translational fusion vector was constructed from the TF promoter sequence including an N-terminal proximal TF segment and the reporter GFP. At the beginning of cell growth, high-level expression was observed only for a small number of TFs. In the exponential phase, approximately 80 % TFs are expressed, but the expressed TF species change upon transfer to the stationary phase. Significant changes in the pattern of TF expression were observed between aerobic and anaerobic conditions. The list of intracellular levels of TFs provides further understanding to the transcription regulation of the E. coli genome under various stressful conditions. PMID- 25037165 TI - Outpatient follow-up appointments for patients having curative treatment for cancer of the head and neck: are the current arrangements in need of change? AB - Although there are recommendations, there is little evidence about the rationale for the frequency and duration of review appointments for patients with cancer of the head and neck. We have recorded the pattern of follow-up in a tertiary cancer centre and its association with survival and recurrent disease. We used clinical letters and a prospectively maintained database to obtain details on 297 patients who were treated curatively for squamous cell carcinoma (SCC) of the oral cavity between 2005 and 2008. Mean (SD) age was 63 (12) years and 58% (n = 171) were male. Most patients were seen about 6 times in year one, 3 times in year 2, twice in year 3, twice in year 4, once or twice in year 5, and once yearly beyond year 5. Fewer clinics were scheduled for and attended by patients over 75 years of age, those with overall clinical grades 0-1, and those treated by operation alone in contrast to those who also had adjuvant radiotherapy. Patients were usually seen about 15 times over the 5 years. Taking into account the stage of the tumour and overall mortality, the number and timing of follow-up visits is adequate for the needs of patients with stage II-IV disease. Those with stage I disease may be considered for discharge after the third year if they are told about the risk factors, and signs and symptoms of recurrent disease, and surveillance in primary care. PMID- 25037166 TI - Astrocyte glycogen as an emergency fuel under conditions of glucose deprivation or intense neural activity. AB - Energy metabolism in the brain is a complex process that is incompletely understood. Although glucose is agreed as the main energy support of the brain, the role of glucose is not clear, which has led to controversies that can be summarized as follows: the fate of glucose, once it enters the brain is unclear. It is not known the form in which glucose enters the cells (neurons and glia) within the brain, nor the degree of metabolic shuttling of glucose derived metabolites between cells, with a key limitation in our knowledge being the extent of oxidative metabolism, and how increased tissue activity alters this. Glycogen is present within the brain and is derived from glucose. Glycogen is stored in astrocytes and acts to provide short-term delivery of substrates to neural elements, although it may also contribute an important component to astrocyte metabolism. The roles played by glycogen awaits further study, but to date its most important role is in supporting neural elements during increased firing activity, where signaling molecules, proposed to be elevated interstitial K(+), indicative of elevated neural firing rates, activate glycogen phosphorylase leading to increased production of glycogen derived substrate. PMID- 25037168 TI - What is the impact of using outdoor spaces such as gardens on the physical and mental well-being of those with dementia? A systematic review of quantitative and qualitative evidence. AB - OBJECTIVE: To examine the impact of gardens and outdoor spaces on the mental and physical well-being of people with dementia who are resident in care homes and understand the views of people with dementia, their carers, and care home staff on the value of gardens and outdoor spaces. DESIGN: Systematic review. METHODS: Fourteen databases were searched from inception to February 2013. Forward and backward citation chasing of included articles was conducted; 38 relevant organizations were contacted to identify unpublished reports. Titles, abstracts, and full texts were screened independently by 2 reviewers in a 2-stage process and were discussed with a third reviewer where necessary. Results were synthesized narratively. RESULTS: Seventeen studies were included: 9 quantitative, 7 qualitative, and 1 mixed methods. The quantitative studies were of poor quality but suggested decreased levels of agitation were associated with garden use. The views and experiences of the garden are discussed in relation to themes of how the garden was used, nature of interactions, impact/effect of the gardens, mechanisms/how the garden was thought to have an effect, and negatives (such as perception of the garden as a hazard and the limited staff time). CONCLUSION: There are promising impacts on levels of agitation in care home residents with dementia who spend time in a garden. Future research would benefit from a focus on key outcomes measured in comparable ways with a separate focus on what lies behind limited accessibility to gardens within the residential care setting. PMID- 25037169 TI - Risk of dementia among patients with asthma: a nationwide longitudinal study. AB - BACKGROUND: Previous studies have suggested an association between asthma and dementia, but the results are still inconsistent. METHODS: Using the Taiwan National Health Insurance Database, we enrolled 11,030 participants aged more than 45 years with asthma and 44,120 (1:4) age-/sex-matched controls between 1998 and 2008, and followed them to the end of 2011. Cases of any dementia or Alzheimer's disease that developed during the follow-up period were identified. RESULTS: Asthma was associated with an increased risk of developing any dementia [hazard ratio (HR): 2.17, 95% confidence interval (CI): 1.87-2.52] and Alzheimer's disease (HR: 2.62, 95% CI: 1.71-4.02). Stratified by age, both asthma in midlife (>45 years and <65 years) and in late life (>=65 years) was associated with a greater likelihood of any dementia (HR: 2.48, 95% CI: 1.80-3.41; HR: 2.06, 95% CI: 1.74-2.44). DISCUSSION: Asthma in midlife and in late life increased the risk of developing any dementia and Alzheimer's disease. The underlying mechanisms between asthma and dementia require further investigation. PMID- 25037167 TI - Bacopa monniera ameliorates cognitive impairment and neurodegeneration induced by intracerebroventricular-streptozotocin in rat: behavioral, biochemical, immunohistochemical and histopathological evidences. AB - The standardized extract of Bacopa monniera (BM) is a complex mixture of ingredients with a uniquely wide spectrum of neuropharmacological influences upon the central nervous system including enhanced learning and memory with known antioxidant potential and protection of the brain from oxidative damage. The present study demonstrates the therapeutic efficacy of BM on cognitive impairment and oxidative damage, induced by intracerebroventricular injection of streptozotocin (ICV-STZ) in rat models. Male Wistar rats were pre-treated with BM at a selected dose (30 mg/Kg) given orally for 2 weeks and then were injected bilaterally with ICV-STZ (3 mg/Kg), while sham operated rats were received the same volume of vehicle. Behavioral parameters were subsequently monitored 2 weeks after the surgery using the Morris water maze (MWM) navigation task then were sacrificed for biochemical, immunohistochemical (Cu/Zn-SOD) and histopathological assays. ICV-STZ-infused rats showed significant loss in learning and memory ability, which were significantly improved by BM supplementation. A significant increase in thiobarbituric acid reactive species and a significant decrease in reduced glutathione, antioxidant enzymes in the hippocampus were observed in ICV STZ rats. Moreover, decrease in Cu/Zn-SOD expression positive cells were observed in the hippocampus of ICV-STZ rats. BM supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. The data suggest that ICV-STZ might cause its neurotoxic effects via the production of free radicals. Our study demonstrates that BM is a powerful antioxidant which prevents cognitive impairment, oxidative damage, and morphological changes in the ICV-STZ-infused rats. Thus, BM may have therapeutic value for the treatment of cognitive impairment. PMID- 25037170 TI - Nursing assistants and quality nursing home care. PMID- 25037171 TI - [Pediatric surgical psychoprophylaxis: a benefit in the quality of care of our youngest patients]. PMID- 25037172 TI - Italian translation, cultural adaptation and validation of the PedsQLTM 3.0 Diabetes Module questionnaire in children with type 1 diabetes and their parents. AB - BACKGROUND: The PedsQLTM3.0 Diabetes Module is a widely used instrument to measure the disease-specific health-related quality of life summary measures in children and adolescents with type 1 diabetes. After cultural adaptation, we confirmed reliability and validity of PedsQLTM3.0 Diabetes Module in its Italian version. METHODS: Participants were 169 Italian children and adolescents with type 1 diabetes aged 5-18 years and 100 parents. Reliability was determined by internal consistency using Cronbach's coefficient alpha, and test-retest reliability by intra-class correlation coefficient (ICC). Validity was assessed through factor validity examined by exploratory factor analysis, and discriminant validity examined through multitrait/multi-item scaling analysis. Discriminant validity with respect to dichotomous patients' characteristics at baseline was also examined through a multivariate analysis on the summary measures using the Wilks' Lambda test. RESULTS: Data completeness was optimal. Item internal consistency was satisfied at 89% for the child self-report scales and at 100% for the parents' proxy-report scales. Most diabetes module scales was acceptable for group comparisons. Discriminant validity was satisfied for 71% of children and adolescents and for 82% of parents. A >=70% Cronbach's alpha coefficient was found for the summary measures of both reports. For the test-retest reliability, the ICC coefficients ranged from 0.66 (i.e., the Worry scale) to 0.82 for the other scales of the child self-report. The ICC coefficients were >=0.87 for all the parents' proxy-report scales. Factor analysis showed that the PedsQLTM3.0 Diabetes Module for child self-report could be summarized in 10 components, which explained the 62% of the variance. For the parent proxy-report the statistical analysis selected 9 factors, which explained about 68% of variance. The external discriminant validity of the PedsQLTM3.0 Diabetes Module summary measures were compared across gender, age, time since diagnosis and HbA1c mean cut off values. Significant differences in the "Treatment adherence" scale and in the "Communication" scale were observed across age, and by time since diagnosis. CONCLUSIONS: The results show the reliability and validity of the Italian translation of the PedsQLTM3.0 Diabetes Module, supporting therefore its use as an outcome measure for diabetes cross-national clinical trials and research. PMID- 25037173 TI - Usability testing of an online self-management program for adolescents with cancer. AB - The objective of this study was to explore the usability of a bilingual (English and French) Internet-based self-management program for adolescents with cancer and their parents and refine the Internet program. A qualitative study design with semistructured, audio-taped interviews and observation was undertaken with 4 iterative cycles. A purposive sample of English-speaking and French-speaking adolescents with cancer and one of their parents/caregivers was recruited. Adolescents and parents provided similar feedback on how to improve the usability of the Internet program. Most changes to the website were completed after the initial cycles of English and French testing. Both groups also found information presented on the website to be appropriate, credible, and relevant to their experiences of going through cancer. Participants reported the program would have been extremely helpful when they were first diagnosed with cancer. Usability testing uncovered some issues that affected the usability of the website that led to refinements in the online program. PMID- 25037174 TI - Best practice for fever management with intravenous acetaminophen in pediatric oncology. AB - Intravenous (IV) acetaminophen was introduced in the United States in 2011 for use as an analgesic and antipyretic agent. While no studies have looked at its utilization specifically in the pediatric oncology population, existing literature suggests IV acetaminophen is safe and effective to use in both children and adults. This article aims to review and apply current data in evaluating whether or not children with cancer can safely benefit from its use. This article provides clinical indications, safety and efficacy profiles, and nursing implications along with recommendations for future study regarding the use of IV acetaminophen in this population. PMID- 25037175 TI - Association of IL-12A and IL-12B polymorphisms with Alzheimer's disease susceptibility in a Han Chinese population. AB - As a pro-inflammatory cytokine belonging to the interleukin (IL)-1 family, IL-12 is recently found to be involved in the pathogenesis of Alzheimer's disease (AD). Here, we investigated the relations of three potentially functional single nucleotide polymorphisms (SNPs) in IL-12A (rs2243115 and rs568408) and IL-12B (rs3212227) with late-onset AD (LOAD) risk in a Northern Han Chinese cohort containing 1133 patients and 1158 healthy controls. Our findings indicated that these SNPs in IL-12A and IL-12B can individually and jointly contribute to LOAD risk in Han Chinese, implying that the genes encoding IL-12 subunits represent novel genetic risk factors for LOAD susceptibility. PMID- 25037176 TI - Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general. AB - Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n=3876). Specific KIR ligands were associated with patients when compared to controls (n=3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated. PMID- 25037177 TI - Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis. AB - Methylprednisolone (MP) pulses are the mainstay for relapse therapy in multiple sclerosis (MS). To improve the efficacy of treatment and reduce the side effects of MP, a long circulating brain-targeted formulation was developed; glutathione polyethylene glycol (PEG)ylated liposomal MP (2B3-201). Here we investigate the efficacy of 2B3-201 in murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of MS. After disease onset, mice were randomized to receive either saline, three injections of free MP (high dose MP, 100mg/kg i.v.), two injections of free MP (low dose MP, 10mg/kg; i.v.), or two injections of 2B3-201 (10mg/kg i.v.). Treatment with a low dose of 2B3-201 significantly reduced the severity of EAE as compared to saline control, similar to treatment with high dose free MP, while a low dose of free MP was not effective. In a histological analysis of the spinal cord, treatment with 2B3-201 significantly decreased T cell as well as macrophage/microglia infiltration in the CNS by about 50%. Moreover, application of a low dose of 2B3-201 or a high dose of free MP reduced the amount of astrocyte activation as well as the extent of axonal loss and also demyelination in spinal cord lesions as compared to low dose MP or sham treatment. In summary, in the murine MOG-EAE model of MS, a glutathione PEGylated liposomal formulation of MP (2B3-201) is clinically and histologically as effective as free MP at one tenth of the dosage as well as at a lower application frequency and clearly more effective than the same dosage of free MP. These positive proof-of-concept efficacy studies warrant further development of 2B3-201 for the treatment of neuroinflammatory conditions such as MS. PMID- 25037178 TI - Epidemiology of HBV subgenotypes D. AB - The natural history of hepatitis B virus infection is not uniform and affected from several factors including, HBV genotype. Genotype D is a widely distributed genotype. Among genotype D, several subgenotypes differentiate epidemiologically and probably clinically. D1 is predominant in Middle East and North Africa, and characterized by early HBeAg seroconversion and low viral load. D2 is seen in Albania, Turkey, Brazil, western India, Lebanon, and Serbia. D3 was reported from Serbia, western India, and Indonesia. It is a predominant subgenotype in injection drug use-related acute HBV infections in Europe and Canada. D4 is relatively rare and reported from Haiti, Russia and Baltic region, Brazil, Kenya, Morocco and Rwanda. Subgenotype D5 seems to be common in Eastern India. D6 has been reported as a rare subgenotype from Indonesia, Kenya, Russia and Baltic region. D7 is the main genotype in Morocco and Tunisia. D8 and D9 are recently described subgenotypes and reported from Niger and India, respectively. Subgenotypes of genotype D may have clinical and/or viral differences. More subgenotype studies are required to conclude on subgenotype and its clinical/viral characteristics. PMID- 25037179 TI - Imaging modalities for the diagnosis of hepatic fibrosis and cirrhosis. AB - Non-invasive methods for liver fibrosis diagnosis are now commonly used as first intention tests for liver fibrosis diagnosis in chronic liver diseases. Even morphological parameters provided by ultrasound is now challenged by blood fibrosis tests and transient elastography, in experienced hands, it performed well and in certain situations, imaging can still be useful to detect patients with fibrosis. In parallel, to ultrasound and Doppler imaging, various methodologies have been explored. Some of them remain confined to clinical research for the moment, as perfusion, MR diffusion-weighted imaging, intravoxel incoherent motion or acoustic structure quantification; others have already taken a place in clinical practice. Regarding fast growing of new technology some methods may become available for daily practice in the near future. Ultrasound tools or automated quantification of different physical parameters of imaging data could provide an opportunity for early diagnosis of liver diseases; MRI techniques could lead to the development of a "global" liver examination. PMID- 25037180 TI - Oral facial jaw mouth cosmetic implant surgeons--what's in a name? PMID- 25037181 TI - Beware of "black swans" and "perfect storms:" the principle of plenitude and office-based anesthesia. AB - A paradigm shift in the training, practice, and study of office-based anesthesia is necessary for our specialty. Practice improvement plans are required to prevent low-probability-high-consequence anesthesia mishaps in our offices. A scarcity of statistical data exists regarding the true risk of office-based anesthesia in oral and maxillofacial surgery. Effective proactive risk management mandates accurate data to correctly outline the problem before solutions can be implemented. Only by learning from our mistakes, will we be able to reduce errors and improve patient safety: "The only real mistake is the one from which we learn nothing"--John Powell. PMID- 25037182 TI - Effect of platelet-rich fibrin on frequency of alveolar osteitis following mandibular third molar surgery: a double-blinded randomized clinical trial. AB - PURPOSE: To evaluate the effectiveness of platelet-rich fibrin (PRF) in preventing the development of alveolar osteitis (AO). MATERIALS AND METHODS: In a double-blinded study, patients with bilateral impacted mandibular third molars underwent surgical extractions, with one socket receiving PRF and the other one serving as a control. The surgeon and patient were unaware of the study or control side. The predictor variable was the PRF application and was categorized as PRF and non-PRF. The outcome variable was the development of AO during the first postoperative week. Other study variables included age, gender, smoking status, irrigation volume, extraction difficulty, surgeon experience, and number of anesthetic cartridges. Data were analyzed using chi(2) and t tests, with the significance level set at a P value less than .05. RESULTS: Seventy-eight patients (mean age, 25 yr) underwent 156 impacted third molar surgeries. The overall frequency of AO was 14.74% for all surgeries. The frequency of AO in the PRF group was significantly lower than in the non-PRF group (odds ratio = 0.44; P < .05). CONCLUSION: Based on the results of the present study, PRF application may decrease the risk of AO development after mandibular third molar surgery. PMID- 25037183 TI - Does ultrasonic resorbable pin fixation offer predictable results for augmentation eminoplasty in recurrent dislocations? AB - PURPOSE: To assess the outcome of interpositional calvarial block grafting fixed with an ultrasonic resorbable system (SonicWeld, KLS Martin, Muhlheim, Germany) for augmentation eminoplasty in chronic recurrent condylar dislocations. PATIENTS AND METHODS: We designed and implemented a retrospective cohort study. Eight female patients (mean age 48 years) were treated. The primary predictor variable was time (preoperative vs postoperative). The primary outcome variable was cessation of dislocation. The secondary outcome variables were the height of the articular eminences (HAE), maximum interincisal opening, pain score (visual analog scale [VAS]), postoperative magnetic resonance imaging (MRI) findings, and facial nerve paralysis. RESULTS: All 8 patients had been experiencing recurrent dislocations a mean of 10 times each month preoperatively. None of the patients had experienced a dislocation at 2 years postoperatively. The preoperative mean HAE was 5.75 and the VAS score for pain was 72.5. The mean vertical HAE was 15.75 mm, and the mean VAS score for pain was 11.2 at 12 months postoperatively. Complete resorption of the SonicWeld pins was observed on the first year follow up computed tomography scans. Of the 8 patients, 3 presented with disc displacement without reduction and 2 with disc displacement with reduction on the postoperative MRI scan, and none of the patients had a facial nerve deficit at 24 months of follow-up. CONCLUSIONS: Fixation of cortical calvarial grafts using the ultrasonic resorbable system for augmentation eminoplasty provided sufficient stabilization and favorable outcomes. Degradation of the osteosynthesis material and the absence of intermaxillary fixation were the most advantageous parts of the technique. PMID- 25037184 TI - Loading of titanium implants with hydrophilic endosteal surface 3 weeks after insertion: clinical and radiological outcome of a 12-month prospective clinical trial. AB - PURPOSE: The aim of this study was to test whether early loading (21 days after insertion) of implants with a hydrophilic surface is safe and reliable in a general clinical practice setting. PATIENTS AND METHODS: This was a prospective multicenter clinical trial conducted in 3 independent surgical practices. Patients were selected according to predefined inclusion and exclusion criteria. Implants were placed in posterior regions into healed alveoli and native bone using a 1-stage (unsubmerged) surgical protocol. Loading was to be performed 21 days thereafter. Patients were followed clinically and radiographically for 1 year. RESULTS: Twenty-one patients who received 23 implants were followed for 1 year. None of the osseointegrated implants were lost. One broken provisional crown was reported during the trial period. The crestal bone remained remarkably stable (ie, approximately 1 mm below the microgap). The most coronal bone-to implant contact stabilized at the level of the first implant thread just beneath the machined collar. CONCLUSION: Within the limitations of this clinical study, the authors confirmed that loading of implants with a hydrophilic surface 3 weeks after placement appears to be a safe and predictable treatment option. No crestal bone loss was observed 1 year after implant placement. Therefore, it appears that crestal bone loss is dependent on the design features of the specific implant line. PMID- 25037185 TI - Oral health-related quality of life of patients with oral lichen planus, oral leukoplakia, or oral squamous cell carcinoma. AB - PURPOSE: To compare oral health-related quality of life (OHRQoL) of patients with oral lichen planus (OLP), oral leukoplakia (OL), or oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Seventy-three patients with OLP, 44 with OL, and 37 with OSCC participated in this prospective study. The German version of the 14 item Oral Health Impact Profile (OHIP-G 14) was used to measure OHRQoL. Descriptive statistics and multivariate analysis of clinical forms, age, gender, alcohol consumption, and smoking habits were evaluated. RESULTS: No association to cumulative OHIP-14 score (P = .086) among the 3 groups was found. However, patients with OLP showed a higher "physical pain" score and a lower "social disability" score (P = .026) than patients with OSCC, followed by patients with OL. Women with OLP had a lower OHRQoL than men. After differentiation of clinical forms of OLP (symptomatic vs asymptomatic), an impact on these patients' OHRQoL in the dimensions "physical pain" and "physical disability" was found. CONCLUSION: Patients with OLP or OSCC and high OHIP-G 14 scores reported physical pain, which emphasizes the need for physical therapy. For improved OHRQoL, patients with symptomatic forms of OLP would gain more from a treatment compared with those with asymptomatic forms. In contrast, patients with asymptomatic OLP or OL and thus with a minimal impact on their OHRQoL might be at risk of delayed consultation, diagnosis, and treatment of their condition. PMID- 25037186 TI - Are all soft tissue calcifications detected by cone-beam computed tomography in the submandibular region sialoliths? AB - Heterotrophic soft tissue calcification occurs with the deposit of calcium salts in soft tissue rather than bone. The aim of this report is to describe cone-beam computed tomographic (CBCT) and ultrasonographic (US) findings of 2 cases of soft tissue calcifications that were initially diagnosed as submandibular or parotid sialolithiasis. Multiple soft tissue calcifications were evaluated by panoramic radiography, CBCT imaging, and US imaging in a 50-year-old male patient and a 30 year-old male patient. Calcifications were detected in the soft tissue of the submandibular area at axial, coronal, and multiplanar reformatted examinations and were prediagnosed as sialolithiasis. US examination was conducted to determine the complete relation between the soft tissues and the calcifications. In conclusion, high-resolution dental volumetric tomography with a low radiation dose is the optimal diagnostic tool to analyze the skeletal structure of the maxillofacial region in 3 dimensions. However, it is not sufficient to examine the soft tissues. US imaging is a useful diagnostic tool to evaluate the relation between the soft tissues and the calcifications in the submandibular area. PMID- 25037187 TI - Rheumatoid nodule in the lower lip of a patient with rheumatoid arthritis: a novel case report and review of literature. AB - PURPOSE: Rheumatoid nodules are a well-characterized common extra-articular manifestation of rheumatoid arthritis. However, the occurrence of a rheumatoid nodule in the oral mucosa is extremely rare. PATIENTS AND METHODS: We present the case of a rheumatoid nodule in the lower lip, which rarely presents with variations in the clinical manifestation, that occurred in a 48-year-old female patient with rheumatoid arthritis. The nodule was totally excised under the clinical diagnosis of either a fibroma or salivary gland lesion. RESULTS: On histopathologic examination, within the deep mucosa, a necrobiotic nodule surrounded by elongated histiocytic cells with a focal palisaded arrangement. The lesion was diagnosed postoperatively as a rheumatoid nodule from the histopathologic and clinical findings. CONCLUSIONS: Few studies have been performed of oral rheumatoid lesions; however, a review of the published data showed that this is the first case of a rheumatoid nodule in the lower lip of a patient with rheumatoid arthritis. PMID- 25037188 TI - A modified lateral canthal approach for the treatment of zygomatic complex fractures. AB - We present a modification of the classic lateral canthal approach by means of which the anatomy of the lateral palpebral edges will remain unscathed, with the incision beginning 2 mm lateral to the external canthus. We have used this technique in 76 patients at 3 major trauma centers in Bogota, Colombia, from January 2006 to January 2012. The approach provided excellent access to the frontozygomatic area, lateral wall of the orbit, and malar body. This method avoids important anatomic structures and offers outstanding cosmetic results, especially in adult patients. PMID- 25037189 TI - Abnormal fibre usage in UC in remission. AB - OBJECTIVE: Colonic fermentation in patients with UC in remission was compared with that in matched healthy subjects on habitual diets and when dietary fibre was increased. DESIGN: Fibre intake, faecal output of fibre (measured as non starch polysaccharide (NSP)), starch, microbiota and fermentation products, and whole gut transit time (WGTT) were assessed in association with habitual diet and when dietary intake of wheat bran (WB)-associated fibre and high amylose associated resistant starch (RS) was increased in an 8-week, randomised, single blind, cross-over study. RESULTS: Despite a tendency to lower habitual fibre intake in UC patients, faecal NSP and starch concentrations were threefold higher than in controls, whereas concentrations of phenols and short-chain fatty acids, pH and WGTT were similar. Increasing RS/WB intake was well tolerated. In controls (n=10), it more than doubled faecal NSP and starch excretion (p=0.002 for both), had no effect on NSP usage and reduced WGTT (p=0.024). In UC patients (n=19), high intake of RS/WB tended to normalise gut transit, but did not increase the proportion of NSP fermented. Increasing intake of RS/WB had little effect on faecal fermentation patterns or the structure of the microbiota. However, faeces from the UC cohort had lower proportions of Akkermansia muciniphila and increased diversity within Clostridium cluster XIVa compared to controls. CONCLUSIONS: Gut fermentation of NSP and starch is diminished in patients with UC. This cannot be explained by abnormal gut transit and was not corrected by increasing RS/WB intake, and may be due to abnormal functioning of the gut microbiota. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12614000271606. PMID- 25037190 TI - Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice. AB - OBJECTIVE: Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis. DESIGN: Mnk1 expression was analysed using immunohistochemistry, RT qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1(-/-) mice by 7 h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI. RESULTS: Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1(-/-) mice is histologically normal. Digestive enzyme content is significantly increased and c Myc and Ccnd1 levels are reduced in Mnk1(-/-) mice. Upon induction of acute pancreatitis, Mnk1(-/-) mice show impaired eIF4E phosphorylation, activation of c Myc and downregulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo. CONCLUSIONS: Mnk1 is a novel pancreatic acinar cell-specific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis. PMID- 25037191 TI - Surveillance in patients with long-segment Barrett's oesophagus: a cost effectiveness analysis. AB - OBJECTIVE: Surveillance is recommended for Barrett's oesophagus (BO) to detect early oesophageal adenocarcinoma (OAC). The aim of this study was to evaluate the cost-effectiveness of surveillance. DESIGN: We included 714 patients with long segment BO in a multicentre prospective cohort study and used a multistate Markov model to calculate progression rates from no dysplasia (ND) to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and OAC. Progression rates were incorporated in a decision-analytic model, including costs and quality of life data. We evaluated different surveillance intervals for ND and LGD, endoscopic mucosal resection (EMR), radiofrequency ablation (RFA) and oesophagectomy for HGD or early OAC and oesophagectomy for advanced OAC. The incremental cost effectiveness ratio (ICER) was calculated in costs per quality-adjusted life-year (QALY). RESULTS: The annual progression rate was 2% for ND to LGD, 4% for LGD to HGD or early OAC and 25% for HGD or early OAC to advanced OAC. Surveillance every 5 or 4 years with RFA for HGD or early OAC and oesophagectomy for advanced OAC had ICERs of ?5.283 and ?62.619 per QALY for ND. Surveillance every five to one year had ICERs of ?4.922, ?30.067, ?32.531, ?41.499 and ?75.601 per QALY for LGD. EMR prior to RFA was slightly more expensive, but important for tumour staging. CONCLUSIONS: Based on a Dutch healthcare perspective and assuming a willingness to-pay threshold of ?35.000 per QALY, surveillance with EMR and RFA for HGD or early OAC, and oesophagectomy for advanced OAC is cost-effective every 5 years for ND and every 3 years for LGD. PMID- 25037192 TI - Raman spectroscopy as a promising tool for noninvasive point-of-care glucose monitoring. AB - Self-monitoring of glucose is important for managing diabetes. Noninvasive glucose monitors are not yet available, but patients would benefit highly from such a device. We present results that may lead to a novel, point-of-care noninvasive system to measure blood glucose based on Raman spectroscopy. A hospitalized cohort of 111 subjects was measured using a custom-made Raman spectrometer system. Blood glucose reference samples were used to correlate Raman data to glucose levels, using advanced preprocessing and analysis algorithms. A correlation coefficient (R (2)) of .83 was found correlating independent Raman based predictions on reference blood glucose for the full cohort. Stratification of the cohort in gender-specific groups raised correlation levels to .88 (females) and .94 (males). Glucose could be measured noninvasively with average errors as low as 0.9 mM. We conclude that this novel system shows promising results for the advance of noninvasive, point-of-care glucose monitoring. PMID- 25037193 TI - Acute versus chronic injury in error grids. PMID- 25037194 TI - Characterizing accuracy and precision of glucose sensors and meters. AB - There is need for a method to describe precision and accuracy of glucose measurement as a smooth continuous function of glucose level rather than as a step function for a few discrete ranges of glucose. We propose and illustrate a method to generate a "Glucose Precision Profile" showing absolute relative deviation (ARD) and /or %CV versus glucose level to better characterize measurement errors at any glucose level. We examine the relationship between glucose measured by test and comparator methods using linear regression. We examine bias by plotting deviation = (test - comparator method) versus glucose level. We compute the deviation, absolute deviation (AD), ARD, and standard deviation (SD) for each data pair. We utilize curve smoothing procedures to minimize the effects of random sampling variability to facilitate identification and display of the underlying relationships between ARD or %CV and glucose level. AD, ARD, SD, and %CV display smooth continuous relationships versus glucose level. Estimates of MARD and %CV are subject to relatively large errors in the hypoglycemic range due in part to a markedly nonlinear relationship with glucose level and in part to the limited number of observations in the hypoglycemic range. The curvilinear relationships of ARD and %CV versus glucose level are helpful when characterizing and comparing the precision and accuracy of glucose sensors and meters. PMID- 25037195 TI - Improvement in quality of life after catheter ablation for paroxysmal versus long standing persistent atrial fibrillation: a prospective study with 3-year follow up. AB - BACKGROUND: Changes in quality of life (QoL) after catheter ablation for long standing persistent atrial fibrillation (LSPAF) are not well described. We sought to compare QoL improvement after catheter ablation of paroxysmal atrial fibrillation (PAF) versus that after LSPAF. METHODS AND RESULTS: A total of 261 PAF and 126 LSPAF ablation recipients were prospectively followed for arrhythmia recurrence, QoL, hospital stay, and sick leave. In PAF versus LSPAF groups, 1.3+/ 0.6 versus 1.6+/-0.7 procedures were performed per patient (P<0.00001) during a 3 year follow-up. Good arrhythmia control was achieved in 86% versus 87% of patients (P=0.69) and in 69% versus 69% of patients not receiving antiarrhythmic drugs (P=0.99). The baseline QoL was better in the PAF than in the LSPAF group (European Quality of Life Group instrument self-report questionnaire visual analog scale: 66.4+/-14.2 versus 61.0+/-14.2, P=0.0005; European Quality of Life Group 3-level, 5-dimensional descriptive system: 71.4+/-9.2 versus 67.7+/-13.8, P=0.002). Postablation 3-year increase in QoL was significant in both groups (all P<0.00001) and significantly lower in PAF versus LSPAF patients (visual analog scale: +5.0+/-14.5 versus +10.2+/-12.8, P=0.001; descriptive system: +5.9+/-14.3 versus +9.3+/-13.9, P=0.03). In multivariate analysis, LSPAF, less advanced age, shorter history of AF and good arrhythmia control were consistently associated with postablation 3-year improvement in QoL. Days of hospital stay for cardiovascular reasons and days on sick leave per patient/year were significantly reduced in both groups. CONCLUSIONS: Patients with LSPAF had worse baseline QoL. The magnitude of QoL improvement after ablation of LSPAF was significantly greater compared with after ablation of PAF, particularly when good arrhythmia control was achieved without the use of antiarrhythmic drugs. PMID- 25037197 TI - Circulating dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin. AB - BACKGROUND: Dickkopf-1 (DKK-1) is a major regulator of the Wnt signaling pathway, involved in inflammation, atherogenesis, and the regulation of glucose metabolism. Because platelets are major contributors to circulating levels of DKK 1 in other clinical settings, we aimed at characterizing the platelet contribution to DKK-1 in type 2 diabetes mellitus (T2DM) and evaluating associations of DKK-1 with glucose metabolism, platelet activation, and endothelial dysfunction. METHODS AND RESULTS: A cross-sectional comparison of DKK 1, soluble CD40L (sCD40L; reflecting platelet-mediated inflammation), asymmetric dimethylarginine (ADMA; marker of endothelial dysfunction), and urinary 11 dehydro-thromboxane B2 (in vivo marker of platelet activation) was performed among 214 diabetic patients (90 receiving aspirin at 100 mg/day) and 30 healthy controls. Plasma DKK-1 levels were markedly higher in patients with T2DM than in healthy patients (P<0.0001). DKK-1 levels were significantly lower in diabetic patients receiving compared with those not on aspirin treatment (P=0.008); in the latter, DKK-1 was significantly correlated with 11-dehydro-thromboxane B2, ADMA, and CD40L (rho=0.303. P<0.0001, rho=0.45. P<0.0001, and rho=0.37, P<0.0001, respectively) but not with glycemic control or DM duration. Among patients not receiving aspirin, improvement of metabolic control in a subgroup of newly diagnosed patients treated with acarbose for 20 weeks and in a group treated with rosiglitazone for 24 weeks was associated with concurrent significant reductions in DKK-1 (P=0.005 and P=0.004) and 11-dehydro-thromboxane B2 (P=0.005 and P=0.004). CONCLUSIONS: Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment. PMID- 25037198 TI - Adult moyamoya disease in an urban center in the United States is associated with a high burden of watershed ischemia. AB - BACKGROUND: Adult moyamoya disease is rare in the United States, and patients mostly present with cerebral ischemia. However, clinical and neurodiagnostic correlates of ischemia are not well known in this population. We sought to characterize the clinical and radiographic features of moyamoya disease in a large urban center in the United States, with a focus on angiographic and neuroimaging patterns of ischemia. METHODS AND RESULTS: We retrospectively reviewed charts of consecutive adult moyamoya disease patients evaluated at 2 centers in Houston, Texas from January 2002 to December 2011. We reviewed all available cerebral angiograms and neuroimaging studies to evaluate the Suzuki grades, presence of intracranial hemorrhage or ischemia, infarct patterns, and vascular territory distribution. Our analysis was mainly descriptive. We identified 31 adults with moyamoya disease who met our inclusion criteria. The female-to-male ratio was 2.4:1. The majority of patients were white, followed by Hispanic, black, and Asian. Most presented with ischemia (61%), followed by headaches, and intracranial hemorrhage. Of the 22 patients with available neuroimaging, 72.7% had ischemic findings, with the vast majority having a watershed pattern (81.3%). CONCLUSIONS: We observed a high burden of ischemia, mostly watershed pattern on neuroimaging in our adult moyamoya disease patients. Long-term monitoring of adult moyamoya disease patients in the United States would be useful to better understand the natural history of this condition. PMID- 25037196 TI - Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment. AB - BACKGROUND: Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP-14 has emerged as a powerful predictor of ACS. METHODS AND RESULTS: We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP-8/14 release in the circulation is related to TX-dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low-dose aspirin-treated ACS patients. In ACS patients, plasma MRP-8/14 and urinary 11-dehydro-TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin-treated ACS patients, MRP-8/14 and 11-dehydro-TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11-dehydro-TXB2 significantly predicted higher MRP-8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R(2)=0.463 and adj R(2)=0.497) after multivariable adjustment. Conversely, plasma MRP-8/14 (P<0.001) and higher urinary 8-iso-prostaglandin F2alpha (P=0.050) levels were significant predictors of residual, on-aspirin, TX biosynthesis in ACS (adjusted R(2)=0.384). CONCLUSIONS: Circulating MRP-8/14 is associated with TX-dependent platelet activation in ACS, even during low-dose aspirin treatment, suggesting a contribution of residual TX to MRP-8/14 shedding, which may further amplify platelet activation. Circulating MRP-8/14 may be a target to test different antiplatelet strategies in ACS. PMID- 25037199 TI - Predicting return to play after hamstring injuries. AB - BACKGROUND: Previous studies on the prognostic value of clinical and MRI parameters for the time to return to play (TTRTP) in acute hamstring injuries showed only limited to moderate evidence for the various investigated parameters. Some studies had multiple methodological limitations, including retrospective designs and the use of univariate analysis only. The aim of this study was to assess the prognostic value of clinical and MRI parameters for TTRTP using multivariate analysis. METHODS: 28 clinical and MRI parameters were prospectively investigated for an association with TTRTP in 80 non-professional athletes with MRI positive hamstring injuries undergoing a standardised rehabilitation programme. The association between possible prognostic parameters and TTRTP was assessed with a multivariate linear regression model. Parameters that had a p value <0.2 on univariate testing were included in this model. RESULTS: 74 athletes were available for analysis. A total of nine variables met the criteria for the multivariate analysis: intensity of sports, level of sports, self predicted TTRTP by the athlete, length of discomfort on palpation, deficit in passive straight leg raise, pain score on isometric knee flexion, isometric knee flexion strength deficit and distance of the proximal pole of the MRI hyperintensity to the tuber ischiadicum. Of these, only self-predicted TTRTP by the athlete and a passive straight leg raise deficit remained significantly associated with TTRTP after stepwise logistic regression. CONCLUSIONS: The clinical parameters self-predicted TTRTP and passive straight leg raise deficit are independently associated with the TTRTP. MRI parameters in grade 1 and 2 hamstring injuries, as described in the literature, are not associated with TTRTP. For clinical practice, prognosis of the TTRTP in these injuries should better be based on clinical parameters. PMID- 25037200 TI - Misunderstanding the female athlete triad: refuting the IOC consensus statement on Relative Energy Deficiency in Sport (RED-S). PMID- 25037202 TI - Medical management of hamstring muscle injury: strained evidence for platelet rich plasma. PMID- 25037201 TI - Clinical findings just after return to play predict hamstring re-injury, but baseline MRI findings do not. AB - BACKGROUND: Acute hamstring re-injuries are common and hard to predict. The aim of this study was to investigate the association between clinical and imaging findings and the occurrence of hamstring re-injuries. METHODS: We obtained baseline data (clinical and MRI findings) of athletes who sustained an acute hamstring injury within 5 days of initial injury. We also collected data of standardised clinical tests within 7 days after return to play (RTP). The number of re-injuries was recorded within 12 months. We analysed the association between the possible predictive variables and re-injuries with a multivariate Cox proportional-hazards regression model. RESULTS: Eighty patients were included at baseline and 64 patients could be included in the final analysis because data after RTP were not available in 16 cases. There were 17 re-injuries (27%). None of the baseline MRI findings were univariately associated with re-injury. A higher number of previous hamstring injuries (adjusted OR (AOR) 1.33; 95% CI 1.11 to 1.61), more degrees of active knee extension deficit after RTP (AOR 1.13; 95% CI 1.03 to 1.25), isometric knee flexion force deficit at 15 degrees after RTP (AOR 1.04; 95% CI 1.01 to 1.07) and presence of localised discomfort on hamstring palpation after RTP (AOR 3.95; 95% CI 1.38 to 11.37) were significant independent predictors of re-injury. Athletes with localised discomfort on hamstring palpation just after RTP were consequently almost four times more likely to sustain a re-injury. CONCLUSIONS: The number of previous hamstring injuries, active knee extension deficit, isometric knee flexion force deficit at 15 degrees and presence of localised discomfort on palpation just after RTP are associated with a higher hamstring re-injury rate. None of the baseline MRI parameters was a predictor of hamstring re-injury. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov number NCT01812564. PMID- 25037203 TI - Dopamine receptor signaling in the forebrain: recent insights and clinical implications. PMID- 25037204 TI - Convulsive status epilepticus and health-related quality of life in children with epilepsy. AB - OBJECTIVES: The objective of this study was to examine the association between convulsive status epilepticus (CSE) and health-related quality of life (HRQL) during a 24-month follow-up in a multisite incident cohort of children with epilepsy. METHODS: Data were collected in the Health-Related Quality of Life Study in Children with Epilepsy Study from 374 families of children with newly diagnosed epilepsy. The Quality of Life in Childhood Epilepsy (QOLCE) Questionnaire was used to evaluate parent-reported child HRQL. Hierarchical linear regression was used to examine the relationship between CSE and HRQL at 24 months postepilepsy. A total of 359 families completed the 24-month assessment. RESULTS: Twenty-two children (6.1%) had experienced CSE during the follow-up. Children with and without CSE were similar, except a larger proportion of children with CSE had partial seizures (p < 0.001). Controlling for clinical, demographic, and family characteristics, CSE was significantly associated with poorer HRQL (beta = -4.65, p = 0.031). The final model explained 47% of the variance in QOLCE scores. CONCLUSIONS: The findings suggested that not only do children with CSE have significantly poorer HRQL compared with their non-CSE counterparts, but that this factor is independent of the effects of demographic and clinical features known to affect HRQL. PMID- 25037205 TI - Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy. AB - OBJECTIVE: We report novel defects of mitochondrial translation elongation factor Ts (EFTs), with high carrier frequency in Finland and expand the manifestations of this disease group from infantile cardiomyopathy to juvenile neuropathy/encephalopathy disorders. METHODS: DNA analysis, whole-exome analysis, protein biochemistry, and protein modeling. RESULTS: We used whole-exome sequencing to find the genetic cause of infantile-onset mitochondrial cardiomyopathy, progressing to juvenile-onset Leigh syndrome, neuropathy, and optic atrophy in 2 siblings. We found novel compound heterozygous mutations, c.944G>A [p.C315Y] and c.856C>T [p.Q286X], in the TSFM gene encoding mitochondrial EFTs. The same p.Q286X variant was found as compound heterozygous with a splice site change in a patient from a second family, with juvenile-onset optic atrophy, peripheral neuropathy, and ataxia. Our molecular modeling predicted the coding-region mutations to cause protein instability, which was experimentally confirmed in cultured patient cells, with mitochondrial translation defect and lacking EFTs. Only a single TSFM mutation has been previously described in different populations, leading to an infantile fatal multisystem disorder with cardiomyopathy. Sequence data from 35,000 Finnish population controls indicated that the heterozygous carrier frequency of p.Q286X change was exceptionally high in Finland, 1:80, but no homozygotes were found in the population, in our mitochondrial disease patient collection, or in an intrauterine fetal death material, suggesting early developmental lethality of the homozygotes. CONCLUSIONS: We show that in addition to early-onset cardiomyopathy, TSFM mutations should be considered in childhood and juvenile encephalopathies with optic and/or peripheral neuropathy, ataxia, or Leigh disease. PMID- 25037206 TI - Naltrexone for impulse control disorders in Parkinson disease: a placebo controlled study. AB - OBJECTIVE: Impulse control disorders (ICDs) in Parkinson disease (PD) are common and can be difficult to manage. The objective of this study was to determine the efficacy and tolerability of naltrexone, an opioid antagonist, for the treatment of ICDs in PD. METHODS: Patients with PD (n = 50) and an ICD were enrolled in an 8-week, randomized (1:1), double-blind, placebo-controlled study of naltrexone 50 100 mg/d (flexible dosing). The primary outcome measure was response based on the Clinical Global Impression-Change score, and the secondary outcome measure was change in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) ICD score. RESULTS: Forty five patients (90%) completed the study. The Clinical Global Impression-Change response rate difference favoring naltrexone in completers was 19.8% (95% confidence interval [CI] -8.7% to 44.2%). While this difference was not significant (odds ratio=1.6, 95% CI 0.5-5.2, Wald chi2 [df]=0.5 [1], p=0.5), naltrexone treatment led to a significantly greater decrease in QUIP-RS ICD score over time compared with placebo (regression coefficient for interaction term in linear mixed-effects model=-7.37, F[df]=4.3 [1, 49], p=0.04). The estimated changes in QUIP-RS ICD scores from baseline to week 8 were 14.9 points (95% CI 9.9-19.9) for naltrexone and 7.5 points (95% CI 2.5-12.6) for placebo. CONCLUSIONS: Naltrexone treatment was not efficacious for the treatment of ICDs in PD using a global assessment of response, but findings using a PD-specific ICD rating scale support further evaluation of opioid antagonists for the treatment of ICD symptoms in PD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with PD and an ICD, naltrexone does not significantly increase the probability of achieving response. However, the study lacked the precision to exclude an important difference in response rates. PMID- 25037207 TI - JCV GCN in a natalizumab-treated MS patient is associated with mutations of the VP1 capsid gene. AB - OBJECTIVE: To describe the clinical, neuroimaging, immunologic, and virologic characteristics of JC virus-associated granule cell neuronopathy (JCV GCN) in a natalizumab-treated patient with multiple sclerosis (MS) who developed immune reconstitution inflammatory syndrome (IRIS) after natalizumab withdrawal. METHODS: We obtained longitudinal clinical data as well as MRI and proton magnetic resonance spectroscopy from this patient with MS. We measured JCV specific cellular immune response in his peripheral blood by intracellular cytokine staining and sequenced a fragment of JCV VP1 capsid gene detected in his CSF. We contrast our findings with the first recently reported case. RESULTS: This patient presented with worsening cerebellar symptoms and progressive cerebellar atrophy without new MS lesions on MRI after 63 months of natalizumab monotherapy. JCV DNA was detected in his CSF by PCR and harbored novel GCN-type mutations in the VP1 gene. He developed IRIS upon discontinuation of natalizumab and plasma exchange, which manifested itself by a worsening of clinical symptoms and contrast enhancement in the cerebellum on MRI. Treatment with corticosteroids resulted in resolution of IRIS, as demonstrated by proton magnetic resonance spectroscopy. The patient had a strong JCV-specific T-cell response in his peripheral blood and remains alive after 15 months from onset of symptoms, although with significant disability. He did not have MS relapse on glatiramer acetate. CONCLUSIONS: JCV GCN should be considered in patients on natalizumab presenting with progressive cerebellar symptoms and cerebellar atrophy, and is associated with mutations in the JCV VP1 gene. Natalizumab withdrawal may be complicated by JCV GCN IRIS, and require treatment with corticosteroids. PMID- 25037208 TI - CPK13, a noncanonical Ca2+-dependent protein kinase, specifically inhibits KAT2 and KAT1 shaker K+ channels and reduces stomatal opening. AB - Ca(2) (+)-dependent protein kinases (CPKs) form a large family of 34 genes in Arabidopsis (Arabidopsis thaliana). Based on their dependence on Ca(2+), CPKs can be sorted into three types: strictly Ca(2+)-dependent CPKs, Ca(2+)-stimulated CPKs (with a significant basal activity in the absence of Ca(2+)), and essentially calcium-insensitive CPKs. Here, we report on the third type of CPK, CPK13, which is expressed in guard cells but whose role is still unknown. We confirm the expression of CPK13 in Arabidopsis guard cells, and we show that its overexpression inhibits light-induced stomatal opening. We combine several approaches to identify a guard cell-expressed target. We provide evidence that CPK13 (1) specifically phosphorylates peptide arrays featuring Arabidopsis K(+) Channel KAT2 and KAT1 polypeptides, (2) inhibits KAT2 and/or KAT1 when expressed in Xenopus laevis oocytes, and (3) closely interacts in plant cells with KAT2 channels (Forster resonance energy transfer-fluorescence lifetime imaging microscopy). We propose that CPK13 reduces stomatal aperture through its inhibition of the guard cell-expressed KAT2 and KAT1 channels. PMID- 25037209 TI - AtGEN1 and AtSEND1, two paralogs in Arabidopsis, possess holliday junction resolvase activity. AB - Holliday junctions (HJs) are physical links between homologous DNA molecules that arise as central intermediary structures during homologous recombination and repair in meiotic and somatic cells. It is necessary for these structures to be resolved to ensure correct chromosome segregation and other functions. In eukaryotes, including plants, homologs of a gene called XPG-like endonuclease1 (GEN1) have been identified that process HJs in a manner analogous to the HJ resolvases of phages, archaea, and bacteria. Here, we report that Arabidopsis (Arabidopsis thaliana), a eukaryotic organism, has two functional GEN1 homologs instead of one. Like all known eukaryotic resolvases, AtGEN1 and Arabidopsis single-strand DNA endonuclease1 both belong to class IV of the Rad2/XPG family of nucleases. Their resolvase activity shares the characteristics of the Escherichia coli radiation and UV sensitive C paradigm for resolvases, which involves resolving HJs by symmetrically oriented incisions in two opposing strands. This leads to ligatable products without the need for further processing. The observation that the sequence context influences the cleavage by the enzymes can be interpreted as a hint for the existence of sequence specificity. The two Arabidopsis paralogs differ in their preferred sequences. The precise cleavage positions observed for the resolution of mobile nicked HJs suggest that these cleavage positions are determined by both the substrate structure and the sequence context at the junction point. PMID- 25037210 TI - Strigolactone involvement in root development, response to abiotic stress, and interactions with the biotic soil environment. AB - Strigolactones, recently discovered as plant hormones, regulate the development of different plant parts. In the root, they regulate root architecture and affect root hair length and density. Their biosynthesis and exudation increase under low phosphate levels, and they are associated with root responses to these conditions. Their signaling pathway in the plant includes protein interactions and ubiquitin-dependent repressor degradation. In the root, they lead to changes in actin architecture and dynamics as well as localization of the PIN-FORMED auxin transporter in the plasma membrane. Strigolactones are also involved with communication in the rhizosphere. They are necessary for germination of parasitic plant seeds, they enhance hyphal branching of arbuscular mycorrhizal fungi of the Glomus and Gigaspora spp., and they promote rhizobial symbiosis. This review focuses on the role played by strigolactones in root development, their response to nutrient deficiency, and their involvement with plant interactions in the rhizosphere. PMID- 25037211 TI - Functional evidence for the critical amino-terminal conserved domain and key amino acids of Arabidopsis 4-HYDROXY-3-METHYLBUT-2-ENYL DIPHOSPHATE REDUCTASE. AB - The plant 4-HYDROXY-3-METHYLBUT-2-ENYL DIPHOSPHATE REDUCTASE (HDR) catalyzes the last step of the methylerythritol phosphate pathway to synthesize isopentenyl diphosphate and its allyl isomer dimethylallyl diphosphate, which are common precursors for the synthesis of plastid isoprenoids. The Arabidopsis (Arabidopsis thaliana) genomic HDR transgene-induced gene-silencing lines are albino, variegated, or pale green, confirming that HDR is essential for plants. We used Escherichia coli isoprenoid synthesis H (Protein Data Bank code 3F7T) as a template for homology modeling to identify key amino acids of Arabidopsis HDR. The predicted model reveals that cysteine (Cys)-122, Cys-213, and Cys-350 are involved in iron-sulfur cluster formation and that histidine (His)-152, His-241, glutamate (Glu)-242, Glu-243, threonine (Thr)-244, Thr-312, serine-379, and asparagine-381 are related to substrate binding or catalysis. Glu-242 and Thr-244 are conserved only in cyanobacteria, green algae, and land plants, whereas the other key amino acids are absolutely conserved from bacteria to plants. We used site-directed mutagenesis and complementation assay to confirm that these amino acids, except His-152 and His-241, were critical for Arabidopsis HDR function. Furthermore, the Arabidopsis HDR contains an extra amino-terminal domain following the transit peptide that is highly conserved from cyanobacteria, and green algae to land plants but not existing in the other bacteria. We demonstrated that the amino-terminal conserved domain was essential for Arabidopsis and cyanobacterial HDR function. Further analysis of conserved amino acids in the amino-terminal conserved domain revealed that the tyrosine-72 residue was critical for Arabidopsis HDR. These results suggest that the structure and reaction mechanism of HDR evolution have become specific for oxygen evolving photosynthesis organisms and that HDR probably evolved independently in cyanobacteria versus other prokaryotes. PMID- 25037212 TI - The apical actin fringe contributes to localized cell wall deposition and polarized growth in the lily pollen tube. AB - In lily (Lilium formosanum) pollen tubes, pectin, a major component of the cell wall, is delivered through regulated exocytosis. The targeted transport and secretion of the pectin-containing vesicles may be controlled by the cortical actin fringe at the pollen tube apex. Here, we address the role of the actin fringe using three different inhibitors of growth: brefeldin A, latrunculin B, and potassium cyanide. Brefeldin A blocks membrane trafficking and inhibits exocytosis in pollen tubes; it also leads to the degradation of the actin fringe and the formation of an aggregate of filamentous actin at the base of the clear zone. Latrunculin B, which depolymerizes filamentous actin, markedly slows growth but allows focused pectin deposition to continue. Of note, the locus of deposition shifts frequently and correlates with changes in the direction of growth. Finally, potassium cyanide, an electron transport chain inhibitor, briefly stops growth while causing the actin fringe to completely disappear. Pectin deposition continues but lacks focus, instead being delivered in a wide arc across the pollen tube tip. These data support a model in which the actin fringe contributes to the focused secretion of pectin to the apical cell wall and, thus, to the polarized growth of the pollen tube. PMID- 25037213 TI - Chloroplast dysfunction causes multiple defects in cell cycle progression in the Arabidopsis crumpled leaf mutant. AB - The majority of research on cell cycle regulation is focused on the nuclear events that govern the replication and segregation of the genome between the two daughter cells. However, eukaryotic cells contain several compartmentalized organelles with specialized functions, and coordination among these organelles is required for proper cell cycle progression, as evidenced by the isolation of several mutants in which both organelle function and overall plant development were affected. To investigate how chloroplast dysfunction affects the cell cycle, we analyzed the crumpled leaf (crl) mutant of Arabidopsis (Arabidopsis thaliana), which is deficient for a chloroplastic protein and displays particularly severe developmental defects. In the crl mutant, we reveal that cell cycle regulation is altered drastically and that meristematic cells prematurely enter differentiation, leading to reduced plant stature and early endoreduplication in the leaves. This response is due to the repression of several key cell cycle regulators as well as constitutive activation of stress-response genes, among them the cell cycle inhibitor SIAMESE-RELATED5. One unique feature of the crl mutant is that it produces aplastidic cells in several organs, including the root tip. By investigating the consequence of the absence of plastids on cell cycle progression, we showed that nuclear DNA replication occurs in aplastidic cells in the root tip, which opens future research prospects regarding the dialogue between plastids and the nucleus during cell cycle regulation in higher plants. PMID- 25037214 TI - Dynamic transcriptome landscape of maize embryo and endosperm development. AB - Maize (Zea mays) is an excellent cereal model for research on seed development because of its relatively large size for both embryo and endosperm. Despite the importance of seed in agriculture, the genome-wide transcriptome pattern throughout seed development has not been well characterized. Using high throughput RNA sequencing, we developed a spatiotemporal transcriptome atlas of B73 maize seed development based on 53 samples from fertilization to maturity for embryo, endosperm, and whole seed tissues. A total of 26,105 genes were found to be involved in programming seed development, including 1,614 transcription factors. Global comparisons of gene expression highlighted the fundamental transcriptomic reprogramming and the phases of development. Coexpression analysis provided further insight into the dynamic reprogramming of the transcriptome by revealing functional transitions during maturation. Combined with the published nonseed high-throughput RNA sequencing data, we identified 91 transcription factors and 1,167 other seed-specific genes, which should help elucidate key mechanisms and regulatory networks that underlie seed development. In addition, correlation of gene expression with the pattern of DNA methylation revealed that hypomethylation of the gene body region should be an important factor for the expressional activation of seed-specific genes, especially for extremely highly expressed genes such as zeins. This study provides a valuable resource for understanding the genetic control of seed development of monocotyledon plants. PMID- 25037215 TI - Tandem amplification of a chromosomal segment harboring 5-enolpyruvylshikimate-3 phosphate synthase locus confers glyphosate resistance in Kochia scoparia. AB - Recent rapid evolution and spread of resistance to the most extensively used herbicide, glyphosate, is a major threat to global crop production. Genetic mechanisms by which weeds evolve resistance to herbicides largely determine the level of resistance and the rate of evolution of resistance. In a previous study, we determined that glyphosate resistance in Kochia scoparia is due to the amplification of the 5-Enolpyruvylshikimate-3-Phosphate Synthase (EPSPS) gene, the enzyme target of glyphosate. Here, we investigated the genomic organization of the amplified EPSPS copies using fluorescence in situ hybridization (FISH) and extended DNA fiber (Fiber FISH) on K. scoparia chromosomes. In both glyphosate resistant K. scoparia populations tested (GR1 and GR2), FISH results displayed a single and prominent hybridization site of the EPSPS gene localized on the distal end of one pair of homologous metaphase chromosomes compared with a faint hybridization site in glyphosate-susceptible samples (GS1 and GS2). Fiber FISH displayed 10 copies of the EPSPS gene (approximately 5 kb) arranged in tandem configuration approximately 40 to 70 kb apart, with one copy in an inverted orientation in GR2. In agreement with FISH results, segregation of EPSPS copies followed single-locus inheritance in GR1 population. This is the first report of tandem target gene amplification conferring field-evolved herbicide resistance in weed populations. PMID- 25037216 TI - Dynamics of the heme-binding bacterial gas-sensing dissimilative nitrate respiration regulator (DNR) and activation barriers for ligand binding and escape. AB - DNR (dissimilative nitrate respiration regulator) is a heme-binding transcription factor that is involved in the regulation of denitrification in Pseudomonas aeruginosa. In the ferrous deoxy state, the heme is 6-coordinate; external NO and CO can replace an internal ligand. Using fluorescence anisotropy, we show that high-affinity sequence-specific DNA binding occurs only when the heme is nitrosylated, consistent with the proposed function of DNR as NO sensor and transcriptional activator. This role is moreover supported by the NO "trapping" properties revealed by ultrafast spectroscopy that are similar to those of other heme-based NO sensor proteins. Dissociated CO-heme pairs rebind in an essentially barrierless way. This process competes with migration out of the heme pocket. The latter process is thermally activated (Ea ~ 7 kJ/mol). This result is compared with other heme proteins, including the homologous CO sensor/transcription factor CooA, variants of the 5-coordinate mycobacterial sensor DosT and the electron transfer protein cytochrome c. This comparison indicates that thermal activation of ligand escape from the heme pocket is specific for systems where an external ligand replaces an internal one. The origin of this finding and possible implications are discussed. PMID- 25037217 TI - Biophysical and structural characterization of the thioredoxin-binding domain of protein kinase ASK1 and its interaction with reduced thioredoxin. AB - Apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase, plays a key role in the pathogenesis of multiple diseases. Its activity is regulated by thioredoxin (TRX1) but the precise mechanism of this regulation is unclear due to the lack of structural data. Here, we performed biophysical and structural characterization of the TRX1-binding domain of ASK1 (ASK1-TBD) and its complex with reduced TRX1. ASK1-TBD is a monomeric and rigid domain that forms a stable complex with reduced TRX1 with 1:1 molar stoichiometry. The binding interaction does not involve the formation of intermolecular disulfide bonds. Residues from the catalytic WCGPC motif of TRX1 are essential for complex stability with Trp(31) being directly involved in the binding interaction as suggested by time-resolved fluorescence. Small-angle x-ray scattering data reveal a compact and slightly asymmetric shape of ASK1-TBD and suggest reduced TRX1 interacts with this domain through the large binding interface without inducing any dramatic conformational change. PMID- 25037218 TI - A retained secretory signal peptide mediates high density lipoprotein (HDL) assembly and function of haptoglobin-related protein. AB - Haptoglobin-related protein (Hpr) is a component of a minor subspecies of high density lipoproteins (HDL) that function in innate immunity. Here we show that assembly of Hpr into HDL is mediated by its retained N-terminal signal peptide, an unusual feature for a secreted protein and the major difference between Hpr and the soluble acute phase protein haptoglobin (Hp). The 18-amino acid signal peptide is necessary for binding to HDL and interacts directly with the hydrocarbon region of lipids. Utilizing model liposomes, we show that the rate of assembly and steady-state distribution of Hpr in lipid particles is mediated by the physical property of lipid fluidity. Dye release assays reveal that Hpr interacts more rapidly with fluid liposomes. Conversely, steady-state binding assays indicate that more rigid lipid compositions stabilize Hpr association. Lipid association also plays a role in facilitating hemoglobin binding by Hpr. Our data may offer an explanation for the distinct distribution of Hpr among HDL subspecies. Rather than protein-protein interactions mediating localization, direct interaction with phospholipids and sensitivity to lipid fluidity may be sufficient for localization of Hpr and may represent a mechanism of HDL subspeciation. PMID- 25037219 TI - Antimicrobial histones and DNA traps in invertebrate immunity: evidences in Crassostrea gigas. AB - Although antimicrobial histones have been isolated from multiple metazoan species, their role in host defense has long remained unanswered. We found here that the hemocytes of the oyster Crassostrea gigas release antimicrobial H1-like and H5-like histones in response to tissue damage and infection. These antimicrobial histones were shown to be associated with extracellular DNA networks released by hemocytes, the circulating immune cells of invertebrates, in response to immune challenge. The hemocyte-released DNA was found to surround and entangle vibrios. This defense mechanism is reminiscent of the neutrophil extracellular traps (ETs) recently described in vertebrates. Importantly, oyster ETs were evidenced in vivo in hemocyte-infiltrated interstitial tissues surrounding wounds, whereas they were absent from tissues of unchallenged oysters. Consistently, antimicrobial histones were found to accumulate in oyster tissues following injury or infection with vibrios. Finally, oyster ET formation was highly dependent on the production of reactive oxygen species by hemocytes. This shows that ET formation relies on common cellular and molecular mechanisms from vertebrates to invertebrates. Altogether, our data reveal that ET formation is a defense mechanism triggered by infection and tissue damage, which is shared by relatively distant species suggesting either evolutionary conservation or convergent evolution within Bilateria. PMID- 25037220 TI - Nuclear factor of activated T cells regulates the expression of interleukin-4 in Th2 cells in an all-or-none fashion. AB - Th2 memory lymphocytes have imprinted their Il4 genes epigenetically for expression in dependence of T cell receptor restimulation. However, in a given restimulation, not all Th cells with a memory for IL-4 expression express IL-4. Here, we show that in reactivated Th2 cells, the transcription factors NFATc2, NF kB p65, c-Maf, p300, Brg1, STAT6, and GATA-3 assemble at the Il4 promoter in Th2 cells expressing IL-4 but not in Th2 cells not expressing it. NFATc2 is critical for assembly of this transcription factor complex. Because NFATc2 translocation into the nucleus occurs in an all-or-none fashion, dependent on complete dephosphorylation by calcineurin, NFATc2 controls the frequencies of cells reexpressing Il4, translates analog differences in T cell receptor stimulation into a digital decision for Il4 reexpression, and instructs all reexpressing cells to express the same amount of IL-4. This analog-to-digital conversion may be critical for the immune system to respond to low concentrations of antigens. PMID- 25037221 TI - Amine oxidase copper-containing 1 (AOC1) is a downstream target gene of the Wilms tumor protein, WT1, during kidney development. AB - Amine oxidase copper-containing 1 (AOC1; formerly known as amiloride-binding protein 1) is a secreted glycoprotein that catalyzes the degradation of putrescine and histamine. Polyamines and their diamine precursor putrescine are ubiquitous to all organisms and fulfill pivotal functions in cell growth and proliferation. Despite the importance of AOC1 in regulating polyamine breakdown, very little is known about the molecular mechanisms that control its expression. We report here that the Wilms tumor protein, WT1, which is necessary for normal kidney development, activates transcription of the AOC1 gene. Expression of a firefly luciferase reporter under control of the proximal AOC1 promoter was significantly enhanced by co-transfection of a WT1 expression construct. Binding of WT1 protein to a cis-regulatory element in the AOC1 promoter was confirmed by electrophoretic mobility shift assay and chromatin immunoprecipitation. Antisense inhibition of WT1 protein translation strongly reduced Aoc1 transcripts in cultured murine embryonic kidneys and gonads. Aoc1 mRNA levels correlated with WT1 protein in several cell lines. Double immunofluorescent staining revealed a co-expression of WT1 and AOC1 proteins in the developing genitourinary system of mice and rats. Strikingly, induced changes in polyamine homeostasis affected branching morphogenesis of cultured murine embryonic kidneys in a developmental stage-specific manner. These findings suggest that WT1-dependent control of polyamine breakdown, which is mediated by changes in AOC1 expression, has a role in kidney organogenesis. PMID- 25037222 TI - A conserved phenylalanine as a relay between the alpha5 helix and the GDP binding region of heterotrimeric Gi protein alpha subunit. AB - G protein activation by G protein-coupled receptors is one of the critical steps for many cellular signal transduction pathways. Previously, we and other groups reported that the alpha5 helix in the G protein alpha subunit plays a major role during this activation process. However, the precise signaling pathway between the alpha5 helix and the guanosine diphosphate (GDP) binding pocket remains elusive. Here, using structural, biochemical, and computational techniques, we probed different residues around the alpha5 helix for their role in signaling. Our data showed that perturbing the Phe-336 residue disturbs hydrophobic interactions with the beta2-beta3 strands and alpha1 helix, leading to high basal nucleotide exchange. However, mutations in beta strands beta5 and beta6 do not perturb G protein activation. We have highlighted critical residues that leverage Phe-336 as a relay. Conformational changes are transmitted starting from Phe-336 via beta2-beta3/alpha1 to Switch I and the phosphate binding loop, decreasing the stability of the GDP binding pocket and triggering nucleotide release. When the alpha1 and alpha5 helices were cross-linked, inhibiting the receptor-mediated displacement of the C-terminal alpha5 helix, mutation of Phe-336 still leads to high basal exchange rates. This suggests that unlike receptor-mediated activation, helix 5 rotation and translocation are not necessary for GDP release from the alpha subunit. Rather, destabilization of the backdoor region of the Galpha subunit is sufficient for triggering the activation process. PMID- 25037223 TI - The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel-like factor 5 (KLF5)-dependent manner. AB - The histone deacetylase inhibitor (HDACi) sodium butyrate promotes differentiation of colon cancer cells as evidenced by induced expression and enzyme activity of the differentiation marker intestinal alkaline phosphatase (ALPi). Screening of a panel of 33 colon cancer cell lines identified cell lines sensitive (42%) and resistant (58%) to butyrate induction of ALP activity. This differential sensitivity was similarly evident following treatment with the structurally distinct HDACi, MS-275. Resistant cell lines were significantly enriched for those harboring the CpG island methylator phenotype (p = 0.036, Chi square test), and resistant cell lines harbored methylation of the ALPi promoter, particularly of a CpG site within a critical KLF/Sp regulatory element required for butyrate induction of ALPi promoter activity. However, butyrate induction of an exogenous ALPi promoter-reporter paralleled up-regulation of endogenous ALPi expression across the cell lines, suggesting the presence or absence of a key transcriptional regulator is the major determinant of ALPi induction. Through microarray profiling of sensitive and resistant cell lines, we identified KLF5 to be both basally more highly expressed as well as preferentially induced by butyrate in sensitive cell lines. KLF5 overexpression induced ALPi promoter reporter activity in resistant cell lines, KLF5 knockdown attenuated butyrate induction of ALPi expression in sensitive lines, and butyrate selectively enhanced KLF5 binding to the ALPi promoter in sensitive cells. These findings demonstrate that butyrate induction of the cell differentiation marker ALPi is mediated through KLF5 and identifies subsets of colon cancer cell lines responsive and refractory to this effect. PMID- 25037224 TI - High throughput screen identifies small molecule inhibitors specific for Mycobacterium tuberculosis phosphoserine phosphatase. AB - The emergence of drug-resistant strains of Mycobacterium tuberculosis makes identification and validation of newer drug targets a global priority. Phosphoserine phosphatase (PSP), a key essential metabolic enzyme involved in conversion of O-phospho-l-serine to l-serine, was characterized in this study. The M. tuberculosis genome harbors all enzymes involved in l-serine biosynthesis including two PSP homologs: Rv0505c (SerB1) and Rv3042c (SerB2). In the present study, we have biochemically characterized SerB2 enzyme and developed malachite green-based high throughput assay system to identify SerB2 inhibitors. We have identified 10 compounds that were structurally different from known PSP inhibitors, and few of these scaffolds were highly specific in their ability to inhibit SerB2 enzyme, were noncytotoxic against mammalian cell lines, and inhibited M. tuberculosis growth in vitro. Surface plasmon resonance experiments demonstrated the relative binding for these inhibitors. The two best hits identified in our screen, clorobiocin and rosaniline, were bactericidal in activity and killed intracellular bacteria in a dose-dependent manner. We have also identified amino acid residues critical for these SerB2-small molecule interactions. This is the first study where we validate that M. tuberculosis SerB2 is a druggable and suitable target to pursue for further high throughput assay system screening. PMID- 25037226 TI - Decreased amyloid-beta pathologies by intracerebral loading of glycosphingolipid enriched exosomes in Alzheimer model mice. AB - Elevated levels of amyloid-beta peptide (Abeta) in the human brain are linked to the pathogenesis of Alzheimer disease. Recent in vitro studies have demonstrated that extracellular Abeta can bind to exosomes, which are cell-secreted nanovesicles with lipid membranes that are known to transport their cargos intercellularly. Such findings suggest that the exosomes are involved in Abeta metabolism in brain. Here, we found that neuroblastoma-derived exosomes exogenously injected into mouse brains trapped Abeta and with the associated Abeta were internalized into brain-resident phagocyte microglia. Accordingly, continuous intracerebral administration of the exosomes into amyloid-beta precursor protein transgenic mice resulted in marked reductions in Abeta levels, amyloid depositions, and Abeta-mediated synaptotoxicity in the hippocampus. In addition, we determined that glycosphingolipids (GSLs), a group of membrane glycolipids, are highly abundant in the exosomes, and the enriched glycans of the GSLs are essential for Abeta binding and assembly on the exosomes both in vitro and in vivo. Our data demonstrate that intracerebrally administered exosomes can act as potent scavengers for Abeta by carrying it on the exosome surface GSLs and suggest a role of exosomes in Abeta clearance in the central nervous system. Improving Abeta clearance by exosome administration would provide a novel therapeutic intervention for Alzheimer disease. PMID- 25037225 TI - The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. AB - Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against neuronal damage associated with neurodegeneration and oxidative stress. Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT22 with recombinant Klotho protected these cells from glutamate and oligomeric amyloid beta (oAbeta)-induced cytotoxicity. In addition, primary hippocampal neurons obtained from Klotho-overexpressing mouse embryos were more resistant to both cytotoxic insults, glutamate and oAbeta, compared with neurons from wild-type littermates. An antioxidative stress array analysis of neurons treated with Klotho revealed that Klotho significantly enhances the expression of the thioredoxin/peroxiredoxin (Trx/Prx) system with the greatest effect on the induction of Prx-2, an antioxidant enzyme, whose increase was confirmed at the mRNA and protein levels. Klotho-induced phosphorylation of the PI3K/Akt pathway, a pathway important in apoptosis and longevity, was associated with sustained inhibitory phosphorylation of the transcription factor forkhead box O3a (FoxO3a) and was essential for the induction of Prx-2. Down-regulation of Prx-2 expression using a lentivirus harboring shRNA almost completely abolished the ability of Klotho to rescue neurons from glutamate-induced death and significantly, but not completely, inhibited cell death mediated by oAbeta, suggesting that Prx-2 is a key modulator of neuroprotection. Thus, our results demonstrate, for the first time, the neuroprotective role of Klotho and reveal a novel mechanism underlying this effect. PMID- 25037227 TI - Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. AB - Modulation of type 1 cannabinoid receptor (CB1) activity has been touted as a potential means of treating addiction, anxiety, depression, and neurodegeneration. Different agonists of CB1 are known to evoke varied responses in vivo. Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor that can signal through multiple pathways. To understand cannabinoid-specific functional selectivity, different groups have examined the effect of individual cannabinoids on various signaling pathways in heterologous expression systems. In the current study, we compared the functional selectivity of six cannabinoids, including two endocannabinoids (2 arachidonyl glycerol (2-AG) and anandamide (AEA)), two synthetic cannabinoids (WIN55,212-2 and CP55,940), and two phytocannabinoids (cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC)) on arrestin2-, Galpha(i/o)-, Gbetagamma-, Galpha(s)-, and Galpha(q)-mediated intracellular signaling in the mouse STHdh(Q7/Q7) cell culture model of striatal medium spiny projection neurons that endogenously express CB1. In this system, 2-AG, THC, and CP55,940 were more potent mediators of arrestin2 recruitment than other cannabinoids tested. 2-AG, AEA, and WIN55,212-2, enhanced Galpha(i/o) and Gbetagamma signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Galpha(q)-dependent pathways. CP55,940 and CBD both signaled through Galpha(s). CP55,940, but not CBD, activated downstream Galpha(s) pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias. PMID- 25037228 TI - The peculiar role of the A2V mutation in amyloid-beta (Abeta) 1-42 molecular assembly. AB - We recently reported a novel Abeta precursor protein mutation (A673V), corresponding to position 2 of Abeta1-42 peptides (Abeta1-42A2V), that caused an early onset AD-type dementia in a homozygous individual. The heterozygous relatives were not affected as an indication of autosomal recessive inheritance of this mutation. We investigated the folding kinetics of native unfolded Abeta1 42A2V in comparison with the wild type sequence (Abeta1-42WT) and the equimolar solution of both peptides (Abeta1-42MIX) to characterize the oligomers that are produced in the early phases. We carried out the structural characterization of the three preparations using electron and atomic force microscopy, fluorescence emission, and x-ray diffraction and described the soluble oligomer formation kinetics by laser light scattering. The mutation promoted a peculiar pathway of oligomerization, forming a connected system similar to a polymer network with hydrophobic residues on the external surface. Abeta1-42MIX generated assemblies very similar to those produced by Abeta1-42WT, albeit with slower kinetics due to the difficulties of Abeta1-42WT and Abeta1-42A2V peptides in building up of stable intermolecular interaction. PMID- 25037229 TI - Trends and correlates of HIV-1 resistance among subjects failing an antiretroviral treatment over the 2003-2012 decade in Italy. AB - BACKGROUND: Despite a substantial reduction in virological failures following introduction of new potent antiretroviral therapies in the latest years, drug resistance remains a limitation for the control of HIV-1 infection. We evaluated trends and correlates of resistance in treatment failing patients in a comprehensive database over a time period of relevant changes in prescription attitudes and treatment guidelines. METHODS: We analyzed 6,796 HIV-1 pol sequences from 49 centres stored in the Italian ARCA database during the 2003 2012 period. Patients (n = 5,246) with viremia > 200 copies/mL received a genotypic test while on treatment. Mutations were identified from IAS-USA 2013 tables. Class resistance was evaluated according to antiretroviral regimens in use at failure. Time trends and correlates of resistance were analyzed by Cochran Armitage test and logistic regression models. RESULTS: The use of NRTI backbone regimens slightly decreased from 99.7% in 2003-2004 to 97.4% in 2010-2012. NNRTI based combinations dropped from 46.7% to 24.1%. PI-containing regimens rose from 56.6% to 81.7%, with an increase of boosted PI from 36.5% to 68.9% overtime. In the same reference periods, Resistance to NRTIs, NNRTIs and PIs declined from 79.1% to 40.8%, from 77.8% to 53.8% and from 59.8% to 18.9%, respectively (p < .0001 for all comparisons). Dual NRTI + NNRTI and NRTI + PI resistance decreased from 56.4% to 33.3% and from 36.1% to 10.5%, respectively. Reduced risk of resistance over time periods was confirmed by a multivariate analysis. CONCLUSIONS: Mutations associated with NRTIs, NNRTIs and PIs at treatment failure declined overtime regardless of specific class combinations and epidemiological characteristics of treated population. This is likely due to the improvement of HIV treatment, including both last generation drug combinations and prescription guidelines. PMID- 25037230 TI - miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias. AB - BACKGROUND: microRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 (KLF4), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL. METHODS: Elevated levels of miR-2909 targeted the tumor suppressor gene KLF4 in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor (AATF), MYC, B-cell lymphoma (BCL3), P21CIP, CCND1 and SP1 in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays. RESULTS: We identified two novel mutations in KLF4 in pediatric T-ALL. A mutation in the 3' untranslated region of the KLF4 gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered KLF4 transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant KLF4 protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene P21CIP confirmed the lack of function of the mutant KLF4 protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate KLF4 and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of KLF4 identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa). CONCLUSIONS: This study identified a novel miR-2909-KLF4 molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker. PMID- 25037231 TI - Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. AB - BACKGROUND: Colorectal cancer is the third most frequently diagnosed cancer and the third cause of cancer deaths in the United States. Despite the fact that tumor cell-intrinsic mechanisms controlling colorectal carcinogenesis have been identified, novel prognostic and diagnostic tools as well as novel therapeutic strategies are still needed to monitor and target colon cancer progression. We and others have previously shown, using mouse models, that the extracellular matrix (ECM), a major component of the tumor microenvironment, is an important contributor to tumor progression. In order to identify candidate biomarkers, we sought to define ECM signatures of metastatic colorectal cancers and their metastases to the liver. METHODS: We have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver in comparison with normal colon and liver samples. RESULTS: We show that robust signatures of ECM proteins characteristic of each tissue, normal and malignant, can be defined using relatively small samples from small numbers of patients. Comparisons with gene expression data from larger cohorts of patients confirm the association of subsets of the proteins identified by proteomic analysis with tumor progression and metastasis. CONCLUSIONS: The ECM protein signatures of metastatic primary colon carcinomas and metastases to liver defined in this study, offer promise for development of diagnostic and prognostic signatures of metastatic potential of colon tumors. The ECM proteins defined here represent candidate serological or tissue biomarkers and potential targets for imaging of occult metastases and residual or recurrent tumors and conceivably for therapies. Furthermore, the methods described here can be applied to other tumor types and can be used to investigate other questions such as the role of ECM in resistance to therapy. PMID- 25037232 TI - Associations between number of sick-leave days and future all-cause and cause specific mortality: a population-based cohort study. AB - BACKGROUND: As the number of studies on the future situation of sickness absentees still is very limited, we aimed to investigate the association between number of sick-leave days and future all-cause and cause-specific mortality among women and men. METHODS: A cohort of 2 275 987 women and 2 393 248 men, aged 20-64 years in 1995 was followed 1996-2006 with regard to mortality. Data were obtained from linked authority-administered registers. The relative risks (RR) and 95% confidence intervals (CI) of mortality with and without a 2-year wash-out period were estimated by multivariate Poisson regression analyses. All analyses were stratified by sex, adjusting for socio demographics and inpatient care. RESULTS: A gradually higher all-cause mortality risk occurred with increasing number of sick-leave days in 1995, among both women (RR 1.11; CI 1.07-1.15 for those with 1 15 sick-leave days to RR 2.45; CI 2.36-2.53 among those with 166-365 days) and men (RR 1.20; CI 1.17-1.24 to RR 1.91; CI 1.85-1.97). Multivariate risk estimates were comparable for the different causes of death (circulatory disease, cancer, and suicide). The two-year washout period had only a minor effect on the risk estimates. CONCLUSION: Even a low number of sick-leave days was associated with a higher risk for premature death in the following 11 years, also when adjusting for morbidity. This was the case for both women and men and also for cause specific mortality. More knowledge is warranted on the mechanisms leading to higher mortality risks among sickness absentees, as sickness certification is a common measure in health care, and most sick leave is due to diagnoses you do not die from. PMID- 25037233 TI - Requirement of dual stimulation by homologous recombinant IL-2 and recombinant IL 12 for the in vitro production of interferon gamma by canine peripheral blood mononuclear cells. AB - BACKGROUND: Very few studies have been carried out so far aiming at modulating cellular immune responses in dogs. In this study, we evaluated the ability of recombinant canine IL-2 (rcaIL-2) and IL-12, in the form of a single-chain fusion protein (rsccaIL-12), to stimulate peripheral blood mononuclear cells (PBMC) of healthy mongrel dogs. RESULTS: Recombinant canine IL-2 purified from Escherichia coli or present in the supernatant of COS-7 cells transfected with pcDNA3.1-caIL 2 (COS-7 caIL-2 supernatant) was able to induce proliferation of CTLL-2 cells, thus showing their functional activity. In addition, purified rcaIL-2 and COS-7 caIL-2 supernatant stimulated resting canine PBMC proliferation to a level higher than baseline level. Neither COS-7 sccaIL-12 supernatant nor COS-7 caIL-2 supernatant alone was able to induce significant production of interferon gamma by resting PBMC. However, COS-7 sccaIL-12 supernatant in combination with COS-7 caIL-2 supernatant induced production of IFN-gamma by those cells. CONCLUSIONS: The data shown herein suggest that the combination of canine recombinant IL-12 and IL-2 can be useful to promote cellular immune responses in dogs. PMID- 25037234 TI - Detection of circulating norovirus genotypes: hitting a moving target. AB - BACKGROUND: Although national surveillance programs are in place to monitor norovirus epidemiology, the emergence of new strains and the genetic diversity among genotypes can be challenging for clinical laboratories. This study evaluated the analytical and clinical performance characteristics of one real time RT-PCR and two end-point RT-PCRs commonly used in microbiology laboratories. METHODS: Lower limit of detection (LoD) was determined using 10-fold dilutions of noroviruses belonging to different genotypes. The clinical performance of the real-time and end-point RT-PCRs was assessed in parallel using nucleic acids extracted from 186 stool specimens. RESULTS: The real-time RT-PCR was highly sensitive and specific for the detection of norovirus genotypes that are currently circulating in Canada. In contrast, the two end-point RT-PCRs displayed poor analytical sensitivity or complete failure to detect certain norovirus genotypes, which was correlated to sequence mismatches in the primer-binding sites. In an attempt to improve norovirus detection with the end-point RT-PCRs, both assays were processed concurrently and detection from either assay was considered a positive result. Concurrent testing resulted in only a modest increase in clinical sensitivity (75.0%) compared to each assay alone (62.5% and 71.9%). However, the false positivity rate increased from 1.98% and 3.36% for the assays alone to 5.47% with concurrent testing. CONCLUSIONS: This study emphasizes the benefits of a real-time method and provides support for routine surveillance to monitor norovirus epidemiology and ongoing proficiency testing to ensure detection of circulating norovirus genotypes. PMID- 25037235 TI - Postdiagnosis body mass index and risk of mortality in colorectal cancer survivors: a prospective study and meta-analysis. AB - PURPOSE: Aim of this study was to investigate the association between postdiagnosis body mass index (BMI) and all-cause mortality in colorectal cancer (CRC) survivors in a prospective study and meta-analysis. METHODS: We conducted a prospective cohort study on 2,143 CRC survivors in Germany. Participants were recruited to the study on average 4 years after diagnosis, and postdiagnosis BMI was assessed at recruitment using a self-administered questionnaire. CRC survivors were followed up for a mean time of 3.5 years. The association between BMI and all-cause mortality was investigated using multivariable Cox proportional hazards models. Additionally, we performed a meta-analysis of studies on postdiagnosis BMI and all-cause mortality (n = 5, including this study) by applying random-effects models. RESULTS: In the prospective analysis, 349 participants died. BMI was not statistically significantly associated with all cause mortality. Compared to normal weight survivors, the hazard ratios (HRs) [95% confidence interval (CI)] for all-cause mortality in underweight, overweight and obese survivors were 1.65 (0.79-3.45), 0.80 (0.62-1.03) and 0.84 (0.62-1.14), respectively. In the meta-analysis, individuals with underweight were at increased risk for all-cause mortality [HR (95% CI) 1.72 (1.18-2.49)], whereas individuals with overweight had a lower risk [HR (95% CI) 0.79 (0.71-0.88)], compared to normal weight subjects. For obesity, the risk of mortality was also reduced with only borderline significance [HR (95% CI) 0.88 (0.77-1.00)]. CONCLUSIONS: While the present study as well as single previously published studies showed that overweight was associated with a non-significant reduced risk for all-cause mortality, our meta-analysis indicated a decreased mortality risk among overweight CRC survivors. PMID- 25037236 TI - A minimum data set approach to post-mortem computed tomography reporting for anthropological biological profiling. AB - Anthropological examination of bones is routinely undertaken in medico-legal investigations to establish an individual's biological profile, particularly their age. This often requires the removal of soft tissue from bone (de fleshing), which, especially when dealing with the recently deceased, is a time consuming and invasive procedure. Recent advances in multi-detector computed tomography have made it practical to rapidly acquire high-resolution morphological skeletal information from images of "fleshed" remains. The aim of this study was to develop a short standard form, created from post-mortem computed tomography images, that contains the minimum image-set required to anthropologically assess an individual. The proposed standard forms were created for 31 juvenile forensic cases with known age-at-death, spanning the full age range of the developing human. Five observers independently used this form to estimate age-at-death. All observers estimated age in all cases, and all estimations were within the accepted ranges for traditional anthropological and odontological assessment. This study supports the implementation of this approach in forensic radiological practice. PMID- 25037237 TI - Nails are a potential alternative matrix to hair for drug analysis in general unknown screenings by liquid-chromatography quadrupole time-of-flight mass spectrometry. AB - PURPOSE: In this study, the usefulness of nail samples instead of hair for a general unknown screening (GUS) for drugs was tested. An alternative matrix for long term detection is still needed in cases where no hair is available for analysis. METHODS: Hair and nail samples from 70 postmortem cases were analyzed by liquid-chromatography quadrupole time-of-flight mass spectrometry. Hair and nail samples were ground by a ball mill and extracted twice for 18 h. Extracts were measured in Auto MS/MS mode (data dependent mode acquisition). RESULTS: Only 10% of the cases showed a disagreement of results in hair and nail analysis where hair samples were tested positive and corresponding nail samples were tested negative in a general unknown screening for drugs. In most of the cases investigated the analysis of the nail clippings and whole nail samples led to results comparable to those obtained from hair analysis. The incorporation of a large number of substances into the nail matrix was proven by the detection of 89 different analytes (e.g. antidepressants, drugs of abuse or antihypertonics) in our tests. CONCLUSION: In cases where the amount of hair available is not sufficient for a general unknown screening for drugs, nails appear to be a useful comparable matrix for the detection of long-term drug consumption due to the comparison of the qualitative GUS results from the hair and nail samples in this study. PMID- 25037239 TI - From cerebellar texture to movement optimization. AB - The cerebellum is a major site for supervised procedural learning and appears to be crucial for optimizing sensorimotor performance. However, the site and origin of the supervising signal are still elusive. Furthermore, its relationship with the prominent neuronal circuitry remains puzzling. In this paper, I will review the relevant information and seek to synthesize a working hypothesis that explains the unique cerebellar structure. The aim of this review was to link the distinctive functions of the cerebellum, as derived from cerebellar lesion studies, with potential elementary computations, as observed by a bottom-up approach from the cerebellar microcircuitry. The parallel fiber geometry is ideal for performing millisecond computations that extract instructive signals. In this scenario, the higher time derivatives of kinematics such as acceleration and/or jerk that occur during motor performance are detected via a tidal wave mechanism and are used (with appropriate gating) as the instructive signal to guide motor smoothing. The advantage of such a mechanism is that movements are optimized by reducing "jerkiness" which, in turn, lowers their energy requirements. PMID- 25037238 TI - Chemical ecology of phytohormones: how plants integrate responses to complex and dynamic environments. PMID- 25037240 TI - Integrate-and-fire neurons driven by asymmetric dichotomous noise. AB - We consider a general integrate-and-fire (IF) neuron driven by asymmetric dichotomous noise. In contrast to the Gaussian white noise usually used in the so called diffusion approximation, this noise is colored, i.e., it exhibits temporal correlations. We give an analytical expression for the stationary voltage distribution of a neuron receiving such noise and derive recursive relations for the moments of the first passage time density, which allow us to calculate the firing rate and the coefficient of variation of interspike intervals. We study how correlations in the input affect the rate and regularity of firing under variation of the model's parameters for leaky and quadratic IF neurons. Further, we consider the limit of small correlation times and find lowest order corrections to the first passage time moments to be proportional to the square root of the correlation time. We show analytically that to this lowest order, correlations always lead to a decrease in firing rate for a leaky IF neuron. All theoretical expressions are compared to simulations of leaky and quadratic IF neurons. PMID- 25037241 TI - Clinical engineering and uncertainty in clinical measurements. PMID- 25037242 TI - Hypoadiponectinemia correlates with arterial stiffness in kidney transplantation patients. AB - BACKGROUND: Adiponectin is a fat-derived hormone produced and secreted exclusively by adipocytes that have anti-atherosclerotic effects. The aim of this study was to evaluate the relationship between fasting serum adiponectin levels and arterial stiffness among kidney transplant (KT) patients. METHODS: Fasting blood samples were obtained from 69 KT patients. Brachial-ankle pulse wave velocity (baPWV) was measured in the right or left brachial artery to the ankle segments using an automatic pulse wave analyzer. Plasma adiponectin levels were measured using a commercial enzyme-linked immunosorbent assay kit. Left or right baPWV values of >14.0 m/s were used to define the high arterial stiffness group. RESULTS: Thirty-five KT patients (35/69; 50.7 %) were defined in high arterial stiffness group. Diabetes (P = 0.013), smoking (P = 0.001), KT duration (P < 0.001), body weight (P = 0.013), waist circumference (P = 0.013), body mass index (P = 0.001), fasting glucose (P = 0.013), systolic blood pressure (P < 0.001), diastolic blood pressure (P = 0.008), and pulse pressure (P = 0.003) were higher, while serum adiponectin level (P = 0.004) was lower in high arterial stiffness group compared with low arterial stiffness group. Multivariate logistic regression analysis showed that adiponectin (odds ratio 0.90, 95 % confidence interval 0.81-0.99, P = 0.034) was still the independent predictors of arterial stiffness among the KT patients. CONCLUSION: Serum fasting adiponectin level was inversely associated with arterial stiffness among KT patients. PMID- 25037243 TI - Intravitreal diclofenac versus intravitreal bevacizumab in naive diabetic macular edema: a randomized double-masked clinical trial. AB - The purpose of the study is to compare single injection of intravitreal diclofenac (IVD) with intravitreal bevacizumab (IVB) in the treatment of eyes with naive diabetic macular edema (DME). In this randomized clinical trial, 57 eyes of 57 patients were randomly assigned to IVD group (30 eyes), cases who received a single intravitreal injection of diclofenac (500 MUg/0.1 ml), and IVB group (27 eyes), cases who received a single intravitreal injection of bevacizumab (1.25 mg). Change in best-corrected visual acuity in logMAR at week 12 was the primary outcome measure. Secondary outcomes included changes in central macular thickness, macular leakage, and potential injection-related complications. Best-corrected visual acuity improved significantly more in the IVD group than in the IVB group (P = 0.033), from 0.57 +/- 0.25 to 0.49 +/- 0.31 versus 0.55 +/- 0.24-0.59 +/- 0.27 logMAR at 12 weeks, respectively. However, the difference of macular thickness changes was in favor of IVB, but not to a significant level. The amount of change in leakage was not significantly different between the groups either. None of the eyes, in either group, developed ocular hypertension (>=23 mmHg) or cataract progression. No important injection related complication was observed during the study period. This study demonstrated the superiority of IVD over IVB in the treatment of naive DME regarding functional, but not anatomical outcomes. Therefore, using IVD as an adjunct or even alternative to other treatments might enhance the functional outcomes in such cases. Further studies are warranted to confirm potential benefit of IVD observed in this study. PMID- 25037244 TI - A gentle ethical defence of homeopathy. AB - Recent discourses about the legitimacy of homeopathy have focused on its scientific plausibility, mechanism of action, and evidence base. These, frequently, conclude not only that homeopathy is scientifically baseless, but that it is "unethical." They have also diminished patients' perspectives, values, and preferences. We contend that these critics confuse epistemic questions with questions of ethics, misconstrue the moral status of homeopaths, and have an impoverished idea of ethics-one that fails to account either for the moral worth of care and of relationships or for the perspectives, values, and preferences of patients. Utilitarian critics, in particular, endeavour to present an objective evaluation-a type of moral calculus-quantifying the utilities and disutilities of homeopathy as a justification for the exclusion of homeopathy from research and health care. But these critiques are built upon a narrow formulation of evidence and care and a diminished episteme that excludes the values and preferences of researchers, homeopaths, and patients engaged in the practice of homeopathy. We suggest that homeopathy is ethical as it fulfils the needs and expectations of many patients; may be practiced safely and prudentially; values care and the virtues of the therapeutic relationship; and provides important benefits for patients. PMID- 25037246 TI - Exploring the influence of demographic and medical characteristics of African American and Latinas on enrollment in a behavioral intervention study for breast cancer survivors. AB - PURPOSE: To better understand research participation among hard-to-reach populations, this exploratory investigation examined characteristics of enrollees and non-enrollees from a population-based longitudinal study with African American and Latina-American breast cancer survivors. METHODS: A mixed-method recruitment approach was utilized to enroll participants from cancer registries and community groups who were 1-6 years post-diagnosis. RESULTS: Four hundred and sixty-eight participants agreed to participate constituting an 81% participation rate; 65 and 55% completed Time-1, and both Time-1 and Time-2 assessments, respectively. African-Americans were more likely to agree to participate and complete the T1 assessment (73%) than Latinas (62%) (p < 0.05). Participation was influenced by educational attainment and comorbidities (p < 0.05) for African Americans. Among Latinas, language proficiency, comorbidities and psychological difficulties (p < 0.01) influenced participation. CONCLUSIONS: Our findings suggest that enrollment in research studies may be influenced by complex and multi-dimensional factors stemming from subjects' characteristics including ethnicity, culture, language proficiency and literary, and socioeconomic status, as well as medical characteristics including co-occurring chronic illness and psychological status. Thus, comprehensive, multi-method research studies are urgently needed to better understand and address the challenge of minority recruitment in biomedical research. To increase research participation among cancer survivors, it is imperative to implement focused strategies that will support and encourage individuals' enrollment and continued participation in studies. PMID- 25037245 TI - Queering know-how: clinical skill acquisition as ethical practice. AB - Our study of queer women patients and their primary health care providers (HCPs) in Halifax, Nova Scotia, reveals a gap between providers' theoretical knowledge of "cultural competency" and patients' experience. Drawing on Patricia Benner's Dreyfusian model of skill acquisition in nursing, we suggest that the dissonance between the anti-heteronormative principles expressed in interviews and the relative absence of skilled anti-heteronormative clinical practice can be understood as a failure to grasp the field of practice as a whole. Moving from "knowing-that" to "knowing-how" in terms of anti-heteronormative clinical skills is not only a desirable epistemological trajectory, we argue, but also a way of understanding better and worse ethical practice. PMID- 25037248 TI - Medical student communication skills and specialty choice. AB - OBJECTIVE: The aim of this study was to determine if communication skills differ for medical students entering person or technique-oriented specialties. METHODS: Communication ratings by clerkship preceptors on an institutionally required end of clerkship medical student performance evaluation (SPE) form were compiled for 2011/2012 academic year (Class of 2013). M3 clerkships and the Class of 2013 match appointments were categorized as person or technique-oriented clerkships/specialties. Mean differences in SPE communication scores were determined by analyses of variance (ANOVA) and independent t tests. Score associations were determined by Pearson correlations. Inter-item reliability was reported with Cronbach alpha. RESULTS: The Class of 2013 match appointments were as follows: person-oriented (N = 91) and technique-oriented (N = 91) residency specialties. There was no significant difference in mean communication scores for medical students who entered person-oriented (mean 7.8, SD 0.4) versus technique oriented (mean 7.9, SD 0.4) specialties (p = 0.258) or for person-oriented clerkship (mean 7.8, SD 0.4) versus technique-oriented clerkship (mean 7.9, SD 0.6) ratings for medical students who matched into person-oriented specialties (p = 0.124). Medical students who matched into technique-oriented specialties (mean 8.1, SD 0.5) received significantly higher (p = 0.001) communication ratings as compared with those matching into person-oriented specialties (mean 7.8, SD 0.5) from technique-oriented clerkships. CONCLUSIONS: Communication with patients and families is a complex constellation of specific abilities that appear to be influenced by the rater's specialty. Further study is needed to determine if technique-oriented specialties communication skill rating criteria differ from those used by raters from person-oriented specialties. PMID- 25037247 TI - Improvement in Th1/Th2 immune homeostasis, antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice. AB - Imbalance in Th1/Th2 immune pathways and cellular antioxidant systems with progressive aging are among the leading causes of increased risk of morbidity and mortality in elderly. Although probiotics have been considered to boost immune system, there is a lack of comprehensive analysis of probiotic effects on aging physiology. The present study aimed at determining anti-immunosenescence potential of milk fermented with probiotic Lactobacillus rhamnosus (LR) in 16 months old mice by concurrent analysis of immunosenescence markers associated with Th1/Th2 profile of splenocytes, inflamm-aging in plasma, neutrophil functions and antibody response in intestine along with analysis of antioxidant enzymes in liver and red blood cells (RBCs) after feeding trials of 1 and 2 months, respectively. An enteropathogenic Escherichia coli (ATCC 14948)-based infection model in aging mice was also designed to validate protective attributes of LR. Splenocytes registered increased IFN-gamma and decreased IL-4 and IL-10 production in LR-fed animals. Neutrophil respiratory burst enzymes and phagocytosis increased significantly while no aggravation in plasma levels of MCP 1 and TNF-alpha was observed. Further, owing to increased Th1 response, antibodies registered a decrease in IgG1/IgG2a ratio and IgE levels in LR groups. No significant variations were observed in secretory IgA and IgA + cells in the intestine. Antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in LR-fed groups recorded increased activities which were more pronounced in the liver than in RBCs. LR supplementation significantly reduced E. coli translocation to organs (intestine, liver, spleen, peritoneal fluid) by enhancing E. coli-specific antibodies (IgA and IgG1) and inflammatory proteins. In conclusion, LR supplementation alleviated immunosenescence-associated Th1/Th2 imbalance, improved antioxidant capacity, and enhanced resistance of aged mice to E. coli infection thereby signifying its potential in augmenting healthy aging. PMID- 25037250 TI - De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation. AB - Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics. PMID- 25037252 TI - Introduction. PMID- 25037251 TI - Impact of continuous glucose monitoring on quality of life, treatment satisfaction, and use of medical care resources: analyses from the SWITCH study. AB - To investigate the impact of continuous glucose monitoring (CGM) on health related quality of life (HRQOL), treatment satisfaction (TS) medical resource use, and indirect costs in the SWITCH study. SWITCH was a multicentre, randomized, crossover study. Patients with type 1 diabetes (n = 153) using continuous subcutaneous insulin infusion (CSII) were randomized to a 12 month sensor-On/Off or sensor-Off/On sequence (6 months each treatment), with a 4-month washout between periods. HRQOL in children and TS in adults were measured using validated questionnaires. Medical resource utilization data were collected. In adults, TS was significantly higher in the sensor-On arm, and there were significant improvements in ratings for treatment convenience and flexibility. There were no clinically significant differences in children's HRQOL or parents' proxy ratings. The incidence of severe hypoglycaemia, unscheduled visits, or diabetes-related hospitalizations did not differ significantly between the two arms. Adult patients made fewer telephone consultations during the sensor-On arm; children's caregivers made similar numbers of telephone consultations during both arms, and calls were on average only 3 min longer during the sensor-On arm. Regarding indirect costs, children with >70 % sensor usage missed fewer school days, compared with the sensor-Off arm (P = 0.0046) but there was no significant difference in the adults days of work off. The addition of CGM to CSII resulted in better metabolic control without imposing an additional burden on the patient or increased medical resource use, and offered the potential for cost offsets. PMID- 25037249 TI - Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. AB - Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets. PMID- 25037253 TI - Epidemiology of severe drug hypersensitivity. AB - Epidemiological studies of severe drug hypersensitivities are important to understanding the morbidity and mortality of this heterogeneous group of disorders. These insights also allow greater identification of at-risk patient groups. However, epidemiological studies of drug hypersensitivity reactions are challenging due to the variable diagnostic criteria applied and incomplete data sets studied. We review the epidemiology of severe drug hypersensitivity reactions with a particular focus on severe cutaneous adverse reactions (SCARs). SCAR diseases include: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, serum-sickness-like reaction and acute generalized exanthematous pustulosis. PMID- 25037254 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. AB - Severe cutaneous adverse reactions are associated with significant morbidity and mortality. They may be life-threatening for the affected patient and difficult to treat. Such conditions include toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms. Due to the fact that prognosis, etiology and treatment of the various reactions differ, a clear diagnosis based on the specific clinical pattern is important. This review will focus on the clinical presentations, pathogenesis, and important diagnostic and therapeutic considerations in the management of SJS and TEN. PMID- 25037255 TI - Severe cutaneous adverse reactions: impact of immunology, genetics, and pharmacology. AB - Severe cutaneous adverse reactions, though rare, represent a mucocutaneous presentation of adverse drug responses associated with significant morbidity and mortality. Here, we review the recent literature highlighting the roles of selective immune responses, genetic factors, and drug metabolism in increasing susceptibility of a given patient to these rare and severe reactions. Further understanding of these factors and their relative contributions to a severe drug reaction may hold important implications for future patient-specific pharmacogenomic and immunologic profiling in an effort to personalize prescribing patterns by clinicians. Emerging concepts, such as the role of viral reactivation and the presence of overlapping clinical features in severe drug eruptions, are also discussed. PMID- 25037256 TI - Dermatologic adverse events to chemotherapeutic agents, part 1: cytotoxics, epidermal growth factor receptors, multikinase inhibitors, and proteasome inhibitors. AB - Dermatologic toxicities have profound effects on patients receiving chemotherapy for cancer treatment. Cytotoxic chemotherapies are associated with a number of nonspecific dermatologic adverse events including alopecia, mucositis, and onychodystrophy. Targeted therapies including epidermal growth factor inhibitors, multikinase inhibitors, and proteasome inhibitors are associated with different skin reactions that are class-specific. In Part 1 of this review, we examine the presentations of the most common dermatologic adverse events associated with the above drugs and discuss the strategies used for their prevention and treatment. PMID- 25037257 TI - Dermatologic adverse events to chemotherapeutic agents, Part 2: BRAF inhibitors, MEK inhibitors, and ipilimumab. AB - The advent of novel targeted chemotherapeutic agents and immunotherapies has dramatically changed the arena of cancer treatment in recent years. BRAF inhibitors, MEK inhibitors, and ipilimumab are among the newer chemotherapy drugs that are being used at an increasing rate. Dermatologic adverse events to these medications are common, and it is important for dermatologists and oncologists alike to learn to recognize and treat such side effects in order to maintain both patients' quality of life and their anticancer treatment. This review describes the cutaneous side effects seen with BRAF inhibitors (eg, maculopapular eruption, photosensitivity, squamoproliferative growths, melanocytic proliferations), MEK inhibitors (eg, papulopustular eruption), and ipilimumab (eg, maculopapular eruption, vitiligo), with a mention of vismodegib and anti-PD-1 agents. PMID- 25037258 TI - Severe drug-induced dermatoses. AB - A variety of common dermatoses are known to have drug-induced variants. This article discusses the clinical presentation, time frames, reported culprit medications, pathophysiology and management of drug-induced lupus, cutaneous vasculitis, pemphigus, pemphigoid, linear IgA bullous dermatosis, Sweet's syndrome, erythema nodosum, pyoderma gangrenosum, pseudolymphoma, lichen planus, and psoriasis. PMID- 25037259 TI - Congenital vesicovaginal fistula: spontaneous or forced? Two cases and literature review. AB - INTRODUCTION AND HYPOTHESIS: Congenital vesicovaginal fistula is an exceedingly rare entity. There is no consensus regarding the nature and origin of this condition. We report two cases with congenital vesicovaginal fistula and compile previously reported cases in the English literature. Theories behind the genesis of this anomaly will be briefly presented. METHODS: We describe the presentation, diagnostic workup, and management of two patients with congenital vesicovaginal fistula. Previously reported cases were retrieved through an extensive English literature review using Medline and PubMed. Cases are tabulated based on the presence or absence of vaginal menstrual outflow obstruction. RESULTS: Two women, aged 23 and 17, had had cyclic hematuria since puberty that was perceived as normal menstruation. One woman presented with an inability to have sexual intercourse, and the other with severe cyclic pelvic pain. Diagnostic workup unveiled congenital vesicovaginal fistula and distal vaginal agenesis in both. One had abnormal ureteric insertion, while the other had a history of anomalies unrelated to the urogenital system. Successful surgical correction of fistula was undertaken in both. An English literature review revealed 23 reported cases of congenital vesicovaginal fistula. While 74 % had concomitant menstrual outflow obstruction, the remaining had normal menstruation per vagina. CONCLUSION: Congenital vesicovaginal fistula can present as an isolated anomaly, or associated with complex malformations of a wide spectrum. The presenting symptoms as well as the age at diagnosis vary widely. While the term "congenital" implies its genesis before birth, a congenital vesicovaginal fistula can be a manifestation of faulty embryological development, but also the result of outflow obstruction. PMID- 25037261 TI - Regulation of nucleocytoplasmic transport by ADP-ribosylation: the emerging role of karyopherin-beta1 mono-ADP-ribosylation by ARTD15. AB - Post-translational modifications of a cellular protein by mono- and poly-ADP ribosylation involve the cleavage of NAD (+) , with the release of its nicotinamide moiety. This is accompanied by the transfer of a single (mono-) or several (poly-) ADP-ribose molecules from NAD (+) to a specific amino-acid residue of the protein. Recent reports have shed new light on the correlation between NAD (+) -dependent ADP-ribosylation reactions and the endoplasmic reticulum, in addition to the well-documented roles of these reactions in the nucleus and mitochondria. We have demonstrated that ARTD15/PARP16 is a novel mono ADP-ribosyltransferase with a new intracellular location, as it is associated with the endoplasmic reticulum. The endoplasmic reticulum, which is a membranous network of interconnected tubules and cisternae, is responsible for specialised cellular functions, including protein folding and protein transport. Maintenance of specialised cellular functions requires the correct flow of information between separate organelles that is made possible through the nucleocytoplasmic trafficking of proteins. ARTD15 appears to have a role in nucleocytoplasmic shuttling, through karyopherin-beta1 mono-ADP-ribosylation. This is in line with the emerging role of ADP-ribosylation in the regulation of intracellular trafficking of cellular proteins. Indeed, other, ADP-ribosyltransferases like ARTD1/PARP1, have been reported to regulate nucleocytoplasmic trafficking of crucial proteins, including p53 and NF-kappaB, and as a consequence, to modulate the subcellular localisation of these proteins under both physiological and pathological conditions. PMID- 25037260 TI - Structural characterization of viral epitopes recognized by broadly cross reactive antibodies. AB - Influenza hemagglutinin (HA) is the major surface glycoprotein on influenza viruses and mediates viral attachment and subsequent fusion with host cells. The HA is the major target of the immune response, but due to its high level of variability, as evidenced by substantial antigenic diversity, it had been historically considered to elicit only a narrow, strain-specific antibody response. However, a recent explosion in the discovery of broadly neutralizing antibodies (bnAbs) to influenza virus has identified two major supersites of vulnerability on the HA through structural characterization of HA-antibody complexes. These commonly targeted epitopes are involved with receptor binding as well as the fusion machinery and, hence, are functionally conserved and less prone to mutation. These bnAbs can neutralize viruses by blocking infection or the spread of infection by preventing progeny release. Structural analyses of these bnAbs show they exhibit striking similarities and trends in recognition of the HA and use recurring recognition motifs, despite substantial differences in their germline genes. This information can be utilized in design of novel therapeutics as well as in immunogens for improved vaccines with greater breadth and efficacy. PMID- 25037262 TI - [Quality of life and job performance resulting from operatively treated tibial plateau fractures]. AB - BACKGROUND: The aim of this article is to present the functional results and the effect on quality of life of surgically treated tibial plateau fractures in physically active and working patients with multiple and serious injuries. In addition, the relationships between functional and radiological outcome were evaluated and compared with activity in daily and professional life. PATIENTS AND METHODS: In all, 41 injured patients were followed up a mean of 47 months after surgical treatment and examined with radiological, functional, as well as quality of life score. RESULTS: In the radiological scoring, a mean value of 72 points (max 100 points) was achieved. In the activity score, there was an average of 63.5 points (max 100 points). When evaluating the health-related quality of life, an average score of 69.6 points was achieved. There was a significant relationship between radiological and activity scores and the radiological and life quality scores. Furthermore, the relationship between activity and quality of life scores was considered significant. Surgeon's influence on the functional outcome could be confirmed. CONCLUSION: The functional and the radiological results were moderate. Quality of life was permanently affected by the consequences of tibial plateau fracture in 12 patients; 11 patients were not re employed. However, the quality of life was assessed as good or very good and 28 patients had returned to work. The quality of life was firmly linked to the radiological and functional parameters, which tended to be influenced by the quality of the primary surgical treatment when looking at the overall population. PMID- 25037264 TI - Association of research self-efficacy with medical student career interests, specialization, and scholarship: a case study. AB - This study used variables proposed in social cognitive career theory (SCCT) to focus the evaluation of a research curriculum at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (CCLCM). Eight cohorts of CCLCM medical students completed a web-based version of the six-scale Clinical Research Appraisal Inventory-Short Form (CRAI-SF) items at matriculation (n = 128) or graduation (n = 111) during 2009-2013. Parametric statistics were used to compare CRAI-SF scales to domains proposed in SCCT: trainees' characteristics (gender, training level, advanced degree), career interests, career intentions (medical specialty), and performance (peer-reviewed publications and required thesis topic). A number of lessons emerged in using theory to frame the evaluation of a complex educational program. Graduates rated their research self efficacy significantly higher on all six CRAI-SF scales with large effect sizes (>.90) on five scales (Conceptualizing a Study, Study Design and Analysis, Responsible Research Conduct, Collaborating with Others, and Reporting a Study). Women and men did not have significantly different scores on CRAI-SF scales (p > .05), suggesting that the research program provides adequate supports for women students. Most thesis projects addressed clinical (36.9 %, n = 41) or translational (34.2 %, n = 38) research topics. The CRAI-SF discriminated between medical school matriculates and graduates, suggesting that research self-efficacy increases with mastery experiences. No significant relationships occurred between CRAI-SF scores and graduates' thesis topics or chosen clinical specialty. Correlations demonstrated significant relationships between graduates' perceptions of research self-efficacy and their interest in clinical research careers. PMID- 25037263 TI - Orbitofrontal neurons acquire responses to 'valueless' Pavlovian cues during unblocking. AB - The orbitofrontal cortex (OFC) has been described as signaling outcome expectancies or value. Evidence for the latter comes from the studies showing that neural signals in the OFC correlate with value across features. Yet features can co-vary with value, and individual units may participate in multiple ensembles coding different features. Here we used unblocking to test whether OFC neurons would respond to a predictive cue signaling a 'valueless' change in outcome flavor. Neurons were recorded as the rats learned about cues that signaled either an increase in reward number or a valueless change in flavor. We found that OFC neurons acquired responses to both predictive cues. This activity exceeded that exhibited to a 'blocked' cue and was correlated with activity to the actual outcome. These results show that OFC neurons fire to cues with no value independent of what can be inferred through features of the predicted outcome. PMID- 25037265 TI - Only Simpson diversity can be estimated accurately from microbial community fingerprints. AB - Lalande et al. (Microb. Ecol. 66(3):647-658, 2013) introduced a promising approach to quantify microbial diversity from fingerprinting profiles. Their analysis is based on extrapolating the abundance of the phylotypes detectable in a fingerprint towards the rare phylotypes of the community. By considering a set of reconstructed communities, Lalande et al. obtained a range of estimates for phylotype richness, Shannon diversity and Simpson diversity. They reported narrow ranges indicating accurate estimation, especially for Shannon and Simpson diversities. Here, we show that a much larger set of reconstructed communities than the one considered by Lalande et al. is consistent with the fingerprint. We find that the estimates for phylotype richness and Shannon diversity vary over orders of magnitude, but that the estimates for Simpson diversity are restricted to a narrow range (around 10 %). We conclude that only Simpson diversity can be estimated accurately from fingerprints. PMID- 25037266 TI - Influences of patient age on deep neck infection: clinical etiology and treatment outcome. AB - OBJECTIVES: To analyze the differences in clinical features, etiology, treatment modalities, and microbiology of the deep neck infections between the elderly and the adults. STUDY DESIGN: Cases series. SETTING: Single hospital. SUBJECTS AND METHODS: A retrospective review was performed on patients older than 18 years of age with diagnosis of deep neck infection from January 2008 to December 2012. A total of 148 patients were enrolled in this study, including 32 elderly (older than 65 years of age) and 116 adults who aged between 18 and 65. Data collected included age, gender, clinical presentations, etiology, treatment modalities, and microbiology. RESULTS: Odontogenic and salivary origin were the most common sources of infection for the elderly group, whereas the odontogenic and tonsillar origin were the most common sources of deep neck infections in the adult group. Compared to the adult group, the elderly group had significantly higher ratio with multiple spaces involved (53.1% vs 30.2%, P = .016), complication (15.6% vs 4.3%, P = .024), and surgical interventions (75.0% vs 38.8%, P < .001), in addition to longer hospital stay (11.1 +/- 7.2 days vs 8.2 +/- 4.5 days, P = .029). CONCLUSION: Compared to the adult group, the elderly patients with deep neck infection had more cases with multiple spaces involvement, complications, surgical interventions, and longer hospital stay. However, the outcome of the elderly group was the same as the adult group. Therefore, the benefits of aggressive management for deep neck infection should not be withheld from patients simply because of the old age. PMID- 25037267 TI - Implicit learning mediates base rate acquisition in perceptual categorization. AB - We explored the possibility, suggested by Koehler (Behavioral and Brain Sciences, 19, 1-53, 1996; also Spellman Behavioral and Brain Sciences, 19, 38, 1996), that implicit learning mediates the influence of base-rates on category knowledge acquired through direct experience. In two experiments, participants learned simple perceptual categories with unequal base-rates (i.e., presentation frequency). In Experiment 1, participants received either response training or observational training. In Experiment 2, participants received response training with either immediate or delayed feedback. In previous studies, observational training and delayed feedback training have been shown to disrupt implicit learning. We found that base-rate influence was weaker in these conditions when category discriminability was low (i.e., when category membership was difficult to determine). This conclusion was based on signal detection beta values as well as decision-bound modeling results. Because these disruptions to implicit learning attenuate the base-rate effect, we conclude that implicit learning does indeed underlie the influence of base-rates learned through direct experience. This suggests that the implicit learning system postulated by the COVIS theory of categorization (Ashby, Alfonso-Reese, Turken, & Waldron Psychological Review, 105, 442-481, 1998) may be involved in developing sensitivity to category base rates. PMID- 25037268 TI - Hemorrhagic hepatic cyst after allogeneic bone marrow transplantation. PMID- 25037269 TI - Lily breeding by using molecular tools and transformation systems. AB - In our review, we highlighted the progresses made in molecular breeding of lily's flowering, including the ABCDE models, the gene cloning, the establishment of regeneration system, the gene transformation methods, the transgene technology application in lily. Meanwhile, questions that were met at present in molecular breeding in flowering of lily were underlined, and we provide viable solutions. Although many researches on lily literature had been published in the world, in our review, we provided a valuable and unique resource and spring-board from which to understand or further study the molecular breeding in flowering of lily. PMID- 25037270 TI - Hepatocellular carcinoma: targeting of oncogenic signaling networks in TRAIL resistant cancer cells. AB - Apoptotic response in hepatocellular carcinoma (HCC) cells is impaired because of interconnectivity of proteins into complexes and signaling networks that are highly divergent in time and space. TNF-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive anticancer agent reported to selectively induce apoptosis in cancer cells. Although diametrically opposed roles of TRAIL are reported both as an inducer of apoptosis and regulator of metastasis, overwhelmingly accumulating experimental evidence highlighting apoptosis inducing activity of TRAIL is directing TRAIL into clinical trials. Insights from TRAIL mediated signaling in HCC research are catalyzing new lines of study that should not only explain molecular mechanisms of disease but also highlight emerging paradigms in restoration of TRAIL mediated apoptosis in resistant cancer cells. It is becoming progressively more understandable that phytochemicals derived from edible plants have shown potential in modelling their interactions with their target proteins. Rapidly accumulating in vitro and in-vivo evidence indicates that phytonutrients have anticancer activity in rodent models of hepatocellular carcinoma. In this review we bring to limelight how phytonutrients restore apoptosis in hepatocellular carcinoma cells by rebalancing pro-apoptotic and anti apoptotic proteins. Evidence has started to emerge, that reveals how phytonutrients target pharmacologically intractable proteins to suppress cancer. Target-based small-molecule discovery has entered into the mainstream research in the pharmaceutical industry and a better comprehension of the genetics of patients will be essential for identification of responders and non-responders. PMID- 25037271 TI - Multiple correlations of mRNA expression and protein abundance in human cytokine profile. AB - With the development of genomic study, researchers found that it is insufficient to predict protein expression from quantitative mRNA data in large scale, which is contrary to the traditional opinion that mRNA expression correlates with protein abundance at the single gene level. To try to solve the apparent conflicting views, here we set up a series of research models and chose soluble cytokines as targets. First, human peripheral blood mononuclear cell (PBMC) from one health donor was treated with 16 continuously changing conditions, the protein and mRNA profile were analyzed by multiplex Luminex and genomic microarray, respectively. Among the tested genes, around half mRNA correlated well with their corresponding proteins (rho > 0.8), however if we put all the genes together, the correlation coefficient for the 16 conditions varied from 0.29 to 0.71. Second, PBMC from 14 healthy donors were stimulated with the same condition and it was found that the correlation coefficient went down (rho < 0.6). Third, 28 rheumatoid arthritis (RA) patients were tested for their response to the same external stimuli and it turned out different individual displayed different protein expression pattern as expect. Lastly, autoimmune disease cohorts (8 diseases including RA, 103 patients in total) were assayed on the whole view. It was observed that there was still some similarity in the protein profile among patients from the single disease type although completely different patterns were displayed across different disease categories. This study built a good bridge between single gene analysis and the whole genome study and may give a reasonable explanation for the two conflicting views in current biological science. PMID- 25037272 TI - A novel measurement of allele discrimination for assessment of allele-specific silencing by RNA interference. AB - Allele-specific silencing by RNA interference (ASP-RNAi) is an atypical RNAi that is capable of discriminating target alleles from non-target alleles, and may be therapeutically useful for specific inhibition of disease-causing alleles without affecting their corresponding normal alleles. However, it is difficult to design and select small interfering RNA (siRNAs) that confer ASP-RNAi. A major problem is that there are few appropriate measures in determining optimal allele-specific siRNAs. Here we show two novel formulas for calculating a new measure of allele discrimination, named "ASP-score". The formulas and ASP-score allow for an unbiased determination of optimal siRNAs, and may contribute to characterizing such allele-specific siRNAs. PMID- 25037273 TI - Functional analysis and molecular characterization of spontaneously outgrown human lymphoblastoid cell lines. AB - In vitro, the infection of human B-cells with the lymphotropic gammaherpesvirus Epstein-Barr virus (EBV) induces formation of permanently growing lymphoblastoid cell lines (LCL). In a spontaneously outgrown LCL (cell line CSIII), we detected nucleotide sequence variations of the EBV nuclear antigen 1 (EBNA1) RNA that was different from the reference sequence of EBNA1 in the prototypic EBV strain B95 8. In the present study, we molecularly and functionally characterized this virus isolate in comparison to LCL with the prototypic nucleotide sequence. Although we detected high functional similarity between CSIII and the other LCL, our data suggest that the lytic cycle might be ineffective in the CSIII LCL. DNA microarray analysis indicated that RNA binding motif, single stranded interacting protein 1 (RBMS1), which is typically expressed in latency III of EBV to prevent the lytic cycle, was the most overexpressed gene in CSIII LCL. PMID- 25037274 TI - Autoimmune diseases association study with the KIAA1109-IL2-IL21 region in a Tunisian population. AB - Autoimmune diseases (ADs) share several genetic factors resulting in similarity of disease mechanisms. For instance polymorphisms from the KIAA1109-interleukin 2 (IL2)-IL21 block in the 4q27 chromosome, has been associated with a number of autoimmune phenotypes. Here we performed a haplotype-based analysis of this AD related region in Tunisian patients. Ten single nucleotide polymorphisms (rs6534347, rs11575812, rs2069778, rs2069763, rs2069762, rs6852535, rs12642902, rs6822844, rs2221903, rs17005931) of the block were investigated in a cohort of 93 systemic lupus erythematosus (SLE), 68 ulcerative colitis (UC), 39 Crohn's disease (CD) patients and 162 healthy control subjects of Tunisian origin. In SLE population, haplotypes AGCAGGGTC, AGAAGAGTC, AGAAGGGTC and AGCCGAGTC provided significant evidence of association with SLE risk (p = 0.013, 0.028, 0.018 and 0.048, respectively). In the UC population, haplotype AGCCGGGTC provided a susceptibility effect for UC (p = 0.025). In the CD population, haplotype CAGGCC showed a protective effect against the development of CD (p = 0.038). Haplotype AAGGTT provided significant evidence to be associated with CD risk (p = 0.007). Our results support the existence of the associations found in the KIAA1109/IL2/IL21 gene region with ADs, thus confirms that the 4q27 locus may contribute to the genetic susceptibility of ADs in the Tunisian population. PMID- 25037275 TI - Primary posterior stabilized total knee arthroplasty: analysis of different instrumentation. AB - BACKGROUND: Intercondylar femoral bone removal during posterior stabilized (PS) total knee arthroplasty (TKA) makes many cruciate substituting implant designs less appealing than cruciate retaining implants. Bone stock conservation is considered fundamental in the prevision of future revision surgeries. The purpose of this study was to compare the quantity of intercondylar bone removable during PS housing preparation using three contemporary PS TKA instrumentations. METHOD: We compared different box cutting jigs which were utilized for the PS housing of three popular PS knee prostheses. The bone removal area from every PS box cutting jig was three-dimensionally measured. RESULTS: Independently from the implant size, the cutting jig for a specific PS TKA always resected significantly less bone than the others: this difference was statistically significant, especially for small- to medium-sized total knee femoral components. CONCLUSION: This study does not establish a clinical relevance of removing more or less bone at primary TKA, but suggests that if a PS design is indicated, it is preferable to select a model which possibly resects less distal femoral bone. PMID- 25037276 TI - Hyaluronidase-loaded PLGA microparticles as a new strategy for the treatment of pulmonary fibrosis. AB - The aim of this work was to develop an innovative tool for the treatment of pulmonary fibrosis based on our previous findings, which demonstrated that intranasally administered soluble bovine hyaluronidase (HYAL) increases the numbers of mesenchymal (MSC)-like cells in the bronchoalveolar fluid (BALF) and thus reduces the bleomycin-induced fibrosis. To this end, we developed poly(D,L lactide-co-glycolide) (PLGA) microparticles (MPs) loaded with HYAL (HYAL-MP) to preserve the enzyme's biological activity and to facilitate its delivery to the lung. Nonloaded MPs (Control-MPs) and HYAL-MPs were prepared using the emulsion and solvent evaporation methods and thoroughly characterized. The HYAL-MPs and Control-MPs exhibited an average diameter of 4.3+/-2.1 and 4.4+/-1.5 MUm, respectively. The encapsulation efficiency of the HYAL-MPs was 68%, and encapsulation led to a reduced release rate. Additionally, the HYAL-MPs were efficiently phagocytosed by J-774.1 cells. Compared with the soluble HYAL, the HYAL-MPs increased the proportion of MSC-like cells in the BALF of C57BL6 mice 96 h after treatment. The efficacy of the HYAL-MPs was also tested in C57BL6 mice that were previously exposed to 4 U/kg of bleomycin to induce lung fibrosis. The results demonstrated that the HYAL-MPs reduced neutrophil recruitment after bleomycin treatment more effectively than did the soluble HYAL, whereas the Control-MPs did not exhibit any effect. The HYAL-MPs also reduced the bleomycin induced fibrosis more efficiently, and 134% of the collagen deposition in the lung compared with the soluble HYAL and the Control-MPs. In summary, our data indicate that HYAL-MPs are an effective delivery system that could feasibly be used in the treatment of pulmonary fibrosis. PMID- 25037277 TI - Left dominance of EEG abnormalities in patients with transient global amnesia. AB - PURPOSE: Transient global amnesia (TGA) is a syndrome of unknown etiology. Electroencephalographic (EEG) abnormalities in TGA have been reported previously. We analyzed the frequency and characteristics of EEG abnormalities in patients with TGA. METHODS: We collected EEGs of patients with a clinical diagnosis of TGA who had visited the emergency room or the outpatient clinic over a period of 8 years and compared clinical and demographic characteristics of the patients with normal EEGs with those with abnormal EEGs. RESULTS: EEG abnormalities were found in 35 (22.9%) out of 153 patients and epileptiform discharges were seen in 26 (74.3%) out of these 35 patients. Spikes or sharp waves were detected on the left side only (48.6%) or on both sides (25.7%), but none of the patients showed spikes or sharp waves on right side only. In six patients the EEG had normalized within three months of presentation, in ten within six months, and in twelve by one year. The EEG remained abnormal in eleven out of the 23 patients one year after presentation. CONCLUSION: In this largest consecutive EEG study at one center, the proportion of patients with TGA in whom epileptiform discharges were demonstrated within days of the episode of TGA was significantly higher than in the previous literature. EEG abnormalities such as spikes or sharp waves spontaneously disappeared in almost half of cases over one-year of follow-up. There was a clear left dominance of EEG abnormalities in patients with TGA. PMID- 25037278 TI - Using Google Flu Trends data in forecasting influenza-like-illness related ED visits in Omaha, Nebraska. AB - INTRODUCTION: Emergency department (ED) visits increase during the influenza seasons. It is essential to identify statistically significant correlates in order to develop an accurate forecasting model for ED visits. Forecasting influenza-like-illness (ILI)-related ED visits can significantly help in developing robust resource management strategies at the EDs. METHODS: We first performed correlation analyses to understand temporal correlations between several predictors of ILI-related ED visits. We used the data available for Douglas County, the biggest county in Nebraska, for Omaha, the biggest city in the state, and for a major hospital in Omaha. The data set included total and positive influenza test results from the hospital (ie, Antigen rapid (Ag) and Respiratory Syncytial Virus Infection (RSV) tests); an Internet-based influenza surveillance system data, that is, Google Flu Trends, for both Nebraska and Omaha; total ED visits in Douglas County attributable to ILI; and ILI surveillance network data for Douglas County and Nebraska as the predictors and data for the hospital's ILI-related ED visits as the dependent variable. We used Seasonal Autoregressive Integrated Moving Average and Holt Winters methods with3 linear regression models to forecast ILI-related ED visits at the hospital and evaluated model performances by comparing the root means square errors (RMSEs). RESULTS: Because of strong positive correlations with ILI-related ED visits between 2008 and 2012, we validated the use of Google Flu Trends data as a predictor in an ED influenza surveillance tool. Of the 5 forecasting models we have tested, linear regression models performed significantly better when Google Flu Trends data were included as a predictor. Regression models including Google Flu Trends data as a predictor variable have lower RMSE, and the lowest is achieved when all other variables are also included in the model in our forecasting experiments for the first 5 weeks of 2013 (with RMSE = 57.61). CONCLUSIONS: Google Flu Trends data statistically improve the performance of predicting ILI-related ED visits in Douglas County, and this result can be generalized to other communities. Timely and accurate estimates of ED volume during the influenza season, as well as during pandemic outbreaks, can help hospitals plan their ED resources accordingly and lower their costs by optimizing supplies and staffing and can improve service quality by decreasing ED wait times and overcrowding. PMID- 25037279 TI - Response to considerations for tetanus infection in an adult with a protective tetanus antibody level. PMID- 25037280 TI - Response to "protective effect of tetanus antibodies". PMID- 25037281 TI - Association of mastocytosis with inflammatory joint diseases: a series of 31 patients. AB - OBJECTIVES: We studied the clinical phenotypes and tolerance to treatments in a series of patients affected by both inflammatory joint diseases and mastocytosis. METHODS: This retrospective multicenter study was conducted on behalf of 3 networks focused on mastocytosis, pediatric, and adults' inflammatory joint diseases. Patients who displayed both mastocytosis and inflammatory joint diseases were included. RESULTS: A total of 31 patients were included. They had spondyloarthritis (SpA) (16 patients), rheumatoid arthritis (6 patients), juvenile idiopathic arthritis (2 patients), and undifferentiated arthritis (7 patients). The median ages at diagnosis of arthritis and mastocytosis were 44 and 40.5 years, respectively. Disease-modifying anti-rheumatic drugs (DMARDs) were required in 22 patients, comprising mostly methotrexate (13 patients), salazopyrin (8 patients), anti-tumor-necrosis-factor agents (7 patients), and corticosteroids (9 patients). They were well tolerated. Adverse events occurred in 2/24 patients receiving non-steroidal anti-inflammatory drugs. The prevalence of SpA among the 600 patients included in the mastocytosis cohort was 2.33%, which is significantly higher than the prevalence of SpA in the French population (p < 0.001). CONCLUSIONS: This study suggests that mastocytosis is associated with a higher prevalence of SpA than expected, and that DMARDs, notably anti TNFalpha agents, are well tolerated in patients with mastocytosis. Mast cells might be involved in the development of SpA. PMID- 25037282 TI - Clinical significance of peripheral blood lymphocyte sensitivity to glucocorticoids for the differentiation of high-risk patients with decreased allograft function after glucocorticoid withdrawal in renal transplantation. AB - PURPOSE: A reliable biomarker to differentiate high-risk recipients who will experience a decrease in allograft function after glucocorticoid withdrawal has not been established in renal transplantation. We examined the clinical significance of peripheral blood lymphocyte sensitivity to glucocorticoids in vitro for the differentiation of the high-risk patients after glucocorticoid reduction/withdrawal in renal transplant recipients. METHODS: The study included 44 renal transplant recipients with stable allograft function. Peripheral lymphocyte responses to suppressive effects of cortisol, methylprednisolone, cyclosporine, and tacrolimus in mitogen assay procedures in vitro were examined. Clinical outcome after glucocorticoid reduction/withdrawal was retrospectively compared between recipients with lymphocytes normally sensitive to the drugs and those with hyposensitivity. The receiver-operating characteristic (ROC) curve analysis was undertaken for setting the cutoff IC50 values of the drugs against the T cell mitogen-induced lymphocyte proliferation to differentiate the high risk recipients with decreased allograft function after glucocorticoid withdrawal. FINDINGS: The median (range) IC50 value for cortisol in the recipients who showed decreased renal function due to glucocorticoid withdrawal was 10,000 (570.9-72,279.3) ng/mL (n = 9), which was significantly higher than the value of 351.6 (2.0-10,000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 35) (P < 0.001). Similarly, the median (range) IC50 value for methylprednisolone in the recipients who showed decreased renal function after glucocorticoid withdrawal was 69.1 (21.5-1442.7) ng/mL (n = 9), which was significantly higher than the value of 13.8 (0.7-1000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 30) (P < 0.003). In contrast, there was no significant difference in the median IC50 values of cyclosporine and tacrolimus between the 2 recipient subgroups. The ROC curve analyses for the IC50 values of the immunosuppressive drugs estimated the cutoff value of cortisol and methylprednisolone to be 3580.0 and 21.5 ng/mL, respectively. The ROC AUCs for cortisol and methylprednisolone were 0.83 and 0.84, respectively. According to the cutoff IC50 value, the incidence of decreased allograft function in the low cortisol sensitivity (IC50 >3580.0 ng/mL) subgroup was 7 of 13 patients, which was significantly higher than that of the higher sensitivity subgroup of 2 of 31 (P = 0.0012). A similar case was observed using the cutoff IC50 value of methylprednisolone (P = 0.0012), whereas recipient grouping according to the cutoff IC50 values of cyclosporine and tacrolimus failed to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal. IMPLICATIONS: Glucocorticoid pharmacodynamics in lymphocytes of individual patient origin is a reliable biomarker for differentiation of renal transplant recipients who will experience a safe reduction/withdrawal of glucocorticoid. PMID- 25037283 TI - Evaluation of bone metastases from breast cancer by bone scintigraphy and positron emission tomography/computed tomography imaging. AB - OBJECTIVE: The aim of this study was to compare bone scintigraphy (BS) and positron emission tomography/computed tomography (PET/CT) for the detection of bone metastases from breast cancer. STUDY DESIGN: Twenty patients with breast cancer and bone pain were submitted to both bone scintigraphy and 18-F fluorodeoxyglucose PET/CT imaging between July 2012 and June 2013. Scintigraphy was performed following an intravenous injection of technetium-99m-methylene diphosphonate (99mTc-MDP) around 10 days before the PET/CT scan, performed using an intravenous injection of 18-F-fluorodeoxyglucose followed by whole-body computed tomography (CT) to characterize metastases by both methods. Student's t test for paired samples was used in the comparative data analysis, with significance at p<0.05. RESULTS: CT identified 429 metastatic implants in the 20 patients, with scintigraphy showing 244 of these lesions (57%) and PET/CT showing 307 (72%); however, there was no statistically significant difference between the mean number of lesions detected per patient with the two imaging modalities (p=0.367). CONCLUSION: In the present study, no difference was found between PET/CT and bone scintigraphy in the detection of bone metastases from breast cancer. PMID- 25037285 TI - Common GSAP promoter variant contributes to Alzheimer's disease liability. AB - Toxic amyloid-beta40-42 (Abeta40-42) peptide cleaved from Abeta protein precursor by beta- and gamma secretases plays a crucial role in the etiology of Alzheimer's disease (AD). Recently, Paul Greengard laboratory described a novel gamma secretase activating protein (gSAP) that specifically increases Abeta40-42 production without affecting the cleavage of another gamma-secretase substrate, Notch. In this study, we show that expression of messenger RNA for GSAP, the gene that encodes the gSAP precursor protein, in human temporal cortex correlates with genotypes of 6 linked single-nucleotide polymorphisms (SNPs) located within the 5' region of GSAP in both Han Chinese and Caucasian populations. One of these SNPs, rs4727380, associates with AD diagnosis in a Han Chinese-based case-control study comprising 397 AD cases and 474 controls and in a Caucasian-based sample comprising 1906 cases and 1475 controls. As predicted, the high-expression allele of rs4727380 was identified as the AD risk allele in both samples. We also determined that rs4727380 correlates with AD diagnosis primarily among APOE4 noncarriers. To our knowledge, this is the first report providing genetic evidence linking GSAP to AD liability. PMID- 25037284 TI - Patient centered decision making: use of conjoint analysis to determine risk benefit trade-offs for preference sensitive treatment choices. AB - Understanding patient preferences facilitates shared decision-making and focuses on patient-centered outcomes. Little is known about relapsing-remitting multiple sclerosis (RRMS) patient preferences for disease modifying therapies (DMTs). We use choice based conjoint (CBC) analysis to calculate patient preferences for risk/benefit trade-offs for hypothetical DMTs. METHODS: Patients with RRMS were surveyed between 2012 and 2013. Our CBC survey mimicked the decision-making process and trade-offs of patients choosing DMTs, based on all possible DMT attributes. Mixed-effects logistic regression analyzed preferences. We estimated maximum acceptable risk trade-offs for various DMT benefits. RESULTS: Severe side effect risks had the biggest impact on patient preference with a 1% risk, decreasing patient preference five-fold compared to no risk. (OR=0.22, p<0.001). Symptom improvement was the most preferred benefit (OR=3.68, p<0.001), followed by prevention of progression of 10 years (OR=2.4, p<0.001). Daily oral administration had the third highest DMT preference rating (OR=2.08, p<0.001). Patients were willing to accept 0.08% severe risk for a year delayed relapse, and 0.22% for 4 vs 2 year prevented progression. CONCLUSION: We provided patient preferences and risk-benefit trade-offs for attributes of all available DMTs. Evaluation of patient preferences is a key step in shared decision making and may significantly impact early drug initiation and compliance. PMID- 25037286 TI - Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice. AB - Loss-of-function mutations in the PINK1 gene lead to recessive forms of Parkinson's disease. Animal models with depleted PINK1 expression have failed to reproduce significant nigral dopaminergic neurodegeneration and clear alpha synuclein pathology, main characteristics of the disease. In this study, we investigated whether alpha-synuclein pathology is altered in the absence of PINK1 in cell culture and in vivo. We observed that downregulation of PINK1 enhanced alpha-synuclein aggregation and apoptosis in a neuronal cell culture model for synucleinopathy. Silencing of PINK1 expression in mouse substantia nigra using recombinant adeno-associated viral vectors did not induce dopaminergic neurodegeneration in a long-term study up to 10 months, nor did it enhance or accelerate dopaminergic neurodegeneration after alpha-synuclein overexpression. However, in PINK1 knockout mice, overexpression of alpha-synuclein in the substantia nigra resulted in enhanced dopaminergic neurodegeneration as well as significantly higher levels of alpha-synuclein phosphorylation at serine 129 at 4 weeks postinjection. In conclusion, our results demonstrate that total loss of PINK1 leads to an increased sensitivity to alpha-synuclein-induced neuropathology and cell death in vivo. PMID- 25037287 TI - Neuronal degeneration associated with sympathosensory plexuses in the trigeminal ganglia of aged mice that overexpress nerve growth factor. AB - Aberrant sympathetic sprouting is seen in the uninjured trigeminal ganglia of transgenic mice that ectopically express nerve growth factor under the control of the glial fibrillary acidic protein promoter. These sympathetic axons form perineuronal plexuses around a subset of sensory somata in 2- to 3-month-old transgenic mice. Here, we show that aged transgenic mice (i.e., 11-14 and 16-18 months old) have dystrophic sympathetic plexuses (i.e., increased densities of swollen axons), and that satellite glial cells, specifically those in contact with dystrophic plexuses in the aged mice display strong immunostaining for tumor necrosis factor alpha. The colocalization of dystrophic plexuses and reactive satellite glial cells in the aged mice coincides with degenerative features in the enveloped sensory somata. Collectively, these novel results show that, with advancing age, sympathetic plexuses undergo dystrophic changes that heighten satellite glial cell reactivity and that together these cellular events coincide with neuronal degeneration. PMID- 25037288 TI - Developing dementia-capable health care systems: a 12-step program. AB - Improving the quality, comprehensiveness, and coordination of health care for people with dementia is a primary goal of the National Alzheimer's Plan. In this article, the key principles of high-quality dementia care for nonspecialist clinicians and health care leaders are synthesized, a framework for operationalizing its components is presented, and simple steps for developing dementia-capable health care systems are offered. PMID- 25037290 TI - Common psychiatric problems in cognitively impaired older patients: causes and management. AB - Although dementias are defined by their cognitive and functional deficits, psychiatric problems are common, contribute to patient distress and caregiver burden, and precipitate institutionalization. Successful treatment involves understanding that physiologic, psychological, and environmental factors can contribute to the development of these symptoms. By carefully assessing each of these factors, clinicians can individualize treatment and flexibly use nonpharmacologic and pharmacologic approaches tailored to patients and the context of care. Although there exist limitations to many treatment options, clinicians can still adapt current knowledge to develop a multifaceted treatment approach that improves the quality of life for patients and their caregivers. PMID- 25037291 TI - Palliative care in advanced dementia. AB - Because neurodegenerative dementias are progressive and ultimately fatal, a palliative approach focusing on comfort, quality of life, and family support can have benefits for patients, families, and the health system. Elements of a palliative approach include discussion of prognosis and goals of care, completion of advance directives, and a thoughtful approach to common complications of advanced dementia. Physicians caring for patients with dementia should formulate a plan for end-of-life care in partnership with patients, families, and caregivers, and be prepared to manage common symptoms at the end of life in dementia, including pain and delirium. PMID- 25037292 TI - Partnering with caregivers. AB - Family caregiving is nonroutine help that is provided to a relative in need. On average, family caregivers have provided assistance for close to 5 years, and close to half help their relatives with 1 or more activities of daily living in the United States. Family caregivers' unmet needs and the negative health outcomes they may experience demand effective, sustained clinical engagement. Clinical interventions that are intensive, individualized, and delivered over time to parallel chronic disease trajectories seem most effective. Principles of clinical assessment, tenets of a partnership-based health care framework, and newly emerging resources are presented to help guide clinicians' efforts to partner with family caregivers. PMID- 25037289 TI - Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. AB - Symptoms of memory loss are caused by a range of cognitive abilities or a general cognitive decline, and not just memory. Clinicians can diagnose the syndromes of dementia (major neurocognitive disorder) and mild cognitive impairment (mild neurocognitive disorder) based on history, examination, and appropriate objective assessments, using standard criteria such as Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. They can then diagnose the causal subtypes of these syndromes using standard criteria for each of them. Brain imaging and biomarkers are making progress in the differential diagnoses among the different disorders. Treatments are still mostly symptomatic. PMID- 25037294 TI - Choosing treatment for depression in older adults and evaluating response. AB - An update is provided on the current information regarding late life depression with regard to assessment, clinical implications, and treatment recommendations. Several treatments are considered evidence-based, but when deployed into field trials, the efficacy of these treatments falls short. It is thought that the lower impact in community trials is due in large part to patient, clinical, environmental, socio-economic, and cognitive correlates that influence treatment response. The aim is to assist providers in making decisions about what type of treatment to recommend based on a sound assessment of these clinical correlates. PMID- 25037293 TI - A systematic approach to pharmacotherapy for geriatric major depression. AB - The broadening use of antidepressants among older Americans has not been associated with a notable decrease in the burden of geriatric depression. This article, based on a selective review of the literature, explores several explanations for this paradox. The authors propose that the effectiveness of antidepressants depends in large part on the way they are used. Evidence supports that antidepressant pharmacotherapy leads to better outcomes when guided by a treatment algorithm as opposed to attempting to individualize treatment. Several published guidelines and pharmacotherapy algorithms developed for the treatment of geriatric depression are reviewed, and an updated algorithm proposed. PMID- 25037295 TI - Suicide in later life: failed treatment or rational choice? AB - Suicide is the deliberate act of causing death by self-directed injurious behavior with intent to die. Assisted dying, also known as assisted suicide, involves others to help hasten death. Physician-assisted dying specifically refers to the participation of a physician in facilitating one's death by providing a lethal means. Any decision to actively end a life has profound emotional and psychological effects on survivors. The article discusses the effects that older adults' deaths through suicide, assisted dying, and physician assisted dying have on survivors and the implications for clinical practice. PMID- 25037296 TI - Posttraumatic stress in older adults: when medical diagnoses or treatments cause traumatic stress. AB - Most older patients adapt after catastrophic medical diagnoses and treatments, but a significant number may develop posttraumatic stress disorder (PTSD) symptoms. PTSD symptoms create added burden for the individual, family, and health care system for the patient's recovery. Medical-related PTSD may be underdiagnosed by providers who may be unaware that these health problems can lead to PTSD symptoms. Treatment research is lacking, but pharmacologic and nonpharmacologic approaches to treatment may be extrapolated and adjusted from the literature focusing on younger adults. Additional study is needed. PMID- 25037299 TI - Community treatment of older adults: principles and evidence supporting mental health service interventions. AB - Health care systems are evolving toward population-based approaches to managing disease, including mental and behavioral health problems. This article describes population-based care management for treatment of geriatric patients in primary care and the challenges of implementation. The article addresses the issues of program fidelity and real-world treatment of those who do not fit the model or do not respond as hoped. It also discusses the special obstacles facing efforts to apply population-based principles of mental health care in nursing homes, where regulatory requirements, more than evidence about effective treatment, drive what interventions are provided. PMID- 25037300 TI - Update in geriatric psychiatry. PMID- 25037298 TI - Substance abuse among older adults. AB - Although the myth that older adults do not use mood-altering substances persists, evidence suggests that substance use among older adults has been underidentified for decades. The baby boom generation is unique in its exposure to, attitudes toward, and prevalence of substance use-causing projected rates of substance use to increase over the next twenty years. Given their unique biological vulnerabilities and life stage, older adults who misuse substances require special attention. Prevalence rates of substance use and misuse among older adults, methods of screening and assessment unique to older adults, and treatment options for older adults are reviewed. PMID- 25037301 TI - Multiple ileal perforations and concomitant cholecystitis with gall bladder gangrene as complication of typhoid fever. AB - Surgical complications of typhoid fever usually involve the small gut, but infrequently typhoid fever also involves the gallbladder. Complications range from acalculous cholecystitis, gangrene to perforation. Here, we present a case of enteric fever with concomitant complication of multiple ileal perforations at its terminal part with acalculous cholecystistis with gangrenous gall bladder. The primary closure of the perforations and cholecystectomy was performed. Post operatively patient developed low-output faecal fistula that was managed conservatively. PMID- 25037297 TI - Sleep in older adults: normative changes, sleep disorders, and treatment options. AB - Approximately 5% of older adults meet criteria for clinically significant insomnia disorders and 20% for sleep apnea syndromes. It is important to distinguish age-appropriate changes in sleep from clinically significant insomnia, with the latter having associated daytime impairments. Non pharmacologic therapies, such as cognitive-behavioral therapy for insomnia, can be highly effective with sustained benefit. Pharmacologic therapies are also available, but may be associated with psychomotor effects. A high index of suspicion is crucial for effective diagnosis of sleep apnea because symptoms commonly noted in younger patients, such as obesity or loud snoring, may not be present in older patients. PMID- 25037302 TI - Laparoscopic resection for torsion of an omental lipoma presenting as an acute abdomen in a 5-year-old girl. AB - Primary tumors of the greater omentum are rare. We report a case of a 5-year-old girl presenting with an acute abdomen who had omental torsion caused by a giant lipoma of the greater omentum, which was diagnosed by a computed tomography scan. Laparoscopy revealed a yellow tumor of the greater omentum with a smooth surface. Tumor excision and partial omentectomy was performed to treat the torsion, and the tumor was retrieved through a 4-cm-wide abdominal incision. Macroscopically, the specimen was 80 * 60 * 25 mm in size and 74.8 g in weight, and histopathological findings were consistent with the diagnosis of lipoma. The present case highlights the possible use of laparoscopic surgery for removing large abdominal lipomas, thus avoiding the drawbacks of laparotomy in terms of postoperative pain and prolonged hospital stay. PMID- 25037303 TI - Spreader graft placement: a simplified technique for young surgeons. AB - The spreader graft is a longitudinal graft placed between the dorsal septum and the upper lateral cartilage in a submucoperichondrial pocket. This graft has functional and aesthetic indications. Although placement and suturing of the spreader graft to the septum is an easy part of rhinoplasty for the experienced surgeon, it can be difficult and time-consuming for young surgeons. Here we suggest a very simple technique for easier placement and suturing of spreader grafts. PMID- 25037305 TI - Cultural competence: a constructivist definition. AB - In nursing education, most of the current teaching practices perpetuate an essentialist perspective of culture and make it imperative to refresh the concept of cultural competence in nursing. The purpose of this article is to propose a constructivist definition of cultural competence that stems from the conclusions of an extensive critical review of the literature on the concepts of culture, cultural competence, and cultural safety among nurses and other health professionals. The proposed constructivist definition is situated in the unitary transformative paradigm in nursing as defined by Newman and colleagues. It makes the connection between the field of competency-based education and the nursing discipline. Cultural competence in a constructivist paradigm that is oriented toward critical, reflective practice can help us develop knowledge about the role of nurses in reducing health inequalities and lead to a comprehensive ethical reflection about the social mandate of health care professionals. PMID- 25037304 TI - Mediators of the association between parental severe mental illness and offspring neurodevelopmental problems. AB - PURPOSE: Parental severe mental illness (SMI) is associated with an increased risk of offspring autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). We conducted a study to examine the extent to which risk of preterm birth, low birth weight, and small for gestational age mediated this association. METHODS: We obtained data on offspring born 1992-2001 in Sweden (n = 870,017) through the linkage of multiple population-based registers. We used logistic and Cox regression to assess the associations between parental SMI, adverse pregnancy outcomes, and offspring ASD and ADHD, as well as tested whether adverse pregnancy outcomes served as mediators. RESULTS: After controlling for measured covariates, maternal and paternal SMI were associated with an increased risk for preterm birth, low birth weight, and gestational age, and for offspring ASD and ADHD. These pregnancy outcomes were also associated with an increased risk of ASD and ADHD. We found that pregnancy outcomes did not mediate the association between parental SMI and offspring ASD and ADHD, as there was no substantial change in magnitude of the risk estimates after controlling for pregnancy outcomes. CONCLUSIONS: Parental SMI and adverse pregnancy outcomes appear to be independent risk factors for offspring ASD and ADHD. PMID- 25037306 TI - Perceptions of Insulin Treatment Among African Americans With Uncontrolled Type 2 Diabetes. AB - PURPOSE: Little is known regarding perception of insulin treatment among midlife and older African American (AA) adults with type 2 diabetes, or how perception affects self-management behaviors. Using the Roy adaptation model, this qualitative descriptive study explored the perception of insulin treatment in midlife and older AAs living with uncontrolled type 2 diabetes. METHOD: Three 1 hour focus groups were conducted with a total of 13 participants. Thematic analysis of transcribed audio recordings used the constant comparative method. RESULTS: Themes identified include (a) insulin as instigator of negative emotions, (b) adapting to a lifestyle with insulin, and (c) becoming an insulin user: a new identity. CONCLUSION: Adapting to insulin is a psychosocial process that commonly results in negative emotions, identity conflict, and new roles. IMPLICATIONS FOR PRACTICE: Further research is needed to understand how AA adults perceive insulin treatment, understand the role of perception in self-management behaviors, and determine whether interventions to change perceptions may be effective in improving adaptation to diabetes. PMID- 25037307 TI - RTeQTL: Real-Time Online Engine for Expression Quantitative Trait Loci Analyses. AB - Our database tool, called Real-Time Engine for Expression Quantitative Trait Loci Analyses (RTeQTL), can efficiently provide eQTL association results that are not available in existing eQTL databases browsers. These functions include (i) single SNP (single-nucleotide polymorphism) and (ii) two-SNP conditional eQTL effects on gene expression regardless of the magnitude of P-values. The database is based on lymphoblastoid cell lines from >900 samples with global gene expression and genome-wide genotyped and imputed SNP data. The detailed result for any pairs of gene and SNPs can be efficiently computed and browsed online, as well as downloaded in batch mode. This is the only tool that can assess the independent effect of a disease- or trait-associated SNP on gene expression conditioning on other SNPs of interest, such as the top eQTL of the same gene. It is also useful to identify eQTLs for candidate genes, which are often missed in existing eQTL browsers, which only store results with genome-wide significant P-value. Additional analyses stratifying by gender can also be easily achieved by this tool. Database URL: http://eqtl.rc.fas.harvard.edu/. PMID- 25037308 TI - Text-mining-assisted biocuration workflows in Argo. AB - Biocuration activities have been broadly categorized into the selection of relevant documents, the annotation of biological concepts of interest and identification of interactions between the concepts. Text mining has been shown to have a potential to significantly reduce the effort of biocurators in all the three activities, and various semi-automatic methodologies have been integrated into curation pipelines to support them. We investigate the suitability of Argo, a workbench for building text-mining solutions with the use of a rich graphical user interface, for the process of biocuration. Central to Argo are customizable workflows that users compose by arranging available elementary analytics to form task-specific processing units. A built-in manual annotation editor is the single most used biocuration tool of the workbench, as it allows users to create annotations directly in text, as well as modify or delete annotations created by automatic processing components. Apart from syntactic and semantic analytics, the ever-growing library of components includes several data readers and consumers that support well-established as well as emerging data interchange formats such as XMI, RDF and BioC, which facilitate the interoperability of Argo with other platforms or resources. To validate the suitability of Argo for curation activities, we participated in the BioCreative IV challenge whose purpose was to evaluate Web-based systems addressing user-defined biocuration tasks. Argo proved to have the edge over other systems in terms of flexibility of defining biocuration tasks. As expected, the versatility of the workbench inevitably lengthened the time the curators spent on learning the system before taking on the task, which may have affected the usability of Argo. The participation in the challenge gave us an opportunity to gather valuable feedback and identify areas of improvement, some of which have already been introduced. Database URL: http://argo.nactem.ac.uk. PMID- 25037309 TI - Urinary composition during decongestive treatment in heart failure with reduced ejection fraction. AB - BACKGROUND: The urinary composition, including sodium (Na(+)) and chloride (Cl( )) concentrations, might provide useful information in addition to urine output during decongestive treatment in heart failure. METHODS AND RESULTS: Consecutive patients with heart failure (n=61), ejection fraction <=45%, worsening symptoms, and scheduled treatment with intravenous loop diuretics were included. Patients received protocol-driven therapy until complete decongestion, assessed clinically and by echocardiography. Three consecutive 24-hour urinary collections were performed. With 2 mg (1-4 mg), 1 mg (0-2 mg), and 1 mg (0-1 mg) bumetanide administered in bolus during consecutive 24-hour intervals, in addition to combinational diuretic therapy in ~70% and both oral spironolactone and vasodilators in ~90%, euvolemia was reached, often within 24 hours. Urine output was higher during the first when compared with the second or third 24-hour interval (2700 versus 1550 or 1375 mL, respectively; P<0.001), but this was no longer significant after correction for diuretic dose (P=0.263), indicating preserved diuretic efficiency during the study. In contrast, urinary Na(+) and Cl(-) excretion both decreased significantly, even after correction for diuretic dose (P=0.040 and 0.004, respectively), leading to decreasing urinary concentrations with progressive decongestion. After reaching euvolemia, lower urinary Na(+)/Cr and Cl(-)/Cr ratios were both associated with urine output <=1500 mL (area under the curve, 0.830 and 0.826, respectively; P<0.001 for both), in contrast to plasma N-terminal pro-B-type natriuretic peptide levels that were not (area under the curve, 0.515; P=0.735) CONCLUSIONS: The urinary composition during progressive decongestion in heart failure with reduced ejection fraction is characterized by a drop in urinary Na(+) and Cl(-) concentrations. The urinary Na(+)/Cr or Cl(-)/Cr ratio might provide insightful information to titrate diuretic therapy. PMID- 25037310 TI - Percutaneous ventricular restoration using the parachute device in patients with ischemic heart failure: three-year outcomes of the PARACHUTE first-in-human study. AB - BACKGROUND: Left ventricle remodeling after anterior wall myocardial infarction leads to increased left ventricle volumes, myocardial stress, and ultimately heart failure (HF). Treatment options are limited for these high-risk HF patients. A study was conducted to assess safety and feasibility of a percutaneous ventricular restoration therapy using the Parachute device in subjects with HF because of a cardiac ischemic event. METHODS AND RESULTS: Thirty nine subjects with New York Heart Association class II to IV ischemic HF, ejection fraction between 15% and 40%, and dilated akinetic or dyskinetic anterior-apical wall without the need to be revascularized were enrolled in a prospective, nonrandomized, multicenter investigation testing percutaneous ventricular restoration using the Parachute device. The safety primary end point was defined as successful procedure without device-related major adverse cardiac events during 6 months. Clinical and echocardiographic outcomes were obtained at 6, 12, 24, and 36 months post-treatment. Echocardiographic and end point data were adjudicated independently. Of the 39 subjects enrolled, device implantation was attempted in 34 and successful in 31 patients. Twenty-three subjects reached 3 years post-treatment with the device implanted. New York Heart Association symptom class was improved or maintained in 85% of subjects. Left ventricle end diastolic volume index and end-systolic volume index were reduced from 128.4+/ 22.1 and 94.9+/-22.3 mL/m(2) preimplant to 115.2+/-23.1 and 87.3+/-18.7 mL/m(2) at 3-year follow-up (end-diastolic volume index, P=0.0056; end-systolic volume index, P=0.4719). The cumulative incidence of HF hospitalization or death was 16.1%, 32.3%, and 38.7% at 12, 24, and 36 months, respectively. By 3-year follow up, 2 (6.5%) of 31 patients with successful implant had died from cardiac reasons, with no cardiac deaths occurring past 6 months post-treatment. CONCLUSIONS: The first series of ischemic HF patients treated with percutaneous ventricular restoration using the Parachute device demonstrates feasibility and safety of the device <=3 years post-treatment. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00573560 (US patients) and NCT01286116 (EU patients). PMID- 25037311 TI - Impact of the number of metastatic brain lesions on survival after Gamma Knife radiosurgery. AB - Effectiveness of Gamma Knife radiosurgery (GKRS: Elekta AB, Stockholm, Sweden) for patients with metastatic brain disease and the prognostic factors influencing their survival were analyzed in a 5 year retrospective data analysis (July 2001 to June 2006). Kaplan-Meier survival curves were constructed using univariate and multivariate analyses with the respective salient prognostic factors. This study analyzed data on 330 patients with brain metastases who underwent GKRS. Lung carcinoma (55%) was the most common primary cancer followed by breast (17.8%), melanoma (9.4%), colorectal (4.8%) and renal (3.9%). The median survival for all patients was 8 months. Survival ranged from 13 months for breast metastases, 10 months for renal, and 8 months for lung to 5 months for colorectal and melanoma. Mean age of patients was 58.5 years (range 18-81). Melanoma patients were younger with a mean age of 49 and also had the highest number of lesions (3.8) when compared to patients with renal (2.5), lung (2.8), colorectal (3) and breast (3.6). When stratified according to the number of lesions patient survival was 8 months (one to three lesions), 7.5 months (four or five lesions) and 7 months (six lesions or more). Mean Karnofsky Performance Status score (KPS) was 77 and survival dropped significantly from 8 months to 4.5 months if KPS was less than 70. Survival improved with a KPS of 70 or more, regardless of the number of lesions treated. Selection of patients based on the number of lesions may not be justified. A prospective trial is required to further define the prognostic factors affecting survival. PMID- 25037312 TI - To repeat or to recreate: a contralateral posterior interhemispheric transfalcine transprecuneus approach for recurrent meningiomas at the trigone of the lateral ventricle. AB - Surgery in the trigone of the lateral ventricle remains a challenge for neurosurgeons. In recurrent trigonal meningiomas (RTM), the disturbance of normal anatomic structures and adhesion due to previous surgeries, significant oedema, and their malignant properties heighten the difficulties associated with their surgical removal. This report presents two patients with recurrent meningiomas with anaplastic transformation at the trigone of the lateral ventricle who were successfully treated with contralateral posterior interhemispheric transfalcine transprecuneus (CITT) surgeries. The primary tumours were both completely removed through a transparietal approach in previous surgeries, but both patients experienced hemianopsia postoperatively. The second surgeries resulted in the complete resection of the recurrent tumours without any new-onset neurological dysfunction. The CITT approach suits most trigonal lesions with advantages of optic radiation preservation, reduction of retraction, improved exposure, and navigation accuracy, and because it addresses the origin of the trigonal lesion. Although the characteristics of RTM heighten the difficulty associated with their surgical removal, these challenges highlight the advantages of the CITT approach. In conclusion, the CITT approach is a safe and effective procedure for the removal of RTM. PMID- 25037314 TI - Three-step anterolateral approaches to the skull base. AB - Adequate intraoperative exposure of the brain is paramount to prevent unnecessary retraction of the brain parenchyma. Lesions in the anterior skull base, the middle fossa and even the upper part of the posterior fossa can be managed anterolaterally through the pterional approach, the orbitozygomatic approach and the transzygomatic approach. Although commonly discussed on a separate basis, these three procedures are here considered to belong in the same spectrum, which includes one, two or three step procedures depending on the case and the level of exposure required. Ten hemispheres were used to describe the surgical technique applied in a three-step anterolateral approach. The pterional approach provides adequate access to the frontal base and the Sylvian fissure, the circle of Willis and the optic nerves. Where access to the temporal base is needed, improved exposure can be afforded by sectioning the zygomatic arch and lowering the masseter muscle. The lateral orbital wall is sectioned to improve the vertical angle of approach and facilitate access to hypothalamic and posterior fossa lesions. The combination of three approaches into one procedure introduces a new perspective on this technique, one which makes them easier to understand and shows how craniotomy may be modified for optimal exposure, even while conducting the surgery. PMID- 25037313 TI - Prognosis by tumor location in adults with intracranial ependymomas. AB - Intracranial ependymomas are rare tumors in adults. Thus, factors affecting prognosis are poorly understood. We performed a study to investigate whether tumor location is an important prognostic factor in adults who undergo surgery for intracranial ependymomas. PubMed was searched to identify studies that reported clinical outcomes in adult patients with intracranial ependymoma. Data were extracted for patient and tumor characteristics, extent of resection, progression-free survival (PFS), and overall survival (OS). Tumors were categorized as supratentorial or infratentorial and extraventricular or intraventricular. Presenting clinical features and tumor characteristics were tabulated. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine PFS and OS by tumor location. Extent of resection was also analyzed by tumor location. A total of 183 patients were included in the meta analysis. Patients presented at a mean of 8.2months with a myriad of clinical features. The mean tumor size was 3.38 cm, and 19.3% of tumors were cystic. Supratentorial tumors were most commonly located in the frontal and parietal lobes, and infratentorial tumors in the fourth ventricle. Supratentorial tumors demonstrated significantly poorer PFS (p<0.001) and OS (p=0.003) than infratentorial tumors, despite a higher rate of gross total resection (GTR) for the supratentorial tumors (72.6% versus 42.1%). Extraventricular ependymomas displayed significantly poorer PFS than intraventricular ependymomas (p=0.009). In summary, supratentorial ependymomas have significantly poorer PFS and OS than their infratentorial counterparts, despite being more conducive to GTR, suggesting increased clinical aggressiveness. Extraventricular location is also associated with significantly poorer PFS than intraventricular location. PMID- 25037315 TI - Single-centre comparison of procedural complications, clinical outcome, and angiographic follow-up between coiling and stent-assisted coiling for posterior communicating artery aneurysms. AB - Aneurysm recurrence is a principle limitation of endovascular coiling procedures, especially in posterior communicating artery aneurysms, with reported recurrence rates of >30%. The adjunctive use of self-expandable stents has revolutionised the treatment of intracranial aneurysms, especially for complex morphologies, wide necks, or unfavourable dome-to-neck ratios. However, there are limited data concerning a direct comparison between simple coiling and stent-assisted coiling in posterior communicating artery aneurysms. This study aimed to compare the durability and outcomes of coiling versus stent-assisted coiling procedures. Imaging data of patients with posterior communicating artery aneurysms treated with coiling or stent-assisted coiling between January 2008 and October 2012 were retrospectively analysed. The initial angiographic results, procedural complications, and clinical outcomes were assessed at discharge. Imaging follow up was performed with cerebral angiography. Complete aneurysm occlusion was achieved on initial angiography in 23/56 (41.1%) stent and 83/235 (35.3%) non stent patients. At the latest follow-up (mean follow-up 14.3 +/- 10.4 months for stent and 13.2 +/- 9.5 months for non-stent patients), aneurysms had recurred in 5/47 (10.6%) stent and 57/203 (28.1%) non-stent patients (p=0.014). Procedural complications occurred in 6/56 (10.7%) stent and 27/235 (11.5%) non-stent aneurysms. No rebleeding occurred during clinical follow-up (mean duration, 46.7 months). Recurrence rates at the latest follow-up were significantly lower in patients undergoing stent-assisted coiling than those undergoing simple coiling. Thus, use of the stent-assisted neck remodelling technique in the treatment of wide-necked posterior communicating artery intracranial aneurysms appears to improve the long-term clinical outcome. PMID- 25037316 TI - Survival outcomes of giant cell glioblastoma: institutional experience in the management of 20 patients. AB - Giant cell glioblastoma (GCG) is a rare subtype of glioblastoma (GBM) that is believed to carry an improved prognosis. However, given the rarity of this tumor, best management practices for GCG have yet to be ascertained. Here, we present our experience in managing GCG tumors at the University of California, San Francisco. Patients were retrospectively identified through chart review, and data pertaining to patient demographics, treatment plans, and follow-up were extracted from existing medical records. Overall survival (OS) and progression free survival (PFS) were the primary and secondary endpoints, respectively. In sum, we identified 22 patients who were managed or followed for GCG. Most patients (78%) initially underwent subtotal resection as primary treatment for their tumor, and most also received post-operative adjuvant therapy (90%), with radiation being the most frequently administered modality (85%). Within this institutional cohort, median OS and PFS were 15.4 months and 5.7 months, respectively. On multivariate survival analysis, age (p=0.84), sex (p=0.05), and adjuvant radiation plus temozolomide (p=0.12) were not associated with prolonged OS. However, adjuvant radiation plus temozolomide was associated with longer PFS (p=0.01), and patients receiving this therapy demonstrated a median PFS of 32.9 months versus 13.1 months. These findings confirm the comparatively improved prognosis of GCG over GBM. Moreover, they suggest that extent of resection may not significantly delay recurrence or extend survival, and that combination radiation with temozolomide may represent the optimum adjuvant paradigm to delay tumor progression. PMID- 25037317 TI - On the origin of information in epigenetic structures in metazoans. AB - Epigenetic inheritance implies the existence of epigenetic information. Great progress has been made in recent years in understanding the role of the changes in epigenetic structures (methylated DNA, histone acetylation/deacetylation and chromatin remodelling) as well as the role of miRNA (MIR) expression patterns in epigenetic processes. However, as of yet, we do not have a satisfactory understanding of the origin of epigenetic information stored in, and conveyed by, these structures. We do not know whether these structures are the ultimate source of the information or whether they are simply media for storing and transmitting epigenetic information for gene expression from upstream sources to the phenotype. Herein an attempt is made to ascertain the ultimate sources of the epigenetic information they contain and transmit by tracing back the causal chain leading to the changes in epigenetic structures. PMID- 25037318 TI - Nanorods of a new metal-biomolecule coordination polymer showing novel bidirectional electrocatalytic activity and excellent performance in electrochemical sensing. AB - Metal organic coordination polymers (CPs), as most attractive multifunctional materials, have been studied extensively in many fields. However, metal biomolecule CPs and CPs' electrochemical properties and applications were studied much less. We focus on this topic aiming at electrochemical biosensors with excellent performance and high biocompatibility. A new nanoscaled metal biomolecule CP, Mn-tyr, containing manganese and tyrosine, was synthesized hydrothermally and characterized by various techniques, including XRD, TEM, EDS, EDX mapping, elemental analysis, XPS, and IR. Electrode modified with Mn-tyr showed novel bidirectional electrocatalytic ability toward both reduction and oxidation of H2O2, which might be due to Mn. With the assistance of CNTs, the sensing performance of Mn-tyr/CNTs/GCE was improved to a much higher level, with high sensitivity of 543 mA mol(-1) L cm(-2) in linear range of 1.00*10(-6) 1.02*10(-4) mol L(-1), and detection limit of 3.8*10(-7) mol L(-1). Mn tyr/CNTs/GCE also showed fast response, high selectivity, high steadiness and reproducibility. The excellent performance implies that the metal-biomolecule CPs are promising candidates for using in enzyme-free electrochemical biosensing. PMID- 25037319 TI - The Royal College of Radiologists' fractionation survey. 1989. PMID- 25037320 TI - Isolation and purification of Mycobacterium tuberculosis from H37Rv infected guinea pig lungs. AB - Evidence suggests that Mycobacterium tuberculosis grown in vivo may have a different phenotypic structure from its in vitro counterpart. In order to study the differences between in vivo and in vitro grown bacilli, it is important to establish a reliable method for isolating and purifying M. tuberculosis from infected tissue. In this study, we developed an optimal method to isolate bacilli from the lungs of infected guinea pigs, which was also shown to be applicable to the interferon-gamma gene knockout mouse model. Briefly, 1) the infected lungs were thoroughly homogenized; 2) a four step enzymatic digestion was utilized to reduce the bulk of the host tissue using collagenase, DNase I and pronase E; 3) residual contamination by the host tissue debris was successfully reduced using percoll density gradient centrifugation. These steps resulted in a protocol such that relatively clean, viable bacilli can be isolated from the digested host tissue homogenate in about 50% yield. These bacilli can further be used for analytical studies of the more stable cellular components such as lipid, peptidoglycan and mycolic acid. PMID- 25037321 TI - Finite-time state-dependent Riccati equation for time-varying nonaffine systems: rigid and flexible joint manipulator control. AB - This article investigates finite-time optimal and suboptimal controls for time varying systems with state and control nonlinearities. The state-dependent Riccati equation (SDRE) controller was the main framework. A finite-time constraint imposed on the equation changes it to a differential equation, known as the state-dependent differential Riccati equation (SDDRE) and this equation was applied to the problem reported in this study that provides general formulation and stability analysis. The following four solution methods were developed for solving the SDDRE; backward integration, state transition matrix (STM) and the Lyapunov based method. In the Lyapunov approach, both positive and negative definite solutions to related SDRE were used to provide suboptimal gain for the SDDRE. Finite-time suboptimal control is applied for robotic manipulator, as finite-time constraint strongly decreases state error and operation time. General state-dependent coefficient (SDC) parameterizations for rigid and flexible joint arms (prismatic or revolute joints) are introduced. By including nonlinear control inputs in the formulation, the actuator's limits can be inserted directly to the state-space equation of a manipulator. A finite-time SDRE was implemented on a 6R manipulator both in theory and experimentally. And a reduced 3R arm was modeled and tested as a flexible joint robot (FJR). Evaluations of load carrying capacity and operation time were investigated to assess the capability of this approach, both of which showed significant improvement. PMID- 25037322 TI - Structural peculiarities of polysaccharide from sterile form of Far Eastern red alga Ahnfeltiopsis flabelliformis. AB - KCl-insoluble sulfated polysaccharide from sterile alga Ahnfeltiopsis flabelliformis was investigated. Partial reductive hydrolysis and NMR spectroscopy showed that the polysaccharide comprises disaccharide units of carrabiose only. According to FT-IR-, 1D, 2D NMR spectroscopies and mass spectrometry this polysaccharide is kappa/beta-carrageenan with ratio of kappa- and beta-types units 3:1 and contains minor amounts of iota- and gamma carrageenans (precursor of beta-carrageenan). In addition, ESIMS/MS data suggested that xylose (minor amount) is present in the polysaccharide as a substituent one of hydroxyl group of galactose. According to aPTT and PT assays the studied carrageenan affected mostly intrinsic pathway of coagulation, while it effect on the extrinsic pathway is absent. PMID- 25037323 TI - Alginate mediate for synthesis controllable sized AgNPs. AB - A new method to prepare silver nanoparticles was reported. Alginate colloidal solution containing chemically synthesized silver nanoparticles (AgNPs) was investigated regarding the nanoparticles stabilization and possibilities for production of alginate based nanoparticles. The formation of AgNPs has been confirmed by UV-visible spectroscopy and monitoring of reducing sugars in the reaction was carried out. The morphology of synthesized silver nanoparticles was characterized by transmission electron microscopy (TEM). The results showed that the morphology of Ag nanoparticles is spherical and the main size is about 1-4 nm. PMID- 25037324 TI - Controlled release of liposome-encapsulated Naproxen from core-sheath electrospun nanofibers. AB - Naproxen (NAP) loaded nanofibers of different structures have been successfully prepared by electrospinning. The structures of the nanofibers are NAP and cellulose acetate (CA) mixed nanofibers (NF-1), nanofibers with NAP/CA mixed core and CA sheath (NF-2), and NAP loaded liposomes and sodium hyaluronate (HA-Na) mixed core with CA sheath (NF-3). The structure and morphology of the nanofibers were characterized and the drug release behaviors were investigated. It was found that NAP can disperse in the HA-Na or CA matrix in molecular level without formation of NAP crystals and dimers. The drug release behaviors of NF-1 and NF-2 show a non-Fickian diffusion mechanism, while the NF-3 shows a specific drug release behavior with a burst release within 8h followed by a sustained drug release for 12 days. The particular two-stage drug release behavior of NF-3 nanofibers offers the materials promising applications as wound dressing materials. PMID- 25037325 TI - Remarkably regioselective deacylation of cellulose esters using tetraalkylammonium salts of the strongly basic hydroxide ion. AB - Tetraalkylammonium hydroxides have been found to mediate regioselective deacylation of cellulose esters. This deacylation surprisingly shows substantial selectivity for the removal of the acyl groups at O-2/3, affording cellulose-6-O esters by a simple, efficient one-step process. The mechanism for this deacylation was investigated by studying the effect of tetraalkylammonium cation size upon ester deacylation selectivity. We hypothesize that coordination of the tetraalkylammonium cation by the ester oxygen atoms of the vicinal 2,3-acetate groups may drive the unexpected regioselectivity at the secondary alcohol esters. Broad scope with respect to ester type was demonstrated; regioselective O-2,3 deacylation was observed with cellulose acetate, propionate, butyrate, hexanoate and benzoate triesters. The scope of this deacylation of cellulose acetates has been investigated to understand how to carry it out most efficiently. Reaction with TBAOH in pyridine was the most effective process, providing the highest selectivity. PMID- 25037326 TI - Branch pattern of starch internal structure influences the glucogenesis by mucosal Nt-maltase-glucoamylase. AB - To produce sufficient amounts of glucose from food starch, both alpha-amylase and mucosal alpha-glucosidases are required. We found previously that the digestion rate of starch is influenced by its susceptibility to mucosal alpha-glucosidases. In the present study, six starches and one glycogen were pre-hydrolyzed by alpha amylase for various time periods, and then further hydrolyzed with the mucosal alpha-glucosidase, the N-terminal subunit of maltase-glucoamylase (Nt-MGAM), to generate free glucose. Results showed that alpha-amylase amplified the Nt-MGAM glucogenesis, and that the amplifications differed in various substrates. The amount of branches within alpha-amylase hydrolysate substrates was highly related to the rate of Nt-MGAM glucogenesis. After de-branching, the hydrolysates showed three fractions, Fraction 1, 2, and 3, in size exclusion chromatographs. We found that the alpha-amylase hydrolysates with higher quantity of the Fraction 3 (molecules with relatively short chain-length) and shorter average chain-length of this fraction had lower rates of Nt-MGAM glucogenesis. This study revealed that the branch pattern of alpha-amylase hydrolysates modulates glucose release by Nt-MGAM. It further supported the hypothesis that the internal structure of starch affects its digestibility at the mucosal alpha-glucosidase level. PMID- 25037327 TI - Synthesis and characterization of composite based on cellulose acetate and hydroxyapatite application to the absorption of harmful substances. AB - The aim of this work is to develop composite materials with hydroxyapatite (HAp) mineral and organic matrix such as cellulosic polymers. We use cellulose acetate with different percentages, and then inorganic-organic films were fabricated by evaporation of solvent. The composite films were characterized using emission scanning electron microscopy (FEG-SEM), thermo-gravimetric analysis (TGA) and Fourier transform infra-red (FT-IR) spectra. Test results show that these films are uniform and have good ductility. A strong interaction existed between HAp and cellulosic polymers, and the method allows the production of very fine particles size of about 92 nm. We have developed a new chromatographic method for the quantification of bisphenol A (BPA) in samples of baby food. The result of this study demonstrates how to use this type of composite materials to remove pollutants. PMID- 25037328 TI - A polysaccharide from Salvia miltiorrhiza Bunge improves immune function in gastric cancer rats. AB - A neutral polysaccharide fraction (SMPA) prepared from the roots of Salvia miltiorrhiza by DEAE-cellulose and Sephadex G-100 chromatography was tested for its immune enhancing function in N-methyl-N'-nitro-nitrosoguanidine (MNNG) induced gastric cancer rats by intragastric administration. SMPA (200mg/kg) treatment not only increased the body weight, but also improved the immune organ indices. Furthermore, studies of various immunological activities in gastric cancer rats revealed that SMPA significantly stimulated splenocyte proliferation, promoted anti-inflammatory cytokines (IL-2, IL-4 and IL-10) production, inhibited pro-inflammatory cytokine (IL-6 and TNF-alpha) secretion, augmented the killing activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), and increased phagocytotic function of macrophages in gastric cancer rats. In addition, SMPA administration evidently elevated total intracellular granzyme-B and IFN-gamma levels produced by splenocytes in gastric cancer rats. Taken together, these results suggested that SMPA could act as an effective immunomodulator and might be explored as a potential supplemental source for gastric cancer therapy. PMID- 25037329 TI - Konjac glucomannan microspheres for low-cost desalting of protein solution. AB - In this study, low-cost konjac glucomannan (KGM) microspheres used for desalting were developed by an inverse dispersion method. High concentration of KGM was pretreated to reduce viscosity by acid hydrolysis method under the condition of high temperature and pressure. The selectivity of the obtained cross-linked KGM gels with different degree of crosslinking was studied by constructing calibration curves (K(av)) of standard molecular weight substances. The stability of the gels was investigated, which showed that the KGM microspheres are tolerant to a wide range of pH and stable in all commonly used aqueous buffers, and insensitive to autoclaving as well. Furthermore, protein-desalting performances of GM-1250, a cross-linked KGM microsphere, were evaluated with two proteins, bovine serum albumin and filamentous hemagglutinin, which turned out that GM-1250 is comparable to the widely used commercial product--Sephadex G25 Fine. From economic considerations, KGM gel is a prospective alternative for dextran gels in protein desalting process. PMID- 25037330 TI - Synthesis, characterization and solution behaviour of oxidized pullulan. AB - Various amounts of carboxyl groups were introduced at C-6 of the non-ionic, water soluble polysaccharide, i.e. pullulan, by applying the well-established TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), sodium hypochlorite/sodium bromide oxidation protocol, varying the reaction time. The oxidized products, more water soluble than pullulan, were further characterized by FT-IR, (1)H NMR and (13)C NMR techniques, in order to assess the degree of oxidation. The absolute molecular weight measurements performed using a multiangle laser light scattering molecular weight analyzer, reveals a sharp drop of the molecular weight of the samples oxidized for longer reaction times. The second virial coefficients (A2), increased from unoxidized pullulan to the oxidized samples. Dynamic light scattering (DLS) measurements provide zeta potentials and hydrodynamic radius for all studied samples. The viscosity of the initial and oxidized pullulan dilute aqueous solutions was studied in detail. All oxidized samples except the highest oxidized pullulan sample (OxPu8) showed strong polyelectrolyte behaviour, whereas this effect is less pronounced for OxPu8 due to the high degradation of the chains. The intrinsic viscosity and the interaction parameter were determined at 25 degrees C as a function of solvent ionic strength according to Wolf approach. The dependence of these parameters on the salt concentration follows Boltzmann sigmoid model. PMID- 25037332 TI - The shear dependence of the methylcellulose gelation phenomena in aqueous solution and in ceramic paste. AB - The gelation temperature of methylcellulose (MC) in aqueous solutions as well as in aqueous ceramic paste depends on the applied shear. Rheological investigations in oscillation vs. shear mode show lower gelation temperature at low shear rates as for the corresponding angular frequencies. Above a critical shear rate the gelation temperature is shifted to higher temperatures. The paste extrusion process uses MC as a plasticizer and runs under high shear conditions. When extruding close to the gelation temperature of the MC in the paste, crack formation and other defects can occur. The upwards shift of the gelation temperature with increasing applied shear gives a larger temperature window during the extrusion process. The understanding of the shear influence on the gelation temperature is important to design the optimal process conditions. PMID- 25037331 TI - Antitumor metastasis activity of pectic polysaccharide purified from the peels of Korean Citrus Hallabong. AB - A polysaccharide fraction, HBE-III, was successfully purified in a high yield (40.4%) from its crude polysaccharide (HBE-0) which was prepared from pectinase hydrolysates of the peels of the Korean Citrus Hallabong. In experimental lung metastasis studies of Colon 26-M3.1 carcinoma cells, prophylactic administration of HBE-III significantly inhibited lung metastasis in a dose-dependent manner. In an in vitro cytotoxicity analysis, HBE-III (up to 1000 MUg/mL) did not affect the growth of Colon 26-M3.1 cells and normal cells. HBE-III enhanced production of IL 6 and IL-12 by murine peritoneal macrophages. In an assay for natural killer (NK) cell activity, HBE-III (1000 MUg/mouse, i.v.) significantly augmented NK cytotoxicity against Yac-1 tumor cells. The depletion of NK cells by injection of mouse anti-asialo GM1 serum abolished the inhibitory effect of HBE-III on lung metastasis of Colon 26-M3.1 cells. These data suggest that HBE-III may inhibit tumor metastasis via activation of macrophages and NK cells. PMID- 25037333 TI - Effect of particle size and temperature on rheology and creep behavior of barley beta-d-glucan concentrate dough. AB - Concentrated beta-D-glucan has been added in the formulation of food products development that attributing human health. The purpose of this study is to assess the role of particle size (74, 105, 149, 297 and 595 MUm) of barley beta-D-glucan concentrate (BGC) on two fundamental rheological properties namely oscillatory rheology and creep in a dough system (sample to water = 1:2). The water holding capacity, sediment volume fraction and protein content increased with an increase in particle size from 74 MUm to 595 MUm, which directly influences the mechanical strength and visco-elasticity of the dough. The dough exhibited predominating solid-like behavior (elastic modulus, G'>viscous modulus, G"). The G' decreased systematically with increasing temperature from 25 to 85 degrees C at the frequency range of 0.1-10 Hz except for the dough having particle size of 105 MUm, which could be associated with increase in protein content in the fraction. A discrete retardation spectrum is employed to the creep data to obtain retardation time and compliance parameters which varied significantly with particle size and the process temperature. All those information could be helpful to identify the particle size range of BGC that could be useful to produce a beta D-glucan enriched designed food. PMID- 25037334 TI - A robust pH-sensitive drug carrier: aqueous micelles mineralized by calcium phosphate based on chitosan. AB - This study developed an exciting alternative to the polymeric delivery system in cancer therapy. In this study, novel organic-inorganic hybrid polymeric micelles based on chitosan were synthesized and found to be robust nanocarriers for intracellular controlled release drug delivery. The polymeric micelles of carboxymethyl chitosan-grafted-p(ethylene glycol)-dodecylamine (CMC-g-PEG-DDA) were readily mineralized in the presence of calcium chloride (CaCl2) and disodium hydrogen phosphate (Na2HPO4). Mineralization reduced polymeric micelles' size from 239 nm to 138 nm and formed a multi-core structure. The mineralized polymeric micelles (MPM) exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized polymeric micelles (MPM@DOX) at physiological pH was efficiently inhibited, At an endosomal pH (pH 5.0), DOX release was facilitated due to rapid dissolution of the calcium phosphate (CaP). These results indicate that mineralized polymeric micelles are potentially as robust carriers that can release DOX at specific sites under mild acidic conditions, such as in an extracellular matrix of tumor tissue and intracellular cell compartments. PMID- 25037335 TI - Efficient removal of malachite green dye using biodegradable graft copolymer derived from amylopectin and poly(acrylic acid). AB - This article reports on the application of a high performance biodegradable adsorbent based on amylopectin and poly(acrylic acid) (AP-g-PAA) for removal of toxic malachite green dye (MG) from aqueous solution. The graft copolymer has been synthesized and characterized using various techniques including FTIR, GPC, SEM and XRD analyses. Biodegradation study suggests that the co-polymer is biodegradable in nature. The adsorbent shows excellent potential (Qmax, 352.11 mg g(-1); 99.05% of MG has been removed within 30 min) for removal of MG from aqueous solution. It has been observed that point to zero charge (pzc) of graft copolymer plays significant role in adsorption efficacy. The adsorption kinetics and isotherm follow pseudo-second order and Langmuir isotherm models, respectively. Thermodynamics parameters suggest that the process of dye uptake is spontaneous. Finally desorption study shows excellent regeneration efficiency of adsorbent. PMID- 25037336 TI - Hydrolysis of dilute acid-pretreated cellulose under mild hydrothermal conditions. AB - The hydrolysis of dilute acid-pretreated cellulose was investigated in a conventional oven and under microwave heating. Two acids--sulfuric and oxalic- were studied. For both hydrothermal conditions (oven and microwave) the resultant total organic carbon (TOC) values obtained by the hydrolysis of the cellulose pretreated with sulfuric acid were higher than those obtained by the hydrolysis of the cellulose pretreated with oxalic acid. However, the dicarboxylic acid exhibited higher hydrolytic efficiency towards glucose. The hydrolysis of cellulose was greatly promoted by microwave heating. The Rietveld method was applied to fit the X-ray patterns of the resultant cellulose after hydrolysis. Oxalic acid preferentially removed the amorphous region of the cellulose and left the crystalline region untouched. On the other hand, sulfuric acid treatment decreased the ordering of the cellulose by partially disrupting its crystalline structure. PMID- 25037337 TI - Synthesis and characterization of a novel chitosan-N-acetyl-homocysteine thiolactone polymer using MES buffer. AB - We report a new "green" approach to synthesize a novel thiolated chitosan conjugate, chitosan-N-acetyl-homocysteine thiolactone (chitosan-AcHcys) using a "Good's buffers", 2-(N-morpholino)ethanesulfonic acid (MES). After that, the crosslinked Xr-chitosan-AcHcys was obtained only in the presence of air, without other reactants. The chitosan-AcHcys spectrum shows a partial incorporation of the thiolactone onto the polymer backbone. The derivative thermogravimetric analysis confirmed that chitosan-AcHcys is slightly less stable than starting chitosan; however, the peak profile is broadened which is indicative of deeper changes in the thermal degradation process. Also, aqueous dispersions with different concentrations of the crosslinked material (Xr-chitosan-AcHcys) were prepared and rheologically characterized. All aqueous dispersions are viscoelastic fluid with shear-thinning behavior. The viscosity of the dispersions (1-7% of chitosan-AcHcys) increases as a function of polymer concentration. So, we have achieved to disperse a high concentration of thiolated-chitosan derivative in water with different rheological characteristics, which could affect the drug release. PMID- 25037338 TI - Effect of retrogradation time on preparation and characterization of proso millet starch nanoparticles. AB - Starch nanoparticles were prepared from proso millet starch using a green and facile method combined with enzymolysis and recrystallization. Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC) and thermal gravimetric analysis (TGA) were used to characterize the morphology and crystal structure of the starch nanoparticles prepared with different retrogradation time (0.5, 4, 12, and 24h). The results showed that the sizes of the starch nanoparticles were between 20 nm and 100 nm. The crystal pattern changed from A type (native starch) to B-type (nanoparticles), and the relative crystallinity of the nanoparticles increased obviously, as compared with the native starch. The nanoparticles prepared with the 12h retrogradation time had the highest degree of crystallinity (47.04%). Compared to conventional acid hydrolysis to make starch nanoparticles, the present approach has the advantage of being quite rapid and presenting a higher yield (about 55%). PMID- 25037339 TI - Chemical structure and biological activity of a highly branched (1 -> 3,1 -> 6) beta-D-glucan from Isochrysis galbana. AB - A highly branched (1 -> 3,1 -> 6)-beta-D-glucan was isolated from the microalga Isochrysis galbana Parke (Isochrysidales, Haptophyta). The polysaccharide structure was analyzed by methylation and Smith degradation, as well as by ESI and MALDI TOF mass spectrometry and NMR spectroscopy. The glucan was shown to contain a (1 -> 6)-linked backbone, where every residue is substituted at position 3 by Glc, which in turn may be substituted at C-6 by a single Glc or by rather short (up to tetrasaccharide) oligosaccharide chains. All the 3-linked Glc residues are present in these side chains. In the biological activity experiments it was demonstrated that the polysaccharide directly inhibits the proliferation of U937 human leukemic monocyte lymphoma cells and therefore has potential anti tumor activity. PMID- 25037340 TI - Review on flammability of biofibres and biocomposites. AB - The subject on flammability properties of natural fibre-reinforced biopolymer composites has not been broadly researched. This is not only evidenced by the minimal use of biopolymer composites and/or blends in different engineering areas where fire risk and hazard to both human and structures is of critical concern, but also the limited amount of published scientific work on the subject. Therefore, it is necessary to expand knowledge on the flammability properties of biopolymers and add value in widening the range of their application. This paper reviews the literature on the recent developments on flammability studies of bio fibres, biopolymers and natural fibre-reinforced biocomposites. It also covers the different types of flame retardants (FRs) used and their mechanisms, and discusses the principles and methodology of various flammability testing techniques. PMID- 25037341 TI - Sequential low and medium frequency ultrasound assists biodegradation of wheat chaff by white rot fungal enzymes. AB - The consequences of ultrasonic pre-treatment using low (40 kHz) and medium (270 kHz) frequency (40 kHz followed by 270 kHz) on the degradation of wheat chaff (8 g 100ml(-1) acetate buffer, pH 5) were evaluated. In addition, the effects of the ultrasonic pre-treatment on the degradation of the wheat chaff when subsequently exposed to enzyme extracts from two white rot fungi (Phanerochaete chrysosporium and Trametes sp.) were investigated. Pre-treatment by sequential low and medium frequency ultrasound had a disruptive effect on the lignocellulosic matrix. Analysis of the phenolic-derived volatiles after enzymatic hydrolysis showed that biodegradation with the enzyme extract obtained from P. chrysosporium was more pronounced compared to that of the Trametes sp. The efficacy of the ultrasonic pre-treatment was attributed to increased enzyme accessibility of the cellulose fibrils due to sonication-induced disruption of the plant surface structure, as shown by changes in the microstructure. PMID- 25037342 TI - Evaluation of the biotechnological potential of Rhizobium tropici strains for exopolysaccharide production. AB - Rhizobium tropici, a member of the Rhizobiaceae family, has the ability to synthesize and secrete extracellular polysaccharides (EPS). Rhizobial EPS have attracted much attention from the scientific and industrial communities. Rhizobial isolates and R. tropici mutants that produced higher levels of EPS than the wild-type strain SEMIA4080 were used in the present study. The results suggested a heteropolymer structure for these EPS composed by glucose and galactose as prevailing monomer unit. All EPS samples exhibited a typical non Newtonian and pseudoplastic fluid flow, and the aqueous solutions apparent viscosities increased in a concentration-dependent manner. These results serve as a foundation for further studies aimed at enhancing interest in the application of the MUTZC3, JAB1 and JAB6 strains with high EPS production and viscosity can be exploited for the large-scale commercial production of Rhizobial polysaccharides. PMID- 25037343 TI - Ion exchange kinetics of magnetic alginate ferrogel beads produced by external gelation. AB - This paper reports on a study of the influence of sodium alginate concentration and iron addition on the ion exchange kinetics of calcium alginate ferrogel beads produced by external gelation. The calcium absorption and sodium release of the beads were fitted to Fick's second law for unsteady state diffusion in order to obtain the effective diffusion coefficients of Na(+) and Ca(2+). The dried beads were characterized concerning their thermal stability, particle size distribution and morphology. The gelation kinetics showed that an increase in alginate concentration from 1% to 2% increased the Ca(2+) equilibrium concentration, but presented no effect on Ca(2+) effective diffusion coefficient. Alginate concentration higher than 2% promoted saturation of binding sites at the bead surfaces. The addition of iron promoted faster diffusion of Ca(2+) inside the gel beads and reduced the Ca(2+) equilibrium concentration. Also, iron particles entrapped in the alginate gel beads promoted greater absorption of water compared to pure alginate gel and lower thermal stability of the beads. The main diffusion of Ca(2+) into and Na(+) out from the bead took place during the first 60 min, during which almost 85-90% of the Ca(2+) equilibrium concentration is achieved, indicating that this period is sufficient to produce a Ca-alginate bead with high crosslinking of the polymer network. PMID- 25037344 TI - Choline chloride based ionic liquid analogues as tool for the fabrication of agar films with improved mechanical properties. AB - In the present paper, we test the suitability of ChCl/urea (DES-U) and ChCl/glycerol (DES-G) eutectic mixtures, each one prepared at 1:2 molar ratio, for the production of agar films. A three-step process is proposed: pre solubilization of polymer in DES followed by compression-molding and subsequent drying. The mechanical properties, water resistance and microstructure of the films were evaluated at different polymer concentrations (i.e. 2-6%, w/w). DES-U showed by far, the best film forming ability. Agreeing with the diffusion and SEM data, films with the best mechanical properties were found at the lowest and highest agar concentrations (tensile strengths of 24.2-42 MPa and elongations of 15.4-38.9%). The water sorption and contact angle studies suggested increased hydrophilicity for the film containing the lowest concentration of agar. The use of choline chloride based ionic liquid analogues as solvent and plasticizer might be a promising tool for the development of new non-aqueous materials based on seaweed polysaccharides. PMID- 25037345 TI - Ellagic acid encapsulated chitosan nanoparticles as anti-hemorrhagic agent. AB - Ellagic acid, a naturally occurring polyphenol was encapsulated in chitosan particles prepared by ionotropic gelation and characterized for its physicochemical properties. A maximum encapsulation efficiency of 49% was achieved. The blood clotting time and clot retraction time were calculated for different concentrations of ellagic acid, chitosan and ellagic acid-encapsulated chitosan. A reduction of 34% in the clot time and 16.4% in the retraction time was observed in ellagic acid-encapsulated chitosan when compared with free ellagic acid at concentrations as low as 0.1mg/mL. The physical blend in comparison to free ellagic acid displayed a reduction of 13.8% and 4.6% in the clotting time and retraction time respectively under similar conditions. This suggests that the encapsulation of ellagic acid favors thrombosis due to synergistic action of chitosan and ellagic acid on same molecular targets. This study demonstrates the potential of ellagic acid-chitosan system as an effective anti-hemorrhagic system. PMID- 25037346 TI - Characterization of an acetyl esterase from Myceliophthora thermophila C1 able to deacetylate xanthan. AB - Screening of eight carbohydrate acetyl esterases for their activity towards xanthan resulted in the recognition of one active esterase. AXE3, a CAZy family CE1 acetyl xylan esterase originating from Myceliophthora thermophila C1, removed 31% of all acetyl groups present in xanthan after a 48 h incubation. AXE3 activity towards xanthan was only observed when xanthan molecules were in the disordered conformation. Optimal performance towards xanthan was observed at 53 degrees C in the complete absence of salt, a condition favouring the disordered conformation. AXE3-deacetylated xanthan was hydrolyzed using cellulases and analyzed for its repeating units using UPLC-HILIC-ELSD/ESI-MS. This showed that AXE3 specifically removes the acetyl groups positioned on the inner mannose and that acetyl groups positioned on the outer mannose are not removed at all. After a prolonged incubation at optimal conditions, 57% of all acetyl groups, representing 70% of all acetyl groups on the inner mannose units, were hydrolyzed. PMID- 25037347 TI - Manganese-containing cellulose nanocomposites: the restrain effect of cellulose treated with NaOH/urea aqueous solutions. AB - In this article, the manganese-containing cellulose nanocomposites were obtained using microcrystalline cellulose and Mn(CH3COO)2 . 4H2O in the NaOH/urea aqueous solutions by a efficient microwave-assisted method. The effects of the heating time and Mn(CH3COO)2 . 4H2O concentration on the cellulose nanocomposites were investigated. It was found that the microcrystalline cellulose pretreated with NaOH/urea aqueous solutions played an important role in the phase, shape, and thermal stability of manganese-containing cellulose nanocomposites. Well crystalline phases of manganese oxides were not observed in the manganese containing cellulose nanocomposites. Furthermore, well-crystalline phases of manganese oxides were not also observed by thermal treatment of the manganese containing cellulose nanocomposites at 600 degrees C for 3h. These results could be attributed to the restrain effect of cellulose treated with NaOH/urea aqueous solutions. It was supposed the possible mechanism during the phase transformation of cellulose nanocomposites. PMID- 25037348 TI - Determination of the degree of deacetylation of chitosan by capillary zone electrophoresis. AB - In this study we have developed a capillary zone electrophoresis (CZE) method for the determination of the degree of deacetylation (DDA) of chitosan. The electrophoretic mobilities of chitosans were measured by using the optimized CZE conditions. An internal standard, hexammine cobalt(III) chloride, was used to improve the precision of the electrophoretic mobility measurement. We have constructed a linear calibration curve between the CZE measured mobilities and the (1)H NMR determined DDAs ranging from 55.3% to 96.2%. Based on the established linear calibration equation and the CZE measured mobilities, we were able to obtain not only the average DDA values but also the DDA distribution profiles of the chitosan samples. Without prior sample treatment or purification, we have successfully employed the newly developed CZE method to characterize the reacetylation derivatives of chitosans and to detect the DDA variability in different lots of chitosan products. PMID- 25037349 TI - Extraction optimization, characterization and immunity activity of polysaccharides from Fructus Jujubae. AB - The versatile Fructus Jujubae is widely used in Chinese and Korean traditional medicine. In this study, the extraction optimization, characterization and immunostimulatory activities of polysaccharides from Fructus Jujubae were investigated. Based on a four-variable-three-level Box-Behnken statistical design, the optimal extraction parameters were optimized as follows: extraction temperature 90 degrees C, extraction time 3.23 h, water to raw material ratio 33:1 and extraction 3 times. Under these conditions, the experimental yield of polysaccharides was 6.47 +/- 0.26%, which was close to the predicted yield value (6.54%). The crude Fructus Jujubae polysaccharide was further purified by DEAE cellulose chromatography repeatedly, and two homogenous fractions, designated as RQP1d and RQP2d with molecular weight of 83.8 and 123.0 kDa respectively, were obtained. Their structures were determined by chemical analysis, Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). Finally, preliminary immunological tests indicated that both RQP1d and RQP2d significantly stimulated NO production in RAW264.7 macrophages, and promoted LPS induced splenocyte proliferation. These data implied Fructus Jujubae polysaccharides had the potential to be explored as novel natural immunostimulant for using in functional foods or medicine. PMID- 25037350 TI - Molecular encapsulation of ascorbyl palmitate in preformed V-type starch and amylose. AB - In the present study, we introduce a simple method to prepare inclusion complexes by "inserting" guest molecules into preformed "empty" V-type amylose helices. Ascorbyl palmitate (AscP) was used as a model guest material to investigate the effect of solvent environment, complexation temperature, annealing and guest concentration on inclusion complex formation. High complexation temperature was not necessary for encapsulating guest molecules in amylose helices, avoiding thermal degradation of guest compounds. This method would also avoid the wasting of guest materials because uncomplexed guest can be reused. It was found in the study that intermediate ethanol and acetone concentrations (generally 40-60%, v/v) at room temperature were appropriate for the complexation between V-amylose and AscP. Annealing, i.e. heat treatment in ethanol solutions at elevated temperatures (45-70 degrees C), was able to significantly increase the crystallinity of V-amylose and V-starch to as high as 65% and facilitate greater complexation evidenced from higher enthalpies, probably due to more regularly arranged helical cavities in larger crystalline phase. The complexation between V amylose and AscP was also found to be enhanced with AscP concentration, while the dissociation temperature experienced a slight decrease. PMID- 25037351 TI - A novel thermostable, alkaline pectate lyase from Bacillus tequilensis SV11 with potential in textile industry. AB - An extracellular pectate lyase was purified and characterized from a UV mutant of Bacillus tequilensis SV11. Purification resulted in a 16.2-fold improvement in the enzyme specific activity, with approximately 40.2% yield. SDS-PAGE showed that the enzyme had two subunits with molecular masses of 135 +/- 2 and 43 +/- 2 kDa. Further, MALDI-TOF MS experiments revealed that the mass spectrum of the second peptide significantly (91% score) matched with the unsaturated rhamnogalacturonyl hydrolase YteR OS-Bacillus subtilis (strain 168) by 27% sequence coverage, nominal mass 43,231 Da, and PI 5.91. The enzyme was optimally active at 60 degrees C, pH 9. Km and Vmax of the purified pectate lyase was found to be 1.220 mg/mL and 1773 U/mL, respectively. The enzyme was studied for its applicability in bioscouring and found to be efficient in the removal of 97.91% pectin of cotton fabric when compared with alkali-treated fabric. PMID- 25037352 TI - Novel starch based nano scale enteric coatings from soybean meal for colon specific delivery. AB - Soybean meal was used to isolate resistant starch and produce nanoparticles, which could be potential coating materials for colonic nutrient and drug deliveries. The nanoparticles were in 40 +/- 33.2 nm ranges. These nanoparticles were stable under simulated human physiological conditions. The degrees of dissolution in both stomach and intestinal conditions were less than 30%. Furthermore, the nanoparticles were less susceptible to pancreatic enzymatic digestion (20%), which was also evidenced by the co-existence of B-type crystalline pattern. In addition to the dissolution and digestion studies in the upper gastrointestinal tract, the nanoparticles were subjected to in vitro fermentation by Bifidobacterium brevis and Lactobacillus casei. Both species showed an increase in growth and activity, while producing short chain fatty acids: acetate, propionate, and butyrates in varying amounts. Overall this study clearly demonstrated a novel method that can be used for colon-specific delivery of bioactive compounds such as drugs and nutrients. PMID- 25037353 TI - Photoresponsive cellulose fibers by surface modification with multifunctional cellulose derivatives. AB - Eucalyptus bleached kraft pulp fibers were modified by adsorption of novel bio based multifunctional cellulose derivatives in order to generate light responsive surfaces. The cellulose derivatives used were decorated with both cationic groups (degree of substitution, DS of 0.34) and photoactive groups (DS of 0.11 and 0.37). The adsorption was studied by UV-vis spectroscopy, surface plasmon resonance (SPR) and time-of-flight secondary ion mass spectroscopy (ToF-SIMS). The adsorption isotherms followed the Freundlich model and it turned out that the main driving force for the adsorption was electrostatic interaction. Moreover, strong indications for hydrophobic interactions between the fibers and the derivatives and the derivatives themselves were found. ToF-SIMS imaging revealed an even distribution of the derivatives on the fiber surfaces. The modified fibers underwent fast photocrosslinking under UV-irradiation as demonstrated by light absorbance and fluorescence measurements. Thus, our results proved that the modified fibers exhibited light-responsive properties and can potentially be used for the manufacture of smart bio-based materials. PMID- 25037354 TI - Composite chitosan/silk fibroin nanofibers for modulation of osteogenic differentiation and proliferation of human mesenchymal stem cells. AB - Nanofibrous membrane scaffolds of chitosan (CS), silk fibroin (SF) and CS/SF blend were prepared by electrospinning and studied for growth and osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). The morphology and physico-chemical properties of all membrane scaffolds were compared. The influence of CS and SF on cell proliferation was assessed by the MTS assay, whereas osteogenic differentiation was determined from the Alizarin Red staining, alkaline phosphatase activity and expression of osteogenic marker genes. The osteogenic differentiation and proliferation of hMSCs were enhanced by CS and SF nanofibers, respectively. Blending CS with SF retained the osteogenesis nature of CS without negatively influencing the cell proliferative effect of SF. By taking advantage of the differentiation/proliferation cues from individual components, the electrospun CS/SF composite nanofibrous membrane scaffold is suitable for bone tissue engineering. PMID- 25037355 TI - Layer-by-layer assembly of chitosan stabilized multilayered liposomes for paclitaxel delivery. AB - Paclitaxel (PTX) loaded multilayered liposomes were prepared using layer-by-layer assembly in an effort to improve the stabilization of the liposomal compositions for PTX delivery. Stearyl amine was used to provide positive charge to the PTX liposomes, and subsequently coated with anionic polyacrylic acid (PAA) followed by cationic chitosan. Various process variables were optimized and the optimum formulation was found to have particle size of 215 +/- 17 nm, zeta potential of +27.9 +/- 3.4 mV and encapsulation efficiency of 70.93 +/- 2.39%. The lyophilized chitosan-PAA-PTX-liposomes formulation was stable in simulated gastrointestinal fluids and at different environmental conditions (4 degrees C and 25 degrees C). In vitro drug release experiments demonstrated that chitosan-PAA-PTX liposomes formulation exhibited obvious sustained release behaviors compared to PTX-liposomes. Furthermore, chitosan-PAA-PTX-liposomes formulation revealed enhanced PTX induced cytotoxicity in human cervical cancer cell culture experiments compared to PTX-liposomes. In conclusion, the approach presented herein will provide a promising solution for PTX delivery. PMID- 25037356 TI - A comprehensive approach to in vitro functional evaluation of Ag/alginate nanocomposite hydrogels. AB - In this work, we present a comprehensive approach to evaluation of alginate microbeads with included silver nanoparticles (AgNPs) at the concentration range of 0.3-5mM for potential biomedical use by combining cytotoxicity, antibacterial activity, and silver release studies. The microbeads were investigated regarding drying and rehydration showing retention of ~ 80-85% of the initial nanoparticles as determined by UV-vis and SEM analyses. Both wet and dry microbeads were shown to release AgNPs and/or ions inducing similar growth delays of Staphylococcus aureus and Escherichia coli at the total released silver concentrations of ~ 10 MUg/ml. On the other hand, these concentrations were highly toxic for bovine chondrocytes in conventional monolayer cultures while nontoxic when cultured in alginate microbeads under biomimetic conditions in 3D perfusion bioreactors. The applied approach outlined directions for further optimization studies demonstrating Ag/alginate microbeads as potentially attractive components of soft tissue implants as well as antimicrobial wound dressings. PMID- 25037357 TI - Optimization of ultrasonic-assisted extraction and in vitro antioxidant activities of polysaccharides from Trametes orientalis. AB - A Box-Behnken design was employed to optimize ultrasonic-assisted extraction of Trametes orientalis polysaccharides (TOP). The crude polysaccharides were purified by DEAE cellulose-52 chromatography, giving a main fraction named as PTOP. The antioxidant properties of PTOP were evaluated by different in vitro antioxidant assays, such as 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities, reducing power, superoxide radical scavenging activities, and chelating ability of ferrous ions. The results showed that optimal extraction parameters were as follows: ratio of water to raw material 30.6 mL/g, ultrasonic power 109.8 W, extraction temperature 40.2 degrees C, and extraction time 42.2 min. Under these conditions, the experimental yield of polysaccharides was 7.49 +/- 0.14%, which agreed closely with the predicted value (7.47%). Furthermore, PTOP exhibited antioxidant capacity in a concentration-dependent manner in all assays. PMID- 25037358 TI - Optimization of polysaccharides extraction from Trametes robiniophila and its antioxidant activities. AB - Based on a single-factor experiment, Box-Behnken design was used to optimize the ultrasound-assisted extraction process of Trametes robiniophila (Huaier) polysaccharides (HPs). The optimum conditions were predicted as follows: ratio of water to raw material, 46.0 mL/g; extraction temperature, 68.9 degrees C; ultrasonic power, 51.3 W; and extraction time, 36.8 min. Under these conditions, the highest yield of HPs obtained was 36.8 +/- 0.12%, which was in good agreement with the predicted value 36.6%. Additionally, chemical analysis of HPs showed a high content (85.3 +/- 1.3%) of carbohydrates containing fucose, arabinose, xylose, mannose, galactose and glucose, with molar percentages 5.82%, 13.11%, 16.88%, 15.85%, 11.40% and 36.94%, respectively. Besides, HPs demonstrated appreciable antioxidant potential on ABTS, superoxide anion and hydroxyl radicals in vitro. These may further provide theoretical basis for the widely application of HPs in medicine and health care products. PMID- 25037359 TI - Effect of spatial distribution of wax and PEG-isocyanate on the morphology and hydrophobicity of starch films. AB - This study proposes a novel method for improving surface hydrophobicity of glycerol plasticized high amylose (HAG) films. We used polyethylene glycol isocyanate (PEG-iso) crosslinker to link HAG and three natural waxes (beeswax, candelilla wax and carnauba wax) to produce HAG+wax+PEG-iso films. The spatial distributions of wax and PEG-iso across the thickness of these films were determined using Synchrotron-based Fourier transform infrared spectroscopy. The hydrophobicity and surface morphology of the films were determined using contact angle (CA) and scanning electron microscopic measurements, respectively. The distribution patterns of wax and the PEG-iso across the thickness of the film, and the nature of crystalline patterns formed on the surface of these films were found to be the key factors affecting surface hydrophobicity. The highest hydrophobicity (CA >90 degrees ) was created when the PEG-iso was primarily distributed in the interior of the films and a hierarchical circular pinnacle structure of solidified wax was formed on the surface. PMID- 25037360 TI - Chitosan/agarose hydrogels: cooperative properties and microfluidic preparation. AB - The preparation of composite biopolymer hydrogels offers the capability to produce biocompatible and biodegradable materials with cooperative properties. In this paper, two natural polymers, namely, chitosan and agarose were employed to prepare composite hydrogels with dual pH and temperature properties. The elastic modulus of the composite hydrogels increased with agarose concentration reaching the value of 1 kPa for the chitosan/agarose gel with a 2% (w/v) concentration of agarose. In addition, composite gels exhibited a higher stability in acidic aqueous solutions, in comparison with agarose gels. The drug release properties of the composite hydrogels were tested by loading a model anticancer drug, 5 Fluorouracil, in the hydrogel interior. At pH=7.4, the cumulative release of 5-FU was ~ 50% within 96 h and decreased to ~ 33% at pH = 5.2, which was attributed to the different solubility of 5-FU as a function of pH. The preparation of composite microgels with controllable dimensions in the range from 42 to 18 MUm and with narrow size distribution (polidispersity not exceeding 1.5%) was achieved by the microfluidic emulsification of an aqueous mixture of chitosan and agarose and subsequent gelation of the precursor droplets by cooling. PMID- 25037361 TI - Preparation and antibacterial activity of the oligosaccharides derived from Rhizoma Phragmites. AB - In this study, we prepared Rhizoma Phragmites derived oligosaccharides (ROs) by hydrolysis with hydrogen peroxide (H2O2). The ROs yield was affected by reaction time, temperature, and H2O2 concentration. Too long reaction time and too high temperature decreased the ROs yield. Maximum ROs yield (11.26%) was obtained at reaction time 4h, temperature 75 degrees C, and H2O2 concentration 3.5% (v/v). The oligosaccharides sample contained 93.16% sugar, of which the average degree was approximately 11, was water-soluble, and showed white. The ROs had the highest antibacterial activity against Staphylococcus aureus, followed by Bacillus subtilis and Escherichia coli at the concentration of 100 MUg/mL. PMID- 25037362 TI - Physicochemical and thermomechanical characterization of tara gum edible films: effect of polyols as plasticizers. AB - The aim of this study was to evaluate tara gum as edible film material as well as the influence of polyols as plasticizers on the properties of the films. Thermomechanical, physicochemical and barrier properties were determined as a function of plasticizer type and concentration. Glycerol, sorbitol and PEG 400 were used in the range of 0.075-0.3g/tarag. Glycerol was the best plasticizer in terms of mechanical properties with the highest elongation (16-44%) and resistance (45-90 MPa). Sorbitol presented the best barrier properties with the lowest hydrophilicity and water vapour permeability (0.24-0.34 g mm m(-2)h(-1) kPa(-1)). Fourier transform infrared (FTIR) spectroscopy showed no significant effect on the structure of the polysaccharide. Dynamic mechanical analysis (DMA) revealed that incorporation of plasticizers increased the mobility of the polymer chains and reduced the glass transition and melting temperature by 30 and 100 degrees C respectively. PMID- 25037363 TI - Thermoresponsive chitosan-agarose hydrogel for skin regeneration. AB - Healing enhancement and pain control are critical issues on wound management. So far, different wound dressings have been developed. Among them, hydrogels are the most applied. Herein, a thermoresponsive hydrogel was produced using chitosan (deacetylation degree 95%) and agarose. Hydrogel bactericidal activity, biocompatibility, morphology, porosity and wettability were characterized by confocal microscopy, MTS assay and SEM. The performance of the hydrogel in the wound healing process was evaluated through in vivo assays, during 21 days. The attained results revealed that hydrogel has a pore size (90-400 MUm) compatible with cellular internalization and proliferation. A bactericidal activity was observed for hydrogels containing more than 188 MUg/mL of chitosan. The improved healing and the lack of a reactive or a granulomatous inflammatory reaction in skin lesions treated with hydrogel demonstrate its suitability to be used in a near future as a wound dressing. PMID- 25037364 TI - The effect of hydrogen peroxide concentration and solid loading on the fractionation of biomass in formic acid. AB - This study investigated the fractionation of biomass using a decomposing mixture of hydrogen peroxide-formic acid as a pretreatment for the biorefining of Miscanthus * giganteus and of sugarcane bagasse. The main parameters investigated were the hydrogen peroxide concentration (2.5, 5.0 and 7.5 wt%) and biomass loading (5.0 and 10.0 wt%). At the highest hydrogen peroxide concentration used (7.5 wt%), the energy released by the decomposition of the H2O2 could heat the reaction mixture up to 180 degrees C in a short time (6-16 min). As a result, highly delignified pulps, with lignin removal as high as 92 wt%, were obtained. This delignification process also solubilised a significant amount of pentosan (82-98 wt%) from the initial biomass feedstock, and the resulting pulp had a high cellulosic content (92 wt%). The biomass loading only affected the reaction rate of hydrogen peroxide decomposition. Various analytical methods, including Fourier transform infrared spectroscopy, and thermogravimetric and elemental analyses, characterized the lignin obtained. PMID- 25037365 TI - Chitosan mouthwash: toxicity and in vivo validation. AB - A previous study showed that a chitosan mouthwash would be a valid alternative to current mouthwashes as it demonstrated, in vitro, significantly higher antibiofilm activity than two commercial mouthwashes. As such, the aim of this work was to verify the safety of the developed product and to validate, in vivo, the biological activity ascertained in vitro. Chitosan mouthwash safety was evaluated through Ames, MTT and V79 chromosomal aberration assay while antimicrobial activity was evaluated through in vivo assays. The results showed that the chitosan mouthwash was safe, presenting lower cytotoxicity than a commercial mouthwash, and that it effectively reduced viable counts of Streptococcus spp. and Enterococcus spp. by ca. 5.5 log of CFU. Furthermore, in direct comparison with a commercial mouthwash the chitosan mouthwash possessed significantly higher antimicrobial activity. The conjunction of these results proves that the chitosan mouthwash is a safe, effective, natural alternative to the existent chemical mouthwashes. PMID- 25037366 TI - Preparation of cellulose based microspheres by combining spray coagulating with spray drying. AB - Porous microspheres of regenerated cellulose with size in range of 1-2 MUm and composite microspheres of chitosan coated cellulose with size of 1-3 MUm were obtained through a two-step spray-assisted approach. The spray coagulating process must combine with a spray drying step to guarantee the formation of stable microspheres of cellulose. This approach exhibits the following two main virtues. First, the preparation was performed using aqueous solution of cellulose as precursor in the absence of organic solvent and surfactant; Second, neither crosslinking agent nor separated crosslinking process was required for formation of stable microspheres. Moreover, the spray drying step also provided us with the chance to encapsulate guests into the resultant cellulose microspheres. The potential application of the cellulose microspheres acting as drug delivery vector has been studied in two PBS (phosphate-buffered saline) solution with pH values at 4.0 and 7.4 to mimic the environments of stomach and intestine, respectively. PMID- 25037367 TI - Impact of regeneration process on the crystalline structure and enzymatic hydrolysis of cellulose obtained from ionic liquid. AB - The present study investigated the impact of regeneration process on the crystalline structure and enzymatic hydrolysis behaviors of microcrystalline cellulose (MCC) regenerated from ionic liquid 1-butyl-3-methylimidazolium chloride. The crystalline structures of these regenerated samples were analyzed by X-ray diffraction. Results suggested that almost amorphous cellulose was obtained by regenerating MCC in acetone (DRC-a), while partial cellulose II structure could be found in these regenerated samples from water and ethanol. Additionally, the enzymatic hydrolysis behaviors of MCC and its regenerated samples were comparatively studied. Results showed that above 90% of cellulose could be converted into glucose within 4h for DRC-a and regenerated cellulose without drying (WRC-w) as compared to that of MCC (9.7%). Therefore, the regeneration process could significantly influence the crystallinity and digestibility of cellulose. PMID- 25037368 TI - Horseradish peroxidase-catalyzed formation of hydrogels from chitosan and poly(vinyl alcohol) derivatives both possessing phenolic hydroxyl groups. AB - Horseradish peroxidase-catalyzed cross-linking was applied to prepare hydrogels from aqueous solutions containing chitosan and poly(vinyl alcohol) derivatives both possessing phenolic hydroxyl groups (denoted as Ph-chitosan and Ph-PVA, respectively). Comparing the hydrogels prepared from the solution of 1.0% (w/v) Ph-chitosan and 3.0% (w/v) Ph-PVA and that of 3.0% (w/v) Ph-chitosan and 1.0% (w/v) Ph-PVA, the gelation time of the former hydrogel was 47 s, while was 10s longer than that of the latter one. The breaking point for the former hydrogel under stretching (114% strain) was approximately twice larger than that for the latter one. The swelling ratio of the former hydrogel in saline was about half of the latter one. Fibroblastic cells did not adhere on the former hydrogel but adhered and spread on the latter one. The growth of Escherichia coli cells was fully suppressed on the latter hydrogel during 48 h cultivation. PMID- 25037369 TI - Chemical characterisation and analysis of the cell wall polysaccharides of duckweed (Lemna minor). AB - Duckweed is potentially an ideal biofuel feedstock due to its high proportion of cellulose and starch and low lignin content. However, there is little detailed information on the composition and structure of duckweed cell walls relevant to optimising the conversion of duckweed biomass to ethanol and other biorefinery products. This study reports that, for the variety and batch evaluated, carbohydrates constitute 51.2% (w/w) of dry matter while starch accounts for 19.9%. This study, for the first time, analyses duckweed cell wall composition through a detailed sequential extraction. The cell wall is rich in cellulose and also contains 20.3% pectin comprising galacturonan, xylogalacturonan, rhamnogalacturonan; 3.5% hemicellulose comprising xyloglucan and xylan, and 0.03% phenolics. In addition, essential fatty acids (0.6%, alpha-linolenic and linoleic/linoelaidic acid) and p-coumaric acid (0.015%) respectively are the most abundant fatty acids and phenolics in whole duckweed. PMID- 25037370 TI - Cellulose nanocrystals (CNC) as carriers for a spirooxazine dye and its effect on photochromic efficiency. AB - Nanocrystalline cellulose (CNC) as a renewable/sustainable material, has received much attention. Herein we studied CNC as carriers for a hydrophobic spirooxazine (SO)-based dye, 1,3-dihydro-1,3,3-trimethylspiro[2H-indole-2,3'-[3H]naphtha[2,1 b][1,4]oxazine], which may have potential applications in reversible memory photo devices, textiles, photo-sensitive paper coatings, and inkjet printing inks. Due to the high cost and water-insolubility of this dye, it is desirable to improve its coloration efficiency and water-dispersibility. The experimental approach was to use CNC as carriers for the SO dye, thus obtaining a stable photochromic dye in aqueous systems. Transmission electron microscope (TEM) observation confirmed that the SO dye adsorbed on the surface of the CNC, which functioned as carriers for the photochromic dye. An impregnation process was adopted to anchor the dye onto cellulosic paper. It was found that the use of CNC resulted in a significant improvement in the SO coloration efficiency. The color stability and fatigue resistance were also studied. The use of CNC as carriers for a hydrophobic compound, its enhancement of associated properties, and its subsequent application were demonstrated. PMID- 25037371 TI - Self-association of sodium deoxycholate with EHEC cellulose cooperatively induced by sodium dodecanoate. AB - Some aspects of ethyl (hydroxyethyl) cellulose (EHEC) aqueous behavior in the presence of ionic surfactants are described in the literature; however, most of the studies reported address moderately concentrated solutions. Few studies have been carried out in the dilute regime using mixtures of biosurfactants. The main purpose of this work is to investigate the interaction of EHEC in the dilute regime and to verify the mixture of two surfactants: sodium deoxycholate (NaDC) and sodium dodecanoate (SDoD). The parameters of the surfactant to polymer association processes such as the critical aggregation concentration (cac) and saturation of the polymer by surfactants (psp) were determined from the plots of surface tension and specific conductivity versus surfactant concentration in basic conditions. The cmc of NaDC-SDoD mixtures showed non-ideal behavior. However, EHEC added to mixtures of SDoD and NaDC acts as a stabilizer for the mixed aggregate during the association process. PMID- 25037372 TI - Decanoic acid grafted oligochitosan nanoparticles as a carrier for insulin transport in the gastrointestinal tract. AB - The objective was to explore the potential of decanoic acid grafted oligochitosan nanoparticles (CSO-DA NPs) as a carrier for insulin. The insulin-loaded CSO-DA NPs obtained by varying the pH and concentrations of CSO and DA had a particle size of 200.6 +/- 71.2 nm, with an entrapment efficiency and loading efficiency of 61.18% and 5.56%, respectively. An in vitro study of the formulation showed typical burst of insulin and pH-dependent characteristics. The NPs administered by the in situ loop method were effective in lowering the serum glucose level of rats which was based on the synergistic effect of adhesion of CSO and permeation enhancing effect of DA. In particular, the 50 IU/kg-dose of CSO-DA NPs reduced the serum glucose level by 57.18%. Histopathology investigations showed that the CSO-DA NPs had a low toxicity. Therefore, CSO-DA nanoparticles appear to be promising vehicles for insulin transport through the intestinal mucosa. PMID- 25037373 TI - Hydrophobic-modified nano-cellulose fiber/PLA biodegradable composites for lowering water vapor transmission rate (WVTR) of paper. AB - New biodegradable nanocomposites have been successfully prepared by incorporating modified nano-cellulose fibers (NCF) in a biodegradable polylactic acid (PLA) matrix in this work. The hydrophobic-modified NCF was obtained by grafting hydrophobic monomers on NCF to improve the compatibility between NCF and PLA during blending. The resulting NCF/PLA composites were then applied on paper surface via a cast-coating process in an attempt to reduce the water vapor transmission rate (WVTR) of paper. The WVTR tests, conducted under various testing conditions and with different coating weights, demonstrated that the modified NCF/PLA composites coating played a critical role in lowering WVTR of paper. The lowest WVTR value was 34 g/m(2)/d, which was obtained with an addition of 1% of modified NCF to PLA and the composites coating weight at 40 g/m(2) and substantially lower than the control value at 1315 g/m(2)/d. The paper coated with the modified biodegradable composite is promising as green-based packaging materials. PMID- 25037374 TI - Characterization of physicochemical properties of carboxymethyl agar. AB - A series of carboxymethyl agars (CMAs) with different degree of substitution (DS) were prepared, and their properties were determined and analyzed. The results showed that with the increase of DS, the dissolving temperature, the gelling temperature, the gel melting temperature, the gel strength, the gel hardness, the gel fracturability, and the solution apparent viscosity of CMA all decreased, except that its gel cohesiveness and gel springiness increased. The variation process of agar molecules in solution from coil to helix could be observed by measuring the optical rotation of the solution at such a low concentration, at which even the solution could not form a gel. The gel skeleton microstructures of both agar and CMA were of porous network structure, and the pore size of CMA became smaller and denser with the increase of its DS. After carboxymethylation, the agar hygroscopicity was improved, but its thermal stability was lowered. PMID- 25037375 TI - Enhanced mechanical and thermal properties of regenerated cellulose/graphene composite fibers. AB - In this study, a wet spinning method was applied to fabricate regenerated cellulose fibers filled with low graphene loading which was systematically characterized by SEM, TEM, FTIR and XRD techniques. Subsequently, the mechanical and thermal properties of the resulting fibers were investigated. With only 0.2 wt% loading of graphene, a ~ 50% improvement of tensile strength and 25% enhancement of Young's modulus were obtained and the modified Halpin-Tsai model was built to predict the mechanical properties of composite fibers. Thermal analysis of the composite fibers showed remarkably enhanced thermal stability and dynamic heat transfer performance of graphene-filled cellulose composite fiber, also, the presence of graphene oxide can significantly enhance the thermal conductivity of the composite fiber. This work provided a facile way to improve mechanical and thermal properties of regenerated cellulose fibers. The resultant composite fibers have potential application in thermal insulation and reinforced fibrous materials. PMID- 25037376 TI - Preparation and properties of organic-inorganic composite superabsorbent based on xanthan gum and loess. AB - A new, low-cost, and eco-friendly organic-inorganic composite superabsorbent was successfully synthesized in aqueous solution by polymerization xanthan gum (XG), neutralized acrylic acid (AA) and loess using ammonium persulfate (APS) as initiator and N,N-methylenebisacrylamide (MBA) as crosslinker. Structure and morphological characterizations of the composite superabsorbent were investigated by Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The loess content, pH values, surfactants, salts and temperature which could affect the swelling and water-retention capabilities of the composite superabsorbent were investigated. The composite superabsorbent exhibits excellent water absorbency (610 g/g in distilled water), pH-stability (pH 5-10), and higher swelling capacity in anionic surfactant solution; on the other hand, the composite superabsorbent can be used for removing multivalent metal ions. PMID- 25037377 TI - Recycled chitosan nanofibril as an effective Cu(II), Pb(II) and Cd(II) ionic chelating agent: adsorption and desorption performance. AB - Mechanically disassembled chitosan nanofibrils were prepared and used as metal ion chelating agents. Structure and morphology of nanofibrils were investigated and ionic adsorption or desorption performance were validated to establish related fitting models. In single metal ion solution, the saturated adsorption capacities of Cu(II), Pb(II), Cd(II), Zn(II), and Ni(II) were 168.66, 118.00 and 60.85, 143.67, and 63.32 mg/g, respectively. In ternary metal ion solution, Cu(II) was more competitive to be adsorbed than Pb(II) and Cd(II) and its removal could arrive at 60%. Ions adsorbed by nanofibrils could be released by EDTA and the recovery could keep above 70% after 3 sorption-desorption cycles. Hence, renewable and recyclable nanofibrillar chitosan exhibited a great promising application in metal treatments attributed to its high adsorption capacity and chelation efficiency. PMID- 25037378 TI - Sodium cobalt hexacyanoferrate encapsulated in alginate vesicle with CNT for both cesium and strontium removal. AB - Sodium cobalt hexacyanoferrate (CoFC)-encapsulating alginate beads reinforced with highly dispersed multiwalled carbon nanotubes were prepared for the aqueous removal of cesium and strontium ions. Carbon nanotubes enhanced the effective surface area, encapsulation ability and adsorption capacity of beads. Equilibrium and kinetic studies were conducted with different mathematical models. The goodness of mathematical fitting of experimental data on the adsorption isotherm model was in the order Langmuir higher than Freundlich. The maximum Cs(+)/Sr(2+) adsorption capacity of beads modified with carbon nanotubes were 133/72 mg/g and that of beads without carbon nanotubes were 121/70 mg/g. Similarly in kinetic models pseudo-second-order gave better fitting than pseudo-first-order. The performance of beads was consistent in a wide range of pH as well as in high ionic competitions. The fixed bed adsorption column analysis indicated that beads can be used for large scale treatment of cesium and strontium contaminated water. PMID- 25037379 TI - Structural elucidation of the exopolysaccharide produced by the mangrove fungus Penicillium solitum. AB - A water soluble extracellular polysaccharide, designated GW-12, was obtained from the liquid culture broth of the mangrove fungus Penicillium solitum by ethanol precipitation, anion-exchange and size-exclusion chromatography. Reversed-phase high performance liquid chromatography analysis showed that GW-12 mainly consisted of d-mannose, and its molecular weight was estimated to be about 11.3 kDa determined by high performance gel permeation chromatography. On the basis of chemical and spectroscopic analyses, including methylation analysis and nuclear magnetic resonance (NMR) spectroscopy, the structure of GW-12 may be represented as a mannan with branches. The main chain of GW-12 was composed of (1 -> 2) linked alpha-D-mannopyranose and (1 -> 6)-linked alpha-D-mannopyranose residues, branched by single alpha-d-mannopyranose units attached to the main chain at C-6 positions of (1 -> 2)-linked alpha-D-mannopyranose residues. There was three branch points for every seven sugar residues in the backbone. PMID- 25037380 TI - Amorphous supramolecular structure of carboxymethyl cellulose in aqueous solution at different pH values as determined by rheology, small angle X-ray and light scattering. AB - Carboxymethyl cellulose (CMC) is one of the most widely used thickening agents in industry. The combination of small-angle X-ray scattering (SAXS), static and dynamic light scattering, as well as viscosity measurements and microscopy at different pH values was utilized to explore the physicochemical properties of CMC on a scale ranging from individual macromolecules to supramolecular assemblies. The supramolecular structure of CMC was represented as a set of characteristic sample subspaces based on SAXS data utilizing the string-of-beads model. The results indicate that at pH 7.0 individual CMC molecules are approximately uniformly distributed in a supramolecular structure owing to strong intra- and intermolecular repulsive interactions. The structure of CMC is most expanded at the value of pKa, where it has the largest radius of gyration, persistence length, and size of heterogeneous regions. Below pKa the majority of the CMC sample volume belongs to the low density subspaces. Most of CMC molecules, however, reside in a few high density subspaces. Dynamically, supramolecular structure of CMC is composed of fast diffusive relaxation processes embedded in a background of non-diffusive slow relaxation process at high pH and mostly slow relaxation processes at low pH. The rheological properties of CMC at different pH values were directly related to the CMC supramolecular structure in the aqueous environment. PMID- 25037382 TI - Enhancement of nanofibrillation of softwood cellulosic fibers by oxidation and sulfonation. AB - In this study, sulfonic acid groups were introduced to milled softwood (SW) bleached kraft fibers by oxidation and sulfonation with sodium periodate followed by sodium bisulfite under relatively mild conditions. The effect of variable amount of sulfonated groups on nanofibrillation of sulfonated cellulose samples was investigated. The cellulose samples, with contents of sulfonated groups of 371-501 MUmol/g, were readily nanofibrillated by homogenization at relatively low pressure. These samples converted to viscous and transparent gels without clogging the homogenizer. By passing through the homogenizer one to four times, the transmittances of homogenized suspensions were up to 98%. SEM characterization of the homogenized and lyophilized fibril suspension indicates that the nanofibrillated fibrils are a network structure with lateral sizes of ~ 15-45 nm and lengths ? 1 MUm. The consecutive periodate oxidation and sulfonation with bisulfite was shown to be an effective pretreatment method to facilitate the nanofibrillation of softwood pulp cellulose and can be expectedly used with other cellulosic resources. PMID- 25037381 TI - Reinforcement of bacterial cellulose aerogels with biocompatible polymers. AB - Bacterial cellulose (BC) aerogels, which are fragile, ultra-lightweight, open porous and transversally isotropic materials, have been reinforced with the biocompatible polymers polylactic acid (PLA), polycaprolactone (PCL), cellulose acetate (CA), and poly(methyl methacrylate) (PMMA), respectively, at varying BC/polymer ratios. Supercritical carbon dioxide anti-solvent precipitation and simultaneous extraction of the anti-solvent using scCO2 have been used as core techniques for incorporating the secondary polymer into the BC matrix and to convert the formed composite organogels into aerogels. Uniaxial compression tests revealed a considerable enhancement of the mechanical properties as compared to BC aerogels. Nitrogen sorption experiments at 77K and scanning electron micrographs confirmed the preservation (or even enhancement) of the surface-area to-volume ratio for most of the samples. The formation of an open-porous, interpenetrating network of the second polymer has been demonstrated by treatment of BC/PMMA hybrid aerogels with EMIM acetate, which exclusively extracted cellulose, leaving behind self-supporting organogels. PMID- 25037383 TI - Reactive coating of soybean oil-based polymer on nanofibrillated cellulose film for water vapor barrier packaging. AB - Nanofibrillated cellulose (NFC) easily forms a high strength film but is unable to withstand the influence of water vapor when used in high moisture situations. The water vapor transmission rate (WVTR) of a NFC film was as high as 5088 g/m(2)24h (38 degrees C, 90% RH). The addition of beeswax latex in a NFC casting film (NFX) lowered the WVTR to 3918 g/m(2)24h. To further reduce the WVTR, a coating agent comprised of acrylated epoxidized soybean oil (AESO) and 3 aminopropyltriethoxysilane (APTS) was applied onto the NFX film using a rod coater. A combination of the suitable AESO/APTS ratio, initiator dosing, curing time and temperature could reduce the WVTR to 188 g/m(2) 24h when the coat weight was 5 g/m(2). Moreover, the coated NFX film was highly hydrophobic along with the improved transparency and thermal stability. This biodegradable polymer-coated NFC film can be used as potential packaging barrier in certain areas. PMID- 25037384 TI - Electrospun chitosan nanofibers with controlled levels of silver nanoparticles. Preparation, characterization and antibacterial activity. AB - The ideal wound dressing would have properties that allow for absorption of exudates, and inhibition of microorganism for wound protection. In this study, we utilized an electrospinning (ELSP) technique to design a novel wound dressing. Chitosan (CTS) nanofibers containing various ratios of silver nanoparticles (AgNPs) were obtained. AgNPs were generated directly in the CTS solution by using a chemical reduction method. The formation and presence of AgNPs in the CTS/AgNPs composite was confirmed by x-ray diffraction (XRD), ultraviolet-visible spectroscopy (UV) and thermogravimetric analysis (TGA). The electrospun CTS/AgNPs nanofibers were characterized morphologically by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These nanofibers were subsequently tested to evaluate their antibacterial activity against gram negative Pseudomonas aeruginosa (P. aeruginosa) and gram-positive Methicillin resistant Staphylococcus aureus (MRSA). Results of this antibacterial testing suggest that CTS/AgNPs nanofibers may be effective in topical antibacterial treatment in wound care. PMID- 25037385 TI - Selective isolation of beta-glucan from corn pericarp hemicelluloses by affinity chromatography on cellulose column. AB - A combination of anion-exchange chromatography and affinity chromatography on a cellulose column was found to be effective for the isolation of beta-(1,3;1,4) glucan (BG) from corn pericarp hemicelluloses (CPHs). CPHs containing 6.6% BG were extracted from corn pericarp with 6M urea-2 wt% NaOH solution and initially fractionated into neutral and acidic parts by anion exchange chromatography to remove acidic arabinoxylan consisting of arabinose (35.6%) and xylose (50.9%). The neutral fraction (yield; 10.1% on the basis of CPHs) consisting of 1.0% arabinose, 10.1% xylose and 80.3% glucose containing 28.4% BG was then applied to a cellulose column of Whatman CF-11. BG could be recovered from the adsorbed fraction on the cellulose column by elution with 2% NaOH in a yield of 2.6% on the basis of CPHs with a purity of 84.7%. The chemical structure of the isolated corn pericarp BG was confirmed by (13)C NMR spectroscopic, methylation and lichenase treatment analyses. The results indicate that the ratios of (1,4)/(1,3) linkage and cellotriosyl/cellotetraosyl segments of the BG were 2.60 and 2.5, respectively. PMID- 25037386 TI - Effect of amylose:amylopectin ratio and rice bran addition on starch films properties. AB - The influence of the amylose:amylopectin ratio on the properties of pea, potato and cassava starch films and the effect of the incorporation of rice bran of two different particle sizes were studied. The structural, mechanical, optical and barrier properties of the films were analyzed after 1 and 5 weeks. The high content of amylose gave rise to stiffer, more resistant to fracture, but less stretchable films, with lower oxygen permeability and greater water binding capacity. Although no changes in the water vapour permeability values of the films were observed during storage, their oxygen permeability decreased. Throughout storage, films became stiffer, more resistant to break, but less stretchable. Rice bran with the smallest particles improved the elastic modulus of the films, especially in high amylose content films, but reduced the film stretchability and its barrier properties, due to the enhancement of the water binding capacity and the introduction of discontinuities. PMID- 25037387 TI - Amputation of congo red dye from waste water using microwave induced grafted Luffa cylindrica cellulosic fiber. AB - The present study deals with the surface modification of Luffa cylindrica fiber through graft copolymerization of methyl acrylate/acrylamide (MA/AAm) via microwave radiation without the use of initiator. Various reaction parameters effecting grafting yield were optimized and physico-chemical properties were evaluated. The grafted Luffa cylindrica fiber showed morphological transformations, thermal stability and chemical resistance. The adsorption potential of modified fiber was investigated using adsorption isotherms for hazardous congo red dye removal from aqueous system. The maximum adsorption capacity of dye onto grafted Luffa cylindrica fiber was found to be 17.39 mg/g with best fit for Langmuir adsorption isotherm. The values of thermodynamic parameters such as enthalpy change, DeltaH(0) (21.27 kJ/mol), entropy change, DeltaS(0) (64.71 J/mol K) and free energy change, DeltaG(0) (-139.52 kJ/mol) were also calculated. Adsorption process was found spontaneous and endothermic in nature. PMID- 25037388 TI - Optimization of enzyme assisted extraction of polysaccharides from Astragalus membranaceus. AB - Astragalus polysaccharide (APS) is known to have a variety of pharmacological activities. In the present study, enzyme assisted extraction of APS from Astragalus mongholicus using various enzymes were examined. Research found that glucose oxidase offered a better performance in enhancement of extraction yields of APS than other ones. Glucose oxidase assisted extraction process was further optimized by using response surface method (RSM) to obtain maximum yield of crude APS. The optimized extraction conditions were as follows: enzyme amount of 3.0%, enzyme treated time of 3.44 d, enzyme treated temperature of 56.9 degrees C and extraction solvent pH of 7.8. Under these conditions, the experimental yield was 29.96 +/- 0.14%, which was well in close agreement with the value (30.19%) predicted by RSM model and increased more than 250% compared with none enzyme treated ones. Pharmacological test showed that enzyme assisted APS had a better antioxidant activity (about 2 times higher) than none enzyme treated ones. PMID- 25037389 TI - Extraction, preliminary characterization and immunostimulatory activity in vitro of a polysaccharide isolated from Strongylocentrotus nudus eggs. AB - A new water-soluble polysaccharide (SEP-2), with a molecular weight of 6.78 * 10(5)Da, was isolated from Strongylocentrotus nudus eggs under the extraction conditions optimized by response surface methodology (RSM). Preliminary characterization of SEP-2 was performed by HPSEC and GC-MS, indicating that SEP-2 could be a D-glucan containing a (1 -> 4)-linked D-Glcp backbone with (1 -> 3) linked D-Glcp side chains. In subsequent immunostimulatory studies, significantly enhanced ROS level, NO production and inflammatory cytokines secretion (IL-1beta, IL-6, and TNF-alpha) were observed in SEP-2 treated murine macrophage cell line RAW264.7. These results suggest that SEP-2 might have the capability to enhance the microbicidal activity and killing function of macrophages through the polarization toward the pro-inflammatory M1 state. PMID- 25037390 TI - Extraction, purification and antioxidant activities of the polysaccharides from maca (Lepidium meyenii). AB - Water-soluble polysaccharides were separated from maca (Lepidium meyenii) aqueous extract (MAE). The crude polysaccharides were deproteinized by Sevag method. During the preparation process of maca polysaccharides, amylase and glucoamylase effectively removed starch in maca polysaccharides. Four Lepidium meyenii polysaccharides (LMPs) were obtained by changing the concentration of ethanol in the process of polysaccharide precipitation. All of the LMPs were composed of rhamnose, arabinose, glucose and galactose. Antioxidant activity tests revealed that LMP-60 showed good capability of scavenging hydroxyl free radical and superoxide radical at 2.0mg/mL, the scavenging rate was 52.9% and 85.8%, respectively. Therefore, the results showed that maca polysaccharides had a high antioxidant activity and could be explored as the source of bioactive compounds. PMID- 25037391 TI - Enhanced electrochemical properties of LiFePO4 (LFP) cathode using the carboxymethyl cellulose lithium (CMC-Li) as novel binder in lithium-ion battery. AB - Novel water-based binder CMC-Li is synthesized using cotton as raw material. The mechanism of the CMC-Li as a binder is reported. Electrochemical properties of batteries cathodes based on commercially available lithium iron phosphate (LiFePO4, LFP) and CMC-Li as a water-soluble binder are investigated. CMC-Li is a novel lithium-ion binder. Compare with conventional poly(vinylidene fluoride) (PVDF) binder, and the battery with CMC-Li as the binder retained 97.8% of initial reversible capacity after 200 cycles at 176 mAh g(-1), which is beyond the theoretical specific capacity of LFP. Constant current charge-discharge test results demonstrate that the LFP electrode using CMC-Li as the binder has the highest rate capability, follow closely by that using PVDF binder. The batteries have good electrochemical property, outstanding pollution-free and excellent stability. PMID- 25037392 TI - Structural and physicochemical characteristics of starch from sugar cane and sweet sorghum stalks. AB - The starch present in sugar cane and sorghum juice has been considered a problem to the sugar industry. The objective of this work was to study the structural and physicochemical characteristics of the starch present in sugar cane and sweet sorghum. Sugar cane and sweet sorghum starches presented small granules (maximum 5.9 and 7.9 MUm), A-type diffraction pattern, high degree of relative crystallinity (44.4 and 42.0%), and low amylose content (17.5 and 16.4%), respectively. Sugar cane starch presented more uniformity in granule shape and size, more homogeneity in amylose chain length, higher number of long lateral chains of amylopectin, and higher susceptibility to enzymatic digestion. Besides being in higher amount in the juice, sweet sorghum starch presented lower values for thermal properties of gelatinization, as well as higher swelling factor, which can cause more problems during processing. Additional studies are needed to evaluate the variety and maturity influence on these properties. PMID- 25037393 TI - FTIR characterization of protein-polysaccharide interactions in extruded blends. AB - Soy protein-based blends were processed by double screw extrusion and the effects of different types and contents of polysaccharides were analyzed. Although extrusion has not been widely used for this type of blends, in this study it was observed that the increase in polysaccharide content in blends caused a decrease in specific mechanical energy (SME), facilitating extrusion process and showing the potential of this process, which is more cost effective at industrial scale. In order to explain this behavior, infrared spectroscopy analysis was carried out, mainly in the amide I and II regions. Moreover, curve fitting analysis showed the conformational changes produced in the blends due to the addition of polysaccharides, which affected protein denaturation. These changes also affected properties such as moisture content (MC) and total solubility matter (TSM). However, conformational changes did not show significant effects with respect to piece density (PD) or in the expansion ratio (ER) of the pellets. The quantitative analysis of the changes in the amide I and II regions provided novel information about the modifications produced in protein-based blends modified with polysaccharides. In this context, infrared spectroscopy provided a convenient and powerful means to monitor interactions between all ingredients used in the blend formulation, which is of great importance in order to explain changes in the functional properties of biodegradable materials used for industrial applications in food and pharmaceutical industries. PMID- 25037394 TI - Cellulase-assisted extraction and antioxidant activity of the polysaccharides from garlic. AB - In the present study, the polysaccharides were prepared from garlic by using a cellulase-assisted extraction method and the antioxidant activity of garlic polysaccharides (GPs) was evaluated. To improve the yield of GPs, the influences of the several factors such as extraction time, temperature, pH, and cellulase amount on the extraction efficiency were studied. The optimal conditions for extraction of GPs were determined as follows: time, 80 min; temperature, 45 degrees C; pH, 5; cellulase amount, 8000 U/g. Under the optimised extraction conditions, the yield of GPS reached up to 35.34%. The GPs product exhibited strong antioxidant activity including hydroxyl radical scavenging activity, 2,2 diphenyl-beta-picrylhydrazyl radical scavenging activity, and reducing power. The results suggest that the GPs could be used as potential antioxidants. PMID- 25037395 TI - Monoacryloyl esters of carbohydrates: synthesis, polymerization and application in ceramic technology. AB - The article presents the interdisciplinary research among organic synthesis, chemistry of polymers and ceramic technology. It presents the synthesis of monoacryloyl esters of fructose and glucose that is 1-O-acryloyl-D-fructose and 3 O-acryloyl-D-glucose, conditions of their polymerization and application in shaping of advanced ceramic powders by the so called gelcasting method. The paper presents the influence of carbohydrate esters on the viscosity of Al2O3 suspensions and microstructure of final ceramic samples. The results showed that synthesized esters of saccharides can play the role of organic monomers able to polymerize in situ and self-cross-linking compounds in gelcasting. The paper presents the proposed structure of polymeric network which is formed from acryloyl ester of glucose during gelcasting process. The paper describes rheological behaviour of slurries composed of synthesized substances and A2O3 powders, wetting angles of alumina substrate by synthesized compounds, differences in glass transition temperatures of polymers and the microstructure of obtained final ceramic samples. PMID- 25037396 TI - Sargassum filipendula alginate from Brazil: seasonal influence and characteristics. AB - The aim of this work is focused on the extraction and characterization of the Brazilian seaweed Sargassum filipendula alginate. Alginates obtained at different seasons were characterized by liquid state nuclear magnetic resonance spectroscopy and scanning electron microscopy. The alginate extraction efficiency was about 20%. Different seasons of the year and different stages in the life cycle of Sargassum sp. in southeastern Brazil influenced the M/G and, consequently, the technological properties of extracted alginates. PMID- 25037397 TI - Stability and physicochemical properties of model salad dressings prepared with pregelatinized potato starch. AB - The effects of pregelatinized potato starch concentration (PSC) ranged from 0 to 5 wt% on the physical stability, color, rheological, textural, and sensory properties of model salad dressings prepared with 2 wt% dried egg yolk (DEY) or sodium caseinate (SC) were explored. All dressings showed shear-thinning behavior with yield stress. Raising PSC increased storage (G') and loss (G") moduli decreasing loss tangent (tandelta) and samples containing >= 3 wt% starch showed a weak gel-like (tandelta<1) response. A generalized Cox-Merz rule was applicable to indicate shear/strain sensitivity of the dressings structures. Rheological characterization based on Bohlin's parameters (A, z) was useful for distinguishing physical stability of dressings made with different formulations. Changes in color were generally very small and mainly PSC-dependent. Correlation analyses revealed that sensory descriptors could be satisfactory modeled with the appropriate instrumental data. Overall, the results proved that pregelatinized potato starch may be suitable ingredient in low-fat dressings applications. PMID- 25037398 TI - Mekabu fucoidan: structural complexity and defensive effects against avian influenza A viruses. AB - Fucoidan from the sporophyll (Mekabu) of brown seaweed Undaria pinnatifida (wakame) is interesting due to its various biological activities. Mekabu fucoidan (Mw ~ 9 kDa) of this study (MF) was previously isolated and characterized by chemical and separation methods including GPC and methylation analysis (Lee, Hayashi, Hashimoto, Nakano, & Hayashi, 2004). It was found that this fucoidan composed of partially sulphated (DS ~ 0.72) fucose and galactose at approximately equal amounts. Methylation analyses revealed complex structure of MF. However, it has been still unclear about the linkages between units and substitution patterns. To solve these structural tasks, spectroscopic methods (FTIR, FT Raman and NMR) were used in the analysis of native MF and its deesterified derivatives. According to obtained results, this polysaccharide was defined as O-acetylated sulphated fucogalactan. The defensive effects of MF were evaluated on mice infected with avian influenza A viruses (H5N3 and H7N2 subtypes); its efficacy was determined in reducing viral replication and increasing antibody production. Oral administration of MF resulted in suppressing virus yields. In addition, the production of neutralizing antibodies and mucosal IgA in the animals inoculated with the avian influenza A viruses was significantly increased. These results suggested that MF could be used for the prevention of viral infection. PMID- 25037399 TI - Bamboo: a new source of carbohydrate for biorefinery. AB - Bamboo is perennial woody grass, which distributed widely in the world and belonged to the Gramineae family and Bambuseae subfamily. It may be consider as a candidate lignocellulosic substrate for bio-ethanol production for its environmental benefits and higher annual biomass yield. The conversion of bamboo into bio-ethanol, bio-methane, natural food, flavonoids, and functional xylo oligosaccharides production were reviewed in this paper. Future prospects for research include pretreatment, enzymatic hydrolysis and fermentation will also be performed to improve the whole process of ethanol production more economical. And revealing the molecular regulation mechanism of the fast growth of bamboo will provide chance for improving bamboo or other energy plants biomass yield through genetic engineering. PMID- 25037400 TI - Inclusion complex of GA-13316 with beta-cyclodextrin: preparation, characterization, molecular modeling, and in vitro evaluation. AB - The inclusion complex of GA-13316 with beta-cyclodextrin (beta-CD) is one of a unique series of gibberellin derivatives possessed of potential anticancer activities. The complex with beta-CD was characterized by means of UV, XRD, DSC, TG, (1)H, and 2D NMR spectroscopy. In addition, we investigated the main aspects of the interaction between GA-13316 and beta-CD using both experimental and molecular modeling approaches. The complex still maintained its anticancer activity, as shown by in vitro cell survival assay on the human colon carcinoma cell line (HCT116) and the human lung cancer cell line (H460). The results showed that the use of beta-CD could be obviously improved the water solubility and stability of GA-13316, implying that the inclusion complex could be a promising future therapeutic agent. PMID- 25037401 TI - Integrated biorefinery based on hydrothermal and alkaline treatments: investigation of sorghum hemicelluloses. AB - An integrated process based on hydrothermal pretreatment (HTP) and alkaline post treatment was proposed to treat sweet sorghum stem. The structural features of the alkali-soluble hemicelluloses (ASHs) obtained from the un-pretreated and hydrothermally pretreated materials were comprehensively investigated by HPAEC, GPC, NMR, FT-IR, and TGA techniques. The ASH with the highest yield (60.6%) was obtained from the HTP residue performed at 130 degrees C for 1.0 h. All the results indicated that the ASHs had a more linear structure with increasing the pretreatment temperature (110-170 degrees C). The molecular weights of the ASHs were decreased with increasing the pretreatment temperature, suggesting that C-O bonds in the ASHs were gradually cleaved, especially at the higher temperatures (>= 170 degrees C). Interestingly, the integrated process yielded more homogeneous ASHs than hemicelluloses obtained from the un-pretreated material. Based on the spectral analyses, the structure of the ASHs was assumed to be L arabino-4-O-methyl-D-glucurono-D-xylan. PMID- 25037402 TI - Antimicrobial and inhibitory enzyme activity of N-(benzyl) and quaternary N (benzyl) chitosan derivatives on plant pathogens. AB - Chemical modification of a biopolymer chitosan by introducing quaternary ammonium moieties into the polymer backbone enhances its antimicrobial activity. In the present study, a series of quaternary N-(benzyl) chitosan derivatives were synthesized and characterized by (1)H-NMR, FT-IR and UV spectroscopic techniques. The antimicrobial activity against crop-threatening bacteria Agrobacterium tumefaciens and Erwinia carotovora and fungi Botrytis cinerea, Botryodiplodia theobromae, Fusarium oxysporum and Phytophthora infestans were evaluated. The results proved that the grafting of benzyl moiety or quaternization of the derivatives onto chitosan molecule was successful in inhibiting the microbial growth. Moreover, increase water-solubility of the compounds by quaternization significantly increased the activity against bacteria and fungi. Exocellular enzymes including polygalacturonase (PGase), pectin-lyase (PLase), polyphenol oxidase (PPOase) and cellulase were also affected at 1000 mg/L. These compounds especially quaternary-based chitosan derivatives that have good inhibitory effect should be potentially used as antimicrobial agents in crop protection. PMID- 25037403 TI - Aerogels from quaternary ammonium-functionalized cellulose nanofibers for rapid removal of Cr(VI) from water. AB - An efficient heavy metal adsorbent from quaternary ammonium-functionalized cellulose nanofiber aerogels was successfully developed. The highly porous aerogel could well retain its large specific surface area, which allowed rapid and effective removal of Cr(VI) from contaminated water. The aerogel adsorbent became mechanically robust after chemical crosslinking. It could be easily separated from water after adsorption without complicated centrifugation or filtration process. With only 1g of aerogel, more than 99% of Cr(VI) in 1L of 1mg/L solution could be removed in 50 min. Besides, the aerogel also exhibited excellent reusability. PMID- 25037404 TI - Effects of tribochemical treatments on the integrity of cellulose. AB - The effects of tribochemical impacts--sonochemical treatments and milling variants--on cellulose were studied, employing multi-detector size exclusion chromatography with group-selective fluorescence labelling ("CCOA method") and diagnostic beta-elimination as the analytical tools. Milling at different temperatures was compared to sonochemical degradation of cellulose by a 24 kHz ultrasound probe system in homogeneous solution. Chain cleavage was generally accompanied by random oxidation of cellulose. The degree of oxidation increased with increasing temperature; at 77K oxidation occurs only to a minor extent. Degradation proceeded towards a final value, the limiting molecular weight (Mw(lim)), beneath which no further decrease of the chain length occurred even at prolonged treatment times. Regardless of the lignin or hemicellulose content of the pulps, the Mw(lim) reached in a specific milling process was largely constant and showed little dependence on the substrate used. The formation of radicals during tribochemical treatments under different conditions and with different substrates was discussed based on theoretical considerations and EPR data. The overall radical content increased with increasing time of milling until a plateau is reached. Here, the mechano-radical content largely depends on the lignin content in the pulp as anticipated. The formation of different radical species and their precursor structures were discussed. PMID- 25037405 TI - Effect of alginate and chitosan on viability and release behavior of Bifidobacterium pseudocatenulatum G4 in simulated gastrointestinal fluid. AB - The main aim of this study was to investigate the effect of different coating materials (i.e. Na-alginate and chitosan) on the viability and release behavior of Bifidobacterium pseudocatenulatum G4 in the simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). This study reports the viability of encapsulated B. pseudocatenulatum G4 coated using different alginate (2-4 g/100mL) and chitosan (0.2-0.8 g/100mL) concentrations. The results indicated that the highest concentration of alginate (4.4142 g/100mL) along with 0.5578 g/100mL chitosan resulted in the highest viability of B. pseudocatenulatum G4. The release behavior of the encapsulated probiotics in SGF (pH 1.5) in 2h followed by 4h in SIF (pH 7.4) was also assessed. The resistance rate of alginate chitosan capsule in SGF was higher than SIF. The alginate-chitosan encapsulated cells had also more resistance than alginate capsules. The current study revealed that alginate encapsulated B. Pseudocatenulatum G4 exhibited longer survival than its free cells (control). PMID- 25037406 TI - Dextranase immobilization on epoxy CIM((r)) disk for the production of isomaltooligosaccharides from dextran. AB - Endodextranase D8144 from Penicillium sp. (EC 3.2.1.2.) was immobilized on an epoxy-activated monolithic Convective Interaction Media (CIM((r))) disk in order to produce isomaltooligosaccharides (IMOS) from Dextran T40 in a continuous IMmobilized Enzymes Reactor (IMER). Enzymatic parameters and structure of IMOS were studied for free and immobilized enzymes. The immobilization efficiency of endodextranase D8144 was about 15.9% (w/w) and the real specific activity was close to 6.5 U mg enz(-1). The Km values (4.8 +/- 0.2 g L(-1)) for free and immobilized enzymes were the same, showing the absence of diffusional limitation. Moreover, specific patterns of DPs (Degrees of Polymerization) distributions were observed during the enzymatic hydrolysis by HPAEC-PAD (High Pressure Anion Exchange Chromatography-Pulsed Amperometric Detection). Thus, sought-after sizes of IMOS (DPs 8-10) were generated all over the hydrolysis. Finally, the results showed the high stability of this IMER since a relative enzymatic activity about 78% was measured after 5400 volumes column. PMID- 25037407 TI - Structural characterization and stimulating effect on osteoblast differentiation of a purified heteropolysaccharide isolated from Hedysarum polybotrys. AB - Radix Hedysari polysaccharides (HPS) is the principal active fraction of Radix Hedysari (RH). The information about HPS3d, the main fraction of HPS3, and its effect on bone is still unknown. In the present study, the purified HPS3d was obtained by anion-exchange column. It consisted of 94.38% polysaccharide, 3.40% protein and 13.30% uronic acid. The molecular weight was measured to be 84.6kDa. The backbone consisted of galactopyranose and galacturonopyranose, and the side chains were composed of glucopyranose, rhamnopyranose and arabinofuranose. The FT IR and elemental analysis showed that HPS3d was the sulfated polysaccharide. HPS3d upregulated alkaline phosphatase (ALP) activity and the expression of other osteogenic marker genes in osteoblast. In addition, HPS3d increased the expression and transcriptional activity of Runt-related transcription factor 2 (Runx-2) and Osterix, the two master genes of osteoblast differentiation. These findings suggest that HPS3d stimulates osteoblast differentiation by activation of Runx-2 and Osterix. PMID- 25037408 TI - Evolution of morphology of bacterial cellulose scaffolds during early culture. AB - Morphological characteristics of a fibrous tissue engineering (TE) scaffold are key parameters affecting cell behavior. However, no study regarding the evolution of morphology of bacterial cellulose (BC) scaffolds during the culture process has been reported to date. In this work, BC scaffolds cultured for different times starting from 0.5h were characterized. The results demonstrated that the formation of an integrated scaffold and its 3D network structure, porosity, fiber diameter, light transmittance, and the morphology of hydroxyapatite (HAp) deposited BC scaffolds changed with culture time. However, the surface and crystal structure of BC fibers did not change with culture time and no difference was found in the crystal structure of HAp deposited on BC templates regardless of BC culture time. The findings presented herein suggest that proper selection of culture time can potentially enhance the biological function of BC TE scaffold by optimizing its morphological characteristics. PMID- 25037409 TI - Effect of phthaloylation on radical-scavenging and moisture-preserving activities of polysaccharide from Enteromorpha linza. AB - In this study, phthaloyl polysaccharide from Enteromorpha linza (PHEP) has been prepared in a homogeneous process by using 1,2-benzenedicarboxylic anhydride and 4-Dimethylaminopyridine as phthaloyl agent and catalyst, respectively. And then the radical-scavenging and moisture-preserving activities of the samples were investigated. The results of chemical composition and FT-IR analysis showed the phthaloyl modifications of polysaccharide were successful. And moreover, the derivative PHEP showed excellent radical-scavenging and moisture-preserving activities, so this derivative needs to be attention and studied in further. PMID- 25037410 TI - One pot green synthesis of Ag, Au and Au-Ag alloy nanoparticles using isonicotinic acid hydrazide and starch. AB - Gold-silver alloy nanoparticles were synthesized via chemical reduction of varying mole fractions of chloroauric acid (HAuCl4) and silver nitrate (AgNO3) by environmentally benign isonicotinic acid hydrazide (INH) in the presence of starch as a capping agent in aqueous medium. The absorption spectra of Au-Ag nanoparticles show blue shift with increasing silver content indicating the formation of alloy nanoparticles. When the Ag content in the alloy decreases the size of the nanoparticles increases and as a result of which the oxidation potential also increases. The emission maximum undergoes a red shift from 443 to 614 nm. The nanoparticles are monodisperse and spherical with an average particle size of 3-18 nm. The catalytic behavior of alloy nanoparticles indicate that the rate constant for the reduction of 4-nitro phenol to 4-amino phenol increases exponentially from metallic Ag to metallic Au as Au content increases in the Au Ag alloy nanoparticles. PMID- 25037411 TI - Preparation and immunomodulating activities of a library of low-molecular-weight alpha-glucans. AB - YCP, an alpha-D-glucan with molecular weight of 2.4 * 10(3)kDa, was isolated from the mycelium of marine fungus Phoma herbarum YS4108. It interacted with TLR2 and TLR4 to induce B cells proliferation and activation. Here, a series of homogenous LMWYCPs (namely LMWYCP-1 to LMWYCP-6) were obtained by acid degradation. LMWYCP-3 and LMWYCP-4 were capable of inducing the proliferation of B cells dramatically. Further research involved TLR defunctionalization and competitive binding assay demonstrated that the immunomodulating activities of LMWYCP-4 was TLR4-dependent but TLR2-independent, while that mediated by LMWYCP-3 was neither TLR2- nor TLR4 dependent. Together with the structural information that LMWYCPs shared the similar structure features with YCP, we deduced that LMWYCP-4 may be the functional unit of YCP responsible for YCP/TLR4 interaction. This is the first time that the probable functional unit of glucan with the structure of alpha-D-(1 4)-linked residues in main chain and alpha-D-(1-6)-linked residues in branches is reported. PMID- 25037412 TI - The synthesis, self-assembling, and biocompatibility of a novel O-carboxymethyl chitosan cholate decorated with glycyrrhetinic acid. AB - O-carboxymethyl chitosan (OCMC) was firstly decorated with cholic acid (CA) to acquire an amphiphilic polymer under alkaline condition. Then glycyrrhetinic acid (GA) was conjugated to the polymer via a succinate linker and finally treated with NaCO3 solution to obtain new conjugates for potential liver targeted delivery. These conjugates formed uniform aggregates with low critical aggregation concentrations (0.028-0.079 mg/mL) in PBS. The average diameter of cholic acid modified carboxymethyl chitosan (CMCA) aggregates (110-257 nm) decreased with the increase of CA substitution degree and became slightly larger after GA modification. Negative zeta potential (-15 mV) of GA decorated CMCA (GA CMCA) revealed that the formation of negatively charged shells and spherical morphology was observed under transmission electron microscopy. Furthermore, hemolysis test, in vitro cytotoxicity assay and cellular uptake study all demonstrated the safety and feasibility of these conjugates as a promising carrier for liver targeted drug delivery. PMID- 25037413 TI - Optimization of polysaccharides extraction from Clematis huchouensis Tamura and its antioxidant activity. AB - In this study, response surface methodology (RSM), based on Box-Behnken design, was employed to optimize the extraction conditions of polysaccharide from Clematis huchouensis Tamura (CP). And then the antioxidant activities of the samples were investigated including scavenging effects of superoxide and hydroxyl radicals and their reducing power. The results of chemical composition and FT-IR spectrum analysis showed the polysaccharide was acidic proteoglycan. And moreover, CP showed excellent antioxidant activity in these three assays. The purification and structure of CP need to be further studied. PMID- 25037414 TI - Application of cellulose acetate to the selective adsorption and recovery of Au(III). AB - Cellulose acetyl derivatives were examined for the selective recovery of Au(III) from acidic chloride solutions as an adsorbent, and cellulose acetate fibers (CAF) were found to be effective for the separation of Au(III) from other metal ions, including the precious metal ions Pt(IV) and Pd(II). The amount of Au(III) adsorbed by the fibers increased with an increase in the hydrochloric acid concentration, but decreased with an increase in the ionic strength of the solution. The adsorption of Au(III) onto CAF took place quickly and an adsorption equilibrium was reached within 1h. The maximum adsorption capacity of Au(III) was determined to be 110 mg/g at 2M hydrochloric acid. The loaded Au(III) was readily recovered by incineration. PMID- 25037415 TI - Optimization of enzyme assisted extraction of Fructus Mori polysaccharides and its activities on antioxidant and alcohol dehydrogenase. AB - In the present study, enzyme assisted extraction of Fructus Mori polysaccharides (FMPS) from F. mori using four kinds of enzymes and three compound enzymes were examined. Research found that glucose oxidase offered a better performance in enhancement of the extraction yields of FMPS, antioxidant and activate alcohol dehydrogenase activities. The glucose oxidase assisted extraction process was further optimized by using response surface method (RSM) to obtain maximum yield of crude FMPS. The results showed that optimized extraction conditions were ratio of enzyme amount 0.40%, enzyme treated time 38 min, treated temperature 58 degrees C and liquid-solid radio 11.0. Under these conditions, the mean experimental value of extraction yield (16.16 +/- 0.14%) corresponded well with the predicted values and increased 160% than none enzyme treated ones. Pharmacological verification tests showed that F. mori crude polysaccharides had good antioxidant and activate alcohol dehydrogenase activities in vitro. PMID- 25037416 TI - Anti-tumor properties of orally administered glucosamine and N-acetyl-D glucosamine oligomers in a mouse model. AB - The current study evaluated the anti-tumor activities of N-acetyl-d-glucosamine oligomer (NACOS) and glucosamine oligomer (COS) after their oral administration in a tumor (colon 26)-bearing mouse model. Compared to the control group, NACOS and COS groups showed significantly suppressed tumor growth, and apparent, marked apoptosis in tumor tissues. Furthermore, serum interleukin-12p70 and interferon gamma levels significantly increased in the NACOS and COS groups compared to the corresponding levels in the control group. Collectively, the results indicate the oral administration of NACOS and COS could enhance innate immunity. Results of experiments in Myd-88 knockout mice revealed that the apparent effects were related to both Myd-88-dependent and Myd-88-independent pathways. The data indicated that oral administration of NACOS and COS produced anti-tumor effects through the induction of apoptosis and stimulation of the immune system, which suggests that NACOS and COS are candidate anti-tumor functional foods. PMID- 25037417 TI - Removal of Cu(II) and Cr(VI) from wastewater by an amphoteric sorbent based on cellulose-rich biomass. AB - A cellulose-rich biomass was modified as a new amphoteric sorbent to eliminate toxic Cu(II) and Cr(VI) from wastewater. The product (WSCA, which stands for modified wheat straw containing both cationic and anionic characters) presents high sorption capacities for the two ions which was evidenced by the comparison with unmodified wheat and other similar samples. Kinetic data and sorption equilibrium isotherms were conducted in batch process. The sorption kinetic analysis revealed that sorption of Cu(II) and Cr(VI) followed the pseudo second order model well during the whole sorption process. The linear Langmuir isotherm model could perfectly describe the equilibrium data for Cu(II), while the sorption data of Cr(VI) were well fitted by the Freundlich. Results of the static test illustrated the complicated interactions between Cr(VI)/Cu(II) and WSCA including complexation and/or electrostatic attraction mechanisms. PMID- 25037418 TI - Cationic hemicellulose-based hydrogels for arsenic and chromium removal from aqueous solutions. AB - In this work the synthesis of hemicellulose-based hydrogels and their application for the removal of arsenic and chromium ions is described. In a first step O acetyl galactoglucomannan (GGM) was subjected to a transesterification applying glycidyl methacrylate (GMA) for the synthesis of novel GGM macromonomers. Two distinguished and purified GGM fractions with molar mass of 7.1 and 28 kDa were used as starting materials. The resulting GGM macromonomers (GGM-MA) contained well-defined amounts of methacrylate groups as determined by (1)H NMR spectroscopy. Selected GGM-MA derivatives were consecutively applied as a crosslinker in the synthesis of tailored hydrogels using [2 (methacryloyloxy)ethyl]trimethylammonium chloride (MeDMA) as monomer. The swelling rate of the hydrogels was determined and the coherence between the swelling rate and the hydrogel composition was examined. The morphology of the GGM-based hydrogels was analysed by SEM and the hydrogels revealed a high surface area and were assessed in respect to their ability to remove arsenate and chromate ions from aqueous solutions. The presented bio-based hydrogels are of high interest especially for the mining industries as a sustainable material for the treatment of their highly contaminated wastewaters. PMID- 25037419 TI - beta-CD assisted dissolution of quaternary ammonium permanganates in aqueous medium. AB - The non-polar internal cavity of beta-cyclodextrin (beta-CD) has been exploited for the entrapment of the hydrophobic tails of two water insoluble quaternary ammonium permanganates (QAPs): cetyltrimethylammonium permanganate (CTAP) and tetrabutylammonium permanganate (TBAP), for solubilization in aqueous medium. The solubilization and organizational behavior of the QAPs in aqueous beta-CD solution have been determined from the comparison of their rates of self oxidation in presence and in absence of beta-CD. Effect of QAP concentration on their observed rate constants (k(obs)) at a fixed beta-CD concentration, phase solubility analysis in varying beta-CD concentration, impact of quaternary ammonium bromides (QABs) on the kobs values of CTAP and TBAP at fixed QAP and beta-CD concentrations, and the temperature effect have been reported. A scheme to explain the solvation of QAPs in aqueous beta-CD has been proposed based on dynamic light scattering (DLS) analysis of the samples. PMID- 25037420 TI - Taguchi design and equilibrium modeling for fluoride adsorption on cerium loaded cellulose nanocomposite bead. AB - The cooperative influence of operational variables for fluoride adsorption on cerium loaded cellulose nanocomposite bead (CCNB) was assessed using Taguchi design tool. The percentage contribution of each operational variable was determined. The solution pH, with a maximum contribution of 80.78%, indicates its highest influence on the response, the adsorption percent of fluoride. The quality and validity of the experimental design were assessed from ANOVA and subsequently by the confirmation experiment. The equilibrium adsorption data showed that the Temkin isotherm is the most suited one compared to the Langmuir and Freundlich model. It is found that almost 90% adsorbed fluoride can be eluted with 0.01 (N) NaOH and the regenerated bead can successively be reused for at least three times. PMID- 25037421 TI - Degradation of fucoidans from Sargassum fulvellum and their biological activities. AB - A fucoidan extracted from Sargassum fulvellum, was degraded by ultrasound (US) or electron beam (EB) irradiation in the presence of hydrogen peroxide aqueous solution. From the energetic point of view, the most effective method for the fucoidan degradation was found to be EB radiation method in H2O2 with a yield of scission Gs 3.310 * 10(-8)mol/J at the reaction condition of 1.5% hydrogen peroxide and irradiation 2.5 kGy. The degradation took place by the formation of a reactive hydroxyl radical due to the dissociation of H2O2 in the presence of US or EB. The low molecular weight fucoidans (LMWFs) prevented P-selectin binding to Sialyl Lewis X with an IC50 (inhibitory concentration 50) of 20 nM as compared to 400 nM for heparin and 25,000 nM for dextran sulfate. The LMWFs showed no hemolytic activity at concentrations up to 950 MUg/ml. PMID- 25037422 TI - Preparation and characterization of guar gum hydrogels as carrier materials for controlled protein drug delivery. AB - Hydrogels were prepared from guar gum (GG) via esterification with 1,2,3,4 butanetetracarboxylic dianhydride (BTCA). Detailed spectroscopic analysis using FTIR and solid-state NMR revealed that an increase in the BTCA feed amount in the preparation mixture led to an increased degree of crosslinking, which affected the swelling behavior and rheological properties of the hydrogels. The hydrogels exhibited enzyme degradability, and after incubation with beta-mannanase and alpha-galactosidase, 30-57% of the hydrogels were degraded. In addition, the hydrogels adsorbed bovine serum albumin and hen egg white lysozyme thorough electrostatic and hydrophobic interactions. The protein-adsorbed GG hydrogels exhibited a slow and steady release of the proteins over a 24h period in buffer solutions after a fast release of proteins in the first hour. As such, GG hydrogels are expected to be efficient drug delivery carriers for protein-based drugs. PMID- 25037423 TI - Characteristics of starch-based films plasticised by glycerol and by the ionic liquid 1-ethyl-3-methylimidazolium acetate: a comparative study. AB - This paper reports the plasticisation effect of the ionic liquid, 1-ethyl-3 methylimidazolium acetate ([Emim][OAc]), as compared with the traditionally used plasticiser, glycerol, on the characteristics of starch-based films. For minimising the additional effect of processing, a simple compression moulding process (which involves minimal shear) was used for preparation of starch-based films. The results show that [Emim][OAc] was favourable for plasticisation, i.e., disruption of starch granules (by scanning electron microscopy), and could result in a more amorphous structure in the starch-based materials (by X-ray diffraction and dynamic mechanical analysis). (13)C CP/MAS and SPE/MAS NMR spectroscopy revealed that not only was the crystallinity reduced by [Emim][OAc], but also the amorphous starch present was plasticised to a more mobile form as indicated by the appearance of amorphous starch in the SPE/MAS spectrum. Mechanical results illustrate that, when either glycerol or [Emim][OAc] was used, a higher plasticiser content could contribute to higher flexibility. In spite of the accelerated thermal degradation of starch by [Emim][OAc] as shown by thermogravimetric analysis, the biodegradation study revealed the antimicrobial effect of [Emim][OAc] on the starch-based materials. Considering the high-amylose starch used here which is typically difficult to gelatinise in a traditional plasticiser (water and/or glycerol), [Emim][OAc] is demonstrated to be a promising plasticiser for starch to develop "green" flexible antimicrobial materials for novel applications. PMID- 25037424 TI - Surface modification of cellulose using silane coupling agent. AB - Recently there has been a growing interest in substituting traditional synthetic polymers with natural polymers for different applications. However, natural polymers such as cellulose suffer from few drawbacks. To become viable potential alternatives of synthetic polymers, cellulosic polymers must have comparable physico-chemical properties to that of synthetic polymers. So in the present work, cellulose polymer has been modified by a series of mercerization and silane functionalization to optimize the reaction conditions. Structural, thermal and morphological characterization of the cellulose has been done using FTIR, TGA and SEM, techniques. Surface modified cellulose polymers were further subjected to evaluation of their properties like swelling and chemical resistance behavior. PMID- 25037425 TI - Characterization and immunomodulatory activity of polysaccharides derived from Dendrobium tosaense. AB - Dendrobium tosaense is a medicinal Dendrobium species widely used in traditional medicine. This study demonstrated some structural characterizations and immunomodulatory activity of the water-soluble polysaccharides derived from the stem of D. tosaense (DTP). DTP was fractioned using DEAE-650 M anion-exchange gel filtration chromatography, producing one neutral polysaccharide fraction (DTP-N), which was investigated for its structural characteristics, using HPAEC-PAD, HP SEC, GC-MS, and NMR spectroscopy. DTP and DTP-N consisted of galactose, glucose, and mannose in ratios of 1:9.1:150.7 and 1:12.2:262.5, respectively. DTP-N comprised (1 -> 4)Man as its main backbone, and its average molecular weight was 220 kDa. We also investigated the immunomodulatory effects of DTP administered orally to BALB/c mice for 3 weeks. DTP substantially boosted the population of splenic natural killer (NK) cells, NK cytotoxicity, macrophage phagocytosis, and cytokine induction in splenocytes. This is the first study to demonstrate the structural characteristics of an active polysaccharide derived from D. tosaense and its immunopharmacological effects in vivo. PMID- 25037426 TI - Insoluble starch composite foams produced through microwave expansion. AB - An insoluble biocomposite composed of potato starch and chitosan was prepared by microwave treatment. The effect of pH on swelling (liquid absorption) behavior of the composites was investigated at pH 2, pH 6.8 and pH 12. Analysis revealed that the solution uptake ratio of composites depends both on the aqueous pH value and the content of the chitosan. Composites exhibited a relatively high swelling ratio at pH environments lower than the pK(a) of amine groups on chitosan (about 6.3). Glucose analysis by ion exchange chromatography showed that there was little hydrolysis of such composites at low pH. When immersed in the same pH solution, composites with higher chitosan content exhibited higher swelling ratios. The microstructure of composites produced was also investigated by FE SEM. PMID- 25037427 TI - Quantitative analysis of the multifunctional finishing of cotton fabric with non formaldehyde agents. AB - Realization of simultaneous hydrophilizing and wrinkle-proofing effects on a cotton fabric is not impossible. This work proves that these objectives can be reached by using adequate multifunctional compounds: Tetronic 701 (T), chitosan (CS) and monochlorotriazine-beta-cyclodextrin (MCT-beta-CD). These were applied by means of three pad-dry-cure type treatments. We have studied, at first, the influences resulted after each stage in order to establish the optimum working fields. The results of the FTIR, XPS, XRD, DSC and TGA analyses confirmed the proposed mechanism. By applying the multiple linear regression as a statistical analysis of the data produced after the third treatment stage, one could determine the quantitative influences produced by the concentrations of the three multifunctional agents on the following parameters: taking-in degree, wrinkle recovery angles (WRA), breaking strength, durability test, immersion time, contact angle, and capillarity. PMID- 25037428 TI - Novel synthetic method for the preparation of amphiphilic hyaluronan by means of aliphatic aromatic anhydrides. AB - The present work describes a novel and efficient method of synthesis of amphiphilic hyaluronan (HA) by esterification with alkyl fatty acids. These derivatives were synthesized under mild aqueous and well controlled conditions using mixed aliphatic aromatic anhydrides. These anhydrides characterized by the general formula RCOOCOC6H2Cl3 can be easily prepared by the reaction of the corresponding fatty acid (R) with 2,4,6-trichlorobenzoyl chloride (TCBC) in the presence of triethylamine. The aliphatic aromatic anhydrides RCOOCOC6H2Cl3 then react with the polysaccharide and enable the synthesis of aliphatic acid esters of HA in good yields. No hydrolytic degradation of hyaluronic acid could be observed. Parameters controlling the degree of esterification were systematically studied. Fatty acids with different chain lengths can be introduced applying this methodology. The degree of substitution was decreasing with increasing length of hydrophobic chain. The reaction products were fully characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), SEC MALLS and chromatographic analyses. Although the esterified HA products exhibited aggregation in solution as demonstrated by NMR, microscopy and rheology, they were still water-soluble. PMID- 25037429 TI - Preparation and characterization of anionic pullulan thermoassociative nanoparticles for drug delivery. AB - Thermoassociative nanoparticles were obtained through the crosslinking reaction of periodate oxidized carboxymethyl pullulan with two difunctional Jeffamines: ED 600 and ED-2003. The nanoparticles were characterized through (1)H NMR spectra; their particle size, determined by dynamic light scattering (DLS) presented a bimodal distribution, with dimensions varying as a function of amount and type of crosslinking agent used; transmission electron microscopy photos confirmed the spherical shape of the nanoparticles and their dimensions determined by DLS. Their amphiphilic character was evidenced by retention of the dyes: hydrophobic (Rose Bengal), amphiphilic (Brilliant Blue) and hydrophilic (Vitamin B12). The thermosensitive properties, more pronounced for ED-2003 crosslinked nanoparticles, were evidenced through absorbance variation, fluorescence and DLS measurements as a temperature function. The nanoparticles retain important amounts of anionic (diclofenac: 40-80 mg/g), cationic (methylene blue: 70-125 mg/g) and hydrophobic (alpha-tocopherol: 220-350 mg/g) drugs. The in vitro characterization of the drug-polymer conjugates recommends the synthesized nanoparticles as supports for drug delivery. PMID- 25037430 TI - Chitosan microbeads for encapsulation of thyme (Thymus serpyllum L.) polyphenols. AB - In this work chitosan microbeads were prepared by emulsion technique and loaded with thyme polyphenols by diffusion from an external aqueous solution of Thymus serpyllum L. The effects of concentrations of chitosan (1.5-3% (w/v)) and GA (glutaraldehyde) (0.1-0.4% (v/v)), as a crosslinking agent on the main properties of microbeads were assessed. The obtained microgel beads from ~ 220 to ~ 790 MUm in diameter were exposed to controlled drying process at air (at 37 degrees C) after which they contracted to irregular shapes (~ 70-230 MUm). The loading of dried microbeads with polyphenols was achieved by swelling in the acidic medium. The swelling rate of microbeads decreased with the increase in GA concentration. Upon this rehydration, thyme polyphenols were effectively encapsulated (active load of 66-114 mg GAE g(beads)(-1)) and the microbeads recovered a spherical shape. Both, the increase in the amount of the crosslinking agent and the presence of polyphenols, contributed to a more pronounced surface roughness of microbeads. The release of encapsulated polyphenols in simulated gastrointestinal fluids was prolonged to 3h. PMID- 25037432 TI - Aggregate and emulsion properties of enzymatically-modified octenylsuccinylated waxy starches. AB - Sorghum and maize waxy starches were hydrophobically modified with octenylsuccinic anhydride (OSA) and treated with enzymes before being used to emulsify beta-carotene (beta,beta-carotene) and oil in water. Enzyme treatment with beta-amylase resulted in emulsions that were broken (separated) earlier and suffered increased degradation of beta-carotene, whereas treatment with pullulanase had little effect on emulsions. Combinations of surfactants with high and low hydrodynamic volume (V(h)) indicated that there is a relationship between V(h) and emulsion stability. Degree of branching (DB) had little direct influence on emulsions, though surfactants with the highest DB were poor emulsifiers due to their reduced molecular size. Results indicate that V(h) and branch length (including linear components) are the primary influences on octenylsuccinylated starches forming stable emulsions, due to the increased steric hindrance from short amphiphilic branches, consistent with current understanding of electrosteric stabilization. The success of OSA-modified sorghum starch points to possible new products of interest in arid climates. PMID- 25037431 TI - pH-sensitive pullulan-based nanoparticle carrier for adriamycin to overcome drug resistance of cancer cells. AB - Urocanic acid was conjugated to pullulan to synthesize O-urocanyl pullulan (URPA) with degree of substitution (DS) of 8.2%. URPA nanoparticles prepared by dialysis method had spherical shapes and a mean diameter of 156.8 +/- 16.8 nm. Adriamycin (ADR) was successfully loaded into URPA nanoparticles and exhibited pH-sensitive in vitro release property. MTT assay showed that ADR-loaded URPA (ADR/URPA) nanoparticles had a significant higher toxicity against drug resistant MCF-7/ADR cells than free ADR, and the reversal index reached up to 9.6. The results of flow cytometry and confocal microscopy showed that URPA nanoparticles efficiently enhanced accumulation and retention of ADR in MCF-7/ADR cells and successfully delivered ADR into cell nucleus. The reversal effect of ADR/URPA nanoparticles on the drug resistance of MCF-7/ADR cells was perhaps related with their cell entry and intracellular drug release mechanisms. PMID- 25037433 TI - A novel melphalan polymeric prodrug: preparation and property study. AB - The clinical application of melphalan (Me), an anticancer drug for the treatment of hematologic malignancies, has been limited due to its poor water solubility, rapid elimination and lack of target specificity. To solve these problems, O,N carboxymethyl chitosan-peptide-melphalan conjugates were synthesized and characterized. All polymeric prodrugs showed satisfactory water solubility. It was found that the molecular weight of O,N-carboxymethyl chitosan (O,N-CMCS) and the peptide spacer played a crucial role in controlling the drug content, diameter and drug release properties of O,N-carboxymethyl chitosan-peptide melphalan conjugates. The studies of in vitro drug release and cell cytotoxicity by MTT assay revealed that, employing the polymeric conjugation strategy and using the peptides glycylglycine (Gly-Gly) as a spacer, the conjugates have good cathepsin X-sensitivity and lower toxicity and the drug release behavior improved remarkably. In conclusion, O,N-carboxymethyl chitosan-peptide-melphalan conjugates could be promising prodrugs for anticancer application. PMID- 25037434 TI - Influence of culture medium growth variables on Ganoderma lucidum exopolysaccharides structural features. AB - In this work the effect of carbon and nitrogen levels and initial pH of the wheat extract culture medium of submerged culture of Ganoderma lucidum on the amount, purity and structural features of exopolysaccharides (EPS) were studied. A low peptone level (1.65 g L(-1)) favored mycelium biomass, EPS purity, but a higher supply of peptone (4.80 g L(-1)) is needed for maximum EPS production. The carbohydrate composition of the EPS and structural features also changed significantly according to the different growing conditions, being observed significant differences in the (1 -> 3)/(1 -> 4)-Glcp ratio and also on the branching degree of EPS. As the biological activities of EPS are highly dependent on the polysaccharide structural features, this variability can have implications on the EPS biological activities, but can also be used advantageously to produce tailor made polysaccharides with specific applications. PMID- 25037435 TI - Purification and antioxidant activities of intracellular zinc polysaccharides from Pleurotus cornucopiae SS-03. AB - Intracellular zinc polysaccharides (IZPS) from Pleurotus cornucopiae SS-03 were extracted and purified, and three subfractions (IZPS-1, IZPS-2, and IZPS-3) were separated by DEAE-52 cellulose anion-exchange column chromatography. They showed certain scavenging effects on superoxide anion (O2(*-)) and 1,1-diphenyl-2 picrylhydrazyl (DPPH) radicals, and positive rising of reducing power in vitro. All the subfractions were found upregulated the enzyme activities of superoxide dismutase (SOD), GSH peroxide (GSH-Px) and catalase (CAT) significantly, decreased the contents of malondialdehyde (MDA) and lipid peroxidation (LPO) remarkably in vivo. In addition, five monosaccharides components, including rhamnose, xylose, mannose, glucose, and galactose with the molar ratio of 1.65:0.05:1:1.50:1.07 and contents of 29.25%, 0.78%, 19.45%, 29.84%, and 20.67%, were investigated by gas chromatography. PMID- 25037436 TI - Influence of HNO3/H3PO4-NANO2 mediated oxidation on the structure and properties of cellulose fibers. AB - The bamboo pulp cellulose fiber was oxidized with HNO3/H3PO4-NaNO2 mixture to obtain oxidized cellulose containing different levels of carboxyl content and with high yields. The effects of HNO3/H3PO4-NaNO2 mediated oxidation on structure and properties of the fiber were investigated. The results showed that an increase in carboxyl content and weight loss of oxidized fibers appeared with increasing oxidation time. Compared with the original cellulose, the oxidized fibers had lower crystallinity (29-40%) and thermal stability. The patterns of (13)C NMR, X-ray diffraction and other testing methods revealed that the oxidation mostly occurred at C6 primary hydroxyl groups of cellulose. Moreover, an oxidized fiber with 94.14-98.59% of high yields and 1.13-3.56% of carboxyl content was obtained in the range of oxidation time from 15 to 60 min, while its mechanical properties did not change significantly. This work presented some detailed information about structure-property correlations of oxidized bamboo pulp cellulose fibers and was useful in planning applications of these products. PMID- 25037437 TI - pH/redox responsive core cross-linked nanoparticles from thiolated carboxymethyl chitosan for in vitro release study of methotrexate. AB - A novel amphiphilic thiolated carboxymethyl chitosan was synthesized. It self assembled into disulfide bond cross-linked nanoparticles in deionized water. The TEM showed that these nanoparticles had a core-shell structure with an average diameter of 160 nm. Dynamic light scattering showed that the nanoparticles were stable in water solution. The particle size changed with pH values and GSH concentrations, and reached a maximum diameter at pH 7.0 and 20mM GSH respectively, exhibiting an obvious pH/redox responsibility. Methotrexate was encapsulated in nanoparticles reaching encapsulation efficiency as much as 43.4%. Release profiles of methotrexate showed a release rate of 19 wt% in pH 7.4 buffer containing 10 MUM GSH, whereas as high as 93 wt% in pH 5.0 buffer containing 20mM GSH, indicating that the nanoparticles may be used for tumor-specific drug release. The anticancer activity test in vitro showed that the inhibition rate of methotrexate-loaded nanoparticles against HeLa cells reached 90%. PMID- 25037438 TI - Facile size-regulated synthesis of silver nanoparticles using pectin. AB - Monodispersed silver nanoparticles capped by pectin were prepared by the reaction of silver nitrate with alkali hydrolyzed pectin at 70 degrees C for 30 min. Spherical and size-regulated silver nanoparticles were prepared using alkali hydrolyzed pectin as a reducing and particle-stabilizing agent. This approach is facile, effective, rapid, and convenient for the large scale preparation of silver nanoparticles. UV-visible spectral analysis confirmed that the nanoparticles consisted of metallic silver. Transmission electron microscopy (TEM) was used to estimate particle size and size distribution of the produced silver nanoparticles. Transmission electron microscopy and size distribution analysis revealed the presence of spherical silver nanoparticles with a main diameter of 5-10nm and have a narrow size distribution. The concentration of reducing sugars was monitored by using dinitrosalicylic acid. A comprehensive schematic mechanism for the formation of silver nanoparticles using pectin is proposed. PMID- 25037439 TI - Isolation and characterization of cellulose nanocrystals from spruce bark in a biorefinery perspective. AB - The present study reports for the first time the isolation of cellulose fibers and cellulose nanocrystals (CNCs) from the bark of Norway spruce. The upgrading of bark cellulose to value-added products, such as CNCs, is part of the "bark biorefinery" concept. The removal of non-cellulosic constituents was monitored throughout the isolation process by detailed chemical composition analyses. The morphological investigation of the CNCs was performed using AFM and showed the presence of nanocrystals with an average length of 175.3 nm and a diameter of 2.8 nm, giving an aspect ratio of around 63. X-ray diffraction (XRD) analyses showed that the crystallinity index increased with successive treatments to reach a final value greater than 80% for CNCs. The thermal degradation of the isolated bark CNCs started at 190 degrees C. Spruce bark appeared to be a new promising industrial source of cellulose fibers and CNCs. PMID- 25037440 TI - Raman spectroscopy of TiO2 thin films formed by hybrid treatment for biomedical applications. AB - The paper presents the results of the investigations of the surface layer obtained after application of the combined hybrid method of oxidation in a fluidized bed (FB) and deposition of the oxide coating by PVD technique. The material used in the study was Ti Grade 2. The process of diffusive saturation was carried out in a fluidized-bed reactor at the temperature of 640 degrees C for 8h in air while the top oxide layer was obtained through PVD method - magnetron sputtering using TiO2 target and argon atmosphere with the pressure of 3*10(-2)mbar and the distance between the substrate to the target of 60mm. In order to determine changes in the properties that occur as a result of modification of the Ti surface, the following examinations were carried out by SEM-EDX, X-ray diffraction methods, Raman spectroscopy, Glow Discharge Optical Spectroscopy (GDOS) and Secondary Ion Mass Spectrometry (SIMS). The coatings obtained were characterized by zonal structure comprising the solution zone of Tialpha(O) and oxide zone of TiO2 with modifications of rutile and anatase, depending on the oxidation method. It was found that formation of oxide layers using the hybrid method (FB+PVD) leads to limitation of defects in the oxide layer after fluidized-bed thermal treatment and obtaining a uniform, tight coating with improved corrosion properties which are important from the biomedical standpoint. PMID- 25037441 TI - Fasting plasma glucose to avoid a full OGTT in the diagnosis of gestational diabetes. AB - AIMS: To evaluate the performance of fasting plasma glucose (FPG) in determining the need for a full oral glucose tolerance test (OGTT) to diagnose gestational diabetes (GDM) by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. METHODS: A multicenter cohort study of 4926 pregnant women 20 years or older consecutively enrolled in prenatal care clinics of the Brazilian National Health Service from 1991 to 1995. All women underwent a single 2 h 75 g OGTT by weeks 24-28 of pregnancy and were followed to detect adverse pregnancy outcomes. RESULTS: A FPG cut-off value of 80 mg/dl indicated that only 38.7% of all women needed to undergo a complete OGTT, while detecting 96.9% of all GDM cases. When the 85 mg/dl cut-off was used, the corresponding percentages were 18.7% and 92.5%, respectively. The fraction of women labeled with GDM who had adverse pregnancy outcomes was nearly identical when using FPG strategies and universal full testing. CONCLUSIONS: Using a FPG cut-off to diagnose GDM and to determine the need for post-load OGTT measurements is a valid strategy to diagnose GDM by IADPSG criteria. This approach may improve feasibility of applying IADPSG diagnostic criteria by reducing costs and increasing convenience. PMID- 25037442 TI - Introducing video recording in primary care midwifery for research purposes: procedure, dataset, and use. AB - BACKGROUND: video recording studies have been found to be complex; however very few studies describe the actual introduction and enrolment of the study, the resulting dataset and its interpretation. In this paper we describe the introduction and the use of video recordings of health care provider (HCP)-client interactions in primary care midwifery for research purposes. We also report on the process of data management, data coding and the resulting data set. METHODS: we describe our experience in undertaking a study using video recording to assess the interaction of the midwife and her client in the first antenatal consultation, in a real life clinical practice setting in the Netherlands. Midwives from six practices across the Netherlands were recruited to videotape 15 20 intakes. The introduction, complexity of the study and intrusiveness of the study were discussed within the research group. The number of valid recordings and missing recordings was measured; reasons not to participate, non-response analyses, and the inter-rater reliability of the coded videotapes were assessed. Video recordings were supplemented by questionnaires for midwives and clients. The Roter Interaction Analysis System (RIAS) was used for coding as well as an obstetric topics scale. FINDINGS: at the introduction of the study, more initial hesitation in co-operation was found among the midwives than among their clients. The intrusive nature of the recording on the interaction was perceived to be minimal. The complex nature of the study affected recruitment and data collection. Combining the dataset with the questionnaires and medical records proved to be a challenge. The final dataset included videotapes of 20 midwives (7 23 recordings per midwife). Of the 460 eligible clients, 324 gave informed consent. The study resulted in a significant dataset of first antenatal consultations involving recording 269 clients and 194 partners. CONCLUSION: video recording of midwife-client interaction was both feasible and challenging and resulted in a unique dataset of recordings of midwife-client interaction. Video recording studies will benefit from a tight design, and vigilant monitoring during the data collection to ensure effective data collection. We provide suggestions to promote successful introduction of video recording for research purposes. PMID- 25037444 TI - The tubular compartment and the spermatogenic dynamics of the wild rodent Oxymycterus nasutus (Rodentia: Cricetidae). AB - Despite the order Rodentia present worldwide distribution and large number of species in the Brazilian fauna, detailed studies on testicular morphophysiology are still scarce. Therefore, this study aimed to analyze the dynamics of the spermatogenic process of Oxymycterus nasutus using morphometrical and stereological tools. Testicles from ten sexually mature males were used, showing a gonadosomatic index of 0.89%. The testicular parenchyma showed one of the highest tubulesomatic indexes reported among wild rodents - 0.82% - from which 65.12% was allocated into seminiferous epithelium. The average tubular diameter was 249.89 MUm, whereas the epithelium height was 62.47 MUm and the total length was 18.62 m per gram of testis. Eight different stages of the seminiferous epithelium cycle were described. Stage 1 was used for counting the germ cell population as well as the Sertoli cells. On average, 3.47 type-A spermatogonia, 24.39 primary spermatocytes in preleptotene/leptotene, 24.13 primary spermatocytes in pachytene, 68.38 round spermatids and 7.33 Sertoli cells were found per tubular cross section. There were 91.02 * 10(6) Sertoli cells per gram of testis and each cell was able to support 9.33 spermatids and 16.43 germ cells. The coefficient of spermatogonial mitosis was 7.02, while 2.83 spermatids were produced for each primary spermatocyte in pachytene. The overall efficiency of spermatogenesis was 19.70 cells, whereas the sperm reserve per gram of testis totalized 849.63 * 10(6) spermatids. Therefore, the presented data showed that O. nasutus shows a high energetic investment in reproduction, corroborating the findings for other species of the Cricetidae family. PMID- 25037443 TI - Molecular identification of a TPR-FGFR1 fusion transcript in an adult with myeloproliferative neoplasm, T-lymphoblastic lymphoma, and a t(1;8)(q25;p11.2). AB - The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal abnormalities involving rearrangement of the fibroblast growth factor receptor 1 (FGFR1) gene. We report herein a rare case of a t(1;8)(q25;p11.2) with a TPR-FGFR1 rearrangement, in which the patient presented with myeloproliferative neoplasm-like symptoms and T-lymphoblastic lymphoma. Sequence analysis revealed a fusion transcript with exon 22 of the TPR gene joined to exon 13 of the FGFR1 gene, which is a novel breakpoint for the TPR gene in the TPR-FGFR1 rearrangement. PMID- 25037445 TI - The heritability of abortion in pedigree Charollais flocks. AB - Foetal death, or abortion at term, in sheep is of major significance to the livestock industry, accounting for more than L24million lost per annum. We have investigated whether there is a genetic component to abortion within two flocks of pedigree Charollais sheep, one followed from 1989 to 2006, the other from 1992 to 2006. Abortion occurred at a rate of 5.74-8.78% per annum against a total mortality rate of 14-24%. By model covariate analysis we have shown that 15.5% aborting ewes went on to have one or more abortions and that this risk increased with parity (p=0.006). Heritability estimates were approximately 0.08 as calculated by SOLAR, pedigreemm and ASReml3, with sire and dam components of 0.046 and 0.048, respectively. Where the lamb was aborted, heritability estimates were highly variable according to the method employed, 0.046-0.378, with sex of the lamb being a significant covariate. This variability indicated one or more underlying, significant factors that were not measured in these analyses, potentially including infectious agents that may be involved. Nevertheless, the ASReml3 estimate (0.179) resolved to 0.074 variance attributable to the sire and 0.092 attributable to the dam, which, while not significant, was suggestive that genetic variants passed by the dam to the lamb may be of more weight than that from the sire in determining whether a lamb will abort. PMID- 25037446 TI - Testing the reliability of software tools in sex and ancestry estimation in a multi-ancestral Brazilian sample. AB - In the framework of forensic anthropology osteometric techniques are generally preferred over visual examinations due to a higher level of reproducibility and repeatability; qualities that are crucial within a legal context. The use of osteometric methods has been further reinforced by incorporating statistically based algorithms and large reference samples in a variety of user-friendly software applications. However, the continued increase in admixture of human populations have made the use of osteometric methods for estimation of ancestry much more complex, which confounds one of major requirements of ancestry assessment - intra-population homogeneity. The present paper tests the accuracy of ancestry and sex assessment using four identification software tools, specifically FORDISC 2.0, FORDISC 3.1.293, COLIPR 1.5.2 and 3D-ID 1.0. Software accuracy was tested in a sample of 174 documented human crania of Brazilian origin composed of different ancestral groups (i.e., European Brazilians, Afro Brazilians, and Japanese Brazilians and of admixed ancestry). The results show that regardless of the software algorithm employed and composition of the reference database, all methods were able to allocate approximately 50% of Brazilian specimens to an appropriate major reference group. Of the three ancestral groups, Afro-Brazilians were especially prone to misclassification. Japanese Brazilians, by contrast, were shown to be relatively easily recognizable as being of Asian descent but at the same time showed a strong affinity towards Hispanic crania, in particularly when the classification based on FDB was carried out in FORDISC. For crania of admixed origin all of the algorithms showed a considerable higher rate of inconsistency with a tendency for misclassification into Asian and American Hispanic groups. Sex assessments revealed an overall modest to poor reliability (60-71% of correctly classified specimens) using the tested software programs with unbalanced individual rates for males and females. The highest and atypically balanced rate of classification for sex assessment was provided by COLIPR software, which reached 78% of correctly assessed crania. PMID- 25037447 TI - Hearing loss in Mexican children treated with cisplatin. AB - OBJECTIVE: Cisplatin is widely used to treat a variety of pediatric solid tumors. One of the most severe and debilitating adverse drug reactions experienced by patients who receive cisplatin therapy is permanent bilateral hearing loss. The aim of this study was to evaluate the incidence and risk factors for cisplatin induced hearing loss in Mexican pediatric patients. METHODS: Detailed medical and drug histories, including use of cisplatin as well as other drugs known to cause hearing loss, were collected from patient medical records. Results of audiology tests on pediatric patients with solid tumors were collected at baseline, during treatment and at the end of cisplatin chemotherapy. Hearing loss was classified according to the Common Terminology Criteria for Adverse Events. Bivariate and multivariate analyses were performed using survival curves. RESULTS: Fifty-nine pediatric patients, median age 11 years (range, 3-17 years) were included in the study. The incidence of cisplatin-induced hearing loss was 56%. Individual risk factors including age (< 5 years), male sex, and concomitant medications were not associated with an increased risk of cisplatin-induced hearing loss. Patients with a diagnosis of osteosarcoma and a cumulative cisplatin dose greater than 400 mg/m(2) were at higher risk of hearing loss compared with all other tumor and cumulative dose combinations (HR = 2.47 [95% CI, 1.043-5.831]). CONCLUSIONS: Cumulative dose and tumor type are associated with an increased risk of cisplatin induced hearing loss. Further research is required to characterize fully the interindividual variation in hearing loss in Mexican patients. PMID- 25037448 TI - Shared symptoms and putative biological mechanisms in chronic liver disease: implications for biobehavioral research. AB - Liver disease affects over 25 million people in the United States and, despite advances in medical management resulting in increased survival, a majority of these individuals report multiple co-occurring symptoms that severely impair functioning and quality of life. The purpose of this review is to (1) propose defining these co-occurring symptoms as a symptom cluster of chronic liver disease (CLD), (2) discuss putative underlying biological mechanisms related to CLD, including the liver-gut-brain axis and influence of the microbiome, and (3) discuss the implications for biobehavioral research in this patient population. Biobehavioral research focusing on the interrelated, and possibly synergistic, mechanisms of these symptoms may lead to the development and testing of targeted symptom management interventions for improving function and quality of life in this growing patient population. PMID- 25037449 TI - The effects of different lying positions on interface pressure, skin temperature, and tissue blood flow in nursing home residents. AB - BACKGROUND: Although repositioning is considered an important intervention to prevent pressure ulcers, tissue response during loading in different lying positions has not been adequately explored. AIM: To compare the effects of different lying positions on interface pressure, skin temperature, and tissue blood flow in nursing home residents. METHOD: From May 2011 to August 2012, interface pressure, skin temperature, and blood flow at three tissue depths were measured for 1 hr over the sacrum in 30 degrees supine tilt and 0 degrees supine positions and over the trochanter major in 30 degrees lateral and 90 degrees lateral positions in 25 residents aged 65 years or older. Measurement of interface pressure was accomplished using a pneumatic pressure transmitter connected to a digital manometer, skin temperature using a temperature sensor, and blood flow using photoplethysmography and laser Doppler flowmetry. RESULTS: Interface pressure was significantly higher in the 0 degrees supine and 90 degrees lateral positions than in 30 degrees supine tilt and 30 degrees lateral positions. The mean skin temperature increased from baseline in all positions. Blood flow was significantly higher in the 30 degrees supine tilt position compared to the other positions. A hyperemic response in the post pressure period was seen at almost all tissue depths and positions. CONCLUSION: The 30 degrees supine tilt position generated less interface pressure and allowed greater tissue perfusion, suggesting that this position is the most beneficial. PMID- 25037450 TI - Recovery sleep does not mitigate the effects of prior sleep loss on paclitaxel induced mechanical hypersensitivity in Sprague-Dawley rats. AB - Society has a rapidly growing accumulative sleep debt due to employment obligations and lifestyle choices that limit sleep opportunities. The degree to which poor sleep may set the stage for adverse symptom outcomes among more than 1.7 million persons who will be diagnosed with cancer is not entirely understood. Paclitaxel (PAC), a commonly used chemotherapy agent, is associated with painful, debilitating peripheral neuropathy of the hands and feet, which may persist long after adjuvant therapy is completed. The aims of this preclinical study were to determine the accumulative and sustained effects of sleep restriction on PAC induced mechanical sensitivity in animals and whether there are male-female differences in mechanical sensitivity in PAC-injected animals. Sixty-two adult Sprague-Dawley rats (n = 31 females) were assigned to three cycles of intraperitoneal injections of PAC (1 mg/kg) versus vehicle (VEH; 1 ml/kg) every other day at light onset for 7 days, followed by seven drug-free days and to sleep restriction versus unperturbed sleep. Sleep restriction involved gentle handling to maintain wakefulness during the first 6 hr of lights on immediately following an injection; otherwise, sleep was unperturbed. Mechanical sensitivity was assessed via von Frey filaments, using the up-down method. Mechanical sensitivity data were Log10 transformed to meet the assumption of normality for repeated measures analysis of variance. Chronic sleep restriction of the PAC injected animals resulted in significantly increased mechanical sensitivity that progressively worsened despite sleep recovery opportunities. If these relationships hold in humans, targeted sleep interventions employed during a PAC protocol may improve pain outcomes. PMID- 25037451 TI - Reproducibility of a peripheral quantitative computed tomography scan protocol to measure the material properties of the second metatarsal. AB - BACKGROUND: Peripheral quantitative computed tomography (pQCT) is an established technology that allows for the measurement of the material properties of bone. Alterations to bone architecture are associated with an increased risk of fracture. Further pQCT research is necessary to identify regions of interest that are prone to fracture risk in people with chronic diseases. The second metatarsal is a common site for the development of insufficiency fractures, and as such the aim of this study was to assess the reproducibility of a novel scanning protocol of the second metatarsal using pQCT. METHODS: Eleven embalmed cadaveric leg specimens were scanned six times; three times with and without repositioning. Each foot was positioned on a custom-designed acrylic foot plate to permit unimpeded scans of the region of interest. Sixty-six scans were obtained at 15% (distal) and 50% (mid shaft) of the second metatarsal. Voxel size and scan speed were reduced to 0.40 mm and 25 mm.sec(-1). The reference line was positioned at the most distal portion of the 2(nd) metatarsal. Repeated measurements of six key variables related to bone properties were subject to reproducibility testing. Data were log transformed and reproducibility of scans were assessed using intraclass correlation coefficients (ICC) and coefficients of variation (CV%). RESULTS: Reproducibility of the measurements without repositioning were estimated as: trabecular area (ICC 0.95; CV% 2.4), trabecular density (ICC 0.98; CV% 3.0), Strength Strain Index (SSI) - distal (ICC 0.99; CV% 5.6), cortical area (ICC 1.0; CV% 1.5), cortical density (ICC 0.99; CV% 0.1), SSI - mid shaft (ICC 1.0; CV% 2.4). Reproducibility of the measurements after repositioning were estimated as: trabecular area (ICC 0.96; CV% 2.4), trabecular density (ICC 0.98; CV% 2.8), SSI distal (ICC 1.0; CV% 3.5), cortical area (ICC 0.99; CV%2.4), cortical density (ICC 0.98; CV% 0.8), SSI - mid shaft (ICC 0.99; CV% 3.2). CONCLUSIONS: The scanning protocol generated excellent reproducibility for key bone properties measured at the distal and mid-shaft regions of the 2(nd) metatarsal. This protocol extends the capabilities of pQCT to evaluate bone quality in people who may be at an increased risk of metatarsal insufficiency fractures. PMID- 25037452 TI - Treatment outcome of new smear positive pulmonary tuberculosis patients in Penang, Malaysia. AB - BACKGROUND: According to the World Health Organization's recent report, in Malaysia, tuberculosis (TB) treatment success rate for new smear positive pulmonary tuberculosis (PTB) patients is still below the global success target of 85%. In this study, we evaluated TB treatment outcome among new smear positive PTB patients, and identified the predictors of unsuccessful treatment outcome and longer duration of treatment (i.e., > 6 months). METHODS: The population in this study consisted of all new smear positive PTB patients who were diagnosed at the chest clinic of Penang General Hospital between March 2010 and February 2011. During the study period, a standardized data collection form was used to obtain socio-demographic, clinical and treatment related data of the patients from their medical charts and TB notification forms (Tuberculosis Information System; TBIS). These data sources were reviewed at the time of the diagnosis of the patients and then at the subsequent follow-up visits until their final treatment outcomes were available. The treatment outcomes of the patients were reported in line with six outcome categories recommended by World Health Organization. Multiple logistic regression analysis was used to find the independent risk factors for unsuccessful treatment outcome and longer treatment duration. Data were analyzed using the PASW (Predictive Analysis SoftWare, version 19.0. Armonk, NY: IBM Corp). RESULTS: Among the 336 PTB patients (236 male and 100 female) notified during the study period, the treatment success rate was 67.26% (n = 226). Out of 110 patients in unsuccessful outcome category, 30 defaulted from the treatment, 59 died and 21 were transferred to other health care facilities. The mean duration of TB treatment was 8.19 (SD 1.65) months. In multiple logistic regression analysis, risk factors for unsuccessful treatment outcome were foreign nationality, male gender and being illiterate. Similarly, risk factors for mortality due to TB included high-grade sputum and presence of lung cavities at the start of treatment, being alcoholic and elderly. Likewise, concurrent diabetes, presence of lung cavities at the start of the treatment and being a smoker were the significant predictors of longer treatment duration. CONCLUSION: Our findings indicated that the treatment success rate among the new smear positive PTB patients was less than the success target set by World Health Organization. The proportion of patients in the successful outcome category may be increased by closely monitoring the treatment progress of the patients with aforementioned high risk characteristics. Similarly, more aggressive follow-up of the treatment defaulters and transferred out patients could also improve the TB treatment success rate. PMID- 25037453 TI - The potential value of integrated natriuretic peptide and echo-guided heart failure management. AB - There is increasing interest in guiding Heart Failure (HF) therapy with Brain Natriuretic Peptide (BNP) or N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP), with the goal of lowering concentrations of these markers (and maintaining their suppression) as part of the therapeutic approach in HF. However, recent European Society of Cardiology (ESC) and American Heart Association/ American College of Cardiology (AHA/ACC) guidelines did not recommend biomarker-guided therapy in the management of HF patients. This has likely to do with the conceptual, methodological, and practical limitations of the Natriuretic Peptides (NP)-based approach, including biological variability, slow time-course, poor specificity, cost and venipuncture, as well as to the lack of conclusive scientific evidence after 15 years of intensive scientific work and industry investment in the field. An increase in NP can be associated with accumulation of extra-vascular lung water, which is a sign of impending acute heart failure. If this is the case, an higher dose of loop diuretics will improve symptoms. However, if no lung congestion is present, diuretics will show no benefit and even harm. It is only a combined clinical, bio-humoral (for instance with evaluation of renal function) and echocardiographic assessment which may unmask the pathophysiological (and possibly therapeutic) heterogeneity underlying the same clinical and NP picture. Increase in B-lines will trigger increase of loop diuretics (or dialysis); the marked increase in mitral insufficiency (at baseline or during exercise) will lead to increase in vasodilators and to consider mitral valve repair; the presence of substantial inotropic reserve during stress will give a substantially higher chance of benefit to beta-blocker or Cardiac Resynchronization Therapy (CRT). To each patient its own therapy, not with a "blind date" with symptoms and NP and carpet bombing with drugs, but with an open-eye targeted approach on the mechanism predominant in that individual patient. A monocular, specialistic, unidimensional approach to HF can miss its pathogenetic and clinical complexity, which only can be overcome with an integrated, versatile and tailored approach. PMID- 25037454 TI - The combined loss of Gads and CD127 reveals a novel function of Gads prior to TCRbeta expression. AB - The Gads adaptor protein is an essential component of the T cell signaling complex critical for T cell receptor-mediated calcium mobilization. After expression of TCRbeta in T cell precursors, Gads is required for optimal Bcl-2 expression and cell survival. Similarly, the IL-7 receptor chain CD127 is also necessary for optimal Bcl-2 expression and cell survival in TCRbeta-expressing thymocytes. Based on these observations, we tested whether Gads and CD127 might regulate convergent or linear signaling pathways by crossing Gads(-/-) mice with CD127(-/-) mice. Thymi from Gads(-/-)CD127(-/-) mice were barely detectable and many of the thymocytes were within the DN1 population. By contrast, B cell development in the Gads(-/-)CD127(-/-) mice was comparable to that of CD127(-/-) mice, indicating that the combined loss of Gads and CD127 did not lead to a global deficit in hematopoiesis. Analysis of Lin(-)Sca-1(+)c-kit(+) bone marrow cells and bone marrow chimera experiments indicated that Gads(-/-)CD127(-/-) T cell precursors either failed to migrate into the thymus or survive in the thymus. These data demonstrate that Gads functions at a stage of T cell development that had not been previously described. PMID- 25037455 TI - Improving adolescent mental health and resilience through a resilience-based intervention in schools: study protocol for a randomised controlled trial. AB - BACKGROUND: Research investigating the effectiveness of universal interventions to reduce the risk of mental health problems remains limited. Schools are a promising setting within which adolescents can receive interventions aimed at promoting their mental health. The aim of this study is to assess the effectiveness of a resilience-based prevention-focused intervention in reducing the risk of mental health problems among adolescents attending secondary school in socio-economically disadvantaged areas. METHODS/DESIGN: A cluster randomised control trial will be conducted, with schools as the unit of randomisation. Initially, 32 secondary schools will be randomly allocated to a control or intervention group (12 control and 20 intervention). An intervention focused on improving student internal and external resilience factors will be implemented in intervention schools. A survey of students in Grade 7 in both intervention and control schools will be conducted (baseline) and repeated three years later when the students are in Grade 10. The Strengths and Difficulties Questionnaire will be used to measure the risk of mental health problems. At follow-up, the risk of mental health problems will be compared between Grade 10 students in intervention and control schools to determine intervention effectiveness. DISCUSSION: The study presents an opportunity to determine the effectiveness of a comprehensive resilience-based intervention in reducing the risk of mental health problems in adolescents attending secondary schools. The outcomes of the trial are of importance to youth, schools, mental health clinicians and policymakers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12611000606987, registered 14 June 2011. PMID- 25037456 TI - Comparative evaluation of the new FDA approved THxIDTM-BRAF test with High Resolution Melting and Sanger sequencing. AB - BACKGROUND: Since patients diagnosed with BRAF V600E and V600K mutated advanced melanoma show response to treatment with MAP kinase inhibitors, several sensitive methods have been developed to determine the V600 allele status of melanoma patients. Vemurafenib (Zelboraf) and dabrafenib (Tafinlar) are specific BRAF V600 inhibitors recently approved by the US FDA as single agent treatments for unresectable or metastatic melanoma in patients with the BRAF V600 mutation. METHODS: We assessed the new CE THxIDTM-BRAF diagnostic test, which is also FDA approved as a companion diagnostic test in the US under a specific reference and compared the results of this assay with both High Resolution Melting (HRM) and Sanger sequencing in 113 melanoma FFPE samples. RESULTS: Invalid results were observed in 0/113 specimen with HRM, 5/113 (4.4%) with Sanger sequencing, and 1/113 (0.9%) with the THxIDTM-BRAF test. Positive percentage agreement (PPA) was 93.5% (95% CI 82.5 - 97.8) for V600E and V600K mutations combined for the THxIDTM BRAF test and HRM, and negative percentage agreement (NPA) was 100.0% (95% CI 94.5 - 100.0). For the THxIDTM-BRAF test and Sanger, PPA was 100.0% (95% CI 92.1 100.0) and NPA 100.0% (95% CI 94.2 - 100.0). One V600E sample identified by THxIDTM-BRAF test was detected as wild-type by HRM and uninterpretable by Sanger. All V600K (n = 3) were detected using the 3 different approaches. Finally, percent agreement values were not significantly different when using punches (n = 77) vs. slides (n = 36) or depending on samples characteristics such as pigmentation, necrosis, and tumor content. CONCLUSIONS: This study demonstrated the high agreement between the FDA approved THxIDTM-BRAF assay, HRM, and Sanger sequencing. It has also highlighted the potential of THxIDTM-BRAF to be applied to a broader range of sample types than claimed in the current "instructions for use", an extension that would require the ad hoc validation and approval. PMID- 25037457 TI - Commentary on "Conceptualizing genetic counseling as psychotherapy in the era of genomic medicine". PMID- 25037458 TI - Beyond ultrasound: advances in multimodality cardiac imaging. AB - The rapid technological evolution accomplished in noninvasive cardiac imaging techniques over the past few decades has provided physicians with a large armamentarium for the evaluation of patients with known or suspected coronary heart disease. Noninvasive assessment of coronary artery calcium or noninvasive coronary angiography may be performed using computed tomography or magnetic resonance imaging. These techniques evaluate the presence of atherosclerosis rather than ischemia. Conversely, nuclear cardiology is the most widely used noninvasive approach for the assessment of myocardial perfusion and function. These techniques coupled with the development of dedicated image fusion software packages to merge data sets from different modalities have paved the way for hybrid imaging. This article provides a description of the available noninvasive imaging techniques in the assessment of coronary anatomy, myocardial perfusion, and cardiac function in patients with known or suspected coronary heart disease. PMID- 25037459 TI - Moderators of neuropsychological mechanism in attention-deficit hyperactivity disorder. AB - Neuropsychological measures have been proposed as both a way to tap mechanisms and as endophenotypes for child ADHD. However, substantial evidence supporting heterogeneity in neuropsychological performance among youth with ADHD as well as apparent effect differences by sex, age, and comorbidity have slowed progress. To address this, it is important to understand sibling effects in relation to these moderators. 461 youth ages 6-17 years (54.8 % male, including 251 youth with ADHD, 107 of their unaffected biological siblings, and 103 non-ADHD controls) completed diagnostic interviews and a theoretically informed battery of neuropsychological functioning. A structural equation model was used to consolidate neuropsychological domains. Group differences between unaffected siblings of youth with ADHD and controls across each domain were first examined as the primary endophenotype test for ADHD. Moderation of these effects was evaluated via investigation of interactions between diagnostic group and both proband and individual level characteristics, including sex, age, and comorbidity status. Unaffected siblings performed worse than control youth in the domains of inhibition, response time variability, and temporal information processing. Individual age moderated these effects, such that differences between controls and unaffected siblings were pronounced among younger children (ages 6-10 years) but absent among older youth (ages 11-17 years). Evidence for moderation of effects by proband sex and comorbidity status produced more variable and smaller effects. Results support the utility of inhibition, response time variability, and temporal processing as useful endophenotypes for ADHD in future genetic associations studies of the disorder, but suggest this value will vary by age among unaffected family members. PMID- 25037460 TI - Attention-deficit/hyperactivity disorder and social skills in youth: a moderated mediation model of emotion dysregulation and depression. AB - Although studies document an association between Attention-Deficit/Hyperactivity Disorder (ADHD) and social problems, little is known about mediating or moderating mechanisms underlying this association. We examined whether, among youth, emotion dysregulation (ED) mediates the negative association between ADHD and social skills, and whether this mediational process is moderated by symptoms of depression. A total of 171 youth with ADHD (76 % male; Mage = 12.15, SD = 0.95) and their parents completed measures of ED, depression, and social skills. Results indicated that, after controlling for oppositional defiant disorder, the negative association between ADHD and social skills was mediated by ED. Further, this indirect effect was relevant for youth with non-clinical and subclinical levels of depression but not for those with clinical levels of depression. These findings underscore the importance of ED in the association between ADHD and social functioning among youth and suggest a need for additional research to understand how and when ED impacts such functioning. PMID- 25037461 TI - Interrelations of maternal expressed emotion, maltreatment, and separation/divorce and links to family conflict and children's externalizing behavior. AB - Research has documented that maternal expressed emotion-criticism (EE-Crit) from the Five-Minute Speech Sample (FMSS) predicts family conflict and children's externalizing behavior in clinical and community samples. However, studies have not examined EE-Crit in maltreating or separated/divorced families, or whether these family risks exacerbate the links between EE-Crit and family conflict and externalizing behavior. The current study examined the associations between maternal EE-Crit, maltreatment, and separation/divorce, and whether maltreatment and separation/divorce moderated associations between EE-Crit and children's externalizing problems, and EE-Crit and family conflict. Participants included 123 children (M = 8.01 years, SD = 1.58; 64.2 % males) from maltreating (n = 83) or low-income, comparison (n = 40) families, and 123 mothers (n = 48 separated/divorced). Mothers completed the FMSS for EE-Crit and the Family Environment Scale for family conflict. Maltreatment was coded with the Maltreatment Classification System using information from official Child Protection Services (CPS) reports from the Department of Human Services (DHS). Trained summer camp counselors rated children's externalizing behavior. Maltreatment was directly associated with higher externalizing problems, and separation/divorce, but not maltreatment, moderated the association between EE Crit and externalizing behavior. Analyses pertaining to family conflict were not significant. Findings indicate that maltreatment is a direct risk factor for children's externalizing behavior and separation/divorce is a vulnerability factor for externalizing behavior in family contexts with high maternal EE-Crit. Intervention, prevention, and policy efforts to promote resilience in high-risk families may be effective in targeting maltreating and critical parents, especially those with co-occurring separation/divorce. Key Words: expressed emotion, EE-Crit, Five-Minute Speech Sample; maltreatment, divorce, externalizing behavior. PMID- 25037462 TI - Hemostatic efficacy of latest-generation fibrin sealant after hepatic resection: a randomized controlled clinical study. AB - PURPOSE: This randomized, controlled, single-blinded multicenter study evaluated the efficacy of latest-generation fibrin sealant containing synthetic aprotinin as fibrinolysis inhibitor as supportive treatment for hemostasis after elective partial hepatectomy. METHODS: Adult subjects undergoing resection of at least one liver segment were assigned to treatment with fibrin sealant or manual compression with a surgical gauze swab if persistent oozing necessitated additional hemostatic measures after primary control of arterial and venous bleeding. The primary outcome measure was the proportion of subjects with intraoperative hemostasis at 4 min after start of randomized treatment application. Secondary efficacy outcome measures included intraoperative hemostasis at 6, 8, and 10 min, intra- and postoperative rebleedings, transfusion requirements, and drainage volume. RESULTS: Seventy subjects were randomized. Hemostasis at 4 min was achieved in 29/35 (82.9 %) fibrin sealant subjects compared with 13/35 (37.1 %) control subjects (p < 0.001). Significantly more fibrin sealant subjects achieved hemostasis at 6 (p < 0.001), 8 (p = 0.028), and 10 min (p = 0.017). The number of rebleedings was low in both study arms. Transfusion requirements and 48-h drainage volumes were similar between the study arms. No adverse events related to study treatment were reported. CONCLUSIONS: Fibrin sealant was shown to be safe and superior to manual compression in the control of parenchymal bleeding after hepatic resection. The use of synthetic aprotinin as fibrinolysis inhibitor further improves the safety margin of fibrin sealant by eliminating the risk of transmission of bovine spongiform encephalopathy and other bovine pathogens. PMID- 25037463 TI - Centipeda periodontii in human periodontitis. AB - This study assessed the subgingival occurrence of the flagellated, Gram-negative, anaerobic rod Centipeda periodontii in chronic periodontitis and periodontal health/gingivitis with species-specific nucleic acid probes, and evaluated the in vitro resistance of subgingival isolates to therapeutic levels of amoxicillin, metronidazole, and doxycycline. Subgingival plaque biofilm specimens from 307 adults with chronic periodontitis, and 48 adults with periodontal health/localized gingivitis, were evaluated with digoxigenin-labeled, whole chromosomal, DNA probes to C. periodontii ATCC 35019 possessing a 10(4) cell detection threshold. Fifty-two C. periodontii subgingival culture isolates were assessed on antibiotic-supplemented enriched Brucella blood agar for in vitro resistance to either amoxicillin at 2 ug/ml, metronidazole at 4 ug/ml, or doxycycline at 2 ug/ml. A significantly greater subgingival occurrence of C. periodontii was found in chronic periodontitis subjects as compared to individuals with periodontal health/gingivitis (13.4 vs. 0 %, P < 0.003), although high subgingival counts of the organism (>= 10(6) cells) were rarely detected (1.3 % of chronic periodontitis subjects). In vitro resistance was not found to amoxicillin or metronidazole, and to doxycycline in only 2 (3.9 %) of the 52 C. periodontii clinical isolates studied. These findings indicate that C. periodontii is not a major constituent of the subgingival microbiome in chronic periodontitis or periodontal health/gingivitis. The potential contribution of C. periodontii to periodontal breakdown in the few chronic periodontitis subjects who yielded high subgingival levels of the organism remains to be delineated. C. periodontii clinical isolates were susceptible in vitro to therapeutic concentrations of three antibiotics frequently used in treatment of human periodontitis. PMID- 25037464 TI - Individual foraging specialisation in a social mammal: the European badger (Meles meles). AB - Individual specialisation has been identified in an increasing number of animal species and populations. However, in some groups, such as terrestrial mammals, it is difficult to disentangle individual niche variation from spatial variation in resource availability. In the present study, we investigate individual variation in the foraging niche of the European badger (Meles meles), a social carnivore that lives in a shared group territory, but forages predominantly alone. Using stable isotope analysis, we distinguish the extent to which foraging variation in badgers is determined by social and spatial constraints and by individual differences within groups. We found a tendency for individual badgers within groups to differ markedly and consistently in their isotope values, suggesting that individuals living with access to the same resources occupied distinctive foraging niches. Although sex had a significant effect on isotope values, substantial variation within groups occurred independently of age and sex. Individual differences were consistent over a period of several months and in some instances were highly consistent across the two years of the study, suggesting long-term individual foraging specialisations. Individual specialisation in foraging may, therefore, persist in populations of territorial species not solely as a result of spatial variation in resources, but also arising from individuals selecting differently from the same available resources. Although the exact cause of this behaviour is unknown, we suggest that specialisation may occur due to learning trade-offs which may limit individual niche widths. However, ecological factors at the group level, such as competition, may also influence the degree of specialisation. PMID- 25037465 TI - Pathophysiology of flow impairment during carotid artery stenting with an embolus protection filter. AB - OBJECTIVE: Carotid artery stenting (CAS) is a well-accepted treatment for atherosclerotic stenosis of carotid arteries. Since the occurrence of distal embolization with CAS is still a major concern embolus protection devices (EPD) are usually employed during the procedure. We examined two types of embolus protection filters (Angioguard XP (AG); Filterwire EZ (FW)) and evaluated the function. Thus, the filter was examined postoperatively and the cause of intraoperative flow impairment was evaluated. MATERIALS AND METHODS: CAS was performed for 54 patients with carotid artery stenosis (55 lesions: 25 AG; 27 FW; 3 others). After completing CAS the filter membrane was stained with hematoxylin eosin (HE) solution and removed from the filter strut. Once mounted on a glass slide the filter was evaluated under a microscope. The area occupied with debris was measured and the relationship to intraoperative flow impairment was evaluated. Furthermore, the relationship between perioperative ischemic complications and intraoperative flow impairment was statistically analyzed. RESULTS: Microscopic observation of the slide revealed the pore density of the FW was 1.5 times higher than that of the AG and the filter area of the FW was 2.5 times wider than than the AG. HE staining facilitated characterization of the debris composition. The area occupied with debris was significantly more in the AG (0.241 +/- 0.13 cm(2)) than in the FW (0.129 +/- 0.093 cm(2)). Thus, fibrin was significantly more precipitated in the AG. Flow impairment occurred in 6 AG cases (24.0 %) and 4 FW cases (14.8 %). It was induced by filter obstruction in the AG and by vasospasms in the FW. Three cases treated with AG (12.0 %) were complicated with cerebral infarction and all of them were related to flow impairment. One FW case (3.7 %) was complicated with cerebral infarction in presence of preserved flow throughout the intervention. CONCLUSION: Filter function is different according to each design. The cause of flow impairment was attributable to filter obstruction in the AG group and to vasospasms in the FW group. Filter obstruction tends to result in cerebral infarction. PMID- 25037466 TI - Augmented reality in the surgery of cerebral arteriovenous malformations: technique assessment and considerations. AB - BACKGROUND: Augmented reality technology has been used for intraoperative image guidance through the overlay of virtual images, from preoperative imaging studies, onto the real-world surgical field. Although setups based on augmented reality have been used for various neurosurgical pathologies, very few cases have been reported for the surgery of arteriovenous malformations (AVM). We present our experience with AVM surgery using a system designed for image injection of virtual images into the operating microscope's eyepiece, and discuss why augmented reality may be less appealing in this form of surgery. METHODS: N = 5 patients underwent AVM resection assisted by augmented reality. Virtual three dimensional models of patients' heads, skulls, AVM nidi, and feeder and drainage vessels were selectively segmented and injected into the microscope's eyepiece for intraoperative image guidance, and their usefulness was assessed in each case. RESULTS: Although the setup helped in performing tailored craniotomies, in guiding dissection and in localizing drainage veins, it did not provide the surgeon with useful information concerning feeder arteries, due to the complexity of AVM angioarchitecture. CONCLUSION: The difficulty in intraoperatively conveying useful information on feeder vessels may make augmented reality a less engaging tool in this form of surgery, and might explain its underrepresentation in the literature. Integrating an AVM's hemodynamic characteristics into the augmented rendering could make it more suited to AVM surgery. PMID- 25037467 TI - Do specialty anticoagulation clinics really outperform primary care at INR management? PMID- 25037468 TI - Clinicopathological significance of RUNX3 gene hypermethylation in hepatocellular carcinoma. AB - Emerging evidence indicates that RUNX3 is a candidate tumor suppressor in several types of human tumors including hepatocellular carcinoma (HCC). However, the correlation between RUNX3 hypermethylation and incidence of HCC remains unclear. Here, we conducted a systematic review and meta-analysis aiming to comprehensively assess the potential role of RUNX3 hypermethylation in the pathogenesis of HCC. A detailed literature search was made from PubMed, EMBASE, and ISI web of knowledge to identify studies for related research publications. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed. Odds ratio (OR) was calculated and summarized, respectively. Final analysis of 821 HCC patients from 14 eligible studies was performed. We observed that RUNX3 hypermethylation was significantly higher in HCC than in normal liver tissue, the pooled OR from eight studies including 382 HCC and 161 normal liver tissue (OR = 39.32, 95 % confidence interval (CI) = 13.72-112.7, p < 0.00001). The pooled analysis showed significantly increased OR of RUNX3 hypermethylation (OR = 5.4, 95 % CI = 2.06-14.17, p < 0.00001) in HCC tissues and non-tumor liver tissues. In addition, statistically significant OR of RUNX3 hypermethylation was obtained from non-tumorous liver tissue of HCC patients and normal liver tissue (OR = 12.57, 95 % CI = 3.56-44.35, p < 0.0001). The results of this meta-analysis suggest that RUNX3 hypermethylation may be implicated in the pathogenesis of HCC. Thus, detection of RUNX3 hypermethylation may be a helpful and valuable biomarker for diagnosis of HCC. PMID- 25037469 TI - Relationship between acute strain pattern and recovery in tako-tsubo cardiomyopathy and acute anterior myocardial infarction: a comparative study using two-dimensional longitudinal strain. AB - After acute-anterior myocardial infarction (AMI), left ventricular (LV) viable myocardial segments show some degree of active deformation (longitudinal shortening) despite wall motion abnormalities (WMA). Tako-tsubo cardiomyopathy (TTC) is characterized by myocardial stunning; however, it is unclear whether in TTC the strain pattern mimics AMI. To compare the strain-pattern in TTC and AMI using the 2D-longitudinal strain by speckle-tracking in segments with WMA, and its relationship with recovery of function at follow-up. 21 consecutive patients with typical TTC and 21 age-matched AMI patients treated by primary angioplasty had an analysis of LV-longitudinal strain at the acute-phase and at follow-up (1 and 6 months later for TTC and AMI respectively). The recovery of a segment was defined as normal wall motion at follow-up. Among the 706 analyzable LV-segments at the acute-phase, 406 had WMA (TTC 229, AMI 177). At follow-up, total recovery was observed for 45 % segments in AMI and 100 % in TTC, (p < 0.01). At the acute phase, systolic lengthening duration (47 +/- 43 vs. 18 +/- 33 %) and amplitude (0.25 +/- 0.29 vs. 0.09 +/- 0.19) and post systolic shortening (67 +/- 53 vs. 39 +/- 38 %) were higher in TTC, when compared to AMI-recovery (all, p < 0.01). In AMI, systolic lengthening duration was an independent predictor of poor recovery in multivariate analysis, linked to segmental longitudinal strain at follow-up (all, p <= 0.01). Furthermore, among the 57 % of segments exhibiting any systolic lengthening duration in AMI, only 1/4 recovered, versus 62 % of such segments in TTC with 100 % recovery (p < 0.001). The systolic passive motion which is closely and inversely linked to recovery in AMI is paradoxically frequent and severe in TTC. This suggests that myocardial stunning in TTC and AMI is different according to longitudinal strain. PMID- 25037470 TI - Usefulness of 3D-PISA as compared to guideline endorsed parameters for mitral regurgitation quantification. AB - This study was intended to evaluate the diagnostic value of three dimensional proximal isovelocity surface area (3D PISA) derived effective regurgitant orifice area (EROA) and the accuracy of automatic 3D PISA detection in a population resembling clinical practice. Quantification of mitral regurgitation (MR) remains challenging and 3D PISA EROA is a novel diagnostic tool with promising results. However its' usefulness compared to guideline endorsed parameters has not been shown. In 93 consecutive patients examined in routine practice conventional parameters and 3D-datasets for offline 3D PISA evaluation were recorded. EROA was determined from the largest (peak) PISA and also averaged over systole for meanEROA. Results of 3D PISA calculation were compared with a combination of expert grading by two examiners and two scores for MR grading. In receiver operator characteristic-analysis the meanEROA as determined by 3D PISA had the best diagnostic value (AUC = 0.907 CI 0.832-0.983) as compared to peakEROA (AUC 0.840 CI 0.739-0.941), vena contracta width (AUC 0.831 CI 0.745-0.918) and 2D PISA (AUC 0.747 CI 0.644-0.850). A meanEROA of 0.15 cm(2) had a sensitivity of 88.2 % and a specificity of 81.4 % for distinguishing severe from non-severe MR. Semiautomatic 3D PISA detection correlated very well with manually corrected values (r = 0.955). Semiautomatic 3D PISA measurement is feasible in a clinical population and has better diagnostic value compared to 2D PISA. Calculation of mean EROA throughout systole further improves diagnostic value compared to conventional parameters. PMID- 25037471 TI - Free breathing motion-corrected T1 mapping for robust assessment of myocardial injury post myocardial infarction. PMID- 25037472 TI - Longitudinal changes of trabecular bone score after estrogen deprivation: effect of menopause and aromatase inhibition. AB - PURPOSE: To examine the effects of the menopausal transition and treatment with aromatase inhibitors (AI) on trabecular bone score (TBS, a newly proposed index of bone architecture derived from DXA vertebral scans) and vertebral bone mineral density (BMD). METHODS: Retrospective cohort study on 29 women who became postmenopausal during a mean follow-up of 2.9 years (MP group) and 34 women treated with AI during a mean follow-up of 2.1 years (AI group). BMD was measured by DXA and TBS with a specific software. RESULTS: TBS decreased after menopause, but the change was significantly lower than that of the lumbar BMD (-4.6 vs. -6.8 %; mean difference: 2.2 %; p = 0.016). An even larger difference was observed in the AI group (-2.1 vs. -5.9 %; mean difference: 3.8 %; p = 0.002). CONCLUSIONS: The decrease of TBS induced by menopause or treatment with AI is significantly lower than that of lumbar BMD. PMID- 25037473 TI - Factors related to mortality in patients with papillary and follicular thyroid cancer in long-term follow-up. AB - PURPOSE: Differentiated thyroid cancer (DTC) includes papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). They have different biological behavior but are frequently analyzed together in studies. We aimed to identify factors associated with mortality in those two different cancer subtypes. METHODS: Case series study, with clinical-pathological analysis of the characteristics of 424 patients with PTC and 89 patients with FTC, correlating them to survival rates in a single institution. RESULTS: Patients were followed from 1983 to 2011. Mean follow-up time was 9.4 years for FTC (range 1-36.6 years) and 6.8 years for PTC (range 1.1-30.7 years). Mean age at diagnosis was 51.2 +/- 15.5 for FTC and 41 +/- 14.7 years for PTC. 50.62% of FTC nodules sized 1.1-4 cm and 20% of PTC sized <=1 cm. Cox multiple regression analysis evidenced distant metastasis at diagnosis (p = 0.0038; relative risk (RR) 41.247, 95% confidence interval (CI) 3.317-512.986), lymph node metastasis at diagnosis (p = 0.0081; RR 50.98, 95% CI 2.783-934.026) and vascular/lymphatic invasion (p = 0.0039; RR 40.424, 95% CI 3.287-497.177) as factors related to mortality in FTC patients. For PTC, the factors were distant metastasis at diagnosis (p < 0.0001; RR 32.5, 95% CI 6.676-158.543) and degree of differentiation (poor versus well differentiated, p = 0.003; RR 10.4, 95% CI 2.218-49.487). CONCLUSION: The common factor that influenced mortality for FTC and PTC patients was distant metastasis at diagnosis, increasing mortality rate by 41 times in FTC and 30 times in PTC patients. The different factors influencing mortality for different DTC types highlight the importance of analyzing them separately. PMID- 25037474 TI - Lipopolysaccharide assembly in the bacterial outer membrane revealed by X-ray crystallography. PMID- 25037477 TI - [Adiponectin as target in rheumatoid arthritis]. PMID- 25037476 TI - Expression analysis of heat shock protein genes during Aeromonas hydrophila infection in rohu, Labeo rohita, with special reference to molecular characterization of Grp78. AB - Heat shock protein (Hsp) genes are stress-related genes that activate the host immune system during infection. Hsp genes expression in fish, studied during bacterial infections, is mostly confined to Hsp70 and Hsp90. The present study is an expression analysis of seven Hsp genes: Apg2, Hsp90, Hsp70, glucose-regulated protein 78 (Grp78), heat shock cognate 70 (Hsc70), Grp75, and Hsp30 during Aeromonas hydrophila infection in rohu, Labeo rohita. Forty-eight rohu juveniles were challenged with 3 * 10(7) cfu bacteria per 20 g of body weight intraperitoneally. The expression of these genes was studied in infected liver, anterior kidney, and spleen tissues of rohu at different time periods: 0, 1, 3, 6, 12, 24, 48, 72 h, 7, and 15 days post-infection by qPCR. The Hsp gene modulation was greater in liver as compared to spleen and kidney tissues. Induced expression of Apg2, Hsp90, Grp78, Grp75, and Hsc70 was noticed during peak periods (3 to 24 h post-challenge) of bacterial infectivity. Hsp70 was found to be down-regulated during the process of infection. In contrast to the other six genes, Hsp30 showed a variable expression pattern in all three tissues. Grp78 was found to be the most highly (1,587-fold) expressed gene in liver at 12 h post challenge. Further, molecular characterization of Grp78 revealed it to be a highly conserved Hsp gene, essential not only during infection but also during early developmental stages of rohu, and its expression was noticed in all organs studied except in gill tissues, which indicated its potential immune regulatory role during infection process. PMID- 25037478 TI - [Interface between university medicine and patient care]. AB - The working profile of university hospitals includes medical education, research and implementation of medical innovations as well as large volume patient care. University hospitals offer inpatient, day care and outpatient care which are of essential value for many patients. Besides their primary role in treating rare and orphan diseases and complex cases, they increasingly support general patient care. There are different kinds of outpatient access and treatment options available. The funding of university hospitals and clinics is based on general university funding, income from third party funds for research, income from patient care and funding from the federal states for investments. In recent years these institutions have suffered more and more from economic deficits, a lack of investment and inadequate funding whereby high performance medicine cannot be sufficiently supported. Professors are developing into scientific managers and are frequently assessed by economic outcome and competitiveness. At the same time they are embedded in the structures of the university and are not in the position to make decisions on their own, in contrast to doctors in private practices. Therefore, processes, necessary investments and restructuring are significantly delayed. There is a need to develop strategies for long-term funding and providing university hospitals and clinics with the means to deliver the necessary services. PMID- 25037479 TI - [Berlin transition program: from adolescents to adults in rheumatology treatment]. AB - BACKGROUND: Transition is a crucial bridge between pediatric and adult rheumatology care and yet is often not a priority in either discipline. There is adequate evidence for the need of specific transition services. Various measures and transition programs have been proposed to support care during transition to adulthood; however, the implementation of youth-friendly services including transitional care has been frustratingly slow. Many structural and psychosocial barriers exist and prevent the widespread implementation of health transition support. Transition is resource consuming. It requires a reorganization of work flow to accommodate a clear, well-documented transitional pathway, including sufficiently long consultation times, age-appropriate communication, addressing of age-specific topics and a close cooperation between pediatric and adult rheumatologists. OBJECTIVES: This article presents the Berlin transition program (BTP) and its development. RESULTS AND PERSPECTIVES: The BTP presented here is the first structured transition program financed by statutory health insurances in Germany. Since January 2013 it can be used for patients with rheumatic and musculoskeletal diseases in some regions of Germany. The BTP supports care at transfer; however, it cannot guarantee a successful transition. There is a need to make the BTP available nationwide and to evaluate its effectiveness. This could be a precondition to recognize transition services as part of regular healthcare. PMID- 25037480 TI - Positive and negative features of a computer assisted drug treatment program delivered by mentors to homeless drug users living in hostels. AB - This paper explores positive and negative features of computer assisted therapy (CAT) delivered by mentors to homeless drug users (HDUs) living in hostels. Qualitative interviews were conducted with 30 HDUs and 15 mentors (all hostel staff) at the beginning and end of a 12-week CAT program. Findings indicate that successful delivery of the CAT relates to: 'program features' (e.g. its accessibility, flexibility, user-friendly interface); 'delivery context' (e.g. privacy, having appropriate computing equipment), 'client characteristics' (HDUs being recovery-focused and committed to using the program), and 'mentor support' (clients having personalized attention from an encouraging and sympathetic other). It is concluded that CATs can be used with HDUs but are unlikely to replace addiction therapists. Rather, they are more likely to be effective when combined with a strong therapeutic relationship. Services using CATs with HDUs need to provide staff training, support, and time to maximize the potential benefits. PMID- 25037481 TI - The impact of Sika deer on vegetation in Japan: setting management priorities on a national scale. AB - Irreversible shifts in ecosystems caused by large herbivores are becoming widespread around the world. We analyzed data derived from the 2009-2010 Sika Deer Impact Survey, which assessed the geographical distribution of deer impacts on vegetation through a questionnaire, on a scale of 5-km grid-cells. Our aim was to identify areas facing irreversible ecosystem shifts caused by deer overpopulation and in need of management prioritization. Our results demonstrated that the areas with heavy impacts on vegetation were widely distributed across Japan from north to south and from the coastal to the alpine areas. Grid-cells with heavy impacts are especially expanding in the southwestern part of the Pacific side of Japan. The intensity of deer impacts was explained by four factors: (1) the number of 5-km grid-cells with sika deer in neighboring 5 km grid-cells in 1978 and 2003, (2) the year sika deer were first recorded in a grid cell, (3) the number of months in which maximum snow depth exceeded 50 cm, and (4) the proportion of urban areas in a particular grid-cell. Based on our model, areas with long-persistent deer populations, short snow periods, and fewer urban areas were predicted to be the most vulnerable to deer impact. Although many areas matching these criteria already have heavy deer impact, there are some areas that remain only slightly impacted. These areas may need to be designated as having high management priority because of the possibility of a rapid intensification of deer impact. PMID- 25037482 TI - Recreational stream crossing effects on sediment delivery and macroinvertebrates in southwestern Virginia, USA. AB - Trail-based recreation has increased over recent decades, raising the environmental management issue of soil erosion that originates from unsurfaced, recreational trail systems. Trail-based soil erosion that occurs near stream crossings represents a non-point source of pollution to streams. We modeled soil erosion rates along multiple-use (hiking, mountain biking, and horseback riding) recreational trails that approach culvert and ford stream crossings as potential sources of sediment input and evaluated whether recreational stream crossings were impacting water quality based on downstream changes in macroinvertebrate based indices within the Poverty Creek Trail System of the George Washington and Jefferson National Forest in southwestern Virginia, USA. We found modeled soil erosion rates for non-motorized recreational approaches that were lower than published estimates for an off-road vehicle approach, bare horse trails, and bare forest operational skid trail and road approaches, but were 13 times greater than estimated rates for undisturbed forests and 2.4 times greater than a 2-year old clearcut in this region. Estimated soil erosion rates were similar to rates for skid trails and horse trails where best management practices (BMPs) had been implemented. Downstream changes in macroinvertebrate-based indices indicated water quality was lower downstream from crossings than in upstream reference reaches. Our modeled soil erosion rates illustrate recreational stream crossing approaches have the potential to deliver sediment into adjacent streams, particularly where BMPs are not being implemented or where approaches are not properly managed, and as a result can negatively impact water quality below stream crossings. PMID- 25037483 TI - Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. AB - INTRODUCTION: Although urinary cytology (C) is the most widely used noninvasive test for the detection and surveillance of bladder cancer (BC), it has poor sensitivity especially for low-grade tumors. We prospectively tested the performance of urine markers on patients with BC using C and 4 commercially available urinary marker tests: Hemoglobin Dipstick (H), BTA Stat (B), NMP22 BladderChek (N), and ImmunoCyt (I). METHODS: Urinary samples from 109 consecutive patients with BC were prospectively collected. All samples were tested using conventional C and available biomarkers. Prior and subsequent surgical specimen reports were examined, and sensitivity and specificity were calculated for each. Collected variables included patient demographics, date of urinary collection, type of specimen (voided, washing, or catheterized), surgical pathology, recurrence, and follow-up. RESULTS: Sensitivity values for each marker were as follows: C, 48% (16% for low-grade tumors and 84% for high-grade [HG] tumors); B, 61% (36% and 91%); H, 51% (38% and 66%); N, 58% (25% and 92%); and I, 62% (47% and 83%). Specificity results for each marker were as follows: C, 86%; B, 78%; H, 58%; N, 85%; and I, 79%. On multivariate analysis, higher stage (C and N) and HG disease (C, H, B, N, and I) were independent prognostic factors for improved test performance. When urinary markers were combined with C, sensitivity/specificity values for HG disease were as follows: C+H, 85%/57%; C+B, 91%/78%; C+N, 94%/84%; and C+I, 90%/78%. CONCLUSIONS: Based on these data, C seems to yield the highest specificity and N the highest sensitivity for HG tumors. The combination "C+N" seems to be the better approach to improve the sensitivity for HG tumors compared with single markers and other combinations. PMID- 25037484 TI - Introduction--Targeting the lesion, not the organ. AB - The current diagnostic and therapeutic strategy for localized prostate cancer is not working. In fact, it is severely flawed and, as such, fraught with controversy. Our current strategy has arisen from the imprecision of our diagnostic pathway. We do not know where the cancer is, so we subject the prostate to randomly placed needles in the hope of hitting the tumor. This leads to overdiagnosis, underdiagnosis, missclassification of risk and overtreatment and undertreatment. If we do find cancer, we usually subject the entire prostate to radiotherapy or surgery, which damages the surrounding structures- neurovascular bundles, external urinary sphincter, rectum, and bladder neck. Multiparametric magnetic resonance imaging, coupled with an intensive sampling strategy (targeted biopsies), might be able to rule out clinically significant lesions with a negative predictive value in the order of 90% to 95%. Focal therapy certainly leads to less genitourinary and rectal side effects. Current data from more than 3,000 men treated internationally show that incontinence after focal therapy is 0% to 5% (radical therapy can lead to incontinence in 15% 20%) whereas erectile dysfunction occurs in 5% to 10% of men with good baseline function (radical therapy rates vary between 30% and 60%). Early to medium cancer control using biopsies after treatment shows between 80% and 90% of patients have a successful treatment, with 10% to 15% of men requiring redo-treatment with minimal additional morbidity. PMID- 25037485 TI - Skin Colonization by Malassezia spp. in hospitalized neonates and infants in a tertiary care centre in North India. AB - Malassezia, a skin colonizer, is associated with multiple skin disorders in adults, and cephalic pustulosis and folliculitis in children. It can cause fungemia in infants and neonates. The time and pattern of colonization, risk factors associated with colonization and causing fungemia in children, are not well understood. The prospective cohort study was conducted to determine the rate of Malassezia species colonization and associated factors in hospitalized neonates and infants. Consecutive 50 neonates and infants admitted in neonatal and pediatric intensive care units were studied. The skin swabs were collected on the day of admission and every fifth day, thereafter, till the patient was discharged or died. Putative risk factors for the colonization of Malassezia species were recorded. Isolates were identified by phenotypic methods and sequencing of the D1 and D2 region of rDNA. Neonates were not colonized at the time of entry in neonatal ICU or at birth. Nineteen (38 %) neonates were colonized with Malassezia species during their hospital stay. Among the infants, three (6 %) came to ICU with Malassezia colonization and 26 (52 %) acquired Malassezia during ICU stay. Mechanical ventilation, duration of hospital stay, central venous catheterization, and antifungal therapy were the significantly associated factors for colonization. Malassezia furfur was the most common species isolated from the skin of infants and neonates. Colonization by Malassezia species in infants and neonates in a hospital is not uncommon and can be a potential source of nosocomial infection. PMID- 25037486 TI - Candida galli as a cause of tinea unguium-molecular characterization of a rare clinical fungal entity. AB - We present the first clinical report of an infection caused by Candida galli, an anamorphic yeast species in the Yarrowia clade. C. galli has been described in the literature only four times, but never before it has been isolated from clinical samples. The colony morphology on Sabouraud medium and morphotype on CHROMagar Candida medium were similar to C. lipolytica as well as the carbon assimilation profile. The phenotypic differences with C. lipolytica were the non assimilation of N-acetyl glucosamine, the absence of urease activity, growth in 10 % NaCl with 5 % glucose and in vitamin-free medium. MALDI-TOF MS could not generate reliable identification of the strain. Molecular analysis based on amplification of the ITS1-5.8S-ITS2 rDNA regions confirmed the identity as C. galli. Antifungal susceptibility test clearly demonstrated high MICs to 5 fluorocytosine, amphotericin B and fluconazole, as in the species belonging to the Yarrowia clade. PMID- 25037487 TI - Computational reconstruction of proteome-wide protein interaction networks between HTLV retroviruses and Homo sapiens. AB - BACKGROUND: Human T-cell leukemia viruses (HTLV) tend to induce some fatal human diseases like Adult T-cell Leukemia (ATL) by targeting human T lymphocytes. To indentify the protein-protein interactions (PPI) between HTLV viruses and Homo sapiens is one of the significant approaches to reveal the underlying mechanism of HTLV infection and host defence. At present, as biological experiments are labor-intensive and expensive, the identified part of the HTLV-human PPI networks is rather small. Although recent years have witnessed much progress in computational modeling for reconstructing pathogen-host PPI networks, data scarcity and data unavailability are two major challenges to be effectively addressed. To our knowledge, no computational method for proteome-wide HTLV-human PPI networks reconstruction has been reported. RESULTS: In this work we develop Multi-instance Adaboost method to conduct homolog knowledge transfer for computationally reconstructing proteome-wide HTLV-human PPI networks. In this method, the homolog knowledge in the form of gene ontology (GO) is treated as auxiliary homolog instance to address the problems of data scarcity and data unavailability, while the potential negative knowledge transfer is automatically attenuated by AdaBoost instance reweighting. The cross validation experiments show that the homolog knowledge transfer in the form of independent homolog instances can effectively enrich the feature information and substitute for the missing GO information. Moreover, the independent tests show that the method can validate 70.3% of the recently curated interactions, significantly exceeding the 2.1% recognition rate by the HT-Y2H experiment. We have used the method to reconstruct the proteome-wide HTLV-human PPI networks and further conducted gene ontology based clustering of the predicted networks for further biomedical research. The gene ontology based clustering analysis of the predictions provides much biological insight into the pathogenesis of HTLV retroviruses. CONCLUSIONS: The Multi-instance AdaBoost method can effectively address the problems of data scarcity and data unavailability for the proteome-wide HTLV-human PPI interaction networks reconstruction. The gene ontology based clustering analysis of the predictions reveals some important signaling pathways and biological modules that HTLV retroviruses are likely to target. PMID- 25037488 TI - Gender-specific risk factors for virologic failure in KwaZulu-Natal: automobile ownership and financial insecurity. AB - We sought to examine which socioeconomic indicators are risk factors for virologic failure among HIV-1 infected patients receiving antiretroviral therapy (ART) in KwaZulu-Natal, South Africa. A case-control study of virologic failure was conducted among patients recruited from the outpatient clinic at McCord Hospital in Durban, South Africa between October 1, 2010 and June 30, 2012. Cases were those failing first-line ART, defined as viral load >1,000 copies/mL. Univariate logistic regression was performed on sociodemographic data for the outcome of virologic failure. Variables found significant (p < 0.05) were used in multivariate models and all models were stratified by gender. Of 158 cases and 300 controls, 35 % were male and median age was 40 years. Gender stratification of models revealed automobile ownership was a risk factor among males, while variables of financial insecurity (unemployment, non-spouse family paying for care, staying with family) were risk factors for women. In this cohort, financial insecurity among women and automobile ownership among men were risk factors for virologic failure. Risk factor differences between genders demonstrate limitations of generalized risk factor analysis. PMID- 25037489 TI - Driving and retarding forces in a chemical reaction. AB - The reaction force F(xi) is the negative gradient of the potential energy of a chemical process along the intrinsic reaction coordinate xi. We extend the rigorous concept of F(xi) to the "activation strain model" of Bickelhaupt et al., to formulate the "strain" force Fstr(xi) that retards a reaction and the "interaction" force Fint(xi) that drives it. These are investigated for a group of Diels-Alder cycloadditions. The results fully support the interpretation of the minimum of F(xi) as defining the beginning of the transition from deformed reactants to eventual products. PMID- 25037490 TI - Is 1-nitro-1-triazene a high energy density material? AB - An azo bridge (-N=N-) can not only desensitize explosives but also dramatically increase their heats of formation and explosive properties. Amino and nitro are two important high energy density functional groups. Here, we present calculations on 1-nitro-1-triazene (NH2-N=N-NO2). Thermal stability and detonation parameters were predicted theoretically at CCSD(T)/6-311G* level, based on the geometries optimized at MP2/6-311G* level. It was found that the p >pi conjugation interaction and the intramolecular hydrogen bonding that exist in the system together increase the thermal stability of the molecule. Moreover, the detonation parameters were evaluated to be better than those of the famous HMX and RDX. Finally, the compound was demonstrated to be a high energy density material. PMID- 25037491 TI - The CH3PH2 and CH3PH isomers: isomerization, hydrogen release, thermodynamic, and spectroscopy properties. AB - In this study was performed a quantum chemical investigation of the methylphosphine molecule and its radical, which may show potential implications in interstellar processes, and may be crucial atmospheric tracer gasses in the atmosphere of Giant planets. The analyses were performed with the density functional theory and coupled cluster methods. The anharmonic vibrational modes were predicted for all the isomers. The atomic charge distribution was analyzed with different methodologies and some methods fail to establish the correct sign for phosphorous atom charges. The CH2PH2/CH3PH and CHPH3/CH3PH energy gap is 16.45-17.43 and 67.05-69.02 kcal mol(-1), respectively. The CH2PH3/CH3PH2 energy difference ranges from 44.62 to 50.05 kcal mol(-1). The ionization energy predicted with the W1BD method for CH3PH and CH3PH2 are 8.73 and 9.01 eV, respectively. The heat of formation at 298 K for each molecule were calculated in kcal mol(-1): CH3PH (24.16-25.27), CH2PH2 (41.20-42.47), CHPH3 (92.50-94.23), CH3PH2 (-4.73-2.83) and CH2PH3 (40.03-42.55). The rotational energy barriers for CH3PH2 and CH2PH3 are 1.65 and 2.81 kcal mol(-1), respectively. The CHPH3->CH2PH2 unimolecular arrangement presents a barrier energy of 29.89 kcal mol(-1), whereas CH3PH->CH2PH2 is accessible overcoming a barrier of 42.42 kcal mol(-1). The H2 release routes for CH2PH2 from carbon and phosphorous atoms show a barrier of 98.19 and 46.67 kcal mol(-1), respectively. For the CH3PH2->CH2PH3 isomerization, an energy barrier of 94.00 kcal mol(-1) was predicted, while for the H2-release pathway for CH3PH2 it is necessary to pass a potential energy barrier of 97.56 kcal mol(-1). PMID- 25037492 TI - An intraoperative device to restore femoral offset in total hip arthroplasty. AB - BACKGROUND: Leg length discrepancy (LLD) after total hip arthroplasty (THA) can lead to unsatisfactory outcome. Our objective was to design and evaluate a simple and reliable intraoperative device (Length-offset Lever) to minimize leg length discrepancy. METHODS: This device was used in 51 patients undergoing primary total hip replacements. The leg length discrepancy was measured pre- and postoperatively based on plain radiographs. RESULTS: Preoperative radiographic leg length discrepancy averaged 13.5 +/- 6.2 mm. Leg length discrepancy showed significant improvement, with a postoperative average of 4.1 +/- 2.3 mm (p < 0.0001). There were no complications associated with this device. CONCLUSIONS: The 'Length-offset Lever' is a useful intraoperative tool to restore anatomic femoral offset and height of femoral head. PMID- 25037494 TI - [Interdisciplinary neuro-oncology: part 2: systemic therapy of primary brain tumors]. AB - By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function has become dramatically more extensive. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6 methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors. PMID- 25037493 TI - [Interdisciplinary neuro-oncology: part 1: diagnostics and operative therapy of primary brain tumors]. AB - By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function is increasingly feasible. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors. PMID- 25037495 TI - Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis. AB - INTRODUCTION: Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality. MATERIALS AND METHODS: We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software). RESULTS: Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, -0.6%; 95% confidence interval -1.0% to -0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis. CONCLUSIONS: The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients. PMID- 25037497 TI - Defining time in therapeutic range for busy clinicians: frequency of dose changes is a good surrogate marker to identify patients with suboptimal anticoagulation with warfarin. AB - INTRODUCTION: Patients on warfarin with sub-optimal time-in-therapeutic-range (TTR) are more likely to have adverse events. Target-specific oral anticoagulants (TSOACs) are approved and can be used as an alternative to warfarin for a number of indications. Further, the efficacy and safety profiles of the TSOACs compared to warfarin are more favourable when the TTR is <=65% for certain indications. OBJECTIVE: We aimed to determine simple, sensitive and specific diagnostic tools to identify TTR <= 65% during the initial three months of warfarin therapy. METHODS: A cross-sectional study including patients newly initiated on warfarin without any interruption for three months was conducted. TTR was calculated using the Rosendaal method. Patients were stratified by TTR (<= 65% or >65%). Number of INR measurements, dose changes and INR measurements of <= 1.7 or >= 4.0 were evaluated as potential diagnostic tools to identify TTR <= 65%. RESULTS: 670 patients were included. The most common indication for anticoagulation was venous thromboembolism. The mean TTR in the first three months was 68 +/- 21% (Range: 10 to 100%). Three or more dose changes identified TTR <= 65% and demonstrated a sensitivity and specificity of 90% (95%CI 86 to 93%) and 56% (95%CI 51 to 61%), respectively. Three or more INR measurements of <= 1.7 during the initial three months of anticoagulation showed a sensitivity and specificity of 37% (95%CI 32 to 43%) and 98% (95%CI 96 to 99%), respectively. CONCLUSION: Three or more dose changes and three or more INR measurements of <= 1.7 could identify patients with a TTR <= 65% in the first three months of warfarin therapy. PMID- 25037496 TI - Are myocardial infarction and venous thromboembolism associated? Population-based case-control and cohort studies. AB - INTRODUCTION: Because the association of myocardial infarction (MI) and venous thromboembolism (VTE) is uncertain, we tested MI as a VTE risk factor and VTE as a predictor of MI. MATERIALS AND METHODS: Using Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents with objectively diagnosed incident VTE over the 13-year period, 1988-2000 (n=1311), one to two resident controls per VTE case (n=1511), and all residents with incident MI over the 31-year period, 1979-2010. For VTE cases and controls, we reviewed their complete medical records in the community for VTE and MI risk factors. Using conditional logistic regression we tested MI as a potential VTE risk factor, both unadjusted and after adjusting for VTE risk factors. We also followed VTE cases and controls without prior MI forward in time for incident MI through 12/31/2010, and using Cox proportional hazards modeling, tested VTE as a predictor of MI, both unadjusted and after adjusting for MI risk factors. RESULTS: The number (%) of MI prior to VTE among cases and controls were 75 (5.7) and 51 (3.4), respectively, and the number (%) of MI after VTE among cases and controls were 58 (4.4) and 77 (5.1), respectively. In univariate analyses, MI was significantly associated with VTE but not after adjusting for VTE risk factors. In both univariate and multivariate analyses, VTE (overall or idiopathic) was not a predictor of MI. CONCLUSIONS: MI is not an independent risk factor for VTE, and VTE is not a predictor of MI. PMID- 25037498 TI - An in vitro study of the impact of 4mT static magnetic field to modify the differentiation rate of rat bone marrow stem cells into primordial germ cells. AB - This investigation was performed to evaluate the differentiation capacity and alteration in genes expression patterns during in vitro differentiation of bone marrow stem cells into primordial germ cells using static magnetic field (4mT) and BMP-4 (25ng/ml). The rate of differentiation was investigated using the Real Time-PCR method for tracing expression of differentiation markers (Oct-4, Nanog, C-Myc, Fragilis, Mvh and Stella). Then, immunocytochemical reaction was carried out for detection of marker proteins (Oct4 and Mvh). Increasing of the exposure time of the 4mT SMF (24 and 48h) and treatment time with 25ng/ml BMP4 (48 and 96h) indicated a marked decrease in expression of pluripotency genes (Oct-4, Nanog and C-Myc) and Oct4 protein and increase in primordial germ cell-specific genes (Fragilis, Mvh and Stella) and Mvh protein compared with the control group. Final results showed that in a synergistic manner, the combination of SMF with BMP4 exaggerates the differentiation potential of BMSCs to PGCs by activating the MAPK pathway and altering the Ca(2+) concentration. PMID- 25037499 TI - The super thin external pudendal artery (STEPA) flap. AB - BACKGROUND: The need for improved microsurgical reconstructive techniques is ongoing given the "ideal" free flap still does not exist. When reconstruction requires a thin flap, options have remained limited and flaps with minimal donor site morbidity that do not require secondary de-bulking have been elusive thus far. The importance of a thin and supple flap cannot be understated when dealing with challenging cases such as the dorsum of the hand or foot. This also applies to other areas such as the head and neck and over the large joints of the knee and elbow. The authors propose a previously un-described free tissue transfer based on the external pudendal artery that fulfills many of the aforementioned goals. An anatomical cadaveric study has been performed describing the super thin external pudendal artery (STEPA) flap. METHODS: Six fresh cadavers were used in the raising of eight hemiscrotal flaps and two bipedicled scrotal flaps based on the external pudendal vessels. 2 hemipelvises underwent cannulation of the external pudendal artery followed by injection of a barium sulphate/gelatin mixture and three-dimensional computed tomographic angiography to evaluate vascular anatomy. Colored-latex was injected into two raised hemiscrotal flaps. Measurements were made on the cadaveric dissections and on a computed tomography workstation. RESULTS: The average external diameter of the external pudendal artery measured 2.81 mm at its origin from the femoral artery, the vein 4.44 mm. The mean pedicle length measured 11 cm (range, 10-12 cm). The mean thickness of the flap measured 1.1 mm. CONCLUSIONS: A new free flap, the STEPA flap, has been described that is the thinnest myocutaneous free flap with over 80% of the thickness of the flap less than 1.1 mm. It has been demonstrated to have reliable anatomy with more than adequate vessel caliber. It has a large surface area and a generous pedicle length for free tissue transfer. Donor site morbidity is favorable. It is accepted that there may be cosmetic issues regarding flap pigmentation and a variable degree of hair in patients where the reconstruction is visible. We would contend that there exist many successful techniques which address pigmentation and depilation, and that this trade-off is acceptable given the functionality and characteristics of this uniquely thin flap. It has the potential to be used in many clinical scenarios where thin supple reconstruction is a high priority. PMID- 25037500 TI - The structure of the basement membrane zone differs between keloids, hypertrophic scars and normal skin: a possible background to an impaired function. AB - Scar tissues were collected from patients with keloids, hypertrophic scars and mature scars. Normal skin was obtained from healthy individuals. Clinical attributes were used to select which tissue to obtain but the distribution of the specific hyaluronan (HA) staining was then used for the definite classification of the various scar types. Light microscopic and ultrastructural analyses were performed with an HA-binding probe, antibodies for collagen I and III and staining for mast cells. Ultrastructural studies of keloids revealed an altered collagen structure in the dermal layers, with an abundance of collagen fibres of similar diameter in both the reticular dermis (RD) and the papillary dermis (PD) compared to normal skin. Furthermore, the keloids displayed epidermal changes, which involved the basement membrane (BM), with fewer hemidesmosomes and an altered shape of desmosomes in the entire enlarged spinous layer. The frequency of mast cells found in keloids was lower than in other scar tissues and normal skin. These alterations in epidermis could influence the hydrodynamic and cell regulatory properties of the wounded skin with impaired function and insufficient regulative capacity to hinder the ever-growing collagen tissue that is characteristic for keloids. PMID- 25037501 TI - Ultrasonic evidence of vascular augmentation of reverse sural artery flap after the vascular delay procedure. PMID- 25037502 TI - The use of intraoperative indocyanine green dye to aid excision of a lymphatic lesion. PMID- 25037504 TI - Assessment of resident operative performance using a real-time mobile Web system: preparing for the milestone age. AB - OBJECTIVE: To satisfy trainees' operative competency requirements while improving feedback validity and timeliness using a mobile Web-based platform. DESIGN: The Southern Illinois University Operative Performance Rating Scale (OPRS) was embedded into a website formatted for mobile devices. From March 2013 to February 2014, faculty members were instructed to complete the OPRS form while providing verbal feedback to the operating resident at the conclusion of each procedure. Submitted data were compiled automatically within a secure Web-based spreadsheet. Conventional end-of-rotation performance (CERP) evaluations filed 2006 to 2013 and OPRS performance scores were compared by year of training using serial and independent-samples t tests. The mean CERP scores and OPRS overall resident operative performance scores were directly compared using a linear regression model. OPRS mobile site analytics were reviewed using a Web-based reporting program. SETTING: Large university-based general surgery residency program. PARTICIPANTS: General Surgery faculty used the mobile Web OPRS system to rate resident performance. Residents and the program director reviewed evaluations semiannually. RESULTS: Over the study period, 18 faculty members and 37 residents logged 176 operations using the mobile OPRS system. There were 334 total OPRS website visits. Median time to complete an evaluation was 45 minutes from the end of the operation, and faculty spent an average of 134 seconds on the site to enter 1 assessment. In the 38,506 CERP evaluations reviewed, mean performance scores showed a positive linear trend of 2% change per year of training (p = 0.001). OPRS overall resident operative performance scores showed a significant linear (p = 0.001), quadratic (p = 0.001), and cubic (p = 0.003) trend of change per year of clinical training, reflecting the resident operative experience in our training program. Differences between postgraduate year-1 and postgraduate year-5 overall performance scores were greater with the OPRS (mean = 0.96, CI: 0.55-1.38) than with CERP measures (mean = 0.37, CI: 0.34-0.41). Additionally, there were consistent increases in each of the OPRS subcategories. CONCLUSIONS: In contrast to CERPs, the OPRS fully satisfies the Accreditation Council for Graduate Medical Education and American Board of Surgery operative assessment requirements. The mobile Web platform provides a convenient interface, broad accessibility, automatic data compilation, and compatibility with common database and statistical software. Our mobile OPRS system encourages candid feedback dialog and generates a comprehensive review of individual and group-wide operative proficiency in real time. PMID- 25037503 TI - The pentose phosphate pathway and cancer. AB - The pentose phosphate pathway (PPP), which branches from glycolysis at the first committed step of glucose metabolism, is required for the synthesis of ribonucleotides and is a major source of NADPH. NADPH is required for and consumed during fatty acid synthesis and the scavenging of reactive oxygen species (ROS). Therefore, the PPP plays a pivotal role in helping glycolytic cancer cells to meet their anabolic demands and combat oxidative stress. Recently, several neoplastic lesions were shown to have evolved to facilitate the flux of glucose into the PPP. This review summarizes the fundamental functions of the PPP, its regulation in cancer cells, and its importance in cancer cell metabolism and survival. PMID- 25037505 TI - Service vs education: situational and perceptional differences in surgery residency. AB - OBJECTIVE: This study determined whether situational or perceptional differences exist when trying to define what constitutes "service" and "education" in surgery residency in relation to the Accreditation Council of Graduate Medical Education (ACGME) survey. DESIGN: An institutional review board-approved, single institute, cross-sectional study was conducted through a survey. Participants were asked to rate common resident tasks. Participants were also asked general questions regarding "service" and "education." SETTING: Wright State University surgery program, Dayton, OH. PARTICIPANTS: The study included 69 participants, which included medical students (19), residents (26), nurses/advanced practitioners (14), and attending surgeons (10). RESULTS: A significantly high number of attending surgeons reported that writing a history and physical examination is educational compared with residents and students. Similar results were found regarding talking with patients/families. Drawing blood and starting peripheral intravenous access were universally rated as service tasks. For laparoscopic cholecystectomy, when the resident had done one previously, it was universally thought educational. When the resident had done more, most attending surgeons thought the task educational, but residents and students thought it much less educational. When analyzing only residents, in talking with families, most interns rated this as service, whereas postgraduate years 2 and 3 reported it as more educational and postgraduate years 4 and 5 ranked it equally as service and educational. Similar results were seen in answering nursing phone calls and writing admission orders. Residents (88%) and attending surgeons (90%) agreed that service is part of residency training. Only 40% of residents, however, stated they know what the term "service" means in regard to the ACGME survey. Overall, 80% of attending surgeons and 44% of residents agree that "service" has not been well defined by the ACGME. CONCLUSIONS: Situational and perceptional differences do exist regarding "service" and "education" in our program, and most participants are unclear about the terms. As the definitions are situational and change with the person queried, then should this be the ACGME standard to assess programs and issue citations? PMID- 25037506 TI - A patient with minimal change disease and acute focal tubulointerstitial nephritis due to traditional medicine: a case report and small literature review. AB - Gongjin-dan (GJD) is a traditional formula that is widely used in Korea and China, and it has been used from 1345 AD in China to improve the circulation between the kidneys and the heart and to prevent all diseases. However, its adverse effects have not yet been reported. We present a patient with minimal change disease and focal tubulointerstitial nephritis associated with GJD. A 72 year-old man visited the clinic for generalized edema 20 days after starting GJD. His serum albumin level was low and nephrotic-range proteinuria was detected. A kidney biopsy showed minimal change disease and acute tubulointerstitial nephritis. After stopping GJD, a spontaneous complete remission was achieved. We discuss the possible pathogenesis of GJD-induced minimal change disease and review the adverse effects of GJD's ingredients and traditional Chinese medicines that can induce proteinuria. We report a new adverse effect of GJD, which might induce increased IL-13 production and an allergic response, leading to minimal change disease and focal tubulointerstitial nephritis. PMID- 25037507 TI - Acute calcium deposits in the hand and wrist. PMID- 25037508 TI - Radiographic prevalence of scaphotrapeziotrapezoid osteoarthrosis. AB - PURPOSE: To define the radiographic prevalence of scaphotrapeziotrapezoid (STT) osteoarthrosis (OA) in a cohort of patients presenting to a hand surgeon for any complaint. The secondary purpose was to evaluate coexisting thumb carpometacarpal (CMC) joint OA. METHODS: Seven hundred radiographs were evaluated for presence and degree of STT and thumb CMC arthritic changes in consecutive patients presenting to a hand clinic for any chief complaint over the study period. RESULTS: OA was noted at the STT joint in 111 of the 700 (16%) radiographs reviewed. Increased age, female sex, presence of a scapholunate (SL) ligament gap greater than 3 mm, and presence of radiographic thumb CMC joint OA were all significantly correlated with presence of STT joint OA. However, logistical regression analysis demonstrated that only increasing age, presence of an SL ligament gap greater than 3 mm, and presence of thumb CMC joint OA were strong predictors of STT joint OA. CONCLUSIONS: STT joint OA is a common finding on hand radiographs of patients presenting to a hand clinic. Its prevalence increases with age, the presence of an SL ligament gap greater than 3 mm, and with the presence of CMC joint OA. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 25037509 TI - Incarcerated medial epicondyle fracture following pediatric elbow dislocation: 11 cases. AB - PURPOSE: To describe outcomes after surgical management of pediatric elbow dislocation with incarceration of the medial epicondyle. METHODS: We conducted a retrospective case review of 11 consecutive children and adolescents with an incarcerated medial epicondyle fracture after elbow dislocation. All patients underwent open reduction internal fixation using a similar technique. We characterized outcomes at final follow-up. RESULTS: Average follow-up was 14 months (range, 4-56 mo). All patients had clinical and radiographic signs of healing at final follow-up. There was no radiographic evidence of loss of reduction at intervals or at final follow-up. There were no cases of residual deformity or valgus instability. Average final arc of elbow motion was 4 degrees to 140 degrees . All patients had forearm rotation from 90 degrees supination to 90 degrees pronation. Average Mayo elbow score was 99.5. Four of 11 patients had ulnar nerve symptoms postoperatively and 1 required a second operation for ulnar nerve symptoms. In addition, 1 required a second operation for flexion contracture release with excision of heterotopic ossification. Three patients had ulnar nerve symptoms at final follow-up. Two of these had mild paresthesia only and 1 had both mild paresthesia and weakness. CONCLUSIONS: Our results suggest that open reduction internal fixation of incarcerated medial epicondyle fractures after elbow dislocation leads to satisfactory motion and function; however, the injury carries a high risk for complications, particularly ulnar neuropathy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25037510 TI - Robot assisted laparoscopic pyeloplasty in obese and non-obese patients. AB - OBJECTIVE: We assessed whether increased BMI has a negative impact in children undergoing robot assisted laparoscopic pyeloplasty (RALP). PATIENTS AND METHODS: Records of patients who underwent RALP were retrospectively reviewed and separated into healthy weight, overweight, and obese cohorts based on age adjusted BMI percentile, and surgical and postsurgical outcomes were evaluated. RESULTS: Of the 103 patients, there were 79 healthy weight and 24 overweight, with 10 of the 24 considered obese (BMI<85th, >=85th, and >=95th percentile for age, respectively). Cohorts were similar in respect to age, sex, laterality and symptoms. Operative time (234 min, 241 min, p=0.642; 254 min, p=0.324), EBL (7.1 ml, 10.5 ml, p=0.293; 6.8 ml, p=0.906), length of stay (1.2d, 1.2d p=0.545; 1.1d p=0.550), and narcotic administration (0.25 mg/kg, 0.25 mg/kg, p=0.545; 0.13 mg/kg, p=0.430) were similar between healthy weight, overweight, and obese cohorts, respectively. Complication rates were similar in regard to minor and major complications. There was no difference in decreased hydronephrosis (92.2%, 89.6%, p=0.440; 88.9%, p=0.730). Four patients (3.4%) required a reoperative procedure (three healthy weight, one overweight; p=NS). CONCLUSIONS: Despite the potential difficulties with surgery in overweight patients, our data indicate that robot-assisted laparoscopic pyeloplasty can be performed as safely and effectively in overweight or obese children as in healthy weight children. PMID- 25037511 TI - Seminars in Perinatology. Cardiac disease in pregnancy. Introduction. PMID- 25037512 TI - Preconception considerations. AB - Heart disease complicates 1-2% of pregnancies, and in preparation for pregnancy, these women should receive comprehensive preconception counseling. Risks to the mother and potential risks to the offspring secondary to the type and severity of maternal cardiac disease, its inheritance pattern, required medical therapy, and palliative or corrective procedures that may be needed must be considered. Life expectancy and the ability to care for a child are somber issues that must be addressed when serious cardiac conditions exist. Pregnancy is still contraindicated in women with pulmonary hypertension, severe systemic ventricular dysfunction, dilated aortopathy, and severe left-sided obstructive lesions, but advances in medical and surgical management have resulted in an increasing number of patients with cardiac disorders who are interested in pursuing pregnancy. A multidisciplinary approach can best determine whether acceptable outcomes can be expected and what management strategies may improve the prognosis for women with heart disease and their offspring. PMID- 25037513 TI - Cardiac imaging and functional assessment in pregnancy. AB - There are multiple imaging modalities available for the assessment of pregnant women with known or suspected cardiac disease. Because of its safety and general availability, echocardiography is the preferred study of choice for the evaluation of ventricular function, valvular heart disease, congenital heart disease, evaluation of the aorta, and the estimation of cardiac hemodynamics in a pregnant patient. Cardiac MRI can be performed, especially for diseases of the aorta and complex congenital heart disease. Radiation exposure for the fetus and the mother will be discussed in the use of CT angiography, nuclear imaging, and left-heart catheterization including coronary angiography for specific indications in the pregnant woman. The use of exercise testing during pregnancy for functional assessment will be presented. PMID- 25037514 TI - Intrapartum obstetric management. AB - Maternal cardiac disease complicates approximately 1-2% of all pregnancies in the United States. Just as during the antepartum period, in the immediate period surrounding delivery, obstetrical patients with cardiac disease (both congenital and acquired) will have specialized needs, tailored to the patient and her specific lesion. While the basic principles of labor and delivery management protocols are relevant to this subgroup of patients, there are certain areas in which adjustments must be made. These include endocarditis prophylaxis, recent anticoagulation, fluid management, and the need for increased maternal cardiac monitoring. Awareness of the challenges of the intrapartum period combined with a multi-disciplinary approach from anesthesia, cardiology, and the obstetrical provider will optimize the patient for a safe delivery. PMID- 25037515 TI - The role of the anesthesiologist in the care of the parturient with cardiac disease. AB - Women with cardiac disease constitute a growing percentage of parturients, and in many series cardiac disease is the leading cause of maternal mortality. Involvement of anesthesiologists in the planning for and management of delivery in these women can improve the experience and potentially the outcome of these patients. Communication with the anesthesiology team about particularly complex cases is essential to avoid both medical complications and inter-disciplinary disagreements. The specific role and contributions of the anesthesiology team will depend significantly on the nature of the institution and the organization of the (obstetric) anesthesiology service. PMID- 25037516 TI - Adult congenital heart disease and pregnancy. AB - Adults with congenital heart disease now form the largest group of women with cardiac disease becoming pregnant in the developed world. This is both a mark of impressive steps forward in the management of congenital heart disease and also a challenge to the medical community to develop systems of care that will best serve these women and their babies. Each woman with congenital heart disease presents a unique pattern of challenges for the cardiologist, obstetrician, and anesthesiologist, and their care should be tailored to deal with their individual circumstances. As this population of patients continues to grow, we must continue to learn and improve our diagnostic tools and management strategies to refine their care. This review intends to focus on reviewing the outcomes in this set of patients and also an approach to the assessment and the management of these patients, primarily for an audience of obstetricians, pediatricians, and anesthesiologists. PMID- 25037517 TI - Valve disease in pregnancy. AB - Maternal cardiac disease is a major cause of non-obstetric morbidity and accounts for 10-25% of maternal mortality. Valvular heart disease may result from congenital abnormalities or acquired lesions, some of which may involve more than one valve. Maternal and fetal risks in pregnant patients with valve disease vary according to the type and severity of the valve lesion along with resulting abnormalities of functional capacity, left ventricular function, and pulmonary artery pressure. Certain high-risk conditions are considered contraindications to pregnancy, while others may be successfully managed with observation, medications, and, in refractory cases, surgical intervention. Communication between the patient's obstetrician, maternal-fetal medicine specialist, obstetrical anesthesiologist, and cardiologist is critical in managing a pregnancy with underlying maternal cardiac disease. The management of the various types of valve diseases in pregnancy will be reviewed here, along with a discussion of related complications including mechanical prosthetic valves and infective endocarditis. PMID- 25037518 TI - Cardiac arrhythmias in pregnancy. AB - As more women with repaired congenital heart disease survive to their reproductive years and many other women are delaying pregnancy until later in life, a rising concern is the risk of cardiac arrhythmias during pregnancy. Naturally occurring cardiovascular changes during pregnancy increase the likelihood that a recurrence of a previously experienced cardiac arrhythmia or a de novo arrhythmia will occur. Arrhythmias should be thoroughly investigated to determine if there is a reversible etiology, and risks/benefits of treatment options should be fully explored. We discuss the approach to working up and treating various arrhythmias during pregnancy with attention to fetal and maternal risks as well as treatment of fetal arrhythmias. Acute management in stable patients includes close monitoring and intravenous pharmacologic therapy, while DC cardioversion should be used to terminate arrhythmias in hemodynamically unstable patients. Long-term management may require continued oral antiarrhythmic therapy, with particular attention to fetal safety, to prevent complications associated with arrhythmias. PMID- 25037519 TI - Pulmonary arterial hypertension in pregnancy. AB - Pulmonary hypertension is a medical condition characterized by elevated pulmonary arterial pressure and secondary right heart failure. Pulmonary arterial hypertension is a subset of pulmonary hypertension, which is characterized by an underlying disorder of the pulmonary arterial vasculature. Pulmonary hypertension can also occur secondarily to structural cardiac disease, autoimmune disorders, and toxic exposures. Although pregnancies affected by pulmonary hypertension and pulmonary arterial hypertension are rare, the pathophysiology exacerbated by pregnancy confers both high maternal and fetal mortality and morbidity. In light of new treatment modalities and the use of a multidisciplinary approach to care, maternal outcomes may be improving. PMID- 25037520 TI - Aortopathy in pregnancy. AB - Up to half of all aortic dissections and ruptures in women younger than 40 years are associated with pregnancy. In pregnancy, women with aortic disease such as arteritis and aortitis are at significant risk of aneurysmal formation and dissection with potential for catastrophic outcomes. Pregnancy places predisposed women at an increased risk of dissection due to physiological and hormonal changes that occur, particularly those with connective tissue disorders, genetic syndromes, congenital heart disease, and other heritable and acquired conditions involving the aorta. Thus, preconception counseling and preparation are advised to determine which patients may cautiously pursue pregnancy, to optimize medical management prior to conception (antihypertensive medications and anticoagulants in the setting of mechanical valves), to identify women in whom aortic root repair should occur prior to pregnancy, and lastly, those in whom pregnancy is contraindicated. Additionally, discussion of the heritable nature of many aortic conditions and associated syndromes is indicated. Preconception and genetic counseling, management by a multidisciplinary team, along with close echocardiographic surveillance and medical management, are recommended if precursors of dissection are identified. PMID- 25037521 TI - Ischemic heart disease in pregnancy. AB - While ischemic heart disease in reproductive-age women is rare, cardiac disease is a leading cause of maternal mortality. In turn, coronary artery disease is one of the most common causes of maternal cardiac death. The incidence of coronary artery disease in pregnancy may be rising due to the increasing prevalence of comorbid risk factors. Diagnosis and clinical management of ischemic cardiac disease is largely similar in the pregnant and non-pregnant patient, and the majority of medications and diagnostic and interventional procedures are compatible with pregnancy with a few important exceptions. Care for ischemic cardiac disease in pregnancy may be suboptimal because: (1) diagnosis is delayed because many symptoms of ischemic cardiac disease are common in pregnancy, (2) a diagnostic workup is insufficiently thorough, and/or (3) consultants may be hesitant to perform diagnostic and interventional procedures in obstetric patients. Obstetric providers should be aware of the possibility of ischemic cardiac disease in pregnancy, particularly in patients with comorbid risk factors. If ischemic cardiac disease is suspected, a thorough workup should be performed. PMID- 25037522 TI - Cardiomyopathy in pregnancy. AB - Cardiomyopathy during pregnancy is uncommon but potentially catastrophic to maternal health, accounting for up to 11% of maternal deaths. Peripartum cardiomyopathy is diagnosed in women without a history of heart disease 1 month before delivery or within 5 months postpartum. About half of all women will have full myocardial recovery within 6 months of diagnosis, but complications such as severe heart failure or death are not rare. African-American women have higher rates of diagnosis and adverse events. Women with preexisting cardiomyopathy, such as dilated or hypertrophic cardiomyopathy, followed closely during pregnancy often tolerate pregnancy and delivery. Risk factors for adverse outcomes include functional status at baseline, severity of systolic dysfunction or outflow tract gradient, or history of prior cardiac event, such as arrhythmia or stroke. The level of brain natriuretic peptide (BNP) can be used to risk stratify women for adverse events. Pregnant women with cardiomyopathy should be followed closely by a multidisciplinary team comprised of nurses, obstetricians, neonatologists, cardiologists, anesthesiologists, and cardiac surgeons. PMID- 25037523 TI - Management of pregnancy in the post-cardiac transplant patient. AB - Over the past 10 years, heart transplantation survival has increased among transplant recipients. Because of improved outcomes in both congenital and adult transplant recipients, the number of male and female patients of childbearing age who desire pregnancy has also increased within this population. While there have been many successful pregnancies in post-cardiac transplant patients reported in the literature, long-term outcome data is limited. Decisions regarding the optimal timing and management of pregnancy in male and female post-cardiac transplant patients are challenging and should be coordinated by a multidisciplinary team of healthcare providers. Pregnant patients will need to be counseled and monitored carefully for complications including rejection, graft dysfunction, and infection. This review focuses on preconception counseling for both male and female cardiac transplant recipients. The maternal and fetal risks during pregnancy and the postpartum period, including risks to the fetus fathered by a male cardiac transplant recipient will be reviewed. It also provides a brief summary of our own transplant experience and recommendations for overall management of pregnancy in the post-cardiac transplant recipient. PMID- 25037524 TI - Impaired functional connectivity of brain reward circuitry in patients with schizophrenia and cannabis use disorder: Effects of cannabis and THC. AB - Cannabis use disorder (CUD) occurs in up to 42% of patients with schizophrenia and substantially worsens disease progression. The basis of CUD in schizophrenia is unclear and available treatments are rarely successful at limiting cannabis use. We have proposed that a dysregulated brain reward circuit (BRC) may underpin cannabis use in these patients. In the present pilot study, we used whole-brain seed-to-voxel resting state functional connectivity (rs-fc) to examine the BRC of patients with schizophrenia and CUD, and to explore the effects of smoked cannabis and orally administered delta-9-tetrahydrocannabinol (THC) on the BRC. 12 patients with schizophrenia and CUD and 12 control subjects each completed two fMRI resting scans, with patients administered either a 3.6% THC cannabis cigarette (n=6) or a 15 mg THC capsule (n=6) prior to their second scan. Results revealed significantly reduced connectivity at baseline in patients relative to controls, with most pronounced hypoconnectivity found between the nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex). Both cannabis and THC administration increased connectivity between these regions, in direct correlation with increases in plasma THC levels. This study is the first to investigate interregional connectivity of the BRC and the effects of cannabis and THC on this circuit in patients with schizophrenia and CUD. The findings from this pilot study support the use of rs-fc as a means of measuring the integrity of the BRC and the effects of pharmacologic agents acting on this circuit in patients with schizophrenia and CUD. PMID- 25037525 TI - Comparison of auditory and visual oddball fMRI in schizophrenia. AB - Individuals with schizophrenia often suffer from attentional deficits, both in focusing on task-relevant targets and in inhibiting responses to distractors. Schizophrenia also has a differential impact on attention depending on modality: auditory or visual. However, it remains unclear how abnormal activation of attentional circuitry differs between auditory and visual modalities, as these two modalities have not been directly compared in the same individuals with schizophrenia. We utilized event-related functional magnetic resonance imaging (fMRI) to compare patterns of brain activation during an auditory and visual oddball task in order to identify modality-specific attentional impairment. Healthy controls (n=22) and patients with schizophrenia (n=20) completed auditory and visual oddball tasks in separate sessions. For responses to targets, the auditory modality yielded greater activation than the visual modality (A-V) in auditory cortex, insula, and parietal operculum, but visual activation was greater than auditory (V-A) in visual cortex. For responses to novels, A-V differences were found in auditory cortex, insula, and supramarginal gyrus; and V A differences in the visual cortex, inferior temporal gyrus, and superior parietal lobule. Group differences in modality-specific activation were found only for novel stimuli; controls showed larger A-V differences than patients in prefrontal cortex and the putamen. Furthermore, for patients, greater severity of negative symptoms was associated with greater divergence of A-V novel activation in the visual cortex. Our results demonstrate that patients have more pronounced activation abnormalities in auditory compared to visual attention, and link modality specific abnormalities to negative symptom severity. PMID- 25037526 TI - Social trait judgment and affect recognition from static faces and video vignettes in schizophrenia. AB - Social impairment is a core feature of schizophrenia, present from the pre-morbid stage and predictive of outcome, but the etiology of this deficit remains poorly understood. Successful and adaptive social interactions depend on one's ability to make rapid and accurate judgments about others in real time. Our surprising ability to form accurate first impressions from brief exposures, known as "thin slices" of behavior has been studied very extensively in healthy participants. We sought to examine affect and social trait judgment from thin slices of static or video stimuli in order to investigate the ability of schizophrenic individuals to form reliable social impressions of others. 21 individuals with schizophrenia (SZ) and 20 matched healthy participants (HC) were asked to identify emotions and social traits for actors in standardized face stimuli as well as brief video clips. Sound was removed from videos to remove all verbal cues. Clinical symptoms in SZ and delusional ideation in both groups were measured. Results showed a general impairment in affect recognition for both types of stimuli in SZ. However, the two groups did not differ in the judgments of trustworthiness, approachability, attractiveness, and intelligence. Interestingly, in SZ, the severity of positive symptoms was correlated with higher ratings of attractiveness, trustworthiness, and approachability. Finally, increased delusional ideation in SZ was associated with a tendency to rate others as more trustworthy, while the opposite was true for HC. These findings suggest that complex social judgments in SZ are affected by symptomatology. PMID- 25037527 TI - An investigation of the factors that regulate muscarinic receptor expression in schizophrenia. AB - We previously identified a group of subjects with schizophrenia who, on average, have a 75% decrease in cholinergic receptor, muscarinic 1 (CHRM1) in Brodmann's area (BA) 9. To extend this finding, we determined i) if the decrease in CHRM1 was present in another functionally related CNS region (BA6), ii) whether the marked decrease in CHRM1 was accompanied by changes in levels of other CHRMs and iii) potential factors responsible for the decreased CHRM1 expression. We measured CHRM1 and CHRM3 using in situ radioligand binding with [(3)H]pirenzepine and [(3)H]4-DAMP respectively in BA6 from 20 subjects with schizophrenia who had low levels of CHRM1 in BA9 (SzLow[(3)H]PZP), 18 subjects with schizophrenia whose levels of CHRM1 were similar to controls (SzNormal[(3)H]PZP) and 20 control subjects. Levels of CHRM1, 3 and 4 mRNA were measured using qPCR and levels of the transcription factors, SP1 and SP3, were determined using Western blots. In BA6, the density of [(3)H]pirenzepine binding was decreased in subjects with SzLow[(3)H]PZP (p<0.001) compared to controls. The density of [(3)H]4-DAMP binding, levels of CHRM1, 3 and 4 mRNA and levels of SP1 and SP3 was not significantly different between the three groups. This study shows that the previously identified decrease in CHRM1 expression is not confined to the dorsolateral prefrontal cortex but is present in other cortical areas. The effect shows some specificity to CHRM1, with no change in levels of binding to CHRM3. Furthermore, this decrease in CHRM1 does not appear to be associated with low levels of CHRM1 mRNA or to simply be regulated by the transcription factors, SP1 and SP3, suggesting that other mechanisms are responsible for the decreased CHRM1 in these subjects. PMID- 25037528 TI - Reconstruction of multiple fingertip injuries with reverse flow homodigital flap. AB - AIM: Hand trauma may lead to multiple fingertip defects, causing functional restrictions. We evaluated the use of reverse-flow homodigital flap reconstruction of the distal phalanx and pulp defects associated with multiple finger injuries. METHODS: We retrospectively evaluated 11 male patients who presented at our emergency department (January 2011-March 2013) with multiple fingertip injuries and who were treated with a reverse-flow homodigital flap. Evaluations included age, sex, defect size, flap survival rate, complications, cold intolerance, two-point discrimination, range of motion (ROM), quick disabilities of the arm, shoulder, and hand (DASH) score, and return to work time. RESULTS: Completely, 22 reverse-flow homodigital flaps were applied to at least two fingertip injuries at the distal phalanx. Ten flaps survived postoperatively. The exception was partial flap loss on one finger. The mean follow-up was 14.2 months. At the final follow-up, the mean static two-point discrimination value was 10.3mm. Mean ROMs of interphalangeal joints were 65.31 degrees (distal) and 105.77 degrees (proximal). Donor sites were covered with full-thickness skin grafts from the wrist or antecubital area. There were no complications related to the donor site and no development of cold intolerance in any finger. The mean quick DASH score was 4.12. All patients returned to work in an average of 8.3 weeks. CONCLUSIONS: The reconstruction of multiple fingertip injuries with reverse-flow homodigital flaps is a safe, effective method that can be combined with other local finger flaps. These flaps can be applied to two consecutive fingers without reducing finger length or function. PMID- 25037529 TI - Statins, the renin-angiotensin-aldosterone system and hypertension - a tale of another beneficial effect of statins. AB - BACKGROUND: Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin-angiotensin aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy. METHOD: In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS. RESULT: Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone. CONCLUSION: Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance. PMID- 25037530 TI - An independent assessment of the 7 nomograms for predicting the probability of additional axillary nodal metastases after positive sentinel lymph node biopsy in a cohort of British patients with breast cancer. AB - INTRODUCTION: Axillary lymph node dissection (ALND) is currently the recommended procedure in patients with tumor-positive sentinel lymph node biopsy (SLNB). A significant proportion of patients with positive SLNs will not have any additional metastases in nonsentinel lymph nodes (NSLNs). Predictive nomograms could identify a subgroup of patients with low or high risk of further disease in whom completion ALND can be avoided or recommended. The aim of this study was to assess the accuracy of the currently available 7 nomograms in a cohort of British patients with breast cancer. PATIENTS AND METHODS: A total of 138 patients with positive SLNs who underwent completion ALND were identified. Data were then used to calculate the probability of further metastases in NSLNs predicted by the 7 nomograms that are currently in use: the MSKCC (Memorial Sloan Kettering Cancer Center), Cambridge, Turkish, Stanford, MDACC (University of Texas MD Anderson Cancer Center), Tenon, and MOU (Masarykuv onkologicky ustav, Masaryk Memorial Cancer Institute) models. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated for each nomogram. RESULTS: Of the 138 patients, 54 (41%) had additional metastases in NSLNs. AUC values for the MSKCC, Cambridge, Turkish, Stanford, MDACC, Tenon, and MOU models are 0.68, 0.68, 0.70, 0.69, 0.56, 0.63, and 0.74, respectively. CONCLUSION: The MOU nomogram was more predictive than the other nomograms, with a better AUC value and false-negative rate. None of the models were able to achieve AUC value >= 0.80 in a cohort of British patients with breast cancer. PMID- 25037531 TI - Antiplatelet therapy for secondary prevention of coronary artery disease. AB - The choice and duration of antiplatelet therapy for secondary prevention of coronary artery disease (CAD) is determined by the clinical context and treatment strategy. Oral antiplatelet agents for secondary prevention include the cyclo oxygenase-1 inhibitor aspirin, and the ADP dependent P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor. Aspirin constitutes the cornerstone in secondary prevention of CAD and is complemented by clopidogrel in patients with stable CAD undergoing percutaneous coronary intervention. Among patients with acute coronary syndrome, prasugrel and ticagrelor improve net clinical outcome by reducing ischaemic adverse events at the expense of an increased risk of bleeding as compared with clopidogrel. Prasugrel appears particularly effective among patients with ST elevation myocardial infarction to reduce the risk of stent thrombosis compared with clopidogrel, and offered a greater net clinical benefit among patients with diabetes compared with patients without diabetes. Ticagrelor is associated with reduced mortality without increasing the rate of coronary artery bypass graft (CABG)-related bleeding as compared with clopidogrel. Dual antiplatelet therapy should be continued for a minimum of 1 year among patients with acute coronary syndrome irrespective of stent type; among patients with stable CAD treated with new generation drug-eluting stents, available data suggest no benefit to prolong antiplatelet treatment beyond 6 months. PMID- 25037532 TI - Evaluation in a clinical setting of the performances of a new rapid confirmatory assay for HIV1/2 serodiagnosis. AB - BACKGROUND AND OBJECTIVES: The performances of the new Geenius rapid confirmatory test (Bio-Rad) were evaluated with emphasis towards identifying acute infection (AHI) and discriminating HIV-1/2 in a clinical setting STUDY DESIGN: Serum samples from individuals attending the L. Spallanzani Institute in Rome, Italy, for HIV diagnosis (one year retrospective collection), repeatedly reactive at 4th generation HIV-1/2 screening assays, confirmed with HIV-1 and HIV-2 Western blot (New LAV I and II Bio-Rad), were retested with Geenius. RESULTS: Of 6,200 samples, 406 resulted repeatedly reactive at screening, including samples from clinically confirmed AHI. New LAV I identified 378 HIV-1-positive samples. Of these, Geenius found 377 HIV-1-positive and one unclassified HIV-positive. New LAV I classified as indeterminate 18 samples, including 14 from AHI. Among these 14, Geenius results were: 12 positive, 1 indeterminate and 1 negative. Of the remaining, 2 resulted Geenius negative (false-positive screening results) and 2 HIV-2. Ten samples were New LAV I-negative (5 AHI). Geenius results were: 1 (AHI) positive and 9 negative. Geenius detected 110 additional positive samples with no p31 reactivity with respect to New LAV I, with an almost similar prevalence of low avidity samples. Geenius confirmed 3 out of 4 HIV-2 infections identified by New LAV II (one coinfected with HIV-1), while rated as HIV-1 the remaining sample, classified as coinfection by New LAV I and II. CONCLUSIONS: Geenius allows fast, sensitive and accurate confirmation of HIV serodiagnosis, including AHI and HIV-2 infections. The high sensitivity, in particular towards AHI, could avoid additional sampling and molecular tests. PMID- 25037533 TI - Pooled nucleic acid testing increases the diagnostic yield of acute HIV infections in a high-risk population compared to 3rd and 4th generation HIV enzyme immunoassays. AB - OBJECTIVES: We compared a 3rd generation (gen) and two 4th gen HIV enzyme immunoassays (EIA) to pooled nucleic acid testing (PNAT) for the identification of pre- and early seroconversion acute HIV infection (AHI). STUDY DESIGN: 9550 specimens from males >18 year from clinics attended by men who have sex with men were tested by Siemens ADVIA Centaur((r)) HIV 1/O/2 (3rd gen) and HIV Combo (4th gen), as well as by Abbott ARCHITECT((r)) HIV Ag/Ab Combo (4th gen). Third gen non-reactive specimens were also tested by Roche COBAS((r)) Ampliprep/COBAS(r) TaqMan HIV-1 Test v.2 in pools of 24 samples. Sensitivity and specificity of the three EIAs for AHI detection were compared. RESULTS: 7348 persons contributed 9435 specimens and had no evidence of HIV infection, 79 (94 specimens) had established HIV infection, 6 (9 specimens) had pre-seroconversion AHI and 9 (12 specimens) had early seroconversion AHI. Pre-seroconversion AHI cases were not detected by 3rd gen EIA, whereas 2/6 (33.3%) were detected by Siemens 4th gen, 4/6 (66.7%) by Abbott 4th gen and 6/6 (100%) by PNAT. All three EIAs and PNAT detected all individuals with early seroconversion AHI. Overall sensitivity/specificity for the EIAs relative to WB or NAT resolved infection status was 93.6%/99.9% for Siemens 3rd gen, 95.7%/99.7% for Siemens 4th gen and 97.9%/99.2% for Abbott 4th gen. CONCLUSIONS: While both 4th gen EIAs demonstrated improved sensitivity for AHI compared to 3rd gen EIA, PNAT identified more AHI cases than either 4th gen assay. PNAT is likely to remain a useful strategy to identify AHI in high-risk populations. PMID- 25037534 TI - The clinical utility of cervical range of motion in diagnosis, prognosis, and evaluating the effects of manipulation: a systematic review. AB - BACKGROUND: Clinicians commonly assess cervical range of motion (ROM), but it has rarely been critically evaluated for its ability to contribute to patient diagnosis or prognosis, or whether it is affected by mobilisation/manipulation. OBJECTIVES: This review summarises the methods used to measure cervical ROM in research involving patients with cervical spine disorders, reviews the evidence for using cervical ROM in patient diagnosis, prognosis, and evaluation of the effects of mobilisation/manipulation on cervical ROM. DATA SOURCES AND STUDY SELECTION: A systematic search of MEDLINE, EMBASE, CINAHL, AMED and ICL databases was conducted, addressing one of four constructs related to cervical ROM: measurement, diagnosis, prognosis, and the effects of mobilisation/manipulation on cervical ROM. STUDY APPRAISAL AND SYNTHESIS: Two independent raters appraised methodological quality using the QUADAS-2 tool for diagnostic studies, the QUIPS tool for prognostic studies and the PEDro scale for interventional studies. Heterogeneity of studies prevented meta-analysis. RESULTS: Thirty-six studies met the criteria and findings showed there is limited evidence for the diagnostic value of cervical ROM in cervicogenic headache, cervical radiculopathy and cervical spine injury. There is conflicting evidence for the prognostic value of cervical ROM, though restricted ROM appears associated with negative outcomes while greater ROM is associated with positive outcomes. There is conflicting evidence as to whether cervical ROM increases or decreases following mobilisation/manipulation. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: Cervical ROM has value as one component of assessment, but clinicians should be cautious about making clinical judgments primarily on the basis of cervical ROM. FUNDING: This collaboration was supported by an internal grant from the Faculty of Health, The University of Newcastle. PMID- 25037535 TI - Australian physiotherapists' priorities for the development of clinical prediction rules for low back pain: a qualitative study. AB - OBJECTIVE: To identify the types of clinical prediction rules (CPRs) for low back pain (LBP) that Australian physiotherapists wish to see developed and the characteristics of LBP CPRs that physiotherapists believe are important. DESIGN: Qualitative study using semi-structured focus groups. SETTING: Metropolitan and regional areas of New South Wales, Australia. PARTICIPANTS: Twenty-six physiotherapists who manage patients with LBP (77% male, 81% private practice). RESULTS: Participants welcomed the development of prognostic forms of LBP CPRs. Tools that assist in identifying serious spinal pathology, likely responders to interventions, patients who are likely to experience an adverse outcome, and patients not requiring physiotherapy management were also considered useful. Participants thought that LBP CPRs should be uncomplicated, easy to remember, easy to apply, accurate and precise, and well-supported by research evidence. They should not contain an excessive number of variables, use complicated statistics, or contain variables that have no clear logical relationship to the dependent outcome. It was considered by participants that LBP CPRs need to be compatible with traditional clinical reasoning and decision-making processes, and sufficiently inclusive of a broad range of management approaches and common clinical assessment techniques. CONCLUSION: There were several identified areas of perceived need for LBP CPR development and a range of characteristics such tools need to encompass to be considered clinically meaningful and useful by physiotherapists in this study. Targeting and incorporating the needs and preferences of physiotherapists is likely to result in the development of tools for LBP with the greatest potential to positively impact clinical practice. PMID- 25037536 TI - Rethinking percutaneous paravalvular leak closure: where do we go from here? PMID- 25037537 TI - The transitive property across randomized controlled trials: if B is better than A, and C is better than B, will C be better than A? PMID- 25037538 TI - Current indications for percutaneous closure of patent foramen ovale. PMID- 25037539 TI - Paravalvular leak closure with the Amplatzer Vascular Plug III device: immediate and short-term results. AB - INTRODUCTION AND OBJECTIVES: Percutaneous paravalvular leak closure is a complex procedure with varying success rates; the lack of closure devices specifically designed for this purpose has hampered this technique. The characteristics of the Amplatzer Vascular Plug III appear to be well suited for paravalvular leak closures; however, the available data are limited to case reports or small series of patients. The aim of this study was to analyze the feasibility and efficacy of paravalvular leak with this device. METHODS: The immediate and 90-day safety and efficacy of mitral and aortic paravalvular leak closures performed with this device at our hospital were analyzed. RESULTS: Percutaneous repair of 34 paravalvular leaks (27 mitral, 7 aortic) was attempted in 33 patients. The device was successfully implanted in 93.9% (in 2 patients, a second planned procedure was needed), and successful closure (defined as regurgitation reduction >= 1 grade) was achieved in 90.9% of patients. Complications included emergency surgery due to disc interference (n=1) and blood transfusion (n=3). There were no reports of procedure-related death, myocardial infarction, or stroke. At 90 days, survival was 100%, and 90.3% of patients showed significant clinical improvement; 4 patients developed vascular complications (pseudoaneurysm). CONCLUSIONS: Mitral and aortic paravalvular leak closure with the Amplatzer Vascular Plug III is feasible and safe, with high clinical and echocardiographic success rates. PMID- 25037540 TI - Immediate and mid-term clinical course after percutaneous closure of paravalvular leakage. AB - INTRODUCTION AND OBJECTIVES: Percutaneous closure of paravalvular leakage is an alternative to surgery in high-risk patients, but its use has been limited by a lack of specific devices. More appropriate devices-like the Amplatzer Vascular Plug III-have recently been developed, but information about their efficacy and safety is still scarce. The objective of the present study was to assess the mid term results of paravalvular leakage closure with this device. METHODS: We analyzed the clinical and echocardiographic course both in-hospital and mid-term (13 [9] months) in a series of 20 consecutive patients (age, 68 years; logistic EuroSCORE, 29) with paravalvular leakage and attempted percutaneous closure. RESULTS: Closure was attempted for 23 leaks (17 mitral and 6 aortic) during 22 procedures in 20 patients. Implantation was successful in 87% of the leaks and the procedure was successful in 83%-with success being defined as a reduction in regurgitation of >= 1 degree. Survival at 1 year was 64.7% and survival free of the composite event of death/surgery was 58.8%. The degree of residual regurgitation was not associated with mortality but was associated with functional status. Survivors showed significant improvement in functional class. CONCLUSIONS: Percutaneous closure of leakage with the Amplatzer Vascular Plug III is safe and efficient in the mid-term. However, mortality among high-risk patients is high independently of the degree of residual regurgitation, indicating that these procedures are performed when heart disease has reached an advanced stage. PMID- 25037541 TI - Metabolic and inflammatory profiles of biomarkers in obesity, metabolic syndrome, and diabetes in a Mediterranean population. DARIOS Inflammatory study. AB - INTRODUCTION AND OBJECTIVES: There is a paucity of data regarding the differences in the biomarker profiles of patients with obesity, metabolic syndrome, and diabetes mellitus as compared to a healthy, normal weight population. We aimed to study the biomarker profile of the metabolic risk continuum defined by the transition from normal weight to obesity, metabolic syndrome, and diabetes mellitus. METHODS: We performed a pooled analysis of data from 7 cross-sectional Spanish population-based surveys. An extensive panel comprising 20 biomarkers related to carbohydrate metabolism, lipids, inflammation, coagulation, oxidation, hemodynamics, and myocardial damage was analyzed. We employed age- and sex adjusted multinomial logistic regression models for the identification of those biomarkers associated with the metabolic risk continuum phenotypes: obesity, metabolic syndrome, and diabetes mellitus. RESULTS: A total of 2851 subjects were included for analyses. The mean age was 57.4 (8.8) years, 1269 were men (44.5%), and 464 participants were obese, 443 had metabolic syndrome, 473 had diabetes mellitus, and 1471 had a normal weight (healthy individuals). High-sensitivity C reactive protein, apolipoprotein B100, leptin, and insulin were positively associated with at least one of the phenotypes of interest. Apolipoprotein A1 and adiponectin were negatively associated. CONCLUSIONS: There are differences between the population with normal weight and that having metabolic syndrome or diabetes with respect to certain biomarkers related to the metabolic, inflammatory, and lipid profiles. The results of this study support the relevance of these mechanisms in the metabolic risk continuum. When metabolic syndrome and diabetes mellitus are compared, these differences are less marked. PMID- 25037542 TI - Uric acid and gamma-glutamyl transferase activity are associated with left ventricular remodeling indices in patients with chronic heart failure. AB - INTRODUCTION AND OBJECTIVES: Uric acid and gamma-glutamyl transferase are prognostic indicators in chronic heart failure. Nevertheless, the mechanism underlying the association between uric acid, gamma-glutamyl transferase, and chronic heart failure progression and prognosis remains largely unknown. METHODS: The association of uric acid and gamma-glutamyl transferase with flow-mediated dilation and echocardiographic indices of cardiac remodeling was addressed in 120 patients with chronic ischemic heart failure. To determine the independent contribution of uric acid and gamma-glutamyl transferase to the flow-mediated dilation and echocardiographic indices of remodeling, a series of multiple linear regression models, based on traditional and nontraditional risk factors impacting upon these parameters, were constructed. RESULTS: Uric acid, but not gamma glutamyl transferase, was an independent predictor of flow-mediated dilation. Uric acid was associated with all the echocardiographic indices of left ventricular dysfunction tested in 3 multiple-regression models. Uric acid correlated with left ventricular end-systolic diameter, left ventricular end diastolic diameter, left ventricular end-systolic volume, and left ventricular end-diastolic volume (r = 0.337; r = 0.340; r = 0.321; r = 0.294; P = .001, respectively). Gamma-glutamyl transferase was an independent predictor of left ventricular end-systolic volume and left ventricular end-diastolic volume, after adjustment for all variables. Gamma-glutamyl transferase correlated with left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume, and left ventricular end-diastolic volume (r = 0.238, P = .009; r = 0.219, P = .016; r = 0.359, P < .001; r = 0.369, P = .001, respectively). CONCLUSIONS: Serum uric acid and gamma-glutamyl transferase levels are associated with left ventricular remodeling in patients with chronic ischemic heart failure. PMID- 25037543 TI - Health care and nonhealth care costs in the treatment of patients with symptomatic chronic heart failure in Spain. AB - INTRODUCTION AND OBJECTIVES: Chronic heart failure is associated with high mortality and utilization of health care and social resources. The objective of this study was to quantify the use of health care and nonhealth care resources and identify variables that help to explain variability in their costs in Spain. METHODS: This prospective, multicenter, observational study with a 12-month follow-up period included 374 patients with symptomatic heart failure recruited from specialized cardiology clinics. Information was collected on the socioeconomic characteristics of patients and caregivers, health status, health care resources, and professional and nonprofessional caregiving. The monetary cost of the resources used in caring for the health of these patients was evaluated, differentiating among functional classes. RESULTS: The estimated total cost for the 1-year follow-up ranged from ? 12,995 to ? 18,220, depending on the scenario chosen (base year, 2010). The largest cost item was informal caregiving (59.1%-69.8% of the total cost), followed by health care costs (26.7%- 37.4%), and professional care (3.5%). Of the total health care costs, the largest item corresponded to hospital costs, followed by medication. Total costs differed significantly between patients in functional class II and those in classes III or IV. CONCLUSIONS: Heart failure is a disease that requires the mobilization of a considerable amount of resources. The largest item corresponds to informal care. Both health care and nonhealth care costs are higher in the population with more advanced disease. PMID- 25037544 TI - Normal left ventricular mechanics by two-dimensional speckle-tracking echocardiography. Reference values in healthy adults. AB - INTRODUCTION AND OBJECTIVES: Two-dimensional speckle-tracking echocardiography is a novel tool to assess myocardial function. The purpose of this study was to evaluate left ventricular myocardial strain and rotation parameters by two dimensional speckle-tracking echocardiography in a large group of healthy adults across a wide age range to establish their reference values and to assess the influence of age, sex, and hemodynamic factors. METHODS: Transthoracic echocardiograms were acquired in 247 healthy volunteers (139 women, 44 years [standard deviation, 16 years old] (range, 18-80 years). We measured longitudinal, circumferential, and radial peak systolic strain values, and left ventricular rotation and twist. RESULTS: Average values of global longitudinal, radial, and circumferential strain were -21.5% (standard deviation, 2.0%), 40.1% (standard deviation, 11.8%) and -22.2% (standard deviation, 3.4%), respectively. Longitudinal strain was significantly more negative in women, whereas radial and circumferential strain and rotational parameters were similar in both sexes. Accordingly, lower limits of normality for the strain components were -16.9% in men and -18.5% in women for longitudinal strain, and -15.4% for circumferential and 24.6% for radial strain, irrespective of sex. Longitudinal strain values were more negative at the base than at apical segments. Mean rotational values were 6.9 degrees (standard deviation, 3.5 degrees ) for the base, 13.0 degrees (standard deviation, 6.5 degrees ) for apical rotation, and 20.0 degrees (standard deviation, 7.3 degrees ) for net twist. CONCLUSIONS: We report the comprehensive assessment of normal myocardial deformation and rotational mechanics in a large cohort of healthy volunteers. We found that women have more negative longitudinal strain, accounting for their higher left ventricular ejection fraction. Availability of reference values for these parameters may foster their implementation in the clinical routine. PMID- 25037545 TI - Weaknesses in regional primary coronary angioplasty programs: is there still a role for a pharmaco-invasive approach? AB - All guidelines recommend primary percutaneous coronary intervention as the default strategy for achieving reperfusion in ST-segment elevation myocardial infarction patients. These recommendations are based upon randomized trials which compared primary percutaneous coronary intervention with stand-alone intravenous fibrinolysis. Since the time these trials were performed, however, it has been shown in further trials that use of rescue percutaneous coronary intervention in patients without signs of reperfusion after lysis, and routine coronary angiography within 24 h of the administration of lysis for all other patients, substantially improved the results of intravenous fibrinolytic treatment. This has led to proposing the pharmaco-invasive strategy as an alternative to primary percutaneous coronary intervention. Actually, it is not uncommon that circumstances prevent performing primary percutaneous coronary intervention within the recommended time limits set by the guidelines. In such cases, using a pharmaco-invasive strategy may constitute a valid alternative. Both the STREAM randomized trial and real-world experience, in particular the long-term results from the FAST-MI registry, suggest that the pharmaco-invasive strategy, when used in an appropriate population, compares favorably with primary percutaneous coronary intervention. Therefore, implementing a pharmaco-invasive strategy protocol may be an important complement to compensate for potential weaknesses in ST-segment elevation myocardial infarction networks. PMID- 25037546 TI - Diagnosis of cardiac amyloidosis by skin lesions. PMID- 25037547 TI - Aortic thrombosis, a rare cause of acute myocardial infarction in young patients. PMID- 25037548 TI - Paroxysmal supraventricular tachycardia immediately following heart transplantation. PMID- 25037549 TI - Heart transplantation in pediatric patients with pulmonary hypertension. PMID- 25037550 TI - Nonvalvular atrial fibrillation: the problem of an undefined definition. PMID- 25037551 TI - Percutaneous closure of baffle leaks in patients with atrial switch operation for D-transposition of the great arteries. PMID- 25037552 TI - Delayed positive response to a flecainide test in a patient with suspected Brugada syndrome: a worrisome finding. PMID- 25037553 TI - Infranodal atrioventricular block as a possible cause of exercise-induced cardiac arrest. PMID- 25037554 TI - Correlation between Agatston scores obtained by cardiac computed tomography studies with and without contrast in asymptomatic population. PMID- 25037555 TI - Medial prefrontal-hippocampal connectivity and motor memory consolidation in depression and schizophrenia. AB - BACKGROUND: Overnight memory consolidation is disturbed in both depression and schizophrenia, creating an ideal situation to investigate the mechanisms underlying sleep-related consolidation and to distinguish disease-specific processes from common elements in their pathophysiology. METHODS: We investigated patients with depression and schizophrenia, as well as healthy control subjects (each n = 16), under a motor memory consolidation protocol with functional magnetic resonance imaging and polysomnography. RESULTS: In a sequential finger tapping task associated with the degree of hippocampal-prefrontal cortex functional connectivity during the task, significantly less overnight improvement was identified as a common deficit in both patient groups. A task-related overnight decrease in activation of the basal ganglia was observed in control subjects and schizophrenia patients; in contrast, patients with depression showed an increase. During the task, schizophrenia patients, in comparison with control subjects, additionally recruited adjacent cortical areas, which showed a decrease in functional magnetic resonance imaging activation overnight and were related to disease severity. Effective connectivity analyses revealed that the hippocampus was functionally connected to the motor task network, and the cerebellum decoupled from this network overnight. CONCLUSIONS: While both patient groups showed similar deficits in consolidation associated with hippocampal-prefrontal cortex connectivity, other activity patterns more specific for disease pathology differed. PMID- 25037556 TI - Poor vitamin D status is prospectively associated with greater muscle mass loss in middle-aged and elderly Chinese individuals. AB - BACKGROUND: Poor vitamin D status can increase age-related muscle mass loss. However, existing prospective evidence is limited and controversial. OBJECTIVE: This study aimed to investigate the association of plasma 25-hydroxyvitamin D [25(OH)D] with muscle mass loss in middle-aged and elderly Chinese individuals over 6 years. DESIGN: We conducted a prospective cohort study. PARTICIPANTS/SETTING: This community-based study included 568 men and women aged 50 to 70 years at baseline. MAIN OUTCOMES MEASURES: Baseline plasma concentrations of 25(OH)D and biomarkers of liver and kidney functions and inflammation were measured. Body composition was assessed at baseline and 6-year follow-up by dual-energy x-ray absorptiometry. Appendicular skeletal muscle mass (ASMM) and trunk lean mass were calculated and total body lean mass was defined as an overall measure of total nonfat and nonbone tissues. STATISTICAL ANALYSES PERFORMED: Descriptive statistics and multiple linear regression were applied. RESULTS: The 6-year loss of ASMM was 1.14 kg (5.3%) in men and 0.47 kg (3.1%) in women (all P values <0.001). Compared with the highest 25(OH)D tertile, participants in the lowest tertile had significantly more absolute loss of ASMM ( 1.21 vs -1.00 kg; P for trend=0.024) after multivariate adjustments for conventional confounders, as well as protein intake. The association persisted after additional adjustment of bone mineral density and inflammatory markers (P for trend=0.017). No significant associations were detected between 25(OH)D and absolute loss of trunk lean mass or total body lean mass. CONCLUSIONS: Lower 25(OH)D concentrations were prospectively associated with greater ASMM loss in middle-aged and elderly Chinese individuals independent of bone mineral density, inflammation, diet, and other risk factors. PMID- 25037557 TI - What's in children's backpacks: foods brought from home. AB - Forty-one percent of elementary schoolchildren bring lunch to school on any given day. Forty-five percent bring snacks. Surprisingly, little is known about the foods and beverages they bring. This cross-sectional analysis of baseline data from the GREEN (Growing Right: Eco-friendly Eating and Nutrition) Project Lunch Box Study sought to characterize foods and beverages brought from home to school by elementary schoolchildren and compare the quality of packed lunches with National School Lunch Program standards and packed snacks with Child and Adult Care Food Program requirements. Lunches and snacks from 626 elementary schoolchildren were assessed and evaluated using digital photography and a supplemental food checklist. Food and beverage types most likely to be provided for lunch were sandwiches (59%), snack foods (42%), fruit (34%), desserts (28%), water (28%), and sugar-sweetened beverages (24%). Twenty-seven percent of lunches met at least three of five National School Lunch Program standards. At snack, snack foods (62%), desserts (35%), and sugar-sweetened beverages (35%) were more common than fruits (30%), dairy foods (10%), and vegetables (3%). Only 4% of snacks met two of four Child and Adult Care Food Program standards. Future research is needed to understand the multiple determinants of food-packing behavior, including constraints faced by families. School wellness policies should consider initiatives that work collaboratively with parents to improve the quality of foods brought from home. PMID- 25037558 TI - The influence of menu labeling on calories selected or consumed: a systematic review and meta-analysis. AB - Recent menu labeling initiatives in North America involve posting the calorie content of standard menu items, sometimes with other nutrients of public health concern, with or without contextual information (such as the recommended daily caloric intake for an average adult) or interpretive information (such as traffic light symbols). It is not clear whether this is an effective method to convey nutrition information to consumers wanting to make more-informed food choices. Of particular concern are those consumers who may be limited in their food and health literacy skills to make informed food choices to meet their dietary needs or goals. The purpose of this systematic review was to determine whether the provision of menu-based nutrition information affects the selection and consumption of calories in restaurants and other foodservice establishments. A secondary objective was to determine whether the format of the nutrition information (informative vs contextual or interpretive) influences calorie selection or consumption. Several bibliographic databases were searched for experimental or quasiexperimental studies that tested the effect of providing nutrition information in a restaurant or other foodservice setting on calories selected or consumed. Studies that recruited generally healthy, noninstitutionalized adolescents or adults were included. When two or more studies reported similar outcomes and sufficient data were available, meta analysis was performed. Menu labeling with calories alone did not have the intended effect of decreasing calories selected or consumed (-31 kcal [P=0.35] and -13 kcal [P=0.61], respectively). The addition of contextual or interpretive nutrition information on menus appeared to assist consumers in the selection and consumption of fewer calories (-67 kcal [P=0.008] and -81 kcal [P=0.007], respectively). Sex influenced the effect of menu labeling on selection and consumption of calories, with women using the information to select and consume fewer calories. The findings of this review support the inclusion of contextual or interpretive nutrition information with calories on restaurant menus to help consumers select and consume fewer calories when eating outside the home. Further exploration is needed to determine the optimal approach for providing this menu based nutrition information, particularly for those consumers who may be limited in their food and health literacy skills. PMID- 25037559 TI - Current concepts in the surgical management of acute diabetic foot infections. AB - Diabetic foot complications are common, costly, and difficult to treat. Peripheral neuropathy, repetitive trauma, and peripheral vascular disease are common reasons that lead to ulcers, infection, and hospitalization. Individuals with diabetes presenting with foot infection require optimal medical and surgical management to accomplish limb salvage and prevent amputation; aggressive short term and meticulous long-term care plans are required. Multiple classification systems have been recommended to ease the understanding and the management of these infections. Multi-disciplinary approach is the mainstay for a successful management. Such teams typically include multiple medical, surgical, and nursing specialties across a variety of public and private health care systems. This article is an overview in how to medically and surgically approach the diabetic foot infection with emphasis in soft tissue infection. PMID- 25037560 TI - CT pulmonary angiography utilization in the emergency department: diagnostic yield and adherence to current guidelines. AB - The aim is to investigate the patterns of computed tomography pulmonary angiography (CTPA) use and adherence to current guidelines. Medical records of patients investigated with CTPA for pulmonary embolism (PE) in a single academic hospital from January 2011 until December 2012 were reviewed. Wells scores were calculated retrospectively by researchers blinded to the results of the CTPA. "Avoidable imaging" was defined as imaging performed against current recommendations of the European Society of Cardiology or the PIOPED investigation group. A total of 646 patients underwent testing; 61 cases of PE were diagnosed (9.4%). Potentially avoidable imaging was performed in 49.5% and 71.5% of patients, depending on the criteria used; 11.5% of imaging studies were performed in low-risk patients with negative D-dimer assays. There is evidence of CTPA overuse and D-dimer underuse. Adherence to guidelines and appropriate use of D dimer assay might reduce avoidable imaging and ionizing radiation exposure. PMID- 25037562 TI - Kidney function and population-based outcomes of initiating oral atenolol versus metoprolol tartrate in older adults. AB - BACKGROUND: Atenolol and metoprolol tartrate are commonly prescribed beta blockers. Atenolol elimination depends on kidney function, whereas metoprolol tartrate does not. We hypothesized that compared to metoprolol tartrate, initiating oral atenolol treatment would be associated with more adverse events in older adults, with the association most pronounced in patients with lower baseline estimated glomerular filtration rates (eGFRs). STUDY DESIGN: Population based matched retrospective cohort study. SETTING & PARTICIPANTS: Older adults (mean age, 75 years) in Ontario, Canada, prescribed oral atenolol versus metoprolol tartrate from April 2002 through December 2011. The 2 groups were well matched (n=75,257 in each group), with no difference in 31 measured baseline characteristics. Patients with end-stage renal disease were ineligible, and 4.6% of patients had chronic kidney disease (median eGFR, 38mL/min/1.73m(2) assessed through a database algorithm). PREDICTORS: beta-Blocker type and eGFR. OUTCOMES: A composite outcome of hospitalization with bradycardia or hypotension and all cause mortality were assessed in 90-day follow-up. RESULTS: Compared to metoprolol tartrate, initiating atenolol treatment was not associated with higher risk of hospitalization with bradycardia or hypotension (incidence, 0.71% vs 0.79%; relative risk, 0.90; 95%CI, 0.80-1.01). Atenolol treatment initiation was associated with lower 90-day risk of mortality than metoprolol tartrate (incidence, 0.97% vs 1.44%; relative risk, 0.68; 95%CI, 0.61-0.74). Lower eGFR did not modify either association (P for interaction=0.5 and 0.6, respectively). LIMITATIONS: Heart rate and blood pressure were not available in our data sources, and effects ascertained from observational studies are subject to residual confounding. CONCLUSIONS: Contrary to our expectation, we found that atenolol versus metoprolol tartrate was associated with lower 90-day risk of mortality in patients regardless of eGFR, with no difference in risk of hospitalization with bradycardia or hypotension. PMID- 25037563 TI - Tract based spatial statistics in multiple system atrophy: a comparison between clinical subtypes. AB - OBJECTIVE: Using a novel method of tract-based spatial statistics (TBSS), this study aimed to investigate micro-structural white matter similarities and differences between the two MSA variants. METHODS: Diffusion tensor image data were acquired from 10 MSA-P, 15 MSA-C patients and 15 controls. Using TBSS, we performed pairwise comparison by examining the fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD) and radial diffusivity (RD) maps of the white matter tract. Clusters showing diffusivity abnormalities were used as region of interests for correlation analysis. RESULTS: Both in MSA-C and MSA-P, we detected significantly decreased FA values in bilateral corticospinal tract (CST) and right anterior thalamic radiation (ATR), increased RD values in bilateral CST, which correlated significantly with clinical severity. Direct comparison of two variants showed higher AD values of superior longitudinal fasciculus (SLF) in MSA P than in MSA-C. CONCLUSIONS: These findings indicate that patients with MSA-C and MSA-P share similar diffusivity abnormalities in the bilateral CST and right ATR. Higher AD values of SLF in MSA-P than in MSA-C might be a reason for faster functional deterioration in MSA-P than in MSA-C. PMID- 25037561 TI - Protein carbamylation in kidney disease: pathogenesis and clinical implications. AB - Carbamylation describes a nonenzymatic posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally increases. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins and have been implicated directly in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation's relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances. PMID- 25037564 TI - Location, location, and location: compartmentalization of Hedgehog signaling at primary cilia. PMID- 25037565 TI - Association beween resting heart rate, shear and flow-mediated dilation in healthy adults. AB - Preclinical data have demonstrated that heart rate (HR) can directly impact vascular endothelial function, in part, through a shear-stress mechanism. This study sought to explore, in humans, the associations between resting heart rate and both shear and endothelial function assessed by flow-mediated dilation (FMD). The brachial artery FMD test was performed in 31 apparently healthy volunteers. Basal (B) and hyperaemic (H) shear were quantified in the following two ways using data from the FMD test: the traditional cumulative shear area under the curve up to peak dilation (Shearcum) method; and our novel method of shear summation (Shearsum), which accounts for HR by summing each individual cardiac cycle shear up to peak dilation. Data were grouped by tertiles based on resting HR as follows: low (LHR = 43-56 beats min(-1); n = 10); middle (MHR = 58-68 beats min(-1); n = 11); and high (HHR = 69-77 beats min(-1); n = 10). Within the LHR group, both B-Shearcum and H-Shearcum were significantly higher (P < 0.001) than B-Shearsum and H-Shearsum, respectively, whereas in the HHR group B-Shearcum and H-Shearcum were significantly lower (P < 0.001) than B-Shearsum and H-Shearsum, respectively. The FMD in the LHR group (8.8 +/- 0.8%) was significantly greater than that in both the MHR group (5.5 +/- 0.8%; P = 0.009) and the HHR group (5.9 +/- 0.8%; P = 0.024). These findings demonstrate the existence of a relationship between heart rate and both shear and endothelial function in humans. Moreover, these findings have implications for considering heart rate as an important physiological variable when quantifying shear and performing the FMD test. PMID- 25037566 TI - Double disruption of alpha2A- and alpha2C-adrenoceptors induces endothelial dysfunction in mouse small arteries: role of nitric oxide synthase uncoupling. AB - Knockout mice lacking both alpha2A- and alpha2C-adrenergic receptors (alpha2A/alpha2C-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. Thus, in the present study we investigated the vascular reactivity of large and small arteries of alpha2A/alpha2C-ARKO mice. Aorta and mesenteric small arteries (MSAs) from 7-month-old male alpha2A/alpha2C-ARKO mice and congenic C57BL6/J mice (wild-type, WT) were studied. In the aorta, noradrenaline- and serotonin-induced contraction was similar between groups, but in MSAs there was an increase in agonist-induced contraction in alpha2A/alpha2C ARKO compared with WT. The l-NAME effect was reduced in MSAs of alpha2A/alpha2C ARKO mice compared with WT mice, as was basal NO evaluated by a 4,5 diaminofluorescein diacetate probe. Increased total endothelial nitric oxide synthase (eNOS) protein expression was observed in MSAs from alpha2A/alpha2C-ARKO mice, while the dimer/monomer ratio of eNOS was decreased. Mesenteric small arteries from alpha2A/alpha2C-ARKO mice showed an increase in ethidium bromide positive nuclei, indicating oxidative stress, which was attenuated by incubation with l-NAME. The sympathetic hyperactivity present in alpha2A/alpha2C-ARKO mice alters vascular reactivity only in certain types of arteries. Moreover, after chronic sympathetic hyperactivity, uncoupling eNOS may be a significant source of superoxide anion and reduced NO bioavailability in small vessels, increasing the contractile tone. PMID- 25037567 TI - Sortilin mediates the release and transfer of exosomes in concert with two tyrosine kinase receptors. AB - The transfer of exosomes containing both genetic and protein materials is necessary for the control of the cancer cell microenvironment to promote tumor angiogenesis. The nature and function of proteins found in the exosomal cargo, and the mechanism of their action in membrane transport and related signaling events are not clearly understood. In this study, we demonstrate, in human lung cancer A549 cells, that the exosome release mechanism is closely linked to the multifaceted receptor sortilin (also called neurotensin receptor 3). Sortilin is already known to be important for cancer cell function. Here, we report for the first time its role in the assembly of a tyrosine kinase complex and subsequent exosome release. This new complex (termed the TES complex) is found in exosomes and results in the linkage of the two tyrosine kinase receptors TrkB (also known as NTRK2) and EGFR with sortilin. Using in vitro models, we demonstrate that this sortilin-containing complex exhibits a control on endothelial cells and angiogenesis activation through exosome transfer. PMID- 25037568 TI - Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP2. AB - KCNQ1 and KCNE1 co-assembly generates the I(KS) K(+) current, which is crucial to the cardiac action potential repolarization. Mutations in their corresponding genes cause long QT syndrome (LQT) and atrial fibrillation. The A-kinase anchor protein, yotiao (also known as AKAP9), brings the I(KS) channel complex together with signaling proteins to achieve regulation upon beta1-adrenergic stimulation. Recently, we have shown that KCNQ1 helix C interacts with the KCNE1 distal C terminus. We postulated that this interface is crucial for I(KS) channel modulation. Here, we examined the yet unknown molecular mechanisms of LQT mutations located at this intracellular intersubunit interface. All LQT mutations disrupted the internal KCNQ1-KCNE1 intersubunit interaction. LQT mutants in KCNQ1 helix C led to a decreased current density and a depolarizing shift of channel activation, mainly arising from impaired phosphatidylinositol-4,5-bisphosphate (PIP2) modulation. In the KCNE1 distal C-terminus, the LQT mutation P127T suppressed yotiao-dependent cAMP-mediated upregulation of the I(KS) current, which was caused by reduced KCNQ1 phosphorylation at S27. Thus, KCNQ1 helix C is important for channel modulation by PIP2, whereas the KCNE1 distal C-terminus appears essential for the regulation of IKS by yotiao-mediated PKA phosphorylation. PMID- 25037569 TI - Differential effects of Akt isoforms on somatic cell reprogramming. AB - Akt plays an important role in cell growth, proliferation and survival. The specific roles of the three Akt isoforms in somatic cell reprogramming have not been investigated. Here we report that, during iPSC generation, enhanced Akt1 activity promotes complete reprogramming mainly through increased activation of Stat3 in concert with leukemia inhibitory factor (LIF) and, to a lesser extent, through promotion of colony formation. Akt1 augments Stat3 activity through activation of mTOR and upregulation of LIF receptor expression. Similarly, enhanced Akt2 or Akt3 activation also promotes reprogramming and coordinates with LIF to activate Stat3. Blocking Akt1 or Akt3 but not Akt2 expression prohibits cell proliferation and reprogramming. Furthermore, the halt in cell proliferation and reprogramming caused by mTOR and Akt inhibitors can be reversed by inhibition of GSK3. Finally, we found that expressing the GSK3beta target Esrrb overrides inhibition of Akt and restores reprogramming. Our data demonstrated that during reprogramming, Akt promotes establishment of pluripotency through co-stimulation of Stat3 activity with LIF. Akt1 and Akt3 are essential for the proliferation of reprogrammed cells, and Esrrb supports cell proliferation and complete reprogramming during Akt signaling. PMID- 25037570 TI - Activation of a TRP-like channel and intracellular Ca2+ dynamics during phospholipase-C-mediated cell death. AB - The model organism Neurospora crassa undergoes programmed cell death when exposed to staurosporine. Here, we show that staurosporine causes defined changes in cytosolic free Ca(2+) ([Ca(2+)]c) dynamics and a distinct Ca(2+) signature that involves Ca(2+) influx from the external medium and internal Ca(2+) stores. We investigated the molecular basis of this Ca(2+) response by using [Ca(2+)]c measurements combined with pharmacological and genetic approaches. Phospholipase C was identified as a pivotal player during cell death, because modulation of the phospholipase C signaling pathway and deletion of PLC-2, which we show to be involved in hyphal development, results in an inability to trigger the characteristic staurosporine-induced Ca(2+) signature. Using Deltacch-1, Deltafig 1 and Deltayvc-1 mutants and a range of inhibitors, we show that extracellular Ca(2+) entry does not occur through the hitherto described high- and low-affinity Ca(2+) uptake systems, but through the opening of plasma membrane channels with properties resembling the transient receptor potential (TRP) family. Partial blockage of the response to staurosporine after inhibition of a putative inositol 1,4,5-trisphosphate (IP3) receptor suggests that Ca(2+) release from internal stores following IP3 formation combines with the extracellular Ca(2+) influx. PMID- 25037571 TI - Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. AB - RATIONALE: Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. OBJECTIVE: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. METHODS AND RESULTS: We showed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18 derived fibroblasts within each operation group exhibit similar gene expression profiles. CONCLUSIONS: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response. PMID- 25037572 TI - Non typable-Haemophilus influenzae biofilm formation and acute otitis media. AB - BACKGROUND: Non-typable Haemophilus influenzae (NT-Hi) infection is frequently associated with acute otitis media (AOM) treatment failure, recurrence or chronic otitis media. Persistence of otopathogens in a biofilm-structured community was implicated in these situations. Here, we compared biofilm production by H. influenzae strains obtained by culture of middle ear fluid (MEF) from children with AOM treatment failure and by strains isolated from nasopharyngeal (NP) samples from healthy children or those with AOM (first episode or recurrence). We aimed to evaluate an association of clinical signs and in vitro biofilm formation and establish risk factors of carrying a biofilm-producing strain. METHODS: We used a modification of the microtiter plate assay with crystal violet staining to compare biofilm production by 216 H. influenzae strains: 41 in MEF from children with AOM treatment failure (group MEF), 43 in NP samples from healthy children (NP group 1), 88 in NP samples from children with a first AOM episode (NP group 2, n = 43) or recurrent (NP group 3, n = 45) and 44 in NP samples from children with AOM associated with conjunctivitis (NP group 4). RESULTS: At all, 106/216 (49%) H. influenzae strains produced biofilm as did 26/43 (60.5%) in NP samples from healthy children. Biofilm production in MEF samples and NP samples did not significantly differ (40.5% vs 60.5%, 55.8%, 56.8% and 31.1% for NP groups 1, 2, 3 and 4, respectively). On multivariate analysis, only presence of conjunctivitis was significantly associated with low biofilm production (OR = 0.3, CI [0.16 0.60], p = 0.001). The ampicillin resistance of H. influenzae produced by penicillin-binding protein modification was significantly associated with low biofilm production (p = 0.029). CONCLUSION: We found no association of biofilm production and AOM treatment failure or recurrence. Biofilm production was low from H. influenzae strains associated with conjunctivitis-otitis syndrome and from strains with modified penicillin-binding protein. PMID- 25037573 TI - LMO1 is a novel oncogene in lung cancer, and its overexpression is a new predictive marker for anti-EGFR therapy. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. We report that one oncogene amplified on chromosome 3q26, LMO1, a master transcriptional regulator of stemness, operates to drive strong growth phenotype in NSCLC. We first validate gene expression changes of LMO genes by real-time quantitative RT-PCR real-time quantitative reverse transcriptase polymerase chain reaction analysis and immunohistochemistry, and we identified gene overexpression of LMO1 compared with non-cancerous tissues (p < 0.01). Next, we discovered that LMO1 promoted cancer cell proliferation in our in vitro/vivo cell proliferation assay, and our cell signaling experiments showed that LMO1 expression correlated with elevated AKT phosphorylation in NSCLC, while the AKT phosphorylation was required for LMO1's oncogenic effects. In addition, we compared complete response rate, stable disease rate, disease progression rate, and the disease control rate of patient with different LMO1 gene expression which pointed to the usefulness of LMO1 overexpression, as a new predictive marker for responsiveness to cetuximab. All in all, LMO1 is a commonly activated tumor promoter that activates AKT signaling in NSCLC and a new predictive marker for targeted therapy. PMID- 25037574 TI - Genetic polymorphisms of TERT and CLPTM1L, cooking oil fume exposure, and risk of lung cancer: a case-control study in a Chinese non-smoking female population. AB - Genetic polymorphisms of telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the risks of lung cancer. This study aimed to investigate the association between polymorphisms in TERT and CLPTM1L genes with the risk of lung cancer, as well as the interaction of the polymorphisms and the environmental risk factors in Chinese non-smoking females. A hospital-based case control study of 524 cases and 524 controls was conducted. Two polymorphisms were determined by Taqman allelic discrimination method. The statistical analyses were performed mostly with SPSS. This study showed that the individuals with the TG or GG genotypes of TERT polymorphism (rs2736100) were at an increased risk for lung cancer compared with those carrying the TT genotype in Chinese non-smoking females [adjusted odds ratios (ORs) were 1.44 and 1.85, 95 % confidence intervals (CIs) were 1.09-1.90 and 1.29-2.65, respectively]. The stratified analysis suggested that increased risks were more pronounced in lung adenocarcinoma (corresponding ORs were 1.71 and 2.30, 95 % CIs were 1.25-2.35 and 1.54-3.43). Our results showed that exposure to cooking oil fume was associated with increased risk of lung cancer in Chinese non-smoking females (adjusted ORs 1.59, 95 % CI 1.13-2.23). However, we did not observe a significant interaction of cooking oil fume and TERT polymorphism on lung cancer among Chinese non-smoking females. TERT polymorphism (rs2736100) might be a genetic susceptibility factor for lung cancer in non-smoking females in China. PMID- 25037575 TI - Expression pattern of Notch intracellular domain (NICD) and Hes-1 in preneoplastic and neoplastic human oral squamous epithelium: their correlation with c-Myc, clinicopathological factors and prognosis in Oral cancer. AB - Notch pathway molecules crosstalk with Wnt/beta-catenin signaling cascade in stem cells and tumors. However, the correlation between the expression pattern of Notch intracellular domain NICD, Hes-1 and c-Myc has not been studied in oral squamous cell carcinoma. The aim of this study is to investigate the correlation and prognostic significance of NICD, Hes-1 and c-Myc in oral cancer. Immunohistochemistry was used to study the expression pattern of NICD, Hes-1 and c-Myc in oral preneoplastic and neoplastic tissues. In addition, double immunofluorescence was used to examine the co-localization of NICD, Hes-1 and c Myc in H314 cells. The expression pattern of NICD and Hes-1 was gradually increased from normal to dysplasia to carcinoma. Interestingly, statistically significant correlation was not observed between NICD, Hes-1 and c-Myc in oral squamous cell carcinoma. Furthermore, NICD+/c-Myc+ and Hes-1+/c-Myc+ double positive cases showed worst survival when compared with other cases in oral cancer. Notch signaling molecules, NICD and Hes-1, are found to be involved in the progression of oral squamous cell carcinoma. Interestingly, NICD, Hes-1 and c Myc may have independent roles in oral cancer. On the other hand, we have demonstrated that NICD+/c-Myc+ and Hes-1+/c-Myc+ double positivity might be used as independent prognostic indicator of oral carcinoma. PMID- 25037576 TI - Coexpression of HMGA2 and Oct4 predicts an unfavorable prognosis in human gastric cancer. AB - High mobility group protein A2 (HMGA2) and octamer-binding transcription factor 4 (Oct4) are transcription factors that play major roles in the acquisition of cancer stemness phenotypes and tumorigenicity of malignant neoplasms. The aim of this study was to analyze the association between HMGA2 and Oct4 expression and various clinicopathologic features in gastric cancer patients including invasion, metastasis, and clinical prognosis, in addition to overall survival. Immunohistochemistry was performed to explore the expression of HMGA2 and Oct4 in 158 gastric cancer and surrounding non-tumor tissues. Moreover, HMGA2 and Oct4 mRNA and protein levels were also detected by qRT-PCR and Western blotting, respectively, in 86 clinical tissue specimens and various gastric epithelial cell lines (GES-1, SGC7901, MKN45, and MKN27). Finally, associations between HMGA2 and Oct4 expression and clinicopathological features were analyzed by Pearson correlation coefficient. Survival analysis was performed by univariate and multivariate analyses. Taken together, we found that HMGA2 and Oct4 expression was significantly higher in gastric cancer tissues compared with non-cancerous tissues (P < 0.01), and HMGA2 and Oct4 protein levels were significantly higher in poorly differentiated gastric cancer cell lines (MKN45), moderately differentiated cell lines (SGC7901), and well-differentiated cell lines (MKN28) compared with human immortalized gastric epithelial cell lines (GES-1) (P < 0.01). Elevated HMGA2 and Oct4 levels were significantly associated with poor clinical prognosis (P < 0.05). Further conclusion showed that coexpression of HMGA2 and Oct4 in gastric cancer correlated with tumor invasion, metastasis, and clinical prognosis and predicted an unfavorable clinical outcome. These transcription factors may represent useful biomarkers to identify patients at high risk of postoperative recurrence. PMID- 25037577 TI - Characteristics and effectiveness of diabetes self-management educational programs targeted to racial/ethnic minority groups: a systematic review, meta analysis and meta-regression. AB - BACKGROUND: It is not clear to what extent educational programs aimed at promoting diabetes self-management in ethnic minority groups are effective. The aim of this work was to systematically review the effectiveness of educational programs to promote the self-management of racial/ethnic minority groups with type 2 diabetes, and to identify programs' characteristics associated with greater success. METHODS: We undertook a systematic literature review. Specific searches were designed and implemented for Medline, EMBASE, CINAHL, ISI Web of Knowledge, Scirus, Current Contents and nine additional sources (from inception to October 2012). We included experimental and quasi-experimental studies assessing the impact of educational programs targeted to racial/ethnic minority groups with type 2 diabetes. We only included interventions conducted in countries members of the OECD. Two reviewers independently screened citations. Structured forms were used to extract information on intervention characteristics, effectiveness, and cost-effectiveness. When possible, we conducted random-effects meta-analyses using standardized mean differences to obtain aggregate estimates of effect size with 95% confidence intervals. Two reviewers independently extracted all the information and critically appraised the studies. RESULTS: We identified thirty-seven studies reporting on thirty-nine educational programs. Most of them were conducted in the US, with African American or Latino participants. Most programs obtained some benefits over standard care in improving diabetes knowledge, self-management behaviors and clinical outcomes. A meta-analysis of 20 randomized controlled trials (3,094 patients) indicated that the programs produced a reduction in glycated hemoglobin of -0.31% (95% CI -0.48% to -0.14%). Diabetes knowledge and self-management measures were too heterogeneous to pool. Meta-regressions showed larger reduction in glycated hemoglobin in individual and face to face delivered interventions, as well as in those involving peer educators, including cognitive reframing techniques, and a lower number of teaching methods. The long-term effects remain unknown and cost-effectiveness was rarely estimated. CONCLUSIONS: Diabetes self management educational programs targeted to racial/ethnic minority groups can produce a positive effect on diabetes knowledge and on self-management behavior, ultimately improving glycemic control. Future programs should take into account the key characteristics identified in this review. PMID- 25037578 TI - High expression of thymosin beta 10 predicts poor prognosis for hepatocellular carcinoma after hepatectomy. AB - BACKGROUND: Thymosin beta 10 (Tbeta10) overexpression has been reported in a variety of human cancers. However, the role of Tbeta10 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to analyze Tbeta10 expression in tumor and matched non-tumorous tissues, and to assess its prognostic significance for HCC after hepatectomy. METHODS: The level of Tbeta10 mRNA and protein in tumor and matched non-tumorous tissues was evaluated in 26 fresh HCC cases by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Additionally, Tbeta10 protein expression in 196 HCC was analyzed by immunohistochemistry (IHC) and correlated with clinicopathological characteristics and survival. RESULTS: Results from RT-PCR and western blot analysis show that the levels of Tbeta10 mRNA and protein were significantly higher in tumor tissues of HCC, compared to that in matched non-tumorous tissues (P = 0.01 and P < 0.001, respectively). IHC staining showed that high expression of Tbeta10 was detected in 58.2% (114/196) of HCC cases. High expression of Tbeta10 was significantly associated with advanced TNM stage (P < 0.001). Survival analysis demonstrated that high Tbeta10 was related to shorter overall survival (OS) (P = 0.000) and disease-free survival (DFS) (P = 0.000). Multivariate analysis showed that high expression of Tbeta10 was an independent prognostic factor for both OS (P = 0.001, HR = 4.135, 95% CI: 2.603 to 6.569) and DFS (P = 0.001, HR = 2.021, 95% CI: 1.442 to 2.832). Subgroup analysis revealed that high expression of Tbeta10 predicts poorer survival for early and advanced stage. CONCLUSIONS: Tbeta10 protein abnormal expression might contribute to the malignant progression of HCC. High expression of Tbeta10 predicts poor prognosis in patients with HCC after hepatectomy. PMID- 25037580 TI - Binge Drinking, Cannabis and Tobacco Use Among Ethnic Norwegian and Ethnic Minority Adolescents in Oslo, Norway. AB - The aim of the study was to assess prevalence and factors associated with binge drinking, cannabis use and tobacco use among ethnic Norwegians and ethnic minority adolescents in Oslo. We used data from a school-based cross-sectional survey of adolescents in junior- and senior high schools in Oslo, Norway. The participants were 10,934 adolescents aged 14-17 years, and just over half were females. The sample was comprised of 73.2 % ethnic Norwegian adolescents, 9.8 % 1st generation immigrants, and 17 % 2nd generation adolescents from Europe, the US, the Middle East, Asia and Africa. Logistic regression models were applied for the data analyses. Age, gender, religion, parental education, parent-adolescent relationships, depressive symptoms and loneliness were covariates in the regression models. Ethnic Norwegian adolescents reported the highest prevalence of binge drinking (16.1 %), whereas the lowest prevalence was found among 2nd generation adolescents from Asia (2.9 %). Likewise, the past-year prevalence for cannabis use ranged from 10.6 % among 2nd generation Europeans and those from the US to 3.7 % among 2nd generation Asians. For daily tobacco use, the prevalence ranged from 12.9 % among 2nd generation Europeans and the US to 5.1 % among 2nd generation Asians. Ethnicity, age, gender, religion, parental education, and parent-adolescent relationships and mental health status were significantly associated with binge drinking, cannabis and tobacco use. These factors partly explained the observed differences between ethnic Norwegians and ethnic minority adolescents in the current study. There are significant differences in substance use behaviors between ethnic Norwegian and immigrant youth. Factors like age, gender, religion, parental education and relationships and mental health status might influence the relationship between ethnicity and substance abuse. The findings have implications for planning selective- as well as universal prevention interventions. PMID- 25037579 TI - The Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study. AB - BACKGROUND: Because early life growth has long-lasting metabolic and behavioral consequences, intervention during this period of developmental plasticity may alter long-term obesity risk. While modifiable factors during infancy have been identified, until recently, preventive interventions had not been tested. The Intervention Nurses Starting Infants Growing on Healthy Trajectories (INSIGHT). Study is a longitudinal, randomized, controlled trial evaluating a responsive parenting intervention designed for the primary prevention of obesity. This "parenting" intervention is being compared with a home safety control among first born infants and their parents. INSIGHT's central hypothesis is that responsive parenting and specifically responsive feeding promotes self-regulation and shared parent-child responsibility for feeding, reducing subsequent risk for overeating and overweight. METHODS/DESIGN: 316 first-time mothers and their full-term newborns were enrolled from one maternity ward. Two weeks following delivery, dyads were randomly assigned to the "parenting" or "safety" groups. Subsequently, research nurses conduct study visits for both groups consisting of home visits at infant age 3-4, 16, 28, and 40 weeks, followed by annual clinic-based visits at 1, 2, and 3 years. Both groups receive intervention components framed around four behavior states: Sleeping, Fussy, Alert and Calm, and Drowsy. The main study outcome is BMI z-score at age 3 years; additional outcomes include those related to patterns of infant weight gain, infant sleep hygiene and duration, maternal responsiveness and soothing strategies for infant/toddler distress and fussiness, maternal feeding style and infant dietary content and physical activity. Maternal outcomes related to weight status, diet, mental health, and parenting sense of competence are being collected. Infant temperament will be explored as a moderator of parenting effects, and blood is collected to obtain genetic predictors of weight status. Finally, second-born siblings of INSIGHT participants will be enrolled in an observation-only study to explore parenting differences between siblings, their effect on weight outcomes, and carryover effects of INSIGHT interventions to subsequent siblings. DISCUSSION: With increasing evidence suggesting the importance of early life experiences on long term health trajectories, the INSIGHT trial has the ability to inform future obesity prevention efforts in clinical settings. TRIAL REGISTRATION: NCT01167270. Registered 21 July 2010. PMID- 25037581 TI - Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. AB - Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies. PMID- 25037582 TI - Childhood obesity and the metabolic syndrome. AB - Although research published during the past year suggests the prevalence of childhood obesity in the USA may have plateaued, it remains unacceptably high and places large numbers of youths at elevated risk of chronic diseases. The concept of the metabolic syndrome (MetS) is frequently used to help capture this increased risk. Use of the MetS concept with children remains controversial, however. Addressing issues related to the definition of the MetS and its utility in clinical and research settings has generated a variety of recent investigative efforts. At the same time, the past year revealed a number of promising prevention and treatment interventions for childhood obesity and the MetS. Still unknown, however, is the optimal combination of diet, exercise, and other behavioral changes for improving the obesity and MetS status of children. These issues are the subject of this review. PMID- 25037583 TI - Piezo channels: from structure to function. AB - Mechanotransduction is the conversion of mechanical stimuli into biological signals. It is involved in the modulation of diverse cellular functions such as migration, proliferation, differentiation, and apoptosis as well as in the detection of sensory stimuli such as air vibration and mechanical contact. Therefore, mechanotransduction is crucial for organ development and homeostasis and plays a direct role in hearing, touch, proprioception, and pain. Multiple molecular players involved in mechanotransduction have been identified in the past, among them ion channels directly activated by cell membrane deformation. Most of these channels have well-established roles in lower organisms but are not conserved in mammals or fail to encode mechanically activated channels in mammals due to non-conservation of mechanotransduction property. A family of mechanically activated channels that counts only two members in human, piezo1 and 2, has emerged recently. Given the lack of valid mechanically activated channel candidates in mammals in the past decades, particular attention is given to piezo channels and their potential roles in various biological functions. This review summarizes our current knowledge on these ion channels. PMID- 25037584 TI - Evaluating posed and evoked facial expressions of emotion from adults with autism spectrum disorder. AB - Though many studies have examined facial affect perception by individuals with autism spectrum disorder (ASD), little research has investigated how facial expressivity in ASD is perceived by others. Here, naive female observers (n = 38) judged the intensity, naturalness and emotional category of expressions produced by adults with ASD (n = 6) and typically developing (TD) adults (n = 6) in both a posed condition and an evoked condition in which emotions were naturalistically elicited and validated. ASD expressions were rated as more intense and less natural than TD expressions but contrary to prediction were identified with greater accuracy, an effect driven primarily by angry expressions. Naturalness ratings of evoked expressions were positively associated with identification accuracy for TD but not ASD individuals. Collectively, these findings highlight differences, but not a reduction, in facial expressivity in ASD that do not hinder emotion recognition accuracy but may affect social interaction quality. PMID- 25037586 TI - The RSNA Image Sharing Network. AB - In the era of health information exchanges, there are trade-offs to consider when sharing a patient's medical record among all providers that a patient might choose. Exchange among in-network partners on the same electronic medical records (EMR) and other integrated information systems is trivial. The patient identifier is common, as are the relevant departmental systems, to all providers. Difficulties arise when patient records including images (and reports) must be shared among different networks and even with the patients themselves. The National Institutes of Health (NIH) challenged Radiological Society of North America (RSNA) to develop a transport method that could supersede the need for physical media (for patients or other providers), replace point-to-point private networks among providers, and enable image exchange on an ad hoc basis between arbitrary health networks without long legal delays. In concert with the evolving US health care paradigm, patient engagement was to be fundamental. With Integrating Healthcare Enterprise's (IHE's) help, the challenge has been met with an operational system. PMID- 25037585 TI - Cardiac myocyte-specific AHR activation phenocopies TCDD-induced toxicity in zebrafish. AB - Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity. PMID- 25037587 TI - Diagnostic classification of specific phobia subtypes using structural MRI data: a machine-learning approach. AB - While neuroimaging research has advanced our knowledge about fear circuitry dysfunctions in anxiety disorders, findings based on diagnostic groups do not translate into diagnostic value for the individual patient. Machine-learning generates predictive information that can be used for single subject classification. We applied Gaussian process classifiers to a sample of patients with specific phobia as a model disorder for pathological forms of anxiety to test for classification based on structural MRI data. Gray (GM) and white matter (WM) volumetric data were analyzed in 33 snake phobics (SP; animal subtype), 26 dental phobics (DP; blood-injection-injury subtype) and 37 healthy controls (HC). Results showed good accuracy rates for GM and WM data in predicting phobia subtypes (GM: 62 % phobics vs. HC, 86 % DP vs. HC, 89 % SP vs. HC, 89 % DP vs. SP; WM: 88 % phobics vs. HC, 89 % DP vs. HC, 79 % SP vs. HC, 79 % DP vs. HC). Regarding GM, classification improved when considering the subtype compared to overall phobia status. The discriminatory brain pattern was not solely based on fear circuitry structures but included widespread cortico-subcortical networks. Results demonstrate that multivariate pattern recognition represents a promising approach for the development of neuroimaging-based diagnostic markers that could support clinical decisions. Regarding the increasing number of fMRI studies on anxiety disorders, researchers are encouraged to use functional and structural data not only for studying phenotype characteristics on a group level, but also to evaluate their incremental value for diagnostic or prognostic purposes. PMID- 25037588 TI - Genetic parameter estimation for pre- and post-weaning traits in Brahman cattle in Brazil. AB - Beef cattle producers in Brazil use body weight traits as breeding program selection criteria due to their great economic importance. The objectives of this study were to evaluate different animal models, estimate genetic parameters, and define the most fitting model for Brahman cattle body weight standardized at 120 (BW120), 210 (BW210), 365 (BW365), 450 (BW450), and 550 (BW550) days of age. To estimate genetic parameters, single-, two-, and multi-trait analyses were performed using the animal model. The likelihood ratio test was verified between all models. For BW120 and BW210, additive direct genetic, maternal genetic, maternal permanent environment, and residual effects were considered, while for BW365 and BW450, additive direct genetic, maternal genetic, and residual effects were considered. Finally, for BW550, additive direct genetic and residual effects were considered. Estimates of direct heritability for BW120 were similar in all analyses; however, for the other traits, multi-trait analysis resulted in higher estimates. The maternal heritability and proportion of maternal permanent environmental variance to total variance were minimal in multi-trait analyses. Genetic, environmental, and phenotypic correlations were of high magnitude between all traits. Multi-trait analyses would aid in the parameter estimation for body weight at older ages because they are usually affected by a lower number of animals with phenotypic information due to culling and mortality. PMID- 25037589 TI - Consequence of altered nitrogen cycles in the coupled human and ecological system under changing climate: The need for long-term and site-based research. AB - Anthropogenically derived nitrogen (N) has a central role in global environmental changes, including climate change, biodiversity loss, air pollution, greenhouse gas emission, water pollution, as well as food production and human health. Current understanding of the biogeochemical processes that govern the N cycle in coupled human-ecological systems around the globe is drawn largely from the long term ecological monitoring and experimental studies. Here, we review spatial and temporal patterns and trends in reactive N emissions, and the interactions between N and other important elements that dictate their delivery from terrestrial to aquatic ecosystems, and the impacts of N on biodiversity and human society. Integrated international and long-term collaborative studies covering research gaps will reduce uncertainties and promote further understanding of the nitrogen cycle in various ecosystems. PMID- 25037590 TI - Associations between laryngeal and cough dysfunction in motor neuron disease with bulbar involvement. AB - True vocal fold (TVF) dysfunction may lead to cough ineffectiveness. In individuals with motor neuron disease (MND), cough impairment in the context of dysphagia increases risk for aspiration and respiratory failure. This study characterizes differences and associations between TVF kinematics and airflow during cough in individuals with bulbar MND. Sequential glottal angles associated with TVF movements during volitional cough were analyzed from laryngeal video endoscopy examinations of adults with bulbar MND (n = 12) and healthy controls (n = 12) and compared with simultaneously collected cough-related airflow measures. Significant group differences were observed with airflow and TVF measures: volume acceleration (p <= 0.001) and post-compression abduction TVF angle average velocity (p = 0.002) were lower and expiratory phase rise time (p = 0.001) was higher in the MND group. Reductions in maximum TVF angle during post-compression abduction in the MND group approached significance (p = 0.09). All subjects demonstrated complete TVF and supraglottic closure during the compression phase of cough, except for incomplete supraglottic closure in 2/12 MND participants. A strong positive relationship between post-compression maximum TVF abduction angle and peak expiratory cough flow was observed in the MND group, though it was not statistically significant (r = 0.55; p = 0.098). Reductions in the speed and extent of TVF abduction are seen during the expulsion phase of cough in individuals with MND. This may contribute to cough impairment and morbidity. PMID- 25037591 TI - Specificity of two monoclonal antibodies against a synthetic glycopeptide, an analogue to the hypo-galactosylated IgA1 hinge region. AB - Increased levels of hypo-galactosylated immunoglobulin (Ig)A1 (HG-IgA1) in IgA nephropathy (IgAN) have been detected using a Helix aspersa agglutinin lectin enzyme-linked immunosorbent assay (ELISA). In this study, we developed monoclonal antibodies to evaluate the HG-IgA1 in IgA nephropathy, aiming to gain a more consistent and reproducible assay. As an analogue to the HG-IgA1 hinge region, a 19 mer synthetic peptide with five GalNAc (sHGP) residues at positions 4, 7, 9, 11 and 15 [VPST(GalNAc)PPT(GalNAc)PS(GalNAc)PS(GalNAc)TPPT (GalNAc)PSPS-NH2] was synthesized. Two monoclonal antibodies against sHGP (35A12 and 44H8) that reacted with human IgA were developed. Also, their reactivities to serum IgA from IgAN patients (n = 49), patients with other forms of kidney diseases (OKD, n = 48), and healthy controls (HC, n = 41) were evaluated using ELISA assays. The binding levels of the two monoclonal antibodies against serum IgA were significantly higher (all comparisons, p < 0.0001, Steel-Dwass non-parametric test) in IgAN patients compared to HC and OKD patients. In each individual, there was a close correlation of IgA binding levels between 35A12 and 44H8 (R(2) = 0.737). These results indicate that the monoclonal antibodies recognize similar epitopes in HG IgA1, which is found predominantly in IgAN patients. The developed antibodies are proposed as a clinically useful tool for IgAN screening. PMID- 25037592 TI - High-dose electron beam sterilization of soft-tissue grafts maintains significantly improved biomechanical properties compared to standard gamma treatment. AB - Allografts have gained increasing popularity in anterior cruciate ligament (ACL) reconstruction. However, one of the major concerns regarding allografts is the possibility of disease transmission. Electron beam (Ebeam) and Gamma radiation have been proven to be successful in sterilization of medical products. In soft tissue sterilization high dosages of gamma irradiation have been shown to be detrimental to biomechanical properties of grafts. Therefore, it was the objective of this study to compare the biomechanical properties of human bone patellar tendon-bone (BPTB) grafts after ebeam with standard gamma irradiation at medium (25 kGy) and high doses (34 kGy). We hypothesized that the biomechanical properties of Ebeam irradiated grafts would be superior to gamma irradiated grafts. Paired 10 mm-wide human BPTB grafts were harvested from 20 donors split into four groups following irradiation with either gamma or Ebeam (each n = 10): (A) Ebeam 25 kGy, (B) Gamma 25 kGy, (C) Ebeam 34 kGy (D) Gamma 34 kGy and ten non irradiated BPTB grafts were used as controls. All grafts underwent biomechanical testing which included preconditioning (ten cycles, 0-20 N); cyclic loading (200 cycles, 20-200 N) and a load-to-failure (LTF) test. Stiffness of non-irradiated controls (199.6 +/- 59.1 N/mm) and Ebeam sterilized grafts did not significantly differ (152.0 +/- 37.0 N/mm; 192.8 +/- 58.0 N/mm), while Gamma-irradiated grafts had significantly lower stiffness than controls at both irradiation dosages (25 kGy: 126.1 +/- 45.4 N/mm; 34 kGy: 170.6 +/- 58.2 N/mm) (p < 0.05). Failure loads at 25 kGy were significantly lower in the gamma group (1,009 +/- 400 N), while the failure load was significantly lower in both study groups at high dose irradiation with 34 kGy (Ebeam: 1,139 +/- 445 N, Gamma: 1,073 +/- 617 N) compared to controls (1,741 +/- 304 N) (p < 0.05). Creep was significantly larger in the gamma irradiated groups (25 kGy: 0.96 +/- 1.34 mm; 34 kGy: 1.06 +/- 0.58 mm) than in the Ebeam (25 kGy: 0.50 +/- 0.34 mm; 34 kGy: 0.26 +/- 0.24 mm) and control (0.20 +/- 0.18 mm) group that did not differ significantly. Strain difference was not different between either control or study groups (controls: 1.0 +/- 0.03; Ebeam 34 kGy 1.04 +/- 0.018; Gamma 34 kGy 1.0 +/- 0.028; 25 kGy: 1.4 +/- 2,0; 34 kGy: 1.1 +/- 1.1). The most important result of this study was that ebeam irradiation showed significantly less impairment of the biomechanical properties than gamma irradiation. Considering the results of this study and the improved control of irradiation application with electronic beam, this technique might be a promising alternative in soft-tissue sterilization. PMID- 25037593 TI - Induced pluripotent stem cells and their implication for regenerative medicine. AB - In 2006 Yamanaka's group showed that stem cells with properties similar to embryonic stem cells could be generated from mouse fibroblasts by introducing four genes. These cells were termed induced pluripotent stem cells (iPSCs). Because iPSCs avoid many of ethical concerns associated with the use of embryonic material, they have great potential in cell-based regenerative medicine. They are suitable also for other various purposes, including disease modelling, personalized cell therapy, drug or toxicity screening and basic research. Moreover, in the future, there might become possible to generate organs for human transplantation. Despite these progresses, several studies have raised the concern for genetic and epigenetic abnormalities of iPSCs that could contribute to immunogenicity of some cells differentiated from iPSCs. Recent methodological improvements are increasing the ease and efficacy of reprogramming, and reducing the genomic modification. However, to minimize or eliminate genetic alternations in the derived iPSC line creation, factor-free human iPSCs are necessary. In this review we discuss recent possibilities of using iPSCs for clinical applications and new advances in field of their reprogramming methods. The main goal of present article was to review the current knowledge about iPSCs and to discuss their potential for regenerative medicine. PMID- 25037594 TI - Mothers' narratives about having a child with cancer: A view through the attachment lens. AB - This study explored mothers' narratives about having a child with cancer through the novel addition of an attachment lens. Six mothers were interviewed about their experiences. Their pattern of attachment was assessed through a separate interview using the Dynamic-Maturational Model of adult attachment. The results showed marked differences in themes and performative aspects between the narratives of mothers classified as Type B pattern of attachment, balanced integration of affect and cognition, and those classified as Type A, focus on cognition and dismissal of affect. For mothers classified as Type B, narrative themes of 'protecting my child' and 'questioning and evaluating the experience' were identified. Mothers classified as Type A discussed narrative themes of 'being strong and positive' and 'playing down feelings'. The presence of unresolved childhood loss or trauma appeared to inhibit ability to construct a coherent and temporally ordered narrative. It was also possible to observe attachment-based strategies operating within these narratives. Clinical implications of the work are discussed. PMID- 25037596 TI - Association of the +331G/A progesterone receptor gene (PgR) polymorphism with risk of endometrial cancer in Caucasian women: a meta-analysis. AB - PURPOSE: The +331G/A progesterone receptor (PgR) gene polymorphism may influence risk of endometrial cancer. However, data from published studies have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and endometrial cancer, we considered all available studies in a meta-analysis. METHODS: We searched PubMed and EMBASE and identified eight studies representing data for 3,790 cases and 6,458 controls. We estimated risk [odds ratio (OR) and 95 % confidence interval] of these associations, which were non-significant in the entire body of results. RESULTS: Overall effects indicated increased risks, slightly pronounced in the homozygous and recessive models (OR 1.16-1.17, p = 0.57-0.60). These effects were exacerbated when confined to studies in Hardy-Weinberg Equilibrium (OR 1.33-1.36, p = 0.33-0.35) and in the underpowered subgroup (OR 1.62-1.68, p = 0.27-0.30). The exception is the powered subgroup which showed reduced risk (OR 0.96-0.97, p = 0.92-0.93). None of the comparisons were heterogeneous, in fact, 10 of the 16 comparisons had zero heterogeneity (I (2) = 0 %). CONCLUSION: In summary, the non-significant results suggest that the PgR +331G/A polymorphism might not be a conspicuous low penetrant risk factor for developing endometrial cancer. PMID- 25037595 TI - HIV-1 transgenic female rat: synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. AB - HIV-1 associated neurocognitive deficits are increasing in prevalence, although the neuronal basis for these deficits is unclear. HIV-1 Tg rats constitutively express 7 of 9 HIV-associated proteins, and may be useful for studying the neuropathological substrates of HIV-1 associated neurocognitive disorders (HAND). In this study, adult female HIV-1 Tg rats and F344 control rats had similar growth rates, estrous cyclicity and startle reflex inhibition to a visual prepulse stimulus. Medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) were ballistically-labeled utilizing the indocarbocyanine dye DiI. The branching complexity of MSNs in the NAcc was significantly decreased in HIV-1 Tg rats, relative to controls; moreover, the shorter length and decreased volume of dendritic spines, but unchanged head diameter, in HIV-1 Tg rats suggested a reduction of longer spines and an increase in shorter, less projected spines, indicating a population shift to a more immature spine phenotype. Collectively, these results from HIV-1 Tg female rats indicated significant synaptodendritic alterations of MSNs in the NAcc occur as a consequence of chronic, low-level, exposure to HIV-1 associated proteins. PMID- 25037597 TI - Identification of differentially expressed proteins in the ovaries of menopausal women. AB - PURPOSE: This study investigated proteins differentially expressed in the ovaries of menopausal women in comparison to childbearing women. METHODS: Differential protein expression was screened by difference gel electrophoresis and 2-D SDS PAGE. Four differentially expressed proteins were excised manually, identified by mass spectrometry and confirmed by immunoblot and immunohistochemistry. RESULTS: The four proteins were identified as serum amyloid P, heat shock protein 27, Glyoxalase I and Ubiquitin carboxy-terminal hydrolase. Serum amyloid P expression was significantly up-regulated in the ovaries of menopausal women by immunoblot analysis (p < 0.05), Glyoxalase I and Ubiquitin carboxy-terminal hydrolase displayed an altered expression pattern, with higher expression in the atretic follicles of menopausal women. Weak Glyoxalase I and Ubiquitin carboxy-terminal hydrolase were observed in the granulosa and theca cells of the follicles of childbearing women. Heat shock protein 27 and serum amyloid P were clearly observed in the atretic follicles of menopausal women, while their expression was restricted to the theca cells and cytoplasm of primordial follicles in the ovaries of childbearing women. All four proteins were predominantly expressed in the atretic follicles of menopausal women. CONCLUSIONS: These data suggest that the identified proteins may play a role in the regulation of follicle atresia in menopausal women, although their functions and mechanism warrant further investigation. PMID- 25037598 TI - Non-thermal atmospheric pressure plasmas as a novel candidate for preventive therapy of melanoma. AB - Due to the increased ultraviolet radiation, the incidence of melanoma is increasing worldwide more than that of any other cancer. In this study, the effects of irradiation of non-thermal atmospheric pressure plasmas (NEAPPs) on benign melanocytic tumors from our original hairless model mice (HL-RET-mice), in which benign melanocytic tumors and melanomas spontaneously develop in the skin stepwise, were examined. Expression levels of melanoma cell adhesion molecule (MCAM) and matrix metalloproteinase-2 (MMP-2) mRNA in melanomas were higher than those in benign melanocytic tumors in the mice. Repeated irradiation of non thermal atmospheric pressure plasmas (NEAPPs) for the benign tumors decreased the expression levels of MCAM and MMP-2 mRNA in the tumors from the mice. Previous studies showed that MCAM sites are upstream of MMP-2, that MCAM regulates transcription of MMP-2 in melanoma cells and that MMP-2 is associated with the conversion of a benign tumor to a malignant tumor. Therefore, our results suggest that the NEAPP irradiation-mediated decrease in the expression level of MMP-2 in benign melanocytic tumors is associated with decreased expression levels of MCAM. Moreover, NEAPP irradiation might be a potential candidate for therapy to prevent melanoma development through suppression of malignant conversion in benign melanocytic tumors. PMID- 25037599 TI - PARP-1 and CASP3 genes are up-regulated in LNCaP and PC-3 prostate cancer cell lines. PMID- 25037601 TI - Cost-effectiveness of training rural providers to identify and treat patients at risk for fragility fractures. AB - This is a cost-effectiveness analysis of training rural providers to identify and treat osteoporosis. Results showed a slight cost savings, increase in life years, increase in treatment rates, and decrease in fracture incidence. However, the results were sensitive to small differences in effectiveness, being cost effective in 70 % of simulations during probabilistic sensitivity analysis. INTRODUCTION: We evaluated the cost-effectiveness of training rural providers to identify and treat veterans at risk for fragility fractures relative to referring these patients to an urban medical center for specialist care. The model evaluated the impact of training on patient life years, quality-adjusted life years (QALYs), treatment rates, fracture incidence, and costs from the perspective of the Department of Veterans Affairs. METHODS: We constructed a Markov microsimulation model to compare costs and outcomes of a hypothetical cohort of veterans seen by rural providers. Parameter estimates were derived from previously published studies, and we conducted one-way and probabilistic sensitivity analyses on the parameter inputs. RESULTS: Base-case analysis showed that training resulted in no additional costs and an extra 0.083 life years (0.054 QALYs). Our model projected that as a result of training, more patients with osteoporosis would receive treatment (81.3 vs. 12.2 %), and all patients would have a lower incidence of fractures per 1,000 patient years (hip, 1.628 vs. 1.913; clinical vertebral, 0.566 vs. 1.037) when seen by a trained provider compared to an untrained provider. Results remained consistent in one-way sensitivity analysis and in probabilistic sensitivity analyses, training rural providers was cost-effective (less than $50,000/QALY) in 70 % of the simulations. CONCLUSIONS: Training rural providers to identify and treat veterans at risk for fragility fractures has a potential to be cost-effective, but the results are sensitive to small differences in effectiveness. It appears that provider education alone is not enough to make a significant difference in fragility fracture rates among veterans. PMID- 25037602 TI - Indonesian men's perceptions of violence against women. AB - This article explores male perceptions and attitudes toward violence against women in Indonesia. It analyzes interview data from Indonesian men collected as part of a large multimethod Australian government-funded project on masculinities and violence in two Asian countries. Reluctance to talk about violence against women was evident, and the accounts of those men who did respond referred to three justificatory discourses: denial, blaming the victim, and exonerating the male perpetrator. The findings support continuation of government and nongovernmental organization (NGO) projects aimed at both empowering women and reeducating men. PMID- 25037600 TI - Bone quality of the newest bone formed after two years of teriparatide therapy in patients who were previously treatment-naive or on long-term alendronate therapy. AB - The results of the present study, involving analysis of biopsies from patients who received teriparatide for 2 years and were previously either treatment-naive or on long-term alendronate therapy, suggest that prior alendronate use does not blunt the favorable effects of teriparatide on bone quality. INTRODUCTION: Examine the effect of 2 years of teriparatide (TPTD) treatment on mineral and organic matrix properties of the newest formed bone in patients who were previously treatment-naive (TN) or on long-term alendronate (ALN) therapy. METHODS: Raman and Fourier transform infrared microspectroscopic analyses were used to determine the mineral/matrix (M/M) ratio, the relative proteoglycan (PG) content, and the mineral maturity/crystallinity (MMC; determined by three methods: carbonate content, full width at half height of the v 1 PO4 band [FWHH], and wavelength at maxima of the v 1 PO4 band), as well as collagen maturity (ratio of pyridinoline/divalent cross-links), in paired iliac crest biopsies at trabecular, endosteal, and osteonal surfaces of newly formed bone in postmenopausal osteoporotic women who were previously either TN (n = 16) or receiving long-term ALN treatment (n = 24). RESULTS: Trabecular M/M ratio increased and matrix content decreased significantly in the ALN pretreated group. Collagen maturity decreased in both patient groups. Endosteal M/M ratio increased significantly in the TN group. Trabecular M/M ratio was higher at endpoint in the ALN pretreated group than in the TN group. Overall, no changes from baseline were observed in PG content, except that PG content was higher in the ALN pretreated group than in the TN group at endosteal surfaces at endpoint. The ability of TPTD treatment to reduce MMC in both patient groups and at the different bone surfaces depended on the measurement tool (relative carbonate content or wavelength at maxima of the v 1 PO4 band). None of the changes in MMC were different between the two patient groups. CONCLUSIONS: The results suggest some favorable impact of TPTD on bone mineral and organic matrix properties of in situ forming bone in terms of increased initial mineralization and decreased MMC and collagen maturity. Moreover, prior long-term ALN administration may have only limited influence on these properties in bone newly formed after 2 years of TPTD treatment. PMID- 25037603 TI - Facial disfigurement stigma: a study of victims of domestic assaults with fire in India. AB - In India, the incidence of fire attacks on women has risen dramatically. Although studies and media accounts describe how and why these attacks occur, no research has investigated the lives of survivors. Qualitative analysis of the texts of two focus groups of women scarred by domestic attacks by fire reveals that these women are heavily stigmatized. Using Yang et al.'s theory that stigma is a response to perceived threats to values of everyday life and feminist theory as guides, the study identified two patterns of moral threat related to disfigurement: (a) Disfigurement challenges values and practices of women's family roles, and (b) disfigurement threatens normative religious sensibilities. PMID- 25037605 TI - Awareness of dementia by family carers of nursing home residents dying with dementia: a post-death study. AB - BACKGROUND: High-quality palliative care for people with dementia should be patient-centered, family-focused, and include well-informed and shared decision making, as affirmed in a recent white paper on dementia from the European Association for Palliative Care. AIM: To describe how often family carers of nursing home residents who died with dementia are aware that their relative has dementia, and study resident, family carer, and care characteristics associated with awareness. DESIGN: Post-death study using random cluster sampling. SETTING/PARTICIPANTS: Structured questionnaires were completed by family carers, nursing staff, and general practitioners of deceased nursing home residents with dementia in Flanders, Belgium (2010). RESULTS: Of 190 residents who died with dementia, 53.2% of family carers responded. In 28% of cases, family carers indicated they were unaware their relative had dementia. Awareness by family carers was related to more advanced stages of dementia 1 month before death (odds ratio = 5.4), with 48% of family carers being unaware when dementia was mild and 20% unaware when dementia was advanced. The longer the onset of dementia after admission to a nursing home, the less likely family carers were aware (odds ratio = 0.94). CONCLUSION: Family carers are often unaware that their relative has dementia, that is, in one-fourth of cases of dementia and one-fifth of advanced dementia, posing considerable challenges for optimal care provision and end-of life decision-making. Considering that family carers of residents who develop dementia later after admission to a nursing home are less likely to be aware, there is room for improving communication strategies toward family carers of nursing home residents. PMID- 25037606 TI - Cathepsin G deficiency reduces periaortic calcium chloride injury-induced abdominal aortic aneurysms in mice. AB - OBJECTIVE: Cathepsin G (CatG) is a serine protease that mediates angiotensin I to angiotensin II (Ang-II) conversion and is highly expressed in human abdominal aortic aneurysms (AAAs). However, it remains untested whether this protease participates in the pathogenesis of AAA. METHODS AND RESULTS: Immunofluorescent double staining demonstrated the expression of CatG in smooth muscle cells (SMCs), macrophages, and endothelial cells in human AAA lesions (n = 12) but not in AAA-free aortas (n = 10). Whereas inflammatory cytokines induced CatG expression, high glucose concentration increased CatG activity in producing Ang II and angiotensin-converting enzyme in SMCs, which could be fully blocked by a CatG-selective inhibitor or its small interfering RNA. To test whether CatG contributes to AAA development, we generated CatG and low-density lipoprotein receptor double deficient (Ldlr(-/-)Ctsg(-/-)) mice and their littermate controls (Ldlr(-/-)Ctsg(+/+)). Absence of CatG did not affect Ang-II infusion-induced AAAs. In contrast, in Ang-II-independent AAAs induced by periaortic CaCl2 injury (n = 12 per group), CatG deficiency significantly reduced aortic diameter increase (58.33% +/- 6.83% vs 31.67% +/- 5.75%; P = .007), aortic lesion area (0.35 +/- 0.04 mm(2) vs 0.21 +/- 0.02 mm(2); P = .005), and aortic wall elastin fragmentation grade (2.75 +/- 0.18 vs 1.58 +/- 0.17; P = .002) along with reduced lesion collagen content grade (2.80 +/- 0.17 vs 2.12 +/- 0.17; P = .009) without affecting indices of lesion inflammation, angiogenesis, cell proliferation, or apoptosis. In vitro elastin degradation assays demonstrated that CaCl2-induced AAA lesions from Ldlr(-/-)Ctsg(-/-) mice contained much lower elastinolytic activity than in those from littermate control mice. Gelatin gel zymogram assay suggested that absence of CatG in CaCl2-induced AAA lesions also reduced the activity of elastinolytic matrix metalloproteinases 2 and 9. CONCLUSIONS: CatG may contribute to CaCl2-induced experimental AAAs directly through its elastinolytic activity and indirectly by regulating lesion matrix metalloproteinases 2 and 9 activities. Increased expression of CatG in vascular and inflammatory cells of human AAAs and its increased activity in producing Ang II and angiotensin-converting enzyme by SMCs suggest an additional mechanism by which CatG contributes to AAA lesion progression. PMID- 25037607 TI - Statin therapy after infrainguinal bypass surgery for critical limb ischemia is associated with improved 5-year survival. AB - OBJECTIVE: Although statin therapy has been linked to fewer short-term complications after infrainguinal bypass, its effect on long-term survival remains unclear. We therefore examined associations between statin use and long term mortality, graft occlusion, and amputation after infrainguinal bypass. METHODS: We used the Vascular Study Group of New England registry to study 2067 patients (71% male; mean age, 67 +/- 11 years; 67% with critical limb ischemia [CLI]) who underwent infrainguinal bypass from 2003 to 2011. Of these, 1537 (74%) were on statins perioperatively and at 1-year follow-up, and 530 received no statin. We examined crude, adjusted, and propensity-matched rates of 5-year surviva1, 1-year amputation, graft occlusion, and perioperative myocardial infarction. RESULTS: Patients taking statins at the time of surgery and at the 1 year follow-up were more likely to have coronary disease (38% vs 22%; P < .001), diabetes (51% vs 36%; P < .001), hypertension (89% vs 77%; P < .001), and prior revascularization procedures (50% vs 38%; P < .001). Despite higher comorbidity burdens, long-term survival was better for patients taking statins in crude (risk ratio [RR], 0.7; P < .001), adjusted (hazard ratio, 0.7; P = .001), and propensity-matched analyses (hazard ratio, 0.7; P = .03). In subgroup analysis, a survival advantage was evident in patients on statins with CLI (5-year survival rate, 63% vs 54%; log-rank, P = .01) but not claudication (5-year survival rate, 84% vs 80%; log-rank, P = .59). Statin therapy was not associated with 1-year rates of major amputation (12% vs 11%; P = .84) or graft occlusion (20% vs 18%; P = .58) in CLI patients. Perioperative myocardial infarction occurred more frequently in patients on a statin in crude analysis (RR, 2.2; P = .01) but not in the matched cohort (RR, 1.9; P = .17). CONCLUSIONS: Statin therapy is associated with a 5-year survival benefit after infrainguinal bypass in patients with CLI. However, 1-year limb-related outcomes were not influenced by statin use in our large observational cohort of patients undergoing revascularization in New England. PMID- 25037608 TI - Association of serum periostin with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Recent studies recommend periostin as a systemic biomarker of eosinophilic airway inflammation to predict responses to novel treatments that targets eosinophilic TH2-driven inflammation in asthmatic patients. OBJECTIVE: To investigate the clinical implications of serum periostin levels in patients with aspirin-exacerbated respiratory disease (AERD) based on its overlapping TH2 mediated pathogenesis with the eosinophilic asthma. METHODS: Serum periostin levels were measured by human periostin enzyme-linked immunosorbent assay (ELISA) in serum samples from 277 adults with asthma. Serum periostin levels were compared between patients with AERD and aspirin tolerant asthma (ATA) with other asthma phenotypes, such as severe or nonsevere asthma and eosinophilic or noneosinophilic asthma. The association of serum periostin levels with clinical parameters (including disease severity and comorbid condition) was analyzed. RESULTS: Serum periostin levels were significantly higher in patients with AERD vs ATA, patients with severe asthma vs nonsevere asthma, and patients with eosinophilic asthma vs noneosinophilic asthma (P=.005, P=.02, and P=.001, respectively). Multivariate regression analysis revealed serum periostin levels as a significant parameter to predict AERD phenotype (P=.006) together with severe asthma phenotype (P=.04). In addition, serum periostin levels correlated with blood eosinophil counts (Spearman n = 0.244, P<.001) and sputum eosinophil counts (Spearman n = 0.261, P < 0.001). Higher serum periostin levels were noted in comorbid AERD patients with more severe chronic rhinosinusitis (Lund-Mackay stages 3 and 4) than those with less severe chronic rhinosinusitis (Lund-Mackay stages 1 and 2) (P = .03). CONCLUSION: Serum periostin levels are significantly elevated in AERD patients and associated with AERD phenotype and disease severity. PMID- 25037609 TI - Relationship between hypogammaglobulinemia and severity of atopic dermatitis. AB - BACKGROUND: Atopic dermatitis is an itchy, inflammatory, chronic, or chronically relapsing skin disease. The disease occurs in people who have an "atopic tendency" or may appear as a clinical sign of primary immunodeficiency. OBJECTIVES: To determine the relation between severity of atopic dermatitis and hypogammaglobulinemia. METHODS: One hundred sixty pediatric patients with atopic dermatitis (98 boys and 62 girls, 1-60 months old, median age 14.5 months) and 95 healthy children (57 boys and 38 girls, median age 16 months; control group) were included in the study. In patients with atopic dermatitis, the severity of disease was determined by the SCORing Atopic Dermatitis index. Serum immunoglobulin levels of all patients and children in the control group were measured by nephelometry on admission. RESULTS: The incidence of hypogammaglobulinemia was higher in patients with atopic dermatitis than in the control group (P = .009). The main reason for this difference was the low level of IgG in the atopic dermatitis group (P = .024). Analysis of the relation between hypogammaglobulinemia and the severity of atopic dermatitis showed no statistically significant difference between the group with mild to moderate atopic dermatitis and the group with severe atopic dermatitis with respect to hypogammaglobulinemia (P = .859), IgG (P = .068), IgA (P = .410), and IgM (P = .776) values. CONCLUSION: Hypogammaglobulinemia was more frequent in patients with atopic dermatitis compared with the control group, mostly owing to the low IgG level. Hypogammaglobulinemia is not associated with the severity of atopic dermatitis. PMID- 25037610 TI - Elevated platelet activation in patients with chronic urticaria: a comparison between aspirin-intolerant and aspirin-tolerant groups. AB - BACKGROUND: Platelets are actively involved in immune inflammatory processes that release inflammatory mediators. Platelet activation has been reported in various inflammatory diseases; however, few studies have described platelet involvement in chronic urticaria (CU). OBJECTIVE: To investigate platelet-activation markers, namely P2Y12 receptor and P-selectin expression, and soluble P-selectin level in patients with aspirin-intolerant CU (AICU) and aspirin-tolerant CU (ATCU). METHODS: Forty-eight patients with CU and 25 normal controls were enrolled in this study. Aspirin intolerance in patients with CU was confirmed by an oral provocation test. P2Y12 and P-selectin expressions on platelets were measured using flow cytometry; soluble P-selectin level in plasma was measured by enzyme linked immunosorbent assay. To study the functional effects of aspirin, platelets were treated with aspirin (2 mmol/L) and the expressions of P2Y12 and P-selectin were compared between the AICU and ATCU groups. RESULTS: The expression of P2Y12 was significantly higher in patients with CU compared with controls, whereas no significant difference was noted in the expression of P-selectin level. The levels were not significantly different according to urticaria symptom score, symptom control status, and aspirin intolerance. Soluble P-selectin level was significantly higher in the AICU group than in the ATCU group compared with controls. Aspirin did not significantly suppress P2Y12 and P-selectin expressions on platelets in the AICU group, whereas significant suppression was noted in the ATCU group. CONCLUSION: These findings suggest that increased platelet activation contributes to skin inflammation in patients with AICU and those with ATCU. The functional difference of platelets in response to aspirin may contribute to persistent skin inflammation in patients with AICU. PMID- 25037611 TI - The value of 4-month neurocognitive function as an endpoint in brain metastases trials. AB - To investigate whether the neurocognitive function at 4 months could be a relevant primary endpoint in clinical trials dealing with brain metastases, we created a Japanese neurocognitive battery and examined the changes in patients' neurocognitive function for 1 year after their brain radiotherapy. In this prospective pilot study, we enrolled 27 patients (20 patients who received whole brain radiation therapy [WBRT] and seven who received stereotactic irradiation [STI] alone) between March 2009 and December 2010. The follow-up neurocognitive data at 4, 8 and 12 months were available in 22 (17 WBRT, 5 STI), 19 patients (14 WBRT, 5 STI) and 13 patients (9 WBRT, 4 STI), respectively. Among the patients who received WBRT, significant deterioration in delayed memory compared to the baseline (p = 0.04) was observed at 4 months, and at 8 months, significant improvements were observed in immediate memory compared to the baseline (p = 0.008) and 4-months scores (p = 0.005). At 12 months, however, the immediate memory scores had returned to the baseline. Similar trends were observed in other functions (delayed memory, attention and executive functions). In these patients, the correlations between 4-months scores of neurocognitive functions and 12 months scores were significant in immediate memory (gamma = 0.68, p = 0.004), delayed memory (gamma = 0.738, p = 0.023) and attention (gamma = 0.817, p = 0.007). Among the patients who received STI, no significant changes were observed in any functions. These results suggest that 4-months changes in neurocognitive functions were transient but could also be a premonitory index for predicting the neurocognitive function 1 year or later after brain radiation therapy. PMID- 25037612 TI - Role of pancreatic juice cytology in the preoperative management of intraductal papillary mucinous neoplasm of the pancreas in the era of international consensus guidelines 2012. AB - BACKGROUND: Routine endoscopic retrograde pancreatography (ERP) for pancreatic juice cytology (PJC) during management of intraductal papillary mucinous neoplasm (IPMN) is not recommended in the international consensus guidelines 2012. The aim of the present study was to investigate the roles of PJC in relation to the new stratification of clinical findings in the consensus guidelines 2012. METHODS: Medical records of 70 consecutive patients who underwent preoperative PJC, subsequent pancreatectomy, and a pathological diagnosis of IPMN were reviewed. Diagnostic ability of PJC to detect malignant lesions was calculated by the stratification of clinical findings. RESULTS: Forty patients had malignant lesions, including 29 with malignant IPMN, 10 with concomitant pancreatic adenocarcinoma, and one with both. Accuracies of PJC in all 70 patients and in 59 patients with IPMN alone were 77 and 80 %, respectively. The sensitivity and accuracy of PJC in patients with "worrisome features" were 100 and 94 %, respectively. Eight of 11 patients with concomitant pancreatic adenocarcinoma had non-malignant IPMN without risk factors, and 3 significant lesions could be diagnosed only by ERP/PJC. In addition, the management plan based on imaging study changed from observation to resection in two patients who had the single "worrisome feature" of branch duct IPMN and positive PJC results. As a result, PJC altered the management plan in 5 patients. CONCLUSIONS: Pancreatic juice cytology potentially has important roles to determine the adequate treatment choice in patients with IPMNs with "worrisome features," and to detect significant lesions that could not be detected by other imaging modalities. PMID- 25037613 TI - Structural and functional diversity of free-living microorganisms in reef surface, Kra island, Thailand. AB - BACKGROUND: Coral reefs worldwide are being harmed through anthropogenic activities. Some coral reefs in Thailand remain well-preserved, including the shallow coral reefs along Kra island, Nakhon Si Thammarat province. Interestingly, the microbial community in this environment remains unknown. The present study identified biodiversity of prokaryotes and eukaryotes of 0.22-30 MUm in sizes and their metabolic potentials in this coral reef surface in summer and winter seasons, using 16S and 18S rRNA genes pyrosequencing. RESULTS: The marine microbial profiles in summer and winter seasons comprised mainly of bacteria, in phylum, particular the Proteobacteria. Yet, different bacterial and eukaryotic structures existed between summer and winter seasons, supported by low Lennon and Yue & Clayton theta similarity indices (8.48-10.43% for 16S rRNA, 0.32 7.81% for 18S rRNA ). The topmost prokaryotic phylum for the summer was Proteobacteria (99.68%), while for the winter Proteobacteria (62.49%) and Bacteroidetes (35.88%) were the most prevalent. Uncultured bacteria in phyla Cyanobacteria, Planctomycetes, SAR406 and SBR1093 were absent in the summer. For eukaryotic profiles, species belonging to animals predominated in the summer, correlating with high animal activities in the summer, whereas dormancy and sporulation predominated in the winter. For the winter, eukaryotic plant species predominated and several diverse species were detected. Moreover, comparison of our prokaryotic databases in summer and winter of Kra reef surface against worldwide marine culture-independent prokaryotic databases indicated our databases to most resemblance those of coastal Sichang island, Chonburi province, Thailand, and the 3 tropical GOS sites close to Galapagos island (GS039, GS040 and GS045), in orderly. CONCLUSIONS: The study investigated and obtained culture independent databases for marine prokaryotes and eukaryotes in summer and winter seasons of Kra reef surface. The data helped understand seasonal dynamics of microbial structures and metabolic potentials of this tropical ecosystem, supporting the knowledge of the world marine microbial biodiversity. PMID- 25037615 TI - Antiaromaticity in nonbenzenoid oligoarenes and ladder polymers. AB - Polycyclic aromatic hydrocarbons (PAHs) and fully-conjugated ladder polymers are leading candidates for organics electronics, as their inherent conformational rigidity encourages electron delocalization. Many of these systems consist of fused benzenoid or heterocyclic aromatic rings. Less frequently, however, PAHs are reported with character that alternates between the aromaticity of benzene fragments and the antiaromaticity of a nonbenzenoid moiety. This chapter will focus on recent work published on the theory, synthesis, and properties of two such systems: [N]phenylenes containing 4pi-electron cyclobutadienoid character, and diaryl[a,e]pentalenes containing 8pi-electron pentalenoid character. PMID- 25037614 TI - Validation of the symptoms and functioning severity scale in residential group care. AB - Tests that measure the emotional and behavioral problems of children and youth are typically not normed and standardized on youth diagnosed with disruptive behavior, particularly those youth in residential care. Yet professional standards mandate that before instruments are used with a specific population the psychometric properties need to be studied and re-established: specifically, psychometric properties, including validity, need to be evaluated (AERA, APA, and NCME, The standards for educational and psychological testing. AERA, Washington, DC, 1999). The purpose of the present study was to assess the validity characteristics of the Symptoms and Functioning Severity Scale (SFSS; Bickman et al., Manual of the Peabody Treatment Progress Battery, Vanderbilt University, Nashville, TN, 2010), a widely used test developed for use in outpatient clinics, with youth in a residential care program. The convergent validity of the SFSS was established with the large correlations (0.78-0.86) with the CBCL. Several binary classification analyses including specificity, area under the receiver operating characteristic curve, positive and negative likelihood ratios, and the Youden Index supported the validity of the SFSS. However, the sensitivity index was somewhat low indicating the test may produce a high level of false negatives. Limitations, future research and implications are discussed. PMID- 25037616 TI - [Verrocous mass on the tongue: oral florid papillomatosis]. PMID- 25037619 TI - Safety and efficacy of high-dose adeno-associated virus 9 encoding sarcoplasmic reticulum Ca(2+) adenosine triphosphatase delivered by molecular cardiac surgery with recirculating delivery in ovine ischemic cardiomyopathy. AB - OBJECTIVE: Therapeutic safety and efficacy are the basic prerequisites for clinical gene therapy. We investigated the effect of high-dose molecular cardiac surgery with recirculating delivery (MCARD)-mediated adeno-associated virus 9 (AAV9)/sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA2a) gene delivery on clinical parameters, oxidative stress, humoral and cellular immune responses, and cardiac remodeling. METHODS: Ischemic cardiomyopathy was generated in a sheep model. The sheep were assigned to 1 of 2 groups: control (n = 10) and study (MCARD, n = 6). The control group underwent no intervention and the study group received 10(14) genome copies of AAV9/SERCA2a 4 weeks after infarction. RESULTS: Our ischemic model produced reliable infarcts leading to heart failure. The baseline ejection fraction in the MCARD group was 57.6% +/- 1.6% versus 61.2% +/- 1.9% in the control group (P > .05). At 12 weeks after infarction, the MCARD group had superior left ventricular function compared with the control group: stroke volume index, 46.6 +/- 1.8 versus 35.8 +/- 2.5 mL/m(2) (P < .05); ejection fraction, 46.2% +/- 1.9% versus 38.7% +/- 2.5% (P < .05); and left ventricular end-systolic and end-diastolic dimensions, 41.3 +/- 1.7 versus 48.2 +/- 1.4 mm and 51.2 +/- 1.5 versus 57.6 +/- 1.7 mm, respectively (P < .05). The markers of oxidative stress were significantly reduced in the infarct zone in the MCARD group. No positive T-cell-mediated immune response was seen in the MCARD group at any point. Myocyte hypertrophy was also significantly attenuated in the MCARD group compared with the control group. CONCLUSIONS: Cardiac overexpression of the SERCA2a gene by way of MCARD is a safe therapeutic intervention. It significantly improves left ventricular function, decreases markers of oxidative stress, abrogates myocyte hypertrophy, arrests remodeling, and does not induce a T-cell mediated immune response. PMID- 25037622 TI - Use of balloon expandable transcatheter valves for valve-in-valve implantation in patients with degenerative stentless aortic bioprostheses: Technical considerations and results. AB - OBJECTIVE: Transcatheter valve-in-valve is an accepted treatment in high-risk patients with degenerative stented bioprostheses in the aortic position. Experience in treating stentless valves is, however, limited. Our aim was to determine the feasibility and single-center outcome of balloon expandable SAPIEN valve placement in degenerated stentless aortic valve bioprostheses. METHODS: From February 2010 to January 2014, 10 patients with failing stentless bioprostheses underwent transcatheter aortic valve implantation using the Edwards SAPIEN transcatheter heart valve (SAPIEN, SAPIEN XT, and SAPIEN 3) at our institution. Seven patients had valve failure due to regurgitation and three to stenosis. The mean age was 73.3 +/- 15.0 years. The mean logistic EuroSCORE was 31.8 +/- 20.3, and the Society of Thoracic Surgeons score was 7.6 +/- 5.4. RESULTS: Technical success was achieved in 9 of 10 patients. One patient required immediate placement of a second valve owing to low placement of the first. Two intraoperative complications developed that needed additional procedures. One patient underwent immediate repair of a right ventricular perforation from a pacing lead, the other, reexploration for epicardial bleeding. No deaths occurred. The median length of stay was 8.5 days (range, 3-44). The mean follow up was 8.1 months (range, 1-21). No late reoperations or reinterventions were required. CONCLUSIONS: Transcatheter aortic valve implantation after previous stentless aortic valve replacement is technically demanding but a safe and feasible approach. The early results were excellent, with consistent improvement in hemodynamics. Prospective long-term follow-up in larger series is needed to evaluate this technique further. PMID- 25037620 TI - Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium. AB - OBJECTIVE: Impaired angiogenesis is a known consequence of metabolic syndrome (MetS); however, the mechanism is not fully understood. Recent studies have shown that the notch signaling pathway is an integral component of cardiac angiogenesis. We tested, in a clinically relevant swine model, the effects of MetS on notch and apoptosis signaling in chronically ischemic myocardium. METHODS: Ossabaw swine were fed either a regular diet (control [CTL], n = 8) or a high-cholesterol diet (MetS, n = 8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, the wine underwent cardiac harvest of the ischemic myocardium. RESULTS: Downregulation of pro-angiogenesis proteins notch2, notch4, jagged2, angiopoietin 1, and endothelial nitric oxide synthase were found in the MetS group compared with the CTL group. Also, upregulation of pro-apoptosis protein caspase 8 and downregulation of anti-angiogenesis protein phosphorylated forkhead box transcription factor 03 and pro-survival proteins phosphorylated P38 and heat shock protein 90 were present in the MetS group. Cell death was increased in the MetS group compared with the CTL group. Both CTL and MetS groups had a similar arteriolar count and capillary density, and notch3 and jagged1 were both similarly concentrated in the smooth muscle wall. CONCLUSIONS: MetS in chronic myocardial ischemia significantly impairs notch signaling by downregulating notch receptors, ligands, and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling, and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, suggesting that inhibition of notch signaling might underlie the decreased angiogenesis in later stages of MetS. PMID- 25037623 TI - Twenty-five years' experience of modified Lecompte procedure for the anomalies of ventriculoarterial connection with ventricular septal defect and pulmonary stenosis. AB - OBJECTIVES: To overcome the drawbacks of the Rastelli operation, the modified Lecompte procedure creates a connection from the left ventricle to the aorta with greater freedom from residual obstruction due to the resection of the outlet septum and avoids the implantation of an extracardiac valved conduit. We evaluated the effectiveness of this technique with analysis of our 25-year long term results. METHODS: We reviewed the records of 50 patients who underwent the modified Lecompte procedure during the past 25 years. The median age at operation was 1.95 years (range, 0.30-12.48 years). The diagnoses involved anomalies of the ventriculoarterial connection with ventricular septal defect and pulmonary outflow tract obstruction, such as transposition of the great arteries, double outlet right ventricle, and double outlet left ventricle. RESULTS: There were 2 early deaths (4.0%). During a mean follow-up of 14.2 +/- 7.9 years (range, 0.2-25 years), there were 4 late deaths. Actuarial survival was 87.3% +/- 4.9% at 25 years. The freedom from arrhythmia and reoperation at 25 years was 87.7% +/- 6.2% and 25.2% +/- 9.4%, respectively. The freedom from reoperation for left ventricular outflow tract obstruction and right ventricular outflow tract obstruction at 25 years was 88.5% +/- 5.4% and 49.6% +/- 9.0%, respectively. At last follow-up, 43 survivors (97.7%) are in New York Heart Association class I. CONCLUSIONS: The modified Lecompte procedure has excellent long-term results for treating anomalies of ventriculoarterial connection with ventricular septal defect and pulmonary outflow tract obstruction. Early repair is possible with low mortality and morbidity in terms of arrhythmia, reoperation for right or left ventricular outflow tract obstruction, and functional class. PMID- 25037617 TI - Technical performance score is associated with outcomes after the Norwood procedure. AB - OBJECTIVES: The technical performance score (TPS) has been reported in a single center study to predict the outcomes after congenital cardiac surgery. We sought to determine the association of the TPS with outcomes in patients undergoing the Norwood procedure in the Single Ventricle Reconstruction trial. METHODS: We calculated the TPS (class 1, optimal; class 2, adequate; class 3, inadequate) according to the predischarge echocardiograms analyzed in a core laboratory and unplanned reinterventions that occurred before discharge from the Norwood hospitalization. Multivariable regression examined the association of the TPS with interval to first extubation, Norwood length of stay, death or transplantation, unplanned postdischarge reinterventions, and neurodevelopment at 14 months old. RESULTS: Of 549 patients undergoing a Norwood procedure, 356 (65%) had an echocardiogram adequate to assess atrial septal restriction or arch obstruction or an unplanned reintervention, enabling calculation of the TPS. On multivariable regression, adjusting for preoperative variables, a better TPS was an independent predictor of a shorter interval to first extubation (P=.019), better transplant-free survival before Norwood discharge (P<.001; odds ratio, 9.1 for inadequate vs optimal), shorter hospital length of stay (P<.001), fewer unplanned reinterventions between Norwood discharge and stage II (P=.004), and a higher Bayley II psychomotor development index at 14 months (P=.031). The TPS was not associated with transplant-free survival after Norwood discharge, unplanned reinterventions after stage II, or the Bayley II mental development index at 14 months. CONCLUSIONS: TPS is an independent predictor of important outcomes after Norwood and could serve as a tool for quality improvement. PMID- 25037626 TI - [Quality assurance, certification and the new Institute for Quality in Medicine]. AB - The political partners of the new coalition federal government in Germany have agreed on the founding of a new Institute for Quality in Medicine based on a law regulating more transparency in the quality assessment of hospitals. How can such an institute find its place in the already existing diverse landscape of quality control and quality management in the German health care system? PMID- 25037627 TI - [Selected services rights for attending physicians]. AB - Individual health insurance companies again and again refuse the remuneration of invoices submitted by attending physicians for purely private patients or for compulsory health insurance patients with additional private insurance. As a rule the refusal is based on legal precedents or sub-statutory regulations. This article aims to help attending physicians to react argumentatively to a possible rejection of private medical billing by insurance companies for inpatient attending physician services provided. PMID- 25037625 TI - Advances in understanding the cell types and approaches used for generating induced pluripotent stem cells. AB - Successfully reprogramming somatic cells to a pluripotent state generates induced pluripotent stem (iPS) cells (or iPSCs), which have extensive self-renewal capacity like embryonic stem cells (ESCs). iPSCs can also generate daughter cells that can further undergo differentiation into various lineages or terminally differentiate to reach their final functional state. The discovery of how to produce iPSCs opened a new field of stem cell research with both intellectual and therapeutic benefits. The huge potential implications of disease-specific or patient-specific iPSCs have impelled scientists to solve problems hindering their applications in clinical medicine, especially the issues of convenience and safety. To determine the range of tissue types amenable to reprogramming as well as their particular characteristics, cells from three embryonic germ layers have been assessed, and the advantages that some tissue origins have over fibroblast origins concerning efficiency and accessibility have been elucidated. To provide safe iPSCs in an efficient and convenient way, the delivery systems and combinations of inducing factors as well as the chemicals used to generate iPSCs have also been significantly improved in addition to the efforts on finding better donor cells. Currently, iPSCs can be generated without c-Myc and Klf4 oncogenes, and non-viral delivery integration-free chemically mediated reprogramming methods have been successfully employed with relatively satisfactory efficiency. This paper will review recent advances in iPS technology by highlighting tissue origin and generation of iPSCs. The obstacles that need to be overcome for clinical applications of iPSCs are also discussed. PMID- 25037628 TI - Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme B+ CD8+ T cells with potential antitumor activity. AB - Although the accumulation of highly-differentiated and granzyme B (GrB) expressing CD8(+)CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques, and mice, and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+)CD8(+) T cells by presenting endogenous antigens and using the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and its capacity to evoke the generation of GrB(+)CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4 1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly. PMID- 25037629 TI - Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. AB - Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4 2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative. PMID- 25037631 TI - The molecular mechanism of species-specific recognition of lipopolysaccharides by the MD-2/TLR4 receptor complex. AB - Lipid A, a component of bacterial lipopolysaccharide, is a conserved microbe associated molecular pattern that activates the MD-2/TLR4 receptor complex. Nevertheless, bacteria produce lipid A molecules of considerable structural diversity. The human MD-2/TLR4 receptor most efficiently recognizes hexaacylated bisphosphorylated lipid A produced by enterobacteria, but in some animal species the immune response can be elicited also by alternative lipid A varieties, such as tetraacylated lipid IVa or pentaacylated lipid A of Rhodobacter spheroides. Several crystal structures revealed that hexaacylated lipid A and tetraacylated lipid IVa activate the murine MD-2/TLR4 in a similar manner, but failed to explain the antagonistic vs. agonistic activity of lipid IVa in the human vs. equine receptor, respectively. Targeted mutagenesis studies of the receptor complex revealed intricate combination of electrostatic and hydrophobic interactions primarily within the MD-2 co-receptor, but with a contribution of TLR4 as well, that contribute to species-specific recognition of lipid A. We will review current knowledge regarding lipid A diversity and species-specific activation of the MD-2/TLR4 receptor complex in different species (e.g. human, mouse or equine) by lipid A varieties. PMID- 25037632 TI - Microbe- and danger-induced inflammation. AB - The ability of the immune system to give rise to an effective response against pathogens while maintaining tolerance towards self-tissues has always been an object of keen interest for immunologist. Over the years, different theories have been proposed to explain if and how the immune system is able to discriminate between self and non-self, including the Infectious Non-self theory from Charles Janeway and Polly Matzinger's Danger theory. Nowadays we know Janeway's theory is largely true, however the immune system does respond to injured, stressed and necrotic cells releasing danger signals (DAMPs) with a potent inflammatory response. To avoid unwanted prolonged autoimmune reactions, though, danger induced inflammation should be tightly regulated. In the present review we discuss how prototypic DAMPs are able to induce inflammation and the peculiarity of danger-induced inflammation, as opposed to a complete immune response to fight pathogen invasions. PMID- 25037630 TI - Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. AB - Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug. PMID- 25037633 TI - A vital role for complement in heart disease. AB - Heart diseases are common and significant contributors to worldwide mortality and morbidity. During recent years complement mediated inflammation has been shown to be an important player in a variety of heart diseases. Despite some negative results from clinical trials using complement inhibitors, emerging evidence points to an association between the complement system and heart diseases. Thus, complement seems to be important in coronary heart disease as well as in heart failure, where several studies underscore the prognostic importance of complement activation. Furthermore, patients with atrial fibrillation often share risk factors both with coronary heart disease and heart failure, and there is some evidence implicating complement activation in atrial fibrillation. Moreover, Chagas heart disease, a protozoal infection, is an important cause of heart failure in Latin America, and the complement system is crucial for the protozoa host interaction. Thus, complement activation appears to be involved in the pathophysiology of a diverse range of cardiac conditions. Determination of the exact role of complement in the various heart diseases will hopefully help to identify patients that might benefit from therapeutic complement intervention. PMID- 25037634 TI - Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. AB - Complement deficiencies comprise between 1 and 10% of all primary immunodeficiencies (PIDs) according to national and supranational registries. They are still considered rare and even of less clinical importance. This not only reflects (as in all PIDs) a great lack of awareness among clinicians and general practitioners but is also due to the fact that only few centers worldwide provide a comprehensive laboratory complement analysis. To enable early identification, our aim is to present warning signs for complement deficiencies and recommendations for diagnostic approach. The genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune diseases whereas individuals, deficient of properdin or of the terminal pathway components (C5 to C9), are highly susceptible to meningococcal disease. Deficiency of C1 Inhibitor (hereditary angioedema, HAE) results in episodic angioedema, which in a considerable number of patients with identical symptoms also occurs in factor XII mutations. New clinical entities are now reported indicating disease association with partial complement defects or even certain polymorphisms (factor H, MBL, MASPs). Mutations affecting the regulators factor H, factor I, or CD46 and of C3 and factor B leading to severe dysregulation of the alternative pathway have been associated with renal disorders, such as atypical hemolytic uremic syndrome (aHUS) and - less frequent with membranoproliferative glomerulonephritis (MPGN). We suggest a multi-stage diagnostic protocol starting based on the recognition of so called warning signs which should aid pediatricians and adult physicians in a timely identification followed by a step-wise complement analysis to characterize the defect at functional, protein and molecular level. PMID- 25037635 TI - Accuracy and efficiency of determining urinary calculi composition using dual energy computed tomography compared with Hounsfield unit measurements for practicing physicians. AB - OBJECTIVE: To compare speed and accuracy for determining urinary calculi composition between dual-energy computed tomography (DECT) and Hounsfield unit (HU) measurements of calculi by a set of reviewers at varying levels of training and practice. MATERIALS AND METHODS: Sixteen patients with known stone composition were randomly selected. Fourteen reviewers of varying levels of practice interpreted DECT and HU images from the selected patients to predict stone composition in 2 sessions (day 1: tutorial or flow sheet available for image interpretation and day 2: tutorial or flow sheet not available). Reviewers recorded HU values, stone color, and predicted stone composition as they were timed. Accuracy of image interpretation, determination of calculi composition, and interpretation time were compared. RESULTS: DECT accuracy: image interpretation 100% (day 1) and 94% (day 2); predicted stone composition: 100% (day 1) and 73% (day 2). Mean interpretation time was the same for both days, 21 seconds per study (range, 11-40 seconds). HU accuracy: image interpretation 97% (day 1) and 91% (day 2); predicted stone composition was 45% accurate on both days. Mean interpretation time was 53 seconds per study (range, 28-79 seconds) and 41 seconds per study (range, 19-71 seconds) on days 1 and 2, respectively. Overall accuracy of determination of stone composition and interpretation time for DECT were essentially double those of the HU images (87% vs 45% and 21 vs 47 seconds, respectively). Reviewer's experience level did not affect accuracy or speed. CONCLUSION: DECT is easier to learn, faster to interpret, and more accurate than HU in determining urinary calculi composition for physicians at various levels of training and practice. PMID- 25037636 TI - A label-free activatable aptamer probe for colorimetric detection of cancer cells based on binding-triggered in situ catalysis of split DNAzyme. AB - A novel label-free tailed hairpin-shaped activatable aptamer probe (THAAP) was developed by rationally integrating an aptamer and a split G-quadruplex into one sequence. Based on target recognition-triggered in situ catalysis of split DNAzyme, the THAAP strategy achieved a simple, fast, washing-free, specific and quantitative colorimetric assay of human leukemic CCRF-CEM cells. PMID- 25037637 TI - Validation of self-reported diagnosis of diabetes in the 1946 British birth cohort. AB - The aim of this study was to validate self-reported diabetes and age at diagnosis among a sample of the British population, using general practitioners (GPs) as the reference standard. Using data from the Medical Research Council National Survey of Health and Development (NSHD), self-reported diabetes was determined either in response to a direct question at five follow-ups between 1977 and 2010, or from other self-reported medical information. A validation questionnaire was sent to the GP for all participants who reported a diagnosis of diabetes and gave permission to contact their GP (172). The validity of self-reported diabetes was assessed by calculating the percentage of self-reported diabetes cases that were confirmed by their GP, i.e. the positive predictive value (PPV). The difference between self-reported and GP-confirmed age at diagnosis was analysed with a Bland Altman plot. Completed questionnaires were obtained from 157 GPs (91.2%). Of these, 149 confirmed their patient self-reported diabetes diagnosis (PPV=94.9%). Results were similar when self-reported diabetes was assessed by responses to direct questions only (PPV=95.4%). The average difference between self-reported and GP-reported age at diagnosis was 0.6 years (95% CI 0.2-1.1). We conclude that among the British population questionnaires are a valid method to assess GP diagnosed diabetes, as measured by responses to a direct question or by patient reported medical information. PMID- 25037638 TI - Guidelines for reporting of statistics in European Urology. PMID- 25037639 TI - The expanding role of body mass in active surveillance for prostate cancer. PMID- 25037640 TI - Reply to Alexander S. Parker, Brad C. Leibovich, Jeanette E. Eckel-Passow, John C. Cheville's letter to the editor re: Samira A. Brooks, A. Rose Brannon, Joel S. Parker, et al. ClearCode34: a prognostic risk predictor for localized clear cell renal cell carcinoma. Eur Urol 2014;66:77-84. PMID- 25037641 TI - Bacterial Anabaena variabilis phenylalanine ammonia lyase: a biocatalyst with broad substrate specificity. AB - Phenylalanine ammonia lyases (PALs) catalyse the regio- and stereoselective hydroamination of cinnamic acid analogues to yield optically enriched alpha-amino acids. Herein, we demonstrate that a bacterial PAL from Anabaena variabilis (AvPAL) displays significantly higher activity towards a series of non-natural substrates than previously described eukaryotic PALs. Biotransformations performed on a preparative scale led to the synthesis of the 2-chloro- and 4 trifluoromethyl-phenylalanine derivatives in excellent ee, highlighting the enormous potential of bacterial PALs as biocatalysts for the synthesis of high value, non-natural amino acids. PMID- 25037642 TI - Estimating daily salt intake based on 24 h urinary sodium excretion in adults aged 18-69 years in Shandong, China. AB - OBJECTIVE: 24 h urinary sodium extretion was used to estimate the daily salt intake of shandong residents aged from 18 to 69 years in China. SETTING: 20 selected counties/districts in Shandong stratified by geographic region (Eastern, Central Southern and North Western) and residence type (urban vs rural). PARTICIPANTS: Among 2184 randomly selected adults, 2061 provided usable 24 h urine samples. Urine volume <500 mL or male creatinine <3.81 (female creatinine <4.57) are not included in the analysis. RESULTS: The mean sodium level excreted over 24 h was 237.61 mmol (95% CI 224.77 to 250.44) mmol. Overall, the estimated mean salt intake was 13.90 g/day (95% CI 13.15 to 14.65). The mean salt intake among rural residents was higher than that among urban residents (14.00 vs 13.68 g; p<0.01). Salt intake in men was higher than that in women (14.40 vs 13.37 g; p<0.01). Approximately 96% of the survey participants had a dietary salt intake of >=6 g/day. CONCLUSIONS: The salt intake in Shandong is alarmingly higher than the current recommended amount (6 g/day). Thus, effective interventions to reduce salt intake levels to combat the increasing burden of non-communicable diseases need to be developed and implemented. PMID- 25037644 TI - Assessing the effect of an interactive decision-aid smartphone smoking cessation application (app) on quit rates: a double-blind automated randomised control trial protocol. AB - INTRODUCTION: In a previous study exploring the feasibility of a smoking cessation application (app), we found that about 77% of the respondents from three countries were ready to quit in the next 30 days without significant differences between countries in terms of age, operating system and number of quitting attempts. However, the efficacy of smartphone apps for smoking cessation has not yet been established. This study tests the efficacy of a smartphone smoking cessation decision-aid app compared with an app that contains only smoking cessation information. METHODS AND ANALYSIS: This is an automated double blind, randomised controlled trial of a smoking cessation app that contains the eligibility requirements and baseline questionnaire and will randomise the participants into one of the two subapps (the intervention and the control). Participants will be recruited directly from the Apple app stores in Australia, Singapore, the UK and the USA. Daily smokers aged 18 and above will be randomised into one of the subapps after completing the baseline questionnaire. Abstinence rates will be measured at 10 days, 1 month, 3 months and 6 months, with the 1 month follow-up abstinence rate as the primary outcome. Logistic regression mixed models will be used to analyse the primary outcome. ETHICS AND DISSEMINATION: This study was approved by the University of Sydney's Human Ethics Committee. The results of the trial will be published in peer-reviewed journals according to the CONSORT statement. TRIAL REGISTRATION NUMBER: Australian New Zealand ClinicalTrial RegistryACTRN12613000833763. PMID- 25037643 TI - Pop, heavy metal and the blues: secondary analysis of persistent organic pollutants (POP), heavy metals and depressive symptoms in the NHANES National Epidemiological Survey. AB - OBJECTIVES: Persistent environmental pollutants, including heavy metals and persistent organic pollutants (POPs), have a ubiquitous presence. Many of these pollutants affect neurobiological processes, either accidentally or by design. The aim of this study was to explore the associations between assayed measures of POPs and heavy metals and depressive symptoms. We hypothesised that higher levels of pollutants and metals would be associated with depressive symptoms. SETTING: National Health and Nutrition Examination Survey (NHANES). PARTICIPANTS: A total of 15 140 eligible people were included across the three examined waves of NHANES. PRIMARY AND SECONDARY OUTCOME MEASURES: Depressive symptoms were assessed using the nine-item version of the Patient Health Questionnaire (PHQ-9), using a cut-off point of 9/10 as likely depression cases. Organic pollutants and heavy metals, including cadmium, lead and mercury, as well as polyfluorinated compounds (PFCs), pesticides, phenols and phthalates, were measured in blood or urine. RESULTS: Higher cadmium was positively associated with depression (adjusted Prevalence Ratios (PR)=1.48, 95% CI 1.16 to 1.90). Higher levels of mercury were negatively associated with depression (adjusted PR=0.62, 95% CI 0.50 to 0.78), and mercury was associated with increased fish consumption (n=5500, r=0.366, p<0.001). In addition, several PFCs (perfluorooctanoic acid, perfluorohexane sulfonic acid, perfluorodecanoic acid and perfluorononanoic acid) were negatively associated with the prevalence of depression. CONCLUSIONS: Cadmium was associated with an increased likelihood of depression. Contrary to hypotheses, many of persistent environmental pollutants were not associated or negatively associated with depression. While the inverse association between mercury and depressive symptoms may be explained by a protective role for fish consumption, the negative associations with other pollutants remains unclear. This exploratory study suggests the need for further investigation of the role of various agents and classes of agents in the pathophysiology of depression. PMID- 25037646 TI - Experimentally induced stress, oxidative load and changes in immunity in a tropical wild bird, Perdicula asiatica: involvement of melatonin and glucocorticoid receptors. AB - Throughout the year, birds encounter various environmental challenges such as extreme temperatures, rainfall and shortage of food. Here we report on the effect of stress on the general immunity of wild birds as measured by several assays including melatonin, an anti-stress hormone. We selected Perdicula asiatica, a wild tropical bird, and exposed them to experimental stressors such as water deprivation, food deprivation and immobilization, i.e., stressors that they would encounter in a natural environment. We measured the oxidative load in the spleen in terms of superoxide dismutase (SOD), catalase activity and thiobarbituric acid reactive substance (TBARS) levels. The immune status was judged by total leukocyte count (TLC), heterophil/lymphocyte ratios (H/L) and percent stimulation ratio of splenocytes (%SR). The peripheral levels of melatonin and corticosterone were also determined and correlated with the expression of melatonin (Mel(1a)/Mel(1b)) and glucocorticoid receptors. Our results showed a significant (p < 0.05) decrease in splenic SOD and catalase activity, while a significant (p < 0.05) increase in TBARS and a corticosterone level was observed. Stressful conditions also decreased the immune status as reflected by the low values of H/L ratios, TLC and %SR. In contrast, melatonin pretreatment significantly (p < 0.05) reduced the oxidative stress and improved the immune parameters when compared to untreated control birds. This suggests that melatonin prevents/alleviates oxidative damage and suppresses the immune status induced by stressful conditions via its membrane receptor expression (Mel(1a) and Mel(1b)) in P. asiatica. PMID- 25037645 TI - Public acceptability of financial incentives for smoking cessation in pregnancy and breast feeding: a survey of the British public. AB - OBJECTIVE: To survey public attitudes about incentives for smoking cessation in pregnancy and for breast feeding to inform trial design. DESIGN: Cross-sectional survey. SETTING AND PARTICIPANTS: British general public. METHODS: Seven promising incentive strategies had been identified from evidence syntheses and qualitative interview data from service users and providers. These were shopping vouchers for: (1) validated smoking cessation in pregnancy and (2) after birth; (3) for a smoke-free home; (4) for proven breast feeding; (5) a free breast pump; (6) payments to health services for reaching smoking cessation in pregnancy targets and (7) breastfeeding targets. Ipsos MORI used area quota sampling and home-administered computer-assisted questionnaires, with randomised question order to assess agreement with different incentives (measured on a five-point scale). Demographic data and target behaviour experience were recorded. Analysis used multivariable ordered logit models. RESULTS: Agreement with incentives was mixed (ranging from 34% to 46%) among a representative sample of 1144 British adults. Mean agreement score was highest for a free breast pump, and lowest for incentives for smoking abstinence after birth. More women disagreed with shopping vouchers than men. Those with lower levels of education disagreed more with smoking cessation incentives and a breast pump. Those aged 44 or under agreed more with all incentive strategies compared with those aged 65 and over, particularly provider targets for smoking cessation. Non-white ethnic groups agreed particularly with breastfeeding incentives. Current smokers with previous stop attempts and respondents who had breast fed children agreed with providing vouchers for the respective behaviours. Up to L40/month vouchers for behaviour change were acceptable (>85%). CONCLUSIONS: Women and the less educated were more likely to disagree, but men and women of childbearing age to agree, with incentives designed for their benefit. Trials evaluating reach, impact on health inequalities and ethnic groups are required prior to implementing incentive interventions. TRIAL REGISTRATION NUMBER: CRD42012001980. PMID- 25037647 TI - Restoration of an endangered plant, Hygrophila pogonocalyx, leads to an adaptive host shift of the chocolate pansy (Junonia iphita iphita). AB - Anthropogenic introduction of a plant species may cause novel encounters between the plant and local herbivores, and initiate evolutionary changes in host plant usage by herbivores. Until recently the endemic aquatic plant Hygrophila pogonocalyx was endangered and had a restricted distribution in Taiwan. Massive restoration efforts since 1997 have led to an expansion of the plant's distribution and a novel encounter between it and an Asian butterfly, the chocolate pansy, Junonia iphita (Nymphalidae). This butterfly appears to have colonized H. pogonocalyx, switching from its original host, Strobilanthes penstemonoides var. formosana. In the present study, we aimed to investigate whether the utilization of H. pogonocalyx as a host plant has initiated a differentiation between butterflies using the novel and the original hosts. To this purpose we collected butterflies from patches of the two host plants which grow sympatrically. We tested oviposition preference for the two hosts and larval performance on them. Female adults exhibited distinct oviposition preference toward the host plant their mothers preferred. Offspring showed greater survivorship and pupal weight when fed on the host plant their mothers preferred. Male adults displayed territorial behaviors on the host plant that their mothers had preferred. Finally, the survival rate of offspring produced from cross-mating between individuals with different host plant preference was lower than that of non-hybrids. Taken together, we suggest that genetic differentiation has occurred between individuals preferring H. pogonocalyx versus S. penstemonoides as host plants via host shifting. This process was likely induced by the mass restoration of the formerly rare and endangered plant species. PMID- 25037648 TI - An Abnormal EXTEM in the Setting of a High Heparin Concentration. PMID- 25037649 TI - Feasibility and precision of subcutaneous continuous glucose monitoring in patients undergoing CABG surgery. AB - OBJECTIVES: To evaluate if subcutaneous continuous glucose monitoring (sCGM) is feasible in cardiac surgery and if reliable glucose values are reported under hypothermic extracorporeal circulation. DESIGN: Feasibility trial. SETTING: University hospital. PARTICIPANTS: Ten consecutive patients undergoing coronary artery bypass grafting. INTERVENTIONS: Prior to surgery, during hypothermic extracorporeal bypass, and 48 hours postoperatively, arterial blood glucose samples were compared with sCGM every 30 minutes. Statistical analysis utilized Clarke's error grid and Bland-Altman plot. MEASUREMENTS AND MAIN RESULTS: Three hundred fifty-one pairs of glucose measurements were recorded including 59 during hypothermic extracorporeal circulation. Agreement between these measurements was acceptable, with a regression line slope of 0.88 and an offset of 17.4 (p = 0.87). Error grid analysis indicated a safe margin of 99.1% within zone A (no clinical action needed) or zone B (values would not lead to inappropriate treatment). Only 0.9% were plotted in zone D (potentially dangerous failure). Measurements during hypothermic extracorporeal circulation were comparable. Correlation coefficient was 0.760. The offset regression line was more pronounced (50.9) with a flatter slope (0.640). Within the error grid all plot values were in zone A or B. CONCLUSIONS: sCGM compared with arterial blood gas glucose monitoring under hypothermic extracorporeal circulation appears to be feasible and reliable. PMID- 25037650 TI - Continuing antiplatelet therapy before cardiac surgery. PMID- 25037651 TI - An elastic band exercise program for older adults using wheelchairs in Taiwan nursing homes: a cluster randomized trial. AB - BACKGROUND: The number of older adults using wheelchairs in nursing homes is over 50% of that population, and many of them use wheelchairs due to muscle weakness in the lower extremities. Muscles of older adults are trainable, and progressive resistance exercises using elastic bands can increase muscle strength in older adults. OBJECTIVES: To test the effectiveness of six-month Wheelchair-bound Senior Elastic Band exercises on the functional fitness of older adults in nursing homes. DESIGN: Cluster randomized trial. SETTINGS: Ten nursing homes, southern Taiwan. PARTICIPANTS: 127 participants were recruited, and 114 of them completed the study. Inclusion criteria were: (1) aged 65 and over, (2) using wheelchairs for mobility, (3) living in the facility for at least three months, (4) cognitively intact, and (5) heavily or moderate dependency in their activities of daily living. The mean age of the participants was 79.15 (7.03) years, and 98.20% of them had chronic illnesses. METHODS: Participants were randomly assigned to the experimental (five nursing homes, n=59) or the control (five nursing homes, n=55) group based on the nursing homes where they stayed. A 40-min Wheelchair-bound Senior Elastic Band exercise program was implemented three times per week for six months for the experimental group participants. The functional fitness (activities of daily living, lung capacity, body flexibilities, muscle power and endurance) of the participants was examined at baseline, after three months, and at the end of the six months study. The mixed design, two-way analysis of variance was used to detect the interaction effects, and one-way repeated measures analysis of variance and analysis of covariance were performed to analyze the within-group and between-group differences. RESULTS: At the end of the six-month study, the Wheelchair-bound Senior Elastic Band group had better performances in all of the functional fitness indicators than the control group (all p<0.05). CONCLUSIONS: The Wheelchair-bound Senior Elastic Band exercises significantly improved the functional fitness of the older adults in wheelchairs. It is suggested that the program be incorporated as a part of daily activities for nursing home older adults in wheelchairs. PMID- 25037652 TI - Postmastectomy radiotherapy: indications and implications. AB - BACKGROUND: Although breast conservation surgery, when combined with radiotherapy, has been shown to provide excellent locoregional control for breast cancer, approximately one third of women with breast cancer require mastectomy. Many of these women are offered immediate reconstruction. Postmastectomy radiotherapy (PMRT) is indicated in some cases, but is associated with side effects, including its impact on the reconstructed breast. OBJECTIVE: To review the pertinent issues surrounding PMRT, including patient selection for radiotherapy and the effect of radiotherapy on reconstructive decisions. METHODS: A literature review was performed using the Medline database. CONCLUSIONS: PMRT is indicated in patients who are deemed to have a high risk of loco-regional recurrence. Although PMRT is strongly recommended for patients with four or more positive lymphnodes, other indications for PMRT remain controversial. Immediate reconstruction post mastectomy has been shown to have favorable outcomes. However, PMRT may increase the need for revision surgery post immediate reconstruction. There are few randomized trials looking at these key issues, and the evidence is largely derived from observational retrospective studies. Patients should be carefully counseled before a decision is made to proceed with immediate reconstruction, where there is a high chance that PMRT may be indicated. PMID- 25037653 TI - Evaluation of somatosensory cortical processing in extremely preterm infants at term with MEG and EEG. AB - OBJECTIVE: Prior studies on extremely preterm infants have reported long-term prognostic value of absent secondary somatosensory cortex (SII) responses in magnetoencephalography (MEG) at term. The present work (i) further examines the potential added value of SII responses in neonatal neurological evaluation of preterm infants, and (ii) tests whether SII responses are detectable in routine neonatal electroencephalogram complemented with median nerve stimulation (EEG SEP). METHODS: Altogether 29 infants born <28 gestational weeks underwent MEG, MRI, and neonatal neurological examination at term age, and Hempel neurological examination at 2-years corrected age. Term-age EEG-SEP was available for seven infants. RESULTS: While in neonatal neurological examination severely abnormal finding predicted unfavorable outcome in 2/2 infants, outcome was unfavorable also in 3/9 (33%) moderately abnormal and in 5/18 (28%) mildly abnormal/normal infants. Of these eight infants four had unilaterally absent SII responses in MEG, compared with only two of the 24 infants with favorable outcome. Furthermore, SII responses (when present in MEG) were also usually detectable in EEG-SEP. CONCLUSIONS: Complementing clinical EEG recording with SEP holds promise for valuable extension of neonatal neurophysiological assessment. SIGNIFICANCE: Multimodal study of EEG and sensory evoked responses is informative, safe, and cheap, and it can be readily performed at bedside. PMID- 25037655 TI - Clinical neurophysiology in multiple sclerosis--from diagnostic tool to biomarker. PMID- 25037654 TI - Motivational significance and cognitive effort elicit different late positive potentials. AB - OBJECTIVE: The interaction between affective and cognitive processes has been examined using the late positive potential (LPP) component of the event-related brain potential. The LPP is elicited not only by affective stimuli but also by nonaffective stimuli that require effortful cognitive processing. However, it is unclear whether these LPPs are equivalent. The present study decomposed the LPP into subcomponents that responded differently to affective content and cognitive demands. METHODS: The participants (N=21) performed four types of revised oddball tasks, in which one affective and five nonaffective pictures were presented. For one of the nonaffective pictures, different cognitive demands were loaded: viewing the display, updating a count, updating two different items, or concealing knowledge of the picture. RESULTS: A temporal-spatial principal component analysis revealed two major subcomponents of the LPP. The central parietal subcomponent was elicited by affective stimuli, whereas the occipital subcomponent was elicited by nonaffective stimuli with cognitive demands in the two-item updating and concealment conditions. CONCLUSIONS: The results suggest that the central-parietal dominant LPP may reflect motivated attentional processing, whereas the occipital dominant LPP may reflect effortful controlled processing. SIGNIFICANCE: Dealing with these two LPP subcomponents separately may be useful for examining the interaction between affective and cognitive processing of stimuli. PMID- 25037656 TI - Rainmaking. PMID- 25037657 TI - Applied kinesiology: response. PMID- 25037658 TI - Applied kinesiology: author reply. PMID- 25037659 TI - Applied kinesiology. PMID- 25037660 TI - Applied kinesiology: response. PMID- 25037661 TI - Naturopathic medicine. PMID- 25037662 TI - FOMA. PMID- 25037663 TI - Osher Centers named at Northwestern and Vanderbilt. PMID- 25037664 TI - Quotidian choices. PMID- 25037665 TI - Modes of hoping: understanding hope and expectation in the context of a clinical trial of complementary and alternative medicine for chronic pain. AB - This article explores the role of hope in participants' assessments of their expectations, experiences and treatment outcomes. Data analysis focused on semi structured, open-ended interviews with 44 participants, interviewed 3-5 times each over the course of a study evaluating Traditional Chinese Medicine (TCM) for temporomandibular disorders (TMD), a form of chronic orofacial pain. Transcripts were coded and analyzed using qualitative and ethnographic methods. A "Modes of Hoping" (Webb, 2007)(1) framework informed our analysis. Five modes of hoping emerged from participant narratives: Realistic Hope, Wishful Hope, Utopian Hope, Technoscience Hope, and Transcendent Hope. Using this framework, hope is demonstrated as exerting a profound influence over how participants assess and report their expectations. This suggests that researchers interested in measuring expectations and understanding their role in treatment outcomes should consider hope as exercising a multi-faceted and dynamic influence on participants' reporting of expectations and their experience and evaluation of treatment. PMID- 25037666 TI - Prediction of insomnia severity based on cognitive, metacognitive, and emotional variables in college students. AB - OBJECTIVE: Insomnia is the most common sleep disorder whose origin is attributed to various variables. The current study aims to predict the symptoms of insomnia by investigating some of its predictors. METHODS: Numerous variables such as depression and anxiety symptoms, worry, pre-sleep arousal (cognitive arousal and somatic arousal), dysfunctional cognitions, and metacognitive beliefs about sleep were assessed as insomnia predictors. A total of 400 students of Tehran University of Medical Sciences completed the Depression Anxiety Stress Scale (DASS), the Penn State Worry Questionnaire (PSWQ), the Pre-Sleep Arousal Scale (PSAS), the Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS-10), the Metacognitions Questionnaire-Insomnia (MCQ-I), and the Insomnia Severity Index (ISI). RESULTS: All variables were significantly correlated with insomnia symptoms (P < .001). Stepwise multiple regression analysis suggested a predictive model for insomnia including cognitive arousal, dysfunctional beliefs about sleep, metacognitive beliefs about sleep, and depressive symptoms. CONCLUSIONS: The findings underline the significant role of cognitive and metacognitive variables for predicting insomnia symptoms. Moreover, the results suggest that metacognitive beliefs about sleep may need to be considered as a significant component in the context of insomnia. PMID- 25037668 TI - Bibliotherapy to decrease stress and anxiety and increase resilience and mindfulness: a pilot trial. AB - INTRODUCTION: Interventions to decrease stress and enhance resiliency and mindfulness are more likely to be widely implemented if they can be offered without the need for in-person training. The purpose of this study was to assess effectiveness of a self-directed Stress Management and Resiliency Training (SMART) program delivered using only written material for improving stress, resiliency, and mindfulness. METHODS: A total of 37 employees at a large medical center were recruited and given written material on the SMART program. Subjects were instructed to practice the skills presented in the written materials without any additional training. The skills included education about the neuropsychology of stress and resilience, training attention to focus in the present moment, and refining interpretations. Primary outcome measures assessed resilience, perceived stress, anxiety, and quality of life. RESULTS: Out of 37 employees, 34 (89%) enrolled subjects completed the study and provided the baseline and follow-up data. A statistically significant improvement in perceived stress, resilience, mindfulness, anxiety, and quality of life was observed at 12 weeks. CONCLUSION: This study demonstrated that a brief, self-directed program to decrease stress and enhance resilience and mindfulness provided excellent short-term effectiveness for enhancing resilience, mindfulness and quality of life, and decreasing stress and anxiety. PMID- 25037667 TI - Hot flashes severity, complementary and alternative medicine use, and self-rated health in women with breast cancer. AB - CONTEXT: Hot flashes (HF) are a common distressing symptom in women with breast cancer (BC). Current pharmacologic options are moderately effective and are associated with bothersome side effects. Complementary and alternative medicine is commonly used by cancer patients. However, information on the association of hot flashes severity with such use and self-rated health is lacking. OBJECTIVE: To examine the hot flashes severity in women with breast cancer and its association with complementary and alternative medicine use and self-rated health (SRH). DESIGN: Longitudinal multicenter study to assess information needs of cancer outpatients. PARTICIPANTS: Patients with a diagnosis of breast cancer who were scheduled to undergo chemotherapy and/or radiotherapy. OUTCOME MEASURES: Hot flashes severity (0 = not present and 10 = as bad as you can imagine), use of complementary and alternative medicine (yes/no), and self-rating of health (SRH) status post-treatment and six-months thereafter (1-5, higher score = better SRH). RESULTS: The majority of women with HF (mean age = 54.4 years) were Caucasian and married, with higher education, and 93% had received surgical treatment for BC. At the end of treatment, 79% women reported experiencing HF [mean severity = 5.87, standard deviation (SD) = 2.9]; significantly more severe HF were reported by younger women with poor SRH, poor performance status, and those reporting doing spiritual practices. At follow-up, 73% had HF (mean severity = 4.86, SD = 3.0), and more severe HF were reported by younger women with poor self-rated health who had undergone chemotherapy plus radiotherapy, used vitamins, and did not exercise. CONCLUSIONS: A high percentage of women experienced hot flashes at the end of treatment and at six-month follow-up. A significant association of hot flashes severity with spiritual practice, increased vitamin use, and reduced exercise emphasize the need for future studies to confirm the results. This can facilitate safe use of complementary and alternative medicine and favorable outcomes while managing cancer-related hot flashes. PMID- 25037669 TI - Reiki brief report: using Reiki to reduce stress levels in a nine-year-old child. AB - A nine-year-old female with a history of perinatal stroke, seizures, and type-I diabetes was seen for six weeks of Reiki to determine the effects of Reiki on relaxation, and in turn, the prevention of future seizures. The secondary and tertiary aims were to determine the effects of Reiki on sleep patterns and the stress levels of the mother. There was a decrease in stress in both the child and the mother, as measured by a modified Perceived Stress Scale and a Perceived Stress Scale, respectively. There was no change in the child's overall sense of well-being, as measured by a global questionnaire. There was a positive change in sleep patterns on 33.3% of the nights during which the study occurred, as reported on a sleep log kept by the mother. The child and the Reiki Master (a Reiki practitioner who has completed all three levels of Reiki certification training and trains and certifies individuals in the practice of Reiki as well as provides Reiki to individuals) experienced warmth and tingling sensations on the same area of the child during the Reiki sessions. The child relaxed within the first five to seven minutes of each session as reported by the Reiki Master. There were no reports of seizures during this study. Reiki may be a useful adjunct for children with increased stress levels and sleep disturbances secondary to their medical condition. Further research is warranted to evaluate the use of Reiki in children, particularly with a large sample size, and to evaluate the long-term use of Reiki and its effects on adequate sleep. PMID- 25037670 TI - Treating the root cause: acupuncture for the treatment of migraine, menopausal vasomotor symptoms, and chronic insomnia. AB - This case report describes the effectiveness of a single intervention, acupuncture, for relieving or abolishing severe migraines, menopausal vasomotor symptoms, and chronic insomnia and, thus, markedly improving quality of life. A 49-year-old woman was referred for acupuncture treatment of her daily migraines, menopausal vasomotor symptoms, and chronic insomnia. The patient had received polypharmacy treatment for these conditions for several years but had rather limited relief of her symptoms. The patient received 10 weekly or biweekly acupuncture treatments over three months. Her migraines reduced in frequency and intensity after her first acupuncture treatment, and she was able to discontinue use of her migraine medications after her eighth treatment. Subsequently, her menopausal vasomotor symptoms and chronic insomnia resolved. This case illustrates successful treatment of the symptoms of three medical conditions with a single complementary, alternative, and integrative medicine procedure, namely, acupuncture, one of the key elements of traditional Chinese medicine. The patient's medical problems had been treated for years with a multitude of medications, which led to adverse effects and little symptomatic improvement. Providers of complementary, alternative, and integrative medicine and providers practicing allopathic medicine should seek treatment options for their patients that promise to be helpful for various symptoms or diseases, that is, treating the root cause rather than using polypharmacy for various symptoms. PMID- 25037671 TI - Acupuncture for acute stroke, peppermint oil for irritable bowel syndrome, yoga for depression and anxiety, hypnotherapy for smoking cessation, and lime juice for sickle cell anemia. PMID- 25037672 TI - Interprofessional education and integrative healthcare. PMID- 25037673 TI - Secondary arrhythmogenic right ventricular cardiomyopathy decades after operative repair of tetralogy of Fallot. AB - We describe a 47-year-old man who underwent heart transplantation (HT) for severe right-sided heart failure and periodic episodes of ventricular tachycardia (VT) 43 years after operative repair of tetralogy of Fallot (T of F). The right ventricular outflow tract, the site where a patch had been placed 4 decades earlier, was aneurysmal. Such development decades after operative repair of T of F of both aneurysm and episodes of VT is probably more common than previously realized. PMID- 25037674 TI - Comparison of one- and 12-month outcomes of transcatheter aortic valve replacement in patients with severely stenotic bicuspid versus tricuspid aortic valves (results from a multicenter registry). AB - The aim of the study was to evaluate the transcatheter aortic valve replacement (TAVR) in high-risk patients with severe bicuspid aortic valve (BAV) stenosis and to compare the outcomes with a matched group of patients with tricuspid aortic valve. TAVR became an alternative treatment method in high-risk patients with symptomatic aortic stenosis; however, BAV stenosis is regarded as a relative contraindication to TAVR. The study population comprised 28 patients with BAV who underwent TAVR. BAV was diagnosed based on a transesophageal echocardiography. CoreValve and Edwards SAPIEN prostheses were implanted. The control group consisted of 84 patients (3:1 matching) with significant tricuspid aortic valve stenosis treated with TAVR. There were no significant differences between patients with and without BAV in device success (93% vs 93%, p = 1.0), risk of annulus rupture (0% in both groups), or conversion to cardiosurgery (4% vs 0%, respectively, p = 0.25). The postprocedural mean pressure gradient (11.5 +/- 6.4 vs 10.4 +/- 4.5 mm Hg, p = 0.33), aortic regurgitation grade >=2 of 4 (32% vs 23%, p = 0.45), 30-day mortality (4% vs 7%, p = 0.68), and 1-year all-cause mortality (19% vs 18%, p = 1.00) did not differ between the groups. Echocardiography showed well-functioning valve prosthesis with a mean prosthetic valve area of 1.6 +/- 0.4 cm(2) versus 1.7 +/- 0.3 cm(2) (p = 0.73), a mean pressure gradient of 10.3 +/- 5.4 versus 9.8 +/- 2.8 mm Hg (p = 0.64), and aortic regurgitation grade >=2 of 4 (22% vs 22%, p = 1.00) for the 2 groups. In conclusion, selected high-risk patients with BAV can be successfully treated with TAVR, and their outcomes are similar to those reported in patients without BAV. PMID- 25037676 TI - Comparison of the use of hemodynamic support in patients >=80 years versus patients <80 years during high-risk percutaneous coronary interventions (from the Multicenter PROTECT II Randomized Study). AB - The outcomes of hemodynamic support during high-risk percutaneous coronary intervention in the very elderly are unknown. We sought to compare outcomes between the patients >=80 years versus patients <80 years enrolled in the PROTECT II (Prospective Randomized Clinical Trial of Hemodynamic Support with the Impella 2.5 versus Intra-Aortic Balloon Pump in Patients undergoing High Risk Percutaneous Coronary Intervention) randomized trial. Patients who underwent high risk percutaneous coronary intervention with an unprotected left main or last patent conduit and a left ventricular ejection fraction <=35% or with 3-vessel disease and a left ventricular ejection fraction <=30% were randomized to receive an intra-aortic balloon pump or the Impella 2.5; 90-day (or the longest follow up) outcomes were compared between patients >=80 years (n = 59) and patients <80 years (n = 368). At 90 days, the composite end point of major adverse events and major adverse cerebral and cardiac events were similar between patients >=80 and <80 years (45.6% vs 44.1%, p = 0.823, and 23.7% vs 26.8%, p = 0.622, respectively). There were no differences in death, stroke, or myocardial infarction rates between the 2 groups, but fewer repeat revascularization procedures were required in patients >=80 years (1.7% vs 10.4%, p = 0.032). Bleeding and vascular complication rates were low and comparable between the 2 age groups (3.4% vs 2.4%, p = 0.671, and 6.8% vs 5.4%, p = 0.677, respectively). Multivariate analysis confirmed that age was not an independent predictor of major adverse events (odds ratio = 1.031, 95% confidence interval 0.459-2.315, p = 0.941), whereas Impella 2.5 was an independent predictor for improved outcomes irrespective of age (odds ratio = 0.601, 95% confidence interval 0.391-0.923, p = 0.020). In conclusion, the use of percutaneous circulatory support is reasonable and feasible in a selected octogenarian population with similar outcomes as those of younger selected patients. Irrespective of age, the use of Impella 2.5 was an independent predictor of favorable outcomes. PMID- 25037675 TI - Reference values of myocardial structure, function, and tissue composition by cardiac magnetic resonance in healthy African-Americans at 3T and their relations to serologic and cardiovascular risk factors. AB - Cardiac magnetic resonance (CMR) is a standard of reference for cardiac structure and function. Recent advances in T1 mapping and spectroscopy also provide assessment of myocardial tissue composition. However, the reference ranges of left ventricular parameters have rarely been assessed in an African-American (AA) population without known cardiac disease. To estimate the reference values of myocardial structure, function, and tissue composition by CMR and to explore their relationships to serologic factors and cardiovascular risk factors in asymptomatic AAs with low Framingham risk, between November 2010 and June 2012, 92 healthy AAs aged >=21 years, from Baltimore, MD, were enrolled in an observational study. CMR examination was performed on a 3T scanner. Proton magnetic resonance spectroscopy was performed to noninvasively quantify myocardial triglyceride content. Native T1 values were obtained from modified Look-Locker inversion recovery sequence. The median age was 37 (interquartile range IQR 27 to 44) years (41% men). The median native T1 time of the myocardium was 1,228 ms (IQR 1,200 to 1,263) with no gender difference. The median myocardial fat content was 0.6% (IQR 0.7% to 4.6%). Native T1 time was not influenced by age, sex, and body mass index. Among the factors investigated, myocardial fat and elevated C-reactive protein (>2.0 mg/dL) were independently associated with T1 relaxation time. Native T1 time was also independently associated with left ventricular end-diastolic volume indexed to body surface area. In conclusion, this study of asymptomatic AAs provides reference ranges for cardiovascular structure, function, and tissue composition. Alterations in myocardial fat are associated with native T1 time, a CMR measure of interstitial fibrosis. PMID- 25037678 TI - Evaluation of apical subtype of hypertrophic cardiomyopathy using cardiac magnetic resonance imaging with gadolinium enhancement. AB - Apical hypertrophic cardiomyopathy (HC) is an uncommon variant of HC. We sought to characterize cardiac magnetic resonance imaging (MRI) findings among apical HC patients. This was a retrospective review of consecutive patients with a diagnosis of apical HC who underwent cardiac MRI examinations at the Mayo Clinic (Rochester, MN) from August 1999 to October 2011. Clinical and demographic data at the time of cardiac MRI study were abstracted. Cardiac MRI study and 2 dimensional echocardiograms performed within 6 months of the cardiac MRI were reviewed; 96 patients with apical HC underwent cardiac MRI examinations. LV end diastolic and end-systolic volumes were 130.7 +/- 39.1 ml and 44.2 +/- 20.9 ml, respectively. Maximum LV thickness was 19 +/- 5 mm. Hypertrophy extended beyond the apex into other segments in 57 (59.4%) patients. Obstructive physiology was seen in 12 (12.5%) and was more common in the mixed apical phenotype than the pure apical (19.3 vs 2.6%, p = 0.02). Apical pouches were noted in 39 (40.6%) patients. Late gadolinium enhancement (LGE) was present in 70 (74.5%) patients. LGE was associated with severe symptoms and increased maximal LV wall thickness. In conclusion, cardiac MRI is well suited for studying the apical form of HC because of difficulty imaging the cardiac apex with standard echocardiography. Cardiac MRI is uniquely suited to delineate the presence or absence of an apical pouch and abnormal myocardial LGE that may have implications in the natural history of apical HM. In particular, the presence of abnormal LGE is associated with clinical symptoms and increased wall thickness. PMID- 25037677 TI - Comparison of epicardial adipose tissue volume and coronary artery disease severity in asymptomatic adults with versus without diabetes mellitus. AB - Epicardial adipose tissue (EAT) has been shown to have important effects on the development of coronary artery disease (CAD) through local paracrine influences on the vascular bed. We compared a cohort of asymptomatic patients with type II diabetes mellitus (DM) without known CAD to an age- and gender-matched group of asymptomatic patients without DM from the CTRAD (Cardiac CT's Role in Asymptomatic Patients with DM-II) study in which patients underwent a cardiac computed tomography angiogram, for early detection of CAD. Mean EAT volumes of 118.6 +/- 43.0 and 70.0 +/- 44.0 cm(3) were found in the DM and non-DM groups, respectively. When stratified by the presence and severity of CAD, it was found that in the DM (p = 0.003) and non-DM groups (p <0.001), there was a statistically significant increase in EAT volume as the patients were found to have increasingly severe CAD. After adjusting for age, race, gender, DM, hypertension, insulin use, body mass index, and coronary artery calcium (CAC) score, the presence of >120 cm(3) of EAT was found to be highly correlated with the presence of significant CAD (adjusted odds ratio 4.47, 95% confidence interval 1.35 to 14.82). We found that not only is EAT volume an independent predictor of CAD but that an increasing volume of EAT predicted increasing severity of CAD even after adjustment for CAC score. PMID- 25037679 TI - New insights on Carpentier I mitral regurgitation from multidetector row computed tomography. AB - The underlying mechanism of mitral regurgitation (MR) because of isolated annulus dilation (Carpentier type I) remains controversial in patients with atrial fibrillation (AF). The present study evaluated changes in mitral valve geometry of patients with AF and structurally and functionally normal left ventricles and mitral leaflets. Grade of MR and left ventricular (LV) function was evaluated with echocardiography. Changes in mitral valve geometry were evaluated with multidetector row computed tomography (MDCT) performed before radiofrequency catheter ablation for AF. From a cohort of 480 patients with drug-refractory AF referred for catheter ablation, 170 patients (mean age 58 +/- 10 years, 67% men) with structural and functional normal left ventricles and mitral leaflets were included. The intercommissural and anteroposterior diameter, perimeter, and area of the mitral annulus and left atrial volume were assessed with MDCT and correlated with the grade of MR as assessed with echocardiography. A total of 49 patients (29%) had MR >=2+. These patients had larger mitral annulus area compared with patients with MR <2+ (665.0 +/- 100.6 mm(2)/m(2) vs 530.5 +/- 66.6 mm(2)/m(2), p <0.001), whereas LV size and function (ejection fraction 64.9 +/- 6.3% vs 63.1 +/- 5.7%, p = 0.08) were similar. After adjusting for age, type of AF, hypertension, left atrial volume, and LV end-systolic volume and ejection fraction, the mitral annulus dimensions remained independently correlated with MR >=2+. In conclusion, in AF patients with structural and functional normal left ventricles and mitral leaflets, MDCT demonstrated that mitral annulus dilation is independently associated with type I MR. PMID- 25037680 TI - Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy. AB - End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and >=60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p <=0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes. PMID- 25037681 TI - Dimeric guaianolides from Artemisia absinthium. AB - Five dimeric guaianolides, absinthins A-E, and seven known dimeric guaianolides were isolated from Artemisia absinthium. Their structures were elucidated based on 1D- and 2D-NMR experiments, including (1)H NMR, (13)C NMR, DEPT, (1)H-(1)H COSY, HSQC, HMBC, and NOESY, and through HRESIMS data analysis. The absolute configuration of the known compound, anabsinthin, was determined by X-ray crystallographic analysis. The isolated compounds were tested to assess their inhibitory activities on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 cells; absinthin C and isoanabsinthin exhibited significant inhibitory effects with IC50 values of 1.52 and 1.98MUM, respectively. PMID- 25037682 TI - Needle track recurrence after transrectal prostate biopsy detected by 18F-Choline PET-CT. PMID- 25037683 TI - The influence of experiential learning on medical equipment adoption in general practices. AB - The benefits of the availability and use of medical equipment for medical outcomes are understood by physicians and policymakers alike. However, there is limited understanding of the decision-making processes involved in adopting and using new technologies in health care organisations. Our study focuses on the adoption of medical equipment in Irish general practices which are marked by considerable autonomy in terms of commercial practice and the range of medical services they provide. We examine the adoption of six items of medical equipment taking into account commercial, informational and experiential stimuli. Our analysis is based on primary survey data collected from a sample of 601 general practices in Ireland on practice characteristics and medical equipment use. We use a multivariate Probit to identify commonalities in the determinants of the adoption. Many factors, such as GP and practice characteristics, influence medical equipment adoption. In addition, we find significant and consistent evidence of the influence of learning-by-using effects on the adoption of medical equipment in a general practice setting. Knowledge generated by experiential or applied learning can have commercial, organisational and health care provision benefits in small health care organisations. PMID- 25037684 TI - A phase 1b, open-label study of trebananib in combination with paclitaxel and carboplatin in patients with ovarian cancer receiving interval or primary debulking surgery. AB - AIM: To evaluate the tolerability, pharmacokinetics and tumour response of first line trebananib plus paclitaxel and carboplatin followed by trebananib maintenance in high-risk or advanced ovarian cancer. METHODS: In this open-label phase 1b study, patients received intravenous (IV) trebananib 15 mg/kg administered weekly (QW) plus paclitaxel 175 mg/m(2) once every 3 weeks (Q3W) and carboplatin 6 mg/mL . min Q3W followed by trebananib 15 mg/kg QW monotherapy for 18 months. End-points were dose-limiting toxicities (DLTs; primary); treatment emergent adverse events (AEs), anti-trebananib antibodies, pharmacokinetics and tumour response (secondary). RESULTS: Twenty seven patients (interval debulking surgery [IDS], n=13) were enrolled. No DLTs occurred. During the combination therapy phase, AEs (>50%) in patients with IDS were nausea, diarrhoea, fatigue, decreased appetite and thrombocytopenia. In patients with primary debulking surgery (PDS), they were nausea, diarrhoea, fatigue and localised oedema. Grade 4 AEs were neutropenia (IDS, PDS; all n=3) and thrombocytopenia (IDS, PDS; all n=1). No deaths occurred. Toxicity results pertaining to trebananib maintenance were immature. The treatment combination did not markedly affect the pharmacokinetics across agents. In patients with IDS (n=14 after one patient was reassigned from PDS to IDS), 12 patients had a partial response (PR), two patients had stable disease. In patients with PDS (n=4), three patients had a complete response, one patient had a PR. CONCLUSIONS: In women with ovarian cancer receiving IDS or PDS, IV trebananib 15 mg/kg QW plus paclitaxel and carboplatin appears tolerable. Results suggest that the treatment combination followed by trebananib 15 mg/kg monotherapy is associated with antitumour activity. PMID- 25037685 TI - Gender and ethnic differences in health-promoting behaviors of rural adolescents. AB - Although much is known about health-risk behaviors of adolescents, less is known about their health-promoting behaviors. The purpose of this analysis was to compare health-promoting behaviors in adolescents in Grades 9-12 by gender and ethnicity and explore how these behaviors changed over time. Data were collected from 878 rural adolescents (47.5% Hispanic; mean age at baseline 14.7 years). Males from all ethnic groups scored significantly higher than all females on physical activity; non-Hispanic Black males and females scored significantly higher than other ethnic groups on safety behaviors. Hispanic and non-Hispanic White females scored higher than males in these ethnic groups on stress management. Nutrition, physical activity, and safety behaviors decreased significantly for most participants from Grade 9 to 12 whereas stress management remained relatively stable. Findings are similar to those from nationally representative samples that analyzed cross-sectional data and have implications for school nursing interventions to improve health-promoting behaviors in rural adolescents. PMID- 25037687 TI - Difficulties in distinguishing between an atlas fracture and a congenital posterior atlas arch defect in postmortem analysis. AB - We found one atlas from a sample of 148 skeletons (0.67%) that presented different anatomical variations which made it difficult to determine whether the vertebra had an atlas fracture, an unusual Type B posterior atlas arch defect, or a combination of both. We carried out a stereomicroscopy, radiographic, and computerized tomography scan study that revealed that the dry atlas we found presented a very uncommon congenital Type B posterior atlas arch defect, simulating a fracture. In short, the present paper has revealed that differentiating Type B posterior atlas arch defects from fractures in post-mortem dry vertebrae is more difficult than expected. Thus we believe that it can be easier than expected to mistake Type B posterior arch defects for fractures and vice versa in postmortem studies. PMID- 25037688 TI - In-hospital peak glycemia in non-diabetic patients with heart failure complicating acute coronary syndrome. PMID- 25037689 TI - Risk stratification using a combination of left ventricular fibrosis and number of morphological types of ventricular premature beats in cardiomyopathy subjects without obstructed coronary arteries. PMID- 25037690 TI - Blood pressure and heart failure risk among diabetic patients. AB - BACKGROUND: Blood pressure (BP) control has been shown to reduce the risk of heart failure (HF) among diabetic patients; however, it is not known whether the lowest clinical BP achieved ultimately results in the lowest risk of HF in diabetic patients. METHODS: We performed a prospective cohort study which included 17,181 African American and 12,446 white diabetic patients without established coronary heart disease and HF at diabetes diagnosis. Cox proportional hazards regression models were used to estimate the association of different levels of BP stratification with incident HF. RESULTS: During a mean follow up of 6.5 years, 5,089 incident HF cases were identified. The multivariable-adjusted hazard ratios of HF associated with different levels of systolic/diastolic BP (<110/65, 110-119/65-69, 120-129/70-80, 130-139/80-90 [reference group], 140 159/90-100, and >= 160/100 mmHg) were 1.79 (95% confidence interval [CI] 1.53 2.11), 1.34 (95% CI 1.16-1.53), 1.02 (95% CI 0.92-1.13), 1.00, 1.04 (95% CI 0.95 1.12), and 1.26 (95% CI 1.16-1.37) using baseline BP measurements, and 2.63 (95% CI 2.02-3.41), 1.84 (95% CI 1.59-2.13), 1.25 (95% CI 1.14-1.37), 1.00, 1.11 (95% CI 1.03-1.19), and 1.32 (95% CI 1.20-1.44) using an updated mean value of BP during follow-up, respectively. The U-shaped association was confirmed in both patients who were and were not taking antihypertensive drugs, and in incident systolic HF (ejection fraction <= 40%) and incident HF with a preserved ejection fraction (ejection fraction >40%). CONCLUSIONS: The current study suggests a U shaped association between observed BP and the risk of HF among diabetic patients. PMID- 25037686 TI - Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system. AB - Understanding of the innate immune response to viral infections is rapidly progressing, especially with regards to the detection of DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a large dsDNA virus that is responsible for three human diseases: Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. The major target cells of KSHV (B cells and endothelial cells) express a wide range of pattern recognition receptors (PRRs) and play a central role in mobilizing inflammatory responses. On the other hand, KSHV encodes an array of immune evasion genes, including several pirated host genes, which interfere with multiple aspects of the immune response. This review summarizes current understanding of innate immune recognition of KSHV and the role of immune evasion genes that shape the antiviral and inflammatory responses. PMID- 25037691 TI - IGF-1 predicts survival in chronic heart failure. Insights from the T.O.S.CA. (Trattamento Ormonale Nello Scompenso CArdiaco) registry. PMID- 25037692 TI - Prosthetic mitral valve tamponade alternans. PMID- 25037693 TI - Contrast-induced nephropathy and bleeding: a bidirectional link with prognostic value in acute coronary syndrome. PMID- 25037694 TI - Testosterone replacement increases aged pulmonary vein and left atrium arrhythmogenesis with enhanced adrenergic activity. AB - BACKGROUND: Aging and testosterone deficiency contribute to the pathogenesis of atrial fibrillation (AF). We determine the effects of testosterone replacement on the electrophysiology and arrhythmogenesis of pulmonary vein (PV) and left atrium (LA) in aged rabbits. METHODS: Electrocardiography, heart rate variability, echocardiography, Western blot and conventional microelectrodes were used in aged rabbits (age, >2 years) with and without (control) testosterone treatment (10mg/kg, 12 weeks). RESULTS: Testosterone-treated aged rabbits had longer corrected QT interval, higher low frequency/high frequency, greater left ventricle (LV) mass but lower LA total emptying fraction and LV ejection fraction than control rabbits. In tissue preparations, the spontaneous rate was faster for testosterone-treated PVs than for control PVs. Angiotensin II concentration dependently increased the amplitude of delayed afterdepolarizations (DADs) in testosterone-treated PVs but only did so at the highest angiotensin II concentration (100 nM) in control PVs. Isoproterenol increased the incidence of early afterdepolarizations (EADs) and DADs in testosterone-treated PVs but not in control PVs. Testosterone-treated PVs had more H2O2-induced burst firing and EADs than control PVs. Testosterone-treated LAs had more isoproterenol-induced DADs and spontaneous activity than did control LAs. However, acetylcholine infusion and rapid atrial pacing (10-20 Hz) induced AF in control LAs but not in testosterone-treated LAs. In addition, as compared with control LAs, testosterone treated LAs expressed more androgen receptor, beta1-adrenergic receptor, and Cav 1.2 and less G protein-coupled receptor kinase-2 and Kv 4.2. CONCLUSIONS: Testosterone replacement increased arrhythmogenesis in PV and LA by enhancing adrenergic activity in aged rabbits. PMID- 25037695 TI - Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. AB - BACKGROUND: Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy. METHODS: In a Phase 3, randomized, double-blind, double-dummy study (NCT01644474), patients (low-density lipoprotein cholesterol [LDL-C] 100-190 mg/dL, 10-year risk of fatal cardiovascular events >= 1%-<5% [systemic coronary risk estimation]) were randomized to ezetimibe 10mg/day (n=51) or alirocumab 75 mg subcutaneously (via 1-mL autoinjector) every 2 weeks (Q2W) (n=52), with dose up-titrated to 150 mg Q2W (also 1 mL) at week 12 if week 8 LDL-C was >= 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks, analyzed using all available data (intent-to-treat approach, ITT). Analyses using on-treatment LDL-C values were also conducted. RESULTS: Mean (SD) baseline LDL-C levels were 141.1 (27.1) mg/dL (alirocumab) and 138.3 (24.5) mg/dL (ezetimibe). The 24-week treatment period was completed by 85% of alirocumab and 86% of ezetimibe patients. Least squares mean (SE) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe (ITT; p<0.0001) and 54 (2)% versus 17 (2)% (on-treatment; p<0.0001). At week 12, before up-titration, alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% (on-treatment). Injection site reactions were infrequent (<2% and <4% of alirocumab and ezetimibe patients, respectively). CONCLUSIONS: Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide >= 50% LDL-C reduction in the majority of the patients. Adverse events were comparable between groups. PMID- 25037696 TI - Mortality in intra-aortic balloon pump therapy in patients with ST elevation myocardial infarction and cardiogenic shock: data from nationwide inpatient sample. PMID- 25037697 TI - Clinical characteristics and CHADS2 score in patients with heart failure and atrial fibrillation: insights from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). PMID- 25037698 TI - Inflammation, coagulation, weather and arrhythmogenesis: is there a linkage? PMID- 25037699 TI - Excess ROS induced by AAPH causes myocardial hypertrophy in the developing chick embryo. AB - BACKGROUND: The developing embryo is very sensitive to oxidative stress and excess reactive oxygen species (ROS) generation is often associated with cardiovascular malformation. However, little is known about the adverse effects of ROS during heart morphogenesis, especially during the formation of the atria and ventricles. METHODS AND RESULTS: We have treated early chick embryos with 2,2 azobis (2-amidinopropane) dihydrochloride (AAPH) to generate free radicals in the developing heart. We established that excess ROS induced by AAPH caused cardiomegaly to develop in 4-, 14- and 17-day-old embryos. The cardiomyocytes of these AAPH-treated hearts were hypertrophic, in both the compact and trabeculated myocardium. The weight of these hearts was also significantly increased in an AAPH dose-dependent fashion. We examined and compared the functions of the AAPH treated and untreated hearts by echocardiography and determined that the ejection fraction was shortened. BrdU incorporation assay was performed and revealed that cell proliferation was not the main cause of cardiomegaly. However, we established that the cardiomyocytes exposed to excess ROS were distinctively larger than control cardiomyocytes - indicting that cardiomegaly was attributed to hypertrophy. We have also found that excess ROS inhibited Wnt signaling but enhanced VEGF signaling. Consequently, this promoted angiogenesis and caused larger coronary arteries to develop in the AAPH-treated hearts. CONCLUSIONS: We have demonstrated that cardiomyocyte hypertrophy and changes in Wnt and VEGF signaling were the main contributing factors in the development of cardiomegaly induced by oxidative stress. PMID- 25037700 TI - Nutraceuticals in lipid-lowering treatment: a narrative review on the role of chitosan. AB - Lipid-lowering drugs may cause adverse effects and, although lipid targets may be achieved, a substantial residual cardiovascular (CV) risk remains. Treatment with agents mimicking proteins present in the body, such as incretin-based therapies, provided promising results. However, in order to improve lipids and CV risk, lifestyle measures remain important. Some researchers focused on nutraceuticals that may beneficially affect metabolic parameters and minimize CV risk. Chitosan, a dietary fiber, can regulate lipids with benefit on anthropometric parameters. The beneficial properties of dietary supplements (such as green tea extract, prebiotics, plant sterols, and stanols) on plasma lipids, lipoproteins, blood pressure, glucose, and insulin levels and their anti-inflammatory and anti oxidant effects are documented. However, larger, prospective clinical trials are required to confirm such benefits. Such treatments may be recommended when lipid lowering drugs are neither indicated nor tolerated as well as in order to achieve therapeutic targets and/or overcome residual CV risk. PMID- 25037701 TI - Pulmonary tuberculous: Symptoms, diagnosis and treatment. 19-year experience in a third level pediatric hospital. AB - BACKGROUND: Pulmonary tuberculosis (PTB) is an infectious disease that involves the lungs and can be lethal in many cases. Tuberculosis (TB) in children represents 5 to 20% of the total TB cases. However, there are few updated information on pediatric TB, reason why the objective of the present study is to know the real situation of PTB in the population of children in terms of its diagnosis and treatment in a third level pediatric hospital. METHODS: A retrospective study based on a revision of clinical files of patients less than 18 years old diagnosed with PTB from January 1994 to January 2013 at Instituto Nacional de Pediatria, Mexico City was carried out. A probable diagnosis was based on 3 or more of the following: two or more weeks of cough, fever, tuberculin purified protein derivative (PPD) +, previous TB exposure, suggestive chest X-ray, and favorable response to treatment. Definitive diagnosis was based on positive acid-fast bacilli (AFB) or culture. RESULTS: In the 19-year period of revision, 87 children were diagnosed with PTB; 57 (65.5%) had bacteriologic confirmation with ZN staining or culture positive (in fact, 22 were ZN and culture positive), and 30 (34.5%) had a probable diagnosis; 14(16.1%) were diagnosed with concomitant disease, while 69/81 were immunized. Median evolution time was 21 days (5-150). Fever was found in 94.3%, cough in 77%, and weight loss in 55.2%. History of contact with TB was established in 41.9%. Chest X-ray showed consolidation in 48.3% and mediastinal lymph node in 47.1%. PPD was positive in 59.2%, while positive AFB was found in 51.7% cases. Culture was positive in 24/79 patients (30.4%), PCR in 20/27 (74.1%). 39 (44.8%) patients were treated with rifampin, isoniazid, and pyrazinamide while 6 (6.9%) received the former drugs plus streptomycin and 42 (48.3%) the former plus ethambutol. There were three deaths. CONCLUSIONS: PTB in pediatric population represents a diagnostic challenge for the fact that clinical manifestations are unspecific and the diagnosis is not confirmed in all cases; that is why clinical suspicion, X-ray findings and PPD are indispensable for opportune start of treatment. PMID- 25037702 TI - Glutamate release machinery is altered in the frontal cortex of rats with experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is an animal model that mimics many of the clinical and pathological features of the human disease multiple sclerosis (MS). Both are inflammatory demyelinating and neurodegenerative pathologies of the central nervous system associated with motor, sensory, and cognitive deficits. In MS, gray matter atrophy is related to the emergence of cognitive deficits and contributes to clinical progression. In particular, prefrontal cortex injury and dysfunction have been correlated to the development of fatigue, one of the most common and disabling symptoms in MS. However, the molecular bases of these changes remain unknown. Taking advantage of EAE similitude, we herein analyze functional and morphological changes in isolated cortical presynaptic terminals (synaptosomes) from an acute rat model. We found impaired glutamate release in the frontal cortex from EAE rats. This defect appeared along with the onset of the disease, reversing when clinical signs were no more evident. Biochemical analysis of EAE synaptosomes revealed alterations in the presynaptic release machinery and in the response to depolarization, which was accompanied by abnormal synapsin I phosphorylation and dispersion. These changes were associated with reduced synaptic vesicle mobility, with no alterations in synaptosomal morphology as evidenced by electron microscopy. The present are the first pieces of evidence unraveling the molecular mechanisms of frontal cortex neuronal dysfunction in EAE and, possibly, MS. PMID- 25037703 TI - Review of performance-based incentives in community-based family planning programmes. AB - BACKGROUND: One strategy for improving family planning (FP) uptake at the community level is the use of performance-based incentives (PBIs), which offer community distributors financial incentives to recruit more users of FP. This article examines the use of PBIs in community-based FP programmes via a literature search of the peer-reviewed and grey literature conducted in April 2013. RESULTS: A total of 28 community-based FP programmes in 21 countries were identified as having used PBIs. The most common approach was a sales commission model where distributors received commission for FP products sold, while a referral payment model for long-term methods was also used extensively. Six evaluations were identified that specifically examined the impact of the PBI in community-based FP programmes. Overall, the results of the evaluations are mixed and more research is needed; however, the findings suggest that easy-to understand PBIs can be successful in increasing the use of FP at the community level. CONCLUSION: For future use of PBIs in community-based FP programmes it is important to consider the ethics of incentivising FP and ensuring that PBIs are non-coercive and choice-enhancing. PMID- 25037704 TI - Socio-economic indicators and predisposing factors associated with traumatic dental injuries in schoolchildren at Brasilia, Brazil: a cross-sectional, population-based study. AB - BACKGROUND: This study assessed the prevalence of traumatic dental injuries (TDI) and its association with sociodemographic and physical characteristics in the anterior permanent teeth of 12-year-old schoolchildren at the city of Brasilia - DF, Brazil. METHODS: A cross-sectional, population-based study was conducted on a sample of 1,389 boys and girls aged 12 years, enrolled in public and private fundamental schools at the Administrative Region (RA) of Brasilia, Brazil, from October 2011 to September 2012. The demographic details were achieved by a structured questionnaire. The study recorded the type of damage, the size of incisal overjet, and whether lip coverage was inadequate. Sociodemographic data included sex, income and educational level of the parents or caretakers. RESULTS: A total of 1118 schoolchildren were examined, yielding a response rate of 80.48%. The prevalence of TDI was 14.63% in public schools and 23.40% in private schools. The students did not differ according to sex, income and educational level of the parents or caretakers concerning the occurrence of traumas in permanent anterior teeth. Increased overjet and inadequate lip coverage were found to be important contributing factors for TDIs. CONCLUSION: In conclusion, this study showed an expressive prevalence of TDI in 12-year-old in schoolchildren at Brasilia DF, Brazil. Sex and educational level of the parents were not associated with trauma. The increased overjet and inadequate lip coverage were significantly associated with dental trauma. PMID- 25037705 TI - Testicular desmoplastic small round cell tumor: a case report and review of literature. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an uncommon and highly aggressive malignancy with undetermined histogenesis and poor prognosis. To date, no case of testicular DSRCT has been reported in the literature. CASE: A 42-year old Chinese man presented with painless swelling of his left testis and a painless palpable nodule in his left inguinal region. Computed tomography showed a solid mass in the left testis and multiple metastases in the body. Laboratory tests gave no abnormal results. Left radical orchiectomy was performed, and histopathological and molecular pathological examination showed typical features of DSRCT. Six cycles of chemotherapy were administrated after the operation, leading to partial remission. Postoperative 9-month follow-up indicated no progression. PMID- 25037706 TI - Standardization of the Colombian version of the PHQ-4 in the general population. AB - BACKGROUND: The PHQ-4 is a widely used open access screening instrument for depression and anxiety in different health care and community settings; however, empirical evidence of its psychometric quality in Colombia is lacking. The objectives of the current study were to generate normative data and to further investigate the construct validity and factorial structure of the PHQ-4 in the general population. METHODS: A nationally representative face-to-face household survey was conducted in Colombia in 2012 (n = 1,500). The item characteristics of the PHQ-4 items, including the inter-item correlations and inter-subscale correlations, were investigated. To measure the scale's reliability, the internal consistency (Cronbach's alpha) was assessed. For factorial validity, the factor structure of the PHQ-4 was examined with confirmatory factor analysis (CFA). RESULTS: The Cronbach's alpha coefficient for the PHQ-4 was 0.84. The confirmatory factor analysis supported a two-factor model, which was structurally invariant between different age and gender groups. Normative data for the PHQ-4 were generated for both genders and different age levels. Women had significantly higher mean scores compared with men [1.4 (SD: 2.1) vs. 1.1 (SD: 1.9), respectively]. The results supported the discriminant validity of the PHQ-4. CONCLUSIONS: The normative data provide a framework for the interpretation and comparisons of the PHQ-4 with other populations in Colombia. The evidence supports the reliability and validity of the two-factor PHQ-4 as a measure of anxiety and depression in the general Colombian population. PMID- 25037707 TI - Androgen actions in the ovary: balance is key. AB - For many decades, elevated androgens in women have been associated with poor reproductive health. However, recent studies have shown that androgens play a crucial role in women's fertility. The following review provides an overall perspective about how androgens and androgen receptor-mediated actions regulate normal follicular development, as well as discuss emerging concepts, latest perceptions, and controversies regarding androgen actions and signaling in the ovary. PMID- 25037708 TI - The lambda sign: a new radiographic indicator of latent syndesmosis instability. AB - BACKGROUND: Latent syndesmotic instability is a common cause of chronic ankle pain. The diagnosis is not readily apparent on static imaging as the fibula remains reduced. The hypothesis of this study was that a previously undescribed novel finding on coronal MRI (lambda sign) is an independent indicator of latent syndesmosis instability. We also report on the utility of classic radiographic and physical exam findings. METHODS: A total of 23 patients with latent syndesmotic instability diagnosed via arthroscopy (group I) were compared to a cohort of 40 patients who were found to have a stable syndesmosis during arthroscopy for unrelated conditions (group II). A retrospective chart review was performed evaluating their clinical history, preoperative physical examination, and radiologic findings. The lambda sign is a high intensity signal seen on coronal MR imaging that resembles the Greek letter lambda. RESULTS: All of the physical exam findings tested were statistically significant. Pain at the syndesmosis had the highest sensitivity (83%), while pain reproduced with the proximal squeeze test resulted in the highest specificity (89%). The external rotation stress test had the highest positive predictive value (75%). Of the radiographic examinations performed, only the lambda sign was found to have statistical significance with a sensitivity of 75% and a specificity of 63%. The presence of a lambda sign on the MRI of patients with physical exam findings suggestive of syndesmotic pain was highly sensitive (75%) and specific (85%). CONCLUSION: The lambda sign noted on the coronal MRI was both sensitive and specific for injuries involving greater than 2 mm of diastasis on arthroscopic stress examination of the syndesmosis. While neither the lambda sign nor any other finding on physical or radiographic examination represented an independent predictor of syndesmotic instability, the presence of a lambda sign in concert with positive physical exam findings might help health care providers determine which patients might benefit from operative intervention or referral. LEVEL OF EVIDENCE: Level III, case control study. PMID- 25037709 TI - An anatomical study comparing two surgical approaches for isolated talonavicular arthrodesis. AB - BACKGROUND: Two operative approaches are commonly used for isolated talonavicular arthrodesis: the medial and the dorsal approach. It is recognized that access to the lateral aspect of the talonavicular joint can be limited when using the medial approach, and it is our experience that using the dorsal approach addresses this issue. We performed an anatomical study using cadaver specimens, to compare the amount of articular surface that can be accessed by each operative approach. METHODS: Medial and dorsal approaches to the talonavicular joint were performed on each of 11 cadaveric specimens (10 fresh frozen, 1 embalmed). Distraction of the joint was performed as used intraoperatively and the accessible area of articular surfaces was marked for each of the 2 approaches using a previously reported technique. Disarticulation was performed and the marked surface area was quantified using an immersion digital microscribe, allowing a 3-dimensional virtual model of the articular surfaces to be assessed. RESULTS: The median percentage of total accessible talonavicular articular surface area for the medial and dorsal approaches was 71% and 92%, respectively (Wilcoxon signed-rank test, P < .001). CONCLUSION: This study provides quantifiable measurements of the articular surface accessible by the medial and dorsal approaches to the talonavicular joint. CLINICAL RELEVANCE: These data support for the use of the dorsal approach for talonavicular arthrodesis, particularly in cases where access to the lateral half of the joint is necessary. PMID- 25037710 TI - Metatarsophalangeal arthritis following fourth metatarsal lengthening treated with distraction arthroplasty: case report. PMID- 25037711 TI - Feasibility and outcome of inferior extensor retinaculum reinforcement in modified Brostrom procedures. AB - BACKGROUND: The purpose of this study was to assess the feasibility of inferior extensor retinaculum (IER) reinforcement and analyze differences in clinical and radiographic outcomes based on whether or not IER reinforcement was performed in modified Brostrom procedures. METHODS: Forty-one patients (41 ankles) who underwent ankle reconstruction with either a Brostrom procedure or modified Brostrom with IER reinforcement were included in this prospective study. During Brostrom procedures, feasibility of IER reinforcement was recorded. Clinical and radiographic outcomes were analyzed between modified Brostrom procedures (MBP group) in which IER reinforcement was feasible and Brostrom procedures (BP group) in which IER reinforcement was not feasible. RESULTS: IER reinforcement was feasible in 31 cases (75.6%) and not feasible in 10 cases (24.4%) due to anatomic variations. The American Orthopaedic Foot and Ankle Society ankle-hindfoot score improved in the MBP group from a preoperative mean of 66.3 to a postoperative mean of 89.4. In the BP group, the score increased from 71.3 to 89.8. The radiographic outcomes assessed by stress radiographs demonstrated that talar anterior translation and talar tilt improved from 6.3 mm to 4.6 mm and from 9.0 degrees to 5.0 degrees, respectively, in the MBP group. In the BP group, talar anterior translation improved from 6.9 mm to 4.9 mm and talar tilt, from 9.5 degrees to 4.9 degrees. No statistically significant difference was observed between the 2 groups. CONCLUSION: IER reinforcement was feasible in 75.6% of patients in whom modified Brostrom procedures had been planned. Postoperative clinical and radiographic outcomes were not significantly different based on whether or not IER reinforcement was performed. These findings suggest that isolated ligament reconstruction without IER may be sufficient to restore ankle stability. LEVEL OF EVIDENCE: Level II, cohort study. PMID- 25037712 TI - Foot disorders associated with overpronated and oversupinated foot function: the Johnston County osteoarthritis project. AB - BACKGROUND: The occurrence of musculoskeletal foot disorders differs by race and obesity, and these disorders may be related to pronated (low arch) or supinated (high arch) foot structure. This cross-sectional analysis examined relationships of foot disorders and foot function by race and obesity in a community-based observational study of adults 50+ years old with and without osteoarthritis. METHODS: Members of a prospective cohort study in North Carolina were included in this analysis (N = 1466, 67.2% women, 29.5% African American, mean age 68.5 years). Foot disorders were identified with a validated assessment tool, and each foot was categorized as overpronated, oversupinated, and referent using the center of pressure excursion index from foot pressure scans during normal-paced walking. Logistic regression models estimated associations between foot function and each foot disorder with age, body mass index (BMI), gender, and race as covariates. RESULTS: Compared to referent, an overpronated foot was associated with hallux valgus (adjusted odds ratio [aOR] 1.36, 95% confidence interval [CI] 1.13-1.65) and overlapping toes (aOR 1.36, 95% CI 1.12-1.64), especially in the obese. An oversupinated foot was inversely associated with hallux valgus (aOR 0.85, 95% CI 0.74-0.97). An oversupinated foot was less likely to be associated with bunionettes among the obese and was more likely to be associated with plantar fasciitis in Caucasians. CONCLUSION: Foot function was related to hallux valgus and overlapping toes, especially among the obese. In clinical patients as well as in the community of older adults, treatments for both the foot disorder and the pronated/supinated foot may be needed. LEVEL OF EVIDENCE: Level II, comparative cohort study. PMID- 25037713 TI - Comparison of statistical, LBP, and multi-resolution analysis features for breast mass classification. AB - Millions of women are suffering from breast cancer, which can be treated effectively if it is detected early. Mammography is broadly recognized as an effective imaging modality for the early detection of breast cancer. Computer aided diagnosis (CAD) systems are very helpful for radiologists in detecting and diagnosing abnormalities earlier and faster than traditional screening programs. An important step of a CAD system is feature extraction. This research gives a comprehensive study of the effects of different features to be used in a CAD system for the classification of masses. The features are extracted using local binary pattern (LBP), which is a texture descriptor, statistical measures, and multi-resolution frameworks. Statistical and LBP features are extracted from each region of interest (ROI), taken from mammogram images, after dividing it into N*N blocks. The multi-resolution features are based on discrete wavelet transform (DWT) and contourlet transform (CT). In multi-resolution analysis, ROIs are decomposed into low sub-band and high sub-bands at different resolution levels and the coefficients of the low sub-band at the last level are taken as features. Support vector machines (SVM) is used for classification. The evaluation is performed using Digital Database for Screening Mammography (DDSM) database. An accuracy of 98.43 is obtained using statistical or LBP features but when both these types of features are fused, the accuracy is increased to 98.63. The CT features achieved classification accuracy of 98.43 whereas the accuracy resulted from DWT features is 96.93. The statistical analysis and ROC curves show that methods based on LBP, statistical measures and CT performs equally well and they not only outperform DWT based method but also other existing methods. PMID- 25037714 TI - An improved retinal vessel segmentation method based on high level features for pathological images. AB - Most of the retinal blood vessel segmentation approaches use low level features, resulting in segmenting non-vessel structures together with vessel structures in pathological retinal images. In this paper, a new segmentation method based on high level features is proposed which can process the structure of vessel and non vessel independently. In this method, segmentation is done in two steps. First, using low level features segmentation is accomplished. Second, using high level features, the non-vessel components are removed. For evaluation, STARE database is used which is publicly available in this field. The results show that the proposed method has 0.9536 accuracy and 0.0191 false positive average on all images of the database and 0.9542 accuracy and 0.0236 false positive average on pathological images. Therefore, the proposed approach shows acceptable accuracy on all images compared to other state of the art methods, and the least false positive average on pathological images. PMID- 25037715 TI - Video summarization based tele-endoscopy: a service to efficiently manage visual data generated during wireless capsule endoscopy procedure. AB - Wireless capsule endoscopy (WCE) has great advantages over traditional endoscopy because it is portable and easy to use. More importantly, WCE combined with mobile computing ensures rapid transmission of diagnostic data to hospitals and enables off-site senior gastroenterologists to offer timely decision making support. However, during this WCE process, video data are produced in huge amounts, but only a limited amount of data is actually useful for diagnosis. The sharing and analysis of this video data becomes a challenging task due the constraints such as limited memory, energy, and communication capability. In order to facilitate efficient WCE data collection and browsing tasks, we present a video summarization-based tele-endoscopy service that estimates the semantically relevant video frames from the perspective of gastroenterologists. For this purpose, image moments, curvature, and multi-scale contrast are computed and are fused to obtain the saliency map of each frame. This saliency map is used to select keyframes. The proposed tele-endoscopy service selects keyframes based on their relevance to the disease diagnosis. This ensures the sending of diagnostically relevant frames to the gastroenterologist instead of sending all the data, thus saving transmission costs and bandwidth. The proposed framework also saves storage costs as well as the precious time of doctors in browsing patient's information. The qualitative and quantitative results are encouraging and show that the proposed service provides video keyframes to the gastroenterologists without discarding important information. PMID- 25037716 TI - A secure medical data exchange protocol based on cloud environment. AB - In recent years, health care technologies already became matured such as electronic medical records that can be easily stored. However, how to get medical resources more convenient is currently concern issue. In spite of many literatures discussed about medical systems, but these literatures should face many security challenges. The most important issue is patients' privacy. Therefore, we propose a secure medical data exchange protocol based on cloud environment. In our scheme, we use mobile device's characteristics, allowing peoples use medical resources on the cloud environment to seek medical advice conveniently. PMID- 25037717 TI - The molecular landscape of pediatric brain tumors in the next-generation sequencing era. AB - Pediatric brain tumors are a leading cause of cancer-related death in children. In recent years, the application of next-generation sequencing and other high throughput technologies to analysis of pediatric brain tumors has generated an abundance of molecular information. This has provided an unprecedented understanding of their biology and is refining tumor classification into clinically relevant subgroups. In this review, we provide an overview of our evolving molecular knowledge of the commonest pediatric brain tumors, pilocytic astrocytomas, ependymomas, medulloblastomas, and pediatric glioblastomas, as well as the biological and potential clinical implications of this new knowledge. Studies aimed at investigating intratumoral heterogeneity are also discussed. PMID- 25037718 TI - Autologous bone marrow transplantation for the treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and represents one of the leading causes of neurologic disability in young adults. Current treatments for MS have shown limited efficacy in patients with either a progressive or an aggressive disease course. Hematopoietic stem cell transplantation (HSCT) has been proposed to control or even cure refractory cases of MS. Indeed, HSCT is able to temporarily eradicate the autoreactive cells and to reset the aberrant immune response to self-antigens. In the last decade, owing to the growing experience in selecting the most appropriate patients to transplant and the recent advances in chemotherapeutic and support regimens, the transplant-related mortality of autologous HSCT in MS patients dropped down to 1,3 % and the progression-free survival ranges from 47 % to 100 %. Altogether, these data support autologous HSCT as a possible second-line therapy for refractory MS. PMID- 25037719 TI - Young Leaf Chlorosis 2 encodes the stroma-localized heme oxygenase 2 which is required for normal tetrapyrrole biosynthesis in rice. AB - MAIN CONCLUSION: Rice heme oxygenase 2 (OsHO2) mutants are chlorophyll deficient with distinct tetrapyrrole metabolite and transcript profiles, suggesting a potential regulatory role of the stromal-localized OsHO2 in tetrapyrrole biosynthesis. In plants, heme oxygenases (HOs) are classified into the subfamilies HO1 and HO2. HO1 are highly conserved plastid enzymes required for synthesizing the chromophore in phytochromes which mediate a number of light regulated responses. However, the physiological and biochemical functions of HO2, which are distantly related to HO1, are not well understood, especially in crop plants. From a population of (60)Cogamma-irradiated rice mutants, we identified the ylc2 (young leaf chlorosis 2) mutant which displays a chlorosis phenotype in seedlings with substantially reduced chlorophyll content. Normal leaf pigmentation is gradually restored in older plants while newly emerged leaves remain yellow. Transmission electron microscopy further revealed defective chloroplast structures in the ylc2 seedlings. Map-based cloning located the OsYLC2 gene on chromosome 3 and it encodes the OsHO2 protein. The gene identification was confirmed by complementation and T-DNA mutant analyses. Subcellular localization and chloroplast fractionation experiments indicated that OsHO2 resides in the stroma. However, recombinant enzyme assay demonstrated that OsHO2 is not a functional HO enzyme. Analysis of tetrapyrrole metabolites revealed the reduced levels of most chlorophyll and phytochromobilin precursors in the ylc2 mutant. On the other hand, elevated accumulation of 5-aminolevulinic acid and Mg-protoporphyrin IX was observed. These unique metabolite changes are accompanied by consistent changes in the expression levels of the corresponding tetrapyrrole biosynthesis genes. Taken together, our work suggests that OsHO2 has a potential regulatory role for tetrapyrrole biosynthesis in rice. PMID- 25037720 TI - Characterisation of novel linear antigen epitopes on North American-type porcine reproductive and respiratory syndrome virus M protein. AB - The M protein, encoded by the porcine reproductive and respiratory syndrome virus (PRRSV) ORF6 gene, is considered to be one of the most conserved PRRSV proteins. In recent decades, highly specific monoclonal antibodies (Mabs) have been exploited to provide reliable diagnoses for many diseases. In this study, two different Mab clones targeting the linear epitopes on the PRRSV M protein were generated and characterized. Both Mabs showed binding activity against the native PRRSV virion and recombinant M protein when analyzed by immunofluorescence assay (IFA) and Western blot. The targeted epitope of each Mab was mapped by serial truncation of the M protein to generate overlapping fragments. Fine epitope mapping was then performed using a panel of expressed polypeptides. The polypeptide sequences of the two epitopes recognized by Mabs 1C8 and 3F7 were (3)SSLD(6) and (155)VLGGRKAVK(163), respectively, with the former being a newly identified epitope on the M protein. In both cases, these two epitopes were finely mapped for the first time. Alignments of Mab epitope sequences revealed that the two epitopes on the M protein were highly conserved between the North American-type strains. These Mabs, along with their mapped epitopes, are useful for the development of diagnostic and research tools, including immunofluorescence, ELISA and Western blot. PMID- 25037721 TI - A GCase chaperone improves motor function in a mouse model of synucleinopathy. AB - Mutation of the lysosomal hydrolase acid-beta-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes alpha-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type alpha synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced alpha-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small alpha-synuclein aggregates, while increasing the number of large alpha-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations. PMID- 25037722 TI - Secretion expression of SOD1 and its overlapping function with GSH in brewing yeast strain for better flavor and anti-aging ability. AB - Superoxide dismutase (SOD) is a significant antioxidant, but unlike glutathione (GSH), SOD cannot be secreted into beer by yeast cells during fermentation, this directly leads to the limited application of SOD in beer anti-aging. In this investigation, we constructed the SOD1 secretion cassette in which strong promoter PGK1p and the sequence of secreting signal factor from Saccharomyces cerevisiae were both harbored to the upstream of coding sequence of SOD1 gene, as a result, the obtained strains carrying this cassette successfully realized the secretion of SOD1. In order to overcome the limitation of previous genetic modification on yeast strains, one new comprehensive strategy was adopted targeting the suitable homologous sites by gene deletion and SOD1 + GSH1 co overexpression, and the new strain ST31 (Deltaadh2::SOD1 + Deltailv2::GSH1) was constructed. The results of the pilot-scale fermentation showed that the diacetyl content of ST31 was lower by 42 % than that of the host, and the acetaldehyde content decreased by 29 %, the GSH content in the fermenting liquor of ST31 increased by 29 % compared with the host. Both SOD activity test and the positive and negative staining assay after native PAGE indicated that the secreted active SOD in the fermenting liquor of ST31 was mainly a dimer with the size of 32,500 Da. The anti-aging indexes such as the thiobarbituric acid and the resistance staling value further proved that the flavor stability of the beer brewed with strain ST31 was not only better than that of the original strain, but also better than that of the previous engineering strains. The multi-modification and comprehensive improvement of the beer yeast strain would greatly enhance beer quality than ever, and the self-cloning strain would be attractive to the public due to its bio-safety. PMID- 25037723 TI - Identification and characterization of a short-chain acyl dehydrogenase from Klebsiella pneumoniae and its application for high-level production of L-2,3 butanediol. AB - Klebsiella pneumoniae synthesize large amounts of L-2,3-butanediol (L-2,3-BD), but the underlying mechanism has been unknown. In this study, we provide the first identification and characterization of an L-2,3-BD dehydrogenase from K. pneumoniae, demonstrating its reductive activities toward diacetyl and acetoin, and oxidative activity toward L-2,3-BD. Optimum pH, temperature, and kinetics determined for reductive and oxidative reactions support the preferential production of 2,3-BD during cell growth. Synthesis of L-2,3-BD was remarkably enhanced by increasing gene dosage, reaching levels that, to the best of our knowledge, are the highest achieved to date. PMID- 25037724 TI - Potential perioperative advantage of colorectal endoscopic submucosal dissection versus laparoscopy-assisted colectomy. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has recently provided a new treatment strategy for large colorectal neoplasms, as an alternative to laparoscopy-assisted colectomy (LAC). Prospective comparative data on the perioperative course of ESD vis-a-vis LAC are scarce. METHODS: We prospectively evaluated the perioperative course of colorectal ESD in 300 patients. We evaluated en bloc and curative resection, procedure duration, postoperative parameters [white blood cell count (WBC), C-reactive protein (CRP), and hemoglobin], pain, recovery duration (time to achieve full mobilization, normal diet, and length of hospitalization), and complications. We also prospectively evaluated 190 patients undergoing LAC as a control group. RESULTS: The median size of the lesions was 30 mm for ESDs (LACs: 20 mm). The median procedure time was 90 min for ESDs (LACs: 185 min). Postoperative pyrexia was reported in 4 % of ESDs (LACs: 54 %). Only 4 % of ESDs required analgesia (LACs: 61 %). Between the preoperative period and postoperative day 1, the mean difference in WBC and CRP was +1,300/MUl for ESDs (LACs: +3,100/MUl), and +0.91 mg/dl for ESDs (LACs: +3.96 mg/dl), respectively. A >=2 g/dl decrease in hemoglobin was observed in 5 % of ESDs (LACs: 30.0 %). Complications were seen in 7 % of ESDs (LACs: 15 %). The rate of delayed bleeding and perforation was 5 and 1.7 % of ESDs, respectively. Although only one of them required laparotomy for peritonitis caused by delayed perforation, others could be managed endoscopically. Additional LAC was required in 16 ESDs due to redefined risk for lymph node metastases. The median hospital stay was 5 days for ESDs (LACs: 10 days). These were consecutive patients with prospective data collection. CONCLUSIONS: Colorectal ESD is effective, minimally invasive and safe in terms of periperative clinical course. Colorectal ESD provides advantages for treatment of large adenomas and early cancers with no risk of lymph node metastasis. PMID- 25037725 TI - Long-term mortality rates (>8-year) improve as compared to the general and obese population following bariatric surgery. AB - INTRODUCTION: Sparse data are available on long-term patient mortality following bariatric surgery as compared to the general population. The purpose of this study was to assess long-term mortality rates and identify risk factors for all cause mortality following bariatric surgery. METHODS: New York State (NYS) Planning and Research Cooperative System (SPARCS) longitudinal administrative data were used to identify 7,862 adult patients who underwent a primary laparoscopic bariatric surgery from 1999 to 2005. The Social Security Death Index database identified >30-day mortalities. Risk factors for mortality were screened using a univariate Cox proportional hazard (PH) model and analyzed using a multiple PH model. Based on age, gender, and race/ethnicity, actuarial projections for NYS mortality rates obtained from Centers of Disease Control were compared to the actual post-bariatric surgery mortality rates observed. RESULTS: The mean bariatric mortality rate was 2.5 % with 8-14 years of follow-up. Mean time to death ranged from 4 to 6 year and did not differ by operation (p = 0.073). From 1999 to 2010, the actuarial mortality rate predicted for the general NYS population was 2.1 % versus the observed 1.5 % for the bariatric surgery population (p = 0.005). Extrapolating to 2013, demonstrated the actuarial mortality predictions at 3.1 % versus the bariatric surgery patients' observed morality rate of 2.5 % (p = 0.01). Risk factors associated with an earlier time to death included: age, male gender, Medicare/Medicaid insurance, congestive heart failure, rheumatoid arthritis, pulmonary circulation disorders, and diabetes. No procedure-specific or perioperative complication impact for time-to death was found. CONCLUSION: Long-term mortality rate of patients undergoing bariatric surgery significantly improves as compared to the general population regardless of bariatric operation performed. Additionally, perioperative complications do not increase long-term mortality risk. This study did identify specific patient risk factors for long-term mortality. Special attention and consideration should be given to these "at risk" patient sub-populations. PMID- 25037726 TI - Laparoscopy versus open surgery for idiopathic intussusception in children. AB - PURPOSE: This study aims to compare the results of laparoscopy and open surgery for idiopathic intussusception in children as well as evaluate the efficacy of ileopexy. METHODS AND MATERIALS: Between January 2007 and July 2013, children aged <18 years who were operated for intussusception in our institution were reviewed. Patients were classified into two groups, laparoscopy (LAP) and open (OPEN). Both groups were further divided into two subgroups, ileopexy (IP) and non-ileopexy (NIP). Parameters investigated included age, gender, operative indication, surgical procedure, type of intussusception, level of intussusceptum, presence of spontaneously reduced intussusception and pathologic lead points, operative time (OP time), time to oral intake (PO time), length of postoperative hospital stay (LOS), and surgical recurrence. RESULTS: There were 23 and 35 patients in LAP and OPEN group, respectively. No significant difference was found on age, operative indication, surgical procedure, type of intussusception, level of intussusceptum, and presence of spontaneously reduced intussusception between both groups. In LAP group, mean OP time was significantly longer; mean PO time and LOS were significantly shorter. One surgical recurrence occurred in each group (p = 0.76). In comparison of LAP-IP (n = 15) and LAP-NIP (n = 8), OP time, PO time, and LOS were similar in both subgroups. One recurrence was noted in LAP IP (p = 0.46). The overall conversion rate was 13.0 % (6.8 vs. 25 %, p = 0.21). Compared to patients with intussusceptum to ascending colon, the conversion rate was significantly higher in patients with intussusceptum to transverse and descending colon. With the exclusion of conversion, OP time was significantly shorter in LAP-NIP (p = 0.01). CONCLUSION: Laparoscopy should be considered the primary modality for radiologically irreducible or recurrent idiopathic intussusception in children. Ileopexy provides no benefit on recurrence prevention but contributes to longer OP time. PMID- 25037727 TI - Adenoma detection at colonoscopy by polypectomy in withdrawal only versus both insertion and withdrawal: a randomized controlled trial. AB - Colonic configuration during insertion phase (IP) and withdrawal phase (WP) is different and some polyps seen during IP are difficult to find during WP and vice versa. To determine if polypectomy performed during both IP and WP of colonoscopy (study arm) increases adenoma detection rate (ADR) compared to WP only (control arm). In this prospective randomized controlled trial, adults undergoing out patient colonoscopy were enrolled. The primary outcome was mean number of adenomas detected per patient. Secondary outcomes were ADR, defined as the proportion of colonoscopies with at least one adenoma, polyp detection rates (PDR), number of patients classified as high-risk group (presence of >=3 adenomas of any size, any adenoma >=1 cm in size, or adenoma with villous component, or high grade dysplasia), procedural times, patients discomfort, and ease of procedure. Among 772 patients enrolled, 610 were included (329 in study arm and 281 in control arm). In both arms, mean number of adenomas detected per patient were similar, 0.78 +/- 1.4 vs. 0.74 +/- 1.5, P = 0.75. Also, ADR (39.2 vs. 38.1 %, P = 0.77) and PDR (57.1 and 54.1 %, P = 0.45) were similar. Mean insertion time was significantly higher in study arm (10.2 +/- 5.8 vs. 9.3 +/- 5.6 min, p = 0.046). Proportion of patients identified as high-risk group were significantly higher in study arm (18.8 vs. 11.7 %, P = 0.016). CONCLUSIONS: Polypectomy performed during both IP and WP compared to the WP only, did not improve ADR or mean number of adenomas detected per patient. TRIAL REGISTRATION: Clinicaltrials.gov, #NCT01025960. PMID- 25037728 TI - Lupeol induces apoptosis and inhibits invasion in gallbladder carcinoma GBC-SD cells by suppression of EGFR/MMP-9 signaling pathway. AB - The cytostatic drug from fruits and other plant derived products have acted as a chemotherapeutic agent used in treatment of a wide variety of cancers. Lupeol, a dietary triterpene, present in many fruits and medicinal plants, has been shown to possess many pharmacological properties including anti-cancer effect in both in vitro and in vivo assay systems. However, the cancer proliferative and invasive inhibitory effects and molecular mechanisms on gallbladder carcinoma GBC SD cells have not been studied. In the present study, GBC-SD cells were treated by lupeol and subjected to methyl thiazolyl tetrazolium analysis, Hoechst 33342 staining, annexin V/propidium iodide double-staining, transwell chamber assay and Western blot analysis. In addition, GBC-SD xenograft tumors were established in male nude BALB/c mice, and lupeol was intravenously administered to evaluate the anti-cancer capacity in vivo. Our results showed that lupeol inhibited the proliferation, migration, invasion and induced apoptosis of GBC-SD cells in a dose-dependent manner in vitro. Furthermore, the expression of p-EGFR, p-AKT and MMP-9 levels were significantly down-regulated. These protein interactions may play a pivotal role in the regulation of apoptosis and invasion. More importantly, our in vivo studies showed that administration of lupeol decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the down-regulation of p-EGFR and MMP-9 in tumor tissues following lupeol treatment, consistent with the in vitro results. Taken together, our findings indicated that lupeol can induce apoptotic cell death and inhibit the migration as well as invasion of GBC-SD cells. The mechanism may be associated with the suppression of EGFR/MMP-9 signaling. These results might offer a therapeutic potential advantage for human gallbladder carcinoma chemoprevention or chemotherapy. PMID- 25037729 TI - ADI1, a methionine salvage pathway enzyme, is required for Drosophila fecundity. AB - BACKGROUND: Methionine, an essential amino acid, is required for protein synthesis and normal cell metabolism. The transmethylation pathway and methionine salvage pathway (MTA cycle) are two major pathways regulating methionine metabolism. Recently, methionine has been reported to play a key role in Drosophila fecundity. RESULTS: Here, we revealed that the MTA cycle plays a crucial role in Drosophila fecundity using the mutant of aci-reductone dioxygenase 1 (DADI1), an enzyme in the MTA cycle. In dietary restriction condition, the egg production of adi1 mutant flies was reduced compared to that of control flies. This fecundity defect in mutant flies was rescued by reintroduction of Dadi1 gene. Moreover, a functional homolog of human ADI1 also recovered the reproduction defect, in which the enzymatic activity of human ADI1 is required for normal fecundity. Importantly, methionine supply rescued the fecundity defect in Dadi1 mutant flies. The detailed analysis of Dadi1 mutant ovaries revealed a dramatic change in the levels of methionine metabolism. In addition, we found that three compounds namely, methionine, SAM and Methionine sulfoxide, respectively, may be required for normal fecundity. CONCLUSIONS: In summary, these results suggest that ADI1, an MTA cycle enzyme, affects fly fecundity through the regulation of methionine metabolism. PMID- 25037730 TI - Radiologic findings of Patterson-Lowry rhizomelic dysplasia in two sisters. AB - We report two sisters who have a rare skeletal abnormality termed Patterson-Lowry rhizomelic dysplasia. The typical findings of these cases on bone survey are isolated shortening and proximal metaphyseal enlargement and cupping of the bilateral humeri. The elder sister also has coxa vara deformity and dysplastic proximal femoral epiphyses on both sides. The younger sister has normal hip joint bones bilaterally, but her proximal femoral epiphyses are smaller than normal. All other bones of the sisters are of normal size and configuration. Our patients are two siblings, and their parents are first degree relatives, suggesting autosomal-recessive (AR) inheritance. The present patients help us to understand the genetic relationships and skeletal variabilities of this rare entity. PMID- 25037731 TI - Multiple surface reactions in arrays with applications to optical biosensors. AB - We analyze surface-volume reactions in the context of optical biosensors with arrays of reacting zones. For arrays having zones with the same rate constants, we consider a two-dimensional reacting zone boundary definition and quantify ligand depletion with the effective Damkohler number. We use asymptotics to obtain ligand depletion results for the one-dimensional case, and also compute results for the circular reacting zone case. For arrays having zones with different rate constants, depletion effects cannot be expressed as the product of time-dependent and space-dependent terms, and we propose two effective rate constant equations for this case. PMID- 25037732 TI - A method to evaluate the effect of contact with excipients on the surface crystallization of amorphous drugs. AB - Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the beta polymorph from two to five times when samples were stored in a desiccator, while D-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients. PMID- 25037733 TI - Diaphyseal osteosarcomas have distinct clinical features from metaphyseal osteosarcomas. AB - AIMS: The aim of this study was to clarify the clinical features and outcomes of diaphyseal osteosarcoma. METHODS: Patients with newly-diagnosed high-grade osteosarcoma occurring in the long bone were eligible for this retrospective study. Clinicopathological information was collected from our database and compared with 36 diaphyseal, 405 proximal and 519 distal metaphyseal, and 14 whole bone osteosarcoma patients. Additionally, case-control study matching by age, gender, site, and metastatic status at diagnosis with 1:3 ratio of 36 diaphyseal to 108 metaphyseal osteosarcomas patients was also conducted. RESULTS: Five-year overall survival and metastasis-free survival of the three groups including diaphyseal, metaphyseal, and whole bone osteosarcoma patients showed significant difference (P = .029 and P = .013, respectively), although there is no difference for the survivals between proximal and distal metaphyseal osteosarcoma patients. Case-control study showed that patients with diaphyseal osteosarcomas had a significantly larger tumour (mean 13.5 cm vs 10 cm, P = .026), and demonstrated higher pathologic fracture rate (28% vs 12%, P = .033), superior 5-year metastasis-free survival (74% vs 40%, P = .0068), and slightly better 5-year overall survival (68% vs 46%, P = .074). Prognostic factor analysis showed that a pathologic fracture significantly decreased the survival of the patients with diaphyseal osteosarcoma. CONCLUSIONS: The current study showed that diaphyseal osteosarcoma has distinct clinical features from metaphyseal osteosarcoma having an increased risk of pathologic fractures but with favorable survival outcome. PMID- 25037734 TI - Generalized or abdominal obesity: which one better identifies cardiometabolic risk factors among children and adolescents? The CASPIAN III study. AB - OBJECTIVES: We investigated the association of generalized and abdominal obesity with cardiometabolic risk factors in children and adolescents. METHODS: Data were obtained from a surveillance system entitled CASPIAN-III study in school students aged 10-18 years in Iran. Data of subjects with normal body mass index (BMI) or above (BMI >= 5th percentile) were analyzed. The associations of obesity with cardiometabolic risk factors were tested using logistic regression models. RESULTS: In the sample of 4641 children and adolescents, overweight/obese children were more likely to have metabolic syndrome and cardiometabolic risk factors compared with their normal weight counterparts. Among these parameters, elevated TG had the strongest association with degree of obesity (overweight: OR = 2.28 [95% CI 1.59-3.26]; obesity: OR = 5.63 [95% CI 4.27,7.43]). Combined generalized and abdominal obesity increased the risk of high blood pressure, elevated triglyceride and total cholesterol. CONCLUSIONS: Combined type of generalized and abdominal obesity is a predictor of cardiometabolic risk factors. PMID- 25037735 TI - Multidrug resistant Acinetobacter baumannii reaches a new frontier: prosthetic hip joint infection. AB - Acinetobacter baumannii is an emerging nosocomial pathogen primarily in countries with a high prevalence of multidrug resistance. Here we report the detection of a bla OXA23 carbapenemase-producing A. baumannii strain in a German patient with prosthetic hip joint infection following several hip joint surgeries but no history of foreign travel. PMID- 25037737 TI - Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history. AB - PURPOSE: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood. EXPERIMENTAL DESIGN: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next generation DNA-sequencing data (n = 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups. RESULTS: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies ~60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of never-smokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma. CONCLUSIONS: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never smokers and a subset of smokers. PMID- 25037736 TI - Is the "3+3" dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design. AB - PURPOSE: Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered. EXPERIMENTAL DESIGN: We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-escalation design. RESULTS: The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose. CONCLUSIONS: Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development. PMID- 25037738 TI - Bis-class: a new classification tool of methylation status using bayes classifier and local methylation information. AB - BACKGROUND: Whole genome sequencing of bisulfite converted DNA ('methylC-seq') method provides comprehensive information of DNA methylation. An important application of these whole genome methylation maps is classifying each position as a methylated versus non-methylated nucleotide. A widely used current method for this purpose, the so-called binomial method, is intuitive and straightforward, but lacks power when the sequence coverage and the genome-wide methylation level are low. These problems present a particular challenge when analyzing sparsely methylated genomes, such as those of many invertebrates and plants. RESULTS: We demonstrate that the number of sequence reads per position from methylC-seq data displays a large variance and can be modeled as a shifted negative binomial distribution. We also show that DNA methylation levels of adjacent CpG sites are correlated, and this similarity in local DNA methylation levels extends several kilobases. Taking these observations into account, we propose a new method based on Bayesian classification to infer DNA methylation status while considering the neighborhood DNA methylation levels of a specific site. We show that our approach has higher sensitivity and better classification performance than the binomial method via multiple analyses, including computational simulations, Area Under Curve (AUC) analyses, and improved consistencies across biological replicates. This method is especially advantageous in the analyses of sparsely methylated genomes with low coverage. CONCLUSIONS: Our method improves the existing binomial method for binary methylation calls by utilizing a posterior odds framework and incorporating local methylation information. This method should be widely applicable to the analyses of methylC-seq data from diverse sparsely methylated genomes. Bis-Class and example data are provided at a dedicated website (http://bibs.snu.ac.kr/software/Bisclass). PMID- 25037739 TI - Circumaortic doubled left brachiocephalic vein: a rare confusing variation. AB - Left brachiocephalic vein (LBCV), one of the major veins draining upper extremity, head and neck region, has rare anatomic variations. Circumaortic type, an extremely uncommon variation, is presented here; this was incidentally detected on computed tomography images. In this case, circumaortic LBCV had two branches; one was normally placed brachiocephalic vein anterior to the aortic arch, and the other one was the anomalous branch with a retroaortic course. PMID- 25037741 TI - Genome-wide pathway analysis of a genome-wide association study on Alzheimer's disease. AB - The aims of this study were to identify candidate single nucleotide polymorphisms (SNPs) and mechanisms of Alzheimer's disease (AD) and to generate SNP to gene to pathway hypotheses. An AD genome-wide association study (GWAS) dataset that included 370,542 SNPs in 1,000 cases and 1,000 controls of European descent was used in this study. Identify Candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 3 candidate SNPs and 2 pathways, which provided 3 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was rs8076604 [non synonymous coding (deleterious)] to MYO18A to negative regulation of programmed cell death [nominal P < 0.001, false discovery rate (FDR) <0.043]. The second was rs2811226 (regulatory region) to ANXA1 to negative regulation of programmed cell death (nominal P < 0.001, FDR 0.043). The third was rs3734166 (non-synonymous coding) to CDC25C to M phase of the mitotic cell cycle (nominal P < 0.001, FDR 0.049). By applying the ICSNPathway analysis to the AD GWAS meta-analysis data, three candidate SNPs, three genes (MYO18A, ANXA1, CDC25C), 2 pathways involving negative regulation of programmed cell death and 1 pathway involving the M phase of the mitotic cell cycle were identified, which may contribute to AD susceptibility. PMID- 25037742 TI - [Interaction of FABP4 with plasma membrane proteins of endothelial cells]. AB - INTRODUCTION: Fatty acid binding protein (FABP4) is an adipose tissue-secreted adipokine implicated in the regulation of the energetic metabolism and inflammation. High levels of circulating FABP4 have been described in people with obesity, atherogenic dyslipidemia, diabetes and metabolic syndrome. Recent studies have demonstrated that FABP4 could have a direct effect on peripheral tissues and, specifically, on vascular function. It is still unknown how the interaction between FABP4 and the endothelial cells is produced to prompt these effects on vascular function. The objective of this work is studying the interaction between FABP4 and the plasma membrane proteins of endothelial cells. METHODOLOGY: HUVEC cells were incubated with and without FABP4 (100 ng/ml) for 5 minutes. Immunolocalization of FABP4 was studied by confocal microscopy. The results showed that FABP4 colocalizates with CD31, a membrane protein marker. A strategy which combines 6XHistidine-tag FABP4 (FABP4-His), incubations with or without FABP4-His (100 ng/ml), formaldehyde cross-linking, cellular membrane protein extraction and western blot, was designed to study the FABP4 interactions with membrane proteins of HUVECs. RESULTS: The results showed different western blot profiles depending of the incubation with or without FABP4-His. The immunoblot revelead three covalent protein complexes of about 108, 77 and 33 kDa containing FAPB4 and its putative receptor. DISCUSSION: The existence of a specific binding protein complex able to bind FABP4 to endothelial cells is supported by these results. The obtained results will permit us advance in the molecular knowledge of FABP4 effects as well as use this protein and its receptor as therapeutic target to prevent cardiovascular. PMID- 25037743 TI - Feral pigs as hosts for Amblyomma sculptum (Acari: Ixodidae) populations in the Pantanal, Mato Grosso do Sul, Brazil. AB - The Pantanal in Brazil is the largest floodplain of the world. This ecosystem, rich in wildlife, has a large feral pig population. Such a large host biomass must have a strong influence on the parasite fauna. In this work, we evaluated the role of feral pigs in the maintenance of Amblyomma sculptum (formerly Amblyomma cajennense), the most prevalent tick species in the Pantanal. Tick infestations were evaluated on 243 feral pigs and their environment. The suitability of domestic pigs, representing their feral relatives, to A. sculptum adults and nymphs was assessed experimentally. Tick infestation of feral pigs was strongly associated with that of the environment: 96 and 97 % of the ticks, respectively, were A. sculptum. The infestation prevalence on this host species was close to 90 % in the dry season and 100 % in the wet season and mean infestation intensity was above 30 ticks in both seasons. Suitability of pigs as hosts for A. sculptum was shown by the high proportion of nymphs and female ticks found engorging on captured feral pigs and adequate biological parameters displayed by ticks from experimental infestations of domestic pigs. Other tick species on feral pigs, albeit in much lower numbers, were Amblyomma parvum and Ornithodorus rostratus. Results show that feral pigs feed a high proportion of the A. sculptum adults and nymphs in their territories and should be a target for tick-borne diseases studies. This is particularly relevant to public health because all the main tick species found on feral pigs are aggressive to humans as well. PMID- 25037744 TI - Oocyte maturation in the sloth's giant tick Amblyomma varium (Acari: Ixodidae) in an ecological context. AB - The sloth's giant tick Amblyomma varium Koch, which is a neotropical species that inhabits tropical rainforests, is the largest tick reported to date. The adult stage of this tick parasitizes mammals from the families Bradypodidae and Magalonychidae (Xenarthra) nearly exclusively. This study aimed to describe morphological and histological features of the reproductive system and the oocyte maturation process of this tick species. The ovary of A. varium is a long single tubular organ that is horseshoe-shaped, winding and arranged in the posterior part of the body. Two oviducts are connected to the ovary on each side; these thicken at certain region forming the uterus (common oviduct), followed by a muscular connecting tube, vagina and genital aperture. A large number of oocytes at different stages of development are attached to the ovary wall by the pedicel, as they reach maturity they are released into the ovary lumen and from there to the genital aperture. These oocytes develop simultaneously and asynchronically along the ovary. Amblyomma varium oocytes were classified into five development stages (i.e., I-V), and specific characteristics were observed; the processes of yolk and chorion deposition begin early in oocytes stage II, and oocytes V exhibit a very thick chorion and eggs of a large size. These characteristics are likely adaptations that enhance the survival and the reproductive success of this extremely host-specific tick, which is limited to a particular environment. PMID- 25037745 TI - Impact of Varroa destructor on honeybee (Apis mellifera scutellata) colony development in South Africa. AB - The devastating effects of Varroa destructor Anderson & Trueman on European honeybee colonies (Apis mellifera L.) have been well documented. Not only do these mites cause physical damage to parasitised individuals when they feed on them, they also transmit viruses and other pathogens, weaken colonies and can ultimately cause their death. Nevertheless, not all honeybee colonies are doomed once Varroa mites become established. Some populations, such as the savannah honeybee, A. m. scutellata, have become tolerant after the introduction of the parasite and are able to withstand the presence of these mites without the need for acaricides. In this study, we measured daily Varroa mite fall, Varroa infestation rates of adult honeybees and worker brood, and total Varroa population size in acaricide treated and untreated honeybee colonies. In addition, honeybee colony development was compared between these groups in order to measure the cost incurred by Varroa mites to their hosts. Daily Varroa mite fall decreased over the experimental period with different dynamics in treated and untreated colonies. Varroa infestation rates in treated adult honeybees and brood were lower than in untreated colonies, but not significantly so. Thus, indicating a minimal benefit of treatment thereby suggesting that A. m. scutellata have the ability to maintain mite populations at low levels. We obtained baseline data on Varroa population dynamics in a tolerant honeybee over the winter period. Varroa mites appeared to have a low impact on this honeybee population, given that colony development was similar in the treated and untreated colonies. PMID- 25037740 TI - Recommendations of the Sleep Study Group of the Italian Dementia Research Association (SINDem) on clinical assessment and management of sleep disorders in individuals with mild cognitive impairment and dementia: a clinical review. AB - Clinical assessment and management of sleep disturbances in patients with mild cognitive impairment and dementia has important clinical and social implications. Poor sleep results in an increased risk of morbidities and mortality in demented patients and is a source of stress for caregivers. Sleep disturbances show high prevalence in mild cognitive impairment and dementia patients and they are often associated one to another in the same patient. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of individuals with cognitive decline. The Sleep Study Group of the Italian Dementia Research Association (SINDem) reviewed evidence from original research articles, meta-analyses and systematic reviews published up to December 2013. The evidence was classified in quality levels (I, II, III) and strength of recommendations (A, B, C, D, E). Where there was a lack of evidence, but clear consensus, good practice points were provided. These recommendations may not be appropriate for all circumstances and should therefore be adopted only after a patient's individual characteristics have been carefully evaluated. PMID- 25037746 TI - Mortality and morbidity in relation to changes in albuminuria, glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies. AB - AIMS/HYPOTHESIS: Urinary albumin excretion is a strong predictor of cardiovascular disease. It is uncertain whether improvement from microalbuminuria or deterioration from normoalbuminuria over time in patients with differing changes in glucose and BP change their cardiovascular risk. METHODS: Data on mortality, cardiovascular and renal outcomes were analysed in 22,984 patients from two large parallel randomised clinical trials followed for 56 months. A central laboratory analysed first morning spot urine samples at baseline and after 24 months, and events were recorded over the subsequent 32 months. Patients were stratified by changes in albuminuria, glucose status and mean systolic BP over 2 years. RESULTS: There was a strong association between albuminuria status and all-cause and cardiovascular mortality and combined cardiovascular and renal endpoints (all p < 0.0001). Changes in systolic BP control had no effect on mortality, whereas glucose status was significantly associated with all outcomes. Irrespective of BP control or glucose status, patients showing an improvement from microalbuminuria to normoalbuminuria after 2 years were at a lower risk of all outcome measures than patients showing deterioration from normoalbuminuria to microalbuminuria (HR for all-cause mortality 0.65 [0.52-0.83], p = 0.0004). CONCLUSIONS/INTERPRETATION: Patients who showed improvement to normoalbuminuria over 2 years were at lower risk of all-cause and cardiovascular mortality and of cardiovascular and renal events than those who deteriorated to microalbuminuria over time. Albuminuria over time was significantly better than glucose status and BP control in predicting mortality and both cardiovascular and renal outcomes in patients at a high cardiovascular risk. PMID- 25037748 TI - Two-dimensional Au lattices featuring unique carrier transport preference and wide forbidden gap. AB - Large-scale 2D Au lattices with honeycomb-like structure are fabricated on Si(111)-7 * 7 surface at room temperature. The growth pattern investigated by reflection high-energy electron diffraction and in situ scanning tunneling microscopy indicates that the 2D Au lattices are composed of two interfacial distinct layers that are completely formed one after another with a close-packed structure. A unique wide forbidden gap of 4.1 eV is measured around the Fermi level of the 2D Au lattices by scanning tunneling spectroscopy. Bias-dependent STM images and theoretical simulations suggest that the in-plane quantum coupling and carrier transport behavior are responsible for the novel electronic properties. In addition to local electronic states, the electronic structures of 2D Au lattices are further modulated by the carrier transport preference that is determined by carrier energy and symmetry of 2D lattices. These findings will provide some references for the controlled fabrication and for routing the carrier transport behavior of low-dimensional metal structures. PMID- 25037747 TI - The intratumoral administration of ferucarbotran conjugated with doxorubicin improved therapeutic effect by magnetic hyperthermia combined with pharmacotherapy in a hepatocellular carcinoma model. AB - BACKGROUND: Local hyperthermia of tumor in conjunction with chemotherapy is a promising strategy for cancer treatment. The aim of this study was to evaluate the efficacy of intratumoral delivery of clinically approved magnetic nanoparticles (MNPs) conjugated with doxorubicin to simultaneously induce magnetic hyperthermia and drug delivery in a hepatocellular carcinoma (HCC) model. MATERIALS AND METHODS: HCC cells expressing luciferase were implanted into the flank of BALB/c-nu mice (n = 19). When the tumor diameter reached 7-8 mm, the animals were divided into four groups according to the injected agents: group A (normal saline, n = 4), group B (doxorubicin, n = 5), group C (MNP, n = 5), and group D (MNP/doxorubicin complex, n = 5). Animals were exposed to an alternating magnetic field (AMF) to receive magnetic hyperthermia, and intratumoral temperature changes were measured. RESULTS: The rise in temperature of the tumors was 1.88 +/- 0.21 degrees C in group A, 0.96 +/- 1.05 degrees C in B, 7.93 +/- 1.99 degrees C in C, and 8.95 +/- 1.31 degrees C in D. The RSI of the tumors at day 14 post-treatment was significantly lower in group D (0.31 +/- 0.20) than in group A (2.23 +/- 1.14), B (0.94 +/- 0.47), and C (1.02 +/- 0.21). The apoptosis rates of the tumors were 11.52 +/- 3.10% in group A, 23.0 +/- 7.68% in B, 25.4 +/ 3.36% in C, and 39.0 +/- 13.2% in D, respectively. CONCLUSIONS: The intratumoral injection of ferucarbotran conjugated with doxorubicin shows an improved therapeutic effect compared with doxorubicin or ferucarbotran alone when the complex is injected into HCC tissues exposed to AMF for magnetic hyperthermia. This strategy of combining doxorubicin and MNP-induced magnetic hyperthermia exhibits a synergic effect on inhibiting tumor growth in an HCC model. PMID- 25037749 TI - Who owns urban waste? Appropriation conflicts in emerging countries. AB - Managing solid waste in developing cities is not an easy task and many public policies have failed to bring the expected results. It is here argued that comprehending the solid waste handling in the South implies reconsidering the proper definition of waste. Where does the product end and where does rubbish begin? The answer to this question is far from being obvious. Solid waste appears as a blurred concept. Such a thorny issue is all the more relevant today, as municipal solid waste management approaches in the developing world are being reformulated: dumping sites are banned, sanitary landfills are imposed, and separate collection is being introduced. The current sector transformations are here analysed through a novel theoretical analysis combined with an original qualitative and quantitative empirical work. Through two case-studies of one million inhabitant cities from emerging countries, it is shown that if appropriation conflicts arise that is because the urban solid waste deposit in Southern countries can be defined as an impure public good. This issue does not only involve private service operators and informal wastepickers; several other actors covet the urban solid waste deposit's cream, that is, recyclable items. In emerging countries, huge industrial groups are starting to target domestic recyclable waste as an alternative for raw materials, which costs are increasing ever more. PMID- 25037750 TI - Efficiency of superstimulatory protocol P-36 associated with the administration of eCG and LH in Nelore cows. AB - Recent work with P-36 demonstrates that the replacement of the last two doses of Follicle-Stimulating Hormone (FSH) with equine chorionic gonadotropin (eCG) increases embryo yields. However, it is unclear if the positive effect of eCG is related to its FSH-like activity, LH-like activity, or both. This study aimed to verify the replacement of eCG with pLH on the last day of superstimulatory treatment. Twenty-five Nelore cows were allocated to four groups: P-36 (control), P-36/eCG, P-36/LH2, and P-36/LH4. All animals underwent four treatments in a crossover design. The control group cows were superstimulated with decreasing doses of porcine Follicle-Stimulating Hormone (pFSH, 133 mg, im). In the P 36/eCG, P-36/LH2, and P-36/LH4 groups, the last two doses of pFSH were replaced in the former group by two doses of eCG (200 IU each dose, im) and in the latter two groups by two doses of pLH (1 and 2 mg each dose, im), respectively. Donors received fixed-time artificial insemination 12 and 24 hours after pLH. Embryo flushing was performed on D16. Data were analyzed by ANOVA (Proc Mixed, SAS). There was a trend of decreasing ovulation rate when comparing groups LH2 and eCG (P = 0.06). However, there was no significant difference in the mean number of viable embryos among groups P-36 (3.3 +/- 0.7), P-36/eCG (4.5 +/- 0.5), P-36/LH2 (3.7 +/- 0.8), and P-36/LH4 (4.2 +/- 1.0). It is concluded that the replacement of eCG by pLH on the last day of superstimulatory treatment can be performed with no significant variation in the production of viable embryos. PMID- 25037751 TI - The inherence heuristic as a source of essentialist thought. AB - Humans are essentialists: They believe hidden "essences" underlie membership in natural and social kinds. Although essentialism has well-established implications for important societal issues (e.g., discrimination), little is known about its origins. According to a recent proposal, essentialism emerges from a broader inherence heuristic-an intuitive tendency to explain patterns in terms of the inherent properties of their constituents (e.g., we have orange juice for breakfast [pattern] because citrus aromas [inherent feature] wake us up). We tested two predictions of this proposal-that reliance on the inherence heuristic predicts endorsement of essentialist beliefs, even when adjusting for potentially confounding variables (Studies 1 and 2), and that reducing reliance on the inherence heuristic produces a downstream reduction in essentialist thought (Studies 3 and 4). The results were consistent with these predictions and thus provided evidence for a new theoretical perspective on the cognitive underpinnings of psychological essentialism. PMID- 25037752 TI - The effect of central retinal venous pressure in patients with central retinal vein occlusion and a high mean area of nonperfusion. AB - PURPOSE: To evaluate the effect of central venous pressure (CVP) on visual outcomes and retinal ischemic consequences in patients with central retinal vein occlusion (CRVO). DESIGN: Prospective, single-center cohort study. PARTICIPANTS: Eighty-eight patients with CRVO and a high overall mean area (21.6 disc areas) of capillary nonperfusion (CNP) who were followed for 18 months before the availability of intravitreal therapy and who were offered standard care of the time. METHODS: Patients were evaluated at baseline and at 3, 8, and 18 months. At each study visit, measurements of CVP, best-corrected visual acuity (BCVA), area of CNP, retinal fluorescein transit time (FTT), and an evaluation for rubeosis iridis were performed. MAIN OUTCOME MEASURES: Evaluation of the effect of different levels of CVP on BCVA, retinal blood flow, and the development of retinal ischemia and rubeosis iridis. RESULTS: Mean BCVA was significantly higher in patients with lower CVP at all time points (P<0.0001). The area of CNP increased significantly with higher levels of CVP and progressed with time. The development of rubeosis iridis was significantly associated with CVP at all time points and was present in 5.6%, 27.9%, and 88.9% of those with low, moderate, and high CVP levels, respectively (P<0.0001), at the 18-month conclusion. Retinal blood flow as measured by FTT was reduced with higher levels of CVP. Spontaneous lowering of CVP had beneficial effects on BCVA, although this diminished with time. CONCLUSIONS: Eyes with increased CVP after more severe CRVO demonstrate significantly reduced vision, reduced retinal blood flow, a higher incidence of rubeosis iridis, and larger areas of CNP that correlate with the degree of CVP elevation. PMID- 25037753 TI - Microstructure of the optic disc pit in open-angle glaucoma. AB - PURPOSE: To investigate the structural and clinical characteristics of the optic disc pit (ODP) in primary open-angle glaucoma (POAG) via enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective, observational case series. PARTICIPANTS: Seventy POAG eyes clinically diagnosed with an ODP via stereo disc photography. METHODS: Optic discs were scanned using EDI SD-OCT. Serial horizontal and vertical B-scan images covering the optic discs were obtained from each eye. The structural characteristics of the ODP were investigated via 3-dimensional images constructed from the serial B-scans, focusing on the presence of alterations in the contour of the lamina cribrosa (LC) or prelaminar tissue (PLT), in conjunction with associated clinical characteristics. MAIN OUTCOME MEASURES: The structural characteristics of the ODP and associated clinical characteristics. RESULTS: In the EDI SD-OCT images, the ODP was viewed as an isolated alteration of the LC (n = 14, 20.0%) or PLT (n = 16, 22.9%) or an alteration of both the LC and PLT (n = 40, 57.1%). Alterations of the LC were located at the mid-periphery near the LC insertion (n = 17) or far periphery adjacent to the LC insertion (n = 37), and the depth of alteration was deep (n = 23), involving nearly full-thickness LC, or shallow (n = 31), with partially visible LC at the base. Fifty-four eyes (77.1%) exhibited parafoveal visual field (VF) defect within 10 degrees of fixation, and in 98.1% of these eyes (53/54) it was spatially associated with the location of ODP. The parafoveal VF defect was more prevalent in eyes with LC alteration than those without (83.3% vs. 56.2%, P = 0.023) and in eyes with deep LC defect than those with shallow defect (95.7% vs. 74.2%, P = 0.036). Disc hemorrhage (32.4% vs. 0.0%, P = 0.008) and peripapillary retinoschisis (18.9 vs. 0.0%, P = 0.055) were more strongly associated with LC alterations located at the far periphery than at the mid periphery. CONCLUSIONS: Enhanced depth imaging SD-OCT facilitated visualization of the varied structure of the ODP, which presented as alteration of the LC or PLT or both. The clinical significance of differing characteristics of ODP microstructure remains to be determined. PMID- 25037754 TI - Comparing 2-[18F]fluoro-2-deoxy-D-glucose and [68Ga]gallium-citrate translocation in Arabidopsis thaliana. AB - 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)FDG) is a glucose surrogate commonly used in clinical or animal imaging but rarely in plant imaging to trace glucose metabolism. Recently, (18)FDG has been employed in plant imaging for studying photoassimilate translocation and glycoside biosynthesis. There is growing evidence that (18)FDG could be used as a tracer in plant imaging studies to trace sugar dynamics. However, to confirm this hypothesis, it was necessary to show that the observed (18)FDG distribution in an intact plant is an outcome of the chemical nature of the introduced radiotracer and not of the plant vascular architecture or radiotracer introduction method. METHODS: In the present work, we fed (18)FDG and [(68)Ga]gallium-citrate ((68)Ga-citrate) solution through mature Arabidopsis thaliana leaf and monitored subsequent radioactivity distribution using positron autoradiography. The possible route of radioactivity translocation was elucidated through stem-girdling experiments. We also employed a bi functional positron emission tomography/computed tomography (PET/CT) modality to capture (18)FDG radiotracer dynamics in one of the plants in order to assess applicability of PET/CT for 4-D imaging in an intact plant. RESULTS: Autoradiography results showed that [(18)F] radioactivity accumulated mostly in roots and young growing parts such as the shoot apex, which are known to act as sinks for photoassimilate. [(18)F] radioactivity translocation, in this case, occurred mainly via phloem. PET/CT results corroborated with autoradiography. [(68)Ga] radioactivity, on the other hand, was mainly translocated to neighboring leaves and its translocation occurred via both xylem and phloem. CONCLUSION: The radioactivity distribution pattern and translocation route observed after (18)FDG feeding is markedly different from that of (68)Ga-citrate. [(18)F] radioactivity distribution pattern in an intact plant is found similar to the typical distribution pattern of photoassimilates. Despite its limitations in quantification and resolution, PET/CT could be a useful tool to elucidate in vivo dynamics of [(18)F] radioactivity in intact plants. PMID- 25037755 TI - In vitro assessment of cytotoxicity and labeling efficiency of 99mTc-HMPAO with stromal vascular fraction of adipose tissue. AB - INTRODUCTION: Noninvasive radionuclide imaging of cells using technetium99m hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) is a potential diagnostic tool for several applications. Herein we aimed to evaluate the labeling efficiency and cellular toxicity of (99m)Tc-HMPAO with Stromal Vascular Fraction (SVF) of adipose tissue to develop a process tool for theranostic purposes, in particular imaging cardiac stem cell therapy. METHODS: Ten million cells of SVF were labeled with (99m)Tc-HMPAO complex and excess radiolabel was cleared off through washing in PBS. The labeling efficiency of (99m)Tc-HMPAO was detected in labeled cells and their subsequent supernatant wash using isotope dose calibrator and gamma camera. The cytotoxicity was assessed for the comparative reactive oxygen species (ROS) by H2DCFDDA, apoptotic events by annexin-V and TUNEL assay and mitochondrial potential by JC-1. RESULTS: An encouraging labeling efficiency of 33% was observed with (99m)Tc-HMPAO complex. The radionuclide labeling of SVF demonstrated significant safety profile as evaluated by apoptotic assays. CONCLUSION: (99m)Tc-HMPAO labeling efficiency of 33% of total SV fraction would produce sufficient radioactive signals that would enable for in vivo tracking of cells by SPECT-CT. The radionuclide did not demonstrate any significant impact on the structural or functional organization of the labeled cells. Our study indicates that SVF can be safely labeled with (99m)Tc-HMPAO without adverse cytotoxic events and for its potential role in imaging cardiac stem cell therapy. PMID- 25037756 TI - Influence of cyclic heating on physical property and biocompatibility of alpha- and beta-form gutta-percha. AB - BACKGROUND/PURPOSE: Thermoplasticized techniques with high temperature and repetitive heating in root canal filling may cause degeneration of gutta-percha, producing cytotoxic byproducts and interfering sealing quality. This study was conducted to investigate the influence of cyclic heating on the physical property and biocompatibility of alpha- and beta-form gutta-perchas. METHODS: Both alpha- and beta-form gutta-perchas were submitted to two heating processes: continuous heating and cyclic heating. Continuous heating was carried out by heating the samples up to 300 degrees C and 400 degrees C. The samples were then analyzed by differential scanning calorimetry, differential thermal analysis (DTA), and thermogravimetry. For cyclic heating process, samples were heated from 30 degrees C to 200 degrees C for seven cycles and analyzed with DTA and thermogravimetry. For cell adhesion assay, samples were treated (30 degrees C to 200 degrees C, one and seven cycles), submitted to cell culture and examined by scanning electron microscope. RESULTS: Differential scanning calorimetry and DTA indicated that alpha-form gutta-percha presented a major endothermic peak at 50-57 degrees C, while beta-form gutta-percha showed two major endothermic peaks at 46-50 degrees C and 60-63 degrees C. Total weight loss of beta-form gutta-percha was about 2 fold greater than that of alpha-form gutta-percha after continuous heating up to 300 degrees C, or cyclic heating for seven times. Scanning electron microscopy showed no obvious difference of cell adhesion on alpha- and beta-form samples, even with seven cyclic heating or one heating cycle. However, the attachment of the cells to the culture plate (the control) is better than to the gutta-percha samples. CONCLUSION: The increase of heating cycles for alpha- and beta-form gutta-percha exerts no adverse influence on their biocompatibility. Because the physical property of beta-form gutta-percha becomes unstable when it is heated at over 300 degrees C or subjected to cyclic heating, beta-form gutta-percha may not be recommended for use in thermoplasticized gutta-percha techniques. PMID- 25037757 TI - The translation and validation of Chinese overactive bladder symptom score for assessing overactive bladder syndrome and response to solifenacin treatment. AB - BACKGROUND/PURPOSE: Overactive bladder symptom score (OABSS) was developed by a Japanese urologist and is widely used in Asian countries. The aim of this study was to develop and validate a Chinese OABSS for assessing overactive bladder (OAB) and treatment outcome after solifenacin. METHODS: The Chinese OABSS was developed by linguistic validation of the original version. Its reliability and validity, and correlations with a three-day bladder diary were tested. Patients answered the Chinese OABSS at enrollment and repeated the questionnaire after a non-treatment period of 2 weeks, and at 4 and 12 weeks after solifenacin (5mg/day). Patients also completed a three-day bladder diary and forms including patient perception of bladder condition, International Prostatic Symptom Score and quality of life index at each study visit (for a total of four visits). An analysis was conducted to evaluate the reliability and validity of the Chinese OABSS and the correlations with a three-day bladder diary and a patient perception of bladder condition, respectively. RESULTS: A total of 60 patients with OAB, including 31 OAB wet and 29 OAB dry, were enrolled. The test-retest reliability of Chinese OABSS was moderate to good with weighted kappa coefficients of 0.515-0.721 for each symptom score and 0.610 for total symptom score. Forty-eight (80%) patients completed the responsiveness study and were followed-up at all time points. Patients' OAB symptoms improved significantly from baseline to 3 months after solifenacin treatment. The changes in OABSS decreased gradually with time within the three months of solifenacin treatment. CONCLUSION: The Chinese OABSS has been validated as a reliable instrument for assessing OAB. Solifenacin 5mg once daily improved urgency and other symptoms of OAB including frequency, urge incontinence, OABSS and International Prostatic Symptom Score. The adverse effects were acceptable and became less significant with time in the three months of treatment. PMID- 25037758 TI - Clinical effectiveness of laser acupuncture in the treatment of temporomandibular joint disorder. AB - BACKGROUND/PURPOSE: Temporomandibular joint disorder (TMD) is a general term for diseases of the temporomandibular joint and orofacial muscles. In this study, we tested whether laser acupuncture was effective for the treatment of TMD. METHODS: Twenty patients with TMD were treated with diode K-Laser (wavelength 800 nm, energy density 100.5 J/cm(2)) once a week at four acupuncture points including three standard ipsilateral local points (ST6, ST7, Ashi point) and one contralateral distal point (LI4). A 10-cm visual analogue scale (0 no pain and 10 the most severe pain) was used for measuring the pain intensity before and after the treatment. RESULTS: Seventeen out of 20 patients (85%) showed various degrees of pain relief after laser acupuncture treatment. The average pain score was 6.3 +/- 1.6 before treatment and 2.5 +/- 2.2 after treatment. Significant pain relief after laser acupuncture treatment was achieved (p = 0.0003, Wilcoxon signed rank test). The 17 patients showed an average pain relief of 63 +/- 31%. There were six patients who showed no TMD symptoms after an average of four treatments of laser acupuncture. The other 11 patients showed partial relief of TMD symptoms after treatment. Although the pain was still present, it was less and was acceptable. No side effects were reported in any patients during or after laser acupuncture treatments. CONCLUSION: Laser acupuncture may be an alternative treatment modality for TMD because it is non-invasive, results in partial or total relief of pain, and has no side effects. PMID- 25037759 TI - Determinants of maternal satisfaction with diagnosis disclosure of autism. AB - BACKGROUND/PURPOSE: Diagnosis disclosure is an important clinical issue in developmental disabilities, which may influence parents' ability to cope with their child's conditions. This paper presents the content and patterns of diagnosis-informed counseling for mothers of children with autism and investigates the determinants for maternal satisfaction with this counseling, in order to improve clinical practice. METHODS: Mothers of 151 children, aged 3-12 years, with DSM-IV autistic disorder, confirmed by the Chinese version of the Autism Diagnostic Interview-Revised, were assessed. We collected information about the mothers' experience with diagnosis-informed counseling, their personality characteristics, and the extent to which they were satisfied with the counseling. RESULTS: Satisfaction with diagnosis-informed counseling was related more to the context of the counseling, including the attitude of the counselors and the timing and duration of counseling, than to its content. Parents' social desirability, educational level, and employment status were negatively associated with their satisfaction with counseling. However, immediate emotion, neuroticism, and extroversion did not have a significant effect on the satisfaction with counseling. Approximately 60% of the mothers preferred to be informed of having an autistic child after the diagnosis had been confirmed. CONCLUSION: Our findings suggest that more efforts are needed to improve the quality of diagnosis informed counseling in autism, particularly in the context of breaking the news to mothers of children with autism. Future study could further examine the moderating effect of diagnostic subtype of autism spectrum disorders, treatment response, or social support on maternal satisfaction with diagnosis-informed counseling (ClinicalTrials.gov number, NCT00494754). PMID- 25037760 TI - Association of pocket epithelial cell proliferation in periodontitis with TLR9 expression and inflammatory response. AB - BACKGROUND/PURPOSE: Inflammatory response is triggered after recognition of microbial ligands by innate receptors such as Toll-like receptors (TLRs) and Nucleotide oligomerization domain (NOD)-like receptors (NLRs). In this study, we examined serial frozen sections of gingival biopsies from patients with gingivitis or periodontitis by immunohistochemical analysis for the topographic expression patterns of selected innate receptors and their association with cell proliferation in clinically healthy and diseased gingival tissues. METHODS: A total of 19 gingival biopsies were collected from patients at the School of Dentistry, National Taiwan University Medical Center according to approved protocol and with informed consent. The specimens were assigned to either the gingivitis group or periodontitis group after clinical evaluation using gingival index. Frozen sections of gingival biopsies were stained with hematoxylin and eosin for histological evaluation. Serial sections of the same samples were stained with a panel of antibodies for immunohistochemical analysis. Expression of each protein marker was compared in the oral versus the sulcular epithelium of the same section. RESULTS: Expression of cytokeratin 19 (CK19) was markedly increased in the basement membranes of the oral epithelium and in all layers of the pocket epithelium where it caused evident cell proliferation and migration of sulcular epithelial cells into the lamina propria of periodontitis tissue. TLR4 and the cytoplasmic NLRP3 were expressed in all sections examined regardless of disease state. However, expression of TLR9-, CK19- and collagenolytic matrix metalloproteinase-13 and activated NF-kappaB subunit p65 was more commonly found in periodontitis tissues than in gingivitis tissues. CONCLUSION: Activation of TLR9 signaling in the pocket epithelium was highly associated with periodontal inflammation and possibly with loss of tissue integrity. Further studies of mechanisms by which TLR9 signaling is activated in the periodontal epithelium may lead to new strategies for treating periodontitis. PMID- 25037761 TI - Why do general medical patients have a lengthy wait in the emergency department before admission? AB - BACKGROUND/PURPOSE: Emergency department (ED) overcrowding is a universal problem, especially with the shortage of hospital beds. We studied the characteristics and outcomes of patients with prolonged ED stays, which has rarely been studied before. METHODS: We conducted a retrospective study at a tertiary medical center in Taiwan. Prolonged stay in the ED was defined as a stay of more than 72 hours in the ED before admission. The medical records were reviewed for data analysis. RESULTS: From November 1, 2009 to January 31, 2010, a total of 1364 general medical patients were enrolled. The mean age was 66.4 +/- 17.8 years, with 53.4% male. The mean Charlson Comorbidity Index (CCI) was 3.0 +/ 3.1. The mean length of ED stay was 43.9 +/- 41.0 hours. The CCI (4.1 +/- 3.5 vs. 2.8 +/- 3.0, p < 0.001) and do-not-resuscitate (DNR) rates (18.8% vs. 10.3%, p = 0.001) of the patients with prolonged ED stays were higher than those of the patients with shorter stays. For patients with high CCI (>=3) and DNR consent, the odds ratio of prolonged ED stay was 1.73 and 1.60, respectively. Patients with prolonged ED stays also had a lower Barthel index (60.3 +/- 34.8 vs. 66.4, p = 0.011) and higher in-hospital mortality (11.6% vs. 6.0%, p = 0.006). CONCLUSION: Complex comorbidities and terminal conditions with DNR consent were associated with the prolonged ED stay for general medical patients. The hospital manager should pay attention to general medical patients with multiple comorbidities as well as those who require palliative care. PMID- 25037762 TI - Gemella sanguinis endocarditis: first case report in Taiwan and review of the literature. AB - We describe a case of infective endocarditis of the native aortic valve due to Gemella sanguinis in a 67-year-old Taiwanese man who had pre-existent valvular heart disease. He was successfully treated with aortic valve replacement accompanying a 6-week intravenous antibiotic treatment. To the best of our knowledge, this is the first report of G sanguinis endocarditis in Taiwan. PMID- 25037763 TI - How fast can a choroid plexus papilloma grow? PMID- 25037764 TI - Cavum septum pellucidum and vergae in an elderly man. PMID- 25037765 TI - Tracheal transection caused by clothesline injury. PMID- 25037766 TI - A case of familial amyloidotic polyneuropathy with a rare Phe33Leu mutation in the TTR gene. PMID- 25037767 TI - Long-term disease-free survival achieved by anti-angiogenic therapy plus surgery in a hepatocellular carcinoma patient with extensive liver involvement and lung metastases. PMID- 25037768 TI - Low frequency repetitive transcranial magnetic stimulation in children with attention deficit/hyperactivity disorder. Preliminary results. PMID- 25037771 TI - Centers for Disease Control "high-risk" donor status does not significantly affect recipient outcome after heart transplantation in children. AB - BACKGROUND: In 2004, the United Network for Organ Sharing (UNOS) added the label "high-risk donor" (HRD) for any organ donor who met the Centers for Disease Control (CDC) criteria for high-risk behavior for infection. The aim of this study was to calculate the rate of HRD graft use in heart transplantation in children and determine the differences in outcome from those who received standard-risk donor (SRD) grafts. METHODS: We reviewed information from the UNOS database regarding transplants performed between June 30, 2004 and July 31, 2012. Heart transplant recipients <18 years old were divided into two groups based on the donor's risk status. Demographic data on donors and recipients were collected. Survival analysis was performed to compare survival based on donor status. We also compared episodes of rejection before hospital discharge and the length of stay after transplantation by donor status. RESULTS: During the study period, 2,782 pediatric heart transplantations were performed and 116 (4.1%) patients received a CDC HRD graft. Recipients of HRD grafts were significantly older and heavier than those who received an SRD graft (8.5 vs 6.5 years, p < 0.001 and 35.7 vs 26.9 kg, p < 0.001). There was no difference in patient survival (log rank, p = 0.88) between groups. There was no difference in rejection prior to discharge (17.2 vs 16.4%, p = 0.81) or length of stay after transplantation (26.1 vs 27.6 days, p = 0.58). CONCLUSIONS: CDC HRD graft status does not appear to significantly affect recipient outcome after heart transplantation in children. PMID- 25037772 TI - Checking the plausibility of psychiatrists' arguments for not prescribing depot medication. AB - Treatment with long-acting depot antipsychotics may yield beneficial effects with regard to long-term adherence and long term outcomes in patients with schizophrenia. However, the implementation of depot treatment is rather low in many settings. Research on this issue helped identifying various potential reasons for this pattern including patient refusal and negative attitudes of psychiatrists. Nevertheless no definite conclusion exists as to what actually hinders the wider implementation of depot treatment. To date there are no studies that surveyed this issue with regard to concrete patients and from both perspectives, of the psychiatrists and the related patients. In the present analysis we therefore analyzed psychiatrists' and patients' behavior regarding depot prescription in N=213 individual doctor-inpatient-dyads in German psychiatric hospitals. A high number of patients (30%) were actually prescribed depot at discharge, even more were informed about the possibility of depot treatment by their psychiatrists (47%). Moreover, 50% of the surveyed patients were generally open toward receiving depot antipsychotics. However, for the high number of patients not receiving depot (70%) the psychiatrists' arguments against depot were often implausible and therefore many more patients might be suitable for receiving depot treatment. Psychiatrists' hesitation to discuss and implement depot might also be founded in concerns regarding patients' acceptance of depot medication. Here doctors should be empowered by teaching communication strategies that may help to convince patients accept treatment. PMID- 25037770 TI - Exo1 independent DNA mismatch repair involves multiple compensatory nucleases. AB - Functional DNA mismatch repair (MMR) is essential for maintaining the fidelity of DNA replication and genetic stability. In hematopoiesis, loss of MMR results in methylating agent resistance and a hematopoietic stem cell (HSC) repopulation defect. Additionally MMR failure is associated with a variety of human malignancies, notably Lynch syndrome. We focus on the 5'->3' exonuclease Exo1, the primary enzyme excising the nicked strand during MMR, preceding polymerase synthesis. We found that nuclease dead Exo1 mutant cells are sensitive to the O6 methylguanine alkylating agent temozolomide when given with the MGMT inactivator, O6benzylguanine (BG). Additionally we used an MMR reporter plasmid to verify that Exo1(mut) MEFs were able to repair G:T base mismatches in vitro. We showed that unlike other MMR deficient mouse models, Exo1(mut) mouse HSC did not gain a competitive survival advantage post temozolomide/BG treatment in vivo. To determine potential nucleases implicated in MMR in the absence of Exo1 nuclease activity, but in the presence of the inactive protein, we performed gene expression analyses of several mammalian nucleases in WT and Exo1(mut) MEFs before and after temozolomide treatment and identified upregulation of Artemis, Fan1, and Mre11. Partial shRNA mediated silencing of each of these in Exo1(mut) cells resulted in decreased MMR capacity and increased resistance to temozolomide/BG. We propose that nuclease function is required for fully functional MMR, but a portfolio of nucleases is able to compensate for loss of Exo1 nuclease activity to maintain proficiency. PMID- 25037773 TI - Possible involvement of corticosterone and serotonin in antidepressant and antianxiety effects of chromium picolinate in chronic unpredictable mild stress induced depression and anxiety in rats. AB - In the present study, we investigated the effects of chromium picolinate (CrP) on behavioural and biochemical parameters in chronic unpredictable mild stress (CUMS) induced depression and anxiety in rats. The normal and stressed male Swiss albino rats were administered CrP (8 and 16MUg/mL in drinking water), they received stressors for seven days (each day one stressor) and this cycle was repeated three times for 21 days. On 22nd day, behaviour assessments followed by biochemical estimations were conducted. The results showed that treatment of CrP produced significant antidepressant effect, which has been evidenced by decrease in immobility time in modified forced swimming test (FST) in chronic unpredictable mild stress (CUMS) induced depression in rats. In elevated plus maze (EPM), CrP (16MUg/mL) showed significant reduction in time spent in open arm. CrP (8MUg/mL and 16MUg/mL) also showed significant decrease in number of entries in open arm that shows antianxiety effect of CrP in CUMS rats. It was also found that CrP (8 and 16MUg/mL) significantly increased 5-HT concentration in the discrete regions of brain (cortex and cerebellum). On the other hand, the plasma corticosterone level was significantly decreased with CrP (16MUg/mL). The results suggested that increase in the concentration of 5-HT and decrease in plasma corticosterone levels could be responsible for improvement in symptoms of depression and anxiety in CUMS induced depression and anxiety in rats. PMID- 25037774 TI - Development of dual-templates molecularly imprinted stir bar sorptive extraction and its application for the analysis of environmental estrogens in water and plastic samples. AB - In this study, a novel dual-template molecularly imprinted polymer (MIP)-coated stir bar was prepared and coupled with high-performance liquid chromatography (HPLC) for the analysis of environmental estrogens in complex samples. Dual template MIP coating was homogeneous and porous with an average thickness of 5MUm. Moreover, it could be used for at least 50 times and be kept for at least 12 months in a dryer without any damage. The MIP-coated stir bar showed excellent selectivity to bisphenols and steroids. The method for the determination of bisphenols and steroids in complex samples via MIP-coated stir bar sorptive extraction coupled with HPLC was developed. The method was successfully applied in the analysis of five estrogens in lake and river water samples with recoveries of 71.2- 96.4% and 62.8-98.0%, respectively. The method was also successfully applied to the analysis of five estrogens in three plastic samples with recoveries of 67.7-99.1%, 68.8-99.9%, and 74.8-101.8%. The limit of quantitation was 1.0-5.0MUg/L. The proposed method is suitable for the simultaneous determination of multiple trace environmental estrogens in water and plastic samples. PMID- 25037775 TI - Direct high-performance liquid chromatographic enantioseparation of secondary amino acids on Cinchona alkaloid-based chiral zwitterionic stationary phases. Unusual temperature behavior. AB - Two chiral stationary phases containing a quinine- or a quinidine-based zwitterionic ion-exchanger as chiral selector were applied for the enantioseparation of 27 unusual cyclic secondary alpha-amino acids. The effects of the nature and concentration of the bulk solvent, the acid and base additives, the structures of the analytes and temperature on the enantioresolution were investigated. To study the effects of temperature and to obtain thermodynamic parameters, experiments were carried out at constant mobile phase compositions in the temperature range -5 to 55 degrees C. The thermodynamic parameters indicated that in most cases the separations were enthalpy-driven, but some entropy-driven separations were also observed. The sequence of elution of the enantiomers was determined in most cases. PMID- 25037776 TI - Use of fluorinated polybrominated diphenyl ethers and simplified cleanup for the analysis of polybrominated diphenyl ethers in house dust. AB - A simple, cost-effective method is described for the analysis of polybrominated diphenyl ethers (PBDEs) in house dust using pressurized fluid extraction, cleanup with modified silica solid phase extraction tubes, and fluorinated internal standards. There are 14 PBDE congeners included in the method, some typically contained in the commercial mixtures used as flame retardants, and some which are not routinely reported in the peer-reviewed literature. A gas chromatographic mass spectrometry instrumental method provides baseline separation in <20 min, detection limits <20 ng/g, and quantitation limits <60 ng/g for most congeners. Method blanks contained an average concentration <9 ng/g for all congeners except BDE209 which had an average around 40 ng/g. Spiked samples showed good accuracy with relative percent difference (RPD) <7%, and good precision with relative standard deviation <22% for all congeners except BDE209. The method was applied to the analysis of a standard dust (NIST Standard Reference Material 2585) and showed good accuracy with RPD <25% except for BDE154. Overall, this method exhibited good performance characteristics in all categories including simplicity, cost, sensitivity, selectivity, accuracy, and precision. PMID- 25037777 TI - Enantioseparation of basic chiral compounds on a clindamycin phosphate silica/zirconia hybrid monolith by capillary electrochromatography. AB - An organic-inorganic silica/zirconia hybrid monolithic capillary column was prepared by sol-gel process in a fused-silica capillary by using triethoxysilylpropylcarbamate (TEOSPC) derivative of clindamycin phosphate (CLIP) as a chiral selector. A sol solution consisting of 6 * 10(-3)M of polyethylene glycol, 1 M of water, 2M of acetic acid and 0.04/0.96 ratio of CLIP-TEOSPC/Zr-Bu resulted in homogeneous monolith having well defined through-pores and tightly anchored to the capillary wall. The column was employed for capillary electrochromatographic enantioseparation of eight basic chiral drugs in mobile phases consisting of acetonitrile, methanol and ammonium acetate (AA, as the electrolyte). Effects of the compositions of solvents and electrolyte in the mobile phase, applied voltage and capillary temperature on chiral separation were investigated. The highest resolution values were obtained with mobile phases consisting of 40/60 MeOH/ACN and 100 mM AA (for citalopram, Troger's base, indapamide, metoprolol, cetirizine and atropine) and 35/65 MeOH/ACN and 100 mM AA (for sertraline and propranolol) using -10 kV applied voltage at 25 degrees C. PMID- 25037778 TI - Optimised extraction of heterocyclic aromatic amines from blood using hollow fibre membrane liquid-phase microextraction and triple quadrupole mass spectrometry. AB - Heterocyclic aromatic amines (HCA) are carcinogenic mutagens formed during cooking of proteinaceous foods, particularly meat. To assist in the ongoing search for biomarkers of HCA exposure in blood, a method is described for the extraction from human plasma of the most abundant HCAs: 2-amino-1-methyl-6 phenylimidazo(4,5-b)pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5 f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8 DiMeIQx) (and its isomer 7,8-DiMeIQx), using hollow fibre membrane liquid-phase microextraction. This technique employs 2.5cm lengths of porous polypropylene fibres impregnated with organic solvent to facilitate simultaneous extraction from an alkaline aqueous sample into a low volume acidic acceptor phase. This low cost protocol is extensively optimised for fibre length, extraction time, sample pH and volume. Detection is by UPLC-MS/MS using positive mode electrospray ionisation with a 3.4min runtime, with optimum peak shape, sensitivity and baseline separation being achieved at pH 9.5. To our knowledge this is the first description of HCA chromatography under alkaline conditions. Application of fixed ion ratio tolerances for confirmation of analyte identity is discussed. Assay precision is between 4.5 and 8.8% while lower limits of detection between 2 and 5pg/mL are below the concentrations postulated for acid-labile HCA-protein adducts in blood. PMID- 25037769 TI - History of cigarette smoking in cognitively-normal elders is associated with elevated cerebrospinal fluid biomarkers of oxidative stress. AB - BACKGROUND: Cigarette smoking in adults is associated with abnormalities in brain neurobiology. Smoking-induced central nervous system oxidative stress (OxS) is a potential mechanism associated with these abnormalities. The goal of this study was to compare cognitively-normal elders on cerebrospinal fluid (CSF) levels of F2-isoprostane biomarkers of OxS. METHODS: Elders with a lifetime history of smoking (smokers; n=50; 75+/-5 years of age; 34+/-28 pack-years; approximately 12% were actively smoking at the time of study) were compared to never-smokers (n=61; 76+/-6 years of age) on CSF iPF2alpha-III and 8,12, iso-iPF2alpha-VI F2 isoprostanes levels. F2-isoprostanes levels were quantitated with HPLC atmospheric pressure chemical ionization-tandem mass spectrometry. Associations between F2-isoprostanes levels, hippocampal volumes, and cigarette exposure measures were also evaluated. RESULTS: Smokers showed higher iPF2alpha-III level than never-smokers. An age*smoking status interaction was observed for 8,12, iso iPF2alpha-VI, where smokers demonstrate a significantly greater concentration with increasing age than never-smokers. In smokers only, higher 8,12, iso iPF2alpha-VI concentration was associated with smaller hippocampal volume, and greater iPF2alpha-III level was related to greater pack years. CONCLUSIONS: This is the first study to demonstrate that a history of cigarette smoking in cognitively-normal elders was associated with significantly elevated CSF F2 isoprostane levels and greater age-related increases in F2-isoprostanes, and that higher F2-isoprostane levels in smokers were related to smaller hippocampal volume. These findings provide additional novel evidence that a history of chronic smoking during adulthood is associated with adverse effects on the human brain that are potentially enduring even with extended smoking cessation. PMID- 25037779 TI - Electrochemical in situ fabrication of titanium dioxide-nanosheets on a titanium wire as a novel coating for selective solid-phase microextraction. AB - A novel TiO2-nanosheets coated fiber for solid-phase microextraction (SPME) was fabricated by anodization of Ti wire substrates in ethylene glycol with concentrated NH4F. The in situ fabricated TiO2-nanosheets were densely embedded into Ti substrates with about 1MUm long, 300nm wide and 80nm thick. The as fabricated TiO2-nanosheets coating was employed to extract polycyclic aromatic hydrocarbons, phthalates and ultraviolet (UV) filters in combination with high performance liquid chromatography-UV detection (HPLC-UV). It was found that the TiO2-nanosheets coating exhibited high extraction capability and good selectivity for some UV filters frequently used in cosmetic sunscreen formulations. The main parameters affecting extraction performance were investigated and optimized. Under the optimized conditions, the calibration graphs were linear in the range of 0.1-400MUgL(-1). The limits of detection of the proposed method were between 0.026MUgL(-1) and 0.089MUgL(-1) (S/N=3). The single fiber repeatability varied from 4.50% to 8.76% and the fiber-to-fiber reproducibility ranged from 7.75% to 9.64% for the extraction of spiked water with 50MUgL(-1) UV filters (n=5). The SPME-HPLC-UV method was successfully established for the selective preconcentration and sensitive detection of target UV filters from real environmental water samples. Recovery of UV filters spiked at 10MUgL(-1) and 25MUgL(-1) ranged from 88.8% to 107% and the relative standard deviations were less than 9.8%. Furthermore the in situ growth of the TiO2-nanosheets coating was performed in a highly reproducible manner and the TiO2-nanosheets coated fiber has high mechanical strength, good stability and long service life. PMID- 25037780 TI - NICE sticks to its advice to drop threshold for prescribing statins. PMID- 25037781 TI - Nurses' perception and comfort level with diabetes management practices in long term care. AB - OBJECTIVE: Increasing numbers of elderly people in long-term care have diabetes mellitus. We explored nurses' perceptions and level of comfort with current diabetes management of patients in long-term care. METHODS: A mixed-methods approach using a cross-sectional survey design, including both quantitative and open-ended questions, was used. The licensed nurses employed in 9 long-term care homes in southwestern Ontario were surveyed. The survey explored nurses' comfort with managing diabetes, detecting hypoglycemia and hyperglycemia, glucose monitoring guidelines, and insulin administration and training. RESULTS: Of 301 nurses invited (130 registered nurses [RNs], 171 registered practical nurses [RPNs]), 165 nurses (77 RNs and 88 RPNs) responded (165 of 280, 59% response rate). Nurses were female (93.3%); their mean age was 45.3 years (SD 11.7). Most noted that the medication administration system and guidelines regarding diabetes management were adequate; RPNs were more comfortable administering insulin than RNs (p=0.048). CONCLUSIONS: The findings suggest RNs and RPNs have different comfort levels and perceptions of diabetes management. PMID- 25037782 TI - The use of donated products to train residents to perform injectable cosmetic procedures. PMID- 25037783 TI - Proposed remedy to chronic back pain among dermatology residents. PMID- 25037784 TI - Scalpel-made holes on exposed scalp bone to promote second intention healing. PMID- 25037785 TI - Change in arterial intima-media thickness: is it an appropriate surrogate for cardiovascular risk in psoriasis patients treated with tumor necrosis factor alpha inhibitors? PMID- 25037786 TI - Juvenile xanthogranulomas are highly prevalent but transient in young children with neurofibromatosis type 1. PMID- 25037787 TI - Current status of surgery in dermatology. PMID- 25037788 TI - Intralesional corticosteroid injections for vitiligo: a new therapeutic option. PMID- 25037789 TI - Response to 'Current status of surgery in dermatology'. PMID- 25037790 TI - Methods and rates of dermoscopy usage: a cross-sectional survey of US dermatologists stratified by years in practice. PMID- 25037791 TI - Academic dermatologists' views on the value of residency letters of recommendation. PMID- 25037792 TI - Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance. PMID- 25037793 TI - Eruptive disseminated porokeratosis: a new classification system. PMID- 25037794 TI - Effect of the endothelin type A-selective endothelin receptor antagonist ambrisentan on digital ulcers in patients with systemic sclerosis: results of a prospective pilot study. PMID- 25037795 TI - Challenges in measuring outcomes: size assessment of an individual cutaneous lesion. PMID- 25037796 TI - A practice gap in pediatric dermatology: does breast-feeding prevent the development of infantile atopic dermatitis? PMID- 25037797 TI - JAAD Grand Rounds quiz: Permanent lip swelling: a precursor of systemic disease? PMID- 25037798 TI - Adult with papular eruption on the central aspect of the face. PMID- 25037799 TI - Asymptomatic facial papules. PMID- 25037800 TI - Cutaneous reactions to chemotherapeutic drugs and targeted therapies for cancer: part I. Conventional chemotherapeutic drugs. AB - Conventional chemotherapy continues to be an important part of cancer management, but may cause various cutaneous reactions because it disturbs specific cell cycle phases. The alkylating agents cyclophosphamide, ifosfamide, and thiotepa can produce hyperpigmentation, while hypersensitivity reactions can be seen with platinum alkylating agents. Antimetabolites vary in reactions from exanthematous to bullous skin lesions. 5-fluorouracil and its derivatives and liposomal doxorubicin and daunorubicin are characteristically known to cause hand-foot syndrome, while bleomycin can cause fibrosis and flagellate dermatitis. Several hypersensitivity reactions may also occur from mitotic inhibitors and topoisomerase inhibitors. These different characteristic presentations are important to dermatologists in identifying the correct diagnosis and management for the cancer patient. PMID- 25037801 TI - Cutaneous reactions to chemotherapeutic drugs and targeted therapy for cancer: Part II. Targeted therapy. AB - Targeted drugs are increasingly being used for cancer management. They are designed to block specific cancer cell processes, and are often better tolerated than conventional chemotherapeutic drugs. Cutaneous reactions, however, are not uncommon, because some target molecules are also present in the skin. Tyrosine kinase inhibitors can cause edema and macular rash, whereas papulopustular rash, paronychia, regulatory changes in hair, itching, and dryness caused by epidermal growth factor receptor inhibitors (PRIDE) syndrome can be seen in patients treated with these drugs. Vismodegib may result in muscle spasms and alopecia. Multiple rashes can be seen with bortezomib, while sunitinib and sorafenib cause hand-foot skin reactions. New melanoma therapies, such as ipilimumab, cause immune-related adverse events of dermatitis and pruritus, while BRAF inhibitors can produce exanthematous rash and lead to an increased risk of squamous cell carcinoma. Dermatologists should be aware of these new therapies and their cutaneous reactions to be able to provide appropriate care and management for cancer patients. PMID- 25037804 TI - Palpebral conjunctiva melanoma with dermoscopic and clinicopathological characteristics. PMID- 25037805 TI - Resizing blister roof grafts for vitiligo surgery. PMID- 25037806 TI - Skin hook: the "free" surgical assistant. PMID- 25037807 TI - Ophthalmic cyclosporine for the treatment of psoriatic conjunctivitis. PMID- 25037808 TI - Chronic granulomatous disease presenting with ecthyma gangrenosum in a neonate. PMID- 25037809 TI - Tubular apocrine adenoma clinically and dermoscopically mimicking basal cell carcinoma. PMID- 25037810 TI - Efficacy of oral alitretinoin for the treatment of Darier disease: a case report. PMID- 25037811 TI - Alitretinoin: a new treatment option for hereditary punctate palmoplantar keratoderma (Brauer-Buschke-Fischer syndrome). PMID- 25037812 TI - Supraumbilical cutaneous lesions after transcatheter arterial chemoembolization for hepatocellular carcinoma. PMID- 25037813 TI - Merkel cell carcinoma presenting as right leg edema in a multiple myeloma patient. PMID- 25037814 TI - Photosensitive lichenoid drug eruption to capecitabine. PMID- 25037815 TI - Expression of interleukin-1 alpha in amicrobial pustulosis of the skin folds with complete response to anakinra. PMID- 25037816 TI - Neurology and psychiatry in Babylon. AB - We here review Babylonian descriptions of neurological and psychiatric disorders, including epilepsy, stroke, psychoses, obsessive compulsive disorder, phobias, psychopathic behaviour, depression and anxiety. Most of these accounts date from the first Babylonian dynasty of the first half of the second millennium BC, within a millennium and a half of the origin of writing. The Babylonians were remarkably acute and objective observers of medical disorders and human behaviour. Their detailed descriptions are surprisingly similar to modern 19th and 20th century AD textbook accounts, with the exception of subjective thoughts and feelings which are more modern fields of enquiry. They had no knowledge of brain or psychological function. Some neuropsychiatric disorders, e.g. stroke or facial palsy, had a physical basis requiring the attention of a physician or asu, using a plant and mineral based pharmacology; some disorders such as epilepsy, psychoses, depression and anxiety were regarded as supernatural due to evil demons or spirits, or the anger of personal gods, and thus required the intervention of the priest or asipu; other disorders such as obsessive compulsive disorder and psychopathic behaviour were regarded as a mystery. The Babylonians were the first to describe the clinical foundations of neurology and psychiatry. We discuss these accounts in relation to subsequent and more modern clinical descriptions. PMID- 25037817 TI - The mRNA expression of amino acid transporters, aminopeptidase N, and the di- and tri-peptide transporter PepT1 in the embryo of the domesticated chicken (Gallus gallus) shows developmental regulation. AB - The mRNA expression profile for 10 amino acid transporters, the di-and tri- peptide transporter (PepT1), and aminopeptidase N (APN) during chick embryogenesis was determined. Fertilized eggs were sampled at d 9, 11, 15, 17, 19, and 20 of incubation. Three to 4 embryos were sampled at each time period. At d 9 and 11, the entire intestine was collected due to its undifferentiated appearance. The ceca, duodenum, midgut, and liver were sampled at d 15, 17, 19, and 20. Gene expression was measured using absolute quantitation quantitative reverse-transcription PCR. In the liver, all genes except for PepT1 were expressed at most time points. At d 9, only the expression of Na+-independent cationic amino acid transporter 1, Na+-independent cationic amino acid transporter 2, and excitatory amino acid transporter 3 was detectable in the intestine, but by d 11, all genes associated with transporters of the basolateral surface were expressed, and at higher levels than genes associated with brush border transporters. By d 15, all of the genes tested were expressed in the duodenum, midgut, and ceca at high levels that remained relatively constant until d 20. Statistical analysis shows that at d 15, 17, 19, and 20 there is a significant interaction between the 2 main effects (days of incubation and region of the gut); therefore, it is likely that gene expression in different regions of the gut is dependent on the age of the embryo. At d 9 and 11, the gut may not function in amino acid uptake from the lumen and possibly relies on other structures such as the yolk sac. As the gut matures and protein becomes available in the lumen, amino acid transporters become highly expressed in all parts of the intestine. The data suggest that by d 15 of embryo development the gut may be capable of amino acid absorption. PMID- 25037818 TI - Apparent metabolizable energy value of expeller-extracted canola meal subjected to different processing conditions for growing broiler chickens. AB - The objective of this study was to investigate the effect of processing conditions and chemical composition on ileal digestible energy (IDE), AME, and AMEn of 6 expeller-extracted canola meal (ECM) samples subjected to conditioning temperature at 90, 95, or 100 degrees C and high or low screw torque over the second presses in a 3 * 2 factorial arrangement. The ECM samples were incorporated into a corn-soybean meal reference diet at 30% by replacing energy yielding ingredients. A total of 210 one-day-old male broiler chicks (Ross 308) were fed common starter and grower diets until d 18, and then assigned to 7 experimental diets replicated 6 times, with 5 chicks per cage. After a 5-d diet acclimation period from d 18 to 22, excreta was collected for 72 h. The difference method was used to determine AME, which was corrected to zero N balance to obtain AMEn. Medium seed conditioning temperature resulted in the highest IDE, AME, and AMEn compared with low or high temperature, and high screw torque resulted in higher energy utilization compared with low torque (P < 0.001). There was also an interaction (P < 0.001) between conditioning temperature and screw torque. For ECM subjected to low or medium conditioning temperature at low screw torque, IDE, AME, and AMEn values ranging from 2,137 to 2,705, 2,089 to 2,655, and 1,977 to 2,482 kcal/kg of DM, respectively, were obtained. The mean AMEn values were 2,260 kcal/kg of DM, indicating a 7% reduction compared with AME values. The AMEn values were negatively correlated with neutral detergent fiber (NDF; r = -0.93; P = 0.001) and NDIN (r = -0.87; P = 0.001). Stepwise regression to predict AMEn value resulted in the following equation: AMEn (kcal/kg of DM) = 3,397.8 + (-100.1 * NDF %) + (279.5 * ash %) + ( 33.8 * ADF %) (R2 = 0.91; SE = 61.9; P = 0.001). These results indicate that AMEn values vary markedly among ECM samples, and chemical constituents, especially the fiber components, may have a considerable effect on AMEn value. PMID- 25037819 TI - Folate supplementation modifies CCAAT/enhancer-binding protein alpha methylation to mediate differentiation of preadipocytes in chickens. AB - Folate, an essential vitamin participating in 1-carbon metabolism leading to a methyl donor function, is a key factor inducing epigenetic changes. This study sought to determine if folate influences the methylation level of cytosine guanine (CpG) islands in the promoters of critical adipogenic genes in chickens, and how this might affect gene expression and differentiation of preadipocytes in vitro. Preadipocytes were treated with 0 to 16 mg/L of folate during the induction of differentiation, and cell proliferation and lipid accumulation were assessed. The folate supplementation resulted in enhanced cell proliferation and decreased content of lipid per adipocyte at d 6 of differentiation. The effects of folate on relative expression of genes critical for adipocyte differentiation and 1-carbon metabolism were measured by quantitative reverse-transcription PCR. Folate caused a dose-dependent decrease in transcript abundance of peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha) gene expression, and the downstream enzyme fatty acid synthase; in contrast, expression of DNA (cytosine-5)-methyltransferase and methylenetetrahydrofolate reductase was obviously upregulated at d 6 of differentiation (P < 0.05). The DNA methylation was examined with the bisulfite sequencing PCR method. Overall CpG methylation in the C/EBPalpha gene promoter region was 21.8% lower (P < 0.05) and the gene's expression was 2.7-fold higher in the absence of folate, compared with cells treated with 16 mg/L of folate, whereas methylation of the PPARgamma promoter was not affected. Overall, the results show that folate increased the proliferation of adipocytes but reduced per-cell lipid accumulation, thereby influencing differentiation; it increased expression of genes involved in 1-carbon metabolism resulting in greater methylation of the C/EBPalpha promoter during differentiation and decreased that gene's expression, perhaps accounting for decreased expression of PPARgamma. PMID- 25037820 TI - Benefits of neutral electrolyzed oxidizing water as a drinking water additive for broiler chickens. AB - In the wake of discussion about the use of drugs in food-producing farms, it seems to be more and more important to search for alternatives and supportive measures to improve health. In this field trial, the influence of electrolyzed oxidizing (EO) water on water quality, drug consumption, mortality, and performance parameters such as BW and feed conversion rate was investigated on 2 broiler farms. At each farm, 3 rearing periods were included in the study. With EO water as the water additive, the total viable cell count and the number of Escherichia coli in drinking water samples were reduced compared with the respective control group. The frequency of treatment days was represented by the number of used daily doses per population and showed lower values in EO-water treated groups at both farms. Furthermore, the addition of EO water resulted in a lower mortality rate. In terms of analyzed performance parameters, no significant differences were determined. In this study, the use of EO water improved drinking water quality and seemed to reduce the drug use without showing negative effects on performance parameters and mortality rates. PMID- 25037821 TI - Development and characterization of mouse monoclonal antibodies reactive with chicken IL-1beta. AB - Interleukin-1beta proteins from chicken, duck, goose, turkey, and pigeon share 77 to 99% amino acid sequence similarity among themselves, and only 31 to 35% sequence similarity is shared between avian and mammalian IL-1beta. There have been no antibodies that specifically detect avian IL-1beta, and the current study was conducted to develop mouse monoclonal antibodies (mAb) against chicken IL 1beta (chIL-1beta) to further define its biochemical and immunological properties. In this study, 2 mouse mAb that are specific for chIL-1beta were produced and characterized. Both mAb identified a 66.0 kDa recombinant chIL-1beta protein expressed in Escherichia coli by Western blot analysis that corresponded to the expected molecular weight of a recombinant fusion protein containing the full-length 23.0 kDa chIL-1beta protein and a 43.0 kDa maltose binding protein tag. Immunohistochemical analysis identified cells producing endogenous chIL 1beta in the cecal tonsils, bursa of Fabricius, and spleen. Purified recombinant chIL-1beta dose-dependently stimulated the proliferation and nitric oxide production by thymocytes, and both activities were inhibited by co-incubation with the 2 chIL-1beta mAb described in this paper. These mAb will be important immune reagents for basic and applied poultry research of IL-1beta in poultry. PMID- 25037822 TI - Effects of naturally mycotoxin-contaminated corn on nutrient and energy utilization of ducks fed diets with or without Calibrin-A. AB - One hundred sixty-two 21-d-old ducks were randomly allotted to 6 treatments with 3 levels of mycotoxin-contaminated corn (0, 50, and 100% M) and 2 levels of Calibrin-A (CA, a clay mycotoxin adsorbent, 0 and 0.1%) to evaluate the effects of increasing levels of mycotoxin-contaminated corn on nutrient utilization in ducks fed diets with or without CA. Endogenous losses were obtained from another 27 ducks. Excreta samples were collected to determine DM, OM, CP, amino acids, and gross energy. Gross energy was analyzed for computation of AME and TME. The apparent digestibility (AD) and true digestibility (TD) of the nutrients in all treatments with and without CA had common (P > 0.05) intercepts and slopes except Pro (P < 0.05). The AME, TME, AD, and TD of DM, OM, Phe, and Gly were linearly (P < 0.05) decreased as the concentration of contaminated corn in the diet increased. Ducks fed the 100% M diet supplemented with 0.1% CA increased AD and TD of Gly compared with the 100% M diet, and ducks fed 50 and 100% M diet supplemented with 0.1% CA increased AD and TD of Pro compared with 50% M and 100% M diet, respectively. In the present study, ducks fed mycotoxin-contaminated corn decreased nutrient digestibility in dose-dependent manner, and 0.1% CA supplementation improved AD and TD of Gly and Pro. PMID- 25037823 TI - Dietary protein and amino acids-consideration of the undigestible fraction. AB - A case is made for the application of true ileal amino acid digestibility and true ileal reactive lysine digestibility (lysine availability) in poultry nutrition. Technical aspects of the true ileal digestibility assays are reviewed, as are factors influencing amino acid digestibility in the broiler. There is considerable variation in amino acid digestibility and lysine availability both within and among diverse feedstuffs. Differences in mean amino acid digestibility among feedstuffs, and the variability in the digestibility of an amino acid within a feedstuff should both be taken into account during least-cost dietary formulation. PMID- 25037824 TI - The effects of environmental enrichment devices on feather picking in commercially housed Pekin ducks. AB - Like other poultry species, Pekin ducks occasionally show an auto-mutilation behavior referred to as feather picking. Self-picking can lead to further pecking by conspecifics and ultimately to reduced feather quality and poor overall health of the bird. Although the reasons underlying feather picking are not clear, it appears to occur when the ducks are transitioning between downy feathers and adult plumage, between 17 and 22 d of age. We hypothesized that giving Pekin ducks a substitute outlet for this behavior in the form of environmental enrichment devices (EED) would decrease feather picking and improve feather quality and duck health and welfare. The EED were plastic Wiffle-style balls, each threaded with 4 zip-ties. In the first experiment, we set out to determine that placement of EED would not induce fear or harmful behaviors. Five barns were each divided into 2 pens, holding an average combined total of approximately 4,500 ducks with one pen per barn used as control. Upon placement of the EED in one pen per barn, both pens were videotaped for a total of 2 h per day. The physical characteristics of 100 ducks per pen were scored at age 7, 21, 28, and 35. Results showed a decrease (P = 0.034) in both self-picking and conspecific pecking in pens with EED compared with pens without EED. Although no differences in body condition scores were observed at 7 d of age, by d 21 ducks with EED showed better (P = 0.021) feather quality and cleanliness scores compared with ducks without EED. In a second experiment, we set out to determine if ducks had a color preference for blue/green, red, or white EED. Again, ducks with EED showed reduced (P = 0.038) feather picking compared with ducks without EED. Ducks interacted considerably more (P = 0.00089) frequently with blue/green EED then either red or white EED. These results suggest that providing environmental enrichment may minimize feather picking and improve feather quality and duck welfare. PMID- 25037825 TI - The effect of nutritional status on myogenic gene expression of satellite cells derived from different muscle types. AB - Satellite cells (SC) are a multipotential stem cell population responsible for facilitating posthatch muscle fiber hypertrophy. The proliferation and differentiation of SC is sensitive to nutritional regimen, and the SC response to nutrition varies depending upon their muscle type of origin. The objective of the current study was to determine the effect of altering protein synthesis on the expression of several key genes regulating SC activity and the effect of muscle type. Satellite cells isolated from the fast glycolytic pectoralis major and the fast oxidative and glycolytic biceps femoris were studied. These genes included the myogenic regulatory factors myogenic determination factor 1 (MyoD) and myogenin, the cell-membrane associated proteoglycans syndecan-4 and glypican-1, the extracellular matrix proteoglycan decorin, and the transcription factor paired box 7. Protein synthesis potential varied by the concentration of the sulfur amino acids Met and Cys during SC proliferation and differentiation. The SC were cultured and treated with 1 of 6 Met/Cys concentrations: 60/192, 30/96 (control), 7.5/24, 3.0/9.6, 1.0/3.2, or 0/0 mg/L. A consistent pattern of gene expression emerged following Met/Cys manipulation as increasing reductions in mRNA expression for all genes were observed as Met/Cys concentration decreased, whereas increased Met/Cys concentration caused either no change or had a small negative effect on mRNA expression. Reduced paired box 7 expression would limit myogenic specification of SC, whereas decreased myogenic regulatory factor expression would affect subsequent myogenic development of the SC. Decreased levels of decorin affect SC response to growth factors like myostatin and transforming growth factor beta, and extracellular matrix organization. These data highlight the importance of nutrition on the expression of genes critical for satellite cell activation, proliferation and differentiation, and growth factor signal transduction. PMID- 25037826 TI - Structure of the O-specific polysaccharide from the lipopolysaccharide of Aeromonas sobria strain Pt312. AB - The O-specific polysaccharide (OPS) obtained by mild-acid degradation of the lipopolysaccharide from Aeromonas sobria strain Pt312 was studied by sugar and methylation analyses along with 1H and 13C NMR spectroscopy, including 2D 1H,1H COSY, TOCSY, NOESY, 1H-detected 1H,13C HSQC, and HMBC experiments. The sequence of the sugar residues was determined using 1H,1H NOESY and 1H,13C HMBC experiments. It was found that the OPS was built up of disaccharide repeating units composed of GlcpNAc and non-stoichiometrically O-acetylated Rhap residues, and had the structure. PMID- 25037827 TI - Complex extreme learning machine applications in terahertz pulsed signals feature sets. AB - This paper presents a novel approach to the automatic classification of very large data sets composed of terahertz pulse transient signals, highlighting their potential use in biochemical, biomedical, pharmaceutical and security applications. Two different types of THz spectra are considered in the classification process. Firstly a binary classification study of poly-A and poly C ribonucleic acid samples is performed. This is then contrasted with a difficult multi-class classification problem of spectra from six different powder samples that although have fairly indistinguishable features in the optical spectrum, they also possess a few discernable spectral features in the terahertz part of the spectrum. Classification is performed using a complex-valued extreme learning machine algorithm that takes into account features in both the amplitude as well as the phase of the recorded spectra. Classification speed and accuracy are contrasted with that achieved using a support vector machine classifier. The study systematically compares the classifier performance achieved after adopting different Gaussian kernels when separating amplitude and phase signatures. The two signatures are presented as feature vectors for both training and testing purposes. The study confirms the utility of complex-valued extreme learning machine algorithms for classification of the very large data sets generated with current terahertz imaging spectrometers. The classifier can take into consideration heterogeneous layers within an object as would be required within a tomographic setting and is sufficiently robust to detect patterns hidden inside noisy terahertz data sets. The proposed study opens up the opportunity for the establishment of complex-valued extreme learning machine algorithms as new chemometric tools that will assist the wider proliferation of terahertz sensing technology for chemical sensing, quality control, security screening and clinic diagnosis. Furthermore, the proposed algorithm should also be very useful in other applications requiring the classification of very large datasets. PMID- 25037828 TI - Enhanced lipid accumulation of green microalga Scenedesmus sp. by metal ions and EDTA addition. AB - Effects of Fe(3+) (0-0.12 g/L), Mg(2+) (0-0.73 g/L) and Ca(2+) (0-0.98 g/L) on the biomass and lipid accumulation of heterotrophic microalgae were investigated in dark environment. The biomass and lipid production exhibited an increasing trend with increasing the concentrations of metal ions. In cultures with 1.2 * 10(-3) g/L Fe(3+), 7.3 * 10(-3) g/L Mg(2+) and 9.8 * 10(-4) g/L Ca(2+), the maximum biomass, total lipid content and lipid productivity reached 3.49 g/L, 47.4% and 275.7 mg/L/d, respectively. More importantly, EDTA addition (1.0 * 10( 3) g/L) could enhance the solubility of metal ions (iron and calcium) and increase their availability by microalgae, which evidently promote the lipid accumulation. Compared with the control, the total lipid content and lipid productivity increased 28.2% and 29.7%, respectively. These show that appropriate concentrations of metal ions and EDTA in the culture medium were beneficial to lipid accumulation of heterotrophic Scenedesmus sp. cells. PMID- 25037829 TI - What passes and fails as health policy and management. AB - The field of health policy and management (HPAM) faces a gap between theory, policy, and practice. Despite decades of efforts at reforming health policy and health care systems, prominent analysts state that the health system is "stuck" and that models for change remain "aspirational." We discuss four reasons for the failure of current ideas and models for redesigning health care: (1) the dominance of microeconomic thinking; (2) the lack of comparative studies of health care organizations and the limits of health management theory in recognizing the importance of local contexts; (3) the separation of HPAM from the rank and file of health care, particularly physicians; and (4) the failure to expose medical students to issues of HPAM. We conclude with suggestions for rethinking how the field of HPAM might generate more-promising policies for health care providers and managers by abandoning the illusion of context-free theories and, instead, seeking to facilitate the processes by which organizations can learn to improve their own performance. PMID- 25037830 TI - I'll be gone, you'll be gone: why American employers underinvest in health. AB - It has become increasingly common to hear a business case for wellness that emphasizes the benefits of having a healthy workforce. This is essentially the same as the case for employers to train their workers; training a worker and investing in the health of the worker both represent a productivity-enhancing investment in the worker by the firm. The problem is that the employer frequently fails to capture the returns on the investment. A healthier or better-skilled worker can command a higher wage and threaten to leave the firm making the investment. This risk of failing to capture the gains from investment produces underinvestment in skills and, by the same mechanism, should produce underinvestment in workforce wellness. We further divide wellness into positive and negative policies: Positive wellness is an investment, expenditure on the workforce in expectation of future increased returns, or perhaps better recruitment and retention. Negative wellness is an effort to reduce the wage bills associated with ill health with, for example, co-pays. Most stable and meaningful employer wellness programs are likely to be negative wellness programs that reduce the effective wages of the sick. PMID- 25037831 TI - What's bad about wellness? What the disability rights perspective offers about the limitations of wellness. AB - With great interest, employers in the United States are using wellness programs to reduce insurance costs and monitor the health of their employees. While these programs are often embraced as benign in their assessments and positive in their outcomes, this perspective fails to consider the discriminatory effects on people with disabilities. The case of Seff v. Broward County in 2012 addressed the question of whether wellness programs violated the Americans with Disabilities Act (ADA). Finding a safe harbor in the ADA for bona fide insurance plans, the court concluded that the initiative did not violate the act, even though employees were penalized monetarily. This article argues that wellness programs institutionalize disability bias and a false perception of health attainability. People with substantial physical or mental impairments will not be able to control many aspects of their health, even with concerted efforts. Embedded in this approach is the notion of responsibility for and control over all aspects of one's health, including disability. This kind of orientation further perpetuates a neoliberal approach to society where autonomy trumps community-based supports and acceptance of differences. PMID- 25037832 TI - Arkansas's alternative to Medicaid expansion raises important questions about how HHS will implement new ACA waiver authority in 2017. AB - This essay presents Arkansas's alternative to Medicaid expansion as a case study motivating John McDonough's assessment of the recommendations states may want to make to the Department of Health and Human Services regarding the implementation of statewide Patient Protection and Affordable Care Act-alternative waivers scheduled to begin in 2017. Arkansas's private option uses federal funds to purchase marketplace silver-level qualified health plans for low-income, low-risk participants, while "medically frail" adults are covered through Medicaid. By improving the size and risk profile of Arkansas's health insurance marketplace, the private option will also encourage entry of and competition among private carriers. If it succeeds in keeping insurance premiums below the level they would otherwise be in the marketplace, Arkansas's private option could reduce subsidy costs for the federal government. Under the broadened scope of section 1332 waivers, states will be able to capture such savings and use them to support innovation across both Medicaid-funded and Treasury-subsidized programs and populations. PMID- 25037833 TI - First impressions: geographic variation in media messages during the first phase of ACA implementation. AB - Many Americans will learn about the implementation of the Patient Protection and Affordable Care Act (ACA) through the mass media. We examined geographic variation in the volume and content of mass media during the initial two-week rollout of the new health insurance marketplaces in October 2013 across 210 US media markets, using data from the Wesleyan Media Project. We found substantial geographic variation in the volume and tone of insurance product advertisements, political advertisements, and news coverage of the ACA marketplaces. News coverage of the ACA airing in media markets located in states operating federal or partnership marketplaces was more negative than coverage airing in markets located in states running their own marketplaces. Intrastate variation in media volume and content was also substantial and appears distinguishable from the local political climate. Variation in exposure to media messages likely affects public sentiment regarding the ACA and could contribute to geographic differences in insurance enrollment and public perceptions of US health care options. Researchers and policy makers evaluating the implementation of the ACA-and insurance enrollment in the marketplaces in particular-should consider addressing media influences. PMID- 25037834 TI - Critical perspectives on wellness. AB - Workplace wellness programs are written into law as exceptions to otherwise protective antidiscrimination provisions, and the Patient Protection and Affordable Care Act expands employers' ability to treat workers differently based on their health. Rather than assume that wellness programs promote health and save money, here I approach them as legally sanctioned discrimination. What exactly wellness discrimination might look like in practice across many contexts is an open question, but there is good reason to be wary of the power of wellness to create and reproduce hierarchy, to promote homogeneity, narrow-mindedness, and moralism about how to live one's life, and to cover for discrimination based on health, weight, income, age, pregnancy, and disability. PMID- 25037835 TI - Wellness as a worldwide phenomenon? AB - This article examines the concept of wellness through a comparative political economy and legal framework. It asks whether wellness, an increasingly defined term within US federal and state legislative instruments including, for example, the Patient Protection and Affordable Care Act, is primarily a US-centric phenomenon. Or is wellness, in its various different guises, a worldwide phenomenon? By focusing on three distinctly different jurisdictions - the United States, Germany, and Australia - this article examines wellness through the lens of employers, the health care system, employment and tort law, and the greater political economy. It notes that while improving employee health, well-being, and productivity is common across the three countries and their respective cultures, the focus on wellness as a distinct legal concept is unique to the United States. PMID- 25037836 TI - What is wellness now? PMID- 25037837 TI - Using reporting requirements to improve employer wellness incentives and their regulation. AB - Employer interest in offering financial incentives for healthy behaviors has been increasing. Some employers have begun to tie health plan-based rewards or penalties to standards involving tobacco use or biometric measures such as body mass index. The Patient Protection and Affordable Care Act attempts to strike a balance between the potential benefits and risks of wellness incentive programs by permitting these incentives but simultaneously limiting their use. Evidence about the implications of the newest generation of incentive programs for health, health costs, and burdens on individual employees will be critical for informing both private and public decision makers. After describing the many pieces of information that would be valuable for assessing these programs, this article proposes more narrowly targeted reporting requirements that could facilitate incentive program development, evaluation, and oversight. PMID- 25037838 TI - Do periodic arm movements during sleep exist in healthy subjects? A polysomnographic study. AB - BACKGROUND: Despite several polysomnographic studies on periodic leg movements (PLM) in healthy sleep, data on the prevalence and characteristics of periodic arm movements (PAM) in normal subjects are lacking. We aimed to investigate PAM and their association with PLM during wakefulness and sleep in healthy subjects. METHODS: Ninety-one participants underwent video-polysomnography according to American Academy of Sleep Medicine 2007 criteria. In addition to standard electromyographic registration, data for both flexor digitorum superficialis muscles were recorded. RESULTS: Sixty-two subjects (68.1%) had a PAM index during wakefulness >5/h (median PAM index during wakefulness, 8.8/h; range, 0-77). Seven subjects (7.7%) had a PAM index >5/h during sleep (median PAM index during sleep, 0.7/h; range, 0-47.4). In 14% of cases, PAM during wakefulness were coincident with PLM during wakefulness. During sleep, this coincidence was not evident. The correlation between PAM and PLM was weak to moderate (during wakefulness: Spearman's rho = 0.576, P < 0.001; during sleep: Spearman's rho = 0.222, P = 0.036). CONCLUSION: In healthy subjects, PAM occur predominantly during wakefulness with no apparent true periodicity. In contrast to classical PLM, some PAM may not present a true periodic phenomenon, but rather random voluntary movements meeting the wide range of periodicity criteria for PLM. PMID- 25037839 TI - U-shaped associations between time in bed and the physical and mental functioning of Japanese civil servants: the roles of work, family, behavioral and sleep quality characteristics. AB - OBJECTIVES: This study aimed to evaluate (i) whether work, family, behavioral and sleep quality characteristics differ among individuals with different time in bed (TIB), and (ii) whether and how much the U-shaped associations between TIB and health can be explained by these characteristics. METHODS: Participants were 3510 employees (2371 males and 1139 females) aged 20-65 years working in local government in Japan. They completed a questionnaire regarding work, family, and behavioral characteristics. Sleep quality and physical and mental functioning were evaluated using the Pittsburgh Sleep Quality Index and the Short Form 36. RESULTS: High job demands, long work hours, and high work-family conflict were more prevalent among those with short TIB. Those with long TIB had daily drinking habits. Whereas those with short TIB had poor sleep, mainly due to poor subjective sleep quality and daytime dysfunction, those with long TIB had poor sleep, mainly due to long sleep latency, poor sleep efficiency and sleep disturbances. The U-shaped associations between TIB and poor physical and mental health, with the best health observed in those spending ~8 h in bed, weakened considerably after adjustment for sleep quality, followed by work and family characteristics. After adjusting for behavioral characteristics and long-standing illnesses, the associations hardly changed. CONCLUSIONS: The U-shaped associations between TIB and health may be explained by U-shaped associations between TIB and poor sleep and psychosocial stress in work and family life. PMID- 25037840 TI - Follow-up management of refractory continuous positive airway pressure therapy: emergent periodic limb movements in sleep. PMID- 25037841 TI - Objective sleep, a novel risk factor for alterations in kidney function: the CARDIA study. AB - OBJECTIVE: To determine the association between objectively measured sleep and 10 year changes in estimated glomerular filtration rate (eGFR). METHODS: From 2003 to 2005, an ancillary sleep study was conducted at the Chicago site of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Community-based black and white adults (aged 32-51 years) wore a wrist actigraph for up to six nights to record sleep duration and fragmentation. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Participants without history of cardiovascular or chronic kidney diseases, proteinuria, or hypertension at the 2000-2001 CARDIA examination were followed over 10 years (n = 463). eGFR was estimated from serum creatinine (eGFRCr) at the 2000-2001, 2005-2006, and 2010 2011 CARDIA examinations, whereas cystatin-C-estimated eGFR (eGFRCys) was measured at the 2000-2001 and 2005-2006 examinations. Generalized estimating equation regression and linear models estimated the associations of each sleep parameter with changes in eGFRCr and eGFRCys, controlling for cardiovascular and renal risk. RESULTS: Sleep parameters were not related to 5-year change in eGFRCys. However, each 1 h decrease in sleep duration was significantly associated with a 1.5 mL/min/1.73 m2 higher eGFRCr [95% confidence interval (CI), 0.2-2.7], and each one-point increase in PSQI was significantly associated with a 0.5 mL/min/1.73 m2 higher eGFRCr (95% CI, 0.04-0.9) over 10 years. CONCLUSION: In this community-based sample, shorter sleep and poorer sleep quality were related to higher kidney filtration rates over 10 years. PMID- 25037842 TI - ECD of tyrosine phosphorylation in a triple quadrupole mass spectrometer with a radio-frequency-free electromagnetostatic cell. AB - A radio frequency-free electromagnetostatic (EMS) cell devised for electron capture dissociation (ECD) of ions has been retrofitted into the collision induced dissociation (CID) section of a triple quadrupole mass spectrometer to enable recording of ECD product-ion mass spectra and simultaneous recording of ECD-CID product-ion mass spectra. This modified instrument can be used to produce easily interpretable ECD and ECD-CID product-ion mass spectra of tyrosine phosphorylated peptides that cover over 50% of their respective amino-acid sequences and readily identify their respective sites of phosphorylation. ECD fragmentation of doubly protonated, tyrosine-phosphorylated peptides, which was difficult to observe with FT-ICR instruments, occurs efficiently in the EMS cell. PMID- 25037843 TI - Moderating effects of parental well-being on parenting efficacy outcomes by intervention delivery model of the early risers conduct problems prevention program. AB - Parent-focused preventive interventions for youth conduct problems are efficacious when offered in different models of delivery (e.g., individual in home, group center-based). However, we know little about the characteristics of parents associated with a positive response to a particular model of delivery. We randomly assigned the parents of an ethnically diverse sample of kindergarten through second grade students (n = 246) displaying elevated levels of aggression to parent-focused program delivery models emphasizing receiving services in a community center largely with groups (Center; n = 121) or receiving services via an individualized in-home strategy (Outreach; n = 125). In both delivery models, parents received parent skills training and goal setting/case management/referrals over an average of 16 months. Structural equation modeling revealed a significant interaction between parental well-being at baseline and intervention delivery model in predicting parenting efficacy at year 2, while controlling for baseline levels of parenting efficacy. Within the Outreach model, parents with lower levels of well-being as reported at baseline appeared to show greater improvements in parenting efficacy than parents with higher levels of well-being. Within the Center model, parental well-being did not predict parenting efficacy outcomes. The strong response of low well-being parents within the Outreach model suggests that this may be the preferred model for these parents. These findings provide support for further investigation into tailoring delivery model of parent-focused preventive interventions using parental well being in order to improve parenting outcomes. PMID- 25037844 TI - The "immigrant paradox" phenomenon: assessing problem behaviors and risk factors among immigrant and native adolescents. AB - We investigated the "immigrant paradox" phenomenon by examining differences in problem behavior engagement and exposure to risk factors across four adolescent groups: 1,157 first-generation, 1,498 second-generation, and 3,316 White and minority third or higher generations. Latent mean differences in problem behavior engagement (i.e., academic failure, aggression, and substance use) and risk factors (i.e., low socioeconomic status, poor family relationship, and low sense of school belonging) were associated with significant differences across adolescent groups. Results supported the generational status effect by demonstrating sequentially greater adolescent problem behavior engagement. However, the difference in exposure to risk factors across adolescent groups only partially supported the immigrant paradox. Further, the multiple group analysis of the relationships between risk factors and engagement in problem behaviors showed increased susceptibility among second generation immigrants for substance use, White natives for academic failure and substance use, and minority natives for physical aggression. Study findings have implications for understanding how the immigrant paradox leads to different adjustment patterns and problem behavior manifestations among immigrant and native adolescents. PMID- 25037845 TI - Prognosis and therapy of tumor-related versus non-tumor-related status epilepticus: a systematic review and meta-analysis. AB - BACKGROUND: Status epilepticus (SE) is a medical emergency with high mortality rates. Of all SE's, 7% are caused by a brain tumor. Clinical guidelines on the management of SE do not make a distinction between tumor-related SE and SE due to other causes. However, pathophysiological research points towards specific mechanisms of epilepsy in brain tumors. We investigated whether clinical features support a distinct profile of tumor-related SE by looking at measures of severity and response to treatment. METHODS: Systematic review of the literature and meta analysis of studies on adult SE that report separate data for tumor-related SE and non-tumor-related SE on the following outcomes: short-term mortality, long term morbidity, duration of SE, and efficacy of anticonvulsant intervention. RESULTS: Fourteen studies on outcome of SE were included. Tumor-related SE was associated with higher mortality than non-tumor-related SE (17.2% versus 11.2%, RR 1.53, 95%-CI 1.24-1.90). After exclusion of patients with hypoxic-ischemic encephalopathy (a group with a known poor prognosis) from the non-tumor-group, the difference in mortality increased (17.2% versus 6.6%; RR 2.78, 95%-CI 2.21 - 3.47). Regarding long-term morbidity and duration of SE there were insufficient data. We did not find studies that systematically compared effects of therapy for SE between tumor- and non-tumor-related SE. CONCLUSIONS: Based on - mostly retrospective - available studies, short-term mortality seems higher in tumor related SE than in SE due to other causes. Further studies on the outcome and efficacy of different therapeutic regimens in tumor-related SE are needed, to clarify whether tumor-related SE should be regarded as a distinct clinical entity. PMID- 25037846 TI - Agnosia for mirror stimuli: a new case report with a small parietal lesion. AB - Only seven cases of agnosia for mirror stimuli have been reported, always with an extensive lesion. We report a new case of an agnosia for mirror stimuli due to a circumscribed lesion. An extensive battery of neuropsychological tests and a new experimental procedure to assess visual object mirror and orientation discrimination were assessed 10 days after the onset of clinical symptoms, and 5 years later. The performances of our patient were compared with those of four healthy control subjects matched for age. This test revealed an agnosia for mirror stimuli. Brain imaging showed a small right occipitoparietal hematoma, encompassing the extrastriate cortex adjoining the inferior parietal lobe. This new case suggests that: (i) agnosia for mirror stimuli can persist for 5 years after onset and (ii) the posterior part of the right intraparietal sulcus could be critical in the cognitive process of mirror stimuli discrimination. PMID- 25037847 TI - Receptors, repressors, PINs: a playground for strigolactone signaling. AB - Strigolactones, previously identified as active stimuli of seed germination in parasitic plants, are now recognized as a new group of plant hormones that are active in both shoots and roots. Here, we review recent insights into the concepts of strigolactones-signal transduction and their mode of action. Although strigolactones are sensed via a cell-specific reception system, at least some aspects of their activity are conducted in a non-cell-autonomous fashion. Strigolactones also affect trafficking and plasma-membrane localization of the auxin transporter PIN, thereby regulating auxin flux. We present a model for strigolactone-signal transduction that might also explain the integration of strigolactones into other hormone-signaling pathways via the regulation of PIN auxin transporters. PMID- 25037848 TI - Estimation of the probability of freedom from bovine virus diarrhoea virus in Norway using scenario tree modelling. AB - Disease caused by Bovine virus diarrhoea virus (BVDV) is notifiable in Norway. An eradication programme started in 1992. The number of herds with restrictions decreased from 2950 in 1994 to zero at the end of 2006. From 2007, the aim of the programme has been surveillance in order to document freedom from the infection. To estimate the probability of freedom from BVDV infection in the Norwegian cattle population by the end of 2011, a scenario tree model of the surveillance program during the years 2007-2011 was used. Three surveillance system components (SSCs) were included in the model: dairy, beef suckler sampled at farms (2007 2010) and beef suckler sampled at slaughterhouses (2011). The design prevalence was set to 0.2% at herd level and to 30% at within-herd level for the whole cattle population. The median probability of freedom from BVDV in Norway at the end of 2011 was 0.996; (0.995-0.997, credibility interval). The results from the scenario tree model support that the Norwegian cattle population is free from BVDV. The highest estimate of the annual sensitivity for the beef suckling SSCs originated from the surveillance at the slaughterhouses in 2011. The change to sampling at the slaughterhouse level further increased the sensitivity of the surveillance. PMID- 25037849 TI - Obinutuzumab: a novel anti-CD20 monoclonal antibody for previously untreated chronic lymphocytic leukemia. AB - OBJECTIVE: To review and summarize data on obinutuzumab, which was approved by the Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). DATA SOURCES: A PubMed literature search (August 2002 to March 2014) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. Data were also obtained through the FDA briefing documents and American Society of Hematology abstracts. STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to human studies published in English. Priority was placed on trials of obinutuzumab in previously untreated CLL. DATA SYNTHESIS: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody, with a higher affinity for CD20 epitope, leading to superior cytotoxicity compared with rituximab. The FDA approval was based on a phase III, randomized trial of chlorambucil monotherapy (n = 118), chlorambucil plus obinutuzumab (n = 333), or rituximab (n =330) in previously untreated elderly CLL patients. Obinutuzumab was administered intravenously as 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 for subsequent cycles. Median progression-free survival was 26.7 months in the chlorambucil plus obinutuzumab arm. The incidence of grade 3 or higher adverse events in the obinutuzumab plus chlorambucil arm was as follows: neutropenia (33%), infusion-related reactions (20%), thrombocytopenia (10%), and infections (7%). CONCLUSION: Obinutuzumab in combination with chlorambucil is a safe and effective new treatment option for previously untreated elderly CLL patients. It should become the new preferred therapy for these patients with significant comorbidities who are not candidates for fludarabine-based therapy. PMID- 25037850 TI - A prospective analysis of inter- and intrafractional errors to calculate CTV to PTV margins in head and neck patients. AB - PURPOSE: To evaluate an institute-specific CTV-PTV margin for head and neck (HN) patients according to a 3-mm action level protocol. METHODS/PATIENTS: Twenty three HN patients were prospectively analysed. Patients were immobilized with a thermoplastic mask. Inter- and intrafractional set-up errors (in the three dimensions) were assessed from portal images (PI) registration. Digitally reconstructed radiographs (DRRs) were compared with two orthogonal PI by matching bone anatomy landmarks. The isocenter was verified during the first five consecutive days of treatment: if the mean error detected was greater than 2 mm the isocenter position was corrected for the rest of the treatment. Isocenter was checked weekly thereafter. Set-up images were obtained before and after treatment administration on 10, 20 and 30 fractions to quantify the intrafractional displacement. For the set-up errors, systematic (Sigma), random (sigma), overall standard deviations, and the overall mean displacement (M), were determined. CTV to PTV margin was calculated considering both inter- and intrafractional errors. RESULTS: A total of 396 portal images was analysed in 23 patients. Systematic interfractional (Sigma(inter)) set-up errors ranged between 0.77 and 1.42 mm in the three directions, whereas the random (sigma (inter)) errors were around 1 1.31 mm. Systematic intrafractional (Sigma(intra)) errors ranged between 0.65 and 1.11 mm, whereas the random (sigma (intra)) errors were around 1.13-1.16 mm. CONCLUSIONS: A verification protocol (3-mm action level) provided by EPIDs improves the set-up accuracy. Intrafractional error is not negligible and contributes to create a larger CTV-PTV margin. The appropriate CTV-PTV margin for our institute is between 3 and 4.5 mm considering both inter- and intrafractional errors. PMID- 25037852 TI - The potential of social enterprise to enhance health and well-being: a model and systematic review. AB - In recent years civil society organisations, associations, institutions and groups have become increasingly involved at various levels in the governance of healthcare systems around the world. In the UK, particularly in the context of recent reform of the National Health Service in England, social enterprise - that part of the third sector engaged in trading - has come to the fore as a potential model of state-sponsored healthcare delivery. However, to date, there has been no review of evidence on the outcomes of social enterprise involvement in healthcare, nor in the ability of social enterprise to address health inequalities more widely through action on the social determinants of health. Following the development of an initial conceptual model, this systematic review identifies and synthesises evidence from published empirical research on the impact of social enterprise activity on health outcomes and their social determinants. Ten health and social science databases were searched with no date delimiters set. Inclusion and exclusion criteria were applied prior to data extraction and quality appraisal. Heterogeneity in the outcomes assessed precluded meta-analysis/meta-synthesis and so the results are therefore presented in narrative form. Five studies met the inclusion criteria. The included studies provide limited evidence that social enterprise activity can impact positively on mental health, self-reliance/esteem and health behaviours, reduce stigmatization and build social capital, all of which can contribute to overall health and well being. No empirical research was identified that examined social enterprise as an alternative mode of healthcare delivery. Due to the limited evidence available, we discuss the relationship between the evidence found and other literature not included in the review. There is a clear need for research to better understand and evidence causal mechanisms and to explore the impact of social enterprise activity, and wider civil society actors, upon a range of intermediate and long term public health outcomes. PMID- 25037851 TI - Two death pathways induced by sorafenib in myeloma cells: Puma-mediated apoptosis and necroptosis. AB - PURPOSE: Sorafenib is a multikinase inhibitor that targets the MAPK pathway and is currently used for the treatment of hepatocellular and renal carcinoma. Recently, it has been shown that sorafenib is also cytotoxic to multiple myeloma (MM) cells. Here, we have further analyzed the mechanism of sorafenib-induced death in MM cells. METHODS: Cell death induced by sorafenib in MM cell lines and in plasma cells from MM patients was evaluated by analysis of gene expression by RT-MLPA and quantitative PCR, protein levels and functionality by Western blot and flow cytometry and gene silencing with siRNA. RESULTS: Cell death was characterized by phosphatidylserine exposure, DeltaPsim loss, cytochrome c release and caspase activation, hallmarks of apoptosis. DL50 at 24 h ranged from 6 to 10 uM. Ex vivo treatment with 20 uM sorafenib induced apoptosis in around 80 % myeloma cells from six multiple myeloma patients. Sorafenib induced caspase dependent degradation of Bcl-xL and Mcl-1 proteins, destabilizing the mitochondria and speeding up the development of apoptosis. Sorafenib treatment increased levels of Puma at mRNA and protein level and gene silencing with siRNA confirmed a relevant role for Puma in the induction of apoptosis. Co-treatment with the pan-caspase inhibitor Z-VAD-fmk prevented cell death to a variable degree depending on the cell line. In RPMI 8226 cells, Z-VAD-fmk prevented most of sorafenib-induced death. However, death in MM.1S was only prevented by co incubation with both Z-VAD-fmk and the RIP1K inhibitor necrostatin-1, indicating that under conditions of inefficient caspase activation, sorafenib induces death by necroptosis. CONCLUSION: Our results demonstrate a key role for Puma in the triggering of sorafenib-induced apoptosis and that this drug can also induce death by necroptosis in multiple myeloma cells. PMID- 25037853 TI - Cohort changes in educational disparities in smoking: France, Germany and the United States. AB - This study investigates the evolution of educational disparities in smoking uptake across cohorts for men and women in three countries. Nationally representative surveys of adults in France, Germany and the United States in 2009 2010 include retrospective measures of age of uptake that are compared for three cohorts (born 1946-1960, 1961-1975, and 1976-1992). Discrete logistic regressions and a relative measure of education are used to model smoking histories until age 34. The following patterns are found: a strengthening of educational disparities in the timing of uptake from older to younger cohorts; an earlier occurrence of the strengthening for men than women and for the United States than France or Germany; a faster pace of the epidemic in France than in the United States, and; a divide between the highest level of education and the others in the United States, as opposed to a gradient across categories in France. Those differences in smoking disparities across cohorts, genders and countries help identify the national and temporal circumstances that shape the size and direction of the relationship between education and health and the need for policies that target educational disparities. PMID- 25037854 TI - Is C-reactive protein testing useful to predict outcome in patients with acute bronchitis? AB - BACKGROUND: A recent clinical trial could not find differences between anti inflammatory drugs, antibiotics and placebo in shortening the duration of symptoms in acute bronchitis. OBJECTIVES: To investigate if C-reactive protein (CRP) concentrations at presentation are predictive of symptom resolution in these patients. METHODS: We performed a secondary analysis of the data from a placebo-controlled, randomized clinical trial carried out in primary care. Patients from 18 to 70 years of age presenting a respiratory tract infection of <1 week of evolution, with cough as the predominant symptom and the presence of discoloured expectoration, were enrolled in the study. On the baseline visit, CRP was determined in capillary blood and a five-item symptom diary was given. Patients were followed up to 30 days. The main outcome measure was the number of days with persistent cough. RESULTS: A total of 312 subjects fulfilled all the criteria for the efficacy analysis and had undergone the CRP test; of these, 56.4% presented a CRP value <8 mg/l and 76% presented <20 mg/l. There were no significant differences in the median duration of cough: 10 days among patients with CRP concentrations <8 mg/l [95% confidence interval (CI): 8-11 days], 11 days among those with concentrations ranging from 8 to 19 mg/l (95% CI: 8-16) and 11 days in those with CRP >20 mg/l (95% CI: 9-12) (P = 0.337). CONCLUSION: Among patients with uncomplicated acute bronchitis and discoloured sputum, the CRP concentrations at presentation are not helpful for predicting symptom resolution. PMID- 25037855 TI - Adalimumab regulates intracellular TNFalpha production in patients with rheumatoid arthritis. AB - INTRODUCTION: Adalimumab is a fully human anti-tumor necrosis factor alpha (anti TNFalpha) monoclonal antibody that specifically blocks the interaction of TNFalpha with its receptors. It binds both soluble and transmembrane TNFalpha. We hypothesized that blocking these TNFalpha signals regulates the altered TNFalpha production in rheumatoid arthritis (RA) patients. METHODS: We compared, by flow cytometry, Toll-like receptor induction levels of membrane and intracellular TNFalpha in monocytes (iTNFalpha + CD14+ cells) from 12 patients before and after adalimumab treatment with those from 5 healthy donors. RESULTS: Before starting the treatment, the percentage of iTNFalpha+ CD14+ cells in the RA patients was significantly lower than that in healthy donors (mean +/- SEM = 33.16 +/- 4.82% vs 66.51 +/- 2.4%, P < 0.001). When we added in vitro TNFalpha to healthy donor culture cells, levels of iTNFalpha+ CD14+ cells decreased, suggesting that the TNFalpha signal was responsible for the iTNFalpha+ CD14+ cell downregulation observed in the RA patients. After 2, 6 and 12 adalimumab injections, we observed significant blocking of membrane and soluble TNFalpha and a progressive increase in iTNFalpha+ CD14+ cells in ten patients with a good to moderate response as defined by the European League Against Rheumatism (EULAR) criteria. Levels of iTNFalpha+ CD14+ cells after 12 injections in these 10 patients were comparable to levels in healthy donors. In two patients, iTNFalpha+ CD14+ cell upregulation was not observed, and their EULAR-defined responses had not improved. The first patient developed antiadalimumab antibodies, explaining why adalimumab was not able to block membrane and soluble TNFalpha. In the second patient, adalimumab was discontinued because of adverse effects, which led to a decrease in iTNFalpha+ CD14+ cells to levels measured before treatment. CONCLUSIONS: Our findings suggest that adalimumab treatment in RA patients can return iTNFalpha levels to those of healthy donors. This effect was not observed in the presence of neutralizing antiadalimumab antibodies. PMID- 25037856 TI - Age-related effects on spatial memory across viewpoint changes relative to different reference frames. AB - Remembering object positions across different views is a fundamental competence for acting and moving appropriately in a large-scale space. Behavioural and neurological changes in elderly subjects suggest that the spatial representations of the environment might decline compared to young participants. However, no data are available on the use of different reference frames within topographical space in aging. Here we investigated the use of allocentric and egocentric frames in aging, by asking young and older participants to encode the location of a target in a virtual room relative either to stable features of the room (allocentric environment-based frame), or to an unstable objects set (allocentric objects based frame), or to the viewer's viewpoint (egocentric frame). After a viewpoint change of 0 degrees (absent), 45 degrees (small) or 135 degrees (large), participants judged whether the target was in the same spatial position as before relative to one of the three frames. Results revealed a different susceptibility to viewpoint changes in older than young participants. Importantly, we detected a worst performance, in terms of reaction times, for older than young participants in the allocentric frames. The deficit was more marked for the environment-based frame, for which a lower sensitivity was revealed as well as a worst performance even when no viewpoint change occurred. Our data provide new evidence of a greater vulnerability of the allocentric, in particular environment-based, spatial coding with aging, in line with the retrogenesis theory according to which cognitive changes in aging reverse the sequence of acquisition in mental development. PMID- 25037857 TI - Relative biological effectiveness of the 60-MeV therapeutic proton beam at the Institute of Nuclear Physics (IFJ PAN) in Krakow, Poland. AB - The aim of the study was to determine the relative biological effectiveness (RBE) of a 60-MeV proton radiotherapy beam at the Institute of Nuclear Physics, Polish Academy of Sciences (IFJ PAN) in Krakow, the first one to operate in Poland. RBE was assessed at the surviving fractions (SFs) of 0.01, 0.1, and 0.37, for normal human fibroblasts from three cancer patients. The cells were irradiated near the Bragg peak of the pristine beam and at three depths within a 28.4-mm spread-out Bragg peak (SOBP). Reference radiation was provided by 6-MV X-rays. The mean RBE value at SF = 0.01 for fibroblasts irradiated near the Bragg peak of pristine beam ranged between 1.06 and 1.15. The mean RBE values at SF = 0.01 for these cells exposed at depths of 2, 15, and 27 mm of the SOBP ranged between 0.95-1.00, 0.97-1.02, and 1.05-1.11, respectively. A trend was observed for RBE values to increase with survival level and with depth in the SOBP: at SF = 0.37 and at the depth of 27 mm, RBE values attained their maximum (1.19-1.24). The RBE values estimated at SF = 0.01 using normal human fibroblasts for the 60-MeV proton radiotherapy beam at the IFJ PAN in Krakow are close to values of 1.0 and 1.1, used in clinical practice. PMID- 25037858 TI - Mobile NBM - Android medical mobile application designed to help in learning how to identify the different regions of interest in the brain's white matter. AB - BACKGROUND: One of the most critical tasks when conducting neurological studies is identifying the different regions of interest in the brain's white matter. Currently few programs or applications are available that serve as an interactive guide in this process. This is why a mobile application has been designed and developed in order to teach users how to identify the referred regions of the brain. It also enables users to share the results obtained and take an examination on the knowledge thus learnt. In order to provide direct user-user or user-developer contact, the project includes a website and a Twitter account. RESULTS: An application has been designed with a basic, minimalist look, which anyone can access easily in order to learn to identify a specific region in the brain's white matter. A survey has also been conducted on people who have used it, which has shown that the application is attractive both in the student (final mean satisfaction of 4.2/5) and in the professional (final mean satisfaction of 4.3/5) environment. The response obtained in the online part of the project reflects the high practical value and quality of the application, as shown by the fact that the website has seen a large number of visitors (over 1000 visitors) and the Twitter account has a high number of followers (over 280 followers). CONCLUSIONS: Mobile NBM is the first mobile application to be used as a guide in the process of identifying a region of interest in the brain's white matter. Although initially not many areas are available in the application, new ones can be added as required by users in their respective studies. Apart from the application itself, the online resources provided (website and Twitter account) significantly enhance users' experience. PMID- 25037859 TI - Predicting fruit consumption: the role of habits, previous behavior and mediation effects. AB - BACKGROUND: This study assessed the role of habits and previous behavior in predicting fruit consumption as well as their additional predictive contribution besides socio-demographic and motivational factors. In the literature, habits are proposed as a stable construct that needs to be controlled for in longitudinal analyses that predict behavior. The aim of this study is to provide empirical evidence for the inclusion of either previous behavior or habits. METHODS: A random sample of 806 Dutch adults (>18 years) was invited by an online survey panel of a private research company to participate in an online study on fruit consumption. A longitudinal design (N = 574) was used with assessments at baseline and after one (T2) and two months (T3). Multivariate linear regression analysis was used to assess the differential value of habit and previous behavior in the prediction of fruit consumption. RESULTS: Eighty percent of habit strength could be explained by habit strength one month earlier, and 64% of fruit consumption could be explained by fruit consumption one month earlier. Regression analyses revealed that the model with motivational constructs explained 41% of the behavioral variance at T2 and 38% at T3. The addition of previous behavior and habit increased the explained variance up to 66% at T2 and to 59% at T3. Inclusion of these factors resulted in non-significant contributions of the motivational constructs. Furthermore, our findings showed that the effect of habit strength on future behavior was to a large extent mediated by previous behavior. CONCLUSIONS: Both habit and previous behavior are important as predictors of future behavior, and as educational objectives for behavior change programs. Our results revealed less stability for the constructs over time than expected. Habit strength was to a large extent mediated by previous behavior and our results do not strongly suggest a need for the inclusion of both constructs. Future research needs to assess the conditions that determine direct influences of both previous behavior and habit, since these influences may differ per type of health behavior, per context stability in which the behavior is performed, and per time frame used for predicting future behavior. PMID- 25037860 TI - Surgical resection and outcome of pancreatic cystic neoplasms in China: analysis of a 16-year experience from a single high-volume academic institution. AB - BACKGROUND: To investigate the clinicopathological features of surgically resected pancreatic cystic neoplasms (PCNs) at a single institution in China. METHODS: The medical charts of patients who operated in the Second Affiliated Hospital, Zhejiang University School of Medicine between 1 January 1997 and 30 June 2013, were pathologically shown to have PCNs. RESULTS: There was a reliable increase trend not just in the overall number of patients (3 to 75) but additionally in the number of incidentally diagnosed patients across the periods (33.3% to 48.0%). In 83 of 111 cases, preoperative diagnoses matched with pathology, whereas the remaining cases (16/28) were misdiagnosed as pancreatic cancer. The proportion of malignancy in mucin producing neoplasms was 24.3% (9 out of 37). Elevated serum carbohydrate antigen (CA19-9) or carcinoembryonic antigen (CEA) was independently associated with malignancy. The overall survival rate was 96.4%. CONCLUSIONS: The proportion of PCNs within this series differs with that revealed in Western countries. Appropriate preoperative differential diagnosing of PCNs remains challenging. It is strongly recommended that patients with elevated CA19-9 or CEA levels undergo surgical resection. PMID- 25037861 TI - Superoxide dismutase enzymosomes: carrier capacity optimization, in vivo behaviour and therapeutic activity. AB - PURPOSE: A strategy not usually used to improve carrier-mediated delivery of therapeutic enzymes is the attachment of the enzymes to the outer surface of liposomes. The aim of our work was to design a new type of enzymosomes with a sufficient surface-exposed enzyme load while preserving the structural integrity of the liposomal particles and activity of the enzyme. METHODS: The therapeutic antioxidant enzyme superoxide dismutase (SOD) was covalently attached to the distal terminus of polyethylene glycol (PEG) polymer chains, located at the surface of lipid vesicles, to obtain SOD-enzymosomes. RESULTS: The in vivo fate of the optimized SOD-enzymosomes showed that SOD attachment at the end of the activated PEG slightly reduced the residence time of the liposome particles in the bloodstream after IV administration. The biodistribution studies showed that SOD-enzymosomes had a similar organ distribution profile to liposomes with SOD encapsulated in their aqueous interior (SOD-liposomes). SOD-enzymosomes showed earlier therapeutic activity than both SOD-liposomes and free SOD in rat adjuvant arthritis. SOD-enzymosomes, unlike SOD-liposomes, have a therapeutic effect, decreasing liver damage in a rat liver ischemia/reperfusion model. CONCLUSIONS: SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases. PMID- 25037862 TI - Decoupling the contribution of surface energy and surface area on the cohesion of pharmaceutical powders. AB - PURPOSE: Surface area and surface energy of pharmaceutical powders are affected by milling and may influence formulation, performance and handling. This study aims to decouple the contribution of surface area and surface energy, and to quantify each of these factors, on cohesion. METHODS: Mefenamic acid was processed by cryogenic milling. Surface energy heterogeneity was determined using a Surface Energy Analyser (SEA) and cohesion measured using a uniaxial compression test. To decouple the surface area and surface energy contributions, milled mefenamic acid was "normalised" by silanisation with methyl groups, confirmed using X-ray Photoelectron Spectroscopy. RESULTS: Both dispersive and acid-base surface energies were found to increase with increasing milling time. Cohesion was also found to increase with increasing milling time. Silanised mefenamic acid possessed a homogenous surface with a surface energy of 33.1 +/- 1.4 mJ/m(2) , for all milled samples. The cohesion for silanised mefenamic acid was greatly reduced, and the difference in the cohesion can be attributed solely to the increase in surface area. For mefenamic acid, the contribution from surface energy and surface area on cohesion was quantified to be 57% and 43%, respectively. CONCLUSIONS: Here, we report an approach for decoupling and quantifying the contribution from surface area and surface energy on powder cohesion. PMID- 25037863 TI - A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors. AB - INTRODUCTION: Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. METHODS: In a 3 + 3 dose escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. RESULTS: Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. CONCLUSIONS: Continuous- or pulsed dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies. PMID- 25037864 TI - How should eosinophilic cystitis be treated in patients with chronic granulomatous disease? AB - BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting from the absence or malfunction of oxidative mechanism in phagocytic cells. The disease is due to a mutation in one of four genes that encode subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Affected patients experience severe infections and granuloma formation due to exuberant inflammatory responses. Some evidence suggests that eosinophilic cystitis (EC) is included in the spectrum of inflammatory manifestations. EC is an inflammatory disease, rare in childhood, which may require different, nonstandardized therapeutic approaches, ranging from antihistamines to cyclosporine. CASE-DIAGNOSIS/TREATMENT: Herein we describe the cases of two CGD patients with CGD who experienced EC during hospitalization for a severe infection. CONCLUSIONS: EC in immunocompetent children seems to have a self limiting course, unlike in CGD patients, in whom it presents a prolonged and recurrent course. We focus on the effective therapy administered to our patients with CGD and review the corresponding literature. PMID- 25037865 TI - Assessment of vision-related quality of life among patients with cataracts and the outcomes of cataract surgery using a newly developed visual function questionnaire: the VFQ-J11. AB - OBJECTIVE: To investigate vision-related quality of life (VRQoL) and associated factors in patients with cataracts and the outcomes of cataract surgery using the newly developed VRQoL instrument: the visual function questionnaire, 11-item Japanese version (the VFQ-J11). METHODS: A total of 457 patients scheduled for cataract surgery at 12 clinical sites from November 2008 through February 2010 were included in the study. The patients completed the VFQ-J11 before and 3 months after surgery. The VFQ-J11 was used to investigate factors associated with VRQoL of the cataract patients, the outcome of cataract surgery, and the predictors of improved VRQoL due to cataract surgery. RESULTS: In a multiple regression model, the VFQ-J11 score was significantly associated with corrected distance visual acuity in the better-seeing eye (better eye VA), and improvement in the VFQ-J11 score after cataract surgery was associated not only with improvement in the better eye VA, but also with improvement in the worse eye VA. Compared to one-eye cataract surgery, both-eyes surgery had a greater impact on VFQ-J11 score improvement. CONCLUSIONS: The VFQ-J11 is a good measure of VRQoL in cataract patients. The present study indicates that by including the domains measured in the VFQ, the VFQ-J11 can provide valid data on VRQoL and be less of a burden for patients. PMID- 25037866 TI - Screening of high toxic Metarhizium strain against Plutella xylostella and its marking with green fluorescent protein. AB - Entomopathogenic fungus is proposed to be one of the best biocontrol agents against the destructive insect pest Plutella xylostella. In this study, we tested the virulence of 11 Metarhizium strain isolates against P. xylostella using a leaf dipping method, and found one strain, named 609, which had displayed the highest pathogenicity. Bioassay results showed that the accumulated corrected mortality rate was 86.7 % on the eighth day after inoculation with a spore concentration 1 * 10(8) conidia/mL, and that the time to 50 % lethality was 5.7 day. The strain was identified as Metarhizium anisopliae var. acridum by internal transcribed spacer (ITS) region sequencing. A green fluorescent protein (GFP) marker containing vector, camben-gfp, was constructed and delivered into strain 609 by Agrobacterium tumefaciens-mediated transformation. Six positive clones expressing GFP were selected and tested for toxicity against P. xylostella, all of which displayed the same toxicity as the parental wild type strain. The survival rate of transformant T1 was investigated by monitoring GFP levels at 4 day intervals after inoculation into soil. We found that the concentration of Metarhizium spores decreased sharply from 1 * 10(7) conidia/g to 1 * 10(6) conidia/g in the first 5 days after inoculation. The decreasing trend then stabilized and the spore count declined to approximately 1 * 10(4)-10(5) conidia/g after 1 month. The results of this study indicate that the expression of gfp gene in strain 609 does not alter the virulence capability of Metarhizium. This strain will therefore be useful for the control of P. xylostella and as a tool to study molecular biology properties and monitor colonization of M. anisopliae in the field. PMID- 25037867 TI - French regional surveillance program of carbapenemase-producing Gram-negative bacilli: results from a 2-year period. AB - In February 2011, the CARB-LR group was created as a sentinel laboratory-based surveillance network to control the emergence of carbapenem-resistant Gram negative bacilli (CR GNB) in a French Southern Region. We report the epidemiological results of a 2-year study. All the Gram-negative bacilli isolates detected in the different labs (hospital and community settings) of a French Southern Region and with reduced susceptibility to ertapenem and/or imipenem were characterised with regard to antibiotic resistance, bla genes content, repetitive sequence-based polymerase chain reaction (rep-PCR) profiles and multilocus sequence typing (MLST). A total of 221 strains were analysed. Acinetobacter baumannii was the most prevalent carbapenemase-producing bacteria, with a majority of OXA-23 producers (n = 37). One isolate co-produced OXA-23 and OXA-58 enzymes. Klebsiella pneumoniae was the most frequent carbapenemase-producing Enterobacteriaceae (CPE) (OXA-48 producer: n = 29, KPC producer: n = 1), followed by Escherichia coli (OXA-48 producer: n = 8, KPC producer: n = 1) and Enterobacter cloacae (OXA-48 producer, n = 1). One isolate of Pseudomonas aeruginosa produced a VIM-1 carbapenemase. A clonal diversity of carbapenemase producing K. pneumoniae and E. coli was noted with different MLSTs. On the other hand, almost all OXA-23-producing A. baumannii strains belonged to the widespread ST2/international clone II. The link between the detection of CR GNB and a foreign country was less obvious, suggesting the beginning of a local cross transmission. The number of CR GNB cases in our French Southern Region has sharply increased very recently due to the diffusion of OXA-48 producers. PMID- 25037868 TI - A close-up on the epidemiology and transmission of multidrug-resistant tuberculosis in Poland. AB - Multidrug-resistant tuberculosis (MDR-TB) poses a serious challenge to the global control of the disease. The purpose of this study was to characterize MDR-TB patients from Poland and to determine the extent of MDR-TB disease attributable to recent transmission. The study included all 46 patients diagnosed with MDR-TB in Poland in 2004 and followed up for 6 years (until 2011). For each patient, sociodemographic and clinical characteristics, treatment outcomes, and bacteriological data were collected by the review of medical and laboratory records. Mycobacterium tuberculosis isolates from all patients were characterized using spoligotyping, mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing, IS6110 restriction fragment length polymorphism (RFLP) analysis, and sequencing analysis of drug resistance-associated loci (katG, mabA-inhA, rpobeta, rpsL, and embB). The majority of patients were male (86.9%), 40-64 years of age (60.8%), with a history of TB treatment (84.8%), and producing smear-positive sputa (86.9%). Twenty-two (47.8%) patients suffered from concomitant diseases and 28 (60.8%) were alcohol abusers. Treatment outcome assessment revealed that 8 (17.4%) patients were cured or completed therapy, while 15 (32.6%) died of TB, 11 (23.9%) defaulted, 8 (17.4%) failed, and 1 (2.2%) was transferred and lost to follow-up. Upon genotyping, 10 (21.7%) isolates were allocated in four clusters. These were further subdivided by mutational profiling. Overall, in 6 (13%) patients, MDR-TB was a result of recent transmission. For 4 (8.7%) of these patients, a direct epidemiological link was established. The study shows that the transmission of MDR-TB occurs at a low rate in Poland. Of urgent need is the implementation of a policy of enforced treatment of MDR-TB patients in Poland. PMID- 25037869 TI - Highly immunoreactive antibodies against the rHup-F2 fragment (aa 63-161) of the iron-regulated HupB protein of Mycobacterium tuberculosis and its potential for the serodiagnosis of extrapulmonary and recurrent tuberculosis. AB - HupB is an iron-regulated protein in Mycobacterium tuberculosis that functions as a positive regulator of mycobactin biosynthesis. It is essential for the growth and survival of the pathogen inside macrophages. Previously, using the full length rHupB of M. tuberculosis, we demonstrated high levels of anti-HupB antibodies in the serum of pulmonary tuberculosis (TB) and, interestingly, extrapulmonary TB patients with negligible levels in household contacts and healthy controls. Here, we used three antigenic fragments of HupB, namely the recombinant HupB-F1 (aa 1-71), HupB-F2 (aa 63-161) and HupB-F3 (aa 164-214), as antigens in enzyme-linked immunosorbent assay (ELISA) to screen serum from TB patients. HupB-F2 showed enhanced immunoreactivity with serum from patients with pulmonary TB (three groups consisting of new cases, defaulters and recurrent cases) and extrapulmonary TB, with negligible levels in normal healthy controls. The negative correlation of the anti-(HupB-F2) antibodies with serum iron was maximal, with a Pearson's correlation coefficient value of -0.415. The study, in addition to strengthening the diagnostic potential of HupB, reflected the superior performance of HupB-F2 as an antigen in screening pulmonary and extrapulmonary TB. PMID- 25037870 TI - High seroprevalence of human herpesvirus type 8 in patients with hepatocellular carcinoma. AB - Cirrhosis patients have immunologic insufficiency and a high seroprevalence of human herpesvirus type 8 (HHV-8). Nearly all hepatocellular carcinoma (HCC) patients are cirrhotic and have immunoabnormalities. This study aimed to assess the HHV-8 seroprevalence and hemograms in HCC patients. Blood samples from 95 HCC patients, 95 age-, sex-, and Child-Pugh class-matched cirrhotics, and 95 age- and sex-matched healthy controls were analyzed for anti-HHV-8 antibodies, HHV-8 DNA, and lymphocyte, monocyte, and platelet counts. HCC patients had lower lymphocyte and platelet counts and a higher monocyte count than the healthy controls (each p < 0.0001). HCC patients, and particularly those with a severe Child-Pugh class, had higher platelet counts than the corresponding cirrhosis patients (p = 0.003 and 0.002, respectively). HHV-8 seropositivity and antibody titers in HCC patients were comparable with values in cirrhosis patients and were much higher than in controls (both p < 0.0001). HCC patients, but not cirrhosis patients, had a higher prevalence of high anti-HHV-8 antibody titers (>= 1:160) than healthy controls (p = 0.003). HCC patients with lymphopenia or thrombocytopenia had lower HHV-8 seropositivity than those without lymphopenia and thrombocytopenia (p = 0.04 and 0.01, respectively). One each of HCC and cirrhosis patients were positive for HHV-8 DNA. HCC patients seemed to suffer from less severe or shorter duration of portal hypertension compared with Child-Pugh class-matched cirrhosis patients. HCC patients had a high HHV-8 seroprevalence, which seemed to be inversely associated with lymphopenia and thrombocytopenia. PMID- 25037872 TI - Molecular imaging: the emerging role of optical imaging in nuclear medicine. PMID- 25037871 TI - Pretreatment metabolic tumour volume is predictive of disease-free survival and overall survival in patients with oesophageal squamous cell carcinoma. AB - PURPOSE: It has been suggested that FDG PET has predictive value for the prognosis of treated oesophageal carcinoma. However, the studies reported in the literature have shown discordant results. The aim of this study was to determine whether pretherapy quantitative metabolic parameters correlate with patient outcomes. METHODS: Included in the study were 67 patients with a histological diagnosis of oesophageal squamous cell carcinoma. Each patient underwent (18)F FDG PET (4.5 MBq/kg) before chemoradiotherapy. Quantitative analysis was performed using the following parameters: age, weight loss, location, N stage, OMS performance status, MTVp and MTVp' (metabolic tumour volume determined by two different physicians), MTV40% (volume for a threshold of 40 % of SUVmax), MTVa (volume automatically determined with a contrast-based adaptive threshold method), SUVmax, SUVmean and TLG (total lesion glycolysis). RESULTS: MTVp and MTV40% were highly correlated (Pearson's index 0.92). SUVmeanp and SUVmean40% were also correlated (Pearson's index 0.86), as were TLGp and TLG40% (Pearson's index 0.98). Similarly, the parameters obtained with the adaptive threshold method (MTVa, SUVmeana and TLGa) were correlated with those obtained manually (MTVp, SUVmeanp and TLGp). The manual metabolic tumour volume determination (MTVp and MTVp') was reproducible. Multivariate analysis for disease-free survival (DFS) showed that a larger MTVp was associated with a shorter DFS (p = 0.004) and that a higher SUVmax was associated with a longer DFS (p = 0.02). Multivariate analysis for overall survival (OS) showed that a larger MTVp was associated with a shorter OS (p = 0.01) and that a tumour in the distal oesophagus was associated with a longer OS (p = 0.005). The associations among the other parameters were not statistically significant. CONCLUSION: Metabolic tumour volume is a major prognostic factor for DFS and OS in patients with oesophageal squamous cell carcinoma. Higher SUVmax values were paradoxically associated with longer survival. The location of the tumour also appeared to affect prognosis. PMID- 25037873 TI - Cognitive phenotype in ataxia-telangiectasia. AB - BACKGROUND: Pediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychologic changes. Such studies may contribute to the further understanding of ataxia telangiectasia and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. METHODS: Twenty-two patients with the classic phenotype of ataxia-telangiectasia were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared with those of healthy control subjects and with standard norms. RESULTS: Patients in AT-I group scored low average compared with standard norms on all tests and were impaired compared with healthy control subjects for verbal intelligence quotient (P < 0.001), vocabulary and comprehension (P = 0.007), processing speed (P = 0.005), visuospatial processing (P = 0.020), and working memory (P = 0.046). Patients in AT-II group scored below average compared with standard norms on all tests and were impaired compared with control subjects for attention (P < 0.001), working memory (P < 0.001), and abstract reasoning (P < 0.001). Comprehension scores were lower for patients in AT-II than in AT-I group (P = 0.002), whereas vocabulary scores showed no difference between groups (P = 0.480). CONCLUSION: Cognitive impairments in ataxia-telangiectasia present early, coinciding with cerebellar pathology and are characteristic of the cerebellar cognitive affective syndrome. Widespread and deeper cognitive deficits manifest in later stages of ataxia telangiectasia when additional noncerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar and/or subcortical contributions to the range of cognitive domains affected in ataxia telangiectasia and need to be confirmed in future studies. PMID- 25037874 TI - Multiple stressors threatening the future of the Baltic Sea-Kattegat marine ecosystem: implications for policy and management actions. AB - The paper discusses the combined effects of ocean acidification, eutrophication and climate change on the Baltic Sea and the implications for current management strategies. The scientific basis is built on results gathered in the BONUS+ projects Baltic-C and ECOSUPPORT. Model results indicate that the Baltic Sea is likely to be warmer, more hypoxic and more acidic in the future. At present management strategies are not taking into account temporal trends and potential ecosystem change due to warming and/or acidification, and therefore fulfilling the obligations specified within the Marine Strategy Framework Directive, OSPAR and HELCOM conventions and national environmental objectives may become significantly more difficult. The paper aims to provide a basis for a discussion on the effectiveness of current policy instruments and possible strategies for setting practical environmental objectives in a changing climate and with multiple stressors. PMID- 25037875 TI - A selection of reference genes and early-warning mRNA biomarkers for environmental monitoring using Mytilus spp. as sentinel species. AB - mRNA biomarkers are promising tools for environmental health assessment and reference genes are needed to perform relevant qPCR analyses in tissue samples of sentinel species. In the present study, potential reference genes and mRNA biomarkers were tested in the gills and digestive glands of native and caged mussels (Mytilus spp.) exposed to harbor pollution. Results highlighted the difficulty to find stable reference genes in wild, non-model species and suggested the use of normalization indices instead of single genes as they exhibit a higher stability. Several target genes were found differentially expressed between mussel groups, especially in gills where cyp32, pi-gst and CuZn sod mRNA levels could be biomarker candidates. Multivariate analyses confirmed the ability of mRNA levels to highlight site-effects and suggested the use of several combined markers instead of individual ones. These findings support the use of qPCR technology and mRNA levels as early-warning biomarkers in marine monitoring programs. PMID- 25037876 TI - Isolation and characterization of biosurfactant producing bacteria from Persian Gulf (Bushehr provenance). AB - Biosurfactants are surface active materials that are produced by some microorganisms. These molecules increase biodegradation of insoluble pollutants. In this study sediments and seawater samples were collected from the coastline of Bushehr provenance in the Persian Gulf and their biosurfactant producing bacteria were isolated. Biosurfactant producing bacteria were isolated by using an enrichment method in Bushnell-Hass medium with diesel oil as the sole carbon source. Five screening tests were used for selection of Biosurfactant producing bacteria: hemolysis in blood agar, oil spreading, drop collapse, emulsification activity and Bacterial Adhesion to Hydrocarbon test (BATH). These bacteria were identified using biochemical and molecular methods. Eighty different colonies were isolated from the collected samples. The most biosurfactant producing isolates related to petrochemical plants of Khark Island. Fourteen biosurfactant producing bacteria were selected between these isolates and 7 isolates were screened as these were predominant producers that belong to Shewanella alga, Shewanella upenei, Vibrio furnissii, Gallaecimonas pentaromativorans, Brevibacterium epidermidis, Psychrobacter namhaensis and Pseudomonas fluorescens. The largest clear zone diameters in oil spreading were observed for G. pentaromativorans strain O15. Also, this strain has the best emulsification activity and reduction of surface tension, suggesting it is the best of thee isolated strains. The results of this study confirmed that there is high diversity of biosurfactant producing bacteria in marine ecosystem of Iran and by application of these bacteria in petrochemical waste water environmental problems can be assisted. PMID- 25037877 TI - Experimental and clinical assessment of three-dimensional cephalometry: a systematic review. AB - OBJECTIVES: This study provides a systematic review of the current scientific literature on three-dimensional (3D) cephalometry. The null hypothesis was that 3D cephalometry is an accurate and reproducible diagnostic technique. To examine this hypothesis, the following three research questions were proposed: 1) What is the accuracy of 3D cephalometric measurements compared to in vitro measurements? 2) What is the intra- and inter-observer reliability of the selection of 3D cephalometric landmarks? 3) What is the reproducibility of the linear and angular measurements? METHODS: A comprehensive database search was performed, using Medline, the Cochrane Central Register of Controlled Trials, Web of Science and Google Scholar. The titles and abstracts obtained from the search were screened and evaluated by two observers according to the inclusion and exclusion criteria. RESULTS: The evaluation process yielded 21 articles. A high level of agreement (<1 mm) between the in vitro measurements and those obtained from 3D cephalometry was observed and some landmarks provided highly reproducible results. However, the linear (0.04-7.49 mm) and angular (0.99-9.30 degrees ) measurements differed greatly. CONCLUSIONS: The null hypothesis was rejected. This study indicates critical points regarding 3D cephalometry and provides guidance for future research in this field. PMID- 25037878 TI - 3D femur model reconstruction from biplane X-ray images: a novel method based on Laplacian surface deformation. AB - PURPOSE: Conventional methods for 3D bone model reconstruction from CT scans can require high-radiation dose, cost and time. A 3D model generated from 2D X-ray images may be a useful alternative. Reconfiguring a 3D template surface mesh model to match bone shape in orthogonal radiographs is a common technique for 3D reconstruction. A computationally efficient 3D bone modeling algorithm was developed and tested. METHOD: An algorithm for bone template reconfiguration is proposed, which uses Kohonen self-organizing maps for 2D-3D correspondence between input X-ray images and the template. Laplacian surface deformation is then used for final deformation of the template. In the literature, Laplacian deformation has been shown to perform better than thin-plate splines and free form deformation in terms of computation time and mesh quality. The method was applied to 22 sets of simulated input contours generated from 3D models of the distal femur. RESULTS: An acceptable range of reconstruction error: 1.5 mm of RMS P2S (root-mean-square point-to-surface) distance and 1.2 mm mean-P2S distance errors was observed based on comparison with the corresponding reference models/ground truth. Computation time for the 3D bone modeling algorithm was less than a minute for each case. CONCLUSION: The new template reconfiguration algorithm based on Laplacian surface deformation provided acceptable reconstruction accuracy and high computation efficiency for 3D modeling of the distal femur using biplane radiographs. This algorithm may provide a useful option for orthopedic modeling applications. PMID- 25037879 TI - Alicyclobacillus tengchongensis sp. nov., a thermo-acidophilic bacterium isolated from hot spring soil. AB - A thermo-acidophilic bacterium, designated strain ACK006(T), was isolated from the soil of a hot spring at Tengchong in China. Cells were Gram-staining positive, motile, catalase-positive and oxidase-negative, spore-forming rods. The isolate grew aerobically at 30-50 degrees C (optimum at 45 degrees C), pH 2.0-6.0 (optimum pH 3.2) and 0-5.0% (w/v) NaCl (optimum 1% NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain ACK006(T) belongs to the genus Alicyclobacillus with the sequence similarity of 92.3, 92.4, 92.5, and 92.8% to Alicyclobacillus cycloheptanicus SCH(T), Alicyclobacillus ferrooxydans TC-34(T), Alicyclobacillus contaminans 3-A191(T) and Alicyclobacillus disulfidooxidans SD-11(T), respectively. Similarity to other species of the genus Alicyclobacillus was 90.3-92.8% and similarity to species of the genus Tumebacillus was 85.9-87.8%. The genomic DNA G+C content was 53.7 mol%. The predominant menaquinone was MK-7. Major fatty acids were omega-cycloheptane C18:0, iso-C17:0 and anteiso-C17:0. The cell-wall peptidoglycan was the A1gamma type; containing meso-diaminopimelic acid as the diagnostic diamino acid. On the basis of polyphasic analysis from this study, strain ACK006(T) represents a novel species of the genus Alicyclobacillus for which the name Alicyclobacillus tengchongensis sp. nov. is proposed. The type strain is ACK006(T) (=KCTC 33022(T) =DSM 25924(T)). PMID- 25037880 TI - Anti-influenza effect of Cordyceps militaris through immunomodulation in a DBA/2 mouse model. AB - The immune-modulatory as well as anti-influenza effects of Cordyceps extract were investigated using a DBA/2 mouse model. Three different concentrations of Cordyceps extract, red ginseng extract, or drinking water were orally administered to mice for seven days, and then the mice were intranasally infected with 2009 pandemic influenza H1N1 virus. Body weight changes and survival rate were measured daily post-infection. Plasma IL-12, TNF-alpha, and the frequency of natural killer (NK) cells were measured on day 4 post-infection. The DBA/2 strain was highly susceptible to H1N1 virus infection. We also found that Cordyceps extract had an anti-influenza effect that was associated with stable body weight and reduced mortality. The anti-viral effect of Cordyceps extract on influenza infection was mediated presumably by increased IL-12 expression and greater number of NK cells. However, high TNF-alpha expression after infection of H1N1 virus in mice not receiving treatment with Cordyceps extract suggested a two sided effect of the extract on host immune regulation. PMID- 25037881 TI - The lability of pedophilic interests as measured by phallometry. PMID- 25037883 TI - Impact of moderate interval exercise versus supine rest on the pharmacokinetics and pharmacodynamic profiles of subcutaneously administered growth hormone in adult growth hormone deficient patients. AB - BACKGROUND: Diurnal variation in serum growth hormone (s-GH) levels after exogenous GH delivery has previously been reported in patients with no endogenous GH secretion. Changes in postural position or physical activity, leading to changes in blood flow and/or lymphatic drainage may be underlying explanations. PRIMARY OBJECTIVES: The primary aim of this study is to study a possible impact of exercise and supine rest on pharmacokinetics (PK) and day-to-day variation of subcutaneously (s.c.) administered GH in adult GH deficient (AGHD) patients. SECONDARY OBJECTIVE: The secondary aim of this study is to compare s-IGF-I, s insulin, and plasma (p)-glucose profiles after a carbohydrate rich breakfast following s.c. GH injection vs. continuous infusion. DESIGN AND METHODS: During supine rest eight AGHD males (59.8+/-8 years, BMI 29.7+/-4.9 kg/m(2)) were treated with one daily s.c. GH injections of 3 mg/24 h for 48 h (treatment sessions A, B) or a continuous s.c. GH infusion of 3 mg/24 h for 60 h (treatment sessions C, D). Exercise comprised 1 h bicycling with 50 W load on two consecutive days during treatment sessions B and D. RESULTS: Administration of GH as a bolus injection, but not as a continuous GH infusion, resulted in about 32% higher s-GH levels during exercise (60 min) as well as 30 min after (s-GH logAUC(B-A) difference was 0.28; 95% CI: 0.14-0.4; p<0.001). However, the total s GH(AUC 0-24 h) (p=0.75) and s-IGF-I(AUC0-48 h) levels (p=0.51) remained unchanged between the two occasions. P-glucose and insulin profiles were significantly higher after carbohydrate rich breakfast before first and second dosing both following s.c. GH injection and continuous infusion (p<0.05). CONCLUSIONS: Moderate exercise intermittently increased s-GH levels. These changes seem to have no clinical short-term relevance, since total s-GH(24 h) and s-IGF-I(48 h) levels were unaffected. PMID- 25037882 TI - Gingipains from Porphyromonas gingivalis play a significant role in induction and regulation of CXCL8 in THP-1 cells. AB - BACKGROUND: Porphyromonas gingivalis is an important bacterial etiological agent involved in periodontitis. The bacterium expresses two kinds of cysteine proteases called gingipains: arginine gingipains (RgpA/B) and lysine gingipain (Kgp). This study evaluated the interaction between P. gingivalis and THP-1 cells, a widely used monocytic cell line, in vitro with a focus on CXCL8 at the gene and protein levels and its fate thereafter in cell culture supernatants. THP 1 cells were stimulated with viable and heat-killed wild-type strains ATCC 33277 or W50 or viable isogenic gingipain mutants of W50, E8 (Rgp mutant) or K1A (Kgp mutant), for 24 hours. RESULTS: ELISA and qPCR results show an elevated CXCL8 expression and secretion in THP-1 cells in response to P. gingivalis, where the heat-killed ATCC33277 and W50 induced higher levels of CXCL8 in comparison to their viable counterparts. Furthermore, the Kgp-deficient mutant K1A caused a higher CXCL8 response compared to the Rgp-deficient E8. Chromogenic quantification of lipopolysaccharide (LPS) in supernatant showed no significant differences between viable and heat killed bacteria except that W50 shed highest levels of LPS. The wild-type strains secreted relatively more Rgp during the co culture with THP-1 cells. The CXCL8 degradation assay of filter-sterilized supernatant from heat-killed W50 treated cells showed that Rgp was most efficient at CXCL8 hydrolysis. Of all tested P. gingivalis strains, adhesion and internalization in THP-1 cells was least conspicuous by Rgp-deficient P. gingivalis (E8), as demonstrated by confocal imaging. CONCLUSIONS: W50 and its Kgp mutant K1A exhibit a higher immunogenic and proteolytic function in comparison to the Rgp mutant E8. Since K1A differs from E8 in the expression of Rgp, it is rational to conclude that Rgp contributes to immunomodulation in a more dynamic manner in comparison to Kgp. Also, W50 is a more virulent strain when compared to the laboratory strain ATCC33277. PMID- 25037884 TI - Interdisciplinary doctorial supervision: lessons for nurse education and practice. AB - BACKGROUND: This paper concerns a reflection on one interdisciplinary doctorate supervision project. It outlines key elements for success within this supervisory context. AIM: The aim of this paper is to present a reflection on interdisciplinary doctorate supervision project experience and examine these experiences in light of literature on the topic. METHODS: Reflection was carried out using Rolfe et al. (2010) framework for reflexivity. FINDINGS: The supervised engineering project aimed to develop, demonstrate and evaluate a new framework for the design of customisable assistive technology (AT) which involved professionals working with AT and users with disabilities. As this research occurs in between disciplines, it required an innovative and interdisciplinary approach, with an ultimate merger between health sciences and design engineering disciplines and external liaison with adults with disabilities and a disability service provider. CONCLUSION: Interdisciplinary research is popular contemporarily and addresses societal needs. In the case outlined, clear understandings were developed, in addition to clear territorial boundaries that helped guide the novel research. Steps to success in interdisciplinary research supervision include selecting the appropriate interdisciplinary team; ensuring open communication; establishing and agreeing boundaries of the research and supervision; keeping an open mind; tolerance of lack of expertise in some areas; regular meetings and communication; keeping the student focused and agreeing publication plans in advance. PMID- 25037885 TI - The bottom quartile for health indices in America vs Europe. AB - The inequities in health outcomes in different parts of the developed world merit further analysis. An index comprising mortality and morbidity factors was composed for American states and European nations. Multiple factors and bottom quartile status were analyzed by regression methodology. The 51 American states (and District of Columbia) showed a "Health Index" value based on life expectancy at birth and morbidity determined by rates of cardiac disease and cancer that ranged from 63 (Mississippi and West Virginia) to 94 (Utah). The 48 of 51 European states with assessable data showed a Health Index based on life expectancy at birth and quality adjusted life years that ranged from 53 (Russia) to 98 (San Marino). American states with the lowest quartile values were clustered in the American South and Appalachian areas. European states ranking in the bottom quartile were typically from Eastern Europe and showed a history of a Communism and recognized governmental corruption. Because American poor health rankings are the result of controllable factors (smoking, adult onset diabetes, obesity), Americans can improve their bottom quartile status more readily than Europeans whose ranking status is a function of history (Communism, civil conflicts) and poverty (Southeastern and Eastern nations). PMID- 25037886 TI - Report of 6 cases of large granular lymphocytic leukemia and plasma cell dyscrasia. PMID- 25037887 TI - Feasibility and outcome of the hyper-CVAD regimen in patients with adult acute lymphoblastic leukemia. AB - BACKGROUND: Current chemotherapy regimens for adults with acute lymphoblastic leukemia (ALL) result in high rates of complete remission (CR), but relapses are still frequent. PATIENTS AND METHODS: In this retrospective single-center study, we evaluated the results of the Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen in 49 ALL patients treated between 2001 and 2013. No exclusion criteria were applied. The primary outcome measure was the CR rate. RESULTS: Forty-six of the 49 patients (93.8%) obtained CR, and 3 (6%) patients died during induction. Philadelphia chromosome was present in 6 patients (12.2%); in all a CR was obtained. Among the 46 patients in CR, 30 (65.2%) received the full planned intensive-phase treatment (8 cycles). Allogeneic hematopoietic cell transplantation was performed in 2 (4%) patients in first CR and in 3 (6%) patients after a second CR. Nonrelapse mortality was observed in 8 patients (16.3%). The median overall survival (OS) and 5-year OS were 24.4 months and 35%, respectively. Initial leukocyte count (> 30 * 10(9)/L) was an important prognostic factor. CONCLUSION: Hyper-CVAD as an induction regimen for adults and adolescents with ALL was feasible and yielded a high rate of CR. Relapse rates and OS were comparable to other series but still unsatisfactory. PMID- 25037888 TI - Comprehensive interrogation of the cellular response to fluorescent, detonation and functionalized nanodiamonds. AB - Nanodiamonds (NDs) are versatile nanoparticles that are currently being investigated for a variety of applications in drug delivery, biomedical imaging and nanoscale sensing. Although initial studies indicate that these small gems are biocompatible, there is a great deal of variability in synthesis methods and surface functionalization that has yet to be evaluated. Here we present a comprehensive analysis of the cellular compatibility of an array of nanodiamond subtypes and surface functionalization strategies. These results demonstrate that NDs are well tolerated by multiple cell types at both functional and gene expression levels. In addition, ND-mediated delivery of daunorubicin is less toxic to multiple cell types than treatment with daunorubicin alone, thus demonstrating the ability of the ND agent to improve drug tolerance and decrease therapeutic toxicity. Overall, the results here indicate that ND biocompatibility serves as a promising foundation for continued preclinical investigation. PMID- 25037889 TI - Patterns of detection of respiratory viruses in nasal swabs from calves in Ireland: a retrospective study. AB - A retrospective analysis was conducted to investigate the prevalence and seasonality of bovine viral diarrhoea virus (BVDV), bovine coronavirus (BoCV), bovine herpesvirus-1 (BoHV-1), bovine respiratory syncytical virus (BRSV) and parainfluenza virus-3 (PI3V) in calves (aged three months and below) in Ireland. Results from real-time PCR testing, including cycle threshold values, conducted on nasal swabs (single or pooled) submitted from 1364 respiratory disease outbreaks between January 1, 2008 and December 31, 2012 were included in this study. One or more viruses were detected in 34.6 per cent of submissions, with BoCV detected most frequently (22.9 per cent), followed by BRSV (11.6 per cent), PI3 V (7.0 per cent), BoHV-1 (6.1 per cent) and BVDV (5.0 per cent). The detection rate of all viruses was higher when pooled multiple swabs were submitted from outbreaks rather than single swabs, with these differences being significant for all except BVDV. Two or more viruses were detected in 39.4 per cent of positive submissions, with BoCV and BRSV most commonly present as one of the two partners in detection. With the exception of BVDV, which was detected all year round, the others showed a clear seasonal pattern, being most commonly detected in winter and spring. PMID- 25037890 TI - Corynebacterium species nasal carriage in pigs and their farmers in Bavaria, Germany: implications for public health. AB - Reports on cases of human diphtheria caused by toxigenic Corynebacterium ulcerans that were linked to occupational swine contact as well as isolation of C ulcerans from wild boars have suggested that pigs might serve as reservoir for human infections. Therefore, a prevalence study on Corynebacterium species nasal carriage in pigs and their farmers was performed between August 1 and December 31, 2009, in 41 swine farms from Bavaria, Germany. All 411 asymptomatic pigs and 29 of 30 healthy farmers were colonised with Corynebacterium strains of up to 11 different species. No potentially toxigenic Corynebacterium strain was isolated either from the pigs or from their farmers, respectively. The patterns of the species composition in the pigs and the farmers were very similar, suggesting a potential transmission of strains between animals and humans. PMID- 25037891 TI - Adolescents' aggression to parents: longitudinal links with parents' physical aggression. AB - PURPOSE: To investigate whether parents' previous physical aggression (PPA) exhibited during early adolescence is associated with adolescents' subsequent parent-directed aggression even beyond parents' concurrent physical aggression (CPA) and to investigate whether adolescents' emotion dysregulation and attitudes condoning child-to-parent aggression moderate associations. METHODS: Adolescents (N = 93) and their parents participated in a prospective longitudinal study. Adolescents and parents reported at waves 1-3 on four types of parents' PPA (mother to adolescent, father to adolescent, mother to father, and father to mother). Wave 3 assessments also included adolescents' emotion dysregulation, attitudes condoning aggression, and externalizing behaviors. At waves 4 and 5, adolescents and parents reported on adolescents' parent-directed physical aggression, property damage, and verbal aggression and on parents' CPA. RESULTS: Parents' PPA emerged as a significant indicator of adolescents' parent-directed physical aggression (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.0 1.55; p = .047), property damage (OR: 1.29, 95% CI: 1.1-1.5, p = .002), and verbal aggression (OR: 1.35, 95% CI: 1.15-1.6, p < .001) even controlling for adolescents' sex, externalizing behaviors, and family income. When controlling for parents' CPA, previous mother-to-adolescent aggression still predicted adolescents' parent-directed physical aggression (OR: 5.56, 95% CI: 1.82-17.0, p = .003), and father-to-mother aggression predicted adolescents' parent-directed verbal aggression (OR: 1.86, 95% CI: 1.0-3.3, p = .036). Emotion dysregulation and attitudes condoning aggression did not produce direct or moderated the effects. CONCLUSIONS: Adolescents' parent-directed aggression deserves greater attention in discourse about lasting, adverse effects of even minor forms of parents' physical aggression. Future research should investigate parent-directed aggression as an early signal of aggression into adulthood. PMID- 25037892 TI - The evolution of sexual dysfunction in young men aged 18-25 years. AB - PURPOSE: To assess the evolution of sexual dysfunctions among young males after an average of 15 months follow-up to determine the predictive factors for this evolution and the characteristics differentiating young males who continue reporting a sexual dysfunction from those who do not. METHODS: We conducted a prospective cohort study in two Swiss military recruitment centers mandatory for all Swiss national males aged 18-25 years. A total of 3,700 sexually active young males filled out a questionnaire at baseline (T0) and follow-up (T1: 15.5 months later). Main outcome measures were self-reported premature ejaculation (PE) and erectile dysfunction (ED). RESULTS: Overall, 43.9% of young males who reported (PE) and 51% of those reporting (ED) at T0 still reported it at T1. Moreover, 9.7% developed a PE problem and 14.4% developed an ED problem between T0 and T1. Poor mental health, depression, and consumption of medication without prescription were predictive factors for PE and ED. Poor physical health, alcohol consumption, and less sexual experience were predictive factors for PE. ED persistence was associated with having multiple sexual partners. CONCLUSIONS: This is the first longitudinal study to examine sexual dysfunctions among young males. Our results show high prevalence rates among young males for maintaining or developing a sexual dysfunction over time. Consequently, when consulting with young males, health professionals should inquire about sexual dysfunctions as part of their routine psychosocial assessment and leave the subject open for discussion. Future research should examine in more detail the relationship between sexual dysfunctions and poor mental health. PMID- 25037893 TI - Parent attitudes about adolescent school-located vaccination and billing. AB - PURPOSE: School-located vaccination programs may need to bill health insurance to be sustainable. This mixed methods study assessed parent attitudes about school located vaccination and billing. METHODS: Seven public schools in Denver, Colorado, participated in a school-located adolescent vaccination program that billed students' insurance. From April through June 2010, a survey was administered to parents of 1,000 randomly selected sixth to eighth grade students in these schools. In March and April 2011, focus groups were conducted with a sample of parents of adolescents attending these schools to further explore and help explain patterns emergent in the survey data. RESULTS: Survey response rate was 66%. Among survey respondents, 56% strongly supported and 29% somewhat supported school-located vaccination. Forty-two percent reported concern about receiving a bill if their child participated in a school-located vaccination program that billed insurance, and 23% did not want to provide insurance information to the school. Four focus groups were conducted with English-speaking (n = 17) and Spanish-speaking (n = 14) parents. Focus group participants indicated strong support for school-located vaccination, emphasizing the convenience of the program for both parents and adolescents. These parents also appreciated the affordability of the program and reported feeling comfortable with in-school vaccination delivery. Very few participants indicated concerns about providing health insurance information to the school, but some expressed concern about potential record scatter. CONCLUSIONS: Although some parents expressed concerns about billing health insurance for school-located vaccination, most parents indicated strong support for school-located vaccination. PMID- 25037894 TI - Understanding the importance of heterogeneity when analyzing medical marijuana laws. PMID- 25037895 TI - Incidence of single and mixed infections with Eimeria kofoidi, E. caucasica and E. legionensis on the health of experimentally infected red-legged partridges (Alectoris rufa). AB - Little is known about Eimeria-induced coccidiosis in partridges. After a coccidiosis outbreak in a farm rearing red-legged partridges (Alectoris rufa) in Brittany (France), three Eimeria species were identified as Eimeria kofoidi, Eimeria caucasica and Eimeria legionensis. This study aimed to reproduce the effects of the disease occurring in field conditions, in the absence of preventive treatments, to further build a coccidiosis model, helpful for coccidiostatic development. The pathogenic effects of a single infection with Eimeria kofoidi, E. caucasica and E. legionensis were evaluated, as well as the effects of multiple infections associating two or three of these species in red legged partridges. Thirty-one-day-old birds were individually inoculated with Eimeria spp. and clinically followed up until 49 days of age. Mortality, lesion scores, daily oocyst production and growth were used as assessment criteria. Single infections with 250,000 E. kofoidi, 30,000 E. caucasica or 100,000 E. legionensis oocysts did not increase mortality rate compared to uninfected birds, whereas the combination of 3 species caused significant 28% mortality (P<0.05). Five days post inoculation, lesions scores in the proximal intestine (duodenum/jejunum) decreased in dual-infected birds and tended to decrease in triple-infected birds compared to lesions in mono-infected birds. The highest caecal lesion score was recorded in birds co-infected with E. kofoidi and E. legionensis. In multi-infected birds, the total number of oocysts excreted per gram of faeces was lower than the sum of oocysts excreted by mono-infected birds. Each single infection caused significant growth depression and even weight loss in E. legionensis infected birds (P<0.05). Dual or triple infections worsened this effect. Eighteen days post inoculation, only mono-infected birds had recovered. Their weight gains were not different from that of uninfected birds, whereas growth was significantly depressed in dual-infected birds, notably in co infected E. kofoidi and E. legionensis birds and worsened in triple-infected birds (-34% and -78% growth depression, respectively). Our results indicate that the oocyst doses used were suitable in single infections or should be slightly reduced for future studies requiring significant growth retardation (about 25%). In mixed-infections, the effects on growth are considerably increased; therefore, oocyst doses must be reduced, approximately 125,000 E. kofoidi+15,000 E. caucasica+50,000 E. legionensis oocysts can be recommended. The study model presented here is valuable to conduct further research such as for assessing the ability of these birds to mount immune response against Eimeria spp. or for selecting efficient molecules to struggle coccidiosis of red-legged partridges. PMID- 25037896 TI - Chronic polyarthritis associated to Cercopithifilaria bainae infection in a dog. AB - Despite the widespread distribution of Cercopithifilaria bainae among canine and tick populations worldwide, this filarioid is currently considered of 'minor importance' in veterinary medicine, particularly when compared to related filarioids, such as Dirofilaria immitis and Dirofilaria repens. To date, only a single case of dermatological alterations possibly associated to infection by C. bainae had been reported in a dog. In the present study, we describe the first case of systemic alterations associated to C. bainae infection in a dog suffering from diffused chronic polyarthritis. The animal had a previous history of reluctance to move and stiff gait and displayed multiple joint pain during manipulation of limbs. No biochemical, haematological and X-ray alterations were detected; microfilariae were observed in the synovial fluids collected from the joints. In spite of the morphological and molecular identification of these microfilariae as C. bainae, the dog did not respond to multiple microfilaricidal treatments with milbemicyn oxyme. The potential role of C. bainae in the pathogenesis of this clinical condition is discussed. Given the potential pathogenicity of this parasite, improved knowledge of this little known tick borne nematode is warranted in order to assist the development of novel and effective treatment strategies. PMID- 25037897 TI - The fracture resistance of a CAD/CAM Resin Nano Ceramic (RNC) and a CAD ceramic at different thicknesses. AB - OBJECTIVES: This study aimed to investigate the influence of restoration thickness to the fracture resistance of adhesively bonded LavaTM Ultimate CAD/CAM, a Resin Nano Ceramic (RNC), and IPS e.max CAD ceramic. METHODS: Polished LavaTM Ultimate CAD/CAM (Group L), sandblasted LavaTM Ultimate CAD/CAM (Group LS), and sandblasted IPS e.max CAD (Group ES) discs (n=8, O=10 mm) with a thickness of respectively 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, and 3.0 mm were cemented to corresponding epoxy supporting discs, achieving a final thickness of 3.5 mm. All the 120 specimens were loaded with a universal testing machine at a crosshead speed of 1 mm/min. The load (N) at failure was recorded as fracture resistance. The stress distribution for 0.5 mm restorative discs of each group was analyzed by Finite Element Analysis (FEA). The results of facture resistances were analyzed by one-way ANOVA and regression. RESULTS: For the same thickness of testing discs, the fracture resistance of Group L was always significantly lower than the other two groups. The 0.5 mm discs in Group L resulted in the lowest value of 1028 (112) N. There was no significant difference between Group LS and Group ES when the restoration thickness ranged between 1.0 mm and 2.0 mm. There was a linear relation between fracture resistance and restoration thickness in Group L (R=0.621, P<0.001) and in Group ES (R=0.854, P<0.001). FEA showed a compressive permanent damage in all groups. SIGNIFICANCE: The materials tested in this in vitro study with the thickness above 0.5 mm could afford the normal bite force. When Lava Ultimate CAD/CAM is used, sandblasting is suggested to get a better bonding. PMID- 25037898 TI - Traditional Chinese medication for rheumatoid arthritis: more than what meets the eye. AB - There is an increasing interest in the role of traditional Chinese medicine (TCM) in rheumatoid arthritis (RA), as evidenced by recent trials comparing their efficacy against established disease-modifying antirheumatic drugs. While the TCM in these trials seem to support a favorable cost-benefit ratio, many products are marketed under the guise of TCM, potentially exposing the user to unpredicted adverse events. We present the case of a patient with RA, who developed side effects from treatment with adulterated TCM. While TCM may be of value in the treatment of rheumatic diseases, their application in routine care continues to warrant careful consideration of safety and reliability. PMID- 25037899 TI - Prevalence of osteoarthritis in former elite athletes: a systematic overview of the recent literature. AB - The aim of this study was to systematically review the recent scientific literature to explore the prevalence of osteoarthritis (OA) in former elite athletes from team and individual sports. A systematic review of observational studies was conducted. Based on three categories of keywords (and synonyms), a sensitive search strategy was built in order to search MEDLINE and SPORTDiscus from 2000 to 2014. The data from included studies presenting a prevalence rate of OA as an outcome measure were extracted using a standardised extraction form, and their methodological quality was described. Fifteen studies were identified through our search strategy, studies being rather heterogeneous with regard to their study population and to the definition and assessment of OA. Hip OA ranged from 2 to 60%, and knee OA from 16 to 95%. Prevalence rates of general, lower limbs or hip/knee OA ranged from 1 to 59%. Prevalence of neck, back, shoulder and ankle OA was reported only in single studies (16, 18, 33 and 3%, respectively). This study showed that prevalence of OA, especially in their lower limbs, seems to be high among former elite athletes from team and individual sports compared to the general population and other occupational sectors. PMID- 25037901 TI - Chiral separations 2013. Preface. PMID- 25037900 TI - The role of tenofovir in preventing and treating hepatitis B virus (HBV) reactivation in immunosuppressed patients. A real life experience from a tertiary center. AB - INTRODUCTION/AIM: Patients who present HBV reactivation during immunosuppressive treatment are prone to develop life threatening decompensation of the liver function, therefore prophylaxis and treatment are strongly recommended. So far there are no data regarding the role of tenofovir in this context. Therefore, the aim of our study was to describe our "real life" experience with the use of tenofovir (TDF) in patients who underwent immunosuppressive treatment. RESULTS: 38 patients with immunosuppression received antiviral treatment with tenofovir (25 patients as prophylaxis and 13 patients as treatment of HBV reactivation). In all 25 patients in whom prophylactic treatment with tenofovir was administered no HBV flare occurred during immunosuppression and the levels of serum HBV-DNA became or remained undetectable during the follow up period (mean follow up 17.2 months, range 6-54). One patient experienced HBsAg seroconversion. In the 13 patients who exhibited HBV reactivation TDF treatment resulted in complete biochemical and virological response within 6 months except two patients with high pretreatment HBV-DNA levels who became HBV-DNA negative at 9 months. No exacerbation of liver disease or liver related death has been observed. One patient who presented with decompensated cirrhosis during HBV reactivation returned into a compensated state after treatment. No side effects of tenofovir have been documented. CONCLUSION: Tenofovir seems to be highly effective and safe in the prophylaxis and rescue treatment of HBV reactivation in patients who receive immunosuppression therapy. PMID- 25037902 TI - Patterns of cerebellar volume loss in dementia with Lewy bodies and Alzheimer's disease: A VBM-DARTEL study. AB - Evidence suggests that the cerebellum contributes to cognition as well as motor function. We investigated cerebellar grey matter (GM) and white matter (WM) changes from magnetic resonance images in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and healthy older subjects using voxel-based morphometry (VBM). Subjects (39 controls, 41 DLB, and 48 AD) underwent magnetic resonance imaging as well as clinical and cognitive assessments. VBM used SPM8 with a cerebellar brain mask to define the subspace for voxel analysis. Statistical analyses were conducted using the general linear model. Relative to findings in controls, VBM analysis revealed cerebellar GM loss in lobule VI bilaterally in AD and in left Crus I and right Crus II regions in DLB. WM deficits were confined to AD in the bilateral middle cerebellar peduncles. DLB demonstrates a different pattern of cerebellar GM loss which, although not significantly different from that in AD, could be an important feature in understanding the neurobiology of DLB and warrants further investigation. PMID- 25037903 TI - Building core capacities at the designated points of entry according to the International Health Regulations 2005: a review of the progress and prospects in Taiwan. AB - BACKGROUND: As designated points of entry (PoEs) play a critical role in preventing the transmission of international public health risks, huge efforts have been invested in Taiwan to improve the core capacities specified in the International Health Regulations 2005 (IHR 2005). This article reviews how Taiwan strengthened the core capacities at the Taoyuan International Airport (TIA) and the Port of Kaohsiung (PoK) by applying a new, practicable model. DESIGN: An IHR PoE program was initiated for implementing the IHR core capacities at designated PoEs. The main methods of this program were 1) identifying the designated PoEs according to the pre-determined criteria, 2) identifying the competent authority for each health measure, 3) building a close collaborative relationship between stakeholders from the central and PoE level, 4) designing three stages of systematic assessment using the assessment tool published by the World Health Organization (WHO), and 5) undertaking action plans targeting the gaps identified by the assessments. RESULTS: Results of the self-assessment, preliminary external assessment, and follow-up external assessment revealed a continuous progressive trend at the TIA (86, 91, and 100%, respectively), and at the PoK (77, 97, and 99.9%, respectively). The results of the follow-up external assessment indicated that both these designated PoEs already conformed to the IHR requirements. These achievements were highly associated with strong collaboration, continuous empowerment, efficient resource integration, and sustained commitments. CONCLUSIONS: Considering that many countries had requested for an extension on the deadline to fulfill the IHR 2005 core capacity requirements, Taiwan's experiences can be a source of learning for countries striving to fully implement these requirements. Further, in order to broaden the scope of public health protection into promoting global security, Taiwan will keep its commitments on multisectoral cooperation, human resource capacity building, and maintaining routine and emergency capacities. PMID- 25037904 TI - Challenges in fertility regulation. PMID- 25037905 TI - Electrocardiographic left ventricular strain pattern: everything old is new again. AB - Electrocardiographic left ventricular hypertrophy (LVH) has many faces with countless features. Beyond the classic measures of LVH, including QRS voltage and duration, the left ventricular (LV) strain pattern is an element whereby characteristic R-ST depression is followed by a concave ST segment that ends in an asymmetrically inverted T wave. The LV strain pattern generally appears in states of increased systemic blood pressure and must be differentiated from similar but not identical ST-T waves indicating ischemia. The LV strain pattern has been found in population studies to be associated with poor prognosis and increased risk of adverse cardiovascular outcomes. Regression of LV strain pattern parallels decline in systemic BP during clinical trials of anti hypertensive therapies but does not indicate or serve as a surrogate for decrease in LV mass. Newer techniques in data collection and processing may allow the process of strain to be studied in more detail to determine the ways in which electrical remodeling of the left ventricle as characterized by LVH with 'repolarization abnormalities' indicates how CV risk might be managed by using LV strain pattern as an electrocardiographic biomarker. PMID- 25037906 TI - Evaluation and management of post-transurethral resection of the prostate lower urinary tract symptoms. AB - Transurethral resection of the prostate (TURP) continues to be the most common treatment in the operative management of benign prostatic hypertrophy (BPH). Several other modalities have shown equivalence to TURP. However, even after surgical treatment, up to one third of patients have bothersome lower urinary tract symptoms (LUTS). This review discusses the pathophysiology, evaluation, and management options for patients with LUTS after TURP. PMID- 25037907 TI - Reply: To PMID 24315296. PMID- 25037908 TI - Poor providers of social care will be put into special measures and closed down if necessary. PMID- 25037909 TI - Breadth of participation in organized and unstructured leisure activities over time and rural adolescents' functioning. AB - Discretionary time outside of school offers a distinct context that can promote adolescent development; however, potential for growth depends in part on how this time is used. In this study, person-centered analyses were used to examine patterns of breadth of participation in both organized and unstructured leisure activities among rural adolescents (N = 276, 49% female) across grades 7, 8, and 10. Adjusting for self-selection factors, the study associated these patterns with 10th grade outcomes. Three profiles of participation emerged: consistently low breadth, consistently average breadth, and consistently high breadth of involvement in both organized and unstructured leisure activities over time. The most popular activity types across profile groups were hanging out with friends, team sports, and outdoor activities. Adolescents involved in a greater breadth of organized activities reported the greatest breadth of involvement in unstructured leisure and the best functioning. Adolescents with low breadth of involvement in both organized and unstructured leisure activities consistently showed poorer outcomes. Adolescents in the high breadth of involvement profile were engaged in all activity types at higher rates than adolescents in the average and low breadth of involvement profiles. We advocate for continued efforts to increase adolescent participation in a variety of different types of out-of-school activities. PMID- 25037910 TI - Changes in sleep habits in adolescents during intensive interdisciplinary pediatric pain rehabilitation. AB - Sleep behaviors play an important role in the experience of chronic pain in adolescence; less well known is the effect of improved sleep in the context of pain rehabilitation. This study examined changes in sleep habits and their association with pain and functioning following day-hospital interdisciplinary pediatric pain rehabilitation. Participants (84% female) were a cohort of 274 youth (ages 10-18, mean age 14.6 years) with neuropathic or musculoskeletal pain and associated disability who completed measures at admission, discharge, and short term (1-3 month) follow-up. Parents reported on the child's sleep habits; participants reported on pain, functional disability, and school functioning. Results show that sleep habits improved over the course of intensive pain rehabilitation treatment, with continued improvements at follow-up. Sleep habits at discharge correlated with concurrent measures of functional disability and mood symptoms, with healthier sleep habits being associated with less disability and fewer mood symptoms. Furthermore, greater sleep duration, less sleep onset delay, and fewer night wakings correlated with lower pain intensity ratings at discharge. Controlling for change in pain with treatment, baseline sleep habits, age, and concurrent depressive symptoms, sleep habits at discharge predicted global functioning and school functioning measured at follow-up. There was modest support for changes in sleep habits over the course of treatment predicting pain reduction at follow-up, with decreased night wakings significantly predicting reduced pain intensity at follow-up. Improvements in sleep habits may be one mechanism of efficacy for intensive pediatric pain rehabilitation. PMID- 25037911 TI - Examining the relationship between pre- and postimplant geometry in prostate low dose-rate brachytherapy and its correlation with dosimetric quality using the similarity concept. AB - PURPOSE: This is a retrospective study in which we define multiple metrics for similarity and then inquire on the relationship between similarity and currently used dosimetric quantities describing preimplant and postimplant plans. METHODS AND MATERIALS: We analyzed a unique cohort of 94 consecutively performed prostate seed implant patients, associated with excellent dosimetric and clinical outcomes. For each patient, an ultrasound (US) preimplant and two CT postimplant (Day 0 and Day 30) studies were available. Measures for similarity were created and computed using feature vectors based on two classes of moments: first, invariant to rotation and translation, and the second polar-radius moments invariant to rotation, translation, and scaling. Both similarity measures were calibrated using controlled perturbations (random and systematic) of seed positions and contours in different size implants, thus producing meaningful numerical threshold values used in the clinical analysis. RESULTS: An important finding is that similarity, for both seed distributions and contours, improves significantly when scaling invariance is added to translation and rotation. No correlation between seed and contours similarity was found. In the setting of preplanned prostate seed implants using preloaded needles, based on our data, similarity between preimplant and postimplant plans does not correlate with either minimum dose to 90% of the volume of the prostate or analogous similarity metrics for prostate contours. CONCLUSIONS: We have developed novel tools and metrics, which will allow practitioners to better understand the relationship between preimplant and postimplant plans. Geometrical similarity between a preplan and an actual implant, although useful, does not seem to be necessary to achieve minimum dose to 90% of the volume of the prostate-good dosimetric implants. PMID- 25037912 TI - High-dose-rate interstitial brachytherapy for T1-T2-stage penile carcinoma: short term results. AB - PURPOSE: Interstitial brachytherapy (IBT) is a preferred treatment option over partial penectomy in selected patients with T1-T2-stage penile carcinoma because of its organ preservation ability. Literature is mostly based on the use of low dose-rate IBT, and experience with high-dose-rate (HDR) IBT is extremely limited. We studied the role of HDR-IBT alone in patients with T1-T2-stage penile carcinoma. METHODS AND MATERIALS: Between April 2010 and July 2013, 14 patients with T1-T2-stage penile carcinoma were treated with HDR-IBT at our center. Size of the primary lesion ranged from 1.5 to 4.0cm. A two-to-four-plane free-hand implant was performed using plastic catheters. The prescribed dose of HDR-IBT was 42-51Gy in 14-17 fractions using twice-a-day fractionation schedule. Patients were followed up regularly for assessment of local control, survival, toxicity, and sexual function. RESULTS: At a median followup of 22 months, 2 patients developed recurrent disease at locoregional site. The 3-year overall survival was 83% with penis preservation rate of 93%. All patients developed acute Grade III skin toxicity that healed during 6-8-weeks time. Urethral stenosis and soft tissue necrosis was not seen in any of the patients. A total of 4 patients experienced mild asymptomatic fibrosis in the implanted area. Around 10 patients had satisfactory sexual function status at the last followup visit. CONCLUSIONS: Although it was a small sample size, our results have demonstrated excellent local control rate and acceptable toxicity with HDR-IBT in patients with T1-T2 stage penile carcinoma. PMID- 25037913 TI - Identification of short untranslated regions that sufficiently enhance translation in high-quality wheat germ extract. AB - High-quality wheat germ extract (hqWGE) is very useful for the high-yield production of various types of protein. The most important key to high productivity is the design of mRNA templates. Although the design has been refined for straightforward and efficient translation in hqWGE, there is still room for improvement in untranslated regions (UTRs), especially the 3' UTR length, because a long, cumbersome 3' UTR is commonly used for translation enhancement. Here we examined some short viral 3' cap-independent translation enhancers (3' CITEs) to identify effective ones for efficient translation in hqWGE. We then combined the most effective 3' CITE and a 5' enhancer to further increase the translation efficiency. mRNA with the optimal short 3' and 5' UTRs, both of whose length was less than 150 nt, exhibited a productivity of 1.4 mg/mL in prolonged large-scale protein synthesis in hqWGE, which was comparable to that of control mRNA with a commonly-used long 3' UTR (~1200 nt). PMID- 25037914 TI - Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety combines dual PPARalpha/gamma activation and dual 5-LO/mPGES-1 inhibition. AB - The concept of dual PPARalpha/gamma activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARalpha as well as PPARgamma activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured pirinixic acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure-activity relationship of these aminothiazole-featured pirinixic acids as dual PPARalpha/gamma agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various pirinixic acid derivatives had already been identified as dual PPARalpha/gamma agonists. However, within this series of aminothiazole-featured pirinixic acids we were able to identify the most potent selective PPARgamma agonistic pirinixic acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen 2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid)). Therefore, docking of 13 on PPARgamma was performed to determine the potential binding mode. PMID- 25037915 TI - Phragmalin-type limonoids with NF-kappaB inhibition from Chukrasia tabularis var. velutina. AB - Chemical investigation on Chukrasia tabularis var. velutina led to the identification of eight new phragmalin-type limonoids (1-8), as well as 20 known analogues. Compounds 1-4 are a rare class of C-15-acyl phragmalin-type limonoids, and particularly compounds 2-4 also possess a delta-lactone ring formed between C 16 and C-30. All the isolates were evaluated for inhibitory effects on NF-kappaB production, and four of which showed significant inhibitions. PMID- 25037916 TI - Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase. AB - A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 MUM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 MUM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%). PMID- 25037917 TI - Novel inhibitors of the high-affinity L-proline transporter as potential therapeutic agents for the treatment of cognitive disorders. AB - The incidence of cognitive disorders such as Alzheimer's disease continues to increase unabated. While cures for such diseases have eluded investigators, progress is being made on alleviating certain symptoms of these diseases. Mouse knockouts of the proline transporter (PROT), a high affinity Na(+)/Cl(-) dependent transporter, indicated its potential as a novel therapeutic target for cognition improvement. Herein we report our investigation into a novel class of PROT inhibitors. PMID- 25037918 TI - Discovery libraries targeting the major enzyme classes: the serine hydrolases. AB - Two libraries of modestly reactive ureas containing either electron-deficient acyl anilines or acyl pyrazoles were prepared and are reported as screening libraries for candidate serine hydrolase inhibitors. Within each library is a small but powerful subset of compounds that serve as a chemotype fragment screening library capable of subsequent structural diversification. Elaboration of the pyrazole-based ureas provided remarkably potent irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki=100-200 pM) complementary to those previously disclosed enlisting electron-deficient aniline-based ureas. PMID- 25037919 TI - Prenatal screening for congenital anomalies: exploring midwives' perceptions of counseling clients with religious backgrounds. AB - BACKGROUND: In the Netherlands, prenatal screening follows an opting in system and comprises two non-invasive tests: the combined test to screen for trisomy 21 at 12 weeks of gestation and the fetal anomaly scan to detect structural anomalies at 20 weeks. Midwives counsel about prenatal screening tests for congenital anomalies and they are increasingly having to counsel women from religious backgrounds beyond their experience. This study assessed midwives' perceptions and practices regarding taking client's religious backgrounds into account during counseling. As Islam is the commonest non-western religion, we were particularly interested in midwives' knowledge of whether pregnancy termination is allowed in Islam. METHODS: This exploratory study is part of the DELIVER study, which evaluated primary care midwifery in The Netherlands between September 2009 and January 2011. A questionnaire was sent to all 108 midwives of the twenty practices participating in the study. RESULTS: Of 98 respondents (response rate 92%), 68 (69%) said they took account of the client's religion. The two main reasons for not doing so were that religion was considered irrelevant in the decision-making process and that it should be up to clients to initiate such discussions. Midwives' own religious backgrounds were independent of whether they paid attention to the clients' religious backgrounds. Eighty midwives (82%) said they did not counsel Muslim women differently from other women. Although midwives with relatively many Muslim clients had more knowledge of Islamic attitudes to terminating pregnancy in general than midwives with relatively fewer Muslim clients, the specific knowledge of termination regarding trisomy 21 and other congenital anomalies was limited in both groups. CONCLUSION: While many midwives took client's religion into account, few knew much about Islamic beliefs on prenatal screening for congenital anomalies. Midwives identified a need for additional education. To meet the needs of the changing client population, counselors need more knowledge of religious opinions about the termination of pregnancy and the skills to approach religious issues with clients. PMID- 25037920 TI - Characterization of Panglial Gap Junction Networks in the Thalamus, Neocortex, and Hippocampus Reveals a Unique Population of Glial Cells. AB - The thalamus plays important roles as a relay station for sensory information in the central nervous system (CNS). Although thalamic glial cells participate in this activity, little is known about their properties. In this study, we characterized the formation of coupled networks between astrocytes and oligodendrocytes in the murine ventrobasal thalamus and compared these properties with those in the hippocampus and cortex. Biocytin filling of individual astrocytes or oligodendrocytes revealed large panglial networks in all 3 gray matter regions. Combined analyses of mice with cell type-specific deletion of connexins (Cxs), semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blotting showed that Cx30 is the dominant astrocytic Cx in the thalamus. Many thalamic astrocytes even lack expression of Cx43, while in the hippocampus astrocytic coupling is dominated by Cx43. Deletion of Cx30 and Cx47 led to complete loss of panglial coupling, which was restored when one allele of either Cxs was present. Immunohistochemistry revealed a unique antigen profile of thalamic glia and identified an intermediate cell type expressing both Olig2 and Cx43. Our findings further the emerging concept of glial heterogeneity across brain regions. PMID- 25037922 TI - The Neural Representation of Voluntary Task-Set Selection in Dynamic Environments. AB - When choosing actions, humans have to balance carefully between different task demands. On the one hand, they should perform tasks repeatedly to avoid frequent and effortful switching between different tasks. On the other hand, subjects have to retain their flexibility to adapt to changes in external task demands such as switching away from an increasingly difficult task. Here, we developed a difficulty-based choice task to investigate how subjects voluntarily select task sets in predictably changing environments. Subjects were free to choose 1 of the 3 task-sets on a trial-by-trial basis, while the task difficulty changed dynamically over time. Subjects self-sequenced their behavior in this environment while we measured brain responses with functional magnetic resonance imaging (fMRI). Using multivariate decoding, we found that task choices were encoded in the medial prefrontal cortex (dorso-medial prefrontal cortex, dmPFC, and dorsal anterior cingulate cortex, dACC). The same regions were found to encode task difficulty, a major factor influencing choices. Importantly, the present paradigm allowed us to disentangle the neural code for task choices and task difficulty, ensuring that activation patterns in dmPFC/dACC independently encode these 2 factors. This finding provides new evidence for the importance of the dmPFC/dACC for task-selection and motivational functions in highly dynamic environments. PMID- 25037921 TI - Satb2 Regulates the Differentiation of Both Callosal and Subcerebral Projection Neurons in the Developing Cerebral Cortex. AB - The chromatin-remodeling protein Satb2 plays a role in the generation of distinct subtypes of neocortical pyramidal neurons. Previous studies have shown that Satb2 is required for normal development of callosal projection neurons (CPNs), which fail to extend axons callosally in the absence of Satb2 and instead project subcortically. Here we conditionally delete Satb2 from the developing neocortex and find that neurons in the upper layers adopt some electrophysiological properties characteristic of deep layer neurons, but projections from the superficial layers do not contribute to the aberrant subcortical projections seen in Satb2 mutants. Instead, axons from deep layer CPNs descend subcortically in the absence of Satb2. These data demonstrate distinct developmental roles of Satb2 in regulating the fates of upper and deep layer neurons. Unexpectedly, Satb2 mutant brains also display changes in gene expression by subcerebral projection neurons (SCPNs), accompanied by a failure of corticospinal tract (CST) formation. Altering the timing of Satb2 ablation reveals that SCPNs require an early expression of Satb2 for differentiation and extension of the CST, suggesting that early transient expression of Satb2 in these cells plays an essential role in development. Collectively these data show that Satb2 is required by both CPNs and SCPNs for proper differentiation and axon pathfinding. PMID- 25037924 TI - fMRI of Simultaneous Interpretation Reveals the Neural Basis of Extreme Language Control. AB - We used functional magnetic resonance imaging (fMRI) to examine the neural basis of extreme multilingual language control in a group of 50 multilingual participants. Comparing brain responses arising during simultaneous interpretation (SI) with those arising during simultaneous repetition revealed activation of regions known to be involved in speech perception and production, alongside a network incorporating the caudate nucleus that is known to be implicated in domain-general cognitive control. The similarity between the networks underlying bilingual language control and general executive control supports the notion that the frequently reported bilingual advantage on executive tasks stems from the day-to-day demands of language control in the multilingual brain. We examined neural correlates of the management of simultaneity by correlating brain activity during interpretation with the duration of simultaneous speaking and hearing. This analysis showed significant modulation of the putamen by the duration of simultaneity. Our findings suggest that, during SI, the caudate nucleus is implicated in the overarching selection and control of the lexico-semantic system, while the putamen is implicated in ongoing control of language output. These findings provide the first clear dissociation of specific dorsal striatum structures in polyglot language control, roles that are consistent with previously described involvement of these regions in nonlinguistic executive control. PMID- 25037923 TI - Dorsolateral Prefrontal Cortex Deactivation in Monkeys Reduces Preparatory Beta and Gamma Power in the Superior Colliculus. AB - Cognitive control requires the selection and maintenance of task-relevant stimulus-response associations, or rules. The dorsolateral prefrontal cortex (DLPFC) has been implicated by lesion, functional imaging, and neurophysiological studies to be involved in encoding rules, but the mechanisms by which it modulates other brain areas are poorly understood. Here, the functional relationship of the DLPFC with the superior colliculus (SC) was investigated by bilaterally deactivating the DLPFC while recording local field potentials (LFPs) in the SC in monkeys performing an interleaved pro- and antisaccade task. Event related LFPs showed differences between pro- and antisaccades and responded prominently to stimulus presentation. LFP power after stimulus onset was higher for correct saccades than erroneous saccades. Deactivation of the DLPFC did not affect stimulus onset related LFP activity, but reduced high beta (20-30 Hz) and high gamma (60-150 Hz) power during the preparatory period for both pro- and antisaccades. Spike rate during the preparatory period was positively correlated with gamma power and this relationship was attenuated by DLPFC deactivation. These results suggest that top-down control of the SC by the DLPFC may be mediated by beta oscillations. PMID- 25037925 TI - Extraintestinal pathogenic Escherichia coli (ExPEC) of human and avian origin belonging to sequence type complex 95 (STC95) portray indistinguishable virulence features. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) strains of certain genetic lineages are frequently implicated in a wide range of diseases in humans and birds. ExPEC strains belonging to the phylogenetic lineage/sequence type complex 95 (STC95) are one such prominent lineage that is commonly isolated from extraintestinal infections such as systemic disease in poultry and urinary tract infections (UTIs), neonatal meningitis and sepsis in humans. Several epidemiological studies have indicated that ST95 strains obtained from such infections may share similar virulence genes and other genomic features. However, data on their ability to establish infections in vivo as deduced from the manifestation of similar virulence phenotypes remain elusive. In the present study, 116 STC95 ExPEC isolates comprising 55 human and 61 avian strains, possessing similar virulence gene patterns, were characterized in vitro using adhesion, invasion, biofilm formation and serum bactericidal assays. Overall, STC95 strains from both groups, namely human and birds, were equally capable of adhering to and invading the two mammalian kidney cell lines. Similarly, these strains were able to form strong biofilms in M63 medium. Furthermore, they were equally resistant to the bactericidal activity of human and avian serum. Our cumulative data reinforce the understanding that ST95 strains from poultry present a potential zoonotic risk and therefore need a One Health strategy for a successfull intervention. PMID- 25037926 TI - Molecular analysis of Coxiella burnetii in Germany reveals evolution of unique clonal clusters. AB - The causative agent of Q fever, Coxiella burnetii, is a query agent occurring naturally all over the world. We studied 104 German Coxiella burnetii strains/DNA samples obtained between 1969 and 2011 using a 14 microsatellite marker Multiple locus variable-number of tandem repeat (VNTR) analysis (MLVA) technique. We were able to divide our collection into 32 different genotypes clustered into four major groups (A-D). Two of these (A and C) formed predominant clonal complexes that covered 97% of all studied samples. Group C consisted exclusively of cattle associated isolates/DNA specimens, while group A comprised all other affected species including all sheep-derived strains/DNA samples. Within this second cluster, two major genotypes (A1, A2) were identified. Genotype A2 occurred in strains isolated from ewes in northern and central Germany, whereas genotype A1 was found in most areas of Germany. MLVA analysis of C. burnetii strains from neighbouring countries revealed a close relationship to German strains. We thus hypothesize that there is a western and central European cluster of C. burnetii. We identified predominant genotypes related to relevant host species and geographic regions which is in line with findings of the Dutch Q fever outbreak (2007-2010). Furthermore three of our analyzed German strains are closely related to the Dutch outbreak clone. These findings support the theory of predominant genotypes in the context of regional outbreaks. Our results show that a combination of 8 MLVA markers provides the highest discriminatory power for attributing C. burnetii isolates to genotypes. For future epidemiological studies we propose the use of three MLVA markers for easy and rapid classification of C. burnetii into 4 main clusters. PMID- 25037927 TI - Genotyping of samples from German patients with ocular, cerebral and systemic toxoplasmosis reveals a predominance of Toxoplasma gondii type II. AB - Toxoplasmosis is an important zoonosis transmitted from animals to humans world wide. In order to determine Toxoplasma gondii genotypes in individuals living in Germany and to compare findings with those in animals, we analysed nine independent and unlinked genetic markers (nSAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico) by PCR-RFLP in 83 archived T. gondii-positive DNA samples from patients with ocular toxoplasmosis (n=35), toxoplasmic encephalitis (n=32), systemic toxoplasmosis after bone-marrow transplantation (n=15) and congenital toxoplasmosis (n=1). In 46 of these 83 samples the presence of T. gondii DNA was confirmed by conventional end-point PCR. Among these, 17 T. gondii-positive samples were typed at all nine loci. The majority (15/17, 88.2%) of these samples were of T. gondii type II (i.e., including both, the Apico type II and Apico type I variants). In addition, in one sample a T. gondii type II/type III allele combination and in another sample a T. gondii genotype displaying type III alleles at all markers was observed. In the remaining 11 samples, in which T. gondii could only be partially typed, exclusively type II (n=10) or type III (n=1) alleles were observed. Results of the present study suggest that the majority of patients in Germany are infected with type II T. gondii regardless of the clinical manifestation of toxoplasmosis. This finding is in accord with the predominance of type II T. gondii in oocysts isolated from cats and in tissues of other intermediate hosts in Germany. PMID- 25037928 TI - Nitrosamines in pilot-scale and full-scale wastewater treatment plants with ozonation. AB - Ozone-based treatment trains offer a sustainable option for potable reuse applications, but nitrosamine formation during ozonation poses a challenge for municipalities seeking to avoid reverse osmosis and high-dose ultraviolet (UV) irradiation. Six nitrosamines were monitored in full-scale and pilot-scale wastewater treatment trains. The primary focus was on eight treatment trains employing ozonation of secondary or tertiary wastewater effluents, but two treatment trains with chlorination or UV disinfection of tertiary wastewater effluent and another with full advanced treatment (i.e., reverse osmosis and advanced oxidation) were also included for comparison. N-nitrosodimethylamine (NDMA) and N-nitrosomorpholine (NMOR) were the most prevalent nitrosamines in untreated (up to 89 ng/L and 67 ng/L, respectively) and treated wastewater. N nitrosomethylethylamine (NMEA) and N-nitrosodiethylamine (NDEA) were detected at one facility each, while N-nitrosodipropylamine (NDPrA) and N-nitrosodibutylamine (NDBA) were less than their method reporting limits (MRLs) in all samples. Ozone induced NDMA formation ranging from <10 to 143 ng/L was observed at all but one site, but the reasons for the variation in formation remain unclear. Activated sludge, biological activated carbon (BAC), and UV photolysis were effective for NDMA mitigation. NMOR was also removed with activated sludge but did not form during ozonation. PMID- 25037929 TI - Need for new powered trials to assess the role of post-operative radiotherapy for stage III non-small cell lung cancer. PMID- 25037930 TI - Are Modic changes related to outcomes in lumbar disc herniation patients treated with imaging-guided lumbar nerve root blocks? AB - OBJECTIVE: To compare outcomes after imaging-guided transforaminal lumbar nerve root blocks in MRI confirmed symptomatic disc herniation patients with and without Modic changes (MC). METHODS: Consecutive adult patients with MRI confirmed symptomatic lumbar disc herniations and an imaging-guided lumbar nerve root block injection who returned an outcomes questionnaire are included. Numerical rating scale (NRS) pain data was collected prior to injection and 20-30 min after injection. NRS and overall improvement were assessed using the patient's global impression of change (PGIC) scale at 1 day, 1 week and 1 month post injection. The proportion of patients with and without MC on MRI as well as Modic I and Modic II was calculated. These groups were compared for clinically relevant 'improvement' using the Chi-squared test. Baseline and follow-up NRS scores were compared for the groups using the unpaired t-test. RESULTS: 346 patients are included with MC present in 57%. A higher percentage of patients without MC reported 'improvement' and a higher percentage of patients with MC reported 'worsening' but this did not reach statistical significance. The numerical scores on the PGIC and NRS scales showed that patients with MC had significantly higher pain and worse overall improvement scores at 1 month (p=0.048 and p=0.03) and a significantly lower 1 month NRS change score (p=0.04). CONCLUSIONS: Patients with MRI confirmed symptomatic lumbar disc herniations and MC report significantly lower levels of pain reduction after a lumbar nerve root block compared to patients without MC. PMID- 25037931 TI - Reducing CT radiation dose with iterative reconstruction algorithms: the influence of scan and reconstruction parameters on image quality and CTDIvol. AB - OBJECTIVES: In this phantom CT study, we investigated whether images reconstructed using filtered back projection (FBP) and iterative reconstruction (IR) with reduced tube voltage and current have equivalent quality. We evaluated the effects of different acquisition and reconstruction parameter settings on image quality and radiation doses. Additionally, patient CT studies were evaluated to confirm our phantom results. METHODS: Helical and axial 256 multi slice computed tomography scans of the phantom (Catphan((r))) were performed with varying tube voltages (80-140kV) and currents (30-200mAs). 198 phantom data sets were reconstructed applying FBP and IR with increasing iterations, and soft and sharp kernels. Further, 25 chest and abdomen CT scans, performed with high and low exposure per patient, were reconstructed with IR and FBP. Two independent observers evaluated image quality and radiation doses of both phantom and patient scans. RESULTS: In phantom scans, noise reduction was significantly improved using IR with increasing iterations, independent from tissue, scan-mode, tube voltage, current, and kernel. IR did not affect high-contrast resolution. Low contrast resolution was also not negatively affected, but improved in scans with doses <5mGy, although object detectability generally decreased with the lowering of exposure. At comparable image quality levels, CTDIvol was reduced by 26-50% using IR. In patients, applying IR vs. FBP resulted in good to excellent image quality, while tube voltage and current settings could be significantly decreased. CONCLUSIONS: Our phantom experiments demonstrate that image quality levels of FBP reconstructions can also be achieved at lower tube voltages and tube currents when applying IR. Our findings could be confirmed in patients revealing the potential of IR to significantly reduce CT radiation doses. PMID- 25037932 TI - 3D dynamic pituitary MR imaging with CAIPIRINHA: initial experience and comparison with 2D dynamic MR imaging. AB - OBJECTIVES: To evaluate the validity of 3D dynamic pituitary MR imaging with controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA), with special emphasis on demarcation of pituitary posterior lobe and stalk. METHODS: Participants comprised 32 patients who underwent dynamic pituitary MR imaging due to pituitary or parasellar lesions. 3D dynamic MR with CAIPIRINHA was performed at 3T with 20-s-interval, precontrast, 1st to 5th dynamic images. Normalized values and enhanced ratios (dynamic postcontrast image values divided by precontrast ones) were compared between 3D and 2D dynamic MR imaging for patients with visual identification of posterior lobe and stalk. RESULTS: In 3D, stalk was identified in 29 patients and unidentified in 3, and posterior lobe was identified in 28 and unidentified in 4. In 2D, stalk was identified in 26 patients and unidentified in 6 patients, and posterior lobe was identified in 15 and unidentified in 17. Normalized values of pituitary posterior lobe and stalk were higher in 3D than 2D (P<0.001). No significant difference in enhancement ratio was seen between 3D and 2D. CONCLUSIONS: 3D dynamic pituitary MR provided better identification and higher normalized values of pituitary posterior lobe and stalk than 2D. PMID- 25037933 TI - Identifying group discriminative and age regressive sub-networks from DTI-based connectivity via a unified framework of non-negative matrix factorization and graph embedding. AB - Diffusion tensor imaging (DTI) offers rich insights into the physical characteristics of white matter (WM) fiber tracts and their development in the brain, facilitating a network representation of brain's traffic pathways. Such a network representation of brain connectivity has provided a novel means of investigating brain changes arising from pathology, development or aging. The high dimensionality of these connectivity networks necessitates the development of methods that identify the connectivity building blocks or sub-network components that characterize the underlying variation in the population. In addition, the projection of the subject networks into the basis set provides a low dimensional representation of it, that teases apart different sources of variation in the sample, facilitating variation-specific statistical analysis. We propose a unified framework of non-negative matrix factorization and graph embedding for learning sub-network patterns of connectivity by their projective non-negative decomposition into a reconstructive basis set, as well as, additional basis sets representing variational sources in the population like age and pathology. The proposed framework is applied to a study of diffusion-based connectivity in subjects with autism that shows localized sparse sub-networks which mostly capture the changes related to pathology and developmental variations. PMID- 25037934 TI - Multilocus sequence typing for the analysis of clonality among Candida albicans strains from a neonatal intensive care unit. AB - Nosocomial Candida albicans infections are a significant problem in neonatal intensive care units (NICUs). We investigated the clonality of C. albicans isolates recovered over an 8-year period from neonates at a NICU. We also validated multilocus sequence typing (MLST) compared with pulsed-field gel electrophoresis (PFGE) for the genotyping of C. albicans strains from the same NICU. A total of 43 clinical isolates (10 blood, 19 urine, and 14 other) were obtained from 43 neonates between 2005 and 2012. Clonal strains were defined as the isolation of two or more strains with identical or similar genotypes as determined with both MLST and PFGE. Using MLST, the 43 isolates yielded 25 diploid sequence types (DSTs) and 10 DSTs were shared by 28 isolates (65.1%). Among the 28 isolates sharing 10 DSTs, isolates from each of seven DSTs had the same or similar PFGE pattern. In addition, two sets of isolates that differed by MLST at only one locus had the same or similar PFGE pattern. Overall, when the MLST and PFGE results were combined, 22 isolates (51.2%) shared eight genotypes, suggesting clonal strains. Strains from each of seven genotypes (total, 19 isolates) were isolated among the 22 clonal strains within a 6-month period, whereas three strains of one genotype were obtained over a 3-year interval. Our findings suggest that horizontal transmission of C. albicans may occur more frequently than vertical transmission among NICU patients and that MLST appears to be a useful method for genotyping C. albicans strains isolated from NICU patients. PMID- 25037935 TI - In reply. PMID- 25037936 TI - Modeling and research on research. PMID- 25037937 TI - Issues related to the study of cannabinoids in exhaled breath. PMID- 25037938 TI - The evaluation of a non-invasive respiratory volume monitor in surgical patients undergoing elective surgery with general anesthesia. AB - Continuous respiratory assessment is especially important during post-operative care following extubation. Respiratory depression and subsequent adverse outcomes can arise due to opioid administration and/or residual anesthetics. A non invasive respiratory volume monitor (RVM) has been developed that provides continuous, real-time, measurements of minute ventilation (MV), tidal volume (TV), and respiratory rate (RR) via a standardized set of thoracic electrodes. Previous work demonstrated accuracy of the RVM versus standard spirometry and its utility in demonstrating response to opioids in postoperative patients. This study evaluated the correlation between RVM measurements of MV, TV and RR to ventilator measurements during general anesthesia (GA). Continuous digital RVM and ventilator traces, as well as RVM measurements of MV, TV and RR, were analyzed from ten patients (mean 62.6+/-7.4 years; body mass index 28.6+/-5.2 kg/m2) undergoing surgery with GA. RVM data were compared to ventilator data and bias, precision and accuracy were calculated. The average MV difference between the RVM and ventilator was -0.10 L/min (bias: -1.3%, precision: 6.6%, accuracy: 9.0%. The average TV difference was 40 mL (bias: 0.4%, precision: 7.3%, accuracy: 9.1%). The average RR difference was -0.22 breaths/minute (bias: -1.8%, precision: 3.7% accuracy: 4.1%). Correlations between the RVM traces and the ventilator were compared at various points with correlations>0.90 throughout. Pairing the close correlation to ventilator measurements in intubated patients demonstrated by this study with previously described accuracy compared to spirometry in non-intubated patients, the RVM can be considered to have the capability to provide continuity of ventilation monitoring post-extubation This supports the use of real-time continuous RVM measurements to drive post-operative and post-extubation protocols, initiate therapeutic interventions and improve patient safety. PMID- 25037939 TI - One-year mortality in patients requiring prolonged mechanical ventilation: multicenter evaluation of the ProVent score. AB - INTRODUCTION: Current severity-of-illness indexes are unable to assess the long term prognosis of patients requiring prolonged mechanical ventilation. A prognostic scoring system (Prognosis for Prolonged Ventilation score - ProVent - score) seems able to evaluate one-year mortality of such patients. However, testing of the model outside the developers' centers has not been reported. So, it is unclear how the ProVent score performs in non-US and non-tertiary ICUs. The goal of our study was to evaluate its performances in a French multicenter, community hospital-based setting. METHODS: In three primary ICUs, 201 patients requiring mechanical ventilation for at least 21 days were enrolled in a retrospective cohort study. ICU mortality was abstracted from medical records and, for patients discharged alive from the ICU, one-year mortality was determined by telephone calls to patients' general practitioners. RESULTS: One year mortality was 60% (n = 120). On day 21 of ventilation, ProVent score value was 0 in 19 patients (9%), 1 in 63 patients (31%), 2 in 64 patients (32%), 3 in 37 patients (18%), and >=4 in 18 patients (9%), respectively. For ProVent score values ranging from 0 to >=4, one-year mortality rates were 21%, 43%, 67%, 78%, and 94%, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve for the ProVent score was 0.74 (95% confidence interval 0.671 to 0.809). Stepwise logistic regression analysis showed that only three variables (age >=65 years, vasopressors, and hemodialysis) were independently associated with one-year mortality in our population. In assigning one point to each variable, we created a French ProVent score. The Hosmer Lemeshow goodness-of-fit statistic was 1.36 (DF = 6, P = 0.857) and the AUC of the ROC curve was 0.742 (95% confidence interval 0.673 to 0.810). One-year mortality rates for French ProVent score ranging from 0 to 3 were 34.6%, 70.9%, 83.3% and 100%, respectively (P <0.0001). CONCLUSIONS: The ProVent score is able, even in non-US ICUs and in community hospitals, to accurately identify among patients requiring prolonged mechanical ventilation those who are at high risk of one-year mortality. Its simplification appears possible. However, further validation of this French ProVent score in a larger external sample is indicated. PMID- 25037940 TI - Metastasis of gastrointestinal stromal tumor to skeletal muscle: a case report. AB - INTRODUCTION: Gastrointestinal stromal tumor is the most common malignant mesenchymal tumor of the gastrointestinal tract. The most common sites of metastasis are the liver and the peritoneum, but gastrointestinal stromal tumors rarely metastasize to the skeletal muscles. Only three cases of gastrointestinal stromal tumor metastasizing to skeletal muscle have been reported in the English literature. Here we present an additional case of skeletal muscle metastasis, and the relevant literature is reviewed. CASE PRESENTATION: A 54-year-old Japanese man presented with a three-month history of an enlarging mass of the left buttock. An excisional biopsy was performed and the tumor was diagnosed as a leiomyosarcoma. However, careful examination of the gastrointestinal tract revealed a tumor located in the small intestine. Surgical resection of the small intestine tumor was performed; histopathological and immunohistochemical examinations identified it as a primary gastrointestinal stromal tumor arising from the small intestine. Despite receiving both chemotherapy and molecular targeted therapy, our patient died of gastrointestinal bleeding six months after the initial diagnosis. CONCLUSIONS: Because it is a mesenchymal tumor, it is difficult to distinguish a gastrointestinal stromal tumor metastasis to skeletal muscle from other primary soft tissue sarcomas. Although metastasis of gastrointestinal stromal tumor to skeletal muscle is rare, the likelihood of finding metastases in these unusual sites is increasing due to prolonged survival of patients with gastrointestinal stromal tumor after the introduction of imatinib therapy. We should include metastases of gastrointestinal stromal tumors as differential diagnosis of spindle cell tumor, and it is necessary to begin appropriate treatment early. PMID- 25037941 TI - Preserving our international heritage of education in congenital heart surgery. PMID- 25037942 TI - Reply to the editor. PMID- 25037943 TI - Encouraging outcomes after mitral valve repair with the GeoForm annuloplasty ring. An extraordinary ring or a very good patient selection? PMID- 25037944 TI - Effect of right ventricular free wall ventriculotomy on right ventricular function: is that the correct question? PMID- 25037945 TI - Reply to the editor. PMID- 25037946 TI - Awake thoracoscopic surgery: safety issues in difficult airway and use of thoracic epidural anesthesia. PMID- 25037947 TI - Reply to the editor. PMID- 25037948 TI - Prevention of open water drowning while boating. PMID- 25037949 TI - Retroduplication and loss of parental genes is a mechanism for the generation of intronless genes in Ciona intestinalis and Ciona savignyi. AB - Tunicates, the sister clade of vertebrates, have miniature genomes and numerous intronless genes compared to other animals. It is still unclear how the tunicates acquired such a large number of intronless genes. Here, we analyzed sequences and intron-exon organizations of homologous genes from two closely related tunicates, Ciona intestinalis and Ciona savignyi. We found seven cases in which ancestral introns of a gene were completely lost in a species after their divergence. In four cases, both the intronless copy and the intron-containing copy were present in the genome, indicating that the intronless copy was generated by retroduplication. In the other three cases, the intron-containing copy was absent, implying it was lost after retroduplication. This result suggests that retroduplication and loss of parental genes is a major mechanism for the accumulation of intronless genes in tunicates. PMID- 25037950 TI - Age estimation based on pictures and videos presumably showing child or youth pornography. PMID- 25037951 TI - Effectiveness of internet-based interventions for children, youth, and young adults with anxiety and/or depression: a systematic review and meta-analysis. AB - BACKGROUND: The majority of internet-based anxiety and depression intervention studies have targeted adults. An increasing number of studies of children, youth, and young adults have been conducted, but the evidence on effectiveness has not been synthesized. The objective of this research is to systematically review the most recent findings in this area and calculate overall (pooled) effect estimates of internet-based anxiety and/or depression interventions. METHODS: We searched five literature databases (PubMed, EMBASE, CINAHL, PsychInfo, and Google Scholar) for studies published between January 1990 and December 2012. We included studies evaluating the effectiveness of internet-based interventions for children, youth, and young adults (age <25 years) with anxiety and/or depression and their parents. Two reviewers independently assessed the risk of bias regarding selection bias, allocation bias, confounding bias, blinding, data collection, and withdrawals/dropouts. We included studies rated as high or moderate quality according to the risk of bias assessment. We conducted meta-analyses using the random effects model. We calculated standardized mean difference and its 95% confidence interval (95% CI) for anxiety and depression symptom severity scores by comparing internet-based intervention vs. waitlist control and internet-based intervention vs. face-to-face intervention. We also calculated pooled remission rate ratio and 95% CI. RESULTS: We included seven studies involving 569 participants aged between 7 and 25 years. Meta-analysis suggested that, compared to waitlist control, internet-based interventions were able to reduce anxiety symptom severity (standardized mean difference and 95% CI = -0.52 [-0.90, -0.14]) and increase remission rate (pooled remission rate ratio and 95% CI =3.63 [1.59, 8.27]). The effect in reducing depression symptom severity was not statistically significant (standardized mean difference and 95% CI = -0.16 [-0.44, 0.12]). We found no statistical difference in anxiety or depression symptoms between internet-based intervention and face-to-face intervention (or usual care). CONCLUSIONS: The present analysis indicated that internet-based interventions were effective in reducing anxiety symptoms and increasing remission rate, but not effective in reducing depression symptom severity. Due to the small number of higher quality studies, more attention to this area of research is encouraged. TRIAL REGISTRATION: PROSPERO registration: CRD42012002100. PMID- 25037952 TI - A systematic review of the literature on 'medication wastage': an exploration of causative factors and effect of interventions. AB - INTRODUCTION: Reducing any wastage, including that of medications, is a paramount objective in promoting appropriate utilisation of finite resources. The objective was to systematically review the published literature, the possible causative factors associated with medication wastage and the effectiveness of any interventions to reduce wastage. METHOD: A systematic review of studies published in English was identified from the following databases: Cumulative Index to Nursing and Allied Health Literature, Embase, Medline, PubMed, Science Citation Index and The Cochrane Library. Data extraction and critical appraisal was undertaken independently by two researchers. RESULTS AND DISCUSSION: Title, abstract and full paper screening reduced the 14,157 studies to 42. A general definition of medication wastage was reported in one paper only. 'Medication changed', 'patient death', 'resolution of patient's condition' and 'expired medications' were most commonly cited reasons for wastage. Only two studies were identified reporting wastage as a research outcome measure following intervention. CONCLUSION: The systematic review has identified a limited literature on medication wastage with a lack of consistency of terms. There is a paucity of robust research focusing on the impact of healthcare interventions on outcomes around medication wastage. PMID- 25037953 TI - Traditional alcohol production and use in three provinces in Vietnam: an ethnographic exploration of health benefits and risks. AB - BACKGROUND: Gaps exist in knowledge about the production and use of traditional alcohols, particularly in Asia. This study adds new information about the nature, production and sale of traditional distilled spirit alcohol in Vietnam. METHOD: This was an ethnographic study of traditional distilled spirit alcohol production in rural areas of three provinces in Vietnam. Researchers interviewed more than 300 individuals and recorded responses to general open-ended questions about local alcohol production. Interviews were recorded, transcribed, and studied to discern what information about traditional alcohol was important to the speakers. RESULTS: Methods of production followed long-held traditions. Participants listed both personal and community benefits (economic, health, and social) from traditional alcohol making. Older people favoured traditional alcohol, while younger people favoured brand-name beer. Typically people consumed 2-4 drinks daily, mainly at meal times. People consumed more alcohol at special events and festivals. Distribution patterns ranged from low-risk distribution to family and neighbours to high-risk distribution by an agent who might combine alcohol from several producers, which increases the opportunity for dilution and adulteration. The most commonly listed health risks associated with locally-made alcohol were local air pollution and water pollution; participants also mentioned traffic crashes and bad public behaviour. Depending on the location, community leaders reported that production may be relatively stable or it may be declining. CONCLUSIONS: Traditional alcohol manufacture, sale, and use in Vietnam is a long standing practice and low- to moderate-risk to health. There do not appear to be instances of accidental or intentional contamination. Urbanization seems to be affecting the market share of traditional alcohol as urbanized youth turn to branded products, mainly beer, making traditional alcohol making and consumption an activity mainly linked to older people in rural areas. In the rural areas surveyed, significant economic and social benefits are derived from traditional alcohol manufacture, sale, and use. Policy makers designing ways to reduce alcohol-related risks and harms need to give thoughtful consideration to the role traditional alcohol plays in the local society and to suggest changes that do not create unintended problems. PMID- 25037954 TI - Osteochondral lesions of the ankle joint in professional soccer players: treatment with autologous matrix-induced chondrogenesis. AB - Acute and recurrent ankle sprains and other trauma to the ankle joint are common injuries in soccer and can be accompanied by or result in osteochondral lesions of the ankle joint, majorly of the talus. Conservative treatment frequently fails. Several operative treatment techniques exist; however, the choice of the right procedure is difficult due to lack of literature with a high level of evidence. We present our treatment method for acute and chronic ankle osteochondral lesions with cystic formation approached by a new surgical technique combining bone plasty and a collagen matrix (autologous matrix-induced chondrogenesis). LEVELS OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 25037955 TI - Plantar flexor muscle architecture changes as a result of eccentric exercise in patients with Achilles tendinosis. AB - Eccentric training for Achilles tendinosis (AT) has been reported to significantly improve patient symptoms. There has been no biomechanical explanation on the mechanism for specific rehabilitation technique. The purpose of this study was to determine changes in muscle architecture that occurred as a result of Achilles tendinosis injury and a subsequent eccentric rehabilitation program. Twenty-five patients (age, 53.3 +/- 17.5 years) diagnosed with AT participated in 6 weeks of rehabilitation. Specific exercises for the ankle plantar flexors consisted of maximal load eccentric muscle action using 3 sets of 15 repetitions. Patients also completed a protocol for AT, which consisting of traditional rehabilitation. Medial gastrocnemius (GM) and lateral gastrocnemius (GL) muscle fascicle length and thickness were measured with ultrasound at 2-week intervals from initial treatment day to the end of 6 weeks of rehabilitation. Medial gastrocnemius fascicle length increased (45.1 +/- 10.5 mm to 51.4 +/- 10.5 mm; P = .22) between the initial day of rehabilitation and after 6 weeks of rehabilitation. But, GM thickness (16.3 +/- 3.5 mm to 16.8 +/- 2.0 mm), GL fascicle length (47.2 +/- 10.0 mm to 47.1 +/- 7.4 mm), and GL thickness (14.9 +/- 5.2 mm to 14.4 +/- 2.7 mm) did not change as a result of rehabilitation. A 6-week eccentric-biased exercise increased the GM muscle fascicle length by 12%, but GM thickness, GL fascicle length, and GL thickness did not change as a result of rehabilitation. Eccentric training for the treatment of AT is well recognized, but the mechanism of action has not been previously reported. A 6-week eccentric training protocol increased the GM muscle fascicle length by 12%, and this correlated with improvement in a validated patient outcome scoring system. Further study is warranted to determine a predictive relationship between improvement of GM fascicle length and outcome scores. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 25037956 TI - Missed peritalar injuries: an analysis of factors in cases of known delayed diagnosis and methods for improving identification. AB - Because of the complex anatomy of the foot, rarity of fractures of the foot, and subtle radiographic cues, foot injuries are commonly overlooked and mis/undiagnosed. This study seeks to investigate a patient population whose peritalar injuries, including fractures and dislocations, were missed on initial examination, in order to analyze factors of known, missed injuries and provide insight into methods for reducing the incidence of missed diagnoses. Surgical cases between January 1999 and May 2011 were queried and retrospectively reviewed to identify missed peritalar injuries. Of 1682 surgical cases reviewed, 27 patients with missed peritalar injury(ies), which were subsequently confirmed by imaging studies, were identified. Using the Orthopaedic Trauma Association classification, fracture and dislocation subtypes were classified. A medical record review was performed to assess demographic and surgical data elements. In this study population, 7 types of peritalar injuries (talus, calcaneal, navicular, and cuboid fractures as well as subtalar, calcaneocuboid, and talonavicular joint dislocations) were diagnosed in 27 patients. All patients required surgical intervention. Talus fractures were the most commonly missed injury. In patients with multiple peritalar injuries, there was a strong correlation between talus and navicular fractures (r = -0.60; P < .01) as well as a moderate correlation between talus fractures and calcaneocuboid dislocations (r = -0.46; P = .02). The presence of a calcaneal fracture significantly decreased the time to definitive diagnosis (P = .01). Male patients' diagnoses were delayed an average of 324 days and females 105 days (P = .04). A moderate correlation was found between patient age at injury and time to diagnosis (r = -0.47; P = .04), with a decreased time to diagnosis as patient age increased. Significant factors were identified in this patient population, including patient sex and age, which may contribute to missed or delayed diagnosis in the clinical setting. Prompt and accurate diagnosis of peritalar injuries may improve long-term outcomes. LEVELS OF EVIDENCE: Care Management, Level V. PMID- 25037957 TI - Joint salvage after neglected intra-articular physeal fracture of the hallux in high-level gymnasts. AB - Chronic sports-related injuries involving the hallux are well known in adult populations. However, they are less frequently described in adolescents. We present 2 cases of elite-level gymnasts with neglected Salter-Harris IV fractures involving the proximal phalanx of the great toe following a severe hyperextension injury to the metatarsophalangeal joint. Both were successfully treated with open reduction and internal fixation with return to pre-injury level of activity, improvement in outcome scores, and demonstration of no disability from injury 2 years after surgical intervention. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case Series. PMID- 25037958 TI - Insights into the effects of long-term artificial selection on seed size in maize. AB - Grain produced from cereal crops is a primary source of human food and animal feed worldwide. To understand the genetic basis of seed-size variation, a grain yield component, we conducted a genome-wide scan to detect evidence of selection in the maize Krug Yellow Dent long-term divergent seed-size selection experiment. Previous studies have documented significant phenotypic divergence between the populations. Allele frequency estimates for ~3 million single nucleotide polymorphisms (SNPs) in the base population and selected populations were estimated from pooled whole-genome resequencing of 48 individuals per population. Using FST values across sliding windows, 94 divergent regions with a median of six genes per region were identified. Additionally, 2729 SNPs that reached fixation in both selected populations with opposing fixed alleles were identified, many of which clustered in two regions of the genome. Copy-number variation was highly prevalent between the selected populations, with 532 total regions identified on the basis of read-depth variation and comparative genome hybridization. Regions important for seed weight in natural variation were identified in the maize nested association mapping population. However, the number of regions that overlapped with the long-term selection experiment did not exceed that expected by chance, possibly indicating unique sources of variation between the two populations. The results of this study provide insights into the genetic elements underlying seed-size variation in maize and could also have applications for other cereal crops. PMID- 25037959 TI - Remote ischemic preconditioning prevents lipopolysaccharide-induced liver injury through inhibition of NF-kappaB activation in mice. AB - PURPOSE: Remote ischemic preconditioning (RIPC) is a potent preconditioning stimulus that may confer subsequent protection to organs subjected to potentially lethal injury. The aim of this study was to investigate the effect of RIPC on nuclear factor (NF)-kappaB activation, tumor necrosis factor (TNF)-alpha release, and hepatic injury in lipopolysaccharide (LPS)-induced sepsis. METHODS: This randomized experimental animal study was performed using 8-week-old mice weighing 35-40 g. Mice were randomized (n = 13 per group) to four groups. RIPC was induced with three 10-min cycles of hind limb ischemia by placing an elastic rubber band tourniquet on the proximal part of the limb, with each ischemia cycle followed by 10 min of reperfusion. The groups were treated as follows: (1) the control group received an injection of saline [intraperitoneally (i.p.)]; (2) the RIPC group was subjected to RIPC, followed immediately by an injection of saline (i.p.); (3) the LPS group received an injection of LPS (20 mg/kg, i.p.); (4) the RIPC/LPS group was subjected to RIPC, followed immediately by an injection of LPS (20 mg/kg, i.p.). TNF-alpha, NF-kappaB, and IkappaB-alpha levels, neutrophil accumulation, and microabscess formation in the liver were evaluated after LPS injection. RESULTS: Among our treatment groups, RIPC significantly attenuated TNF alpha release in response to endotoxin and inhibited NF-kappaB activation, neutrophil accumulation, and microabscess formation in the liver. CONCLUSION: The results demonstrate that RIPC has protective effects in liver injury via attenuation of TNF-alpha production in LPS-induced sepsis. The suppressive effect on TNF-alpha production may be mediated through inhibition of NF-kappaB activation. PMID- 25037961 TI - In search of Homo economicus. AB - Homo economicus, a model for humans in neoclassical economics, is a rational maximizer of self-interest. However, many social scientists regard such a person as a mere imaginary creature. We found that 31 of 446 residents of relatively wealthy Tokyo suburbs met the behavioral definition of Homo economicus. In several rounds of economic games, participants whose behavior was consistent with this model always apportioned the money endowed by the experimenter to themselves, leaving no share for their partners. These participants had high IQs and a deliberative decision style. An additional 39 participants showed a similar disregard for other people's welfare, although they were slightly more altruistic than those in the Homo economicus group. The psychological composition of these quasi-Homo economicus participants was distinct from that of participants in the Homo economicus group. Although participants in the latter group behaved selfishly on the basis of rational calculations, those in the former group made selfish choices impulsively. The implications of these findings concerning the two types of extreme noncooperators are discussed. PMID- 25037962 TI - Illusory motion of the motion aftereffect induces postural sway. PMID- 25037960 TI - A prospective, randomized, double-blind, multicenter trial to evaluate the therapeutic efficacy and safety of palonosetron in the treatment of postoperative nausea and vomiting over a 72-h period. AB - PURPOSE: We performed a multicenter, randomized, double-blind trial to assess the efficacy and safety of a single, fixed, intravenous dose of palonosetron (0.075 mg) in the treatment of established postoperative nausea and vomiting (PONV). METHODS: Three hundred and eighty-four patients who had at least one risk factors of PONV and underwent surgery under general anesthesia were screened. Those who developed PONV were randomized to receive either 0.075 mg intravenous palonosetron or a placebo. The incidence of nausea and vomiting, severity of nausea, requirements for rescue anti-emetics, and adverse effects at 2, 24, and 72 h after drug administration were evaluated. Complete response (CR) and complete control (CC) rate were compared for 24 and 72 h. RESULTS: Among the 384 patients, 152 (39.6 %) developed PONV and were randomized to either the palonosetron (n = 75) or placebo (n = 77) group. The number of patients with CR at 24 and 72 h was higher in the palonosetron group than the placebo group [0-24 h: n = 49 (68.1 %) vs. n = 30 (40.5 %), p < 0.001; 0-72 h: n = 47 (65.3 %) vs. n = 28 (37.8 %), p < 0.001]. The incidence of PONV at 2, 24, and 72 h periods was lower in the palonosetron group than the placebo group (29.2, 45.8, and 50.0 % in the palonosetron group vs. 50.0, 62.2, and 66.2 % in the placebo group, p = 0.010, 0.048, 0.047, respectively). The incidence of adverse events was not different between the groups. CONCLUSION: A single 0.075 mg IV dose of palonosetron effectively increased the CR rates at 24 and 72 h in these moderate risk patients with established PONV. PMID- 25037963 TI - When knowledge is demotivating: subjective knowledge and choice overload. AB - People find it appealing to have more options to choose from, but the provision of choice often leads to adverse consequences for decision makers' motivation, satisfaction, and willingness to act. We propose that the effect of the number of choice options on willingness to purchase is moderated by people's subjective knowledge (SK). The results of three studies provide converging evidence that, paradoxically, people who feel unknowledgeable (low-SK people) in a certain domain are especially willing to purchase when more choice options are available, which is consistent with the notion of "more is better." This pattern is reversed for people who feel knowledgeable (high-SK people), which is consistent with prior evidence for choice overload. We also show that this pattern is influenced by the informativeness of the features of the available choice options and that subjective knowledge mediates this effect. PMID- 25037964 TI - Assessing regional environmental quality by integrated use of remote sensing, GIS, and spatial multi-criteria evaluation for prioritization of environmental restoration. AB - This study was an attempt to analyse the regional environmental quality with the application of remote sensing, geographical information system, and spatial multiple criteria decision analysis and, to project a quantitative method applicable to identify the status of the regional environment of the study area. Using spatial multi-criteria evaluation (SMCE) approach with expert knowledge in this study, an integrated regional environmental quality index (REQI) was computed and classified into five levels of regional environment quality viz. worse, poor, moderate, good, and very good. During the process, a set of spatial criteria were selected (here, 15 criterions) together with the degree of importance of criteria in sustainability of the regional environment. Integrated remote sensing and GIS technique and models were applied to generate the necessary factors (criterions) maps for the SMCE approach. The ranking, along with expected value method, was used to standardize the factors and on the other hand, an analytical hierarchy process (AHP) was applied for calculating factor weights. The entire process was executed in the integrated land and water information system (ILWIS) software tool that supports SMCE. The analysis showed that the overall regional environmental quality of the area was at moderate level and was partly determined by elevation. Areas under worse and poor quality of environment indicated that the regional environmental status showed decline in these parts of the county. The study also revealed that the human activities, vegetation condition, soil erosion, topography, climate, and soil conditions have serious influence on the regional environment condition of the area. Considering the regional characteristics of environmental quality, priority, and practical needs for environmental restoration, the study area was further regionalized into four priority areas which may serve as base areas of decision making for the recovery, rebuilding, and protection of the environment. PMID- 25037965 TI - Cumulative influences of a small city and former mining activities on the sediment quality of a subtropical estuarine protected area. AB - This study aimed to evaluate the sediment quality in the estuarine protected area known as Cananeia-Iguape-Peruibe (CIP-PA), located on the southeastern coast of Brazil. The study was designed considering possible negative effects induced by the city of Cananeia on the sediment quality of surrounding areas. This evaluation was performed using chemical and ecotoxicological analyses. Sediments were predominantly sandy, with low CaCO3 contents. Amounts of organic matter varied, but higher contents occurred closer to the city, as well as did Fe and Total Recoverable Oils and Greases (TROGs) concentrations. Contamination by Cd and Cu was revealed in some samples, while concentrations of Zn were considered low. Chronic toxicity was detected in all tested sediments and acute toxicity occurred only in sediments collected near the city. The principal component analysis (PCA) revealed an association among Cd, Cu, Fe, TROG, fines, organic matter, CaCO3, and chronic toxicity, whereas acute toxicity was found to be associated with Zn and mud. However, because Zn levels were low, acute toxicity was likely due to a contaminant that was not measured. Results show that there is a broad area within the CIP-PA that is under the influence of mining activities (chronic toxicity, moderate contamination by metals), whereas poorer conditions occur closer to Cananeia (acute toxicity); thus, the urban area seems to constitute a relevant source of contaminants for the estuarine complex. These results show that contamination is already capable of producing risks for the local aquatic biota, which suggests that the CIP-PA effectiveness in protecting estuarine biota may be threatened. PMID- 25037966 TI - Co-occurrence profiles of trace elements in potable water systems: a case study. AB - Potable water samples (N = 74) from 19 zip code locations in a region of Greece were profiled for 13 trace elements composition using inductively coupled plasma mass spectrometry. The primary objective was to monitor the drinking water quality, while the primary focus was to find novel associations in trace elements occurrence that may further shed light on common links in their occurrence and fate in the pipe scales and corrosion products observed in urban drinking water distribution systems. Except for arsenic at two locations and in six samples, rest of the analyzed elements was below maximum contaminant levels, for which regulatory values are available. Further, we attempted to hierarchically cluster trace elements based on their covariances resulting in two groups; one with arsenic, antimony, zinc, cadmium, and copper and the second with the rest of the elements. The grouping trends were partially explained by elements' similar chemical activities in water, underscoring their potential for co-accumulation and co-mobilization phenomena from pipe scales into finished water. Profiling patterns of trace elements in finished water could be indicative of their load on pipe scales and corrosion products, with a corresponding risk of episodic contaminant release. Speculation was made on the role of disinfectants and disinfection byproducts in mobilizing chemically similar trace elements of human health interest from pipe scales to tap water. It is warranted that further studies may eventually prove useful to water regulators from incorporating the acquired knowledge in the drinking water safety plans. PMID- 25037967 TI - The development of stream temperature model in a mountainous river of Taiwan. AB - Formosan landlocked salmon is an endangered species and is very sensitive to stream temperature change. This study attempts to improve a former stream temperature model (STM) which was developed for the salmon's habitat to simulate stream temperature more realistically. Two modules, solar radiation modification (SRM) and surface/subsurface runoff mixing (RM), were incorporated to overcome the limitation of STM designed only for clear-sky conditions. It was found that daily temperature difference is related to cloud cover and can be used to adjust the effects of cloud cover on incident solar radiation to the ground level. The modified model (STM + SRM) improved the simulation during a baseflow period in both winter and summer with the Nash-Sutcliffe efficiency coefficient improved from 0.37 (by STM only) to 0.71 for the winter and from -0.18 to 0.70 for the summer. On the days with surface/subsurface runoff, the incorporation of the two new modules together (STM + SRM + RM) improved the Nash-Sutcliffe efficiency coefficient from 0.00 to 0.65 and from 0.29 to 0.83 in the winter and the summer, respectively. Meanwhile, the contributions of major thermal sources to stream temperature changes were identified. Groundwater is a major controlling factor for regulating seasonal changes of stream temperature while solar radiation is the primary factor controlling daily stream temperature variations. This study advanced our understanding on short-term stream temperature variation, which could be useful for the authorities to restore the salmon's habitat. PMID- 25037968 TI - Effect of low-level laser therapy on inflammatory mediator release during chemotherapy-induced oral mucositis: a randomized preliminary study. AB - Patients undergoing hematopoietic stem cell transplantation (HSCT) are submitted to a conditioning regimen of high-dose chemotherapy, with or without radiation therapy, which usually results in oral ulcerations and mucosal barrier breakdown. Oral mucositis (OM) is a common and debilitating toxicity side effect of autologous and allogeneic HSCT. The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) on the severity of OM and inflammatory mediator (TNF-alpha, IL-6, IL-1beta, IL-10, TGF-beta, metalloproteinases, and growth factors) levels in saliva and blood of HSCT patients. Thirty patients were randomly assigned to two groups: control (n = 15) and laser (n = 15). LLLT was applied from the first day of the conditioning regimen until day 7 post-HSCT (D + 7). Saliva and blood were collected from patients on admission (AD), D-1, D + 3, D + 7, and on marrow engraftment day (ME). Clinical results showed less severe OM in the laser group (p < 0.05). The LLLT group showed increased matrix metalloproteinase 2 (MMP-2) levels in saliva on D + 7 (p = 0.04). Significant differences were also observed for IL-10 on D + 7 and on ME in blood plasma, when compared to the control group (p < 0.05). No significant differences were seen in saliva or blood for the other inflammatory mediators investigated. LLLT was clinically effective in reducing the severity of chemotherapy-induced OM in HSCT patients, and its mechanism of action does not seem to be completely linked to the modulation of pro- or anti-inflammatory cytokines, growth factors or matrix metalloproteinases. PMID- 25037969 TI - Effect of PIPS technique at different power settings on irrigating solution extrusion. AB - The aim of this study was to determine the effect of photon-induced photoacoustic streaming (PIPS) technique at different power settings on extrusion of irrigating solution. Root canal preparation was performed up to a #30 file on 64 extracted single-rooted mandibular premolar teeth, which were then divided into four groups. Each group was irrigated with one of the following irrigation methods: (a) irrigation with conventional irrigation open-ended needles, (b) continuous ultrasonic irrigation, (c) 0.3 W PIPS, or (d) 0.9 W PIPS. Apical extrusion of irrigating solution was evaluated using a modified model. The net weight of the extruded irrigating solution was measured for each group, and the resulting data were analysed statistically using Kruskal-Wallis at a 95 % confidence level (P < 0.05). Although the 0.9 W PIPS group resulted in the largest quantity of irrigation solution, the ultrasonic group was the smallest. However, the difference between these groups was not statistically significant at the 95 % level of confidence (P > 0.05). PIPS at both 0.3 W and 0.9 W resulted similar solution extrusion to the conventional irrigation or ultrasonic irrigation. PMID- 25037970 TI - Applying polygenic risk scores to postpartum depression. AB - The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p = 0.02. The proportion of variance (R (2)) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p = 0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R (2) > 1.1 %, p < 0.008), where the majority of cases met criteria for MDD. The genetic overlap between BPD and MDD was not significant in larger Australian and Dutch MDD case/control cohorts after excluding PPD cases (R (2) = 0.06 %, p = 0.08), despite the larger MDD group affording more power. Our results suggest an empirical genetic evidence for a more important shared genetic etiology between BPD and PPD than between BPD and MDD. PMID- 25037971 TI - FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO multicenter prospective observational cohort. AB - BACKGROUND: First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA). PATIENTS AND METHODS: From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center's multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery. RESULTS: Seventy-seven patients were enrolled. They received a median number of five cycles (1-30). Grade 3-4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2-3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65-86) and 1-year progression-free survival rate was 59 % (95 % CI 46 70). CONCLUSION: First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial. PMID- 25037972 TI - Radiation delivery in patients undergoing therapeutic nipple-sparing mastectomy. AB - BACKGROUND: Although guidelines exist for radiation delivery in the setting of mastectomy or breast-conservation therapy, radiation delivery after nipple sparing mastectomy (NSM) remains variable. Our goal is to determine whether patients who undergo therapeutic NSM are more likely to receive radiation than patients who undergo non-NSM and whether National Comprehensive Cancer Network (NCCN) guidelines for radiation after mastectomy are observed in NSM patients. METHODS: Female patients who underwent NSM or non-NSM for breast cancer from 2006 to 2010 were isolated from the Surveillance, Epidemiology, and End Results database. Univariate analysis stratified by tumor size and lymph node status, and multivariate analyses were used to compare odds of radiation in NSM and mastectomy patients. Adherence to NCCN guidelines based on tumor size and lymph node status was also investigated. RESULTS: A total of 112,817 patients were included: 470 (0.4 %) underwent NSM, and 112,347 (99.6 %) underwent non-NSM. NSM patients with 0 nodes/size <=2 cm, 0 nodes/size 2-5 cm, and unexamined axilla/size <=2 cm had higher odds of radiation when compared with size- and node matched mastectomy patients. Multivariate logistic regression showed that NSM patients had higher odds of radiation (odds ratio 2.01, p < 0.001) than mastectomy patients. Radiation was given to 18 % of NSM patients who did not meet NCCN guidelines according to size or lymph node involvement, compared with 6 % of mastectomy patients. CONCLUSIONS: Patients who undergo therapeutic NSM are more likely to receive radiation compared with mastectomy patients. This may reflect a concern with leaving ductal tissue in the nipple-areolar complex. PMID- 25037973 TI - Radiosynthesis and bioevaluation of [68Ga]-labeled 5,10,15,20-tetra(4 methylpyridyl)-porphyrin for possible application as a PET radiotracer for tumor imaging. AB - PURPOSE: Porphyrins have inherent ability to localize preferentially in tumor lesions. Cationic porphyrins are readily water soluble and reported to exhibit strong DNA-binding capabilities. Therefore, attempt has been made to prepare a water soluble [(68)Ga]-labeled cationic porphyrin, viz., 5,10,15,20-tetra(4 methylpyridyl)porphyrin (TMP), and evaluate its potential as a positron emission tomography (PET) radiotracer for tumor imaging. PROCEDURES: The cationic porphyrin TMP was synthesized following a two-step procedure and subsequently radiolabeled with Ga-68, eluted from a commercial (68)Ge/(68)Ga generator. Purification of the [(68)Ga]-labeled porphyrin derivative was carried out using Sep-Pak((r)) cartridges. The tumor-targeting potential of the [(68)Ga]-labeled 5,10,15,20-tetra(4-methylpyridyl)porphyrin was evaluated by biodistribution studies in Swiss mice bearing fibrosarcoma tumor. RESULTS: Under optimized reaction conditions, [(68)Ga]-labeled TMP was obtained with ~90 % radiochemical purity which was subsequently improved to >99 % after purification through Sep Pak((r)) cartridges. Biodistribution studies revealed high tumor uptake of the radiotracer within 30-min post-injection (6.47 +/- 0.87 % of injected activity) and retention until the final 2 h post-administration (4.48 +/- 1.11 % of injected activity) time point. The initial uptake observed in non-target organs cleared away with time resulting in gradually improving tumor/blood and tumor/muscle ratios. CONCLUSION: Preliminary bioevaluation studies indicated the potential of the radiolabeled porphyrin derivative for tumor imaging, and further detailed studies are warranted to evaluate the true potential of the developed radiotracer. PMID- 25037974 TI - Scarcity of atrial fibrillation in a traditional African population: a community based study. AB - BACKGROUND: In western societies, atrial fibrillation is an increasingly common finding among the elderly. Established risk factors of atrial fibrillation include obesity, diabetes, hypertension, and cardiovascular disease. Atrial fibrillation has almost exclusively been studied in western populations where these risk factors are widely present. Therefore, we studied the epidemiology of atrial fibrillation in a traditional African community. METHODS: In rural Ghana, among 924 individuals aged 50 years and older, we recorded electrocardiograms to detect atrial fibrillation. As established risk factors, we documented waist circumference, body mass index (BMI), capillary glucose level, blood pressure, and electrocardiographic myocardial infarction. In addition, we determined circulating levels of interleukin-6 (IL6), a proinflammatory cytokine, and C reactive protein (CRP), a marker of systemic inflammation. We compared the risk factors with reference data from the USA. RESULTS: Atrial fibrillation was detected in only three cases, equalling 0.3% (95% CI 0.1-1.0%). Waist circumference, BMI, and capillary glucose levels were very low. Hypertension and myocardial infarction were uncommon. Circulating levels of IL6 were similar, but those of CRP were lower compared with the USA. CONCLUSION: Atrial fibrillation is very scarce in this traditional African community. Its low prevalence compared with western societies can be explained by the rareness of its established risk factors, which are closely related to lifestyle, and by possible unmeasured differences in other risk factors or genetic factors. PMID- 25037975 TI - Developing patient-specific dose protocols for a CT scanner and exam using diagnostic reference levels. AB - The management of image quality and radiation dose during pediatric CT scanning is dependent on how well one manages the radiographic techniques as a function of the type of exam, type of CT scanner, and patient size. The CT scanner's display of expected CT dose index volume (CTDIvol) after the projection scan provides the operator with a powerful tool prior to the patient scan to identify and manage appropriate CT techniques, provided the department has established appropriate diagnostic reference levels (DRLs). This paper provides a step-by-step process that allows the development of DRLs as a function of type of exam, of actual patient size and of the individual radiation output of each CT scanner in a department. Abdomen, pelvis, thorax and head scans are addressed. Patient sizes from newborns to large adults are discussed. The method addresses every CT scanner regardless of vendor, model or vintage. We cover adjustments to techniques to manage the impact of iterative reconstruction and provide a method to handle all available voltages other than 120 kV. This level of management of CT techniques is necessary to properly monitor radiation dose and image quality during pediatric CT scans. PMID- 25037978 TI - Diversity of dechlorination pathways and organohalide respiring bacteria in chlorobenzene dechlorinating enrichment cultures originating from river sludge. AB - Anaerobic reductive dechlorination of hexachlorobenzene (HCB) and three isomers of tetrachlorobenzene (TeCB) (1,2,3,4-, 1,2,3,5- and 1,2,4,5-TeCB) was investigated in microcosms containing chloroaromatic contaminated river sediment. All chlorobenzenes were dechlorinated to dichlorobenzene (DCB) or monochlorobenzene. From the sediment, a methanogenic sediment-free culture was obtained which dechlorinated HCB, pentachlorobenzene, three TeCB isomers, three trichlorobenzene (TCB) isomers (1,2,3-, 1,2,4- and 1,3,5-TCB) and 1,2-DCB. Dechlorination involved multiple pathways including the removal of doubly flanked, singly flanked and isolated chlorine substituents. 454-pyrosequencing of partial bacterial 16S rRNA genes amplified from selected chlorobenzene dechlorinating sediment-free enrichment cultures revealed the presence of a variety of bacterial species, including Dehalobacter and Dehalococcoides mccartyi, that were previously documented as organohalide respiring bacteria. A genus with apparent close relationship to Desulfitobacterium that also has been associated with organohalide respiration, composed the major fraction of the operational taxonomic units (OTUs). Another major OTU was linked with Sedimentibacter sp., a genus that was previously identified in strict co-cultures of consortia reductively dehalogenating chlorinated compounds. Our data point towards the existence of multiple interactions within highly chlorinated benzene dechlorinating communities. PMID- 25037977 TI - Disseminating policy and environmental change interventions: insights from obesity prevention and tobacco control. AB - BACKGROUND: Public health and other practitioners increasingly are being asked to implement policy and environmental change interventions, yet many practitioners lack the knowledge, skills, and resources to do so. In response to this need, a growing number of organizations are disseminating evidence-based interventions (EBIs) and building practitioners' capacity to use those interventions in practice. Although advances have been made on approaches to disseminating individual-level EBIs, little is known about the optimal way to disseminate EBIs to promote policy and environmental change. PURPOSE: This paper describes the approach that two projects developed to disseminate policy and environmental change interventions. The Center for Training and Research Translation (Center TRT) disseminates EBIs to promote physical activity and healthy eating. Counter Tobacco disseminates EBIs to counter tobacco product sales and marketing in the retail environment. METHOD: Both Centers (1) identify the best available evidence, (2) disseminate menus of intervention strategies, (3) provide implementation guidance, (4) incorporate stories from the field, (5) build practitioners' capacity, and (6) integrate dissemination into practitioners' existing social networks. The Centers' process evaluations included website analytics and online surveys. RESULT: Over 26,000 unique visitors accessed the Center TRT website in 2012 and over 17,000 have accessed Counter Tobacco's site since its launch in August 2011. The majority of respondents to Centers' surveys agreed that resources were easy to access and use. CONCLUSION: Both Centers have had success reaching their intended audiences. Research is now needed to assess the extent of practitioners' use of Center resources and the impact of the resulting interventions. PMID- 25037979 TI - Accuracy and completeness of the New Zealand Cancer Registry for staging of invasive breast cancer. AB - PURPOSE: Population based cancer registries are an invaluable resource for monitoring incidence and mortality for many types of cancer. Research and healthcare decisions based on cancer registry data rely on the case completeness and accuracy of recorded data. This study was aimed at assessing completeness and accuracy of breast cancer staging data in the New Zealand Cancer Registry (NZCR) against a regional breast cancer register. METHODOLOGY: Data from 2562 women diagnosed with invasive primary breast cancer between 1999 and 2011 included in the Waikato Breast Cancer Register (WBCR) were used to audit data held on the same individuals by the NZCR. WBCR data were treated as the benchmark. RESULTS: Of 2562 cancers, 315(12.3%) were unstaged in the NZCR. For cancers with a known stage in the NZCR, staging accuracy was 94.4%. Lower staging accuracies of 74% and 84% were noted for metastatic and locally invasive (involving skin or chest wall) cancers, respectively, compared with localized (97%) and lymph node positive (94%) cancers. Older age (>80 years), not undergoing therapeutic surgery and higher comorbidity score were significantly (p<0.01) associated with unstaged cancer. The high proportion of unstaged cancer in the NZCR was noted to have led to an underestimation of the true incidence of metastatic breast cancer by 21%. Underestimation of metastatic cancer was greater for Maori (29.5%) than for NZ European (20.6%) women. Overall 5-year survival rate for unstaged cancer (NZCR) was 55.9%, which was worse than the 5-year survival rate for regional (77.3%), but better than metastatic (12.9%) disease. CONCLUSIONS: Unstaged cancer and accuracy of cancer staging in the NZCR are major sources of bias for the NZCR based research. Improving completeness and accuracy of staging data and increasing the rate of TNM cancer stage recording are identified as priorities for strengthening the usefulness of the NZCR. PMID- 25037980 TI - Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene. AB - Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) is a rare mitochondrial disorder that has previously been associated with mutations in PUS1 and YARS2. In the present report, we describe a 6-year old male with an MLASA plus phenotype. This patient had features of MLASA in the setting of developmental delay, sensorineural hearing loss, epilepsy, agenesis of the corpus callosum, failure to thrive, and stroke-like episodes. Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N). Whole exome sequencing did not identify mutations or variants in PUS1 or YARS2 or any known nuclear genes that could affect mitochondrial function and explain this phenotype. Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect. Thus, this mutation in MT-ATP6 may represent the first mtDNA point mutation associated with the MLASA phenotype. PMID- 25037981 TI - Hepatocellular carcinoma associated with sarcoidosis. AB - INTRODUCTION: The association of hepatic sarcoidosis with hepatocellular carcinoma (HCC) is considerably rare. Here we report a rare case of HCC associated with sarcoidosis. PRESENTATION OF CASE: A 75-year-old male with no history of alcohol addiction or viral hepatitis was referred to our hospital because of an abnormal liver mass. Subsegmentectomy of the liver was performed for the diagnosis of HCC. A histopathological examination revealed small non necrotizing granulomas with a tendency to coalesce that were scattered in and around the carcinoma. No features of cirrhosis, steatohepatitis, and any other liver diseases were observed. Furthermore, swelling of the bilateral lung hilar lymph nodes with uptake of 18F-fluorodeoxyglucose was found on positron emission tomography/computed tomography and the tuberculin reaction test results were negative. On the basis of these findings, the final diagnosis of HCC associated with sarcoidosis was confirmed. DISCUSSION: By reviewing previous cases, we found only five cases that described patients diagnosed with HCC associated with sarcoidosis. Of these, four patients died within two years after diagnosis because of ruptures or inoperable huge tumors. In contrast, radical hepatectomy was performed at an earlier stage of disease in two patients, including ours, and both these patients have remained healthy with no recurrences or metastases at the latest follow-up visit. CONCLUSION: Periodic checkups of the liver should be conducted for patients with systemic sarcoidosis, regardless of the presence of liver cirrhosis. PMID- 25037983 TI - Anomalous long-range repulsion between silica surfaces induced by density inhomogeneities in supercritical ethanol. AB - Anomalous long-range repulsion, extending over several micrometres, emerged between silica surfaces around the ridge of density fluctuations in supercritical ethanol at temperatures and pressures near the gas/liquid critical point (T(c) = 241 degrees C, P(c) = 6.14 MPa). Analysis shows that augmentation of ethanol density around silica surfaces in the presence of density fluctuations facilitates dissociation of silanol groups, leading to long-range electrostatic repulsion in the nonpolar medium. PMID- 25037982 TI - Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma. AB - BACKGROUND: Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus mesothelin, singly or in combination. METHODS: Fibulin-3 and soluble mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease. RESULTS: Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9 months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers. CONCLUSIONS: Soluble mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with mesothelin. PMID- 25037984 TI - Methodological quality of systematic reviews addressing femoroacetabular impingement. AB - PURPOSE: As the body of literature on femoroacetabular impingement (FAI) continues to grow, clinicians turn to systematic reviews to remain current with the best available evidence. The quality of systematic reviews in the FAI literature is currently unknown. The goal of this study was to assess the quality of the reporting of systematic reviews addressing FAI over the last 11 years (2003-2014) and to identify the specific methodological shortcomings and strengths. METHODS: A search of the electronic databases, MEDLINE, EMBASE and PubMed, was performed to identify relevant systematic reviews. Methodological quality was assessed by two reviewers using the revised assessment of multiple systematic reviews (R-AMSTAR) scoring tool. An intraclass correlation coefficient (ICC) with 95 % confidence intervals (CI) was used to determine agreement between reviewers on R-AMSTAR quality scores. RESULTS: A total of 22 systematic reviews were assessed for methodological quality. The mean consensus R-AMSTAR score across all studies was 26.7 out of 40.0, indicating fair methodological quality. An ICC of 0.931, 95 % CI 0.843-0.971 indicated excellent agreement between reviewers during the scoring process. CONCLUSIONS: The systematic reviews addressing FAI are generally of fair methodological quality. Use of tools such as the R-AMSTAR score or PRISMA guidelines while designing future systematic reviews can assist in eliminating methodological shortcomings identified in this review. These shortcomings need to be kept in mind by clinicians when applying the current literature to their patient populations and making treatment decisions. Systematic reviews of highest methodological quality should be used by clinicians when possible to answer clinical questions. PMID- 25037985 TI - Intensive supervision of rehabilitation programme improves balance and functionality in the short term after bilateral total knee arthroplasty. AB - PURPOSE: To evaluate the short-term results of the rehabilitation programme with two different supervision on balance and functionality after simultaneously bilateral total knee arthroplasty (SBTKA) in patients with osteoarthritis and to compare the results with those of healthy individuals. METHODS: This study was a single-blind randomized controlled study. Two exercise groups who underwent primary bilateral total knee arthroplasty (Group 1, n = 20 and Group 2, n = 20) and a control group of healthy individuals (Group 3, n = 20) included in the study. Group 1 applied exercise programme with intensive supervision of the physiotherapist for a period of 1 month (2 days/1 week). Group 2 performed exercise programme under the control of same physiotherapist twice monthly (1 day/2 weeks), and the patients were checked every week by telephone interview. Pre-operative and post-operative blind evaluations were made at first and second month. Static balance with single leg stance test, dynamic balance with timed get up & go (TGUG), functionality with walking cadence, stair climbing test (SCT) and Western Ontario McMaster Universities (WOMAC) index were assessed. RESULTS: Group 1 improved statistically significantly better in terms of SLST (p = 0.0 (right), p = 0.0 (left)) and WOMAC function (p = 0.0) at first month, and SLST (p = 0.0), TGUG (p = 0.0), SCT (p = 0.0), WOMAC pain (p = 0.0), stiffness (p = 0.0) and function (p = 0.0) at second month. In Group 1, TGUG, walking cadence, SCT, WOMAC pain, stiffness and function results reached the levels of healthy individuals at second month, and SLST was better for two legs as compared to healthy individuals. In Group 2, cadence results were similar to healthy individuals at second month. CONCLUSIONS: The osteoarthritis patients who had the applied rehabilitation programme after SBTKA with intensive supervision of the physiotherapist for 1 month have obtained more improvements in balance and functional parameters, and it was demonstrated that their performances approached the healthy control group values. As a clinical relevance of our study, intensive supervision of rehabilitation programme should be provided to the patients after SBTKA surgery to accomplish early balance and functional improvements. PMID- 25037986 TI - Peripheral arterial disease in patients with type 2 diabetes. PMID- 25037987 TI - Risk of hospitalization and healthcare cost associated with Diabetes Complication Severity Index in Taiwan's National Health Insurance Research Database. AB - OBJECTIVE: The aim of this study is to test the validity of adapted Diabetes Complication Severity Index (aDCSI) in predicting the risk of hospitalization and healthcare cost in type 2 diabetic patients using a nationally-representative claims database. STUDY DESIGN: Retrospective cohort study used 4years of claims data from Taiwan's National Health Insurance Research Database (NHIRD). METHODS: Type 2 diabetic patients who had 4-years of enrollment were identified as study subjects (N=136,372). The aDCSI score (sum of diabetic complication with severity levels, range 0-13) and complication count (sum of diabetic complications, range 0-7) were generated using diagnostic codes for each patient. Poisson model and linear regression model were conducted to predict risk of hospitalization and healthcare costs associated with aDCSI score and count of diabetic complications. RESULTS: The aDCSI score (risk ratio 1.51 to 10.32 categorically, and 1.41 linearly) and count of diabetic complications (risk ratio 1.56 to 12.20 categorically, and 1.66 linearly) were significantly positively associated with risk of hospitalization. A one-point increase in the aDCSI score was positively associated with increased healthcare costs. CONCLUSIONS: The performance of aDCSI in predicting risk of hospitalization and healthcare cost in the nationally representative claims database is similar to those reported in the original study. It may serve as an efficient tool for stratifying type 2 diabetic patients for disease management programs and population-based studies. PMID- 25037988 TI - Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. AB - BACKGROUND: Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. METHODS: This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6-18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. FINDINGS: Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15-18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1.17 [95% CI 0.68-2.03]; p=0.58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0.5%] patient; HR 0.15 [0.02-1.20]; p=0.073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0.26 [0.07-0.91]; p=0.04). INTERPRETATION: Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. FUNDING: Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM. PMID- 25037989 TI - Pertussis vaccine in pregnancy--first dose for every infant? PMID- 25037990 TI - Effectiveness of maternal pertussis vaccination in England: an observational study. AB - BACKGROUND: In October, 2012, a pertussis vaccination programme for pregnant women was introduced in response to an outbreak across England. We aimed to assess the vaccine effectiveness and the overall effect of the vaccine programme in preventing pertussis in infants. METHODS: We undertook an analysis of laboratory-confirmed cases and hospital admissions for pertussis in infants between Jan 1, 2008, and Sept 30, 2013, using data submitted to Public Health England as part of its enhanced surveillance of pertussis in England, to investigate the effect of the vaccination programme. We calculated vaccine effectiveness by comparing vaccination status for mothers in confirmed cases with estimates of vaccine coverage for the national population of pregnant women, based on data from the Clinical Practice Research Datalink. FINDINGS: The monthly total of confirmed cases peaked in October, 2012 (1565 cases), and subsequently fell across all age groups. For the first 9 months of 2013 compared with the same period in 2012, the greatest proportionate fall in confirmed cases (328 cases in 2012 vs 72 cases in 2013, -78%, 95% CI -72 to -83) and in hospitalisation admissions (440 admissions in 2012 vs 140 admissions in 2013, -68%, -61 to -74) occurred in infants younger than 3 months, although the incidence remained highest in this age group. Infants younger than 3 months were also the only age group in which there were fewer cases in 2013 than in 2011 (118 cases in 2011 vs 72 cases in 2013), before the resurgence. 26?684 women included in the Clinical Practice Research Datalink had a livebirth between Oct 1, 2012 and Sept 3, 2013; the average vaccine coverage before delivery based on this cohort was 64%. Vaccine effectiveness based on 82 confirmed cases in infants born from Oct 1, 2012, and younger than 3 months at onset was 91% (95% CI 84 to 95). Vaccine effectiveness was 90% (95% CI 82 to 95) when the analysis was restricted to cases in children younger than 2 months. INTERPRETATION: Our assessment of the programme of pertussis vaccination in pregnancy in England is consistent with high vaccine effectiveness. This effectiveness probably results from protection of infants by both passive antibodies and reduced maternal exposure, and will provide valuable information to international policy makers. FUNDING: Public Health England. PMID- 25037991 TI - Dual antiplatelet treatment after stenting: is longer better? PMID- 25037992 TI - Post-traumatic growth in adults following a burn. AB - It is well established that a burn can result in negative psychological consequences. Throughout the literature there is also reference to individuals reporting positive changes post-burn. The concept of 'post-traumatic growth' (PTG) refers to such individuals, whose recovery exceeds pre-trauma levels of well-being. To date there has only been one quantitative analysis directly examining PTG post-burn. The present study builds on this, examining the prevalence of PTG and related constructs, including: social support, coping styles, dispositional optimism, functioning, post-traumatic stress symptoms, severity and time since burn. Seventy-four participants recruited through a regional burns unit completed a battery of self-report questionnaires. Burn survivors were found to experience PTG, although to a lesser degree than previous research suggests (GM=1.26, range=0-4.67). Severity of burn, post-burn functioning and trauma symptoms significantly correlated with PTG. Regression analysis proposed a model explaining 51.7% of the variance, with active coping, perceived social support and avoidance coping as significant predictors of PTG. Results support the theory that distress and trauma symptoms act as a catalyst for PTG. Coping styles and social support appear to facilitate this process. Clinical implications are discussed. PMID- 25037993 TI - [Attentional bias and emotional suppression in borderline personality disorder]. AB - OBJECTIVE: Emotion regulation dysfunctions marked by negative affectivity are a core feature of borderline personality disorder (BPD). In addition, patients with BPD show disturbed attentional processes which become particularly apparent in the domain of selective attention when emotional stimuli are presented (negative attentional bias). Assuming that emotion regulation is linked to attentional deployment processes, this study aimed (1) to determine whether a negative attentional bias is established by using film clips of fearful faces and (2) to investigate the association between dysfunctional emotion regulation strategies (emotional suppression) and negative attention bias in BPD. METHODS: We investigated 18 inpatients with BPD and 18 healthy control participants using the modified version of the fearful face-paradigm to assess the inhibition of emotional stimuli. We also administered self-report emotion regulation questionnaires. RESULTS: Compared to the healthy controls, patients with BPD showed significant longer reaction times during the emotional versus the neutral film stimuli in the modified fearful face-paradigm. With regard to the second hypothesis, we failed to find an association between the negative attentional bias and the habitual use of emotional suppression in BPD. CONCLUSIONS: In this study, we could confirm an attentional bias for negative stimuli, using complex, dynamic material. Future studies need to address the impact of confounding variables (e. g. comorbid disorders) on the relationship between maladaptive emotion regulation and selective attentional bias. PMID- 25037994 TI - Quantitative PCR analysis of Mycoplasma suis shedding patterns during experimental infection. AB - The uncultivable hemotrophic bacterium Mycoplasma suis causes infectious anemia in pigs worldwide. The mechanisms by which M. suis is transmitted from pig to pig are largely unknown. Thus, the present study aimed at investigating urine, feces, saliva, nasal and vaginal secrets as well as environmental samples for the presence of M. suis DNA to get insights into potential transmission routes. Seven pigs were experimentally infected with M. suis KI3806. Samples were taken for 8 days post infection (p.i.). A quantitative LightCycler msg1 PCR was used to detect and quantify M. suis. Shedding was found in saliva as well as nasal and vaginal secrets from day 6 p.i. on with a quantity of 3.4 * 10(2) to 2.7 * 10(5)M. suis/swab. In urine M. suis DNA could be detected in 100.0% of the samples from day 6 p.i. on with a quantity of 4.7 * 10(2) to 6.3 * 10(5)M. suis per mL. When shedding patterns were correlated to the median bacterial blood loads shedding was observed at loads of 2.0 * 10(9)-7.0 * 10(10)M. suis per mL blood. No M. suis DNA could be amplified from feces. Dust and water samples of the pig drinking troughs were positive for M. suis on days 2 and 6 post infection, air samples were M. suis-negative throughout the experiment. Our results indicate that blood independent direct transmission as well as indirect transmission via environmental contamination could play a role in the epidemiology of M. suis infections. PMID- 25037995 TI - Adaptation of a natural reassortant H5N2 avian influenza virus in mice. AB - It is reported that the H5N2 highly pathogenic avian influenza virus A/chicken/Hebei/1102/2010 (HB10) is a natural reassortant between circulating H5N1 and endemic H9N2 influenza viruses. To evaluate the potential of its interspecies transmission, the wild-type HB10 was adapted in mice through serial lung passages. Increased virulence was detectable in 5 sequential lung passages in mice and a highly virulent mouse-adapted strain (HB10-MA) with a 50% mouse lethal dose of 10(2.5) 50% egg infectious dose was obtained in 15 passages. The virulence and the replication efficiency of HB10-MA in mice were significantly higher than those of HB10 while HB10-MA grew faster and to significantly higher titers than HB10 in MDCK and A549 cells. Only five amino acid mutations in four viral proteins (HA-S227N, PB2-Q591K, PB2-D701N, PA-I554V and NP-R351K) of HB10-MA virus were found when compared with those of HB10, indicating that they may be responsible for the adaptation of the novel reassortant H5N2 avian influenza virus in mice with increased virulence and replication efficiency. The results in this study provide helpful insights into the pathogenic potential of novel reassortant H5N2 viruses to mammals that deserves further attentions. PMID- 25037996 TI - Identification of wheat non-specific lipid transfer proteins involved in chilling tolerance. AB - KEY MESSAGE: Three TaLTPs were found to enhance chilling tolerance of transgenic Arabidopsis, which were characterized by analyzes of promoter-GUS activity, subcellular localization, chromosomal location and transcriptional profile. Non specific lipid transfer proteins (nsLTP) are abundantly expressed in plants, however, their functions are still unclear. In this study, we primarily characterized the functions of 3 type I TaLTP genes that were localized on chromosomes 3A, 3B, and 5D, respectively. The transcripts of TaLTPIb.1 and TaLTPIb.5 were induced under chilling, wound, and drought conditions, while TaLTPId.1 was only up-regulated by dark treatment. All the 3 TaLTP genes could be stimulated by the in vitro treatment of salicylic acid, while TaLTPId.1 was also positively regulated by methyljasmonic acid. Furthermore, the promoter-reporter assay of TaLTPIb.1 in the transgenic brachypodium showed a typical epidermis specific expression pattern of this gene cluster. When fused with EGFP, all the 3 proteins were shown to localize on the plasma membrane in transgenic tobacco, although a signal in chloroplasts was also observed for TaLTPId.1. Heterogeneous overexpression of each of the TaLTP genes in Arabidopsis resulted in longer root length compared with wild type plants under chilling condition. These results suggest that type I TaLTPs may have a conserved functionality in chilling tolerance by lipid permeation in the plasma membrane of epidermal cells. On the other hand, the type I TaLTPs may exert functional divergence mainly through regulatory subfunctionalization. PMID- 25037997 TI - [Clinical phenotype of a patient with FOXP1 deletion]. PMID- 25037998 TI - DJ-1 plays an important role in caffeic acid-mediated protection of the gastrointestinal mucosa against ketoprofen-induced oxidative damage. AB - Ketoprofen is widely used to alleviate pain and inflammation in clinical medicine; however, this drug may cause oxidative stress and lead to gastrointestinal (GI) ulcers. We previously reported that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in protecting cells against reactive oxygen species, and it facilitates the prevention of ketoprofen induced GI mucosal ulcers. Recent reports suggested that Nrf2 becomes unstable in the absence of DJ-1/PARK7, attenuating the activity of Nrf2-regulated downstream antioxidant enzymes. Thus, increasing Nrf2 translocation by DJ-1 may represent a novel means for GI protection. In vitro, caffeic acid increases the nuclear/cytosolic Nrf2 ratio and the mRNA expression of the downstream antioxidant enzymes, Upsilon-glutamyl cysteine synthetase, glutathione peroxidase, glutathione reductase, and heme oxygenase-1, by activating the JNK/p38 pathway in Int-407 cells. Moreover, knockdown of DJ-1 also reversed caffeic acid-induced nuclear Nrf2 protein expression in a JNK/p38-dependent manner. Our results also indicated that treatment of Sprague-Dawley rats with caffeic acid prior to the administration of ketoprofen inhibited oxidative damage and reversed the inhibitory effects of ketoprofen on the antioxidant system and DJ-1 protein expression in the GI mucosa. Our observations suggest that DJ-1 plays an important role in caffeic acid-mediated protection against ketoprofen induced oxidative damage in the GI mucosa. PMID- 25038000 TI - Concurrent chemoradiotherapy for patients with postoperative recurrence of surgically resected non-small-cell lung cancer. AB - BACKGROUND: A few reports have evaluated the outcomes of concurrent chemoradiotherapy (CRT) for patients with postoperative recurrence of non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of those, 280 patients had experienced postoperative recurrence by the end of 2012. Thirty-five patients received concurrent CRT as initial treatment of the recurrent disease. We retrospectively reviewed these cases, analyzed the outcomes of concurrent CRT after surgical resection, and examined the factors that predict long-term postrecurrence survival. RESULTS: The most common sites of recurrence in this cohort were the lymph nodes in 24 patients, followed by the lung in 5 patients and bone in 6 patients. The median radiation dose given as the initial treatment of recurrence was 60 Gy (range, 30-60 Gy). Chemotherapy included a platinum agent in all cases; cisplatin-based chemotherapy was administered in 23 cases, and a carboplatin-based chemotherapy regimen was administered in 12. The median progression-free and postrecurrence survival after CRT was 13 months (range, 4-127 months) and 31 months (range, 5-127 months), respectively. Seven patients were still alive without evidence of disease for > 3 years after the recurrence diagnosis. The ECOG performance status (PS), surgical procedure, and types of platinum agents used were independent prognostic factors for postrecurrence survival. CONCLUSION: Concurrent CRT for recurrent NSCLC is a promising therapy for selected patients. A poor PS and postpneumonectomy state were poor prognostic factors for patients who received concurrent CRT. PMID- 25038001 TI - Dignity as an empirical lifeworld construction-in the field of surgery in Denmark. AB - Patient dignity is a complex yet central phenomenon. Disrespect for dignity can mean retention of sick role, loss of self-care and control, decreased participation and therefore influence healing. At the same time, nurses have an obligation to respect dignity, and patients expect it. In clinical practice, with the focus on efficiency and economy, dignity can be compromised. The surgical patient may be particularly vulnerable to loss of dignity, when focus is solely on surgical procedure, efficiency, and productivity. The aim of the article is to describe the characteristics of the importance of dignity perceived by four surgical patients at a university hospital in Denmark. The hermeneutic phenomenological approach of Van Manen is used to analyse and interpret data collected from in-depth semi-structured interviews. The interviews explored the lived experience with two women and two men who had undergone a surgical intervention in a Danish vascular surgery department. The thematic analysis led to the basic theme: "To be an important person" illustrated by the themes: "Being a co-player," "Over exposure," and "To swallow the bitter pill." The findings provide a better understanding of patient's perspective of dignity, which is characterized by a complex interaction of several factors. Nurses should be concerned with balancing expectations, values, and opinions to maintain dignity in nursing and create a common platform for collaboration. This collaboration makes it possible for patients to be involved and have a voice in relation to nursing, treatment, and administering of time even though it could be at the expense of the terms of the system. PMID- 25038002 TI - EUS-guided hepaticojejunostomy combined with antegrade stent placement. PMID- 25038003 TI - Hemorrhagic pancreatic necrosis drainage by using an esophageal stent. PMID- 25038004 TI - Intramucosal injection: part of the spectrum of outcomes from submucosal injection during endoscopic resection. PMID- 25038005 TI - Anticoagulation for noncardiac indications in neurologic patients: comparative use of non-vitamin k oral anticoagulants, low-molecular-weight heparins, and warfarin. AB - OPINION STATEMENT: Patients with neurologic disorders may develop a wide variety of thromboembolic events, both as a primary manifestation and as a consequence of their underlying neurologic condition. There are many available options for anticoagulation, ranging from warfarin to the parenteral subcutaneously administered anticoagulants to the non-vitamin K oral anticoagulants (NOACs). Warfarin is orally available, well-studied, and easily reversible in the setting of bleeding, but has a prolonged onset of action, measured in days, and equally slow offset; requires frequent monitoring for dose titration; and has multiple drug-drug and food-drug interactions. Parenteral heparin-based anticoagulants are well-studied and have more predictable pharmacokinetics but are often more expensive, only partially reversible, and require daily injections, which can be difficult for patients to tolerate over long periods of time. The NOACs are easy to administer and have predictable pharmacokinetics but are expensive, not easily reversible, and are not as extensively studied. Specific agents are preferable in some defined neurologic conditions. For acute ischemic stroke, we do not recommend immediate anticoagulation with any agent. For patients with intracranial malignancy (either primary or metastatic), we recommend a low molecular-weight heparin (LMWH) rather than warfarin or a NOAC. For thromboembolic disease in the setting of spinal cord injury, warfarin, LMWH, or the NOACs are reasonable options. In the setting of VTE or stroke related to antiphospholipid antibody syndrome (APS), we recommend long-term warfarin anticoagulation with an INR goal of 2-3, pending the results of ongoing research involving the NOACs. For cerebral venous sinus thrombosis not related to malignancy or APS, we recommend the use of LMWH in the acute setting, followed by at least three months of warfarin. In this article, we discuss the pharmacology, pathophysiology, and comparative research that served as a basis for our recommendations. PMID- 25038006 TI - Implementing a standardized perioperative antibiotic prophylaxis protocol for neonates undergoing cardiac surgery. AB - BACKGROUND: A lack of perioperative antibiotic prophylaxis guidelines for neonates undergoing cardiac surgery has resulted in a wide variation in practice. We sought to do the following: (1) Determine the safety of a perioperative antibiotic prophylaxis protocol for neonatal cardiac surgery as measured by surgical site infections (SSIs) rates before and after implementation of the protocol; and (2) evaluate compliance with selected process measures for perioperative antibiotic prophylaxis. METHODS: This quasi-experimental study included all cardiac procedures performed on neonates from July 2009 to June 2012 at a single center. An interdisciplinary task force developed a standardized perioperative antibiotic prophylaxis protocol in the fourth quarter of 2010. The SSI rates were compared in the preintervention (July 2009 to December 2010) versus the postintervention periods (January 2011 to June 2012). Compliance with process measures (appropriate drug, dose, timing, and discontinuation of perioperative antibiotic prophylaxis) was compared in the 2 periods. RESULTS: During the study period, 283 cardiac procedures were performed. The SSI rates were similar in the preintervention and postintervention periods (6.21 vs 5.80 per 100 procedures, respectively). Compliance with the 4 process measures significantly improved postintervention. CONCLUSIONS: Restricting the duration of perioperative antibiotic prophylaxis after neonatal cardiac surgery to 48 hours in neonates with a closed sternum and to 24 hours after sternal closure was safe and did not increase the rate of SSIs. Compliance with selected process measures improved in the postintervention period. Additional multicenter studies are needed to develop national guidelines for perioperative prophylaxis for this population. PMID- 25038007 TI - Ex vivo lung perfusion allows successful transplantation of donor lungs from hanging victims. AB - BACKGROUND: Donor lungs acquired from victims of asphyxiation by hanging are not routinely used for lung transplantation because of the associated lung injury. Ex vivo lung perfusion (EVLP) is a technique to evaluate marginal donor lungs before transplantation. We report here our experience with the use of EVLP in donor lungs procured from victims of asphyxia by hanging. METHODS: Lungs from 5 donors who became brain dead secondary to hanging were evaluated by EVLP. Donor organs were perfused according to trial protocol. Donor lungs were accepted for transplantation if they maintained a PaO2 greater than or equal to 350 mm Hg, had a clear roentgenogram, and had no significant worsening of physiologic metrics. RESULTS: Perfused organs included single and double lung blocs, and all were perfused without technical incident. Three of the 5 donor organs evaluated met criteria for transplantation after 3 hours of EVLP and were transplanted. Donor organs rejected for transplantation showed either signs of worsening PaO2 or deterioration of physiologic metrics. There were no intraoperative complications in the patients who underwent transplantation, and all were alive at 30 days. CONCLUSIONS: We report here the successful use of EVLP to assess donor lungs acquired from victims of asphyxiation by hanging. The use of EVLP in this particular group of donors has the potential to expand the available donor pool. We demonstrate that EVLP is a viable option for evaluating the function of lung allografts before transplantation and would recommend that all donor lungs obtained from hanging victims undergo EVLP to assess their suitability for transplantation. PMID- 25038008 TI - Signet ring cells in esophageal adenocarcinoma predict poor response to preoperative chemoradiation. AB - BACKGROUND: The purpose of this study was to examine the significance of signet ring cell histology to predict response to preoperative chemoradiotherapy in patients with esophageal adenocarcinoma. METHODS: Two groups of patients with locoregional esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery were studied: those with signet ring cell adenocarcinoma (n = 85) and a reference group (n = 638) with usual and other types of adenocarcinoma. Surgical specimens were reviewed for degree of pathologic response and pathologic stage. Cox regression models were used to assess the effects of clinicopathologic variables on survival. RESULTS: Tumors from patients in the signet ring cell group had a lower rate of complete pathologic response (9% versus 26%, p < 0.001) and more frequent positive margins (24% versus 10%, p < 0.001) compared with tumors from the reference group. Median overall survival (22 versus 48 months, p = 0.003) and disease-free survival (16 versus 35 months, p = 0.007) were shorter in the signet ring cell group than in the reference group. Signet ring cell histology and high pathologic stage were significant predictors of decreased overall survival and disease-free survival. Survival durations for patients whose resected specimens showed downstaging after neoadjuvant chemoradiation did not significantly differ from survival durations of patients whose specimens did not show downstaging in the signet ring cell group, unlike the reference group. CONCLUSIONS: Signet ring cell histology on pretreatment biopsy predicts a decreased likelihood of complete pathologic response and survival for patients with esophageal adenocarcinoma treated with preoperative chemoradiation and surgery. PMID- 25038009 TI - Congenital heart operations performed in the first year of life: does geographic variation exist? AB - BACKGROUND: Geographic variations associated with surgical intervention for congenital heart disease are ill defined. This study uses a large clinical registry to assess frequency of surgical intervention for various infant congenital heart diseases overall and across US geographic regions. METHODS: Patients younger than 1 year of age in the Society of Thoracic Surgeons Congenital Heart Surgery Database (January 2010 through June 2012) were included. Index operations were classified on the basis of seven major diagnostic groups and 10 specific diagnoses and were compared across geographic regions using a chi(2) test. Region was defined by patient residence. RESULTS: The study included 23,379 patients (94 centers). Septal defects (26.2%) were the most frequently reported diagnostic group, and tetralogy of Fallot (10.6%) was the most frequent specific diagnosis. Significant geographic variation was noted for all seven major diagnostic groups. The proportion of patients undergoing surgery for septal defects varied from 23.9% to 30.2% (p = 0.001); pulmonary venous anomalies, 2.8% to 4.5% (p = 0.03); right heart lesions, 15.7% to 21.4% (p < 0.0001); left heart lesions, 22.7% to 30.4% (p = 0.0002); single-ventricle lesions, 7.3% to 11.4% (p < 0.0001); transposition of the great arteries and double-outlet right ventricle, 9.0% to 15.3% (p < 0.0001); and coronary artery anomalies, 0.4% to 1.4% (p = 0.04). Significant regional variation was also observed for 7 of the 10 specific diagnoses examined. CONCLUSIONS: These data demonstrate significant variation in congenital heart disease diagnostic groups requiring surgery before 1 year of age across US geographic regions. PMID- 25038010 TI - Surgical unroofing of anomalous aortic origin of a coronary artery: a single center experience. AB - BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) has been associated with myocardial ischemia and sudden death. The optimal management of patients with AAOCA is controversial. We examined our experience with surgical unroofing of AAOCA to determine the midterm effect of surgical repair. METHODS: From October 1992 through December 2011, 75 patients with AAOCA underwent surgical unroofing. RESULTS: Mean age was 39.6 +/- 19.6 years; 23 patients (32%) were aged younger than 30 years. Angina, shortness of breath, or syncope was present in 55 patients (72%); 2 (3%) had history of sudden cardiac arrest. Of 40 patients (53%) who had preoperative stress tests, results were abnormal in 20 (50%). Coronary or computed tomography angiography demonstrated an anomalous right coronary artery (RCA) arising from the left sinus in 69 patients (92%) and the left main coronary artery arising from the right sinus in 6 (8%). Two patents (3%) were referred for recurrent anginal symptoms after previous RCA bypass with the right internal mammary artery. Minimally invasive partial upper sternal split was performed in 17 patients (22%). Two patients (3%) needed right internal mammary artery-to-RCA grafting due to flow acceleration at the RCA ostium. There were no early deaths. One late death (1%) occurred related to noncardiac causes. At follow-up (mean, 18 months; maximum, 7 years), all patients remained free of cardiac symptoms. CONCLUSIONS: Surgical unroofing of AAOCA is associated with low morbidity and mortality. At intermediate follow-up, resolution of symptoms and freedom from sudden death can be expected. The threshold for offering intervention should be low. PMID- 25038011 TI - Engineering patient-specific valves using stem cells generated from skin biopsy specimens. AB - BACKGROUND: Pediatric patients requiring valve replacement will likely require reoperations due to a progressive deterioration of valve durability and limited repair and growth potential. To address these concerns, we sought to generate a biologically active pulmonary valve using patient-specific valvular cells and decellularized human pulmonary valves. METHODS: We generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblast cells. We then differentiated iPSCs to mesenchymal stem cells (iPCSs-MSCs) using culture conditions that favored an epithelial-to-mesenchymal transition. Next, decellularized human pulmonary heart valves were seeded with iPCS-MSCs using a combination of static and dynamic culture conditions and cultured up to 30 days. RESULTS: The iPSCs MSCs displayed cluster of differentiation CD105 and CD90 expression exceeding 90% after four passages and could differentiate into osteocytes, chondrocytes, and adipocytes (n = 4). Consistent with an MSC phenotype, iPSCs-MSCs lacked expression of CD45 and CD34. Compared with bone marrow MSCs, iPSCs-MSC proliferated more readily by twofold but maintained a gene expression profile exceeding 80% identical to bone marrow MSCs. In repopulated pulmonary valves compared with decellularized pulmonary valves, immunohistochemistry demonstrated increased cellularity, alpha-smooth muscle actin expression, and increased presence of extracellular matrix components, such as proteoglycans and glycosaminoglycans, suggesting sustained cell function and maturation. CONCLUSIONS: Our results demonstrate the feasibility of constructing a biologically active human pulmonary valve using a sustainable and proliferative cell source. The bioactive pulmonary valve is expected to have advantages over existing valvular replacements, which will require further validation. PMID- 25038012 TI - Antimicrobial peptides are highly abundant and active in postoperative pleural drainage fluids. AB - BACKGROUND: The human lung is considered a nonsterile organ, and surgical interventions therefore take place in a more or less contaminated operating field. Nevertheless, infectious complications of the pleural cavity are low after major lung resections. Antimicrobial peptides (AMPs) are part of the innate immunity and display a broad capacity to kill pathogens. We hypothesized that the pleural space must have a high natural antimicrobial barrier and that AMPs might effectively protect the pleural cavity. METHODS: Pleural effusions were collected after lung operations. Antimicrobial activity of the fluids against gram-positive and gram-negative pathogens was analyzed by microdilution assays. AMPs were determined by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and immunohistochemical analysis. The impact of proinflammatory triggers on AMP release from pleural mesothelial cells was evaluated. RESULTS: Antimicrobial activity assays revealed high bactericidal properties of postoperative pleural drainage fluids. They effectively killed gram-negative pathogens (Escherichia coli, Pseudomonas aeruginosa) as well as gram-positive pathogens (Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes). A variety of AMPs was detected at constantly high concentrations in the pleural fluids. They mainly derived from leukocytes and pleural epithelium. Although proinflammatory cytokine levels were elevated in the postoperative pleural fluids, AMP expression could not be augmented by Toll-like receptor (TLR) triggering or by the proinflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)alpha. CONCLUSIONS: We provide the first evidence of a high abundance of AMPs in postoperative pleural fluids. Our findings might explain the broad protection against infectious complications of the pleural space after major lung operations. PMID- 25038013 TI - Is sleeve lobectomy comparable in terms of short- and long-term results with pneumonectomy after induction therapy? A multicenter analysis. AB - BACKGROUND: Sleeve lobectomy (SL) is considered a valid therapeutic option in untreated, centrally located non-small cell lung cancer (NSCLC) even in patients "fit" for pneumonectomy (PN). Nevertheless, SL feasibility and long-term results after induction therapy (IT) have been only rarely investigated. We herein report the results of a multicenter retrospective study on NSCLC patients who underwent PN or SL after IT for locally advanced NSCLC. METHODS: From January 1992 to January 2012, 119 consecutive patients (94 males, 25 females) underwent in three tertiary referral centers either SL (bronchial, arterial, or both) or PN for locally advanced NSCLC after IT (chemotherapy alone or combined chemoradiotherapy). The indication for SL was based on technical feasibility. Clinical and pathologic variables were retrospectively reviewed, and treatment results were assessed and compared in both groups. Survival was calculated by Kaplan-Meier method and compared by the log-rank test as well the Cox regression model. RESULTS: Sleeve lobectomy was performed in 51 patients and PN, in 68 patients. Thirty-day mortality and morbidity rates were 3.9% and 9.8% for SL and 2.9% and 22.1% for PN, respectively. Five-year survival rates were 53.8% after SL and 43.1% after PN, respectively (p = 0.28). Overall recurrence rate was 42.8% after SL and 47.0% after PN (p = 0.34); relapse was locoregional in 22.4% of SL cases and 12.1% after PN, respectively (p = 0.011). The Cox analysis suggested pN status and right side as independent risk factors for death in the SL group (hazard ratio, 1.96; 95% confidence interval, 1.12 to 3.44; p = 0.018; and hazard ratio, 2.96; 95% confidence interval, 1.13 to 8.66; p = 0.047, respectively). As well, pN status and right side were a strong predictor of relapse (hazard ratio, 2.33; 95% confidence interval, 1.17 to 4.64; p = 0.016; and hazard ratio, 2.96; 95% confidence interval, 1.13 to 8.66; p = 0.046, respectively) in SL patients. CONCLUSIONS: For locally advanced NSCLC, SL represents a safe and effective surgical option when compared with PN even after IT, with substantially comparable early and long-term results. Nevertheless, further investigations on a large cohort of patients are needed. PMID- 25038014 TI - Preoperative assessment of chest wall invasion in non-small cell lung cancer using surgeon-performed ultrasound. AB - BACKGROUND: Chest wall invasion in operable lung cancer upgrades the stage and can affect operative planning. Diagnosing chest wall invasion preoperatively is important in patient consent, in the choice of operative incision placement, and can be helpful in choosing an operative approach (open vs thoracoscopic). The objectives of this study were to determine the diagnostic accuracy of preoperative, surgeon-performed ultrasound (US) in assessing tumoral chest wall invasion (T3) in non-small cell lung cancer (NSCLC) patients and to compare its accuracy vs preoperative computed tomography (CT). METHODS: This study was a prospective clinical trial (ClinicalTrials.gov: NCT01206894) that prospectively enrolled patients between September 2010 and January 2013. Eligible patients included those with NSCLC abutting the parietal pleura or invading the chest wall on preoperative CT scan of the chest and who were planned for surgical resection. Criteria for chest wall invasion on US included (1) disruption of the parietal pleura, (2) invasion of the ribs, or (3) impairment of pleural movement with respiration. The US chest wall examination was performed by the thoracic surgical team immediately before the surgical intervention. Sensitivity and specificity for CT scan and US in assessing chest wall invasion were calculated using definitive chest wall invasion on final pathologic analysis as the gold standard for chest wall invasion. RESULTS: During a 28-month period, 28 patients (15 men and 13 women) patients were prospectively enrolled. Mean age was 62 +/- 11 years, and mean body mass index was 25.3 +/- 4.5 kg/m(2). The average time for surgeon performed US assessment looking for chest wall invasion was 5.3 +/- 5 minutes. The sensitivity of US in evaluating chest wall invasion was 90.9% and the specificity was 85.7%. CT scan was associated with a sensitivity of 61.5% and a specificity of 84.6%. The positive and negative predictive values of surgeon performed US for tumoral chest wall invasion were 83.3% and 92.3%, respectively, compared with 80% and 68.8% for CT scan. CONCLUSIONS: Surgeon-performed preoperative chest wall US can reliably diagnose tumoral chest wall invasion in patients with NSCLC. CT scan has poor sensitivity in predicting chest wall invasion preoperatively. Surgeon-performed US can be considered as a complementary adjunct to preoperative imaging in patients with pulmonary lesions abutting the chest wall to improve preoperative diagnosis, staging, and operative planning. PMID- 25038015 TI - Thoracoscopic esophagectomy in prone versus decubitus position: ergonomic evaluation from a randomized and controlled study. AB - BACKGROUND: The prone position (PP) and decubitus position (DP) have both been used for thoracoscopic esophagectomy. However, which of these positions is ergonomically better for the operating surgeon is unknown. In this randomized controlled trial (NCT01144325), we aimed to assess the surgeon's physical and mental stress in operating on patients in the PP compared with that in the DP. METHODS: From October 2012 to June 2013, 67 consecutive patients who underwent a three-stage minimally invasive esophagectomy were randomly assigned to the DP or the PP during the thoracic stage. The same senior surgeon performed all operations. Objectively, the surgeon's spontaneous eye blink rate was recorded during thoracoscopic esophagectomy. Subjectively, the physician's musculoskeletal symptoms were rated on a scale ranging from 1 (uninfluenced) to 10 (maximum fatigue). Clinical characteristics, including patient demographics and operative features of the two patient groups, were statistically compared. RESULTS: There were 35 patients in the PP group and 32 in the DP group. The two groups were comparable in patient demographics. The thoracic stage of the operation was longer in the DP group than in the PP group (87 +/- 24 minutes vs 68 +/- 22 minutes, p < 0.001), and the volume of blood loss was higher (89 +/- 18 mL vs 67 +/- 16 mL, p < 0.001). The surgeon's eye blink rate at the end of thoracic stage decreased more from baseline in the DP group than in the PP group (3.0 +/- 1.4 blinks/min vs 1.2 +/- 0.9 blinks/min, p < 0.001), and the surgeon's symptom scale score was higher after operation with the patient in the DP than in the PP (6.29 +/- 1.54 vs 3.13 +/- 2.82, p < 0.001). No conversion to open thoracotomy was recorded in either group. CONCLUSIONS: Thoracoscopic esophagectomy in the PP provided less workload and better ergonomic results than the DP. Further study based on a larger number of patients is required to confirm these findings. PMID- 25038016 TI - Pulmonary artery reconstruction with pulmonary vein conduit for lung cancer: medium-term results. AB - BACKGROUND: The use of an autologous pulmonary vein (PV) conduit for reconstruction of the pulmonary artery (PA) in lung-sparing resections was first described in 2009, but to date only two case reports appeared and no medium-term and long-term results have been reported, to our knowledge. We present the first case series with medium-term follow-up. METHODS: Between December 2009 and December 2012, 9 patients undergoing PA sleeve resection for centrally located lung cancer received reconstruction by this technique. Three of these patients underwent induction chemotherapy. The venous graft was obtained from the proximal extraparenchymal portion of the superior PV and was sutured to the proximal and distal PA stumps with the standard anastomotic technique. RESULTS: All 9 patients underwent left upper lobectomy with sleeve resection of the PA without associated bronchoplasty. The postoperative morbidity rate was 33% (1 chylothorax, 1 atrial fibrillation, and 1 parenchymal atelectasis). No adverse events related to the reconstructive procedure occurred. There was no postoperative mortality. Complete patency of the reconstructed PA was shown in all patients by postoperative contrast computed tomography every 6 months. All patients are alive at a mean follow-up time of 32 +/- 12.4 months (range, 6 to 42 months). Tumor recurrence has been observed in 2 patients (1 local, 1 systemic). The median survival time is 38 months. The median disease-free survival time is 33 months. CONCLUSIONS: Reconstruction of the PA by a PV graft is a feasible and effective option for parenchymal-sparing resections. The PV conduit shows tissue characteristics similar to those of the arterial wall. This technique is safe and is supported by good medium-term results. PMID- 25038017 TI - Anterior mediastinal tracheostomy as salvage operation. AB - BACKGROUND: This study aimed to assess early and long-term results after anterior mediastinal tracheostomy (AMT) as a salvage operation for recurrent neck malignancies. METHODS: Between October 2006 and February 2013, 12 patients (mean age, 57 years) underwent AMT. All patients had experienced stomal recurrence, with or without esophageal involvement, after laryngectomy. All patients had undergone previous radiotherapy (50.3 +/- 6.2 [43-60] Gy) and previous surgical treatment: total laryngectomy (n = 11) and thyroidectomy (n = 2). RESULTS: The mean length of resected trachea was 3.7 +/- 2.7 (2.5-6) cm. Resection was complete in 10 patients. All patients required relocation of the remaining trachea below the innominate artery and myocutaneous flap for coverage/stoma construction. AMT was associated with esophagectomy (n = 4) and supraaortic trunk resection (innominate artery, n = 2; carotid artery, n = 3). Seven patients required resection of the pharyngoesophageal region, and 4 patients underwent reconstruction, including primary closure of a pharyngeal remnant (n = 1) and gastric pull-up (n = 3). There was 1 operative death (8.3%) resulting from an infectious process leading to bypass fistulization. Major complications were partial tracheal necrosis (n = 3), pharyngeal fistula (n = 1), pneumonia (n = 4), and flap dehiscence (n = 2). Length of hospital stay was 30 +/- 22.8 (13-86) days. Actuarial overall 5-year survival was 58.3%, and median estimated disease free survival was 53 (31-75) months. CONCLUSIONS: Our experience with AMT as salvage therapy has shown acceptable long-term results if complete resection is achieved. This procedure is not risk free, and very careful patient selection is required because of a tortuous postoperative course, especially in combined pharyngeal-esophageal and vascular reconstruction. PMID- 25038018 TI - Impact of preoperative location on outcomes in congenital heart surgery. AB - BACKGROUND: Little is known about the impact of preoperative location on outcomes in infants undergoing cardiac surgery for congenital heart disease. This study was designed to evaluate the morbidity and mortality among infants who were cared for in a neonatal ICU (NICU) versus dedicated cardiovascular intensive care unit (CVICU) prior to cardiac surgery in a multi-institutional population. METHODS: Data were obtained from a multicenter, administrative, national dataset, Pediatric Health Information System (PHIS). Patients 0 to 45 days undergoing surgery for congenital heart disease (with or without cardiopulmonary bypass) at a PHIS-participating hospital (2004 to 2013) were included. Propensity score matching was performed to match the NICU and the CVICU patients with similar demographic and preoperative clinical characteristics. RESULTS: A total of 5,376 patients from 20 hospitals met inclusion criteria. By propensity score matching, 2,456 patients matched 1 to 1 between the NICU and the CVICU groups. Outcomes including mortality (NICU vs CVICU, 11.9% vs 8.8%, p < 0.001), preoperative and total hospital length of stay (LOS), and total length of mechanical ventilation were significantly greater among the NICU patients compared with the CVICU patients. There was no significant difference in mortality among the patients undergoing "low" complexity operations (NICU vs CVICU, 8.4% vs 6.7%, p = 0.22), and patients undergoing treatment at high volume hospitals (NICU vs CVICU, 9.6% vs 9.5%, p = 0.95). CONCLUSIONS: This study demonstrates that preoperative location might impact outcomes in children undergoing operation for congenital heart disease. It is possible that preoperative location may be surrogate for other factors that may bias the results. Further study is warranted. PMID- 25038019 TI - Pulmonary annulus growth after the modified Blalock-Taussig shunt in tetralogy of Fallot. AB - BACKGROUND: In tetralogy of Fallot (TOF), it is well known that postoperative pulmonary regurgitation reduces right ventricular function during long-term follow-up. Complete repair without a transannular patch should help avoid pulmonary regurgitation. Recently, primary complete repair has been preferred to the staged repair with use of a Blalock-Taussig shunt (BTS) even in neonates or small infants; however, little has been reported about the influence of a BTS on pulmonary annular growth. METHODS: We examined 40 patients with TOF or double outlet right ventricle with pulmonary stenosis. Twenty-one patients received a BTS before complete repair, whereas 19 patients underwent primary complete repair. Pulmonary annular size was measured by echocardiography before BTS, complete repair, or both, and ventricular volume was measured by cardiac catheterization. RESULTS: There were no significant differences in complete repair age or body size between the groups. Pulmonary annulus sizes in the BTS group were smaller than those in the primary repair group (Z score, -5.1 +/- 2.5 vs -3.7 +/- 1.8). After the BTS, significant annular growth (Z score, -2.8 +/- 2.1) was observed (p = 0.0028), with a significant increase in left ventricular end-diastolic volume (p = 0.015). When patients with severe pulmonary stenosis (Z score > -7.0) were excluded, pulmonary annular preservation at complete repair was achieved in 64.7% (11/17) of the BTS group and 36.8% (7/19) of the primary repair group (p = 0.088). CONCLUSIONS: The BTS increased the pulmonary annular size and the left ventricular volume during the 6 months before complete repair, resulting in preservation of the pulmonary valve function. PMID- 25038020 TI - Endobronchial ultrasonography versus mediastinoscopy: a single-institution cost analysis and waste comparison. AB - BACKGROUND: Mediastinoscopy (MED) and endobronchial ultrasonography with transbronchial needle aspiration (EBUS-TBNA) have similar accuracy for mediastinal lymph node sampling (MLNS). The threatened financial and environmental sustainability of our health care system mandate that surgeons consider cost and environmental impact in clinical decision making of similarly effective procedures. We performed a cost and waste comparison of MED versus EBUS TBNA for MLNS to raise awareness of the financial and environmental implications of our practices. METHODS: We conducted a retrospective review of outpatients who underwent MLNS under general anesthesia in the OR with MED or EBUS-TBNA (September 2007 to December 2009). We analyzed direct costs based on hospital charges, calculated expected payment using a decision support model, and profit margins (modeled expected payment-direct costs). Our waste comparison was measured in kilograms of solid waste per case. RESULTS: We performed MLNS in 148 patients (89 EBUS-TBNA, 39 MED, 20 EBUS + MED). Direct costs were lower for MED ($2,356) compared with EBUS-TBNA ($2,503), whereas expected payment was greater (MED, $3,449; EBUS-TBNA, $3,249), resulting in a profit margin that was $347 greater for MED. The amount of solid waste for each MED was 1.8 kg versus 0.5 kg for EBUS-TBNA. CONCLUSIONS: MED costs less than EBUS-TBNA in the OR setting but generates 3.6 times the amount of EBUS-TBNA waste. The cost of EBUS-TBNA may improve by performance in the endoscopy suite, and surgical pack revision could reduce the amount of MED solid waste. This comparison sets the stage for sophistication of our clinical decision making, taking into consideration the major threats to our health care system. PMID- 25038021 TI - Second primary lung cancers: smokers versus nonsmokers after resection of stage I lung adenocarcinoma. AB - BACKGROUND: Smokers have a higher risk of developing non-small cell lung cancer (NSCLC) than never-smokers, but the relative risk of developing second primary lung cancer (SPLC) is unclear. Determining the risk of SPLC in smokers versus never-smokers after treatment of an initial cancer may help guide recommendations for long-term surveillance. METHODS: Patients who underwent resection for stage I adenocarcinoma were identified from a prospectively maintained institutional database. Patients with other histologies, synchronous lesions, or who received neoadjuvant or adjuvant therapy were excluded. The SPLCs were identified based on Martini criteria. RESULTS: From 1995 to 2012, a total of 2,151 patients underwent resection for stage I adenocarcinoma (308 never-smokers [14%] and 1,843 ever smokers [86%]). SPLC developed in 30 never-smokers (9.9%) and 145 ever-smokers (7.8%). The SPLC was detected by surveillance computed tomography scan in the majority of patients (161; 92%). In total, 87% of never-smokers and 83% of ever smokers had stage I SPLC. There was no significant difference in the cumulative incidence of SPLC between never-smokers and ever-smokers (p = 0.18) in a competing-risks analysis. The cumulative incidence at 10 years was 20.3% for never-smokers and 18.2% for ever-smokers. CONCLUSIONS: Although smokers have a greater risk of NSCLC, the risk of a second primary cancer developing after resection of stage I lung cancer is comparable between smokers and never-smokers. The majority of these second primary cancers are detectable at a curable stage. Ongoing postoperative surveillance should be recommended for all patients regardless of smoking status. PMID- 25038023 TI - Evolutionary rescue in a changing world. AB - Evolutionary rescue occurs when adaptive evolutionary change restores positive growth to declining populations and prevents extinction. Here we outline the diagnostic features of evolutionary rescue and distinguish this phenomenon from demographic and genetic rescue. We then synthesize the rapidly accumulating theoretical and experimental studies of evolutionary rescue, highlighting the demographic, genetic, and extrinsic factors that affect the probability of rescue. By doing so, we clarify the factors to target through management and conservation. Additionally, we identify several putative cases of evolutionary rescue in nature, but conclude that compelling evidence remains elusive. We conclude with a horizon scan of where the field might develop, highlighting areas of potential application, and suggest areas where experimental evaluation will help to evaluate theoretical predictions. PMID- 25038028 TI - Relating color working memory and color perception. AB - Color is the most frequently studied feature in visual working memory (VWM). Oddly, much of this work de-emphasizes perception, instead making simplifying assumptions about the inputs served to memory. We question these assumptions in light of perception research, and we identify important points of contact between perception and working memory in the case of color. Better characterization of its perceptual inputs will be crucial for elucidating the structure and function of VWM. PMID- 25038029 TI - Direct Leishmania species typing in Old World clinical samples: evaluation of 3 sensitive methods based on the heat-shock protein 70 gene. AB - In the diagnosis of leishmaniasis, identification of the causative Leishmania species is relevant for treatment, prognosis, and epidemiology. Three new hsp70 based PCR variants were developed and recently validated on clinical samples from Peru, without the need for culturing. We evaluated their performance on 133 clinical samples (bone marrow, blood, buffy coat, lymph node aspirates, lesion biopsies) from 42 cutaneous and 56 visceral leishmaniasis patients and 35 negative cases, all from Old World countries (Italy, Sudan, Israel, and Tunisia). The 3 new PCRs were significantly more sensitive than those previously described for hsp70, and their respective restriction fragment analyses were more efficient for species identification. In 79% of the parasitologically confirmed positive samples, the species could be identified directly from sample DNA. This evaluation demonstrated that these new tools are globally applicable in different geographical, clinical, and sampling contexts, and they could become the reference method for identification of Leishmania species in clinical specimens. PMID- 25038030 TI - Transcatheter valve-in-valve implantation: a systematic review of literature. AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) has become an alternative to open surgery in those deemed high risk. The purpose of this study was to evaluate the effectiveness and outcomes of this emerging procedure. We have examined available literature to provide an overview of valve-in-valve implantation using transcatheter heart valves (THVs) in aortic, mitral, pulmonary, tricuspid positions. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. RESULTS: Only 61 studies met full criteria and were included the review. This included 31 studies reporting transcatheter aortic valve-in-valve implantation, mitral valve-in-valve implantation (13 studies), tricuspid valve-in-valve implantation (12 studies), and pure native aortic valve regurgitation (nine studies). One of the limitations of this review is that most of the studies included were case reports, together with some case series. CONCLUSION: Valve-in-valve implantation can be considered as an acceptable alternative to conventional open heart surgery for elderly high risk surgical patients with bioprosthetic degeneration. Long-term follow-up of treated patients will be necessary to establish the true role of valve-in-valve implantation for bioprosthetic degeneration. Patients should be evaluated on an individual basis until outcomes are proven in large cohort studies or randomised trials. PMID- 25038031 TI - Replacement of the aortic root with a composite valve-graft conduit: risk factor analysis in 246 consecutive patients. AB - BACKGROUND: Composite valve-graft (CVG) replacement of the aortic root is a well studied and recognised treatment for various aortic root conditions, including valvular disease with associated aortopathy. There have been few previous studies of the procedure in large numbers in an Australian setting. METHOD: From January 2006 to June 2013, 246 successive patients underwent CVG root replacements at our institution. Mean age was 56.8 years, 85.4% were male, and 87 had evidence of bicuspid aortic valve. Indications for operation included ascending aortic aneurysm in 222 patients, annuloaortic ectasia in 67 patients, and aortic dissection in 38 patients. RESULTS: The overall unit 30-day mortality was 5.7%, including: elective 30-day mortality of 2.2%, and emergent 30-day mortality of 17.2%. Statistically significant multivariate predictors of 30-day mortality were: acute aortic dissection (OR=20.07), peripheral vascular disease (OR=11.17), new ventricular tachycardia (OR=30.17), re-operation for bleeding (OR=14.42), concomitant mitral stenosis (OR=68.30), and cerebrovascular accident (OR=144.85). CONCLUSIONS: Low postoperative mortality in our series matches closely with results from similar sized international studies, demonstrating that this procedure can be performed with low risk in centres with sufficient experience in the operative procedure. PMID- 25038032 TI - Food mechanical properties, feeding ecology, and the mandibular morphology of wild orangutans. AB - Bornean orangutan mandibular morphology has been functionally linked to the exploitation of hard and tough foods, based on evidence that Pongo pygmaeus wurmbii spends a greater percentage of time feeding on bark, seeds and vegetation compared with Pongo abelii (Sumatran orangutans) and the assumption that these tissues are more challenging to process than fruit pulp. We measured and compared toughness (R) and Young's modulus (E) of ripe and unripe foods exploited by P. abelii and P. p. wurmbii. Additionally, we recorded and compared the percentage of time these orangutans fed on plants/plant parts of varying degrees of R and E. Compared with P. abelii, P. p. wurmbii consumed significantly tougher and more displacement limited (R/E)(0.5) fruit parts, leaves and inner bark, and spent a significantly greater percentage of time feeding on immature leaves, unripe fruit and other vegetation. Modulus did not vary as expected between species, likely because we failed to capture the high-end range of modulus values for tissues consumed by P. p. wurmbii. Notably, P. p. wurmbii spent ~40% of its feeding time on the toughest foods consumed (between 1000 and 4000 J m(-2)). Thus, the hypothesis that mandibular robusticity in P. p. wurmbii is functionally linked to feeding on tough foods is supported and is likely related to countering relatively larger external forces and/or repetitive loads required to process the toughest tissues. The importance of elastic modulus on morphological divergence awaits future studies capturing the full range of this material property for P. p. wurmbii. Finally, phenophase and fruit availability influence orangutan species differences in food material properties and percentage of time spent feeding on various foods, emphasizing the importance of incorporating these variables in future studies of feeding ecology and craniodental morphology in extant taxa. PMID- 25038033 TI - Orangutan fish eating, primate aquatic fauna eating, and their implications for the origins of ancestral hominin fish eating. AB - This paper presents new evidence of fish eating in rehabilitant orangutans living on two Bornean islands and explores its contributions to understanding nonhuman primates' aquatic fauna eating and the origins of ancestral hominin fish eating. We assessed the prevalence of orangutans' fish eating, their techniques for obtaining fish, and possible contributors (ecology, individual differences, humans). We identified 61 events in which orangutans tried to obtain fish, including 19 in which they ate fish. All the orangutans were juvenile-adolescent; all the fish were disabled catfish; and most were obtained and eaten in drier seasons in or near shallow, slow-moving water. Orangutans used several techniques to obtain fish (inadvertent, opportunistic and deliberate hand-catch, scrounge, tool-assisted catch) and probably learned them in that order. Probable contributing factors were orangutan traits (age, pre-existing water or tool skills), island features (social density, water accessibility), and local human fishing. Our review of primates' aquatic fauna eating showed orangutans to be one of 20 species that eat aquatic fauna, one of nine confirmed to eat fish, and one of three that use tools to obtain fish. Primate fish eating is also site-specific within species, partly as a function of habitat (e.g., marine-freshwater, seasonality) and human influence (possibly fostered eating fish or other aquatic fauna at most sites, clearly induced it at some). At tropical freshwater sites, fish eating occurred most often in drier seasons around shallow water. Orangutan and primate findings are generally consistent with Stewart's (2010) reconstruction of the origins of ancestral hominin fish eating, but suggest that it, and tool-assisted fish catching, were possible much earlier. PMID- 25038034 TI - Synthesis of a new cyclosporine-based stationary phase and separation behaviors toward aromatic positional isomers by high-performance liquid chromatography. AB - A new cyclosporine-bonded stationary phase has been synthesized through the Staudinger reaction between azido cyclosporine A (CsA) and aminopropyl silica gel and applied in separations of six disubstituted aromatic analytes by high performance liquid chromatography. For dimethyl phthalate, nitroaniline and chloronitrobenzene, their positional isomers were well-separated on this CsA stationary phase, in which the separation factor for m-/o-dimethyl phthalates was the biggest. For nitrotoluene, dichlorobenzene and benzenediol, the m-/o-isomers were co-eluted. Then, effects of chromatographic conditions (such as types and content of alcoholic modifiers) on separation of nitroaniline positional isomers have been investigated. Retention behaviors of nitroaniline isomers on the column exhibited the strengthening trend along with increasing carbon number of alcohols, from ethanol to 1-propanol, and to 1-butanol. A similar phenomenon was observed by lowering the content of alcohol. PMID- 25038035 TI - Interruptions and multi-tasking: moving the research agenda in new directions. PMID- 25038036 TI - The WHO surgical safety checklist: survey of patients' views. AB - BACKGROUND: Evidence suggests that full implementation of the WHO surgical safety checklist across NHS operating theatres is still proving a challenge for many surgical teams. The aim of the current study was to assess patients' views of the checklist, which have yet to be considered and could inform its appropriate use, and influence clinical buy-in. METHOD: Postoperative patients were sampled from surgical wards at two large London teaching hospitals. Patients were shown two professionally produced videos, one demonstrating use of the WHO surgical safety checklist, and one demonstrating the equivalent periods of their operation before its introduction. Patients' views of the checklist, its use in practice, and their involvement in safety improvement more generally were captured using a bespoke 19-item questionnaire. RESULTS: 141 patients participated. Patients were positive towards the checklist, strongly agreeing that it would impact positively on their safety and on surgical team performance. Those worried about coming to harm in hospital were particularly supportive. Views were divided regarding hearing discussions around blood loss/airway before their procedure, supporting appropriate modifications to the tool. Patients did not feel they had a strong role to play in safety improvement more broadly. CONCLUSIONS: It is feasible and instructive to capture patients' views of the delivery of safety improvements like the checklist. We have demonstrated strong support for the checklist in a sample of surgical patients, presenting a challenge to those resistant to its use. PMID- 25038037 TI - The morbidity and mortality conference as an adverse event surveillance tool in a paediatric intensive care unit. AB - OBJECTIVE: To determine if standardised chart review applied to records of patients discussed at a paediatric intensive care unit (PICU) morbidity and mortality conference (MMC) yields additional or different information regarding safety event occurrence and characteristics. DESIGN: Retrospective record review. SETTING: Single tertiary referral PICU in Baltimore, Maryland, USA. PARTICIPANTS: 96 patients discussed at the PICU MMC over 14 months (November 2011-December 2012). MAIN OUTCOME MEASURES: Safety events and their characteristics (medical error category, severity and preventability). RESULTS: A total of 275 safety events were identified through the MMC and/or chart review. The MMC identified 131 (48%) events, 53 (19%) of which were identified through the MMC alone. After chart review was performed, an additional 144 (52%) events were identified. 78 (28%) events were identified through both. High severity adverse events potentially contributing to permanent harm or death were more likely to be identified through both the MMC and chart review (47%) compared with either alone. The MMC alone identified more near-misses (21%) and preventable events (96%) compared with chart review alone or both MMC and chart review. Although chart review alone helped to identify many healthcare-associated infections, medication errors and sedation/pain control issues not elicited through the MMC, the MMC alone identified more communication errors and workflow problems. The MMC alone also identified 40% of all diagnostic errors, which would not have been discovered otherwise despite chart review by itself identifying 50% of such misdiagnoses. CONCLUSIONS: Standardised chart review applied to records of patients discussed at a PICU MMC identified significantly more safety events not initially discovered through the MMC. However, the MMC was superior to chart review in identifying broader problems such as communication errors, workflow issues and certain diagnostic errors not captured by chart review, which can potentially affect many aspects of care. PMID- 25038038 TI - 'It sounds like a great idea but...': a qualitative study of GPs' attitudes towards the development of a national diabetes register. AB - OBJECTIVE: The aim of this study was to investigate the attitudes of general practitioners (GPs) to the development of a national diabetes register as a way of improving the quality of care. DESIGN: Qualitative study using semistructured interviews. SETTING: General practice, Ireland. PARTICIPANTS: Purposive sample of 29 GPs and two practice nurses. Participants' practices varied by (a) location (rural/urban), (b) size (single-handed/group practice) and (c) extent of computerisation. METHODS: The semistructured topic guide focused on experiences of change in the health system at a local and national level and attitudes towards the development of a national diabetes register. Analysis was conducted using the Framework approach. RESULTS: Participants were sceptical about the development of a national diabetes register. The main advantage was 'knowing the numbers' for epidemiological and policy purposes. However, participants questioned the benefits for their practice and patients. There were concerns that it would drain resources from other priorities and distract from patient management. These attitudes were strongly influenced by previous experience of change in the health system. Participants felt that remuneration would be necessary to ensure full engagement, reflecting wider frustrations with payment structures for general practice. There was a sense of wariness towards health service administration which was not specific to diabetes care but which coloured some participants' attitudes towards a national register. In contrast, participants referred to positive experiences of change at a local level, facilitated by a 'practice ethos' and professional leadership. CONCLUSIONS: This study highlights the growing sense of scepticism and inertia towards change within the health system. This inertia stems from previous experience and the competing demands of maintaining versus improving care in a system with dwindling resources. PMID- 25038039 TI - After Mid Staffordshire: from acknowledgement, through learning, to improvement. PMID- 25038040 TI - Kremen1 restricts Dkk activity during posterior lateral line development in zebrafish. AB - Canonical Wnt signaling plays crucial roles during development and disease. How Wnt signaling is modulated in different in vivo contexts is currently not well understood. Here, we investigate the modulation of Wnt signaling in the posterior lateral line primordium (pLLP), a cohort of ~100 cells that collectively migrate along the trunk of the zebrafish embryo. The pLLP comprises proliferative progenitor cells and organized epithelial cells that will form the mechanosensory organs of the posterior lateral line. Wnt signaling is active in the leading progenitor zone of the pLLP and restricted from the trailing zone through expression of the secreted Wnt inhibitors dkk1b and dkk2. We have identified a zebrafish strain, krm1(nl10), which carries a mutation in the kremen1 gene, a non obligate co-receptor for the Dkk family of proteins. Previous studies have shown that Kremen1 inhibits Wnt signaling by facilitating internalization of the Kremen1-Dkk-Lrp5/6 complex. Surprisingly, we found that disruption of Kremen1 in the pLLP exhibited molecular and cellular phenotypes associated with a decrease rather than overactivation of Wnt signaling. Transplantation of wild-type cells into the mutant primordia failed to rescue the krm1(nl10) phenotype, thus revealing that the effects of Kremen1 loss are non-cell-autonomous. Finally, ectopic expression of Dkk1b-mTangerine protein revealed larger spread of the fusion protein in the mutant primordia compared with the wild type. Based on our data, we propose a novel mechanism in which Kremen1 modulates Wnt activity by restricting the range of secreted Dkk proteins during collective cell migration in the pLLP. PMID- 25038041 TI - p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis. AB - Apical constriction (AC) is a widely utilized mechanism of cell shape change whereby epithelial cells transform from a cylindrical to conical shape, which can facilitate morphogenetic movements during embryonic development. Invertebrate epithelial cells undergoing AC depend on the contraction of apical cortex spanning actomyosin filaments that generate force on the apical junctions and pull them toward the middle of the cell, effectively reducing the apical circumference. A current challenge is to determine whether these mechanisms are conserved in vertebrates and to identify the molecules responsible for linking apical junctions with the AC machinery. Utilizing the developing mouse eye as a model, we have uncovered evidence that lens placode AC may be partially dependent on apically positioned myosin-containing filaments associated with the zonula adherens. In addition we found that, among several junctional components, p120 catenin genetically interacts with Shroom3, a protein required for AC during embryonic morphogenesis. Further analysis revealed that, similar to Shroom3, p120 catenin is required for AC of lens cells. Finally, we determined that p120 catenin functions by recruiting Shroom3 to adherens junctions. Together, these data identify a novel role for p120-catenin during AC and further define the mechanisms required for vertebrate AC. PMID- 25038042 TI - Tcf3 expression marks both stem and progenitor cells in multiple epithelia. AB - The Lef/Tcf-family transcription factor Tcf3 has important roles in development, stem cell function and malignancy. Previous gain- and loss-of-function studies have suggested that Tcf3 is a mediator of self-renewal and an undifferentiated state in stem and progenitor cells in skin, but little is known of its role in other postnatal tissues. Here, we explore the distribution and behavior of Tcf3 expressing cells in several adult tissues using a novel Tcf3-CreER knock-in mouse model. By lineage tracing in dorsal skin, we verify that Tcf3-expressing cells in the hair follicle bulge are self-renewing stem cells with multilineage potential. We then demonstrate, for the first time, the presence of Tcf3-expressing cells in the basal layer of several other stratified epithelia, including the paw skin, tongue and esophagus. By lineage tracing, we demonstrate that the Tcf3-expressing population in these tissues includes persistent stem cells, transient progenitors and cells undergoing active differentiation. Our observations here suggest that the role of Tcf3 in cell-fate decision is more complex than previously appreciated and is highly dependent on cellular context. PMID- 25038043 TI - Vangl-dependent planar cell polarity signalling is not required for neural crest migration in mammals. AB - The role of planar cell polarity (PCP) signalling in neural crest (NC) development is unclear. The PCP dependence of NC cell migration has been reported in Xenopus and zebrafish, but NC migration has not been studied in mammalian PCP mutants. Vangl2(Lp/Lp) mouse embryos lack PCP signalling and undergo almost complete failure of neural tube closure. Here we show, however, that NC specification, migration and derivative formation occur normally in Vangl2(Lp/Lp) embryos. The gene family member Vangl1 was not expressed in NC nor ectopically expressed in Vangl2(Lp/Lp) embryos, and doubly homozygous Vangl1/Vangl2 mutants exhibited normal NC migration. Acute downregulation of Vangl2 in the NC lineage did not prevent NC migration. In vitro, Vangl2(Lp/Lp) neural tube explants generated emigrating NC cells, as in wild type. Hence, PCP signalling is not essential for NC migration in mammals, in contrast to its essential role in neural tube closure. PCP mutations are thus unlikely to mediate NC-related birth defects in humans. PMID- 25038044 TI - Dual roles for Id4 in the regulation of estrogen signaling in the mammary gland and ovary. AB - The HLH transcriptional regulator Id4 exerts important roles in different organs, including the neural compartment, where Id4 loss usually results in early lethality. To explore the role of this basally restricted transcription factor in the mammary gland, we generated a cre-inducible mouse model. MMTV- or K14-cre mediated deletion of Id4 led to a delay in ductal morphogenesis, consistent with previous findings using a germ-line knockout mouse model. A striking increase in the expression of ERalpha (Esr1), PR and FoxA1 was observed in both the basal and luminal cellular subsets of Id4-deficient mammary glands. Together with chromatin immunoprecipitation of Id4 on the Esr1 and Foxa1 promoter regions, these data imply that Id4 is a negative regulator of the ERalpha signaling axis. Unexpectedly, examination of the ovaries of targeted mice revealed significantly increased numbers of secondary and antral follicles, and reduced Id4 expression in the granulosa cells. Moreover, expression of the cascade of enzymes that are crucial for estrogen biosynthesis in the ovary was decreased in Id4-deficient females and uterine weights were considerably lower, indicating impaired estrogen production. Thus, compromised ovarian function and decreased circulating estrogen likely contribute to the mammary ductal defects evident in Id4-deficient mice. Collectively, these data identify Id4 as a novel regulator of estrogen signaling, where Id4 restrains ERalpha expression in the basal and luminal cellular compartments of the mammary gland and regulates estrogen biosynthesis in the ovary. PMID- 25038046 TI - Understanding road safety in Kenya: views of matatu drivers. AB - BACKGROUND: Road traffic accidents (RTAs) are estimated to cause 1.3 million deaths and 20-50 million injuries worldwide. Road safety is a challenge in Kenya with causes being multi-factorial. Matatus (minibuses) are involved in a large proportion of accidents. METHODS: A literature review was completed to identify key issues and refine the scope of the study. The fieldwork included 20 semi structured interviews with matatu drivers. All participants were male, with driving experience of 1-20 years. Thematic framework was used for analysis. Some unstructured observations on different road users and their behaviours were also recorded. RESULTS: Literature showed that the causes of RTAs in Kenya are multi factorial, but that human factors play a large part. There is also an evidence gap concerning matatu drivers, who are key stakeholders in road safety. Fieldwork showed that the matatu industry creates financial pressures on drivers and an excessive level of competition, leading to dangerous driving. Corruption of traffic police appears to be a major barrier to improving road safety, as road safety legislation is not enforced, and bribery has become the cultural norm. The general public, including passengers and private vehicles owners, also cause problems by failing to understand their role in road safety and placing the blame on others. CONCLUSIONS: The key policy implication for improving road safety in Kenya is seeking measures to ensure responsibility by all road users through awareness raising in the short-term and reforming the matatu industry and addressing the root causes of corruption in the longer term. PMID- 25038047 TI - Study shows use of high doses of antibiotics to clear infections may have the potential to promote increased cross-resistance in clinics. PMID- 25038045 TI - Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration. AB - Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine. PMID- 25038048 TI - Blame it on the chimps: researchers resolve evolutionary origins of human herpes viruses. PMID- 25038049 TI - Eukaryotic origins: How and when was the mitochondrion acquired? AB - Comparative genomics has revealed that the last eukaryotic common ancestor possessed the hallmark cellular architecture of modern eukaryotes. However, the remarkable success of such analyses has created a dilemma. If key eukaryotic features are ancestral to this group, then establishing the relative timing of their origins becomes difficult. In discussions of eukaryote origins, special significance has been placed on the timing of mitochondrial acquisition. In one view, mitochondrial acquisition was the trigger for eukaryogenesis. Others argue that development of phagocytosis was a prerequisite to acquisition. Results from comparative genomics and molecular phylogeny are often invoked to support one or the other scenario. We show here that the associations between specific cell biological models of eukaryogenesis and evolutionary genomic data are not as strong as many suppose. Disentangling these eliminates many of the arguments that polarize current debate. PMID- 25038050 TI - The relationship between sexual selection and sexual conflict. AB - Evolutionary conflicts of interest arise whenever genetically different individuals interact and their routes to fitness maximization differ. Sexual selection favors traits that increase an individual's competitiveness to acquire mates and fertilizations. Sexual conflict occurs if an individual of sex A's relative fitness would increase if it had a "tool" that could alter what an individual of sex B does (including the parental genes transferred), at a cost to B's fitness. This definition clarifies several issues: Conflict is very common and, although it extends outside traits under sexual selection, sexual selection is a ready source of sexual conflict. Sexual conflict and sexual selection should not be presented as alternative explanations for trait evolution. Conflict is closely linked to the concept of a lag load, which is context-dependent and sex specific. This makes it possible to ask if one sex can "win." We expect higher population fitness if females win. PMID- 25038051 TI - The role of SPRASA in female fertility. AB - Fertility is a complex process and infertility can have many causes. Sperm protein reactive with antisperm antibody (SPRASA)/sperm lysozyme-like protein 1 is a protein discovered as the target of autoantibodies in infertile men and previously thought to be expressed only in sperm. Using a bovine in vitro fertilization model, we have shown that SPRASA antiserum reduced sperm binding to zona-free oocytes and the development of embryos to morulae but did not affect the postfertilization cleavage rate to 2 cells or sperm motility. We demonstrated that SPRASA was expressed in ovarian follicles, corpora lutea, and oocytes by a combination of reverse transcription-polymerase chain reaction and immunohistochemistry. Female mice immunized with SPRASA had profound infertility following timed matings and those mice that did become pregnant had reduced fetal viability. The levels of antibodies reactive with SPRASA in 204 fertile and 202 infertile couples were elevated in 3 infertile but no fertile women. Together, these results indicate that SPRASA has a role in female fertility. PMID- 25038056 TI - Communication in pediatric critical care: A proposal for an evidence-informed framework. AB - The aim of this investigation was to conduct a comprehensive examination of communication between parents and health care professionals (HCPs) in the pediatric intensive care unit (PICU). A secondary analysis was performed on data from 3 previous qualitative studies, which included 30 physicians, 37 nurses, and 38 parents in France and Quebec (Canada). All three studies examined a mix of cases where children either survived or died. All data referring to communication between parents (and patients when applicable) and HCPs were examined to identity themes that related to communication. Thematic categories for parents and HCPs were developed. Three interrelated dimensions of communication were identified: (1) informational communication, (2) relational communication, and (3) communication and parental coping. Specific themes were identified for each of these 3 dimensions in relation to parental concerns as well as HCP concerns. This investigation builds on prior research by advancing a comprehensive analysis of PICU communication that includes (a) cases where life-sustaining treatments were withdrawn or withheld as well as cases where they were maintained, (b) data from HCPs as well as parents, and (c) investigations conducted in 4 different sites. An evidence-informed conceptual framework is proposed for PICU communication between parents and HCPs. We also outline priorities for the development of practice, education, and research. PMID- 25038052 TI - Sox2 gene amplification significantly impacts overall survival in serous epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Recently, the existence of ovarian cancer stem cells has been reported. Sox2, Nanog and Oct4 are key markers of "stemness". The objective of this study was to determine whether Sox2, Nanog, and Oct4 are associated with EOC and poor outcome. The expression of these markers was assessed by immunofluorescence staining and real time RT-PCR in human EOC cell lines MDAH-2774 and SKOV-3, while the cancer genome atlas (TCGA) dataset was analyzed for associations with survival. Sox2, Nanog and Oct4 (POU5F1) were all detected by immunofluorescence staining and these results were confirmed by real-time RT-PCR. The TCGA dataset revealed a 26%, 9%, and 6% amplification of Sox2, Nanog and POU5F1, respectively. Additionally, K-M survival analyses showed a significant median overall survival difference (41 versus 48.3 months, P = .01) for Sox2 amplification, but not for Nanog (44.1 versus 36.2 months, P > .05) and POU5F1 (43.5 versus 45.0 months, P > .05). Our results suggest that Sox2 gene amplification significantly influences overall survival. PMID- 25038053 TI - Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. AB - Plasma high-density lipoprotein (HDL) levels show a strong inverse correlation with atherosclerotic vascular disease. Previous studies have demonstrated that antagonism of miR-33 in vivo increases circulating HDL and reverse cholesterol transport (RCT), thereby reducing the progression and enhancing the regression of atherosclerosis. While the efficacy of short-term anti-miR-33 treatment has been previously studied, the long-term effect of miR-33 antagonism in vivo remains to be elucidated. Here, we show that long-term therapeutic silencing of miR-33 increases circulating triglyceride (TG) levels and lipid accumulation in the liver. These adverse effects were only found when mice were fed a high-fat diet (HFD). Mechanistically, we demonstrate that chronic inhibition of miR-33 increases the expression of genes involved in fatty acid synthesis such as acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS) in the livers of mice treated with miR-33 antisense oligonucleotides. We also report that anti-miR-33 therapy enhances the expression of nuclear transcription Y subunit gamma (NFYC), a transcriptional regulator required for DNA binding and full transcriptional activation of SREBP-responsive genes, including ACC and FAS. Taken together, these results suggest that persistent inhibition of miR-33 when mice are fed a high-fat diet (HFD) might cause deleterious effects such as moderate hepatic steatosis and hypertriglyceridemia. These unexpected findings highlight the importance of assessing the effect of chronic inhibition of miR-33 in non-human primates before we can translate this therapy to humans. PMID- 25038057 TI - Therapeutic use of anti-CTLA-4 antibodies. AB - Targeting CTLA-4 represents a new type of immunotherapeutic approach, namely immune checkpoint inhibition. Blockade of CTLA-4 by ipilimumab was the first strategy to achieve a significant clinical benefit for late-stage melanoma patients in two phase 3 trials. These results fueled the notion of immunotherapy being the breakthrough strategy for oncology in 2013. Subsequently, many trials have been set up to test various immune checkpoint modulators in malignancies, not only in melanoma. In this review, recent new ideas about the mechanism of action of CTLA-4 blockade, its current and future therapeutic use, and the intensive search for biomarkers for response will be discussed. Immune checkpoint blockade, targeting CTLA-4 and/or PD-1/PD-L1, is currently the most promising systemic therapeutic approach to achieve long-lasting responses or even cure in many types of cancer, not just in patients with melanoma. PMID- 25038058 TI - Prevalence and predictors of vitamin D deficiency and response to oral supplementation in patients receiving long-term home parenteral nutrition. AB - Previous studies have suggested a high prevalence of vitamin D deficiency in patients receiving long-term home parenteral nutrition (HPN). The aim of this study was to determine the prevalence and predictors of vitamin D deficiency in long-term HPN patients. METHODS: A retrospective, institutional review board approved study was performed on all adult patients followed by the Cleveland Clinic HPN program receiving HPN therapy >6 months between 1989 and 2013 with a 25-(OH) D3 level reported. Patients were categorized by serum vitamin D status as follows: sufficient, insufficient, and deficient with respective 25-(OH) D3 levels of >=30 ng/mL, 20-30 ng/mL, and <20 ng/mL. RESULTS: Seventy-nine patients were categorized based on serum vitamin D status as follows: 35 (44.3%) deficient, 24 (30.4%) insufficient, and 20 (25.3%) sufficient. The mean age of the cohort at the initiation of HPN was 52.0 +/- 12.7 years, and 26 (32.9%) were male. The median HPN duration was 39 months, and the most common indication was inflammatory bowel disease (36.7%). Most (82.3%) patients had at least 1 prescription of oral vitamin D supplement (50,000 International Units) during this time. History of jejunal resection (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.9-15.1; P = .002) and lack of oral vitamin D supplementation (OR, 0.7; 95% CI, 0.52-0.93; P = .038) were the strongest predictors of vitamin D deficiency. CONCLUSION: Vitamin D deficiency is common among patients receiving long-term HPN despite oral supplementation. PMID- 25038059 TI - Why public trust in health care systems matters and deserves greater research attention. AB - Considering the underlying importance of trust, there is too little research into the understanding, protection and recovery of trust in health care systems, not only for the effective functioning of health care systems but also for society in general. Several researchers have pointed towards a contemporary crisis of trust in health care systems and there have been many examples that show the severe effects of mistrust. More research into public trust in health care systems could contribute to improving efficiency while protecting the health of the public. PMID- 25038060 TI - Repositioning drugs for inflammatory disease - fishing for new anti-inflammatory agents. AB - Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning - the process of finding new uses for existing drugs - is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs. PMID- 25038062 TI - The implementation of a clinical toolkit and adolescent depression screening program in primary care. AB - PROBLEM/BACKGROUND: Adolescent depression is a growing problem for today's society with only 30% receiving services. AIM AND METHODS: The aim of this project was to increase identification and treatment of depressed adolescents, and comfort levels of primary care providers with the implementation of a depression-screening program and use of a clinical depression toolkit within a primary care setting. SETTING: The setting was a private pediatric practice in central Maine. RESULTS: Over an 8-week period, 266 adolescents were screened. Twelve adolescents (4.5%) received a diagnosis of depression and 11 received treatment within 8 days. Survey results showed a significant increase in providers' feelings of comfort and accountability. CONCLUSION: This project demonstrates that it is feasible to implement a depression screening and treatment program in primary care. It demonstrates that primary care providers can increase their comfort and feelings accountability in treating depression in primary care, thus increasing access for this monumental and potential catastrophic problem. PMID- 25038061 TI - Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. AB - In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a 'gene modifier' in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia-reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-kappaB, NADPH oxidase 2, interleukin-1beta, interleukin-10 and brain derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease. PMID- 25038063 TI - Aspartame Administration and Insulin Treatment Altered Brain Levels of CYP2E1 and CYP3A2 in Streptozotocin-Induced Diabetic Rats. AB - This study demonstrates that aspartame consumption and insulin treatment in a juvenile diabetic rat model leads to increase in cytochrome P450 (CYP) 2E1 and CYP3A2 isozymes in brain. Diabetes mellitus was induced in postweaned 21-day-old Wistar male rat by streptozotocin. Animals were randomly assigned to one of the following groups: untreated control, diabetic (D), D-insulin, D-aspartame, or the D-insulin + aspartame-treated group. Brain and liver tissue samples were used to analyze the activity of CYP2E1 and CYP3A2 and protein levels. Our results indicate that combined treatment with insulin and aspartame in juvenile diabetic rats significantly induced CYP2E1 in the cerebrum and cerebellum without modifying it in the liver, while CYP3A2 protein activity increased both in the brain and in the liver. The induction of CYP2E1 in the brain could have important in situ toxicological effects, given that this CYP isoform is capable of bioactivating various toxic substances. Additionally, CYP3A2 induction in the liver and brain could be considered a decisive factor in the variation of drug response and toxicity. PMID- 25038064 TI - Intensive rehabilitation treatment in early Parkinson's disease: a randomized pilot study with a 2-year follow-up. AB - BACKGROUND: Although physical exercise improves motor aspects of Parkinson's disease (PD), it is not clear whether it may also have a neuroprotective effect. Objective. In this 2-year follow-up study, we determined whether intensive exercise in the early stages of the disease slows down PD progression. METHODS: Forty newly diagnosed patients with PD were treated with rasagiline and randomly assigned to 2 groups: MIRT Group (two 28-day multidisciplinary intensive rehabilitation treatments [MIRT], at 1-year interval) and Control Group (only drug). In both groups, Unified Parkinson's Disease Rating Scale Section II (UPDRS II), UPDRS III, 6-minute walking test (6MWT), Timed Up-and-Go test (TUG); PD Disability Scale (PDDS), and l-dopa equivalents were assessed at baseline (T0), 6 months (T1), 1 year (T2), 18 months (T3), and 2 years (T4) later. RESULTS: Over 2 years, UPDRS II, UPDRS III, TUG, and PDDS differentially progressed in the 2 groups: In the MIRT Group, all scores at T4 were better than at T0 (all Ps < .03). No changes were noted in the Control Group. l-dopa equivalent dosages increased significantly only in the Control Group (P = .0015), with a decrease in the percentages of patients in monotherapy (T1 40%; T2, T3, and T4 20%). In the MIRT Group, the percentages of such patients remained higher (T1 and T2 100%; T3 89%; T4 75%). CONCLUSIONS: These results suggest that MIRT might slow down the progression of motor decay, it might delay the need for increasing drug treatment, and thus, it might have a neuroprotective effect. PMID- 25038065 TI - Colonization state influences the hemocyte proteome in a beneficial squid-Vibrio symbiosis. AB - The squid Euprymna scolopes and the luminescent bacterium Vibrio fischeri form a highly specific beneficial light organ symbiosis. Not only does the host have to select V. fischeri from the environment, but it must also prevent subsequent colonization by non-symbiotic microorganisms. Host macrophage-like hemocytes are believed to play a role in mediating the symbiosis with V. fischeri. Previous studies have shown that the colonization state of the light organ influences the host's hemocyte response to the symbiont. To further understand the molecular mechanisms behind this process, we used two quantitative mass-spectrometry-based proteomic techniques, isobaric tags for relative and absolute quantification (iTRAQ) and label-free spectral counting, to compare and quantify the adult hemocyte proteomes from colonized (sym) and uncolonized (antibiotic treated/cured) squid. Overall, iTRAQ allowed for the quantification of 1,024 proteins with two or more peptides. Thirty-seven unique proteins were determined to be significantly different between sym and cured hemocytes (p value < 0.05), with 20 more abundant proteins and 17 less abundant in sym hemocytes. The label free approach resulted in 1,241 proteins that were identified in all replicates. Of 185 unique proteins present at significantly different amounts in sym hemocytes (as determined by spectral counting), 92 were more abundant and 93 were less abundant. Comparisons between iTRAQ and spectral counting revealed that 30 of the 37 proteins quantified via iTRAQ exhibited trends similar to those identified by the label-free method. Both proteomic techniques mutually identified 16 proteins that were significantly different between the two groups of hemocytes (p value < 0.05). The presence of V. fischeri in the host light organ influenced the abundance of proteins associated with the cytoskeleton, adhesion, lysosomes, proteolysis, and the innate immune response. These data provide evidence that colonization by V. fischeri alters the hemocyte proteome and reveals proteins that may be important for maintaining host-symbiont specificity. PMID- 25038067 TI - Individualised pelvic floor muscle training is an effective conservative treatment in women with pelvic organ prolapse. PMID- 25038066 TI - In-depth characterization of the cerebrospinal fluid (CSF) proteome displayed through the CSF proteome resource (CSF-PR). AB - In this study, the human cerebrospinal fluid (CSF) proteome was mapped using three different strategies prior to Orbitrap LC-MS/MS analysis: SDS-PAGE and mixed mode reversed phase-anion exchange for mapping the global CSF proteome, and hydrazide-based glycopeptide capture for mapping glycopeptides. A maximal protein set of 3081 proteins (28,811 peptide sequences) was identified, of which 520 were identified as glycoproteins from the glycopeptide enrichment strategy, including 1121 glycopeptides and their glycosylation sites. To our knowledge, this is the largest number of identified proteins and glycopeptides reported for CSF, including 417 glycosylation sites not previously reported. From parallel plasma samples, we identified 1050 proteins (9739 peptide sequences). An overlap of 877 proteins was found between the two body fluids, whereas 2204 proteins were identified only in CSF and 173 only in plasma. All mapping results are freely available via the new CSF Proteome Resource (http://probe.uib.no/csf-pr), which can be used to navigate the CSF proteome and help guide the selection of signature peptides in targeted quantitative proteomics. PMID- 25038068 TI - HIV-1 DNA concentrations and evolution among African HIV-1-infected children under antiretroviral treatment (ANRS 1244/1278). AB - OBJECTIVES: The objectives of this study were to describe the pretreatment HIV-1 DNA concentrations in children infected with HIV and to evaluate the impact of antiretroviral therapy (ART) on HIV-DNA concentrations. METHODS: This was a retrospective analysis of all children followed up in the 'Programme Enfant Yopougon' cohort, Abidjan, Cote d'Ivoire, from 2000 to 2004, who had cryopreserved peripheral blood mononuclear cells (PBMCs) and plasma samples. HIV DNA was measured using a real-time PCR assay. Mixed-model analysis was used to analyse the factors associated with change in HIV-DNA concentration. RESULTS: The study included 121 children infected with HIV-1. The median age at inclusion was 6 years (IQR: 3.5-9) and children were at an advanced stage of HIV disease (46.6% and 20.3% presenting CDC stage B and CDC stage C, respectively). At baseline, the median HIV-DNA concentration was 3.4 log10 copies/10(6) PBMCs (IQR: 3.1-3.6). Fifty-four children were initiated on ART during follow-up. After 24 months of ART, HIV-DNA load decreased by 0.32 (IQR: 0.08-0.57) log10 copies/10(6) PBMCs. The only factor associated with the HIV-DNA decrease was a concomitant low HIV RNA viral load result. Children with efficient ART had a 0.51 log10 copies (IQR: 0.40-0.86) HIV-DNA decrease per million PBMCs. CONCLUSIONS: HIV-DNA concentrations decreased following ART initiation in a large African paediatric cohort. This decline was exclusively associated with the decrease in ongoing replication level achieved. Our study points out that a strong adherence is needed for ART to be efficient on the viral reservoirs, and further reinforces that adherence support is also essential to diminish the reservoir. PMID- 25038070 TI - Hierarchical mixture models for longitudinal immunologic data with heterogeneity, non-normality, and missingness. AB - It is a common practice to analyze longitudinal data frequently arisen in medical studies using various mixed-effects models in the literature. However, the following issues may standout in longitudinal data analysis: (i) In clinical practice, the profile of each subject's response from a longitudinal study may follow a "broken stick" like trajectory, indicating multiple phases of increase, decline and/or stable in response. Such multiple phases (with changepoints) may be an important indicator to help quantify treatment effect and improve management of patient care. To estimate changepoints, the various mixed-effects models become a challenge due to complicated structures of model formulations; (ii) an assumption of homogeneous population for models may be unrealistically obscuring important features of between-subject and within-subject variations; (iii) normality assumption for model errors may not always give robust and reliable results, in particular, if the data exhibit non-normality; and (iv) the response may be missing and the missingness may be non-ignorable. In the literature, there has been considerable interest in accommodating heterogeneity, non-normality or missingness in such models. However, there has been relatively little work concerning all of these features simultaneously. There is a need to fill up this gap as longitudinal data do often have these characteristics. In this article, our objectives are to study simultaneous impact of these data features by developing a Bayesian mixture modeling approach-based Finite Mixture of Changepoint (piecewise) Mixed-Effects (FMCME) models with skew distributions, allowing estimates of both model parameters and class membership probabilities at population and individual levels. Simulation studies are conducted to assess the performance of the proposed method, and an AIDS clinical data example is analyzed to demonstrate the proposed methodologies and to compare modeling results of potential mixture models under different scenarios. PMID- 25038069 TI - Whole-genome sequencing reveals clonal expansion of multiresistant Staphylococcus haemolyticus in European hospitals. AB - OBJECTIVES: Staphylococcus haemolyticus is an emerging cause of nosocomial infections, primarily affecting immunocompromised patients. A comparative genomic analysis was performed on clinical S. haemolyticus isolates to investigate their genetic relationship and explore the coding sequences with respect to antimicrobial resistance determinants and putative hospital adaptation. METHODS: Whole-genome sequencing was performed on 134 isolates of S. haemolyticus from geographically diverse origins (Belgium, 2; Germany, 10; Japan, 13; Norway, 54; Spain, 2; Switzerland, 43; UK, 9; USA, 1). Each genome was individually assembled. Protein coding sequences (CDSs) were predicted and homologous genes were categorized into three types: Type I, core genes, homologues present in all strains; Type II, unique core genes, homologues shared by only a subgroup of strains; and Type III, unique genes, strain-specific CDSs. The phylogenetic relationship between the isolates was built from variable sites in the form of single nucleotide polymorphisms (SNPs) in the core genome and used to construct a maximum likelihood phylogeny. RESULTS: SNPs in the genome core regions divided the isolates into one major group of 126 isolates and one minor group of isolates with highly diverse genomes. The major group was further subdivided into seven clades (A-G), of which four (A-D) encompassed isolates only from Europe. Antimicrobial multiresistance was observed in 77.7% of the collection. High levels of homologous recombination were detected in genes involved in adherence, staphylococcal host adaptation and bacterial cell communication. CONCLUSIONS: The presence of several successful and highly resistant clones underlines the adaptive potential of this opportunistic pathogen. PMID- 25038071 TI - Double propensity-score adjustment: A solution to design bias or bias due to incomplete matching. AB - Propensity-score matching is frequently used to reduce the effects of confounding when using observational data to estimate the effects of treatments. Matching allows one to estimate the average effect of treatment in the treated. Rosenbaum and Rubin coined the term "bias due to incomplete matching" to describe the bias that can occur when some treated subjects are excluded from the matched sample because no appropriate control subject was available. The presence of incomplete matching raises important questions around the generalizability of estimated treatment effects to the entire population of treated subjects. We describe an analytic solution to address the bias due to incomplete matching. Our method is based on using optimal or nearest neighbor matching, rather than caliper matching (which frequently results in the exclusion of some treated subjects). Within the sample matched on the propensity score, covariate adjustment using the propensity score is then employed to impute missing potential outcomes under lack of treatment for each treated subject. Using Monte Carlo simulations, we found that the proposed method resulted in estimates of treatment effect that were essentially unbiased. This method resulted in decreased bias compared to caliper matching alone and compared to either optimal matching or nearest neighbor matching alone. Caliper matching alone resulted in design bias or bias due to incomplete matching, while optimal matching or nearest neighbor matching alone resulted in bias due to residual confounding. The proposed method also tended to result in estimates with decreased mean squared error compared to when caliper matching was used. PMID- 25038072 TI - Transform-both-sides nonlinear models for in vitro pharmacokinetic experiments. AB - Transform-both-sides nonlinear models have proved useful in many experimental applications including those in pharmaceutical sciences and biochemistry. The maximum likelihood method is commonly used to fit transform-both-sides nonlinear models, where the regression and transformation parameters are estimated simultaneously. In this paper, an analysis of variance-based method is described in detail for estimating transform-both-sides nonlinear models from randomized experiments. It estimates the transformation parameter from the full treatment model and then the regression parameters are estimated conditionally on this estimate of the transformation parameter. The analysis of variance method is computationally simpler compared with the maximum likelihood method of estimation and allows a more natural separation of different sources of lack of fit. Simulation studies show that the analysis of variance method can provide unbiased estimators of complex transform-both-sides nonlinear models, such as transform both-sides random coefficient nonlinear regression models and transform-both sides fixed coefficient nonlinear regression models with random block effects. PMID- 25038073 TI - Dependent censoring in piecewise exponential survival models. AB - There are often reasons to suppose that there is dependence between the time to event and time to censoring, or dependent censoring, for survival data, particularly when considering medical data. This is because the decision to treat or not is often made according to prognosis, usually with the most ill patients being prioritised. Due to identifiability issues, sensitivity analyses are often used to assess whether independent censoring can lead to misleading results. In this paper, a sensitivity analysis method for piecewise exponential survival models is presented. This method assesses the sensitivity of the results of standard survival models to small amounts of dependence between the time to failure and time to censoring variables. It uses the same assumption about the dependence between the time to failure and time to censoring as previous sensitivity analyses for both standard parametric survival models and the Cox model. However, the method presented in this paper allows the use of more flexible models for the marginal distributions whilst remaining computationally simple. A simulation study is used to assess the accuracy of the sensitivity analysis method and identify the situations in which it is suitable to use this method. The study found that the sensitivity analysis performs well in many situations, but not when the data have a high proportion of censoring. PMID- 25038075 TI - Randomised controlled trials: missing data. PMID- 25038074 TI - Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. AB - OBJECTIVE: To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels. DESIGN: Meta analysis. STUDIES REVIEWED: Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke). RESULTS: 117,411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference. CONCLUSIONS: Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept. PMID- 25038076 TI - Not so "good" cholesterol. PMID- 25038077 TI - India sets target to build 5.2 million toilets in rural areas by end of August. PMID- 25038078 TI - First case of locally acquired chikungunya is reported in US. PMID- 25038079 TI - Intra-dialytic training accelerates oxygen uptake kinetics in hemodialysis patients. AB - BACKGROUND: End-stage renal disease is associated with several hemodynamic and peripheral muscle abnormalities that could slow the rate of change in oxygen uptake ([Formula: see text]O2) at the onset and at the end of exercise. This study was performed to determine whether an intra-dialytic aerobic training program would speed [Formula: see text]O2 kinetics at the transition to and from moderate and high-intensity exercise. DESIGN: This study was a randomized controlled trial. METHODS: Twenty-four patients with end-stage renal disease (14 females; 47.0 +/- 11.9 years) were randomly assigned to either 12-week cycle ergometer-based training at moderate exertion or a similar control period. At initial and final evaluations, patients underwent 6 min moderate and high intensity tests to exercise intolerance (Tlim). RESULTS: Training improved Tlim by ~90% (median (inter-quartile range) = 232 (59) s to 445 (451) s, p < 0.05); in contrast, Tlim decreased by ~30% in controls (291 (134) s to 202 (131) s). [Formula: see text]O2 kinetics at the onset of moderate-intensity exercise were significantly accelerated with training leading to lower oxygen (O2) deficit (mean +/- standard deviation (SD) = 3.2 +/- 1.3 l vs 2.3 +/- 1.2 l). Similar positive effects were found at the high-intensity test either at the onset of, or recovery from, exercise (p < 0.05). "Excess" [Formula: see text]O2 at the high intensity test was also lessened with training. Changes in Tlim correlated with faster [Formula: see text]O2 kinetics and lower "excess" [Formula: see text]O2 (Spearman's rho = -0.56 and -0.75, respectively; p < 0.01). CONCLUSIONS: A symptom-targeted intra-dialytic training program improved sub-maximal aerobic metabolism and endurance exercise capacity. [Formula: see text]O2 kinetics are valuable in providing relatively effort-independent information on the efficacy of exercise interventions in this patient population. PMID- 25038080 TI - Calculated and perceived cardiovascular risk in asymptomatic subjects submitted to a routine medical evaluation: The perception gap. AB - BACKGROUND: Poor adherence to medical treatment represents a major health problem. A subject's misperception of his own cardiovascular risk has been indicated as a key driver for low compliance with preventive measures. This study analysed the relationship between objectively calculated short- and long-term cardiovascular risk and its subjective perception. DESIGN: Cross-sectional study in asymptomatic Brazilian subjects. METHODS: Individuals (N = 6544, mean age 49.1 +/- 7 years, 22.2% female) who underwent a routine mandatory health evaluation were studied. A questionnaire in which each individual rated his own cardiovascular risk as low, intermediate or high according to his own perception was used. The 10-year and lifetime cardiovascular risk were calculated respectively using the Framingham risk (FRS) and Lifetime risk (LRS) scores. Individuals were classified as hypo-perceivers (i.e. perceived risk lower than estimated risk), normo-perceivers (i.e. perceived risk coincident with estimated risk) and hyper-perceivers (i.e. perceived risk higher than estimated risk). RESULTS: Cardiovascular risk, using the FRS, was low in 77.9% (N = 5071), intermediate in 14.4% (N = 939) and high in 7.7% (N = 499) of subjects. Cardiovascular risk, using the LRS, was low in 7.6% (N = 492), intermediate in 43.1% (N = 2787) and high in 49.3% (N = 3184) of the study population. The prevalence of normo-perceivers was 57.6% using the FRS and only 20.6% using the LRS. Using the LRS, 72.3% of the intermediate and 91.2% of the high-risk subjects were hypo-perceivers. CONCLUSIONS: In a large sample of asymptomatic individuals, there was a gap between calculated and perceived cardiovascular risk. Using a long-term risk score, most of the intermediate- and high-risk subjects were hypo perceivers. PMID- 25038081 TI - Adults with complex congenital heart disease have impaired skeletal muscle function and reduced confidence in performing exercise training. AB - BACKGROUND: Adults with congenital heart disease (ACHD) usually have reduced aerobic exercise capacity compared with controls. However, their skeletal muscle function is less studied. MATERIAL AND METHODS: In this cross-sectional study, unilateral isotonic shoulder flexion, unilateral isotonic heel-lift, maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were tested in 85 patients with ACHD (35 women, mean age 36.8 +/- 14.8 years), classed as either 'complex' (n = 43) or 'simple' (n = 42), and 42 age and gender matched controls (16 women, mean age 36.9 +/- 14.9). Maximum number of shoulder flexions and heel lifts were measured. MIP/MEP was tested using a handheld respiratory pressure meter. Exercise self-efficacy, measuring confidence in performing exercise training, was evaluated. RESULTS: Adults with complex lesions performed fewer shoulder flexions compared with controls and patients with simple lesions (28.2 +/- 11.1 vs. 63.6 +/- 40.4, p < 0.001 and 28.2 +/- 11.1 vs. 54.9 +/- 24.9, p < 0.001), as well as fewer heel-lifts compared with controls and patients with simple lesions (17.6 +/- 7.7 vs. 26.3 +/- 12.8, p < 0.001 and 17.6 +/- 7.7 vs. 23.2 +/- 7.0, p = 0.024), lower MIP than controls (80.7 +/- 26.7 vs. 111.1 +/- 29.9 cm H2O, p < 0.001) and lower MEP compared with controls (110.8 +/- 39.9 vs. 141.8 +/- 39.5, p < 0.001). Their exercise self-efficacy was lower than controls (28.0 +/- 8.3 vs. 33.4 +/- 6.1, p = 0.002). In a linear regression model complex heart lesions were independently associated with impaired limb muscle function. CONCLUSION: Adults with complex congenital heart disease have impaired skeletal muscle function compared with patients with simple lesions and healthy controls. They also had lower confidence in performing exercise training. Thus, this population might have a potential for rehabilitation focusing on improving muscle function and confidence in performing exercise training. PMID- 25038082 TI - The contribution of Candida albicans vacuolar ATPase subunit V1B, encoded by VMA2, to stress response, autophagy, and virulence is independent of environmental pH. AB - Candida albicans vacuoles are central to many critical biological processes, including filamentation and in vivo virulence. The V-ATPase proton pump is a multisubunit complex responsible for organellar acidification and is essential for vacuolar biogenesis and function. To study the function of the V1B subunit of C. albicans V-ATPase, we constructed a tetracycline-regulatable VMA2 mutant, tetR VMA2. Inhibition of VMA2 expression resulted in the inability to grow at alkaline pH and altered resistance to calcium, cold temperature, antifungal drugs, and growth on nonfermentable carbon sources. Furthermore, V-ATPase was unable to fully assemble at the vacuolar membrane and was impaired in proton transport and ATPase-specific activity. VMA2 repression led to vacuolar alkalinization in addition to abnormal vacuolar morphology and biogenesis. Key virulence-related traits, including filamentation and secretion of degradative enzymes, were markedly inhibited. These results are consistent with previous studies of C. albicans V-ATPase; however, differential contributions of the V-ATPase Vo and V1 subunits to filamentation and secretion are observed. We also make the novel observation that inhibition of C. albicans V-ATPase results in increased susceptibility to osmotic stress. Notably, V-ATPase inhibition under conditions of nitrogen starvation results in defects in autophagy. Lastly, we show the first evidence that V-ATPase contributes to virulence in an acidic in vivo system by demonstrating that the tetR-VMA2 mutant is avirulent in a Caenorhabditis elegans infection model. This study illustrates the fundamental requirement of V-ATPase for numerous key virulence-related traits in C. albicans and demonstrates that the contribution of V-ATPase to virulence is independent of host pH. PMID- 25038083 TI - Cross kingdom functional conservation of the core universally conserved threonylcarbamoyladenosine tRNA synthesis enzymes. AB - Threonylcarbamoyladenosine (t(6)A) is a universal modification located in the anticodon stem-loop of tRNAs. In yeast, both cytoplasmic and mitochondrial tRNAs are modified. The cytoplasmic t(6)A synthesis pathway was elucidated and requires Sua5p, Kae1p, and four other KEOPS complex proteins. Recent in vitro work suggested that the mitochondrial t(6)A machinery of Saccharomyces cerevisiae is composed of only two proteins, Sua5p and Qri7p, a member of the Kae1p/TsaD family (L. C. K. Wan et al., Nucleic Acids Res. 41:6332-6346, 2013, http://dx.doi.org/10.1093/nar/gkt322). Sua5p catalyzes the first step leading to the threonyl-carbamoyl-AMP intermediate (TC-AMP), while Qri7 transfers the threonyl-carbamoyl moiety from TC-AMP to tRNA to form t(6)A. Qri7p localizes to the mitochondria, but Sua5p was reported to be cytoplasmic. We show that Sua5p is targeted to both the cytoplasm and the mitochondria through the use of alternative start sites. The import of Sua5p into the mitochondria is required for this organelle to be functional, since the TC-AMP intermediate produced by Sua5p in the cytoplasm is not transported into the mitochondria in sufficient amounts. This minimal t(6)A pathway was characterized in vitro and, for the first time, in vivo by heterologous complementation studies in Escherichia coli. The data revealed a potential for TC-AMP channeling in the t(6)A pathway, as the coexpression of Qri7p and Sua5p is required to complement the essentiality of the E. coli tsaD mutant. Our results firmly established that Qri7p and Sua5p constitute the mitochondrial pathway for the biosynthesis of t(6)A and bring additional advancement in our understanding of the reaction mechanism. PMID- 25038086 TI - Liverpool Care Pathway: life-ending pathway or palliative care pathway? PMID- 25038084 TI - Regulation of natural mRNAs by the nonsense-mediated mRNA decay pathway. AB - The nonsense-mediated mRNA decay (NMD) pathway is a specialized mRNA degradation pathway that degrades select mRNAs. This pathway is conserved in all eukaryotes examined so far, and it triggers the degradation of mRNAs that prematurely terminate translation. Originally identified as a pathway that degrades mRNAs with premature termination codons as a result of errors during transcription, splicing, or damage to the mRNA, NMD is now also recognized as a pathway that degrades some natural mRNAs. The degradation of natural mRNAs by NMD has been identified in multiple eukaryotes, including Saccharomyces cerevisiae, Drosophila melanogaster, Arabidopsis thaliana, and humans. S. cerevisiae is used extensively as a model to study natural mRNA regulation by NMD. Inactivation of the NMD pathway in S. cerevisiae affects approximately 10% of the transcriptome. Similar percentages of natural mRNAs in the D. melanogaster and human transcriptomes are also sensitive to the pathway, indicating that NMD is important for the regulation of gene expression in multiple organisms. NMD can either directly or indirectly regulate the decay rate of natural mRNAs. Direct NMD targets possess NMD-inducing features. This minireview focuses on the regulation of natural mRNAs by the NMD pathway, as well as the features demonstrated to target these mRNAs for decay by the pathway in S. cerevisiae. We also compare NMD-targeting features identified in S. cerevisiae with known NMD-targeting features in other eukaryotic organisms. PMID- 25038087 TI - Why sore throats don't aggregate against a life, but arms do. PMID- 25038088 TI - Revealing the results of whole-genome sequencing and whole-exome sequencing in research and clinical investigations: some ethical issues. AB - The introduction of new sequencing technologies whole-genome sequencing (WGS) and whole-exome sequencing (WES) that are much less finely targeted than previous genetic tests has resulted in ethical debate about what should be done with clinically significant findings that may arise during the sequencing process. In this piece we argue that, in addition to whether the finding has been intentionally sought or arises incidentally, the ethical issues concerning what should be done with WES and WGS findings are also influenced by whether sequencing occurs in a clinical or research setting. We argue that decisions about the disclosure of WGS and WES findings generated in the clinical context are much less ethically contentious than decision making about the feedback of research results. We conclude by calling for greater transparency about the purpose of sample collection, more explicit protocols for transitioning between research and clinical contexts and patients and research participants to be warned of the potential for incidental findings to be generated, their potential significance and the actions that might be taken as a result. PMID- 25038091 TI - Vitamin B6 generated by obligate symbionts is critical for maintaining proline homeostasis and fecundity in tsetse flies. AB - The viviparous tsetse fly utilizes proline as a hemolymph-borne energy source. In tsetse, biosynthesis of proline from alanine involves the enzyme alanine glyoxylate aminotransferase (AGAT), which requires pyridoxal phosphate (vitamin B6) as a cofactor. This vitamin can be synthesized by tsetse's obligate symbiont, Wigglesworthia glossinidia. In this study, we examined the role of Wigglesworthia produced vitamin B6 for maintenance of proline homeostasis, specifically during the energetically expensive lactation period of the tsetse's reproductive cycle. We found that expression of agat, as well as genes involved in vitamin B6 metabolism in both host and symbiont, increases in lactating flies. Removal of symbionts via antibiotic treatment of flies (aposymbiotic) led to hypoprolinemia, reduced levels of vitamin B6 in lactating females, and decreased fecundity. Proline homeostasis and fecundity recovered partially when aposymbiotic tsetse were fed a diet supplemented with either yeast or Wigglesworthia extracts. RNA interference-mediated knockdown of agat in wild-type flies reduced hemolymph proline levels to that of aposymbiotic females. Aposymbiotic flies treated with agat short interfering RNA (siRNA) remained hypoprolinemic even upon dietary supplementation with microbial extracts or B vitamins. Flies infected with parasitic African trypanosomes display lower hemolymph proline levels, suggesting that the reduced fecundity observed in parasitized flies could result from parasite interference with proline homeostasis. This interference could be manifested by competition between tsetse and trypanosomes for vitamins, proline, or other factors involved in their synthesis. Collectively, these results indicate that the presence of Wigglesworthia in tsetse is critical for the maintenance of proline homeostasis through vitamin B6 production. PMID- 25038092 TI - Haloalkylphosphorus hydrolases purified from Sphingomonas sp. strain TDK1 and Sphingobium sp. strain TCM1. AB - Phosphotriesterases catalyze the first step of organophosphorus triester degradation. The bacterial phosphotriesterases purified and characterized to date hydrolyze mainly aryl dialkyl phosphates, such as parathion, paraoxon, and chlorpyrifos. In this study, we purified and cloned two novel phosphotriesterases from Sphingomonas sp. strain TDK1 and Sphingobium sp. strain TCM1 that hydrolyze tri(haloalkyl)phosphates, and we named these enzymes haloalkylphosphorus hydrolases (TDK-HAD and TCM-HAD, respectively). Both HADs are monomeric proteins with molecular masses of 59.6 (TDK-HAD) and 58.4 kDa (TCM-HAD). The enzyme activities were affected by the addition of divalent cations, and inductively coupled plasma mass spectrometry analysis suggested that zinc is a native cofactor for HADs. These enzymes hydrolyzed not only chlorinated organophosphates but also a brominated organophosphate [tris(2,3-dibromopropyl) phosphate], as well as triaryl phosphates (tricresyl and triphenyl phosphates). Paraoxon-methyl and paraoxon were efficiently degraded by TCM-HAD, whereas TDK-HAD showed weak activity toward these substrates. Dichlorvos was degraded only by TCM-HAD. The enzymes displayed weak or no activity against trialkyl phosphates and organophosphorothioates. The TCM-HAD and TDK-HAD genes were cloned and found to encode proteins of 583 and 574 amino acid residues, respectively. The primary structures of TCM-HAD and TDK-HAD were very similar, and the enzymes also shared sequence similarity with fenitrothion hydrolase (FedA) of Burkholderia sp. strain NF100 and organophosphorus hydrolase (OphB) of Burkholderia sp. strain JBA3. However, the substrate specificities and quaternary structures of the HADs were largely different from those of FedA and OphB. These results show that HADs from sphingomonads are novel members of the bacterial phosphotriesterase family. PMID- 25038094 TI - Microcystin production and regulation under nutrient stress conditions in toxic microcystis strains. AB - Microcystin is a common and well-known cyanobacterial toxin whose intracellular role is still under investigation. Increasing knowledge on microcystin gene expression and regulation can contribute to the understanding of its putative cellular function. In this work, reverse transcription-quantitative PCR (RT-qPCR) was used to investigate the transcriptional response of the mcyD gene to nitrogen (nitrate and ammonium) and phosphorus limitation in two toxic Microcystis strains. The existence of a direct correlation between transcripts of mcyD and ntcA genes was also identified. In previous studies, NtcA (global nitrogen regulator) has been described as a potential component in the control of microcystin biosynthesis. This research showed that stress agents linked to nutrient deprivation could lead to a significant increase of microcystin production in both strains studied. The more toxic strain proved to be more resistant to nutrient limitation. The similar outcomes of mcyD regulation observed for all nutrients suggest that this response can be linked to oxidative stress of cells undergoing adverse growth conditions. PMID- 25038093 TI - Decoration of outer membrane vesicles with multiple antigens by using an autotransporter approach. AB - Outer membrane vesicles (OMVs) are spherical nanoparticles that naturally shed from Gram-negative bacteria. They are rich in immunostimulatory proteins and lipopolysaccharide but do not replicate, which increases their safety profile and renders them attractive vaccine vectors. By packaging foreign polypeptides in OMVs, specific immune responses can be raised toward heterologous antigens in the context of an intrinsic adjuvant. Antigens exposed at the vesicle surface have been suggested to elicit protection superior to that from antigens concealed inside OMVs, but hitherto robust methods for targeting heterologous proteins to the OMV surface have been lacking. We have exploited our previously developed hemoglobin protease (Hbp) autotransporter platform for display of heterologous polypeptides at the OMV surface. One, two, or three of the Mycobacterium tuberculosis antigens ESAT6, Ag85B, and Rv2660c were targeted to the surface of Escherichia coli OMVs upon fusion to Hbp. Furthermore, a hypervesiculating DeltatolR DeltatolA derivative of attenuated Salmonella enterica serovar Typhimurium SL3261 was generated, enabling efficient release and purification of OMVs decorated with multiple heterologous antigens, exemplified by the M. tuberculosis antigens and epitopes from Chlamydia trachomatis major outer membrane protein (MOMP). Also, we showed that delivery of Salmonella OMVs displaying Ag85B to antigen-presenting cells in vitro results in processing and presentation of an epitope that is functionally recognized by Ag85B-specific T cell hybridomas. In conclusion, the Hbp platform mediates efficient display of (multiple) heterologous antigens, individually or combined within one molecule, at the surface of OMVs. Detection of antigen-specific immune responses upon vesicle-mediated delivery demonstrated the potential of our system for vaccine development. PMID- 25038095 TI - Polyhydroxyfullerene binds cadmium ions and alleviates metal-induced oxidative stress in Saccharomyces cerevisiae. AB - The water-soluble polyhydroxyfullerene (PHF) is a functionalized carbon nanomaterial with several industrial and commercial applications. There have been controversial reports on the toxicity and/or antioxidant properties of fullerenes and their derivatives. Conversely, metals have been recognized as toxic mainly due to their ability to induce oxidative stress in living organisms. We investigated the interactive effects of PHF and cadmium ions (Cd) on the model yeast Saccharomyces cerevisiae by exposing cells to Cd (<=5 mg liter(-1)) in the absence or presence of PHF (<=500 mg liter(-1)) at different pHs (5.8 to 6.8). In the absence of Cd, PHF stimulated yeast growth up to 10.4%. Cd inhibited growth up to 79.7%, induced intracellular accumulation of reactive oxygen species (ROS), and promoted plasma membrane disruption in a dose- and pH-dependent manner. The negative effects of Cd on growth were attenuated by the presence of PHF, and maximum growth recovery (53.8%) was obtained at the highest PHF concentration and pH. The coexposure to Cd and PHF decreased ROS accumulation up to 36.7% and membrane disruption up to 30.7% in a dose- and pH-dependent manner. Two mechanisms helped to explain the role of PHF in alleviating Cd toxicity to yeasts: PHF decreased Cd-induced oxidative stress and bound significant amounts of Cd in the extracellular medium, reducing its bioavailability to the cells. PMID- 25038097 TI - Distinct effects of sorbic acid and acetic acid on the electrophysiology and metabolism of Bacillus subtilis. AB - Sorbic acid and acetic acid are among the weak organic acid preservatives most commonly used to improve the microbiological stability of foods. They have similar pKa values, but sorbic acid is a far more potent preservative. Weak organic acids are most effective at low pH. Under these circumstances, they are assumed to diffuse across the membrane as neutral undissociated acids. We show here that the level of initial intracellular acidification depends on the concentration of undissociated acid and less on the nature of the acid. Recovery of the internal pH depends on the presence of an energy source, but acidification of the cytosol causes a decrease in glucose flux. Furthermore, sorbic acid is a more potent uncoupler of the membrane potential than acetic acid. Together these effects may also slow the rate of ATP synthesis significantly and may thus (partially) explain sorbic acid's effectiveness. PMID- 25038096 TI - Using transcriptional control to increase titers of secreted heterologous proteins by the type III secretion system. AB - The type III secretion system (T3SS) encoded at the Salmonella pathogenicity island 1 (SPI-1) locus secretes protein directly from the cytosol to the culture media in a concerted, one-step process, bypassing the periplasm. While this approach is attractive for heterologous protein production, product titers are too low for many applications. In addition, the expression of the SPI-1 gene cluster is subject to native regulation, which requires culturing conditions that are not ideal for high-density growth. We used transcriptional control to increase the amount of protein that is secreted into the extracellular space by the T3SS of Salmonella enterica. The controlled expression of the gene encoding SPI-1 transcription factor HilA circumvents the requirement of endogenous induction conditions and allows for synthetic induction of the secretion system. This strategy increases the number of cells that express SPI-1 genes, as measured by promoter activity. In addition, protein secretion titer is sensitive to the time of addition and the concentration of inducer for the protein to be secreted and SPI-1 gene cluster. Overexpression of hilA increases secreted protein titer by >10-fold and enables recovery of up to 28+/-9 mg/liter of secreted protein from an 8-h culture. We also demonstrate that the protein beta-lactamase is able to adopt an active conformation after secretion, and the increase in secreted titer from hilA overexpression also correlates to increased enzyme activity in the culture supernatant. PMID- 25038098 TI - Carbohydrate coating reduces adhesion of biofilm-forming Bacillus subtilis to gold surfaces. AB - The growth of bacterial biofilms in pipes and food tanks causes severe problems in industry. Biofilms growing on medical implants or catheters are of great concern, as they can cause serious infections and decrease the functionality of the medical device. The prevention of bacterial adhesion--the first step in colonization and biofilm formation--is therefore very important. Current research comprises alterations in surface properties, the prevention of adhesin biosynthesis, inhibition with receptor analogs, or the development of anti adhesive vaccines. We present a new approach that allows us to study bacterial adhesion with high sensitivity in real-time while testing several different surfaces in parallel. Using the cantilever-array technique we demonstrate that coating of gold surfaces with mono- or disaccharides results in a reduction of the bacterial adhesion of the biofilm-forming bacterium Bacillus subtilis NCIB 3610 to these gold surfaces. This reduction in bacterial adhesion is independent of the studied carbohydrate. Using several mutant strains, we investigate the underlying molecular interactions, and our results suggest that adhesion to gold surfaces is mediated by thiol groups present in proteins of the bacterial cell membrane or biofilm matrix proteins expressed at low levels by the wild-type strain. Furthermore, our data indicate that the adhesion of B. subtilis NCIB 3610 to carbohydrate-coated gold surfaces is facilitated by interactions between carbohydrates installed on the cantilever gold surface and an exopolysaccharide expressed by this strain. Understanding general and specific contributions of molecular interactions mediating bacterial adhesion will enable its prevention in the future. PMID- 25038099 TI - Effect of metformin on metabolic improvement and gut microbiota. AB - Metformin is commonly used as the first line of medication for the treatment of metabolic syndromes, such as obesity and type 2 diabetes (T2D). Recently, metformin-induced changes in the gut microbiota have been reported; however, the relationship between metformin treatment and the gut microbiota remains unclear. In this study, the composition of the gut microbiota was investigated using a mouse model of high-fat-diet (HFD)-induced obesity with and without metformin treatment. As expected, metformin treatment improved markers of metabolic disorders, including serum glucose levels, body weight, and total cholesterol levels. Moreover, Akkermansia muciniphila (12.44%+/-5.26%) and Clostridium cocleatum (0.10%+/-0.09%) abundances increased significantly after metformin treatment of mice on the HFD. The relative abundance of A. muciniphila in the fecal microbiota was also found to increase in brain heart infusion (BHI) medium supplemented with metformin in vitro. In addition to the changes in the microbiota associated with metformin treatment, when other influences were controlled for, a total of 18 KEGG metabolic pathways (including those for sphingolipid and fatty acid metabolism) were significantly upregulated in the gut microbiota during metformin treatment of mice on an HFD. Our results demonstrate that the gut microbiota and their metabolic pathways are influenced by metformin treatment. PMID- 25038100 TI - Dead or alive: molecular assessment of microbial viability. AB - Nucleic acid-based analytical methods, ranging from species-targeted PCRs to metagenomics, have greatly expanded our understanding of microbiological diversity in natural samples. However, these methods provide only limited information on the activities and physiological states of microorganisms in samples. Even the most fundamental physiological state, viability, cannot be assessed cross-sectionally by standard DNA-targeted methods such as PCR. New PCR based strategies, collectively called molecular viability analyses, have been developed that differentiate nucleic acids associated with viable cells from those associated with inactivated cells. In order to maximize the utility of these methods and to correctly interpret results, it is necessary to consider the physiological diversity of life and death in the microbial world. This article reviews molecular viability analysis in that context and discusses future opportunities for these strategies in genetic, metagenomic, and single-cell microbiology. PMID- 25038101 TI - Evidence of environmental and vertical transmission of Burkholderia symbionts in the oriental chinch bug, Cavelerius saccharivorus (Heteroptera: Blissidae). AB - The vertical transmission of symbiotic microorganisms is omnipresent in insects, while the evolutionary process remains totally unclear. The oriental chinch bug, Cavelerius saccharivorus (Heteroptera: Blissidae), is a serious sugarcane pest, in which symbiotic bacteria densely populate the lumen of the numerous tubule like midgut crypts that the chinch bug develops. Cloning and sequence analyses of the 16S rRNA genes revealed that the crypts were dominated by a specific group of bacteria belonging to the genus Burkholderia of the Betaproteobacteria. The Burkholderia sequences were distributed into three distinct clades: the Burkholderia cepacia complex (BCC), the plant-associated beneficial and environmental (PBE) group, and the stinkbug-associated beneficial and environmental group (SBE). Diagnostic PCR revealed that only one of the three groups of Burkholderia was present in ~89% of the chinch bug field populations tested, while infections with multiple Burkholderia groups within one insect were observed in only ~10%. Deep sequencing of the 16S rRNA gene confirmed that the Burkholderia bacteria specifically colonized the crypts and were dominated by one of three Burkholderia groups. The lack of phylogenetic congruence between the symbiont and the host population strongly suggested host-symbiont promiscuity, which is probably caused by environmental acquisition of the symbionts by some hosts. Meanwhile, inspections of eggs and hatchlings by diagnostic PCR and egg surface sterilization demonstrated that almost 30% of the hatchlings vertically acquire symbiotic Burkholderia via symbiont-contaminated egg surfaces. The mixed strategy of symbiont transmission found in the oriental chinch bug might be an intermediate stage in evolution from environmental acquisition to strict vertical transmission in insects. PMID- 25038102 TI - A novel agarolytic beta-galactosidase acts on agarooligosaccharides for complete hydrolysis of agarose into monomers. AB - Marine red macroalgae have emerged to be renewable biomass for the production of chemicals and biofuels, because carbohydrates that form the major component of red macroalgae can be hydrolyzed into fermentable sugars. The main carbohydrate in red algae is agarose, and it is composed of D-galactose and 3,6-anhydro-L galactose (AHG), which are alternately bonded by beta1-4 and alpha1-3 linkages. In this study, a novel beta-galactosidase that can act on agarooligosaccharides (AOSs) to release galactose was discovered in a marine bacterium (Vibrio sp. strain EJY3); the enzyme is annotated as Vibrio sp. EJY3 agarolytic beta galactosidase (VejABG). Unlike the lacZ-encoded beta-galactosidase from Escherichia coli, VejABG does not hydrolyze common substrates like lactose and can act only on the galactose moiety at the nonreducing end of AOS. The optimum pH and temperature of VejABG on an agarotriose substrate were 7 and 35 degrees C, respectively. Its catalytic efficiency with agarotriose was also similar to that with agaropentaose or agaroheptaose. Since agarotriose lingers as the unreacted residual oligomer in the currently available saccharification system using beta agarases and acid prehydrolysis, the agarotriose-hydrolyzing capability of this novel beta-galactosidase offers an enormous advantage in the saccharification of agarose or agar in red macroalgae for its use as a biomass feedstock for fermentable sugar production. PMID- 25038103 TI - Exercise training can attenuate the inflammatory milieu in women with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation. This study sought to assess the effects of an exercise training program on cytokines and soluble TNF receptors (sTNFRs) in response to acute exercise in SLE women. Eight SLE women and 10 sex-, age-, and body mass index-comparable healthy controls (HC) participated in this study. Before and after a 12-wk aerobic exercise training program, cytokines and sTNFRs were assessed at rest and in response to single bouts of acute moderate/intense exercise. HC performed the acute exercise bouts only at baseline. After the exercise training program, there was a decrease in resting TNFR2 levels (P = 0.025) and a tend to reduction interleukin (IL)-10 levels (P = 0.093) in SLE. The resting levels of IL-6, IL-10, and TNF-alpha after the exercise training in SLE reached HC levels (P > 0.05). In response to a single bout of acute moderate exercise, the area under the curve (AUC) of IL-10 was significantly reduced after the exercise training program in SLE (P = 0.043), and the AUC of IL-10, IL-6, TNF alpha, and sTNFR1 of SLE approached control values (P > 0.05). In response to a single bout of acute intense exercise, the AUC of IL-10 was significantly reduced in SLE (P = 0.015). Furthermore, the AUC of sTNFR2 tended to decrease after exercise training program in SLE (P = 0.084), but it did not reach control values (P = 0.001). An aerobic exercise training program attenuated the inflammatory milieu in SLE women, revealing a novel homeostatic immunomodulatory role of exercise in an autoimmunity condition. PMID- 25038106 TI - Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple breath washout. AB - Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis. PMID- 25038107 TI - Invited editorial on "Surface tension in situ in flooded alveolus unaltered by albumin". PMID- 25038104 TI - VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries. AB - Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the hypothesis that chronic hypoxia produces sustained increases in smooth muscle VEGF receptor density that mediate long-term vascular effects of hypoxia. Carotid arteries from adult sheep maintained at sea level or altitude (3,820 m) for 110 days were harvested and denuded of endothelium. VEGF levels were similar in chronically hypoxic and normoxic arteries, as determined by immunoblotting. In contrast, VEGF receptor levels were significantly increased by 107% (VEGF-R1) and 156% (VEGF-R2) in hypoxic compared with normoxic arteries. In arteries that were organ cultured 24 h with 3 nM VEGF, VEGF replicated effects of hypoxia on abundances of smooth muscle alpha actin (SMalphaA), myosin light chain kinase (MLCK), and MLC20 and the effects of hypoxia on colocalization of MLC20 with SMalphaA, as measured via confocal microscopy. VEGF did not replicate the effects of chronic hypoxia on colocalization of MLCK with SMalphaA or MLCK with MLC20, suggesting that VEGF's role in hypoxic remodeling is highly protein specific, particularly for contractile protein organization. VEGF effects in organ culture were inhibited by VEGF receptor blockers vatalinib (240 nM) and dasatinib (6.3 nM). These findings support the hypothesis that long-term upregulation of VEGF receptors help mediate sustained effects of hypoxia on the abundance and colocalization of contractile proteins in arterial smooth muscle. PMID- 25038105 TI - Measuring diffusion limitation with a perfusion-limited gas--hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis. AB - Although xenon is classically taught to be a "perfusion-limited" gas, (129)Xe in its hyperpolarized (HP) form, when detected by magnetic resonance (MR), can probe diffusion limitation. Inhaled HP (129)Xe diffuses across the pulmonary blood-gas barrier, and, depending on its tissue environment, shifts its resonant frequency relative to the gas-phase reference (0 ppm) by 198 ppm in tissue/plasma barrier and 217 ppm in red blood cells (RBCs). In this work, we hypothesized that in patients with idiopathic pulmonary fibrosis (IPF), the ratio of (129)Xe spectroscopic signal in the RBCs vs. barrier would diminish as diffusion limitation delayed replenishment of (129)Xe magnetization in RBCs. To test this hypothesis, (129)Xe spectra were acquired in 6 IPF subjects as well as 11 healthy volunteers to establish a normal range. The RBC:barrier ratio was 0.55 +/- 0.13 in healthy volunteers but was 3.3-fold lower in IPF subjects (0.16 +/- 0.03, P = 0.0002). This was caused by a 52% reduction in the RBC signal (P = 0.02) and a 58% increase in the barrier signal (P = 0.01). Furthermore, the RBC:barrier ratio strongly correlated with lung diffusing capacity for carbon monoxide (DLCO) (r = 0.89, P < 0.0001). It exhibited a moderate interscan variability (8.25%), and in healthy volunteers it decreased with greater lung inflation (r = -0.78, P = 0.005). This spectroscopic technique provides a noninvasive, global probe of diffusion limitation and gas-transfer impairment and forms the basis for developing 3D MR imaging of gas exchange. PMID- 25038109 TI - Erratum. PMID- 25038113 TI - Herpes zoster and stroke: implications for therapy and vaccination. PMID- 25038112 TI - Reply to He et al. PMID- 25038115 TI - Statistics and reevaluation of the risk of fetal death and malformation after Q fever. PMID- 25038114 TI - Incidence and risk factors for invasive pneumococcal disease in HIV-infected and non-HIV-infected individuals before and after the introduction of combination antiretroviral therapy: persistent high risk among HIV-infected injecting drug users. AB - BACKGROUND: Invasive pneumococcal disease (IPD) is an important cause of morbidity among individuals infected with human immunodeficiency virus (HIV). We described incidence and risk factors for IPD in HIV-infected and uninfected individuals. METHODS: Nationwide population-based cohort study of HIV-infected adults treated at all Danish HIV treatment centers during 1995-2012. Nineteen population-matched controls per HIV-infected individual were retrieved. The risk of IPD was assessed using Poisson regression. RESULTS: The incidence of IPD was 304.7 cases per 100 000 person-years of follow-up (PYFU) in HIV-infected and 12.8 per 100 000 PYFU in HIV-uninfected individuals. After adjusting for confounders, HIV infection (relative risk [RR], 24.4 [95% confidence interval [CI], 23.7 25.1]), male sex (RR, 1.20 [95% CI, 1.16-1.24]), increasing age (per year) (RR, 1.03 [95% CI, 1.03-1.04]), and calendar period (pre-cART RR, 2.80 [95% CI, 2.70 2.91] compared with late cART) were significantly associated with an increased risk of IPD. Among HIV-infected individuals, male sex (RR, 1.57 [95% CI, 1.49 1.66]), smoking (RR, 1.34 [95% CI, 1.26-1.42]), and injecting drug use (RR, 2.51 [95% CI, 2.26-2.67]) were associated with an increased risk of IPD. Detectable viral loads (RR, 1.88 [95% CI, 1.79-1.98]) and a relative fall in CD4 T-cell counts were also associated with an increased risk (>=500 to 350-500 CD4 T cells/uL: RR, 1.29 [95% CI, 1.21-1.37] and <100 cells/uL: RR, 7.4 [95% CI, 6.87 8.02]). The risk of IPD declined over time, although this was not the case for IDUs where the risk remained unchanged. CONCLUSIONS: The incidence of IPD in HIV infected individuals remained significantly higher than the incidence observed in non-HIV-infected subjects, despite the widespread use of cART. IDUs have a persistently high risk of IPD. Injecting drug use, smoking, and the receipt of cART are suitable targets for preventive measures in the future. PMID- 25038116 TI - Rapid disease progression in HIV-1 subtype C-infected South African women. AB - BACKGROUND: Whereas human immunodeficiency virus (HIV) subtype B-infected individuals generally progress to AIDS within 8-10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C-infected South African women. METHODS: Prospective seroincidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n = 245) or every 3 months (n = 594) for up to 4 years. Rapid disease progression was defined as CD4 decline to <350 cells/uL by 2 years postinfection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models. RESULTS: Sixty-two women were identified at a median of 42 days postinfection (interquartile range, 34-59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months postinfection in women with preinfection measurements. CD4 decline to <350 cells/uL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years postinfection, respectively, and to <500 cells/uL in 69%, 79%, and 81% at equivalent timepoints. Predictors of rapid progression were CD4 count at 3 months postinfection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31-3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51-9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31-15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non rapid progression (HR, 0.19; 95% CI, .05-.74; P = .016). CONCLUSIONS: Nearly half of subtype C-infected women progressed to a CD4 count <350 cells/uL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4 count <500 cells/uL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection. PMID- 25038117 TI - Assessment of total retinal blood flow using Doppler Fourier Domain Optical Coherence Tomography during systemic hypercapnia and hypocapnia. AB - The purpose of this study was to investigate changes in total retinal blood flow (RBF) using Doppler Fourier Domain Optical Coherence Tomography (Doppler FD-OCT) in response to the manipulation of systemic partial pressure of CO2 (PETCO2). Double circular Doppler blood flow scans were captured in nine healthy individuals (mean age +/- standard deviation: 27.1 +/- 4.1, six males) using the RTVue(TM) FD-OCT (Optovue). PETCO2 was manipulated using a custom-designed computer-controlled gas blender (RespirAct(TM)) connected to a sequential gas delivery rebreathing circuit. Doppler FD-OCT measurements were captured at baseline, during stages of hypercapnia (+5/+10/+15 mmHg PETCO2), return to baseline and during stages of hypocapnia (-5/-10/-15 mmHg PETCO2). Repeated measures analysis of variance (reANOVA) and Tukey's post hoc analysis were used to compare Doppler FD-OCT measurements between the various PETCO2 levels relative to baseline. The effect of PETCO2 on TRBF was also investigated using linear regression models. The average RBF significantly increased by 15% (P < 0.0001) with an increase in PETCO2 and decreased significantly by 10% with a decrease in PETCO2 (P = 0.001). Venous velocity significantly increased by 3.11% from baseline to extreme hypercapnia (P < 0.001) and reduced significantly by 2.01% at extreme hypocapnia (P = 0.012). No significant changes were found in the average venous area measurements under hypercapnia (P = 0.36) or hypocapnia (P = 0.40). Overall, increased and decreased PETCO2 values had a significant effect on RBF outcomes (P < 0.002). In healthy individuals, altered end-tidal CO2 levels significantly changed RBF as measured by Doppler FD-OCT. PMID- 25038118 TI - Condition-dependent ornaments, life histories, and the evolving architecture of resource-use. AB - Over the past 20 years, researchers have emphasized condition-dependency as a core feature of many sexually selected ornaments. This empirical focus has been motivated by the assumption that condition-dependent ornaments should function as honest indicators of other fitness-related traits. However, evidence remains mixed regarding whether condition-dependent ornaments are consistently correlated with the expression of other key traits such as immunocompetence. I argue that the diversity of the observed relationships between condition-dependent ornaments and other fitness-related traits can be understood, and even predicted, based on attention to the structure of organisms' life histories. More specifically, these relationships are influenced by the relative variation between individuals within a population in their acquisition of resources versus the allocation of those resources to various physiological functions. However, characterizing these two core attributes of life histories requires that researchers quantify condition, a persistently challenging concept to measure empirically. In this review, I first highlight key concepts related to condition-dependency and life history theory. I then outline why measuring the acquisition and allocation of relevant resources is critical for advancing our understanding of sexually selected ornaments. As attempts to tackle these issues have been hampered in the past by empirical challenges, I offer a number of suggestions that aim to identify more tractable approaches to measuring condition, as well as its acquisition and allocation. I conclude by pointing to the broader value of pursuing these concepts empirically as well as to exciting new directions opened by this perspective. PMID- 25038120 TI - Late prosthetic graft infection after frozen elephant trunk presenting by haemoptysis and positive 18F-fluorodeoxyglucose-positron emission tomography/computed tomography. AB - In cardiothoracic surgery, prosthetic graft infection represents a diagnostic and therapeutic challenge. Although clinical assessment, imaging techniques and microbiological investigations are helpful, late graft infection can be difficult to identify using classical diagnostic tools. An aggressive surgical approach involving removal and replacement of all prosthetic materials is technically demanding but remains the best strategy to eradicate infection. Herein, we report a case of a late aortic graft infection, after frozen elephant trunk implantation with atypical presentation, diagnosed with (18)F-fluorodeoxyglucose-positron emission tomography and treated successfully through a radical surgical strategy. This case emphasizes the emerging diagnostic role of positron emission tomography and encourages the adoption of an aggressive surgical approach. PMID- 25038119 TI - Survival after primary prevention implantable cardioverter-defibrillator placement among patients with chronic kidney disease. AB - BACKGROUND: Guidelines recommend that implantable cardioverter-defibrillator (ICD) candidates have an estimated longevity of >=1 year. Longevity can be affected by chronic kidney disease (CKD). METHODS AND RESULTS: Using the National Cardiovascular Data Registry ICD registry linked with the Social Security Death Master File, we assessed the rate of death after primary prevention ICD placement between January 1, 2006, and December 31, 2007, according to CKD stage. Using Cox models, we identified factors associated with death among patients with CKD. Compared with patients without CKD (n=26,056), those with CKD (n=21,226) were older, less commonly men, more often white, and more frequently had comorbid illness. Compared with patients without CKD, patients with a glomerular filtration rate 30 to 60, glomerular filtration rate <30, and end-stage renal disease on dialysis had a higher risk of death after ICD placement (hazard ratio, 2.08; 95% confidence interval, 1.99-2.18; P<0.0001; hazard ratio, 4.20; 95% confidence interval, 3.92-4.50; P<0.0001; and hazard ratio, 4.80; 95% confidence interval, 4.46-5.17; P<0.0001, respectively). Corresponding 1-year death rates were 4.4%, 9.1%, 20.2%, and 22.4%. Among patients with CKD, factors associated with increased risk of death included CKD severity, age >65 years, heart failure symptoms, diabetes mellitus, lung disease, serum sodium <140 mEq/L, atrial fibrillation or flutter, and a lower ejection fraction. CONCLUSIONS: The risk of death after primary prevention ICD placement is proportional to CKD severity. Among patients with CKD, several factors are prognostically significant and could inform clinical decision making on primary prevention ICD candidacy. PMID- 25038121 TI - Therapeutic surgery without a definitive diagnosis can be an option in selected patients with suspected lung cancer. AB - OBJECTIVES: With the recent improvements in the diagnostic accuracy of radiographic modalities, it might be an option to perform therapeutic surgery without a definitive diagnosis for selected patients with suspected lung cancer based on the findings of diagnostic imaging. METHODS: Between April 2008 and December 2012, all nodules without a definitive diagnosis were classified into five categories according to the probability of lung cancer based on the diagnostic imaging: Category 1 (Benign), Category 2 (Probably benign), Category 3 (Intermediate), Category 4 (Suspected malignancy) and Category 5 (Highly suggestive of malignancy). In this study, the 232 surgical candidates for suspected clinical stage I lung cancer without a preoperative definitive diagnosis were considered to be Category 3 (n = 29), Category 4 (n = 46) and Category 5 (n = 157). Eighty-two patients (72% of Category 3, 46% of Category 4 and 25% of Category 5) had an intraoperative diagnosis during surgery, whereas the remaining 150 patients did not. The final pathological diagnosis and surgical outcomes were analysed. RESULTS: The final pathological diagnosis of the 232 suspicious nodules revealed 214 lung cancers (52% of Category 3, 93% of Category 4 and 99% of Category 5). Wedge resection was performed for all seven benign tumours. In the multiple regression analysis, intraoperative diagnosis was a significant factor for the length of the operation. In the multivariate logistic regression analysis, the length of the operation was a significant factor predicting both the postoperative morbidity and a prolonged hospital stay. CONCLUSIONS: Based on a careful clinical decision made using the current diagnostic imaging strategies, patients with a high probability of lung cancer are good candidates for therapeutic surgery, even without a preoperative or intraoperative definitive diagnosis. PMID- 25038122 TI - Etiologic spectrum of biopsy-proven peripheral neuropathies in childhood from a resource-poor setting. AB - There are only a few studies describing the etiologic spectrum of biopsy-proven peripheral neuropathies in children. This study reviewed the clinical, electrophysiological, and pathologic profile of 239 children (<=18 years of age) who have undergone nerve biopsy in a tertiary care centre for neurologic disorders and analyzed the etiologic spectrum and utility of nerve biopsy. The clinical profile, neuropathologic findings, and other investigations were combined to infer the final diagnosis. Neuropathy was detected in 199 biopsies; axonal pathology in 43%; demyelination in 41%; mixed pattern in 8%; and nonspecific findings in 8%. The major diagnostic categories included hereditary neuropathies (48%), heredodegenerative and metabolic disorders (27%), and inflammatory neuropathies (12%). Nerve biopsy proved most helpful in diagnosis of demyelinating and inflammatory neuropathies, reiterating its usefulness in specific situations. PMID- 25038123 TI - Epilepsy in children with Menkes disease: a systematic review of literature. AB - Menkes disease is a lethal multisystemic disorder of copper metabolism characterized by connective tissue abnormalities, progressive neurodegeneration and peculiar "kinky hair." Epilepsy is one of the main clinical features of this disease but it has been described in detail by only a few authors. Most patients develop seizures from 2 to 3 months of age, accompanied by a neurodevelopmental regression. The history of epilepsy is usually characterized by 3 stages: an early stage with focal clonic seizures and status epilepticus, an intermediate stage with infantile spasms, and a late stage with multifocal, myoclonic, and tonic seizures. At the onset, epilepsy can be controlled with anticonvulsant therapy, whereas with the progression of disease, it becomes extremely resistant to all antiepileptic drugs. In this article, we analyze clinical and electroencephalographic (EEG) characteristics of epilepsy in patients with this syndrome. PMID- 25038124 TI - Upper Extremity Multifocal Neuropathy in a 10-Year-Old Boy Associated With NS6S Disaccharide Antibodies. AB - We present a 10-year-old boy with a predominantly motor multifocal neuropathy with demyelinating and axonal changes with sensory involvement, affecting only one upper extremity. Laboratory studies revealed an elevated titer of immunoglobulin M (IgM) antibodies against the NS6S antigen. He responded to treatment with high dose intravenous immunoglobulins. Focal or multifocal immune mediated neuropathies are not common in children and may be underdiagnosed. PMID- 25038125 TI - An additional patient with 3q27.3 microdeletion syndrome. AB - The 3q27.3 microdeletion syndrome has been recently delineated in 7 subjects from 5 families sharing a 1.4 Mb smallest region of overlap. This condition appears recognizable by the association of Marfanoid habitus, mild but distinctive facial dysmorphism, intellectual disability, psychosis, and mood disorder. Here, we describe an additional 17-year-old man with an ~7.7-Mb deletion encompassing the 3q27.3 microdeletion critical region, previously run undetected at standard karyotyping. The constellation of major clinical findings overlaps with those reported in the 7 previously published patients and thus confirms the existence of a strongly recognizable syndrome linked to imbalance of 3q27.3. The role of AHSG and, possibly, of other genes in determining the 3q27.3 microdeletion habitus is discussed by comparison of the deleted segments. The involvement of adjacent loci and genes, such as OPA1 and GP5, may contribute in this patient to novel satellite features, such as optic atrophy and subclinical coagulopathy. PMID- 25038126 TI - Childhood autism spectrum disorders with and without epilepsy: clinical implications. AB - This prospective cross-sectional study compared 25 children with pervasive developmental disorder and epilepsy and 25 children having pervasive developmental disorder without epilepsy on pervasive developmental disorder scores, Childhood Autism Rating Scale scores, language disability, presence of regression, and epileptiform abnormalities. Epilepsy phenotype was also studied. Children with pervasive developmental disorder and epilepsy had higher pervasive developmental disorder scores (P = .001), higher Childhood Autism Rating Scale scores (P = .016), and lower social quotient (P = .09). More than 50% of children with pervasive developmental disorder and epilepsy and 12% of children having pervasive developmental disorder without epilepsy had epileptiform abnormalities in electroencephalography (EEG). Regression of milestones was significantly associated with epilepsy and epileptiform abnormalities. Children with pervasive developmental disorder and epilepsy might have a worse developmental trajectory requiring intensive management. A behavioral phenotype of autism may coexist often in children with epilepsy, EEG abnormalities, and regression. Seizures might be difficult to control in these children despite adequate compliance. Studies with larger sample size and longitudinal follow-up will provide better understanding. PMID- 25038127 TI - The relationship between visual orienting responses and clinical characteristics in children attending special education for the visually impaired. AB - We recently introduced a method based on quantification of orienting responses toward visual stimuli to assess the quality of visual information processing in children. In the present study, we examined the relationship between orienting responses and factors that are associated with visual processing impairments in current clinical practice. Response time and fixation quality to visual features such as form, contrast, motion, and color stimuli were assessed in 104 children from 1 to 12 years attending special education for the visually impaired. Using regression analysis, we investigated whether these parameters were affected by clinical characteristics of children. Response times significantly depended on stimulus type. Responses to high-contrast cartoons were significantly slower in children with a clinical diagnosis of cerebral visual impairment. Fixation quality was significantly affected by visual acuity and nystagmus. The results suggest that the quantitative measurement of orienting responses is strongly related to cerebral visual impairment in children. PMID- 25038128 TI - Severe Acute Subdural Hemorrhage in a Patient With Glutaric Aciduria Type I After Minor Head Trauma: A Case Report. AB - Glutaric aciduria type I is a rare metabolic disorder caused by deficiency of glutaryl-coenzyme A dehydrogenase. Chronic subdural hematomas have been reported in glutaric aciduria type I and are considered as important differential diagnosis of nonaccidental head trauma. However, chronic subdural hematomas are usually thought to remain clinically silent in these patients. Here we report on a hitherto asymptomatic glutaric aciduria type I patient who developed severe, acute subdural hemorrhage after minor accidental head injury at age 23 months. Computed tomography confirmed significant mass effect on the brain necessitating decompressive hemicraniectomy. Subdural hemorrhage caused large hypoxic lesions of the cerebral cortex and subcortical regions resulting in spastic tetraplegia, dystonia, and loss of developmental milestones. This report emphasizes that acute subdural hemorrhage may be a life-threatening complication in glutaric aciduria type I patients after minor head trauma and should be considered in those patients presenting with neurologic deterioration after accidental head injury. PMID- 25038129 TI - Phenotypic analysis of epilepsy in the mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes-associated mitochondrial DNA A3243G mutation. AB - The A to G mitochondrial DNA point mutation at position 3243 (A3243G) is the most common cause of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), a systemic multiorgan disease. Epilepsy is a common finding but there is wide phenotypic variation that has not been thoroughly explored. We report the epilepsy phenotypes of 7 patients with the A3243G mutation. Most presented with typical MELAS and epilepsy characterized by infrequent prolonged focal seizures, including epilepsia partialis continua, hemiclonic status epilepticus, nonconvulsive status, and occipital status epilepticus. Seizures usually occurred during the acute phase of a strokelike episode. Periodic lateralized epileptiform discharges may be seen electrographically. Some patients with this mutation are completely asymptomatic or have mild symptoms typical for mitochondrial diseases. Slow spike-wave activity consistent with Lennox-Gastaut syndrome and electrographic status epilepticus was seen in 1 patient who responded to ethosuximide. PMID- 25038130 TI - Risk factors and imaging characteristics of childhood stroke in china. AB - There are scarce reports of childhood stroke from China. Our objective was to describe the clinical spectrum, risk factors, and imaging characteristics of childhood stroke in China. Using a hospital discharge database, children with stroke who were first admitted from 2002 to 2011 were retrospectively enrolled. We identified 478 first admissions with childhood stroke, including 229 cases of ischemic stroke and 249 hemorrhagic stroke. Boys accounted for more than 60% in all stroke types (62.2% for ischemic stroke, intracerebral hemorrhage for 66.2%). The leading cause was moyamoya for ischemic stroke and arteriovenous malformations for intracerebral hemorrhage. Hemiplegia and headache were the most common presenting features. Internal carotid artery and middle cerebral artery were the most involved arteries according to imaging examination in the ischemic stroke. A total of 8 patients died of intracerebral hemorrhage. The prevalence of hemorrhagic stroke was more than that of ischemic stroke. As Western countries, arteriopathy was the most common cause of childhood stroke. PMID- 25038131 TI - Intracranial hypertension without headache in children. AB - We aimed to determine the frequency of intracranial hypertension without headache in children. We retrospectively analyzed patients evaluated in a pediatric intracranial hypertension referral center. Patients were divided into 2 groups depending on whether they complained of headache at the time of presentation. Age, body mass index, and opening cerebrospinal fluid pressures were considered continuous variables and compared by Wilcoxon rank-sum test because of non normality. A P value of .05 was considered significant. A total of 228 charts were reviewed; 152 patients met the criteria for intracranial hypertension and 22/152 patients (14.5%) met the criteria of optic nerve edema without headache. There were clinically significant differences in age and body mass index between the 2 groups. The group without headache was typically younger and not obese. The opening pressure and modified opening pressure were not clinically significant between the 2 groups. PMID- 25038132 TI - The epidemiology of epilepsy in children: a report from a Turkish pediatric neurology clinic. AB - This retrospective cohort study aims to assess the distribution of seizure types and epileptic syndromes in children with epilepsy who were followed up in a tertiary outpatient pediatric neurology clinic between January 2004 and December 2009. The findings of 533 children aged between 2 months and 16 years were evaluated. The International League Against Epilepsy criteria (of 1981 and 1989) were used for diagnosis and classification. The rate of partial seizures (56.5%) was higher than that of generalized seizures (43.5%). Partial seizures were more common during late childhood (P < .001). Localization-related epilepsies (53.3%) were more frequent than generalized epilepsies (37.1%). Generalized epilepsies were more frequent during the first year of life, whereas localization-related epilepsies were more common at later ages (P < .001). The majority had a symptomatic etiology (47.1%). The increased frequency of symptomatic etiologies attributed to perinatal insults suggests that intractable epilepsies during childhood represent an important health issue for developing countries. PMID- 25038133 TI - Viscum Album in the Treatment of a Girl With Refractory Childhood Absence Epilepsy. AB - Viscum album (European mistletoe) extracts have known immunomodulatory effects but little data exist on anticonvulsant activity despite its usefulness having been reported for centuries. A 41/2-year-old girl with childhood absence epilepsy and global developmental delay was treated with different antiepileptic drugs and ketogenic diet but failed to become seizure free over a 2-year period. She also received different herbal remedies as part of an integrative medicine approach. Initial improvement occurred on valproate-ethosuximide, a further improvement was seen after adding clobazam to valproate. Final cessation of absence activity occurred after a dose increase of V album. She was still seizure free at the 12 month follow-up. V album appears to have been a necessary adjunct treatment for this child to become seizure free. We call on physicians to report their experiences of V album in epilepsy and suggest further study. PMID- 25038134 TI - High Factor VIII and Von Willebrand Factor Levels Are Not Risk Factors of Cryptogenic Arterial Ischemic Stroke in Thai Children. AB - High factor VIII levels and a risk factor of arterial ischemic stroke is controversial. Levels of factor VIII depend on ethnicity, age, and sex. This report included 24 Thai children with cryptogenic arterial ischemic stroke and 41 controls, with a mean (standard deviation) age of 11.5 (6.3) and 9.0 (4.7), respectively. The study was performed during the post-arterial ischemic stroke events to avoid acute phase reaction of factor VIII and von Willebrand factor. The levels of factor VIII activity and von Willebrand factor antigen in patients were not significantly different compared to controls (119.8 +/- 41.3% vs 138.0 +/- 48.7%, P = .29 and 92.8 +/- 29.8% vs 103.7 +/- 39.1%, P = .4, respectively). Therefore, high factor VIII and von Willebrand factor antigen levels were not risk factors of cryptogenic arterial ischemic stroke in Thai children. PMID- 25038135 TI - Outbreaks due to Mycobacterium abscessus subsp. bolletii in southern Brazil: persistence of a single clone from 2007 to 2011. AB - Outbreaks associated with rapidly growing mycobacteria (RGM) have been increasingly reported worldwide, including in Brazil. Among the RGM, the Mycobacterium abscessus complex is the most pathogenic and related to multidrug resistance. The aim of this study was to evaluate the antimicrobial susceptibility and molecular profile of RGM isolates involved in new postsurgical infection outbreaks in Brazil since 2007. Of the 109 cases reported in the state of Rio Grande do Sul between 2007 and 2011, 43 (39 %) had confirmed mycobacterial growth in culture. Clinical isolates were obtained from biopsy specimens or abscess aspirates. PRA-hsp65 restriction pattern identified the isolates as M. abscessus type 2, and partial rpoB sequencing confirmed the identification as M. abscessus subsp. bolletii. All isolates were susceptible to amikacin and resistant to ciprofloxacin, doxycycline, sulfamethoxazole, moxifloxacin and tobramycin. Most isolates (72 %) were fully susceptible to cefoxitin but six isolates (14 %) were fully resistant to clarithromycin. The latter differed from the susceptibility profiles of the previously described BRA100 clone from other Brazilian regions. Nevertheless, pulsed-field gel electrophoresis analysis revealed that these isolates belonged to a single BRA100 clone. In conclusion, our study reports the persistence of an emergent single and highly resistant clone of M. abscessus subsp. bolletii for several years even after national implementation of infection control measures. PMID- 25038136 TI - Characteristics of microbial drug resistance and its correlates in chronic diabetic foot ulcer infections. AB - While virulence factors and the biofilm-forming capabilities of microbes are the key regulators of the wound healing process, the host immune response may also contribute in the events following wound closure or exacerbation of non-closure. We examined samples from diabetic and non-diabetic foot ulcers/wounds for microbial association and tested the microbes for their antibiotic susceptibility and ability to produce biofilms. A total of 1074 bacterial strains were obtained with staphylococci, Pseudomonas, Citrobacter and enterococci as major colonizers in diabetic samples. Though non-diabetic samples had a similar assemblage, the frequency of occurrence of different groups of bacteria was different. Gram negative bacteria were found to be more prevalent in the diabetic wound environment while Gram-positive bacteria were predominant in non-diabetic ulcers. A higher frequency of monomicrobial infection was observed in samples from non diabetic individuals when compared to samples from diabetic patients. The prevalence of different groups of bacteria varied when the samples were stratified according to age and sex of the individuals. Several multidrug resistant strains were observed among the samples tested and most of these strains produced moderate to high levels of biofilms. The weakened immune response in diabetic individuals and synergism among pathogenic micro-organisms may be the critical factors that determine the delicate balance of the wound healing process. PMID- 25038138 TI - Use of the 5' untranslated region and VP1 region to examine the molecular diversity in enterovirus B species. AB - Human enteroviruses evolve quickly. The 5' untranslated region (UTR) is fundamentally important for efficient viral replication and for virulence; the VP1 region correlates well with antigenic typing by neutralization, and can be used for virus identification and evolutionary studies. In order to investigate the molecular diversity in EV-B species, the 5' UTR and VP1 regions were analysed for 208 clinical isolates from a single public-health laboratory (serving New South Wales, Australia), representing 28 EV-B types. Sequences were compared with the 5' UTR and VP1 regions of 98 strains available in GenBank, representing the same 28 types. The genetic relationships were analysed using two types of software (mega and BioNumerics). The sequence analyses of the 5' UTR and VP1 regions of 306 EV-B strains demonstrated that: (i) comparing the two regions gives strong evidence of epidemiological linkage of strains in some serotypes; (ii) the intraserotypic genetic variation within each gene reveals that they evolve distinctly largely due to their different functions; and (iii) mutation and possible recombination in the two regions play significant roles in the molecular diversity of EV-B. Understanding the tempo and pattern of molecular diversity and evolution is of great importance in the pathogenesis of EV-B enteroviruses, information which will assist in disease prevention and control. PMID- 25038137 TI - Emergence of carbapenem-resistant Acinetobacter baumannii as the major cause of ventilator-associated pneumonia in intensive care unit patients at an infectious disease hospital in southern Vietnam. AB - Ventilator-associated pneumonia (VAP) is a serious healthcare-associated infection that affects up to 30 % of intubated and mechanically ventilated patients in intensive care units (ICUs) worldwide. The bacterial aetiology and corresponding antimicrobial susceptibility of VAP is highly variable, and can differ between countries, national provinces and even between different wards in the same hospital. We aimed to understand and document changes in the causative agents of VAP and their antimicrobial susceptibility profiles retrospectively over an 11 year period in a major infectious disease hospital in southern Vietnam. Our analysis outlined a significant shift from Pseudomonas aeruginosa to Acinetobacter spp. as the most prevalent bacteria isolated from quantitative tracheal aspirates in patients with VAP in this setting. Antimicrobial resistance was common across all bacterial species and we found a marked proportional annual increase in carbapenem-resistant Acinetobacter spp. over a 3 year period from 2008 (annual trend; odds ratio 1.656, P = 0.010). We further investigated the possible emergence of a carbapenem-resistant Acinetobacter baumannii clone by multiple-locus variable number tandem repeat analysis, finding a blaOXA-23 positive strain that was associated with an upsurge in the isolation of this pathogen. We additionally identified a single blaNDM-1-positive A. baumannii isolate. This work highlights the emergence of a carbapenem-resistant clone of A. baumannii and a worrying trend of antimicrobial resistance in the ICU of the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. PMID- 25038139 TI - High resolution melting analysis for the differentiation of Mycobacterium species. AB - A quantitative real-time PCR (qPCR) followed by high resolution melting (HRM) analysis was developed for the differentiation of Mycobacterium species. Rapid differentiation of Mycobacterium species is necessary for the effective diagnosis and management of tuberculosis. In this study, the 16S rRNA gene was tested as the target since this has been identified as a suitable target for the identification of mycobacteria species. During the temperature gradient and primer optimization process, the melting peak (Tm) analysis was determined at a concentration of 50 ng DNA template and 0.3, 0.4 and 0.5 uM primer. The qPCR assay for the detection of other mycobacterial species was done at the Tm and primer concentration of 62 degrees C and 0.4 uM, respectively. The HRM analysis generated cluster patterns that were specific and sensitive to distinguished small sequence differences of the Mycobacterium species. This study suggests that the 16S rRNA-based real-time PCR followed by HRM analysis produced unique cluster patterns for species of Mycobacterium and could differentiate the closely related mycobacteria species. PMID- 25038140 TI - Use of Ranolazine in the Prevention and Treatment of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery. PMID- 25038141 TI - Coronary artery disease in offender populations: incarceration as a risk factor and a point of intervention. AB - Coronary artery disease (CAD) is a significant health problem and global burden. Research on antisocial behaviors has identified some groups of offenders as vulnerable to the development of cardiovascular disorders. This article reviews the relationship between criminal offending and CAD, with a particular emphasis on incarcerated populations. Existing research supports this link, with incarceration demonstrating substantial associations with numerous cardiac risk factors, development of cardiac problems, and cardiovascular disease mortality. Comprehensive multicomponent prevention programs, while often available in the community, have received little research attention in prison settings. In addition to clarifying the relationship between incarceration and heart disease, this article reviews various treatment and management responses made by prison officials. PMID- 25038142 TI - Qualitative analysis of transgender inmates' correspondence: implications for departments of correction. AB - Claims of inadequate health care and safety afforded to transgender inmates have become the subject of litigation. This article reviews 129 unsolicited letters from transgender inmates writing from 24 states and the Federal Bureau of Prisons to identify their concerns. Among the letters reviewed were reports from 10 inmates who had filed lawsuits naming departments of correction (DOCs) as defendants, claiming inadequate access to transgender health care. Five of these lawsuits have gone to trial. In all of those cases, the defendant settled the matter or was found liable as of the time of this report. Claims of inadequate care for transgendered patients that have sufficient merit to be fully litigated in U.S. courts appear likely to produce verdicts in favor of plaintiff inmates. The information gleaned from reviewing letters from transgendered inmates may alert staffs of DOCs to concerns worth addressing proactively to avoid the costs associated with transgender-related lawsuits. PMID- 25038143 TI - Ectopic trypsin in the myocardium promotes dilated cardiomyopathy after influenza A virus infection. AB - We have previously reported that ectopic trypsin in the myocardium triggers acute myocarditis after influenza A virus (IAV) infection. As myocarditis is a common precursor to dilated cardiomyopathy (DCM), the aim of the present study was to investigate the influence of trypsin on the progression of DCM after IAV infection. IAV-infected mice treated with saline or trypsin inhibitor were euthanized on days 0, 9, 20, 40 and 60 postinfection. Trypsin expression colocalized with myocardial inflammatory loci and IAV-induced myocarditis peaked on day 9 postinfection and alleviated by day 20 but persisted until day 60 postinfection, even though replication of IAV was not detected from day 20 postinfection. Similar time courses were observed for the activation of pro matrix metalloproteinase (pro-MMP)-9 and expression of the proinflammatory cytokines IL-6, IL-1beta, and TNF-alpha. Degradation of collagen type I, proliferation of ventricular interstitial collagen, and expression of collagen type I and III mRNA increased significantly during acute and chronic phases; collagen type III mRNA increased more significantly than collagen type I mRNA. Cardiac function progressively deteriorated with progressive left ventricular dilation. The trypsin inhibitor aprotinin suppressed pro-MMP-9 activation and cytokine release, alleviated myocardial inflammation, and restored collagen metabolism during acute and chronic phases of myocarditis. This effectively prevented ventricular dilation and improved cardiac function. These results suggest that ectopic trypsin in the myocardium promoted DCM through chronic activation of pro-MMP-9, persistent induction of cytokines, and mediation of collagen remodeling. Pharmacological inhibition of trypsin activity might be a promising approach for the prevention of viral cardiomyopathy. PMID- 25038144 TI - Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells. AB - Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT. PMID- 25038145 TI - An afferent explanation for sexual dimorphism in the aortic baroreflex of rat. AB - Sex differences in baroreflex (BRx) function are well documented. Hormones likely contribute to this dimorphism, but many functional aspects remain unresolved. Our lab has been investigating a subset of vagal sensory neurons that constitute nearly 50% of the total population of myelinated aortic baroreceptors (BR) in female rats but less than 2% in male rats. Termed "Ah," this unique phenotype has many of the nonoverlapping electrophysiological properties and chemical sensitivities of both myelinated A-type and unmyelinated C-type BR afferents. In this study, we utilize three distinct experimental protocols to determine if Ah type barosensory afferents underlie, at least in part, the sex-related differences in BRx function. Electron microscopy of the aortic depressor nerve (ADN) revealed that female rats have less myelin (P < 0.03) and a smaller fiber cross-sectional area (P < 0.05) per BR fiber than male rats. Electrical stimulation of the ADN evoked compound action potentials and nerve conduction profiles that were markedly different (P < 0.01, n = 7 females and n = 9 males). Selective activation of ADN myelinated fibers evoked a BRx-mediated depressor response that was 3-7 times greater in female (n = 16) than in male (n = 17) rats. Interestingly, the most striking hemodynamic difference was functionally dependent upon the rate of myelinated barosensory fiber activation. Only 5-10 Hz of stimulation evoked a rapid, 20- to 30-mmHg reduction in arterial pressure of female rats, whereas rates of 50 Hz or higher were required to elicit a comparable depressor response from male rats. Collectively, our experimental results are suggestive of an alternative myelinated baroreceptor afferent pathway in females that may account for, at least in part, the noted sex-related differences in autonomic control of cardiovascular function. PMID- 25038146 TI - Increased aortic stiffness elevates pulse and mean pressure and compromises endothelial function in Wistar rats. AB - An increase in pulse pressure (PP) is highly associated with hypertension. The goal of this study was to determine the effect of increased aortic stiffness on PP and endothelial dysfunction as precursors to hypertension. A rat model of suddenly increased aortic stiffness by use of a nonconstrictive restraint (glue coating) on aortic surface was created to investigate the change of PP and mean arterial pressure (MAP). Group I (n = 16) underwent aorta restraint for 4 wk. Group II (n = 12) underwent aortic restraint for 4 wk, followed by restraint removal to evaluate extent of reversibility for additional 4 wk. The aortic and peripheral endothelial function was assessed by ACh-stimulated endothelium dependent vasodilation. The level of nitrate/nitrite (NOx), endothelin-1 (ET-1), and prostacyclin (PGI2) were measured in the serum and artery tissue. We found that aortic stiffening causes a significant increase in PP and MAP (P < 0.05). The endothelial function was markedly blunted (P < 0.05) in both aorta and small peripheral artery. After removal of the restraint, the impaired endothelium function persisted in the aorta likely due to sustained deterioration of aortic wall, but was partially restored in peripheral artery. The endothelial dysfunction was correlated with a decrease in NOx and PGI2 (P < 0.05) and an increase in ET-1 (P < 0.05). Our results show that aortic stiffening results in widening of PP, which affected endothelium function through changes in synthesis of NOx, ET-1, and PGI2. These findings suggest that increased aortic stiffness may be a cause of increased PP and a precursor to hypertension. PMID- 25038147 TI - Dantrolene suppresses spontaneous Ca2+ release without altering excitation contraction coupling in cardiomyocytes of aged mice. AB - Cardiac dysfunction in the aged heart reflects abnormalities in cardiomyocyte Ca(2+) homeostasis including altered Ca(2+) cycling through the sarcoplasmic reticulum (SR). The ryanodine receptor antagonist dantrolene exerts antiarrhythmic effects by preventing spontaneous diastolic Ca(2+) release from the SR. We tested the hypothesis that dantrolene prevents spontaneous Ca(2+) release without altering excitation-contraction coupling in aged myocardium. Left ventricular cardiomyocytes isolated from young (3 to 4 mo) and aged (24-26 mo) C57BL/6 mice were loaded with the Ca(2+) indicator fluo-4. Amplitudes of action potential-induced Ca(2+) transients at 1-Hz pacing were similar between young and aged mice, yet cell shortening was impaired in aged mice. Isoproterenol (1 MUM) increased Ca(2+) transient amplitude and cell shortening to identical levels in young and aged; dantrolene (1 MUM) had no effect on Ca(2+) transients or cell shortening during pacing. Under Ca(2+) overload conditions induced with 10 mM extracellular Ca(2+) concentration, spontaneous Ca(2+) waves were of diminished amplitude and associated with lower SR Ca(2+) content in aged versus young mice. Despite no effect in young mice, dantrolene increased SR Ca(2+) content and Ca(2+) wave amplitude in aged mice. In the presence of isoproterenol following rest from 1-Hz pacing, Ca(2+) spark frequency was elevated in aged mice, yet the time to spontaneous Ca(2+) wave was similar between young and aged mice; dantrolene decreased Ca(2+) spark frequency and prolonged the time to Ca(2+) wave onset in aged mice with no effect in young mice. Thus dantrolene attenuates diastolic Ca(2+) release in the aged murine heart that may prove useful in preventing cardiac dysfunction. PMID- 25038149 TI - Study Habits, Motives, and Strategies of College Students With Symptoms of ADHD. AB - OBJECTIVE: Studies on ADHD in educational settings indicate that a student's motivation for learning is significantly related with the student's grade point average. The present study examined the relationship between ADHD symptoms and student academic achievement by considering the student's approach to and motivation for learning. METHOD: Participants completed a questionnaire that breaks down learning strategies into a surface or deep approach. Each approach is then divided into a deep or surface motivation and strategy. RESULTS: A multivariate analysis of variance determined that those in the control group were using the deep approach, whereas those in the ADHD group strongly favored the surface approach. Furthermore, ADHD participants preferred surface motive and surface strategy. A factor analysis of a study-habits questionnaire identified five categories, with collaborative learning approaching significant levels. CONCLUSION: Implications for guiding ADHD college students toward effective study strategies are discussed in light of their preference for surface approach, motive, and strategy. PMID- 25038148 TI - Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion. AB - We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 +/- 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Delta, exercise - rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (DeltaFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 +/- 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = -0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA. PMID- 25038150 TI - Culture of how Washington pays for medical care. PMID- 25038151 TI - I. Advances in trauma care: a quiet revolution. PMID- 25038152 TI - II. Major trauma networks in England. PMID- 25038153 TI - Pre-hospital anaesthesia: the same but different. AB - Advanced airway management is one of the most controversial areas of pre-hospital trauma care and is carried out by different providers using different techniques in different Emergency Medical Services systems. Pre-hospital anaesthesia is the standard of care for trauma patients arriving in the emergency department with airway compromise. A small proportion of severely injured patients who cannot be managed with basic airway management require pre-hospital anaesthesia to avoid death or hypoxic brain injury. The evidence base for advanced airway management is inconsistent, contradictory and rarely reports all key data. There is evidence that poorly performed advanced airway management is harmful and that less experienced providers have higher intubation failure rates and complication rates. International guidelines carry many common messages about the system requirements for the practice of advanced airway management. Pre-hospital rapid sequence induction (RSI) should be practiced to the same standard as emergency department RSI. Many in-hospital standards such as monitoring, equipment, and provider competence can be achieved. Pre-hospital and emergency in-hospital RSI has been modified from standard RSI techniques to improve patient safety, physiological disturbance, and practicality. Examples include the use of opioids and long-acting neuromuscular blocking agents, ventilation before intubation, and the early release of cricoid pressure to improve laryngoscopic view. Pre-hospital RSI is indicated in a small proportion of trauma patients. Where pre-hospital anaesthesia cannot be carried out to a high standard by competent providers, excellent quality basic airway management should be the mainstay of management. PMID- 25038154 TI - Observational study of the success rates of intubation and failed intubation airway rescue techniques in 7256 attempted intubations of trauma patients by pre hospital physicians. AB - BACKGROUND: Effective airway management is a priority in early trauma management. Data on physician pre-hospital tracheal intubation are limited; this study was performed to establish the success rate for tracheal intubation in a physician led system and examine the management of failed intubation and emergency surgical cricothyroidotomy in pre-hospital trauma patients. Failed intubation rates for anaesthetists and non-anaesthetists were compared. METHODS: A retrospective database review was conducted to identify trauma patients undergoing pre-hospital advanced airway management between September 1991 and December 2012. The success rate of tracheal intubation and the use and success of rescue techniques were established. Success rates of tracheal intubation by individuals and by speciality were recorded. RESULTS: The doctor-paramedic team attended 28 939 patients; 7256 (25.1%) required advanced airway management. A surgical airway was performed immediately, without attempted laryngoscopy, in 46 patients (0.6%). Tracheal intubation was successful in 7158 patients (99.3%). Rescue surgical airways were performed in 42 patients, seven had successful insertion of supraglottic devices, and two patients had supraglottic device insertion and a surgical airway. One patient breathed spontaneously with bag-valve-mask support during transfer. All rescue techniques were successful. Non-anaesthetists performed 4394 intubations and failed to intubate in 41 cases (0.9%); anaesthetists performed 2587 intubations and failed in 11 (0.4%) (P=0.02). CONCLUSIONS: This is the largest series of physician pre-hospital tracheal intubation; the success rate of 99.3% is consistent with other reported data. All rescue airways were successful. Non-anaesthetists were twice as likely to have to perform a rescue airway intervention than anaesthetists. Surgical airway rates reported here (0.7%) are lower than most other physician-led series (median 3.1%, range 0.1-7.7%). PMID- 25038155 TI - Early management of the severely injured major trauma patient. AB - The major trauma team relies on an efficient, communicative team to ensure patients receive the best quality care. This requires a comprehensive handover, rapid systematic review, and early management of life- and limb-threatening injuries. These multiple injured patients often present with complex conditions in a dynamic situation. The importance of team work, communication, senior decision-making, and documentation cannot be underestimated. PMID- 25038156 TI - Damage control surgery in the era of damage control resuscitation. AB - Damage control surgery (DCS) is a concept of abbreviated laparotomy, designed to prioritize short-term physiological recovery over anatomical reconstruction in the seriously injured and compromised patient. Over the last 10 yr, a new addition to the damage control paradigm has emerged, referred to as damage control resuscitation (DCR). This focuses on initial hypotensive resuscitation and early use of blood products to prevent the lethal triad of acidosis, coagulopathy, and hypothermia. This review aims to present the evidence behind DCR and its current application, and also to present a strategy of overall damage control to include DCR and DCS in conjunction. The use of DCR and DCS have been associated with improved outcomes for the severely injured and wider adoption of these principles where appropriate may allow this trend of improved survival to continue. In particular, DCR may allow borderline patients, who would previously have required DCS, to undergo early definitive surgery as their physiological derangement is corrected earlier. PMID- 25038157 TI - Damage control radiology in the severely injured patient: what the anaesthetist needs to know. AB - In the treatment of severely injured patients, the term 'damage control radiology' has been used to parallel the modern concept of damage control surgery and the allied development of continuous damage control resuscitation from patient retrieval, through all transfers, to appropriate primary treatment. The aims of damage control radiology are (i) rapid identification of life-threatening injuries including bleeding sites, (ii) identification or exclusion of head or spinal injury, and (iii) prompt and accurate triage of patients to the operating theatre for thoracic, abdominal, or both surgeries or the angiography suite for endovascular haemorrhage control. If we are to achieve these aims, patients must have immediate access to modern multidetector computed tomography (MDCT) which is without doubt the most potent weapon in the diagnostic armamentarium. The most severely injured patients are those who have the most to benefit from early diagnosis and life-saving therapies. The traditional teaching that these patients should go immediately to surgery is challenged by technological developments in MDCT and recent clinical evidence. PMID- 25038158 TI - Haemodynamic changes in trauma. AB - Trauma is the leading cause of death during the first four decades of life in the developed countries. Its haemodynamic response underpins the patient's initial ability to survive, and the response to treatment and subsequent morbidity and resolution. Trauma causes a number of insults including haemorrhage, tissue injury (nociception) and, predominantly, in military casualties, blast from explosions. This article discusses aspects of the haemodynamic responses to these insults and subsequent treatment. 'Simple' haemorrhage (blood loss without significant volume of tissue damage) causes a biphasic response: mean arterial blood pressure (MBP) is initially maintained by the baroreflex (tachycardia and increased vascular resistance, Phase 1), followed by a sudden decrease in MAP initiated by a second reflex (decrease in vascular resistance and bradycardia, Phase 2). Phase 2 may be protective. The response to tissue injury attenuates Phase 2 and may cause a deleterious haemodynamic redistribution that compromises blood flow to some vital organs. In contrast, thoracic blast exposure augments Phase 2 of the response to haemorrhage. However, hypoxaemia from lung injury limits the effectiveness of hypotensive resuscitation by augmenting the attendant shock state. An alternative strategy ('hybrid resuscitation') whereby tissue perfusion is increased after the first hour of hypotensive resuscitation by adopting a revised normotensive target may ameliorate these problems. Finally, morphine also attenuates Phase 2 of the response to haemorrhage in some, but not all, species and this is associated with poor outcome. The impact on human patients is currently unknown and is the subject of a current physiological investigation. PMID- 25038159 TI - Trauma scoring systems and databases. AB - This review considers current trauma scoring systems and databases and their relevance to improving patient care. Single physiological measures such as systolic arterial pressure have limited ability to diagnose severe trauma by reflecting raised intracranial pressure, or significant haemorrhage. The Glasgow coma score has the greatest prognostic value in head-injured and other trauma patients. Trauma triage tools and imaging decision rules-using combinations of physiological cut-off measures with mechanism of injury and other categorical variables-bring both increased sophistication and increased complexity. It is important for clinicians and managers to be aware of the diagnostic properties (over- and under-triage rates) of any triage tool or decision rule used in their trauma system. Trauma registries are able to collate definitive injury descriptors and use survival prediction models to guide trauma system governance, through individual patient review and case-mix-adjusted benchmarking of hospital and network performance with robust outlier identification. Interrupted time series allow observation in the changes in care processes and outcomes at national level, which can feed back into clinical quality-based commissioning of healthcare. Registry data are also a valuable resource for trauma epidemiological and comparative effectiveness research studies. PMID- 25038160 TI - Critically ill patients admitted in post-anaesthesia care units: a survey of current practices in France. PMID- 25038161 TI - Acceptability of auricular vs frontal bispectral index values. PMID- 25038162 TI - Ferric carboxymaltose increases epoetin-alpha response and prevents iron deficiency before elective orthopaedic surgery. PMID- 25038163 TI - Malleable stylet in difficult intubation: a modified technique. PMID- 25038164 TI - Real-time ultrasound-guided epidural anaesthesia technique can be improved by new echogenic Tuohy needles: a pilot study in cadavers. PMID- 25038165 TI - 'Do as you would be done by': the ethics of using outdated equipment in medical charity. PMID- 25038166 TI - Arterial blood gases from central venous lines: a sign for malformation. PMID- 25038167 TI - Preoperative evaluation of Montgomery tube: a stitch in time saves nine. PMID- 25038168 TI - Virtual laryngoscopy and combined laryngoscopic-bronchoscopic approach for safe management of obstructive upper airways lesions. PMID- 25038169 TI - Under pressure? Alopecia related to surgical duration. PMID- 25038175 TI - The neurokinin-1 receptor in addictive processes. AB - Stress can trigger drug-seeking behavior, increase self-administration rates, and enhance drug reward. A number of stress-related neuropeptides have been shown to mediate these behavioral processes. The most studied peptide in this category is corticotropin-releasing hormone (CRH), which has been shown to mediate stress induced reinstatement of drug seeking, escalated self-administration, and drug withdrawal, but it does not seem to be involved in baseline drug self administration or cue-induced reinstatement. This pattern of effects holds for many classes of drugs, including alcohol, opiates, and psychostimulants. The neurokinin-1 receptor (NK1R) is the preferred receptor for the endogenous stress related neuropeptide substance P (SP). The SP/NK1R system is a major mediator of stress and anxiety, and over the last several years, it has been demonstrated that the SP/NK1R system can have effects similar to those of CRH on drug taking and drug seeking. Specifically, NK1R inhibition attenuates escalated self administration of alcohol as well as stress-induced reinstatement of alcohol and cocaine seeking; however, in contrast to other stress systems, the NK1R also appears to have a role in primary reward and reinforcement for opiates. This review outlines the role of NK1R in drug-seeking behaviors and highlights recent results from clinical studies that suggest that the NK1R may be a promising drug target going forward. PMID- 25038176 TI - The effectiveness and safety of acupuncture for poor semen quality in infertile males: a systematic review and meta-analysis. AB - The aim of this review is to evaluate the effectiveness and safety of acupuncture for poor semen quality in infertile men. We searched for relevant trials registered up to May 2013 in 14 databases. We selected randomized controlled trials (RCTs) that compared acupuncture, with or without additional treatment, against placebo, sham, no treatment, or the same additional treatment. Two reviewers independently performed the study selection, data extraction, risk of bias and reporting quality appraisal. Risk of bias and reporting quality were appraised by the Cochrane risk of bias tool, the consolidated standards of reporting trials and Standards for Reporting Interventions in Clinical Trials of Acupuncture. The outcomes were sperm motility, sperm concentration, pregnancy rate, and adverse events. Pregnancy was defined as a positive pregnancy test. Four RCTs met the eligibility criteria. Acupuncture increased the percentage of sperm with rapid progression (mean difference - 6.35, 95% confidence interval (CI): 4.38-8.32, P< 0.00001) and sperm concentration (mean difference - 6.42, 95% CI: 4.91-7.92, P< 0.00001), but these two outcomes were substantially heterogeneous among the studies (I2 = 72% and 58%, respectively). No differences in pregnancy rate were found between acupuncture and control groups (odds ratio 1.60, 95% CI: 0.70-3.69, P= 0.27, I2 = 0%). No participants experienced adverse events. The current evidence showing that acupuncture might improve poor semen quality is insufficient because of the small number of studies, inadequacy of procedures and/or insufficient information for semen analysis, high levels of heterogeneity, high risk of bias, and poor quality of reporting. Further large, well-designed RCTs are required. PMID- 25038177 TI - Genetic variations of the ADIPOQgene and risk of prostate cancer in Chinese Han men. AB - Adiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQ are thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hospital based case-control study of 917 prostate cancer (PCa) cases and 1036 cancer-free controls, we evaluated the association of single nucleotide polymorphisms in ADIPOQ with risk of PCa and adiponectin levels in Chinese Han men. Variants of ADIPOQ were genotyped by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in a subset of cases and controls. We found that the ADIPOQ rs3774262 variant AA genotype was associated with both decreased PCa risk [adjusted odds ratio (OR): 0.66, 95% confidence interval (CI) =0.48-0.92] and increased plasma adiponectin levels (P = 0.036 and 0.043), with significant difference by tumor grade, clinical stage, and aggressiveness. A significant interaction between ADIPOQ rs3774262 and body mass index was observed in modifying the risk of PCa (P = 6.7 * 10-3). ADIPOQ rs266729 and rs182052 were not related to PCa risk or plasma adiponectin levels. Our data support that ADIPOQ rs3774262 may affect PCa risk in combination with plasma adiponectin levels in Chinese Han men. It may contribute to the molecular basis for the association between obesity and PCa. PMID- 25038178 TI - A laboratory modification to testicular sperm preparation technique improves spermatogenic cell yield. AB - Testicular sperm extraction is a common procedure used to find spermatogenic cells in men with nonobstructive azoospermia. The laboratory processing of biopsied testicular tissues needs to be performed meticulously to acquire a high yield of cells. In this study, the effectiveness of mincing the tissues after testicular biopsy was assessed using histological evaluation, as was the possible adverse effect of residual tissue on the migration of spermatogenic cells during density gradient centrifugation. Our results indicate that testicular residual tissue, when laid on the density gradient medium along with the sperm wash, hinders the spermatogenic cells' forming a pellet during centrifugation, and therefore impairs the intracytoplasmic sperm injection procedure. Whereas the mean number of recovered cells from the sperm wash medium (SWM) with residual tissue is 39.435 +/- 24.849, it was notably higher (60.189 +/- 28.214 cells) in the SWM without minced tissues. The remaining tissue contained no functional seminiferous tubules or spermatogenic cells in histological sections. In conclusion, the remaining residual tissue after mincing biopsied testicular tissue does not add any functional or cellular contribution to spermatogenic cell retrieval; in fact, it may block the cellular elements in the accompanying cell suspension from migrating through the gradient layers to form a pellet during centrifugation and cause loss of spermatogenic cells. PMID- 25038179 TI - HoLEP does not affect the overall sexual function of BPH patients: a prospective study. AB - We aimed to prospectively evaluate the influence of holmium laser enucleation of the prostate (HoLEP) on the overall postoperative sexual function of benign prostatic hyperplasia (BPH) patients with lower urinary tract symptoms (LUTS) and to explore the relationship between sexual function and LUTS. From January 2010 to December 2011, sixty sexually active consecutive patients with BPH who underwent HoLEP were prospectively enrolled in the study. All patients filled out the Male Sexual Health Questionnaire (MSHQ) for evaluation of their overall sexual function and the International Prostatic Symptom Score (IPSS) for pre- and post-operative 6 months evaluation of their voiding symptoms. The LUTS and sexual function changes were statistically analyzed. The preoperative and 6 months postoperative status of the patients was compared using uroflowmetry and IPSS questionnaires. The analysis revealed significant improvements following HoLEP. Among the sub-domains of the MSHQ, postoperative sexual function, including erection, ejaculation, sexual satisfaction, anxiety or sexual desire, did not significantly change after HoLEP (P > 0.05), whereas satisfaction scores decreased slightly due to retrograde ejaculation in 38 patients (63.3%). Sexual satisfaction improved significantly and was correlated with the improvements of all LUTS and the quality-of-life (QoL) domains in IPSS after surgery (QoL; relative risk [RR]: -0.293; total symptoms, RR: -0.411; P < 0.05). The nocturia score was associated with the erectile function score (odds ratio 0.318, P = 0.029). The change in ejaculatory scores did not show significant association with IPSS scores. HoLEP did not influence overall sexual function, including erectile function. In addition, sexual satisfaction improved in proportion with the improvement of LUTS. PMID- 25038180 TI - 11beta-hydroxysteroid dehydrogenase types 1 and 2 in postnatal development of rat testis: gene expression, localization and regulation by luteinizing hormone and androgens. AB - 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and type 2 (11beta-HSD2) are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11beta HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone (LH) and androgens. mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day (PND) 7, 14, 21, 35, and 90, and from rats treated with LH, 7alpha-methyl-19-nortestosterone (MENT) and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11beta-HSD in rat testis at PND 7, 14, and 90. We found that 11beta-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11beta-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11beta-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11beta-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11beta-HSD1 and 11beta HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis. PMID- 25038181 TI - Significance of preoperatively observed detrusor overactivity as a predictor of continence status early after robot-assisted radical prostatectomy. AB - Several recent studies have reported the involvement of bladder dysfunction in the delayed recovery of urinary continence following radical prostatectomy (RP). The objective of this study was to investigate the significance of detrusor overactivity (DO) as a predictor of the early continence status following robot assisted RP (RARP). This study included 84 consecutive patients with prostate cancer undergoing RARP. Urodynamic studies, including filling cystometry, pressure flow study, electromyogram of the external urethral sphincter and urethral pressure profile, were performed in these patients before surgery. Urinary continence was defined as the use of either no or one pad per day as a precaution only. DO was preoperatively observed in 30 patients (35.7%), and 55 (65.5%) and 34 (40.5%) were judged to be incontinent 1 and 3 months after RARP, respectively. At both 1 and 3 months after RARP, the incidences of incontinence in patients with DO were significantly higher than in those without DO. Of several demographic and urodynamic parameters, univariate analyses identified DO and maximal urethral closure pressure (MUCP) as significant predictors of the continence status at both 1 and 3 months after RARP. Furthermore, DO and MUCP appeared to be independently associated with the continence at both 1 and 3 months after RARP on multivariate analysis. These findings suggest that preoperatively observed DO could be a significant predictor of urinary incontinence early after RARP; therefore, it is recommended to perform urodynamic studies for patients who are scheduled to undergo RARP in order to comprehensively evaluate their preoperative vesicourethral functions. PMID- 25038182 TI - Regulation of cell adhesion in the testis: a new role for p73. AB - The dramatic changes that male germ cells in the adult testis undergo in gene expression profile and morphology as they transition from spermatogonial stem cells through to mature spermatozoa is dependent upon their association with Sertoli cells. Sertoli cells are crucial for survival and maturation of male germ cells. Two recent papers, Holembowski et al. and Inoue et al. have described a surprising role for the p53 family member, p73, in regulation of germ cell Sertoli cell adhesion. PMID- 25038183 TI - Which one is the real matchmaker for the pair? AB - A fundamental question for meiosis is how homologous chromosomes (homologs) find each other and pair together to ensure homologous recombination and segregation. Intuitively, the answer to the question is related to the interaction between homologous sequences. However, that is not the whole story according to some studies on the role of cohesins in homolog pairing. The most recent one by Ishiguro et al.[1] of the Watanabe group indicates that chromosome architecture defined by a meiosis-specific cohesin protein RAD21L is the key to homology searching. Moreover, they report that homologous pairing is dependent on neither SPO11, an evolutionarily conserved type 2 isomerase responsible for generating DNA double-strand breaks (DSBs), nor SUN1, which tethers the ends of chromosomes to the nuclear envelop (NE) and facilitates chromosome movement and bouquet formation. These discoveries are quite some surprises! PMID- 25038184 TI - Extended lymph node dissection in robot-assisted radical prostatectomy: lymph node yield and distribution of metastases. AB - In this study, we reported our experience performing robotic extended lymph node dissection (eLND) in patients with prostate cancer. A total of 147 patients with intermediate and high-risk prostate cancer who underwent robotic eLND from May 2008 to December 2011 were included in this analysis. The dissection template extended to the ureter crossing the iliac vessels. We assessed lymph node yield, lymph node positivity, and perioperative outcomes. Lymph node positivity was also evaluated according to the number of lymph nodes (LNs) removed (<22 vs >=22). The median number of LNs removed was 22 (11-51), and 97 positive LNs were found in 24 patients (16.3%). While the obturator fossa was the most common site for LN metastases (42.3%, 41/97), the internal iliac area was the most common area for a single positive LN packet (20.8%, 5/24). Eight patients (33.3%, 8/24) had positive LNs at the common iliac area. The incidence of positive LNs did not differ according to the number of LNs removed. Complications associated with eLND occurred in 21 patients (14.3%) and symptomatic lymphocele was found in five patients (3.4%). In conclusion, robotic eLND can be performed with minimal morbidity. Furthermore, LN yield and the node positive rate achieved using this robotic technique are comparable to those of open series. In addition, the extent of dissection is more important than the absolute number of LNs removed in eLND, and the robotic technique is not a prohibitive factor for performing eLND. PMID- 25038185 TI - Unraveling the intricacies of mammalian fertilization. AB - It is imperative to understand the molecular basis of various steps involved during fertilization. In the manuscript by Bianchi et al. a novel protein, Juno on egg membrane (oolemma) has been characterized that binds to sperm specific protein, Izumo-1. Monoclonal antibodies against Juno inhibited in vitro fertilization. Juno knock-out female mice failed to deliver litters on mating. It is rapidly shed from oolemma after fertilization, suggesting its role in preventing polyspermy. Taken together these studies will help in our understanding of sperm-egg recognition mechanisms and also facilitate development of new fertility treatment regimens and novel contraceptives. PMID- 25038187 TI - Should cross-sex hormone treatment of transsexual subjects vary with ethnic group? PMID- 25038188 TI - Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy. AB - Viral pneumonia is a major cause of acute respiratory distress syndrome (ARDS). Anti-inflammatory therapies for viral-induced lung injury show promise in preclinical models. Mesenchymal stem/stromal cells (MSCs) are multipotent, self renewing cells that secrete anti-inflammatory cytokines and epithelial and endothelial growth factors. We inoculated mice intranasally with influenza A (murine-adapted Puerto Rico/8/34) or PBS, and the mice were killed at multiple time points after infection for measures of lung injury and viral load. We report that influenza induces marked, long-lasting dysfunction of the alveolar-capillary barrier peaking at 1 wk but lasting longer than 3 wk postinfection. Weight loss, commonly employed as a criterion for euthanasia (and hence "survival"), was found to be poorly predictive of the severity of lung injury at its peak; rather, persistent weight loss 11 days postinfection identified mice with impaired injury resolution. Murine and human bone marrow-derived MSCs (obtained from the National Institutes of Health repository) were then administered intravenously during the rapid phase of injury progression. Murine MSCs (mMSCs) given two times 24 h apart failed to improve weight loss, lung water, bronchoalveolar lavage inflammation, or histology. However, mMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load at day 7. Human MSCs administered intravenously showed a similar lack of efficacy. The results demonstrate that the influenza murine model bears important similarities to the slow resolution of ARDS in patients. Despite their potent therapeutic effects in many models of acute inflammation and lung injury, MSCs do not improve influenza-mediated lung injury in mice. PMID- 25038190 TI - Unaffected contractility of diaphragm muscle fibers in humans on mechanical ventilation. AB - Several studies have indicated that diaphragm dysfunction develops in patients on mechanical ventilation (MV). Here, we tested the hypothesis that the contractility of sarcomeres, i.e., the smallest contractile unit in muscle, is affected in humans on MV. To this end, we compared diaphragm muscle fibers of nine brain-dead organ donors (cases) that had been on MV for 26 +/- 5 h with diaphragm muscle fibers from nine patients (controls) undergoing surgery for lung cancer that had been on MV for less than 2 h. In each diaphragm specimen we determined 1) muscle fiber cross-sectional area in cryosections by immunohistochemical methods and 2) the contractile performance of permeabilized single muscle fibers by means of maximum specific force, kinetics of cross-bridge cycling by rate of tension redevelopment, myosin heavy chain content and concentration, and calcium sensitivity of force of slow-twitch and fast-twitch muscle fibers. In case subjects, we noted no statistically significant decrease in outcomes compared with controls in slow-twitch or fast-twitch muscle fibers. These observations indicate that 26 h of MV of humans is not invariably associated with changes in the contractile performance of sarcomeres in the diaphragm. PMID- 25038189 TI - Promotion of lung tumor growth by interleukin-17. AB - Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro- and antitumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-Ras(LA1) mice) with lung delivery of a recombinant adenovirus that expresses IL-17A. Virus-mediated expression of IL-17A in K Ras(LA1) mice at 8-10 wk of age doubled lung tumor growth in 3 wk relative to littermates that received a green fluorescent protein-expressing control adenovirus. IL-17 induced matrix metalloproteinase-9 (MMP-9) expression in vivo and in vitro. In accord with this finding, selective and specific inhibitors of MMP-9 repressed the increased motility and invasiveness of IL-17-treated lung tumor cells in culture. Knockdown or mutation of p53 promoted the motility of murine lung tumor cells and abrogated the promigratory role of IL-17. Coexpression of siRNA-resistant wild-type, but not mutant, human p53 rescued both IL-17-mediated migration and MMP-9 mRNA induction in p53 knockdown lung tumor cells. IL-17 increased MMP-9 mRNA stability by reducing interaction with the mRNA destabilizing serine/arginine-rich splicing factor 1 (SRSF1). Taken together, our results indicate that IL-17 stimulates lung tumor growth and regulates MMP-9 mRNA levels in a p53- and SRSF1-dependent manner. PMID- 25038192 TI - Prevalence and factors associated with physical fighting among Malaysian adolescents. AB - Physical fighting among adolescents is one manifestation of interpersonal violence that is an important issue globally, but attention to this problem in Malaysia has been limited. We analyzed data available from the Malaysia Global School-Based Health Survey conducted in 2012. Of the 25 507 respondents, 27.4% reported having been in a physical fight in the past 12 months. Being bullied (adjusted odds ratio [aOR] = 3.01; 95% confidence interval [CI] = 2.67-3.39) was significantly and highly associated with involvement in physical fighting. Smoking (aOR = 2.56; 95% CI = 2.20-2.97), males (aOR = 1.77; 95% CI = 1.62-1.93), using drugs (aOR = 1.73; 95% CI = 1.09-2.15), and drinking alcohol (aOR = 1.42; 95% CI = 1.24-1.63) were other factors associated with physical fighting. Parental supervision showed no significant association with physical fighting. These findings indicate that more attention needs to be given to bullying at school by school authorities and parents. PMID- 25038191 TI - Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice. AB - Chlorine (Cl2) is a highly reactive oxidant gas that, when inhaled, may cause acute lung injury culminating in death from respiratory failure. In this study, we tested the hypothesis that exposure of mice to Cl2 causes intra-alveolar and systemic activation of the coagulation cascade that plays an important role in development of lung injury. C57Bl/6 mice were exposed to Cl2 (400 for 30 min or 600 ppm for 45 min) in environmental chambers and then returned to room air for 1 or 6 h. Native coagulation (NATEM) parameters such as blood clotting time and clot formation time were measured in whole blood by the viscoelastic technique. D dimers and thrombin-anti-thrombin complexes were measured in both plasma and bronchoalveolar lavage fluid (BALF) by ELISA. Our results indicate that mice exposed to Cl2 gas had significantly increased clotting time, clot formation time, and D-dimers compared with controls. The thrombin-anti-thrombin complexes were also increased in the BALF of Cl2 exposed animals. To test whether increased coagulation contributed to the development of acute lung injury, mice exposed to Cl2 and returned to room air were treated with aerosolized heparin or vehicle for 20 min. Aerosolized heparin significantly reduced protein levels and the number of inflammatory cells in the BALF at 6 h postexposure. These findings highlight the importance of coagulation abnormities in the development of Cl2-induced lung injury. PMID- 25038193 TI - Methodology of the National School-based Health Survey in Malaysia, 2012. AB - The National School-Based Health Survey 2012 was a nationwide school health survey of students in Standard 4 to Form 5 (10-17 years of age), who were schooling in government schools in Malaysia during the period of data collection. The survey comprised 3 subsurveys: the Global School Health Survey (GSHS), the Mental Health Survey, and the National School-Based Nutrition Survey. The aim of the survey was to provide data on the health status of adolescents in Malaysia toward strengthening the adolescent health program in the country. The design of the survey was created to fulfill the requirements of the 3 subsurveys. A 2-stage stratified sampling method was adopted in the sampling. The methods for data collection were via questionnaire and physical examination. The National School Based Health Survey 2012 adopted an appropriate methodology for a school-based survey to ensure valid and reliable findings. PMID- 25038194 TI - Parental smoking status, stress, anxiety, and depression are associated with susceptibility to smoking among non-smoking school adolescents in Malaysia. AB - Susceptibility to smoking is a reliable predictor of smoking initiation. This article describes its prevalence and associated factors among Malaysian school adolescents. Data were obtained from the Global School-Based Student Health Survey (GSHS) 2012, a nationwide representative sample of school adolescents. The overall prevalence of susceptibility to smoking was 6.0% and significantly higher among males (9.5%) compared with females (3.6%). Multivariable analyses revealed that males (adjusted odds ratio [aOR] 3.34, 95% confidence interval [CI] 2.70 4.18) and school adolescents of indigenous Sabahan or Sarawakian descents (aOR 1.62, 95%CI 1.21-2.18) were significantly more likely to be susceptible to smoking. Susceptible school adolescents had a slightly higher likelihood to have symptoms of stress (aOR 1.31, 95% CI 1.02-1.70), anxiety (aOR 1.19, 95% CI 1.01 1.40), depression (aOR 1.56, 95% CI 1.25-1.96), including those whose one or both parents/guardians were smokers (aOR 1.48, 95% CI 1.21-1.82; aOR 2.33, 95% CI 1.22 4.44, respectively). The findings from this study point out the need for proactive measures to reduce smoking initiation among Malaysian adolescents with particular attention toward factors associated with susceptibility to smoking. PMID- 25038195 TI - Illicit drug use among school-going adolescents in Malaysia. AB - Illicit drug use among adolescents has become a public health issue in Malaysia. This study was from the Global School-Based Student Health Survey (GSHS) and aimed to determine the prevalence of and factors associated with illicit drug use among school-going adolescents in Malaysia. A 2-stage stratified cluster sampling method was used and data were collected via a self-administered questionnaire. A total of 25 507 students participated in the study. The prevalence of adolescents who ever used illicit drugs was 1.7%. Adolescents who ever used illicit drugs were associated with current smoking (adjusted odds ratio [aOR] = 6.99; 95% CI = 5.19, 9.40), current alcohol use (aOR = 4.63; 95% CI = 3.43, 6.26), ever having sex (aOR = 4.76; 95% CI = 3.54, 6.41), truancy (aOR = 1.43; 95% CI = 1.07, 1.90), lack of peer support (aOR = 1.47; 95% CI = 1.07, 2.03), and lack of parental monitoring (aOR = 1.71; 95% CI = 1.22, 2.39). Public health intervention should be addressed to prevent illicit drug used among adolescents. PMID- 25038196 TI - Prevalence, comorbidities, and cofactors associated with alcohol consumption among school-going adolescents in Malaysia. AB - Alcohol is deleterious to physical and mental health as well as social well being. This study aims to examine the prevalence of alcohol consumption and factors associated with its use among school-going Malaysian adolescents. The Global School-Based Student Health Survey (GSHS) 2012 employed 2-stage clustering design to Malaysian secondary school respondents aged 12 to 17 years. The prevalence of current alcohol usage was 8.9% (95% confidence interval [CI]: 7.8 10.07) overall, 11.2% (95% CI: 9.80-12.80) among males, and 23.4 (95% CI: 21.40 25.50) among Chinese students. Multivariate logistic regression showed that adolescents who had used alcohol were more likely to have used substance (adjusted odds ratio [aOR] = 3.39; 95% CI: 2.33-4.99), experienced injury (aOR = 1.53; 95% CI: 1.20-1.95), and engaged in sexual behaviors (aOR = 1.42, 95% CI: 1.12-1.79), and fights (aOR = 1.23; 95% CI: 1.08-1.41). The current national policies on alcohol should be strengthened to curb alcohol consumption among adolescents. PMID- 25038197 TI - Towards creating the perfect electronic prescription. AB - Significant strides have been made in electronic (e)-prescribing standards and software applications that have further fueled the adoption and use of e prescribing. However, for e-prescribing to realize its full potential for improving the safety, effectiveness, and efficiency of prescription drug delivery, important work remains to be carried out. This perspective describes the ultimate goal of all e-prescribing stakeholders including prescribers and dispensing pharmacists: a clear, complete, and unambiguous e-prescription order that can be seamlessly received, processed, and fulfilled at the dispensing pharmacy without the need for additional clarification from the prescriber. We discuss the challenges to creating the perfect e-prescription by focusing on selected data segments and data fields that are available in the new e prescription transaction as defined in the NCPDP SCRIPT Standard and suggest steps that could be taken to move the industry closer to achieving this vision. PMID- 25038198 TI - A methodology for a minimum data set for rare diseases to support national centers of excellence for healthcare and research. AB - BACKGROUND: Although rare disease patients make up approximately 6-8% of all patients in Europe, it is often difficult to find the necessary expertise for diagnosis and care and the patient numbers needed for rare disease research. The second French National Plan for Rare Diseases highlighted the necessity for better care coordination and epidemiology for rare diseases. A clinical data standard for normalization and exchange of rare disease patient data was proposed. The original methodology used to build the French national minimum data set (F-MDS-RD) common to the 131 expert rare disease centers is presented. METHODS: To encourage consensus at a national level for homogeneous data collection at the point of care for rare disease patients, we first identified four national expert groups. We reviewed the scientific literature for rare disease common data elements (CDEs) in order to build the first version of the F MDS-RD. The French rare disease expert centers validated the data elements (DEs). The resulting F-MDS-RD was reviewed and approved by the National Plan Strategic Committee. It was then represented in an HL7 electronic format to maximize interoperability with electronic health records. RESULTS: The F-MDS-RD is composed of 58 DEs in six categories: patient, family history, encounter, condition, medication, and questionnaire. It is HL7 compatible and can use various ontologies for diagnosis or sign encoding. The F-MDS-RD was aligned with other CDE initiatives for rare diseases, thus facilitating potential interconnections between rare disease registries. CONCLUSIONS: The French F-MDS RD was defined through national consensus. It can foster better care coordination and facilitate determining rare disease patients' eligibility for research studies, trials, or cohorts. Since other countries will need to develop their own standards for rare disease data collection, they might benefit from the methods presented here. PMID- 25038199 TI - Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility. AB - It is now clear that anti-CTLA-4 (alpha-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included alpha-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When alpha-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because alpha-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-cell motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-cell exhaustion in persistent viral infections. PMID- 25038200 TI - Social media and physicians: Exploring the benefits and challenges. AB - Healthcare professionals' use of social media platforms, such as blogs, wikis, and social networking web sites has grown considerably in recent years. However, few studies have explored the perspectives and experiences of physicians in adopting social media in healthcare. This article aims to identify the potential benefits and challenges of adopting social media by physicians and demonstrates this by presenting findings from a survey conducted with physicians. A qualitative survey design was employed to achieve the research goal. Semi structured interviews were conducted with 24 physicians from around the world who were active users of social media. The data were analyzed using the thematic analysis approach. The study revealed six main reasons and six major challenges for physicians adopting social media. The main reasons to join social media were as follows: staying connected with colleagues, reaching out and networking with the wider community, sharing knowledge, engaging in continued medical education, benchmarking, and branding. The main challenges of adopting social media by physicians were also as follows: maintaining confidentiality, lack of active participation, finding time, lack of trust, workplace acceptance and support, and information anarchy. By revealing the main benefits as well as the challenges of adopting social media by physicians, the study provides an opportunity for healthcare professionals to better understand the scope and impact of social media in healthcare, and assists them to adopt and harness social media effectively, and maximize the benefits for the specific needs of the clinical community. PMID- 25038201 TI - Reliability and concurrent validity of a peripheral pulse oximeter and health-app system for the quantification of heart rate in healthy adults. AB - There are downloadable applications (Apps) for cell phones that can measure heart rate in a simple and painless manner. The aim of this study was to assess the reliability of this type of App for a Smartphone using an Android system, compared to the radial pulse and a portable pulse oximeter. We performed a pilot observational study of diagnostic accuracy, randomized in 46 healthy volunteers. The patients' demographic data and cardiac pulse were collected. Radial pulse was measured by palpation of the radial artery with three fingers at the wrist over the radius; a low-cost portable, liquid crystal display finger pulse oximeter; and a Heart Rate Plus for Samsung Galaxy Note(r). This study demonstrated high reliability and consistency between systems with respect to the heart rate parameter of healthy adults using three systems. For all parameters, ICC was > 0.93, indicating excellent reliability. Moreover, CVME values for all parameters were between 1.66-4.06 %. We found significant correlation coefficients and no systematic differences between radial pulse palpation and pulse oximeter and a high precision. Low-cost pulse oximeter and App systems can serve as valid instruments for the assessment of heart rate in healthy adults. PMID- 25038202 TI - Smartphone applications for seizure management. AB - Technological advancements continue to provide innovative ways of enhancing patient care in medicine. In particular, the growing popularity of smartphone technology has seen the recent emergence of a myriad of healthcare applications (or apps) that promise to help shape the way in which health information is delivered to people worldwide. While limited research already exists on a range of such apps, our study is the first to examine the salient features of smartphone applications as they apply to the area of seizure management. For the purposes of this review, we conducted a search of the official online application stores of the five major smartphone platforms: iPhone, Android, Blackberry, Windows Mobile and Nokia-Symbian. Apps were included if they reported to contain some information or tools relating to seizure management and excluded if they were aimed exclusively at health professionals. A total of 28 applications met these criteria. Overall, we found an increasing number of epilepsy apps available on the smartphone market, but with only a minority offering comprehensive educational information alongside tools such as seizure diaries, medication tracking and/or video recording. PMID- 25038203 TI - The role of short messaging service in supporting the delivery of healthcare: An umbrella systematic review. AB - Short messaging service (SMS) messages may present a convenient and cost effective method to support healthcare interventions. This work assesses the effects of short messaging service on various healthcare interventions found in systematic reviews. The search strategy was based on two key concepts: short messaging service and healthcare delivery. The initial search was conducted in December 2012 and was updated in June 2013. Of the 550 identified references, 13 systematic reviews met the inclusion criteria, of which 8 were published in peer reviewed journals and 5 were retrieved from the Cochrane library. Data analysis shows that low to moderate research evidence exists on the benefits of short messaging service interventions for appointment reminders, promoting health in developing countries and preventive healthcare. In many interventions, however, there were a few studies that were of high quality, and most of the studies were rated from low to moderate quality or had no rating at all. Healthcare organizations, policy makers, or clinicians using short messaging service messages to support healthcare interventions should (1) implement interventions that have been found to work in healthcare settings, (2) continue evaluating short messaging service interventions that have not been adequately assessed, and (3) improve collaboration between various healthcare entities to develop studies targeted at specific populations to evaluate the long-term impact of short messaging service on healthcare outcomes. PMID- 25038204 TI - Distinguishing between Crohn's disease, tuberculosis, and lymphoma: still in murky waters. PMID- 25038205 TI - Swallow syncope: clinical presentation, diagnostic criteria, and therapeutic options. AB - We recently encountered three patients with episodes of syncope associated with food ingestion. A 31-year-old woman had an episode of syncope in the hospital while drinking soda. Transient asystole was noted on the telemonitor, confirming the diagnosis of swallow syncope. The other two patients were 78- and 80 year old gentlemen, respectively, who presented with recurrent and transient episodes of dizziness during deglutition. Extensive work-up of syncope was negative in both cases and a diagnosis of swallow syncope was made by clinical criteria. These cases illustrate the challenging problem of swallow syncope. The diagnosis can be suspected on the basis of clinical presentation and confirmed with the demonstration of transient brady-arrhythmia during deglutition. Medical management includes avoiding trigger foods, use of anticholinergics, and/or placement of a permanent cardiac pacemaker. PMID- 25038206 TI - Epidemiology and pattern of antibiotic resistance in Helicobacter pylori: scenario from Saudi Arabia. AB - Helicobacter pylori is recognized as a major cause of gastritis, peptic ulcer, gastric cancer, and mucosa-associated lymphoma. Infection with this gram-negative microaerophile has been treated using combination of antibiotics and proton pump inhibitors for different gastrointestinal diseases. The most commonly used treatment is triple therapy which consists of administration of a proton pump inhibitor, clarithromycin, and amoxicillin. Many factors contribute to treatment failure, but one of the main reasons is development of bacterial antibiotic resistance. The percent prevalence of antibiotic resistance varies among different countries; it appears to be partly determined by the geographic factors and its ability to undergo frequent homologous recombination. The aim of this paper is to review the prevalence of H. pylori infection, association of clinical outcomes with H. pylori genotypes, and current status of antibiotic resistance in H. pylori in Saudi Arabia. It also discusses the different alternative approaches for the treatment of H. pylori using antibiotics. In addition, association of antibiotic resistance with H. pylori virulent genotypes in Saudi population and its underlying resistance mechanism will also be discussed. PMID- 25038207 TI - A Korean experience of the use of Boston bowel preparation scale: a valid and reliable instrument for colonoscopy-oriented research. AB - BACKGROUND/AIMS: Few bowel preparation scales have been validated. The Boston Bowel Preparation Scale (BBPS) is a novel bowel preparation scale in western countries. We validated the BBPS in Korean patients and assessed the relationship between the colon polyp detection rate and BBPS score. PATIENTS AND METHODS: This study was a prospective, single-center trial. The BBPS is a 10-point scale that assesses bowel preparation after the completion of all cleansing maneuvers. We assessed three segment scores (the right side, transverse section, and left side) and total BBPS scores during screening colonoscopy. In addition, we compared the BBPS scores with clinically meaningful outcomes such as the polyp detection rate and colonoscope withdrawal times. RESULTS: We enrolled 482 screening colonoscopies between January 2011 and January 2012. The mean (+/- standard deviation [SD]) BBPS score was 8.1 +/- 1.1. Higher BBPS scores (>=8 vs <8) were associated with a higher polyp detection rate (44.9% vs. 33.0%, P = 0.042). The BBPS scores were inversely correlated with colonoscope withdrawal times (r = 0.167, P < 0.001). CONCLUSIONS: The BBPS is a valid and reliable measure for assessing bowel preparation during colonoscopy in Korean patients. The polyp detection rate is higher in patients with higher BBPS scores than in those with lower BBPS scores during a colonoscopic procedure. PMID- 25038208 TI - Effect of rifaximin, probiotics, and l-ornithine l-aspartate on minimal hepatic encephalopathy: a randomized controlled trial. AB - BACKGROUND/AIMS: Minimal hepatic encephalopathy (MHE) implies subtle impairment of cognitive functions in the absence of features of overt encephalopathy. We aimed to determine the prevalence of MHE in patients with liver cirrhosis and to find out the effect of rifaximin, probiotics, and l-ornithine l-aspartate (LOLA) individually in reversal of MHE by comparing it with placebo group. PATIENTS AND METHODS: This study was carried out in two phases. Phase I included the recruitment of 250 apparently healthy controls and extraction of normative data utilizing three neuropsychometric tests (NPTs) and critical flicker frequency (CFF) test. Phase II consisted of screening and recruitment of patients of MHE followed by drugs trial. A total of 317 cirrhotics were screened; 111 were excluded and the remaining 206 cirrhotics were screened for MHE using NPTs and/or CFF test. Of these, 124 patients with MHE were randomized to receive LOLA (n = 31), rifaximin (n = 31), probiotics (n = 32), for 2 months and were compared with patients who were given placebo (n = 30). RESULTS: Out of 206 cirrhotics, 124 (60.19%) had MHE. Among these 124 MHE patients, 87 (70.16%) patients had CFF <39Hz, 112 (90.32%) patients with MHE had two or more abnormal NPTs, and 75 (60.48%) patients had abnormality on both the CFF values and more than two abnormal NPTs. Intention-to-treat analysis showed the number of patients who improved after giving treatment were 67.7% (21/31), 70.9% (22/31), 50% (16/32), and 30% (9/30) for LOLA, rifaximin, probiotics, and placebo, respectively. CFF scores and improvement in psychometric tests after treatment were significantly higher (P < 0.05) for LOLA, rifaximin, and probiotics as compared with placebo group. CONCLUSIONS: Prevalence of MHE is high in patients with cirrhosis of liver. Rifaximin, LOLA, and probiotics are better than giving placebo in patients with MHE. PMID- 25038209 TI - Association of help-seeking behavior with depression and anxiety disorders among gastroenterological patients in Saudi Arabia. AB - BACKGROUND/AIMS: There is a high prevalence of depression and anxiety disorders among gastroenterological outpatients. Relatively few studies have been done on the help-seeking behavior among those who suffer from gastrointestinal symptoms with or without psychiatric disorders. We aimed to characterize the help-seeking behavior of gastroenterological outpatients and to evaluate if this behavior is linked to the presence of depression and anxiety. PATIENTS AND METHODS: A cross sectional study was carried out in gastroenterology clinics in four hospitals in Riyadh between February and September 2013. A self-administrated questionnaire was developed and administered to patients. Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) questionnaires were used to diagnose depression and anxiety, respectively. RESULTS: A total of 440 patients completed the study questionnaire. The average age was 36.0 +/- 12.8 years and 69% of the patients were males. Complaints included abdominal pain (58%), heartburn (29%), diarrhea or constipation (25%), appetite or weight changes (22%), and nausea or vomiting (16%). Depression was diagnosed in 36%, while anxiety was diagnosed in 28% of the patients. The first intervention was use of medications (68%) and undergoing endoscopy (16%), while few patients initially used herbs or Islamic incantation (7.5%). This first intervention was done primarily (59%) in private sector hospitals rather than government sector hospitals (36%). The rates of depression and anxiety in our patients were higher among those who suffered from multiple complaints for longer durations and with less satisfaction with the offered services. CONCLUSION: Depression and anxiety are common comorbidities in gastroenterological outpatient population, especially those who have a chronic course of multiple gastrointestinal complaints. PMID- 25038210 TI - Differential diagnosis of intestinal tuberculosis from Crohn's disease and primary intestinal lymphoma in China. AB - BACKGROUND/AIMS: There are many similarities and overlaps in clinical, radiological, endoscopic, and histological features among intestinal tuberculosis (ITB), Crohn's disease (CD), and primary intestinal lymphoma (PIL), and the differential diagnosis of ITB can be very challenging for clinicians. PATIENTS AND METHODS: The clinical, radiologic, endoscopic, and pathological data of 213 patients were analyzed retrospectively. According to the diagnostic criteria and exclusive criteria of ITB, CD, and PIL, 83 patients were recruited and divided into three groups, including 30 cases in the ITB group, 38 cases in the CD group, and 15 cases in the PIL group, and the medical data and statistical analysis were recorded. RESULTS: Rural patients with abdominal pain as the first symptom and with transverse ulcer and caseating granulomas were more common in the ITB group than the CD group, whereas urban patients with stool change as the first symptom, moderate or severe anemia, thickening of intestinal wall, rectal involvement, skipping distribution, prominent lymphoid aggregates, and irregular glands were more common in CD group than ITB group (P < 0.05). Young patients (age < 30 years) with fever, weakness, fatigue, abdominal mass, intestinal perforation, and emergent operation were more common in ITB group than PIL group, whereas thickening of intestinal wall, malignant lymphocytes, limited distribution, and involvement of small intestine occurred more in PIL group than ITB group (P < 0.05). CONCLUSION: The differential diagnosis of ITB from CD and PIL can be made by a combination of clinical manifestation, endoscopy, and pathological examinations. PMID- 25038211 TI - Prevalence of symptoms of gastroesopahgeal reflux in a cohort of Saudi Arabians: a study of 1265 subjects. AB - BACKGROUND/AIMS: In this study, we aimed to determine the prevalence of gastroesophageal reflux disease (GERD) in the general population of the capital city of Riyadh and to assess its association with other factors including age, smoking, body mass index (BMI), asthma, as well as the presence of other co morbid diseases. MATERIALS AND METHODS: We used the Gastroesophageal Reflux Disease Questionnaire (GerdQ) for diagnosing GERD, based on a GerdQ score of 8 or more. Riyadh was divided into four quadrants, and from each area, a single shopping mall was chosen randomly to conduct our surveys. Data collected included age, sex, history of smoking, history of asthma or any other medical condition, dietary habits, monthly household income, history and frequency of heartburn, epigastric pain, regurgitation of food, nausea, sleep disturbance from heartburn, the use of common over-the-counter antacids for the control of their symptoms, and their height and weight. RESULTS: Over a 4-week period from the 19 December 2012 to 17 January 2013, a total of 1265 individuals were included in the survey. The mean age was 29.97 +/- 11.58 years. Females formed 67.81% of the respondents and 62.73% had one or more episodes of heartburn per week. Based on a cutoff GERDQ score of 8, the prevalence of GERD in the surveyed population was 45.4%. GERD was more prevalent in older individuals (mean age 31.9 vs. 30.0 years, P < 0.001) and in those with a higher BMI (27.29 vs. 26.31 kg/m 2 , P = 0.02). There was no difference between males (45.43%) and females (45.13%) (P = 0.92); there was a trend of a higher prevalence in smokers (51.63% vs. 44.41%), but it did not reach statistical significance (P = 0.09). CONCLUSION: Symptoms suggestive of GERD as determined by the translated GerdQ are prevalent among this study population. PMID- 25038213 TI - Lymphangioma of the ileocecal valve clinically masquerading as a submucosal small intestinal GIST: report of a case and literature review. AB - Lymphangiomas are rare tumors affecting the gastrointestinal tract, and may be seen in the bowel, gall bladder, and pancreas. They resemble hemangiomas, but consist of spaces of variable sizes containing lymph. In this report, we describe the case of a 53-year-old male who presented with abdominal pain and constipation. Computerized tomography (CT) scan showed a polypoidal lesion at the ileocecal valve which was thought to be a gastrointestinal stromal tumor. Resected specimen did, however, show a lymphangioma. We also describe the clinicopathologic features of gastrointestinal lymphangiomas with a literature review. PMID- 25038212 TI - Hepatic fibrinogen storage disease due to the fibrinogen gamma375 Arg -> Trp mutation "fibrinogen Aguadilla" is present in Arabs. AB - The mutation gamma375Arg -> Trp (fibrinogen Aguadilla) is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont) capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen gamma-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a gamma375Arg -> Trp mutation (fibrinogen Aguadilla) in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease. PMID- 25038214 TI - Extending the construct validity of dependency among conjugally bereaved adults. AB - The Relationship Profile Test is a widely used measure of dependency, detachment, and healthy dependency that has been examined in both clinical and nonclinical settings, though researchers have yet to validate this measure among conjugally bereaved adults. The present study examines the construct validity of a three facet model of dependency-detachment by comparing relationships among self report, semistructured interview-rated, and knowledgeable informant-rated functioning among conjugally bereaved adults. Participants (N = 112) included bereaved adults (M = 51.1 years; SD = 9.7) who had experienced the loss of a spouse 1.5 to 3 years prior to taking part in this study. Findings indicate adequate psychometric properties and theoretically expected associations with various measures of wellness and health including satisfaction with life, coping flexibility, somatic complaints, and ego resiliency. Results draw attention to adaptive correlates of dependency, suggesting potentially beneficial mental health interventions. PMID- 25038215 TI - Enriching psychological assessment using a person-specific analysis of interpersonal processes in daily life. AB - We present a series of methods and approaches for clinicians interested in tracking their individual patients over time and in the natural settings of their daily lives. The application of person-specific analyses to intensive repeated measurement data can assess some aspects of persons that are distinct from the valuable results obtained from single-occasion assessments. Guided by interpersonal theory, we assess a psychotherapy patient's interpersonal processes as they unfold in his daily life. We highlight specific contexts that change these processes, use an informant report to examine discrepancies in his reported interpersonal processes, and examine how his interpersonal processes differ as a function of varying levels of self-esteem and anger. We advocate for this approach to complement existing psychological assessments and provide a scoring program to facilitate initial implementation. PMID- 25038216 TI - Stochastic mediation contrasts in epidemiologic research: interpregnancy interval and the educational disparity in preterm delivery. AB - Low maternal education is consistently associated with increased risk of preterm delivery (PTD). The interpregnancy interval (IPI), defined as the time between the date of a previous birth and the conception date of the index pregnancy, may mediate this relationship. We estimated controlled direct effects to assess whether hypothetical interventions designed to increase IPIs would reduce the educational disparity in PTD. We introduce a technique for estimating controlled direct effects under interventions that set only some persons in the population to a specific mediator value. We used data from 847,618 singleton livebirths occurring in Quebec, Canada, between 1989 and 2010. Compared with mothers with some university education (>=14 years), mothers with less than high school (<11 years), high school (11 years), and some college (12-13 years) had excess PTD risks of 2.6% (95% confidence interval (CI): 2.4, 2.8), 1.5% (95% CI: 1.4, 1.7), and 1.0% (95% CI: 0.9, 1.1), respectively. Risk differences under an intervention corresponding to the Healthy People 2020 objective of reducing the number of mothers with IPIs less than 18 months by 3% were no different from those for the total relationship. Our results suggest that interventions designed to increase the length of short IPIs will yield no important change in the PTD disparity by maternal educational level. PMID- 25038217 TI - Re: "Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup". PMID- 25038221 TI - First widespread look at evolution of venomous centipedes. PMID- 25038222 TI - Diverting victims of commercial sexual exploitation from juvenile detention: development of the InterCSECt screening protocol. AB - Identifying victims of commercial sexual exploitation in the juvenile justice system is a challenging complexity requiring concerted organizational commitment. Using a three-tiered, trauma-informed screening process, a 31/2-month pilot intervention was implemented in Clark County Juvenile Court (Washington) to identify victims in an effort to connect them to community youth advocates and sexual assault resources. A total of 535 boys and girls ages 9 to 19 were screened during intake; 47 of these youth reported risk factors associated with commercial sexual exploitation of children (CSEC) and were subsequently referred to community advocates. Six youth (all girls) were confirmed CSEC victims and were successfully diverted from juvenile detention. Study results suggest that despite the lack of reliable data surrounding the prevalence of CSEC, juvenile justice agencies need to become educated on the risk factors to triage victims to services. PMID- 25038223 TI - The co-occurrence of physical and cyber dating violence and bullying among teens. AB - This study examined the overlap in teen dating violence and bullying perpetration and victimization, with regard to acts of physical violence, psychological abuse, and-for the first time ever-digitally perpetrated cyber abuse. A total of 5,647 youth (51% female, 74% White) from 10 schools participated in a cross-sectional anonymous survey. Results indicated substantial co-occurrence of all types of teen dating violence and bullying. Youth who perpetrated and/or experienced physical, psychological, and cyber bullying were likely to have also perpetrated/experienced physical and sexual dating violence, and psychological and cyber dating abuse. PMID- 25038224 TI - Sibling bullying perpetration: associations with gender, grade, peer perpetration, trait anger, and moral disengagement. AB - This study investigated bullying among siblings in both traditional and cyber forms, and the associations of gender, grade, peer bullying perpetration, trait anger, and moral disengagement. The participants were 455 children in Grades 5 to 12 (262 girls and 177 boys with 16 unknown gender) who had a sibling. As the number of siblings who only bullied by technology was low, these associations were not able to be calculated. However, the findings showed that the percentage of sibling traditional bullying perpetration (31.6%) was higher than peer bullying perpetration (9.8%). Sibling bullies reported engaging in complex behaviors of perpetration and victimization in both the physical and in cyber settings, although the number was small. Gender, trait anger, moral disengagement, and bullying peers at school (but not grade) were all significantly associated with sibling traditional bullying perpetration. The implications of the findings are discussed for bullying intervention and prevention programs to understand childhood bullying in diverse contexts. PMID- 25038225 TI - Distinctive and common neural underpinnings of major depression, social anxiety, and their comorbidity. AB - Assessing neural commonalities and differences among depression, anxiety and their comorbidity is critical in developing a more integrative clinical neuroscience and in evaluating currently debated categorical vs dimensional approaches to psychiatric classification. Therefore, in this study, we sought to identify patterns of anomalous neural responding to criticism and praise that are specific to and common among major depressive disorder (MDD), social anxiety disorder (SAD) and comorbid MDD-SAD. Adult females who met formal diagnostic criteria for MDD, SAD or MDD-SAD and psychiatrically healthy participants underwent functional magnetic resonance imaging as they listened to statements directing praise or criticism at them or at another person. MDD groups showed reduced responding to praise across a distributed cortical network, an effect potentially mediated by thalamic nuclei undergirding arousal-mediated attention. SAD groups showed heightened anterior insula and decreased default-mode network response to criticism. The MDD-SAD group uniquely showed reduced responding to praise in the dorsal anterior cingulate cortex. Finally, all groups with psychopathology showed heightened response to criticism in a region of the superior frontal gyrus implicated in attentional gating. The present results suggest novel neural models of anhedonia in MDD, vigilance-withdrawal behaviors in SAD, and poorer outcome in MDD-SAD. Importantly, in identifying unique and common neural substrates of MDD and SAD, these results support a formulation in which common neural components represent general risk factors for psychopathology that, due to factors that are present at illness onset, lead to distinct forms of psychopathology with unique neural signatures. PMID- 25038226 TI - Macrophage inflammatory protein derivative ECI301 enhances the alarmin-associated abscopal benefits of tumor radiotherapy. AB - Radiotherapy can produce antitumor benefits beyond the local site of irradiation, an immune-based phenomenon known as the abscopal effect, but the mechanisms underlying these benefits are poorly understood. Preclinical studies of ECI301, a mutant derivative of macrophage inhibitory protein-1alpha, have shown that its administration can improve the antitumor effects of radiotherapy in a manner associated with a tumor-independent abscopal effect. In this article, we report that i.v. administration of ECI301 after intratumoral injection of tumor cell lysates can inhibit tumor growth, not only at the site of injection but also at nontreated sites. Effects of the tumor lysate were further recapitulated by intratumoral injection [corrected] of the alarmins HSP70 or HMGB1, but not HSP60, and i.v. administration [corrected] of ECI301 + HSP70 were sufficient to inhibit tumor growth. Although i.v. administration [corrected] of ECI301 + HMGB1 did not inhibit tumor growth, we found that administration of a neutralizing HMGB1 antibody neutralized the cooperative effects of ECI301 on tumor irradiation. Moreover, mice genetically deficient in TLR4, an immune pattern receptor that binds alarmins, including HMGB1 and HSP70, did not exhibit antitumor responses to irradiation with ECI301 administration. Although ECI301 was cleared rapidly from peripheral blood, it was found to bind avidly to HSP70 and HMGB1 in vitro. Our results suggest a model in which sequential release of the alarmins HSP70 and HMGB1 from a tumor by irradiation may trap circulating ECI301, thereby licensing or restoring tumor immunosurveillance capabilities of natural killer cells or CD4(+) and CD8(+) T cells against tumor cells that may evade irradiation. Cancer Res; 74(18); 5070-8. (c)2014 AACR. PMID- 25038227 TI - NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis. AB - The Notch signaling pathway governs many distinct cellular processes by regulating transcriptional programs. The transcriptional response initiated by Notch is highly cell context dependent, indicating that multiple factors influence Notch target gene selection and activity. However, the mechanism by which Notch drives target gene transcription is not well understood. Herein, we identify and characterize a novel Notch-interacting protein, Notch activation complex kinase (NACK), which acts as a Notch transcriptional coactivator. We show that NACK associates with the Notch transcriptional activation complex on DNA, mediates Notch transcriptional activity, and is required for Notch-mediated tumorigenesis. We demonstrate that Notch1 and NACK are coexpressed during mouse development and that homozygous loss of NACK is embryonic lethal. Finally, we show that NACK is also a Notch target gene, establishing a feed-forward loop. Thus, our data indicate that NACK is a key component of the Notch transcriptional complex and is an essential regulator of Notch-mediated tumorigenesis and development. PMID- 25038228 TI - Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling. AB - Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions that are inhibited by the prototypic Th2 cytokine IL4 and the TGFbeta superfamily members TGFbeta1 and activin-A. Interestingly, the largest subgroup of the TGFbeta superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling on NK cell effector functions have not been evaluated. Here, we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8, which mediate BMP family member signaling. In opposition to the inhibitory effects of TGFbeta1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L-activated NK cells revealed that BMP signaling optimized IFNgamma and global cytokine and chemokine production, phenotypic activation and proliferation, and autologous dendritic cell activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one that might be therapeutically manipulated to help eradicate tumors. Cancer Res; 74(18); 5019-31. (c)2014 AACR. PMID- 25038229 TI - Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling. AB - Drug-induced gene-expression profiles that invert disease profiles have recently been illustrated to be a starting point for drug repositioning. In this study, we validate this approach and focus on prediction of novel drugs for colorectal cancer, for which there is a pressing need to find novel antimetastatic compounds. We computationally predicted three novel and still unknown compounds against colorectal cancer: citalopram (an antidepressant), troglitazone (an antidiabetic), and enilconazole (a fungicide). We verified the compounds by in vitro assays of clonogenic survival, proliferation, and migration and in a subcutaneous mouse model. We found evidence that the mode of action of these compounds may be through inhibition of TGFbeta signaling. Furthermore, one compound, citalopram, reduced tumor size as well as the number of circulating tumor cells and metastases in an orthotopic mouse model of colorectal cancer. This study proposes citalopram as a potential therapeutic option for patients with colorectal cancer, illustrating the potential of systems pharmacology. PMID- 25038230 TI - Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity. AB - Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignant glioma cells suppress NK immune surveillance by overexpressing the beta galactoside-binding lectin galectin-1. Conversely, galectin-1-deficient glioma cells could be eradicated by host NK cells before the initiation of an antitumor T-cell response. In vitro experiments demonstrated that galectin-1-deficient GL26 Cit glioma cells are ~3-fold more sensitive to NK-mediated tumor lysis than galectin-1-expressing cells. Our findings suggest that galectin-1 suppression in human glioma could improve patient survival by restoring NK immune surveillance that can eradicate glioma cells. Cancer Res; 74(18); 5079-90. (c)2014 AACR. PMID- 25038232 TI - Analysis of a triose phosphate/phosphate translocator-deficient mutant reveals a limited capacity for starch synthesis in rice leaves. PMID- 25038231 TI - HSV-sr39TK positron emission tomography and suicide gene elimination of human hematopoietic stem cells and their progeny in humanized mice. AB - Engineering immunity against cancer by the adoptive transfer of hematopoietic stem cells (HSC) modified to express antigen-specific T-cell receptors (TCR) or chimeric antigen receptors generates a continual supply of effector T cells, potentially providing superior anticancer efficacy compared with the infusion of terminally differentiated T cells. Here, we demonstrate the in vivo generation of functional effector T cells from CD34-enriched human peripheral blood stem cells modified with a lentiviral vector designed for clinical use encoding a TCR recognizing the cancer/testes antigen NY-ESO-1, coexpressing the PET/suicide gene sr39TK. Ex vivo analysis of T cells showed antigen- and HLA-restricted effector function against melanoma. Robust engraftment of gene-modified human cells was demonstrated with PET reporter imaging in hematopoietic niches such as femurs, humeri, vertebrae, and the thymus. Safety was demonstrated by the in vivo ablation of PET signal, NY-ESO-1-TCR-bearing cells, and integrated lentiviral vector genomes upon treatment with ganciclovir, but not with vehicle control. Our study provides support for the efficacy and safety of gene-modified HSCs as a therapeutic modality for engineered cancer immunotherapy. Cancer Res; 74(18); 5173-83. (c)2014 AACR. PMID- 25038233 TI - Integration of carbon assimilation modes with photosynthetic light capture in the green alga Chlamydomonas reinhardtii. AB - The unicellular green alga Chlamydomonas reinhardtii is capable of using organic and inorganic carbon sources simultaneously, which requires the adjustment of photosynthetic activity to the prevailing mode of carbon assimilation. We obtained novel insights into the regulation of light-harvesting at photosystem II (PSII) following altered carbon source availability. In C. reinhardtii, synthesis of PSII-associated light-harvesting proteins (LHCBMs) is controlled by the cytosolic RNA-binding protein NAB1, which represses translation of particular LHCBM isoform transcripts. This mechanism is fine-tuned via regulation of the nuclear NAB1 promoter, which is activated when linear photosynthetic electron flow is restricted by CO(2)-limitation in a photoheterotrophic context. In the wild-type, accumulation of NAB1 reduces the functional PSII antenna size, thus preventing a harmful overexcited state of PSII, as observed in a NAB1-less mutant. We further demonstrate that translation control as a newly identified long-term response to prolonged CO(2)-limitation replaces LHCII state transitions as a fast response to PSII over-excitation. Intriguingly, activation of the long term response is perturbed in state transition mutant stt7, suggesting a regulatory link between the long- and short-term response. We depict a regulatory circuit operating on distinct timescales and in different cellular compartments to fine-tune light-harvesting in photoheterotrophic eukaryotes. PMID- 25038234 TI - Tanning Shade Gradations of Models in Mainstream Fitness and Muscle Enthusiast Magazines: Implications for Skin Cancer Prevention in Men. AB - Tanned skin has been associated with perceptions of fitness and social desirability. Portrayal of models in magazines may reflect and perpetuate these perceptions. Limited research has investigated tanning shade gradations of models in men's versus women's fitness and muscle enthusiast magazines. Such findings are relevant in light of increased incidence and prevalence of melanoma in the United States. This study evaluated and compared tanning shade gradations of adult Caucasian male and female model images in mainstream fitness and muscle enthusiast magazines. Sixty-nine U.S. magazine issues (spring and summer, 2013) were utilized. Two independent reviewers rated tanning shade gradations of adult Caucasian male and female model images on magazines' covers, advertisements, and feature articles. Shade gradations were assessed using stock photographs of Caucasian models with varying levels of tanned skin on an 8-shade scale. A total of 4,683 images were evaluated. Darkest tanning shades were found among males in muscle enthusiast magazines and lightest among females in women's mainstream fitness magazines. By gender, male model images were 54% more likely to portray a darker tanning shade. In this study, images in men's (vs. women's) fitness and muscle enthusiast magazines portrayed Caucasian models with darker skin shades. Despite these magazines' fitness-related messages, pro-tanning images may promote attitudes and behaviors associated with higher skin cancer risk. To date, this is the first study to explore tanning shades in men's magazines of these genres. Further research is necessary to identify effects of exposure to these images among male readers. PMID- 25038235 TI - Paying attention to the preciseness of conclusion. PMID- 25038236 TI - Response to: 'paying attention to enthesitis in early untreated arthritis: MRI for the evaluation of enthesitis', by Zhou et al. PMID- 25038237 TI - Treatment of chronic hepatitis C complicated by mixed cryoglobulinemia with new protease inhibitor, sofosbuvir. PMID- 25038238 TI - Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. AB - OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions. PMID- 25038239 TI - Mitochondrial flashes: new insights into mitochondrial ROS signalling and beyond. AB - Respiratory mitochondria undergo stochastic, intermittent bursts of superoxide production accompanied by transient depolarization of the mitochondrial membrane potential and reversible opening of the membrane permeability transition pore. These discrete events were named 'superoxide flashes' for the reactive oxygen species (ROS) signal involved, and 'mitochondrial flashes' (mitoflashes) for the entirety of the multifaceted and intertwined mitochondrial processes. In contrast to the flashless basal ROS production of 'homeostatic ROS' for redox regulation, bursting ROS production during mitoflashes may provide 'signalling ROS' at the organelle level, fulfilling distinctly different cell functions. Mounting evidence indicates that mitoflash frequency is richly regulated over a broad range, and represents a novel, universal, and 'digital' readout of mitochondrial functional status and of the mitochondrial stress response. An emerging view is that mitoflashes participate in vital processes including metabolism, cell differentiation, the stress response and ageing. These recent advances shed new light on the role of mitochondrial functional dynamics in health and disease. PMID- 25038240 TI - Adenosine modulates light responses of rat retinal ganglion cell photoreceptors througha cAMP-mediated pathway. AB - Adenosine is an established neuromodulator in the mammalian retina, with A1 adenosine receptors being especially prevalent in the innermost ganglion cell layer. Activation of A1 receptors causes inhibition of adenylate cyclase, decreases in intracellular cyclic AMP (cAMP) levels and inhibition of protein kinase A (PKA). In this work, our aim was to characterize the effects of adenosine on the light responses of intrinsically photosensitive retinal ganglion cells (ipRGCs) and to determine whether these photoreceptors are subject to neuromodulation through intracellular cAMP-related signalling pathways. Using multielectrode array recordings from postnatal and adult rat retinas, we demonstrated that adenosine significantly shortened the duration of ipRGC photoresponses and reduced the number of light-evoked spikes fired by these neurons. The effects were A1 adenosine receptor-mediated, and the expression of this receptor on melanopsin-containing ipRGCs was confirmed by calcium imaging experiments on isolated cells in purified cultures. While inhibition of the cAMP/PKA pathway by adenosine shortened ipRGC light responses, stimulation of this pathway with compounds such as forskolin had the opposite effect and lengthened the duration of ipRGC spiking. Our findings reveal that the modification of ipRGC photoresponses through a cAMP/PKA pathway is a general feature of rat ganglion cell photoreceptors, and this pathway can be inhibited through activation of A1 receptors by adenosine. As adenosine levels in the retina rise at night, adenosinergic modulation of ipRGCs may serve as an internal regulatory mechanism to limit transmission of nocturnal photic signals by ipRGCs to the brain. Targeting retinal A1 adenosine receptors for ipRGC inhibition represents a potential therapeutic target for sleep disorders and migraine associated photophobia. PMID- 25038241 TI - The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. AB - The critical influence of the white adipose tissue (WAT) on metabolism is well appreciated in obesity, but adipose tissue dysfunction as a mechanism underlying age-associated metabolic dysfunction requires elucidation. To explore this possibility, we assessed metabolism and measures of epididymal (e)WAT mitochondria and artery function in young (6.1 +/- 0.4 months) and old (29.6 +/- 0.2 months) B6D2F1 mice. There were no group differences in average daily oxygen consumption, fasted blood glucose or plasma free fatty acids, but fasted plasma insulin and the homeostatic model assessment of insulin resistance (HOMA-IR%) were higher in the old (~50-85%, P < 0.05). Tissue mass (P < 0.05) and adipocyte area were lower (~60%) (P < 0.01) and fibrosis was greater (sevenfold, P < 0.01) in eWAT with older age. The old also exhibited greater liver triglycerides (~60%, P < 0.05). The mitochondrial respiratory oxygen flux after the addition of glutamate and malate (GM), adenosine diphosphate (d), succinate (S) and octanoyl carnitine (O) were one- to twofold higher in eWAT of old mice (P < 0.05). Despite no change in the respiratory control ratio, substrate control ratios of GMOd/GMd and GMOSd/GMd were ~30-40% lower in old mice (P < 0.05) and were concomitant with increased nitrotyrosine (P < 0.05) and reduced expression of brown adipose markers (P < 0.05). Ageing reduced vascularity (~50%, P < 0.01), angiogenic capacity (twofold, P < 0.05) and expression of vascular endothelial growth factor (~50%, P < 0.05) in eWAT. Finally, endothelium-dependent dilation was lower (P < 0.01) in isolated arteries from eWAT arteries of the old mice. Thus, metabolic dysfunction with advancing age occurs in concert with dysfunction in the adipose tissue characterized by both mitochondrial and arterial dysfunction. PMID- 25038242 TI - Silencing of Kir2 channels by caveolin-1: cross-talk with cholesterol. AB - A growing number of studies show that different types of ion channels localize in caveolae and are regulated by the level of membrane cholesterol. Furthermore, it has been proposed that cholesterol-induced regulation of ion channels might be attributed to partitioning into caveolae and association with caveolin-1 (Cav-1). We tested, therefore, whether Cav-1 regulates the function of inwardly rectifying potassium channels Kir2.1 that play major roles in the regulation of membrane potentials of numerous mammalian cells. Our earlier studies demonstrated that Kir2.1 channels are cholesterol sensitive. In this study, we show that Kir2.1 channels co-immunoprecipitate with Cav-1 and that co-expression of Kir2.1 channels with Cav-1 in HEK293 cells results in suppression of Kir2 current indicating that Cav-1 is a negative regulator of Kir2 function. These observations are confirmed by comparing Kir currents in bone marrow-derived macrophages isolated from Cav-1(-/-) and wild-type animals. We also show, however, that Kir2 channels maintain their sensitivity to cholesterol in HEK293 cells that have very low levels of endogenous Cav-1 and in bone marrow-derived macrophages isolated from Cav-1(-/-) knockout mice. Thus, these studies indicate that Cav-1 and/or intact caveolae are not required for cholesterol sensitivity of Kir channels. Moreover, a single point mutation of Kir2.1, L222I that abrogates the sensitivity of the channels to cholesterol also abolishes their sensitivity to Cav-1 suggesting that the two modulators regulate Kir2 channels via a common mechanism. PMID- 25038243 TI - Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner. AB - Physical inactivity that accompanies ageing and disease may hasten disability by reducing skeletal muscle contractility. To characterize skeletal muscle functional adaptations to muscle disuse, we compared contractile performance at the molecular, cellular and whole-muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced-stage, symptomatic knee osteoarthritis (OA) (n = 16). OA patients showed reduced (P < 0.01) knee extensor function. At the cellular level, single muscle fibre force production was reduced in OA patients in myosin heavy chain (MHC) I and IIA fibres (both P < 0.05) and differences in IIA fibres persisted after adjustments for fibre cross sectional area (P < 0.05). Although no group differences in contractile velocity or power output were found for any fibre type, sex was found to modify the effect of OA, with a reduction in MHC IIA power output and a trend towards reduced shortening velocity in women, but increases in both variables in men (P < 0.05 and P = 0.07, respectively). At the molecular level, these adaptations in MHC IIA fibre function were explained by sex-specific differences (P <= 0.05) in myosin actin cross-bridge kinetics. Additionally, cross-bridge kinetics were slowed in MHC I fibres in OA patients (P < 0.01), attributable entirely to reductions in women with knee OA (P < 0.05), a phenotype that could be reproduced in vitro by chemical modification of protein thiol residues. Our results identify molecular and cellular functional adaptations in skeletal muscle that may contribute to reduced physical function with knee OA-associated muscle disuse, with sex specific differences that may explain a greater disposition towards disability in women. PMID- 25038244 TI - Influence of intramuscular heat stimulation on modulation of nociception: complex role of central opioid receptors in descending facilitation and inhibition. AB - It has been reported that the threshold to activate 'silent' or inactive descending facilitation of nociception is lower than that of descending inhibition. Thus, the development of pain therapy to effectively drive descending inhibition alone, without the confounding influences of facilitation is a challenge. To address this issue we investigated the effects of intramuscular stimulation with a heating-needle on spinal nociception, assessed by measuring nociceptive paw withdrawal reflex in rats. Additionally, involvement of the thalamic 'nociceptive discriminators' (thalamic mediodorsal (MD) and ventromedial (VM) nuclei), and opioid-mediated mechanisms were further explored. Descending facilitation and inhibition were elicited by 46 degrees C noxious heating-needle stimulation, and were regulated by thalamic MD and VM nuclei, respectively. In contrast, innocuous heating-needle stimulation at a temperature of 43 degrees C elicited descending inhibition modulated by the thalamic VM nucleus alone. Microinjection of MU/delta/kappa-opioid receptor antagonists beta-funaltrexamine hydrochloride/naltrindole/nor-binaltorphimine, into the VM nucleus attenuated the 46 degrees C intramuscular heating-needle stimulation-evoked descending inhibition, whereas treatment of the MD nucleus with beta-funaltrexamine hydrochloride significantly decreased the descending facilitation. By contrast, descending inhibition evoked by 43 degrees C heating-needle stimulation was only depressed by naltrindole, as opposed to MU- and kappa-opioid receptor antagonists, which failed to influence descending inhibition. The present study reveals distinct roles of MU-opioid receptors in the function of thalamic MD and VM nuclei,which exert facilitatory and inhibitory actions on nociception. Furthermore, innocuous, but not noxious, intramuscular heating-needle stimulation targeting delta-opioid receptors is suggested to be a promising avenue for the effective inhibition of pain. PMID- 25038245 TI - Sensory end-organs: signal processing in the periphery: a symposium presented at the 2013 Annual Meeting of the Society for Neuroscience, San Diego, CA, USA. PMID- 25038246 TI - Capillary force seeding of hydrogels for adipose-derived stem cell delivery in wounds. AB - Effective skin regeneration therapies require a successful interface between progenitor cells and biocompatible delivery systems. We previously demonstrated the efficiency of a biomimetic pullulan-collagen hydrogel scaffold for improving bone marrow-derived mesenchymal stem cell survival within ischemic skin wounds by creating a "stem cell niche" that enhances regenerative cytokine secretion. Adipose-derived mesenchymal stem cells (ASCs) represent an even more appealing source of stem cells because of their abundance and accessibility, and in this study we explored the utility of ASCs for hydrogel-based therapies. To optimize hydrogel cell seeding, a rapid, capillary force-based approach was developed and compared with previously established cell seeding methods. ASC viability and functionality following capillary hydrogel seeding were then analyzed in vitro and in vivo. In these experiments, ASCs were seeded more efficiently by capillary force than by traditional methods and remained viable and functional in this niche for up to 14 days. Additionally, hydrogel seeding of ASCs resulted in the enhanced expression of multiple stemness and angiogenesis-related genes, including Oct4, Vegf, Mcp-1, and Sdf-1. Moving in vivo, hydrogel delivery improved ASC survival, and application of both murine and human ASC-seeded hydrogels to splinted murine wounds resulted in accelerated wound closure and increased vascularity when compared with control wounds treated with unseeded hydrogels. In conclusion, capillary seeding of ASCs within a pullulan-collagen hydrogel bioscaffold provides a convenient and simple way to deliver therapeutic cells to wound environments. Moreover, ASC-seeded constructs display a significant potential to accelerate wound healing that can be easily translated to a clinical setting. PMID- 25038248 TI - Proceedings: international regulatory considerations on development pathways for cell therapies. AB - Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field's development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses. PMID- 25038247 TI - Testicular niche required for human spermatogonial stem cell expansion. AB - Prepubertal boys treated with high-dose chemotherapy do not have an established means of fertility preservation because no established in vitro technique exists to expand and mature purified spermatogonial stem cells (SSCs) to functional sperm in humans. In this study, we define and characterize the unique testicular cellular niche required for SSC expansion using testicular tissues from men with normal spermatogenesis. Highly purified SSCs and testicular somatic cells were isolated by fluorescence-activated cell sorting using SSEA-4 and THY1 as markers of SSCs and somatic cells. Cells were cultured on various established niches to assess their role in SSC expansion in a defined somatic cellular niche. Of all the niches examined, cells in the SSEA-4 population exclusively bound to adult testicular stromal cells, established colonies, and expanded. Further characterization of these testicular stromal cells revealed distinct mesenchymal markers and the ability to undergo differentiation along the mesenchymal lineage, supporting a testicular multipotent stromal cell origin. In vitro human SSC expansion requires a unique niche provided exclusively by testicular multipotent stromal cells with mesenchymal properties. These findings provide an important foundation for developing methods of inducing SSC growth and maturation in prepubertal testicular tissue, essential to enabling fertility preservation for these boys. PMID- 25038249 TI - Author's response. PMID- 25038250 TI - Structural determinants of an internal ribosome entry site that direct translational reading frame selection. AB - The dicistrovirus intergenic internal ribosome entry site (IGR IRES) directly recruits the ribosome and initiates translation using a non-AUG codon. A subset of IGR IRESs initiates translation in either of two overlapping open reading frames (ORFs), resulting in expression of the 0 frame viral structural polyprotein and an overlapping +1 frame ORFx. A U-G base pair adjacent to the anticodon-like pseudoknot of the IRES directs +1 frame translation. Here, we show that the U-G base pair is not absolutely required for +1 frame translation. Extensive mutagenesis demonstrates that 0 and +1 frame translation can be uncoupled. Ribonucleic acid (RNA) structural probing analyses reveal that the mutant IRESs adopt distinct conformations. Toeprinting analysis suggests that the reading frame is selected at a step downstream of ribosome assembly. We propose a model whereby the IRES adopts conformations to occlude the 0 frame aminoacyl-tRNA thereby allowing delivery of the +1 frame aminoacyl-tRNA to the A site to initiate translation of ORFx. This study provides a new paradigm for programmed recoding mechanisms that increase the coding capacity of a viral genome. PMID- 25038251 TI - FANCM-associated proteins MHF1 and MHF2, but not the other Fanconi anemia factors, limit meiotic crossovers. AB - Genetic recombination is important for generating diversity and to ensure faithful segregation of chromosomes at meiosis. However, few crossovers (COs) are formed per meiosis despite an excess of DNA double-strand break precursors. This reflects the existence of active mechanisms that limit CO formation. We previously showed that AtFANCM is a meiotic anti-CO factor. The same genetic screen now identified AtMHF2 as another player of the same anti-CO pathway. FANCM and MHF2 are both Fanconi Anemia (FA) associated proteins, prompting us to test the other FA genes conserved in Arabidopsis for a role in CO control at meiosis. This revealed that among the FA proteins tested, only FANCM and its two DNA binding co-factors MHF1 and MHF2 limit CO formation at meiosis. PMID- 25038252 TI - The human Piwi protein Hiwi2 associates with tRNA-derived piRNAs in somatic cells. AB - The Piwi-piRNA pathway is active in animal germ cells where its functions are required for germ cell maintenance and gamete differentiation. Piwi proteins and piRNAs have been detected outside germline tissue in multiple phyla, but activity of the pathway in mammalian somatic cells has been little explored. In particular, Piwi expression has been observed in cancer cells, but nothing is known about the piRNA partners or the function of the system in these cells. We have surveyed the expression of the three human Piwi genes, Hiwi, Hili and Hiwi2, in multiple normal tissues and cancer cell lines. We find that Hiwi2 is ubiquitously expressed; in cancer cells the protein is largely restricted to the cytoplasm and is associated with translating ribosomes. Immunoprecipitation of Hiwi2 from MDAMB231 cancer cells enriches for piRNAs that are predominantly derived from processed tRNAs and expressed genes, species which can also be found in adult human testis. Our studies indicate that a Piwi-piRNA pathway is present in human somatic cells, with an uncharacterised function linked to translation. Taking this evidence together with evidence from primitive organisms, we propose that this somatic function of the pathway predates the germline functions of the pathway in modern animals. PMID- 25038253 TI - Pseudoprogression in patients with glioblastoma: clinical relevance despite low incidence. AB - BACKGROUND: According to the Response Assessment in Neuro-Oncology criteria, new enhancement within the radiation field on contrast enhanced T1-weighted images within 12 weeks after completion of radiotherapy should not qualify for progressive disease, since up to 50% of these cases may be pseudoprogression (PsP). To validate this concept, we assessed incidence and overall survival (OS) of patients with suspected and confirmed PsP dependent on different time intervals and definitions of PsP. METHODS: Patients with newly diagnosed glioblastoma and an enhancement increase of at least 25% after completion of standard radiochemotherapy at month 1, 4, 7, or 10 were eligible. Based on the development of the enhancement in follow-up examinations, patients were categorized as either PsP (subgrouped as complete resolution/decrease >50% and decrease <50%/stable) or true progression. RESULTS: Out of 548 patients, 79 fulfilled the inclusion criteria. Of these 79 patients, 9 (11.4%) showed PsP (6/45 patients at 1 month, 2/17 at 4 months, 1/9 at 7 months, and 0/8 at 10 months). Complete resolution of the enhancement was found in 1, decrease >50% in 3, decrease <50% in 2, and stable enhancement in 3 patients with PsP. Patients with PsP showed a significantly longer OS (P < .012). No difference in OS was found among PsP subgroups. CONCLUSIONS: This series challenges the current concept of PsP. Even though we could confirm a prolonged OS of patients with PsP, the incidence of PsP was lower than reported previously and extended beyond 12 weeks. PMID- 25038254 TI - Overexpression of a novel Arabidopsis PP2C isoform, AtPP2CF1, enhances plant biomass production by increasing inflorescence stem growth. AB - In contrast to mammals, higher plants have evolved to express diverse protein phosphatase 2Cs (PP2Cs). Of all Arabidopsis thaliana PP2Cs, members of PP2C subfamily A, including ABI1, have been shown to be key negative regulators of abscisic acid (ABA) signalling pathways, which regulate plant growth and development as well as tolerance to adverse environmental conditions. However, little is known about the enzymatic and signalling roles of other PP2C subfamilies. Here, we report a novel Arabidopsis subfamily E PP2C gene, At3g05640, designated AtPP2CF1. AtPP2CF1 was dramatically expressed in response to exogenous ABA and was expressed in vascular tissues and guard cells, similar to most subfamily A PP2C genes. In vitro enzymatic activity assays showed that AtPP2CF1 possessed functional PP2C activity. However, yeast two-hybrid analysis revealed that AtPP2CF1 did not interact with PYR/PYL/RCAR receptors or three SnRK2 kinases, which are ABI1-interacting proteins. This was supported by homology-based structural modelling demonstrating that the putative active- and substrate-binding site of AtPP2CF1 differed from that of ABI1. Furthermore, while overexpression of ABI1 in plants induced an ABA-insensitive phenotype, Arabidopsis plants overexpressing AtPP2CF1 (AtPP2CF1oe) were weakly hypersensitive to ABA during seed germination and drought stress. Unexpectedly, AtPP2CF1oe plants also exhibited increased biomass yield, mainly due to accelerated growth of inflorescence stems through the activation of cell proliferation and expansion. Our results provide new insights into the physiological significance of AtPP2CF1 as a candidate gene for plant growth production and for potential application in the sustainable supply of plant biomass. PMID- 25038255 TI - Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. AB - NO produced by inducible NO synthase (iNOS) contributes to ischemic brain injury, but the cell types expressing iNOS and mediating tissue damage have not been elucidated. To examine the relative contribution of iNOS in resident brain cells and peripheral leukocytes infiltrating the ischemic brain, we used bone marrow (BM) chimeric mice in which the middle cerebral artery was occluded and infarct volume was determined 3 d later. iNOS(-/-) mice engrafted with iNOS(+/+) BM exhibited larger infarcts (44 +/- 2 mm(3); n = 13; mean +/- SE) compared with autologous transplanted iNOS(-/-) mice (24 +/- 3 mm(3); n = 10; p < 0.01), implicating blood-borne leukocytes in the damage. Furthermore, iNOS(+/+) mice transplanted with iNOS(-/-) BM had large infarcts (39 +/- 6 mm(3); n = 13), similar to those of autologous transplanted iNOS(+/+) mice (39 +/- 4 mm(3); n = 14), indicating the resident brain cells also play a role. Flow cytometry and cell sorting revealed that iNOS is highly expressed in neutrophils and endothelium but not microglia. Surprisingly, postischemic iNOS expression was enhanced in the endothelium of iNOS(+/+) mice transplanted with iNOS(-/-) BM and in leukocytes of iNOS(-/-) mice with iNOS(+/+) BM, suggesting that endothelial iNOS suppresses iNOS expression in leukocytes and vice versa. To provide independent evidence that neutrophils mediate brain injury, neutrophils were isolated and transferred to mice 24 h after stroke. Consistent with the result in chimeric mice, transfer of iNOS(+/+), but not iNOS(-/-), neutrophils into iNOS(-/ ) mice increased infarct volume. The findings establish that iNOS in both neutrophils and endothelium mediates tissue damage and identify these cell types as putative therapeutic targets for stroke injury. PMID- 25038256 TI - Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype. AB - Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes. PMID- 25038257 TI - Scavenger receptor function of mouse Fcgamma receptor III contributes to progression of atherosclerosis in apolipoprotein E hyperlipidemic mice. AB - Recent studies showed loss of CD36 or scavenger receptor-AI/II (SR-A) does not ameliorate atherosclerosis in a hyperlipidemic mouse model, suggesting receptors other than CD36 and SR-A may also contribute to atherosclerosis. In this report, we show that apolipoprotein E (apoE)-CD16 double knockout (DKO; apoE-CD16 DKO) mice have reduced atherosclerotic lesions compared with apoE knockout mice. In vivo and in vitro foam cell analyses showed apoE-CD16 DKO macrophages accumulated less neutral lipids. Reduced foam cell formation in apoE-CD16 DKO mice is not due to change in expression of CD36, SR-A, and LOX-1. This led to a hypothesis that CD16 may have scavenger receptor activity. We presented evidence that a soluble form of recombinant mouse CD16 (sCD16) bound to malondialdehyde-modified low density lipoprotein (MDALDL), and this binding is blocked by molar excess of MDA- modified BSA and anti-MDA mAbs, suggesting CD16 specifically recognizes MDA epitopes. Interestingly, sCD16 inhibited MDALDL binding to macrophage cell line, as well as soluble forms of recombinant mouse CD36, SR-A, and LOX-1, indicating CD16 can cross-block MDALDL binding to other scavenger receptors. Anti-CD16 mAb inhibited immune complex binding to sCD16, whereas it partially inhibited MDALDL binding to sCD16, suggesting MDALDL binding site may be in close proximity to the immune complex binding site in CD16. Loss of CD16 expression resulted in reduced levels of MDALDL-induced proinflammatory cytokine expression. Finally, CD16 deficient macrophages showed reduced MDALDL-induced Syk phosphorylation. Collectively, our findings suggest scavenger receptor activity of CD16 may, in part, contribute to the progression of atherosclerosis. PMID- 25038259 TI - The worst of both worlds: examining the hypervirulence of the shigatoxigenic/enteroaggregative Escherichia coli O104:H4. PMID- 25038260 TI - A new simple and rapid LC-ESI-MS/MS method for quantification of plasma oxysterols as dimethylaminobutyrate esters. Its successful use for the diagnosis of Niemann-Pick type C disease. AB - Two oxysterols, cholestan-3beta,5alpha,6beta-triol (C-triol) and 7 ketocholesterol (7-KC), have been recently proposed as diagnostic markers of Niemann-Pick type C (NP-C) disease, representing a potential alternative diagnostic tool to the more invasive and time consuming filipin test in cultured fibroblasts. Usually, the oxysterols are detected and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using atmospheric pressure chemical ionization (APCI) or electro-spray-ionization (ESI) sources, after a variety of derivatization procedures to enhance sensitivity. We developed a sensitive LC-MS/MS method to quantify the oxysterols in plasma as dimethylaminobutyrate ester, suitable for ESI analysis. This method, with an easy liquid-phase extraction and a short derivatization procedure, has been validated to demonstrate specificity, linearity, recovery, lowest limit of quantification, accuracy and precision. The assay was linear over a concentration range of 0.5 200ng/mL for C-triol and 1.0-200ng/mL for 7-KC. Intra-day and inter-day coefficients of variation (CV%) were <15% for both metabolites. Receiver operating characteristic analysis estimates that the area under curve was 0.998 for C-triol, and 0.972 for 7-KC, implying a significant discriminatory power for the method in this patient population of both oxysterols. In summary, our method provides a simple, rapid and non-invasive diagnostic tool for the biochemical diagnosis of NP-C disease. PMID- 25038258 TI - The presence of the pAA plasmid in the German O104:H4 Shiga toxin type 2a (Stx2a) producing enteroaggregative Escherichia coli strain promotes the translocation of Stx2a across an epithelial cell monolayer. AB - BACKGROUND: A Shiga toxin type 2a (Stx2a)-producing enteroaggregative Escherichia coli (EAEC) strain of serotype O104:H4 caused a large outbreak in 2011 in northern Europe. Pathogenic mechanisms for this strain are unclear. We hypothesized that EAEC genes encoded on the pAA virulence plasmid promoted the translocation of Stx2a across the intestinal mucosa. METHODS: We investigated the potential contribution of pAA by using mutants of Stx-EAEC strain C227-11, either cured of the pAA plasmid or deleted for individual known pAA-encoded virulence genes (ie, aggR, aggA, and sepA). The resulting mutants were tested for their ability to induce interleukin 8 (IL-8) secretion and translocation of Stx2a across a polarized colonic epithelial (T84 cell) monolayer. RESULTS: We found that deletion of aggR or aggA significantly reduced bacterial adherence and (independently) translocation of Stx2a across the T84-cell monolayer. Moreover, deletion of aggR, aggA, sepA, or the Stx2a-encoding phage from C227-11 resulted in reduced secretion of IL-8 from the infected monolayer. CONCLUSIONS: Our data suggest that the AggR-regulated aggregative adherence fimbriae I enhance inflammation and enable the outbreak strain to both adhere to epithelial cells and translocate Stx2a across the intestinal epithelium. PMID- 25038261 TI - Photo-decolorization and detoxification of toxic dyes using titanium dioxide impregnated chitosan beads. AB - The removal of three different dyes namely Reactive Red 2 (RR), Methylene Blue (MB) and Rhodamine B (RB) using titanium dioxide impregnated chitosan beads (TCB) by photocatalytic method has been studied. The TCB was characterized by Fourier transform Infrared (FTIR) Spectral studies and Scanning Electron Microscope (SEM), Energy Dispersive Analysis of X-ray (EDAX). The photocatalytic activity of TCB for the decolorization of the three dyes is much higher than that of bare titanium dioxide, which can be attributed to the synergistic effect of TiO2 and chitosan. The chitosan adsorbs dye molecule which continuously supplies, dye molecule for degradation by TiO2 thereby preventing the electron-hole recombination. The photocatalytic experiment was carried out by varying different parameters such as irradiation time, dosage, pH, substrate concentration and co ions. The kinetics of decolorization of dyes are explained on the basis of Langmuir-Hinshelwood mechanism. The mineralization of dyes has also been confirmed by COD measurements. PMID- 25038262 TI - Hemodynamic effect and safety of intermittent sequential pneumatic compression leg sleeves in patients with congestive heart failure. AB - BACKGROUND: Pneumatic leg sleeves are widely used after prolonged operations for prevention of venous stasis. In healthy volunteers they increase cardiac function. We evaluated the hemodynamic effects and safety of intermittent sequential pneumatic compression (ISPC) leg sleeves in patients with chronic congestive heart failure (CHF). METHODS AND RESULTS: We studied 19 patients with systolic left ventricular dysfunction and CHF. ISPC leg sleeves, each with 10 air cells, were operated by a computerized compressor, exerting 2 cycles/min. Hemodynamic and echocardiographic parameters were measured before, during, and after ISPC activation. The baseline mean left ventricular ejection fraction was 29 +/- 9.2%, median 32%, range 10%-40%. Cardiac output (from 4.26 to 4.83 L/min; P = .008) and stroke volume (from 56.1 to 63.5 mL; P = .029) increased significantly after ISPC activation, without a reciprocal increase in heart rate, and declined after sleeve deactivation. Systemic vascular resistance (SVR) decreased significantly (from 1,520 to 1,216 dyne-s/cm5; P = .0005), and remained lower than the baseline level throughout the study. There was no detrimental effect on diastolic function and no adverse clinical events, despite increased pulmonary venous return. CONCLUSIONS: ISPC leg sleeves in patients with chronic CHF do not exacerbate symptoms and transiently improve cardiac output through an increase in stroke volume and a reduction in SVR. PMID- 25038263 TI - Cognitive and psycholologic considerations in pediatric heart failure. AB - Because children with heart failure live longer both before and after cardiac transplantation, there is renewed focus on the quality and preservation of their intellectual functioning and psychosocial health. Children with chronic heart failure are at risk for delays in both cognitive development and psychologic functioning, though the extent and permanence of impairment is not well understood. Children with medically managed heart failure have been shown to be at increased risk for anxiety and depression, with a prevalence of emotional disorders similar to that of other children with congenital heart disease. The use of ventricular assist devices as a bridge to transplantation offers both risks and benefits for the preservation of intellectual and emotional function, with an increased risk for ischemic injury to the brain, but offers the advantage of allowing for cognitive stimulation and improved social interactions. A new population of children with heart failure, those outfitted with permanent ventricular assist devices in lieu of cardiac transplantation, may represent a particular risk group regarding social and cognitive function, but as of yet this is not well studied. Early intervention and school accommodations are recommended for those with cognitive, social, or emotional deficits, and brain imaging should be considered for those with persistent difficulties. Whenever possible, patients should be referred to psychologists and developmental specialists with experience in treating this patient population. PMID- 25038264 TI - Clinical utility of central venous saturation for the calculation of cardiac index in cardiac patients. AB - BACKGROUND: Mixed venous saturation (MVS) obtained from the distal pulmonary artery (PA) during Swan-Ganz catheterization is the criterion standard for calculating cardiac output (CO) and cardiac index (CI) with the use of the Fick method. We think that calculating CI with the use of central venous saturation (CVS) instead of PA-MVS is both feasible and accurate. Earlier studies were small, enrolled heterogeneous patient populations, and resulted in inconsistent findings. METHODS: All patients undergoing right heart catheterization from January 2011 to January 2012 in our catheterization lab with simultaneous measurements of MVS obtained from the distal PA and CVS obtained from the superior vena cava (SVC) or right atrium (RA) were included. Out of the 902 patients enrolled, we excluded patients (n = 50) who had known cardiac shunt or dialysis fistula, had duplicate medical records, or were septic. We calculated the CI with the use of the assumed Fick method using both MVS (criterion standard) and CVS (SVC or RA saturations) in the remaining 852 patients. We measured the correlation and the agreement between the 2 methods with the use of the Pearson correlation coefficient and Bland-Altman analysis. RESULTS: Totals of 112 patients with simultaneous PA and RA saturation measurements (group I) and 740 patients with simultaneous PA and SVC saturation measurements (group II) were included. We found an excellent linear correlation between SVC and PA saturation (r = 0.928) and between RA and PA saturation (r = 0.95). There was also an excellent correlation between CI calculated with the use of PA saturation and CI calculated with the use of SVC (r = 0.87) or RA (r = 0.93) saturation. The mean bias of CVS-derived CI compared with MVS-derived CI (criterion standard) was -0.1 (95% limits of agreement [LOA] -1 to +0.77) in the SVC group and -0.006 (LOA 0.68 to +0.69) in the RA group. Patients with low CI had stronger correlation and smaller bias between the 2 methods compared with those with normal or high CI. The presence of baseline hypoxemia, valvular heart disease, or acute coronary syndrome had no significant effect on the correlation or the bias between the 2 methods. CONCLUSIONS: In cardiac patients, CVS can be used as a surrogate to true MVS in the calculation of CI. This method is readily available in patients who have central venous access, and may aid in early goal-directed treatment when cardiogenic shock is suspected. PMID- 25038265 TI - Oxidative stress response induced by atrazine in Palaemonetes argentinus: the protective effect of vitamin E. AB - The widespread contamination and persistence of the herbicide atrazine residues in the environment resulted in the exposure of non-target organisms. The present study was undertaken to investigate the effect of atrazine in the response of oxidative stress biomarkers in the freshwater shrimp Palaemonetes argentinus and the protective effect of vitamin-E against atrazine-induced toxicity. Therefore, two batches of P. argentinus were fed for 21 days with a commercial food enriched in proteins (D1) or with D2, composed of D1 enriched with vitamin-E (6.8 and 16.0mg% of vitamin-E, respectively). Subsequently, half of the individuals of each group were exposed to atrazine (0.4mgL(-1)) for 24h and the others remained as controls. Atrazine promoted oxidative stress response in P. argentinus fed with D1 as indicated by enhanced H2O2 content and induction of superoxide dismutase, glutathione-S-transferases and glutathione reductase. This antioxidant activity would prevent the increment of thiobarbituric acid reactive substances in the shrimp tissues. P. argentinus fed with D2 reversed the response of the biomarkers measured. However, the activation of antioxidants response had an energetic cost, which was revealed by a decrease in lipids storage in shrimps. These results show the modulatory effect of vit-E on oxidative stress and its potential use as an effective antioxidant to be applied in chemoprotection strategies during aquaculture. PMID- 25038266 TI - Effect of soil organic matter content and pH on the toxicity of ZnO nanoparticles to Folsomia candida. AB - Organic matter (OM) and pH may influence nanoparticle fate and effects in soil. This study investigated the influence of soil organic matter content and pH on the toxicity of ZnO-NP and ZnCl2 to Folsomia candida in four natural soils, having between 2.37% and 14.7% OM and [Formula: see text] levels between 5.0 and 6.8. Porewater Zn concentrations were much lower in ZnO-NP than in ZnCl2 spiked soils, resulting in higher Freundlich sorption constants for ZnO-NP. For ZnCl2 the porewater Zn concentrations were significantly higher in less organic soils, while for ZnO-NP the highest soluble Zn level (23mgZn/l) was measured in the most organic soil, which had the lowest pH. Free Zn(2+) ion concentrations were higher for ZnCl2 than for ZnO-NP and were greatly dependent on pH (pHpw) and dissolved organic carbon content of the pore water. The 28-d EC50 values for the effect of ZnCl2 on the reproduction of F. candida increased with increasing OM content from 356 to 1592mgZn/kg d.w. For ZnO-NP no correlation between EC50 values and OM content was found and EC50 values ranged from 1695 in the most organic soil to 4446mgZn/kg d.w. in the higher pH soil. When based on porewater and free Zn(2+) concentrations, EC50 values were higher for ZnCl2 than for ZnO-NP, and consistently decreased with increasing pHpw. This study shows that ZnO-NP toxicity is dependent on soil properties, but is mainly driven by soil pH. PMID- 25038267 TI - Bioaccumulation, distribution and metabolism of BDE-153 in the freshwater fish Carassius auratus after dietary exposure. AB - Polybrominated diphenyl ethers (PBDEs) are of great environmental concern due to bioaccumulation and biomagnification in different food chains. However, significant biotransformation of some congeners via reductive debromination has been observed during in vivo and in vitro laboratory exposures. Little is known about the fate of 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153) in fish. In the present study, crucian carp (Carassius auratus) were exposed to BDE-153 at a concentration of 10MUg/g in food for 28 days. BDE-153 and its metabolites in different tissues were identified and quantified using gas chromatography coupled with tandem mass spectrometry and ultra-high performance liquid chromatography coupled with tandem mass spectrometry. In addition to eight debrominated metabolites, four oxidative metabolites were detected 4'-hydroxy-2,2',4,5'-tetra BDE, 6-hydroxy-2,2',4,4'-tetra-BDE, 2,4-dibromophenol and 2,4,6-tribromophenol. With regard to the concentrations of BDE-153 and the major metabolites, the contribution order of different tissues was bile>brain>liver>gill>muscle. The highest concentrations of BDE-153 and metabolite 2,2',4,4'-tetrabromodiphenyl ether were detected in bile at 808ng/g and 157ng/g, respectively. Our results suggested that three possible metabolic pathways of BDE-153 occurred in crucian carp via dietary exposure: debromination, hydroxylation and cleavage of the diphenyl ether bond. These findings indicated evidence of the bioavailability of BDE-153 from food in the form of debrominated metabolites and oxidative metabolites in freshwater fish, which is critical to understanding the complete risks associated with PBDE bioaccumulation and metabolism in humans and wildlife. PMID- 25038268 TI - Assessment of cadmium bioaccumulation and distribution in the kernels of peanut widely cultivated in China. AB - To determine the low Cd accumulation genotypes of peanut and the key factor contributing to high Cd accumulation in peanut kernels, cadmium (Cd) bioaccumulation and distribution in the kernels of nineteen genotypes of peanut widely cultivated in China were estimated in field experiment during duration of 130 days. Results showed that only four genotypes (Yuhua9626, Jihua9606, Luhua11 and Quanhua646) were identified as low-Cd accumulation group according to hierarchical cluster analysis. Cd accumulated in the nutritional tissues of the kernels followed in the order: extracted protein>residues>peanut oil. The protein plays a key role in the abnormal accumulation of Cd in the kernels of peanut. Thus, the control of human ingestion risk can be done by the extraction of peanut oil during deep processing of peanut. Meanwhile, the protein and residues of peanut should be paid more public attention when they enter into the food chain. PMID- 25038269 TI - Optimizing adsorption of Pb(II) by modified litchi pericarp using the response surface methodology. AB - Litchi pericarp was chemically modified as a novel bioadsorbent (MLP) for Pb(II) adsorption in this study. Operating parameters such as contact time, adsorbent dosage, and initial pH of solution were investigated using batch assays and further optimized using response surface methodology (RSM). The results showed that the MLP exhibited a high adsorption efficiency of 99.97% for Pb(II), which was optimal at a contact time of 71.56min, a initial pH of 6.81, and an adsorbent dose of 3.80g/L. Adsorption processes of Pb(II) by MLP could be well described with Langmuir or Freundlich isotherms and a pseudo-second-order kinetic model. The maximum adsorption capacity of Pb(II) by MLP was determined as 163.93mg/g, suggesting a highly promising potential for MLP to be used as a new bioadsorbent. Additionally, the thermodynamic study indicated that the adsorption process of Pb(II) by MLP was spontaneously and exothermic. PMID- 25038270 TI - Mercury in Pleurozium schreberi and Polytrichum commune from areas with various levels of Hg pollution--an accumulation and desorption experiment with microscopic observations. AB - Because of its high mobility in ecosystems, mercury is one of the main toxic threats to the environment, and its concentration must be carefully controlled. To fulfill this need, we selected terrestrial mosses with different characteristic life forms: orthotropic and endohydric Polytrichum commune and plagiotropic and ectohydric Pleurozium schreberi. The concentrations of mercury were determined in both species growing together at sites situated approximately 0.75, 1.5, 3 and 6km to the north, south, east and west, respectively of five known mercury polluters. The mercury concentrations reflected the emissions produced by the surrounding industry, reaching values of 0.44mgkg(-1) in P. schreberi and 0.79mgkg(-1) in P. commune in the vicinity of the chlor-alkali industry. To determine how long a load of Hg would remain in the mosses after mercury emitters restricted releases of Hg to the atmosphere, accumulation and desorption experiments were performed. We compared the two moss species collected from clean and moderately and heavily mercury-polluted sites. After eight days of exposure to mercury, P. schreberi accumulated up to 25mgkg(-1) of Hg, and P. commune accumulated up to 31mgkg(-1). Both in the field and in the experiment, P. commune accumulated significantly higher concentrations of Hg than did P. schreberi, most likely because of its surface morphology, which is likely to enhance the capture of metal from the atmosphere. After sixteen days of exposure, mercury changed the structure of the plasma membrane and affected organelles such as the nuclei and chloroplasts, leading to cell disintegration and death. The negative effects of mercury on the functioning of living cells appeared first in the older leaves of P. schreberi. After 64 days growing in the absence of Hg, P. schreberi clearly retained only 10-14% of the initially accumulated Hg, while P. commune retained 10-21%. PMID- 25038271 TI - Non-carcinogenic and carcinogenic health risk assessment of selected metals in soil around a natural water reservoir, Pakistan. AB - Contaminants in surface soil can directly pose significant human health risks through oral ingestion, dermal contact and particle inhalation, especially for children. Both non-cancer and cancer risks associated with selected metal levels (Cd, Cr, Cu, Fe, Mn, Pb and Zn) were evaluated in surface soil around Mangla Lake during summer and winter. The results based on average pseudo-total metal concentrations followed the decreasing order: Fe (4038mg/kg)>Mn (394mg/kg)>Zn (40mg/kg)>Pb (17mg/kg)>Cr (21mg/kg)>Cu (15mg/kg)>Cd (1.3mg/kg) during summer and Fe (3673mg/kg)>Mn (407mg/kg)>Zn (30mg/kg)>Cr (26mg/kg)>Pb (26mg/kg)>Cu (14mg/kg)>Cd (1.8mg/kg) during winter. Present metal levels in the soil were also compared with other studies and guideline values which showed significant increase in the metal concentrations in this study. The metal levels also showed considerable spatial variations around the lake. The correlation study and multivariate principal component analysis revealed significant anthropogenic contributions of the metals in soils. Aqua-regia extractable (pseudo-total) contents were used as the reference to establish the percentage of bioavailability. After considering the bioavailability (Cd>Pb>Cr>Zn>Cu>Fe>Mn during both seasons), the non-cancer and cancer risks posed by Cd, Pb and Cr was relatively higher than rest of the metals, though the overall hazard index (HI) and cancer risk levels were within the safe limits (1.0 and 1.0E-06, respectively). The overall cancer risk to the adults based on pseudo-total metal concentrations exceeded the target value (1.0E-06), mainly contributed by Cr. A method considering bioavailability is suggested to produce a more realistic estimation for human health risks of trace metals contamination in soil. PMID- 25038272 TI - Translocation of the proto-oncogene Bcl-6 in human glioblastoma multiforme. AB - Bcl-6 translocation is a genetic alteration that is commonly detected in Primary Central Nervous System Lymphoma. The role of this protein in cerebral tumors is unclear. In this study we investigated Bcl-6 translocation and its transcriptional and translational levels in formalin-fixed, paraffin-embedded cerebral tissue sections from glioblastoma (GBM), low-grade glioma (Astrocytoma grade II and III), and meningioma patients, and correlated them with apoptotic processes and p53 and caspase-3 expression. The results showed a frequency of 36.6% of Bcl-6 translocation in GBM patients and a decreased expression in low grade glioma patients, correlated with the severity of the disease. Bcl-6 translocation induced an overexpression of both Bcl-6 protein and messenger in GBM, inhibiting apoptotic processes and caspases 3 expression. On the contrary, in low-grade gliomas and meningiomas Bcl-6 expression was reduced, resulting in an increase of apoptotic processes. Finally, p53 expression levels in brain tumors were comparable to Bcl-6 levels. Overall, these data demonstrate, for the first time, that the Bcl-6 gene translocates in GBM patients and that its translocation and expression are correlated with apoptosis inhibition, indicating a key role for this gene in the control of cellular proliferation. This study offers further insights into glioblastoma biology, and supports Bcl-6 as a new diagnostic marker to evaluate the disease severity. PMID- 25038273 TI - A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients. AB - A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VOCs and of in vitro blood-tissue partition coefficients for volatile organic compounds and other compounds. Linear free energy relationships for tissues such as brain, muscle, liver, lung, kidney, heart, skin and fat are available and once the Abraham descriptors are known for a compound, no more than simple arithmetic is required to estimate air-tissue and blood-tissue partitions. PMID- 25038274 TI - Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. AB - Prostaglandin E2 (PGE2) is one of the most typical lipid mediators produced from arachidonic acid (AA) by cyclooxygenase (COX) as the rate-limiting enzyme, and acts on four kinds of receptor subtypes (EP1-EP4) to elicit its diverse actions including pyrexia, pain sensation, and inflammation. Recently, the molecular mechanisms underlying the PGE2 actions mediated by each EP subtype have been elucidated by studies using mice deficient in each EP subtype as well as several compounds highly selective to each EP subtype, and their findings now enable us to discuss how PGE2 initiates and exacerbates inflammation at the molecular level. Here, we review the recent advances in PGE2 receptor research by focusing on the activation of mast cells via the EP3 receptor and the control of helper T cells via the EP2/4 receptor, which are the molecular mechanisms involved in PGE2 induced inflammation that had been unknown for many years. We also discuss the roles of PGE2 in acute inflammation and inflammatory disorders, and the usefulness of anti-inflammatory therapies that target EP receptors. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". PMID- 25038275 TI - Identification of 23 novel conserved microRNAs in three rice cultivars. AB - Plant microRNAs (miRNAs) play important roles as modulators of gene expression at the post-transcriptional level. Previous studies have shown that high-throughput sequencing is a powerful tool for the identification of miRNAs, and it is believed that many more miRNAs remain to be discovered. Here, we found 23 novel conserved miRNAs from three rice cultivars by high-throughput sequencing and further identified these through subsequent cloning and quantitative real-time polymerase chain reaction (qPCR). Eight of these novel miRNAs were detected with significant signals in the three rice cultivars by northern blotting assays. The quantitative analysis of their expression profiles showed that most of these miRNAs were perfectly or imperfectly negatively correlated with their target genes, which suggests that these miRNAs may play important roles during rice development. This is the first genome-wide investigation of miRNAs from different rice cultivars, and the data obtained expand the known rice miRNA inventory and provide further information about the regulatory roles played by miRNAs in rice development. PMID- 25038276 TI - Cloning and functional expression of a cDNA encoding stearoyl-ACP Delta9 desaturase from the endosperm of coconut (Cocos nucifera L.). AB - Coconut (Cocos nucifera L.) is an economically tropical fruit tree with special fatty acid compositions. The stearoyl-acyl carrier protein (ACP) desaturase (SAD) plays a key role in the properties of the majority of cellular glycerolipids. In this paper, a full-length cDNA of a stearoyl-acyl carrier protein desaturase, designated CocoFAD, was isolated from cDNA library prepared from the endosperm of coconut (C. nucifera L.). An 1176 bp cDNA from overlapped PCR products containing ORF encoding a 391-amino acid (aa) protein was obtained. The coded protein was virtually identical and shared the homology to other Delta9-desaturase plant sequences (greater than 80% as similarity to that of Elaeis guineensis Jacq). The real-time fluorescent quantitative PCR result indicated that the yield of CocoFAD was the highest in the endosperm of 8-month-old coconut and leaf, and the yield was reduced to 50% of the highest level in the endosperm of 15-month-old coconut. The coding region showed heterologous expression in strain INVSc1 of yeast (Saccharomyces cerevisiae). GC-MS analysis showed that the levels of palmitoleic acid (16:1) and oleic acid (18:1) were improved significantly; meanwhile stearic acid (18:0) was reduced. These results indicated that the plastidial Delta9 desaturase from the endosperm of coconut was involved in the biosynthesis of hexadecenoic acid and octadecenoic acid, which was similar with other plants. These results may be valuable for understanding the mechanism of fatty acid metabolism and the genetic improvement of CocoFAD gene in palm plants in the future. PMID- 25038277 TI - Effects of anti-inflammatory drugs in primary kidney cell culture of a freshwater fish. AB - The non-steroidal anti-inflammatory drugs are emerging contaminants in aquatic ecosystems. This study aimed to evaluate toxic effects of some representative drugs of this pharmaceutical group on primary culture of monocytic lineage of Hoplias malabaricus anterior kidney. The effects of diclofenac, acetaminophen and ibuprofen in cell viability, lipopolysaccharide (LPS)-induced NO production and genotoxicity were evaluated. Cytometry analysis CD11b(+) cells showed 71.5% of stem cells, 19.5% of macrophages and 9% of monocytes. Cell viability was lower in the ficoll compared to percoll separation. LPS-induced NO production by these cells was blocked after treatment with dexamethasone and NG-Methyl-L-Arginine (L NMMA). Exposure of the cells to diclofenac (0.2-200 ng/mL), acetaminophen (0.025 250 ng/mL) ibuprofen (10-1000 ng/mL) reduced basal NO production and inhibited LPS-induced NO production at all concentrations after 24 h of exposure. Genotoxicity occurred at the highest concentration of diclofenac and at the intermediary concentration of acetaminophen. Genotoxicity was also observed by ibuprofen. In summary, the pharmaceuticals influenced NO production and caused DNA damage in monocytic cells suggesting that these drugs can induce immunosuppression and genotoxicity in fish. PMID- 25038278 TI - Molecular cloning, sequencing and tissue-level expression of complement C3 of Labeo rohita (Hamilton, 1822). AB - Complement component C3 plays a central role in all known complement activation pathways. In the present study, we cloned, sequenced and analyzed the full-length cDNA sequence of Labeo rohita complement C3 (LRC3). The expression pattern of complement C3 mRNA in different tissues of healthy rohu and after challenge with Aeromonas hydrophila were evaluated using real-time PCR. The LRC3 cDNA sequence of rohu comprised of 5081 bp encoding a predicted protein of 1645 amino acids. The deduced amino acid sequence had the characteristic domain architecture. About eight domains specific to complement C3 are present in the sequence starting from signal peptide to netrin C345C (NTR) domain. The post-translational processing signal sequence (RKRR), the C3-convertase cleavage site sequence (LAR) and the canonical thiol-ester motif (GCGEQ) were found to be conserved in the LRC3. Real time PCR analysis revealed the highest expression of C3 in liver and extra hepatic expression of C3 was also observed in all the tissues studied. A. hydrophila challenge resulted in significant up-regulated expression of C3 transcripts in both liver and kidney at 6, 12, 24, 48 and 72 h post-infection. PMID- 25038279 TI - Identification and functional characterization of SIMPL in Crassostrea gigas reveals its ancient origin and involvement in the regulation of Rel/NF-kappaB transcription activity. AB - SIMPL (Signaling Molecule that associates with the mouse Pelle-Like Kinase) has been recently identified as a co-regulator of NF-kappaB dependent transcription. Here, we report the discovery and functional analysis of the SIMPL in a mollusk, Crassostrea gigas, which terms as CgSIMPL. CgSIMPL is comprised of 252 amino acids and shares significant homology with vertebrate homologs. Over-expression of CgSIMPL does not activate the NF-kappaB reporter in the HEK293 cell line, but can enhance Rel-dependent NF-kappaB transactivation. The dominant-negative effect of CgSIMPL was observed after the deletion of NLS, strongly suggesting that NLS is required for the enhancement of Rel-dependent NF-kappaB transactivation. Furthermore, CgSIMPL mRNA is constitutively expressed in various tissues and is inducible at late stages of infection, supporting its regulatory function in innate immunity. Altogether, our studies reveal that SIMPL is reserved and co evolved with NF-kappaB in chordate and mollusk, supporting its ancient origin and involvement in regulation of NF-kappaB signaling pathway. PMID- 25038280 TI - Effects of chito-oligosaccharides supplementation on growth performance, intestinal cytokine expression, autochthonous gut bacteria and disease resistance in hybrid tilapia Oreochromis niloticus ? * Oreochromis aureus ?. AB - We investigated the effects of incorporating chitinase (ChiB565)-hydrolyzed shrimp shell chitin into the diet of hybrid tilapia (Oreochromis niloticus ? * Oreochromis aureus ?) with regard to production, intestinal immune status and autochthonous gut bacteria, and protection against bacterial pathogen Aeromonas hydrophila. Five experimental diets were formulated by supplementing the basal diet with the hydrolyzed shrimp shell chitin (0.0%, T1 control; 0.8%, T3; 1.6%, T4; or 2.4%, T5) or 0.1% commercial chitosan-oligosaccharides as commercial recommendation dose (T2, positive control). After a 35-day feeding trial, we found no significant difference in weight gain, feed conversion ratio or survival rate in tilapia among all treatment groups. However, the levels of mRNAs encoding the pro-inflammatory protein tumor necrosis factor-alpha and the stress-response protein heat shock protein 70 were much lower in groups T2, T3, T4 and T5 (p < 0.001). The levels of transforming growth factor-beta were higher in groups T2 and T4 (p < 0.001 and p < 0.0001, respectively). In addition, group T3 and T4 with 0.8% and 1.6% hydrolyzed shrimp shell chitin supplementation respectively changed marginally their autochthonous gut bacteria (0.60 < Cs < 0.80). When challenged with A. hydrophila, the mortality of groups fed chito-oligosaccharides was lower than the control, especially in groups T4 and T5 (p < 0.05). These results indicate that dietary intake of chito-oligosaccharides can improve intestinal health, changed autochthonous gut bacteria, and improve resistance to infection by A. hydrophila, even with higher efficiency than receiving the manufacturer recommended dose of the commercial chitosan-oligosaccharides. PMID- 25038281 TI - Molecular cloning and characterization of cathepsin L from freshwater mussel, Cristaria plicata. AB - Cathepsin L is one of the crucial enzyme superfamilies and involved in the immune responses. The Cathepsin L cDNA and genome of Cristaria plicata(CpCL) was cloned from the hemocytes using degenerate primers by the rapid amplification of cDNA ends (RACE) PCR. The genomic DNA was 9353 bp long and had a total of six introns and seven exons. The full-length cDNA of CpCL was 1144 bp, the cDNA contained a 5' untranslated region (UTR) of 34 nucleotides, the 3' UTR of 108 bp with a canonical polyadenylation signal sequence AATAAA and a polyA tail, and an open reading frame (ORF) of 1002 bp, encoding 333 amino acid residues with 37.65 kDa predicted molecular weight. The theoretical isoelectric point was 8.61. The prepro-cathepsin L was consisted of a typical signal peptide (Met1-Gly20), a pro region peptide (Leu21-Glu116) and a mature peptide (Tyr117-Val333). Many members of the papain family possessed of a proline residue at position 2 in the mature enzymem, this was also observed in CpCL. The preproprotein included an oxyanion hole (Gln 135), the active center formed by Cys141, His280 and Asn 300, the potential N-glycosylation site (Asn38, Asn 113 and Asn 272) and the conserved GCXGG motifs, which was characteristic of cathepsin, the conserved ERWNIN and GNFD motifs, which were characteristic for cathepsin L. Homology analysis revealed that the CpCL shared 49-87% identity to other known cathepsin L sequences. The phylogenetic tree showed that the CpCL clustered with the invertebrate cathepsin L cysteine proteases, and was closely related to the cathepsin L of Hyriopsis cumingii. The expression of CpCL mRNA was detected in hepatopancreas, hemocytes, mantle, gills and adductor muscle, and the higher expression level was in hepatopancreas. After A. hydrophila stimulation, the expression of the CpCL mRNA was up-regulated in hemocytes and hepatopancreas, and the expression level was significantly lower in gill than one after PBS challenge group. PMID- 25038282 TI - Identification and characterization of a Macrobrachium nipponense ferritin subunit regulated by iron ion and pathogen challenge. AB - Ferritin, a major iron storage protein in most living organisms, plays a crucial role in iron metabolism. In this study, the ferritin subunit MnFer was identified in the oriental river prawn (Macrobrachium nipponense) and functionally characterized. The full-length cDNA of MnFer is 999 bp in size with a 122-bp 5' untranslated region (UTR), a 364-bp 3'-UTR and a 513-bp open reading frame that encodes a protein possessing 171 amino acids and a deduced molecular weight of 19.40 kDa. Prawn ferritin transcripts are expressed in muscle, heart, hepatopancreas, gill, hemocytes, ovary and testis. Quantitative real-time PCR revealed that the abundance of ferritin transcript was highest in the hepatopancreas followed by muscle. Ferritin transcript expression in muscle increased six-fold 3 h after the injection of iron. In the gill, a four-fold increase in ferritin transcript expression was detected 3 h post-injection; the expression remained elevated for 48 h. Heart ferritin mRNA expression increased up to seven-fold at 24 h post-injection. No significant difference was found in the hepatopancreas. The iron binding capacity of recombinant ferritin protein was also demonstrated in this study. In hemocyte experiments, the transcriptional expression of MnFer showed the strongest response to Aeromonas hydrophila. As a whole, our study suggested that the ferritin from M. nipponense may play critical roles in cellular and organismic iron homeostasis along with in innate immune defense. PMID- 25038283 TI - A modified method to detect the phagocytic ability of eosinophilic and basophilic haemocytes in the oyster Crassostrea plicatula. AB - The immune defence system of bivalve species largely depends on haemocytes. Haemocytes are generally classified as hyalinocytes (H) or granulocytes (G), and each cell type is further sub-classified as eosinophilic (E) or basophilic (B) haemocytes. Until recently, research on eosinophilic and basophilic haemocytes has primarily focused on their morphologies, dye affinities and intracellular components. Few studies have investigated their phagocytic ability because of the absence of appropriate experimental methods. In this study, we introduce a modified method suitable to detect the phagocytic ability of eosinophilic and basophilic haemocytes. This modified method involves neutral red staining by employing fluorescent microspheres as the phagocytosed medium. Specifically, haemocytes are incubated with fluorescent microspheres and then stained with neutral red. Next, the stained haemocytes are fixed by acetone and are counterstained by propidium iodide. Finally, the haemocytes are observed under a multifunctional microscope to analyse the phagocytic ability by counting the number of eosinophilic or basophilic haemocytes involved in phagocytosis (calculation for phagocytic rate, PR) and the number of phagocytosed microspheres by each eosinophilic or basophilic haemocyte (calculation for phagocytic index, PI). By employing this modified method in the oyster Crassostrea plicatula, we found that the PRs of G and H were very similar to the data obtained by another method, flow cytometry, indicating that this modified method has high accuracy. Additionally, we also found that the PR and PI in E-G were 70.9 +/- 7.3% and 1.0 +/- 0.2, respectively, which were both significantly higher than those in B-G (53.1 +/- 6.4% and 0.7 +/- 0.1). The PR and PI in E-H were 16.3 +/- 2.8% and 0.2 +/- 0.1, respectively, while in B-H, the PR and PI were 13.3 +/- 3.6% and 0.2 +/- 0.1, respectively, with no significant difference observed. Based on this result, eosinophilic granulocytes are more active in phagocytosis than basophilic granulocytes in the oyster immune defence system. PMID- 25038284 TI - Up-regulation of nuclear factor E2-related factor 2 upon SVCV infection. AB - Nuclear factor E2 - related factor 2 (Nrf2) is a crucial transcription factor that regulates the basal and inducible expression of many antioxidant response element (ARE)-dependent genes, including heme oxygenase-1 (HO-1) and superoxide dismutase 1 (SOD1). The Nrf2/ARE pathway has been regarded as a critical switch in the initiation of cellular defence systems for surviving oxidative insults and viral infection. In this study, the Nrf2 gene of EPC cells, which is originally derived from Pimephales promelas, was cloned, and an investigation on the interactions between Nrf2 and spring viraemia of carp virus (SVCV) was performed. These results demonstrated that the virus facilitated the nuclear accumulation of Nrf2 and up-regulated its transcriptional and protein profiles in EPC cells. In addition, exogenous activation of Nrf2 conferred EPC cells with a higher cellular total antioxidant capacity via an increase in the expression of HO-1 and SOD1, but did not suppress the replication of SVCV. PMID- 25038285 TI - Cloning, characterisation, and expression analysis of the cathepsin D gene from rock bream (Oplegnathus fasciatus). AB - Cathepsins are lysosomal cysteine proteases belonging to the papain family, members of which play important roles in normal metabolism for the maintenance of cellular homeostasis. Rock bream (Oplegnathus fasciatus) cathepsin D (RbCTSD) cDNAs were identified by expressed sequence tag analysis of a lipopolysaccharide stimulated rock bream liver cDNA library. The full-length RbCTSD cDNA (1644 bp) contained an open reading frame of 1191 bp encoding 396 amino acids. Alignment analysis revealed that the active sites and N-glycosylation sites of the deduced protein were well conserved. Phylogenetic analysis revealed that RbCTSD is most closely related to the Mi-iuy croaker (Miichthys miiuy) cathepsin D. RbCTSD was ubiquitously expressed in all the examined tissues, predominantly in muscle and kidneys. RbCTSD mRNA expression was also examined in several tissues under conditions of bacterial and viral challenge. All examined tissues of fish infected with Edwardsiella tarda (E. tarda), Streptococcus iniae (S. iniae), and red sea bream iridovirus (RSIV) showed significant increases in RbCTSD expression compared with the control. In the kidney and spleen, RbCTSD mRNA expression was markedly upregulated following infection with all tested pathogens. These findings indicate that RbCTSD plays an important role in the innate immune response of rock bream. Furthermore, these results provide important information for the identification of other cathepsin D genes in various fish species. PMID- 25038286 TI - Protective immunity against infectious spleen and kidney necrosis virus induced by immunization with DNA plasmid containing mcp gene in Chinese perch Siniperca chuatsi. AB - Infectious spleen and kidney necrosis virus (ISKNV) is the causative agent of a disease leading to high mortality and economic losses in Chinese perch, Siniperca chuatsi. There is an urgent need to develop an effective vaccine against this fatal disease. In this study, the mcp gene encoding the major capsid protein, the predominant structural component of the iridovirus particles, was cloned into a eukaryotic expression vector pcDNA3.1+, and the recombinant plasmid, designated as pcMCP, was constructed. Expression of the mcp gene was confirmed in transfected cells and muscle tissues of vaccinated fish by RT-PCR, immunodot blot and western blot. Immune response was induced by intramuscular injection of Chinese perch with pcMCP added QCDC adjuvant. The expression levels of type I IFN system genes including IRF-7, IRAK1, Mx and Viperin were up-regulated at 6 h, and reached a peak at 48 h. In addition, there was a second peak of the expression levels of IRF-7 and Mx gene on the 21st day post-vaccination. Before the 21st day post-vaccination, the levels of IgM did not show a significant difference among all groups, but there was a remarkable increase on the 28th day post-vaccination. The relative percent survival (RPS) of Chinese perch vaccinated with pcMCP added QCDC adjuvant was 80% in a challenge trial on the 28th day post-vaccination. Moreover, real-time PCR demonstrated that the levels of viral load in the dead fish of the vaccinated group were significantly higher than those in mock vaccinated fish. Together, these results indicate that pcMCP is a potential candidate DNA vaccine against ISKNV disease. PMID- 25038287 TI - The association of serous tubal intraepithelial carcinoma with gynecologic pathologies and its role in pelvic serous cancer. AB - OBJECTIVES: Possible primary sites of pelvic serous cancers are, fallopian tubes, ovaries or peritoneum. Recent studies have revealed that a portion of these tumors originates from serous tubal intraepithelial carcinoma (STIC) at the distal end of fallopian tubes. In this study, the association of STIC with pelvic serous carcinomas and the pathologic parameters that indicate the tubes as the primary site were assessed. METHODS: In total, 495 pairs of fallopian tubes obtained via total abdominal hysterectomy and bilateral salpingo-oophorectomy between 2011 and 2013 were examined according to SEE-FIM protocol. Hematoxylin and eosin-stained slides were examined by pathologists. Suspicious areas were immunostained with p53 and Ki-67 to diagnose STIC precisely. RESULTS: Of the 495 cases, 110 cases were malignant. Among 34 cases of non-uterine serous carcinomas, 13 were diagnosed with STIC. STIC was located at the fimbrial end of the fallopian tubes in 12 cases. No STIC was identified in the gynecologic malignancies other than non-uterine serous pelvic carcinomas and benign gynecologic pathologies. Comparison of the ovarian and tubal cancer cases with and without STIC did not reveal a factor that helps to define the primary site. STIC was an important factor associated in a higher portion of the cases with bilateral ovarian cancer. CONCLUSION: The role of STIC in carcinogenesis continues to be discussed as it is unknown whether STIC is the precursor lesion or just associates with the malignancies. Discovering the accurate precursor lesions and tumor carcinogenesis is essential to prevent these malignancies and to develop early diagnostic methods. PMID- 25038288 TI - Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor. AB - OBJECTIVE: Constitutive activation of STAT3 is a hallmark of various human cancers, however an increased pSTAT3 expression in high grade human endometrial cancer has not been reported. In the present study, we examine the expression of STAT family of proteins in endometrial cancer cell lines and the efficacy of HO 3867, a novel STAT3 inhibitor designed in our lab. METHODS: Expression of STAT family proteins was evaluated via Western blot. The cell viability, post treatment with HO-3867, was assessed using MTT, cell-cycle profile and Annexin assay. In vivo efficacy of HO-3867 was evaluated using xenograft mice. RESULTS: Expression of activated STATs was inconsistent among the cell lines and 18 human endometrial cancer specimens tested. While pSTAT3 Tyr705 was not expressed in any of the cell lines, pSTAT3 Ser727 was highly expressed in endometrial cancer cell lines and tumor specimens. HO-3867 decreased the expression of pSTAT3 Ser727 while total STAT3 remained constant; cell viability decreased by 50-80% and induced G2/M arrest in 55% of Ishikawa cells at the G2/M cell cycle checkpoint. There was an increase in p53, a decrease in Bcl2 and Bcl-xL, and cleavage of caspase-3, caspase-7 and PARP. HO-3867 mediated a dosage-dependent inhibition of the growth of xenografted endometrial tumors. CONCLUSIONS: HO-3867 treatment decreases the high levels of pSTAT3 Ser727 in endometrial cancer cells by inducing cell cycle arrest and apoptosis. This suggests a specific role of serine phosphorylated STAT3, independent of tyrosine phosphorylation in the oncogenesis of endometrial cancer. HO-3867 could potentially serve as an adjunctive targeted therapy. PMID- 25038290 TI - Chemical olfactory signals and parenthood in mammals. AB - This article is part of a Special Issue "Chemosignals and Reproduction". In mammalian species, odor cues emitted by the newborn are essential to establish maternal behavior at parturition and coordinate early mother-infant interactions. Offspring odors become potent attractive stimuli at parturition promoting the contact with the young to ensure that normal maternal care develops. In some species odors provide a basis for individual recognition of the offspring and highly specialized neural mechanisms for learning the infant signals have evolved. Both the main and the accessory olfactory systems are involved in the onset of maternal care, but only the former contributes to individual odor discrimination of the young. Electrophysiological and neurochemical changes occur in the main olfactory bulb leading to a coding of the olfactory signature of the familiar young. Olfactory neurogenesis could also contribute to motherhood and associated learning. Parturition and interactions with the young influence neurogenesis and some evidence indicates a functional link between olfactory neurogenesis and maternal behavior. Although a simple compound has been found which regulates anogenital licking in the rat, studies identifying the chemical nature of these odors are lacking. Neonatal body odors seem to be particularly salient to human mothers who are able to identify their infant's odors. Recent studies have revealed some neural processing of these cues confirming the importance of mother-young chemical communication in our own species. PMID- 25038289 TI - Otoacoustic emissions, auditory evoked potentials and self-reported gender in people affected by disorders of sex development (DSD). AB - Both otoacoustic emissions (OAEs) and auditory evoked potentials (AEPs) are sexually dimorphic, and both are believed to be influenced by prenatal androgen exposure. OAEs and AEPs were collected from people affected by 1 of 3 categories of disorders of sex development (DSD) - (1) women with complete androgen insensitivity syndrome (CAIS); (2) women with congenital adrenal hyperplasia (CAH); and (3) individuals with 46,XY DSD including prenatal androgen exposure who developed a male gender despite initial rearing as females (men with DSD). Gender identity (GI) and role (GR) were measured both retrospectively and at the time of study participation, using standardized questionnaires. The main objective of this study was to determine if patterns of OAEs and AEPs correlate with gender in people affected by DSD and in controls. A second objective was to assess if OAE and AEP patterns differed according to degrees of prenatal androgen exposure across groups. Control males, men with DSD, and women with CAH produced fewer spontaneous OAEs (SOAEs) - the male-typical pattern - than control females and women with CAIS. Additionally, the number of SOAEs produced correlated with gender development across all groups tested. Although some sex differences in AEPs were observed between control males and females, AEP measures did not correlate with gender development, nor did they vary according to degrees of prenatal androgen exposure, among people with DSD. Thus, OAEs, but not AEPs, may prove useful as bioassays for assessing early brain exposure to androgens and predicting gender development in people with DSD. PMID- 25038291 TI - Tolerating DNA damage during eukaryotic chromosome replication. AB - In eukaryotes, the evolutionarily conserved RAD6/RAD18 pathway of DNA damage tolerance overcomes unrepaired DNA lesions that interfere with the progression of replication forks, helping to ensure the completion of chromosome replication and the maintenance of genome stability in every cell cycle. This pathway uses two different strategies for damage bypass: translesion DNA synthesis, which is carried out by specialized polymerases that can replicate across the lesions, and DNA damage avoidance, a process that relies on a switch to an undamaged-DNA template for synthesis past the lesion. In this review, we summarise the current knowledge on DNA damage tolerance mechanisms mediated by RAD6/RAD18 that are used by eukaryotic cells to cope with DNA lesions during chromosome replication. PMID- 25038293 TI - Evaluation of an online psychoeducation intervention to promote mental health help seeking attitudes and intentions among young adults: randomised controlled trial. AB - BACKGROUND: Research has consistently identified a disparity between the prevalence of mental health concerns among young adults and their rates of formal help seeking. However, a few randomised controlled trials have identified effective interventions for increasing formal help seeking among young adults. The aim of this study was to evaluate the effectiveness of a brief online psychoeducational intervention, targeting depression, anxiety and suicide stigma, for increasing positive attitudes towards help seeking and increasing help seeking intentions among young adults. METHOD: The study followed a single-blind parallel group randomized controlled trial design with 67 young adult (18-25 years) Australian participants, assigned to receive online psychoeducation (n=33) or online attention-matched control information (n=34) over 3 weeks. Participants in the experimental group received information on depression, anxiety, and suicide. The control group received information unrelated to mental health. Primary outcome measures were mental health literacy, mental illness stigma, attitudes toward professional help seeking and intentions to seek help. Secondary outcome variables were symptomology, satisfaction and adherence. RESULTS: Significant between-group differences were found for the pre- to post-test, including increased anxiety literacy (Cohen's d=0.65), decreased depression stigma (d=0.53), and increased help seeking attitudes and intentions for the experimental group (d=0.58 and d=0.53, respectively). LIMITATIONS: Due to the small sample size and homogenous nature of the sample, generalisations should be made with caution. CONCLUSIONS: This study demonstrates the utility and effectiveness of a brief online psychoeducation intervention for promoting help seeking among young adults. PMID- 25038294 TI - Exploring mechanisms of change: the relationships between cognitions, symptoms, and quality of life over the course of group cognitive-behaviour therapy. AB - BACKGROUND: This study aimed to explain how quality of life changes during psychotherapy, using a cognitive-behavioural theoretical framework, and examined whether changes in symptoms or changes in cognitions were more influential with regard to quality of life change. Three different hypotheses were tested that might explain the mechanisms by which quality of life changes during group cognitive-behaviour therapy (CBT) for anxiety and depression. METHODS: 127 outpatients with anxiety and/or depression enrolled in a four-week group CBT programme participated. Measures of anxiety and depression symptoms, cognitive change, and quality of life were administered at baseline and post-treatment. Baseline to post-treatment change scores were calculated and entered into multiple regression analyses. RESULTS: Reductions in anxiety and depression symptoms were related to increases in quality of life, whereas cognitive changes were not consistently related to changes in quality of life. LIMITATIONS: The main limitation was that the study's design was not able to assess whether changes in cognitions or symptoms preceded changes in quality of life, as all variables were measured at the same two points in time. CONCLUSIONS: These results provided evidence that quality of life changes as a result of or, simultaneously with, symptom change. It appears that group CBT does not improve quality of life through strategies designed to change patients' cognitions. PMID- 25038295 TI - Human group A rotavirus infections in children in Denmark: detection of reassortant G9 strains and zoonotic P[14] strains. AB - One of the leading causes of severe childhood gastroenteritis are group A rotaviruses, and they have been found to be associated with ~40% of the annual gastroenteritis-associated hospitalizations in young Danish children <5years of age (Fischer et al., 2011). In this study, we investigated the diversity of rotavirus strains circulating among young children <5years of age, presenting with gastroenteritis disease either at the general practitioner or in the hospital, during the period 2009-2013. A total of 831 rotavirus positive stool samples were genotyped in the study period, and the majority of samples (74%) were from hospitalized children. G and P genotypes were successfully determined for 826 of samples, with G1P[8] being the most commonly detected genotype. Detection of G1 showed a decreasing trend over time, and an inverse trend was seen for the emerging G9P. The common human genotypes (G1/G3/G4/G9P[8] and G2P[4]) were detected in the majority of samples (n=733, 88.2%). Rare genotype combinations such as G6P[14] were detected in <1% of samples. Rare genotype strains and strains which failed to amplify in genotyping RT-PCR were subjected to genetic characterization by sequencing one or all of the following genes; VP7, VP4, VP6 and NSP4. Sequences of sufficient length and quality were available for all 4 genes for 28 strains. Phylogenetic analysis revealed that reassortant G9P[4] strains circulated with 3 different genotype combinations. As rotavirus vaccines are not widely used in Denmark or its neighboring countries, the diversity of rotavirus strains identified in this study most likely reflects naturally occurring selection pressures and viral evolution. PMID- 25038296 TI - Phylogeographic analysis on the travel-related introduction of HIV-1 non-B subtypes to Northern Poland. AB - Phylodynamic, sequence data based reconstructions for the surveillance of the geographic spatial spread are a powerful tool in molecular epidemiology. In this study region of origin for the set of 57 partial pol sequences derived from the patients the history of travel-related HIV transmission was analyzed using phylogeographic approach. Maximum likelihood trees based on the sets of country annotated reference sequences were inferred for identified non-B variants. Region of sequence import was assigned using on the highest approximate likelihood ratios. Import of the A1 clades was traced to the Eastern Europe and associated with immigration from this region. Subtype C infections clustered most frequently with sequences of the South African origin while majority of subtype Ds were similar to the European clades. Subtype G sequences clustered with Portuguese lineage, CRF01_AE with Eastern or South-Eastern Asian. Eastern European, Middle African or Western African lineage was assigned for the CFR02_AG. Rare circulating recombinants originated either from Central Africa (CRF11_cpx - Democratic Republic of Congo, CRF13_cpx - Central African Republic, CRF37_cpx - Cameroon) or South America (CRF28_BF and CRF46_BF - Brazil). Import of the HIV-1 non-B variants, including recombinant forms previously rarely found in Poland and Europe is frequent among travelers. Observed founder events result in the heterosexually-driven introduction of the novel HIV-1 variants into the population. PMID- 25038297 TI - Two novel ail-positive biotype 1A strains of Yersinia enterocolitica isolated in China with unequal adhesion and invasion properties. AB - Yersinia enterocolitica is an enteric pathogen having six biotypes: 1A, 1B, 2, 3, 4, and 5. Different bioserotypes have been associated with varying pathogenicity, and the strains of biotype 1A lack the virulence-associated pYV-bearing genes and were once considered to be avirulent. However, there is growing epidemiological, clinical, and experimental evidence to suggest some biotype 1A isolates are virulent and can cause gastrointestinal disease. Here, we describe two biotype 1A strains discovered from 3807 isolates that carry the ail (attachment and invasion locus) gene. The two strains showed unique PFGE patterns compared to all other isolates in the Chinese Y. enterocolitica isolate PFGE database. Strain SDWL-003 isolated from a sheep shared ail sequence identical to A1 pattern, and the foxA (ferrioxamine receptor) sequence was identical to the pathogenic F5 pattern, besides, the PFGE patterns of SDWL-003 was also cluster to pathogenic branch; however it does not attach to or invade Hep-2 cells. The ail sequence of strain 2006RAT isolated from a Microtus fortis showed several mutations compared to other published genomes, and therefore formed an entirely new pathogenic pattern. Though it clustered to non-pathogenic block with foxA sequence polymorphism analysis or PFGE assay, the strain 2006RAT showed adhesion properties. The data here bring new insights into the molecular genetics of Y. enterocolitica biotype 1A, show some isolates of 1A biotype gaining potential pathogenicity using the function of the virulence gene - ail, and indicate the lateral gene transfer of ail virulence genes proceeded between pathogenic and nonpathogenic Y. enterocolitica. PMID- 25038298 TI - Treatment of dyslipidemia: the problem of reaching the goal. AB - Dyslipidemia is a major contributor to cardiovascular morbidity and mortality. Although awareness of the importance of the risk of dyslipidemia has increased, treatment of dyslipidemia has not improved accordingly. Even though the actual number of individuals receiving treatment has increased, the proportion of those who are treated but did not reach the recommended treatment goal, is still disturbing. This problem is highlighted in this issue of Atherosclerosis by the article of S. Zhao et al. who in a cross-sectional study involving 25,697 Chinese individuals found that overall 38.5% of those receiving lipid-lowering treatment did not achieve the treatment goal for low density lipoprotein. Of particular concern is the authors' finding that the majority of these were individuals with a high cardiovascular risk and/or with type 2 diabetes mellitus. Some of the main reasons for this problem relate to patients' compliance with treatment and inertia on the side of physicians and patients to increase the dose of a given medication or move to a combination treatment. New medications with various and different pharmacological modes of actions and increased possibility for combination treatment may help to improve the treatment for dyslipidemia. PMID- 25038299 TI - Cellular metabolic rates from primary dermal fibroblast cells isolated from birds of different body masses. AB - The rate of metabolism is the speed at which organisms use energy, an integration of energy transformations within the body; it governs biological processes that influence rates of growth and reproduction. Progress at understanding functional linkages between whole organism metabolic rate and underlying mechanisms that influence its magnitude has been slow despite the central role this issue plays in evolutionary and physiological ecology. Previous studies that have attempted to relate how cellular processes translate into whole-organism physiology have done so over a range of body masses of subjects. However, the data still remains controversial when observing metabolic rates at the cellular level. To bridge the gap between these ideas, we examined cellular metabolic rate of primary dermal fibroblasts isolated from 49 species of birds representing a 32,000-fold range in body masses to test the hypothesis that metabolic rate of cultured cells scales with body size. We used a Seahorse XF-96 Extracellular flux analyzer to measure cellular respiration in fibroblasts. Additionally, we measured fibroblast size and mitochondrial content. We found no significant correlation between cellular metabolic rate, cell size, or mitochondrial content and body mass. Additionally, there was a significant relationship between cellular basal metabolic rate and proton leak in these cells. We conclude that metabolic rate of cells isolated in culture does not scale with body mass, but cellular metabolic rate is correlated to growth rate in birds. PMID- 25038300 TI - Cholesterol deregulation induced by chronic corticosterone (CORT) stress in pectoralis major of broiler chickens. AB - Chronic endogenous glucocorticoid (GC) excess in mammals is associated with metabolic dysfunction and dyslipidemia that are characterized by increased plasma triglyceride and total cholesterol (Tch) levels. However, the effects of chronic GC administration on cholesterol metabolism, particularly in muscle tissues of broiler chickens, are unknown. In this study, broiler chickens were treated chronically with vehicle (CON) or corticosterone (CORT) for 2 weeks. Chronic CORT treatment significantly increased Tch levels in pectoralis major muscle (PMC) (p<0.001) as well as in leg muscle (p<0.01), and CORT enhanced triglyceride levels in the PMC (p<0.001). Real-time PCR results showed that HMGCR (p<0.05) mRNA expression was up-regulated by CORT in PMC, and 11beta-HSD1 gene transcription (p=0.08) was not significantly downregulated, whereas glucocorticoid receptor (GR) mRNA expression, 11beta-HSD2, CYP7A1, CYP27A1, ApoB and LDLR were unchanged by CORT (p>0.05). Western blot results showed that the levels of total GR (p=0.08) tended to be increased and nuclear GR protein (p<0.05) was increased in PMC by CORT administration. Parallel to an increase in gene expression, HMGCR protein expression in PMC was significantly increased (p<0.05) by CORT. Moreover, LDLR (p<0.05), ApoA1 (p=0.06) and 11beta-HSD2 (p=0.07) protein expression in PMC tended to be increased by CORT compared to control. These results indicate that chronic CORT administration causes cholesterol accumulation in PMC tissues of broiler chickens by increasing cholesterol synthesis and uptake. PMID- 25038301 TI - Mindful attention regulation and non-judgmental orientation in depression: a multi-method approach. AB - The use of questionnaires to measure two facets of mindfulness, 'regulation of attention' and 'non-judgmental orientation,' has been criticized. Furthermore, the assumption that depressed individuals show deficits in both facets has not yet been proven. In an attempt to minimize several biases associated with mindfulness questionnaires, we asked 43 currently depressed and 36 never depressed participants to observe their breathing. The 'regulation of attention' facet of mindfulness was measured by the number of times participants' focus drifted off of their breathing. The 'non-judgmental orientation' facet was assessed using skin conductance response (SCR) and corrugator activity measured by electromyography (EMG), as indicators associated with arousal and negative emotions following drifting, and also by a self-report questionnaire. Depressed patients showed deficits in both facets of mindfulness. Specifically, compared to never-depressed controls, depressed patients drifted focus from their breathing more often, had significantly higher self-reported self-criticism, and displayed an increase in corrugator activity after drifting from breathing. PMID- 25038302 TI - The effect of baroreceptor stimulation on pain perception depends on the elicitation of the reflex cardiovascular response: evidence of the interplay between the two branches of the baroreceptor system. AB - We examined the impact of baroreceptor stimulation on pain and cardiovascular responses in 39 healthy participants. Carotid baroreceptors were stimulated with external suction (-50 mmHg, stimulation) or pressure (+8 mmHg, control). Pain was induced by pressure to the nail of the left-index finger and quantified by a visual analog scale. Pain decreased heart rate (HR) and increased blood pressure (BP). Baroreceptor stimulation further decreased HR and reduced the BP increase. Pain experience failed to differ between baroreceptor stimulation conditions. However, significant results were obtained when trials were categorized according to the magnitude of the HR deceleration elicited by baroreceptor stimulation. In trials with strong baroreceptor-elicited HR deceleration pain intensity was lower than in trials both with inactive baroreceptor stimulation (pressure trials) or trials with small baroreceptor-elicited HR responses. Anti-nociceptive effects of baroreceptor stimulation depend on the activation of the reflex cardiovascular response. Central nervous inhibition due to baroreceptor stimulation only occurs if the peripheral cardiovascular response is engaged. PMID- 25038303 TI - Rated and measured impulsivity in children is associated with diminished cardiac reactions to acute psychological stress. AB - This study examined the association between impulsivity and heart rate reactions to a brief psychological stress in pre-adolescent children. Impulsivity was assessed by two response inhibition tasks and maternal self-report. Heart rate was measured at rest and in response to a mental arithmetic challenge. Children high in impulsivity showed blunted cardiac stress reactions. This result resonates with previous findings that blunted stress reactivity is characteristic of a range of problematic behaviours often associated with impulsivity. PMID- 25038304 TI - Improving heartbeat perception in patients with medically unexplained symptoms reduces symptom distress. AB - Distortions in interoceptive accuracy have been linked to somatoform disorders. In line with cognitive theories of symptom formation in somatoform disorders, decreases in interoceptive accuracy have recently been observed to co-occur with more severe symptom reports. The current study tested the hypothesis that experimentally increasing interoceptive accuracy should decrease symptom severity in somatoform disorders. Twenty-nine patients with somatoform disorders were instructed in a newly developed heartbeat perception training procedure. Heartbeat perception, as a proxy for interoceptive accuracy, was assessed with a mental tracking task. Although there were no significant differences between the training group and a waiting control group (n=23) regarding increases in heartbeat perception, health anxiety served as a moderator and significant reductions in state symptom reports were observed after training. These findings suggest a relation between lower interoceptive accuracy and the perception of bodily symptoms in somatoform disorders. PMID- 25038306 TI - Long-term effects of an intensive intervention in HIV-infected patients with moderate-high atherosclerotic cardiovascular risk. AB - OBJECTIVES: To evaluate the 5 year effects of an intensive intervention versus the standard-of-care intervention on cardiovascular risk factors in HIV-infected patients on antiretroviral therapy (ART). METHODS: This was a longitudinal study including virologically suppressed patients with at least two cardiovascular risk factors or a Framingham risk score >=10%. Intensive and standard-of-care interventions aimed for low-density lipoprotein cholesterol (LDL-C) <100 and <130 mg/dL, respectively, by using lipid-lowering drugs. In the intensive group, switching ART when needed to achieve the LDL-C target and low-dose aspirin were used. Achievement of LDL-C targets and changes in carotid intima-media thickness (cIMT) and cardiovascular biomarkers were compared between groups at different timepoints through a 5 year period. RESULTS: Twenty-two and 25 patients in the intensive and standard intervention groups, respectively, were followed up. At 5 years, pre-specified LDL-C targets were achieved in 82% (intensive) and 81% (standard of care) of patients. The median (IQR) change in LDL-C in the intensive and standard intervention groups was -78 (-96/-39.7) and -49 (-72/-3) mg/dL, respectively (P = 0.04), and in the Framingham score was -4% (-8%/-1%) and 0% ( 4%/6.5%), respectively (P = 0.01). There were no significant intra- or between group changes in cIMT measurements. A significant decrease was observed in the intensive and standard groups in interleukin 6 (P = 0.001 and P = 0.002, respectively) and in tumour necrosis factor alpha (P = 0.023 and P = 0.052, respectively). Asymptomatic creatine phosphokinase elevations were observed in two patients assigned to the standard intervention group. CONCLUSIONS: An intensive intervention on cardiovascular risk factors in HIV-infected patients on ART was feasible, safe and capable of achieving LDL-C targets in the long term. Both intensive and standard interventions were accompanied by antiatherosclerotic changes in inflammatory cytokines and lack of cIMT progression. PMID- 25038305 TI - Pre-pregnancy obesity and maternal circadian cortisol regulation: Moderation by gestational weight gain. AB - We investigated main and interactive effects of maternal pre-pregnancy obesity and gestational weight gain on circadian cortisol from the second to third trimester. A diverse sample of 215 pregnant women was enrolled. Maternal height and most recent pre-pregnancy weight were collected at study initiation (22% obese). Weight and circadian salivary cortisol samples were measured during second (24+/-4) and third (35+/-1 weeks) trimesters. During the third trimester, women who were obese prior to conception showed elevated evening cortisol versus normal weight women. This pattern was moderated by weight gain in excess of Institute of Medicine guidelines, such that women who were obese prior to conception and gained greater than 7.94kg by the 35+/-1 week visit displayed greatest elevations in evening cortisol. Given links between excessive prenatal glucocorticoid exposure and both poor maternal and offspring health outcomes, elevated maternal cortisol may be one mechanism underlying links between maternal obesity and adverse perinatal outcomes. PMID- 25038307 TI - Laminar shear stress regulates mitochondrial dynamics, bioenergetics responses and PRX3 activation in endothelial cells. AB - Endothelial cells in the vascular system are constantly subjected to the frictional force of shear stress due to the pulsatile nature of blood flow. Although several proteins form part of the shear stress mechano-sensing pathway, the identification of mechano-transducing pathways is largely unknown. Given the increasing evidence for a signaling function of mitochondria in endothelial cells, the aim of this study was to investigate their role as mechano-sensor organelles during laminar shear stress (LSS). We demonstrated that LSS activates intracellular signaling pathways that modulate not only mitochondrial dynamics but also mitochondrial function. At early time points of LSS, the fission-related protein Drp1 was recruited from the cytosol to mitochondria and activated mitochondrial fission. LSS-dependent increase in intracellular Ca(2+) concentration was indispensable for mitochondrial fission. As alterations in mitochondrial dynamics have been related to changes in bioenergetics profiles, we studied mitochondrial function after LSS. We found that LSS decreased respiration rate, increased mitochondrial membrane potential and promoted the mitochondrial generation of ROS with the subsequent oxidation and activation of the antioxidant enzyme PRX3. Our data support a novel and active role for mitochondria in endothelial cells as active players, able to transduce the mechanical force of shear stress in the vascular endothelium into a biological response. PMID- 25038308 TI - Egocentric representations of space co-exist with allocentric representations: evidence from spatial neglect. AB - The brain transforms sensory input to motor coordinates to accommodate for changes of posture and gaze direction. Neurophysiological and neuropsychological evidence supports the existence of multiple representations of space. A debated issue regards whether objects that we see are encoded in egocentric frames only or also maintain an object-centered frame of reference. Previous clinical studies were unable to discriminate between these models as the stimuli used to determine object-based (allocentric) biases are contaminated by body-centered (egocentric) effects. To address this, we used stimuli where allocentric side was elicited by gestalt configuration rather than egocentric location. We then displayed these stimuli at different egocentric positions allowing us to independently measure the effects of allocentric position, egocentric position as well as their interaction. In a group of stroke patients with neglect we demonstrate that allocentric biases are modulated as a function of egocentric position. These findings help adjudicate between the different models of space representation, demonstrating that specific allocentric deficits not only exist but also often co exist with egocentric biases. PMID- 25038309 TI - Automatic domain-general processing of sound source identity in the left posterior middle frontal gyrus. AB - Identifying sound sources is fundamental to developing a stable representation of the environment in the face of variable auditory information. The cortical processes underlying this ability have received little attention. In two fMRI experiments, we investigated passive adaptation to (Exp. 1) and explicit discrimination of (Exp. 2) source identities for different categories of auditory objects (voices, musical instruments, environmental sounds). All cortical effects of source identity were independent of high-level category information, and were accounted for by sound-to-sound differences in low-level structure (e.g., loudness). A conjunction analysis revealed that the left posterior middle frontal gyrus (pMFG) adapted to identity repetitions during both passive listening and active discrimination tasks. These results indicate that the comparison of sound source identities in a stream of auditory stimulation recruits the pMFG in a domain-general way, i.e., independent of the sound category, based on information contained in the low-level acoustical structure. pMFG recruitment during both passive listening and explicit identity comparison tasks also suggests its automatic engagement in sound source identity processing. PMID- 25038310 TI - Inhibition of bone resorption by the cathepsin K inhibitor odanacatib is fully reversible. AB - The cathepsin K (CatK) inhibitor odanacatib (ODN) is currently being developed for the treatment of osteoporosis. In clinical trials, efficacy and resolution of effect of ODN treatment on bone turnover biomarkers and accrued bone mass have been demonstrated. Here, we examine the effects of continuing treatment and discontinuation of ODN versus alendronate (ALN) on osteoclast (OC) function. First, accessibility and reversible engagement of active CatK in intracellular vesicles and resorption lacunae of actively resorbing OCs were demonstrated by the selective and reversible CatK inhibitors, BODIPY-L-226 (IC50=39nM) and L 873,724 (IC50=0.5nM). Next, mature human OCs on bone slices were treated with vehicle, ODN, or ALN for 2days, followed by either continuing with the same treatment, or replacement of the inhibitors by vehicle for additional times as specified per experimental conditions. Maintaining OCs on ODN or ALN significantly reduced CTx-I release compared to vehicle controls. However, only the treatment of OCs with ODN resulted in the formation of small shallow discrete resorption pits, retention of intracellular vesicles enriched with CatK and other lysosomal enzymes, increase in 1-CTP release and number of TRAP(+) OCs. Upon discontinuation of ODN treatment, OCs rapidly resumed bone resorption activity, as demonstrated by a return of OC functional markers (CTx-I, 1-CTP), cell number and size, morphology and number of resorption pits, and vesicular secretion of CatK toward the respective vehicle levels. As expected, discontinuation of ALN did not reverse the treatment-related inhibition of OC activity in the time frame of the experiment. In summary, this study demonstrated rapid kinetics of inhibition and reversibility of the effects of ODN on OC bone resorption, that differentiated the cellular mechanism of CatK inhibition from that of the bisphosphate antiresorptive ALN. PMID- 25038311 TI - Nutritional aspects of honey bee-collected pollen and constraints on colony development in the eastern Mediterranean. AB - Pollen is the main protein and lipid source for honey bees (Apis mellifera), and nutritionally impoverished landscapes pose a threat to colony development. To determine colony nutritional demands, we analyzed a yearly cycle of bee-collected pollen from colonies in the field and compared it to colony worker production and honey bee body composition, for the first time in social insects. We monitored monthly bee production in ten colonies at each of seven sites throughout Israel, and trapped pollen bi-monthly in five additional colonies at each of four of these sites. Pollen mixtures from each sampling date and site were analyzed for weight, total protein, total fatty acids (FAs), and FA composition. Compared to more temperate climates, the eastern Mediterranean allows a relatively high yearly colony growth of ca. 300,000-400,000 bees. Colonies at higher elevation above sea level showed lower growth rates. Queen egg-laying rate did not seem to limit growth, as peaks in capped brood areas showed that queens lay a prolific 2000 eggs a day on average, with up to 3300 eggs in individual cases. Pollen uptake varied significantly among sites and seasons, with an overall annual mean total 16.8kg per colony, containing 7.14kg protein and 677g fat. Overall mean pollen protein content was high (39.8%), and mean total FA content was 3.8%. Production cost, as expressed by the amount of nutrient used per bee, was least variable for linoleic acid and protein, suggesting these as the best descriptive variables for total number of bees produced. Linolenic acid levels in pollen during the autumn were relatively low, and supplementing colonies with this essential FA may mitigate potential nutritional deficiency. The essentiality of linoleic and linolenic acids was consistent with these FAs' tendency to be present at higher levels in collected pollen than in the expected nutrients in bee bodies, demonstrating a well-developed adjustment between pollinator nutritional demands and the nutritional value of food offered by pollinated plants. PMID- 25038314 TI - Beta-carotene reduces oxidative stress, improves glutathione metabolism and modifies antioxidant defense systems in lead-exposed workers. AB - The aim of this study was to determine whether beta-carotene administration reduces oxidative stress and influences antioxidant, mainly glutathione-related, defense systems in workers chronically exposed to lead. The population consisted of two randomly divided groups of healthy male volunteers exposed to lead. Workers in the first group (reference group) were not administered any antioxidants, while workers in the second group (CAR group) were treated orally with 10mg of beta-carotene once a day for 12weeks. Biochemical analysis included measuring markers of lead-exposure and oxidative stress in addition to the levels and activities of selected antioxidants. After treatment, levels of malondialdehyde, lipid hydroperoxides and lipofuscin significantly decreased compared with the reference group. However, the level of glutathione significantly increased compared with the baseline. Treatment with beta-carotene also resulted in significantly decreased glutathione peroxidase activity compared with the reference group, while the activities of other glutathione-related enzymes and of superoxide dismutase were not significantly changed. However, the activities of glucose-6-phosphate dehydrogenase and catalase, as well as the level of alpha-tocopherol, were significantly higher after treatment compared with the baseline. Despite controversy over the antioxidant properties of beta carotene in vivo, our findings showed reduced oxidative stress after beta carotene supplementation in chronic lead poisoning. PMID- 25038312 TI - HPV vaccination among lesbian and bisexual women: Findings from a national survey of young adults. AB - BACKGROUND: Human papillomavirus (HPV) infection and associated cervical disease are common among all women, regardless of sexual identity, yet limited research has examined HPV vaccination among lesbian and bisexual women. METHODS: A national sample of lesbian and bisexual women ages 18-26 (n=543) completed our online survey during Fall 2013. We used multivariable logistic regression to identify correlates of HPV vaccine initiation (receipt of at least 1 dose) and completion (receipt of all 3 recommended doses among initiators). RESULTS: Overall, 45% of respondents had initiated HPV vaccine and 70% of initiators reported completing the series. HPV vaccine initiation was higher among respondents who were students, had received a healthcare provider's recommendation, perceived greater positive social vaccination norms, or anticipated greater regret if they did not get vaccinated and later got HPV. Initiation was lower among those who perceived greater HPV vaccine harms or greater barriers to getting the vaccine (all p<.05). HPV vaccine completion was higher among initiators who had a college degree while it was lower among those who perceived a greater likelihood of acquiring HPV or who anticipated greater regret if they got the vaccine and fainted (all p<.05). Among HPV vaccine initiators who had not yet completed the series, about half (47%) intended to get the remaining doses. CONCLUSIONS: Many lesbian and bisexual women are not getting vaccinated against HPV. Healthcare provider recommendations and women's health beliefs may be important leverage points for increasing vaccination among this population. PMID- 25038313 TI - Magnolol protects neurons against ischemia injury via the downregulation of p38/MAPK, CHOP and nitrotyrosine. AB - Magnolol is isolated from the herb Magnolia officinalis, which has been demonstrated to exert pharmacological effects. Our aim was to investigate whether magnolol is able to act as an anti-inflammatory agent that brings about neuroprotection using a global ischemic stroke model and to determine the mechanisms involved. Rats were treated with and without magnolol after ischemia reperfusion brain injury by occlusion of the two common carotid arteries. The inflammatory cytokine production in serum and the volume of infarction in the brain were measured. The proteins present in the brains obtained from the stroke animal model (SAM) and control animal groups with and without magnolol treatment were compared. Magnolol reduces the total infarcted volume by 15% and 30% at dosages of 10 and 30mg/kg, respectively, compared to the untreated SAM group. The levels of acute inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 were attenuated by magnolol. Magnolol was also able to suppress the production of nitrotyrosine, 4-hydroxy-2-nonenal (4 HNE), inducible NO synthase (iNOS), various phosphorylated p38 mitogen-activated protein kinases and various C/EBP homologues. Furthermore, this modulation of ischemia injury factors in the SAM model group treated with magnolol seems to result from a suppression of reactive oxygen species production and the upregulation of p-Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). These findings confirm the anti-oxidative properties of magnolol, including the inhibition of ischemic injury to neurons; this protective effect seems to involve changes in the in vivo activity of Akt, GSK3beta and NF kappaB. PMID- 25038315 TI - Methyl parathion inhibits the nuclear maturation, decreases the cytoplasmic quality in oocytes and alters the developmental potential of embryos of Swiss albino mice. AB - Methyl parathion (MP) is one of the most commonly used and extremely toxic organophosphorous group of pesticide. A large number of studies in the literature suggest that it has adverse effects on the male reproductive system. However, there is limited information about its toxicity to the female reproductive system. In the present study we report the toxic effects of methyl parathion on the female reproductive system using Swiss albino mice as the experimental model. The female mice were administered orally with 5, 10 and 20mg/kg of MP. One week later, the mice were superovulated with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) to study the quality of the oocytes, spindle organization, developmental potential of early embryos and the DNA integrity in blastocysts. MP exposure resulted in a non-significant decrease in the number of primordial follicles and increased DNA damage in granulosa cells. Though MP did not have any effect on the ovulation it had a significant inhibitory effect on the nuclear maturity of oocytes which was associated with spindle deformity. In addition, the oocytes had higher cytoplasmic abnormalities with depleted glutathione level. Even though it did not have any effect on the fertilization and blastocyst rate at lower doses, at 20 mg/kg MP it resulted in a significant decrease in blastocyst hatching, decrease in cell number and high DNA damage. While low body weight gain was observed in F1 generation from 5mg/kg group, at higher dose, the body weight in F1 generation was marginally higher than control. Post-natal death in F1 generation was observed only in mice treated with 20mg/kg MP. In conclusion, we report that MP has adverse effects on the oocyte quality, developmental potential of the embryo and reproductive outcome. PMID- 25038316 TI - Carotid blowout syndrome: endovascular management of acute hemorrhage with tapering overlapped covered stents. AB - Carotid blowout is a rare fatal complication most commonly observed in head and neck cancer patients, especially after radiation therapy. Traditional surgical approaches carry extremely high morbidity and mortality rates. We present a case of acute hemorrhage from extracranial carotid artery in a 64-year-old man with history of total laryngectomy, tracheostomy, and chemoradiotherapy for laryngeal cancer. Tumor was noted to be encasing and eroding into the internal and common carotid artery with a large soft tissue neck defect. Hemorrhage was successfully controlled employing 3 Viabahn covered stents of increasing diameter in the internal and common carotid artery in an overlapping fashion under local anesthesia. Deployment of tapering overlapped covered stents in common and internal carotid artery may safely be performed to obtain endovascular control of active hemorrhage in a hostile neck. PMID- 25038317 TI - Quantifying the effects of the division of labor in metabolic pathways. AB - Division of labor is commonly observed in nature. There are several theories that suggest diversification in a microbial community may enhance stability and robustness, decrease concentration of inhibitory intermediates, and increase efficiency. Theoretical studies to date have focused on proving when the stable co-existence of multiple strains occurs, but have not investigated the productivity or biomass production of these systems when compared to a single 'super microbe' which has the same metabolic capacity. In this work we prove that if there is no change in the growth kinetics or yield of the metabolic pathways when the metabolism is specialized into two separate microbes, the biomass (and productivity) of a binary consortia system is always less than that of the equivalent monoculture. Using a specific example of Escherichia coli growing on a glucose substrate, we find that increasing the growth rates or substrate affinities of the pathways is not sufficient to explain the experimentally observed productivity increase in a community. An increase in pathway efficiency (yield) in specialized organisms provides the best explanation of the observed increase in productivity. PMID- 25038318 TI - Niacin attenuates the production of pro-inflammatory cytokines in LPS-induced mouse alveolar macrophages by HCA2 dependent mechanisms. AB - Niacin has been reported to have potent anti-inflammatory effects in LPS-induced acute lung injury. However, the molecular mechanism of niacin has not been fully understood. The aim of the present study was to investigate the effects of niacin on the production of pro-inflammatory cytokines TNF-alpha, IL-6 and IL-1beta in LPS-induced mouse alveolar macrophages and explore its underlying mechanism. Mouse alveolar macrophages were incubated in the presence or absence of various concentrations of niacin (1, 10, 100 MUmol/l) 1h before LPS (1 MUg/ml) challenge. The results showed that niacin reduced the levels of TNF-alpha, IL-6 and IL-1beta in LPS-challenged alveolar macrophages. Furthermore, NF-kappaB activation was inhibited by niacin through blocking the phosphorylation of NF-kappaB p65 and IkappaBalpha. In addition, silencing HCA2 abrogated the effect of niacin on the production of pro-inflammatory cytokines. These findings suggested that niacin attenuated the LPS-induced pro-inflammatory cytokines possibly mediated by HCA2 in LPS-challenged alveolar macrophages. PMID- 25038319 TI - Cimetidine effects on the immunosuppression induced by burn injury. AB - Although many studies on the immune response following burn injuries have been reported, more attention has been given to the immunosuppression mechanism and mediators that shape the process of immune suppression. Specifically, information is not available concerning the immunomodulatory effects of the drugs which are involved in the immune response restoration. In this study, we investigated the effects of Cimetidine on the modulation of immune response in patients with burn injury of 20-60%. Two groups of patients were involved in this study; the patients in one group were treated with 15 mg/kg per day of Cimetidine while the patients in the other group were treated with placebo. Peripheral blood mononuclear cell (PBMC) expressing CD3, CD4, CD8, CD19 and CD3/HLA-DR was analyzed by flow cytometry. Cell proliferation assay using H3 thymidine was performed on PBMC samples. The proliferation assay showed a significant suppression of cell proliferation rate in post-burn patients (p = 0.001). We observed a significant reduction in the lymphocyte count (p = 0.001) and frequency of CD3 (p = 0.007) and CD4 (p = 0.001) T cells in post-burn patients. Also, the frequency of CD 19+ and HLA DR+ cells was increased compare to normal donors following burn injury. Treatment with Cimetidine increased the frequency of CD8+ T cells in the patient's peripheral blood. The PBMC proliferation rate was restored following the treatment with Cimetidine (p = 0.02). Our data indicates that Cimetidine may have beneficial effects on cell mediated immunity following burn injury. PMID- 25038321 TI - Autoantibodies to estrogen receptors and their involvement in autoimmune diseases and cancer. AB - The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several diseases including some cancers, most notably breast cancer, and autoimmune disorders. Estrogenic signal is transferred via estrogen receptors (ER) which have dual localization, predominantly intracellular but also in plasma membrane. The discovery of membrane-associated ER (mER) has greatly expanded our understanding of estrogen action; upon ligand binding, mER rapidly activate different signaling pathways inducing downstream transcription factors. Some target genes of the mER pathway may be activated independently of the intracellular ER. Additionally, intracellular ER action can be modulated by mER-initiated signaling. Most notably, the identification of autoantibodies reacting with ER (ERAB) and their possible pathogenic role in autoimmunity and cancer have opened a new path for the research in the estrogen-related receptor activity. In this review, we briefly recapitulate the localization and function of ER and mostly discuss the possible role of ERAB as novel potential prognostic and/or predictive tools in autoimmunity and cancer. PMID- 25038320 TI - Ellagic acid protects Lipopolysaccharide/D-galactosamine-induced acute hepatic injury in mice. AB - Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has been reported to have anti-inflammatory, anti-tumor, and antioxidant activities. However, the effects of ellagic acid on acute hepatic injury have not been reported. In the present study, we investigated the effects of ellagic acid on Lipopolysaccharide/d-galactosamine-induced acute hepatic injury in mice. The results showed that LPS/GalN increased hepatic malondialdehyde (MDA) content, TNF alpha level, serum ALT and AST levels and TNF-alpha level. However, these changes were attenuated by ellagic acid. Western blot analysis showed that ellagic acid inhibited LPS/GalN-induced NF-kappaB activation. Furthermore, ellagic acid induced the expression of Nrf2 and heme oxygenase-1. In conclusion, our results showed that ellagic acid protected against LPS/GalN-induced liver injury by enhancing the antioxidative defense system and reducing inflammatory response. PMID- 25038322 TI - A steroidogenic pathway for sulfonated steroids: the metabolism of pregnenolone sulfate. AB - In many tissues sulfonated steroids exceed the concentration of free steroids and recently they were also shown to fulfill important physiological functions. While it was previously demonstrated that cholesterol sulfate (CS) is converted by CYP11A1 to pregnenolone sulfate (PregS), further conversion of PregS has not been studied in detail. To investigate whether a steroidogenic pathway for sulfonated steroids exists similar to the one described for free steroids, we examined the interaction of PregS with CYP17A1 in a reconstituted in-vitro system. Difference spectroscopy revealed a Kd-value of 74.8+/-4.2MUM for the CYP17A1-PregS complex, which is 2.5-fold higher compared to the CYP17A1-pregnenolone (Preg) complex. Mass spectrometry experiments proved for the first time that PregS is hydroxylated by CYP17A1 at position C17, identically to pregnenolone. A higher Km and a lower kcat-value for CYP17A1 using PregS compared with Preg were observed, indicating a 40% reduced catalytic efficiency when using the sulfonated steroid. Furthermore, we analyzed whether the presence of cytochrome b5 (b5) has an influence on the CYP17A1 dependent conversion of PregS, as was demonstrated for Preg. Interestingly, with 17OH-PregS no scission of the 17,20-carbon-carbon bond occurs, when b5 is added to the reconstituted in-vitro system, while b5 promotes the formation of DHEA from 17OH-Preg. When using human SOAT-HEK293 cells expressing CYP17A1 and CPR, we could confirm that PregS is metabolized to 17OH PregS, strengthening the potential physiological meaning of a pathway for sulfonated steroids. PMID- 25038323 TI - Engineering disulfide bonds within an antibody. AB - Antibodies have evolved to function in oxidative, extracellular environments. A pair of cysteines in close proximity will oxidatively react to form a disulfide bond that fixes and stabilizes the tertiary structure of a protein. Immunoglobulin G (IgG) includes several disulfide bonds, and the patterns of inter-chain disulfide bonds characterize different IgG sub-classes. Moreover, the Ig-fold domains are characterized by a buried intra-domain disulfide bond, which is important for its structural stability. However, the intra-domain disulfide bond can be replaced without crucial effects on the structure and function, if the domain structure is intrinsically stable or has been stabilized by protein engineering. In previous studies, disulfide bonds were removed by amino-acid substitution indicating that Val and/or Ala (i.e. Ala-Ala, Ala-Val, Val-Ala, and Val-Ala) pairs were preferred for cysteine replacement in the Ig-fold domain. As such, these mutations may be useful for the intracellular use of antibodies. Recently, additional intra-domain disulfide bonds have been shown to stabilize Ig fold domains and whole IgGs. In heavy chain variable or light chain variable domains, the introduction of additional disulfide bonds into the framework region did not reduce antigen-binding affinity, suggesting that generating disulfide bonds may be a method for stabilizing IgG and antibody fragments, such as the antigen-binding fragment, and single-chain and single-domain antibodies. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody. PMID- 25038324 TI - The effect of the uncertainty in the number of contributors to mixed DNA profiles on profile interpretation. AB - The effect of uncertainty in the number of contributors to a profile is a matter of some contention in forensic DNA interpretation. Interpretation methods are moving towards continuous models. Within this paper the effect of misspecification of the number of contributors to a profile caused by one artefactual peak, either a large back stutter or a forward stutter, was investigated using a continuous model. The misassignment of the number of contributors to a profile either has no significant effect or decreases the LR for the true contributors. It often increases the chance of an adventitious link. PMID- 25038325 TI - Current sequencing technology makes microhaplotypes a powerful new type of genetic marker for forensics. AB - SNPs that are molecularly very close (<10kb) will generally have extremely low recombination rates, much less than 10(-4). Multiple haplotypes will often exist because of the history of the origins of the variants at the different sites, rare recombinants, and the vagaries of random genetic drift and/or selection. Such multiallelic haplotype loci are potentially important in forensic work for individual identification, for defining ancestry, and for identifying familial relationships. The new DNA sequencing capabilities currently available make possible continuous runs of a few hundred base pairs so that we can now determine the allelic combination of multiple SNPs on each chromosome of an individual, i.e., the phase, for multiple SNPs within a small segment of DNA. Therefore, we have begun to identify regions, encompassing two to four SNPs with an extent of <200bp that define multiallelic haplotype loci. We have identified candidate regions and have collected pilot data on many candidate microhaplotype loci. Here we present 31 microhaplotype loci that have at least three alleles, have high heterozygosity, are globally informative, and are statistically independent at the population level. This study of microhaplotype loci (microhaps) provides proof of principle that such markers exist and validates their usefulness for ancestry inference, lineage-clan-family inference, and individual identification. The true value of microhaplotypes will come with sequencing methods that can establish alleles unambiguously, including disentangling of mixtures, because a single sequencing run on a single strand of DNA will encompass all of the SNPs. PMID- 25038326 TI - Long overall survival after dendritic cell vaccination in metastatic uveal melanoma patients. AB - PURPOSE: To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma. DESIGN: Interventional case series. METHODS: We analyzed 14 patients with metastatic uveal melanoma treated with dendritic cell vaccination. Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase. The main outcome measures were safety, immunologic response, and overall survival. RESULTS: Tumor specific immune responses were induced with dendritic cell vaccination in 4 (29%) of 14 patients. Dendritic cell-vaccinated patients showed a median overall survival with metastatic disease of 19.2 months, relatively long compared with that reported in the literature. No severe treatment-related toxicities (common toxicity criteria grade 3 or 4) were observed. CONCLUSIONS: Dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell based immunotherapy is potent to enhance the host's antitumor immunity against uveal melanoma in approximately one third of patients. Compared with other prospective studies with similar inclusion criteria, dendritic cell vaccination may be associated with longer than average overall survival in patients with metastatic uveal melanoma. PMID- 25038327 TI - Salvage proton beam therapy in local recurrent uveal melanoma. AB - PURPOSE: To evaluate survival and ocular outcome in recurrent uveal melanoma treated with proton beam therapy as salvage therapy. DESIGN: Retrospective, interventional case series. METHODS: We evaluated 48 patients with local recurrence of uveal melanoma after primary treatment with brachytherapy, transpupillary thermotherapy, proton beam therapy, laser photocoagulation, CyberKnife radiation, or photodynamic therapy. All patients received proton beam therapy as a salvage therapy at the Helmholtz Zentrum Berlin between July 2000 and December 2010. Kaplan-Meier analysis was used to obtain survival rates. RESULTS: The Kaplan-Meier estimator for local tumor control was 92.1% at 10 years after secondary treatment with proton beam therapy. Local recurrence developed in 3 patients; 1 of them underwent enucleation. During follow-up, 20.8% of the patients died (16.7% of metastasis, 4.1% of other causes or not specified). The most frequent surgical interventions were phacoemulsification (20.8%) and pars plana vitrectomy (10.4%). The Kaplan-Meier estimators were 77.4% for survival and 70.1% for the absence of metastasis 10 years after the primary treatment. CONCLUSIONS: Proton beam therapy as a salvage treatment resulted in high local tumor control rates in recurrent uveal melanoma, especially if the primary therapy was transpupillary thermotherapy or plaque brachytherapy. Preservation of the globe was possible in most patients. Enucleations were indicated only in case of re-recurrences of uveal melanoma, but not because of secondary complications like intractable pain or secondary glaucoma. Retreatment was associated with vision deterioration, but loss of vision remained exceptional. Further larger prospective studies are needed to confirm the presented results of our retrospective analysis. PMID- 25038328 TI - Myeloperoxidase gene expression and cognitive functions in depression. AB - PURPOSE: Most researchers agree that there are multiple factors influencing the development of recurrent depressive disorder (rDD). Previous studies have found that myeloperoxidase (MPO) may be a key inflammatory enzyme involved in this disorder. The purpose of this study was to determine the mRNA and protein levels of MPO in patients with rDD and to define the relationship between serum MPO levels and cognitive performance. MATERIAL/METHODS: The study comprised 236 subjects: patients with rDD (n=131) and healthy subjects (n=105, HS). Assessment of cognitive function was based on performance on the Trail Making Test, the Stroop Test, the Verbal Fluency Test (VFT) and the Auditory-Verbal Learning Test (AVLT). RESULTS: MPO gene expression at mRNA level and at protein level was significantly higher in the rDD group when compared to the HS (p<0.01). There were no significant correlations for each group separately, but in the entire group, statistically significant correlations occurred between both mRNA and protein levels and following test: TMT part A and part B (positive correlations), part RCNb and part NCWd of the Stroop Test (positive correlation), the Verbal Fluency Test (negative correlation) and the AVLT (negative correlation). CONCLUSIONS: Our study provides evidence that the MPO enzyme coding gene and MPO expression are important for the regulation of cognitive functioning. PMID- 25038331 TI - Woman with child: Pablo Picasso. PMID- 25038332 TI - Physicians' group discourages routine pelvic examination. PMID- 25038345 TI - An HIV cure: feasibility, discovery, and implementation. PMID- 25038346 TI - Reconsideration of the lifetime ban on blood donation by men who have sex with men. PMID- 25038347 TI - Realization of an AIDS-free generation: ensuring sustainable treatment for children. PMID- 25038348 TI - Maximizing benefits of new strategies to prevent mother-to-child HIV transmission without harming existing services. PMID- 25038349 TI - A piece of my mind. Water, water, everywhere. PMID- 25038350 TI - A piece of my mind. Pause, listen, share. PMID- 25038351 TI - Quantum leaps, microeconomics, and the treatment of patients with hepatitis C and HIV coinfection. PMID- 25038352 TI - Integrating HIV prevention into practice. PMID- 25038353 TI - HIV/AIDS: gaining ground and forging forward. PMID- 25038354 TI - Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. AB - IMPORTANCE: Treatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon. OBJECTIVE: To determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment. DESIGN, SETTING, AND PARTICIPANTS: Open label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/MUL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/MUL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants. INTERVENTIONS: Treatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary study outcome was the proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks (SVR12) after cessation of HCV therapy. RESULTS: Among treatment-naive participants, 87 patients (76%) of 114 (95% CI, 67%-84%) with genotype 1, 23 patients (88%) of 26 with genotype 2 (95% CI, 70% 985), and 28 patients (67%) of 42 with genotype 3 (95% CI, 51%-80%) achieved SVR12. Among treatment-experienced participants, 22 patients (92%) of 24 with genotype 2 (95% CI, 73%-99%) and 16 patients (94%) of 17 (95% CI, 71%-100%) achieved SVR12. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12. Further studies of this oral regimen in diverse populations of coinfected patients are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01667731. PMID- 25038355 TI - Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. AB - IMPORTANCE: Antiretroviral preexposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF) and combination emtricitabine/tenofovir disoproxil fumarate (FTC+TDF), is efficacious for prevention of human immunodeficiency virus (HIV) acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined. OBJECTIVE: To assess pregnancy incidence and outcomes among women using PrEP during the periconception period. DESIGN, SETTING, AND PARTICIPANTS: Randomized trial among 1785 HIV-serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda. INTERVENTIONS: Daily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo. Pregnancy testing occurred monthly and study medication was discontinued when pregnancy was detected. MAIN OUTCOMES AND MEASURES: Pregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth. RESULTS: A total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% CI, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, 1.3; 95% CI, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, -5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, -4.6%; 95% CI, -18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, -16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo. CONCLUSIONS AND RELEVANCE: Among HIV-serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination FTC+TDF compared with placebo at conception. Given that PrEP was discontinued when pregnancy was detected and that CIs for the birth outcomes were wide, definitive statements about the safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00557245. PMID- 25038356 TI - Effect of optional home initiation of HIV care following HIV self-testing on antiretroviral therapy initiation among adults in Malawi: a randomized clinical trial. AB - IMPORTANCE: Self-testing for HIV infection may contribute to early diagnosis of HIV, but without necessarily increasing antiretroviral therapy (ART) initiation. OBJECTIVE: To investigate whether offering optional home initiation of HIV care after HIV self-testing might increase demand for ART initiation, compared with HIV self-testing accompanied by facility-based services only. DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized trial conducted in Blantyre, Malawi, between January 30 and November 5, 2012, using restricted 1:1 randomization of 14 community health worker catchment areas. Participants were all adult (>=16 years) residents (n = 16,660) who received access to home HIV self-testing through resident volunteers. This was a second-stage randomization of clusters allocated to the HIV self-testing group of a parent trial. INTERVENTIONS: Clusters were randomly allocated to facility-based care or optional home initiation of HIV care (including 2 weeks of ART if eligible) for participants reporting positive HIV self-test results. MAIN OUTCOMES AND MEASURES: The preplanned primary outcome compared between groups the proportion of all adult residents who initiated ART within the first 6 months of HIV self-testing availability. Secondary outcomes were uptake of HIV self-testing, reporting of positive HIV self-test results, and rates of loss from ART at 6 months. RESULTS: A significantly greater proportion of adults in the home group initiated ART (181/8194, 2.2%) compared with the facility group (63/8466, 0.7%; risk ratio [RR], 2.94, 95% CI, 2.10-4.12; P < .001). Uptake of HIV self-testing was high in both the home (5287/8194, 64.9%) and facility groups (4433/8466, 52.7%; RR, 1.23; 95% CI, 0.96-1.58; P = .10). Significantly more adults reported positive HIV self-test results in the home group (490/8194 [6.0%] vs the facility group, 278/8466 [3.3%]; RR, 1.86; 95% CI, 1.16-2.97; P = .006). After 6 months, 52 of 181 ART initiators (28.7%) and 15 of 63 ART initiators (23.8%) in the home and facility groups, respectively, were lost from ART (adjusted incidence rate ratio, 1.18; 95% CI, 0.62-2.25, P = .57). CONCLUSIONS AND RELEVANCE: Among Malawian adults offered HIV self-testing, optional home initiation of care compared with standard HIV care resulted in a significant increase in the proportion of adults initiating ART. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01414413. PMID- 25038357 TI - Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. AB - IMPORTANCE: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown. OBJECTIVE: To investigate the effect of tesamorelin on visceral and liver fat. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized, placebo controlled trial conducted among 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation at Massachusetts General Hospital in Boston. The first patient was enrolled on January 10, 2011; for the final patient, the 6-month study visit was completed on September 6, 2013. INTERVENTIONS: Participants were randomized to receive tesamorelin, 2 mg (n=28), or placebo (n=22), subcutaneously daily for 6 months. MAIN OUTCOMES AND MEASURES: Primary end points were changes in visceral adipose tissue and liver fat. Secondary end points included glucose levels and other metabolic end points. RESULTS: Forty-eight patients received treatment with study drug. Tesamorelin significantly reduced visceral adipose tissue (mean change, -34 cm2 [95% CI, -53 to -15 cm2] with tesamorelin vs 8 cm2 [95% CI, -14 to 30 cm2] with placebo; treatment effect, -42 cm2 [95% CI, -71 to -14 cm2]; P = .005) and liver fat (median change in lipid to water percentage, -2.0% [interquartile range {IQR}, 6.4% to 0.1%] with tesamorelin vs 0.9% [IQR, -0.6% to 3.7%] with placebo; P = .003) over 6 months, for a net treatment effect of -2.9% in lipid to water percentage. Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL [95% CI, 5-13 mg/dL] vs 2 mg/dL [95% CI, -3 to 8 mg/dL] in the placebo group; treatment effect, 7 mg/dL [95% CI, 1-14 mg/dL]; P = .03), but changes at 6 months in fasting glucose (mean change, 4 mg/dL [95% CI, -2 to 10 mg/dL] with tesamorelin vs 2 mg/dL [95% CI, -4 to 7 mg/dL] with placebo; treatment effect, 2 mg/dL [95% CI, -6 to 10 mg/dL]; P = .72 overall across time points) and 2-hour glucose (mean change, -1 mg/dL [95% CI, -18 to 15 mg/dL] vs -8 mg/dL [95% CI, -24 to 8 mg/dL], respectively; treatment effect, 7 mg/dL [95% CI, 16 to 29 mg/dL]; P = .53 overall across time points) were not significant. CONCLUSIONS AND RELEVANCE: In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01263717. PMID- 25038358 TI - HIV prevention in clinical care settings: 2014 recommendations of the International Antiviral Society-USA Panel. AB - IMPORTANCE: Emerging data warrant the integration of biomedical and behavioral recommendations for human immunodeficiency virus (HIV) prevention in clinical care settings. OBJECTIVE: To provide current recommendations for the prevention of HIV infection in adults and adolescents for integration in clinical care settings. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: Data published or presented as abstracts at scientific conferences (past 17 years) were systematically searched and reviewed by the International Antiviral (formerly AIDS) Society-USA HIV Prevention Recommendations Panel. Panel members supplied additional relevant publications, reviewed available data, and formed recommendations by full-panel consensus. RESULTS: Testing for HIV is recommended at least once for all adults and adolescents, with repeated testing for those at increased risk of acquiring HIV. Clinicians should be alert to the possibility of acute HIV infection and promptly pursue diagnostic testing if suspected. At diagnosis of HIV, all individuals should be linked to care for timely initiation of antiretroviral therapy (ART). Support for adherence and retention in care, individualized risk assessment and counseling, assistance with partner notification, and periodic screening for common sexually transmitted infections (STIs) is recommended for HIV-infected individuals as part of care. In HIV uninfected patients, those persons at high risk of HIV infection should be prioritized for delivery of interventions such as preexposure prophylaxis and individualized counseling on risk reduction. Daily emtricitabine/tenofovir disoproxil fumarate is recommended as preexposure prophylaxis for persons at high risk for HIV based on background incidence or recent diagnosis of incident STIs, use of injection drugs or shared needles, or recent use of nonoccupational postexposure prophylaxis; ongoing use of preexposure prophylaxis should be guided by regular risk assessment. For persons who inject drugs, harm reduction services should be provided (needle and syringe exchange programs, supervised injection, and available medically assisted therapies, including opioid agonists and antagonists); low-threshold detoxification and drug cessation programs should be made available. Postexposure prophylaxis is recommended for all persons who have sustained a mucosal or parenteral exposure to HIV from a known infected source and should be initiated as soon as possible. CONCLUSIONS AND RELEVANCE: Data support the integration of biomedical and behavioral approaches for prevention of HIV infection in clinical care settings. A concerted effort to implement combination strategies for HIV prevention is needed to realize the goal of an AIDS-free generation. PMID- 25038359 TI - Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. AB - IMPORTANCE: New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE: To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS: Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE: After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions. PMID- 25038360 TI - Recurrent erythema multiforme. PMID- 25038361 TI - Dolutegravir (Tivicay) for HIV. PMID- 25038362 TI - Trends in diagnoses of HIV infection in the United States, 2002-2011. PMID- 25038363 TI - Evaluating a multipayer medical home intervention. PMID- 25038364 TI - Evaluating a multipayer medical home intervention. PMID- 25038365 TI - Evaluating a multipayer medical home intervention. PMID- 25038366 TI - Liver transplants among US veterans. PMID- 25038367 TI - Evaluating a multipayer medical home intervention--reply. PMID- 25038368 TI - Early descriptions of closed-chest cardiac massage. PMID- 25038369 TI - Liver transplants among US veterans--reply. PMID- 25038370 TI - Early descriptions of closed-chest cardiac massage--reply. PMID- 25038372 TI - Screening test for HTLV-III (AIDS agent) antibodies: specificity, sensitivity, and applications. PMID- 25038373 TI - JAMA patient page. Medications to prevent HIV infection. PMID- 25038374 TI - Increased risk of venous thromboembolic events with corticosteroid vs biologic therapy for inflammatory bowel disease. AB - BACKGROUND & AIMS: We investigated whether treatment of active inflammatory bowel disease with biologic agents is associated with a reduced risk of venous thromboembolic events (VTEs) compared with corticosteroid therapy. METHODS: We performed a retrospective analysis of 15,100 adults with inflammatory bowel disease who were identified from the Truven Health MarketScan databases. We analyzed data from patients who received 6 months of continuous medical and prescription coverage before and 12 months after their first diagnosis and had no VTE during the 6 months before they first received biologic or corticosteroid therapy. The outcome assessed was any VTE that occurred during the 12-month follow-up period. A multivariate logistic regression model was used to evaluate the effects of biologic, corticosteroid, and combination therapies (biologics and corticosteroids) on VTE risk. RESULTS: Three hundred twenty-five VTEs occurred during the study period (in 2.25% of patients receiving only corticosteroids, in 0.44% of patients receiving biologics, and in 2.49% of patients receiving combination therapy). Compared with patients receiving only corticosteroids, the odds ratio for VTE in patients receiving only biologics was 0.21 (95% confidence interval, 0.05-0.87) in the multivariate model, and the odds ratio for VTE in patients on combination therapy was 1.01. CONCLUSIONS: Compared with treatment with only a biologic agent, corticosteroid therapy is associated with a nearly 5 fold increase in risk for VTE. Combination therapy with corticosteroids and biologic agents was associated with the same risk for VTE as that of corticosteroids alone. Corticosteroids therefore appear to increase risk for VTE. PMID- 25038375 TI - When a child dies: parents' experiences of palliative care-an integrative literature review. AB - The aim of this integrative review was to increase knowledge about parents' experiences of palliative care when their child is dying or has died due to illness using Whittemore and Knafl (2005) analysis process. Computerized databases were used to search the literature. Nine papers met the inclusion criteria. The analysis resulted in five categories: genuine communication, sincere relationships, respect as an expert, and alleviation of suffering and need of support, including 15 subcategories. Health professionals need education to provide high-quality pediatric palliative care. They especially need training concerning existential issues, and further studies need to be performed. PMID- 25038376 TI - Riverbank filtration potential of pharmaceuticals in a wastewater-impacted stream. AB - Pharmaceutical contamination of shallow groundwater is a substantial concern in effluent-dominated streams, due to high aqueous mobility, designed bioactivity, and effluent-driven hydraulic gradients. In October and December 2012, effluent contributed approximately 99% and 71%, respectively, to downstream flow in Fourmile Creek, Iowa, USA. Strong hydrologic connectivity was observed between surface-water and shallow-groundwater. Carbamazepine, sulfamethoxazole, and immunologically-related compounds were detected in groundwater at greater than 0.02 MUg L(-1) at distances up to 6 m from the stream bank. Direct aqueous injection HPLC-MS/MS revealed 43% and 55% of 110 total pharmaceutical analytes in surface-water samples in October and December, respectively, with 16% and 6%, respectively, detected in groundwater approximately 20 m from the stream bank. The results demonstrate the importance of effluent discharge as a driver of local hydrologic conditions in an effluent-impacted stream and thus as a fundamental control on surface-water to groundwater transport of effluent-derived pharmaceutical contaminants. PMID- 25038377 TI - Fate and metabolism of tetrabromobisphenol A in soil slurries without and with the amendment with the alkylphenol degrading bacterium Sphingomonas sp. strain TTNP3. AB - Transformation of ring-(14)C-labelled tetrabromobisphenol-A (TBBPA) was studied in an oxic soil slurry with and without amendment with Sphingomonas sp. strain TTNP3, a bacterium degrading bisphenol-A. TBBPA degradation was accompanied by mineralization and formation of metabolites and bound-residues. The biotransformation was stimulated in the slurry bio-augmented with strain TTNP3, via a mechanism of metabolic compensation, although this strain did not grow on TBBPA. In the absence and presence of strain TTNP3, six and nine metabolites, respectively, were identified. The initial O-methylation metabolite (TBBPA monomethyl ether) and hydroxytribromobisphenol-A were detected only when strain TTNP3 was present. Four primary metabolic pathways of TBBPA in the slurries are proposed: oxidative skeletal rearrangements, O-methylation, ipso-substitution, and reductive debromination. Our study provides for the first time the information about the complex metabolism of TBBPA in oxic soil and suggests that type II ipso-substitution could play a significant role in the fate of alkylphenol derivatives in the environment. PMID- 25038378 TI - [Turkish validation study of Morisky 8-item medication adherence questionnaire (MMAS-8) in patients with asthma and chronic obstructive pulmonary disease]. AB - INTRODUCTION: Chronic diseases are the major causes of death in the world, and chronic respiratory diseases are important public health problems in our country due to theirhigh mortality and morbidity rates. Adherence to medication is an important issue in the treatment of these diseases. Morisky-8 item medication adherence questionnaire is one of the most widely used instruments for this purpose in the world. This study aimed to validate this scale in Turkish patients. MATERIALS AND METHODS: Turkish translation of Morisky-8 item scale consisted forward translation to Turkish, Turkish linguistic controls, back translation into English, English linguistic controls, and reporting of the process by the physician. Then, Turkish version of the scale was applied to the patients, and evaluated whether the patients understand the questions accurately. Fifty nine patients were included in this study, whomwere consulted in Gazi University Faculty of Medicine Department of Chest Diseases, and met the inclusion criteria. RESULTS: Mean ages of patients with asthma and chronic obstructive pulmonary disease (COPD) were 46.2 +/- 15.1 and 64.0 +/- 12.1 years, and duration of these diseases were 96.5 +/- 102.3 and 66.2 +/- 71.5 months, respectively. Patients had similar lengths of drug use. There was no significant differences for responses between groups, but two patients misunderstood two questions, and the remaining questions understood well by the patients. Medication adherence was 74.2% in patients with asthma, and 46.4% in patients with COPD. CONCLUSION: Turkish version of Morisky-8 scale was shown to be a reliable tool for determining the medication adherence in patients with asthma and COPD. PMID- 25038379 TI - The opinion of catering sector about the smoking ban and the evaluation of establishments. AB - INTRODUCTION: We aimed to evaluate the knowledge and perspective of employees/employers in the catering sector in our city regarding the smoking ban, as well as to determine the changes in the number of customers and income after the bans implementation. MATERIALS AND METHODS: In this two phased cross sectional study 337 and 310 adults were evaluated respectively. Before the smoking ban was implemented we visited 84 workplaces in city center, after 18 months later 97 workplaces were visited in the same region. In both phases, the participants' opinions about the necessity/applicability of the ban were evaluated. In the second phase, they were also asked whether they had any changes in their income. RESULTS: In both phases, participants' general characteristics were similar. When all participants were evaluated, we determined that their knowledge and belief in the necessity/applicability of the ban did not change over time. It was determined that non-smokers more strongly believed in the necessity/applicability of the ban. Thirty-eight participants were included in both phases; 44.7% of them reported a decrease in the number of customers, and 60% of employers reported an increase in their income. CONCLUSION: The smokers were less convinced about the applicability/necessity of this ban than non smokers. According to our results it could be said that smoking can also adversely affect implementation of the related ban. Employers should be informed that the ban will not affect their income. PMID- 25038380 TI - Comparison of QuantiFERON-TB gold in-tube test with tuberculin skin test in children who had no contact with active tuberculosis case. AB - INTRODUCTION: In this study, we aimed to compare QuantiFERON-TB gold in-tube test (QFT-GIT) and tuberculin skin test (TST) as a diagnosis of latent tuberculosis infection in the children with Bacille Calmette-Guerin (BCG) vaccine. MATERIALS AND METHODS: We evaluated 81 children in the study who have positive TST result without a known history of tuberculosis contact from 2008 to 2011 prospectively. Patients were separated into groups according to their ages, the reason of TST application, number of BCG vaccination scars and diameter of TST induration. Posteroanterior, lateral chest radiographies and computerized tomography, if necessary, were performed. RESULTS: The study consists of 48 (59.3%) boys and 33 (40.7%) girls with a mean age of 94.8 +/- 51.9 months (ranged from 6 to 193 months). Sixty nine (85.2%) children had one and 12 (14.8%) had two BCG vaccination scars. The TST induration diameters were 15-19 mm in 65 (80.2%) children and >= 20 mm in 16 (19.8%) children. QFT-GIT positivity was found in 12 (14.8%) of the evaluated patients. QFT-GIT positive patients were treated with triple anti-tuberculosis regime or isoniazid (INH). In three years period of study, there were no tuberculosis disease observed among the children who had not been treated with anti-tuberculosis drugs. CONCLUSION: As a result of the study it is suggested to confirm positive TST results with tests based on interferon gamma (IFN-gamma) because it can reduce false positive diagnosis and treatment of latent tuberculosis infection, thus adverse reactions of drugs, in countries where BCG vaccination is routinely recommended especially for low risk children. PMID- 25038381 TI - [Mycobacterium tuberculosis strains isolated from Van region four different sensitivity detection method antimycobacterial agents]. AB - INTRODUCTION: The purpose of this study is detecting the susceptibility rates of 58 Mycobacterium tuberculosis complex strains which were isolated from patient specimens sent to our mycobacteriology laboratory, for major anti-tuberculosis drugs like streptomycin, isoniazid, rifampicin and ethambutol with three different systems and agar proportion method and compare the accessibility, speed, specificity and sensitivity of these three systems. MATERIALS AND METHODS: With this purpose, 58 (96.6%) strains out of 60 which were isolated from the patients attended to the mycobacteriology laboratory were identified as M. tuberculosis complex with conventional methods. These strains susceptibilities to four major anti-tuberculosis drugs were detected with Manuel MGIT AST SIRE system, BacT/ALERT 3D system MB/BacT SIRE, TK anti-TB system and compared with reference method in Middlebrook 7H10 media. RESULTS: As a result, INH resistance in Van province with agar proportion method was detected as 12%, followed by INH + RIF resistance of 1.7% and INH + SM resistance of 1.7%. These result compared with other studies conducted country wide are in median range. The systems included in our study were determined to have 100% sensitivity for all of the drugs for detecting resistance and sensitivity rates. Specificities for INH for TK anti-TB, MGIT and MB/BacT were detected as 98%, 96% and 95% respectively. Multidrug resistance rates were detected in 100% sensitivity and specificity with all of the three systems. Only MB/BacT system gave a false negative RIF resistance for 1 strain. Fastest system according to resistance determination times is found to be the MGIT system. CONCLUSION: However, presence of INH + RIF resistance pattern, indicates inadequate treatment programs in our region. As a result these three systems are fast and reliable systems for antimicrobial susceptibility testing of Mycobacterium spp. to be used in routine mycobacteriology laboratories. PMID- 25038382 TI - [The frequency of performing smoking cessation outpatient clinic in chest disease specialists who are members of Turkish Thoracic Society and factors affecting this performance]. AB - INTRODUCTION: Although helping patients to stop smoking is a good clinical practice that has to be carried out by physicians everywhere and in every area, it is known that carrying out this help systematically in accordance to a programme in smoking cessation outpatient clinics significantly improves the chance of success. MATERIALS AND METHODS: The study is a cross-sectional survey performed among chest disease specialists who are members of Turkish Thoracic Society (TTS), between June 2010 and February 2011. As independent variables relevant to status of performing/not performing Smoking Cessation Outpatient Clinic (SCOC); sex, age (younger or older than 40), being graduated before or after 1996, being or not being in a consultant position, work place (Hospital of Ministry of Health/private hospital/university hospital), having or not having an education for smoking cessation help and being or not being member of a City Tobacco Control Committee (CTCC) were investigated. Data was collected via a web questionnaire prepared by using WHO Global Health Professionals Questionnaire which was sent to members through TTS secreteriat. RESULTS: 41% (699/1701) of members of TTS responded. 39.5% of responders reported that they perform SCOC. When the factors possibly affecting the performance of SCOC are evaluated with logistic regression analysis; being graduated after 1996, having an education for smoking cessation help, being a member of CTCC and not being an active smoker are found to improve this performance. CONCLUSION: Our study showed that having an education for smoking cessation help (and tobacco control) makes chest disease specialists get more responsibility on this topic. Accordingly, continuous efforts for improving awareness of personal and social responsibilities of all physicians, especially chest disease specialists, have to be made to provide their taking active roles in tobacco control. PMID- 25038383 TI - [Smoking related behaviours in Izmir]. AB - INTRODUCTION: The aim of the study is to determine the people's smoking related behaviours, using tobacco products except cigarette and characteristics about second hand smoke in Izmir. MATERIALS AND METHODS: Questionnaire including 47 questions was performed to 600 people, who were selected by Turkey Statistics Instutition to present population of Izmir. RESULTS: 53.7% of participants were female and 46.3% was male; the mean age was 41.5 +/- 15.6. 232 (39%) were smoking, 257 (42%) never smoked and 111 (19%) quited smoking. The average age for a new smoker is 18.7 +/- 6.6; men start smoking earlier than women statistically (p= 0.0001). 10.7% of participants were using tobacco products except cigarette. The smoke cessation percentage of women was statistically significantly higher than men(p= 0.006). 70.7% of active smokers were thinking about quitting. CONCLUSION: The frequency of smoking was higher than Turkey's avarage in Izmir. The mean age of starting smoking was below 18. There must be extra effort for preventing women and under 18 age who are the targets of tobacco industry from smoking. Use of tobacco products except cigarette, especially water pipe may be an emerging problem for men, high education level and under age of 35 population. Although most of the participants know about their rights of protection from smoke and the harms of second hand smoke, it is worrying to see that children have to face second hand smoke in special ownerships. Most of the smokers think to quit smoking and use medical methods for quitting. The people who think about quitting should be guided to smoking cessation clinics; by this way, the more we use scientific methods for quitting, the more we get high quit rates of smoking. PMID- 25038384 TI - Skin metastasis from small cell lung cancer. AB - Patients with skin metastasis always had disseminated metastases in many organs. We herein report an unusual case with skin metastasis from small cell lung cancer (SCLC). The patient was treated with platinum-containing chemotherapy, and the response to the therapy was evaluated as partial response. The patient had slowly progressive disease and died of SCLC 16 months after the diagnosis of the diseases. If skin lesions, whether it may be typical or not, are found in SCLC patients, biopsy from the lesion would be considered to perform. Although trunk may be the most common sites, it is important to suspect such metastasis occurs in patients with SCLC. PMID- 25038385 TI - Catamenial hemoptysis: a case report. AB - Herein we present a 25-year-old female patient who was admitted with recurrent hemoptysis in menstrual period. At the thorax computed tomography taken during menstruation of patient, diffuse ground glass density and acinar nodules at superior segment of lower lobe at left lung were detected. There was no this findings at the thorax tomography taken in non-menstruation period. Therefore, patient was considered catamenial hemoptysis with clinical and radiological findings. Pulmonary endometriosis is rarely seen disease of the lung, so we are presenting it in the light of the literature knowledge. PMID- 25038386 TI - [The risk of pneumococcal diseases in lung diseases and the importance of adult vaccination]. PMID- 25038387 TI - [Since little time remained to 2015; how far Turkey has achieved to reach the tuberculosis targets?]. AB - Tuberculosis still continues to be a globally major health problem. The one of the priorities of Millennium Development Goals, which was adopted by "United Nations Summit" in 2000 to overcome the obstacles in the development of countries is tuberculosis. The targets about the tuberculosis are the outcome indicators which are used to evaluate of effectiveness in tuberculosis's control. By the effective activities of the national tuberculosis control program; the "Millennium Development Goals" and "Stop TB Strategy Goals" have been completely achieved in Turkey before 2015. PMID- 25038388 TI - [Asthma, environment and epigenetic]. AB - Epigenetic defines long-lasting changes in gene expression independently from DNA sequence. Current evidence revealed that epigenetic mechanisms may have role into immune response and asthma. The purpose of this article is to review basic epigenetic mechanisms in asthma. PMID- 25038389 TI - FDG-PET/CT scan in a skin metastasis from lung cancer. PMID- 25038390 TI - Lung cancer superimposed opacity of aortic arch. PMID- 25038391 TI - Tracheoesophageal fistula in a treatment naive patient with lung cancer. PMID- 25038392 TI - Inhibition of p38 mitogen-activated protein kinase activation in the rostral anterior cingulate cortex attenuates pain-related negative emotion in rats. AB - The emotional components of pain are far less studied than the sensory components. Previous studies have indicated that the rostral anterior cingulate cortex (rACC) is implicated in the affective response to noxious stimuli. Activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord has been documented to play an important role in diverse kinds of pathological pain states. We used formalin-induced conditioned place aversion (F-CPA) in rats, an animal model believed to reflect the emotional response to pain, to investigate the involvement of p38 MAPK in the rACC after the induction of affective pain. Intraplantar formalin injection produced a significant activation of p38 MAPK, as well as mitogen-activated kinase kinase (MKK) 3 and MKK6, its upstream activators, in the bilateral rACC. p38 MAPK was elevated in both NeuN-positive neurons and Iba1-positive microglia in the rACC, but not GFAP-positive cells. Blocking p38 MAPK activation in the bilateral rACC using its specific inhibitor SB203580 or SB239063 dose-dependently suppressed the formation of F-CPA. Inhibiting p38 MAPK activation did not affect formalin-induced two-phase spontaneous nociceptive response and low intensity electric foot-shock induced CPA. The present study demonstrated that p38 MAPK signaling pathway in the rACC contributes to pain-related negative emotion. Thus, a new pharmacological strategy targeted at the p38 MAPK cascade may be useful in treating pain-related emotional disorders. PMID- 25038393 TI - Response to: "Cancer risk due to contamination: consideration from market basket survey in Qatar". PMID- 25038394 TI - Evaluation of the mutagenicity and genotoxic potential of carvacrol and thymol using the Ames Salmonella test and alkaline, Endo III- and FPG-modified comet assays with the human cell line Caco-2. AB - Currently, direct antimicrobial and antioxidant additives derived from essential oils are used in food packaging and are perceived by consumers as low-health-risk compounds. In this study, we investigated the potential mutagenicity and genotoxicity of carvacrol and thymol, major compounds in several essential oils, using the Ames Salmonella test and the alkaline, Endo III- and formamidopyrimidine glycosylase (FPG)-modified comet assays, respectively. Thymol did not show any mutagenic activity at any concentration assayed (0-250 MUM), whereas carvacrol exhibited mutagenic potential, displaying greater activity in presence of the metabolic fraction (29-460 MUM). The genotoxic effects were evaluated in the human colon carcinoma cell line Caco-2, and the standard comet assay revealed that neither carvacrol (0-460 MUM) nor thymol (0-250 MUM) had any affects at 24 and 48 h. The FPG-modified comet assay showed that the highest concentration of carvacrol (460 MUM) caused DNA damage, indicating damage to the purine bases. These results should be used to identify the appropriate concentrations of carvacrol and thymol as additives in food packaging. Moreover, further studies are necessary to explore the safety and/or the toxicity mechanisms of these compounds. PMID- 25038395 TI - Estimated versus measured glomerular filtration rate in children before hematopoietic cell transplantation. AB - An accurate assessment of kidney function before hematopoietic cell transplantation (HCT) can help to properly dose conditioning chemotherapy and follow patients for the development of chronic kidney disease. We cross sectionally examined 94 children and young adults before HCT to compare formal nuclear glomerular filtration rate (GFR) testing with estimated GFR using creatinine and cystatin C-based equations, including the original Schwartz formula and the more recent formulas developed in the Chronic Kidney Disease in Children (CKiD) cohort. The median age of the cohort was 5.9 years (range, .26 to 30.5 years). The mean cohort nuclear GFR was 107.4 +/- 24.7 mL/min/1.73 m(2), with 18 of 94 subjects (19.1%) having abnormal kidney function (GFR < 90 mL/min/1.73 m(2)) before HCT. The creatinine-based original Schwartz and bedside CKiD formulas showed significant bias, overestimating the nuclear GFR by 57.4 (95% confidence interval [CI], 49.0 to 65.8) and 14.1 (95% CI, 7.1 to 21.1) mL/min/1.73 m(2), respectively. Cystatin C formulas had less mean bias and improved accuracy but also had decreased sensitivity to detect abnormal kidney function before HCT. The Full CKiD equation showed the best performance, with a mean bias of -3.6 mL/min/1.73 m(2) (95% CI, -8.4 to 1.2) that was not significantly different from the measured value and 87.7% of estimates within +/ 30% of the nuclear GFR. Although the more recent bedside CKiD formula performed better than the original Schwartz formula, both formulas had poor sensitivity for detecting a low GFR. An abnormal pretransplant nuclear GFR was not associated with post-HCT acute kidney injury, the need for dialysis, or death in the first 100 days. In conclusion, we observed cystatin C-based equations outperformed creatinine-based equations in estimating GFR in children before HCT. However, all formulas had decreased sensitivity to detect impaired GFR. Formal measurement of kidney function should be considered in children and young adults who need an accurate assessment of kidney function before HCT. PMID- 25038396 TI - Helicobacter pylori infection and gastric cardia cancer in Chaoshan region. AB - Helicobacter pylori (H. pylori) infection represents the most important risk factor for gastric cancer, while its association with gastric cardia cancer (GCC) has not been recognized yet. In this current study, we aim to investigate the status of H. pylori infection in the gastric cardia tissue samples from high-risk populations in Chaoshan littoral region, and the relationship between H. pylori infection and chronic inflammation as well as the proliferative activity of the gastric cardia epithelial cells. A total of 706 gastric cardia biopsy specimens were obtained from 372 GCC cases and 334 tumor-free controls in Chaoshan littoral, a high-risk region for esophageal and gastric cardia cancer. Immunohistochemistry and Giemsa staining were employed for the verification of H. pylori infection. H. pylori infection rate was significantly higher in GCC (81.5%, P < 0.01) and gastric carditis (80.1%, P < 0.01) in comparison with that in the healthy group (34.8%). A significant higher prevalence of chronic inflammation was found in H. pylori+ samples (96.9%) than that in H. pylori- specimens (80.5%) (P < 0.01). To explore the possible role of H. pylori infection related chronic inflammation in the GCC, we found that the expression of Ki-67 was progressively increased in tissues with chronic inflammation degrees from normal to severe inflammation (P < 0.01). Collectively, these results suggest that persistent H. pylori infection and the related chronic inflammation may contribute to the high incidence of GCC in Chaoshan littoral. PMID- 25038399 TI - The robustness and innovability of protein folds. AB - Assignment of protein folds to functions indicates that >60% of folds carry out one or two enzymatic functions, while few folds, for example, the TIM-barrel and Rossmann folds, exhibit hundreds. Are there structural features that make a fold amenable to functional innovation (innovability)? Do these features relate to robustness--the ability to readily accumulate sequence changes? We discuss several hypotheses regarding the relationship between the architecture of a protein and its evolutionary potential. We describe how, in a seemingly paradoxical manner, opposite properties, such as high stability and rigidity versus conformational plasticity and structural order versus disorder, promote robustness and/or innovability. We hypothesize that polarity--differentiation and low connectivity between a protein's scaffold and its active-site--is a key prerequisite for innovability. PMID- 25038397 TI - Valley fever: danger lurking in a dust cloud. AB - Coccidioides immitis and Coccidioides posadasii contribute to the development of Valley Fever. The ability of these fungal pathogens to evade the host immune system creates difficulty in recognition and treatment of this debilitating infection. In this review, we describe the current knowledge of Valley Fever and approaches to improve prevention, detection, and treatment. PMID- 25038398 TI - Production of feather hydrolysates with antioxidant, angiotensin-I converting enzyme- and dipeptidyl peptidase-IV-inhibitory activities. AB - The antioxidant and antihypertensive activities of feather hydrolysates obtained with the bacterium Chryseobacterium sp. kr6 were investigated. Keratin hydrolysates were produced with different concentrations of thermally denatured feathers (10-75 g l(-1)) and initial pH values (6.0-9.0). Soluble proteins accumulated in high amounts in media with 50 and 75 g l(-1) of feathers, reaching values of 18.5 and 22 mg ml(-1), respectively, after 48 hours of cultivation. In media with 50 g l(-1) of feathers, initial pH had minimal effect after 48 hours. Maximal protease production was observed after 24 hours of cultivation, and feather concentration and initial pH values showed no significant effect on enzyme yields at this time. Feather hydrolysates displayed in vitro antioxidant properties, and optimal antioxidant activities were observed in cultures with 50 g l(-1) feathers, at initial pH 8.0, after 48 hours growth at 30 degrees C. Also, feather hydrolysates were demonstrated to inhibit the angiotesin I-converting enzyme by 65% and dipeptidyl peptidase-IV by 44%. The bioconversion of an abundant agroindustrial waste such as chicken feathers can be utilized as a strategy to obtain hydrolysates with antioxidant and antihypertensive activities. Feather hydrolysates might be employed as supplements in animal feed, and also as a potential source of bioactive molecules for feed, food and drug development. PMID- 25038400 TI - Chronic pain prevalence and associated factors in a segment of the population of Sao Paulo City. AB - A cross-sectional epidemiologic survey was performed to determine the prevalence of chronic pain (CP) and to identify associated factors in a random sample of persons 15 years or older from a segment of the population of Sao Paulo City, Brazil. A total of 1,108 eligible participants were randomly selected, and face to-face interviews were performed with 826 individuals (74.5%) between December 2011 and February 2012. Chronic Pain Grade, Hospital Anxiety and Depression Scale, and EuroQol-5D were used to verify pain characteristics and the associated signs of psychological distress. A prevalence of 42% (95% confidence interval, 38.6-45.4) was observed for CP, and the participants with CP had an average pain intensity of 5.9 (standard deviation = 1.9) and a pain-related disability of 4.1 (standard deviation = 3.2) on a 0 to 10 scale. Persistent pain was present in 68.6% of those with CP, and 32.8% of the population sample had high-intensity or high-interference pain (Chronic Pain Grade II, III, and IV). Quality of life was significantly worse among the CP individuals. The following factors were independently associated with CP: female gender, age 30 years or older, <= 4 years of education, symptoms consistent with anxiety, and intense physical strain. Indicators of pain severity increased with pain grades. PERSPECTIVE: CP is highly prevalent in the city of Sao Paulo and has a considerable impact on health-related quality of life. Demographic, socioeconomic, and psychological factors are independently associated with this condition. PMID- 25038401 TI - Longitudinal interactions of pain and posttraumatic stress disorder symptoms in U.S. Military service members following blast exposure. AB - Military personnel returning from conflicts in Iraq and Afghanistan often endorse pain and posttraumatic stress disorder (PTSD) symptoms, either separately or concurrently. Associations between pain and PTSD symptoms may be further complicated by blast exposure from explosive munitions. Although many studies have reported on the prevalence and disability associated with polytraumatic injuries following combat, less is known about symptom maintenance over time. Accordingly, this study examined longitudinal interactive models of co-occurring pain and PTSD symptoms in a sample of 209 military personnel (mean age = 27.4 years, standard deviation = 7.6) who experienced combat-related blast exposure. Autoregressive cross-lagged analysis examined longitudinal associations between self-reported pain and PTSD symptoms over a 1-year period. The best-fitting covariate model indicated that pain and PTSD were significantly associated with one another across all assessment periods, chi2 (3) = 3.66, P = .30, Tucker-Lewis index = .98, comparative fit index = 1.00, root mean squared error of approximation = .03. PTSD symptoms had a particularly strong influence on subsequent pain symptoms. The relationship between pain and PTSD symptoms is related to older age, race, and traumatic brain injury characteristics. Results further the understanding of complex injuries among military personnel and highlight the need for comprehensive assessment and rehabilitation efforts addressing the interdependence of pain and co-occurring mental health conditions. PERSPECTIVE: This longitudinal study demonstrates that pain and PTSD symptoms strongly influence one another and interact across time. These findings have the potential to inform the integrative assessment and treatment of military personnel with polytrauma injuries and who are at risk for persistent deployment related disorders. PMID- 25038402 TI - Transcriptional regulation of gene expression of infectious salmon anaemia virus segment 7. AB - The nuclear replication and gene splicing of orthomyxoviruses are unique among RNA viruses. Segment 7 of infectious salmon anaemia virus (ISAV) is the only segment that undergoes splicing. Two proteins are encoded by this segment, the non-structural antagonist (ISAV-NS) of the innate immune response that is translated from the unspliced collinear transcript, and a nuclear exporting protein (ISAV-NEP) that is translated from the spliced mRNA. Here we report the transcription profiles for these ISAV proteins. The appearance of the spliced ISAV-NEP mRNA was delayed and the relative amount was less but slowly accumulated to 20-30% to that of the collinear NS mRNA. In cells transfected with segment 7 the ratio between spliced and collinear mRNA was approximately 10%. A highly conserved, possible structured RNA, in the region of the 3' splicing site of the segment is speculated as being important for the regulation of the efficiency of the splicing. PMID- 25038403 TI - MicroRNAs responding to southern rice black-streaked dwarf virus infection and their target genes associated with symptom development in rice. AB - Southern rice black-streaked dwarf virus (SRBSDV) is a recently emerged rice virus that has spread across Asia. This devastating virus causes rice plants to produce a variety of symptoms during different growth stages. MicroRNAs (miRNAs) comprise a large group of 21-24-nt RNA molecules that are important regulators of plant development processes and stress responses. In this study, we used microarray profiling to investigate rice miRNAs responding to SRBSDV infection at 3, 9, 15, and 20 days post-inoculation (dpi). Expression levels of 56 miRNAs were altered in SRBSDV-infected rice plants, with these changes classified into eight different regulation patterns according to their temporal expression dynamics. Fourteen miRNAs belonging to six families (miR164, R396, R530, R1846, R1858, and R2097) were significantly regulated at 20 dpi. We used RT-qPCR to search for expression level correlations between members of these families and their putative targets at 3, 9, and 15 dpi. Some members of the miR164, R396, R530, and R1846 families were found to be positively or negatively correlated with their respective targets during 3-15 days after SRBSDV infection, whereas in more cases the rice miRNAs were not in correlation with their targets along the post inoculation period, suggesting that some additional factors may be involved in rice miRNA-target interactions. The reported functions of rice genes targeted by the miR164, R396, R530, R1846, and R1858 families indicated that these genes are associated with symptom development. These results provide insights into miRNA mediated SRBSDV-rice interactions. PMID- 25038404 TI - Human APOBEC3F incorporation into human immunodeficiency virus type 1 particles. AB - APOBEC3 proteins are a family of cytidine deaminases that exhibit broad antiretroviral activity. Among APOBEC3 proteins, APOBEC3G (hA3G) and APOBEC3F (hA3F) exhibit the most potent anti-HIV-1 activities. Although the incorporation of hA3F into virions is a prerequisite for exerting its antiviral function, the detail mechanism underlying remains incompletely understood. In this work, we present data showing that the nucleocapsid (NC) domain of HIV-1 Gag and a linker sequence between the two cytidine deaminase domains within hA3F, i.e., 104-156 amino acids, are required for viral packaging of hA3F. A detailed mapping study reveals that the cluster of basic residues surrounding the N-terminal zinc finger (ZF) and the linker region between the ZFs of HIV-1 NC play an important role in A3F incorporation, in addition, at least one of two ZFs is required. A hA3F fragment is able to compete with both hA3G and hA3F for viral incorporation, suggesting a common mechanism underlying virion encapsidation of hA3G and hA3F. Taken together, these results shed a light on the detail mechanism underlying viral incorporation of hA3F. PMID- 25038405 TI - The control of anaplastic thyroid carcinoma cell lines by oncolytic poxviruses. AB - BACKGROUND AND SIGNIFICANCE: Anaplastic thyroid cancer (ATC) is rare, but its clinical presentation is often dramatic and aggressive and is nearly uniformly fatal. Oncolytic viral therapy is a potential strategy to improve outcomes for patients suffering with this disease. METHODS: Seven established ATC cell lines were infected with a panel of poxviruses to identify which virus had the most potential as an oncolytic agent. These included myxoma, vaccinia, and tanapox viruses, all modified to express green fluorescence protein (GFP). Viral proliferation was assessed by fluorescence and viral amplification. The effect on cell line growth was assessed by the Presto Blue metabolic assay and a live-dead assay. A replication assay was performed to assess the production of infectious progeny. An additional five ATC cell lines were tested using the assays described above for susceptibility to vaccinia virus. RESULTS: ATC cell lines were differentially susceptible to each virus. Vaccinia virus was superior to myxoma and tanapox viruses for the control of anaplastic thyroid cancer in vitro. Although subsequent investigation using an expanded panel of cell lines revealed differential susceptibility to vaccinia virus, effective control of cell proliferation was still achieved using higher titers. CONCLUSIONS: Vaccinia virus was the most potent of the tested poxviruses and was highly effective in controlling proliferation and inducing cell death in ATC cell lines. The efficacy of these viruses offers hope for improving outcomes for patients suffering with ATC. PMID- 25038406 TI - The associations of meals and snacks on family meals among a sample of grade 7 students from Southwestern Ontario. AB - BACKGROUND: Research has shown the positive associations of family meals and diet quality. However, little is known about how other meals/snacks may be associated with family meals. OBJECTIVE: The purpose was to determine the associations among the frequency and calorie consumption of meals/snacks and family dinners. DESIGN: Cross-sectional. Data were collected using Web-based Eating Behaviour Questionnaire (WEB-Q), including a 24-h diet recall for breakfast, morning snack, lunch, afternoon snack, dinner, and evening snack. Measured height and weight were used to determine body weight status (BMI). PARTICIPANTS/SETTING: Participants included 1068 grade 7 students (52% males) from 26 schools in Windsor Essex County, Ontario, Canada. MAIN OUTCOME MEASURES: Meal, snack, and total daily caloric intake; meal and snack frequency; with whom dinner was consumed, and weekly family dinner frequency. STATISTICAL ANALYSES PERFORMED: Exploratory one-way ANOVAs and chi-square tests; nominal and ordinal logistic regression. RESULTS: Ninety-three percent of participants consumed dinner with family members on the night prior to the survey and 77% reported usually consuming dinner/supper with at least one parent on six to seven nights/week. Those who had dinner with family members consumed 4.88 (SD 1.1) meals/snacks per day compared with 4.40 (SD 1.3) and 4.40 (SD 1.3) times/day for consuming dinner alone or with friends, respectively (p=0.006). On the day prior to the survey, participants were less likely to consume a family meal if they consumed a lower number of meals and snacks per day (OR=0.69 (95% CI: 0.55, 0.87), p<0.001). Similarly, participants were less likely to consume regular family meals if they consumed a lower number of meals and snacks per day (OR=0.84 (95% CI: 0.74, 0.96), p=0.009). CONCLUSIONS: While specific meals and snacks were not associated with family dinner, overall eating frequency was positively associated with family meals. PMID- 25038407 TI - Interpretive front-of-pack nutrition labels. Comparing competing recommendations. AB - Many stakeholders support introducing an interpretive front-of-pack (FOP) nutrition label, but disagree over the form it should take. In late 2012, an expert working group established by the New Zealand government recommended the adoption of an untested summary rating system: a Star label. This study used a best-worst scaling choice experiment to estimate how labels featuring the new Star rating, the Multiple Traffic Light (MTL), Daily Intake Guide (DIG), and a no FOP control affected consumers' choice behaviours and product perceptions. Nutrient-content and health claims were included in the design. We also assessed whether respondents who used more or less information during the choice tasks differed in their selection patterns. Overall, while respondents made broadly similar choices with respect to the MTL and Star labels, the MTL format had a significantly greater impact on depressing preference as a food's nutritional profile became less healthy. Health claims increased rankings of less nutritious options, though this effect was less pronounced when the products featured an MTL. Further, respondents were best able to differentiate products' healthiness with MTL labels. The proposed summary Stars system had less effect on choice patterns than an MTL label and our findings highlight the need for policy makers to ensure that decisions to introduce FOP labels are underpinned by robust research evidence. These results suggest that the proposed summary Stars system will have less effect on shifting food choice patterns than interpretive FOP nutrition label featuring traffic light ratings. PMID- 25038408 TI - An LC-MS/MS method for the simultaneous determination of goserelin and testosterone in rat plasma for pharmacokinetic and pharmacodynamic studies. AB - A liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI MS/MS) method was developed, using testosterone-d3 as a surrogate analyte, for the simultaneous quantification of goserelin and testosterone in rat plasma. According to this method, the pharmacokinetic and pharmacodynamic data were obtained from a single plasma sample aliquot. The method involved the addition of alarelin as an internal standard (IS) for goserelin and testosterone-(13)C3 for testosterone or testosterone-d3. The conditions for the separation of these two compounds were achieved on a ZORBAX Eclipse Plus C18 column (Agilent, 2.1 * 50 mm, 1.8 MUm, Stockport, UK) in a single chromatographic run at a flow rate of 400 MUL/min. In order to minimize interferences of complex matrix, the extraction of plasma consisted of a protein precipitation step using methanol, followed by purification using an Oasis((r)) HLB solid-phase extraction column. The method was validated in the concentration range of 0.01-30.0 ng/mL for goserelin and 0.05-30.0 ng/mL for testosterone-d3, respectively. The within- and between-run precisions were 1.7-9.2% and 2.1-6.9%, respectively. The within- and between-run accuracies were -1.8 to 5.3% and -4.9 to 4.0%, respectively. This accurate and highly specific assay provides a useful method to evaluate the pharmacokinetics and pharmacodynamics of goserelin in rats. PMID- 25038409 TI - Characterization of the non-specific DNA binding properties of the Adenoviral IVa2 protein. AB - Human Adenovirus (Ad) is a non-enveloped, icosahedral virus with a linear, double stranded DNA genome. The Ad IVa2 protein is involved in multiple viral processes including viral late gene transcription and virus assembly. Previous studies have shown that IVa2 loads additional viral proteins onto conserved DNA elements within the Ad genome to regulate these viral processes. IVa2 also possesses strong non-specific DNA binding activity, and it is likely it uses this activity to recruit proteins to the conserved DNA elements. Here we have investigated the non-specific DNA binding activity of IVa2 using nitrocellulose/DEAE filter binding and sedimentation equilibrium techniques. We have analyzed our data using the McGhee and Von Hippel approach [1], and find that IVa2 binds with strong, positive nearest-neighbor cooperativity. In addition, we describe how to apply the McGhee and von Hippel approach to directly analyze sedimentation equilibrium data using non-linear least-squares methods. We discuss the implications of these results with respect to current virus assembly mechanisms. PMID- 25038410 TI - RNA binding of PRC2: promiscuous or well ordered? AB - The polycomb repressive complex 2 (PRC2) methylates histones for epigenetic silencing and associates with thousands of protein-coding and noncoding RNAs. How the recruitment of PRC2 to specific sites is facilitated is currently unclear. Two recent studies have deciphered the impact of RNA binding on PRC2 recruitment and activity (Cifuentes-Rojas et al., 2014; Davidovich et al., 2013). PMID- 25038411 TI - Localization of NADPH production: a wheel within a wheel. AB - In this issue of Molecular Cell, Lewis et al. (2014) describe a new method to determine where in the cell NADPH is produced, contributing to a growing appreciation that the THF cycle is an important source of mitochondrial NADPH. PMID- 25038412 TI - A million peptide motifs for the molecular biologist. AB - A molecular description of functional modules in the cell is the focus of many high-throughput studies in the postgenomic era. A large portion of biomolecular interactions in virtually all cellular processes is mediated by compact interaction modules, referred to as peptide motifs. Such motifs are typically less than ten residues in length, occur within intrinsically disordered regions, and are recognized and/or posttranslationally modified by structured domains of the interacting partner. In this review, we suggest that there might be over a million instances of peptide motifs in the human proteome. While this staggering number suggests that peptide motifs are numerous and the most understudied functional module in the cell, it also holds great opportunities for new discoveries. PMID- 25038415 TI - Disrupting SMA activity modulates explicit and implicit emotional responses: an rTMS study. AB - Supplementary Motor Area (SMA) has been considered as an interface between the emotional/motivational system and motor effector system. Here, we investigated whether it is possible to modulate emotional responses using non-invasive brain stimulation of the SMA. 1Hz repetitive transcranial magnetic stimulation (rTMS) trains were applied over the SMA of healthy subjects performing a task requiring to judge the valence and arousal of emotional stimuli. rTMS trains over the SMA increased the perceived valence of emotionally negative visual stimuli, while decreasing the perceived valence of emotionally positive ones. The modulatory effect on emotional valence was specific for stimuli with emotional content, since it was not observed for neutral visual stimuli. The effect was also specific for the site of stimulation, since rTMS of the visual cortex failed to modulate either perceived valence or arousal. These findings provide the first example of neuromodulation of emotional responses based on non-invasive brain stimulation. PMID- 25038413 TI - Dynamic heterogeneity and DNA methylation in embryonic stem cells. AB - Cell populations can be strikingly heterogeneous, composed of multiple cellular states, each exhibiting stochastic noise in its gene expression. A major challenge is to disentangle these two types of variability and to understand the dynamic processes and mechanisms that control them. Embryonic stem cells (ESCs) provide an ideal model system to address this issue because they exhibit heterogeneous and dynamic expression of functionally important regulatory factors. We analyzed gene expression in individual ESCs using single-molecule RNA FISH and quantitative time-lapse movies. These data discriminated stochastic switching between two coherent (correlated) gene expression states and burst-like transcriptional noise. We further showed that the "2i" signaling pathway inhibitors modulate both types of variation. Finally, we found that DNA methylation plays a key role in maintaining these metastable states. Together, these results show how ESC gene expression states and dynamics arise from a combination of intrinsic noise, coherent cellular states, and epigenetic regulation. PMID- 25038414 TI - Intergeniculate leaflet lesions result in differential activation of brain regions following the presentation of photic stimuli in Nile grass rats. AB - The intergeniculate leaflet (IGL) plays an important role in the entrainment of circadian rhythms and the mediation of acute behavioral responses to light (i.e., masking). Recently, we reported that IGL lesions in diurnal grass rats result in a reversal in masking responses to light as compared to controls. Here, we used Fos as a marker of neural activation to examine the mechanisms by which the IGL may influence this masking effect of light in grass rats. Specifically, we examined the patterns of Fos activation in retinorecipient areas and in brain regions that receive IGL inputs following 1-h light pulses given during the early night in IGL-lesioned and sham-operated grass rats. Three patterns emerged: (1) IGL lesions had no effect on the Fos response to light, (2) IGL lesions resulted in a reversal in Fos responses to light, and (3) IGL lesions resulted in a lack of a Fos response to light. Of specific interest were the suprachiasmatic nucleus (SCN) and the olivary pretectal nucleus (OPT), both of which are retinorecipient and connect reciprocally with the IGL. Light-induced Fos expression in the SCN was unaffected by IGL lesions, whereas the OPT exhibited a significant reduction in Fos expression following a light pulse in animals with IGL lesions. Altogether, our results suggest that the OPT, but not the SCN, exhibits a reversal in Fos responses to light following IGL lesions that reverse masking responses in diurnal grass rats. Our results suggest that interconnections between the IGL and downstream brain areas (e.g., OPT) may play a role in determining the direction of the behavioral response to light. PMID- 25038416 TI - Effects of transcranial magnetic stimulation during voluntary and non-voluntary stepping movements in humans. AB - Here, we compared motor evoked potentials (MEP) in response to transcranial magnetic stimulation of the motor cortex and the H-reflex during voluntary and vibration-induced air-stepping movements in humans. Both the MEPs (in mm biceps femoris, rectus femoris and tibialis anterior) and H-reflex (in m soleus) were significantly smaller during vibration-induced cyclic leg movements at matched amplitudes of angular motion and muscle activity. These findings highlight differences between voluntary and non-voluntary activation of the spinal pattern generator circuitry in humans, presumably due to an extra facilitatory effect of voluntary control/triggering of stepping on spinal motoneurons and interneurons. The results support the idea of active engagement of supraspinal motor areas in developing central pattern generator-modulating therapies. PMID- 25038417 TI - Does outstretching the arms improve postural stability? AB - We spontaneously outstretch our arms when standing upon challenging surfaces, yet the effect of stretching the arms upon postural stability is unknown. We investigated whether stretching out the arms laterally improves postural control during tandem stance on a narrow beam. Twelve healthy participants stood upon a beam, right foot in front of the left foot, for 30s with arms outstretched or down to the side, with eyes open and closed. Mediolateral head movement was characterised by Root Mean Square amplitude (RMS), sway path, velocity during the largest excursion and power spectrum. Spectra for lateral forces from a force platform beneath the beam were also recorded. Outstretching the arms significantly reduced RMS, sway path and velocity of maximum displacement of head movement with eyes closed but not with eyes open. A similar trend was present in the power spectra of head motion and sway platform lateral forces. In conclusion, outstretching the arms helps postural stability in challenging situations such as tandem stance on a narrow beam with eyes closed. Although the exact mechanisms require further investigation, the effects are most likely mediated by changes in segmental inertia and the ability to make corrective arm movements. PMID- 25038418 TI - Neuroprotection by Orexin-A via HIF-1alpha induction in a cellular model of Parkinson's disease. AB - Orexin-A, a neuropeptide secreted by hypothalamic neurons, may be neuroprotective in many neurological conditions such as cerebral ischaemia. One mechanism postulated to be involved in the neuroprotection by Orexin-A is the induction of hypoxia inducible factor 1 alpha (HIF-1alpha). Parkinson's disease (PD) is a progressive neurodegenerative disorder and mitochondrial dysfunction has been demonstrated to play a role in its pathogenesis. Mitochondrial dysfunction may cause reduction of O2 consumption and subsequently activate prolyl hydroxylase, which leads to decreased level of HIF-1alpha. In this study, we used MPP(+) treated SH-SY5Y cells as an in vitro cellular model of PD to test the role of Orexin-A as an inducer of HIF-1alpha. Our results showed that Orexin-A not only induced HIF-1alpha but also activated downstream targets of HIF-1alpha, such as vascular endothelial growth factor and erythropoietin. Thus, Orexin-A treatment attenuated MPP(+)-induced cell injury and this effect was blocked when HIF-1alpha was suppressed. Hence, we conclude that induction of HIF-1alpha is one of the mechanisms involved in the neuroprotection by Orexin-A. PMID- 25038419 TI - Promotion of mouse embryonic stem cell differentiation by Rho kinase inhibitor Y 27632. AB - Rho kinase (ROCK) is one of the major downstream mediators of Rho. Rho plays crucial regulatory roles in the cellular proliferation and differentiation. Because a ROCK inhibitor, Y-27632, is known to inhibit the dissociation-induced cell death in human embryonic stem (ES) cells, we investigated the effects of this ROCK inhibitor on the differentiation of the mouse ES cells. The ROCK inhibitor promoted the differentiation of the ES cells into neurons, particularly motor and sensory neurons. The addition of both ROCK inhibitor and nerve growth factor (NGF) strongly stimulated the differentiation of the ES cells into neurons. Moreover, the ROCK inhibitor promoted the differentiation of the ES cells into muscle cells. The ES cells primarily differentiated into neurons rather than muscle cells. We found that the ROCK inhibitor may promote the neuronal differentiation of the ES cells by activating the extracellular signal regulated kinase (ERK) signaling pathway. These results suggest that the ROCK inhibitor has a significant potential to regulate the differentiation of the ES cells. PMID- 25038420 TI - One's own country and familiar places in the mind's eye: different topological representations for navigational and non-navigational contents. AB - Visual mental imagery is a process that draws on different cognitive abilities and is affected by the contents of mental images. Several studies have demonstrated that different brain areas subtend the mental imagery of navigational and non-navigational contents. Here, we set out to determine whether there are distinct representations for navigational and geographical images. Specifically, we used a Spatial Compatibility Task (SCT) to assess the mental representation of a familiar navigational space (the campus), a familiar geographical space (the map of Italy) and familiar objects (the clock). Twenty one participants judged whether the vertical or the horizontal arrangement of items was correct. We found that distinct representational strategies were preferred to solve different categories on the SCT, namely, the horizontal perspective for the campus and the vertical perspective for the clock and the map of Italy. Furthermore, we found significant effects due to individual differences in the vividness of mental images and in preferences for verbal versus visual strategies, which selectively affect the contents of mental images. Our results suggest that imagining a familiar navigational space is somewhat different from imagining a familiar geographical space. PMID- 25038421 TI - DNA methyltransferase haplotype is associated with Alzheimer's disease. AB - Epigenetic mechanisms have been implicated in syndromes associated with neuropsychiatric disorders, but little is known about the role of epigenetics in Alzheimer's disease (AD). DNA methylation, one of the main epigenetic mechanisms, is a complex process carried out by specific enzymes, such as DNMT1 and DNMT3B. This study aimed to investigate the association between DNMT1 and DNMT3B polymorphisms and AD. Two hundred and ten elderly subjects (108 healthy controls and 102 with AD-NINCDS/ARDA, DSM-IV-TR criteria) were assessed. DNA was obtained from whole blood, and genotypes were detected by an allelic discrimination assay using TaqMan((r)) MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560, rs759920 (DNMT1) and rs998382, rs2424913, rs2424932 (DNMT3B). For both genes, the polymorphisms were in strong linkage disequilibrium. Carriers of the DNMT3B TGG haplotype were associated with AD (OR=3.03, 95% CI 1.63 to 5.63, P<0.001). No significant difference between AD and the control group were observed for DNMT1 polymorphisms. This study is one of the first describing a significant association between DNMT3B polymorphisms and AD. This enzyme, which is responsible for methylation in a general way, may be involved in AD. PMID- 25038422 TI - Depression following adult, non-penetrating traumatic brain injury: a meta analysis examining methodological variables and sample characteristics. AB - BACKGROUND: Depression is one of the most frequently reported psychological problems following TBI, however prevalence estimates vary widely. Methodological and sampling differences may explain some of this variability, but it is not known to what extent. METHODS: Data from 99 studies examining the prevalence of clinically diagnosed depression (MDD/dysthymia) and self-reports of depression (clinically significant cases or depression scale scores) following adult, non penetrating TBI were analysed, taking into consideration diagnostic criteria, measure, post-injury interval, and injury severity. RESULTS: Overall, 27% of people were diagnosed with MDD/dysthymia following TBI and 38% reported clinically significant levels of depression when assessed with self-report scales. Estimates of MDD/dysthymia varied according to diagnostic criteria (ICD 10: 14%; DSM-IV: 25%; DSM-III: 47%) and injury severity (mild: 16%; severe: 30%). When self-report measures were used, the prevalence of clinically significant cases of depression differed between scales (HADS: 32%; CES-D: 48%) method of administration (phone: 26%; mail 46%), post-injury interval (range: 33-42%), and injury severity (mild: 64%; severe: 39%). CONCLUSION: Depression is very common after TBI and has the potential to impact on recovery and quality of life. However, the diagnostic criteria, measure, time post-injury and injury severity, all impact on prevalence rates and must therefore be considered for benchmarking purposes. PMID- 25038423 TI - Reply to "The association of red blood cell distribution width and morbid obesity" by Aydin et al. PMID- 25038424 TI - Amoxicillin-associated interference in an HPLC-EC assay for urinary fractionated metanephrines: potential pitfall in pheochromocytoma biochemical diagnosis. AB - OBJECTIVE: Measurement of urinary fractionated metanephrines represents a first line test for the biochemical diagnosis of pheochromocytoma. The high performance liquid chromatography coupled to electrochemical detection (HPLC-EC) assays used in the routine clinical laboratory can be subjected to analytical interferences by the presence of drugs or their metabolites. In this paper we describe the interference on urinary normetanephrine (uNMN) caused by amoxicillin. DESIGN AND METHODS: Two pediatric patients suspected of pheochromocytoma had very high uNMN levels (2543 and 4227MUg/g Cr respectively; upper reference value: 339MUg/g Cr). Amoxicillin interference was assessed by comparison for co-elution with uNMN and by LC-MS/MS analysis. RESULTS: After amoxicillin interference was suspected and the therapy was stopped uNMN levels returned to normal (149 and 214MUg/g Cr respectively). Chromatograms obtained by HPLC-EC clearly showed that amoxicillin co-elutes with uNMN. Patients' uNMN levels measured by LC-MS/MS were in the normal range. CONCLUSION: Amoxicillin is responsible for analytical interference on HPLC-EC assay for uNMN. This finding can be of help in distinguishing true positive from false-positive results in the course of a biochemical diagnosis for pheochromocytoma. PMID- 25038425 TI - Use of synthetic urine as a matrix substitute for standard and quality control materials in the clinical assessment of iodine by inductively coupled plasma mass spectrometry. AB - OBJECTIVES: We developed and validated the use of synthetic urine as a matrix substitute for standard and quality control material preparation in the clinical assessment of iodine status in urine. DESIGN AND METHODS: Measurement of iodine in urine was conducted using inductively coupled-plasma mass spectrometry. Analytical and clinical recoveries were assessed to investigate comparability between synthetic urine and pooled patient urine. Method performance characteristics were determined in accordance with clinical laboratory standards. RESULTS: Established assay performance characteristics included inter- and intra assay imprecision <10%, carryover of <0.2%, analytical measurement range of 5 to 1000MUg/L, limit of quantification of 5MUg/L (coefficient of variation <10%), proportional bias of 0.92 and constant bias of 8.8 in comparison to an outside reference laboratory. CONCLUSIONS: Synthetic urine is an appropriate alternative matrix for standard and quality control material preparation for the measurement of iodine in urine. PMID- 25038426 TI - Dissociable contributions of the prefrontal cortex to hippocampus- and caudate nucleus-dependent virtual navigation strategies. AB - The hippocampus and the caudate nucleus are critical to spatial- and stimulus response-based navigation strategies, respectively. The hippocampus and caudate nucleus are also known to be anatomically connected to various areas of the prefrontal cortex. However, little is known about the involvement of the prefrontal cortex in these processes. In the current study, we sought to identify the prefrontal areas involved in spatial and response learning. We used functional magnetic resonance imaging (fMRI) and voxel-based morphometry to compare the neural activity and grey matter density of spatial and response strategy users. Twenty-three healthy young adults were scanned in a 1.5 T MRI scanner while they engaged in the Concurrent Spatial Discrimination Learning Task, a virtual navigation task in which either a spatial or response strategy can be used. In addition to increased BOLD activity in the hippocampus, spatial strategy users showed increased BOLD activity and grey matter density in the ventral area of the medial prefrontal cortex, especially in the orbitofrontal cortex. On the other hand, response strategy users exhibited increased BOLD activity and grey matter density in the dorsal area of the medial prefrontal cortex. Given the prefrontal cortex's role in reward-guided decision-making, we discuss the possibility that the ventromedial prefrontal cortex, including the orbitofrontal cortex, supports spatial learning by encoding stimulus-reward associations, while the dorsomedial prefrontal cortex supports response learning by encoding action-reward associations. PMID- 25038427 TI - The ultrastructure of the midgut epithelium in millipedes (Myriapoda, Diplopoda). AB - The midgut epithelia of the millipedes Polyxenus lagurus, Archispirostreptus gigas and Julus scandinavius were analyzed under light and transmission electron microscopies. In order to detect the proliferation of regenerative cells, labeling with BrdU and antibodies against phosphohistone H3 were employed. A tube shaped midgut of three millipedes examined spreads along the entire length of the middle region of the body. The epithelium is composed of digestive, secretory and regenerative cells. The digestive cells are responsible for the accumulation of metals and the reserve material as well as the synthesis of substances, which are then secreted into the midgut lumen. The secretions are of three types - merocrine, apocrine and microapocrine. The oval or pear-like shaped secretory cells do not come into contact with the midgut lumen and represent the closed type of secretory cells. They possess many electron-dense granules (J. scandinavius) or electron-dense granules and electron-lucent vesicles (A. gigas, P. lagurus), which are accompanied by cisterns of the rough endoplasmic reticulum. The regenerative cells are distributed individually among the basal regions of the digestive cells. The proliferation and differentiation of regenerative cells into the digestive cells occurred in J. scandinavius and A. gigas, while these processes were not observed in P. lagurus. As a result of the mitotic division of regenerative cells, one of the newly formed cells fulfills the role of a regenerative cell, while the second one differentiates into a digestive cell. We concluded that regenerative cells play the role of unipotent midgut stem cells. PMID- 25038428 TI - Photocatalytic degradation of nicotine in an aqueous solution using unconventional supported catalysts and commercial ZnO/TiO2 under ultraviolet radiation. AB - Nicotine, a highly toxic alkaloid, has been detected in effluents, surface and groundwater and even bottled mineral water. The present work studied the photocatalytic degradation of nicotine in aqueous solution, under ultraviolet irradiation. The experiments were carried out using commercial (ZnO, TiO2) and non-conventional catalysts, which were prepared from industrial and laboratory waste. Two experimental designs (CCD) were performed for both commercial catalysts, and initial nicotine concentration, catalyst concentration and initial solution pH effects were studied. Then, the synthesized catalysts were tested under the optimal conditions which were found through CCDs. Using commercial catalysts, about 98% of the alkaloid was degraded by ZnO, and 88% by TiO2, in 1h. Among the non-conventional catalysts, the highest photocatalytic degradation (44%) was achieved using the catalyst prepared from a petrochemical industry residue. PMID- 25038429 TI - Measurement of partition coefficients for selected polycyclic aromatic hydrocarbons between isolated plant cuticles and water. AB - Partition coefficients between plant cuticles and water (Kcutw) were measured for 10 selected polycyclic aromatic hydrocarbons (PAHs) to evaluate the sorption capacity of plant cuticular layers for hydrophobic organic chemicals. The partitioning properties of PAHs between cuticles and water were evaluated by using (1) isolated cuticular layers and (2) leaf homogenate. The abaxial and adaxial cuticular layers of Euonymus japonicus were isolated by enzymatic digestion. A third-phase partitioning method using poly(dimethylsiloxane) (PDMS) was used to obtain Kcutw. The Kcutw values for the selected PAHs showed no significant differences between the abaxial and adaxial cuticular layers and ranged between 10(4.1) and 10(7.6). These values are close to or slightly higher than their 1-octanol/water partition coefficient (log Kow), indicating high sorption capacity of plant cuticles. On the contrary, partition coefficients between the lipid tissues of homogenized leaves and water were lower than those obtained using isolated cuticular layers by factors of 3.7-190, which is likely due to the breakdown of lipid layers. This indicates that the sorption of hydrophobic organic chemicals by plant leaves is better evaluated using isolated cuticles and that the sorption potential of plant leaves may be underestimated when leaf homogenates are used. PMID- 25038430 TI - Environmental profile of paddy rice cultivation with different straw management. AB - Italy is the most important European country in terms of paddy rice production. North Italian districts such as Vercelli, Pavia, Novara, and Milano are known as some of the world's most advanced rice cultivation sites. In 2013 Italian rice cultivation represented about 50% of all European rice production by area, and paddy fields extended for over 216,000 ha. Cultivation of rice involves different agricultural activities which have environmental impacts mainly due to fossil fuels and agrochemical requirements as well as the methane emission associated with the fermentation of organic material in the flooded rice fields. In order to assess the environmental consequences of rice production in the District of Vercelli, the cultivation practices most frequently carried out were inventoried and evaluated. The general approach of this study was not only to gather the inventory data for rice production and quantify their environmental impacts, but also to identify the key environmental factors where special attention must be paid. Life Cycle Assessment methodology was applied in this study from a cradle to-farm gate perspective. The environmental profile was analyzed in terms of seven different impact categories: climate change, ozone depletion, human toxicity, terrestrial acidification, freshwater eutrophication, marine eutrophication, and fossil depletion. Regarding straw management, two different scenarios (burial into the soil of the straw versus harvesting) were compared. The analysis showed that the environmental impact was mainly due to field emissions, the fuel consumption needed for the mechanization of field operations, and the drying of the paddy rice. The comparison between the two scenarios highlighted that the collection of the straw improves the environmental performance of rice production except that for freshwater eutrophication. To improve the environmental performance of rice production, solutions to save fossil fuel and reduce the emissions from fertilizers (leaching, volatilization) as well as methane emissions should be implemented. PMID- 25038431 TI - Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials. AB - BACKGROUND & AIMS: No therapy has been proven to prevent the recurrence of diverticulitis. Mesalamine has shown efficacy in preventing relapse in inflammatory bowel disease, and there is preliminary evidence that it might be effective for diverticular disease. We investigated the efficacy of mesalamine in preventing recurrence of diverticulitis in 2 identical but separate phase 3, randomized, double-blind, placebo-controlled, multicenter trials (identical confirmatory trials were conducted for regulatory reasons). METHODS: We evaluated the efficacy and safety of multimatrix mesalamine vs placebo in the prevention of recurrent diverticulitis in 590 (PREVENT1) and 592 (PREVENT2) adult patients with >=1 episodes of acute diverticulitis in the previous 24 months that resolved without surgery. Patients received mesalamine (1.2 g, 2.4 g, or 4.8 g) or placebo once daily for 104 weeks. The primary end point was the proportion of recurrence free patients at week 104. Diverticulitis recurrence was defined as surgical intervention at any time for diverticular disease or presence of computed tomography scan results demonstrating bowel wall thickening (>5 mm) and/or fat stranding consistent with diverticulitis. For a portion of the study, recurrence also required the presence of abdominal pain and an increase in white blood cells. RESULTS: Mesalamine did not reduce the rate of diverticulitis recurrence at week 104. Among patients in PREVENT1, 53%-63% did not have disease recurrence, compared with 65% of those given placebo. Among patients in PREVENT2, 59%-69% of patients did not have disease recurrence, compared with 68% of those given placebo. Mesalamine did not reduce time to recurrence, and the proportions of patients requiring surgery were comparable among treatment groups. No new adverse events were identified with mesalamine administration. CONCLUSIONS: Mesalamine was not superior to placebo in preventing recurrent diverticulitis. Mesalamine is not recommended for this indication. ClinicalTrials.gov ID: NCT00545740 and NCT00545103. PMID- 25038432 TI - Signatures of protective memory immune responses during hepatitis C virus reinfection. AB - BACKGROUND & AIMS: Development of a vaccine against hepatitis C virus (HCV) has been hindered by our limited understanding of immune correlates of protection during real-life exposure to the virus. We studied the immune response during HCV reinfection. METHODS: We analyzed blood samples from participants in the Montreal Acute Hepatitis C Injection Drug User Cohort Study who were reinfected with HCV from 2009 to 2012. Five patients spontaneously resolved their second infection and 4 developed chronic infections. We monitored the phenotypic and functional dynamics of HCV-specific memory T cell responses in all subjects during natural re-exposure and re-infection. RESULTS: Populations of CD4(+) and CD8(+) T cells with HCV-specific polyfunctional memory were expanded in all 5 individuals who resolved 2 successive HCV infections. We detected CD127(hi) HCV-specific memory CD8(+) T cells before reinfection regardless of a subject's ability to clear subsequent infections. Protection against viral persistence was associated with the expansion of a CD127(neg), PD1(lo) effector memory T cells at the peak of the response. We also observed broadening of T-cell response, indicating generation of de novo T-cell responses. The 4 individuals who failed to clear their subsequent infection had limited expansion of HCV-specific CD4(+) and CD8(+) memory T cells and expressed variable levels of the exhaustion marker PD1 on HCV specific CD8(+) T cells. Dominant epitope regions of HCV strains isolated from patients with persistent reinfection had sequence variations that were not recognized by the pre-existing memory T cells. CONCLUSIONS: Protection from persistent HCV reinfection depends on the magnitude, breadth, and quality of the HCV-specific memory T-cell response. Sequence homology among viruses and ability of T cells to recognize multiple strains of HCV are critical determinants of protective memory. PMID- 25038433 TI - ADAM10 regulates Notch function in intestinal stem cells of mice. AB - BACKGROUND & AIMS: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a cell surface sheddase that regulates physiologic processes, including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types, but the requirement for ADAM10 signaling in crypt homeostasis is not well defined. METHODS: We analyzed intestinal tissues from mice with constitutive (Vil Cre;Adam10(f/f) mice) and conditional (Vil-CreER;Adam10(f/f) and Leucine-rich repeat-containing GPCR5 [Lgr5]-CreER;Adam10(f/f) mice) deletion of ADAM10. We performed cell lineage-tracing experiments in mice that expressed a gain-of function allele of Notch in the intestine (Rosa26(NICD)), or mice with intestine specific disruption of Notch (Rosa26(DN-MAML)), to examine the effects of ADAM10 deletion on cell fate specification and intestinal stem cell maintenance. RESULTS: Loss of ADAM10 from developing and adult intestine caused lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion led to the replacement of intestinal cell progenitors with 2 distinct, post-mitotic, secretory cell lineages: intermediate-like (Paneth/goblet) and enteroendocrine cells. Based on analysis of Rosa26(NICD) and Rosa26(DN-MAML) mice, we determined that ADAM10 controls these cell fate decisions by regulating Notch signaling. Cell lineage-tracing experiments showed that ADAM10 is required for survival of Lgr5(+) crypt-based columnar cells. Our findings indicate that Notch-activated stem cells have a competitive advantage for occupation of the stem cell niche. CONCLUSIONS: ADAM10 acts in a cell autonomous manner within the intestinal crypt compartment to regulate Notch signaling. This process is required for progenitor cell lineage specification and crypt-based columnar cell maintenance. PMID- 25038434 TI - Tanshinone IIA, a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Salvia milthorriza Bunge (Lamiaceae) known as "Danshen", are used in Traditional Chinese Medicine as a remedy for activating blood and eliminating stasis. TIIA, a diterpenoid of Salvia milthorriza, is one of active components in Danshen that exhibits a significant improvement of the blood flow in the coronary circulatory system and a reduction of myocardial infarction. However, its effect on platelet and underlying mechanism remains largely unknown. On this basis, this compound could be a promising agent to improve blood viscosity and microcirculation and to prevent CVD. MATERIALS AND METHODS: In order to investigate the effects of TIIA on platelet functionality and its interaction with various platelet activation pathways, rat PRP were incubated with TIIA for 1 min at 37 degrees C prior the addition of the stimuli (ADP or collagen). Aggregation was monitored in a light transmission aggregometer measuring changes in turbidity with continuous observation up to 10 min after the addition of the stimuli. MAPK signaling pathway and tubulin acetylation were analyzed by a Western blot technique. The effect of the TIIA was also studied in vivo on bleeding time in mice. RESULTS: TIIA selectively inhibited rat platelet aggregation induced by reversible ADP stimuli (3 MUM) in a concentration-dependent manner (0.5-50 MUM). Nevertheless, TIIA was less active against the irreversible stimuli induced by ADP (10 MUM) and collagen (10 MUg/mL). Moreover, experiments performed on platelet lysates collected at different time-point after the addition of the stimuli shown that TIIA modulated tubulin acetylation and inhibited Erk-2 phosphorylation. Concomitantly, TIIA administrated i.p. at 10 mg/kg significantly amplified the mice bleeding time with an increase of 58% compared to its control (2.06+/-0.29 min vs 1.30+/-0.07). ASA was used as reference drug for in vitro and in vivo experiments. CONCLUSIONS: This study clarifies the intracellular signaling pathway involved in antiplatelet action of TIIA and also gives preliminary evidences for its anticoagulant activity. On this basis, this compound could be a promising agent to improve blood viscosity and microcirculation and to prevent CVD. PMID- 25038436 TI - Striatum in stimulus-response learning via feedback and in decision making. AB - Cognitive deficits are recognized in Parkinson's disease. Understanding cognitive functions mediated by the striatum can clarify some of these impairments and inform treatment strategies. The dorsal striatum, a region impaired in Parkinson's disease, has been implicated in stimulus-response learning. However, most investigations combine acquisition of associations between stimuli, responses, or outcomes (i.e., learning) and expression of learning through response selection and decision enactment, confounding these separate processes. Using neuroimaging, we provide evidence that dorsal striatum does not mediate stimulus-response learning from feedback but rather underlies decision making once associations between stimuli and responses are learned. In the experiment, 11 males and 5 females (mean age 22) learned to associate abstract images to specific button-press responses through feedback in Session 1. In Session 2, they were asked to provide responses learned in Session 1. Feedback was omitted, precluding further feedback-based learning in this session. Using functional magnetic resonance imaging, dorsal striatum activation in healthy young participants was observed at the time of response selection and not during feedback, when greatest learning presumably occurs. Moreover, dorsal striatum activity increased across the duration of Session 1, peaking after most associations were well learned, and was significant during Session 2 where no feedback was provided, and therefore no feedback-based learning occurred. Preferential ventral striatum activity occurred during feedback and was maximal early in Session 1. Taken together, the results suggest that the ventral striatum underlies learning associations between stimuli and responses via feedback whereas the dorsal striatum mediates enacting decisions. PMID- 25038435 TI - Functional mapping of the magnocellular and parvocellular subdivisions of human LGN. AB - The magnocellular (M) and parvocellular (P) subdivisions of primate LGN are known to process complementary types of visual stimulus information, but a method for noninvasively defining these subdivisions in humans has proven elusive. As a result, the functional roles of these subdivisions in humans have not been investigated physiologically. To functionally map the M and P subdivisions of human LGN, we used high-resolution fMRI at high field (7 T and 3 T) together with a combination of spatial, temporal, luminance, and chromatic stimulus manipulations. We found that stimulus factors that differentially drive magnocellular and parvocellular neurons in primate LGN also elicit differential BOLD fMRI responses in human LGN and that these responses exhibit a spatial organization consistent with the known anatomical organization of the M and P subdivisions. In test-retest studies, the relative responses of individual voxels to M-type and P-type stimuli were reliable across scanning sessions on separate days and across sessions at different field strengths. The ability to functionally identify magnocellular and parvocellular regions of human LGN with fMRI opens possibilities for investigating the functions of these subdivisions in human visual perception, in patient populations with suspected abnormalities in one of these subdivisions, and in visual cortical processing streams arising from parallel thalamocortical pathways. PMID- 25038437 TI - Contralateral dominance of corticomuscular coherence for both sides of the tongue during human tongue protrusion: an MEG study. AB - Sophisticated tongue movements contribute to speech and mastication. These movements are regulated by communication between the bilateral cortex and each tongue side. The functional connection between the cortex and tongue was investigated using oscillatory interactions between whole-head magnetoencephalographic (MEG) signals and electromyographic (EMG) signals from both tongue sides during human tongue protrusion compared to thumb data. MEG-EMG coherence was observed at 14-36 Hz and 2-10 Hz over both hemispheres for each tongue side. EMG-EMG coherence between tongue sides was also detected at the same frequency bands. Thumb coherence was detected at 15-33 Hz over the contralateral hemisphere. Tongue coherence at 14-36 Hz was larger over the contralateral vs. ipsilateral hemisphere for both tongue sides. Tongue cortical sources were located in the lower part of the central sulcus and were anterior and inferior to the thumb areas, agreeing with the classical homunculus. Cross-correlogram analysis showed the MEG signal preceded the EMG signal. The cortex-tongue time lag was shorter than the cortex-thumb time lag. The cortex-muscle time lag decreased systematically with distance. These results suggest that during tongue protrusions, descending motor commands are modulated by bilateral cortical oscillations, and each tongue side is dominated by the contralateral hemisphere. PMID- 25038438 TI - The right temporo-parietal junction contributes to visual feature binding. AB - We investigated the neural basis of conjoined processing of color and spatial frequency with functional magnetic resonance imaging (fMRI). A multivariate classification algorithm was trained to differentiate between either isolated color or spatial frequency differences, or between conjoint differences in both feature dimensions. All displays were presented in a singleton search task, avoiding confounds between conjunctive feature processing and search difficulty that arose in previous studies contrasting single feature and conjunction search tasks. Based on patient studies, we expected the right temporo-parietal junction (TPJ) to be involved in conjunctive feature processing. This hypothesis was confirmed in that only conjoined color and spatial frequency differences, but not isolated feature differences could be classified above chance level in this area. Furthermore, we could show that the accuracy of a classification of differences in both feature dimensions was superadditive compared to the classification accuracies of isolated color or spatial frequency differences within the right TPJ. These data provide evidence for the processing of feature conjunctions, here color and spatial frequency, in the right TPJ. PMID- 25038440 TI - Sparse encoding of automatic visual association in hippocampal networks. AB - Intelligent action entails exploiting predictions about associations between elements of ones environment. The hippocampus and mediotemporal cortex are endowed with the network topology, physiology, and neurochemistry to automatically and sparsely code sensori-cognitive associations that can be reconstructed from single or partial inputs. Whilst acquiring fMRI data and performing an attentional task, participants were incidentally presented with a sequence of cartoon images. By assigning subjects a post-scan free-association task on the same images we assayed the density of associations triggered by these stimuli. Using multivariate Bayesian decoding, we show that human hippocampal and temporal neocortical structures host sparse associative representations that are automatically triggered by visual input. Furthermore, as predicted theoretically, there was a significant increase in sparsity in the Cornu Ammonis subfields, relative to the entorhinal cortex. Remarkably, the sparsity of CA encoding correlated significantly with associative memory performance over subjects; elsewhere within the temporal lobe, entorhinal, parahippocampal, perirhinal and fusiform cortices showed the highest model evidence for the sparse encoding of associative density. In the absence of reportability or attentional confounds, this charts a distribution of visual associative representations within hippocampal populations and their temporal lobe afferent fields, and demonstrates the viability of retrospective associative sampling techniques for assessing the form of reflexive associative encoding. PMID- 25038439 TI - Bringing CLARITY to gray matter atrophy. AB - Gray matter atrophy has been shown to be a strong correlate to clinical disability in multiple sclerosis (MS) and its most commonly used animal model, experimental autoimmune encephalomyelitis (EAE). However, the relationship between gray mater atrophy and the spinal cord pathology often observed in EAE has never been established. Here EAE was induced in Thy1.1-YFP mice and their brains imaged using in vivo magnetic resonance imaging (MRI). The brains and spinal cords were subsequently optically cleared using Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY). Axons were followed 5mm longitudinally in three dimensions in intact spinal cords revealing that 61% of the axons exhibited a mean of 22 axonal ovoids and 8% of the axons terminating in axonal end bulbs. In the cerebral cortex, we observed a decrease in the mean number of layer V pyramidal neurons and a decrease in the mean length of the apical dendrites of the remaining neurons, compared to healthy controls. MRI analysis demonstrated decreased cortical volumes in EAE. Cross modality correlations revealed a direct relationship between cortical volume loss and axonal end bulb number in the spinal cord, but not ovoid number. This is the first report of the use of CLARITY in an animal model of disease and the first report of the use of both CLARITY and MRI. PMID- 25038441 TI - Discrimination of cortical laminae using MEG. AB - Typically MEG source reconstruction is used to estimate the distribution of current flow on a single anatomically derived cortical surface model. In this study we use two such models representing superficial and deep cortical laminae. We establish how well we can discriminate between these two different cortical layer models based on the same MEG data in the presence of different levels of co registration noise, Signal-to-Noise Ratio (SNR) and cortical patch size. We demonstrate that it is possible to make a distinction between superficial and deep cortical laminae for levels of co-registration noise of less than 2mm translation and 2 degrees rotation at SNR > 11 dB. We also show that an incorrect estimate of cortical patch size will tend to bias layer estimates. We then use a 3D printed head-cast (Troebinger et al., 2014) to achieve comparable levels of co-registration noise, in an auditory evoked response paradigm, and show that it is possible to discriminate between these cortical layer models in real data. PMID- 25038442 TI - Wedge MUSIC: a novel approach to examine experimental differences of brain source connectivity patterns from EEG/MEG data. AB - We introduce a novel method to estimate bivariate synchronization, i.e. interacting brain sources at a specific frequency or band, from MEG or EEG data robust to artifacts of volume conduction. The data driven calculation is solely based on the imaginary part of the cross-spectrum as opposed to the imaginary part of coherency. In principle, the method quantifies how strong a synchronization between a distinct pair of brain sources is present in the data. As an input of the method all pairs of pre-defined locations inside the brain can be used which is computationally exhaustive. In contrast to that, reference sources can be used that have been identified by any source reconstruction technique in a prior analysis step. We introduce different variants of the method and evaluate the performance in simulations. As a particular advantage of the proposed methodology, we demonstrate that the novel approach is capable of investigating differences in brain source interactions between experimental conditions or with respect to a certain baseline. For measured data, we first show the application on resting state MEG data where we find locally synchronized sources in the motor-cortex based on the sensorimotor idle rhythms. Finally, we show an example on EEG motor imagery data where we contrast hand and foot movements. Here, we also find local interactions in the expected brain areas. PMID- 25038443 TI - Bioinformatic exploration of RIO protein kinases of parasitic and free-living nematodes. AB - Despite right open reading frame kinases (RIOKs) being essential for life, their functions, substrates and cellular pathways remain enigmatic. In the present study, gene structures were characterised for 26 RIOKs from draft genomes of parasitic and free-living nematodes. RNA-seq transcription profiles of riok genes were investigated for selected parasitic nematodes and showed that these kinases are transcribed in developmental stages that infect their mammalian host. Three dimensional structural models of Caenorhabditis elegans RIOKs were predicted, and elucidated functional domains and conserved regions in nematode homologs. These findings provide prospects for functional studies of riok genes in C. elegans, and an opportunity for the design and validation of nematode-specific inhibitors of these enzymes in socioeconomic parasitic worms. PMID- 25038444 TI - A non-peptide oxytocin receptor agonist, WAY-267,464, alleviates novelty-induced hypophagia in mice: insights into changes in c-Fos immunoreactivity. AB - Anxiety caused by the novelty of food or of the environment where the food is presented leads to suppression of consumption (hyponeophagia) reflected by an increased latency to begin feeding and decreased food intake. Studies suggest that some anxiolytics, mainly benzodiazepines and SSRIs, resolve hyponeophagia. Though the neurohormone oxytocin (OT) affects both anxiety responsiveness and feeding-related homeostasis, the link between OT and hyponeophagia has not been established. The current experiments examined the effect of OT receptor stimulation on hyponeophagia in mice and associated changes in brain activity. We found that the OT receptor agonist, WAY-267,464, at 10 and 30 mg/kg b. wt. IP, reduced the latency to approach food and increased the amount of food eaten in hyponeophagia tests differing in animals' motivation to eat (hunger, reward) and the anxiogenic context of environmental novelty (illumination and type of the cage). This effect was abolished by the pretreatment with the OT receptor antagonist, L-368,899, at 10mg/kg b. wt. The antagonist also suppressed social transmission of preference for novel food. Mice subjected to novelty conditions causing hypophagia showed significant changes in c-Fos immunoreactivity in the hippocampus, lateral septum, cingulate and piriform cortex and in the bed nucleus of the stria terminalis, lateral division, posterolateral part (STLP). The pretreatment with WAY-267,464 restored c-Fos levels in the STLP to values detected in control animals subjected to non-anxiogenic conditions. We conclude that OT plays a role in shaping the magnitude of the novelty stress-provoked hypophagia and the activity of the relevant neural networks. PMID- 25038445 TI - Pretreatment with antiasthmatic drug ibudilast ameliorates Abeta 1-42-induced memory impairment and neurotoxicity in mice. AB - Amyloid-beta peptide (Abeta) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease (AD). However, effective neuroprotective approaches against Abeta neurotoxicity are unavailable. Here, we investigated possible preventive effects of ibudilast, as a pharmacologic phosphodiesterase inhibitor, currently used for treatment of inflammatory diseases such as asthma, on Abeta 1-42-induced neuroinflammatory, apoptotic responses and memory impairment. We found that pretreatment with ibudilast (4 or 12 mg/kg, i.p.) significantly ameliorated impaired spatial learning and memory in intracerebroventricularly (ICV) Abeta 1-42-injected mice, as evidenced by decrease in escape latency during acquisition trials and increase in exploratory activities in the probe trial in Morris water maze (MWM) task, and by increase in the number of correct choices and decrease in latency to enter the shock-free compartment in Y-maze test. Further study showed that ibudilast prevented generation of pro-inflammatory cytokines such as NF-kappaB p65 and TNF-alpha as well as pro-apoptotic molecule caspase-3 activation and anti-apoptotic protein Bcl-2 downregulation in both hippocampus and cortex of ICV Abeta 1-42-injected mice. Taken together, our findings suggest that ibudilast has preventive effects on Abeta-induced cognitive impairment via inhibiting neuroinflammatory and apoptotic responses. PMID- 25038446 TI - mtDNA sequence, phylogeny and evolution of laboratory mice. AB - Laboratory mice are important tools for biomedical research. Aiming to investigate the phylogeny and evolution of laboratory mice, we investigated the mtDNA sequences of classic inbred strains, classic outbred stocks and wild derived inbred strains. Our results showed that the most classic outbred stocks and classic inbred strains are descended from a single mtDNA ancestor. The phylogenic analysis supports the topology of M. m. castaneus/M. m. domesticus as sister subspecies, and the divergence time between the two sister subspecies and M. m. musculus was 493,000 (435,000-557,000) years ago. Furthermore, the mtDNA polymorphisms accumulated in the last 100years in the laboratory mice are under a relaxed purifying selection. PMID- 25038447 TI - Wax esters of different compositions produced via engineering of leaf chloroplast metabolism in Nicotiana benthamiana. AB - In a future bio-based economy, renewable sources for lipid compounds at attractive cost are needed for applications where today petrochemical derivatives are dominating. Wax esters and fatty alcohols provide diverse industrial uses, such as in lubricant and surfactant production. In this study, chloroplast metabolism was engineered to divert intermediates from de novo fatty acid biosynthesis to wax ester synthesis. To accomplish this, chloroplast targeted fatty acyl reductases (FAR) and wax ester synthases (WS) were transiently expressed in Nicotiana benthamiana leaves. Wax esters of different qualities and quantities were produced providing insights to the properties and interaction of the individual enzymes used. In particular, a phytyl ester synthase was found to be a premium candidate for medium chain wax ester synthesis. Catalytic activities of FAR and WS were also expressed as a fusion protein and determined functionally equivalent to the expression of individual enzymes for wax ester synthesis in chloroplasts. PMID- 25038448 TI - Effects of chitosan-stabilized selenium nanoparticles on cell proliferation, apoptosis and cell cycle pattern in HepG2 cells: comparison with other selenospecies. AB - Selenium is an essential element that plays an important role in many biological functions. Many studies have reported the potential beneficial effects of Se intake for cancer therapy and prevention, which are not only dose-dependent but also closely related to the properties of specific selenospecies. Selenium nanoparticles are considered a novel selenium compound with excellent antioxidant properties; however, little is known about the properties of selenium nanoparticles in comparison to other well-studied selenospecies. Here, we combined different independent bioanalytical approaches to carry out a comparison between the effects of selenium nanoparticles and other selenocompounds (inorganic and organic selenospecies) using an in-vitro model. The bioanalytical characterization of different parameters such as cell proliferation, apoptosis and cell cycle pattern on HepG2 cells has shown the unique properties of this relatively novel compound that support and complete prior evidences for future applications as chemotherapeutic agent. PMID- 25038449 TI - How familiar characters influence children's judgments about information and products. AB - Children are exposed to advertisements and products that incorporate familiar characters, such as Dora the Explorer and Bob the Builder, virtually from birth. How does the presence of these characters influence children's judgments about information and products? Three experiments (N=125) explored how 4-year-olds evaluate messages from familiar characters and how their trust in a familiar character's testimony relates to their product preferences. Children endorsed objective and subjective claims made by a familiar character more often than those made by a perceptually similar but unfamiliar character even in situations where they had evidence that the familiar character was unreliable. Children also preferred low-quality products bearing a familiar character's image over high quality products without a character image up to 74% of the time (whereas control groups preferred the low-quality products less than 6% of the time when they did not include a character image). These findings suggest that young children are powerfully influenced by familiar characters encountered in the media, leaving them vulnerable to advertising messages and clouding their judgments about products. PMID- 25038450 TI - Blood vessel cell death during prion disease: implications for disease management and infection control. PMID- 25038451 TI - Farm residence and lymphohematopoietic cancers in the Iowa Women's Health Study. AB - BACKGROUND: Cancer incidence in male farmers has been studied extensively; however, less is known about risk among women residing on farms or in agricultural areas, who may be exposed to pesticides by their proximity to crop fields. We extended a previous follow-up of the Iowa Women's Health Study cohort to examine farm residence and the incidence of lymphohematopoietic cancers. Further, we investigated crop acreage within 750 m of residences, which has been associated with higher herbicide levels in Iowa homes. METHODS: We analyzed data for a cohort of 37,099 Iowa women aged 55-69 years who reported their residence location (farm, rural (not a farm), town size based on population) at enrollment in 1986. We identified incident lymphohematopoietic cancers (1986-2009) by linkage with the Iowa Cancer Registry. Using a geographic information system, we geocoded addresses and calculated acreage of pasture and row crops within 750 m of homes using the 1992 National Land Cover Database. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariate analyses of cancer risk in relation to both residence location and crop acreage. RESULTS: As found in an earlier analysis of residence location, risk of acute myeloid leukemia (AML) was higher among women living on farms (HR=2.23, 95%CI: 1.25-3.99) or rural areas (but not on a farm) (HR=1.95, 95%CI: 0.89-4.29) compared with women living in towns of >10,000 population. We observed no association between farm or rural residence and non-Hodgkin lymphoma (NHL; overall or for major subtypes) or multiple myeloma. In analyses of crop acreage, we observed no association between pasture or row crop acreage within 750 m of homes and risk of leukemia overall or for the AML subtype. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) risk was nonsignificantly elevated among women with pasture acreage within 750 m of their home (HRs for increasing tertiles=1.8, 1.8 and 1.5) and with row crop acreage within 750 m (HRs for increasing tertiles of acreage=1.4, 1.5 and 1.6) compared to women with no pasture or row crop acreage, respectively. CONCLUSIONS: Iowa women living on a farm or in a rural area were at increased risk of developing AML, which was not related to crop acreage near the home. Living near pasture or row crops may confer an increased risk of CLL/SLL regardless of residence location. Further investigation of specific farm-related exposures and these cancers among women living on farms and in agricultural areas is warranted. PMID- 25038452 TI - Differential requirements of arrestin-3 and clathrin for ligand-dependent and independent internalization of human G protein-coupled receptor 40. AB - G protein-coupled receptor 40 (GPR40) is believed to be an attractive target to enhance insulin secretion in patients with type 2 diabetes. GPR40 has been found to couple to Gq protein, leading to the activation of phospholipase C and subsequent increases in the intracellular Ca(2+) level. However, the underlying mechanisms that regulate the internalization and desensitization of GPR40 remain to be elucidated. In the present study, a construct of GPR40 fused with enhanced green fluorescent protein (EGFP) at its C-terminus was constructed for direct imaging of the localization and internalization of GPR40 by confocal microscopy. In stably transfected HEK-293 cells, GPR40 receptors underwent rapid agonist induced internalization and constitutive ligand-independent internalization. Our data demonstrated that the agonist-mediated internalization of GPR40 was significantly blocked by hypertonic sucrose treatment and by siRNA mediated depletion of the heavy chain of clathrin. In contrast, constitutive GPR40 internalization was not affected by hypertonic sucrose or by knock-down of clathrin expression, but it was affected by treatment with methyl-beta cyclodextrin (MbetaCD) and nystatin. Furthermore, our results using an arrestin-3 EGFP redistribution assay and siRNA-mediated knock-down of arrestin-3 and GRK2 expression revealed that arrestin-3 and GRK2 play an essential role in the regulation of agonist-mediated GPR40 internalization, but are not involved in the regulation of constitutive GPR40 internalization. Additionally, our observation showed that upon activation by agonist, the internalized GPR40 receptors were rapidly recycled back to the plasma membrane via Rab4/Rab5 positive endosomes, whereas the constitutively internalized GPR40 receptors were recycled back to the cell surface through Rab5 positive endosomes. Because FFA receptors exhibit a high level of homology, our observations could be applicable to other members of this family. PMID- 25038453 TI - CNOT7/hCAF1 is involved in ICAM-1 and IL-8 regulation by tristetraprolin. AB - Tristetraprolin (TTP) is an RNA-binding protein which can bind to the AU-rich elements (AREs) at the 3'-untranslated region (3'-UTR) of target mRNA and promote mRNA deadenylation and degradation. We have shown in a previous study that TTP regulates tumor necrosis factor-alpha (TNF-alpha)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8), both of whose mRNAs have AREs in the 3'-UTR, in human pulmonary microvascular endothelial cells (HPMEC) through destabilizing target mRNAs, nevertheless, the mechanism by which TTP promotes mRNA decay remains unclear. Observations have indicated that TTP can interact with CAF1 (CNOT7/hCAF1 in human), a subunit of the CCR4-NOT complex with deadenylase activity. Another study illustrated that TTP can directly bind to CNOT1, the scaffold subunit of the CCR4-NOT complex. The present study showed that TTP bound to the AREs of ICAM-1 and IL-8 mRNAs and was coimmunoprecipitated with intracellular ICAM-1 and IL-8 mRNAs. TTP, CNOT7 and CNOT1 were coimmunoprecipitated in HPMEC. CNOT7 silencing stabilized ICAM-1 and IL-8 mRNAs and increased ICAM-1 and IL-8 production following TNF-alpha stimulation. These results, together with our previous study, suggest that CNOT7/hCAF1 is involved in ICAM-1 and IL-8 regulation by TTP in HPMEC. PMID- 25038454 TI - Carnosic acid stimulates glucose uptake in skeletal muscle cells via a PME 1/PP2A/PKB signalling axis. AB - Carnosic acid (CA) is a major constituent of the labiate herbal plant Rosemary (Rosmarinus officinalis), which has been shown to exhibit a number of beneficial health properties. In particular, recently there has been growing interest into the anti-obesity effects conveyed by CA, including its ability to counteract obesity-associated hyperglycaemia and insulin resistance. However, the mechanisms underlying its anti-diabetic responses are not fully understood. In this study, we hypothesized that CA may act to improve glycaemic status through enhancing peripheral glucose clearance. Herein, we demonstrate that CA acts to mimic the metabolic actions of insulin by directly stimulating glucose uptake in rat skeletal L6 myotubes, concomitant with increased translocation of the GLUT4 glucose transporter to the plasma membrane. Mechanistically, CA-induced glucose transport was found to be dependent on protein kinase B (PKB/Akt) but not AMPK, despite both kinases being activated by CA. Crucially, in accordance with its ability to activate PKB and stimulate glucose uptake, we show that CA conveys these effects through a pathway involving PME-1 (protein phosphatase methylesterase-1), a key negative regulator of the serine/threonine phosphatase PP2A (protein phosphatase 2A). Herein, we demonstrate that CA promotes PME-1 mediated demethylation of the PP2A catalytic subunit leading to its suppressed activity, and in doing so, alleviates the repressive action of PP2A towards PKB. Collectively, our findings provide new insight into how CA may improve glucose homeostasis through enhancing peripheral glucose clearance in tissues such as skeletal muscle through a PME-1/PP2A/PKB signalling axis, thereby mitigating pathological effects associated with the hyperglycaemic state. PMID- 25038455 TI - MRTF-A and STAT3 synergistically promote breast cancer cell migration. AB - Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. But the exact molecular mechanism on metastasis is still not fully understood; we now report that both MRTF-A and STAT3 play important role in breast cancer migration of MDA-MB-231 cells. Moreover, MRTF-A and STAT3 synergistically increased MDA-MB-231 cell migration by promoting the expression of migration markers Myl-9 and Cyr-61. Importantly, we identified a detailed molecular mechanism of MDA-MB-231 cell migration controlled via physical interaction between MRTF-A and STAT3, which synergistically promote the transactivity of the migration marker Myl-9 and Cyr-61 by CArG box binding. Interestingly, the two signaling pathways RhoA-MRTF-A and JAK-STAT3 across talk to regulate MDA-MB-231 cell migration. Our data thus provide important and novel insights into the roles of MRTF-A and STAT3 in regulating MDA-MB-231 cell migration. PMID- 25038456 TI - miR-709 inhibits 3T3-L1 cell differentiation by targeting GSK3beta of Wnt/beta catenin signaling. AB - Adipocyte differentiation is tightly regulated by altering gene expression in which microRNAs might be strong post-transcriptional regulators. In this study, we examined the roles of miR-709 in adipogenic differentiation of 3T3-L1 preadipocyte. We found that miR-709 expression was down-regulated during adipogenesis after MDI (1-methyl-3-isobutylxanthine, dexamethasone and insulin) stimulation in normal cultured 3T3-L1 cells, while up-regulated after LiCl treatment. Overexpression of miR-709 inhibited adipogenic differentiation of 3T3 L1 cells. We demonstrated that miR-709 directly targeted 3' UTR of GSK3beta (glycogen synthase kinase 3 beta). Overexpression of miR-709 decreased GSK3beta protein but not mRNA level. Furthermore, the inhibition of miR-709 could be counteracted by overexpression of GSK3beta during 3T3-L1 adipogenic differentiation. In addition, miR-709 increased both protein and mRNA levels of beta-catenin, which is the downstream effector of GSK3beta in Wnt/beta-catenin signaling pathway, and subsequently elevated the expression of target of beta catenin which represses adipogenesis. These data indicate that miR-709 inhibits adipocyte differentiation through targeting GSK3beta and subsequently activating Wnt/beta-catenin signaling pathway. PMID- 25038457 TI - Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis. AB - Wnt signaling plays a major role in bone homeostasis and mechanotransduction, but its role and regulatory mechanism in osteoclast development are not fully understood. Through genome-wide in silico analysis, we examined Wnt3a-driven regulation of osteoclast development. Mouse bone marrow-derived cells were incubated with RANKL in the presence and absence of Wnt3a. Using microarray mRNA expression data, we conducted principal component analysis and predicted transcription factor binding sites (TFBSs) that were potentially involved in the responses to RANKL and Wnt3a. The principal component analysis predicted potential Wnt3a responsive regulators that would reverse osteoclast development, and a TFBS prediction algorithm indicated that the AP1 binding site would be linked to Wnt3a-driven suppression. Since c-Fos was upregulated by RANKL and downregulated by Wnt3a in a dose-dependent manner, we examined its role using RNA interference. The partial silencing of c-Fos suppressed RANKL-driven osteoclastogenesis by downregulating NFATc1, a master transcription factor of osteoclast development. Although the involvement of c-Myc was predicted and partially silencing c-Myc slightly reduced the level of TRAP, c-Myc silencing did not alter the expression of NFATc1. Collectively, the presented systems-biology approach demonstrates that Wnt3a attenuates RANKL-driven osteoclastogenesis by blocking c-Fos expression and suggests that mechanotransduction of bone alters the development of not only osteoblasts but also osteoclasts through Wnt signaling. PMID- 25038458 TI - Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms. AB - Angiotensin II (Ang II) promotes development of ascending aortic aneurysms (AAs), but progression of this pathology is undefined. We evaluated factors potentially involved in progression, and determined the temporal sequence of tissue changes during development of Ang II-induced ascending AAs. Ang II infusion into C57BL/6J mice promoted rapid expansion of the ascending aorta, with significant increases within 5 days, as determined by both in vivo ultrasonography and ex vivo sequential acquisition of tissues. Rates of expansion were not significantly different in LDL receptor-null mice fed a saturated fat-enriched diet, demonstrating a lack of effect of hypercholesterolemia. Augmenting systolic blood pressure with norepinephrine infusion had no significant effect on ascending aortic expansion. Pathological changes observed within 5 days of Ang II infusion included increased medial thickness and intramural hemorrhage characterized by erythrocyte extravasation in outer lamellar layers of the media. Intramedial hemorrhage was not observed after prolonged Ang II infusion, although partial medial disruption was present. Elastin fragmentation and transmural medial breaks of the ascending aorta were observed with continued Ang II infusion, which were restricted to anterior aspects. CD45(+) cells accumulated in adventitia but were minimal in media. Similar pathology was observed in tissues obtained from patients with ascending AAs. In conclusion, Ang II promotes ascending AAs through region-specific changes that are independent of hypercholesterolemia or systolic blood pressure. PMID- 25038459 TI - Standardization of enterococci density estimates by EPA qPCR methods and comparison of beach action value exceedances in river waters with culture methods. AB - The U.S. EPA has published recommendations for calibrator cell equivalent (CCE) densities of enterococci in recreational waters determined by a qPCR method in its 2012 recreational water quality criteria (RWQC). The CCE quantification unit stems from the calibration model used to estimate enterococci densities in recreational beach waters in the EPA National Epidemiological and Environmental Assessment of Recreational (NEEAR) Water Study and directly informed the derivation of the RWQC recommendations. Recent studies have demonstrated that CCE estimates from the method can vary when using different cultured Enterococcus cell preparations in calibrator samples. These differences have been attributed to differences in the quantities of targeted gene copies (target sequences) that are recovered per nominal calibrator cell by DNA extraction. Standardization of results from the calibration model will require the estimation of target sequence recoveries from the calibrator and water samples. In addition, comparisons of water sample results with the RWQC values will require a knowledge of target sequence recoveries from the NEEAR study calibrator samples. In this study recoveries of target sequences and the mean target sequence/cell ratio for the NEEAR study calibrator samples were retrospectively estimated with a corroborated standard curve. A modification of the calibration model was then used to estimate enterococci target sequence quantities in water samples from eight midwestern U.S. rivers. CCE estimates were obtained by dividing these target sequence quantities by the mean NEEAR study target sequence/cell ratio. This target sequence-based quantification approach resulted in a high degree of agreement in beach action decisions (determinations of whether bacterial fecal indicator densities are above or below RWQC-recommended values) from CCE results of the qPCR method and from culture dependent enumeration of both enterococci and Eschericia coli in the corresponding water samples. PMID- 25038460 TI - Normalization of test and evaluation of biothreat detection systems: overcoming microbial air content fluctuations by using a standardized reagent bacterial mixture. AB - Test and evaluation of engineered biothreat agent detection systems ("biodetectors") are a challenging task for government agencies and industries involved in biosecurity and biodefense programs. In addition to user friendly features, biodetectors need to perform both highly sensitive and specific detection, and must not produce excessive false alerts. In fact, the atmosphere displays a number of variables such as airborne bacterial content that can interfere with the detection process, thus impeding comparative tests when carried out at different times or places. To overcome these bacterial air content fluctuations, a standardized reagent bacterial mixture (SRBM), consisting in a collection of selected cultivable environmental species that are prevalent in temperate climate bioaerosols, was designed to generate a stable, reproducible, and easy to use surrogate of bioaerosol sample. The rationale, design, and production process are reported. The results showed that 8.59; CI 95%: 8.46-8.72 log cfu distributed into vials underwent a 0.95; CI 95%: 0.65-1.26 log viability decay after dehydration and subsequent reconstitution, thus advantageously mimicking a natural bioaerosol sample which is typically composed of cultivable and uncultivable particles. Dehydrated SRBM was stable for more than 12months at 4 degrees C and allowed the reconstitution of a dead/live cells aqueous suspension that is stable for 96h at +4 degrees C, according to plate counts. Specific detection of a simulating biothreat agent (e.g. Bacillus atrophaeus) by immuno-magnetic or PCR assays did not display any significant loss of sensitivity, false negative or positive results in the presence of SRBM. This work provides guidance on testing and evaluating detection devices, and may contribute to the establishment of suitable standards and normalized procedures. PMID- 25038461 TI - Quantitative fluorometric assay for the measurement of endo-1,4-beta-glucanase. AB - There is a growing demand for research tools to aid the scientific community in the search for improved cellulase enzymes for the biofuel industry. In this work, we describe a novel fluorometric assay for cellulase (endo-1,4-beta-glucanase) which is based on the use of 4,6-O-benzylidene-4-methylumbelliferyl-beta cellotrioside (BzMUG3) in the presence of an ancillary beta-glucosidase. This assay can be used quantitatively over a reasonable linear range, or qualitatively as a solution screening tool which may find extensive use in the area of metagenomics. PMID- 25038462 TI - Controlled release of sphingosine-1-phosphate agonist with gelatin hydrogels for macrophage recruitment. AB - The objective of this study is to design a drug delivery system (DDS) for the in vivo promotion of macrophage recruitment. As the drug, a water-insoluble agonist of sphingosine-1-phosphate type 1 receptor (SEW2871) was selected. SEW2871 (SEW) was water-solubilized by micelle formation with gelatin grafted by L-lactic acid oligomer. SEW micelles were mixed with gelatin, followed by dehydrothermal crosslinking of gelatin to obtain gelatin hydrogels incorporating SEW micelles. SEW was released from the hydrogels incorporating SEW micelles in vitro and in vivo. The water-solubilized SEW showed in vitro macrophage migration activity. When implanted into the back subcutis or the skin wound defect of mice, the hydrogel incorporating SEW micelles promoted macrophage migration toward the tissue around the implanted site to a significantly great extent compared with SEW-free hydrogel and that mixed with SEW micelles. The hydrogel is a promising DDS to enhance macrophage recruitment in vivo. PMID- 25038463 TI - Identification of candidate odorant degrading gene/enzyme systems in the antennal transcriptome of Drosophila melanogaster. AB - The metabolism of volatile signal molecules by odorant degrading enzymes (ODEs) is crucial to the ongoing sensitivity and specificity of chemoreception in various insects, and a few specific esterases, cytochrome P450s, glutathione S transferases (GSTs) and UDP-glycosyltransferases (UGTs) have previously been implicated in this process. Significant progress has been made in characterizing ODEs in Lepidoptera but very little is known about them in Diptera, including in Drosophila melanogaster, a major insect model. We have therefore carried out a transcriptomic analysis of the antennae of D. melanogaster in order to identify candidate ODEs. Virgin male and female and mated female antennal transcriptomes were determined by RNAseq. As with the Lepidoptera, we found that many esterases, cytochrome P450 enzymes, GSTs and UGTs are expressed in D. melanogaster antennae. As olfactory genes generally show selective expression in the antennae, a comparison to previously published transcriptomes for other tissues has been performed, showing preferential expression in the antennae for one esterase, JHEdup, one cytochrome P450, CYP308a1, and one GST, GSTE4. These largely uncharacterized enzymes are now prime candidates for ODE functions. JHEdup was expressed heterologously and found to have high catalytic activity against a chemically diverse group of known ester odorants for this species. This is a finding consistent with an ODE although it might suggest a general role in clearing several odorants rather than a specific role in clearing a particular odorant. Our findings do not preclude the possibility of odorant degrading functions for other antennally expressed esterases, P450s, GSTs and UGTs but, if so, they suggest that these enzymes also have additional functions in other tissues. PMID- 25038464 TI - Wnt/beta-catenin signaling regulates Helicoverpa armigera pupal development by up regulating c-Myc and AP-4. AB - Seasonally changing environmental conditions perceived by insect brains can be converted into hormonal signals that prompt insects to make a decision to develop or enter developmental arrest (diapause). Diapause is a complex physiological response, and many signaling pathways may participate in its regulation. However, little is known about these regulatory pathways. In this study, we cloned four genes related to the Wnt/beta-catenin signaling pathway from Helicoverpa armigera, a pupal diapause species. Western blotting shows that expression of Har Wnt1, Har-beta-catenin, and Har-c-Myc are higher in non-diapause pupal brains than in diapause-destined brains. Har-Wnt1 can promote the accumulation of Har beta-catenin in the nucleus, and Har-beta-catenin in turn increases the expression of Har-c-Myc. The blockage of Wnt/beta-catenin signaling by the inhibitor XAV939 significantly down-regulates Har-beta-catenin and Har-c-Myc expression and delays pupal development, suggesting that the Wnt/beta-catenin pathway functions in insect development. Furthermore, Har-c-Myc binds to the promoter of Har-AP-4 and regulates its expression. It has been reported that Har AP-4 activates diapause hormone (DH) expression and that DH up-regulates the growth hormone ecdysteroid for pupal development. Thus, pupal development is regulated by Wnt/beta-catenin signaling through the pathway Wnt-beta-catenin-c Myc-AP-4-DH-ecdysteroid. In contrast, the down-regulation of Wnt/beta-catenin signaling is likely to induce insects to enter diapause. PMID- 25038465 TI - Differential proteomic analysis of midguts from Nosema ceranae-infected honeybees reveals manipulation of key host functions. AB - Many invasive pathogens effectively bypass the insect defenses to ensure the completion of their life cycle. Among those, an invasive microsporidian species, Nosema ceranae, can cause nosemosis in honeybees. N. ceranae was first described in the Asian honeybee Apis cerana and is suspected to be involved in Western honeybee (Apis mellifera) declines worldwide. The midgut of honeybees is the first barrier against N. ceranae attacks. To bring proteomics data on honeybee/N. ceranae crosstalk and more precisely to decipher the worker honeybee midgut response after an oral inoculation of N. ceranae (10days post-infection), we used 2D-DIGE (2-Dimensional Differential In-Gel Electrophoresis) combined with mass spectrometry. Forty-five protein spots produced by the infected worker honeybee group were shown to be differentially expressed when compared to the uninfected group; 14 were subsequently identified by mass spectrometry. N. ceranae mainly caused a modulation of proteins involved in three key host biological functions: (i) energy production, (ii) innate immunity (reactive oxygen stress) and (iii) protein regulation. The modulation of these host biological functions suggests that N. ceranae creates a zone of "metabolic habitat modification" in the honeybee midgut favoring its development by enhancing availability of nutrients and reducing the worker honeybee defense. PMID- 25038466 TI - Ureteral reimplantation in adults: open versus robotic. PMID- 25038467 TI - Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. AB - Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing ("cotesting") every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1011092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided. Three-year risks following an HPV-negative result were lower than 3-year risks following a Pap-negative result (CIN3+ = 0.069% vs 0.19%, P < .0001; Cancer = 0.011% vs 0.020%, P < .0001) and 5 year risks following an HPV-negative/Pap-negative cotest (CIN3+ = 0.069% vs 0.11%, P < .0001; Cancer = 0.011% vs 0.014%, P = .21). These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening. PMID- 25038468 TI - Practice-based evidence for primary HPV testing in the United States. PMID- 25038469 TI - Assessing the impact of water treatment on bacterial biofilms in drinking water distribution systems using high-throughput DNA sequencing. AB - Biofilm control in drinking water distribution systems (DWDSs) is crucial, as biofilms are known to reduce flow efficiency, impair taste and quality of drinking water and have been implicated in the transmission of harmful pathogens. Microorganisms within biofilm communities are more resistant to disinfection compared to planktonic microorganisms, making them difficult to manage in DWDSs. This study evaluates the impact of four unique drinking water treatments on biofilm community structure using metagenomic DNA sequencing. Four experimental DWDSs were subjected to the following treatments: (1) conventional coagulation, (2) magnetic ion exchange contact (MIEX) plus conventional coagulation, (3) MIEX plus conventional coagulation plus granular activated carbon, and (4) membrane filtration (MF). Bacterial biofilms located inside the pipes of each system were sampled under sterile conditions both (a) immediately after treatment application ('inlet') and (b) at a 1 km distance from the treatment application ('outlet'). Bacterial 16S rRNA gene sequencing revealed that the outlet biofilms were more diverse than those sampled at the inlet for all treatments. The lowest number of unique operational taxonomic units (OTUs) and lowest diversity was observed in the MF inlet. However, the MF system revealed the greatest increase in diversity and OTU count from inlet to outlet. Further, the biofilm communities at the outlet of each system were more similar to one another than to their respective inlet, suggesting that biofilm communities converge towards a common established equilibrium as distance from treatment application increases. Based on the results, MF treatment is most effective at inhibiting biofilm growth, but a highly efficient post-treatment disinfection regime is also critical in order to prevent the high rates of post-treatment regrowth. PMID- 25038470 TI - Cytotoxic eburnamine-aspidospermine type bisindole alkaloids from Bousigonia mekongensis. AB - Four new eburnamine-aspidospermine type bisindole alkaloids, namely, mekongenines C-F (1-4), along with 27 known indole alkaloids were isolated from the twigs and leaves of Bousigonia mekongensis. Their structures with the absolute configurations were elucidated by spectroscopic methods and ECD analyses. All new compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Alkaloids 1-4 exhibited inhibitory effects with IC50 values comparable to those of cisplatin. PMID- 25038471 TI - Diphenyl ethers from Aspergillus sp. and their anti-Abeta42 aggregation activities. AB - Two new compounds with the character of diphenyl ether structure, oxisterigmatocystin D (1) and 9-acetyldiorcinol B (6), were isolated from the endolichenic fungal strain Aspergillus sp. (No. 16-20-8-1), along with six known compounds, oxisterigmatocystin A (2), oxisterigmatocystin C (3), sterigmatocystin (4), diorcinol B (5), violaceol-I (7), and violaceol-II (8). The structures of the new compounds were determined by extensive NMR spectroscopic data, and the absolute configuration of 1 was established by single-crystal X-ray diffraction analysis. Moreover, the Abeta42 aggregation inhibitory activities of 5-8 were evaluated by the standard thioflavin T (ThT) fluorescence assay using epigallocatechin gallate (EGCG) as the positive control. Compounds 7 and 8 displayed significant anti-Abeta42 aggregation activity with IC50 values of 5.1 and 2.3MUM, respectively. Preliminary structure-activity relationship of these diphenyl ethers as anti-Abeta42 aggregation inhibitors was proposed. PMID- 25038472 TI - The influence of visual target information on the online control of movements. AB - The continuously changing properties of our environment require constant monitoring of our actions and updating of our motor commands based on the task goals. Such updating relies upon our predictions about the sensory consequences of our movement commands, as well as sensory feedback received during movement execution. Here we focus on how visual information about target location is used to update and guide ongoing actions so that the task goal is successfully achieved. We review several studies that have manipulated vision of the target in a variety of ways, ranging from complete removal of visual target information to changes in visual target properties after movement onset to examine how such changes are accounted for during motor execution. We also examined the specific role of a critical neural structure, the parietal cortex, and argue that a fundamental challenge for the future is to understand how visual information about target location is integrated with other streams of information, during movement execution, to estimate the state of the body and the environment in order to ensure optimal motor performance. PMID- 25038473 TI - Binocular capture: the role of non-linear position mechanisms. AB - When monocular Vernier targets are presented with binocular disparate elements, an increase in vertical separation elevates alignment thresholds and also shifts its perceived visual direction towards the visual direction of the binocular disparate surround. This observation has been termed binocular capture. There is increasing evidence that this shift in the visual direction of the monocular target may be related to the type of position encoding mechanism involved in processing the relative position signal. This study investigated the interaction between capture magnitude and vertical separation for stimulus conditions that favored the recruitment of linear or non-linear position encoding mechanisms. Relative alignment thresholds and bias were measured for a pair of vertically separated (8', 30', 60', 120') monocular Gabor gratings (1, 2, 4 and 8 cpd). Grating stimuli were constructed to constrain relative alignment judgments to the carrier grating (CO) or to the envelope (EO). Relative alignment thresholds and bias were also measured for a pair of vertically separated monocular Gabor gratings comprising a 1 cpd vertical square wave grating (SQ) or a 1 cpd missing fundamental grating (MF). Capture magnitudes were significantly larger across vertical separation and varied proportionally with relative alignment threshold for the EO and MF conditions. This was not evident with the CO and SQ conditions. The stark difference in capture magnitudes between the stimuli conditions suggest that the increase in capture magnitude observed with increasing vertical separation is intimately related to the transition from a "capture-immune" first order spatial filter mechanism to a "capture-vulnerable" non-linear/feature-based position encoding mechanism. PMID- 25038474 TI - Transcriptional regulation of genes encoding ABA metabolism enzymes during the fruit development and dehydration stress of pear 'Gold Nijisseiki'. AB - To investigate the contribution of abscisic acid (ABA) in pear 'Gold Nijisseiki' during fruit ripening and under dehydration stress, two cDNAs (PpNCED1 and PpNCED2) which encode 9-cis-epoxycarotenoid dioxygenase (NCED) (a key enzyme in ABA biosynthesis), two cDNAs (PpCYP707A1 and PpCYP707A2) which encode 8' hydroxylase (a key enzyme in the oxidative catabolism of ABA), one cDNA (PpACS3) which encodes 1-aminocyclopropane-1-carboxylic acid (ACC), and one cDNA (PpACO1) which encodes ACC oxidase involved in ethylene biosynthesis were cloned from 'Gold Nijisseiki' fruit. In the pulp, peel and seed, expressions of PpNCED1 and PpNCED2 rose in two stages which corresponded with the increase of ABA levels. The expression of PpCYP707A1 dramatically declined after 60-90 days after full bloom (DAFB) in contrast to the changes of ABA levels during this period, while PpCYP707A2 stayed low during the whole development of fruit. Application of exogenous ABA at 100 DAFB increased the soluble sugar content and the ethylene release but significantly decreased the titratable acid and chlorophyll contents in fruits. When fruits harvested at 100 DAFB were stored in the laboratory (25 degrees C, 50% relative humidity), the ABA content and the expressions of PpNCED1/2 and PpCYP707A1 in the pulp, peel and seed increased significantly, while ethylene reached its highest value after the maximum peak of ABA accompanied with the expressions of PpACS3 and PpACO1. In sum the endogenous ABA may play an important role in the fruit ripening and dehydration of pear 'Gold Nijisseiki' and the ABA level was regulated mainly by the dynamics of PpNCED1, PpNCED2 and PpCYP707A1 at the transcriptional level. PMID- 25038475 TI - Effects of selective IKr channel blockade by E-4031 on ventricular electro mechanical relationship in the halothane-anesthetized dogs. AB - An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+ current (IKr)-selective blockade by E-4031 on the electro-mechanical relationship in vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset of IKr inhibitor-induced arrhythmias. PMID- 25038476 TI - Tissue deposition and residue depletion in rainbow trout following continuous voluntary feeding with various levels of melamine or a blend of melamine and cyanuric acid. AB - This study determined the deposition and depletion in rainbow trout after continuous administration of melamine (MEL) alone or a blend of MEL and cyanuric acid (CYA). The plasma, muscles, kidneys, liver and gills were sampled at 0, 3, 7, 13, 21, 28 and 42d. After the final sampling at 42d, fish from the MEL0.05, MEL20 and MCA groups were fed the control diet (MEL0) for the depletion test. Co administration with cyanuric acid accelerated the deposition time to the Css for melamine; during the withdrawal phrase, the melamine and CYA concentrations in the tissues decreased exponentially. Compared to the t(1/2) for single oral administration, the t(1/2) for melamine and cyanuric acid after 42d continuous feeding was prolonged. The presence of trace CYA in the plasma and kidneys of trout was detected in the MEL20 group, indicating that MEL can convert into CYA in rainbow trout. PMID- 25038477 TI - Stimulation of gene expression and activity of antioxidant related enzyme in Sprague Dawley rat kidney induced by long-term iron toxicity. AB - The trace elements such as iron are vital for various enzyme activities and for other cellular proteins, but iron toxicity causes the production of reactive oxygen species (ROS) that causes alterations in morphology and function of the nephron. The present study was designed to determine the effect of long-term iron overload on the renal antioxidant system and to determine any possible correlation between enzymatic and molecular levels. Our data showed that reduced glutathione (GSH) levels, which is a marker for oxidative stress, strikingly decreased with a long-term iron overload in rat kidney. While renal mRNA levels of glucose 6-phosphate dehydrogenase (G6pd), 6-phosphogluconate dehydrogenase (6pgd) and glutathione peroxidase (Gpx) were significantly affected in the presence of ferric iron, no changes were seen for glutathione reductase (Gsr) and glutathione S-transferases (Gst). While the iron affected the enzymatic activity of G6PD, GSR, GST, and GPX, it had no significant effect on 6PGD activity in the rat kidney. In conclusion, we reported here that the gene expression of G6pd, 6pgd, Gsr, Gpx, and Gst did not correlate to enzyme activity, and the actual effect of long-term iron overload on renal antioxidant system is observed at protein level. Furthermore, the influence of iron on the renal antioxidant system is different from its effect on the hepatic antioxidant system. PMID- 25038478 TI - Oxytocin facilitates fidelity in well-established marmoset pairs by reducing sociosexual behavior toward opposite-sex strangers. AB - Behavioral strategies that facilitate the maintenance of social bonds are critical for the preservation of high-quality social relationships. Central oxytocin (OT) activity modulates the behavioral features of socially monogamous relationships in a number of mammalian species (including marmoset monkeys), and plays a vital role in the behavioral maintenance of long-term social relationships. Two distinct variants of OT have been identified in some New World primates (including marmosets; Lee et al., 2011). The marmoset variant of the oxytocin ligand (Pro(8)-OT) is structurally distinct from the consensus mammalian variant of the oxytocin ligand (Leu(8)-OT), due to a proline substitution at the 8th amino-acid position. The goal of the present study was to determine if treating marmosets with Pro(8)-OT, relative to treatments with Leu(8)-OT, control saline, or an OT antagonist, had modulatory effects on the behavioral maintenance of long-term social relationships in marmosets. Treatment with the Pro(8) variant, but not the Leu(8) variant, of OT facilitated fidelity with a long-term partner by reducing time spent in close proximity with an opposite-sex stranger. However, this facilitative effect of Pro(8)-OT on proximity behavior manifested itself differently in male and female marmosets, such that females preferred to interact socially with their partner rather than a stranger when treated with Pro(8)-OT, while males spent less time in close proximity with both their partner and a stranger when treated with Pro(8)-OT. Furthermore, treatment with Pro(8) OT, but not Leu(8)-OT, significantly delayed the expression of sexual solicitation behavior toward an opposite-sex stranger in both male and female marmosets, but had no effect on sociosexual behavior directed toward a long-term partner. These results suggest that the OT system is highly involved in reducing fidelity-threatening behaviors in well-established marmoset pairs, and that the effects were only produced by species-specific OT ligands. PMID- 25038479 TI - Sexually dimorphic responses to early adversity: implications for affective problems and autism spectrum disorder. AB - During gestation, development proceeds at a pace that is unmatched by any other stage of the life cycle. For these reasons the human fetus is particularly susceptible not only to organizing influences, but also to pathogenic disorganizing influences. Growing evidence suggests that exposure to prenatal adversity leads to neurological changes that underlie lifetime risks for mental illness. Beginning early in gestation, males and females show differential developmental trajectories and responses to stress. It is likely that sex dependent organization of neural circuits during the fetal period influences differential vulnerability to mental health problems. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two developmental disorders: affective problems (greater female prevalence) and autism spectrum disorder (greater male prevalence). Recent prospective studies illustrating the neurodevelopmental consequences of fetal exposure to stress and stress hormones for males and females are considered here. Plausible biological mechanisms including the role of the sexually differentiated placenta are discussed. PMID- 25038481 TI - The Brugia malayi neuropeptide receptor-4 is activated by FMRFamide-like peptides and signals via Galphai. AB - Genetic studies undertaken in the model organism Caenorhabditis elegans have demonstrated the importance of neuropeptidergic signalling in nematode physiology. Disruption of this signalling may have deleterious phenotypic consequences, including altered locomotion, feeding behaviour, and reproduction. Neuropeptide G protein-coupled receptors (GPCRs) that transduce many of these signals therefore represent cogent drug targets. Recently published genomic sequencing data for a number of parasitic helminths of medical and veterinary importance has revealed the apparent conservation of a number of neuropeptides, and neuropeptide receptors between parasitic and free-living species, raising the intriguing possibility of developing broad-spectrum anthelmintic therapeutics. Here, we identify and clone a neuropeptide receptor, NPR-4, from the human filarial nematode Brugia malayi and demonstrate its activation in vitro, by FMRFamide-like peptides of the FLP-18 family, and intracellular signalling via Galphai mediated pathways. These data represent the first example of deorphanisation of a neuropeptide GPCR in any parasitic helminth species. PMID- 25038482 TI - Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABA(A) receptor agonists. AB - A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9 11, 14-16) display low to mid-micromolar GABA(A)R binding affinities to native GABA(A) receptors (K(i) 1.1-24 MUM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K(i) 0.044 MUM) and equipotency as an agonist to GABA itself as well as the standard GABA(A) agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a alpha1beta2gamma2 GABA(A) receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABA(A)R agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABA(A)R area. PMID- 25038480 TI - Recent advances in QM/MM free energy calculations using reference potentials. AB - BACKGROUND: Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way. SCOPE OF REVIEW: Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field. MAJOR CONCLUSIONS: The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed. GENERAL SIGNIFICANCE: As was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics. PMID- 25038483 TI - Ambidalmines A-E and ambidimerine F: bioactive dihydrobenzophenanthridine alkaloids from Corydalis ambigua var. amurensis. AB - Ten new scarce dihydrobenzophenanthridine alkaloids, including seven monomers, ambidalmines A(1/2), B(1/2)-E (1(a/b), 2(a/b)-5), and three dimers, ambidimerines F1 (6a), F2 (6b) and F3 (6c), were isolated from the tubers of Corydalis ambigua var. amurensis. All of these compounds were discovered in the forms of enantiomers. The structures were elucidated based on extensive spectroscopic analysis, with absolute configurations of the enantiomeric compounds assigned by single-crystal X-ray diffraction analysis, circular dichroism (CD) and optical rotations. Bioactivity evaluation showed that compounds 1a, 2a, 2b and 6b exhibit comparable protective effects on hypoxic H9C2 cells. PMID- 25038484 TI - Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity. AB - A series of C-3 thiourea functionalized beta-lactams, beta-lactam-7 chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives were prepared with the aim of probing antimalarial structure-activity relationships. 7 Chlorquinoline-thiohydantoin derivatives were found to be potent inhibitors of cultured Plasmodium falciparum, with the most potent and non-cytotoxic compound exhibiting an IC50 of 39.8 nM. Studies of beta-hematin formation suggested that inhibition of haemozoin formation could be primary mechanism of action, with IC50 values comparable to those of chloroquine. Evaluation of cytotoxicity against HeLa cells demonstrated high selective indices. PMID- 25038485 TI - Ultrasound-assisted synthesis of novel 1,2,3-triazoles coupled diaryl sulfone moieties by the CuAAC reaction, and biological evaluation of them as antioxidant and antimicrobial agents. AB - A series of 1,2,3-triazoles coupled diaryl sulfone containing compounds were synthesized by the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction in benign solvents under ultrasound irradiation. In situ formation of azides from alpha-bromoketones together with the CuAAC reaction in one pot allowed safe handling and good availability of azides for the development of a small library of compounds. The sonication reduced reaction time and increased yields compared to otherwise same conditions. All synthesized compounds were evaluated for antibacterial, antifungal and antioxidant activities. Compounds 3b, 6b and 9e-9g were found to be the most potent antifungal agents with minimal inhibitory concentration (MIC) at 25 MUg/mL; moreover other compounds revealed good to moderate antimicrobial activity. Compound 8e showed an excellent antioxidant activity using a DPPH free radical scavenging assay. PMID- 25038486 TI - Randomized trial of asunaprevir plus peginterferon alfa and ribavirin for previously untreated genotype 1 or 4 chronic hepatitis C. AB - BACKGROUND & AIMS: Asunaprevir is a selective HCV NS3 protease inhibitor, active against genotypes 1, 4, 5, and 6 in vitro. We evaluated asunaprevir plus peginterferon alfa-2a/ribavirin (PegIFNalpha/RBV) for genotype 1 and 4 chronic HCV. METHODS: In this phase 2b, double-blind, placebo-controlled study, treatment naive adults with genotype 1 (n=213) or 4 (n=25) were randomly assigned (3:1) to asunaprevir 200mg or placebo twice daily plus PegIFNalpha/RBV. Asunaprevir recipients, achieving protocol-defined response (HCV-RNA below quantification limit at week 4 and undetectable at week 10), were rerandomized at week 12 to continue asunaprevir-based triple therapy or receive placebo plus PegIFNalpha/RBV for weeks 13-24. Patients without protocol-defined response (PDR) and placebo recipients continued PegIFNalpha/RBV through week 48. Co-primary end points were undetectable HCV-RNA at week 4 and 12 (eRVR) and 24 weeks posttreatment (SVR24). RESULTS: Most patients were male (64.3%), white (83.6%), and had non-CC IL28B genotypes (71.3%). Among genotype 1 patients, eRVR rates (asunaprevir vs. placebo) were 67% (80% CI 62, 72) vs. 6% (80% CI 2, 10); corresponding SVR24 rates were 64% (80% CI 59, 68) vs. 44% (80% CI 36, 53). SVR24 among genotype 4 patients was 89% (asunaprevir) vs. 43% (placebo). Rates of rash and haematologic adverse events were similar between treatment groups. Five asunaprevir-treated patients had grade 4 alanine aminotransferase elevations that resolved following discontinuation (n=4) or with continued dosing (n=1). CONCLUSIONS: Addition of asunaprevir to PegIFNalpha/RBV in treatment-naive genotype 1- or 4-infected patients improves response rates and is well tolerated, with aminotransferase elevations that were manageable with appropriate monitoring. ClinicalTrials.gov ID: NCT01030432. PMID- 25038487 TI - Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase. AB - BACKGROUND & AIMS: Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia. METHODS: All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400 W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests. RESULTS: At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser(1176). This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress. CONCLUSIONS: iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection. PMID- 25038488 TI - Expanding the donor pool for liver transplant recipients using HBsAg positive grafts. PMID- 25038489 TI - Biomechanical and cellular segmental characterization of human meniscus: building the basis for Tissue Engineering therapies. AB - OBJECTIVE: To overcome current limitations of Tissue Engineering (TE) strategies, deeper comprehension on meniscus biology is required. This study aims to combine biomechanical segmental analysis of fresh human meniscus tissues and its correlation with architectural and cellular characterization. METHOD: Morphologically intact menisci, from 44 live donors were studied after division into three radial segments. Dynamic mechanical analysis (DMA) was performed at physiological-like conditions. Micro-computed tomography (CT) analysis of freeze dried samples assessed micro-structure. Flow cytometry, histology and histomorphometry were used for cellular study and quantification. RESULTS: Anterior segments present significantly higher damping properties. Mid body fresh medial meniscus presents higher values of E' compared to lateral. Cyclic loads influence the viscoelastic behavior of menisci. By increasing the frequency leads to an increase in stiffness. Conversely, with increasing frequencies, the capacity to dissipate energy and damping properties initially decrease and then rise again. Age and gender directly correlate with higher E' and tan delta. Micro CT analysis revealed that mean porosity was 55.5 (21.2-89.8)% and 64.7 (47.7 81.8)% for freeze-dried lateral and medial meniscus, respectively. Predominant cells are positive for CD44, CD73, CD90 and CD105, and lack CD31, CD34 and CD45 (present in smaller populations). Histomorphometry revealed that cellularity decreases from vascular zone 1 to zone 3. Anterior segments of lateral and medial meniscus have inferior cellularity as compared to mid body and posterior ones. CONCLUSION: Menisci are not uniform structures. Anterior segments have lower cellularity and higher damping. Cyclic loads influence viscoelastic characteristics. Future TE therapies should consider segmental architecture, cellularity and biomechanics of fresh tissue. PMID- 25038490 TI - Single cell sorting identifies progenitor cell population from full thickness bovine articular cartilage. AB - OBJECTIVE: To date, no approved clinical intervention successfully prevents the progressive degradation of injured articular cartilage that leads to osteoarthritis (OA). Stem/progenitor cell populations within tissues of diarthrodial joint have shown their therapeutic potential in treating OA. However, this potential has not been fully realized due in part to the heterogeneity of these subpopulations. Characterization of clonal populations derived from a single cell may help identify more homogenous stem/progenitor populations within articular cartilage. Moreover, chondrogenic potential of clonal populations from different zones could be further examined to elucidate their differential roles in maintaining articular cartilage homeostasis. METHOD: We combined Fluorescence-activated cell sorting (FACS) and clonogenicity screening to identify stem/progenitor cells cloned from single cells. High efficiency colony-forming cells (HCCs) were isolated, and evaluated for stem/progenitor cell characteristics. HCCs were also isolated from different zones of articular cartilage. Their function was compared by lineage-specific gene expression, and differentiation potential. RESULTS: A difference in colony forming efficiency was observed in terms of colony sizes. HCCs were highly clonogenic and multipotent, and overexpressed stem/progenitor cell markers. Also, proliferation and migration associated genes were over-expressed in HCCs. HCCs showed zonal differences with deep HCCs more chondrogenic and osteogenic than superficial HCCs. CONCLUSION: Our approach is a simple yet practical way to identify homogeneous stem/progenitor cell populations with clonal origin. The discovery of progenitor cells demonstrates the intrinsic self-repairing potential of articular cartilage. Differences in differentiation potential may represent the distinct roles of superficial and deep zone stem/progenitor cells in the maintenance of articular cartilage homeostasis. PMID- 25038491 TI - Comparison of culture based methods for the isolation of Clostridium difficile from stool samples in a research setting. AB - Effective isolation of Clostridium difficile from stool samples is important in the research setting, especially where low numbers of spores/vegetative cells may be present within a sample. In this study, three protocols for stool culture were investigated to find a sensitive, cost effective and timely method of C. difficile isolation. For the initial enrichment step, the effectiveness of two different rich media, cycloserine-cefoxitin fructose broth (CCFB) and cycloserine cefoxitin mannitol broth with taurocholate and lysozyme (CCMB-TAL) were compared. For the comparison of four different, selective solid media; Cycloserine cefoxitin fructose agar (CCFA), Cycloserine-cefoxitin egg yolk agar (CCEY), ChromID C. difficile and tryptone soy agar (TSA) with 5% sheep's blood with and without preceding broth enrichment were used. As a means to enable differentiation between C. difficile and other fecal flora, the effectiveness of the inclusion of a pH indictor (1% Neutral Red), was also evaluated. The data derived indicated that CCFB is more sensitive than CCMB-TAL, however, the latter had an improved recovery rate. A broth enrichment step had a reduced sensitivity over direct plating. ChromID C. difficile showed the best recovery rate whereas CCEY egg yolk agar was the most sensitive of the four. The addition of 1% Neutral Red did not show sufficient colour change when added to CCEY egg yolk agar to be used as a differential medium. For a low cost, timely and sensitive method of isolating C. difficile from stool samples we recommend direct plating onto CCEY egg yolk agar after heat shock. PMID- 25038492 TI - Pose-independent surface matching for intra-operative soft-tissue marker-less registration. AB - One of the main challenges in computer-assisted soft tissue surgery is the registration of multi-modal patient-specific data for enhancing the surgeon's navigation capabilities by observing beyond exposed tissue surfaces. A new approach to marker-less guidance involves capturing the intra-operative patient anatomy with a range image device and doing a shape-based registration. However, as the target organ is only partially visible, typically does not provide salient features and underlies severe non-rigid deformations, surface matching in this context is extremely challenging. Furthermore, the intra-operatively acquired surface data may be subject to severe systematic errors and noise. To address these issues, we propose a new approach to establishing surface correspondences, which can be used to initialize fine surface matching algorithms in the context of intra-operative shape-based registration. Our method does not require any prior knowledge on the relative poses of the input surfaces to each other, does not rely on the detection of prominent surface features, is robust to noise and can be used for overlapping surfaces. It takes into account (1) similarity of feature descriptors, (2) compatibility of multiple correspondence pairs, as well as (3) the spatial configuration of the entire correspondence set. We evaluate the algorithm on time-of-flight (ToF) data from porcine livers in a respiratory liver motion simulator. In all our experiments the alignment computed from the established surface correspondences yields a registration error below 1cm and is thus well suited for initializing fine surface matching algorithms for intra operative soft-tissue registration. PMID- 25038493 TI - Alcohol use among adolescents, aggressive behaviour, and internalizing problems. AB - Alcohol use is common among adolescents, but its association with behavioural and emotional problems is not well understood. This study aimed to investigate how self-reported psychosocial problems were associated with the use of alcohol in a community sample consisting of 4074 Finnish adolescents aged 13-18 years. Aggressive behaviour associated with alcohol use and a high level of alcohol consumption, while internalizing problems did not associate with alcohol use. Having problems in social relationships associated with abstinence and lower alcohol consumption. Tobacco smoking, early menarche and attention problems also associated with alcohol use. PMID- 25038494 TI - Short-term exposure to fluconazole induces chromosome loss in Candida albicans: an approach to produce haploid cells. AB - Candida albicans is considered to be an obligate diploid fungus. Here, we describe an approach to isolate aneuploids or haploids induced by the short-term (12-16 h) exposure of diploid reference strains SC5314 and CAI4 to the most commonly used antifungal drug, fluconazole, followed by repeated single-cell separation among small morphologically distinct colonies in the inhibition zone. The isolated strains had altered cell morphology and LOH events in the MTL and other marker alleles of the analyzed loci at 8 chromosomes of C. albicans with decreased DNA content. The present study employed next-generation sequencing (NGS) combined flow cytometry analysis of the DNA content to analyze the haploid, autodiploid, and aneuploid strains that arose from the fluconazole treatment instead of using the conventional single nucleotide polymorphism/comparative genome hybridization (SNP/CGH) method. A multiple-alignment tool was also developed based on sequenced data from NGS to establish haplotype mapping for each chromosome of the selected strains. These findings revealed that C. albicans experiences 'concerted chromosome loss' to form strains with homozygous alleles and that it even has a haploid status after short-term exposure to fluconazole. Additionally, we developed a new platform to analyze chromosome copy number using NGS. PMID- 25038496 TI - Increasing magnetite contents of polymeric magnetic particles dramatically improves labeling of neural stem cell transplant populations. AB - Safe and efficient delivery of therapeutic cells to sites of injury/disease in the central nervous system is a key goal for the translation of clinical cell transplantation therapies. Recently, 'magnetic cell localization strategies' have emerged as a promising and safe approach for targeted delivery of magnetic particle (MP) labeled stem cells to pathology sites. For neuroregenerative applications, this approach is limited by the lack of available neurocompatible MPs, and low cell labeling achieved in neural stem/precursor populations. We demonstrate that high magnetite content, self-sedimenting polymeric MPs [unfunctionalized poly(lactic acid) coated, without a transfecting component] achieve efficient labeling (>=90%) of primary neural stem cells (NSCs)-a 'hard-to label' transplant population of major clinical relevance. Our protocols showed high safety with respect to key stem cell regenerative parameters. Critically, labeled cells were effectively localized in an in vitro flow system by magnetic force highlighting the translational potential of the methods used. PMID- 25038495 TI - Polysilsesquioxane nanoparticles for triggered release of cisplatin and effective cancer chemoradiotherapy. AB - Chemoradiotherapy is a well-established treatment paradigm in oncology. There has been strong interest in identifying strategies to further improve its therapeutic index. An innovative strategy is to utilize nanoparticle (NP) chemotherapeutics in chemoradiation. Since the most commonly utilized chemotherapeutic with radiotherapy is cisplatin, the development of an NP cisplatin for chemoradiotherapy has the highest potential impact on this treatment. Here, we report the development of an NP comprised of polysilsesquioxane (PSQ) polymer crosslinked by a cisplatin prodrug (Cisplatin-PSQ) and its utilization in chemoradiotherapy using non-small cell lung cancer as a disease model. Cisplatin PSQ NP has an exceptionally high loading of cisplatin. Cisplatin-PSQ NPs were evaluated in chemoradiotherapy in vitro and in vivo. They demonstrated significantly higher therapeutic efficacy when compared to cisplatin. These results suggest that the Cisplatin-PSQ NP holds potential for clinical translation in chemoradiotherapy. PMID- 25038497 TI - The nanomedicines alliance: an industry perspective on nanomedicines. AB - The field of nanomedicines has expanded significantly in recent years in the breadth of compounds under development as well as in the types of technology that are being applied to generate nanomedicines. The pathway to licensure of new nanomedicines is sufficiently well defined by existing regulations and guidance. The future of nanomedicines requires collaboration between industry and regulatory agencies to ensure that safe and effective nanomedicines emerge from this field. FROM THE CLINICAL EDITOR: With the expansion of translational nanomedicine research, the "last steps" of translation, such as making sure all regulatory approvals are met, the availability of appropriate larger-scale production technologies, are becoming critically important. This review provides a perspective from the biomedical and pharmaceutical industry on the above issues. PMID- 25038498 TI - Relationship between nitric oxide- and calcium-dependent signal transduction pathways in growth hormone release from dispersed goldfish pituitary cells. AB - Nitric oxide (NO) and Ca(2+) are two of the many intracellular signal transduction pathways mediating the control of growth hormone (GH) secretion from somatotropes by neuroendocrine factors. We have previously shown that the NO donor sodium nitroprusside (SNP) elicits Ca(2+) signals in identified goldfish somatotropes. In this study, we examined the relationships between NO- and Ca(2+) dependent signal transduction mechanisms in GH secretion from primary cultures of dispersed goldfish pituitary cells. Morphologically identified goldfish somatotropes stained positively for an NO-sensitive dye indicating they may be a source of NO production. In 2h static incubation experiments, GH release responses to the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) were attenuated by CoCl2, nifedipine, verapamil, TMB-8, BHQ, and KN62. In column perifusion experiments, the ability of SNP to induce GH release was impaired in the presence of TMB-8, BHQ, caffeine, and thapsigargin, but not ryanodine. Caffeine-elicited GH secretion was not affected by the NO scavenger PTIO. These results suggest that NO-stimulated GH release is dependent on extracellular Ca(2+) availability and voltage-sensitive Ca(2+) channels, as well as intracellular Ca(2+) store(s) that possess BHQ- and/or thapsigargin-inhibited sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases, as well as TMB-8- and/or caffeine-sensitive, but not ryanodine-sensitive, Ca(2+)-release channels. Calmodulin kinase-II also likely participates in NO-elicited GH secretion but caffeine-induced GH release is not upstream of NO production. These findings provide insights into how NO actions many integrate with Ca(2+)-dependent signalling mechanisms in goldfish somatotropes and how such interactions may participate in the GH-releasing actions of regulators that utilize both NO- and Ca(2+)-dependent transduction pathways. PMID- 25038499 TI - Hydrolytic pathway of 5-fluorouracil in aqueous solutions for clinical use. AB - The purpose of the study was to investigate the degradation pathway of 5 fluorouracil (FU) in the situation of commercial formulations for clinical use, namely FU dissolved in sodium hydroxide (NaOH) solutions or Tris buffer at pH 8.5 9. Combination of data from (19)F, (1)H and (13)C NMR and in some cases MS led to the identification of 8 and 13 FU degradation products in NaOH and Tris solutions respectively. In FU NaOH solutions, the first stage of FU degradation is a stereoselective hydration of the C5-C6 double bond leading to 5,6-dihydro-5 fluoro-6-hydroxyuracil, the cis stereoisomer being predominant relative to the trans. The second stage involves either a defluorination step with formation of fluoride ion and 5-hydroxyuracil or the cleavage of the N3-C4 bond giving the two diastereoisomeric 2-fluoro-3-hydroxy-3-ureidopropanoic acids. The subsequent N1 C6 bond breakdown of these compounds releases urea and 2-fluoro-3-oxopropanoic acid (FOPA) which in turn losses easily carbon dioxide leading to the formation of fluoroacetaldehyde (Facet). The degradation pathway in FU-Tris solutions is identical, except that Tris reacts with the aldehydes FOPA and Facet to form oxazolidine adducts stable at pH 8.5 but in equilibrium with the aldehyde forms at physiological pH, whereas the high reactivity of free aldehydes leads to numerous unidentified degradation compounds all in very low amounts. The FOPA diastereoisomeric adducts react with Facet to form four diastereoisomeric fused bicyclic five-membered ring compounds. Facet and FOPA are highly cardiotoxic. In Tris formulations, they are trapped as stable oxazolidine adducts which release the free aldehydes at physiological pH thus explaining the higher cardiotoxicity of FU in Tris solutions compared to that of FU in NaOH solutions. PMID- 25038500 TI - Delayed diagnosis of Addison's disease: an approach to management. AB - Addison's disease accounts for the majority of cases of adrenal failure that are detected during hospital admissions. Unfortunately, prompt diagnosis of this condition is often delayed due to varied atypical manifestations and inadequate assessment at the time of presentation. We report a case of a 52-year-old woman who was detected to have hypotension during routine colonoscopy for evaluation of anaemia and progressive weight loss. During admission for evaluation of hypotension, she was also detected to have hyponatremia. Hyponatremia and hypotension failed to improve despite fluid resuscitation. Our endocrinological opinion was sought for and on further evaluation she was diagnosed with primary adrenal insufficiency. Glucocorticoid and mineralocorticoid replacement therapy were eventually instituted, which was followed by restoration of blood pressure and normalisation of serum sodium levels. PMID- 25038501 TI - A very rare cause of chronic foot pain in a child: metatarsal tubercular osteomyelitis. AB - Pure tubercular osteomyelitis without joint involvement is rare and easily missed. Moreover the lesion is common in spine and large joints like hip and knee. The involvement of isolated metatarsal has been described rarely, only as few sporadic case reports. We present one such case of isolated first metatarsal involvement in an 8-year-old child who presented with chronic pain in left foot for over 6 months. The X-rays suggested a lytic lesion and lesion was confirmed on histopathology and acid-fast bacteria staining. The patient was treated with multidrug antitubercular chemotherapy. The results were excellent with complete healing of the lesion. PMID- 25038502 TI - Survival and death kinetics of Salmonella strains at low relative humidity, attached to stainless steel surfaces. AB - Salmonella is a major pathogen of concern for low water activity foods and understanding its persistence in dry food processing environments is important for producing safe food. The studies sought to assess the survival of 15 isolates of Salmonella on stainless steel surfaces. Additionally, the aim was to select a suitable model to describe and understand the strains' survival kinetics. Salmonella isolates were dried onto stainless steel surfaces, placed in controlled temperature (25 degrees C) and humidity (33%) conditions and their viability assessed at times from 1h to 30days. The highest survival rate was associated with S. Typhimurium DT104, S. Muenchen, and S. Typhimurium (NCTC 12023), where, after 30days, the reduction ranged from 1.3log10 cfu/surface to 1.6log10 cfu/surface. The lowest survival was linked to a S. Typhimurium strain used in European Standard disinfectant approval tests and S. Typhimurium isolated from whey powder. For most of the strains, following an initial reduction in viability in the first hours (<72h), no further reduction was seen over the 30day period; therefore a 2-population Weibull model was fitted to model the survival kinetics. The overall survival was neither serotype nor time related. All strains had two different subpopulations, one more resistant to desiccation than the other. The results indicate the possibility of the long term survival of Salmonella on environmental surfaces (at least 30days) and suggest the most suitable model to describe and predict survival kinetics. The results also identify strains that may be used to study stress response mechanisms and potential factory control measures in future studies. PMID- 25038503 TI - The predominance, biodiversity and biotechnological properties of Kluyveromyces marxianus in the production of Pecorino di Farindola cheese. AB - Pecorino di Farindola is a handicraft cheese made by farmers on small scale using raw ewes' milk and pig rennet. In this study, yeast consortia were evaluated during Pecorino di Farindola making and ripening. Molecular identification of 156 isolates was achieved by a combination of PCR-RFLP of the 5.8S ITS rRNA region and sequencing of the D1/D2 domain of the 26S rRNA gene. Kluyveromyces marxianus was the predominant species, while other species (Pichia kudriavzevii, Candida parapsilosis, Candida glaebosa and Candida zeylanoides) were present only during the early weeks of ripening. Moreover, the isolates were differentiated both by RAPD-PCR and a sequence alignment of D1/D2 26S rRNA gene, revealing different K. marxianus profiles and variants, and suggesting the role of local selective pressure as the origin of distinctive K. marxianus populations. The strains were characterized also on the basis of different dairy properties such as growth temperature, lactose, galactose, lactate and citrate assimilation at different NaCl concentrations, as well as lipolytic and caseinolytic activities. Moreover, 39 selected K. marxianus strains were inoculated in pasteurized whey to evaluate their growth kinetics, besides lactose, lactate and free amino acids metabolism. The growth kinetics distinguished different biotypes and different metabolic behavior were determined. The general picture of K. marxianus population from Pecorino di Farindola shows a high biodiversity at genetic and phenotypic levels that potentially offers many opportunities for new and advanced knowledge at species level, providing in the meantime a good basis to study the relationship between genetic variability and functional diversities. PMID- 25038504 TI - Radiotherapy versus observation following surgical resection of atypical meningioma (the ROAM trial). PMID- 25038506 TI - Deoxy-liquefaction of three different species of macroalgae to high-quality liquid oil. AB - Three species of macroalgae (Ulva lactuca, Laminaria japonica and Gelidium amansii) were converted into liquid oils via deoxy-liquefaction. The elemental analysis, FTIR and GC-MS results showed that the three liquid oils were all mainly composed of aromatics, phenols, alkanes and alkenes, other oxygen containing compounds, and some nitrogen-containing compounds though there were some differences in terms of their types or contents due to the different constituents in the macroalgae feedstocks. The oxygen content was only 5.15-7.30% and the H/C molar ratio was up to 1.57-1.73. Accordingly, the HHV of the three oils were 42.50, 41.76 and 40.00 MJ/kg, respectively. The results suggested that U. lactuca, L. japonica and G. amansii have potential as biomass feedstock for fuel and chemicals and that deoxy-liquefaction technique may be an effective way to convert macroalgae into high-quality liquid oil. PMID- 25038505 TI - Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis. AB - BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive disease with no evidence of effect from adjuvant therapy. It is further associated with the hereditary syndrome neurofibromatosis type 1 (NF1). Silencing of the tumor suppressor gene RASSF1A through DNA promoter hypermethylation is known to be involved in cancer development, but its impact in MPNSTs remains unsettled. METHODS: The RASSF1A promoter was analyzed by methylation-specific PCR in 113 specimens, including 44 NF1-associated MPNSTs, 47 sporadic MPNSTs, 21 benign neurofibromas, and 1 nonneoplastic nerve sheath control. RESULTS: RASSF1A methylation was found only in the malignant samples (60%) and identified a subgroup among patients with NF1-associated MPNST with a poor prognosis. These patients had a mean 5-year disease-specific survival of 27.3 months (95% CI: 17.2-37.4) versus 47.4 months (95% CI: 37.5-57.2) for NF1 patients with unmethylated promoters, P = 0.014. In multivariate Cox regression analysis, methylated RASSF1A remained an adverse prognostic factor independent of clinical risk factors, P = .013 (hazard ratio: 5.2; 95% CI: 1.4-19.4). CONCLUSION: A considerable number of MPNST samples display hypermethylation of the RASSF1A gene promoter, and for these tumors, this is the first molecular marker that if validated can characterize a subgroup of patients with inferior prognosis, restricted to individuals with NF1. PMID- 25038507 TI - Protein tyrosine phosphatases: Ligand interaction analysis and optimisation of virtual screening. AB - Docking-based virtual screening is an established component of structure-based drug discovery. Nevertheless, scoring and ranking of computationally docked ligand libraries still suffer from many false positives. Identifying optimal docking parameters for a target protein prior to virtual screening can improve experimental hit rates. Here, we examine protocols for virtual screening against the important but challenging class of drug target, protein tyrosine phosphatases. In this study, common interaction features were identified from analysis of protein-ligand binding geometries of more than 50 complexed phosphatase crystal structures. It was found that two interactions were consistently formed across all phosphatase inhibitors: (1) a polar contact with the conserved arginine residue, and (2) at least one interaction with the P-loop backbone amide. In order to investigate the significance of these features on phosphatase-ligand binding, a series of seeded virtual screening experiments were conducted on three phosphatase enzymes, PTP1B, Cdc25b and IF2. It was observed that when the conserved arginine and P-loop amide interactions were used as pharmacophoric constraints during docking, enrichment of the virtual screen significantly increased in the three studied phosphatases, by up to a factor of two in some cases. Additionally, the use of such pharmacophoric constraints considerably improved the ability of docking to predict the inhibitor's bound pose, decreasing RMSD to the crystallographic geometry by 43% on average. Constrained docking improved enrichment of screens against both open and closed conformations of PTP1B. Incorporation of an ordered water molecule in PTP1B screening was also found to generally improve enrichment. The knowledge-based computational strategies explored here can potentially inform structure-based design of new phosphatase inhibitors using docking-based virtual screening. PMID- 25038508 TI - Prospective case controlled clinical study of post-endodontic pain after rotary root canal preparation performed by a single operator. AB - OBJECTIVES: The aim of this study was to assess the influence of the shaping technique on incidence, intensity, duration and type of postoperative pain (PP). METHODS: Root canal treatments were carried out with rotary instrumentation (n=80) during a single-visit, and data about pre-treatment conditions were collected. Patients were given a questionnaire to record the presence or absence of post-endodontic pain, its duration and level of discomfort. A matching patient (same pre-treatment conditions but manual instrumentation) was randomly selected from a pool (n = 374) and assigned to the control group. A total of 44 pairs of patients matched completely and were included in the study. Incidence (yes/no) of PP was assessed using Chi-square tests, intensity (mild, moderate, severe) with trend tests and duration (days) with Mann-Whitney U tests. RESULTS: A significantly greater proportion of the patients in the control group reported pain than did patients in the rotary shaping group (p < 0.05). However, pain duration was shorter (p = 0.008) in the control group. Differences in level of discomfort were not statistically significant. CONCLUSIONS: The results of this prospective in vivo study suggest that a higher incidence of PP should be expected after manual root canal preparation. However a second major finding of the study is that when present, PP after a rotary canal preparation is expected to last longer. CLINICAL SIGNIFICANCE: There has been an increase in the use of rotary techniques among dentists in recent years. The present study analyses the differences in the incidence and characteristics of postoperative pain that should be expected after rotary canal preparation compared to traditional manual methods that had not been reported yet. PMID- 25038509 TI - Randomised in situ trial on the effect of milk and CPP-ACP on dental erosion. AB - OBJECTIVES: This randomised in situ study aimed to analyse the effect of milk (with or without 5ppm F) and CPP-ACP pastes (with or without 900ppm F) on dental erosion. METHODS: The study was a seven phase (5 days each) crossover design involving 15 participants wearing intraoral appliances with enamel and dentine specimens. Specimens were extraorally eroded (erosive soft drink, 6*90s/day) and brushed (2*30s/day, 2N) using a non-fluoridated toothpaste (negative control). The test products were milk, milk+5ppm F (twice daily, each 100ml/2min), CPP-ACP paste, CPP-ACP paste+900ppm F (3min/day) or a SnCl2/AmF/NaF mouthrinse (positive control, 30s/day), which were applied immediately after erosion with the appliances in the oral cavity. In an additional group, a fluoridated toothpaste was used without any additional test product. Tissue loss was determined profilometrically after 5 days and statistically analysed by linear mixed models methodologies (p<0.05). RESULTS: Compared with the negative control (non fluoridated toothpaste only, enamel: 2.2+/-1.3MUm; dentine: 3.8+/-2.2MUm), enamel and dentine loss was significantly reduced by the use of fluoridated toothpaste (enamel: 1.1+/-1.0MUm; dentine: 2.4+/-1.7MUm) and the SnCl2/AmF/NaF mouthrinse (1.5+/-1.5MUm; dentine: 1.8+/-1.9MUm). CONCLUSIONS: Milk and CPP-ACP were not effective in reducing enamel and dentine loss significantly, independently of the presence of fluoride. CLINICAL SIGNIFICANCE: Enamel and dentine erosion were significantly reduced by the use of a fluoridated toothpaste or a SnCl2/AmF/NaF mouthrinse, but not by milk or CPP-ACP under the conditions of the present study. CLINICAL TRIALS REGISTRATION: NCT01566357. PMID- 25038510 TI - A novel method to generate and culture human mast cells: Peripheral CD34+ stem cell-derived mast cells (PSCMCs). AB - The identification and characterization of human mast cell (MC) functions are hindered by the shortage of MC populations suitable for investigation. Here, we present a novel technique for generating large numbers of well differentiated and functional human MCs from peripheral stem cells (=peripheral stem cell-derived MCs, PSCMCs). Innovative and key features of this technique include 1) the use of stem cell concentrates, which are routinely discarded by blood banks, as the source of CD34+ stem cells, 2) cell culture in serum-free medium and 3) the addition of LDL as well as selected cytokines. In contrast to established and published protocols that use CD34+ or CD133+ progenitor cells from full blood, we used a pre-enriched cell population obtained from stem cell concentrates, which yielded up to 10(8) differentiated human MCs per batch after only three weeks of culture starting with 10(6) total CD34+ cells. The total purity on MCs (CD117+, FcepsilonR1+) generated by this method varied between 55 and 90%, of which 4-20% were mature MCs that contain tryptase and chymase and show expression of FcepsilonRI and CD117 in immunohistochemistry. PSCMCs showed robust histamine release in response to stimulation with anti-FcepsilonR1 or IgE/anti-IgE, and increased proliferation and differentiation in response to IL-1beta or IFN-gamma. Taken together, this new protocol of the generation of large numbers of human MCs provides for an innovative and suitable option to investigate the biology of human MCs. PMID- 25038511 TI - Plasma copeptin as a predictor of intoxication severity and delayed neurological sequelae in acute carbon monoxide poisoning. AB - The present study was designed to assess the usefulness of measuring plasma levels of copeptin (a peptide co-released with the hypothalamic stress hormone vasopressin) as a biomarker for the severity of carbon monoxide (CO) poisoning and for predicting delayed neurological sequelae (DNS). Seventy-two patients with CO poisoning and 72 sex and age matched healthy individuals were recruited. Plasma copeptin levels were measured on admission from CO poisoning patients and for healthy individuals at study entry by using a sandwich immunoassay. The CO poisoning patients were divided into two groups according to severity (unconscious and conscious) and occurrence of DNS. The mean plasma copeptin levels (52.5+/-18.5 pmol/L) in the unconscious group were significantly higher than in the conscious group (26.3+/-12.7 pmol/L) (P<0.001). Plasma copeptin levels of more than 39.0 pmol/L detected CO poisoning with severe neurological symptoms e.g. unconsciousness (sensitivity 84.6% and specificity 81.4%). The plasma copeptin levels were higher in patients with DNS compared to patients without DNS (52.2+/-20.6 pmol/L vs. 27.9+/-14.8 pmol/L, P<0.001). Plasma copeptin levels higher than 40.5 pmol/L predicted the development of DNS (sensitivity 77.8%, specificity 82.1%). Plasma copeptin levels were identified as an independent predictor for intoxication severity [odds ratio (OR) 1.261, 95% confidence interval (CI) 1.112-1.638, P=0.002] and DNS (OR 1.313, 95% CI 1.106 1.859, P=0.001). Thus, plasma copeptin levels independently related to intoxication severity and were identified as a novel biomarker for predicting DNS after acute CO poisoning. PMID- 25038512 TI - Angiotensin IV induced contractions in human jejunal wall musculature in vitro. AB - Angiotensin II (AngII) has been reported to mediate contractile actions in rats and human jejunal wall musculature. However, except for one report showing the angiotensin IV (AngIV) contractile effects on the internal anal sphincter of rats, no data is available describing the action of AngIV on smooth muscle in human small intestine. The aim of this study was to investigate the expression and localization of the enzymes responsible to AngIV formation, as well as the receptor, and to elucidate the contractile function of AngIV in the muscular layer of human jejunum in vitro. Jejunal smooth muscle was taken from 23 patients undergoing Roux-en-Y gastric bypass surgery and was used to record isometric tension in vitro in response to AngIV alone and in the presence of losartan or PD123319. ELISA, western blot and immunohistochemistry were used to investigate the expression and localization of key components for AngIV formation: the enzymes aminopeptidases-A, B, M, and the AngIV receptor insulin-regulated aminopeptidase (IRAP). AngIV elicited concentration-dependent contraction in both longitudinal and circular smooth-muscle preparation. Presence of losartan abolished AngIV-induced contraction, but not PD123319. The main peptide AngII, as well as the enzymes aminopeptidases-A, B and M was detected in all muscle samples. Immunohistochemistry localized the enzymes and IRAP in the myenteric plexus between longitudinal and circular muscle layers. The present study indicates that all enzymes necessary for AngIV formation exist in human jejunal smooth muscle and that the contractile action elicited by AngIV is primarily mediated through the AngII type 1 receptor. PMID- 25038513 TI - FTIR studies of metal ligands, networks of hydrogen bonds, and water molecules near the active site Mn4CaO5 cluster in Photosystem II. AB - The photosynthetic conversion of water to molecular oxygen is catalyzed by the Mn4CaO5 cluster in Photosystem II and provides nearly our entire supply of atmospheric oxygen. The Mn4CaO5 cluster accumulates oxidizing equivalents in response to light-driven photochemical events within Photosystem II and then oxidizes two molecules of water to oxygen. The Mn4CaO5 cluster converts water to oxygen much more efficiently than any synthetic catalyst because its protein environment carefully controls the cluster's reactivity at each step in its catalytic cycle. This control is achieved by precise choreography of the proton and electron transfer reactions associated with water oxidation and by careful management of substrate (water) access and proton egress. This review describes the FTIR studies undertaken over the past two decades to identify the amino acid residues that are responsible for this control and to determine the role of each. In particular, this review describes the FTIR studies undertaken to characterize the influence of the cluster's metal ligands on its activity, to delineate the proton egress pathways that link the Mn4CaO5 cluster with the thylakoid lumen, and to characterize the influence of specific residues on the water molecules that serve as substrate or as participants in the networks of hydrogen bonds that make up the water access and proton egress pathways. This information will improve our understanding of water oxidation by the Mn4CaO5 catalyst in Photosystem II and will provide insight into the design of new generations of synthetic catalysts that convert sunlight into useful forms of storable energy. This article is part of a Special Issue entitled: Vibrational spectroscopies and bioenergetic systems. PMID- 25038514 TI - A short-chain alkyl derivative of Rhodamine 19 acts as a mild uncoupler of mitochondria and a neuroprotector. AB - Limited uncoupling of oxidative phosphorylation is known to be beneficial in various laboratory models of diseases. The search for cationic uncouplers is promising as their protonophorous effect is self-limiting because these uncouplers lower membrane potential which is the driving force for their accumulation in mitochondria. In this work, the penetrating cation Rhodamine 19 butyl ester (C4R1) was found to decrease membrane potential and to stimulate respiration of mitochondria, appearing to be a stronger uncoupler than its more hydrophobic analog Rhodamine 19 dodecyl ester (C12R1). Surprisingly, C12R1 increased H(+) conductance of artificial bilayer lipid membranes or induced mitochondria swelling in potassium acetate with valinomycin at concentrations lower than C4R1. This paradox might be explained by involvement of mitochondrial proteins in the uncoupling action of C4R1. In experiments with HeLa cells, C4R1 rapidly and selectively accumulated in mitochondria and stimulated oligomycin sensitive respiration as a mild uncoupler. C4R1 was effective in preventing oxidative stress induced by brain ischemia and reperfusion in rats: it suppressed stroke-induced brain swelling and prevented the decline in neurological status more effectively than C12R1. Thus, C4R1 seems to be a promising example of a mild uncoupler efficient in treatment of brain pathologies related to oxidative stress. PMID- 25038515 TI - Differential gene expression in the respiratory tree of the sea cucumber Apostichopus japonicus during aestivation. AB - Sea cucumbers, Apostichopus japonicus, experience seasonally high water temperatures during the summer months and enter aestivation to survive. Aestivation is characterized by strong metabolic rate depression which is supported by a series of strategies including reorganizing metabolic processes, suppressing cell functions, enhancing cytoprotective mechanisms, and altered gene expression. The respiratory tree tissue of the sea cucumber is an excellent material for studying aestivation, undergoing obvious atrophy during aestivation. The present study analyzed the global gene expression profile of respiratory tree tissue of A. japonicus during aestivation by constructing and screening three libraries representing key stages of aestivation: non-aestivation (NA), deep aestivation (DA), and arousal from aestivation (AA) using RNA-seq. A total of 1240, 1184 and 303 differentially expressed genes (DEGs) were identified following the criteria of |log2 ratio|>=1 and FDR<=0.001 in comparisons of DA vs. NA, AA vs. NA and DA vs. AA. A set of respiratory tree specific DEGs was identified the first time and, in addition, common DEGs that were responsive to aestivation in both respiratory tree and intestine were identified. Functional analysis of DEGs was further performed by GO enrichment analysis and respiratory tree specific GO terms were screened out and provide interesting hints for further studies of the molecular regulation of aestivation in A. japonicus. PMID- 25038516 TI - Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype. AB - Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC( /-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT( /-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction. PMID- 25038517 TI - The role of multi-target policy instruments in agri-environmental policy mixes. AB - The Tinbergen Rule has been used to criticise multi-target policy instruments for being inefficient. The aim of this paper is to clarify the role of multi-target policy instruments using the case of agri-environmental policy. Employing an analytical linear optimisation model, this paper demonstrates that there is no general contradiction between multi-target policy instruments and the Tinbergen Rule, if multi-target policy instruments are embedded in a policy-mix with a sufficient number of targeted instruments. We show that the relation between cost effectiveness of the instruments, related to all policy targets, is the key determinant for an economically sound choice of policy instruments. If economies of scope with respect to achieving policy targets are realised, a higher cost effectiveness of multi-target policy instruments can be achieved. Using the example of organic farming support policy, we discuss several reasons why economies of scope could be realised by multi-target agri-environmental policy instruments. PMID- 25038518 TI - Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. AB - Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Muller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies. PMID- 25038519 TI - Development of multifocal leukoencephalopathy in patients undergoing allogeneic stem cell transplantation-can preemptive detection of John Cunningham virus be useful? AB - Therapeutic options for progressive multifocal leukoencephalopathy (PML) caused by reactivation of John Cunningham virus (JCV) are limited and inefficient in preventing neurological progression and death. The current study investigated the course of JCV reactivation resulting in PML in patients undergoing allogeneic stem cell transplantation (allo-SCT) and assessed the feasibility and potential significance of preemptive JCV detection in peripheral blood, enabling early cessation of immunosuppressive therapy and immune restoration. Two allografted patients were diagnosed with PML at 188 and 808 days post-allo-SCT. Stored DNA samples of both patients, originally obtained for quantitative cytomegalovirus PCR analysis since transplantation, were evaluated for JCV. JCV reactivation in peripheral blood was found to precede the appearance of neurological symptoms by 126 and 105 days. JCV blood levels were found to be highly correlated with the steroid dosage administered for treating graft-versus-host disease (GVHD). In one patient, the cessation of immunosuppression, including steroids, led to the disappearance of JCV in peripheral blood, with a remarkable improvement in neurological symptoms. In conclusion, the current study suggests the feasibility of early detection of JCV reactivation in blood. Immune restoration at that point may prevent PML development; however prospective studies are warranted to elucidate these issues. PMID- 25038520 TI - The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells. AB - Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARgamma antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2alpha (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2alpha. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention. PMID- 25038521 TI - Aging and age-related diseases--from endocrine therapy to target therapy. AB - Aging represents an important health issue not only for the individual, but also for society in general. Burdens associated with aging are expanding as longevity increases. This has led to an enhanced focus on issues related to aging and age related diseases. Until recently, anti-aging endocrine-therapy has been largely limited to hormone-replacement therapy (HRT) that is associated with multiple side effects, including an increased risk of cancer. This has greatly limited the application of HRT in anti-aging therapy. Recently, the focus of anti-aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks. In this regard, the GHRH-GH-IGF-1/Insulin, TOR-S6K1,NAD(+) Sirtuin, P53, Klotho and APOE pathways have been linked to processes associated with age-related diseases, including cancer, cardiovascular disease, diabetes, osteoporosis, and neurodegenerative diseases, all of which directly influence health in aging, and represent key targets in anti-aging therapy. PMID- 25038522 TI - Model-based estimation of loop gain using spontaneous breathing: a validation study. AB - Non-invasive assessment of ventilatory control stability or loop gain (which is a key contributor in a number of sleep-related breathing disorders) has proven to be cumbersome. We present a novel multivariate autoregressive model that we hypothesize will enable us to make time-varying measurements of loop gain using nothing more than spontaneous fluctuations in ventilation and CO2. The model is adaptive to changes in the feedback control loop and therefore can account for system non-stationarities (e.g. changes in sleep state) and it is resistant to artifacts by using a signal quality measure. We tested this method by assessing its ability to detect a known increase in loop gain induced by proportional assist ventilation (PAV). Subjects were studied during sleep while breathing on continuous positive airway pressure (CPAP) alone (to stabilize the airway) or on CPAP+PAV. We show that the method tracked the PAV-induced increase in loop gain, demonstrating its time-varying capabilities, and it remained accurate in the face of measurement related artifacts. The model was able to detect a statistically significant increase in loop gain from 0.14+/-10 on CPAP alone to 0.21+/-0.13 on CPAP+PAV (p<0.05). Furthermore, our method correctly detected that the PAV induced increase in loop gain was predominantly driven by an increase in controller gain. Taken together, these data provide compelling evidence for the validity of this technique. PMID- 25038523 TI - Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing. AB - The control of breathing is commonly viewed as being a "brainstem affair". As the topic of this special issue of Respiratory Physiology and Neurobiology indicates, we should consider broadening this notion since the act of breathing is also tightly linked to many functions other than close regulation of arterial blood gases. Accordingly, "non-brainstem" structures can exert a powerful influence on the core elements of the respiratory control network and as it is often the case, the importance of these structures is revealed when their dysfunction leads to disease. There is a clear link between respiration and anxiety and key theories of the psychopathology of anxiety (including panic disorders; PD) focus on respiratory control and related CO2 monitoring system. With that in mind, we briefly present the respiratory manifestations of panic disorder and discuss the role of the dorso-medial/perifornical hypothalamus, the amygdalar complex, and the periaqueductal gray in respiratory control. We then present recent advances in basic research indicating how adult rodent previously subjected to neonatal stress may provide a very good model to investigate the pathophysiology of PD. PMID- 25038524 TI - Maternal sensitivity and infant response to frustration: the moderating role of EEG asymmetry. AB - Two hundred and thirty-three 5-month-old infants and their mothers participated in a study designed to examine the influence of maternal sensitivity and infant neurophysiology, as well as interactions between these, on infants' regulatory behavior and reactivity to emotional challenge. Maternal sensitivity was measured during two mother-child free-play episodes prior to the challenge task. Infant neurophysiology was derived from a measure of resting EEG asymmetry collected during a baseline episode. Infant regulatory behaviors (mother orienting and distraction) and reactivity to challenge (negative affect) were assessed during an arm restraint procedure. Maternal sensitivity predicted mother-orienting behavior for all infants, regardless of baseline EEG asymmetry. Maternal sensitivity also predicted more distraction behaviors for infants with left frontal EEG asymmetry at baseline. In contrast, maternal sensitivity predicted more negative affect for infants with right frontal EEG asymmetry at baseline. These findings lend support for the hypothesis that maternal sensitivity and infant neurophysiological functioning interact to predict regulatory behavior and reactivity and are discussed in terms of the significance for understanding infant regulatory development in the first year of life. PMID- 25038526 TI - Insights into the lysine acetylproteome of human sperm. AB - Protein lysine acetylation is a dynamic and reversible post-modification that is known to play diverse functions in eukaryotes. Nevertheless, the composition and function of non-histone lysine acetylation in gametes remain unknown. In humans, only capacitated sperm have the capacity to fertilize an egg. In the present study, we found complex composition of lysine acetylated proteins in capacitated human sperm. In vitro fertilization inhibition assay by anti-acetyllysine antibody showed essential roles of lysine acetylation in fertilization. And inhibition of lysine deacetylases, the histone deacetylases, by trichostatin A and nicotinamide, could significantly suppress sperm motility. After immunopurification enrichment of acetylpeptides with anti-acetyllysine antibody and high-throughput liquid chromatography-tandem mass spectrometry identification, we characterized 1206 lysine acetylated sites, corresponding to 576 lysine acetylated proteins in human capacitated sperm. Bioinformatics analysis showed that these proteins are associated with sperm functions, including motility, capacitation, acrosome reaction and sperm-egg interaction. Thus, lysine acetylation is expected to be an important regulatory mechanism for sperm functions. And our characterization of lysine acetylproteome could be a rich resource for the study of male fertility. BIOLOGICAL SIGNIFICANCE: Mature sperm are almost transcriptionally and translationally silent, thus post translational modifications play important roles in sperm functions. Till now, only two types of PTMs, phosphorylation and glycosylation, are well studied in normal human sperm based on large scale proteomics. In the present study, we established the acetylproteome of capacitated human sperm. Over 1000 lysine acetylated sites were identified. Bioinformatics analysis shows that lysine acetylated proteins participate in many biological events of sperm functions. We further provided functional data that the lysine acetylation is essential for sperm motility and fertilization using histone acetylase inhibitors and anti acetyllysine antibody. These data can be strong evidences for the important function of lysine acetylation in human sperm. PMID- 25038525 TI - Matrix density alters zyxin phosphorylation, which limits peripheral process formation and extension in endothelial cells invading 3D collagen matrices. AB - This study was designed to determine the optimal conditions required for known pro-angiogenic stimuli to elicit successful endothelial sprouting responses. We used an established, quantifiable model of endothelial cell (EC) sprout initiation where ECs were tested for invasion in low (1 mg/mL) and high density (5 mg/mL) 3D collagen matrices. Sphingosine 1-phosphate (S1P) alone, or S1P combined with stromal derived factor-1alpha (SDF) and phorbol ester (TPA), elicited robust sprouting responses. The ability of these factors to stimulate sprouting was more effective in higher density collagen matrices. S1P stimulation resulted in a significant increase in invasion distance, and with the exception of treatment groups containing phorbol ester, invasion distance was longer in 1mg/mL compared to 5mg/mL collagen matrices. Closer examination of cell morphology revealed that increasing matrix density and supplementing with SDF and TPA enhanced the formation of multicellular structures more closely resembling capillaries. TPA enhanced the frequency and size of lumen formation and correlated with a robust increase in phosphorylation of p42/p44 Erk kinase, while S1P and SDF did not. Also, a higher number of significantly longer extended processes formed in 5mg/mL compared to 1mg/mL collagen matrices. Because collagen matrices at higher density have been reported to be stiffer, we tested for changes in the mechanosensitive protein, zyxin. Interestingly, zyxin phosphorylation levels inversely correlated with matrix density, while levels of total zyxin did not change significantly. Immunofluorescence and localization studies revealed that total zyxin was distributed evenly throughout invading structures, while phosphorylated zyxin was slightly more intense in extended peripheral processes. Silencing zyxin expression increased extended process length and number of processes, while increasing zyxin levels decreased extended process length. Altogether these data indicate that ECs integrate signals from multiple exogenous factors, including changes in matrix density, to accomplish successful sprouting responses. We show here for the first time that zyxin limited the formation and extension of fine peripheral processes used by ECs for matrix interrogation, providing a molecular explanation for altered EC responses to high and low density collagen matrices. PMID- 25038527 TI - NK and B cell deficiency in a MPS type II family with novel mutation in the IDS gene. AB - The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. Whereas the lysosome is essential to the functioning of the immune system, some authors suggest that the MPS patients have abnormalities in the immune system similar to the patients with primary immunodeficiency. In this study, we evaluated 8 male MPS type II patients of the same family with novel mutation in the IDS gene. We found in this MPS family a quantitative deficiency of NK and B cells with normal values of IgG, IgM and IgA serum antibodies and normal response to polysaccharide antigens. Interestingly, abnormalities found in these patients were not observed in other MPS patients, suggesting that the type of mutation found in the IDS gene can be implicated in the immunodeficiency. PMID- 25038528 TI - In silico identification of natural product inhibitors of JAK2. AB - Emodic acid (1) and 6-chloroemodic acid (2) have been identified from a natural product database as useful scaffolds for the future development of novel JAK2 inhibitors using structure-based high-throughput virtual screening. Low-energy binding conformations of 1 and 2 in the JAK2 PTK domain were generated by virtual ligand docking and were found to overlap considerably with the binding pose of CMP6, a known JAK2 inhibitor. Compounds 1 and 2 displayed low micromolar efficacies against JAK2 enzyme activity and JAK2 autophosphorylation in human erythroleukemia cells, and inhibited STAT3 DNA-binding activity in a human hepatocarcinoma cell line. PMID- 25038529 TI - Epigenetic regulation of tissue factor inducibility in endothelial cell senescence. AB - Cellular senescence, a programmed state induced by multiple deleterious triggers, is characterised by permanent cell-cycle exit and altered gene expression and cell morphology. In humans it is considered a tumor suppressor mechanism, mediating removal of damaged or mutated cells from the cell-cycle pool, and may also contribute to the ageing process. In this study, we show that senescent human umbilical vein endothelial cells lose their ability to induce tissue factor (TF), a transmembrane protein with important roles in hemostasis and cancer progression, in response to thrombin or - independently of cell-surface receptors - phorbol-12-myristate-13-acetate. This phenomenon could not be explained by senescence-related alterations in the downstream signal transduction cascade or by accelerated TF mRNA degradation. Rather, using chromatin immuno-precipitation we could show that loss of TF gene inducibility during senescence occurs following chromatin remodelling of the TF promoter resulting from hypo acetylation of histone H3. These findings were reversible after transduction of presenescent cultures with telomerase reverse transcriptase, enabling late passage cultures to escape senescence. These results extend the involvement of heterochromatic gene silencing in senescence beyond cell cycle-related genes and suggest a novel anti-cancer mechanism of senescence through inhibition of TF inducibility. PMID- 25038530 TI - Interactions of the natural product kendomycin and the 20S proteasome. AB - Natural products are a valuable source for novel lead structures in drug discovery, but for the majority of isolated bioactive compounds, the cellular targets are unknown. The structurally unique ansa-polyketide kendomycin (KM) was reported to exert its potent cytotoxic effects via impairment of the ubiquitin proteasome system, but the exact mode of action remained unclear. Here, we present a systematic biochemical characterization of KM-proteasome interactions in vitro and in vivo, including complex structures of wild type and mutant yeast 20S proteasome with KM. Our results provide evidence for a polypharmacological mode of action for KM's cytotoxic effect on cancer cells. PMID- 25038531 TI - Physicians' beliefs about effectiveness of cancer screening tests: a national survey of family physicians, general internists, and obstetrician-gynecologists. AB - OBJECTIVE: To study physicians' beliefs about the effectiveness of different tests for cancer screening. METHODS: Data were examined from the Women's Health Survey of 1574 Family Medicine, Internal Medicine, and Obstetrics-Gynecology physicians to questions about their level of agreement about the clinical effectiveness of different tests for breast, cervical, ovarian, and colorectal cancer screening among average risk women. Data were weighted to the U.S. physician population based on the American Medical Association Masterfile. Multivariable logistic regression identified physician and practice characteristics significantly associated with physicians' beliefs. RESULTS: There were 1574 respondents, representing a 62% response rate. The majority of physicians agreed with the effectiveness of mammography for women aged 50 69years, Pap tests for women aged 21-65years, and colonoscopy for individuals aged >=50years. A substantial proportion of physicians believed that non recommended tests were effective for screening (e.g., 34.4% for breast MRI and 69.1% for annual pelvic exam). Physicians typically listed their respective specialty organizations as a top influential organization for screening recommendations. CONCLUSIONS: There were several substantial inconsistencies between physician beliefs in the effectiveness of cancer screening tests and the actual evidence of these tests' effectiveness which can lead both to underuse and overuse of cancer screening tests. PMID- 25038533 TI - Uptake of National AfterSchool Association physical activity standards among US after-school sites. AB - OBJECTIVE: In 2011, the National AfterSchool Association (NAA) adopted standards to guide delivery of physical activity (PA). We assessed after school sites' uptake of the five PA standards. METHOD: We conducted a descriptive study in fall 2013. NAA emailed 14,000 members requesting that afterschool site directors complete an online questionnaire regarding site characteristics, awareness and use of the standards, and implementation. We calculated implementation scores for each standard by summing points for their component best practices, and examined associations among site characteristics, implementation scores, and awareness and use of the standards. RESULTS: Among 595 respondents, 60% were aware of the PA standards and 43% used them for program planning. Awareness and use were significantly higher among NAA members and among sites that were accredited, licensed, or operated by a parent organization. PA content and quality scores were higher among those aware of and using the standards (p<0.01) and correlated with scores for staff training and for program, social, and environmental support (p<0.0001). CONCLUSION: We observed high recognition and use of the NAA PA standards in a national convenience sample of afterschool programs. Their uptake and use are promising lever for increasing the quality of PA in the afterschool setting. PMID- 25038532 TI - Non-compliance with the initial screening exam visit in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. AB - OBJECTIVE: Identify predictors of non-compliance with first round screening exams in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. METHOD: The PLCO was conducted from 1993 to 2011 at 10 US institutions. A total of 154,897 healthy men and women ages 55-74 years were randomized. Intervention arm participants were invited to receive gender-appropriate screening exams for prostate, lung, colorectal and ovarian cancer. Using intervention-arm data (73,036 participants), non-compliance percentages for 13 covariates were calculated, as were unadjusted and adjusted odds ratios (ORs), and 95% confidence intervals. Covariates included demographic factors as well as factors specific to PLCO (e.g., method of consent, distance from screening center). RESULTS: The rate of non-compliance was 11% overall but varied by screening center. Significant associations were observed for most covariates but indicated modest increases or decreases in odds. An exception was the use of a two-step consent process (consented intervention arm participants for exams after randomization) relative to a one-step process (consented all participants prior to randomization) (OR: 2.2, 95% CI: 2.0-2.5). Non-compliance percentages increased with further distance from screening centers, but ORs were not significantly different from 1. CONCLUSIONS: Many factors modestly influenced compliance. Consent process was the strongest predictor of compliance. PMID- 25038534 TI - The experience of new sensorimotor contingencies by sensory augmentation. AB - Embedded in the paradigm of embodied cognition, the theory of sensorimotor contingencies (SMCs) proposes that motor actions and associated sensory stimulations are tied together by lawful relations termed SMCs. We aimed to investigate whether SMCs can be learned by means of sensory augmentation. Therefore we focused on related perceptual changes. Subjects trained for 7 weeks with the feelSpace belt mapping information of the magnetic north to vibrotactile stimulation around the waist. They experienced substantial changes in their space perception. The belt facilitated navigation and stimulated the usage of new navigation strategies. The belt's vibrating signal changed to a kind of spatial information over time while the belt's appeal and perceived usability increased. The belt also induced certain emotional states. Overall, the results show that learning new SMCs with this relatively small and usable device leads to profound perceptual and emotional changes, which are fully compatible with embodied theories of cognition. PMID- 25038535 TI - Metacognitive model of mindfulness. AB - Mindfulness training has proven to be an efficacious therapeutic tool for a variety of clinical and nonclinical health problems and a booster of well-being. In this paper we propose a multi-level metacognitive model of mindfulness. We postulate and discuss following hypothesis: (1) mindfulness is related to the highest level of metacognition; (2) mindfulness depends on dynamic cooperation of three main components of the metacognition (metacognitive knowledge, metacognitive experiences and metacognitive skills); (3) a mindful meta-level is always conscious while the other meta-cognitive processes can occur implicitly; (4) intentionally practiced mindfulness decreases dissociations between awareness and meta-awareness; (5) components of mindful meta-level develop and change during continuous practice. The current model is discussed in the light of empirical data and other theoretical approaches to mindfulness concept. We believe that presented model provides some helpful avenues for future research and theoretical investigations into mindfulness and the mechanisms of its actions. PMID- 25038536 TI - An arsenic-specific biosensor with genetically engineered Shewanella oneidensis in a bioelectrochemical system. AB - Genetically engineered microbial biosensors have yet to realize commercial success in environmental applications due, in part, to difficulties associated with transducing and transmitting traditional bioluminescent information. Bioelectrochemical systems (BESs) output a direct electric signal that can be incorporated into devices for remote environmental monitoring. Here, we describe a BES-based biosensor with genetically encoded specificity for a toxic metal. By placing an essential component of the metal reduction (Mtr) pathway of Shewanella oneidensis under the control of an arsenic-sensitive promoter, we have genetically engineered a strain that produces increased current in response to arsenic when inoculated into a BES. Our BES-based biosensor has a detection limit of ~40 MUM arsenite with a linear range up to 100 MUM arsenite. Because our transcriptional circuit relies on the activation of a single promoter, similar sensing systems may be developed to detect other analytes by the swap of a single genetic part. PMID- 25038537 TI - An amperometric immunosensor for diagnosis of celiac disease based on covalent immobilization of open conformation tissue transglutaminase for determination of anti-tTG antibodies in human serum. AB - A new amperometric immunosensor based on the covalent immobilization of tissue transglutaminase enzyme in its open conformation (open-tTG) was developed and optimized for determination of anti-tissue transglutaminase antibodies (anti-tTG) in human serum. Experimental design allowed us to find the optimal conditions for quantification of both IgA and IgG isotypes of anti-tTG in order to assess suitability of the device for diagnostic purposes. The glassy carbon electrodic substrate was electrochemically functionalized with gold nanoparticles and subsequently derivatized with a self-assembled monolayer of 11-mercaptoundecanoic acid for the covalent anchoring of the enzyme. This step was performed under carefully controlled conditions in order to keep the open conformation of the tTG. The immunosensor showed good analytical performance with limit of detection levels (1.7 AU mL(-1) for IgA and 2.7 AU mL(-1) for IgG) below the diagnostic threshold value (3.0 AU mL(-1)) and inter-sensor reproducibility giving RSD lower than 10%. The developed sensor was validated in serum samples from pediatric patients for clinical applications, using two ELISA kits specific for the determination of anti-tTG IgA and IgG antibodies as reference methods; good recovery rates ranging from 74% to 117% were calculated. PMID- 25038538 TI - Choline and acetylcholine detection based on peroxidase-like activity and protein antifouling property of platinum nanoparticles in bovine serum albumin scaffold. AB - Platinum nanoparticles (PtNPs) in the scaffold of bovine serum albumin (BSA) through biomineralization are found to possess excellent peroxidase-like activity that can catalyze N-ethyl-N-(3-sulfopropyl)-3-methylaniline sodium salt (TOPS) coupled with 4-amino-antipyrine (4-AAP) by the action of hydrogen peroxide to give an obvious purple product. Based on this phenomenon, acetylcholinesterase (AChE) and choline oxidase (ChOx) are used to catalyze ACh and choline to form the active product H2O2 and the as-produced H2O2 is detected optically. Owning to the protection effect of the protein shell, BSA-PtNPs turn out to be very stable and preserve the catalytic activity in the presence of protein and even in the real plasma samples. This protein antifouling property makes the BSA-PtNPs suitable for a wide range of applications in sensors for biological samples. Choline in infant formula and ACh in plasma have been successfully detected. PMID- 25038539 TI - Signal amplification of glucosamine-6-phosphate based on ribozyme glmS. AB - Ribozyme glmS based isothermal amplification assay is developed for the colorimetric detection of glucosamine-6-phosphate (GlcN6P). Upon binding to the metabolite target GlcN6P, self-cleavage of glmS ribozyme is initiated to release RNA fragment that can trigger the cascade signal amplification to release large amount of G-quadruplex DNAzymes as reporter for colorimetric detection. Given the importance of GlcN6P for cell wall biosynthesis, the glmS riboswitch has become a new drug target for the development of antibiotics. This assay not only offers a convenient detection of GlcN6P with high specificity and sensitivity, but also provides a platform for high-throughput screening of antibiotics based on glmS riboswitches. PMID- 25038540 TI - Parallel recognition of cancer cells using an addressable array of solid-state micropores. AB - Early stage detection and precise quantification of circulating tumor cells (CTCs) in the peripheral blood of cancer patients are important for early diagnosis. Early diagnosis improves the effectiveness of the therapy and results in better prognosis. Several techniques have been used for CTC detection but are limited by their need for dye tagging, low throughput and lack of statistical reliability at single cell level. Solid-state micropores can characterize each cell in a sample providing interesting information about cellular populations. We report a multi-channel device which utilized solid-state micropores array assembly for simultaneous measurement of cell translocation. This increased the throughput of measurement and as the cells passed the micropores, tumor cells showed distinctive current blockade pulses, when compared to leukocytes. The ionic current across each micropore channel was continuously monitored and recorded. The measurement system not only increased throughput but also provided on-chip cross-relation. The whole blood was lysed to get rid of red blood cells, so the blood dilution was not needed. The approach facilitated faster processing of blood samples with tumor cell detection efficiency of about 70%. The design provided a simple and inexpensive method for rapid and reliable detection of tumor cells without any cell staining or surface functionalization. The device can also be used for high throughput electrophysiological analysis of other cell types. PMID- 25038541 TI - Effects of water-filtered infrared-A and of heat on cell death, inflammation, antioxidative potential and of free radical formation in viable skin--first results. AB - The effects of water-filtered infrared-A (wIRA) and of convective heat on viability, inflammation, inducible free radicals and antioxidative power were investigated in natural and viable skin using the ex vivo Bovine Udder System (BUS) model. Therefore, skin samples from differently treated parts of the udder of a healthy cow were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test, by prostaglandin E2 (PGE2) measurement and by electron spin resonance (ESR) spectroscopy. Neither cell viability, the inflammation status, the radical status or the antioxidative defence systems of the skin were significantly affected by wIRA applied within 30 min by using an irradiance of 1900 W m(-2) which is of relevance for clinical use, but which exceeded the maximum solar IR-A irradiance at the Earth's surface more than 5 times and which resulted in a skin surface temperature of about 45 degrees C without cooling and of about 37 degrees C with convective cooling by air ventilation. No significant effects on viability and on inflammation were detected when convective heat was applied alone under equivalent conditions in terms of the resulting skin surface temperatures and exposure time. As compared with untreated skin, free radical formation was almost doubled, whereas the antioxidative power was reduced to about 50% after convective heating to about 45 degrees C. PMID- 25038542 TI - Role of diversion ileostomy in low rectal cancer: a randomized controlled trial. AB - INTRODUCTION: Rectal cancer continues to be devastating malignancy worldwide. Sphincter preservation is the need of the hour. Distal anastomosis is more prone to leaks. Proximal diversion in form of ileostomy may be used to protect distal anastomosis. AIM: To compare two groups of low anterior resection with and without diversion ileostomy in rectal cancer patients. MATERIAL AND METHODS: A prospective, hospital based study of 78 rectal carcinoma patients were taken for the study. Inclusion criteria was operable rectal cancer 4-12 cm from anal verge. Patients were randomized into two groups. Group - A (34 patient) patients with low anterior resection with ileostomy (LAR with ileostomy); Group - B (44 patients) patients with low anterior resection without ileostomy (LAR without ileostomy). Quality of life was assessed by scoring done by self designed method. A total score of 0-20 given for various parameters. RESULTS: Skin excoriation was the commonest complication. Stomal retraction and stomal obstruction was seen in 1 patient each (3%). Hypokalemia was the commonest electrolyte imbalance present in ileostomy group. Anastomotic leak was present in 6% of Group A and 11% of Group B patients. Mean time of closure of ileostomy was 16 +/- 4.3 weeks. CONCLUSION: LAR with ileostomy has certain advantages over LAR without ileostomy in terms of anastomotic leak, postoperative ileus, resumption of diet, wound infection, small bowel obstruction and in terms mortality and recurrence. However stoma related complications were main disadvantage in LAR with ileostomy. PMID- 25038543 TI - Comparison of surficial CO2 efflux to other measures of subsurface crude oil degradation. AB - At a spill site near Bemidji, Minnesota, crude oil at the water table has been undergoing anaerobic biodegradation for over 30years. Previous work at this site has shown that methane produced from biodegradation of the oil migrates upward and is oxidized in a methanotrophic zone midway between the water table and the surface. To compare microbial activity measurement methods from multiple locations in the oil body, surficial carbon dioxide efflux, methanogen and methanotroph concentrations, and oil degradation state were collected. Carbon dioxide effluxes over the oil body averaged more than four times those at the background site. Methanotrophic bacteria concentrations measured using pmoA were over 10(5) times higher above the oil-contaminated sediments compared with the background site. Methanogenic archaea measured using mcrA ranged from 10(5) to over 10(7) in the oil and were below detection in the background. Methanogens correlated very well with methanotroph concentrations (r=0.99), n alkylcyclohexane losses as a proxy for degradation state (r=-0.96), and somewhat less well with carbon dioxide efflux (r=0.92). Carbon dioxide efflux similarly correlated to methanotroph concentrations (r=0.90) and n-alkylcyclohexane losses (r=-0.91). PMID- 25038544 TI - Targeted gene integration using the combination of a sequence-specific DNA binding protein and phiC31 integrase. AB - PhiC31 integrase-based vectors can integrate therapeutic genes selectively into attP or pseudo-attP sites in genomes, but considerable numbers of pseudo-attP sites in human genomes exist inside endogenous gene-coding regions. To avoid endogenous gene disruptions, we aimed to enhance the integration site-specificity of the phiC31 integrase-based vector using a sequence-specific DNA-binding protein containing Gal4 and LexA DNA-binding motifs. The dual DNA-binding protein was designed to tether the UAS-containing donor vector to the target sequence, the LexA operator, and restrict integration to sites close to the LexA operator. To analyze the site-specificity in chromosomal integration, a human cell line having LexA operators on the genome was established, and the cell line was transfected with donor vectors expressing the DNA-binding protein and the phiC31 integrase expression vector (helper vector). Quantitative PCR indicated that integration around the LexA operator was 26-fold higher with the UAS-containing donor vector than with the control. Sequence analysis confirmed that the integration occurred around the LexA operator. The dual DNA-binding protein-based targeted integration strategy developed herein would allow safer and more reliable genetic manipulations for various applications, including gene and cell therapies. PMID- 25038545 TI - Induced regulatory T-cells (iTregs) generated by activation with anti-CD3/CD28 antibodies differ from those generated by the physiological-like activation with antigen/APC. AB - Regulatory T-cells (Tregs) are responsible for homeostasis of the immune system, as well as for inhibition of pathogenic autoimmune processes. Induced-(i)-Tregs, can be generated in vitro by activation of CD4 cells in the presence of TGF-beta. A commonly used activation mechanism is by antibodies against CD3 and CD28. The physiological-like activation of T-cells, however, is with the specific target antigen presented by antigen-presenting cells (APC). The two modes of activation have been considered to yield the same populations of iTregs. Here, we compared between iTreg populations generated by either one of the two methods and found differences between their capacities to inhibit T-lymphocyte proliferative response, their expression of cell surface antigens and particularly, in their transcript expression profiles of certain chemokines and chemokine receptors. Our data thus indicate that iTregs generated by activation with anti-CD3/CD28 antibodies cannot be considered identical to iTregs generated by antigen/APC. PMID- 25038546 TI - Remarkable regression of a lung recurrence from an undifferentiated embryonal sarcoma of the liver treated with a DC vaccine combined with immune cells: a case report. AB - Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant tumor that occurs predominantly in children and has a poor prognosis. Here, we report a novel case in which the UESL presented in the left lobe of the liver and metastasized into both lungs after surgical resection. The patient recovered after our administration of an immunotherapeutic combination of DCs (Dendritic Cells) and multi-immune cells, such as cytokine-induced killer cells (CIKs) and natural killer cells (NKs). After the third cycle of immunotherapy, a CT scan showed a remarkable regression of the lung metastases. This finding supports the conclusion that the DC-based treatment is a promising potential strategy for treating patients with relapsed UESL. PMID- 25038547 TI - Immune-related effects from predation risk in Neotropical blue-black grassquits (Volatinia jacarina). AB - Predation is a major force shaping natural history traits of birds because of their vulnerability during nesting and higher visibility during diurnal activities. For most birds in the Neotropics, predation is the major cause of nest failure due to the region's high diversity and abundance of predators. The blue-black grassquit (Volatinia jacarina), similarly to other small passerines in the savanna region of central Brazil, suffers extremely high rates of nest predation. Additionally, males may be particularly vulnerable to predators since they are very conspicuous when executing courtship displays. We assessed some of the non-lethal costs of predation risk on this species by comparing physiological and morphological parameters of birds exposed to predator vocalizations with that of control subjects exposed to non-predator vocalizations. Birds exposed to the predator vocalizations exhibited an immune-related reaction (changes in their H/L ratio), but no changes were observed in other biological parameters measured. This article is part of a Special Issue entitled: Neotropical Behaviour. PMID- 25038548 TI - Degradation of phenazone in aqueous solution with ozone: influencing factors and degradation pathways. AB - Oxidation kinetics and degradation pathways of phenazone (an analgesic and antipyretic drug) upon reaction with O3 were investigated. Kinetic studies on degradation of phenazone were carried out under different operating conditions such as temperature, pH, anions and H2O2 addition. Results showed that the degradation followed the pseudo-first-order kinetic model. The reaction rate constant (kobs) of phenazone reached the maximum at 20 degrees C (9.653*10(-3) s(-1)). The presence of NO3(-) could enhance the degradation rate, while the addition of HCO3(-), SO4(2)(-), Cl(-) and the rise of pH showed negative effects on the ozonation of phenazone. H2O2 addition increased the phenazone degradation efficiency by 45.9% with the optimal concentration of 0.135 mM. Reaction by products were evaluated by UPLC-Q-TOF-MS, which allowed the identification of a total of 10 by-products. The transformation pathways of phenazone ozonation consisted mainly of electrophilic addition and substitution, pyrazole ring opening, hydroxylation, dephenylization and coupling. The toxicity of these intermediate products showed that they are expected not to be more toxic than phenazone, with the exception of P7 (aniline) and P10 (1,5-dimethyl-4-((1-methyl 2-phenylhydrazinyl)methoxy)-2-phenyl-1H-pyrazol-3(2H)-one). PMID- 25038549 TI - The effect of pathophysiology on pharmacokinetics in the critically ill patient- concepts appraised by the example of antimicrobial agents. AB - Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward. PMID- 25038550 TI - Patients with Parkinson's disease are less affected than healthy persons by relevant response-unrelated features in visual search. AB - Patients with Parkinson's disease (PD) respond more readily than healthy controls to irrelevant stimuli that contain task-relevant, response-priming features. This behavior may reflect oversensitivity to response-relevant features of irrelevant stimuli or failure to select relevant stimuli. To decide between these alternatives, we investigated in a "contingent-capture" paradigm whether PD patients are also oversensitive to task-relevant features that do not prime responses. PD patients and healthy controls had to report the orientation of bars in target color, presented among bars of other colors. Critically, target arrays were preceded by arrays of rings, all gray except one which might be the target color and might be presented at the same position as the upcoming target. Replicating earlier results from young healthy participants (Eimer, Kiss, Press, & Sauter, 2009), signal rings in target color induced an N2pc component over contralateral visual cortex and some positivity at anterior sites (d-P200), both indicative of attentional capture. Correspondingly, signals in target color facilitated correct responding to upcoming targets presented at the same location and impeded correct responses otherwise. Patients with PD had diminished N2pc, lacked the frontal focus of d-P200, and their responses tended to be less affected than healthy participants' by signal position. Thus PD patients appeared less affected than healthy persons by stimuli with relevant features. This outcome is compatible with the notion that PD patients have poorer internal representations of what is relevant in a given task. PMID- 25038551 TI - Dopamine system genes are associated with orienting bias among healthy individuals. AB - Healthy individuals display subtle orienting bias, manifested as a tendency to direct greater attention toward one hemispace, and evidence suggests that this bias reflects an individual trait, which may be modulated by asymmetric dopamine signaling in striatal and frontal regions. The current study examined the hypothesis that functional genetic variants within dopaminergic genes (DAT1 3' VNTR, dopamine D2 receptor Taq1A (rs1800497) and COMT Val158Met (rs4680)) contribute to individual differences in orienting bias, as measured by the greyscales paradigm, in a sample of 197 young healthy Israeli Jewish participants. For the Taq1A variant, homozygous carriers of the A2 allele displayed significantly increased leftward orienting bias compared to the carriers of the A1 allele. Additionally, and as previously reported by others, we found that bias towards leftward orienting of attention was significantly greater among carriers of the 9-repeat allele of the DAT1 3' VNTR as compared to the individuals who were homozygous for the 10-repeat allele. No significant effect of the COMT Val158Met on orienting bias was found. Taken together, our findings support the potential influence of genetic variants on inter-individual differences in orienting bias, a phenotype relevant to both normal and impaired cognitive processes. PMID- 25038552 TI - Therapeutic approach to respiratory infections in lung transplantation. AB - Lung transplant recipients (LTRs) are at life-long risk for infections and disseminated diseases owing to their immunocompromised state. Besides organ failure and sepsis, infection can trigger acute and chronic graft rejection which increases mortality. Medical prophylaxis and treatment are based on comprehensive diagnostic work-up including previous history of infection and airway colonisation to reduce long-term complications and mortality. Common bacterial pathogens include Pseudomonas and Staphylococcus, whilst Aspergillus and Cytomegalovirus (CMV) are respectively the commonest fungal and viral pathogens. Clinical symptoms can be various in lung transplant recipients presenting an asymptomatic to severe progress. Regular control of infection parameters, daily lung function testing and lifelong follow-up in a specialist transplant centre are mandatory for early detection of bacterial, viral and fungal infections. After transplantation each patient receives intensive training with rules of conduct concerning preventive behaviour and to recognize early signs of post transplant complications. Early detection of infection and complications are important goals to reduce major complications after lung transplantation. PMID- 25038553 TI - OntoVIP: an ontology for the annotation of object models used for medical image simulation. AB - This paper describes the creation of a comprehensive conceptualization of object models used in medical image simulation, suitable for major imaging modalities and simulators. The goal is to create an application ontology that can be used to annotate the models in a repository integrated in the Virtual Imaging Platform (VIP), to facilitate their sharing and reuse. Annotations make the anatomical, physiological and pathophysiological content of the object models explicit. In such an interdisciplinary context we chose to rely on a common integration framework provided by a foundational ontology, that facilitates the consistent integration of the various modules extracted from several existing ontologies, i.e. FMA, PATO, MPATH, RadLex and ChEBI. Emphasis is put on methodology for achieving this extraction and integration. The most salient aspects of the ontology are presented, especially the organization in model layers, as well as its use to browse and query the model repository. PMID- 25038555 TI - Limestone: high-throughput candidate phenotype generation via tensor factorization. AB - The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in consultation with a medical expert, we confirmed 82% of the top 50 candidates automatically extracted by Limestone are clinically meaningful. PMID- 25038554 TI - Size matters: how population size influences genotype-phenotype association studies in anonymized data. AB - OBJECTIVE: Electronic medical records (EMRs) data is increasingly incorporated into genome-phenome association studies. Investigators hope to share data, but there are concerns it may be "re-identified" through the exploitation of various features, such as combinations of standardized clinical codes. Formal anonymization algorithms (e.g., k-anonymization) can prevent such violations, but prior studies suggest that the size of the population available for anonymization may influence the utility of the resulting data. We systematically investigate this issue using a large-scale biorepository and EMR system through which we evaluate the ability of researchers to learn from anonymized data for genome phenome association studies under various conditions. METHODS: We use a k anonymization strategy to simulate a data protection process (on data sets containing clinical codes) for resources of similar size to those found at nine academic medical institutions within the United States. Following the protection process, we replicate an existing genome-phenome association study and compare the discoveries using the protected data and the original data through the correlation (r(2)) of the p-values of association significance. RESULTS: Our investigation shows that anonymizing an entire dataset with respect to the population from which it is derived yields significantly more utility than small study-specific datasets anonymized unto themselves. When evaluated using the correlation of genome-phenome association strengths on anonymized data versus original data, all nine simulated sites, results from largest-scale anonymizations (population ~100,000) retained better utility to those on smaller sizes (population ~6000-75,000). We observed a general trend of increasing r(2) for larger data set sizes: r(2)=0.9481 for small-sized datasets, r(2)=0.9493 for moderately-sized datasets, r(2)=0.9934 for large-sized datasets. CONCLUSIONS: This research implies that regardless of the overall size of an institution's data, there may be significant benefits to anonymization of the entire EMR, even if the institution is planning on releasing only data about a specific cohort of patients. PMID- 25038556 TI - Classifying obstructive sleep apnea using smartphones. AB - Obstructive sleep apnea (OSA) is a serious sleep disorder which is characterized by frequent obstruction of the upper airway, often resulting in oxygen desaturation. The serious negative impact of OSA on human health makes monitoring and diagnosing it a necessity. Currently, polysomnography is considered the gold standard for diagnosing OSA, which requires an expensive attended overnight stay at a hospital with considerable wiring between the human body and the system. In this paper, we implement a reliable, comfortable, inexpensive, and easily available portable device that allows users to apply the OSA test at home without the need for attended overnight tests. The design takes advantage of a smatrphone's built-in sensors, pervasiveness, computational capabilities, and user-friendly interface to screen OSA. We use three main sensors to extract physiological signals from patients which are (1) an oximeter to measure the oxygen level, (2) a microphone to record the respiratory effort, and (3) an accelerometer to detect the body's movement. Finally, we examine our system's ability to screen the disease as compared to the gold standard by testing it on 15 samples. The results showed that 100% of patients were correctly identified as having the disease, and 85.7% of patients were correctly identified as not having the disease. These preliminary results demonstrate the effectiveness of the developed system when compared to the gold standard and emphasize the important role of smartphones in healthcare. PMID- 25038557 TI - Phthalate exposure and child development: the Polish Mother and Child Cohort Study. AB - BACKGROUND: Widespread phthalate exposure has prompted investigations concerning their potential adverse health effects. AIM: The objective of this study was to evaluate the impact of pre and early postnatal phthalate exposure on child psychomotor development based on the data from the prospective Polish Mother and Child Cohort Study (REPRO PL). STUDY DESIGN, SUBJECTS AND OUTCOME MEASURES: Phthalate exposure was determined by measuring 11 phthalate metabolites (MEP, MiBP, MnBP, 3OH-MnBP, MBzP, MEHP, 5OH-MEHP, 5oxo-MEHP, OH-MiNP, oxo-MiNP, and MnOP) in the urine collected from mothers during the third trimester of pregnancy (prenatal exposure) and from their children at the 24th month of age (postnatal exposure). The analysis was performed by the HPLC-MS/MS method. Psychomotor development was assessed in children at the age of 2years by the Bayley Scales of Infant and Toddler Development. RESULTS: Child motor development was inversely associated with natural log concentrations (MUg/g creatinine) of 3OH-MnBP (beta= 2.3; 95% CI -4.0 to -0.6), 5OH-MEHP (beta= -1.2; 95% CI -2.2 to -0.3), 5oxo-MEHP (beta= -1.8; 95% CI -3.3 to -0.2) and sum of DEHP metabolites (beta= -2.2; 95% CI -3.6 to -0.8), DnBP metabolites (beta= -1.9; 95% CI -3.4 to -0.4), and high molecular weight phthalates (beta= -2.5; 95% CI -4.1 to -0.9) in the urine collected from mothers during pregnancy after adjustment for a variety of potential confounders. Additional adjustment for postnatal phthalate exposure did not change the results. Postnatal child exposure to phthalates was not associated with any of the measured scores of child psychomotor development. CONCLUSIONS: The study findings add further support to the possibility that prenatal phthalate exposure may be detrimental to child neurodevelopment and underscore the importance of policies and public health interventions aiming at reduction of such exposure. PMID- 25038558 TI - Rationale, design, and implementation of a cluster randomized trial using certified diabetes educators to intensify treatment for glycemia, blood pressure and lipid control: REMEDIES 4D. AB - BACKGROUND: Evidence supports that adequate treatment of hyperglycemia, hypercholesterolemia, and hypertension can reduce morbidity and mortality in people with diabetes, however achieving treatment goals remains elusive. The majority of diabetes care occurs in the primary care setting; however there are often missed opportunities for timely intervention during office visits. This paper describes a systematic redesign of current diabetes treatment in primary care by implementing evidence-based protocols. MATERIALS/METHODS: This is a cluster randomized controlled trial using certified diabetes educators (CDEs) to intensify therapeutic management. Fifteen primary care practices from the University of Pittsburgh Medical Center were recruited. Practices were randomized to intervention (implementation of diabetes management protocols) or usual care. Eligibility criteria included diagnosis of type 2 diabetes at least one year prior to baseline and an A1C >= 7%, LDLc >= 100 mg/dl or blood pressure >= 130/80 mmHg which were the goal levels established by the American Diabetes Association at study inception. Treatment was intensified according to preapproved protocols. Participants also received diabetes education during their visits. Research assessments were done at baseline, three, six and twelve months. Clinical visits were scheduled between research visits, as needed, to adjust medications. Primary outcomes were achievement of glycemic, blood pressure, or lipid control goals. Secondary outcomes included quality of life, medication and diabetes care satisfaction, medication adherence, and cost-effectiveness. CONCLUSIONS: Results from this study will provide the evidence to support expanded roles for CDEs in primary care. Using this model to deliver diabetes care may offer a more cost effective approach for diabetes management. PMID- 25038559 TI - Dosimetry for 131Cs and 125I seeds in solid water phantom using radiochromic EBT film. AB - PURPOSE: To measure the 2D dose distributions with submillimeter resolution for (131)Cs (model CS-1 Rev2) and (125)I (model 6711) seeds in a Solid Water phantom using radiochromic EBT film for radial distances from 0.06cm to 5cm. To determine the TG-43 dosimetry parameters in water by applying Solid Water to liquid water correction factors generated from Monte Carlo simulations. METHODS: Each film piece was positioned horizontally above and in close contact with a (131)Cs or (125)I seed oriented horizontally in a machined groove at the center of a Solid Water phantom, one film at a time. A total of 74 and 50 films were exposed to the (131)Cs and (125)I seeds, respectively. Different film sizes were utilized to gather data in different distance ranges. The exposure time varied according to the seed air-kerma strength and film size in order to deliver doses in the range covered by the film calibration curve. Small films were exposed for shorter times to assess the near field, while larger films were exposed for longer times in order to assess the far field. For calibration, films were exposed to either 40kV (M40) or 50kV (M50) x-rays in air at 100.0cm SSD with doses ranging from 0.2Gy to 40Gy. All experimental, calibration and background films were scanned at a 0.02cmpixel resolution using a CCD camera-based microdensitometer with a green light source. Data acquisition and scanner uniformity correction were achieved with Microd3 software. Data analysis was performed using ImageJ, FV, IDL and Excel software packages. 2D dose distributions were based on the calibration curve established for 50kV x-rays. The Solid Water to liquid water medium correction was calculated using the MCNP5 Monte Carlo code. Subsequently, the TG 43 dosimetry parameters in liquid water medium were determined. RESULTS: Values for the dose-rate constants using EBT film were 1.069+/-0.036 and 0.923+/ 0.031cGyU(-1)h(-1) for (131)Cs and (125)I seed, respectively. The corresponding values determined using the Monte Carlo method were 1.053+/-0.014 and 0.924+/ 0.016cGyU(-1)h(-1) for (131)Cs and (125)I seed, respectively. The radial dose functions obtained with EBT film measurements and Monte Carlo simulations were plotted for radial distances up to 5cm, and agreed within the uncertainty of the two methods. The 2D anisotropy functions obtained with both methods also agreed within their uncertainties. CONCLUSION: EBT film dosimetry in a Solid Water phantom is a viable method for measuring (131)Cs (model CS-1 Rev2) and (125)I (model 6711) brachytherapy seed dose distributions with submillimeter resolution. With the Solid Water to liquid water correction factors generated from Monte Carlo simulations, the measured TG-43 dosimetry parameters in liquid water for these two seed models were found to be in good agreement with those in the literature. PMID- 25038560 TI - Ammonium tolerance and toxicity of Actinoscirpus grossus--a candidate species for use in tropical constructed wetland systems. AB - Actinoscirpus grossus, a native species in tropical wetlands of South-East Asia, North Australia and the Pacific islands, has been reported to perform well in experimental scale constructed wetland (CW) systems. However, little is known about how high NH4(+) concentrations prevailing in wastewater affect growth and performance of this species. We examined growth, morphological and physiological responses of A. grossus to NH4(+) concentrations of 0.5, 2.5, 5, 10 and 15mM under hydroponic growth conditions. The relative growth rates (RGR) of the plants were highest at 2.5mM NH4(+) but significantly reduced at 10 and 15mM NH4(+). The roots of the plants were stunted and produced subepidermal lignified-cell layers at exposure to 10 and 15mM NH4(+). The photosynthetic rates did not differ between treatments (average An=21.3+/-0.4umolCO2m(-2)s(-1)) but the photosynthetic nitrogen and carbon use efficiency (PNUE and PCUE) were significantly depressed at 10 and 15mM NH4(+) treatments. The concentration of NH4(+) in the roots, but not in the leaves, reflected the NH4(+) concentration in the growth medium suggesting that the species is unable to regulate the NH4(+) uptake. The high root respiration rates in concert with high tissue NH4(+) and declined C/N ratio at 10 and 15mM NH4(+) suggest that the NH4(+) assimilation occurs primarily in the roots and the plant has inadequate C-skeletons for NH4(+) assimilation and exudation at high NH4(+) concentration in the external solution. The concentrations of mineral cations were generally reduced and the root membrane permeability increased at high external NH4(+) concentrations. Our study shows that A. grossus tolerates NH4(+) concentrations up to 5mM which is characteristic of most types of wastewater. Hence, A. grossus is a good native candidate species for use in CW systems in tropical and subtropical climates in South-East Asia, North Australia and the Pacific islands. PMID- 25038561 TI - Redistribution of voltage-gated sodium channels after nerve decompression contributes to relieve neuropathic pain in chronic constriction injury. AB - Nerve decompression is an important therapeutic strategy to relieve neuropathic pain and promote the peripheral nerve regeneration. To address these issues, we investigated the effects of nerve decompression on relief of neuropathic pain behaviors, redistribution of voltage-gated sodium channels (VGSCs), and skin reinnervation with chronic constriction injury (CCI). At post-operative week (POW) 4, animals were divided into a decompression group, in which the ligatures were removed, and a CCI group, in which the ligatures remained. Thermal hyperalgesia and mechanical allodynia at POW 8 had distinct reductions in decompression group compared to CCI group. At that time in CCI group, morphological evidence of pan VGSCs (Pan Nav) and isoforms of VGSCs (Nav1.6, Nav1.9, except for Nav1.8) were shown the widely distribution along the injured sciatic nerve. All of the VGSCs in decompression group became clustering around the node of Ranvier, similar to the pattern of control sciatic nerve at POW 8. Skin reinnervation was demonstrated by epidermal nerve density (END) for protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) nerve fibers and a significant difference between groups only at POW 24 (p=0.01). Growth-associated protein 43 (GAP-43) is participated in the nerve fiber growth and sprouting, a difference in END for GAP-43-IR nerve fibers at POW 24 between groups were also significant (p=0.02). These observations demonstrated that nerve decompression was accompanied with the disappearance of neuropathic pain behaviors after CCI. Morphological studies provided the evidence that redistribution of VGSCs along the injured sciatic nerve but still with an incomplete skin reinnervation. These significant findings demonstrated a role of VGSCs in the pathogenesis of neuropathic pain, and gave an approaching in pharmacological basis of therapeutics. PMID- 25038563 TI - In vivo magnetic resonance imaging at 11.7 Tesla visualized the effects of neonatal transection of infraorbital nerve upon primary and secondary trigeminal pathways in rats. AB - Using 11.7T ultra high-field T2-weighted MRI, the present study aimed to investigate pathological changes of primary and secondary trigeminal pathways following neonatal transection of infraorbital nerve in rats. The trigeminal pathways consist of spinal trigeminal tract, trigeminal sensory nuclear complex, medial lemniscus, ventromedial portion of external medullary lamina and ventral posterior nucleus of thalamus. By selecting optimum parameters of MRI such as repetition time, echo time, and slice orientation, this study visualized the trigeminal pathways in rats without any contrast agents. Pathological changes due to the nerve transection were found at 8 weeks of age as a marked reduction of the areas of the trigeminal pathways connecting from the injured nerve. In addition, T2-weighted MR images of the trigeminal nerve trunk and the spinal trigeminal tract suggest a communication of CSF through the trigeminal nerve between the inside and outside of the brain stem. These results support the utility of ultra high-field MRI system for noninvasive assessment of effects of trigeminal nerve injury upon the trigeminal pathways. PMID- 25038564 TI - Nonclinical safety assessment of Efinaconazole Solution (10%) for onychomycosis treatment. AB - Efinaconazole is a triazole developed as a 10% solution for topical treatment of onychomycosis, a common fungal nail infection. Efinaconazole solution and topical formulation vehicle administered dermally to mice (13weeks), rats (6months) and minipigs (9months) produced transient erythema, minimal to modest hyperkeratosis, and mild microscopic skin inflammation. The liver was the target organ of systemic toxicity; reversible, minimal to moderate vacuolated changes were noted in the rat dermal study at 15 and 50mg/kg/day. No systemic toxicity was observed in mice and minipigs, at approximate high dermal doses of 930 and 170mg/kg/day, respectively. Daily subcutaneous injection of propylene glycol vehicle or efinaconazole to rats for 6months produced severe local inflammation and systemic spread, evidenced by peritoneal adhesions, spinal cord necrosis and urinary tract disease. Mortalities occurred in all groups but were increased at the high dose (30 or 40mg/kg/day), suggesting that vehicle effects were exacerbated by efinaconazole. Efinaconazole was not carcinogenic in a 2-year mouse dermal study and was not genotoxic. Exposure-based safety margins at the NOAEL were 70-698 relative to onychomycosis patients. In conclusion, efinaconazole demonstrated low/moderate toxicity, consistent with other azole antifungals, and high safety margins for topical onychomycosis therapy. PMID- 25038562 TI - Nifedipine and nimodipine protect dopaminergic substantia nigra neurons against axotomy-induced cell death in rat vibrosections via modulating inflammatory responses. AB - Neurodegeneration of cholinergic and dopaminergic neurons is a major hallmark in Alzheimer's or Parkinson's disease, respectively. A dysregulation in calcium homeostasis may be part of this process and counteracting calcium influx may have neuroprotective properties in both diseases. Therefore, we investigated the putative neuroprotective or neurotoxic activity of L-type calcium channel (LTCC) inhibitors on cholinergic and dopaminergic neurons in a rat organotypic vibrosection model. Sagittal or coronal vibrosections (200 MUm thick) of postnatal day 10 rats were cultured on 0.4 MUm semipermeable membranes for 2 weeks with 10 ng/ml nerve growth factor (NGF) and/or glial-cell line derived neurotrophic factor (GDNF) to maintain survival of cholinergic or dopaminergic neurons, respectively. Thereafter, sections were incubated with 0.1, 1 or 10 MUM isradipine, nicardipine or verapamil for 2 weeks to explore cytotoxicity. Alternatively, in order to explore neuroprotective activity, vibrosections were incubated without growth factors but with isradipine or verapamil or with nicardipine, nimodipine or nifedipine from the beginning for 4 weeks. Our data show that all LTCC inhibitors exhibited no neurotoxic effect on cholinergic and dopaminergic neurons. Further, LTCC inhibitors did not have any neuroprotective activity on cholinergic neurons. However, nimodipine and nifedipine significantly enhanced the survival of dopaminergic substantia nigra (SN) but not ventral tegmental area (VTA) neurons, while nicardipine, isradipine and verapamil had no effect. Nifedipine (and more potently GDNF) reduced inflammatory cytokines (macrophage inflammatory protein-2, tumor necrosis factor-alpha), but did not influence oxidative stress or caspase-3 activity and did not interfere with iron mediated overload. Our data show that nifedipine and nimodipine are very potent to enhance the survival of axotomized SN neurons, possibly influencing inflammatory processes. PMID- 25038565 TI - An integrative risk assessment approach for persistent chemicals: a case study on dioxins, furans and dioxin-like PCBs in France. AB - For persistent chemicals slowly eliminated from the body, the accumulated concentration (body burden), rather than the daily exposure, is considered the proper starting point for the risk assessment. This work introduces an integrative approach for persistent chemical risk assessment by means of a dynamic body burden approach. To reach this goal a Kinetic Dietary Exposure Model (KDEM) was extended with the long term time trend in the exposure (historic exposure) and the comparison of bioaccumulation with body burden references for toxicity. The usefulness of the model was illustrated on the dietary exposure to PolyChlorinatedDibenzo-p-Dioxins (PCDDs), PolyChlorinatedDibenzoFurans (PCDFs) and PolyChlorinated Biphenyls (PCBs) in France. Firstly the dietary exposure to these compounds was determined in 2009 and combined with its long term time trend. In order to take differences between the kinetics of PCDD/F and dl-PCBs into account, three groups of congeners were considered i.e. PCDD/Fs, PCB 126 and remaining dl-PCBs. The body burden was compared with reference body burdens corresponding to reproductive, hepatic and thyroid toxicity. In the case of thyroid toxicity this comparison indicated that in 2009 the probability of the body burden to exceed its reference ranged from 2.8% (95% CI: 1.5-4.9%) up to 3.9% (95% CI: 2.7-7.1%) (18-29 vs. 60-79year olds). Notwithstanding the decreasing long-term time trend of the dietary dioxin exposure in France, this probability still is expected to be 1.5% (95% CI: 0.3-2.5%) in 2030 in 60-79 olds. In the case of reproductive toxicity the probability of the 2009 body burden to exceed its reference ranged from 3.1% (95% CI: 1.4-5.0%) (18-29year olds) to 3.5% (95% CI: 2.2-5.2%) (30-44year olds). In 2030 this probability is negligible in 18-29year olds, however small though significant in 30-44year olds (0.7%, 95% CI: 0-1.6%). In the case of hepatic toxicity the probability in 2009 even in 60-79year olds already was negligible. In conclusion this approach indicates that in France dioxin levels in food form a declining, though still present, future health risk with respect to thyroid and reproductive toxicity. PMID- 25038567 TI - A new peptide (Ruviprase) purified from the venom of Daboia russelii russelii shows potent anticoagulant activity via non-enzymatic inhibition of thrombin and factor Xa. AB - Compounds showing dual inhibition of thrombin and factor Xa (FXa) are the subject of great interest owing to their broader specificity for effective anticoagulation therapy against cardiovascular disorders. This is the first report on the functional characterization and assessment of therapeutic potential of a 4423.6 Da inhibitory peptide (Ruviprase) purified from Daboia russelii russelii venom. The secondary structure of Ruviprase is composed of alpha-helices (61.9%) and random coils (38.1%). The partial N-terminal sequence (E(1)-V(2)-X(3) W(4)-W(5)-W(6)-A(7)-Q(8)-L(9)-S(10)) of Ruviprase demonstrated significant similarity (80.0%) with an internal sequence of apoptosis-stimulating protein reported from the venom of Ophiophagus hannah and Python bivittatus; albeit Ruviprase did not show sequence similarity with existing thrombin/FXa inhibitors, suggesting its uniqueness. Ruviprase demonstrated a potent in vitro anticoagulant property and inhibited both thrombin and FXa following slow binding kinetics. Ruviprase inhibited thrombin by binding to its active site via an uncompetitive mechanism with a Ki value and dissociation constant (KD) of 0.42 MUM and 0.46 MUM, respectively. Conversely, Ruviprase demonstrated mixed inhibition (Ki = 0.16 MUM) of FXa towards its physiological substrate prothrombin. Furthermore, the biological properties of Ruviprase could not be neutralized by commercial polyvalent or monovalent antivenom. Ruviprase at a dose of 2.0 mg/kg was non toxic and showed potent in vivo anticoagulant activity after 6 h of intraperitoneal treatment in mice. Because of the potent anticoagulant property as well as non-toxic nature of Ruviprase, the possible application of the peptide as an antithrombotic agent for combating thrombosis-associated ailments appears promising. PMID- 25038568 TI - Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations. AB - We have carried out extended set of MUs-scale explicit solvent MD simulations of all possible G-triplexes which can participate in folding pathways of the human telomeric quadruplex. Our study accumulates almost 60 MUs of simulation data, which is by about three orders of magnitude larger sampling compared to the earlier simulations of human telomeric G-DNA triplexes. Starting structures were obtained from experimental quadruplex structures by deleting either the first or the last strand. The life-times of antiparallel triplexes with lateral and diagonal loops are at least on MUs-scale, which should be sufficient to contribute to the folding pathways. However, the triplex states may involve structures with various local deviations from the ideal triplexes, such as strand tilting and various alternative and incomplete triads. The simulations reveal easy rearrangements between lateral and diagonal loop triplex topologies. Propeller loops of antiparallel triplexes may to certain extent interfere with the G-triplexes but these structures are still viable candidates to participate in the folding. In contrast, all-parallel all-anti triplexes are very unstable and are unlikely to contribute to the folding. Although our simulations demonstrate that antiparallel G-triplexes, if folded, would have life-times sufficient to participate in the quadruplex folding, the results do not rule out the possibility that the G-triplexes are out-competed by other structures not included in our study. Among them, numerous possible misfolded structures containing guanine quartets can act as off-path intermediates with longer life times than the triplexes. Besides analyzing the structural dynamics of a diverse set of G-DNA triplexes, we also provide a brief discussion of the limitations of the simulation methodology, which is necessary for proper understanding of the simulation data. PMID- 25038566 TI - Bound cardiolipin is essential for cytochrome c oxidase proton translocation. AB - The proton pumping activity of bovine heart cytochrome c oxidase (CcO) is completely inhibited when all of the cardiolipin (CL) is removed from the enzyme to produce monomeric CcO containing only 11 subunits. Only dimeric enzyme containing all 13 subunits and 2-4 cardiolipin per CcO monomer exhibits a "normal" proton translocating stoichiometry of ~1.0 H(+) per/e(-) when reconstituted into phospholipid vesicles. These fully active proteoliposomes have high respiratory control ratios (RCR = 7-15) with 75-85% of the CcO oriented with the cytochrome c binding sites exposed to the external medium. In contrast, reconstitution of CL-free CcO results in low respiratory control ratios (RCR < 5) with the enzyme randomly oriented in the vesicles, i.e., ~50 percent oriented with the cytochrome c binding site exposed on the outside of the vesicle. Addition of exogenous CL to the CL-free enzyme completely restores electron transport activity, but restoration of proton pumping activity does not occur. This is true whether CL is added to CL-free CcO prior to reconstitution into phospholipid vesicles, or whether CL is included in the phospholipid mixture that is used to form the vesicles. Another consequence of CL removal is the inability of the 11-subunit, CL-free enzyme to dimerize upon exposure to either cholate or the cholate/PC/PE/CL mixture used during proteoliposome formation (monomeric, 13 subunit, CL-containing CcO completely dimerizes under these conditions). Therefore, a major difference between reconstitution of CL-free and CL-containing CcO is the incorporation of monomeric, rather than dimeric CcO into the vesicles. We conclude that bound CL is necessary for proper insertion of CcO into phospholipid vesicles and normal proton translocation. PMID- 25038569 TI - 2-[5-Selenocyanato-pentyl]-6-amino-benzo[de]isoquinoline-1,3-dione inhibits angiogenesis, induces p53 dependent mitochondrial apoptosis and enhances therapeutic efficacy of cyclophosphamide. AB - The present study embodies a detailed investigation of the chemoenhancement property of a synthetic organoselenium compound, 2-[5-selenocyanato-pentyl]-7 amino benzo[de]isoquinoline-1,3-dione (ANOS) in tumor bearing Swiss albino mice. The results accumulated from this study illustrated that the administration of ANOS significantly potentiated the therapeutic efficacy of cyclophosphamide by reducing the tumor burden and chemotherapy induced toxicity in the host. Ability of ANOS in inducing apoptosis and inhibiting angiogenesis was thought to be the crucial effecter for enhancing the therapeutic efficacy of cyclophosphamide. Fluorescence microscopic study revealed that ANOS was capable of penetrating tumor cells and distributed in the subcellular compartments. We showed that ANOS induced apoptosis, as evidenced by the TUNEL assay and cleavage of poly(ADP ribose) polymerase (PARP), involved ROS production and DNA damage in tumor cells. ROS production subsequently activated p53 phosphorylation at Ser-15. This in turn activated cytochrome c (cyt c) release from mitochondria via Bcl-2 and Bax. Finally activation of caspase 3 led to PARP cleavage and apoptosis. These results suggested that p53 dependent mitochondrial pathway was playing an important role in ANOS induced apoptosis of tumor cells. Administration of ANOS also resulted in significant improvement of tumor vasculature and sprouting of the peritoneal cavity along with the normalization of MMP-9 level in serum and ascites fluid of tumor bearing mice. This potential antiangiogenic activity of ANOS also facilitated the therapeutic efficacy of the combination therapy. Furthermore, ANOS significantly suppressed cyclophosphamide-induced liver, hematopoietic and genetic damages. A concomitant decrease in drug-induced toxicity by ANOS might also have enhanced the efficacy of cyclophosphamide by improving the intrinsic defense machineries of the host. PMID- 25038570 TI - N-terminal transmembrane domain of lipase LipA from Pseudomonas protegens Pf-5: A must for its efficient folding into an active conformation. AB - LipA from Pseudomonas protegens Pf-5 has been proven not to be secreted into the extracytoplasmic space, proposing that it is a membrane protein in virtue of its N-terminal transmembrane domain predicted by the TMHMM 2.0. However, LipA was confirmed to be an intracellular protein through determining the effects of lipA deletion or overexpression on the lipase activities in the whole-cell, lysis supernatant and lysis pellet, even through its transmembrane domain being able to make heterologous LacZ locate on the cytoplasmic membrane via construction of beta-galactosidase reporter strains. Subsequently, lipase activity assays showed that the transmembrane domain played an indispensable role for the catalytic function of LipA through construction of the markerless deletion mutant of transmembrane domain sequence of lipA and the expression and purification of LipA and LipADeltaTMD. To further investigate why the transmembrane domain lost its membrane localization function and significantly affected the catalytic function of LipA, the 3D structures of LipA and LipADeltaTMD were constructed. The results indicated that the transmembrane domain, located in the interior of LipA, helped the alpha-helical lid to form an open conformation by the mediation of alpha5 helix. It seems to act as a kind of intramolecular chaperone like the beta-roll motif of subfamily I.3 lipases, which is novel and is the first to notify the intramolecular chaperone of a subfamily I.1 lipase. PMID- 25038571 TI - Diphenyl diselenide protects endothelial cells against oxidized low density lipoprotein-induced injury: Involvement of mitochondrial function. AB - Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major risk factors for atherosclerosis and cardiovascular morbidity. The early stages of atherosclerosis are initiated by the accumulation of oxLDL and the induction of toxic effects on endothelial cells, resulting in endothelial dysfunction. The aim of this study was to investigate how diphenyl diselenide (DD), an organoselenium compound, protect vascular endothelial cells against the toxic effects of oxLDL in vitro. Our data showed that the treatment of bovine endothelial aortic cells (BAEC) with DD (0.1-1 MUM) for 24 h protected from oxLDL induced reactive species (RS) production and reduced glutathione (GSH) depletion. Moreover, DD (1 MUM) per se improved the maximal mitochondrial respiratory capacity and prevented oxLDL-induced mitochondrial damage. In addition, DD could prevent apoptosis induced by oxLDL in BAEC. Results from this study may provide insight into a possible molecular mechanism underlying DD suppression of oxLDL mediated vascular endothelial dysfunction. PMID- 25038572 TI - The role of Asn-212 in the catalytic mechanism of human endonuclease APE1: stopped-flow kinetic study of incision activity on a natural AP site and a tetrahydrofuran analogue. AB - Mammalian AP endonuclease 1 is a pivotal enzyme of the base excision repair pathway acting on apurinic/apyrimidinic sites. Previous structural and biochemical studies showed that the conserved Asn-212 residue is important for the enzymatic activity of APE1. Here, we report a comprehensive pre-steady-state kinetic analysis of two APE1 mutants, each containing amino acid substitutions at position 212, to ascertain the role of Asn-212 in individual steps of the APE1 catalytic mechanism. We applied the stopped-flow technique for detection of conformational transitions in the mutant proteins and DNA substrates during the catalytic cycle, using fluorophores that are sensitive to the micro-environment. Our data indicate that Asn-212 substitution by Asp reduces the rate of the incision step by ~550-fold, while Ala substitution results in ~70,000-fold decrease. Analysis of the binding steps revealed that both mutants continued to rapidly and efficiently bind to abasic DNA containing the natural AP site or its tetrahydrofuran analogue (F). Moreover, transient kinetic analysis showed that N212A APE1 possessed a higher binding rate and a higher affinity for specific substrates compared to N212D APE1. Molecular dynamics (MD) simulation revealed a significant dislocation of the key catalytic residues of both mutant proteins relative to wild-type APE1. The analysis of the model structure of N212D APE1 provides evidence for alternate hydrogen bonding between Asn-212 and Asp-210 residues, whereas N212A possesses an extended active site pocket due to Asn removal. Taken together, these biochemical and MD simulation results indicate that Asn-212 is essential for abasic DNA incision, but is not crucial for effective recognition/binding. PMID- 25038573 TI - Preferential removal and immobilization of stable and radioactive cesium in contaminated fly ash with nanometallic Ca/CaO methanol suspension. AB - In this work, the capability of nanometallic Ca/CaO methanol suspension in removing and/or immobilizing stable ((133)Cs) and radioactive cesium species ((134)Cs and (137)Cs) in contaminated fly ash was investigated. After a first methanol and second water washing yielded only 45% of (133)Cs removal. While, after a first methanol washing, the second solvent with nanometallic Ca/CaO methanol suspension yielded simultaneous enhanced removal and immobilization about 99% of (133)Cs. SEM-EDS analysis revealed that the mass percent of detectable (133)Cs on the fly ash surface recorded a 100% decrease. When real radioactive cesium contaminated fly ash (containing an initial 14,040Bqkg( 1)(134)Cs and (137)Cs cumulated concentration) obtained from burning wastes from Fukushima were reduced to 3583Bqkg(-1) after treatment with nanometallic Ca/CaO methanol suspension. Elution test conducted on the treated fly ash gave 100BqL( 1) total (134)Cs and (137)Cs concentrations in eluted solution. Furthermore, both ash content and eluted solution concentrations of (134)Cs and (137)Cs were much lower than the Japanese Ministry of the Environment regulatory limit of 8000Bqkg( 1) and 150BqL(-1) respectively. The results of this study suggest that the nanometallic Ca/CaO methanol suspension is a highly potential amendment for the remediation of radioactive cesium-contaminated fly ash. PMID- 25038574 TI - Optimizing the electrical excitation of an atmospheric pressure plasma advanced oxidation process. AB - The impact of pulse-modulated generation of atmospheric pressure plasma on the efficiency of organic dye degradation has been investigated. Aqueous samples of methyl orange were exposed to low temperature air plasma and the degradation efficiency was determined by absorbance spectroscopy. The plasma was driven at a constant frequency of 35kHz with a duty cycle of 25%, 50%, 75% and 100%. Relative concentrations of dissolved nitrogen oxides, pH, conductivity and the time evolution of gas phase ozone were measured to identify key parameters responsible for the changes observed in degradation efficiency. The results indicate that pulse modulation significantly improved dye degradation efficiency, with a plasma pulsed at 25% duty showing a two-fold enhancement. Additionally, pulse modulation led to a reduction in the amount of nitrate contamination added to the solution by the plasma. The results clearly demonstrate that optimization of the electrical excitation of the plasma can enhance both degradation efficiency and the final water quality. PMID- 25038575 TI - Effectiveness of recombinant protein AlnA in enhancing the extractability of polychlorinated biphenyls from contaminated soils. AB - One of the major limitations in bioremediation of polychlorinated biphenyls (PCBs) in contaminated soils is their low water solubility and high adsorbability. In the present study, effectiveness of recombinant protein AlnA as a biosurfactant in increasing extractability of PCBs was first investigated. The AlnA surface tension measurements allowed for determination of the minimum value of 37.89mN/m with critical micelle concentration of 1.07g/L. The solubilization of PCBs and desorption experiments were performed. It was observed that AlnA at 20MUg/mL could enhance solubility of selected crystal PCBs varying from 1.87 to 6.12 folds and it is easier to recover PCBs from contaminated soils compared with Tween-80 and cyclodextrin. Pot experiments indicated AlnA elevated 1.4-2.1-fold PCBs accumulation in roots by Alfalfa. The homology modeling and docking revealed PCBs congeners had different interactions with AlnA and higher-chlorinated PCBs possessed higher binding affinity. Results showed AlnA had considerable application potential in remediation of PCBs pollution. PMID- 25038576 TI - Unintended emission of nanoparticle aerosols during common laboratory handling operations. AB - Common laboratory operations such as pouring, mashing in an agate mortar, transferring with a spatula, have been assessed as potential sources for emission of engineered nanoparticles in simulated occupational environments. Also, the accidental spilling from an elevated location has been considered. For workplace operations, masses of 1500 or 500mg of three dry-state engineered nanoparticles (SiO2, TiO2 and Ce-TiO2) with all dimensions under 30nm, and one fibrous nanomaterial (MWCNT) with diameter under 10nm and length about 1.5MUm were used. The measured number emission factors (NEF) for every operation and material in this work were in the range of 10(5) #s(-1). The traceability of emitted nanoparticles has been improved using Ce-doping on TiO2 nanoparticles. With this traceable material it was possible to show that generated aerosol nanoparticles are rapidly associated with background particles to form large-sized aerosol agglomerates. PMID- 25038577 TI - Effects of various TiO2 nanostructures and graphene oxide on photocatalytic activity of TiO2. AB - The nanostructures of TiO2 significantly affect its photocatalytic activity. In this work, various TiO2 nanostructures have been successfully synthesized, including one-dimensional (1D) TiO2 nanotube, 1D TiO2 nanowire, three-dimensional (3D) TiO2 sphere assembled by nanoparticles (TiO2 sphere-P) and 3D TiO2 sphere assembled by nanosheets (TiO2 sphere-S). The results of photodegradation activity towards acid orange 7 (AO7) indicate that the photodegradation efficiency of TiO2 sphere-S is the highest among the investigated TiO2 nanostructures, even though the specific surface area of TiO2 sphere-S is lower than that of TiO2 nanotube. The best photodegradation activity of TiO2 sphere-S can be attributed to the highest light harvesting capacity resulted from multiple reflections of light, and hierarchical mesoporous structure. In addition, the combination of TiO2 sphere-S with graphene oxide (GO) sheets can further enhance the photodegradation efficiency of AO7 and disinfection activity of Escherichia coli (E. coli) under solar light, which is more energy efficient. The promising photocatalytic activity of GO-TiO2 composites is originated from the enhanced light absorption and efficient charge separation. Hence, this study paves a way for improving the performance of other photocatalysts. PMID- 25038578 TI - Oxidative degradation of endotoxin by advanced oxidation process (O3/H2O2 & UV/H2O2). AB - The presence of endotoxin in water environments may pose a serious public health hazard. We investigated the effectiveness of advanced oxidative processes (AOP: O3/H2O2 and UV/H2O2) in the oxidative degradation of endotoxin. In addition, we measured the release of endotoxin from Escherichia coli following typical disinfection methods, such as chlorine, ozone alone and UV, and compared it with the use of AOPs. Finally, we tested the AOP-treated samples in their ability to induce tumor necrosis factor alpha (TNF-alpha) in mouse peritoneal macrophages. The production of hydroxyl radical in AOPs showed superior ability to degrade endotoxin in buffered solution, as well as water samples from Korean water treatment facilities, with the ozone/H2O2 being more efficient compared to UV/H2O2. In addition, the AOPs proved effective not only in eliminating E. coli in the samples, but also in endotoxin degradation, while the standard disinfection methods lead to the release of endotoxin following the bacteria destruction. Furthermore, in the experiments with macrophages, the AOPs deactivated endotoxin lead to the smallest induction of TNF-alpha, which shows the loss of inflammation activity, compared to ozone treatment alone. In conclusion, these results suggest that AOPs offer an effective and mild method for endotoxin degradation in the water systems. PMID- 25038579 TI - Application of loop-mediated isothermal amplification assay combined with lateral flow dipstick for detection of Plasmodium falciparum and Plasmodium vivax. AB - Malaria is largely a preventable and curable disease. However, a delay or an inappropriate treatment can result in serious adverse outcomes for patient. Rapid, simple and cost-effective diagnostic tests that can be easily adapted and rapidly scaled-up at the field or community levels are needed. In this study, accelerated detection methods for the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) dihydrofolate reductase-thymidylate synthase were developed based on the loop-mediated isothermal amplification (LAMP) method. The developed methods included the use of species-specific biotinylated primers to amplify LAMP amplicons, which were then hybridized to specific FITC-labeled DNA probes and visualized on a chromatographic lateral flow dipstick (LFD). The total LAMP-LFD assay time was approximately 1.5h. The LAMP-LFD assays showed similar detection limit to conventional PCR assay when performed on plasmid DNA carrying the malaria dhfr-ts genes. The LAMP-LFD showed 10 folds higher detection limit than PCR when performed on genomic DNA samples from Pf and Pv parasites. The dhfr-ts LAMP-LFD assays also have the advantages of reduced assay time and easy format for interpretation of results. PMID- 25038580 TI - Contemporary girlhood: maternal reports on sexualized behaviour and appearance concern in 4-10 year-old girls. AB - It is widely accepted that the sexualization of girls has increased markedly over time. The overall aim of the present study was to offer a description of the behaviours of young girls, with a particular focus on potentially sexualized behaviours and appearance concern. A sample of 815 mothers of 4-10 year-old girls completed a questionnaire about a range of behaviours exhibited by their daughters, in addition to measures of their own self-objectification and material concern. It was found that many girls engaged with teen culture and used a variety of beauty products, but few exhibited more overtly sexualized behaviours. Involvement with teen culture, using beauty products, attention to clothes, and personal grooming were all associated with the measure of appearance concern, as were maternal self-objectification and material concern. It was concluded that young girls do engage in 'grown up' behaviours and that such engagement is not benign for their development. PMID- 25038581 TI - Tumoral reprogramming: Plasticity takes a walk on the wild side. AB - Cellular plasticity is the capacity that cells have to change their fate and adopt a new identity. Plasticity is essential for normal development and for tissue regeneration and, in an experimental setting, for the induction of pluripotency. All these processes involve a reprogramming of the cellular identity, mediated by signals from the environment and/or by internal changes at the transcriptional and epigenetic levels. Tumorigenesis is a process in which normal cells acquire a new malignant identity and give rise to a clonal aberrant population. This is only possible if the initiating cell has the necessary plasticity to undergo such changes, and if the oncogenic event(s) initiating cancer has the essential reprogramming capacity so as to be able to lead a change in cellular identity. The molecular mechanisms underlying tumoral reprogramming are the pathological counterparts of the normal processes regulating developmental plasticity or experimentally-induced reprogramming. In this review we will first revise the main features of non-pathological examples of reprogramming, and then we will describe the parallelisms with tumoral reprogramming, and we will also delineate how the precise knowledge of the reprogramming mechanisms offers the potential for the development of new therapeutical interventions. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID- 25038582 TI - Aromatase, estrogen receptors and brain development in fish and amphibians. AB - Estrogens affect brain development of vertebrates, not only by impacting activity and morphology of existing circuits, but also by modulating embryonic and adult neurogenesis. The issue is complex as estrogens can not only originate from peripheral tissues, but also be locally produced within the brain itself due to local aromatization of androgens. In this respect, teleost fishes are quite unique because aromatase is expressed exclusively in radial glial cells, which represent pluripotent cells in the brain of all vertebrates. Expression of aromatase in the brain of fish is also strongly stimulated by estrogens and some androgens. This creates a very intriguing positive auto-regulatory loop leading to dramatic aromatase expression in sexually mature fish with elevated levels of circulating steroids. Looking at the effects of estrogens or anti-estrogens in the brain of adult zebrafish showed that estrogens inhibit rather than stimulate cell proliferation and newborn cell migration. The functional meaning of these observations is still unclear, but these data suggest that the brain of fish is experiencing constant remodeling under the influence of circulating steroids and brain-derived neurosteroids, possibly permitting a diversification of sexual strategies, notably hermaphroditism. Recent data in frogs indicate that aromatase expression is limited to neurons and do not concern radial glial cells. Thus, until now, there is no other example of vertebrates in which radial progenitors express aromatase. This raises the question of when and why these new features were gained and what are their adaptive benefits. This article is part of a Special Issue entitled: Nuclear receptors in animal development. PMID- 25038583 TI - Somatic embryogenesis - Stress-induced remodeling of plant cell fate. AB - Plants as sessile organisms have remarkable developmental plasticity ensuring heir continuous adaptation to the environment. An extreme example is somatic embryogenesis, the initiation of autonomous embryo development in somatic cells in response to exogenous and/or endogenous signals. In this review I briefly overview the various pathways that can lead to embryo development in plants in addition to the fertilization of the egg cell and highlight the importance of the interaction of stress- and hormone-regulated pathways during the induction of somatic embryogenesis. Somatic embryogenesis can be initiated in planta or in vitro, directly or indirectly, and the requirement for dedifferentiation as well as the way to achieve developmental totipotency in the various systems is discussed in light of our present knowledge. The initiation of all forms of the stress/hormone-induced in vitro as well as the genetically provoked in planta somatic embryogenesis requires extensive and coordinated genetic reprogramming that has to take place at the chromatin level, as the embryogenic program is under strong epigenetic repression in vegetative plant cells. Our present knowledge on chromatin-based mechanisms potentially involved in the somatic-to embryogenic developmental transition is summarized emphasizing the potential role of the chromatin to integrate stress, hormonal, and developmental pathways leading to the activation of the embryogenic program. The role of stress-related chromatin reorganization in the genetic instability of in vitro cultures is also discussed. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID- 25038584 TI - Impact of MYC in regulation of tumor cell metabolism. AB - The MYC proto-oncoproteins including c-MYC, MYCN and MYCL exert their functions as heterodimers with MAX, which in turn binds to E-box sequences at target promoters to regulate gene expression. It has been shown that MYC binds to 10-15% of all promoter regions and regulates genes involved in a wide variety of cellular functions. In normal cells the expression of MYC is tightly controlled whereas it is deregulated in the majority of human tumors. MYC contributes to malignant transformation by promoting multiple processes including uncontrolled cell proliferation, cell growth and genomic instability. Importantly, MYC promotes growth by activating genes involved in ribosomal and mitochondrial biogenesis, glucose and glutamine metabolism as well as lipid synthesis. Hence, MYC is contributing to the metabolic reprogramming essential for cancer cells to adapt to the tumor microenvironment. Here we give an overview of the role of MYC in regulation of metabolic pathways in tumor cells. This article is part of a Special Issue entitled: MYC proteins in cell biology and pathology. PMID- 25038585 TI - Stress as a fundamental theme in cell plasticity. AB - Over a decade of intensive investigation of the possible plasticity of mammalian cells has eventually substantiated that mammalian species are endowed with a remarkable capacity to change mature cell fates. We review below the evidence for the occurrence of processes such as dedifferentiation and transdifferentiation within mammalian tissues in vivo, and in cells removed from their protective microenvironment and seeded in culture under conditions poorly resembling their physiological state in situ. Overall, these studies point to one major conclusion: stressful conditions, whether due to in vivo tissue damage or otherwise to isolation of cells from their in vivo restrictive niches, lead to extreme fate changes. Some examples of dedifferentiation are discussed in detail showing that rare cells within the population tend to turn back into less mature ones due to severe cell damage. It is proposed that cell stress, mechanistically sensed by isolation from neighboring cells, leads to dedifferentiation, in an attempt to build a new stem cell reservoir for subsequent regeneration of the damaged tissue. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID- 25038586 TI - Wavelet-based denoising method for real phonocardiography signal recorded by mobile devices in noisy environment. AB - The main obstacle in development of intelligent autodiagnosis medical systems based on the analysis of phonocardiography (PCG) signals is noise. The noise can be caused by digestive and respiration sounds, movements or even signals from the surrounding environment and it is characterized by wide frequency and intensity spectrum. This spectrum overlaps the heart tones spectrum, which makes the problem of PCG signal filtrating complex. The most common method for filtering such signals are wavelet denoising algorithms. In previous studies, in order to determine the optimum wavelet denoising parameters the disturbances were simulated by Gaussian white noise. However, this paper shows that this noise has a variable character. Therefore, the purpose of this paper is adaptation of a wavelet denoising algorithm for the filtration of real PCG signal disturbances from signals recorded by a mobile devices in a noisy environment. The best results were obtained for Coif 5 wavelet at the 10th decomposition level with the use of a minimaxi threshold selection algorithm and mln rescaling function. The performance of the algorithm was tested on four pathological heart sounds: early systolic murmur, ejection click, late systolic murmur and pansystolic murmur. PMID- 25038587 TI - Improving quality through process change: a scoping review of process improvement tools in cancer surgery. AB - BACKGROUND: Surgery is a cornerstone of treatment for malignancy. However, significant variation has been reported in patterns and quality of cancer care for important health outcomes, including perioperative mortality. Surgical process improvement tools (SPITs) have been developed that focus on enhancing the processes of care at the point of care, as a means of quality improvement. This study describes SPITs and develops a conceptual framework by synthesizing the available literature on these novel quality improvement tools. METHODS: A scoping review was conducted based on instruments developed for quality improvement in surgery. The search was executed on electronically indexed sources (MEDLINE, EMBASE, and the Cochrane library) from January 1990 to March 2011. Data were extracted, tabulated and reported thematically using a narrative synthesis approach. These results were used to develop a conceptual framework that describes and classifies SPITs. RESULTS: 232 articles were reviewed for data extraction and analysis. SPITs identified were classified into 3 groups: clinical mapping tools, structure communication tools and error reduction instruments. The dominant instrument reported were clinical mapping tools, including: clinical pathways (113, 48%), fast track (46, 20%) and enhanced recovery after surgery protocols (36, 15%). Outcomes reported included: length of stay (174, 75%), readmission rates (116, 50%), morbidity (116, 50%), mortality (104, 45%), and economic (60, 26%). Many gaps in the literature were recognized. CONCLUSION: We have developed a conceptual framework of SPITs and identified gaps in current knowledge. These results will guide the design and development of new quality instruments in surgery. PMID- 25038588 TI - Importance of plasticity and local adaptation for coping with changing salinity in coastal areas: a test case with barnacles in the Baltic Sea. AB - BACKGROUND: Salinity plays an important role in shaping coastal marine communities. Near-future climate predictions indicate that salinity will decrease in many shallow coastal areas due to increased precipitation; however, few studies have addressed this issue. The ability of ecosystems to cope with future changes will depend on species' capacities to acclimatise or adapt to new environmental conditions. Here, we investigated the effects of a strong salinity gradient (the Baltic Sea system--Baltic, Kattegat, Skagerrak) on plasticity and adaptations in the euryhaline barnacle Balanus improvisus. We used a common garden approach, where multiple batches of newly settled barnacles from each of three different geographical areas along the Skagerrak-Baltic salinity gradient were exposed to corresponding native salinities (6, 15 and 30 PSU), and phenotypic traits including mortality, growth, shell strength, condition index and reproductive maturity were recorded. RESULTS: We found that B. improvisus was highly euryhaline, but had highest growth and reproductive maturity at intermediate salinities. We also found that low salinity had negative effects on other fitness-related traits including initial growth and shell strength, although mortality was also lowest in low salinity. Overall, differences between populations in most measured traits were weak, indicating little local adaptation to salinity. Nonetheless, we observed some population-specific responses--notably that populations from high salinity grew stronger shells in their native salinity compared to the other populations, possibly indicating adaptation to differences in local predation pressure. CONCLUSIONS: Our study shows that B. improvisus is an example of a true brackish-water species, and that plastic responses are more likely than evolutionary tracking in coping with future changes in coastal salinity. PMID- 25038589 TI - Quinestrol induces spermatogenic apoptosis in vivo via increasing pro-apoptotic proteins in adult male mice. AB - The effects of quinestrol on spermatogenesis were investigated in adult male mice by daily intragastric administration of quinestrol with various doses of 5, 10, 50 and 100mg/kg body weight for 10 days. The sperm counts declined while the number of abnormal spermatozoa went up in mice treated with quinestrol. The testicular weight and seminiferous tubular area gradually declined with increasing dosages of quinestrol to 50 and 100mg/kg. Rarefied germ cells showed irregular distributions in the seminiferous tubules of mice treated with 50 and 100mg/kg quinestrol. Apoptosis was highly pronounced in spermatogonia, spermatocytes, spermatids and Leydig cells. Antioxidant enzyme activities - superoxide dismutase and glutathione peroxidase - as well as total antioxidant capacity significantly reduced, while malondialdehyde contents increased. The number of germ cells expressing caspase-3, p53, Bax and FasL significantly increased whereas cells expressing Bcl-2 significantly decreased in groups treated with 50 and 100mg/kg quinestrol compared with the control. The concentration of nitrogen monoxidum also increased significantly under these dosages. The results suggest that quinestrol stimulates oxidative stress to induce apoptosis in spermatogenic cells through the mitochondrial and death receptor pathways in adult male mice. PMID- 25038590 TI - Genome-wide transcriptome and functional analysis of two contrasting genotypes reveals key genes for cadmium tolerance in barley. AB - BACKGROUND: Cadmium (Cd) is a severe detrimental environmental pollutant. To adapt to Cd-induced deleterious effects, plants have evolved sophisticated defence mechanisms. In this study, a genome-wide transcriptome analysis was performed to identify the mechanisms of Cd tolerance using two barley genotypes with distinct Cd tolerance. RESULTS: Microarray expression profiling revealed that 91 genes were up-regulated by Cd in Cd-tolerant genotype Weisuobuzhi and simultaneously down-regulated or non-changed in Cd-sensitive Dong17, and 692 genes showed no change in Weisuobuzhi but down-regulated in Dong17. Novel genes that may play significant roles in Cd tolerance were mainly via generating protectants such as catalase against reactive oxygen species, Cd compartmentalization (e.g. phytochelatin-synthase and vacuolar ATPase), and defence response and DNA replication (e.g. chitinase and histones). Other 156 up regulated genes in both genotypes also included those encoding proteins related to stress and defence responses, and metabolism-related genes involved in detoxification pathways. Meanwhile, biochemical and physiological analysis of enzyme (ATPase and chitinase), phytohormone (ethylene), ion distribution and transport (Cd, Na(+), K(+), Ca(2+), ABC transporter) demonstrated that significantly larger Cd-induced increases of those components in Weisuobuzhi than those in Dong17. In addition, Cd-induced DNA damage was more pronounced in Dong17 than that in Weisuobuzhi. CONCLUSIONS: Our findings suggest that combining microarray, physiological and biochemical analysis has provided valuable insights towards a novel integrated molecular mechanism of Cd tolerance in barley. The higher expression genes in Cd tolerant genotype could be used for transgenic overexpression in sensitive genotypes of barley or other cereal crops for elevating tolerance to Cd stress. PMID- 25038591 TI - Long-acting beta-agonists plus inhaled corticosteroids safety: a systematic review and meta-analysis of non-randomized studies. AB - BACKGROUND: Although several systematic reviews investigated the safety of long acting beta-agonists (LABAs) in asthma, they mainly addressed randomized clinical trials while evidence from non-randomized studies has been mostly neglected. We aim to assess the risk of serious adverse events in adults and children with asthma treated with LABAs and Inhaled Corticosteroids (ICs), compared to patients treated only with ICs, from published non-randomized studies. METHODS: The protocol registration number was CRD42012003387 (http://www.crd.york.ac.uk/Prospero). Literature search for articles published since 1990 was performed in MEDLINE and EMBASE. Two authors selected studies independently for inclusion and extracted the data. A third reviewer resolved discrepancies. To assess the risk of serious adverse events, meta-analyses were performed calculating odds ratio summary estimators using random effect models when heterogeneity was found, and fixed effect models otherwise. RESULTS: Of 4,415 candidate articles, 1,759 abstracts were reviewed and 220 articles were fully read. Finally, 19 studies met the inclusion criteria. Most of them were retrospective observational cohorts. Sample sizes varied from 50 to 514,216. The meta-analyses performed (69,939-624,303 participants according to the outcome considered) showed that odds ratio of the LABAs and ICs combined treatment when compared with ICs alone was: 0.88 (95% CI 0.69-1.12) for asthma-related hospitalization; 0.75 (95% CI 0.66-0.84) for asthma-related emergency visits; 1.02 (95% CI 0.94-1.10) for systemic corticosteroids; and 0.95 (95% CI 0.9-1.0) for the combined outcome. CONCLUSIONS: Evidence from observational studies shows that the combined treatment of LABAs and ICs is not associated with a higher risk of serious adverse events, compared to ICs alone. Major gaps identified were prospective design, paediatric population and inclusion of mortality as a primary outcome. PMID- 25038592 TI - Occurrence of additive brominated flame retardants in aquatic organisms from Tai Lake and Yangtze River in Eastern China, 2009-2012. AB - Since the phase-out of PBDEs, reports regarding occurrences of these compounds in the environment have become less frequent. To characterize potential influences of the phase-out of PBDEs' on concentrations in the environment, trends in concentrations as a function of time were investigated for two additive brominated flame retardants, PBDEs and HBCDs. Three aquatic species, including shrimp, common carp, and yellow catfish, were collected from Meiliang Bay of Tai Lake, 2009-2012. The analysis of PBDEs in three aquatic organisms has shown a downward-trend in the first three years but a significant upward-trend in the final year. Concentrations of HBCDs have not shown temporal increases in the investigated environments. Concentrations of both PBDEs and HBCDs in the three studied organisms increased as a function of trophic level, which suggested that these additive flame retardants can be biomagnified through the food web of Tai Lake. In accordance with previous publications, PBDE-47 contributed the greatest proportion of ?PBDEs and had a detection frequency of 100%. alpha-HBCD was the predominate isomer that contributed to ?HBCDs. Both beta-HBCD and gamma-HBCD were likely detected at lesser concentrations than the alpha-isomer due to differences in bioavailability. Concentrations of ?PBDEs in the three aquatic organisms from Tai Lake ranged from 1.13 to 97.59 ng g(-1) lipid. These concentrations were generally less than those in biota from other countries, but equal to those found at other locations in China. Specimens from the Yangtze River had greater concentrations of ?HBCDs (169.6-316.5 ng g(-1) lipid) than those collected at Tai Lake, which were comparatively greater than many reported concentrations in freshwater organisms from other countries. PMID- 25038593 TI - A case of growth-hormone staining pituitary adenoma with renal cyst and hepatic cyst: are they related manifestations of a single disease? AB - Growth-hormone staining pituitary adenoma is a popular disease of the central nervous system. We noticed some patients have accompanying cystic disorders. Several cases of concomitant growth-hormone (GH)-staining pituitary adenoma and other cystic changes have been reported but with no further investigation. We report a case of adult growth-hormone staining pituitary adenoma with accompanying polycystic changes of multiple systems, as well as hypertension and nephrolithiasis. Preoperative clinical assessment revealed intrasellar tumor, multinodular thyroid disorder, renal cysts, and hepatic cysts, with increased serum growth-hormone level and normal thyroid hormone level. The total tumor resection was performed via endoscopic transsphenoidal approach. The pathologic analysis reported growth-hormone staining pituitary adenoma. The postoperative course was uneventful. The endocrine testing was normal soon after the operation and the patient remained well for a follow-up period of eight months. This is the fifth report about simultaneous growth-hormone staining pituitary adenoma and polycystic changes of the kidneys and the liver. With review of the literature we speculate that the abnormal growth hormone secretion of the pituitary adenoma may arouse sequential cystic changes of multiple systems through some IGF-I involved pathways. PMID- 25038594 TI - A ten-year observation of somatic development of a first group of Polish children with Silver-Russell syndrome. AB - OBJECTIVE: Silver-Russell syndrome is heterogeneous both clinically and genetically. The best known genetic aberrations existing in this syndrome are an 11p15 epimutation, present in 20-60% patients, and a maternal uniparental chromosome 7 disomy (7-15%) (upd(7)mat). Children with SRS suffer from physical growth impairments - intrauterine and after birth. MATERIAL AND METHODS: The study group consisted of 38 children aged 2 to 17 (x=8.9 +/- 4.0 years). These children had undergone a genetic analysis in search for the 11p15 epimutation and the upd(7)mat. Somatic growth was also analysed in terms of birth parameters and postnatal BMI, weight and height. The aforementioned parameters were compared in a subgroup of children with the genetic aberrations and with a control group of children born with IUGR. RESULTS: In the study group a mean weight SD on birth was -3.41 +/- 1.22, the birth height was -1.25 +/- 2.08 SD and a head circumference of -3.56 +/- 1.93 SD. No significant differences were noted between the SRS study group and the control group in reference to weight and head circumference (p>0.05). Such difference was, however, seen in birth height. Children with 11p15 epimutation had significantly lower weight and height at birth, but a significantly larger head circumference than children without this genetic aberration. When analysing further development of children with SRS, a significantly smaller height SD, body mass and BMI was observed, compared with children from the control group. CONCLUSIONS: Children with SRS present impaired somatic development compared to children with IUGR, and these with a genetic aberration develop worse. PMID- 25038595 TI - Anti-Mullerian hormone concentration as a biomarker of pregnancy success or failure. AB - OBJECTIVE: This study was conducted to determine serum anti-Mullerian hormone (AMH) concentration influence on pregnancy outcome. STUDY DESIGN: In this study we investigated sixty one infertile women (aged 27 to 44 years) who were diagnosed and treated between 2011 and 2013. We determine ovarian reserve measured by AMH concentration. Patients were divided in three groups according to their serum AMH concentration (<1 ng/ml; 1-2.5 ng/ml; >2.5 ng/ml respectively). We investigated the relationship between clinical pregnancy rate and AMH concentration. In addition, anti-thyroid antibodies (anti-TG and/or anti-TPO) positivity and insulin concentration were correlated with AMH level and pregnancy outcome in the study groups. RESULTS: We found no statistical differences between AMH concentration regarding number of pregnancies (42.3%; 41.1 %; 38.9% respectively in study groups; p>0.05). The miscarriage rate was highest in women with AMH>2.5 ng/mL (27.3%, 0%, 86% respectively in study groups; p>0.05). We found that anti-thyroid positivity is more frequent in women with lower AMH concentration (23.1%; 11.7%; 5.5% respectively; p>0.05) and patients with lower serum AMH had higher serum insulin concentration (p<0.05). CONCLUSIONS: It seems that AMH concentration might not reflect oocyte quality and the chance of pregnancy, but increased AMH concentration may be associated with negative pregnancy outcome. Moreover, it cannot be excluded that presence of anti-thyroid antibodies and increased insulin serum concentration may be connected to diminished ovarian reserve measured by AMH concentration. PMID- 25038596 TI - Cerebral salt wasting in a postoperative period. AB - Cerebral salt wasting syndrome (CSW-cerebral salt wasting) was first described in 1950 by Peters. This syndrome can occur in patients who have sustained damage to the central nervous system (e.g. patients with subarachnoid bleeding, bacterial meningitis or after neurosurgery). Patients present with excessive natriuresis and hyponatremic dehydration. Differentiating this syndrome with the syndrome of inappropriate antidiuretic hormone secretion (SIADH-syndrome of inappropriate antidiuretic hormone secretion), which may occur in the same group of patients, is necessary in order to administer the correct treatment which consists of fluid restriction and sodium replacement in SIADH and fluid and sodium replacement as well as occasional mineralocorticoid therapy in CSW. PMID- 25038597 TI - Evaluation of uterine myomas during pregnancy using magnetic resonance imaging. AB - Patients with infertility commonly undergo various diagnostic and therapeutic procedures that may affect the future course of the pregnancy. In this presented case a female patient with infertility has been subjected to laparoscopic myomectomy and chromoscopy of the fallopian tubes, as it turned out later, 4 days after spontaneous conception. Due to severe pain in the 19th week of pregnancy the uterus area with the scar resulted from the removed myoma was visualised by magnetic resonance imaging (MRI). The MRI showed an active red degeneration in one of the myomas. At the same time the thickness of the uterus wall in previous myomectomy area was normal. The control MRI performed in the 36th week of pregnancy showed a hyaline degeneration of the myoma, underlying its dynamic refraction. The MRI approach enabled a non-invasive treatment and delivery in term. PMID- 25038598 TI - Fractionated plasmatic separation and adsorption does not alter haemodynamic parameters in experimental acute liver failure. AB - OBJECTIVE: Acute liver failure (ALF) is a rare disease with a bad prognosis. Its start is accompanied by haemodynamic instability. The aim of our study was to evaluate the influence of fractionated plasmatic separation and adsorption (FPSA) on body haemodynamics using a large animal experimental model of ALF. METHODS: ALF was induced by the devascularisation of 21 laboratory pigs. FPSA was applied in 14 animals and seven animals formed a control group. Values of systemic vascular resistance index (SVRI), heart rate (HR), pulmonary artery wedge pressure (PAWP) and cardiac index (CI) at hours 3, 6, 9 and 12 of the experiment were compared. The values from laboratory tests conducted with FPSA-treated vs. untreated ALF animals were compared using Student's t-test, paired or unpaired, as required, and Mann-Whitney U-test using EXCEL and QUATRO spreadsheet applications. RESULTS: We found no significant differences in mean arterial pressure, SVRI, or plasma lactate (p>0.05) in the FPSA-treated group but there was a significant decrease(p<0.05) in intracranial pressure (ICP). Furthermore, we observed a significant decrease in HR at hour 3. A significant increase in CI at hour 9 and a significant decrease in pulmonary artery wedge pressure at hours 6 and 12 were also observed. CONCLUSION: Our study of FPSA application (Prometheus device) for treatment of experimental ALF in a large animal model did not confirm the earlier reported development of changes in body haemodynamics. PMID- 25038599 TI - Kinematic and dynamic biomechanical values in relation to muscle activity during contact head impact. AB - OBJECTIVE: For the evaluation of neck injury the relative distance was observed between a marker placed on the forehead and a marker placed on the shoulder and also by change of the angle. To compare the severity of head injury a value of maximum head acceleration was used, HIC and a 3 ms criterion. All criteria were related to the activity of musculus sternocleidomastoideus and musculus trapezius in a situation of expected or unexpected contact impact. MATERIALS AND METHODS: The situation was recorded using a Qualisys system, head acceleration of probands in three axes was recorded using the accelerometer, activity of neck muscles was monitored by a mobile EMG. RESULTS: Maximum head acceleration was 5.61 g for non visual and 5.03 g for visual. HIC36 was 6.65 non visual and 5.97 for visual. 3-ms criterion was 5.37 g for non-visual and 4.89 g for visual and max. force was 291 N for non-visual and 314 N for visual. The average time of muscle activation of the observed group without visual perception is 0.355 s after hitting an obstacle, with visual perception 0.085 s before the crash. CONCLUSIONS: Kinematic values indicate more favourable parameters for neck injuries for visual. Head injury criteria show an average decrease of about 10% for visual. We can conclude that the visual perception means a significant increase in pre-activation of the observed muscle group of almost 745% and lower activation in following phase of approximately 90%. PMID- 25038600 TI - Neuronal excitability after water intoxication in young rats. AB - OBJECTIVES: Our previous experiments with animal models revealed that water intoxication induces brain oedema and opens plasma membranes. Present study is aimed to determine whether the standard method of hyperhydration can influence cerebral microenvironment also in young rats. Neuronal functions were tested by standard electrical cortical stimulation. METHODS: Hyperhydration was induced by administration of distilled water (DW) intraperitoneally. Three groups of young rats were used: 12, 25, and 35-day-old. Cortical excitability was tested 19 to 20 hours after DW administration by electrical stimulation of the sensorimotor cortex with intensity necessary to elicit cortical afterdischarges (AD). Water content in the brain was estimated by dry/wet ratio and value of natremia by standard biochemical examination. Control animals of the same age groups were tested in the same way, only they did not receive DW. RESULTS: Brain water content in hyperhydrated animals was smaller than in controls in all studied age groups. Natremia was the same (normal) in both the hyperhydrated and control animals aged 25 days. Excitability of cortical neurons in young hyperhydrated animals was significantly inhibited in comparison to the same age groups of controls. CONCLUSION: Hyperhydration induced in young rats (12, 25, 35-day-old) had different effects than in adults. Absence of hyponatremia, lower water content in the brain and significant inhibition of cortical excitability can be explained on the basis of ontogenetically dependent aquaporine expression (AQP 4) and different activity of ionic membrane transporters. PMID- 25038601 TI - Salivary cortisol in two professions: daily cortisol profiles in school teachers and firefighters. AB - BACKGROUND: It's indicated negative-perceived stress could induce worse health status and change of cortisol secretion. OBJECTIVES: To assess salivary cortisol levels in two occupations with a high psychosocial workload, but different features, teachers and firefighters. METHODS: The study population consisted of 142 school teachers and 136 firefighters. Four saliva samples were collected from pedagogical participants during their busiest workday. The cortisol measures used were: morning values, evening values, slope of decline, ratio (evening value divided by morning value), and area under the curve (AUC). RESULTS: The salivary cortisol measurements in both genders were almost equal regarding morning values, slope, and AUC increase. Evening values were lower and the relative reactivity was higher (lower ratio) for female teachers, compared to male teachers. There was a tendency of a lower total daytime output of cortisol (AUC ground) among female teachers. Firefighters had lower levels of cortisol, lower total daytime output, and higher relative reactivity (lower ratio), but lower absolute reactivity, regarding both slope and AUC increase. CONCLUSION: Overall, male teachers might be the group most affected by stress in this study, even if some of their cortisol values were almost equal to the female teachers' values. Male teachers also seemed to be more affected by stress, according to salivary cortisol, compared to male firefighters, even if there were some inconsistencies. PMID- 25038602 TI - Serotonin syndrome. AB - Serotonin syndrome is a potentially serious clinical condition. In this article, the authors put serotonin syndrome into historical context, discuss its pathophysiology, review in detail its clinical presentations, diagnostic criteria, differential diagnosis and treatment. Special attention is given to drugs that most often cause serotonin syndrome, and the gene polymorphisms involved in the metabolism of these drugs. PMID- 25038604 TI - Streptococcus group B serotype distribution in anovaginal isolates of women in term pregnancy. AB - BACKGROUND: To evaluate Streptococcus group B (GBS) serotype distribution in anovaginal isolates of women in term pregnancy and to assess the correlation of the distribution with socio-epidemiological variables and neonatal outcomes. DESIGN: An observational study. SETTINGS: Department of Gynecology and Obstetrics, Specialist Teaching Hospital in Tychy, Poland. POPULATION: 80 women between 37 and 40 gestation weeks with preserved fetal membranes and who had not been treated with antibiotics for at least two weeks before the study. MATERIAL AND METHODS: The specimens from the vagina and the rectum of pregnant women were collected. GBS colonization tests were conducted in compliance with Centers for Disease Control and Prevention recommendations. Serotyping of the isolates was performed using the Essum GBS Serotyping Kit (Umea, Sweden) according to manufacturer's instruction. Mein outcome measures. GBS serotype distribution in the population of Polish women in term pregnancy. RESULTS: In the studied group of 80 pregnant women GBS colonization rate was 28.7%. Four GBS serotypes were observed (Ia, V, III and II). Serotype Ia was the most predominant - 43.47%. For GBS Ia, V and III serotypes, no significant difference in the prevalence of diabetes mellitus and neonatal outcomes was observed. Only in one case early onset sepsis was diagnosed in the neonate and serotype Ia was determined. CONCLUSIONS: 1) From among four identified GBS serotypes in the population of Polish pregnant women, serotype Ia was the most dominant. 2) For GBS serotypes, no significant difference in the prevalence of diabetes mellitus and neonatal outcomes was observed. 3) Active immunization aimed for preventing GBS colonization in mothers should include not only serotypes V, II and III but also Ia in order to be an effective and safe in preventing life threatening neonatal infections. PMID- 25038603 TI - Sonohysterography in peri- and postmenopausal women with abnormal uterine bleeding or abnormal endometrial appearance. AB - OBJECTIVES: To assess the usefulness of SIS and to compare its diagnostic accuracy with conventional transvaginal ultrasound (TVS) and hysteroscopy (HSC) to detect intracavitary abnormalities in peri- and postmenopausal women with abnormal endometrial appearance or abnormal uterine bleeding (AUB) prior to admission. DESIGN AND SETTING: The study group consisted of 40 patients in peri- and postmenopausal period referred to the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw due to AUB or abnormal endometrial appearance on TVS between January 2013 and June 2013. All the participants underwent TVS followed by SIS in order to plan further management. Only the patients with uterine abnormalities on TVS examination, proved by SIS were qualified for HSC. Hysteroscopical guided biopsies were taken in cases with focal lesions. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVS, SIS and HSC were calculated by comparison with the final pathological diagnosis as the gold standard. RESULTS: The comparison of the three diagnostic procedures revealed that the diagnostic accuracy of SIS and HSC is superior to conventional TVS. SIS and HSC had identical accuracy for submucosal myomas (PPV and NPV 1.0 for both), while in case of polypoid lesions the accuracy of HSC was higher than of SIS (HSC: PPV 0.8, NPV 1.0; SIS: PPV 0.75; NPV 0.75). CONCLUSIONS: Due to its accuracy and cost effectiveness, SIS could be regarded as a primary diagnostic method allowing proper qualification for further invasive diagnostic or therapeutic procedures in the detection of uterine abnormalities among peri- and postmenopausal women. PMID- 25038605 TI - Sudden loss of vision due to breast cancer metastasis to the eyeball. AB - Intraocular choroidal metastasis is a very rare cause of blindness. Carcinoma of breast is the most common primary malignancy the accounts for choroidal metastasis in females. Other primary neoplasms which can uncommonly metastasize to the choroid are gastrointestinal tract, thyroid, pancreas, prostate and testis. Metastatic neoplasm to the eye outnumbers the primary tumors such as retinoblastoma and malignant melanoma. We present a case of sudden loss of vision due to breast cancer metastasis to the eyeball. The interval between the diagnosis of the primary tumor and the choroidal metastasis was 4 years. PMID- 25038606 TI - The optimal control of blood glucose is associated with normal blood pressure 24 hours profile and prevention of the left ventricular remodeling in the patients with gestational diabetes mellitus. AB - OBJECTIVE: The aim of this study was to evaluate the impact of the optimal diabetes control on the left ventricular parameters and ambulatory blood pressure in women with gestational diabetes mellitus (GDM). METHODS: The patients with GDM were followed up according to predetermined protocol in order to optimize blood glucose and optimal weight gain. Ambulatory blood pressure monitoring (ABPM) and transthoracal and tissue echocardiography were examined in 36th week of pregnancy. RESULTS: The age of 35 women with GDM was 33.1+/-3 and 30.5+/-4.4 years in 31 healthy control subjects (p=0.2). Fasting plasma glucose (FPG) in the patients with GDM was 5.0+/-0.5 mmol/L compared to 4.6+/-0.3 mmol/L in control subjects (p=0.002). Average weight gain during pregnancy was significantly lower in women with GDM; 10+/-7.6 kg vs. 13.1+/-3.7 kg in healthy pregnant women (p=0.05). No significant differences were recorded in 24 hours mean heart rate, systolic and diastolic blood pressure and number of nondippers between both groups. The significant correlation was detected between FPG and blood pressure dipping in subjects with GDM. Interventricular septal, posterior wall and relative wall thickness of the left ventricle were significantly higher in patients with GDM comparing to healthy pregnant women but no significant differences of the left ventricular functions were recorded. CONCLUSION: The optimal control of diabetes in GDM is associated with normal 24 hours blood pressure profile and prevention of the left ventricular function changes in GDM patients. The differences in the left ventricular walls thicknesses may be explained by metabolic changes in GDM. PMID- 25038607 TI - Trigeminal nerve asymmetry in classic trigeminal neuralgia - pretreatment volumetry and clinical evaluation in patients irradiated by Leksell Gamma Knife. AB - OBJECTIVES: The etiology of classic trigeminal neuralgia (CTN) is still under debate and, together with neurovascular compression (NVC), other anatomical abnormalities have been considered, including differences of trigeminal nerve (TN) volume. DESIGN: We evaluated the volumes of affected and non-affected nerves and the presence and type of NVC in large group of 84 CTN subjects prior to gamma knife treatment (GKS) on MR images. Correlation between affected nerve volume and NVC, treatment outcome and demographic characteristics were explored. RESULTS: NVC was detected in 71% of affected nerves, 52% of non-affected nerves, and in 31% of subjects bilaterally. Lower trigeminal nerve volume was detected on the affected side (p<0.001, affected mean 34.9 mm3 +/- 14.4 SD, non-affected mean 41.9 mm3 +/- 17.7 SD), however, no correlation between affected nerve volume and the presence and type NVC, treatment outcome or demographic data was detected. CONCLUSION: Our results suggest that NVC may trigger CTN in susceptible subjects but is not a reliable disease marker. Lower trigeminal nerve volume appears to manifest independently of NVC, and may represent nerve asymmetry rather than atrophy. No correlation between volumetry and clinical data was detected including treatment outcome after GKS. PMID- 25038608 TI - No one left behind: the road to 80% by 2018. PMID- 25038609 TI - Protocol for evaluation of the cost-effectiveness of ePrescribing systems and candidate prototype for other related health information technologies. AB - BACKGROUND: This protocol concerns the assessment of cost-effectiveness of hospital health information technology (HIT) in four hospitals. Two of these hospitals are acquiring ePrescribing systems incorporating extensive decision support, while the other two will implement systems incorporating more basic clinical algorithms. Implementation of an ePrescribing system will have diffuse effects over myriad clinical processes, so the protocol has to deal with a large amount of information collected at various 'levels' across the system. METHODS/DESIGN: The method we propose is use of Bayesian ideas as a philosophical guide.Assessment of cost-effectiveness requires a number of parameters in order to measure incremental cost utility or benefit - the effectiveness of the intervention in reducing frequency of preventable adverse events; utilities for these adverse events; costs of HIT systems; and cost consequences of adverse events averted. There is no single end-point that adequately and unproblematically captures the effectiveness of the intervention; we therefore plan to observe changes in error rates and adverse events in four error categories (death, permanent disability, moderate disability, minimal effect). For each category we will elicit and pool subjective probability densities from experts for reductions in adverse events, resulting from deployment of the intervention in a hospital with extensive decision support. The experts will have been briefed with quantitative and qualitative data from the study and external data sources prior to elicitation. Following this, there will be a process of deliberative dialogues so that experts can "re-calibrate" their subjective probability estimates. The consolidated densities assembled from the repeat elicitation exercise will then be used to populate a health economic model, along with salient utilities. The credible limits from these densities can define thresholds for sensitivity analyses. DISCUSSION: The protocol we present here was designed for evaluation of ePrescribing systems. However, the methodology we propose could be used whenever research cannot provide a direct and unbiased measure of comparative effectiveness. PMID- 25038611 TI - In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia. AB - PURPOSE: The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan. METHODS: Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation. RESULTS: Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels. CONCLUSIONS: Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML. PMID- 25038610 TI - Chronic nicotine pretreatment is sufficient to upregulate alpha4* nicotinic receptors and increase oral nicotine self-administration in mice. AB - BACKGROUND: Understanding the underlying causes of nicotine addiction will require a multidisciplinary approach examining the key molecular, cellular and neuronal circuit functional changes that drive escalating levels of nicotine self administration. In this study, we examined whether mice pretreated with chronic nicotine, at a dosing regimen that results in maximal nicotinic acetylcholine receptor (nAChR) upregulation, would display evidence of nicotine-dependent behaviour during nicotine self-administration. RESULTS: We investigated oral self administration of nicotine using a two-bottle choice paradigm in which one bottle contained the vehicle (saccharine-sweetened water), while the other contained nicotine (200 MUg/ml) in vehicle. Knock-in mice with YFP-tagged alpha4 nAChR subunits (alpha4YFP) were implanted with osmotic pumps delivering either nicotine (2 mg/kg/hr) or saline for 10 days. After 10 days of pretreatment, mice were exposed to the nicotine self-administration paradigm, consisting of four days of choice followed by three days of nicotine abstinence repeated for five weeks. Mice pre-exposed to nicotine had upregulated alpha4YFP nAChR subunits in the hippocampal medial perforant path and on ventral tegmental area GABAergic neurons as compared to chronic saline mice. Compared to control saline-pretreated mice, in a two bottle-choice experiment, nicotine-primed mice ingested a significantly larger daily dose of nicotine and also exhibited post-abstinence binge drinking of nicotine. CONCLUSIONS: Chronic forced pre-exposure of nicotine is sufficient to induce elevated oral nicotine intake and supports the postulate that nAChR upregulation may be a key factor influencing nicotine self-administration. PMID- 25038612 TI - Biweekly S-1 plus paclitaxel (SPA) as second-line chemotherapy after failure from fluoropyrimidine and platinum in advanced gastric cancer: a phase II study. AB - PURPOSE: Second-line chemotherapy is now considered a standard therapy option in patients with advanced gastric cancer (AGC) who failed from first-line chemotherapy. Single agents, such as irinotecan, docetaxel or paclitaxel, provided an overall response rate of about 10 %. However, the efficacy was not satisfactory. The authors conducted a phase II study to investigate biweekly regimen of S-1 plus paclitaxel in Chinese AGC in second-line setting, with response rate as the primary end point. PATIENTS AND METHODS: Patients with AGC failed from first-line chemotherapy with fluoropyrimidine/platinum who had measurable lesions were enrolled. Paclitaxel was administered intravenously on day 1 at a dose of 120 mg/m(2), and oral S-1 was administered twice a day from days 1 to 7, followed by a 7-day drug-free interval. RESULTS: A total of 30 patients with pretreated AGC were accrued. No complete responses were observed. Partial responses were documented in 10 (33.3 %) patients. Ten (33.3 %) patients had stable disease. The median progression-free survival was 3.6 months and the overall survival was 7.2 months. The main toxicity was bone marrow suppression. The most frequent grade 3/4 hematological toxicities were neutropenia and anemia, which were observed in 8 (26.7 %) and 6 (20 %) patients, respectively. The most common grade 3/4 non-hematological toxicity was neuropathy, which was reported in 4 (13.3 %) patients. CONCLUSION: Biweekly S-1 plus paclitaxel showed promising activity with acceptable toxicities as second-line chemotherapy in pretreated patients with AGC. This regimen deserves further investigation in a phase III trial. PMID- 25038613 TI - Inhibition of Hec1 as a novel approach for treatment of primary liver cancer. AB - PURPOSE: Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer. METHODS: In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target. RESULTS: In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50) > 10 MUM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression. CONCLUSION: Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers. PMID- 25038614 TI - Iron repletion is associated with reduction in platelet counts in non-dialysis chronic kidney disease patients independent of erythropoiesis-stimulating agent use: a retrospective cohort study. AB - BACKGROUND: Iron deficiency is common in non-dialysis chronic kidney disease (ND CKD) patients and, on occasion, requires parenteral iron therapy. We investigated the effect of intravenous iron repletion on platelet counts in ND-CKD patients with and without concomitant darbepoetin administration. METHODS: We conducted a retrospective analysis of ND-CKD patients with iron deficiency anemia treated with low molecular weight iron dextran (LMWID) between 2005 and 2009 at our CKD clinic. The primary end-point was change in platelet count 60 days post infusion of LMWID in those with and without concomitant darbepoetin administration. Secondary end-points were the correlations between changes in platelet count and iron indices. RESULTS: A total of 108 patients met inclusion and exclusion criteria. The decrease in platelet counts in response to iron repletion was statistically significant (305.72 +/- 108.86 vs 255.58 +/- 78.97, P = < .0001). The decrease in platelet count was independent of concomitant darbepoetin use. Bivariate regression analysis between baseline platelet count and transferrin saturation by iron (TSAT) showed a negative association (betaTSAT = -5.82, P = .0007) and moderate correlation (R = 0.32). Following iron treatment, the within individual changes in platelet count in 60 days were not related to changes in TSAT (betaDeltaTSAT = -0.41, P = .399) and demonstrated a poor correlation (R = 0.10). CONCLUSIONS: Parenteral iron treatment by LMWID is associated with reduction in platelet counts in iron deficient anemic ND-CKD patients. However, ESA use in the majority of patients prior to intravenous iron administration could have altered platelet production through bone marrow competition. PMID- 25038617 TI - New expensive treatments for hepatitis C infection. PMID- 25038616 TI - Expression profiling of genes modulated by minocycline in a rat model of neuropathic pain. AB - BACKGROUND: The molecular mechanisms underlying neuropathic pain are constantly being studied to create new opportunities to prevent or alleviate neuropathic pain. The aim of our study was to determine the gene expression changes induced by sciatic nerve chronic constriction injury (CCI) that are modulated by minocycline, which can effectively diminish neuropathic pain in animal studies. The genes associated with minocycline efficacy in neuropathic pain should provide insight into the etiology of neuropathic pain and identify novel therapeutic targets. RESULTS: We screened the ipsilateral dorsal part of the lumbar spinal cord of the rat CCI model for differentially expressed genes. Out of 22,500 studied transcripts, the abundance levels of 93 transcripts were altered following sciatic nerve ligation. Percentage analysis revealed that 54 transcripts were not affected by the repeated administration of minocycline (30 mg/kg, i.p.), but the levels of 39 transcripts were modulated following minocycline treatment. We then selected two gene expression patterns, B1 and B2. The first transcription pattern, B1, consisted of 10 mRNA transcripts that increased in abundance after injury, and minocycline treatment reversed or inhibited the effect of the injury; the B2 transcription pattern consisted of 7 mRNA transcripts whose abundance decreased following sciatic nerve ligation, and minocycline treatment reversed the effect of the injury. Based on the literature, we selected seven genes for further analysis: Cd40, Clec7a, Apobec3b, Slc7a7, and Fam22f from pattern B1 and Rwdd3 and Gimap5 from pattern B2. Additionally, these genes were analyzed using quantitative PCR to determine the transcriptional changes strongly related to the development of neuropathic pain; the ipsilateral DRGs (L4-L6) were also collected and analyzed in these rats using qPCR. CONCLUSION: In this work, we confirmed gene expression alterations previously identified by microarray analysis in the spinal cord and analyzed the expression of selected genes in the DRG. Moreover, we reviewed the literature to illustrate the relevance of these findings for neuropathic pain development and therapy. Further studies are needed to elucidate the roles of the individual genes in neuropathic pain and to determine the therapeutic role of minocycline in the rat neuropathic pain model. PMID- 25038618 TI - Modified protection using far proximal portion of self-expandable closed-cell stents for embolization of wide-necked intracranial aneurysms. AB - INTRODUCTION: Stent-assisted embolization is sometimes limited in wide-necked aneurysms involving the acute-angled origins of tortuous branching arteries, and occasionally, Y-shaped stenting is required to remedy the sweeping effects of a broad aneurysmal neck on arterial branches. Described herein is a modified stent assisted coil embolization technique entailing strategic placement of far proximal stent ("distal stenting") as an alternate approach in such scenarios. METHODS: For this particular technique, stent placement is confined to a branch artery, allowing far proximal stent to cover aneurysmal neck, with no bridge to parent artery. Kinking of stents deployed in tortuous arteries is thereby avoided, and better coverage of aneurysmal neck is achieved, compared with traditional stent protection. Records of 12 consecutive patients with wide-necked aneurysms, all treated by coil embolization with distal stenting between January 2009 and February 2014, were retrieved from a prospective data repository at our institution. Outcomes were analyzed in terms of morphologic features and clinical status. RESULTS: This modified technique was largely applied to aneurysms of middle cerebral artery, followed by posterior communicating artery and anterior communicating artery sites. With one exception, all aneurysms treated were successfully occluded. There were no complications directly related to distal stenting. At final follow-up (mean interval, 16.8 +/- 9.7 months), complete aneurysmal occlusion was sustained in 81.8%. Delayed stent migration was observed in one patient (8.3%). CONCLUSION: Our study suggests that distal stenting in wide-necked aneurysms is a reasonable alternative to traditional stent protection, despite the potential for delayed stent migration. PMID- 25038619 TI - Treatment with alpha-lipoic acid enhances the bone healing after femoral fracture model of rats. AB - This study investigated the fracture-healing effects of alpha-lipoic acid (alpha LA), which was applied orally once daily in preventive treatment mode during 1 month after fracture induction. Rats were randomly divided into sham-operated group (group 1), femoral fracture control (group 2), femoral fracture + 25 mg/kg alpha-LA (group 3), and femoral fracture + 50 mg/kg alpha-LA (group 4). Rats in the experimental groups were orally administered 25 or 50 mg/kg alpha-LA once daily for 30 days starting from postoperative day 1. Thirty days postoperatively, the rats underwent X-ray imaging and were then euthanized for blood and tissue collection. Histopathological, biochemical, molecular, computed tomography (CT), and mechanical strength tests were performed on samples. The serum levels of osteocalcin (OC), osteopontin (OP), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) did not differ significantly between groups 2 and 3. Serum OC, OP, TNF-alpha, and IL-6 levels in group 4 were significantly lower than those in group 3. From X-ray images, staging for fracture healing was scored as <2 in group 2, >2 in group 3, and >3 in group 4. In group 2, the average score of less than 2 suggests insufficient fracture healing; those of both the alpha-LA groups were >2, indicating progression of healing. Transforming growth factor beta (TGF beta) messenger RNA (mRNA) levels were significantly higher in the sham group than in the femoral fracture control. Both doses of alpha-LA increased TGF-beta mRNA expression compared to the fracture group. CT results and biomechanical testing at 4 week after fracture demonstrated that alpha-LA has fastened bone healing, which was confirmed by stereological analyses in which 50 mg/kg alpha-LA increased the number of osteoclasts. Our findings indicate that alpha-LA supplementation promotes healing of femoral fractures in rats. PMID- 25038620 TI - Comparison of outcome of unilateral locking plate and dual plating in the treatment of bicondylar tibial plateau fractures. AB - BACKGROUND: Tibial plateau fracture (TPF) includes different fracture patterns with varied degrees of articular depression and displacement. Many kinds of fixators, including newly designed plate with locking screws, were applied to treat these complicated fractures. We intended to follow up the surgical outcomes of (1) unilateral locking plate, (2) classic dual plates, or (3) hybrid dual plates for TPF. MATERIALS AND METHODS: We retrospectively reviewed 76 patients with TPF, Schatzker types V and VI, who we operated from June 2006 to May 2009 in our institute. Excluding patients who expired due to other medical conditions and without complete follow-up, 45 patients were sorted out in this series. The scheme of surgical intervention was designed by visiting staff, and 15 patients, as group I, were treated with unilateral locking plate. The other 19 patients, as group II, were treated with classic dual plates. The residual 11 patients, as group III, were treated with hybrid dual plates (one lateral approach locking compression plate (LCP) + medial anti-gliding plate). All patients were under periodic F/U at about 6 weeks interval for at least 18 months postoperatively. RESULTS: In group I, 13 cases achieved solid bony union without obvious traumatic OA change, limitation of ROM, or malalignment. In groups II and III, 15 and 10 patients reached the same goal, respectively. By analysis of the recorded parameters with statistical software (SPSS 12.0), there were five parameters with significant difference, including Schatzker classification, operation time, staged treatment or not, hospitalization period, and hardware impingement. CONCLUSIONS: There was no significant statistical difference of union rate between these three groups in our series. Based on our clinical follow-up, several key points were emphasized: (1) Soft tissue problems should be kept in mind, and usage of locking plate can reduce the discomfort of hardware impingement effectively. (2) The single lateral approach technique for TPF with locking plate results in less operation time and shorter hospitalization period. (3) If the medial buttress cannot be established by reduction of the lateral fracture, then open reduction of the medial side is necessary and buttresses the medial fragment by dual plates. PMID- 25038621 TI - Analysis of the response of human keratinocytes to Malassezia globosa and restricta strains. AB - Malassezia spp. are saprophyte yeasts involved in skin diseases with different degrees of severity. The aim of our study was to analyze the response of human epidermal keratinocytes to Malassezia globosa and restricta strains evaluating the host defence mechanisms induced by Malassezia spp. colonization. Our results showed a different modulation of the inflammatory and immunomodulatory cytokine pathways obtained with the different strains of Malassezia tested. In addition, this expression is altered by blocking the TLR2 receptor. In comparison with M. furfur, M. globosa and restricta displayed an unexpected and striking cytotoxicity on keratinocytes. The differences observed could be related to the different modalities of interaction between keratinocytes and Malassezia strains, but also to their growth condition. Taken together, these results indicate that M. globosa or M. restricta colonization exert a different control on the cytokine inflammatory response activated in the human keratinocyte in which TLR2 might be involved. M. globosa and M. restricta may play a synergistic role in the exacerbation of skin diseases in which both are found. PMID- 25038622 TI - Functional significance of long non-coding RNAs in breast cancer. AB - Most of the genome is transcribed to transcripts of no protein-coding potential. However, these transcripts do not represent transcriptional 'noise', rather they play an important role in cellular metabolism and development. Non-coding transcripts of 200 bases to 100 kb length are termed as long non-coding RNAs, majority of which are yet to be characterised thoroughly. Long non-coding RNAs (lncRNAs) play a significant role in cellular process ranging from transcriptional to post-transcriptional regulation. In this review, we highlight the recent efforts to characterise the major functions of lncRNAs in breast cancer. lncRNA expression is altered in several cancer types. Further, the aberrant regulation of lncRNAs promotes tumour development as they are involved in several cancer-associated pathways. PMID- 25038623 TI - Latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint. AB - Informative exposure-response modeling of clinical endpoints is important in drug development. There has been much recent progress in latent variable modeling of ordered categorical endpoints, including the application of indirect response (IDR) models and accounting for residual correlations between multiple categorical endpoints. This manuscript describes a framework of latent-variable based IDR models that facilitate easy simultaneous modeling of a continuous and a categorical clinical endpoint. The model was applied to data from two phase III clinical trials of subcutaneously administered ustekinumab for the treatment of psoriatic arthritis, where Psoriasis Area and Severity Index scores and 20, 50, and 70 % improvement in the American College of Rheumatology response criteria were used as efficacy endpoints. Visual predictive check and external validation showed reasonable parameter estimation precision and model performance. PMID- 25038624 TI - Engaging academia to advance the science and practice of environmental public health tracking. AB - Public health agencies at the federal, state, and local level are responsible for implementing actions and policies that address health problems related to environmental hazards. These actions and policies can be informed by integrating or linking data on health, exposure, hazards, and population. The mission of the Centers for Disease Control and Prevention's National Environmental Public Health Tracking Program (Tracking Program) is to provide information from a nationwide network of integrated health, environmental hazard, and exposure data that drives actions to improve the health of communities. The Tracking Program and federal, state, and local partners collect, integrate, analyze, and disseminate data and information to inform environmental public health actions. However, many challenges exist regarding the availability and quality of data, the application of appropriate methods and tools to link data, and the state of the science needed to link and analyze health and environmental data. The Tracking Program has collaborated with academia to address key challenges in these areas. The collaboration has improved our understanding of the uses and limitations of available data and methods, expanded the use of existing data and methods, and increased our knowledge about the connections between health and environment. Valuable working relationships have been forged in this process, and together we have identified opportunities and improvements for future collaborations to further advance the science and practice of environmental public health tracking. PMID- 25038625 TI - Segmental differences in the orientation of smooth muscle cells in the tunica media of porcine aortae. AB - The orientation of vascular smooth muscle cells of porcine aortae was assessed to test the widely accepted assumption that these smooth muscle cells are arranged in two helices. We used tangential histological sections of 82 samples of five anatomical segments of thoracic and abdominal porcine aortae and three age groups in animals ranging in age from 5 to 210 days. The distribution of the orientation of smooth muscle cell nuclei in five proximodistal segments of the porcine aortae was determined using an algorithm that fitted a mixture of one to five von Mises probability distributions of the data retrieved from histological micrographs. Automated tracking of the nuclei was confirmed by and consistent with manual histological analysis. The orientation of the vascular smooth muscle cells was successfully fitted using two von Mises distributions in most of the samples with different ages, wall thicknesses, and anatomical positions, which corresponds to two populations of vascular smooth muscle cells. A minor fraction of samples also required a tertiary von Mises distribution to describe the orientation of the smooth muscle cell nuclei. The distribution of vascular smooth muscle cells in five aortic segments ranging from the thoracic ascending aorta to the abdominal intrarenal aorta exhibited similar main directions but different shapes. These results are consistent with the widely used model of two muscular helices intermingling in the arterial wall. Furthermore, we calculated the central angles of symmetry and the mean value of angles between the two assumed smooth muscle directions. We also successfully approximated the orientation of the smooth muscle cells using a mixture of von Mises distributions and our open-source software named dist_mixtures. This method is openly available to researchers who are interested in mathematically assessing the orientation of cell nuclei in various tissues. PMID- 25038626 TI - DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria. AB - BACKGROUND: DDX39B (BAT1) encodes an RNA helicase known to regulate expression of TNF and IL-6. Elevated levels of these two cytokines are associated with increased severity of clinical malaria. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in the DDX39B, TNF and IL6 genes and the clinical outcomes of patients with Plasmodium vivax malaria. METHODS: Cross-sectional investigations were carried out in two regions of the Brazilian Amazon where several studies on the pathogenesis of vivax malaria had been performed. Individuals were categorized according to infection status as well as clinical presentation into the following groups: uninfected, asymptomatic infection, mild infection, or complicated infection. Polymorphisms were identified using PCR restriction fragment-length polymorphism analysis and the restriction enzymes NlaIII or NcoI. The plasma levels of cytokines were determined using ELISA. RESULTS: The G allele of DDX39B-22C > G was associated with absent or decreased manifestations of malaria and the C allele was a risk factor for disease complications. Study participants heterozygous for TNF-308 (GA) and DDX39B-348 (CT) had higher TNF levels than wild-type participants. Haplotypes that included DDX39B (-22C > G and -348C > T) and TNF polymorphisms were not directly associated with mild or complicated malaria infections; however, haplotypes AGC, ACC, GGT, AGT and ACT were associated with increased TNF levels. Participants with genotype combinations GC/CC/GG/GG and GG/CT/GG/GG (DDX39B-22/DDX39B-348/TNF-308/IL6-176) had decreased and increased risk of mild malaria, respectively, compared with asymptomatic and uninfected participants. GC/CC/GG/GG was linked to decreased TNF and IL-6 levels. CONCLUSIONS: This is the first study to describe patients with DDX39B and IL6 SNPs who had vivax malaria. These findings support the postulation that a set of mutations in immune-related genes is associated with inflammatory mediators and the clinical outcomes of patients with malaria. PMID- 25038627 TI - Lipid emulsions differentially affect LPS-induced acute monocytes inflammation: in vitro effects on membrane remodeling and cell viability. AB - The aim of this study was to assess how lipid emulsions for parenteral nutrition affect lipopolysaccharide (LPS)-induced acute monocyte inflammation in vitro. An 18 h long LPS induced human monocyte leukemia cell stimulation was performed and the cell-growth medium was supplemented with three different industrial lipid emulsions: Intralipid((r)), containing long-chain triglycerides (LCT--soybean oil); Medialipid((r)), containing LCT (soybean oil) and medium-chain triglycerides (MCT--coconut oil); and SMOFlipid((r)), containing LCT, MCT, omega 9 and -3 (soybean, coconut, olive and fish oils). Cell viability and apoptosis were assessed by Trypan blue exclusion and flow cytometry respectively. Monocyte composition and membrane remodeling were studied using gas chromatography and NR12S staining. Microparticles released in supernatant were measured by prothrombinase assay. After LPS challenge, both cellular necrosis and apoptosis were increased (threefold and twofold respectively) and microparticle release was enhanced (sevenfold) after supplementation with Medialipid((r)) compared to Intralipid((r)), SMOFlipid((r)) and monocytes in the standard medium. The monocytes differentially incorporated fatty acids after lipid emulsion challenge. Finally, lipid-treated cells displayed microparticles characterized by disrupted membrane lipid order, reflecting lipid remodeling of the parental cell plasma membrane. Our data suggest that lipid emulsions differentially alter cell viability, monocyte composition and thereby microparticle release. While MCT have deleterious effects, we have shown that parenteral nutrition emulsion containing LCT or LCT and MCT associated to n-3 and n-9 fatty acids have no effect on endotoxin-induced cell death and inflammation. PMID- 25038628 TI - Factors influencing readiness to deploy in disaster response: findings from a cross-sectional survey of the Department of Veterans Affairs Disaster Emergency Medical Personnel System. AB - BACKGROUND: The Disaster Emergency Medical Personnel System (DEMPS) program provides a system of volunteers whereby active or retired Department of Veterans Affairs (VA) personnel can register to be deployed to support other VA facilities or the nation during national emergencies or disasters. Both early and ongoing volunteer training is required to participate. METHODS: This study aims to identify factors that impact willingness to deploy in the event of an emergency. This analysis was based on responses from 2,385 survey respondents (response rate, 29%). Latent variable path models were developed and tested using the EQS structural equations modeling program. Background demographic variables of education, age, minority ethnicity, and female gender were used as predictors of intervening latent variables of DEMPS Volunteer Experience, Positive Attitude about Training, and Stress. The model had acceptable fit statistics, and all three intermediate latent variables significantly predicted the outcome latent variable Readiness to Deploy. RESULTS: DEMPS Volunteer Experience and a Positive Attitude about Training were associated with Readiness to Deploy. Stress was associated with decreased Readiness to Deploy. Female gender was negatively correlated with Readiness to Deploy; however, there was an indirect relationship between female gender and Readiness to Deploy through Positive Attitude about Training. CONCLUSIONS: These findings suggest that volunteer emergency management response programs such as DEMPS should consider how best to address the factors that may make women less ready to deploy than men in order to ensure adequate gender representation among emergency responders. The findings underscore the importance of training opportunities to ensure that gender-sensitive support is a strong component of emergency response, and may apply to other emergency response programs such as the Medical Reserve Corps and the American Red Cross. PMID- 25038630 TI - Obsessive compulsive symptoms and sleep difficulties: exploring the unique relationship between insomnia and obsessions. AB - BACKGROUND: Sleep complaints have been linked with Obsessive Compulsive Disorder (OCD), though there is a dearth of research exploring the association between a range of disturbed sleep indicators and obsessive compulsive symptoms (OCS). Two separate studies were conducted to rigorously investigate this relationship in further detail, considering a number of different sleep indices and also the heterogeneous nature of OCS. METHODS: Study 1 (n = 167) examined the relationship between OCS and the gold standard self-report assessments for delayed bedtime, sleep quality, nightmares, and insomnia symptoms. Study 2 (n = 352) replicated the primary findings from Study 1 in an independent sample and with an alternative measure of OCD, which takes into account the different OCS dimensions. RESULTS: Results revealed a significant, independent link between obsessions and insomnia symptoms, but not between insomnia and compulsions. When examining the different OCS dimensions, insomnia was again found to bear a specific relationship to obsessions, above and beyond that with the other dimensions. Although depression is often highly comorbid with both OCD and sleep disturbances, depressive symptoms did not explain the OCS-sleep relationship in either study, suggesting a unique association between obsessions and insomnia. CONCLUSIONS: Findings indicate that high levels of intrusive thoughts exhibit a specific association with insomnia symptoms-one that is not observed with other OCS. Future research may help elucidate the mechanisms and causal nature of this relationship. PMID- 25038629 TI - Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder. AB - OBJECTIVE: Siever and Davis' (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT. METHODS: Event-related fMRI was obtained pre- and post-12 months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale. RESULTS: fMRI results showed the predicted Group * Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale). CONCLUSION: These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity-part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation. PMID- 25038631 TI - A theoretical study on diastereoselective oxidative dearomatization by iodoxybenzoic acid. AB - The reaction mechanism of diastereoselective oxidative dearomatization by iodoxybenzoic acid of key compounds involved in the total synthesis of epicocconone analogs, which are efficient fluorophores with a wide range of applications in protein staining and separation, was studied using density functional theory. In particular, the conformational space was investigated, as was the role of the so-called hypervalent twist move, which is thought to be the rate-determining step. Both kinetic and thermodynamical aspects of the mechanism were considered from static and dynamic viewpoints, including solvent effects. The results were then rationalized using conceptual density functional theory and Bader's atoms-in-molecules framework, which demonstrated how complementary these two approaches are when studying organic chemistry reactions theoretically. PMID- 25038632 TI - Hydrogen bond coupling in sodium dihydrogen triacetate. AB - The coupling of hydrogen bonds is central to structures and functions of biological systems. Hydrogen bond coupling in sodium dihydrogen triacetate (SDHTA) is investigated as a model for the hydrogen bonded systems of the type O H...O. The two-dimensional potential energy surface is derived from the full dimensional one by selecting the relevant vibrational modes of the hydrogen bonds. The potential energy surfaces in terms of normal modes describing the anharmonic motion in the vicinity of the equilibrium geometry of SDHTA are calculated for the different species, namely, HH, HD, DH, and DD isotopomers. The ground state wave functions and their relation to the hydrogen bond structural parameters are discussed. It has been found that the hydrogen bonds in SDHTA are uncoupled, that is elongation of the deuterated hydrogen bond does not affect the non-deuterated one. PMID- 25038634 TI - Structure, aromaticity, stability, and energetic performance of the analogues and derivatives of s-heptazine. AB - s-heptazine is one of the most attractive polycyclic C-N precursors for graphitic carbon nitride materials (CNx). In this paper in order to find the relationships between the structure, aromaticity, and stability for this novel compound, its analogues with three conjoint six-membered rings (I~V) and derivatives with different substituents (VI-1~VI-5) were investigated using the density functional theory method. Aromaticity was predicted using the magnetic criterion iso chemical shielding surface in the Z direction (ICSSzz) obtained with the gauge independent atomic orbital (GIAO) method. Stability was estimated by the band gap and the topological properties obtained from the atoms in molecules theory. Results show that replacement of the CH groups with the nitrogen atoms in the tricyclic core enhances both the aromaticity and the stability. s-heptazine (VI) that has the maximum number of N atoms among analogues I~VI possesses the largest aromaticity and the best stability. Substitutions of -NH2, -NHNH2, and -N3 groups increase not only the aromaticity but also the stability; -NO2 increases the aromaticity while decreases the stability; -CN decreases both the aromaticity and the stability. Furthermore, the energetic performance of VI-1~VI-5 was evaluated according to the estimated specific impulse (Is). The obtained Is has the order of VI-5>VI-4>VI-3>VI>VI-1>VI-2. The Is of VI-5 is higher than that of HMX (1, 3, 5, 7-tetranitro-1, 3, 5, 7-tetraazacyclooctane). PMID- 25038633 TI - Examine the characterization of biofilm formation and inhibition by targeting SrtA mechanism in Bacillus subtilis: a combined experimental and theoretical study. AB - Bacillus subtilis is one of the well-known biofilm-forming organisms associated with plants, animals, and also used as a model organism for all Bacillus sp. In B. subtilis, SrtA enzyme plays the imperative roles in mechanism of signaling pathway and microbial adherence toward the host. SrtA is highly considered as a universal drug target for all Gram positive pathogens. Because of unresolved 3D structure of SrtA in Gram positive bacteria including B. subtilis, we developed a homology model protein using structural alignments of similar SrtA from B. anthracis. While the structural model of SrtA is analyzed because of its significance in biofilm formation by screening the suitable active site based compounds and analyzing the ability of bacterial biofilm inhibition. Druggability site based screening able to retrieve the active compounds against SrtA and checked the activity of the screened compounds through experimental biochemical assays and in situ microscopic analysis. Here in this study we concluded the computationally screened SrtA inhibitors showed high level of biofilm inhibition despite difficulties in bacterial membrane rigidification. Hence this study leads a way to the new compounds that may be useful to treat the bacterial infections. PMID- 25038635 TI - Association between body mass index and perceived weight status with self-rated health and life satisfaction in Iranian children and adolescents: the CASPIAN-III study. AB - PURPOSE: Adolescent obesity is a well-known worldwide issue with growing prevalence and complications. The concept of body image and complications of its misperception has been noted more recently. Life satisfaction (LS) and self-rated health (SRH) have also been known as independent morbidity and mortality factors. The objective of this study was to evaluate the associations of perceived weight status (body image) and actual body mass index (BMI), with LS and SRH in a nationally representative sample of a pediatric population in Iran, as a country located in the Middle East and North Africa region. METHODS: This nationwide population-based survey was conducted among 5,570 (2,784 female and 2,786 male) Iranian students, aged 10-18 years, living in urban and rural areas of 27 provinces, which were selected via multistage sampling method. Agreement between BMI and perceived weight status (underweight, about right and overweight/obesity) was assessed. Adjusted association between BMI and perceived weight status with LS and SRH was assessed using multiple logistic regressions after adjustment for potential confounders. RESULTS: Nearly 40 % of the participants misperceived their body image. Misperception as overweight or underweight was found to be associated with lower odds for both LS and SRH [overweight SRH OR 0.796 (95 % CI 0.647-980), underweight SRH OR 0.701 (95 % CI 0.588-0.835), overweight LS OR 0.884 (95 % CI 0.718-998), underweight LS OR = 0.676 (95 % CI 0.577-0.793)], whereas the association between actual BMI with LS and SRH was not statistically significant (P value > 0.05). CONCLUSION: A mismatch between BMI and body weight perception was found in this study. Moreover, LS and SRH were not related with BMI, but had negative association with body weight perception. PMID- 25038636 TI - Validation and reliability of a Spanish version of Simple Shoulder Test (SST-Sp). AB - BACKGROUND: The Simple Shoulder Test (SST-Sp) is a widely used outcome measure. OBJECTIVE: The purpose of this study was to develop and validate a Spanish version SST (SST-Sp). METHODS: A two-stage observational study was conducted. The SST was initially cross-culturally adapted to Spanish through double forward and backward translation and then validated for its psychometric characteristics. Participants (n = 66) with several shoulder disorders completed the SST-Sp, DASH, VAS and SF-12. The full sample was employed to determine factor structure, internal consistency and concurrent criterion validity. Reliability was determined in the first 24-48 h in a subsample of 21 patients. RESULTS: The SST Sp showed three factors that explained the 56.1% of variance, and the internal consistency for each factor was alpha = 0.738, 0.723 and 0.667, and reliability was ICC = 0.687-0.944. The factor structure was three-dimensional and supported construct validity. Criterion validity determined from the relationship between the SST-Sp and DASH was strong (r = -0.73; p < 0.001) and fair for VAS (r = 0.537; p < 0.001). Relationships between SST-Sp and SF-12 were weak for both physical (r = -0.47; p < 0.001) and mental (r = -0.43; p < 0.001) dimensions. CONCLUSIONS: The SST-Sp supports the findings of the original English version as being a valid shoulder outcome measure with similar psychometric properties to the original English version. PMID- 25038637 TI - A simple method for finding a protein's ligand-binding pockets. AB - BACKGROUND: This paper provides a simple and rapid method for a protein clustering strategy. The basic idea implemented here is to use computational geometry methods to predict and characterize ligand-binding pockets of a given protein structure. In addition to geometrical characteristics of the protein structure, we consider some simple biochemical properties that help recognize the best candidates for pockets in a protein's active site. RESULTS: Our results are shown to produce good agreement with known empirical results. CONCLUSIONS: The method presented in this paper is a low-cost rapid computational method that could be used to classify proteins and other biomolecules, and furthermore could be useful in reducing the cost and time of drug discovery. PMID- 25038640 TI - The management of substance abuse in the critically ill. PMID- 25038638 TI - Neural differentiation of mesenchymal stem cells influences their chemotactic responses to stromal cell-derived factor-1alpha. AB - Mesenchymal stem cells (MSCs) are proposed as a promising source for cell-based therapies in neural disease. Although increasing numbers of studies have been devoted to the delineation of factors involved in the migration of MSCs, the relationship between the chemotactic response and the differentiation status of these cells is still unclear. In the present study, we demonstrated that MSCs in varying neural differentiation states display various chemotactic responses to stromal cell-derived factor-1alpha (SDF-1alpha). The chemotactic responses of MSCs under different differentiation stages in response to SDF-1alpha were analyzed by Boyden chamber, and the results showed that cells of undifferentiation, 24-h preinduction, 5-h induction, and 18-h maintenance states displayed a stronger chemotactic response to SDF-1alpha, while 48-h maintenance did not. Further, we found that the phosphorylation levels of PI3K/Akt, ERK1/2, SAPK/JNK, and p38MAPK are closely related to the differentiation states of MSCs subjected to SDF-1alpha, and finally, inhibition of SAPK/JNK signaling significantly attenuates SDF-1alpha-stimulated transfilter migration of MSCs of undifferentiation, 24-h preinduction, 18-h maintenance, and 48-h maintenance, but not MSCs of 5-h induction. Meanwhile, interference with PI3K/Akt, p38MAPK, or ERK1/2 signaling prevents only cells at certain differentiation state from migrating in response to SDF-1alpha. Collectively, these results demonstrate that MSCs in varying neural differentiation states have different migratory capacities, thereby illuminating optimization of the therapeutic potential of MSCs to be used for neural regeneration after injury. PMID- 25038641 TI - The effect of high speed shearing on disaggregation and degradation of pectin from creeping fig seeds. AB - The effect of high speed shearing (HSS) on disaggregation and degradation of pectin from creeping fig seeds was investigated. It was found that disaggregation and degradation occurred during the whole shearing process. When pectin solution was sheared at 24,000 rpm for less than 8h, degradation happened but disaggregation was dominant during this period. After 8h, degradation became obvious, however, a small amount of aggregates remained even after 24h treatment, indicating that HSS may not eliminate aggregates efficiently. The presence of aggregates is one of the most probable causes for the inaccurate determination of molecular weight of pectin. A new method was proposed for calculating more accurately the molecular weight based on the change of the reducing sugar content and the variation of molecular weight. Determination of unsaturated uronide and FT-IR spectra analysis indicated that neither beta-elimination nor demethoxylation occurred during the HSS, and no new functional group was formed during the HSS process. PMID- 25038642 TI - Determination of lead in soybean sauces by the diffusive gradients in thin films technique. AB - A diffusive gradients in thin films (DGT) device with sodium poly (aspartic acid) (PASP) as a novel binding agent (PASP DGT) combined with graphite furnace atomic absorption spectrometry (GFAAS) was developed for the sampling and measurement of lead in soybean sauce samples. The performance of PASP DGT was independent of pH in the range of 3-6 and salinity in the range from 4 to 14 g/L (as NaCl). There was no significant difference between PASP DGT technique and hydride generation atomic fluorescence spectrometry (HG-AFS) method for the measurement of lead in soybean sauce samples. The recoveries of lead in spiked soybean sauce samples determined by PASP DGT coupled with GFAAS were 94.3-97.2% with the relative standard deviations of 2.52-3.09%. The concentrations of Pb in twelve soybean sauce samples determined by PASP DGT coupled with GFAAS were in the range of 0.09 0.71 mg/L. PMID- 25038643 TI - Combination of grape seed proanthocyanidin extract and docosahexaenoic acid-rich oil increases the hepatic detoxification by GST mediated GSH conjugation in a lipidic postprandial state. AB - The ingestion of dietary lipids leads to oxidative stress. This postprandial oxidative stress may potentiate the adverse effects of postprandial hyperlipidaemia. Proanthocyanidins have been shown to alleviate oxidative stress and hypertriglyceridaemia associated with the postprandial state. Additionally, omega-3 polyunsaturated fatty acids (PUFAs) also have beneficial effects on lipoprotein metabolism and oxidative stress. The present study was designed to investigate the possible additive effects in liver of an acute dose of grape seed proanthocyanidins extract (GSPE) and oil rich in docosahexaenoic acid (DHA-OR) on lipidic postprandial oxidative stress in Wistar rats. GSPE+DHA-OR modifies the hepatic antioxidant enzymatic activities (GST and GPx), clearly showing that this combination increases the detoxification of postprandial xenobiotics via the GST action mediated hepatic GSH conjugation. In conclusion, this study provides evidence that the combination of GSPE and DHA-OR ameliorate the transient imbalance between the lipid hydroperoxide level and antioxidant status related to a lipidic postprandial state. PMID- 25038644 TI - Study by 31P NMR spectroscopy of the triacylglycerol degradation processes in olive oil with different heat-transfer mechanisms. AB - The thermal degradation of olive oil using conventional and microwave heating under the same experimental conditions were compared. A powerful identification and quantification technique based on (31)P NMR has been developed to characterise the differences between the minor components including diacylglycerol and free fatty acids in the heated samples. The (31)P NMR spectra of the degraded olive oils, which contain OH groups derivatised with a phosphorus reagent, showed that conventional heating is more detrimental to the oil than microwave technique. Conventional heating leads to a significant increase in the diacylglycerol and free fatty acid contents as well as in the number of degradation compounds, which damage the olive oil quality. However, the main process that takes place on using microwave heating is isomerisation between diacylglycerols, a change that could give a potential longer shelf life to the olive oil. PMID- 25038645 TI - Optimisation of pulsed ultrasonic and microwave-assisted extraction for curcuminoids by response surface methodology and kinetic study. AB - A response surface methodology and a kinetic study were used to optimise the pulsed ultrasonic and microwave techniques in the extraction of curcuminoids. Microwave-assisted extraction had the same efficiency as pulsed ultrasonic assisted extraction, and both methods were better than continuous ultrasonic extraction of curcuminoids. For the pulsed ultrasonic-assisted extraction, the optimal conditions were 60% amplitude (AMP), 83% ethanol (v/v), 3/1 (s/s) pulsed duration/interval time and 10 min irradiation time. For the microwave-assisted extraction, the optimal conditions were 82% ethanol, 10% power level and 7 min of extraction time. Both methods used a 1:200 mass to solvent ratio. PMID- 25038646 TI - Discrimination of fresh fruit juices by a fluorescent sensor array for carboxylic acids based on molecularly imprinted titania. AB - Design of chemical sensor arrays that can discriminate real-world samples has been highly attractive in recent years. Herein a fluorescent indicator displacement sensor array for discrimination of fresh fruit juices was developed. By coupling the unique high affinity of titania to electron-donating anions and the cross-reactivity of molecularly imprinted materials to structurally similar species, a small array was fabricated using only one rhodamine-based fluorescent dye and three synthesized materials. Citric, malic, succinic and tartaric acids were chosen as indices. The recognition mechanism was investigated by spectrofluorimetric titration using a non-linear Langmuir-type adsorption model. The proposed method was applied to discriminate thirteen fruit juices through their carboxylic acid contents. Principal component analysis of the data clearly grouped the thirteen juices with the first principal component owning 98.2% of the total variation. The comparison of the sensor array with HPLC determination of the carboxylic acids was finally made. PMID- 25038647 TI - Inhibitory effects of polyphenols from water chestnut (Trapa japonica) husk on glycolytic enzymes and postprandial blood glucose elevation in mice. AB - Water chestnut is an annual aquatic plant that grows in Asia and Europe. Although water chestnut has been used as food and herbal medicine, its physiological functions and active ingredients are unknown. Here, we extracted polyphenols from the husk of the Japanese water chestnut (Trapa japonica) and assessed their effects on blood glucose levels. Three hydrolysable polyphenolics (WCPs), eugeniin, 1,2,3,6-tetra-O-galloyl-beta-d-glucopyranose, and trapain, were predominant with dry-weight contents of 2.3 +/- 0.0, 2.7 +/- 0.1, and 1.2 +/- 0.1g/100g, respectively. These WCPs exhibited inhibitory activity against alpha amylase and alpha-glucosidase. Whereas (-)-epigallocatechin gallate does not inhibit alpha-amylase, WCPs exhibited high inhibitory activity (>80% at 0.15 mg/mL). In mice, administration of WCPs (40 mg/kg) significantly reduced blood glucose and serum insulin levels as assessed by the carbohydrate tolerance test. PMID- 25038648 TI - Effect of Robola and Cabernet Sauvignon extracts on platelet activating factor enzymes activity on U937 cells. AB - A number of studies support the anti-atherogenic effect of wine compounds. The scope of this study was to examine the effect of a red (Cabernet Sauvignon-CS) and a white (Robola-R) wine, as well as resveratrol and quercetin, on the platelet activating factor (PAF) biosynthetic enzymes, acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAF-AT) and DTT-insensitive CDP-choline 1-alkyl-2-acetyl sn-glycerol cholinephosphotransferase (PAF-CPT), and its main catabolic enzyme (PAF acetylhydrolase; PAF-AH), on U937 cells, in cell free and in intact cell experiments. In cell free experiments, phenolic compounds and wine extracts inhibited PAF biosynthetic enzymes, however in higher concentrations than intact cell experiments. In the latter cases, polar lipids of both wines inhibited in the same order of magnitude the action of lyso-PAF-AT and of PAF-CPT. The water fractions possessed a dual action, in lower concentrations they activated both enzymes, while in higher concentrations only inhibited PAF-CPT. All fractions either did not affect or slightly activated PAF-AH activity. In conclusion, wine compounds may exert their anti-inflammatory activity by reducing PAF levels through modulation of the PAF metabolic enzymes. PMID- 25038649 TI - Multiple optimization of chemical components and texture of purple maize expanded by IVDV treatment using the response surface methodology. AB - A new process, Intensification of Vaporization by Decompression to the Vacuum (IVDV), is proposed for texturizing purple maize. It consists in exposing humid kernels to high steam pressure followed by a decompression to the vacuum. Response surface methodology with three operating parameters (initial water content (W), steam pressure (P) and processing time (T)) was used to study the response parameters: Total Anthocyanins Content, Total Polyphenols Content, Free Radical Scavenging Activity, Expansion Ratio, Hardness and Work Done. P was the most important variable, followed by T. Pressure drop helped the release of bound phenolics arriving to their expulsion outside the cell. Combined with convenient T and W, it caused kernels expansion. Multiple optimization of expansion and chemical content showed that IVDV resulted in good texturization of maize while preserving the antioxidant compounds and activity. Optimal conditions were: W=29%, P=5 bar and T=37s. PMID- 25038650 TI - Effects of PEF and heat pasteurization on PME activity in orange juice with regard to a new inactivation kinetic model. AB - The inactivation kinetics of pectin methyl esterase (PME) during the shelf life (4 degrees C-180 days) of freshly squeezed orange juice samples processed by both pulsed electric fields (PEF) and heat pasteurization (HP) was evaluated in the study. The PME inactivation level after the PEF (25.26 kV/cm-1206.2 MUs) and HP (90 degrees C-20s) treatments were 93.8% and 95.2%, respectively. The PME activity of PEF-processed samples decreased or did not change, while that of HP samples increased during storage (p<0.01). A kinetic model was developed expressing PME inactivation as a function of the PEF treatment conditions, and this enabled the estimation of the reaction rate constant (587.8-2375.4s(-1)), and the time required for a 90% reduction (De, 3917.7-969.5s). Quantification of the increase in PEF energy to ensure a ten-fold reduction in De (ze, 63.7 J), activation electric fields (-921.2 kV cm(-1)mol(-1)), and electrical activation energy (12.9 kJ mol(-1)) was also carried out. Consequently, PEF processing was very effective for the inactivation of PME and for providing stability of orange juice during storage. PMID- 25038651 TI - Extraction kinetics of anthocyanins from skin to pulp during carbonic maceration of winegrape berries with different ripeness levels. AB - The evolution of the content and profile of anthocyanins was studied in the skin and pulp of Gamay winegrapes during twelve days of carbonic maceration. The ripening effect was also investigated using berries belonging to two density classes (A=1094-1100 kg/m(3) and B=1107-1115 kg/m(3)). The ripest berries showed a higher extraction yield, even though the differences among density classes tended to decline towards the end of the process, and few significant differences were found in the anthocyanin profile. The maceration time influenced strongly not only the content and extraction yield, but also the qualitative composition of anthocyanins towards the predominance of malvidin derivatives. Finally, the extraction yield of anthocyanins was positively related with the ethanol formed and the skin mechanical properties using linear regression models, which showed that the skin hardness is likely to be an important variable in modelling daily anthocyanin extraction during carbonic maceration, particularly from the sixth day. PMID- 25038652 TI - Thermal degradation of folates under varying oxygen conditions. AB - Folate losses in thermally treated foods are mainly due to oxidation. Other mechanisms and folate vitamers behaviour are poorly described. Our study evaluated oxygen impact on total folate degradation and derivatives' evolution during thermal treatments. Spinach and green bean purees were heated, in an instrumented reactor, in anaerobic conditions, under an oxygen partial pressure of 40 kPa. Folates were stable in the absence of oxygen, whilst they were degraded under 40 kPa of oxygen. Total folate showed a sharp decrease in the first hour driven by the degradation of 5-CH3-H4folate, followed by a plateau due to the formyl derivatives and minor compounds stability. The different evolution of the main derivatives was confirmed by the degradation of 5-CH3-H4folate and folic acid in solution, under the same conditions of oxygen concentrations. The stability of folic acid and the high susceptibility of 5-CH3-H4folate to degradation in the presence of oxygen were confirmed. PMID- 25038653 TI - Identification of a new angiotensin-converting enzyme (ACE) inhibitor from Thai edible plants. AB - Eight Thai edible plants were tested for their inhibitory activity against an angiotensin-converting enzyme (ACE) using an in vitro assay. The methanol extract of Apium graveolens exhibited significant ACE inhibitory activity with an IC50 value of 1.7 mg/ml, and was then subjected to an isolation procedure that resulted in identification of a pure active constituent, junipediol A 8-O-beta-d glucoside (1-beta-d-glucosyloxy-2-(3-methoxy-4-hydroxyphenyl)-propane-1,3-diol) (1), which had good ACE inhibitory activity with an IC50 value of 76 MUg/ml. Another eight known compounds, isofraxidin-beta-d-glucoside (2), roseoside (3), apigenin-7-O-beta-d-glucoside (4), luteolin-7-O-beta-d-glucoside (5), icariside D2 (6), apiin (7), chrysoeriol-7-O-beta-d-apiosylglucoside (8), and 11,21-dioxo-3 beta,15 alpha,24-trihydroxyurs-12-ene-24-O-beta-d-glucopyranoside (9) were also identified. Although each of these five constituents (2-6) isolated from the same fraction as 1 showed no activity at concentrations of 500 MUM, together, when each was present at 300 MUg/ml, they enhanced the inhibitory activity of 500 MUM of 1 from 64% to 81%. PMID- 25038654 TI - Characterisation of phosvitin phosphopeptides using MALDI-TOF mass spectrometry. AB - Putative phosphopeptides produced from enzyme hydrolysis of phosvitin were identified and characterised using MALDI-TOF/MS. Phosvitin was heat-pretreated and then hydrolysed using pepsin, thermolysin, and trypsin at their optimal pH and temperature conditions with or without partial dephosphorylation. Pepsin and thermolysin were not effective in producing phosphopeptides, but trypsin hydrolysis produced many peptides from phosvitin: 12 peptides, 10 of which were phosphopeptides, were identified from the trypsin hydrolysate. Twelve peptides were also identified from the trypsin hydrolysate of partially dephosphorylated phosvitin, but the phosphate groups remaining with the peptides were much smaller than those from the trypsin hydrolysate of intact phosvitin. This suggested that the phosphopeptides produced from the partially dephosphorylated phosvitin lost most of their phosphate groups during the dephosphorylation step. Therefore, partial dephosphorylation of phosvitin before trypsin hydrolysis may not be always recommendable in producing functional phosphopeptides if the phosphate groups play important roles for their functionalities. PMID- 25038655 TI - Effect of human and simulated gastric juices on the digestion of whey proteins and carboxymethylcellulose-stabilised O/W emulsions. AB - In this study, we analysed the impact of carboxymethylcellulose (CMC) on lipid digestion and physicochemical properties of whey proteins (WP)-stabilised emulsions during in vitro digestion with either artificial or human gastrointestinal juices. The emulsions were made by adsorbing WP on the fat droplets and subsequently adding CMC, which does not interact with the adsorbed proteins. The limited hydrolysis of lipids and their higher physical stability was recorded for WP-stabilised emulsions in the presence of CMC under simulated gastrointestinal conditions. The possible mechanism by which CMC lowers the digestion of WP-stabilised emulsions is related to the limited interaction of fat droplets with gastrointestinal fluids due to the extended thickening network formed by CMC in the continuous phase. The digestion of WP- and CMC-stabilised emulsions in the in vitro model with human gastric fluids led to greater lipid hydrolysis, although the enzymatic activity in both in vitro models was observed at the same level. PMID- 25038656 TI - Formulating essential oil microemulsions as washing solutions for organic fresh produce production. AB - Applications of plant-derived organic essential oils (EOs) as antimicrobials for post-harvest produce operations are limited by their low water solubility. To dissolve EOs in water, microemulsions were studied using two surfactants permitted for organic production, sucrose octanoate ester (SOE) and soy lecithin that were mixed at various mass ratios before dilution with water to 40% w/w. EOs were then mixed with the surfactant solution by hand shaking. Based on visual transparency, intermediate lecithin:SOE mass ratios favoured the formation of microemulsions, e.g., up to 4.0% clove bud oil at ratios of 2:8 and 3:7, and 4.0% cinnamon bark oil and 3.0% thyme oil at ratios of 2:8 and 1:9, respectively. Microemulsions with intermediate lecithin:SOE mass ratios had a relatively low viscosity and better ability to wet fresh produce surfaces. The microemulsions established in this work may be used as washing solutions to enhance the microbial safety of organic fresh produce. PMID- 25038657 TI - 1H Nuclear Magnetic Resonance monitoring of the degradation of margarines of varied compositions when heated to high temperature. AB - In this study, (1)H Nuclear Magnetic Resonance was used to monitor the evolution of three margarines of varied compositions when submitted to heating at 180 degrees C in an oven with aeration. Heating causes degradation of polyunsaturated acyl groups and this depends not only on their unsaturation degree, but also on the concentration of the different acyl groups. The evolution of monounsaturated groups varies depending on the disappearance rate of the groups with higher unsaturation degree. Heat treatment also causes hydrolysis reactions that lead to a reduction in 1-monoglycerides and an increase in 1,2-diglycerides, especially in the margarines with higher water content, as well as degradation of some vegetable sterols. Different types of aldehydes and epoxides were identified and quantified, above all in the margarine with the highest proportion of polyunsaturated groups, especially linoleic; some of these are toxic, such as 4 hydroxy- and 4,5-epoxy-2-alkenals. PMID- 25038658 TI - Identification of a NFkappaB inhibitory peptide from tryptic beta-casein hydrolysate. AB - Several bioactive peptides are encrypted within the sequence of major milk proteins, requiring enzymatic proteolysis for release and activation. The present study aimed at the identification of potential anti-inflammatory activities in tryptic hydrolysates of bovine beta-casein. Inflammatory processes involve in most cases an activation of Nuclear factor Kappa-light-chain enhancer of activated B cells (NFkappaB), which is a pro-inflammatory transcription factor of several genes. Hence, a NFkappaB reporter cell line was established, and TNF alpha mediated activation of NFkappaB was used as a measurement. Bovine beta casein (beta-CN) was hydrolysed by trypsin and fractionated by ultrafiltration. Total proteolysate as well as the fraction containing peptides between 1 and 5 kDa showed an inhibitory effect in the cell-based assay, while the fraction containing molecules smaller than 1 kDa did not. This anti-inflammatory effect was ascribed to a group of large, hydrophobic peptides, which were identified using LC-MS. The main peptide was synthesised and showed a significant anti inflammatory effect in HEK(nfkb-RE)-cells. Thus, for the first time, a casein derived peptide having an anti-inflammatory effect in vitro has been identified. PMID- 25038659 TI - A sharper characterization of the geographical origin of Lebanese wines by a new interpretation of the hydrogen isotope ratios of ethanol. AB - The hydrogen isotope ratios of the methyl [(D/H)I] and methylene [(D/H)II] groups in ethanol can be used as geographical origin tracers of wines. These ratios reflect not only the deuterium content of sugars but also that of water in the grape medium, and hence are influenced by the irrigation, the degree of ripeness at harvest, and other viticultural and enological practices. Thus, the isotopic redistribution coefficients between water in the grape must and the methyl and methylene sites of ethanol were determined and then used to compute an isotopic ratio [(D/H)Is] representing the contribution of the fermentable sugars to (D/H)I. To evaluate the discrimination power of (D/H)Is, the ethanol D/H ratios of 78 Lebanese wine samples from different vineyards were determined using the SNIF-NMR method. An improved classification at the subregional level was obtained using (D/H)Is which exhibits an inverse linear correlation with the annual precipitation amount. Furthermore, the variations of the ethanol D/H ratios with the degree of grape ripeness and with the juice fractions obtained from the inner and peripheral pulps of the grape berries were studied on a small sample set. These factors should be considered when using the SNIF-NMR results to characterize the geographical origin of wines. PMID- 25038660 TI - Psidium cattleianum fruit extracts are efficient in vitro scavengers of physiologically relevant reactive oxygen and nitrogen species. AB - Psidium cattleianum, an unexploited Brazilian native fruit, is considered a potential source of bioactive compounds. In the present study, the in vitro scavenging capacity of skin and pulp extracts from P. cattleianum fruits against reactive oxygen species (ROS) and reactive nitrogen species (RNS) was evaluated by in vitro screening assays. Additionally, the composition of phenolic compounds and carotenoids in both extracts was determined by LC-MS/MS. The major phenolic compounds identified and quantified (dry matter) in the skin and pulp extracts of P. cattleianum were ellagic acid (2213-3818 MUg/g extracts), ellagic acid deoxyhexoside (1475-2,070 MUg/g extracts) and epicatechin gallate (885-1,603 MUg/g extracts); while all-trans-lutein (2-10 MUg/g extracts), all-trans antheraxanthin (1.6-9 MUg/g extracts) and all-trans-beta-carotene (4-6 MUg/g extracts) were the major carotenoids identified in both extracts. P. cattleianum pulp extract showed higher scavenging capacity than skin extract for all tested ROS and RNS. Considering the potential beneficial effects to human health, P. cattleianum may be considered as a good source of natural antioxidants and may be useful for the food and phytopharmaceutical industry. PMID- 25038661 TI - Storage of parbaked bread affects shelf life of fully baked end product: a 1H NMR study. AB - Full baking of earlier partially baked (parbaked) bread can supply fresh bread to the consumer at any time of the day. When parbaked bread loaves were stored at 25, 4 or 23 degrees C, the extent of crumb to crust moisture migration and amylopectin retrogradation differed with storage temperature, and the firming rate was evidently lowest during frozen storage. The extent of crumb to crust moisture migration during parbaked bread storage largely determined the mass of the fresh finished bread, and its crumb and crust moisture contents. Initial NMR proton mobility, initial resilience, the extent of amylopectin retrogradation and changes in firmness and resilience during storage of fully baked bread were affected by its crumb moisture content. The lowest firming rate was observed for finished bread resulting from parbaked bread stored at -25 degrees C, while the highest firming rate was observed for finished bread from parbaked bread stored at 23 degrees C. PMID- 25038662 TI - Primary and secondary metabolite profiling of doenjang, a fermented soybean paste during industrial processing. AB - In this study, a comprehensive metabolite profile analysis of doenjang, a fermented soybean paste, at various steps of its industrial 5-step production process was conducted, by combining gas and liquid chromatography-mass spectrometry techniques with multivariate analysis. From the partial least squares discriminant analysis of primary and secondary metabolites, the patterns were clearly distinguishable between the various processing steps (step 1: steaming, step 2: drying, step 3: meju fermentation, step 4: brining, step 5: doenjang aging). Of the primary metabolites, most of the monosaccharides, amino acids, and fatty acids increased in steps 3-5. Isoflavone and soyasaponin derivatives were major secondary metabolites identified during the processing of doenjang. Isoflavone glycosides gradually decreased after step 1, while isoflavone aglycones distinctly increased in steps 4-5. Soyasaponins generally decreased during processing after step 2. Increased isoflavone aglycones, such as daidzein, glycitein, and genistein, were observed in steps 4-5 showed the strongest positive correlation with doenjang's antioxidant potential and total phenolic content. PMID- 25038663 TI - Effect of ultrasound pretreatment on rennet-induced coagulation properties of goat's milk. AB - The effects of ultrasound (US) pretreatment on goat milk before rennet-induced coagulation were studied in order to improve the milk coagulation properties. Skimmed goat milk was subjected to US at 800 W for different times (0-20 min) and various parameters were evaluated. The particle sizes in US pretreated goat milk under the transmission electron microscopy were smaller than in untreated samples. For US pretreated samples, the degree of whey protein denaturation, contents of soluble calcium and phosphorus increased by 9.57%, 16.90% and 13.68%, respectively. The gel firmness, coagulum strength, final storage modulus, cohesiveness, water holding capacity and cross-linking of gels demonstrated marked increase. The turbiscan stability index (TSI) also confirmed the improvement of goat milk coagulation properties with increasing duration of US pretreatment, whereas the gelation time was prolonged. PMID- 25038664 TI - Haze activity of different barley trypsin inhibitors of the chloroform/methanol type (BTI-CMe). AB - Our previous study found that the critical protein in SE (silica eluted) proteins is BTI-CMe, and assumed that SE-ve malt for brewing may improve the haze stability in beer. In this study, we investigated the difference in gene sequence and corresponding amino acid sequence of BTI-CMe between SE+ve and SE-ve types. The results showed that there were 7 amino acid differences between Yerong (SE ve) and Franklin (SE+ve). Two types BTI-CMe were expressed in vitro and purified successfully. By adding the purified BTI-CMe into commercial beer, we found that both original turbidity and alcohol chill haze degree of beer were increased. BTI CMe of SE-ve haplotype showed a lower level of haze formation in beer than SE+ve haplotype. Response surface methodology (RSM) was conducted to determine the relationship between BTI-CMe and tannic acid, and their effects on haze formation. It was found that (1) higher content of BTI-CMe and/or tannic acid in beer would give rise to higher turbidity; (2) there was a significant interaction between BTI-CMe and tannic acid; (3) haze activity disparity of BTI-CMe between two types was significantly and positively correlated with the tannic acid concentration. PMID- 25038665 TI - Botanical discrimination of Greek unifloral honeys with physico-chemical and chemometric analyses. AB - The aim of the present study was to investigate the possibility of characterisation and classification of Greek unifloral honeys (pine, thyme, fir and orange blossom) according to botanical origin using volatile compounds, conventional physico-chemical parameters and chemometric analyses (MANOVA and Linear Discriminant Analysis). For this purpose, 119 honey samples were collected during the harvesting period 2011 from 14 different regions in Greece known to produce unifloral honey of good quality. Physico-chemical analysis included the identification and semi quantification of fifty five volatile compounds performed by Headspace Solid Phase Microextraction coupled to gas chromatography/mass spectroscopy and the determination of conventional quality parameters such as pH, free, lactonic, total acidity, electrical conductivity, moisture, ash, lactonic/free acidity ratio and colour parameters L, a, b. Results showed that using 40 diverse variables (30 volatile compounds of different classes and 10 physico-chemical parameters) the honey samples were satisfactorily classified according to botanical origin using volatile compounds (84.0% correct prediction), physicochemical parameters (97.5% correct prediction), and the combination of both (95.8% correct prediction) indicating that multi element analysis comprises a powerful tool for honey discrimination purposes. PMID- 25038666 TI - Influence of side chain structure changes on antioxidant potency of the [6] gingerol related compounds. AB - [6]-Gingerol and [6]-shogaol are the major pungent components in ginger with a variety of biological activities including antioxidant activity. To explore their structure determinants for antioxidant activity, we synthesized eight compounds differentiated by their side chains which are characteristic of the C1-C2 double bond, the C4-C5 double bond or the 5-OH, and the six- or twelve-carbon unbranched alkyl chain. Our results show that their antioxidant activity depends significantly on the side chain structure, the reaction mediums and substrates. Noticeably, existence of the 5-OH decreases their formal hydrogen-transfer and electron-donating abilities, but increases their DNA damage- and lipid peroxidation-protecting abilities. Additionally, despite significantly reducing their DNA strand breakage-inhibiting activity, extension of the chain length from six to twelve carbons enhances their anti-haemolysis activity. PMID- 25038667 TI - Simplification of the DPPH assay for estimating the antioxidant activity of wine and wine by-products. AB - The DPPH assay is one of the most commonly employed methods for measuring antioxidant activity. Even though this method is considered very simple and efficient, it does present various limitations which make it complicated to perform. The range of linearity between the DPPH inhibition percentage and sample concentration has been studied with a view to simplifying the method for characterising samples of wine origin. It has been concluded that all the samples are linear in a range of inhibition below 40%, which allows the analysis to be simplified. A new parameter more appropriate for the simplification, the EC20, has been proposed to express the assay results. Additionally, the reaction time was analysed with the object of avoiding the need for kinetic studies in the method. The simplifications considered offer a more functional method, without significant errors, which could be used for routine analysis. PMID- 25038668 TI - Bioactive peptides from caseins released by cold active proteolytic enzymes from Arsukibacterium ikkense. AB - Proteolytic enzymes secreted by the cold-adapted microorganism Arsukibacterium ikkense were tested for their ability to degrade caseins at low temperature and produce bioactive peptides. The caseins were extensively degraded (90%) after 24h of hydrolysis at 5 degrees C and completely degraded at 25 degrees C, and many novel peptides were formed. The most hydrolysed sample showed high angiotensin I converting enzyme (ACE)-inhibitory and antioxidant activity, and a number of potent ACE-inhibitory and antioxidant peptides were identified. The presence of tyrosine seemed fundamental for both ACE-inhibitory and antioxidant activity, while phenylalanine seemed to potentiate the antioxidant activity. The novel peptide YPELF was found to have strong radical scavenging and lipid oxidation inhibitory activities, with IC50 for both around 3.5MUM. None of the hydrolysates showed antimicrobial activity. Secreted enzymes from cultures of A. ikkense could thus be a valuable enzyme preparation for inexpensive, energy-efficient production of potent bioactive peptides from caseins in milk at low temperatures. PMID- 25038669 TI - Purification and characterisation of plantaricin ZJ008, a novel bacteriocin against Staphylococcus spp. from Lactobacillus plantarum ZJ008. AB - A novel bacteriocin, plantaricin ZJ008 produced by Lactobacillus plantarum ZJ008 isolated from fresh milk, was purified by XAD 2, cation exchange chromatograph, gel chromatograph, and RP-HPLC. Mass spectrometry based on MALDI-TOF indicated that the bacteriocin had a molecular of 1334.77 Da. Only five of twenty amino acids could be identified by Edman degradation. This bacteriocin was highly thermostable (121 degrees C, 30 min) and exhibited narrow pH stability (pH 4.0 5.0). It was sensitive to alpha-Chymotrypsin, trypsin, papain, and pepsin. However it still had 80% of activity after treatment by proteinase K. The action mode of this peptide functioned as bactericidal, but it did not lead to lysis of cells. This bacteriocin exhibited broad-spectrum antimicrobial activity against tested Gram-positive and Gram-negative bacteria, especially Staphylococcus spp. These results suggested that this bacteriocin appears potentially very useful to control and inhibit Staphylococcus spp. in the food industry. PMID- 25038670 TI - Involvement of chloroplast peroxidase on chlorophyll degradation in postharvest broccoli florets and its control by UV-B treatment. AB - Chlorophyll (Chl)-degrading peroxidase (POX) was purified from green and green yellow broccoli florets to elucidate the physiological role and cell localisation of Chl-degrading POX. Effect of UV-B treatment on Chl-degrading POX activity was also determined. The Chl-degrading POX activity was separated by an ion exchange chromatography into 3 fractions, Chl-POX1, Chl-POX2 and Chl-POX3. The activities of Chl-POX2 and Chl-POX3, but especially that of Chl-POX3, were found in green yellow florets and were clearly suppressed by UV-B irradiation. The protein molecular sizes of cPOX1 and cPOX3 purified from Chl-POX1 and POX3 were 43 and 34kDa, respectively. The cPOX1 was not located within chloroplast fraction, whereas the cPOX3 was found in intact chloroplasts extracted from senescing broccoli florets. We propose that cPOX3 is a chloroplast POX and the activity was suppressed by UV-B treatment, suggesting that cPOX3 might be involved in Chl degradation in stored broccoli florets. PMID- 25038671 TI - Development of gluten-free bread using tartary buckwheat and chia flour rich in flavonoids and omega-3 fatty acids as ingredients. AB - In this study, chia seed flour, which is rich in omega-3 alpha-linolenic acid, and common and tartary buckwheat flour, which has a high antioxidant activity, were integrated into different types of bread with the aim of improving their nutritional value and healthy features. Our results indicate that bread made with chia and tartary buckwheat flour was more acceptable in many nutritional aspects compared to the control (common wheat bread); it contained a higher amount of protein (20%), insoluble dietary fibres (74%), ash (51%), and alpha-linolenic acid (67.4%). Moreover, this bread possessed lower energy (14%) and carbohydrate contents (24%) compared to the control. Tartary buckwheat also improved the total antioxidant capacity of the bread (about 75%) and provided a considerable amount of flavonoids, which are healthy non-nutritional compounds. Overall, chia and tartary buckwheat represent excellent raw materials for the formulation of gluten free bread with high nutritional value. PMID- 25038672 TI - NMR (1H, ROESY) spectroscopic and molecular modelling investigations of supramolecular complex of beta-cyclodextrin and curcumin. AB - In this paper we have investigated the solubility enhancement of curcumin through inclusion complexation by beta-cyclodextrin as well as the topology and geometry of interaction between curcumin and carrier. For this purpose, the phase solubility of curcumin was assessed using Higuchi and Connors method, and the inclusion complex was characterised by 1D (1)H and 2D ROESY NMR analysis, and finally confirmed by molecular modelling. The phase solubility diagram demonstrated the AL-type which confirms an increase in curcumin solubility by increasing the concentration of beta-cyclodextrin. (1)H NMR and ROESY spectra results showed a cross-peak between H-3 proton of beta-cyclodextrin and the aromatic rings group of curcumin. This revealed the hydrophobic interactions between aromatic rings of curcumin and the cavity of beta-cyclodextrin. Finally, the enthalpy of formation was obtained from molecular modelling results which in turn indicated that the process is exothermic and low-energy interactions are involved in the inclusion complex formation. PMID- 25038673 TI - Nutritional compositions and bioactivities of Dacryodes species: a review. AB - Dacryodes species are evergreen, perennial trees with fleshy fruits and belong to the family Buseraseae. Many Dacryodes species are underutilized but are widely applied in traditional folk medicine to treat malaria, fever and skin diseases. The nutritional compositions, phytochemicals and biological activities of Dacryodes edulis, Dacryodes rostrata, Dacryodes buettneri, Dacryodes klaineana and Dacryodes hexandra are presented. The edible fruits of D. edulis are rich in lipids, proteins, vitamins, fatty acids and amino acids. Its extracts (leaf, fruit and resin) exhibit antioxidant, anti-microbial, anti-carcinogenic and other bioactivities. D. rostrata fruit has significant nutrient content, and is rich in proteins, lipids and minerals. These fruits are also highly rich in polyphenols, anthocyanins and antioxidant activities. This comprehensive review will assist the reader in understanding the nutritional benefits of Dacryodes species and in identifying current research needs. PMID- 25038674 TI - A study of multi-ligand beta-lactoglobulin complex formation. AB - Beta-lactoglobulin (beta-LG), the principal whey protein, possesses multiple sites for binding ligands. Most studies of beta-LG-ligand interactions have focused on the formation and dissociation of protein complexes with single ligands, such as alpha-tocopherol, resveratrol or folic acid. In this study, the possibility of a plurality of bioactive compounds binding simultaneously to beta LG was analysed using protein intrinsic fluorescence quenching. It was found that beta-LG could bind two or three ligands simultaneously, although the sequence in which the ligands were added affected binding affinity. The impact of binding to beta-LG on physicochemical properties of these three ligands is discussed in view of fluorescence spectroscopy and high performance liquid chromatography results. The data obtained in this study suggest the feasibility of developing beta-LG based carriers of a plurality of active compounds. PMID- 25038675 TI - Antioxidant and antibacterial activities of sulphated polysaccharides from Pleurotus eryngii and Streptococcus thermophilus ASCC 1275. AB - Polysaccharides from Pleurotus eryngii (PEPS) and exopolysaccharides from Streptococcus thermophilus ASCC 1275 (ST1275 EPS) were sulphated, and antioxidant and antibacterial activities of sulphated and crude polysaccharides were determined. Degree of sulphonation of PEPS and ST1275 EPS was 0.69 and 0.31, respectively. Characteristic bands in FT-IR spectra indicated that the sulphate group was at the C6 position of the galactose skeleton. Antioxidant activities of PEPS and ST1275 EPS were significantly (P<0.05) improved after sulphonation. For tested crude and sulphated polysaccharides, sulphated PEPS had the largest inhibition zone against Escherichia coli ATCC 25922 and Staphylococcus aureus CMCC 26003 while sulphated ST1275 EPS had the largest inhibition zone against Listeria monocytogenes CMCC 54001. Furthermore, sulphated PEPS had the lowest minimum inhibitory concentration (MIC) for E. coli ATCC 25922, and both sulphated PEPS and sulphated ST1275 EPS had the lowest MICs on S. aureus CMCC 26003 and L. monocytogenes CMCC 54001. PMID- 25038676 TI - Modulation of the phenolic composition and colour of red wines subjected to accelerated ageing by controlling process variables. AB - The aim of the present work was to evaluate the effect of the main factors conditioning accelerated ageing processes (oxygen dose, chip dose, wood origin, toasting degree and maceration time) on the phenolic and chromatic profiles of red wines by using a multivariate strategy based on experimental design methodology. The results obtained revealed that the concentrations of monomeric anthocyanins and flavan-3-ols could be modified through the application of particular experimental conditions. This fact was particularly remarkable since changes in phenolic profile were closely linked to changes observed in chromatic parameters. The main strength of this study lies in the possibility of using its conclusions as a basis to make wines with specific colour properties based on quality criteria. To our knowledge, the influence of such a large number of alternative ageing parameters on wine phenolic composition and chromatic attributes has not been studied previously using a comprehensive experimental design methodology. PMID- 25038677 TI - Evolution of watermelon fruit physicochemical and phytochemical composition during ripening as affected by grafting. AB - Flesh reflectance colorimetry, mechanical texture analysis, pH, titratable acidity (TA), and soluble solid (SS), soluble carbohydrate, lycopene and citrulline content of watermelon fruit were assessed throughout ripening (30-50 days post-anthesis; dpa) in grafted and self-rooted plants. Grafting increased firmness, TA, and lycopene content though it delayed its peak. Lycopene content was mostly ripening-dependant, highly correlated and synchronous with changes in pulp chroma (C) and colour a. The sweetness was affected only by ripening. However, total sugars and SS peaked later in fruit of grafted plants than in non grafted ones, and significant interaction of ripening with grafting was observed. Citrulline content increased with ripening in fruit of grafted plants, reaching a peak at 45 dpa; whereas in non-grafted ones it was unchanged between 30 and 45 dpa and declined at 50 dpa. As ripening overall was retarded by grafting, fruit quality of grafted watermelon may benefit from belated harvest. PMID- 25038678 TI - Optimisation of antioxidant extraction from Solanum tuberosum potato peel waste by surface response methodology. AB - This study reports the optimised conditions (temperature, ethanol concentration and processing-time) for antioxidant extraction from potato peel (Agria variety) waste. At short extraction times (34 min), optimal yields of phenolic (TP) and flavonoid (Fv) compounds were reached at 89.9 degrees C and ethanol concentrations of 71.2% and 38.6%, respectively. The main phenolic compounds identified in the extracts were chlorogenic (Cl) and ferulic (Fer) acids. A significant positive correlation was found between antioxidant activity and TP, Fv, Fer and Cl responses. Potato peel extracts were able to stabilize soybean oil under accelerated oxidation conditions, minimising peroxide, totox and p anisidine indices. The production of hexanal and 2-hexenal in soybean oil samples was maximal for extracts obtained at intermediate temperatures and ethanol concentrations. Our results demonstrate potato peel waste is a good source of antioxidants able to effectively limit oil oxidation, while contributing to the revalorisation of these agrifood by-products. PMID- 25038679 TI - Profiling of carotenoids and antioxidant capacity of microalgae from subtropical coastal and brackish waters. AB - Carotenoids are associated with various health benefits, such as prevention of age-related macular degeneration, cataract, certain cancers, rheumatoid arthritis, muscular dystrophy and cardiovascular problems. As microalgae contain considerable amounts of carotenoids, there is a need to find species with high carotenoid content. Out of hundreds of Australian isolates, 12 microalgal species were screened for carotenoid profiles, carotenoid productivity, and in vitro antioxidant capacity (total phenolic content (TPC) and ORAC). The top four carotenoid producers at 4.68-6.88 mg/g dry weight (DW) were Dunaliella salina, Tetraselmis suecica, Isochrysis galbana, and Pavlova salina. TPC was low, with D. salina possessing the highest TPC (1.54 mg Gallic Acid Equivalents/g DW) and ORAC (577 MUmol Trolox Equivalents/g DW). Results indicate that T. suecica, D. salina, P. salina and I. galbana could be further developed for commercial carotenoid production. PMID- 25038680 TI - Free-radical scavenging activity and antibacterial impact of Greek oregano isolates obtained by SFE. AB - The antioxidant and antibacterial properties of Greek oregano extracts obtained by fractional supercritical fluid extraction (SFE) with carbon dioxide were investigated and compared with the properties of essential oil obtained by hydrodistillation. According to DPPH, hydroxyl radical and superoxide anion radical scavenging activity assays, the supercritical extracts expressed stronger antioxidant activity comparing to the essential oil. The most effective was the supercritical extract obtained by fractional extraction at 30 MPa and 100 degrees C after the volatile fraction had been extracted at lower pressure. At the same time this extract showed strong antibacterial activity against staphylococci, including MRSA strain, but did not affect Escherichia coli of normal intestinal flora. The essential oil obtained by hydrodistillation showed stronger antibacterial activity against E. coli, Salmonella and Klebsiella pneumoniae, comparing to the supercritical extracts but at the same affected the normal gut flora. PMID- 25038681 TI - Data fusion for food authentication. Combining rare earth elements and trace metals to discriminate "Fava Santorinis" from other yellow split peas using chemometric tools. AB - "Fava Santorinis", is a protected designation of origin (PDO) yellow split pea species growing only in the island of Santorini in Greece. Due to its nutritional quality and taste, it has gained a high monetary value. Thus, it is prone to adulteration with other yellow split peas. In order to discriminate "Fava Santorinis" from other yellow split peas, four classification methods utilising rare earth elements (REEs) measured through inductively coupled plasma-mass spectrometry (ICP-MS) are studied. The four classification processes are orthogonal projection analysis (OPA), Mahalanobis distance (MD), partial least squares discriminant analysis (PLS-DA) and k nearest neighbours (KNN). Since it is known that trace elements are often useful to determine geographical origin of food products, we further quantitated for trace elements using ICP-MS. Presented in this paper are results using the four classification processes based on the fusion of the REEs data with the trace element data. Overall, the OPA method was found to perform best with up to 100% accuracy using the fused data. PMID- 25038682 TI - Development of chitosan/montmorillonite nanocomposites with encapsulated alpha tocopherol. AB - Nanocomposites of chitosan (CS) were developed and characterized in a full factorial design with varying levels of montmorillonite (MMTNa) and encapsulated tocopherol (toc-encap). The structural properties (XRD, FTIR), morphology (TEM), hygroscopic properties (water vapour permeability, hydrophobicity, sorption isotherms) and optical properties (haze, CIELab parameters) of the resulting materials were evaluated. Toc-encap contents up to 10% influenced the intercalation of MMTNa in the CS matrix, resulting in films with reduced water vapour permeability (3.48*10(-11)(g/msPa)), increased hydrophobicity (DeltaGHydroph |7.93-59.54|mJm(-2)) and lower equilibrium moisture content (EMC), thus showing potential for active food packaging materials. At levels above 10%, toc-encap agglomerates occurred, which deteriorated the properties of the resulting films, as shown with the TEM. As the toc-encap content increased, the films became slightly more yellow, more irregular and less transparent, with a higher haze index. PMID- 25038683 TI - Lipophilic profile of the edible halophyte Salicornia ramosissima. AB - Salicornia ramosissima J. Woods is considered, in the Iberian Peninsula and France, a gourmet product. Nevertheless, is one of the less studied Salicornia species. In this work, GC-MS was employed to, for the first time; fully characterise the lipophilic profile of S. ramosissima and to assess the effect of natural and extra irrigation in that profile. The obtained data showed esterified and free fatty acids, fatty alcohol, sterols, alkanes and aromatic acid derivatives, being palmitic acid, tetracosanol and octacosanol the most abundant compounds. The extra irrigation increases significantly (P<0.001) the content of esterified lipophilic compounds. Stigmastanol, 24-ethyl-delta(22)-coprostenol, several secondary fatty alcohols and dicarboxylic acids were identified for the first time in Salicornia genus. Several of the detected compounds are known to have health benefits and our results suggest that S. ramosissima should be considered as an important dietary source of lipophilic phytochemicals. PMID- 25038684 TI - The level of heat shock protein 90 in pig Longissimus dorsi muscle and its relationship with meat pH and quality. AB - The 90 kDa heat shock protein (HSP90) is a molecular chaperone that participates in various cellular processes, the role and significance of HSP90 in postmortem muscle though remains unclear. In the present study, pig Longissimus dorsi muscles, categorized into three pH groups, were tested for HSP90 levels and meat quality parameters (i.e. water holding capacity, colour, tenderness and lipid oxidation). The muscles with a high initial pH (pHi) group (pH>6.4) possessing the greatest water holding capacity and lightness, contained the highest HSP90 level, followed by intermediate (6.0-6.4) and low pHi groups (pH<6.0). Statistical analysis indicated HSP90 level was significantly and negatively correlated with cooking loss, drip loss, and lightness (r=-0.797, -0.785, -0.604, respectively, P<0.01). The results suggest that HSP90 may play a crucial role in water retention of meat and may be involved in postmortem meat quality development. PMID- 25038686 TI - How to gain insight into the polydispersity of tannins: a combined MS and LC study. AB - In the context of the potential health benefits of food polyphenols, the bioavailability of tannins (i.e. proanthocyanidins) is a major issue, which is strongly influenced by the polydispersity and the degree of polymerisation of tannins. The average degree of polymerisation (DP) of tannins is usually determined using depolymerisation methods, which do not provide any information about their polymer distribution. Moreover, it is still a challenge to characterise tannin fractions of high polydispersity and/or containing polymers of high molecular weights, due to the limit of detection of direct mass spectrometry (MS) analysis methods. In the present work, the polydispersity of several tannin fractions is investigated by two complementary methods: a MALDI-MS method and a semi-preparative sub-fractionation. Using a combination of these methods we are able to gain insight into the DP distributions of the fractions consisting of tannins of medium and high DP. Moreover combining analyses can be useful to assess and compare the DP distributions of most tannin fractions. PMID- 25038685 TI - Natamycin based sol-gel antimicrobial coatings on polylactic acid films for food packaging. AB - In this work a comprehensive study on a new active packaging obtained by a hybrid organic-inorganic coating with antimicrobial properties was carried out. The packaging system based on polylactic acid was realised by sol-gel processing, employing tetraethoxysilane as a precursor of the inorganic phase and polyvinyl alcohol as the organic component, and incorporating natamycin as the active agent. Films with different organic-inorganic ratios (in a range between 1:19 and 1:4) were prepared, and the amount of antimycotic entrapped was found to be modulated by the sol composition, and was between 0.18 and 0.25mg/dm(2). FTIR microspectroscopic measurements were used to characterise the prepared coatings. The antifungal properties of the films were investigated against mould growth on the surface of commercial semi-soft cheese. The release of natamycin from the films to ethanol 50% (v/v) was studied by means of HPLC UV-DAD. The maximal level released was about 0.105 mg/dm(2), which is far below the value allowed by legislation. PMID- 25038687 TI - Bioactive compounds and the antioxidant capacity in new kiwi fruit cultivars. AB - The aim of this investigation was to find the best among seven different kiwi fruit cultivars ('Hayward', 'Daheung', 'Haenam', 'Bidan', 'Hort16A', 'Hwamei' and 'SKK12') for human consumption and to classify them as groups. Therefore, the contents of bioactive compounds and the level of antioxidant capacities of these cultivars were determined in four different extracts and compared. It was found that the contents of the bioactive compounds and the level of antioxidant capacities in different extracts differ significantly (P<0.05). Bioactive compounds and the antioxidant capacities were significantly higher in 'Bidan' and 'SKK12' cultivars than in other studied samples. The ethanol and water extracts of these cultivars exhibited high binding properties with human serum albumin (HSA) in comparison with catechin. In conclusion, based on fluorescence profiles the seven new kiwi fruit cultivars can be classified for three groups: 'Hayward' (including 'Daheung', 'Haenam', Hwamei' and 'SKK12'), 'Bidan' and 'Hort 16A'. In MS - profiles some differences in the peaks were found between the cultivar groups. All studied fruits could be a valuable addition to known disease preventing diets. PMID- 25038688 TI - Delivery of phytochemicals of tropical fruit by-products using poly (DL-lactide co-glycolide) (PLGA) nanoparticles: synthesis, characterization, and antimicrobial activity. AB - Nanoencapsulation offers great potential in natural compounds delivery as it protects them from degradation, improves their aqueous solubility, and delivers active compounds to the action site. Poly (dl-lactide-co-glycolide) (PLGA) nanoparticles of acerola, guava, and passion fruit by-product extracts were synthesized using the emulsion-evaporation method. PLGA with different lactide to glycolide (50:50 and 65:35) ratios were used to determine how polymer composition affected nanoparticles properties and antimicrobial efficiency. Controlled release experiments showed an initial burst followed by a slower release rate for all encapsulated fruit by-products inside PLGA matrix. Nanoparticle properties were more dependent on by-product extract than on PLGA type. Fruit by-products and their nanoparticles were analyzed for antimicrobial activity against Listeria monocytogenes Scott A and Escherichia coli K12. All fruit by-products encapsulated in PLGA inhibited both bacteria at lower (P<0.05) concentration than corresponding unencapsulated fruit by-product. Both PLGA types improved fruit by products delivery to pathogens and enhanced antimicrobial activity. PMID- 25038689 TI - Automated analytical standard production with supercritical fluid chromatography for the quantification of bioactive C17-polyacetylenes: a case study on food processing waste. AB - Food processing enterprises produce enormous amounts of organic waste that contains valuable phytochemicals (e.g. C17-polyacetylenes). Knowledge on the phytochemicals content is a first step towards valorisation. Quantification of C17-polyacetylenes is however often hampered by the lack of commercially available standards or by tedious multistep in-house standard production procedures. In the current study, a new and straightforward supercritical fluid chromatography purification procedure is described for the simultaneous production of 2 analytical C17-polyacetylene standards. Respectively, 5 and 6 mg of falcarinol and falcarindiol were purified in 17 h on analytical scale. After confirming the identity and quality (97% purity) by Nuclear Magnetic Resonance, accurate mass-Mass Spectrometry (am-MS) and Photo Diode Array (PDA) detection the C17-polyacetylene standards were used for the analysis of industrial vegetable waste with Liquid Chromatography coupled to PDA and am-MS detection. Measurements showed varying concentrations of C17-polyacetylenes in the organic waste depending on its nature and origin. PMID- 25038690 TI - Effect of sprouting and light cycle on antioxidant activity of Brassica oleracea varieties. AB - The antioxidant activity of sprouts from four Brassica oleracea varieties was evaluated using "in vitro" methods (total phenolic and flavonoid content; radical scavenging assays: DPPH, hydroxyl and peroxyl; and Ferrous Ion-chelating Ability Assay). Light cycles and sprouting influenced the potential antioxidant activity of sprouts and significant differences were observed between varieties. Generally, antioxidant activity decreased with sprouting and increased in the presence of light, whose discriminant effect was highly significant (P<0.001). Red cabbage sprouts produced under light cycles showed the highest antioxidant activity (57.11 MUg mL(-1) Ferrous Ion-chelating Ability, 221.46 MUg mL(-1) Hydroxyl radical scavenging, 279.02 MUg mL(-1) Peroxyl radical scavenging). Among the traditional Portuguese brassica varieties, Penca cabbage sprouts produced under light presented higher antioxidant capacity, and also higher phenolic and flavonoid content (54.04 mg GAEg(-1) d.w. extract and 21.33 QEg(-1) d.w. extract, respectively) than Galega kale. The phenolic content of Brassica sprouts had a significant contribution to the antioxidant capacity. PMID- 25038692 TI - Cross-reactivity among non-specific lipid-transfer proteins from food and pollen allergenic sources. AB - Non-specific lipid-transfer proteins (nsLTPs) are a family of pan-allergens present in foods and pollen. However, sequence homology among them is limited. The objective of this study was to evaluate the IgE-mediated cross-reactivity between nsLTPs from different sources and evaluate the allergenic properties of LTPs from peach (Pru p 3) and pellitory (Par j 1/Par j 2), major fruit and pollen allergens. Both proteins were purified and characterised. Cross-reactivity studies among nsLTPs from different foods and pollens were performed by immunoblot inhibition using sera specific to peach or pellitory pollen. Cross reactivity with Pru p 3 was observed in hazelnut, onion, corn, peanut and apple while in pollens, none of the extracts was inhibited with Par j 1/2. In conclusion, Pru p 3 did not inhibit LTPs from most fruits. Therefore, although Pru p 3 covers the largest number of epitopes, diagnosis with only this allergen may not detect all LTP sensitivities. PMID- 25038691 TI - Profiling temporal changes in bovine milk lactoferrin glycosylation using lectin microarrays. AB - The bovine milk glycoprotein bovine lactoferrin (bLF) has a variety of biological activities related to its constituent glycans. However, little is known about bLF's oligosaccharide structural changes over the course of lactation. BLF was isolated at 13 time points during the first three months of lactation from three individual cows and glycosylation changes were profiled by lectin microarrays. Substantial profile differences between early and late lactation were observed and accompanying monosaccharide analysis revealed that the occurrence of the non human sialic acid, N-glycolylneuraminic acid, was greater during early stage milk production. Overall, the data suggested that more diverse complex-type oligosaccharide structures were present on bLF during early lactation with an abundance of oligomannose type glycans in later lactation. The differences in the glycoprofiles of bLF from colostrum to mature milk suggest that these may have different functionality in vivo. PMID- 25038693 TI - Glycyl endopeptidase from papaya latex: partial purification and use for production of fish gelatin hydrolysate. AB - An aqueous two-phase system (ATPS) in combination with ammonium sulphate ((NH4)2SO4) precipitation was applied to fractionate glycyl endopeptidase from the papaya latex of Red Lady and Khack Dum cultivars. ATPS containing polyethylene glycol (PEG 2000 and 6000) and salts ((NH4)2SO4 and MgSO4) at different concentrations were used. Glycyl endopeptidase with high purification fold (PF) and yield was found in the salt-rich bottom phase of ATPS with 10%PEG 6000-10% (NH4)2SO4. When ATPS fraction from Red Lady cultivar was further precipitated with 40-60% saturation of (NH4)2SO4, PF of 2.1-fold with 80.23% yield was obtained. Almost all offensive odorous compounds, particularly benzyl isothiocyanate, were removed from partially purified glycyl endopeptidase (PPGE). The fish gelatin hydrolysates prepared using PPGE showed higher ABTS radical scavenging activity and less odour, compared with those of crude extract (CE). Thus antioxidative gelatin hydrolysate with negligible undesirable odour could be prepared with the aid of PPGE. PMID- 25038694 TI - Purification and characterisation of a novel amylase enzyme from red pitaya (Hylocereus polyrhizus) peel. AB - An amylase enzyme from pitaya peel was purified 234.2-folds with 72.1% recovery using ammonium sulphate precipitation, gel filtration and ion exchange chromatography. Gel filtration chromatography and SDS-PAGE revealed that the enzyme is monomeric with a molecular weight of 42.1kDa. The apparent Km and Vmax of the amylase were 2.7 mg/ml and 34.30 u/min/mg of protein, respectively. The enzyme was highly active and stable over a wide pH range from pH 3 to pH 11.0, with optimum activity being observed at pH 5.0. The enzyme was highly selective for soluble starch, amylopectin, glycogen and pulullan. The purified amylase did not require calcium and displayed extreme stability with regard to surfactants and oxidising agents. EDTA, a powerful chelating agent, did not have any significant effect on the stability of the enzyme. Such characteristics have not been previously reported for this type of enzyme from fruit peel. This enzyme, which possesses unique properties, could be widely used in different types of industries, especially in food and biotechnological applications. PMID- 25038695 TI - Ultrasensitive aptamer based detection of beta-conglutin food allergen. AB - Lupine has been increasingly used in food applications due to its high nutritional value and excellent functional properties. However, there has been a response to the increasing number of severe cases of lupine allergies reported during the last decade, and as a result lupine was recently added to the list of substances requiring mandatory advisory labelling on foodstuffs sold in the European Union. In this paper we report the robust and ultrasensitive detection of the anaphylactic beta-conglutin allergen using Apta-PCR achieving a detection limit of 85 pM (25 ng mL(-1)). No cross-reactivity with other conglutins or plant species potentially used in lupine containing foodstuffs was observed. This robust method provides an effective analytical tool for the detection and quantification of the toxic beta-conglutin subunit present in lupine flour. PMID- 25038696 TI - Hibiscus sabdariffa L. - a phytochemical and pharmacological review. AB - Hibiscus sabdariffa L. (Hs, roselle; Malvaceae) has been used traditionally as a food, in herbal drinks, in hot and cold beverages, as a flavouring agent in the food industry and as a herbal medicine. In vitro and in vivo studies as well as some clinical trials provide some evidence mostly for phytochemically poorly characterised Hs extracts. Extracts showed antibacterial, anti-oxidant, nephro- and hepato-protective, renal/diuretic effect, effects on lipid metabolism (anti cholesterol), anti-diabetic and anti-hypertensive effects among others. This might be linked to strong antioxidant activities, inhibition of alpha-glucosidase and alpha-amylase, inhibition of angiotensin-converting enzymes (ACE), and direct vaso-relaxant effect or calcium channel modulation. Phenolic acids (esp. protocatechuic acid), organic acid (hydroxycitric acid and hibiscus acid) and anthocyanins (delphinidin-3-sambubioside and cyanidin-3-sambubioside) are likely to contribute to the reported effects. More well designed controlled clinical trials are needed which use phytochemically characterised preparations. Hs has an excellent safety and tolerability record. PMID- 25038697 TI - Methylglyoxal is associated with bacteriostatic activity of high fructose agave syrups. AB - Three alpha-ketoaldehydes, potentially present in high fructose agave syrups (HFASs) as intermediates of the Maillard reaction, were determined. A previously reported HPLC-FLD procedure based on pre-column derivatisation with 4-methoxy-o phenylenediamine was adopted, yielding the method quantification limits 0.11 mg/kg, 0.10mg/kg, 0.09 mg/kg for glyoxal, methylglyoxal (MGo) and diacetyl, respectively. The obtained results revealed high concentrations of methylglyoxal in HFASs (average 102 +/- 91 mg/kg, range 15.6-315 mg/kg) as compared to commercial Mexican bee honeys or corn syrups. Hydrogen peroxide was generated in all HFASs upon dilution, yet to less extent than in bee honeys. HFASs presented bacteriostatic activity against Bacillus subtilis and Escherichia coli; catalase addition had minimum effect on the assay results in syrups with elevated MGo. Principal component analysis revealed direct association between growth inhibition and MGo. It is concluded that elevated concentration of MGo in HFASs is at least in part responsible for their non-peroxide bacteriostatic activity. PMID- 25038698 TI - Electronic structure of some thymol derivatives correlated with the radical scavenging activity: theoretical study. AB - Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of upmost importance in the living cell. Thymol derivatives exhibit various antioxidant activities and potential health benefits. Exploration of structure-radical scavenging activity (SAR) was approached with a wide range of thymol derivatives. To accomplish this task, the DPPH experimental assay along with quantum-chemical calculations were also employed for these compounds. By comparing the structural properties of the derivatives of interest, their antioxidant activity was explained by the formation of an intramolecular hydrogen bond and the presence of unsaturated double bond (-CHCH substituent) in their radical spices. Moreover, the delocalization of odd electrons in these radicals has been investigated by natural bond orbital analysis and interpretation of spin density maps. Reactivity order of the compound towards the ROS: HO, HOO, and O2( ) was found to be as HO>HOO >> O2(-). PMID- 25038699 TI - Phenolic profile, antioxidant, anti-inflammatory and cytotoxic activities of black (Tuber aestivum Vittad.) and white (Tuber magnatum Pico) truffles. AB - The aim of this study was a comprehensive investigation on phenolic profile, antioxidant, anti-inflammatory and cytotoxic activity of the still insufficiently explored black summer truffles (Tuber aestivum Vittad.) and white (Tuber magnatum Pico) truffles. Methanol and water extracts, obtained by maceration and Soxhlet extraction, were examined. Forty-five phenolics was studied using LC-MS/MS: presence of 14 compounds was confirmed, with the most dominant being p hydroxybenzoic acid, baicalein and kaempferol (T. aestivum), epicatechin and catechin (T. magnatum). Moderate antioxidant activity of both species was determined through several assays. Only T. magnatum showed anti-inflammatory potential by inhibiting COX-1 and 12-LOX pathway products synthesis. Methanol extracts exerted cytotoxicity against some tumour cell lines (HeLa, MCF7, HT-29), besides the prominent activity of water extracts towards breast adenocarcinoma (MCF7). To conclude, these results support further investigations of phytochemicals and biological activity towards verification of nutraceutical use of both species. PMID- 25038700 TI - The potential of e-nose aroma profiling for identifying the geographical origin of licorice (Glycyrrhiza glabra L.) roots. AB - Licorice roots cultivated commercially in distinct geographical areas such as China, Iran, Italy (Abruzzo, Basilicata, Calabria and Sicily) and Turkey were classified using an artificial olfactive system (e-nose) based on metal oxide semiconductor sensors (MOS). The resultant instrumental data were processed using a multivariate statistical analysis method in order to classify the raw samples according to its origin. The e-nose odourprintings were obtained by a canonical discriminant analysis carried out with the aim of relating the specific data-sets corresponding to whole licorice roots aroma with the e-nose reference dataset. E nose results were compared to those obtained by SPME/GC-MS. The HS-SPME/GC/MS analysis was used as a control system to check for the actual existence of differences in the chemical composition of sample headspace. These results imply the possibility to use an electronic nose as a tool for a quick, effective and non-destructive authentication of licorice roots. PMID- 25038701 TI - An improved UHPLC-UV method for separation and quantification of carotenoids in vegetable crops. AB - Carotenoid identification and quantitation is critical for the development of improved nutrition plant varieties. Industrial analysis of carotenoids is typically carried out on multiple crops with potentially thousands of samples per crop, placing critical needs on speed and broad utility of the analytical methods. Current chromatographic methods for carotenoid analysis have had limited industrial application due to their low throughput, requiring up to 60 min for complete separation of all compounds. We have developed an improved UHPLC-UV method that resolves all major carotenoids found in broccoli (Brassica oleracea L. var. italica), carrot (Daucus carota), corn (Zea mays), and tomato (Solanum lycopersicum). The chromatographic method is completed in 13.5 min allowing for the resolution of the 11 carotenoids of interest, including the structural isomers lutein/zeaxanthin and alpha-/beta-carotene. Additional minor carotenoids have also been separated and identified with this method, demonstrating the utility of this method across major commercial food crops. PMID- 25038702 TI - Food allergy and cross-reactivity-chickpea as a test case. AB - Chickpea has become one of the most abundant crops consumed in the Mediterranean and also in western world. Chickpea allergy is reported in specific geographic areas and is associated with lentil and/or pea allergy. We investigated cross reactivity between chickpea and pea/lentil/soybean/hazelnut. The IgE-binding profiles of chickpea globulin and pea/lentil/soybean/hazelnut extracts were analyzed by immunoblotting and immunoblot-inhibition studies. Inhibition-assay with pea/lentil completely suppressed IgE-binding to chickpea globulin allergens, while not so in the reciprocal inhibition. Pre-absorption of sera with chickpea globulin caused the disappearance of IgE-binding to protein on an immunoblot of soybean/hazelnut protein extract. These results suggest that cross-reactivity exists between chickpea and pea/lentil/soybean/hazelnut. Chickpea allergy is associated with lentil and/or pea allergy, but evidently may not present independently. This, together with the described asymmetric cross-reactivity and phylogenetic aspects, suggest that chickpea allergy is merely an expression of cross-reactivity, caused by pea and/or lentil as the "primary" allergen. PMID- 25038703 TI - An in silico model to predict the potential of dietary proteins as sources of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides. AB - An in silico approach was developed to predict the potential of 72 dietary proteins to act as a source of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides. The model takes 68 DPP-IV inhibitory peptides (having an IC50 value <2000 MUM) and the specific contribution of their amino acids into account. Bovine alpha-lactalbumin (alpha-La) and kappa-casein (CN) displayed the highest protein coverage (PC, 43.9%) and potency index (PI, 17.9 10(-6) MUM(-1)g(-1)), respectively for DPP-IV inhibitory peptides. Sequence alignment of 39 DPP-IV inhibitory peptides having IC50's<200 MUM revealed the frequent occurrence of Trp at the N-terminus and Pro at position 2. Canola, chicken egg, oat and wheat were identified as potential sources of DPP-IV inhibitory peptides. In silico approaches may assist in the selection of food proteins for the enzymatic release of DPP-IV inhibitory peptides. The results are relevant to the generation of biofunctional ingredients for glycaemic management. PMID- 25038704 TI - Quantitative metabolite profiling of edible onion species by NMR and HPLC-MS. AB - Allium genus is a treasure trove of valuable bioactive compounds with potentially therapeutically important properties. This work utilises HPLC-MS and a constrained total-line-shape (CTLS) approach applied to (1)H NMR spectra to quantify metabolites present in onion species to reveal important inter-species differences. Extensive differences were detected between the sugar concentrations in onion species. Yellow onion contained the highest and red onion the lowest amounts of amino acids. The main flavonol-glucosides were quercetin 3,4' diglucoside and quercetin 4'-glucoside. In general, the levels of flavonols were, higher in yellow onions than in red onions, and garlic and leek contained a lower amount of flavonols than the other Allium species. Our results highlight how (1)H NMR together with HPLC-MS can be useful in the quantification and the identification of the most abundant metabolites, representing an efficient means to pinpoint important functional food ingredients from Allium species. PMID- 25038705 TI - Study of the influence of maceration time and oenological practices on the aroma profile of Vranec wines. AB - Vranec is one of the most important red grape varieties in Republic of Macedonia, grown in all vineyards, mostly in the Tikves wine region. In this study, Vranec wines produced with different maceration times (4, 7, 14 and 30 days) in presence of enzyme and oak chips during fermentation were studied in order to determine the influence of vinification conditions on the aroma profile. The volatile compounds were determined using headspace solid phase microextraction (HS-SPME) with a PDMS/Carboxen/DVB fibre, coupled with gas chromatography-mass spectrometry (GC-MS). In total 63 aroma compounds were detected revealing a complex aroma profile of Vranec wines composed of esters, alcohols, fatty acids, aldehydes, ketones and sulphur compounds. The content of aroma compounds was related mostly to maceration time, observing increased relative amount of alcohols, esters and fatty acids from the fourth to seventh day of maceration and the presence of oak chips during the fermentation enhanced their formation. The Student-Newman-Keuls test has been applied to ascertain possible significant differences between the studied wines, and principal component analysis has been employed, showing separation and grouping of the wines according to maceration time and oak chips treatment. PMID- 25038706 TI - Synthesis of Mannich bases: 2-(3-Phenylaminopropionyloxy)-benzoic acid and 3 Phenylamino-1-(2,4,6-trimethoxy-phenyl)-propan-1-one, their toxicity, ionization constant, antimicrobial and antioxidant activities. AB - Mannich bases 2-(3-Phenylaminopropionyloxy)-benzoic acid (A) and 3-Phenylamino-1 (2,4,6-trimethoxy-phenyl)-propan-1-one (B) were synthesized. Structures were confirmed by ultraviolet/visible and infra-red spectroscopies. The ionization constant (pKa) values at 8.3 and 8.0 reported for compounds A and B, respectively, indicated that protonation might occur at physiological pH. The LC50 values of 145,595 MUg/ml (A) and 82,526 MUg/ml (B) obtained from Brine shrimp lethality testing showed that both compounds were non-toxic. The two compounds possessed significant antimicrobial activity against bacterial and fungal strains; Escherichia coli, Staphylococcus aereus, Bacillus subtilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonellae typhi, Candida albicans, Rhizopus stolonifer, Aspergillus niger and Penicillium notatum when compared with standards, gentamicin and tioconazole for bacteria and fungi, respectively. In vitro antioxidant screening by the DPPH free radical scavenging method and the scavenging effect on hydrogen peroxide showed that the compounds possessed significant antioxidant activity when compared with antioxidant standards ascorbic acid, butylated hydroxylanisole and alpha-tocopherol. PMID- 25038707 TI - Stability and biological activity of wild blueberry (Vaccinium angustifolium) polyphenols during simulated in vitro gastrointestinal digestion. AB - Wild blueberries are rich in polyphenols and have several potential health benefits. Understanding the factors that affect the bioaccessibility and bioavailability of polyphenols is important for evaluating their biological significance and efficacy as functional food ingredients. Since the bioavailability of polyphenols such as anthocyanins is generally low, it has been proposed that metabolites resulting during colonic fermentation may be the components that exert health benefits. In this study, an in vitro gastrointestinal model comprising sequential chemostat fermentation steps that simulate digestive conditions in the stomach, small intestine and colon was used to investigate the breakdown of blueberry polyphenols. The catabolic products were isolated and biological effects tested using a normal human colonic epithelial cell line (CRL 1790) and a human colorectal cancer cell line (HT 29). The results showed a high stability of total polyphenols and anthocyanins during simulated gastric digestion step with approximately 93% and 99% of recovery, respectively. Intestinal digestion decreased polyphenol- and anthocyanin- contents by 49% and 15%, respectively, by comparison to the non-digested samples. During chemostat fermentation that simulates colonic digestion, the complex polyphenol mixture was degraded to a limited number of phenolic compounds such as syringic, cinnamic, caffeic, and protocatechuic acids. Only acetylated anthocyanins were detected in low amounts after chemostat fermentation. The catabolites showed lowered antioxidant activity and cell growth inhibition potential. Results suggest that colonic fermentation may alter the biological activity of blueberry polyphenols. PMID- 25038708 TI - Simultaneous multi-determination and transfer of eight pesticide residues from green tea leaves to infusion using gas chromatography. AB - A method for determining eight pesticide (cyhalothrin, flufenoxuron, fenitrothion, EPN, bifenthrin, difenoconazole, triflumizole, and azoxystrobin) residues in made green tea as well as a tea infusion (under various brewing water temperatures; 60, 80, and 100 degrees C) using gas chromatography (GC) micro electron capture detector (MUECD) was developed and validated. The extraction method adopted the relatively commonly used approach of solid sample hydration, with the green tea hydrated before being extracted through salting out with acetonitrile followed by a cleanup procedure. The analytes were confirmed using GC-coupled to tandem mass spectrometry (GC/MS/MS) with a triple quadrupole. The linearity of the calibration curves yielded determination coefficients (R(2)) >0.995. Recoveries were carried out using blank samples spiked with all analytes at two levels. The results demonstrated that all pesticides were recovered within the range of 77-116% with a relative standard deviation (RSD) ?14%. The quantification limits of 0.015-0.03 mg/kg were lower than the maximum residue limits (MRLs) set by the Korea Food and Drug Administration (KFDA) for all analytes (0.05-10mg/kg). The infusion study indicated that cyhalothrin, flufenoxuron, and bifenthrin did not infuse into the tea brew from the made tea. Increases in brewing time resulted in increased transfer of azoxystrobin, fenitrothion, and difenoconazole from the made tea to the brew; however, this was not the case with triflumizole or EPN. We conclude that transfer of pesticides appeared to be dependent on their water solubilities and drinking a cup of tea is recommended to be at a water temperature of 60 degrees C. PMID- 25038709 TI - Characterization of the most aroma-active compounds in cherry tomato by application of the aroma extract dilution analysis. AB - Aroma and aroma-active compounds of cherry tomato (Lycopersicum esculentum) was analyzed by gas chromatography-mass spectrometry-olfactometry (GC-MS-O). According to sensory analysis, the aromatic extract obtained by liquid-liquid extraction was representative of tomato odour. A total of 49 aroma compounds were identified and quantified in fresh cherry tomato. Aldehydes were qualitatively and quantitatively the most dominant volatiles in cherry tomato, followed by alcohols. Aroma extract dilution analysis (AEDA) was used for the determination of aroma-active compounds of tomato sample. A total of 21 aroma-active compounds were detected in aromatic extract of fresh tomato, of which 18 were identified. On the basis of the flavour dilution (FD) factor, the most powerful aroma-active compounds identified in the extract were (Z)-3-hexenal (FD=1024) and (E)-2 hexenal (FD=256), which were described as the strong green-grassy and green-leafy odour, respectively. The major organic acid and sugar found were citric acid and fructose, respectively. PMID- 25038710 TI - Changes in non-volatile taste components of button mushroom (Agaricus bisporus) during different stages of freeze drying and freeze drying combined with microwave vacuum drying. AB - Button mushroom slices were dehydrated using freeze drying (FD) or FD combined with microwave vacuum drying (FMVD), and the non-volatile component profiles were studied. The results showed that the level of non-volatile components in button mushroom firstly increased during sublimation of FD/FMVD process and then fell during desorption in FD process and MVD in FMVD process. Compared to FD products, the contents of soluble sugars and polyols in FMVD products were relatively low, whereas the contents of total free amino acids were significantly higher, close to the level of fresh mushroom. However, there was no significant difference in the contents of 5'-nucleotides and organic acids between FD and FMVD products. The equivalent umami concentration (EUC) values for FD and FMVD products did not differ from fresh, indicating that both drying methods could effectively preserve MSG (monosodium glutamate)-like components in button mushroom. PMID- 25038711 TI - Detection of adulteration in mulberry pekmez samples added various sugar syrups with 13C/12C isotope ratio analysis method. AB - Mulberry pekmez can be adulterated in different ways either during the production process or after production is completed. To identify these adulterations, stable carbon isotope ratio analysis (SCIRA) was performed on the model examples prepared by adding saccharose syrup (SS), glucose syrup (GS) and high fructose corn syrup (HFCS) into two different pure mulberry pekmez samples in the ratios of 0%, 10%, 30% and 50%. The delta(13)C ratio of the pure mulberry pekmez was determined as -26.600/00 on average, the saccharose syrup as -24.800/00, the glucose syrup as -11.200/00 and the high-fructose corn syrup as -11.400/00. In identifying the adulteration made to pekmez, especially with the high-fructose corn syrup, which is obtained from corn starch, and with the glucose syrup, the delta(13)C ratio comes into prominence. However it remains impossible identify the adulterations made with the saccharose, which is obtained from beet sugar, or invert sugar syrups. PMID- 25038712 TI - Chemical composition, antimicrobial property and microencapsulation of Mustard (Sinapis alba) seed essential oil by complex coacervation. AB - In this study, the essential oil from mustard seed was isolated by simultaneous steam distillation and extraction (SDE) and analyzed by gas chromatography-mass spectrometry (GC-MS). Fourteen components were identified in the mustard seed essential oil with allyl isothiocyanate being the main component (71.06%). The essential oil has a broad-spectrum antimicrobial activity with inhibition zones and MIC values in the range of 9.68-15.57 mm and 128-512 MUg/mL respectively. The essential oil was subsequently encapsulated in complex coacervation microcapsules with genipin, a natural water-soluble cross-linker. The optimum parameters for the hardening effectiveness of the genipin-hardened essential oil microcapsules were 8h at 40 degrees C and pH 10.0 with a genipin concentration of 0.075 g/g gelatin. The genipin-hardened microcapsules had a particle size of mainly 5-10 MUm and strong chemistry stability which is potential for its application in food preservation. PMID- 25038713 TI - Rapid determination of vitamin D3 in milk-based infant formulas by liquid chromatography-tandem mass spectrometry. AB - A rapid and simple sample preparation method for vitamin D3 (cholecalciferol) was developed for emulsified dairy products such as milk-based infant formulas. A sample was mixed in a 50 mL centrifuge tube with the same amount of water and isopropyl alcohol to achieve chemical extraction. Ammonium sulfate was used to induce phase separation. No-heating saponification was performed in the sample tube by adding KOH, NaCl, and NH3. Vitamin D3 was then separated and quantified using liquid chromatography-tandem mass spectrometry. The results for added recovery tests were in the range 93.11-110.65%, with relative standard deviations between 2.66% and 2.93%. The results, compared to those obtained using a certified reference material (SRM 1849a), were within the range of the certificated values. This method could be implemented in many laboratories that require time and labour saving. PMID- 25038714 TI - Jatropha curcas leaves analysis, reveals it as mineral source for low sodium diets. AB - Jatropha curcas is a perennial herb, belonging to the family Euphorbiaceae, found in countries such as India, Mexico and Venezuela. In the present study, proximate composition and mineral content on the leaves of J. curcas was analysed and compared to spinach (Spinacia oleracea L.) using a ICP-AES. The bromatologic test (dry material) results for ashes, proteins, lipids and carbohydrates revealed 23.4%, 28.0%, 3.2% and 45.4% for J. curcas; whereas for S. oleracea values were 28.9%, 20.8%, 0.5% and 49.9%. Furthermore, minerals found in both species ashes were: calcium, potassium, magnesium, iron and phosphorus, resulting that leaves of J. curcas are composed by three times the iron and calcium amount comparing to spinach; while sodium was absent from the former species. In this study Cu and Zn were found only in spinach, while Pb and As were not detected in any of the studied species. These results indicate that J. curcas leaves might be considered as mineral source suitable for animal and human consumption, especially for people who requires a low sodium diet. PMID- 25038715 TI - Impact of selenium supply on Se-methylselenocysteine and glucosinolate accumulation in selenium-biofortified Brassica sprouts. AB - Brassica sprouts are widely marketed as functional foods. Here we examined the effects of Se treatment on the accumulation of anticancer compound Se methylselenocysteine (SeMSCys) and glucosinolates in Brassica sprouts. Cultivars from the six most extensively consumed Brassica vegetables (broccoli, cauliflower, green cabbage, Chinese cabbage, kale, and Brussels sprouts) were used. We found that Se-biofortified Brassica sprouts all were able to synthesize significant amounts of SeMSCys. Analysis of glucosinolate profiles revealed that each Brassica crop accumulated different types and amounts of glucosinolates. Cauliflower sprouts had high total glucosinolate content. Broccoli sprouts contained high levels of glucoraphanin, a precursor for potent anticancer compound. Although studies have reported an inverse relationship between accumulation of Se and glucosinolates in mature Brassica plants, Se supply generally did not affect glucosinolate accumulation in Brassica sprouts. Thus, Brassica vegetable sprouts can be biofortified with Se for the accumulation of SeMSCys without negative effects on chemopreventive glucosinolate contents. PMID- 25038716 TI - Comparison of QuEChERS sample preparation methods for the analysis of pesticide residues in canned and fresh peach. AB - Original, citrate and acetate QuEChERS methods were studied in order to evaluate the extraction efficiency and the matrix effect in the extraction of pesticides from canned peach samples. Determinations were performed by gas chromatography coupled to mass spectrometry (GC-MS). The proposed method with extraction using the original QuEChERS method and determination by GC-MS was validated. LOQs ranged between 1 and 10 MUg kg(-1) and all analytical curves showed r values higher than 0.99. Recovery values varied from 69% to 125% with RSDs less than 20%. The matrix effect was evaluated and most compounds showed signal enrichment. Robustness was demonstrated using fresh peaches, which provided recovery values within acceptable limits. The applicability of the method was verified and residues of tebuconazole and dimethoate were found in the samples. PMID- 25038717 TI - Zn(II) chelating with peptides found in sesame protein hydrolysates: identification of the binding sites of complexes. AB - Two metal-chelating peptides identified from sesame protein hydrolysates, Ser-Met (SM) and Asn-Cys-Ser (NCS) were chemically synthesized in order to study zinc peptide complexes. The stability constants of two peptides and their zinc complexations were measured by pH-potentiometric techniques, and the molecular masses of the Zn-peptide complexes were determined by electrospray ionization mass spectrometry. The structures of the complexes were studied by infrared spectroscopy and quantum chemistry and possible conformations of the Zn-peptide complexes were determined by molecular modeling to obtain direct insights into the molecular mechanism of Zn(2+) chelation with peptides. The results confirmed that the zinc ion-to-ligand ratio is 1:1 for the two peptides and that water is involved in the formation of the complexes. Among the functional groups of SM and NCS, the carboxyl, hydroxyl, and sulfhydryl groups showed the strongest bonding abilities with Zn(2+) and the carbonyl group of the peptide bond and water (O) regularly participate in coordination by weaker interactions with Zn(2+). PMID- 25038718 TI - Multi-parametric MRI findings of transitional zone prostate cancers: correlation with 3-dimensional transperineal mapping biopsy. AB - PURPOSE: A preliminary project to correlate MR findings with mapping prostate biopsy to help differentiate malignant transitional zone lesions form benign prostatic hyperplasia (BPH) nodules. MATERIALS AND METHODS: Institutional IRB approved retrospective study with 14 patients suspected of having prostate cancer who underwent both prostate 3T MRI using endorectal coil and 3D transperineal mapping prostate biopsy. MR exams were independently reviewed by two abdominal radiologists blinded to pathology with disagreement resolved by consensus. An MRI lesion was defined as having hypointense T2 signal subjectively without corresponding T1 high signal intensity and low signal on ADC maps in the central gland. Mapping biopsy consisted of systematic transperineal US guided biopsy with 55-108 cores per patient. RESULTS: Twenty-nine lesions were detected on MRI. Of these, 13 correlated with Gleason 6 or higher biopsy samples. 16 were biopsy negative. Among the various MRI characteristics assessed, lack of T2 hypointense rim demonstrated the highest specificity (93%) and positive predictive value (89%). Highest sensitivity (85%) and negative predictive value (78%) were seen with ill-defined nodules. When suspicious MR characteristics were combined, the specificity and PPV rose to 100% while sensitivity decreased to 45% and NPV decreased to 73%. CONCLUSIONS: Preliminary study indicates MR findings which can help differentiate a BPH nodule from transitional zone prostate cancers which could help direct biopsy in the large and growing number of people suspected of having prostate cancer. Further work will be needed for validation. PMID- 25038719 TI - Oscillating devices for airway clearance in people with cystic fibrosis. AB - BACKGROUND: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in people with cystic fibrosis. Oscillating devices generate intra- or extra-thoracic oscillations orally or external to the chest wall. Internally they create variable resistances within the airways, generating controlled oscillating positive pressure which mobilises mucus. Extra-thoracic oscillations are generated by forces outside the respiratory system, e.g. high frequency chest wall oscillation. OBJECTIVES: To identify whether oscillatory devices, oral or chest wall, are effective for mucociliary clearance and whether they are equivalent or superior to other forms of airway clearance in the successful management of secretions in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. Latest search of the Cystic Fibrosis Trials Register: 13 January 2014. SELECTION CRITERIA: Randomised controlled studies and controlled clinical studies of oscillating devices compared with any other form of physiotherapy in people with cystic fibrosis. Single-treatment interventions (therapy technique used only once in the comparison) were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria to publications and assessed the quality of the included studies. MAIN RESULTS: The searches identified 68 studies with a total of 288 references; 35 studies (total of 1050 participants) met the inclusion criteria. Studies varied in duration from up to one week to one year; 20 of the studies were cross-over in design. The studies also varied in type of intervention and the outcomes measured, furthermore data were not published in sufficient detail in most of these studies, so meta-analysis was limited. Few studies were considered to have a low risk of bias in any domain. It is not possible to blind participants and clinicians to physiotherapy interventions, but 10 studies did blind the outcome assessors.Forced expiratory volume in one second was the most frequently measured outcome. One long-term study (seven months) compared oscillatory devices with either conventional physiotherapy or breathing techniques and found statistically significant differences in some lung function parameters in favour of oscillating devices. One study identified an increase in frequency of exacerbations requiring antibiotics whilst using high frequency chest wall oscillation when compared to positive expiratory pressure. There were some small but significant changes in secondary outcome variables such as sputum volume or weight, but not wholly in favour of oscillating devices. Participant satisfaction was reported in 15 studies but this was not specifically in favour of an oscillating device, as some participants preferred breathing techniques or techniques used prior to the study interventions. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high level evidence. AUTHORS' CONCLUSIONS: There was no clear evidence that oscillation was a more or less effective intervention overall than other forms of physiotherapy; furthermore there was no evidence that one device is superior to another. The findings from one study showing an increase in frequency of exacerbations requiring antibiotics whilst using an oscillating device compared to positive expiratory pressure may have significant resource implications. More adequately-powered long-term randomised controlled trials are necessary and outcomes measured should include frequency of exacerbations, patient preference, adherence to therapy and general satisfaction with treatment. Increased adherence to therapy may then lead to improvements in other parameters, such as exercise tolerance and respiratory function. Additional evidence is needed to evaluate whether oscillating devices combined with other forms of airway clearance is efficacious in people with cystic fibrosis. PMID- 25038720 TI - Early infant feeding and risk of developing islet autoimmunity and type 1 diabetes. AB - We investigated whether food supplementation within the first year life or age at introduction of gluten-containing foods influenced the risk of developing islet autoimmunity and type 1 diabetes. A total of 2,291 children with a family history of type 1 diabetes were prospectively followed from birth for 28,983 patient years (median 13.1 years). Dietary exposure data were collected by questionnaires, food records and by family interview. Exposure to gluten containing foods before age 3 months, which occurred in 19 children, increased the risk of developing islet autoantibodies (n = 4), multiple islet autoantibodies (n = 4), and type 1 diabetes (n = 3) compared to exclusive breastfeeding within the first 3 months [adjusted hazard ratio (HR) 3.97 (95 % confidence interval 1.41-11.17), 5.39 (1.89-15.35), and 3.45 (1.04-11.48), respectively] and also compared to first exposure to gluten between 3.1 and 6.0 months of age [adjusted HR 3.40 (1.19-9.70), 4.25 (1.47-12.26), and 3.43 (1.01 11.66), respectively]. Children who received infant formula or other solid food within the first 3 months and children who received gluten-containing foods after age 6 months did not have an increased risk of islet autoantibodies, multiple islet autoantibodies or type 1 diabetes. Our present data affirm that compliance to infant feeding guidelines is a possible way to reduce type 1 diabetes risk in genetically susceptible children. PMID- 25038721 TI - Source identification and health risk assessment of metals in indoor dust in the vicinity of phosphorus mining, Guizhou Province, China. AB - An investigation was performed to identify the sources of arsenic (As) and heavy metals in house dust and to assess the associated human health risks in the vicinity of phosphorus (P) mining in Guizhou, China. The concentrations and spatial distributions of mercury (Hg), As, cadmium (Cd), lead (Pb), iron (Fe), copper (Cu), manganese (Mn), and P in 23 house dust samples from the study area were determined. Greater concentrations of As and Pb were found compared with values in other investigations in various countries. Pollution sources were identified using multivariate statistical analysis. As, Pb, Mn, and Hg pollution was mainly attributed to mining activities, and Mn and Cd levels were largely associated with automobile emissions. The dominant wind direction and the distance of the residence from the mining region were found to play an important role in element distributions. A health risk assessment showed that As and Pb should be paid more attention, although the noncancer risks of the studied elements were within the safe range and the cancer risks of As and Cd are within the acceptable range under present conditions. PMID- 25038722 TI - Effects of paraquat on photosynthetic pigments, antioxidant enzymes, and gene expression in Chlorella pyrenoidosa under mixotrophic compared with autotrophic conditions. AB - Only limited information is available on herbicide toxicity to algae under mixotrophic conditions. In the present study, we studied the effects of the herbicide paraquat on growth, photosynthetic pigments, antioxidant enzymes, and gene expression in Chlorella pyrenoidosa under mixotrophic compared with autotrophic conditions. The mean measured exposure concentrations of paraquat under mixotrophic and autotrophic conditions were in the range of 0.3-3.4 and 0.6 3.6 MUM, respectively. Exposure to paraquat for 72 h under both autotrophic and mixotrophic conditions induced decreased growth and chlorophyll (Chl) content, increased superoxide dismutase and peroxidase activities, and decreased transcript abundances of three photosynthesis-related genes (light-independent protochlorophyllide reductase subunit, photosystem II protein D1, and ribulose 1,5-bisphosphate carboxylase/oxygenase large subunit [rbcL]). Compared with autotrophic conditions, the inhibition percentage of growth rate under mixotrophic conditions was lower at 0.8 MUM paraquat, whereas it was greater at 1.8 and 3.4 MUM paraquat. With exposure to 0.8-3.4 MUM paraquat, the inhibition rates of Chl a and b content under mixotrophic conditions (43.1-52.4% and 54.6 59.7%, respectively) were greater compared with autotrophic conditions, whereas the inhibition rate of rbcL gene transcription under mixotrophic conditions (35.7 44.0%) was lower. These data showed that similar to autotrophic conditions, paraquat affected the activities of antioxidant enzymes and decreased Chl synthesis and transcription of photosynthesis-related genes in C. pyrenoidosa under mixotrophic conditions, but a differential susceptibility to paraquat toxicity occurred between autotrophically versus mixotrophically grown cells. PMID- 25038723 TI - The role of D-dimers in the diagnosis of acute aortic dissection. AB - Acute aortic dissection (AAD) is a life threatening cardiovascular medical emergency with a poor prognosis. To explore the utility of D-dimers (DD) in the diagnosis of AAD, we performed a prospective study and conducted a meta-analysis of previous studies. 368 suspected patients were enrolled, including AAD n = 89, PE n = 12, AMI n = 167, normal controls n = 100. All patients had a DD test immediately after admission. We then performed a comprehensive computer search to identify studies investigating using DD as a screening tool for AAD. Finally, we pooled these data to estimate sensitivity, specificity, positive and negative likelihood ratios (LRs) by using DerSimonian-Laird random-effects models. The DD concentrations in the AAD group were significantly higher than those in the AMI and normal control groups. However, the DD level of 500 ng/ml had a poor sensitivity of 51.7 % and specificity of 89.2 % in the diagnosis of AAD. Subgroup analyses found that DD only showed a well discriminative ability of distinguishing AAD patients from normal controls (specificity and positive LR was 97 % and 17.2, respectively). The pooled sensitivity, specificity, positive and negative LR in our meta-analysis was 89, 68 %, 2.71, 0.07, respectively. In conclusion, our results suggest that plasma DD levels cannot add to the certainty of AAD diagnosis and it is not a good biomarker for AAD. In the future, prospective research on patients from many parts of the world is warranted to validate our findings. In addition, different controls, methods of plasma DD assays and other factors should be considered. PMID- 25038724 TI - Molecular characterization of PXR and two sulfotransferases and hepatic transcripts of PXR, two sulfotransferases and CYP3A responsive to bisphenol A in rare minnow Gobiocypris rarus. AB - Bisphenol A (BPA), a wide distributed endocrine-disrupting chemical, has attracted many attentions. To explore the effect of BPA on hepatic metabolic pathways in Gobiocypris rarus, full-length cDNAs of pregnane X receptor (PXR) and two sulfotransferases (SULT1 ST4 and SULT1 ST6) were firstly isolated and characterized. We detected tissues distribution of PXR, CYP3A, SULT1 ST4 and SULT1 ST6 in adult G. rarus. Then we investigated hepatic transcript profiles of these four genes in adult G. rarus exposed to BPA at concentrations of 5, 15, and 50 ug/L for 14 and 35 days. It demonstrates that these four genes are all highly expressed in liver of both male and female adult G. rarus. In response to BPA, sexual dimorphism of expression patterns for PXR, CYP3A, and SULT1 ST6 shows in G. rarus, which includes increase of mRNA levels in females and decrease of mRNA levels in males in both exposure durations of 14 and 35 days. SULT1 ST6 mRNA demonstrates high responsiveness to BPA in both genders and we recommended SULT1 ST6 as a candidate biomarker for BPA exposure. PMID- 25038725 TI - Association study of a common genetic variant in pre-miR-1596 with chicken performance traits. AB - Increasing reports have verified that miRNAs had an important effect on the growth and development in farm animals. To evaluate the possible effect of miR 1596 polymorphisms on chicken economic traits, directly sequencing and polymerase chain reaction-restriction fragment length polymorphism, association analysis as well as online software were used. The results showed that a C > T polymorphism existed in the miR-1596 gene of the Gushi * Anka F2 resource population. The association analysis showed that it was significantly relevant with the potential of hydrogen of leg muscle, fat content of dry sample and fat content of fresh sample, shank length at 0 day and 4 weeks of age; leg weight, leg muscle weight, and breast muscle weight (P < 0.05); and highly significant association with shank girth at 8 weeks of age and abdominal fat weight (P < 0.01). We predicted the secondary structure of Gallus gallus-miR-1596 (gga-miR-1596) and the free energy by using M-fold, which were not altered. MiR-1596 is conserved between chicken and turkey. Our data implied that miR-1596 might participate in regulating the muscle development and adipogenesis. PMID- 25038726 TI - A response to the "call to action" on pathologic reporting of lymph node metastases in differentiated thyroid cancer from the college of american pathologists. PMID- 25038727 TI - Metabolically healthy obesity from childhood to adulthood - Does weight status alone matter? AB - Up to 30% of obese people do not display the "typical" metabolic obesity associated complications. For this group of patients, the term "metabolically healthy obese (MHO)" has been established during the past years and has been the focus of research activities. The development and severity of insulin resistance as well as (subclinical) inflammations seems to play a key role in distinguishing metabolically healthy from metabolically non-healthy individuals. However, an internationally consistent and accepted classification that might also include inflammatory markers as well as features of non-alcoholic fatty liver disease is missing to date, and available data - in terms of prevalence, definition and severity - are heterogeneous, both during childhood/adolescence and during adulthood. In addition, the impact of MHO on future morbidity and mortality compared to obese, metabolically non-healthy as well as normal weight, metabolically healthy individuals is absolutely not clear to date and even conflicting. This review summarizes salient literature related to that topic and provides insight into our current understanding of MHO, covering all age spans from childhood to adulthood. PMID- 25038728 TI - Adiponectin, cardiovascular disease, and mortality: parsing the dual prognostic implications of a complex adipokine. PMID- 25038729 TI - Non-thermal separation of electronic and structural orders in a persisting charge density wave. AB - The simultaneous ordering of different degrees of freedom in complex materials undergoing spontaneous symmetry-breaking transitions often involves intricate couplings that have remained elusive in phenomena as wide ranging as stripe formation, unconventional superconductivity or colossal magnetoresistance. Ultrafast optical, X-ray and electron pulses can elucidate the microscopic interplay between these orders by probing the electronic and lattice dynamics separately, but a simultaneous direct observation of multiple orders on the femtosecond scale has been challenging. Here we show that ultrabroadband terahertz pulses can simultaneously trace the ultrafast evolution of coexisting lattice and electronic orders. For the example of a charge density wave (CDW) in 1T-TiSe2, we demonstrate that two components of the CDW order parameter- excitonic correlations and a periodic lattice distortion (PLD)--respond very differently to 12-fs optical excitation. Even when the excitonic order of the CDW is quenched, the PLD can persist in a coherently excited state. This observation proves that excitonic correlations are not the sole driving force of the CDW transition in 1T-TiSe2, and exemplifies the sort of profound insight that disentangling strongly coupled components of order parameters in the time domain may provide for the understanding of a broad class of phase transitions. PMID- 25038730 TI - Visualization of oscillatory behaviour of Pt nanoparticles catalysing CO oxidation. AB - Many catalytic reactions under fixed conditions exhibit oscillatory behaviour. The oscillations are often attributed to dynamic changes in the catalyst surface. So far, however, such relationships were difficult to determine for catalysts consisting of supported nanoparticles. Here, we employ a nanoreactor to study the oscillatory CO oxidation catalysed by Pt nanoparticles using time-resolved high resolution transmission electron microscopy, mass spectrometry and calorimetry. The observations reveal that periodic changes in the CO oxidation are synchronous with a periodic refacetting of the Pt nanoparticles. The oscillatory reaction is modelled using density functional theory and mass transport calculations, considering the CO adsorption energy and the oxidation rate as site-dependent. We find that to successfully explain the oscillations, the model must contain the phenomenon of refacetting. The nanoreactor approach can thus provide atomic-scale information that is specific to surface sites. This will improve the understanding of dynamic properties in catalysis and related fields. PMID- 25038732 TI - Overlooking atrial arrhythmia in paced electrocardiograms: error of man and machine. PMID- 25038731 TI - Separation of rare gases and chiral molecules by selective binding in porous organic cages. AB - The separation of molecules with similar size and shape is an important technological challenge. For example, rare gases can pose either an economic opportunity or an environmental hazard and there is a need to separate these spherical molecules selectively at low concentrations in air. Likewise, chiral molecules are important building blocks for pharmaceuticals, but chiral enantiomers, by definition, have identical size and shape, and their separation can be challenging. Here we show that a porous organic cage molecule has unprecedented performance in the solid state for the separation of rare gases, such as krypton and xenon. The selectivity arises from a precise size match between the rare gas and the organic cage cavity, as predicted by molecular simulations. Breakthrough experiments demonstrate real practical potential for the separation of krypton, xenon and radon from air at concentrations of only a few parts per million. We also demonstrate selective binding of chiral organic molecules such as 1-phenylethanol, suggesting applications in enantioselective separation. PMID- 25038733 TI - A pilot controlled trial of a combination of dense cranial electroacupuncture stimulation and body acupuncture for post-stroke depression. AB - BACKGROUND: Our previous studies have demonstrated the treatment benefits of dense cranial electroacupuncture stimulation (DCEAS), a novel brain stimulation therapy in patients with major depression, postpartum depression and obsessive compulsive disorder. The purpose of the present study was to further evaluate the effectiveness of DCEAS combined with body acupuncture and selective serotonin reuptake inhibitors (SSRIs) in patients with post-stroke depression (PSD). METHODS: In a single-blind, randomized controlled trial, 43 patients with PSD were randomly assigned to 12 sessions of DCEAS plus SSRI plus body electroacupuncture (n = 23), or sham (non-invasive cranial electroacupuncture, n CEA) plus SSRI plus body electroacupuncture (n = 20) for 3 sessions per week over 4 weeks. Treatment outcomes were measured using the 17-item Hamilton Depression Rating Scale (HAMD-17), the Clinical Global Impression - Severity scale (CGI-S) and Barthel Index (BI), a measure used to evaluate movement ability associated with daily self-caring activity. RESULTS: DCEAS produced a significantly greater reduction of both HAMD-17 and CGI-S as early as week 1 and CGI-S at endpoint compared to n-CEA, but subjects of n-CEA group exhibited a significantly greater improvement on BI at week 4 than DCEAS. Incidence of adverse events was not different in the two groups. CONCLUSIONS: These results indicate that DCEAS could be effective in reducing stroke patients' depressive symptoms. Superficial electrical stimulation in n-CEA group may be beneficial in improving movement disability of stroke patients. A combination of DCEAS and body acupuncture can be considered a treatment option for neuropsychiatric sequelae of stroke. TRIAL REGISTRATION: http://www.clinicaltrials.gov, NCT01174394. PMID- 25038734 TI - The specificity of protection against cationic antimicrobial peptides by lactoferrin binding protein B. AB - A variety of Gram-negative pathogens possess host-specific lactoferrin (Lf) receptors that mediate the acquisition of iron from host Lf. The integral membrane protein component of the receptor, lactoferrin binding protein A specifically binds host Lf and is required for acquisition of iron from Lf. In contrast, the role of the bi-lobed surface lipoprotein, lactoferrin binding protein B (LbpB), in Lf binding and iron acquisition is uncertain. A common feature of LbpBs from most species is the presence of clusters of negatively charged amino acids in the protein's C-terminal lobe. Recently it has been shown that the negatively charged regions from the Neisseria meningitidis LbpB are responsible for protecting against an 11 amino acid cationic antimicrobial peptide (CAP), lactoferricin (Lfcin), derived from human Lf. In this study we investigated whether the LbpB confers resistance to other CAPs since N. meningitidis is likely to encounter other CAPs from the host. LbpB provided protection against the cathelicidin derived peptide, cathelicidin related antimicrobial peptide (mCRAMP), but did not confer protection against Tritrp 1 or LL37 under our experimental conditions. When tested against a range of rationally designed synthetic peptides, LbpB was shown to protect against IDR-1002 and IDR 0018 but not against HH-2 or HHC10. PMID- 25038737 TI - Gut microbial translocation in the pathogenesis of systemic inflammation in patients with end-stage renal disease. PMID- 25038738 TI - Idiopathic limbic encephalitis associated with antibodies to glutamic acid decarboxylase. PMID- 25038736 TI - Targeting apoptosis in autoimmune hepatitis. AB - Apoptosis is the predominant mechanism of liver cell death in autoimmune hepatitis, and interventions that can modulate this activity are emerging. The aim of this review was to describe the apoptotic mechanisms, possible aberrations, and opportunities for intervention in autoimmune hepatitis. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, apoptosis in liver disease, apoptosis mechanisms, and apoptosis treatment were examined. Apoptosis is overactive in autoimmune hepatitis, and the principal pathway of cell death is receptor mediated. Surface death receptors are activated by extrinsic factors including liver-infiltrating cytotoxic T cells and the cytokine milieu. The executioner caspases 3 and 7 cleave nuclear deoxyribonucleic acid, and the release of apoptotic bodies can stimulate inflammatory, immune, and fibrotic responses. Changes in mitochondrial membrane permeability can be initiated by caspase 8, and an intrinsic pathway of apoptosis can complement the extrinsic pathway. Defects in the apoptosis of activated effector cells can prolong their survival and sustain the immune response. Caspase inhibitors have been used in diverse experimental and human diseases to retard apoptosis. Oligonucleotides that inhibit the signaling of toll-like receptors can limit the presentation of auto-antigens, and inhibitors of apoptosis that extend the survival of effector cells can be blocked by antisense oligonucleotides. Mechanisms that enhance the clearance of apoptotic bodies and affect key signaling pathways are also feasible. Interventions that influence the survival of liver and effector cells by altering their apoptosis are candidates for study in autoimmune hepatitis. PMID- 25038739 TI - Viewpoint survey of mental health service users' experiences of discrimination in England 2008-2012. AB - PURPOSE: Research suggests levels of discrimination among mental health service users in England are high, but fell over the course of the first phase of the Time to Change programme to reduce stigma and discrimination (2008-2011). The aim of this study was to determine changes in discrimination levels, both overall and by the area of life in which discrimination is experienced, since Time to Change began and over the first year of its second phase (2011-2012). METHOD: Separate samples of mental health service users were interviewed annually from 2008 to 2012 using the Discrimination and Stigma Scale. In 2011 and 2012, social capital was also measured using the Resource Generator-UK. RESULTS: Sample percentages of participants reporting the experience of discrimination in one or more life areas for years 2008-2012 were 91.4, 86.5, 86.2, 87.9 and 91.0 %, respectively. A multivariable logistic regression model was performed to test for significant differences by study year, weighted to match the study population and adjusted for employment status and diagnosis as potential confounding factors. The odds of reporting discrimination in one or more life areas were significantly lower as compared to 2008 for all subsequent years except for 2012 (0.76, 95 % CI 0.49 1.19). However, a weighted multiple regression model provided evidence of decreased mean overall discrimination in 2012 as compared to 2008 (mean decrease 7.57, 95 % CI -11.1 to -4.0, p < 0.001). The weighted mean number of social resources was 13.5 in 2012 as compared to 14.0 in 2011 (mean difference -0.60, 95 % CI -1.25 to 0.06). CONCLUSIONS: While the overall level of discrimination across the life areas studied has fallen over 2008-2012, there is no evidence that more people using mental health services experience no discrimination. We suggest that the pattern suggesting a recent rise in discrimination following an earlier reduction may be linked to economic austerity. Further, the welfare benefits system has become an increasing source of discriminatory experience. PMID- 25038740 TI - Optical coherence tomography-guided classification of epiretinal membranes. AB - To study and classify epiretinal membranes (ERMs) based on spectral domain optical coherence tomography (SD-OCT) findings. One hundred and twelve patients with ERMs were examined clinically and underwent OCT examination. The anatomical structure of the macula and vitreoretinal interface was studied. ERMs were classified in two categories: A, with posterior vitreous detachment (PVD) (91 cases), and B, with the absence of PVD (21 cases). Category A was divided into two subcategories: A1, without contraction of the ERM (37 cases), and A2, with the presence of membrane contraction (54 cases). A2 was further subdivided into A2.1, with retinal folding (15 cases), A2.2, with edema (23 cases), A2.3, with cystoid macular edema (9 cases), and A2.4, with lamellar macular hole (7 cases). Category B was divided in two subcategories: B1, without vitreomacular traction (VMT) (4 cases), and B2, with the presence of VMT (17 cases). Category B2 was subdivided into B2.1, with edema (9 cases), B2.2, presenting retinal detachment (5 cases), and B2.3, with schisis (3 cases). OCT classification of ERMs provides useful information on the anatomical structure of the retina, and the accurate estimation of vitreoretinal interface. PMID- 25038741 TI - Constant-sum paired comparisons for eliciting stated preferences: a tutorial. AB - There is growing recognition of the importance of formally including public preferences and values in societal decision-making processes. Constant-sum paired comparison (CSPC), sometimes known as a 'budget pie' task, is a stated preference method than can be used to elicit and measure these preferences and values. It requires respondents to allocate resources between two alternatives, and the relative allocation of this resource is assumed to reflect the importance or priority that respondents attach to the attribute levels in each alternative. CSPC is useful in addressing questions over preferences for the distribution of resources, and allows for an explicit linkage of budget constraints, opportunity costs, outcomes and group characteristics. A key property of CSPC is the ability to allocate some resources to the less preferred alternative, forcing respondents to reflect on the relative value of both alternatives, and possibly giving it an advantage in contexts such as healthcare where respondents may find it ethically difficult or objectionable to make all-or-nothing allocations. This tutorial will outline the theory underlying CSPC, and will work through a detailed example of administering and interpreting a CSPC elicitation, including defining attributes and levels, constructing experimental design, task presentation, and analysis and interpretation. PMID- 25038742 TI - The synaptic proteome. AB - Synapses are focal hot spots for signal transduction and plasticity in the brain. A synapse comprises an axon terminus, the presynapse, the synaptic cleft containing extracellular matrix proteins as well as adhesion molecules, and the postsynaptic density as target structure for chemical signaling. The proteomes of the presynaptic and postsynaptic active zones control neurotransmitter release and perception. These tasks demand short- and long-term structural and functional dynamics of the synapse mediated by its proteinaceous inventory. This review addresses subcellular fractionation protocols and the related proteomic approaches to the various synaptic subcompartments with an emphasis on the presynaptic active zone (PAZ). Furthermore, it discusses major constituents of the PAZ including the amyloid precursor protein family members. Numerous proteins regulating the rearrangement of the cytoskeleton are indicative of the functional and structural dynamics of the pre- and postsynapse. The identification of protein candidates of the synapse provides the basis for further analyzing the interaction of synaptic proteins with their targets, and the effect of their deletion opens novel insights into the functional role of these proteins in neuronal communication. The knowledge of the molecular interactome is also a prerequisite for understanding numerous neurodegenerative diseases. PMID- 25038743 TI - Segregation of neuronal and neuroendocrine differentiation in the sympathoadrenal lineage. AB - Neuronal and neuroendocrine cells possess the capacity for Ca(2+)-regulated discharge of messenger molecules, which they release into synapses or the blood stream, respectively. The neural-crest-derived sympathoadrenal lineage gives rise to the sympathetic neurons of the autonomic nervous system and the neuroendocrine chromaffin cells of the adrenal medulla. These cells provide an excellent model system for studying common and distinct developmental mechanisms underlying the acquisition of neuroendocrine and neuronal properties. As catecholaminergic cells, they possess common markers related to noradrenaline synthesis, storage and release, but they also display diverging gene expression patterns and are morphologically and functionally different. The precise mechanisms that underlie the diversification of sympathoadrenal cells into neurons and neuroendocrine cells are not fully understood. However, in the past we could show that the establishment of a chromaffin phenotype does not depend on signals from the adrenal cortex and that chromaffin cells and sympathetic neurons apparently differ from the onset of their catecholaminergic differentiation. Nevertheless, the cues that specifically induce neuroendocrine features remain elusive. The early development of the progenitors of chromaffin cells and sympathetic neurons depends on a common set of transcription factors with overlapping but distinct influences on their development. In addition to the well-defined role of transcription factors as developmental regulators, our understanding of post transcriptional gene regulation by microRNAs has substantially increased within the last few decades. This review highlights the major similarities and differences between chromaffin cells and sympathetic neurons, summarizes our current knowledge of the roles of selected transcription factors, microRNAs and environmental signals for the neuroendocrine differentiation of sympathoadrenal cells, and draws comparisons with the development of other endocrine and neuronal cells. PMID- 25038744 TI - Expression of nucleobindin 1 (NUCB1) in pancreatic islets and other endocrine tissues. AB - The protein nucleobindin 1 (NUCB1; also known as CALNUC or Nuc) contains an intriguing combination of DNA- and calcium-binding motifs, a trait that it shares with the protein nucleobindin 2 (NUCB2; also known as nesfatin). NUCB2 has been implicated in several aspects of metabolic control and has been identified in a number of endocrine organs. No such comprehensive mapping of NUCB1 has been presented. We have explored the expression and distribution of NUCB1 in tissues and cells of the mouse endocrine system, with particular focus on the endocrine pancreas. Using reverse transcription plus the polymerase chain reaction (RT-PCR) and Western blot, we demonstrate that NUCB1 is present in the endocrine islets of Langerhans but absent from the exocrine acinar cells. Immunofluorescence studies have revealed that all islet cell types contain NUCB1, including the NUCB2 expressing beta cells. RT-PCR, Western blot and immunofluorescence have shown that NUCB1 is expressed in the pituitary, thyroid, parathyroid, gastrointestinal tract, adrenals and gonads. However, within these tissues, NUCB1 expression is not ubiquitous. For example, in the testis, NUCB1 occurs in the seminiferous tubules but not in the Leydig-cell-containing interstitial tissue. Similarly, the lamina propria of the duodenum lacks NUCB1, despite its presence in enterocytes. Where present, NUCB1 consistently appears to be associated with the Golgi apparatus. Thus, NUCB1 is broadly, but not ubiquitously, expressed in cells of the mouse endocrine system. Together with its location in the Golgi apparatus and its putative Ca(2+)-binding ability, this distribution suggests a role for NUCB1 in Ca(2+) handling/sensing in secretory cells. PMID- 25038745 TI - The benefits of pramipexole selection in the treatment of Parkinson's disease. AB - Levodopa administration as a gold standard in Parkinson's disease (PD) treatment is very valuable, however, long-term administration may cause some motor complications such as abnormal unintended movements and shortening response to each dose (wearing off phenomenon). Dopamine agonists were developed to reduce duration of immobile off periods and dependence to levodopa for improving motor impairments (Clarke et al., Cochrane Libr 1:1-23, 2000). Pramipexole is one of these nonergot dopamine agonists with high relative in vitro specificity and full intrinsic activity at D2 subfamily of dopamine receptors, with a higher binding affinity to D3 than to D4 or D2 receptor subtypes (Piercey, Clin Neuropharmacol 21:141-151, 1998). It can be advantageously administered as monotherapy or adjunctive therapy to levodopa to decrease side effects and increase effectiveness in both early and advanced PD treatment. PMID- 25038746 TI - (1)H, (13)C and (15)N chemical shift assignments of the NDH-1 complex subunit CupS. AB - The cyanobacterial NDH-1 complex is involved in respiratory as well as in cyclic electron transfer around photosystem I. Here, we report both backbone and side chain chemical shift assignments of CupS, a small subunit of the multisubunit membrane protein complex NDH-1 from Thermosynechococcus elongatus. The construct contains 159 amino acids including a Strep-tag and two additional amino acids. PMID- 25038747 TI - A practical guide for the isolation and maintenance of stem cells from tendon. AB - Stem cells are unspecialized cells that can self-renew and have the ability to develop into cells of highly specialized functions. The study of stem cells holds enormous promise in the medical field ranging from their uses in cell therapies to their uses for greater understanding of tissue development and disease pathologies. Stem cells have been isolated from tendon tissue recently. These tendon-derived stem cells (TDSCs) are particularly relevant for tendon repair and the study of the potential roles of stem cells in tendon pathology as they are isolated from tendon tissues. This paper aims to describe the step-by-step protocol and the practical tips for the isolation and verification of stem cell characteristics of TDSCs. The cell seeding density and hence cell-cell contact has a significant impact on the isolation and expansion of TDSCs. Hence, I also describe our established protocol for the determination of the optimal seeding density for TDSC isolation and culture. PMID- 25038749 TI - Risk and resistance factors associated with paternal adjustment to obstetrical brachial plexus injuries. AB - This study aimed to identify risk and resistance factors associated with the psychological adjustment of fathers of children with obstetrical brachial plexus injuries (OBPI). Participants were 34 fathers of children with OBPI recruited from an Australian OBPI clinic. Measures completed were OBPI severity, disability related stress, family functioning and social support. Together the risk and resistance factors of severity and family functioning accounted for 28% of the total variance in paternal psychological adjustment. Family functioning explained 12% of the variance in psychological adjustment in addition to that explained by severity. These findings highlight the importance of considering paternal perceptions of OBPI severity and family functioning when providing health care to families of children with OBPI. PMID- 25038748 TI - Depression and adherence to antiretroviral therapy in low-, middle- and high income countries: a systematic review and meta-analysis. AB - We investigated the associations between depressive symptoms and adherence to antiretroviral therapy (ART) among people living with HIV (PLHIV). We searched the PubMed, EMBASE and Cochrane CENTRAL databases for studies that reported an association between depression and adherence to ART as a primary or secondary outcome. We used a random-effect model to pool the risk estimates from the individual studies. The odds ratio (OR) with their 95 % CIs were used as summary estimates. Of 2861 citations, 111 studies that recruited 42,366 PLHIV met our inclusion criteria. When reported, the rate of PLHIV with depressive symptoms ranged from 12.8 to 78 % and the proportion of PLHIV who achieved good adherence (>= 80 %) ranged from 20 to 98 %. There were no significant differences in rate of depressive symptoms in PLHIV by country income group; however, the proportion of PLHIV who achieved good adherence was significantly higher in lower-income countries (as defined in the 2012 World Bank Country Income Groups) (pooled rate=86 %) compared to higher-income countries (pooled rate=67.5 %; p< .05). We found that the likelihood of achieving good ART adherence was 42 % lower among those with depressive symptoms compared to those without (pooled OR=0.58, 95 % CI 0.55 to 0.62). The relationship between depressive symptoms and adherence to ART was consistent across the country's income group, study design and adherence rates. We found that the magnitude of the association significantly decreases with more recent publications and increasing study sample size. The higher the prevalence of depressive symptoms of PLHIV recruited in the studies, the lower the likelihood of achieving good adherence to ART. In conclusion, the likelihood of achieving good adherence was lower among those with depressive symptoms compared to those without. PMID- 25038750 TI - Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. AB - Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome. PMID- 25038752 TI - Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma. AB - Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations. PMID- 25038751 TI - The common marmoset genome provides insight into primate biology and evolution. AB - We report the whole-genome sequence of the common marmoset (Callithrix jacchus). The 2.26-Gb genome of a female marmoset was assembled using Sanger read data (6*) and a whole-genome shotgun strategy. A first analysis has permitted comparison with the genomes of apes and Old World monkeys and the identification of specific features that might contribute to the unique biology of this diminutive primate, including genetic changes that may influence body size, frequent twinning and chimerism. We observed positive selection in growth hormone/insulin-like growth factor genes (growth pathways), respiratory complex I genes (metabolic pathways), and genes encoding immunobiological factors and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibited evidence of rapid sequence evolution. This genome sequence for a New World monkey enables increased power for comparative analyses among available primate genomes and facilitates biomedical research application. PMID- 25038753 TI - Most genetic risk for autism resides with common variation. AB - A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ~52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation. PMID- 25038755 TI - Calcified granulomatous disease: occupational associations and lack of familial aggregation. AB - PURPOSE: The acute host response to histoplasma capsulatum infection varies according to exposure and susceptibility. Late sequelae include calcifications in the lung, thoracic lymphatics, and spleen. Determinants of calcified granuloma formation are poorly studied and may differ from those affecting acute response. We examined the occupational associations and familial aggregation of radiographic calcified granulomatous disease to characterize the determinants of calcified granuloma formation. METHODS: We analyzed prospectively collected cross sectional data including computed tomograms from 872 adult members of the Old Order Amish of Lancaster County. RESULTS: Granulomas were present in 71 % of participants. Granulomas were present in the lung of 57 % of participants, in the hilar or mediastinal lymph nodes of 55 % of participants, and in the spleen of 29 % of participants. No significant differences were observed in the presence of granulomas between men and women. Each year of age was associated with 4 % higher odds of splenic calcifications, and a primary occupation of farming was associated with an 84 % higher odds of splenic calcifications. A compelling pattern of familial aggregation was not observed. CONCLUSIONS: Calcified granulomatous disease does not appear to aggregate in families. Determinants influencing patterns of granulomatous disease include occupation, age, and geographic location. PMID- 25038754 TI - Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. AB - In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82*10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67*10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25*10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. PMID- 25038757 TI - Cost-effectiveness of liver cancer screening in adults at high risk for liver cancer in the republic of Korea. AB - PURPOSE: This study was conducted in order to determine the most cost-effective strategy, in terms of interval and age range, forliver cancer screening in the high-risk population of Korea. MATERIALS AND METHODS: A stochastic modelwas used to simulate the cost-effectiveness ofliver cancer screening by combined ultrasonography and alpha-fetoprotein testing when varying both screening intervals and age ranges. The effectiveness of these screening strategies in the high-risk population was defined as the probability of detecting preclinical liver cancer, and costwas based on the direct cost ofthe screening and confirmative tests. Optimal cost-effectiveness was determined using the incremental cost-effectiveness ratio. RESULTS: Among the 36 alternative strategies, one-year or two-year interval screening for men aged between 50 and 80 years, six-month or one-year interval screening for men aged between 40 and 80 years, and six-month interval screening for men aged between 30 and 80 years were identified as non-dominated strategies. For women, identified non-dominated strategies were: one-year interval screening between age 50 and 65 years, one year or six-month interval screening between age 50 and 80 years, six-month interval screening between age 40 and 80 years, and six-month interval screening between age 30 and 80 years. CONCLUSION: In Korea, a one-year screening interval for men aged 50 to 80 years would be marginally cost-effective. Further studies should be conducted in order to evaluate effectiveness of liver cancer screening, and compare the cost effectiveness of different liver cancer screening programs with a final outcome indicator such as qualityadjusted life-years or disability adjusted life-years. PMID- 25038758 TI - A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer. AB - PURPOSE: The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. MATERIALS AND METHODS: Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m(2), and the dose of HM30181A was escalated from 30 210 mg/m(2). RESULTS: A total of twenty-four patients were enrolled. Only one patient experienced a doselimiting toxicity-a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m(2) of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m(2) and the area under the curve of plasma concentration- time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m(2). The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m(2). The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m(2). Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. CONCLUSION: The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m(2). PMID- 25038756 TI - Regulation and Role of EZH2 in Cancer. AB - Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2. PMID- 25038759 TI - Outcome of Local Excision Following Preoperative Chemoradiotherapy for Clinically T2 Distal Rectal Cancer: A Multicenter Retrospective Study (KROG 12-06). AB - PURPOSE: The aim of this study was to examine the clinical implications of a pathologically complete response after neoadjuvant chemoradiotherapy (CRT) followed by local excision for patients with cT2 rectal cancer who refused radical surgery. MATERIALS AND METHODS: Seventeen patients with cT2 primary rectal cancer within 6 cm from the anal verge who received neoadjuvant CRT and local excision because of patient refusal of radical surgery or poor performance status were included. Two patients had clinical involvement of a regional lymph node. Preoperative radiotherapy was delivered to the whole pelvis at a dose of 44 to 50.4 Gy in 22 to 28 fractions. All patients underwent transanal excision and eight patients (47%) received postoperative chemotherapy. RESULTS: Ten patients (59%) achieved ypT0. At a median follow-up period of 75 months (range, 22 to 126 months), four (24%) patients developed recurrence (two locoregional and two distant). The 5-year disease-free survival of all patients was 82%, and was higher in patients with ypT0 (90%) than in patients with ypT1-2 (69%, p=0.1643). Decreased disease-free survival was also observed in patients receiving capecitabine compared with 5-fluorouracil (54% vs. 100%, p=0.0298). CONCLUSION: Local excision could be a feasible alternative to radical surgery in patients with ypT0 after neoadjuvant CRT for cT2 distal rectal cancer without further radical surgery. PMID- 25038760 TI - A case-control study to identify risk factors for totally implantable central venous port-related bloodstream infection. AB - PURPOSE: To date, the risk factors for central venous port-related bloodstream infection (CVPBSI) in solid cancer patients have not been fully elucidated. We conducted this study in order to determine the risk factors for CVP-BSI in patients with solid cancer. MATERIALS AND METHODS: A total of 1,642 patients with solid cancer received an implantable central venous port for delivery of chemotherapy between October 2008 and December 2011 in a single center. CVP-BSI was diagnosed in 66 patients (4%). We selected a control group of 130 patients, who were individually matched with respect to age, sex, and catheter insertion time. RESULTS: CVP-BSI occurred most frequently between September and November (37.9%). The most common pathogen was gram-positive cocci (n=35, 53.0%), followed by fungus (n=14, 21.2%). Multivariate analysis identified monthly catheter-stay as a risk factor for CVP-BSI (p=0.000), however, its risk was lower in primary gastrointestinal cancer than in other cancer (p=0.002). Initial metastatic disease and long catheter-stay were statistically significant factors affecting catheter life span (p=0.005 and p=0.000). Results of multivariate analysis showed that recent transfusion was a risk factor for mortality in patients with CVP-BSI (p=0.047). CONCLUSION: In analysis of the results with respect to risk factors, prolonged catheter-stay should be avoided as much as possible. It is necessary to be cautious of CVP-BSI in metastatic solid cancer, especially non gastrointestinal cancer. In addition, avoidance of unnecessary transfusion is essential in order to reduce the mortality of CVP-BSI. Finally, considering the fact that confounding factors may have affected the results, conduct of a well designed prospective controlled study is warranted. PMID- 25038761 TI - Low-dose whole brain radiotherapy with tumor bed boost after methotrexate-based chemotherapy for primary central nervous system lymphoma. AB - PURPOSE: The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL). MATERIALS AND METHODS: We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively. RESULTS: With a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025). CONCLUSION: Low-dose WBRT with tumor bed boost after methotrexate based chemotherapy might be an effective method for management of PCNSL. PMID- 25038762 TI - Early postoperative intraperitoneal chemotherapy for macroscopically serosa invading gastric cancer patients. AB - PURPOSE: Peritoneal recurrence is one of the most common patterns of recurrence after gastric cancer surgery and it has a poor prognosis despite all efforts. The aim of this study is to evaluate the prognostic impact of early postoperative intraperitoneal chemotherapy (EPIC) after surgery with curative intent for macroscopically serosa-invading gastric cancer patients. MATERIALS AND METHODS: The records of 245 patients under the age of 70 were reviewed. These patients were suffering from macroscopically seroa-invading gastric cancer and they underwent curative surgery from 1995 to 2004 at the Kyungpook National University Hospital, Daegu, Korea. The overall survival, gastric cancer-specific survival, complications, and patterns of recurrence were compared between the patients who were treated with EPIC and those who were not. RESULTS: EPIC was administered to 65 patients, and the remaining 180 patients did not receive this treatment. The 5 year overall and gastric cancer-specific survival rates for the EPIC group were 47.4% and 53.1%, respectively, and those for the non-EPIC group were 26.7% and 29.7%, respectively (p=0.012 for overall survival and p=0.011 for gastric cancer specific survival). The rates of peritoneal recurrence for the EPIC group and the non-EPIC group were 18.5% and 32.2%, respectively (p=0.038). There were no significant differences in the morbidity or mortality between the two groups. Based on a multivariate analysis of the factors with prognostic significance in univariate analyses, EPIC, pathological lymph node metastasis, differentiation, and the extent of gastric resection were independent prognostic factors. CONCLUSION: The use of EPIC to treat gastric cancer patients with macroscopic serosal invasions resulted in better survival rate by reducing the risk of peritoneal recurrence. PMID- 25038763 TI - A New Isolated Mediastinal Lymph Node or Small Pulmonary Nodule Arising during Breast Cancer Surveillance Following Curative Surgery: Clinical Factors That Differentiate Malignant from Benign Lesions. AB - PURPOSE: A newly isolated mediastinal lymph node (LN) or a small pulmonary nodule, which appears during breast cancer surveillance, may pose a diagnostic dilemma with regard to malignancy. We conducted this study to determine which clinical factors were useful for the differentiation of malignant lesions from benign lesions under these circumstances. MATERIALS AND METHODS: We enrolled breast cancer patients who were presented with a new isolated mediastinal LN or small pulmonary nodule that arose during surveillance, and whose lesions were pathologically confirmed. Tissue diagnosis was made by mediastinoscopy, video assisted thoracic surgery or thoracotomy. RESULTS: A total of 43 patients were enrolled (mediastinal LN, 13 patients; pulmonary nodule, 30 patients). Eighteen patients (41.9%) were pathologically confirmed to have a benign lesion (benign group), and 25 patients (58.1%) were confirmed to have malignant lesion (malignant group). Between the two groups, the initial tumor size (p=0.096) and N stage (p=0.749) were similar. Hormone receptor negativity was more prevalent in the malignant group (59.1% vs. 40.9%, p=0.048). The mean lesion size was larger in the malignant group than in the benign group (20.8 mm vs. 14.4 mm, p=0.024). Metastatic lesions had a significantly higher value of maximal standardized uptake (mSUV) than that of benign lesions (6.4 vs. 3.4, p=0.021). CONCLUSION: Hormone receptor status, lesion size, and mSUV on positron emission tomography are helpful in the differentiation of malignant lesions from benign lesions in breast cancer patients who were presented with a new isolated mediastinal LN or small pulmonary nodule during surveillance. PMID- 25038764 TI - Impact of hyperglycemia on survival and infection-related adverse events in patients with metastatic colorectal cancer who were receiving palliative chemotherapy. AB - PURPOSE: Non-metastatic colorectal cancer patients with diabetes have poor overall survival than those without diabetes. However, the effect of hyperglycemia on survival after diagnosis of metastatic colorectal cancer (CRC) has not been assessed. Therefore, we assessed the impact of hyperglycemia on the survival and infection-related adverse events (AEs) in patients with metastatic CRC. MATERIALS AND METHODS: We reviewed the records of 206 patients with newly diagnosed metastatic CRC who were treated with palliative chemotherapy from March 2000 to December 2012 at Chungbuk National University Hospital. The mean glucose level of each patient was calculated using all available glucose results. RESULTS: The mean glucose levels ranged between 76.8 and 303.5 mg/dL, and patients were categorized into quartiles in accordance to their mean glucose level: group 1 (< 106.7 mg/dL), group 2 (106.7-117.2 mg/dL), group 3 (117.3-142.6 mg/dL), and group 4 (> 142.6 mg/dL). The median overall survival for patients in groups 1, 2, 3, and 4 were 22.6, 20.1, 18.9, and 17.9 months, respectively; however, this difference was not statistically significant (p=0.643). Compared with patients in group 1, those in groups 2, 3, and 4 were at a higher risk of infection-related AEs, according to a multivariate analysis (p=0.002). CONCLUSION: Hyperglycemia was not associated with shorter survival; however, it was associated with infection-related AEs in patients with newly diagnosed metastatic CRC receiving palliative chemotherapy. PMID- 25038766 TI - Unusual manifestation of intravascular large B-cell lymphoma: severe hypercalcemia with parathyroid hormone-related protein. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. It usually presents with nonspecific symptoms, such as fever, rather than with overt lymphadenopathy. Reports of hypercalcemia, as the initial presentation of IVLBCL, are limited in the literature, despite it being a well known complication of various solid cancers. We present a 68-year-old male with severe hypercalcemia and increased levels of serum parathyroid hormone-related protein. He was diagnosed with IVLBCL, involving the bone marrow and spleen, and was successfully treated with rituximab-containing chemotherapy. A few previous case reports have shown hypercalcemia in patients with IVLBCL. Much like our case, previous cases with hypercalcemia had advanced diseases, including bone marrow invasion. Although it was an extremely rare manifestation of IVLBCL, we suggest that IVLBCL should be a part of the differential diagnosis in patients with unexplained hypercalcemia. Therefore, an active work-up might be recommended, including positron emission tomography/ computed tomography scan and bone marrow examination, which may be useful for early diagnosis. PMID- 25038765 TI - Interleukin-17 Indirectly Promotes M2 Macrophage Differentiation through Stimulation of COX-2/PGE2 Pathway in the Cancer Cells. AB - PURPOSE: Interleukin-17 (IL-17) is a proinflammatory cytokine that plays important roles in inflammation, autoimmunity, and cancer. The purpose of this study was to determine if IL-17 indirectly regulates macrophage differentiation through up-regulation of cyclooxygenase-2 (COX-2) expression in the cancer cell lines. MATERIALS AND METHODS: Human cervical cancer HeLa, human lung cancer A549, and mouse prostate cancer Myc-CaP/CR cell lines were treated with recombinant IL 17; Western blot analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction analysis were utilized to examine the cellular responses. RESULTS: IL-17 up-regulated expression of COX-2 mRNA and protein in HeLa, A549, and Myc- CaP/CR cell lines. IL-17's effects were mediated through nuclear factor-kappaB and ERK1/2 signaling pathways as the inhibitors of these pathways could inhibit IL-17- induced COX-2 expression. The conditional medium obtained from the cancer cells contained prostaglandin E2, the levels of which were increased by IL-17 treatment. When treated with the conditional medium, particularly with the IL-17-induced conditional medium, mouse RAW264.7 macrophages and human THP-1 monocytes expressed higher levels of IL-10 (a marker of M2 macrophages) than inducible nitric oxide synthase or tumor necrosis factor alpha (markers of M1 macrophages). In contrast, when RAW264.7 and THP-1 cells were treated directly with IL-17, expression of these marker genes was not markedly changed. CONCLUSION: The results of this study suggest that IL-17 indirectly promotes M2 macrophage differentiation through stimulation of the COX 2/PGE2 pathway in the cancer cells, thus IL-17 plays an indirect role in regulating the tumor immune microenvironment. PMID- 25038767 TI - Cyclosporine A as a Primary Treatment for Panniculitis-like T Cell Lymphoma: A Case with a Long-Term Remission. AB - Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a distinctive cutaneous lymphoma characterized by an infiltration of subcutaneous tissue by neoplastic T cells, similar to panniculitis. It is well-established that patients who are diagnosed with SPTL usually respond poorly to chemotherapy, showing fatal outcome. As a first line treatment for SPTL, anthracycline-based chemotherapy was most frequently used. For the treatment of SPTL, the efficacy of cyclosporine A has been recently reported in relapsed SPTL after anthracycline-based chemotherapy. However, it is still not clear whether cyclosporine A can be used as a first-line treatment against SPTL. Here, we report a case of SPTL, which achieved complete remission for nine years after first-line cyclosporine A therapy. This study suggests that cyclosporine A can induce a complete long-term remission as a first-line treatment. PMID- 25038768 TI - Case Report of Pulmonary Sarcoidosis Suspected to be Pulmonary Metastasis in a Patient with Breast Cancer. AB - Standard endocrine therapy and chemotherapy can induce long-term remission in breast cancer patients; however, breast cancer can recur at any site. Pulmonary nodules with lymphadenopathy in advanced cancer patients are likely to be assumed as metastases. A 44-year-old woman with a history of breast cancer was presented to our institution with abnormal findings on 18-fluorodeoxyglucose positron emission tomography imaging, which suggested lung metastasis. She had previously been diagnosed with breast cancer (T1N2M0, Stage IIIa, intraductal carcinoma, triple negative cancer). Histological analysis of the mediastinal lymph node biopsy demonstrated sarcoidosis, showing a chronic, non-caseating, granulomatous inflammation. Our case highlights the need for non-malignant diagnoses in those with prior malignancies, and the need for histological evaluations in the event of first recurrence following potentially curative therapy. PMID- 25038769 TI - Simultaneous analysis of amphetamine-type stimulants in plasma by solid-phase microextraction and gas chromatography-mass spectrometry. AB - Brazil is considered one of the countries with the highest number of amphetamine type stimulant (ATS) users worldwide, mainly diethylpropion (DIE) and fenproporex (FEN). The use of ATS is mostly linked to diverted prescription stimulants and this misuse is widely associated with (ab)use by drivers. A validated method was developed for the simultaneous analysis of amphetamine (AMP), DIE and FEN in plasma samples employing direct immersion-solid-phase microextraction, and gas chromatographic/mass spectrometric analysis. Trichloroacetic acid 10% was used for plasma deproteinization. In situ derivatization with propylchloroformate was employed. The linear range of the method covered from 5.0 to 100 ng/mL. The detection limits were 1.0 (AMP), 1.5 (DIE) and 2.0 ng/mL (FEN). The accuracy assessment of the control samples was within 85.58-108.33% of the target plasma concentrations. Recoveries ranged from 46.35 to 84.46% and precision was <15% of the value of relative standard deviation. This method is appropriate for screening and confirmation in plasma forensic toxicology analyses of these basic drugs. PMID- 25038770 TI - Ultrasound of the male genital tract in relation to male reproductive health. AB - BACKGROUND: Infertility affects ~7% of all men. Despite much progress, mainly in genetics, its etiology remains obscure in ~50% of cases. To fill this gap, imaging of the male genital tract (MGT) has progressively expanded, providing useful information in the assessment of MGT abnormalities. METHODS: A critical, systematic review of the available literature was performed using Medline, with no restrictions regarding date of publication (i.e. from inception date until March 2014), along with analysis of previous reports in color Doppler ultrasound (CDUS) atlas textbooks. Normal anatomy and sonographic characteristics of the MGT have also been summarized. RESULTS: Testicular volume (TV) is tightly associated with both sperm and hormonal parameters. Ultrasound (US) offers a greater accuracy in TV measurement than Prader orchidometer (PO). However US- and PO derived TV are closely related, making PO-derived TV informative enough in the work-up of the infertile man in everyday clinical practice. US-derived TV might play an independent role in specific clinical conditions (i.e. large hydrocele, inguinal testis, enlarged epididymis). Scrotal US may detect signs of testicular dysgenesis, often related to an impaired spermatogenesis and to a higher risk of malignancy, or testicular lesions suggestive of malignancy. A decreased testis vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions (i.e. lymphoma, leukemia). The impact of varicocele detection and surgical correction on sperm parameters/fatherhood is debated. At present, the clinical management of varicocele is mainly based on physical examination. However, CDUS is useful in assessing venous reflux, when palpation is unreliable and/or in detecting recurrence/persistence after surgery. Epididymis head and/or tail dilation is suggestive of MGT obstruction or inflammation and both are related, along with echo-texture abnormalities, to impaired sperm parameters. Scrotal and transrectal US (TRUS) are useful in detecting congenital uni- or bilateral absence of vas deferens (CBAVD), which may be associated with epididymis, seminal vesicles (SV) or kidney abnormalities/agenesis. TRUS plays a key role in assessing obstructive azoospermia and detecting distal CBAVD or anomalies related to ejaculatory ducts obstruction, such as ejaculatory duct abnormalities, prostate median cysts or SV enlargement/emptying impairment. TRUS findings lead to operational decision making, such as testicular sperm extraction in the case of CBAVD, cyst aspiration in the case of a large prostatic median cyst, and surgical treatment if ejaculatory duct abnormalities are observed. TRUS may reveal prostate volume reduction (suggestive of hypogonadism) or enlargement, which can be related to aging or even metabolic abnormalities. Finally, TRUS may reveal prostate and SV echo-texture abnormalities suggestive of inflammation or SV stasis. CONCLUSIONS: MGT-CDUS is a useful tool in detecting abnormalities related to impaired male reproductive health. However, it suffers from a lack of standardization and often produces subjective/vague diagnoses. To fill this gap, the European Academy of Andrology has promoted an ongoing multicenter study aimed at defining the MGT CDUS characteristics of healthy, fertile men. PMID- 25038771 TI - The effect of postretrieval extinction of nicotine pavlovian memories in rats trained to self-administer nicotine. AB - INTRODUCTION: Retrieval (reactivation) of smoking-related memories is a potent trigger of relapse among ex-smokers, and manipulation of smoking-related memories is considered to be a promising target for therapeutic intervention. Recent studies have shown that postreactivation extinction attenuates drug-related memories and relapse to drug-seeking both in rodents and in humans. We investigated the effect of postreactivation extinction in a rat model of relapse to nicotine-seeking. METHODS: Rats were trained to self-administer nicotine in context A (CxA). Pressing the active lever resulted in the nicotine infusion paired with a cue-light (CS). Nicotine-related Pavlovian memories were then reactivated via presentation of 3 non-contingent CS. We then extinguished nicotine-related memories in a distinct context (CxB) followed 24hr later by the assessment of renewal of responding in CxA. RESULTS: Postreactivation extinction, applied 1 but not 6hr after reactivation, induced a significant reduction of the rate of responding on renewal compared to responding during nicotine self administration, whereas no such effect of CS-Extinction was observed in No Reactivation group. However, between-group comparisons of responding during renewal did not show any significant difference. CONCLUSIONS: Current results show that the reactivation of nicotine-related Pavlovian memories may reduce the effect of renewal to exert nicotine-seeking. However, it appears that this effect is small in size and is not significantly different from CS-Extinction alone. PMID- 25038772 TI - Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. AB - This report is the first description of dosing procedures, pharmacokinetics, biochemical action, and general tolerability of the antiaging drug rapamycin in the common marmoset, a small and short-lived monkey. Eudragit-encapsulated rapamycin was given orally to trained marmosets in a short-term (3 weeks) and a long-term (14 months) study. Circulating trough rapamycin levels (mean = 5.2 ng/mL; 1.93-10.73 ng/mL) achieved at roughly 1.0 mg/kg/day was comparable to those reported in studies of rodents and within the therapeutic range for humans. Long-term treated animals (6/8) indicated a reduction in mammalian target of rapamycin complex 1 signaling as noted by a decrease in the phospho rpS6 to total rpS6 ratio after 2 weeks of treatment. All long-term treated subjects had detectable concentrations of rapamycin in liver (4.7-19.9 pg/mg) and adipose tissue (2.2-32.8 pg/mg) with reduced mammalian target of rapamycin signaling in these tissues. There was no evidence of clinical anemia, fibrotic lung changes, or mouth ulcers. The observed death rate in the long-term study was as expected given the animals' ages. The ability to rapidly and reliably dose socially housed marmosets with an oral form of rapamycin that is well tolerated and that demonstrates a suppression of the mammalian target of rapamycin pathway leads us to conclude that this species offers a viable model for rapamycin testing to establish safety and efficacy for long-term antiaging intervention. PMID- 25038773 TI - Simultaneous editing of three homoeoalleles in hexaploid bread wheat confers heritable resistance to powdery mildew. AB - Sequence-specific nucleases have been applied to engineer targeted modifications in polyploid genomes, but simultaneous modification of multiple homoeoalleles has not been reported. Here we use transcription activator-like effector nuclease (TALEN) and clustered, regularly interspaced, short palindromic repeats (CRISPR) Cas9 (refs. 4,5) technologies in hexaploid bread wheat to introduce targeted mutations in the three homoeoalleles that encode MILDEW-RESISTANCE LOCUS (MLO) proteins. Genetic redundancy has prevented evaluation of whether mutation of all three MLO alleles in bread wheat might confer resistance to powdery mildew, a trait not found in natural populations. We show that TALEN-induced mutation of all three TaMLO homoeologs in the same plant confers heritable broad-spectrum resistance to powdery mildew. We further use CRISPR-Cas9 technology to generate transgenic wheat plants that carry mutations in the TaMLO-A1 allele. We also demonstrate the feasibility of engineering targeted DNA insertion in bread wheat through nonhomologous end joining of the double-strand breaks caused by TALENs. Our findings provide a methodological framework to improve polyploid crops. PMID- 25038774 TI - Association between clinical presentations before myocardial infarction and coronary mortality: a prospective population-based study using linked electronic records. AB - BACKGROUND: Ischaemia in different arterial territories before acute myocardial infarction (AMI) may influence post-AMI outcomes. No studies have evaluated prospectively collected information on ischaemia and its effect on short- and long-term coronary mortality. The objective of this study was to compare patients with and without prospectively measured ischaemic presentations before AMI in terms of infarct characteristics and coronary mortality. METHODS AND RESULTS: As part of the CALIBER programme, we linked data from primary care, hospital admissions, the national acute coronary syndrome registry and cause-specific mortality to identify patients with first AMI (n = 16,439). We analysed time from AMI to coronary mortality (n = 5283 deaths) using Cox regression (median 2.6 years follow-up), comparing patients with and without recent ischaemic presentations. Patients with ischaemic presentations in the 90 days before AMI experienced lower coronary mortality in the first 7 days after AMI compared with those with no prior ischaemic presentations, after adjusting for age, sex, smoking, diabetes, blood pressure and cardiovascular medications [HR: 0.64 (95% CI: 0.57-0.73) P < 0.001], but subsequent mortality was higher [HR: 1.42 (1.13 1.77) P = 0.001]. Patients with ischaemic presentations closer in time to AMI had the lowest seven day mortality (P-trend = 0.001). CONCLUSION: In the first large prospective study of ischaemic presentations prior to AMI, we have shown that those occurring closest to AMI are associated with lower short-term coronary mortality following AMI, which could represent a natural ischaemic preconditioning effect, observed in a clinical setting. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier NCT01604486. PMID- 25038775 TI - Hypertrophic cardiomyopathy in the developing world: focus on India. PMID- 25038777 TI - Efficient genome engineering in eukaryotes using Cas9 from Streptococcus thermophilus. AB - The Streptococcus thermophilus CRISPR3-Cas (StCas9) system has been shown to mediate DNA cleavage in its original host and in E. coli as well as in vitro. Here, we have reconstituted the StCas9 system in yeast and conducted a systematic optimization of the sgRNA structure, including the minimal length of tracrRNA, loop structure, Match II region, Bulge motif, the minimal length of guide sequence within the crRNA, tolerance of mismatches and target sequence preference. The optimal sgRNA design for the StCas9 system achieved up to 12 and 40 % targeting efficiencies in yeast and human cells, respectively. This study provides important insight into the sequence and structural requirements necessary to develop a targeted and highly efficient eukaryotic gene editing platform using CRISPR-Cas systems. PMID- 25038779 TI - Optical trapping of individual human immunodeficiency viruses in culture fluid reveals heterogeneity with single-molecule resolution. AB - Optical tweezers use the momentum of photons to trap and manipulate microscopic objects, contact-free, in three dimensions. Although this technique has been widely used in biology and nanotechnology to study molecular motors, biopolymers and nanostructures, its application to study viruses has been very limited, largely due to their small size. Here, using optical tweezers that can simultaneously resolve two-photon fluorescence at the single-molecule level, we show that individual HIV-1 viruses can be optically trapped and manipulated, allowing multi-parameter analysis of single virions in culture fluid under native conditions. We show that individual HIV-1 differs in the numbers of envelope glycoproteins by more than one order of magnitude, which implies substantial heterogeneity of these virions in transmission and infection at the single particle level. Analogous to flow cytometry for cells, this fluid-based technique may allow ultrasensitive detection, multi-parameter analysis and sorting of viruses and other nanoparticles in biological fluid with single-molecule resolution. PMID- 25038778 TI - Synonymous codons, ribosome speed, and eukaryotic gene expression regulation. AB - Quantitative control of gene expression occurs at multiple levels, including the level of translation. Within the overall process of translation, most identified regulatory processes impinge on the initiation phase. However, recent studies have revealed that the elongation phase can also regulate translation if elongation and initiation occur with specific, not mutually compatible rate parameters. Translation elongation then limits the overall amount of protein that can be made from an mRNA. Several recently discovered control mechanisms of biological pathways are based on such elongation control. Here, we review the molecular mechanisms that determine ribosome speed in eukaryotic organisms, and discuss under which conditions ribosome speed can become the controlling parameter of gene expression levels. PMID- 25038776 TI - Mechanisms of endothelial cell migration. AB - Cell migration plays a central role in a variety of physiological and pathological processes during our whole life. Cellular movement is a complex, tightly regulated multistep process. Although the principle mechanisms of migration follow a defined general motility cycle, the cell type and the context of moving influences the detailed mode of migration. Endothelial cells migrate during vasculogenesis and angiogenesis but also in a damaged vessel to restore vessel integrity. Depending on the situation they migrate individually, in chains or sheets and complex signaling, intercellular signals as well as environmental cues modulate the process. Here, the different modes of cell migration, the peculiarities of endothelial cell migration and specific guidance molecules controlling this process will be reviewed. PMID- 25038780 TI - Explosives detection in a lasing plasmon nanocavity. AB - Perhaps the most successful application of plasmonics to date has been in sensing, where the interaction of a nanoscale localized field with analytes leads to high-sensitivity detection in real time and in a label-free fashion. However, all previous designs have been based on passively excited surface plasmons, in which sensitivity is intrinsically limited by the low quality factors induced by metal losses. It has recently been proposed theoretically that surface plasmon sensors with active excitation (gain-enhanced) can achieve much higher sensitivities due to the amplification of the surface plasmons. Here, we experimentally demonstrate an active plasmon sensor that is free of metal losses and operating deep below the diffraction limit for visible light. Loss compensation leads to an intense and sharp lasing emission that is ultrasensitive to adsorbed molecules. We validated the efficacy of our sensor to detect explosives in air under normal conditions and have achieved a sub-part-per billion detection limit, the lowest reported to date for plasmonic sensors with 2,4-dinitrotoluene and ammonium nitrate. The selectivity between 2,4 dinitrotoluene, ammonium nitrate and nitrobenzene is on a par with other state-of the-art explosives detectors. Our results show that monitoring the change of the lasing intensity is a superior method than monitoring the wavelength shift, as is widely used in passive surface plasmon sensors. We therefore envisage that nanoscopic sensors that make use of plasmonic lasing could become an important tool in security screening and biomolecular diagnostics. PMID- 25038781 TI - Target metabolite and gene transcription profiling during the development of superficial scald in apple (Malus x domestica Borkh). AB - BACKGROUND: Fruit quality features resulting from ripening processes need to be preserved throughout storage for economical reasons. However, during this period several physiological disorders can occur, of which superficial scald is one of the most important, due to the development of large brown areas on the fruit skin surface. RESULTS: This study examined the variation in polyphenolic content with the progress of superficial scald in apple, also with respect to 1-MCP, an ethylene competitor interacting with the hormone receptors and known to interfere with this etiology. The change in the accumulation of these metabolites was further correlated with the gene set involved in this pathway, together with two specific VOCs (Volatile Organic Compounds), alpha-farnesene and its oxidative form, 6-methyl-5-hepten-2-one. Metabolite profiling and qRT-PCR assay showed these volatiles are more heavily involved in the signalling system, while the browning coloration would seem to be due more to a specific accumulation of chlorogenic acid (as a consequence of the activation of MdPAL and MdC3H), and its further oxidation carried out by a polyphenol oxidase gene (MdPPO). In this physiological scenario, new evidence regarding the involvement of an anti apoptotic regulatory mechanism for the compartmentation of this phenomenon in the skin alone was also hypothesized, as suggested by the expression profile of the MdDAD1, MdDND1 and MdLSD1 genes. CONCLUSIONS: The results presented in this work represent a step forward in understanding the physiological mechanisms of superficial scald in apple, shedding light on the regulation of the specific physiological cascade. PMID- 25038782 TI - Rapid screening for phenotype-genotype associations by linear transformations of genomic evaluations. AB - BACKGROUND: Currently, association studies are analysed using statistical mixed models, with marker effects estimated by a linear transformation of genomic breeding values. The variances of marker effects are needed when performing the tests of association. However, approaches used to estimate the parameters rely on a prior variance or on a constant estimate of the additive variance. Alternatively, we propose a standardized test of association using the variance of each marker effect, which generally differ among each other. Random breeding values from a mixed model including fixed effects and a genomic covariance matrix are linearly transformed to estimate the marker effects. RESULTS: The standardized test was neither conservative nor liberal with respect to type I error rate (false-positives), compared to a similar test using Predictor Error Variance, a method that was too conservative. Furthermore, genomic predictions are solved efficiently by the procedure, and the p-values are virtually identical to those calculated from tests for one marker effect at a time. Moreover, the standardized test reduces computing time and memory requirements.The following steps are used to locate genome segments displaying strong association. The marker with the highest - log(p-value) in each chromosome is selected, and the segment is expanded one Mb upstream and one Mb downstream of the marker. A genomic matrix is calculated using the information from those markers only, which is used as the variance-covariance of the segment effects in a model that also includes fixed effects and random genomic breeding values. The likelihood ratio is then calculated to test for the effect in every chromosome against a reduced model with fixed effects and genomic breeding values. In a case study with pigs, a significant segment from chromosome 6 explained 11% of total genetic variance. CONCLUSIONS: The standardized test of marker effects using their own variance helps in detecting specific genomic regions involved in the additive variance, and in reducing false positives. Moreover, genome scanning of candidate segments can be used in meta-analyses of genome-wide association studies, as it enables the detection of specific genome regions that affect an economically relevant trait when using multiple populations. PMID- 25038783 TI - A decision exercise to engage cancer patients and families in deliberation about Medicare coverage for advanced cancer care. AB - BACKGROUND: Concerns about unsustainable costs in the US Medicare program loom as the number of retirees increase and experiences serious and costly illnesses like cancer. Engagement of stakeholders, particularly cancer patients and their families, in prioritizing insured services offers a valuable strategy for informing Medicare coverage policy. We designed and evaluated a decision exercise that allowed cancer patients and family members to choose Medicare benefits for advanced cancer patients. METHODS: The decision tool, Choosing Health plans All Together (CHAT) was modified to select services for advanced cancer patients. Patients with a cancer history (N = 246) and their family members (N = 194) from North Carolina participated in 70 CHAT sessions. Variables including participants' socio-demographic characteristics, health status, assessments of the exercise and results of group benefit selections were collected. Routine descriptive statistics summarized participant characteristics and Fisher's exact test compared group differences. Qualitative analysis of group discussions were used to ascertain reasons for or against selecting benefits. RESULTS: Patients and family members (N = 440) participated in 70 CHAT exercises. Many groups opted for such services as palliative care, nursing facilities, and services not currently covered by the Medicare program. In choosing among four levels of cancer treatment coverage, no groups chose basic coverage, 27 groups (39%) selected intermediate coverage, 39 groups (56%) selected high coverage, and 4 groups (6%) chose the most comprehensive cancer coverage. Reasons for or against benefit selection included fairness, necessity, need for prioritizing, personal experience, attention to family needs, holistic health outlook, preference for comfort, freedom of choice, and beliefs about the proper role of government. Participants found the exercise very easy (59%) or fairly easy (39%) to understand and very informative (66%) or fairly informative (31%). The majority agreed that the CHAT exercise led to fair decisions about priorities for coverage by which they could abide. CONCLUSIONS: It is possible to involve cancer patients and families in explicit discussions of their priorities for affordable advanced cancer care through the use of decision tools designed for this purpose. A key question is whether such a conversation is possible on a broader, national level. PMID- 25038784 TI - The effect of parametric stimulus size variation on individual face discrimination indexed by fast periodic visual stimulation. AB - BACKGROUND: The human brain is frequently exposed to individual faces across a wide range of different apparent sizes, often seen simultaneously (e.g., when facing a crowd). Here we used a sensitive and objective fast periodic visual stimulation approach while recording scalp electroencephalogram (EEG) to test the effect of size variation on neural responses reflecting individual face discrimination. METHODS: EEG was recorded in ten observers presented with the same face identity at a fixed rate (5.88 Hz, frequency F) and different oddball face identities appearing every five faces (F/5, i.e., 1.18 Hz). Stimulus size was either constant (6.5 * 4 degrees of visual angle) or changed randomly at each stimulation cycle, by 2:1 ratio increasing values from 10% to 80% size variation in four conditions. Absolute stimulus size remained constant across conditions. RESULTS: The base rate 5.88 Hz EEG response increased with image size variation, particularly over the right occipito-temporal cortex. In contrast, size variation decreased the oddball response marking individual face discrimination over the right occipito-temporal cortex. At constant stimulus size, the F/5 change of identity generated an early (about 100 ms) oddball response reflecting individual face discrimination based on image-based cues. This early component disappeared with a relatively small size variation (i.e., 20%), leaving a robust high-level index of individual face discrimination. CONCLUSIONS: Stimulus size variation is an important manipulation to isolate the contribution of high-level visual processes to individual face discrimination. Nevertheless, even for relatively small stimuli, high-level individual face discrimination processes in the right occipito-temporal cortex remain sensitive to stimulus size variation. PMID- 25038785 TI - Evolutionary relationship of two ancient protein superfolds. AB - Proteins are the molecular machines of the cell that fold into specific three dimensional structures to fulfill their functions. To improve our understanding of how the structure and function of proteins arises, it is crucial to understand how evolution has generated the structural diversity we observe today. Classically, proteins that adopt different folds are considered to be nonhomologous. However, using state-of-the-art tools for homology detection, we found evidence of homology between proteins of two ancient and highly populated protein folds, the (betaalpha)8-barrel and the flavodoxin-like fold. We detected a family of sequences that show intermediate features between both folds and determined what is to our knowledge the first representative crystal structure of one of its members, giving new insights into the evolutionary link of two of the earliest folds. Our findings contribute to an emergent vision where protein superfolds share common ancestry and encourage further approaches to complete the mapping of structure space onto sequence space. PMID- 25038786 TI - Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis. AB - Proteases are ubiquitous in nature, whereas naturally occurring peptide ligases, enzymes catalyzing the reverse reactions of proteases, are rare occurrences. Here we describe the discovery of butelase 1, to our knowledge the first asparagine/aspartate (Asx) peptide ligase to be reported. This highly efficient enzyme was isolated from Clitoria ternatea, a cyclic peptide-producing medicinal plant. Butelase 1 shares 71% sequence identity and the same catalytic triad with legumain proteases but does not hydrolyze the protease substrate of legumain. Instead, butelase 1 cyclizes various peptides of plant and animal origin with yields greater than 95%. With Kcat values of up to 17 s(-1) and catalytic efficiencies as high as 542,000 M(-1) s(-1), butelase 1 is the fastest peptide ligase known. Notably, butelase 1 also displays broad specificity for the N terminal amino acids of the peptide substrate, thus providing a new tool for C terminus-specific intermolecular peptide ligations. PMID- 25038787 TI - A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. AB - Kinases are principal components of signal transduction pathways and the focus of intense basic and drug discovery research. Irreversible inhibitors that covalently modify non-catalytic cysteines in kinase active sites have emerged as valuable probes and approved drugs. Many protein classes, however, have functional cysteines, and therefore understanding the proteome-wide selectivity of covalent kinase inhibitors is imperative. Here, we accomplish this objective using activity-based protein profiling coupled with quantitative MS to globally map the targets, both specific and nonspecific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent nonkinase proteins that, notably, have conserved active site cysteines. We define windows of selectivity for covalent kinase inhibitors and show that, when these windows are exceeded, rampant proteome-wide reactivity and kinase target-independent cell death conjointly occur. Our findings, taken together, provide an experimental road map to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors. PMID- 25038788 TI - Crystal structure and mechanistic investigation of the twister ribozyme. AB - We present a crystal structure at 2.3-A resolution of the recently described nucleolytic ribozyme twister. The RNA adopts a previously uncharacterized compact fold based on a double-pseudoknot structure, with the active site at its center. Eight highly conserved nucleobases stabilize the core of the ribozyme through the formation of one Watson-Crick and three noncanonical base pairs, and the highly conserved adenine 3' of the scissile phosphate is bound in the major groove of an adjacent pseudoknot. A strongly conserved guanine nucleobase directs its Watson Crick edge toward the scissile phosphate in the crystal structure, and mechanistic evidence supports a role for this guanine as either a general base or acid in a concerted, general acid-base-catalyzed cleavage reaction. PMID- 25038789 TI - Drug discovery: tools and rules for macrocycles. PMID- 25038790 TI - How proteins bind macrocycles. AB - The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules. PMID- 25038791 TI - Comprehensive analysis of loops at protein-protein interfaces for macrocycle design. AB - Inhibiting protein-protein interactions (PPIs) with synthetic molecules remains a frontier of chemical biology. Many PPIs have been successfully targeted by mimicking alpha-helices at interfaces, but most PPIs are mediated by nonhelical, nonstrand peptide loops. We sought to comprehensively identify and analyze these loop-mediated PPIs by writing and implementing LoopFinder, a customizable program that can identify loop-mediated PPIs within all of the protein-protein complexes in the Protein Data Bank. Comprehensive analysis of the entire set of 25,005 interface loops revealed common structural motifs and unique features that distinguish loop-mediated PPIs from other PPIs. 'Hot loops', named in analogy to protein hot spots, were identified as loops with favorable properties for mimicry using synthetic molecules. The hot loops and their binding partners represent new and promising PPIs for the development of macrocycle and constrained peptide inhibitors. PMID- 25038792 TI - IMP3 as a cytoplasmic biomarker for early serous tubal carcinogenesis. AB - BACKGROUND: Serous tubal intraepithelial carcinoma (STIC) and the p53 signature in tubal mucosa have been supported to be precursor lesions in high-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum. It remains critical to find biomarkers for precursor lesions in order to detect HGSCs efficiently. IMP3 is an oncoprotein that has been explored in human malignancies. No studies have specifically addressed the expression of IMP3 in precursor or early lesions of HGSC. The main purposes of this study are to evaluate if IMP3 plays any role in the process of pelvic serous carcinogenesis by examining its expression in HGSC precursor lesions, to examine the relationship between IMP3 and p53 in those precursor lesions, and to check if IMP3 can be used as a biomarker for early diagnosis. METHODS: Immunohistochemistry for IMP3 and p53 was performed and evaluated in 48 HGSCs with STIC, 62 HGSCs without STIC, and 60 benign cases as negative controls. Sections of fallopian tubes with or without STIC , as well as cancers within the ovaries, were studied. IMP3 signature was defined as strong IMP3 cytoplasmic staining in 10 or more consecutive benign looking tubal epithelial cells. The relationship between IMP3 and p53 overexpression was examined. RESULTS: In the 48 HGSC patients with STIC, IMP3 was positive in 46% of STIC lesions and had a similar positive rate in the invasive components of HGSC. IMP3 was also expressed in normal appearing tubal epithelia (IMP3 signature) in 15 (31%) of 48 HGSC cases with STIC and 10 (16%) of 62 cases without STIC. In contrast, no single IMP3 signature was found in the benign control group. Concordant expression of IMP3 and p53 signatures in the STIC group was found in up to one-third of the cases. There were also five (10%) STIC cases with positive IMP3 and negative p53. CONCLUSIONS: We conclude that IMP3 may be involved in the process and progression of pelvic HGSC and may serve as a complimentary biomarker in diagnosing STIC. PMID- 25038793 TI - Experimental study of PLLA/INH slow release implant fabricated by three dimensional printing technique and drug release characteristics in vitro. AB - BACKGROUND: Local slow release implant provided long term and stable drug release in the lesion. The objective of this study was to fabricate biodegradable slow release INH/PLLA tablet via 3 dimensional printing technique (3DP) and to compare the drug release characteristics of three different structured tablets in vitro. METHODS: Three different drug delivery systems (columnar-shaped tablet (CST), doughnut-shaped tablet (DST) and multilayer doughnut-shaped tablet (MDST)) were manufactured by the three dimensional printing machine and isoniazid was loaded into the implant. Dynamic soaking method was used to study the drug release characteristics of the three implants. MTT cytotoxicity test and direct contact test were utilized to study the biocompatibility of the implant. The microstructures of the implants' surfaces were observed with electron microscope. RESULTS: The PLLA powder in the tablet could be excellently combined through 3DP without disintegration. Electron microscope observations showed that INH distributed evenly on the surface of the tablet in a "nest-shaped" way, while the surface of the barrier layer in the multilayer doughnut shaped tablet was compact and did not contain INH. The concentration of INH in all of the three tablets were still higher than the effective bacteriostasis concentration (Isoniazid: 0.025 ~ 0.05 MUg/ml) after 30 day's release in vitro. All of the tablets showed initial burst release of the INH in the early period. Drug concentration of MDST became stable and had little fluctuation starting from the 6th day of the release. Drug concentration of DST and CST decreased gradually and the rate of decrease in concentration was faster in DST than CST. MTT cytotoxicity test and direct contact test indicated that the INH-PLLA tablet had low cytotoxicity and favorable biocompatibility. CONCLUSIONS: Three dimensional printing technique was a reliable technique to fabricate complicated implants. Drug release pattern in MDST was the most stable among the three implants. It was an ideal drug delivery system for the antibiotics. Biocompatibility tests demonstrated that the INH-PLLA implant did not have cytotoxicity. The multilayer donut-shaped tablet provided a new constant slow release method after an initial burst for the topical application of the antibiotic. PMID- 25038794 TI - Chronic bacterial prostatitis: efficacy of short-lasting antibiotic therapy with prulifloxacin (Unidrox(r)) in association with saw palmetto extract, lactobacillus sporogens and arbutin (Lactorepens(r)). AB - BACKGROUND: Bacterial prostatitis (BP) is a common condition accounting responsible for about 5-10% of all prostatitis cases; chronic bacterial prostatitis (CBP) classified as type II, are less common but is a condition that significantly hampers the quality of life, (QoL) because not only is it a physical condition but also a psychological distress. Commonly patients are treated with antibiotics alone, and in particular fluoroquinolones are suggested by the European Urology guidelines. This approach, although recommended, may not be enough. Thus, a multimodal approach to the prolonged antibiotic therapy may be helpful. METHODS: 210 patients affected by chronic bacterial prostatitis were enrolled in the study. All patients were positive to Meares-Stamey test and symptoms duration was > 3 months. The purpose of the study was to evaluate the efficacy of a long lasting therapy with a fluoroquinolone in association with a nutraceutical supplement (prulifloxacin 600 mg for 21 days and an association of Serenoa repens 320 mg, Lactobacillus Sporogens 200 mg, Arbutin 100 mg for 30 days). Patients were randomized in two groups (A and B) receiving respectively antibiotic alone and an association of antibiotic plus supplement. RESULTS: Biological recurrence at 2 months in Group A was observed in 21 patients (27.6%) and in Group B in 6 patients (7.8%). Uropathogens found at the first follow-up were for the majority Gram - (E. coli and Enterobacter spp.). A statistically significant difference was found at the time of the follow-up between Group A and B in the NIH-CPSI questionnaire score, symptoms evidence and serum PSA. CONCLUSIONS: Broad band, short-lasting antibiotic therapy in association with a nutritional supplement (serenoa repens, lactobacillus sporogens and arbutin) show better control and recurrence rate on patients affected by chronic bacterial prostatitits in comparison with antibiotic treatment alone. TRIAL REGISTRATION: NCT02130713. Date of trial Registration: 30/04/2014. PMID- 25038795 TI - No effect of ablation of surfactant protein-D on acute cerebral infarction in mice. AB - BACKGROUND: Crosstalk between the immune system in the brain and the periphery may contribute to the long-term outcome both in experimental and clinical stroke. Although, the immune defense collectin surfactant protein-D (SP-D) is best known for its role in pulmonary innate immunity, SP-D is also known to be involved in extrapulmonary modulation of inflammation in mice. We investigated whether SP-D affected cerebral ischemic infarction and ischemia-induced inflammatory responses in mice. METHODS: The effect of SP-D was studied by comparing the size of ischemic infarction and the inflammatory and astroglial responses in SP-D knock out (KO) and wild type (WT) mice subjected to permanent middle cerebral artery occlusion. SP-D mRNA production was assessed in isolated cerebral arteries and in the whole brain by PCR, and SP-D protein in normal appearing and ischemic human brain by immunohistochemistry. Changes in plasma SP-D and TNF were assessed by ELISA and proximity ligation assay, respectively. RESULTS: Infarct volumetric analysis showed that ablation of SP-D had no effect on ischemic infarction one and five days after induction of ischemia. Further, ablation of SP-D had no effect on the ischemia-induced increase in TNF mRNA production one day after induction of ischemia; however the TNF response to the ischemic insult was affected at five days. SP-D mRNA was not detected in parenchymal brain cells in either naive mice or in mice subjected to focal cerebral ischemia. However, SP-D mRNA was detected in middle cerebral artery cells in WT mice and SP-D protein in vascular cells both in normal appearing and ischemic human brain tissue. Measurements of the levels of SP-D and TNF in plasma in mice suggested that levels were unaffected by the ischemic insult. Microglial-leukocyte and astroglial responses were comparable in SP-D KO and WT mice. CONCLUSIONS: SP-D synthesis in middle cerebral artery cells is consistent with SP-D conceivably leaking into the infarcted area and affecting local cytokine production. However, there was no SP-D synthesis in parenchymal brain cells and ablation of SP-D had no effect on ischemic cerebral infarction. PMID- 25038796 TI - Different dynamics of genome content shuffling among host-specificity groups of the symbiotic actinobacterium Frankia. AB - BACKGROUND: Frankia is a genus of soil actinobacteria forming nitrogen-fixing root-nodule symbiotic relationships with non-leguminous woody plant species, collectively called actinorhizals, from eight dicotyledonous families. Frankia strains are classified into four host-specificity groups (HSGs), each of which exhibits a distinct host range. Genome sizes of representative strains of Alnus, Casuarina, and Elaeagnus HSGs are highly diverged and are positively correlated with the size of their host ranges. RESULTS: The content and size of 12 Frankia genomes were investigated by in silico comparative genome hybridization and pulsed-field gel electrophoresis, respectively. Data were collected from four query strains of each HSG and compared with those of reference strains possessing completely sequenced genomes. The degree of difference in genome content between query and reference strains varied depending on HSG. Elaeagnus query strains were missing the greatest number (22-32%) of genes compared with the corresponding reference genome; Casuarina query strains lacked the fewest (0-4%), with Alnus query strains intermediate (14-18%). In spite of the remarkable gene loss, genome sizes of Alnus and Elaeagnus query strains were larger than would be expected based on total length of the absent genes. In contrast, Casuarina query strains had smaller genomes than expected. CONCLUSIONS: The positive correlation between genome size and host range held true across all investigated strains, supporting the hypothesis that size and genome content differences are responsible for observed diversity in host plants and host plant biogeography among Frankia strains. In addition, our results suggest that different dynamics of shuffling of genome content have contributed to these symbiotic and biogeographic adaptations. Elaeagnus strains, and to a lesser extent Alnus strains, have gained and lost many genes to adapt to a wide range of environments and host plants. Conversely, rather than acquiring new genes, Casuarina strains have discarded genes to reduce genome size, suggesting an evolutionary orientation towards existence as specialist symbionts. PMID- 25038797 TI - Differential expression of ANXA1 in benign human gastrointestinal tissues and cancers. AB - BACKGROUND: Annexin-1 contributes to the pathological consequence and sequelae of most serious human diseases including cardiovascular disease and cancer. Although diverse roles in carcinogenesis have been postulated, its role in human gastrointestinal cancers still remains controversial. METHODS: The mRNA and protein expression profiles of ANXA1 were studied in human esophageal, gastric, pancreatic, colorectal, liver, and bile duct cancers using Real-Time PCR, western blotting, and immunohistochemistry. Gain/loss-of-function by pcDNA3.1-ANXA1 and ANXA1-shRNA was performed in gastric cancer cells. RESULTS: ANXA1 was widely expressed in adult gastrointestinal tissue. All methods showed that ANXA1 was down-regulated in esophageal, gastric, and bile duct cancers, but up-regulated in pancreatic cancer. Forced ANXA1 expression in gastric cancer cells leads to cell growth inhibition and concomitantly modulates COX-2 expression. We confirm loss of ANXA1 and overexpression of COX-2 in clinical gastric cancer, suggesting that the anti-proliferative function of ANXA1 against COX-2 production might be lost. CONCLUSIONS: ANXA1 expression is "tumor-specific" and might play a multifaceted role in cancer development and progression. ANXA1 was widely expressed in normal gastrointestinal epithelium, suggesting its role in the maintenance of cellular boundaries. Furthermore, ANXA1 regulates GC cell viability via the COX-2 pathway. PMID- 25038798 TI - Parallel universes of Black Six biology. AB - Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as "Black Six", stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign "essential" and "redundant" qualifiers to numerous genes, thus creating an internally consistent "parallel universe" of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of "strain-unawareness" will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of "parallel universes" should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor's strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified. REVIEWERS: This article was reviewed by Dr. Neil Smalheiser and Dr. Miguel Andrade-Navarro. PMID- 25038799 TI - Burden of herpes zoster in the UK: findings from the zoster quality of life (ZQOL) study. AB - BACKGROUND: Herpes zoster (HZ) is a painful condition that can have a substantial negative impact on patients' lives. However, UK-specific data on the debilitating impact of HZ, in terms of patients' experience of pain and impairments in Health Related Quality of Life (HRQoL) are limited. The Zoster Quality of Life (ZQOL) study, a large-scale UK cross-sectional study, was conducted to quantify the burden of HZ in UK patients. METHODS: A total of 229 HZ patients aged 50 years or over were recruited from primary and secondary/tertiary care centres throughout the UK. Patients completed a battery of validated questionnaires, including the Zoster Brief Pain Inventory (ZBPI), the Medical Outcomes Study Short-Form 36 (SF 36) and the EuroQol-5 Dimensions (EQ-5D) on initial presentation to the doctor and again 7-14 days later. At follow-up patients also completed the Treatment Satisfaction with Medication (TSQM) questionnaire. Where available, mean questionnaire scores in the HZ population were compared to scores for age-matched norms to investigate the burden associated with HZ. RESULTS: Pain was prominent among patients, with 57.9% at the initial study visit reporting pain in the preceding 24 hours at levels typically considered to have a significant impact on HRQoL (i.e. ZBPI worst pain >= 5). This was reflected in SF-36 and EQ-5D scores that were significantly lower for patients when compared to age-matched norms (p < 0.05) - except for the SF-36 domain of physical functioning. HRQoL was inversely associated with levels of reported pain, with those patients in the greatest amount of pain reporting the greatest HRQoL impact. However, there was no association between pain severity and participant age. The majority of patients (69.4%) received antivirals within 72 hours of rash appearing and 69.9% of patients were also taking analgesics for the management of HZ pain. TSQM scores indicated that patients were least satisfied with the effectiveness of their prescribed treatment. CONCLUSIONS: The acute presentation of HZ is a painful experience that can have a significant impact on the physical and mental wellbeing of sufferers. Findings highlight significant unmet need among patients, particularly in terms of the effectiveness of therapies for the management of HZ. PMID- 25038800 TI - Anti-lipoapoptotic effect of Artemisia capillaris extract on free fatty acids induced HepG2 cells. AB - BACKGROUND: Artemisia capillaris (AC) has been recognized as one of the promising candidates for hepatoprotective, hypoglycemic, hypolipidemic, antiobesitic and anti-inflammatory therapeutic effectiveness. This study evaluated the inherent mechanism and anti-apoptotic activity of 30% ethanol extract of AC (AC extract) 100 MUg/ml on free fatty acids (FFAs)-induced HepG2 cellular steatosis and lipoapoptosis. METHODS: Hepatic steatosis was induced by culturing HepG2 cells with a FFAs mixture (oleic and palmitic acid at the proportion of 2:1) for 24 h, thus ultimately giving rise to lipoapoptosis. Cell viability and lipid accumulation were detected by MTT assay and Oil Red O staining method respectively and Caspase-3, -9, Bax, Bcl-2, p-JNK and PUMA were measured for lipoapoptosis after 24 hours. RESULTS: AC extract significantly improved the FFAs induced steatosis without cytotoxicity and Caspase-3, -9, Bax and Bcl-2 were modulated profitably to HepG2 cells after AC treatment. In addition, AC extract inhibited the activation of c-Jun NH2 terminal kinase (JNK) and PUMA, which mechanism is related to non-alcoholic steatohepatitis (NASH). CONCLUSIONS: Combined together, AC extract exerted an obvious hypolipidemic and anti-apoptotic effect, indicating that AC extract might have potential therapeutic herb against NASH. PMID- 25038801 TI - Enhancement of catecholamine release from PC12 cells by the traditional Japanese medicine, rikkunshito. AB - BACKGROUND: Rikkunshito is a traditional Japanese herbal medicine that is used to treat appetite loss associated with cancer and other disorders. The formulation contains various constituents that influence cell signaling, and rikkunshito may accordingly affect human homeostasis through multiple regulatory pathways, including those governed by the endocrine system. We investigated the actions of rikkunshito on catecholamine release from PC12 cells, an adrenal chromaffin cell line. METHODS: The actions of rikkunshito on PC12 cells were evaluated by measuring intracellular cAMP levels, tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP) mRNA expression levels, and catecholamine levels in the culture medium. The transcriptional activation of VIP gene by rikkunshito was assessed by using a VIP promoter-driven reporter gene assay. RESULTS: Rikkunshito dose-dependently enhanced forskolin-induced elevations in cAMP in PC12 cells, and also increased the gene expression of TH and VIP. The transcriptional activation of VIP gene by rikkunshito was confirmed. Norepinephrine and dopamine secretion into the culture medium of PC12 cells were also dose-dependently augmented by rikkunshito and/or forskolin, but experiments with a protein kinase C (PKC) activator and a phosphodiesterase inhibitor revealed that the effects of rikkunshito were not simply due to the modulation of PKC or phosphodiesterase activity. CONCLUSIONS: These findings suggest that rikkunshito enhances the release of catecholamines by a novel mechanism involving cAMP. PMID- 25038802 TI - Identification of genes in toxicity pathways of trinucleotide-repeat RNA in C. elegans. AB - Myotonic dystrophy disorders are caused by expanded CUG repeats in noncoding regions. Here we used Caenorhabditis elegans expressing CUG repeats to identify genes that modulate the toxicity of such repeats. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and that modulate formation of nuclear foci by CUG-repeat RNA. These genes regulate CUG repeat-induced toxicity through distinct mechanisms including RNA export and clearance, thus suggesting that CUG-repeat toxicity is mediated by multiple pathways. A subset of the genes are also involved in other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway has a conserved role in regulating CUG-repeat-RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3'-untranslated-region GC-nucleotide content. Our studies suggest a broader surveillance role for NMD in which variations in this pathway influence multiple degenerative diseases. PMID- 25038803 TI - Allosteric enhancement of MAP kinase p38alpha's activity and substrate selectivity by docking interactions. AB - Mitogen-activated protein kinases (MAPKs) are essential to intracellular signal transduction. MAPKs anchor their pathway-specific substrates through so-called 'docking interactions' at locations distal from the active site. Docking interactions ensure efficient substrate recognition, but their contribution to the kinase reaction itself remains unclear. Herein, we use solution NMR to analyze the interaction between dually phosphorylated, active human p38alpha and the C-terminal fragments of its substrate MK2. p38alpha phosphorylation and ATP loading collaboratively induce the active conformation; subsequently, p38alpha accommodates MK2 phosphoacceptor residues in its active site. The docking interaction enhances binding of ATP and the phosphoacceptor to p38alpha, accelerating the phosphotransfer reaction. Thus, the docking interaction enhances p38alpha's enzymatic activity toward pathway-specific substrates allosterically as well as by the anchor effect. These findings clarify how MAPK cascades are organized in cells, even under ATP-depleted conditions often associated with environmental stress. PMID- 25038804 TI - Principles and clinical application of ultrasound elastography for diffuse liver disease. AB - Accurate assessment of the degree of liver fibrosis is important for estimating prognosis and deciding on an appropriate course of treatment for cases of chronic liver disease (CLD) with various etiologies. Because of the inherent limitations of liver biopsy, there is a great need for non-invasive and reliable tests that accurately estimate the degree of liver fibrosis. Ultrasound (US) elastography is considered a non-invasive, convenient, and precise technique to grade the degree of liver fibrosis by measuring liver stiffness. There are several commercial types of US elastography currently in use, namely, transient elastography, acoustic radiation force impulse imaging, supersonic shear-wave imaging, and real time tissue elastography. Although the low reproducibility of measurements derived from operator-dependent performance remains a significant limitation of US elastography, this technique is nevertheless useful for diagnosing hepatic fibrosis in patients with CLD. Likewise, US elastography may also be used as a convenient surveillance method that can be performed by physicians at the patients' bedside to enable the estimation of the prognosis of patients with fatal complications related to CLD in a non-invasive manner. PMID- 25038805 TI - Contrast-enhanced endoscopic ultrasonography: advance and current status. AB - Endoscopic ultrasonography (EUS) technology has undergone a great deal of progress along with the color and power Doppler imaging, three-dimensional imaging, electronic scanning, tissue harmonic imaging, and elastography, and one of the most important developments is the ability to acquire contrast-enhanced images. The blood flow in small vessels and the parenchymal microvasculature of the target lesion can be observed non-invasively by contrast-enhanced EUS (CE EUS). Through a hemodynamic analysis, CE-EUS permits the diagnosis of various gastrointestinal diseases and differential diagnoses between benign and malignant tumors. Recently, mechanical innovations and the development of contrast agents have increased the use of CE-EUS in the diagnostic field, as well as for the assessment of the efficacy of therapeutic agents. The advances in and the current status of CE-EUS are discussed in this review. PMID- 25038806 TI - Positive predictive value of additional synchronous breast lesions in whole breast ultrasonography at the diagnosis of breast cancer: clinical and imaging factors. AB - PURPOSE: To evaluate the positive predictive value (PPV) of bilateral whole breast ultrasonography (BWBU) for detection of synchronous breast lesions on initial diagnosis of breast cancer and evaluate factors affecting the PPV of BWBU according to varying clinicoimaging factors. METHODS: A total of 75 patients who had synchronous lesions with pathologic confirmation at the initial diagnosis of breast cancer during January 2007 and December 2007 were included. The clinical factors of the patients were evaluated. One observer retrospectively reviewed the imaging studies of the index breast cancer lesion and the synchronous lesion. The PPV for additional biopsy was calculated for BWBU and various clinical and imaging factors affecting the PPV for BWBU were evaluated. RESULTS: The overall PPV for additional biopsy was 25.7% (18 of 70). The PPV for synchronous lesions detected both on mammography and BWBU, and detected only on BWBU, was 76.9% (10 of 13) and 14.3% (7 of 49), respectively. There was no clinical factor affecting the PPV for BWBU. Among the imaging factors, ipsilateral location of the synchronous lesion to the index lesion (P=0.06) showed a marginal statistically significant correlation with malignancy in the synchronous breast lesion. A mass with calcification on mammography presentation (P<0.01), presence of calcification among the ultrasonography findings (P<0.01), and high Breast Imaging Reporting and Data System final assessment (P<0.01) were imaging factors that were associated with malignancy in the additional synchronous lesion. CONCLUSION: BWBU can detect additional synchronous malignancy at the diagnosis of breast cancer with a relatively high PPV, especially when mammography findings are correlated with ultrasonographic findings. PMID- 25038807 TI - Ultrasonographic diagnosis of ovary-containing hernias of the canal of Nuck. AB - PURPOSE: The purpose of this study is to describe the ultrasonographic findings of ovary-containing hernias of the canal of Nuck. METHODS: This was a retrospective analysis of 22 hernia cases of the canal of Nuck. The following gray scale and color Doppler ultrasonographic features were analyzed: the site and the size of the hernia, the texture of the hernia contents, and the presence or absence of blood flow in the hernia contents. RESULTS: All of the patients had swelling of the right inguinal region (n=10), left inguinal region (n=8), or both (n=2). On ultrasonography, the hernias appeared as either solid masses (n=17) or solid masses containing cysts (n=5). The mean anteroposterior diameter of the hernia sac of the canal of Nuck was 9.1 mm (range, 5 to 18 mm). The mean anteroposterior diameters of the hernia sac were 11.6 mm (range, 7.6 to 18 mm) for hernias containing an ovary, and 8.3 mm (range, 5 to 13 mm) for hernias containing omental fat. During surgery, among the 17 cases with solid-appearing hernia contents on ultrasonography, omental fat was identified in the hernia sac in four cases, but no structure was identified in 13 cases. All five cases that appeared as solid masses containing cysts on ultrasonography contained ovary tissue in the hernia sac. Among the four cases of ovary-containing hernias, color Doppler ultrasonography identified blood flow within the ovary in three cases, but no flow signal was seen in one case of incarcerated hernia. CONCLUSION: Ultrasonography may be helpful for the diagnosis of ovary-containing hernias of the canal of Nuck by detecting solid masses containing small cysts. PMID- 25038808 TI - Transperineal ultrasonography for evaluation of the perianal fistula and abscess in pediatric Crohn disease: preliminary study. AB - PURPOSE: To assess the feasibility and effectiveness of transperineal ultrasonography (TPUS) for the evaluation of perianal Crohn disease (PCD) in pediatric patients. METHODS: Between September 2010 and August 2013, 64 TPUS examinations were performed in 43 patients (34 males and 9 females; mean age+/ standard deviation, 13.3+/-2.4 years; age range, 6 to 17 years) to evaluate PCD. The pain severity, location, and activity of perianal fistula, the presence of an abscess, and anal canal hyperemia were retrospectively evaluated. Spearman rank correlation analysis was performed to assess the relationship between the severity of the pain and the fistula activity, the presence of an abscess, and anal canal hyperemia. RESULTS: All examinations were successfully performed. Thirty-nine examinations (60.9%) were performed without any pain experienced by the patient, 19 examinations (29.7%) with mild pain, five examinations (7.8%) with moderate pain, and one examination (1.6%) with severe pain. The pain severity was correlated with the fistula activity (P<0.01). An anterior fistula location was more common than a posterior location. Active fistulas and abscesses were identified during 30 examinations (46.9%) and 12 examinations (18.8%), respectively. Anal canal hyperemia was identified in 31 examinations (48.4%). CONCLUSION: TPUS with a color Doppler study is useful for visualizing a perianal fistula or abscess and for assessing its inflammatory activity in pediatric Crohn patients. PMID- 25038809 TI - Portable high-intensity focused ultrasound system with 3D electronic steering, real-time cavitation monitoring, and 3D image reconstruction algorithms: a preclinical study in pigs. AB - PURPOSE: The aim of this study was to evaluate the safety and accuracy of a new portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system with a 3-dimensional (3D) electronic steering transducer, a simultaneous ablation and imaging module, real-time cavitation monitoring, and 3D image reconstruction algorithms. METHODS: To address the accuracy of the transducer, hydrophones in a water chamber were used to assess the generation of sonic fields. An animal study was also performed in five pigs by ablating in vivo thighs by single-point sonication (n=10) or volume sonication (n=10) and ex vivo kidneys by single-point sonication (n=10). Histological and statistical analyses were performed. RESULTS: In the hydrophone study, peak voltages were detected within 1.0 mm from the targets on the y- and z-axes and within 2.0-mm intervals along the x-axis (z-axis, direction of ultrasound propagation; y- and x-axes, perpendicular to the direction of ultrasound propagation). Twenty-nine of 30 HIFU sessions successfully created ablations at the target. The in vivo porcine thigh study showed only a small discrepancy (width, 0.5-1.1 mm; length, 3.0 mm) between the planning ultrasonograms and the pathological specimens. Inordinate thermal damage was not observed in the adjacent tissues or sonic pathways in the in vivo thigh and ex vivo kidney studies. CONCLUSION: Our study suggests that this new USg-HIFU system may be a safe and accurate technique for ablating soft tissues and encapsulated organs. PMID- 25038810 TI - Benign core biopsy of probably benign breast lesions 2 cm or larger: correlation with excisional biopsy and long-term follow-up. AB - PURPOSE: To evaluate the accuracy of benign core biopsy of probably benign breast lesions (category 3) 2 cm or larger on the basis of excisional biopsy and long term follow-up. METHODS: We retrospectively reviewed 146 category 3 lesions in 146 patients 2 cm or larger which were diagnosed as benign by ultrasound (US) guided core biopsy. Patients were initially diagnosed as benign at core needle biopsy and then followed up with excisional biopsy (surgical excision, n=91; US guided vacuum assisted excision, n=35) or breast ultrasonography (n=20). RESULTS: Of the 126 patients who underwent surgical excision or US-guided vacuum-assisted excision, 114 patients were diagnosed with benign lesions, 10 patients with borderline lesions (benign phyllodes tumor), and two patients with malignant phyllodes tumors. The probabilities of lesions being benign, borderline and malignant were 91.8% (134/146), 6.8% (10/146), and 1.4% (2/146), respectively. Of 13 patients who had growing masses on follow-up ultrasonography, three (23.1%) were non-benign (two benign phyllodes tumors and one malignant phyllodes tumor). CONCLUSION: US-guided core needle biopsy of probably benign breast mass 2 cm or larger was accurate (98.6%) enough to rule out malignancy. But, it was difficult to rule out borderline lesions even when they were diagnosed as benign. PMID- 25038811 TI - Comparison of hormonal receptor and HER2 status between ultrasound-guided 14 gauge core needle biopsy and surgery in breast cancer patients. AB - PURPOSE: To evaluate the concordance of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) statuses between ultrasound (US)-guided 14-gauge core needle biopsy (CNB) and surgery and to analyze whether the clinicopathological and imaging features including those from mammography and ultrasonography can predict the concordance in breast cancer patients. METHODS: The concordance of receptor status between CNB and surgery was assessed for 55 breast cancers in 55 women who underwent CNB before treatment. The clinicopathological and imaging features and the concordance rates were compared between the non-neoadjuvant chemotherapy (non-NAC) group and the NAC group according to the initial treatment. The concordance rates were analyzed according to the clinicopathological and imaging features, by using the chi-square or Fisher exact test and McNemar test for the categorical and the independent t-test for continuous variables. RESULTS: Among 55 women, 22 women (40%) were part of the non-NAC group and 33 women (60%) were part of the NAC group. The concordance rates were 0.86-1.00 in the non-NAC group and 0.76-0.88 in the NAC group. In all three receptors, the difference in the concordance rate between the two groups was not significant. In the NAC group, the absence of axillary lymph node metastasis (1.00, P=0.02) and visibility of cancer on mammography (0.93, P=0.04) showed the higher concordance of the HER2 status. CONCLUSION: Concordance of the receptor status between surgery and US-guided 14-gauge CNB was feasible in breast cancer patients. The absence of axillary lymph node metastasis after NAC and the visibility of cancer on mammography prior to NAC may be helpful for predicting the concordance of HER2 in breast cancer patients. PMID- 25038812 TI - Ultrasonographic diagnosis of round ligament varicosities mimicking inguinal hernia: report of two cases with literature review. AB - Round ligament varicosities are rare, and the mass mimics an inguinal hernia. Round ligament varicosities should be considered in the differential diagnosis of a groin swelling in a female, especially during pregnancy. The diagnosis of round ligament varicosities can be established on grayscale and color Doppler ultrasonography. We report two cases of round ligament varicosities in a 33-year old non pregnant woman and a 28-year-old pregnant woman, and these patients were diagnosed using ultrasonography. We also reviewed the literature on round ligament varicosities including the present cases. Ultrasonography is diagnostic and can prevent unnecessary surgical intervention and associated morbidity. PMID- 25038813 TI - Incidentally diagnosed Takayasu arteritis on thyroid ultrasonography showing prominent collateral vessels of thyroidal arteries and common carotid artery occlusion. AB - We report a case of middle-aged woman incidentally diagnosed with Takayasu arteritis during the ultrasonography of a thyroid gland nodule. Prominent collaterals of the thyroidal arteries and a thin common carotid artery with mural thickening and deficient intraluminal flow signals were initially depicted on the ultrasonography with color Doppler. Subsequent magnetic resonance angiography and computed tomography aortography confirmed the diagnosis with the imaging features of a bilateral long segment common carotid artery occlusion and segmental stenosis of the left subclavian artery in addition to the suggestive physical findings. PMID- 25038814 TI - ASYMMETRIC LEAVES1 regulates abscission zone placement in Arabidopsis flowers. AB - BACKGROUND: The sepals, petals and stamens of Arabidopsis flowers detach via abscission zones formed at their boundaries with the underlying receptacle. The ASYMMETRIC LEAVES1 (AS1) MYB transcription factor plays a critical role in setting boundaries between newly formed leaf primordia and the shoot meristem. By repressing expression of a set of KNOTTED1-LIKE HOMEODOMAIN (KNOX) genes from developing leaf primordia, AS1 and its partner ASYMMETRIC LEAVES2 allow the patterning and differentiation of leaves to proceed. Here we show a unique role for AS1 in establishing the positions of the sepal and petal abscission zones in Arabidopsis flowers. RESULTS: In as1 mutant flowers, the sepal abscission zones are displaced into inverted V-shaped positions, leaving behind triangular stubs of tissue when the organs abscise. Movement of the petal abscission zones is also apparent. Abscission of the medial sepals is delayed in as1 flowers; loss of chlorophyll in the senescing sepals contrasts with proximal zones that remain green. AS1 has previously been shown to restrict expression of the KNOX gene, BREVIPEDICELLUS (BP), from the sepals. We show here that loss of BP activity in as1 flowers is sufficient to restore the positions of the sepal and petal abscission zones, the sepal-receptacle boundary of the medial sepals and the timing of their abscission. CONCLUSIONS: Our results indicate that AS1 activity is critical for the proper placement of the floral organ abscission zones, and influences the timing of organ shedding. PMID- 25038816 TI - Variant detection sensitivity and biases in whole genome and exome sequencing. AB - BACKGROUND: Less than two percent of the human genome is protein coding, yet that small fraction harbours the majority of known disease causing mutations. Despite rapidly falling whole genome sequencing (WGS) costs, much research and increasingly the clinical use of sequence data is likely to remain focused on the protein coding exome. We set out to quantify and understand how WGS compares with the targeted capture and sequencing of the exome (exome-seq), for the specific purpose of identifying single nucleotide polymorphisms (SNPs) in exome targeted regions. RESULTS: We have compared polymorphism detection sensitivity and systematic biases using a set of tissue samples that have been subject to both deep exome and whole genome sequencing. The scoring of detection sensitivity was based on sequence down sampling and reference to a set of gold-standard SNP calls for each sample. Despite evidence of incremental improvements in exome capture technology over time, whole genome sequencing has greater uniformity of sequence read coverage and reduced biases in the detection of non-reference alleles than exome-seq. Exome-seq achieves 95% SNP detection sensitivity at a mean on-target depth of 40 reads, whereas WGS only requires a mean of 14 reads. Known disease causing mutations are not biased towards easy or hard to sequence areas of the genome for either exome-seq or WGS. CONCLUSIONS: From an economic perspective, WGS is at parity with exome-seq for variant detection in the targeted coding regions. WGS offers benefits in uniformity of read coverage and more balanced allele ratio calls, both of which can in most cases be offset by deeper exome seq, with the caveat that some exome-seq targets will never achieve sufficient mapped read depth for variant detection due to technical difficulties or probe failures. As WGS is intrinsically richer data that can provide insight into polymorphisms outside coding regions and reveal genomic rearrangements, it is likely to progressively replace exome-seq for many applications. PMID- 25038815 TI - Magnetic resonance imaging during life: the key to unlock cerebral malaria pathogenesis? AB - Understanding the mechanisms underlying the pathophysiology of cerebral malaria in patients with Plasmodium falciparum infection is necessary to implement new curative interventions. While autopsy-based studies shed some light on several pathological events that are believed to be crucial in the development of this neurologic syndrome, their investigative potential is limited and has not allowed the identification of causes of death in patients who succumb to it. This can only be achieved by comparing features between patients who die from cerebral malaria and those who survive. In this review, several alternative approaches recently developed to facilitate the comparison of specific parameters between fatal, non-fatal cerebral malaria and uncomplicated malaria patients are described, as well as their limitations. The emergence of neuroimaging as a revolutionary tool in identifying critical structural and functional modifications of the brain during cerebral malaria is discussed and highly promising areas of clinical research using magnetic resonance imaging are highlighted. PMID- 25038817 TI - Sleep deprivation leads to a loss of functional connectivity in frontal brain regions. AB - BACKGROUND: The restorative effect of sleep on waking brain activity remains poorly understood. Previous studies have compared overall neural network characteristics after normal sleep and sleep deprivation. To study whether sleep and sleep deprivation might differentially affect subsequent connectivity characteristics in different brain regions, we performed a within-subject study of resting state brain activity using the graph theory framework adapted for the individual electrode level.In balanced order, we obtained high-density resting state electroencephalography (EEG) in 8 healthy participants, during a day following normal sleep and during a day following total sleep deprivation. We computed topographical maps of graph theoretical parameters describing local clustering and path length characteristics from functional connectivity matrices, based on synchronization likelihood, in five different frequency bands. A non parametric permutation analysis with cluster correction for multiple comparisons was applied to assess significance of topographical changes in clustering coefficient and path length. RESULTS: Significant changes in graph theoretical parameters were only found on the scalp overlying the prefrontal cortex, where the clustering coefficient (local integration) decreased in the alpha frequency band and the path length (global integration) increased in the theta frequency band. These changes occurred regardless, and independent of, changes in power due to the sleep deprivation procedure. CONCLUSIONS: The findings indicate that sleep deprivation most strongly affects the functional connectivity of prefrontal cortical areas. The findings extend those of previous studies, which showed sleep deprivation to predominantly affect functions mediated by the prefrontal cortex, such as working memory. Together, these findings suggest that the restorative effect of sleep is especially relevant for the maintenance of functional connectivity of prefrontal brain regions. PMID- 25038818 TI - IgG4-related tubulointerstitial nephritis accompanied with cystic formation. AB - BACKGROUND: An immunoglobulin G4 (IgG4)-related disease is important disease in differential diagnosis of tumors in kidney, pancreas, lung and other organs. The imaging findings of IgG4-related kidney diseases are usually expressed as defect contrast region, while cystic formation in kidney is extremely rare. Here, we report a case of IgG4-related tubulointerstitial nephritis with renal cystic change caused by the narrowing or obstruction of collecting duct in renal medulla. CASE PRESENTATION: Abdominal contrasted CT scan showed a 31 * 24 mm cystic tumor at the upper pole of the right kidney and multiple low-attenuation areas in the left kidney. 18 F-fluorodeoxyglucose (FDG)-PET/CT scan showed moderate FDG accumulation of cystic tumor in marginal lesion. In addition, FDG PET/CT scan also showed moderate FDG accumulation in the pancreatic body. Laparoscopic right nephrectomy was performed. Histological examination was revealed lymphoplasmacytic infiltrate with focal fibrosis and severe narrowing or obstruction of lumen of collecting duct in renal medulla. Furthermore, the IgG4 positive plasma cells infiltrated exceeding 10 cells per one high-power field in renal medulla. The ratio of IgG4-plasma cells to IgG-positive plasma cells was about 50%. The serum level of IgG4 was also elevated (218 mg/dl). Based on these findings, we finally diagnosed IgG4-related tubulointerstitial nephritis with renal cystic change. CONCLUSION: IgG4-related kidney disease might cause cystic formation by severe narrowing and obstruction of collecting duct. PMID- 25038819 TI - GACT: a Genome build and Allele definition Conversion Tool for SNP imputation and meta-analysis in genetic association studies. AB - BACKGROUND: Genome-wide association studies (GWAS) have successfully identified genes associated with complex human diseases. Although much of the heritability remains unexplained, combining single nucleotide polymorphism (SNP) genotypes from multiple studies for meta-analysis will increase the statistical power to identify new disease-associated variants. Meta-analysis requires same allele definition (nomenclature) and genome build among individual studies. Similarly, imputation, commonly-used prior to meta-analysis, requires the same consistency. However, the genotypes from various GWAS are generated using different genotyping platforms, arrays or SNP-calling approaches, resulting in use of different genome builds and allele definitions. Incorrect assumptions of identical allele definition among combined GWAS lead to a large portion of discarded genotypes or incorrect association findings. There is no published tool that predicts and converts among all major allele definitions. RESULTS: In this study, we have developed a tool, GACT, which stands for Genome build and Allele definition Conversion Tool, that predicts and inter-converts between any of the common SNP allele definitions and between the major genome builds. In addition, we assessed several factors that may affect imputation quality, and our results indicated that inclusion of singletons in the reference had detrimental effects while ambiguous SNPs had no measurable effect. Unexpectedly, exclusion of genotypes with missing rate > 0.001 (40% of study SNPs) showed no significant decrease of imputation quality (even significantly higher when compared to the imputation with singletons in the reference), especially for rare SNPs. CONCLUSION: GACT is a new, powerful, and user-friendly tool with both command-line and interactive online versions that can accurately predict, and convert between any of the common allele definitions and between genome builds for genome-wide meta-analysis and imputation of genotypes from SNP-arrays or deep-sequencing, particularly for data from the dbGaP and other public databases. GACT SOFTWARE: http://www.uvm.edu/genomics/software/gact. PMID- 25038820 TI - Birth preparedness and complication readiness in Robe Woreda, Arsi Zone, Oromia Region, Central Ethiopia: a cross-sectional study. AB - BACKGROUND: Globally, an estimated 287 000 maternal deaths occurred in 2010 annually as a result of complications of pregnancy and childbirth. Sub-Saharan Africa and Southern Asia were accounted for 85% of the global burden (245 000 maternal deaths) including Ethiopia. Obstetric related complications cannot be reliably predicted. Hence, insignificant decline of maternal mortality ratio might be due to the non use of birth preparedness and complication readiness strategies. Therefore, this paper aimed to assess knowledge and practices towards birth preparedness and complication readiness and associated factors among women of reproductive age group (15-49) in Robe Woreda, Arsi Zone, Oromia Region, Ethiopia. METHOD: Community-based cross-sectional study supplemented by qualitative design was conducted in January, 2012. A total of 575 women from 5 kebeles were selected after proportionally allocated to population size and interviewed using structured and semi-structured, pre-tested questionnaires. Univariate and bivariate analysis was performed. Multiple logistic regression analysis was also done to control for possible confounding variables. RESULTS: Taking into account place of delivery identification, means of transportation, skilled attendant identification and saving money, about 16.5% of the respondents were prepared for birth and its complications. Preparation for birth and its complication was higher among educated mothers (AOR=6.23, 95% CI=1.5, 25.87). Monthly income of >716 Ethiopian birr (AOR=1.94, 95% CI=1.01, 3.87), ANC visit (AOR=5.68, 95% CI=1.27, 25.4), knowledge of obstetric complications (AOR=2.94, 95% CI=1.61, 5.37) and those who had given birth at health facility before their last delivery (AOR=3.9, 95% CI=2.04, 7.46) were also significantly associated with birth preparedness and complication readiness. CONCLUSION: The study identified very low magnitude of birth preparedness and complication readiness in the study area and poor knowledge and practices of preparation for birth and its complication. Community education about preparation for birth and its complication and empowerment of women through expansion of educational opportunities are important steps in improving birth preparedness. In all health facilities during antenatal care emphasis should given to preparation for birth and its complication and provide information and education to all pregnant women. PMID- 25038821 TI - Differentiation therapy: sesamin as an effective agent in targeting cancer stem like side population cells of human gallbladder carcinoma. AB - BACKGROUND: Recent studies have demonstrated that side population (SP) cells isolated from various cancer cell lines and primary tumors possess stem cell-like properties. Sesamin, a food-derived agent, possesses anti-cancer activities both in vitro and in vivo. The present study was designed to determine whether sesamin also have effects on cancer stem-like SP cells from gallbladder cancer (GBC). METHODS: In this study, we sorted SP cells by flow cytometry. SP cells were cultured and treated with sesamin. Tumor-sphere formation, colony formation, Matrigel invasion and tumorigenic potential were determined. Expression of nuclear NF-kappaB, IL-6, p-Stat3, Twist, E-cadherin and Vimentin was measured by Western blot, immunofluorescence staining or RT-PCR analysis. Nuclear NF-kappaB activity and IL-6 protein level were assessed with ELISA. Xenograft tumors were generated in nude mice. RESULTS: After treated with sesamin, SP cells differentiated into cells expressing the epithelial marker (E-cadherin). Sesamin effectively affected SP cells stem cell-like characteristics (i.e., tumor-sphere formation, colony-formation, Matrigel invasion), weakened the drug-resistance of SP cells and inhibited tumor growth both in vitro and in vivo. Treatment with sesamin significantly reduced the expression of nuclear NF-kappaB, IL-6, p-Stat3, Twist and Vimentin (a mesenchymal marker) in SP cells. Nuclear NF-kappaB activity and IL-6 level were also decreased after treatment with sesamin. CONCLUSION: Food derived sesamin directs the epithelial differentiation of cancer stem-like SP cells from GBC, which is associated with attenuation of NF-kappaB-IL-6-Stat3 Twist signal pathway. PMID- 25038822 TI - Comparison of four lung scoring systems for the assessment of the pathological outcomes derived from Actinobacillus pleuropneumoniae experimental infections. AB - BACKGROUND: In this study, four lung lesion scoring methods (Slaughterhouse Pleurisy Evaluation System [SPES], Consolidation Lung Lesion Score [LLS], Image analyses [IA] and Ratio of lung weight/body weight [LW/BW]) were compared for the assessment of the different pathological outcomes derived from an Actinobacillus pleuropneumoniae (App) experimental infection model. Moreover, pathological data was coupled with clinical (fever, inappetence and clinical score), production (average daily weigh gain [ADWG]) and diagnostic (PCR, ELISA and bacterial isolation) parameters within the four infection outcomes (peracute, acute, subclinically infected and non-infected). RESULTS: From the 61 inoculated animals, 9 were classified as peracute (presence of severe App-like clinical signs and lesions and sudden death or euthanasia shortly after inoculation), 31 as acutely affected (presence of App-like clinical signs and lesions and survival until the end of the experiment), 12 as subclinically infected (very mild or no clinical signs but App infection confirmed) and 9 as non-infected animals (lack of App-like clinical signs and lack of evidence of App infection). A significant correlation between all lung lesion scoring systems was found with the exception of SPES score versus LW/BW. SPES showed a statistically significant association with all clinical, production and diagnostic (with the exception of PCR detection of App in the tonsil) variables assessed. LLS and IA showed similar statistically significant associations as SPES, with the exception of seroconversion against App at necropsy. In contrast, LW/BW was statistically associated only with App isolation in lungs, presence of App-like lesions and ELISA OD values at necropsy. CONCLUSIONS: In conclusion, SPES, LLS and IA are economic, fast and easy-to perform lung scoring methods that, in combination with different clinical and diagnostic parameters, allow the characterization of different outcomes after App infection. PMID- 25038823 TI - Intelligent Therapy Assistant (ITA) for cognitive rehabilitation in patients with acquired brain injury. AB - BACKGROUND: This paper presents the design, development and first evaluation of an algorithm, named Intelligent Therapy Assistant (ITA), which automatically selects, configures and schedules rehabilitation tasks for patients with cognitive impairments after an episode of Acquired Brain Injury. The ITA is integrated in "Guttmann, Neuro Personal Trainer" (GNPT), a cognitive tele rehabilitation platform that provides neuropsychological services. METHODS: The ITA selects those tasks that are more suitable for the specific needs of each patient, considering previous experiences, and improving the personalization of the treatment. The system applies data mining techniques to cluster the patients according their cognitive impairment profile. Then, the algorithm rates every rehabilitation task, based on its cognitive structure and the clinical impact of executions done by similar patients. Finally, it configures the most suitable degree of difficulty, depending on the impairment of the patient and his/her evolution during the treatment. RESULTS: The ITA has been evaluated during 18 months by 582 patients. In order to evaluate the effectiveness of the ITA, a comparison between the traditional manual planning procedure and the one presented in this paper has been done, taking into account: a) the selected tasks assigned to rehabilitation sessions; b) the difficulty level configured for the sessions; c) and the improvement of their cognitive capacities after completing treatment. CONCLUSIONS: The obtained results reveal that the rehabilitation treatment proposed by the ITA is as effective as the one performed manually by therapists, arising as a new powerful support tool for therapists. The obtained results make us conclude that the proposal done by the ITA is very close to the one done by therapists, so it is suitable for real treatments. PMID- 25038824 TI - Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer. AB - BACKGROUND: The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients. METHODS: In a dose escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee. RESULTS: From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade >=3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months. CONCLUSIONS: The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2. TRIAL REGISTRATION: http://www.clinicaltrials.gov: NCT00422773. PMID- 25038825 TI - A plasmonic chip for biomarker discovery and diagnosis of type 1 diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease, whereas type 2 diabetes (T2D) results from insulin resistance and beta cell dysfunction. Previously, the onset of these two separate diseases was easily distinguished, with children being most at risk for T1D and T2D occurring in overweight adults. However, the dramatic rise in obesity, coupled with the notable increase in T1D, has created a large overlap in these previously discrete patient populations. Delayed diagnosis of T1D can result in severe illness or death, and rapid diagnosis of T1D is critical for the efficacy of emerging therapies. However, attempts to apply next generation platforms have been unsuccessful for detecting diabetes biomarkers. Here we describe the development of a plasmonic gold chip for near-infrared fluorescence-enhanced (NIR-FE) detection of islet cell-targeting autoantibodies. We demonstrate that this platform has high sensitivity and specificity for the diagnosis of T1D and can be used to discover previously unknown biomarkers of T1D. PMID- 25038826 TI - Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. AB - Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes. PMID- 25038827 TI - The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. AB - The HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi Goutieres syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1 for defects in RNase or dNTPase activity, we identify SAMHD1 point mutants that cause loss of one or both functions. The RNase-positive and dNTPase-negative SAMHD1D137N mutant is able to restrict HIV-1 infection, whereas the RNase-negative and dNTPase-positive SAMHD1Q548A mutant is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of cell infection. SAMHD1 silencing in macrophages and CD4(+) T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in cells and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 infection by directly degrading the HIV-1 RNA. PMID- 25038828 TI - Huntington's disease is a four-repeat tauopathy with tau nuclear rods. AB - An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds. PMID- 25038829 TI - Loss of tight junction proteins (Claudin 1, 4, and 7) correlates with aggressive behavior in colorectal carcinoma. AB - BACKGROUND: Tight junction proteins in the cell organize paracellular permeability and they play a critical role in apical cell-to-cell adhesion and epithelial polarity. Claudins are major integral membrane proteins of tight junctions, especially Claudin 1, 4, and 7, which are known as the impermeability Claudins. In this study, we investigated the importance of loss of Claudin 1, 4, and 7 expression, and their relation to tumor progression in colorectal cancer patients. MATERIAL/METHODS: Loss of Claudin 1, 4, and 7 expression was examined by immunohistochemical method in 70 patients diagnosed with colorectal cancer. Cases with loss of Claudin expression in <1/3 of tumor cells were classified as mild loss, whereas cases with loss of Claudin expression 31/3 of tumor cells were classified as moderate-to-marked loss in order to evaluate the relation between loss of Claudin 1, 4, and 7 expression and clinicopathologic data. RESULTS: The severe suppression of Claudin 1, 4, and 7 expression was found to be significantly related to the depth of tumor invasion, positive regional lymph nodes, histological grade, lymphovascular invasion, perineural invasion, and lymphocytic response. Additionally, severity of loss in Claudin 4 expression was found to have a relation with distant metastasis. CONCLUSIONS: Claudin 1, 4, and 7 are important building blocks of paracellular adhesion molecules. Their decreased expression in colorectal cancer seems to have critical effects on cell proliferation, motility, invasion, and immune response against the tumor. PMID- 25038830 TI - Decreases in self-reported alcohol consumption following HIV counseling and testing at Mulago Hospital, Kampala, Uganda. AB - BACKGROUND: Alcohol use has a detrimental impact on the HIV epidemic, especially in sub-Saharan Africa. HIV counseling and testing (HCT) may provide a contact opportunity to intervene with hazardous alcohol use; however, little is known about how alcohol consumption changes following HCT. METHODS: We utilized data from 2056 participants of a randomized controlled trial comparing two methods of HCT and subsequent linkage to HIV care conducted at Mulago Hospital in Kampala, Uganda. Those who had not previously tested positive for HIV and whose last HIV test was at least one year in the past were eligible. Participants were asked at baseline when they last consumed alcohol, and prior three month alcohol consumption was measured using the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) at baseline and quarterly for one year. Hazardous alcohol consumption was defined as scoring >=3 or >=4 for women and men, respectively. We examined correlates of alcohol use at baseline, and of hazardous and non hazardous drinking during the year of follow-up using multinomial logistic regression, clustered at the participant level to account for repeated measurements. RESULTS: Prior to HCT, 30% were current drinkers (prior three months), 27% were past drinkers (>3 months ago), and 44% were lifetime abstainers. One-third (35%) of the current drinkers met criteria for hazardous drinking. Hazardous and non-hazardous self-reported alcohol consumption declined after HCT, with 16% of baseline current drinkers reporting hazardous alcohol use 3 months after HCT. Independent predictors (p < 0.05) of continuing non-hazardous and hazardous alcohol consumption after HCT were sex (male), alcohol consumption prior to HCT (hazardous), and HIV status (negative). Among those with HIV, non hazardous drinking was less likely among those taking antiretroviral therapy (ART). CONCLUSIONS: HCT may be an opportune time to intervene with alcohol consumption. Those with HIV experienced greater declines in alcohol consumption after HCT, and non-hazardous drinking decreased for those with HIV initiating ART. HCT and ART initiation may be ideal times to intervene with alcohol consumption. Screening and brief intervention (SBI) to reduce alcohol consumption should be considered for HCT and HIV treatment venues. PMID- 25038831 TI - The importance of detecting and managing comorbidities in people with dementia? PMID- 25038832 TI - Non-linear associations between serum 25-OH vitamin D and indices of arterial stiffness and arteriosclerosis in an older population. AB - BACKGROUND: several studies have been pointing towards a non-linear relationship between serum 25(OH)D and cardiovascular disease. Next to vitamin D deficiency, also higher levels of 25(OH)D have been reported to be associated with increased cardiovascular risk. We aimed to investigate the nature of the relationship between serum 25(OH)D and measures of arterial stiffness and arteriosclerosis in an elderly population. DESIGN: cross-sectional. SETTING/SUBJECTS: a subgroup of the B-PROOF study was included to determine associations between serum 25(OH)D and arterial stiffness and atherosclerosis (n = 567, 57% male, age 72.6 +/- 5.6 years, mean serum 25(OH)D 54.6 +/- 24.1 nmol/l). METHODS: carotid intima media thickness (IMT) was assessed using ultrasonography and pulse wave velocity (PWV) was determined with applanation tonometry. Associations were tested using multivariable restricted cubic spline functions and stratified linear regression analysis. RESULTS: the associations between serum 25(OH)D and carotid IMT or PWV were non-linear. Spline functions demonstrated a difference between 25(OH)D deficient and sufficient individuals. In serum 25(OH)D sufficient participants (>=50 nmol/l; n = 287), a positive association with IMT and serum 25(OH)D was present (beta 1.24; 95%CI [0.002; 2.473]). PWV levels were slightly lower in vitamin D deficient individuals, but the association with 25(OH)D was not significant. CONCLUSION: our study demonstrates that associations of serum 25(OH)D and PWV and IMT in an elderly population are not linear. In particular from serum 25(OH)D levels of 50 nmol/l and up, there is a slight increase of IMT with increasing 25(OH)D levels. PMID- 25038833 TI - Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. AB - OBJECTIVES: to determine the effect of drugs with anti-cholinergic properties on relevant health outcomes. DESIGN: electronic published and unpublished literature/trial registries were systematically reviewed. Studies evaluating medications with anti-cholinergic activity on cognitive function, delirium, physical function or mortality were eligible. RESULTS: forty-six studies including 60,944 participants were included. Seventy-seven percent of included studies evaluating cognitive function (n = 33) reported a significant decline in cognitive ability with increasing anti-cholinergic load (P < 0.05). Four of five included studies reported no association with delirium and increasing anti cholinergic drug load (P > 0.05). Five of the eight included studies reported a decline in physical function in users of anti-cholinergics (P < 0.05). Three of nine studies evaluating mortality reported that the use of drugs with anti cholinergic properties was associated with a trend towards increased mortality, but this was not statistically significant. The methodological quality of the evidence-base ranged from poor to very good. CONCLUSION: medicines with anti cholinergic properties have a significant adverse effect on cognitive and physical function, but limited evidence exists for delirium or mortality outcomes. PMID- 25038834 TI - A very unusual organism causing stroke-like symptoms. AB - A 78-year-old man presented to hospital with new onset confusion and fever. The working diagnosis was of delirium due to an infection of unknown source, and empirical i.v. antibiotic treatment was given. Two days later, he deteriorated and developed clinical features in keeping with a total anterior circulation stroke. Brain imaging was unremarkable. Blood cultures grew an organism subsequently identified as Facklamia languida. Following treatment with broad spectrum antibiotics, his condition improved. A diagnosis of F. languida septicaemia, leading to presumed (unwitnessed) seizure and Todd's paresis was made. The patient went on to make a full recovery and was discharged home. Stroke mimics are common and may be eminently treatable. Around a quarter of patients initially suspected to have a stroke are subsequently found to have an alternative diagnosis. PMID- 25038835 TI - Systematic review investigating the reporting of comorbidities and medication in randomized controlled trials of people with dementia. AB - OBJECTIVES: dementia is a debilitating condition characterised by global loss of cognitive and intellectual functioning, which reduces social and occupational performance. This population frequently presents with medical co-morbidities such as hypertension, cardiovascular disease and diabetes. The CONSORT statement outlines recommended guidance on reporting of participant characteristics in clinical trials. It is, however, unclear how much these are adhered to in trials assessing people with dementia. This paper assesses the reporting of medical co morbidities and prescribed medications for people with dementia within randomised controlled trial (RCT) reports. DESIGN: a systematic review of the published literature from the databases AMED, CINAHL, MEDLINE, EMBASE and the Cochrane Clinical Trial Registry from 1 January 1997 to 9 January 2014 was undertaken in order to identify RCTs detailing baseline medical co-morbidities and prescribed medications . Eligible studies were appraised using the Critical Appraisal Skills Programme (CASP) RCT appraisal tool, and descriptive statistical analyses were calculated to determine point prevalence. RESULTS: nine trials, including 1474 people with dementia, were identified presenting medical co-morbidity data. These indicated neurological disorders (prevalence 91%), vascular disorders (prevalence 91%), cardiac disorders (prevalence 74%) and ischaemic cerebrovascular disease (prevalence 53%) were most frequently seen. CONCLUSIONS: published RCTs poorly report medical co-morbidities and medications for people with dementia. Future trials should include the report of these items to allow interpretation of whether the results are generalisable to frailer older populations. PROSPERO REGISTRATION: CRD42013006735. PMID- 25038837 TI - Variations of the popliteal artery branching with multidetector CT angiography. AB - OBJECTIVE: To date the anatomy of the popliteal artery variations using multidetector-row computed tomography angiography (MD CTA) was not assessed. The objective of this study is to establish 3D CT anatomy of the popliteal artery variations. MATERIALS AND METHODS: A total of 126 lower limbs that underwent CTA using 64-detector MDCT were retrospectively reviewed. The anatomical variations of the distal popliteal artery branching were assessed. RESULTS: Ninety-seven lower limbs (83.6%) had the usual branching pattern (type 1 A) with tibialis anterior artery (TA) arising first followed by the tibial-peroneal trunk, which then gives rise to the tibialis posterior artery (TP) and peroneal artery. Variations in popliteal branching pattern were seen in 19 (16.4%) limbs. The commonest variation was first branch of the TP in 5 (4.4%) of the limbs (type 1 C) or high origin with anterior course of popliteus muscle of the TA in 5 (4.4%) limbs (type 2 A II). CONCLUSION: Many variations exist in the running patterns of the branching pattern of the popliteal artery. Knowledge of the branching pattern of the popliteal artery will be beneficial to radiologist for the evaluation of CT angiograms and interventional vascular procedures, and to vascular surgeons for various surgical approaches. MD CTA provides noninvasive means of assessing distal popliteal artery variations. PMID- 25038838 TI - Morphological and volumetric evaluation of the nasopalatinal canal in a Turkish population using cone-beam computed tomography. AB - PURPOSE: To establish (nasopalatine canal) NPC morphology and obtain linear and volumetric measurements using CBCT images. METHODS: We evaluated CBCT scans of 252 patients. NPC shape was classified as belonging to six groups. Following measurements were recorded: M1, nasal foramen diameter; M2, incisive foramen diameter; M3, NPC length; M4, distance from the buccal border of the incisive foramen to the facial aspect of the buccal bone plate; M5, distance from the buccal bone wall of the NPC to the facial aspect of the buccal bone plate; and M6, distance from the buccal border in the middle of the NPC to the facial aspect of the buccal bone plate. Volume and surface area measurements of the NPC were also conducted. Sex, age and maxillary anterior teeth status (MCI) were recorded. Four-way repeated ANOVA was performed. Significance level was set at p < 0.05. RESULTS: With the exception of M4 and M5, the relationship between MCI and all linear measurements was statistically significant. Patient sex had a significant effect on all NPC measurements with the exception of nasal foramen diameter, with all measurements greater in males than females (p < 0.001). NPC volume was found to vary significantly by patient sex (p = 0.042), with mean NPC volume values of 55.171 mm(3) for females and 72.966 mm(3) for males. CONCLUSION: The measurements conducted around nasopalatine canal provided useful information prior to implant placement in the anterior maxilla. PMID- 25038839 TI - Negative purifying selection drives prion and doppel protein evolution. AB - The prion protein (PrP) when misfolded into the pathogenic conformer PrP(Sc) is the major causative agent of several lethal transmissible spongiform encephalopathies in mammals. Studies of evolutionary pressure on the corresponding gene using different datasets have yielded conflicting results. In addition, putative PrP or PrP interacting partners with strong similarity to PrP such as the doppel protein have not been examined to determine if the same evolutionary mechanisms apply to prion paralogs or if there are coselected sites that might indicate how and where the proteins interact. We examined several taxonomic groups that contain model organisms of prion diseases focusing on primates, bovids, and an expanded dataset of rodents for selection pressure on the prion gene (PRNP) and doppel gene (PRND) individually and for coevolving sites within. Overall, the results clearly indicate that both proteins are under strong selective constraints with relaxed selection on amino acid residues connecting alpha-helices 1 and 2. PMID- 25038840 TI - Molecular evolution of the odorant and gustatory receptor genes in lepidopteran insects: implications for their adaptation and speciation. AB - Lepidoptera (comprised of butterflies and moths) is one of the largest groups of insects, including more than 160,000 described species. Chemoreception plays important roles in the adaptation of these species to a wide range of niches, e.g., plant hosts, egg-laying sites, and mates. This study investigated the molecular evolution of the lepidopteran odorant (Or) and gustatory receptor (Gr) genes using recently identified genes from Bombyx mori, Danaus plexippus, Heliconius melpomene, Plutella xylostella, Heliothis virescens, Manduca sexta, Cydia pomonella, and Spodoptera littoralis. A limited number of cases of large lineage-specific gene expansion are observed (except in the P. xylostella lineage), possibly due to selection against tandem gene duplication. There has been strong purifying selection during the evolution of both lepidopteran odorant and gustatory genes, as shown by the low omega values estimated through CodeML analysis, ranging from 0.0093 to 0.3926. However, purifying selection has been relaxed on some amino acid sites in these receptors, leading to sequence divergence, which is a precursor of positive selection on these sequences. Signatures of positive selection were detected only in a few loci from the lineage-specific analysis. Estimation of gene gains and losses suggests that the common ancestor of the Lepidoptera had fewer Or genes compared to extant species and an even more reduced number of Gr genes, particularly within the bitter receptor clade. Multiple gene gains and a few gene losses occurred during the evolution of Lepidoptera. Gene family expansion may be associated with the adaptation of lepidopteran species to plant hosts, especially after angiosperm radiation. Phylogenetic analysis of the moth sex pheromone receptor genes suggested that chromosomal translocations have occurred several times. New sex pheromone receptors have arisen through tandem gene duplication. Positive selection was detected at some amino acid sites predicted to be in the extracellular and transmembrane regions of the newly duplicated genes, which might be associated with the evolution of the new pheromone receptors. PMID- 25038841 TI - Management of CSF leak following spinal surgery. AB - PURPOSE: Postoperative CSF leak is a known complication of spinal surgery especially after surgery for neural tube defects (NTD). The problem can metamorphose into a severe infection. This article hopes to shed some light on the management of these problems and suggests precautions so as to reduce their occurrence. MATERIALS AND METHODS: A retrospective analysis of 102 children, between the ages of 1 day and 12 years, operated for various spinal pathologies, over the past 2.5 years by the same surgeon (CB) was done. The various methods of dural closure were noted. The methods of management of postoperative CSF leaks were analysed, and the patients were followed till discharge. RESULTS: The incidence of CSF leak was found to be 12.7%. The methods of management included lumbar drain only (n = 7), lumbar drain with re-exploration (n = 3), lumbar drain followed by lumboperitoneal shunt (n = 2) and only lumboperitoneal shunt (n = 1). The use of fibrin glue did not seem to significantly prevent the incidence of CSF leak in cases. CONCLUSIONS: Primary and meticulous dural closure is sine qua non in preventing postoperative CSF leak. A lumbar drain is a convenient and economical method of managing the problem initially failing which more invasive methods like re-exploration may be employed. PMID- 25038842 TI - Screening depression during and after pregnancy using the EPDS. PMID- 25038843 TI - Minimally invasive cystocele repair technique using a polypropylene mesh introduced with the transobturator route. AB - PURPOSE: Evaluation of the safety and efficacy of the use of polypropylene mesh for cystocele repair using minimally invasive technique. METHODS: We retrospectively evaluated the perioperative events, short-term postoperative side effects, and follow up for 152 patients who underwent repair for cystocele grade 2 or more using a polypropylene mesh. The repair was performed through a small anterior vaginal wall incision, with the arms of the mesh passed through a transobturator route using a corkscrew needle. Stress urinary incontinence (SUI) tests and the International Continence Society Pelvic Organ Prolapse Quantification (POP-Q) staging systems were documented before and after surgery. RESULTS: The average time and blood loss for the procedure were 18 min and 100 cc, respectively. Bladder injury and excess bleeding (>500 cc) occurred in one and two cases during the procedure, respectively. The early postoperative complications included pain (10.5 %), mesh erosion (1.3 %), fever (1.3 %), and urinary tract infection (7.9 %). Among the 122 patients who were followed up (median follow-up time, 18.2 months), the subjective and objective cure rates for the prolapse were 98 and 95 %, respectively. Complications during the follow up included mesh erosion (four cases) and persistent dyspareunia (four cases). CONCLUSIONS: Cystocele repair with mesh placement through transobturator route can be considered a minimally invasive, promising method for the correction of cystocele and SUI based on the low rate of complications, the high rate of success, and the low incidence of recurrence. PMID- 25038844 TI - An easy insertion procedure of Bakri balloon during cesarean section for placenta previa: use of Nelaton rubber catheter. PMID- 25038846 TI - What is hiding in the hindgut sac? Looking beyond rectal carcinoma. AB - OBJECTIVES: Although rectal cancer is by far and large the most common pathology involving the rectum that needs imaging, there are many other important but less common pathological conditions affecting anorectal region. The objective of this pictorial review is to discuss the cross-sectional imaging features of less common anorectal and perirectal diseases. RESULTS: Although a specific histological diagnosis cannot usually be made due to considerable overlap in the imaging appearances of anorectal diseases, this review illustrates the cross sectional imaging findings with emphasis on magnetic resonance imaging (MRI) that can help in narrowing down the differentials to a reasonable extent. TEACHING POINTS: * Variety of pathology exists in the anorectum apart from common rectal carcinoma * Anorectal diseases present as non-specific wall thickening indistinguishable from rectal carcinoma * Computed tomography (CT) and MRI can help in narrowing down the differentials, although often biopsy is warranted. PMID- 25038847 TI - Raman molecular imaging of brain frozen tissue sections. AB - Raman spectroscopy provides a molecular signature of the region being studied. It is ideal for neurosurgical applications because it is non-destructive, label free, not impacted by water concentration, and can map an entire region of tissue. The objective of this paper is to demonstrate the meaningful spatial molecular information provided by Raman spectroscopy for identification of regions of normal brain, necrosis, diffusely infiltrating glioma and solid glioblastoma (GBM). Five frozen section tissues (1 normal, 1 necrotic, 1 GBM, and 2 infiltrating glioma) were mapped in their entirety using a 300-um-square step size. Smaller regions of interest were also mapped using a 25-um step size. The relative concentrations of relevant biomolecules were mapped across all tissues and compared with adjacent hematoxylin and eosin-stained sections, allowing identification of normal, GBM, and necrotic regions. Raman peaks and peak ratios mapped included 1003, 1313, 1431, 1585, and 1659 cm(-1). Tissue maps identified boundaries of grey and white matter, necrosis, GBM, and infiltrating tumor. Complementary information, including relative concentration of lipids, protein, nucleic acid, and hemoglobin, was presented in a manner which can be easily adapted for in vivo tissue mapping. Raman spectroscopy can successfully provide label-free imaging of tissue characteristics with high accuracy. It can be translated to a surgical or laboratory tool for rapid, non-destructive imaging of tumor margins. PMID- 25038848 TI - Effect of neoadjuvant temozolomide upon volume reduction and resection of diffuse low-grade glioma. AB - Maximal safe resection is associated with prolonged survival in patients with low grade glioma (LGG). It has been suggested that neoadjuvant temozolomide may provide sufficient tumor shrinkage to facilitate aggressive surgical debulking. We examined the impact of temozolomide upon volume reduction and resectability of LGG. We retrospectively identified 20 adult patients with biopsy-proven, deemed not totally resectable LGGs, treated initially with temozolomide. Volumetric 3D (calculated from serial FLAIR images) and 2D tumor measurements were obtained prior to treatment and at 3 months post-treatment. The anticipated extent of resection (EOR) at the 2 time points was measured based on anatomical limitations, calculated as: [(total tumor volume - unresectable tumor volume)/total tumor volume] *100. Eloquent cortex, deep structures and corpus callosum were considered unresectable. Mean tumor volume was 68.4 cm(3) pre treatment and 49.5 cm(3) at 3 months post-treatment. The mean change from baseline to 3 months after treatment was -32.5 % (p < 0.001). Mean 2D pre treatment area was 28.6 and 23.3 cm(2) at 3 months post-treatment. The 2D change was also significant, with mean change of -17% (p < 0.001). 5% had partial response; 40% minor response; 45% stable disease; and 10% progressive disease by RANO criteria. Mean pre-treatment anticipated EOR was 67.2 and 71.5% at 3 months post-treatment. The mean change from baseline was 4.3% (p = 0.10). Our findings demonstrate significant volumetric and 2D reduction of LGG with temozolomide. Although this tumor shrinkage might facilitate radical surgical resection in some cases, our data failed to show statistically significant improvement in anticipated EOR. PMID- 25038845 TI - Spatiotemporal relationships between the abundance, distribution, and potential activities of ammonia-oxidizing and denitrifying microorganisms in intertidal sediments. AB - The primary objective of this study was to gain an understanding of how key microbial communities involved in nitrogen cycling in estuarine sediments vary over a 12-month period. Furthermore, we sought to determine whether changes in the size of these communities are related to, or indicative of, seasonal patterns in fixed nitrogen dynamics in Elkhorn Slough--a small, agriculturally impacted estuary with a direct connection to Monterey Bay. We assessed sediment and pore water characteristics, abundance of functional genes for nitrification (bacterial and archaeal amoA, encoding ammonia monooxygenase subunit A) and denitrification (nirS and nirK, encoding nitrite reductase), and measurements of potential nitrification and denitrification activities at six sites. No seasonality in the abundance of denitrifier or ammonia oxidizer genes was observed. A strong association between potential nitrification activity and the size of ammonia oxidizing bacterial communities was observed across the estuary. In contrast, ammonia-oxidizing archaeal abundances remained relatively constant in space and time. Unlike many other estuaries, salinity does not appear to regulate the distribution of ammonia-oxidizing communities in Elkhorn Slough. Instead, their distributions appear to be governed over two different time scales. Long-term niche characteristics selected for the gross size of archaeal and bacterial ammonia-oxidizing communities, yet covariation in their abundances between monthly samples suggests that they respond in a similar manner to short-term changes in their environment. Abundances of denitrifier and ammonia oxidizer genes also covaried, but site-specific differences in this relationship suggest differing levels of interaction (or coupling) between nitrification and denitrification. PMID- 25038849 TI - End of life care in high-grade glioma patients in three European countries: a comparative study. AB - Exploring cross-national differences is useful to evaluate whether different patterns of end of life (EOL) care meet patient's specific needs. This study aimed to (1) compare EOL care processes for high-grade glioma (HGG) patients in three European countries, (2) explore differences in perceived quality of care (QOC), and (3) identify aspects of good QOC in the EOL phase. We analyzed 207 questionnaires from relatives of deceased HGG patients, using a similar retrospective study design in three countries [The Netherlands (n = 83), Austria (n = 72) and the UK (n = 52)], and examined four subthemes: (1) organization of EOL care, (2) treatment preferences, (3) experiences with EOL care, (4) perceived QOC. Three months before death 75 % of patients were at home. In all countries, on average, 50 % were transferred to a hospital at least once and received effective symptom treatment during the last 3 months. In The Netherlands, Austria and UK, respectively, patients most often died at home (60 %), in a hospital (41 %) or hospice (41 %) (p < 0.001). Advance directives were present in 46 % of Dutch, 36 % of British and 6 % of Austrian patients (p < 0.001). Fifty-three percent of patients experienced good QOC, irrespective of country. Dying at the preferred place, satisfaction with information provided and effective symptom treatment were independently associated with good QOC. There are various cross national differences in organization and experiences with EOL care for HGG, but patient's perceived QOC is similar in the three countries. As symptom treatment was considered effective in only half of HGG patients, and independently predicted good QOC, this particularly needs further improvement in all countries. PMID- 25038850 TI - Chemical exchange saturation transfer MR imaging of Parkinson's disease at 3 Tesla. AB - OBJECTIVES: To demonstrate the feasibility of using chemical exchange saturation transfer (CEST) imaging to detect Parkinson's disease (PD) in patients at 3 Tesla. METHODS: Twenty-seven PD patients (17 men and 10 women; age range, 54-77 years) and 22 age-matched normal controls (13 men and 9 women; age range, 55-73 years) were examined on a 3-Tesla MRI system. Magnetization transfer spectra with 31 different frequency offsets (-6 to 6 ppm) were acquired at two transverse slices of the head, including the basal ganglia and midbrain. One-way analysis of variance tests was used to compare the differences in CEST imaging signals between PD patients and normal controls. RESULTS: Total CEST signal between the offsets of 0 and 4 ppm in the substantia nigra was significantly lower in PD patients than in normal controls (P = 0.006), which could be associated with the loss of dopaminergic neurons. Protein-based CEST imaging signals at the offset of 3.5 ppm in the globus pallidus, putamen and caudate were significantly increased in PD patients, compared to normal controls (P < 0.001, P = 0.003, P < 0.001, respectively). CONCLUSIONS: CEST imaging signals could potentially serve as imaging biomarkers to aid in the non-invasive molecular diagnosis of PD. KEY POINTS: * Total CEST signal in substantia nigra decreased in PD patients * Protein-based CEST signals in basal ganglia increased in PD patients * CEST could assist with the non-invasive molecular diagnosis for PD patients. PMID- 25038851 TI - Simple measurements on diffusion-weighted MR imaging for assessment of complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. AB - PURPOSE: To determine diagnostic performance of simple measurements on diffusion weighted MR imaging (DWI) for assessment of complete tumour response (CR) after neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC) by signal intensity (SI) and apparent diffusion coefficient (ADC) measurements. MATERIALS AND METHODS: Sixty-five patients with LARC who underwent neoadjuvant CRT and subsequent surgery were included. Patients underwent pre-CRT and post-CRT 3.0 T MRI. Regions of interest of the highest brightness SI were included in the tumour volume on post-CRT DWI to calculate the SIlesion, rSI, ADClesion and rADC; diagnostic performance was compared by using the receiver operating characteristic (ROC) curves. In order to validate the accuracy and reproducibility of the current strategy, the same procedure was reproduced in 80 patients with LARC at 1.5 T MRI. RESULTS: Areas under the ROC curve for identification of a CR, based on SIlesion, rSI, ADClesion, and rADC, respectively, were 0.86, 0.94, 0.66, and 0.71 at 3.0 T MRI, and 0.92, 0.91, 0.64, and 0.61 at 1.5 T MRI. CONCLUSION: Post-CRT DWI SIlesion and rSI provided high diagnostic performance in assessing CR and were significantly more accurate than ADClesion, and rADC at 3.0 T MRI and 1.5 T MRI. KEY POINTS: * Signal intensity (SI lesion ) and rSI are accurate for assessment of complete response. * rSI seems to be superior to SI lesion at 3.0 T MRI. * ADC or rADC measurements are not accurate for assessment of complete response. PMID- 25038852 TI - "Black Bone" MRI: a potential alternative to CT with three-dimensional reconstruction of the craniofacial skeleton in the diagnosis of craniosynostosis. AB - OBJECTIVES: To determine the potential of novel gradient echo parameters, "Black Bone" MRI as an alternative to CT in the identification of normal and prematurely fused cranial sutures both in 2D and 3D imaging. METHODS: Thirteen children with a clinical diagnosis of craniosynostosis underwent "Black Bone" MRI in addition to routine cranial CT. "Black Bone" datasets were compared to CT and clinical findings. "Black Bone" imaging was subsequently used to develop 3D reformats of the craniofacial skeleton to enhance further visualisation of the cranial sutures. RESULTS: Patent cranial sutures were consistently identified on "Black Bone" MRI as areas of increased signal intensity. In children with craniosynostosis the affected suture was absent, whilst the remaining patent sutures could be visualised, consistent with CT and clinical findings. Segmentation of the "Black Bone" MRI datasets was successful with both threshold and volume rendering techniques. The cranial sutures, where patent, could be visualised throughout their path. CONCLUSIONS: Patent cranial sutures appear as areas of increased signal intensity on "Black Bone" MRI distinct from the cranial bone, demonstrating considerable clinical potential as a non-ionising alternative to CT in the diagnosis of craniosynostosis. KEY POINTS: * Patent cranial sutures appear hyperintense on "Black Bone" MRI * Prematurely fused cranial sutures are distinct from patent sutures * Minimal soft tissue contrast permits 3D-rendered imaging of the craniofacial skeleton. PMID- 25038853 TI - Emphysema progression is visually detectable in low-dose CT in continuous but not in former smokers. AB - OBJECTIVES: To evaluate interobserver agreement and time-trend in chest CT assessment of emphysema, airways, and interstitial abnormalities in a lung cancer screening cohort. METHODS: Visual assessment of baseline and fifth-year examination of 1990 participants was performed independently by two observers. Results were standardised by means of an electronic score sheet; kappa and time trend analyses were performed. RESULTS: Interobserver agreement was substantial in early emphysema diagnosis; highly significant (p < 0.001) time-trends in both emphysema presence and grading were found (higher prevalence and grade of emphysema in late CT examinations). Significant progression in emphysema was seen in continuous smokers, but not in former smokers. Agreement on centrilobular emphysema subtype was substantial; agreement on paraseptal subtype, moderate. Agreement on panlobular and mixed subtypes was only fair. Agreement was fair regarding airway analysis. Interstitial abnormalities were infrequent in the cohort, and agreement on these was fair to moderate. A highly significant time trend was found regarding interstitial abnormalities, which were more frequent in late examinations. CONCLUSIONS: Visual scoring of chest CT is able to characterise the presence, pattern, and progression of early emphysema. Continuous smokers progress; former smokers do not. KEY POINTS: * Substantial interobserver consistency in determining early-stage emphysema in low-dose CT. * Longitudinal analyses show clear time-trends for emphysema presence and grading. * For continuous smokers, progression of emphysema was seen in all lung zones. * For former smokers, progression of emphysema was undetectable by visual assessment. * Onset and progression of interstitial abnormalities are visually detectable. PMID- 25038854 TI - Diffusion-weighted MR imaging for the diagnosis of abscess complicating fistula in-ano: preliminary experience. AB - OBJECTIVE: To investigate the role of diffusion-weighted magnetic resonance imaging (DWMRI) in the diagnosis of abscess-complicating fistula-in-ano. METHODS: This retrospective study was approved by our Institutional Review Board and informed consent was waived. MRI examinations, including fat-suppressed T2 weighted turbo spin-echo (T2-TSE) MRI and DWMRI, of 24 patients with a fistula-in ano, were reviewed by two independent readers for the presence and number of visible fistulas, conspicuity and apparent diffusion coefficient (ADC) measurement of suspected fistula tracks and pelvic collections. The reference standard was surgical with follow-up findings. RESULTS: Sensitivity was 91.2 % [95 % CI: 76 %-98 %] for T2-weighted TSE MRI and 100 % [95 % CI: 90 %-100 %] for DWMRI detecting fistulas. ADC values were lower in abscesses than in inflammatory masses (P = 0.714.10(-6)). The area under the ROC curve was 0.971 and the optimal cut-off ADC value was 1.186 * 10(-3) mm(2)/s, yielding a sensitivity of 100 % [95 % CI: 77 %-100 %], a specificity of 90 % [95 % CI: 66 %-100 %], a positive predictive value of 93 % [95 % CI: 82.8 %-100 %] and a negative predictive value of 90 % [95 % CI: 78 %-100 %] for an abscess diagnosis. Fistula conspicuity was greater with DWMRI than with T2-TSE MRI for the two observers (P = 0.0034 and P = 0.0007). CONCLUSION: DWMRI shows high sensitivity and specificity for the diagnosis of perianal abscesses and helps discriminate between an abscess and inflammatory mass. Conspicuity of fistulas-in-ano is greater with DWMRI than with T2-weighted TSE MRI. KEY POINTS: * DWMRI can differentiate between pelvic abscess and inflammatory mass. * DWMRI helps avoid gadolinium-chelate administration in patients with a suspected fistula-in-ano. * DWMRI provides high degrees of conspicuity for fistula-in-ano. * Conspicuity of fistulas is better with DWMRI imaging than with T2-TSE-weighted MRI. PMID- 25038855 TI - High temporal versus high spatial resolution in MR quantitative pulmonary perfusion imaging of two-year old children after congenital diaphragmatic hernia repair. AB - OBJECTIVES: Congenital diaphragmatic hernia (CDH) leads to lung hypoplasia. Using dynamic contrast-enhanced (DCE) MR imaging, lung perfusion can be quantified. As MR perfusion values depend on temporal resolution, we compared two protocols to investigate whether ipsilateral lung perfusion is impaired after CDH, whether there are protocol-dependent differences, and which protocol is preferred. METHODS: DCE-MRI was performed in 36 2-year old children after CDH on a 3 T MRI system; protocol A (n = 18) based on a high spatial (3.0 s; voxel: 1.25 mm(3)) and protocol B (n = 18) on a high temporal resolution (1.5 s; voxel: 2 mm(3)). Pulmonary blood flow (PBF), pulmonary blood volume (PBV), mean transit time (MTT), and peak-contrast-to-noise-ratio (PCNR) were quantified. RESULTS: PBF was reduced ipsilaterally, with ipsilateral PBF of 45 +/- 26 ml/100 ml/min to contralateral PBF of 63 +/- 28 ml/100 ml/min (p = 0.0016) for protocol A; and for protocol B, side differences were equivalent (ipsilateral PBF = 62 +/- 24 vs. contralateral PBF = 85 +/- 30 ml/100 ml/min; p = 0.0034). PCNR was higher for protocol B (30 +/- 18 vs. 20 +/- 9; p = 0.0294). Protocol B showed higher values of PBF in comparison to protocol A (p always <0.05). CONCLUSIONS: Ipsilateral lung perfusion is reduced in 2-year old children following CDH repair. Higher temporal resolution and increased voxel size show a gain in PCNR and lead to higher perfusion values. Protocol B is therefore preferred. KEY POINTS: * Quantitative lung perfusion parameters depend on temporal and spatial resolution. * Reduction of lung perfusion in CDH can be measured with different MR protocols. * Temporal resolution of 1.5 s with spatial resolution of 2 mm (3) is suitable. PMID- 25038856 TI - In vivo high-resolution magnetic resonance elastography of the uterine corpus and cervix. AB - OBJECTIVES: To apply 3D multifrequency MR elastography (3DMMRE) to the uterus and analyse the viscoelasticity of the uterine tissue in healthy volunteers considering individual variations and variations over the menstrual cycle. METHODS: Sixteen healthy volunteers participated in the study, one of whom was examined 12 times over two menstrual cycles. Pelvic 3DMMRE was performed on a 1.5 T scanner with seven vibration frequencies (30-60 Hz) using a piezoelectric driver. Two mechanical parameter maps were obtained corresponding to the magnitude (|G (*) |) and the phase angle (phi) of the complex shear modulus. RESULTS: On average, the uterine corpus had higher elasticity, but similar viscosity compared with the cervix, reflected by |G (*) |uterine corpus = 2.58 +/ 0.52 kPa vs. |G (*) |cervix = 2.00 +/- 0.34 kPa (p < 0.0001) and phi uterine corpus = 0.54 +/- 0.08, phi cervix = 0.57 +/- 0.12 (p = 0.428). With 2.23 +/- 0.26 kPa, |G (*) | of the myometrium was lower in the secretory phase (SP) compared with that of the proliferative phase (PP, |G (*) | = 3.01 +/- 0.26 kPa). For the endometrium, the value of |G (*) | in SP was 68% lower than during PP (PP, |G (*) | = 3.34 +/- 0.42 kPa; SP, |G (*) | = 1.97 +/- 0.34 kPa; p = 0.0061). CONCLUSION: 3DMMRE produces high-resolution mechanical parameter maps of the uterus and cervix and shows sensitivity to structural and functional changes of the endometrium and myometrium during the menstrual cycle. KEY POINTS: MR elastography provided for the first time spatially resolved viscoelasticity maps of uterus. Uterine corpus had a higher elasticity, but similar viscosity compared with cervix. The stiffness of both endometrium and myometrium decreases during the menstrual cycle. PMID- 25038857 TI - Persistent pulmonary subsolid nodules: model-based iterative reconstruction for nodule classification and measurement variability on low-dose CT. AB - OBJECTIVES: To compare the pulmonary subsolid nodule (SSN) classification agreement and measurement variability between filtered back projection (FBP) and model-based iterative reconstruction (MBIR). METHODS: Low-dose CTs were reconstructed using FBP and MBIR for 47 patients with 47 SSNs. Two readers independently classified SSNs into pure or part-solid ground-glass nodules, and measured the size of the whole nodule and solid portion twice on both reconstruction algorithms. Nodule classification agreement was analyzed using Cohen's kappa and compared between reconstruction algorithms using McNemar's test. Measurement variability was investigated using Bland-Altman analysis and compared with the paired t-test. RESULTS: Cohen's kappa for inter-reader SSN classification agreement was 0.541-0.662 on FBP and 0.778-0.866 on MBIR. Between the two readers, nodule classification was consistent in 79.8 % (75/94) with FBP and 91.5 % (86/94) with MBIR (p = 0.027). Inter-reader measurement variability range was -5.0-2.1 mm on FBP and -3.3-1.8 mm on MBIR for whole nodule size, and was -6.5-0.9 mm on FBP and -5.5-1.5 mm on MBIR for solid portion size. Inter reader measurement differences were significantly smaller on MBIR (p = 0.027, whole nodule; p = 0.011, solid portion). CONCLUSIONS: MBIR significantly improved SSN classification agreement and reduced measurement variability of both whole nodules and solid portions between readers. KEY POINTS: * Low-dose CT using MBIR algorithm improves reproducibility in the classification of SSNs. * MBIR would enable more confident clinical planning according to the SSN type. * Reduced measurement variability on MBIR allows earlier detection of potentially malignant nodules. PMID- 25038858 TI - CT volumetry for gastric carcinoma: association with TNM stage. AB - OBJECTIVES: We evaluated the feasibility of performing CT volumetry of gastric carcinoma (GC) and its correlation with TNM stage. METHODS: This institutional review board-approved retrospective study was performed on 153 patients who underwent a staging CT study for histologically confirmed GC. CT volumetry was performed by drawing regions of interest including abnormal thickening of the stomach wall. Reproducibility of tumour volume (Tvol) between two readers was assessed. Correlation between Tvol and TNM/peritoneal staging derived from histology/surgical findings was evaluated using ROC analysis and compared with CT evaluation of TNM/peritoneal staging. RESULTS: Tvol was successfully performed in all patients. Reproducibility among readers was excellent (r = 0.97; P = 0.0001). The median Tvol of GC showed an incremental trend with T-stage (T1 = 27 ml; T2 = 32 ml; T3 = 53 ml and T4 = 121 ml, P < 0.01). Tvol predicted with good accuracy T stage (>=T2:0.95; >=T3:0.89 and T4:0.83, P = 0.0001), M-stage (0.87, P = 0.0001), peritoneal metastases (0.87, P = 0.0001) and final stage (>=stage 2:0.89; >=stage 3:0.86 and stage 4:0.87, P = 0.0001), with moderate accuracy for N-stage (>=N1:0.75; >=N2:0.74 and N3:0.75, P = 0.0001). Tvol was significantly (P < 0.05) more accurate than standard CT staging for prediction of T-stage, N3-stage, M stage and peritoneal metastases. CONCLUSION: CT volumetry may provide useful adjunct information for preoperative staging of GC. KEY POINTS: CT volumetry of gastric carcinoma is feasible and reproducible. Tumour volume <19.4 ml predicts T1-stage gastric cancer with 91% sensitivity and 100% specificity (P = 0.0001). Tumour volume >95.7 ml predicts metastatic gastric cancer with 87% sensitivity and 78.5% specificity (P = 0.0001). CT volumetry may be a useful adjunct for staging gastric carcinoma. PMID- 25038859 TI - Next generation coronary CT angiography: in vitro evaluation of 27 coronary stents. AB - OBJECTIVES: To evaluate in-stent lumen visibility of 27 modern and commonly used coronary stents (16 individual stent types, two stents at six different sizes each) utilising a third-generation dual-source CT system. METHODS: Stents were implanted in a plastic tube filled with contrast. Examinations were performed parallel to the system's z-axis for all stents (i.e. 0 degrees ) and in an orientation of 90 degrees for stents with a diameter of 3.0 mm. Two stents were evaluated in different diameters (2.25 to 4.0 mm). Examinations were acquired with a collimation of 96 * 0.6 mm, tube voltage of 120 kVp with 340 mAs tube current. Evaluation was performed using a medium-soft (Bv40), a medium-sharp (Bv49) and a sharp (Bv59) convolution kernel optimised for vascular imaging. RESULTS: Mean visible stent lumen of stents with 3.0 mm diameter ranged from 53.3 % (IQR 48.9 - 56.7 %) to 73.9 % (66.7 - 76.7 %), depending on the kernel used at 0 degrees , and was highest at an orientation of 90 degrees with 80.0 % (75.6 - 82.8 %) using the Bv59 kernel, strength 4. Visible stent lumen declined with decreasing stent size. CONCLUSIONS: Use of third-generation dual-source CT enables stent lumen visibility of up to 80 % in metal stents and 100 % in bioresorbable stents. KEY POINTS: * Blooming artefacts impair in-stent lumen visibility of coronary stents in CT angiography. * CT enables stent lumen visibility of up to 80 % in metal stents. * Stent lumen visibility varies with stent orientation and size. * CT angiography may be a valid alternative for detecting in-stent restenosis. PMID- 25038860 TI - Thyroid nodules with initially non-diagnostic, fine-needle aspiration results: comparison of core-needle biopsy and repeated fine-needle aspiration. AB - OBJECTIVE: To evaluate the role of core-needle biopsy (CNB) by comparing the results of CNB and repeated fine-needle aspiration (FNA) for thyroid nodules with initially non-diagnostic FNA results. METHODS: From October 2008 to December 2011, 360 nodules - 180 consecutive repeated FNAs and 180 consecutive CNBs -- from 360 patients (83 men, 277 women; mean age, 54.4 years) with initially non diagnostic FNA results were analyzed retrospectively. The incidence of non diagnostic results, inconclusive results, diagnostic surgery, and diagnostic performance of repeated FNA and CNB were assessed, and factors affecting second non-diagnostic results were evaluated. RESULTS: CNB achieved a significantly lower non-diagnostic and inconclusive rate than repeated FNA (1.1 % versus 40.0 %, P < 0.001; 7.2 % versus 72.0 %, P < 0.001). All diagnostic performances with CNB were higher than repeated FNA. The diagnostic surgery rate was lower with CNB than with repeated FNA (3.6 % versus 16.7 %, P = 0.047). Multivariate logistic regression analysis showed that repeated FNA was the most important factor for second non-diagnostic results (OR = 56.06, P < 0.001), followed by nodules with rim calcification (OR = 7.46, P = 0.003). CONCLUSIONS: CNB is more useful than repeated FNA for reducing the number of non-diagnostic and inconclusive results and for preventing unnecessary diagnostic surgery for thyroid nodules with initially non-diagnostic FNA results. KEY POINTS: * Core-needle biopsy achieved a lower number of non-diagnostic and inconclusive results. * Core-needle biopsy achieved better diagnostic performance. * Use of core-needle biopsy could prevent unnecessary diagnostic surgery. * Repeated fine-needle aspiration was significantly associated with a second non-diagnosis. PMID- 25038861 TI - DTI for the assessment of disease stage in patients with glomerulonephritis- correlation with renal histology. AB - OBJECTIVES: To investigate whether DTI allows assessment of renal impairment and pathology in patients with chronic glomerulonephritis. MATERIALS AND METHODS: Seventy-five patients and 20 healthy volunteers were enrolled in this study. Renal function and kidney biopsies were evaluated. For DTI, a respiratory triggered coronal EPI sequence was performed (TR, 1400 ms; TE, 76 ms; diffusion direction, 6; NEX, 4; b values, 0 and 600 s/mm2; slices thickness, 6 mm, with no intersection gap). Renal ADC and FA values were calculated and compared between the groups. Correlations between ADC/FA and histopathology were evaluated. RESULTS: ADC values decreased with increased stages. ADC differences in renal parenchyma at different disease stages were found, with the exception of the control group compared with stage 1 patients; similar results were obtained for FA. ADC values in the cortex and medulla in stage 1-3 patients were both statistically different, similar to the FA values. A significant negative correlation was found between the percentage of glomerulosclerosis and FA in the renal cortex (r = -0.74), similar to the degree of tubulointerstitial fibrosis with FA in the medulla (r = -0.76). CONCLUSIONS: ADC and FA values are correlated with the degree of renal impairment, the percentage of glomerulosclerosis, and area of interstitial fibrosis. KEY POINTS: * DTI can be used to assess renal function impairment in patients with chronic glomerulonephritis. * ADC and FA values were correlated with tubulointerstitial fibrosis and glomerulosclerosis. * Identification of renal impairment is helpful for timely treatment. * DTI can be used for non-invasive assessment of renal pathology. PMID- 25038862 TI - Management of dural carotid cavernous fistulas: a single-centre experience. AB - OBJECTIVES: To report the epidemiological features, clinical presentation, angiographic characteristics and therapeutic options, success and complication rates in patients with dural carotid cavernous fistulas (dural CCFs). METHODS: Retrospective evaluation of patients followed in our institution between January of 2005 and September of 2013. RESULTS: There were 38 patients, 76 % females, with an average age of 63 years. Ocular symptoms and signs were the most frequent clinical findings. Dural CCFs were Barrow type B in 8%, type C in 10% and type D in 82%. Cortical venous reflux was present in 50% of cases. Medical treatment was performed in 16% of patients, external ocular compression in 8%, transarterial embolisation in 13%, transvenous embolisation in 60% and radiosurgery in 3%. Clinical and angiographic follow-up data were available in 89% and 82% of patients with a mean follow-up time of 9 and 7 months, respectively. Clinical cure was achieved in 58% of patients and improvement in 24%. Anatomical cure was demonstrated in 68%. Transient worsening or new onset of ocular symptoms was observed in 29%. There was no permanent morbidity or mortality. CONCLUSIONS: In properly selected patients, endovascular embolisation, particularly by transvenous approach, represents a safe and effective treatment for dural CCFs. KEY POINTS: Dural carotid cavernous fistulas are more common in elderly women. Dural CCFs most commonly present with ocular symptoms and signs. Endovascular treatment is effective and safe in properly selected patients. PMID- 25038863 TI - Molecular population genetics of the NADPH cytochrome P450 reductase (CPR) gene in Anopheles minimus. AB - Development of insecticide resistance (IR) in mosquito vectors is a primary huddle to malaria control program. Since IR has genetic basis, and genes constantly evolve with response to environment for adaptation to organisms, it is important to know evolutionary pattern of genes conferring IR in malaria vectors. The mosquito Anopheles minimus is a major malaria vector of the Southeast (SE) Asia and India and is susceptible to all insecticides, and thus of interest to know if natural selection has shaped variations in the gene conferring IR. If not, the DNA fragment of such a gene could be used to infer population structure and demography of this species of malaria vector. We have therefore sequenced a ~569 bp DNA segment of the NADPH cytochrome P450 reductase (CPR) gene (widely known to confer IR) in 123 individuals of An. minimus collected in 10 different locations (eight Indian, one Thai and one Vietnamese). Two Indian population samples were completely mono-morphic in the CPR gene. In general, low genetic diversity was found with no evidence of natural selection in this gene. The data were therefore analyzed to infer population structure and demography of this species. The 10 populations could be genetically differentiated into four different groups; the samples from Thailand and Vietnam contained high nucleotide diversity. All the 10 populations conform to demographic equilibrium model with signature of past population expansion in four populations. The results in general indicate that the An. minimus mosquitoes sampled in the two SE Asian localities contain several genetic characteristics of being parts of the ancestral population. PMID- 25038864 TI - Genetic structure in the Amazonian catfish Brachyplatystoma rousseauxii: influence of life history strategies. AB - The Dorado or Plateado (Gilded catfish) Brachyplatystoma rousseauxii (Pimelodidae, Siluriformes) is a commercially valuable migratory catfish performing the largest migration in freshwaters: from the Amazonian headwaters in the Andean foothills (breeding area) to the Amazon estuary (nursery area). In spite of its importance to inform management and conservation efforts, the genetic variability of this species has only recently begun to be studied. The aim of the present work was to determine the population genetic structure of B. rousseauxii in two regions: the Upper Madera Basin (five locations in the Bolivian Amazon) and the Western Amazon Basin (one regional sample from the Uyucali-Napo-Maranon-Amazon basin, Peru). Length polymorphism at nine microsatellite loci (284 individuals) was used to determine genetic variability and to identify the most probable panmictic units (using a Bayesian approach), after a significant departure from Hardy-Weinberg equilibrium was observed in the overall dataset (Western Amazon + Upper Madera). Bayesian analyses revealed at least three clusters in admixture in the five locations sampled in the Bolivian Amazon, whereas only two of these clusters were observed in the Western Amazon. Considering the migratory behaviour of B. rousseauxii, different life history strategies, including homing, are proposed to explain the cluster distribution. Our results are discussed in the light of the numerous threats to the species survival in the Madera basin, in particular dam and reservoir construction. PMID- 25038865 TI - Breaking through the stress barrier: the role of BolA in Gram-negative survival. AB - The morphogene bolA plays a significant role in the adaptation of Escherichia coli to general stresses. In general, bacteria can thrive and persist under harsh conditions, counteracting external stresses by using varied mechanisms, including biofilm formation, changes in cell shape, size and protein content, together with alterations in the cell wall structure, thickness and permeability. In E. coli, an increased expression of bolA occurs mainly under stress challenges and when bacterial morphology changes from rod-like to spherical. Moreover, BolA is able to induce biofilm formation and changes in the outer membrane, making it less permeable to harmful agents. Although there has been substantial progress in the description of BolA activity, its role on global cell physiology is still incomplete. Proteins with strong homology to BolA have been found in most living organisms, in many cases also exerting a regulatory role. In this review we summarize current knowledge on the role of BolA, mainly in E. coli, and discuss its implication in global regulation in relation to stress. PMID- 25038866 TI - Estradiol increases cAMP in the oviductal secretory cells through a nongenomic mechanism. AB - In the rat oviduct, estradiol (E2) accelerates egg transport by a nongenomic action that requires previous conversion of E2 to methoxyestrogens via catechol-O methyltranferase (COMT) and activation of estrogen receptor (ER) with subsequent production of cAMP and inositol triphosphate (IP3). However, the role of the different oviductal cellular phenotypes on this E2 nongenomic pathway remains undetermined. The aim of this study was to investigate the effect of E2 on the levels of cAMP and IP3 in primary cultures of secretory and smooth muscle cells from rat oviducts and determine the mechanism by which E2 increases cAMP in the secretory cells. In the secretory cells, E2 increased cAMP but not IP3, while in the smooth muscle cells E2 decreased cAMP and increased IP3. Suppression of protein synthesis by actinomycin D did not prevent the E2-induced cAMP increase, but this was blocked by the ER antagonist ICI 182 780 and the inhibitors of COMT OR 486, G protein-alpha inhibitory (Galphai) protein pertussis toxin and adenylyl cyclase (AC) SQ 22536. Expression of the mRNA for the enzymes that metabolizes estrogens, Comt, Cyp1a1, and Cyp1b1 was found in the secretory cells, but this was not affected by E2. Finally, confocal immunofluorescence analysis showed that E2 induced colocalization between ESR1 (ERalpha) and Galphai in extranuclear regions of the secretory cells. We conclude that E2 differentially regulates cAMP and IP3 in the secretory and smooth muscle cells of the rat oviduct. In the secretory cells, E2 increases cAMP via a nongenomic action that requires activation of COMT and ER, coupling between ESR1 and Galphai, and stimulation of AC. PMID- 25038867 TI - Ketamine administration in depressive disorders: a systematic review and meta analysis. AB - INTRODUCTION: Ketamine's efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine's effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment. METHODS: Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic. RESULTS: We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = -0.99; 95 % CI 1.23, -0.75; p < 0.01). Ketamine's efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = -0.91; 95 % CI -1.19,-0.64; p < 0.01), in bipolar depression (SMD = -1.34; 95 % CI -1.94, -0.75), and in drug free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = -0.56; 95 % CI -1.10, -0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine's effects was assessed in only two non-ECT studies and seemed to persist for 2-3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine's use should remain cautious in patients with a cardiovascular history. CONCLUSION: The present meta-analysis confirms ketamine's efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy. PMID- 25038868 TI - Effects of desipramine treatment on stress-induced up-regulation of norepinephrine transporter expression in rat brains. AB - RATIONALE: Many studies demonstrate down-regulation of the norepinephrine transporter (NET) by desipramine (DMI) in vitro and in stress-naive rats. Little is known regarding regulation of the NET in stressed animals. OBJECTIVE: The present study was designed to investigate effects of DMI on the expression of NET and protein kinases in the stress rat. METHODS: Adult Fischer 344 rats were subjected to chronic social defeat (CSD) for 4 weeks. DMI (10 mg/kg, intraperitoneal (i.p.)) was administered concurrently with CSD or 1 or 2 weeks after cessation of CSD. Sucrose consumption, NET expression, and protein kinases were measured. RESULTS: CSD significantly increased messenger RNA (mRNA) and protein levels of NET in the locus coeruleus, as well as NET protein levels in the hippocampus, frontal cortex, and amygdala. These effects were nearly abolished when DMI was administered concurrently with CSD. CSD-induced up regulation of NET expression in the locus coeruleus, hippocampus, and amygdala lasted at least 2 weeks after cessation of CSD, an effect that was significantly attenuated by 1 or 2 weeks of DMI treatment starting from cessation of the CSD. Concurrent administration of DMI with CSD did not markedly interfere with CSD induced decreases in protein levels of protein kinases A and C in these brain regions, but it did reverse the CSD-induced reduction in phosphorylated cAMP response element-binding (pCREB) protein levels in most brain regions. CONCLUSION: These findings suggest that NET regulation by DMI occurs in both stressed and behaviorally naive rats, and DMI-induced changes in pCREB may be involved. PMID- 25038869 TI - Time-course of extracellular nicotine and cotinine levels in rat brain following administration of nicotine: effects of route and ethanol coadministration. AB - RATIONALE: Nicotine and ethanol are commonly coabused drugs, and nicotine-laced ethanol products are growing in popularity. However, little is known about time course changes in extracellular nicotine and cotinine levels in rat models of ethanol and nicotine coabuse. OBJECTIVES: The objective of the present study was to determine the time-course changes in brain levels of nicotine and cotinine following subcutaneous (SC) and intragastric (IG) nicotine administration in alcohol-preferring (P) and Wistar rats. METHODS: In vivo microdialysis was used to collect dialysate samples from the nucleus accumbens shell (NACsh) for nicotine and cotinine determinations, following SC administration of (-)-nicotine (0.18, 0.35, and 0.70 mg/kg) in female P and Wistar rats or IG administration of (-)-nicotine (0.35 and 0.70 mg/kg) in 15 % (v/v) ethanol or water in female P rats. RESULTS: SC nicotine produced nicotine and cotinine dialysate levels as high as 51 and 14 ng/ml, respectively. IG administration of 15 % EtOH + 0.70 mg/kg nicotine in P rats resulted in maximal nicotine and cotinine dialysate levels of 19 and 14 ng/ml, respectively, whereas administration of 0.70 mg/kg nicotine in water resulted in maximal nicotine and cotinine levels of 21 and 25 ng/ml, respectively. Nicotine and cotinine levels were detectable within the first 15 and 45 min, respectively, after IG administration. CONCLUSIONS: Overall, the results of this study suggest that nicotine is rapidly adsorbed and produces relevant extracellular brain concentrations of nicotine and its pharmacologically active metabolite, cotinine. The persisting high brain concentrations of cotinine may contribute to nicotine addiction. PMID- 25038870 TI - Delta-9-tetrahydrocannabinol, neural oscillations above 20 Hz and induced acute psychosis. AB - RATIONALE: An acute challenge with delta-9-tetrahydrocannabinol (THC) can induce psychotic symptoms including delusions. High electroencephalography (EEG) frequencies, above 20 Hz, have previously been implicated in psychosis and schizophrenia. OBJECTIVES: The objective of this study is to determine the effect of intravenous THC compared to placebo on high-frequency EEG. METHODS: A double blind cross-over study design was used. In the resting state, the high-beta to low-gamma magnitude (21-45 Hz) was investigated (n = 13 pairs + 4 THC only). Also, the event-related synchronisation (ERS) of motor-associated high gamma was studied using a self-paced button press task (n = 15). RESULTS: In the resting state, there was a significant condition * frequency interaction (p = 0.00017), consisting of a shift towards higher frequencies under THC conditions (reduced high beta [21-27 Hz] and increased low gamma [27-45 Hz]). There was also a condition * frequency * location interaction (p = 0.006), such that the reduction in 21-27-Hz magnitude tended to be more prominent in anterior regions, whilst posterior areas tended to show greater 27-45-Hz increases. This effect was correlated with positive symptoms, as assessed on the Positive and Negative Syndrome Scale (PANSS) (r = 0.429, p = 0.042). In the motor task, there was a main effect of THC to increase 65-130-Hz ERS (p = 0.035) over contra-lateral sensorimotor areas, which was driven by increased magnitude in the higher, 85-130 Hz band (p = 0.02) and not the 65-85-Hz band. CONCLUSIONS: The THC-induced shift to faster gamma oscillations may represent an over-activation of the cortex, possibly related to saliency misattribution in the delusional state. PMID- 25038871 TI - Dopamine precursors depletion impairs impulse control in healthy volunteers. AB - The aim of the present study was to decipher the role of the dopamine system in impulse control. Impulsive actions entail (i) activation of the motor system by an impulse, which is an urge to act and (ii) a failure to suppress that impulse, when inappropriate, in order to prevent an error. These two aspects of action impulsivity can be experimentally disentangled in conflict reaction time tasks such as the Simon task, which measures susceptibility to acting on spontaneous impulses (as well as the proficiency of suppressing these impulses). In 12 healthy volunteers performing a Simon task, dopamine availability was reduced with an amino acid drink deficient in the dopamine precursors, phenylalanine and tyrosine. Classic behavioral measures were augmented with an analysis of the electromyographic activity of the response effectors. Electromyography allows one to detect covert activations undetectable with strictly behavioral measures and further reveals the participants' ability to quickly suppress covert activations before they result in an overt movement. Following dopamine depletion, compared with a placebo condition, participants displayed comparable impulse activation but were less proficient at suppressing the interference from this activation. These results provide evidence that the dopamine system is directly involved in the suppression of maladaptive response impulses. PMID- 25038872 TI - Role of vacuolating cytotoxin VacA and cytotoxin-associated antigen CagA of Helicobacter pylori in the progression of gastric cancer. AB - Helicobacter (H.) pylori strains that express the cagA and s1a vacA genes are associated with an increased risk for gastric cancer. Here, we examined the association between the products of these virulence genes with the development of gastric cancer by immunohistochemical staining of gastric biopsy specimens taken from 208 routine gastroscopies and 43 gastric cancer patients. The correlation was analyzed by multivariate logistic regression. CagA and VacA expressions in gastric mucosa were significantly associated with chronic gastritis (CG) and intestinal metaplasia (IM), respectively, accompanying CG independent of age. The association of CagA expression with IM accompanying CG was increased in patients over 50-year old (p < 0.01) and that of VacA with CG was significant in patients younger than 50 year (p < 0.05). VacA and CagA were associated with mild IM incidence (p = 0.025 and p = 0.076, respectively) but not advanced IM. In the 43 gastric cancer patients, positivity for VacA was significantly higher in cases of CG and IM than carcinoma (p = 0.042), while that for CagA was slightly higher for individuals with carcinoma than those with CG and IM. These results indicate that CagA and VacA are critical factors for inducing CG and the subsequent progression of IM from CG with an increasing age. PMID- 25038873 TI - Time- and frequency-domain parameters of heart rate variability and sympathetic skin response in Parkinson's disease. AB - The autonomic nervous system (ANS) is regularly affected in Parkinson's disease (PD). Information on autonomic dysfunction can be derived from e.g. altered heart rate variability (HRV) and sympathetic skin response (SSR). Such parameters can be quantified easily and measured repeatedly which might be helpful for evaluating disease progression and therapeutic outcome. In this 2-center study, HRV and SSR of 45 PD patients and 26 controls were recorded. HRV was measured during supine metronomic breathing and analyzed in time- and frequency-domains. SSR was evoked by repetitive auditory stimulation. Various ANS parameters were compared (1) between patients and healthy controls, (2) to clinical scales (Unified Parkinson's disease rating scale, Mini-Mental State Examination, Becks Depression Inventory), and (3) to disease duration. Root mean square of successive differences (RMSSD) and low frequency/high frequency (LF/HF) ratio differed significantly between PD and controls. Both, HRV and SSR parameters showed low or no association with clinical scores. Time-domain parameters tended to be affected already at early PD stages but did not consistently change with longer disease duration. In contrast, frequency-domain parameters were not altered in early PD phases but tended to be lower (LF, LF/HF ratio), respectively higher (HF) with increasing disease duration. This report confirms previous results of altered ANS parameters in PD. In addition, it suggests that (1) these ANS parameters are not relevantly associated with motor, behavioral, and cognitive changes in PD, (2) time-domain parameters are useful for the assessment of early PD, and (3) frequency-domain parameters are more closely associated with disease duration. PMID- 25038874 TI - HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. AB - BACKGROUND: In the Trastuzumab for GAstric cancer (ToGA) study, trastuzumab plus chemotherapy improved median overall survival by 2.7 months in patients with human epidermal growth factor receptor 2 (HER2)-positive [immunohistochemistry (IHC) 3+/fluorescence in situ hybridization-positive] gastric/gastroesophageal junction cancer compared with chemotherapy alone (hazard ratio 0.74). Post hoc exploratory analyses in patients expressing higher HER2 levels (IHC 2+/fluorescence in situ hybridization-positive or IHC 3+) demonstrated a 4.2 month improvement in median overall survival with trastuzumab (hazard ratio 0.65). The ToGA study provides the largest screening dataset available on HER2 overexpression/amplification in this indication. We further analyzed correlation(s) of HER2 overexpression/amplification with clinical and epidemiological factors. METHODS: HER2-positivity was analyzed by histological subtype, tumor location, geographic region, and specimen type. Exploratory efficacy analyses were performed. RESULTS: The HER2-positivity rate was 22.1 % across analyzed tumor samples. Rates were similar between European and Asian patients (23.6 % vs. 23.9 %), but higher in intestinal- vs. diffuse-type (31.8 % vs. 6.1 %), and gastroesophageal junction cancer versus gastric tumors (32.2 % vs. 21.4 %). Across all IHC scores, variability in HER2 staining (<=30 % stained cells) was observed in almost 50 % of cases, with increasing rates in lower IHC categories, and did not affect treatment outcome. The polysomy rate was 4 %. CONCLUSIONS: HER2 expression varies by tumor location and type. All patients with advanced gastric or gastroesophageal junction cancer should be tested for HER2 status, preferably using IHC initially. Due to the unique characteristics of gastric cancer, specific testing/scoring guidelines should be adhered to. PMID- 25038875 TI - Protein profiling reveals antioxidant and signaling activities of NAP (Davunetide) in rodent hippocampus exposed to hypobaric hypoxia. AB - NAP (davunetide) is a clinical octapeptide and reportedly possesses neuroprotective, neurotrophic and cognitive protective properties. The information for NAP-mediated neuroproteome changes and associated signaling pathways during hypoxia will help in drug development programmes across the world. In the present study, we have evaluated the antioxidant activities of NAP in rat hippocampus exposed to hypobaric hypoxia (25,000 ft, 282 mm Hg) for 3, 6 and 12 h respectively. Using 2D-gel electrophoresis (2D-GE) with matrix-assisted laser desorption ionization time of flight (MALDI-TOF/TOF) mass spectrometry, we have identified altered expression of 80 proteins in NAP-supplemented hippocampus after hypoxia. Pathway analysis revealed that NAP supplementation significantly regulated oxidative stress response, oxidoreductase activity and cellular response to stress pathways during hypoxia. Additionally, NAP supplementation also regulated energy production pathways along with AMP-activated protein kinase (AMPK) signaling and signaling by Rho family GTPases pathways. We observed higher expression of antioxidant Sod1, Eno1, Prdx2 and Prdx5 proteins that were subsequently validated by Western blotting. A higher level of Prdx2 was also observed by immunohistochemistry in NAP-supplemented hippocampus during hypoxia. In corroboration, we are able to detect significant lower level of protein carbonyls in NAP-supplemented hypoxic hippocampus suggesting amelioration of oxidant molecules by NAP supplementation. These results emphasize the antioxidant and signaling properties of NAP in rodent hippocampus during hypobaric hypoxia. PMID- 25038877 TI - Leptomeningeal disease and breast cancer: the importance of tumor subtype. AB - Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. We aimed to characterize clinical features and outcomes of patients with LMD based on BC subtypes. We retrospectively reviewed records of 233 patients diagnosed with LMD from BC between 1997 and 2012. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Of 190 patients with BC subtype available, 67 (35 %) had hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative BC, 56 (29 %) had HER2+BC, and 67 (35 %) had triple-negative BC (TNBC). Median age at LMD diagnosis was 50 years. Median overall survival (OS) from LMD diagnosis was 4.4 months for HER2+BC (95 % CI 2.8, 6.9), 3.7 months (95 % CI 2.4, 6.0) for HR+/HER2-BC, and 2.2 months (95 % CI 1.5, 3.0) for TNBC (p = 0.0002). Older age was associated with worse outcome (p < 0.0001). Patients with HER2+BC and LMD were more likely to receive systemic therapy (ST) (p = 0.001). Use of intrathecal therapy (IT) (52 %) was similar (p = 0.35). Both IT (p < 0.0001) and ST (p < 0.0001) administration were associated with improved OS. After adjusting for age, IT, extracranial disease, and ST, patients with HER2+BC had better OS compared with HR+/HER2-BC (HR 1.72; 95 %CI 1.07-2.76) and TNBC (HR 3.30; 95 %CI 1.98-5.52). LMD carries a dismal prognosis. Modest survival differences by tumor subtype were seen. Patients with HER2+BC had the best outcome. There is an urgent need to develop effective treatment strategies. PMID- 25038876 TI - 17beta-estradiol ameliorates light-induced retinal damage in Sprague-Dawley rats by reducing oxidative stress. AB - Oxidative stress is considered as a major cause of light-induced retinal neurodegeneration. The protective role of 17beta-estradiol (betaE2) in neurodegenerative disorders is well known, but its underlying mechanism remains unclear. Here, we utilized a light-induced retinal damage model to explore the mechanism by which betaE2 exerts its neuroprotective effect. Adult male and female ovariectomized (OVX) rats were exposed to 8,000 lx white light for 12 h to induce retinal light damage. Electroretinogram (ERG) assays and hematoxylin and eosin (H&E) staining revealed that exposure to light for 12 h resulted in functional damage to the rat retina, histological changes, and retinal neuron loss. However, intravitreal injection (IVI) of betaE2 significantly rescued this impaired retinal function in both female and male rats. Based on the level of malondialdehyde (MDA) production (a biomarker of oxidative stress), an increase in retinal oxidative stress followed light exposure, and betaE2 administration reduced this light-induced oxidative stress. Quantitative reverse-transcriptase (qRT)-PCR indicated that the messenger RNA (mRNA) levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were downregulated in female OVX rats but were upregulated in male rats after light exposure, suggesting a gender difference in the regulation of these antioxidant enzyme genes in response to light. However, betaE2 administration restored or enhanced the SOD and Gpx expression levels following light exposure. Although the catalase (CAT) expression level was insensitive to light stimulation, betaE2 also increased the CAT gene expression level in both female OVX and male rats. Further examination indicated that the antioxidant proteins thioredoxin (Trx) and nuclear factor erythroid 2-related factor 2 (Nrf2) are also involved in betaE2-mediated antioxidation and that the cytoprotective protein heme oxygenase-1 (HO-1) plays a key role in the endogenous defense mechanism against light exposure in a betaE2 independent manner. Taken together, we provide evidence that betaE2 protects against light-induced retinal damage via its antioxidative effect, and its underlying mechanism involves the regulation of the gene expression levels of antioxidant enzymes (SOD, CAT, and Gpx) and proteins (Trx and Nrf2). Our study provides conceptual evidence in support of estrogen replacement therapy for postmenopausal women to reduce the risk of age-related macular degeneration. PMID- 25038878 TI - Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases. AB - A significant variation in the metastatic pattern among breast cancer patients exists. Clinical observations suggest that these differences are related to time to recurrence (TTR), thus suggesting a common systemic growth signal at the time of surgery. Our goal was to identify a marker for synchronized growth of micrometastases. To quantify the metastatic pattern at first relapse, 180 patients with metastatic breast cancer were studied. Standard deviation (SD) of lesions size and lesion number was calculated and served as a marker for variation. Patients with low SD (multiple/similar sized lesions) were assumed to have synchronized growth, whereas patients with high SD were assumed to have unsynchronized growth. Patients were grouped according to TTR; early (< 3 years-) or late (> 3 years- after surgery). In patients not receiving systemic adjuvant treatment, median SD was significantly lower in the early group (2.5 mm) compared with 6.4 mm in the late group (p = 0.005). In node negative patients, median SD was significantly lower in the early group (3.0 mm) when compared with the late group (5.7 mm, p = 0.02). An additional drop in SD was observed immediately after end of adjuvant endocrine therapy. Our results identify SD as a marker of synchronized metastatic growth in breast cancer. A metastatic phenotype characterized by multiple similar sized metastases, suggesting synchronized onset of growth of micrometastases was predominantly found in patients recurring early after surgery and was counteracted by adjuvant treatment. Systemic growth signals caused by surgery might be antagonized during the time window following surgery. PMID- 25038879 TI - Cardiac glycosides and the risk of breast cancer in women with chronic heart failure and supraventricular arrhythmia. AB - The aim of this study is to determine whether the use of cardiac glycosides (CGs), drugs used in the treatment of congestive heart failure (CHF) and supra ventricular arrhythmia, is associated with an increased risk of breast cancer. A cohort of 53,454 women newly diagnosed with CHF or supra-ventricular arrhythmia between January 1, 1988 and December 31, 2010, followed until December 31, 2012, was identified using the United Kingdom Clinical Practice Research Datalink. A nested case-control analysis was performed, where all incident cases of breast cancer occurring during follow-up were identified and matched with up to 10 controls on age, cohort entry date, and duration of follow-up. Conditional logistic regression models were used to estimate adjusted odds ratios (ORs) with 95 % confidence intervals (CIs) of incident breast cancer associated with the use of CGs, along with measures of cumulative duration of use and dose. All analyses considered a one year lag period prior to the event, necessary for latency considerations and to minimize detection bias. The 898 breast cancer cases diagnosed beyond one year of follow-up were matched to 8,940 controls. Overall, use of CGs was not associated with an increased risk of breast cancer when compared to non-use (OR 1.07, 95 % CI 0.90-1.26). Furthermore, the risk did not vary with cumulative duration of use or cumulative dose. The findings of this large population-based study indicate that the use of CGs is not associated with an increased risk of breast cancer. This should provide reassurance to physicians and patients using these drugs. PMID- 25038880 TI - Notch2 activation is protective against anticancer effects of zerumbone in human breast cancer cells. AB - We showed previously that zerumbone (ZER), a sesquiterpene isolated from subtropical ginger, inhibited in vitro (MCF-7 and MDA-MB-231cells) and in vivo (MDA-MB-231 cells) growth of human breast cancer cells in association with apoptosis induction. Here, we investigated the role of Notch receptors in anticancer effects of ZER (cell migration inhibition and apoptosis induction) using breast cancer cells. Western blotting was performed to determine protein expression changes. Effect of ZER on transcriptional activity of Notch was assessed by luciferase reporter assays. Transfection with small hairpin RNA or small interfering RNA was performed for knockdown of Notch2 or Presenilin-1 protein. Cell migration and apoptosis were quantitated by Boyden chamber assay and flow cytometry, respectively. Exposure of MDA-MB-231, MCF-7, and SUM159 cells to ZER resulted in increased cleavage of Notch2 in each cell line. On the other hand, levels of cleaved Notch1 and Notch4 proteins were decreased following ZER treatment. Increased cleavage of Notch2 in ZER-treated cells was accompanied by induction of Presenilin-1 protein and transcriptional activation of Notch. Inhibition of cell migration as well as apoptosis induction resulting from ZER exposure was significantly augmented by knockdown of Notch2 protein. ZER-mediated cleavage of Notch2 protein in MDA-MB-231 cells was markedly attenuated upon RNA interference of Presenilin-1. Knockdown of Presenilin-1 protein also resulted in escalation of ZER-induced apoptosis. The present study indicates that Notch2 activation by ZER inhibits its proapoptotic and anti-migratory response at least in breast cancer cells. PMID- 25038881 TI - Posterior tibial displacement in the PCL-deficient knee is reduced compared to the normal knee during gait. AB - PURPOSE: Most individuals with an isolated posterior cruciate ligament (PCL) injury do not complain of disability even if posterior instability is objectively revealed by a static physical examination, such as the posterior drawer test. This suggests it is insufficient to only evaluate posterior instability under static conditions. Therefore, we have investigated the effect of isolated PCL injury on the detailed kinematics of the knee in a dynamic environment such as during gait. METHODS: Eight unilateral PCL-deficient males and eight healthy control volunteers participated in this study. Isolated PCL injury was diagnosed by clinical examination. Stress X-ray imaging showed an average side-to-side difference of 12.7 +/- 3.5 mm. Knee kinematics including anteroposterior tibial displacement were analysed during walking using the point cluster technique. RESULTS: Posterior tibial displacement from initial contact was significantly smaller during 9-22 % of the gait cycle by an average of 0.4 cm in the PCL group, compared to controls. In the PCL-deficient knee, the external rotational angle increased by an average of 3.3 degrees at the loading response during 3-11 % of the gait cycle and the varus angle from initial contact increased by an average of 2.0 degrees during 28-52 % of the gait cycle, compared to controls. CONCLUSIONS: Dynamic changes in the rotation and posterior translation patterns were seen after isolated PCL injury, suggesting the kinematics of PCL-deficient knees might be different to normal knees. These factors may contribute to long term osteoarthritic change. Consequently, when choosing conservative treatment for PCL injury, these changes should be considered to prevent osteoarthritic change. LEVEL OF EVIDENCE: III. PMID- 25038883 TI - Different femorotibial contact points between fixed- and mobile-bearing TKAs do not show clinical impact. AB - PURPOSE: In anteroposterior (AP)-gliding mobile-bearing total knee arthroplasty (TKA), the femoral component can theoretically slide forward resulting in a more anterior contact point, causing pain due to impingement. A lower lever arm of the extensor apparatus can also attribute to higher patella pressures and pain. The goal of this study was to determine the contact point in a cohort of mobile- and fixed-bearing TKAs, to determine whether the contact point lies more anteriorly in mobile-bearing TKA and to confirm whether this results in anterior knee pain. METHODS: We used 38 fixed-bearing TKA and 40 mobile-bearing TKA from a randomized trial with straight lateral knee X-rays and measured the contact point. The functional outcome was measured by Knee Society Score at 12 months postoperatively. Pain scores were analysed using a VAS score (0-100 mm) in all patients at rest and when moving. Difficulty at rising up out of a chair was also assessed using a VAS score. RESULTS: The contact point in mobile-bearing TKA was situated at 59.5 % of the AP distance of the tibia and in the fixed-bearing TKA group at 66.1 % (P< 0.05). Patients with mobile- and fixed-bearing TKAs had similar knee scores, pain scores and difficulty in chair rise. No significant correlation was found between contact point and knee pain. CONCLUSION: The hypothesis of a more anterior contact point in the mobile-bearing cohort was confirmed but no correlation with functional and pain scores in this cohort could be found. The tibiofemoral contact point could not be correlated with a different clinical outcome and higher incidence of anterior knee pain. This study further adds to the knowledge on possible differences between mobile- and fixed-bearing prostheses. Next to that, bad outcomes could not be explained by CP. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 25038882 TI - Validation of a novel ultrasound measurement of achilles tendon length. AB - PURPOSE: A clinically applicable and accurate method for measuring Achilles tendon length is needed to investigate the influence of elongation of the Achilles tendon after acute rupture. The purpose of this study was to develop and validate an ultrasonographic (US) length measurement of the Achilles tendon aponeurosis complex. METHODS: Both legs of 19 non-injured subjects were examined by magnetic resonance imaging (MRI) and US. The length from calcaneus to the medial head of m. Gastrocnemius was measured by three independent US examiners. Repeated US measurements were performed and compared to MRI measurements. Intra rater and inter-rater reliability and the agreement between MRI and US were determined. Data were evaluated using the intraclass correlation coefficient (ICC), the standard error of the measurement (SEM) and the minimal detectable change (MDC). RESULTS: Intra-rater reliability of US assessment showed no significant differences between test days: ICC 0.96, SEM 4 mm and MDC 10 mm. Inter-rater reliability showed a systematic difference between US observers of 2 5 mm (p = 0.001-0.036); ICC 0.97, SEM 3 mm and MDC 9 mm. MRI measurements were on average 4 mm longer than US (p = 0.001). CONCLUSION: The novel ultrasound measurement showed good reliability and accuracy. For comparison between groups of non-injured subjects differences of more than 4 mm can be detected. For repeated assessment of individual subjects differences of more than 10 mm can be detected. The measurement needs to be further assessed in the setting of acute Achilles tendon rupture. CLINICAL RELEVANCE: This new ultrasound measurement might allow for length measurement of ruptured Achilles tendons in the acute and chronic state after rupture. LEVEL OF EVIDENCE: II. PMID- 25038884 TI - Effect of codon-optimized E. coli signal peptides on recombinant Bacillus stearothermophilus maltogenic amylase periplasmic localization, yield and activity. AB - Recombinant proteins can be targeted to the Escherichia coli periplasm by fusing them to signal peptides. The popular pET vectors facilitate fusion of target proteins to the PelB signal. A systematic comparison of the PelB signal with native E. coli signal peptides for recombinant protein expression and periplasmic localization is not reported. We chose the Bacillus stearothermophilus maltogenic amylase (MA), an industrial enzyme widely used in the baking and brewing industry, as a model protein and analyzed the competence of seven, codon optimized, E. coli signal sequences to translocate MA to the E. coli periplasm compared to PelB. MA fusions to three of the signals facilitated enhanced periplasmic localization of MA compared to the PelB fusion. Interestingly, these three fusions showed greatly improved MA yields and between 18- and 50-fold improved amylase activities compared to the PelB fusion. Previously, non-optimal codon usage in native E. coli signal peptide sequences has been reported to be important for protein stability and activity. Our results suggest that E. coli signal peptides with optimal codon usage could also be beneficial for heterologous protein secretion to the periplasm. Moreover, such fusions could even enhance activity rather than diminish it. This effect, to our knowledge has not been previously documented. In addition, the seven vector platform reported here could also be used as a screen to identify the best signal peptide partner for other recombinant targets of interest. PMID- 25038885 TI - Heavy oils, principally long-chain n-alkanes secreted by Aureobasidium pullulans var. melanogenum strain P5 isolated from mangrove system. AB - In this study, the yeast strain P5 isolated from a mangrove system was identified to be a strain of Aureobasidium pullulans var. melanogenum and was found to be able to secrete a large amount of heavy oil into medium. After optimization of the medium for heavy oil production and cell growth by the yeast strain P5, it was found that 120.0 g/l of glucose and 0.1 % corn steep liquor were the most suitable for heavy oil production. During 10-l fermentation, the yeast strain P5 produced 32.5 g/l of heavy oil and cell mass was 23.0 g/l within 168 h. The secreted heavy oils contained 66.15 % of the long-chain n-alkanes and 26.4 % of the fatty acids, whereas the compositions of the fatty acids in the yeast cells were only C16:0 (21.2 %), C16:1(2.8 %), C18:0 (2.9 %), C18:1 (39.8 %), and C18:2 (33.3 %). We think that the secreted heavy oils may be used as a new source of petroleum in marine environments. This is the first report of yeast cells which can secrete the long-chain n-alkanes. PMID- 25038886 TI - Lacinutrix jangbogonensis sp. nov., a psychrophilic bacterium isolated from Antarctic marine sediment and emended description of the genus Lacinutrix. AB - A Gram-negative, strictly aerobic, non-motile, rod-shaped and psychrophilic bacterial strain, PAMC 27137(T), was isolated from the marine sediment of the Ross Sea, Antarctica. Strain PAMC 27137(T) was observed to grow at 4-10 degrees C, at pH 6.5-7.5 and in the presence of 2.5-4.0 % (w/v) sea salts. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain PAMC 27137(T) belongs to the genus Lacinutrix showing the high similarities with Lacinutrix mariniflava JCM 13824(T) (97.6 %) and Lacinutrix algicola JCM 13825(T) (97.1 %). Genomic relatedness analyses based on the average nucleotide identity and the genome-to-genome distance showed that strain PAMC 27137(T) is clearly distinguished from the most closely related Lacinutrix species. The major fatty acids (>5 %) were identified as iso-C15:1 G (19.9 %), iso-C15:0 (19.3 %), iso C17:0 3-OH (11.3 %), summed feature 9 (C16:0 10-methyl and/or iso-C17:1 omega9c as defined by MIDI, 9.1 %), iso-C15:0 3-OH (7.5 %), and anteiso-C15:1 A (5.8 %). The polar lipids were found to consist of phosphatidylethanolamine, an unidentified aminolipid, an unidentified aminophospholipid, and five unidentified phospholipids. The major respiratory quinone was identified as MK-6. The genomic DNA G+C content was determined to be 32.1 mol%. Based on the data from this polyphasic taxonomic study, strain PAMC 27137(T) is considered to represent a novel species of the genus Lacinutrix, for which the name Lacinutrix jangbogonensis sp. nov. is proposed. The type strain is PAMC 27137(T) (=KCTC 32573(T)=JCM 19883(T)). PMID- 25038887 TI - Motiliproteus sediminis gen. nov., sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, rod-to-spiral-shaped, oxidase- and catalase- positive and facultatively aerobic bacterium, designated HS6(T), was isolated from marine sediment of Yellow Sea, China. It can reduce nitrate to nitrite and grow well in marine broth 2216 (MB, Hope Biol-Technology Co., Ltd) with an optimal temperature for growth of 30-33 degrees C (range 12-45 degrees C) and in the presence of 2-3% (w/v) NaCl (range 0.5-7%, w/v). The pH range for growth was pH 6.2-9.0, with an optimum at 6.5-7.0. Phylogenetic analysis based on 16S rRNA gene sequences demonstrated that the novel isolate was 93.3% similar to the type strain of Neptunomonas antarctica, 93.2% to Neptunomonas japonicum and 93.1% to Marinobacterium rhizophilum, the closest cultivated relatives. The polar lipid profile of the novel strain consisted of phosphatidylethanolamine, phosphatidylglycerol and some other unknown lipids. Major cellular fatty acids were summed feature 3 (C(16:1) omega7c/iso-C15:0 2-OH), C(18:1) omega7c and C(16:0) and the main respiratory quinone was Q-8. The DNA G+C content of strain HS6(T) was 61.2 mol%. Based on the phylogenetic, physiological and biochemical characteristics, strain HS6(T) represents a novel genus and species and the name Motiliproteus sediminis gen. nov., sp. nov., is proposed. The type strain is HS6(T) (=ATCC BAA-2613(T)=CICC 10858(T)). PMID- 25038888 TI - When xenarthrans had enamel: insights on the evolution of their hypsodonty and paleontological support for independent evolution in armadillos. AB - All xenarthrans known to date are characterized by having permanent teeth that are both high crowned and open rooted, i.e., euhypsodont, and with a type of hypsodonty different from that of the rest of Placentalia: dentine hypsodonty. Also, most xenarthrans lack enamel; however, its presence has been reported in the fossil armadillo Utaetus buccatus and in living Dasypus. Considering the divergence of Xenarthra from other eutherians that possessed enameled teeth, the absence of enamel is a derived character. Diverse specializations are known in the dentition of xenarthrans, but the primitive pattern of their teeth and dentitions is still unknown. Here, we describe the mandible and teeth of a fossil armadillo, Astegotherium dichotomus (Astegotheriini, Dasypodidae), from the early Middle Eocene of Argentine Patagonia, with teeth showing both true enamel and closed roots. It is the oldest xenarthran with mandibular remains exhibiting protohypsodonty and is therefore likely representative of ancestral cingulates and xenarthrans generally. Astegotherium supports a recent hypothesis based on molecular data that enamel loss occurred independently not only within xenarthrans but also within dasypodid armadillos. PMID- 25038889 TI - Diagnostic performance of serum high-sensitivity procalcitonin and serum C reactive protein tests for detecting bacterial infection in febrile neutropenia. AB - PURPOSE: Although a few prospective studies have addressed the question as to which biomarker of infection in adult patients with febrile neutropenia (FN) is superior, procalcitonin (PCT) or C-reactive protein (CRP), the results have been inconsistent and inconclusive. This was possibly due to the poor sensitivity of previous PCT tests that have a functional sensitivity of 0.5 ng/ml. METHODS: Between November 2010 and February 2012, we prospectively compared the diagnostic utility of serum high-sensitivity (hs) PCT (lower limit of detection, 0.02 ng/ml) and CRP levels for detecting bacterial infection in patients with FN. Serum was collected within 72 h after the onset of FN in patients with hematological disorders. RESULTS: Seventy-five febrile episodes were evaluable. The areas under the receiver operating characteristic curves for life-threatening infection defined as septic shock and bacteremia caused by non-coagulase negative staphylococcus were 0.824 (95% CI 0.711-0.937; P = 0.001) for hsPCT and 0.673 (0.505-0.842; P = 0.068) for CRP, respectively. In contrast, CRP, but not hsPCT, tended to increase significantly with the clinical severity, as indicated by the diagnostic classification (P = 0.002 for trend). CONCLUSIONS: The serum hsPCT test may be more useful than the serum CRP test in the detection of life threatening infection at an early phase after the onset of FN. In contrast, the serum CRP test may be more useful in diagnosing the severity of infection. However, neither of these tests was able to differentiate the cause of FN with a low probability of fatal outcome. PMID- 25038890 TI - Anesthesia report card - a customizable tool for performance improvement. AB - PURPOSE: Measuring and providing performance feedback to physicians has gained momentum not only as a way to comply with regulatory requirements, but also as a way to improve patient care. Measurement of structural, process, and outcome metrics in a reliable, evidence-based, specialty-specific manner maximizes the probability of improving physician performance. The manner in which feedback is provided influences whether the measurement tool will be successful in changing behavior. We created an innovative reporting tool template for anesthesiology practitioners designed to provide detailed, continuous feedback covering many aspects of clinical practice. METHODS: The literature regarding quality metric measurement and feedback strategies was examined to design a reporting tool that could provide high quality information and result in improved performance of clinical and academic tasks. A committee of department leaders and information technology professionals was tasked with determining the measurement criteria and infrastructure needed to generate these reports. Data was collected in a systematic, unbiased manner, and reports were populated with information from multiple databases and software systems. Feedback would be based on frequently updated information and allow for analysis of historical performance as well as comparison amongst peers. RESULTS: A template for an anesthesia report card was created. Categories included compliance, credentialing and qualifications, education, clinical and operating room responsibilities, and academic achievements. Physicians were able to choose to be evaluated in some of the categories and had to meet a minimum number of criteria within each category. This allowed for customization to each practitioner's practice. Criteria were derived from the measures of academic and clinical proficiency, as well as quality metrics. Criteria were objective measures and data gathering was often automated. Reports could be generated that were updated daily and provided historical information, and information about peers in the department and within each subspecialty group. CONCLUSIONS: We demonstrate the creation of an online anesthesia report card that incorporates metrics most likely to engender positive changes in practice and academic responsibilities. This tool provides timely and customized information for each anesthesia practitioner, designed to be easily modifiable to improve the quantity, quality, and substance of metrics being measured. Finally, our tool could serve as a template for a performance measuring tool that can be customizable to a wide variety of practice settings, and upon which both monetary and non-monetary incentives might be based in the future. PMID- 25038891 TI - Determinants of telemedicine acceptance in selected public hospitals in Malaysia: clinical perspective. AB - The purpose of this study is to explore the determinants of telemedicine acceptance in selected public hospitals in Malaysia and to investigate the effect of health culture on the relationship between these determinants and telemedicine acceptance. Data were gathered by means of a survey of physicians and nurses as the main group of users of telemedicine technology from hospitals that are currently using telemedicine technology. The results indicated that government policies, top management support, perception of usefulness and computer self efficiency have a positive and significant impact on telemedicine acceptance by public hospitals in Malaysia. The results also confirmed the moderating role of health culture on the relationship between government policies as well as perceived usefulness on telemedicine acceptance by Malaysian hospitals. The results are useful for decision-makers as well as managers to recognize the potential role of telemedicine and assist in the process of implementation, adoption and utilization, and, therefore, spread the usage of telemedicine technology in more hospitals in the country. PMID- 25038892 TI - Mannose-Binding Lectin (MBL) and MBL-associated serine protease-2 (MASP-2) in women with malignant and benign ovarian tumours. AB - Mannose-Binding Lectin (MBL) is a serum pattern recognition molecule, able to activate complement in association with MASP proteases. Serum levels of MBL and MASP-2, activities of MBL-MASP complexes, single nucleotide polymorphisms of the MBL2 and MASP2 genes and/or their specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary ovarian cancer (OC) and compared with 197 controls (C), encompassing both patients with benign ovarian tumours (n = 123) and others with no ovarian pathology (n = 74). MBL deficiency associated genotypes were more common among OC patients than among controls. The O/O group of genotypes was associated with ovarian cancer (OR 3.5, p = 0.02). In A/A homozygotes, MBL concentrations and activities were elevated in the OC group and correlated with C-reactive protein. Moreover, high MBL serum levels were associated with more advanced disease stage. No differences in distribution of the MASP2 +359 A>G (D120G) SNP or MASP-2 serum levels were found between cancer patients and their controls. However, the highest frequency of the A/G (MASP2) and LXA/O or O/O (MBL2) genotypes was found among OC patients with tumours of G1 2 grade (well/moderately differentiated). Furthermore, MBL deficiency-associated genotypes predicted prolonged survival. None of the parameters investigated correlated with CA125 antigen or patients' age. The local expression of MBL2 and MASP2 genes was higher in women with ovarian cancer compared with controls. It is concluded that the expression of MBL and MASP-2 is altered in ovarian cancer, possibly indicating involvement of the lectin pathway of complement activation in the disease. PMID- 25038893 TI - Analysis of perioperative factors associated with increased cost following abdominal wall reconstruction (AWR). AB - BACKGROUND: Ventral hernias are a common, challenging, and expensive problem for both the general and reconstructive surgeons; therefore, the aim of this study is to critically assess perioperative factors related to cost in abdominal wall reconstructions (AWR). METHODS: A retrospective review of AWR patients from 2007 and 2012 was performed. Analysis of perioperative factors associated with total cost of reconstruction was performed. Linear regression analyses were used to assess independent predictors of total cost. RESULTS: 134 consecutive AWR performed by a single surgeon over a 5-year period at an academic teaching center were included. The average total cost of AWR was $61,251 +/- 55,624. Linear regression analysis demonstrated that diabetes (P = 0.026), increased American Society of Anesthesiologists score (P = 0.002), preoperative anemia (P = 0.001), and hernias derived from trauma (P = 0.015) were independently associated with added cost in AWR when controlling for confounding variables. In addition, patients requiring intra-abdominal procedures (P = 0.012) and those receiving an AWR using Acellular Dermal Matrix (P = 0.015) accrued significantly greater cost. Interestingly, preoperative placement of an epidural (P = 0.011) was independently associated with significant cost savings and reduced medical morbidity. Major surgical complications (P < 0.001) and length of stay (P < 0.001) were independently associated with increased cost following AWR. CONCLUSION: We present a critical assessment of cost in AWR at a major academic teaching hospital and quantify the impact of reconstruction in the setting of medical morbidities and reconstructive complexities. The data from this study can be used to adjust reimbursement schemes and to critically assess the cost-benefit of performing AWR. PMID- 25038894 TI - Outcome of patients with chronic mesh infection following abdominal wall hernia repair. AB - PURPOSE: Mesh infection following incisional hernia repair has been reported at around 6-10 %. The aim of this study is to assess the outcome of patients following treatment for chronically infected mesh after repair of an abdominal wall hernia. METHODS: Data were gathered on all patients with chronically infected mesh following failed conservative management treated under the care of one surgeon between January 2004 and December 2010. This included patient demographics, reason for first operation, number of previous operations and the number of previous hernia repairs. In addition, the type of mesh removed was recorded as was the organism cultured from the wound. Patients were followed up in a clinic at 1 month, 3 months and 1 year after surgery. RESULTS: 15 patients had 18 operations under general anaesthesia for infected mesh (10 partial and 8 complete mesh excisions). The interval between the last mesh implantation or abdominal operation and re-operation for infection was a median of 17 months (range 7-49 months). All patients who had complete mesh removal had complete healing of their wound at 3 months compared with four in the partial excision group (P = 0.011). At a median follow-up of 19 months, only five in the complete and three in the partial excision group had complete wound healing (P = 0.184). CONCLUSION: The outcome of patients treated for chronic mesh infection is unsatisfactory with high risk of recurrent herniation and development of further chronic abdominal wall sepsis; therefore, every effort should be made to prevent this problem in the first instance. PMID- 25038895 TI - The impact of developing a comprehensive hernia center on the referral patterns and complexity of hernia care. AB - BACKGROUND: Complex hernia repairs represent a formidable surgical challenge. Several comprehensive hernia centers, including ours, with advanced expertise have recently emerged across the country. However, the effects of tertiary specialization remain largely unclear. We aimed to evaluate the impact of developing a comprehensive hernia center on the referral patterns and costs of patients with complex hernias. METHODS: A prospectively maintained database was used to identify all patients undergoing open ventral hernia repair (VHR) between 2006 and 2013 at the Case Comprehensive Hernia Center. Patients were separated into two groups by zip code: those traveling either <25 or >100 miles. Demographics, operative characteristics, length of stay and costs data were analyzed. RESULTS: Of all patients who underwent open VHR during the study period, 287 met the inclusion criteria. Hernia length, width and area were all significantly larger for patients traveling >100 miles (P < 0.01 for all). These patients were also more likely to have active mesh infections (OR 3.57) and non healing wounds (OR 5.00) when compared with local patients. Length of hospital stay was significantly longer for patients traveling >100 miles compared to those traveling <25 miles (9.7 vs. 6.8; P < 0.0001). Surgical site occurrence, infection and hernia recurrence rates were similar between the two groups during the follow-up period. Patients who traveled >100 miles incurred significantly higher fixed direct and variable direct costs compared to those who traveled <25 miles (P < 0.05 for both). CONCLUSION: The development of a comprehensive hernia center results in centralization of complex hernia care. Patients traveling >100 miles for ventral hernia repair have significantly larger and more complex hernias. The implications for improved patient outcomes and potential reimbursement issues for providing this care should be carefully evaluated. PMID- 25038897 TI - DataCite and DOI names for research data. AB - The publication of research data is still not a widespread practice in many disciplines. The lack of acceptance of data as scientific output equal to scientific articles, and the lack of suitable infrastructures for the storage of data make it difficult to publish and cite data independently. The global consortium DataCite was established in 2009 to overcome the challenges of data citation. The aim of the consortium is to establish easy access to data, to increase the acceptance of data publication and to support data archiving. The use of Digital Object Identifiers (DOI) provides an easy method to access and re use research data. The DOI facilitates the citation of data and therefore increases the availability and acknowledgement of research data. PMID- 25038896 TI - Illegitimate recombination between T cell receptor genes in humans and pigs (Sus scrofa domestica). AB - T cell receptor (TCR) genes (TRA/TRD, TRB and TRG) reside in three regions on human chromosomes (14q11.2, 7q34 and 7p14, respectively) and pig chromosomes (7q15.3-q21, 18q11.3-q12 and 9q21-22, respectively). During the maturation of T cells, TCR genes are rearranged by site-specific recombination. Occasionally, interlocus recombination of different TCR genes takes place, resulting in chromosome rearrangements. It has been suggested that the absolute number of these "innocent" trans-rearrangements correlates with the risk of lymphoma. The aims of this work were to assess the frequencies of rearrangements with breakpoints in TCR genes in domestic pig lymphocytes and to compare these with the frequencies of corresponding rearrangements in human lymphocytes by using fluorescence in situ hybridization with chromosome painting probes. We show that frequencies of trans-rearrangements involving TRA/TRD locus in pigs are significantly higher than the frequency of translocations with breakpoints in TRB and TRG genes in pigs and the frequencies of corresponding trans-rearrangements involving TRA/TRD locus in humans. Complex structure of the pig TRA/TRD locus with high number of potential V(D)J rearrangements compared to the human locus may account for the observed differences. Furthermore, we demonstrated that trans rearrangements involving pig TRA/TRD locus occur at lower frequencies in gammadelta T cells than in alphabeta T lymphocytes. The decrease of the frequencies in gammadelta T cells is probably caused by the absence of TRA recombination during maturation of this T cell lineage. High numbers of innocent trans-rearrangements in pigs may indicate a higher risk of T-cell lymphoma than in humans. PMID- 25038898 TI - Academic librarians at play in the field of cheminformatics: building the case for chemistry research data management. AB - There are compelling needs from a variety of camps for more chemistry data to be available. While there are funder and government mandates for depositing research data in the United States and Europe, this does not mean it will be done well or expediently. Chemists themselves do not appear overly engaged at this stage and chemistry librarians who work directly with chemists and their local information environments are interested in helping with this challenge. Our unique understanding of organizing data and information enables us to contribute to building necessary infrastructure and establishing standards and best practices across the full research data cycle. As not many support structures focused on chemistry currently exist, we are initiating explorations through a few case studies and focused pilot projects presented here, with an aim of identifying opportunities for increased collaboration among chemists, chemistry librarians, cheminformaticians and other chemistry professionals. PMID- 25038899 TI - Contemporary outcome of the surgical management of prosthetic graft infection after a thoracic aortic replacement: is there a room to consider vacuum-assisted wound closure as an alternative? AB - OBJECTIVE: Once a replaced prosthetic graft is infected, it is usually necessary to re-replace the thoracic aorta to achieve complete resolution of the infection. It is, however, an exceedingly invasive approach to perform such a repeat surgery on patients in a poor condition. We have managed both re-replacement of an infected prosthetic graft and conservative therapy with vacuum-assisted wound closure (VAC) without re-replacement. These two treatment modalities were retrospectively assessed. METHODS: Retrospective clinical chart review was undertaken on 21 patients with prosthetic graft infection after thoracic aortic replacement between December 1999 and December 2012. Surgical outcomes were evaluated between the two groups: re-replacement group (group R, n = 14) and no replacement group (group NR, n = 7). RESULTS: In-hospital survival rates were 64.3% in group R and 85.7% in group NR. Mortality in group R included five patients, sepsis in two patients, and intraoperative aortic rupture, heart failure, and cerebral infarction in one. Mortality in group NR included one patient (sepsis). In terms of long-term outcome, one patient in group R and one patient in group NR died of rupture of a residual aortic aneurysm, and one patient in group NR died of renal disease during follow-up (52.8 +/- 41.5 months for R and 43.2 +/- 28.5 months for NR; mean +/- standard deviation). CONCLUSIONS: Re-replacement of an infected prosthetic graft after a thoracic aortic operation still carries a significant risk for mortality. VAC therapy may provide an acceptable option for such a subgroup of patients with this serious condition. PMID- 25038900 TI - Pneumocephalus and subcutaneous scalp emphysema in a neonate on a low-flow nasal cannula. AB - A 15-day-old boy after intracardiac repair was discharged from the intensive care unit with a low-flow nasal cannula for oxygen administration. The cannula was a 4 Fr multi-purpose tube with a side hole that was inserted into his left nostril. Next day, he suddenly developed pneumocephalus emerging from the right periorbital swelling and extending to his face and subcutaneous scalp over the next 6 h. A computed tomography (CT) scan revealed massive air pockets in the orbit, subdural space, subcutaneous scalp, and face. The nasal cannula was found to have been inserted deeper than we thought and was thus presumed to be the source of the air pockets. We immediately removed the cannula. Follow-up CTs revealed rapid resolution of the intracranial and subcutaneous air. The subcutaneous emphysema completely disappeared over the next 4 days, and he was discharged without any incident. PMID- 25038901 TI - Fine-scale spatial age segregation in the limited foraging area of an inshore seabird species, the little penguin. AB - Competition for food resources can result in spatial and dietary segregation among individuals from the same species. Few studies have looked at such segregations with the combined effect of sex and age in species with short foraging ranges. In this study we examined the 3D spatial use of the environment in a species with a limited foraging area. We equipped 26 little penguins (Eudyptula minor) of known age, sex, and breeding output with GPS (location) and accelerometer (body acceleration and dive depth) loggers. We obtained dietary niche information from the isotopic analysis of blood tissue. We controlled for confounding factors of foraging trip length and food availability by sampling adults at guard stage when parents usually make one-day trips. We observed a spatial segregation between old (>11 years old) and middle-aged penguins (between 5 and 11 years old) in the foraging area. Old penguins foraged closer to the shore, in shallower water. Despite observing age-specific spatial segregation, we found no differences in the diving effort and foraging efficiency between age classes and sexes. Birds appeared to target similar prey types, but showed age specific variation in their isotopic niche width. We hypothesize that this age specific segregation was primarily determined by a "cohort effect" that would lead individuals sharing a common life history (i.e. having fledged and dispersed around the same age) to forage preferentially together or to share similar foraging limitations. PMID- 25038903 TI - Effects of vitamin D supplements on bone density. PMID- 25038904 TI - Association of height with peripheral arterial disease in type 2 diabetes. AB - OBJECTIVE: To investigate whether height is associated with peripheral arterial disease (PAD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was an observational study performed in 4,528 Chinese patients with type 2 diabetes. Anthropometric measures and the ankle-brachial index (ABI) were performed on each subject. PAD was defined as those patients with a history of revascularization or amputation due to ischemia, or an ABI <0.9. RESULTS: A total of 23.3 % of T2DM patients had PAD (men 22.9 % and women 23.7 %). The mean age and height were 57.8 +/- 12.5 years and 170.5 cm for men, and 60.0 +/- 11.7 years and 158.9 cm for women, respectively. The ABI and frequency of PAD were higher with decreasing height quartiles. An inverse association was observed between height- and gender-adjusted risk of PAD. This relationship remained unchanged following further adjustment for potential confounders. Subjects in the shortest stature group had of 1.174 times higher risk of PAD for men and 1.143 times for women, compared with those in the tallest stature group. The multivariate adjusted hazard ratios (95 % CI) of PAD for a 10-cm height increase were 0.85 (95 % CI 0.78-0.94). CONCLUSION: A short stature seems to be associated with higher risk of PAD in Chinese diabetic patients. However, the cross-sectional nature of the study limits conclusions regarding the direction or causality. Further longitudinal study is warranted in this and other ethnic groups. PMID- 25038902 TI - Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. PMID- 25038906 TI - Validation of a short-scan-time imaging protocol for thallium-201 myocardial SPECT with a multifocal collimator. AB - OBJECTIVE: IQ-SPECT (Siemens AG, Munich, Germany) is a highly sensitive single photon-emission computed tomography (SPECT) myocardial perfusion imaging (MPI) system that uses a multifocal collimator. We searched for a suitable protocol for short-time imaging by IQ-SPECT in thallium-201 (Tl-201) MPI by evaluating phantom images and also by comparing human IQ-SPECT images with conventional SPECT images as reference standards. METHODS: We assessed the image quality using the normalized mean square error (NMSE) and drew up count profiles in Tl-201 SPECT images acquired with IQ-SPECT in a phantom study. We also performed Tl-201 stress myocardial SPECT/CT in 21 patients and compared delayed images acquired by using IQ-SPECT with 36 or 17 views per head with images obtained by using conventional SPECT. RESULTS: The NMSE of SPECT images from IQ-SPECT with 36 views was approximately one-fifth of that with 17 views. The myocardial count profile of images with 17 views was lower than those of images with 36 or 104 views in some regions. Defect scores were significantly lower, and image quality scores higher, in images from conventional SPECT than in those from IQ-SPECT with 17 views. Defect scores and image quality scores were equivalent in images from conventional SPECT and those from IQ-SPECT with 36 views. Agreement with the results of conventional SPECT in terms of coronary artery territory-based defect judgment was the best in IQ-SPECT with 36 views with computed tomography-derived attenuation correction (CTAC): the kappa values for IQ-SPECT with 36 views were 0.76 (without CTAC) and 0.83 (with CTAC), and those for IQ-SPECT with 17 views were 0.62 (without CTAC) and 0.59 (with CTAC). The difference in quantitative tracer uptake between conventional SPECT images and IQ-SPECT images was significantly greater for IQ-SPECT images with 17 views than for those with 36 views. CONCLUSIONS: Scanning with 36 views per head with CTAC may be appropriate for Tl-201 MPI using IQ-SPECT, because it provides images equivalent to those using conventional SPECT. PMID- 25038905 TI - All roads bring to Rome: a different way for predicting success in the therapy of obesity through psychological features. AB - PURPOSE: Obesity treatment based on lifestyle modifications is characterized by a high proportion of treatment failures. The study of predictors of success could be useful for a better definition of therapeutic needs in individual patients. Few studies have attempted a comprehensive assessment of psychological factors related with treatment response. Aim of the study is the identification of psychological and psychopathological features associated with a good treatment response in patients referring for obesity. METHODS: This prospective observational study was conducted on a consecutive series of 270 obese patients and a six-month follow-up was performed. At enrollment, a complete medical history was collected and, psychopathology and psychological features were assessed with: General psychopathology: Symptom Checklist 90-revised, Eating Disorder Examination-Questionnaire, Obesity Related well-being and Treatment, Motivation and Readiness test. RESULTS: Among the 231 patients evaluated at follow-up, the mean weight loss was 3.2% of initial body weight and 68 patients (29.4%) reached the pre-defined therapeutic target of 5% weight loss. Higher psychopathology was associated with a worse outcome in women only; whereas motivation was higher in patients achieving therapeutic targets among men, but not in women. CONCLUSIONS: Mean weight loss obtained with lifestyle interventions is confirmed to be rather small and a more accurate selection of patients to be enrolled in lifestyle intervention programs is needed. The present study provides some intriguing information on predictors of weight loss, which could be useful for the identification of patients with a higher chance of succeeding with lifestyle programs for the treatment of obesity. PMID- 25038907 TI - Preparation of (99m)Tc carbonyl DTPA-bevacizumab and its bioevaluation in a melanoma model. AB - OBJECTIVE: The objective of this study was to explore the potential of (99m)Tc carbonyl labeled DTPA-bevacizumab as a tumor imaging agent. Bevacizumab (Avastin) is a humanized monoclonal antibody (MoAb) that inhibits the vascular endothelial growth factor (VEGF). METHODS: Bevacizumab was conjugated with paraisothiocyanatobenzyl diethylenetriamine pentaacetic acid (p-SCN-Bn-DTPA) and subsequently radiolabeled with (99m)Tc via the (99m)Tc carbonyl synthon. The radioconjugate after purification was characterized by SE-HPLC and its in vitro stability was determined by histidine challenge experiments. Biodistribution studies to determine the uptake by tumors were carried out in melanoma model. RESULTS: The radiochemical purity of (99m)Tc carbonyl labeled antibody was >98 %. The radiolabeled antibody exhibited good stability in the histidine challenge experiments up to 24 h when stored at 37 degrees C. Biodistribution studies in mice bearing melanoma showed significant tumor uptake (6.9 +/- 2.2 % ID/g at 24 h p.i.) which was reduced to 1.6 +/- 0.4 % ID/g on co-injection with cold Bevacizumab. CONCLUSIONS: The (99m)Tc carbonyl-DTPA-bevacizumab conjugate with good radiochemical purity, excellent stability and good specificity for VEGF indicates its potential as a radioimmunoscintigraphy agent for various cancers. PMID- 25038908 TI - Spectral-domain optical coherence tomography findings in pediatric tilted disc syndrome. AB - PURPOSE: To report a novel spectral-domain optical coherence tomography (SD-OCT) finding in children affected by tilted disc syndrome (TDS), and to correlate it with early visual field defects. METHODS: Patients between 5 and 17 years old with TDS were enrolled in this study. The diagnosis of TDS was made by stereoscopic fundus photography, when the upper edge of the optic disc protruded anteriorly relative to its lower edge. All eyes were examined with 12 radial SD OCT B-scans of 12 mm centered on the optic disc; the fundus area encompassing the optic nerve was additionally scanned using several vertical and horizontal scans.. C-scan SD-OCT were acquired using the Macular Cube 512 x 128 to create the en face image. Standard automated perimetry 24-2 tests were performed on all patients. RESULTS: Thirty-eight eyes of 20 pediatric patients with TDS syndrome were enrolled during this 24-months clinical trial. Their mean age was 10.9 +/- 2.7 years (range 7-15 years), 12 (60%) were male and eight (40%) were female. The OCT images of the optic discs showed a protrusion of the upper edge of Bruch's membrane and choroid at the nasal edge of the optic disc in 39.5% of the eyes. The retinal nerve fiber tissue appeared to be herniated into this protrusion and bent superiorly in 15 eyes. This severe bending corresponded to early visual field anomalies that were not reduced by corrective lenses in 46.7% of the eyes. CONCLUSION: Visual field defects that do not improve by increased myopic correction in TDS may be due to the severe bending of the retinal nerve fiber tissue, which would impair axonal flow. PMID- 25038909 TI - Visual outcome and prognostic factors after surgery for a secondary epiretinal membrane associated with branch retinal vein occlusion. AB - PURPOSE: To assess the visual outcome and prognostic factors after surgery for a secondary epiretinal membrane (ERM) due to branch retinal vein occlusion (BRVO). METHODS: Medical records of 33 patients (33 eyes) were retrospectively reviewed. All patients underwent vitrectomy and completed at least one year of follow-up. Patients characteristics, including baseline best-corrected visual acuity (BCVA; logMAR, logarithm of the minimum angle resolution), fluorescein angiography and optical coherence tomography findings were analyzed. RESULTS: Twenty eyes (60.6%) were non-ischemic and nine eyes (27.3%) had ischemic maculopathy. The mean BCVA was 0.82 +/-0.56 logMAR (20/132 Snellen equivalent) at baseline and 0.43 +/-0.37 logMAR (20/53 Snellen equivalent) at 1 year (p = 0.001). At 1 year three eyes (9.1%) had visual loss with 0.3 logMAR or more deterioration than baseline whereas 16 eyes (48.5%) gained vision. The mean central macular thickness (CMT) was 407.3 +/-138.8 MUm at baseline and 274.71 +/-40.5 MUm at 1 year after surgery (p = 0.001). Photoreceptor integrity was intact in 20 eyes (60.6%). Photoreceptor integrity (B = 0.248, p = 0.001) at baseline was significantly correlated with visual outcome after surgery. CONCLUSION: Surgery for a secondary ERM associated with BRVO led to a relatively favorable visual outcome. The integrity of photoreceptors at baseline seems to be useful in predicting visual outcome in these patients. PMID- 25038910 TI - Proton beam therapy for presumed and confirmed iris melanomas: a review of 36 cases. AB - BACKGROUND: To report the clinical features and outcomes of iris melanomas treated by proton beam therapy. MATERIALS AND METHODS: A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon, Department of Ophthalmology, in 36 patients treated by proton beam therapy for presumed (n = 29) and confirmed (n = 7) iris melanomas between July 1997 and October 2010. Ciliary body melanomas with iris involvement were excluded. The patients' mean age was 54.4 years (range, 22-82 years). The average tumor diameter was 3.8 mm (range, 2.5-8.0). The iridocorneal angle was invaded by the tumor in 47% of cases (n = 17), the ciliary body in 17% of cases (n = 6), and the sclera in 3% (n = 1). Raised intraocular pressure was present before treatment in 11.1 % of cases (n = 4). Tumor biopsy was performed in 19% of cases (n = 7). Four patients had undergone an initial incomplete surgical excision of tumor before radiotherapy. Surgical preparation of the eye with tantalum ring positioning had been performed in all cases 3-4 weeks before irradiation. The prescribed dose was 60 Cobalt Gray Equivalent (CGE) of proton beam radiotherapy delivered in four fractions on four consecutive days. RESULTS: The median follow-up was 50 months (mean 60.5, range 15-136). One patient (2.7%) was lost to follow-up. None of the patients showed tumor progression, local recurrence, or metastasis. None of the patients required secondary enucleation. Cataract was developed in 62% of patients, glaucoma in two cases (6%) after irradiation, and hyphema with the aggravation of pre-existing glaucoma in one patient. No patients developed neovascular glaucoma. CONCLUSIONS: Proton beam therapy appears to be the treatment of choice for the conservative treatment of iris melanomas with excellent tumor control and an acceptable rate of complications. Longer follow-up studies on a larger series is necessary to consolidate these results. PMID- 25038911 TI - The effect of posterior corneal flat meridian and astigmatism amount on the total corneal astigmatism estimated from anterior corneal measurements. AB - BACKGROUND: To evaluate the effects of posterior corneal astigmatism and the absolute flat meridian difference between anterior and posterior corneal surfaces (AMDAnt-Post) on the estimation of total corneal astigmatism using anterior corneal measurements (simulated keratometry [K]). METHODS: Ninety-nine eyes of 99 healthy participants were enrolled. Anterior, posterior, and total mean corneal power, cylinder power, flat meridian, and vector components J0, and J45 measured by a dual Scheimpflug camera were analyzed. The correlation between the posterior corneal cylinder power, AMDAnt-Post, and the difference in the cylinder power between simulated K and total cornea (cylinder power differenceSimK-Tot) were evaluated. RESULTS: The cylinder power differenceSimK-Tot was positively correlated with the posterior corneal cylinder power (rho = 0.704 and P < 0.001) and negatively correlated with AMDAnt-Post (rho = -0.717 and P < 0.001). In the multivariate linear regression analysis, anterior corneal J0 was strongly associated with the posterior corneal cylinder power and the AMDAnt-Post. When corneal J0 had a positive value, the cylinder power of simulated K tended to be larger than the total corneal cylinder power. In comparison, the opposite trend was presented in eyes with negative anterior corneal J0. When anterior corneal J0 was larger than 1.0 or smaller than -0.9, the errors from estimating the total corneal cylinder power using anterior corneal measurements tended to be larger than 0.25 D. CONCLUSION: Posterior corneal astigmatism should be considered for more accurate corneal astigmatism predictions, especially in eyes with anterior corneal astigmatism greater than 2.0 D of with-the-rule astigmatism or greater than 1.8 D of against-the-rule astigmatism. PMID- 25038912 TI - Polymorphism of DNA repair gene xrcc1 and lung cancer risk. AB - The current large-scale meta-analysis was performed to reach a reliable conclusion on the association between X-ray repair cross-complementing 1 (xrcc1) rs1799782 and the development of lung cancer. Studies that investigated the association between rs1799782 and lung cancer risk were identified by searching PubMed. We calculated odds ratio (OR) with corresponding 95 % confidence interval (CI) for Trp/Trp vs Arg/Arg, Trp/Trp + Arg/Trp vs Arg/Arg, and Trp/Trp vs Arg/Trp + Arg/Arg contrast models. Combining all 25 studies, we yielded three summary ORs: 1.07 (95 % CI 0.92-1.23) for Trp/Trp vs Arg/Arg, 0.93 (95 % CI 0.87-1.00) for Trp/Trp + Arg/Trp vs Arg/Arg, and 1.08 (95 % CI 0.94-1.25) for Trp/Trp vs Arg/Trp + Arg/Arg, suggesting rs1799782 was not associated with overall risk of lung cancer. Strikingly, a significantly deceased risk was found among Caucasian populations (Trp/Trp + Arg/Trp vs Arg/Arg, OR = 0.86, 95 % CI 0.76-0.97). This study confirms that xrcc1 rs1799782 may lower the risk of lung cancer among Caucasians. PMID- 25038913 TI - Perioperative medullary complications in spinal and extra-spinal surgery in mucopolysaccharidosis: a case series of three patients. AB - The mucopolysaccharidoses (MPS) are genetic lysosomal storage diseases. Peripheral bone dysplasia and spinal involvement are the predominant orthopedic damage. The risk of spinal cord compression due to stenosis of the craniocervical junction is well known in these patients, whereas the thoracolumbar kyphosis is often well tolerated over a long period of time. Thus, signs of spinal cord compression at this level occur later and more insidiously. The authors describe three cases of patients with thoracolumbar kyphosis who suffered from postoperative spinal cord compression in the absence of direct surgical trauma. Analysis of these cases and review of the literature helped identify causal factors resulting in spinal cord ischemia. The risk of perioperative spinal cord complications related to a thoracolumbar kyphosis must be discussed with patients with MPS and their families prior to any surgery, including extra-spinal procedures. PMID- 25038914 TI - Randomized controlled trial comparing Moviprep(r) and Phosphoral(r) as bowel cleansing agents in patients undergoing colonoscopy. AB - BACKGROUND: Introducing colonoscopy as part of colorectal cancer screening on a national level, we aimed at evaluating the efficacy of the two most common bowel cleansing agents, Moviprep((r)) and Phosphoral((r)). Secondly, we evaluated the benefit for the patient and society in terms of sick leave and discomfort. METHODS: In a single-blinded randomized equivalence trial, Phosphoral((r)) (NaP) was compared with Moviprep((r)) (2 l polyethylene glycol + ascorbic acid) in patients undergoing colonoscopy due to suspicion of cancer. Patients filled out questionnaires concerning stool consistency, discomfort and number of sick days due to bowel cleansing. Blinded colonoscopists estimated the efficiency of the cleansing using the validated Harefield Cleansing Scale. RESULTS: Two hundred and sixty-six patients were included 250 of whom underwent full colonoscopy. There was no difference in the percentage of acceptable bowel cleansings in the two groups; however, a significantly higher number of A scores were observed in the Moviprep((r)) group (p = 0.028). We found no correlation between stool consistency and outcome of the cleansing and no difference in subjective discomfort during cleansing. Vomiting during cleansing occurred more often in the Phosphoral((r)) group (p = 0.002). There was a trend toward a smaller number of sick days in patients who used Moviprep((r)) compared with Phosphoral((r)). CONCLUSIONS: Moviprep((r)) and Phosphoral((r)) provided equally efficient bowel cleansing in 90 % of patients, but Moviprep((r)) provided a higher quality of cleansings graded as successful. The two agents were equally tolerated, and no difference was found in the related number of sick days. PMID- 25038915 TI - Downregulation of PEBP4, a target of miR-34a, sensitizes drug-resistant lung cancer cells. AB - The aim of this study was to determine the relationship and underlying mechanisms between ectopic expression of phosphatidylethanolamine-binding protein 4 (PEBP4) and cisplatin (DDP)-induced cytotoxicity in the lung cancer cell line A549 to provide an experimental basis for future chemotherapeutic applications involving PEBP4 in human lung cancer. A recombinant plasmid, pcDNA3-PEBP4, and a PEBP4 targeting small hairpin RNA (shRNA) were transfected into the lung cancer cell line A549. The PEBP4 protein expression levels were determined for each group by Western blot, and after 48 h of cisplatin (DDP) treatment, the viability of cells in the treatment and control groups was determined by 3-[4,5-dimethylthiazol-2 yl]-3,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis in each treatment group was determined using flow cytometry. Western blotting was used to examine expression of the p53 protein in A549 cells from each group. We employed a luciferase reporter-gene assay to confirm PEBP4 as a target gene of miR-34a. Western blotting was used to determine the effects of miR-34a on PEBP4 protein expression in A549 cells. Following transfection of A549 cells with either the recombinant plasmid pcDNA3-PEBP4 or a PEBP4-targeting shRNA, Western blotting analyses showed PEBP4 protein expression was significantly higher in the pcDNA3 PEBP4-transfected group compared with the control or PEBP4-shRNA-transfected groups (p < 0.01). Furthermore, PEBP4 protein expression was significantly reduced in the PEBP4-shRNA-transfected group (p < 0.01). After 48 h of DDP treatment, MTT assays indicated that A549 cell viability was significantly lower in the DDP-treated group compared with the control group (p < 0.01). The viability of A549 cells in the pcDNA3-PEBP4-transfected group was lower than that in the control group (p < 0.05) but higher than that in either the DDP-treated or PEBP4-shRNA-transfected groups (p < 0.05). Moreover, the viability of A549 cells in the PEBP4-shRNA-transfected group was significantly lower than that in either the control (p < 0.01) or DDP-treated (p < 0.05) groups. Flow cytometry and Western blotting analyses indicated that the number of apoptotic cells and p53 protein expression were significantly higher in the DDP-treated group compared with the control group (p < 0.01). In the pcDNA3-PEBP4-transfected group, the number of apoptotic cells and p53 protein expression level were higher than those in the control group (p < 0.05) but lower than those in the DDP-treated and PEBP4 shRNA-transfected groups (p < 0.05). The number of apoptotic cells and p53 protein expression level in the PEBP4-shRNA-transfected group were higher than those in the control (p < 0.01) and DDP-treated (p < 0.05) groups. The luciferase reporter-gene assay showed that the relative luciferase activity after transfection with a miR-34a mimic was significantly reduced compared with the control group (p < 0.01). Western blotting analysis demonstrated that PEBP4 protein expression was significantly decreased in A549 cells 48 h after transfection with a miR-34a mimic compared with the control group (p < 0.01). In conclusion, overexpression of PEBP4 reduced the sensitivity of A549 cells to DDP induced cytotoxicity, mainly through the altered expression of the p53 protein or the modulation of miR-34a. PMID- 25038917 TI - Video-assisted thoracic surgery for bronchogenic cysts: is this the surgical approach of choice? AB - OBJECTIVES: Although there is no consensus on the management of bronchogenic cyst, most surgeons advocate early removal, even in asymptomatic patients. To evaluate the feasibility and safety of video-assisted thoracic surgery (VATS) in the management of bronchogenic cysts and long-term follow-up, a retrospective analysis was performed. METHODS: From January 1995 to April 2013, we retrospectively reviewed the charts of 113 patients who underwent VATS resection of bronchogenic cysts in our institution. Resection of the bronchogenic cysts by VATS was initially performed in patients who had a cyst in the thoracic cavity and no evidence of severely dense adhesion to other organs or tissues on a CT scan. Also, patients with a history of previous thoracic surgeries, in addition to those with concomitant diseases requiring surgical treatment, were enrolled in our series. Operations were carried out using the conventional three-port technique and histological examinations confirmed the diagnosis of benign bronchogenic cyst containing a ciliated columnar epithelial lining. RESULTS: The median size of the cysts was 3.7 cm in their greatest diameter (range, 1-10 cm). One hundred and nine patients with bronchogenic cyst were resected completely by VATS. In 4 cases, VATS was converted to open thoracotomy or median sternotomy: major adhesion to the bronchus in 2, left innominate venous injury in 1 and repair of bronchial tear by surgery in 1. We identified 5 intraoperative complications of tracheobronchial tear, vascular injury and oesophageal laceration. The median operation time was 96.8 min (range, 15-320 min). There were no operative mortalities or major postoperative complications. Patients with VATS excision were discharged after a median of 3.7 days postoperatively. The long-term follow-up ranged from 1 to 11 years, with a median follow-up of 4.2 years. There were no late complications or recurrences. CONCLUSIONS: Considering the low conversion and complication rate, VATS was safe and effective in the resection of the bronchogenic cysts. The size and the location of cysts were not important considerations in selecting the surgical method. VATS excision should be considered the primary therapeutic option in the management of patients with bronchogenic cysts. PMID- 25038916 TI - Transarterial embolization with or without chemotherapy for advanced hepatocellular carcinoma: a systematic review. AB - Transarterial chemoembolization (TACE) and transarterial embolization (TAE) are commonly used as first-line treatment for patients with advanced hepatocellular carcinoma (HCC) and have been shown to improve overall survival (OS). However, there remain concerns regarding whether the benefit of the prolonged survival achieved with TACE is superior to the maximum cytotoxic effect of the associated chemotherapeutics. This systematic review aims to compare the efficiency of TACE and TAE based on randomized controlled trials (RCTs). MEDLINE, EMBASE, the Cochrane library, the Science Citation Index, and the Chinese National Knowledge Infrastructure databases were systematically searched through the end of April 2014. Risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated. Meta analysis of the RCTs was conducted to estimate the mortality and survival rate between the TACE and TAE groups. The analysis included five RCTs involving 582 patients. For all-cause mortality, TACE did not result in a statistically significant reduced incidence of adverse events than TAE with a pooled RR of 1.21 (95 % CI = 0.74-1.98, P = 0.16). In addition, 6-, 9-, 12-, 24-, and 36-month OS of the TACE group were not significantly higher than that of the TAE group (all P > 0.05). Interestingly, TACE resulted in a significantly higher rate of advanced events. The efficacy of TACE is not superior to TAE in advanced HCC patients. Moreover, TACE was associated with an increased rate of adverse events than TAE. Improved strategies are needed to reduce the risk of post-TACE complications. PMID- 25038918 TI - Impact of active surveillance, chlorambucil, and other therapy on health-related quality of life in patients with CLL/SLL in the Netherlands. AB - As survival of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) increases and the number of patients who live long rises, health-related quality of life (HRQoL) becomes a relevant endpoint. Few studies investigated this, mainly as a secondary endpoint in randomized clinical trials where patients with early stage CLL/SLL, and elderly/frail patients were underrepresented. The aim of our study was to assess HRQoL in a population-based setting, including these previously underrepresented patients. Out of 175 patients diagnosed with CLL/SLL between 2004 and 2011, 136 (78 %) returned the HRQoL questionnaire. The outcomes were compared to an age- and sex-matched norm population. Detailed data on stage and treatment were extracted from a population based hematological registry (PHAROS). Patients ever treated for CLL/SLL reported significantly poorer HRQoL than the norm population (p < 0.01 with large clinically important differences. Interestingly, no differences were observed between the norm population and patients under active surveillance. In contrast to our hypothesis, patients treated with chlorambucil reported the lowest HRQoL scores. Drastic, long-lasting negative effects of starting treatment on HRQoL cannot be excluded, whereas active surveillance does not seem to provoke worrying, anxiety, or depressive symptoms. Further elaborate research into the impact of starting therapy on HRQoL is needed, especially in patients that are underrepresented in most clinical trials, and thoroughly consider its results during revision of treatment guidelines. PMID- 25038919 TI - Efficacy and safety of lenalidomide in relapse/refractory multiple myeloma--real life experience of a tertiary cancer center. AB - Lenalidomide was approved for the treatment of relapsed and refractory multiple myeloma (rrMM) based on MM009 and MM010 clinical trials. However, its effectiveness and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 90 consecutive patients treated in our center with lenalidomide and dexamethasone (LenDex) between 2007 and 2012. The overall response rate to this treatment was 68 % and the median duration of response was 13.6 months. Patients treated in first relapse and those treated with LenDex longer than 1 year achieved the best responses. Cytogenetics was associated with PFS and best response to treatment was the only variable associated with longer PFS and OS in univariate and multivariate analyses. Our analysis confirmed that LenDex is effective in rrMM patient, well tolerated, and applicable to the majority of patients outside clinical trials; patients achieving a complete response, even in the context of relapse, have a longer survival; quality of response is better when lenalidomide is used in second line than later on and it is a good surrogate marker for OS. Accordingly, CR should be aimed in the rrMM setting, especially in fit patients. Previous treatment with thalidomide should not hamper the option for lenalidomide therapy. PMID- 25038921 TI - Ceramic on ceramic hip prostheses: a review of past and modern materials. AB - Ceramic on ceramic hip prostheses are an increasingly popular choice for hip replacement. Modern manufacturing techniques and developments have increased the strength and reliability of ceramic materials. The alternative bearing couples such as metal-on-polyethylene and metal-on-metal are more inclined to wear and produce particulate debris. Despite reports of fractures and stripe wear, harder, more inert and more wear resistant, modern ceramic-ceramic hip replacements provide a strong alternative to traditional bearings. PMID- 25038920 TI - The Sedentary Time and Activity Reporting Questionnaire (STAR-Q): reliability and validity against doubly labeled water and 7-day activity diaries. AB - We determined measurement properties of the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), which was designed to estimate past-month activity energy expenditure (AEE). STAR-Q validity and reliability were assessed in 102 adults in Alberta, Canada (2009-2011), who completed 14-day doubly labeled water (DLW) protocols, 7-day activity diaries on day 15, and the STAR-Q on day 14 and again at 3 and 6 months. Three-month reliability was substantial for total energy expenditure (TEE) and AEE (intraclass correlation coefficients of 0.84 and 0.73, respectively), while 6-month reliability was moderate. STAR-Q-derived TEE and AEE were moderately correlated with DLW estimates (Spearman's rhos of 0.53 and 0.40, respectively; P < 0.001), and on average, the STAR-Q overestimated TEE and AEE (median differences were 367 kcal/day and 293 kcal/day, respectively). Body mass index-, age-, sex-, and season-adjusted concordance correlation coefficients (CCCs) were 0.24 (95% confidence interval (CI): 0.07, 0.36) and 0.21 (95% CI: 0.11, 0.32) for STAR-Q-derived versus DLW-derived TEE and AEE, respectively. Agreement between the diaries and STAR-Q (metabolic equivalent-hours/day) was strongest for occupational sedentary time (adjusted CCC = 0.76, 95% CI: 0.64, 0.85) and overall strenuous activity (adjusted CCC = 0.64, 95% CI: 0.49, 0.76). The STAR-Q demonstrated substantial validity for estimating occupational sedentary time and strenuous activity and fair validity for ranking individuals by AEE. PMID- 25038922 TI - Nonfluoroscopic catheter visualization in atrial fibrillation ablation: experience from 375 consecutive procedures. AB - BACKGROUND: A technological platform (MediGuide) has been recently introduced for nonfluoroscopic catheter tracking. No data on the safety of this technology are yet available in a large cohort of patients. METHODS AND RESULTS: Data from a prospective ablation registry were analyzed. All patients undergoing atrial fibrillation ablation procedures supported by nonfluoroscopic catheter visualization technology were included. Patient characteristics and procedural data and complications within the first 3 months were recorded. Between May 2012 and February 2014, a total of 375 patients underwent atrial fibrillation ablation using nonfluoroscopic catheter visualization technology. The patients were predominantly men (68%); the majority were ablated for the first time (71%); left atrium was 43+/-6 mm; and left ventricular function was normal (59+/-9%). The median ablation procedure time was 135 (113-170) minutes, median fluoroscopy time 2.8 (1.5-4.4) minutes, and median radiation dose 789 (470-1466) cGy*cm(2). Regression analysis demonstrated a significant decrease of fluoroscopy time, dose, and procedure time. To confirm the result and show overall changes, the initial 50 cases (group 1) to the last 50 cases (group 2) of the series were compared: fluoroscopy time decreased from 6.0 (4.1-10.3) minutes in group 1 to 1.1 (0.7-1.5) minutes in group 2 and radiation dose from 2363 (1413-3475) to 490 (230-654) cGy*cm(2), respectively. Ten patients (2.7%) experienced complications: 5 cardiac tamponades (1.4%), 4 pseudoaneurysms (1.1%), and 1 stroke (0.3%). CONCLUSIONS: Atrial fibrillation ablation using the nonfluoroscopic catheter visualization technology is safe with a rate of complications of 2.7%. Procedure time (135 minutes) is not prolonged. A dramatic reduction in fluoroscopy time and dose was achieved. PMID- 25038924 TI - Retraction. Electrical transmission between mammalian neurons is supported by a small fraction of gap junction channels. PMID- 25038923 TI - Warwick Hillier: a tribute. AB - Warwick Hillier (October 18, 1967-January 10, 2014) made seminal contributions to our understanding of photosynthetic water oxidation employing membrane inlet mass spectrometry and FTIR spectroscopy. This article offers a collection of historical perspectives on the scientific impact of Warwick Hillier's work and tributes to the personal impact his life and ideas had on his collaborators and colleagues. PMID- 25038925 TI - PPCPs removal by aerobic granular sludge membrane bioreactor. AB - An aerobic granular sludge membrane bioreactor (GMBR) was applied to the treatment of pharmaceutical and personal care products (PPCPs) wastewater. The influence of granular sludge on five antibiotic and antiphlogistic PPCPs wastewater and the removal effect of methyl alcohol and conventional organic matter were investigated while constantly reducing the density of inflow organic matter. The results showed that the sludge granulation process in the system was rapid but unstable, and that the system exhibits a dissolution-reunion dynamic equilibrium. The reactor demonstrated varying removal effects of PPCPs on different objects. The use of a GMBR was more effective for the removal of prednisolone, naproxen, and ibuprofen; the first two drugs were lower the average removal rate of which reached 98.46 and 84.02 %, respectively; whereas the average removal rate of ibuprofen was 63.32 %. By contrast, the GMBR has an insignificant degradation effect on antibiotics such as amoxicillin, indicating that such antibiotic medicine is not easily degraded by microorganisms, which plays different roles in system operation. Because of the different chemical structures and characteristics of drugs that result in various degradation behavior. During the GMBR granulation process, the value of mixed liquor volatility suspended solids (MLVSS) gradually increases from 1.5 to 4.1 g/L during the GMBR granulation process, and the removal rate of CODCr reaches up to 87.98 %. After reducing the density of organic matter is reduced, the removal rates of NH3-N and TP both reach more than 90 %, respectively. Moreover, the proposed technique is considerably effective in the removal of methanol. PMID- 25038926 TI - Biochemical and biophysical characterization of PlyGRCS, a bacteriophage endolysin active against methicillin-resistant Staphylococcus aureus. AB - The increasing rate of resistance of pathogenic bacteria, such as Staphylococcus aureus, to classical antibiotics has driven research toward identification of other means to fight infectious disease. One particularly viable option is the use of bacteriophage-encoded peptidoglycan hydrolases, called endolysins or enzybiotics. These enzymes lyse the bacterial cell wall upon direct contact, are not inhibited by traditional antibiotic resistance mechanisms, and have already shown great promise in the areas of food safety, human health, and veterinary science. We have identified and characterized an endolysin, PlyGRCS, which displays dose-dependent antimicrobial activity against both planktonic and biofilm S. aureus, including methicillin-resistant S. aureus (MRSA). The spectrum of lytic activity for this enzyme includes all S. aureus and Staphylococcus epidermidis strains tested, but not other Gram-positive pathogens. The contributions of the PlyGRCS putative catalytic and cell wall binding domains were investigated through deletion analysis. The cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) catalytic domain displayed activity by itself, though reduced, indicating the necessity of the binding domain for full activity. In contrast, the SH3_5 binding domain lacked activity but was shown to interact directly with the staphylococcal cell wall via fluorescent microscopy. Site directed mutagenesis studies determined that the active site residues in the CHAP catalytic domain were C29 and H92, and its catalytic functionality required calcium as a co-factor. Finally, biochemical assays coupled with mass spectrometry analysis determined that PlyGRCS displays both N-acetylmuramoyl-L alanine amidase and D-alanyl-glycyl endopeptidase hydrolytic activities despite possessing only a single catalytic domain. These results indicate that PlyGRCS has the potential to become a revolutionary therapeutic option to combat bacterial infections. PMID- 25038927 TI - An exceptionally cold-adapted alpha-amylase from a metagenomic library of a cold and alkaline environment. AB - A cold-active alpha-amylase, AmyI3C6, identified by a functional metagenomics approach was expressed in Escherichia coli and purified to homogeneity. Sequence analysis showed that the AmyI3C6 amylase was similar to alpha-amylases from the class Clostridia and revealed classical characteristics of cold-adapted enzymes, as did comparison of the kinetic parameters K m and k cat to a mesophilic alpha amylase. AmyI3C6 was shown to be heat-labile. Temperature optimum was at 10-15 degrees C, and more than 70 % of the relative activity was retained at 1 degrees C. The pH optimum of AmyI3C6 was at pH 8-9, and the enzyme displayed activity in two commercial detergents tested, suggesting that the AmyI3C6 alpha-amylase may be useful as a detergent enzyme in environmentally friendly, low-temperature laundry processes. PMID- 25038928 TI - Application of cell co-culture system to study fat and muscle cells. AB - Animal cell culture is a highly complex process, in which cells are grown under specific conditions. The growth and development of these cells is a highly unnatural process in vitro condition. Cells are removed from animal tissues and artificially cultured in various culture vessels. Vitamins, minerals, and serum growth factors are supplied to maintain cell viability. Obtaining result homogeneity of in vitro and in vivo experiments is rare, because their structure and function are different. Living tissues have highly ordered complex architecture and are three-dimensional (3D) in structure. The interaction between adjacent cell types is quite distinct from the in vitro cell culture, which is usually two-dimensional (2D). Co-culture systems are studied to analyze the interactions between the two different cell types. The muscle and fat co-culture system is useful in addressing several questions related to muscle modeling, muscle degeneration, apoptosis, and muscle regeneration. Co-culture of C2C12 and 3T3-L1 cells could be a useful diagnostic tool to understand the muscle and fat formation in animals. Even though, co-culture systems have certain limitations, they provide a more realistic 3D view and information than the individual cell culture system. It is suggested that co-culture systems are useful in evaluating the intercellular communication and composition of two different cell types. PMID- 25038929 TI - Isolation of a Bluetongue virus group-specific monoclonal antibody and application to a diagnostic competitive ELISA. AB - The Bluetongue virus (BTV) VP7 protein represents an important group-specific antigen that can serve as a basis for diagnostic tests. Here, we report the generation of a novel BTV group-specific monoclonal antibody (Mab; herein named 4H7) that recognizes a conformational epitope in the VP7 protein. We used a phage displayed peptide screen and site-directed mutagenesis to define the VP7 amino acid residues that most strongly contribute to the conformational epitope recognized by Mab 4H7. Amino acid residues at positions 175, 185, 186, and 278 of the BTV VP7 protein strongly contributed to Mab 4H7 binding. These key amino acid residues are conserved among all BTV serotypes, whereas related Orbiviruses possess at least one amino acid substitution at these positions. We developed a competitive enzyme-linked immunosorbent assay (c-ELISA) using Mab 4H7 and recombinant BTV VP7 protein to detect serum antibodies against this BTV group specific VP7 epitope. The c-ELISA was used to screen 833 clinical samples collected from animals in three provinces of China. BTV seroprevalence in the three provinces ranged from 25.42 to 47.45 %. This work provides the foundation for a new diagnostic c-ELISA that can be further applied to BTV surveillance activities and informs our understanding of the structure of the BTV VP7 protein. PMID- 25038930 TI - Efficient enzymatic systems for synthesis of novel alpha-mangostin glycosides exhibiting antibacterial activity against Gram-positive bacteria. AB - Two enzymatic systems were developed for the efficient synthesis of glycoside products of alpha-mangostin, a natural xanthonoid exhibiting anti-oxidant, antibacterial, anti-inflammatory, and anticancer activities. In these systems, one-pot reactions for the synthesis of UDP-alpha-D-glucose and UDP-alpha-D-2 deoxyglucose were modified and combined with a glycosyltransferase (GT) from Bacillus licheniformis DSM-13 to afford C-3 and C-6 position modified glucose and 2-deoxyglucose conjugated novel alpha-mangostin derivatives. alpha-Mangostin 3-O beta-D-glucopyranoside, alpha-mangostin 6-O-beta-D-glucopyranoside, alpha mangostin 3,6-di-O-beta-D-glucopyranoside, alpha-mangostin 3-O-beta-D-2 deoxyglucopyranoside, alpha-mangostin 6-O-beta-D-2-deoxyglucopyranoside, and alpha-mangostin 3,6-di-O-beta-D-2-deoxyglucopyranoside were successfully produced in practical quantities and characterized by high-resolution quadruple time-of flight electrospray ionization-mass spectrometry (HR-QTOF ESI/MS), (1)H and (13)C NMR analyses. In excess of the substrate, the maximum productions of three alpha mangostin glucopyranosides (4.8 mg/mL, 86.5 % overall conversion of alpha mangostin) and three alpha-mangostin 2-deoxyglucopyronosides (4.0 mg/mL, 79 % overall conversion of alpha-mangostin) were achieved at 4-h incubation period. All the alpha-mangostin glycosides exhibited improved water solubility, and their antibacterial activity against three Gram-positive bacteria Micrococcus luteus, Bacillus subtilis, and Staphylococcus aureus was drastically enhanced by the glucosylation at C-3 position. In this study, diverse glycosylated alpha mangostin were produced in significant quantities by using inexpensive starting materials and recycling co-factors within a reaction vessel without use of expensive NDP-sugars in the glycosylation reactions. PMID- 25038931 TI - Expansion of the role of web-based social networks related to synthetic mesh/tape complications. AB - PURPOSE: To update a prior report on web-based networks and frequently visited forums used by patients affected by synthetic mesh and/or tape (SMT) complications and to present the new developments in this dynamic SMT field following recent FDA notifications. METHODS: A review of available blogs and forums on SMT complications was conducted using the terms "mesh complications", "mesh blogs", and "polypropylene mesh removal" in Internet search engines for the United States and several other countries. Forums from a prior report were analyzed for updates, and new forums with their founders were identified using same search methodology. The number of posts and new fields from 07/2011 to 10/2013 was recorded, and then divided into categories based on broad content (personal stories, supportive replies to complaints, patients recommending physicians, legal stories, newspaper/article stories with reactions, other). RESULTS: Although four social networks became inactive, four expanded and at least five new major ones surfaced. While personal stories and support remained a prominent topic of discussion, other categories increased, such as the number of posts discussing physician referrals and reactions to news stories. Additionally, the number of posts designated to personal stories decreased. Finally, discussion about the topic expanded internationally. CONCLUSION: Web-based social networks for women suffering from SMT have expanded and the contents have broadened with new domains being introduced. Patient networking remains a dynamic force in the current debate on the future of these procedures. PMID- 25038932 TI - Inflammatory appendix mass in patients with acute appendicitis: CT diagnosis and clinical relevance. AB - The purpose of our study was to analyze the clinical relevance of computerized tomography (CT) in providing the diagnosis of inflammatory appendix mass (IAM) in patients with acute appendicitis. The CT images of 134 patients were reviewed. Two groups of patients were made according to the presence (group 1; n = 21) or the absence (group 2; n = 113) of IAM. Clinical signs of patients, CT features, complications at surgery, and histological examinations were noted. Inter observer agreement was assessed by using kappa statistics. Twenty-one patients presenting with CT features of IAM were diagnosed. An excellent inter-observer agreement (kappa = 0.94) was assessed for the diagnosis of IAM. No significant statistical difference in the age distribution was observed between patients with IAM (mean age 55) and patients without (mean age 45) (p = 0.2232). No clinical sign showed a statistically significant association with the presence of IAM (p = 0.707) or with complication encountered at surgery (p = 0.180). Delay to CT examination was 5.4 days in patients presenting with CT features of IAM and of 1.7 days for patients presenting without (p = 0.0001). Conversely to acute appendicitis complicated by simple perforation (p = 0.153) or peri-appendicular abscess (p = 0.501), acute appendicitis presenting with IAM showed a statistically significant association with complications encountered at surgery (p = 0.0003) and the need for conversion to open surgery (p = 0.001). Performing CT in complicated acute appendicitis provides the diagnosis of IAM. Distinction of IAM appeared to be of clinical relevance, since immediate surgery in IAM was statistically associated with surgical complications and conversion to open surgery in our study. PMID- 25038933 TI - Overexpression of the PLAP-1 gene inhibits the differentiation of BMSCs into osteoblast-like cells. AB - Periodontal ligament-associated protein-1 (PLAP-1) is a newly discovered member of the extracellular matrix family of proteins known as proteoglycans and is a negative regulator that plays a crucial role in the homeostasis of periodontal tissues. It can protect the periodontal ligament from excessive osteogenesis. However, the molecular mechanisms of PLAP-1 during osteogenic differentiation and osteogenesis remain unclear. In this study, we constructed a PLAP-1 recombinant retroviral plasmid vector named pBABE-hygro-PLAP-1. We transfected this plasmid into rat bone marrow stromal cells (rBMSCs) to obtain a stable cell line with overexpression of PLAP-1 to verify whether PLAP-1 also acts as an inhibitory factor in rBMSCs during bone mineralization. A rBMSC line stably overexpressing PLAP-1 was established successfully as determined by the mRNA levels of PLAP-1, which were measured by real time-qPCR (RT-qPCR), and protein expression, which was measured by immunocytochemistry and western blot analysis. At the same time, a Cell Counting Kit-8 assay did not reveal any statistically significant changes in the transfected cells (P > 0.05). Then, mineral-inducing cultures were performed, and mineralized nodules were observed at weeks 2, 3 and 4 under a microscope. Alizarin Red (Sigma) staining was performed at 4 week to illustrate calcium accumulation. The mineralized nodules in the PLAP-1-transfected rBMSC group were fewer than those in the control groups. The time span of the formation of the mineralized nodules was prolonged. Meanwhile, osteogenic genes were also detected in the mineral-inducing cells by RT-qPCR. An RT-qPCR analysis demonstrated that the levels of the osteoblast markers of rBMSCs that were transfected with pBABE-hygro-PLAP-1, including Runx2, Osterix, alkaline phosphatase, bone sialoprotein and osteocalcin, were lower than those in the non transfected rBMSCs and rBMSCs that were transfected with empty vector (P < 0.01). These results suggest that PLAP-1 has an inhibitory function in rBMSCs when they differentiate into osteoblast-like cells. PMID- 25038934 TI - It's Time: The Case for PrEP as an Active Comparator in HIV Biomedical Prevention Trials. AB - In July 2012, based on evidence from two major trials, the United States Food and Drug Administration approved the use of combined oral tenofovir/emtricitabine as pre-exposure prophylaxis (PrEP) for people at high risk of HIV acquisition. PrEP effectiveness is marred by poor adherence, however, even in trial populations, thus it is not a magic bullet for HIV prevention. It is, however, the most effective biomedical HIV prevention intervention available for people at high risk of HIV, particularly those who have receptive sex and lack the power to negotiate condom use. Accordingly, there are compelling reasons to compare future experimental HIV prevention interventions against PrEP. The interests both of trial participants and of science are served by using PrEP as comparator: Not only would HIV incidence be reduced, but also the question of whether new interventions were superior to best proven interventions, in a given setting, would be answered comprehensively. PMID- 25038935 TI - Reflechi twop--thinking too much: description of a cultural syndrome in Haiti's Central Plateau. AB - A rich Haitian ethnopsychology has been described, detailing concepts of personhood, explanatory models of illness, and links between mind and body. However, little research has engaged explicitly with mental illness, and that which does focuses on the Kreyol term fou (madness), a term that psychiatrists associate with schizophrenia and other psychoses. More work is needed to characterize potential forms of mild-to-moderate mental illness. Idioms of distress provide a promising avenue for exploring common mental disorders. Working in Haiti's Central Plateau, we aimed to identify idioms of distress that represent cultural syndromes. We used ethnographic and epidemiologic methods to explore the idiom of distress reflechi twop (thinking too much). This syndrome is characterized by troubled rumination at the intersection of sadness, severe mental disorder, suicide, and social and structural hardship. Persons with "thinking too much" have greater scores on the Beck Depression Inventory and Beck Anxiety Inventory. "Thinking too much" is associated with 8 times greater odds of suicidal ideation. Untreated "thinking too much" is sometimes perceived to lead to psychosis. Recognizing and understanding "thinking too much" may allow early clinical recognition and interventions to reduce long-term psychosocial suffering in Haiti's Central Plateau. PMID- 25038936 TI - Transcription factors controlling innate lymphoid cell fate decisions. AB - The mucosal epithelium is in direct contact with symbiotic and pathogenic microorganisms. Therefore, the mucosal surface is the principal portal of entry for invading pathogens and immune cells accumulated in the intestine to prevent infections. In addition to these conventional immune system functions, it has become clear that immune cells during steady-state continuously integrate microbial and nutrient-derived signals from the environment to support organ homeostasis. A major role in both processes is played by a recently discovered group of lymphocytes referred to as innate lymphoid cells (ILCs) Innate lymphoid cells (ILCs) that are specifically enriched at mucosal surfaces but are rather rare in secondary lymphoid organs. In analogy to the dichotomy between CD8 and CD4 T cells, we propose to classify ILCs into interleukin-7 receptor alpha negative cytotoxic ILCs and IL-7Ralpha(+) helper-like ILCs. Dysregulated immune responses triggered by the various ILC subsets have been linked to inflammatory diseases such as inflammatory bowel disease, atopic dermatitis and airway hyperresponsiveness. Here, we will review recent progress in determining the transcriptional and developmental programs that control ILC fate decisions. PMID- 25038938 TI - Inactivated and adjuvanted influenza vaccines. AB - Inactivated influenza vaccines are produced every year to fight against the seasonal epidemics of influenza. Despite the nonoptimal coverage, even in subjects at risk like the elderly, pregnant women, etc., these vaccines significantly reduce the burden of mortality and morbidity linked to the influenza infection. Importantly, these vaccines have also contributed to reduce the impact of the last pandemics. Nevertheless, the performance of these vaccines can be improved mainly in those age groups, like children and the elderly, in which their efficacy is suboptimal. The use of adjuvants has proven effective to this scope. Oil-in-water adjuvants like MF59 and AS03 have been licensed and widely used, and shown efficacious in preventing influenza infection in the last pandemic. MF59-adjuvanted inactivated vaccine was more efficacious than non adjuvanted vaccine in preventing influenza infection in young children and in reducing hospitalization due to the influenza infection in the elderly. Other adjuvants are now at different stages of development and some are being tested in clinical trials. The perspective remains to improve the way inactivated vaccines are prepared and to accelerate their availability, mainly in the case of influenza pandemics, and to enhance their efficacy/effectiveness for a more successful impact at the public health level. PMID- 25038939 TI - Skin immunization with influenza vaccines. AB - Problems with existing influenza vaccines include the strain specificity of the immune response, resulting in the need for frequent reformulation in response to viral antigenic drift. Even in years when the same influenza strains are prevalent, the duration of immunity is limited, and results in the need for annual revaccination. The immunogenicity of the present split or subunit vaccines is also lower than that observed with whole inactivated virus, and the vaccines are not very effective in high risk groups such as the young or the elderly. Vaccine coverage is incomplete, due in part to concerns about the use of hypodermic needles for delivery. Alternative approaches for vaccination are being developed which address many of these concerns. Here we review new approaches which focus on skin immunization, including the development of needle-free delivery systems which use stable dry formulations and induce stronger and longer lasting immune responses. PMID- 25038940 TI - Host detection and the stealthy phenotype in influenza virus infection. AB - The innate host response to influenza virus infection plays a critical role in determining the subsequent course of infection and the clinical outcome of disease. The host has a diverse array of detection and effector mechanisms that are able to recognize and initiate effective antiviral responses. In opposition, the virus utilizes a number of distinct mechanisms to evade host detection and effector activity in order to remain "stealthy" throughout its replication cycle. In this review, we describe these host and viral mechanisms, including the major pattern recognition receptor families (the TLRs, NLRs, and RLRs) in the host and the specific viral proteins such as NS1 that are key players in this interaction. Additionally, we explore nonreductive mechanisms of viral immune evasion and propose areas important for future inquiry. PMID- 25038941 TI - Preparing for microbicide introduction, rollout, and sustained access. AB - Two topical vaginal microbicide candidates for HIV prevention are at an advanced stage of clinical testing, with efficacy results from three clinical trials expected within the next 2 years. Therefore, preparations for introducing and ensuring access to these products in the event that they are proven safe and effective now require increased attention. Microbicides are expected to fill an important global public health need for HIV prevention options for women. They have been developed almost exclusively with public and private funding through academic and nongovernmental institutions and minimal involvement of commercial pharmaceutical partners. Efficient and rapid introduction of a new public health technology requires a broad range of expertise and collaborations, some of which are new to the microbicide field as products are at last completing late-stage pivotal licensure studies. Strong leadership, political commitment, and considerable financial investments will be required to ensure successful distribution as well as uptake and continued access to this new product class. This paper highlights work conducted since 2000 by scientists, advocates, and public health officials to prepare for microbicide introduction, and discusses some of the needed actions to ensure that products will become readily accessible to the women who need them. PMID- 25038937 TI - Molecular determinants of influenza virus pathogenesis in mice. AB - Mice are widely used for studying influenza virus pathogenesis and immunology because of their low cost, the wide availability of mouse-specific reagents, and the large number of mouse strains available, including knockout and transgenic strains. However, mice do not fully recapitulate the signs of influenza infection of humans: transmission of influenza between mice is much less efficient than in humans, and influenza viruses often require adaptation before they are able to efficiently replicate in mice. In the process of mouse adaptation, influenza viruses acquire mutations that enhance their ability to attach to mouse cells, replicate within the cells, and suppress immunity, among other functions. Many such mouse-adaptive mutations have been identified, covering all 8 genomic segments of the virus. Identification and analysis of these mutations have provided insight into the molecular determinants of influenza virulence and pathogenesis, not only in mice but also in humans and other species. In particular, several mouse-adaptive mutations of avian influenza viruses have proved to be general mammalian-adaptive changes that are potential markers of pre pandemic viruses. As well as evaluating influenza pathogenesis, mice have also been used as models for evaluation of novel vaccines and anti-viral therapies. Mice can be a useful animal model for studying influenza biology as long as differences between human and mice infections are taken into account. PMID- 25038942 TI - Single port video-assisted thoracic surgery: advancing scope technology. PMID- 25038943 TI - Reply to Ng et al. PMID- 25038944 TI - Dietary fiber intake and risk of renal cell carcinoma: evidence from a meta analysis. AB - The aim of this study was to investigate the possible relationships between dietary fiber intake and risk of renal cell carcinoma (RCC). Electronic databases including MEDLINE, EMBASE and Web of Science were searched to find eligible studies. Random-effects relative risk (RR) and its corresponding 95 % confidence interval (CI) were used. Besides, random-effects dose-response analyses were also performed to clarify the dose-response relations. Finally, publication bias was assessed by Egger's test and Begg's test. All p values were two tailed. Seven studies, including two cohort studies and five case-control studies, were eligible and included in this meta-analysis. Overall analysis in highest versus lowest level revealed that total dietary fiber intake was associated with reduced RCC risk (RR 0.84, 95 % CI 0.74-0.96). In addition, pooled estimated data showed that risk of RCC was significantly associated with vegetable and legume fiber intake (RR 0.70, RR 0.80, respectively), but not with fruit and cereal fiber intake (RR 0.92, RR 1.04, respectively). However, in dose-response analysis, no significant association was reported. Finally, no publication bias was detected by Egger's or Begg's test. The dietary fiber intake, especially vegetable and legume fiber, may be associated with reduced RCC risk. Considering the limitations of the included studies, more well-designed prospective studies will be needed to confirm our findings. PMID- 25038945 TI - Bacterioplanes sanyensis gen. nov., sp. nov., a PHB-accumulating bacterium isolated from a pool of Spirulina platensis cultivation. AB - A Gram-negative, poly-3-hydroxybutyrate-accumulating rod bacterium, strain GYP 2(T), was isolated from a pool of marine Spirulina platensis cultivation, Sanya, China. Growth was observed at 10-45 degrees C and pH 6-10 in the presence of 1 10 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the new isolate belonged to Gammaproteobacteria and displayed 93.8-95.3 % 16S rRNA gene sequences similarities to members of the genera Thalassolituus, Oleibacter, and Oceanobacter, but house-keeping gene gyrB (encode DNA gyrase beta subunit) demonstrated that the new isolate was distantly related to Thalassolituus, Oleibacter, and Oceanobacter species (only 77-83 % gene gyrB sequences similarities).The G+C content of genomic DNA was 55 mol%. The major respiratory quinone was Q-9, while that for Oceanobacter kriegii LMG 6238(T) was Q-8. Major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. On the basis of its physiological, chemotaxonomic, and molecular properties, strain GYP-2(T) is suggested to represent a novel species of a new genus in Gammaproteobacteria, for which the name Bacterioplanes sanyensis gen. nov., sp. nov. is proposed. The type strain is GYP-2(T) (=CGMCC 1.12392(T)=KCTC 32220(T)). PMID- 25038947 TI - Continuous monitoring of endotracheal tube positioning: closer to the sangreal? PMID- 25038948 TI - Rapid detection of Listeria monocytogenes in raw milk and soft cheese by a redox potential measurement based method combined with real-time PCR. AB - The incidence of outbreaks of foodborne listeriosis has indicated the need for a reliable and rapid detection of the microbe in different foodstuffs. A method combining redox potential measurement and real-time polymerase chain reaction (PCR) was developed to detect Listeria monocytogenes in artificially contaminated raw milk and soft cheese. Food samples of 25 g or 25 ml were homogenised in 225 ml of Listeria Enrichment Broth (LEB) with Oxford supplement, and the redox potential measurement technique was applied. For Listeria species the measuring time was maximum 34 h. The absence of L. monocytogenes could reliably be proven by the redox potential measurement method, but Listeria innocua and Bacillus subtilis could not be differentiated from L. monocytogenes on the basis of the redox curves. The presence of L. monocytogenes had to be confirmed by real-time PCR. The combination of these two methods proved to detect < 10 cfu/g of L. monocytogenes in a cost- and time-effective manner. This method can potentially be used as an alternative to the standard nutrient method for the rapid detection of L. monocytogenes in food. PMID- 25038946 TI - DNA repair abnormalities leading to ataxia: shared neurological phenotypes and risk factors. AB - Since identification of mutations in the ATM gene leading to ataxia telangiectasia, enormous efforts have been devoted to discovering the roles this protein plays in DNA repair as well as other cellular functions. Even before the identification of ATM mutations, it was clear that other diseases with different genomic loci had very similar neurological symptoms. There has been significant progress in understanding why cancer and immunodeficiency occur in ataxia telangiectasia even though many details remain to be determined, but the field is no closer to determining why the nervous system requires ATM and other DNA repair genes. Even though rodent disease models have similar DNA repair abnormalities as the human diseases, they have no consistent, robust neuropathological phenotype making it difficult to understand the neurological underpinnings of disease. Therefore, it may be useful to reassess the neurological and neuropathological characteristics of ataxia-telangiectasia in human patients to look for potential commonalities in DNA repair diseases that result in ataxia. In doing so, it is clear that ataxia-telangiectasia and similar diseases share neurological features other than merely ataxia, such as length-dependent motor and sensory neuropathies, and that the neuroanatomical localization for these symptoms is understood. Cells affected in ataxia-telangiectasia and similar diseases are some of the largest single nucleated cells in the body. In addition, a subset of these diseases also has extrapyramidal movements and oculomotor apraxia. These neurological and neuropathological similarities may indicate a common DNA repair related pathogenesis with very large cell size as a critical risk factor. PMID- 25038949 TI - Effect of arginine or glutamine supplementation on production, organ weights, interferon gamma, interleukin 6 and antibody titre of broilers. AB - The objective of this study was designed to test whether supplementation of the diet with arginine (Arg) or glutamine (Gln) or their combination influences the production, organ weights and humoral immune response of broilers. A total of 432 one-day-old male Ross 308 broiler chickens were divided into 6 treatment groups: control, Arg-0.5%, Arg-1%, Gln-0.5%, Gln-1% and Arg-0.5%+Gln-0.5%. Drinking water and feed were provided ad libitum. On day 18 of the experiment 50% of chickens in each treatment group were immunised with bovine serum albumin. Ten and 21 days after immunisation blood samples were collected to determine the anti-albumin IgY titre, interleukin 6 (IL6) and interferon gamma (IFNG) and to measure the weight of the liver, spleen, bursa of Fabricius and thymus. Arg or Gln supplementation of the diets influenced neither the production nor the organ weights until 18 days of age. Between 18 and 39 days of age both Arg (0.5% and 1%) and Arg + Gln supplementation improved the feed conversion ratio (FCR) by 3.7%, 6.3% and 4.9%, respectively, while Gln-1% worsened it by 15%. Immunisation slightly (-0.79%) depressed the body weight gain of broilers fed the control diet, which was significantly improved by both Arg (0.5 or 1%) and Arg + Gln supplementation. Immunisation increased the weight of the spleen, bursa and thymus and decreased that of the liver. Supplementation with 1% Gln depressed (-5.13%) the body weight gain of the immunised chickens but strongly stimulated the immune response. Supplementations with Arg and Gln did not influence the IL6 and IFNG level of the blood; however, on day 10 after immunisation these two parameters showed a negative correlation with each other. Regarding production, organ weights and immunity, Arg supplementation should be recommended in the grower phase, while Gln supplementation can be useful in pullets raised for egg production, where a good immune response to vaccinations is an important factor. PMID- 25038950 TI - Non-primate hepacivirus infection with apparent hepatitis in a horse - Short communication. AB - Non-primate hepacivirus (NPHV) is a recently identified hepacivirus (family Flaviviridae) in dog and horse; however, the disease associations remain unknown. This study reports the detection of natural NPHV infection in a horse with apparent hepatitis, liver damage and high-level viraemia. NPHV could be hepatotropic and associated with hepatitis in horses. PMID- 25038951 TI - A new operative technique for aural haematoma in dogs: A retrospective clinical study. AB - Aural haematoma is treated either by surgical or by conservative treatment. Both techniques usually require several interventions and re-checks. A new operation technique has been evaluated that requires only a single procedure but is as effective as the techniques used previously. The haematoma is opened, cleaned surgically and the two layers of the auricular cartilage are appositioned inside with several suture lines placed on both sides of the incision, alternating the sides approaching to the sagittal cavity. None of the suture lines is stitched through the auricle completely as they all run intradermally on the side of the haematoma and to the cartilage on the other side. Twenty-three dogs with aural haematoma were treated between 2006 and 2012. In 21 (91%) of them, the haematoma healed without any auricle deformity. No secondary intervention was necessary in any of the cases. None of the 23 animals experienced a relapse during follow-up. The new method offers a minor risk of postoperative complications while accomplishing high healing rates. PMID- 25038952 TI - Viability and discrimination of avian peripheral blood mononuclear cells and thrombocytes intended for improvement of wound healing in birds. AB - Birds often suffer from skin injuries of different aetiology. Platelet-rich plasma (PRP) is successfully used for improvement of wound healing in humans and in some mammalian species (e.g. horses, dogs and cats), but experience with its application in avian patients has not yet been published. Therefore, the aim of this study was to test a quick method for the counting of isolated avian platelets and mononuclear leukocytes and to find an appropriate carrier for their application to the wounds of birds. It seems that flow cytometry can be used for the quick counting of isolated cells and the discrimination of thrombocytes, lymphocytes and eventually monocytes or debris. Of the tested gels and sponges routinely used for improvement of wound healing, a gelatin sponge (Gelaspon(r)) providing the highest numbers and viability of isolated cells proved to be the best carrier. PMID- 25038953 TI - In vitro effects of doxorubicin and deracoxib on oxidative-stress-related parameters in canine mammary carcinoma cells. AB - The present study evaluated the effects of doxorubicin (DOX) and deracoxib (DER), as single agents and in combination treatments, on antioxidant parameters in the canine mammary carcinoma cell line CMT-U27. The cells were exposed to DOX and DER for 24, 48 and 72 h. The viability and malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and total glutathione (GSH) activities of CMT-U27 cells were determined. The half inhibition concentration (IC50) of DOX was found to be ~0.9 MUM in the 72-h period. IC50 and 1/10 IC50 concentrations of DOX were combined with all concentrations of DER (50-1000 MUM) in the combination experiments. The results showed increased oxidative status associated with significant decreases of CAT and GSH levels in CMT-U27 cells exposed to 10-MUM and higher concentrations of DOX compared to control cells. In contrast, there were no significant changes in the groups tested with any of the concentrations of DER (50-1000 MUM). In combination treatments, DER attenuated DOX-induced oxidative damage by modulating the enzymatic and non-enzymatic components in CMT-U27 cells. We suggest that the combination of DOX and DER can be beneficial in the treatment of cancer cells by increasing cellular responses to oxidative stress. In conclusion, the use of COX inhibitor in conjunction with a chemotherapeutic agent may provide a basis for new concepts of cancer treatment through systematic modulation of the antioxidant defence systems in mammary cancers of animals. PMID- 25038954 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters steroid secretion but does not affect cell viability and the incidence of apoptosis in porcine luteinised granulosa cells. AB - The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a by-product of human industrial activity, was found to affect ovarian steroidogenesis in animals, but the mechanism of its action is still unclear. The aims of the study were to examine the effect of TCDD on (1) progesterone (P4) and oestradiol (E2) production by granulosa cells isolated from medium (3-6 mm) and preovulatory (>= 8 mm) porcine follicles, (2) the viability of the cells, and (3) the incidence of apoptosis. Porcine granulosa cells were cultured (48 h) with or without TCDD (100 pM, 100 nM). Steroid hormone concentrations in the medium were determined by radioimmunoassay. The viability of granulosa cells was tested spectrophotometrically (alamarBlueTM assay). Apoptosis was evaluated by flow cytometry using Annexin V and by TUNEL assay. The higher dose of TCDD (100 nM) significantly inhibited P4 and stimulated E2 production by luteinised granulosa cells isolated from medium follicles. The lower dose of TCDD (100 pM) significantly stimulated P4 and inhibited E2 secretion by the cells isolated from preovulatory follicles. None of the two TCDD doses affected cell viability or induced apoptosis in granulosa cells. In conclusion, TCDD directly affected steroid production by granulosa cells obtained from mature pigs, but the effect of TCDD was not due to its cytotoxicity. PMID- 25038955 TI - Impact of a vendor-specific motion-correction algorithm on image quality, interpretability, and diagnostic performance of daily routine coronary CT angiography: influence of heart rate on the effect of motion-correction. AB - To investigate the impact of a vendor-specific motion-correction algorithm on morphological assessment of coronary arteries using coronary CT angiography (cCTA) and to evaluate the influence of heart rate (HR) on the motion-correction effect of this algorithm. Eighty-four patients (mean age 56.3 +/- 11.4 years; 53 males) were divided into two groups with a HR of >=65 and <65 bpm during cCTA, respectively. Images were assigned quality scores (graded 1-4) on coronary segments. Interpretability was defined as a grade >1. Catheter angiography was used to determine the diagnostic accuracy of cCTA for detecting significant stenosis (>=50 %). We compared the image quality, interpretability and diagnostic accuracy between the standard and motion-correction reconstructions in both groups. The motion-correction reconstructions showed significantly (p < 0.05) higher image quality in the proximal and middle right coronary artery (RCA) in the low HR group (57.2 +/- 5.0 bpm; n = 51) and proximal-to-distal RCA, posterior descending artery, and proximal and distal left circumflex artery in the high HR group (71.1 +/- 4.6 bpm; n = 33). The per-segment interpretability was significantly higher using motion-correction algorithm in the middle RCA in the low HR group and in the proximal and middle RCA in high HR group. Overall, the image quality and interpretability were improved using motion-correction reconstructions in both groups (p < 0.05). Motion-correction reconstruction demonstrated higher (p < 0.05) diagnostic accuracy in 25 patients from both groups. Use of the motion-correction algorithm improves the overall image quality and interpretability of cCTA in both groups. However, it may be more beneficial to the patients with a higher HR. PMID- 25038956 TI - The adenylyl cyclase Rv2212 modifies the proteome and infectivity of Mycobacterium bovis BCG. AB - All organisms have the capacity to sense and respond to environmental changes. These signals often involve the use of second messengers such as cyclic adenosine monophosphate (cAMP). This second messenger is widely distributed among organisms and coordinates gene expression related with pathogenesis, virulence, and environmental adaptation. Genomic analysis in Mycobacterium tuberculosis has identified 16 adenylyl cyclases (AC) and one phosphodiesterase, which produce and degrade cAMP, respectively. To date, ten AC have been biochemically characterized and only one (Rv0386) has been found to be important during murine infection with M. tuberculosis. Here, we investigated the impact of hsp60-driven Rv2212 gene expression in Mycobacterium bovis Bacillus Calmette-Guerin (BCG) during growth in vitro, and during macrophage and mice infection. We found that hsp60-driven expression of Rv2212 resulted in an increased capacity of replication in murine macrophages but an attenuated phenotype in lungs and spleen when administered intravenously in mice. Furthermore, this strain displayed an altered proteome mainly affecting proteins associated with stress conditions (bfrB, groEL-2, DnaK) that could contribute to the attenuated phenotype observed in mice. PMID- 25038957 TI - Ecomorphology and phylogenetic risk: Implications for habitat reconstruction using fossil bovids. AB - Reconstructions of paleohabitats are necessary aids in understanding hominin evolution. The morphology of species from relevant sites, understood in terms of functional relationships to habitat (termed ecomorphology), offers a direct link to habitat. Bovids are a speciose radiation that includes many habitat specialists and are abundant in the fossil record. Thus, bovids are extremely common in ecomorphological analyses. However, bovid phylogeny and habitat preference are related, which raises the possibility that analyses linking habitat with morphology are not 'taxon free' but 'taxon-dependent.' Here we analyze eight relative dimensions and one shape index of the metatarsal for a sample of 72 bovid species and one antilocaprid. The selected variables have been previously shown to have strong associations with habitat and to have functional explanations for these associations. Phylogenetic generalized least squares analyses of these variables, including habitat and size, resulted in estimates for the parameter lambda (used to model phylogenetic signal) varying from zero to one. Thus, while phylogeny, morphology, and habitat all march together among the bovids, the odds that phylogeny confounds ecomorphological analyses may vary depending on particular morphological characteristics. While large values of lambda do not necessarily indicate that habitat differences are unimportant drivers of morphology, we consider the low value of lambda for relative metatarsal width suggestive that conclusions about habitat built on observations of this particular morphology carry with them less 'phylogenetic risk.' We suggest that the way forward for ecomorphology is grounded in functionally relevant observations and careful consideration of phylogeny designed to bracket probable habitat preferences appropriately. Separate consideration of different morphological variables may help to determine the level of 'phylogenetic risk' attached to conclusions linking habitat and morphology. PMID- 25038958 TI - Physical mechanisms of coherent acoustic phonons generation by ultrafast laser action. AB - In this review we address the microscopic mechanisms that are involved in the photogeneration processes of GHz-THz coherent acoustic phonons (CAP) induced by an ultrafast laser pulse. Understanding and describing the underlying physics is necessary indeed for improving the future sources of coherent acoustic phonons useful for the non-destructive testing optoacoustic techniques. Getting more physical insights on these processes also opens new perspectives for the emerging field of the opto-mechanics where lattice motions (surface and/or interfaces ultrafast displacements, nanostructures resonances) are controlled by light. We will then remind the basics of electron-phonon and photon-phonon couplings by discussing the deformation potential mechanism, the thermoelasticity, the inverse piezoelectric effect and the electrostriction in condensed matter. Metals, semiconductors and oxide materials will be discussed. The contribution of all these mechanisms in the photogeneration process of sound will be illustrated over several examples coming from the rich literature. PMID- 25038959 TI - Compliance with recommended care at trauma centers: association with patient outcomes. AB - BACKGROUND: State health departments and the American College of Surgeons focus on the availability of optimal resources to designate hospitals as trauma centers, with little emphasis on actual delivery of care. There is no systematic information on clinical practices at designated trauma centers. The objective of this study was to measure compliance with 22 commonly recommended clinical practices at trauma centers and its association with in-hospital mortality. STUDY DESIGN: This retrospective observational study was conducted at 5 Level I trauma centers across the country. Participants were adult patients with moderate to severe injuries (n = 3,867). The association between compliance with 22 commonly recommended clinical practices and in-hospital mortality was measured after adjusting for patient demographics and injuries and their severity. RESULTS: Compliance with individual clinical practices ranged from as low as 12% to as high as 94%. After adjusting for patient demographics and injury severity, each 10% increase in compliance with recommended care was associated with a 14% reduction in the risk of death. Patients who received all recommended care were 58% less likely to die (odds ratio = 0.42; 95% CI, 0.28-0.62) compared with those who did not. CONCLUSIONS: Compliance with commonly recommended clinical practices remains suboptimal at designated trauma centers. Improved adoption of these practices can reduce mortality. PMID- 25038960 TI - Identifying variations in blood use based on hemoglobin transfusion trigger and target among hepatopancreaticobiliary surgeons. AB - BACKGROUND: Transfusion practice among surgeons varies despite several trials supporting the restrictive use of blood products. We sought to define the variation in surgeon transfusion hemoglobin (Hb) triggers and targets among patients undergoing hepatopancreaticobiliary (HPB) procedures, as well as assess perioperative outcomes among patients receiving transfusions under a restrictive vs liberal transfusion strategy. STUDY DESIGN: Using prospectively collected data, variations in transfusion Hb triggers, targets, and overall use of blood were examined among 1,554 patients undergoing an HPB procedure by 1 of 11 surgeons at Johns Hopkins Hospital between 2009 and 2013. Perioperative outcomes were compared among patients treated with a restrictive (Hb < 8 g/dL) vs liberal (Hb >= 8 g/dL) transfusion strategy. RESULTS: Among the 1,554 patients included in the cohort, 504 (32.4%) received at least 1 transfusion of red cells. Patients who received a transfusion were older and had more medical comorbidities (both p < 0.001). Among 620 patients who met inclusion for blood use analysis, 344 (55.5%) received a transfusion using a restrictive trigger, 160 (25.8%) with a liberal trigger, and 116 (18.7%) patients had an Hb < 8 g/dL but did not receive a transfusion. The mean transfusion Hb trigger was 7.7 +/- 1.1 g/dL and the mean target was 9.3 +/- 1.1 g/dL. Patients transfused with a higher Hb trigger were older, male, white, and had more medical comorbidities and higher intraoperative estimated blood loss (all p < 0.05). Hemoglobin transfusion triggers varied among different surgeons (p < 0.001). Perioperative mortality, complications, and length of stay did not differ between those treated with a restrictive vs liberal transfusion strategy (p > 0.05). CONCLUSIONS: Nearly 1 in 3 patients undergoing an HPB procedure received a blood transfusion in the perioperative period. Transfusion use, indication ("trigger"), and dose ("target") varied among surgeons. The use of a restrictive transfusion strategy did not affect perioperative outcomes. PMID- 25038961 TI - Gracilis muscle transposition for complex perineal fistulas and sinuses: a systematic literature review of surgical outcomes. PMID- 25038962 TI - American Society of Anesthesiologists on Children's Surgical Care. PMID- 25038963 TI - Pedicled cross-leg flaps. PMID- 25038964 TI - Reply: To PMID 24468231. PMID- 25038965 TI - The President's been shot. PMID- 25038967 TI - Greater omentum binding: a simple technique to cover the pancreatic remnant after distal pancreatectomy. PMID- 25038968 TI - Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues. AB - Traditional tissue engineering approaches to the restoration of orthopaedic tissues promise to be expensive and not well suited to treating large numbers of patients. Advances in gene transfer technology offer the prospect of developing expedited techniques in which all manipulations can be performed percutaneously or in a single operation. This rests on the ability of gene delivery to provoke the sustained synthesis of relevant gene products in situ without further intervention. Regulated gene expression is also possible, but its urgency is reduced by our ignorance of exactly what levels and periods of expression are needed for specific gene products. This review describes various strategies by which gene therapy can be used to expedite the repair and regeneration of orthopaedic tissues. Strategies include the direct injection of vectors into sites of injury, the use of genetically modified, allogeneic cell lines and the intra-operative harvest of autologous tissues that are quickly transduced and returned to the body, either intact or following rapid cell isolation. Data obtained from pre-clinical experiments in animal models have provided much encouragement that such approaches may eventually find clinical application in human and veterinary medicine. PMID- 25038969 TI - Comparison between reverse shoulder arthroplasty and Humerusblock in three- and four-part proximal humerus fractures in elderly patients. AB - PURPOSE: We set out to compare osteosynthesis using the minimally invasive, semi rigid, Humerusblock to reverse shoulder arthroplasty (RSA) for primary fracture treatment in three- and four-part fractures in patients over 65 years old. METHODS: In the study period from 2008 to 2011, we conducted a matched-pair analysis of 25 patients treated with reverse shoulder arthroplasty (group 1) to 25 patients treated with the Humerusblock (group 2). At the time of follow-up, a complete physical examination of the shoulders, including evaluation with the Constant-Murley score and the VAS pain scale, was performed. In addition, standard radiographs (true AP and axillary views) were taken to evaluate signs of malreduction, malunion, nonunion, scapular notching or radiolucent lines around the prosthesis. RESULTS: After a minimum follow-up of 12 months, the mean CMS differed significantly between groups 1 and 2 (47.4 vs 64.4, p<0.01). The mean abduction (97.6 degrees vs 126.8 degrees , p<0.01), anterior flexion (103.2 degrees vs 139.6 degrees , p<0.01) and external rotation (16 degrees vs 39.6 degrees ; p<0.01) were significantly worse in group 1. The VAS pain score was significantly lower in group 2 compared to group 1 (0.92 vs 3.12, p<0.01). CONCLUSIONS: This is the first study that compared the Humerusblock to reverse shoulder arthroplasty for primary fracture treatment. In this study, the functional outcome was superior in the Humerusblock group. PMID- 25038970 TI - Analysis of failure and clinical outcome after unsuccessful medial patellofemoral ligament reconstruction in young patients. AB - PURPOSE: Reconstruction of the medial patellofemoral ligament (MPFL) has become a popular procedure for patients with patellofemoral instability. Nevertheless, complication rates of up to 26 % have been reported. This study presents the analysis of failure and clinical outcome of subsequent revision surgery in young patients following unsuccessful medial patellofemoral ligament reconstruction. METHODS: Nineteen consecutive patients with unsuccessful MPFL reconstruction underwent revision surgery. Pre-operative assessment included physical examination, radiographs and magnetic resonance imaging to assess the MPFL graft, trochlear dysplasia, tibial tubercle-trochlear groove (TT-TG) distance, patella alta and femoral tunnel positioning. Evaluation also included the detection of cartilage injuries as well as visual analog scale (VAS), knee function scores and patient satisfaction. Each complication was analysed and an appropriate revision procedure was performed according to the identified technical or untreated anatomical risk factor. RESULTS: The average age at the time of the index operation was 20.2 years (range, 16-27 years). The average age at the time of the primary MPFL reconstruction was 18.4 years (range, 15-25). Three main reasons for failure after MPFL reconstruction could be identified: failure to consider additional risk factors, intra-operative technical errors and inappropriate patient selection. In five patients severe trochlear dysplasia and in two patients concomitant excessive femoral anteversion as additional risk factors were detected. Seven patients experienced medial retinacular pain with limited flexion due to technical errors caused in three patients by anterior placement of the femoral tunnel and in four others by overtensioning of the MPFL graft. Four patients with patellofemoral pain were found to have ICRS grade III or IV cartilage injuries. The median postoperative Kujala scores improved from 57 (34 - 73) pre-operatively to 83 (49 - 94), the median knee function improved from 5 (range, 2 - 6) pre-operatively to 8 (range, 3 - 10). Median VAS scores improved from 4 (2 - 7) to 2 (0 - 5). A total of 78.9% of patients were satisfied or very satisfied, 15.8% were partially satisfied and one patient (5.3%) was not satisfied with the result after revision surgery. CONCLUSION: Failure to consider additional risk factors, technical intra-operative errors and inappropriate patient selection were identified as reasons for revision surgery after MPFL reconstruction. Identifying the potential causes of failure can help to treat and possibly prevent future complications. PMID- 25038971 TI - Acetabular reconstruction using a free fibular autograft in total hip arthroplasty revisions. AB - PURPOSE: Acetabular reconstruction for segmentary bone loss aims for primary stability and long-lasting integration. The use of a fibular autograft has been described after tumour resection and in traumatology. The hypothesis of this study is that it offers a mechanically reliable solution with good functional results and acceptable morbidity. METHODS: This is a two center retrospective study of 26 operated hips. Indication was mechanical loosening in every case. The operative technique included fibular grafting of a segmental bone loss associated with an acetabular metal reinforcement. RESULTS: Mean follow up was 88 months (three to 165). The PMA score increased from 8.5 (five to 12) to 15 (six to 18) (p <0.001). Acetabular migration was 2 mm (0-4) vertically and 1 mm (0-2) medially. Three graft failures were observed. No major morbidity was observed. CONCLUSION: Fibular autograft after mechanical loosening and segmentary bone loss in total hip arthroplasty revisions offers a mechanically reliable solution for acetabular reconstruction. The results seem to be at least equivalent to other techniques. PMID- 25038972 TI - Radial tunnel syndrome: results of surgical decompression by a postero-lateral approach. AB - PURPOSE: Our purpose is to describe the results obtained in surgical treatment of a series of patients with symptoms of radial tunnel syndrome. METHODS: We performed a prospective study on 42 patients (43 limbs) operated for radial tunnel syndrome between 1996 and 2010, using a posterior-external approach. RESULTS: Using the Roles and Maudsley criteria, 21 patients had excellent results (48.8%), 16 good (37.2%) and six fair results (13.9%). Most patients were satisfied with the surgery, reporting symptom relief and improved functionality. CONCLUSIONS: Radial tunnel syndrome consists of intermittent compression of the posterior interosseous nerve in the forearm, with pain and functional disability of the forearm, without motor or sensory electromyogram alterations. Because it is often confused with enthesitis of the epicondyle muscle insertions (an entity often occurring simultaneously), differential diagnosis is necessary with treatment-resistant epicondylitis. The most effective treatment is surgical, releasing all possible nerve compression sites. PMID- 25038973 TI - Saving life and limb: limb salvage using external fixation, a multi-centre review of orthopaedic surgical activities in Medecins Sans Frontieres. AB - PURPOSE: While the orthopaedic management of open fractures has been well documented in developed settings, limited evidence exists on the surgical outcomes of open fractures in terms of limb salvage in low- and middle-income countries. We therefore reviewed the Medecins Sans Frontieres-Operational Centre Brussels (MSF-OCB) orthopaedic surgical activities in the aftermath of the 2010 Haiti earthquake and in three non-emergency projects to assess the limb salvage rates in humanitarian contexts in relation to surgical staff skills. METHODS: This was a descriptive retrospective cohort study conducted in the MSF-OCB surgical programmes in the Democratic Republic of Congo (DRC), Afghanistan, and Haiti. Routine programme data on surgical procedures were aggregated and analysed through summary statistics. RESULTS: In the emergency post-earthquake response in Haiti, 81% of open fracture cases were treated by amputation. In a non-emergency project in a conflict setting in DRC, relying on non-specialist surgeons receiving on-site supervision and training by experienced orthopaedic surgeons, amputation rates among open fractures decreased by 100 to 21% over seven years of operations. In two trauma centres in Afghanistan (national surgical staff supported from the outset by expatriate orthopaedic surgeons) and Haiti (national musculoskeletal surgeons trained in external fixation), amputation rates among long bone open fracture cases were stable at 20% and <10%, respectively. CONCLUSIONS: Introduction of and training on the proper use of external fixators reduced the amputation rate for open fractures and consequently increased the limb salvage rates in humanitarian contexts where surgical care was provided. PMID- 25038974 TI - Transcutaneous electromagnetic induction heating of an intramedullary nickel titanium shape memory implant. AB - PURPOSE: Inadequate mechanical stimuli are a major cause for nonunions following surgery for femoral and tibial shaft fractures. Adapting fixation rigidity during the course of fracture healing requires additional surgery. Nickel-titanium (NiTi) implants can change shape and rigidity by employing a temperature dependent shape-memory effect. As a first step in the development of advanced intramedullary (IM) NiTi devices for fracture healing, this study aimed to test the feasibility and safety of transcutaneous electromagnetic induction heating of an IM NiTi implant in a rat model. METHODS: In 51 rats, NiTi implants were introduced into the left distal femur. Forty-four animals were transferred to an induction coil, and the implant was electromagnetically heated to temperatures between 40 degrees and 60 degrees C Blood samples were drawn before and four hours after the procedure. Interleukin (IL)-1, IL-4, IL-10, tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were measured. Animals were sacrificed at three weeks. Histological specimens from the hind leg and liver were retrieved and examined for inflammatory changes, necrosis or corrosion pits. RESULTS: All animals successfully underwent the surgical procedure. Following transcutaneous induction heating, target temperature was confirmed in 37/44 rats. Postoperative controls showed no signs of undue limitations. Neither cytokine measurements nor histological specimens showed any significant differences between groups. There were no corrosion pits or necrosis. CONCLUSION: We conclude that electromagnetic induction heating of IM NiTi implants is feasible and safe in a rat femur model. These findings reflect a further step in the development of novel concepts for IM fracture fixation that might lead to better fracture healing, less patient discomfort and less need for surgical interventions. PMID- 25038976 TI - Primary central pulmonary artery plasty for single ventricle with ductal associated pulmonary artery coarctation. AB - BACKGROUND: Infants with a single ventricle who require a modified Blalock Taussig shunt can have stenosis at the ductal insertion site on the pulmonary artery (PA). We hypothesized that primary PA plasty in the first palliation would limit PA stenosis and unbalanced pulmonary perfusion, and thereby facilitate safe accomplishment of the next operation. METHODS: From 1998 to 2012, functional single-ventricle patients with pulmonary atresia were managed as follows: initial operative strategy based on midline approach, using cardiopulmonary bypass, and central PA plasty (resection of all ductal tissue). All patients underwent catheter study and lung perfusion test before bidirectional cavopulmonary shunt (BCPS). RESULTS: Forty consecutive patients (heterotaxy, n = 27; others, n = 13) were enrolled in this study. Seven patients (17.5%) had repair of obstructed total anomalous pulmonary venous drainage, and 4 (10%) had repair of common atrioventricular valve at the first palliative operation. Fifteen patients (37.5%) underwent first palliation in the neonatal period. The mean PA index (mm(2)/m(2)) before BCPS was 230.7 +/- 101.7. No pulmonary stenosis was detected before BCPS. Pulmonary artery diameter ratio (nonshunt side/shunt side) was 0.93 +/- 0.25; pulmonary lung perfusion ratio (nonshunt side/shunt side) was 0.9 +/- 0.2. A multivariate analysis identified persistent total anomalous pulmonary venous drainage (extracardiac type; p = 0.002) as a factor associated with unbalanced branch pulmonary arteries at BCPS. Thirty-five patients underwent BCPS, and 31 underwent Fontan procedures. There were 4 early deaths and 4 late deaths. CONCLUSIONS: The strategies we have employed facilitate safe accomplishment of the next-stage operation in diverse anatomic groups, with avoidance of unbalanced pulmonary vascular bed. PMID- 25038975 TI - Proximal humeral fractures: an understanding of the ideal plate positioning. AB - PURPOSE: The present study aims to evaluate if the bicipital groove can be used as a parameter for ideal plate positioning in proximal humeral fixation applying locking compression plate. METHOD: The authors questioned whether the bicipital groove can be used as a parameter for ideal plate positioning applying locking compression plate for proximal humeral fractures. A method using the bicipital groove as the main parameter was developed using computed tomography scan (CT scan). Seventy shoulders presenting fracture absence were used to calculate proper plate positioning, allowing the largest area for locked screw placement into the humeral head. Intraclass correlation coefficient and Bland and Altman graphics calculated intra-observer reliability for CT-scan evaluation. RESULTS: All observers presented satisfactory plate positioning using this method. The mean differences for observers were close to zero, suggesting high interobserver reproducibility. A significant (p <0.0001) intra-observer agreement existed for the three evaluators. Observer 2 agreement was the strongest (ICC = 0.98), showing almost perfect reproducibility measurement, followed by observer 3 (ICC = 0.84) with good reproducibility, and lastly observer 1 demonstrated moderate degree agreement (ICC = 0.47). CONCLUSION: Considering the CT-scan analysis, the bicipital groove can be used as a parameter for ideal plate positioning in proximal humeral fractures. This method demonstrated satisfactory intra-observer reproducibility. Adopting this method, longer and better distributed screw placement provides more stable fixation for proximal humeral fractures. PMID- 25038978 TI - [Intraoperative protective ventilation: we could do better!]. PMID- 25038977 TI - Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder. AB - OBJECTIVES: A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. METHODS: In this 9-week, double-blind, active-controlled study, patients aged 6-17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients <70 kg: 0.5-1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients >=70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (>=25, >=30 or >=50 %) or a Clinical Global Impressions (CGI)-Improvement (CGI-I) score of 1 or 2 throughout weeks 4-9. CGI-Severity (CGI-S) scores were also assessed, as an indicator of remission. RESULTS: A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX treated patients (ADHD-RS-IV >=25, 66.1 %; ADHD-RS-IV >=30, 61.4 %; ADHD-RS-IV >=50, 41.7 %; CGI-I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV >=25, 51.1 %; ADHD-RS-IV >=30, 47.4 %; ADHD-RS-IV >=50, 23.7 %; CGI-I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI-S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI-S category. CONCLUSIONS: Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI-S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies. PMID- 25038979 TI - [Cold and medical safety: from guidelines to practice]. PMID- 25038980 TI - Assessment of contamination, distribution and chemical speciation of trace metals in water column in the Dakar coast and the Saint Louis estuary from Senegal, West Africa. AB - The water column from Dakar coast and Saint Louis estuary in Senegal, West Africa, was sampled in order to measure the contamination level by trace metals. The speciation of metals in water allowed performing a distribution between dissolved and particulate trace metals. For the dissolved metals, the metallic concentration and repartition between the organic fraction and the inorganic fraction were performed. The results show that the pollution of the estuary was more serious than in Dakar coast for Co, Cr, Ni, Pb and Zn; while, Cd and Cu were higher in Dakar coast. A strong affinity between metals and suspended particles has been revealed. Dissolved metals that have a tendency to form organic metal complexes are in decreasing order: Cd, Zn, Pb, Co=Cr=Mn, Cu and Ni. The results showed that the mobility of trace metals in estuary is controlled by dissolved organic carbon, while in coast it depends on chlorides. PMID- 25038981 TI - An overview of historical harmful algae blooms outbreaks in the Arabian Seas. AB - Harmful algae blooms (HABs), often composed of oceanic plants called phytoplankton, are potentially harmful to the marine life, water quality, human health, and desalination plants, a chief source of potable water in the Arabian Gulf. The last decade has seen a noticeable increase in the frequency of HAB outbreaks in the Arabian Seas. This increase is mainly caused by the unprecedented economic growth in the region. The increased human activities in the region have added more stress to the marine environment and contributed to the changes observed in the properties of the marine ecosystem: high temperature and salinity, high evaporation rates, limited freshwater inflow, shallow nature, pollution. However, very few studies that cover the HAB outbreaks, causes, impacts and biological characteristics over the region have been published. This work presents a comprehensive overview of historical HAB outbreaks recorded in the region, and investigate their causes and impact, and seasonal variability. PMID- 25038982 TI - Monitoring plant response to phenanthrene using the red edge of canopy hyperspectral reflectance. AB - To investigate the mechanisms and potential for the remote sensing of phenanthrene-induced vegetation stress, we measured field canopy spectra, and associated plant and soil parameters in the field controlled experiment in the Yellow River Delta of China. Two widely distributed plant communities, separately dominated by reed (Phragmites australis) and glaucous seepweed (Suaeda salsa), were treated with different doses of phenanthrene. The canopy spectral changes of plant community resulted from the decreases of biomass and foliar projective coverage, while leaf photosynthetic pigment concentrations showed no significance difference among treatments. The spectral response to phenanthrene included a flattened red edge, with decreased first derivative of reflectance. The red edge slope and area consistently responded to phenanthrene, showing a strong relationship with aboveground biomass, coverage and canopy pigments density. These results suggest the potential of remote sensing and the importance of field validation to correctly interpret the causes of the spectral changes. PMID- 25038983 TI - Estimation of the annual flow and stock of marine debris in South Korea for management purposes. AB - The annual flow and stock of marine debris in the Sea of Korea was estimated by summarizing previous survey results and integrating them with other relevant information to underpin the national marine debris management plan. The annual inflow of marine debris was estimated to be 91,195 tons [32,825 tons (36% of the total) from sources on land and 58,370 tons (64%) from ocean sources]. As of the end of 2012, the total stock of marine debris on all South Korean coasts (12,029 tons), the seabed (137,761 tons), and in the water column (2451 tons) was estimated to be 152,241 tons. In 2012, 42,595 tons of marine debris was collected from coasts, seabeds, and the water column. This is a very rare case study that estimated the amount of marine debris at a national level, the results of which provide essential information for the development of efficient marine debris management policies. PMID- 25038984 TI - Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain. AB - BACKGROUND: The neurobiological basis of action of noncompetitive N-methyl-D aspartate acid receptor (NMDA-R) antagonists is poorly understood. Electrophysiological studies indicate that phencyclidine (PCP) markedly disrupts neuronal activity with an overall excitatory effect and reduces the power of low frequency oscillations (LFO; <4 Hz) in thalamocortical networks. Because the reticular nucleus of the thalamus (RtN) provides tonic feed-forward inhibition to the rest of the thalamic nuclei, we examined the effect of PCP on RtN activity, under the working hypothesis that NMDA-R blockade in RtN would disinhibit thalamocortical networks. METHODS: Drug effects (PCP followed by clozapine) on the activity of RtN (single unit and local field potential recordings) and prefrontal cortex (PFC; electrocorticogram) in anesthetized rats were assessed. RESULTS: PCP (.25-.5 mg/kg, intravenous) reduced the discharge rate of 19 of 21 RtN neurons to 37% of baseline (p < .000001) and the power of LFO in RtN and PFC to ~20% of baseline (p < .001). PCP also reduced the coherence between PFC and RtN in the LFO range. A low clozapine dose (1 mg/kg intravenous) significantly countered the effect of PCP on LFO in PFC but not in RtN and further reduced the discharge rate of RtN neurons. However, clozapine administration partly antagonized the fall in coherence and phase-locking values produced by PCP. CONCLUSIONS: PCP activates thalamocortical circuits in a bottom-up manner by reducing the activity of RtN neurons, which tonically inhibit thalamic relay neurons. However, clozapine reversal of PCP effects is not driven by restoring RtN activity and may involve a cortical action. PMID- 25038985 TI - Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized controlled trial. AB - BACKGROUND: Tobacco smoking is the leading cause of preventable death in developed countries. Our previous studies in animal models and humans suggest that repeated activation of cue-induced craving networks followed by electromagnetic stimulation of the dorsal prefrontal cortex (PFC) can cause lasting reductions in drug craving and consumption. We hypothesized that disruption of these circuitries by deep transcranial magnetic stimulation (TMS) of the PFC and insula bilaterally can induce smoking cessation. METHODS: Adults (N = 115) who smoke at least 20 cigarettes/day and failed previous treatments were recruited from the general population. Participants were randomized to receive 13 daily sessions of high-frequency, low-frequency or sham stimulation following, or without, presentation of smoking cues. Deep TMS was administered using an H-coil version targeting the lateral PFC and insula bilaterally. Cigarette consumption was evaluated during the treatment by measuring cotinine levels in urine samples and recording participants' self-reports as a primary outcome variable. Dependence and craving were assessed using standardized questionnaires. RESULTS: High (but not low) frequency deep TMS treatment significantly reduced cigarette consumption and nicotine dependence. The combination of this treatment with exposure to smoking cues enhanced reduction in cigarette consumption leading to an abstinence rate of 44% at the end of the treatment and an estimated 33% 6 months following the treatment. CONCLUSIONS: This study further implicates the lateral PFC and insula in nicotine addiction and suggests the use of deep high-frequency TMS of these regions following presentation of smoking cues as a promising treatment strategy. PMID- 25038986 TI - Predictors of return to work in cancer survivors in the Royal Air Force. AB - PURPOSE: Return to work (RTW) is beneficial for cancer survivors, employers and society. However, little is known about predictors of RTW in the military environment. METHODS: A cohort of 194 Royal Air Force (RAF) personnel aged 18-58 who survived primary cancer treatment between 2001 and 2011 were followed up for 18 months. Information was obtained from occupational health and primary care records. Personal, occupational and clinical predictors of RTW were identified by Cox proportional hazards regression. RESULTS: The median sickness absence before RTW was 107 days. Six months after diagnosis 54 % of participants had RTW, and reached 80 % by 12 months. Time taken to RTW was predicted by age at diagnosis, rank, trade group, pre-diagnosis sickness absence, site of cancer, treatment modality, and prognosis. RTW at 18 months were predicted by higher rank (HR = 2.31; 95 % CI 1.46-3.65), and having melanoma (9.75; 4.97-19.13). Those receiving chemotherapy were significantly less likely to have RTW compared to other treatment modalities (0.18; 0.10-0.32). CONCLUSIONS: Rank, cancer diagnostic group, and treatment modality are the most important predictors of RTW in cancer survivors in the RAF. These predictors can be used to inform rehabilitation programmes and decisions on RTW. PMID- 25038987 TI - Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4). AB - Over-expression of chemokine receptor 4 (CXCR4) is present in a majority of cancers, has been linked to an aggressive phenotype, and may indicate the metastatic potential of primary tumor. Several CXCR4 targeted therapeutics are in clinical trials and the development of the corresponding imaging agents is an area of active interest. Previously, (64)Cu-labeled imaging agents for CXCR4 have provided clear images of CXCR4-bearing tissues in relevant experimental models but demonstrated fast washout from tissues harboring receptor. Addition of stabilizing bridges is known to provide more robust chelator-Cu(II) complexes. In addition, bridged cyclam-based CXCR4 binding agents demonstrated increased receptor residence times relative to existing agents. Based on that knowledge we synthesized several bridged cyclam analogs of AMD3465, a monocyclam-based CXCR4 imaging agent, to increase the retention time of the tracer bound to the receptor to allow for protracted imaging and improved target-to-non-target ratios. Specific accumulation of two radiolabeled, cross-bridged analogs ([(64)Cu] RAD1 24 and [(64)Cu]RAD1-52) was observed in U87-stb-CXCR4 tumors in both PET/CT imaging and biodistribution studies. At 90min post-injection of radiotracer, tumor-to-muscle and tumor-to-blood ratios reached 106.05+/-17.19 and 28.08+/ 4.78, respectively, for cross-bridged pyrimidine analog [(64)Cu]RAD1-52. Receptor blockade performed in vivo denoted target binding specificity. The biodistribution and PET/CT imaging studies with the radiolabeled bridged cyclams demonstrated longer tumor retention and comparable uptake to [(64)Cu]AMD3465, though [(64)Cu]AMD3465 demonstrated superior overall pharmacokinetics. PMID- 25038988 TI - Introduction: oxidation and inflammation, a molecular link between non communicable diseases. AB - Non-communicable diseases are, by definition, those chronic diseases that are non infectious and non-transmissible. The most common non-communicable diseases are obesity, diabetes, cancer, and cardiovascular, chronic respiratory and neurological diseases. Altogether, they are the commonest cause of death and disability in modern world. Recent investigations show that many of these diseases share common pathophysiological mechanisms and are, at least in part, different manifestations in different organs of similar molecular alterations. Mitochondrial alterations, oxidative stress and inflammation are inextricably linked and play major roles in the onset and development of non-communicable diseases. Therefore, it is conceivable that pharmacological or nutritional manipulation of oxidation and inflammation allows a significant decrease in the mortality and morbility associated to these diseases. PMID- 25038989 TI - Oxidative stress and DNA damage in obesity-related tumorigenesis. AB - Reactive oxygen species induce oxidative modification of critical macromolecules. Oxygen derived free radicals may act as potential cytotoxic intermediates inducing inflammatory and degenerative processes, or as signal messengers for the regulation of gene expression. This dual effect mainly depends on the availability of free radicals in terms of concentration, as well as on the environmental characteristics in which they are produced. The formation of free radicals has been proposed to be the linking factor between certain metabolic disturbances and cancer. Circulating mononuclear cells of patients with high cholesterol levels, insulin resistance, metabolic syndrome or obesity present lower levels of antioxidant enzymes and increased concentrations of oxidative stress by-products such as isoprostanes or the DNA oxidized and highly mutagenic base 8-oxo-7,8-dihydro-2'-deoxyguanosine. Overweight or obese subjects also exhibit hormonal changes as a consequence of the increase of mass fat, and these hormonal alterations have been implicated in the alteration of different signal transduction mechanisms and in cell growth and differentiation. A significant correlation has been found between body mass index and cancer. The biological factors and molecular mechanisms implicated in obesity associated cancer susceptibility will be reviewed. PMID- 25038990 TI - High density lipoproteins and ischemia reperfusion injury: the therapeutic potential of HDL to modulate cell survival pathways. AB - The clinical importance of high density lipoproteins has grown in recent years with demonstrations of their impact on diverse pathological mechanisms implicated not only in vascular disease, but also in other physiological systems. This is related to the multiple functions associated with high-density lipoproteins (HDL), notably their ability to limit oxidant and inflammatory processes, which are common to different disease states. A second feature of particular clinical relevance is the possibility of synthesising a simplified form of HDL that exhibits some of the functions of the mature lipoprotein. The therapeutic potential of synthetic HDL is already under clinical scrutiny. To illustrate these points, the present chapter will discuss the role of HDL in limiting damage to the heart consequent to myocardial ischemia. It will review molecular survival pathways stimulated by HDL to combat oxidative stress and the potential of synthetic HDL to activate such pathways. PMID- 25038991 TI - The DING family of phosphate binding proteins in inflammatory diseases. AB - Human paraoxonase 1 (hPON-1) is a protein that has been studied in relation to its antioxidant and anti-atherosclerotic properties. Despite extensive studies, the molecular mechanisms responsible for its functional properties remain unclear. During the last decade, a new partner of hPON-1 has been identified. Hidden for a long time because of a similar molecular weight with hPON-1, this protein, termed human phosphate-binding protein (HPBP), may contribute to the biological functions of hPON-1. Belonging to the DING protein, a sub-family of phosphate binding proteins (PBP or pstS), HPBP stabilizes hPON-1 and might prevent calcification of arteries in case of advance atherosclerosis. The role of other DING proteins in some calcification processes (i.e. nephrolithiasis) and the identification of HPBP in the atheroma plaque support this hypothesis. Nevertheless, the relevance of hPON-1/HPBP as well as the molecular determinants in atherosclerosis remains to be elucidated. PMID- 25038993 TI - Autophagy is an inflammation-related defensive mechanism against disease. AB - The inflammatory response is an energy-intensive process. Consequently, metabolism is closely associated with immune function. The autophagy machinery plays a role in metabolism by providing energy but may also be used to attack invading pathogens (xenophagy). The autophagy machinery may function to protect against not only the threats of infection but also the threats of the host's own response acting on the central immunological tolerance and the negative regulation of innate and inflammatory signaling. The balance between too little and too much autophagy is critical for the survival of immune cells because autophagy is linked to type 2-cell death programmed necrosis and apoptosis. Changes in inflammatory cells are driven by extracellular signals; however, the mechanisms by which cytokines mediate autophagy regulation and govern immune cell function remain unknown. Certain cytokines increase autophagy, whereas others inhibit autophagy. The relationship between autophagy and inflammation is also important in the pathogenesis of metabolic, non-communicable diseases. Inflammation per se is not the cause of obesity-associated diseases, but it is secondary to both the positive energy balance and the specific cellular responses. In metabolic tissues, the suppression of autophagy increases inflammation with the overexpression of cytokines, resulting in an activation of autophagy. The physiological role of these apparently contradictory findings remains uncertain but exemplifies future challenges in the therapeutic modulation of autophagy in the management of disease. PMID- 25038992 TI - Inflammation, infection, cancer and all that...the role of paraoxonases. AB - The paraoxonase (PON) gene family consists of three members, PON1, PON2 and PON3. All PON proteins possess antioxidant properties and lipo-lactonase activities, and are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis, Alzheimer's, Parkinson's, diabetes and cancer. Despite the role of PON proteins in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON proteins function as anti-inflammatory proteins remain largely unknown. PON1 is found exclusively extracellular and associated solely with high-density lipoprotein (HDL) particles in the circulation, and, in part, confers the anti-oxidant and anti-inflammatory properties associated with HDL. Recent studies demonstrated that the intracellular PON proteins; PON2 and PON3 (i) are associated with mitochondria and mitochondria-associated membranes, (ii) modulate mitochondria-dependent superoxide production, and (iii) prevent apoptosis. Overexpression of PON2 and PON3 genes protected (i) mitochondria from antimycin or oligomycin mediated mitochondrial dysfunction and (ii) ER stress and ER stress mediated mitochondrial dysfunction. These studies illustrate that the anti-inflammatory effects of PON2 and PON3 may, in part, be mediated by their role in mitochondrial and associated organelle function. Since oxidative stress as a result of mitochondrial dysfunction is implicated in the development of inflammatory diseases including atherosclerosis and cancer, these recent studies on PON2 and PON3 proteins may provide a mechanism for the scores of epidemiological studies that show a link between PON genes and numerous inflammatory diseases. Understanding such mechanisms will provide novel routes of intervention in the treatment of diseases associated with pro-inflammatory oxidative stress. PMID- 25038994 TI - Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid related pathways with pleiotropic influences in health and disease. AB - Polyunsaturated fatty acids (PUFA) play pleiotropic and crucial roles in biological systems. Both blood and tissue levels of PUFA are influenced not only by diet, but to a large extent also by genetic heritability. Delta-5 (D5D) and delta-6 desaturases (D6D), encoded respectively by FADS1 and FADS2 genes, are the rate-limiting enzymes for PUFA conversion and are recognized as main determinants of PUFA levels. Alterations of D5D/D6D activity have been associated with several diseases, from metabolic derangements to neuropsychiatric illnesses, from type 2 diabetes to cardiovascular disease, from inflammation to tumorigenesis. Similar results have been found by investigations on FADS1/FADS2 genotypes. Recent genome wide association studies showed that FADS1/FADS2 genetic locus, beyond being the main determinant of PUFA, was strongly associated with plasma lipids and glucose metabolism. Other analyses suggested potential link between FADS1/FADS2 polymorphisms and cognitive development, immunological illnesses, and cardiovascular disease. Lessons from both animal models and rare disorders in humans further emphasized the key role of desaturases in health and disease. Remarkably, some of the above mentioned associations appear to be influenced by the environmental context/PUFA dietary intake, in particular the relative prevalence of omega-3 and omega-6 PUFA. In this narrative review we provide a summary of the evidences linking FADS1/FADS2 gene variants and D5D/D6D activities with various traits of human physiopathology. Moreover, we focus also on the potentially useful therapeutic application of D5D/D6D activity modulation, as suggested by anti-inflammatory and tumor-suppressing effects of D6D inhibition in mice models. PMID- 25038995 TI - Systemic inflammation, intestine, and paraoxonase-1. AB - Serum paraoxonase 1 (PON1) has been shown to act as an important guardian against cellular damage from oxidized lipids in low-density lipoprotein (LDL), plasma membrane, against toxic agents such as pesticide residues including organophosphates and against bacterial endotoxin. PON1 associated with circulating high-density lipoprotein (HDL) has the ability to prevent the generation of pro inflammatory oxidized phospholipids by reactive oxygen species. The activities of the HDL-associated PON1 and several other anti-inflammatory factors in HDL are in turn negatively regulated by these oxidized lipids. In rabbits, mice, and humans there appears to be an increase in the formation of these oxidized lipids during the acute phase response. This results in the association of acute phase proteins with HDL and inhibition of the HDL-associated PON1 that renders HDL pro inflammatory.In populations, low serum HDL-cholesterol is a risk factor for atherosclerosis and efforts are directed toward therapies to improve the quality and the relative concentrations of LDL and HDL. Apolipoprotein A-I (apoA-I) has been shown to reduce atherosclerotic lesions in laboratory animals. ApoA-I, however, is a large protein that is costly and needs to be administered parenterally. Our group has developed apoA-I mimetic peptides that are much smaller than apoA-I (18 amino acids long vs 243 in ApoA-I itself). These HDL mimetic peptides are much more effective in removing the oxidized phospholipids and other oxidized lipids. They improve LDL and HDL composition and function and reduce lesion formation in animal models of atherogenesis. Following is a brief description of some of the HDL mimetic peptides that can improve HDL and the effect of the peptide on PON1 activity. PMID- 25038996 TI - Serotonin modulation of macrophage polarization: inflammation and beyond. AB - Macrophages display a ample plethora of effector functions whose acquisition is promoted by the surrounding cytokine and cellular environment. Depending on the stimulus, macrophages become specialized ("polarized") for either pathogen elimination, tissue repair and wound healing or immunosuppression. This "polarization" versatility allows macrophages to critically contribute to tissue homeostasis, as they promote initiation and resolution of inflammatory responses. As a consequence, deregulation of the tissue macrophage polarization balance is an etiological agent of chronic inflammation, autoimmune diseases, cancer and even obesity and insulin resistance. In the present review we describe current concepts on the molecular basis and the patho-physiological implications of macrophage polarization, and describe its modulation by serotonin (5-HT), a neurotransmitter that regulates inflammation and tissue repair via a large set of receptors (5-HTR1-7). 5-HT modulates the phenotypic and functional polarization of macrophages, and contributes to the maintenance of an anti-inflammatory state mainly via 5-HTR2B and 5-HTR7, whose activation has a great impact on macrophage gene expression profile. The identification of 5-HTR2B and 5-HTR7 as functionally relevant polarization markers suggests their therapeutic value in inflammatory pathologies as well as their potential involvement in linking the immune and nervous systems. PMID- 25038997 TI - Energy metabolism and metabolic sensors in stem cells: the metabostem crossroads of aging and cancer. AB - We are as old as our adult stem cells are; therefore, stem cell exhaustion is considered a hallmark of aging. Our tumors are as aggressive as the number of cancer stem cells (CSCs) they bear because CSCs can survive treatments with hormones, radiation, chemotherapy, and molecularly targeted drugs, thus increasing the difficulty of curing cancer. Not surprisingly, interest in stem cell research has never been greater among members of the public, politicians, and scientists. But how can we slow the rate at which our adult stem cells decline over our lifetime, reducing the regenerative potential of tissues, while efficiently eliminating the aberrant, life-threatening activity of "selfish", immortal, and migrating CSCs? Frustrated by the gene-centric limitations of conventional approaches to aging diseases, our group and other groups have begun to appreciate that bioenergetic metabolism, i.e., the production of fuel & building blocks for growth and division, and autophagy/mitophagy, i.e., the quality-control, self-cannibalistic system responsible for "cleaning house" and "recycling the trash", can govern the genetic and epigenetic networks that facilitate stem cell behaviors. Indeed, it is reasonable to suggest the existence of a "metabostem" infrastructure that operates as a shared hallmark of aging and cancer, thus making it physiologically plausible to maintain or even increase the functionality of adult stem cells while reducing the incidence of cancer and extending the lifespan. This "metabostemness" property could lead to the discovery of new drugs that reprogram cell metabotypes to increase the structural and functional integrity of adult stem cells and positively influence their lineage determination, while preventing the development and aberrant function of stem cells in cancer tissues. While it is obvious that the antifungal antibiotic rapamycin, the polyphenol resveratrol, and the biguanide metformin already belong to this new family of metabostemness-targeting drugs, we can expect a rapid identification of new drug candidates (e.g., polyphenolic xenohormetins) that reverse or postpone "geroncogenesis", i.e., aging-induced metabolic decline as a driver of tumorigenesis, at the stem cell level. PMID- 25038998 TI - Molecular promiscuity of plant polyphenols in the management of age-related diseases: far beyond their antioxidant properties. AB - The use of plant-derived polyphenols for the management of diseases has been under debate in the last decades. Most studies have focused on the specific effects of polyphenols on particular targets, while ignoring their pleiotropic character. The multitargeted character of polyphenols, a plausible consequence of their molecular promiscuity, may suppose an opportunity to fight multifactorial diseases. Therefore, a wider perspective is urgently needed to elucidate whether their rational use as bioactive food components may be valid for the management of diseases. In this chapter, we discuss the most likely targets of polyphenols that may account for their salutary effects from a global perspective. Among these targets, the modulation of signalling and energy-sensitive pathways, oxidative stress and inflammation-related processes, mitochondrial functionality, epigenetic machinery, histone acetylation and membrane-dependent processes play central roles in polyphenols' mechanisms of action.Sufficient evidence on polyphenols has accumulated for them to be considered a serious option for the management of non-communicable diseases, such as cancer and obesity, as well as infectious diseases. The remaining unresolved issues that must be seriously addressed are their bioavailability, metabolite detection, specific molecular targets, interactions and toxicity. The Xenohormesis hypothesis, which postulates that polyphenols are the product of plant evolutive adaptation to stress and conferee their resistance to mammals, offers a reasonable explanation to justify the beneficial and non-toxic effects of plant mixtures, but do not fully meet expectations. Hence, future research must be supported by the use of complex polypharmacology approaches and synergic studies focused on the understanding of the pleiotropic effects of polyphenols. Revisiting polyphenol mechanisms of action with the help of these techniques may allow for the improvement of human health and wellness by using intelligent nutritional intervention. PMID- 25038999 TI - Postprandial inflammation: targeting glucose and lipids. AB - Many risk factors have been identified as being responsible for the process of atherogenesis. Several of these risk factors are related to inflammation, which is an obligatory feature of the atherosclerotic plaque. Increasing evidence suggests that postprandial lipoproteins and glucose may be involved in the inflammatory process preceding the development of atherosclerosis. During the postprandial situation, remnants of chylomicrons and very low-density lipoproteins bind to circulating leukocytes and endothelial cells, leading to a state of acute activation with the expression of integrins on different cells, the generation of oxidative stress, production of cytokines and complement activation. Elevated plasma glucose levels may also induce leukocyte activation in humans. In addition, advanced glycation end products, formed during hyperglycemia, cause inflammation and endothelial damage. This chain of events results in a situation of acute inflammation causing endothelial dysfunction, which may be one of the earliest defects in atherogenesis. Interestingly, while this may occur several times each day after each meal, there is only limited information on the contribution of different nutrients on the postprandial inflammatory processes. In this review, we will focus on the available evidence and we will discuss the role of lifestyle and pharmaceutical interventions in modulating postprandial inflammation. PMID- 25039001 TI - The axis AGE-RAGE-soluble RAGE and oxidative stress in chronic kidney disease. AB - Chronic kidney disease (CKD) has been shown to be associated with high oxidative stress and cardiovascular disease. In this chapter our focus will be on the role of advanced glycation end products (AGE) and their receptor, RAGE in CKD progression and their role on cardiovascular complications. We provide a succinct, yet comprehensive summary of the current knowledge, the challenges and the future therapeutic avenues that are stemming out from novel recent findings. We first briefly review glycation and AGE formation and the role of the kidney in their metabolism. Next, we focus on the RAGE, its signaling and role in oxidative stress. We address the possible role of soluble RAGEs as decoys and the controversy regarding this issue. We then provide the latest information on the specific role of both AGE and RAGE in inflammation and perpetuation of kidney damage in diabetes and in CKD without diabetes, which is the main purpose of the review. Finally, we offer an update on new avenues to target the AGE-RAGE axis in CKD. PMID- 25039000 TI - Dynamic interplay between metabolic syndrome and immunity. AB - Obesity and its co-morbidities as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases are major health problems worldwide. Several reports indicated that nutrient excess and metabolic syndrome are linked with altered immune response. Indeed, metabolic syndrome is characterized by insulin resistance and chronic low-grade inflammation, which conditions are the consequences of the complex interaction between adipocytes and immune cells. Enlarged white adipose tissue is infiltrated by immune cells and secretes various bioactive substances, like adipokines, cytokines and other inflammatory mediators. Due to its special architecture in which metabolic and immune cells are in intimate proximity, metabolic and immunologic pathways are closely integrated in adipose tissue. With the contribution of altered gut microbiota, adipokines and cytokines modulate insulin signaling and immune response leading to adipose tissue inflammation and systemic insulin resistance. In this chapter, we focus on the cellular and molecular mechanisms that lead to impaired insulin sensitivity and chronic low-grade inflammation in obesity. We also detail the potential role of adipokines and immune cells in this deleterious process, and the concerns of vaccination in metabolic syndrome. Finally, we address the links between obesity and gut microbiota as an emerging new field of interest, and scratch the surface of potential therapeutic opportunities. PMID- 25039002 TI - The chemokine (C-C motif) ligand 2 in neuroinflammation and neurodegeneration. AB - Among all the chemokines known so far, chemokine (C-C motif) ligand 2 (CCL2) is probably the best characterized. This is mainly due to the therapeutic potential attributed to its regulation. The suppression of CCL2 function may reduce the attraction of immune cells to the sites of inflammation and therefore slow down the progression of inflammation and the tissue damage that may be associated to it. While this has proven to be right in diverse conditions, it has also been described to have deleterious consequences such as a dual effect that is also frequently observed in other endogenous defense systems. This review discusses current knowledge about CCL2 involvement in different neurodegenerative diseases as well as its anti-inflammatory and neuro-protective actions. PMID- 25039003 TI - Molecular cloning and characterization of two novel autophagy-related genes belonging to the ATG8 family from the cattle tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - Rhipicephalus (Boophilus) microplus is an obligate haematophagous arthropod and the major problem for cattle industry due to economic losses it causes. The parasite shows a remarkable adaptability to changing environmental conditions as well as an exceptional ability to survive long-term starvation. This ability has been related to a process of intracellular protein degradation called autophagy. This process in ticks is still poorly understood and only few autophagy-related (ATG) genes have been characterized. The aim of the present study was to examine the ESTs database, BmiGI, of R. microplus searching for ATG homologues. We predicted five putative ATG genes, ATG3, ATG4, ATG6 and two ATG8s. Further characterization led to the identification of RmATG8a and RmATG8b, homologues of GABARAP and MAP1LC3, respectively, and both of them belonging to the ATG8 family. PCR analyses showed that the expression level of RmATG8a and RmATG8b was higher in egg and larval stages when compared to ovary and midgut from adult ticks. This up-regulation coincides with the period in which ticks are in a starvation state, suggesting that autophagy is active in R. microplus. PMID- 25039004 TI - Multivariate discrimination among cryptic mites of the genus Androlaelaps (Acari: Mesostigmata: Laelapidae) parasitic of sympatric akodontine rodents (Cricetidae: Sigmodontinae) in northeastern Argentina: possible evidence of host switch followed by speciation, with the description of two new species. AB - Laelapids are among the most common ectoparasites of rodents. Currently, it is under discussion whether there is a single polixenous species that parasites a variety of hosts, or whether there are cryptic species highly host specific. Herein, multivariate morphometric analyses of cryptic sympatric laelapids of the genus Androlaelaps allowed us to identify different species. These species are specific of their akodontine hosts, Akodon montensis and Thaptomys nigrita, in localities situated in northeastern Argentina. In addition, we analyzed similar laelapids associated with the akodontines Deltamys kempi and Akodon cursor. Using principle component analyses we differentiated four laelapid species, each one host specific, independent of sympatry of the hosts, and without geographical variation. From these four species, we described two new species (Androlaelaps navonae n. sp. and Androlaelaps wingei n. sp.). We determined the four species based on a range of variations in several characters, mainly size. These four laelapid species belong to the Androlaelaps rotundus species group, specific to akodontines. These species are very similar among them but differ from the remainder species of the group by their small size, distance between j6 setae similar to the distance between the z5 setae, strong ventral setae, opisthogaster with 13 pairs of strong setae (one close to the distal margin of epigynal shield), and anal shield wider than long. Further studies will elucidate whether they constitute a new laelapid genus. Phylogenetic and ecological factors influencing host-specificity are discussed, and we propose that host colonization could have taken place by host switching of a single laelapid species among rodent species, followed by speciation. PMID- 25039005 TI - Acaricidal activity of ethanolic extract of Artemisia absinthium against Hyalomma anatolicum ticks. AB - The aim of the study was to evaluate the in vitro efficacy of different concentrations of ethanolic extract obtained from the aerial parts of Artemisia absinthium in comparison to amitraz on adults, eggs and larvae of Hyalomma anatolicum using the adult immersion test (AIT), egg hatchability test and larval packet test (LPT), respectively. Four concentrations of the extract (2.5, 5, 10 and 20%) with three replications for each concentration were used in all the bioassays. In AIT, the mortality rates at 2.5, 5 and 10% were significantly different (p < 0.05) in comparison to the control group; however, at 20%, it was similar to the positive control group. Maximum mortality of 86.7% was recorded at 20%. The LC50 and LC95 values were calculated as 6.51 and 55.43%, respectively. The oviposition was reduced significantly by 36.8 and 59.1% at concentrations of 10 and 20%, respectively. Egg hatchability was reduced significantly at all concentrations (2.5-20%) in comparison to the control. In LPT, the extract caused 100% mortality of larvae at all the concentrations after 24 h. The results show that ethanolic extract obtained from the aerial parts of A. absinthium has acaricidal properties and could be useful in controlling H. anatolicum. PMID- 25039006 TI - Experimental analysis of intermittency in electrohydrodynamic instability. AB - The properties of turbulent electroconvective fluctuations generated in a nematic liquid crystal under the action of an external oscillating electric field are investigated. In particular, the spectral properties and the scaling behaviour of probability density functions (PDFs) of light intensity fluctuations are considered at different voltages. At intermediate voltage, in the weak turbulent regime, PDFs are Gaussian at large scales and show increasingly enhanced wings at smaller scales, recalling the typical signature of intermittency in isotropic fluid flows. When the voltage is increased, dynamical scattering regimes appear, characterized by increasing complexity. In order to get a quantitative estimate of intermittency, PDFs are modeled through the Castaing distribution, and structure functions are estimated in the framework of Extended Self-Similarity. Results support the generation of small-scale fluctuations through a fragmentation process of large-scale structures. The persistent anisotropic properties of the fluctuations are highlighted by the results. PMID- 25039007 TI - The secondary buckling transition: wrinkling of buckled spherical shells. AB - We theoretically explain the complete sequence of shapes of deflated spherical shells. Decreasing the volume, the shell remains spherical initially, then undergoes the classical buckling instability, where an axisymmetric dimple appears, and, finally, loses its axisymmetry by wrinkles developing in the vicinity of the dimple edge in a secondary buckling transition. We describe the first axisymmetric buckling transition by numerical integration of the complete set of shape equations and an approximate analytic model due to Pogorelov. In the buckled shape, both approaches exhibit a locally compressive hoop stress in a region where experiments and simulations show the development of polygonal wrinkles, along the dimple edge. In a simplified model based on the stability equations of shallow shells, a critical value for the compressive hoop stress is derived, for which the compressed circumferential fibres will buckle out of their circular shape in order to release the compression. By applying this wrinkling criterion to the solutions of the axisymmetric models, we can calculate the critical volume for the secondary buckling transition. Using the Pogorelov approach, we also obtain an analytical expression for the critical volume at the secondary buckling transition: The critical volume difference scales linearly with the bending stiffness, whereas the critical volume reduction at the classical axisymmetric buckling transition scales with the square root of the bending stiffness. These results are confirmed by another stability analysis in the framework of Donnel, Mushtari and Vlasov (DMV) shell theory, and by numerical simulations available in the literature. PMID- 25039008 TI - Usefulness, methods and rationale of lymph nodes HPV-DNA investigation in estimating risk of early stage cervical cancer recurrence: a systematic literature review. AB - Metastatic involvement of pelvic lymph-nodes (LNs), generally found in 0-29.3 % of early stages, is the most important prognostic factor in cervical cancer (CC). However, even in non-metastatic LNs, recurrence rate reaches 10-15 %. The role of HPV-DNA presence in pelvic LNs has been a point of debate in the last two decades. The aim of this systematic review is to collect all available data about LNs HPV-DNA detection in patients affected by early-stage CC in order to elucidate its clinical and surgical usefulness to choose the best surgical treatment, the necessity of adjuvant therapy and to estimate the overall oncological prognosis. The available data in this field results very patchy and often conflicting in the results. The high correlation between HPV-DNA genome detected in primary lesion and the one detected in LNs, as well as the high correlation between LNs metastatic involvement and HPV-DNA presence, lead to hypothesize that LNs HPV presence represents a potential risk-factor for recurrence and poor oncological prognosis. The large disparities in recurrence rate of cases with LNs positive for HPV-DNA test and negative for metastases could be explained by the relative "inappropriateness" of PCR test to discriminate the presence of HPV-genome alone (condition necessary but not sufficient) or in association with squamous cells (condition necessary and sufficient). The use of ISH test for HPV-DNA detection in LNs, particularly if associated to CK19-assay, improve the accuracy of micro-metastasis detection, and the identification of patients with negative histology but potentially at high risk of recurrence and poor oncological prognosis. PMID- 25039010 TI - Current research topics in embodied social cognition. PMID- 25039009 TI - Indolosesquiterpene alkaloids from the Cameroonian medicinal plant Polyalthia oliveri (Annonaceae). AB - The stem bark of Polyalthia oliveri was screened for its chemical constituents using liquid chromatography high resolution mass spectrometry resulting in the isolation of three indolosesquiterpene alkaloids named 8alpha-polyveolinone (1), N-acetyl-8alpha-polyveolinone (2) and N-acetyl-polyveoline (3), together with three known compounds, dehydro-O-methylisopiline (4), N-methylurabaine (5) and polycarpol (6). The structures of the compounds were elucidated by means of high resolution mass spectrometry and different NMR techniques and chemical transformations. Their absolute configurations were assigned by ab-initio calculation of CD and ORD data (for 2 and 3) and X-ray diffraction analysis (for 2). Compounds 2 and 3 exhibited moderate antiplasmodial activity against erythrocytic stages of chloroquine-sensitive Plasmodium falciparum NF54 strain and low cytotoxicity on rat skeletal myoblast (L6) cell line. PMID- 25039011 TI - The magic of words. PMID- 25039012 TI - Predictors of decline in overall mental health, PTSD and alcohol use in OEF/OIF veterans. AB - This study identified predictors of worsening mental health (including PTSD and alcohol use) over a 6-month period following return from deployment to Iraq (OIF) or Afghanistan (OIF). Using a national sample of 512 OEF/OIF veterans surveyed within 12 months of return from deployment (T1), and 6 months later (T2), we obtained demographic and deployment characteristics, risk and resilience factors, mental health status, PTSD and alcohol abuse. We performed logistic regression analyses to identify predictors of worse mental health, PTSD or alcohol use between T1 and T2, controlling for initial levels. Of the sample, 14-25% showed clinically worse mental health, PTSD or alcohol use. Each outcome was associated with some shared and some unique predictors. For example, younger age and recent medical care were both associated with worse alcohol use. Lack of adequate deployment training was uniquely associated with worse PTSD symptoms. PMID- 25039013 TI - Blood transfusion products contain mitochondrial DNA damage-associated molecular patterns: a potential effector of transfusion-related acute lung injury. AB - BACKGROUND: Transfusion-related acute lung injury (TRALI) is the most frequent and severe complication in patients receiving multiple blood transfusions. Current pathogenic concepts hold that proinflammatory mediators present in transfused blood products are responsible for the initiation of TRALI, but the identity of the critical effector molecules is yet to be determined. We hypothesize that mtDNA damage-associated molecular patterns (DAMPs) are present in blood transfusion products, which may be important in the initiation of TRALI. METHODS: DNA was extracted from consecutive samples of packed red blood cells, fresh frozen plasma (FFP), and platelets procured from the local blood bank. Quantitative real-time polymerase chain reaction was used to quantify ~200 bp sequences from the COX1, ND1, ND6, and D-loop regions of the mitochondrial genome. RESULTS: A range of mtDNA DAMPs were detected in all blood components measured, with FFP displaying the largest variation. CONCLUSIONS: We conclude that mtDNA DAMPs are present in packed red blood cells, FFP, and platelets. These observations provide proof of the concept that mtDNA DAMPs may be mediators of TRALI. Further studies are needed to test this hypothesis and to determine the origin of mtDNA DAMPs in transfused blood. PMID- 25039014 TI - Appendiceal carcinoids in children--management and outcomes. AB - BACKGROUND: Appendiceal carcinoid tumors are very rare in children, and management has been guided by adult presentations and outcomes. Here, we present our experience with pediatric appendiceal carcinoid tumors. METHODS: We undertook a retrospective review of all cases of appendiceal carcinoids in children over a 20-y period. Data regarding clinical presentation, diagnosis, pathology, follow up, and outcomes were collected and analyzed. RESULTS: We identified 13 cases of appendiceal carcinoids. All cases were diagnosed after appendectomy for presumed appendicitis (nine acute and four interval;), with no patient having carcinoid syndrome. Mean age at diagnosis was 13.7 y, and all but one case was female. Tumor size ranged from microscopic foci of tumor cells to 2.1 cm (mean, 0.93 cm). Seven cases had invasion of the mesoappendix, three of which underwent a subsequent right hemicolectomy. The patient with the largest tumor (2.1 cm) had evidence of lymphatic invasion with three nodes positive for tumor after right colectomy. No patient had elevation of 5-hydroxyindoleacetic acid or serum chromogranin A, and surveillance computed tomographic scans did not reveal any liver metastases. CONCLUSIONS: This is a relatively large series of carcinoids of the appendix in children. We found no evidence of carcinoid syndrome or metastatic disease in these cases other than lymphatic. The need for a secondary colectomy is perhaps questionable. PMID- 25039015 TI - Identification and characterization of functional Smad8 and Smad4 homologues from Echinococcus granulosus. AB - Smad family proteins are essential cellular mediators of the transforming growth factor-beta superfamily. In the present study, we identified two members of the Smad proteins, Smad8 and Smad4 homologues (termed as EgSmadE and EgSmadD, respectively), from Echinococcus granulosus, the causative agent of cystic echinococcosis (CE). Phylogenetic analysis placed EgSmadE in the Smad1, 5, and 8 subgroup of the R-Smad sub-family and EgSmadD in the Co-Smad family. Furthermore, EgSmadE and EgSmadD attained a high homology to EmSmadE and EmSmadD of E. multilocularis, respectively. Both EgSmadE and EgSmadD were co-expressed in the larval stages and exhibited the highest transcript levels in activated protoscoleces, and their encoded proteins were co-localized in the sub-tegumental and tegumental layer of the parasite. As shown by yeast two-hybrid and pull-down analysis, EgSmadE displayed a positive binding interaction with EgSmadD. In addition, EgSmadE localized in the nuclei of Mv1Lu cells (mink lung epithelial cells) upon treatment with human TGF-beta1 or human BMP2, indicating that EgSmadE is capable of being translocated into nucleus, in vitro. Our study suggests that EgSmadE and EgSmadD may take part in critical biological processes, including echinococcal growth, development, and parasite-host interaction. PMID- 25039017 TI - Heterogeneous fascicle behavior within the biceps femoris long head at different muscle activation levels. AB - Magnetic resonance and ultrasound imaging have shown hamstring strain injuries occur most often in the biceps femoris long head (BFLH), and particularly in the proximal vs. distal region of this muscle. Animal research and musculoskeletal modeling (MSK) have detected heterogeneous fascicle behavior within muscle regions, and within fascicles. Understanding architectural behavior differences during muscle contractions may help to discern possible mechanisms behind proximal BFLH injuries. The purpose of our study was to assess the magnitude of shortening of the proximal and distal fascicles of the BFLH under a range of muscle activation levels under isometric conditions using ultrasound imaging (US). Thirteen healthy adults performed targeted sustained isometric contractions while US were taken of the entire BFLH. Measurements of fascicle lengths in both muscle regions were compared at 20%, 30%, 50%, and 67% MVIC. The results showed that while both regions shortened significantly with activation, the proximal fascicles were significantly longer, regardless of activation level (~38%), and shortened significantly more than the distal fascicles overall (~40%), and cumulatively at higher activation levels (30% and above). No significant strain differences were found between the two regions. These data suggest heterogeneous fascicle behavior exists in an absolute sense; however, differences in behavior are eliminated when normalized (strain). Coupled with MSK literature, the absence of regional fascicle strain differences in this study may indicate strain heterogeneity is not detectable at the whole fascicle level. Further knowledge of this commonly strained muscle's regional behavior during dynamic movements could provide evidence of proximal hamstring strain predisposition. PMID- 25039016 TI - Allergic reactions to Anisakis found in fish. AB - The food-borne parasite Anisakis is an important hidden food allergen. Anisakis is a parasitic nematode which has a third-stage larval form that infects mainly fish, and ingestion of contaminated seafood can result in severe allergic reactions. Symptoms experienced due to exposure to this parasite include gastrointestinal disorders, urticaria, dermatitis, asthma and even anaphylaxis. Accurate prevalence data of allergic sensitisation to Anisakis are difficult to estimate due to the lack of well-designed population-based studies. Current diagnostic approaches rely on the detection of serum IgE antibodies to allergenic proteins, which however demonstrate considerable immunological cross-reactivity to other invertebrate allergens. While exposure to this parasite seems to increase due to the increasing consumption of seafood worldwide, the immunology of infection and allergic sensitization is not fully understood. PMID- 25039019 TI - Relaxation for perimenopausal and postmenopausal symptoms. AB - BACKGROUND: Since the time of publication of the Women's Health Initiative (WHI) study, menopausal symptom management has become more complex because of increased awareness of the risks associated with hormone replacement therapy (HRT). Currently, a wide range of management options is available. Some women take prescription drugs, and others use self care strategies, including lifestyle modifications, over-the-counter preparations and complementary and alternative therapies, such as herbal preparations, exercise programmes and relaxation techniques. Relaxation techniques consist of a group of behavioural interventions. They are considered relatively harmless, but their effectiveness in treating vasomotor symptoms and sleep disturbances remains debatable. OBJECTIVES: To determine the effectiveness of relaxation techniques as treatment for vasomotor symptoms and associated sleep disturbances in perimenopausal and postmenopausal women. SEARCH METHODS: Searches of the following electronic bibliographic databases were performed in February 2014 to identify randomised controlled trials (RCTs): the Cochrane Menstrual Disorders and Subfertility Group Specialised Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, PsycINFO, Social Science Citation Index and CINAHL. Handsearches of trial registers, relevant journals and published conference abstracts were also performed. SELECTION CRITERIA: RCTs were included if they compared any type of relaxation intervention with no treatment or other treatments (except hormones) for vasomotor symptoms in symptomatic perimenopausal/postmenopausal women. DATA COLLECTION AND ANALYSIS: Two review authors selected studies, assessed quality and extracted data. Included studies were combined, if appropriate, by using a random-effects model to calculate pooled mean differences and 95% confidence intervals. MAIN RESULTS: Four studies were eligible for inclusion (281 participants): Two studies compared relaxation with electroacupuncture or superficial needling, one study compared relaxation with paced respiration or placebo control (alpha-wave electroencephalographic biofeedback) and one study compared relaxation with no treatment.No evidence was found of a difference between relaxation and acupuncture or superficial needle insertion in the number of hot flushes per 24 hours (mean difference (MD) 0.05, 95% confidence interval (CI) -1.33 to 1.43, two studies, 72 participants, I(2) = 0%; very low-quality evidence). Nor did any evidence suggest a difference between the two interventions in hot flush severity, measured using the Kupperman Index (MD -1.32, 95% CI -5.06 to 2.43, two studies, 72 participants, I(2) = 0%; very low-quality evidence).The other two studies found no clear evidence of a difference in hot flush frequency between relaxation and paced respiration, placebo or no treatment. The data for these comparisons were unsuitable for analysis.None of these studies reported night sweats, sleep disturbances associated with night sweats or adverse effects as an outcome.The main limitations of identified evidence were lack of data, imprecision and failure to report study methods in adequate detail. AUTHORS' CONCLUSIONS: Evidence is insufficient to show the effectiveness of relaxation techniques as treatment for menopausal vasomotor symptoms, or to determine whether this treatment is more effective than no treatment, placebo, acupuncture, superficial needle insertion or paced respiration. PMID- 25039020 TI - Impact of water abstraction on storage and breakdown of coarse organic matter in mountain streams. AB - Water abstraction is a prevalent impact in streams and rivers, which is likely to increase in the near future. Because abstraction reduces discharge, the dimensions of the wetted channel and water depth and velocity, it can have strong influence on stream ecosystem functioning. Although the impacts of large dams on stream and river ecosystems are pretty well known, the effects of diversion schemes associated with low dams are still poorly understood. Furthermore, the remote location of many diversion schemes and the lack of collaboration by power companies often make it difficult to know the volume of water diverted and its environmental consequences. To assess the impact of water abstraction on the storage and breakdown of coarse particulate organic matter in streams we compared reaches upstream and downstream from five low dams that divert water to hydropower plants in mountain streams in N Spain. We measured the storage of organic matter and the breakdown of alder leaves in winter and spring, and calculated the results at the patch (i.e., per square meter of bed) and at the reach scale (i.e., per lineal meter of channel). Water diversion significantly reduced discharge, and the width and depth of the wetted channel, but did not affect water quality. Diversion significantly reduced the storage and breakdown of organic matter in winter but not in spring. The number of shredders colonizing litter bags was also significantly reduced. The results point to an important effect of water abstraction on the storage and breakdown of organic matter in streams at least in some periods, which could affect downstream reaches, global carbon fluxes, and associated ecosystem services. PMID- 25039018 TI - Demographics of paediatric renal replacement therapy in Europe: a report of the ESPN/ERA-EDTA registry. AB - BACKGROUND: The ESPN/ERA-EDTA Registry collects data on European children with end-stage renal disease receiving renal replacement therapy (RRT) who are listed on national and regional renal registries in Europe. In this paper we report on the analysis of demographic data collected from 2009 to 2011. METHODS: Data on primary renal disease, incidence, prevalence, 4-year survival, transplantation rate and causes of death in paediatric patients receiving RRT were extracted from the ESPN/ERA-EDTA Registry for 37 European countries. RESULTS: The incidence of RRT in paediatric patients in Europe during the study period was 5.5 cases per million age-related population (pmarp) in patients aged 0-14 years and varied markedly between countries (interquartile range 3.4-7.0 years). The prevalence of RRT was 27.9 pmarp and increased with age, with 67 % of prevalent patients living with a functioning graft. The probability of receiving a transplant within 4 years was 76.9 % and was lowest in patients aged 0-4 years (68.9 %). Mortality in paediatric patients treated with RRT was 55-fold higher than that of the general EU paediatric population. Overall survival at 4 years was 93.7 %, with the poorest survival in patients aged 0-4 years and in patients starting on dialysis. Infections (19.9 %) were the primary cause of death in European paediatric RRT patients. CONCLUSION: Considerable variation exists in the current demographics of children treated with RRT across Europe. PMID- 25039021 TI - Ablation of atrial fibrillation: twenty years' experience. PMID- 25039022 TI - Medical management of stable angina. PMID- 25039024 TI - Transaortic aortic valve replacement using the Edwards Sapien-XT Valve and the Medtronic CoreValve: initial experience. AB - INTRODUCTION: Transcatheter aortic valve replacement (TAVR) is now an established treatment for certain patients with severe aortic valve stenosis (AS). However, as the number of patients screened for TAVR increases, many are found to have absolutely no option for peripheral artery access. Transaortic valve replacement (TAoVR) has been proposed as a new alternative route in patients deemed unsuitable for conventional approaches. We present our first series of TAoVR cases using the Edwards Sapien-XT and the Medtronic CoreValve prostheses. METHODS: Twenty-five (25) symptomatic patients (mean age 78 +/- 8 years, mean logistic EuroSCORE I 25 +/- 11%) with severe AS underwent TAoVR using the Sapien XT valve (10 patients) or the CoreValve (15 patients). RESULTS: The mean fluoroscopy time was 15.6 +/- 4.2 minutes, the mean time in the intensive care unit was 1.9 +/- 1.0 days, and the mean hospital stay was 6.4 +/- 1.6 days. The mean effective aortic valve area increased (from 0.68 +/- 0.15 cm(2) to 1.82 +/- 0.34 cm(2), p<0.001) and the mean transvalvular pressure gradient declined (from 48 +/- 15 mmHg to 9 +/- 5 mmHg, p<0.05) post implantation. The procedural mortality was 0% and the in-hospital mortality was 4% (one death at day 3 due to cardiogenic shock). The mean NYHA functional class improved from 3.2 +/- 0.4 to 1.5 +/- 0.9 at 30 days. CONCLUSIONS: Our initial experience with the TAoVR approach using both the Edwards Sapien-XT and the Medtronic CoreValve prosthesis demonstrated that it could be performed safely, resulting in substantial acute echocardiographic and early clinical improvement. PMID- 25039023 TI - Management of atrial fibrillation in Greece: the MANAGE-AF study. AB - BACKGROUND: Although atrial fibrillation (AF) is a highly prevalent health problem with high morbidity and mortality, data regarding the clinical characteristics and management of AF in the Greek population are scarce. The "Current Clinical Practice in the MANAGEment of Atrial Fibrillation in Greece" study (MANAGEAF) aimed to assess the epidemiological features as well as the daily clinical practice in the management of Greek patients with AF. METHODS: Taking into consideration the distribution of the Greek population, 603 consecutive patients over 18 years of age, with any type of AF, presenting at the emergency departments or outpatient clinics of 27 different centers, were included in our study. RESULTS: The mean age of the patients was 68.5 +/- 12.1 years, with male patients representing 52.5% of the study population. The most common AF type in our cohort was non-paroxysmal AF (60%), including the patients with permanent (24.1%), persistent (17.4%), long-standing (4.8%) and first diagnosed AF (13.8%). Hypertension was the most common comorbidity (70.3%). A history of stroke or transient ischemic attack was detected in 9.2% of the patients, while 6.2% had a history of gastrointestinal bleeding. About half of the patients (49.3%) were treated with anticoagulant drugs, mainly vitamin K antagonists (46.9%), while 34.2% were on antiplatelet drugs, aspirin and/or clopidogrel. The mean INR level (1.7 +/- 0.8) was sub-therapeutic, although the mean values for CHADS2 and CHA2DS2-VASc scores were 1.6 +/- 1.2 and 3.0 +/- 1.7, respectively. CONCLUSION: The MANAGE-AF baseline results indicate unsatisfactory levels of compliance with the current guidelines for the management of AF in Greece. Considering the undisputed effectiveness of anticoagulant treatment for preventing AF-related strokes, MANAGE-AF demonstrates the need for optimization of our therapeutic strategies for the management of cardioembolic stroke risk. PMID- 25039025 TI - Prevalence of peripheral arterial disease in subjects at moderate cardiovascular risk: Greek results of the PANDORA study. AB - INTRODUCTION: Peripheral arterial disease (PAD) is a form of atherosclerotic disease that confers a cardiovascular (CV) risk equivalent to that of coronary heart disease. Despite its association with high CV risk, PAD is potentially underdiagnosed. The primary objective of the study was to assess the prevalence of asymptomatic PAD through measurement of the ankle-brachial index (ABI) in subjects at moderate CV risk. Secondary objectives included the assessment of the prevalence of CV risk factors and lifestyle habits in the total population and in subjects with or without PAD, as well as the identification of factors associated with PAD. METHODS: PANDORA (NCT00689377) was a cross-sectional study conducted in 6 European countries. The study required a single visit in which males aged 45 or females 55 years, with at least 1 additional risk factor, but no overt CV disease or diabetes, underwent ABI measurement. Data on patient demographics, vital signs, CV risk factors, lipid levels and current treatment were recorded. RESULTS: Eight hundred forty subjects (789 evaluable) were enrolled by 120 office based physicians across Greece. Age was 62.1 +/- 9.1 years and body-mass index 29.6 +/- 4.3 kg/m(2); 61.2% of the subjects were male, 47% were smokers, and 73.5% hypertensive. The prevalence of asymptomatic PAD, defined as ABI0.90, was 28.0% (95% CI: 24.88-31.14). In logistic regression analysis, hypertension (OR: 2.48, 95% CI: 1.58-3.89, p<0.0001), low high-density lipoprotein cholesterol (OR: 2.27, 95% CI: 1.55-3.32, p<0.0001), and divorced marital status (OR: 2.63, 95% CI: 1.14-6.07, p=0.023), were found to be strong determinants for PAD. CONCLUSIONS: Asymptomatic PAD was highly prevalent in subjects with moderate CV risk treated by officebased physicians in Greece. ABI measurement is a significant tool for identifying subjects at higher risk who may require earlier and possibly more aggressive intervention. PMID- 25039026 TI - Value of apical circumferential strain in the early post-myocardial infarction period for prediction of left ventricular remodeling. AB - BACKGROUND: Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is related to increased morbidity and mortality. The aim of the present study was to examine whether LV deformational and torsional parameters can predict LV remodeling in patients with AMI. METHODS: Forty-two patients (age 57 +/- 14 years) presenting with an anterior ST-elevation AMI and treated with primary percutaneous transluminal coronary angioplasty (PTCA) were included in the study. Four days post MI, LV ejection fraction (EF), LV torsion, longitudinal (4-, 3- & 2-chamber) and circumferential strain of the LV apex were evaluated by conventional and speckle-tracking echocardiography. The echocardiographic study was repeated at 3 months post-AMI and patients with LV remodeling, i.e. an increase >15% in LV end-systolic volume (LVESV), were identified. RESULTS: The 13 patients with LV remodeling had significantly more impaired apical circumferential strain (-7.3 +/- 2.2% vs. -18.9 +/- 5.2%, p=0.001), EF (42 +/- 7% vs. 48.9 +/- 6%, p=0.005), LV apical rotation (6.8 +/- 4.8 degrees vs. 11.1 +/- 4.0 degrees , p=0.027), and LV global longitudinal strain (-9.7 +/- 1.9% vs. 12.9 +/- 2.9%, p=0.03) on the 4th day post-AMI, in comparison to those without LV remodeling. Apical circumferential strain on the 4th day post-AMI showed the strongest correlation with the LVESV 3 months post-AMI (r=0.76, p=0.001), compared to EF (r=-0.60, p=0.001), global longitudinal strain (r=0.56, p=0.001), and LV apical rotation (r=-0.53, p=0.001). Furthermore, apical circumferential strain demonstrated the highest diagnostic accuracy: area under the receiver operating characteristic (ROC) curve 0.98, with sensitivity 100% and specificity 96% for prediction of LV remodeling, using a cutoff value <-11.0%. CONCLUSION: In patients with anterior AMI, LV apical circumferential strain in the early post-MI period constitutes a significant prognostic factor for LV remodeling at 3 months. Assessment of this parameter may identify patients at high risk for heart failure development. PMID- 25039027 TI - Incident atrial fibrillation in systemic sclerosis: the predictive role of B-type natriuretic peptide. AB - INTRODUCTION: Atrial fibrillation (AF) is common in patients with systemic sclerosis (SSc) and is associated with significant morbidity, mortality, and healthcare expenditures. The aim of this study was to prospectively determine the incidence and the independent predictors of AF in this patient population. METHODS: Forty-nine patients (age 50.15 +/- 9.25 years, 87.8% female) and 21 healthy controls, all in sinus rhythm, were studied. Evaluation included blood sampling, B-type natriuretic peptide (BNP) measurement, comprehensive electrocardiography and echocardiography at baseline, and 24h ambulatory Holter monitoring at baseline and every 6 months. RESULTS: During a mean follow-up of 72 +/- 24 months, 18 SSc patients (36.7%) developed AF (SSc-AF group) while 31 remained in sinus rhythm (SSc-SR group); all subjects in the control group (Cl group) remained in SR. Baseline differences between SSc-AF, SSc-SR, and Cl groups included: a) left ventricular (LV) mass: 84.5 +/- 26 vs. 71.8 +/- 18.6 vs. 60.5 +/- 32.6 g/m(2), respectively (p=0.017); b) mitral tissue Doppler imaging E velocity: 14.5 +/- 2.8 vs. 17.5 +/- 3.4 vs. 20.5 +/- 4.4 cm/s (p<0.001); c) left atrial (LA) volume: 18.8 +/- 7.8 vs. 13.5 +/- 5.1 vs. 9.7 +/- 5.4 cm(3)/m(2) (p<0.001); d) LA active emptying volume: 7.6 +/- 2.7 vs. 4.7 +/- 3.2 vs. 3.3 +/- 2.2 cm(3)/m(2) (p<0.001); and e) logBNP: 1.78 +/- 0.47 vs. 1.31 +/- 0.54 vs. 0.66 +/- 0.38 pg/mL (p<0.001). In Cox proportional hazard analysis, BNP was the only independent predictor of incident AF. CONCLUSION: Incident AF was high in SSc, especially in the presence of LV diastolic dysfunction with LA mechanical overload and elevated BNP levels. BNP was the only independent predictor of incident AF; therefore, it should be considered for risk stratification in this population. PMID- 25039028 TI - Diagnostic value of soluble adhesion molecule kinetics in patients with suspected myocardial ischemia undergoing dobutamine stress echocardiography. AB - INTRODUCTION: Previous studies have shown an exercise-induced increase in circulating adhesion molecules (sICAM-1 and sVCAM-1) in patients with coronary artery disease (CAD). The aim of this study was to evaluate the diagnostic role of changes in serum adhesion molecules in the setting of a dobutamine stress echocardiogram (DSE). METHODS: Thirty patients (18 men and 12 women aged 63.3 +/- 10.67 years) with suspected myocardial ischemia underwent a DSE in our department's laboratory of echocardiography in order to identify inducible ischemia. Dobutamine was infused in incremental doses from 5 MUg/kg/min up to 40 MUg/kg/min. Blood samples were drawn at baseline as well as at peak stress and circulating adhesion molecules sVCAM-1 and sICAM-1 levels were measured by ELISA. Patients with a positive DSE underwent coronary arteriography within 2 weeks of the DSE study. RESULTS: Sixteen patients had a positive DSE for inducible ischemia while 14 had a negative test. Among the patients with positive DSE, 12 had angiographically significant CAD as well as statistically significantly higher levels of sICAM-1 than DSE negative patients (n=14), both at baseline (302.57 +/- 43.37 vs. 267.47 +/- 28.03 ng/mL, p=0.028) and at peak stress (322.07 +/- 49.64 vs. 260.43 +/- 36.45 ng/mL, p=0.001). A significant increase from baseline to peak stress was also noted in this group (from 302.57 +/- 43.37 to 322.07 +/- 49.64 ng/mL, p=0.043). There were no statistically significant differences in the levels of sVCAM-1 between groups at baseline and there was no change from baseline to peak stress. CONCLUSION: Plasma levels of sICAM-1 were found to be elevated in subjects with a positive DSE and angiographically significant CAD compared to patients with a negative DSE, both before and after inducible ischemia. In contrast, no changes were noted regarding sVCAM-1 levels. PMID- 25039029 TI - Revascularization strategies in multivessel and left main coronary artery disease: SYNTAX and beyond. PMID- 25039030 TI - The right ventricle in systemic sclerosis: insights from cardiac magnetic resonance imaging. PMID- 25039031 TI - Transcatheter valve-in-valve implantation for a degenerated mitral valve bioprosthesis under echocardiographic guidance. PMID- 25039032 TI - Paravalvular aortic prosthetic valve leak closure: technical aspects of the percutaneous approach. AB - We describe the successful closure of an aortic paravalvular bioprosthetic valve leak with the simultaneous percutaneous deployment of two vascular plugs. PMID- 25039033 TI - Transcatheter aortic valve replacement: current status and future prospects. PMID- 25039034 TI - The viability and performance of the Greek national health system: a brief overview of some selected data. PMID- 25039036 TI - [Changes in the regulations on medical prescriptions and prescribing orders that affect the family doctor]. PMID- 25039035 TI - Fear of evaluation in social anxiety: mediation of attentional bias to human faces. AB - Social anxiety disorder (SAD) is a debilitating psychological disorder characterised by excessive fears of one or more social or performance situations, where there is potential for evaluation by others. A recently expanded cognitive behavioural model of SAD emphasizes that both the fear of negative evaluation (FNE) and the fear of positive evaluation (FPE) contribute to enduring symptoms of SAD. Research also suggests that socially anxious individuals may show biases toward threat relevant stimuli, such as angry faces. The current study utilised a modified version of the pictorial dot-probe task in order to examine whether FNE and FPE mediate the relationship between social anxiety and an attentional bias. A group of 38 participants with moderate to high levels of self-reported social anxiety were tested in groups of two to four people and were advised that they would be required to deliver an impromptu speech. All participants then completed an assessment of attentional bias using angry-neutral, happy-neutral, and angry happy face pairs. Conditions were satisfied for only one mediation model, indicating that the relationship between social anxiety and attentional avoidance of angry faces was mediated by FPE. These findings have important clinical implications for types of treatment concerning cognitive symptoms of SAD, along with advancing models of social anxiety. Limitations and ideas for future research from the current study were also discussed. PMID- 25039037 TI - Body composition and mortality in a large cohort with preserved ejection fraction: untangling the obesity paradox. AB - OBJECTIVE: To evaluate the effects of body composition as a function of lean mass index (LMI) and body fat (BF) on the correlation between increasing body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and decreasing mortality, which is known as the obesity paradox. PATIENTS AND METHODS: We retrospectively assessed 47,866 patients with preserved left ventricular ejection fraction (>=50%). We calculated BF by using the Jackson Pollock equation and LMI using (1 - BF) * BMI. The population was divided according to the sex-adjusted BMI classification, sex-adjusted LMI classification, and sex-adjusted BF tertiles. The population was analyzed by using multivariate analysis for total mortality over a mean follow-up duration of 3.1 years by using the National Death Index, adjusting for left ventricular ejection fraction, left ventricular mass index, age, sex, and relative wall thickness. RESULTS: In the entire population, higher BMI was narrowly associated (hazard ratio [HR], 0.99; P<.001) with lower mortality. The higher LMI group was clearly protective (HR, 0.71; P<.001), whereas BF tertile was associated with lower mortality only if no adjustment was made for LMI (HR, 0.87; P<.001 without LMI; HR, 0.97; P=.23 with LMI). In the lean patients, low BMI was clearly associated with higher mortality (HR, 0.92; P<.001) and lower BF tertile was associated with lower mortality only if no adjustment was made for LMI (HR, 0.80; P<.001 without LMI; HR, 1.01; P=.83 with LMI). The underweight patients stratified by BF seemed to have an increased mortality (HR, 1.91; 95% CI, 1.56 2.34) that was independent of LMI. However, in obese patients, both BMI (HR, 1.03; P<.001) and BF (HR, 1.18; P=.003) were associated with higher mortality, even after adjusting for LMI, which remained protective (HR, 0.57; P<.001) independently of BF. CONCLUSION: Body composition could explain the inverse J shape of the mortality curve noted with increasing BMI. Body fat seems to be protective in this cohort only if no adjustment was made for LMI, although being underweight stratified by BF seems to be an independent risk factor. Lean mass index seems to remain protective in obese patients even when BMI is not. PMID- 25039038 TI - Relationship of body mass index with total mortality, cardiovascular mortality, and myocardial infarction after coronary revascularization: evidence from a meta analysis. AB - OBJECTIVE: To investigate the relationship of body mass index (BMI) with total mortality, cardiovascular (CV) mortality, and myocardial infarction (MI) after coronary revascularization procedures (coronary artery bypass grafting [CABG] and percutaneous coronary intervention [PCI]). PATIENTS AND METHODS: Systematic search of studies was conducted using PubMed, CINAHL, Cochran CENTRAL, Scopus, and the Web of Science databases. We identified studies reporting the rate of MI, CV mortality, and total mortality among coronary artery disease patients' postcoronary revascularization procedures in various BMI categories: less than 20 (underweight), 20-24.9 (normal reference), 25-29.9 (overweight), 30-34.9 (obese), and 35 or more (severely obese). Event rates were compared using a random effects model assuming interstudy heterogeneity. RESULTS: A total of 36 studies (12 CABG; 26 PCI) were selected for final analyses. The risk of total mortality (relative risk [RR], 2.59; 95% CI, 2.09-3.21), CV mortality (RR, 2.67; 95% CI, 1.63-4.39), and MI (RR, 1.79; 95% CI, 1.28-2.50) was highest among patients with low BMI at the end of a mean follow-up period of 1.7 years. The risk of CV mortality was lowest among overweight patients (RR, 0.81; 95% CI, 0.68-0.95). Increasing degree of adiposity as assessed by BMI had a neutral effect on the risk of MI for overweight (RR, 0.92; 95% CI, 0.84-1.01), obese (RR, 0.99; 95% CI, 0.85-1.15), and severely obese (RR, 0.93; 95% CI, 0.78-1.11) patients. CONCLUSION: After coronary artery disease revascularization procedures (PCI and CABG), the risk of total mortality, CV mortality, and MI was highest among underweight patients as defined by low BMI and CV mortality was lowest among overweight patients. PMID- 25039039 TI - Simulation in laparoscopic surgery. AB - Nowadays surgical trainees are faced with a more reduced surgical practice, due to legal limitations and work hourly constraints. Also, currently surgeons are expected to dominate more complex techniques such as laparoscopy. Simulation emerges as a complementary learning tool in laparoscopic surgery, by training in a safe, controlled and standardized environment, without jeopardizing patient' safety. Simulation' objective is that the skills acquired should be transferred to the operating room, allowing reduction of learning curves. The use of simulation has increased worldwide, becoming an important tool in different surgical residency programs and laparoscopic training courses. For several countries, the approval of these training courses are a prerequisite for the acquisition of surgeon title certifications. This article reviews the most important aspects of simulation in laparoscopic surgery, including the most used simulators and training programs, as well as the learning methodologies and the different key ways to assess learning in simulation. PMID- 25039040 TI - Shagrination during acute otitis media. PMID- 25039041 TI - Effects of a sustained inflation in preterm infants at birth. AB - OBJECTIVE: To assess the clinical effect of an initial sustained inflation of 10 seconds and 25 cmH2O in preterm infants at birth. STUDY DESIGN: In this observational study inflation pressures and tidal volumes were recorded with the use of respiratory function monitoring of preterm infants <32 weeks' gestation receiving a sustained inflation. Inspiratory tidal volume (Vti) and expiratory tidal volume (Vte) of sustained inflation and cumulative Vti and Vte of breaths during sustained inflation were determined. Heart rate and oxygen saturation were measured before and after the sustained inflation. RESULTS: Seventy infants were included (median [IQR]: gestational age 29 [27-30] weeks). Mean (SD) sustained inflation duration was 10.5 seconds (2.9 seconds) with positive inflation pressure 24.2 cmH2O (2.3 cmH2O) and positive end-expiratory pressure 6.0 cmH2O (1.8 cmH2O). In 20 of 70 infants, no volumes were delivered during the sustained inflation because of mask leak. No leak occurred in 50 of 70 infants, of whom 36 of 50 breathed during the sustained inflation. In 14 of the infants who did not breathe, Vti and Vte were 0.9 mL/kg (0.4-2.7 mL/kg) and 0.6 mL/kg (0.1-2.0 mL/kg) with a functional residual capacity (FRC) gain of 0.0 (-0.5 to 0.6) mL/kg. In 36 of 50 infants who breathed during the sustained inflation, Vti was 2.9 mL/kg (0.9 9.2 mL/kg) and Vte 3.8 mL/kg (1.0-5.9 mL/kg), whereas cumulative Vti of breaths was 16.4 mL/kg (6.8-23.3 mL/kg) and cumulative Vte of breaths was 5.8 mL/kg (1.2 16.8 mL/kg) with an FRC gain of 7.1 mL/kg (1.7-15.9 mL/kg). Heart rate and oxygen saturation did not increase immediately after the sustained inflation. CONCLUSIONS: A sustained inflation of 10 seconds and 25 cmH2O in preterm infants at birth was not effective unless infants breathed. Although large mask leak accounted for approximately one-third of failures, as FRC gain was only associated with breathing, we speculate that active glottic adduction may be responsible for most failures. PMID- 25039042 TI - Red blood cell transfusion is not associated with necrotizing enterocolitis: a review of consecutive transfusions in a tertiary neonatal intensive care unit. AB - OBJECTIVE: To explore the association between red blood cell transfusion and necrotizing enterocolitis (NEC) in a neonatal intensive care unit with liberal transfusion practices. STUDY DESIGN: A retrospective cohort study was conducted for all infants weighing <1500 g who received at least 1 packed red blood cell transfusion between January 2008 and June 2013 in a tertiary neonatal intensive care unit. The primary outcome was NEC, defined as Bell stage II or greater. The temporal association of NEC and transfusion was assessed using multivariate Poisson regression. RESULTS: The study sample included 414 very low birth weight infants who received 2889 consecutive red blood cell transfusions. Twenty-four infants (5.8%) developed NEC. Four cases of NEC occurred within 48 hours of a previous transfusion event. Using multivariate Poisson regression, we did not find evidence of a temporal association between NEC and transfusion (P = .32). CONCLUSION: There was no association between NEC and red blood cell transfusion. Our results differ from previous studies and suggest that the association between NEC and transfusion may be contextual. PMID- 25039044 TI - Growth comparison in children with and without food allergies in 2 different demographic populations. AB - OBJECTIVE: To examine the effects of food avoidance on the growth of children with food allergies. STUDY DESIGN: A retrospective chart review was performed for children with and without food allergies followed at 2 New York City general pediatric practices. Charts were selected based on codes from the International Classification of Diseases, 9th Revision, for well child visit, food allergy, anaphylaxis, and/or epinephrine autoinjector prescriptions. Heights and weights were obtained to calculate body mass index, height, and weight z-scores. RESULTS: Of the 9938 children seen, 439 (4.4%) were avoiding one or more foods. Of those with commercial insurance, children with food allergies were significantly shorter (mean height z-score = 0.06; P = .01) and weighed less (mean weight z score -0.1; P = .006) than children without food allergies (mean height z-score = 0.42; mean weight z-score = 0.07). In contrast, children with food allergies and state insurance were not smaller in height or weight compared with children without food allergies. Among white subjects, there was a significant effect of food allergies on height and weight (ANOVA for height P = .012, for weight P = .0036) that was not observed for Hispanic/Latino, black, or Asian subjects. Children with allergies to milk weighed significantly less than children without milk allergies (P = .0006). CONCLUSIONS: Children with food allergies and commercial insurance have significant impairment in growth compared with those without food allergies. Additionally, children avoiding all forms of milk are shorter and weigh less than matched counterparts. Therefore, height and weight measurements should be assessed routinely in children with food allergies because there is risk for growth impairment in this population. PMID- 25039043 TI - Lipoprotein particle concentrations in children and adults following Kawasaki disease. AB - OBJECTIVE: To test the hypothesis that children and adults with a history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk for developing atherosclerosis later in life. STUDY DESIGN: Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy (LipoScience Inc, Raleigh, North Carolina), and serum was assayed for total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) cholesterol (HDL-C). Low-density lipoprotein (LDL) cholesterol was estimated using the Friedewald formula. Data were analyzed in a least-square means model, with adjustment for age and sex and with the use of Holm correction for multiple comparisons. RESULTS: Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very low density lipoprotein-chylomicron particles, intermediate-density lipoproteins, triglycerides, and TC concentrations. Pediatric subjects with KD had significantly lower LDL particle and LDL cholesterol concentrations and lower mean TC/HDL-C ratio (P < .001). In contrast, the adult subjects with KD had significantly lower HDL particle, small HDL particle, and HDL-C concentrations (P < .001), but HDL-C was within normal range. CONCLUSIONS: Nuclear magnetic resonance lipoprotein particle analysis suggests that pediatric and adult subjects with KD, regardless of their aneurysm status, are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis. PMID- 25039045 TI - Quality of childcare influences children's attentiveness and emotional regulation at school entry. AB - OBJECTIVE: To examine the association between domain-specific qualities of formal childcare at age 2-3 years and children's task attentiveness and emotional regulation at age 4-5 and 6-7 years. STUDY DESIGN: We used data from the Longitudinal Study of Australian Children (n = 1038). Three domain-specific aspects of childcare quality were assessed: provider and program characteristics of care, activities in childcare, and carer-child relationship. Two self regulatory abilities were considered: task attentiveness and emotional regulation. Associations between domain-specific qualities of childcare and self regulation were investigated in linear regression analyses adjusted for confounding, with imputation for missing data. RESULTS: There was no association between any provider or program characteristics of care and children's task attentiveness and emotional regulation. The quality of activities in childcare were associated only with higher levels of emotional regulation at age 4-5 years (beta = 0.24; 95% CI, 0.03-0.44) and 6-7 years (beta = 0.26; 95% CI, 0.04-0.48). Higher-quality carer-child relationships were associated with higher levels of task attentiveness (beta = 0.20; 95% CI, 0.05-0.36) and emotional regulation at age 4-5 years (beta = 0.19; 95% CI, 0.04-0.34) that persisted to age 6-7 years (beta = 0.26; 95% CI, 0.10-0.42; beta = 0.31; 95% CI, 0.16-0.47). CONCLUSION: Among children using formal childcare, those who experienced higher-quality relationships were better able to regulate their attention and emotions as they started school. Higher emotional regulation was also observed for children engaged in more activities in childcare. Beneficial effects were stable over time. PMID- 25039046 TI - Baseline sodium may matter. PMID- 25039047 TI - Reply: To PMID 24529619. PMID- 25039048 TI - Health-related quality of life and physical activity in children and adolescents 2 years after an inpatient weight-loss program. AB - OBJECTIVES: To investigate changes in health-related quality of life (HRQOL), body mass index (BMI), physical activity, and sedentary behavior at 24 months after an inpatient weight-loss program and to examine correlations between changes in HRQOL and BMI or physical activity. STUDY DESIGN: This prospective study included 707 overweight and obese individuals (mean age, 14 +/- 2 years; 57% girls) participating in a 4- to 6-week inpatient weight-loss program, 381 of whom completed a 24-month follow-up. HRQOL, physical activity, sedentary behavior, and BMI were assessed at baseline, at discharge, and at 6, 12, and 24 months after starting therapy. Longitudinal analyses were conducted using repeated-measures mixed models, adjusted for age, sex, and baseline outcome and accounting for attrition over time. RESULTS: All variables improved over treatment and 6-month follow-up (P < .05). At 24 months, overall HRQOL indicated improvements relative to baseline (3 points on a scale of 0-100; 95% CI, 1.68 4.47; P < .001). Of the 6 HRQOL domains, the greatest improvement was observed for self-esteem (11 points; 95% CI, 8.40-13.14; P < .001). BMI was 0.5 kg/m(2) lower than at baseline (95% CI, -0.92 to -0.02; P = .04). Long-term changes in physical activity explained 30% of the variation in overall HRQOL (P = .01), and change in BMI was not associated with a change in HRQOL. CONCLUSIONS: This inpatient weight-loss program was associated with positive changes in HRQOL over the long term, with particular improvements in self-esteem. The results indicate the potential role of physical activity in improving HRQOL without a substantial change in body composition. PMID- 25039050 TI - New time-frequency method for cerebral autoregulation in newborns: predictive capacity for clinical outcomes. AB - OBJECTIVE: To describe an alternative analysis in the frequency-domain of the temporal relationship between 2 biological signals and evaluate the method's predictive capacity for classifying infants at risk for an adverse outcome. STUDY DESIGN: We studied 54 infants (mean gestational age 27 weeks) with invasive mean arterial blood pressure monitoring. The bivariate autoregressive spectral coherence (BiAR-COH) method and the spectral coherence methods were used to analyze the relationship between spontaneous changes in mean arterial blood pressure and the near-infrared tissue oxygenation index. RESULTS: The mean postnatal age at the beginning and end of the autoregulation study was 6.0 (3.0) and 29.0 (7.5) hours, respectively. The BiAR-COH was superior to the spectral coherence in predicting low superior vena cava (SVC) flow (<= 41 mL/kg per minute), with an area under the receiver operating characteristic curve of 0.84 (95% CI, 0.77-0.90; P < .001). The BiAR-COH threshold for identifying low SVC flow was 0.577, with 0.8 sensitivity and 0.76 specificity. After adjusting for the repeated measures effect (multiple epochs) in a given patient, the averaged BiAR-COH per patient and averaged COH per patient were calculated as the average value per patient. The pBiAR-COH (but not the pCOH) was associated with intraventricular hemorrhage grades 3 and 4 and predicted mortality. CONCLUSIONS: The BiAR-COH classifier identifies low SVC flow infants who are at risk for brain hypoperfusion. The BiAR-COH is superior to frequency domain methods in predicting adverse outcomes in infants. PMID- 25039049 TI - Feeding impairments associated with plasma sterols in Smith-Lemli-Opitz syndrome. AB - OBJECTIVE: To quantitatively evaluate feeding impairment in children with Smith Lemli-Opitz syndrome (SLOS) and to correlate feeding impairment with clinical and biochemical indices of disease severity. STUDY DESIGN: The study subjects were 26 children with SLOS ranging in age from 0.4 to 19 years. Clinical severity was measured using an existing scoring system. We created a tool to quantitatively evaluate feeding. Plasma sterol concentrations were measured, and statistical associations (correlations) with feeding scores were calculated. RESULTS: Oral hyposensitivity or hypersensitivity, adverse behaviors, and risk for dysphagia were seen in ~65% of the children with SLOS. Thirteen of the 26 children experienced failure to thrive, and 10 children required gastrostomy. Plasma concentration of 7-dehydrocholesterol, as a measure of severity, was correlated with total feeding score and oral function subcategory score (P < .001) and less so with oral structure score, adverse behaviors, or dysphagia. Correlations with cholesterol concentrations were less statistically significant. A plasma 7 dehydrocholesterol concentration >0.24 mmol/L or cholesterol concentration <1.95 mmol/L was predictive of gastrostomy tube use. Feeding impairments may improve with age. CONCLUSION: Feeding impairment is common and complex in patients with SLOS. Our findings confirm that oral sensitivities, adverse feeding behaviors, and risk of oral phase dysphagia are amenable to quantitative evaluation and analysis. Feeding difficulties in children with SLOS are correlated with plasma sterol concentrations, suggesting a link between the biochemical severity of SLOS and feeding function. These findings expand the behavioral phenotype of SLOS and begin to provide insight into the biological causes of feeding difficulties. PMID- 25039051 TI - Trends in pharmacotherapy for neonatal hypotension. AB - OBJECTIVE: To determine trends in pharmacotherapy for neonatal hypotension in all infants and in extremely low birth weight (ELBW, birth weight 300-1000 g) infants. STUDY DESIGN: We queried the Pediatric Health Information System database for all infants <=28 days with a diagnosis code for hypotension that were discharged between January 2001 and December 2012. Patients were excluded if they had complex congenital heart disease or cardiac surgery, sepsis or meningitis, or had extracorporeal membrane oxygenation. We determined trends in pharmacotherapy for hypotension in all infants and ELBW infants, an especially vulnerable group. RESULTS: A total of 8019 hypotensive infants met study criteria. The 2 most prescribed medications were dopamine (65.3%) and dobutamine (19.9%). For 1487 hypotensive ELBW infants, the 2 most prescribed medications were dopamine (83.4%) and hydrocortisone (33%). During the study period, the use of dobutamine decreased, and hydrocortisone and vasopressin use increased for all infants and for ELBW infants. CONCLUSIONS: Treatment of neonatal hypotension varies widely between institutions and individual practitioners, and pharmacotherapy for neonatal hypotension has changed over the past decade. Although dopamine and dobutamine were the most frequently used agents, their use has declined and the uses of hydrocortisone and vasopressin have increased. PMID- 25039052 TI - Growth inhibition of Mycobacterium smegmatis by mycobacteriophage-derived enzymes. AB - We report the ability of mycobacteriophage-derived endolysins to inhibit the growth of Mycobacterium smegmatis. We expressed and purified LysB from mycobacteriophage Bxz2 and compared its activity with that of a previously reported LysB from mycobacteriophage Ms6. The esterase activity of Bxz2 LysB with pNP esters was 10-fold higher than that of the previously reported LysB but its lipolytic activity was significantly lower. The presence of surfactant - Tween 80 or Triton X-100 - significantly increased the activity of LysB. Characterization of LysB-treated M. smegmatis cells and LysB-treated purified cell wall by mass spectroscopy confirmed the hydrolytic activity of the enzyme. Both enzymes were equally effective in inhibiting the growth of M. smegmatis, demonstrating their potential as bacteriostatic agents. PMID- 25039053 TI - An inhibitory enzyme electrode for hydrogen sulfide detection. AB - An enzymatic biosensing system has been developed to study the capability of ascorbate oxidase (AOx), EC (1.10.3.3), in hydrogen sulfide (H2S) detection, based on the inhibition of AOx activity. The immobilization parameters including glutaraldehyde (GA) concentration and pH were optimized using experimental design. The optimized values of GA concentration and pH were found to be 12.5% (w/w) and 7, respectively, where the enzymatic reaction reached the steady-state level within 55 s. A linear relationship was observed between the decrease in the oxygen concentration and H2S concentration, where H2S concentration is in the range of 1-15 mg/L. Moreover, to investigate the selectivity of the biosensor, a certain H2S concentration (9 mg/L) was used against different ions. The results indicated that Fe(3+) and SO4(-2) ions had no significant (11% error) effect on the H2S detection. The operational stability of the biosensing system was determined in terms of response to H2S concentration, at optimal working conditions. The enzyme electrode could retain 73% of its original sensitivity after this period, which has made it possible for the system to measure H2S with concentrations as low as 0.5 mg/L. PMID- 25039054 TI - Xylose and xylose/glucose co-fermentation by recombinant Saccharomyces cerevisiae strains expressing individual hexose transporters. AB - Since the uptake of xylose is believed to be one of the rate-limiting steps for xylose ethanol fermentation by recombinant Saccharomyces cerevisiae strains, we transformed a hxt-null strain lacking the major hexose transporters (hxt1Delta hxt7Delta and gal2Delta) with an integrative plasmid to overexpress the genes for xylose reductase (XYL1), xylitol dehydrogenase (XYL2) and xylulokinase (XKS1), and analyzed the impact that overexpression of the HXT1, HXT2, HXT5 or HXT7 permeases have in anaerobic batch fermentations using xylose, glucose, or xylose plus glucose as carbon sources. Our results revealed that the low-affinity HXT1 permease allowed the maximal consumption of sugars and ethanol production rates during xylose/glucose co-fermentations, but was incapable to allow xylose uptake when this sugar was the only carbon source. The moderately high-affinity HXT5 permease was a poor glucose transporter, and it also did not allow significant xylose uptake by the cells. The moderately high-affinity HXT2 permease allowed xylose uptake with the same rates as those observed during glucose consumption, even under co-fermentation conditions, but had the drawback of producing incomplete fermentations. Finally, the high-affinity HXT7 permease allowed efficient xylose fermentation, but during xylose/glucose co-fermentations this permease showed a clear preference for glucose. Thus, our results indicate that approaches to engineer S. cerevisiae HXT transporters to improve second generation bioethanol production need to consider the composition of the biomass sugar syrup, whereby the HXT1 transporter seems more suitable for hydrolysates containing xylose/glucose blends, whereas the HXT7 permease would be a better choice for xylose-enriched sugar streams. PMID- 25039055 TI - High-level production of recombinant trypsin in transgenic rice cell culture through utilization of an alternative carbon source and recycling system. AB - Productivity of recombinant bovine trypsin using a rice amylase 3D promoter has been studied in transgenic rice suspension culture. Alternative carbon sources were added to rice cell suspension cultures in order to improve the production of recombinant bovine trypsin. It was demonstrated that addition of alternative carbon sources such as succinic acid, fumaric acid and malic acid in the culture medium could increase the productivity of recombinant bovine trypsin 3.8-4.3-fold compared to those in the control medium without carbon sources. The highest accumulated trypsin reached 68.2 mg/L on day 5 in the culture medium with 40 mM fumaric acid. The feasibility of repeated use of the cells for recombinant trypsin production was tested in transgenic rice cell suspension culture with the culture medium containing the combination of variable sucrose concentration and 40 mM fumaric acid. Among the used combinations, the combination of 1% sucrose and 40 mM fumaric acid resulted in a yield of up to 53 mg/L five days after incubation. It also increased 31% (W/W) of dry cell weight and improved 43% of cell viability compared to that in control medium without sucrose. Based on these data, recycling of the trypsin production process with repeated 1% sucrose and 40 mM fumaric acid supplying-harvesting cycles was developed in flask scale culture. Recombinant bovine trypsin could be stably produced with a yield of up to 53-39 mg/L per cycle during five recycling cycles. PMID- 25039056 TI - Gene encoding a novel invertase from a xerophilic Aspergillus niger strain and production of the enzyme in Pichia pastoris. AB - beta-Fructofuranosidases or invertases (EC 3.2.1.26) are enzymes that are widely used in the food industry, where fructose is preferred over sucrose, because it is sweeter and does not crystallize easily. Since Aspergillus niger GH1, an xerophilic fungus from the Mexican semi-desert, has been reported to be an invertase producer, and because of the need for new enzymes with biotechnological applications, in this work, we describe the gene and amino acid sequence of the invertase from A. niger GH1, and the use of a synthetic gene to produce the enzyme in the methylotrophic yeast Pichia pastoris. In addition, the produced invertase was characterized biochemically. The sequence of the invertase gene had a length of 1770 bp without introns, encodes a protein of 589 amino acids, and presented an identity of 93% and 97% with invertases from Aspergillus kawachi IFO 4308 and A. niger B60, respectively. A 4.2 L culture with the constructed recombinant P. pastoris strain showed an extracellular and periplasmic invertase production at 72 h induction of 498 and 3776 invertase units (U), respectively, which corresponds to 1018 U/L of culture medium. The invertase produced had an optimum pH of 5.0, optimum temperature of 60 degrees C, and specific activity of 3389 U/mg protein, and after storage for 96 h at 4 degrees C showed 93.7% of its activity. This invertase could be suitable for producing inverted sugar used in the food industry. PMID- 25039057 TI - Enzymatic hydrolysis of penicillin and in situ product separation in thermally induced reversible phase-separation of ionic liquids/water mixture. AB - Enzymatic hydrolysis of penicillin G to produce 6-aminopenicillanic acid, key intermediate for the production of semisynthetic beta-lactam antibiotics, is one of the most relevant example of industrial implementation of biocatalysts. The hydrolysis reaction is traditionally carried out in aqueous buffer at pH 7.5-8. However, the aqueous rout exhibits several drawbacks in enzyme stability and product recovery. In this study, several ionic liquids (ILs) have been used as media for enzymatic hydrolysis of penicillin G. The results indicated that hydrophobic ILs/water two-phase system were good media for the reaction. In addition, a novel aqueous two-phase system based on the lower critical solution temperature type phase changes of amino acid based ILs/water mixture was developed for in situ penicillin G hydrolysis and product separation. For instance, hydrolysis yield of 87.13% was obtained in system containing 30 wt% [TBP][Tf-ILe] with pH control (pH 7.6). Since the phase-separation of this medium system can be reversible switched from single to two phases by slightly changing the solution temperature, enzymatic hydrolytic reaction and product recovery were more efficient than those of aqueous system. In addition, the ILs could be reused for at least 5 cycles without significant loss in hydrolysis efficiency. PMID- 25039058 TI - Enhanced PCR efficiency of high-fidelity DNA polymerase from Thermococcus waiotapuensis. AB - Twa DNA polymerase from hyperthermophilic archaeon Thermococcus waiotapuensis has exceedingly high fidelity among family B DNA polymerases. However, Twa DNA polymerase has significant shortcomings in terms of a low extension rate and poor processivity. To resolve these weaknesses, we focused on two amino acid residues (N565 and H633) in the palm and thumb subdomains of the Twa DNA polymerase. These two residues were replaced by site-directed mutagenesis and the enzymatic properties of the mutants were analyzed. Here, Twa H633R DNA polymerase showed significantly improved polymerase function compared to wild-type Twa DNA polymerase in terms of processivity (2-fold), extension rate (1.5-fold) and PCR efficiency. Kinetic analysis using DNA as a template revealed that the kcat value of the Twa H633R mutant was similar to that of wild-type, but the Km of the Twa H633R mutant was about 1.6-fold lower than that of the wild-type. These results showed that the Arg residue substitution at H633 located in the thumb subdomain has a positive effect on processivity, extension rate and PCR efficiency, suggesting that the Twa H633R mutant allows a conformational change for easy access of the primer-template to the binding site of the polymerase domain. PMID- 25039059 TI - Synthesis of Mycoplasma arginine deiminase in E. coli using stress-responsive proteins. AB - We found Escherichia coli proteins, elongation factor Ts (Tsf), and malate dehydrogenase (Mdh) that can exist in the form of native and soluble proteins even under stress situation such as heat shock and protein denaturing condition. To examine their property as solubility enhancers, aggregation-prone Mycoplasma arginine deiminase (mADI), which has been suggested as anti-cancer agent, was fused to the C-terminal of each of them and cloned into pET28a to be expressed in the E. coli cytoplasm. When mADI was fused to fusion partners (Mdh, Tsf), a significant portion of the recombinant mADI was expressed in a soluble fraction (>90%) whereas the directly expressed mADI was aggregated to the inclusion body. In addition, recombinant mADI released from the fusion tag retained its soluble form and presented its specific enzymatic activity of converting l-arginine into citrulline (>10 U/mg). These results show that Tsf and Mdh could serve as effective solubility enhancers for aggregation-prone proteins (e.g. mADI in this case) when used as fusion expression partners in bacterial expression systems. PMID- 25039060 TI - Enhancing catalytic performance of beta-glucosidase via immobilization on metal ions chelated magnetic nanoparticles. AB - A novel magnetic Fe3O4 nanoparticles (MNPs) coupled with agarose (AMNPs) was synthesized using co-precipitation via alkaline condition and span-80 surfactants in organic solvent. Iminodiacetate was first attached to the MNPs through epichlorohydrin agent and then chelated with metal ions. The morphology and chemical properties of these prepared supports were characterized by scanning electron microscopy (SEM), X-ray power diffraction (XRD), vibrating sample magnetometer (VSM), and Fourier transform infrared spectroscopy (FT-IR). Among them, the Co(2+)-chelated AMNPs (AMNPs-ECH-IDA-Co(2+)) showed the second highest enzyme adsorption capacity of 1.81 mg/g particles, and achieved the largest activity recovery of 117% per protein gram in immobilization of beta-glucosidase (BGL). The Michaelis constant (Km) and Vmax of the immobilized BGL were 0.904 mM and 0.057 MUmol/min, respectively, and its activation energy was much lower than the free form. Moreover, the immobilized enzyme exhibited enhanced thermostability and operational stability. It still retained more than 90% of its initial activity after being operated for 15 successive batches. This study demonstrates that the immobilized beta-glucosidase has a good prospect in industrial applications. PMID- 25039061 TI - Production of functional human vascular endothelial growth factor(165) in transgenic rice cell suspension cultures. AB - Vascular endothelial growth factors (VEGFs) are secreted by tumor cells and other cells exposed to hypoxia, and play a critical role in the development and differentiation of the vascular system. In this study, we investigated the production of functional recombinant human VEGF165 (rhVEGF165) in transgenic rice cell suspension culture. Complementary DNA was synthesized from human leukemia HL60 cells and cloned into expression vectors under the control of the rice alpha amylase 3D (RAmy3D) promoter. The rice seed (Oryza sativa L. cv. Dongjin) was transformed with this recombinant vector by the Agrobacterium mediated method and the integration of the target gene into the plant genome was confirmed by genomic PCR. The expression of rhVEGF165 in the rice cells was determined by Northern blot and Western blot analyses. The accumulated rhVEGF165 protein in the culture medium was 19 mg/L after 18 days of culturing in a sugar-free medium. The rhVEGF165 was purified using a heparin HP column and its biological activity was tested on human umbilical vein endothelial cells (HUVECs). The purified rhVEGF165 significantly increased the proliferative activity of the HUVECs. Therefore, it was demonstrated that functional rhVEGF165 could be produced using transgenic rice suspension culture vector under the control of the RAmy3D promoter. PMID- 25039062 TI - Characterization and site-directed mutagenesis of a novel class II 5 enopyruvylshikimate-3-phosphate (EPSP) synthase from the deep-sea bacterium Alcanivorax sp. L27. AB - The 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) is a key enzyme in the aromatic amino acid biosynthetic pathway in microorganisms and plants, which catalyzes the formation of 5-enolpyruvylshikimate-3-phosphate (EPSP) from shikimate-3-phosphate (S3P) and phosphoenolpyruvate (PEP). In this study, a novel AroA-encoding gene was identified from the deep sea bacterium Alcanivorax sp. L27 through screening the genomic library and termed as AroAA.sp. A phylogenetic analysis revealed that AroAA.sp (1317 bp and 438 amino acids) is a class II AroA. This enzyme exhibited considerable activity between pH 5.5 and pH 8.0 and notable activity at low temperatures. The KM for PEP and IC50 [glyphosate] values (the concentration of glyphosate that inhibited enzyme activity by 50%) of AroAA.sp were 78 MUM and 1.5 mM, respectively. Furthermore, site-directed mutagenesis revealed that the G100A mutant had a 30-fold increase in the IC50 [glyphosate] value; while the L105P mutant showed only 20% catalytic activity compared to wild type AroAA.sp. The specific activity of the wild-type AroAA.sp, the G100A mutant and the L105P mutant were 7.78 U/mg, 7.26 U/mg and 1.76 U/mg, respectively. This is the first report showing that the G100A mutant of AroA displays considerably improved glyphosate resistance and demonstrates that Leu105 is essential for the enzyme's activity. PMID- 25039063 TI - Associations between the decrease in bovine clinical mastitis and changes in dairy farmers' attitude, knowledge, and behavior in the Netherlands. AB - The aim of this study was to associate changes in dairy farmers' self-reported attitude, knowledge, and behavior with the decrease in incidence rate of clinical mastitis (IRCM). Farmer-diagnosed clinical mastitis cases were obtained from two surveys conducted before (July 2004-June 2005) and at the end (2009) of a mastitis control program in the Netherlands. Information on farmers' attitude, knowledge, and behavior was also obtained by sending the farmers the same questionnaire during both surveys. Multivariable linear regression models identified that the herd level 2004 IRCM explained 28% of the variation in the decrease of IRCM. Changes in farmers' attitude and knowledge, and changes in farmers' behavior additionally explained 24% and 5%, respectively. These results suggest that the way management measures are executed may be at least as important as the fact that they are executed. No control group was available for this study because the intervention was applied at the national level. We therefore do not claim any causal relationships. PMID- 25039064 TI - Prevalence and molecular characterization of Hepatozoon canis in dogs from urban and rural areas in Southeast Brazil. AB - The objective of this survey was to investigate the prevalence of Hepatozoon infection in dogs in the rural and urban areas of Uberlandia, Brazil by PCR and molecular characterization. DNA was obtained from blood samples collected from 346 local dogs from both genders and various ages. Seventeen PCR products from positive blood samples of urban dogs and 13 from the rural dogs were sequenced. Partial sequences of the 18S rRNA gene indicated that all 30 dogs were infected with Hepatozoon canis similar in sequence to H. canis from southern Europe. Four local dog sequences were submitted to GenBank (accessions JN835188; KF692038; KF692039; KF692040). This study indicates that H. canis is the cause of canine hepatozoonosis in Uberlandia and that infection is similarly widespread in rural and urban dogs. PMID- 25039065 TI - Differential expression of microRNA-206 in the gastrocnemius and biceps brachii in response to CSF from sporadic amyotrophic lateral sclerosis patients. PMID- 25039066 TI - Enhanced selectivity and search speed for method development using one-segment per-component optimization strategies. AB - Linear gradient programs are very frequently used in reversed phase liquid chromatography to enhance the selectivity compared to isocratic separations. Multi-linear gradient programs on the other hand are only scarcely used, despite their intrinsically larger separation power. Because the gradient-conformity of the latest generation of instruments has greatly improved, a renewed interest in more complex multi-segment gradient liquid chromatography can be expected in the future, raising the need for better performing gradient design algorithms. We explored the possibilities of a new type of multi-segment gradient optimization algorithm, the so-called "one-segment-per-group-of-components" optimization strategy. In this gradient design strategy, the slope is adjusted after the elution of each individual component of the sample, letting the retention properties of the different analytes auto-guide the course of the gradient profile. Applying this method experimentally to four randomly selected test samples, the separation time could on average be reduced with about 40% compared to the best single linear gradient. Moreover, the newly proposed approach performed equally well or better than the multi-segment optimization mode of a commercial software package. Carrying out an extensive in silico study, the experimentally observed advantage could also be generalized over a statistically significant amount of different 10 and 20 component samples. In addition, the newly proposed gradient optimization approach enables much faster searches than the traditional multi-step gradient design methods. PMID- 25039067 TI - Double opposite end injection capillary electrophoresis with contactless conductometric detection for simultaneous determination of chloride, sodium and potassium in cystic fibrosis diagnosis. AB - A novel approach for diagnosis of cystic fibrosis is presented. A simple and fast procedure to obtain sweat sample was developed. It consists of repeatedly wiping the skin of the forearm with deionized water moisturized cotton swab and extraction in 1mL of deionized water. Double opposite end injection capillary electrophoresis with contactless conductometric detection is used for the analysis of the extract. Chloride, sodium and potassium as the three target ions that participate in the ion transfer across the cellular membranes, and are affected by CF, are simultaneously determined in approximately 3min in a background electrolyte containing 20mM 2-(N-morpholino)ethanesulfonic acid, 20mM l-histidine and 2mM 18-crown-6. By using the target ion ratios rather than the concentrations of each individual ion combined with principal component analysis, the diagnosis of CF can be made more accurately and greatly reduce the number of false positive or negative results as is often the case when single ion (chloride) is analyzed. PMID- 25039068 TI - Enantioseparation of pyroglutamide derivatives on polysaccharide based chiral stationary phases by high-performance liquid chromatography and supercritical fluid chromatography: a comparative study. AB - Analytical enantioseparation of three pyroglutamide derivatives with pharmacological activity against the purinergic receptor P2X7, was run in both high-performance liquid chromatography and supercritical fluid chromatography. Four polysaccharide based chiral stationary phases, namely amylose and cellulose tris (3,5-dimethylphenylcarbamate), amylose tris ((S)-alpha methylbenzylcarbamate) and cellulose tris (4-methylbenzoate) with various mobile phases consisted of either heptane/alcohol (ethanol and 2-propanol) or carbon dioxide/alcohol (methanol or ethanol) mixtures, were investigated. After analytical screenings, the best conditions were transposed, for compound 1, to semi-preparative scale. Each approach was fully validated to meet the International Conference on Harmonisation requirements and compared. Whereas the limits of detection and quantification were near six-fold better in HPLC than in SFC (respectively 0.20 and 0.66 MUM versus 1.11 and 3.53 MUM for one of the enantiomers), in terms of low solvent consumption (7.2 mL of EtOH versus 3.2 mL of EtOH plus 28.8 mL of toxic and inflammable heptane per injection in SFC and HPLC, respectively), time effective cost (9 min versus 40 min per injection in SFC and HPLC, respectively) and yields (98% versus 71% in SFC and HPLC, respectively), the latter method proved its ecological superiority. PMID- 25039069 TI - A statistical approach to determine fluxapyroxad and its three metabolites in soils, sediment and sludge based on a combination of chemometric tools and a modified quick, easy, cheap, effective, rugged and safe method. AB - An effective method for the quantification of fluxapyroxad and its three metabolites in soils, sediment and sludge was developed using ultrahigh performance chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Both the extraction and clean-up steps of the QuEChERS procedure were optimised using a chemometric tool, which was expected to facilitate the rapid analysis with minimal procedures. Several operating parameters (MeCN/acetic acid ratio in the extraction solution (i.e., acetic acid percentage), water volume, extraction time, PSA amount, C18 amount, and GCB amount) were investigated using a Plackett Burman (P-B) screening design. Afterward, the significant factors (acetic acid percentage, water volume, and PSA amount) obtained were optimised using central composite design (CCD) combined with the desirability function (DF) to determine the optimum experimental conditions. The optimised procedure provides high-level linearity for all studied compounds with correlation coefficients ranging between 0.9972 and 0.9999. The detection limits were in the range of 0.1 to 1.0MUg/kg and the limits of quantitation (LOQs) were between 0.5 and 3.4MUg/kg with relative standard deviations (RSD) between 2.3% and 9.6% (n=6). Therefore, the developed protocol can serve as a simple and sensitive tool for monitoring fluxapyroxad and its three metabolites in soil, sediment and sludge samples. PMID- 25039070 TI - Advanced materials for separation science. Foreword. PMID- 25039071 TI - Alteration of plant physiology by glyphosate and its by-product aminomethylphosphonic acid: an overview. AB - It is generally claimed that glyphosate kills undesired plants by affecting the 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS) enzyme, disturbing the shikimate pathway. However, the mechanisms leading to plant death may also be related to secondary or indirect effects of glyphosate on plant physiology. Moreover, some plants can metabolize glyphosate to aminomethylphosphonic acid (AMPA) or be exposed to AMPA from different environmental matrices. AMPA is a recognized phytotoxin, and its co-occurrence with glyphosate could modify the effects of glyphosate on plant physiology. The present review provides an overall picture of alterations of plant physiology caused by environmental exposure to glyphosate and its metabolite AMPA, and summarizes their effects on several physiological processes. It particularly focuses on photosynthesis, from photochemical events to C assimilation and translocation, as well as oxidative stress. The effects of glyphosate and AMPA on several plant physiological processes have been linked, with the aim of better understanding their phytotoxicity and glyphosate herbicidal effects. PMID- 25039072 TI - Photosynthetic activity influences cellulose biosynthesis and phosphorylation of proteins involved therein in Arabidopsis leaves. AB - Cellulose is one of the most important organic compounds in terrestrial ecosystems and represents a major plant structural polymer. However, knowledge of the regulation of cellulose biosynthesis is still rather limited. Recent studies have shown that the phosphorylation of cellulose synthases (CESAs) may represent a key regulatory event in cellulose production. However, the impact of environmental conditions on the carbon flux of cellulose deposition and on phosphorylation levels of CESAs has not been fully elucidated. Here, we took advantage of gas exchange measurements, isotopic techniques, metabolomics, and quantitative phosphoproteomics to investigate the regulation of cellulose production in Arabidopsis rosette leaves in different photosynthetic contexts (different CO2 mole fractions) or upon light/dark transition. We show that the carbon flux to cellulose production increased with photosynthesis, but not proportionally. The phosphorylation level of several phosphopeptides associated with CESA1 and 3, and several enzymes of sugar metabolism was higher in the light and/or increased with photosynthesis. By contrast, a phosphopeptide (Ser126) associated with CESA5 seemed to be more phosphorylated in the dark. Our data suggest that photosynthetic activity affects cellulose deposition through the control of both sucrose metabolism and cellulose synthesis complexes themselves by protein phosphorylation. PMID- 25039073 TI - Variation in chilling tolerance for photosynthesis and leaf extension growth among genotypes related to the C4 grass Miscanthus *giganteus. AB - The goal of this study was to identify cold-tolerant genotypes within two species of Miscanthus related to the exceptionally chilling-tolerant C4 biomass crop accession: M. *giganteus 'Illinois' (Mxg) as well as in other Mxg genotypes. The ratio of leaf elongation at 10 degrees C/5 degrees C to that at 25 degrees C/25 degrees C was used to identify initially the 13 most promising Miscanthus genotypes out of 51 studied. Net leaf CO2 uptake (A sat) and the maximum operating efficiency of photosystem II (FPSII) were measured in warm conditions (25 degrees C/20 degrees C), and then during and following a chilling treatment of 10 degrees C/5 degrees C for 11 d. Accessions of M. sacchariflorus (Msa) showed the smallest decline in leaf elongation on transfer to chilling conditions and did not differ significantly from Mxg, indicating greater chilling tolerance than diploid M. sinensis (Msi). Msa also showed the smallest reductions in A sat and FPSII, and greater chilling-tolerant photosynthesis than Msi, and three other forms of Mxg, including new triploid accessions and a hexaploid Mxg 'Illinois'. Tetraploid Msa 'PF30153' collected in Gifu Prefecture in Honshu, Japan did not differ significantly from Mxg 'Illinois' in leaf elongation and photosynthesis at low temperature, but was significantly superior to all other forms of Mxg tested. The results suggested that the exceptional chilling tolerance of Mxg 'Illinois' cannot be explained simply by the hybrid vigour of this intraspecific allotriploid. Selection of chilling-tolerant accessions from both of Mxg's parental species, Msi and Msa, would be advisable for breeding new highly chilling-tolerant Mxg genotypes. PMID- 25039074 TI - SlNCED1 and SlCYP707A2: key genes involved in ABA metabolism during tomato fruit ripening. AB - Abscisic acid (ABA) plays an important role in fruit development and ripening. Here, three NCED genes encoding 9-cis-epoxycarotenoid dioxygenase (NCED, a key enzyme in the ABA biosynthetic pathway) and three CYP707A genes encoding ABA 8' hydroxylase (a key enzyme in the oxidative catabolism of ABA) were identified in tomato fruit by tobacco rattle virus-induced gene silencing (VIGS). Quantitative real-time PCR showed that VIGS-treated tomato fruits had significant reductions in target gene transcripts. In SlNCED1-RNAi-treated fruits, ripening slowed down, and the entire fruit turned to orange instead of red as in the control. In comparison, the downregulation of SlCYP707A2 expression in SlCYP707A2-silenced fruit could promote ripening; for example, colouring was quicker than in the control. Silencing SlNCED2/3 or SlCYP707A1/3 made no significant difference to fruit ripening comparing RNAi-treated fruits with control fruits. ABA accumulation and SlNCED1transcript levels in the SlNCED1-RNAi-treated fruit were downregulated to 21% and 19% of those in control fruit, respectively, but upregulated in SlCYP707A2-RNAi-treated fruit. Silencing SlNCED1 or SlCYP707A2 by VIGS significantly altered the transcripts of a set of both ABA-responsive and ripening-related genes, including ABA-signalling genes (PYL1, PP2C1, and SnRK2.2), lycopene-synthesis genes (SlBcyc, SlPSY1 and SlPDS), and cell wall degrading genes (SlPG1, SlEXP, and SlXET) during ripening. These data indicate that SlNCED1 and SlCYP707A2 are key genes in the regulation of ABA synthesis and catabolism, and are involved in fruit ripening as positive and negative regulators, respectively. PMID- 25039076 TI - In situ ETEM synthesis of NiGa alloy nanoparticles from nitrate salt solution. AB - Metallic alloy nanoparticles (NPs) are synthesized in situ in an environmental transmission electron microscope. Atomic level characterization of the formed alloy NPs is carried out at synthesis conditions by use of high-resolution transmission electron microscopy, electron diffraction and electron energy-loss spectroscopy. PMID- 25039078 TI - [Painful papulae developing at the inguinal and lower abdominal regions in a man in his 40s following cord blood stem cell transplantation]. PMID- 25039077 TI - [Case of severe tropical malaria with a suspicion of hemolytic anemia due to a artemisinin derivative]. PMID- 25039079 TI - The latest from the military virtual affiliate. PMID- 25039075 TI - Cucumber metal transport protein MTP8 confers increased tolerance to manganese when expressed in yeast and Arabidopsis thaliana. AB - Cation diffusion facilitator (CDF) proteins are ubiquitous divalent cation transporters that have been proved to be essential for metal homeostasis and tolerance in Archaebacteria, Bacteria, and Eukaryota. In plants, CDFs are designated as metal tolerance proteins (MTPs). Due to the lack of genomic resources, studies on MTPs in other plants, including cultivated crops, are lacking. Here, the identification and organization of genes encoding members of the MTP family in cucumber are described. The first functional characterization of a cucumber gene encoding a member of the Mn-CDF subgroup of CDF proteins, designated as CsMTP8 based on the highest homology to plant MTP8, is also presented. The expression of CsMTP8 in Saccharomyces cerevisiae led to increased Mn accumulation in yeast cells and fully restored the growth of mutants hypersensitive to Mn in Mn excess. Similarly, the overexpression of CsMTP8 in Arabidopsis thaliana enhanced plant tolerance to high Mn in nutrition media as well as the accumulation of Mn in plant tissues. When fused to green fluorescent protein (GFP), CsMTP8 localized to the vacuolar membranes in yeast cells and to Arabidopsis protoplasts. In cucumber, CsMTP8 was expressed almost exclusively in roots, and the level of gene transcript was markedly up-regulated or reduced under elevated Mn or Mn deficiency, respectively. Taken together, the results suggest that CsMTP8 is an Mn transporter localized in the vacuolar membrane, which participates in the maintenance of Mn homeostasis in cucumber root cells. PMID- 25039080 TI - Karmanos Cancer Center clinical nurse specialist receives Oakland University's Nightingale Award for clinical excellence. PMID- 25039081 TI - The history of "Exercise Is Medicine" in ancient civilizations. AB - In 2007, the American College of Sports Medicine, with endorsement from the American Medical Association and the Office of the Surgeon General, launched a global initiative to mobilize physicians, healthcare professionals and providers, and educators to promote exercise in their practice or activities to prevent, reduce, manage, or treat diseases that impact health and the quality of life in humans. Emerging from this initiative, termed Exercise Is Medicine, has been an extensively documented position stand by the American College of Sports Medicine that recommended healthy adults perform 150 min of moderate dynamic exercise per week. The purpose of this article is to demonstrate the foundation for this global initiative and its exercise prescription for health and disease prevention has roots that began in antiquity more than two millennia ago. Individuals and concepts to remember are that Susruta of India was the first "recorded" physician to prescribe moderate daily exercise, Hippocrates of Greece was the first "recorded" physician to provide a written exercise prescription for a patient suffering from consumption, and the global influence of Galen from Rome combined with his recommendation on the use of exercise for patients in the management of disease prevailed until the 16th century. Historically intertwined with these concepts was exercise being advocated by select physicians to minimize the health problems associated with obesity, diabetes, and inactivity. PMID- 25039082 TI - Avengers Assemble! Using pop-culture icons to communicate science. AB - Engaging communication of complex scientific concepts with the general public requires more than simplification. Compelling, relevant, and timely points of linkage between scientific concepts and the experiences and interests of the general public are needed. Pop-culture icons such as superheroes can represent excellent opportunities for exploring scientific concepts in a mental "landscape" that is comfortable and familiar. Using an established icon as a familiar frame of reference, complex scientific concepts can then be discussed in a more accessible manner. In this framework, scientists and the general public use the cultural icon to occupy a commonly known performance characteristic. For example, Batman represents a globally recognized icon who represents the ultimate response to exercise and training. The physiology that underlies Batman's abilities can then be discussed and explored using real scientific examples that highlight truths and fallacies contained in the presentation of pop-culture icons. Critically, it is not important whether the popular representation of the icon shows correct science because the real science can be revealed in discussing the character through this lens. Scientists and educators can then use these icons as foils for exploring complex ideas in a context that is less threatening and more comfortable for the target audience. A "middle-ground hypothesis" for science communication is proposed in which popculture icons are used to exploring scientific concepts in a bridging mental landscape that is comfortable and familiar. This approach is encouraged for communication with all nonscientists regardless of age. PMID- 25039083 TI - Mechanisms in cardiovascular diseases: how useful are medical textbooks, eMedicine, and YouTube? AB - The aim of this study was to assess the contents of medical textbooks, eMedicine (Medscape) topics, and YouTube videos on cardiovascular mechanisms. Medical textbooks, eMedicine articles, and YouTube were searched for cardiovascular mechanisms. Using appraisal forms, copies of these resources and videos were evaluated independently by three assessors. Most textbooks were brief in explaining mechanisms. Although the overall average percentage committed to cardiovascular mechanisms in physiology textbooks (n=7) was 16.1% and pathology textbooks (n=4) was 17.5%, there was less emphasis on mechanisms in most internal medicine textbooks (n=6), with a total average of 6.9%. In addition, flow diagrams explaining mechanisms were lacking. However, eMedicine topics (n=48) discussed mechanisms adequately in 22.9% (11 of 48) topics, and the percentage of content allocated to cardiovascular mechanisms was higher (15.8%, 46.2 of 292) compared with that of any internal medicine textbooks. Only 29 YouTube videos fulfilled the inclusion criteria. Of these, 16 YouTube were educationally useful, scoring 14.1 +/- 0.5 (mean +/- SD). The remaining 13 videos were not educationally useful, scoring 6.1 +/- 1.7. The concordance between the assessors on applying the criteria measured by kappa score was in the range of 0.55-0.96. In conclusion, despite the importance of mechanisms, most textbooks and You-Tube videos were deficient in cardiovascular mechanisms. eMedicine topics discussed cardiovascular mechanisms for some diseases, but there were no flow diagrams or multimedia explaining mechanisms. These deficiencies in learning resources could add to the challenges faced by students in understanding cardiovascular mechanisms. PMID- 25039085 TI - The method of loci as a mnemonic device to facilitate learning in endocrinology leads to improvement in student performance as measured by assessments. AB - Cognitive psychology has demonstrated that the way knowledge is structured in memory determines the ability to retain, recall, and use it to solve problems. The method of loci (MOL) is a mnemonic device that relies on spatial relationships between "loci" (e.g., locations on a familiar route or rooms in a familiar building) to arrange and recollect memorial content. In the present study, we hypothesized that the use of MOL leads to better understanding of the topic among students, which can be observed through better student performance on assessments. Students were divided into two groups: group 1 was taught insulin and diabetes mellitus through didactic lectures and a self-directed learning session, whereas group 2 was taught insulin and diabetes mellitus through didactic lectures and MOL. Memory palaces for insulin and diabetes mellitus were generated by students under supervision of the teacher and taught by students as well. A questionnaire survey and open-ended questions were given to the participants. Group 2, which underwent didactic lectures followed by a MOL interactive session, showed significantly improved performance on the assessments compared with group 1, which had been taught through didactic lectures and a self directed learning session. Descriptive analysis showed that all students found MOL to be a helpful technique. PMID- 25039086 TI - But science is international! Finding time and space to encourage intercultural learning in a content-driven physiology unit. AB - Internationalization of the curriculum is central to the strategic direction of many modern universities and has widespread benefits for student learning. However, these clear aspirations for internationalization of the curriculum have not been widely translated into more internationalized course content and teaching methods in the classroom, particularly in scientific disciplines. This study addressed one major challenge to promoting intercultural competence among undergraduate science students: finding time to scaffold such learning within the context of content-heavy, time-poor units. Small changes to enhance global and intercultural awareness were incorporated into existing assessments and teaching activities within a second-year biomedical physiology unit. Interventions were designed to start a conversation about global and intercultural perspectives on physiology, to embed the development of global awareness into the assessment and to promote cultural exchanges through peer interactions. In student surveys, 40% of domestic and 60% of international student respondents articulated specific learning about interactions in cross-cultural groups resulting from unit activities. Many students also identified specific examples of how cultural beliefs would impact on the place of biomedical physiology within the global community. In addition, staff observed more widespread benefits for student engagement and learning. It is concluded that a significant development of intercultural awareness and a more global perspective on scientific understanding can be supported among undergraduates with relatively modest, easy to implement adaptations to course content. PMID- 25039084 TI - Neural control of the immune system. AB - Neural reflexes support homeostasis by modulating the function of organ systems. Recent advances in neuroscience and immunology have revealed that neural reflexes also regulate the immune system. Activation of the vagus nerve modulates leukocyte cytokine production and alleviates experimental shock and autoimmune disease, and recent data have suggested that vagus nerve stimulation can improve symptoms in human rheumatoid arthritis. These discoveries have generated an increased interest in bioelectronic medicine, i.e., therapeutic delivery of electrical impulses that activate nerves to regulate immune system function. Here, we discuss the physiology and potential therapeutic implications of neural immune control. PMID- 25039087 TI - [Active surveillance in prostate cancer. Introduction]. PMID- 25039088 TI - [Editorial. Monographic: Active surveillance in prostate cancer]. PMID- 25039089 TI - Dietary deficiencies.Preface. PMID- 25039090 TI - Practice of sense and nonsense in the medicine, readers' views. PMID- 25039091 TI - Practice of sense and nonsense in the medicine, readers' views. Author reply. PMID- 25039092 TI - A critique of traditional medicine, readers' views. PMID- 25039093 TI - A critique of traditional medicine, readers' views. Authors reply. PMID- 25039094 TI - [Establishing associations]. PMID- 25039096 TI - Peroxisomes. Preface. PMID- 25039095 TI - [The author's response]. PMID- 25039097 TI - Gene Farley tribute. PMID- 25039098 TI - "Resident wellness behaviors" and ideas for future research. PMID- 25039099 TI - Author's response. PMID- 25039100 TI - [Integration of clinical and basic medicine]. PMID- 25039101 TI - [Patho-mechanism and treatment of non specific low back pain]. PMID- 25039102 TI - [Future perspectives of hepatitis C therapeutics]. PMID- 25039103 TI - [Clinical and pathologic features of tonsil-associated skin-bone-joint-kidney diseases]. PMID- 25039104 TI - [Progress of dementia medicine: Special reference to Alzheimer's disease]. PMID- 25039105 TI - Ejection experience in Serbian Air Force, 1990-2010. AB - BACKGROUND/AIM: Ejection injuries are the problem for air forces. The present risk for injuries is still too high, approximately 30-50%. The aim of this study was to determine factors responsible for and contributing to injuries in the Serbian Air Force (SAF) in the last two decades. METHODS: All ejection cases in the SAF between 1990 and 2010 were analyzed. The collected data were: aircraft type, ejection seat generation, pilots" age and experience, causes of ejection, aeronautical parameters, the condition of aircraft control and types of injuries. For ease of comparison the US Air Force Safety Regulations were used to define major injuries: hospitalization for 5 days or more, loss of consciousness for over 5 min, bone fracture, joint dislocation, injury to any internal organ, any third-degree burn, or second-degree burn over 5% of the body surface area. RESULTS: There were 52 ejections (51 pilots and 1 mechanic) on 44 airplanes. The ejected persons were from 22 to 46 years, average 32 years. Major injuries were present in 25.49% cases. Of all the ejected pilots 9.61% had fractures of the thoracic spine, 11.53% fractures of the legs, 3.48% fractures of the arms. Of all major injuries, fractures of the thoracic spine were 38.46%. None of the pilots had experienced ejection previously. CONCLUSION: Our results suggest that taking preventive measures is obligatory. Namely, magnetic resonance imaging (MRL) scan must be included in the standard pilot selection procedure and procedure after ejection, physical conditioning of pilots has to be improved, training on ejection trainer has to be accomplished, too. PMID- 25039106 TI - A cephalometric analysis of the cranial base and frontal part of the face in patients with mandibular prognathism. AB - BACKGROUND/AIM: The literature suggests different views on the correlation between the cranial base morphology and size and saggital intermaxillary relationships. The aim of this study was to investigate the cranial base morphology, including the frontal facial part in patients with mandibular prognathism, to clarify a certain ambiguities, in opposing viewspoints in the literature. METHODS: Cephalometric radiographies of 60 patients were analyzed at the Dental Clinic of the Military Medical Academy, Belgrade, Serbia. All the patients were male, aged 18-35 years, with no previous orthodontic treatment. On the basis of dental and sceletal relations of jaws and teeth, the patients were divided into two groups: the group P (patients with mandibular prognathism) and the group E (the control group or eugnathic patients). A total of 15 cephalometric parametres related to the cranial base, frontal part of the face and sagittal intermaxillary relationships were measured and analyzed. RESULTS: The results show that cranial base dimensions and the angle do not play a significant role in the development of mandibular prognathism. Interrelationship analysis indicated a statistically significant negative correlation between the cranial base angle (NSAr) and the angles of maxillary (SNA) and mandibular (SNB) prognathism, as well as a positive correlation between the angle of inclination of the ramus to the cranial base (GoArNS) and the angle of sagittal intermaxillary relationships (ANB). Sella turcica dimensions, its width and depth, as well as the nasal bone length were significantly increased in the patients with mandibular prognathism, while the other analyzed frontal part dimensions of the face were not changed by the malocclusion in comparison with the eugnathic patients. CONCLUSION: This study shows that the impact of the cranial base and the frontal part of the face on the development of profile in patients with mandibular prognathism is much smaller, but certainly more complex, so that morphogenetic tests of the maxillomandibular complex should be included in further assessment of this impact. PMID- 25039107 TI - Resection or radiofrequency ablation of colorectal liver metastasis. AB - BACKGROUND/AIM: Liver resection is the treatment of choice for solitary colorectal liver metastases in suitable candidates. Recently, radiofrequency ablation (RFA) has become a very popular procedure in the treatment of liver metastases. The aim of this study was to compare outcomes in patients with solitary colorectal liver metastasis who had been subjected to resection or ablation. METHODS: In this retrospective study we analyzed and compared patients with solitary colorectal liver metastases treated by resection or ablation in the University Hospital Centre "Dr Dragisa Misovic" in Belgrade from January 2002 until December 2009. RESULTS: In this study 94 (67.1%) patients underwent resection whereas 46 (32.9%) patients underwent RFA. Most of the resected patients (59.6%) required major hepatectomy. The median follow-up time was 28.4 months. Tumor ablation was a significant predictor of the overall survival (p = 0.002; OR 3.75; 95% CI 1.696-8.284). Our study demonstrated longer disease free survival in the group of resected patients compared to the RFA group (37.6 vs 22.3 months, p = 0.073). The median overall survival was 56.3 months for patients who underwent resection vs 25.1 months for those in the RFA group (p = 0.005). CONCLUSION: This study shows that the patients with solitary hepatic colorectal cancer metastases should be considered for hepatic resection whenever it is feasible, because this procedure provides superior long-term survival as compared to radiofrequency ablation. PMID- 25039108 TI - Surface enlargement of a new arterialised venous flap by the surgical delay method. AB - BACKGROUND/AIM: The delay method is a surgical, pharmacological and combined method that includes two or more time separated phases, which gives bigger flap surface. In our research we explored the possibility of flap surface enlargement in a new arterialised venous flap (AVF) on an experimental rabbit ear model by the delay surgical method. The aim of this research was to establish vitality surface of our AVF and to maintain the difference in flap vital surface between AVF flaps, with or without performing the delay surgery method. METHODS: We used both ears of "Big Chinchilla" rabbits in 10 experimental male animals, divided into two groups, average weight 3-3.5 kg, and average age 8-10 months. In the first (experimental) group, a venous flap was arterialised by our method. In the second (control) group, the venous flap was arterialised 14 days after the delay surgical method. AVF surface was measured on the 1 and 14 days by the method of trapezoid rule. RESULTS: Vital surface on our AVF experimental model was bigger than 87% of elevated flap surface after the delay surgical method. Vital surface on AVF without delay on our experimental model was bigger than 30% of elevated flap surface (p < 0.001). CONCLUSION: Analysis of previous experimental models on the rabbit ear, non-delayed and delayed (to enlarge flap surface) led us to conclusion that previously created experimental models of non-delayed AVF are hemodynamically negative. Our experimental non-delay AVF model is hemodynamically more positive than previously created models of non-delay AVF and provides better conditions for AVF survival and enlargement of vital flap surface of elevated flap. On the other hand, surgical delay method significantly enlarges vital surface of AFF. PMID- 25039109 TI - Cerebral edema in drug addicts. AB - BACKGROUND/AIM: The effect of drugs leaves permanent consequences on the brain, organic in type, followed by numerous manifestations, and it significantly affects the development of mental dysfunctions. The clinicians are often given a task to estimate a patient's personality during treatment or during experts estimate of a drug addict. The aim of this research was to determine the differences, if any, in characteristics of addicts experience and personality traits in drug addicts with or without cerebral edema. METHODS: The research was conducted on a sample of 252 male drug addicts, the average age of 23.3 (SD = 4.3) years. Cerebral edema was confirmed on magnetic resonance (MR) images of the brain performed during the treatment of the addicts. The participants were tested by the psychologists using Minnesota Multiphasic Personality Inventory (MMPI-201) test, and the data were processed using canonical discriminate analysis within the SPSS program. The dependent variable in the study was cerebral edema. A block of independent variables, designed for the requirements of this study, consisted of two subgroups. The first one consisted of 12 variables describing the relevant characteristics of drug abuse. The second subgroup consisted of 8 psychopathological tendencies in the personality defined by the mentioned test. RESULTS: Cerebral edema was confirmed in 52 (20.63%) of the drug addicts. The differences between the groups of drug addicts with and without cerebral edema were determined in the following: the time span of taking drugs (0.301), use of alcohol parallel with drugs (0.466), and treatment for addiction (0.603). In the drug addicts with a cerebral edema, MMPI-201 confirmed the increase in the scales for hypochondria, psychopathic deviations and psychastenia, and the decrease in the scales for schizophrenia and depression. CONCLUSION: Our study confirmed a possible connection between cerebral edema and personality traits in a number of the examined drug addicts. Considering the fact that practice often requires personality estimation, regardless whether it is about treatment or expert's estimate, it is necessary to further research in this direction. PMID- 25039110 TI - Bone turnover markers in medicamentous and physiological hyperprolactinemia in female rats. AB - BACKGROUND/AIM: There is a lack of data on the effects of prolactin on calcium metabolism and bone turnover in hyperprolactinemia of various origins. The aim of this study was to compare the influence of medicamentous and physiological hyperprolactinemia on bone turnover in female rats. METHODS: Experimental animals (18 weeks old, Wistar female rats) were divided as follows: the group P - 9 rats, 3 weeks pregnant; the group M3-10 rats that were intramuscularly administrated sulpirid (10 mg/kg) twice daily for 3 weeks, the group M6 - 10 rats that were intramuscularly administrated with sulpirid (10 mg/kg) twice daily for 6 weeks, and age matched nulliparous rats as the control group: 10 rats, 18-week-old (C1) and 7 rats, 24 weeks old (C2). Laboratory investigations included serum ionized calcium and phosphorus, urinary calcium and phosphorous excretion, osteocalcin and serum procollagen type 1 N-terminal propeptide (P1NP). RESULTS: Experimental animals in the group P compared to the control group, displayed lower mean serum ionized calcium (0.5 +/- 0.2 vs 1.12 +/- 0.04 mmol/L; p < 0.001); higher mean serum phosphorus (2.42 +/- 0.46 vs 2.05 +/- 0.2 mmol/L; p < 0.05); increased urinary calcium (3.90 +/- 0.46 vs 3.05 +/- 0.58; p < 0.01) and significantly increased P1NP (489.22 +/- 46.77 vs 361.9 +/- 53.01 pg/mL; p < 0.001). Experimental animals in the group M3 had significantly decreased P1NP, compared to the contol group. Prolongated medicamentous hyperprolactinemia (the group M6) induced increased serum ionized calcium (1.21 +/- 0.03 vs 1.15 +/- 0.02 mmol/L; p < 0.001); decreased serum phosphorus (1.70 +/- 0.13 vs 1.89 +/- 0.32 mmol/L; p < 0.001); decreased osteocalcin and P1NP. CONCLUSIONS: Physiological hyperprolactinemia does not have such harmful effect on bone metabolism as medicamentous hyperprolactinemia. Chronic medicamentous hyperprolactinemia produces lower serum levels of bone formation markers. Assessment of bone turnover markers in prolongated medicamentous hyperprolactinemia provides an opportunity for earlier diagnosis of bone metabolism disturbances and should be considered as mandatory. PMID- 25039111 TI - Psychopathology and resilience in relation to abuse in childhood among youth first referred to the psychiatrist. AB - BACKGROUND/AIM: Child abuse may be related to adverse psychological outcomes in adult life. However, little is known about specific clinical, family and resilience profiles of adolescents that have experienced child abuse. The aim of this study was to investigate clinical symptoms, family functioning and resilience characteristics of adolescents with the experience of abuse, first referred to psychiatrists. METHODS: The study included 84 young participants (mean age 14.90 +/- 3.10, ranging from 11 to 18 years) as consecutive first referrals to the Clinic for Children and Youth of the Institute of Mental Health, Belgrade, Serbia. The sample consisted of two groups, based on the Child Abuse Matrices of Risks. The first group included adolescents with the experience of abuse in childhood (n = 38, 13 males, 25 females), whereas the second, control group, comprised of non-abused adolescents (n = 47, 20 males, 27 females). The presence of abuse was evaluated by the Child Abuse Matrices of Risks. The study used the following questionnaires: Youth Self-Report (YSR), Adolescent Resilience Attitudes Scale (ARAS), and Self-Report Family Inventory (SFI). RESULTS: Significant differences were found only among females. According to YSR, the abused girls had significantly higher scores on the Delinquent Behavior scale and marginally higher scores on Anxious/Depressed and Social Problems scales. Analyses of the SFI showed significantly lower family functioning among the girls with the child abuse history for all scales except for the Directive Leadership. The abused girls also showed significantly lower scores on the Insight scale, and marginally lower Initiative scores at the ARAS. CONCLUSIONS: These findings may have practical application in the creation of specific preventive and treatment strategies, particularly focused on delinquent tendencies, as well as on enhancing resilience through providing positive environments within families, schools and communities. PMID- 25039112 TI - Effect of neuropeptide Y on norepinephrine-induced constriction in the rabbit facial artery after carotid artery occlusion. AB - BACKGROUND/AIM: Atherosclerotic-occlusive changes could be observed in orofacial branches of the external carotid artery. Atherosclerosis-induced ischemia caused alteration in production and release of endothelial factors. The aim of this study was to investigate the influence of carotid artery occlusion (10, 30 and 60 min) on vascular effects of norepinephrine (NOR) and neuropeptide Y (NPY) in the isolated glandular branch of the rabbit facial artery, the main feeding artery for the submandibular gland. METHOD: Changes in isometric tension were recorded in organ bath studies with arterial rings, before and after carotid artery occlusion. RESULTS: Concentration-dependent vasocontractile effect of NOR was significantly augmented after 30 and 60 min of carotid occlusion, but only in the rings with intact endothelium. Given alone, NPY showed no effect in isolated glandular branch of the rabbit facial artery, but enhanced NOR vasoconstriction in all the investigated rings. NOR vasocontractile effect enhancement in the presence of NPY was attenuated after 30 and 60 min of carotid occlusion. Also, enhancement of NOR vasoconstriction by NPY was significantly higher in endothelium-intact rings compared to endothelium-denuded rings obtained after 30 and 60 min of carotid occlusion. CONCLUSION: The present investigation provides results of increased vasocontractile effect of NOR and decreased enhancing effect of NPY on NOR vasoconstriction in the rabbit facial artery after carotid occlusion that is related to altered endothelium function. PMID- 25039113 TI - Are there any association between polycistic ovary syndrome and congenital abnormalities of Mullerian ducts. AB - BACKGROUND/AIM: There are many specificities of merital infertility and sometimes surprising connections between some thinks with no connections at first sight. Examinations of these patients imply diagnostic actions such as the blood basal hormone sample, doing hysterosalpingography, ultrahysterosonography, ultrasound examinations, and sometimes laparoscopy and hysteroscopy if there are necessary. The aim of the study was to determine the characteristics of the connection between policystic ovary (PCO) syndrome (Sy) and congenital Mullerian ducts abnormalities. METHODS: This study included 356 patients treated in the period from January 1, to December 31, 2009, in the Department of Infertility of the Clinic for Obstetrics and Gynecology in Nis, Serbia. Exclusion criteria were no myoma, ovary cysts, tubal and male factors of infertility. RESULTS: A total of 180 patients were divided into 3 groups: the group I with PCO sy, the group II with uterine congenital malformation and the group III with a combination of these disorders. The middle age of patients was 29.6 +/- 4.8, body mass index (BMI) was 26.1 +/- 4,8 kg/m2 the middle thicknes of endometrium was 5.2 + 2.7 mm, and there were no significant differences between the examined groups. There were no significant among in a number of miscarriages in the examined groups. We found that PCO Sy and congenital abnormalities of Mullerian ducts were conjoint in 30% of examined patients. CONCLUSION: Conjoined PCO Sy and congenital abnormalities of Mullerian ducts do not result in a higher number of miscarriages than only either PCO Sy or abnormalities of Mullerian ducts. It is important to check BMI, basal level of follicle stimulating hormone and number of antral follicles because the induction protocol and concentracion of inductors depends on these characteristics, thus, the succsessful cycles and pregnancy. PMID- 25039114 TI - Significance, aetiology and prevention of venous thromboembolism in pregnancy and puerperium. PMID- 25039115 TI - Terms of clinical research consent's validity. PMID- 25039116 TI - Myeloma multiplex with pulmonary dissemination. AB - INTRODUCTION: Multiple myeloma is a hemathological malignancy characterized by the clonal proliferation of plasma cells in the bone the marrow. Extramedullary dissemination of multiple myeloma is uncommon. In several cases only, the multiple myeloma malignant plasma cells had diseminated to the lung parenchyma. CASE REPORT: We presented a case of multiple myeloma with lung plasmacytoma, in a 79 year-old patient, hospitalized for febrility and infiltrative mass in the right lung. Two months before the patient was admitted, because of developing terminal renal failure, hemodialysis treatment had started three times a week. Since then, the patient was oliguric, but because of febrility and hemoptysis that appeared, at first he was treated with dual antibiotic therapy which resulted in temporary improvement of his general condition, but pleural effusion remained. After thoracocentesis, followed by myelogram, the multiple myeloma diagnosis was established. CONCLUSION: In patients of middle and older age, with general weakness, exhaustion, loss of weight, renal failure which progresses to the end stage rapidly, if symptoms of respiratory tract occur, consider this uncommon disease--extramedullary dissemination of multiple myeloma. PMID- 25039117 TI - Papillary fibroelastoma of the aortic valve. AB - INTRODUCTION: Primary tumors of the heart are rare, usually benign and occur mostly in adults, and usually originate from the endocardium, followed by the myocardium and rarest of the pericardium. Papillary fibroelastoma accounts for less than 10% of all cardiac tumors, but they are most common valvular tumors. The clinical presentation of papillary fibroelastoma varies from asymptomatic cases to cases which have severe clinical presentation that is most likely due to embolic complications. Tumor can usually be discovered by echocardiography or during autopsy. CASE REPORT: We reported a case of 53-year-old man submitted to routine echocardiographic examination. The patient had the history of hypertension for five years, without any other symptoms. Echocardiography found a round tumor attached to the noncoronary cuspis of the aortic valve. The tumor was surgically removed and pathohistological examination confirmed diagnosis of papillary fibroelastoma. After surgery the patient fully recovered without tumor recurrence or aortic regurgitation. CONCLUSION: Histologically, papilary fibroelastoma is benign tumor of the heart. As demonstrated in this case, a papillary fibroelastoma can be an incidental finding discovered during echocardiography in patients with the history of hypertension. PMID- 25039118 TI - Acute psychosis followed by fever--malignant neuroleptic syndrome or viral encephalitis? AB - INTRODUCTION: Neuroleptic malignant syndrome is rare, but potentially fatal idiosyncratic reaction to antipsychotic medications. It is sometimes difficult to diagnose some clinical cases as neuroleptic malignant syndrome and differentiate it from the acute viral encephalitis. CASE REPORT: We reported a patient diagnosed with acute psychotic reaction which appeared for the first time. The treatment started with typical antipsychotic, which led to febrility. The clinical presentation of the patient was characterised by the signs and symptoms that might have indicated the neuroleptic malignant syndrome as well as central nervous system viral disease. In order to make a detailed diagnosis additional procedures were performed: electroencephalogram, magnetic resonance imaging of the head, lumbar puncture and a serological test of the cerebrospinal fluid. Considering that after the tests viral encephalitis was ruled out and the diagnosis of neuroleptic malignant syndrome made, antipsychotic therapy was immediately stopped. The patient was initially treated with symptomatic therapy and after that with atypical antipsychotic and electroconvulsive therapy, which led to complete recovery. CONCLUSION: We present the difficulties of early diagnosis at the first episode of acute psychotic disorder associated with acute febrile condition. Concerning the differential diagnosis it is necessary to consider both neuroleptic malignant syndrome and viral encephalitis, i.e. it is necessary to make the neuroradiological diagnosis and conduct cerebrospinal fluid analysis and blood test. In neuroleptic malignant syndrome treatment a combined use of electroconvulsive therapy and low doses of atypical antipsychotic are confirmed to be successful. PMID- 25039119 TI - Terminology, diagnostics and therapy of laryngopharyngeal reflux--a glimpse into the past. PMID- 25039120 TI - [Research on fast implementation method of image Gaussian RBF interpolation based on CUDA]. AB - Image interpolation is often required during medical image processing and analysis. Although interpolation method based on Gaussian radial basis function (GRBF) has high precision, the long calculation time still limits its application in field of image interpolation. To overcome this problem, a method of two dimensional and three-dimensional medical image GRBF interpolation based on computing unified device architecture (CUDA) is proposed in this paper. According to single instruction multiple threads (SIMT) executive model of CUDA, various optimizing measures such as coalesced access and shared memory are adopted in this study. To eliminate the edge distortion of image interpolation, natural suture algorithm is utilized in overlapping regions while adopting data space strategy of separating 2D images into blocks or dividing 3D images into sub volumes. Keeping a high interpolation precision, the 2D and 3D medical image GRBF interpolation achieved great acceleration in each basic computing step. The experiments showed that the operative efficiency of image GRBF interpolation based on CUDA platform was obviously improved compared with CPU calculation. The present method is of a considerable reference value in the application field of image interpolation. PMID- 25039121 TI - [Monitoring depth of anesthesia and effect analysis in primary visual cortex of rats based on complexity of local field potential]. AB - In the present study carried out in our laboratory, we recorded local field potential (LFP) signals in primary visual cortex (V1 area) of rats during the anesthesia process in the electrophysiological experiments of invasive microelectrode array implant, and obtained time evolutions of complexity measure Lempel-ziv complexity (LZC) by nonlinear dynamic analysis method. Combined with judgment criterion of tail flick latency to thermal stimulus and heart rate, the visual stimulation experiments are carried out to verify the reliability of anesthetized states by complexity analysis. The experimental results demonstrated that the time varying complexity measures LZC of LFP signals of different channels were similar to each other in the anesthesia process. In the same anesthesia state, the difference of complexity measure LZC between neuronal responses before and after visual stimulation was not significant. However, the complexity LZC in different anesthesia depths had statistical significances. Furthermore, complexity threshold value represented the depth of anesthesia was determined using optimization method. The reliability and accuracy of monitoring the depth of anesthesia using complexity measure LZC of LFP were all high. It provided an effective method of realtime monitoring depth of anesthesia for craniotomy patients in clinical operation. PMID- 25039122 TI - [Remote intelligent Brunnstrom assessment system for upper limb rehabilitation for post-stroke based on extreme learning machine]. AB - In order to realize an individualized and specialized rehabilitation assessment of remoteness and intelligence, we set up a remote intelligent assessment system of upper limb movement function of post-stroke patients during rehabilitation. By using the remote rehabilitation training sensors and client data sampling software, we collected and uploaded the gesture data from a patient's forearm and upper arm during rehabilitation training to database of the server. Then a remote intelligent assessment system, which had been developed based on the extreme learning machine (ELM) algorithm and Brunnstrom stage assessment standard, was used to evaluate the gesture data. To evaluate the reliability of the proposed method, a group of 23 stroke patients, whose upper limb movement functions were in different recovery stages, and 4 healthy people, whose upper limb movement functions were normal, were recruited to finish the same training task. The results showed that, compared to that of the experienced rehabilitation expert who used the Brunnstrom stage standard table, the accuracy of the proposed remote Brunnstrom intelligent assessment system can reach a higher level, as 92.1%. The practical effects of surgery have proved that the proposed system could realize the intelligent assessment of upper limb movement function of post-stroke patients remotely, and it could also make the rehabilitation of the post-stroke patients at home or in a community care center possible. PMID- 25039123 TI - [Gravity frequency and its monitoring application of EEG spectrum in the vigilance operation]. AB - It is an important means to study the electrical activity of the brain's nerve cells by exploring physiological information of the EEGs from the frequency domain. The gravity frequency is one of the global parameters with using this method. We used the multitaper spectrum method (MTM) spectrum estimation method of good performance to calculate the EEG spectrum and its gravity frequency of subjects under vigilance and vigilance decrement state. The results showed that the gravity frequency of vigilance state was higher than that of vigilance decrement state, the gravity frequency became smaller along with the vigilance decrement, and the location of the gravity frequency shifted to the left in the spectrum. Finally, the monitoring curve of the gravity frequency was acquired by designing an algorithm, and it was used to online monitoring vigilance operators. PMID- 25039124 TI - [The impact of mood on the intrinsic functional connectivity]. AB - Although a great number of studies have investigated the changes of resting-state functional connectivity (rsFC) in patients with mental disorders, such as depression and schizophrenia etc, little is known how stable the changes are, and whether temporal sad or happy mood can modulate the intrinsic rsFC. In our experiments, happy and sad video clips were used to induce temporally happy and sad mood states in 20 healthy young adults. We collected functional magnetic resonance imaging (fMRI) data while participants were watching happy or sad video clips, which were administrated in two consecutive days. Seed-based functional connectivity analyses were conducted using the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), and amygdala as seeds to investigate neural network related to executive function, attention, and emotion. We also investigated the association of the rsFC changes with emotional arousability level to understand individual differences. There is significantly stronger functional connectivity between the left DLPFC and posterior cingulate cortex (PCC) under sad mood than that under happy mood. The increased connectivity strength was positively correlated with subjects' emotional arousability. The increased positive correlation between the left DLPFC and PCC under sad relative to happy mood might reflect an increased processing of negative emotion-relevant stimuli. The easier one was induced by strong negative emotion (higher emotional arousability), the greater the left DLPFC-PCC connectivity was indicated, the greater the instability of the intrinsic rsFC was shown. PMID- 25039125 TI - [Nonparametric method of estimating survival functions containing right-censored and interval-censored data]. AB - Missing data represent a general problem in many scientific fields, especially in medical survival analysis. Dealing with censored data, interpolation method is one of important methods. However, most of the interpolation methods replace the censored data with the exact data, which will distort the real distribution of the censored data and reduce the probability of the real data falling into the interpolation data. In order to solve this problem, we in this paper propose a nonparametric method of estimating the survival function of right-censored and interval-censored data and compare its performance to SC (self-consistent) algorithm. Comparing to the average interpolation and the nearest neighbor interpolation method, the proposed method in this paper replaces the right censored data with the interval-censored data, and greatly improves the probability of the real data falling into imputation interval. Then it bases on the empirical distribution theory to estimate the survival function of right censored and interval-censored data. The results of numerical examples and a real breast cancer data set demonstrated that the proposed method had higher accuracy and better robustness for the different proportion of the censored data. This paper provides a good method to compare the clinical treatments performance with estimation of the survival data of the patients. This pro vides some help to the medical survival data analysis. PMID- 25039126 TI - [Recognition of walking stance phase and swing phase based on moving window]. AB - Wearing transfemoral prosthesis is the only way to complete daily physical activity for amputees. Motion pattern recognition is important for the control of prosthesis, especially in the recognizing swing phase and stance phase. In this paper, it is reported that surface electromyography (sEMG) signal is used in swing and stance phase recognition. sEMG signal of related muscles was sampled by Infiniti of a Canadian company. The sEMG signal was then filtered by weighted filtering window and analyzed by height permitted window. The starting time of stance phase and swing phase is determined through analyzing special muscles. The sEMG signal of rectus femoris was used in stance phase recognition and sEMG signal of tibialis anterior is used in swing phase recognition. In a certain tolerating range, the double windows theory, including weighted filtering window and height permitted window, can reach a high accuracy rate. Through experiments, the real walking consciousness of the people was reflected by sEMG signal of related muscles. Using related muscles to recognize swing and stance phase is reachable. The theory used in this paper is useful for analyzing sEMG signal and actual prosthesis control. PMID- 25039127 TI - [Shock shape representation of sinus heart rate based on cloud model]. AB - The present paper is to analyze the trend of sinus heart rate RR interphase sequence after a single ventricular premature beat and to compare it with the two parameters, turbulence onset (TO) and turbulence slope (TS). Based on the acquisition of sinus rhythm concussion sample, we in this paper use a piecewise linearization method to extract its linear characteristics, following which we describe shock form with natural language through cloud model. In the process of acquisition, we use the exponential smoothing method to forecast the position where QRS wave may appear to assist QRS wave detection, and use template to judge whether current cardiac is sinus rhythm. And we choose some signals from MIT-BIH Arrhythmia Database to detect whether the algorithm is effective in Matlab. The results show that our method can correctly detect the changing trend of sinus heart rate. The proposed method can achieve real-time detection of sinus rhythm shocks, which is simple and easily implemented, so that it is effective as a supplementary method. PMID- 25039128 TI - [A P-wave detection method based on multi-feature]. AB - Generally, P-wave is the wave of low-frequency and low-amplitude, and it could be affected by baseline drift, electromyography (EMG) interference and other noises easily. Not every heart beat contains the P-wave, and it is also a major problem to determine the P-wave exist or not in a heart beat. In order to solve the limitation of suiting the diverse morphological P-wave using wavelet-amplitude transform algorithm and the limitation of selecting the pseudo-P-wave sample using the wavelet transform and neural network, we presented new P-wave detecting method based on wave-amplitude threshold and using the multi-feature as the input of neural networks. Firstly, we removed the noise of ECG through the wavelet transform, then determined the position of the candidate P-wave by calculating modulus maxima of the wavelet transform, and then determine the P-wave exist or not by wave-amplitude threshold method initially. Finally we determined whether the P-wave existed or not by the neural networks. The method is validated based on the QT database which is supplied with manual labels made by physicians. We compared the detection effect of ECG P-waves, which was obtained with the method developed in the study, with the algorithm of wavelet threshold value and the method based on "wavelet-amplitude-slope", and verified the feasibility of the proposed algorithm. The detected ECG signal, which is recorded in the hospital ECG division, was consistent with the doctor's labels. Furthermore, after detecting the 13 sets of ECG which were 15 min long, the detection rate for the correct P-wave is 99.911%. PMID- 25039129 TI - [Design of an embedded stroke rehabilitation apparatus system based on Linux computer engineering]. AB - A realizaton project of electrical stimulator aimed at motor dysfunction of stroke is proposed in this paper. Based on neurophysiological biofeedback, this system, using an ARM9 S3C2440 as the core processor, integrates collection and display of surface electromyography (sEMG) signal, as well as neuromuscular electrical stimulation (NMES) into one system. By embedding Linux system, the project is able to use Qt/Embedded as a graphical interface design tool to accomplish the design of stroke rehabilitation apparatus. Experiments showed that this system worked well. PMID- 25039130 TI - [Design of a multifunctional and transparent urinary system model]. AB - This article describes a novel Multifunctional and Transparent Urinary System Model (MTUSM), which can be applied to anatomy teaching, operational training of clinical skills as well as simulated experiments in vitro. This model covers kidneys, ureters, bladder, prostate, male and female urethra, bracket and pedestal, etc. Based on human anatomy structure and parameters, MTUSM consists of two transparent layers i. e. transparent organic glass external layer, which constraints the internal layer and maintains shape of the model, and transparent silica gel internal layer, which possesses perfect elasticity and deformability. It is obvious that this model is preferable in simulating the structure of human urinary system by applying hierarchical fabrication. Meanwhile, the transparent design, which makes the inner structure, internal operations and experiments visual, facilitates teaching instruction and understanding. With the advantages of simple making, high-findelity, unique structure and multiple functions, this model will have a broad application prospect and great practical value. PMID- 25039131 TI - [Study on establishing a project concerning the process quality control of treating liver cancer with CyberKnife]. AB - In order to guarantee the safety and accuracy of the whole treating process as well as better link up of each section during the treatment, we did research in order to establish a project concerning the process quality control (PQC) of treating liver cancer with CyberKnife. From the safety and accuracy point of view, we divided the whole process of treating liver cancer with CyberKnife into ten links, i.e. the registration of patients' information, the im plantation of fiducial markers, fixation of body posture, CT localization, target delineation, design of the treatment plan, quality assurance in physics, implementation of the treatment plan, inspection on the correctness and data archiving. We analyzed the possible mistakes in each link and the consequences brought by them. To smoothly connect all the links, a special part "Attention" was added between every two links. Various wrong operations which may influence the safety and accuracy of treatment were illustrated, and the consequences brought by them were also ex plained. The "Attention" part among links offers important information for the next step, and gives us reminding and warnings. The project of quality control covers all the important links when treating liver cancer with Cy berKnife. It offers regulations, reminding and warning for us so that the safety and accuracy of treatment can be guaranteed, and the work of all staff could be closely connected. PMID- 25039132 TI - [Application of linear and nonlinear characteristics of heart rate variability in assessment of autonomic nervous system activity]. AB - Calculation of linear parameters, such as time-domain and frequency-domain analysis of heart rate variability (HRV), is a conventional method for assessment of autonomic nervous system activity. Nonlinear phenomena are certainly involved in the genesis of HRV. In a seemingly random signal the Poincare plot can easily demonstrate whether there is an underlying determinism in the signal. Linear and nonlinear analysis methods were applied in the computer words inputting experiments in this study for physiological measurement. This study therefore demonstrated that Poincare plot was a simple but powerful graphical tool to describe the dynamics of a system. PMID- 25039133 TI - [Long-term characteristics and clinical significance of echocardiogram in patients after mechanical prosthesis aortic valve replacement]. AB - The main purpose of this study is to observe and analyze the characteristics and the clinical significance of long-term echocardiogram data in patients after mechanical aortic valve replacement operation. Fifty-five cases were recruited over 5 years after mechanical aortic valve replacement operation, with complete echocardiogram examination profiles. The 55 subjects were divided into predominate aortic stenosis group and predominate aortic regurgitation group, based on preoperative examinations. And another way of division was also carried out that according to the effective orifice area index (EOAI), the subjects were divided into three groups, i. e. , severe prosthesis-patient mismatch (PPM) group, moderate PPM group, and non PPM group. Characteristics of long-term echocardiogram data of the subjects were analyzed. Patients with aortic stenosis showed significantly decreased thickness of intraventricular septum and left ventricular posterior wall about half a year after operation (P < 0.05). Half a year after operation, patients with aortic regurgitation showed decreased left ventricular internal dimension diastole and left ventricular internal dimension systole, and increased ejection fraction (P < 0.05). Differences in mean aortic valve pressure gradient, forward blood flow across the aortic valves, and ejection fraction were not significant among those with severe PPM, moderate PPM, and non PPM groups (P > 0.05). Number of cases of ascending aorta dimension increased as time goes on and pathogenesis of other valve diseases. A conclusion could be drawn that the heart function of patients with aortic valve disease could be improved after mechanical aortic valve replacement operation, but pathologies in other valves and ascending aorta might be increased, and therefore periodical postoperative echocardiogram evaluation with long-term pharmaceutical therapy could be necessary. PMID- 25039134 TI - [Effect of respiratory movement on cone beam computed tomography images]. AB - To investigate the impact of respiratory movement to determine the target volume on cone beam CT (CBCT) for lung tumor, we used CIRS dynamic thorax phantom (Model CIRS008) to simulate the sinusoidal motion of lung tumor. With a constant amplitude, the ratio of the time of near-end-expiratory and near-end-inspiratory (E/I) changed when it was scanned with CBCT. We analyzed the contrast changes of target by extracting the CT value of each pixel on the center line of the target movement direction. The targets were contoured with region growing method and compared with the motion volume generated by the tumor trajectory method. The result showed that the contrast of near-end-expiratory increased and the contrast of near-end-inspiratory decreased with increasing E/I. The contoured volume generated by region growing method decreased with increasing E/I. When E/I = 4, the amplitude A = 1 cm, diameter of 1 cm and 3 cm target volumes were reduced by 48.2% and 22.7%. The study showed that CBCT was not suitable to be used to accurately determine the range of lung tumor movement. The internal target volume (ITV) may be underestimated in CBCT images. PMID- 25039135 TI - [Systematic review of transfusion strategies for cardiac surgery]. AB - This paper is aimed to assess the effects of red blood cell (RBC) transfusion on clinical outcomes in cardiac surgery. Trials were identified by computer searches of the Pubmed, MEDLINE, Cochrane Library (Issue 10, 2012), from January 1980 to October 2012. References in identified trials and review articles were checked and experts contacted to identify any additional trials. The homogeneous randomized controlled trials (RCTs) were analyzed with RevMan 5.1 software. Five trials involving a total of 1,203 patients were identified. The results of meta analyses showed that restrictive transfusion strategies reduced the risk of receiving a RBC transfusion (MD = - 1.46, 95% CI -1.18(-) -1.1) and the volume of RBCs transfusion (RR = 0.69, 95% CI 0.53-0.89). No significant difference was noted between the two strategies in terms of mortality, adverse events and hospital or intensive care length of stay. Based on the results mentioned above, one can draw a conclusion that restrictive transfusion strategies reduced the risk of receiving RBC transfusion and the volume of RBCs transfused. Restrictive transfusion strategies did not appear to impact on the rate of adverse events and hospital or intensive care length of stay, compared to liberal transfusion strategies. PMID- 25039136 TI - [Reconstruction of inferior alveolar nerve canal based on shape feature]. AB - It is difficult to distinguish the inferior alveolar nerve (IAN) from other tissues inside the IAN canal due to their similar CT values in the X image which are smaller than that of the bones. The direct reconstruction, therefore, is difficult to achieve the effects. The traditional clinical treatments mainly rely on doctors' manually drawing the X images so that some subjective results could not be avoided. This paper proposes the partition reconstruction of IAN canal based on shape features. According to the anatomical features of the IAN canal, we divided the image into three parts and treated the three parts differently. For the first, the directly part of the mandibular, we used Shape-driven Level set Algorithm Restrained by Local Information (BSLARLI) segment IAN canal. For the second part, the mandibular body, we used Space B-spline curve fitting IAN canal's center, then along the center curve established the cross section. And for the third part, the mental foramen, we used an adaptive threshold Canny algorithm to extract IAN canal's edge to find center curve, and then along it established the cross section similarly. Finally we used the Visualization Toolkit (VTK) to reconstruct the CT data as mentioned above. The VTK reconstruction result by setting a different opacity and color values of tissues CT data can perspectively display the INA canal clearly. The reconstruction result by using this method is smoother than that using the segmentation results and the anatomical structure of mental foramen position is similar to the real tissues, so it provides an effective method for locating the spatial position of the IAN canal for implant surgeries. PMID- 25039137 TI - [In vivo anatomical study of inferior attachment of renal fascia in adult with acute pancreatitis as shown on multidetector computed tomography]. AB - This study aims to explore the inferior adhesion of the renal fascia (RF), and the inferior connectivity of the perirenal spaces (PS) with multidetector computed tomography (MDCT), and to investigate the diagnostic value of CT for showing this anatomy. From May to July 2012, eighty-two patients with acute pancreatitis presented in our hospital were enrolled into this study and underwent contrast-enhanced CT scans. All the image data were used to perform three dimensional reconstruction to show the inferior attachment of RF and the inferior connectivity of PS. The fusion of anterior renal fascia (ARF) and posterior renal fascia (PRF) next to the plane of iliac fossa were found on the left in 71.95% (59/82) cases, and on the right in 75.61% (62/82). In these cases, bilateral perirenal spaces, and anterior and posterior pararenal spaces were not found to be connected with each other. No fusion of ARF and PRF below the level of bilateral kidneys occurred on the left side in 28.05% (23/82) cases and on the right side in 24.39% (20/82). In these patients, the PS extended to the extraperitoneal space of the pelvic cavity and further to the inguinal region, and bilateral anterior and posterior pararenal spaces were not found to be connected with each other. Three-dimensional reconstruction on contrast-enhanced MDCT could be a valuable procedure for depicting inferior attachment of RF, and the inferior connectivity of PS. PMID- 25039138 TI - [Integrins mediate the migration of HepG2 cells induced by low shear stress]. AB - Low shear stress is a component of the tumor microenvironment in vivo and plays a key role in regulating cancer cell migration and invasion. The integrin, as a mechano-sensors mediating and integrating mechanical and chemical signals, induce the adhesion between cells and extracellular matrix (ECM). The purpose of this study is to investigate the effect of low shear stress (1.4 dyn/cm2)on the migration of HepG2 cells and the expression of integrin. Scratch wound migration assay was performed to examine the effect of low shear stress on the migration of HepG2 cells at 0 h, 1 h, 2 h and 4 h, respectively. F-actin staining was used to detect the expression of F-actin in HepG2 cells treated with low shear stress at 2 h and 4 h. Western blot analysis was carried out to determine the effect of low shear stress on the expression of integrin at different durations. The results showed that the migrated distance of HepG2 cells and the expression of F-actin increased significantly compared with the controls. The integrin alpha subunits showed a different time-dependent expression, suggesting that various subunits of integrin exhibit different effects in low shear stress regulating cancer cells migration. PMID- 25039139 TI - [3D hemodynamic numerical simulation of carotid artery aneurysm before and after surgery based on CT date]. AB - Hemodynamic situation is an important factor of recurrence of postoperative carotid artery aneurysm. In order to investigate the hemodynamic factors of postoperative carotid artery aneurysm affect carotid artery aneurysm recurrence, we established a 3D finite element carotid artery aneurysm for the preoperative and postoperative periods using the three-dimensional reconstruction techniques. And then we measured the hemodynamic factors of carotid artery aneurysm of preoperative and postoperative by the finite element method. The carotid artery aneurysm model has an accurate and realistic shape; the pressure of the recurrence of aneurysm was reduced significantly after surgery,wall shear stress increased significantly at residual neck, and blood flow velocity increased significantly, which will increase the risk of recurrence. The hemodynamic analysis provides a reference for development of aneurysm clinical treatment programs and prevention of recurrence. PMID- 25039140 TI - [Hemocompatibility of polyoxymethylene used for bileaflet heart valve]. AB - The possibility of polyoxymethylene (POM) as heart valve leaflet material was investigated by comparing the hemocompatibility with that of 316L stainless steel and low-temperature isotropic pyrolytic carbon (LTIC). Surface hydrophobicity was characterized by water contact angle measurement. Platelet adhesion, APTT/PT/TT and hemolysis rate tests were applied for evaluating hemocompatibility. The results showed that POM was hydrophobic and had a low hemolytic rate, adhesion amount and activation degree of platelets on POM surface were less than 316L stainless steel, and was similar to LTIC. This research pointed out potential application of POM as heart valve leaflets. PMID- 25039141 TI - [Comparative studies on the material performances of natural bone-like apatite from different bone sources]. AB - The compressive strength of the original bone tissue was tested, based on the raw human thigh bone, bovine bone, pig bone and goat bone. The four different bone like apatites were prepared by calcining the raw bones at 800 degrees C for 8 hours to remove organic components. The comparison of composition and structure of bone-like apatite from different bone sources was carried out with a composition and structure test. The results indicated that the compressive strength of goat bone was similar to that of human thigh bone, reached (135.00 +/ 7.84) MPa; Infrared spectrum (IR), X-ray diffraction (XRD) analysis results showed that the bone-like apatite from goat bone was much closer to the structure and phase composition of bone-like apatite of human bones. Inductively Coupled Plasma (ICP) test results showed that the content of trace elements of bone-like apatite from goat bone was closer to that of apatite of human bone. Energy Dispersive Spectrometer (EDS) results showed that the Ca/P value of bone-like apatite from goat bone was also close to that of human bone, ranged to 1.73 +/- 0.033. Scanning electron microscopy (SEM) patterns indicated that the macrographs of the apatite from human bone and that of goat bone were much similar to each other. Considering all the results above, it could be concluded that the goat bone-like apatite is much similar to that of human bone. It can be used as a potential natural bioceramic material in terms of material properties. PMID- 25039142 TI - [Preparation and property evaluation of graphene oxide based silver nanoparticles composite materials]. AB - We prepared silver nanoparticles/polyethyleneimine-reduction graphene oxide (AgNP/rGO-PEI) composite materials, and evaluated their quality performance in our center. Firstly, we prepared AgNP/rGO-PEI, and then analysed its stability, antibacterial activity, and cellular toxicity by comparing the AgNP/rGO-PEI with the silver nanoparticles (PVP/AgNP) modified by polyvinylpyrrolidone. We found in the study that silver nanoparticles (AgNP) distributed relatively uniformly in AgNP/rGO-PEI surface, silver nanoparticles mass fraction was 4.5%, and particle size was 6-13 nm. In dark or in low illumination light intensity of 3 000 lx meter environment (lux) for 10 days, PVP/AgNP aggregation was more obvious, but the AgNP/rGO-PEI had good dispersibility and its aggregation was not obvious; AgNP/rGO-PEI had a more excellent antibacterial activity, biological compatibility and relatively low biological toxicity. It was concluded that AgNP/rGO-PEI composite materials had reliable quality and good performance, and would have broad application prospects in the future. PMID- 25039143 TI - [Effects of different surface conditioning agents on the bond strength of resin opaque porcelain composite]. AB - The objective of this research is to evaluate the effects of different silane coupling agents on the bond strength between Ceramco3 opaque porcelain and indirect composite resin. Five groups of Co-Cr metal alloy substrates were fabricated according to manufacturer's instruction. The surface of metal alloy with a layer of dental opaque porcelain was heated by fire. After the surface of opaque porcelain was etched, five different surface treatments, i.e. RelyX Ceramic Primer (RCP), Porcelain Bond Activator and SE Bond Primer (mixed with a proportion of 1:1) (PBA), Shofu Porcelain Primer (SPP), SE bond primer (SEP), and no primer treatment (as a control group), were used to combine P60 and opaque porcelain along with resin cement. Shear bond strength of specimens was tested in a universal testing machine. The failure modes of specimens in all groups were observed and classified into four types. Selected specimens were subjected to scanning electron microscope and energy disperse spectroscopy to reveal the relief of the fracture surface and to confirm the failure mode of different types. The experimental results showed that the values of the tested items in all the tested groups were higher than that in the control group. Group PBA exhibited the highest value [(37.52 +/- 2.14) MPa] and this suggested a fact that all of the specimens in group PBA revealed combined failures (failure occurred in metal porcelain combined surface and within opaque porcelain). Group SPP and RCP showed higher values than SEP (P < 0.05) and most specimens of SPP and RCP performed combined failures (failure occurred in bond surface and within opaque porcelain or composite resin) while all the specimens in group SEP and control group revealed adhesive failures. Conclusions could be drawn that silane coupling agents could reinforce the bond strength of dental composite resin to metal opaque porcelain substrate. The bond strength between dental composite resin and dental opaque porcelain could meet the clinical requirements. PMID- 25039144 TI - [SPIO-labeled rat bone marrow mesenchymal stem cells: alterations of biological activity and labeling efficiency assay in vitro]. AB - This study aimed to characterize and magnetic resonance imaging (MRI) track the mesenchymal stem cells labeled with polylysine-coated superparamagnetic iron oxide (PLL-SPIO). Rat bone marrow derived mesenchymal stem cells (rMSCs) were labeled with 25, 50 and 100 microg/mL PLL-SPIO for 24 hours. The labeling efficiency was assessed by iron content, Prussian blue staining, electron microscopy and in vitro MR imaging. The labeled cells were also analyzed for cytotoxicity and differentiation potential. Electron microscopic observations and Prussian blue staining revealed that 75% -100% of cells were labeled with iron particles. PLL-SPIO did not show any cytotoxicity up to 100 microg/mL concentration. Both 25 microg/mL and 50 microg/mL PLL-SPIO labeled stem cells did not exhibit any significant alterations in the adipo/osteo/chondrogenic differentiation potential compared to unlabeled control cells. The lower concentration of 25 microg/mL iron labeled cells emitted an obvious dark signal in T1W, T2WI and T2 * WI MR image. The novel PLL-SPIO enables to label and track rMSCs for in vitro MRI without cellular alteration. Therefore PLL-SPIO may potentially become a better MR contrast agent especially in tracking the transplanted stem cells and other cells without compromising cell functional quality. PMID- 25039145 TI - [Effect of microencapsulation on the expression of the oxidative stress genes of HepG2 cells and exogenous regulation]. AB - The aim of this research is to investigate the influence of microencapsulation on the expression of the oxidative stress genes and exogenous regulation of HepG2 cells. We compared the expression of hemeoxygenase-1 (HO-1) and glutathione S transferases-A1 (GST-A1) in HepG2 cells under different culture conditions through real-time PCR. The effects of exogenous antioxidants on cell viability and albumin levels were also evaluated through MTT assay and ELISA assay. The results showed that after culturing for 6 and 16 days, the expression levels of HO-1 in encapsulated cells were approximately 4.9 and 3.1 times higher than that of monolayer cells at the same culture period; As for the expression levels of GST-A1, they were elevated to 11.2 and 33 times of monolayer cells (P < 0.05). Accordingly, we found that NAC at 5-10 mmol/L significantly increased the viability by 40%-70% and the biosynthetic function by 20%-30% in microencapsulated HepG2 cells (P < 0.05). GSH increased the viability of the encapsulated cells by 20%-55% and the biosynthetic function by 15% (P < 0.05). In conclusion, oxidative stress exists in the microcapsules and affects genes expression. Exogenous antioxidants can prevent the inhibition effects of oxidative stress on cellular growth. PMID- 25039146 TI - [Preliminary investigation into the mechanism of cardiomyocyte hypertrophy induced by visfatin]. AB - The aim of the current study is to investigate the effect of visfatin on cardiomyocyte hypertrophy. Cultured H9c2 cardiomyocytes were exposed to visfatin at different concentrations for different periods of time, and the markers of cardiomyocyte hypertrophy were detected. Moreover, pravastatin, the inhibitor of endoplasmic reticulum stress (ERS) or thapsigargin, an ERS agonist was used respectively to pre-treat the cells before visfatin stimulation. F-actin staining was performed to measure the cell surface change. The mRNA expressions of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ERS markers including glucose-regulated protein 78(GRP78), C/EPB homologous protein (CHOP) and activating transcription factor 6 (ATF6) were assessed by real time RT-PCR. The change of protein level of GRP78 and CHOP was detected by Western blot. The experimental data demonstrated that exposure to 100 or 150 ng/mL concentrations of visfatin for 24 h, or 100 ng/mL of visfatin for 24 or 48 h, significantly increased the expression of markers for cardiomyocyte hypertrophy. Visfatin stimulation provoked ERS in H9c2 cells. Furthermore, pre-treatment with pravastatin partially inhibited the visfatin-induced mRNA expression of ANP and BNP in H9c2 cells, whereas thapsigargin promoted the visfatin-induced expression of cardiomyocyte hypertrophy markers. The results suggest that visfatin might induce cardiomyocyte hypertrophy via ERS -dependent pathways. PMID- 25039147 TI - [The rescue effect of RANKL on zoledronate induced acid inhibition of osteoclastogenesis and gene expression of NF-kappaB p50 and c-Jun]. AB - In this study, the rescue effect of receptor activator for nuclear factor-kappaB ligand (RANKL) on zoledronate acid (ZOL) induced inhibition of osteoclastogenesis and gene expression of NF-kappaB p50 and c-Jun was investigated. Mice calvarial osteoblasts (OBs) were harvested and co-cultured with RAW264.7 cells and the cells were divided into 4 groups and received treatment with ZOL and RANKL, either single or combined. The formation of multi-nucleated osteoclast (OC) was examined and gene expression of NF-kappaB p50 and c-Jun was detected. Group B (ZOL) showed least multi-nucleated OC and resorption lacunae among the 4 groups (P < 0.05 or P < 0.01) and it was followed by group C (ZOL+RANKL). Group D (RANKL) showed highest OC and resorption lacunae while it was similar to Group A (control) (P > 0.05). Gene expression of NF-kappaB p50 and c-Jun was the lowest in group B (P < 0.05 or P < 0.01) among the four groups and was significantly increased in group C when compared with group B (P < 0.05). Group A and D showed highest gene expression and they were similar to each other (P > 0.05). This study suggest that RANKL might partly rescue ZOL induced inhibition of osteoclastogenesis, and the effect of RANKL and ZOL on osteoclastogenesis may be mediated by NF-kappaB p50 and c-Jun. PMID- 25039148 TI - [Study on the differentiation of human mesenchymal stem cells into vascular endothelial-like cells]. AB - To explore the feasibility of mesenchymal stem cells (MSCs) acting as seed cells in tissue engineering, we isolated human bone marrow MSCs and differentiated them into vascular endothelial-like cells (ELCs) in vitro. Bone marrow mononuclear cells (BMSCs) were isolated by the method of percoll density centrifugation, and seeded in Dulbecco Modified Eagle Medium supplemented with 10% fetal bovine serum. MSCs were purified through multiple adherent cultures, and differentiated into ELCs induced by endothelial cell growth medium-2 (EBM-2) medium containing vascular endothelial growth factor (VEGF), human fibroblast growth factor (hFGF), insulin like growth factors 1 (IGF-1), and human epidermal growth factor (hEGF). The relative biologic characteristics of ELCs including cell morphology and phenotype were studied by inverted microscope and flow cytometry. The induced cells were identified by immunofluorescence with CD31 and Von Willebrand factor (vWF). The results showed that the morphology of MSCs was long-spindle and vortex like growth. After induction of differentiation, the cells were round, and similar to vascular endothelial cells (ECs). Flow cytometric analysis revealed that ELCs expressed ECs specific surface markers of CD31 and vascular endothelial cadherin (VE-cadherin), but not CD133. Immunofluorescence results also confirmed that ELCs expressed CD31 and vWF. The results suggested that ELCs possed similar cell biological characteristics with ECs. In one word, human MSCs derived from bone marrow have the potential to differentiate into ECs in vitro, and show clinical feasibility acting as ideal donor cells of vascular tissue engineering. PMID- 25039149 TI - [Effect of tetramethylpyrazine and rat CTGF miRNA plasmids on connective tissue growth factor, transforming growth factor-beta in high glucose stimulated hepatic stellate cells]. AB - The aim of this research is to evaluate the effect of tetramethylpyrazine (TMP) and connective tissue growth factor (CTGF) miRNA plasmids on the expressive levels of CTGF, transforming growth factor-beta (TGFbeta) and type I collagen of rat hepatic stellate cells (HSC) which are stimulated by high glucose. The rat HSCs which were successfully transfected rat CTGF miRNA plasmids and the rat HSCs which were successfully transfected negative plasmids were cultured in vitro. After stimulus of the TMP and the high glucose, the protein levels and gene expressive levels of CTGF, TGF-beta and type I collagen were tested. The results indicated that high glucose increased the expression of CTGF mRNA, CTGF protein, TGF-beta mRNA,TGF-beta protein and type I collagen (P < 0.05). The expressive levels of CTGF mRNA, CTGF protein, TGF-beta mRNA, TGF-beta and type I collagen in TMP group were lower than those in high glucose group and showed statistically significant differences (P < 0.05). Compared with high glucose group, the expressive levels of CTGF mRNA, CTGF protein, TGF-beta mRNA, TGF-beta and type I collagen in rat CTGF miRNA plasmid interference group were significantly lower (P < 0.05). However, no statistically significant difference was found in CTGF mRNA and CTGF protein levels between TMP group and CTGF miRNA group (P > 0.05), while type I collagen levels showed statistically significant differences (P < 0.05). It is concluded that high glucose could promote the expressions of CTGF, TGF-beta and type I collagen, and TMP and rat CTGF miRNA plasmids could reduce the expressions of CTGF, TGF-beta, type I collagen. PMID- 25039150 TI - [Effects of amantadine and biphenyl dimethyl dicarboxylate on hepatitis B virus in hepatitis B virus replication mice]. AB - This study sought to investigate the in vivo antiviral effect of amantadine (AM) and biphenyl dimethyl dicarboxylate (DDB) on hepatitis B virus (HBV) in HBV replication mice. HBV replication-competent plasmid was transferred into male BALB/c mice by using hydrodynamics-based in vivo transfection procedure to develop HBV replication mouse model. The model mice were matched by body weigh, age and serum levels of hepatitis B e antigen (HBeAg) and were divided into four groups: AM group, DDB group, AM+DDB group and NS group, with the last one as control, and the mice of each group were administered corresponding agent orally twice a day, in a medication course lasting 3 d. On the third day, the mice were sacrificed 4-6 h after the last oral intake. HBV DNA replication intermediates in liver were analyzed by Southern blot hybridization. The serum hepatitis B surface antigen (HBsAg) and HBeAg were detected by enzyme linked immunosorbent assay (ELISA). Compared to the animals in the control group, HBV DNA replication intermediates in liver and HBsAg and HBeAg in serum from the AM and AM plus DDB group of mice decreased, and there was no difference between these two groups of mice. The levels of HBV DNA intermediate from liver and the serum HBsAg and HBeAg between the control and DDB group, however, were not obviously different. In conclusion, the inhibition effect of AM on HBV was detected, but treatment with DDB for 3 days did not influence the viral replication and expression of HBV in the HBV replication mice. PMID- 25039151 TI - [Three-dimensional CT liver image segmentation based on hierarchical contextual active contour]. AB - In this paper, we propose a new active contour algorithm, i. e. hierarchical contextual active contour (HCAC), and apply it to automatic liver segmentation from three-dimensional CT (3D-CT) images. HCAC is a learning-based method and can be divided into two stages. At the first stage, i.e. the training stage, given a set of abdominal 3D-CT training images and the corresponding manual liver labels, we tried to establish a mapping between automatic segmentations (in each round) and manual reference segmentations via context features, and obtained a series of self-correcting classifiers. At the second stage, i.e. the segmentation stage, we firstly used the basic active contour to segment the image and subsequently used the contextual active contour (CAC) iteratively, which combines the image information and the current shape model, to improve the segmentation result. The current shape model is produced by the corresponding self-correcting classifier (the input is the previous automatic segmentation result). The proposed method was evaluated on the datasets of MICCAI 2007 liver segmentation challenge. The experimental results showed that we would get more and more accurate segmentation results by the iterative steps and the satisfied results would be obtained after about six rounds of iterations. PMID- 25039152 TI - [An approach for segmentation of X-ray angiographic image based on region-growing and structure inferring]. AB - We presented a new method for vessel segmentation and vascular structure recognition for coronary angiographic images. During vessel segmentation, a new vessel function was proposed to attain vessel feature map. Then the region growing algorithm was implemented with an automatic selection of seed point, extraction of main vessel branch, and vessel detail repairing. In the algorithm of vascular structure recognition, a fuzzy operator was used, which can detect the structures of vascular segments, bifurcations, crosses, and tips. The experimental results indicated that there was about 5 percent larger vessel region which was extracted by the proposed segmentation method than that by the simple region growing algorithm, and several thinner vessels were resumed from the lower gray region. The results also indicated that the fuzzy operator could correctly infer the simulative and real vessel structure with 100% and 90.59% correctness rate on the average, respectively. PMID- 25039153 TI - [A new parameter measurement system for electrosurgery output]. AB - Accurate measurements of voltage and current from electrosurgery are the basis of development of electrosurgery with feedback function. We, therefore, developed a parameter measurement system based on PC, with high voltage and current from electrosurgery being sensed with transformers, amplified, filtered, transformed into single-ended signals, and then into RMS signals. The root mean square (RMS) signals were transformed into digital signals through DAQ card and the data was processed in PC with Labview. The process included sampling, displaying and storage. The experiment results indicated that the measurement system could measure the output parameters from electrosurgery steadily and correctly so that the development of the system has been successful. It can be the basis of development of embedded parameters measurement system and can provide accurate feedback information for intellectual electrosurgery. PMID- 25039154 TI - [Experimental study on novel hybrid artificial trachea transplantation]. AB - We developed and designed a new type of artificial trachea. The basic structure of the artificial trachea was polytetrafluoroethylene vascular prosthesis linked with titanium rings on both sides. Dualmesh was sutured on titanium rings. This experimentation follows the replacement of trachea in dogs with a combined artificial trachea to investigate the feasibility of this type of prosthesis. Sixteen dogs were implanted with the combined artificial trachea after resection of 5 cm of cervical trachea. The 5 cm-long trachea of dogs on the necks were resected and the reconstruction of the defect of the trachea was performed with trachea prosthesis. According to the method of trachea reconstruction, the models were divided into 2 groups, artificial trachea implantation group (the control group, n = 8) and group of artificial trachea implantation with growth factor (the experimental group, n = 8). Then computer tomography scan (CT), bronchoscope and pathologic examination were conducted periodically to observe the healing state of the hybrid artificial trachea. None of the dogs died during operation of cervical segmental trachea construction. But four dogs in the control group died of apnea in succession because artificial trachea was displaced and the lumen was obstructed, while 2 dogs died in the experimental group. In the first month there was granulation around anastomosis with slight stenosis. The rest of dogs were well alive until they were sacrificed 14 months later. The mean survival time of the experimental group was longer than that of the control group. The rate of infection, anastomotic dehiscence, severe stenosis and accidental death in the experimental group were lower than the control group (P < 0.05). Artificial trachea was encapsulated by fibrous tissue and no mucous membrane was seen in the lumen of the artificial trachea. The artificial trachea can be used to reconstruction of the defect of the trachea with long-term survival of the animals. The unique design of artificial trachea reduces stenosis around anastomosis effectively but infections and split or displacement of the artificial trachea are still major problems affecting long-term survival of the animals. Application of growth factors to a certain extent promotes tissue healing by changing the local environment. PMID- 25039155 TI - [Optimization of expression conditions of an induction strategy for improving liver targeted interferon (IFN-CSP) production in E. coli]. AB - Expression conditions of induction strategies for the cytoplasmic inclusion bodies (IBs) production of liver targeted interferon IFN-CSP by recombinant Escherichia coli (E. coli) BL21 (DE3) were optimized in shake-flask cultures in this study. The factors of the optimized protocol included in the present study were pH, inducer IPTG (isopropyl beta-D-thiogalactoside) concentration, culture growth temperature, incubation time and induction point. The effects of those factors were investigated by 'single variable at a time' method, aimed to analyze characterization of the recombinant strain. Orthogonal experimental design was further used to optimize the above critical factors for IFN-CSP production. According to the expression optimization result, it was confirmed that the main influence factors were cell density and induction temperature. The IFN-CSP gene expression optimized conditions were: pH value of the culture medium was 6.0, culture temperature 37 degrees C, adding IPTG to final concentration 0.4 mmol/L when the recombinant strain growth density OD600 achieved 0.8 and induction time 4 h. At this point, the IBs represented 74.3% of the total cellular protein. Compared with the non-optimized condition, IFN-CSP production obtained in optimized induction strategies were increased by approx. 1.2-fold. The optimized induction strategy yielded 688.8 mg/L of IFN-CSP, providing experimental data to study the biology activity and productive technology of IFN-CSP. PMID- 25039156 TI - [The design of plantar pressure distribution monitoring system and preliminary clinical application]. AB - Plantar pressure distribution can reflect the force of several key points on foot while standing and walking. A comprehensive understanding of the plantar pressure distribution makes great sense in the following aspects: the understanding of the normal foot biomechanics and function, clinical diagnosis, measurement of disease extent, postoperative efficacy evaluation, and rehabilitation research. A simple plantar pressure measurement device was designed in this study. This paper uses FlexiForce flexible sensor to pickup plantar pressure signal and USB A/D board to do data acquisition. The data are transferred into a laptop and processed by a VB based software which can display, remember and replay the data. We chose patients with hallux valgus and normal people to measure the pressure distribution and make contrast analysis of plantar pressure with this device. It can be concluded that people with hallux valgus have higher pressure on the second metatarsophalangeal joint and the distribution move outward. The plantar pressure of patients postoperative could be greatly improved compared to the preoperative. The function of this device has been confirmed. PMID- 25039157 TI - [Application progress of 18F-FDG positron emission tomograph in differentiated thyroid cancer]. AB - Positron emission tomography (PET) is a highly sensitive and low invasive technology for cancer biological imaging. Integrated PET/computed tomography (PET/CT) cameras combine functional and anatomical information in a synergistic manner that improves diagnostic interpretation. The role of 18F FDG PET/CT in differentiated thyroid cancer (DTC) is well established, particularly in patients presenting with elevated thyroglobulin (Tg) levels and negative radioactive iodine scan. This review presents the evidence supporting the use of 18F FDG PET/CT throughout the diagnosis and management of thyroid cancer, and provides suggestions for its clinical uses. PMID- 25039158 TI - [Application of the inspiratory impedance threshold device and its research progress]. AB - The inspiratory impedance threshold device (ITD) was put forward by Lurie in 1995, and was assigned as a class II a recommendation by the International Liaison Committee on Resuscitation (ILCOR) resuscitation guidelines in 2005. The ITD is used to augment negative intrathoracic pressure during recoil of the chest so as to enhance venous return and cardiac output, and to decrease intracranial pressure. In the recent years many researches on the ITD have been1 carried out, but all the researches can not take out a clear evidence to support or refute the use of the ITD. This paper introduces the structure and working principle of the ITD in detail, the research results and the debates about the use of the ITD for the past years. PMID- 25039159 TI - [Progress of research on intracranial pressure monitoring]. AB - At present, the monitoring methods fwor intracranial pressure adopted in clinical practice are almost all invasive. The invasive monitoring methods for intracranial pressure were accurate, but they were harmful to the patient's body. Therefore, non-invasive methods for intracranial pressure monitoring must be developed. Since 1980, many non-invasive methods have been sprung out in succession, but they can not be used clinically. In this paper, research contents and progress of present non-invasive intracranial pressure monitoring are summarized. Advantages and disadvantages of various ways are analyzed. And finally, perspectives of development for intracranial pressure monitoring are presented. PMID- 25039160 TI - [Research progress on application of gold magnetic nanocomposite in biomedicine]. AB - This paper provides a brief overview of the current research activities which focused on the bio-application of gold magnetic nanocomposite particles. By combining the magnetic characteristics of the iron oxide core with the unique features of nano-gold particles such as targeting by surface modification and optical properties, such composite nanoparticles have a wide range of applications in cancer hyperthermia, CT and MRI imaging, bio-separation, bio sensors, gene diagnosis, drug targeting and many other biomedical fields. PMID- 25039161 TI - [Progress and prospect of applications of silk fibroin in construction of tissue engineering scaffold]. AB - With the development of tissue engineering, a variety of forms of silk fibroin (SF) scaffolds has been applied to research of constructing variety of organization based on cells, which has become scientific focus in recent years. In this paper we introduced the source and structure of SF and the fabrication method of the scaffold, and also address the SF application progress in several relevant fields of tissue engineering, such as bone, cartilage, skin, blood vessel and nerves. Finally, we discuss the future leading prospect of the SF in order to provide reference for subsequent research. PMID- 25039162 TI - [The progress of magnetic nanomaterials in application of biomedicine]. AB - Magnetic nanomaterials is widely used in medical diagnosis, drug delivery, biomedical and other fields due to their unique structure and excellent properties. The magnetic nanometer material in biomedical applications, such as biological separation and purification, application of controlled drug release and magnetic resonance imaging are reviewed in the present paper, and the development trend of magnetic nanomaterials is also forecasted. PMID- 25039163 TI - [Hyperbaric oxygenation and penis erectile dysfunction]. AB - Relaxation and contraction factors influencing penile erection are produced and released by the central and peripheral nerves as well as intracavernosal sinus gap and vascular endothelial cells. Aging, diabetes, cardiovascular disease and spinal cord injury can influence these factors. Further researches of hyperbaric oxygenation (HBO) on the erectile dysfunction (ED) can provide some theoretical evidences for the clinical treatment of ED. PMID- 25039164 TI - [Key-point investigation list of traditional Chinese medicinal materials for national survey of Chinese material medica resources]. AB - Base on the traditional Chinese medicinal materials list that include Pharmacopoeia of the People's Republic of China, Dao-di Herbs, the common used herbs, endangered species, to analyze the key-point investigation traditional Chinese medicinal materials list was analysed. Results displayed that the variety number of traditional Chinese medicinal materials in Pharmacopoeia of the People's Republic of China is 894, the variety number of Dao-di Herbs is 495, the variety number of the common use is 326, the variety number of traditional Chinese medicinal materials from endangered species is 280, and during the third national survey of Chinese material medica resources the variety number of traditional Chinese medicinal materials that were analysed is 360. In the list of Dao-di Herbs and common used herbs over 85% are in the list of Pharmacopoeia of the People's Republic of China, in the list of the common used herbs over 80% are in the list of Dao-di Herbs, in the list of Pharmacopoeia of the People's Republic of China and Dao-di Herbs over 10% are in the list of endangered species. The key-point investigation traditional Chinese medicinal materials list includes three part, the first part includes 563 variery traditional Chinese medicinal materials that need to statistics quantity of resource by field investigation, the second part includes 457 variery that need to monitor the changing situation, the third part includes 280 variery that need to estimated endangered situation. PMID- 25039165 TI - [Research status and translational application of new extraction techniques of traditional Chinese medicine]. AB - Extraction is the critical link during pharmaceutical process of traditional Chinese medicine (TCM), which is directly related to the quality of drugs. So the key to technology upgrading of pharmaceutical equipment in Chinese materia medica enterprise is the development of new extraction techniques, which concerns the modernization of TCM. In this paper, fundamentals, traits, and development status of new extraction technologies were firstly introduced, including ultrasound extraction, microwave extraction, super fluid extraction, semi-bionic extraction method, enzymatic treatment extraction, continuous countercurrent extraction, vacuum extraction. Then information of projects supported by the National Natural Science Foundation of China was analyzed in order to recognize the assistance and research results of new extraction techniques. The patents authorized by the State Intellectual Property Office were also summarized for the purpose of understanding the achievement transformation. The information about extraction equipments was collected and screened to acquire the characteristics and market situation. The results showed that there are still problems about new extraction technologies, such as weak basic study, hard transformation of achievements, and the disconnection between research study and practical application. It is necessary to discuss the approaches and methods for accelerating the transformation of fundamental research, which will provide references for the long-term development of new extraction techniques of TCM. PMID- 25039166 TI - [Advance in studies on anti-diabetic mechanism of Gardeniae Fructus and its active ingredient geniposide]. AB - The diabetes is mainly treated by the oral administration of western medicines at present. Despite their rapid curative effect, there have been still many reports for the western medicines about their clinical adverse reactions, failure of effective prevention and treatment of complications and drug resistance. Hence, they are not suitable for long-term administration. Traditional Chinese medicines have a long history in treating diabetes mellitus (DM) , which is commonly known as Xiaokezheng in the theory of traditional Chinese medicines. In recent years, many scholars have taken extracts from traditional Chinese medicines or separated active constituents as the study objects in the expectation of developing new type drugs for treating and preventing diabetes. Therefore, a large number of study reports have been emerged in this field. Due to their significant glucose reducing effect and specific effect in treating complications of diabetes, traditional Chinese medicine Gardeniae Fructus and its iridoid component geniposide shall be given full attention. This paper summarized the advance in studies on the curative effect and action mechanism of Gardeniae Fructus and geniposide in preventing and treating diabetes. PMID- 25039167 TI - [Progress of berberine for treatment of type 2 diabetes]. AB - Berberine is the major component of Coptidis Rhizoma and it has been used as anti infection, anti-inflammation drug for gastrointestinal diseases. In recent years, evidence showed that it could regulate glucose and lipid metabolism. Moreover, its activity had been tested by clinical trials and animal researches. The mechanisms of berberine in diabetes include: improving the function of beta-cell; prompting insulin secretion and islets regeneration, lowing lipid level, regulating glucose and lipid metabolic by influence transcriptional factors expression such as PPARgamma, C/EBPalpha, SREBP-1c, LXR, having the activities of anti-oxidation and inhibiting reductase to repress oxidative stress state and regulate metabolic signal pathway. Although numbers of data supported that berberine could improving insulin resistance by clinical trials and animal studies, the large scale, multicenter clinical trials are needed to evaluate the effects of berberine for diabetes and its complications in the time of evidence based medicine. PMID- 25039168 TI - [Numerical taxonomy of agronomic trait in cultivated Lonicera japonica]. AB - Sixty-three morphological traits from 743 specimens of the 41 taxa within the cultivated Lonicera japonica were observed and measured, such as the height of plants, the length of leaf, the width of leaf, the length of anther, the alabastrum's number of one branch, the color of alabastrum and so on. A numerical taxonomy is presented by using the cluster analysis, principal components analysis (PCA) and factor analysis. Sixteen of 63 characters were screened by means of PCA and used for cluster analysis of 41 taxa with the method of Ward linkage and average euclidean distance. The cluster analysis showed that the 41 taxa could be divided into 5 groups when the Euclidean distance coefficient was 11.84. The factor analysis indicated that the shape of leaf, color of alabastrum, the pilosity and color of twiggery were of significance for the cultivated L. japonica classification. The results of this study will be a base for the core collection and breeding of L. japonica. PMID- 25039169 TI - [Biological characteristics of Fusarium oxysporum and inhibitory effects of five fungicides]. AB - The mycelium growth and sporulation in different temperature, pH value and light conditions were detected by using the crossing and haemocytometer method. The toxicity of five fungicides to Fusarium oxysporum was tested by mycelia growth method, so as to provide the reference for prevention and control against F. oxysporum. The optimum temperature and pH value of F. oxysporum to grow and spore were 28 degrees C and 6-7. Alternating light and darkness promoted growth and sporulation of bacterial colony. As for five fungicides, the EC50 of tebuconazole was 10.02 mg x L(-1), 92.50 times as much as carbendazim. The EC50 of myclobutanil and Fuxing was 91.23, 96.68 mg x L(-1), respectively. Tebuconazole showed the most tremendous inhibitory effect and control efficiency on F. oxysporum. PMID- 25039170 TI - [Impact of priming on seed germination and seedling growth of Oldenlandia diffusa under drought stress]. AB - Current study was carried out to optimize the priming condition of Oldenlandia diffusa seeds, and improve germination rate and seed vigor of 0. diffusa seeds under drought conditions. Uniform design was used to optimize the concentration and priming time of three priming materials (PEG, KNO3, GA3). Different concentrations of polyethylene glycol (PEG) was used to simulate drought stress. The seedling was cultured in 1/4 Hoagland medium for 30 d. The results showed that seed priming treatment with 366 mg x kg(-1) GA3 for 1h resulted in significant increase in germination rate, germination index, vigor, root length, plant height and biomass of O. diffusa seeds under drought stress (15% PEG), while seed priming with 3.0% KNO3 for 1 h showed little effect on germination and growth of O. diffusa seeds under drought stress. Seed priming treatment with appropriate GA3 concentration and priming time could enhance seed germination and drought resistance of O. diffusa in seedling stage. PMID- 25039171 TI - [Influence of different original processing methods on quality of Salvia Miltiorrhizae Radix et Rhizoma from Shandong]. AB - In this paper the contents of rosmarinic acid, salvianolic acid B, crytotanshinone, tanshinone II(A) in samples of different original processed Salvia Miltiorrhizae Radix et Rhizoma were determined by HPLC. Different processing methods have varied influences on four active ingredients in Salvia Miltiorrhizae Radix et Rhizoma. Sun-drying reduced the content of crytotanshinone, tanshi-none II(A) and rosmarinic acid, integralsamples were better than those cut into segments. Oven dry method had great influence on water -soluble ingredients, high temperature (80-100 degrees C) could easily cause big loss of rosmarinic acid and salvianolic acid B. The role of traditional processing method "fahan: was complicated, the content of rosmarinic acid decreased, crytotanshinone and tanshinone II(A) increased, and salvianolic acid B showed no difference after "fahan". Drying in the shade and oven dry under low temperatrure (40-60 degrees C) were all effective to keep active ingredients of Salvia Miltiorrhizae Radix et Rhizoma, and, there was no difference between integral samples and samples cut into segments. Therefore, considering comprehensively the content of active ingredients in Salvia Miltiorrhizae Radix et Rhizoma, and processing costing etc., shade-drying or oven dry underlow temperature (40-60 degrees C) should be the most suitable original processing method. PMID- 25039172 TI - [Effects of hormone treatment, light and temperatures on sprouting characteristics of Bupleurum chinense]. AB - Seeds of Bupleurum chinense cultivar, Zhongchai No. 1, were sowed in plastic pots which used the arable layer soil as the nursery bed and putted in the artificial climate incubator at various temperatures (15, 20, 25, 15-25 degrees C) and light (8,12 h) to germinate, respectively. The lower constant temperature (15 degrees ) and the higher constant temperature (25 "C) were not conducive to the sprouting characteristics of B. chinese. While they were able to enhance root activity to some extent; The seeding growth of B. chinese was significantly better in the variable temperature than correspondence in the constant temperature, significantly. The emergence speed, emergence index, vigor index and root activity of Bupleurum were improved under the 12 h of light-time, but the germination rate was not improved. The sprouting of Bupleurum's seeds could be improved to some extent by soaking with hormone, such as gibberellin, cytokinin, salicylic acid. Gibberellin promoted seeds' sprouting and seedings's root activity of Bupleurum, while salicylic acid increased the root activity of seeding. There is a significant influence of light, temperatures and hormone treatment on the germination of Zhongchai No. 1 seeds, and all three are remarkably interacted; It is beneficial to promote seed germination by the temperature (20 + 5) degrees C, lighting (8 h) and gibberellin concentration (10 x 10(-6)). PMID- 25039173 TI - [Resource situation investigation about Rheum tanguticum and its sustainable utilization analysis in main production area of China]. AB - This study was conducted to investigate the wild and cultivated resource situation of Rheum tanguticum in main production area of China, estimate its reserves, and put forward the feasible approach for the sustainable utilization of R. tanguticum. On the basis of the literature data about R. tanguticum, conbined with interview, investigation and sampling investigation, the total reserve of resources is estimated using the route-quadrat method and the vegetation and soil-type map area method proposed by our research group. The results indicate that there is no obvious change between the present distribution ranges of the wild R. tanguticum and its historical records, but its population density has changed clearly. The reserve of the wild R. tanguticum has seriously declined in lots of place, even faced the exhaustion in some regions. According to the investigation, the resource reserve of the wild R. tanguticum is no more than 5 000 t, and the cultivated is about 1 607 t. The resource reserve of the wild R. tanguticum is nearly depleted, and this suggests that the wild R. tanguticum should be enrolled in the protection plant list, and the cultivated will become the main resource of Rhubarb in the future. So it is extremely neccessary to collect and protect the germplasm resource of R. tanguticum, establish the germplasm nursery and repository, and conduct breeding research on those bases. PMID- 25039174 TI - [Study on process and principle of lactose grinding modification to decrease hygroscopic of Rhodiolae Crenulatae Radix et Rhizoma extract]. AB - In this paper, Rhodiolae Crenulatae Radix et Rhizoma extract,with high hygroscopic,was selected as research model, while lactose was selected as modifiers to study the effect of the grinding modification method on the hygroscopic. Subsequently, particle size distribution, scannin electron microscopy, infrared spectroscopy and surface properties were adopted for a phase analysis. The results showed that the modified extract, prepared by Rhodiolae Crenulatae Radix et Rhizoma extract grinding 5 min with the same amount of lactose UP2, which hygroscopic initial velocity, acceleration, and critical relative humidity moisture were less than that of Rhodiolae Crenulatae Radix et Rhizoma extract and the mixture dramatically. In addition, compared with the mixture, the size distribution of modified extract was much less, the microstructure was also difference, while the infrared spectroscopy and surface properties were similar with that of lactose. It is the main principle that lactose particle adhered to the surface of Rhodiolae Crenulatae Radix et Rhizoma extract after grinding mofication to decress the moisture obviously. PMID- 25039176 TI - [Evaluation of drug release behavior in vitro of ginkgolides component drug release unit]. AB - Traditional Chinese medicine (TCM) composition is a multi-component multiple drug release system and more components preparation system. How to evaluate the drug release behavior of diversification has been a block for the modernization of TCM. This article through to study of more representative components of ginkgolides drug release and similarity analysis of more representative components of ginkgolides drug release behavior and use Weight coefficient method to integrate the multicomponent drug release curve. So it can provide the idea and method for drug evaluation of TCM component preparation. PMID- 25039175 TI - [Influence of reverse osmosis concentrate on physicochemical parameters of Sini decoction material system and their relevance]. AB - OBJECTIVE: By studying the process of reverse osmosis system for traditional Chinese medicine materials physicochemical parameters affecting the osmotic pressure of its relevance, new compound system reverse osmosis process design methods were explored. METHOD: Three concentrations materials for high, middle and low were dubbed with Sini decoction as a model drug, and pretreated by 50 thousand relative molecular weight cut-off ultrafiltration membrane. The viscosity, turbidity, conductivity, salinity, TDS, pH value and osmotic pressure of each sample were determined after the reverse osmosis to study the physical and chemical parameters between their respective correlations with the osmotic pressure, and characterized by HPLC chromatograms showing changes before and after the main chemical composition of samples of reverse osmosis. RESULT: Conductivity-osmotic pressure, salinity-osmotic pressure of the linear correlation coefficient, TDS-osmotic pressure between the three sets of parameters were 0.963 8, 0.932 7, 0.973 7, respectively. Reverse osmosis concentrate and its characteristic spectrum ultrafiltrate HPLC similarity were up to 0. 968 or more, except the low concentrations. CONCLUSION: There is a significant correlation between the three physicochemical parameters (conductivity, salinity, TDS) and osmotic pressure of each sample system, and there is also significant linear correlation between salinity, conductivity, TDS. The original chemical composition of Sini decoction material concentrate was completely remained after the process of reverse osmosis. PMID- 25039177 TI - [Influence of particle sizes and content of effective compositions of Panax notoginseng powders crashing by superfine somminution technique]. AB - In this study, superfine comminution technique was applied to destroy the cell wall of the Panax notoginseng, and then the influence of the particle sizes and the content of effective composition of the P. notoginseng powders were learned, comparing with the common powders. Superfine comminution technique was used for 0.5, 1, 1.5, 2 h, respectively and the particle sizes, unifirmity were regarded as the evaluation index. Then, the sizes of the powders was measured that were crashed with different time by Malvern Mastersizer 2000 + Scricco 2000 and the total content of ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 in the superfine powder of P. notoginseng were determined by HPLC-ELSD. Finally, the powder that crashed for two hours possess the more uniform in sizes that is at cell level, D50 is about 9.599 microm, the size distribution was presented as one peak, the other three samples were two peaks. The total content of the three saponins in the four samples that crashed for 0.5, 1, 1.5, 2 h by superfine comminution technique were 7.7%, 7.5%, 7.5%, 8.3%. However, the total content of the three ingredients in the common powder was 5.0%. This investigation indicated that superfine comminution technique has remarkable effect on particle size and uniformity of the common powder of P. notoginseng. By comparing the superfine powder and common powder, it was found that the method obviously improved the total content of the saponins and provided a basis for reducing dosage of notoginseng in clinical application, but the content and the crashed time were not the linear relationship. The crashed time can be chosen by combining with the demand partical sizes in the production. PMID- 25039178 TI - [Fermentation transformed ginsenoside by Lactobacillus plantarum]. AB - OBJECTIVE: To explore ginseng fermentation process by Lactobacillus plantarum, and to make part of total saponins transformed into more reactive ginsenoside Rd. METHOD: Microbial fermentation was carried out by still dark culture. Total saponins were extracted by Soxhlet extraction, and determined by UV visible spectrophotometry with colours reaction by vanillin-sulfuric acid. Ginsenoside Rd was determined by HPLC method. RESULT: The fermentation process was: MRS medium, 35 degrees C, pH 5.0, cultured for 2 days. The content of total saponins was inhance 32%, and the content of ginsenoside Rd was increased 4.864 mg x g(-1). CONCLUSION: The fermentation system's process was reasonable, and it's suitable for mass production, important significance for ginsenoside microbial transformation. PMID- 25039179 TI - [A new chromone glycoside from roots of Polygonum multiflorum]. AB - Several kinds of column chromatography methods were used to investigate the chemical constituents of roots of Polygonum multiflorum. The structures of the isolated compounds were identified based on their physicochemical properties, spectral data and chemical methods. A new chromone glycoside was isolated and its structure was identified as (S)-2-(2'-hydroxypropyl)-5-methyl7-hydroxychromone-7 0-alpha-L-fucopyranosyl (1-->2)-beta-D-glucopyranoside (1). PMID- 25039180 TI - [Chemical constituents of leaf of Eucommia ulmoides]. AB - Ten compounds were isolated from the leaf of Eucommia ulmoides by means of recrystallization and chromatographic techniques such as D-101 macroporous resin, MCI resin, ODS gel, Sephadex LH-20 and Rp-HPLC. Their structures were identified by NMR spectral analyses as kaempferide 3-O-beta-D-glucoside (1), quercetin-3-O beta-D-glucoside (2), quercetin (3), quercetin-3-O-beta-D-xylosyl-(1-->2)-beta-D galactoside (4), kaempferol-3-O-alpha-L-rhamnosyl-(1-->6)-beta-D-glucoside (5), (2S,3S)-taxifolin 3-O-beta-D-glucoside (6) ,4-hydroxy cinnamic acid (7), (+) cycloolivil (8), pinoresinol beta-D-glucoside (9), squalene (10). Among them compounds 1,5-7,10 were isolated from the Eucommia genus for the first time. In the DPPH free radical scavenging assay, compound 2 exhibited significant activity (IC50 13.7 micromol x L(-1)), compared with vitamin C (IC50 59.9 micromol x L( 1)); compounds 1, 3 and 9 showed moderate activity (IC50 161,137, 214 micromol x L(-1)), compared with 2,6-di-tert-butyl-4-methylphenol (IC50 236 micromol x L( 1)); compound 4 and 6 showed weak activity (IC50 264, 299 micromol x L(-1)). PMID- 25039181 TI - [C21 steroids from roots of Cynanchum otophyllum]. AB - Eleven C21 steroids were isolated from chloroform extract of roots of Cynanchum otophyllumby silica gel, MCI, ODS columns, and semi-preparative HPLC. Their structures were determined by spectroscopic data analysis as otophylloside B(1), caudatin-3-O-beta-D-cymaropyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta D-cymaropyranosyl-(1-->4)-beta-D-cymaropyranoside (2), caudatin-3-O-beta-D oleandropyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-D-cymaropyranosyl (1-->4)-beta-D-cymaropyranoside (3), caudatin-3-O-beta-D-oleandropyranosyl-(1- >4)-beta-D-digitoxopyranosyl-(1-->4)-beta-D-cymaropyranoside (4), otophylloside O (5), gagamine-3-O-beta-D-oleandropyranosyl-(1-->4)-beta-D-cymaropyranosyl-(1-->4) beta-D-cymaropyranoside (6), sinomarinoside B (7), mucronatosides C (8), wallicoside J (9), stephanoside H (10), and qinyangshengenin-3-O-beta-D oleandropyranosyl-(1-->4)-beta-D-cymaropyranosyl-(1-->4)-beta-D digitoxopyranoside (11). Among them, compounds 2-3, and 6-11 were separated from the roots of this plant for the first time. PMID- 25039182 TI - [Chemical quality of Chrysanthemum morifolium cv. 'Hangju' (HJ) induced by sulfur fumigation processing]. AB - Eight compounds from six Chrysanthemum morifolium cv. 'Hangju' were determined and multivariate statistics, including principle component analysis (PCA) and partial least squares discriminate analysis (PLS-DA) were used to investigate the potential damaging effect of sulfr-fumigating process. Meanwhile, S, Mn, Fe, Cu, Pb were also detected by using ICP-MS and ICP-OES. In this study, dramatic chemical changes were found that the contents of flavonoid aglycones remarkably increased while those of glycosides and hydroxycinnamoylquinic acids were significantly reduced. The PCA score plots showed six samples were clearly classified into the non-fumigated and sulfur-fumigated types. And according to VIP > 1, the most important chemical markers were luteolin, apigenin and luteolin 7-O-glucoside which indicated that the extracted three components might have a marked effect on the discrimination among different group samples. And then, it was found that the residue of sulfur of SHJ were significantly higher than NHJ (P < 0.05). The established approach was applied to rapidly discriminate sulfur fumigated HJ with combining the quantitative chemical analysis and multivariate statistical analysis, and then the result will provide some evidence to evaluat the quality of HJ and control its processing. PMID- 25039183 TI - [Determination of amino acids in Galli Gigerii endothelium corneum by HPLC with pre-column derivatization]. AB - Hydrolytic amino acids were extracted by acid hydrolysis method, then derivatized with phenyl isothiocyanate (PITC). And the samples were analysed by HPLC on an Ultimate Prime C18 (4.6 mm x 250 mm, 5 microm) column with gradient elution of 0.1 mol x L(-1) sodium acetate buffer solution (adjusted to pH 6. 5)-acetonitrile (93:7) (A) and acetonitrile-water (8:2) (B) at a flow rate of 1.0 mL x min(-1). Column temperature was 40 degrees C and the detected wavelength was 254 nm. Amino acids derivative solution remained stable in 36 hours. The response was linear for 16 amino acids with a correlation coefficient r > 0.999 5. The average recoveries were 98.01% -101.8%. The method is reliable with good accuracy and repeatability, which is useful for the determination of amino acids in Galli Gigerii Endothelium Corneum. PMID- 25039184 TI - [Effect of tanshinone II(A) on expression of different components in renin angiotensin system of left ventricles of hypertensive rats]. AB - OBJECTIVE: To investigate the effect of tanshinone II(A) on the expression of different components in the renin-angiotensin system of left ventricles of renal hypertensive rats. METHOD: The renal hypertension model was established in rats by the two-kidney-one-clip (2K1C) method. In the experiment, all of the rats were randomly divided into four groups (n = 15 per group) before the operation: the sham-operated (Sham) group, the hypertensive model (Model) group, the low-dose tanshinone II(A) group and the high-dose tanshinone II(A) group. At 5 week after the renal artery narrowing, the third and fourth groups were administered with 35 mg kg(-1) x d(-1) and 70 mg x kg(-1) x d(-1) of tanshinone II(A), respectively. The blood pressure in rats was determined by the standard tail-cuff method in each week after the operation. After the drug treatment for 8 weeks, all the rats were put to death, and their left ventricles were separated to determine the ratio of left ventricle weight to body weight (LVW/BW), the myocardial collagen content, and the expressions of different components in myocardial RAS, including angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), angiotensin 1-type receptor (AT1R), Mas receptor mRNA expression and angiotensin II (Ang II) and angiotensin (1-7) [Ang (1-7)] content. RESULT: Compared with the sham group, the hypertensive model group exhibited a markable increase in the content of Ang II and Ang (1-7) and the mRNA expressions of ACE, ACE2, AT1R and Mas (P < 0.01). However, the treatment with tanshinone II(A) showed the does dependence, inhibited left ventricle hypertrophy, decreased myocardial Ang II content and the mRNA expression of ACE and AT, R in renal hypertensive rats (P < 0. 01) , further increased the myocardial Ang (1-7) content and the mRNA expression of ACE2 and Mas (P < 0.01) , but without any change in the blood pressure of hypertensive rats. CONCLUSION: The treatment with tanshinone II(A) could inhibit left ventricle hypertrophy of renal hypertensive rats. Its mechanism may be partially related to the expression of different components in the renin-angiotensin system for regulating myocardial tissues. PMID- 25039185 TI - [Reverse effect of Yinchenhao decoction in dimethyl nitrosamine-induced hepatic fibrosis in rats]. AB - OBJECTIVE: To discuss the reverse effect of Yinchenhao decoction(YCHD) in dimethyl nitrosamine (DMN)-induced hepatic fibrosis in rats. METHOD: The rat hepatic fibrosis model was established through the intraperitoneal injection with 1% dimethyl nitrosamine (DMN) with a dose of 1.0 mL x kg(-1) x d(-1) for consecutively three weeks, once for the first three days of each. The rats were randomly divided into six groups: the silymarin positive control group (50.0 mg x kg(-1) x d(-1), YCHD high (20.0 g x kg(-1) d(-1)), middle (8.0 g x kg(-1) x d( 1)) and low (3.2 g x kg(-1) x d(-1)) dose groups, the model group and the normal control group. The model group and the normal control group were orally administered with normal saline for consecutively five weeks. The pathologic changes in liver tissues were observed by HE staining. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), g-glutamyltransferase (g-GGT), hyaluronic acid (HA), laminin (LN), collagen type IV (CIV) and type III procollagen amino terminal peptide (PIIINP) in serum were determined. The metabolite profiling of amino acid and the content of hydroxyproline in liver tissues were also measured. RESULT: Compared with the model group, YCHD high and middle dose groups could significantly reverse the pathologic changes in liver tissues of rats. YCHD could reduce the levels of ALT, AST, gamma-GGT, HA, LN, CIV, PIIINP in serum and the content of hydroxyproline in liver tissues in a dose dependent manner, and altered the metabolite profiling of amino acid in rat liver tissues. CONCLUSION: YCHD has the effect in reversing dimethyl nitrosamine induced hepatic fibrosis in rats. PMID- 25039186 TI - [Biochemical regulatory mechanism of asiaticoside in preventing and treating stent restenosis]. AB - OBJECTIVE: To discuss whether asiaticosides could effectively reduce the endothelial cell damage as a biochemical modulator, so as to further inhibit the post-stenting intima-media membrane hyperplasia. METHOD: Human aortic smooth muscle cells and aortic fibroblasts were selected and divided into the blank group, the rapamycin group and the asiaticoside group and the rapamycin and asiaticoside group. The expressions of muscle cells and fibroblasts TGF-beta1, Smad7 and I-collagen gene were determined by RT-PCR. The expression quantity of I collagen protein was assayed by ELISA. The coefficient of drug interaction (CDI) between rapamycin and asiaticoside was calculated. Additionally, 16 Chinese mini swines were randomly divided into group A and group B. One sirolimus drug-eluting stent of the same type was implanted after the high-pressure pre-expansion of anterior descending artery balloon. After the operation, the group A was intravenously injected with normal saline 30 mL x d(-1). Whereas the group B was intravenously injected with asiaticoside 30 mg x kg(-1) x d(-1)(diluted to 30 mL). The expressions of plasma vWF of the two groups were measured at the 7th and 14th days after the operation. At the 28th day after the operation, tissues of the stented vessel segments were sliced and stained to calculate the vessel area, inner stent area, lumen area and neointima area RESULT: Compared with the control group, the combination group showed significant up-regulation in smooth muscle cells and fibroblast Smad7 gene, down-regulation in TGF-beta, and obvious inhibition of I-collagen gene expression (P < 0.01). As for smooth muscle cells, there was no difference in the expression of I-collagen between the combination group and the rapamycin group, with CDI at 0. 83. As for fibroblasts, there was a significant difference in the expression of I-collagen between the combination group and the rapamycin group (P < 0.05), with CDI at 0.77. Plasma vWF of the group B was significantly lower than that of the group A (P < 0.05) at the 7th and 14th days after the operation. At the 28th day after the operation, no difference was observed in vessel area and stent area between the two groups. However, the lumen area in the group B was significantly larger than that of the group A(P < 0.05), and the neointima area of the group B was significantly smaller than that of the group A (P < 0.05). CONCLUSION: As an effective biochemical modulator for rapamycin, asiaticosides could inhibit TGF-beta expression, significantly decrease the synthesis and secretion of extracellular matrix, further inhibit the post-stenting intima-media membrane hyperplasia and reduce the endothelial cell damage by effectively up-regulate the expression of Smad7 protein. PMID- 25039187 TI - [Experimental study on inhibitory effect of wogonin on proliferation and invasion of breast cancer cells]. AB - OBJECTIVE: To study the inhibitory effect of wogonin on the growth and proliferation of breast cancer cells MDA-MB-23, and observe its effect on the adhesion, migration and invasion of MDA-MB-23 cells, in order to further study its molecular mechanism. METHOD: MTT assay was used to detect the effect of wogonin on MDA-MB-23 cell growth. Ki-67 assay was adopted to test the effect of wogonin on cell proliferation. Scratch test, adherence test and invasion chamber assay were taken to detect the effect on the migration and invasion abilities of MDA-MB-231 cells. Proliferation and metastasis-related proteins and relevant signaling pathways were detected by Western blotting. RESULT: Wogonin could remarkably inhibit the growth and proliferation of MDA-MB-231 cells, significantly inhibit migration, adhesion and invasion abilities of breast cancer cells at a low concentration, and effectively inhibit the expression of Survivin, Bcl-2, ICAM-1, MMP-2, MMP-9 proteins of MDA-MB-231 cells. CONCLUSION: Wogonin could notably inhibit growth and proliferation of breast cancer cells, and inhibit migration, adhesion and invasion of MDA-MB-231 cells. Its invasive and adhesive effects on MDA-MB-231 cells may be related to the decrease in ICAM-1, MMP-2, MMP-9 expressions. PMID- 25039188 TI - [Preliminary study on pharmacodynamic evaluation method of Houpo formula particles]. AB - To discuss the feasibility of the pharmacodynamic evaluation method for traditional Chinese medicine (TCM) formula particles, with traditional decoction for reference and the intervention of Magnoliae Officinalis Cortex in rats with ulcerative colitis (UC). First of all, the similarity of traditional Magnoliae Officinalis Cortex decoction and formula particles of different manufacturers was defined by using the IR fingerprint. The UC rat model was established and given Houpo formula particles of different doses and manufacturers, with the decoction for reference, in order to observe disease activity index (DAI), colon mucosa damage index (CMDI), pathologic changes, nitric oxide (NO), endothdin (ET), substance P, vasoactive intestinal peptide (VIP). Their intervention effects on UC rats were compared to study the difference between Sanjiu and Tianjiang Houpo formula particles, in order to demonstrate the feasibility of the pharmacodynamic evaluation method for Houpo formula particles. According to the results, Houpo formula particles showed similar pharmacodynamic actions with the traditional decoction. The pharmacodynamic comparison of Houpo formula particles of different manufacturers showed no statistical significance. The experiment showed that on the basis of the TCM compounds, a prescription dismantlement study was conducted to define target points of various drugs. The traditional decoction was selected for reference in the comparison of corresponding formula particles for their pharmacodynamic equivalence. This method could avoid controversies about single or combined boiling of formula particles, and give objective comments on the pharmacodynamic effect of the formula particles. The method is proved to be feasible. PMID- 25039189 TI - [Effect of curcumin in inducing apoptosis of MDA-MB-213 cells by activating endoplasmic reticulum stress]. AB - OBJECTIVE: To explore the possible mechanism of curcumin in inducing the apoptosis of breast cancer cell MDA-MB-231. METHOD: Curcumin of different concentrations at 0, 10 25, 50, 100, 150, 200 micromol x L(-1) were used to intervene breast cancer cells MDA-MB-231 for 24 hours. MTT was used to observe its effect on the proliferation of breast cancer cells. The flow cytometry was used to detect its effect on the cell apoptosis. The real-time quantitative PCR and Western blot was used to assess the expression levels of GRP78 and CHOP in breast cancer cells. RESULT: Curcumin could inhibit the proliferative ability of breast cancer cells by inducing them in a concentration-dependent manner. Curcumin could significantly increase the expression levels of GRP78 and CHOP in breast cancer cells. CONCLUSION: Curcumin could induce the apoptosis of breast cancer cells MDA-MB-231 by activating endoplasmic reticulum stress. PMID- 25039190 TI - [Experimental study on anti-tumor effect of xihuang pill and its immune clearance function]. AB - OBJECTIVE: To discuss the anti-tumor effect of Xihuang pill on tumor-bearing rats and its effect on the immune clearance function of tumor-bearing organisms. METHOD: Walker256 tumor cells were adopted to establish the tumor-bearing rat model. The rats were randomly divided into five groups: the normal control group, the model control group, the lentinan group and Xihuang pill low dose, middle dose and high dose groups, with 10 rats in each group, and continuously treated and given drugs for 14 d after modeling. Blood and tumors were collected from abdominal aorta to calculate the tumor inhibition rate. The content of CD3+, CD4+, CD8+ T cells and adhesion molecule B7-1 (CD80) in peripheral blood were detected by flow cytometry (FCM). The expressions of IL-2 and IFN-gamma in were determined by ELISA. RESULT: The tumor inhibition rate of the Xihuang pill high dose group was 33. 1 percent. Compared with the model group, the Xihuang pill large dose group showed significantly low IL-2, IFN-gamma, CD3+, CD4+, B7-1 in peripheral blood, with statistical significance in their differences (P < 0.05). CONCLUSION: Xihuang pill could show its anti-tumor effect by enhancing the immune clearance function and increasing IL-2, IFN-gamma, CD3+ T, CD4+ T, B7-1 in peripheral blood. PMID- 25039192 TI - [Research on volatile components of gualou guizhi decoction and its components in rat brain by GC-MS]. AB - To investigate the role of volatile components in the compound and to find the substance foundation of Gualou Guizhi decoction (GLGZD) for curing extremities spasticity after stroke. The chemical compositions of essential oil, obtained by hydrodistillation from Gualou Guizhi decoction and its major constituting herbs (Trichosanthis Radix, Paeoniae Alba Radix, Cinnamomi Ramulus, Zingiberis Recens Rhizoma, Glycyrrhizae Radix, Ziziphi Jujubae Fructus) were analyzed by GC-MS to evaluate the correlativity between volatile components of GLGZD and its major constituting herbs, and volatile components after oral administration of GLGZD in the rats' brain. Volatile components of GLGZD are mainly derived from Cinnamomi Ramulus, Zingiberis Recens Rhizoma, Ziziphi Jujubae Fructus, Trichosanthis Radix. The volatile components in the brain is mostly derived from radix trichosanthis. Compared with individual herbs of GLGZD, the dissolution of the components increase or new components appear after compatibility of six herbs. Adminstrated with GLGZD, the results point out that volatile components in the brain play a neuroprotective role through passing the brain. PMID- 25039191 TI - [Studies on effects of Achyranthes bidentata on tongsaimai pellets main active ingredients chlorogenic acid, isoliquiritin, harpagoside and glycyrrhizin in vivo pharmacokinetics]. AB - To study on the effects of Achyranthes bidentata on Tongsaimai pellets main active ingredients chlorogenic acid, isoliquiritin, harpagoside and glycyrrhizin in rats in vivo pharmacokinetic behaviors, a method for the simultaneous determination of chlorogenic acid, isoliquiritin, harpagoside and liquiritigenin in rat plasma was established by UPLC-MS/MS. The analysis was performed on a waters Acquity BEH C18 column (2.1 mm x 100 mm, 1.7 microm) with the mixture of acetonitrile and 0.1% formic acid/water as mobile phase, and the gradient elution at a flow rate of 0.3 mL x min(-1). The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source and in the multiple reaction monitoring (MRM) mode. It turned out that the analytes of Tongsaimai pellets groups C(max) and AUC(Q-infinity) values were higher than that with A. bidentata group, and the C(max) values of chlorogenic acid had significantly difference (P < 0.05), the AUC(0-infinity) values of chlorogenic acid and glycyrrhizin had significantly difference (P < 0.05); The T(max) and CL values of two groups had no significantly difference. Results showed that the established method was specific, rapid, accurate and sensitive for the studies of Tongsaimai pellets four main active ingredients in rat in vivo pharmacokinetic, and A. bidentata have varying degrees of effects on Tongsaimai pellets four main active ingredients in rat in vivo pharmacokinetic behaviors. PMID- 25039193 TI - [Preliminary research on multi-neurotransmitters' change regulation in 120 depression patients' brains]. AB - In view of the effective traditional Chinese medicine (TCM) in the treatment of clinical depression, the mechanism is not clear, this study attempts to research the cause of depression in a complex situation to lay the foundation for the next step of TCM curative effect evaluation. Based on the brain wave of 120 depression patients and 40 ordinary person, the change regulation of acetylcholine, dopamine, norepinephrine, depression neurotransmitters and excited neurotransmitters in the whole and various encephalic regions' multi neurotransmitters of depression patients-serotonin are analysed by search of encephalo-telex (SET) system, which lays the foundation for the diagnosis of depression. The result showed that: contrased with the normal person group, the mean value of the six neurotransmitters in depression patients group are: (1) in the whole encephalic region of depression patients group the dopamine fall (P < 0.05), and in the double centralregions, right temporal region and right parietal region distinct fall (P < 0.01); (2) in the right temporal region of depression patients group the serotonin rise (P < 0.05); (3) in the right central region, left parietal region of depression patients group the acetylcholine fall (P < 0.05), left rear temporal region fall obviously (P < 0.01). The correlation research between antagonizing pairs of neurotransmitters and neurotransmitters: (1) the three antagonizing pairs of neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression neurotransmitters and excited neurotransmitters, in ordinary person group and depression patients group are characterizeed by middle or strong negative correlation. Serotonin and dopamine, which are characterized by weak negative correlation in the right rear temporal region of ordinary person group, are characterized by strong negative correlation in the other encephalic regions and the whole encephalic (ordinary person group except the right rear temporal region: the range of [r] is [0.82, 0.92], P < 0.01)/(depression patients group:the range of [r] is [0.88, 0.94], P < 0.01); acetylcholine and norepinephrine, in the whole and various encephalic region are characterized by middle negative correlation(ordinary person group:the range of [r] is [0.39, 0.76], P < 0.01 or P < 0.05)/(depression patients group: the range of [Ir] is [0.56, 0.64], P < 0.01); depression neurotransmitters and excited neurotransmitters are characterized by middle strong negative correlation (ordinary person group: the range of [r] is [0.57, 0.80], P < 0.01)/(depression patients group: the range of [r] is [0.68, 0.78], P < 0.01). (2) The two neurotransmitters which are not antagonizing pairs of neurotransmitters, serotonin and excited neurotransmitters, or acetylcholine and depression neurotra nsmitters, or dopamine and depression neurotransmitters in the various encephalic regions are characterized by weak negative correlation. Serotonin and excited neurotransmitters are characterizeed by weak negative correlation (ordinary person group: in the right central region, left parietal region, double front temporal regions, right rear temporal region, the range of [r] is [0.25, 0.50], P < 0.01 or P < 0.05)/(depression patients group: in the whole encephalic regions, double parietal regions, double occipital regions, right front temporal region, left central region, left frontal region, the range of [r] is [0.18, 0.37], P < 0.01 or P < 0.05); acetylcholine and depression, neurotransmitters are characterized by weak negative correlation (ordinary person group: in the double frontal regions, left parietal region, left front temporal region, right rear temporal region, the range of [r] is [0.31, 0.46], P < 0.01 or P < 0.05)/(depression patients group: in double rear temporal regions, right front temporal region, double occipital regions, left central region, the range of [r] is [0.20, 0.32] , P < 0.01 or P < 0.05); do-pamine and depression neurotransmitters are characterized by weak middle negative correlation (ordinary person group: in left parietal region, right central region, left frontal region, left occipital region, double front temporal regions, the range of [r] is [0.33, 0.68], P < 0.01 or P < 0.05)/(depression patients group: in the whole region and other various regions except the left frontal region, right central region, the range of Irl is [0.21, 0.34], P < 0.01 or P < 0.05). Dopamine and acetylcholine or norepinephrine and serotonin are characterized by weak positive correlation in all encephalic regions. Dopamine and acetylcholine are characterized by weak positive correlation (ordinary person group: in left frontal region, right parietal region, left front temporal region and left rear temporal region, the range of [r] is [0.37, 0.46], P < 0.01)/(depression patients group: in the whole region and the orther various regions except the double central regions, the range of [r] is [0.23, 0.5], P < 0.01 or P < 0.05); norepinephrine and serotonin are characterized by weak positive correlation (ordinary person group: in double front temporal regions, double rear temporal regions, right frontal region and left parietal region, the range of [r] is [0.34, 0.48], P < 0.01 or P < 0.05)/(depression patients group: in the whole and various regions, the range of [r] is [0.18, 0.42], P < 0.01). The main differences between the depression patients group and ordinary person group are: (1) In the whole regin, left frontal region and right central region of depression patients group, the six neurotransmitters all fall normally (P < 0.05). (2) The percent of dopamine falling or including dopamine falling, or including dopamine falling and serotonin rising in depression patients group increases. The percent of dopamine falling or including dopamine falling in the whole region, right frontal region, right central region increases (P < 0.01), such as dopamine decreasing, serotonin increasing dopamine decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing, dopamine decreasing norepinephrine increasing depression neurotransmitters decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing neurotransmitters increasing and so on. (3) The percent of acetylcholine falling, or including acetylcholine falling, or including acetylcholine falling and neurotransmitters (beta)-receptor)rising in depression patients group increases. The percent of acetylcholine falling, or including acetylcholine falling in the right temporal region, double central regions increases (P < 0.05 or P < 0.01), such as acetylcholine decreasing, acetylcholine decreasing neurotransmitters increaseng, acetylcholine decreasing neurotransmitters increasing depression neurotransmitters decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing neurotransmitters increasing and so on. It's showed in research that depression patients' brain are characterized by multi-neurotransmitters abnormal, the synchronous change of multi-neurotransmitters has some certain regularities, which are not the simple linear relation. It's conformed that the three antagonizing pairs, neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression eurotransmitters and excited neurotransmitters of ordinary person group and depression patients group, are both characterized by strong antagonizing relation, that the two neurotransmitters which are not antagonizing pairs of neurotransmitters are characterized by weak positive correlation or negative correlation, prompt maybe has the indirect causal relationship. And the change of six neurotransmitters in depression patients' various encephalic regions is rather complex. It's conformed preliminarily that the right frontal region and right central region are characterized by dopamine decreasing, acetylcholine decreasing, serotonin increasing dopamine decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing, dopamine decreasing norepinephrine increasing excited neurotransmitters decreasing, serotonin increasing acetylcholine decreasing dopamine decreasing neurotransmitters increasing, acetylchoine decreasing neurotransmitters increasing, acetylcholine decreasing neurotransmitters increasing excited neurotransmitters decreasing and so on. Contrasted with the ordinary person group, the depression patients group have the notable difference. PMID- 25039194 TI - [Original plant identification of Dai nationality herb "Daibaijie"]. AB - OBJECTIVE: To identify the original plant of "Daibaijie", commonly used Dai herb. METHOD: The literature review, morphology and anatomy, pharmacognosy, molecular biology, chemistry were used to analysis. RESULT: Daibaijie's historical scientific name, Dregea sinensis Hemsl., was mistakenly given "Daibaijie" and D. sinensis have significant differences from the distribution, morphology and anatomy, pharmacognosy, molecular biology and chemical composition. "Daibaijie" matches with the characteristics of Marsdenia tenacissima (Roxb.) Moon in Flora of China in English. CONCLUSION: Daibaijie's original plant is M. tenacissima (Roxb.) Moon. The description and illustration of M. tenacissima (Roxb.) Moon in Flora of China in China are wrong. The illustration of M. tenacissima in Flora of China in English is wrong too. PMID- 25039195 TI - [Briefly analysis on academic origins of traditional Chinese medicine dispensing]. AB - Through collecting and collating the development process of traditional Chinese medicine dispensing, the development of modern Chinese medicine dispensing on the basis of experience could be promoted. "Heyaofenji", "Hehe", " Heji" in ancient Chinese medicine, herbal medicine literature and law were collected, and then things were sorted out according to traditional Chinese medicine dispensing theory, skills and legal norms. Firstly, "Tang Ye Jing Fa" is the earliest book which marks the rudiment of traditional Chinese medicine dispensing. Secondly, traditional Chinese medicine dispensing theory formed in "Shen Nong's herbal classic". Thirdly, Zhang Zhongjing's "Treatise on Febrile Diseases" marked the formation of Chinese medicine dispensing skills. Lastly, Provisions in Tang Dynasty law marks the development of traditional Chinese medicine dispensing. PMID- 25039196 TI - [Special impact of supramolecular chemistry on Chinese medicine theories]. AB - The paper aimed to elucidate the specific impact of supramolecular chemistry on the Chinese medicine theories (CMT) in their modernization, after had summarized up the research status of supramolecular chemistry and analyzed the possible supramolecular forms of Chinese medicine (CM), as well as considered the problems in modernization of CM theories. On comparison of the classical chemistry that delt with chemical bonds among atoms, the supramolecular chemistry was rather concerned with varietes of weak noncovalent bonds intermolecules, and reflected the macro-apparent chemical properties of each molecules, and was the most appropriate chemical theories to explain the CMT and microcosmic materials. The molecules in the human body and Chinese material medica (CMM) formed supramolecules by way of self-assembly, self-organization, self-recognition and self-replication, with themselves or with complexation, composition, chelation, inclusion, neutralization etc. Meridian and Zang-fu viscera in CMT might be a space channel structure continuously consisted of unique molecules cavity that was imprinted with the supramolecularly template inside and outside of cells, through which the molecules in CMM interacted with the meridian and Zang-fu viscera. When small molecules in human body imprinted with macromolecules in meridian and Zang-fu viscera, in other words, they migrated along within imprinting channels of meridian and Zang-fu viscera on behavior of "Qi chromatography" impulsed by the heart beat, finally showed up on macroscopic the anisotropy of tissue and organ, as described namely as visceral manifestation in Chinese medical science. When small molecules in CMM interacted with imprinting channel on meridian and Zang-fu viscera, the natural properties and efficacy regularities of CMM was reflected on macroscopic. Therefore, the special representation forms of basic CMT is based on the macroscopic expression of "Qi chromatography" abided by imprinting effect regularities, and on whether the imprinted template of small molecules matched with cavity template of macromolecules in meridian and Zang-fu viscera, only is the adequate representation of supramolecular chemistry for them. The CMM materials is the mixture including single molecules and supramolecules. The compatibility for CM prescriptions can significantly change the function rules. Therefore in the study of basic CMT, we should pay special attention to the laws of supramolecular chemistry. It is the most essential differences of the CMT from the modern medicine which established by the laws of single molecular theories. PMID- 25039197 TI - [Anti-arrhythmic research situation and thinking of traditional Chinese medicine monomer]. AB - The basic physiological function of anti-arrhythmic drugs is affects myocardial cell membrane ion channels. Change the ion flow and affect cell electrophysiological properties, change the conduction velocity, eliminate retrace, inhibit autorhythmicity and trigger events, inhibit the occurrence of arrhythmia, but will trigger a new activities, new retrace, produce new arrhythmia. In recent years, with the improvement of the theoretical system of traditional Chinese medicine and the production of new research methods, Chinese medicine treatment of arrhythmia has a new development. This article summarized the recent decades of which Chinese medicine monomer anti-arrhythmic drugs that had been proved by the influence of monomer anti-arrhythmic drugs, lists the differents traditional Chinese medicinal materials which chemical composition and the effective of the anti-arrhythmic effects, shows the unique advantages of Chinese medicine in the aspect of anti-arrhythmic, and points out that the current Chinese medicine in anti-arrhythmic (monomer) existing problems and solutions. PMID- 25039198 TI - Public health and components of particulate matter: the changing assessment of black carbon. PMID- 25039199 TI - Public health and components of particulate matter: the changing assessment of black carbon. AB - In 2012, the WHO classified diesel emissions as carcinogenic, and its European branch suggested creating a public health standard for airborne black carbon (BC). In 2011, EU researchers found that life expectancy could be extended four to nine times by reducing a unit of BC, vs reducing a unit of PM2.5. Only recently could such determinations be made. Steady improvements in research methodologies now enable such judgments. In this Critical Review, we survey epidemiological and toxicological literature regarding carbonaceous combustion emissions, as research methodologies improved over time. Initially, we focus on studies of BC, diesel, and traffic emissions in the Western countries (where daily urban BC emissions are mainly from diesels). We examine effects of other carbonaceous emissions, e.g., residential burning of biomass and coal without controls, mainly in developing countries. Throughout the 1990s, air pollution epidemiology studies rarely included species not routinely monitored. As additional PM2.5. chemical species, including carbonaceous species, became more widely available after 1999, they were gradually included in epidemiological studies. Pollutant species concentrations which more accurately reflected subject exposure also improved models. Natural "interventions"--reductions in emissions concurrent with fuel changes or increased combustion efficiency; introduction of ventilation in highway tunnels; implementation of electronic toll payment systems -demonstrated health benefits of reducing specific carbon emissions. Toxicology studies provided plausible biological mechanisms by which different PM species, e.g, carbonaceous species, may cause harm, aiding interpretation of epidemiological studies. Our review finds that BC from various sources appears to be causally involved in all-cause, lung cancer and cardiovascular mortality, morbidity, and perhaps adverse birth and nervous system effects. We recommend that the US. EPA rubric for judging possible causality of PM25. mass concentrations, be used to assess which PM2.5. species are most harmful to public health. IMPLICATIONS: Black carbon (BC) and correlated co-emissions appear causally related with all-cause, cardiovascular, and lung cancer mortality, and perhaps with adverse birth outcomes and central nervous system effects. Such findings are recent, since widespread monitoring for BC is also recent. Helpful epidemiological advances (using many health relevant PM2.5 species in models; using better measurements of subject exposure) have also occurred. "Natural intervention" studies also demonstrate harm from partly combusted carbonaceous emissions. Toxicology studies consistently find biological mechanisms explaining how such emissions can cause these adverse outcomes. A consistent mechanism for judging causality for different PM2.5 species is suggested. PMID- 25039200 TI - Nonvolatile, semivolatile, or volatile: redefining volatile for volatile organic compounds. AB - Although widely used in air quality regulatory frameworks, the term "volatile organic compound" (VOC) is poorly defined. Numerous standardized tests are currently used in regulations to determine VOC content (and thus volatility), but in many cases the tests do not agree with each other, nor do they always accurately represent actual evaporation rates under ambient conditions. The parameters (time, temperature, reference material, column polarity, etc.) used in the definitions and the associated test methods were created without a significant evaluation of volatilization characteristics in real world settings. Not only do these differences lead to varying VOC content results, but occasionally they conflict with one another. An ambient evaporation study of selected compounds and a few formulated products was conducted and the results were compared to several current VOC test methodologies: SCAQMD Method 313 (M313), ASTM Standard Test Method E 1868-10 (E1868), and US. EPA Reference Method 24 (M24). The ambient evaporation study showed a definite distinction between nonvolatile, semivolatile, and volatile compounds. Some low vapor pressure (LVP) solvents, currently considered exempt as VOCs by some methods, volatilize at ambient conditions nearly as rapidly as the traditional high-volatility solvents they are meant to replace. Conversely, bio-based and heavy hydrocarbons did not readily volatilize, though they often are calculated as VOCs in some traditional test methods. The study suggests that regulatory standards should be reevaluated to more accurately reflect real-world emission from the use of VOC containing products. IMPLICATIONS: The definition of VOC in current test methods may lead to regulations that exclude otherwise viable alternatives or allow substitutions of chemicals that may limit the environmental benefits sought in the regulation. A study was conducted to examine volatility of several compounds and a few formulated products under several current VOC test methodologies and ambient evaporation. This paper provides ample evidence to warrant a reevaluation of regulatory standards and provides a framework for progressive developments based on reasonable and scientifically justifiable definitions of VOCs. PMID- 25039201 TI - Laboratory testing of a continuous emissions monitor for hydrochloric acid. AB - Continuous monitoring of exhaust flue gas has become a common practice in power plants in response to Federal Mercury and Air Toxics Standards (MATS) standards. Under the current rules, hydrochloric acid (HCl) is not continuously measured at most plants; however, MATS standards have been proposed for HCl, and tunable diode laser (TDL) absorption spectroscopy is one method that can be used to measure HCl continuously. The focus of this work is on the evaluation and verification of the operation performance of an HCL TDL over a range of real world operating environments. The testing was conducted at the University of California at Riverside (UCR) spectroscopy evaluation laboratory. Laboratory tests were conducted at three separate temperatures, 25 degrees C, 100 degrees C, and 200 degrees C, and two distinct moisture levels for the enhanced temperatures, 0%, (2 tests) and 4%, over a concentration range from 0 ppmv to 25 ppmv-m at each of the elevated temperatures. The results showed good instrument accuracy as afunction of changing temperature and moisture. Data analysis showed that the average percentage difference between the ammonia concentration and the calibration source was 3.33% for varying moisture from 0% to 4% and 2.69%for varying temperature from 25 to 100/200 degrees C. An HCl absorption line of 1.742 microm was selected for by the manufacturer for this instrument. The Hi Tran database indicated that CO2 is probably the only major interferent, although the CO2 absorption is very weak at that wavelength. Interference tests for NO, CO, SO2, NH3, and CO2 for a range of concentrations typical of flue gasses in coal fired power plants did not show any interference with TDL HCl measurements at 1.742 microm. For these interference tests, CO2 was tested at a concentration of 11.9% concentration in N2 for these tests. Average precision over the entire range for all 10 tests is 3.12%. IMPLICATIONS: The focus of this study was.an evaluation of the operation performance of a tunable diode laser (TDL) for the measurement of hydrochloric acid (HCl) over a range of real-world operating environments. The results showed good instrument accuracy as a function of changing temperature from 25 degrees C to 200 degrees C and moisture from 0% to 4%. Such as an instrument could be used for continuous monitoring of exhaust flue gas in power plants once the Federal Mercury and Air Toxics Standards (MATS) standards have been fully implemented. PMID- 25039202 TI - An uncertainty analysis of mean flow velocity measurements used to quantify emissions from stationary sources. AB - Point velocity measurements conducted by traversing a Pitot tube across the cross section of a flow conduit continue to be the standard practice for evaluating the accuracy of continuous flow-monitoring devices. Such velocity traverses were conducted in the exhaust duct of a reduced-scale analog of a stationary source, and mean flow velocity was computed using several common integration techniques. Sources of random and systematic measurement uncertainty were identified and applied in the uncertainty analysis. When applicable, the minimum requirements of the standard test methods were used to estimate measurement uncertainty due to random sources. Estimates of the systematic measurement uncertainty due to discretized measurements of the asymmetric flow field were determined by simulating point velocity traverse measurements in a flow distribution generated using computational fluid dynamics. For the evaluated flow system, estimates of relative expanded uncertainty for the mean flow velocity ranged from +/- 1.4% to +/- 9.3% and depended on the number of measurement locations and the method of integration. IMPLICATIONS: Accurate flow measurements in smokestacks are critical for quantifying the levels of greenhouse gas emissions from fossil-fuel-burning power plants, the largest emitters of carbon dioxide. A systematic uncertainty analysis is necessary to evaluate the accuracy of these measurements. This study demonstrates such an analysis and its application to identify specific measurement components and procedures needing focused attention to improve the accuracy of mean flow velocity measurements in smokestacks. PMID- 25039203 TI - Effect of low-density polyethylene on smoke emissions from burning of simulated debris piles. AB - Low-density polyethylene (LDPE) plastic is used to keep piled debris from silvicultural activities--activities associated with development and care of forests--dry to enable efficient disposal by burning. The effects of inclusion of LDPE in this manner on smoke emissions are not well known. In a combustion laboratory experiment, 2-kg mixtures of LDPE and manzanita (Arctostaphylos sp.) wood containing 0, 0.25, and 2.5% LDPE by mass were burned. Gaseous and particulate emissions were sampled in real time during the entire flaming, mixed combustion phase--when the flaming and smoldering phases are present at the same time--and during a portion of the smoldering phase. Analysis of variance was used to test significance of modified combustion efficiency (MCE)--the ratio of concentrations of fire-integrated excess CO2 to CO2 plus CO--and LDPE content on measured individual compounds. MCE ranged between 0.983 and 0.993, indicating that combustion was primarily flaming; MCE was seldom significant as a covariate. Of the 195 compounds identified in the smoke emissions, only the emission factor (EF) of 3M-octane showed an increase with increasing LDPE content. Inclusion of LDPE had an effect on EFs of pyrene and fluoranthene, but no statistical evidence of a linear trend was found. Particulate emission factors showed a marginally significant linear relationship with MCE (0.05 < P-value < 0.10). Based on the results of the current and previous studies and literature reviews, the inclusion of small mass proportions of LDPE in piled silvicultural debris does not appear to change the emissions produced when low-moisture-content wood is burned. In general, combustion of wet piles results in lower MCEs and consequently higher levels of emissions. IMPLICATIONS: Current air quality regulations permit the use of burning to dispose of silvicultural piles; however, inclusion of low-density polyethyelene (LDPE) plastic in silvicultural piles can result in a designation of the pile as waste. Waste burning is not permitted in many areas, and there is also concern that inclusion of LDPE leads to toxic air emissions. PMID- 25039204 TI - An integrated simulation and optimization approach for managing human health risks of atmospheric pollutants by coal-fired power plants. AB - This research developed a simulation-aided nonlinear programming model (SNPM). This model incorporated the consideration of pollutant dispersion modeling, and the management of coal blending and the related human health risks within a general modeling framework In SNPM, the simulation effort (i.e., California puff [CALPUFF]) was used to forecast the fate of air pollutants for quantifying the health risk under various conditions, while the optimization studies were to identify the optimal coal blending strategies from a number of alternatives. To solve the model, a surrogate-based indirect search approach was proposed, where the support vector regression (SVR) was used to create a set of easy-to-use and rapid-response surrogates for identifying the function relationships between coal blending operating conditions and health risks. Through replacing the CALPUFF and the corresponding hazard quotient equation with the surrogates, the computation efficiency could be improved. The developed SNPM was applied to minimize the human health risk associated with air pollutants discharged from Gaojing and Shijingshan power plants in the west of Beijing. Solution results indicated that it could be used for reducing the health risk of the public in the vicinity of the two power plants, identifying desired coal blending strategies for decision makers, and considering a proper balance between coal purchase cost and human health risk. IMPLICATIONS: A simulation-aided nonlinear programming model (SNPM) is developed. It integrates the advantages of CALPUFF and nonlinear programming model. To solve the model, a surrogate-based indirect search approach based on the combination of support vector regression and genetic algorithm is proposed. SNPM is applied to reduce the health risk caused by air pollutants discharged from Gaojing and Shijingshan power plants in the west of Beijing. Solution results indicate that it is useful for generating coal blending schemes, reducing the health risk of the public, reflecting the trade-offbetween coal purchase cost and health risk. PMID- 25039205 TI - A multi-objective assessment of an air quality monitoring network using environmental, economic, and social indicators and GIS-based models. AB - In the United States, air pollution is primarily measured by Air Quality Monitoring Networks (AQMN). These AQMNs have multiple objectives, including characterizing pollution patterns, protecting the public health, and determining compliance with air quality standards. In 2006, the U.S. Environmental Protection Agency issued a directive that air pollution agencies assess the performance of their AQMNs. Although various methods to design and assess AQMNs exist, here we demonstrate a geographic information system (GIS)-based approach that combines environmental, economic, and social indicators through the assessment of the ozone (O3) and particulate matter (PM10) networks in Maricopa County, Arizona. The assessment was conducted in three phases: (1) to evaluate the performance of the existing networks, (2) to identify areas that would benefit from the addition of new monitoring stations, and (3) to recommend changes to the AQMN. A comprehensive set of indicators was created for evaluating differing aspects of the AQMNs' objectives, and weights were applied to emphasize important indicators. Indicators were also classified according to their sustainable development goal. Our results showed that O3 was well represented in the county with some redundancy in terms of the urban monitors. The addition of weights to the indicators only had a minimal effect on the results. For O3, urban monitors had greater social scores, while rural monitors had greater environmental scores. The results did not suggest a need for adding more O3 monitoring sites. For PM10, clustered urban monitors were redundant, and weights also had a minimal effect on the results. The clustered urban monitors had overall low scores; sites near point sources had high environmental scores. Several areas were identified as needing additional PM10 monitors. This study demonstrates the usefulness of a multi-indicator approach to assess AQMNs. Network managers and planners may use this method to assess the performance of air quality monitoring networks in urban regions. IMPLICATIONS: The U.S. Environmental Protection Agency issued a directive in 2006 that air pollution agencies assess the performance of their AQMNs; as a result, we developed a GIS-based, multi-objective assessment approach that integrates environmental, economic, and social indicators, and demonstrates its use through assessing the O3 and PM10 monitoring networks in the Phoenix metropolitan area. We exhibit a method of assessing network performance and identifying areas that would benefit from new monitoring stations; also, we demonstrate the effect of adding weights to the indicators. Our study shows that using a multi-indicator approach gave detailed assessment results for the Phoenix AQMN. PMID- 25039206 TI - Study on particulates and volatile organic compounds removal with TiO2 nonwoven filter prepared by electrospinning. AB - In this study, polyvinyl alcohol (PVA) and titania (TiO2) Degussa P-25 were mixed to generate TiO2 nonwoven filters using electrospinning. The wires of titanium dioxide and the nonwoven binding titania nanofibers were formed using 14 kV voltage and a distance of 15 cm. A single-factor experimental method was used to investigate the effects of parameters such as initial concentration, retention time, and light source on acetone removal by nonwoven binding titania nanofibers. Furthermore, the effects of parameters such as gas pressure, particle size, initial concentration, and retention time on the removal of particulates were also assessed. The results showed that the degradation efficiency increased with decreasing initial concentrations and increasing retention time. The best operational conditions during this study for the removal of acetone using the TiO2 nonwoven filters were a retention time of 100 sec, initial acetone concentration of 250 ppm, and ultraviolet (UV) light source of 254 nm. Under those conditions, 99% acetone removal efficiency was obtained. In addition, 90% particulate matter removal efficiency was reached when the particulate size was greater than 200 nm and the reaction time was longer than 5 minutes. The prepared TiO2/nanofiber has good performance for volatile organic compounds (VOCs) and particulate removal at the same time. IMPLICATIONS: In this study, polyvinyl alcohol (PVA) and titania (TiO2) Degussa P-25 were mixed to generate TiO2 nonwoven filters using electrospinning. The results showed that the optimum operating conditions for the removal of acetone using the TiO2 nonwoven filters were a retention time of 100 sec, initial acetone concentration of 250 ppm, and UV light source of 254 nm. Under those conditions, 99% acetone removal efficiency was obtained. PMID- 25039207 TI - Extreme stresses, niches, and positive species interactions along stress gradients. AB - Since proposed two decades ago, the stress-gradient hypothesis (SGH), suggesting that species interactions shift from competition to facilitation with stress, has been widely examined. Despite broad support across species and ecosystems, ecologists debate whether the SGH applies to extreme environments, arguing that species interactions switch to competition or collapse under extreme stress. We show that facilitation often expands distributions on species borders. SGH exceptions occur when weak stress gradients or stresses outside of species' niches are examined, multiple stresses co-occur canceling out their effects, temporally dependent effects are involved, or results are improperly analyzed. We suggest that ecologists resolve debates by standardizing key SGH terms, such as fundamental and realized niche, stress gradients vs. environmental gradients, by quantitatively defining extreme stress, and by critically evaluating the functionality of stress gradients. We also suggest that new research examine the breadth and relevance of the SGH. More rigor needs to be applied to SGH tests to identify actual exceptions rather than those due to failures to meet its underlying assumptions, so that the general principles of the SGH and its exceptions can be incorporated into ecological theory, conservation strategies, and environmental change predictions. PMID- 25039208 TI - The matrix alters the role of path redundancy on patch colonization rates. AB - Landscape connectivity is central to many problems in ecology and conservation. Recently, the role of path redundancies on movement of organisms has been emphasized for understanding connectivity, because increasing the number of potential paths (i.e., redundancy) is predicted to increase movement rates, which can alter predictions for foraging theory and population dynamics. Nonetheless, experiments that test for the effects of path redundancies on connectivity remain scarce. We tested for the role of path redundancies on the movements of a habitat specialist, Chelinidea vittiger, using experimental arenas that altered path redundancy by varying the amount and configuration of stepping stones across a gradient of matrix resistance. We found that stepping-stone redundancies increased colonization rates to target patches, but the effects differed depending on the configuration of redundancy and the structure of the matrix. In addition, matrix effects were better explained through the use of effective distance measures that incorporate redundancy in the matrix than those that ignore redundancy. Our results provide experimental evidence that measures that ignore redundancies may be inadequate for capturing functional connectivity, illustrate the ways in which redundancies alter colonization rates, and emphasize how habitat configuration and matrix structure can interact to guide movement of individuals across landscapes. PMID- 25039209 TI - Experimenting with ecosystem interaction networks in search of threshold potentials in real-world marine ecosystems. AB - Thresholds profoundly affect our understanding and management of ecosystem dynamics, but we have yet to develop practical techniques to assess the risk that thresholds will be crossed. Combining ecological knowledge of critical system interdependencies with a large-scale experiment, we tested for breaks in the ecosystem interaction network to identify threshold potential in real-world ecosystem dynamics. Our experiment with the bivalves Macomona liliana and Austrovenus stutchburyi on marine sandflats in New Zealand demonstrated that reductions in incident sunlight changed the interaction network between sediment biogeochemical fluxes, productivity, and macrofauna. By demonstrating loss of positive feedbacks and changes in the architecture of the network, we provide mechanistic evidence that stressors lead to break points in dynamics, which theory predicts predispose a system to a critical transition. PMID- 25039210 TI - Community context mediates the top-down vs. bottom-up effects of grazers on rocky shores. AB - Interactions between grazers and autotrophs are complex, including both top-down consumptive and bottom-up facilitative effects of grazers. Thus, in addition to consuming autotrophs, herbivores can also enhance autotroph biomass by recycling limiting nutrients, thereby increasing nutrient availability. Here, we evaluated these consumptive and facilitative interactions between snails (Littorina littorea) and seaweeds (Fucus vesiculosus and Ulva lactuca) on a rocky shore. We partitioned herbivores' total effects on seaweeds into their consumptive and facilitative effects and evaluated how community context (the presence of another seaweed species) modified the effects of Littorina on a focal seaweed species. Ulva, the more palatable species, enhanced the facilitative effects of Littorina on Fucus. Ulva did not modify the consumptive effect of Littorina on Fucus. Taken together, the consumptive and facilitative effects of snails on Fucus in the presence of Ulva balanced each other, resulting in no net effect of Littorina on Fucus. In contrast, the only effect of Fucus on Ulva was to enhance consumptive effects of Littorina on Ulva. Our results highlight the necessity of considering both consumptive and facilitative effects of herbivores on multiple autotroph species in order to gain a mechanistic understanding of grazers' top-down and bottom-up roles in structuring communities. PMID- 25039211 TI - Sunscreening fungal pigments influence the vertical gradient of pendulous lichens in boreal forest canopies. AB - Pendulous lichens dominate canopies of boreal forests, with dark Bryoria species in the upper canopy vs. light Alectoria and Usnea species in lower canopy. These genera offer important ecosystem services such as winter forage for reindeer and caribou. The mechanism behind this niche separation is poorly understood. We tested the hypothesis that species-specific sunscreening fungal pigments protect underlying symbiotic algae differently against high light, and thus shape the vertical canopy gradient of epiphytes. Three pale species with the reflecting pigment usnic acid (Alectoria sarmentosa, Usnea dasypoga, U. longissima) and three with dark, absorbing melanins (Bryoria capillaris, B. fremontii, B. fuscescens) were compared. We subjected the lichens to desiccation stress with and without light, and assessed their performance with chlorophyll fluorescence. Desiccation alone only affected U. longissima. By contrast, light in combination with desiccation caused photoinhibitory damage in all species. Usnic lichens were significantly more susceptible to light during desiccation than melanic ones. Thus, melanin is a more efficient light-screening pigment than usnic acid. Thereby, the vertical gradient of pendulous lichens in forest canopies is consistent with a shift in type and functioning of sunscreening pigments, from high-light-tolerant Bryoria in the upper to susceptible Alectoria and Usnea in the lower canopy. PMID- 25039212 TI - Native leaf-tying caterpillars influence host plant use by the invasive Asiatic oak weevil through ecosystem engineering. AB - We tested the effect of leaf-tying caterpillars, native ecosystem engineers, on the abundance and host feeding of an invasive insect, the Asiatic oak weevil, Cyrtepistomus castaneus (Roelofs). Leaf quality was previously thought to be the sole factor determining host use by C. castaneus, but adult weevils congregate in leaf ties made by lepidopteran larvae (caterpillars). Adult weevil abundance was naturally higher on Quercus alba and Q. velutina compared to four other tree species tested (Acer rubrum, Carya ovata, Cornus florida, and Sassafras albidum). These differences were associated with more natural leaf ties on the two Quercus species. In the laboratory, weevils fed on all six species but again preferred Q. alba and Q. velutina. When artificial ties were added to all six tree species, controlling for differences in leaf-tie density, adult weevil density increased on all six tree species, damage increased on all species but A. rubrum, and host ranking changed based on both abundance and damage. We conclude that leaf ties increase the local abundance of C. castaneus adults and their feeding. Thus, these native leaf-tying caterpillars engender the success of an invasive species via structural modification of potential host plants, the first described example of this phenomenon. PMID- 25039213 TI - Direct and indirect effects of warming on aphids, their predators, and ant mutualists. AB - Species exist within communities of other interacting species, so an exogenous force that directly affects one species can indirectly affect all other members of the community. In the case of climate change, many species may be affected directly and subsequently initiate numerous indirect effects that propagate throughout the community. Therefore, the net effect of climate change on any one species is a function of the direct and indirect effects. We investigated the direct and indirect effects of climate warming on corn leaf aphids, a pest of corn and other grasses, by performing an experimental manipulation of temperature, predators, and two common aphid-tending ants. Although warming had a positive direct effect on aphid population growth rate, warming reduced aphid abundance when ants and predators were present. This occurred because winter ants, which aggressively defend aphids from predators under control temperatures, were less aggressive toward predators and less abundant when temperatures were increased. In contrast, warming increased the abundance of cornfield ants, but they did not protect aphids from predators with the same vigor as winter ants. Thus, warming broke down the ant-aphid mutualism and counterintuitively reduced the abundance of this agricultural pest. PMID- 25039214 TI - Community stoichiometry in a changing world: combined effects of warming and eutrophication on phytoplankton dynamics. AB - The current changes in our climate will likely have far-reaching consequences for aquatic ecosystems. These changes in the climate, however, do not act alone, and are often accompanied by additional stressors such as eutrophication. Both global warming and eutrophication have been shown to affect the timing and magnitude of phytoplankton blooms. Little is known about the combined effects of rising temperatures and eutrophication on the stoichiometry of entire phytoplankton communities. We exposed a natural phytoplankton spring community to different warming and phosphorus-loading scenarios using a full-factorial design. Our results demonstrate that rising temperatures promote the growth rate of an entire phytoplankton community. Furthermore, both rising temperatures and phosphorus loading stimulated the maximum biomass built up by the phytoplankton community. Rising temperatures led to higher carbon: nutrient stoichiometry of the phytoplankton community under phosphorus-limited conditions. Such a shift towards higher carbon: nutrient ratios, in combination with a higher biomass buildup, suggests a temperature-driven increase in nutrient use efficiency, the phytoplankton community. Importantly, with higher carbon: nutrient stoichiometry, phytoplankton is generally of poorer nutritional value for zooplankton. Thus, although warming may result in higher phytoplankton biomass, this may be accompanied by a stoichiometric mismatch between phytoplankton and their grazers, with possible consequences for the entire aquatic food web. PMID- 25039215 TI - Whole-lake experiments reveal the fate of terrestrial particulate organic carbon in benthic food webs of shallow lakes. AB - Lake ecosystems are strongly linked to their terrestrial surroundings by material and energy fluxes across ecosystem boundaries. However, the contribution of terrestrial particulate organic carbon (tPOC) from annual leaf fall to lake food webs has not yet been adequately traced and quantified. In this study, we conducted whole-lake experiments to trace artificially added tPOC through the food webs of two shallow lakes of similar eutrophic status, but featuring alternative stable regimes (macrophyte rich vs. phytoplankton dominated). Lakes were divided with a curtain, and maize (Zea mays) leaves were added, as an isotopically distinct tPOC source, into one half of each lake. To estimate the balance between autochthonous carbon fixation and allochthonous carbon input, primary production and tPOC and tDOC (terrestrial dissolved organic carbon) influx were calculated for the treatment sides. We measured the stable isotope ratios of carbon (delta13C) of about 800 samples from all trophic consumer levels and compared them between lake sides, lakes, and three seasons. Leaf litter bag experiments showed that added maize leaves were processed at rates similar to those observed for leaves from shoreline plants, supporting the suitability of maize leaves as a tracer. The lake-wide carbon influx estimates confirmed that autochthonous carbon fixation by primary production was the dominant carbon source for consumers in the lakes. Nevertheless, carbon isotope values of benthic macroinvertebrates were significantly higher with maize additions compared to the reference side of each lake. Carbon isotope values of omnivorous and piscivorous fish were significantly affected by maize additions only in the macrophyte dominated lake and delta13C of zooplankton and planktivorous fish remained unaffected in both lakes. In summary, our results experimentally demonstrate that tPOC in form of autumnal litterfall is rapidly processed during the subsequent months in the food web of shallow lakes and is channeled to secondary and tertiary consumers predominantly via the benthic pathways. A more intense processing of tPOC seems to be connected to a higher structural complexity in littoral zones, and hence may differ between shallow lakes of alternative stable states. PMID- 25039216 TI - Autochthonous resources are the main driver of consumer production in dystrophic boreal lakes. AB - Dystrophic lakes are widespread in temperate regions and intimately interact with surrounding terrestrial ecosystems in energy and nutrient dynamics, yet the relative importance of autochthonous and allochthonous resources to consumer production in dystrophic lakes remains controversial. We argue that allochthonous organic matter quantitatively dominates over photosynthetic autotrophs in dystrophic lakes, but that autotrophs are higher in diet quality and more important for consumers as they contain essential polyunsaturated fatty acids (PUFA). In a field study, we tested the hypotheses that (1) autochthonous primary production is the main driver for consumer production, despite being limited by light availability and low nutrient supplies, and greater supply of allochthonous carbon, (2) the relative contribution of autotrophs to consumers is directly related to their tissue PUFA concentrations, and (3) methane-oxidizing bacteria (MOB) provide an energy alternative for consumers. Pelagic and benthic consumer taxa representing different trophic levels were sampled from five dystrophic lakes: isopod Asellus aquaticus, megalopteran Sialis lutaria, dipteran Chaoborus flavicans, and perch Perca fluviatilis. Based on carbon and nitrogen stable isotopes, the relative contributions of autochthonous (biofilms and seston) and allochthonous (coarse particulate and dissolved organic matter) resources and MOB to these taxa were 47-79%, 9-44% and 7-12% respectively. Results from fatty acid (FA) analyses show that the relative omega3-FA and PUFA concentrations increased with trophic level (Asellus < Sialis and Chaoborus < Perca). Also, eicosapentaenoic-acid (EPA), omega3-FA and PUFA concentrations increased with the autochthonous contribution in consumers, i.e., a 47-79% biofilm and/or seston diet resulted in tissue EPA of 4.2-18.4, omega3 FAs of 11.6-37.0 and PUFA of 21.6 61.0 mg/g dry mass. The results indicate that consumers in dystrophic lakes predominantly rely on energy from autotrophs and that their PUFA concentrations are dependent on the relative contribution of these autochthonous resources. The limited energy support from MOB suggests they are not negligible and are potentially an integral part of the food webs. Our findings show that autochthonous resources are the main driver of secondary production even in dystrophic lakes and offer new insights into the functioning of these ecosystems. PMID- 25039217 TI - Rapid evolution of constitutive and inducible defenses against an invasive predator. AB - Invasive alien predators can impose strong selection on native prey populations and induce rapid evolutionary change in the invaded communities. However, studies on evolutionary responses to invasive predators are often complicated by the lack of replicate populations differing in coexistence time with the predator, which would allow the determination of how prey traits change during the invasion. The red swamp crayfish Procambarus clarkii has invaded many freshwater areas worldwide, with negative impacts for native fauna. Here, we examined how coexistence time shapes antipredator responses of the Iberian waterfrog (Pelophylax perezi) to the invasive crayfish by raising tadpoles from five populations differing in historical exposure to P. clarkii (30 years, 20 years, or no coexistence). Tadpoles from non-invaded populations responded to the presence of P. clarkii with behavioral plasticity (reduced activity), whereas long-term invaded populations showed canalized antipredator behavior (constant low activity level). Tadpoles from one of the long-term invaded populations responded to the crayfish with inducible morphological defenses (deeper tails), reflecting the use of both constitutive and inducible antipredator defenses against the exotic predator by this population. Our results suggest that, while naive P. perezi populations responded behaviorally to P. clarkii, the strong predation pressure imposed by the crayfish has induced the evolution of qualitatively different antipredator defenses in populations with longer coexistence time. These responses suggest that strong selection by invasive predators may drive rapid evolutionary change in invaded communities. Examining responses of prey species to biological invasions using multiple populations will help us better forecast the impact of invasive predators in natural communities. PMID- 25039218 TI - Mechanisms causing variation in sexual size dimorphism in three sympatric, congeneric lizards. AB - Sexual differences in adult body size (sexual size dimorphism, or SSD) ultimately can be favored by selection because larger males are more likely to be successful competitors for females, because larger females bear larger clutches, or because intersexual size differences reduce resource competition. Natural selection during juvenile development can influence sexual dimorphism of adults, and selection on adults and juveniles may differ. Studies that address the relative contributions of adult body shape dimorphism and sexually dimorphic patterns of growth and maturity are particularly useful in understanding the evolution of size dimorphism, yet they are rare. We investigated three sympatric, congeneric lizard species with different degrees and directions of adult sexual dimorphism and compared their growth patterns, survival probabilities, and intersexual trophic niche differences. Different mechanisms, even within these closely related, sympatric species, acted on juvenile lizards to produce species differences in adult SSD. Both degree and direction of dimorphism resulted from differences between the sexes in either the duration of growth or the rate of growth, but not from differences in rates of survival or selection on juvenile growth rate. Species- and sex-specific trade-offs in the allocation of energy to growth and reproduction, as well as differential timing of maturation, thus caused the growth patterns of the sexes to diverge, producing SSD. The differences that we observed in the direction of SSD among these species is consistent with their different social systems, suggesting that differential selection on adult body size has been responsible for the observed species specific differences in juvenile growth rates and maturational timing. PMID- 25039219 TI - Bathing birds bias beta-diversity: frequent dispersal by gulls homogenizes fauna in a rock-pool metacommunity. AB - Metacommunity theory generally predicts that regional dispersal of organisms among local habitat patches should influence spatial patterns of species diversity. In particular, increased dispersal rates are generally expected to increase local (alpha) diversity, yet homogenize local communities across the region (decreasing beta-diversity), resulting in no change in regional (gamma) diversity. Although the effect of dispersal on alpha-diversity has garnered much experimental attention, the influence of dispersal rates on diversity at larger spatial scales (beta and gamma) is poorly understood. Furthermore, these theoretical predictions are not well tested in the field, where other environmental factors (e.g., habitat size, resource density) likely also influence species diversity. Here, we used a system of freshwater rock pools on Appledore Island, Maine, USA, to test the effects of dispersal rate on species diversity in metacommunities. The pools exist in clusters (metacommunities) that experience different levels of dispersal imposed by gulls (Larus spp.), which we show to be frequent passive dispersers of rock-pool invertebrates. Although previous research has suggested that waterbirds may disperse aquatic invertebrates, our study is the first to quantify the rate at which such dispersal occurs and determine its effects on species diversity. In accordance with theory, we found that metacommunities experiencing higher dispersal rates had significantly more homogeneous local communities (reduced beta-diversity) and that gamma-diversity was not influenced by dispersal rate. Contrary to theoretical predictions, however, alpha-diversity in the rock pools was not significantly influenced by dispersal. Rather, local diversity was significantly positively related to local habitat size, and both alpha- and gamma-diversity were influenced by the physicochemical environment of the pools. These results provide an important field test of metacommunity theory, highlighting how local and regional factors interact to drive patterns of species diversity in metacommunities, and demonstrate that waterbirds are indeed important dispersal vectors for aquatic invertebrates. PMID- 25039220 TI - Species- and sex-specific connectivity effects of habitat fragmentation in a suite of woodland birds. AB - Loss of functional connectivity following habitat loss and fragmentation could drive species declines. A comprehensive understanding of fragmentation effects on functional connectivity of an ecological assemblage requires investigation of multiple species with different mobilities, at different spatial scales, for each sex, and in different landscapes. Based on published data on mobility and ecological responses to fragmentation of 10 woodland-dependent birds, and using simulation studies, we predicted that (1) fragmentation would impede dispersal and gene flow of eight "decliners" (species that disappear from suitable patches when landscape-level tree cover falls below species-specific thresholds), but not of two "tolerant" species (whose occurrence in suitable habitat patches is independent of landscape tree cover); and that fragmentation effects would be stronger (2) in the least mobile species, (3) in the more philopatric sex, and (4) in the more fragmented region. We tested these predictions by evaluating spatially explicit isolation-by-landscape-resistance models of gene flow in fragmented landscapes across a 50 x 170 km study area in central Victoria, Australia, using individual and population genetic distances. To account for sex biased dispersal and potential scale- and configuration-specific effects, we fitted models specific to sex and geographic zones. As predicted, four of the least mobile decliners showed evidence of reduced genetic connectivity. The responses were strongly sex specific, but in opposite directions in the two most sedentary species. Both tolerant species and (unexpectedly) four of the more mobile decliners showed no reduction in gene flow. This is unlikely to be due to time lags because more mobile species develop genetic signatures of fragmentation faster than do less mobile ones. Weaker genetic effects were observed in the geographic zone with more aggregated vegetation, consistent with gene flow being unimpeded by landscape structure. Our results indicate that for all but the most sedentary species in our system, the movement of the more dispersive sex (females in most cases) maintains overall genetic connectivity across fragmented landscapes in the study area, despite some small-scale effects on the more philopatric sex for some species. Nevertheless, to improve population viability for the less mobile bird species, structural landscape connectivity must be increased. PMID- 25039221 TI - Nutrient enrichment is related to two facets of beta diversity for stream invertebrates across the United States. AB - Beta diversity, the spatial or temporal variability of species composition, is a key concept in community ecology. However, our ability to predict the relative importance of the main drivers of beta diversity (e.g., environmental heterogeneity, dispersal limitation, and environmental productivity) remains limited. Using a comprehensive data set on stream invertebrate assemblages across the continental United States, we found a hump-shaped relationship between beta diversity and within-ecoregion nutrient concentrations. Within-ecoregion compositional dissimilarity matrices were mainly related to environmental distances in most of the 30 ecoregions analyzed, suggesting a stronger role for species-sorting than for spatial processes. The strength of these relationships varied considerably among ecoregions, but they were unrelated to within-ecoregion environmental heterogeneity or spatial extent. Instead, we detected a negative correlation between the strength of species sorting and nutrient concentrations. We suggest that eutrophication is a major mechanism disassembling invertebrate assemblages in streams at a continental scale. PMID- 25039222 TI - Coexistence and environmental filtering of species-specific biomass in an African savanna. AB - Biomass density is a key metric of vegetation abundance, but understanding how community assembly processes, such as environmental filtering and competitive exclusion, affect biomass distributions of coexisting species has proven logistically challenging. Here we apply airborne remote sensing to study the ecosystem-scale distribution of species-specific, woody plant biomass and its relation to topographic and hydrologic gradients in a South African savanna. We also spatially analyzed variation in biomass among species to understand patterns of coexistence, mapping the species and biomass over one million trees across 10500 ha. We found the biomass of dominant woody species to be weakly but significantly related to environmental filters, where a combination of 10 topographic and edaphic variables accounted for < 15% of the variance in the biomass of any given species. Distance to nearest stream was the only environmental variable significantly correlated to all species' biomass. Despite an overall negative trend observed between the biomass of species pairs, we found a number of regions where the biomass of two species was similar or equal, and all species pairs exhibited some level of co-occurrence. This suggests that even weak stabilizing mechanisms (e.g., environmental niches) can overcome fitness differences and balance competitive exclusion, enabling coexistence. Future work of repeated measurements of species-specific biomass will provide a novel advance in understanding woody plant community assembly processes in natural ecosystems. Characterizing the species composition of biomass is an important advance in understanding the balance of community assembly processes and its control over current species assemblages. PMID- 25039223 TI - Herbivory and climate interact serially to control monoterpene emissions from pinyon pine forests. AB - The emission of volatile monoterpenes from coniferous trees impacts the oxidative state of the troposphere and multi-trophic signaling between plants and animals. Previous laboratory studies have revealed that climate anomalies and herbivory alter the rate of tree monoterpene emissions. However, no studies to date have been conducted to test these relations in situ. We conducted a two-year field experiment at two semiarid sites dominated by pinyon pine (Pinus edulis) during outbreaks of a specialist herbivore, the southwestern tiger moth (Lophocampa ingens: Arctiidae). We discovered that during the early spring, when herbivory rates were highest, monoterpene emission rates were approximately two to six times higher from undamaged needles on damaged trees, with this increase in emissions due to alpha-pinene, beta-pinene, and camphene at both sites. During mid-summer, emission rates did not differ between previously damaged and undamaged trees at the site on the Western Slope of the Rocky Mountains, but rather tracked changes in the temperature and precipitation regime characteristic of the region. As the mid-summer drought progressed at the Eastern Slope site, emission rates were low, but differences between previously damaged and undamaged trees were not statistically significant. Despite no difference in emissions, mid summer tissue monoterpene concentrations were significantly lower in previously damaged trees at both sites. With the onset of monsoon rains during late summer, emission rates from previously damaged trees increased to levels higher than those of undamaged trees despite the lack of herbivory. We conclude that (1) herbivory systemically increases the flux of terpenes to the atmosphere during the spring, (2) drought overrides the effect of past herbivory as the primary control over emissions during the mid-summer, and (3) a release from drought and the onset of late-summer rains is correlated with a secondary increase in emissions, particularly from herbivore-damaged trees, possibly due to a drought delayed stimulation of induced monoterpene synthesis and/or increases in stomatal conductance. A greater understanding of the interactive effects of seasonality and herbivory on monoterpene emissions provides much needed information regarding the atmospheric and ecological consequences that these compounds will have for semiarid ecosystems. PMID- 25039224 TI - Long-term changes in liana abundance and forest dynamics in undisturbed Amazonian forests. AB - Lianas (climbing woody vines) are important structural parasites of tropical trees and may be increasing in abundance in response to global-change drivers. We assessed long-term (-14-year) changes in liana abundance and forest dynamics within 36 1-ha permanent plots spanning -600 km2 of undisturbed rainforest in central Amazonia. Within each plot, we counted each liana stem (> or = 2 cm diameter) and measured its diameter at 1.3 m height, and then used these data to estimate liana aboveground biomass. An initial liana survey was completed in 1997 1999 and then repeated in 2012, using identical methods. Liana abundance in the plots increased by an average of 1.00% +/- 0.88% per year, leading to a highly significant (t = 6.58, df = 35, P < 0.00001) increase in liana stem numbers. Liana biomass rose more slowly over time (0.32% +/- 1.37% per year) and the mean difference between the two sampling intervals was nonsignificant (t = 1.46, df = 35, P = 0.15; paired t tests). Liana size distributions shifted significantly (chi2 = 191, df = 8, P < 0.0001; Chi-square test for independence) between censuses, mainly as a result of a nearly 40% increase in the number of smaller (2 3 cm diameter) lianas, suggesting that lianas recruited rapidly during the study. We used long-term data on rainfall and forest dynamics from our study site to test hypotheses about potential drivers of change in liana communities. Lianas generally increase with rainfall seasonality, but we found no significant trends over time (1997-2012) in five rainfall parameters (total annual rainfall, dry season rainfall, wet-season rainfall, number of very dry months, CV of monthly rainfall). However, rates of tree mortality and recruitment have increased significantly over time in our plots, and general linear mixed-effect models suggested that lianas were more abundant at sites with higher tree mortality and flatter topography. Rising concentrations of atmospheric CO2, which may stimulate liana growth, might also have promoted liana increases. Our findings clearly support the view that lianas are increasing in abundance in old-growth tropical forests, possibly in response to accelerating forest dynamics and rising CO2 concentrations. The aboveground biomass of trees was lowest in plots with abundant lianas, suggesting that lianas could reduce forest carbon storage and potentially alter forest dynamics if they continue to proliferate. PMID- 25039225 TI - Do small spores disperse further than large spores? AB - In species that disperse by airborne propagules an inverse relationship is often assumed between propagule size and dispersal distance. However, for microscopic spores the evidence for the relationship remains ambiguous. Lagrangian stochastic dispersion models that have been successful in predicting seed dispersal appear to predict similar dispersal for all spore sizes up to -40 microm diameter. However, these models have assumed that spore size affects only the downwards drift of particles due to gravitation and have largely omitted the highly size sensitive deposition process to surfaces such as forest canopy. On the other hand, they have assumed that spores are certain to deposit when the air parcel carrying them touches the ground. Here, we supplement a Lagrangian stochastic dispersion model with a mechanistic deposition model parameterized by empirical deposition data for 1-10 microm spores. The inclusion of realistic deposition improved the ability of the model to predict empirical data on the dispersal of a wood-decay fungus (aerodynamic spore size 3.8 microm). Our model predicts that the dispersal of 1-10 microm spores is in fact highly sensitive to spore size, with 97-98% of 1 microm spores but only 12-58% of 10-microm spores dispersing beyond 2 km in the simulated range of wind and canopy conditions. Further, excluding the assumption of certain deposition at the ground greatly increased the expected dispersal distances throughout the studied spore size range. Our results suggest that by evolutionary adjustment of spore size, release height and timing of release, fungi and other organisms with microscopic spores can change the expected distribution of dispersal locations markedly. The complex interplay of wind and canopy conditions in determining deposition resulted in some counterintuitive predictions, such as that spores disperse furthest under intermediate wind, providing intriguing hypotheses to be tested empirically in future studies. PMID- 25039226 TI - Competitive impacts of an invasive nectar thief on plant-pollinator mutualisms. AB - Plant-pollinator mutualisms are disrupted by a variety of competitive interactions between introduced and native floral visitors. The invasive western yellowjacket wasp, Vespula pensylvanica, is an aggressive nectar thief of the dominant endemic Hawaiian tree species, Metrosideros polymorpha. We conducted a large-scale, multiyear manipulative experiment to investigate the impacts of V. pensylvanica on the structure and behavior of the M. polymorpha pollinator community, including competitive mechanisms related to resource availability. Our results demonstrate that V. pensylvanica, through both superior exploitative and interference competition, influences resource partitioning and displaces native and nonnative M. polymorpha pollinators. Furthermore, the restructuring of the pollinator community due to V. pensylvanica competition and predation results in a significant decrease in the overall pollinator effectiveness and fruit set of M. polymorpha. This research highlights both the competitive mechanisms and contrasting effects of social insect invaders on plant-pollinator mutualisms and the role of competition in pollinator community structure. PMID- 25039227 TI - No evidence for phylogenetic constraint on natural defense evolution among wild tomatoes. AB - Plant defense traits can be shaped by evolutionary and physiological constraints, as well as local ecological selection. We assessed the relative importance of these factors in shaping defense trait variation across the wild tomato clade (a group of 13 closely related species) using an herbivore bioassay (Manduca sexta). With phylogenetic comparative methods, we evaluated patterns of constitutive and induced defense variation, and the extent of coupling between alternative defense strategies. We detected substantial variation among species and found no evidence for phylogenetic conservatism among defensive traits, unlike for two other ecologically relevant (reproductive) traits. In addition, constitutive and induced defense syndromes were unassociated. These data indicate that, in this group, there is no evidence for either phylogenetic conservatism of shared consumer guilds that shape defense traits, or for constraints on defense trait evolution, including mechanistic trade-offs between defense strategies. Our data suggest that defense trait variation in this clade instead results from rapid responses to local ecological conditions. PMID- 25039228 TI - Exotic plants contribute positively to biodiversity functions but reduce native seed production and arthropod richness. AB - Although exotic plants comprise a substantial portion of floristic biodiversity, their contributions to community and ecosystem processes are not well understood. We manipulated plant species richness in old-field communities to compare the impacts of native vs. exotic species on plant biomass, seed production, and arthropod community structure. Plants within diverse communities, regardless of whether they were native or exotic, had higher biomass and seed production than in monocultures and displayed positive complementarity. Increasing native or exotic plant richness also enhanced the richness of arthropods on plants, but exotics attracted fewer arthropod species for a given arthropod abundance than did natives. Additionally, when exotic and native plants grew together, exotics suppressed seed production of native species. Thus, exotic plants appear to contribute positively to some biodiversity functions, but may impact native communities over longer time frames by reducing native seed production and recruiting fewer arthropod species. PMID- 25039229 TI - Links between deep-sea respiration and community dynamics. AB - It has been challenging to establish the mechanisms that link ecosystem functioning to environmental and resource variation, as well as community structure, composition, and compensatory dynamics. A compelling hypothesis of compensatory dynamics, known as "zero-sum" dynamics, is framed in terms of energy resource and demand units, where there is an inverse link between the number of individuals in a community and the mean individual metabolic rate. However, body size energy distributions that are nonuniform suggest a niche advantage at a particular size class, which suggests a limit to which metabolism can explain community structuring. Since 1989, the composition and structure of abyssal seafloor communities in the northeast Pacific and northeast Atlantic have varied interannually with links to climate and resource variation. Here, for the first time, class and mass-specific individual respiration rates were examined along with resource supply and time series of density and biomass data of the dominant abyssal megafauna, echinoderms. Both sites had inverse relationships between density and mean individual metabolic rate. We found fourfold variation in echinoderm respiration over interannual timescales at both sites, which were linked to shifts in species composition and structure. In the northeastern Pacific, the respiration of mobile surface deposit feeding echinoderms was positively linked to climate-driven particulate organic carbon fluxes with a temporal lag of about one year, respiring - 1-6% of the annual particulate organic carbon flux. PMID- 25039230 TI - A depth refugium from catastrophic coral bleaching prevents regional extinction. AB - Species intolerant of changing climate might avoid extinction within refugia buffered from extreme conditions. Refugia have been observed in the fossil record but are not well documented or understood on ecological time scales. Using a 37 year record from the eastern Pacific across the two most severe El Nino events on record (1982-1983 and 1997 1998) we show how an exceptionally thermally sensitive reef-building hydrocoral, Millepora intricata, twice survived catastrophic bleaching in a deeper-water refuge (> 11 m depth). During both events, M. intricata was extirpated across its range in shallow water, but showed recovery within several years, while two other hydrocorals without deep-water populations were driven to regional extinction. Evidence from the subfossil record in the same area showed shallow-water persistence of abundant M. intricata populations from 5000 years ago, through severe El Nino-Southern Oscillation cycles, suggesting a potential depth refugium on a millennial timescale. Our data confirm the deep refuge hypothesis for corals under thermal stress. PMID- 25039231 TI - Reconstructing transoceanic migration patterns of Pacific bluefin tuna using a chemical tracer toolbox. AB - Large pelagic predators play important roles in oceanic ecosystems, and may migrate vast distances to utilize resources in different marine ecoregions. Understanding movement patterns of migratory marine animals is critical for effective management, but often challenging, due to the cryptic habitat of pelagic migrators and the difficulty of assessing past movements. Chemical tracers can partially circumvent these challenges by reconstructing recent migration patterns. Pacific bluefin tuna (Thunnus orientalis; PBFT) inhabit the western and eastern Pacific Ocean, and are in steep decline due to overfishing. Understanding age-specific eastward transpacific migration patterns can improve management practices, but these migratory dynamics remain largely unquantified. Here, we combine a Fukushima-derived radiotracer (134Cs) with bulk tissue and amino acid stable isotope analyses of PBFT to distinguish recent migrants from residents of the eastern Pacific Ocean. The proportion of recent migrants to residents decreased in older year classes, though the proportion of older PBFT that recently migrated across the Pacific was greater than previous estimates. This novel toolbox of biogeochemical tracers can be applied to any species that crosses the North Pacific Ocean. PMID- 25039232 TI - Infections do not predict shedding in co-infections with two helminths from a natural system. AB - Given the health and economic burden associated with the widespread occurrence of co-infections in humans and agricultural animals, understanding how coinfections contribute to host heterogeneity to infection and transmission is critical if we are to assess risk of infection based on host characteristics. Here, we examine whether host heterogeneity to infection leads to similar heterogeneity in transmission in a population of rabbits single and co-infected with two helminths and monitored monthly for eight years. Compared to single infections, co-infected rabbits carried higher Trichostrongylus retortaeformis intensities, shorter worms with fewer eggs in utero, and shed similar numbers of parasite eggs. In contrast, the same co-infected rabbits harbored fewer Graphidium strigosum with longer bodies and more eggs in utero, and shed more eggs of this helminth. A positive density-dependent relationship between fecundity and intensity was found for T. retortaeformis but not G. strigosum in co-infected rabbits. Juvenile rabbits contributed to most of the infection and shedding of T. retortaeformis, while adult hosts were more important for G. strigosum dynamics of infection and transmission, and this pattern was consistent in single and co-infected individuals. This host-parasite system suggests that we cannot predict the pattern of parasite shedding during co-infections based on intensity of infection alone. We suggest that a mismatching between susceptibility and infectiousness should be expected in helminth coinfections and should not be overlooked. PMID- 25039233 TI - Biotic mechanisms of community stability shift along a precipitation gradient. AB - Understanding how biotic mechanisms confer stability in variable environments is a fundamental quest in ecology, and one that is becoming increasingly urgent with global change. Several mechanisms, notably a portfolio effect associated with species richness, compensatory dynamics generated by negative species covariance and selection for stable dominant species populations can increase the stability of the overall community. While the importance of these mechanisms is debated, few studies have contrasted their importance in an environmental context. We analyzed nine long-term data sets of grassland species composition to investigate how two key environmental factors, precipitation amount and variability, may directly influence community stability and how they may indirectly influence stability via biotic mechanisms. We found that the importance of stability mechanisms varied along the environmental gradient: strong negative species covariance occurred in sites characterized by high precipitation variability, whereas portfolio effects increased in sites with high mean annual precipitation. Instead of questioning whether compensatory dynamics are important in nature, our findings suggest that debate should widen to include several stability mechanisms and how these mechanisms vary in importance across environmental gradients. PMID- 25039234 TI - Temporal fluctuation scaling in populations and communities. AB - Taylor's law, one of the most widely accepted generalizations in ecology, states that the variance of a population abundance time series scales as a power law of its mean. Here we reexamine this law and the empirical evidence presented in support of it. Specifically, we show that the exponent generally depends on the length of the time series, and its value reflects the combined effect of many underlying mechanisms. Moreover, sampling errors alone, when presented on a double logarithmic scale, are sufficient to produce an apparent power law. This raises questions regarding the usefulness of Taylor's law for understanding ecological processes. As an alternative approach, we focus on short-term fluctuations and derive a generic null model for the variance-to-mean ratio in population time series from a demographic model that incorporates the combined effects of demographic and environmental stochasticity. After comparing the predictions of the proposed null model with the fluctuations observed in empirical data sets, we suggest an alternative expression for fluctuation scaling in population time series. Analyzing population fluctuations as we have proposed here may provide new applied (e.g., estimation of species persistence times) and theoretical (e.g., the neutral theory of biodiversity) insights that can be derived from more generally available short-term monitoring data. PMID- 25039235 TI - Rethinking computer design from a disabilities rights standpoint. PMID- 25039236 TI - Evaluating Callous-Unemotional Traits as a Personality Construct. AB - We evaluate the importance of callous-unemotional (CU) traits as a personality construct in isolation from other facets of psychopathy. Specifically, we review research suggesting that these traits are useful for designating a subgroup of youth with serious conduct problems who differ from other antisocial youth on important biological, emotional, cognitive, and social characteristics. In addition, the temperamental features related to CU traits are risk factors for impairments in conscience development in young children. Thus, these traits could advance theoretical models explaining the development of severe antisocial behavior and psychopathy. CU traits also have important clinical utility because they designate a particularly severe and impaired subgroup of antisocial youth, leading to their inclusion in the DSM-5. As a result of this inclusion in diagnostic classification, there has been an increased focus on how to best assess CU traits, and we discuss several key issues in their assessment, highlighting several limitations in existing measures. Finally, the increased use of CU traits, separately from other facets of psychopathy, makes it important to determine how these traits relate to other personality constructs. Thus, we examine how measures of CU traits relate to the broader construct of psychopathy and to other basic personality dimensions. PMID- 25039237 TI - Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis. AB - BACKGROUND AND PURPOSE: The cyclopentapeptide FC131 (cyclo(-L-Arg(1) -L-Arg(2) -L 2-Nal(3) -Gly(4) -D-Tyr(5) -)) is an antagonist at the CXC chemokine receptor CXCR4, which plays a role in human immunodeficiency virus infection, cancer and stem cell recruitment. Binding modes for FC131 in CXCR4 have previously been suggested based on molecular docking guided by structure-activity relationship (SAR) data; however, none of these have been verified by in vitro experiments. EXPERIMENTAL APPROACH: Heterologous (125) I-12G5-competition binding and functional assays (inhibition of CXCL12-mediated activation) of FC131 and three analogues were performed on wild-type CXCR4 and 25 receptor mutants. Computational modelling was used to rationalize the experimental data. KEY RESULTS: The Arg(2) and 2-Nal(3) side chains of FC131 interact with residues in TM-3 (His(113) , Asp(171) ) and TM-5 (hydrophobic pocket) respectively. Arg(1) forms charge-charge interactions with Asp(187) in ECL-2, while D-Tyr(5) points to the extracellular side of CXCR4. Furthermore, the backbone of FC131 interacts with the chemokine receptor-conserved Glu(288) via two water molecules. Intriguingly, Tyr(116) and Glu(288) form a H-bond in CXCR4 crystal structures and mutation of either residue to Ala abolishes CXCR4 activity. CONCLUSIONS AND IMPLICATIONS: Ligand modification, receptor mutagenesis and computational modelling approaches were used to identify the binding mode of FC131 in CXCR4, which was in agreement with binding modes suggested from previous SAR studies. Furthermore, insights into the mechanism for CXCR4 activation by CXCL12 were gained. The combined findings will facilitate future design of novel CXCR4 antagonists. PMID- 25039238 TI - Climate refugia: joint inference from fossil records, species distribution models and phylogeography. AB - Climate refugia, locations where taxa survive periods of regionally adverse climate, are thought to be critical for maintaining biodiversity through the glacial-interglacial climate changes of the Quaternary. A critical research need is to better integrate and reconcile the three major lines of evidence used to infer the existence of past refugia - fossil records, species distribution models and phylogeographic surveys - in order to characterize the complex spatiotemporal trajectories of species and populations in and out of refugia. Here we review the complementary strengths, limitations and new advances for these three approaches. We provide case studies to illustrate their combined application, and point the way towards new opportunities for synthesizing these disparate lines of evidence. Case studies with European beech, Qinghai spruce and Douglas-fir illustrate how the combination of these three approaches successfully resolves complex species histories not attainable from any one approach. Promising new statistical techniques can capitalize on the strengths of each method and provide a robust quantitative reconstruction of species history. Studying past refugia can help identify contemporary refugia and clarify their conservation significance, in particular by elucidating the fine-scale processes and the particular geographic locations that buffer species against rapidly changing climate. PMID- 25039239 TI - Trauma patients requiring treatment on the intensive care unit (ICU) need antimicrobial prophylaxis to prevent pneumonia. PMID- 25039240 TI - Improving environmental and social targeting through adaptive management in Mexico's payments for hydrological services program. AB - Natural resource managers are often expected to achieve both environmental protection and economic development even when there are fundamental trade-offs between these goals. Adaptive management provides a theoretical structure for program administrators to balance social priorities in the presence of trade-offs and to improve conservation targeting. We used the case of Mexico's federal Payments for Hydrological Services program (PSAH) to illustrate the importance of adaptive management for improving program targeting. We documented adaptive elements of PSAH and corresponding changes in program eligibility and selection criteria. To evaluate whether these changes resulted in enrollment of lands of high environmental and social priority, we compared the environmental and social characteristics of the areas enrolled in the program with the characteristics of all forested areas in Mexico, all areas eligible for the program, and all areas submitted for application to the program. The program successfully enrolled areas of both high ecological and social priority, and over time, adaptive changes in the program's criteria for eligibility and selection led to increased enrollment of land scoring high on both dimensions. Three factors facilitated adaptive management in Mexico and are likely to be generally important for conservation managers: a supportive political environment, including financial backing and encouragement to experiment from the federal government; availability of relatively good social and environmental data; and active participation in the review process by stakeholders and outside evaluators. PMID- 25039241 TI - Regulatory T cell microRNA expression changes in children with acute Kawasaki disease. AB - Kawasaki disease (KD) is a type of systemic vasculitis syndrome related to immune dysfunction. Previous studies have implicated that dysfunctional regulatory T cells (Treg ) may be associated with the immune dysfunction in KD. In the absence of microRNAs (miRNAs), forkhead box protein 3 (FoxP3)(+) Treg develop but fail to maintain immune homeostasis. This study was designed to investigate the effects of miR-155, miR-21 and miR-31 on Treg in children with KD. The proportions of CD4(+) CD25(+) FoxP3(+) Treg and the mean fluorescence intensity (MFI) of phosphorylated-signal transducer and activator of transcription (pSTAT) 5 and pSTAT-3 protein in CD4(+) CD25(+) Treg were analysed by flow cytometry. The concentration of interleukin (IL)-6 in plasma was measured by cytometric bead array. Real-time polymerase chain reaction was performed to detect the levels of microRNAs and associated factors in CD4(+) CD25(+) Treg . The proportion of Treg and the mRNA levels of the associated factors [FoxP3, glucocorticoid-induced tumour necrosis factor-receptor (GITR), cytotoxic T lymphocyte antigen (CTLA)-4)] were significantly lower in KD patients (P < 0.05). MiR-155 and miR-21 levels were significantly down-regulated and miR-31 expression was higher in KD patients (P < 0.05). Plasma interleukin (IL)-6 concentrations, pSTAT-3 protein levels and suppressors of cytokine signalling (SOCS)-1 mRNA expression were remarkably elevated in acute KD (P < 0.05), while pSTAT-5 protein levels were remarkably decreased in acute KD (P < 0.05). These findings were reversed after intravenous immunoglobulin treatment (P < 0.05). Our results demonstrate that FoxP3 mRNA levels were primarily affected by the miR-155/SOCS1 and the miR-31 signalling pathways. These results suggest that the decrease in FoxP3(+) Treg might be associated with decreased expression of miR-155, leading to aberrant SOCS1/STAT-5 signalling and overexpression of miR-31 in patients with acute KD. PMID- 25039242 TI - Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves' orbitopathy: A five-year follow-up study. AB - Abstract The aim of this investigations was to study the effectiveness of anti CD20 antibody therapy in Graves' orbitopathy (GO) resistant to glucocorticoids. Five patients were entered in the study. The protocol required no improvement of orbital status after a recent course of glucocorticoids. Activity of GO was confirmed by three independent techniques: clinical activity score (CAS), (99m)Tc labeled diethylene triamine pentaacetic acid ((99m)Tc DTPA) single photon emission computed tomography and magnetic resonance imaging. Rituximab (RTX) was given as weekly infusions of 375 mg/m(2) body surface area for four weeks. The mean follow-up period was 67 (range 58-81) months. Improvement of GO has been observed in all patients: CAS before therapy was 6.5 +/- 1.7 and decreased to 3.4 +/- 1.6 by one month (p < 0.05) and remained unchanged (3.2 +/- 1.7) at 12 months. No further CAS change, in either direction, was detected during the yearly follow-up visits. The mean DTPA uptake before therapy was 16.52 +/- 4.51 MBq/cm(3) and decreased to 11.97 +/- 2.36 MBq/cm(3) at one year (p < 0.002). The mean of T2 relaxation times before and one year after therapy were 96.91 +/- 17.61 ms and 84.29 +/- 9.41 ms, respectively (p < 0.001). The mean serum TSH receptor antibody (TRAb) levels before therapy, at the one month and one year control visits were 7.4 +/- 3.4 U/L, 5.6 +/- 4.5 U/L and 1.7 +/- 1.5 U/L, respectively (p < 0.004). No correlation between changes of TRAb and activity parameters has been found. Anti-CD20 treatment seems to influence positively the clinical course of GO, and this effect seems to be stable for five years. To our knowledge, this is the longest published follow-up of RTX treatment in GO. PMID- 25039243 TI - Nevoid hypomelanosis associated with unilateral palmoplantar keratoderma: a result of genetic mosaicism. PMID- 25039244 TI - A comparison of a 5% potassium hydroxide solution with a 5-fluorouracil and salicylic acid combination in the treatment of patients with anogenital warts: a randomized, open-label clinical trial. AB - Anogenital warts are caused by human papillomavirus (HPV), over 30 types of which are infectious for the anogenital tract. Without treatment, warts may regress spontaneously, remain unchanged, or increase in number and size. This study compared the efficacy of a topical 5% potassium hydroxide (KOH) solution with that of a topical 0.5% 5-fluorouracil (5-FU) and 10% salicylic acid (SA) combination in the treatment of anogenital warts. Sixty patients were randomly assigned to receive topical KOH or 5-FU + SA. Both groups demonstrated a significant decrease in numbers of lesions (P < 0.05), but this difference was not significant at week 12 (P > 0.05). The mean number of lesions decreased from baseline to week 12 from 17.03 +/- 12.64 to 3.73 +/- 7.30 and from 16.13 +/- 12.97 to 3.10 +/- 4.90 in the KOH and 5-FU + SA groups, respectively (P < 0.001). Excellent clearance was achieved by 70.0 and 76.7% of patients in the KOH and 5 FU + SA groups, respectively. Marked improvement was seen in 13.3 and 20.0% of patients in the KOH and 5-FU + SA groups, respectively. At week 16, relapse was observed in two patients in the KOH group and three in the 5-FU + SA group (P > 0.05). No serious adverse events were reported. Neither treatment was more efficacious. Safety and ease of application are important goals in treatments for anogenital warts. A 5% KOH solution is a promising alternative treatment because it is effective and inexpensive and causes minimal side effects. PMID- 25039246 TI - Suspicious mammographic masses in the breast: splenosis in an unusual body site due to a remote ballistic trauma. PMID- 25039247 TI - Abstracts for the fifty-fourth Annual Meeting of the Society for Psychophysiological Research, September 10-14, 2014, Atlanta, Georgia, USA. PMID- 25039245 TI - Intranasal peptide-induced tolerance and linked suppression: consequences of complement deficiency. AB - A role for complement, particularly the classical pathway, in the regulation of immune responses is well documented. Deficiencies in C1q or C4 predispose to autoimmunity, while deficiency in C3 affects the suppression of contact sensitization and generation of oral tolerance. Complement components including C3 have been shown to be required for both B-cell and T-cell priming. The mechanisms whereby complement can mediate these diverse regulatory effects are poorly understood. Our previous work, using the mouse minor histocompatibility (HY) model of skin graft rejection, showed that both C1q and C3 were required for the induction of tolerance following intranasal peptide administration. By comparing tolerance induction in wild-type C57BL/6 and C1q-, C3-, C4- and C5 deficient C57BL/6 female mice, we show here that the classical pathway components including C3 are required for tolerance induction, whereas C5 plays no role. C3 deficient mice failed to generate a functional regulatory T (Treg) -dendritic cell (DC) tolerogenic loop required for tolerance induction. This was related to the inability of C3-deficient DC to up-regulate the arginine-consuming enzyme, inducible nitric oxide synthase (Nos-2), in the presence of antigen-specific Treg cells and peptide, leading to reduced Treg cell generation. Our findings demonstrate that the classical pathway and C3 play a critical role in the peptide mediated induction of tolerance to HY by modulating DC function. PMID- 25039248 TI - The Asthma Control Questionnaire as a clinical trial endpoint: past experience and recommendations for future use. AB - The goal of asthma treatment is to control the disease according to guidelines issued by bodies such as the Global Initiative for Asthma. Effective control is dependent upon evaluation of symptoms, initiation of appropriate treatment and minimization of the progressive adverse effects of the disease and its therapies. Although individual outcome measures have been shown to correlate with asthma control, composite endpoints are preferred to enable more accurate and robust monitoring of the health of the individual patient. A number of validated instruments are utilized to capture these component endpoints; however, there is no consensus on the optimal instrument for use in clinical trials. The Asthma Control Questionnaire (ACQ) has been shown to be a valid, reliable instrument that allows accurate and reproducible assessment of asthma control that compares favourably with other commonly used instruments. This analysis provides a summary of the use of ACQ in phase II, III and IV asthma trials. Comparisons between the ACQ and other instruments are also presented. Our analysis suggests that the ACQ is a valid and robust measure for use as a primary or secondary endpoint in future clinical trials. PMID- 25039249 TI - Case of semicircular lipoatrophy: relation between its characteristic distribution and anatomical muscle structure. AB - Semicircular lipoatrophy is characterized by one or more partial, horizontal, band-like depressions, usually on the anterolateral thigh or thighs. We report the case of a 47-year-old woman who presented with a 1-month history of bilateral, parallel, symmetrical depressions on the anterolateral aspects of her thighs. She had been wearing a tight girdle, and the girdle's folds matched the cutaneous bands. Ultrasound examination of the affected areas showed that the muscle tensor fasciae latae became its tendon at this level, and the muscle rectus femoris originated at the same level in the deeper layer. Although semicircular lipoatrophy has a predisposition for the anterolateral aspect of the thigh, and has often been considered to be caused by repetitive mild trauma to the site, we speculate that it is also attributed to the vulnerability of the site, as explained by the muscle structure. PMID- 25039250 TI - Where we stand with human hypertrophic and keloid scar models. AB - We have yet to create a human scar model that demonstrates the complex nature of hypertrophic scar and keloid formation as well as ways to prevent them despite emerging advances in our understanding of the immune system, the inflammatory response, and proteomic and genomic changes after injury. Despite more complex in vitro models, we fail to explain the fundamental principles to scar formation, and the timeline of their development. The solution to developing the ideal in vitro scar model is one that mimics the heterogeneous cellular and molecular interactions, as well as the evolving structure and function of human skin. PMID- 25039251 TI - Illness-course modulates suicidality-related prefrontal gray matter reduction in women with bipolar disorder. AB - OBJECTIVE: Explore interrelationships between suicide attempt history (Objective 1) or suicide attempt severity (Objective 2) with prefrontal cortex gray matter (PFCGM ) volume and illness-course in patients with bipolar disorder (BD). METHOD: Ninety-three women with BD-I or -II diagnosis (51 with and 42 without suicide attempt history) underwent structural MRI and filled out questionnaires. Measured were GM volumes of 11 PFC regions, BD illness-course, and attempt history and severity. Effects were examined with repeated measures GLM or logit analyses. RESULTS: Objective 1: Attempt history was associated with increased trait impulsivity and aggression, and higher prevalence of BD-I, past drug use disorder, and past psychiatric hospitalization. PFCGM volume was lower in patients with than without attempt history in those with past psychiatric hospitalization. PFCGM volume was higher in patients with than without attempt history in those without hospitalization. Higher trait aggression predicted attempt history. Objective 2: Increased frontal pole volume and younger age at first hospitalization predicted many suicide attempts. CONCLUSION: Attempt history in patients with BD related to PFCGM volume reduction or increase. Volume modulation by psychiatric hospitalization could reflect effects of illness-course or care. Attempt severity was not related to volume reduction. Research on suicidality-brain relationships should include illness-course and attempt severity measures. PMID- 25039252 TI - Study of the photodegradation kinetics and pathways of hexaflumuron in liquid media. AB - Hexaflumuron, one of the benzoylphenylurea insect growth regulators, can be leached into surface water and thus having a potential impact on aquatic organisms. In this study, the photodegradation processes of hexaflumuron under high-pressure mercury lamp irradiation were assessed. The photodegradation kinetics were studied, as were the effects of pH, different light sources, organic solvents and environmental substances, including nitrate ions (NO3(-)), nitrite ions (NO2(-)), ferrous ions (Fe(2+)), ferric ions (Fe(3+)), humic acid, sodium dodecyl sulfate (SDS) and hydrogen peroxide (H2O2). Three photodegradation products in methanol were identified by gas chromatography-mass spectrometry (GC MS). In general, the degradation of hexaflumuron followed first-order kinetics. In the four media studied, the photodegradation rate order was n-hexane > methanol > ultrapure water > acetone. Faster degradation was observed under high pressure mercury lamp irradiation than under xenon lamp irradiation. The pH had a considerable effect, with the most rapid degradation occurring at pH 5.0. The photodegradation rate of hexaflumuron was promoted in the presence of NO3(-), NO2(-), Fe(2+), humic acid, SDS and H2O2, but inhibited by Fe(3+). Moreover, the presumed photodegradation pathway was proposed to be the cleavage of the urea linkage. PMID- 25039254 TI - Modeling Adversaries in Counterterrorism Decisions Using Prospect Theory. AB - Counterterrorism decisions have been an intense area of research in recent years. Both decision analysis and game theory have been used to model such decisions, and more recently approaches have been developed that combine the techniques of the two disciplines. However, each of these approaches assumes that the attacker is maximizing its utility. Experimental research shows that human beings do not make decisions by maximizing expected utility without aid, but instead deviate in specific ways such as loss aversion or likelihood insensitivity. In this article, we modify existing methods for counterterrorism decisions. We keep expected utility as the defender's paradigm to seek for the rational decision, but we use prospect theory to solve for the attacker's decision to descriptively model the attacker's loss aversion and likelihood insensitivity. We study the effects of this approach in a critical decision, whether to screen containers entering the United States for radioactive materials. We find that the defender's optimal decision is sensitive to the attacker's levels of loss aversion and likelihood insensitivity, meaning that understanding such descriptive decision effects is important in making such decisions. PMID- 25039253 TI - Crystal structure of the antimicrobial peptidase lysostaphin from Staphylococcus simulans. AB - Staphylococcus simulans biovar staphylolyticus lysostaphin efficiently cleaves Staphylococcus aureus cell walls. The protein is in late clinical trials as a topical anti-staphylococcal agent, and can be used to prevent staphylococcal growth on artificial surfaces. Moreover, the gene has been both stably engineered into and virally delivered to mice or livestock to obtain resistance against staphylococci. Here, we report the first crystal structure of mature lysostaphin and two structures of its isolated catalytic domain at 3.5, 1.78 and 1.26 A resolution, respectively. The structure of the mature active enzyme confirms its expected organization into catalytic and cell-wall-targeting domains. It also indicates that the domains are mobile with respect to each other because of the presence of a highly flexible peptide linker. The high-resolution structures of the catalytic domain provide details of Zn(2+) coordination and may serve as a starting point for the engineering of lysostaphin variants with improved biotechnological characteristics. STRUCTURED DIGITAL ABSTRACT: lysostaphin by x ray crystallography (1, 2). PMID- 25039255 TI - A hemolytic anti-LKE associated with a rare LKE-negative, "weak P" red blood cell phenotype: alloanti-LKE and alloanti-P recognize galactosylgloboside and monosialogalactosylgloboside (LKE) antigens. AB - BACKGROUND: "Weak P" is a rare red blood cell (RBC) phenotype, characterized by a global decrease in P(k) and P antigens. We now describe a second weak P individual who also typed LKE-negative (LKE-N) and possessed a clinically significant anti-LKE. STUDY DESIGN AND METHODS: Patient RBCs and plasma were examined by standard serology and flow cytometry. Glycosphingolipids (GSLs) from patient, P(k) , and LKE-strong (LKE-S) RBCs were isolated and analyzed by high performance thin-layer chromatography (HPTLC). To confirm antibody specificity, patient serum and 30 human polyclonal controls, including alloanti-P and anti-PP1 P(k) , were tested against a panel of GSLs by HPTLC immunostaining. RESULTS: The patient typed P1 +, P+, and LKE-N and possessed a "P-like" panagglutinin. In a two-stage indirect antiglobulin test, the patient's plasma caused hemolysis of LKE-S cells but not p, P(k) , or LKE-N cells. Clinically, transfusion of P+ RBCs compatible by a prewarmed technique had shortened RBC survival with laboratory evidence of hemolysis. Analysis of the patient's isolated RBC GSLs showed a 30% relative decrease in Gb3 (P(k) ) and Gb4 (P) and a 90% decrease in monosialogalactosylgloboside (MSGG, LKE), accompanied by increased lactosylceramide (CDH), paragloboside, and GM3. On HPTLC immunostaining, the patient's plasma strongly bound MSSG with weak binding to galactosylgloboside (Gb5). Binding to MSGG, Gb5, and Gb4 was also observed with some examples of alloanti-P from P(k) individuals, but not anti-PP1 P(k) , autoanti-P, or normal controls. CONCLUSIONS: We describe the first example of a clinically significant anti-LKE in the setting of a rare weak P background. Human alloanti-LKE and some alloanti-P recognized Gb5 and MSGG. PMID- 25039256 TI - Presence of ochratoxin A (OTA) mycotoxin in alcoholic drinks from southern European countries: wine and beer. AB - The main filamentous fungi producers of mycotoxins are Aspergillus spp., Penicillium spp., and Fusarium spp. Their effect can provoke a broad range of toxic properties including carcinogenicity and neurotoxicity, as well as reproductive and developmental toxicities. Ochratoxin A (OTA) is produced by Aspergillus and Penicillium spp. The purpose of this review was to evaluate the risk assessment of OTA in alcoholic drinks (beer and wine) by compiling the results obtained from studies and reviews related to the presence of OTA in these two drinks from southern European countries in the period 2005-2013 and comparing those results with the legislation available in the European Union. PMID- 25039257 TI - How topography induces reproductive asynchrony and alters gypsy moth invasion dynamics. AB - Reproductive asynchrony, a temporal mismatch in reproductive maturation between an individual and potential mates, may contribute to mate-finding failure and Allee effects that influence the establishment and spread of invasive species. Variation in elevation is likely to promote variability in maturation times for species with temperature-dependent development, but it is not known how strongly this influences reproductive asynchrony or the population growth of invasive species. We examined whether spatial variation in reproductive asynchrony, due to differences in elevation and local heterogeneity in elevation (hilliness), can explain spatial heterogeneity in the population growth rate of the gypsy moth, Lymantria dispar (L.), along its invasion front in Virginia and West Virginia, USA. We used a spatially explicit model of the effects of reproductive asynchrony on mating success to develop predictions of the influences of elevation and elevational heterogeneity on local population growth rates. Population growth rates declined with increased elevation and more modestly with increased elevational heterogeneity. As in earlier work, we found a positive relationship between the population growth rate and the number of introduced egg masses, indicating a demographic Allee effect. At high elevations and high heterogeneity in elevation, the population growth rate was lowest and the density at which the population tended to replace itself (i.e. the Allee threshold) was highest. An analysis of 22 years of field data also showed decreases in population growth rates with elevation and heterogeneity in elevation that were largely consistent with the model predictions. These results highlight how topographic characteristics can affect reproductive asynchrony and influence mate-finding Allee effects in an invading non-native insect population. Given the dependence of developmental rates on temperature in poikilotherms, topographic effects on reproductive success could potentially be important to the population dynamics of many organisms. PMID- 25039258 TI - The effects of fibrinogen concentration on fibrin/atelocollagen composite gel: an in vitro and in vivo study in rabbit calvarial bone defect. AB - OBJECTIVE: This study aimed to optimize the fibrinogen concentration in fibrin and atelocollagen (AT-COL) (fibrin/AT-COL) composite gel for improving bone regeneration. METHODS AND MATERIALS: The fibrin/AT-COL composite gels were fabricated using various fibrinogen concentrations, and the microstructure and mechanical properties of the resulting composite gels analyzed. The cytocompatibility of the composite gels was examined using human mesenchymal stem cell (hMSCs). Furthermore, in nine rabbits, the in vivo bone regeneration efficiency was evaluated using a rabbit calvarial defects model at 2 weeks (n = 3), 4 weeks (n = 3), and 8 weeks (n = 3). RESULTS: Scanning electron microscopy analysis revealed the formation of a fibrin layer matrix and collagen fibril networks. The composite gel containing 40 mg/ml fibrinogen showed a densely packed fibrin matrix and displayed superior mechanical properties. Cells cultured in the composite gels prepared with 5-20 mg/ml fibrinogen appeared elongated, with a spindle-like morphology. At a higher fibrinogen concentration (40 mg/ml), many cells were rounded and showed limited viability. In an in vivo study, at 8 weeks, the volume of fibrin/AT-COL gel (P = 0.02) was significantly higher than that of fibrin gel alone in the newly formed bone. Histological analysis revealed more islands of newly formed bone filling the central area of the defect in the fibrin/AT-COL gel-implanted animals. CONCLUSION: Our results demonstrate that optimization of the fibrinogen content of fibrin/AT-COL composites should be beneficial for bone tissue engineering. PMID- 25039260 TI - Quantitative assessment of growing hair counts, thickness and colour during and after treatments with a low-fluence, home-device laser: a randomized controlled trial. AB - BACKGROUND: At-home laser and intense pulsed-light hair removal continues to grow in popularity and availability. A relatively limited body of evidence is available on the course of hair growth during and after low-fluence laser usage. OBJECTIVES: To assess growing hair counts, thickness and colour quantitatively during and after cessation of low-fluence laser treatment. METHODS: Thirty-six women with skin phototypes I-IV and light to dark-brown axillary hairs were included. Entire axillary regions were randomized to zero or eight self administered weekly treatments with an 810-nm home-use laser at 5.0-6.4 J cm(-2). Standardized clinical photographs were taken before each treatment and up to 3 months after the final treatment for computer-aided quantification of growing hair counts, thickness and colour. RESULTS: Thirty-two women completed the study protocol. During sustained treatment, there was a reduction in growing hair that reached a plateau of up to 59%, while remaining hairs became up to 38% thinner and 5% lighter (P < 0.001). The majority of subjects (77%) reported 'moderately' to 'much less hair' in treated than untreated axilla, and assessed remaining hairs as thinner and lighter (>= 60%). After treatment cessation, hair growth gradually returned to baseline levels, and 3 months after the final treatment the count and thickness of actively growing hair exceeded pretreatment values by 29% and 7%, respectively (P <= 0.04). CONCLUSIONS: Sustained usage of low-fluence laser induced a stable reduction of growing hair counts, thickness and colour. The reduction was reversible and hairs regrew beyond baseline values after cessation of usage. Computer-aided image analysis was qualified for quantification of hair counts, thickness and colour after laser epilation. PMID- 25039259 TI - Depression, antidepressants, and bone health in older adults: a systematic review. AB - OBJECTIVES: To examine the association between depression, antidepressant use, and bone health in older adults and the implications for treatment. DESIGN: Systematic review. SETTING: All studies that measured depression or antidepressant exposure and bone mineral density (BMD). PARTICIPANTS: Adults aged 60 and older. MEASUREMENTS: Age, site of BMD measurement using dual-energy X-ray absorptiometry (DXA), measure of depression or depressive symptoms, association between BMD changes, and depression or antidepressant use. RESULTS: Nineteen observational studies met the final inclusion criteria; no experimental studies were found. Several cross-sectional and longitudinal studies found that depression or depressive symptoms were associated with a decrease in BMD. Few studies and only two longitudinal studies addressed the association between serotonin reuptake inhibitor (SRI) antidepressant use and a decrease in BMD and they had conflicting results. CONCLUSION: Depression and depressive symptoms are associated with low bone mass and accelerated bone loss in older adults; putative mechanisms underlying this relationship are discussed. There is insufficient evidence that SRI antidepressants adversely affect bone health. Thus, a change in current recommendations for the use of antidepressants in older adults is not justified at the present time. Given the high public health significance of this question, more studies are required to determine whether (and in whom) antidepressants may be deleterious for bone health. PMID- 25039261 TI - Association study of MTHFD1 coding polymorphisms R134K and R653Q with migraine susceptibility. AB - OBJECTIVE: There is evidence that folate metabolism has a role in migraine pathophysiology, particularly in the migraine with aura (MA) subtype. In this study, we investigate whether two non-synonymous single nucleotide polymorphisms (SNPs), rs1950902 (C401T; R134K) and rs2236225 (G1958A; R653Q), in MTHF dehydrogenase (MTHFD1) are associated with migraine in an Australian case-control population. BACKGROUND: Increased plasma levels of homocysteine, one of the metabolites produced in the folate pathway, has been found to be a risk factor for migraine. There is also a genetic link: a common polymorphism (rs1801133, C667T) that reduces the catalytic activity of the enzyme that catalyzes the formation of homocysteine, methylenetetrahydrofolate reductase (MTHFR), is associated with an increase in risk of MA. MTHFD1 is a crucial multifunctional enzyme that catalyzes three separate reactions of the folate pathway and therefore variants in MTHFD1 may also influence migraine susceptibility. METHODS: The R134K and R653Q variants in MTHFD1 were genotyped in an Australian cohort of 520 unrelated migraineurs (162 were diagnosed with migraine without aura [MO] and 358 with MA) and 520 matched controls. Data were analyzed for association with migraine and for interaction with the MTHFR C667T polymorphism. RESULTS: We find no significant differences in genotype or allele frequencies for either SNP between migraineurs and controls, or when either MO or MA cases were compared with controls. In addition, these MTHFD1 polymorphisms did not appear to influence the risk of MA conferred by the MTHFR 667T allele. CONCLUSIONS: We find no evidence for association of the MTHFD1 R134K and R653Q polymorphisms with migraine in our Australian case-control population. However, as folate metabolism appears to be important in migraine, particularly with respect to the aura component, future studies using high throughput methods to expand the number of SNPs in folate-related genes genotyped and investigation of interactions between SNPs may be justified. PMID- 25039262 TI - The relation between X chromosome parental origin and aortic stiffness in patients with Turner's syndrome: role of hypertension and antihypertensive drugs. PMID- 25039263 TI - Self-rated health, nutritional intake and mortality in adult hospitalized patients. AB - BACKGROUND: In the general population, poor self-rated health (SRH) is associated with malnutrition; however, these associations have not been studied in hospitalized patients. We aimed to evaluate SRH, indicators of nutrition, nutritional status and their association with in-hospital mortality. MATERIALS AND METHODS: The study is based on data from the nutritionDay, a multinational, multicentre European-wide standardized 1-day cross-sectional survey of nutritional factors, food intake and in-hospital mortality in hospitalized patients. A data set of surveys on SRH in 2010 and 2011 was used in the analysis. RESULTS: Complete sets of data were available for 28 106 patients (64 +/- 18 years, 50% men, 7% terminally ill). In relation to body mass index, 7% were undernourished and 16% were obese. Fair/poor SRH was reported by 59% of patients and was associated with low food intake during the previous week or on survey day (P < 0.005). Thirty-day in-hospital mortality was 3%; in adjusted multivariate survival analysis, fair/poor SRH [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.14-2.05] and reduced food intake [nothing eaten (HR 2.13, 95% CI 1.46 3.11) or not allowed to eat on nutritionDay (HR 2.01, 95% CI 1.30-3.11)] predicted fatal outcome. At particularly high risk were patients who rated their health poor and had reduced food intake on the survey day or within the previous week with relative risks of 7.37 and 8.80, respectively. CONCLUSIONS: We demonstrated high prevalence of poor SRH and insufficient food intake in hospitalized patients. This was associated, particularly in combination, with increased risk of in-hospital mortality. PMID- 25039264 TI - RavA/RavR two-component system regulates Xanthomonas campestris pathogenesis and c-di-GMP turnover. AB - The two-component system (TCS), consisting of a response regulator (RR) and a cognate histidine kinase (HK), responds to extra-/intercellular cues and triggers adaptive changes. The RR, RavR, has been reported to act as a positive virulence regulator and a c-di-GMP hydrolase in Xanthomonas campestris pv. campestris (Xcc). Here, we identified the cognate HK, RavA, that regulate RavR phosphorylation levels and bacterial pathogenesis. Deletion of ravA, a putative HK gene flanking ravR, dramatically attenuated Xcc virulence. Phenotypes of the double mutant DeltaravR/DeltaravA were similar to those of DeltaravR, suggesting that RavR is a downstream component of RavA signaling. RavA interacts with RavR and positively influences the phosphorylated RavR levels. In vitro analysis suggests that RavR is a bifunctional enzyme involved in c-di-GMP synthesis and degradation. Importantly, mutation and enzyme activity assays indicate that the phosphorylation level affects RavR c-di-GMP turnover activity. These results show that RavA acts as the RavR cognate HK, which fine-tunes RavR functions and enables bacteria to adapt quickly to intracellular changes. PMID- 25039265 TI - Left atrial deformation predicts pulmonary capillary wedge pressure in pediatric heart transplant recipients. AB - BACKGROUND: Pulmonary capillary wedge pressure (PCWP) is an important indicator in pediatric heart transplant patients, but commonly used noninvasive surrogates, such as ratio of early diastolic mitral inflow velocity to annular velocity (E/E'), have limitations in this population. This study aimed to evaluate the relation of left atrial (LA) peak systolic strain and distensibility with PCWP in pediatric heart transplant recipients. METHODS: Consecutive pediatric heart transplant patients were enrolled at time of cardiac catheterization, with echocardiogram immediately afterward. E/E' ratio at the lateral and medial mitral annulus, peak LA systolic longitudinal strain by speckle tracking, and LA distensibility were measured from echocardiograms and compared to invasively measured PCWP. RESULTS: In 38 patients (11.1 +/- 5.8 years old), PCWP correlated with peak LA systolic strain (r = -0.44, P = 0.01) and LA distensibility (r= 0.43, P = 0.02), but not with E/E'. On receiver operating characteristics analysis, LA strain had a higher area under the curve than LA distensibility (0.846 vs. 0.606). LA strain <18.9% had sensitivity 62% and specificity 95%, with likelihood ratio 12.3 for PCWP >=12. However, LA strain had lower intra-observer and inter-observer reproducibility than distensibility (intra-class correlation coefficients 0.89 and 0.75 vs. 0.93 and 0.90). CONCLUSIONS: Peak LA systolic strain and LA distensibility may be more useful surrogates of left ventricular filling pressure than E/E' in the pediatric heart transplant population, with greater reproducibility of LA distensibility. Longitudinal studies are needed to evaluate which parameters track changes in PCWP and clinical outcome. PMID- 25039266 TI - Acquired lecithin:cholesterol acyltransferase deficiency as a major factor in lowering plasma HDL levels in chronic kidney disease. AB - OBJECTIVES: It has been suggested that a low plasma high-density lipoprotein cholesterol (HDL-C) level contributes to the high cardiovascular disease risk of patients with chronic kidney disease (CKD), especially those undergoing haemodialysis (HD). The present study was conducted to gain further understanding of the mechanism(s) responsible for the low HDL-C levels in patients with CKD and to separate the impact of HD from that of the underlying CKD. METHODS: Plasma lipids and lipoproteins, HDL subclasses and various cholesterol esterification parameters were measured in a total of 248 patients with CKD, 198 of whom were undergoing HD treatment and 40 healthy subjects. RESULTS: Chronic kidney disease was found to be associated with highly significant reductions in plasma HDL-C, unesterified cholesterol, apolipoprotein (apo)A-I, apoA-II and LpA-I:A-II levels in both CKD cohorts (with and without HD treatment). The cholesterol esterification process was markedly impaired, as indicated by reductions in plasma lecithin:cholesterol acyltransferase (LCAT) concentration and activity and cholesterol esterification rate, and by an increase in the plasma prebeta-HDL content. HD treatment was associated with a further lowering of HDL levels and impaired plasma cholesterol esterification. The plasma HDL-C level was highly significantly correlated with LCAT concentration (R = 0.438, P < 0.001), LCAT activity (R = 0.243, P < 0.001) and cholesterol esterification rate (R = 0.149, P = 0.031). Highly significant correlations were also found between plasma LCAT concentration and levels of apoA-I (R = 0.432, P < 0.001), apoA-II (R = 0.275, P < 0.001), LpA-I (R = 0.326, P < 0.001) and LpA-I:A-II (R = 0.346, P < 0.001). CONCLUSION: Acquired LCAT deficiency is a major cause of low plasma HDL levels in patients with CKD, thus LCAT is an attractive target for therapeutic intervention to reverse dyslipidaemia, and possibly lower the cardiovascular disease risk in these patients. PMID- 25039267 TI - The advance of poststructuralism and its influence on family therapy. AB - Postmodernism began to influence family therapy very early in the 1980s with articles referencing postmodern ideas, focusing on meaning and multiplicity. With the appearance of narrative therapy on the scene in the 1990s there was a shift toward poststructural thinking, which refined the movement and politicized the clinical work. Even with a bit of a backlash, whether because this was a new idea or it somehow threatened a positivistic culture, a poststructural view has continued to have effects on family therapy. This article explores the variety of influences: the expansion of narrative ideas, the innovation of Madsen's collaborative helping, and also more nuanced effects. I argue that a poststructural view has effectively changed how many family therapists think and may also be subtly influencing how they might work. PMID- 25039270 TI - Evidence for perceptual neglect of environmental features in hippocampal-lesioned pigeons during homing. AB - The importance of the vertebrate hippocampus in spatial cognition is often related to its broad role in memory. However, in birds, the hippocampus appears to be more specifically involved in spatial processes. The maturing of GPS tracking technology has enabled a revolution in navigation research, including the expanded possibility of studying brain mechanisms that guide navigation in the field. By GPS-tracking homing pigeons released from distant, unfamiliar sites prior to and after hippocampal lesion, we observed, as has been reported previously, impaired navigational performance post-lesion over the familiar/memorized space near the home loft, where topographic features constitute an important source of navigational information. The GPS-tracking revealed that many of the lost pigeons, when lesioned, approached the home area, but nevertheless failed to locate their loft. Unexpectedly, when they were hippocampal-lesioned, the pigeons showed a notable change in their behaviour when navigating over the unfamiliar space distant from home; they actually flew straighter homeward-directed paths than they did pre-lesion. The data are consistent with the hypothesis that, following hippocampal lesion, homing pigeons respond less to unfamiliar visual, topographic features encountered during homing, and, as such, offer the first evidence for an unforeseen, perceptual neglect of environmental features following hippocampal damage. PMID- 25039268 TI - Exploring genetic variation in the tomato (Solanum section Lycopersicon) clade by whole-genome sequencing. AB - We explored genetic variation by sequencing a selection of 84 tomato accessions and related wild species representative of the Lycopersicon, Arcanum, Eriopersicon and Neolycopersicon groups, which has yielded a huge amount of precious data on sequence diversity in the tomato clade. Three new reference genomes were reconstructed to support our comparative genome analyses. Comparative sequence alignment revealed group-, species- and accession-specific polymorphisms, explaining characteristic fruit traits and growth habits in the various cultivars. Using gene models from the annotated Heinz 1706 reference genome, we observed differences in the ratio between non-synonymous and synonymous SNPs (dN/dS) in fruit diversification and plant growth genes compared to a random set of genes, indicating positive selection and differences in selection pressure between crop accessions and wild species. In wild species, the number of single-nucleotide polymorphisms (SNPs) exceeds 10 million, i.e. 20-fold higher than found in most of the crop accessions, indicating dramatic genetic erosion of crop and heirloom tomatoes. In addition, the highest levels of heterozygosity were found for allogamous self-incompatible wild species, while facultative and autogamous self-compatible species display a lower heterozygosity level. Using whole-genome SNP information for maximum-likelihood analysis, we achieved complete tree resolution, whereas maximum-likelihood trees based on SNPs from ten fruit and growth genes show incomplete resolution for the crop accessions, partly due to the effect of heterozygous SNPs. Finally, results suggest that phylogenetic relationships are correlated with habitat, indicating the occurrence of geographical races within these groups, which is of practical importance for Solanum genome evolution studies. PMID- 25039269 TI - Clinical predictors of recurrent Clostridium difficile infection in out-patients. AB - BACKGROUND: Clostridium difficile infection (CDI) recurs in 20-30% of patients. AIM: To describe the predictors of recurrence in out-patients with CDI. METHODS: Out-patient cases of CDI in Olmsted County, MN residents diagnosed between 28 June 2007 and 25 June 2010 were identified. Recurrent CDI was defined as recurrence of diarrhoea with a positive C. difficile PCR test from 15 to 56 days after the initial diagnosis with interim resolution of symptoms. Patients who had two positive tests within 14 days were excluded. Cox proportional hazard models were used to assess the association of clinical variables with time to recurrence of CDI. RESULTS: The cohort included 520 out-patients; 104 had recurrent CDI (cumulative incidence of 17.5% by 30 days). Univariate analysis identified increasing age and antibiotic use to be associated with recurrent CDI. Severe CDI, peripheral leucocyte count and change in serum creatinine >1.5-fold were not. In a multiple variable model, concomitant antibiotic use was associated with risk of recurrent CDI (HR = 5.4, 95% CI 1.6-17.5, P = 0.005), while age (HR per 10 year increase = 1.1, 95% CI 0.9-1.3, P = 0.22); peripheral leucocyte count >15 * 10(9) /L (HR = 1.0, 95% CI 0.5-2.1, P = 0.92); and change in serum creatinine greater than 1.5-fold (HR = 0.8, 95% CI 0.4-1.5, P = 0.44) were not. CONCLUSIONS: Antibiotic use was independently associated with a dramatic risk of recurrent Clostridium difficile infection in an out-patient cohort. It is important to avoid unnecessary systemic antibiotics in patients with Clostridium difficile infection, and patients with ongoing antibiotic use should be monitored closely for recurrent infection. PMID- 25039271 TI - Peroxisomal APX knockdown triggers antioxidant mechanisms favourable for coping with high photorespiratory H2 O2 induced by CAT deficiency in rice. AB - The physiological role of peroxisomal ascorbate peroxidases (pAPX) is unknown; therefore, we utilized pAPX4 knockdown rice and catalase (CAT) inhibition to assess its role in CAT compensation under high photorespiration. pAPX4 knockdown induced co-suppression in the expression of pAPX3. The rice mutants exhibited metabolic changes such as lower CAT and glycolate oxidase (GO) activities and reduced glyoxylate content; however, APX activity was not altered. CAT inhibition triggered different changes in the expression of CAT, APX and glutathione peroxidase (GPX) isoforms between non-transformed (NT) and silenced plants. These responses were associated with alterations in APX, GPX and GO activities, suggesting redox homeostasis differences. The glutathione oxidation-reduction states were modulated differently in mutants, and the ascorbate redox state was greatly affected in both genotypes. The pAPX suffered less oxidative stress and photosystem II (PSII) damage and displayed higher photosynthesis than the NT plants. The improved acclimation exhibited by the pAPX plants was indicated by lower H2 O2 accumulation, which was associated with lower GO activity and glyoxylate content. The suppression of both pAPXs and/or its downstream metabolic and molecular effects may trigger favourable antioxidant and compensatory mechanisms to cope with CAT deficiency. This physiological acclimation may involve signalling by peroxisomal H2 O2 , which minimized the photorespiration. PMID- 25039272 TI - Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first-line sildenafil monotherapy. AB - OBJECTIVE: To evaluate the efficacy and safety of combination therapy of sildenafil plus vacuum erection devices in men with type 2 diabetes mellitus with moderate to severe erectile dysfunction who are dissatisfied with the results of using sildenafil alone. METHODS: The study included 66 diabetes mellitus patients presenting erectile dysfunction for at least 6 months and dissatisfied with the use of 100 mg sildenafil monotherapy. The patients were randomized in two groups. Those in group A (n = 33) were instructed to use a vacuum erection device only, whereas those in group B (n = 33) were treated with combination therapy, including sildenafil 100 mg and a vacuum erection device. Erectile function was evaluated subjectively using the International Index of Erectile Function, Sexual Encounter Profile questionnaire questions 2 and 3 at visit 1 (baseline; study entry), visit 2 (4 weeks after baseline), and visit 3 (12 weeks after baseline; study end). RESULTS: There were no significant differences in average patient age, duration of diabetes, duration of erectile dysfunction, baseline International Index of Erectile Function scores, hypertension, blood testosterone, smoking and alcohol consumption between two groups. Mean International Index of Erectile Function scores were significantly higher for group B at the 1-month (14.86 +/- 2.17 vs 12.41 +/- 2.63; P < 0.0001) and 3 months (17.53 +/- 2.95 vs 14.29 +/- 2.81; P < 0.0001) visits. Men in group B had better successful penetration (73.3% vs 46.6%) and successful intercourse (70% vs 46.6%) at 3 months compared with group A. CONCLUSION: Combined use of sildenafil and vacuum erection device therapy significantly enhances erectile function, and it is well tolerated by diabetes mellitus patients not responding to first-line sildenafil alone. PMID- 25039273 TI - Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects. AB - AIM: The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. METHODS: This was a phase 1, placebo controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. RESULTS: All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. CONCLUSION: A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. PMID- 25039274 TI - Efficacy and safety of combined radiotherapy with EGFR inhibitors and chemotherapy for laryngeal organ preservation in patients with locally advanced hypopharyngeal carcinomas. AB - BACKGROUND: The present study was designed to evaluate the efficacy and safety of a combination of helical tomotherapy (HT) or intensity-modulated radiotherapy (IMRT) and EGFR (epidermal growth factor receptor) inhibitor (Cetuximab or Nimotuzumab) with or without chemotherapy in patients with locally advanced hypopharyngeal carcinoma. PATIENTS AND METHODS: The retrospective study included forty-six patients (12 stage III and 34 stage IV) with locally advanced hypopharyngeal cancer. Among them, 20 were treated with induction chemotherapy with docetaxel and cisplatin (TP) followed by concurrent chemoradiotherapy with cisplatin and EGFR inhibitor, 13 received concurrent chemoradiotherapy with cisplatin and EGFR inhibitor, and 13 were treated with concurrent radiotherapy plus EGFR inhibitor. HT and IMRT were performed in 33 and 13 patients, respectively. Side effects were evaluated with the established CTCAE (Common Terminology Criteria for Adverse Events) 3.0 criteria. RESULTS: The median follow up time was 39.4 months (range 3-69 months). All patients completed the planned RT without any treatment breaks. The 3-year local control survival, disease-free survival, overall survival, and laryngeal preservation survival rates were 66.8%, 59.0%, 68.9%, and 86.7%, respectively. The most common grade 3 or higher side effect was oropharyngeal mucositis. One patient required dilatation of a pharyngeal stricture 18 months after treatment. No patient required percutaneous gastrostomy and tracheostomy tube. CONCLUSION: The treatment with EGFR inhibitor in combination with non-surgical combined modality in patients with hypopharyngeal carcinoma was well tolerated and resulted in encouraging laryngeal preservation survival rate. HT or IMRT, EGFR inhibitor, and effective management of severe oropharyngeal mucositis contributed to the positive outcomes. PMID- 25039275 TI - Prion-promoted phosphorylation of heterologous amyloid is coupled with ubiquitin proteasome system inhibition and toxicity. AB - Many neurodegenerative diseases are associated with conversion of a soluble protein into amyloid deposits, but how this is connected to toxicity remains largely unknown. Here, we explore mechanisms of amyloid associated toxicity using yeast. [PIN(+)], the prion form of the Q/N-rich Rnq1 protein, was known to enhance aggregation of heterologous proteins, including the overexpressed Q/N rich amyloid forming domain of Pin4 (Pin4C), and Pin4C aggregates were known to attract chaperones, including Sis1. Here we show that in [PIN(+)] but not [pin( )] cells, overexpression of Pin4C is deadly and linked to hyperphosphorylation of aggregated Pin4C. Furthermore, Pin4C aggregation, hyperphosphorylation and toxicity are simultaneously reversed by Sis1 overexpression. Toxicity may result from proteasome overload because hyperphosphorylated Pin4C aggregation is associated with reduced degradation of a ubiquitin-protein degradation reporter. Finally, hyperphosphorylation of endogenous full-length Pin4 was also facilitated by [PIN(+)], revealing that a prion can regulate post-translational modification of another protein. PMID- 25039277 TI - Victorian Audit of Surgical Mortality is associated with improved clinical outcomes. AB - BACKGROUND: Improved outcomes are desirable results of clinical audit. The aim of this study was to use data from the Victorian Audit of Surgical Mortality (VASM) and the Victorian Admitted Episodes Dataset (VAED) to highlight specific areas of clinical improvement and reduction in mortality over the duration of the audit process. METHODS: This study used retrospective, observational data from VASM and VAED. VASM data were reported by participating public and private health services, the Coroner and self-reporting surgeons across Victoria. Aggregated VAED data were supplied by the Victorian Department of Health. Assessment of outcomes was performed using chi-squared trend analysis over successive annual audit periods. Because initial collection of data was incomplete in the recruitment phase, statistical analysis was confined to the last 3-year period, 2010-2013. RESULTS: A 20% reduction in surgical mortality over the past 5 years has been identified from the VAED data. Progressive increase in both surgeon and hospital participation, significant reduction in both errors in management as perceived by assessors and increased direct consultant involvement in cases returned to theatre have been documented. CONCLUSIONS: The benefits of VASM are reflected in the association with a reduction of mortality and adverse clinical outcomes, which have clinical and financial benefits. It is a purely educational exercise and continued participation in this audit will ensure the highest standards of surgical care in Australia. This also highlights the valuable collaboration between the Victorian Department of Health and the RACS. PMID- 25039276 TI - Mortality and cardiovascular disease among older live kidney donors. AB - Over the past two decades, live kidney donation by older individuals (>=55 years) has become more common. Given the strong associations of older age with cardiovascular disease (CVD), nephrectomy could make older donors vulnerable to death and cardiovascular events. We performed a cohort study among older live kidney donors who were matched to healthy older individuals in the Health and Retirement Study. The primary outcome was mortality ascertained through national death registries. Secondary outcomes ascertained among pairs with Medicare coverage included death or CVD ascertained through Medicare claims data. During the period from 1996 to 2006, there were 5717 older donors in the United States. We matched 3368 donors 1:1 to older healthy nondonors. Among donors and matched pairs, the mean age was 59 years; 41% were male and 7% were black race. In median follow-up of 7.8 years, mortality was not different between donors and matched pairs (p = 0.21). Among donors with Medicare, the combined outcome of death/CVD (p = 0.70) was also not different between donors and nondonors. In summary, carefully selected older kidney donors do not face a higher risk of death or CVD. These findings should be provided to older individuals considering live kidney donation. PMID- 25039278 TI - Association between resolution of fragmented QRS and response to cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) has been recommended for patients with symptomatic heart failure and a wide QRS. Fragmented QRS (fQRS) on a 12-lead electrocardiography (ECG) has been shown to predict cardiac events. We aimed to investigate the relationship between resolution of fQRS and response to CRT. METHODS: Sixty-seven consecutive patients (38 men, mean age 65 +/- 11) with left bundle branch block and fQRS on ECG undergoing CRT were studied. The presence of fQRS was assessed using standardized criteria. Echocardiographic response to CRT was defined by a >=15% reduction in left ventricular end-systolic volume (LVESV) and resolution of fQRS was defined as decrease in number of leads with fQRS on ECG at 6 months follow-up. RESULTS: Thirty-nine patients (58%) had response to CRT. LVESV significantly decreased from 150 +/- 64 to 100 +/- 48 in responders (P = 0.001). There was not any significant decrease in nonresponders (LVESV; from 157 +/- 70 to 153 +/- 66, P = 0.45). The number of leads with fQRS was decreased from 4.4 +/- 1.8 to 1.7 +/- 1.6 in responder patients (P < 0.001). The number of leads with fQRS was not significantly changed in nonresponders. (4.2 +/- 2.2 vs. 5.1 +/- 2.4, P = 0.06). In multivariate analysis, significant associates of response to CRT was evaluated adjusting for etiology of cardiomyopathy, baseline QRS width, left ventricular ejection fraction, number of leads with fQRS and resolution of fQRS. Resolution of fQRS was the only predictor of response to CRT (OR 0.018, 95% CI, 0.004-0.083, P < 0.001). CONCLUSIONS: After adjusting for potential confounders, resolution of fQRS, is associated with response to CRT. PMID- 25039279 TI - Evidence that the pregnane X and retinoid receptors PXR, RAR and RXR may regulate transcription of the transporter hOCT1 in chronic myeloid leukaemia cells. AB - The expression and activity of the uptake transporter human organic cation transporter 1 (hOCT1; SLC22A1) is an independent predictor of response to imatinib treatment in patients with chronic myeloid leukaemia (CML). We have recently shown that peroxisome proliferator-activated receptor (PPAR) activation can increase the killing effect of imatinib in CML cells, due to upregulated hOCT1 gene expression and increased imatinib uptake. To investigate the role of activation of nuclear receptors other than PPAR in the transcriptional regulation of hOCT1, CML cells were treated with agonists for 13 adopted orphan receptors and endocrine receptors. It was found that hOCT1 expression was upregulated by the agonists for pregnane X receptor (PXR), retinoid acid receptor (RAR) and retinoid X receptor (RXR) in CML cell line and primary CML cells (P = 0.04; Wilcoxon rank test). Hence, agonists for PXR, RAR and RXR may be potentially used to improve the efficacy of imatinib in patients with CML. PMID- 25039280 TI - Dynamics of vitamin K antagonist and new oral anticoagulants use in atrial fibrillation: a Danish drug utilization study. AB - BACKGROUND: Detailed data on real-life utilization of vitamin K antagonists (VKAs) and new oral anticoagulants (NOACs) in atrial fibrillation are sparse. OBJECTIVES: To describe the dynamics of VKA and NOAC use: that is, (i) how patients moved in and out of, as well as between, use of VKAs and NOACs; (ii) how patients adhered to treatment; and (iii) which type of prescriber initiated, maintained, and changed treatment with VKAs and NOACs. METHODS: We conducted a drug utilization study in the region of southern Denmark (population 1.2 million) using prescription data. We included all subjects using VKAs or NOACs during the period of August 22, 2011, through June 30, 2013, restricted to subjects with a diagnosis of atrial fibrillation. RESULTS: We identified 20,911 subjects, of whom 20,769 and 1639 used VKAs and NOACs, respectively. The number of VKA users was stable at ~ 14,000 subjects during the study period, whereas the number of NOAC users increased to 903. The majority of NOAC users had previously used VKAs (n = 974), whereas 389 anticoagulant-naive users initiated NOAC therapy. Among the latter, 51.2% had changed to VKAs within 6 months. 57.3% of VKA users were initiated by a hospital physician, whereas maintenance treatment was predominantly handled by the patient's general practitioner (97.6%). Switches from NOAC to VKA were initiated by a general practitioner in 69.2% of the cases. For users of NOACs, these numbers were 73.5%, 94.0%, and 63.3%. CONCLUSIONS: A large proportion of NOAC users switch to a VKA within a short time frame. The reasons for this are not clear. PMID- 25039281 TI - Gelsolin and adipokines are associated with protein-energy wasting in hemodialysis patients. AB - Protein-energy wasting (PEW) contributes to mortality in hemodialysis (HD) patients. Adipokines regulate energy homeostasis and body weight. Circulating gelsolin can modulate inflammation and is correlated with HD mortality. Whether adipokines and gelsolin play important roles in PEW remains unclear. Based on the criteria proposed by the International Society of Renal Nutrition and Metabolism, we examined the associations between PEW and biomarkers (gelsolin, leptin, adiponectin, interleukin-6, tumor necrosis factor alpha [TNF-alpha]) in 188 stable HD patients. Patients with PEW had significantly lower serum leptin levels, and tended to have higher adiponectin, TNF-alpha, and lower gelsolin levels. Logistic regression analysis revealed that gelsolin, leptin, adiponectin, and blood urea nitrogen were independently associated with PEW score. Serum creatinine, TNF-alpha, gender, renin-angiotensin system (RAS) blockade, and lipid lowering agents were not associated with PEW score. Patients on lipid-lowering agents had lower PEW scores and those with RAS blockade had higher PEW scores. Our study confirms that gelsolin, adiponectin, and leptin are significant associates with PEW in HD patients. Further understanding of how these factors contribute to PEW may help design novel therapeutic strategies for PEW in chronic kidney disease. PMID- 25039282 TI - Phase II study of bortezomib in combination with rituximab, cyclophosphamide and prednisone with or without doxorubicin followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma. AB - This non-comparative phase II study (ClinicalTrials.gov: NCT00715208) evaluated bortezomib in place of vincristine in established rituximab-chemotherapy regimens in relapsed/refractory follicular (FL) or marginal zone lymphoma (MZL). Patients were allocated (physician/patient preference) to receive six 21-d cycles of: bortezomib 1.6 mg/m(2) (days 1, 8), rituximab 375 mg/m(2) (day 1), cyclophosphamide 1000 mg/m(2) (day 1) and prednisone 100 mg (days 1-5; VR-CP; 47 FL, 1 MZL patients); or bortezomib, rituximab, prednisone per VR-CP, cyclophosphamide 750 mg/m(2) and doxorubicin 50 mg/m(2) (day 1; VR-CAP; 4 FL, 2 MZL, 1 chronic lymphocytic leukaemia patients). With VR-CP, the response rate was 77%, with a 27% complete response rate. After a median follow-up of 10.9 months, 40% of patients had relapsed/progressed or died. Median duration of response and progression-free survival was 21.9 and 14.9 months, respectively. Common drug related grade >=3 adverse events were neutropenia (25%), thrombocytopenia (6%) and lymphopenia (6%). Thirteen (27%) patients reported peripheral neuropathy (one grade 3). With VR-CAP, one FL patient achieved complete response and three FL and two MZL patients achieved partial responses. Three patients reported drug-related grade 1/2 peripheral neuropathy. Weekly bortezomib and rituximab represents an active, feasible treatment platform in FL. VR-CP was active and well tolerated in patients with relapsed/refractory FL. PMID- 25039283 TI - Induction of epithelial-mesenchymal transition and loss of podoplanin expression are associated with progression of lymph node metastases in human papillomavirus related oropharyngeal carcinoma. AB - AIMS: To examine human papillomavirus (HPV) status, the expression of podoplanin and epithelial-mesenchymal transition (EMT) markers and lymphatic vessel counts (LVC) in oropharyngeal squamous cell carcinoma (OPSCC) tissues, and to evaluate whether these factors were associated with survival and nodal status. METHODS AND RESULTS: A total of 53 OPSCC specimens were evaluated for HPV status and expression of proteins such as podoplanin and EMT markers by immunohistochemistry. E-cadherin-negative and vimentin-positive specimens were defined as EMT-positive. Twenty-two OPSCCs were HPV-positive. There was significant progression of nodal status in patients with HPV-positive tumours (P = 0.0475). HPV-positive cases had significantly lower expression of podoplanin (P = 0.0016) and were more frequently EMT-positive (P = 0.0172). Podoplanin-negative cases and EMT-positive cases showed significantly more advanced nodal status than their respective counterparts (P = 0.0082 and P = 0.0186, respectively). LVC correlated with neither HPV nor nodal status. Multivariate analyses revealed that HPV infection was an independent marker of longer disease-specific survival (P = 0.014). CONCLUSIONS: HPV-positivity in OPSCC was associated with loss of podoplanin expression and with EMT induction, which resulted in progression of nodal status. The mechanisms leading to an improved prognosis in HPV-positive OPSCC patients requires elucidation, as this is inconsistent with the aggressive phenotype with lymph node metastases. PMID- 25039284 TI - Effects of milk replacer and starter diet provided as creep feed for suckling pigs on pre- and post-weaning growth. AB - This study was aimed at investigating the long-term effects of provision of liquid milk replacer (MR) and solid starter diet (SD) during lactation on post weaning (PW) growth of pigs. In experiment 1, 33 cross-bred litters were allotted to four treatments: no supplement (CON), MR ad libitum, SD ad libitum and 100 g SD/litter/day from lactation day 4 through weaning at day 21 during late fall. In experiment 2, 40 litters received MR or none in July. PW pigs received commercial diets to marketing. In experiment 1, weaning weight (WW), pre-weaning average daily gain (ADG) and mortality (2.4%) were not influenced by creep-feeding MR or SD. ADG was greater (P < 0.05) in the MR group versus CON during days 21-54, but did not differ across the treatments during days 54-162. In experiment 2, ADG during lactation and WW were greater in the MR group versus CON, with mortality lower in the former (5.6 vs. 10.3%). However, PW ADG to day 175 did not differ between the two groups. Results suggest that creep-feeding MR or SD has no effect on PW growth. However, it remains possible that MR reduces PW mortality during the hot season. PMID- 25039285 TI - Cryoablation of septal accessory pathways in children: midterm results. AB - BACKGROUND: Radiofrequency (RF) catheter ablation in the septal arrhythmia substrates has an increased risk of irreversible atrioventricular block. Despite its safety profile, several studies reported a lower acute success rate and a higher recurrence rate with cryoablation of septal accessory pathways (APs) when compared to RF ablation. The aim of this study was to assess the efficacy and safety of cryoablation of right septal APs using an electroanatomical mapping system guidance. METHODS AND RESULTS: A total of 43 consecutive patients (13.2 +/ 5.5 years) underwent cryoablation for right septal APs. The EnSite system (St. Jude Medical, St. Paul, MN, USA) was used in all procedures. No fluoroscopy was used in 90% of patients (39/43). The mean fluoroscopy time in the remaining four patients was 3.7 +/- 0.7 minutes. An electrophysiology catheter with 2-mm distal spacing was used to determine the precise AP location. The majority of the patients (20/43) had anteroseptal, and remaining of the patients had posteroseptal (15/43) and midseptal (8/43) APs. A 6-mm-tip catheter was used in 33 patients and 8-mm-tip catheter was used in nine patients (both catheters were used in one patient). The mean procedure duration and number of complete cryoablation lesions were 181.5 +/- 60.6 minutes and 6.1 +/- 3.1 minutes, respectively. Acute success was achieved in 40 of 43 patients (93%). No complications were noted. During a mean follow-up of 8.8 +/- 4.8 months, five patients (12.5%) experienced recurrence. CONCLUSIONS: Our data suggest that cryoablation of septal APs can be performed safely with comparable efficacy to the reported RF ablation results using a limited fluoroscopy approach. PMID- 25039286 TI - Expression of Oct-4, SOX-2, and MYC in dental papilla cells and dental follicle cells during in-vivo tooth development and in-vitro co-culture. AB - During tooth development, the special structure of dental follicle and dental papilla enables dental papilla cells (DPCs) and dental follicle cells (DFCs) to make contact with each other. Octamer-binding transcription factor 4 (Oct-4), sex determining region Y box-2 (SOX-2), and cellular homologue of avian myelocytomatosis virus oncogene (MYC) (OSM) are associated with reprogramming and pluripotency. However, whether the expression of OSM could be activated through cell-cell communication is not known. In this study, the distribution of OSM in rat tooth germ was investigated by immunohistochemical staining. An in-vitro co culture system of DPCs and DFCs was established. Cell proliferation, cell apoptosis, cell cycle stages, and expression of OSM were investigated by Cell Counting Kit 8 (CCK8) analysis, flow cytometry, real-time PCR, and immunohistochemical staining. We found that Oct-4 and SOX-2 were strongly expressed in tooth germ on days 7 and 9 after birth, whereas MYC was expressed only on day 9. Cell proliferation and apoptosis were inhibited, the cell cycle was arrested in the G0/G1 phase, and the propidium iodide (PI) value was downregulated. Expression of Oct-4 and SOX-2 was significantly elevated in both cell types after 3 d of co-culture, whereas expression of MYC was not significantly elevated until day 5. These results indicate that the optimized microenvironment with cell-cell communication enhanced the expression of reprogramming markers associated with reprogramming capacity in DPCs and DFCs, both in vivo and in vitro. PMID- 25039287 TI - Effect of modulated photo-activation on polymerization shrinkage behavior of dental restorative resin composites. AB - This study investigated the influence of modulated photo-activation on axial polymerization shrinkage, shrinkage force, and hardening of light- and dual curing resin-based composites. Three light-curing resin composites (SDR bulk fill, Esthet X flow, and Esthet X HD) and one dual-curing material (Rebilda DC) were subjected to different irradiation protocols with identical energy density (27 J cm(-2) ): high-intensity continuous light (HIC), low-intensity continuous light (LIC), soft-start (SS), and pulse-delay curing (PD). Axial shrinkage and shrinkage force of 1.5-mm-thick specimens were recorded in real time for 15 min using custom-made devices. Knoop hardness was determined at the end of the observation period. Statistical analysis revealed no significant differences among the curing protocols for both Knoop hardness and axial shrinkage, irrespective of the composite material. Pulse-delay curing generated the significantly lowest shrinkage forces within the three light-curing materials SDR bulk-fill, Esthet X flow, and Esthet X HD. High-intensity continuous light created the significantly highest shrinkage forces within Esthet X HD and Rebilda DC, and caused significantly higher forces than LIC within Esthet X flow. In conclusion, both the composite material and the applied curing protocol control shrinkage force formation. Pulse-delay curing decreases shrinkage forces compared with high-intensity continuous irradiation without affecting hardening and axial polymerization shrinkage. PMID- 25039288 TI - Management and outcome of 35 cases with foetal/neonatal alloimmune neutropenia. AB - AIM: The aim of this study was to provide an overview of foetal/neonatal alloimmune neutropenia (FNAIN), together with advice on the clinical management. METHODS: Neutrophil serology in the Netherlands is centralised at Sanquin Diagnostic Services. We examined FNAIN cases between January 1, 1991, and July 1, 2013, to determine the number of cases diagnosed, the relationship with human neutrophil antigen (HNA) antibody, the clinical presentation and therapeutic interventions. RESULTS: We identified 35 FNAIN cases. The detected HNA antibodies were as follows: anti-HNA-1a (n = 7), anti-HNA-1b (n = 12), anti-HNA-1c (n = 2), anti-HNA-2 (n = 8), anti-HNA-3a (n = 1), anti-HNA-5a (n = 1) and anti FcgammaRIIIb (n = 4). No infections were diagnosed in 14 neonates, and the other 21 neonates suffered from omphalitis (n = 6), urinary tract infection (n = 1), candida mucositis (n = 1), fever of unknown origin (n = 6) and sepsis (n = 7, 20%). Parity, gestational age, birthweight, neutrophil counts and antibody specificity were not significantly different for cases with, and without, infections. All the infected children were treated with antibiotics. No children died. CONCLUSION: More than half (21) of the 35 cases of FNAIN presented with infections and most implicated were HNA-1a, HNA-1b and HNA-2. Treatment with antibiotics seemed adequate. A neonatal neutropenia workflow model for use in neonatal intensive care units is presented. PMID- 25039289 TI - Halotolerance and survival kinetics of lactic acid bacteria isolated from jalapeno pepper (Capsicum annuum L.) fermentation. AB - The microbiota associated with spontaneous fermentation of vegetables in a saline substrate may represent an important group of bacteria in the food industry. In this work, the lactic acid bacteria (LAB) Weissella cibaria, Lactobacillus plantarum, Lactobacillus paraplantarum, and Leuconostoc citreum were identified by partial 16S rRNA gene sequence analysis. In addition, entophytic bacteria such as Pantoea eucalypti, Pantoea anthophila, Enterobacter cowanii, and Enterobacter asburiae were detected, but they were irrelevant for the fermentation process and were inhibited after 12 h of fermentation when the pH decreased from 6.5 to 4.9. Moreover, 2 species of yeast were isolated and identified as Hanseniaspora pseudoguilliermondii and Kodamaea ohmeri by their partial 26S rRNA gene sequence. The growth of LAB was evaluated at different sodium chloride contents. L. citreum was the most halotolerant species followed by L. plantarum and W. cibaria with a concentration index to obtain a 50% population reduction (IC(50)) of 7.2%, 6.6%, and 5.2%, respectively. Furthermore, the growth of LAB and Escherichia coli O157:H7 was evaluated in the presence of the main phenylpropanoids from chilli peppers such as p-coumaric and ferulic acid. It was determined that LAB can grow in both acids at 4 mM, unlike E. coli O157:H7, whose growth is inhibited in the presence of these acids. PMID- 25039291 TI - Breast cancer risk and aging--misquoted data and public information. AB - The "risk of breast cancer in women increases with age" is a longtime misstatement that does not conform to statistical data. Contrary to the common perception and widely publicized statements, the overall risk of developing breast cancer decreases in women as they grow old. PMID- 25039290 TI - Effects of early institutionalization on the development of emotion processing: a case for relative sparing? AB - We tested the capacity to perceive visual expressions of emotion, and to use those expressions as guides to social decisions, in three groups of 8- to 10-year old Romanian children: children abandoned to institutions then randomly assigned to remain in 'care as usual' (institutional care); children abandoned to institutions then randomly assigned to a foster care intervention; and community children who had never been institutionalized. Experiment 1 examined children's recognition of happy, sad, fearful, and angry facial expressions that varied in intensity. Children assigned to institutional care had higher thresholds for identifying happy expressions than foster care or community children, but did not differ in their thresholds for identifying the other facial expressions. Moreover, the error rates of the three groups of children were the same for all of the facial expressions. Experiment 2 examined children's ability to use facial expressions of emotion to guide social decisions about whom to befriend and whom to help. Children assigned to institutional care were less accurate than foster care or community children at deciding whom to befriend; however, the groups did not differ in their ability to decide whom to help. Overall, although there were group differences in some abilities, all three groups of children performed well across tasks. The results are discussed in the context of theoretical accounts of the development of emotion processing. PMID- 25039292 TI - A systematic review and Bayesian network meta-analysis of randomized clinical trials on non-surgical treatments for peri-implantitis. AB - BACKGROUND/AIM: It remains unclear which type of non-surgical treatment is most appropriate as first-line intervention against peri-implantitis. This systematic review and Bayesian network meta-analysis aimed to compare the clinical effect of various non-surgical peri-implantitis therapies. METHODS: The PubMed, SCOPUS, CINAHL, DARE and Web of Knowledge databases were searched in duplicate for randomized controlled trials (RCTs) up to and including 01 January 2014. Additional relevant literature was identified using handsearching of reference lists within published systematic reviews, and screenings of OpenGrey, ClinicalTrials.gov and Controlled-Trials.com. Probing pocket depth (PPD) was the outcome measure assessed. Multilevel mixed modelling was used to perform the network meta-analysis, and Markov Chain Monte Carlo simulation to obtain random effects. RESULTS: Eleven studies were included in the network meta-analysis. Debridement in conjunction with antibiotics achieved the greatest additional PPD reduction in comparison to debridement only (0.490 mm; 95% credible interval: 0.647;1.252). The highest probabilities of being the most effective interventions were achieved by Vector system (p = 20.60%), debridement plus periochip (p = 20.00%) and photodynamic therapy (p = 18.90%). CONCLUSION: The differences between various non-surgical treatments were relatively small with large credible intervals. On the basis of currently available RCTs, there is insufficient evidence to support that any particular non-surgical treatment for peri implantitis showed better performance than debridement alone. PMID- 25039293 TI - Associations between social inequality and tooth loss in a household sample of elderly Thai people aged >=60 years old. AB - OBJECTIVE: To assess the relationship between social inequality and the number of remaining teeth in an elderly Thai population. BACKGROUND: Having twenty or more remaining teeth is an important indicator of optimal oral health in the elderly. METHODS: The data for this study were derived from the Survey of Older Persons in Thailand, conducted by the National Statistical Office, based on face-to-face interviews with people aged >=60. The total sample was 30 427. The oral health measure was self-reported remaining number of teeth. Income, education and possession of durable goods were utilised as measures of social inequality. RESULTS: More than half of the sample (57.0%) was women. The majority (73.2%) was in the age range 60-74 years old. Less than a fifth (15.5%) had 7 or more years of education. A third earned <20 000 Thai Baht (THB) per annum (defined as poor). More than half (52.8%) of the sample had <20 remaining teeth. There was a link between social inequalities and tooth loss. In the adjusted model, elderly people, who were older than 75, who were not under a married status, had a lower level of education, had a lower income, and who did not own luxury goods, were 2.84 (CI 95% 2.66-3.03), 1.31 (CI 95% 1.21-1.41), 1.44 (CI 95% 1.34-1.56), 1.12 (CI 95% 1.13-1.29) and 1.21 (CI 95% 1.13-1.29) times more likely to have 19 or fewer teeth remaining, respectively. CONCLUSION: Social inequality is related to the number of remaining teeth in elderly Thai people. PMID- 25039294 TI - Connecting alveolate cell biology with trophic ecology in the marine plankton using the ciliate Favella as a model. AB - Planktonic alveolates (ciliates and dinoflagellates), key trophic links in marine planktonic communities, exhibit complex behaviors that are underappreciated by microbiologists and ecologists. Furthermore, the physiological mechanisms underlying these behaviors are still poorly understood except in a few freshwater model ciliates, which are significantly different in cell structure and behavior than marine planktonic species. Here, we argue for an interdisciplinary research approach to connect physiological mechanisms with population-level outcomes of behaviors. Presenting the tintinnid ciliate Favella as a model alveolate, we review its population ecology, behavior, and cellular/molecular biology in the context of sensory biology and synthesize past research and current findings to construct a conceptual model describing the sensory biology of Favella. We discuss how emerging genomic information and new technical methods for integrating research across different levels of biological organization are paving the way for rapid advance. These research approaches will yield a deeper understanding of the role that planktonic alveolates may play in biogeochemical cycles, and how they may respond to future ocean conditions. PMID- 25039295 TI - Gender segregation as a benefit - a qualitative study from Pakistan. AB - AIM: To explore the possibility of exploiting gender segregation as a benefit for registered female nurses. BACKGROUND: Nursing is a highly gendered profession in Pakistan with 95% of nurses comprising females who suffer from low professional status, negative identity and unfavourable work environments. METHODS: A qualitative research design was used to interview 12 nurses in management positions through purposive sampling. Face-to-face in-depth interviews were conducted to explore the views of female nurses on the benefits, if any, of gender segregation in the nursing profession. RESULTS: Content analysis identified three major categories of benefits of gender segregation for female nurses including: (1) demand for female nurses compared with demand for males, (2) resilience of female nurses in the face of difficult work environments and (3) comfort and safety of female co-workers in a male-dominated setting. CONCLUSION: Realising the benefits of gender segregation could mobilise nurse teamwork and union efforts in order to improve nurse identity, professional status and work environments. IMPLICATIONS FOR NURSE MANAGEMENT: The present study highlights the nurse manager role in advancing knowledge of gender segregation benefits, team-building for gender solidarity, control of nurse supply, union mobilization and raising community awareness for women's health development. PMID- 25039296 TI - Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. PMID- 25039298 TI - Effects of supplementation level and particle size of alfalfa hay on growth characteristics and rumen development in dairy calves. AB - The aim of this study was to assess the effects of particle size (PS) of alfalfa hay on growth characteristics and rumen development in dairy calves at two levels of alfalfa supplementation. Fifty newborn dairy calves (42.7 +/- 2.2 kg BW) were used in a 2 * 2 factorial arrangement with the factors supplementation level (low, 8%; or high, 16% on DM basis) and PS (medium, 2.92 mm; or long, 5.04 mm as geometrical means) of alfalfa hay. In addition, a control group without alfalfa hay was used. Hence, treatments were: control (C); low level with medium PS (LM); low level with long PS (LL); high level with medium PS (HM) or high level with long PS (HL). Growth performance of alfalfa-fed calves did not differ from control calves, but alfalfa supplementation decreased corneum thickness of the rumen wall. In alfalfa-fed calves, post-weaning starter intake was greater for LL calves than for LM calves. During the entire rearing period, starter intake was 26-32% higher for LL and HM calves than for LM calves. Pre-weaning average daily gain was higher for LL and HM calves than for HL calves, but this effect was not persistent over the entire rearing period. Final body weight decreased from 86 to 79 kg when the level of long PS alfalfa hay increased from 8 to 16%, but increased from 78 to 87 kg when the level of medium PS alfalfa increased from 8 to 16%. Regardless of PS and level, morphometric characteristics of rumen wall were generally similar among alfalfa feeding groups, but corneum thickness decreased from 8.7 to 6.1 MUm with greater PS at the low level. These results indicate that adequate, but not excessive, physical stimulation is required for appropriate rumen development and growth performance of dairy calves. PMID- 25039299 TI - Role of interventional pulmonology in the management of complicated parapneumonic pleural effusions and empyema. AB - Pleural infection is a major problem that affects 80,000 cases per year in the UK and USA. It is increasing in incidence, and in an ageing population, it presents a complex challenge that requires a combination of medical therapies and may lead to the need for surgery. This article focuses on the role of the interventional pulmonologist in the diagnosis and management of pleural infection. In particular, we examine the role of pleural ultrasound in diagnostics, thoracocentesis and real-time guided procedures, and the current management strategies, including the controversial role of medical thoracoscopy. PMID- 25039297 TI - Stimulatory role of the chemokine CCL2 in the migration and peptide expression of embryonic hypothalamic neurons. AB - Neuroinflammation is a feedback mechanism against infection, with recent studies suggesting a neuromodulatory role. The chemokine, (C-C motif) ligand 2 (CCL2), and its receptor, (C-C motif) receptor type 2 (CCR2), affect neuromodulation and migration in response to damage. Although CCL2 co-localizes with neuropeptides in the hypothalamus that control voluntary behavior, the function of CCL2/CCR2 is unknown. This led us to consider the possibility that CCL2 acting through CCR2, under natural conditions, may affect the migration and peptide levels of hypothalamic neurons that control voluntary behavior. This study used primary embryonic hypothalamic neurons to examine the effect of CCL2 on migratory behavior and on levels of the peptides, enkephalin (ENK) and galanin. Treatment with CCL2 led to a significant, dose-dependent increase in the number of migrated neurons and an increase in the velocity and distance traveled. CCL2 also significantly increased the number of ENK-expressing and CCR2/ENK co-expressing neurons and the percentage of neurons that contain higher levels of ENK. Lastly, CCL2 produced a dose-dependent increase in expression of ENK and galanin. These results provide evidence for a stimulatory effect of CCL2 on embryonic hypothalamic neurons involving changes in migratory behavior, expression, and synthesis of neuropeptides that function in controlling behavior. Our results demonstrate that the chemokine, CCL2, functions through its receptor, CCR2, to stimulate the migration and expression of the orexigenic peptides, enkephalin (ENK) and galanin (GAL), in developing embryonic hypothalamic neurons that are important for controlling ingestive behavior. This evidence reveals broad effects of CCL2 in the developing hypothalamus, showing this chemokine system to be tightly linked to the hypothalamic peptide neurons. PMID- 25039300 TI - Functional capacity after pediatric liver transplantation: a pilot study. AB - The prospective cross-sectional study investigated the 6MWT performance in pediatric group of liver transplant recipients (6-17 yr, median post transplantation time of 22 months) and compared to the normal values obtained in healthy children as well as evaluated the reproducibility of the 6MWT. We analyzed the relationship between walked distance and the 6MWw, distance walked * body weight) with the anthropometric, clinical, and pulmonary functions. In post transplanted group, the average walked distance was significantly shorter compared with control (687 +/- 80 m vs. 511 +/- 72 m, p < 0.001). The calculated ICC coefficient confirmed the reproducibility among tests. The Pearson correlation revealed that only walked distance in the 6MWT was moderately correlated with tidal volume. Conversely, the 6MWw was significantly correlated with age, weight, height, BMI, FVC, PEF rate, and volume expiratory. According to multiple regression analysis, age, VE and FVC factors explained 80% of the variance in the 6MWw. In conclusion, the pediatric liver transplant recipients' performance in the 6MWT is significantly lower than the values for healthy children of the same age. Notably, the 6MWw may provide relevant information, constituting an additional parameter in the determination of functional capacity. PMID- 25039303 TI - Bilobalide attenuates hypoxia induced oxidative stress, inflammation, and mitochondrial dysfunctions in 3T3-L1 adipocytes via its antioxidant potential. AB - Excessive expansion of white adipose tissue leads to hypoxia which is considered as a key factor responsible for adipose tissue dysfunction in obesity. Hypoxia induces inflammation, insulin resistance, and other obesity related complications. So the hypoxia-signalling pathway is expected to provide a new target for the treatment of obesity-associated complications. Inhibition or downregulation of the HIF-1 pathway could be an effective target for the treatment of obesity related hypoxia. In the present study, we evaluated the effect of hypoxia on functions of 3T3-L1 adipocytes emphasising on oxidative stress, antioxidant status, inflammation and mitochondrial functions. We have also evaluated the protective role of bilobalide, a bioactive from Gingko biloba, on hypoxia induced alterations. The results revealed that hypoxia significantly altered all the vital parameters of adipocyte biology like HIF-1alpha expression (103.47% ?), lactate and glycerol release (184.34% and 69.1% ?, respectively), reactive oxygen species (ROS) production (432.53% ?), lipid and protein oxidation (376.6% and 566.6% ?, respectively), reduction in antioxidant enzymes (superoxide dismutase and catalase) status, secretion of inflammatory markers (TNF-alpha, IL 6, IL-1beta and IFN-gamma) and mitochondrial functions (mitochondrial mass, membrane potential, permeability transition pore integrity, superoxide generation). Bilobalide significantly protected adipocytes from adverse effects of hypoxia in a dose-dependent manner by attenuating oxidative stress, inflammation and protecting mitochondria. Acriflavine (HIF-1 inhibitor) was used as positive control. On the basis of this study, a detailed investigation is needed to delineate the mechanism of action of bilobalide to develop it as therapeutic target for obesity. PMID- 25039301 TI - Associations of OPRM1 A118G and alcohol sensitivity with intravenous alcohol self administration in young adults. AB - Human laboratory and animal models implicate variation in the MU-opioid receptor gene (OPRM1) as relevant for alcohol-related reward. OPRM1 is associated with alcohol self-administration in non-human primate studies, but the relevance of this finding to human models is unclear. This study used computer-assisted self infusion of ethanol (CASE) to examine associations among OPRM1 A118G genotype, subjective responses to alcohol and intravenous alcohol self-administration in young heavy drinkers (n = 40, mean age = 19.95 years, SD = 0.82). Participants completed a 2-hour CASE session comprising a priming phase followed by ad libitum self-administration in a free-access paradigm. Participants achieved a mean peak breath alcohol concentration (BrAC) of 81.18 mg% (SD = 24.96). Those with the OPRM1 118G variant (GA or GG genotypes) achieved significantly higher peak BrAC (M = 94.90 mg%, SD = 16.56) than those with the AA genotype (M = 74.46 mg%, SD = 25.36), reflecting a significantly greater number of alcohol requests among GA/GG participants. Eighty percent of GA/GG participants surpassed a threshold defining a laboratory analog of heavy alcohol exposure (80 mg%) compared with 46 percent of AA participants. Results indicated significant associations between subjective measures of alcohol sensitivity and CASE outcomes, although the pattern of findings differed across self-report measures. Subjective responses did not differ by OPRM1 status. These results offer further support for the feasibility of the CASE paradigm and provide initial evidence for an association of OPRM1 with alcohol self-administration in a human laboratory context. PMID- 25039302 TI - Effect of dietary N-carbamylglutamate levels on reproductive performance of gilts. AB - The effect of dietary N-carbamylglutamate (NCG) supplementation during the entire gestation on reproductive performance of gilts was determined. At the initial day of gestation, forty-five cross-bred (Landrace * Large white) gilts were randomly assigned to five groups receiving a basal diet (control group) and basal diet supplemented with 0.05%, 0.10%, 0.15% and 0.20% NCG until parturition, respectively. At parturition, total litter size, live litter size and rate of stillbirth were not markedly affected by NCG supplementation. However, gilts in 0.05% NCG-supplemented group had more pigs born alive than gilts in control group (+1.11 pigs, p = 0.12), and live litter weight was increased (+12.13-19.17%, p < 0.05) in 0.05%, 0.10% and 0.15% NCG-supplemented groups relative to control group. And also, average birthweight of piglets born alive was higher (+6.57%, p < 0.05) in 0.05% NCG-supplemented group than in control group. Furthermore, on days 30, 60, 90 and 110 of gestation, concentrations of arginine and ornithine in plasma were higher (p < 0.05) in 0.05%, 0.10%, 0.15% and 0.20% NCG-supplemented groups than in control group, respectively. In addition, the chorioallantois gene expression of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor A (VEGF-A), placental growth factor (PLGF) and angiopoietin-2 (ANG 2) was all increased (p < 0.05) in 0.05%, 0.10% and 0.15% NCG-supplemented groups than in control group. In conclusion, dietary supplementation with 500 mg/kg NCG during the entire gestation significantly improves pregnancy outcomes in gilts, which may be associated with the improved concentrations of arginine in plasma and placental angiogenic factors gene expression of gilts. PMID- 25039304 TI - Topical 5-azacytidine accelerates skin wound healing in rats. AB - The development of new methods to improve skin wound healing may affect the outcomes of a number of medical conditions. Here, we evaluate the molecular and clinical effects of topical 5-azacytidine on wound healing in rats. 5-Azacytidine decreases the expression of follistatin-1, which negatively regulates activins. Activins, in turn, promote cell growth in different tissues, including the skin. Eight-week-old male Wistar rats were submitted to 8.0-mm punch-wounding in the dorsal region. After 3 days, rats were randomly assigned to receive either a control treatment or the topical application of a solution containing 5 azacytidine (10 mM) once per day. Photo documentation and sample collection were performed on days 5, 9, and 15. Overall, 5-azacytidine promoted a significant acceleration of complete wound healing (99.7% +/- 0.7.0 vs. 71.2% +/- 2.8 on day 15; n = 10; p < 0.01), accompanied by up to threefold reduction in follistatin expression. Histological examination of the skin revealed efficient reepithelization and cell proliferation, as evaluated by the BrdU incorporation method. 5-Azacytidine treatment also resulted in increased gene expression of transforming growth factor-beta and the keratinocyte markers involucrin and cytokeratin, as well as decreased expression of cytokines such as tumor necrosis factor-alpha and interleukin-10. Lastly, when recombinant follistatin was applied to the skin in parallel with topical 5-azacytidine, most of the beneficial effects of the drug were lost. Thus, 5-azacytidine acts, at least in part through the follistatin/activin pathway, to improve skin wound healing in rodents. PMID- 25039305 TI - Arsenic biotransformation by Streptomyces sp. isolated from rice rhizosphere. AB - Isolation and functional analysis of microbes mediating the methylation of arsenic (As) in paddy soils is important for understanding the origin of dimethylarsinic acid (DMA) in rice grains. Here, we isolated from the rice rhizosphere a unique bacterium responsible for As methylation. Strain GSRB54, which was isolated from the roots of rice plants grown in As-contaminated paddy soil under anaerobic conditions, was classified into the genus Streptomyces by 16S ribosomal RNA sequencing. Sequence analysis of the arsenite S adenosylmethionine methyltransferase (arsM) gene revealed that GSRB54 arsM was phylogenetically different from known arsM genes in other bacteria. This strain produced DMA and monomethylarsonic acid when cultured in liquid medium containing arsenite [As(III)]. Heterologous expression of GSRB54 arsM in Escherichia coli promoted methylation of As(III) by converting it into DMA and trimethylarsine oxide. These results demonstrate that strain GSRB54 has a strong ability to methylate As. In addition, DMA was detected in the shoots of rice grown in liquid medium inoculated with GSRB54 and containing As(III). Since Streptomyces are generally aerobic bacteria, we speculate that strain GSRB54 inhabits the oxidative zone around roots of paddy rice and is associated with DMA accumulation in rice grains through As methylation in the rice rhizosphere. PMID- 25039306 TI - Beliefs about the true self explain asymmetries based on moral judgment. AB - Past research has identified a number of asymmetries based on moral judgments. Beliefs about (a) what a person values, (b) whether a person is happy, (c) whether a person has shown weakness of will, and (d) whether a person deserves praise or blame seem to depend critically on whether participants themselves find the agent's behavior to be morally good or bad. To date, however, the origins of these asymmetries remain unknown. The present studies examine whether beliefs about an agent's "true self" explain these observed asymmetries based on moral judgment. Using the identical materials from previous studies in this area, a series of five experiments indicate that people show a general tendency to conclude that deep inside every individual there is a "true self" calling him or her to behave in ways that are morally virtuous. In turn, this belief causes people to hold different intuitions about what the agent values, whether the agent is happy, whether he or she has shown weakness of will, and whether he or she deserves praise or blame. These results not only help to answer important questions about how people attribute various mental states to others; they also contribute to important theoretical debates regarding how moral values may shape our beliefs about phenomena that, on the surface, appear to be decidedly non moral in nature. PMID- 25039307 TI - Crohn disease and ulcerative colitis in children: an update for 2014. AB - Crohn disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), have become increasingly common in Australasian children and adolescents in recent years. Furthermore, CD and UC are seen more often in younger children. These conditions are typically more extensive in children and tend to follow more severe disease courses than in adults. Although many children may present with typical symptoms (such as abdominal pain or bloody diarrhoea), others have atypical features (including oral ulceration, short stature or skin manifestations). In addition, many children with IBD will have altered growth or nutrition, which may compromise normal linear growth and pubertal development. Early identification and full assessment of children presenting with possible IBD are essential to avoid consequences of diagnostic delay and to optimise short- and long-term outcomes. Management of IBD encompasses various options and should be undertaken within a team-based, child and family-focused, multidisciplinary setting. PMID- 25039308 TI - What is genetic differentiation, and how should we measure it--GST, D, neither or both? AB - Estimates of the fixation index, F(ST), have been used as measures of population differentiation for many decades. However, there have been persistent voices in the literature suggesting that these statistics do not measure true differentiation. In particular, the statistics Nei's G(ST) and Wier and Cockerham's theta have been criticized for being 'constrained' to not equal one in some situations that seem to represent maximal differentiation. Here, we address the issue of how to evaluate exactly how much information a particular statistic contains about the process of differentiation. This criterion can be used to counter most concerns about the performance of G(ST) (and related statistics), while also being reconciled with the insights of those who have proposed alternative measures of differentiation. In particular, the likelihood based framework that we put forward can justify the use of G(ST) as an effective measure of differentiation, but also shows that in some situations G(ST) is insufficient on its own and needs supplementing by another measure such as Jost's D or Hedrick's G'(ST). This approach will become increasingly important in the future, as greater emphasis is placed on analysing large data sets. PMID- 25039309 TI - Topical long-term therapy of psoriasis with vitamin D3 analogues, corticosteroids and their two compound formulations: position paper on evidence and use in daily practice. AB - BACKGROUND: Current data from daily practice show that vitamin D3 analogues, corticosteroids and their fixed combination products are used heterogeneously for topical long-term treatment of psoriasis. AIM: To evaluate scientific evidence about topical long-term therapy with vitamin D3 analogues, corticosteroids and their two-compound-products in psoriasis vulgaris and scalp psoriasis and to develop daily practice recommendations. METHODS: Systematic literature review via PubMed and Embase and informal expert consensus. RESULTS: The search strategy identified 21 relevant clinical trials. Best evidence regarding topical long term treatment was available for the two-compound-formulation containing calcipotriene and betamethasone. In a comparative trial in psoriasis vulgaris the two-compound formulation showed superior tolerability and cost effectiveness compared to monotherapy. In scalp psoriasis the two-compound-gel was superior compared to calcipotriene monotherapy. Standardized and simplified treatment application modes resulted in a better clinical outcome comparing to on-demand therapies. DAILY PRACTICE RECOMMENDATIONS: Patients should be proactively involved in the choice of treatment, formulation and mode of application. Besides long-term treatment with the two-compound-formulation other treatment regimens including calcipotriene monotherapy can also be considered. Due to a favorable risk-benefit ratio in maintenance trials and due to better cost-effectiveness the application of two-compound-products once or twice a week after initial therapy is recommended. PMID- 25039310 TI - Cytoplasmic TDP-43 accumulation in cells of the adrenal medulla in individuals with or without amyotrophic lateral sclerosis. AB - The transactive response DNA-binding protein of 43 kDa (TDP-43) is normally located predominantly in the nucleus, whereas pathological TDP-43 is mostly found in the cytoplasm. Cytoplasmic TDP-43 accumulation has not yet been reported in normal general organs. In our preliminary study, paraffin sections of the general organs of individuals with or without amyotrophic lateral sclerosis (ALS) were immunostained with antibodies against TDP-43 and phosphorylated TDP-43 (pTDP-43). Diffuse and granular immunostaining pattern of TDP-43 and pTDP-43 were observed frequently in the cytoplasm of renal tubular cells, and less frequently in the cells of several organs; however, the majority of these immunoreactivities were nonspecific biotin reactions. Conversely, many TDP-43-positive and pTDP-43 negative cytoplasmic accumulations were observed in the adrenal medulla in every individual (with or without ALS). Skein-like or round inclusions were not observed. The cells in the adrenal medulla were well preserved, and the cytoplasmic TDP-43 accumulations were frequent in the cells of all routine autopsy cases without loss of nuclear TDP-43 immunostaining; therefore, we considered that this was a physiological phenomenon. This is the first study that demonstrated the cytoplasmic accumulation of TDP-43 in routinely autopsied cases. PMID- 25039311 TI - Transverse vaginal septae: management and long-term outcomes. PMID- 25039312 TI - Detection and management of the deteriorating ward patient: an evaluation of nursing practice. AB - AIMS AND OBJECTIVES: To audit ward nursing practice in the adherence to an early warning scoring protocol in the detection and initial management of the deteriorating ward patient and investigate factors that may impact on practice. BACKGROUND: Hospital inpatients can experience unexpected physiological deterioration leading to poor outcomes and death. Although deterioration can be signalled in the patients' physiological symptoms, evidence suggests that ward staff can miss, misinterpret or mismanage the signs. Rapid response systems have been implemented to address this problem. The rapid response systems consists of two phases: the afferent phase involves monitoring the patient, recognising deterioration and referring to more expert help and the efferent phase involves expert teams assessing and treating the patient. Research has tended to concentrate on the efferent phase of the process and has so far failed to show a significant impact on patient outcome. METHODS: Using cardiac arrest as a surrogate marker for deterioration, patient records were retrospectively reviewed during the 12 hours prior to the cardiac arrest event. Data relating to nursing practice and adherence to the early warning scoring protocol were extracted and analysed. FINDINGS: The findings suggest that ward nurses' monitoring of patients' observations has improved compared with earlier research, but errors in early warning scoring and nonadherence to referral protocols are still a problem. A number of potentially influential factors on nursing practice were tested, but only deterioration occurring outside normal weekdays was associated with a reduced quality of nursing adherence to protocol. CONCLUSIONS: The implementation of rapid response systems may have been an oversimplified solution to the highly complex problem of undetected patient deterioration. There are a multitude of contributory factors to the problem of noncompliance to early warning scoring protocols, and possible solutions will need to reflect the breadth, depth and complexity of the problem if we are to improve patient experience and outcome. RELEVANCE TO CLINICAL PRACTICE: An audit of nursing practice against an early warning scoring protocol based on national recommendations and standards in the recording of and response to physiological deterioration in the ward patient has shown that vital signs recording has improved, but early warning scoring accuracy and referral to more expert help remain suboptimal. By identifying areas of suboptimal practice, strategies for education and training and service development can be better informed. More in-depth evidence on factors that may impact the quality of nursing practice has been identified. Problems with rapid response systems assumptions have been highlighted, which may facilitate the implementation of more realistic solutions for managing the deteriorating ward patient. PMID- 25039313 TI - The suppressive function of human CD8(+) iTregs is inhibited by IL-1beta and TNFalpha. AB - CD8(+) Tregs display an immunoregulatory activity and may play an essential role in the immunopathology of several diseases. Therefore, their therapeutic potential is exquisite and further studies on their differentiation and function are essential. The aim of this study was to evaluate the role of the innate immune system in CD8(+) iTreg differentiation and function. Naive human CD8(+) CD25(-) CD45RA(+) T cells were cultured in Treg-inducing conditions with or without IL-1beta, TNFalpha or monocyte-derived dendritic cells (DCs). The differentiation of CD8(+) CD127(-) CD25(hi) FoxP3(hi) -induced Tregs (CD8(+) iTregs) is dependent on TGF-beta1 and IL-2, which had synergistic effect upon their differentiation. CD8(+) iTregs were also induced in a coculture with allogeneic mature DCs (mDCs). The CD8(+) iTregs suppressive function was confirmed, which was diminished in the presence of IL-1beta and TNFalpha. The IL 1beta-prevented suppressive function was associated with reduced secretion of IL 10 and IFNgamma, whereas the presence of TNFalpha did not affect their secretion. Furthermore, the presence of TNFalpha reduced IL-10 and TGF-beta1 secretion by CD8(+) iTregs, whereas only IL-10 secretion was decreased by IL-1beta. Together, these results suggest that IL-1beta and TNFalpha prevent IL-2- and TGF-beta1 driven CD8(+) iTregs suppressive function in human T cells. Such pro-inflammatory innate immune response possibly mediates its negative tolerogenic effect through reduced IFNgamma-, IL-10- and TGF-beta1-driven mechanism. PMID- 25039314 TI - Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B in bipolar offspring: a follow-up study from adolescence into adulthood. AB - OBJECTIVES: There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro-immune changes in a prospective study on children of patients with bipolar disorder. METHODS: Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1beta (IL-1beta), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls. RESULTS: During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages. CONCLUSIONS: This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value. PMID- 25039315 TI - Chiasmatic-hypothalamic masses in adults: a case series and review of the literature. AB - Chiasmatic-hypothalamic masses are commonly seen in children with neurofibromatosis type 1 and often demonstrate a benign clinical course. These masses are, however, rare in adults and require tissue sampling for diagnosis. Here, we present four cases of chiasmatic-hypothalamic masses in adults with pathologically proven diagnoses. We also provide a review of the literature and propose a limited differential in this age group. PMID- 25039316 TI - Effectiveness of single-nucleotide polymorphisms to investigate cattle rustling. AB - Short tandem repeats (STR)s have been the eligible markers for forensic animal genetics, despite single-nucleotide polymorphisms (SNP)s became acceptable. The technology, the type, and amount of markers could limit the investigation in degraded forensic samples. The performance of a 32-SNP panel genotyped through OpenArrays(TM) (real-time PCR based) was evaluated to resolve cattle-specific forensic cases. DNA from different biological sources was used, including samples from an alleged instance of cattle rustling. SNPs and STRs performance and repeatability were compared. SNP call rate was variable among sample type (average = 80.18%), while forensic samples showed the lowest value (70.94%). The repeatability obtained (98.7%) supports the used technology. SNPs had better call rates than STRs in 12 of 20 casework samples, while forensic index values were similar for both panels. In conclusion, the 32-SNPs used are as informative as the standard bovine STR battery and hence are suitable to resolve cattle rustling investigations. PMID- 25039317 TI - A decade of temporal trends in overweight/obesity in youth with type 1 diabetes after the Diabetes Control and Complications Trial. AB - BACKGROUND: Youth with type 1 diabetes (T1D) are at risk for weight gain due to the epidemic of childhood overweight/obesity and common use of intensive insulin therapy; the latter resulted in weight gain in the Diabetes Control and Complications Trial. OBJECTIVE: To assess overweight/obesity prevalence and intensive insulin therapy use in youth with T1D over a decade and identify factors associated with weight status and glycemic control. METHODS: We obtained cross-sectional data from four unique cohorts (1999, 2002, 2006, and 2009). Youth (N = 507, 49% male) were 8-16 yr old with T1D duration >=6 months, A1c 6.0-12.0% (42-108 mmol/mol), and daily insulin dose >=0.5 U/kg. RESULTS: Across cohorts, age, body mass index (BMI) percentile, and A1c ranged from 12.0 +/- 2.2 to 12.8 +/- 2.3 yr, 70 +/- 22 to 72 +/- 21, and 8.3 +/- 1.0 (67 +/- 11) to 8.5 +/- 1.1% (69 +/- 12 mmol/mol), respectively. Intensive insulin therapy use increased from 52 to 97% (p < 0.001) between 1999 and 2009. However, prevalence of overweight/obesity remained similar, 27% (1999), 36% (2002), 33% (2006), and 31% (2009) (p = 0.54), as did z-BMI. In multivariate analysis, higher A1c was related to higher insulin dose (p < 0.01), less frequent blood glucose monitoring (p < 0.001), and non-white race (p < 0.001); A1c was not related to z-BMI, intensive insulin therapy, or cohort. z-BMI was related to insulin dose (p < 0.005) but not intensive insulin therapy or cohort. CONCLUSIONS: Despite near-universal implementation of intensive insulin therapy, overweight/obesity prevalence in youth with T1D remained stable over a decade, similar to the general pediatric population. However, A1c remained suboptimal, underscoring the need to optimize T1D treatment to reduce future complication risk. PMID- 25039318 TI - The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. AB - Inflammation at the level of the beta cell appears to be involved in progressive beta-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on beta-cell function. Sixteen participants with impaired glucose tolerance were treated with 150 mg anakinra daily for 4 weeks in a double blind, randomized, placebo-controlled cross-over study with a wash-out period of 4 weeks. At the end of each treatment period, oral glucose tolerance tests (OGTTs) and hyperglycaemic clamps were performed. First-phase insulin secretion improved after anakinra treatment compared with placebo, 148 +/- 20 versus 123 +/ 14 mU/l, respectively (p = 0.03), and the insulinogenic index was higher after anakinra treatment. These results support the concept of involvement of IL-1beta in the (progressive) decrease of insulin secretion capacity associated with type 2 diabetes. PMID- 25039319 TI - Access blood flow testing. PMID- 25039320 TI - The effect of the inspired oxygen fraction on arterial blood oxygenation in spontaneously breathing, isoflurane anaesthetized horses: a retrospective study. AB - OBJECTIVES: To investigate the influence of two inspired oxygen fractions (FiO(2)) on the arterial oxygenation in horses anaesthetized with isoflurane. STUDY DESIGN: Retrospective, case-control clinical study. ANIMALS: Two hundred equine patients undergoing non-abdominal surgery (ASA class 1-2), using a standardized anaesthetic protocol and selected from anaesthetic records of a period of three years, based on pre-defined inclusion criteria. METHODS: In group O (n = 100), medical oxygen acted as carrier gas, while in group M (n = 100), a medical mixture of oxygen and air (FiO(2) 0.60) was used. Demographic data, FiO(2), arterial oxygen tension (PaO(2)) and routinely monitored physiologic data were recorded. The alveolar-arterial oxygen tension difference [P(A-a)O(2)] and PaO(2)/FiO(2) ratio were calculated. The area under the curve, standardized to the anaesthetic duration, was calculated and statistically compared between groups using t-tests or Mann-Whitney tests as appropriate. Categorical data were compared using Chi-square tests. RESULTS: No significant differences in age, body weight, sex, breed, surgical procedure, position, anaesthetic duration or arterial carbon dioxide tension were found. Mean FiO(2) was 0.78 in group O and 0.60 in group M. Compared to group O, significantly lower values for PaO(2) and for P(A-a)O(2) were found in group M. In contrast, the PaO(2)/FiO(2) ratio and the percentage of horses with a PaO(2) <100 mmHg (13.33 kPa) were comparable in both groups. CONCLUSIONS: Although a reduction of the inspired oxygen fraction resulted in a lower PaO(2), the P(A-a)O(2) was also lower and the number of horses with PaO(2) values <100 mmHg was comparable. CLINICAL RELEVANCE: In healthy isoflurane anaesthetized horses, the use of a mixture of oxygen and air as carrier gas seems acceptable, but further, prospective studies are needed to confirm whether it results in a lower degree of ventilation/perfusion mismatching. PMID- 25039321 TI - Endotracheal intubation in the pediatric emergency department. AB - BACKGROUND AND OBJECTIVES: Prospective safety data on emergency department (ED) intubation in children are limited. We aimed to describe the practice and adverse events associated with endotracheal intubation in a large urban pediatric ED. METHODS: Prospective observational study at a tertiary pediatric ED with an annual census of 82,000. The primary outcome measure was the adverse event rate. Secondary outcome measures were incidence of difficult laryngoscopy and first pass success rate without desaturation or hypotension. RESULTS: Over a 12-month period in 2013, there were 71 intubations in 66 patients (9/10,000 ED visits). Median age was 3 years, with 25% in infants <1 year of age. Indications were as follows: trauma (21%) and medical conditions (79%); most frequently status epileptics (31%). Forty-four percent had cardiovascular compromise, 87% had respiratory compromise, and 70% had a GCS <9 prior to intubation. Adverse events occurred in 39%, the most common being hypotension (21%) and desaturation (14%). One anticipated and one unanticipated difficult laryngoscopy were encountered (both Cormack and Lehane grade 3). Overall first pass success rate was 78%, although first pass success without desaturation or hypotension was only 49%. Seven percent required more than two attempts for successful intubation. CONCLUSION: Intubation of children in the ED is a low-frequency, high-risk procedure. The incidence of adverse events, particularly desaturation and hypotension, is high. The incidence of difficult laryngoscopy is low. First pass success rate without desaturation or hypotension is low. Strategies to avoid desaturation and hypotension in the peri-intubation setting should be prioritized. PMID- 25039322 TI - Integron-bearing Gram-negative bacteria in lake waters. AB - The aim of the study was to determine the occurrence of integron-bearing Gram negative bacteria in the water of four lakes located in Wielkopolski National Park, Poland. Altogether, 17 isolates harbouring class 1 or class 2 integrons were found. The integron-bearing bacteria were identified as Escherichia coli, Klebsiella pneumoniae, Pasteurella multocida and Aeromonas hydrophila. The variable regions of the class 1 integrons contained aadA1 and dfrA1-aadA1 gene cassettes, whereas class 2 integrons carried dfrA1-sat2-aadA1 gene cassette array. The isolates were resistant to 3-20 antimicrobials. One of them produced SHV-type extended-spectrum beta-lactamase. SIGNIFICANCE AND IMPACT OF THE STUDY: Integrons play a major role in the spread of antibiotic resistance among bacteria. They are frequently found in clinical bacterial strains, but are also detected in environmental isolates in sites affected by anthropogenic pressure. Little is known, however, about the presence and characteristics of integrons in bacteria living in water environments in areas of nature preservation. To the best of our knowledge, this is the first study focused on detection and characterization of integrons in bacteria living in water ecosystems in a national park. PMID- 25039323 TI - The effectiveness of repeat lumbar transforaminal epidural steroid injections. AB - OBJECTIVE: The aim of this study was to determine 1) if repeat lumbar transforaminal epidural steroid injections (TFESIs) resulted in recovery of pain relief, which has waned since an index injection, and 2) if cumulative benefit could be achieved by repeat injections within 3 months of the index injection. DESIGN: Retrospective observational study with statistical modeling of the response to repeat TFESI. SETTING: Academic radiology practice. PATIENTS: Two thousand eighty-seven single-level TFESIs were performed for radicular pain on 933 subjects. Subjects received repeat TFESIs >2 weeks and <1 year from the index injection. METHODS: Hierarchical linear modeling was performed to evaluate changes in continuous and categorical pain relief outcomes after repeat TFESI. Subgroup analyses were performed on patients with <3 months duration of pain (acute pain), patients receiving repeat injections within 3 months (clustered injections), and in patients with both acute pain and clustered injections. RESULTS: Repeat TFESIs achieved pain relief in both continuous and categorical outcomes. Relative to the index injection, there was a minimal but statistically significant decrease in pain relief in modeled continuous outcome measures with subsequent injections. Acute pain patients recovered all prior benefit with a statistically significant cumulative benefit. Patients receiving clustered injections achieved statistically significant cumulative benefit, of greater magnitude in acute pain patients. CONCLUSION: Repeat TFESI may be performed for recurrence of radicular pain with the expectation of recovery of most or all previously achieved benefit; acute pain patients will likely recover all prior benefit. Repeat TFESIs within 3 months of the index injection can provide cumulative benefit. PMID- 25039324 TI - All in the blink of an eye: new insight into cerebellar and brainstem function in DYT1 and DYT6 dystonia. AB - BACKGROUND AND PURPOSE: Traditionally dystonia has been considered a disorder of basal ganglia dysfunction. However, recent research has advocated a more complex neuroanatomical network. In particular, there is increasing interest in the pathophysiological role of the cerebellum. Patients with cervical and focal hand dystonia have impaired cerebellar associative learning using the paradigm eyeblink conditioning. This is perhaps the most direct evidence to date that the cerebellum is implicated in patients. METHODS: Eleven patients with DYT1 dystonia and five patients with DYT6 dystonia were examined and rates of eyeblink conditioning were compared with age-matched controls. A marker of brainstem excitability, the blink reflex recovery, was also studied in the same groups. RESULTS: Patients with DYT1 and DYT6 dystonia have a normal ability to acquire conditioned responses. Blink reflex recovery was enhanced in DYT1 but this effect was not seen in DYT6. CONCLUSIONS: If the cerebellum is an important driver in DYT1 and DYT6 dystonia our data suggest that there is specific cerebellar dysfunction such that the circuits essential for conditioning function normally. Our data are contrary to observations in focal dystonia and suggest that the cerebellum may have a distinct role in different subsets of dystonia. Evidence of enhanced blink reflex recovery in all patients with dystonia was not found and recent studies calling for the blink recovery reflex to be used as a diagnostic test for dystonic tremor may require further corroboration. PMID- 25039325 TI - The impact of adopting person-centred care approach for people with Alzheimer's on professional caregivers' burden: an interventional study. AB - This study described the impact of adopting person-centred care approach for people with Alzheimer's disease on professional caregivers' burden. The participants were subjected to a 4-week structured training programme about person-centred care. The programme's effectiveness was proven by using the Global Behavior Scale. Then a qualitative descriptive phenomenological approach was used to explore the impact of applying this programme on professional caregivers' burden. Data were collected from a sample of 10 professional caregivers using semi-structured interviews. A total of three themes were identified: acceptance of disease-related behaviours of people with Alzheimer's, therapeutic understanding of people with Alzheimer's feelings (empathy) and enhanced caregivers' adaptation to people with Alzheimer's demands (resiliency). Findings suggested that adopting person-centred care approach for people with Alzheimer's disease reduces professional caregivers' burden. PMID- 25039326 TI - Access to medicines in developing countries: ethical demands and moral economy. PMID- 25039327 TI - How much exposure to English is necessary for a bilingual toddler to perform like a monolingual peer in language tests? AB - BACKGROUND: Bilingual children are under-referred due to an ostensible expectation that they lag behind their monolingual peers in their English acquisition. The recommendations of the Royal College of Speech and Language Therapists (RCSLT) state that bilingual children should be assessed in both the languages known by the children. However, despite these recommendations, a majority of speech and language professionals report that they assess bilingual children only in English as bilingual children come from a wide array of language backgrounds and standardized language measures are not available for the majority of these. Moreover, even when such measures do exist, they are not tailored for bilingual children. AIMS: It was asked whether a cut-off exists in the proportion of exposure to English at which one should expect a bilingual toddler to perform as well as a monolingual on a test standardized for monolingual English-speaking children. METHODS & PROCEDURES: Thirty-five bilingual 2;6-year-olds exposed to British English plus an additional language and 36 British monolingual toddlers were assessed on the auditory component of the Preschool Language Scale, British Picture Vocabulary Scale and an object-naming measure. All parents completed the Oxford Communicative Development Inventory (Oxford CDI) and an exposure questionnaire that assessed the proportion of English in the language input. Where the CDI existed in the bilingual's additional language, these data were also collected. OUTCOMES & RESULTS: Hierarchical regression analyses found the proportion of exposure to English to be the main predictor of the performance of bilingual toddlers. Bilingual toddlers who received 60% exposure to English or more performed like their monolingual peers on all measures. K-means cluster analyses and Levene variance tests confirmed the estimated English exposure cut off at 60% for all language measures. Finally, for one additional language for which we had multiple participants, additional language CDI production scores were significantly inversely related to the amount of exposure to English. CONCLUSIONS & IMPLICATIONS: Typically developing 2;6-year-olds who are bilingual in English and an additional language and who hear English 60% of the time or more, perform equivalently to their typically developing monolingual peers. PMID- 25039328 TI - Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. AB - BACKGROUND: Chronic gastrointestinal dysmotility greatly impacts the quality of life. Treatment options are limited and generally symptomatic. Neural autoimmunity is an under-recognized etiology. We evaluated immunotherapy as an aid to diagnosing autoimmune gastrointestinal dysmotility (AGID). METHODS: Twenty three subjects evaluated at the Mayo Clinic for suspected AGID (August 2006 February 2014) fulfilled the following criteria: (1) prominent symptoms of gastrointestinal dysmotility with abnormalities on scintigraphy-manometry; (2) serological evidence or personal/family history of autoimmune disease; (3) treated by immunotherapy on a trial basis, 6-12 weeks (intravenous immune globulin, 16; or methylprednisolone, 5; or both, 2). Response was defined subjectively (symptomatic improvement) and objectively (gastrointestinal scintigraphy/manometry studies). KEY RESULTS: Symptoms at presentation: constipation, 18/23; nausea or vomiting, 18/23; weight loss, 17/23; bloating, 13/23; and early satiety, 4/23. Thirteen patients had personal/family history of autoimmunity. Sixteen had neural autoantibodies and 19 had extra-intestinal autonomic testing abnormalities. Cancer was detected in three patients. Preimmunotherapy scintigraphy revealed slowed transit (19/21 evaluated; gastric, 11; small bowel, 12; colonic, 11); manometry studies were abnormal in 7/8. Postimmunotherapy, 17 (74%) had improvement (both symptomatic and scintigraphic, five; symptomatic alone, eight; scintigraphic alone, four). Nine responders re evaluated had scintigraphic evidence of improvement. The majority of responders who were re-evaluated had improvement in autonomic testing (six of seven) or manometry (two of two). CONCLUSIONS & INFERENCES: This proof of principle study illustrates the importance of considering an autoimmune basis for idiopathic gastrointestinal dysmotility and supports the utility of a diagnostic trial of immunotherapy. PMID- 25039330 TI - In memoriam: Donald G. Lindmark (1942-2013). PMID- 25039329 TI - The Ultrastructural Relationship Between Osteocytes and Dental Implants Following Osseointegration. AB - BACKGROUND: Osteocytes, the most abundant cells in bone, have multiple functions, including acting as mechanosensors and regulating mineralization. It is clear that osteocytes influence bone remodeling by controlling the differentiation and activity of osteoblasts and osteoclasts. Determining the relationship between titanium implants and osteocytes may therefore benefit our understanding of the process of osseointegration. PURPOSE: The aim of this study was to visualize the ultrastructural relationship between osteocytes and the titanium implant surface following osseointegration in vivo. MATERIALS AND METHODS: Titanium implants were placed in the maxillary molar regions of eight female Sprague Dawley rats, 3 months old. The animals were sacrificed 8 weeks after implantation, and undecalcified tissue sections were prepared. Resin-cast samples were subsequently acid-etched with 37% phosphoric acid prior to examination using scanning electron microscopy. RESULTS: Compared with mature bone, where the osteocytes were arranged in an ordered fashion, the osteocytes appeared less organized in the newly formed bone around the titanium implant. Further, a layer of mineralization with few organic components was observed on the implant surface. This study shows for the first time that osteocytes and their dendrites are directly connected with the implant surface. CONCLUSIONS: This study shows the direct anchorage of osteocytes via dendritic processes to a titanium implant surface in vivo. This suggests an important regulatory role for osteocytes and their lacunar canalicular network in maintaining long-term osseointegration. PMID- 25039331 TI - Fracture resistance and failure mode of fatigued endodontically treated teeth restored with fiber-reinforced resin posts and metallic posts in vitro. AB - BACKGROUND: Fracture of restored endodontically treated teeth is a common complication. The mechanical properties of post systems may play a role in the incidence of tooth fracture. AIM: The purpose of this study was to evaluate in vitro the fracture resistance and pattern of fracture of endodontically treated teeth restored with three different post systems. MATERIAL AND METHODS: Posts used were fiber-reinforced composite resin posts (FRC post), custom cast silver palladium, and nickel-chromium posts and cores. A 3-point bending test was performed to calculate flexural strengths and elastic moduli of the specimens. Sixty extracted human maxillary canines were endodontically treated and divided into three groups (n = 20). All-ceramic crowns were fabricated and cemented with Variolink II resin cement. Ten specimens of each group were subjected to a constantly increasing load until fracture. The other 10 specimens were fatigued for 106 cycles in a custom-made fatigue machine. Recorded failure loads and modes were statistically compared with one-way anova and Tukey-HSD tests (alpha = 0.05). RESULTS: The resistance to fracture of teeth restored with FRC posts, composite resin cores, and Empress II crowns was similar to that of teeth restored with cast posts and cores (P = 0.162). Supracrestal (above root/level of acrylic resin base) oblique fracture was the predominant mode of fracture associated with teeth restored with FRC posts (70%), while vertical root fractures were more common with teeth restored with cast posts and cores. CONCLUSIONS: Teeth restored with the FRC post system did not exhibit vertical root fractures and were less likely to show root fracture. Sixty to 80% of teeth restored with both types of cast posts and cores showed vertical and subcrestal root fractures. PMID- 25039332 TI - Assessment of a portable prothrombin time analyzer (CoaguChek-XS) in dogs. AB - OBJECTIVES: To assess the performance of a portable prothrombin time (PT) analyzer (CoaguChek-XS) in dogs. ANIMALS: Ninety-seven dogs composed of 20 healthy dogs, 45 ill dogs, and 32 ill dogs with altered coagulation. PROCEDURES: Samples were concurrently obtained and PT was measured using the CoaguChek-XS and an automated coagulation analyzer. Agreement between methods was assessed using Spearman's correlation and Bland-Altman analysis. RESULTS: The reference interval for PT using the CoaguChek-XS was 9.6-11.5 s. The CoaguChek-XS was easy to use, required a small volume of whole blood, and gave results within 1 min. The mean difference in PT between the 2 methods was 2.58 s (SD 3.10), and 94% of the samples fell within limits of agreement. The correlation was moderate, but significant (r = 0.35, P < 0.001). Sensitivity and specificity of the CoaguCheck XS PT compared to analyzer PT were 92% and 56%, respectively, and increased to 95% and 77% on intent to treat basis. The coefficient of variance was 0.72%. The CoaguChek-XS identified all 8 dogs with anticoagulant rodenticide intoxication, although a discrepancy was noted from the analyzer results. In anemic dogs (PCV<=25%), the CoaguChek-XS did not display accurate results. CONCLUSIONS: The CoaguChek-XS is a simple, user-friendly, highly precise PT analyzer. Results had moderate correlation and good agreement with a standard method. It can be used reliably for screening dogs when the PT is normal. However, when the CoaguChek-XS PT is prolonged or when the PCV is <=25%, results should be confirmed using a standard method. PMID- 25039333 TI - Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). AB - BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD). A liver biopsy is considered the "gold standard" for diagnosing/staging NASH. Identification of NAFLD/NASH using non-invasive tools is important for intervention. The study aims were to: develop/validate the predictive performance of a non-invasive model (index of NASH [ION]); assess the performance of a recognized non-invasive model (fatty liver index [FLI]) compared with ION for NAFLD diagnosis; determine which non invasive model (FLI, ION, or NAFLD fibrosis score [NFS]) performed best in predicting age-adjusted mortality. METHODS: From the National Health and Nutrition Examination Survey III database, anthropometric, clinical, ultrasound, laboratory, and mortality data were obtained (n = 4458; n = 861 [19.3%] NAFLD by ultrasound) and used to develop the ION model, and then to compare the ION and FLI models for NAFLD diagnosis. For validation and diagnosis of NASH, liver biopsy data were used (n = 152). Age-adjusted Cox proportional hazard modeling estimated the association among the three non-invasive tests (FLI, ION, and NFS) and mortality. RESULTS: FLI's threshold score > 60 and ION's threshold score > 22 had similar specificity (FLI = 80% vs ION = 82%) for NAFLD diagnosis; FLI < 30 (80% sensitivity) and ION < 11 (81% sensitivity) excluded NAFLD. An ION score > 50 predicted histological NASH (92% specificity); the FLI model did not predict NASH or mortality. The ION model was best in predicting cardiovascular/diabetes related mortality; NFS predicted overall or diabetes-related mortality. CONCLUSIONS: The ION model was superior in predicting NASH and mortality compared with the FLI model. Studies are needed to validate ION. PMID- 25039334 TI - Chemotherapy-related cardiomyopathy: a neglected aspect of cancer survivorship. AB - Improvements in survival from cancer have led to a large population who are at risk of late complications of chemotherapy. One of the most serious cardiovascular complications is chemotherapy-related cardiomyopathy (CRC), which may become clinically overt years or even decades after treatment and has over threefold higher mortality rate compared with idiopathic dilated cardiomyopathy. The early stages of this condition appear to respond well to cardioprotective medications (i.e. angiotensin-converting enzyme inhibitors, beta-blockers). Periodic cardiac monitoring is necessary in this population to identify patients who would benefit from treatment. Cardio-oncology clinics have been established in recognition of this hazard in survivorship. This review summarises the epidemiology and pathophysiology of CRC, the evidence base for different non invasive imaging modalities for screening and diagnosis and the rationale for treatment. PMID- 25039335 TI - Ocular infections in sub-Saharan Africa in the context of high HIV prevalence. AB - Healthy eyes and good vision are important determinants of populations' health across the globe. Sub-Saharan Africa is affected by simultaneous epidemics of ocular infections and human immunodeficiency virus (HIV). Ocular infection and its complications, along with cataract and ocular trauma, are common conditions in this region with great impact on daily life. In this review, we discuss the epidemiology, clinical manifestations and microbial aetiology of the most important infectious ocular conditions in sub-Saharan Africa: conjunctivitis, keratitis and uveitis. We focus specifically on the potential association of these infections with HIV infection, including immune recovery uveitis. Finally, challenges and opportunities for clinical management are discussed, and recommendations made to improve care in this neglected but very important clinical field. PMID- 25039337 TI - A moment in history. PMID- 25039336 TI - Expression of receptors of advanced glycation end product (RAGE) and types I, III and IV collagen in the vastus lateralis muscle of men in early stages of knee osteoarthritis. AB - Alterations in the contractile and non-contractile proteins of the skeletal muscle may reduce muscle function in knee osteoarthritis (OA), and the formation and accumulation of advanced glycation end products, particularly in collagen, can influence the quality of these muscle proteins. The objective of this study was to evaluate the reactivity of types I, III and IV collagen and the expression and localization of receptor for advanced glycation end products (RAGE) in the vastus lateralis (VL) muscle in early stages of knee OA. The hypothesis was that these patients present a higher expression of RAGE and increased immunoreactivity in the collagen. Thirty-five men were divided into two groups: the control group (CG; n = 17) and the osteoarthritis group (OAG; n = 18). All participants were submitted to a biopsy of the VL. The muscle samples were analyzed by immunohistochemistry for collagen and for RAGE and laminin. The expression of RAGE was counted (intracellular, extracellular and total). Student's t-test for independent samples and Mann-Whitney U test were used for the RAGE's intergroup analysis (alpha <= 0.05). A semiquantitative analysis was performed to assess the collagen reactivity. No significant differences were observed in the intracellular, extracellular or total localization of RAGE (p > 0.05). Higher immunoreactivity was observed in the OAG for all types of collagen, with more reactivity for collagen III and IV. We concluded that in the initial stages of knee OA, no differences were observed for RAGE levels between the groups. However, the OAG's higher collagen expression may represent adaptations for reducing muscle stiffness and avoiding injury. PMID- 25039338 TI - Effective management in male urinary incontinence. AB - Effective assessment is key to the effective management of male urinary incontinence. Identification of the specific type of incontinence being experienced by the patient will inform the treatment plan, and the holistic needs of the patient need to be considered before making a decision in this regard. This article describes the different types of male lower urinary tract symptoms and gives recommendations for managing and treating each specific type. It will also consider potential issues surrounding treatment of male urinary incontinence, such as communication issues from the perspective of the health care professional and the patient themselves, before giving containment strategies and methods. PMID- 25039339 TI - The prevalence of malnutrition in elderly residents in a warden-assisted setting compared with a home-living environment. AB - Malnutrition in elderly people is associated with many adverse clinical outcomes. However, few studies exist investigating malnutrition in the community setting. This study aimed to report the prevalence of malnutrition in elderly people living in warden-assisted (WA) accommodation compared with those living at home. A total of 20 WA and 20 home-living (HL) participants were assessed using hand grip strength and the Mini Nutritional Assessment (MNA). Some 30% of the WA group were malnourished, compared with 10% of the HL group. This study demonstrates an alarmingly large proportion of individuals in WA accommodation to be either malnourished or at risk of malnutrition. This is a relatively small study, and further research into the key factors influencing malnutrition and interventions to minimise malnutrition with WA accommodation are clearly warranted. PMID- 25039340 TI - Extending virtual wards to palliative care delivered in the community. PMID- 25039341 TI - Hospital admission avoidance through the introduction of a virtual ward. AB - The ageing British population is placing increased demands on the delivery of care in mainstream health-care institutions. While people are living longer, a significant percentage is also living with one or more long-term conditions. These issues, alongside continuing financial austerity measures, require a radical improvement in the care of patients away from hospitals. The Wyre Forest Clinical Commissioning Group introduced a virtual ward model for two main purposes: to save on spiralling costs of hospital admissions, and, secondly, to ensure the preferred wishes of most patients to be cared for and even die at home were achieved. This commentary describes how the virtual ward model was implemented and the impact of preventing unplanned emergency admissions to hospitals. The setting up of enhanced care services and virtual wards in one county is discussed, aiming to highlight success points and potential pitfalls to avoid. The results from the implementation of the virtual ward model show a significant reduction in emergency and avoidable patient admissions to hospital. The success of virtual wards is dependent on integrated working between different health-care disciplines. PMID- 25039342 TI - Does paracetamol help or hinder healing in bacterial infections? AB - Community nursing teams, alongside other primary care services and nurses in working in community hospitals, are caring for people who are older, sicker and require more complex care. The nurse's ability to use evidence to make informed judgements is vitally important to patient care. Nurses often give paracetamol that is prescribed on an 'as required' basis to patients with bacterial infections who are pyrexial. This practice is supported by guidelines from the National Institute of Health and Care Excellence and the British National Formulary. This article reviews the evidence and suggests that the administration of paracetamol in people with pyrexia should be reconsidered and given on an individualised basis rather than as a routine. PMID- 25039343 TI - Case management and long-term conditions: the evolution of community matrons. AB - It is now 10 years since the NHS Improvement Plan described a new clinical role for nurses and introduced the concept of community matrons for long-term conditions. This included conditions such as chronic obstructive pulmonary disease, diabetes, dementia, neurological conditions, heart failure, stroke and people with long and enduring mental illness. Despite initial concerns and scepticism about the role, community matrons continue to work with people to provide advanced clinical nursing care, often within a case-management model. Community matrons have continued to shape and develop this role around the main aims of preventing unnecessary emergency admissions, improving quality of life and outcomes for patients, and coordinating all elements of care. This article reviews the evidence, implementation and evolvement of case management within the role of the community matron. PMID- 25039344 TI - Enabling the health and wellbeing of carers through district nursing support. AB - Carers provide care because they want to help the people they care about, and because their care recipient could not manage without them. For many carers, looking after their own health, combining caring with work, getting access to training or having time off can be a major challenge. Patients' and carers' experiences of home-based care are a key factor in the appraisal of the quality of the professional care services they receive. This article presents the evidence from a literature review that builds a substantial body of knowledge to inform district nursing teams and community nurses to develop a supportive approach towards carers' needs. The aim of the study was to appraise the published evidence base relating to carers' needs and how professionals can support carers' needs when providing care to patients in the community. The studies consistently reported carers' requirements of practical support and information as a theme across studies, suggesting that effective ways of delivering information and support to caregivers need to be developed and implemented as a matter of priority. It also highlighted the needs of the professionals providing support to carers, to ensure the health and wellbeing needs of carers, to include signposting and referral to avoid reaching crisis point and resultant burnout. PMID- 25039345 TI - Helping community-based students on a final consolidation placement make the transition to registered practice. AB - The pressure of role transition on new nurse registrants has affected recruitment and retention, which, along with an ageing workforce, has resulted in a global shortage of nurses that is now reaching crisis point. This article examines and discusses what can be done to attract and prepare the future workforce in the community, focusing on helping students to make the transition to registered practice that begins during their final consolidation of practice placement. There is currently limited evidence on the effectiveness of how community placement teams prepare finalist students for registered practice and this could be seen as an opportunity lost given the urgent need to recruit more registered nurses to work in primary care. Recommendations for enhancing this crucial stage of the student journey are made, and a case for the need to know more from students about how they experience their final practice placement when allocated to a community setting is presented. PMID- 25039346 TI - District nurse responsibilities in relation to 'do not attempt resuscitation' decisions. AB - The Court of Appeal has ruled that patients and their relatives have the right to be consulted prior to a 'do not attempt resuscitation' notice being placed on file by a health professional. Failing to do so would be in breach of the patient's right to respect for a private and family life under the European Convention of Human Rights, article 8. This article sets out the steps that district nurses must take to ensure that 'do not attempt resuscitation' notices placed on the file of their patients are lawful. PMID- 25039347 TI - Achieving greatest impact. PMID- 25039348 TI - Structure, function, and pathogenesis of SHP2 in developmental disorders and tumorigenesis. AB - Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the human PTPN11 gene, is a ubiquitously expressed protein tyrosine phosphatase (PTP) that consists of two tandem Src homology (SH2) domains (N-SH2 and C-SH2), a PTP catalytic domain, and a C-terminal tail with tyrosyl phosphorylation sites. It plays critical roles in numerous cellular processes through the regulation of various signaling pathways in PTP catalytic activity-dependent and -independent manners. Dysfunction of SHP2 resulting from pathogenic mutations and aberrant expression leads to the dysregulation of multiple signaling pathways, thus contributing to different human disorders. Germline and somatic mutations in PTPN11 are involved in Noonan syndrome (NS), LEOPARD syndrome (LS), and hematological malignancies, as well as several solid tumors. In this report, we provide an overview of the current knowledge of the structure and function of SHP2, and further discuss the molecular and pathogenic mechanism of SHP2 in human diseases, with a special focus on tumorigenesis. Furthermore, we summarize that SHP2 might itself represent a potential drug target for cancer prevention and treatment. Ongoing research and development of SHP2-specific inhibitors would enhance this potential. PMID- 25039349 TI - Perilipin 3 modulates specific lipogenic pathways in SZ95 sebocytes. AB - Lipid droplets (LD) are dynamic organelles that manage cellular lipid synthesis, storage and retrieval. Although LD-associated proteins, including the perilipin family (PLIN1-PLIN5), are essential for these functions, they have been poorly characterized in sebocytes. Here, we employed siRNAs to downregulate PLIN3 in SZ95 sebaceous gland cells and evaluated the consequences in lipid accumulation by nile red staining and mass spectrometry. Nile red staining revealed that siRNA mediated downregulation of PLIN3 significantly impaired linoleic acid-induced lipid accumulation in SZ95 sebocytes. Mass spectrometry revealed that PLIN3 was implicated in the metabolism of linoleic acid, a lipid source used in the build up of triglycerides, among other acyl lipids. Furthermore, the expression of key enzymes of sebaceous lipogenesis was altered in PLIN3-deficient sebocytes, consistent with the changes observed in the neutral lipid abundance, suggesting that PLIN3 functions are intertwined with the lipogenic pathways implicated in sebaceous lipogenesis, such as desaturation and triglyceride synthesis. PMID- 25039350 TI - Exposure of chronic myelogenous leukemia cells to imatinib results in the post transcriptional induction of manganese superoxide dismutase. AB - The treatment of chronic myelogenous leukemia (CML) with specific tyrosine kinase inhibitors typically results in clinical success, although therapeutic failure frequently occurs. In order to investigate the biological consequences of treating CML cells with such drugs, we previously reported that the antioxidant selenoprotein glutathione peroxidase-1 (GPx-1) was induced by imatinib in both patient samples and cultured cells. Here, we extend these findings to demonstrate that the treatment of CML cell lines, but not non-CML cells, results in an approximately four-fold increase in the levels of another important antioxidant protein, manganese superoxide dismutase (MnSOD), without altering the steady state levels of the corresponding transcript. PMID- 25039351 TI - Clinical outcome and prognosis of patients with primary sinonasal tract diffuse large B-cell lymphoma treated with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy: a study by the Consortium for Improving Survival of Lymphoma. AB - We evaluated the clinical outcomes and relapse patterns of 80 patients with primary sinonasal tract diffuse large B-cell lymphoma (SN-DLBCL) treated with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy at 22 institutions. A total of 59 (73.8%) patients received R-CHOP chemotherapy alone, whereas 21 (26.3%) were treated with R-CHOP followed by involved field radiotherapy (IFRT). In 73 patients with Ann Arbor stage I-II disease, no significant difference was found in the response rate or overall survival (OS) between R-CHOP alone (n = 52) and R-CHOP followed by IFRT (n = 21). Among 11 relapsed patients in this study, the most common pattern of relapse was local (n = 8, 11.8%), whereas central nervous system (CNS) relapse was observed in only one (1.9%) patient. These results suggest that patients with primary SN DLBCL treated with R-CHOP have a relatively low CNS relapse rate and better OS compared to previous studies before the introduction of R. PMID- 25039352 TI - Diabetes insipidus in myelodysplastic syndrome: what we learnt from a case regarding its diagnosis, pathophysiology and management. PMID- 25039353 TI - Psychopathy and the DSM. AB - Psychopathy is one of the more well-established personality disorders. However, its relationship with the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) has been controversial. The purpose of this article is to trace and discuss the history of this relationship from the very first edition of the DSM to the current fifth edition. Emphasized in particular is the problematic relationship of DSM antisocial personality disorder with the diagnosis of psychopathy by Cleckley (1941, 1976) and the Psychopathy Checklist- Revised (Hare, 2003), as well as with the more recently developed models of psychopathy by Lilienfeld and Widows (2005), Lynam et al. (2011), and Patrick, Fowles, and Krueger (2009). PMID- 25039354 TI - Eosinophilic folliculitis occurring after stem cell transplant for acute lymphoblastic leukemia: a case report and review. AB - BACKGROUND: Eosinophilic folliculitis (EF) comprises classic eosinophilic pustular folliculitis (EPF), human immunodeficiency virus (HIV)-related EF, and infantile EPF subtypes. A fourth proposed subtype describes EF associated with hematologic malignancy. Recently, EF has occurred after bone marrow or stem cell transplantation (SCT). OBJECTIVES: We report a unique case of EF after haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL) and review the literature for similar cases. METHODS: A 56-year-old, HIV-negative ALL patient presented with an intensely pruritic papulopustular eruption. He had undergone haploidentical allogeneic SCT 65 days earlier, which he had tolerated well. Histopathology revealed a moderately dense perifollicular and perivascular lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat. Fungal stains were negative. These findings were highly consistent with EF. RESULTS: Therapy with a class II topical corticosteroid ointment, oral doxepin, and emollients achieved near-resolution of the lesions within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patient's ALL remains in remission. CONCLUSIONS: A fourth proposed subtype of EF is associated with HIV negative hematologic disease. This subtype is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the 2-3 months after transplant. PMID- 25039355 TI - The injury and cumulative effects on human skin by UV exposure from artificial fluorescence emission. AB - The injury and cumulative effects of UV emission from fluorescence lamp were studied. UV intensity from fluorescence lamp was measured, and human skin samples (hips, 10 volunteers) were exposed to low-dose UV irradiation (three times per week for 13 consecutive weeks). Three groups were examined: control group without UV radiation; low-dose group with a cumulative dose of 50 J cm(-2) which was equivalent to irradiation of the face during indoor work for 1.5 years; and high dose group with 1000 J cm(-2) cumulative dose equivalent to irradiation of the face during outdoor activities for 1 year. Specific indicators were measured before and after UVA irradiation. The findings showed that extending the low-dose UVA exposure decreased the skin moisture content and increased the transepidermal water loss as well as induced skin color changes (decreased L* value, increased M index). Furthermore, irradiated skin showed an increased thickness of cuticle and epidermis, skin edema, light color and unclear staining collagen fibers in the dermis, and elastic fiber fragmentation. In addition, MMP-1, p53 and SIRT1 expression was also increased. Long-term exposure of low-dose UVA radiation enhanced skin photoaging. The safety of the fluorescent lamp needs our attention. PMID- 25039356 TI - Paternal influences on offspring development: behavioural and epigenetic pathways. AB - Although mammalian parent-offspring interactions during early life are primarily through the mother, there is increasing evidence for the impact of fathers on offspring development. A critical issue concerns the pathways through which this paternal influence is achieved. In the present review, we highlight the literature suggesting several of these routes of paternal effects in mammals. First, similar to mothers, fathers can influence offspring development through the direct care of offspring, as has been observed in biparental species. Second, there is growing evidence that, even in the absence of contact with offspring, fathers can transmit environmentally-induced effects (i.e. behavioural, neurobiological and metabolic phenotypes induced by stress, nutrition and toxins) to offspring and it has been speculated that these effects are achieved through inherited epigenetic variation within the patriline. Third, fathers may also impact the quality of mother-infant interactions and thus achieve an indirect influence on offspring. Importantly, these pathways of paternal influence are not mutually exclusive but rather serve as an illustration of the complex mechanisms through which parental influence is achieved. These influences may serve to transmit traits across generations, thus leading to a transgenerational transmission of neurobiological and behavioural phenotypes. PMID- 25039357 TI - Bullous systemic contact dermatitis caused by an intra-articular steroid injection. PMID- 25039358 TI - Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability. AB - BACKGROUND AND PURPOSE: The short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. EXPERIMENTAL APPROACH: Four cysteine-modified GLP-1 analogues (1-4) were prepared using Gly8 -GLP-1(7-36)-NH2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6 13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro. In vivo, effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. KEY RESULTS: Most conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t1/2 than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. CONCLUSIONS AND IMPLICATIONS: Cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation. PMID- 25039359 TI - Monoclonal anti-A activity against the FORS1 (Forssman) antigen. AB - BACKGROUND: The FORS blood group system (originally recognized as the Apae phenotype) was discovered by sporadic activity against polyclonal anti-A reagents and activity against the lectin Helix pomatia. The extent of monoclonal anti-A reagent activity against the FORS1 antigen is serologically and immunochemically incomplete. STUDY DESIGN AND METHODS: In the absence of natural FORS1-positive red blood cells (RBCs), kodecytes were created with synthetic disaccharide and pentasaccharide Forssman function-spacer-lipid (FSL) constructs, Fsdi -kodecytes, and FORS1-kodecytes, respectively. FSL constructs were also applied to solid surfaces and used in solid-phase enzyme immunoassays. A range of characterized monoclonal anti-A and anti-B reagents were then serologically and immunochemically characterized against these Forssman antigens. Polyclonal human anti-A, anti-B, the lectin H. pomatia serologic reagents; and canine RBCs were used as serologic controls. RESULTS: None of 19 different monoclonal anti-A reagents were able to detect the pentasaccharide Forssman on FORS1-kodecytes, while three reagents were able to detect disaccharide Forssman on Fsdi kodecytes. Most anti-A reagents were immunochemically reactive with both the di- and the pentasaccharide Forssman antigens in the solid-phase assays. Historic polyclonal human anti-A and the lectin H. pomatia reacted strongly with the FORS1 kodecytes, correlating with the discovery of the Apae phenotype and supporting the use of FORS1-kodecytes as FORS1 surrogates. CONCLUSIONS: Monoclonal anti-A reagents, despite showing reactivity against the FORS1 antigen in solid-phase assays are unlikely to cause the agglutination of FORS1 antigen-positive RBCs. PMID- 25039360 TI - An unusual narrow QRS complex tachycardia: what is the mechanism? AB - The electrocardiogram of a 72-year-old woman showed episodes of nonsustained narrow QRS complex tachycardia. Tracing analysis suggested that the arrhythmia was due to interpolated atrial extrasystoles occurring in bigeminal rhythm. Interpolation of atrial extrasystoles is a rare phenomenon. In this condition, a premature atrial beat is "sandwiched" between 2 normal sinus beats, and sinus PP interval containing the extrasystole is often longer than unaffected sinus cycles. Alternative mechanisms for the arrhythmia are discussed, such as: (1) sinus node reentry; (2) 1:2 response to atrial ectopy over the fast and the slow atrioventricular nodal pathways; and (3) couplets of atrial extrasystoles. PMID- 25039362 TI - A patient with skin lesions, osteosclerosis and hepatosplenomegaly. PMID- 25039361 TI - Increased incidence of another cancer in myeloproliferative neoplasms patients at the time of diagnosis. AB - Several studies have reported an increased incidence of coexistent cancer in patients with myeloproliferative neoplasms (MPN), and myelosuppressive treatment has been speculated to be one of the causes. In this study, we have concentrated on malignancies diagnosed before the MPN diagnosis to eliminate the possible influence of MPN treatment. The patients were recruited from the Swedish and Norwegian cancer registries. One thousand seven hundred and 45 patients from the Swedish MPN Quality Registry and 468 patients from the Norwegian National Cancer Registry were included in this study covering a 3-yr period. The results show that primary concurrent cancer is higher among patients with MPN compared to the general population. When pooled together, the Swedish and the Norwegian cohort showed increased prevalence of all types of cancer in general compared with the general population, standard prevalence ratio (SPR) of 1.20 (95% CI 1.07-1.34). Significantly high SPRs were reached for skin malignant melanoma [1.89 (95% CI 1.33-2.62)], prostate cancer [1.39 (95% CI 1.11-1.71)], and hematologic cancer [1.49 (95% CI 1.00-2.12)]. In the polycythemia vera group, the risk of having prior malignant melanoma of the skin was significant, with an SPR of 2.20 (95% CI 1.17-3.77). For patients with essential thrombocythemia and primary myelofibrosis, no significant risks were found. Coexisting cancers have a high impact on the treatment strategies of MPN, as it narrows down the treatment options. Chronic inflammation, as a common denominator of MPN with other cancers, can catalyze each other's existence and progression. PMID- 25039363 TI - Flowering time QTL in natural populations of Arabidopsis thaliana and implications for their adaptive value. AB - The genetic basis of phenotypic traits is of great interest to evolutionary biologists, but their contribution to adaptation in nature is often unknown. To determine the genetic architecture of flowering time in ecologically relevant conditions, we used a recombinant inbred line population created from two locally adapted populations of Arabidopsis thaliana from Sweden and Italy. Using these RILs, we identified flowering time QTL in growth chambers that mimicked the natural temperature and photoperiod variation across the growing season in each native environment. We also compared the genomic locations of flowering time QTL to those of fitness (total fruit number) QTL from a previous three-year field study. Ten total flowering time QTL were found, and in all cases, the Italy genotype caused early flowering regardless of the conditions. Two QTL were consistent across chamber environments, and these had the largest effects on flowering time. Five of the fitness QTL colocalized with flowering time QTL found in the Italy conditions, and in each case, the local genotype was favoured. In contrast, just two flowering time QTL found in the Sweden conditions colocalized with fitness QTL and in only one case was the local genotype favoured. This implies that flowering time may be more important for adaptation in Italy than Sweden. Two candidate genes (FLC and VIN3) underlying the major flowering time QTL found in the current study are implicated in local adaptation. PMID- 25039364 TI - Alemtuzumab in lung transplantation: an open-label, randomized, prospective single center study. AB - Induction therapy with alemtuzumab followed by lower maintenance immunosuppression (IS) has been associated with reduced morbidity and mortality in abdominal and heart transplantation (TX). In the current study, alemtuzumab, in combination with reduced levels of maintenance IS, was compared to thymoglobulin in combination with standard IS. Sixty consecutive patients who underwent lung transplantation (LUTX) at a single center were prospectively randomized in two groups: group A received alemtuzumab in conjunction with reduced doses of tacrolimus, steroids and mycophenolate mofetil. Group B received thymoglobulin in association with standard dose IS. Patient and graft survival, freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, bronchiolitis obliterans syndrome, kidney function, infectious complications and posttransplant lymphoproliferative disorder were analyzed. Alemtuzumab induction therapy resulted in complete the absence of ACR episodes >= A2 within the first year post-TX. The difference to thymoglobulin was significant (alemtuzumab 0 vs. ATG 0.33; p = 0.019). All other factors studied did not show any differences between the two groups. Alemtuzumab induction therapy after LUTX in combination with reduced maintenance IS significantly reduces higher-grade rejection rates. This novel therapeutic agent had no impact on survival, infections rates, kidney function and incidence of malignancies. PMID- 25039365 TI - Role of aquaporins in determining transpiration and photosynthesis in water stressed plants: crop water-use efficiency, growth and yield. AB - The global shortage of fresh water is one of our most severe agricultural problems, leading to dry and saline lands that reduce plant growth and crop yield. Here we review recent work highlighting the molecular mechanisms allowing some plant species and genotypes to maintain productivity under water stress conditions, and suggest molecular modifications to equip plants for greater production in water-limited environments. Aquaporins (AQPs) are thought to be the main transporters of water, small and uncharged solutes, and CO2 through plant cell membranes, thus linking leaf CO2 uptake from the intercellular airspaces to the chloroplast with water loss pathways. AQPs appear to play a role in regulating dynamic changes of root, stem and leaf hydraulic conductivity, especially in response to environmental changes, opening the door to using AQP expression to regulate plant water-use efficiency. We highlight the role of vascular AQPs in regulating leaf hydraulic conductivity and raise questions regarding their role (as well as tonoplast AQPs) in determining the plant isohydric threshold, growth rate, fruit yield production and harvest index. The tissue- or cell-specific expression of AQPs is discussed as a tool to increase yield relative to control plants under both normal and water-stressed conditions. PMID- 25039366 TI - Histopathological comparative analysis of peri-implant soft tissue response after dental implant placement with flap and flapless surgical technique. Experimental study in pigs. AB - AIM: The aim of this study was comparing the effect of flapless vs. flap technique of implant placement on inflammation degree of peri-implant soft tissue, through histopathological analysis. METHOD: The experiment was conducted on five domestic pigs. Nine weeks after tooth extraction, implants were installed. Each animal received six implants in mandible. According to split mouth design, randomly one side was used for flapless technique using mini incision, while on the other side, flap was raised. After 7, 14, 21, 28, and 90 days, the experimental animals were sacrificed. Samples for histopathological analyzes were taken from the buccal side of peri-implant mucosa next to the neck of implants, from three levels. The degree of inflammatory response in the peri implant soft tissue was estimated through ordinal scores from 0 to 3. RESULTS: In the flap group Score 3 indicating high degree of inflammation was present from day 7 to day 21, in contrast to flapless group where Score 3 was not recorded during the entire follow-up. Three months after implantation, there were no signs of inflammation neither around flap nor around flapless implants. CONCLUSION: Flapless surgical implantation technique using mini-incision decreases peri implant soft tissue inflammatory reaction compared with flap surgery. PMID- 25039367 TI - Cluster belly: a variant of irritable bowel syndrome. AB - Cluster headache (CH) and irritable bowel syndrome (IBS) are pain disorders that possess relationships with circadian rhythms. However, they have not been compared to assess similarities that could yield pathophysiologic insights. A young male adult with periodic episodes of abdominal pain highly reminiscent of CH is described. Since childhood, he experienced severe attacks featuring excruciating, abdominal pain accompanied by prominent restlessness, lasting 30 120 minutes, occurring in the evening and in discrete 2- to 8-week periods, interspersed with remissions where typical triggers did not lead to attacks. Although all of the patient's symptoms fell within the spectrum of IBS, the semiology was highly evocative of CH, based on the attack duration, restlessness, periodicity, and selective vulnerability to particular triggers only during attack periods. A subset of patients thought to have IBS may feature similar attack profiles and could suggest the importance of the hypothalamus in its pathophysiology, akin to CH. PMID- 25039368 TI - Medium-chain triglyceride as an alternative of in-feed colistin sulfate to improve growth performance and intestinal microbial environment in newly weaned pigs. AB - Five hundred and twenty-eight newly weaned pigs were given four treatments, with eight replicates per treatment. Sixteen to 18 pigs were assigned per replicate and were fed diets supplemented with 0 or 3% medium-chain triglyceride (MCT) and 0 or 40 ppm colistin sulfate (CS) in a 2 * 2 factorial arrangement for 2 weeks. The results showed that dietary supplementation with MCT improved the gain-to feed ratio during days 3-7 and in the overall period (P < 0.05). Dietary supplementation with MCT decreased coliforms counts (C) in colon and rectum content (P < 0.05). Dietary supplementation with CS decreased C and lactic acid bacteria plus C counts (L + C) in cecum (P < 0.05), and C, L + C (P < 0.01) and ratio of L and C (P < 0.05) in colon and rectum contents. The lack of interactions between MCT and CS indicates different modes of action and additive effects between the two supplementations. In conclusion, supplementation with MCT in diet with or without CS could improve the intestinal microbial environment and the feed utilization efficiency of newly weaned pigs. PMID- 25039369 TI - Levels of somatic hypermutations in B cell receptors increase during childhood. AB - Somatic hypermutation (SHM) is an important step in antigen-driven B cell development creating B lymphocytes expressing high-affinity antibody receptors. It is known that the peripheral B lymphocyte compartments of healthy children and adults differ considerably. However, the development of SHM with age has not been studied in detail previously. Therefore, we used the immunoglobulin (Ig)kappa restriction enzyme hot-spot mutation assay (Igkappa-REHMA) to gain an estimation of SHM levels in different age groups in order to relate this to the size of the memory B lymphocyte subpopulations. We show that the level of SHM increases rapidly during the first 2 years of life. This reflects the changes of the memory B cell subpopulations, but also changes in the SHM within memory B cell subsets, probably reflecting an increase of secondary memory B cell responses. PMID- 25039370 TI - Editorial Comment from Dr Golebiewski to Long-term outcome of hand-assisted laparoscopic radical nephrectomy for T1 renal cell carcinoma. PMID- 25039371 TI - Incubation temperature, osmolarity, and salicylate affect the expression of resistance-nodulation-division efflux pumps and outer membrane porins in Acinetobacter baumannii ATCC19606T. AB - In this study, we examined the impact of various environmental conditions on the expression of resistance-nodulation-division (RND) efflux pumps and outer membrane (OM) porins, two key determinants of Acinetobacter baumannii's intrinsic resistance, an organism known to cause various multidrug resistant infections in immunocompromised individuals. Quantitative RT-PCR was used to analyze the expression of adeB, adeG, and adeJ (genes encoding RND pumps) and 33 kDa, carO, and oprD (genes encoding OM porins) of A. baumannii ATCC19606(T) under different incubation temperatures (30, 37, and 42 degrees C) and in the presence of high osmolarity and salicylate. Downregulation of all three RND pumps was observed at 30 degrees C, while downregulation of all three porins tested was observed at increased osmolarity. Downregulation of RND efflux pumps, particularly AdeABC, was consistent with increased susceptibility to antibiotics that are substrates of this pump. Expression of the adeR response regulator gene of the AdeRS system, the activator of the AdeABC pump, was also analyzed. Our work shows that various environmental stress conditions can influence the expression of RND pumps and porins in A. baumannii ATCC19606(T) and thus may play a role in the modulation of its antibiotic resistance. PMID- 25039372 TI - Plant root exudates mediate neighbour recognition and trigger complex behavioural changes. AB - Some plant species are able to distinguish between neighbours of different genetic identity and attempt to pre-empt resources through root proliferation in the presence of unrelated competitors, but avoid competition with kin. However, studies on neighbour recognition have met with some scepticism because the mechanisms by which plants identify their neighbours have remained unclear. In order to test whether root exudates could mediate neighbour recognition in plants, we performed a glasshouse experiment in which plants of Deschampsia caespitosa were subjected to root exudates collected from potential neighbours of different genetic identities, including siblings and individuals belonging to the same or a different population or species. Our results show that root exudates can carry specific information about the genetic relatedness, population origin and species identity of neighbours, and trigger different responses at the whole root system level and at the level of individual roots in direct contact with locally applied exudates. Increased root density was mainly achieved through changes in morphology rather than biomass allocation, suggesting that plants are able to limit the energetic cost of selfish behaviour. This study reveals a new level of complexity in the ability of plants to interpret and react to their surroundings. PMID- 25039373 TI - Expression and functional regulation of the nuclear receptors AHR, PXR, and CAR, and the transcription factor Nrf2 in rat parotid gland. AB - Nuclear receptors and transcription factors regulate the functions of many genes involved in cellular physiology and pathology (e.g. tumorigenesis and autoimmune diseases). The present study was performed to define the expression and the regulation of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), and nuclear factor E2-related factor 2 (Nrf2) in the rat parotid gland. Constitutive expression, as well as expression after stimulation with specific inducers for AhR [2,3,7,8-tetrachloro-dibenzylo-p dioxin (TCDD)], Nrf2(oltipraz), PXR (dexamethasone), and CAR (phenobarbital), was evaluated using the quantitative PCR. Cellular localization of the nuclear receptors and the transcription factor was visualized by immunohistochemical staining. The study revealed constitutive expression of AhR as well as Nrf2, and their induction by TCDD andoltipraz, respectively. Immunohistochemical analysis revealed constitutive, predominantly cytoplasmic, expression of the AhR receptor, especially in interlobular striated duct cells, with nuclear shift upon exposure to TCDD. Inducible expression of Nfr2 was found mainly in the cytoplasm of intralobular striated duct cells. Constitutive expression of PXR and CAR was not found. Bearing in mind the involvement of AhR and Nrf2 in the regulation of many genes, it seems that these factors may play also a role in salivary gland physiology and pathology. PMID- 25039374 TI - Differences in activities of daily living (ADL) abilities of children across world regions: a validity study of the assessment of motor and process skills. AB - BACKGROUND: One important goal of paediatric occupational therapy services is to improve activities of daily living (ADL) abilities of children. In order to plan and evaluate the effectiveness of targeted interventions, valid assessments are critically needed. The Assessment of Motor and Process Skills (AMPS) is an internationally standardized assessment of ADL performance that has not been validated for use with children in Middle Europe. AIM: To evaluate for (i) significant differences in mean ADL motor and mean ADL process ability measures among children from Middle Europe compared with children from North America, UK/Republic of Ireland, Nordic countries, Western Europe, Australia/New Zealand and Asia; and (ii) meaningful differences between the international age-normative means of the AMPS and those for children from Middle Europe. METHOD: We analysed data of children across world regions extracted from the international AMPS database using many-facet Rasch and two-way anova analyses and by estimating contrasts to evaluate for significant group differences. RESULTS: anova analyses of data for 11 189 children ages 2-15 revealed significant effects for mean ADL motor and ADL process ability by region [F >= 15.32, d.f. = (6, 11 091), MSE >= 0.20, P < 0.001, eta(2) >= 0.008], and age [F >= 253.47, d.f. = (13, 11 091), MSE >= 0.20, P < 0.001, eta(2) >= 0.229], and a significant interaction effect for mean ADL process ability [F = 1.48, d.f. = (78, 11 091), P = 0.004, eta(2) = 0.010]. Out of 168 estimated contrasts between Middle Europe and the other world regions for mean ADL motor and ADL process ability, seven were statistically significant (4.17%), but none exceeded +/-1SE from the international means. CONCLUSION: The AMPS remains free of relevant differences in mean ADL ability measures between Middle Europe and other world regions, indicating that the international age-normative mean values are likely to be applicable to children from Middle Europe. The AMPS can be used internationally to evaluate ADL performance in children and to determine if the child is eligible for occupational therapy services. PMID- 25039375 TI - Prevalence and long-term prognosis of patients with complete bundle branch block (right or left bundle branch) with normal left ventricular ejection fraction referred for stress echocardiography. AB - BACKGROUND: The prognostic value of stress echocardiography (SE) in patients with complete bundle branch blocks (BBB) with normal left ventricular ejection fraction (LVEF) has not been well described. We sought to determine the prognostic value of SE in patients with BBB and normal LVEF. METHODS: We analyzed 7214 patients (58 +/- 14 years; 57% female) with a mean follow-up time of 9 +/- 4 years. Dobutamine SE was performed in 51% of patients and exercise SE was performed in 49%. All-cause mortality data were obtained from the Social Security Death Index. RESULTS: There were 222 (3%) patients with right bundle branch block (RBBB) and 50 (0.7%) patients with left bundle branch block (LBBB). Patients with LBBB were 3 times more likely to have an abnormal stress test after adjusting for age, gender, mode of stress test, and coronary artery disease risk factors (OR = 3.3; 95% CI: 1.86-5.92; P < 0.001). The mortality rates were 4.5%/year for patients with LBBB, 2.5%/year for patients with RBBB, and 1.9%/year for patients without BBB (P < 0.001). Among patients with a normal SE, those with LBBB had similar mortality to those without LBBB (HR = 0.9; 95% CI: 0.4-2.2; P = 0.8). Patients with LBBB and abnormal SE had more than 2 times greater risk of all cause mortality (HR = 2.4; 95% CI: 1.4-4.2; P = 0.002). CONCLUSION: A normal stress echocardiogram in LBBB is associated with benign prognosis while those with LBBB and abnormal SE have the worst outcomes. PMID- 25039376 TI - Tubulin beta-III: a novel immunohistochemical marker for intrahepatic peripheral cholangiocarcinoma. AB - AIMS: Our recent proteomic study identified tubulin beta-III (TUBB3) as a potential tissue marker for intrahepatic cholangiocarcinomas (CCs). This validation study was conducted to see whether or not TUBB3 can serve as a novel immunohistochemical marker for peripheral CCs, using a large cohort (n = 197) covering various liver tumours and premalignant conditions. METHODS AND RESULTS: Immunostaining using a monoclonal antibody demonstrated TUBB3 expression in 14/28 cases of peripheral CCs (50%), while its expression was significantly less common in perihilar CCs (6/40, 15%) (P = 0.002). No significant difference was identified in clinicopathological features between TUBB3-positive and -negative cases. TUBB3 expression was entirely negative in hepatocellular carcinomas, biliary premalignant lesions (i.e., biliary intraepithelial neoplasias, intraductal papillary neoplasms), peribiliary gland hamartomas (bile duct adenomas), and non-neoplastic biliary epithelium. TUBB3 expression was only focally noted in 2/12 cases of mixed hepatocellular and cholangiocarcinomas (<10% of cancer cells). Compared with other biliary (CK7 and CK19) and malignant markers (p53 and MUC1), TUBB3 was less sensitive but more specific for peripheral CCs. TUBB3 was also expressed in 40% of metastatic colorectal or breast cancers. CONCLUSIONS: This study revealed that TUBB3 is a moderately sensitive and highly specific tissue marker for discriminating peripheral CCs from other primary liver tumours. PMID- 25039378 TI - Indebted to the bank or the profession? New doctor debt and its effect on access to care. PMID- 25039377 TI - Skin sensitization induced Langerhans' cell mobilization: variable requirements for tumour necrosis factor-alpha. AB - Upon antigen/allergen recognition, epidermal Langerhans' cells (LC) are mobilized and migrate to the local lymph node where they play a major role in initiating or regulating immune responses. It had been proposed that all chemical allergens induce LC migration via common cytokine signals delivered by TNF-alpha and IL 1beta. Here the dependence of LC migration on TNF-alpha following treatment of mice with various chemical allergens has been investigated. It was found that under standard conditions the allergens oxazolone, paraphenylene diamine, and trimellitic anhydride, in addition to the skin irritant sodium lauryl sulfate, were unable to trigger LC mobilization in the absence of TNF-alpha signalling. In contrast, two members of the dinitrohalobenezene family (2,4-dinitrochlorobenzene [DNCB] and 2,4-dinitrofluorobenzene [DNFB]) promoted LC migration independently of TNF-R2 (the sole TNF-alpha receptor expressed by LC) and TNF-alpha although the presence of IL-1beta was still required. However, increasing doses of oxazolone overcame the requirement of TNF-alpha for LC mobilization, whereas lower doses of DNCB were still able to induce LC migration in a TNF-alpha independent manner. These novel findings demonstrate unexpected heterogeneity among chemical allergens and furthermore that LC can be induced to migrate from the epidermis via different mechanisms that are either dependent or independent of TNF-alpha. Although the exact mechanisms with regard to the signals that activate LC have yet to be elucidated, these differences may translate into functional speciation that will likely impact on the extent and quality of allergic sensitization. PMID- 25039379 TI - Oral health champions in long-term care facilities-a pilot study. AB - This preintervention/postintervention pilot study examined impact of onsite support by a dental hygiene champion (DHC) on oral health and quality of life (QOL) of elderly residents in three long-term care facilities (LTCFs) in Arkansas. Oral health and oral health-related QOL were operationalized using the Oral Health Assessment Tool (OHAT) and Geriatric Oral Health Assessment Index (GOHAI), respectively. CNAs in Facility A received standardized oral health education/materials with onsite DHC support. Facility B received education/materials only. Facility C served as control. Data analyses included Wilcoxon-signed rank tests (OHAT) and repeated measures ANOVA (GOHAI) (p <= .05). OHAT postintervention data in Facility A showed significant improvements in three measured areas (tongue health, denture status, and oral cleanliness); in Facility B, one area (tongue health); and none in Facility C. No significant differences were found in GOHAI scores across facilities. Findings suggest that the presence of DHCs in LTCFs may positively impact the oral health of CNA-assisted residents. PMID- 25039380 TI - Caries risk profile of Korean dental patients with severe intellectual disabilities. AB - This study evaluated the caries risk profile of patients with severe intellectual disabilities (IDs) who received dental treatment under general anesthesia. One hundred and two patients with ID [ID group, mean age (SD); 23.8(9.3)] and 100 healthy patients without ID [NID group, mean age (SD); 23.19(3.3)] were included. Medication, disability type, oral hygiene maintenance, and cooperation of the patients were investigated. Dietary habits, plaque index, mutans streptococci counts, fluoride availability, and salivary buffering were scored and analyzed using the Cariogram. The mean chance of avoiding caries (SD) was 28.1(20.4) in the ID group and 54.7(18.4) in the NID group. The ID group had significantly higher numbers of decayed and missing teeth, but fewer filled teeth than the NID group (p < .05). Significant disparities existed in the distributions of all caries-related factors except for mutans streptococci counts between the two groups (p < .05). The low chance to avoid future caries in ID patients was closely associated with insufficient oral hygiene maintenance (p < .05). Fluoride availability was strongly associated with the chance of avoiding caries in the ID group. Dental patients with severe ID exhibited a higher risk of developing caries than normal patients. Among several caries-related factors, insufficient oral hygiene maintenance and low fluoride availability most contributed to the high risk. PMID- 25039381 TI - Adverse skeletal effects of drugs - beyond Glucocorticoids. AB - Osteoporotic fractures are an important public health problem with significant individual and societal costs. In addition to the major risk factors for osteoporotic fracture, low bone mineral density (BMD), age, low body weight and history of fracture or falls, some drugs are now considered to be important secondary risk factor for bone loss and fracture, particularly amongst predisposed individuals. Currently available data are often generated from small observational clinical studies, making risk assessment and development of management guidelines difficult. In many cases, the exposed population has a low baseline risk for fracture and additional assessment and treatment may not be necessary. In this review, we focus on drugs other than glucocorticoids identified as potentially causing adverse skeletal effects, summarizing the existing evidence from preclinical and clinical studies, and suggest recommendations for patient management. PMID- 25039382 TI - Academic freedom: alive and well or victim of the conservative creep? PMID- 25039383 TI - Dramatic regression of recalcitrant human papillomavirus type 1-related palmar verrucae and squamous cell carcinoma in situ following R-CHOP chemotherapy and transition to sirolimus in a renal transplant patient with diffuse large B cell lymphoma. PMID- 25039384 TI - Transmission dynamics of the monogenean Gyrodactylus salaris under seminatural conditions. AB - Tracking individual variation in the dynamics of parasite infections in wild populations is often complicated by lack of knowledge of the epidemiological history of hosts. Whereas the dynamics and development of Gyrodactylus salaris Malmberg, 1957, on Atlantic salmon, Salmo salar L., are known from laboratory studies, knowledge about infection development on individual wild fishes is currently sparse. In this study, the dynamics of an infection of G. salaris on individually marked Atlantic salmon parr was followed in a section of a natural stream. During the 6-week experiment, the prevalence increased from 3.3 to 60.0%, with an average increase in intensity of 4.1% day(-1) . Survival analyses showed an initially high probability (93.6%) of staying uninfected by G. salaris, decreasing significantly to 37% after 6 weeks. The results showed that even at subarctic water temperatures and with an initially low risk of infection, the parasite spread rapidly in the Atlantic salmon population, with the capacity to reach 100% prevalence within a short summer season. The study thus track individual infection trajectories of Atlantic salmon living under near-natural conditions, providing an integration of key population parameters from controlled experiments with the dynamics of the epizootic observed in free-living living populations. PMID- 25039385 TI - Ductal carcinoma in-situ arising in a complex sclerosing lesion with secretory endometrium-like changes. PMID- 25039386 TI - JMFT Best Article of the Year Award: spotlighting excellence within a context of excellence. PMID- 25039387 TI - From scared to repaired: using an attachment-based perspective to understand situational couple violence. AB - Situational couple violence (SCV) is a common problem in couples presenting for therapy. SCV, as seen through the lens of attachment, can be viewed as a result of an insecure attachment system within the couple. Although several authors have discussed individual attachment styles as predictors of both the receipt and perpetration of violence, in this article we seek to portray the attachment system as a relational and changing construct. As such, we argue for conjoint treatment for SCV as a way to restructure a more secure attachment system within the couple. Cautions for the appropriateness of couples counseling with ongoing violence are included. Finally, we discuss the use of an attachment-based safety plan and time-out strategy to use with couples experiencing SCV. PMID- 25039391 TI - Weight change, body composition, and risk of mobility disability and mortality in older adults: a population-based cohort study. AB - OBJECTIVES: To examine associations between weight change, body composition, risk of mobility disability, and mortality in older adults. DESIGN: Prospective, longitudinal, population-based cohort. SETTING: The Health, Aging, and Body Composition Study. PARTICIPANTS: Women (n = 1,044) and men (n = 931) aged 70 to 79. MEASUREMENTS: Weight and lean and fat mass from dual-energy X-ray absorptiometry measured annually over 5 years. Weight was defined as stable (n = 664, reference), loss (n = 662), gain (n = 321), or cycling (gain and loss, n = 328) using change of 5% from year to year or from Year 1 to 6. Mobility disability (two consecutive reports of difficulty walking one-quarter mile or climbing 10 steps) and mortality were determined for 8 years after the weight change period. Associations were analyzed using Cox proportional hazards regression adjusted for covariates. RESULTS: During follow-up, 313 women and 375 men developed mobility disability, and 322 women and 378 men died. There was no risk of mobility disability or mortality with weight gain. Weight loss (hazard ratio (HR) = 1.88, 95% confidence interval (CI) = 1.40-2.53) and weight cycling (HR = 1.59, 95% CI = 1.11-2.29) were associated with mobility disability in women, and weight loss was associated with mobility disability in men (HR = 1.30, 95% CI = 1.01-1.69). Weight loss and weight cycling were associated with mortality risk in women (weight loss: HR = 1.47, 95% CI = 1.07-2.01; weight cycling: HR = 1.62, 95% CI = 1.15-2.30) and in men (weight loss: HR = 1.41, 95% CI = 1.09-1.83; weight cycling: HR = 1.50, 95% CI = 1.08-2.08). Adjustment for lean and fat mass and change in lean and fat mass from Year 1 to 6 attenuated the relationships between weight loss and mobility disability in men and between weight loss and mortality in men and women. CONCLUSION: Weight cycling and weight loss predict impending mobility disability and mortality in old age, underscoring the prognostic importance of weight history. PMID- 25039392 TI - The NTT transcription factor promotes replum development in Arabidopsis fruits. AB - Fruits are complex plant structures that nurture seeds and facilitate their dispersal. The Arabidopsis fruit is termed silique. It develops from the gynoecium, which has a stigma, a style, an ovary containing the ovules, and a gynophore. Externally, the ovary consists of two valves, and their margins lay adjacent to the replum, which is connected to the septum that internally divides the ovary. In this work we describe the role for the zinc-finger transcription factor NO TRANSMITTING TRACT (NTT) in replum development. NTT loss of function leads to reduced replum width and cell number, whereas increased expression promotes replum enlargement. NTT activates the homeobox gene BP, which, together with RPL, is important for replum development. In addition, the NTT protein is able to bind the BP promoter in yeast, and when this binding region is not present, NTT fails to activate BP in the replum. Furthermore, NTT interacts with itself and different proteins involved in fruit development: RPL, STM, FUL, SHP1 and SHP2 in yeast and in planta. Moreover, its genetic interactions provide further evidence about its biological relevance in replum development. PMID- 25039393 TI - The influence of tonsillectomy on total serum antibody levels. PMID- 25039395 TI - The role of behavioral inhibition and parenting for an unfavorable emotional trauma response and PTSD. AB - OBJECTIVE: The role of behavioral inhibition (BI) and parenting for an unfavorable emotional trauma response (DSM-IV criterion A2) and post-traumatic stress disorder (PTSD) development is unclear. METHOD: A community sample of adolescents and young adults (aged 14-24) was followed up over 10 years (N=2378). Traumatic events, criterion A2, and PTSD (according to DSM-IV-TR) were assessed using the M-CIDI. BI and parenting were assessed using the Retrospective Self Report of Inhibition and the Questionnaire of Recalled Parenting Rearing Behavior. Multiple logistic regressions adjusted for sex, age, and number of traumata were used to examine associations of BI as well as maternal and paternal overprotection, rejection, and reduced emotional warmth with (i) criterion A2 in those with trauma (N=1794) and (ii) subsequent PTSD in those with criterion A2 (N=1160). RESULTS: Behavioral inhibition (BI; odds ratio, OR=1.32) and paternal overprotection (OR=1.27) predicted criterion A2 in those with trauma, while only BI (OR=1.53) predicted subsequent PTSD. BI and paternal emotional warmth interacted on subsequent PTSD (OR=1.32), that is, BI only predicted PTSD in those with low paternal emotional warmth. CONCLUSION: Our findings suggest that BI and adverse parenting increase the risk of an unfavorable emotional trauma response and subsequent PTSD. Paternal emotional warmth buffers the association between BI and PTSD development. PMID- 25039394 TI - EspI regulates the ESX-1 secretion system in response to ATP levels in Mycobacterium tuberculosis. AB - The function of EspI, a 70 kDa protein in Mycobacterium tuberculosis, has remained unclear. Although EspI is encoded by a gene within the esx-1 locus, in this study we clarify previous conflicting results and show that EspI is not essential for ESX-1-mediated secretion or virulence in M. tuberculosis. We also provide evidence that reduction of cellular ATP levels in wild-type M. tuberculosis using the drug bedaquiline completely blocks ESX-1-mediated secretion. Remarkably, M. tuberculosis lacking EspI fails to exhibit this phenotype. Furthermore, mutagenesis of a highly conserved ATP-binding motif in EspI renders M. tuberculosis incapable of shutting down ESX-1-mediated secretion during ATP depletion. Collectively these results show that M. tuberculosis EspI negatively regulates the ESX-1 secretion system in response to low cellular ATP levels and this function requires the ATP-binding motif. In light of our results the potential significance of EspI in ESX-1 function during latent tuberculosis infection and reactivation is also discussed. PMID- 25039396 TI - Impulsivity predicts time to reach euthymia in adults with bipolar disorder. AB - OBJECTIVES: Specific demographic and illness characteristics have been identified as predictors of overall morbidity and treatment course among individuals with bipolar disorder. However, the role of specific cognitive limitations on disease severity and treatment response is unclear. The present study evaluated whether impulsiveness during acute mania was a significant predictor of achieving euthymia within one year following psychiatric hospitalization. METHODS: Participants were 94 adult inpatients (60 manic) with bipolar I disorder. Baseline symptom severity was assessed using the Young Mania Rating Scale and the Montgomery-Asberg Depression Rating Scale. Impulsivity was measured with the Stop Signal Task, Degraded Stimulus Continuous Performance Task, Delayed Response Task, and Barratt Impulsiveness Scale-11. RESULTS: Individual predictors of time to reach euthymia included fewer depressive symptoms and better impulse control at baseline, later age at illness onset, shorter illness duration, and the absence of comorbid attention-deficit hyperactivity disorder. Self-reported impulsivity was a significant independent predictor of time to euthymia, even after accounting for relevant clinical variables. CONCLUSIONS: Better trait impulse control may be associated with better treatment responsiveness among adults with bipolar disorder. PMID- 25039397 TI - Multiscale factors affecting human attitudes toward snow leopards and wolves. AB - The threat posed by large carnivores to livestock and humans makes peaceful coexistence between them difficult. Effective implementation of conservation laws and policies depends on the attitudes of local residents toward the target species. There are many known correlates of human attitudes toward carnivores, but they have only been assessed at the scale of the individual. Because human societies are organized hierarchically, attitudes are presumably influenced by different factors at different scales of social organization, but this scale dependence has not been examined. We used structured interview surveys to quantitatively assess the attitudes of a Buddhist pastoral community toward snow leopards (Panthera uncia) and wolves (Canis lupus). We interviewed 381 individuals from 24 villages within 6 study sites across the high-elevation Spiti Valley in the Indian Trans-Himalaya. We gathered information on key explanatory variables that together captured variation in individual and village-level socioeconomic factors. We used hierarchical linear models to examine how the effect of these factors on human attitudes changed with the scale of analysis from the individual to the community. Factors significant at the individual level were gender, education, and age of the respondent (for wolves and snow leopards), number of income sources in the family (wolves), agricultural production, and large-bodied livestock holdings (snow leopards). At the community level, the significant factors included the number of smaller-bodied herded livestock killed by wolves and mean agricultural production (wolves) and village size and large livestock holdings (snow leopards). Our results show that scaling up from the individual to higher levels of social organization can highlight important factors that influence attitudes of people toward wildlife and toward formal conservation efforts in general. Such scale-specific information can help managers apply conservation measures at appropriate scales. Our results reiterate the need for conflict management programs to be multipronged. PMID- 25039398 TI - Porcine acellular dermal matrix for delayed abdominal wall closure after pediatric liver transplantation. AB - Children are one of the groups with the highest mortality rate on the waiting list for LT. Primary closure of the abdominal wall is often impossible in the pediatric population, due to a size mismatch between a large graft and a small recipient. We present a retrospective cohort study of six pediatric patients, who underwent delayed abdominal wall closure with a biological mesh after LT, and in whom early closure was impossible. A non-cross-linked porcine-derived acellular dermal matrix (Strattice(TM) Reconstructive Tissue Matrix; LifeCell Corp, Bridgewater, NJ, USA) was used in all of the cases of the series. After a mean follow-up of 26 months (21-32 months), all patients were asymptomatic, with a functional abdominal wall after physical examination. Non-cross-linked porcine derived acellular dermal matrix (Strattice(TM) ) is a good alternative for delayed abdominal wall closure after pediatric LT. Randomized controlled trials are necessary to determine the best moment and the best technique for abdominal wall closure. PMID- 25039399 TI - Adenocarcinoma arising from intracranial recurrent mature teratoma and featuring mutated KRAS and wild-type BRAF genes. AB - Malignant transformation or recurrence of intracranial mature teratoma is an extremely rare occurrence, compared to the usual ovarian counterpart. Previously, yolk sac tumor elements have been considered to be selective progenitors of enteric-type adenocarcinoma arising from intracranial germ cell tumors. However, the present case demonstrates the occurrence of enteric-type adenocarcinoma in recurrent intracranial mature cystic teratoma 12 years after gross total removal, a case of which has not previously been documented in the literature. The 11.5-cm long, dura mater-based tumor on the right fronto-temporal lobe displaced the brain; however, the patient had no neurologic symptoms or discomfort other than pus-like discharge on the scalp. Microscopic examinations revealed a small focus of adenocarcinoma and dysplastic colonic mucosa in the mature cystic teratoma. No immature elements were seen. The cystic wall was almost denuded and showed an exuberant xanthogranulomatous reaction with foreign-body type giant cells engulfing keratin materials and cholesterol clefts, suggesting that chronic inflammation due to repeated cyst wall rupture and the previous resection may contribute to malignant transformation. The adenocarcinoma showed strong immunohistochemical expression of CK20 and p53, but CK7 in patches. The molecular profile of the adenocarcinoma showed a mutation in KRAS and wild-type BRAF, which might be associated with malignant transformation of intracranial mature teratomas. In conclusion, the intracranial mature teratomas should require long term follow-up, and clinicians, radiologists and pathologists should be aware of the potential for malignant progression of recurrent intracranial mature cystic teratoma despite gross total resection and no neurologic symptoms. PMID- 25039400 TI - Response to letter to the editor 'Is red cell distribution width a biomarker in risk assessment of diabetes mellitus?'. PMID- 25039401 TI - The effectiveness of quarter turn from prone in maintaining respiratory function in premature infants. AB - AIM: The aim of this study was to determine the effectiveness of quarter turn from prone compared with supine and prone positioning in maintaining respiratory function in premature infants managed in a neonatal intensive care unit. METHODS: The study was a prospective, randomised, cross-over trial with concealed allocation and intention to treat analysis. Fifty-four infants <=32 weeks gestation were randomly allocated to the order of the positions supine, prone and quarter turn from prone. Distribution of ventilation was assessed by measurement of regional impedance amplitude, global inhomogeneity index and phase angle analysis using electrical impedance tomography 30 min after each position change. Physiological characteristics of heart rate, respiratory rate (RR), oxygen saturation and inspired oxygen were also measured. RESULTS: There was a significant difference between positions for RR with the RR in quarter turn from prone significantly lower than for supine (mean difference 6.53 breaths/min; 2.04 11.02), but not compared with the prone position. No significant differences between positions were found for any of the other outcomes measured. CONCLUSION: This study demonstrated that quarter turn from prone had an immediate positive positional effect on the RR of premature infants. The position of quarter turn from prone was comparable with prone in the maintenance of lung function and had a superior effect over supine on RR. These findings support the view that a quarter turn from prone can be confidently used in neonatal nurseries to manage premature infants. PMID- 25039402 TI - Mastoparan peptide causes mitochondrial permeability transition not by interacting with specific membrane proteins but by interacting with the phospholipid phase. AB - The mastoparan peptide is known as an inducer of the mitochondrial permeability transition. Although mastoparan was suggested to interact with a proteinaceous target in mitochondria to induce this transition, the action sites of mastoparan have not yet been investigated. To clarify whether specific interactions of mastoparan with receptors or enzymes are associated with the induction of this permeability transition, we examined the effects of d-isomeric peptides, which were synthesized using d-amino acids assembled in endogenous (inverso mastoparan) and reverse (retro-inverso mastoparan) orientations. When we added inverso mastoparan to isolated mitochondria, the peptide caused the permeability transition in a partially cyclosporin A-sensitive manner at lower doses and in a cyclosporin A-insensitive manner at higher ones. The manners of action and the potencies of inverso mastoparan were close to those of parent mastoparan, indicating that the targets of mastoparan for induction of the permeability transition were neither receptors, nor enzymes in the mitochondria. Retro-inverso mastoparan also had the same effect on the mitochondria as mastoparan, although the potencies of the effect were weaker. Not only on mitochondria, but also on phospholipid vesicles, mastoparan and inverso mastoparan showed massive permeabilization effects at the same potencies, although retro-inverso mastoparan showed weaker ones. These results indicate that mastoparan interacted with the phospholipid phase of the mitochondrial membrane (and not with specific proteins) to induce the permeabilization in cyclosporin A-sensitive and -insensitive manners. PMID- 25039403 TI - The effects of propofol vs. sevoflurane on post-operative pain and need of opioid. AB - BACKGROUND: Post-operative pain continues to be a major problem. Some previous studies have suggested that patients anaesthetised with propofol have less pain after surgery than those anesthetised with volatiles. However, the results of previous studies are conflicting. We designed a large-scale trial to study, whether propofol or sevoflurane is more analgesic than the other. We measured opioid consumption in the acute post-operative phase after laparoscopic hysterectomy. METHODS: In a randomised, prospective single-blind trial, we evaluated the consumption of oxycodone and pain intensity in 148 women for 20 h after laparoscopic hysterectomy under propofol or sevoflurane anaesthesia. The primary endpoint was the cumulative amount of oxycodone consumed. Secondary endpoints were pain scores [numeric rating scale (NRS)] at rest and with coughing, severity of nausea and state of sedation. RESULTS: The consumption of oxycodone and the NRS pain scores did not differ between the groups. The oxycodone consumed during first 20 h after surgery was 42.5 (95% confidence interval 38.3-46.6) mg and 42.8 (37.3-48.4) mg in propofol- and sevoflurane anaesthetised patients, respectively (P = 0.919). NRS scores for nausea were higher in the patients receiving sevoflurane during the first 60 min in the post anaesthesia care unit, leading to higher consumption of rescue antiemetics. Sedation scores differed in favour of sevoflurane only at 4 h time point after anaesthesia. Patient characteristics did not differ. CONCLUSIONS: In this study, comparing sevoflurane with propofol for maintenance of general anaesthesia, the choice of anaesthetic had no effect on the requirement of oxycodone or intensity of pain after surgery. PMID- 25039404 TI - Scleroderma renal crisis following pericardial effusion in a Japanese female. AB - Scleroderma renal crisis (SRC) occurs in 4-5% of Japanese patients with systemic sclerosis (SSc) and is one of the most severe complications, along with interstitial pneumonia and pulmonary hypertension, which lead to a poor outcome. The factors predicting SRC include diffuse progressive skin thickening, a duration of SSc of 4 years or less, having autoantibodies against RNA polymerase III, systemic corticosteroid (CS) administration and recent cardiac events, including pericarditis. We herein report a female case of SRC preceded by pericardial effusion during the treatment with CS for rapidly progressive skin thickening. She had none of the known autoantibodies and was successfully treated with an angiotensin II receptor blocker. PMID- 25039406 TI - Impact of food restriction on ovarian development, RFamide-related peptide-3 and the hypothalamic-pituitary-ovarian axis in pre-pubertal ewes. AB - RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of gonadotropin inhibiting hormone, has been implicated as a mediator between reproduction and energy balance. This study aimed to investigate the physiological effects of RFRP 3 on the process of ovarian development in food-restricted pre-pubertal ewes. The results showed that food restriction significantly inhibited the ovarian development and follicular growth. The data of qPCR in the hypothalamic-pituitary ovarian (HPO) axis showed that food restriction not only upregulated RFRP-3 mRNA expression but also downregulated the mRNA expression of gonadotropin-releasing hormone receptor, follicle-stimulating hormone receptor and luteinizing hormone receptor (LHR). Immunohistochemistry of RFRP-3 in the ovaries suggested that RFRP 3 may regulate the follicular development. These results suggested that the changes of RFRP-3 in response to food restriction might influence the HPO axis and inhibit ovarian development. PMID- 25039405 TI - Single-chain factor XII exhibits activity when complexed to polyphosphate. AB - BACKGROUND: The mechanism underpinning factor XII autoactivation was originally characterized with non-physiological surfaces, such as dextran sulfate (DS), ellagic acid, and kaolin. Several 'natural' anionic activating surfaces, such as platelet polyphosphate (polyP), have now been identified. OBJECTIVE: To analyze the autoactivation of FXII by polyP of a similar length to that found in platelets (polyP70 ). METHODS AND RESULTS: PolyP70 showed similar efficacy to DS in stimulating autoactivation of FXII, as detected with amidolytic substrate. Western blotting revealed different forms of FXII with the two activating surfaces: two-chain alphaFXIIa was formed with DS, whereas single-chain FXII (scFXII; 80 kDa) was formed with polyP70 . Dissociation of scFXII from polyP70 abrogated amidolytic activity, suggesting reversible exposure of the active site. Activity of scFXII-polyP70 was enhanced by Zn(2+) and was sensitive to NaCl concentration. A bell-shaped concentration response to polyP70 was evident, as is typical of surface-mediated reactions. Reaction of scFXII-polyP70 with various concentrations of S2302 generated a sigmoidal curve, in contrast to a hyperbolic curve for alphaFXIIa, from which a Hill coefficient of 3.67 was derived, indicative of positive cooperative binding. scFXII-polyP70 was more sensitive to inhibition by H-d-Pro-Phe-Arg-chloromethylketone and corn trypsin inhibitor than alphaFXIIa, but inhibition profiles for C1-inhibitor were similar. Active scFXII polyP70 was also able to cleave its physiological targets FXI and prekallikrein to their active forms. CONCLUSIONS: Autoactivation of FXII by polyP, of the size found in platelets, proceeds via an active single-chain intermediate. scFXII polyP70 shows activity towards physiological substrates, and may represent the primary event in initiating contact activation in vivo. PMID- 25039407 TI - Injuries of the head from backface deformation of ballistic protective helmets under ballistic impact. AB - Modern ballistic helmets defeat penetrating bullets by energy transfer from the projectile to the helmet, producing helmet deformation. This deformation may cause severe injuries without completely perforating the helmet, termed "behind armor blunt trauma" (BABT). As helmets become lighter, the likelihood of larger helmet backface deformation under ballistic impact increases. To characterize the potential for BABT, seven postmortem human head/neck specimens wearing a ballistic protective helmet were exposed to nonperforating impact, using a 9 mm, full metal jacket, 124 grain bullet with velocities of 400-460 m/s. An increasing trend of injury severity was observed, ranging from simple linear fractures to combinations of linear and depressed fractures. Overall, the ability to identify skull fractures resulting from BABT can be used in forensic investigations. Our results demonstrate a high risk of skull fracture due to BABT and necessitate the prevention of BABT as a design factor in future generations of protective gear. PMID- 25039408 TI - The incidence and aetiology of acute kidney injury in children in Norway between 1999 and 2008. AB - AIM: Primary acute kidney injury (AKI) is a direct cause of hospitalisation in children, but can also result from other conditions. There is limited information on the epidemiology of this condition. Our aim was to describe the national incidence rate and aetiology of acute kidney injury in children under the age of 16 in Norway from 1999 to 2008. METHODS: We carried out a retrospective study of medical records provided by all 18 of the paediatric hospital departments that specialise in treating paediatric patients with AKI. RESULTS: We identified 315 cases of AKI (53% male), with an estimated average annual incidence rate of 3.3 cases per 100 000 children and a median annual occurrence of 33 cases. Most cases (43%) were in children under five. We identified 53 aetiologies and classified these into 30 aetiological groups: 24% of the cases were prerenal (n = 75), 74% were intrinsic/renal (n = 234) and 2% were postrenal (n = 5). Nephritic syndromes was the major cause (44%) of AKI, followed by haemolytic-uraemic syndrome (HUS) (15%). CONCLUSION: Nephritic syndromes and HUS are the most common aetiologies of AKI in Norway. Although our results could indicate a low incidence of paediatric AKI in Norway, the lack of other national studies makes comparisons difficult. PMID- 25039409 TI - Comparing data sets: implicit summaries of the statistical properties of number sets. AB - Comparing datasets, that is, sets of numbers in context, is a critical skill in higher order cognition. Although much is known about how people compare single numbers, little is known about how number sets are represented and compared. We investigated how subjects compared datasets that varied in their statistical properties, including ratio of means, coefficient of variation, and number of observations, by measuring eye fixations, accuracy, and confidence when assessing differences between number sets. Results indicated that participants implicitly create and compare approximate summary values that include information about mean and variance, with no evidence of explicit calculation. Accuracy and confidence increased, while the number of fixations decreased as sets became more distinct (i.e., as mean ratios increase and variance decreases), demonstrating that the statistical properties of datasets were highly related to comparisons. The discussion includes a model proposing how reasoners summarize and compare datasets within the architecture for approximate number representation. PMID- 25039410 TI - Wall shear stress in major cerebral arteries as a function of age and gender--a study of 301 healthy volunteers. AB - BACKGROUND: The hemodynamic force of wall shear stress (WSS) has demonstrated a critical role in atherogenesis. PURPOSE: To study the effect of age and gender on mean WSS (MWSS) values in major cerebral arteries. METHOD: Thirteen cerebral arterial location sites in 301 healthy (157 M, 144 F; mean 47 +/- 15 years; range 18-84 years old) were studied. Quantitative magnetic resonance angiography was used to obtain volume flow and diameter, and subsequently to calculate MWSS via the Hagen-Poiseuille equation. RESULTS: MWSS decreased significantly with age in all vessels, declining from 9.5 to 5.7 dynes/cm(2) in the neck vessels and from 22.9 to 16.2 dynes/cm2 in the intracranial vessels. MWSS is significantly higher in females than in males in all six neck vessels. The most significant drop in MWSS occurred between the age groups 48-57 and 58-67 (P < .05 for 12 vessels). CONCLUSION: The overall decline in MWSS observed with age may be due to a decrease in flow. However, the marked drop in MWSS between the 48-57 and 58-67 age groups corresponded with an increase in diameter and systolic blood pressure rather than a significant drop in flow. PMID- 25039411 TI - Taking it to the streets: family therapy and family-centered services. AB - This article examines the interconnections between family therapy, specifically postmodern and poststructural approaches, and family-centered services. It introduces particular applications of family-centered services such as systems of care, wraparound, family-driven care, the recovery movement, and family group conferencing and then summarizes the heart of family-centered approaches as a shift in how services are provided to families. It examines the "fit" between the values and principles of family-centered practice and postmodern/poststructural approaches and then offers particular ideas and practices from these approaches that can help frontline workers inhabit a spirit of respect, connection, curiosity and hope in their work. PMID- 25039412 TI - Randomised clinical study: comparison of acceptability, patient tolerance, cardiac stress and endoscopic views in transnasal and transoral endoscopy under local anaesthetic. AB - BACKGROUND: Transnasal endoscopy (TNE) with ultrathin endoscopes has been advocated as an attractive alternative, for diagnostic upper endoscopy. AIM: To assess tolerability, acceptability and quality of TNE, in comparison with standard upper endoscopy (SOGD, standard oesophago-gastro-duodenoscopy) under local anaesthetic. METHODS: We prospectively recruited 157 patients (83 females/74 males) mean age 57 years. The Fujinon EG530N (5.9 mm) and EG530WR (9.4 mm) endoscopes were used. The endoscopist and all patients completed detailed questionnaires regarding tolerability, acceptance and quality of endoscopy using standard visual analogue scales (VAS). Oxygen saturation (SaO2 ), heart rate (HR) and systolic blood pressure (SBP) were recorded. Quality of biopsies was evaluated. RESULTS: Analysis included 161 procedures (TNE:79, SOGD:82) with duodenal intubation achieved in all patients. VAS scores for patient comfort were significantly better in the TNE group (7.3 vs. 5.3 respectively, P < 0.001). Twenty patients with previous experience of standard endoscopy were randomised to TNE and 19 of them (95.5%) preferred the TNE. Gagging was significantly less in the TNE group (0.12 vs. 3.41 respectively, P < 0.001). Cardiovascular stress was significantly less in the TNE group irrespective of the degree of gagging or comfort. TNE biopsies were smaller, but adequate for definitive diagnosis, similarly to standard endoscopy. CONCLUSIONS: Transnasal endoscopy is superior to SOGD in terms of comfort and patient acceptance with significantly less cardiovascular stress. TNE can routinely be used as alternative to SOGD under local anaesthetic, for diagnosis and should be preferentially offered in cardiorespiratory compromised patients. PMID- 25039413 TI - Infection, inflammation and Alzheimer's disease. PMID- 25039414 TI - Efficacy of patient-initiated follow-up clinics in secondary care: a systematic review. AB - Patient-initiated follow up (PIFU) is an initiative that allows patients to initiate hospital follow-up appointments on an 'as required' basis compared with the traditional 'physician-initiated' model. The main principle is to reduce inappropriate regular follow-up appointments. In this systematic review, we attempt to address its efficacy for outpatient secondary level care. Using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, an electronic literature search was performed independently by two authors using pre defined search terms across EMBASE, Ovid MedLine, PubMed, PSYCINFO and the Cochrane Library databases. Articles were included if they specifically evaluated any aspect of PIFU. Studies evaluating non-outpatient-based, primary level-based and nurse-led clinic appointments were excluded. A total of 747 articles was reviewed, and six were finally included for the systematic review. Three studies analysed efficacy of PIFU with regards to rheumatological disease and found that there was no deleterious clinical effect and a trend towards increased satisfaction and quality of life including lower costs in the PIFU group. Two studies looked at PIFU and inflammatory bowel disease and identified some clinical benefit and lower costs and equivalent satisfaction and QoL with the PIFU group. A further study looked at PIFU in stage 1 breast cancer and did not find any significant differences in outcomes. There is evidence to suggest that PIFU systems result in fewer overall outpatient appointments in secondary care led services while maintaining equivalent if not better patient satisfaction, quality of life and clinical outcomes across a range of chronic conditions. PMID- 25039415 TI - Studying the dynamics of autonomic activity during emotional experience. AB - Recent theories emphasize the dynamic aspects of emotions. However, the physiological measures and the methodological approaches that can capture the dynamics of emotions are underdeveloped. In the current study, we investigated whether moment-to-moment changes in autonomic nervous system (ANS) activity are reliably associated with the unfolding of emotional experience. We obtained cardiovascular and electrodermal signals from participants while they viewed emotional movies. We found that the ANS signals were temporally aligned across individuals, indicating a reliable stimulus-driven response. The degree of response reliability was associated with the emotional time line of the movie. Finally, individual differences in ANS response reliability were strongly correlated with the subjective emotional responses. The current research offers a methodological approach for studying physiological responses during dynamic emotional situations. PMID- 25039416 TI - Neurophysiological evidence for motor planning limitations in children with cerebral palsy. PMID- 25039417 TI - Hyaluronan in wound healing: rediscovering a major player. AB - Wound healing involves a series of carefully modulated steps, from initial injury and blood clot to the final reconstituted tissue or scar. A dynamic reciprocity exists throughout between the wound, blood elements, extracellular matrix, and cells that participate in healing. Multiple cytokines and signal transduction pathways regulate these reactions. A major component throughout most of the process is hyaluronan, a straight-chain carbohydrate extracellular matrix polymer. Hyaluronan occurs in multiple forms, chain length being the only distinguishing characteristic between them. Levels of hyaluronan in its high molecular-weight form are prominent in the earliest stages of wound repair. Progressively more fragmented forms occur in a manner not previously appreciated. We outline here steps in the wound healing cascade in which hyaluronan participates, as well as providing a review of its metabolism. Although described by necessity in a series of quantum steps, the healing process is constituted by a smooth continuum of overlapping reactions. The prevalence of hyaluronan in the wound (initially termed "hexosamine-containing mucopolysaccharide"), particularly in its early stages, was pointed out over half a century ago by the Harvard surgeon J. Engelbert Dunphy. It appears we are now returning to where we started. PMID- 25039418 TI - Effects of granule swelling on starch saccharification by granular starch hydrolyzing enzyme. AB - The effects of granule swelling on enzymatic saccharification of normal corn starch by granular starch hydrolyzing enzyme were investigated. After swelling, Km values for the saccharification of granular starch decreased compared with native granular starch, indicating that granule swelling caused granular starch hydrolyzing enzyme to have higher affinity for starch granules. The partial swelling of starch granules enhanced starch saccharification. Furthermore, the enhancement at an earlier stage of enzymatic reaction was much more significant than that at later stages. For granular starch pretreated at 67.5 degrees C for 30 min, conversions to glucose after incubation with the enzyme at 32 degrees C for 4 and 24 h were approximately 3-fold and 26% higher than for native granular starch, respectively. As a result, proper heat pretreatment of granular starch before simultaneous saccharification and fermentation has great potential to facilitate industrial production of ethanol by use of granular starch hydrolyzing enzyme. PMID- 25039419 TI - Effects of age and zinc supplementation on transport properties in the jejunum of piglets. AB - Zinc is effective in the prevention and treatment of post-weaning diarrhoea and in promoting piglet growth. Its effects on the absorption of nutrients and the secretory capacity of the intestinal epithelium are controversial. We investigated the effects of age, dietary pharmacological zinc supplementation and acute zinc exposure in vitro on small-intestinal transport properties of weaned piglets. We further examined whether the effect of zinc on secretory responses depended on the pathway by which chloride secretion is activated. A total of 96 piglets were weaned at 26 days of age and allocated to diets containing three different levels of zinc oxide (50, 150 and 2500 ppm). At the age of 32, 39, 46 and 53 days, piglets were killed, and isolated epithelia from the mid-jejunum were used for intestinal transport studies in conventional Ussing chambers, with 23 MUm ZnSO4 being added to the serosal side for testing acute effects. Absorptive transport was stimulated by mucosal addition of d-glucose or l glutamine. Secretion was activated by serosal addition of prostaglandin E2 , carbachol or by mucosal application of Escherichia coli heat-stable enterotoxin (Stp ). Jejunal transport properties showed significant age-dependent alterations (p < 0.03). Both absorptive and secretory responses were highest in the youngest piglets (32 d). The dietary zinc supplementation had no significant influence on jejunal absorptive and secretory responses. However, the pre-treatment of epithelia with ZnSO4 in vitro led to a small but significant decrease in both absorptive and secretory capacities (p < 0.05), with an exception for carbachol (p = 0.07). The results showed that, in piglets, chronic supplementation with zinc did not sustainably influence the jejunal transport properties in the post weaning phase. Because transport properties are influenced by the addition of zinc in vitro, we suggest that possible epithelial effects of zinc depend on the acute presence of this ion. PMID- 25039420 TI - Noninvasive cardiac output monitoring using bioreactance-based technique in pediatric patients with or without ventricular septal defect during anesthesia: in comparison with echocardiography. AB - BACKGROUND: We evaluated the use of bioreactance-based noninvasive cardiac output (CO) monitoring technique (NICOM(TM), CO(NICOM)) in pediatric patients with or without ventricular septal defect (VSD) during anesthesia induction to determine its agreement with the measurements assessed by echocardiography (echo, CO(ECHO)). METHODS: Twenty-eight pediatric patients with normal heart anatomy (group NHA) and 32 with isolated ventricular septal defects (group VSD) were included in this study. The cardiac output was measured simultaneously in minute by-minute using NICOM and echo (Simpson's rule) during anesthesia induction and intubation. Linear regression and revised Bland-Altman analyses were performed to evaluate the agreement by comparing the paired CO results. The mean percent error ((CO(ECHO)-CO(NICOM))/CO(ECHO) * 100%) was used to assess the impact of congenital heart disease on the agreement. RESULTS: The measurements of CO by NICOM and echo techniques were highly correlated in group NHA (gamma = 0.96, P < 0.005) and VSD (gamma = 0.84, P < 0.005). The mean bias (CO(ECHO) - CO(NICOM)) between the two methods was 0.03 and 0.31 l.min(-1) with the limits of agreement (LOA) -0.29 to +0.35 l.min(-1) and -0.44 to +1.05 l.min(-1), which include 96.9% (31/32) and 89.3% (25/28) of all patients' different data in group NHA and VSD, respectively. The median percent errors were significantly lower at all time points in group NHA than those in group VSD (all P < 0.05). CONCLUSION: In children without heart defects, the CO measured by NICOM shows a good agreement with the echo during anesthesia induction. The NICOM technique underestimates echo although a strong correlation exists between two methods in children with ventricular septal defect. PMID- 25039421 TI - Improving the Quality of Host Country Ethical Oversight of International Research: The Use of a Collaborative 'Pre-Review' Mechanism for a Study of Fexinidazole for Human African Trypanosomiasis. AB - Developing countries face numerous barriers to conducting effective and efficient ethics reviews of international collaborative research. In addition to potentially overlooking important scientific and ethical considerations, inadequate or insufficiently trained ethics committees may insist on unwarranted changes to protocols that can impair a study's scientific or ethical validity. Moreover, poorly functioning review systems can impose substantial delays on the commencement of research, which needlessly undermine the development of new interventions for urgent medical needs. In response to these concerns, the Drugs for Neglected Diseases Initiative (DNDi), an independent nonprofit organization founded by a coalition of public sector and international organizations, developed a mechanism to facilitate more effective and efficient host country ethics review for a study of the use of fexinidazole for the treatment of late stage African Trypanosomiasis (HAT). The project involved the implementation of a novel 'pre-review' process of ethical oversight, conducted by an ad hoc committee of ethics committee representatives from African and European countries, in collaboration with internationally recognized scientific experts. This article examines the process and outcomes of this collaborative process. PMID- 25039422 TI - An evaluation of fresh gas flow rates for spontaneously breathing cats and small dogs on the Humphrey ADE semi-closed breathing system. AB - OBJECTIVE: To evaluate the fresh gas flow (FGF) rate requirements for the Humphrey ADE semi-closed breathing system in the Mapleson A mode; to determine the FGF at which rebreathing occurs, and compare the efficiency of this system to the Bain (Mapleson D) system in spontaneously breathing cats and small dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: Twenty-five healthy (ASA score I or II) client-owned cats and dogs (mean +/- SD age 4.7 +/- 5.0 years, and body weight 5.64 +/- 3.26 kg) undergoing elective surgery or minor procedures. METHODS: Anaesthesia was maintained with isoflurane delivered via the Humphrey ADE system in the A mode using an oxygen FGF of 100 mL kg(-1) minute(-1). The FGF was then reduced incrementally by 5-10 mL kg(-1) minute(-1) at approximately five minute intervals, until rebreathing (inspired CO(2) >5 mmHg (0.7 kPa)) was observed, after which flow rates were increased. In six animals, once the minimum FGF at which rebreathing occurred was found, the breathing system was changed to the Bain, and the effects of this FGF delivery examined, before FGF was increased. RESULTS: Rebreathing did not occur at the FGF recommended by the manufacturer for the ADE. The mean +/- SD FGF that resulted in rebreathing was 60 +/- 20 mL kg(-1) minute(-1). The mean minimum FGF at which rebreathing did not occur with the ADE was 87 +/- 39 mL kg(-1) minute(-1). This FGF resulted in significant rebreathing (inspired CO(2) 8.8 +/- 2.6 mmHg (1.2 +/- 0.3 kPa)) on the Bain system. CONCLUSIONS: The FGF rates recommended for the Humphrey ADE are adequate to prevent rebreathing in spontaneously breathing cats and dogs <15 kg. CLINICAL RELEVANCE: The Humphrey ADE system used in the A mode is a more efficient alternative to the Bain system, for maintenance of gaseous anaesthesia in spontaneously breathing cats and small dogs. PMID- 25039423 TI - Characterization of bacterial knot disease caused by Pseudomonas savastanoi pv. savastanoi on pomegranate (Punica granatum L.) trees: a new host of the pathogen. AB - This study aimed to isolate and identify the causal organism causing hyperplastic outgrowths (knots) on stems and branches of pomegranate trees in the Eastern Mediterranean region of Turkey. Bacterial colonies were isolated from young knots on plates containing selective nutrient media. Biochemical tests, fatty acid analysis and PCR were performed to identify possible causal disease agent. Representative isolates were identified as Pseudomonas.pv.savastanoi (Psv) using biochemical tests, fatty acid profiling and PCR. Following inoculation of pomegranate plants (cv. hicaz) with bacterial suspensions, 25 of 54 bacterial isolates caused typical knots at the site of inoculation. PCR analysis, using specific primer for Psv, generated a single amplicon from all isolates. The similarity of the sequence of Turkish pomegranate isolate was 99% similar to the corresponding gene sequences of Psv in the databases. Based on symptoms, biochemical, molecular, pathogenicity tests and sequence analyses, the disease agent of knots observed on the pomegranate trees is Psv. To the best of our knowledge, this research has revealed pomegranate as a natural host of Psv, which extends the list of host plant species affected by the pathogen in the world and Turkey. SIGNIFICANCE AND IMPACT OF THE STUDY: Pomegranate trees were affected by the disease with outgrowths (galls or knot) disease. Currently, there is no published study on disease agent(s) causing the galls or knots on pomegranate trees in worldwide. Bacterial colonies were isolated from young knots. The causal agent of the knot Pseudomonas savastanoi pv.savastanoi (Psv) was identified based on symptoms, biochemical, molecular methods, pathogenicity tests and sequence analysis. To the best of our knowledge, this is the first report of Psv on pomegranate as a natural host, which extends the growing list of plant species affected by this bacterium in the world and Turkey. PMID- 25039424 TI - Empirical tests of harvest-induced body-size evolution along a geographic gradient in Australian macropods. AB - Life-history theory predicts the progressive dwarfing of animal populations that are subjected to chronic mortality stress, but the evolutionary impact of harvesting terrestrial herbivores has seldom been tested. In Australia, marsupials of the genus Macropus (kangaroos and wallabies) are subjected to size selective commercial harvesting. Mathematical modelling suggests that harvest quotas (c. 10-20% of population estimates annually) could be driving body-size evolution in these species. We tested this hypothesis for three harvested macropod species with continental-scale distributions. To do so, we measured more than 2000 macropod skulls sourced from wildlife collections spanning the last 130 years. We analysed these data using spatial Bayesian models that controlled for the age and sex of specimens as well as environmental drivers and island effects. We found no evidence for the hypothesized decline in body size for any species; rather, models that fit trend terms supported minor body size increases over time. This apparently counterintuitive result is consistent with reduced mortality due to a depauperate predator guild and increased primary productivity of grassland vegetation following European settlement in Australia. Spatial patterns in macropod body size supported the heat dissipation limit and productivity hypotheses proposed to explain geographic body-size variation (i.e. skull size increased with decreasing summer maximum temperature and increasing rainfall, respectively). There is no empirical evidence that size-selective harvesting has driven the evolution of smaller body size in Australian macropods. Bayesian models are appropriate for investigating the long-term impact of human harvesting because they can impute missing data, fit nonlinear growth models and account for non-random spatial sampling inherent in wildlife collections. PMID- 25039425 TI - Leptin inhibits amyloid beta-protein fibrillogenesis by decreasing GM1 gangliosides on the neuronal cell surface through PI3K/Akt/mTOR pathway. AB - Leptin is a centrally acting hormone that controls metabolic pathways. Recent epidemiological studies suggest that plasma leptin is protective against Alzheimer's disease. However, the mechanism that underlies this effect remains uncertain. To investigate whether leptin inhibits the assembly of amyloid beta protein (Abeta) on the cell surface of neurons, we treated primary neurons with leptin. Leptin treatment decreased the GM1 ganglioside (GM1) levels in the detergent-resistant membrane microdomains (DRMs) of neurons. The increase in GM1 expression induced by leptin was inhibited after pre-treatment with inhibitors of phosphatidylinositol 3-kinase (LY294002), Akt (triciribine) and the mammalian target of rapamycin (i.e. rapamycin), but not by an inhibitor of extracellular signal-regulated kinase (PD98059). In addition, pre-treatment with these reagents blocked the induction of GM1 in DRMs by leptin. Furthermore, Abeta assembly on the cell surface of neurons was inhibited greatly after treatment with leptin. This reduction was markedly inhibited after pre-treatment with LY294002, triciribine, and rapamycin. These results suggest that leptin significantly inhibits Abeta assembly by decreasing GM1 expression in DRMs of the neuronal surface through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. These findings highlight the importance of understanding the function of leptin in AD brains. In this study, our aim was to determine whether leptin regulates the expression and localization of GM1 on the neuronal membrane and if it induces the formation of Abeta assembly on the cell surface of neurons. Our results suggest that leptin regulates the expression of GM1 in DRMs of the neuronal membranes. Moreover, leptin does not seem to facilitate fibrillogenesis of exogenously added soluble Abeta from the cell surface of neurons. PMID- 25039426 TI - A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis following failed epithelial repair. Mesenchymal stromal cells (MSC), a key component of the stem cell niche in bone marrow and possibly other organs including lung, have been shown to enhance epithelial repair and are effective in preclinical models of inflammation-induced pulmonary fibrosis, but may be profibrotic in some circumstances. METHODS: In this single centre, non-randomized, dose escalation phase 1b trial, patients with moderately severe IPF (diffusing capacity for carbon monoxide (DLCO ) >= 25% and forced vital capacity (FVC) >= 50%) received either 1 * 10(6) (n = 4) or 2 * 10(6) (n = 4) unrelated-donor, placenta-derived MSC/kg via a peripheral vein and were followed for 6 months with lung function (FVC and DLCO ), 6-min walk distance (6MWD) and computed tomography (CT) chest. RESULTS: Eight patients (4 female, aged 63.5 (57-75) years) with median (interquartile range) FVC 60 (52.5-74.5)% and DLCO 34.5 (29.5-40)% predicted were treated. Both dose schedules were well tolerated with only minor and transient acute adverse effects. MSC infusion was associated with a transient (1% (0-2%)) fall in SaO2 after 15 min, but no changes in haemodynamics. At 6 months FVC, DLCO , 6MWD and CT fibrosis score were unchanged compared with baseline. There was no evidence of worsening fibrosis. CONCLUSIONS: Intravenous MSC administration is feasible and has a good short-term safety profile in patients with moderately severe IPF. PMID- 25039427 TI - Consultation about urinary and faecal incontinence in the year after childbirth: a cohort study. AB - OBJECTIVE: To investigate the extent to which primary-care practitioners routinely inquire about postpartum urinary and faecal incontinence, and assess the proportion of women who disclose symptoms. DESIGN: Prospective pregnancy cohort study of nulliparous women. SETTING: Melbourne, Australia. SAMPLE: A total of 1507 nulliparous women recruited in early pregnancy. METHOD: Women were recruited from six public maternity hospitals, with follow up at 3, 6, 9 and 12 months postpartum. MAIN OUTCOME MEASURES: Standardised measures of urinary and bowel symptoms, and measures of health service use. RESULTS: In the first 12 months postpartum, the period prevalence of urinary incontinence was 47%, and of faecal incontinence was 17%. In all, 86% of women visited a primary health-care practitioner at least once to discuss their own health in the first year after childbirth. However, only around a quarter were asked about urinary incontinence, and fewer than one in five women were asked about faecal incontinence. Discussion of symptoms with health professionals was most likely to occur in the first 3 months postpartum, and happened only rarely during the remainder of the first postnatal year. Over 70% of women reporting severe urinary incontinence and/or faecal incontinence had not discussed symptoms with a health professional. CONCLUSION: The findings provide robust evidence that many women experiencing postpartum urinary and faecal incontinence-including women with moderate and severe symptoms-do not receive adequate primary-care follow up in the first 12 months postpartum. Systems of maternal health surveillance need to include routine inquiry about urinary and faecal incontinence to overcome women's reluctance to seek help. PMID- 25039428 TI - Peripheral and cognitive signs: delineating the significance of impaired catecholamine metabolism in Parkinson's disease progression. PMID- 25039429 TI - Korean speech-language pathologists' attitudes toward stuttering according to clinical experiences. AB - BACKGROUND: Negative attitudes toward stuttering and people who stutter (PWS) are found in various groups of people in many regions. However the results of previous studies examining the influence of fluency coursework and clinical certification on the attitudes of speech-language pathologists (SLPs) toward PWS are equivocal. Furthermore, there have been few empirical studies on the attitudes of Korean SLPs toward stuttering. AIMS: To determine whether the attitudes of Korean SLPs and speech-language pathology students toward stuttering would be different according to the status of clinical certification, stuttering coursework completion and clinical practicum in stuttering. METHODS & PROCEDURES: Survey data from 37 certified Korean SLPs and 70 undergraduate students majoring in speech-language pathology were analysed. All the participants completed the modified Clinician Attitudes Toward Stuttering (CATS) Inventory. OUTCOMES & RESULTS: Results showed that the diagnosogenic view was still accepted by many participants. Significant differences were found in seven out of 46 CATS Inventory items according to the certification status. In addition significant differences were also found in three items and one item according to stuttering coursework completion and clinical practicum experience in stuttering, respectively. CONCLUSIONS & IMPLICATIONS: Clinical and educational experience appears to have mixed influences on SLPs' and students' attitudes toward stuttering. While SLPs and students may demonstrate more appropriate understanding and knowledge in certain areas of stuttering, they may feel difficulty in their clinical experience, possibly resulting in low self-efficacy. PMID- 25039430 TI - Minimally invasive access for central extracorporeal life support: how we do it. AB - Central extracorporeal life support (ECLS) is an effective treatment method of cardiogenic shock patients with or without lung failure. However, complications like infection and bleeding are common. The classical implantation approach requires full sternotomy, mobilization of the heart, with the well-known risks of bleeding and mediastinal infections. We present our minimally invasive technique for central ECLS through a nonsternotomy incision. Minimized right-sided thoracotomy is performed. Flexible arterial and venous cannulas are tunneled toward the right thoracotomy incision through the eighth intercostal space. A sewing ring is secured to the right atrium and a tube graft is anastomosed to the ascending aorta. Following full-dose heparinization, the arterial cannula is inserted with the tip into the vascular graft of the ascending aorta and the venous cannula via the ring into the right atrium. After meticulous deairing, the central ECLS is set at full flow. PMID- 25039432 TI - Smoking rate and periodontal disease prevalence: 40-year trends in Sweden 1970 2010. AB - AIM: To investigate the relationship between smoking rate and periodontal disease prevalence in Sweden. MATERIAL AND METHODS: National smoking rates were found from Swedish National Statistics on smoking habits. Based on smoking rates for the years 1970-2010, periodontal disease prevalence estimates were calculated for the age bracket 40-70 years and smoking-associated relative risks between 2.0 and 20.0. The impact of smoking on the population was estimated according to the concept of population attributable fraction. RESULTS: The age-standardized smoking rate in Sweden declined from 44% in 1970 to 15% in 2010. In parallel with the smoking decline the calculated prevalence estimate of periodontal disease dropped from 26% to 12% assuming a 10-fold smoking-associated relative risk. Even at more moderate magnitudes of the relative risk, e.g. 2-fold or 5-fold, the prevalence decrease was quite tangible, suggesting that the current prevalence in Sweden is about 20-50% of the level 40 years ago. The population attributable fraction, estimating the portion of the disease that would have been avoided in the absence of smoking, was 80% in 1970 and 58% in 2010 at a ten-fold relative risk. CONCLUSION: Calculated estimates of periodontal disease prevalence are closely related to real changes in smoking rate. As smoking rate drops periodontal disease prevalence will drop. PMID- 25039431 TI - A common hypofunctional genetic variant of GPER is associated with increased blood pressure in women. AB - AIMS: Activation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown. METHODS: To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic. RESULTS: Expression of the GPER P16L variant (V) vs. wild type (WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1 MUm, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1 stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/P16: 80 +/- 1 mmHg (n = 204) vs. P16L carriers: 82 +/- 1 mmHg (n = 127), 95% CI for difference: 0.6, 4.0 mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 +/- 1 mmHg vs. P16L carriers: 108 +/- 1 mmHg, 95% CI for difference:1.0, 5.1 mmHg, P < 0.05], [diastolic blood pressure: P16/P16: 66 +/- 0.5 mmHg vs. P16L carriers 68 +/- 0.7, 95% CI for difference: 0.2, 3.6 mmHg, P < 0.05]. Further, the P16L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05). CONCLUSIONS: The common genetic variant, GPER P16L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension. PMID- 25039433 TI - Reactive oxygen and nitrogen species during viral infections. AB - Oxygen and nitrogen radicals are frequently produced during viral infections. These radicals are not only a physiological mechanism for pathogen clearance but also result in many pathological consequences. Low concentrations of radicals can promote viral replication; however, high concentrations of radicals can also inhibit viral replication and are detrimental to the cell due to their mitogenic activity. We reviewed the detailed mechanisms behind oxygen and nitrogen radical production and focused on how viruses induce radical production. In addition, we examined the effects of oxygen and nitrogen radicals on both the virus and host. We also reviewed enzymatic and chemical detoxification mechanisms and recent advances in therapeutic antioxidant applications. Many molecules that modulate the redox balance have yielded promising results in cell and animal models of infection. This encourages their use in clinical practice either alone or with existing therapies. However, since the redox balance also plays an important role in host defence against pathogens, carefully designed clinical trials are needed to assess the therapeutic benefits and secondary effects of these molecules and whether these effects differ between different types of viral infections. PMID- 25039434 TI - Variation in mouthguard thickness due to different heating conditions during fabrication: part 2. AB - The purpose of this study was to determine changes in the thickness of mouthguard sheets under different heating conditions during fabrication. Mouthguards were fabricated with polyolefin-polystyrene co-polymer (OS) and olefin co-polymer (OL) sheets (4.0-mm thick) utilizing a vacuum-forming machine under the following three conditions: (A) the sheet was moulded when it sagged 15 mm below the sheet frame (i.e. the normally used position); (B) the sheet frame was lowered to and heated at 30 mm below the top of the post and moulded when it sagged by 15 mm; and (C) the sheet frame was lowered to and heated at 50 mm below the top of the post and moulded when it sagged by 15 mm. The working model was trimmed to a height of 20 mm at the incisor and 15 mm at the first molar. Post-moulding thickness was determined for the incisal portion (incisal edge and labial surface) and molar portion (cusp, central groove and buccal surface). Dimensions were measured, and differences in the change in thickness due to heating condition were analysed using the Kruskal-Wallis test. Under condition C, OS and OL decreased in thickness from 0.36-0.54 mm to 0.26-0.30 mm, respectively, at the incisal portion and from 0.34-0.66 mm to 0.17-0.47 mm, respectively, at the molar portion. It may be clinically useful when moulding a mouthguard to maintain the thickness of the incisal and molar portions by adjusting the height of the sheet frame. PMID- 25039435 TI - Oven, microwave, and combination roasting of peanuts: comparison of inactivation of salmonella surrogate Enterococcus faecium, color, volatiles, flavor, and lipid oxidation. AB - Peanut safety and quality were evaluated for different roasting technologies. Shelled raw peanuts were roasted using an oven at 163 to 204 degrees C, microwave, or oven and microwave combinations. The lethal effect of these treatments was investigated on peanuts inoculated with the Salmonella surrogate, Enterococcus faecium and stored at room temperature for 1 h, 24 h, or 7 d before roasting. Roasted peanut color, odor activity values (OAVs), descriptive sensory panel analysis, free fatty acid, and peroxide values were determined. Color and OAVs were also analyzed on 2 commercial peanut butters. OAVs were calculated using volatile levels quantified with selected ion flow tube mass spectrometry and known odor thresholds. All treatments resulted in a minimum of 3 log reduction of inoculated bacterial population. Resistance to the process was not influenced by storage of inoculated peanuts prior to treatment. Roasting by different methods produced equivalent, commercially ideal L* color. Based on the OAVs, treatments had similar volatiles important to flavor compared to the commercial samples. Descriptive sensory analysis showed no significant difference between the roasting treatments for most of the sensory attributes. Lipid oxidation was not significantly different between the roasting methods, displaying no evidence that roasting time or temperature affected lipid oxidation, when ideal color was produced. These results suggest that oven, microwave, or combination roasting should be sufficient to mitigate the threat of Salmonella contamination and produce similar color, OAVs, sensory attributes, and lipid oxidation results. PMID- 25039436 TI - Editorial: from perfume oils to discovering and making new molecules: an international chemical biology journey. PMID- 25039437 TI - Successful sequential treatment with itraconazole and ALA-PDT for chromoblastomycosis because of Alternaria alternata. AB - Alternaria alternata is a rare etiology of phaeohyphomycosis in immunocompromised patients, which has never been reported to cause chromoblastomycosis. As far as we know, this is the first chromoblastomycosis case successfully treated with a short course of systemic antifungals and subsequent 5-aminolevulinic acid photodynamic therapy. PMID- 25039438 TI - Healthcare-associated and nosocomial bacterial infections in cirrhosis: predictors and impact on outcome. AB - BACKGROUND & AIMS: Population-based data on the occurrence of healthcare associated (HCA) and hospital-acquired (HA) bacterial infections in cirrhosis, their predictors, and their impact on outcome are limited. METHODS: All patients with incident cirrhosis in 2001-2010 residing in an area of 600,000 inhabitants were retrospectively identified. All serious bacterial infections (resulting in or occurring during an inpatient hospital episode) during this period were registered. Acquisition type, site of infection, occurrence of infection-related acute-on-chronic liver failure (ACLF), acute kidney injury (AKI) and bacterial resistance were analysed. Patients were followed longitudinally until death, transplant or end of 2011. RESULTS: A total of 398 serious infections occurred in 241/633 (38%) patients. Forty-seven per cent were HCA and 21% HA. Proton pump inhibitor (PPI) use was more common in HA (80%) vs. HCA (64%) vs. community acquired (44%) infections (P < 0.001). In regression analysis, decompensated status, use of antibiotics and PPIs at infection diagnosis were independent predictors of HCA/HA infections (P < 0.05). After adjustment for confounders, HCA/HA infections were significantly related to infection-related ACLF (P < 0.05), but not severe sepsis, AKI or infection-related mortality (P > 0.05). Antibiotic-resistant infections were more frequent among HA (17%) than HCA (6%) or community-acquired (8%) infections (P < 0.05). Antibiotic-resistant HCA/HA infections were independently related to severe sepsis (P < 0.05). CONCLUSIONS: In a population-based cirrhotic cohort, two-thirds of serious bacterial infections were HCA or HA. Decompensated liver disease, antibiotics and PPIs were predictors of serious HCA/HA infections, which were associated with the development of ACLF. Antibiotic resistance was frequent, especially in HA infections, and contributed to risk of severe sepsis. PMID- 25039439 TI - Bisphosphonates, healthcare professionals and oral health. AB - OBJECTIVE: General medical and dental practitioner and pharmacists all encounter patients on bisphosphonates and as such require adequate knowledge regarding osteonecrosis of the jaw, a potential complication associated with its use. The cross-sectional study investigated perceived implications of and attitudes towards bisphosphonate use in oral health among general medical and dental practitioners and pharmacists. MATERIALS AND METHODS: Medical and dental practitioners and pharmacists registered in Victoria, Australia, completed an online survey (SurveyMonkey(c)). Data analysis consisted of chi-square tests with significance as p < 0.05. RESULTS: One hundred and thirty six doctors (general medical practitioners, GMPs), 283 dentists (GDPs) and 26 pharmacists (PHs) participated. 70, 38 and 80%, respectively, reviewed patients prescribed bisphosphonates (BPs). GMPs (88%), GDPs (76%) and PHs (85%) were aware of osteonecrosis of the jaws (ONJ). GMPs (76%) and PHs (100%) advised patients to inform dentists. GMPs (45%) referred patients for dental assessments prior to commencing BPs with 71.9% of GDPs received such referrals. In terms of available information on oral health and BPs, GMPs (56%), GDPs (50%) and PH (53.8%) were either unsure any existed or reported receiving sufficient information. CONCLUSIONS: Discrepancies exist amongst different healthcare professionals in terms of BP use and oral health, and common consensus guidelines are warranted. PMID- 25039441 TI - The role of beliefs: lessons from a pilot study on illness perception, psychological distress and quality of life in patients with primary cicatricial alopecia. AB - BACKGROUND: While alopecia has been shown to have substantial psychological consequences, previous studies have not explicitly explored the key beliefs of patients with primary cicatricial alopecia (PCA) and the relationship between clinical and psychological measures. OBJECTIVES: To identify the key psychological factors and quality of life (QoL) of patients with PCA and the relationship between these factors and established clinical measures. METHODS: In total 105 patients with PCA were recruited from a specialist hair research clinic in Manchester, U.K. Patients completed the revised Illness Perception Questionnaire, Hospital Anxiety and Depression Scale (HADS) and Dermatology Life Quality Index. These psychological measures were correlated with disease activity in patients with lichen planopilaris (LPP) and frontal fibrosing alopecia, using the LPP Activity Index (LPPAI). RESULTS: Patients perceived PCA as a chronic condition with significant personal consequences and emotional impact, and reported that they had low levels of control over the condition and its treatment. Considerable levels of psychological distress were observed (mean HADS total score 11.3 +/- 8.1). Impaired QoL was associated with strong beliefs that the symptoms were attributed to their disease (P < 0.001), and that alopecia had serious consequences (P < 0.001) and was distressing (P < 0.001). Disease activity (LPPAI) showed a significant positive correlation with HADS-Depression (r = 0.343, P = 0.026). CONCLUSIONS: Patients with PCA experience significant psychological distress and impaired QoL, both of which are associated with key beliefs about illness. Management of PCA should involve assessment of the beliefs and emotions that drive patients' psychological distress, as well as giving access to psychological therapy. PMID- 25039440 TI - Sex differences in the incidence of severe pain events following surgery: a review of 333,000 pain scores. AB - OBJECTIVE/BACKGROUND: Prior work has not addressed sex differences in the incidence of severe postoperative pain episodes. The goal of this study was to examine sex differences in clinical postoperative pain scores across an array of surgical procedures using direct comparisons of numeric rating scale pain scores as well as using the incidence of severe pain events (SPEs). DESIGN/SETTING: Retrospective cohort study of over 300,000 clinical pain score observations recorded from adult patients undergoing nonambulatory surgery at a tertiary care academic medical center over a 1-year period. METHODS/PATIENTS: To test the hypothesis that the number of SPE on postoperative day (POD) 1 differed by sex after controlling for procedure, we calculated Cochran-Mantel-Haenszel statistics of sex by count of SPE, controlling for type of surgery. ASSESSMENT TOOLS/OUTCOMES: Pain scores were collected from clinical nursing records where they were documented using the numeric rating scale. RESULTS: In female patients, 10,989 (25.09%) of 43,806 POD 1 pain scores were considered SPE compared with 10,786 (22.45%) of 48,055 POD 1 pain scores in male patients. This produced an overall odds ratio of 1.16 (99% confidence interval 1.11-1.20) for females vs males to report an SPE for a pain score on POD 1. Estimates of the odds that a given pain observation represents an SPE for female vs male patients after controlling for type of surgery yielded an odds ratio of 1.14 (99% confidence interval, 1.10-1.19). CONCLUSION: Female patients experience greater mean pain scores, as well as a higher incidence of SPE, on POD 1 for a variety of surgical procedures. PMID- 25039442 TI - Narrative review of health-related quality of life and its predictors among patients with coronary heart disease. AB - This paper summarizes the empirical evidence concerning health-related quality of life (HRQoL) of patients with coronary heart disease (CHD) and attempts to identify its significant predictors. A systematic search of the literature from 2002 to 2012 was conducted using seven electronic databases (CINAHL, ScienceDirect, Medline, Scopus, PsycINFO, PubMed and Web of Science) using the search terms 'HRQoL'. 'CHD', 'social support', 'depression', 'anxiety', 'psychosocial factors', 'sociodemographic factors', 'clinical factors' and 'predictors'. A total of 1052 studies were retrieved, of which 24 articles were included in this review. Previous studies have consistently demonstrated the negative impact of CHD on HRQoL, citing three major types of predictive factors: sociodemographic, clinical and psychosocial factors. Studies have also highlighted the advantageous use of HRQoL as a gauge for treatment satisfaction and efficacy. There are, however, few studies that collectively investigate the relationship among concepts such as HRQoL, anxiety and depression, social support, and sociodemographic and clinical factors in relation to CHD. This review highlights the need to conduct further study on HRQoL of patients with CHD in the Asian context. Such research will promote patient-centric care and improved patient satisfaction through incorporation of the concept of HRQoL into clinical practice. PMID- 25039443 TI - The consequences of early-life adversity: neurobiological, behavioural and epigenetic adaptations. AB - During the perinatal period, the brain is particularly sensitive to remodelling by environmental factors. Adverse early-life experiences, such as stress exposure or suboptimal maternal care, can have long-lasting detrimental consequences for an individual. This phenomenon is often referred to as 'early-life programming' and is associated with an increased risk of disease. Typically, rodents exposed to prenatal stress or postnatal maternal deprivation display enhanced neuroendocrine responses to stress, increased levels of anxiety and depressive like behaviours, and cognitive impairments. Some of the phenotypes observed in these models of early-life adversity are likely to share common neurobiological mechanisms. For example, there is evidence for impaired glucocorticoid negative feedback control of the hypothalamic-pituitary-adrenal axis, altered glutamate neurotransmission and reduced hippocampal neurogenesis in both prenatally stressed rats and rats that experienced deficient maternal care. The possible mechanisms through which maternal stress during pregnancy may be transmitted to the offspring are reviewed, with special consideration given to altered maternal behaviour postpartum. We also discuss what is known about the neurobiological and epigenetic mechanisms that underpin early-life programming of the neonatal brain in the first generation and subsequent generations, with a view to abrogating programming effects and potentially identifying new therapeutic targets for the treatment of stress-related disorders and cognitive impairment. PMID- 25039444 TI - Osteoporosis in the at-risk asthmatic. AB - The effect of inhaled glucocorticosteroids (ICS) on bone metabolism and subsequent osteoporosis is controversial. Explanations for this controversy include various study designs, duration of use, outcome measures, and population demographics of research studies with intranasal or inhalational ICS. Patients with poorly controlled asthma are at greatest risk of osteoporosis because they are commonly treated with intermittent or continuous systemic corticosteroids (SCS) or high-dose ICS. A 45-year-old Caucasian woman presents with moderate-to severe asthma with frequent albuterol use and nighttime awakenings at least once weekly. She is on fluticasone/salmeterol 500/50 MUg one inhalation twice daily and montelukast 10 mg/day. She requires prednisone 15 mg three times per day for 5 days up to three times a year. Is this patient at greater risk of osteopenia, characterized by a T-score between -1.0 and -2.5, and subsequent osteoporosis and an increased risk of fractures? If she has osteopenia, should she be treated with a bisphosphonate? The risk of osteoporosis and fracture increases significantly with frequent administration of SCS, and patients on such medications should undergo preventative measures and treatment. This study discuses factors that contribute to an increased risk of osteoporosis/osteopenia in patients with asthma and suggests recommendations based on the current literature. PMID- 25039445 TI - Development of dialysis disequilibrium-like clinical signs during postobstructive management of feline urethral obstruction. AB - OBJECTIVE: To describe the clinical features, treatment, and outcome of a cat with acute neurologic signs subsequent to relief of urethral obstruction and rapid resolution of severe azotemia, suggesting a process similar to dialysis disequilibrium syndrome. CASE SUMMARY: A male castrated domestic short-hair cat was presented for weakness and dull mentation. Initial physical examination was consistent with urethral obstruction and laboratory data demonstrated severe azotemia, hyperkalemia, and acidemia. Interventions for hyperkalemia and urethral catheterization were performed without complication. The patient demonstrated a marked postobstructive diuresis and 7 hours after presentation suffered a grand mal seizure and was neurologically inappropriate. These changes corresponded with marked decreases in blood urea nitrogen (from 89.25 mmol/L to 19.99 mmol/L [250 mg/dL to 56 mg/dL]) and calculated serum osmolality (429 mOsm/kg to 359 mOsm/kg) from initial presentation without other apparent cause for seizure activity. The patient was treated with hypertonic saline (bolus and continuous infusion) for presumed osmotic injury (dialysis disequilibrium-like clinical signs) along with other supportive care. All neurologic signs resolved within 48 hours, the urinary catheter was removed, and the patient was discharged after 24 hours of observation of spontaneous urination. NEW OR UNIQUE INFORMATION PROVIDED: Dialysis disequilibrium syndrome has been documented in small animals, but similar signs have not been reported as a sequelae of treatment of feline urethral obstruction. Urethral obstruction is a common emergency and practitioners should be aware of this potential complication as a cause of delayed neurologic recovery or seizures in the postobstructive period. PMID- 25039446 TI - Cocaine's fall and marijuana's rise: questions and insights based on new estimates of consumption and expenditures in US drug markets. AB - AIMS: Drug policy strategies and discussions often use prevalence of drug use as a primary performance indicator. However, three other indicators are at least as relevant: the number of heavy users, total expenditures and total amount consumed. This paper stems from our efforts to develop annual estimates of these three measures for cocaine (including crack), heroin, marijuana and methamphetamine in the United States. METHODS: The estimates exploit complementary strengths of a general population survey (National Survey on Drug Use and Health) and both survey and urinalysis test result data for arrestees (Arrestee Drug Abuse Monitoring Program), supplemented by many other data sources. RESULTS: Throughout the 2000s US drug users spent in the order of $100 billion annually on these drugs, although the spending distribution and use patterns changed dramatically. From 2006 to 2010, the amount of marijuana consumed in the United States probably increased by more than 30%, while the amount of cocaine consumed in the United States fell by approximately 50%. These figures are consistent with supply-side indicators, such as seizures and production estimates. For all the drugs, total consumption and expenditures are driven by the minority of users who consume on 21 or more days each month. CONCLUSIONS: Even for established drugs, consumption can change rapidly. The halving of the cocaine market in five years and the parallel (but independent) large rise in daily/near-daily marijuana use are major events that were not anticipated by the expert community and raise important theoretical, research, and policy issues. PMID- 25039447 TI - A call for quality research on salt intake and health: from the World Hypertension League and supporting organizations. PMID- 25039448 TI - Higher insulin detemir doses are required for the similar glycemic control: comparison of insulin detemir and glargine in children with type 1 diabetes mellitus. AB - OBJECTIVE: We aimed to compare hemoglobin A1c (HbA1c), total and basal insulin doses, basal insulin injection frequencies, and body mass index (BMI) in children with type 1 diabetes mellitus (T1DM) who are receiving detemir and glargine as basal insulin in a basal-bolus therapy. METHOD: This retrospective study included 117 (53 females) children and adolescents with T1DM older than 4 yr of age, minimum diabetes duration of 2 yr, and receiving basal-bolus insulin regimen (at least 4 injections/d, insulin aspart or lispro as bolus insulin). Comparisons were made for those receiving insulin detemir (n = 32) or glargine (n = 85) as the basal insulin. RESULTS: Age, pubertal status, BMI standard deviation scores, and diabetes duration were similar in detemir and glargine groups. Glycemic control was similar in both groups (HbA1c levels 8.9 +/- 2.1% vs. 8.5 +/- 1.7% for detemir and glargine, respectively; p = 0.497). Both mean basal insulin (0.52 vs. 0.41 U/kg/d, p < 0.001) and mean total daily insulin (1.11 vs. 0.93 U/kg/d, p < 0.001) doses were higher in the detemir group. Furthermore, higher ratio of twice-daily basal insulin injection was detected in the detemir group (62.5 vs. 32.9% p = 0.004). Subgroup analysis according to pubertal status, or the number of daily basal injections showed similar results. CONCLUSION: Insulin detemir provides similar glycemic control with glargine, but, approximately 27% higher mean basal and 19% higher mean total insulin doses with two-fold more twice-daily basal insulin injection requirement. PMID- 25039450 TI - Acute myeloid leukaemia with myelodysplastic features in children: a report of Japanese Paediatric Leukaemia/Lymphoma Study Group. AB - The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found 'AML with myelodysplasia-related changes' (AML-MRC) according to the 2008 World Health Organization classification in 93 (21.0%), in whom 59 were diagnosed from myelodysplasia-related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with 'AML, not otherwise specified' (AML-NOS), patients with 'AML-MRC' presented at a younger age, with a lower white blood cell count, higher incidence of 20-30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations. Complete remission rate and 3-year probability of event-free survival were significantly worse in 'AML-MRC' patients (67.7 vs. 85.6%, P < 0.01, 37.1% vs. 53.8%, P = 0.02, respectively), but 3-year overall survival and relapse-free survival were comparable with 'AML-NOS' patients. By multivariate analysis, FLT3-ITD was solely associated with worse overall survival. These results support the distinctive features of the category 'AML-MRC' even in children. PMID- 25039451 TI - Follow up after curative colorectal cancer resection - aggregation of marginal gains. PMID- 25039456 TI - Diagnostic testing for peritonitis in patients undergoing peritoneal dialysis. PMID- 25039449 TI - Targeting the histone orthography of cancer: drugs for writers, erasers and readers. AB - Gene expression is dynamically controlled by epigenetics through post translational modifications of histones, chromatin-associated proteins and DNA itself. All these elements are required for the maintenance of chromatin structure and cell identity in the context of a normal cellular phenotype. Disruption of epigenetic regulation is a common event in human cancer. Here, we review the key protein families that control epigenetic signalling through writing, erasing or reading specific post-translational modifications. By exploiting the leading role of epigenetics in tumour development and the reversibility of epigenetic modifications, promising novel epigenetic-based therapies are being developed. In this article, we highlight the emerging low MW inhibitors targeting each class of chromatin-associated protein, their current use in preclinical and clinical trials and the likelihood of their being approved in the near future. PMID- 25039458 TI - Nutrition in palliative and end-of-life care. AB - Recent publications regarding nutrition highlight the importance of eating and drinking for patients and their family/carer. This article focuses on the importance of nutrition and early nutritional intervention, giving guidance for nurses when caring for patients with palliative and end-of-life care needs when the focus of nutrition centres around symptom control and quality of life. Clear, sensitive communication, with agreed nutritional goals set with the patient and their family/carer, and regular review and adaptation throughout any 'cancer journey' are paramount in order to minimise anxiety and distress. A multidisciplinary team approach is often required in order to support ethical decision-making and to assist in devising an individualised nutritional management plan. Although this article aims to focus upon the nutritional aspects associated with advancing cancer, many aspects will clearly be transferrable to patients with other life-limiting illnesses such as dementia and advanced cardiac and pulmonary disease. PMID- 25039457 TI - Discrepancies between c-Kit positive and Ano1 positive ICC-SMP in the W/Wv and wild-type mouse colon; relationships with motor patterns and calcium transients. AB - BACKGROUND: Interstitial cells of Cajal associated with the submuscular plexus (ICC-SMP) generate omnipresent slow-wave activity in the colon and are associated with prominent motor patterns. Our aim was to investigate colon motor dysfunction in W/W(v) mice in which the ICC are reportedly reduced. METHODS: Whole organ colon motility was studied using spatio-temporal mapping; immunohistochemical staining was carried out for c-Kit and Ano1; calcium imaging was applied to ICC SMP. KEY RESULTS: Discrepancies between Ano1 and c-Kit staining were found in both wild-type and W/W(v) colon. ICC-SMP were reduced to ~50% in the W/W(v) mouse colon according to c-Kit immunohistochemistry, but Ano1 staining indicated a normal network of ICC-SMP. The latter was consistent with rhythmic calcium transients occurring at the submucosal border of the colon in W/W(v) mice, similar to the rhythmic transients in wild-type ICC-SMP. Furthermore, the motor pattern associated with ICC-SMP pacemaking, the so-called 'ripples' were normal in the W/W(v) colon. CONCLUSIONS & INFERENCES: c-Kit is not a reliable marker for quantifying ICC-SMP in the mouse colon. Ano1 staining revealed a normal network of ICC-SMP consistent with the presence of a normal 'ripples' motor pattern. We detected a class of Ano1 positive c-Kit negative cells that do not depend on Kit expression for maintenance, a feature shared with ICC progenitors. PMID- 25039459 TI - Dementia and its relationship with food. AB - This article provides an overview of dementia and how it relates to nutrition. It examines the evidence for food and nutrition preventing, causing and treating dementia. The article highlights how malnutrition can affect the individual with dementia. The remainder of the article provides an in-depth, focused discussion on the difficulties people may experience in the community in relation to food and eating and the impact this has on family caregivers, with recommendations for achieving optimum nutrition. PMID- 25039460 TI - Nutrition in early life and the risk of asthma and allergic disease. AB - The prevalence of reported cases of asthma and allergic disease has seen a marked increase throughout the world since the 1960s, particularly in more developed, westernised countries. A key focus of research in this area has been the possible adverse effects of foetal and infant exposure to food allergens. There is some evidence that foetal and infant exposure to a range of allergens via the mother and her breast milk is important in the development of normal immune tolerance. Current advice is that pregnant and breastfeeding women do not need to avoid potential food allergens unless they are allergic themselves, or are advised to modify their diet by a health professional. Delaying the introduction of common food allergies beyond 6 months is unlikely to reduce the likelihood of food allergy and allergic disease. The findings of current ongoing trials investigating the potential benefits of early introduction on allergenic foods into the diet of children-as well as the comprehensive review of complementary and young-child feeding advice currently being conducted by the Scientific Advisory Committee on Nutrition-will help inform guidance in this area. PMID- 25039461 TI - Interview with Liz Evans. PMID- 25039462 TI - Nutritional screening: a community dietitian's perspective. AB - Malnutrition in the UK is well documented and highlighted by the British Association of Parenteral and Enteral Nutrition, who advocate the use of a screening tool to facilitate the identification and subsequent management of undernutrition. Nurses are ideally placed to support this process, but their role has many conflicting priorities. For nurses working in the community, there also exists the problem of identifying those who are at risk of undernutrition but remain unknown to nursing services. This article provides a review of malnutrition and nutrition screening and aims to promote a pragmatic approach to the identification and management of undernutrition in the community. The article concludes with a brief review of current opportunities for improving nutritional care in the community. PMID- 25039463 TI - Baseline characteristics and 1-year follow-up of Chinese atrial fibrillation patients according to age: a registry study. AB - BACKGROUND: The prevalence of atrial fibrillation (AF) increases with age, and may lead to complications and reduced quality of life. The aim of this study was to determine the characteristics, management, and prognosis of Chinese AF patients and whether there were differences according to age. METHODS: This registry-based study enrolled ambulatory, outpatient clinic, or hospitalized patients with AF in four sites in China. Based on the Birmingham 2009 schema, patients without and with valve lesion were stratified into three groups according to age. RESULTS: Between September 2008 and April 2011, 2,016 patients were enrolled, including 1,606 patients without valve lesion and 410 patients with valve lesion. Compared with the other two groups, patients >74 years of age were more likely to have morbidity and a CHADS2 score >1, and less likely to receive oral anticoagulants and rhythm-control drugs. At the 1-year follow-up, patients >74 years of age were more likely to have died or suffered a cerebrovascular event or systemic embolism. Age as a continuous variable (subdivided hazard ratio [SHR] 0.98, 95% confidence interval [CI] 0.96-1.01, P = 0.29) was not associated with risk of a cerebrovascular event or systemic embolism at 1-year but age >=75 years (SHR 1.73, 95% CI 1.05-2.87, P = 0.03) was an independent risk factor for the outcome at 1-year when all AF patients were included. CONCLUSIONS: Elderly AF patients are inadequately studied and treated compared with younger patients. Education on evidence-based management and the design of randomized controlled trials, specifically targeting the elderly, especially the Chinese elderly, should improve the management and prognosis of this frail segment of the AF population. PMID- 25039464 TI - Red light interferes in UVA-induced photoaging of human skin fibroblast cells. AB - The possible regulation mechanism of red light was determined to discover how to retard UVA-induced skin photoaging. Human skin fibroblasts were cultured and irradiated with different doses of UVA, thus creating a photoaging model. Fibroblasts were also exposed to a subtoxic dose of UVA combined with a red light emitting diode (LED) for five continuous days. Three groups were examined: control, UVA and UVA plus red light. Cumulative exposure doses of UVA were 25 J cm(-2), and the total doses of red light were 0.18 J cm(-2). Various indicators were measured before and after irradiation, including cell morphology, viability, beta-galactosidase staining, apoptosis, cycle phase, the length of telomeres and the protein levels of photoaging-related genes. Red light irradiation retarded the cumulative low-dose UVA irradiation-induced skin photoaging, decreased the expression of senescence-associated beta-galactosidase, upregulated SIRT1 expression, decreased matrix metalloproteinase MMP-1 and the acetylation of p53 expression, reduced the horizon of cell apoptosis and enhanced cell viability. Furthermore, the telomeres in UVA-treated cells were shortened compared to those of cells in the red light groups. These results suggest that red light plays a key role in the antiphotoaging of human skin fibroblasts by acting on different signaling transduction pathways. PMID- 25039465 TI - Use of proton pump inhibitors decrease cellular oxidative burst in patients with decompensated cirrhosis. AB - BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are commonly used antisecretory drugs and have been linked to an increased risk of bacterial infections in cirrhosis. We investigated whether the treatment with PPIs in cirrhosis affects the oxidative burst activity of granulocytes and monocytes and its possible interference with serum norfloxacin (Nflx) levels in these patients. METHODS: 70 patients with cirrhosis and ascitic fluid and 24 healthy controls were included in the study and distributed into groups according to the regular use of PPIs and/or norfloxacin. The blood granulocyte and monocyte's phagocytic activity and oxidative burst were evaluated by flow cytometry. Blood levels of norfloxacin were measured by HPLC and bacterial translocation was evaluated by detection of bacterial DNA in blood. RESULTS: Use of PPIs was associated with a decreased granulocyte and monocyte oxidative burst, but not of phagocytic activity, as compared with patients not receiving PPIs. PPIs use did not affect serum norfloxacin levels in patients. A not significant trend to an increased bacterial DNA translocation was observed in patients receiving PPIs, including patients simultaneously receiving norfloxacin. CONCLUSIONS: PPIs significantly decrease cellular oxidative burst in cirrhosis. This fact may provide a pathogenic explanation to the reported high rates of bacterial infections in this setting, and strongly suggests that PPIs should only be used in patients with cirrhosis when clinically indicated. PMID- 25039466 TI - Toward a Resolution of the Tripartite Structure of Subjective Well-Being. AB - Diener (1984) introduced the concept of "subjective well-being" (SWB) as comprising three primary components: life satisfaction (LS), positive affect (PA), and negative affect (NA). Busseri and Sadava (2011) identified multiple competing conceptualizations of the tripartite structure of SWB and delineated problems with this ambiguity with respect to defining, operationalizing, analyzing, and synthesizing information concerning SWB. The present work provides an empirical evaluation of four competing structural approaches in which SWB is conceptualized variously as three separate components (Model 1), a hierarchical construct (Model 2), a causal system (Model 3), and a composite (Model 4). Data from a longitudinal study of middle-aged Americans (N = 3,707; 20-75 years old, 55% female, 94% Caucasian) were used to examine the relatedness versus independence of the three SWB components within and across time, as well as predictive effects on SWB. The various structural models differ in how adequately they accommodate the joint relatedness/independence of the SWB components and lead to different conclusions concerning predictive effects on SWB. Conceptual and empirical considerations are considered within and across models. Implications and next steps for further understanding the tripartite structure of SWB are discussed. PMID- 25039467 TI - Accelerating bleaching in vitiligo: balancing benefits versus risks. AB - While the goal of available treatment in vitiligo is to regain pigmentation, some patients affected by extensive and treatment-resistant vitiligo, with a major social and emotional impact, may benefit from depigmentation therapy. However, results from such therapy may not always be satisfactory. So to achieve better, faster and complete bleaching, Webb et al. propose a synergistic approach that combines topical application of bleaching phenols which targets melanocytes and initiate local inflammation with immune adjuvants so as to obtain an enhanced immune response against remaining melanocytes. This strategy could be reliable, but should be evaluated cautiously in future studies, in terms of potential side effects and induction of undesired autoimmunity. PMID- 25039468 TI - Screening for latent tuberculosis infection in psoriasis and psoriatic arthritis patients in a tuberculosis-endemic country: a comparison of the QuantiFERON(r)-TB Gold In-Tube test and tuberculin skin test. AB - Since the introduction of biologic therapies for tuberculosis (TB), screening for latent TB infection has increased in importance, especially in countries in which TB is endemic. The aim of this study was to evaluate the effect of psoriasis on tuberculin skin test (TST) results and to compare two TB screening tests, the TST and QuantiFERON((r))-TB Gold In-Tube (QFT-GIT) test, in psoriasis and psoriatic arthritis (PA) patients living in a TB-endemic country (Turkey). This prospective study included 61 psoriasis and 40 PA patients, and 58 healthy controls. Demographic data, medical history, human immunodeficiency virus (HIV) status, level of education, smoking status, exposure to TB, personal and family histories of TB, and bacillus Calmette-Guerin (BCG) vaccination status were recorded for all participants. The TST and QFT-GIT were performed in all participants. The mean +/- standard deviation TST indurations in the patient and control groups were 12.6 +/- 6.4 mm and 10.2 +/- 6.5 mm, respectively (P = 0.051). The TST positivity rate was higher in patients than in controls (86.1% vs. 37.9%; P < 0.001), whereas QFT-GIT positivity did not differ significantly (patients: 20.8%; controls: 17.2%; P = 0.737). False positive results can lead to unnecessary prophylactic TB treatment; therefore, the cut-off point for TST positivity in psoriasis and PA patients should be re-evaluated, or other tests, such as the QFT GIT, should be used. PMID- 25039470 TI - Formulation and pharmacokinetics of gelucire solid dispersions of flurbiprofen. AB - CONTEXT: Development of solid dispersions is to improve the therapeutic efficacy by increasing the drug solubility, dissolution rate, bioavailability as well as to attain rapid onset of action. OBJECTIVE: The present research deals with the development of solid dispersions of flurbiprofen which is poorly water soluble to improve the solubility and dissolution rate using gelucires. MATERIALS AND METHODS: In this study, solid dispersions were prepared following solvent evaporation method using gelucire 44/14 and gelucire 50/13 as carriers in different ratios. Then the formulations were evaluated for different physical parameters, solubility studies, DSC, FTIR studies and in vitro dissolution studies to select the best formulation that shows rapid dissolution rate and finally subjected to pharmacokinetic studies. RESULTS AND DISCUSSION: From the in vitro dissolution study, formulation F3 showed the better improvement in solubility and dissolution rate. From the pharmacokinetic evaluation, the control tablets produced peak plasma concentration (Cmax) of 9140.84 +/- 614.36 ng/ml at 3 h Tmax and solid dispersion tablets showed Cmax = 11 445.46 +/- 149.23 ng/ml at 2 h Tmax. The area under the curve for the control and solid dispersion tablets was 31 495.16 +/- 619.92 and 43 126.52 +/- 688.89 ng h/ml and the mean resident time was 3.99 and 3.68 h, respectively. CONCLUSION: From the above results, it is concluded that the formulation of gelucire 44/14 solid dispersions is able to improve the solubility, dissolution rate as well as the absorption rate of flurbiprofen than pure form of drug. PMID- 25039469 TI - Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis. AB - OBJECTIVES: Cotrimoxazole prophylactic treatment (CPT) prevents opportunistic infections in HIV-infected or HIV-exposed children, but estimates of the effectiveness in preventing malaria vary. We reviewed studies that examined the effect of CPT on incidence of malaria in children in sub-Saharan Africa. METHODS: We searched PubMed and EMBASE for randomised controlled trials (RCTs) and cohort studies on the effect of CPT on incidence of malaria and mortality in children and extracted data on the prevalence of sulphadoxine-pyrimethamine resistance conferring point mutations. Incidence rate ratios (IRR) from individual studies were combined using random effects meta-analysis; confounder-adjusted estimates were used for cohort studies. The importance of resistance was examined in meta regression analyses. RESULTS: Three RCTs and four cohort studies with 5039 children (1692 HIV-exposed; 2800 HIV-uninfected; 1486 HIV-infected) were included. Children on CPT were less likely to develop clinical malaria episodes than those without prophylaxis (combined IRR 0.37, 95% confidence interval: 0.21 0.66), but there was substantial between-study heterogeneity (I-squared = 94%, P < 0.001). The protective efficacy of CPT was highest in an RCT from Mali, where the prevalence of antifolate resistant plasmodia was low. In meta-regression analyses, there was some evidence that the efficacy of CPT declined with increasing levels of resistance. Mortality was reduced with CPT in an RCT from Zambia, but not in a cohort study from Cote d'Ivoire. CONCLUSIONS: Cotrimoxazole prophylactic treatment reduces incidence of malaria and mortality in children in sub-Saharan Africa, but study designs, settings and results were heterogeneous. CPT appears to be beneficial for HIV-infected and HIV-exposed as well as HIV uninfected children. PMID- 25039471 TI - Sudden paradoxical QT-interval prolongation exacerbating T-wave alternans in a patient with type 3 long QT syndrome. AB - We report a case with type 3 congenital long QT syndrome, who exhibited a sudden paradoxical QT-interval prolongation during a progressive increase in heart rate, which exacerbated T-wave alternans. PMID- 25039472 TI - Phage-bacteria network analysis and its implication for the understanding of coral disease. AB - Multiple studies have explored microbial shifts in diseased or stressed corals; however, little is known about bacteriophage interactions with microbes in this context. This study characterized microbial 16S rRNA amplicons and phage metagenomes associated with Montastraea annularis corals during a concurrent white plague disease outbreak and bleaching event. Phage consortia differed between bleached and diseased tissues. Phages in the family Inoviridae were elevated in diseased or healthy tissues compared with bleached portions of diseased tissues. Microbial communities also differed between diseased and bleached corals. Bacteria in the orders Rhodobacterales and Campylobacterales were increased while Kiloniellales was decreased in diseased compared with other tissues. A network of phage-bacteria interactions was constructed of all phage strains and 11 bacterial genera that differed across health states. Phage bacteria interactions varied in specificity: phages interacted with one to eight bacterial hosts while bacteria interacted with up to 59 phages. Six phages were identified that interacted exclusively with Rhodobacterales and Campylobacterales. These results suggest that phages have a role in controlling stress-associated bacteria, and that networks can be utilized to select potential phages for mitigating detrimental bacterial growth in phage therapy applications. PMID- 25039473 TI - Sickle cell disease in children: chronic complications and search of predictive factors for adverse outcomes. AB - BACKGROUND: Sickle cell disease (SCD) has extremely variable phenotypes, and several factors have been associated with the severity of the disease. OBJECTIVES: To analyze the chronic complications of SCD and look for predictive risk factors for increased severity and number of complications. METHODS: Retrospective study including all children followed for SCD in the Paediatric Haematology Unit of a tertiary hospital in Portugal, who completed 17 yr old between the years 2004 and 2013. RESULTS: We identified 44 patients, 55% female and 98% black. Chronic complications occurred in 80% of cases. Slight dilatation of the left ventricle was the most frequent complication (47.7%), followed by respiratory function disturbs (43.2%), microlithiasis or cholelithiasis (40.9%), increased flow velocity of cerebral arteries (31.8%), enuresis, delayed puberty and bone abnormalities (6.8% each), sickle cell retinopathy and leg ulcer (4.6% each) and recurrent priapism (2.3%). We identified a statistically significant association between leukocytes >15 000/MUL and a higher number of hospitalizations (P < 0.001) and chronic complications of the disease (P = 0.035). The occurrence of dactylitis in first year of life was also significantly associated with a higher number of hospitalizations (P = 0.004) and chronic complications (P = 0.018). The presence of alpha-thalassemia was associated with a lower number of chronic complications (P = 0.036). CONCLUSIONS: Leucocytosis and dactylitis in the first year of life can be predictors of SCD severity, while the presence of alpha-thalassemia can be protective. The determination of early predictors of chronic complications of SCD may improve the comprehensive care of these patients. PMID- 25039474 TI - Decreased urinary nerve growth factor reflects prostatic volume reduction and relief of outlet obstruction in patients with benign prostatic enlargement treated with dutasteride. AB - OBJECTIVES: To examine urinary nerve growth factor before and after dutasteride treatment, and to analyze correlations between clinical parameters and change of urinary nerve growth factor in patients with benign prostatic enlargement. METHODS: We prospectively studied 30 patients with benign prostatic enlargement who had not been satisfied with alpha-adrenergic antagonist monotherapy for more than 3 months. Before and 24 weeks after dutasteride add-on treatment, we assessed International Prostate Symptom Score, prostatic volume, filling cystometry and pressure-flow study. Urinary nerve growth factor was measured by enzyme-linked immunosorbent assay, and normalized to the urinary creatinine (nerve growth factor/creatinine) before and 24 weeks after dutasteride add-on treatment. RESULTS: In baseline characteristics before dutasteride, there was no significant correlation between urinary nerve growth factor/creatinine and any clinical parameters including age, International Prostate Symptom Score, prostatic volume, presence of detrusor overactivity, detrusor pressure at maximum flow rate, bladder outlet obstruction index or bladder contractility index. Dutasteride significantly reduced prostatic volume (from 68 +/- 31 mL to 49 +/- 28 mL) and improved International Prostate Symptom Score (from 17.2 +/- 8.7 to 13.1 +/- 6.8), storage (from 8.0 +/- 4.3 to 6.0 +/- 2.9) and voiding symptom subscore of International Prostate Symptom Score (from 9.3 +/- 5.7 to 7.1 +/- 4.5). In urodynamic study, detrusor pressure at maximum flow rate (from 77 +/- 32 cmH2 O to 59 +/- 24 cmH2 O) and bladder outlet obstruction index (from 62 +/- 32 to 42 +/- 27) were significantly decreased after dutasteride treatment. Urinary nerve growth factor/creatinine was significantly decreased after dutasteride from 2.61 +/- 2.50 to 1.64 +/- 1.68. The change of urinary nerve growth factor/creatinine significantly correlated only with the change of prostatic volume (r = 0.38) and bladder outlet obstruction index (r = 0.36). CONCLUSIONS: Urinary nerve growth factor decreases in association with reduction of prostatic volume and relief of bladder outlet obstruction. Urinary nerve growth factor might be useful as a biomarker to monitor the improvement of bladder outlet obstruction in patients with benign prostatic enlargement. PMID- 25039475 TI - Alemtuzumab induction in lung transplantation: time to move on? AB - This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the challenges encountered with alemtuzumab induction in other solid organs. See article by Jaksch et al on page 1839. PMID- 25039476 TI - Photostable bipolar fluorescent probe for video tracking plasma membranes related cellular processes. AB - Plasma membranes can sense the stimulations and transmit the signals from extracellular environment and then make further responses through changes in locations, shapes or morphologies. Common fluorescent membrane markers are not well suited for long time tracking due to their shorter retention time inside plasma membranes and/or their lower photostability. To this end, we develop a new bipolar marker, Mem-SQAC, which can stably insert into plasma membranes of different cells and exhibits a long retention time over 30 min. Mem-SQAC also inherits excellent photostability from the BODIPY dye family. Large two-photon absorption cross sections and long wavelength fluorescence emissions further enhance the competitiveness of Mem-SQAC as a membrane marker. By using Mem-SQAC, significant morphological changes of plasma membranes have been monitored during heavy metal poisoning and drug induced apoptosis of MCF-7 cells; the change tendencies are so distinctly different from each other that they can be used as indicators to distinguish different cell injuries. Further on, the complete processes of endocytosis toward Staphylococcus aureus and Escherichia coli by RAW 264.7 cells have been dynamically tracked. It is discovered that plasma membranes take quite different actions in response to the two bacteria, information unavailable in previous research reports. PMID- 25039478 TI - High light decreases xylem contribution to fruit growth in tomato. AB - Recently, contradicting evidence has been reported on the contribution of xylem and phloem influx into tomato fruits, urging the need for a better understanding of the mechanisms involved in fruit growth. So far, little research has been performed on quantifying the effect of light intensity on the different contributors to the fruit water balance. However, as light intensity affects both transpiration and photosynthesis, it might be expected to induce important changes in the fruit water balance. In this study, tomato plants (Solanum lycopersicum L.) were grown in light and shade conditions and the fruit water balance was studied by measuring fruit growth of girdled and intact fruits with linear variable displacement transducers combined with a model-based approach. Results indicated that the relative xylem contribution significantly increased when shading lowered light intensity. This resulted from both a higher xylem influx and a lower phloem influx during the daytime. Plants from the shade treatment were able to maintain a stronger gradient in total water potential between stem and fruits during daytime, thereby promoting xylem influx. It appeared that the xylem pathway was still functional at 35 days after anthesis and that relative xylem contribution was strongly affected by environmental conditions. PMID- 25039477 TI - SWOG0919: a Phase 2 study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukaemia. AB - Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukaemia (AML) blasts to chemotherapy. A Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also demonstrated an encouraging response rate. The Southwestern Oncology Group (SWOG) trial, SWOG S0919, was a Phase 2 trial evaluating the complete remission (CR) rate in a larger number of patients with relapsed AML treated with idarubicin, cytarabine and pravastatin. This study closed to accrual after meeting the defined criterion for a positive study. Thirty-six patients with a median age of 59 years (range 23-78) were enrolled. The median time from diagnosis to registration was 18 months. Relapse status was first relapse, 17 patients (47%); second relapse, 15 patients (42%); third relapse, two patients (5.5%) and fourth relapse, two patients (5.5%). The response rate was 75% [95% confidence interval: 58-88%; 20 CRs, 7 CR with incomplete count recovery (CRi)], and the median overall survival was 12 months. The P-value comparing 75-30% (the null response rate based on prior SWOG experience) was 3.356 * 10(-4) . Given the encouraging CR/CRi rate, this regimen should be considered for testing in a prospective randomized trial against best conventional therapy. PMID- 25039479 TI - Contrasting soil fungal community responses to experimental nitrogen addition using the large subunit rRNA taxonomic marker and cellobiohydrolase I functional marker. AB - Human activities have resulted in increased nitrogen inputs into terrestrial ecosystems, but the impact of nitrogen on ecosystem function, such as nutrient cycling, will depend at least in part on the response of soil fungal communities. We examined the response of soil fungi to experimental nitrogen addition in a loblolly pine forest (North Carolina, USA) using a taxonomic marker (large subunit rDNA, LSU) and a functional marker involved in a critical step of cellulose degradation (cellobiohydrolase, cbhI) at five time points that spanned fourteen months. Sampling date had no impact on fungal community richness or composition for either gene. Based on the LSU, nitrogen addition led to increased fungal community richness, reduced relative abundance of fungi in the phylum Basidiomycota and altered community composition; however, similar shifts were not observed with cbhI. Fungal community dissimilarity of the LSU and cbhI genes was significantly correlated in the ambient plots, but not in nitrogen-amended plots, suggesting either functional redundancy of fungi with the cbhI gene or shifts in other functional groups in response to nitrogen addition. To determine whether sequence similarity of cbhI could be predicted based on taxonomic relatedness of fungi, we conducted a phylogenetic analysis of publically available cbhI sequences from known isolates and found that for a subset of isolates, similar cbhI genes were found within distantly related fungal taxa. Together, these findings suggest that taxonomic shifts in the total fungal community do not necessarily result in changes in the functional diversity of fungi. PMID- 25039480 TI - Effect of Massachusetts health reform on chronic disease outcomes. AB - OBJECTIVE: To determine whether Massachusetts Health Reform improved health outcomes in uninsured patients with hyperlipidemia, diabetes, or hypertension. DATA SOURCE: Partners HealthCare Research Patient Data Registry (RPDR). STUDY DESIGN: We examined 1,463 patients with hyperlipidemia, diabetes, or hypertension who were uninsured in the 3 years before the 2006 Massachusetts Health Reform implementation. We assessed mean quarterly total cholesterol, glycosylated hemoglobin, and systolic blood pressure in the respective cohorts for five follow up years compared with 3,448 propensity score-matched controls who remained insured for the full 8-year study period. We used person-level interrupted time series analysis to estimate changes in outcomes adjusting for sex, age, race, estimated household income, and comorbidity. We also analyzed the subgroups of uninsured patients with poorly controlled disease at baseline, no evidence of established primary care in the baseline period, and those who received insurance in the first follow-up year. PRINCIPAL FINDINGS: In 5 years after Massachusetts Health Reform, patients who were uninsured at baseline did not experience detectable trend changes in total cholesterol (-0.39 mg/dl per quarter, 95 percent confidence interval [-1.11 to 0.33]), glycosylated hemoglobin (-0.02 percent per quarter [-0.06 to 0.03]), or systolic blood pressure (-0.06 mmHg per quarter [-0.29 to 0.18]). Analyses of uninsured patients with poorly controlled disease, no evidence of established primary care in the baseline period, and those who received insurance in the first follow-up year yielded similar findings. CONCLUSIONS: Massachusetts Health Reform was not associated with improvements in hyperlipidemia, diabetes, or hypertension control after 5 years. Interventions beyond insurance coverage might be needed to improve the health of chronically ill uninsured persons. PMID- 25039481 TI - Increase of homogenous new bone formation using osteoinductive factor rhGDF-5 during sinus floor augmentation in Goettingen Minipigs. AB - OBJECTIVES: The aim of this study was to test the hypothesis that recombinant human growth and differentiation factor-5 (rhGDF-5) induces an increased and homogenous distribution of new bone formation across the entire volume of sinus floor augmentation in 12 Goettingen Minipigs. MATERIAL AND METHODS: In a randomized split-mouth design, one maxillary sinus was augmented with the bone substitute beta-TCP, whereas a combination of beta-TCP and the osteoinductive growth factor rhGDF-5 was used on the contralateral side. To evaluate the influence of dose and time on the effectiveness of the factor, two different concentrations of rhGDF-5 (400 MUg and 800 MUg) and healing periods (4 and 12 weeks) were each analysed. RESULTS: After 4 weeks, a homogenous gradient of bone formation could be observed for all dosage groups, with decreasing bone density from the local bone towards the sinus membrane. Both test groups, however, achieved a higher total level of bone formation compared with the control group, which was only significant in the low-dose group (P = 0.0184). After 12 weeks, the influence of the growth factor significantly depends on the region (P = 0.023). In the low-dose group, the new bone formation did not differ significantly within the examined regions of the graft (P = 0.1118), suggesting a homogeneous bone formation over the entire augmentation. The gradient of the high dose group was similar to the control group with a decrease of local bone development. CONCLUSIONS: rhGDF-5 delivered on a beta-TCP scaffold material leads to an increase in homogeneous new bone formation across the entire volume of the sinus floor augmentation. PMID- 25039482 TI - Topology of the Bacillus subtilis SpoIISA protein and its role in toxin-antitoxin function. AB - SpoIISAB is a toxin-antitoxin module encoded on the chromosomes of Bacillus subtilis and related Bacilli species. The SpoIISA toxin was previously shown to target the cytoplasmic membrane and to induce lysis in both B. subtilis and Escherichia coli; however, the precise manner of SpoIISA toxicity remains unknown. In this work, we focused on the N-terminal, transmembrane domain of SpoIISA and verified the prediction of its topology. Using truncated SpoIISA constructs, we show that the entire transmembrane domain is required for its toxicity. Moreover, we propose that the oligomerization of this transmembrane domain is crucial for activity of SpoIISA, possibly by forming a pore-like structure. PMID- 25039483 TI - Dental fear affects adolescent perception of interaction with dental staff. AB - The main purpose of this study was to explore whether subjective perception of interaction with dental staff is associated with dental fear in a population based sample of 18-yr-old adolescents (n = 773). The interaction was measured using the Patient Dental Staff Interaction Questionnaire (PDSIQ), validated with exploratory and confirmatory factor analyses, which yielded the factors of 'kind atmosphere and mutual communication', 'roughness', 'insecurity', 'trust and safety', and 'shame and guilt'. Dental fear was measured using the Modified Dental Anxiety Scale (MDAS). Gender and sense of coherence (SOC) were included as potential confounding variables. Adolescents with high dental fear more often perceived their interaction with dental staff negatively and more often felt insecure than others. This difference persisted after adjustment for gender and SOC. In conclusion, adolescents with high dental fear may perceive their interaction with dental staff more positively if the staff succeed in creating a positive, trusting, approving, and supportive atmosphere with kindness, calmness, and patience. The communication and interaction skills of dental staff may play a particularly important role when encountering highly fearful dental patients. PMID- 25039484 TI - Effects of a selection of additives on in vitro ruminal methanogenesis and in situ and in vivo NDF digestibility. AB - The effects of 18 essential oils, yeast, Quebracho tannin and Quillaja saponin on ruminal methane and gas production (GP) were studied in vitro. A lactating cow diet was incubated with rumen inoculum. Doses of the additives (mg/L) were: essential oils = 500; tannin = 67; yeast = 8.35 and 16.7; and saponin = 300. Lemongrass, estragole, eugenol, geraniol, limonen, thyme oil and thymol produced less gas (overall mean 33.8 mL/200 mg dry matter (DM)) than control (43.6 mL/200 mg DM; P < 0.001). Methane produced (mL/200 mg DM) by guaiacol (10.7), lemongrass (9.6), limonene (11.4), thyme oil (10.9) and thymol (2.1) was lower than control (12.5) (P < 0.001). Methane percentage on total GP was lower (P < 0.001) for cinnamic alcohol (25.4), guaiacol (24.5), thymol (19.7) and vanillin (26.3) than control (28.8). In a second experiment, thymol, guaiacol and yeast were added to the diet of dry fistulated cows to determine in situ neutral detergent fiber digestibility (NDFD) of six forages and in vivo dietary NDFD. Thymol and yeast decreased in situ NDFD after 24 h (33.9% and 33.5% vs. 38.1%; P = 0.008). Thymol decreased in vivo total tract NDFD (40.8% vs. 51.4%; P = 0.02). Differences in GP and methane levels were registered within classes of additives. A careful selection of additives may allow for the manipulation of ruminal fermentation. PMID- 25039485 TI - Two CYP4 genes of the Chinese white pine beetle, Dendroctonus armandi (Curculionidae: Scolytinae), and their transcript levels under different development stages and treatments. AB - Bark beetles oxidize the defensive monoterpenes of their host trees both to detoxify them and to convert them into components of their pheromone system. This oxidation is catalysed by cytochrome P450 (CYP) enzymes and occurs in different stages of the insect. We identified two new CYP4 genes in the Chinese white pine beetle (Dendroctonus armandi), and carried out bioinformatic analysis one the full-length nucleic acid sequences and deduced amino acid sequences. Differential expression of the CYP4 genes was observed between sexes, and within these significant differences amongst development stages, fed on phloem of Pinus armandi and exposed to stimuli((+/-)- alpha-pinene, (R)-(+)- alpha-pinene, (S)-( )-alpha-pinene, (S)-(-)-beta-pinene and (+)-3-carene) at 8 and 24 h, and their interactions were found upon exposure to host monoterpenes. Increased expression of CYP4 genes suggested that they play a role in the detoxification of monoterpenes released by the host trees. The differential transcript accumulation patterns of these bark beetle CYP4 genes provides insight into the ecological interactions of D. armandi with its host pine. PMID- 25039486 TI - Co-localization of agminated congenital melanocytic nevi with vitiligo vulgaris: an unusual presentation. PMID- 25039487 TI - Stratified mucin-producing intraepithelial lesion (SMILE): report of a case series with associated pathological findings. AB - AIMS: Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon premalignant cervical lesion showing morphological overlap with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS)/cervical glandular intraepithelial neoplasia. Given the limited literature on SMILE, we aimed to document its frequency and assess the associated pathology in a large series of cases. METHODS AND RESULTS: Over a 6-year period, we documented all cases of SMILE and the associated findings. SMILE was diagnosed in 69 specimens from 60 patients (50 loop excisions and 19 punch biopsy specimens), constituting 0.6% of cervical specimens. Overall, SMILE coexisted with high-grade CIN in 93% of cases, AIS in 42%, and a carcinoma in 10%. When SMILE was diagnosed on a cervical punch biopsy, there was high-grade CIN in the follow-up loop in most cases. SMILE was consistently diffusely p16-positive and IMP3-negative. CONCLUSIONS: Given the morphological overlap and significant association with high-grade CIN and AIS, we believe that SMILE is best regarded as a form of high grade reserve cell dysplasia, probably arising from reserve or stem cells with the capacity for multidirectional differentiation. We recommend that management of SMILE should be as for AIS. PMID- 25039488 TI - Limitations in the approach health caregivers can take in end-of-life care decisions. AB - BACKGROUND: In the terminal stages of neuro-metabolic diseases, parents can begin to experience a sense of loss even before the child dies, and might accept death prematurely. CASES: A 2.5-year-old female patient with Sandoff Disease (diagnosed at 9 months of age), and a 17-month-old male Krabbe patient (diagnosed at 5 months of age) were admitted to the hospital with hypernatraemic dehydration and bronchopneumonia, respectively, within 10 days of each other. Both patients developed respiratory arrest short after admission and were supported with mechanical ventilation. Both families gave written consent to end life support, but their wishes could not be accepted according to Turkish law. CONCLUSIONS: Specialists are expected to communicate well with families and give continuous care while respecting the opinions of patients' families on the timing of the withdrawal of life support. However, ethical and legal regulations on the conduct of health care professionals in these circumstances are unclear in Turkey and should be developed rapidly. PMID- 25039491 TI - IKKbeta regulates endothelial thrombomodulin in a Klf2-dependent manner. AB - BACKGROUND: Endothelial thrombomodulin (TM) is critically involved in anticoagulation, anti-inflammation, cytoprotection and normal fetal development. Tumor necrosis factor alpha (TNFalpha) suppresses TM expression. OBJECTIVE: TNFalpha has been shown to down-regulate TM partly via activation of nuclear factor kappa B (NF-kappaB). However, because the TM promoter lacks an NF-kappaB binding site, the direct involvement of NF-kappaB has been controversial. We investigated the role of the upstream regulatory serine kinase, inhibitory kappa B kinase-beta (IKKbeta), in TM expression and function with or without TNFalpha treatment. METHODS: Inhibition of IKKbeta was achieved by specific chemical inhibitors, siRNA or shRNA. TM expression was assessed by qRT-PCR, Western blot, flow cytometry, luciferase reporter assay and chromatin immune-precipitation (ChIP) assay. TM function was estimated by generation of activated protein C (APC). NF-kappaB activation was determined by immunocytochemistry. RESULTS AND CONCLUSIONS: IKKbeta inhibition increased TM expression and function, and attenuated TNFalpha-mediated TM down-regulation. In contrast, inhibition of downstream canonical NF-kappaB protein family members p50 and p65 (RelA) failed to up-regulate TM expression and did not affect IKKbeta inhibition-mediated TM over-expression. However, knockdown of cRel and RelB, family members of the canonical and non-canonical NF-kappaB pathway, respectively, resulted in TM over expression. IKKbeta inhibition caused over-expression, increased promoter activity and enhanced binding of Kruppel-like factor 2 (Klf2) to the TM promoter, which positively regulates TM expression. Finally, knockdown of Klf2 completely attenuated IKKbeta inhibition-mediated TM up-regulation. We conclude that IKKbeta regulates TM in a Klf2-dependent manner. PMID- 25039492 TI - The carrier AUXIN RESISTANT (AUX1) dominates auxin flux into Arabidopsis protoplasts. AB - The ability of the plant hormone auxin to enter a cell is critical to auxin transport and signaling. Auxin can cross the cell membrane by diffusion or via auxin-specific influx carriers. There is little knowledge of the magnitudes of these fluxes in plants. Radiolabeled auxin uptake was measured in protoplasts isolated from roots of Arabidopsis thaliana. This was done for the wild-type, under treatments with additional unlabeled auxin to saturate the influx carriers, and for the influx carrier mutant auxin resistant 1 (aux1). We also used flow cytometry to quantify the relative abundance of cells expressing AUX1-YFP in the assayed population. At pH 5.7, the majority of auxin influx into protoplasts - 75% - was mediated by the influx carrier AUX1. An additional 20% was mediated by other saturable carriers. The diffusive influx of auxin was essentially negligible at pH 5.7. The influx of auxin mediated by AUX1, expressed as a membrane permeability, was 1.5 +/- 0.3 MUm s(-1) . This value is comparable in magnitude to estimates of efflux permeability. Thus, auxin-transporting tissues can sustain relatively high auxin efflux and yet not become depleted of auxin. PMID- 25039493 TI - Factors associated with cognition recovery among elders with mild cognitive impairment in Korea. AB - BACKGROUND: Of elders with mild cognitive impairment, around half recover their cognitive function at some point in time. However, very little is known about the factors that influence their cognitive change towards recovery. AIM: This study evaluated the role of depression, instrumental activity of daily living and sleep quality as they affect cognition recovery among community-dwelling elders. METHODS: The study follows a longitudinal comparative research design using secondary data analysis. Community-dwelling elders with mild cognitive impairment were assessed twice with a 1-year interval to assess their levels of cognition. Adult participants were drawn from those who visited a community health centre, were aged 65 or over and who were assessed as having MCI. RESULTS: Those with mild cognitive impairment when compared with the normal cognition group were more likely to be younger, have more education, living with their spouses and had better cognitive function at baseline assessment than other participants. Predictors for cognitive recovery among elders with mild cognitive impairment were age, depression and cognitive function at baseline assessment. LIMITATIONS: Participants included only those who visit a community health centre in an urban area of Korea, so the findings may not be applicable to other elders with less mobility or who live in rural areas. IMPLICATIONS FOR NURSING AND HEALTH POLICY: With the understanding that cognitive function and depression predict the recovery of mild cognitive function, nurses might be able to identify and target those older adults who are likely to achieve recovery of cognitive function. Additionally, health policy options, as suggested by the study as having the potential to improve mild cognitive impairment recovery, could include public education strategies. PMID- 25039494 TI - The use of Google Glass for airway assessment and management. AB - Currently, information about airway assessment and tracheal intubation is communicated verbally or in writing. Google Glass can record this information in real time with minimal disruption to work flow, using standard operating room lighting. PMID- 25039495 TI - Is red cell distribution width a useful biomarker for risk assessment of diabetes mellitus? PMID- 25039496 TI - Burn injury to a reconstructed breast via a cigarette causing implant exposure. The importance of the patient's education. PMID- 25039497 TI - The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. AB - International interest on the benefits of using the steroid hormone Dehydroepiandrosterone (DHEA) on various aspects of human health, including the regulation of mood, is increasing. This study aimed to review the scientific literature on the use of DHEA in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses. PubMed, ISI Web of Knowledge and Virtual Health Library (VHL) databases were independently searched by two researchers using the following terms: depression, treatment, DHEA, and mood. Clinical studies were considered eligible when subjects were treated with DHEA and psychological assessments of depression were conducted. No time limits or language for this research were imposed. One 183 references were identified, and 22 references were selected to compose this review. Significant improvements related to the use of DHEA in patients with depression were observed, in addition to improvements in depressive symptoms in patients with schizophrenia, anorexia nervosa, HIV and adrenal insufficiency. No significant improvements were observed regarding depressive symptoms in patients with fibromyalgia; the results observed in patients with autoimmune diseases and healthy individuals remain contradictory. Although the selected studies demonstrated good methodological applications, most studies consisted of small samples, and only 3 studies were conducted in a young population. Therefore, we concluded that the studies published to date indicate promising results regarding the use of DHEA in the treatment of depression and depressive symptoms, especially in depression that is mild or resistant to conventional therapy. PMID- 25039498 TI - Challenges to and opportunities for improving mental health services for lesbian, gay, bisexual, and transgender people in Ireland: a narrative account. AB - The views and opinions of people who use mental health services are being increasingly acknowledged in relation to rights-based, socially-inclusive, and recovery-oriented care. However, little is known of the experiences of lesbian, gay, bisexual, and transgender (LGBT) people in this respect. The aim of the present study was to explore the experiences and needs of LGBT people in relation to mental health services. The study was an exploratory design utilizing mixed methods. Both quantitative and qualitative data were collected using a survey instrument (n = 125) and in-depth semistructured interviews (n = 20) with a sample of people who had completed the survey. This paper will report on the findings from the interview data. The data were thematically analysed, and the main themes that emerged included accessing services, treatment choices, mental health service experiences, and other supports. The findings inform the discussion, and recommendations are made in terms of future mental health practice, education, and research. PMID- 25039499 TI - Derivation and evaluation of thresholds for core and tissue at risk of infarction using CT perfusion. AB - BACKGROUND AND PURPOSE: Computed tomography perfusion provides information on tissue viability according to proposed thresholds. We evaluated thresholds for ischemic core and tissue at risk and subsequently tested their accuracy in independent datasets. MATERIALS AND METHODS: Tissue at risk was evaluated in patients with persistent arterial occlusions, and ischemic core thresholds in patients with recanalization and major clinical improvement. Scans were randomly allocated to derivation or validation groups for tissue at risk and core analysis. Optimum thresholds using mean transit time (MTT), cerebral blood flow (CBF), cerebral blood volume, and delay time (DT) were assessed. RESULTS: Absolute MTT, relative MTT and DT were best derived predictors of tissue at risk with thresholds of >= 7 seconds, >= 125%, and >= 2 seconds respectively. DT >= 2 seconds was the best predictor in the validation dataset (95% agreement levels = 44 to +30 mL, Bias = -6.9). Absolute and relative MTT were the best derived predictors of infarct volume in the core group (8 seconds and 125% respectively) but relative CBF of <= 45% performed best in the core validation dataset. CONCLUSIONS: Time-based perfusion thresholds perform well as predictors of tissue at risk of infarction with DT the best predictor. Relative CBF was the best predictor of ischemic core. Evaluation in larger populations is needed to confirm the performance of tissue viability thresholds. PMID- 25039500 TI - Normal long-term health-related quality of life can be achieved in patients with functional pituitary adenomas having surgery as primary treatment. AB - BACKGROUND: Previous studies report impaired health-related quality of life (HRQoL) in patients with functional pituitary adenomas (FPA). We assessed HRQoL in FPA patients having undergone surgery at our University Central Hospital between 2000 and 2010, with combined adjuvant treatment given to achieve strict hormonal control. DESIGN: A cross-sectional study including a large control population. PATIENTS AND METHODS: HRQoL was assessed by the 15D in 100 FPA patients (acromegaly n = 47, Cushing's disease n = 21, prolactinoma n = 26, TSH adenoma n = 2, gonadotropinoma n = 4), operated on a mean 7.4 (range 2.1-13.0) years earlier. An age- and gender-standardized sample of the general population (n = 4924) served as controls. HRQoL determinants were assessed by independent samples t-test and multiple regression analysis. RESULTS: Hormonal remission rate was 90.9% and 43.9% of the patients received replacement therapy. The mean 15D scores were similar in patients and controls (0.917 vs 0.922, P = 0.568). On single dimensions, patients were worse off regarding speech and sexual activity (both P < 0.05) and better off regarding discomfort and symptoms (P < 0.05). Age (P = 0.001), co-morbidities (P = 0.009), Cushing's disease (P = 0.034), and thyroxine dose (P = 0.002) predicted impaired HRQoL, but not hypopituitarism, hydrocortisone replacement, radiotherapy, or time after surgery. CONCLUSIONS: It is possible to achieve near-normal HRQoL in surgically treated FPA patients given adjuvant treatment to achieve strict hormonal remission. However, in addition to age and co-morbidities, Cushing's disease and need for thyroxine replacement therapy predict impaired HRQoL. PMID- 25039501 TI - Reciprocal Associations Among Maternal and Child Characteristics of At-Risk Families: A Longitudinal Actor-Partner Interdependence Model. AB - Researchers have found linear associations among maternal and child characteristics. However, family systems theorists suggest that relationships are more complex and family members are interdependent. We used actor-partner interdependence modeling to unravel associations among maternal and child characteristics to predict outcomes in adolescence. We used data from 361 mother child dyads from the Longitudinal Studies of Child Abuse and Neglect and found both actor and partner effects. Maternal depression and history of victimization were associated with children's later reports of lower mother-adolescent relationship quality. Children's perceptions of relationship quality were also associated with mothers' later depressive symptoms and perceptions of relationship quality. Overall, results highlighted interdependence among mothers and their children over time. We discuss implications for marriage and family therapists. PMID- 25039502 TI - Development of a two-step, non-probed multiplex real-time PCR for surveilling Vibrio anguillarum in seawater. AB - Vibrio anguillarum is an aggressive and halophilic bacterial pathogen most commonly originating from seawater. Vibrio anguillarum presence in fisheries and aquaculture facilities causes significant morbidity and mortality among aquaculture species primarily from haemorrhaging of the body and skin of the infected fish that eventually leads to death, collectively recognized as the disease vibriosis. This study served to develop a non-probe, multiplex real-time PCR assay to rapidly detect V. anguillarum presence in seawater. Specific primers targeting genes vah1, empA and rpoN of V. anguillarum were selected for multiplex reaction among 11 different primer sets and the extension step was eliminated. Primer concentration, denaturation time as well as annealing time and temperature of DNA amplification were optimized, thus reducing reaction duration. The two step, non-probed multiplex real-time PCR set forth by this study detects as little as 3 CFU mL(-1) of V. anguillarum presence in sea water, without enrichment cultivation, in 70 min with molecular precision and includes melting curve confirmation. PMID- 25039503 TI - Explaining pragmatic performance in traumatic brain injury: a process perspective on communicative errors. AB - BACKGROUND: The purpose of this study is to investigate the pragmatic abilities of individuals with traumatic brain injury (TBI). Several studies in the literature have previously reported communicative deficits in individuals with TBI, however such research has focused principally on communicative deficits in general, without providing an analysis of the errors committed in understanding and expressing communicative acts. Within the theoretical framework of Cognitive Pragmatics theory and Cooperative principle we focused on intermediate communicative errors that occur in both the comprehension and the production of various pragmatic phenomena, expressed through both linguistic and extralinguistic communicative modalities. AIMS: To investigate the pragmatic abilities of individuals with TBI. METHODS & PROCEDURES: A group of 30 individuals with TBI and a matched control group took part in the experiment. They were presented with a series of videotaped vignettes depicting everyday communicative exchanges, and were tested on the comprehension and production of various kinds of communicative acts (standard communicative act, deceit and irony). The participants' answers were evaluated as correct or incorrect. Incorrect answers were then further evaluated with regard to the presence of different intermediate errors. OUTCOMES & RESULTS: Individuals with TBI performed worse than control participants on all the tasks investigated when considering correct versus incorrect answers. Furthermore, a series of logistic regression analyses showed that group membership (TBI versus controls) significantly predicted the occurrence of intermediate errors. This result holds in both the comprehension and production tasks, and in both linguistic and extralinguistic modalities. CONCLUSIONS & IMPLICATIONS: Participants with TBI tend to have difficulty in managing different types of communicative acts, and they make more intermediate errors than the control participants. Intermediate errors concern the comprehension and production of the expression act, the comprehension of the actors' meaning, as well as the respect of the Cooperative principle. PMID- 25039504 TI - The influence of incubation time, sample preparation and exposure to oxygen on the quality of the MALDI-TOF MS spectrum of anaerobic bacteria. AB - With matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), bacteria can be identified quickly and reliably. This accounts especially for anaerobic bacteria. Because growth rate and oxygen sensitivity differ among anaerobic bacteria, we aimed to study the influence of incubation time, exposure to oxygen and sample preparation on the quality of the spectrum using the Bruker system. Also, reproducibility and inter-examiner variability were determined. Twenty-six anaerobic species, representing 17 genera, were selected based on gram-stain characteristics, growth rate and colony morphology. Inter-examiner variation showed that experience in the preparation of the targets can be a significant variable. The influence of incubation time was determined between 24 and 96 h of incubation. Reliable species identification was obtained after 48 h of incubation for gram-negative anaerobes and after 72 h for gram positive anaerobes. Exposure of the cultures to oxygen did not influence the results of the MALDI-TOF MS identifications of all tested gram-positive species. Fusobacterium necrophorum and Prevotella intermedia could not be identified after >24 h and 48 h of exposure to oxygen, respectively. Other tested gram-negative bacteria could be identified after 48 h of exposure to oxygen. Most of the tested species could be identified using the direct spotting method. Bifidobacterium longum and Finegoldia magna needed on-target extraction with 70% formic acid in order to obtain reliable species identification and Peptoniphilus ivorii a full extraction. Spectrum quality was influenced by the amount of bacteria spotted on the target, the homogeneity of the smear and the experience of the examiner. PMID- 25039505 TI - Effect on motor skills of elderly adults of a 12-week randomized controlled trial of vigorous exercise. PMID- 25039506 TI - The unique needs of older adults readmitted to the hospital. PMID- 25039507 TI - Extremely short-duration high-intensity training substantially improves the physical function and self-reported health status of elderly adults. PMID- 25039508 TI - Electronic communication capabilities of residential care facilities at times of transition. PMID- 25039509 TI - Effects of day service use on the progression of Alzheimer's disease. PMID- 25039510 TI - Association between leukocyte telomere length and vascular dementia and cancer mortality in an elderly population. PMID- 25039511 TI - Infrequent older adult-primary care provider discussion and documentation of dietary supplements. PMID- 25039512 TI - Recruitment of older drivers from primary care clinics for on-road fitness-to drive testing: results of a pilot study. PMID- 25039513 TI - Training of specialized geriatric physicians to meet the needs of an aging population--a unique care of the elderly physician program in Canada. PMID- 25039514 TI - Can we exclude dementia in older adults with suspected cognitive impairment who attend the clinical encounter alone? PMID- 25039515 TI - Cognitive impairment is associated with high coated-platelet levels in individuals with carotid atherosclerosis. PMID- 25039516 TI - Mini Nutritional Assessment and functional status as predictors of development of pressure ulcers in acute setting of care. PMID- 25039517 TI - Preoperative comprehensive geriatric assessment: outcomes in elective lower limb joint replacement surgery for complex older adults. PMID- 25039518 TI - Vitamin D status in elderly inpatients in a tertiary hospital in Singapore. PMID- 25039519 TI - Inflammatory markers in frail elderly Egyptian adults and the difference between the sexes. PMID- 25039520 TI - Assessment of the health status of centenarians in the south of China: a cross sectional study. PMID- 25039521 TI - Endocrine and metabolic abnormalities in a girl with childhood Werner syndrome: case report. PMID- 25039522 TI - Once-weekly tolvaptan for chronic symptomatic hyponatremia due to syndrome of inappropriate secretion of anti-diuretic hormone. PMID- 25039523 TI - Inherited cancer susceptibility in an elderly adult. PMID- 25039524 TI - A hidden cause of recurrent asthmatic attacks. PMID- 25039525 TI - Urolithiasis as an unusual cause of failure to thrive. PMID- 25039526 TI - Pseudodelusions in individuals with dementia. PMID- 25039527 TI - Misuse of Beers criteria. PMID- 25039528 TI - Pain treatment--bad news and good. PMID- 25039529 TI - Methodology of studying incident delirium after hip fracture. PMID- 25039530 TI - Response to Paul Regal. PMID- 25039532 TI - Eschewing certainties: the creation of family therapists in the 21st century. AB - I reflect here on Family Therapy's origins, our present dilemmas, and future possibilities. Using the lens of training new Family Therapists for current public sector domains, I examine our field's strengths, vulnerabilities, and contradictions. I critique the current vogue of model certainty and branding. Our responsibilities to trainees, young practitioners, and the families we serve are highlighted. PMID- 25039531 TI - The burden and management of FXIII deficiency. AB - Factor XIII congenital deficiency (FXIII CD) is a serious bleeding disorder resulting in a lifelong bleeding tendency, defective wound healing and recurrent miscarriage. The aim of this study was to review available literature on the burden and management of FXIII CD. To this end, Medline, Embase and Cochrane databases were searched. In current literature, FXIII CD is described as one of the most severe forms of a congenital coagulation disorder, primarily due to a high risk of severe bleeding events. The published literature suggests that over 50% of untreated FXIII CD patients experience severe bleeding symptoms. Intracranial haemorrhage (ICH)--a major cause of death and morbidity--is reported to occur in up to one-third of patients. Nonetheless, data on the social and financial burden in patients with FXIII CD are sparse. Identified reports on the effectiveness and safety of recommended treatments support that patients with FXIII CD should receive prophylactic treatment as early as possible in their lives to prevent the occurrence of bleeds, including potentially life-threatening ICHs. In conclusion, limited data on the social and economic consequences related specifically to FXIII CD have been published to date. However, it is widely acknowledged that the high risk of severe bleeds and ICH results in a high level of burden in patients with bleeding disorders. To inform future clinical decision making and reimbursement decisions, further research is required to gain insight in how specifically FXIII CD affects quality of life and to fully understand associated economic consequences. PMID- 25039533 TI - Normal pediatric data for isovolumic acceleration at the lateral tricuspid valve annulus-a heart rate - dependent measure of right ventricular contractility. AB - BACKGROUND: Quantitative assessment of right ventricular (RV) function is important for the management of patients with congenital heart disease. Tissue Doppler (TDI)-derived myocardial acceleration during isovolumic contraction (IVA) is an echocardiographic measure of contractility that is independent of loading conditions. The aim of this study was to establish normative data for IVA at the lateral tricuspid valve annulus (RV IVA). METHODS: This is a retrospective study of 340 children who had normal echocardiograms. We analyzed RV IVA in relation to age, body surface area (BSA), gender, heart rate (HR), tricuspid annular plane systolic excursion (TAPSE), and TDI-derived S' (RV S'). RESULTS: RV IVA showed a positive correlation with HR (r = 0.58, P<0.001) and a negative correlation with age and BSA (r = -0.44, P<0.001, for both). RV IVA ranged from 2.3 m/sec(2) (+/-2 SD: 1-3.7 m/sec(2) ) at a HR of <60 beats per minute (bpm) to 4.9 m/sec(2) (+/-2 SD: 3.5-6.4 m/sec(2) ) at a HR of >160 bpm. When RV IVA was corrected for HR (RV IVAc), it became independent of HR, age, BSA, and gender. The mean RV IVAc was 2.3 m/sec(1.5) (+/-2 SD: 1.1-3.6 m/sec(1.5) ). There was a correlation of normalized RV IVAc with normalized TAPSE and RV S'. CONCLUSION: RV IVA, a marker of RV contractility, shows a strong dependence on HR. HR corrected RV IVA (RV IVAc) is independent of age, BSA, gender, and HR. We suggest measuring RV IVAc routinely in patients at risk for RV dysfunction. PMID- 25039535 TI - Information processing and dynamics in minimally cognitive agents. AB - There has been considerable debate in the literature about the relative merits of information processing versus dynamical approaches to understanding cognitive processes. In this article, we explore the relationship between these two styles of explanation using a model agent evolved to solve a relational categorization task. Specifically, we separately analyze the operation of this agent using the mathematical tools of information theory and dynamical systems theory. Information-theoretic analysis reveals how task-relevant information flows through the system to be combined into a categorization decision. Dynamical analysis reveals the key geometrical and temporal interrelationships underlying the categorization decision. Finally, we propose a framework for directly relating these two different styles of explanation and discuss the possible implications of our analysis for some of the ongoing debates in cognitive science. PMID- 25039534 TI - Elevated miR-122 serum levels are an independent marker of liver injury in inflammatory diseases. AB - BACKGROUND & AIMS: Serum concentrations of miR-122 were proposed as a marker for various inflammatory diseases, but the mechanisms driving alterations in miR-122 serum levels are unknown. METHODS: We analysed miR-122 serum levels and hepatic miR-122 expression in mice after hepatic ischaemia and reperfusion (I/R) injury. These data were compared with data from mice after caecal pole ligation and puncture (CLP) procedure. To translate these data into the human, we analysed miR 122 serum concentrations in a cohort of 223 patients with critical illness and 57 patients with cirrhosis. RESULTS: We detected strongly elevated levels of miR-122 in mice after hepatic I/R injury. miR-122-concentrations correlated with the degree of liver damage according to AST/ALT and were associated with the presence of hepatic cell death detected by TUNEL staining. miR-122 levels were elevated in the cellular supernatants in an in vitro model of hepatocyte injury, supporting the hypothesis that the passive release of miR-122 represents a surrogate for hepatocyte death in liver injury. Moreover, miR-122 levels were almost normal in patients with cirrhosis without ongoing liver damage, but were elevated when liver injury was present. In contrast to previous assumptions, miR-122 concentrations were independent of the presence of infection/sepsis in mice or human patients. miR-122 levels did not correlate with disease severity or mortality in critically ill patients. In contrast, serum miR-122 levels strictly correlated with the presence of hepatic injury in these patients. CONCLUSION: In mice and humans, miR-122 levels represent an independent and potent marker of ongoing liver injury and hepatic cell death regardless of the underlying disease. PMID- 25039536 TI - Polypharmacy among nonagenarians/centenarians in rural China. AB - BACKGROUND: Little is known about the prevalence and relevant factors of polypharmacy in nonagenarian and centenarians. AIM: The aim of this study is to examine the prevalence and associated factors of polypharmacy in a sample of nonagenarians and centenarians living in a rural area of China. METHODS: The data were from the 'Project of Longevity and Aging in Dujiangyan' study. Medication use and relevant covariates were obtained by face-to-face interviews. Minor polypharmacy was defined as the concomitant use of two to four medications, whereas major polypharmacy referred to the concomitant use of five or more medications. RESULTS: We included 859 participants with mean age of 93.7 +/- 3.3 years. The number of chronic diseases was 1.4 +/- 1.2 per subject, whereas the number of drugs was 0.8 +/- 1.4 per subject. The prevalence of minor polypharmacy and major polypharmacy was 16.5% and 3.7% respectively. Illiteracy (odds ratio (OR) 2.93, 95% confidence interval (CI) 1.52 to 5.66), cognitive impairment (OR 3.15, 95% CI 1.44 to 6.88), hypertension (OR 2.88, 95% CI 1.46 to 5.67), respiratory disease (OR 2.22, 95% CI 1.08 to 4.58), osteoarthritis (OR 1.24, 95% CI 1.01 to 1.51), and cancer (OR 10.70, 95% CI 1.90 to 126.80) were positively associated with minor polypharmacy. Illiteracy (OR 4.24, 95% CI 1.53 to 11.81), hypertension (OR 3.40, 95% CI 1.22 to 9.49) and cancer (OR 3.40, 95% CI 1.14 to 10.12) were also positively associated with major polypharmacy. CONCLUSIONS: Although most subjects suffer from some chronic diseases, minor polypharmacy and major polypharmacy are not common among nonagenarians/centenarians in rural China. PMID- 25039537 TI - Pemphigoid gestationis with prepartum flare. PMID- 25039538 TI - Use of long-distance migration patterns of an endangered species to inform conservation planning for the world's largest marine protected area. AB - Large marine protected areas (MPAs), each hundreds of thousands of square kilometers, have been set up by governments around the world over the last decade as part of efforts to reduce ocean biodiversity declines, yet their efficacy is hotly debated. The Chagos Archipelago MPA (640,000 km(2) ) (Indian Ocean) lies at the heart of this debate. We conducted the first satellite tracking of a migratory species, the green turtle (Chelonia mydas), within the MPA and assessed the species' use of protected versus unprotected areas. We developed an approach to estimate length of residence within the MPA that may have utility across migratory taxa including tuna and sharks. We recorded the longest ever published migration for an adult cheloniid turtle (3979 km). Seven of 8 tracked individuals migrated to distant foraging grounds, often >=1000 km outside the MPA. One turtle traveled to foraging grounds within the MPA. Thus, networks of small MPAs, developed synergistically with larger MPAs, may increase the amount of time migrating species spend within protected areas. The MPA will protect turtles during the breeding season and will protect some turtles on their foraging grounds within the MPA and others during the first part of their long-distance postbreeding oceanic migrations. International cooperation will be needed to develop the network of small MPAs needed to supplement the Chagos Archipelago MPA. PMID- 25039539 TI - Immediate postoperative percutaneous stenting of superior vena cava obstruction following heart transplantation in adult patients with pacemaker leads. AB - Vena cava superior syndrome is a serious complication after heart transplantation, leading to low cardiac output, cerebral edema, and multi-organ dysfunction. We report three adult patients who underwent heart and heart-lung transplantation and required immediate postoperative balloon angioplasty and stent placement by interventional radiology. The observed obstructions were located at sites of intraoperatively removed pacemaker or defibrillator wires. Percutaneous stent placement immediately improved the hemodynamic condition of the patients. Early recognition of the complication and availability of immediate intervention are essential to prevent further deterioration. PMID- 25039540 TI - Activating calcium-sensing receptor gene variants in children: a case study of infant hypocalcaemia and literature review. AB - Autosomal dominant hypocalcaemia (ADH) is caused by activating variants in the calcium-sensing receptor (CASR) gene, but detailed information on the paediatric phenotype is limited. The current paper presents a case of severe ADH and systematically reviews the literature on ADH in children. CONCLUSION: We found that the severity of clinical neurological symptoms was inversely related to serum calcium levels and a high prevalence of renal calcifications and/or basal ganglia calcifications in children with ADH. PMID- 25039541 TI - Cutaneous squamous cell carcinoma in two pediatric lung transplant patients on prolonged voriconazole treatment. AB - Oral voriconazole is commonly used for treatment and prophylaxis of invasive fungal disease post-LTx. Development of cutaneous SCC has been described in adult LTx recipients, although it is extremely rare in children. We describe two Caucasian children who developed cutaneous SCC beyond three yr post-LTx. Both developed severe photosensitivity, actinic keratosis and required curative surgical excision of the cutaneous SCC lesions. Neither patient developed metastatic lesions nor had allograft dysfunction as a result of the SCC or the change in medical treatments. The effect of voriconazole on the development of malignant skin lesions is discussed and a recommendation on dermatologic surveillance, preventive measures against phototoxicity and early treatment of SCC are provided. PMID- 25039542 TI - Medical students' attitudes on and experiences with evidence-based medicine: a qualitative study. AB - RATIONALE, AIMS AND OBJECTIVES: This qualitative study was designed to determine the attitudes towards and experiences of medical students on evidence-based medicine (EBM). METHODS: The study was conducted using the phenomenological method. Medical students' attitudes about and experiences with evidence-based medicine were determined through semi-structured interviews. Forty senior medical students were chosen by purposive sampling from medical sciences students of Tabriz University and Shahid Beheshti University. The context of interviews was analysed using the content analysis method. RESULTS: Medical students' attitudes and experiences were ascertained through four main questions, and their answers were divided in to 12 categories and 31 subcategories. According to the subjects of the study, two basic concepts that they understood about EBM were its being up to date and requiring research skills. To the question what is necessary for EBM, the students' answers were summarized as follows: access to information, teamwork and faculty members who could provide modeling and organizational support. Students reported having used EBM for problem solving, thinking and self confidence. On the other hand, lack of equipment and facilities, human factors and organizational factors were considered the main barriers to EBM use. CONCLUSION: According to the results of this study, providing suitable conditions and appropriate planning to address identified barriers and encouraging students can promote EBM practice. Also, more extensive EBM integration in medical curricula and clinical settings by leading faculty members would prompt medical students to use EBM in their daily practice. PMID- 25039543 TI - Discovery of the first light-dependent protochlorophyllide oxidoreductase in anoxygenic phototrophic bacteria. AB - In all photosynthetic organisms, chlorophylls function as light-absorbing photopigments allowing the efficient harvesting of light energy. Chlorophyll biosynthesis recurs in similar ways in anoxygenic phototrophic proteobacteria as well as oxygenic phototrophic cyanobacteria and plants. Here, the biocatalytic conversion of protochlorophyllide to chlorophyllide is catalysed by evolutionary and structurally distinct protochlorophyllide reductases (PORs) in anoxygenic and oxygenic phototrophs. It is commonly assumed that anoxygenic phototrophs only contain oxygen-sensitive dark-operative PORs (DPORs), which catalyse protochlorophyllide reduction independent of the presence of light. In contrast, oxygenic phototrophs additionally (or exclusively) possess oxygen-insensitive but light-dependent PORs (LPORs). Based on this observation it was suggested that light-dependent protochlorophyllide reduction first emerged as a consequence of increased atmospheric oxygen levels caused by oxygenic photosynthesis in cyanobacteria. Here, we provide experimental evidence for the presence of an LPOR in the anoxygenic phototrophic alpha-proteobacterium Dinoroseobacter shibae DFL12(T). In vitro and in vivo functional assays unequivocally prove light dependent protochlorophyllide reduction by this enzyme and reveal that LPORs are not restricted to cyanobacteria and plants. Sequence-based phylogenetic analyses reconcile our findings with current hypotheses about the evolution of LPORs by suggesting that the light-dependent enzyme of D. shibae DFL12(T) might have been obtained from cyanobacteria by horizontal gene transfer. PMID- 25039544 TI - Comparison of short-term infusion regimens of N-acetylcysteine plus intravenous fluids, sodium bicarbonate plus intravenous fluids, and intravenous fluids alone for prevention of contrast-induced nephropathy in the emergency department. AB - BACKGROUND: There is no evidence regarding the several short-term prophylaxis protocols for contrast-induced nephropathy (CIN) that may be most feasibly convenient in emergency settings. OBJECTIVES: The purpose of this study was to compare the efficacies of short-term CIN prophylaxis protocols of normal saline, N-acetylcysteine (NAC) plus saline, and sodium bicarbonate plus saline in emergency department (ED) patients at moderate or high risk of CIN after receiving intravenous (IV) contrast agent. METHODS: This single-center, randomized, nonblinded clinical trial was conducted in the ED with adult patients requiring contrast-enhanced computed tomography (CT). Patients with moderate to high risk of CIN according to the Mehran risk score, who consented to participate, were eligible. Patients with continuous renal replacement therapy or who reported contrast allergy were excluded. Enrolled patients were randomly assigned to receive 150 mg/kg NAC in 1000 mL of 0.9% sodium chloride (NaCl), 150 mEq of sodium bicarbonate in 1000 mL of 0.9% NaCl, or 1000 mL of IV saline infusion, all given at 350 mL/hr for 3 hours. All of the patients were administered less than 100 mL of nonionic, low-osmolality contrast agent. The primary outcome of CIN was defined as a 25% increase or a greater than 0.5 mg/dL increase in the serum creatinine level 48 to 72 hours later compared with the baseline measurement. RESULTS: A total of 107 patients were randomized to NAC (n = 36), sodium bicarbonate (n = 36), and saline prophylaxis (n = 35). The mean age of the patients was 71 years (95% confidence interval [CI] = 65 to 77 years), and 58 (54.2%) were male. The groups were similar regarding baseline characteristics and nephropathy risks. Of the 16 (14.9%) patients who eventually developed CIN, seven (19.4%) were in the NAC plus saline group, four (11.1%) were in the sodium bicarbonate plus saline group, and five (14.2%) were in the saline group. There were no significant differences between the groups in terms of the prevention of CIN (p = 0.60). CONCLUSIONS: None of the short-term protocols with normal saline, NAC, or sodium bicarbonate was superior in ED patients requiring contrast enhanced CT who had a moderate or high risk of CIN. PMID- 25039545 TI - Emergency physician perspectives on central venous catheterization in the emergency department: a survey-based study. AB - OBJECTIVES: The objective was to assess clinician experience, training, and attitudes toward central venous catheterization (CVC) in adult emergency department (ED) patients in a health system promoting increased utilization of CVC for severely septic ED patients. METHODS: The authors surveyed all emergency physicians (EPs) within a 21-hospital integrated health care delivery system that had recently instituted a modified Rivers protocol for providing early goal directed therapy (EGDT) to patients with severe sepsis or septic shock, including CVC if indicated. This initiative was accompanied by a structured, but optional, systemwide hands-on training for EPs in real-time ultrasound-guided CVC (US CVC). EPs' responses to questions regarding self-reported experience with CVC in the ED are reported. Data included frequency of CVC (by type) and US CVC training opportunities: both during and after residency and informal ("on-the-job training involving actual ED patients under the oversight of someone more experienced than yourself") and formal ("off-the-job training not involving actual ED patients"). The survey also asked respondents to report their comfort levels with different types of CVC as well as their agreement with possible barriers (philosophical, time-related, equipment-related, and complication-related) to CVC in the ED. Multivariable ordinal logistic regression was used to identify provider characteristics and responses associated with higher yearly CVC volumes. RESULTS: The survey response rate among eligible participants was 365 of 465 (78%). Overall, 154 of 365 (42%) respondents reported performing 11 or more CVCs a year, while 46 of 365 (13%) reported doing two or fewer. Concerning CVC techniques, 271 of 358 (76%) of respondents reported being comfortable with the internal jugular approach with US guidance, compared to 200 of 345 (58%) with the subclavian approach without US. Training rates were reported as 1) in residency, formal 167 of 358 (47%) and informal 189 of 364 (52%); and 2) postresidency, formal 236 of 359 (66%) and informal 260 of 365 (71%). The most commonly self-reported barriers to CVC were procedural time (56%) and complication risk (61%). After multivariate adjustment, the following were significantly associated with greater self reported CVC use (p < 0.01): 1) informal bedside CVC training after residency, 2) male sex, 3) disagreement with complication-related barrier questions, and 4) self-reported comfort with placing US-guided internal jugular catheters. CONCLUSIONS: In this cross-sectional survey-based study, EPs reported varying experience with CVC in the ED and reported high comfort with the US CVC technique. Postresidency informal training experience, male sex, negative responses to complication-related barrier questions, and comfort with placing US guided internal jugular catheters were associated with yearly CVC volume. These results suggest that higher rates of CVC in eligible patients might be achieved by informal training programs in US and/or by disseminating existing evidence about the low risk of complications associated with the procedure. PMID- 25039546 TI - Characteristics and thirty-day outcomes of emergency department patients with elevated creatine kinase. AB - OBJECTIVES: Rhabdomyolysis, as defined by an elevation in creatine kinase (CK), may lead to hemodialysis and death in emergency department (ED) patients, but the patient characteristics, associated conditions, and 30-day outcomes of patients with CK values over 1,000 U/L have not been described. METHODS: All consecutive ED patients with serum CK values over 1,000 U/L between January 1, 2006, and December 31, 2008, were retrospectively identified from two urban hospitals. Patient characteristics, ED treatment, and ED discharge diagnoses were determined by medical record review. Provincial databases were linked to identify patients who died or were treated with hemodialysis within 30 days. The primary outcome was the combined occurrence of death or need for hemodialysis within 30 days. Secondary outcomes included the incidence of acute kidney injury (AKI) and the proportion of patients with initial estimated glomerular filtration rates (eGFR) > 60 mL/min/1.73 m(2) who died or required hemodialysis. RESULTS: Four-hundred patients were identified, the median age was 50 years (interquartile range [IQR] = 35 to 69 years), and 77% were male, with 35% of patients discharged home from the ED. The most common ED discharge diagnoses were related to recreational drug use, infections, and traumatic or musculoskeletal complaints. Within 30 days, 32 (8.0%, 95% confidence interval [CI] = 5.3% to 11%) experienced primary outcomes, with 18 (4.5%, 95% CI = 2.55% to 6.5%) requiring hemodialysis and 21 deaths (5.3%, 95% CI = 3.1% to 7.4%). AKI occurred in 151 patients (38%, 95% CI = 33% to 43%). Of the 257 patients (64%) with initial eGFRs > 60 mL/min/1.73 m(2) , none required hemodialysis. CONCLUSIONS: In ED patients with initial CK > 1,000 U/L, the incidence of death or hemodialysis was 8% within 30 days. Patients with initial eGFRs > 60 mL/min/1.73 m(2) appear to be at a low risk of these outcomes from rhabdomyolysis. PMID- 25039547 TI - A comparison of cosmetic outcomes of lacerations on the extremities and trunk using absorbable versus nonabsorbable sutures. AB - OBJECTIVES: The primary objective was to compare the cosmetic outcomes of traumatic trunk and extremity lacerations repaired using absorbable versus nonabsorbable sutures. The secondary objective was to compare complication rates between the two groups. METHODS: This was a randomized controlled trial comparing wounds repaired with Vicryl Rapide and Prolene sutures. Pediatric and adult patients with lacerations were enrolled in the study. At a 10-day follow-up, the wounds were evaluated for infection and dehiscence. After 3 months, patients returned to have the wounds photographed. Two plastic surgeons blinded to the method of closure rated the cosmetic outcome of each wound using a 100-mm visual analog scale (VAS). Using a noninferiority design, a VAS score of 13 mm or greater was considered to be a clinically significant difference. We used a Student's t-test to compare differences between mean VAS scores and odds ratios (ORs) to compare differences in complication rates between the two groups. RESULTS: Of the 115 patients enrolled, 73 completed the study including 35 in the Vicryl Rapide group and 38 in the Prolene group. The mean (+/-SD) age of patients who completed the study was 22.1 (+/-15.5) years, and 39 were male. We found no significant differences in the age, race, sex, length of wound, number of sutures, or layers of repair in the two groups. The observer's mean VAS for the Vicryl Rapide group was 54.1 mm (95% confidence interval [CI] = 44.5 to 67.0 mm) and for the Prolene group was 54.5 mm (95% CI = 45.7 to 66.3 mm). The resulting mean difference was 0.5 mm (95% CI = -12.1 to 17.2 mm; p = 0.9); thus noninferiority was established. Statistical testing showed no differences in the rates of complications between the two groups, but a higher percentage of the Vicryl Rapide wounds developed complications. CONCLUSIONS: The use of absorbable sutures for the repair of simple lacerations on the trunk and extremities should be considered as an alternative to nonabsorbable suture repair. PMID- 25039548 TI - Diagnostic yields, charges, and radiation dose of chest imaging in blunt trauma evaluations. AB - BACKGROUND: Chest radiography (CXR) is the most common imaging in adult blunt trauma patient evaluation. Knowledge of the yields, attendant costs, and radiation doses delivered may guide effective chest imaging utilization. OBJECTIVES: The objectives were to determine the diagnostic yields of blunt trauma chest imaging (CXR and chest computed tomography [CT]), to estimate charges and radiation exposure per injury identified, and to delineate assessment points in blunt trauma evaluation at which decision instruments for selective chest imaging would have the greatest effect. METHODS: From December 2009 to January 2012, we enrolled patients older than 14 years who received CXR during blunt trauma evaluations at nine U.S. Level I trauma centers in this prospective, observational study. Thoracic injury seen on chest imaging and clinical significance of the injury were defined by a trauma expert panel. Yields of imaging were calculated, as well as mean charges and effective radiation dose (ERD) per injury. RESULTS: Of 9,905 enrolled patients, 55.4% had CXR alone, 42.0% had both CXR and CT, and 2.6% had CT alone. The yields for detecting thoracic injury were CXR 8.4% (95% confidence intervals [CIs]) = 7.8% to 8.9%), chest CT 28.8% (95% CI = 27.5% to 30.2%), and chest CT after normal CXR 15.0% (95% CI = 13.9% to 16.2%). The mean charges and ERD (millisievert [mSv]) per injury diagnosis of CXR, chest CT, and chest CT after normal CXR were $3,845 (0.24 mSv), $10,597 (30.9 mSv), and $20,347 (59.3 mSv), respectively. The mean charges and ERD per clinically major thoracic injury diagnosis on chest CT after normal CXR were $203,467 and 593 mSv. CONCLUSIONS: Despite greater diagnostic yield, chest CT entails substantially higher charges and radiation dose per injury diagnosed, especially when performed after a normal CXR. Selective chest imaging decision instruments should identify patients who require no chest imaging and patients who may benefit from chest CT after a normal CXR. PMID- 25039549 TI - Prevalence of nonmedical problems among older adults presenting to the emergency department. AB - OBJECTIVES: Health outcomes among older emergency department (ED) patients may be influenced by physical, economic, and psychological problems not routinely identified during the ED visit. The objective of this study was to characterize such problems among older adults presenting to the ED. METHODS: This was a prevalence study with enrollment during 4-hour periods randomly selected between 9 a.m. and 9 p.m. on random days of the week over a period of 8 weeks at an academic ED in the southeast United States. Participants were noninstitutionalized, cognitively intact adults aged 65 years or older without life-threatening illness or injury. Consenting patients were asked about the frequency of 10 prespecified problems during the past year. RESULTS: Patients (N = 138) were non-Hispanic white (69%) and female (57%) and almost all had primary providers (95%) and health insurance (98%). Forty percent reported their overall health as fair (21%) or poor (19%). Hazardous drinking habits were reported by 10% of patients. The prevalence of problems occurring either "sometimes" or "often" in the past year were pain (60%), difficulty walking (47%), lack of money (32%), isolation and loneliness (14%), lack of transportation (12%), difficulty scheduling a doctor's appointment (4%), difficulty getting prescriptions filled (4%), and lack of dental care (6%). Nine patients (7%) reported experiencing physical or psychological abuse at some point in the past year. Females, minorities, and individuals living in urban areas reported higher rates of most problems. CONCLUSIONS: Nonmedical problems are common among cognitively intact, independent living, non-critically ill older patients presenting to an ED in the southeast United States. PMID- 25039550 TI - Assessment of dyspnea early in acute heart failure: patient characteristics and response differences between likert and visual analog scales. AB - BACKGROUND: Dyspnea is the most common symptom in acute heart failure (AHF), yet how to best measure it has not been well defined. Prior studies demonstrate differences in dyspnea improvement across various measurement scales, yet these studies typically enroll patients well after the emergency department (ED) phase of management. OBJECTIVES: The aim of this study was to determine predictors of early dyspnea improvement for three different, commonly used dyspnea scales (i.e., five-point absolute Likert scale, 10-cm visual analog scale [VAS], or seven-point relative Likert scale). METHODS: This was a post hoc analysis of URGENT Dyspnea, an observational study of 776 patients in 17 countries enrolled within 1 hour of first physician encounter. Inclusion criteria were broad to reflect real-world clinical practice. Prior literature informed the a priori definition of clinically significant dyspnea improvement. Resampling-based multivariable models were created to determine patient characteristics significantly associated with dyspnea improvement. RESULTS: Of the 524 AHF patients, approximately 40% of patients did not report substantial dyspnea improvement within the first 6 hours. Baseline characteristics were similar between those who did or did not improve, although there were differences in history of heart failure, coronary artery disease, and initial systolic blood pressure. For those who did improve, patient characteristics differed across all three scales, with the exception of baseline dyspnea severity for the VAS and five-point Likert scale (c-index ranged from 0.708 to 0.831 for each scale). CONCLUSIONS: Predictors of early dyspnea improvement differ from scale to scale, with the exception of baseline dyspnea. Attempts to use one scale to capture the entirety of the dyspnea symptom may be insufficient. PMID- 25039551 TI - Rapid response team activations within 24 hours of admission from the emergency department: an innovative approach for performance improvement. AB - OBJECTIVES: Performance improvement programs in emergency medicine (EM) have evolved beyond peer reviews of referred cases and now encompass a large set of quality metrics that are measured proactively. However, peer review of cases continues to be an important element of performance improvement, and selection of cases tends to be driven by an ad hoc referral process based on concerns about problems with care in the emergency department (ED). In the past decade, there has been widespread hospital adoption of rapid response teams (RRTs) that respond to patients who decline clinically to reduce adverse outcomes. In an effort to cast a wider net, to take a more systematic approach, and to avoid "blind spots" from individual variability in criteria for referring cases, the institution instituted a new process for selecting cases for ED peer review based on RRT activations within 24 hours of admission from the ED. The hypothesis was that a formal process for review of these activation cases would increase the number of cases for peer review. METHODS: This was a prospective, observational study conducted from July 1, 2012, to June 30, 2013, at an urban, academic medical center with an EM residency program. A new automated monthly report was created, capturing all RRT activations within 24 hours of admission from the ED. All events were reviewed by three physicians from the ED performance improvement committee to examine for systems issues, individual provider issues, or both, that might yield opportunities for improvement. Cases with potential opportunities were reviewed by the full ED performance improvement committee. Cases were classified according to the indication for response team activation using the system outlined by the U.S. Agency for Healthcare Research and Quality. RESULTS: During the study period 61,814 patients were treated in the ED, and 13,067 were admitted to inpatient status. Thirty-two RRT activations within 24 hours of admission from the ED occurred among these admitted patients, representing 0.24% of admissions (95% confidence interval [CI] = 0.16% to 0.33%). Of the 32 cases, only one was also referred independently for ED performance improvement review via the traditional ad hoc process. During the same period of time, 85 cases were referred to the ED performance improvement committee via the traditional ad hoc referral process. Thus, the RRT cases added an additional 31 cases, or 36.5%, to the 85 cases reviewed in ED performance improvement. Of the 32 cases, two were determined by the performance improvement committee to have individual provider factors in their ED care, which contributed to the clinical decline triggering the response teams; none had system factors. Most of the response team activations were for neurologic changes (n = 13) and respiratory status changes (n = 12). In two cases there was long-term morbidity or mortality related to the team activation event; in neither of these cases were ED system or individual provider factors judged to have contributed. CONCLUSIONS: The review of RRT activations within 24 hours of admission from the ED significantly supplemented the typical ad hoc referral system for peer review of cases, highlighting cases that likely would not have received attention within the ED. This novel and unique case review process revealed opportunities for education and performance improvement. This and other systematic approaches to case detection may be useful adjuncts to traditional case referrals for review. PMID- 25039552 TI - "Rewarding and challenging at the same time": emergency medicine residents' experiences caring for patients who are homeless. AB - OBJECTIVES: The objectives were to examine how emergency medicine (EM) residents learn to care for patients in the emergency department (ED) who are homeless and how providing care for patients who are homeless influences residents' education and professional development as emergency physicians. METHODS: We conducted in depth, one-on-one interviews with EM residents from two programs. A random sample of residents stratified by training year was selected from each site. Interviews were digitally recorded and professionally transcribed. A team of researchers with diverse content-relevant expertise reviewed transcripts independently and applied codes to text segments using a grounded theory approach. The team met regularly to reconcile differences in code interpretations. Data collection and analysis occurred iteratively, and interviews continued until theoretical saturation was achieved. RESULTS: Three recurring themes emerged from 23 resident interviews. First, residents learn unique aspects of EM by caring for patients who are homeless. This learning encompasses both specific knowledge and skills (e.g., disease processes infrequently seen in other populations) and professional development as an emergency physician (e.g., the core value of service in EM). Second, residents learn how to care for patients who are homeless through experience and informal teaching rather than through a formal curriculum. Residents noted little formal curricular time dedicated to homelessness and instead learned during clinical shifts through personal experience and by observing more senior physicians. One unique method of learning was through stories of "misses," in which patients who were homeless had bad outcomes. Third, caring for patients who are homeless affects residents emotionally in complex, multifaceted ways. Emotions were dominated by feelings of frustration. This frustration was often related to feelings of futility in truly helping homeless patients, particularly for patients who were frequent visitors to the ED and who had concomitant alcohol dependence. CONCLUSIONS: Caring for ED patients who are homeless is an important part of EM residency training. Our findings suggest the need for increased formal curricular time dedicated to the unique medical and social challenges inherent in treating patients who are homeless, as well as enhanced support and resources to improve the ability of residents to care for this vulnerable population. Future research is needed to determine if such interventions improve EM resident education and, ultimately, result in improved care for ED patients who are homeless. PMID- 25039553 TI - Council of Emergency Medicine Residency Directors' standardized letter of recommendation: the program director's perspective. AB - OBJECTIVES: The standardized letter of evaluation (SLOE) was created in 1997 to provide residency program directors (PDs) with a summative evaluation that incorporates normative grading (i.e., comparisons to peers applying to emergency medicine [EM] training). Although the standard letter of recommendation (SLOR) has become increasingly popular and important in decision-making, it has not been studied in the past 12 years. To assess the SLOR's effectiveness and limitations, the perspective of EM PDs was surveyed in this study. METHODS: After validation of the questionnaire by 10 retired PDs, the survey was sent to the PD of each of the 159 EM residencies that existed at that time. The survey was circulated via the Council of Emergency Medicine Residency Directors' (CORD) listserv from January 24, 2013, to February 13, 2013. Weekly e-mail reminders to all PDs served to increase participation. RESULTS: A total of 150 of 159 PDs (94.3%) completed the questionnaire. Nearly all respondents (149 of 150; 99.3%) agreed that the SLOR is an important evaluative tool and should continue to be used. In the application process, 91 of 150 (60.7%) programs require one or more SLORs, and an additional 55 (36.7%) recommend but do not require a SLOR to be considered for interview. When asked to identify the top three factors in deciding who should be interviewed, the SLOR was ranked first (139 of 150; 92.7%), with EM rotation grades ranked second (73 of 150; 48.7%). The factors that were most often identified as the top three that diminish the value of the SLOR in order were 1) "inflated evaluations" (121 of 146; 82.9%), 2) "inconsistency between comments and grades" (106 of 146; 72.6%), and 3) "inadequate perspective on candidate attributes in the written comments" and "inexperienced authors" (60 of 146; 41.1% each). CONCLUSIONS: The SLOR appears to be the most important tool in the EM PD's armamentarium for determining which candidates should be interviewed for residency training. Although valuable, the SLOR's potential utility is hampered by a number of factors, the most important of which is inflated evaluations. Focused changes in the SLOR template should be mindful that it appears, in general, to be successful in its intended purpose. PMID- 25039554 TI - Delaying the American Board of Emergency Medicine qualifying examination is associated with poorer performance. AB - OBJECTIVES: The initial step in certification by the American Board of Emergency Medicine (ABEM) requires passing a multiple-choice-question qualifying examination. The qualifying examination is typically taken in the first year after residency training. This study was undertaken to determine if a delay in taking the qualifying examination is associated with poorer performance. The authors also examined the relationship between in-training examination scores and qualifying examination scores. METHODS: This was a pooled time-series cross section study. Primary measurements were initial qualifying examination scores, the timing of the qualifying examination, and in-training examination scores. The three groups, based on qualifying examination timing, were immediate, 1-year delay, and >=2-year delay. In-training examination scores were analyzed to determine the relationship between intrinsic ability, examination timing, and qualifying examination scores. For analysis, a generic pooled ordinary least squares dummy variable model with robust standard errors was used. A pre hoc level of significance was determined to be alpha < 0.01. RESULTS: There were 16,353 qualifying examination test administrations between 2000 and 2012. In training examination scores were positively correlated with qualifying examination scores (p < 0.001). The group pass rates were 98.9% immediate, 95.6% 1-year delay, and 86.6% >=2-year delay. After controlling for in-training examination scores, delay taking the qualifying examination of 1 year was associated with a decrease in score of -0.6 (p = 0.003). A delay in taking the qualifying examination >=2 years was associated with a decrease in score of -2.5 points (p < 0.001). CONCLUSIONS: After accounting for innate ability using in training examination scores, delay taking the qualifying examination was associated with poorer performance. This effect was more pronounced if the delay was >=2 years. PMID- 25039555 TI - Programmatic assessment of level 1 milestones in incoming interns. AB - OBJECTIVES: With the Accreditation Council for Graduate Medical Education (ACGME) Next Accreditation System, emergency medicine (EM) residency programs will be required to report residents' progress through the EM milestones. The milestones include five progressively advancing skill levels, with Level 1 defining the skill set of a medical school graduate and Level 5, that of an attending physician. The ACGME stresses that multiple forms of assessment should be used to ensure capture of the multifaceted competencies. The objective of this study was to determine the feasibility and results of programmatic assessment of Level 1 milestones using multisource assessments for incoming EM interns in July. METHODS: The study population was interns starting in 2012 and 2013. Interns' Level 1 milestone assessment was done with four distinct methods: 1) the postgraduate orientation assessment (POA) by the Graduate Medical Education Office for all incoming interns (this multistation examination covers nine of the EM milestones and includes standardized patient cases, task completion, and computer-based stations); 2) direct observation of patient encounters by core faculty using a milestones-based clinical skills competency checklist; 3) the global monthly assessment at the end of the intern orientation month that was updated to reflect the EM milestones; and 4) faculty assessment during procedural labs. These occurred during the July orientation month that included the POA, clinical shifts, didactic sessions, and procedure labs. RESULTS: In the POA, interns were competent in 48% to 93% of the milestones assessed. Overall, competency was 70% to 80%, with low scores noted in aseptic technique (patient care Milestone 13 [PC13]) and written and verbal hand-off (interpersonal communications skills [ICS]2). In overall communication, 70% of interns demonstrated competency. In excess of 80% demonstrated competency in critical values interpretation (PC3), informed consent (PC9), pain assessment (PC11), and geriatric functional assessment (PC3). On direct observation, almost all Level 1 milestones were achieved (93% to 100%); however, only 78% of interns achieved competency in pharmacotherapy (PC5). On global monthly evaluations, all interns met Level 1 milestones. CONCLUSIONS: A multisource assessment of EM milestones is feasible and useful to determine Level 1 milestones achievement for incoming interns. A structured assessment program, used in conjunction with more traditional forms of evaluation such as global monthly evaluations and direct observation, is useful for identifying deficits in new trainees and may be able inform the creation of early intervention programs. PMID- 25039556 TI - "Doctor, we have no saline today": the curious case of the generic injectable drug shortage. PMID- 25039557 TI - Contrast-induced acute kidney injury: time for a step backward. PMID- 25039558 TI - Critical drug shortages: implications for emergency medicine. AB - Prescription drug shortages have become increasingly common and more severe over the past decade. In addition, reported shortages are longer in duration and have had a greater effect on patient care. Some of the causes of current drug shortages are multifactorial, including the consolidation of drug manufacturers, quality problems at production plants that restrict the supply of drugs, and a lack of financial incentives for manufacturers to produce certain products, particularly generic medications. Generic injectable medications are most commonly affected by shortages because the production process is complex and costly for these drugs, and profit margins are often smaller than for branded medications. Many commonly used emergency department (ED) generic injectables have been affected by shortages, including multiple resuscitation and critical care drugs. Several reports have shown that shortages can potentially have major effects on the quality of medical care, including medication errors, treatment delays, adverse outcomes, and increased health care costs. Currently, no published data exist outside of case reports that directly link ED-based drug shortages to overall patient safety events; however, there are several examples in the ED where first-line therapies for life-saving medications have been in short supply, and alternatives have higher rates of adverse events, narrower therapeutic indexes, or both. Aside from increasing notification about shortages, the U.S. Food and Drug Administration has little power to coerce manufacturers to produce medications during a shortage. Therefore, ED providers must learn to mitigate the effects of shortages locally, through active communication with pharmacy staff to identify safe and effective alternatives for commonly used medications when possible. Particularly given the effect on critical care medications, therapeutic alternatives should be clearly communicated to all staff so that providers have easy access to this information during resuscitations. This review focuses on the etiology of drug shortages, their effect on the ED, and potential solutions and mitigation strategies. PMID- 25039559 TI - Protocols for uncontrolled donation after circulatory death: a comprehensive approach to refractory cardiac arrest. PMID- 25039561 TI - Characteristics of backspatter on the firearm and shooting hand--an experimental analysis of close-range gunshots. AB - Contact and close-range gunshot injuries can produce bloodstains on the shooting hand and weapon. In this study, backspatter was analyzed in experimental horizontal pistol shots into blood-filled sponges. The shooting distances were set between 0 and 45 cm. With increasing shooting distance, there was a significant decrease in the degree of backspatter. Microspatter could be detected on the weapon and shooting hand up to a shooting distance of 40 cm. They were predominantly located on thumb and index finger as well as the radial dorsal aspects of the hand. Fine spray of microspatter combined with elongated droplets in the shape of exclamation marks was found at contact and 2-cm distance shots. An angular calculation based on the shape of the bloodstains was possible up to a shooting distance of 2 cm. No bloodstains were detected beyond 45 cm. PMID- 25039562 TI - Delirium recognition by family: European Portuguese validation study of the family confusion assessment method. AB - OBJECTIVES: To present the validation study of the European Portuguese version of the Family Confusion Assessment Method (FAM-CAM) and to assess the level of psychological distress in families and caregivers of elderly hospitalized adults with delirium. DESIGN: Validation study. SETTING: Intermediate care unit of the Intensive Medicine Service of the Sao Joao Hospital Center, Porto, Portugal. PARTICIPANTS: Families and caregivers of elderly hospitalized adults (>=48 hours). Inclusion criteria were sufficient knowledge about the individual to enable reporting on his or her mental and physical abilities and staying at the individual's bedside daily during hospitalization. Families and caregivers younger than 18 and those who did not speak Portuguese were excluded. MEASUREMENTS: A trained researcher translated the FAM-CAM according to International Society For Pharmacoeconomics and Outcomes Research guidelines. All individuals were assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) (reference standard) and the Confusion Assessment Method (CAM). A trained researcher administered the FAM-CAM to families and caregivers. The level of family-perceived distress was evaluated on a numerical rating scale from 0 to 4. RESULTS: The sample included 40 families and caregivers (58% adult children). According to the DSM-IV-TR, 20% of individuals had delirium. The FAM-CAM had moderate sensitivity (75%) and good specificity (91%) when assessed against the DSM-IV-TR and better sensitivity (86%) and specificity (91%) than the CAM. Fifty-seven percent of families and caregivers classified delirium as an extremely distressing experience. CONCLUSION: These preliminary results suggest that FAM-CAM is a sensitive screening tool for family detection of delirium in elderly hospitalized adults. The high level of psychological distress found corroborated previous studies. Future studies with larger samples will be needed for further validation and to allow the analysis of other psychometric properties. PMID- 25039563 TI - The neurophysiological bases of EEG and EEG measurement: a review for the rest of us. AB - A thorough understanding of the EEG signal and its measurement is necessary to produce high quality data and to draw accurate conclusions from those data. However, publications that discuss relevant topics are written for divergent audiences with specific levels of expertise: explanations are either at an abstract level that leaves readers with a fuzzy understanding of the electrophysiology involved, or are at a technical level that requires mastery of the relevant physics to understand. A clear, comprehensive review of the origin and measurement of EEG that bridges these high and low levels of explanation fills a critical gap in the literature and is necessary for promoting better research practices and peer review. The present paper addresses the neurophysiological source of EEG, propagation of the EEG signal, technical aspects of EEG measurement, and implications for interpretation of EEG data. PMID- 25039564 TI - Quercetin protects radiation-induced DNA damage and apoptosis in kidney and bladder tissues of rats. AB - Ionizing radiation (IR) can induce cell damage and cell death through the reactive oxygen species generated by radiolytic hydrolysis. The present study was aimed to determine the possible protective effects of quercetin, a well-known antioxidant agent, against IR-induced bladder and kidney damage in rats. Sprague Dawley rats were exposed to 8-Gy whole-abdominal IR and given either vehicle or quercetin (20 mg/kg, ip). Rats were decapitated at either 36 h or 10 days following IR, where quercetin or vehicle injections were repeated once daily, and kidney and bladder samples were obtained for the determination of myeloperoxidase and caspase-3 activities, an index of tissue neutrophil infiltration and apoptosis, respectively. Radiation-induced inflammation was evaluated through tissue cytokine, TNF-alpha levels. In order to examine oxidative DNA damage, tissue 8-hydroxydeoxyguanosine (8-OHdG) levels were measured. All tissues were also examined microscopically. In the saline-treated irradiation groups, myeloperoxidase and caspase-3 activities, 8-OHdG and TNF-alpha levels were found to be increased in both tissues (p < 0.05). In the quercetin-treated-IR groups, all these oxidant responses were prevented significantly (p < 0.05). The present data demonstrate that quercetin, through its free radical scavenging and antioxidant properties, attenuates irradiation-induced oxidative organ injury, suggesting that quercetin may have a potential benefit in radiotherapy by minimizing the adverse effects and will improve patient care. PMID- 25039565 TI - Obesity and prognosis in muscle-invasive bladder cancer: the continuing controversy. AB - OBJECTIVES: To investigate the association between body mass index and clinicopathological features of bladder cancer, and to assess the prognostic value of body mass index in patients undergoing radical cystectomy for bladder cancer. METHODS: The medical records of 714 patients who underwent radical cystectomy for bladder cancer were reviewed. The association of body mass index at surgery with clinicopathological features was examined, and the prognostic value of body mass index for recurrence-free survival and cancer-specific survival was analyzed using the Kaplan-Meier method and Cox regression models. Additional survival analyses were carried out in a subgroup of 534 patients with N0M0 disease. RESULTS: Of 714 patients, 304 (42.6%), 184 (25.8%) and 226 (31.7%) had a body mass index of <23 (normal), 23-25 (overweight), and >=25 (obese) kg/m(2) , respectively. Patients with high body mass index had a lower pathological T stage, fewer lymph node metastases and a lower frequency of lymphovascular invasion than those with low body mass index (P < 0.05). Multivariable analysis showed that obese status was an independent predictor of recurrence-free survival (obese vs normal: P < 0.001; overweight vs normal: P = 0.008) and cancer-specific survival (obese vs normal: P < 0.001; overweight vs normal: P = 0.019), along with pathological T stage, lymph node metastasis, and lymphovascular invasion. In addition, obesity was significantly associated with recurrence-free survival (P = 0.018) and cancer-specific survival (P = 0.019) in patients with N0M0 status. CONCLUSIONS: The present findings suggest that overweight and obesity are associated with favorable pathological features and prognosis in patients with bladder cancer undergoing radical cystectomy. PMID- 25039566 TI - Marie T. Filbin. PMID- 25039567 TI - Impact of renal insufficiency on patients with hepatocellular carcinoma undergoing radiofrequency ablation. AB - BACKGROUND AND AIM: Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). We aimed to investigate the impact of RI on the long-term survival of HCC patients undergoing radiofrequency ablation (RFA) and to determine the optimal staging strategy for these patients. METHODS: RI was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) . A total of 123 and 344 patients with and without RI undergoing RFA, respectively, were enrolled. A one-to-one propensity score matching analysis with preset caliper width was performed. The prognostic ability of four currently used staging systems was compared by the Akaike information criterion (AIC). RESULTS: HCC patients with RI undergoing RFA were older (P < 0.001) and had significantly different baseline characteristics. Of all patients, RI was significantly associated with a decreased long-term survival (P = 0.03). After matching in the propensity model, the baseline characteristics were similar between patients with (n = 92) and without (n = 92) RI. In the propensity model, RI was not significantly associated with a shortened survival (P = 0.273). In the Cox multivariate analysis, Child-Turcotte-Pugh class B or C was identified as the only independent predictor of poor prognosis. Among patients with RI undergoing RFA, the Taipei Integrated Scoring (TIS) system provided the highest homogeneity and lowest AIC value among the currently used staging systems. CONCLUSIONS: The long-term survival of HCC patients undergoing RFA is not affected by RI. The TIS staging system may provide a better prognostic prediction for HCC patients with RI undergoing RFA. PMID- 25039568 TI - Common pathways of intracranial calcification and the role of the pericyte: insights from neuropathology. PMID- 25039569 TI - Plasticity in sex allocation in the plant Mercurialis annua is greater for hermaphrodites sampled from dimorphic than from monomorphic populations. AB - Plants are notoriously variable in gender, ranging in sex allocation from purely male through hermaphrodite to purely female. This variation can have both a genetic and an adaptive plastic component. In gynodioecious species, where females co-occur with hermaphrodites, hermaphrodites tend to shift their allocation towards greater maleness when growing under low-resource conditions, either as a result of hermaphrodites shifting away from an expensive female function, or because of enhanced siring advantages in the presence of females. Similarly, in the androdioecious plant Mercurialis annua, where hermaphrodites co exist with males, hermaphrodites also tend to enhance their relative male allocation under low-resource conditions. Here, we ask whether this response differs between hermaphrodites that have been evolving in the presence of males, in a situation analogous to that supposed for gynodioecious populations, vs. those that have been evolving in their absence. We grew hermaphrodites of M. annua from populations in which males were either present or absent under different levels of nutrient availability and compared their reaction norms. We found that, overall, hermaphrodites from populations with males tended to be more female than those from populations lacking males. Importantly, hermaphrodites' investment in pollen and seed production was more plastic when they came from populations with males than without them, reducing their pollen production at low resource availability and increasing their seed production at high resource availability. These results are consistent with the hypothesis that plasticity in sex allocation is enhanced in hermaphrodites that have likely been exposed to variation in mating opportunities due to fluctuations in the frequency of co occurring males. PMID- 25039570 TI - 'What's up, (R)DoC?'--can identifying core dimensions of early functioning help us understand, and then reduce, developmental risk for mental disorders? AB - In the U.S. the National Institute of Mental Health (NIMH), the main funder of mental health research in the world, has recently changed its funding model to promote a radically new perspective for mental health science. This bold, and for some controversial, initiative, termed the Research Diagnostic Criteria (or RDoC for short), intends to shift the focus of research, and eventually clinical practice, away from existing diagnostic categories, as recently updated in the DSM-5, towards 'new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures.' This reorientation from discrete categorical disorder manifestations to underlying cross-cutting dimensions of individual functioning has generated considerable debate across the community of mental health researchers and clinicians (with strong views voiced both pro and con). Given its pivotal role in defining the research agenda globally, there is little doubt that this US science funding initiative will also have ramifications for researchers and clinicians worldwide. In this Editorial we focus specifically on the translational potential of the dimensional RDoC approach, properly extended to developmental models of early risk, in terms of its value as a potential driver of early intervention/prevention models; in the current issue of the JCPP this is exemplified by a number of papers thata address the mapping of underlying dimensions of core functioning to disorder risk, providing evidence for their potential predictive power as early markers of later disorder processes. PMID- 25039571 TI - The strength of multivariate twin studies: testing for shared and distinctive aetiology among different sets of behavioural traits--reflections on Lewis et al. (2014). AB - This contribution discusses the article by Lewis et al. on the relationship between variation in normal personality and adolescent behavioural problems and puts the study into the perspective of the value of twin studies of multivariate behavioural traits, which enable the analyses of genetic pleiotropy and causality. PMID- 25039572 TI - Sensory subtypes in children with autism spectrum disorder: latent profile transition analysis using a national survey of sensory features. AB - BACKGROUND: Sensory features are highly prevalent and heterogeneous among children with ASD. There is a need to identify homogenous groups of children with ASD based on sensory features (i.e., sensory subtypes) to inform research and treatment. METHODS: Sensory subtypes and their stability over 1 year were identified through latent profile transition analysis (LPTA) among a national sample of children with ASD. Data were collected from caregivers of children with ASD ages 2-12 years at two time points (Time 1 N = 1294; Time 2 N = 884). RESULTS: Four sensory subtypes (Mild; Sensitive-Distressed; Attenuated Preoccupied; Extreme-Mixed) were identified, which were supported by fit indices from the LPTA as well as current theoretical models that inform clinical practice. The Mild and Extreme-Mixed subtypes reflected quantitatively different sensory profiles, while the Sensitive-Distressed and Attenuated-Preoccupied subtypes reflected qualitatively different profiles. Further, subtypes reflected differential child (i.e., gender, developmental age, chronological age, autism severity) and family (i.e., income, mother's education) characteristics. Ninety one percent of participants remained stable in their subtypes over 1 year. CONCLUSIONS: Characterizing the nature of homogenous sensory subtypes may facilitate assessment and intervention, as well as potentially inform biological mechanisms. PMID- 25039573 TI - Is C-reactive protein useful in prognostication for colorectal cancer? A systematic review. AB - AIM: With the advent of several different therapeutic strategies to manage the different stages of colorectal cancer, it would be beneficial to allow substratification of patients into groups who are most likely to benefit from costly interventions. The purpose of this review is to analyse the evidence from several retrospective studies examining the prognostic significance of C-reactive protein (CRP). METHOD: A literature search was performed using PubMed, Embase, Cochrane Library, CINAHL and Google Scholar databases to identify studies that analysed CRP and its prognostic significance in all stages of operable colorectal cancer. The primary end-points of interest were overall survival and disease-free survival. RESULTS: In all, 205 studies were identified by the search. Twelve involving 1705 patients fulfilled the inclusion criteria and were included. Three of the included studies including 305 patients considered Stage IV colorectal cancer and the impact of CRP on survival. Overall survival and disease-free survival were shorter in the presence of an elevated preoperative CRP in local and advanced colorectal cancer. CONCLUSION: CRP may be useful for prognosis in patients with primary and metastatic colorectal cancer, but currently there is insufficient evidence to justify its routine use. Further well-designed prospective studies are needed to validate its role in substratification of patients for consideration of (neo)adjuvant therapies. PMID- 25039574 TI - Metered-dose inhaler ipratropium bromide in moderate acute asthma in children: A single-blinded randomised controlled trial. AB - AIM: To determine if the addition of ipratropium bromide (IB) by metered-dose inhaler in moderate acute asthma in children affects hospital admission rates when compared with inhaled salbutamol and oral prednisolone alone. METHODS: A prospective, single-blinded, randomised, controlled, equivalence trial in a tertiary paediatric emergency department. Patients aged 2-15 years with acute, moderate asthma were randomised to two groups, one receiving salbutamol, prednisolone and IB, the other receiving only salbutamol and prednisolone. The managing doctor was blinded to treatment. Admission rates were compared, and less than 15% difference was accepted as statistically equivalent. RESULTS: Recruitment ran from June 2007 until January 2011. Three hundred forty-seven subjects were analysed. The admission rate in the IB group was 70.1% (122/174) compared with 64.2% (111/173) in the non-IB group. The absolute difference of +5.9% (95% confidence interval -4.0% to 15.8%) is not statistically equivalent but does not show a statistically significant decrease in admission rates when IB was given. Adverse effects were more prevalent in the IB group, at 13.2% (23/174), compared with 4.6% (8/173) in the non-IB group, a relative risk of 2.86 (95% confidence interval 1.31-6.21). CONCLUSION: In children with acute asthma of moderate severity who are treated with adequate doses of salbutamol and prednisolone, the addition of IB is not significantly associated with a reduction in admission rates. There is a significantly higher rate of adverse effects if IB is given. IB should be reserved for children with severe asthma exacerbations. PMID- 25039575 TI - Systems approach identifies TGA1 and TGA4 transcription factors as important regulatory components of the nitrate response of Arabidopsis thaliana roots. AB - Nitrate acts as a potent signal to control global gene expression in Arabidopsis. Using an integrative bioinformatics approach we identified TGA1 and TGA4 as putative regulatory factors that mediate nitrate responses in Arabidopsis roots. We showed that both TGA1 and TGA4 mRNAs accumulate strongly after nitrate treatments in roots. Global gene expression analysis revealed 97% of the genes with altered expression in tga1 tga4 double mutant plants respond to nitrate treatments, indicating that these transcription factors have a specific role in nitrate responses in Arabidopsis root organs. We found TGA1 and TGA4 regulate the expression of nitrate transporter genes NRT2.1 and NRT2.2. Specific binding of TGA1 to its cognate DNA sequence on NRT2.1 and NRT2.2 promoters was confirmed by chromatin immunoprecipitation assays. The tga1 tga4 double mutant plants exhibit nitrate-dependent lateral and primary root phenotypes. Lateral root initiation is affected in both tga1 tga4 and nrt1.2 nrt2.2 double mutants, suggesting TGA1 and TGA4 regulate lateral root development at least partly via NRT2.1 and NRT2.2. Additional root phenotypes of tga1 tga4 double mutants indicate that these transcription factors play an important role in root developmental responses to nitrate. These results identify TGA1 and TGA4 as important regulatory factors of the nitrate response in Arabidopsis roots. PMID- 25039576 TI - Effect of clinical nursing pathway for endoscopic thyroidectomy in Chinese patients: A meta-analysis. AB - The aim of this study was to assess the effect of the use of a clinical nursing pathway for patients undergoing endoscopic thyroidectomy by conducting a meta analysis. Electronic databases were searched for relevant controlled trials published prior to August 2013. Only papers that compared the use of a clinical nursing pathway to usual care for patients undergoing endoscopic thyroidectomy were selected. The outcome measures were mean difference and 95% confidence interval for length of hospital stay and hospital charges and risk ratio for patient satisfaction. Six controlled trials were identified. The use of a clinical nursing pathway reduced the length of hospital stay and hospital charges. Furthermore, it improved patient satisfaction. This meta-analysis indicates that application of a clinical nursing pathway appears to reduce length of hospital stay and hospital charges and improve patient satisfaction for patients undergoing endoscopic thyroidectomy. PMID- 25039577 TI - Assessment of the efficacy of the utilisation of conventional and electric toothbrushes by the elderly. AB - Objective: To evaluate the efficacy of electric and conventional toothbrushes for a group of elderly individuals. Background: Although the electric toothbrush has been recommended for elderly individuals, there had previously never been a study regarding its efficacy. Material and methods: Sixty independent elders of both genders with different oral conditions from the Center Adult Day Vitoria, Espirito Santo, Brazil, were randomly divided into two groups of 30 individuals. One group received the Oral B CrossAction Power electric toothbrush, whereas the other received a conventional Bitufo Class 32 soft toothbrush to perform oral hygiene. The bacterial plaque index (O'Leary Plaque Index) and DMFT index were assessed as a measure of oral hygiene and oral health. The data were analysed using the Shapiro-Wilk, Mann-Whitney and Wilcoxon tests. Results: The results of the efficacy of the Oral B Cross Action Power electric toothbrush demonstrated that on the 7th and 15th days, the bacterial plaque indexes were 24.91 +/- 12.81 and 22.11 +/- 14.46, respectively, which corresponds to a 50.24% removal of bacterial plaque on the 7th and 55.83% on the 15th days. Although the electric toothbrush removed more bacterial plaque than the conventional toothbrush, the difference was not statistically significant. Conclusion: Both the conventional and the electric toothbrushes were effective in removing bacterial plaque within the elderly group. More studies are necessary to test the efficacy of electric toothbrushes in relation to conventional toothbrushes for elderly patients. PMID- 25039578 TI - Melanocytic naevi with globular and reticular dermoscopic patterns display distinct BRAF V600E expression profiles and histopathological patterns. AB - BACKGROUND: BRAF (v-raf murine sarcoma viral oncogene homologue B) V600E mutations have been detected with high frequency in melanocytic naevi. Few studies have stratified analyses by naevus dermoscopic pattern. OBJECTIVES: To determine the frequency of BRAF V600E expression and histopathological pattern in acquired melanocytic naevi distinguished by a globular vs. reticular dermoscopic pattern. METHODS: We retrospectively identified histologically proven melanocytic naevi with banal reticular or globular dermoscopic patterns and evaluated BRAF V600E expression using immunohistochemistry. RESULTS: BRAF V600E expression was detected in 11 of 12 globular naevi vs. four of 13 reticular naevi (91.7% vs. 30.1%, P = 0.004). A predominantly dermal growth pattern (P < 0.001) and the presence of large junctional nests (P = 0.017) were each associated with a globular dermoscopic pattern. The presence of either a predominantly dermal growth pattern or large junctional nests was found in 13 of 15 naevi positive for BRAF V600E and in two of 10 naevi negative for BRAF V600E (86.7% vs. 20%, P = 0.002). CONCLUSIONS: The frequency of BRAF V600E mutations differs in naevi distinguished by unique dermoscopic structures and microanatomical growth patterns. Globular naevi, which most often histologically correspond to a predominantly dermal growth pattern and/or the presence of large junctional nests, are significantly more likely to express BRAF V600E than reticular naevi. These preliminary results require validation, but may directly inform future studies of naevogenesis and melanoma genesis. PMID- 25039579 TI - Strengths and weaknesses in the implementation of maternal and perinatal death reviews in Tanzania: perceptions, processes and practice. AB - OBJECTIVES: Tanzania institutionalised maternal and perinatal death reviews (MPDR) in 2006, yet there is scarce evidence on the extent and quality of implementation of the system. We reviewed the national policy documentation and explored stakeholders' involvement in, and perspectives of, the role and practices of MPDR in district and regional hospitals, and assessed current capacity for achieving MPDR. METHODS: We reviewed the national MPDR guidelines and conducted a qualitative study using semi-structured interviews. Thirty-two informants in Mara Region were interviewed within health administration and hospitals, and five informants were included at the central level. Interviews were analysed for comparison of statements across health system level, hospital, profession and MPDR experience. RESULTS: The current MPDR system does not function adequately to either perform good quality reviews or fulfil the aspiration to capture every facility-based maternal and perinatal death. Informants at all levels express differing understandings of the purpose of MPDR. Hospital reviews fail to identify appropriate challenges and solutions at the facility level. Staff are committed to the process of maternal death review, with routine documentation and reporting, yet action and response are insufficient. CONCLUSION: The confusion between MPDR and maternal death surveillance and response results in a system geared towards data collection and surveillance, failing to explore challenges and solutions from within the remit of the hospital team. This reduces the accountability of the health workers and undermines opportunities to improve quality of care. We recommend initiatives to strengthen the quality of facility-level reviews in order to establish a culture of continuous quality of care improvement and a mechanism of accountability within facilities. Effective facility reviews are an important peer-learning process that should remain central to quality of care improvement strategies. PMID- 25039580 TI - Videoscope-assisted minimally invasive periodontal surgery (V-MIS). AB - AIM: Small incision surgery has become routine in many areas of medicine but has not been widely accepted in periodontal therapy. A videoscope to assist minimally invasive surgery (MIS) has been developed. The clinical outcomes from MIS performed using this videoscope (V-MIS) are reported. MATERIALS AND METHODS: Patients were evaluated for residual defects following non-surgical therapy consisting of root planing with local anaesthetic. Thirty patients having 110 sites with residual pocket probing depth (PPD) of at least 5 mm, 2 mm loss of clinical attachment level (CAL), and radiographic evidence of bone loss were surgically treated. V-MIS was performed utilizing the videoscope for surgical visualization. RESULTS: At re-evaluation 6 months post surgery, there was a statistically significant improvement (p < .001) in mean PPD and CAL (PPD 3.88 +/ 1.02 mm, CAL 4.04 +/- 1.38 mm) in 1, 2, and 3 wall defects. All PPD at re evaluation were 3 mm or less. There was a mean post-surgical increase in soft tissue height (0.13 +/- 0.61 mm, p = 0.168) with a decrease in recession. CONCLUSIONS: The improvement in PPD and CAL from V-MIS, in the authors' opinion, appears to be favourable when compared to previously reported results of periodontal regenerative surgery. The lack of post-surgical recession following V MIS has not been reported with traditional regenerative surgery. PMID- 25039581 TI - The isotopic biosignatures of photo- vs. thiotrophic bivalves: are they preserved in fossil shells? AB - Symbiont-bearing and non-symbiotic marine bivalves were used as model organisms to establish biosignatures for the detection of distinctive symbioses in ancient bivalves. For this purpose, the isotopic composition of lipids (delta13C) and bulk organic shell matrix (delta13C, delta34S, delta15N) from shells of several thiotrophic, phototrophic, or non-symbiotic bivalves were compared (phototrophic: Fragum fragum, Fragum unedo, Tridacna maxima; thiotrophic: Codakia tigerina, Fimbria fimbriata, Anodontia sp.; non-symbiotic: Tapes dorsatus, Vasticardium vertebratum, Scutarcopagia sp.). ?13C values of bulk organic shell matrices, most likely representing mainly original shell protein/chitin biomass, were depleted in thio- and phototrophic bivalves compared to non-symbiotic bivalves. As the bulk organic shell matrix also showed a major depletion of delta15N (down to -2.2 0/00) for thiotrophic bivalves, combined delta13C and delta15N values are useful to differentiate between thio-, phototrophic, and non-symbiotic lifestyles. However, the use of these isotopic signatures for the study of ancient bivalves is limited by the preservation of the bulk organic shell matrix in fossils. Substantial alteration was clearly shown by detailed microscopic analyses of fossil (late Pleistocene) T. maxima and Trachycardium lacunosum shell, demonstrating a severe loss of quantity and quality of bulk organic shell matrix with time. Likewise, the composition and delta13C-values of lipids from empty shells indicated that a large part of these compounds derived from prokaryotic decomposers. The use of lipids from ancient shells for the reconstruction of the bivalve's life style therefore appears to be restricted. PMID- 25039582 TI - A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. AB - OBJECTIVE: To compare the growth and development of children born to mothers with gestational diabetes mellitus (GDM) requiring pharmacological treatment, and randomised to treatment with metformin or insulin. DESIGN: Follow-up of a randomised controlled trial (RCT) comparing metformin and insulin treatment of GDM. SETTING: Data were gathered during routine visits to child welfare clinics at the ages of 6, 12, and 18 months, including weight and height measurements, and assessment of motor, social, and linguistic development. SAMPLE: The children of mothers with GDM randomised to metformin (n = 47) or insulin (n = 50) treatment during pregnancy. METHODS: Data were collected from the structured questionnaire filled in at the child welfare clinics. MAIN OUTCOME MEASURES: The growth and development of the children until the age of 18 months. RESULTS: Children exposed to metformin were significantly heavier (10.47 versus 9.85 kg, 95% CI 0.04-1.20) at the age of 12 months and taller and heavier (83.9 vs 82.2 cm, 95% CI 0.23-3.03, 12.05 vs 11.32 kg, 95% CI 0.04-1.43) at the age of 18 months. The mean ponderal index (PI) did not differ significantly. The motor, social, or linguistic development evaluated at the age of 18 months did not differ between the groups. CONCLUSIONS: Children prenatally exposed to metformin were heavier at the 12 months measurements and taller and heavier at the 18 months measurements than those exposed to insulin, but their body composition defined by PI did not differ. Over the short term, metformin does not seem to be harmful with regards to early motor, linguistic, or social development. PMID- 25039583 TI - Differences in the thickness of mouthguards fabricated from ethylene vinyl acetate copolymer sheets with differently arranged v-shaped grooves: part 2 - effect of shape on the working model. AB - The aim of this study was to evaluate the change in thickness of a working model mouthguard sheet due to different shape. Mouthguards were fabricated with ethylene vinyl acetate (EVA) sheets (4.0 mm thick) using a vacuum-forming machine. Two shapes of the sheet were compared: normal sheet or v-shaped groove 10-40 mm from the anterior end. Additionally, two shapes of the working model were compared; the basal plane was vertical to the tooth axis of the maxillary central incisor (condition A), and the occlusal plane was parallel to the basal plane (condition B). Sheets were heated until they sagged 15 mm below the clamp. Postmolding thickness was determined for the incisal portion (incisal edge and labial surface) and molar portion (cusp and buccal surface). Differences in the change in thickness due to the shape of the sheets and model were analyzed using two-way anova followed by a Bonferroni's multiple comparison tests. The thickness of the mouthguard sheet with v-shaped grooves was more than that of the normal sheet at all measuring points under condition A and condition B (P < 0.01). The thickness of condition B was less than that of condition A, there the incisal portion in the normal sheet and the incisal edge in the sheet with v-shaped grooves (P < 0.01). The present results suggested that thickness after molding was secured by the use of the sheet with v-shaped grooves. In particular, the model with the undercut on the labial surface may be clinically useful. PMID- 25039584 TI - Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease. AB - BACKGROUND: Adalimumab is an effective treatment for Crohn's disease (CD). Anti adalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre-disposing factors for treatment failure. AIMS: To assess adalimumab and AAA serum levels, and to examine their association and discriminatory ability with clinical response and serum C-reactive protein (CRP). METHODS: We performed a cross-sectional study using trough sera from adalimumab treated CD patients. Demographical data, Montreal classification, treatment regimen and clinical status were recorded. Serum adalimumab, AAA and CRP were measured. Receiver operating characteristic analysis and a multivariate regression model were performed to find drug and antibody thresholds for predicting disease activity at time of serum sampling. RESULTS: One hundred and eighteen trough serum samples were included from 71 patients. High adalimumab trough serum concentration was associated with disease remission (Area Under Curve 0.748, P < 0.001). A cut-off drug level of 5.85 MUg/mL yielded optimal sensitivity, specificity and positive likelihood ratio for remission prediction (68%, 70.6% and 2.3, respectively). AAA were inversely related with adalimumab drug levels (Spearman's r = -0.411, P < 0.001) and when subdivided into categorical values, positively related with disease activity (P < 0.001). High drug levels and stricturing vs. penetrating or inflammatory phenotype, but not AAA levels, independently predicted disease remission in a multivariate logistic regression model. CONCLUSIONS: Adalimumab drug levels were inversely related to disease activity. High levels of anti-adalimumab antibodies were positively associated with disease activity, but this association was mediated mostly by adalimumab drug levels. PMID- 25039585 TI - Effect of enzyme-aided cell wall disintegration on protein extractability from intact and dehulled rapeseed (Brassica rapa L. and Brassica napus L.) press cakes. AB - Cell-wall- and pectin-degrading enzyme preparations were used to enhance extractability of proteins from rapeseed press cake. Rapeseed press cakes from cold pressing of intact Brassica rapa and partially dehulled Brassica napus seeds, containing 36-40% protein and 35% carbohydrates, were treated with pectinolytic (Pectinex Ultra SP-L), xylanolytic (Depol 740L), and cellulolytic (Celluclast 1.5L) enzyme preparations. Pectinex caused effective disintegration of embryonic cell walls through hydrolysis of pectic polysaccharides and glucans and increased protein extraction by up to 1.7-fold in comparison to treatment without enzyme addition. Accordingly, 56% and 74% of the total protein in the intact and dehulled press cakes was extracted. Light microscopy of the press cakes suggested the presence of pectins colocalized with proteins inside the embryo cells. Hydrolysis of these intracellular pectins and deconstruction of embryonic cell walls during Pectinex treatment were concluded to relate with enhanced protein release. PMID- 25039586 TI - Patient recall of health care provider counseling for opioid-acetaminophen prescriptions. AB - OBJECTIVE: The aim of this study was to determine the frequency and nature of physician, nurse, and pharmacist verbal counseling at the time of a new prescription for an opioid-acetaminophen containing medication as recalled by patients. DESIGN: A mixed methods approach with data from cross sectional, structured interviews was used. SETTING: The settings were one academic emergency department in Chicago, IL and one outpatient pharmacy at a public hospital in Atlanta, GA. PATIENTS: One hundred forty-nine patients receiving a new prescription for an opioid-acetaminophen medication were enrolled. METHODS: Interviews assessed patient recall of counseling they received from their physician, nurse, and pharmacist upon receiving the new prescription. Their responses were unitized and assigned to categories. RESULTS: One hundred forty nine patients were enrolled; 61.1% African American and 58.4% female. Seven major categories of responses were noted; frequencies of patient recall for counseling in these categories were reported. Four categories related to the content of the counseling discussion were (1) details of administration (patient recall counseling from: physician/nurse only 44.3%, pharmacist only 5.4%, both providers 12.8%); (2) activities to avoid and side effects (36.2%, 4.7%, 8.7%); (3) medication indication (32.9%, 4%, 4%); and (4) addictive potential (9.3%, 1.3%, 0%). Three categories describe patients' recall of the interaction in broad terms: (5) being referred to print informational material accompanying the prescription (MD/RN only 7.4%, pharmacist only 20.1%, both providers 2.7%); (6) having questions solicited (0%, 11.4%, 0%); (7) having no interaction relating to medication counseling (3.4%, 32.2%, 1.3%). CONCLUSIONS: Patients infrequently recall counseling from providers on topics that are important to prevent harm from opioid-acetaminophen prescriptions. Future patient-centered clinical research should target identifying optimal strategies to convey these critical messages. PMID- 25039587 TI - Effectiveness of hyaluronic acid for treating diabetic foot: a systematic review and meta-analysis. AB - Diabetic foot ulceration is a major complication of diabetes mellitus. Hyaluronic acid (HA) is used in the treatment of diabetic foot. This meta-analysis was designed to evaluate if HA increased the complete healing rate of diabetic foot compared with controls. We searched Medline, Cochrane, EMBASE, Google Scholar (until January 31, 2014) databases for prospective randomized controlled trials that assessed the effectiveness of HA in treating foot ulcers resulting from diabetes. The primary outcome for the study was complete healing rate of the ulcer at 12 weeks. Three hundred twenty-eight patients were identified from four studies that evaluated the rate of healing of diabetic foot that were treated with HA or controls. Among the four studies, odd ratios (OR) ranged from 1.19 to 8.86, with the overall OR being 1.71 (p = 0.047; 95% confidence interval = 1.01 to 2.90). In summary, our meta-analysis strengthens the findings that HA is beneficial in treating diabetic foot by increasing the rate of wound healing. These findings support the use of HA in treating diabetic foot. PMID- 25039588 TI - Genetic mapping of horizontal stripes in Lake Victoria cichlid fishes: benefits and pitfalls of using RAD markers for dense linkage mapping. AB - The genetic dissection of naturally occurring phenotypes sheds light on many fundamental and longstanding questions in speciation and adaptation and is a central research topic in evolutionary biology. Until recently, forward-genetic approaches were virtually impossible to apply to nonmodel organisms, but the development of next-generation sequencing techniques eases this difficulty. Here, we use the ddRAD-seq method to map a colour trait with a known adaptive function in cichlid fishes, well-known textbook examples for rapid rates of speciation and astonishing phenotypic diversification. A suite of phenotypic key innovations is related to speciation and adaptation in cichlids, among which body coloration features prominently. The focal trait of this study, horizontal stripes, evolved in parallel in several cichlid radiations and is associated with piscivorous foraging behaviour. We conducted interspecific crosses between Haplochromis sauvagei and H. nyererei and constructed a linkage map with 867 SNP markers distributed on 22 linkage groups and total size of 1130.63 cM. Lateral stripes are inherited as a Mendelian trait and map to a single genomic interval that harbours a paralog of a gene with known function in stripe patterning. Dorsolateral and mid-lateral stripes were always coinherited and are thus under the same genetic control. Additionally, we directly quantify the genotyping error rates in RAD markers and offer guidelines for identifying and dealing with errors. Uncritical marker selection was found to severely impact linkage map construction. Fortunately, by applying appropriate quality control steps, a genotyping accuracy of >99.9% can be reached, thus allowing for efficient linkage mapping of evolutionarily relevant traits. PMID- 25039589 TI - Spatial resolution of defibrillator electrograms to detect distinct exit sites of scar-related ventricular tachycardia. AB - BACKGROUND: Analysis of implantable cardioverter-defibrillator electrograms (IEGMs) with pacing along the scar edge is often used to approximate distinct exit sites of scar-related ventricular tachycardia (VT). We evaluated the spatial resolution of IEGMs in identifying distinct exit sites of scar-related VT. METHODS AND RESULTS: Seventeen patients with scar-related VT were included. Threshold pacing (500-ms cycle length) was performed at sites spaced 10 mm apart along the scar border, as defined by high-density bipolar voltage mapping. Twelve lead electrocardiogram and near-field and far-field IEGMs were recorded at each pacing site and assessed for morphology. The average scar size was 60 +/- 30 cm(2) and the scar border perimeter measured 28 +/- 9 cm. A median of 18 pacing sites per patient were collected, spaced 14 +/- 11 mm apart. The mean spatial resolution for the near-field, far-field, and combination of both was 82.7 +/- 76 mm, 62.7 +/- 53.6 mm, and 56.7 +/- 50 mm (P for trend < 0.001). In all cases, IEGM analysis failed to identify distinct VT exit sites spaced <2 cm apart. CONCLUSIONS: Analysis of IEGM morphology with pacing around the edge of the scar is unable to distinguish distinct VT exit sites spaced <2 cm apart, with an average spatial resolution of 5 cm. Given the wide range of values observed, detailed pace mapping over a perimeter of 10-15 cm along the scar edge appears crucial to define the boundaries of a linear ablation strategy to target the VT exit site based on IEGM pace match alone. PMID- 25039590 TI - The effect of electrode placement and interphase interval on force production during stimulation of the dorsiflexor muscles. AB - The aims of this study were to investigate whether introducing an interphase interval (IPI) to biphasic pulses during stimulation of the dorsiflexor muscles would affect force production and to determine whether the IPI effect is dependent on electrode position. Twelve healthy volunteers participated in the study. Each subject participated in one session during which electrically induced contraction (EIC) forces of the ankle dorsiflexors were measured with five different IPI settings ranging from 0 to 400 MUs. Forces of EICs were assessed with the electrodes placed either with the proximal electrode positioned over the common peroneal nerve and the second electrode over the dorsiflexor muscles or with both electrodes located over the dorsiflexor muscles. The order of electrode placements and of the different IPI settings was randomized across subjects. The results indicated that the introduction of a 100-MUs-long IPI may enhance force production when one electrode is located over the common peroneal nerve. However, increasing the duration of the IPI beyond 100 MUs did not result in further increase in force production. In contrast, the introduction of an IPI did not increase force production when both electrodes were located over the dorsiflexor muscles. These findings may help to optimize stimulation settings during functional electrical stimulation to prevent foot-drop. PMID- 25039591 TI - Motor nerves of the head and neck that are susceptible to damage during dermatological surgery. AB - As the incidence of non melanoma skin cancer rises, dermatologists will increasingly be called upon to perform excisions in the head and neck region. Damage to the motor nerves of the head and neck represents an important adverse event for patients, and a source of litigation for surgeons. Understanding the anatomy of this region is key to counselling patients about the possibility of motor nerve injury associated with particular skin surgical procedures. We describe the anatomy of the motor nerves of the head and neck that are most vulnerable to injury during dermatological surgery. The consequences of injury are outlined, and the surface anatomy and anatomical landmarks that may be used to identify the relevant danger zones are described. PMID- 25039592 TI - Clinical triage of cutaneous squamous cell carcinoma and basal cell carcinoma to avoid treatment delay: value of an electronic booking system. AB - BACKGROUND: Provisional clinical diagnosis is the first step in planning skin surgery. Different clinical priorities are given to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). Discriminating between SCC and BCC can be difficult. The rate of misdiagnosis of SCC as BCC is reported as 5.7-87.6%, and can cause treatment delay. We have developed a web-based surgery booking system that requires clinical commitment to a putative differential diagnosis category, rather than a single diagnosis, at the time of consultation. This includes a crucial overlap category of 'SCC or SCC/BCC'. AIM: To assess whether our system helped avoid treatment delay to patients with SCC, and to measure the number needed to treat (NNT). METHODS: This was a retrospective analysis from April 2012 to August 2013, comprising all patients undergoing booked excisional surgery in our unit. The clinical triaging category was compared with the histological diagnosis. Sensitivity, specificity, positive predictive value, negative predictive value (NPV), NNT and mean Breslow thickness were calculated. RESULTS: In total, 1455 lesions were excised, identifying 789 (54.2%) invasive malignancies (86 MM, 115 SCC, 583 BCC, 5 other), 100 in situ lesions and 150 dysplastic lesions. The majority (83.2%) of malignancies were designated into the correct malignant category. Misdiagnosis of SCC as BCC was 5.2%. Sensitivity and NPV for SCC were 94.8% and 99.4%, respectively. NNT was 1.26, 4.12 and 3.19 for BCC, SCC and MM respectively, and 1.73 for all malignancies. Mean invasive Breslow thickness was 1.29 mm [0.78 mm including melanoma in situ (MMIS)], and the MM to MMIS was 1.6. CONCLUSION: An overlap triage category of 'SCC or SCC/BCC' helps to prevent delay in the treatment for patients with SCC. PMID- 25039593 TI - Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis. AB - BACKGROUND: Psoriasis is a chronic, recurrent skin disease that affects approximately 2-3% of the world's population, and can significantly impair patients' wellbeing and their physical and mental functioning. AIM: To systematically evaluate the efficacy and safety of ustekinumab versus placebo for psoriasis. METHODS: We performed a systematic review of all the relevant published literature relating to randomized controlled trials (RCTs) of ustekinumab from 1990 to August 2013. Relative ratios (RRs) and 95% confidence intervals (CIs) were calculated, and meta-analysis was conducted with Revman5.2.6 software, while GRADE Profile 3.6 was used to evaluate the quality of the evidence. RESULTS: In total, 9 RCTs involving 11 381 patients were included. The meta-analysis results were as follows. (i) At the end of 12 weeks, the ustekinumab group had a larger number of patients with improvement in Psoriasis Area and Severity Index (PASI) of at least 50% (PASI50), at least 75% (PASI75) and at least 90% (PASI90); a larger number with improvement in Physician's Global Assessment (PGA), and a larger number with improvement in Dermatology Life Quality Index (DLQI) to a score of 0 or 1 (no effect at all on patient's life). (ii) There was no significant difference in efficacy between 45 mg and 90 mg ustekinumab at the end of 12 weeks. (iii) There was no obvious difference between the ustekinumab and placebo groups in the incidence of adverse events over 5 years. There was also no obvious difference between the two doses of ustekinumab after 5 years. CONCLUSION: Our results indicate that ustekinumab is safe for patients with moderate to severe plaque psoriasis over a period of 5 years, and it is effective after 12 weeks. There was no significant superiority in efficacy between the 45 mg and 90 mg doses for short-term therapy. Results of the long term safety evaluation are consistent with short-term reports of ustekinumab safety. More long-term studies and RCTs are needed to validate these results. PMID- 25039594 TI - Subungual sarcoidosis: a rare entity. AB - Sarcoidosis is a multisystem disease, and nail involvement is rare. We report a case of subungual sarcoidosis involving both great toes. This was treated with intradermal steroid injections, with good symptomatic and clinical response. PMID- 25039595 TI - Can early administration of pregabalin reduce the incidence of postherpetic neuralgia? PMID- 25039596 TI - Denture-induced fibroma. PMID- 25039597 TI - Use of skin adhesive in dermatological surgery. PMID- 25039599 TI - Prevalence of and risk factors for actinic cheilitis in Brazilian fishermen and women. AB - OBJECTIVES: This study was conducted to investigate the prevalence of and risk factors for actinic cheilitis (AC) in Brazilian fishermen and women. METHODS: A cross-sectional study was carried out in a representative sample (n = 210) of fishermen and women. Data related to age, skin color, cumulative and daily exposure to solar radiation, smoking, sun protection measures, and the presence of AC were collected. A Poisson regression model was created to estimate the prevalence ratio of variables. RESULTS: The prevalence of AC was 11.4% (95% confidence interval 7.8-16.4%). The disease was more prevalent in fishermen and women with fair skin and in those aged >50 years, those with cumulative exposure to solar radiation of >30 years, those with daily exposure of >4 hours, and those who did not use sunscreen. CONCLUSIONS: Brazilian fishermen and women constitute a population at risk for lip cancer. Public health programs that encourage the use of sunscreens and a lower daily exposure to solar radiation should be established. PMID- 25039600 TI - Developing predictive rules for coordination geometry from visible circular dichroism of copper(II) and nickel(II) ions in histidine and amide main-chain complexes. AB - Circular dichroism (CD) spectroscopy in the visible region (vis-CD) is a powerful technique to study metal-protein interactions. It can resolve individual d-d electronic transitions as separate bands and is particularly sensitive to the chiral environment of the transition metals. Modern quantum chemical methods enable CD spectra calculations from which, along with direct comparison with the experimental CD data, the conformations and the stereochemistry of the metal protein complexes can be assigned. However, a clear understanding of the observed spectra and the molecular configuration is largely lacking. In this study, we compare the experimental and computed vis-CD spectra of Cu(2+)-loaded model peptides in square-planar complexes. We find that the spectra can readily discriminate the coordination pattern of Cu(2+) bound exclusively to main-chain amides from that involving both main-chain amides and a side-chain (i.e. histidine side-chain). Based on the results, we develop a set of empirical rules that relates the appearance of particular vis-CD spectral features to the conformation of the complex. These rules can be used to gain insight into coordination geometries of other Cu(2+)- or Ni(2+)-protein complexes. PMID- 25039601 TI - Effects of frozen storage on survival of Staphylococcus aureus and enterotoxin production in precooked tuna meat. AB - This study investigated the survival of Staphylococcus aureus in precooked tuna meat for producing canned products during frozen storage (-20 +/- 2 degrees C) as well as its growth and enterotoxin production at 35 to 37 degrees C after the storage. Samples (50 +/- 5 g) of precooked albacore (loin, chunk, and flake) and skipjack (chunk and flake) tuna were inoculated with 5 enterotoxin-producing strains of S. aureus at a level of approximately 3.5 log CFU/g and individually packed in a vacuum bag after 3 h incubation at 35 to 37 degrees C. Vacuum-packed samples were stored in a freezer (-20 +/- 2 degrees C) for 4 wk. The frozen samples were then thawed in 37 degrees C circulating water for 2 h and incubated at 35 to 37 degrees C for 22 h. Populations of S. aureus in all precooked tuna samples decreased slightly (<0.7 log CFU/g) after 4 wk of storage at -20 +/- 2 degrees C, but increased rapidly once the samples were thawed and held at 35 to 37 degrees C. Total S. aureus counts in albacore and skipjack samples increased by greater than 3 log CFU/g after 6 and 8 h of exposure to 35 to 37 degrees C, respectively. All samples became spoiled after 10 h of exposure to 35 to 37 degrees C, while no enterotoxin was detected in any samples. However, enterotoxins were detected in albacore loin and other samples after 12 and 24 h of incubation at 35 to 37 degrees C, respectively. Frozen precooked tuna meat should be used for producing canned tuna within 6 to 8 h of thawing to avoid product spoilage and potential enterotoxin production by S. aureus in contaminated precooked tuna meat. PMID- 25039602 TI - Detecting monoclonal light chains in urine: microLC-ESI-Q-TOF mass spectrometry compared to immunofixation electrophoresis. PMID- 25039603 TI - An ex vivo evaluation of efficacy of refrigerated canine plasma. AB - OBJECTIVES: To determine thawing times of fresh frozen plasma (FFP), and to evaluate the activity of hemostatic proteins (coagulation factors V, VII, VIII, IX, X, and fibrinogen), clotting times (prothrombin time and activated partial thromboplastin time), and sterility of canine plasma stored refrigerated. DESIGN: Prospective laboratory-based study. SETTING: Veterinary teaching hospital blood bank. INTERVENTIONS: Phase 1: Six units of canine FFP were retrieved from the blood bank and thawed individually in a warm water bath. Time for thaw was recorded in minutes and reported as mean +/- SD. Phase 2: One unit of fresh whole blood was collected from 9 dogs and processed routinely. Resulting plasma was divided into 2 aliquots, 1 stored as refrigerated plasma (RP) and 1 as frozen plasma. Samples from the RP were taken at 0, 1, 5, 7, and 14 days and from the FFP at days 0 and 14 for determination of clotting factor activity (V, VII, VIII, IX, and X and fibrinogen) and clotting times. Coagulation factors and clotting times were analyzed using a mixed effects linear model for ANOVA, comparing changes over time as well as differences between groups. For all comparisons, a P value of <0.05 was considered significant. Batch bacterial aerobic and anaerobic cultures of the RP samples were submitted on days 7 and 14 and from the frozen plasma on day 14. MEASUREMENTS AND MAIN RESULTS: Time to thaw for FFP units was 34.7 +/- 1.38 minutes. Refrigerated storage resulted in significant decreases in the activity of all clotting factors and a subsequent prolongation in clotting times. However, no values were outside of the reference interval. All bacterial cultures yielded no growth. CONCLUSIONS: Refrigerated storage results in only minor loss of coagulation factor activity in canine plasma. The use of RP, therefore, may be a viable option in high-volume veterinary hospitals for rapid correction of coagulopathy in critical care patients. PMID- 25039604 TI - Genetics of Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): current knowledge and future directions. AB - Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are thought to be autoimmune diseases. There have been many attempts to find a human leukocyte antigen (HLA) association with GBS and CIDP with little success. There have been studies of other plausible genes in GBS and CIDP and the role of these genes in GBS and CIDP and the data from these genetic studies is reviewed. Some of the genes that have been studied are immune related and some others have nervous system effects. The studies are limited by small numbers. Some of the genes show association with disease severity rather than disease susceptibility. The need for more detailed molecular studies of the role of HLA molecules and the need for modern genetic approaches to GBS and CIDP are explained. PMID- 25039605 TI - Biomechanical determinants of elite rowing technique and performance. AB - In rowing, the parameters of injury, performance, and technique are all interrelated and in dynamic equilibrium. Whilst rowing requires extreme physical strength and endurance, a high level of skill and technique is essential to enable an effective transfer of power through the rowing sequence. This study aimed to determine discrete aspects of rowing technique, which strongly influence foot force production and asymmetries at the foot-stretchers, as these are biomechanical parameters often associated with performance and injury risk. Twenty elite female rowers performed an incremental rowing test on an instrumented rowing ergometer, which measured force at the handle and foot stretchers, while three-dimensional kinematic recordings of the ankle, knee, hip, and lumbar-pelvic joints were made. Multiple regression analyses identified hip kinematics as a key predictor of foot force output (R(2) = 0.48), whereas knee and lumbar-pelvic kinematics were the main determinants in optimizing the horizontal foot force component (R(2) = .41). Bilateral asymmetries of the foot stretchers were also seen to significantly influence lumbar-pelvic kinematics (R(2) = 0.43) and pelvic twisting (R(2) = 0.32) during the rowing stroke. These results provide biomechanical evidence toward aspects of technique that can be modified to optimize force output and performance, which can be of direct benefit to coaches and athletes. PMID- 25039606 TI - Functional characterization of sex pheromone receptors in the purple stem borer, Sesamia inferens (Walker). AB - The sex pheromone communication system in moths is highly species-specific and extremely sensitive, and pheromone receptors (PRs) are thought to be the most important factors in males. In the present study, three full-length cDNAs encoding PRs were characterized from Sesamia inferens antennae. These three PRs were all male-specific in expression, but their relative expression levels were very different; SinfOR29 was 17- to 23-fold higher than the other two PRs. Phylogenetic and motif pattern analyses showed that these three PRs were allocated to different PR subfamilies with different motif patterns. Functional analysis using the heterologous expression system of Xenopus oocytes demonstrated that SinfOR29 specifically and sensitively responded to the major pheromone component, Z11-16:OAc [concentration for 50% of maximal effect (EC50 ) = 3.431 * 10(-7) M], while SinfOR21 responded robustly to a minor pheromone component Z11 16:OH (EC50 = 1.087 * 10(-6) M). SinfOR27, however, displayed no response to any of the three pheromone components, but, interestingly, it was sensitive to a non sex pheromone component Z9,E12-14:OAc (EC50 = 1.522 * 10(-6) M). Our results provide insight into the molecular mechanisms of specificity and sensitivity of the sex pheromone communication system in moths. PMID- 25039607 TI - Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. AB - Low endogenous erythropoietin levels and limited red blood cell transfusion history can predict response to erythropoiesis-stimulating agents in anaemic patients with myelodysplastic syndromes (MDS). The relationship between endogenous thrombopoietin (THPO) levels and platelet response to romiplostim is unknown. Variables including baseline endogenous THPO levels, transfusion needs, and platelet response were analysed in a randomized trial of 250 thrombocytopenic, lower-risk MDS patients (International Prognostic Scoring System low/intermediate-1). A predictive scoring system was developed based on log-likelihood ratios and logistic coefficients. Patients with HI-P (haematological improvement - platelets) responses had lower mean baseline THPO levels (P = 0.0497) and were more likely to have <6 platelet units transfused in the past year (P = 0.0027), as did patients with platelet responses >=50% of weeks on romiplostim (P = 0.001 and P = 0.0037, respectively). A model for predicting response to romiplostim was developed and validated in a separate MDS cohort (N = 72). Patients in low-, intermediate-, and high-response groups had response rates of 17.4%, 29.6%, and 50.7%, respectively, for HI-P, and 17.4%, 33.8%, and 65.2%, respectively, for >=50% response. For thrombocytopenic patients with lower-risk MDS, lower baseline THPO levels (<500 pg/ml) and limited platelet transfusion history predicted a greater likelihood of a subsequent platelet response to romiplostim. PMID- 25039608 TI - Negative density dependence of seed dispersal and seedling recruitment in a neotropical palm. AB - Negative density dependence (NDD) of recruitment is pervasive in tropical tree species. We tested the hypotheses that seed dispersal is NDD, due to intraspecific competition for dispersers, and that this contributes to NDD of recruitment. We compared dispersal in the palm Attalea butyracea across a wide range of population density on Barro Colorado Island in Panama and assessed its consequences for seed distributions. We found that frugivore visitation, seed removal and dispersal distance all declined with population density of A. butyracea, demonstrating NDD of seed dispersal due to competition for dispersers. Furthermore, as population density increased, the distances of seeds from the nearest adult decreased, conspecific seed crowding increased and seedling recruitment success decreased, all patterns expected under poorer dispersal. Unexpectedly, however, our analyses showed that NDD of dispersal did not contribute substantially to these changes in the quality of the seed distribution; patterns with population density were dominated by effects due solely to increasing adult and seed density. PMID- 25039609 TI - Evening dosing of antihypertensive therapy to reduce cardiovascular events: a third type of evidence based on a systematic review and meta-analysis of randomized trials. AB - Nighttime blood pressure strongly predicts cardiovascular events (CVEs). Further, a preliminary trial has shown decreased CVEs from evening vs morning dosing of antihypertensive therapy. Is there additional evidence for evening dosing? The authors systematically classified all hypertension trials as evening dosing trials (EDTs) or usual dosing trials (UDTs). Meta-analyses provided standardized hazard ratios for CVEs for EDTs (HREDT s ) and UDTs (HRUDT s ). HREDT s /HRUDT s gave the relative risk (RR) from evening vs usual dosing. Among 175 trials, 5 EDTs were discovered. The RR for CVEs (95% confidence limits) from evening vs usual dosing was 0.63 (0.43-0.92; P=.016). After adjustment for drug class, the RR was 0.54 (0.34-0.85; P=.008). Unlike other EDTs, the Heart Outcomes Prevention Evaluation (HOPE) study administered its entire antihypertensive dose prior to sleep and gave the greatest risk reduction. This study provides a third type of evidence suggesting a beneficial effect from evening dosing of antihypertensive therapy. Head-to-head, multicenter trials are needed to test this strategy. PMID- 25039611 TI - Linear poly(ethylenimine) cross-linked by methyl-beta-cyclodextrin for gene delivery. AB - Poly(ethylenimine) (PEI) is a cationic polymer extensively exploited for non viral gene delivery; however, its wide application has been impeded by its cytotoxicity. PEI can assume either a branched or linear configuration. Whereas branched PEI (bPEI) is more chemically reactive and can form smaller complexes with DNA under salt-containing conditions, lPEI is generally less toxic and exhibits higher transfection efficiency. In this study, we cross-linked low molecularweight lPEI with methyl beta-cyclodextrin (MbetaCD) to form MbetaCD-lPEI (MLP). The structure of MLP was successfully characterized by NMR, FT-IR, MALDI TOF and elemental analysis. In the standard serum-free transfection environment, MLP could effectively transfect glioblastoma, melanoma and hepatocarcinoma cells. A high transfection efficiency was maintained in the presence of serum. Apart from its high transfection efficiency, MLP was found to have negligible cytotoxicity over a wide range of concentrations and to exhibit a low membrane disruptive capacity ex vivo. MLP warrants further development as a promising gene delivery system for future research. PMID- 25039612 TI - Gene-Based Therapeutic Angiogenesis for Peripheral Arterial Disease. AB - Peripheral artery disease (PAD) is a highly prevalent disease, which still has unmet medical needs. Therapeutic angiogenesis for PAD, achieved by gene therapy, has achieved promising results in preclinical studies and early-phase clinical trials, yet few late-phase clinical trials have been conducted or have not shown efficacy. This article provides an overview of the progression of angiogenesis research in gene therapy field as it applies to PAD. The focus of angiogenic growth factors and clinical trials are introduced as a frontier of therapeutic angiogenesis. The article also includes insights into future directions from bench to bedside. PMID- 25039610 TI - Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma. AB - BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control. PMID- 25039613 TI - Impact of DNA vector topology on non-viral gene therapeutic safety and efficacy. AB - Gene therapy continues to grow as an emerging treatment strategy toward numerous diseases. However, such prospects are hindered by the use of viral vectors prompting significant safety concerns along with limitations concerning repeat administrations, size of delivered gene construct, scale-up, high production costs, contamination during production, and lack of desired tissue selectivity. Non-viral gene delivery demonstrates the potential to address the abovementioned limitations, but itself generally suffers from low efficacy. Continuing efforts have been made to develop innovative delivery systems, synthetic gene carriers, and DNA vectors in a concerted attempt to enhance gene delivery suitable for clinical applications. In this review, we focus on the advances in the design of novel DNA vectors catered to enhance transfection and transgene expression and their influences on the efficacy and safety of existing and emerging delivery systems and synthetic vectors for non viral gene delivery. PMID- 25039614 TI - The human desmin promoter drives robust gene expression for skeletal muscle stem cell-mediated gene therapy. AB - Lentiviral vectors (LVs) represent suitable candidates to mediate gene therapy for muscular dystrophies as they infect dividing and non-dividing cells and integrate their genetic material into the host genome, thereby theoretically mediating longterm expression. We evaluated the ability of LVs where a GFP reporter gene was under the control of five different promoters, to transduce and mediate expression in myogenic and non-myogenic cells in vitro and in skeletal muscle fibres and stem (satellite) cells in vivo. We further analysed lentivirally-transduced satellite cell-derived myoblasts following their transplantation into dystrophic, immunodeficient mouse muscles. The spleen focus forming virus promoter mediated the highest gene expression in all cell types; the CBX3-HNRPA2B1 ubiquitously-acting chromatin opening element (UCOE) promoter was also active in all cells, whereas the human desmin promoter in isolation or fused with UCOE had lower activity in non-muscle cells. Surprisingly, the human skeletal muscle actin promoter was also active in immune cells. The human desmin promoter mediated robust, persistent reporter gene expression in myogenic cells in vitro, and satellite cells and muscle fibres in vivo. The human desmin promoter combined with UCOE did not significantly increase transgene expression. Therefore, our data indicate that the desmin promoter is suitable for the development of therapeutic purposes. PMID- 25039615 TI - Vitamin D and miRNAs in cancer. AB - Vitamin D is a steroid hormone that regulates mineral homeostasis, bone metabolism and many other physiological processes. The active metabolite of vitamin D, 1alpha, 25-dihydroxyvitamin D (1,25D(3)), has broad spectrum antitumor activities and potentiates the effects of a number of chemotherapeutic agents. 1,25D(3) exerts its anti-tumor effects mainly through genomic mechanisms involving the regulation of gene transcription through vitamin D response elements (VDREs). More recently, miRNAs have been shown to be regulated by 1,25D(3). miRNAs are short non-coding RNAs that post-transcriptionally modulate the expression of a wide range of genes. Therefore, they have important regulatory roles in the development and progression of many diseases including cancer. This review focuses on the regulation of miRNA expression by 1,25D(3) in cancer model systems and the contribution of the regulated miRNAs to the anti tumor effect of 1,25D(3). In addition, the impact of miRNAs on 1,25D(3) signaling is discussed. PMID- 25039616 TI - Intracellular delivery of potential therapeutic genes: prospects in cancer gene therapy. AB - Conventional therapies for malignant cancer such as chemotherapy and radiotherapy are associated with poor survival rates owing to the development of cellular resistance to cancer drugs and the lack of targetability, resulting in unwanted adverse effects on healthy cells and necessitating the lowering of therapeutic dose with consequential lower efficacy of the treatment. Gene therapy employing different types of viral and non-viral carriers to transport gene(s) of interest and facilitating production of the desirable therapeutic protein(s) has tremendous prospects in cancer treatments due to the high-level of specificity in therapeutic action of the expressed protein(s) with diminished off-target effects, although cancer cell-specific delivery of transgene(s) still poses some challenges to be addressed. Depending on the potential therapeutic target genes, cancer gene therapy could be categorized into tumor suppressor gene replacement therapy, immune gene therapy and enzyme- or prodrug-based therapy. This review would shed light on the current progress of delivery of potentially therapeutic genes into various cancer cells in vitro and animal models utilizing a variety of viral and non-viral vectors. PMID- 25039617 TI - Dual receptor-specific peptides modified liposomes as VEGF siRNA vector for tumor targeting therapy. AB - Tumor angiogenesis involves multiple signaling pathways that provide potential therapeutic targets to inhibit tumor growth and metastasis. Regarding the significant role of vascular endothelial growth factor (VEGF) in angiogenesis and tumor progression, VEGF sequence-specific small interfering RNA (siRNA) for anti angiogenic tumor therapy are under development. In the present study, dual modified liposomes (At-Lp) was designed by attaching two receptorspecific peptides, Angiopep and tLyP-1, which specifically targeting low-density lipoprotein receptor (LRP) for brain tumor targeting and neuropilin-1 receptor (NRP-1) for tumor penetration, respectively. Gene transfection and silencing, and antitumor effect of the At-Lp loaded with VEGF siRNA were evaluated in vitro and in orthotopic xenograft models of U87 MG tumor. The At-Lp significantly enhanced cellular uptake (2-fold) and down-regulated expression of VEGF in U87 MG glioblastoma cells compared with non-modified and single-modified liposomes. The internalization of the At-Lp into tumor cells was taken via the enhanced permeability and retention effect and receptor-mediated endocytosis, followed by an effective endosomal escape of loaded siRNA into the cytoplasm. The At-Lp showed great superiority in inhibition of tumor growth, anti-angiogenesis, expression of VEGF and apoptosis effect after in vivo application against nude mice bearing U87 MG glioblastoma without activation of system-associated toxicity and the innate immune response. These results demonstrated that the combination of two receptor-specific peptides-mediated liposomes presented a promising platform for effective targeting delivery of siRNA for cancer anti-angiogenic therapy. PMID- 25039618 TI - Editorial Comment to Performance comparisons in major uro-oncological surgeries between the USA and Japan. PMID- 25039619 TI - Clear cell sarcoma: a case report from clinic to cytogenetic studies. PMID- 25039621 TI - Contemporary vocational rehabilitation in Australia. AB - PURPOSE: There is a strong connection between disability and decreased participation rates in the Australian labour market. Australian government policy recognises vocational rehabilitation as a key strategy to increase employment rates of people with disabilities. METHODS: This paper examines current Australian disability employment policies and practices. It also reviews vocational rehabilitation competency research to identify knowledge and skill domains central to quality service provision, and explores the delivery of tertiary level vocational rehabilitation education. RESULTS: Policy changes in Australia over the last decade have been aimed at addressing the unsustainable increase in disability benefits. In this context vocational rehabilitation services continue to be viewed as crucial in assisting people with disabilities to maintain employment and reduce disengagement. Competencies research has consistently identified vocational counselling, personal counselling, professional practice and case management as central to quality vocational rehabilitation service provision. Two competencies identified in recent research, workplace disability case management and workplace interventions and program management, reflect the centrality of vocational rehabilitation to disability management. CONCLUSIONS: Changes in the policy environment to reduce the number of disability pension recipients will inevitably lead to an increased demand for trained vocational rehabilitation personnel. Given the development of strong accreditation standards for vocational rehabilitation education and practice that underpin the provision of tertiary level rehabilitation counselling training programs, professionally qualified rehabilitation counsellors are ideally placed to address the complex employment needs of people with a disability. IMPLICATIONS FOR REHABILITATION: It is important to understand changes that may occur in policy environments in terms of their impact on vocational rehabilitation service delivery for people with disabilities. Variable levels of training in the vocational rehabilitation sector result in people with complex needs not consistently receiving the services they need to access and maintain employment. Practitioners need to focus increasingly on individualized service delivery where the client has significant control over decisions about their rehabilitation program. PMID- 25039620 TI - Identification of novel insulin mimetic drugs by quantitative total internal reflection fluorescence (TIRF) microscopy. AB - BACKGROUND AND PURPOSE: Insulin stimulates the transport of glucose in target tissues by triggering the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Resistance to insulin, the major abnormality in type 2 diabetes, results in a decreased GLUT4 translocation efficiency. Thus, special attention is being paid to search for compounds that are able to enhance this translocation process in the absence of insulin. EXPERIMENTAL APPROACH: Total internal reflection fluorescence (TIRF) microscopy was applied to quantify GLUT4 translocation in highly insulin-sensitive CHO-K1 cells expressing a GLUT4-myc-GFP fusion protein. KEY RESULTS: Using our approach, we demonstrated GLUT4 translocation modulatory properties of selected substances and identified novel potential insulin mimetics. An increase in the TIRF signal was found to correlate with an elevated glucose uptake. Variations in the expression level of the human insulin receptor (hInsR) showed that the insulin mimetics identified stimulate GLUT4 translocation by a mechanism that is independent of the presence of the hInsR. CONCLUSIONS AND IMPLICATIONS: Taken together, the results indicate that TIRF microscopy is an excellent tool for the quantification of GLUT4 translocation and for identifying insulin mimetic drugs. PMID- 25039622 TI - French-Canadian translation of the WheelCon-M (WheelCon-M-F) and evaluation of its validity evidence using telephone administration. AB - PURPOSE: The objectives of this study were to: (1) translate the Wheelchair Use Confidence Scale for Manual Wheelchair Users (WheelCon-M) into a French-Canadian version (WheelCon-M-F); and (2) evaluate the WheelCon-M-F validity evidence based on response processes, internal structure, and relations with other variables. METHODS: The WheelCon-M was translated from English to French using the Translation and Cultural Adaptation of Patient Reported Outcomes Measures - Principles of Good Practice guidelines. We used a test-retest design to examine the validity of the WheelCon-M-F with 24 community dwelling, experienced manual wheelchair users who had a variety of musculoskeletal and neurological diagnoses. RESULTS: The mean +/- SD WheelCon-M-F score was 63.8 +/- 19.9. All WheelCon-M-F items were either identical or similar in meaning to the WheelCon-M items. Clarification issues were identified with 27/63 items. Cronbach's alpha was 0.98 and the retest intraclass correlation coefficient was 0.87. The standard error of measurement and smallest real difference were 7.2 and 19.9, respectively. There were no floor or ceiling effects. WheelCon-M-F correlations with social support and participation were r = 0.54 and 0.78, respectively. CONCLUSIONS: The WheelCon M-F is a valid outcome measure for assessing manual wheelchair confidence in the French-Canadian population. IMPLICATIONS FOR REHABILITATION: The WheelCon-M-F is a valid outcome measure available for assessing wheelchair confidence, a modifiable barrier to wheelchair use. Translation of the WheelCon-M into the WheelCon-M-F allows collection of both clinical and research wheelchair confidence data using the two official Canadian languages, English and French. PMID- 25039623 TI - Respiratory disease and respiratory physiology: putting lung function into perspective interstitial lung disease. AB - The interstitial lung diseases pathologically involve the pulmonary interstitium but may also involve the airways, pleura and pulmonary circulation. They may be idiopathic, be part of other conditions, or be related to drug or environmental exposures. This review will focus on diagnostic and prognostic information provided by lung function tests in the idiopathic interstitial pneumonias, particularly idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. These disorders are characterized by small stiff lungs with impaired gas exchange. Lung function tests, particularly lung volumes and gas transfer, used initially on patient presentation and then repeatedly on follow up, together with high-resolution computed tomography scans, can generate predictive formulae which are superior to single tests and can be used to provide useful information to assess the natural history of the disease or guide therapy. The concomitant presence of emphysema may mask the degree of restriction and may have adverse prognostic implications when accompanied by pulmonary hypertension. PMID- 25039624 TI - Performance-enhancing drugs and public health. PMID- 25039625 TI - Dysphagia, nutrition and hydration post stroke. PMID- 25039626 TI - Support and practical advice for the use of nutrition support teams. AB - There are many guidelines recommending that provision of parenteral nutrition (PN) should be supervised by nutrition support teams (NSTs). There is some evidence that these teams make economic sense, decrease complications and result in greater delivery of target nutritional requirements. Moreover, a recent report on the quality of PN care in the UK found only 19% was considered to be consistent with current good practice. Recommendations exist on how to set up teams, but advice on the practical aspects of doing the job is lacking. In this article, the authors outline the NST method of practice at North Shore Hospital in Auckland, New Zealand, including its assessment sheet and a description of its working acronym LIFEWRAP, which is used to ensure consistent assessment and care. PMID- 25039627 TI - Nasogastric tube depth: the 'NEX' guideline is incorrect. AB - Misplacing 17-23% of nasogastric (NG) tubes above the stomach ( Rollins et al, 2012 ; Rayner, 2013 ) represents a serious risk in terms of aspiration, further invasive (tube) procedures, irradiation from failed X-ray confirmation, delay to feed and medication. One causal factor is that in the National Patient Safety Agency (NPSA) guidance to place a tube, length is measured from nose to ear to xiphisternum (NEX) ( NSPA, 2011 ); NEX is incorrect because it only approximates the nose to gastro-oesophageal junction (GOJ) distance and is therefore too short. To overcome this and because the xiphisternum is more difficult to locate, local policy is to measure in the opposite direction; xiphisternum to ear to nose (XEN), then add 10 cm. The authors determined whether external body measurements can be used to estimate the NG tube length to safely reach the gastric body. This involved testing the statistical association of body length, age, sex and XEN in consecutive critically ill patients against internal anatomical landmarks determined from an electromagnetic (EM) trace of the tube path. XEN averaged 50 cm in 71 critically ill patients aged 53+/-20 years. Tube marking and the EM trace were used to determine mean insertion distances at pre-gastro-oesophageal junction (GOJ) (48 cm), where the tube first turns left towards the stomach and becomes shallow on the trace; gastric body (62 cm), where the tube reaches the left-most part of the stomach; and gastric antrum (73 cm) at the midline on the EM trace. Using body length, age, sex and XEN in a linear regression model, only 25% of variability was predicted, showing that external measurements cannot reliably predict the length of tube required to reach the stomach. A tube length of XEN (or NEX) is too short to guarantee gastric placement and is unsafe. XEN+10 cm or more complex measurements will reach the gastric body (mid-stomach) in most patients, but because of wide variation, external measurements often fail to predict a safe distance. Only the EM trace or possibly direct vision can show in real time whether the tip has safely reached the gastric body. PMID- 25039628 TI - Orchestrating the management of patients with high-output stomas. AB - Working in isolation, managing high-output stomas can be stressful and difficult, with patient outcomes varying significantly. For the stoma care clinical nurse specialist, managing the choice of stoma appliance is only a small part of the care provided. To standardise and improve outcomes for patients with high-output stomas, team working is required. After contacting other stoma care services and using guidance from the High Impact Actions for Stoma Care document ( Coloplast, 2010 ), it was evident that the team should put together an algorithm/flow chart to guide both specialists and ward nursing staff in the evidence-based and standardised management of patients with high-output stomas. This article presents the flowchart that was produced and uses case studies to demonstrate improvements. PMID- 25039629 TI - Urinary sheaths for male incontinence. PMID- 25039630 TI - Nursing and aggression in the workplace: a systematic review. AB - Personal experiences of aggression or violence in the workplace lead to serious consequences for nurses, their patients, patient care and the organisation as a whole. While there is a plethora of research on this topic, no review is available that identifies types of aggression encountered, individuals perceived to be most at risk and coping strategies for victims. The aim of this systematic review was to examine occupational anxiety related to actual aggression in the workplace for nurses. Databases (MEDLINE, CINAHL and PsycINFO) were searched, resulting in 1543 titles and abstracts. After removal of duplicates and non relevant titles, 137 papers were read in full. Physical aggression was found to be most frequent in mental health, nursing homes and emergency departments while verbal aggression was more commonly experienced by general nurses. Nurses exposed to verbal or physical abuse often experienced a negative psychological impact post incident. PMID- 25039631 TI - Relationship between the 'two-week rule' and colorectal cancer diagnosis. AB - This literature review explored the relationship between the 'two-week rule' (TWR) and the diagnosis of colorectal cancer (CRC). The Cochrane Review, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), NHS Evidence and Medline databases were searched and produced 12 relevant studies. Since the introduction of the TWR, the CRC detection rate has been poor and there appears to be disagreement in the literature regarding the efficacy of the TWR to detect CRC at an earlier disease stage. There have also been variations in the use of the TWR guidelines by GPs. These factors may lead to poor outcomes for patients with CRC. PMID- 25039632 TI - Encouraging lapsed registrants to return to nursing practice. PMID- 25039633 TI - Reflection: from staff nurse to nurse consultant: part 10: helping others reflect. PMID- 25039634 TI - Hillsborough part 2: advance decisions and futile treatment. AB - In the second article on the impact of the Hillsborough football stadium disaster on healthcare law, Richard Griffith discusses the case of Tony Bland, who suffered prolonged hypoxia due to the crushing crowd surge, leaving him in a persistent vegetative state. Some 3 years after the incident, the judicial committee of the House of Lords was asked to rule on whether it would be lawful to withdraw his artificial nutrition and hydration, resulting in death. The opinions of the law lords in Airedale NHS Trust v Bland [1993] continue to inform health law 25 years after the disaster, shaping and developing the use of advance decisions to refuse treatment and setting out when it would be lawful to withdraw futile life-sustaining treatment. PMID- 25039635 TI - Doing your best as a health professional to keep patients safe. PMID- 25039636 TI - A chance to inspire the next crop of nurses. PMID- 25039637 TI - Pursuing concordance: moving away from paternalism. AB - In the second of two articles exploring the value and application of concordance across nursing practice the discussion is aimed at clinical settings and patient groups where concordance may have been viewed as impractical. The author harnesses Cribb and Entwhistle's broader conception of shared decision making and the notion of decision-making capacity as a continuum to argue that concordance can be pursued effectively in challenging settings such as childcare practice, mental health and the care of older people. As in the first paper ( McKinnon, 2013 ) the discussion is not limited to medicines management but remains engaged with all aspects of nursing practice. Legal and ethical frameworks, social participation theory and research across healthcare practice are sourced to argue for concordant approaches in the care of patients who may at times have compromised decision-making capacity. Ideas of direct and indirect concordance are explored. PMID- 25039638 TI - Workforce development and effective evaluation of projects. AB - The success of a project or programme is typically determined in relation to outputs. However, there is a commitment among UK public services to spending public funds efficiently and on activities that provide the greatest benefit to society. Skills for Health recognised the need for a tool to manage the complex process of evaluating project benefits. An integrated evaluation framework was developed to help practitioners identify, describe, measure and evaluate the benefits of workforce development projects. Practitioners tested the framework on projects within three NHS trusts and provided valuable feedback to support its development. The prospective approach taken to identify benefits and collect baseline data to support evaluation was positively received and the clarity and completeness of the framework, as well as the relevance of the questions, were commended. Users reported that the framework was difficult to complete; an online version could be developed, which might help to improve usability. Effective implementation of this approach will depend on the quality and usability of the framework, the willingness of organisations to implement it, and the presence or establishment of an effective change management culture. PMID- 25039639 TI - Dementia-friendly clinical areas. PMID- 25039640 TI - In vitro investigations on the effect of dermal fibroblasts on keratinocyte responses to ultraviolet B radiation. AB - Exposure to ultraviolet radiation is closely linked to the development of skin cancers in humans. The ultraviolet B (UVB) radiation wavelength (280-320 nm), in particular, causes DNA damage in epidermal keratinocytes, which are linked to the generation of signature premalignant mutations. Interactions between dermal fibroblasts and keratinocytes play a role in epidermal repair and regeneration after UVB-induced damage. To investigate these processes, established two and three-dimensional culture models were utilized to study the impact of fibroblast keratinocyte crosstalk during the acute UVB response. Using a coculture system it was observed that fibroblasts enhanced keratinocyte survival and the repair of cyclobutane pyrimidine dimers (CPDs) after UVB radiation exposure. These findings were also mirrored in irradiated human skin coculture models employed in this study. Fibroblast coculture was shown to play a role in the expression and activation of members of the apoptotic cascade, including caspase-3 and Bad. Interestingly, the expression and phosphorylation of p53, a key player in the regulation of keratinocyte cell fate postirradiation, was also shown to be influenced by fibroblast-produced factors. This study highlights the importance of synergistic interactions between fibroblasts and keratinocytes in maintaining a functional epidermis while promoting repair and regeneration following UVB radiation-induced damage. PMID- 25039641 TI - Hair type-specific function of canonical Wnt activity in adult mouse skin. AB - Wnt/beta-catenin signalling is a key regulator of hair follicle (HF) morphogenesis and life-long HF regeneration. In a recently published issue of Experimental Dermatology, Lei et al. report that sustained WNT10B supply and pathway activation in regenerating mouse HF increased the width of hair bulbs, hair shafts and the dermal papilla (DP), and enlarged the CD34(+) HF bulge cell compartment. Notably, WNT10B affected primarily zigzag HFs, while size and morphology of other HF types remained largely unaffected. Thus, these findings raise a number of questions regarding a HF type-specific function of Wnt/beta catenin and on the role of the WNT-stimulated DP in this process. PMID- 25039642 TI - Prevalence of esophageal motility abnormalities increases with longer disease duration in adult patients with eosinophilic esophagitis. AB - BACKGROUND: During the natural course of eosinophilic esophagitis (EoE), the risk for esophageal stricture formation increases. It remains unknown whether motility abnormalities in EoE also develop over time. We aimed to determine the relationship between disease duration, clinical characteristics, and manometric pattern of EoE patients. METHODS: We compared esophageal high-resolution manometry (HRM) measurements of 31 adult EoE patients with HRM data from 31 GERD controls and 31 healthy controls. Subsequently, we assessed differences in disease duration and clinical characteristics between EoE patients with normal and those with abnormal esophageal motility. KEY RESULTS: In EoE patients, peristaltic integrity was more frequently failed (12 vs 6%) or weak (27 vs 15%; p < 0.001) compared with healthy controls; however, this pattern was also seen in GERD controls (failed 14%, weak 27%). We found no differences regarding symptoms and signs of EoE between EoE patients with normal (42%) and abnormal motility (58%). However, disease duration was longer in EoE patients with abnormal motility than in those with normal motility (13 (6-18) years vs 4 (1-11) years; p < 0.05). In EoE, but not GERD, disease duration was identified as a risk factor for abnormal motility (OR for each year 1.142; 95% CI 1.004-1.299), and with longer disease duration, the prevalence of abnormal motility increased from 36% (duration 0-5 years) to 83% (duration >=16 years; p < 0.05). CONCLUSIONS & INFERENCES: Weak and failed peristaltic integrity are more often present in adult EoE patients than in healthy controls. The prevalence of manometric abnormalities in EoE patients increases with longer disease duration. PMID- 25039643 TI - The dilemma of reporting suspicions of child maltreatment in pediatric dentistry. AB - This study examined the factors that lead specialists in pediatric dentistry to suspect child abuse or neglect and the considerations that influence the decision to report these suspicions to social services. Focus group discussions were used to identify new aspects of child maltreatment suspicion and reporting. Such discussions illuminate the diversity of informants' experiences, opinions, and reflections. Focus groups included 19 specialists and postgraduate students in pediatric dentistry. We conducted video-recorded focus group discussions at the informants' dental clinics. All sessions lasted approximately 1.5 h. We transcribed the discussions verbatim and studied the transcripts using thematic analysis, a method well-suited to evaluating the experiences discussed and how the informants understand them. The analysis process elicited key concepts and identified one main theme, which we labeled 'the dilemma of reporting child maltreatment'. We found this dilemma to pervade a variety of situations and divided it into three sub-themes: to support or report; differentiating concern for well-being from maltreatment; and the supportive or unhelpful consultation. Reporting a suspicion about child maltreatment seems to be a clinical and ethical dilemma arising from concerns of having contradicting professional roles, difficulties confirming suspicions of maltreatment, and perceived shortcomings in the child-protection system. PMID- 25039644 TI - The impact of domestication on resistance to two generalist herbivores across 29 independent domestication events. AB - The domestication of crops is among the most important innovations in human history. Here, we test the hypothesis that cultivation and artificial selection for increased productivity of crops reduced plant defenses against herbivores. We compared the performance of two economically important generalist herbivores - the leaf-chewing beet armyworm (Spodoptera exigua) and the phloem-feeding green peach aphid (Myzus persicae) - across 29 crop species and their closely related wild relatives. We also measured putative morphological and chemical defensive traits and correlated them with herbivore performance. We show that, on average, domestication significantly reduced resistance to S. exigua, but not M. persicae, and that most independent domestication events did not cause differences in resistance to either herbivore. In addition, we found that multiple plant traits predicted resistance to S. exigua and M. persicae, and that domestication frequently altered the strength and direction of correlations between these traits and herbivore performance. Our results show that domestication can alter plant defenses, but does not cause strong allocation tradeoffs as predicted by plant defense theory. These results have important implications for understanding the evolutionary ecology of species interactions and for the search for potential resistance traits to be targeted in crop breeding. PMID- 25039646 TI - Magnetic resonance imaging in ESRD patients: what are the options? PMID- 25039645 TI - Serum 25-hydroxyvitamin D and risk of venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Some evidence suggests that an inadequate vitamin D level may increase the risk for atherosclerotic cardiovascular disease. Whether a low vitamin D level plays a role in venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, is largely unexplored. OBJECTIVES: We tested prospectively, in the Atherosclerosis Risk in Communities (ARIC) cohort, whether the serum level of 25-hydroxyvitamin D (25[OH]D) is inversely associated with VTE incidence, and whether it partly explains the African American excess of VTE in the ARIC Study. PATIENTS AND METHODS: We measured 25(OH)D by using mass spectroscopy in stored samples of 12 752 ARIC Study participants, and followed them over a median of 19.7 years (1990-1992 to 2011) for the incidence of VTE (n = 537). RESULTS: The seasonally adjusted 25(OH)D level was not associated with VTE incidence. In a model adjusted for age, race, sex, hormone replacement therapy, and body mass index, the hazard ratios of VTE across 25(OH)D quintiles 5 (high) to 1 (low) were: 1 (ref.), 0.84 (95% confidence interval [CI] 0.65-1.08), 0.88 (95% CI 0.68-1.13), 1.04 (95% CI 0.78-1.38), and 0.90 (95% CI 0.64-1.27). The lowest 25(OH)D quintile contained 59% African Americans, whereas the highest quintile contained 7% African Americans. However, lower 25(OH)D levels explained little of the 63% greater VTE risk of African Americans over whites in this cohort. CONCLUSIONS: A low 25(OH)D level was not a risk factor for VTE in this prospective study. However, the totality of the literature (three studies) suggests that a low 25(OH)D level might modestly increase VTE risk in whites, but this needs further confirmation. PMID- 25039647 TI - Directing vascular cell selectivity and hemocompatibility on patterned platforms featuring variable topographic geometry and size. AB - It is great challenge to generate multifunctionality of vascular grafts and stents to enable vascular cell selectivity and improve hemocompatibility. Micro/nanopatterning of vascular implant surfaces for such multifunctionality is a direction to be explored. We developed a novel patterned platform featuring two typical geometries (groove and pillar) and six pattern sizes (0.5-50 MUm) in a single substrate to evaluate the response of vascular cells and platelets. Our results indicate that targeted multifunctionality can be indeed instructed by rationally designed surface topography. The pillars nonselectively inhibited the growth of endothelial and smooth muscle cells. By contrast, the grooves displayed selective effects: in a size-dependent manner, the grooves enhanced endothelialization but inhibited the growth of smooth muscle cells. Moreover, our studies suggest that topographic cues can affect response of vascular cells by regulating focal adhesion and stress fiber development, which define cytoskeleton organization and cell shape. Notably, both the grooves and the pillars at 1 MUm size drastically reduced platelet adhesion and activation. Taken together, these findings suggest that the topographic pattern featuring 1 MUm grooves may be the optimal design of surface multifunctionality that favors vascular cell selectivity and improves hemocompatibility. PMID- 25039649 TI - Metabolomic analysis reveals rewiring of Synechocystis sp. PCC 6803 primary metabolism by ntcA overexpression. AB - NtcA is a cAMP receptor protein-type transcription factor conserved among cyanobacteria and is essential for gene expression in response to nitrogen status. NtcA has been widely studied; however, no metabolomic analysis has been conducted using the ntcA mutant. Here, we generated a strain that overexpresses ntcA in Synechocystis sp. PCC 6803, named NOX10, and performed physiological, transcriptomic and metabolomic analyses. NOX10 grew faster than the wild-type strain under photoautotrophic conditions, but slower under light-activated heterotrophic conditions. Transcriptome analysis revealed that the expression of genes related to primary metabolism was altered by ntcA overexpression particularly under nitrogen-depleted conditions. Metabolomic analysis revealed that metabolite levels in sugar, purine/pyrimidine nucleotide, organic acid and amino acid metabolism were widely altered by ntcA overexpression. The protein levels of nitrogen-regulated transcriptional regulators were altered by ntcA overexpression during nitrogen starvation. These results demonstrate the alteration of primary metabolism by genetic engineering of NtcA, and they contribute to the current understanding of metabolic regulation of unicellular cyanobacteria. PMID- 25039648 TI - Prognostic value of pro-adrenomedullin, procalcitonin and C-reactive protein in predicting outcome of febrile urinary tract infection. AB - Bacterial infections such as febrile urinary tract infection (fUTI) may run a complicated course that is difficult to foretell on clinical evaluation only. Because the conventional biomarkers erythrocyte sedimentation rate (ESR), leucocyte count, C-reactive protein (CRP) and procalcitonin (PCT) have a limited role in the prediction of a complicated course of disease, a new biomarker-plasma midregional pro-adrenomedullin (MR-proADM)-was evaluated in patients with f UTI. We conducted a prospective multicentre cohort study including consecutive patients with f UTI at 35 primary-care centres and eight emergency departments. Clinical and microbiological data were collected and plasma biomarker levels were measured at presentation to the physician. Survival was assessed after 30 days. Of 494 fUTI patients, median age was 67 (interquartile range 49-78) years, 40% were male; two-thirds of them had significant co-existing medical conditions. Median MR-proADM level was 1.42 (interquartile range 0.67-1.57) nM; significantly elevated MR-proADM levels were measured in patients with bacteraemia, those admitted to the intensive care unit, and in 30-day and 90-day non-survivors, compared with patients without these characteristics. The diagnostic accuracy for predicting 30-day mortality in fUTI, reflected by the area-under-the-curve of receiver operating characteristics were: MR-proADM 0.83 (95% CI 0.71-0.94), PCT 0.71 (95% CI 0.56-0.85); whereas CRP, ESR and leucocyte count lacked diagnostic value in this respect. This study shows that MR-proADM assessed on first contact predicts a complicated course of disease and 30-day mortality in patients with fUTI and in this respect has a higher discriminating accuracy than the currently available biomarkers ESR, CRP, PCT and leucocyte count. PMID- 25039650 TI - Effects of interruptions of controlled-rate freezing on the viability of umbilical cord blood stem cells. AB - BACKGROUND: An optimal cooling rate is critical for cryopreserving cord blood stem cells, so it is generally achieved by using controlled-rate freezers (CRFs). The cooling rate can be interrupted by many factors during cooling; therefore, a proper response to the interruption in cryopreservation is crucial to prevent the loss of valuable cells. STUDY DESIGN AND METHODS: Cord blood samples (n = 6) containing 10% dimethyl sulfoxide were cooled from 4 to -80 degrees C using a CRF. At different temperatures during cooling, cells were transferred either to liquid nitrogen vapor phase (LNVP) directly or a -80 degrees C mechanical freezer where they were stored for 18.1 +/- 0.6 hours before transferring to LNVP. The cells were stored in LNVP for 127 +/- 48.1 hours before postthaw recovery, viability, and survival of total nucleated cells and/or CD45+ cells, CD34+ cells, and colony-forming unit-granulocyte-macrophage (CFU-GM) were assessed. RESULTS: For all types of postthaw evaluations, there were no significant differences when cells were transferred to a -80 degrees C freezer before LNVP, regardless of the temperature at which cooling was interrupted. In contrast, there were significant differences when cells were transferred to LNVP directly, but the differences were determined by the type of assays and how viability was calculated. CONCLUSIONS: Cord blood samples can be transferred to a -80 degrees C freezer anytime during controlled-rate cooling, but should only be transferred to LNVP when the samples have been cooled to -40 degrees C or lower. Percent postthaw survival of CFU-GM should be routinely assessed when controlled-rate cooling is interrupted. PMID- 25039651 TI - Novel nonribosomal peptide synthetase (NRPS) genes sequenced from intertidal mudflat bacteria. AB - Nonribosomal peptide synthetases (NRPS) are actively sought out, due to pharmacologically important activities of their metabolites. In marine environment, the most prevalent nonribosomal peptide antibiotic producers are sponges inhabiting microorganisms. Conversely, strains from marine sediments and more especially from intertidal mudflats have not been extensively screened for the presence of new NRPS. In this study, for the first time, a collection of one hundred intertidal mudflat bacterial isolates (Marennes-Oleron Bay, France) was assessed for (1) the presence of NRPS genes by degenerated PCR targeting conserved adenylation domains and (2) for their production of antimicrobial molecules. (1) Bacteria with adenylation domains (14 strains) were identified by 16S rRNA gene sequence analysis and grouped into Firmicutes (one strain) and Proteobacteria (13 strains). In silico analysis of the NRPS amino acid sequences (n = 7) showed 41-58% ID with sequences found in the NCBI database. Three new putative adenylation domain signatures were found. (2) The culture supernatant of one of these strains, identified as a Bacillus, was shown to strongly inhibit the growth of Staphylococcus aureus, S. epidermidis, and Enterococcus faecalis. This study portends that the intertidal mudflat niche could be of interest for the discovery of new NRPS genes and antimicrobial producing strains. PMID- 25039652 TI - Helping health service researchers and policy makers speak the same language. PMID- 25039653 TI - Effects of nutritional level of concentrate-based diets on meat quality and expression levels of genes related to meat quality in Hainan black goats. AB - The present study investigated the effects of the nutritional levels of diets on meat quality and related gene expression in Hainan black goat. Twenty-four goats were divided into six dietary treatments and were fed a concentrate-based diet with two levels of crude protein (CP) (15% or 17%) and three levels of digestive energy (DE) (11.72, 12.55 or 13.39 MJ/kg DM) for 90 days. Goats fed the concentrate-based diet with 17% CP had significantly (P < 0.05) higher average daily gains (ADG) and better feed conversion rates (FCR). The pH 24h value tended to decrease (P < 0.05) with increasing DE levels. The tenderness of Longissimus dorsi muscle (LD) and Semimembranosus muscle (SM) reduced with increasing CP levels (P < 0.05). With increasing DE levels, tenderness was increased (P < 0.05). The heart fatty acid-binding protein (H-FABP) mRNA expression levels in LD and SM increased with increasing DE levels (P < 0.05), but decreased with increasing CP levels (P < 0.05). The calpastatin (CAST) and MU-calpain mRNA expressions levels in LD and SM were affected significantly (P < 0.05) by CP and DE levels in the diet. Therefore, the nutritional levels of diets affect meat quality and expression levels of genes associated with meat quality in Hainan black goats. PMID- 25039654 TI - T regulatory cell adoptive therapy for tolerance induction in autoimmunity and transplantation. PMID- 25039655 TI - Contributions of medical family therapy to the changing health care system. AB - Medical family therapy is a form of professional practice that uses a biopsychosocial approach and systemic family therapy principles in the collaborative treatment of individuals and families dealing with medical problems. It emerged out of the experience of family therapists working in primary medical care settings in the 1980s and 1990s. This article describes how contemporary medical family therapy can contribute to a transformed health care system in four areas: the patient experience of health care, the health of the population, the containment of health care costs, and enhanced practice environments. PMID- 25039656 TI - Glycosylated hemoglobin level is associated with hearing impairment in older Japanese: the Kurabuchi Study. AB - OBJECTIVES: To examine the association between glycemic levels (glycosylated hemoglobin (HbA1c)) and hearing impairment in a general older population. DESIGN: Community-based prospective longitudinal cohort study. SETTING: Kurabuchi Town, Gunma Prefecture, Japan. PARTICIPANTS: Residents (N = 831; 350 men, 481 women) aged 65 and older were examined in 2005 and 2006 and analyzed in a cross sectional study. Residents without hearing impairment at baseline who participated in audiometric re-examinations 4 years later were analyzed (n = 338). MEASUREMENTS: Hearing impairment was defined as failure to hear a 30-dB signal at 1 kHz and a 40-dB signal at 4 kHz in the better ear in pure-tone audiometric tests. RESULTS: Mean HbA1c level (National Glycohemoglobin Standardization Program) was 5.8 +/- 0.8% (40 mmol/mol). Odds ratios (ORs) and 95% confidence intervals (CIs) of hearing impairment associated with HbA1c were estimated using a logistic regression model. In the cross-sectional analysis, HbA1c levels were positively associated with hearing impairment (OR per 1.0% increase in HbA1c = 1.30, 95% CI = 1.00-1.68). This association persisted even after excluding 58 participants with a self-reported history of diagnosed diabetes mellitus. Longitudinal analysis revealed the temporality of the discussed association (OR = 1.52, 95% CI = 1.03-2.23). CONCLUSION: The present study provides supportive evidence for a causal link between hyperglycemia and age-related hearing loss. PMID- 25039658 TI - Development of different forms of skill learning throughout the lifespan. AB - The acquisition of complex motor, cognitive, and social skills, like playing a musical instrument or mastering sports or a language, is generally associated with implicit skill learning (SL). Although it is a general view that SL is most effective in childhood, and such skills are best acquired if learning starts early, this idea has rarely been tested by systematic empirical studies on the developmental pathways of SL from childhood to old age. In this paper, we challenge the view that childhood and early school years are the prime time for skill learning by tracking age-related changes in performance in three different paradigms of SL. We collected data from participants between 7 and 87 years for (1) a Serial Reaction Time Task (SRT) testing the learning of motor sequences, (2) an Artificial Grammar Learning (AGL) task testing the extraction of regularities from auditory sequences, and (3) Probabilistic Category Learning in the Weather Prediction task (WP), a non-sequential categorization task. Results on all three tasks show that adolescence and adulthood are the most efficient periods for skill learning, since instead of becoming less and less effective with age, SL improves from childhood into adulthood and then later declines with aging. PMID- 25039657 TI - Functional significance of hormonal changes in mammalian fathers. AB - In the 5-10% of mammals in which both parents routinely provide infant care, fathers as well as mothers undergo systematic endocrine changes as they transition into parenthood. Although fatherhood-associated changes in such hormones and neuropeptides as prolactin, testosterone, glucocorticoids, vasopressin and oxytocin have been characterised in only a small number of biparental rodents and primates, they appear to be more variable than corresponding changes in mothers, and experimental studies typically have not provided strong or consistent evidence that these endocrine shifts play causal roles in the activation of paternal care. Consequently, their functional significance remains unclear. We propose that endocrine changes in mammalian fathers may enable males to meet the species-specific demands of fatherhood by influencing diverse aspects of their behaviour and physiology, similar to many effects of hormones and neuropeptides in mothers. We review the evidence for such effects, focusing on recent studies investigating whether mammalian fathers in biparental species undergo systematic changes in (i) energetics and body composition; (ii) neural plasticity, cognition and sensory physiology; and (iii) stress responsiveness and emotionality, all of which may be mediated by endocrine changes. The few published studies, based on a small number of rodent and primate species, suggest that hormonal and neuropeptide alterations in mammalian fathers might mediate shifts in paternal energy balance, body composition and neural plasticity, although they do not appear to have major effects on stress responsiveness or emotionality. Further research is needed on a wider variety of biparental mammals, under more naturalistic conditions, to more fully determine the functional significance of hormone and neuropeptide profiles of mammalian fatherhood and to clarify how fatherhood may trade off with (or perhaps enhance) aspects of organismal function in biparental mammals. PMID- 25039659 TI - The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma. AB - Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression-free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks. PMID- 25039660 TI - Further evidence for the topography and connectivity of the corpus callosum: an FMRI study of patients with partial callosal resection. AB - BACKGROUND AND PURPOSE: This functional MRI study was designed to describe activated fiber topography and trajectories in the corpus callosum (CC) of six patients carrying different degree of partial callosal resection. METHODS: Patients receiving gustatory, tactile, and visual stimulation according to a block-design protocol were scanned in a 1.5 Tesla magnet. Diffusion tensor imaging (DTI) data were also acquired to visualize spared interhemispheric fibers. RESULTS: Taste stimuli evoked bilateral activation of the primary gustatory area in all patients and foci in the anterior CC, when spared. Tactile stimuli to the hand evoked bilateral foci in the primary somatosensory area in patients with an intact posterior callosal body and only contralateral in the other patients. Callosal foci occurred in the CC body, if spared. In patients with an intact splenium central visual stimulation induced bilateral activation of the primary visual area as well as foci in the splenium itself. CONCLUSION: Present data show that interhemispheric fibers linking sensory areas crossed through the CC at the sites where the different sensory stimuli evoked activation foci, and that topography of callosal foci evoked by sensory stimulation in spared CC portions is consistent with that previously observed in subjects with intact CC. PMID- 25039661 TI - Student nurses' perceived challenges of nursing in India. AB - BACKGROUND: A profound nursing shortage exists in India. Increasingly nursing students in India are opting to migrate to practise nursing abroad upon graduation. Perceptions and attitudes about nursing are shaped during student experiences. PURPOSE: The purpose in conducting this research was to illuminate student nurses' perceived challenges of nursing in India. SETTING AND SAMPLE: This study took place at a hospital-based, private mission non-profit school of nursing in Bengaluru, India. Purposive sampling of nursing students yielded 14 participants. METHODS: Photovoice, a qualitative participatory action research methodology, was used. Data were collected between August 2013 and January 2014. A strong international collaboration between researchers resulted in qualitative thematic interpretation of photographs, critical group dialogue transcripts, individual journal entries and detailed field notes. RESULTS: Two main themes were identified including the perceived challenges of a hierarchal system and challenges related to limited nursing workforce capacity. Subcategories of a hierarchal system included challenges related to image, safety, salary and balance. Subcategories of limited workforce capacity were migration, work overload, physical demand, incongruence between theory and practice, and knowledge. DISCUSSION: Nursing as a profession in India is still in its infancy when measured against standard criteria. IMPLICATIONS FOR HEALTH POLICY: Change in health policy is needed to improve salary, safety for nurses, and nurse to patient ratios to address hierarchal and workforce capacity challenges in India. PMID- 25039662 TI - HIV-related stigma in the dental setting: a qualitative study. AB - PURPOSE: To explore the experiences and expectations of HIV-related stigma in dental settings. METHODS: This was a cross-sectional study of 60 HIV+ adult volunteers. We conducted audio-recorded interviews; responses to four open-ended questions were analyzed qualitatively for theme and content. RESULTS: Twenty seven participants (45%) reported ever having anticipated being judged, stigmatized or treated with disrespect in a dental setting due to HIV status. Thematic response categories included concerns about: (i) receiving humane and respectful treatment, (ii) being judged or stereotyped and (iii) giving HIV to the dentist. Regarding hesitancy to visit the dentist, subjects equally endorsed fear of the dentist (35%) and concerns about confidentiality and receiving humane treatment (35%). CONCLUSION: HIV+ individuals encounter many fears and concerns related to dental care; fear of the dentist and concerns about confidentiality and receiving humane treatment appear to be central issues. Dental providers should be aware of and better manage these issues. PMID- 25039663 TI - Anti-nociceptive and sedative effects of romifidine, tramadol and their combination administered intravenously slowly in ponies. AB - OBJECTIVE: To evaluate the anti-nociceptive and sedative effects of slow intravenous (IV) injection of tramadol, romifidine, or a combination of both drugs in ponies. STUDY DESIGN: Within-subject blinded. ANIMALS: Twenty ponies (seven male, 13 female, weighing mean +/- SD 268.0 +/- 128 kg). METHODS: On separate occasions, each pony received one of the following three treatments IV; romifidine 50 MUg kg(-) (R) tramadol 3 mg kg(-1) given over 15 minutes (T) or tramadol 3 mg kg(-1) followed by romifidine 50 MUg kg(-1) (RT). Physiologic parameters and caecal borborygmi (CB) were measured and sedation and response to electrical stimulation of the coronary band assessed before and up to 120 minutes following drugs administration. Results were analyzed using the Friedman's test and 2 way anova as relevant. RESULTS: When compared to baseline, heart (HR, beats minute(-1) ) and respiratory rates (fR , breaths minute(-1) ) increased with treatment T (highest mean +/- SD, HR 43 +/- 1; fR 33 +/- 2) and decreased with R (lowest HR 29 +/- 1 and fR 10 +/- 4) and RT (lowest HR 32 +/- 1 and fR 9 +/- 3). There were no changes in other measured physiological variables. The height of head from the ground was lower following treatments R and TR than T. There was slight ataxia with all three treatments. No excitatory behavioural effects were observed. The response to electrical stimulation was reduced for a prolonged period relative to baseline following all three treatments, the effect being significantly greatest with treatment RT. CONCLUSION: Tramadol combined with romifidine at the stated doses proved an effective sedative and anti-nociceptive combination in ponies, with no unacceptable behavioural or physiologic side effects. CLINICAL RELEVANCE: Slow controlled administration of tramadol should reduce the occurrence of adverse behavioural side effects. PMID- 25039664 TI - ISPAD Clinical Practice Consensus Guidelines 2014. Diabetes in adolescence. PMID- 25039665 TI - Role of three-dimensional echocardiography in management of acquired intracardiac shunts. AB - Gerbode defect and sinus of Valsalva aneurysm fistula are congenital and acquired forms of intracardiac shunt. The increasing prevalence of invasive, recurrent cardiovascular procedures cause tissue damage and has led to more iatrogenic and acquired cases of predominantly congenital shunt over time. We report 2 cases of acquired intracardiac fistula precisely defined by Real time three-dimensional transesophageal echocardiography (3DTEE). The first case is a 70-year-old male with Gerbode defect after second aortic valve replacement surgery due to prosthetic valve endocarditis and the other case is a 41-year-old male with sinus of Valsalva aneurysm fistula between aorta and right atrium post subclinical infective endocarditis. Advanced cardiac imaging techniques such as cardiac computerized tomography, MRI and Real time three-dimensional (3D) echocardiography help to precisely detect intracardiac fistula and provide detailed anatomic and physiologic information. The relatively low cost, lack of radiation exposure, portability and guiding characteristic make real time 3DTEE an imaging technique with arguably the most advantages. Surgical repair is the usual treatment for intracardiac shunt, and percutaneous catheter-based closure is a less invasive alternative. PMID- 25039666 TI - Tidal ventilation distribution during pressure-controlled ventilation and pressure support ventilation in post-cardiac surgery patients. AB - BACKGROUND: Inhomogeneous ventilation is an important contributor to ventilator induced lung injury. Therefore, this study examines homogeneity of lung ventilation by means of electrical impedance tomography (EIT) measurements during pressure-controlled ventilation (PCV) and pressure support ventilation (PSV) using the same ventilation pressures. METHODS: Twenty mechanically ventilated patients were studied after cardiac surgery. On arrival at the intensive care unit, ventilation distribution was measured with EIT just above the diaphragm for 15 min. After awakening, PCV was switched to PSV and EIT measurements were again recorded. RESULTS: Tidal impedance variation, a measure of tidal volume, increased during PSV compared with PCV, despite using the same ventilation pressures (P = 0.045). The distribution of tidal ventilation to the dependent lung region was more pronounced during PSV compared with PCV, especially during the first half of the inspiration. An even distribution of tidal ventilation between the dependent and non-dependent lung regions was seen during PCV at lower tidal volumes (< 8 ml/kg) and PSV at higher tidal volumes (>= 8 ml/kg). In addition, the distribution of tidal ventilation was predominantly distributed to the dependent lung during PSV at low tidal volumes. CONCLUSION: In post-cardiac surgery patients, PSV showed improved ventilation of the dependent lung region due to the contribution of the diaphragm activity, which is even more pronounced during lower assist levels. PMID- 25039668 TI - The need to disentangle key concepts from ecosystem-approach jargon. AB - The ecosystem approach--as endorsed by the Convention on Biological Diversity (CDB) in 2000-is a strategy for holistic, sustainable, and equitable natural resource management, to be implemented via the 12 Malawi Principles. These principles describe the need to manage nature in terms of dynamic ecosystems, while fully engaging with local peoples. It is an ambitious concept. Today, the term is common throughout the research and policy literature on environmental management. However, multiple meanings have been attached to the term, resulting in confusion. We reviewed references to the ecosystem approach from 1957 to 2012 and identified 3 primary uses: as an alternative to ecosystem management or ecosystem-based management; in reference to an integrated and equitable approach to resource management as per the CBD; and as a term signifying a focus on understanding and valuing ecosystem services. Although uses of this term and its variants may overlap in meaning, typically, they do not entirely reflect the ethos of the ecosystem approach as defined by the CBD. For example, there is presently an increasing emphasis on ecosystem services, but focusing on these alone does not promote decentralization of management or use of all forms of knowledge, both of which are integral to the CBD's concept. We highlight that the Malawi Principles are at risk of being forgotten. To better understand these principles, more effort to implement them is required. Such efforts should be evaluated, ideally with comparative approaches, before allowing the CBD's concept of holistic and socially engaged management to be abandoned or superseded. It is possible that attempts to implement all 12 principles together will face many challenges, but they may also offer a unique way to promote holistic and equitable governance of natural resources. Therefore, we believe that the CBD's concept of the ecosystem approach demands more attention. PMID- 25039669 TI - Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010. AB - The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII <= 0.01 IU mL(-1) ). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty-four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high-risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg(-1) day(-1) X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99-1.23) with each increase of 100 dose-intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14-27.17) and 5.08 (95% CI: 1.11-23.31) respectively. ID according to FVIII concentrate used was: Advate ((r)) 18/50 (36%), Kogenate FS((r)) or Helixate FS((r)) 15/36 (42%), Wilate((r)) 0/11 and Xyntha((r)) 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11-122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08-18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure. PMID- 25039670 TI - Cyclin A1 expression predicts progression in pT1 urothelial carcinoma of bladder: a tissue microarray study of 149 patients treated by transurethral resection. AB - AIMS: To evaluate the immunoexpression of cyclin A1 in pT1 urothelial carcinomas of the bladder (UC) from a cohort of patients treated by transurethral resection of the bladder (TURB), to determine its value in predicting tumour recurrence, tumour progression, or systemic metastases. METHODS AND RESULTS: Five tissue microarrays (TMAS) were constructed from representative paraffin blocks of high grade pT1 UC from 149 consecutive patients. Cyclin A1 immunoexpression was evaluated as the percentage of tumour cells with positive nuclear staining estimated at each TMA spot. The cutoff for cyclin A1 positivity was set at 10% of cells. Outcome variables included tumour recurrence and tumour progression as the primary endpoints. Cyclin A1 positivity was associated with tumour progression but not with tumour recurrence or the presence of adjacent carcinoma in situ in the biopsy. Also, patients with pT1b at biopsy and cyclin A1 expression showed higher progression rates than patients with pT1a at biopsy and without cyclin A1 expression, respectively. Combining pT1 stage at biopsy and cyclin A1 expression more accurately predicted tumour progression than pT1 stage at biopsy alone and cyclin A1 expression alone. CONCLUSIONS: Cyclin A1 immunoexpression is of potential utility in predicting disease progression in patients with pT1 UC. PMID- 25039671 TI - Gesture-speech integration in children with specific language impairment. AB - BACKGROUND: Previous research suggests that speakers are especially likely to produce manual communicative gestures when they have relative ease in thinking about the spatial elements of what they are describing, paired with relative difficulty organizing those elements into appropriate spoken language. Children with specific language impairment (SLI) exhibit poor expressive language abilities together with within-normal-range nonverbal IQs. AIMS: This study investigated whether weak spoken language abilities in children with SLI influence their reliance on gestures to express information. We hypothesized that these children would rely on communicative gestures to express information more often than their age-matched typically developing (TD) peers, and that they would sometimes express information in gestures that they do not express in the accompanying speech. METHODS & PROCEDURES: Participants were 15 children with SLI (aged 5;6-10;0) and 18 age-matched TD controls. Children viewed a wordless cartoon and retold the story to a listener unfamiliar with the story. Children's gestures were identified and coded for meaning using a previously established system. Speech-gesture combinations were coded as redundant if the information conveyed in speech and gesture was the same, and non-redundant if the information conveyed in speech was different from the information conveyed in gesture. OUTCOMES & RESULTS: Children with SLI produced more gestures than children in the TD group; however, the likelihood that speech-gesture combinations were non redundant did not differ significantly across the SLI and TD groups. In both groups, younger children were significantly more likely to produce non-redundant speech-gesture combinations than older children. CONCLUSIONS & IMPLICATIONS: The gesture-speech integration system functions similarly in children with SLI and TD, but children with SLI rely more on gesture to help formulate, conceptualize or express the messages they want to convey. This provides motivation for future research examining whether interventions focusing on increasing manual gesture use facilitate language and communication in children with SLI. PMID- 25039672 TI - Hyponatraemia in older medical patients: implications for falls and adverse outcomes of hospitalisation. AB - BACKGROUND: Recent evidence suggests an association between hyponatraemia and falls. AIMS: To determine the association of hyponatraemia with admission associated falls (i.e. falls as part of the presenting complaint or during admission) and predefined adverse outcomes of hospitalisation. METHODS: A case control study of patients aged >=65 years admitted with hyponatraemia during a 6 month period was conducted. The relevant data were collected by review of medical records and analysed in univariate and multivariate models. RESULTS: The prevalence of hyponatraemia was 22% and more likely to be associated with the admission diagnoses of cardiovascular (P = 0.04) and metabolic disorders (P < 0.001), use of diuretics (P = 0.037) and a higher Charlson comorbidity score (P = 0.035). Hyponatraemia was independently associated with admission-associated falls (odds ratio (OR) 3.12, confidence interval (CI) 1.84-4.38, P < 0.001). The increased odds of falling were similar for mild (OR 3.15, CI 1.75-5.66) vs moderate to severe hyponatraemia (OR 3.07, CI 1.57-6.03). Although hyponatraemia had a significant independent association with increased length of stay (LOS) (OR 1.48, CI 1.22-1.79, P < 0.001) and change in residential care status to a more dependent category at discharge (OR 4.28, CI 1.68-10.859, P = 0.002), it was not associated with mortality or time to first unplanned readmission. Hyponatraemia was significantly associated with the need for inpatient rehabilitation; however, this was no longer significant when adjusted for falls. CONCLUSION: Hyponatraemia is independently associated with increased risk of admission-associated falls. The degree of falls risk is similar regardless of the severity of hyponatraemia. Hyponatraemia is also an important determinant of many adverse outcomes of hospitalisation. PMID- 25039673 TI - Determinants of house dust, endotoxin, and beta-(1->3)-D-glucan in homes of Danish children. AB - Little is known about the geographic variation and determinants of bacterial endotoxin and beta-(1,3)-D-glucan in Danish house dust. In a population of 317 children, we: (i) described loads and concentrations of floor dust, endotoxin, and beta-(1->3)-D-glucan and (ii) their correlations and (iii) assessed their determinants; (iv) Finally, we compared our findings with previous European studies. Bedroom floor dust was analyzed for endotoxin content by the kinetic limulus amoebocyte lysate assay and for beta-(1->3)-D-glucan by the inhibition enzyme immunoassay. The parents answered questions regarding potential determinants. We found: geometric means (geometric standard deviations) 186 mg/m(2) (4.3) for dust; 5.46 * 10(3) EU/m(2) (8.0) and 31.1 * 10(3) EU/g (2.6) for endotoxin; and 142 MUg/m(2) (14.3) and 0.71 * 10(3) MUg/g (7.3) for beta-(1 >3)-D-glucan. High correlations (r > 0.75) were found between floor dust and endotoxin and beta-(1->3)-D-glucan loads, while endotoxin and beta-(1->3)-D glucan concentrations were moderately correlated (r = 0.36-0.41) with the dust load. Having a carpet was positively associated with dust load and with endotoxin and beta-(1->3)-D-glucan concentrations. Pet keeping, dwelling type, and dwelling location were determinants of endotoxin concentrations. No other determinants were associated with beta-(1->3)-D-glucan concentrations. Compared with other European studies, we found lower beta-(1->3)-D-glucan loads and concentrations but higher endotoxin loads and concentrations suggesting a geographically determined different composition of Danish floor dust compared with other European regions. PMID- 25039674 TI - Threats to xylem hydraulic function of trees under 'new climate normal' conditions. AB - Climate models predict increases in frequency and intensity of extreme environmental conditions, such as changes to minimum and maximum temperatures, duration of drought periods, intensity of rainfall/snowfall events and wind strength. These local extremes, rather than average climatic conditions, are closely linked to woody plant survival, as trees cope with such events over long lifespans. While the xylem provides trees with structural strength and is considered the most robust part of a tree's structure, it is also the most physiologically vulnerable as tree survival depends on its ability to sustain water supply to the tree crown under variable environmental conditions. Many structural, functional and biological tree properties evolved to protect xylem from loss of transport function because of embolism or to restore xylem transport capacity following embolism formation. How 'the new climate normal' conditions will affect these evolved strategies is yet to be seen. Our understanding of xylem physiology and current conceptual models describing embolism formation and plant recovery from water stress, however, can provide insight into near-future challenges that woody plants will face. In addition, knowledge of species specific properties of xylem function may help guide mitigation of climate change impacts on woody plants in natural and agricultural tree communities. PMID- 25039675 TI - Comparison of the effects on glycaemic control and beta-cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide, insulin or pioglitazone: a multicentre randomized parallel-group trial (the CONFIDENCE study). AB - OBJECTIVE: Progressive beta-cell dysfunction hinders the maintenance of glycaemic control in type 2 diabetes, but comparative data on beta-cell-protective therapies are lacking in the early stage of type 2 diabetes. Here we evaluated the comparative glycaemic efficacy and impact on beta-cell function of three antihyperglycaemic agents that have a beta-cell-protective effect, exenatide, insulin and pioglitazone, in newly diagnosed patients with type 2 diabetes. DESIGN AND METHODS: In this 48-week, multicentre, parallel-group study, 416 patients newly diagnosed with type 2 diabetes were randomly assigned 1 : 1 : 1 to receive exenatide, insulin or pioglitazone. The primary end-point was the change in glycosylated haemoglobin (HbA1c) from baseline. Secondary end-points included effects on weight, blood pressure, lipid profiles and beta-cell function assessed by homeostasis model assessment, fasting proinsulin:insulin (PI/I), disposition index (DI) and acute insulin response (AIR). RESULTS: At week 48, mean [95% confidence interval (CI)] HbA1c changes from baseline were -1.8% (-1.55% to 2.05%) with exenatide, -1.7% (-1.52% to -1.96%) with insulin and -1.5% (-1.23% to -1.71%) with pioglitazone. Treatment differences were -0.20% (95% CI -0.46% to 0.06%) for exenatide versus insulin (P = 0.185), and -0.37% (95% CI -0.63% to 0.12%) for exenatide versus pioglitazone (P = 0.002). Significant improvements from baseline in AIR, PI/I and DI were observed with all treatments, with the greatest improvements in DI, as well as weight, blood pressure and lipid profile, observed with exenatide. CONCLUSIONS: All three agents showed efficacy regarding glycaemic control and metabolic benefits; however, exenatide showed the greatest efficacy. beta-cell function improved in all treatment groups; hence, early initiation of beta-cell-protective therapy may halt the decline in beta-cell function in type 2 diabetes. PMID- 25039676 TI - Interleukin-28B genetic variants in untreated Italian HCV-infected patients: a multicentre study. AB - BACKGROUND & AIMS: Different prevalence of favourable IL28BCC genotype have been reported in studies performed in different countries around the world. Data on distribution of IL28B genotypes in healthy Italian subjects are lacking. METHODS: Studies on prospectively collected untreated chronic HCV-infected Italian patients led to conflicting results. To investigate the prevalence of IL28B genotypes in untreated HCV-infected patients and in subjects able to clear HCV, and to compare them to the prevalence registered in healthy Italian controls. To evaluate IL28B prevalence across different HCV genotypes. RESULTS: IL28BCC was observed in 30.9% of chronic HCV patients, in 71.0% of subjects able to clear HCV infection and in 41.6% of the Italian controls. The frequency of IL28BCC was higher in HCV genotype 2 and 3 than in 1 (38.3 vs. 28.2) (P = 0.02). Levels of ALT higher in IL28BCC than in non-CC were observed regardless of HCV genotypes (P = 0.0014). CONCLUSIONS: IL28BCC frequencies progressively decline from subjects with spontaneous HCV clearance to normal non-infected subjects and to chronically infected. This study suggests that patients with IL28BCC, if genotype 1, are able to clear HCV more often than if genotype 2 and 3 infected, and that CC genotype is associated with higher grade of necro-inflammation. PMID- 25039677 TI - Supervised independent component analysis as an alternative method for genomic selection in pigs. AB - The objective of this work was to evaluate the efficiency of the supervised independent component regression (SICR) method for the estimation of genomic values and the SNP marker effects for boar taint and carcass traits in pigs. The methods were evaluated via the agreement between the predicted genetic values and the corrected phenotypes observed by cross-validation. These values were also compared with other methods generally used for the same purposes, such as RR BLUP, SPCR, SPLS, ICR, PCR and PLS. The SICR method was found to have the most accurate prediction values. PMID- 25039678 TI - Maternal singing during kangaroo care led to autonomic stability in preterm infants and reduced maternal anxiety. AB - AIM: Kangaroo care (KC) and maternal singing benefit preterm infants, and we investigated whether combining these benefitted infants and mothers. METHODS: A prospective randomised, within-subject, crossover, repeated-measures study design was used, with participants acting as their own controls. We evaluated the heart rate variability (HRV) of stable preterm infants receiving KC, with and without maternal singing. This included low frequency (LF), high frequency (HF) and the LF/HF ratio during baseline (10 min), singing or quiet phases (20 min) and recovery (10 min). Physiological parameters, maternal anxiety and the infants' behavioural state were measured. RESULTS: We included 86 stable preterm infants, with a postmenstrual age of 32-36 weeks. A significant change in LF and HF, and lower LF/HF ratio, was observed during KC with maternal singing during the intervention and recovery phases, compared with just KC and baseline (all p values <0.05). Maternal anxiety was lower during singing than just KC (p = 0.04). No differences in the infants' behavioural states or physiological parameters were found, with or without singing. CONCLUSION: Maternal singing during KC reduces maternal anxiety and leads to autonomic stability in stable preterm infants. This effect is not detected in behavioural state or physiological parameters commonly used to monitor preterm infants. PMID- 25039679 TI - Liquid nitrogen cryotherapy for fibromas in tarpon, Megalops atlanticus, Valenciennes 1847, and neoplasia in lined sea horse, Hippocampus erectus, Perry 1810. PMID- 25039680 TI - Ultrasound competency assessment in emergency medicine residency programs. AB - OBJECTIVES: In the Model of the Clinical Practice of Emergency Medicine (EM), bedside ultrasound (US) is listed as one of the essential procedural skills. EM milestones released by Accreditation Council for Graduate Medical Education and American Board of Emergency Medicine require residents to demonstrate competency in bedside US. The purpose of this study was to assess the current methods used by EM residency training programs to evaluate resident competency in bedside US. METHODS: This was a cross-sectional survey study. A questionnaire on US education and competency assessment was electronically sent to all EM residency program directors and emergency US directors. The survey consisted of questions regarding the US rotation, structure of US curriculum, presence of US fellowship, image archiving, quality assurance methods, feedback, competency assessment tools, and frequency of assessment. The survey responses are reported as the percentages of total respondents along with 95% confidence intervals (CIs). RESULTS: A total of 124 of 161 EM residency programs participated in this study, representing a 77% response rate. Twenty-six percent (95% CI = 18% to 34%) of programs assess competency only at the end of the US rotation. Eight percent (95% CI = 3% to 13%) assess competency only every 6 months, and 13% (95% CI = 7% to 19%) assess competency only annually. Eight percent (95% CI = 3% to 13%) assess competency only during the final year of training. Thirty percent (95% CI = 22% to 38%) of programs assess competency with a combination of the above intervals, and 16% (95% CI = 10% to 22%) do not assess US competency. Fourteen percent (95% CI = 8% to 20%) use objective structured clinical examinations (OSCEs), and 21% (95% CI = 14% to 28%) use standardized direct observation tools (SDOTs) to assess resident competency in US. Approximately one-third (33%, 95% CI = 24% to 41%) of standardized testing for US competency is conducted with multiple-choice questions. Thirty percent (95% CI = 21% to 38%) administer practical examinations to assess US skills. CONCLUSIONS: Currently, a majority of EM residency programs assess resident competency in bedside US. However, there is significant variation in the methods of competency assessment. PMID- 25039682 TI - A glimpse into the past and predictions for the future: the molecular evolution of the tuberculosis agent. AB - Recent advances in genomics and molecular biology are providing an excellent opportunity to get a glimpse into the past, to examine the present, and to predict the future evolution of pathogenic mycobacteria, and in particular that of Mycobacterium tuberculosis, the agent of human tuberculosis. The recent availability of genome sequences of several Mycobacterium canettii strains, representing evolutionary early-branching tubercle bacilli, has allowed the genomic and molecular features of the putative ancestor of the M. tuberculosis complex (MTBC) to be reconstituted. Analyses have identified extensive lateral gene transfer and recombination events in M. canettii and/or the MTBC, leading to suggestions of a past environmental reservoir where the ancestor(s) of the tubercle bacilli might have adapted to an intracellular lifestyle. The daily increases in M. tuberculosis genome data and the remaining urgent Public Health problem of tuberculosis make it more important than ever to try and understand the origins and the future evolution of the MTBC. Here we critically discuss a series of questions on gene-loss, acquisition, recombination, mutation and conservation that have recently arisen and which are key to better understand the outstanding evolutionary success of one of the most widespread and most deadly bacterial pathogens in the history of humankind. PMID- 25039683 TI - Nonagenarians undergoing cardiac surgery. AB - BACKGROUND: As life expectancy continues to rise and cardiac surgical outcomes improve, the number of nonagenarian (age > 90 years) patients undergoing cardiac operations is increasing. However, little has been reported on cardiac surgical outcomes in this select patient population. The purpose of this study was to examine current cardiac surgical outcomes for nonagenarian patients and determine the impact of extreme age on contemporary risk calculations. STUDY DESIGN: From 2002 to 20012, 61,303 patients underwent cardiac operations as reported in a statewide Society of Thoracic Surgeons (STS) Adult Cardiac Surgery database, including 108 nonagenarians. Patient and operative factors, including STS Predicted Risk of Mortality (PROM), were analyzed in order to compare to estimated risk measures. RESULTS: Nonagenarian patients (median age = 92 years) had a high prevalence of preoperative cerebrovascular disease (23.1% [25/108]) and arrhythmia (55.6% [60/108]). Isolated coronary artery bypass grafting (CABG) (39.8% [43/108]) was the most common operation performed within this cohort, followed by aortic valve replacement (AVR: 35.2% [38/108], AVR + CABG 23.1% [25/108]) operations. Overall nonagenarian mortality was 13% [14/108] and was greatest for AVR. Among nonagenarians with calculated STS PROM, observed to expected (O:E) ratios for mortality ranged from 1.45 to 2.65 annually over the study period. CONCLUSIONS: Nonagenarian patients represent a high-risk, elderly patient population with higher morbidity than predicted. Mortality is greatest following aortic valve operations. These results suggest that current risk calculations may underestimate the impact of extreme age on perioperative mortality. PMID- 25039684 TI - A quantitative risk assessment for the safety of carcase storage systems for scrapie infected farms. AB - AIMS: To determine the risk associated with the use of carcase storage vessels on a scrapie infected farm. METHODS AND RESULTS: A stochastic quantitative risk assessment was developed to determine the rate of accumulation and fate of scrapie in a novel low-input storage system. For an example farm infected with classical scrapie, a mean of 10(3.6) Ovine Oral ID50 s was estimated to accumulate annually. Research indicates that the degradation of any prions present may range from insignificant to a magnitude of one or two logs over several months of storage. CONCLUSIONS: For infected farms, the likely partitioning of remaining prion into the sludge phase would necessitate the safe operation and removal of resulting materials from these systems. If complete mixing could be assumed, on average, the concentrations of infectivity are estimated to be slightly lower than that measured in placenta from infected sheep at lambing. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first quantitative assessment of the scrapie risk associated with fallen stock on farm and provides guidance to policy makers on the safety of one type of storage system and the relative risk when compared to other materials present on an infected farm. PMID- 25039685 TI - Choosing the right journal for your systematic review. AB - RATIONALE, AIMS AND OBJECTIVES: The importance of systematic reviews (SRs) as an aid to decision making in health care has led to an increasing interest in the development of this type of study. When selecting a target journal for publication, authors generally seek out higher impact factor journals. This study aimed to determine the percentage of scientific medical journals that publish SRs according to their impact factors (>2.63) and to determine whether those journals require tools that aim to improve SR reporting and meta-analyses. METHODS: In our cross-sectional study showing how to choose the right journal for a SR, we selected and analysed scientific journals available in a digital library with a minimum Institute for Scientific Information impact factor of 2.63. RESULTS: We analysed 622 scientific journals, 435 (69.94%) of which publish SRs. Of those 435 journals, 135 (21.60%) provide instructions for authors that mention SRs. Three hundred journals (48.34%) do not discuss criteria for article acceptance in the instructions for authors section, but do publish SRs. Only 118 (27.00%) scientific journals require items to be reported in accordance with the specific SR reporting forms. CONCLUSIONS: The majority of the journals do not mention the acceptance of SRs in the instructions for authors section. Only a few journals require that SRs meet specific reporting guidelines, making interpretation of their findings across studies challenging. There is no correlation between the impact factor of the journal and its acceptance of SRs for publication. PMID- 25039686 TI - Elevated hair cortisol concentrations in children with adrenal insufficiency on hydrocortisone replacement therapy. AB - BACKGROUND: Glucocorticoid replacement therapy in patients with adrenal insufficiency needs to be tailored to the individual patient based on body composition and clinical signs and symptoms as no objective method for assessment of treatment adequacy is available. Current treatment regimens are often not satisfactory, which is shown by the adverse metabolic profile and doubled mortality rates in treated adrenal insufficiency patients. Measurement of cortisol concentrations in hair reflect the long-term systemic cortisol exposure and may be of use in refinement of hydrocortisone treatment. OBJECTIVE: We aimed to study whether long-term cortisol (hydrocortisone) levels, as measured in scalp hair, are similar in children with adrenal insufficiency and healthy children. MATERIAL AND METHODS: We set up a case control study, measuring anthropometric characteristics and hair cortisol concentrations (HCC) in 54 hydrocortisone substituted children with adrenal insufficiency (AI patients) in the age of 4-18 years and 54 healthy children matched for gender and age. RESULTS: Mean HCC were significantly higher in AI patients compared with healthy controls (mean 13.3 vs 8.2 pg/mg, P = 0.02). AI patients also had a higher BMI (P < 0.001) and waist circumference (WC) (P = 0.02). HCC was significantly associated with BMI (P = 0.002) and WC (P = 0.002). HCC explained 13% of the difference in BMI and 29% of the difference in WC between AI patients and controls. CONCLUSION: Hydrocortisone treated AI patients have increased HCC and adverse anthropometric characteristics compared with healthy controls. HCC measurement may be of value in identifying overtreatment and thereby improve hydrocortisone replacement therapy. PMID- 25039687 TI - High-dose chemotherapy with autologous stem cell rescue for treatment of retinoblastoma: report of five cases. AB - RB is a primarily pediatric cancer arising from the retina, initiated by biallelic loss of the RB1 gene. We report five children with bilateral RB (n = 3), extra-ocular disseminated RB, or disseminated relapsed RB, who were treated with tandem high-dose chemotherapy and autologous stem cell rescue. All patients received at least 2.2 * 10(6) /kg CD34(+) (median, 3.9 * 10(6) /kg) cells. The preparative regimen for course 1 was carboplatin, thiotepa, etoposide, and for course 2, CM and melphalan. ANC of at least 0.5 * 10(9) /L occurred at a median of 11 days (range, 10-12) and 15 days (range, 12-16) after the first and second procedure, respectively. Platelet engraftment occurred at a median of 13 days (range, 12-17) and 15 days (range, 14-22) after the first and second procedure, respectively. All of the five patients treated remain alive and disease free at the last follow-up time, ranging between 21 and 44 months after completion of autologous transplant. Additional therapy was required in one patient, in whom enucleation had to be performed because of early disease relapse, refractory to local therapy. Intensification of chemotherapy with repeated high-dose chemotherapy and autologous rescue appears an acceptable choice in selected cases with bilateral or extra-ocular disease, either recurrent or refractory. PMID- 25039688 TI - The interplay between semantic and phonological constraints during spoken-word comprehension. AB - This study addresses how top-down predictions driven by phonological and semantic information interact on spoken-word comprehension. To do so, we measured event related potentials to words embedded in sentences that varied in the degree of semantic constraint (high or low) and in regional accent (congruent or incongruent) with respect to the target word pronunciation. The data showed a negative amplitude shift following phonological mismatch (target pronunciation incongruent with respect to sentence regional accent). Here, we show that this shift is modulated by sentence-level semantic constraints over latencies encompassing auditory (N100) and lexical (N400) components. These findings suggest a fast influence of top-down predictions and the interplay with bottom-up processes at sublexical and lexical levels of analysis. PMID- 25039689 TI - Analysis of ecstasy tablets using capillary electrophoresis with capacitively coupled contactless conductivity detection. AB - A method for the identification of 3,4-methylenedioxymethamphetamine (MDMA) and meta-chlorophenylpiperazine (mCPP) was developed employing capillary electrophoresis (CE) with capacitively coupled contactless conductivity detection (C(4) D). Sample extraction, separation, and detection of "Ecstasy" tablets were performed in <10 min without sample derivatization. The separation electrolyte was 20 mm TAPS/Lithium, pH 8.7. Average minimal detectable amounts for MDMA and mCPP were 0.04 mg/tablet, several orders of magnitude lower than the minimum amount encountered in a tablet. Seven different Ecstasy tablets seized in Rio de Janeiro, Brazil, were analyzed by CE-C(4) D and compared against routine gas chromatography-mass spectrometry (GC-MS). The CE method demonstrated sufficient selectivity to discriminate the two target drugs, MDMA and mCPP, from the other drugs present in seizures, namely amphepramone, fenproporex, caffeine, lidocaine, and cocaine. Separation was performed in <90 sec. The advantages of using C(4) D instead of traditional CE-UV methods for in-field analysis are also discussed. PMID- 25039690 TI - Effects of home-based primary care on Medicare costs in high-risk elders. AB - OBJECTIVES: To determine the effect of home-based primary care (HBPC) on Medicare costs and mortality in frail elders. DESIGN: Case-control concurrent study using Medicare administrative data. SETTING: HBPC practice in Washington, District of Columbia. PARTICIPANTS: HBPC cases (n = 722) and controls (n = 2,161) matched for sex, age bands, race, Medicare buy-in status (whether Medicaid covers Part B premiums), long-term nursing home status, cognitive impairment, and frailty. Cases were eligible if enrolled in MedStar Washington Hospital Center's HBPC program during 2004 to 2008. Controls were selected from Washington, District of Columbia, and urban counties in Virginia, Maryland, and Pennsylvania. INTERVENTION: HBPC clinical service. MEASUREMENTS: Medicare costs, utilization events, mortality. RESULTS: Mean age was 83.7 for cases and 82.0 for controls (P < .001). A majority of both groups was female (77%) and African American (90%). During a mean 2-year follow-up, in univariate analysis, cases had lower Medicare ($44,455 vs $50,977, P = .01), hospital ($17,805 vs $22,096, P = .003), and skilled nursing facility care ($4,821 vs $6,098, P = .001) costs, and higher home health ($6,579 vs $4,169; P < .001) and hospice ($3,144 vs. $1,505; P = .005) costs. Cases had 23% fewer subspecialist visits (P = .001) and 105% more generalist visits (P < .001). In a multivariate model, cases had 17% lower Medicare costs, averaging $8,477 less per beneficiary (P = .003) over 2 years of follow-up. There was no difference between cases and controls in mortality (40% vs 36%, hazard ratio = 1.06, P = .44) or in average time to death (16.2 vs 16.8 months, P = .30). CONCLUSION: HBPC reduces Medicare costs for ill elders, with similar survival outcomes in cases and controls. PMID- 25039692 TI - Corrigendum. PMID- 25039691 TI - Root coverage by coronally advanced flap with connective tissue graft and/or enamel matrix derivative: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: Previous systematic reviews have reported that the use of a coronally advanced flap (CAF) combined with a connective tissue graft (CTG) or enamel matrix derivative (EMD) is more likely to achieve complete root coverage (CRC) than other modalities. However, the details of periodontal parameters and comparisons among a variety of combinations of CAF with CTG and/or EMD are left to be investigated. This study aimed to analyze the differences in periodontal parameters between these treatment modalities. MATERIAL AND METHODS: A literature search was performed using the Cochrane library and MEDLINE (PubMed) for studies focused on the treatment of gingival recession (Miller Class I, II and III) with CAF alone or combined with CTG, EMD or both up to December 2011. Randomized controlled clinical trials with a follow-up duration >= 6 mo were included. The outcome analysis included changes in periodontal probing depth (PPD), clinical attachment level, recession depth (RED) and keratinized tissue width (KTW). RESULTS: Thirteen randomized controlled clinical trials, including 529 Miller Class I-III defects from 321 patients were included. For an increase in KTW, CAF + CTG significantly improved more than CAF alone. CAF + EMD also gained more KTW than CAF alone. EMD reduced PPD, however, a significant difference was not found. Furthermore, the effects on changes of RED and clinical attachment level were not identified in the study. CONCLUSION: When combined with CAF, CTG contributed more in the increase of KTW, while EMD seemed helpful for wound healing by its potential in PPD reduction. However, further research is needed to clarify the effects on changes in RED and clinical attachment level. PMID- 25039693 TI - Self-concept of left-behind children in China: a systematic review of the literature. AB - The aim of our study was to systematically review studies which had compared self concept in left-behind children with the general population of children in China. Relevant studies about self-concept of left-behind children in China published from 2004 to 2014 were sought by searching online databases including Chinese Biological Medicine Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, Vip Database, PubMed Database, Google Scholar and Web of Science. The methodological quality of the articles was assessed by using Newcastle-Ottawa Scale (NOS). Poled effect size and associated 95% confidence interval (CI) were calculated using the random effects model. Cochrane's Q was used to test for heterogeneity and I(2) index was used to determine the degree of heterogeneity. Nineteen studies involving 7758 left-behind children met the inclusion criteria and 15 studies were included in a meta-analysis. The results indicated that left-behind group had a lower score of self-concept and more psychological problems than the control group. The factors associated with self concept in left-behind children were gender, age, grade and the relationships with parents, guardians and teachers. Left-behind children had lower self-concept and more mental health problems compared with the general population of children. The development of self-concept may be an important channel for promoting mental health of left-behind children. PMID- 25039694 TI - Education and Imaging. Hepatology: images of hydatid cyst of the liver mimicking an hepatic abscess. PMID- 25039695 TI - Case of pheochromocytoma associated with neurofibromatosis type 1 developing postoperative hypertension. PMID- 25039696 TI - The peer relationships of girls with ASD at school: comparison to boys and girls with and without ASD. AB - BACKGROUND: This study examines the social relationships of elementary school children with high-functioning autism, focusing on how gender relates to social preferences and acceptance, social connections, reciprocal friendships, and rejection. METHOD: Peer nomination data were analyzed for girls with and without ASD (n = 50) and boys with and without ASD (n = 50). Girls and boys with ASD were matched by age, gender, and IQ. Each child with ASD was matched by age and gender to a typically developing classmate. RESULTS: Consistent with typically developing populations, children with ASD preferred, were accepted by, and primarily socialized with same-gender friends. With fewer nominations and social relationships, girls and boys with ASD appear more socially similar to each other than to the same-gender control group. Additionally, girls and boys with ASD showed higher rates of social exclusion than their typically developing peers. However, boys with ASD were more overtly socially excluded compared to girls with ASD, who seemed to be overlooked, rather than rejected. CONCLUSIONS: Our data suggest a number of interesting findings in the social relationships of children with ASD in schools. Like typically developing populations, children with ASD identify with their own gender when socializing and choosing friends. But given the social differences between genders, it is likely that girls with ASD are experiencing social challenges that are different from boys with ASD. Therefore, gender is an important environmental factor to consider when planning social skills interventions at school. PMID- 25039697 TI - Height estimation using long bone segment length is unlikely to play a role in the routine measurement of healthy preschool children. PMID- 25039698 TI - Polyandrous females found fitter populations. AB - Multiple mating by females (polyandry) requires an evolutionary explanation, because it carries fitness costs in many species. When mated females disperse alone to a new habitat, their offspring may have no option but to mate with their siblings and incur inbreeding depression. However, some of the offspring of polyandrous females may only be half siblings, reducing inbreeding depression when isolated groups of siblings only have each other as mates. We investigated this putative benefit of polyandry over monandry by initiating multiple genetically isolated populations of Callosobruchus maculatus beetles, each founded by a single female, who received a complete ejaculate from either one or two males. The early generations had comparable fitness, but the F4 and F5 descendants of doubly inseminated females were more numerous and had higher egg to-adult survival than the descendants of singly inseminated females. This fitness benefit was of similar magnitude whether beetles were reared on their standard food plant, or on a less favourable food source. Our results suggest that polyandrous females produce fitter descendants in inbred founder populations and therefore that polyandry may affect movement ecology and invasion biology. PMID- 25039699 TI - Microscopic colitis: a review. AB - AIM: In recent years, microscopic colitis has been increasingly diagnosed. This review was carried out to evaluate demographic factors for microscopic colitis and to perform a systematic assessment of available treatment options. METHOD: Relevant publications up to December 2013 were identified following searches of PubMed and Google Scholar using the key words 'microscopic colitis', 'collagenous colitis' and 'lymphocytic colitis'. Two-hundred and forty-eight articles were identified. RESULTS: The term microscopic colitis includes lymphocytic colitis and collagenous colitis. Both have common clinical symptoms but are well defined histopathologically. The clinical course is usually benign, but serious complications, including death, may occur. A peak incidence from 60 to 70 years of age with a female preponderance is observed. Although most cases are idiopathic, associations with autoimmune disorders, such as coeliac disease and hypothyroidism, as well as with exposure to nonsteroidal anti-inflammatory drugs and proton-pump inhibitors, have been observed. The incidence and prevalence of microscopic colitis is rising and good-quality epidemiological research is needed. Treatment is currently largely based on anecdotal evidence and on results from limited clinical trials of budesonide. Long-term follow-up of these patients is not well established. CONCLUSION: The review synthesizes work on the definition of microscopic colitis and the relationship between collagenous and lymphocytic colitis. It reviews the international epidemiology and work on aetiology. In addition, it critically considers the efficacy of a range of treatments. PMID- 25039700 TI - High flow nasal cannula for continuous positive airway pressure weaning in preterm neonates: A single-centre experience. AB - AIM: High flow nasal cannula therapy (HFNC) is an emerging method of non-invasive respiratory support therapy for premature infants. Recent evidence around its safety and efficacy for post-extubation respiratory support is encouraging. However, its effect on long-term respiratory outcomes is not known. The aim of this study is to determine the effect of HFNC on respiratory outcomes (chronic lung disease (CLD), need for home oxygen) when used to wean babies from continuous positive airway pressure (CPAP). METHODS: This retrospective study compared respiratory outcomes in infants born <32 weeks gestation needing any respiratory support at birth in two epochs - epoch I (2004-2007) verus epoch II (2008-2011). HFNC was available to be used as a CPAP weaning modality in epoch II. RESULTS: A total of 1286 infants (epoch I: 597 vs. epoch II: 689), mean (standard deviation) gestation, 28.1 (2.2) versus 28.5 (2.3) weeks were enrolled, with 222 (32%) receiving HFNC in epoch II. Overall median duration of respiratory support increased by 150 h in epoch II (P = 0.03), primarily as HFNC hours. A reduction in duration of invasive ventilation and CPAP along with 6% (P = 0.01) reduction in CLD rates was observed in epoch II. No change in home oxygen therapy rates was noted. In logistic regression, HFNC had no significant effect on rates of CLD or home oxygen. CONCLUSIONS: Introduction of HFNC for weaning nasal CPAP seems to have a minimal effect on CLD rates. The effect of HFNC on long-term outcomes needs to be further evaluated. PMID- 25039701 TI - A key general stress response motif is regulated non-uniformly by CAMTA transcription factors. AB - Plants cope with environmental challenges by rapidly triggering and synchronizing mechanisms governing stress-specific and general stress response (GSR) networks. The GSR acts rapidly and transiently in response to various stresses, but the underpinning mechanisms have remained elusive. To define GSR regulatory components we have exploited the Rapid Stress Response Element (RSRE), a previously established functional GSR motif, using Arabidopsis plants expressing a 4xRSRE::Luciferase (RSRE::LUC) reporter. Initially, we searched public microarray datasets and found an enrichment of RSRE in promoter sequences of stress genes. Next, we treated RSRE::LUC plants with wounding and a range of rapidly stress-inducible hormones and detected a robust LUC activity solely in response to wounding. Application of two Ca(2+) burst inducers, flagellin22 (flg22) and oligogalacturonic acid, activated RSRE strongly and systemically, while the Ca(2+) chelator ethylene glycol tetraacetic acid (EGTA) significantly reduced wound induction of RSRE::LUC. In line with the signaling function of Ca(2+) in transduction events leading to activation of RSRE, we examined the role of CALMODULIN-BINDING TRANSCRIPTIONAL ACTIVATORs (CAMTAs) in RSRE induction. Transient expression assays displayed CAMTA3 induction of RSRE and not that of the mutated element mRSRE. Treatment of selected camta mutant lines integrated into RSRE::LUC parent plant, with wounding, flg22, and freezing, established a differential function of these CAMTAs in potentiating the activity of RSRE. Wound response studies using camta double mutants revealed a cooperative function of CAMTAs2 and 4 with CAMTA 3 in the RSRE regulation. These studies provide insights into governing components of transduction events and reveal transcriptional modules that tune the expression of a key GSR motif. PMID- 25039702 TI - The effect on pain of three different methods of intramuscular injection: A randomized controlled trial. AB - This paper is the report of a study to determine the effect on pain of internally rotating the foot, pointing the toes down and/or using the Z-track technique during intramuscular injection and to investigate differences in pain perception related to gender and body mass index. A randomized controlled trial was carried out from September to November 2010 on 75 patients receiving diclofenac sodium intramuscularly at a university hospital in Zonguldak, Turkey. The primary outcome measure collected was pain intensity, measured on a visual analogue scale. Each subject received three injections by the same investigator using three different techniques. The three techniques were randomly allocated, and the subjects were blinded to the injection technique being used. After each injection, another investigator, who had no prior knowledge of which injection technique was used, immediately assessed pain intensity using the visual analogue scale. Research findings demonstrated that the Z-track and internally rotated foot techniques significantly reduced pain intensity during intramuscular injection. Statistically significant differences in pain intensity were observed between the three injection techniques. The results supported the hypothesis that the internally rotated foot and Z-track techniques significantly reduce pain intensity. PMID- 25039703 TI - Analysis of 36 cases of Blaschkoid dyspigmentation: reading between the lines of Blaschko. AB - Genetic mosaicism indicated by lines of Blaschko pigmentary changes has been described under a number of different and confusing terms, including hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, nevus depigmentosus, and cutis tricolor. Moreover, extracutaneous findings, particularly serious neurologic defects, have been reported in a large number of these cases. We reviewed the cutaneous and extracutaneous findings in 36 patients referred to the Harriet Lane Pediatric Dermatology Clinic, Johns Hopkins University, from June 12, 2008, to May 24, 2009, for evaluation of macular lesions along the lines of Blaschko. Patients with dyspigmentation along the lines of Blaschko and no history of preceding inflammatory skin lesions were identified for inclusion in a database at their initial visit. Information on age at presentation; sex; age when first diagnosed; type, pattern, and location of the pigmentary anomaly; and extracutaneous abnormalities noted on a review-of systems questionnaire and physical examination was recorded for each child. Patients were asked to follow up within 6 to 12 months of the initial visit. Patients included 13 boys and 23 girls ages 3 months to 15 years with lesions noted from birth to 12 years. Lesions were hypopigmented in 21 patients and hyperpigmented in 15. No patients presented with hypopigmented and hyperpigmented lesions. Extracutaneous findings were noted in five children (13.9%). Historically, cases of Blaschkoid hypopigmentation and hyperpigmentation have been associated with a high percentage of extracutaneous manifestations, particularly neurologic and neurodevelopmental defects. In our study, only five patients (13.9%) were noted to have extracutaneous abnormalities, and these findings may have been coincidental. We propose the term 'Blaschkoid dyspigmentation' to describe the cutaneous findings. Although serious extracutaneous findings may occur in children with Blaschkoid dyspigmentation and results of careful physical examination and review of systems should direct an evaluation, serious extracutaneous findings occur in a minority of patients. PMID- 25039704 TI - A teenage girl with green hair. AB - An adolescent girl with blond hair, her family, and classmates noted that her hair was progressively turning green. Initially the green color was thought to be secondary to chlorine from the local swimming pool. This was not the real cause. The chlorotrichosis was actually caused by an excessive amount of dissolved copper from copper pipes in the home plumbing system. Copper had leached from the plumbing and accumulated in the pipes because the rented house had been vacant for many months. Risk factors for chlorotrichosis include light-colored hair, copper plumbing, long periods when the water was not thoroughly flushed out of the copper pipes, and frequent shampooing. PMID- 25039705 TI - Chronic erythematous plaque on the leg of an 18 month-old boy. PMID- 25039706 TI - Rough skin-colored papules on the arms, legs, and trunk. PMID- 25039707 TI - Multiple papules and nodules in a child with Bartonella infection. PMID- 25039708 TI - Dermatitis herpetiformis: not only in adults. PMID- 25039709 TI - A response from the authors of An unusual case of dermatitis herpetiformis:. PMID- 25039710 TI - Improving malaria treatment and prevention in India by aiding district managers to manage their programmes with local information: a trial assessing the impact of Lot Quality Assurance Sampling on programme outcomes. AB - OBJECTIVES: This paper reports the first trial of Lot Quality Assurance Sampling (LQAS) assessing associations between access to LQAS data and subsequent improvements in district programming. This trial concerns India's approach to addressing an increase in malaria-attributable deaths by training community health workers to diagnose, treat and prevent malaria, while using LQAS to monitor sub-district performance and make programme improvements. METHODS: The Ministry of Health introduced LQAS into four matched high malaria burden districts (Annual Parasite Incidence >5) (N > 5 million). In each sub-district, we sampled four populations in three 6-monthly surveys: households, children <5 years, people with fever in the last 2 weeks and community health workers. In three districts, trained local staff collected, analysed and used data for programme management; in one control district, non-local staff collected data and did not disseminate results. For eight indicators, we calculated the change in proportion from survey one to three and used a Difference-in-Differences test to compare the relative change between intervention and control districts. RESULTS: Coverage increased from survey one to three for 24 of 32 comparisons. Difference in-Differences tests revealed that intervention districts exhibited significantly greater change in four of six vertical strategies (insecticide treated bed-nets and indoor residual spraying), one of six treatment-seeking behaviours and four of 12 health worker capacity indicators. The control district displayed greater improvement than two intervention districts for one health worker capacity indicator. One district with poor management did not improve. CONCLUSIONS: In this study, LQAS results appeared to support district managers to increase coverage in underperforming areas, especially for vertical strategies in the presence of diligent managers. PMID- 25039711 TI - Homozygous IL36RN mutation and NSD1 duplication in a patient with severe pustular psoriasis and symptoms unrelated to deficiency of interleukin-36 receptor antagonist. PMID- 25039712 TI - Organic geochemical studies of modern microbial mats from Shark Bay: Part I: Influence of depth and salinity on lipid biomarkers and their isotopic signatures. AB - The present study investigated the influence of abiotic conditions on microbial mat communities from Shark Bay, a World Heritage area well known for a diverse range of extant mats presenting structural similarities with ancient stromatolites. The distributions and stable carbon isotopic values of lipid biomarkers [aliphatic hydrocarbons and polar lipid fatty acids (PLFAs)] and bulk carbon and nitrogen isotope values of biomass were analysed in four different types of mats along a tidal flat gradient to characterize the microbial communities and systematically investigate the relationship of the above parameters with water depth. Cyanobacteria were dominant in all mats, as demonstrated by the presence of diagnostic hydrocarbons (e.g. n-C17 and n-C17:1). Several subtle but important differences in lipid composition across the littoral gradient were, however, evident. For instance, the shallower mats contained a higher diatom contribution, concordant with previous mat studies from other locations (e.g. Antarctica). Conversely, the organic matter (OM) of the deeper mats showed evidence for a higher seagrass contribution [high C/N, 13C-depleted long-chain n-alkanes]. The morphological structure of the mats may have influenced CO2 diffusion leading to more 13C-enriched lipids in the shallow mats. Alternatively, changes in CO2 fixation pathways, such as increase in the acetyl COA-pathway by sulphate-reducing bacteria, could have also caused the observed shifts in delta13C values of the mats. In addition, three smooth mats from different Shark Bay sites were analysed to investigate potential functional relationship of the microbial communities with differing salinity levels. The C25:1 HBI was identified in the high salinity mat only and a lower abundance of PLFAs associated with diatoms was observed in the less saline mats, suggesting a higher abundance of diatoms at the most saline site. Furthermore, it appeared that the most and least saline mats were dominated by autotrophic biomass using different CO2 fixation pathways. PMID- 25039713 TI - Discrete choice experiments: helping to understand how patients make decisions and promoting non-paternalistic care. PMID- 25039714 TI - Social oral epidemi(olog)(2) y where next: one small step or one giant leap? AB - Since the early 1990s, there has been heated debate critically reflecting on social epidemiology. Yet, very little of this debate has reached oral epidemiology. This is no more noticeable than in the field of oral health inequalities. One of the significant achievements of social oral epidemiology has been the persistent documentation of social patterning of oral disease. Nevertheless, where social oral epidemiology has fallen down is going beyond description to explaining these patterns. Thinking how and in what way things happen, not just in relation to oral health inequalities but also more broadly, requires a more creative approach which links to scholarship outside of dentistry, including the work from critical epidemiologists to that within the social sciences. The aim of this review study is to provide a critical commentary on key aspects of more general epidemiological debates in order to inform and develop social oral epidemiology theory and methodology. In the first section, 'Where are we now?', six key debates are reflected upon: (i) analysis of variance versus analysis of causes, (ii) the fallacy of independent effects, (iii) black box thinking, (iv) theory and the understanding of mechanisms, (v) individualization of risk and (vi) the meaning of 'social'. In the second section, 'Where to next?' we draw on a number of fundamental issues from within the social science literature in order to highlight possible channels of future inquiry. Our overriding goal throughout is to facilitate a critical engagement in order to improve understanding and generate knowledge in relation to population oral health. PMID- 25039715 TI - The incidence rate of colectomy for medically refractory ulcerative colitis has declined in parallel with increasing anti-TNF use: a time-trend study. AB - BACKGROUND: Medical therapy is standard treatment for ulcerative colitis with colectomy reserved for medically refractory disease or malignancy. The introductions of ciclosporin in 1994 and anti-TNF therapy in 2005 have extended medical management options. AIM: To determine whether the colectomy incidence rate for medically refractory ulcerative colitis has changed since the introduction of anti-TNF therapy. METHODS: Adult patients with a diagnosis of ulcerative colitis and who subsequently underwent an urgent or elective colectomy for medically refractory disease in Edmonton, Canada between 1 January 1998 and 31 December 2011 were identified. Log-linear regression was used to estimate the annual percent change in the total colectomy incidence rate (urgent and elective combined) and the urgent and elective incidence rates individually, before and after 2005, the year infliximab was approved for use in ulcerative colitis. Temporal trends of drug utilisation in this study population were also described. RESULTS: During 1998-2011, 481 patients with ulcerative colitis underwent a colectomy for medically refractory disease. There was negligible change in the total colectomy incidence rate from 1998 to 2005, with an annual percent change of 4.4% (95% confidence interval (CI): -1.12% to 10.16%). From 2005-2011, following the approval and increasing use of anti-TNF therapy, the total colectomy incidence rate decreased by 16.1% (95% CI: -21.32% to -10.54%) every year to 0.9 per 100 ulcerative colitis patients in 2011. CONCLUSION: The total incidence rate of colectomy for medically refractory ulcerative colitis has declined substantially since 2005, paralleling the increased use of anti-TNF therapy in this patient population. PMID- 25039716 TI - alpha-Selective ribofuranosylation of alcohols with ribofuranosyl iodides and triphenylphosphine oxide. AB - Ribofuranosylation of a variety of alcohols with ribofuranosyl iodides in the presence of a base and triphenylphosphine oxide afforded the corresponding alpha ribofuranosides with diastereoselectivities >= 99:1. This reaction can be carried out under mildly basic conditions and is thus compatible with acid-sensitive functional groups. PMID- 25039717 TI - A collaborative effort: planning group suggests a goal of 1000 more transplants a year for the next five years. PMID- 25039720 TI - Bovine pericardium diaphragm repair of diaphragmatic hernia after LVAD explantation and heart transplantation. PMID- 25039721 TI - Sex differences in chronic pain management practices for patients receiving opioids from the Veterans Health Administration. AB - BACKGROUND: Women experience chronic pain and use pain-related health care at higher rates than men. It is not known whether the pain-related health care female veterans receive is consistent with clinical practice guideline recommendations or whether receipt of this care differs between men and women. OBJECTIVE: The aim of this study was to identify whether sex differences in chronic pain management care exist for patients served by the Veterans Health Administration (VHA). DESIGN: Data on patient demographics, diagnostic criteria, and health care utilization were extracted from VHA administrative databases for fiscal year 2010 (FY10). PATIENTS: Patients in this study included all VHA patients (excluding metastatic cancer patients) who received more than 90 days of a short-acting opioid medication or a long-acting opioid medication prescription in FY10 study. MEASURES: Multilevel logistic regressions were conducted to identify sex differences in receipt of guideline-recommended chronic pain management. RESULTS: A total of 480,809 patients met inclusion criteria. Female patients were more likely to receive most measures of guideline-recommended care for chronic pain including mental health assessments, psychotherapy, rehabilitation therapy, and pharmacy reconciliation. However, women were more likely to receive concurrent sedative prescriptions, which is inconsistent with guideline recommendations. Most of the observed sex differences persisted after controlling for key demographic and diagnostic differences. CONCLUSIONS: Findings suggest that female VHA patients are more likely to receive an array of pain management practices than male patients, including both contraindicated and recommended polypharmacy. Quality improvement efforts to address underutilization of mental health and rehabilitative services for pain by male patients and polypharmacy in female patients should be considered. PMID- 25039722 TI - Geographic differences in vertical connectivity in the Caribbean coral Montastraea cavernosa despite high levels of horizontal connectivity at shallow depths. AB - The deep reef refugia hypothesis proposes that deep reefs can act as local recruitment sources for shallow reefs following disturbance. To test this hypothesis, nine polymorphic DNA microsatellite loci were developed and used to assess vertical connectivity in 583 coral colonies of the Caribbean depth generalist coral Montastraea cavernosa. Samples were collected from three depth zones (<=10, 15-20 and >=25 m) at sites in Florida (within the Upper Keys, Lower Keys and Dry Tortugas), Bermuda, and the U.S. Virgin Islands. Migration rates were estimated to determine the probability of coral larval migration from shallow to deep and from deep to shallow. Finally, algal symbiont (Symbiodinium spp.) diversity and distribution were assessed in a subset of corals to test whether symbiont depth zonation might indicate limited vertical connectivity. Overall, analyses revealed significant genetic differentiation by depth in Florida, but not in Bermuda or the U.S. Virgin Islands, despite high levels of horizontal connectivity between these geographic locations at shallow depths. Within Florida, greater vertical connectivity was observed in the Dry Tortugas compared to the Lower or Upper Keys. However, at all sites, and regardless of the extent of vertical connectivity, migration occurred asymmetrically, with greater likelihood of migration from shallow to intermediate/deep habitats. Finally, most colonies hosted a single Symbiodinium type (C3), ruling out symbiont depth zonation of the dominant symbiont type as a structuring factor. Together, these findings suggest that the potential for shallow reefs to recover from deep-water refugia in M. cavernosa is location-specific, varying among and within geographic locations likely as a consequence of local hydrology. PMID- 25039723 TI - Remarkable improvement of relapsing dyshidrotic eczema after treatment of coexistant hyperhidrosis with oxybutynin. AB - Dyshidrotic hand eczema is a common condition, which can be resistant to various treatments. Although a number of etiologic factors are involved in the pathogenesis of dyshidrotic eczema, hyperhidrosis is assumed to play a significant role. Oxybutynin is an alternative treatment for hyperhidrosis. We present the cases of two patients suffering from hyperhidrosis and dyshidrotic eczema, who were treated with oxybutynin with impressive results. PMID- 25039724 TI - Refinement of ischemic stroke risk in patients with atrial fibrillation and CHA2 DS2 -VASc score of 1. AB - BACKGROUND: Patients with atrial fibrillation (AF) with CHA2 DS2 -VASc score of 1 (where CHA2 DS2 -VASc is CHA2 DS2 -Vascular disease, Age 65-74 years, Sex category) are recommended to receive antithrombotic therapy. Nonetheless, it remains unclear whether individual components that constitute CHA2 DS2 -VASc score contribute equally to the ischemic stroke risk, particularly in patients with CHA2 DS2 -VASc score of 1. The objective was to describe and compare the risk of ischemic stroke of the six individual components constituting CHA2 DS2 VASc among AF patients with CHA2 DS2 -VASc score of 1. METHODS AND RESULTS: We studied all patients with CHA2 DS2 -VASc score of 1 and no antithrombotic therapy from our cohort of 9,727 Chinese AF patients. A total of 548 patients were studied: 190 patients with CHA2 DS2 -VASc score of 0 and 358 patients with CHA2 DS2 -VASc score of 1. Of those with a baseline CHA2 DS2 -VASc score of 1, 51.1% patients aged 65-75; 29.3% patients were female; 12.0% had hypertension; 4.5% had heart failure; 2.5% had diabetes; and 0.6% had vascular disease. After 1,758 patient-years of follow-up, the annual incidence of stroke was 2.4% and 6.6% for patients with CHA2 DS2 -VASc score of 0 and 1, respectively. Compared with patients with CHA2 DS2 -VASc score of 0, patients with hypertension leading to CHA2 DS2 -VASc score of 1 were at the highest risk of stroke (Hazard ratio [HR]: 9.8, 95% confidence interval [CI]: 2.7-35.6), followed by patients aged 65-74 (HR: 3.9, 95% CI: 2.3-6.6) and female gender (HR: 2.3, 95% CI: 1.1-4.8). Heart failure, diabetes mellitus, and vascular disease were not associated with stroke. CONCLUSION: In AF patients with CHA2 DS2 -VASc score of 1, hypertension confers the highest risk for stroke among other risk factors comprising the score. A more aggressive thromboprophylaxis strategy may be justified among AF patients with CHA2 DS2 -VASc score of 1 due to hypertension. PMID- 25039726 TI - Lessons learned by those prepared to greet chance head on. PMID- 25039727 TI - When is enough enough? Judging the sufficiency of evidence in medical education. PMID- 25039728 TI - The missing self: competence, the person and Foucault. PMID- 25039729 TI - A (good) look at the rating of teaching effectiveness: towards holistic and programmatic assessment. PMID- 25039730 TI - When I say...grounded theory. PMID- 25039731 TI - How much evidence does it take? A cumulative meta-analysis of outcomes of simulation-based education. AB - CONTEXT: Studies that investigate research questions that have already been resolved represent a waste of resources. However, the failure to collect sufficient evidence to resolve a given question results in ambiguity. OBJECTIVES: The present study was conducted to reanalyse the results of a meta-analysis of simulation-based education (SBE) to determine: (i) whether researchers continue to replicate research studies after the answer to a research question has become known, and (ii) whether researchers perform enough replications to definitively answer important questions. METHODS: A systematic search of multiple databases to May 2011 was conducted to identify original research evaluating SBE for health professionals in comparison with no intervention or any active intervention, using skill outcomes. Data were extracted by reviewers working in duplicate. Data synthesis involved a cumulative meta-analysis to illuminate patterns of evidence by sequentially adding studies according to a variable of interest (e.g. publication year) and re-calculating the pooled effect size with each addition. Cumulative meta-analysis by publication year was applied to 592 comparative studies using several thresholds of 'sufficiency', including: statistical significance; stable effect size classification and magnitude (Hedges' g +/- 0.1), and precise estimates (confidence intervals of less than +/- 0.2). RESULTS: Among studies that compared the outcomes of SBE with those of no intervention, evidence supporting a favourable effect of SBE on skills existed as early as 1973 (one publication) and further evidence confirmed a quantitatively large effect of SBE by 1997 (28 studies). Since then, a further 404 studies were published. Among studies comparing SBE with non-simulation instruction, the effect initially favoured non-simulation training, but the addition of a third study in 1997 brought the pooled effect to slightly favour simulation, and by 2004 (14 studies) this effect was statistically significant (p < 0.05) and the magnitude had stabilised (small effect). A further 37 studies were published after 2004. By contrast, evidence from studies evaluating repetition continued to show borderline statistical significance and wide confidence intervals in 2011. CONCLUSIONS: Some replication is necessary to obtain stable estimates of effect and to explore different contexts, but the number of studies of SBE often exceeds the minimum number of replications required. PMID- 25039732 TI - Medical education research: a vibrant community of research and education practice. AB - OBJECTIVES: Medical education research is thriving. In recent decades, numbers of journals and publications have increased enormously, as have the number and size of medical education meetings around the world. The aim of this paper is to shed some light on the origins of this success. My central argument is that dialogue between education practice (and its teachers) and education research (and its researchers) is indispensable. REFLECTIONS: To illustrate how I have come to this perspective, I discuss two crucial developments of personal import to myself. The first is the development of assessment theory informed by both research findings and insights emerging from implementations conducted in collaboration with teachers and learners. The second is the establishment of a department of education that includes many members from the medical domain. CONCLUSIONS: Medical education is thriving because it is shaped and nourished within a community of practice of collaborating teachers, practitioners and researchers. This obviates the threat of a fissure between education research and education practice. The values of this community of practice - inclusiveness, openness, supportiveness, nurture and mentorship - are key elements for its sustainability. In pacing the development of our research in a manner that maintains this synergy, we should be mindful of the zone of proximal development of our community of practice. PMID- 25039733 TI - Lessons learned in the pursuit of a dream. AB - CONTEXT: The author describes a career in which he combined clinical surgery with the formal study of medical education. In the 1980s, when the author embarked on this career track, it was an uncommon pathway. Over the last 30 years there has been an exponential increase in the number of individuals who have made medical education their principal academic focus. This paper provides examples from the author's personal story and lessons derived from that experience. PROCESS: The author outlines his experience of attaining formal training in education and concludes that this training was a foundational element in his pursuit of a career in health education research. The author describes his involvement in the transition from paper and pencil-based tests to performance-based testing in high stakes examinations. He describes the development of a research centre in health professions education and the establishment of a simulation centre. The author's experiences in the development of an examination intended to measure technical skills, in the adoption of surgical safety checklists and in the elaboration of a programme in competency-based education are discussed. DISCUSSION: The author describes several of the lessons learned in the course of his career in medical education. He argues that successful enterprises in scholarship in medicine are almost invariably the product of interdisciplinarity. He describes the power of a joint venture between a university and an academic hospital. He argues that the geographical footprint of an emerging centre is critical. He discusses the importance of graduate studentship in an emerging discipline and enterprise. PMID- 25039734 TI - Excellence in clinical teaching: knowledge transformation and development required. AB - CONTEXT: Clinical teachers in medicine face the daunting task of mastering the many domains of knowledge needed for practice and teaching. The breadth and complexity of this knowledge continue to increase, as does the difficulty of transforming the knowledge into concepts that are understandable to learners. Properly targeted faculty development has the potential to expedite the knowledge transformation process for clinical teachers. METHODS: Based on my own research in clinical teaching and faculty development, as well as the work of others, I describe the unique forms of clinical teacher knowledge, the transformation of that knowledge for teaching purposes and implications for faculty development. RESULTS: The following forms of knowledge for clinical teaching in medicine need to be mastered and transformed: (i) knowledge of medicine and patients; (ii) knowledge of context; (iii) knowledge of pedagogy and learners, and (iv) knowledge integrated into teaching scripts. This knowledge is employed and conveyed through the parallel processes of clinical reasoning and clinical instructional reasoning. Faculty development can facilitate this knowledge transformation process by: (i) examining, deconstructing and practising new teaching scripts; (ii) focusing on foundational concepts; (iii) demonstrating knowledge-in-use, and (iv) creating a supportive organisational climate for clinical teaching. CONCLUSIONS: To become an excellent clinical teacher in medicine requires the transformation of multiple forms of knowledge for teaching purposes. These domains of knowledge allow clinical teachers to provide tailored instruction to learners at varying levels in the context of fast-paced and demanding clinical practice. Faculty development can facilitate this knowledge transformation process. PMID- 25039735 TI - The 'missing person' in roles-based competency models: a historical, cross national, contrastive case study. AB - CONTEXT: The use of roles such as medical expert, advocate or communicator to define competencies is currently popular in health professions education. CanMEDS is one framework that has been subject to great uptake across multiple countries and professions. The examination of the historical and cultural choices of names for roles generates insight into the nature and construction of roles. One role that has appeared in and disappeared from roles-based frameworks is that of the 'person'. METHODS: In order to examine the implications of explicitly including or excluding the role of the 'physician as person' in a competency framework, we conducted a contrastive analysis of the development of frameworks in Canada and the Netherlands. We drew upon critical social science theoretical understandings of the power of language in our analysis. RESULTS: In Canada, the 'person' role was a late addition to the precursory work that informed CanMEDS, and was then excluded from the final set of CanMEDS role names. In the Netherlands, a 'reflector' role was added in some Dutch schools and programmes when CanMEDS was adopted. This was done in order to explicitly emphasise the importance of the 'person' of the trainee. CONCLUSIONS: In analysing choices of names for roles, we have the opportunity to see how cultural and historical contexts affect conceptions of the roles of doctors. The taking up and discarding of the 'person' role in Canada and the Netherlands suggest that as medical educators we may need to further consider the ways in which we wish the trainee as a person to be made visible in the curriculum and in assessment tools. PMID- 25039736 TI - Effects of free, cued and modelled reflection on medical students' diagnostic competence. AB - CONTEXT: Structured reflection while practising the diagnosing of cases has been shown to improve medical students' learning of clinical diagnosis. The present study investigated whether additional instructional guidance increases the benefits of reflection by comparing the effects of free, cued and modelled reflection on learning. METHODS: Fifty-eight Year 5 and 57 Year 6 medical students participated in a three-phase experiment. During the learning phase, participants diagnosed eight clinical cases under different experimental conditions: free reflection; cued reflection, and modelled reflection. In an immediate test and a delayed test administered 1 week later, they diagnosed new sets of eight different cases, four of which presented diseases they had studied during the learning phase. Learning was measured according to diagnostic accuracy on the cases that involved the four diseases that appeared in all phases. RESULTS: Repeated-measures analysis of variance (anova) of mean scores for diagnostic accuracy (range: 0-1) showed a significant main effect of experimental condition (p < 0.001), year of training (p = 0.013), and performance moment (p = 0.003), without significant interaction effects. Overall, the modelled reflection group and the cued reflection group did not differ in performance (p = 1.00), but both outperformed the free reflection group (p < 0.001 for both comparisons). Overall performance increased in the delayed test relative to the immediate test (p = 0.004) and to the learning phase (p = 0.03), but did not differ in the latter two phases. Both Year 6 and Year 5 students rated studying examples of reflection as less effortful than either cued or free reflection in the learning phase (p < 0.001 for all comparisons). CONCLUSIONS: Students apparently learn more with less effort by studying correct structured reflection while practising the diagnosing of cases than by reflecting without any instructional guidance. Examples of reflection and cued reflection were more beneficial for learning than free reflection and may represent a useful instructional strategy for clinical teaching. PMID- 25039737 TI - The power of questions: a discourse analysis about doctor-student interaction. AB - CONTEXT: During clerkships, teaching and learning in day-to-day activities occur in many moments of interaction among doctors, patients, peers and other co workers. How people talk with one another influences their identity, their position and what they are allowed to do. This paper focuses on the opportunities and challenges of such moments of interaction between doctors and students during a clerkship characterised by short supervisory relationships. METHODS: This study was conducted in a 10-week internal medicine clerkship. Nine students and 10 doctors who worked with these nine students participated by regularly describing moments of interaction, using dictaphones. We performed critical discourse analysis of material sourced from a total of 184 audio diary entries and seven student debriefing interviews to reveal how participants discursively shaped the way they could think, speak and conduct themselves. RESULTS: The ways in which doctors and students posed and answered questions represented a recurrent and influential feature in the diaries. This Question and Answer dynamic revealed six discourses of Basic Learning Need, Care and Attention, Power Game, Exchange of Currency, Distance, and Equality and Reciprocity. These discourses and the interplay among them revealed both students' and doctors' frameworks of needs and expectations in a culturally defined power structure. The interplay among the discourses reflected the ways in which doctor-student interactions afforded meaningful contributions to their medical or educational practice such as in the exchange of authentic professional or personal experience. CONCLUSIONS: By purposefully bringing power structures to the surface, we have addressed the complexity of learning and teaching as it occurs in day-to-day moments of interaction in a clerkship with little continuity in supervision. Both doctors and students should be supported to reflect critically on how they contribute to supervisory relationships with reference to, for example, the ways in which they ask or answer questions. PMID- 25039738 TI - Clinical supervision and learning opportunities during simulated acute care scenarios. AB - CONTEXT: Closer clinical supervision has been increasingly promoted to improve patient care. However, the continuous bedside presence of supervisors may threaten the model of progressive independence traditionally associated with effective clinical training. Studies have shown favourable effects of closer supervision on trainees' learning, but have not paid specific attention to the learning processes involved. METHODS: We conducted a simulation-based study to explore the learning opportunities created during simulated resuscitation scenarios under different levels of supervision. Fifty-three residents completed a supervised scenario. Residents were randomised to one of three levels of supervision: telephone (distant); in-person after telephone consultation (immediately available), and in-person from the beginning of the simulation (direct). These interactions were converted into 234 pages of transcripts for analysis. We performed an inductive thematic analysis followed by a deductive analysis using situated learning theory as a theoretical framework. RESULTS: Learning opportunities created during simulated scenarios were identified as belonging to either of two categories, incidental and engineered opportunities. The themes resulting from this framework contributed to our understanding of trainees' contributions to patient care, supervisors' influences on patient care, and trainee-supervisor interactions. All forms of supervision offered trainees incidental opportunities for practice, although the nature of these contributions could be affected by the bedside presence of supervisors. Supervisors' involvement in patient care by telephone and in person was associated with a shift of responsibility for patient care, but represented, respectively, engineered and incidental opportunities for observation. In-person supervisor trainee interactions added value to observation and created additional opportunities for incidental feedback and engineered practice. CONCLUSIONS: The shift of responsibility for patient care occurred during both direct and distant supervision, and did not necessarily translate into a lack of opportunities for trainee participation and practice. PMID- 25039739 TI - How do medical students form impressions of the effectiveness of classroom teachers? AB - CONTEXT: Teaching effectiveness ratings (TERs) are used to provide feedback to teachers on their performance and to guide decisions on academic promotion. However, exactly how raters make decisions on teaching effectiveness is unclear. OBJECTIVES: The objectives of this study were to identify variables that medical students appraise when rating the effectiveness of a classroom teacher, and to explore whether the relationships among these variables and TERs are modified by the physical attractiveness of the teacher. METHODS: We asked 48 Year 1 medical students to listen to 2-minute audio clips of 10 teachers and to describe their impressions of these teachers and rate their teaching effectiveness. During each clip, we displayed either an attractive or an unattractive photograph of an unrelated third party. We used qualitative analysis followed by factor analysis to identify the principal components of teaching effectiveness, and multiple linear regression to study the associations among these components, type of photograph displayed, and TER. RESULTS: We identified two principal components of teaching effectiveness: charisma and intellect. There was no association between rating of intellect and TER. Rating of charisma and the display of an attractive photograph were both positively associated with TER and a significant interaction between these two variables was apparent (p < 0.001). The regression coefficient for the association between charisma and TER was 0.26 (95% confidence interval [CI] 0.10-0.41) when an attractive picture was displayed and 0.83 (95% CI 0.66 1.00) when an unattractive picture was displayed (p < 0.001). CONCLUSIONS: When medical students rate classroom teachers, they consider the degree to which the teacher is charismatic, although the relationship between this attribute and TER appears to be modified by the perceived physical attractiveness of the teacher. Further studies are needed to identify other variables that may influence subjective ratings of teaching effectiveness and to evaluate alternative strategies for rating teaching effectiveness. PMID- 25039740 TI - Progression in competency-based education. PMID- 25039741 TI - Cholestatic hepatic injury associated with vismodegib, aspirin, and naproxen use: a case study and review of vismodegib safety. AB - BACKGROUND: Vismodegib is a novel hedgehog pathway inhibitor approved to treat advanced and metastatic basal cell carcinoma (BCC) in the United States. Several studies have demonstrated efficacy for treatment of new and existing BCC in both basal cell nevus syndrome (BCNS) and non-BCNS patients. However, severe and numerous adverse events are associated with vismodegib use. Therefore, we have also examined all of the currently published clinical trials and tabulated the available adverse events for review. The most frequently reported adverse events include muscle spasms (53.4%), dysgeusia/ageusia (49.3%), alopecia (38.8%), fatigue (32.0%), nausea (28.4%), weight loss (24.2%), and decreased appetite (16.5%). CASE STUDY: We report a case of a previously healthy 72-year-old male with a history of innumerable BCCs who developed severe nausea, jaundice, and cholestasis with significantly elevated BUN, creatinine, and liver enzymes one month after starting vismodegib. The patient began using over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) to treat severe, vismodegib-induced myalgia. No other new medications were started. Our patient had no history of liver disease. CONCLUSIONS: Herein, we describe a potential serious adverse effect associated with vismodegib use. Whether the illness is directly attributable to the medication or the result of drug-drug interactions between vismodegib and NSAIDs, practitioners should be aware of the possibility of hepatic injury in patients on vismodegib. Furthermore, patients need to be informed of the potential risks of vismodegib and should be monitored closely to ensure that life-threatening complications of treatment are avoided. PMID- 25039742 TI - Generation of eGFP and Cre knockin rats by CRISPR/Cas9. AB - The type II bacterial CRISPR/Cas [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)] system is a very valuable genome engineering tool, which has been widely used in genome editing of a variety of organisms. Previously, we generated floxed alleles in rats by CRISPR/Cas9. Here, we successfully use a two-cut strategy with one circular vector, which contains the exogenous cDNAs with homology arm regions, in generating knockin rats at the Trdmt1, Nestin and Cck loci. The efficiency of CRISPR/Cas9-mediated knockin was up to 54%. Furthermore, by crossing the Nestin Cre rat with the Dnmt3b floxed rat and Cck-Cre with the Dnmt1 floxed rat, we detected Cre/loxP-mediated recombination in the F1 generation of rats. We also show that the knockin alleles were germline transmitted. These results provided a simple and flexible engineering strategy for the establishment of knockin rats. PMID- 25039743 TI - Antioxidant and antimicrobial activity of commercial propolis extract in beef patties. AB - The objective of this study was to evaluate the efficacy of propolis extract (PE) to reduce lipid oxidation and microbial growth on beef patties during refrigerated storage. Beef patties were manufactured by incorporating PE in 4 different treatments: (1) Control (no PE addition); (2) commercial propolis 1 (2% w/w; CP1); (3) commercial propolis 2 (2% w/w; CP2); and (4) noncommercial propolis (2% w/w; NCP). Raw patties were wrapped with polyvinyl chloride and stored at 2 degrees C for 8 d. Total phenolic content (TPC), free-radical scavenging activity (FRS), and polyphenolic content of the PE were evaluated using high-performance liquid chromatography (HPLC). Lipid oxidation (thiobarbituric acid-reactive substances (TBARS), conjugated dienes (CnDs), metmyoglobin (MetMb%), pH variation, and color (L*, a*, b*, C*, and h*), and microbial growth (mesophilic and psychrotrophic bacteria) of patty samples were measured. NCP treatment demonstrated the highest FRS (64.8% at 100 MUg/mL), which correlated with TPC and the presence of polyphenolic compounds. Lipid oxidation (78.54%, TBARS; 45.53%, CnD; 58.57%, MetMb) and microbial mesophilic and psychrotrophic growth (19.75 and 27.03%, respectively) values were reduced by NCP treatment in refrigerated samples after 8 d. These results indicate that PE has great potential as a natural antioxidant and antimicrobial additive to extend the shelf life of beef patties. PMID- 25039745 TI - Influence of cross-match on posttransfusion packed cell volume in feline packed red blood cell transfusion. AB - OBJECTIVE: To evaluate the influence of major cross-match on transfusion efficacy based on the change in PCV following packed red blood cell (pRBC) administration in cats. DESIGN: Retrospective study from January 2000 to December 2010. SETTING: University Teaching Hospital. ANIMALS: Two hundred nine cats received 233 type specific pRBC transfusions as treatment for anemia. Forty-three transfusions were cross-match compatible and 190 were not screened with cross-match. INTERVENTIONS: Pretransfusion major cross-match. MEASUREMENTS AND MAIN RESULTS: Signalment, body weight, dosage of pRBC transfusion, pretransfusion PCV, posttransfusion PCV, IV fluid volumes administered between the measurement of the pretransfusion PCV and posttransfusion PCV, time delay between pretransfusion PCV measurement and transfusion administration, time between administration of transfusion and posttransfusion PCV measurement, and major cross-match testing data were extracted from the medical records of cats receiving pRBC transfusions and were evaluated for their influence on posttransfusion PCV scaled to dose of pRBC administered. The mean pretransfusion PCV was significantly lower for cross-match compatible transfusions (13.7 +/- 4.2%) compared to noncross-matched transfusions (16.1 +/- 4.5%; independent samples t-test, P < 0.0001). The PCV increase posttransfusion scaled by dose was significantly greater for cross-match compatible transfusions (1.02 +/- 0.51%/mL/kg) than for noncross-matched transfusions (0.74 +/- 0.65%/mL/kg; independent samples t-test, P = 0.0093). Of age, dose of pRBCs, cross-match status, reason for transfusion, pretransfusion PCV, and dose of IV fluids administered between the pretransfusion and posttransfusion PCV, only pRBC dose, cross-match status, and pretransfusion PCV were independent predictors of change in PCV with transfusion on multiple regression analysis (coefficient = 0.507, P < 0.0001; coefficient = 1.64, P = 0.041; coefficient = -0.235, P = 0.0009, respectively). CONCLUSIONS: In this retrospective study, administration of type-specific, cross-match compatible pRBC transfusions resulted in significantly greater increases in the posttransfusion PCV when compared to administration of typed, noncross-matched pRBCs. Future prospective studies evaluating the effect of cross-match on transfusion efficacy in cats are warranted. PMID- 25039744 TI - A novel canine model of immune thrombocytopenia: has immune thrombocytopenia (ITP) gone to the dogs? AB - Canine immune thrombocytopenia (ITP) is analogous to human ITP, with similar platelet counts and heterogeneity in bleeding phenotype among affected individuals. With a goal of ultimately investigating this bleeding heterogeneity, a canine model of antibody-mediated ITP was developed. Infusion of healthy dogs with 2F9, a murine IgG2a monoclonal antibody to the canine platelet glycoprotein GPIIb (a common target of autoantibodies in ITP) resulted in profound, dose dependent thrombocytopenia. Model dogs developed variable bleeding phenotypes, e.g. petechiae and haematuria, despite similar degrees of thrombocytopenia. 2F9 infusion was not associated with systemic inflammation, consumptive coagulopathy, or impairment of platelet function. Unexpectedly however, evaluation of cytokine profiles led to the identification of platelets as a potential source of serum interleukin-8 (IL8) in dogs. This finding was confirmed in humans with ITP, suggesting that platelet IL8 may be a previously unrecognized modulator of platelet-neutrophil crosstalk. The utility of this model will allow future study of bleeding phenotypic heterogeneity including the role of neutrophils and endothelial cells in ITP. PMID- 25039746 TI - Spinal and supraspinal motor control predictors of rate of torque development. AB - During explosive movements and potentially injurious situations, the ability to rapidly generate torque is critical. Previous research has suggested that different phases of rate of torque development (RTD) are differentiately controlled. However, the extent to which supraspinal and spinal mechanisms predict RTD at different time intervals is unknown. RTD of the plantarflexors across various phases of contraction (i.e., 0-25, 0-50, 0-100, 0-150, 0-200, and 0-250 ms) was measured in 37 participants. The following predictor variables were also measured: (a) gain of the resting soleus H-reflex recruitment curve; (b) gain of the resting homonymous post-activation depression recruitment curve; (c) gain of the GABAergic presynaptic inhibition recruitment curve; (d) the level of postsynaptic recurrent inhibition at rest; (e) level of supraspinal drive assessed by measuring V waves; and (f) the gain of the resting soleus M wave. Stepwise regression analyses were used to determine which variables significantly predicted allometrically scaled RTD. The analyses indicated that supraspinal drive was the dominant predictor of RTD across all phases. Additionally, recurrent inhibition predicted RTD in all of the time intervals except 0-150 ms. These results demonstrate the importance of supraspinal drive and recurrent inhibition to RTD. PMID- 25039747 TI - Odorant-binding protein (OBP) genes affect host specificity in a fig-pollinator mutualistic system. AB - The interaction between figs and their pollinating wasps is regarded as a model system for studying specialized co-evolved mutualism. Chemoreception of fig wasps plays an important role in this interaction, and odorant-binding proteins (OBP) function in the first step of odorant detection. The OBP repertoire of the fig wasp Ceratosolen solmsi is reported to be one of the smallest among insects; however, it is unknown how these OBPs are related to the complicated mating process occurring within the fig cavity and the extreme host specificity of the species. In the present study, we combined a structural analysis of the conserved cysteine pattern and motif order, a phylogenetic analysis, and previous studies on ligand-binding assays to deduce the function of OBPs. We also quantified the expression of OBP genes in different life stages of female and male fig wasps by using real-time quantitative PCR, which can help to predict the function of these genes. The results indicated that CsolOBP1 and CsolOBP2 (or CsolOBP5) in males may bind to pheromones and play important roles in mate choice, whereas CsolOBP4 and CsolOBP5 may primarily function in host localization by females through binding of volatile compounds emitted by receptive figs. PMID- 25039748 TI - Quantification of rare NPM1 mutation subtypes by digital PCR. PMID- 25039749 TI - Intracytoplasmic inclusion bodies and myoid-type of differentiation in the stroma of a benign phyllodes tumor. PMID- 25039750 TI - The ameliorative effects of exogenous melatonin on grape cuttings under water deficient stress: antioxidant metabolites, leaf anatomy, and chloroplast morphology. AB - Grapes are an important economic crop and are widely cultivated around the world. Most grapes are grown in arid or semi-arid regions, and droughts take a heavy toll in grape and wine production areas. Developing effective drought-resistant cultivation measures is a priority for viticulture. Melatonin, an indoleamine, mediates many physiological processes in plants. Herein, we examined whether exogenously applied melatonin could improve the resistance of wine grape seedlings grown from cuttings to polyethylene glycol-induced water-deficient stress. The application of 10% polyethylene glycol (PEG) markedly inhibited the growth of cuttings, caused oxidative stress and damage from H2 O2 and O2?-, and reduced the potential efficiency of Photosystem II and the amount of chlorophyll. Application of melatonin partially alleviated the oxidative injury to cuttings, slowed the decline in the potential efficiency of Photosystem II, and limited the effects on leaf thickness, spongy tissue, and stoma size after application of PEG. Melatonin treatment also helped preserve the internal lamellar system of chloroplasts and alleviated the ultrastructural damage induced by drought stress. This ameliorating effect may be ascribed to the enhanced activity of antioxidant enzymes, increased levels of nonenzymatic antioxidants, and increased amount of osmoprotectants (free proline). We conclude that the application of melatonin to wine grapes is effective in reducing drought stress. PMID- 25039751 TI - Salt preferences of normotensive and hypertensive older individuals. AB - The aim of this study was to evaluate the preference for salt in hypertensive and normotensive older individuals. Hypertensive (group 1: n=32, aged 73.7+/-6.3 years) or normotensive patients (group 2: n=26, aged 71.5+/-8.0 years) were submitted to a test to determine their preference for bread samples with different salt concentrations: 1.5%, 2.0% (usual concentration), and 2.7%, and were reevaluated 2 weeks later using the same salt concentrations, but with the addition of oregano. Twenty-four-hour urinary sodium excretion (UNaV), blood pressure (BP), and body mass index (BMI) were obtained. Systolic BP, BMI, and UNaV were higher in group 1. In the first analysis, group 1 showed greater preference for the saltiest sample (P=.001). Comparing the first evaluation and the second, a greater preference for less salty samples was observed in both groups (P<.01). Hypertensive older patients consumed more salt and showed a greater salt preference than the normotensive patients. The use of the spice reduced the preference for salt in both groups. PMID- 25039752 TI - Selection for cheating across disparate environments in the legume-rhizobium mutualism. AB - The primary dilemma in evolutionarily stable mutualisms is that natural selection for cheating could overwhelm selection for cooperation. Cheating need not entail parasitism; selection favours cheating as a quantitative trait whenever less cooperative partners are more fit than more-cooperative partners. Mutualisms might be stabilised by mechanisms that direct benefits to more-cooperative individuals, which counter selection for cheating; however, empirical evidence that natural selection favours cheating in mutualisms is sparse. We measured selection on cheating in single-partner pairings of wild legume and rhizobium lineages, which prevented legume choice. Across contrasting environments, selection consistently favoured cheating by rhizobia, but did not favour legumes that provided less benefit to rhizobium partners. This is the first simultaneous measurement of selection on cheating across both host and symbiont lineages from a natural population. We empirically confirm selection for cheating as a source of antagonistic coevolutionary pressure in mutualism and a biological dilemma for models of cooperation. PMID- 25039753 TI - Two missense mutations in melanocortin 1 receptor (MC1R) are strongly associated with dark ventral coat color in reindeer (Rangifer tarandus). AB - The protein-coding region of melanocortin 1 receptor (MC1R) was sequenced to identify potential variation affecting coat color in reindeer (Rangifer tarandus). A T->C sequence variation at nucleotide position 218 (c.218T>C) causing an amino acid (aa) change from methionine to threonine at aa position 73 (p.Met73Thr) was identified. In addition, a T->G sequence variation was found at nucleotide position 839 (c.839T>G), causing phenylalanine to be exchanged by cysteine at aa position 280 (p.Phe280Cys). The two sequence variants (c.218C and c.839G) were found to be closely associated with a darker belly coat compared with animals not having any of these two variants. The aa acid change p.Met73Thr affects the same position as p.Met73Lys previously reported to give constitutive activation of MC1R in black sheep (Ovis aries), whereas p.Phe280Cys is identical to one of two variants previously reported to be associated with dark coat color in Arctic fox (Alopex lagopus), supporting that the two variants found in reindeer are functional. The complete absence of Thr73 and Cys280 among the 51 wild reindeer analyzed provides some evidence that these variants are more common in the domestic herds. PMID- 25039754 TI - Female urethra is actively opened out by an external striated muscle mechanism during micturition, exponentially reducing intraurethral resistance to flow. PMID- 25039755 TI - The prevalence of Behcet's disease in a city in Central Anatolia in Turkey. AB - BACKGROUND: The prevalence of Behcet's disease (BD) is much higher in countries along the ancient Silk Route, extending from Japan to Mediterranean countries including Turkey, than in northern Europe and the USA. OBJECTIVES: The present study aimed to investigate the prevalence of BD in Kayseri, a city in Central Anatolia in Turkey. METHODS: This study investigated cross-sectional prevalences of BD in individuals aged >10 years in Kayseri, Turkey, in two stages. The first stage aimed to identify individuals with recurrent oral ulcers (ROUs) through home visits, and the second stage aimed to further examine those with ROUs for the presence of other BD-related manifestations under hospital conditions. The study was conducted using the criteria defined by the International Study Group for Behcet's Disease. The sample size was determined to be 4697 with an expected sampling error of 5.5 per 10,000, with a 95% confidence interval. A standard questionnaire was administered to a total of 5218 individuals. RESULTS: A history of ROU was recorded in 470 (9.0%) of the 5218 residents, and a previous diagnosis of BD was recorded in nine individuals. The prevalence rate of BD was estimated as 17 cases per 10,000 population in Kayseri, Turkey. CONCLUSIONS: The present study contributes towards estimations of prevalences of BD in Turkey and towards raising public awareness about the disease. It also supports previous studies that have reported the world's highest prevalences of BD in Turkey. PMID- 25039757 TI - Standing on the shoulders of giants, and looking ahead. PMID- 25039756 TI - Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma. AB - BACKGROUND AND PURPOSE: Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti tumour activity of its major metabolite, 4-oxo-13-cRA. EXPERIMENTAL APPROACH: Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. KEY RESULTS: Six major metabolites of 13 cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13 cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor beta mRNA and protein levels. CONCLUSIONS AND IMPLICATIONS: We showed that 4-oxo 13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. PMID- 25039759 TI - The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials: reply. PMID- 25039758 TI - Effect of immunosuppressants tacrolimus and mycophenolate mofetil on the keratinocyte UVB response. AB - Nonmelanoma skin cancer, derived from epidermal keratinocytes, is the most common malignancy in organ transplant recipients, causes serious morbidity and mortality, and is strongly associated with solar ultraviolet (UV) exposure. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, the immunosuppressants are used to prevent graft rejection. Until now, immunosuppression has been assumed to be the major factor leading to skin cancer in this setting. However, the mechanism of skin carcinogenesis in organ transplant recipients has not been understood to date; specifically, it remains unknown whether these cancers are immunosuppression-dependent or -independent. In particular, it remains poorly understood what is the mechanistic carcinogenic action of the newer generation of immunosuppressants including tacrolimus and mycophenolate mofetil (MMF). Here, we show that tacrolimus and MMF impairs UVB-induced DNA damage repair and apoptosis in human epidermal keratinocytes. In addition, tacrolimus inhibits UVB-induced checkpoint signaling. However, MMF had no effect. Our findings have demonstrated that tacrolimus and MMF compromises proper UVB response in keratinocytes, suggesting an immunosuppression-independent mechanism in the tumor-promoting action of these immunosuppressants. PMID- 25039760 TI - Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene. AB - We present a case of a patient whose L1CAM gene in X-chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X-linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH. PMID- 25039761 TI - Association between EGFR gene polymorphisms, skin rash and response to anti-EGFR therapy in metastatic colorectal cancer patients. AB - Cetuximab and panitumumab are epidermal growth factor receptor (EGFR) inhibitors used in metastatic colorectal cancer (mCRC). Most patients develop a papulopustular rash that may predict tumor response to treatment. EGFR gene polymorphisms may also determine tumor response and appearance of skin rash. We hypothesized an association between EGFR gene polymorphisms, papulopustular rash and response to anticancer treatment. Four EGFR polymorphisms (-216, -191, CA SSR, R521K) were analysed in 51 patients with mCRC receiving anti-EGFR. Severity of cutaneous rash and tumor response was measured following standard scales. We report an association between SNP-216 and tumor response (P = 0.003): no tumor progression occurred in TT genotype. Moreover, 92.3% of the responder patients developed skin rash, 62.9% of them presenting a grade >=2 (P = 0.015). Thus, although underpowered, our preliminary data suggest that SNP-216 polymorphism of the EGFR gene could be useful in predicting tumor response and the appearance of severe skin rash might also be associated. PMID- 25039762 TI - Cytosolic lipid droplets: from mechanisms of fat storage to disease. AB - The lipid droplet (LD) is a phylogenetically conserved organelle. In eukaryotes, it is born from the endoplasmic reticulum, but unlike its parent organelle, LDs are the only known cytosolic organelles that are micellar in structure. LDs are implicated in numerous physiological and pathophysiological functions. Many aspects of the LD has captured the attention of diverse scientists alike and has recently led to an explosion in information on the LD biogenesis, expansion and fusion, identification of LD proteomes and diseases associated with LD biology. This review will provide a brief history of this fascinating organelle and provide some contemporary views of unanswered questions in LD biogenesis. PMID- 25039763 TI - Chemical tools to explore nutrient-driven O-GlcNAc cycling. AB - Posttranslational modifications (PTM) including glycosylation, phosphorylation, acetylation, methylation and ubiquitination dynamically alter the proteome. The evolutionarily conserved enzymes O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase are responsible for the addition and removal, respectively, of the nutrient-sensitive PTM of protein serine and threonine residues with O-GlcNAc. Indeed, the O-GlcNAc modification acts at every step in the "central dogma" of molecular biology and alters signaling pathways leading to amplified or blunted biological responses. The cellular roles of OGT and the dynamic PTM O-GlcNAc have been clarified with recently developed chemical tools including high-throughput assays, structural and mechanistic studies and potent enzyme inhibitors. These evolving chemical tools complement genetic and biochemical approaches for exposing the underlying biological information conferred by O-GlcNAc cycling. PMID- 25039764 TI - The Ded1/DDX3 subfamily of DEAD-box RNA helicases. AB - In eukaryotic organisms, the orthologs of the DEAD-box RNA helicase Ded1p from yeast and DDX3 from human form a well-defined subfamily that is characterized by high sequence conservation in their helicase core and their N- and C- termini. Individual members of this Ded1/DDX3 subfamily perform multiple functions in RNA metabolism in both nucleus and cytoplasm. Ded1/DDX3 subfamily members have also been implicated in cellular signaling pathways and are targeted by diverse viruses. In this review, we discuss the considerable body of work on the biochemistry and biology of these proteins, including the recently discovered link of human DDX3 to tumorigenesis. PMID- 25039765 TI - Savanna fire and the origins of the 'underground forests' of Africa. AB - The origin of fire-adapted lineages is a long-standing question in ecology. Although phylogeny can provide a significant contribution to the ongoing debate, its use has been precluded by the lack of comprehensive DNA data. Here, we focus on the 'underground trees' (=geoxyles) of southern Africa, one of the most distinctive growth forms characteristic of fire-prone savannas. We placed geoxyles within the most comprehensive dated phylogeny for the regional flora comprising over 1400 woody species. Using this phylogeny, we tested whether African geoxyles evolved concomitantly with those of the South American cerrado and used their phylogenetic position to date the appearance of humid savannas. We found multiple independent origins of the geoxyle life-form mostly from the Pliocene, a period consistent with the origin of cerrado, with the majority of divergences occurring within the last 2 million yr. When contrasted with their tree relatives, geoxyles occur in regions characterized by higher rainfall and greater fire frequency. Our results indicate that the geoxylic growth form may have evolved in response to the interactive effects of frequent fires and high precipitation. As such, geoxyles may be regarded as markers of fire-maintained savannas occurring in climates suitable for forests. PMID- 25039766 TI - Comment on 'p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small-vessel occlusion in elderly Japanese males'. PMID- 25039767 TI - Response to Satomura et al. PMID- 25039769 TI - Dependence of bronchoconstrictor and bronchodilator responses on thoracic gas compression volume. AB - BACKGROUND AND OBJECTIVE: During forced expiration, alveolar pressure (PALV ) increases and intrathoracic gas is compressed. Thus, 1-s forced expiratory volume measured by spirometry (FEV1-sp ) is smaller than 1-s forced expiratory volume measured by plethysmography (FEV1-pl ). Thoracic gas compression volume (TGCV) depends on the amount of gas within the lung when expiratory flow limitation occurs in the airways. We therefore tested the hypothesis that bronchoconstrictor and bronchodilator responses using FEV1-sp are biased by height and gender, which are major determinants of lung volume. METHODS: We studied 54 asthmatics during methacholine challenge and 55 subjects with airway obstruction (FEV1-sp increase >200 mL and >12% after salbutamol) measuring at the same time FEV1-sp or FEV1-pl . RESULTS: During methacholine challenge, TGCV increased more in males than females, correlated with PALV , total lung capacity (TLC) and height, and the provocative dose was lower using FEV1-sp than FEV1-pl . With salbutamol, FEV1-pl increased <200 mL and <12% in 28 subjects, predominantly tall males, with larger TLC, TGCV and PALV . CONCLUSIONS: Bronchoconstrictor and bronchodilator responses are overestimated by standard spirometry in subjects with larger lungs because of TGCV. PMID- 25039770 TI - Hyperkalemia in hemodialysis patients. AB - Hyperkalemia contributes significantly to high mortality among ESRD patients. Excess intake and inadequate removal are the most common etiologies in HD patients. Although dialysis is the definitive treatment, classical medical therapy must be employed as a temporizing measure to acutely lower serum potassium. Reducing potassium intake through dietetic/nutritional support is critical to reducing the K+ load in ESRD patients and preventing this condition. PMID- 25039771 TI - Intracranial aneurysms; in need of early diagnostic and treatment using bio- and nanotechnology. AB - Intracranial aneurysms are present in 1-5% of population and can be described as "ticking time bombs" that can go off at any time and cause serious harms including permanent disability and death. There are two routinely practiced treatment options for this disease; endovascular coiling and surgical clipping. In recent years other promising methods, such as stent-assisted coiling, flow diverting devices and Onyx embolic agent, have also been developed and tested. The studies reviewed here suggest endovascular coiling to be the most commonly chosen treatment method and that there are reservations on using the newly developed techniques, despite studies suggesting their safety and effectiveness. Therefore, it is now becoming clear that a competent management system, in which treatment methods are chosen to best fit the characterisation of the patient and the aneurysm, should be developed in order to effectively diagnose and treat intracranial aneurysms. One way to develop such a system could be through the advancements of nanotechnology and smart materials. Neurosurgery, like many other areas of the medical field, is moving towards adopting the exciting and rapidly developing technologies based on nanomaterials as the nano-approach to detect and treat intracranial aneurysms could offer surgical opportunities that were more invasive or out of rich at the microneurosurgery level. PMID- 25039772 TI - Intracranial stents past, present and the future trend: stents made with nano particle or nanocomposite biomaterials. AB - Stroke or cerebral vascular accidents are among the leading causes of death in the world. With the availability of Digital Subtraction Angiography, transluminal angioplasty has become feasible in many situations and the role of intracranial stents is becoming ever more important in the management of cerebral vascular diseases. In current review, we outline the chronological development of various stents namely; balloon expandable stent, self-expandable open cell stent, self expandable close cell stent and the flow diverting stent. Further we discuss their advantages and limitations in terms of stent migration, thromboemboli, damage to vessels during procedure, in-stent stenosis and hyper-perfusion damage. We also discuss the importance of in-situ endothelialization, controlled expandability and hemodynamic manipulation in stent design. Further, we summarized the role and need for further development in the areas of bio compatible materials, endothelial progenitor cell capture technique, bio functionalized-magnetic-nano-particles and nanotechnology which are significant in intracranial stent development. PMID- 25039773 TI - Nose-to-brain drug delivery by nanoparticles in the treatment of neurological disorders. AB - Many potential drugs for the treatment of neurological diseases are unable to reach the brain in sufficient enough concentrations to be therapeutic because of the blood brain barrier. On the other hand, direct delivery of drugs to the brain provides the possibility of a greater therapeutic-toxic ratio than with systemic drug delivery. The use of intranasal delivery of therapeutic agents to the brain provides a means of bypassing the blood brain barrier in a non-invasive manner. In this respect, nanosized drug carriers were shown to enhance the delivery of drugs to CNS compared to equivalent drug solution formulations. Neurological conditions that have been studied in animal models that could benefit from nose to-brain delivery of nanotherapeutics include pain, epilepsy, neurodegenerative disease and infectious diseases. The delivery of drugs to the brain via the nose to-brain route holds great promise, on the basis of preclinical research by means of drug delivery systems such as polymeric nanoparticles and clinical data related to intranasal delivery to CNS of large molecular weight biologics administered in solution, but safety issues about toxicity on nasal mucosa, Np transport into the brain, delivery only to specific brain regions and variability in the adsorbed dose still represent research topics that need to be considered, with a view of clinical translation of these delivery systems. PMID- 25039774 TI - Challenges in the design of clinically useful brain-targeted drug nanocarriers. AB - Nowadays, the delivery of drugs by means of intravenously administered nanosized drug carriers - polymerdrug conjugates, liposomes and micelles, is technically possible. These delivery systems are mainly designed for tumour therapy, and accumulate passively into tumours by means of the well known EPR effect. Targeted nanocarriers, that additionally contain ligands for receptors expressed on cell surfaces, are also widely studied but products of this kind are not marketed, and only a few are in clinical trial. Polymeric nanoparticles (Np) able to deliver drugs to the CNS were pioneered in 1995; a number of papers have been published dealing with brain-targeted drug delivery using polymeric Np able to cross the BBB, mainly for the treatment of brain tumours. At present, however, the translation potential of these Np seems to have been exceeded by targeted liposomes, a platform based on a proven technology. This drug delivery system entered clinical trials soon after its discovery, while the challenges in formulation, characterization and manufacturing of brain-targeted polymeric Np and the cost/benefit ratio could be the factors that have prevented their development. A key issue is that it is virtually impossible to define the in vivo fate of polymers, especially in the brain, which is a regulatory requirement; perhaps this is why no progress has been made. The most advanced Np for brain tumours treatment will be compared here with the published data available for those in clinical trial for tumours outside the CNS, to highlight the knowledge gaps that still penalise these delivery systems. At present, new approaches for brain tumours are emerging, such as lipid Np or the use of monoclonal antibody (mAb)-drug conjugates, which avoid polymers. The success or failure in the approval of the polymeric Np currently in clinical trials will certainly affect the field. At present, the chances of their approval appear to be very low. PMID- 25039775 TI - Nanomedicine and its application in treatment of microglia-mediated neuroinflammation. AB - Nanomedicine, an emerging therapeutic tool in current medical frontiers, offers targeted drug delivery for many neurodegenerative disorders. Neuroinflammation, a hallmark of many neurodegenerative disorders, is mediated by microglia, the resident immunocompetent cells of the central nervous system (CNS). Microglial cells respond to various stimuli in the CNS resulting in their activation which may have a beneficial or a detrimental effect. In general, the activated microglia remove damaged neurons and infectious agents by phagocytosis, therefore being neuroprotective. However, their chronic activation exacerbates neuronal damage through excessive release of proinflammatory cytokines, chemokines and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. Hence, controlling microglial inflammatory response and their proliferation has been considered as an important aspect in treating neurodegenerative disorders. Regulatory factors that control microglial activation and proliferation also play an important role in microglia-mediated neuroinflammation and neurotoxicity. Various anti-inflammatory drugs and herbal compounds have been identified in treating microglia-mediated neuroinflammation in the CNS. However, hurdles in crossing blood brain barrier (BBB), expression of metabolic enzymes, presence of efflux pumps and several other factors prevent the entry of these drugs into the CNS. Use of non-degradable delivery systems and microglial activation in response to the drug delivery system further complicate drug delivery to the CNS. Nanomedicine, a nanoparticle-mediated drug delivery system, exhibits immense potential to overcome these hurdles in drug delivery to the CNS enabling new alternatives with significant promises in revolutionising the field of neurodegenerative disease therapy. This review attempts to summarise various regulatory factors in microglia, existing therapeutic strategies in controlling microglial activation, and how nanotechnology can serve to improve the delivery of therapeutic drugs across the BBB for treating microglia- mediated neuroinflammation and neurodegeneration. PMID- 25039776 TI - Interactions between nanosized materials and the brain. AB - The current rapid development of nanotechnologies and engineered nanomaterials (ENM) will impact the society in a major fashion during the coming decades. This development also causes substantial safety concerns. Among the many promising applications of ENM, products that can be used for diagnosis and treatment of diseases, including conditions that affect the nervous system, are under development. ENM can pass the blood brain barrier (BBB) and accumulate within the brain. It seems that the nano-form rather than the bulk form of the chemicals pass the BBB, and that there is an inverse relationship between particle size and the ability to penetrate the BBB. Although translocation of ENM to the brain is possible during experimental conditions, the health relevance for real-life situations is far from clear. One major reason for this is that studies have been using nanoparticle concentrations that are far higher than the ones that can be expected during realistic exposures. However, very high exposure to the CNS can cause effects on neurotransmission, redox homeostasis and behavior. Available studies have been focusing on possible effects of the first generation of ENM. It will be necessary to study possible health effects also of expected novel sophisticated materials, independent of the outcome of present studies. The prospects for intended or targeted medical applications are promising since it has been shown that ENM can be made to pass the BBB and reach specific regions or cells within the brain. PMID- 25039777 TI - Nanotechnology and Alzheimer's disease: what has been done and what to do. AB - Up to date, Alzheimer's Disease (AD) is considered as an "urgency" for public health, since it represents one of the most dramatic causes of death in adults. The drugs currently used for AD are only symptomatic, thus not curing the pathology, but only trying to slow or delay the progression of the pathology. Moreover, there is a total lack of early identification, with only "probable'' or ''possible'' diagnosis of AD patients. With this review, we aimed to individuate and to highlight the most promising approaches for AD therapy and diagnosis. In this view, at the cutting-edge of innovation, nanocarriers as polymeric nanoparticles, liposomes, nanoassembly and dendrimers, have been studied and investigated in order to ameliorate the detection (in vitro and in vivo) and/or the therapeutic options in AD. In this review, the most outstanding nanomedicine driven approaches in AD imaging/detection and treatments are summarized in order to help in individuating values and criticisms. Moreover, an overview of one of the most innovative strategies in AD management, namely theranostic nanomedicine, is reported and commented. PMID- 25039778 TI - Nanomedicine based nanoparticles for neurological disorders. AB - Human health is severely hampered by a majority of the neurological disorders such as the brain tumors, degenerative Alzheimer's disease, Parkinson's disease and those involving inflammatory component. Owing to the stringent protection offered by the blood brain barrier, conventional therapeutics gain limited access and therefore, are therapeutically suboptimal. Hence, research has now focused to develop the novel drug delivery systems with a prime motto of maintaining therapeutic drug levels inside the brain, avoiding non-specific tissue distribution. The introduction of nanotechnology has addressed few of these objectives and opened up new avenues for even more improvization. To some extent, nanodelivery systems were successful in crossing the blood brain barrier and accessing the remote areas of the brain. They also have shown tremendous potential in delivering the therapeutic and diagnostic aids following systemic administration. What revolutionised the nano applications is the development of "smart" nanosystems, whose surface is tailor made for the effective theranostic delivery. However, a detailed understanding of the long term nanoformulation toxicities, along with the neuropathology, is the critical future question to be addressed. In this review, a brief introduction of the prominent neurological disorders and detailed applications of nanotechnology are discussed. PMID- 25039779 TI - Accessing targeted nanoparticles to the brain: the vascular route. AB - The blood-brain barrier (BBB), formed by brain capillary endothelial cells, prevents the entry of several drug molecules to the brain, especially molecules hydrophilic in nature. Advanced drug carriers like nanoparticles share the potential to allow entry of therapeutic proteins and genetic molecules into the central nervous system (CNS). Taking a targeting approach by conjugating molecules acting as ligands or monoclonal antibodies with affinity for proteins expressed on the luminal side of brain capillary endothelial cells, the nanoparticles can be designed to enable transport into the brain endothelium, or perhaps even through the endothelium leading to blood to brain transport. Currently, the iron-binding protein transferrin or antibodies raised against the transferrin receptor denote the most feasible molecule for targeting purposes at the BBB. This manuscript reviews the targetability of nanoparticles to the brain capillary endothelial cells, how nanocarriers may enter and transfer through the brain endothelium, and how likely restraints denoted by the threedimensional mesh of the extracellular proteins forming the brain capillary basement membrane challenge the possibilities for enabling transport of large molecules through the BBB encapsulated in nanoparticles. PMID- 25039780 TI - Editorial: Neuronanomedicine - (Part II). PMID- 25039781 TI - General aspects of metal toxicity. AB - This review is focused on the general mechanisms of metal toxicity in humans. The possible and mainly confirmed mechanisms of their action are discussed. The metals are divided into four groups due to their toxic effects. First group comprises of metal ions acting as Fenton reaction catalyst mainly iron and copper. These types of metal ions participate in generation of the reactive oxygen species. Metals such as nickel, cadmium and chromium are considered as carcinogenic agents. Aluminum, lead and tin are involved in neurotoxicity. The representative of the last group is mercury, which may be considered as a generally toxic metal. Fenton reaction is a naturally occurring process producing most active oxygen species, hydroxyl radical: Fe(2+) + He2O2 <-> Fe(3+) + OH(-) + OH(*) It is able to oxidize most of the biomolecules including DNA, proteins, lipids etc. The effect of toxicity depends on the damage of molecules i.e. production site of the hydroxyl radical. Chromium toxicity depends critically on its oxidation state. The most hazardous seems to be Cr(6+) (chromates) which are one of the strongest inorganic carcinogenic agents. Cr(6+) species act also as oxidative agents damaging among other nucleic acids. Redox inactive Al(3+), Cd(2+) or Hg(2+) may interfere with biology of other metal ions e.g. by occupying metal binding sites in biomolecules. All these aspects will be discussed in the review. PMID- 25039782 TI - Interaction of chemokines with their receptors--from initial chemokine binding to receptor activating steps. AB - The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system's primary function in leukocyte migration, it has a central role in immune homeostasis and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity-contributing interactions are attributed to different domains and known to occur in two steps. Here, knowledge on chemokine and receptor domains involved in the first binding-step and the second activation step is reviewed. A mechanism comprising at least two steps seems consistent; however, several intermediate interactions possibly occur, resulting in a multi step process, as recently proposed for other 7TM receptors. Overall, the N terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly interact with or rely on transmembrane receptor residues, while CXC-chemokines use residues located further exterior. Moreover, different chemokines for the same receptor often bind at different sites, uncovering the existence of several orthosteric sites thereby adding another level of complexity. This gives rise to a probe-dependency of small molecule "drug-like" ligands, which, depending on the chemokine interaction, may bind allosteric for some, and orthosteric for other chemokines targeting the same receptor, thereby resulting in probedependent pharmacodynamics. PMID- 25039783 TI - Nanoparticles in melanoma. AB - Malignant melanoma is one of the most common causes of cancer and cancer deaths in young people. Until few years ago, scarce drugs have proven efficacy in metastatic setting. However, in the recent years, the treatment of metastatic malignant melanoma has undergone the incorporation of effective treatment such as immunotherapy, the use of tyrosine kinase inhibitors and the emergence of other cytostatic compounds, like the nanoparticles. This review aims to propose a standardization to classify the different types of nanoparticles, according to chemical aspects, and update the clinical research with nanoparticles and their use in melanoma field. PMID- 25039785 TI - Effects of tetrahydrohyperforin in mouse hippocampal slices: neuroprotection, long-term potentiation and TRPC channels. AB - Tetrahydrohyperforin (IDN5706) is a semi-synthetic compound derived from hyperforin (IDN5522) and is the main active principle of St. John's Wort. IDN5706 has shown numerous beneficial effects when administered to wild-type and double transgenic (APPswe/PSEN1DeltaE9) mice that model Alzheimer's disease. However, its mechanism of action is currently unknown. Toward this end, we analysed field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal slices incubated with IDN5706 and in the presence of the TRPC3/6/7 activator 1-oleoyl-2-acetyl-sn glycerol (OAG), the TRPC channel blocker SKF96365, and neurotoxic amyloid beta protein (Abeta) oligomers. To study spatial memory, Morris water maze (MWM) behavioural tests were conducted on wild-type mice treated with IDN5706 and SKF96365. In silico studies were conducted to predict a potential pharmacophore. IDN5706 and OAG had a similar stimulating effect on fEPSPs, which was inhibited by SKF96365. IDN5706 protected from reduced fEPSPs induced by Abeta oligomers. IDN5706 improved spatial memory in wild-type mice, an effect that was counteracted by co-administration of SKF96365. Our in silico studies suggest strong pharmacophore similarity of IDN5706 and other reported TRPC6 activators (IDN5522, OAG and Hyp9). We propose that the effect of IDN5706 is mediated through activation of the TRPC3/6/7 channel subfamily. The unveiling of the drug's mechanism of action is a necessary step toward the clinical use of IDN5706 in Alzheimer's disease. PMID- 25039786 TI - Editorial: current research, knowledge and controversies on high density lipoprotein. PMID- 25039787 TI - The impact of infectious disease specialists on antibiotic prescribing in hospitals. AB - Given the current bacterial resistance crisis, antimicrobial stewardship programmes are of the utmost importance. We present a narrative review of the impact of infectious disease specialists (IDSs) on the quality and quantity of antibiotic use in acute-care hospitals, and discuss the main factors that could limit the efficacy of IDS recommendations. A total of 31 studies were included in this review, with a wide range of infections, hospital settings, and types of antibiotic prescription. Seven of 31 studies were randomized controlled trials, before/after controlled studies, or before/after uncontrolled studies with interrupted time-series analysis. In almost all studies, IDS intervention was associated with a significant improvement in the appropriateness of antibiotic prescribing as compared with prescriptions without any IDS input, and with decreased antibiotic consumption. Variability in the antibiotic prescribing practices of IDSs, informal (curbside) consultations and the involvement of junior IDSs are among the factors that could have an impact on the efficacy of IDS recommendations and on compliance rates, and deserve further investigation. We also discuss possible drawbacks of IDSs in acute-care hospitals that are rarely reported in the published literature. Overall, IDSs are valuable to antimicrobial stewardship programmes in hospitals, but their impact depends on many human and organizational factors. PMID- 25039788 TI - Development of probiotic-based immunoparticles for pulmonary immunization against Hepatitis B. AB - OBJECTIVES: The present study was oriented towards the development of pulmonary vaccine for Hepatitis B using probiotic biomass as an adjuvant. METHODS: The antigen was spray dried in presence of heat treated, formalin treated and live probiotic biomass. KEY FINDINGS: The results indicated that the biomass itself without any additional cryoprotectant is capable of protecting the structural integrity of the antigen. We were able to retain more than 80% of the antigenicity. The scanning electron microscopic images indicated that the formulation bearing live probiotic biomass have spherical size, while the formulations with heat and formalin treated biomass shows irregular shaped particles. The developed formulations were further evaluated for in-vivo immune response. Immunoglobulin G (IgG) titre results were found to be comparable with marketed (aluminium adsorbed) formulations while significantly higher secretory immunoglobulin A titre showed better mucosal immune response than marketed formulation. CONCLUSION: Therefore, the probiotic biomass can be utilized as a potential cryoprotectant as well as a potent immunomodulator. PMID- 25039789 TI - Superhydrophobic silanized melamine sponges as high efficiency oil absorbent materials. AB - Superhydrophobic sponges and sponge-like materials have attracted great attention recently as potential sorbent materials for oil spill cleanup due to their excellent sorption capacity and high selectivity. A major challenge to their broad use is the fabrication of superhydrophobic sponges with superior recyclability, good mechanical strength, low cost, and manufacture scalability. In this study, we demonstrate a facile, cost-effective, and scalable method to fabricate robust, superhydrophobic sponges through the silanization of commercial melamine sponges via a solution-immersion process. The silanization was achieved through secondary amine groups on the surface of the sponge skeletons with alkylsilane compounds, forming self-assembled monolayers on the surface of sponge skeletons. This resulted in our ability to tune the surface properties of the sponges from being hydrophilic to superhydrophobic with a water contact angle of 151.0 degrees . The superhydrophobic silanized melamine sponge exhibited excellent sorption capacity for a wide range of organic solvents and oils, from 82 to 163 times its own weight, depending on the polarity and density of the employed organic solvents and oils, and high selectivity and outstanding recyclability with an absorption capacity retention greater than 90% after 1000 cycles. These findings offer an effective approach for oil spill containment and environmental remediation. PMID- 25039784 TI - A glimpse of matrix metalloproteinases in diabetic nephropathy. AB - Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-beta, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy. PMID- 25039791 TI - AS-7 improved in vitro quality of red blood cells prepared from whole blood held overnight at room temperature. AB - BACKGROUND: Extended room temperature (RT) hold of whole blood (WB) may affect the quality of red blood cell (RBC) components produced from these donations. The availability of better RBC additive solutions (ASs) may help reduce the effects. A new AS, AS-7 (SOLX, Haemonetics Corporation), was investigated for improved in vitro quality of RBCs prepared from WB held overnight at RT. STUDY DESIGN AND METHODS: Sixteen WB units were held for 21.4 hours +/- 40 minutes at 22 degrees C on cooling plates before processing. Each pair of ABO-matched WB units were pooled, divided into a WB filter pack containing saline-adenine-glucose-mannitol (control) and a LEUKOSEP WB-filter pack containing SOLX, and processed according to manufacturer's instructions. RBCs were stored at 2 to 6 degrees C and sampled weekly until expiry. Glycophorin A (GPA+) and annexin V-binding microparticles (MPs) were quantitated using flow cytometry. Osmotic fragility, intracellular pH (pHi), adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG), and routine quality variables were measured. Adhesion of RBCs to human endothelial cells (ECs) was evaluated by flow perfusion under low shear stress (0.5 dyne/cm(2) ), similar to low blood flow in microvessels. RESULTS: ATP and 2,3-DPG levels were improved for SOLX-RBCs. SOLX-RBCs maintained higher pHi, increased resistance to hypotonic stress, and reduced numbers of GPA+ MPs. No significant difference was observed between annexin V binding to MPs or adhesion of RBCs to ECs under shear stress. CONCLUSION: SOLX-stored RBCs showed increased osmotic resistance, pHi, and reduced GPA+ MPs and together with higher ATP and 2,3-DPG levels demonstrated improved in vitro RBC quality measures during 42 days of storage. PMID- 25039792 TI - Genetic diversity along the life cycle of the cyanobacterium Microcystis: highlight on the complexity of benthic and planktonic interactions. AB - Microcystis is a toxic freshwater cyanobacterium with an annual life cycle characterized by the alternation of a planktonic proliferation stage in summer and a benthic resting stage in winter. Given the importance of both stages for the development and the survival of the population, we investigated the genotypic composition of the planktonic and benthic Microcystis subpopulations from the Grangent reservoir (France) during two distinct proliferation periods. Our results showed a succession of different dominant genotypes in the sediment as well as in the water all along the study periods with some common genotypes to both compartments. Analysis of molecular variance and UniFrac analysis confirmed the similarity between some benthic and planktonic samples, thus evidencing exchanges of genotypes between water and sediment. Thanks to these data, recruitment and sedimentation were proven not to be restricted to spring and autumn, contrary to what was previously thought. Finally, genetic diversity was significantly higher in the sediment than in the water (P < 0.01; Student's t test). Taken together, our results shed light on the hidden contribution of the benthic compartment in maintaining the genetic diversity of Microcystis populations throughout their annual cycle, which could explain their ecological success in aquatic ecosystems. PMID- 25039790 TI - Bacteria associated with arbuscular mycorrhizal fungi within roots of plants growing in a soil highly contaminated with aliphatic and aromatic petroleum hydrocarbons. AB - Arbuscular mycorrhizal fungi (AMF) belong to phylum Glomeromycota, an early divergent fungal lineage forming symbiosis with plant roots. Many reports have documented that bacteria are intimately associated with AMF mycelia in the soil. However, the role of these bacteria remains unclear and their diversity within intraradical AMF structures has yet to be explored. We aim to assess the bacterial communities associated within intraradical propagules (vesicles and intraradical spores) harvested from roots of plant growing in the sediments of an extremely petroleum hydrocarbon-polluted basin. Solidago rugosa roots were sampled, surface-sterilized, and microdissected. Eleven propagules were randomly collected and individually subjected to whole-genome amplification, followed by PCRs, cloning, and sequencing targeting fungal and bacterial rDNA. Ribotyping of the 11 propagules showed that at least five different AMF OTUs could be present in S. rugosa roots, while 16S rRNA ribotyping of six of the 11 different propagules showed a surprisingly high bacterial richness associated with the AMF within plant roots. Most dominant bacterial OTUs belonged to Sphingomonas sp., Pseudomonas sp., Massilia sp., and Methylobacterium sp. This study provides the first evidence of the bacterial diversity associated with AMF propagules within the roots of plants growing in extremely petroleum hydrocarbon-polluted conditions. PMID- 25039793 TI - An evaluation of the effects of a breastfeeding support program on health outcomes. AB - OBJECTIVE: To estimate the causal effect of a Michigan peer counselor (PC) breastfeeding support program for low-income women on infant health outcomes. DATA SOURCES: Program referral forms, program forms (enrollment, birth, and exit data), and state administrative data from the Women Infants and Children program, Medicaid, and Vital Records. STUDY DESIGN: Quasi-random enrollment due to the excess demand for PC breastfeeding support services allowed us to compare the infants of women who requested services and were enrolled in the program (the treatment group, N = 274) to the infants of women who requested services and were not enrolled (the control group, N = 572). Data were analyzed using regression. PRINCIPAL FINDINGS: The PC program increased the fraction breastfeeding at birth by 19.3 percent and breastfeeding duration by 2.84 weeks. Program participation also reduced the fraction of infants with gastrointestinal disorders by a statistically significant 7.9 percent. The program, if anything, increased the overall health care utilization. CONCLUSIONS: This Michigan PC breastfeeding support program resulted in improvements in breastfeeding and infant health outcomes as measured by the diagnosis of ailments while increasing health care utilization. PMID- 25039794 TI - Persistent effect of broody hens on behaviour of chickens. AB - We reported previously that behavioral development of chicks was promoted remarkably by the presence of a broody hen. Here we report that these effects at an early age persist after maturity. A total of 60 female chicks were randomly assigned to one of two treatment groups: six pens with five chicks (brooded group) each were reared by a broody hen and six pens with five chicks (non brooded group) each were provided with an infrared heating lamp. We evaluated the persistent effects of broody hens by measures of behavior, physical condition and production at 9, 16, 35 and 55 weeks of age. The numbers of threatening, aggressive pecking, fighting and severe feather pecking behaviors were higher in non-brooded than in brooded chickens (all P < 0.05). Egg production was lower in brooded than in non-brooded chickens (P < 0.05), while the number of brooding chickens was higher in the brooded than in the non-brooded group (P < 0.05). In conclusion, the presence of broody hens at an early stage of chicks' lives has a persistent effect on behavior. Although brooded chickens showed more brooding and lower egg production than non-brooded chickens, feather pecking and aggressive interaction were decreased in brooded hens. PMID- 25039795 TI - Expanding the spectrum of Grik2 mutations: intellectual disability, behavioural disorder, epilepsy and dystonia. PMID- 25039796 TI - American Geriatrics Society feeding tubes in advanced dementia position statement. AB - When eating difficulties arise, feeding tubes are not recommended for older adults with advanced dementia. Careful hand feeding should be offered because hand feeding has been shown to be as good as tube feeding for the outcomes of death, aspiration pneumonia, functional status, and comfort. Moreover, tube feeding is associated with agitation, greater use of physical and chemical restraints, healthcare use due to tube-related complications, and development of new pressure ulcers. Efforts to enhance oral feeding by altering the environment and creating patient-centered approaches to feeding should be part of usual care for older adults with advanced dementia. Tube feeding is a medical therapy that an individual's surrogate decision-maker can decline or accept in accordance with advance directives, previously stated wishes, or what it is thought the individual would want. It is the responsibility of all members of the healthcare team caring for residents in long-term care settings to understand any previously expressed wishes of the individuals (through review of advance directives and with surrogate caregivers) regarding tube feeding and to incorporate these wishes into the care plan. Institutions such as hospitals, nursing homes, and other care settings should promote choice, endorse shared and informed decision-making, and honor preferences regarding tube feeding. They should not impose obligations or exert pressure on individuals or providers to institute tube feeding. PMID- 25039798 TI - Culture: copying, compression, and conventionality. AB - Through cultural transmission, repeated learning by new individuals transforms cultural information, which tends to become increasingly compressible (Kirby, Cornish, & Smith, ; Smith, Tamariz, & Kirby, ). Existing diffusion chain studies include in their design two processes that could be responsible for this tendency: learning (storing patterns in memory) and reproducing (producing the patterns again). This paper manipulates the presence of learning in a simple iterated drawing design experiment. We find that learning seems to be the causal factor behind the increase in compressibility observed in the transmitted information, while reproducing is a source of random heritable innovations. Only a theory invoking these two aspects of cultural learning will be able to explain human culture's fundamental balance between stability and innovation. PMID- 25039797 TI - Hippocampal plasticity during the peripartum period: influence of sex steroids, stress and ageing. AB - The peripartum period is accompanied by dramatic changes in hormones and a host of new behaviours in response to experience with offspring. Both maternal experience and maternal hormones can have a significant impact upon the brain and behaviour. This review outlines recent studies demonstrating modifications in hippocampal plasticity across the peripartum period, as well as the putative hormonal mechanisms underlying these changes and their modulation by stress. In addition, the impact of reproductive experience upon the ageing hippocampus is discussed. Finally, we consider how these changes in hippocampal structure may play a role in postpartum cognitive function and mood disorders, as well as age related cognitive decline. PMID- 25039799 TI - Impact of self-administration of romiplostim by patients with chronic immune thrombocytopenia compared with administration by a healthcare provider. AB - OBJECTIVE: This post hoc analysis evaluated romiplostim self-administration (SA group) vs. romiplostim administration by a healthcare provider in a clinical setting (HCP group) in patients with chronic immune thrombocytopenia (ITP). METHODS: Outcomes from 3 ITP trials allowing self-administration in patients achieving a stable romiplostim dose for >=3 consecutive weeks were compared. Evaluations were conducted for 12-wk treatment intervals. Efficacy endpoints included percentage of patients and weeks with platelets within the target range of 50-200 * 10(9) /L and safety. RESULTS: Baseline characteristics suggested less severe disease in the SA groups (n = 563) than in the HCP groups (n = 241). The SA groups had greater proportions of patients achieving the target platelet range (55-58% vs. 40-52%) and greater proportions of weeks with a platelet response (75 88% vs. 47-76%) than the HCP groups. The rate of romiplostim discontinuation was twofold to fivefold lower in the SA groups than in the HCP groups. Rates of duration-adjusted adverse events (AEs), serious AEs and treatment-related AEs were also lower in the SA groups. CONCLUSIONS: In conclusion, in adults with ITP receiving romiplostim, self-administration was comparable to healthcare provider administration in terms of efficacy and safety profiles, suggesting that self administration of romiplostim is a feasible option for certain patients with ITP. PMID- 25039800 TI - Possible morphological pathomechanisms of ischemic stroke in the posterior circulation of patients with vertebral artery hypoplasia. AB - BACKGROUND: The clinical significance of vertebral artery hypoplasia (VAH) and the possible pathomechanism of ischemic stroke in patients with VAH are still not completely clear. METHODS: In a group of 80 posterior circulation strokes (PCS) patients, we compared the location of the ischemic areas in VAH (n = 26) and non VAH (n = 54) group. We assessed the side of VAH (diameter equal to or less than 2.5 mm) with the stroke localization. RESULTS: The possible morphological stroke pathomechanisms in the VAH group--"blood flow reorganization" (n = 11) and "pathway liberation for embolization" (n = 10) - were represented equally and may also act together (n = 3). In two cases, the stroke pathomechanism was unknown. The frequency of the presence of conventional risk factors--hypertension (p = 1.0), diabetes mellitus (p = 0.62), hyperlipidemia (p= 1.0) and smoking (p = 1.0) -and the stroke etiology--cardioembolism (p = 0.80), atherosclerotic changes of large (p = 0.76) and small vessels (p = 0.79)--did not differ between the two subgroups. CONCLUSION: In patients with VAH, the combination of several pathomechanisms of ischemic stroke and the contribution of several risk factors can cause the clinical manifestation of PCS. PMID- 25039801 TI - Factors associated with post-natal anxiety among primiparous mothers in Nepal. AB - BACKGROUND: In Nepal, new mothers are fatigued by childcare responsibilities because of lack of knowledge and preparation for their new role. Knowledge deficit and adherence to traditional health practices place infants at risk. Some cultural practices for the care of newborns may cause tetanus, hypothermia or other life-threatening illnesses. Maternal education, previous experience of newborn care, economic status, relationship problems with husband or mothers-in law and dissatisfaction with social relations are the variables of interest for this study. AIMS: To examine the association between socio-demographic variables and post-natal anxiety among primiparous mothers in Nepal. DESIGN: The study was designed as a correlational study. SETTING: A major maternity hospital in Kathmandu, Nepal. PARTICIPANTS: The sample were 216 primiparous mothers who were followed at 5-6 weeks after delivery. METHODS: Three instruments were used for data collection: a demographics questionnaire, the Newborn Care Knowledge Questionnaire and the State-Trait Anxiety Inventory for Adults. RESULTS: The mothers' knowledge of newborn care, general educational level and income were inversely related to maternal anxiety, that is, mothers with a lower educational level and socio-economic status demonstrated a higher level of post-natal anxiety. Poor relationships with husbands or mothers-in-law and low social support presented potential for the development of anxiety and depression during post-partum period. CONCLUSION: Maternal education, socio-economic status and knowledge of newborn care were major factors of post-natal anxiety. On the other hand, women with low income and education, poor relationships with their husbands or mothers-in-law, and insufficient social support are vulnerable to the development of moderate to severe anxiety. HEALTH POLICY: Policy implications from these results indicate the need for support and funding from the Ministry of Health for education for women at hospitals, which must work together to offer newborn care education during the ante-natal and post-natal periods. PMID- 25039802 TI - Clinical and oral findings in an Afro-Brazilian family with Gorlin-Goltz syndrome: case series and literature review. AB - Gorlin-Goltz syndrome (GGS) seems to be unusual in black persons. The authors present an Afro-Brazilian family case report of GGS. The main complaint of the index case was a painless swelling of the left mandible, which was diagnosed as an odontogenic keratocyst. Further classical features of the Syndrome were present in this patient. Other two family members were diagnosed as cases of GGS and one of them presented 11 clinical findings characteristic of the syndrome. From the three cases reported, two of them presented five major diagnostic criteria for the GGS, and the diagnosis was only made because of an oral complaint. This case series emphasizes the importance of carefully examining the patient and close relatives for signs of GGS, even if they belong to an ethnic group in which this diagnosis is unusual. PMID- 25039803 TI - Antinociceptive effects of epidural magnesium sulphate alone and in combination with morphine in dogs. AB - OBJECTIVE: To compare the antinociceptive effects of magnesium sulphate (MgSO(4)) when administered epidurally alone and in combination with morphine. STUDY DESIGN: Experimental, randomized, 'blinded', crossover study. ANIMALS: Six healthy adult Beagle dogs. METHODS: Evaluated treatments were MgSO(4) (2.5 mg kg( 1)) alone (Mg), morphine (0.1 mg kg(-1)) alone (Mo), MgSO(4) in combination with morphine (Mm), and sterile water (0.115 mL kg(-1) ; Co) that were injected in the lumbosacral epidural space using an epidural catheter. Antinociception was measured using the von Frey mechanical threshold device applied to the carpal pads, both sides of the thorax and metatarsi. Measurements were obtained at time points: before treatment (baseline) and 0.5, 1, 2, 4, 6, 12, 18 and 24 hours after the epidural injection. Sedation, behaviour score and presence of motor deficits were assessed. Data were analyzed using a linear mixed model and Bonferroni adjustments, with significance set at p < 0.05. RESULTS: There were significant effects of treatment and time in all regions. Overall threshold values in grammes force [median (interquartile range)] when stimulation regions were combined were significantly higher in Mg [164 (135-200)], Mo [156 (129-195)] and Mm [158 (131-192)] compared to Co [145 (120-179)]. Thresholds were significantly higher compared to Co in Mg, Mo and Mm at the thorax and metatarsi, but only in Mg and Mo at the carpal pads. No motor deficits were observed at any time point. Thresholds (combined regions) were increased from baseline at one or more time points with all treatments, including control. CONCLUSION AND CLINICAL RELEVANCE: Epidural MgSO(4) produced an antinociceptive effect characterised by an increase in the mechanical thresholds of similar magnitude to that produced by epidural morphine, compared with the control group, without causing any motor deficits. No potentiation of morphine antinociception was observed. The onset and offset times of antinociception could not be clearly established. To what extent these results can be extrapolated to clinical cases requires further investigation. PMID- 25039805 TI - Physical activity in type 2 diabetes: Have we got it correct? PMID- 25039804 TI - Effect of docosahexaenoic acid supplementation on inflammatory cytokine levels in infants at high genetic risk for type 1 diabetes. AB - OBJECTIVE: Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic beta-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D. RESEARCH DESIGN AND METHODS: This was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell (RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide (LPS), 1 ug/mL. RESULTS: The levels of RBC DHA were increased by 61-100% in treated compared to control infants at ages 6-36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1beta, TNFalpha, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein (hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing >=two persistently positive biochemical islet autoantibodies. CONCLUSIONS: This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced. PMID- 25039806 TI - Early intensive care unit-acquired hypernatremia in severe sepsis patients receiving 0.9% saline fluid resuscitation. AB - BACKGROUND: Intensive care unit (ICU)-acquired hypernatremia is associated with increased mortality and ascribed to excessive sodium/insufficient free water intakes. We aimed to determine whether the volume of intravenous 0.9% saline fluid resuscitation was associated with hypernatremia in severe sepsis. METHODS: We retrospectively reviewed the charts of patients admitted to our medical ICU over 1 year with severe sepsis, and recorded all fluid intakes and plasma sodium levels (Nap ) for 5 days along with clinical data. DeltaNap was defined as the difference between maximal Nap reached and initial Nap . Hypernatremia was defined as Nap > 145 mmoles/l. RESULTS: Among 95 patients with severe sepsis, 29 developed hypernatremia within 5 days (31%), reaching a maximum Nap of 149.1 +/- 2.5 mmoles/l on average 3.8 +/- 1.5 days after admission. For every 50-ml/kg increase in 0.9% saline intake for the first 48 h, the odds of hypernatremia were 1.61 times larger [confidence interval (CI): 0.98-2.62; P = 0.06] and the mean of DeltaNap increased by 1.86 mmoles/l (CI: 0.86-2.86; P < 0.001). Compared with non hypernatremic patients, hypernatremic patients received more 0.9% saline within the first 48 h (111 +/- 50 ml/kg vs. 92 +/- 42 ml/kg, P < 0.05) and more other fluids from 48 to 96 h (64 +/- 38 ml/kg vs. 42 +/- 24 ml/kg, P < 0.05). Patients developing hypernatremia had increased length of mechanical ventilation (12.0 +/- 12.6 vs. 9.1 +/- 7.2 days, P < 0.05) and ICU mortality (38.5% vs. 13%, P < 0.01). CONCLUSIONS: Early acquired hypernatremia is a frequent complication in severe sepsis patients and is associated with the volume of 0.9% saline received during the first 48 h of admission. PMID- 25039807 TI - Use of double-blind peer review to increase author diversity. PMID- 25039808 TI - IgG4 positive mucosa associated lymphoid tissue lymphoma of the orbit - lesson of the month. PMID- 25039809 TI - Patient data meta-analysis of Post-Authorization Safety Surveillance (PASS) studies of haemophilia A patients treated with rAHF-PFM. AB - A Post-Authorization Safety Study (PASS) global program was designed to assess safety and effectiveness of rAHF-PFM (ADVATE) use in haemophilia patients in routine clinical settings. The main aim of this project was to estimate the rate of inhibitors and other adverse events across ADVATE-PASS studies by meta analysing individual patient data (IPD). Eligible Studies: PASS studies conducted in different countries, between 2003 and 2013, for which IPD were provided. Eligible patients: haemophilia A patients with baseline FVIII:C < 5%, with a known number of prior exposure days (EDs). PRIMARY OUTCOME: de novo inhibitors in severe, previously treated patients (PTPs) with > 150 EDs. SECONDARY OUTCOMES: de novo inhibitors according to prior exposure and disease severity; other adverse events; annualized bleeding rate (ABR). ANALYSIS: random-effects logistic regression. Five of seven registered ADVATE-PASS (Australia, Europe, Japan, Italy and USA) and 1188 patients were included (median follow-up 384 days). Among severe PTPs with > 150 EDs, 1/669 developed de novo inhibitors (1.5 per 1000; 95% confidence interval [CI] 0.2, 10.6 per 1000). Among all patients included in the PASS studies, 21 developed any type of inhibitors (2.0%, 95% CI: 0.8%, 4.7%). Less than 1% of patients presented with other serious adverse events possibly related to ADVATE. The overall median ABR was 3.83 bleeds/year (first, third quartiles: 0.60, 12.90); 1.66 (0, 4.78) in the 557 patients continuously on prophylaxis >= twice/week. Meta-analysing PASS data from different countries confirmed the overall favourable safety and effectiveness profile of ADVATE in routine clinical settings. PMID- 25039810 TI - Emotional and behavioural problems in children with language impairments and children with autism spectrum disorders. AB - BACKGROUND: Although it is well-established that children with language impairment (LI) and children with autism spectrum disorders (ASD) both show elevated levels of emotional and behavioural problems, the level and types of difficulties across the two groups have not previously been directly compared. AIMS: To compare levels of emotional and behavioural problems in children with LI and children with ASD recruited from the same mainstream schools. METHODS & PROCEDURES: We measured teacher-reported emotional and behavioural problems using the Strengths and Difficulties Questionnaire (SDQ) in a sample of 5-13-year-old children with LI (N = 62) and children with ASD (N = 42) attending mainstream school but with identified special educational needs. OUTCOMES & RESULTS: Both groups showed similarly elevated levels of emotional, conduct and hyperactivity problems. The only differences between the LI and ASD groups were on subscales assessing peer problems (which were higher in the ASD group) and prosocial behaviours (which were higher in the LI group). Overall, there were few associations between emotional and behavioural problems and child characteristics, reflecting the pervasive nature of these difficulties in children with LI and children with ASD, although levels of problems were higher in children with ASD with lower language ability. However, in the ASD group only, a measure of family social economic status was associated with language ability and attenuated the association between language ability and emotional and behavioural problems. CONCLUSIONS & IMPLICATIONS: Children with LI and children with ASD in mainstream school show similarly elevated levels of emotional and behavioural problems, which require monitoring and may benefit from intervention. Further work is required to identify the child, family and situational factors that place children with LI and children with ASD at risk of emotional and behavioural problems, and whether these differ between the two groups. This work can then guide the application of evidence-based interventions to these children. PMID- 25039811 TI - Ductal carcinoma in situ: breast-conserving surgery without radiotherapy. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is commonly managed with breast conserving surgery (BCS) and adjuvant radiotherapy. Oncoplastic BCS allows wide excision without compromising the breast's natural shape. We use 'level one' techniques to excise a 'sector' of tissue (apex at the nipple) rather than traditional 'lumpectomy'. There are concerns that some DCIS is over-treated and radiotherapy administered unnecessarily incurring the associated cost, time and morbidity without added benefit. This study aims to determine if pure DCIS can be managed safely without relying upon adjuvant therapies with an acceptable breast conservation rate. METHOD: A retrospective clinical study of 96 patients who underwent BCS alone for pure DCIS between 1995 and 2009. Data were collected on patient's demographics, presentation, excision margins, re-excision and final margins, size, grade and nuclear architecture of DCIS, recurrent ipsilateral breast events, contralateral breast events, date of the last follow-up with mammography and patients' assessment of cosmetic outcome (scale 1-5: very dissatisfied, somewhat dissatisfied, somewhat satisfied, satisfied, very satisfied). RESULTS: Twelve (12.5%) had an ipsilateral recurrence. Mean follow-up was 7.6 years (median 7.4); yearly recurrence rate was 1.67%. Of the 52 patients who gave an assessment of cosmetic outcome, 46 were satisfied. CONCLUSION: Ipsilateral recurrence rates were favourable compared with previous trials where DCIS was treated with lumpectomy and radiotherapy. Oncoplastic techniques may be used to successfully treat pure DCIS with BCS alone without adjuvant therapies. PMID- 25039813 TI - Are leaves 'freewheelin'? Testing for a wheeler-type effect in leaf xylem hydraulic decline. AB - A recent study found that cutting shoots under water while xylem was under tension (which has been the standard protocol for the past few decades) could produce artefactual embolisms inside the xylem, overestimating hydraulic vulnerability relative to shoots cut under water after relaxing xylem tension (Wheeler et al. 2013). That study also raised the possibility that such a 'Wheeler effect' might occur in studies of leaf hydraulic vulnerability. We tested for such an effect for four species by applying a modified vacuum pump method to leaves with minor veins severed, to construct leaf xylem hydraulic vulnerability curves. We tested for an impact on leaf xylem hydraulic conductance (Kx ) of cutting the petiole and minor veins under water for dehydrated leaves with xylem under tension compared with dehydrated leaves after previously relaxing xylem tension. Our results showed no significant 'cutting artefact' for leaf xylem. The lack of an effect for leaves could not be explained by narrower or shorter xylem conduits, and may be due to lesser mechanical stress imposed when cutting leaf petioles, and/or to rapid refilling of emboli in petioles. These findings provide the first validation of previous measurements of leaf hydraulic vulnerability against this potential artefact. PMID- 25039812 TI - Effect of indoor air pollution from biomass and solid fuel combustion on symptoms of preeclampsia/eclampsia in Indian women. AB - Available evidence concerning the association between indoor air pollution (IAP) from biomass and solid fuel combustion and preeclampsia/eclampsia is not available in developing countries. We investigated the association between exposure to IAP from biomass and solid fuel combustion and symptoms of preeclampsia/eclampsia in Indian women by analyzing cross-sectional data from India's third National Family Health Survey (NFHS-3, 2005-2006). Self-reported symptoms of preeclampsia/eclampsia during pregnancy such as convulsions (not from fever), swelling of legs, body or face, excessive fatigue or vision difficulty during daylight, were obtained from 39,657 women aged 15-49 years who had a live birth in the previous 5 years. Effects of exposure to cooking smoke, ascertained by type of fuel used for cooking on preeclampsia/eclampsia risk, were estimated using logistic regression after adjusting for various confounders. Results indicate that women living in households using biomass and solid fuels have two times higher likelihood of reporting preeclampsia/eclampsia symptoms than do those living in households using cleaner fuels (OR = 2.21; 95%: 1.26-3.87; P = 0.006), even after controlling for the effects of a number of potentially confounding factors. This study is the first to empirically estimate the associations of IAP from biomass and solid fuel combustion and reported symptoms suggestive of preeclampsia/eclampsia in a large nationally representative sample of Indian women and we observed increased risk. These findings have important program and policy implications for countries such as India, where large proportions of the population rely on polluting biomass fuels for cooking and space heating. More epidemiological research with detailed exposure assessments and clinical measures of preeclampsia/eclampsia is needed in a developing country setting to validate these findings. PMID- 25039814 TI - eGFR decrease during antiviral C therapy with first generation protease inhibitors: a clinical significance? AB - BACKGROUND & AIMS: Renal toxicity of first generation protease inhibitors (PIs) was not a safety signal in phase III clinical trials, but was recently reported in recent studies. It appeared important to determine the clinical significance of these findings. METHODS: We retrospectively analysed 101 HCV patients receiving triple therapy with telaprevir (n = 36) or boceprevir (n = 26) or double therapy (n = 39) with peginterferon and ribavirin and having a close monitoring of eGFR (MDRD formula) during and after treatment. EGFR decline over time was assessed by a linear mixed-effects model (LMEM) with search for possible explanatory covariates. RESULTS: Patients treated with telaprevir presented a significant decrease of eGFR with the same kinetics: initial decrease at W (week) 4, nadir at W8 (mean decrease 17.0 +/- 18.9 ml/min/1.73 m(2)) and return to baseline at W16. The W8 eGFR was correlated with the D0 eGFR (R(2) = 0.49). The LMEM showed that interindividual variability in the slope of eGFR vs time between D0 and W8 was non-significant and eGFR nadir could be predicted from eGFR obtained at D0. In multivariate analysis, eGFR intercept (i.e. baseline value) was associated with older age and male sex. CONCLUSION: The eGFR significantly varied in telaprevir group only. Our model showed that eGFR nadir mainly depended on initial eGFR. As telaprevir has been shown to inhibit mostly the drug transporter OCT2 which interacts with creatinine transport, the early decrease of eGFR observed could be a benign phenomenon. However, as unpredictable true renal toxicity may occur during therapy, we recommend a thorough follow-up of eGFR. PMID- 25039816 TI - Differences between genomic-based and pedigree-based relationships in a chicken population, as a function of quality control and pedigree links among individuals. AB - This work studied differences between expected (calculated from pedigree) and realized (genomic, from markers) relationships in a real population, the influence of quality control on these differences, and their fit to current theory. Data included 4940 pure line chickens across five generations genotyped for 57,636 SNP. Pedigrees (5762 animals) were available for the five generations, pedigree starting on the first one. Three levels of quality control were used. With no quality control, mean difference between realized and expected relationships for different type of relationships was <= 0.04 with standard deviation <= 0.10. With strong quality control (call rate >= 0.9, parent-progeny conflicts, minor allele frequency and use of only autosomal chromosomes), these numbers reduced to <= 0.02 and <= 0.04, respectively. While the maximum difference was 1.02 with the complete data, it was only 0.18 with the latest three generations of genotypes (but including all pedigrees). Variation of expected minus realized relationships agreed with theoretical developments and suggests an effective number of loci of 70 for this population. When the pedigree is complete and as deep as the genotypes, the standard deviation of difference between the expected and realized relationships is around 0.04, all categories confounded. Standard deviation of differences larger than 0.10 suggests bad quality control, mistakes in pedigree recording or genotype labelling, or insufficient depth of pedigree. PMID- 25039815 TI - Influenza A infection enhances antigen-induced airway inflammation and hyperresponsiveness in young but not aged mice. AB - BACKGROUND: Although morbidity and mortality rates from asthma are highest in patients > 65 years of age, the effect of older age on airway inflammation in asthma is not well established. OBJECTIVE: To investigate age-related differences in the promotion of allergic inflammation after influenza A viral respiratory infection on antigen-specific IgE production, antigen-induced airway inflammation and airway hyperresponsiveness in mice. METHODS: To accomplish this objective, the following model system was used. Young (6 week) and aged (18 months) BALB/c mice were first infected with a non-lethal dose of influenza virus A (H/HKx31). Mice were then ovalbumin (OVA)-sensitized during the acute infection (3-days post inoculation) and then chronically underwent challenge to the airways with OVA. Forty-eight hours after the final OVA challenge, airway hyperresponsiveness (AHR), bronchoalveolar fluid (BALF) cellular and cytokine profile, antigen specific IgE and IgG1, and lung tissue inflammation were measured. RESULTS: Age specific differences were noted on the effect of a viral infection, allergic sensitization, airway inflammation and airway hyperresponsiveness. Serum OVA specific IgE was significantly increased in only the aged mice infected with influenza virus. Despite greater morbidity (e.g. weight loss and sickness scores) during the acute infection in the 18-month old mice that were OVA-sensitized, there was little effect on the AHR and BALF cellular differential. In contrast, BALF neutrophils and AHR increased, but eosinophils decreased in 6-week mice that were OVA-sensitized during an acute influenza infection. CONCLUSION: With increased age in a mouse model, viral infection prior to antigen sensitization affects the airway and systemic allergic response differently. These differences may reflect distinct phenotypic features of allergic inflammation in older patients with asthma. PMID- 25039817 TI - Impaired balance and neurodevelopmental disabilities among children with congenital cytomegalovirus infection. AB - AIM: Although cytomegalovirus (CMV) is the most common congenital infection, existing research has not provided us with a full picture of how this can affect children in the future. The aim of this case-control study was to evaluate disabilities in a well-defined group of children with congenital cytomegalovirus (CMV) infection, who had been fitted with cochlear implants because of severe hearing impairment. METHODS: A multidisciplinary team assessed 26 children with congenital CMV infection for balance difficulties, neurodevelopmental disabilities and language and visual impairment. We also included a control group of 13 children with severe hearing impairment due to connexin 26 mutations. RESULTS: The majority of the children with congenital CMV infection (88%) displayed balance disturbances, including walking at a later age, but there were no cases in the control group. The CMV group also displayed frequent neurodevelopmental disabilities and feeding difficulties. CONCLUSION: Congenital CMV infection affects the general development of the brain and gives rise to a complex pattern of difficulties. Identifying comorbid conditions is very important, as children with associated difficulties and disabilities need more support than children with just hearing impairment. Congenital CMV infection needs to be considered in children with hearing impairment and/or balance disturbance and/or neurodevelopmental disabilities. PMID- 25039818 TI - Boston Violence Intervention Advocacy Program: a qualitative study of client experiences and perceived effect. AB - OBJECTIVES: This study intended to explore clients' experiences and provide a contextual basis for understanding their perceptions of the effectiveness of the Boston Medical Center (BMC) Violence Intervention Advocacy Program (VIAP). METHODS: This was an exploratory, qualitative study conducted in an urban, Level I trauma center from July 1, 2011 to February 24, 2012. Emergency department (ED) patients older than 18 years with penetrating trauma, and who were enrolled in the VIAP, were eligible. Two trained, qualitative interviewers who were not part of the VIAP obtained consent and conducted in-depth, semistructured interviews. Interviews were audiotaped, transcribed, deidentified, coded, and analyzed. Thematic content analysis consistent with grounded theory was used to identify themes related to client experiences with VIAP, life circumstances, challenges to physical and emotional healing postinjury, services provided by VIAP, and perceptions of VIAP's effectiveness. RESULTS: Twenty subjects were interviewed. Most were male, African American, and younger than 30 years of age, reflecting the overall program's clientele. Most subjects perceived their advocates as caring adults in their lives and cited aspects of the peer support model that helped establish trusting relationships. Major challenges to healing were fear and safety, trust, isolation as a coping mechanism, bitterness, and symptoms of posttraumatic stress disorder (PTSD). Every subject noted important services provided by VIAP advocates. Most subjects explicitly stated that they had positive experiences with the VIAP and perceived advocates' roles as a positive influence, providing client-centered advocacy, education, and support. CONCLUSIONS: This study provides insight into the lives of 20 BMC VIAP clients and contextualizes their unique challenges. Participants described positive, life changing behaviors on their journey to healing through connections to caring, supportive adults. Information gained from this study will help the VIAP to further support its clients. However, future research is needed to identify best practices for ED-based violence intervention programs and to measure community wide efficacy in different settings. PMID- 25039819 TI - Surveillance of diarrhea-causing pathogens in dairy and beef cows in Yamagata Prefecture, Japan from 2002 to 2011. AB - The economic consequences of bovine diarrhea are serious. Few long-term epidemiological data are available concerning the causative pathogens of bovine diarrhea in Japan. From 2002 to 2011, surveillance of enteric pathogens was performed in cows of various breed and age from 302 farms in which diarrhea had occurred in Yamagata Prefecture, Japan. Differences between dairy and beef cows in the number of cases of diarrhea and rates of infection by Salmonella spp. and Eimeria spp. were found. Clinical symptoms (duration of epidemic, hematochezia and complications) caused by bovine rotavirus infection were milder than those caused by bovine coronavirus infection. PMID- 25039820 TI - Nine years' experience with the chordal cutting technique in ischemic mitral regurgitation. AB - OBJECTIVES: The optimal surgical management of chronic ischemic mitral regurgitation has not yet been clearly defined. Among the various approaches proposed, the excision of strut (or main) chordae, along with complete annuloplasty to relieve tethering, has been the one preferred by our institution to treat this particular subset of mitral disease. METHODS: Between October 2004 and May 2013, 11 patients underwent surgery for chronic ischemic mitral regurgitation. RESULTS: There was no perioperative death. No patient was lost to follow-up. There was one late death due to respiratory failure three years after the operation, and one patient received a ventricular assist device ten months after surgery. The remaining patients are all alive with residual trivial-to-mild regurgitation. CONCLUSION: Chordal cutting associated with complete annuloplasty may be a good surgical option in chronic ischemic mitral regurgitation. PMID- 25039821 TI - Interactions among the three adaptation systems of Bacillus subtilis chemotaxis as revealed by an in vitro receptor-kinase assay. AB - The Bacillus subtilis chemotaxis pathway employs three systems for sensory adaptation: the methylation system, the CheC/CheD/CheYp system, and the CheV system. Little is known in general about how these three adaptation systems contribute to chemotaxis in B. subtilis and whether they interact with one another. To further understand these three adaptation systems, we employed a quantitative in vitro receptor-kinase assay. Using this assay, we were able to determine how CheD and CheV affect receptor-kinase activity as a function of the receptor modification state. CheD was found to increase receptor-kinase activity, where the magnitude of the increase depends on the modification state of the receptor. The principal new findings concern CheV. Little was known about this protein before now. Our data suggest that this protein has two roles depending on the modification state of the receptor, one for sensory adaptation when the receptors are modified (methylated) and the other for signal amplification when they are unmodified (unmethylated). In addition, our data suggest that methylation of site 630 tunes the strength of the CheV adaptation system. Collectively, our results provide new insight regarding the integrated function of the three adaptation systems in B. subtilis. PMID- 25039822 TI - New carbohydrate-active enzymes identified by screening two metagenomic libraries derived from the soil of a winter wheat field. AB - AIMS: Soils are rich, diversified environments where beta-glucosidases abound because of their importance in organic matter degradation. The aim of this work was to discover new beta-glucosidases by constructing two metagenomic DNA libraries from soil samples collected in winter and spring from a field of winter wheat. METHODS AND RESULTS: Both libraries were screened on esculin-supplemented medium so as to isolate candidates showing beta-glucosidase activity. Candidate analysis revealed seven putative beta-glycosidases and two putative glycosyltransferases, displaying 25 to 82% identity to known enzymes. The putative beta-glycosidases belong to families GH1, GH3 and GH20 and the two putative glycosyltransferases, probably, to new families. In characterization tests performed on bacteria in suspension or spread on agar plates, some candidates appeared to hydrolyse several natural and synthetic substrates. These tests also highlighted interesting industrial characteristics, such as the activity of four beta-glycosidases under alkaline conditions and the esculin hydrolysing activity of a beta-glucosidase candidate in the presence of glucose. CONCLUSIONS: Seven putative beta-glycosidases and two putative glycosyltransferases were found by functional screening of two metagenomic DNA libraries derived from agricultural soil. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has identified beta-glycosidases and putative glycosyltransferases that have or may have interesting industrial characteristics. PMID- 25039823 TI - Where is philosophy of medicine headed? A report of the International Advanced Seminar in the Philosophy of Medicine (IASPM). PMID- 25039825 TI - A calibration test for latent fingerprint development on thermal paper. AB - A calibration test is described for monitoring the operation of equipment used to develop latent fingerprints on thermal paper by the application of either controlled or uncontrolled heat. A working solution of a water/glycerol emulsion and butylene glycol is applied to thermal paper by means of either a vinyl stamp and pad, or a marker pen. Varying the amount of butylene glycol enables the thermal paper to change color at different temperatures between approximately 40 and 60 degrees C, which is below the normal color change temperature of the paper. The described test may be used to verify the correct operation, at different temperatures, of a controlled heat source during and after fingerprint development (such as the Hot Print System) or to monitor the paper temperature with an uncontrolled heat source (such as a warm air blower), thereby avoiding unintentional coloring of the entire paper surface. PMID- 25039824 TI - Fibroblast growth factor-21, body composition, and insulin resistance in pre pubertal and early pubertal males and females. AB - OBJECTIVE: Accumulating evidence derived primarily from animal models suggests that fibroblast growth factor-21 (FGF-21) may affect the musculoskeletal system via effects on the capacity of tissues to respond to insulin. A proportion of musculoskeletal properties and underpinnings of promoting/preventing insulin resistance are established early in the pubertal transition. Thus, the objective of this study was to test the hypothesis that insulin resistance and/or obesity will promote greater FGF-21 concentration which will be inversely associated with musculoskeletal parameters [lean mass and bone mineral content (BMC)] in pre /early pubertal children. Given the sexual dimorphic nature of musculoskeletal development of fat mass accrual, differences by obesity status and sex were also investigated. DESIGN: Cross-sectional. PATIENTS: Children ages 7-12 years (n = 69, 38% male, 48% non-Hispanic black, 45% obese). MEASUREMENTS: Fasting FGF-21, glucose and insulin measures were obtained. An estimate of insulin resistance was derived using the homoeostatic model assessment of insulin resistance (HOMA-IR). Body composition (BMC, lean mass and fat mass) was assessed by DXA. Multivariate regression analysis was used to evaluate the influence of FGF-21 on BMC, lean mass and HOMA-IR as dependent variables. Obesity status was established based on BMI z-score. RESULTS: FGF-21 concentrations did not differ by obesity status or by sex. There was an inverse association between FGF-21 and BMC among nonobese individuals (P = 0.01) and an inverse association between FGF-21 and lean mass among females (P = 0.02), which were both independent of fat mass. FGF-21 was inversely associated with HOMA-IR in males, but not females (P = 0.04). CONCLUSIONS: The existence of relationships of FGF-21 with musculoskeletal parameters and insulin resistance raises the possibility of crosstalk between these systems. These findings suggest that circulating FGF-21 may differ in its association with bone, lean mass and insulin resistance depending on sex and weight status. PMID- 25039826 TI - Racial disparities in pediatric kidney transplantation in New Zealand. AB - Racial disparities in transplantation rates and outcomes have not been investigated in detail for NZ, a country with unique demographics. We studied a retrospective cohort of 215 patients <18 yr who started renal replacement therapy in NZ 1990-2012, using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). Primary outcomes were time to first kidney transplant, death censored graft survival, and retransplantation after loss of primary graft. Europeans and Asians were most likely to receive a transplant (92% and 91% transplanted within five yr, respectively), and Pacific and Maori patients were less likely to receive a transplant than Europeans (51% and 46%, respectively), reflecting disparities in live donor transplantation. Pacific patients were more likely to have glomerulonephritis and FSGS. Pacific patients had five-yr death censored graft survival of 31%, lower than Maori (61%) and Europeans (88%). No Pacific patients who lost their grafts were re-transplanted within 72 patient years of follow-up, whereas 14% of Maori patients and 36% of European and Asian patients were retransplanted within five yr. Current programs to improve live and deceased donation within Maori and Pacific people and management of recurrent kidney disease are likely to reduce these disparities. PMID- 25039827 TI - Clarifying the sequential processes involved in a cued continuous performance test. AB - We aimed to clarify sequential processes for cue and imperative stimuli (targets/nontargets) in a continuous performance test (CPT), and how the preparatory contingent negative variation (CNV) affects physiological and behavioral responses. Single-trial event-related potentials (ERPs) obtained from 70 participants during a cued CPT were baselined to the cue (BtC) to include the CNV, or to the imperatives (BtI) to remove the CNV. Principal components analysis obtained cue and imperative ERP components, and congruence coefficients (rc ) evaluated similarities. The cue and imperative components were comparable, more so for the BtI- than BtC-imperative components (rc = .85). N1, PN, P2, N2c, and SW components were similar, but not the N2b and P3s. Imperative ERPs were largely unaffected by the resolving CNV. Similar cue and imperative components suggest similar sequential processes, while preparatory CNV activity enhanced physiological and behavioral responses. PMID- 25039828 TI - Periodontitis mainly increases osteoclast formation via enhancing the differentiation of quiescent osteoclast precursors into osteoclasts. AB - BACKGROUND AND OBJECTIVES: Tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts are formed in sequential steps: proliferation and differentiation of hematopoietic progenitors into quiescent osteoclast precursors (QOPs), followed by fusion of QOPs. In this study, we investigated whether enhancement of osteoclast formation by periodontitis is derived from the stimulation of proliferation of hematopoietic progenitors or the differentiation of QOPs into osteoclasts. MATERIAL AND METHODS: Ligatures were placed around the first molars in the left mandibles of Fischer 344 inbred rats. The rats received drinking water containing bromodeoxyuridine (BrdU) (which can be incorporated into dividing nuclei) after ligation during the experimental period. The number of inflammatory cells in the distal area was counted. Alveolar bone loss was histologically estimated by measuring the distance from the cementoenamel junction to the alveolar bone crest in the distal area and determining the percentage of periodontal ligament area in the furcation. The number of osteoclasts and percentage of BrdU(+) nuclei in total osteoclasts nuclei were counted after TRAP and BrdU double labeling. RESULTS: The number of polymorphonuclear cells increased on day 1 and then rapidly decreased. The number of mononuclear cells increased in a time-dependent manner up to day 5 and remained the same until day 10. Alveolar bone loss of ligatured teeth increased in a time-dependent manner. The number of osteoclasts peaked on day 3 then gradually decreased. At peak, the percentage of BrdU(+) nuclei in total osteoclasts nuclei in the distal and furcation areas were 7.9% and 4.1%, respectively. CONCLUSION: These results indicate that most of the osteoclasts formed after periodontitis induction are derived from preformed QOPs, suggesting that enhancement of osteoclast formation by periodontitis might be mainly caused by stimulating the differentiation of QOPs into osteoclasts. PMID- 25039829 TI - Is screening for congenital colour vision deficiency in school students worthwhile? A review. AB - This review analyses the literature on screening for congenital colour vision deficiency in school students, which predominantly uses the Ishihara test. The review was framed with respect to the established Wilson and Jungner criteria for screening programs. These criteria relate to the characteristics of the condition concerned, the performance of the screening test, the existence of treatment options and the performance of screening programs. The literature reviewed suggests that congenital colour vision deficiency has not been shown to increase risk of road traffic crashes and is not a preclusion to driver licensing in most developed countries. The occurrence of congenital colour vision deficiency has been used to limit entry into certain occupations; however, the value of screening school students with regard to occupational preclusion is questionable. Stronger evidence exists indicating no association between congenital colour vision deficiency and level of educational achievement. Studies showing any association between congenital colour vision deficiency and other health and lifestyle impacts were rare. The most commonly used screening test (using Ishihara pseudoisochromatic plates) performs well with respect to detecting red green colour vision deficiencies. Finally, the only interventions we identified for congenital colour vision deficiency were management ones around the availability of specific tinted lenses and computer programs to aid colour perception in certain tasks. Given this picture, the weight of evidence appears to be in favour of not adopting (or discontinuing) routine colour vision screening programs for school students; however, it may be worthwhile for a career advisor to refer school students to an optometrist or ophthalmologist for colour vision screening, upon expression of interest in an occupation where normal colour vision is either particularly desirable or is a regulatory requirement. PMID- 25039830 TI - In vitro antioxidant and antiproliferative activities of nine Salvia species. AB - Supported by a growing increase of scientific research attesting the health properties of salvia species, we have decided to investigate nine Salvia namely Salvia sclarea, Salvia atropatana, Salvia sahendica, Salvia hydrangea, Salvia xanthocheila, Salvia macrosiphon, Salvia glutinosa, Salvia chloroleuca and Salvia ceratophylla species for their antioxidant and antiproliferative activities. In order to correlate the bioactivity with their phytochemical content, the total phenol and total flavonoid contents were also determined. S. ceratophylla exhibited the strongest activity against C32 cells with an IC50 value of 20.8 MUg mL(- 1), while S. glutinosa exhibited an IC50 value of 29.5 MUg mL(- 1) against ACHN cell line. Interestingly, S. glutinosa displayed also the highest DPPH radical-scavenging activity with an IC50 of 3.2 MUg mL(- 1). These species are characterised by the highest total phenol and flavonoid contents. The obtained results suggest that Salvia species are healthy plant foods. PMID- 25039831 TI - Editorial Comment from Dr Inamoto and Dr Azuma to Obesity and prognosis in muscle invasive bladder cancer: the continuing controversy. PMID- 25039833 TI - Supporting parents following childhood traumatic brain injury: a qualitative study to examine information and emotional support needs across key care transitions. AB - INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of death and acquired disability in childhood. Research has demonstrated that TBI can lead to long-term physical, cognitive, emotional and behavioural difficulties for children and parental stress. Less is known about how parents experience a childhood brain injury and their information and support needs. This study aimed to examine parents' experiences and support needs following a childhood TBI from the time of the accident to their child's discharge home. METHODS: Qualitative semi-structured interviews were conducted with 29 parents/carers of children who had experienced a severe TBI. Participants were recruited from one children's tertiary centre in the UK. Data were analysed using the Framework approach. RESULTS: Parents had unmet information and emotional support needs across the care trajectory from the time of the accident to their child's return home. Information needs related to the impact of the TBI on their child; current and future treatment/rehabilitation plans; helping their child and managing their behaviour; accessing services/support. They lacked information and support for care transitions. In different settings parents faced particular barriers to having their information needs met. Parents' felt they needed emotional support in coming to terms with witnessing the accident and the loss of their former child. Lack of community support related not only to service availability but to a general lack of understanding of the impact of TBI on children, particularly when this was invisible. Overall parents felt unsupported in coping with children's behavioural and psychological difficulties. DISCUSSION: Taking a holistic approach to examining parents' experiences and support needs has enabled their changing needs to be highlighted across key care transitions within hospital and community settings and the service implications identified. Improvements in care co-ordination across care transitions are needed to ensure continuity of care and integration of support. PMID- 25039832 TI - Comorbidity in dementia: update of an ongoing autopsy study. AB - OBJECTIVES: To examine systemic and central nervous system (CNS) comorbidities of individuals with dementia evaluated during general autopsy. DESIGN: Retrospective cohort study. SETTING: A large tertiary academic medical center in Los Angeles, California. PARTICIPANTS: Individuals with clinically and neuropathologically diagnosed dementia who received complete autopsies (n = 86) and individuals with dementia who received partial (brain only) autopsies (n = 132). MEASUREMENTS: Information on cause of death and systemic and CNS comorbidities was obtained from autopsy reports and clinical information as available from the medical records. Findings were tabulated with respect to type of dementia, semiquantitative assessment of the severity of cerebral amyloid angiopathy, semiquantitative assessment of the severity of cerebrovascular disease, and evidence of ischemic damage in the brain. RESULTS: Of 218 subjects with dementia, 175 (80.3%) had Alzheimer's disease alone or in combination with other lesions that might contribute to cognitive impairment, such as cerebrovascular disease and diffuse Lewy body disease (DLBD), 14 (6.4%) had frontotemporal dementia, and seven (3.2%) had isolated DLBD. The most common cause of death in participants with dementia was pneumonia (n = 57, 66.3%), followed by cardiovascular disease (n = 14, 16.3%). Eighteen subjects (20.9%) had lung disease, and 16 (18.6%) had evidence of an old or recent myocardial infarction. Clinically undiagnosed neoplasms included colonic adenocarcinoma, metastatic pulmonary neuroendocrine carcinoma, meningioma, and Schwannoma. CONCLUSION: Significant comorbidities were discovered at autopsy in individuals with dementia. Understanding the causes of death and associated comorbidities in individuals with various subtypes of dementia is important in the assessment of end-of-life care in these individuals. PMID- 25039834 TI - Careful clinical observation continues to improve understanding of the phenotype in individuals with tuberous sclerosis complex. PMID- 25039835 TI - Multigenerational response to artificial selection for biased clutch sex ratios in Tigriopus californicus populations. AB - Polygenic sex determination (PSD) is relatively rare and theoretically evolutionary unstable, yet has been reported across a range of taxa. Evidence for multilocus PSD is provided by (i) large between-family variance in sex ratio, (ii) paternal and maternal effects on family sex ratio and (iii) response to selection for family sex ratio. This study tests the polygenic hypothesis of sex determination in the harpacticoid copepod Tigriopus californicus using the criterion of response to selection. We report the first multigenerational quantitative evidence that clutch sex ratio responds to artificial selection in both directions (selection for male- and female-biased families) and in multiple populations of T. californicus. In the five of six lines that showed a response to selection, realized heritability estimated by multigenerational analysis ranged from 0.24 to 0.58. Divergence of clutch sex ratio between selection lines is rapid, with response to selection detectable within the first four generations of selection. PMID- 25039836 TI - A glutathione responsive rice glyoxalase II, OsGLYII-2, functions in salinity adaptation by maintaining better photosynthesis efficiency and anti-oxidant pool. AB - Glyoxalase II (GLY II), the second enzyme of glyoxalase pathway that detoxifies cytotoxic metabolite methylglyoxal (MG), belongs to the superfamily of metallo beta-lactamases. Here, detailed analysis of one of the uncharacterized rice glyoxalase II family members, OsGLYII-2 was conducted in terms of its metal content, enzyme kinetics and stress tolerance potential. Functional complementation of yeast GLY II mutant (?GLO2) and enzyme kinetics data suggested that OsGLYII-2 possesses characteristic GLY II activity using S lactoylglutathione (SLG) as the substrate. Further, Inductively Coupled Plasma Atomic Emission spectroscopy and modelled structure revealed that OsGLYII-2 contains a binuclear Zn/Fe centre in its active site and chelation studies indicated that these are essential for its activity. Interestingly, reconstitution of chelated enzyme with Zn(2+), and/or Fe(2+) could not reactivate the enzyme, while addition of Co(2+) was able to do so. End product inhibition study provides insight into the kinetics of GLY II enzyme and assigns hitherto unknown function to reduced glutathione (GSH). Ectopic expression of OsGLYII-2 in Escherichia coli and tobacco provides improved tolerance against salinity and dicarbonyl stress indicating towards its role in abiotic stress tolerance. Maintained levels of MG and GSH as well as better photosynthesis rate and reduced oxidative damage in transgenic plants under stress conditions seems to be the possible mechanism facilitating enhanced stress tolerance. PMID- 25039837 TI - Incidence and risk factors for colorectal neoplasia in patients with oral squamous cell carcinoma. AB - AIM: Colorectal adenoma and cancer are not regarded as being associated with primary oral cancer. The aim of this study was to determine whether screening colonoscopy should be performed for patients with oral cancer in addition to the upper gastrointestinal endoscopic screening that is now routinely performed. METHOD: Between 2007 and 2013, 162 patients with oral squamous cell carcinoma were enrolled at Tokyo Dental College, Ichikawa General Hospital, and 136 individuals were assigned to colonoscopic surveillance. Advanced neoplasia was defined as an adenoma >= 10 mm, adenoma with villous histology or high-grade dysplasia regardless of size and invasive cancer. Associations between advanced neoplasia and clinical factors, including age, sex, body mass index, physical activity, smoking, alcohol consumption and oral cancer site and staging were determined. RESULTS: Advanced neoplasia, including five invasive cancers, was identified in 32 (23.5%) patients. An age- and sex-adjusted multivariate analysis revealed that smoking (Brinkmann index > 400; OR = 3.24, 95% CI = 1.28-8.18), alcohol consumption (lifetime pure ethanol consumption > 600 l; OR = 2.84, 95% CI = 1.18-6.79) and a diagnosis of cancer of the floor of the mouth (OR = 7.97, 95% CI = 2.49-25.46) were independent risk factors for advanced colorectal neoplasia. CONCLUSION: The prevalence of advanced colorectal neoplasia is unexpectedly high in patients with oral cancer. It should be recognized as a second primary tumour of oral cancer. Screening of oral cancer patients by colonoscopy should be routine practice, particularly among smokers and patients with a high intake of alcohol and cancer of the floor of the mouth. PMID- 25039838 TI - Hypertension and treatment outcomes in Palestine refugees in United Nations Relief and Works Agency primary health care clinics in Jordan. AB - OBJECTIVE: In six United Nations Relief and Works Agency (UNRWA) primary health care clinics in Jordan serving Palestine refugees diagnosed with hypertension, to determine the number, characteristics, programme outcomes and measures of disease control for those registered up to 30 June, 2013, and in those who attended clinic in the second quarter of 2013, the prevalence of disease-related complications between those with hypertension only and hypertension combined with diabetes mellitus. METHOD: Retrospective cohort study with programme and outcome data collected and analysed using E-Health. RESULTS: There were 18 881 patients registered with hypertension with females (64%) and persons aged >= 40 years (87%) predominating. At baseline, cigarette smoking was recorded in 17%, physical inactivity in 48% and obesity in 71% of patients. 77% of all registered patients attended clinic in the second quarter of 2013; of these, 50% had hypertension and diabetes and 50% had hypertension alone; 9% did not attend the clinics and 10% were lost to follow-up. Amongst those attending clinic, 92% had their blood pressure measured, of whom 83% had blood pressure <140/90 mm Hg. There were significantly more patients with hypertension and diabetes (N = 966, 13%) who had disease-related complications than patients who had hypertension alone (N = 472, 6%) [OR 2.2, 95% CI 2.0-2.5], and these differences were found for both males [18% vs. 10%, OR 1.9, 95% CI 1.6-2.2] and females [11% vs. 5%, OR 2.4, 95% CI 2.1 2.9]. CONCLUSION: Large numbers of Palestine refugees are being registered and treated for hypertension in UNRWA primary health care clinics in Jordan. Cohort analysis and E-Health can be used to regularly assess caseload, programme outcomes, clinic performance, blood pressure control and cumulative prevalence of disease-related complications. Current challenges include the need to increase clinic attendance and attain better control of blood pressure. PMID- 25039839 TI - Cutaneous leishmaniasis: treatment with low-dose oral fluconazole with an excellent cosmetic result. AB - We report the successful treatment of cutaneous leishmaniasis in a 6-year-old girl who presented with a solitary lesion on the cheek. A low dose of 3 mg/kg/day of fluconazole was used, with remarkable improvement at 6 weeks and complete regression at 12 weeks, excellent cosmetic results, and no relapse during a follow-up of 1 year. PMID- 25039840 TI - Rethinking Medicare: Part 2. PMID- 25039841 TI - Rethinking quality in qualitative research. PMID- 25039842 TI - Mental health service use: is there a difference between rural and non-rural women in service uptake? AB - This study examines differences in uptake of the Medicare items rolled out in 2006 under the 'Better Access Scheme' (BAS) between rural and non-rural Australian women. It compares differences in women's uptake of the BAS services by area of residence (ARIA+) across time using the Australian Longitudinal Study of Women's Health (ALSWH) survey data linked to Medicare data. Women aged 28-33 years at the time the BAS was introduced that responded to the self-reported question on depression/anxiety and consented to linkage of their survey data with Medicare data (n=4,316). Participants were grouped by ARIA+ according to BAS use, diagnoses of anxiety/depression but no BAS use and other eligible women. Across all areas, women born 1973-1978 with a self-reported diagnosis of depression/anxiety or having treatment under the BAS had a significantly lower mean mental health score compared to other women. Significantly more women living in non-rural areas had used at least one service provided under the BAS initiative compared to women in outer regional, inner regional or remotes areas (21% versus 18% versus 13% versus 7%, respectively), and across all areas, 12% of women reported having a diagnosis of depression/anxiety but not been treated under the BAS. While there is a gradual uptake of the new BAS services, a large percentage of women who have a diagnosis of depression/anxiety have not been treated under the BAS. The data suggest that women in urban areas have been better able to take up the services compared to non-urban women. PMID- 25039843 TI - Peritoneal dialysis outcomes of Indigenous Australian patients of remote Kimberley origin. AB - OBJECTIVES: To compare clinical outcomes and mortality rates between Kimberley Indigenous, other Indigenous and non-Indigenous Australian patients on peritoneal dialysis (PD). DESIGN AND PARTICIPANTS: Patients commencing renal replacement therapy (RRT) with PD for the first time from 1 January 2003 to 31 December 2009 were retrospectively identified. Secondary data from medical records and the Australian and New Zealand Dialysis and Transplant Registry from 1 January 2003 to 31 December 2010 were used to compare outcomes between patients. MAIN OUTCOME MEASURES: Time to first peritonitis; failure and death rates per 100 patient years, hazard ratios, unadjusted and adjusted (for age, sex, comorbid conditions, PD not the first RRT modality used). Comparison of the two PD systems used in the Kimberley. RESULTS: Kimberley patients had significantly shorter median time to first peritonitis (11.2 versus 21.5 months), higher technique failure (46.0 versus 25.2 per 100 patient-years) and shorter median survival on PD (17.5 versus 22.4 months) but similar adjusted mortality (hazard ratio 1.32; 95% CI, 0.76 2.29) as non-Indigenous patients. They also had a significantly higher technique failure rate than other Indigenous patients (46.0 versus 31.4 per 100 patient years) and nearly double the average peritonitis episodes previously reported for Indigenous Australians (2.0 versus 1.15 per patient-year). CONCLUSIONS: PD can bring patients closer to home; however, it is relatively short term and potentially hazardous. PD remains an important therapy for suitable remote patients to get closer to home, providing they are fully informed of the options. The current expansion of safer Kimberley haemodialysis options needs to continue. PMID- 25039844 TI - Travelling to the city for hospital care: access factors in country Aboriginal patient journeys. AB - OBJECTIVE: This study described the challenges for rural and remote Aboriginal people requiring transport to city hospitals for tertiary care. DESIGN: Semi structured qualitative interviews. SETTING: South Australian rural and remote health services and tertiary hospitals. PARTICIPANTS: Twenty-eight urban health professionals from six hospitals and 32 health professionals from four rural and remote regions were interviewed. Twelve patients, three carers, four people responding as patient and carers, and one patient and carer couple were also interviewed, with eight elder women meeting as a focus group. MAIN OUTCOME MEASURES: The study identified specific structural barriers in urban health services or policy that prevented rural and remote Indigenous patients from receiving optimum care. RESULTS: Problems accessing transport were identified as the most significant factor affecting access to care by the majority of patients and staff. They reported that travel to an urban hospital was costly, and coordination of travel with care was poor. A further problem was travelling while unwell. CONCLUSIONS: Travelling to a city hospital is a significant barrier for rural and remote Indigenous patients. Arranging and supporting travel is a time consuming work that is not recognised by the health care system. PMID- 25039845 TI - Provision of maternity care for women in remote Far West New South Wales: how far have we come? AB - BACKGROUND: The National Maternity Services Review in 2009 sought to address the ongoing issues of access, workforce capacity and inequalities in health outcomes for women and their babies in rural and remote Australia. The subsequent National Maternity Services Plan describes the type of care that should be offered to all women in Australia. OBJECTIVE: The aim of our study was to better understand the local context and progress in delivering recommendations of the National Plan to improve maternity services for women in remote communities of Far West New South Wales. DESIGN: Semistructured questionnaires. SETTING: Maternity care in Far West New South Wales involves long-standing partnerships between three service providers to provide antenatal and postnatal care to women in remote communities with birthing predominantly occurring at the Broken Hill Health Service. MAIN OUTCOME MEASURES: The degree of information sharing and communication, use of guidelines and policies, the effectiveness of workforce retention strategies and the current level of maternity care provided. PARTICIPANTS: Fourteen clinicians and policy makers. RESULTS: Participants reported clarity in roles and responsibilities of health staff, the appropriateness of antenatal care policies to the context, confidence in practising to their full professional scope and the existence of quality improvement initiatives across all providers. However, participants also reported being constrained by environmental and organisational factors in regards to risk assessment and referral of pregnant women. Key issues for local health service partners include adherence to antenatal care policies and a need to improve local workforce capacity. CONCLUSIONS: Local health service partners are demonstrably ready to address the modifiable factors of organisational capacity and interprofessional collaboration in accordance with the recommendations of the National Maternity Services Review. PMID- 25039846 TI - Rural New South Wales women's access to abortion services: highlights from an exploratory qualitative study. AB - OBJECTIVE: The aim of the study was to identify factors that New South Wales (NSW) rural women experience in relation to their ability to access an abortion service and follow-up care. DESIGN: The qualitative responses from interviews are reported. SETTING: Rural and regional NSW. PARTICIPANTS: Staff from community based non-government Women's Health Centres across regional/rural NSW and women in rural NSW who had accessed an abortion in the preceding fifteen years. MAIN OUTCOMES: A number of barriers that NSW rural women experience in relation to their ability to access an abortion and follow-up care were identified. RESULTS: The main barrier rural women experienced was travelling relatively long distances to access an abortion clinic because of lack of services in their local area. Women with limited financial resources needed to borrow money for the procedure and associated costs of travel and accommodation. Women's Health Centres provide a range of support and referral information. Lack of integrated care was reported. CONCLUSIONS: Rural women's access to abortion services are impacted by the availability, accessibility and affordability of services and prevailing negative social attitudes. This exploratory study provides a snapshot of women's experiences of the process of seeking an abortion in rural NSW, where they are not available locally and women have to travel out of the area to access services. Findings indicate rural women experience multiple barriers in relation to their ability to access abortion services and follow-up care, which may impact on overall health outcomes. PMID- 25039847 TI - Evaluation of an ear health pathway in remote communities: improvements in ear health access. AB - OBJECTIVE: Reduce long waiting lists for ear, nose and throat (ENT) specialist review and improve primary ear health care. DESIGN: A retrospective evaluation of ear health care after the implementation of an ear health program (EHP). SETTING AND PARTICIPANTS: School children in Aboriginal communities in the Fitzroy Valley of Western Australia. KEY MEASURES FOR IMPROVEMENT: Access number of children screened for ear disease, effectiveness-referral letter completeness (history, otoscopy, tympanometry, audiometry), patient management and waiting time until first ENT contact. INTERVENTIONS: EHP--an electronic referral template, ear health nurse, ear health educator and telehealth ENT specialist review. MAIN OUTCOME MEASURES: Screening rates, timely ENT review and improved primary care management. RESULTS: Number of children screened increased from 148 per 18 months to 710. Nearly twofold increase in numbers of patients referred to ENT (32, 66). A reduction in median waiting time from 141 days to 22 days for ENT review using telehealth. Content of referral letters showed an increase in essential information--otoscopy, audiometry and tympanometry. Primary care management in accordance with guidelines improved. CONCLUSIONS: The addition of an ear health team increased access to appropriate primary care management and the time to contact with ENT was reduced by using an electronic template and telehealth sessions. PMID- 25039848 TI - What factors influence physiotherapy service provision in rural communities? A pilot study. AB - OBJECTIVE: To obtain stakeholder perspectives on factors influencing rural physiotherapy service provision and insights into decision making about service provision. DESIGN: Purposive sampling, open-ended survey questions and semi structured interviews were used in this exploratory, qualitative study. SETTING: A rural centre and its regional referral centre formed the pilot sites. PARTICIPANTS: Nine participant perspectives were obtained on rural physiotherapy services. MAIN OUTCOME MEASURES: Stakeholder perspectives on factors influencing rural physiotherapy service provision and service level decision making. RESULTS: Workforce capacity and capability, decision maker's knowledge of the role and scope of physiotherapy, consideration of physiotherapy within resource allocation decisions and proof of practice emerged as key issues. The latter three were particularly reflected in public sector participant comments. Business models and market size were identified factors in influencing private practice. CONCLUSION: Influencing factors described by participants both align and extend our understanding of issues described in the rural physiotherapy literature. Participant insights add depth and meaning to quantitative data by revealing impacts on local service provision. Available funding and facility priorities were key determinants of public sector physiotherapy service provision, with market size and business model appearing more influential in private practice. The level of self direction or choice about which services to provide, emerged as a point of difference between public and private providers. Decisions by public sector physiotherapists about service provision appear constrained by existing capacity and workload. Further research into service level decision making might provide valuable insights into rural health service delivery. PMID- 25039849 TI - Development of the 'Easy Step-by-Step Cookbook' for use in group homes in rural New South Wales: involving student dietitians in a practical community project. PMID- 25039850 TI - It's a record for rural people. PMID- 25039851 TI - Anaerobic oxidation of methane by sulfate in hypersaline groundwater of the Dead Sea aquifer. AB - Geochemical and microbial evidence points to anaerobic oxidation of methane (AOM) likely coupled with bacterial sulfate reduction in the hypersaline groundwater of the Dead Sea (DS) alluvial aquifer. Groundwater was sampled from nine boreholes drilled along the Arugot alluvial fan next to the DS. The groundwater samples were highly saline (up to 6300 mm chlorine), anoxic, and contained methane. A mass balance calculation demonstrates that the very low delta(13) CDIC in this groundwater is due to anaerobic methane oxidation. Sulfate depletion coincident with isotope enrichment of sulfur and oxygen isotopes in the sulfate suggests that sulfate reduction is associated with this AOM. DNA extraction and 16S amplicon sequencing were used to explore the microbial community present and were found to be microbial composition indicative of bacterial sulfate reducers associated with anaerobic methanotrophic archaea (ANME) driving AOM. The net sulfate reduction seems to be primarily controlled by the salinity and the available methane and is substantially lower as salinity increases (2.5 mm sulfate removal at 3000 mm chlorine but only 0.5 mm sulfate removal at 6300 mm chlorine). Low overall sulfur isotope fractionation observed ((34) epsilon = 17 +/- 3.50/00) hints at high rates of sulfate reduction, as has been previously suggested for sulfate reduction coupled with methane oxidation. The new results demonstrate the presence of sulfate-driven AOM in terrestrial hypersaline systems and expand our understanding of how microbial life is sustained under the challenging conditions of an extremely hypersaline environment. PMID- 25039852 TI - Searching for factors to improve regulatory T cell therapy in organ transplantation. PMID- 25039853 TI - Health-related quality of life in patients with melanoma expressed as utilities and disability weights. AB - BACKGROUND: Few studies about health-related quality of life (HRQoL) in patients with melanoma have expressed their results in terms of utilities or disability weights (DWs). Utilities are required for calculating quality-adjusted life years and therefore for cost-effectiveness analyses. DWs are useful to assess the burden of diseases through disability-adjusted life years. OBJECTIVES: To provide utilities and DWs regarding patients with melanoma. METHODS: The patients were classified into eight groups using four stages based on the 2009 American Joint Committee on Cancer stages, with each stage subdivided into treatment and remission phases. The EuroQoL Five Dimensions Five Levels (EQ-5D-5L) questionnaire was completed by the patients with melanoma to provide a mean utility for each group. In addition to this, the EuroQoL visual analogue scale (VAS) and a validated quality-of-life questionnaire dedicated to patients with melanoma [Functional Assessment of Cancer Therapy Melanoma (FACT-M)] were completed by the same patients in order to compare their results with the obtained utilities. DWs were obtained by calculating, for each patient, the difference between his/her utility and the corresponding sex- and age-specific population norm. RESULTS: A total of 395 questionnaire sets were completed. Utilities and DWs showed significant differences between follow-up groups. Treatment groups had similar utilities and DWs but these results were obtained during different treatment durations and therefore have different weights. The VAS and the FACT-M were found to be less sensitive. Nevertheless, the FACT-M identified some problems not found by the EQ-5D-5L questionnaire. CONCLUSIONS: The EQ-5D-5L questionnaire seems adequate to provide utilities and DWs in patients with melanoma. Lower HRQoL in female patients with melanoma is probably linked to lower HRQoL in the general population. PMID- 25039854 TI - Inequalities in oral impacts and welfare regimes: analysis of 21 European countries. AB - OBJECTIVE: Very few studies have analysed the relationship between political factors and oral health inequalities, and only one study has compared the magnitude of inequalities in oral health-related quality of life (OHRQoL) across welfare state regimes. This study aimed to compare socioeconomic inequalities in oral impacts on daily life among 21 European countries with different welfare state regimes (Scandinavian, Anglo-Saxon, Bismarckian, Southern, and Eastern). METHODS: We analysed data from the Eurobarometer 72.3, a survey carried out in 2009 among adults in European countries. Inequalities in oral impacts by education, occupational social class and subjective social status (SSS) were estimated by means of age-standardized prevalence rates, odds ratios (ORs), the relative index of inequality (RII) and the slope index of inequality (SII). RESULTS: Educational inequalities in the form of social gradients were observed in all welfare regimes. The Scandinavian and Southern welfare regimes also showed gradients for all SEP measures. There were not significant differences in the magnitude of relative inequalities (RII) across welfare state regimes. Absolute educational inequalities were largest in the Anglo-Saxon welfare regime (SII = 17.57; 95% CI: 7.80-27.33) and smallest in the Bismarckian (SII = 3.32; 95% CI: 2.18 to 8.83). CONCLUSIONS: A significant difference in the magnitude of inequalities across welfare regimes was found for absolute educational inequalities but not for relative inequalities. Welfare state regimes may influence the relationship between knowledge-related resources and oral impacts on daily life. PMID- 25039855 TI - Nail bed onychomatricoma. AB - Onychomatricoma is a rare tumor originating from the nail matrix, and, in rare conditions, from the ventral aspect of the proximal nailfold. Here we report a rare case of a 51-year-old man presenting with melanonychia mainly involving the distal nail plate. Histopathologic examination showed typical findings of onychomatricoma mainly involving the nail bed, while the nail matrix was largely uninvolved. We also identified fungal infection in a focal area of the distal nail plate. Our findings indicate that onychomatricoma can develop in the surrounding epithelial tissue of the nail unit, including the nail bed, and suggest that fungal infection may represent a secondary phenomenon of onychomatricoma. PMID- 25039857 TI - Gestation-specific perinatal mortality probably differs by race. PMID- 25039858 TI - Optoelectronic properties and structural effects of the incremental addition of pyridyl moieties on a rhodium dimer. AB - The synthesis and characterization of five C-C coupling products obtained from the reaction of a paddlewheel tetrakis 4-bromo-N,N'-diphenylbenzamidinate dirhodium dimer with 4-pyridineboronic acid pinacol ester are reported. The coupling reactions occur on one to four amidinate ligands, leading to rhodium dimers containing [tetrakis, tris, cis-bis, trans-bis, or mono]-N,N'-diphenyl-4 (pyridin-4-yl)benzamidinate ligands, effectively creating new binding sites on the metal complexes. The new compounds were isolated by column chromatography, and the exact conformations were verified by X-ray crystallography. Redox processes showed only a small variation within the coupling products and included two oxidations (1.30 +/- 0.02 V, 0.27 +/- 0.01 V vs SCE) and one reduction (-1.55 +/- 0.02 V vs SCE), all centered on the Rh-Rh core. Time-dependent density functional theory (TD-DFT) was used to analyze this series with four other fully characterized N,N'-diphenyl-aryl-amidinate rhodium dimers that were found in the literature. The two main absorption bands of these nine rhodium dimers were compared to TD-DFT calculations, both giving excellent correlation. The first, a metal-to-metal (MM) transition around 11800 cm(-1) (845 nm) was blue-shifted in the calculation, with an average difference of 1378 cm(-1) but had only a 15 cm( 1) standard deviation, showing a strong correlation despite the energy difference. The second, a metal-to-ligand charge transfer (MLCT) transition around 18900 cm(-1) (530 nm) was a near perfect match with only a 64 cm(-1) average difference and a 35 cm(-1) standard deviation. The electronic transition, redox potentials, and HOMO and LUMO energies of all dimers were plotted versus the Hammett parameter (sigma) of the aryl group and Taft's model with 2 components: field effects (sigmaF) and resonance (sigmaR). The properties involving only the Rh-Rh core (MM band, all oxidation potentials, HOMO and LUMO) were fit with a single set of sigmaF and sigmaR contributions (73% and 27%), with a goodness-of-fit (R(2)) value ranging from 90% to 99.7%. The metal-dimer to ligand charge-transfer band, involving the amidinate ligand, displayed different values of contribution with 45% and 55% for the sigmaF and sigmaR, respectively, with a fit of 94.8%. The accuracy of these fits enables the designed modification of amidinate-based dirhodium complexes to achieve desirable redox and spectroscopic properties. PMID- 25039856 TI - Burden of illness associated with peripheral and central neuropathic pain among adults seeking treatment in the United States: a patient-centered evaluation. AB - OBJECTIVE: The aim of this study was to evaluate patient-reported burden associated with peripheral and central neuropathic pain (NeP) by pain severity and NeP condition. DESIGN: Six hundred twenty-four subjects with one of six NeP conditions were recruited during routine office visits. Subjects consented to retrospective chart review and completed a one-time questionnaire (including EuroQol-5 dimensions, 12-item Short-Form Health Survey, Brief Pain Inventory Short Form, Medical Outcomes Study Sleep Scale, Hospital Anxiety and Depression Scale, and demographic and clinical characteristics). Pain severity scores were used to stratify subjects by mild, moderate, and severe pain. Summary statistics and frequency distributions were calculated. Differences by severity level were compared using Kruskal-Wallis (continuous variables) and chi-square or Fisher's exact test (categorical variables). Effect size was computed with Cohen's d (mild vs severe). RESULTS: Subjects' mean age was 55.5. The majority (80.8%) had moderate or severe pain. Patient-reported outcomes (health status, physical and mental health, pain interference with function, sleep, anxiety, and depression) were significantly worse among subjects with greater pain severity (all P < 0.0001). Severe pain subjects were negatively impacted by >=30% in each outcome compared with mild pain subjects; standardized effect size was moderate for anxiety (0.59) and large (>0.95) for all others. The observed burden was most substantial among chronic low back pain-NeP, although the pattern of disease burden was similar across the six NeP conditions. CONCLUSIONS: Subjects across NeP conditions exhibited high pain levels, which were significantly associated with poor function, compromised health status and sleep, and increased anxiety and depression. Results indicate substantial patient burden across broad NeP, particularly among subjects with severe pain. PMID- 25039860 TI - QTL mapping of freezing tolerance: links to fitness and adaptive trade-offs. AB - Local adaptation, defined as higher fitness of local vs. nonlocal genotypes, is commonly identified in reciprocal transplant experiments. Reciprocally adapted populations display fitness trade-offs across environments, but little is known about the traits and genes underlying fitness trade-offs in reciprocally adapted populations. We investigated the genetic basis and adaptive significance of freezing tolerance using locally adapted populations of Arabidopsis thaliana from Italy and Sweden. Previous reciprocal transplant studies of these populations indicated that subfreezing temperature is a major selective agent in Sweden. We used quantitative trait locus (QTL) mapping to identify the contribution of freezing tolerance to previously demonstrated local adaptation and genetic trade offs. First, we compared the genomic locations of freezing tolerance QTL to those for previously published QTL for survival in Sweden, and overall fitness in the field. Then, we estimated the contributions to survival and fitness across both field sites of genotypes at locally adaptive freezing tolerance QTL. In growth chamber studies, we found seven QTL for freezing tolerance, and the Swedish genotype increased freezing tolerance for five of these QTL. Three of these colocalized with locally adaptive survival QTL in Sweden and with trade-off QTL for overall fitness. Two freezing tolerance QTL contribute to genetic trade-offs across environments for both survival and overall fitness. A major regulator of freezing tolerance, CBF2, is implicated as a candidate gene for one of the trade off freezing tolerance QTL. Our study provides some of the first evidence of a trait and gene that mediate a fitness trade-off in nature. PMID- 25039861 TI - Metabolic syndrome delays HBeAg seroclearance in Chinese patients with hepatitis B. AB - BACKGROUND: Delayed hepatitis B e antigen (HBeAg) seroclearance increases the risk of cirrhosis and hepatocellular carcinoma (HCC). The effect of metabolic syndrome (MetS) on HBeAg seroclearance in chronic hepatitis B (CHB) patients remains unclear. AIMS: To examine the effect of MetS on HBeAg seroclearance. METHODS: A prospective cohort of 413 treatment-naive HBeAg-positive CHB patients from 2005 to 2012 was studied. Clinical, virological and histological parameters were evaluated. The patients were classified into three groups according to the metabolic characteristics; normal, pre-MetS and MetS based on the International Diabetes Federation criteria. The primary outcome was age at HBeAg seroclearance. RESULTS: The overall HBeAg seroclearance rate was 11.4% per annum during 19 351 patient-months of follow-up with no difference in HBeAg seroclearance rates between 162 treatment-free and 251 patients receiving nucleos(t)ide analogues. Patients with pre-MetS and MetS were older when HBeAg seroclearance occurred (44 +/- 12 and 53 +/- 7 years, respectively) than the normal patients (37 +/- 9 years, all P < 0.01). Patients with pre-MetS and MetS had more advanced liver fibrosis (33.0% and 53.1%, respectively) than the normal patients (18.4%, all P < 0.05). By the age of 50, 59.3% of the metabolic normal patients, 42.1% of the pre MetS and 18.7% of the MetS patients had achieved HBeAg seroclearance (all P < 0.05, except P = 0.07 for pre-MetS vs. MetS). In multivariate analysis, MetS and type II diabetes at baseline were predictors of delayed HBeAg seroclearance after adjusting for viral load, anti-viral therapy and necroinflammatiom. CONCLUSION: Chinese patients with chronic hepatitis B and with pre-metabolic syndrome or metabolic syndrome have delayed HBeAg seroclearance. PMID- 25039862 TI - Retrospective Comparison of Gastrosplenic Entrapment of the Small Intestine to Other Strangulating Small Intestinal Lesions in Adult Horses. AB - OBJECTIVE: To compare clinical data of horses with entrapment of the small intestine by the gastrosplenic ligament (ESIGL) to clinical data of horses with other strangulating small intestinal lesions. STUDY DESIGN: Retrospective case series. METHODS: Medical records (January 2001-December 2011) of horses that had exploratory celiotomy for acute abdominal pain associated with strangulating small intestinal lesions were reviewed. Signalment, physical examination findings, clinicopathologic variables, surgical findings and surgical procedures performed, postoperative data and short-term survival were recorded. RESULTS: Clinical findings included excessive nasogastric reflux and abnormal abdominal fluid. Horses with ESIGL were significantly more likely to require intestinal resection and anastomosis and produced significantly less reflux postoperatively than horses with other strangulating small intestinal obstructions. Geldings were significantly more likely to develop ESIGL than mares or stallions. Quarter Horse or Quarter Horse type breeds were predisposed to ESIGL. Survival to hospital discharge in horses with ESIGL (16/22; 72.7%) was significantly higher than that of horses with other strangulating small intestinal obstructions (92/183; 50%). CONCLUSIONS: ESIGL was more prevalent in this population of horses evaluated for acute abdominal pain than in previous studies, accounting for 10.7% of all horses with strangulating small intestinal lesions. Geldings and Quarter Horse or Quarter Horse related breeds are predisposed to this condition. The prognosis for survival to hospital discharge was fair to good. PMID- 25039863 TI - Arrhythmia risk assessment using heart rate variability parameters in patients with frequent ventricular ectopic beats without structural heart disease. AB - BACKGROUND: Ventricular ectopic beats (VEBs) are usually considered a benign condition that can be managed with conservative measures. Heart rate variability (HRV), which is one of the most important methods for assessing autonomic activity, is a noninvasive, quantitative method of analyzing autonomic effects on the heart. We aimed to investigate the risk of arrhythmia in patients with VEBs and without cardiovascular disease by using HRV parameters. METHODS: Patients with frequent VEBs (more than 30 times in 1 hour, according to the Lown classification) were identified. Identified patients were evaluated by 24-hour ECG recording. Our study included 43 patients with frequent VEBs and 43 controls. RESULTS: General characteristics of the study population were similar. The LF (low frequency)/HF (high frequency) ratio was significantly higher in the frequent VEBs group than in the control group (P < 0.001). The rate of paroxysmal atrial fibrillation (PAF) was higher in the frequent VEB group than in the control group (P = 0.003). The number of VEBs was correlated with LF/HF ratio and PAF (r = 0.339, P = 0.001 and r = 0.294, P = 0.006, respectively). CONCLUSIONS: Our study showed that the sympathetic nervous system is dominant in young patients with VEBs and without significant comorbidities. There is a higher risk of atrial fibrillation in patients with VEBs and they should be monitored closely for atrial fibrillation. PMID- 25039864 TI - Safety of performing invasive acne scar treatment and laser hair removal in patients on oral isotretinoin: a retrospective study of 110 patients. AB - BACKGROUND: It is reported that patients on oral isotretinoin have greater risk of developing scars and delayed wound healing with invasive procedures. It is recommended that these procedures be resumed 6-12 months after the last dose of oral isotretinoin. AIM: To assess and compare the safety and look for delayed wound healing, during invasive acne scar treatment and laser hair removal on (a) patients who were on oral isotretinoin, and (b) patients who were not on oral isotretinoin. METHODS: A comparative, retrospective study of 110 patients was done. Fifty-five patients with either acne scars or hirsutism who underwent procedures while on oral isotretinoin, and 55 patients who were not on oral isotretinoin were selected and grouped into A and B respectively. Group A patients were on 0.5 mg/kg/day isotretinoin orally through the entire procedure duration, while group B patients received topical medications alone. The subjects from both groups underwent invasive acne scar treatment and laser hair removal. Clinical and photographic assessment was done at baseline followed by four sessions with an interval of six weeks between each. RESULTS: Isotretinoin had not resulted in any untoward effects in patients who underwent the procedures. Atypical scarring, delayed wound healing, keloids, or hypertrophic scars were not observed in any patient. CONCLUSION: Isotretinoin does not appear to delay wound healing, and hence invasive procedures can be considered on patients on oral isotretinoin without any compromise on the outcome. PMID- 25039865 TI - Morbidity and mortality of live lung donation: results from the RELIVE study. AB - The Renal and Lung Living Donors Evaluation Study assesses outcomes of live lung (lobectomy) donors. This is a retrospective cohort study at University of Southern California (USC) and Washington University (WASHU) Medical Centers (1993 2006), using medical records to assess morbidity and national databases to ascertain postdonation survival and lung transplantation. Serious complications were defined as those that required significant treatment, were potentially life threatening or led to prolonged hospitalization. The 369 live lung donors (287 USC, 82 WASHU) were predominantly white, non-Hispanic and male; 72% had a biological relationship to the recipient, and 30% were recipient parents. Serious complications occurred in 18% of donors; 2.2% underwent reoperation and 6.5% had an early rehospitalization. The two centers had significantly different incidences of serious complications (p < 0.001). No deaths occurred and no donors underwent lung transplantation during 4000+ person-years of follow-up (death: minimum 4, maximum 17 years; transplant: minimum 5, maximum 19). Live lung donation remains a potential option for recipients when using deceased donor lungs lacks feasibility. However, the use of two live donors for each recipient and the risk of morbidity associated with live lung donation do not justify this approach when deceased lung donors remain available. Center effects and long-term live donor outcomes require further evaluation. PMID- 25039866 TI - From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. AB - This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (M(pro) ) and the papain-like protease (PL(pro) ). The role of X-ray crystallography in structure-assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002 2003 and of the MERS coronavirus 10 years later and the origins of these viruses. The crystal structure of the free SARS coronavirus M(pro) and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PL(pro) and its complex with ubiquitin is also discussed, as is its orthologue from MERS coronavirus. Efforts at predictive structure-based inhibitor development for bat coronavirus M(pro) s to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure-based discovery of antivirals in an academic setting. PMID- 25039867 TI - A review of poly(lactic acid)-based materials for antimicrobial packaging. AB - Poly(lactic acid) (PLA) can be synthesized from renewable bio-derived monomers and, as such, it is an alternative to conventional petroleum-based polymers. Since PLA is a relatively new polymer, much effort has been directed toward its development in order to make it an acceptable and effective option to the more traditional petroleum-based polymers. Commercially, PLA has received considerable attention in food packaging applications with a focus on films and coatings that are suitable for short shelf life and ready-to-eat food products. The potential for PLA to be used in active packaging has also been recognized by a number of researchers. This review focuses on the use of PLA in antimicrobial systems for food packaging applications and explores the engineering characteristics and antimicrobial activity of PLA films incorporated and/or coated with antimicrobial agents. PMID- 25039868 TI - Paclitaxel, topotecan and rituximab: long term outcomes of an effective salvage programme for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. AB - Relapsed aggressive lymphomas are often treated with platinum-based chemotherapy (PBC) followed by an autologous stem cell transplant (ASCT). Response rates to PBC in patients with relapsed aggressive lymphomas are c. 60%, and non-responders have a dismal prognosis. Novel therapies for aggressive lymphomas, including those failing PBC, are needed. We performed a phase II study of paclitaxel, topotecan and rituximab (TTR) in patients with relapsed or refractory diffuse large B-cell, follicular grade IIIB, or transformed lymphomas, including those who previously failed PBC. The median age of the 72 patients enrolled was 54 years. Responding patients were offered ASCT after two courses. The overall response rate was 69% for all patients (n = 49/71) and 45% for those who previously failed PBC (n = 9/20). With a median follow up of 125 months for the censored observations, the overall survival (OS) and progression-free survival at 5 years was 39% and 27%, respectively. Responding patients who received ASCT had an OS of 63% at 5 years. Our results demonstrate that TTR is an effective salvage regimen for patients with relapsed aggressive B-cell lymphomas, including those who previously failed PBC. Given the declining therapeutic outcomes of salvage PBC in the rituximab era, further evaluation of TTR is warranted. PMID- 25039869 TI - The effect of hetastarch 670/0.75 administered in vivo as a constant rate infusion on platelet closure time in the dog. AB - OBJECTIVE: To evaluate the effects of hetastarch 670/0.75 on canine platelet function and clinical bleeding following its administration as a constant rate infusion (CRI) at 1 mL/kg/h and 2 mL/kg/h for 24 hours. DESIGN: In vivo, prospective, open-label, crossover study. SETTING: Research laboratory at a university veterinary facility. ANIMALS: Eight healthy, adult male research dogs. INTERVENTIONS: Each dog received 1 mL/kg/h hetastarch for 24 hours then 2 mL/kg/h with a washout period of 10 weeks between each experiment. Platelet closure time (CT) was measured using a platelet function analyzer with collagen adenosine diphosphate (ADP) cartridges. CT measurements were performed at baseline and 6, 12, and 24 hours following initiation of hetastarch infusion. MEASUREMENTS AND MAIN RESULTS: At 1 mL/kg/h, mean CT was significantly increased at the 12- and 24 hour time point relative to the baseline value, although mean CT never rose to a value above the reference interval during the 24-hour infusion. At 2 mL/kg/h, median CT was also significantly increased at the 12- and 24-hour time point relative to the baseline value. Administration of 2 mL/kg/h did progressively prolong the median CT value though only exceeded the reference interval at the 24 hour time point. Despite the prolongation of median CT, there was no clinical evidence of spontaneous bleeding in any dog during the 24-hour infusion at either CRI rate. CONCLUSIONS: Hetastarch 670/0.75 when used as a 24-hour CRI at 1 and 2 mL/kg/h prolongs CT in healthy dogs at 6, 12, and 24 hours. Median CT only exceeded the reference interval at 24 hours at 2 mL/kg/h. PMID- 25039870 TI - Oxymetazoline (Afrin(r)): maybe there is more that we need to know. PMID- 25039871 TI - A national survey of aseptic precautions for pediatric caudal blockade. PMID- 25039872 TI - External reinforcement of tracheal tube by using polyvinyl chloride tube. PMID- 25039873 TI - Response to Furstein and Sadhasivam regarding their comment on our paper 'Ultrasound-guided parasacral approach to the sciatic nerve block in children'. PMID- 25039874 TI - Considerable tracheal mucosal damage by high volume, low pressure cuffs in piglets. PMID- 25039875 TI - Data, not debate! PMID- 25039876 TI - Distal tracheoesophageal fistula in pediatric patient - an anesthetic challenge. PMID- 25039877 TI - Recurrent cardiomyopathy from recurrent pheochromocytoma in a pediatric patient. PMID- 25039878 TI - LMX4 leads to poor IV dressing adherence. PMID- 25039879 TI - The use of nasotracheal Airtraq(r) laryngoscope with reinforced endotracheal tube: our experience. AB - The authors describe the use of nasotracheal AirtraQ((r)) laryngoscope to perform orotracheal intubation with reinforced endotracheal tube in patients with difficult airways. The choice of nasotracheal AirtraQ((r)) instead of orotracheal device resulted from the difficulty that they sometimes found using orotracheal AirtraQ((r)) with reinforced endotracheal tube. The nasotracheal AirtraQ((r)) may be successfully used to perform orotracheal intubation with styletted reinforced endotracheal tube, specially in case of difficulty in advancing it inside the tube-guiding channel of orotracheal AirtraQ((r)). PMID- 25039880 TI - Yes we can (intubate children without relaxant)! But why should we? PMID- 25039881 TI - Transesophageal echocardiography during noncardiac pediatric surgery. PMID- 25039882 TI - Scalp blocks in nonsyndromic craniosynostosis surgery - a retrospective case series review. PMID- 25039883 TI - Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression. AB - Osteoarthritis (OA) is a common musculoskeletal disorder characterized by slow progression and joint tissue degeneration. Aging is one of the most prominent risk factors for the development and progression of OA. OA is not, however, an inevitable consequence of aging and age-related changes in the joint can be distinguished from those that are the result of joint injury or inflammatory disease. The question that remains is whether OA can be prevented by undertaking regular physical activity. Would moderate physical activity in the elderly cartilage (and lubricin expression) comparable to a sedentary healthy adult? In this study we used physical exercise in healthy young, adult, and aged rats to evaluate the expression of lubricin as a novel biomarker of chondrocyte senescence. Immunohistochemistry and western blotting were used to evaluate the expression of lubricin in articular cartilage, while enzyme-linked immunosorbent assay was used to quantify lubricin in synovial fluid. Morphological evaluation was done by histology to monitor possible tissue alterations. Our data suggest that moderate physical activity and normal mechanical joint loading in elderly rats improve tribology and lubricative properties of articular cartilage, promoting lubricin synthesis and its elevation in synovial fluid, thus preventing cartilage degradation compared with unexercised adult rats. PMID- 25039884 TI - Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study. AB - Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0.1-19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty-five of 338 children (7.4%) had PCD. Mean age at first TE onset was 10 years (range 0.1 18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7.4%; 1.5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population. PMID- 25039885 TI - Cellular sources of IL-17 in psoriasis: a paradigm shift? AB - Psoriasis is a common chronic inflammatory skin disease that results from interplay between the immune system and the epithelium. In the light of very successful anticytokine therapies for psoriasis, the focus has been directed towards the adaptive immune system. Expression studies, genetic studies and treatments specifically targeting players of the IL-23/IL-17 pathway, point at an important role for IL-17 in the pathogenesis of psoriasis. IL-17 stimulates the keratinocytes to produce psoriasis-associated molecules, eventually leading to chronic skin inflammation. The current opinion is that IL-17 is mainly produced by T cells, so-called T-helper 17 (Th17) cells, in psoriasis. However, evidence is accumulating that cells of the innate immune system, like neutrophils, mast cells, gammadelta T cells and innate lymphoid cells are the main source of IL-17 in psoriasis, rather than T cells. The paradigm in this field of research is shifting. With this viewpoint article, we will address this novel concept by critically summarizing the current literature on this subject. In psoriatic arthritis and atherosclerosis, important conditions related to psoriasis, it was also found that the majority of IL-17 is associated with cells of the innate immune system. This new concept changes our view of IL-17. Blocking IL-17 with targeted treatments might be more far-reaching than previously thought; not only IL-17 production by T cells but also by innate immune cells is blocked. Furthermore, therapies specifically targeting IL-17 may not only improve psoriasis, but also comorbidity that is associated with the IL-17 pathway, hereby preventing serious complications on the long term. PMID- 25039886 TI - Transcriptome comparison between inactivated and activated ovaries of the honey bee Apis mellifera L. AB - Ovarian activity not only influences fertility, but is also involved with the regulation of division of labour between reproductive and behavioural castes of female honey bees. In order to identify candidate genes associated with ovarian activity, we compared the gene expression patterns between inactivated and activated ovaries of queens and workers by means of high-throughput RNA sequencing technology. A total of 1615 differentially expressed genes (DEGs) was detected between ovaries of virgin and mated queens, and more than 5300 DEGs were detected between inactivated and activated worker ovaries. Intersection analysis of DEGs amongst five libraries revealed that a similar set of genes (824) participated in the ovary activation of both queens and workers. A large number of these DEGs were predominantly related to cellular, cell and cell part, binding, biological regulation and metabolic processes. In addition, over 1000 DEGs were linked to more than 230 components of Kyoto Encyclopedia of Genes and Genomes pathways, including 25 signalling pathways. The reliability of the RNA sequencing results was confirmed by means of quantitative real-time PCR. Our results provide new insights into the molecular mechanisms involved in ovary activation and reproductive division of labour. PMID- 25039888 TI - Epidermal inclusion cyst following autologous breast reconstruction--an unusual cause of a breast lump. PMID- 25039887 TI - Caffeic acid O-methyltransferase is involved in the synthesis of melatonin by methylating N-acetylserotonin in Arabidopsis. AB - Although a plant N-acetylserotonin methyltransferase (ASMT) was recently cloned from rice, homologous genes appear to be absent in dicotyledonous plants. To clone an ASMT de novo from a dicotyledonous plant, we expressed eight Arabidopsis thaliana O-methyltransferase (OMT) cDNAs in Escherichia coli and screened for ASMT activity by measuring melatonin production after the application of 1 mm N acetylserotonin (NAS). Among the eight strains harboring the full-length cDNAs, the OMT3 strain produced high levels of melatonin, suggesting that OMT3 encodes an active ASMT. OMT3 is already known as caffeic acid OMT (COMT), suggesting multiple functions for this enzyme. The purified recombinant A. thaliana COMT (AtCOMT) showed high ASMT activity, catalyzing the conversion of NAS to melatonin. The Km and Vmax values for ASMT activity were 233 MUm and 1800 pmol/min/mg protein, while the Km and Vmax values for COMT activity were 103 MUm and 564,000 pmol/min/mg protein, respectively. The catalytic efficiency (Vmax /Km ) for ASMT activity was 709-fold lower than for COMT. In vitro, ASMT activity was dramatically decreased by the addition of caffeic acid in a dose-dependent manner, but the activity of COMT was not altered by NAS. Lastly, the Arabidopsis comt knockout mutant exhibited less production of melatonin than the wild type when Arabidopsis leaves were infiltrated with 1 mm NAS, suggestive of in vivo role of COMT in melatonin biosynthesis in plants. PMID- 25039889 TI - Effect of add-on aliskiren to type 1 angiotensin receptor blocker therapy on endothelial function and autonomic nervous system in hypertensive patients with ischemic heart disease. AB - The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 +/- 9.8 to 66.3 +/- 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD. PMID- 25039890 TI - Global imprint of historical connectivity on freshwater fish biodiversity. AB - The relative importance of contemporary and historical processes is central for understanding biodiversity patterns. While several studies show that past conditions can partly explain the current biodiversity patterns, the role of history remains elusive. We reconstructed palaeo-drainage basins under lower sea level conditions (Last Glacial Maximum) to test whether the historical connectivity between basins left an imprint on the global patterns of freshwater fish biodiversity. After controlling for contemporary and past environmental conditions, we found that palaeo-connected basins displayed greater species richness but lower levels of endemism and beta diversity than did palaeo disconnected basins. Palaeo-connected basins exhibited shallower distance decay of compositional similarity, suggesting that palaeo-river connections favoured the exchange of fish species. Finally, we found that a longer period of palaeo connection resulted in lower levels of beta diversity. These findings reveal the first unambiguous results of the role played by history in explaining the global contemporary patterns of biodiversity. PMID- 25039891 TI - Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes. AB - Litter size (LS) in sheep is determined mainly by ovulation rate (OR). Several polymorphisms have been identified in the growth differentiation factor 9 (GDF9) gene that result in an increase in OR and prolificacy of sheep. Screening the databank of the Brazilian Sheep Breeders Association for triplet delivery, we identified flocks of prolific Ile de France ewes. After resequencing of GDF9, a point mutation (c.943C>T) was identified, resulting in a non-conservative amino acid change (p.Arg315Cys) in the cleavage site of the propeptide. This new allele was called Vacaria (FecG(v) ). A flock of half-sib ewes was evaluated for OR in the first three breeding seasons, and Vacaria heterozygotes had higher OR (P < 0.001), averaging 2.1 +/- 0.1 when compared to 1.2 +/- 0.1 in wild-type ewes. The OR was also influenced by age, increasing in the second and third breeding seasons (P < 0.001). In flocks segregating this allele, the LS was higher in mutant sheep (P < 0.001), averaging 1.61 +/- 0.07 in heterozygotes and 1.29 +/- 0.03 in wild-type ewes. Analysis of homozygote reproductive tract morphology revealed uterine and ovarian hypoplasia. Ovarian follicles continue to develop up to small antral stages, although with abnormal oocyte morphology and altered arrangement of granulosa cells. After the collapse of the oocyte in most follicles, the remaining cells formed clusters that persisted in the ovary. This SNP is useful to improve selection for dam prolificacy and also as a model to investigate GDF9 post-translation processing and the fate of the follicular cells that remain after the oocyte demise. PMID- 25039892 TI - Chronic lymphocytic leukemia: cutaneous involvement associated with nodular amyloidosis. PMID- 25039893 TI - Interobserver variability of Clavien-Dindo scoring in urology. AB - OBJECTIVES: To assess the interobserver variability of Clavien-Dindo scoring in urology. METHODS: A thematic survey was carried out simultaneously in nine Polish urological centers among 171 responders - 81 urologists and 90 urologists-in training, made up of 16 women and 155 men. After Clavien-Dindo classification was presented, respondents were asked to grade nine typical urological complications according to Clavien-Dindo classification. Interobserver agreement, reproducibility of answers, as well as the influencing factors were analyzed. Questions in the survey related to complications of variable severity after basic urological operations, including four open, one laparoscopic and four endourological. RESULTS: Agreement on the grade of complication was moderate (kappa = 0.45) and it was noticed in 69% of respondents (range 38-87%). No effect of surgical approach (classic vs endoscopic, 70% vs 67%, P = 0.64), or physician professional experience (resident vs urologist, 71% vs 66%, P = 0.77) was observed. The most significant discrepancies were found in cases of local complications after transurethral surgery (accordance in 39%) and laparoscopic radical prostatectomy (accordance in 55%), and in cases of severe general complications after Bricker operation (accordance in 58%). CONCLUSIONS: The variability of Clavien-Dindo classification scoring among urologists is significant. Thus, the Clavien-Dindo classification might require detailing before its eventual implementation in urology, together with appropriate training of specialists. However, despite some disadvantages, the simplicity, reproducibility and logical scheme of the Clavien-Dindo classification make it a promising tool for quality assessment in different fields of urology. PMID- 25039895 TI - Therapeutic management of hypertrophic obstructive cardiomyopathy: alcohol septal ablation or surgical myomectomy? AB - Hypertrophic cardiomyopathy (HCM) is characterized as left ventricular hypertrophy unexplained by abnormal loading conditions. Approximately 30% of patients with HCM will develop left ventricular outflow obstruction under resting conditions. In the 5-10% of patients with drug-refractory symptoms, surgical septal myectomy has been shown to reduce outflow obstruction and relieve symptoms; however, some patients may be at increased risk for surgery. Since 1994, when alcohol septal ablation was introduced, an increasing number of patients have opted for the percutaneous approach, which aims to mimic the anatomic and hemodynamic effects of surgical septal myectomy. The less-invasive version of septal reduction therapy comes at a price: a larger number of pacemaker implantations and, sometimes, depending on the individual's coronary anatomy, a higher residual gradient. Despite these shortcomings and the absence of randomized trials, alcohol septal ablation has established itself as a viable option for patients with obstructive HCM. PMID- 25039894 TI - Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise. AB - BACKGROUND AND PURPOSE: The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts. EXPERIMENTAL APPROACH: The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro. KEY RESULTS: During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH regulated 'switch' in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2 O2 , a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibroblasts and cardiomyocytes from necrosis induced by H2 O2 , but elevated caspase-3 and apoptosis instead. Similar to in vivo findings, where GSH therapy in normoglycaemic mice suppressed endogenous antioxidants and augmented caspase-3 activity, GCLc overexpression during staurosporine-induced death, which was not characterized by ROS, increased GSH efflux and aggravated death in fibroblasts and cardiomyocytes, confirming that oxidative stress is required for GSH-mediated cytoprotection. CONCLUSIONS AND IMPLICATIONS: While GSH treatment is useful for reducing mOXS and attenuating necrosis and fibrosis in ageing T2D hearts during exercise, such antioxidant treatment could be counterproductive in the healthy heart during exercise. PMID- 25039896 TI - Enhanced light-harvesting capacity by micellar assembly of free accessory chromophores and LH1-like antennas. AB - Biohybrid light-harvesting antennas are an emerging platform technology with versatile tailorability for solar-energy conversion. These systems combine the proven peptide scaffold unit utilized for light harvesting by purple photosynthetic bacteria with attached synthetic chromophores to extend solar coverage beyond that of the natural systems. Herein, synthetic unattached chromophores are employed that partition into the organized milieu (e.g. detergent micelles) that house the LH1-like biohybrid architectures. The synthetic chromophores include a hydrophobic boron-dipyrrin dye (A1) and an amphiphilic bacteriochlorin (A2), which transfer energy with reasonable efficiency to the bacteriochlorophyll acceptor array (B875) of the LH1-like cyclic oligomers. The energy-transfer efficiencies are markedly increased upon covalent attachment of a bacteriochlorin (B1 or B2) to the peptide scaffold, where the latter likely acts as an energy-transfer relay site for the (potentially diffusing) free chromophores. The efficiencies are consistent with a Forster (through-space) mechanism for energy transfer. The overall energy transfer efficiency from the free chromophores via the relay to the target site can approach those obtained previously by relay-assisted energy transfer from chromophores attached at distant sites on the peptides. Thus, the use of free accessory chromophores affords a simple design to enhance the overall light harvesting capacity of biohybrid LH1-like architectures. PMID- 25039897 TI - Dietary intake of high-dose biotin inhibits spermatogenesis in young rats. AB - To characterize a new function of the water-soluble vitamin, biotin, in reproduction and early growth in mammals, the effects of high dietary doses of biotin on early spermatogenesis were biochemically and histologically investigated in male rats. Weaned rats were fed a CE-2 (control) diet containing 0.00004% biotin, or a control diet supplemented with 0.01%, 0.1%, or 1.0% biotin. Pair-fed rats were fed a control diet that was equal in calories to the amount ingested by the 1.0% biotin group, because food intake was decreased in the 1.0% biotin group. Food intake and body weight gain were lower in the 1.0% biotin group than in the control group. The kidney, brain and testis weights were significantly lower in the 1.0% biotin group than in the pair-fed group after 6 weeks of feeding. The accumulation of biotin in the liver and testis increased in a dose-dependent manner. In the 1.0% biotin group, the number of mature sperm was markedly lower, that of sperm with morphologically abnormal heads, mainly consisting of round heads, had increased. In addition, the development of seminiferous tubules was inhibited, and few spermatogonia and no spermatocytes were histologically observed. These results demonstrated that the long-term intake of high-dose biotin inhibited spermatogenesis in young male rats. PMID- 25039898 TI - Prothrombin complex concentrate for non-vitamin K oral anticoagulant reversal: good enough for now? PMID- 25039899 TI - DC-T cell virological synapses and the skin: novel perspectives in dermatology. AB - Virological synapses (VS) increase cell-to-cell viral transmission and facilitate propagation of human immunodeficiency virus type 1 (HIV-1) and human T-cell leukaemia virus type 1 (HTLV-1). VS formation also plays a more general role in viral replication and dissemination. VS have been observed in vitro and ex vivo between uninfected T cells and T cells infected with HIV-1 or HTLV-1. In addition, dendritic cells (DC) infected with HIV-1 also play an important role in viral transmission to uninfected CD4+ T cells via VS formation. Recent studies revealed that several DC subsets are also infected with HTLV-1. These findings may help explain the rapid dissemination of both viruses within secondary lymphoid tissues in vivo. VS also explain, at least in part, why HIV-1 can propagate in the mucosal sites during sexual transmission. Furthermore, in the case of HTLV-1, VS can potentially explain some of the features of HTLV-1 associated dermatitis as infected T cells in the skin contribute to the pathogenesis of this condition. PMID- 25039900 TI - Polyphosphate accumulation is driven by transcriptome alterations that lead to near-synchronous and near-equivalent uptake of inorganic cations in an arbuscular mycorrhizal fungus. AB - Arbuscular mycorrhizal (AM) fungi accumulate a massive amount of phosphate as polyphosphate to deliver to the host, but the underlying physiological and molecular mechanisms have yet to be elucidated. In the present study, the dynamics of cationic components during polyphosphate accumulation were investigated in conjunction with transcriptome analysis. Rhizophagus sp. HR1 was grown with Lotus japonicus under phosphorus-deficient conditions, and extraradical mycelia were harvested after phosphate application at prescribed intervals. Levels of polyphosphate, inorganic cations and amino acids were measured, and RNA-Seq was performed on the Illumina platform. Phosphate application triggered not only polyphosphate accumulation but also near synchronous and near-equivalent uptake of Na(+) , K(+) , Ca(2+) and Mg(2+) , whereas no distinct changes in the levels of amino acids were observed. During polyphosphate accumulation, the genes responsible for mineral uptake, phosphate and nitrogen metabolism and the maintenance of cellular homeostasis were up regulated. The results suggest that inorganic cations play a major role in neutralizing the negative charge of polyphosphate, and these processes are achieved by the orchestrated regulation of gene expression. Our findings provide, for the first time, a global picture of the cellular response to increased phosphate availability, which is the initial process of nutrient delivery in the associations. PMID- 25039901 TI - The vegetative state/unresponsive wakefulness syndrome: a systematic review of prevalence studies. AB - One of the worst outcomes of acquired brain injury is the vegetative state, recently renamed 'unresponsive wakefulness syndrome' (VS/UWS). A patient in VS/UWS shows reflexive behaviour such as spontaneous eye opening and breathing, but no signs of awareness of the self or the environment. We performed a systematic review of VS/UWS prevalence studies and assessed their reliability. Medline, Embase, the Cochrane Library, CINAHL and PsycINFO were searched in April 2013 for cross-sectional point or period prevalence studies explicitly stating the prevalence of VS/UWS due to acute causes within the general population. We additionally checked bibliographies and consulted experts in the field to obtain 'grey data' like government reports. Relevant publications underwent quality assessment and data-extraction. We retrieved 1032 papers out of which 14 met the inclusion criteria. Prevalence figures varied from 0.2 to 6.1 VS/UWS patients per 100 000 members of the population. However, the publications' methodological quality differed substantially, in particular with regards to inclusion criteria and diagnosis verification. The reliability of VS/UWS prevalence figures is poor. Methodological flaws in available prevalence studies, the fact that 5/14 of the studies predate the identification of the minimally conscious state (MCS) as a distinct entity in 2002, and insufficient verification of included cases may lead to both overestimation and underestimation of the actual number of patients in VS/UWS. PMID- 25039902 TI - Diagnosis and treatment of urea cycle disorder in Japan. AB - Urea cycle disorder (UCD) is an inborn error of the metabolic pathway producing urea from ammonia, which occurs primarily in the liver. Decreased excretion of nitrogen in the urea cycle due to deficiency of carbamoyl phosphate synthase I (CPSI), ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and N-acetyl glutamate synthase (NAGS) causes hyperammonemia. We examined the clinical manifestations, treatment, and prognosis of 177 patients with UCD from January 1999 to March 2009 in Japan. Compared with a previous study conducted in Japan, a larger number of patients survived without mental retardation, even when the peak blood ammonia was >360 MUmol/L. In those with peak blood ammonia >360 MUmol/L, an indicator of poor prognosis, the frequency of convulsions, mental retardation, brain abnormality on magnetic resonance imaging, hemodialysis, liver transplantation, and intake of non-protein formulas was significantly higher than in those with peak blood ammonia <360 MUmol/L. In this article, we have reported the current state of UCD to evaluate prognosis and its relationship with peak blood ammonia and hemodialysis. PMID- 25039903 TI - Enterovirus infections in England and Wales, 2000-2011: the impact of increased molecular diagnostics. AB - There have recently been significant changes in diagnostic practices for detecting enterovirus (EV) infections across England and Wales. Reports of laboratory-confirmed EV infections submitted by National Health Service (NHS) hospital laboratories to Public Health England (PHE) over a 12-year period (2000 2011) were analysed. Additionally, the PHE Virus Reference Department (VRD) electronic database containing molecular typing data from 2004 onwards was interrogated. Of the 13,901 reports, there was a decline from a peak of 2254 in 2001 to 589 in 2006, and then an increase year-on-year to 1634 in 2011. This increase coincided with increasing PCR-based laboratory diagnosis, which accounted for 36% of reported cases in 2000 and 92% in 2011. The estimated annual incidence in 2011 was 3.9/100,000 overall and 238/100,000 in those aged <3 months, who accounted for almost one-quarter of reported cases (n = 2993, 23%). During 2004-2011, 2770 strains were submitted for molecular typing to the VRD, who found no evidence for a predominance of any particular strain. Thus, the recent increase in reported cases closely reflects the increase in PCR testing by NHS hospitals, but is associated with a lower proportion of samples being submitted for molecular typing. The high EV rate in young infants merits further investigation to inform evidence-based management guidance. PMID- 25039904 TI - Techniques for the assessment of volume status in patients with end stage renal disease. AB - While advances in assessing extracellular volume status have occurred, no methodology is sufficiently robust and accurate in all patients to recommend routine use in clinical practice. All of the methods described also perform best when measured serially in patients and when correlated with other ancillary methods of volume assessment such as body weight, physical examination and determination of vital signs and symptomatology. Perhaps, the best method for assessing and modifying dry weight is to utilize multiple complementary methods such as advocated by Ronco et in the "5B" approach (39). In this approach, the clinician utilizes data from: fluid balance (body weight changes), blood pressure, biomarkers (such as the natriuretic peptides), bioimpedance, and blood volume changes. Body (thoracic and IVC) ultrasound can also be included (Fig. 1). These combined data sources will likely lead to greater detection of subtle volume overload, a finding likely to contribute to excess mortality and morbidity. Clinical trials of such strategies are needed to better inform clinicians. PMID- 25039905 TI - Increased aqueous solubility and proapoptotic activity of potassium koetjapate against human colorectal cancer cells. AB - OBJECTIVES: Recently, we have isolated koetjapic acid (KA) from Sandoricum koetjape and identified its selective anticancer potentiality against colorectal carcinoma. KA is quite likely to be useful as a systemic anticancer agent against colorectal malignancy. However, with extremely low solubility, KA has to be converted into a biocompatible solubilized form without compromising the bioefficacy. Objective of this study is to enhance solubility of KA and to evaluate anticancer efficacy of potassium koetjapate in human colorectal cancer cells. METHODS: (2-Hydroxypropyl)-beta-cyclodextrin inclusion complex and solid dispersions (carboxymethyl cellulose, polyvinylpyrrolidone and sodium lauryl sulphate) of KA were prepared. In addition, a salt of KA, potassium koetjapate was synthesized. KEY FINDINGS: Potassium koetjapate demonstrated higher solubility than the other tested formulations with enhanced cytotoxicity against HCT 116 cells. The enhanced efficacy of potassium koetjapate is attributed to apoptotic induction of nuclear condensation and disruption of mitochondrial membrane potential in the cells. Interestingly, potassium koetjapate was found to be safe in rats after oral administration (LD50 > 2000 mg/kg). CONCLUSIONS: The salt formulation of KA appears to modulate the capability of the parent compound by enhancing its solubility and improves its bioefficacy against colon cancer cells, suggesting attractive roles for its applications in medicine. PMID- 25039907 TI - The effect of Medicaid primary care provider reimbursement on access to early childhood caries preventive services. AB - OBJECTIVE: To examine receipt of early childhood caries preventive services (ECCPS) in two states' Medicaid programs before and after the implementation of reimbursement to medical primary care providers (M-PCPs). DATA SOURCES: Enrollment and claims data from the Florida and Texas Medicaid programs for children <=54 months of age during the period 2006-2010. STUDY DESIGN: We conducted time trend-adjusted, difference-in-differences analyses by using modified Poisson regressions combined with generalized estimating equations (GEEs) to analyze the effect of M-PCP reimbursement on the likelihood that an enrollee had an ECCPS visit after controlling for age, sex, health status, race/ethnicity, geographic location, and enrollment duration. DATA EXTRACTION METHODS: Enrollment data were linked to claims data to create a panel dataset with child-month observations. PRINCIPAL FINDINGS: Reimbursement to M-PCPs was associated with an increased likelihood of ECCPS receipt in general and topical fluoride application specifically in both states. CONCLUSIONS: Reimbursement to M PCPs can increase access to ECCPS. However, ECCPS receipt continues to fall short of recommended care, presenting opportunities for performance improvement. PMID- 25039908 TI - RcsB positively regulates the Yersinia Ysc-Yop type III secretion system by activating expression of the master transcriptional regulator LcrF. AB - The Rcs phosphorelay is a complex signaling pathway used by the family Enterobacteriaceae to sense, respond and adapt to environmental changes during free-living or host-associated lifestyles. In this study, we show that the Rcs phosphorelay pathway positively regulates the virulence plasmid encoded Ysc-Yop type III secretion system (T3SS) in the enteropathogen Yesinia pseudotuberculosis. Both the overexpression of the wild-type Rcs regulator RcsB or the constitutive active RscB(D56E) variant triggered more abundant Ysc-Yop synthesis and secretion, whereas the non-phosphorylatable mutant RcsB(D56Q) negated this. Congruently, enhanced Yops expression and secretion occurred in an in cis rscB(D56E) mutant but not in an isogenic rscB(D56Q) mutant. Screening for regulatory targets of RcsB identified the virG-lcrF operon that encodes for LcrF, the Ysc-Yop T3SS master regulator. Protein-DNA binding assays confirmed that RcsB directly bound to this operon promoter, which subsequently caused stimulated lcrF transcription. Moreover, active RcsB enhanced the ability of bacteria to deliver Yop effectors into immune cells during cell contact, and this promoted an increase in bacterial viability. Taken together, our study demonstrates the role of the Rcs system in regulating the Ysc-Yop T3SS in Yersinia and reports on RcsB being the first transcriptional activator known to directly control lcrF transcription. PMID- 25039909 TI - Leptospiral lipopolysaccharide stimulates the expression of toll-like receptor 2 and cytokines in pig fibroblasts. AB - Pigs throughout the world are afflicted with leptospirosis, causing serious economic losses and potential hazards to human health. Although it has been known that leptospiral lipopolysaccharide (L-LPS) is involved in an immunological reaction between an antigen and a host cell, little is known about how the immune system of pigs can respond to L-LPS. Here, we stimulated pig fibroblasts by L-LPS and then quantitatively measured gene and protein expression levels of two toll like receptors (TLRs), TLR2 and TLR4, by real-time PCR and Western blotting. As a result, expression of TLR2 was found to be significantly up-regulated within 24 h after L-LPS stimulation whereas induction of TLR4 expression was relatively weak. We also revealed that of myeloid differentiation primary response gene 88 (MyD88), interleukin 6 (IL-6) and IL-8 gene expressions were markedly up regulated by L-LPS stimulation. These results may suggest that the pig cell can activate TLR2 rather than TLR4 by L-LPS stimulation, thereby inducing expression of cytokines. PMID- 25039910 TI - Cutaneous adverse drug reactions caused by antituberculosis drugs. AB - Multidrug antituberculosis regimen is associated with diverse clinical patterns of cutaneous adverse drug reactions (CADR), ranging from mild and moderate such as pruritus, maculopapular exanthems, lichenoid eruptions, fixed drug eruptions and urticaria to severe and even life threatening ones like acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These adverse reactions to antituberculosis drugs are commonly observed adverse events. This is of particular importance for high HIV prevalence settings and developing countries where tuberculosis is common infection resulting in higher occurrence rate of these reactions. There is still significant heterogenity in definition and classification of CADR, as well as diversity in treatment modalities following adverse reactions and rechallenge management. The aim of this review is to discuss clinical presentation, occurrence of CADR caused by antituberculosis drugs, to identify risk factors for intolerance of the standard therapy as well as to draw attention to importance of multi-disciplinary approach, early detection, prompt diagnosis and in time management of antituberculosis drugs associated CADR. CADR can cause significant treatment interruption and alteration, resulting in increased risk of treatment failure, drug resistance, relapses and increased risk of complications including even lethal outcome. Finally, it can be concluded that it is of great importance to identify the best possible treatment and preventive regimens in order to enable continuity of the antituberculosis therapy to the full extent. PMID- 25039911 TI - Platelets are not all gray in GFI1B disease. PMID- 25039912 TI - Simulating water-quality trends in public-supply wells in transient flow systems. AB - Models need not be complex to be useful. An existing groundwater-flow model of Salt Lake Valley, Utah, was adapted for use with convolution-based advective particle tracking to explain broad spatial trends in dissolved solids. This model supports the hypothesis that water produced from wells is increasingly younger with higher proportions of surface sources as pumping changes in the basin over time. At individual wells, however, predicting specific water-quality changes remains challenging. The influence of pumping-induced transient groundwater flow on changes in mean age and source areas is significant. Mean age and source areas were mapped across the model domain to extend the results from observation wells to the entire aquifer to see where changes in concentrations of dissolved solids are expected to occur. The timing of these changes depends on accurate estimates of groundwater velocity. Calibration to tritium concentrations was used to estimate effective porosity and improve correlation between source area changes, age changes, and measured dissolved solids trends. Uncertainty in the model is due in part to spatial and temporal variations in tracer inputs, estimated tracer transport parameters, and in pumping stresses at sampling points. For tracers such as tritium, the presence of two-limbed input curves can be problematic because a single concentration can be associated with multiple disparate travel times. These shortcomings can be ameliorated by adding hydrologic and geologic detail to the model and by adding additional calibration data. However, the Salt Lake Valley model is useful even without such small-scale detail. PMID- 25039913 TI - Effectiveness and safety of a high-dose weekly vitamin D (20,000 IU) protocol in older adults living in residential care. AB - OBJECTIVES: To report 25 hydroxyvitamin D (25OHD) concentrations, an indicator of vitamin D status, in older adults living in residential care 1 year after a protocol of weekly 20,000 IU of vitamin D was started. DESIGN: Cross-sectional. SETTING: Five residential care facilities in British Columbia, Canada. PARTICIPANTS: Residents aged 65 and older from five facilities (N=236). MEASUREMENTS: Participants provided a blood sample. Demographic and health information was obtained from the medical record. RESULTS: Mean 25OHD was 102 nmol/L (95% confidence interval (CI)=98-106 nmol/L). Three percent of residents had a 25OHD concentration of less than 40 nmol/L, 6% <50 nmol/L, and 19% <75 nmol/L. In those who received 20,000 IU/wk or more for 6 months or longer (n=147), mean 25OHD was 112 nmol/L (95% CI=108-117 nmol/L), and none had a 25OHD level of less than 50 nmol/L. Hypercalcemia (>2.6 mmol/L), a potential consequence of too much vitamin D, was present in 14%, although 25OHD levels did not differ in those with and without hypercalcemia (108 vs 101 nmol/L; P=.17). CONCLUSION: Twelve months after implementation of a 20,000-IU/wk vitamin D protocol for older adults in residential care, mean 25OHD concentrations were high, and there was no evidence of poor vitamin D status. Given the absence of demonstrated benefit of high 25OHD concentrations to the residential care population, dosages less than 20,000 IU/wk of vitamin D are recommended. PMID- 25039914 TI - Pituitary gonadotrophic hormone synthesis, secretion, subunit gene expression and cell structure in normal and follicle-stimulating hormone beta knockout, follicle stimulating hormone receptor knockout, luteinising hormone receptor knockout, hypogonadal and ovariectomised female mice. AB - To investigate the relationship between gonadotroph function and ultrastructure, we have compared, in parallel in female mice, the effects of several different mutations that perturb the hypothalamic-pituitary-gonadal axis. Specifically, serum and pituitary gonadotrophin concentrations, gonadotrophin gene expression, gonadotroph structure and number were measured. Follicle-stimulating hormone beta knockout (FSHbetaKO), follicle-stimulating hormone receptor knockout (FSHRKO), luteinising hormone receptor knockout (LuRKO), hypogonadal (hpg) and ovariectomised mice were compared with control wild-type or heterozygote female mice. Serum levels of LH were elevated in FSHbetaKO and FSHRKO compared to heterozygote females, reflecting the likely decreased oestrogen production in KO females, as demonstrated by the threadlike uteri and acyclicity. As expected, there was no detectable FSH in the serum or pituitary and an absence of expression of the FSHbeta subunit gene in FSHbetaKO mice. However, there was a significant increase in expression of the FSHbeta and LHbeta subunit genes in FSHRKO female mice. The morphology of FSHbetaKO and FSHRKO gonadotrophs was not significantly different from the control, except that secretory granules in FSHRKO gonadotrophs were larger in diameter. In LuRKO and ovariectomised mice, stimulation of LHbeta and FSHbeta mRNA, as well as serum protein concentrations, were reflected in subcellular changes in gonadotroph morphology, including more dilated rough endoplasmic reticula and fewer, larger secretory granules. In the gonadotophin-releasing hormone deficient hpg mouse, gonadotrophin mRNA and protein levels were significantly lower than in control mice and gonadotrophs were correspondingly smaller with less abundant endoplasmic reticula and reduced numbers of secretory granules. In summary, major differences in pituitary content and serum concentrations of the gonadotrophins LH and FSH were found between control and mutant female mice. These changes were associated with changes in expression of the gonadotrophin subunit genes and were reflected in the cellular structure and secretory granule appearance within the gonadotroph cells. PMID- 25039915 TI - Rituximab, Gemcitabine, Cisplatin and Methylprednisolone (R-GEM-P) is an effective regimen in relapsed diffuse large B-cell lymphoma. AB - BACKGROUND: Patients with relapsed diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Gemcitabine, methylprednisolone, cisplatin +/- rituximab (GEM-P+/ R) is a salvage regimen with limited overlap in toxicity with first-line therapy and short duration of inpatient delivery. METHODS: We assessed the efficacy and safety of GEM-P+/-R in a retrospective single-centre analysis including patients meeting criteria of >= 18 yr of age, histologically proven DLBCL, treated between 2001 and 2011 in second-line with gemcitabine 1000 mg/m(2) day 1, 8 and 15, methylprednisolone 1000 mg day 1-5, cisplatin 100 mg/m(2) day 15 (replaced with carboplatin AUC5 if contraindication/toxicity) +/- rituximab 375 mg/m(2) day 1 and 15, every 28 d. RESULTS: Forty-five patients aged 25-74 received a median of three cycles of GEM-P+/-R; 64% received rituximab. In 44 evaluable patients receiving GEM-P+/-R, overall response rate (ORR) was 48%; in 28 evaluable patients treated with rituximab + GEM-P (R-GEM-P), ORR was 61%. With median follow-up of 50.5 months (95% CI: 28.3-72.7), 3-yr overall survival (OS) from start of GEM-P+/-R was 31.4% (95% CI: 16.5-46.3); in patients treated with R-GEM P, 3-yr OS was 49.1% (95% CI: 28.7-69.5). Predominant grade >= 3 toxicities were haematological; thrombocytopenia 69%, neutropenia 60% and febrile neutropenia 7%. CONCLUSION: R-GEM-P is a deliverable regimen with useful activity in second-line treatment of DLBCL. Our data suggest that rituximab should be given concurrently. PMID- 25039917 TI - Visualising microorganisms from molecules to cells. AB - 10 images from FEMS articles have been selected to show the diversity of visualisation used in microbiology. PMID- 25039916 TI - MRS in mild cognitive impairment: early differentiation of dementia with Lewy bodies and Alzheimer's disease. AB - BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) precedes both Alzheimer's disease (AD) dementia and with Lewy bodies (DLB). We investigated proton magnetic resonance spectroscopy (MRS) characteristics of MCI patients who progressed to DLB compared to those who progressed to AD dementia or remained stable. METHODS: Consecutive MCI patients who underwent single voxel MRS at baseline and progressed to DLB (n = 10) were identified during a median follow-up period of 18 months. From the same cohort, we identified age- and sex-matched MCI patients who progressed to AD dementia (n = 27) or remained stable (n = 20) during a similar follow-up period. This study was approved by the Institutional Review Board and informed consent was from every subject. RESULTS: MCI patients who progressed to AD dementia were characterized by lower N-acetylaspartate (NAA)/Cr ratio in the posterior cingulate voxel compared to those who progressed to DLB (P = .001). Decreased NAA/Cr in the posterior cingulate voxel differentiated MCI patients who progressed to DLB from those who progressed to AD with an area under the receiver operating characteristic curve of .85 (P < .001) on logistic regression analysis. CONCLUSIONS: MRS may be useful in differentiating MCI patients with prodromal AD dementia from those with prodromal DLB for early disease-specific interventions. PMID- 25039918 TI - Postoperative analgesic effects of either a constant rate infusion of fentanyl, lidocaine, ketamine, dexmedetomidine, or the combination lidocaine-ketamine dexmedetomidine after ovariohysterectomy in dogs. AB - OBJECTIVE: To evaluate the postoperative analgesic effects of a constant rate infusion (CRI) of either fentanyl (FENT), lidocaine (LIDO), ketamine (KET), dexmedetomidine (DEX), or the combination lidocaine-ketamine-dexmedetomidine (LKD) in dogs. STUDY DESIGN: Randomized, prospective, blinded, clinical study. ANIMALS: Fifty-four dogs. METHODS: Anesthesia was induced with propofol and maintained with isoflurane. Treatments were intravenous (IV) administration of a bolus at start of anesthesia, followed by an IV CRI until the end of anesthesia, then a CRI at a decreased dose for a further 4 hours: CONTROL/BUT (butorphanol 0.4 mg kg(-1), infusion rate of saline 0.9% 2 mLkg(-1) hour(-1)); FENT (5 MUg kg( 1), 10 MUg kg(-1) hour(-1), then 2.5 MUg kg(-1) hour(-1)); KET (1 mgkg(-1) , 40 MUg kg(-1) minute(-1), then 10 MUg kg(-1) minute(-1) ; LIDO (2 mg kg(-1), 100 MUg kg(-1) minute(-1), then 25 MUg kg(-1) minute(-1)); DEX (1 MUgkg(-1), 3 MUg kg(-1) hour(-1), then 1 MUg kg(-1) hour(-1)); or a combination of LKD at the aforementioned doses. Postoperative analgesia was evaluated using the Glasgow composite pain scale, University of Melbourne pain scale, and numerical rating scale. Rescue analgesia was morphine and carprofen. Data were analyzed using Friedman or Kruskal-Wallis test with appropriate post-hoc testing (p < 0.05). RESULTS: Animals requiring rescue analgesia included CONTROL/BUT (n = 8), KET (n = 3), DEX (n = 2), and LIDO (n = 2); significantly higher in CONTROL/BUT than other groups. No dogs in LKD and FENT groups received rescue analgesia. CONTROL/BUT pain scores were significantly higher at 1 hour than FENT, DEX and LKD, but not than KET or LIDO. Fentanyl and LKD sedation scores were higher than CONTROL/BUT at 1 hour. CONCLUSIONS AND CLINICAL RELEVANCE: LKD and FENT resulted in adequate postoperative analgesia. LIDO, CONTROL/BUT, KET and DEX may not be effective for treatment of postoperative pain in dogs undergoing ovariohysterectomy. PMID- 25039919 TI - Dental care and oral health in Aagenaes syndrome/lymphedema cholestasis syndrome 1. AB - Aagenaes syndrome/lymphedema cholestasis syndrome 1 (LCS1) is a rare genetic disorder characterized by neonatal cholestasis and lymphedema. The aim was to assess dental care and oral health in adults with LCS1. Fifteen (9M, 6F) individuals diagnosed with LCS1, aged 19-59 years participated. The study evaluated salivary secretion rate, dental radiographs, intraoral photos and included a questionnaire. Eight (53%) had regular dental checkups. Three had received subsidized dental care. Seven (47%) had two or more subjective symptoms of xerostomia. Three (20%) had a decreased stimulated salivary secretion rate below 0.7 mL/minute. Seven (47%) had dentin caries. Marginal periodontitis was found in all six patients above 35 years of age, but not before that age. Thirteen (87%) had tooth discoloration, which was extensive in three (20%). CONCLUSION: Several patients with LCS1 have problems with periodontitis and tooth discoloration. Frequent dental checkups are therefore recommended. PMID- 25039920 TI - Secretory Leukocyte Protease Inhibitor (SLPI) expression downregulates E cadherin, induces beta-catenin re-localisation and triggers apoptosis-related events in breast cancer cells. AB - BACKGROUND INFORMATION: Epithelial cadherin (E-cadherin) is involved in cell-cell adhesion through its extracellular domain, whereas the intracellular domain interacts with adaptor proteins, i.e. beta-catenin, links E-cadherin to the actin cytoskeleton and participates in signal transduction events. E-cadherin protects mammary epithelial cells from apoptosis and its loss during tumour progression has been documented. Secretory Leukocyte Protease Inhibitor (SLPI) has anti- and pro-tumourigenic activities but its role in breast cancer has not been fully elucidated. Notwithstanding its relevance, how SLPI affects E-cadherin in breast cancer is still unknown. This study evaluated the effect of SLPI upon E cadherin/beta-catenin expression and apoptosis-related markers in murine (F3II) and human (MCF-7) breast tumour cells either treated with exogenous recombinant human SLPI (rhSLPI) or stably transfected with a plasmid encoding its sequence. RESULTS: Addition of rhSLPI to F3II cells caused a decrease (P < 0.05) in E cadherin transcript and protein levels. Similar results were observed in SLPI stable F3II transfectants (2C1), and treatment of 2C1 cells with a siRNA toward SLPI restored E-cadherin to control levels. SLPI-expressing cells showed disruption of E-cadherin/beta-catenin complex and increased (P < 0.05) percentage of cells depicting nuclear beta-catenin localisation. Associated to these changes, 2C1 cells showed increased Bax/Bcl-2 ratio and p21 protein levels, decreased c-Myc protein levels and decreased Cyclin D1 and Claudin-1 transcript levels. No differences in N- and P-cadherin were observed between SLPI transfected cells and controls. Addition of rhSLPI to MCF-7 cells or stable transfection with SLPI caused a decrease (P < 0.05) in E-cadherin expression (transcript/protein) and its redistribution to the cytoplasm, as well as beta catenin re-localisation to the cell nucleus. CONCLUSIONS: Expression of SLPI was associated to a decrease in E-cadherin expression and re-localisation of E cadherin to the cell cytoplasm and beta-catenin to the cell cytoplasm and nucleus, and had pro-apoptotic and cell cycle-arrest effects. PMID- 25039921 TI - Prevalence and predictors of severe hypoglycemia in Danish children and adolescents with diabetes. AB - OBJECTIVE: To investigate the prevalence of severe hypoglycemia in Danish children and adolescents with type 1 diabetes and to pinpoint predictors of this acute complication in children on modern treatment modalities. RESEARCH DESIGN AND METHODS: The study is based on data from DanDiabKids, a national diabetes register for children and adolescents. The register contains data on patients with type 1 diabetes with an ascertainment rate of 99%. Data from 3320 patients aged 0-18 yr was included in the study period from 1998 to 2009 and analyzed using a negative binomial model. RESULTS: One thousand nine hundred and ninety nine episodes of severe hypoglycemia in 867 patients were registered conferring an overall incidence of severe hypoglycemia of 15.1 [95% confident interval (CI): 13.8; 16.4] per 100 patient years. This remained unchanged during the study period. Duration of diabetes, age and treatment in centers managing less than 100 patients significantly increased the risk of severe hypoglycemia (p < 0.001). Patients on insulin pump therapy had a 42% reduced risk of severe hypoglycemia compared with pen treated patients (p = 0.01). Patients treated with five or more daily insulin injections had a 31% (95% CI: 17; 49) reduced risk of severe hypoglycemia compared to patients on fewer daily injections (p = 0.015). CONCLUSIONS: Despite improvements in metabolic control over a decade the prevalence of severe hypoglycemic events remained unchanged. More intensive treatments such as insulin pump therapy and multiple daily injections on a national level seems to be a protective factor for developing severe hypoglycemia up to 2009. PMID- 25039922 TI - Characterizations, relationship, and potential sources of outdoor and indoor particulate matter bound polycyclic aromatic hydrocarbons (PAHs) in a community of Tianjin, Northern China. AB - Polycyclic aromatic hydrocarbons (PAHs) are among the most toxic air pollutants in China. However, because there are unsubstantial data on indoor and outdoor particulate PAHs, efforts in assessing inhalation exposure and cancer risk to PAHs are limited in China. This study measured 12 individual PAHs in indoor and outdoor environments at 36 homes during the non-heating period and heating period in 2009. Indoor PAH concentrations were comparable with outdoor environments in the non-heating period, but were lower in the heating period. The average indoor/outdoor ratios in both sampling periods were lower than 1, while the ratios in the non-heating period were higher than those in the heating period. Correlation analysis and coefficient of divergence also verified the difference between indoor and outdoor PAHs, which could be caused by high ventilation in the non-heating period. To support this conclusion, linear and robust regressions were used to estimate the infiltration factor to compare outdoor PAHs to indoor PAHs. The calculated infiltration factors obtained by the two models were similar in the non-heating period but varied greatly in the heating period, which may have been caused by the influence of ventilation. Potential sources were distinguished using a diagnostic ratio and a mixture of coal combustion and traffic emission, which are major sources of PAHs. PMID- 25039923 TI - Immunohistochemical application of a highly sensitive and specific murine monoclonal antibody recognising the extracellular domain of the human hepatocyte growth factor receptor (MET). AB - AIMS: Development of novel targeted therapies directed against hepatocyte growth factor (HGF) or its receptor (MET) necessitates the availability of quality diagnostics to facilitate their safe and effective use. Limitations of some commercially available anti-MET antibodies have prompted development of the highly sensitive and specific clone A2H2-3. Here we report its analytical properties when applied by an automated immunohistochemistry method. METHODS AND RESULTS: Excellent antibody specificity was demonstrated by immunoblot, ELISA, and IHC evaluation of characterised cell lines including NIH3T3 overexpressing the related kinase MST1R (RON). Sensitivity was confirmed by measurements of MET in cell lines or characterised tissues. IHC correlated well with FISH and quantitative RT-PCR assessments of MET (P < 0.001). Good total agreement (89%) was observed with the anti-MET antibody clone SP44 using whole-tissue sections, but poor positive agreement (21-47%) was seen in tissue microarray cores. Multiple lots displayed appropriate reproducibility (R(2) > 0.9). Prevalence of MET positivity by IHC was higher in non-squamous cell NSCLC, MET or EGFR amplified cases, and in tumours harbouring abnormalities in EGFR exon 19 or 21. CONCLUSIONS: The anti-MET antibody clone A2H2-3 displays excellent specificity and sensitivity. These properties make it suitable for clinical trial investigations and development as a potential companion diagnostic. PMID- 25039924 TI - Robot-assisted oesophageal and gastric surgery for benign disease: antireflux operations and Heller's myotomy. AB - BACKGROUND: Robot-assisted general surgery operations are being performed more frequently. This review investigates whether robotic assistance results in significant advantages or disadvantages for the operative treatment of gastro oesophageal reflux disease and achalasia. METHODS: The electronic databases (Medline, Embase, PubMed) were searched for original English language publications for antireflux surgery and Heller's myotomy between January 1990 and December 2013. RESULTS: Thirty-three publications included antireflux operations and 20 included Heller's myotomy. The publications indicate that the safety and effectiveness of robotic surgery is similar to that of conventional minimally invasive surgery for both operations. The six randomized trials of robot-assisted versus laparoscopic antireflux surgery showed no significant advantages but significantly higher costs for the robotic method. Gastric perforation during non redo robotic fundoplication occurred in four trials. CONCLUSIONS: No consistent advantage for robot-assisted antireflux surgery has been demonstrated, and there is an increased cost with current robotic technology. A reported advantage for robotic in reducing the perforation rate during Heller's myotomy for achalasia remains unproven. Gastric perforation during robotic fundoplication may be due to the lack of haptic feedback combined with the superhuman strength of the robot. PMID- 25039925 TI - Chronic rhinocerebral mucormycosis: a rare case report and review of the literature. AB - Rhinocerebral mucormycosis is an invasive infection caused by filamentous fungi of the Mucoraceae family. The rhinocerebral form of the disease represents the most common form and has two distinct clinical entities. The common presentation consists of a rapidly progressive infection with high mortality rate, while the other presentation is that of a chronic infection with lower mortality. In the present paper we report a rare case of chronic rhinocerebral mucormycosis. An 85 year-old male with a 6-month history of purulent and odorous nasal discharge, and sporadic episodes of epistaxis and anosmia, presented to the outpatient department of our clinic. Initial cultures were positive only for Pseudomonas aeruginosa. The patient was unresponsive to ciprofloxacin treatment, developing necrotic areas of the nasal septum suspicious for rhinocerebral mucormycosis. Admission to the ENT clinic followed, with histopathologic evaluation of the vomer bone confirming the diagnosis. The patient was treated with amphotericin B and was discharged 3 weeks later on oral posaconazole therapy. Chronic rhinocerebral mucormycosis may present with atypical symptoms or coinfection with another agent. A high degree of clinical suspicion is required for correct diagnosis and prompt initiation of appropriate treatment. PMID- 25039926 TI - The presence of mast cell clonality in patients with unexplained anaphylaxis. AB - BACKGROUND: The mechanisms by which mast cells in patients with unexplained anaphylaxis (UEA) are triggered remain elusive. Onset of episodes is unpredictable and often recurrent. The substantial overlap between the clinical manifestations of UEA and clonal mast cell disorders (CMD) suggests an association between these rare disorders. The two forms of CMD characterized to date are systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS). OBJECTIVE: To examine the hypothesis that the pathogenesis of UEA reflects the presence of aberrant subpopulations of mast cells. METHODS: Thirty (14 men, 16 women) patients (>= 18 years) suffering from UEA and with no signs of cutaneous mastocytosis were recruited. Patients underwent an initial complete allergy work-up to confirm the diagnosis of UEA. Level of baseline serum tryptase (sBT) and total IgE were determined. In addition, a bone marrow examination was performed on all 30 patients to investigate possible underlying CMD. RESULTS: Fourteen (47%) of our cases (nine men, five women) were diagnosed with CMD: 10 with SM and four with MMAS. Four of the 10 patients with SM had mast cell aggregates in their bone marrow. All patients with SM exhibited a sBT level > 11.4 ng/mL, whereas this level was elevated in only two of those with MMAS and four with UAE but not diagnosed with CMD. Total IgE levels were lower in the group of patients with CMD (P < 0.03). CONCLUSION AND CLINICAL RELEVANCE: The pathogenic mechanism underlying UEA could be explained by the presence of immunophenotypically aberrant mast cells with clonal markers in 47% of our subjects, indicating that clonal mast cell disorders are present in a substantial subset of these patients. Thus, the presence of CMD should be considered in patients with UEA if they have an elevated level of sBT (>= 11.4 ng/mL) and cardiovascular symptoms such as syncope. PMID- 25039927 TI - Use of single large or several small policies as strategies to manage people-park interactions. AB - Biodiversity conservation has been criticized for undermining or ignoring social well-being. Currently efforts to mutually promote social justice, rural development, and biodiversity conservation, which have been contentious and yielded mixed results, continue to spread despite a general dearth of effective management strategies. We contend that social and economic concerns should be integral to conservation planning and propose that the scale of these phenomena is also critical. To evaluate the merit of this proposal, we adopted and expanded a conservation management strategy framework developed by Joel Heinen and examined how population density, economic disparity, and ethnic heterogeneity vary spatially surrounding 2 contrasting protected areas in East Africa: Kibale National Park in Uganda and Tarangire National Park in Tanzania. Analyses of demographic, wealth, and ethnicity data from regional censuses and household surveys conducted in 2009 and 2010 indicated that choice of scale (landscape or community) changed the management strategies recommended by the model. Therefore, "several small" people-park management strategies varying around a given protected area may be more appropriate than a "single large" people-park strategy applied across an entire protected area. Correspondingly, scale adjusted Heinen recommendations offered new strategies for effective conservation management within these human landscapes not incorporated in current in situ management plans. PMID- 25039928 TI - Short general anaesthesia induces prolonged changes in gene expression in the mouse hippocampus. AB - BACKGROUND: The long-term molecular changes in the central nervous system constitute an important aspect of general anaesthesia, but little is known about to what extent these molecular changes are affected by anaesthesia duration. The aim of the present study was to evaluate the effects of short duration (20 min) general anaesthesia with isoflurane or avertin on the expression of 20 selected genes in the mouse hippocampus at 1 and 4 days after anaesthesia. METHODS: Nine to eleven-weeks-old male mice received one of the following treatments: 20 min of avertin-induced anaesthesia (n=11), 20 min of isoflurane-induced anaesthesia (n=10) and no anaesthesia (n=5). One and four days after anaesthesia, gene expression in the hippocampus was determined with reverse transcription quantitative real-time polymerase chain reaction. RESULTS: We found that anaesthesia led to the upregulation of six genes: Hspd1 (heat shock protein 1), Plat (tissue plasminogen activator) and Npr3 (natriuretic peptide receptor 3) were upregulated only 1 day after anaesthesia, whereas Thbs4 (thrombospondin 4) was upregulated only 4 days after anaesthesia. Syp (synaptophysin) and Mgst1 (microsomal glutathione S-transferase 1) were upregulated at both time points. Hspd1, Mgst1 and Syp expression was increased regardless of the anaesthetic used, Npr3 and Plat were increased only in mice exposed to avertin, and Thbs4 was upregulated only after isoflurane-induced anaesthesia. CONCLUSIONS: This study shows that some of the effects of short general anaesthesia on gene expression in the mouse hippocampus persist for at least 4 days. PMID- 25039929 TI - The effect of horse simulator riding on visual analogue scale, body composition and trunk strength in the patients with chronic low back pain. AB - BACKGROUND: Chronic low back pain (CLBP) is one of the most common musculoskeletal disorders, and thus effective treatments are required. Recently, real horseback riding has been reported to be beneficial for the patients. However, it has some limitations, such as limited approaches and safety issues. OBJECTIVE: The purpose of this study was to investigate the effect of horse simulator riding on back pain, body composition and trunk strength in the patients with CLBP. PARTICIPANTS: Forty-seven men with CLBP (mean age 20.55 +/- 1.38 years) were randomly divided into a control group (n = 23) and a horse simulator riding group (n = 24), and visual analogue scale (VAS), body composition and isokinetic trunk strength were measured after 8 weeks for which subjects in a horse simulator riding group had performed the horse simulator exercise (HSE). RESULTS: Horse simulator exercise significantly reduced pain scores of VAS and enhanced isokinetic torques of trunk at 30 and 90 degrees /s. There were also significantly increased muscle mass and decreased fat mass in horse simulator riding group. CONCLUSION: It can be inferred that HSE may be helpful in relief of back pain and recovery of back function through developing trunk strength and balancing the ratio of trunk flexor/extensor muscles. PMID- 25039931 TI - The sensory profile of children with asthma. AB - AIM: Sensory hypersensitivity is one expression of sensory processing disorders (SPD) and results from the inability to regulate an appropriate response to a sensory input in an adaptive manner. We explored the sensory processing profile of children with asthma, based on reports from parents. METHODS: We studied 86 children between the ages of four and 11 years: 37 diagnosed with asthma and 49 healthy controls. The parents of all participants filled out the Short Sensory Profile (SSP) that measures the child's behavioural reactions to sensory stimuli in daily environments. RESULTS: Sensory processing disorders were more prevalent among children with asthma (F7,71 = 4.16, p = 0.001; eta(2) = 0.29) than among healthy controls and were mainly reflected by hypersensitivity. While about 90% of the healthy children were reported to actively seek sensory stimuli, only 53% of the asthmatic children showed this trend. In the study group, 25.7% of the children's scores reflected abnormal sensory performance, compared with 0% of the controls (chi(2) =21.93; p < 0.001). CONCLUSION: Children with asthma may suffer from SPD. Our finding supports previous reports that suggest that the central nervous system is involved in the pathogenesis of atopic conditions. The sensory profile of children with asthma should be evaluated and treated as required. PMID- 25039932 TI - Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage-like phenotype in vivo. AB - The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4(+) cells in response to anti-CD3 stimulation. FhTeg induces a RELMalpha expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMalpha in FhTeg stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMalpha expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions. PMID- 25039930 TI - Two-year outcomes in initial survivors with acute liver failure: results from a prospective, multicentre study. AB - BACKGROUND & AIMS: The long-term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2-year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG). METHODS: Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed. RESULTS: Two year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous survivors (SS) (89.5%) and 200 non-APAP SS (75.5%) (P < 0.0001). The causes of death were similar in the three groups but the time to death was significantly longer in the LT recipients (P < 0.0001). Independent predictors of 2-year mortality in the APAP group were a high serum phosphate level and patient age (c-statistic = 0.65 (0.54, 0.76)), patient age and days from jaundice to ALF onset in the non-APAP group (c statistic = 0.69 (0.60, 0.78)), and patient age, days from jaundice, and higher coma grade in the LT recipients (c-statistic = 0.74 (0.61, 0.87)). The LT recipients were significantly more likely to be employed and have a higher educational level (P < 0.05). CONCLUSIONS: Two-year outcomes in initial survivors of ALF are generally good but non-APAP patients have a significantly lower survival which may relate to pre-existing medical comorbidities. Spontaneous survivors with APAP overdose experience substantial morbidity during follow-up from ongoing psychiatric and substance abuse issues. PMID- 25039933 TI - Improvement of national blood safety profile: effect of contract fractionation of plasma in resource limited countries, the Moroccan experience. PMID- 25039934 TI - Assessment of probiotic potential and anticancer activity of newly isolated vaginal bacterium Lactobacillus plantarum 5BL. AB - Numerous bacteria in and on its external parts protect the human body from harmful threats. This study aimed to investigate the potential beneficial effects of the vaginal ecosystem microbiota. A type of bacteria was isolated from vaginal secretions of adolescent and young adult women, cultured on an appropriate specific culture medium, and then molecularly identified through 16S rDNA gene sequencing. Results of 16S rDNA sequencing revealed that the isolate belongs to the Lactobacillus plantarum species. The isolated strain exhibited probiotic properties such as low pH and high bile salt concentration tolerance, antibiotic susceptibility and antimicrobial activity against some pathogenic bacteria. The anticancer effects of the strain on human cancer cell lines (cervical, HeLa; gastric, AGS; colon, HT-29; breast, MCF-7) and on a human normal cell line (human umbilical vein endothelial cells [HUVEC]) were investigated. Toxic side effects were assessed by studying apoptosis in the treated cells. The strain exhibited desirable probiotic properties and remarkable anticancer activity against the tested human cancer cell lines (P <= 0.05) with no significant cytotoxic effects on HUVEC normal cells (P <= 0.05). Overall, the isolated strain showed favorable potential as a bioactive therapeutic agent. Therefore, this strain should be subjected to the other required tests to prove its suitability for clinical therapeutic application. PMID- 25039935 TI - Comparison of emergency care delivered to children and young adults with complex chronic conditions between pediatric and general emergency departments. AB - OBJECTIVES: Increasing attention is being paid to medically complex children and young adults, such as those with complex chronic conditions, because they are high consumers of inpatient hospital days and resources. However, little is known about where these children and young adults with complex chronic conditions seek emergency care and if the type of emergency department (ED) influences the likelihood of admission. The authors sought to generate nationwide estimates for ED use by children and young adults with complex chronic conditions and to evaluate if being of the age for transition to adult care significantly affects the site of care and likelihood of hospital admission. METHODS: This was a cross sectional study using discharge data from the 2008 Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality to evaluate visits to either pediatric or general EDs by pediatric-aged patients (17 years old or younger) and transition aged patients (18 to 24 years old) with at least one complex chronic condition. The main outcome measures were hospital admission, ED charges for treat-and release visits, and total charges for admitted patients. RESULTS: In 2008, 69% of visits by pediatric-aged and 92% of visits by transition-aged patients with multiple complex chronic conditions occurred in general EDs. Not surprisingly, pediatric age was the strongest predictor of seeking care in a pediatric ED (odds ratio [OR] = 15.86; 95% confidence interval [CI] = 12.3 to 20.5). Technology dependence (OR = 1.56; 95% CI =1.2 to 2.0) and presence of multiple complex chronic conditions (OR = 1.39; 95% CI = 1.2 to 1.6) were also associated with higher odds of seeking care in a pediatric ED. When controlling for patient and hospital characteristics, type of ED was not a significant predictor of admission (p = 0.87) or total charges (p = 0.26) in either age group. CONCLUSIONS: Overall, this study shows that, despite their complexity, the vast majority of children and young adults with multiple complex chronic conditions are cared for in general EDs. When controlling for patient and hospital characteristics, the admission rate and total charges for hospitalized patients did not differ between pediatric and general EDs. This result highlights the need for increased attention to the care that these medically complex children and young adults receive outside of pediatric-specialty centers. These results also emphasize that any future performance metrics developed to evaluate the quality of emergency care for children and young adults with complex chronic conditions must be applicable to both pediatric and general ED settings. PMID- 25039936 TI - Development of a phylogenetic microarray for comprehensive analysis of ruminal bacterial communities. AB - AIMS: The aim of the study was to develop a microarray dedicated to comprehensive analysis of the diverse rumen bacteria. METHODS AND RESULTS: All the 16S rRNA gene (rrs) sequences of rumen origin were retrieved from the RDP database, and operational taxonomic units (OTUs) were calculated at 97% sequence similarity. A total of 1666 OTU-specific probes were designed and synthesized on microarray slides (referred to as RumenBactArray) in a 6 * 5 k format with each probe being represented in triplicate. The specificity, sensitivity and linear range of detection were determined using pools of rrs clones of known sequences. The RumenBactArray detected as few as approx. 10(6) copies of a target and had a linear detection range of >4 orders of magnitude. The utility of the RumenBactArray was tested using fractionated rumen samples obtained from sheep fed two different diets. More than 300 different OTUs were detected across the four fractionated samples, and differences in bacterial communities were found between the two diets. CONCLUSIONS: This is the first phylochip dedicated to analysis of ruminal bacteria, and it enables comprehensive and semiquantitative analysis of ruminal bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: RumenBactArray can be a robust tool to comparatively analyse ruminal bacteria needed in nutritional studies of ruminant animals. PMID- 25039937 TI - Coronary stent implantation for an acute iatrogenic ascending aortic dissection. PMID- 25039938 TI - Comparison of multi- and single-frequency bioelectrical impedance analysis with dual-energy X-ray absorptiometry for assessment of body composition in post menopausal women: effects of body mass index and accelerometer-determined physical activity. AB - BACKGROUND: Bioelectric impedance analysis (BIA) is commonly used in research to assess body composition. However, studies that validate the accuracy of BIA exclusively in post-menopausal women are lacking. The main purpose of the present study was to evaluate the agreement of multi-frequency (MF)-BIA and single frequency (SF)-BIA with dual-energy X-ray absorptiometry (DXA) in the estimation of fat mass (FM) and fat-free mass (FFM) among post-menopausal women with variation in body mass index (BMI) and physical activity (PA). METHODS: FM and FFM were estimated by BIA and DXA in 146 post-menopausal women with a mean (SD) age of 62.8 (5.2) years. PA was determined by an accelerometer. RESULTS: The mean (SD) difference between MF-BIA and DXA was -1.8 (1.8) kg (P = 0.08) and 1.3 (1.8) kg (P = 0.01) for FM and FFM, respectively. SF-BIA provided a significantly lower estimate of FM [-2.0 (2.2) kg; P = 0.04] and a higher estimate of FFM [1.8 (2.4) kg; P < 0.01] compared to DXA. MF-BIA provided significantly better estimates of FM and FFM with narrower limits of agreement than SF-BIA in obese and insufficiently active subjects. In other BMI and PA groups, both BIA devices showed a similar deviation from DXA. CONCLUSIONS: BIA tends to underestimate FM and overestimate FFM relative to DXA. MF-BIA appears to be a more appropriate method for the assessment of body composition than SF-BIA in post-menopausal woman with BMI >30 kg/m(2) and in those who are insufficiently active. PMID- 25039939 TI - Conventions or foundations? A response to Miles Little's ex nihilo nihil fit? Medicine rests on solid foundations. AB - In this essay, I respond to the critique of my work by Professor Miles Little. PMID- 25039940 TI - Should all patients with acromegaly receive somatostatin analogue therapy before surgery and, if so, for how long? AB - Current guidelines do not recommend the routine use of somatostatin analogue pretreatment prior to surgery in patients with growth hormone-secreting pituitary tumours. In theory, presurgical use of somatostatin analogues should improve metabolic control and reduce soft tissue swelling, leading to improved anaesthetic outcomes. Shrinkage of tumours prior to surgery might also improve surgical remission rates. Hence, this article addresses the question: Should all patients with acromegaly receive a somatostatin analogue prior to surgery? Clinical trials published before December 2013 were reviewed, although literature in this area remains relatively deficient. We conclude: (i) On the basis of limited data available, somatostatin analogue pretreatment does not improve anaesthetic or immediate postoperative outcomes (i.e. hospital stay, rates of surgical complications and postoperative pituitary dysfunction). (ii) Somatostatin analogues should be considered in all patients with growth hormone secreting macroadenomas, including invasive macroadenomas, when the overall surgical remission rate for macroadenomas at the treating centre is below 50%. Four recent RCTs have demonstrated increased rates of surgical remission using such an approach. (iii) When deemed appropriate, patients should be treated with somatostatin analogues for at least 3 months before surgery; there is currently no evidence that treatment beyond 6 months provides any additional benefit. Patients with minimally invasive macroadenomas are those most likely to benefit in terms of improved surgical remission. PMID- 25039941 TI - Reliability of event-related EEG functional connectivity during visual entrainment: magnitude squared coherence and phase synchrony estimates. AB - There is an increasing trend towards using noninvasive electroencephalography (EEG) to quantify functional brain connectivity. However, little is known about the psychometrics of commonly used functional connectivity indices. We examined the internal consistency of two different connectivity metrics: magnitude squared coherence and phase synchrony. EEG was recorded during visual entrainment to elicit a strong oscillatory component of known frequency. We found acceptable to good split-half reliability for the connectivity metrics when computing all possible pairwise interactions and after selecting an a priori seed reference. We also compared reliability estimates when using average referenced sensor versus reference independent current source density EEG data. Additional considerations were given to determining how reliability was influenced by factors including trial number, signal-to-noise ratio, and frequency content. PMID- 25039942 TI - Low serum level of 1,25(OH)2 D is associated with chronic periodontitis. AB - BACKGROUND AND OBJECTIVES: Vitamin D has been studied primarily for its involvement in calcium and phosphate absorption and bone metabolism. The active form of vitamin D-1,25(OH)2 D-has also been investigated for its immune modulatory properties. We explored associations between serum levels of 25(OH)D and 1,25(OH)2 D and periodontal health. SUBJECTS AND METHODS: This case-control study included 55 subjects with chronic periodontitis (cases) and 30 periodontally healthy subjects (controls). Their serum levels of 25(OH)D, 1,25(OH)2 D, ultrasensitive C-reactive protein and high-density lipoprotein cholesterol were determined. Associations between vitamin D and periodontal health status were studied using logistic regression analysis. RESULTS: A statistically significant association was found between serum 1,25(OH)2 D level and periodontal health status; in that subjects with a low 1,25(OH)2 D were more likely to belong to the periodontitis group (OR = 0.97, 95% CI = 0.95-1.00). There was practically no association between 25(OH)D level and periodontal health status. CONCLUSION: In this case-control study low serum 1,25(OH)2 D level appeared to be associated with periodontitis, which was in line with the previously reported associations between serum 1,25(OH)2 D levels and other inflammatory diseases. Whether this association is causal in nature, remains to be confirmed in future studies. PMID- 25039944 TI - Anti-quorum sensing activity of selected sponge extracts: a case study of Pseudomonas aeruginosa. AB - The anti-quorum sensing activities towards the bacterium Pseudomonas aeruginosa PA01 (pyocyanin production, biofilm formation and twitching and flagella motility) of two crude extracts (methanol and acetone) of the freshwater sponge Ochridaspongia rotunda (Arndt, 1937) were evaluated in vitro for the first time. Both extracts demonstrated P. aeruginosa pyocyanin inhibitory activity, reducing its production for 49.90% and 42.44%, respectively. In addition, they both showed higher anti-biofilm activity (48.29% and 53.99%, respectively) than ampicillin (30.84%). Finally, O. rotunda extracts effectively reduced twitching and flagella motility of P. aeruginosa. Taken all together, these results suggest that endemic sponge species from the oldest lake in Europe may offer novel bioactive natural products with promising medicinal potential towards P. aeruginosa infections. PMID- 25039943 TI - Protective role of the RpoE (sigmaE) and Cpx envelope stress responses against gentamicin killing of nongrowing Escherichia coli incubated under aerobic, phosphate starvation conditions. AB - The viability of Escherichia coli starved of nitrogen (N) or phosphorus (P) decreased by up to seven orders of magnitude during prolonged incubation under aerobic conditions when exposed to high levels of the antibiotic gentamicin, whereas viability of cells starved of carbon (C) was barely affected. However, the initial rate of killing was lower for P-starved cells than for N-starved cells. The transient resistance of P-starved cells was partially dependent upon the expression of the phosphate (Pho) and Cpx responses. Constitutive activity of the Cpx and RpoE (sigma(E)) envelope stress regulons increased the resistance of P- and N-starved cells. The level of expression of the RpoE regulon was fourfold higher in P-starved cells than in N-starved cell at the time gentamicin was added. Gentamicin killing of nongrowing cells may thus require ongoing aerobic glucose metabolism and faulty synthesis of structural membrane proteins. However, membrane protein damage induced by gentamicin can be eliminated or repaired by RpoE- and Cpx-dependent mechanisms pre-emptively induced in P-starved cells, which reveals a novel mechanism of resistance to gentamicin that is active in certain circumstances. PMID- 25039945 TI - Analysis of patient and technical factors associated with midurethral sling mesh exposure and perforation. AB - OBJECTIVES: To evaluate the technical and patient characteristics associated with the development of mesh perforation and exposure in patients after midurethral sling surgeries. METHODS: After a retrospective review of referred patients, the risk of mesh perforation of the urinary tract over exposure in the vagina was analyzed with multivariate logistic regression, adjusting for the possible predictors of age, body mass index, smoking status at the time of mesh placement, presence of diabetes, type of sling placed, type of surgeon and trocar injury at the time of mesh placement. RESULTS: A total of 77 women were identified, 27 with mesh perforation and 50 with mesh exposure. The patients' average body mass index was 29.2, and 13% were diabetic. Nine (33%) patients in the perforation group and two (4%) patients in the exposure group had evidence of trocar injury to the bladder or urethra at the time of mesh placement (P < 0.001). After multivariate logistic regression analysis, trocar injury (odds ratio 25.90, 95% confidence interval 2.84-236.58, P = 0.004) and diabetes (odds ratio 9.90, 95% confidence interval 1.1.25-78.64, P = 0.03) were associated with an increased risk of mesh perforation. Increased body mass index (odds ratio 0.88, 95% confidence interval 0.77-0.99, P = 0.05) was associated with a decreased risk of mesh perforation. Finally, postoperative hematomas and blood transfusions occurred more commonly in the mesh perforation group (15% vs 0%, P = 0.01). CONCLUSIONS: Trocar injury, diabetes and bleeding complications at the time of surgery are associated with higher risk of mesh perforation in patients undergoing midurethral sling placement. PMID- 25039946 TI - Measuring maternal responsiveness in a community-based sample of slow-to-talk toddlers: a cross-sectional study. AB - BACKGROUND: Maternal responsiveness is important in early language development, but its measurement by direct observation has to date been unrealistic in community settings because of training and time constraints. We report on the development and cross-sectional comparison of a global rating of maternal responsiveness against a detailed measure of responsiveness at age 24 months. METHODS: The community-based sample comprised 246 toddlers and their mothers, identified as being slow-to-talk at age 18 months within the Let's Learn Language population-based randomized controlled trial. At age 24 months, mother-child dyads were videotaped during 15 minutes of free-play and children undertook a standardized language assessment. Videos were blindly rated on both the new global measure, comprising a single rating of responsiveness on a five-point Likert scale, and a detailed rating of responsiveness known to predict language outcomes, comprising a sum of specific maternal responsive behaviours. RESULTS: The global rating scale required relatively little training and ratings could be conducted in real time. The global and detailed ratings of maternal responsiveness showed moderate correlation (r = 0.44; P < 0.001). Small positive correlations were found between the global rating and expressive (r = 0.23; P < 0.001), receptive (r = 0.28, P < 0.001) and total language (r = 0.28; P < 0.001) at age 24 months. CONCLUSION: The global rating scale was efficient and moderately effective as a measure of maternal responsiveness. It is possible that, combined with other risk measures including concurrent language skills, it could strengthen prediction of which children will and will not go on to experience lasting language difficulties. PMID- 25039947 TI - Should supraglottic airway devices be used by lifeguards at all? PMID- 25039948 TI - Supraglottic airway use by lifeguards. PMID- 25039949 TI - A reply. PMID- 25039950 TI - A reply. PMID- 25039951 TI - Desflurane vapour discolouration. PMID- 25039952 TI - Epidural anaesthesia and analgesia for liver resection. PMID- 25039953 TI - Other potential uses of serratus anterior plane block. PMID- 25039954 TI - Is 10 litres of 4% dextrose in 0.18% saline NICE? PMID- 25039955 TI - A reply. PMID- 25039956 TI - A reply. PMID- 25039957 TI - Common sense medicine and cerebrospinal lavage. PMID- 25039958 TI - Infant Airtraq for adult bougie placement. PMID- 25039959 TI - Opening Portex EpifuseTM connectors. PMID- 25039960 TI - Anaesthesia induction--kids play. PMID- 25039962 TI - Stereotypic movement disorder: a case for Procrustes? PMID- 25039961 TI - Treatment mechanism in the MRC preschool autism communication trial: implications for study design and parent-focussed therapy for children. AB - BACKGROUND: The PACT randomised-controlled trial evaluated a parent-mediated communication-focused treatment for children with autism, intended to reduce symptom severity as measured by a modified Autism Diagnostic Observation Schedule Generic (ADOS-G) algorithm score. The therapy targeted parental behaviour, with no direct interaction between therapist and child. While nonsignificant group differences were found on ADOS-G score, significant group differences were found for both parent and child intermediate outcomes. This study aimed to better understand the mechanism by which the PACT treatment influenced changes in child behaviour though the targeted parent behaviour. METHODS: Mediation analysis was used to assess the direct and indirect effects of treatment via parent behaviour on child behaviour and via child behaviour on ADOS-G score. Alternative mediation was explored to study whether the treatment effect acted as hypothesised or via another plausible pathway. Mediation models typically assume no unobserved confounding between mediator and outcome and no measurement error in the mediator. We show how to better exploit the information often available within a trial to begin to address these issues, examining scope for instrumental variable and measurement error models. RESULTS: Estimates of mediation changed substantially when account was taken of the confounder effects of the baseline value of the mediator and of measurement error. Our best estimates that accounted for both suggested that the treatment effect on the ADOS-G score was very substantially mediated by parent synchrony and child initiations. CONCLUSIONS: The results highlighted the value of repeated measurement of mediators during trials. The theoretical model underlying the PACT treatment was supported. However, the substantial fall-off in treatment effect highlighted both the need for additional data and for additional target behaviours for therapy. PMID- 25039963 TI - Experimental evolution for generalists and specialists reveals multivariate genetic constraints on thermal reaction norms. AB - Theory predicts the emergence of generalists in variable environments and antagonistic pleiotropy to favour specialists in constant environments, but empirical data seldom support such generalist-specialist trade-offs. We selected for generalists and specialists in the dung fly Sepsis punctum (Diptera: Sepsidae) under conditions that we predicted would reveal antagonistic pleiotropy and multivariate trade-offs underlying thermal reaction norms for juvenile development. We performed replicated laboratory evolution using four treatments: adaptation at a hot (31 degrees C) or a cold (15 degrees C) temperature, or under regimes fluctuating between these temperatures, either within or between generations. After 20 generations, we assessed parental effects and genetic responses of thermal reaction norms for three correlated life-history traits: size at maturity, juvenile growth rate and juvenile survival. We find evidence for antagonistic pleiotropy for performance at hot and cold temperatures, and a temperature-mediated trade-off between juvenile survival and size at maturity, suggesting that trade-offs associated with environmental tolerance can arise via intensified evolutionary compromises between genetically correlated traits. However, despite this antagonistic pleiotropy, we found no support for the evolution of increased thermal tolerance breadth at the expense of reduced maximal performance, suggesting low genetic variance in the generalist-specialist dimension. PMID- 25039964 TI - Graft-transmissible movement of inverted-repeat-induced siRNA signals into flowers. AB - In plants, small interfering RNAs (siRNA) and microRNAs move to distant tissues where they control numerous developmental and physiological processes such as morphogenesis and stress responses. Grafting techniques and transient expression systems have been employed to show that sequence-specific siRNAs with a size of 21-24 nucleotides traffic to distant organs. We used inverted-repeat constructs producing siRNA targeting the meiosis factor DISRUPTED MEIOTIC cDNA 1 (DMC1) and GFP to test whether silencing signals move into meiotically active tissues. In grafted Nicotiana tabacum, a transgenic DMC1 siRNA signal made in source tissues preferably entered the anthers formed in the first flowers. Here, the DMC1 siRNA interfered with meiotic progression and, consequently, the flowers were at least partially sterile. In agro-infiltrated N. benthamiana plants, a GFP siRNA signal produced in leaves was allocated and active in most flower tissues including anthers. In hypocotyl-grafted Arabidopsis thaliana plants, the DMC1 silencing signal consistently appeared in leaves, petioles, and stem, and only a small number of plants displayed DMC1 siRNA signals in flowers. In all three tested plant species the systemic silencing signal penetrated male sporogenic tissues suggesting that plants harbour an endogenous long-distance small RNA transport pathway facilitating siRNA signalling into meiotically active cells. PMID- 25039965 TI - A systematic review of enhanced recovery care after colorectal surgery in elderly patients. AB - AIM: Enhanced recovery after surgery (ERAS) can decrease complications and reduces hospital stay. Less certain is whether elderly patients can fully adhere to and benefit from ERAS. We aimed to determine the safety, feasibility and efficacy of enhanced recovery after colorectal surgery in patients aged >= 65 years old. METHOD: A systematic search of Medline, EMBASE and Cochrane was performed to identify (i) studies comparing elderly patients managed with ERAS vs traditional care, (ii) cohort studies of ERAS with results of elderly vs younger patients and (iii) any case series of ERAS in elderly patients. End-points of interest were length of hospital stay, complications, mortality, readmission and re-operation, and ERAS protocol adherence. RESULTS: Sixteen studies were included. Two randomized controlled trials demonstrated shorter hospital stay in elderly patients with ERAS compared with elderly patients with non-ERAS (9 vs 13.2 days, P < 0.001; 5.5 vs 7 days, P < 0.0001). Fewer complications occurred with ERAS in both randomized controlled trials (27.4% vs 58.6%, P < 0.0001; 5% vs 21.1%, P = 0.045). The majority of observational studies did not show differences in outcome between elderly and younger patients in terms of hospital stay, morbidity or mortality. Inconsistent findings between cohort studies may reflect the disparities in ERAS protocol definitions or differences in study populations. CONCLUSION: ERAS can be safely applied to elderly patients to reduce complications and shorten length of hospital stay. Further studies are required to assess whether elderly patients are able to adhere to, and benefit from, ERAS protocols to the same extent as younger patients. PMID- 25039966 TI - Diarrhoea in slum children: observation from a large diarrhoeal disease hospital in Dhaka, Bangladesh. AB - OBJECTIVES: To determine and compare socio-demographic, nutritional and clinical characteristics of children under five with diarrhoea living in slums with those of children who do not live in slums of Dhaka, Bangladesh. METHODS: From 1993 to 2012, a total of 28 948 under fives children with diarrhoea attended the Dhaka Hospital of icddr,b. Data were extracted from the hospital-based Diarrhoea Disease Surveillance System, which comprised 17 548 under fives children from slum and non-slum areas of the city. RESULTS: Maternal illiteracy [aOR = 1.57; 95% confidence interval (1.36, 1.81), P-value <0.001], paternal illiteracy [1.37 (1.21, 1.56) <0.001], mother's employment [1.59 (1.37, 1.85) <0.001], consumption of untreated water [2.73 (2.26, 3.30) <0.001], use of non-sanitary toilets [3.48 (3.09, 3.93) <0.001], 1st wealth quintile background [3.32 (2.88, 3.84) <0.001], presence of fever [1.14 (1.00, 1.29) 0.047], some or severe dehydration [1.21 (1.06, 1.40) 0.007], stunting [1.14 (1.01, 1.29) 0.030] and infection with Vibrio cholerae [1.21 (1.01, 1.45) 0.039] were significantly associated with slum dwelling children after controlling for co-variates. Measles immunisation [0.52 (0.47, 0.59) P < 0.001] and vitamin A supplementation rates [0.36 (0.31, 0.41) P < 0.001] amongst children 12-59 months were lower for slum dwellers than other children in univarate analysis only. CONCLUSIONS: Slum-dwelling children are more malnourished, have lower immunisation rates (measles vaccination and vitamin A supplementation) and higher rates of measles, are more susceptible to diarrhoeal illness due to V. cholerae and suffer from severe dehydration more often than children from non-slum areas. Improved health and nutrition strategies should give priority to children living in urban slums. PMID- 25039967 TI - Pediatric dermatology: past, present, and future. AB - Up to 30% percent of pediatric primary care visits include a skin-related problem, and referrals are hampered by appointment wait times among the longest of any pediatric subspecialty. Despite the clear demand for pediatric dermatologists, there has been a long-standing shortage of providers, leaving dermatology as one of the most underserved pediatric subspecialties. Another consequence of the workforce shortage is the limited opportunity for pediatric dermatology training for residents and postgraduate general pediatricians and dermatologists. This review includes the evolution of the subspecialty from conception through the present, along with obstacles to workforce expansion and potential solutions to improve access to care for children with skin diseases. PMID- 25039968 TI - Organic and mineral imprints in fossil photosynthetic mats of an East Antarctic lake. AB - Lacustrine microbial mats in Antarctic ice-free oases are considered modern analogues of early microbial ecosystems as their primary production is generally dominated by cyanobacteria, the heterotrophic food chain typically truncated due to extreme environmental conditions, and they are geographically isolated. To better understand early fossilization and mineralization processes in this context, we studied the microstructure and chemistry of organo-mineral associations in a suite of sediments 50-4530 cal. years old from a lake in Skarvsnes, Lutzow Holm Bay, East Antarctica. First, we report an exceptional preservation of fossil autotrophs and their biomolecules on millennial timescales. The pigment scytonemin is preserved inside cyanobacterial sheaths. As non-pigmented sheaths are also preserved, scytonemin likely played little role in the preservation of sheath polysaccharides, which have been cross-linked by ether bonds. Coccoids preserved thylakoids and autofluorescence of pigments such as carotenoids. This exceptional preservation of autotrophs in the fossil mats argues for limited biodegradation during and after deposition. Moreover, cell shaped aggregates preserved sulfur-rich nanoglobules, supporting fossilization of instable intracellular byproducts of chemotrophic or phototrophic S-oxidizers. Second, we report a diversity of micro- to nanostructured CaCO3 precipitates intimately associated with extracellular polymeric substances, cyanobacteria, and/or other prokaryotes. Micro-peloids Type 1 display features that distinguish them from known carbonates crystallized in inorganic conditions: (i) Type 1A are often filled with globular nanocarbonates and/or surrounded by a fibrous fringe, (ii) Type 1B are empty and display ovoid to wrinkled fringes of nanocrystallites that can be radially oriented (fibrous or triangular) or multilayered, and (iii) all show small-size variations. Type 2 rounded carbonates 1-2 MUm in diameter occurring inside autofluorescent spheres interpreted as coccoidal bacteria may represent fossils of intracellular calcification. These organo-mineral associations support organically driven nanocarbonate crystallization and stabilization, hence providing potential markers for microbial calcification in ancient rocks. PMID- 25039969 TI - SIRPB1 copy-number polymorphism as candidate quantitative trait locus for impulsive-disinhibited personality. AB - Impulsive-disinhibited personality (IDP) is a behavioral trait mainly characterized by seeking immediate gratification at the expense of more enduring or long-term gains. This trait has a major role in the development of several disinhibitory behaviors and syndromes, including psychopathy, attention-deficit and hyperactivity disorder, cluster-B personality disorders, criminality and alcoholism. Available data consistently support a strong heritable component, accounting for 30-60% of the observed variance in personality traits. A genome wide analysis of copy-number variants was designed to identify novel genetic pathways associated with the IDP trait, using a series of 261 male participants with maximized opposite IDP scores. Quantitative trait locus analysis of candidate copy-number variants (CNVs) was conducted across the entire IDP continuum. Functional effects of associated variants were evaluated in zebrafish embryos. A common CNV mapping to the immune-related gene SIRPB1 was significantly associated with IDP scores in a dose-dependent manner (beta=-0.172, P<0.017). Expression quantitative trait locus analysis of the critical region revealed higher SIRPB1 mRNA levels associated with the haplotype containing the deleted allele (P<0.0007). Epigenetic marks highlighted the presence of two potential insulators within the deleted region, confirmed by functional assays in zebrafish embryos, which suggests that SIRPB1 expression rates are affected by the presence/absence of the insulator regions. Upregulation of SIRPB1 has been described in prefrontal cortex of patients with schizophrenia, providing a link between SIRPB1 and diseases involving disinhibition and failure to control impulsivity. We propose SIRPB1 as a novel candidate gene to account for phenotypic differences observed in the IDP trait. PMID- 25039970 TI - Patient-centred care: barriers and opportunities in the dental surgery. AB - OBJECTIVES: This paper explores the practice of patient-centred care (PCC) within dentistry. The aim of this research was to explore the barriers and opportunities dentists face in practicing PCC. METHODS: The results of N = 20 thematically analysed, in-depth semi-structured qualitative interviews with a range of dentists working across clinical and teaching positions within a large UK dental school are presented. RESULTS: PCC was generally considered a positive, to be embraced concept which dentists believe they practice daily in the absence of any formal training. PCC presented dentists with opportunities to deliver treatment to highly compliant patients. The main barriers revolved around patients (e.g. disengaged or overly inquisitive) and practice factors (e.g. time and funding). CONCLUSIONS: PCC is a concept that is generally seen as important in the dental surgery, presenting dentists with opportunities for compliance-enhanced practice. Significant work is needed if dentists are going to be supported in overcoming self-identified barriers to their delivery of PCC as per UK General Dental Council guidelines. PMID- 25039971 TI - Mohs micrographic surgery in the U.K.: are we discriminating against people with blood-borne infections? PMID- 25039972 TI - Foreign body giant cell reaction to tarSysTM xenograft. AB - OBJECTIVE: A foreign body giant cell (FBGC) reaction may occur in response to implanted xenogenic biomaterials. Here we report a FBGC reaction to the recently introduced xenogenic biomaterial, tarSysTM, used for correction of lower eyelid retraction. METHOD: A retrospective chart review of two patients with FBGC reaction to tarSysTM implantation was performed. RESULTS: Two patients (aged 51, 58 year) with lower eyelid retraction underwent surgical implantation of tarSysTM spacer grafts for correction. Both patients subsequently experienced chronic swelling requiring graft removal. Examination of the specimens showed a palisading FBGC reaction around acellular pink fibrillar material. CONCLUSION: A FBGC reaction may follow implantation of the tarSysTM xenograft. PMID- 25039973 TI - Re-examining the theory about the collectivity of changes in alcohol consumption. PMID- 25039974 TI - Impact of race and sex on pain management by medical trainees: a mixed methods pilot study of decision making and awareness of influence. AB - OBJECTIVE: Previous research suggests female and black patients receive less optimal treatment for their chronic pain compared with male and white patients. Provider-related factors are hypothesized to contribute to unequal treatment, but these factors have not been examined extensively. This mixed methods investigation examined the influence of patients' demographic characteristics on providers' treatment decisions and providers' awareness of these influences on their treatment decisions. METHODS: Twenty medical trainees made treatment decisions (opioid, antidepressant, physical therapy) for 16 virtual patients with chronic low back pain; patient sex and race were manipulated across patients. Participants then indicated from a provided list the factors that influenced their treatment decisions, including patient demographics. Finally, individual interviews were conducted to discuss the role of patient demographics on providers' clinical decisions. RESULTS: Individual regression analyses indicated that 30% of participants were reliably influenced by patient sex and 15% by patient race when making their decisions (P < 0.05 or P < 0.10). Group analyses indicated that white patients received higher antidepressant recommendations, on average, than black patients (P < 0.05). Half of the medical trainees demonstrated awareness of the influence of demographic characteristics on their decision making. Participants, regardless of whether they were influenced by patients' demographics, discussed themes related to patient sex and race; however, participants' discussion of patient demographics in the interviews did not always align with their online study results. CONCLUSIONS: These findings suggest there is a considerable variability in the extent to which medical trainees are influenced by patient demographics and their awareness of these decision making influences. PMID- 25039975 TI - Coffee and tea consumption in pregnancy not associated with gestational diabetes mellitus. PMID- 25039976 TI - Assistance of the iron porphyrin ligands to the binding interaction between the Fe center and small molecules in solution. AB - Solute-solvent electronic structure interactions of iron porphyrin at very low concentration in dichloromethane (CH2Cl2) liquid solution are reported. Two iron porphyrin complexes are investigated here-iron octaethylporphyrin chloride (FeOEP Cl) and iron tetraphenylporphyrin chloride (FeTPP-Cl)-using X-ray absorption and emission spectroscopy at the Fe L2,3 edge, and spectra are interpreted with the help of density functional theory/restricted open-shell configuration interaction singles (DFT/ROCIS) calculations. It is argued that the Fe center of FeOEP-Cl is more capable of binding small solvent molecules, exemplified here for Cl2CH2, than FeTPP-Cl in solution. The proposed binding mechanism is through the assistance of the dipole interaction between the porphyrin-ligand system and the solvent molecule, in a situation where the ligand structure and arrangement maximize the binding interactions. Our studies demonstrate that even small ligands, depending on their structure and arrangement, can have considerable effects on porphyrin's metal center chemistry in liquid solution. PMID- 25039977 TI - The role of wounding therapies in preventing squamous cell carcinoma. PMID- 25039978 TI - Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression. AB - BACKGROUND: Little is known regarding patient characteristics that influence the speed of reflux oesophagitis (RO) healing. AIM: To investigate patient characteristics that may influence RO healing rates. METHODS: A post hoc analysis of clinical trial data for potent acid suppression treatment of RO (esomeprazole or AZD0865) was conducted. Group A underwent endoscopy at baseline, week 2 and 4, and group B at baseline, week 4 and 8. Group A patients were sub-grouped as 'rapid' (healed at 2 weeks) or unhealed at 2 weeks. Group B patients were sub grouped as 'slow' (healed at 8 weeks, not at 4 weeks) or 'refractory' (not healed at 8 weeks). Logistic regression analysis was performed only for comparisons within group A. RESULTS: At 2, 4 and 8 weeks, RO had healed in 68%, 65% and 61% of patients unhealed at previous endoscopy, respectively. Low-grade [vs. high grade (C or D)] RO was the only independent predictor of rapid healing in group A after logistic regression analysis. Significantly more rapid healers had low grade RO (A or B) at baseline than patients with refractory RO (84% vs. 49%; P < 0.001), and significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63%; P = 0.039). CONCLUSIONS: Low- (vs. high ) grade RO determines the most rapid benefit from acid suppression. Roughly two thirds of patients healed with each time increment of potent acid suppression therapy. This suggests that some unhealed patients may still heal with continued therapy and that truly refractory RO is rare. (ClinicalTrials.gov: NCT00206245). PMID- 25039979 TI - Chromosomal variation segregates within incipient species and correlates with reproductive isolation. AB - Reproductive isolation is a critical step in the process of speciation. Among the most important factors driving reproductive isolation are genetic incompatibilities. Whether these incompatibilities are already present before extrinsic factors prevent gene flow between incipient species remains largely unresolved in natural systems. This question is particularly challenging because it requires that we catch speciating populations in the act before they reach the full-fledged species status. We measured the extent of intrinsic postzygotic isolation within and between phenotypically and genetically divergent lineages of the wild yeast Saccharomyces paradoxus that have partially overlapping geographical distributions. We find that hybrid viability between lineages progressively decreases with genetic divergence. A large proportion of postzygotic inviability within lineages is associated with chromosomal rearrangements, suggesting that chromosomal differences substantially contribute to the early steps of reproductive isolation within lineages before reaching fixation. Our observations show that polymorphic intrinsic factors may segregate within incipient species before they contribute to their full reproductive isolation and highlight the role of chromosomal rearrangements in speciation. We propose different hypotheses based on adaptation, biogeographical events and life history evolution that could explain these observations. PMID- 25039980 TI - Identification, management and outcome of postoperative hemoperitoneum in 23 horses after emergency exploratory celiotomy for gastrointestinal disease. AB - OBJECTIVE: To investigate postoperative hemoperitoneum in a population of horses that had surgery for colic. STUDY DESIGN: Retrospective case series. ANIMALS: Horses (n = 23). METHODS: Preoperative, intraoperative, and postoperative information was obtained from medical records (1985-2012) of horses with postoperative hemoperitoneum after emergency exploratory celiotomy. Pre-existing hemoperitoneum during surgery and nonsurgical hemoperitoneum were excluded. RESULTS: Of 4520 horses that had emergency exploratory celiotomy for gastrointestinal disease, 23 horses met inclusion criteria; an incidence of 0.5%. Horse signalment approximated the colic population, although Thoroughbreds were significantly overrepresented. Hemoperitoneum was significantly associated with intestinal resection. Postoperative hemoperitoneum was recognized a mean (+/- SD) of 1.0 +/- 0.7 days after surgery and associated with tachycardia, decreasing hematocrit, incisional drainage, or ultrasonographic identification of swirling, echogenic abdominal fluid. Primary treatments included intravenous fluid therapy (n = 23), colloid support (20), blood transfusion (13), and antifibrinolytic agents (11). Fifteen horses (65%) survived to discharge, which was associated with admission lactate and days of hospitalization. CONCLUSIONS: Postoperative hemoperitoneum is a rare complication of exploratory celiotomy in horses that should be considered when there are signs of abdominal discomfort and declining hematocrit in the early postoperative period. Prognosis is guarded because of potential sequelae of septic peritonitis and adhesion formation. PMID- 25039981 TI - Frequent premature ventricular complex is associated with left atrial enlargement in patients with normal left ventricular ejection fraction. AB - BACKGROUND: Premature ventricular complex (PVC) has been regarded as benign; however, when frequent, the arrhythmia can induce left ventricular (LV) systolic dysfunction. Meanwhile, the influence of PVCs on cardiac structural remodeling and functional change before occurrence of overt systolic heart failure has not been fully described. In this study, we attempted to identify early cardiac structural/functional manifestations of frequent PVCs in patients with normal LV systolic function. METHODS: A total of 146 patients (age: 55 +/- 15 years, 48 males) with frequent PVCs observed on 24-hour Holter monitoring (>10/h) and normal LV ejection fraction (LV EF >= 55% on echocardiography) were enrolled. Clinical characteristics and echocardiographic parameters of the patients were compared with those of an age-/sex-matched control group (n = 292, age: 55 +/- 15 years, 96 males). RESULTS: Patients with frequent PVCs had significantly larger left atrial volume index (LAVI [28 +/- 9 mL/m(2) vs. 24 +/- 7 mL/m(2) ]), along with larger LV end-diastolic dimension (49.4 +/- 4.4 mm vs. 48.5 +/- 3.9 mm), lower LV EF (63 +/- 7% vs. 66 +/- 6%), and lower peak systolic mitral annular velocity (7 +/- 2 cm/s vs. 8 +/- 2 cm/s; P < 0.05 for all), whereas other clinical characteristics were similar. In particular, in patients with frequent PVCs, LAVI showed linear correlation with PVC burden (R = 0.30, P < 0.001), and, in a multiple regression model, PVC burden independently estimated LAVI, even after controlling for age, sex, comorbidities, and systolic function (beta = 0.309, P < 0.001). CONCLUSION: Frequent PVC is associated with LA enlargement in patients with normal LV EF. Atrial anatomical remodeling may precede LV geometry change and systolic dysfunction in patients with frequent PVCs. PMID- 25039982 TI - Amplification and overexpression of CMET is a common event in brain metastases of non-small cell lung cancer. AB - BACKGROUND: CMET represents an emerging therapy target for monoclonal antibodies and tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). METHODS: We investigated CMET gene amplification status by fluorescence in-situ hybridization (FISH) and CMET protein expression by immunohistochemistry in a large series of 209 NSCLC brain metastases (BM; 165 adenocarcinoma, 20 squamous cell carcinoma, 11 adenosquamous carcinomas, 11 large cell carcinomas and two large cell neuroendocrine carcinomas) and correlated our results to clinic-pathological parameters and molecular data from previous studies. RESULTS: We found CMET gene amplification in 36/167 (21.6%) and CMET protein expression in 87/196 (44.4%) of evaluable BM. There was a strong correlation between the presence of CMET gene amplification and CMET protein expression (P < 0.001, chi-square test). Furthermore, presence of CMET amplification correlated positively with presence of ALK amplifications (P = 0.039, chi-square test) and high HIF1 alpha index (P = 0.013, Mann-Whitney U-test). Neither CMET expression nor CMET gene amplification status correlated with patient outcome parameters or known prognostic factors. CONCLUSIONS: CMET overexpression and CMET amplification are commonly found in NSCLC BM and may represent a promising therapeutic target. PMID- 25039983 TI - Titanium mesh in the reconstruction of a malar defect: a case report. AB - BACKGROUND: Increasing rates of non-melanoma skin cancer support the use of prosthetic materials for the closure of post-surgical defects with cartilage or bone involvement. The use of allografts, especially titanium, is well established in maxillofacial procedures but is uncommon in dermatologic surgery. METHODS: A 92-year-old man presented with a basal cell carcinoma measuring 2*3 cm on the right cheek. Computed tomography showed infiltration of the anterior maxillary sinus wall. The tumor was excised under general anesthesia. The final defect comprised skin, muscle, the central portion of the maxillary bone and part of the maxillary sinus mucous. The defect was closed with titanium mesh and covered with a rotation flap from the right cheek. The secondary defect created by the preauricular rotation was closed with a free skin graft from the supraclavicular area. RESULTS: The use of titanium mesh enabled satisfactory esthetic and functional results to be achieved safely and quickly. CONCLUSIONS: Titanium mesh facilitates the repair of large defects and avoids the second intervention and increased risk for infection associated with bone grafting. Reconstruction with titanium mesh is considered a valuable technique in post-trauma fractures and post-oncologic defects but remains underused in dermatologic surgery. The present experience supports its use as a reliable option in bone replacement. PMID- 25039984 TI - Defective glucagon secretion during hypoglycemia after intrahepatic but not nonhepatic islet autotransplantation. AB - Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from nondiabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus nonhepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 +/- 6, pg/mL, mean +/- SE, n = 9, p = ns; symptom score = 1 +/- 1, p = ns). When islets were transplanted in both intrahepatic + nonhepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H + NH: glucagon increment = 54 +/- 14, n = 5; symptom score = 7 +/- 3; control glucagon increment = 67 +/- 15, n = 5; symptom score = 8 +/- 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 +/- 8, n = 7). Transplantation of a portion of the islets into a nonhepatic site should be seriously considered in TP/IAT to avoid posttransplant abnormalities in glucagon and symptom responses to hypoglycemia. PMID- 25039985 TI - The intrinsically disordered structural platform of the plant defence hub protein RPM1-interacting protein 4 provides insights into its mode of action in the host pathogen interface and evolution of the nitrate-induced domain protein family. AB - Arabidopsis thaliana (At) RPM1-interacting protein 4 (RIN4), targeted by many defence-suppressing bacterial type III effectors and monitored by several resistance proteins, regulates plant immune responses to pathogen-associated molecular patterns and type III effectors. Little is known about the overall protein structure of AtRIN4, especially in its unbound form, and the relevance of structure to its diverse biological functions. AtRIN4 contains two nitrate induced (NOI) domains and is a member of the NOI family. Using experimental and bioinformatic approaches, we demonstrate that the unbound AtRIN4 is intrinsically disordered under physiological conditions. The intrinsically disordered polypeptide chain of AtRIN4 is interspersed with molecular recognition features (MoRFs) and anchor-identified long-binding regions, potentially allowing it to undergo disorder-to-order transitions upon binding to partner(s). A poly-l proline II structure, often responsible for protein recognition, is also identified in AtRIN4. By performing bioinformatics analyses on RIN4 homologues from different plant species and the NOI proteins from Arabidopsis, we infer the conservation of intrinsic disorder, MoRFs and long-binding regions of AtRIN4 in other plant species and the NOI family. Intrinsic disorder and MoRFs could provide RIN4 proteins with the binding promiscuity and plasticity required to act as hubs in a pivotal position within plant defence signalling cascades. PMID- 25039986 TI - Expression of tumour necrosis factor-alpha and its receptors in Hodgkin lymphoma. PMID- 25039987 TI - Sensory characterization of young South American red wines classified by varietal and origin. AB - Typicality is the set of sensory characteristics that identify a distinctive type of wine. Thus, the aim of this research was to identify the sensory characteristics that contribute to define typicality of young South American red wines based on their varietal and origin, and to evaluate the effect of the vintage on this identification. To achieve this objective, visual appearance, odor, and taste of 138 wines from 2 vintages were submitted to a sensory evaluation using a descriptive analysis complemented with the frequency of citation method, performed by wine experts. The intensity of 17 odor and taste attributes was evaluated using a 5 points rating structured scale. The panel performance evaluation demonstrated its high level of expertise and reproducibility. The wines were separated into 3 clusters by multivariate analyses. Cluster 1 was primarily composed of Carmenere, Malbec, and Syrah wines from Chile. Cluster 2 was predominantly composed of Tannat wines from Uruguay and Brazil, while Cluster 3 contained a higher proportion of Malbec and Merlot wines from Argentina and Brazil. Cabernet Sauvignon was equally distributed into all clusters. Wine experts were able to identify the wines according to their varietal and origin, suggesting that there is typicality in young South American red wines. The combination of descriptive analysis with the frequency of citation was useful in characterizing most of the wines, but the typicality perceived by the panelists was not achieved by multivariate analysis. Vintage did not alter the sensory characterization of the wines, and this result could be due the new viticulture or oenological practices used by the winemakers to compensate the environmental variation. PMID- 25039988 TI - Morphology and phylogeny of Thelohanellus marginatus n. sp. (Myxozoa: Myxosporea), a parasite infecting the gills of the fish Hypophthalmus marginatus (Teleostei: Pimelodidae) in the Amazon River. AB - Thelohanellus marginatus n. sp., a new myxosporean parasite infecting the primary gill filaments of the teleost fish Hypophthalmus marginatus (Pimelodidae) in the Amazon River, is described on the basis of microscopic and molecular procedures. The parasite forms whitish and ellipsoidal cysts up to 250 MUm in diam. Myxospores ellipsoidal with a slightly more pointed anterior end, measuring 17.1 +/- 0.6 MUm in length, 6.9 +/- 0.4 MUm in width, and 5.1 +/- 0.5 MUm in thickness. A single pyriform polar capsule, 9.0 +/- 0.3 MUm long and 6.1 +/- 0.4 MUm wide, positioned slightly right to the medial plane in valvular view, contains a polar filament arranged in 4-5 coils. Molecular analysis of the SSU rRNA gene by Maximum Parsimony, Neighbor-Joining, and Maximum Likelihood revealed the parasite clustering among other myxobolids, namely Henneguya and Myxobolus. Host affinity is supported as an important evolutionary signal for the phylogeny of myxobolids. The parasite here described represents the first record of the genus Thelohanellus Kudo, 1933 from the South American fauna. PMID- 25039989 TI - Karl D. Nolph, MD, FACP, FRCPS (Glasgow). PMID- 25039990 TI - Elderly patients starting outpatient dialysis not at excessive mortality risk. PMID- 25039991 TI - Unanticipated concerns in initiating dialysis therapy for very old adults are common. PMID- 25039992 TI - Hand temperature responses to local cooling after a 10-day confinement to normobaric hypoxia with and without exercise. AB - The study examined the effects of a 10-day normobaric hypoxic confinement (FiO2: 0.14), with [hypoxic exercise training (HT); n = 8)] or without [hypoxic ambulatory (HA; n = 6)] exercise, on the hand temperature responses during and after local cold stress. Before and after the confinement, subjects immersed their right hand for 30 min in 8 degrees C water [cold water immersion (CWI)], followed by a 15-min spontaneous rewarming (RW), while breathing either room air (AIR), or a hypoxic gas mixture (HYPO). The hand temperature responses were monitored with thermocouples and infrared thermography. The confinement did not influence the hand temperature responses of the HA group during the AIR and HYPO CWI and the HYPO RW phases; but it impaired the AIR RW response (-1.3 degrees C; P = 0.05). After the confinement, the hand temperature responses were unaltered in the HT group throughout the AIR trial. However, the average hand temperature was increased during the HYPO CWI (+0.5 degrees C; P <= 0.05) and RW (+2.4 degrees C; P <= 0.001) phases. Accordingly, present findings suggest that prolonged exposure to normobaric hypoxia per se does not alter the hand temperature responses to local cooling; yet, it impairs the normoxic RW response. Conversely, the combined stimuli of continuous hypoxia and exercise enhance the finger cold-induced vasodilatation and hand RW responses, specifically, under hypoxic conditions. PMID- 25039993 TI - Waldenstrom macroglobulinaemia and intestinal lymphangiectasia. PMID- 25039995 TI - Cloning and characterization of microbial activated Aedes aegypti MEK4 (AaMEK4): influences of noncatalytic domains on enzymatic activity. AB - Protein kinases are known to be involved in a number of signal transduction cascades. Both the stress-activated Jun N-terminal kinase (JNK) and mitogen activated protein kinase (MAPK) p38 pathways have been shown to correlate with the insect immune response to microbial infection. MAP kinase kinase 4 (MEK4) is an upstream kinase of JNK and p38 kinase. The cDNA of AaMEK4 was cloned and characterized. AaMEK4 was activated by microbial lysates of Gram-positive, Gram negative bacteria and yeast. The conserved lysine (K112 ) and the putative phosphorylation sites (S238 and T242 ) were shown to be important for kinase activity by site-directed mutagenesis. A common MAPK docking site (MAPK_dsA) was found and in addition, a new nearby docking site, MAPK_dsB, was identified in the N-terminal noncatalytic domain of AaMEK4. MAPK_dsB was shown to be a unique element in the MEK4 family. In this study, both MAPK_dsA and _dsB were demonstrated to be important to AaMEK4 enzymatic activity for the downstream protein kinase, Aap38. PMID- 25039994 TI - Epigenetic control of skin and hair regeneration after wounding. AB - Skin wound healing is a complex regenerative phenomenon that can result in hair follicle neogenesis. Skin regeneration requires significant contribution from the immune system and involves substantial remodelling of both epidermal and dermal compartments. In this viewpoint, we consider epigenetic regulation of reepithelialization, dermal restructuring and hair neogenesis. Because little is known about the epigenetic control of these events, we have drawn upon recent epigenetic mapping and functional studies of homeostatic skin maintenance, epithelial-mesenchymal transition in cancer, and new works on regenerative dermal cell lineages and the epigenetic events that may shape their conversion into myofibroblasts. Finally, we speculate on how these various healing components might converge for wound-induced hair follicle neogenesis. PMID- 25039996 TI - Behcet's disease and breast cancer. PMID- 25039997 TI - The effects of catheter-based radiofrequency renal denervation on renal function and renal artery structure in patients with resistant hypertension. AB - There are no clinical studies on the effects of catheter-based radiofrequency renal denervation (RDN) on renal artery structure using 64-detector computed tomography (CT). A total of 39 patients with resistant hypertension received RDN and 38 patients received drug treatment. Mean systolic pressure and diastolic pressure in the RDN group decreased after 1, 3, 6, and 12 months of procedure (P<.05) and urinary protein level significantly decreased after 6 and 12 months (P<.05). The diameter, length, and sectional area of the renal artery; number of cases of atherosclerosis; and plaque burden of 64-detector CT renal arteriography did not change at 12 months of follow-up (P<.05), whereas the plaque burden increased significantly in the control group (P<.05). RDN significantly and persistently reduced blood pressure and decreased urinary protein excretion rate in patients with resistant hypertension and did not exhibit any adverse effect on renal function and renal artery structure. PMID- 25039998 TI - miRNome of Italian Large White pig subcutaneous fat tissue: new miRNAs, isomiRs and moRNAs. AB - Small RNAs, such as micro-RNAs (miRNAs), are decisive regulators of gene expression, and they could determine adipose tissue traits. A better knowledge of porcine fat genomics is relevant given that the pig is a biomedical model for metabolic and cardiovascular human pathologies. Adipose tissue is particularly important for the meat industry. We explored the miRNome of two adult Italian Large White pig backfat samples by Illumina RNA-Seq. Using custom bioinformatic methods, the expressed miRNAs were identified and quantified and the nucleotide sequence variability of miRNA isoforms were analysed. We detected 222 known miRNAs, 68 new miRNAs and 17 miRNA-offset RNAs (moRNAs) expressed from known hairpins, and 312 new miRNAs expressed from 253 new hairpins. Porcine transcripts targeted by the most expressed miRNAs were predicted, showing that these miRNAs may have an impact on Wnt, insulin signalling and axon guidance pathways. The expression of five small RNAs, including moRNA ssc-5'-moR-21 and a miRNA from a new hairpin, was validated by a qRT-PCR assay, thus confirming the robustness of our results. The depicted miRNome complexity suggests that quantitative and qualitative features of miRNAs and non-canonical products of their precursors are worthy of further investigation to clarify their roles in the adipose tissue biology. PMID- 25039999 TI - Cooperative investment in public goods is kin directed in communal nests of social birds. AB - The tragedy of the commons predicts social collapse when public goods are jointly exploited by individuals attempting to maximize their fitness at the expense of other social group members. However, animal societies have evolved many times despite this vulnerability to exploitation by selfish individuals. Kin selection offers a solution to this social dilemma, but in large social groups mean relatedness is often low. Sociable weavers (Philetairus socius) live in large colonies that share the benefits of a massive communal nest, which requires individual investment for construction and maintenance. Here, we show that despite low mean kinship within colonies, relatives are spatially and socially clustered and that nest-building males have higher local relatedness to other colony members than do non-building males. Alternative hypotheses received little support, so we conclude that the benefits of the public good are shared with kin and that cooperative investment is, despite the large size and low relatedness of these communities, kin directed. PMID- 25040000 TI - Psoriasis induced by growth hormone therapy in a patient with Turner's syndrome. PMID- 25040001 TI - Cyclic lipopeptides from Bacillus subtilis activate distinct patterns of defence responses in grapevine. AB - Non-self-recognition of microorganisms partly relies on the perception of microbe associated molecular patterns (MAMPs) and leads to the activation of an innate immune response. Bacillus subtilis produces three main families of cyclic lipopeptides (LPs), namely surfactins, iturins and fengycins. Although LPs are involved in induced systemic resistance (ISR) activation, little is known about defence responses induced by these molecules and their involvement in local resistance to fungi. Here, we showed that purified surfactin, mycosubtilin (iturin family) and plipastatin (fengycin family) are perceived by grapevine plant cells. Although surfactin and mycosubtilin stimulated grapevine innate immune responses, they differentially activated early signalling pathways and defence gene expression. By contrast, plipastatin perception by grapevine cells only resulted in early signalling activation. Gene expression analysis suggested that mycosubtilin activated salicylic acid (SA) and jasmonic acid (JA) signalling pathways, whereas surfactin mainly induced an SA-regulated response. Although mycosubtilin and plipastatin displayed direct antifungal activity, only surfactin and mycosubtilin treatments resulted in a local long-lasting enhanced tolerance to the necrotrophic fungus Botrytis cinerea in grapevine leaves. Moreover, challenge with specific strains overproducing surfactin and mycosubtilin led to a slightly enhanced stimulation of the defence response compared with the LP-non producing strain of B. subtilis. Altogether, our results provide the first comprehensive view of the involvement of LPs from B. subtilis in grapevine plant defence and local resistance against the necrotrophic pathogen Bo. cinerea. Moreover, this work is the first to highlight the ability of mycosubtilin to trigger an immune response in plants. PMID- 25040002 TI - TMPRSS2 Met160Val polymorphism: significant association with sporadic prostate cancer, but not with latent prostate cancer in Japanese men. AB - OBJECTIVES: To investigate the association between the TMPRSS2 Met160Val polymorphism and the risk of prostate cancer in Japanese men. METHODS: Genomic DNA samples from 518 Japanese sporadic prostate cancer patients, 433 controls and 154 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results were genotyped for the TMPRSS2 Met160Val polymorphism using a TaqMan assay. Logistic regression analyses were carried out to estimate the odds ratios and 95% confidence intervals. The relationship between the presence of the polymorphism, and clinicopathology and survival was also examined. RESULTS: The T allele frequency of the control group was 0.372, of the sporadic prostate cancer group was 0.435 and of the latent prostate cancer group was 0.370. The CT and TT genotypes were significantly associated with risk for sporadic prostate cancer; age-adjusted odds ratios (95% confidence intervals) were 1.418 (1.027-1.960) for CT, 1.907 (1.224-2.990) for TT and 1.524 (1.123-2.072) for CT/TT genotypes. There was no significant association observed between the TMPRSS2 Met160Val polymorphism and the risk for latent prostate cancer. The TMPRSS2 Met160Val polymorphism was not significantly associated with any clinicopathological features or prognosis. CONCLUSIONS: The TMPRSS2 Met160Val polymorphism is a genetic risk factor for sporadic prostate cancer in a Japanese population. PMID- 25040003 TI - Spatial mental representations derived from spatial descriptions: the predicting and mediating roles of spatial preferences, strategies, and abilities. AB - The aim of this research was to investigate how spatial self-assessments and spatial cognitive abilities jointly influence the construction of mental representations derived from spatial descriptions. Two studies were conducted using the path models approach to test to what extent spatial self-assessments (Study 1, 194 participants) and the combination of the latter with spatial abilities (Study 2, 206 participants) can be modelled to predict memory for spatial descriptions. In both studies, we recorded spatial representation preferences (distinguishing between survey, route, and landmark-focused mode) and self-reported strategies used to memorize descriptions (distinguishing between survey, route, and verbal strategies); in Study 2, we also measured spatial abilities by testing mental rotation (MR) and visuo-spatial working memory (VSWM). Participants listened to spatial descriptions and then completed recall tasks. In both studies, the final path models showed that spatial preferences influenced spatial recall through the mediation of congruent strategies: that is a survey (route) preference influenced spatial recall mediated by a survey (route) strategy. MR predicted spatial recall, mediated by both VSWM and survey strategy (Study 2). Overall, these findings indicate that spatial preferences (particularly for a survey mode) in association with spatial abilities effectively concur to help form mental representations derived from spatial descriptions. PMID- 25040004 TI - Gender responses to psychological distress among Palestinians: risk and protective factors. AB - This study investigated the extent to which differences in the presence of trauma, political and normative stressors, resources, coping, and hardiness could account for variation in gender responses to psychological distress among Palestinians. Participants were 624 males and females aged 27-56 years. Questionnaires were administered in an interview format with participants at home. Results indicated that female gender has been associated with psychological distress. The females in this study reported feeling distressed by intrafamily strains, whereas males reported feeling distressed by work and family strains as well as losses. Political stressors were more predictive of psychological distress than was the presence of trauma or normative stressors. The sociodemographics had different patterns of relations with psychological distress. Females' education was negatively related to psychological distress, whereas the family income was negatively related to psychological distress in males. No significant differences between males and females were found in their coping responses. However, cognitive and behavioural strategies Family Crisis Oriented Personal Evaluation Scales (F-COPES) seem to combine and had an impact on psychological distress of females only. Also, family hardiness was evidenced to have an influence on perceived psychological distress in both genders. The clinical and policy implications of these conclusions were discussed. PMID- 25040005 TI - Is the hijab protective? An investigation of body image and related constructs among British Muslim women. AB - Previous studies have reported equivocal findings concerning the impact of wearing a hijab, or Islamic head- and body-cover, on Muslim women's body image. Here, we sought to examine that impact using a larger sample of Muslim women than has been relied upon and a wider range of body image measures. A total of 587 British Muslim women completed a battery of scales assessing their frequency and conservativeness of hijab use, body image variables, attitudes towards the media and beauty ideals, importance of appearance, and religiosity. Preliminary results indicated that 218 women never used the hijab and 369 women used some form of the hijab at least rarely. Controlling for religiosity, women who wore the hijab had more positive body image, lower internalization of media messages about beauty standards, and placed less importance on appearance than women who did not wear the hijab. Among women who wore the hijab, hijab use significantly predicted weight discrepancy and body appreciation over and above religiosity. These results are discussed in terms of the possible protective impact among British Muslim women of wearing the hijab. PMID- 25040006 TI - Men's strategic preferences for femininity in female faces. AB - Several evolutionarily relevant sources of individual differences in face preference have been documented for women. Here, we examine three such sources of individual variation in men's preference for female facial femininity: term of relationship, partnership status and self-perceived attractiveness. We show that men prefer more feminine female faces when rating for a short-term relationship and when they have a partner (Study 1). These variables were found to interact in a follow-up study (Study 2). Men who thought themselves attractive also preferred more feminized female faces for short-term relationships than men who thought themselves less attractive (Study 1 and Study 2). In women, similar findings for masculine preferences in male faces have been interpreted as adaptive. In men, such preferences potentially reflect that attractive males are able to compete for high-quality female partners in short-term contexts. When a man has secured a mate, the potential cost of being discovered may increase his choosiness regarding short-term partners relative to unpartnered men, who can better increase their short-term mating success by relaxing their standards. Such potentially strategic preferences imply that men also face trade-offs when choosing relatively masculine or feminine faced partners. In line with a trade off, women with feminine faces were seen as more likely to be unfaithful and more likely to pursue short-term relationships (Study 3), suggesting that risk of cuckoldry is one factor that may limit men's preferences for femininity in women and could additionally lead to preferences for femininity in short-term mates. PMID- 25040007 TI - Examination of the bidirectional influences of leisure activity and memory in old people: a dissociative effect on episodic memory. AB - The present study examined the relationships between different types of social and cognitive activities and different types of episodic and semantic memory. A total of 794 adult men and women from five age cohorts (aged 65-85 at baseline), participating in the longitudinal Betula project on ageing, memory, and health, were included in the study. The participants were studied over 10 years (1995 2005) in three waves. Recognition and recall were used as episodic memory tasks, and knowledge and verbal fluency as semantic memory tasks. The results, after controlling for age, gender, education, and some diseases, including heart disease and hypertension, as covariates, showed unidirectional effects of social activity on episodic memory on all test occasions (beta = .10). Also, episodic memory predicted change in cognitive activity for all test waves (beta = .21 .22). Findings suggest that social activity can be seen as protective factor against memory decline. It also seems that episodic memory performance is a predictor of cognitive activity in old people. However, the opposite direction does not hold true. PMID- 25040008 TI - Towards an integrative attachment-based model of relationship functioning. AB - Based on attachment theory, this study developed a theory-based model of heterosexual relationship functioning that examined both proximal and distal factors and both actor and partner effects. A particular focus was on the underexplored issue of double-mediated effects between attachment orientation and relationship satisfaction. Data were collected from a community sample of 95 cohabiting and married couples with a mean age of 39.30 years. Participants completed measures of attachment, commitment, provision of partner support, trust, intimacy, destructive conflict management, and relationship satisfaction. The hypothesized model was largely supported. The association between attachment orientation and relationship satisfaction was mediated through a series of actor and partner variables. No gender differences were found across actor paths; however, differences were found in partner effects for men and women. The model has important implications for relationship researchers and practitioners. PMID- 25040009 TI - Methodological and applied concerns surrounding age-related weighting within health economic evaluation. AB - Economic evaluations that measure the benefits of health interventions in terms of units of health gain inevitably require decision-makers to make judgments about the 'value for money' of those health gains. Decision-making bodies have also commonly returned to the position that a unit of health gain, such as an additional quality-adjusted life year, is of equal value regardless of the characteristics of the recipient. This paper focuses on whether and how health gains in economic evaluation should be differentially weighted by age of recipient. The paper presents a structured overview of evidence from the revealed preference and stated preference literature in this area. It discusses a number of methodological issues raised by differential weighting of health gains by age of recipient. These include identifying appropriate samples for the derivation of age-related weights, methodological issues surrounding the application of the quality-adjusted life year measure, the relative merits of alternative valuation techniques for weighting exercises, the impact of context and design effects on derived values and operational concerns surrounding the application of age related weights within economic evaluation. The paper ends with pointers for potential future research in this area. PMID- 25040010 TI - Validation and application of a model of oxygen consumption and diffusion during photodynamic therapy in vitro. AB - The photophysical parameters for the photosensitizer Pd(II) meso-Tetra(4 carboxyphenyl) porphine (PdT790) acquired in a previous study were incorporated into the PDT oxygen diffusion models for cell suspensions and cell monolayers. The time-dependent phosphorescence signals generated by the diffusion models are shown to match signals previously measured by M.A.W. and M.S.P. when reasonable physical and photophysical parameters are used. Simulations were performed to investigate the effects of metabolic and photodynamic oxygen consumption rates on the PDT dose in each of the treatment geometries. It was found that in cell suspensions of <1 million cells per mL, PDT should not be inhibited by hypoxia if the photodynamic consumption rate is <1 mm s(-1). For cell monolayers the optimal photodynamic oxygen consumption rate was found to depend on the metabolic rate of oxygen consumption. If cells remained well oxygenated in the absence of PDT, then maximum PDT dose was delivered with the lowest practical photodynamic oxygen consumption rate. Simulations of PDT treatments for multicell tumor spheroids showed that large anoxic cores develop within the spheroids and, as a consequence, less PDT dose is delivered in comparison with similar treatments in cell suspensions and cell monolayers. PMID- 25040011 TI - Value assignment to the WHO 3rd International Standard for Blood Coagulation Fibrinogen Plasma (09/264): communication from the SSC of the ISTH. PMID- 25040012 TI - Hypospadias: Prevalence, birthweight and associated major congenital anomalies. AB - The aim of this study was to determine the prevalence of hypospadias over 24 years in a Danish population and to describe the relation to birthweight and associated major congenital anomalies. It is a population-based study of all cases (live births, fetal deaths and elective terminations of pregnancy) with hypospadias born in the period 1986-2009 in Funen County and reported to the EUROCAT registry of congenital anomalies. Cases were included only if surgery for hypospadias was performed. 223 cases of hypospadias were registered during the period 1986-2009 with an overall prevalence of 16.9 per 10 000 births. The prevalence was significantly higher in 2000-2009 compared to 1986-1999 (P < 0.001). We found a three times higher occurrence of VLBW (very low birthweight) infants among cases with hypospadias. Infants with isolated hypospadias were more likely to have mild hypospadias (68%) while cases with associated major congenital anomalies were less likely to have mild hypospadias (42%) (P < 0.05). Hypospadias was associated with VLBW and the severity of the defect was related to the presence of major congenital anomalies. The prevalence of hypospadias has increased during the study period. The relation to VLBW could indicate a causal relationship for hypospadias or a shared pathogenic factor. PMID- 25040013 TI - Identifying mouse models for skin cancer using the Mouse Tumor Biology Database. AB - In recent years, the scientific community has generated an ever-increasing amount of data from a growing number of animal models of human cancers. Much of these data come from genetically engineered mouse models. Identifying appropriate models for skin cancer and related relevant genetic data sets from an expanding pool of widely disseminated data can be a daunting task. The Mouse Tumor Biology Database (MTB) provides an electronic archive, search and analysis system that can be used to identify dermatological mouse models of cancer, retrieve model specific data and analyse these data. In this report, we detail MTB's contents and capabilities, together with instructions on how to use MTB to search for skin related tumor models and associated data. PMID- 25040014 TI - The flower of Hibiscus trionum is both visibly and measurably iridescent. AB - Living organisms can use minute structures to manipulate the reflection of light and display colours based on interference. There has been debate in recent literature over whether the diffractive optical effects produced by epoxy replicas of petals with folded cuticles persist and induce iridescence in the original flowers when the effects of petal pigment and illumination are taken into account. We explored the optical properties of the petal of Hibiscus trionum by macro-imaging, scanning and transmission electron microscopy, and visible and ultraviolet (UV) angle-resolved spectroscopy of the petal. The flower of Hibiscus trionum is visibly iridescent, and the iridescence can be captured photographically. The iridescence derives from a diffraction grating generated by folds of the cuticle. The iridescence of the petal can be quantitatively characterized by spectrometric measurements with several square-millimetres of sample area illuminated. The flower of Hibiscus trionum has the potential to interact with its pollinators (honeybees, other bees, butterflies and flies) through iridescent signals produced by its cuticular diffraction grating. PMID- 25040015 TI - Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: a post hoc analysis. AB - BACKGROUND AND PURPOSE: Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER DP) when administered alone or with low-dose aspirin (ASA+ER-DP). METHODS: This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20,332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model. RESULTS: In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06). CONCLUSIONS: Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function. PMID- 25040016 TI - Infections in solid organ transplant HIV-infected patients. AB - Solid organ transplantation (SOT) is an appropriate therapeutic option for HIV infected patients with end-stage organ disease. Recent experience in North America and Europe indicates that 3- to 5-year survival in HIV/HCV-coinfected liver recipients is lower than that of HCV-monoinfected recipients. Conversely, 3 to 5-year survival of non-HCV-coinfected transplant patients (liver, kidney and heart) was similar to that of non-HIV-infected patients. Preliminary experience with lung transplantation and combined kidney and pancreas transplantation is also satisfactory. Infections in HIV-infected recipients during the post transplant period are similar to those seen in non-HIV-infected patients, although the incidence rates of tuberculosis and fungal infections seem to be higher. HIV-infected patients who are being evaluated for SOT should follow the same recommendations as those used for non-HIV-infected patients in order to prevent infections during the pre-transplant period. After transplantation, HIV infected SOT recipients must follow recommendations on post-SOT and anti-HIV immunization and on antimicrobial prophylaxis. The recommended antiretroviral regimen is one based on raltegravir or dolutegravir plus two nucleos(t)ide reverse transcriptase inhibitors (tenofovir + emtricitabine or abacavir + lamivudine), because it can prevent pharmacokinetic interactions between antiretroviral drugs, immunosuppressive drugs and some of the antimicrobial agents used to treat or prevent post-transplant infections. In this manuscript, we review current recommendations for preventing infections both before and after transplantation. We also analyse the incidence, aetiology and clinical characteristics of opportunistic and non-opportunistic bacterial, mycobacterial, fungal and viral infections in HIV-infected SOT recipients during the post transplant period. PMID- 25040017 TI - Should monitoring of fibroblast growth factor-23 levels in dialysis patients be a part of routine clinical practice? PMID- 25040018 TI - Anxiety sensitivity: changes with puberty and cardiovascular variables. AB - BACKGROUND: Anxiety sensitivity (AS) is a relatively stable dispositional variable that may increase the risk for anxiety-related symptoms, particularly panic attack, among individuals of all age groups. Changes in AS during adolescence in healthy individuals, however, has not been previously investigated. The aim of this study was therefore to investigate the relationship of AS with puberty level, pulse rate, and blood pressure in healthy adolescents. METHODS: The sample consisted of 133 healthy adolescents (70 boys, 63 girls) aged 10-17 years. Puberty stage (i.e. Tanner stage), pulse rate, and blood pressure of each participant were determined. The Childhood Anxiety Sensitivity Inventory was used to identify AS. The correlations between AS and the clinical variables were assessed. RESULTS: AS was negatively correlated with pubertal stage when age and gender were controlled. Also, AS was correlated with diastolic blood pressure when age, gender, and pubertal stage were controlled (P < 0.05). Neither systolic blood pressure nor heart rate were correlated with AS. CONCLUSION: AS, which is reported to be a trait-like variable, may change during adolescence, due to the effect of pubertal growth and blood pressure interacting with AS during adolescence. PMID- 25040019 TI - Cost-effectiveness of a disease management program for early childhood caries. AB - OBJECTIVES: To assess the cost-effectiveness of a pilot disease management (DM) program aimed at preventing early childhood caries among children younger than 5 years. METHODS: The DM program was implemented in the Boston Children's Hospital based dental practice in 2008. Health care costs were obtained from the hospital finance department and non-health care costs were estimated through a parent survey. The measure of effectiveness was avoided hospital-based visits for restorative treatment or extractions. Incremental costs (2011 US$) and effectiveness were estimated from a health care system, societal, and public payer perspectives over 3, 6, and 12 months, by comparing DM participants (n = 395) to a historical comparison group (n = 123) using generalized linear models. Bootstrapping and other sensitivity analyses were used to incorporate uncertainty in the analyses. RESULTS: The DM program was associated with a reduction in societal costs of $20 (p = 0.85), $215 (p = 0.24), and $669 (p < 0.01) per patient and a reduction in the number of hospital-based visits for restorative treatment or extractions by 0.44 (p < 0.01), 0.42 (p < 0.01), and 0.45 (p < 0.01) per patient over 3, 6, and 12 months, respectively. The probability of it being less costly and more effective was 61.5 percent, 81.9 percent, and 98.6 percent over 3, 6, and 12 months, respectively. Consistent results were observed from a health care system and public payer perspectives. CONCLUSIONS: The DM program appears cost-effective and has the potential to reduce health care costs. Our results justify a multicenter trial to evaluate the DM program on a larger scale. PMID- 25040020 TI - Evaluation of a universal point-of-issue assay for bacterial detection in buffy coat platelet components. AB - Bacterial contamination of platelet concentrates poses a major post-transfusion infectious risk. This study was aimed at evaluating the efficacy of the BacTx((r)) assay (Immunetics Inc.) for bacterial detection in leucocyte-reduced buffy coat platelet pools and for its sensitivity in detecting clinical isolates, including bacteria that form surface-attached aggregates (biofilm positives). Platelet pools were inoculated at bacterial concentrations of 0.8-13 CFU/ml. The BacTx((r)) assay detected all species at concentrations >=10(3) CFU/ml within 20 69 h of platelet incubation. Detection of slow-growing and biofilm-forming strains was delayed in comparison with the other strains. This assay could be used as a point-of-issue method to increase the safety of the platelet supply. PMID- 25040021 TI - The impact of prior authorization on buprenorphine dose, relapse rates, and cost for Massachusetts Medicaid beneficiaries with opioid dependence. AB - OBJECTIVE: To assess the impact of a 2008 dose-based prior authorization policy for Massachusetts Medicaid beneficiaries using buprenorphine + naloxone for opioid addiction treatment. Doses higher than 16 mg required progressively more frequent authorizations. DATA SOURCES: Mediciaid claims for 2007 and 2008 linked with Department of Public Health (DPH) service records. STUDY DESIGN: We conducted time series for all buprenorphine users and a longitudinal cohort analysis of 2,049 individuals who began buprenorphine treatment in 2007. Outcome measures included use of relapse-related services, health care expenditures per person, and buprenorphine expenditures. DATA COLLECTION/EXTRACTION METHODS: We used ICD-9 codes and National Drug Codes to identify individuals with opioid dependence who filled prescriptions for buprenorphine. Medicaid and DPH data were linked with individual identifiers. PRINCIPAL FINDINGS: Individuals using doses >24 mg decreased from 16.5 to 4.1 percent. Relapses increased temporarily for some users but returned to previous levels within 3 months. Buprenorphine expenditures decreased but total expenditures did not change significantly. CONCLUSION: Prior authorization policies strategically targeted by dose level appear to successfully reduce use of higher than recommended buprenorphine doses. Savings from these policies are modest and may be accompanied by brief increases in relapse rates. Lower doses may decrease diversion of buprenorphine. PMID- 25040022 TI - A decrease in bulk water and mannitol and accumulation of trehalose and trehalose based oligosaccharides define a two-stage maturation process towards extreme stress resistance in ascospores of Neosartorya fischeri (Aspergillus fischeri). AB - Fungal propagules survive stresses better than vegetative cells. Neosartorya fischeri, an Aspergillus teleomorph, forms ascospores that survive high temperatures or drying followed by heat. Not much is known about maturation and development of extreme stress resistance in fungal cells. This study provides a novel two-step model for the acquisition of extreme stress resistance and entry into dormancy. Ascospores of 11- and 15-day-old cultures exhibited heat resistance, physiological activity, accumulation of compatible solutes and a steep increase in cytoplasmic viscosity. Electron spin resonance spectroscopy indicated that this stage is associated with the removal of bulk water and an increase of chemical stability. Older ascospores from 15- to 50-day-old cultures showed no changes in compatible solute content and cytoplasmic viscosity, but did exhibit a further increase of heat resistance and redox stability with age. This stage was also characterized by changes in the composition of the mixture of compatible solutes. Mannitol levels decreased and the relative quantities of trehalose and trehalose-based oligosaccharides increased. Dormant ascospores of N. fischeri survive in low-water habitats. After activation of the germination process, the stress resistance decreases, compatible solutes are degraded and the cellular viscosity drops. After 5 h, the hydrated cells enter the vegetative stage and redox stability has decreased notably. PMID- 25040023 TI - Effects of chronic mild food restriction on behavior and the hypothalamic malonyl CoA signaling pathway. AB - Depression induces anorexia, leading to suppressed feeding behaviors and energy intake. Previously, we revealed that chronic social defeat induced a mild suppression of feeding in rats with elevated levels of hypothalamic malonyl-CoA which regulates feeding. Therefore, we attempted to elucidate the effects of chronic mild food restriction on behavior and on hypothalamic malonyl-CoA. The chronic mild food restricted rats were fed a restricted diet approximately 80% to 90% amount of diet compared to the control for 5 weeks. Ratios of restriction were adjusted with feed consumption in the chronic social defeat stressed rats. Chronic mild food restricted rats exhibited a suppression of body weight gain similar to that of the chronic social defeat stressed rats. Also these rats showed increased time spent in the center area of an open field (OF), prolonged immobility time in forced swim, increased phosphorylation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase and a decreased concentration of hypothalamic malonyl-CoA. Weight of the adrenal glands, locomotion in an OF, mitogen-activated protein kinase cascade and calcium/calmodulin-dependent protein kinases II in the hippocampus were not affected by chronic mild food restriction. Our findings suggest that chronic mild food restriction activates AMPK following a decreased hypothalamic malonyl-CoA. PMID- 25040024 TI - Causes of death determined in medicolegal investigations in residents of nursing homes: a systematic review. AB - OBJECTIVES: To systematically review published research characterizing the nature and circumstances surrounding the death of older people in nursing homes specifically using information generated for medicolegal death investigations. DESIGN: Systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement using the key words death, nursing homes, and medicolegal death investigation. SETTING: Cross-sectional data from original, peer-reviewed articles published in English between 2000 and 2013 describing deaths of nursing home residents. MEASUREMENTS: Information was extracted for analysis about study and population characteristics, number and type of deaths, study design, findings, and limitations. RESULTS: Thirteen studies were identified. The studies examined external causes of deaths from suicide, choking, restraint or bed-related injuries, falls, and pressure injuries. Deaths were more frequent in women with existing comorbidities. Suicide was predominant in men. Identified risk factors and opportunities to reduce harm were identified at individual, organizational, and structural levels. Overall, the quality of the studies limited the aggregation and comparability of findings. CONCLUSION: This systematic review informs researchers, clinicians and policy makers about how to reduce external causes of death in nursing homes. PMID- 25040025 TI - Pdx1 and USF transcription factors co-ordinately regulate Alx3 gene expression in pancreatic beta-cells. AB - Alterations in transcription factors expressed in insulin-producing islet beta cells generate pancreatic dysfunction leading to diabetes. The homeodomain transcription factor Alx3 (aristaless-like homeobox 3) expressed in pancreatic islets participates in the regulated expression of several islet genes, and its deficiency in mice leads to islet cell apoptosis and glucose intolerance. In the present study, we investigated the mechanisms that regulate expression of Alx3 in pancreatic islets at the transcriptional level. We found that the Alx3 promoter contains at least eight putative regulatory elements with an E-box consensus sequence, three of which were determined to be functional and required for Alx3 promoter activity by mutational analysis in transfected MIN6 beta-cells. We determined that these E-box elements are recognized by the basic helix-loop-helix transcription factors USF1 (upstream stimulatory factor 1) and USF2. We also identified a highly conserved A-box in the Alx3 promoter that is recognized by the islet-specific transcription factor Pdx1 (pancreatic and duodenal homeobox 1). Pdx1-mediated transactivation of the Alx3 promoter requires the integrity of the three functional E-boxes and the co-operation with USF transcription factors bound to them. The results from the present study indicate that Pdx1 contributes to the transcriptional transactivation of Alx3 in pancreatic beta-cells by acting in co-ordination with USF1 and USF2. PMID- 25040026 TI - Uncertainty analysis of a groundwater flow model in East-central Florida. AB - A groundwater flow model for east-central Florida has been developed to help water-resource managers assess the impact of increased groundwater withdrawals from the Floridan aquifer system on heads and spring flows originating from the Upper Floridan Aquifer. The model provides a probabilistic description of predictions of interest to water-resource managers, given the uncertainty associated with system heterogeneity, the large number of input parameters, and a nonunique groundwater flow solution. The uncertainty associated with these predictions can then be considered in decisions with which the model has been designed to assist. The "Null Space Monte Carlo" method is a stochastic probabilistic approach used to generate a suite of several hundred parameter field realizations, each maintaining the model in a calibrated state, and each considered to be hydrogeologically plausible. The results presented herein indicate that the model's capacity to predict changes in heads or spring flows that originate from increased groundwater withdrawals is considerably greater than its capacity to predict the absolute magnitudes of heads or spring flows. Furthermore, the capacity of the model to make predictions that are similar in location and in type to those in the calibration dataset exceeds its capacity to make predictions of different types at different locations. The quantification of these outcomes allows defensible use of the modeling process in support of future water-resources decisions. The model allows the decision-making process to recognize the uncertainties, and the spatial or temporal variability of uncertainties that are associated with predictions of future system behavior in a complex hydrogeological context. PMID- 25040028 TI - Derangement of the T-cell repertoire in patients with B-cell non-Hodgkin's lymphoma. AB - Although a number of studies suggest that different immune pathways may play a role in the pathogenesis of non-Hodgkin's lymphomas (NHL), the shape of the T cell compartment has been only superficially explored in these patients. In our study, we analyzed the peripheral T-cell receptor (TCR) repertoire and the distribution of different T-cell subsets - including regulatory T cells (Treg) - in 30 patients with NHL, by combining flow cytometry and spectratyping. We first demonstrated by flow cytometry an increased frequency of expanded T-cell subpopulations expressing the same TCR beta variable (BV) subfamilies in CD8+ cells from NHL patients when compared with healthy controls, beside a higher frequency of Treg. Moreover, NHL patients were characterized by a higher percentage of BVs showing a skewed CDR3 profile both in CD4+ and CD8+ cells when analyzed by spectratyping. Our data suggest that the T-cell branch of the immune system of patients with B-cell NHL is deeply deranged, as witnessed by the increased degree of activation and skewing of their TCR repertoire along with the higher frequency of Treg. PMID- 25040029 TI - Stroke echoscan protocol: a fast and accurate pathway to diagnose embolic strokes. AB - BACKGROUND AND PURPOSE: Cardiac Echoscan is the simplified transthoracic echocardiogram focused on the main source of emboli detection in the acute stroke diagnosis (Stroke Echoscan). We describe the clinical impact related to the Stroke Echoscan protocol in our Center. METHODS: Acute stroke patients who underwent the Stroke Echoscan by a trained stroke neurologist were included (Echoscan group). All examinations were reviewed by cardiologists. The main embolic stroke etiologies were: ventricular akinesia (VA), severe aortic atheroma (AA) plaque and cardiac shunt (SHUNT). The rate of the embolic stroke etiologies and the median length of stay (LOS) were compared with a cohort of patients studied by cardiologist (Echo group). RESULTS: Eighty acute stroke patients were included. The sensitivity (S) and specificity (E) were: VA (S 98.6%, E 66.7%, k = .7), AA (S 93.3%, E 96.9%, k = .88) and SHUNT (S 100%, E 100%, k = 1), respectively. The rate of AA diagnosis was significantly higher in Echoscan group (18.8% vs. 8.9%; P = .05). Echoscan protocol significantly reduced the LOS: 6 days (IQR 3-10) versus Echo group 9 days (IQR 6-13; P < .001). CONCLUSION: The Echoscan protocol was an accurate quick test, which reduced the length of stay and increased the percentage of severe AA plaque diagnosis. PMID- 25040030 TI - Interspecies comparison of stellate cell-containing macula flavae and vitamin A storage in vocal fold mucosa. AB - The macula flavae (MF), populated by vitamin A-storing stellate cells (SCs), are believed to play a fundamental role in development, maintenance and repair of the vocal fold (VF) mucosa; however, to date, they have mostly been examined in observational human cadaver studies. Here, we conducted an interspecies comparison of MF and SC phenotype, as well as vitamin A quantification and localization, in human, pig, dog, rabbit and rat VF mucosae. MF containing vitamin A-positive SCs were only identified in human and rat specimens. Pig, dog and rabbit VF mucosae contained no discernable MF, but rather exhibited preferential vitamin A localization to mucous (pig), serous (dog) or mixed (rabbit) glands. This glandular vitamin A storage corresponded to exceedingly high concentrations of retinol in pig and dog mucosae, and retinyl ester in dog mucosa. These findings have significant implications for the presumed role of the MF and SCs in VF biology, the nature of vitamin A storage within the VF mucosa, and the selection of an appropriate animal model for future experimental studies. PMID- 25040031 TI - A comparison of cardiopulmonary function, recovery quality, and total dosages required for induction and total intravenous anesthesia with propofol versus a propofol-ketamine combination in healthy Beagle dogs. AB - OBJECTIVE: To compare cardiopulmonary function, recovery quality, and total dosages required for induction and 60 minutes of total intravenous anesthesia (TIVA) with propofol (P) or a 1:1 mg mL(-1) combination of propofol and ketamine (KP). STUDY DESIGN: Randomized crossover study. ANIMALS: Ten female Beagles weighing 9.4 +/- 1.8 kg. METHODS: Dogs were randomized for administration of P or KP in a 1:1 mg mL(-1) ratio for induction and maintenance of TIVA. Baseline temperature, pulse, respiratory rate (fR), noninvasive mean blood pressure (MAP), and hemoglobin oxygen saturation (SpO2) were recorded. Dogs were intubated and spontaneously breathed room air. Heart rate (HR), fR, MAP, SpO2, end tidal carbon dioxide tension (Pe'CO2), temperature, and salivation score were recorded every 5 minutes. Arterial blood gas analysis was performed at 10, 30, and 60 minutes, and after recovery. At 60 minutes the infusion was discontinued and total drug administered, time to extubation, and recovery score were recorded. The other treatment was performed 1 week later. RESULTS: KP required significantly less propofol for induction (4.0 +/- 1.0 mg kg(-1) KP versus 5.3 +/-1.1 mg kg(-1) P, p = 0.0285) and maintenance (0.3 +/- 0.1 mg kg(-1) minute(-1) KP versus 0.6 +/-0.1 mg kg(-1) minute(-1) P, p = 0.0018). Significantly higher HR occurred with KP. Both P and KP caused significantly lower MAP compared to baseline. MAP was significantly higher with KP at several time points. P had minimal effects on respiratory variables, while KP resulted in significant respiratory depression. There were no significant differences in salivation scores, time to extubation, or recovery scores. CONCLUSIONS AND CLINICAL RELEVANCE: Total intravenous anesthesia in healthy dogs with ketamine and propofol in a 1:1 mg mL(-1) combination resulted in significant propofol dose reduction, higher HR, improved MAP, no difference in recovery quality, but more significant respiratory depression compared to propofol alone. PMID- 25040032 TI - Cowden syndrome--a case report emphasizing the role of the dental surgeon in diagnosis. AB - Cowden syndrome or multiple hamartoma syndrome, is a rare genetic condition inherited in an autosomal dominant pattern characterized by cutaneous manifestations, polyps, thyroid gland neoplasias, and macrocephaly. This report presents the case of a 36-year-old patient who looked for dental treatment for a gingival nodule. Current and past medical history and oral and facial manifestations led to the diagnosis of Cowden syndrome. This case report emphasizes the role of the dental surgeon in the diagnosis of this systemic disease, based on the analysis of medical history and manifestations in the oral cavity. PMID- 25040027 TI - Stress and the reproductive axis. AB - There exists a reciprocal relationship between the hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes, wherein the activation of one affects the function of the other and vice versa. For example, both testosterone and oestrogen modulate the response of the HPA axis, whereas activation of the stress axis, especially activation that is repeating or chronic, has an inhibitory effect upon oestrogen and testosterone secretion. Alterations in maternal care can produce significant effects on both HPG and HPA physiology, as well as behaviour in the offspring at adulthood. For example, changes in reproductive behaviour induced by altered maternal care may alter the expression of sex hormone receptors such as oestrogen receptor (ER)alpha that govern sexual behaviour, and may be particularly important in determining the sexual strategies utilised by females. Stress in adulthood continues to mediate HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine into the ovary, which produces a noncyclic anovulatory ovary that develops cysts. In the opposite direction, sex differences and sex steroid hormones regulate the HPA axis. For example, although serotonin (5-HT) has a stimulatory effect on the HPA axis in humans and rodents that is mediated by the 5-HT1A receptor, only male rodents respond to 5-HT1A antagonism to show increased corticosterone responses to stress. Furthermore, oestrogen appears to decrease 5-HT1A receptor function at presynaptic sites, yet increases 5-HT1A receptor expression at postsynaptic sites. These mechanisms could explain the heightened stress HPA axis responses in females compared to males. Studies on female rhesus macaques show that chronic stress in socially subordinate female monkeys produces a distinct behavioural phenotype that is largely unaffected by oestrogen, a hyporesponsive HPA axis that is hypersensitive to the modulating effects of oestrogen, and changes in 5-HT1A receptor binding in the hippocampus and hypothalamus of social subordinate female monkeys that are restored or inverted by oestrogen replacement. This review summarises all of these studies, emphasising the profound effect that the interaction of the reproductive and stress axes may have on human reproductive health and emotional wellbeing. PMID- 25040033 TI - Analysis of metabolic alterations in Arabidopsis following changes in the carbon dioxide and oxygen partial pressures. AB - As sessile organisms, plants are subject to a multitude of environmental variations including several which directly affect their interaction with the atmosphere. Given the indiscriminant nature of Rubisco, the relative rates of photosynthesis and photorespiration are known to be responsive to changes in gas composition. However, comprehensive profiling methods have not yet been applied in order to characterize the wider consequences of these changes on primary metabolism in general. Moreover, although transcriptional profiling has revealed that a subset of photorespiratory enzymes are co-expressed, whether transcriptional responses play a role in short-term responses to atmospheric compositional changes remains unknown. To address these questions, plants Arabidopsis thaliana (Arabidopsis) ecotype Columbia (Col-O) grown under normal air conditions were transferred to different CO2 and O2 concentrations and characterized at the physiological, molecular, and metabolic levels following this transition. The results reveal alterations in the components, which are directly involved in, or supporting, photorespiration, including transcripts and metabolite levels. The results further highlight that the majority of the regulation of these pathways is not mediated at the level of transcription and that the photorespiratory pathway is essential also in conditions in which flux through the pathway is minimized, yet suggest that flux through this pathway is not mediated at the level of transcription. PMID- 25040034 TI - The basal insulin dose; a lesson from prolonged fasting in young individuals with type 1 diabetes. AB - BACKGROUND AND OBJECTIVE: The insulin requirement for type 1 diabetes during prolonged fasting is unclear. In order to define this for clinical purposes, we investigated the total insulin dose associated with successful completion of a 25 h religious fast. SUBJECTS AND METHODS: Questionnaires were filled in during telephone interviews performed before and after 88 fasts in 57 young individuals with type 1 diabetes (age 20.4 +/- 5.3, range: 12.3-31.2 yr). Duration of their diabetes was 8.7 +/- 6.1 yr (range: 0.5-21.8) and latest HbA1c was 8.5 +/- 1.9% (5.7-13.7). Twenty-eight patients fasted using multiple daily injections (MDI) and 30 were on continuous subcutaneous insulin infusion (CSII), including one who fasted in both categories. Subjects were instructed either to act as they had done for previous successful fasts or, for first-time fasts, to inject half their daily basal insulin injection or halve their basal CSII rate throughout the fast. The total daily insulin dose associated with successful completion of the fast was determined. RESULTS: Among those who completed the fast, average total insulin was 0.19 +/- 0.16 U/kg, patients who discontinued their fast took on average 0.34 +/- 0.15 U/kg. Seven MDI patients and 12 CSII patients terminated their fast early, mostly for mild hypoglycemia. No severe hypoglycemia or other serious adverse event occurred during any of the fasts. CONCLUSIONS: Fasting for 25 h is safe and can be undertaken in individuals with type 1 diabetes. The recommended total daily dose is 0.2 U/kg/day. This recommendation may possibly be used for other situations in which abstention from oral intake is required. PMID- 25040035 TI - John Paley's challenge. PMID- 25040037 TI - Prognostic factors in 151 patients with surgically resected non-functioning pancreatic neuroendocrine tumours. AB - BACKGROUND: Recently, non-functioning pancreatic neuroendocrine tumors (NF-PNETs) are increasing. It is important to know about the prognostic factors and long term survival rates in patients with NF-PNET for the management of these diseases. METHODS: We retrospectively analysed the records of 151 patients with NF-PNET who had pancreatic resection between January 1995 and December 2010. RESULT: The 10-year overall survival, disease-specific survival and disease-free survival rate of the patients who underwent surgery for NF-PNET were 72.6%, 85.1% and 57.2% respectively. The three staging systems (2004 World Health Organization classification, 2006 European Neuroendocrine Tumor Society stages and 2010 grading system) showed comparable prognostic relevance in disease-specific survival of patients with resected NF-PNETs. Lymph nodes metastasis, high Ki-67 index and mitotic rate were the independent poor prognostic factors for disease specific survival in the patients with surgically resected NF-PNET on multivariate analysis. CONCLUSION: We suggested that the three staging systems accurately reflect the prognosis in disease-specific survival of patients with resected NF-PNETs. Presence of lymph nodes metastases and high Ki-67 index and mitotic rate were the independent poor prognostic factors after resection of NF PNET. PMID- 25040038 TI - Exposition of dermatophyte Trichophyton mentagrophytes to L-cystine induces expression and activation of cysteine dioxygenase. AB - Cysteine dioxygenase (CDO) is involved in regulation of intracellular cysteine levels by catabolising the cysteine to sulphite and sulphate. In keratinolytic fungi, sulphite is actively excreted to reduce disulphide bridges in keratin before its enzymatic degradation. The pathogenicity role of CDO was confirmed in cysteine-hypersensitive and growth-defective DeltaCdo mutant of Arthroderma benhamiae on hair and nails. We analysed the CDO expression regulation in T. mentagrophytes (anamorph of A. benhamiae) mycelia by determining the Cdo mRNA and CDO protein levels and by analysing the proportion of two molecular forms of CDO in response to l-cystine exposure. Cdo mRNA levels in mycelia lysates were detected by reverse-transcription real-time polymerase chain reaction and CDO protein by western blot using mouse CDO-specific hyperimmune serum. The Cdo mRNA level increased gradually 2.5-4.5 h after exposure of the mycelium to l-cystine. The CDO protein, detected as two bands of different mobility, appeared earlier in comparison to mRNA (1 h) and culminated after 24 h. More mobile form prevailed after 4.5 h. The comparison of the dynamics in the Cdo mRNA and CDO protein levels indicates that T. mentagrophytes responds to l-cystine by increased transcription and apparently decreased degradation of the CDO and by changing towards higher mobility molecular form, similar to previous reports describing mammalian analogue. PMID- 25040039 TI - The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. AB - BACKGROUND: SH2-containing inositol-5'-phosphatase 1 (SHIP1) is an endogenous inhibitor of the phosphoinositide-3-kinase pathway that is involved in the activation and chemotaxis of inflammatory cells. AQX-1125 is a first-in-class, oral SHIP1 activator with a novel anti-inflammatory mode of action. OBJECTIVE: To evaluate the effects of AQX-1125 on airway responses to allergen challenge in mild-to-moderate asthmatic patients. METHODS: A randomized, double-blind, placebo controlled, two-way crossover study was performed in 22 steroid-naive mild-to moderate asthmatics with a documented late-phase response to inhaled allergen (LAR). AQX-1125 (450 mg daily) or placebo was administered orally for 7 days. Allergen challenge was performed on day 6 (2 h postdose), followed by methacholine challenge (day 7), and induced sputum collection and fractional exhaled nitric oxide (FeNO). RESULTS: AQX-1125 significantly attenuated the late phase response compared with placebo (FEV1 4-10 h: mean difference 150 mL, 20%; P = 0.027) and significantly increased the minimum FEV1 during LAR (mean difference 180 mL; P = 0.014). AQX-1125 had no effect on the early-phase response. AQX-1125 showed a trend in reduction of sputum eosinophils, neutrophils and macrophages although this did not achieve significance as there were only 11 paired samples for analysis. There was no effect on methacholine responsiveness or FeNO. Pharmacokinetic data showed AQX-1125 was rapidly absorbed with geometric mean Cmax and AUC0-24 h values of 1417 ng/mL and 16 727 h ng/mL, respectively. AQX 1125 was well tolerated, but mild GI side-effects (dyspepsia, nausea and abdominal pain) were described in 4/22 subjects on active treatment. These side effects were mild self-limiting, required no further treatment and did not lead to discontinuation of therapy. CONCLUSION AND CLINICAL RELEVANCE: AQX-1125, a novel oral SHIP1 activator, significantly reduces the late response to allergen challenge, with a trend to reduce airway inflammation. AQX-1125 was safe and well tolerated and merits further investigation in inflammatory disorders. PMID- 25040040 TI - Problems with mitigation translocation of herpetofauna. AB - Mitigation translocation of nuisance animals is a commonly used management practice aimed at resolution of human-animal conflict by removal and release of an individual animal. Long considered a reasonable undertaking, especially by the general public, it is now known that translocated subjects are negatively affected by the practice. Mitigation translocation is typically undertaken with individual adult organisms and has a much lower success rate than the more widely practiced conservation translocation of threatened and endangered species. Nonetheless, the public and many conservation practitioners believe that because population-level conservation translocations have been successful that mitigation translocation can be satisfactorily applied to a wide variety of human-wildlife conflict situations. We reviewed mitigation translocations of reptiles, including our own work with 3 long-lived species (Gila monsters [Heloderma suspectum], Sonoran desert tortoises [Gopherus morafkai], and western diamond-backed rattlesnakes [Crotalus atrox]). Overall, mitigation translocation had a low success rate when judged either by effects on individuals (in all studies reviewed they exhibited increased movement or increased mortality) or by the success of the resolution of the human-animal conflict (translocated individuals often returned to the capture site). Careful planning and identification of knowledge gaps are critical to increasing success rates in mitigation translocations in the face of increasing pressure to find solutions for species threatened by diverse anthropogenic factors, including climate change and exurban and energy development. PMID- 25040041 TI - Predicting intracerebral hemorrhage by baseline magnetic resonance imaging in stroke patients undergoing systemic thrombolysis. AB - OBJECTIVES: Intracerebral hemorrhage (ICH) remains a serious complication in ischemic stroke patients undergoing systemic thrombolysis. Here, we examined whether the risk of treatment-associated hemorrhage can be predicted from magnetic resonance imaging (MRI) using fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) within 3 h after symptom onset. METHODS: In this single-center observational study involving 122 ischemic stroke patients between January 2005 and December 2008, the incidence of FLAIR-positive lesions within diffusion-restricted areas was determined on baseline MRI, which was carried out prior to treatment with tissue plasminogen activator (Actilyse((r)) ) within 3 h from symptom onset. The rate of ICH was assessed by computed tomography performed within 24 h after treatment. Relationships between FLAIR-positive lesions, DWI lesion size, proportion of FLAIR/DWI-positive lesions, and occurrence of bleeding were explored. RESULTS: Data from 97 patients were evaluated. FLAIR-positive lesions were present in 25 patients (25.8%) and ICH occurred in 32 patients (33.0%). FLAIR-positive lesions were associated with a bleeding rate of 80.0% compared with 16.7% in FLAIR-negative patients (P < 0.001; odds ratio 20.0, positive predictive value 0.8). DWI lesion size was significantly correlated with the rate of ICH (P = 0.001). In contrast, FLAIR/DWI proportion was not associated with ICH (P = 0.788). CONCLUSIONS: In ischemic stroke patients within 3 h from symptom onset, the existence of FLAIR-positive lesions on pretreatment MRI is significantly associated with an increased bleeding risk due to systemic thrombolysis. Therefore, considering FLAIR-positive lesions on baseline MRI might guide treatment decisions in ischemic stroke. PMID- 25040042 TI - The outcome of care in people with type 1 diabetes after switching to insulin glargine-based regimens in a real-life setting: a long-term observational study. AB - BACKGROUND: Different insulin preparations are used as basal insulins in type 1 diabetes. The aim of this study was to assess long-term efficacy and safety of insulin glargine after switching from other basal insulins in type 1 diabetes in a real-life setting. METHODS: In the clinic's database, 87 subjects treated with glargine for > 1 year were identified. In all patients, HbA1c level, insulin doses, episodes of severe hypoglycaemia, diabetic complications, comorbidities, body mass index (BMI), blood pressure and concomitant medications' use were monitored throughout the entire follow-up period. RESULTS: During observation, lasting mean 61.9 +/- 27.6 months HbA1c level decreased from 8.86 +/- 1.60% (73.3 mmol/mol) to 8.25 +/- 1.40% (66.7 mmol/mol), p < 0.001. This improvement was maintained up to 8 years. Frequency of severe hypoglycaemia was 6.24/100 patient years. Total insulin requirement did not changed significantly. BMI increased from 23.57 +/- 2.90 to 24.52 +/- 3.46 kg/m(2) (p < 0.001). Significant weight gain (> 5%) occurred in 30 subjects, while 10 patients lost weight. Mean systolic blood pressure (SBP) increased from 136.3 +/- 13.4 to 140.7 +/- 15.1 mmHg (p = 0.008), while diastolic blood pressure remained unchanged. Development or progression of diabetic complications was revealed in 11 subjects. CONCLUSIONS: Following switch from other basal insulins to insulin glargine in type 1 diabetic patients, glycaemic control significantly improved, with unchanged total insulin requirement and with low risk of severe hypoglycaemia. Weight gain and elevation of SBP observed in this study require special attention and educational efforts. In summary, insulin glargine can be recommended as an effective and safe basal insulin in type 1 diabetes in a real-life setting. PMID- 25040044 TI - Later rather than sooner: the impact of clinical management on timing and modes of death in the last decade. AB - AIM: Technological and clinical advances have reduced neonatal deaths, and this study explored how the mode and timing of neonatal deaths has changed in a tertiary neonatal intensive care unit (NICU) over 10 years. METHODS: We carried out a retrospective chart review on NICU deaths in 2000-2002 and 2007-2010, categorising deaths and compared the timing, cause and mode of death in the two cohorts. RESULTS: We analysed 204 neonatal deaths and found that the average age at death doubled from 9.71 days in 2000-2002 to 18.8 days (p = 0.014) in 2007 2010 and that the number of deaths in the first 48 h of life fell from 52% to 29% (p < 0.001). Mode of death and ethical decision-making was similar. In both cohorts, 26% of patients who died had a do not resuscitate order and 9% of the 151 patients without an order died while receiving cardiopulmonary resuscitation. Most neonates received medication to keep them comfortable and their use was similar in both cohorts. CONCLUSION: Changes in neonatal management have led to a reduction in early deaths and an increase in age at death. The impact of later deaths on families and healthcare providers deserves further research. PMID- 25040043 TI - microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. AB - BACKGROUND & AIMS: miR-122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty liver disease, is regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). Here, we hypothesized that reduced miR-122 has a pathogenic role in steatohepatitis. METHODS: miR-122 and its target genes were evaluated in mouse livers and/or isolated hepatocytes after methionine-choline deficient (MCD) or methionine-choline-supplemented (MCS) diet. RESULTS: Liver and hepatocyte miR-122 expression was significantly decreased in steatohepatitis. A maximum reduction in miR-122 occurred at the fibrosis stage (8 weeks of MCD diet). MAP3K3, a miR-122 target gene, was induced at all stages of non-alcoholic steatohepatitis (NASH; 3-8 weeks) only at the mRNA level. Increased NF-kappaB activation was found in MCD diet-fed mice and MAP3K3 regulated the NF-kappaB DNA binding in naive hepatocytes. HIF-1alpha mRNA and DNA binding and expression of the HIF-1alpha target gene, profibrotic lysyl oxidase, was increased in advanced steatohepatitis (8 weeks). In addition, increase in vimentin and Sirius red staining (liver fibrosis) was found at 8 weeks of MCD diet. Using miR-122 overexpression and inhibition approaches, we confirmed that HIF-1alpha, vimentin and MAP3K3 are novel miR-122 targets in hepatocytes. We report transcriptional repression of miR-122 in NASH. Decreased liver miR-122 was associated with elevated circulating miR-122 in both exosome-rich and protein-rich serum fractions. CONCLUSIONS: Our novel data suggest that decreased liver miR-122 contributes to upregulation of modulators of tissue remodelling (HIF-1alpha, vimentin and MAP3K3) and might play a role in NASH-induced liver fibrosis. PMID- 25040045 TI - HBV/HDV co-infection in the Western Brazilian Amazonia: an intriguing mutation among HDV genotype 3 carriers. AB - HDV infection still remains a serious public health problem in Amazonia. There are few data regarding the biomolecular aspects of HBV/HDV co-infection in this region. We studied 92 patients HBsAg(+) /anti-HDV IgG(+) followed at the Hepatitis Referral Centers of Porto Velho (RO), Rio Branco and Cruzeiro do Sul (AC), Brazil, from March 2006 to March 2007 for whom the HDV and/or the HBV genotype could be determined. The HDV genotype could be determined in 90 patients, while the HBV genotypes could be positively determined in 74. HBV subgenotype F2 is the most prevalent (40.2%), followed by the subgenotypes A1 (15.2%) and D3 (8.7%), while 16.4% were other subgenotypes or genotypes, 4.3% were discordant and 15.2% were unamplifiable. Surprisingly, HDV genotype 3 (HDV 3) was found in all of the HBV/HDV-infected patients that could be genotyped for HDV, confirming that HDV-3 can associate with non-F HBV genotypes. However, a HDV 3 mutant was found in 29.3% of patients and was more frequently associated with non-F HBV genotypes (P < 0.001) than were nonmutant strains, suggesting that the mutation may facilitate association of HDV-3 with non-F HBV genotypes. PMID- 25040046 TI - A food-borne outbreak of gastroenteritis due to genotype G1P[8] rotavirus among adolescents in Japan. AB - Six high school students in Tochigi prefecture, Japan, developed gastroenteritis after eating at a pork cutlet shop. Molecular epidemiologic analyses showed that the causative agent was genotype G1P[8] rotavirus (RV), this being detected in stool samples from both the patients and the asymptomatic food handlers. The detected RV strains were closely related genetically. The only uncooked food that all victims had eaten was raw sliced cabbage. These findings results suggest that uncooked foods contaminated with RV may be sources of infectious gastroenteritis in adolescents. PMID- 25040047 TI - The immunobiology of myiasis infections--whatever happened to vaccination? AB - The current state of myiasis vaccine technologies are reviewed mainly in the primary research genera of Lucilia and Hypoderma. The importance of myiasis flies as primary causes of morbidity and mortality in agricultural species and man has not diminished despite the existence of good control strategies. However, the development of vaccines against myiasis infections has been relatively quiescent for more than 10 years despite the rapid development of genomic and proteomic analysis and of skills in data interpretation. The value of vaccine research in an era of chemical primacy is analysed. In fact, recent findings of drug resistance and the impact of animal welfare concerns should mean a renewed interest in alternative controls. The reasons that this has not been true to date are explored and new possibilities discussed. PMID- 25040048 TI - Perioperative endothelin levels in patients undergoing intracardiac repair for tetralogy of Fallot. AB - BACKGROUND: Endothelin, a pro-inflammatory molecule, had been extensively studied in patients with cardiovascular illness. Impact on the perioperative outcome of patients with cyanotic congenital heart defects is still unknown. In the present study, we report perioperative changes in endothelin levels and their correlation with preoperative factors and clinical outcomes in a group of patients with tetralogy of Fallot (TOF) undergoing definitive repair. METHODOLOGY: 167 patients with TOF undergoing intracardiac repair under cardiopulmonary bypass were studied. Endothelin levels were taken at three different points of time and correlated with different clinical variables. RESULTS: The baseline endothelin level correlated with patients' nutritional status and degree of cyanosis. The magnitude of inflammatory response in the post-cardiopulmonary bypass (post-CPB) period as measured by endothelin level was much higher and correlated more consistently with adverse clinical outcomes in the younger age group. On multivariable analysis, age at operation, preoperative degree of hypoxemia, and endothelin levels were found to be independent predictors of clinical outcomes. CONCLUSIONS: A rise in serum endothelin levels in patients with TOF undergoing definitive repair on CPB, with preoperative severity of cyanosis, nutritional status, and adverse clinical outcomes. The endothelin levels may be monitored to identify patients with cyanosis at an increased risk of exhibiting augmented inflammatory response to CPB. PMID- 25040049 TI - Pulmonary embolism workup in five steps. AB - A workup for pulmonary embolism (PE) is complex, with multiple clinical decision rules to remember. A proper diagnostic workup can safely rule out PE without the use of computed tomography, which is both expensive and exposes patients to radiation and intravenous contrast. However, once PE has been diagnosed, it is important to risk stratify patients according to severity to both treat and disposition them correctly. PQRsTU is a simple, easy-to-remember mnemonic for the workup of PE that considers five phases: PERC phase (PE rule-out criteria), Quantify gestalt phase (to determine proper use of D-dimer or direct to imaging), Risk stratification phase (once PE has been diagnosed), Treatment phase, and Unit or floor (patient disposition). This structured method for evaluating PE will help clinicians develop a systematic, evidence-based approach to this complex and potentially lethal disease. Video is available at https://vimeo.com/91406117 Password: perls. PMID- 25040050 TI - Teleological care and the last years of life. AB - The final years of life present challenges for care. In middle-/high-income countries, the percentage of people of advanced age in the population is growing, and the dying process continues to become more complex and protracted. We propose that a new understanding of care, 'teleological care', be considered as an important response to the contemporary challenges of the final years of life. Teleological care is a philosophy of care built around the root idea of a telos (i.e. end) in three senses: (1) the end of life as a temporal limit; (2) the ends of life as the individual's purpose and meaning; (3) the end of life as the meaning of life as a whole. In its practice, teleological care adheres to principles of (1) fidelity of practitioner to patient; (2) generalism of practitioners; and (3) coordination of care within existing services. With this philosophy and practice, care is administered by generalist health care professionals arranging for flow between care that attempts to reverse, stop or slow the disease process when appropriate, with care to address symptoms, and with care that responds to the difficulties of dying. Teleological care involves already existing programmes in roughly their present forms, serving as an overarching layer of organization added to the existing systems. Teleological care refocuses the concept of care to the patient's perspective with emotional, spiritual and practical support for facing the end of life, and a space for narrative and reflection within a wider circle of care. PMID- 25040051 TI - CREB signalling in bipolar disease (commentary on Gaspar et al.): commentary on Gaspar et al. 2014. PMID- 25040052 TI - Evaluation of high-resolution melting and other molecular methods in discrimination of Lactobacillus isolates. AB - AIMS: Fermented and probiotic products are mainly based on the activity of diverse Lactobacillus species. Distinguishing of these species, especially the closely related ones might be problematic. Our aim was to compare and evaluate molecular methods that have the potential of discrimination and might serve as alternatives of traditional microbiological techniques. METHODS AND RESULTS: In our experiments, PCR methods using general and species-specific bacterial primers, RFLP, sequencing and HRM assays were tested and their efficiency compared. A new universal primer pair was designed for amplification of short fragments of the 16S rDNA of six Lactobacillus, a Lactococcus and a Streptococcus species; furthermore, successful HRM analysis was performed on them that resulted in the separation of each species, including the almost indistinguishable Lact. paracasei ssp. paracasei and Lact. paracasei ssp. tolerans subspecies. CONCLUSIONS: The results showed that HRM might be a useful, time- and cost-saving one-step tool for preliminary classification of isolates, although the use of additional techniques, like species-specific PCR, analysis of RFLP patterns and sequencing, might be necessary for confirmation of the results. SIGNIFICANCE AND IMPACT OF THE STUDY: The newly developed HRM primers offer a quick and efficient tool for discrimination of lactobacilli, including very closely related Lactobacillus subspecies. PMID- 25040053 TI - New thyroid fine needle aspiration biopsy needle. Prospective, randomized, clinical study. AB - Nodular disease of thyroid in the adult population is common [1]. Estimated prevalence of thyroid nodules on the basis of palpation ranges from 3% to 7% [2]. During the past two decades, according to widespread use of ultrasonography (US) for evaluation of thyroid and nonthyroid neck diseases prevalence of clinically inapparent thyroid nodules is increased, estimated at 20% to 76% in the general population [3,4]. This article is protected by copyright. All rights reserved. PMID- 25040054 TI - The trauma of peer victimization: psychophysiological and emotional characteristics of memory imagery in subjects with social anxiety disorder. AB - The study investigated the role of an associative information network as a mechanism underlying the relation of peer victimization and social anxiety disorder (SAD). A sample of N = 80 was divided according to diagnosis (SAD vs. no diagnosis) and amount of peer victimization (low vs. high). Responses to memory of a personally experienced aversive social situation and to imagining a standardized negative social situation were assessed. In terms of skin conductance level, subjects with SAD and peer victimization were more reactive to the memory script than the other three groups while responses to the standardized script did not vary. As to heart rate, there were no differences between the groups. Emotional responses presented with an inconsistent pattern. The results provide a first indication that associative memory structures resulting from aversive social experiences might play a role in the development and maintenance of SAD, but further research is needed. PMID- 25040055 TI - Accessing osteocyte lacunar geometrical properties in human jaw bone on the submicron length scale using synchrotron radiation MUCT. AB - The architectural properties of the osteocyte cell network provide a valuable basis for understanding the mechanisms of bone remodelling, mineral homeostasis, ageing and pathologies. Recent advances in synchrotron microtomography enable unprecedented three-dimensional imaging of both the bone lacunar network and the extracellular matrix. Here, we investigate the three-dimensional morphological properties of osteocyte lacunae in human healthy and bisphosphonate-related osteonecrotic jaw bone based on synchrotron X-ray computed tomography images, with a spatial isotropic voxel size of 300 nm. Bisphosphonate-related osteonecrosis of the jaw is a relatively new disease with increasing incidence, which remains poorly understood. A step forward in elucidating this malady is to assess whether, and how, the morphology of the osteocyte lacunar network is modified in the affected jaw tissue. We evaluate thousands of cell lacunae from five specimens of which three originate from patients diagnosed with bisphosphonate-associated osteonecrosis. In this exploratory study, we report three-dimensional quantitative results on lacunar volumes (296-502 MUm(3)), shape (approximated by an ellipsoidal shape with principal axes a > b > c, such that a = 2.2b and a = 4c) and spatial distribution (i.e., 50% of the mineralized matrix volume is located within 12 MUm to the closest lacunar boundary) at submicron resolution on such specimens. We observe that the average lacunar volumes of the bisphosphonate-related osteonecrotic jaw specimens were within the range of volumes found in the two specimens originating from healthy donors and conclude that lacunar volumes are not the key element in the course of bisphosphonate related osteonecrotic jaw. In three out of five specimens we observe lacunar volume sizes in segmented osteons to be significantly different compared to lacunar volumes in the adjacent tissue regions. Furthermore, we quantify the number of lacunae containing small dense objects (on average 9%). In contrast to lacunar morphology we report the lacunar density (16,000-50,000 per mm(3)) to be different in jaw bone tissue compared to what has been reported in femoral sites. PMID- 25040056 TI - Change in activity of serine palmitoyltransferase affects sensitivity to syringomycin E in yeast Saccharomyces cerevisiae. AB - Syringomycin E is a cyclic lipodepsipeptide produced by strains of the plant bacterium Pseudomonas syringae pv. syringae. Genetic studies involving the yeast Saccharomyces cerevisiae have revealed that complex sphingolipids play important roles in the action of syringomycin E. Here, we found a novel mutation that confers resistance to syringomycin E on yeast; that is, a deletion mutant of ORM1 and ORM2, which encode negative regulators of serine palmitoyltransferase catalyzing the initial step of sphingolipid biosynthesis, exhibited resistance to syringomycin E. On the contrary, overexpression of Orm2 resulted in high sensitivity to the toxin. Moreover, overexpression of Lcb1 and Lcb2, catalytic subunits of serine palmitoyltransferase, causes resistance to the toxin, whereas partial repression of expression of Lcb1 had the opposite effect. Partial reduction of complex sphingolipids by repression of expression of Aur1, an inositol phosphorylceramide synthase, also resulted in high sensitivity to the toxin. These results suggested that an increase in sphingolipid biosynthesis caused by a change in the activity of serine palmitoyltransferase causes resistance to syringomycin E. PMID- 25040057 TI - Multiple intracranial space-occupying lesions in a renal transplant recipient from an area endemic for tuberculosis (TB): TB vs. toxoplasmosis. AB - Renal transplant recipients may present with intracranial space-occupying lesions (SOLs) due to infections as well as a post-transplant lymphoproliferative disorder (PTLD). Here, we discuss a renal transplant recipient who presented with neurologic symptoms and magnetic resonance imaging (MRI) of the brain showed multiple focal SOLs. Tuberculosis (TB), toxoplasmosis, nocardiosis, fungal infections, and PTLD were considered in the differential diagnosis. MRI spectroscopy was suggestive of an infectious cause, such as toxoplasmosis or TB. Serologic tests using Toxoplasma were negative. A brain biopsy followed by immunohistochemical staining using Toxoplasma antibody demonstrated multiple intravascular cysts of toxoplasma. This case highlights the diagnostic dilemma in an immunocompromised patient with multiple focal brain lesions, especially in areas where TB is endemic. PMID- 25040059 TI - Direct imaging electron microscopy (EM) methods in modern structural biology: overview and comparison with X-ray crystallography and single-particle cryo-EM reconstruction in the studies of large macromolecules. AB - Determining the structure of macromolecules is important for understanding their function. The fine structure of large macromolecules is currently studied primarily by X-ray crystallography and single-particle cryo-electron microscopy (EM) reconstruction. Before the development of these techniques, macromolecular structure was often examined by negative-staining, rotary-shadowing and freeze etching EM, which are categorised here as 'direct imaging EM methods'. In this review, the results are summarised by each of the above techniques and compared with respect to four macromolecules: the ryanodine receptor, cadherin, rhodopsin and the ribosome-translocon complex (RTC). The results of structural analysis of the ryanodine receptor and cadherin are consistent between each technique. The results obtained for rhodopsin vary to some extent within each technique and between the different techniques. Finally, the results for RTC are inconsistent between direct imaging EM and other analytical techniques, especially with respect to the space within RTC, the reasons for which are discussed. Then, the role of direct imaging EM methods in modern structural biology is discussed. Direct imaging methods should support and verify the results obtained by other analytical methods capable of solving three-dimensional molecular architecture, and they should still be used as a primary tool for studying macromolecule structure in vivo. PMID- 25040058 TI - Increased and correlated expression of connective tissue growth factor and transforming growth factor beta 1 in surgically removed periodontal tissues with chronic periodontitis. AB - BACKGROUND AND OBJECTIVE: Both gingival tissue destruction and regeneration are associated with chronic periodontitis, although the former overwhelms the latter. Studies have shown that transforming growth factor beta 1 (TGF-beta1), a growth factor largely involved in tissue regeneration and remodeling, is upregulated in chronic periodontitis. However, the gingival expression of connective tissue growth factor (CTGF or CCN2), a TGF-beta1-upregulated gene, in patients with periodontitis remains undetermined. Although both CTGF/CCN2 and TGF-b1 increase the production of extracellular matrix, they have many different biological functions. Therefore, it is important to delineate the impact of periodontitis on gingival CTGF/CCN2 expression. MATERIAL AND METHODS: Periodontal tissue specimens were collected from seven individuals without periodontitis (group 1) and from 14 with periodontitis (group 2). The expression of CTGF and TGFbeta1 mRNAs were quantified using real-time PCR. RESULTS: Analysis using the nonparametric Mann Whitney U-test showed that the levels of expression of both CTGF/CCN2 and TGFbeta1 mRNAs were significantly increased in individuals with periodontitis compared with individuals without periodontitis. Furthermore, analysis using a nonparametric correlation (Spearman r) test showed a positive correlation between TGFbeta1 and CTGF/CCN2 mRNAs. CONCLUSION: The gingival expression levels of CTGF/CCN2 and TGFbeta1 mRNAs in individuals with periodontitis are upregulated and correlated. PMID- 25040060 TI - Rapid molecular screening for multidrug-resistant tuberculosis in a resource limited region of China. AB - OBJECTIVE: To investigate the molecular characteristics of MDR and XDR strains circulating in Chongqing, China. METHODS: The drug target genes conferring for rifampicin (RIF), isoniazid (INH), ethambutol (EMB), ofloxacin (OFLX) and kanamycin (KAN) resistance were screened by DNA sequencing to determine the mutation frequencies in this area. RESULTS: Drug susceptibility of 208 MDR isolates revealed that 132 (63.46%) were resistant to streptomycin (SM), 96 (46.15%) to ethambutol (EMB), 51 (24.52%) to ofloxacin (OFLX), and 26 (12.50%) to kanamycin (KAN); six (2.88%) isolates had XDR profiles. In comparison with the drug susceptibility phenotype, the sensitivity of drug resistance by DNA sequencing was 91.83% for RIF, 87.50% for INH, 66.67% for EMB, 74.51% for OFLX and 53.85% for KAN resistance. 12.50% of EMB- and 1.27% of OFLX-susceptible isolates were harboured genetic mutations in embB and gyrA, respectively. CONCLUSION: Our findings demonstrate that the hot-spot regions localised in rpoB, katG and inhA genes serve as excellent markers for the corresponding drug resistance, while EMB, OFLX or KAN drug-resistant TB cases may not be identifiable by scanning embB, gyrA, rrs and eis promoter in Chongqing, indicating that further studies on the drug resistance mechanisms of EMB, OFLX and KAN are urgently needed to elucidate the low sensitivity between genomic substitutions and drug-resistant phenotype. PMID- 25040061 TI - Older siblings as potential supervisors of younger siblings: sibling supervisors' recognition of injury-risk behaviours and beliefs about supervisee risk taking and potential injury outcomes. AB - BACKGROUND: Past research has shown that increased injury risk for supervisees during sibling supervision is in part due to the supervision practices of older siblings. METHODS: The current study used a photo sorting task to examine older siblings' recognition of injury-risk behaviours, their perceived likelihood of supervisees engaging in, or being injured while engaging in, these behaviours, and awareness of past risk-taking behaviours of supervisees. Mothers completed the same measures and an interview about sibling supervision in the home. RESULTS: Mothers reported that sibling supervision occurred most frequently in the kitchen, living room, and children's bedrooms, for approximately 39 min/day, and that the more time the children spent together in a room, the more frequently the older sibling supervised the younger one. The most common reasons mothers gave for why sibling supervision was allowed included beliefs that the older child knows about hazards and unsafe behaviours and that the child could provide adequate supervision. Photo sort results revealed that older siblings were able to correctly identify about 98% of risk behaviours, with these scores significantly higher than what mothers expected (79%). However, compared with mothers, older siblings were less aware of risk behaviours that their younger siblings had engaged in previously. In addition, mothers rated supervisees as 'fairly likely' both to engage in risk behaviours and to experience an injury if they tried these behaviours, whereas sibling supervisors rated both supervisee risk behaviour and injury outcomes as 'not likely' to occur. CONCLUSION: Older siblings showed good knowledge of hazards but failed to realize that younger children often engage in injury-risk behaviours. Efforts to improve the supervision practices of sibling supervisors need to include changing their perception of supervisees' injury vulnerability and potential injury severity, rather than targeting to increase knowledge of injury-risk behaviours per se. PMID- 25040062 TI - Family matters - social competence in children with epilepsy. PMID- 25040063 TI - A systematic review and meta-analysis of the i-gel((r)) vs laryngeal mask airway in adults. AB - We systematically reviewed 31 adult randomised clinical trials of the i-gel((r)) vs laryngeal mask airway. The mean (95% CI) leak pressure difference and relative risk (95% CI) of insertion on the first attempt were similar: 0.40 (-1.23 to 2.02) cmH2 O and 0.98 (0.95-1.01), respectively. The mean (95% CI) insertion time and the relative risk (95% CI) of sore throat were less with the i-gel: by 1.46 (0.33-2.60) s, p = 0.01, and 0.59 (0.38-0.90), p = 0.02, respectively. The relative risk of poor fibreoptic view through the i-gel was 0.29 (0.16-0.54), p < 0.0001. All outcomes displayed substantial heterogeneity, I(2) >= 75%. Subgroup analyses did not decrease heterogeneity, but suggested that insertion of the i gel was faster than for first-generation laryngeal mask airways and that the i gel leak pressure was higher than first generation, but lower than second generation, laryngeal mask airways. A less frequent sore throat was the main clinical advantage of the i-gel. PMID- 25040064 TI - New phenolics from the root of Scutellaria prostrata JACQ. ex BENTH. AB - Scutellaria prostrata (Lamiaceae), a perennial herb growing as a lonely species in Kashmir, Himalayas, was subjected to repetitive column and flash chromatographic isolation for its chemical documentation-cum-bioevaluation. The methanolic extract of S.prostrata afforded the isolation of ten compounds (1-10), including two new compounds - scutellapbiflavanone (1) and scutellaprostin M (2). The known compounds were found to be scutellarin (3), hispidulin-7-O-beta-D glucopyranoside (4), baicalin (5), wogonoside (6), scutellaprostin C (7), acetoside (8), martynoside (9) and scutellaric acid-3-O-beta-D-glucopyranoside (10). Isolation of biflavonoids, phenolics and phenylethanoid compounds from S. prostrata seals a deal of chemotaxonomic importance of this particular species. The characterisation of the compounds was achieved by (1)H, (13)C, (1)H-(1)H DFQ COSY, HMBC, HSQC, HMQC and ROESY NMR experiments. All the compounds were tested for antioxidant, antimicrobial and cytotoxic activities. PMID- 25040065 TI - Do mites evolving in alternating host plants adapt to host switch? AB - A fluctuating environment may be perceived as a composition of different environments, or as an environment per se, in which it is the fluctuation itself that poses a selection pressure. If so, then organisms may adapt to this alternation. We tested this using experimental populations of spider mites that have been evolving for 45 generations in a homogeneous environment (pepper or tomato plants), or in a heterogeneous environment composed of an alternation of these two plants approximately at each generation. The performance (daily oviposition rate and juvenile survival) of individuals from these populations was tested in each of the homogeneous environments, and in two alternating environments, one every 3 days and the other between generations. To discriminate between potential genetic interactions between alleles conferring adaptation to each host plant and environmental effects of evolving in a fluctuating environment, we compared the performance of all lines with that of a cross between tomato and pepper lines. As a control, two lines within each selection regime were also crossed. We found that crosses between alternating lines and between pepper and tomato lines performed worse than crosses between lines evolving in homogeneous environments when tested in that environment. In contrast, alternating lines performed either better or similarly to lines evolving in homogeneous environments when tested in a fluctuating environment. Our results suggest that fluctuating environments are more than the juxtaposition of two environments. Hence, tests for adaptation of organisms evolving in such environments should be carried out in fluctuating conditions. PMID- 25040066 TI - Treatment of a chronic vesicocutaneous fistula and abdominal wall defect after resection of a soft tissue sarcoma using a bipedicled latissimus dorsi and serratus anterior free flap. AB - We present a surgical treatment for bladder reconstruction in a case of chronic vesicocutaneous radiation-induced fistula and reconstruction of the abdominal wall after resection of a liposarcoma in the rectus abdominis muscle. Fistulas are sequelae after radiotherapy. To regain bladder function and reconstitute abdominal wall stability, a microsurgical flap approach should be considered. A male patient underwent resection of a liposarcoma in the rectus abdominis muscle with adjuvant radiotherapy, suffering from a chronic vesicocutaneous fistula. A bipedicled combined latissimus dorsi and serratus anterior flap was carried out after resection of the fistula for reconstruction of the urine bladder and the abdominal wall. Ascending urethrography 4 weeks postoperatively showed no leakage. In the 4-month follow-up period, no signs of recurrence of the fistula or herniation occurred. A bipedicled flap allowed reconstruction of the urine bladder and the abdominal wall. Using non-irradiated, well-perfused intra abdominal muscle tissue over the urine bladder prevented recurrence of the fistula. PMID- 25040067 TI - Mothers' early depressive symptoms predict children's low social competence in first grade: mediation by children's social cognition. AB - BACKGROUND: This study examined whether social-cognitive processes in children mediate relations between mothers' depressive symptoms across the first 3 years and children's first-grade social competence. Three maladaptive cognitions were examined: self-perceived social inadequacy, hostile attribution, and aggressive response generation. METHOD: One thousand three hundred and sixty-four mothers reported depressive symptoms across early development, first-grade children reported target social cognitions, and children's first-grade social competence was observed and reported by multiple informants. RESULTS: Findings demonstrated that (a) mothers' average depressive symptoms from 6 to 36 months predicted children's maladaptive social cognition in first grade, (b) low mother-child responsiveness mediated this relation, and (c) maladaptive social cognition mediated relations between mothers' early depressive symptoms and low first-grade social competence independent of later depressive symptoms. CONCLUSION: When mothers' depressive symptoms occur early in development, they may set in motion low-responsive dyadic patterns that promote children's maladaptive social cognition and, as a result, low social competence. PMID- 25040069 TI - The dental development in patients with Aperts syndrome. AB - OBJECTIVES: The aim of this retrospective study was to quantify the level of dental developmental delay in a group of patients with Aperts syndrome when compared to matched controls. METHODS: Twenty-six Dental Panoramic Tomographic (DPT) radiographs of patients with Apert syndrome attending Great Ormond Street Hospital were compared to controls (n = 29) from the Eastman Dental Hospital, UK. Dental development was assessed using the staging systems of Demirjian and Haavikko, and dental age (DA) was estimated using the weighted averages method. RESULTS: Dental age, as estimated using the 12 stages of Haavikko and eight stages of Demirjian, suggested no statistical evidence of developmental delay between the Aperts and control group. CONCLUSIONS: The hypothesis 'that there is no difference in the dental development of subjects with Apert syndrome, when compared to a group of matched controls', was accepted. PMID- 25040068 TI - Standardized severe maternal morbidity review: rationale and process. AB - Severe maternal morbidity and mortality have been rising in the United States. To begin a national effort to reduce morbidity, a specific call to identify all pregnant and postpartum women experiencing admission to an intensive care unit or receipt of four or more units of blood for routine review has been made. While advocating for review of these cases, no specific guidance for the review process was provided. Therefore, the aim of this expert opinion is to present guidelines for a standardized severe maternal morbidity interdisciplinary review process to identify systems, professional, and facility factors that can be ameliorated, with the overall goal of improving institutional obstetric safety and reducing severe morbidity and mortality among pregnant and recently pregnant women. This opinion was developed by a multidisciplinary working group that included general obstetrician-gynecologists, maternal-fetal medicine subspecialists, certified nurse-midwives, and registered nurses all with experience in maternal mortality reviews. A process for standardized review of severe maternal morbidity addressing committee organization, review process, medical record abstraction and assessment, review culture, data management, review timing, and review confidentiality is presented. Reference is made to a sample severe maternal morbidity abstraction and assessment form. PMID- 25040070 TI - Millennial-scale ocean acidification and late Quaternary decline of cryptic bacterial crusts in tropical reefs. AB - Ocean acidification by atmospheric carbon dioxide has increased almost continuously since the last glacial maximum (LGM), 21,000 years ago. It is expected to impair tropical reef development, but effects on reefs at the present day and in the recent past have proved difficult to evaluate. We present evidence that acidification has already significantly reduced the formation of calcified bacterial crusts in tropical reefs. Unlike major reef builders such as coralline algae and corals that more closely control their calcification, bacterial calcification is very sensitive to ambient changes in carbonate chemistry. Bacterial crusts in reef cavities have declined in thickness over the past 14,000 years with largest reduction occurring 12,000-10,000 years ago. We interpret this as an early effect of deglacial ocean acidification on reef calcification and infer that similar crusts were likely to have been thicker when seawater carbonate saturation was increased during earlier glacial intervals, and thinner during interglacials. These changes in crust thickness could have substantially affected reef development over glacial cycles, as rigid crusts significantly strengthen framework and their reduction would have increased the susceptibility of reefs to biological and physical erosion. Bacterial crust decline reveals previously unrecognized millennial-scale acidification effects on tropical reefs. This directs attention to the role of crusts in reef formation and the ability of bioinduced calcification to reflect changes in seawater chemistry. It also provides a long-term context for assessing anticipated anthropogenic effects. PMID- 25040072 TI - Deep rectal shaving using plasma energy for endometriosis causing rectal stenosis - a video vignette. PMID- 25040071 TI - Diazepam improves aspects of social behaviour and neuron activation in NMDA receptor-deficient mice. AB - NR1 knockdown (NR1KD) mice are genetically modified to express low levels of the NR1 subunit of N-methyl-D-aspartate (NMDA) receptors, and show deficits in affiliative social behaviour. In this study, we determined which brain regions were selectively activated in response to social stimulation and asked whether differences in neuronal activation could be observed in mice with reduced sociability. Furthermore, we aimed to determine whether brain activation patterns correlated with the amelioration of social deficits through pharmacological intervention. The cingulate cortex, lateral septal nuclei, hypothalamus, thalamus and amygdala showed an increase in c-Fos immunoreactivity that was selective for exposure to social stimuli. NR1KD mice displayed a reduction in social behaviour and a reduction in c-Fos immunoreactivity in the cingulate cortex and septal nuclei. Acute clozapine did not significantly alter sociability; however, diazepam treatment did increase sociability and neuronal activation in the lateral septal region. This study has identified the lateral septal region as a neural substrate of social behaviour and the GABA system as a potential therapeutic target for social dysfunction. PMID- 25040073 TI - Capillary malformation-arteriovenous malformation syndrome with spinal involvement. AB - Capillary malformation-arteriovenous malformation (CM-AVM) is a recently identified autosomal dominant disorder. Arteriovenous lesions have been reported in the brain, limbs, and face. We report a 7-year-old patient with CM-AVM with spinal AVM, which is a rarely reported association. PMID- 25040074 TI - Fluoride effectiveness in high caries risk and medically complex Veterans. AB - BACKGROUND: The Global Burden of Disease Study showed there was a 34.5% increase in years lived with disability due to dental caries from 1990 to 2010. With the aging of 76 million baby boomers, dental caries will continue to pose a significant challenge for older adults. OBJECTIVE: Test the effectiveness of prescription or professionally applied fluoride in the prevention of new dental restorations in a clinical setting where patients are medically compromised and more dentally impaired than the general population. METHODS: A retrospective cohort study, using multiple electronic databases within the Department of Veterans Affairs. Propensity scores were used to adjust for confounding by indication and logistic regression modeled the outcome and included all expected covariates. RESULTS: The study sample included 140,114 high caries risk Veterans with a mean of 3.4 physical comorbidities, 1.2 mental comorbidities, and 11 medication groups per patient. Patients who received clinical fluoride treatments had 17-20% decreased odds of requiring a restoration during the follow-up period. CONCLUSIONS: Prescription self-applied or professionally applied fluoride provided either before or during an episode of care significantly reduced the likelihood of new restorations in high caries risk and medically compromised Veterans. PMID- 25040075 TI - The role of cytokines and chemokines in the T-cell-mediated autoimmune process in alopecia areata. AB - The aetiology of alopecia areata (AA) is still not fully understood. However, recent clinical and experimental studies have provided insights into the pathomechanisms of AA and revealed that it is an organ-specific and cell-mediated autoimmune disease. Some triggers, such as viral infections, trauma, hormones and emotional/physical stressors, may cause activation of autoreactive T cells that target hair follicle (HF) autoantigens. In these immunological responses, cytokines and chemokines are regarded as key players that mediate the autoimmune inflammation. This results in the collapse of HF immune privilege, which is central to the pathogenesis of AA. This essay will focus on how cytokines and chemokines contribute to the immunological aspects of AA. The management of AA often remains difficult in a number of cases. Our review suggests that novel therapies for AA may involve targeting cytokines and chemokines. PMID- 25040076 TI - An unusual case of bilateral pyoderma gangrenosum with Achilles tendon rupture. AB - Pyoderma gangrenosum (PG) is a rare, noninfectious, inflammatory disease characterized by neutrophilic infiltration of the dermis and destruction of tissue. PG is a diagnostic challenge, which can lead to late diagnosis, delayed treatment and detrimental surgical interventions. We describe a presentation not previously reported, affecting deep muscle and tendon leading to tendon rupture. Furthermore, we show the multidisciplinary team approach to management of a patient with PG and the reconstructive surgical element. A 31-year-old woman presented with a rapid onset painful, tender, left calf and ankle, which was associated with a mild flare of ulcerative colitis. Investigations revealed a white cell count of 26 * 10(9) cells L(-1) , a C-reactive protein count of 226 mg L(-1) , no deep vein thrombosis on ultrasound, no bone or joint involvement on X ray and no organisms on joint aspirate. Debridement was undertaken after the left ankle developed a foul-smelling discharging wound. Repeat debridement led to worsening of the condition (pathergy). Intraoperative tissue cultures and microscopy showed no evidence of fungi, bacteria or mycobacteria. Histology showed granulation, inflammatory infiltrate, abscess formation and focal necrotizing vasculitis. Dermatology opinion confirmed PG. Awareness of the diagnosis of PG, and early involvement of dermatology, in a rapidly progressing wound is essential to avoid delayed treatment and prevent worsening through pathergy. PMID- 25040077 TI - A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects in TP53. AB - Chronic lymphocytic leukaemia (CLL) is an indolent B-cell malignancy with heterogeneous outcomes. Chromosomal abnormalities in CLL are predictive of the natural disease course; del(11q) and del(17p) are recognized as high risk genetic lesions. Del(17p) is associated with an impaired function of TP53, a key tumour suppressor, and is particularly problematic. Such patients respond poorly to chemo-immunotherapy and have significantly shorter survival compared to patients with standard and low-risk cytogenetics. While TP53 pathway defects are rare at initial diagnosis, their frequency increases in relapsed CLL. Until very recently, this group of patients represented an unmet clinical need with few therapeutic options. However, the advent of targeted therapies has expanded the drug armamentarium and introduced new hope for these highly refractory patients. Agents that target B-cell receptor signalling, BH3-mimetics and others induce apoptosis of the neoplastic B-cells in a TP53-independent manner. Their use in the clinic is associated with remarkable activity in patients with del(17p). In this review we discuss the frequency and clinical significance of del(17p) and genetic mutations leading to disrupted TP53, the putative role of other TP53 homologues, and the results of key clinical trials involving both conventional chemotherapy and novel agents. PMID- 25040078 TI - Intake of dairy products and calcium and prevalence of depressive symptoms during pregnancy in Japan: a cross-sectional study. AB - OBJECTIVE: To examine the relationship between the intake of dairy products and calcium and the prevalence of depressive symptoms during pregnancy. DESIGN: Cross sectional study. SETTING: Kyushu Okinawa Maternal and Child Health Study (KOMCHS). SAMPLE: A cohort of 1745 pregnant Japanese women. METHODS: Dietary intake during the preceding month was assessed using a self-administered diet history questionnaire. Scores of 16 or higher on the Center for Epidemiologic Studies Depression Scale denoted depressive symptoms. Adjustment was made for age, gestation, region of residence, number of children, family structure, history of depression, family history of depression, smoking, secondhand smoke exposure at home and at work, job type, household income, education, and body mass index. In our analyses regarding dairy products in general, adjustment was also made for fish intake; in our analysis regarding calcium, adjustment was also made for the intake of saturated fatty acids, eicosapentaenoic acid plus docosahexaenoic acid, and vitamin D. MAIN OUTCOME MEASURES: Depressive symptoms during pregnancy. RESULTS: Higher intake levels of yogurt and calcium were independently related to a lower prevalence of depressive symptoms during pregnancy: the adjusted odds ratios between extreme quartiles were 0.69 (95% CI 0.48-0.99, P for trend = 0.03) and 0.59 (95% CI 0.40-0.88, P for trend = 0.006), respectively. No relationships were observed between the intake of all dairy products, milk, or cheese and depressive symptoms during pregnancy. CONCLUSIONS: The current results suggest that a higher intake of yogurt and calcium may be associated with a lower prevalence of depressive symptoms during pregnancy. PMID- 25040079 TI - Prominent intraspecific genetic divergence within Anopheles gambiae sibling species triggered by habitat discontinuities across a riverine landscape. AB - The Anopheles gambiae complex of mosquitoes includes malaria vectors at different stages of speciation, whose study enables a better understanding of how adaptation to divergent environmental conditions leads to evolution of reproductive isolation. We investigated the population genetic structure of closely related sympatric taxa that have recently been proposed as separate species (An. coluzzii and An. gambiae), sampled from diverse habitats along the Gambia river in West Africa. We characterized putatively neutral microsatellite loci as well as chromosomal inversion polymorphisms known to be associated with ecological adaptation. The results revealed strong ecologically associated population subdivisions within both species. Microsatellite loci on chromosome-3L revealed clear differentiation between coastal and inland populations, which in An. coluzzii is reinforced by a unusual inversion polymorphism pattern, supporting the hypothesis of genetic divergence driven by adaptation to the coastal habitat. A strong reduction of gene flow was observed between An. gambiae populations west and east of an extensively rice-cultivated region apparently colonized exclusively by An. coluzzii. Notably, this 'intraspecific' differentiation is higher than that observed between the two species and involves also the centromeric region of chromosome-X which has previously been considered a marker of speciation within this complex, possibly suggesting that the two populations may be at an advanced stage of differentiation triggered by human made habitat fragmentation. These results confirm ongoing ecological speciation within these most important Afro-tropical malaria vectors and raise new questions on the possible effect of this process in malaria transmission. PMID- 25040081 TI - Laryngeal mask airway placement in children prior to an intravenous line utilizing heart rate as an indicator of anesthetic depth. AB - INTRODUCTION: The usual practice in pediatric anesthesia cases requiring a laryngeal mask airway is to place an intravenous line (IV) prior to laryngeal mask airway placement. A different approach that has several clinical advantages is to place the laryngeal mask airway prior to the IV. We describe our experience with this technique, using heart rate as an indicator of adequate anesthetic depth. In addition, we analyzed heart rate data in children undergoing sevoflurane inductions, looking for age-related differences. METHODS: Following a sevoflurane induction, heart rates were recorded every 12 s for 3 min in 127 ASA I-II children under age 7. Laryngeal mask airway placement occurred when the heart rate dropped at least 10% from its maximum level or at 3 min. Ease of laryngeal mask airway placement was graded using a scale from 0 to 3. Endtidal sevoflurane concentration, occurrence of laryngospasm and blood pressure at laryngeal mask airway placement were also recorded. RESULTS: The laryngeal mask airway was successfully placed on the first attempt in all 127 children. Easy placement was noted in 98.4%. The youngest children's heart rates peaked earlier than the oldest (P < 0.001), while time to laryngeal mask airway placement increased with increasing age (P < 0.0001). CONCLUSIONS: Laryngeal mask airway placement before an IV is a safe alternative to the usual mask-IV-laryngeal mask airway sequence. Our data compare favorably to other studies where ease of laryngeal mask airway placement was reported. This technique has several advantages including securing the airway first for an anticipated difficult IV placement. Heart rate changes during a sevoflurane induction appear to be age dependent. PMID- 25040082 TI - Mechanical comparison of loop and crimp configurations for extracapsular stabilization of the cranial cruciate ligament-deficient stifle. AB - OBJECTIVE: To biomechanically compare different loop and crimp configurations used for extracapsular suture stabilization of the CCL-deficient stifle. STUDY DESIGN: In vitro study. SAMPLE POPULATION: Crimped loop constructs of 100 lb Ande type nylon leader line in 7 different configurations comprising single and double loops, single and double crimps, and the interlocking loop configuration. METHODS: Constructs premade on external skeletal fixator bars 60 mm apart and tested in tension with a custom-made split circular arm mounted on a table-top materials testing machine. Data were derived from force/displacement plots. In "load to failure" test (10/group) constructs were loaded to failure with distraction rates of 10 mm/min; ultimate load, tension at 2 mm elongation and failure were recorded. In "staircase" test (5/group) constructs cycled at 100 N/s from 75 N with incremental increases of 50 N/cycle; ultimate load, maximum tension before elongation at rest over 2 mm and failure were recorded. In "cycling and jumping" test (10/group) 3 of 7 constructs cycled at 100 N/s 100 times from 50 to 100 N, then 5 times from 50 to 600 N; failure and elongation at cycles 1, 50 and 100 and at jumps 1 to 5 recorded. RESULTS: Double-loop double crimp configurations were statistically superior to all other configurations in ultimate load, and to single-loop and interlocking loop configurations in elongation in "load to failure" and "staircase" tests. In "cycling and jumping" test the interlocking loop configuration specimens elongated significantly more than the others and only in the double-loop double-crimp group did all constructs complete the test. CONCLUSIONS: Double-loop double-crimp configurations are mechanically superior to other previously described configurations. PMID- 25040083 TI - Polihexanide solution is more efficient than alcohol to remove phenol in chemical matricectomy: an in vitro study. AB - For treatment of ingrown toenails, a phenolization approach is often chosen. Many reports describe a lavage of the wound with alcohol to neutralize any residual phenol; however, it remains uncertain if there is a more effective solution for use in the lavage step. The aim of our study was to analyze the suitability and effectiveness of 0.1% polihexanide solution compared with isopropyl alcohol in the removal of excess phenol after treatment for ingrown toenails. We performed an in vitro study using human matrix and a diffusion cell apparatus to measure the amount of phenol remaining after two lavage washes. The effect of phenol evaporation was also examined.When phenol was irrigated with alcohol alone, 27.43 +/- 4.10 mg (57.74%) of the initial amount of phenol was recovered. If irrigated with 0.1% polihexanide, 35.98 +/- 2.93 mg (75.74%) of phenol was recovered. These results indicate that a polihexanide lavage step has significantly higher efficiency for removing excess phenol relative to alcohol. PMID- 25040084 TI - Big data in organ transplantation: registries and administrative claims. AB - The field of organ transplantation benefits from large, comprehensive, transplant specific national data sets available to researchers. In addition to the widely used Organ Procurement and Transplantation Network (OPTN)-based registries (the United Network for Organ Sharing and Scientific Registry of Transplant Recipients data sets) and United States Renal Data System (USRDS) data sets, there are other publicly available national data sets, not specific to transplantation, which have historically been underutilized in the field of transplantation. Of particular interest are the Nationwide Inpatient Sample and State Inpatient Databases, produced by the Agency for Healthcare Research and Quality. The USRDS database provides extensive data relevant to studies of kidney transplantation. Linkage of publicly available data sets to external data sources such as private claims or pharmacy data provides further resources for registry-based research. Although these resources can transcend some limitations of OPTN-based registry data, they come with their own limitations, which must be understood to avoid biased inference. This review discusses different registry-based data sources available in the United States, as well as the proper design and conduct of registry-based research. PMID- 25040087 TI - Tool for BiV capture diagnosis. PMID- 25040086 TI - Off-Line Multidimensional Liquid Chromatography and Auto Sampling Result in Sample Loss in LC/LC-MS/MS. AB - Large-scale proteomics often employs two orthogonal separation methods to fractionate complex peptide mixtures. Fractionation can involve ion exchange separation coupled to reversed-phase separation or, more recently, two reversed phase separations performed at different pH values. When multidimensional separations are combined with tandem mass spectrometry for protein identification, the strategy is often referred to as multidimensional protein identification technology (MudPIT). MudPIT has been used in either an automated (online) or manual (offline) format. In this study, we evaluated the performance of different MudPIT strategies by both label-free and tandem mass tag (TMT) isobaric tagging. Our findings revealed that online MudPIT provided more peptide/protein identifications and higher sequence coverage than offline platforms. When employing an off-line fractionation method with direct loading of samples onto the column from an eppendorf tube via a high-pressure device, a 5.3% loss in protein identifications is observed. When off-line fractionated samples are loaded via an autosampler, a 44.5% loss in protein identifications is observed compared with direct loading of samples onto a triphasic capillary column. Moreover, peptide recovery was significantly lower after offline fractionation than in online fractionation. Signal-to-noise (S/N) ratio, however, was not significantly altered between experimental groups. It is likely that offline sample collection results in stochastic peptide loss due to noncovalent adsorption to solid surfaces. Therefore, the use of the offline approaches should be considered carefully when processing minute quantities of valuable samples. PMID- 25040088 TI - Systematic review: the role of the gut microbiota in chemotherapy- or radiation induced gastrointestinal mucositis - current evidence and potential clinical applications. AB - BACKGROUND: Gastrointestinal mucositis is defined as inflammation and/or ulcers of the gastrointestinal tract occurring as a complication of chemotherapy and radiation therapy, and affects about 50% of all cancer patients. AIM: To assess the role of gut microbiota in the pathogenesis of gastrointestinal mucositis and the potential for manipulations of the microbiota to prevent and to treat mucositis. METHODS: Search of the literature published in English using Medline, Scopus and the Cochrane Library, with main search terms 'intestinal microbiota', 'bacteremia', 'mucositis', 'chemotherapy-induced diarrhoea', 'chemotherapy induced mucositis', 'radiotherapy-induced mucositis'. RESULTS: The gut microbiota plays a major role in the maintenance of intestinal homoeostasis and integrity. Patients receiving cytotoxic and radiation therapy exhibit marked changes in intestinal microbiota, with most frequently, decrease in Bifidobacterium, Clostridium cluster XIVa, Faecalibacterium prausnitzii, and increase in Enterobacteriaceae and Bacteroides. These modifications may contribute to the development of mucositis, particularly diarrhoea and bacteraemia. The prevention of cancer therapy-induced mucositis by probiotics has been investigated in randomised clinical trials with some promising results. Three of six trials reported a significantly decreased incidence of diarrhoea. One trial reported a decrease in infectious complications. CONCLUSIONS: The gut microbiota may play a major role in the pathogenesis of mucositis through the modification of intestinal barrier function, innate immunity and intestinal repair mechanisms. Better knowledge of these effects may lead to new therapeutic approaches and to the identification of predictive markers of mucositis. PMID- 25040089 TI - Response to correspondence on 'low concordance of biomarkers in histopathological and cytological material from breast cancer'. PMID- 25040090 TI - Utilization of a maltotetraose-producing amylase as a whole wheat bread improver: dough rheology and baking performance. AB - A maltotetraose-producing enzyme (G4-amylase) was utilized to improve the baking performance of whole-grain wheat flour. Whole-grain bread dough prepared with G4 amylase showed reduced water absorption and increased development time, while the dough stability was not affected. Also, the G4-amylase-treated samples exhibited lower Mixolab torque values than the control upon heating and cooling. Rheological measurements showed the decreased ratio of Rmax /E and increased tan delta, clearly demonstrating that the viscous characteristics of whole-grain bread dough became dominant with increasing levels of G4-amylase. The use of G4 amylase produced whole-grain wheat breads with a variety of maltooligosaccharides, primarily maltotetraose that positively contributed to the bread volume (1.2-fold higher than the control). Moreover, G4-amylase delayed the crumb firming of whole-grain wheat bread during a 7-d storage period, showing that it can function as an antiretrogradation agent to enhance the quality attributes of whole-grain wheat bread. PMID- 25040091 TI - Editorial Comment to Transurethral resection of the prostate after radiotherapy for prostate cancer: impact on quality of life. PMID- 25040092 TI - Late nipple necrosis after breast reduction and microvascular angina in same patient: is there a link? PMID- 25040093 TI - Morphology, ontogeny, and phylogeny of two brackish urostylid ciliates (Protist, Ciliophora, Hypotricha). AB - The diversity of hypotrichous ciliates has encouraged numerous researchers to use a combination of morphological, morphogenetic, and phylogenetic data to provide a better understanding of the evolutionary relationships within this complex group. In this study, we investigate the morphology and morphogenesis of Pseudourostyla subtropica sp. nov., isolated from mangrove wetland. The new species can be distinguished from its congeners by the huge body size, many more adoral membranelles and marginal cirral rows, and numerous macronuclear nodules. In addition, we provide a morphological characterization of a population of Pseudourostyla nova Wiackowski 1988 from an estuarine habitat. The main events during binary fission of P. subtropica sp. nov. and the Chinese population of P. nova are also revealed to be conservative. The morphological, ontogenetic, and phylogenetic analyses based on the SSU rDNA sequences corroborate the monophyly of Pseudourostyla Borror, 1972, which corresponds well with previous research. The phylogenetic analyses also show that Pseudourostyla and Hemicycliostyla Stokes, 1886, both of which are assigned to the family Pseudourostylidae based on morphological and morphogenetic data, in fact fall into separated clades. The approximately unbiased tests, however, do not reject the possibility that the family Pseudourostylidae is a monophyletic lineage. PMID- 25040094 TI - A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. AB - Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS. Thirty-four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty-nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m(2) daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose-limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well-tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation. PMID- 25040095 TI - A study of Shar-Pei dogs refutes association of the 'meatmouth' duplication near HAS2 with Familial Shar-Pei Fever. PMID- 25040096 TI - Nephrotic syndrome and acute renal failure during pegylated liposomal doxorubicin treatment. PMID- 25040097 TI - Pain myths and the genesis of central pain. PMID- 25040098 TI - Clinical and experimental assessment of the effects of a new topical treatment with praziquantel in the management of rosacea. AB - BACKGROUND: Rosacea is a common, chronic, and inflammatory skin disease. The burden imposed by this condition requires that new topical treatments be sought to enlarge the arsenal of drugs available in order to better manage this disease. OBJECTIVES: This study was conducted to carry out an in vitro/in vivo evaluation of the antimicrobial activity of 3% praziquantel (PZQ) ointment and to determine its efficacy and safety in the treatment of rosacea. METHODS: Patients with rosacea (n = 65) participated in a 16-week, randomized, single-blind pilot study of the effects of twice-daily monotherapy with 3% PZQ ointment vs. placebo (vehicle ointment). Efficacy was assessed clinically using the Investigator's Global Assessment Scale (IGAS) and the Clinical Erythema Assessment Scale (CEAS). Patients' quality of life was also determined using the Dermatology Life Quality Index (DLQI). The antimicrobial potential of 3% PZQ ointment was assessed by agar diffusion assay. RESULTS: Scores on the IGAS and CEAS showed PZQ ointment to have a statistically significant therapeutic advantage over the placebo treatment (P < 0.001). At week 16, the PZQ group demonstrated a statistically significant greater reduction in CEAS score than the placebo group (P < 0.001). Analysis of CEAS scores showed that 41.9% of patients in the PZQ group and 18.2% of those in the placebo group achieved a CEAS score equivalent to a rating of "none". Mean scores on the DLQI at baseline and at the end of the study were, respectively, 15.8 and 4.1 in the praziquantel group. The PZQ-treated group also experienced a statistically significant improvement in comparison with the placebo group at week 16 (P < 0.001). The inhibitory zone indicating the extent of antimicrobial activity of 3% PZQ ointment ranged from 6 mm to 17 mm. No serious treatment related adverse events occurred in either treatment group. CONCLUSIONS: Use of 3% PZQ ointment twice daily for 12 weeks resulted in significantly better effects than a placebo treatment in improving rosacea and the patient's quality of life. PMID- 25040099 TI - How an accidental discovery paved the way for the treatment of complicated infantile haemangiomas. PMID- 25040100 TI - Homeodomain-interacting protein kinase (Hipk) phosphorylates the small SPOC family protein Spenito. AB - The Drosophila homeodomain-interacting protein kinase (Hipk) is a versatile regulator involved in a variety of pathways, such as Notch and Wingless signalling, thereby acting in processes including the promotion of eye development or control of cell numbers in the nervous system. In vertebrates, extensive studies have related its homologue HIPK2 to important roles in the control of p53-mediated apoptosis and tumour suppression. Spenito (Nito) belongs to the group of small SPOC family proteins and has a role, amongst others, as a regulator of Wingless signalling downstream of Armadillo. In the present study, we show that both proteins have an enzyme-substrate relationship, adding a new interesting component to the broad range of Hipk interactions, and we map several phosphorylation sites of Nito. Furthermore, we were able to define a preliminary consensus motif for Hipk target sites, which will simplify the identification of new substrates of this kinase. PMID- 25040101 TI - Epigenetics in extracellular matrix remodeling and hyaluronan metabolism. AB - Cell behavior is determined by both genetic and environmental factors. The cell microenvironment is not only a scene in which various actors play a role, but is itself an active participant, able to influence many cellular responses by binding signaling molecules or by modulating intracellular signaling cascades. Further, extracellular matrix remodeling is a critical step to allow physiological as well as pathological processes. As environmental factors are able to modulate gene expression by epigenetic modifications, this review focuses on new aspects of the regulation of extracellular matrix remodeling enzymes. Moreover, as one of the main components of cell microenvironment is the glycosaminoglycan hyaluronan, novel findings regarding the control of hyaluronan synthesis are discussed in terms of epigenetics and from the post-translational point of view. PMID- 25040102 TI - The use of sirolimus to treat Kaposi's sarcoma in an HIV-negative rheumatoid arthritis patient on disease-modifying drug therapies. PMID- 25040103 TI - Ecological release exposes genetically based niche variation. AB - The evolutionary trajectories of ecological niches have profound impacts on community, population and speciation dynamics, yet the underlying causes of niche lability vs. stasis are poorly understood. Here, we conducted a field experiment to quantify the effects of competition and, conversely, competitive release on the microevolutionary processes driving microhabitat niche evolution in an annual plant population restricted to California vernal pool wetlands. Removing competitors generated a strong increase in mean fitness, the exposure of genetically based niche variation and directional selection for niche evolution in the experimental population. In contrast, genetic variation in the microhabitat niche and directional selection for niche evolution were not detected in individuals growing with competitors. These results indicate that ecological opportunity (here, the removal of competitors) can trigger the immediate expression of latent, heritable niche variation that is necessary for rapid evolutionary responses; conversely, competitors may restrict niche evolution, contributing to niche conservatism in saturated communities. PMID- 25040104 TI - Monitoring the anticoagulant effect after a massive rivaroxaban overdose. AB - Rivaroxaban is a direct factor Xa inhibitor approved for prevention of stroke, prevention and treatment of venous thromboembolism and secondary prevention of acute coronary syndrome in many countries. As the use of this agent increases, so does the potential for overdose, both intentional and unintentional. Clinical data on overdoses of rivaroxaban in humans are limited. We report the case of a 42-year-old man who took an overdose of 1400 mg of rivaroxaban and describe how resolution of the anticoagulant effect was monitored using readily available coagulation assays. PMID- 25040105 TI - Difference in left ventricular mass index between hypertensive patients with and without renal artery stenosis by propensity score analysis. AB - This study aimed to define the difference in cardiac hypertrophy between hypertensive patients with and without renal artery stenosis (RAS). When cardiac ultrasonographic examination was performed in 971 consecutive hypertensive outpatients, renal peak systolic velocity (PSV) was examined. Compared with patients without RAS, those with RAS (PSV >=180 cm/s, 4.1%) were significantly older and included a higher proportion of male patients and had a higher left ventricular mass index (LVMI). A stratified analysis in the selected 120 patients showed that the LVMI was significantly higher in patients with RAS than in those without RAS for each confounding factor such as age and blood pressure. RAS was independently associated with a higher LVMI on propensity score analysis and multivariate analysis. Thus, the difference in LVMI between hypertensive patients with and without RAS was confirmed, irrespective of age and blood pressure, by stratified propensity score analysis and multivariate regression analysis. PMID- 25040107 TI - Horizontal chromosome transfer and rational strategies to manage Fusarium vascular wilt diseases. PMID- 25040108 TI - Wearable computing: Will it make people prosocial? AB - We recently reported that people who wear an eye tracker modify their natural looking behaviour in a prosocial manner. This change in looking behaviour represents a potential concern for researchers who wish to use eye trackers to understand the functioning of human attention. On the other hand, it may offer a real boon to manufacturers and consumers of wearable computing (e.g., Google Glass), for if wearable computing causes people to behave in a prosocial manner, then the public's fear that people with wearable computing will invade their privacy is unfounded. Critically, both of these divergent implications are grounded on the assumption that the prosocial behavioural effect of wearing an eye tracker is sustained for a prolonged period of time. Our study reveals that on the very first wearing of an eye tracker, and in less than 10 min, the prosocial effect of an eye tracker is abolished, but by drawing attention back to the eye tracker, the implied presence effect is easily reactivated. This suggests that eye trackers induce a transient social presence effect, which is rendered dormant when attention is shifted away from the source of implied presence. This is good news for researchers who use eye trackers to measure attention and behaviour; and could be bad news for advocates of wearable computing in everyday life. PMID- 25040106 TI - Plasma N-acetyl-glucosaminidase in advanced gastro-intestinal adenocarcinoma correlates with age, stage and outcome. AB - BACKGROUND: N-acetyl-glucosaminidase (NAG) is a potential marker of genotoxicity. We retrospectively analyzed plasma NAG and clinico-pathologic features in advanced gastrointestinal adenocarcinoma patients. METHODS: Plasma from 118 patients and 51 healthy volunteers was analyzed for associations between NAG levels and age, disease presence, stage, treatment responses and survival. RESULTS: Pretreatment NAG correlated with age but was independently increased in metastatic versus locally advanced disease, particularly in gastric/esophageal patients. NAG was also associated with reduced overall survival. In subgroup analysis, increased NAG activity between day 1 and 2 of chemotherapy cycle 1 correlated with treatment response. CONCLUSION: We demonstrated that NAG correlates with gastrointestinal cancer outcomes. Further studies are required to determine if plasma markers of genotoxicity can be useful for disease monitoring. PMID- 25040109 TI - Signaling regulating inner ear development: cell fate determination, patterning, morphogenesis, and defects. AB - The membranous labyrinth of the inner ear is a highly complex organ that detects sound and balance. Developmental defects in the inner ear cause congenital hearing loss and balance disorders. The membranous labyrinth consists of three semicircular ducts, the utricle, saccule, and endolymphatic ducts, and the cochlear duct. These complex structures develop from the simple otic placode, which is established in the cranial ectoderm adjacent to the neural crest at the level of the hindbrain at the early neurula stage. During development, the otic placode invaginates to form the otic vesicle, which subsequently gives rise to neurons for the vestibulocochlear ganglion, the non-sensory and sensory epithelia of the membranous labyrinth that includes three ampullary crests, two maculae, and the organ of Corti. Combined paracrine and autocrine signals including fibroblast growth factor, Wnt, retinoic acid, hedgehog, and bone morphogenetic protein regulate fate determination, axis formation, and morphogenesis in the developing inner ear. Juxtacrine signals mediated by Notch pathways play a role in establishing the sensory epithelium, which consists of mechanosensory hair cells and supporting cells. The highly differentiated organ of Corti, which consists of uniformly oriented inner/outer hair cells and specific supporting cells, develops during fetal development. Developmental alterations/arrest causes congenital malformations in the inner ear in a spatiotemporal-restricted manner. A clearer understanding of the mechanisms underlying inner ear development is important not only for the management of patients with congenital inner ear malformations, but also for the development of regenerative therapy for impaired function. PMID- 25040110 TI - Prevalence of overweight and obesity among children and adolescents of the Indian subcontinent: a meta-analysis. AB - In order to examine the prevalence of overweight and obesity in childhood within the Indian subcontinent, a meta-analysis of studies was conducted. Within the data sets analyzed, six homogeneous statistical subgroups were observed and three levels of prevalence were discernible (low, intermediate, and high). The pooled estimates of the prevalence of overweight and obesity in children were 2% (95% confidence interval [CI], 2-3%) to 6% (95% CI, 6-7%) for the low-prevalence group, 11% (95% CI, 11-12%) to 18% (95% CI, 17-18%) for the intermediate prevalence group, and 23% (95% CI, 22-24%) to 36% (95% CI, 34-37%) for the high prevalence group. Data on subjects in the low-prevalence group were obtained from national-level data and from data sets in which urban and rural subjects were combined. Neither the intermediate- nor the high-prevalence category contained any data from the rural or national level. The intermediate group largely included urban children, whereas the high-prevalence group generally included affluent children within major urban centers. Most of the data sets reported the prevalence of overweight and obesity among children in the 10-18-year age range. The prevalence of overweight and obesity was higher among boys than girls, and had increased among urban dwellers during the last decade. PMID- 25040111 TI - The lymphocyte transformation test for the diagnosis of Lyme borreliosis could fill a gap in the difficult diagnostics of borreliosis. PMID- 25040112 TI - An association analysis of the rs1572931 polymorphism of the RAB7L1 gene in Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy in China. AB - BACKGROUND AND PURPOSE: Recently, the rs1572931 single-nucleotide polymorphism (SNP) of the putative promoter of the member RAS oncogene family-like 1 (RAB7L1) gene was reported to be associated with reduced risk for Parkinson's disease (PD) in the Ashkenazi Jewish population. Ethnic-specific effects are an important consideration in genome-wide association studies. Considering that the clinical manifestations and pathological characteristics overlap between PD, amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA), the possible associations between the rs1572931 SNP and these three diseases were studied in the Chinese population. METHODS: A total of 1011 PD patients, 778 sporadic ALS (SALS) patients, 264 MSA patients and 516 healthy controls (HC) were included in this study. All subjects were genotyped for the rs1572931 SNP by using polymerase chain reaction and direct sequencing. RESULTS: Significant differences were observed in the genotype and minor allele frequency (MAF) of rs1572931 between PD and HC (P = 0.0001 and P = 1.08E-04, respectively) and between late-onset PD and matched controls (P = 0.0011 and P = 0.0002, respectively). However, no differences were observed between early-onset PD and HC. The number of minor allele carriers was significantly lower in PD patients than in HC (P = 2.96E-05, odds ratio 0.63, 95% confidence interval 0.51-0.78). No differences were observed between groups with respect to sex, onset symptoms, absence or presence of cognition impairment, anxiety or depression. In addition, no differences were found in the genotype and MAF of rs1572931 between SALS and HC or between MSA and HC. CONCLUSION: Our results suggest that rs1572931 decreases the risk for PD but not for ALS and MSA in the Chinese population. However, the polymorphism is unlikely to be a common cause of SALS and MSA in the Chinese population. PMID- 25040113 TI - hCTLA4-Ig transgene expression in keratocytes modulates rejection of corneal xenografts in a pig to non-human primate anterior lamellar keratoplasty model. AB - BACKGROUND: Human corneal allografting is an established procedure to cure corneal blindness. However, a shortage of human donor corneas as well as compounding economic, cultural, and organizational reasons in many countries limit its widespread use. Artificial corneas as well as porcine corneal xenografts have been considered as possible alternatives. To date, all preclinical studies using de-cellularized pig corneas have shown encouraging graft survival results; however, relatively few studies have been conducted in pig to non-human primate (NHP) models, and particularly using genetically engineered donors. METHODS: In this study, we assessed the potential benefit of using either hCTLA4-Ig transgenic or alpha1,3-Galactosyl Transferase (GT) Knock Out (KO) plus transgenic hCD39/hCD55/hCD59/fucosyl-transferase pig lines in an anterior lamellar keratoplasty pig to NHP model. RESULTS: Corneas from transgenic animals expressing hCTLA4-Ig under the transcriptional control of a neuron specific enolase promoter showed transgene expression in corneal keratocytes of the stroma and expression was maintained after transplantation. Although a first acute rejection episode occurred in all animals during the second week post keratoplasty, the median final rejection time was 70 days in the hCTLA4-Ig group vs. 21 days in the wild-type (WT) control group. In contrast, no benefit for corneal xenograft survival from the GTKO/transgenic pig line was found. At rejection, cell infiltration in hCTLA4Ig transgenic grafts was mainly composed of macrophages with fewer CD3+ CD4+ and CD79+ cells than in other types of grafts. Anti-donor xenoantibodies increased dramatically between days 9 and 14 post surgery in all animals. CONCLUSIONS: Local expression of the hCTLA4-Ig transgene dampens rejection of xenogeneic corneal grafts in this pig-to-NHP lamellar keratoplasty model. The hCTLA4-Ig transgene seems to target T-cell responses without impacting humoral responses, the control of which would presumably require additional peripheral immunosuppression. PMID- 25040114 TI - Levels of alcohol use and history of HIV testing among female sex workers in Mombasa, Kenya. AB - HIV testing is a critical first step to accessing HIV care and treatment, particularly for high-risk groups such as female sex workers (FSWs). Alcohol use may be a barrier to accessing HIV services, including HIV testing. We analyzed data from a cross-sectional survey of 818 FSWs in Mombasa, Kenya, and estimated the association between different levels of alcohol use and having never tested for HIV. In multivariable analyses, higher levels of alcohol consumption were associated with having never tested for HIV (PR 1.60; 95% CI: 1.07, 2.40). Future interventions should explore whether reducing harmful drinking improves HIV testing among FSWs. PMID- 25040115 TI - The impact of a physical activity intervention program on academic achievement in a Swedish elementary school setting. AB - BACKGROUND: Despite the emerging body of research on the potential of physical activity to improve learning and academic achievement, conclusive evidence regarding the effects of physical activity on academic achievement is lacking. The objective of this study was to determine the impact of a physical activity intervention program on academic performance. METHODS: A controlled cross sectional design was used to investigate the hypothesis that the intervention program would increase the proportion of students in grade 5 who achieved the national learning goals in Swedish, mathematics, and English compared with 3 reference schools. Academic results from the years prior to and during the intervention program were analyzed. Logistic regression analyses assessed the odds of achieving the national learning goals when the intervention program was integrated into the elementary curricula. RESULTS: Higher proportions of students in the intervention school achieved the national goals in all 3 subjects compared with the reference schools after initiation of the intervention program. The odds for achieving the national learning goals in the intervention school increased 2 fold (p < .05), whereas these odds either did not change or decreased in the reference schools. CONCLUSION: Promoting physical activity in school by means of a curriculum-based intervention program may improve children's educational outcome. PMID- 25040116 TI - In preparation of the nationwide dissemination of the school-based obesity prevention program DOiT: stepwise development applying the intervention mapping protocol. AB - BACKGROUND: The school-based Dutch Obesity Intervention in Teenagers (DOiT) program is an evidence-based obesity prevention program. In preparation for dissemination throughout the Netherlands, this study aimed to adapt the initial program and to develop an implementation strategy and materials. METHODS: We revisited the Intervention Mapping (IM) protocol, using results of the previous process evaluation and additional focus groups and interviews with students, parents, teachers, and professionals. RESULTS: The adapted 2-year DOiT program consists of a classroom, an environmental and a parental component. The year 1 lessons aim to increase awareness and knowledge of healthy behaviors. The lessons in year 2 focus on the influence of the (obesogenic) environment. The stepwise development of the implementation strategy resulted in objectives that support teachers' implementation. We developed a 7-step implementation strategy and supporting materials by translating the objectives into essential elements and practical strategies. CONCLUSIONS: This study illustrates how revisiting the IM protocol resulted in an adapted program and tailored implementation strategy based on previous evaluations as well as input from different stakeholders. The stepwise development of DOiT can serve as an example for other evidence-based programs in preparation for wider dissemination. PMID- 25040117 TI - Usual source of cigarettes and alcohol among US high school students. AB - BACKGROUND: Cigarette and alcohol use are common among youth. We examined sources of cigarettes and alcohol among youth who were current cigarette and alcohol users. METHODS: We analyzed nationally representative data from the 2009 and 2011 national Youth Risk Behavior Surveys-biennial, school-based surveys of high school students in the United States. Students completed anonymous, self administered questionnaires. Overall response rates were 71% for both years. RESULTS: Among the 17.3% of current cigarette users <18 years, 27.3% usually gave someone else money to buy their cigarettes and 27.7% usually borrowed (bummed) them. Fewer (14.1%) usually bought their own cigarettes in a store. Among the 40.3% of current alcohol users, 24.3% usually gave someone else money to buy it and 41.2% usually had someone give it to them. A few (4.5%) usually bought their own alcohol in a store. Age and intensity of use were positively associated with students buying their own cigarettes or alcohol, but negatively associated with students borrowing or having someone else give it to them. CONCLUSIONS: Because social and commercial sources of cigarettes and alcohol are common, multiple strategies are needed to reduce the ability for youth to obtain them and reduce their desire for them. PMID- 25040118 TI - Positive school climate is associated with lower body mass index percentile among urban preadolescents. AB - BACKGROUND: Schools are an important environmental context in children's lives and are part of the complex web of factors that contribute to childhood obesity. Increasingly, attention has been placed on the importance of school climate (connectedness, academic standards, engagement, and student autonomy) as 1 domain of school environment beyond health policies and education that may have implications for student health outcomes. The purpose of this study is to examine the association of school climate with body mass index (BMI) among urban preadolescents. METHODS: Health surveys and physical measures were collected among fifth- and sixth-grade students from 12 randomly selected public schools in a small New England city. School climate surveys were completed district-wide by students and teachers. Hierarchical linear modeling was used to test the association between students' BMI and schools' climate scores. RESULTS: After controlling for potentially confounding individual-level characteristics, a 1 unit increase in school climate score (indicating more positive climate) was associated with a 7-point decrease in students' BMI percentile. CONCLUSIONS: Positive school climate is associated with lower student BMI percentile. More research is needed to understand the mechanisms behind this relationship and to explore whether interventions promoting positive school climate can effectively prevent and/or reduce obesity. PMID- 25040119 TI - Area disparity in children's perceptions of access to tobacco and cigarette purchasing experiences in Taiwan. AB - BACKGROUND: Adolescents who perceive easy access to tobacco are more likely to acquire cigarettes and experience smoking. This study assesses area disparities in perceptions of access to tobacco and cigarette purchasing experiences among schoolchildren. METHODS: Data on children's tobacco-related variables were obtained from the Control of School-Aged Children Smoking Study Survey in Taiwan. A stratified random sample of 65 primary schools was included. Polytomous logistic regression analyzed factors associated with tobacco accessibility and purchasing experiences. RESULTS: More than half of the children reported that tobacco retailers often or always sold cigarettes to them. Rural and mountainous children were more likely to have access to cigarettes (adjusted odds ratio [AOR] = 2.01 and 3.01, respectively) and have cigarette purchasing experiences (AOR = 3.06 and 13.76, respectively). Cigarette purchasing from retailers (AOR = 1.84) was significantly associated with children's perceptions of access to tobacco. The factors associated with cigarette purchasing experiences were families smoking (AOR = 8.90), peers smoking (AOR = 2.22), frequent exposure to entertainer smoking on TV and in films (AOR = 2.15), and perceived access to tobacco (AOR = 1.51). CONCLUSIONS: The health department should strictly enforce laws regarding retailers selling tobacco to underage, particularly in remote areas. Schools can reinforce tobacco-use prevention messages. PMID- 25040120 TI - Happiness in motion: emotions, well-being, and active school travel. AB - BACKGROUND: A pan-Canadian School Travel Planning intervention promoted active school travel (AST). A novel component was exploring emotion, well-being, and travel mode framed by the concept of "sustainable happiness." Relationships between travel mode and emotions, parent perceptions of their child's travel mode on well-being, and factors related to parent perceptions were examined. METHODS: Questionnaires were administered to families (N = 5423) from 76 elementary schools. Explanatory variables were demographics (age and sex), school travel measures (mode, distance, accompaniment by an adult, safety, and barriers), and emotions (parent and child). Outcomes examined parent perceived benefits of travel mode on dimensions of well-being (physical, emotional, community, and environmental). Descriptive statistics, chi-square tests and hierarchical regression were used. RESULTS: Parents and children who used AST reported more positive emotions versus passive travelers. Parents of active travelers reported stronger connections to dimensions of well-being. AST had the strongest association with parents' perceptions of their child's well-being, and positive emotions (parent and child) were also significantly related to well-being on the trip to school. CONCLUSIONS: As an additional potential benefit of AST, interventions should raise awareness of the positive emotional experiences for children and their parents. Future research should experimentally examine if AST causes these emotional benefits. PMID- 25040121 TI - The role of school-based health centers in increasing universal and targeted delivery of primary and preventive care among adolescents. AB - BACKGROUND: School-based health centers (SBHC) can provide equitable and comprehensive care for adolescents; yet, few studies have described how patterns of health service utilization differ among groups. The purpose of this study was to investigate differences in utilization and perceptions of SBHC care among adolescents. METHODS: This study sample included 414 adolescent respondents to the Healthy Schools, Healthy Communities User Survey. Three outcome measures represented utilization of care, while 4 represented perceptions of care. Multivariate logistic regressions modeled the effects of user characteristics on outcome measures. RESULTS: There were few notable and significant differences in either utilization or perceptions of care, based on sociodemographic or health status characteristics. CONCLUSIONS: SBHCs can eliminate differences in utilization based on sociodemographic characteristics. However, null findings show that they fall short in delivering comprehensive care to high-risk adolescents, and may not be capitalizing on opportunities to offer targeted services. Results showing positive perceptions of care suggest that adolescents would be amenable to additional counseling or education services offered at SBHCs. To foster positive health outcomes among adolescents, SBHC administrators should regularly evaluate their scope of services and support quality improvement efforts. PMID- 25040122 TI - The association between physical fitness and academic achievement in Texas state house legislative districts: an ecologic study. AB - BACKGROUND: The association of physical fitness with cognitive function in children and adolescents is unclear. The purpose of this ecological study was to describe the association between academic achievement, body mass index (BMI), and cardiovascular fitness (CVF) in a large sample of elementary, middle, and high school students in Texas. METHODS: FITNESSGRAM((r)) results for 2,550,144 students were matched with standardized composite academic test (TAKS) results from 2008 to 2009. Analyses were conducted on the percent of students meeting TAKS standards by BMI and CVF quintiles. Analyses of variance with Tukey adjustment examined differences between the most favorable 5th quintile (referent) and all other quintiles. RESULTS: The prevalence of students meeting the TAKS standard was significantly higher in the highest fitness category for BMI and CVF compared to all other categories, regardless of sex or grade category (p < .05). Linear modeling suggested a 5% increase in the prevalence of students meeting healthy BMI and CVF standards would result in a 2.25% and 0.65% increase in the prevalence of students meeting the TAKS standard (both p < .05). CONCLUSION: Findings suggest a healthy BMI and CVF are associated with higher academic achievement, and the need for additional research examining the role of potential confounders and/or effect modifiers longitudinally. PMID- 25040124 TI - Kinetic studies of a ferredoxin-dependent cyanobacterial nitrate reductase. AB - A flash photolysis study of electron transfer (ET) kinetics from reduced ferredoxin (photoreduced by Photosystem I) to the ferredoxin-dependent nitrate reductase from the cyanobacterium Synechococcus sp. PCC 7942 has been carried out. In the presence of nitrate, under conditions where only a single electron is transferred to nitrate reductase, the rate of enzyme reduction shows a biphasic concentration dependence: At low enzyme concentrations the dependence is approximately linear, with an estimated second-order rate constant of 7.4 +/- 0.8 * 10(7) M(-1) s(-1); at concentrations above 2 MUM, the rate increases nonlinearly to an asymptotic value of approximately 300 s(-1), indicating the presence of a rate-limiting step in the process. The spectrum of the one-electron reduced enzyme suggests that Mo centers are largely reduced with a minor contribution of iron-sulfur cluster reduction. Under conditions favoring two electron reduction of the enzyme, the redox difference spectrum can be accounted for by the oxidation of two reduced ferredoxins, suggesting that the enzyme has completed one full catalytic cycle. The spectral changes observed in the absence of nitrate are significantly different from those seen in the presence of nitrate. Experiments in the absence of nitrate revealed that the singly reduced enzyme exhibits different absorption characteristics and reoxidation kinetics, compared to those observed with nitrate present, and exhibits a much faster binding by reduced ferredoxin than the oxidized enzyme. The implications of these observations for understanding the enzyme mechanism are discussed. PMID- 25040123 TI - Community partnership to address snack quality and cost in after-school programs. AB - BACKGROUND: Policies call on after-school programs (ASPs) to serve more nutritious snacks. A major barrier for improving snack quality is cost. This study describes the impact on snack quality and expenditures from a community partnership between ASPs and local grocery stores. METHODS: Four large-scale ASPs (serving ~500 children, aged 6-12 years, each day) and a single local grocery store chain participated in this study. The nutritional quality of snacks served was recorded preintervention (18 weeks spring/fall 2011) and postintervention (7 weeks spring 2012) via direct observation, along with cost/child/snack/day. RESULTS: Preintervention snacks were low-nutrient-density salty snacks (eg, chips, 3.0 servings/week), sugar-sweetened beverages (eg, powdered-lemonade, 1.9 servings/week), and desserts (eg, cookies, 2.1 servings/week), with only 0.4 servings/week of fruits and no vegetables. By postintervention, fruits (3.5 servings/week) and vegetables (1.2 servings/week) were increased, whereas sugar sweetened beverages and desserts were eliminated. Snack expenditures were $0.26 versus $0.24 from preintervention to postintervention. Partnership savings versus purchasing snacks at full retail cost was 24.5% or $0.25/serving versus $0.34/serving. CONCLUSIONS: This innovative partnership can serve as a model in communities where ASPs seek to identify low-cost alternatives to providing nutritious snacks. PMID- 25040125 TI - Targeting parathyroid hormone levels in dialysis patients. PMID- 25040126 TI - Physical activity cut-offs and risk factors for preventing child obesity in Japan. AB - BACKGROUND: There is no official recommendations for physical activity level or steps for preventing and improving child obesity in Japan. METHODS: Three hundred and two Japanese children aged 9-12 years were recruited wore 3-D speed sensors. Subjects were divided into two groups using the criteria for child obesity in Japan. Body composition was measured on bioelectrical impedance analysis. Physical fitness test was done to evaluate physical strength. Twenty-four hour total steps, energy expenditure, and metabolic equivalents (MET) from Monday to Sunday were consecutively measured. The cut-offs for steps and physical activity level for preventing child obesity were evaluated on receiver operating characteristic curves. Daily life-related risk factors for child obesity were assessed on logistic regression analysis. RESULTS: In both sexes, body volume; bodyweight, body mass index, fat mass, and percentage body fat in the obese group was significantly higher than in the normal group, but age and height were not different (P < 0.001). Aerobic power, running speed, and explosive strength in the obese group were inferior to those in the normal group (P < 0.001). More than 40 min of 4 MET exercise, defined as moderate-vigorous exercise, and 11,000 steps per day are essential to prevent child obesity. Additionally, >2 h TV viewing per day is a significant risk factor for child obesity (OR, 3.43; 95%CI: 1.27-9.31). CONCLUSION: Cut-offs for physical activity and potential risk factors for child obesity have been identified. Recommendations for changes to daily lifestyle for school-aged Japanese children are given. PMID- 25040127 TI - The soybean (Glycine max) nodulation-suppressive CLE peptide, GmRIC1, functions interspecifically in common white bean (Phaseolus vulgaris), but not in a supernodulating line mutated in the receptor PvNARK. AB - Legume plants regulate the number of nitrogen-fixing root nodules they form via a process called the Autoregulation of Nodulation (AON). Despite being one of the most economically important and abundantly consumed legumes, little is known about the AON pathway of common bean (Phaseolus vulgaris). We used comparative- and functional-genomic approaches to identify central components in the AON pathway of common bean. This includes identifying PvNARK, which encodes a LRR receptor kinase that acts to regulate root nodule numbers. A novel, truncated version of the gene was identified directly upstream of PvNARK, similar to Medicago truncatula, but not seen in Lotus japonicus or soybean. Two mutant alleles of PvNARK were identified that cause a classic shoot-controlled and nitrate-tolerant supernodulation phenotype. Homeologous over-expression of the nodulation-suppressive CLE peptide-encoding soybean gene, GmRIC1, abolished nodulation in wild-type bean, but had no discernible effect on PvNARK-mutant plants. This demonstrates that soybean GmRIC1 can function interspecifically in bean, acting in a PvNARK-dependent manner. Identification of bean PvRIC1, PvRIC2 and PvNIC1, orthologues of the soybean nodulation-suppressive CLE peptides, revealed a high degree of conservation, particularly in the CLE domain. Overall, our work identified four new components of bean nodulation control and a truncated copy of PvNARK, discovered the mutation responsible for two supernodulating bean mutants and demonstrated that soybean GmRIC1 can function in the AON pathway of bean. PMID- 25040128 TI - Nitrogen digestion and urea recycling in Hokkaido native horses fed hay-based diets. AB - Nitrogen (N) digestion and urea-N metabolism in Hokkaido native horses fed roughage-based diets containing different types and levels of protein sources were studied. Horses (173 +/- 4.8 kg) fitted with an ileum cannula were fed four diets consisting of 100% timothy hay (TH), 88% TH and 12% soybean meal (SBM), 79% TH and 21% SBM, and 51% TH and 49% alfalfa hay at 2.2% of body weight. Dietary protein content varied from 5% to 15% of dry matter. Apparent N digestibilities in the pre-cecum and total tract for the TH diet were lower than those for other diets. However, the proportion of post-ileum N digestion to N intake was not affected by the diets. Urea-N production was linearly related to N intake, but gut urea-N entry was not affected by the diets. The proportion of gut urea-N entry to urea-N production tended to be higher for the TH diet (57%) than the two SBM diets (39%). Anabolic use of urea-N entering the gut was not affected by the diets (20-36% of gut urea-N entry). These results indicate that urea-N recycling provides additional N sources for microbial fermentation in the hindgut of Hokkaido native horses fed low-quality roughages. PMID- 25040129 TI - Functionality and prevalence of trehalose-based oligosaccharides as novel compatible solutes in ascospores of Neosartorya fischeri (Aspergillus fischeri) and other fungi. AB - Ascospores of Neosartorya, Byssochlamys and Talaromyces can be regarded as the most stress-resistant eukaryotic cells. They can survive exposure at temperatures as high as 85 degrees C for 100 min or more. Neosartorya fischeri ascospores are more viscous and more resistant to the combined stress of heat and desiccation than the ascospores of Talaromyces macrosporus which contain predominantly trehalose. These ascospores contain trehalose-based oligosaccharides (TOS) that are novel compatible solutes, which are accumulated to high levels. These compounds are also found in other members of the genus Neosartorya and in some other genera within the order Eurotiales that also include Byssochlamys and Talaromyces. The presence of oligosaccharides was observed in species that had a relatively high growth temperature. TOS glasses have a higher glass transition temperature (Tg ) than trehalose, and they form a stable glass with crystallizing molecules, such as mannitol. Our data indicate that TOS are important for prolonged stabilization of cells against stress. The possible unique role of these solutes in protection against dry heat conditions is discussed. PMID- 25040130 TI - Reforming medicare's dialysis payment policies: implications for patients with secondary hyperparathyroidism. AB - OBJECTIVE: To demonstrate how expanding services covered by a "bundled payment" can also expand variation in the costs of treating patients under the bundle, using the Medicare dialysis program as an example. DATA SOURCES/STUDY SETTING: Observational claims-based study of 197,332 Medicare hemodialysis beneficiaries enrolled for at least one quarter during 2006-2008. STUDY DESIGN: We estimated how resource utilization (all health services, dialysis-related services, and medications) changes with intensity of secondary hyperparathyroidism (sHPT) treatment. DATA EXTRACTION METHODS: Using Medicare claims, a patient-quarter level dataset was constructed, including a measure of sHPT treatment intensity. PRINCIPAL FINDINGS: Under the existing, narrow dialysis bundle, utilization of covered services is relatively constant across treatment intensity groups; under a broader bundle, it rises more rapidly with treatment intensity. CONCLUSIONS: The broader Medicare dialysis bundle reimburses providers uniformly, even though patients treated more intensively for sHPT cost more to treat. Absent any payment adjustments or efforts to ensure quality, this flat payment schedule may encourage providers to avoid high-intensity patients or reduce their treatment intensity. The first incentive harms efficiency. The second may improve or worsen efficiency, depending on whether it reduces appropriate or inappropriate treatment. PMID- 25040131 TI - Letter on Bacterial contamination in platelet concentrates. PMID- 25040133 TI - Diabetes Mellitus, Physical Activity, and Longevity Between the Ages of 70 and 90. AB - OBJECTIVES: To determine the effect of physical activity (PA) on survival in older adults (70-90) with diabetes mellitus (DM). DESIGN: The Jerusalem Longitudinal Cohort Study (1990-2010) prospectively follows up a representative cohort born in 1920-1921. SETTING: Home-based assessment. PARTICIPANTS: Individuals aged 70 in 1990 (n = 463), 78 in 1998 (n = 972), and 85 in 2005 (n = 1,181). MEASUREMENTS: Comprehensive geriatric assessment; self-reported PA dichotomized to active (>=4 hours of activity/wk) or inactive (<4 hours of activity/wk); mortality data (1990-2010). RESULTS: Prevalence of DM was 15.7% at age 70, 18.4% at age 78, and 21.3% at age 85. DM was associated with greater morbidity. Survival was higher in active than inactive with DM (aged 70-77: 78.8% vs 48.7%, P = .008; aged 78-84: 60.0% vs 40%, P = .01; aged 85-90: 70.2% vs 49.6%, P < .001) and without DM (aged 70-77: 85.9% vs 74.1%, P = .002; aged 78 84: 75.0% vs 64.0%, P = .004; aged 85-90: 82.3% vs 60.3%, P < .001). Cox proportional hazards ratios (HRs) according to PA status compared active subjects without DM (reference) with inactive subjects without DM, active subjects with DM, and inactive subjects with DM after adjusting for sex, self-rated health, ischemic heart disease, hypertension, smoking, and body mass index. Adjusted HRs were 1.39 for inactive subjects without DM, 1.34 for active subjects with DM, and 3.54 for inactive subjects with DM for age 70 to 77 (P < .001); 1.43 for inactive subjects without DM, 1.55 for active subjects with DM, and 3.74 for inactive subjects with DM for age 78 to 84 (P < .001); and 1.98 for inactive subjects without DM, 1.56 for active subjects with DM, and 2.18 for inactive with DM for age 85 to 90 (P < .001). CONCLUSION: In adults with DM, greater survival continues to be associated with PA up to and including very old adults (70-90). These findings support the encouragement of regular PA in people with DM regardless of advancing age. PMID- 25040132 TI - Neurokinin-3 receptor activation in the retrochiasmatic area is essential for the full pre-ovulatory luteinising hormone surge in ewes. AB - Neurokinin B (NKB) is essential for human reproduction and has been shown to stimulate luteinising hormone (LH) secretion in several species, including sheep. Ewes express the neurokinin-3 receptor (NK3R) in the retrochiasmatic area (RCh) and there is one report that placement of senktide, an NK3R agonist, therein stimulates LH secretion that resembles an LH surge in ewes. In the present study, we first confirmed that local administration of senktide to the RCh produced a surge-like increase in LH secretion, and then tested the effects of this agonist in two other areas implicated in the control of LH secretion and where NK3R is found in high abundance: the preoptic area (POA) and arcuate nucleus (ARC). Bilateral microimplants containing senktide induced a dramatic surge-like increase in LH when given in the POA similar to that seen with RCh treatment. By contrast, senktide treatment in the ARC resulted in a much smaller but significant increase in LH concentrations suggestive of an effect on tonic secretion. The possible role of POA and RCh NK3R activation in the LH surge was next tested by treating ewes with SB222200, an NK3R antagonist, in each area during an oestradiol-induced LH surge. SB222200 in the RCh, but not in the POA, reduced the LH surge amplitude by approximately 40% compared to controls, indicating that NK3R activation in the former region is essential for full expression of the pre-ovulatory LH surge. Based on these data, we propose that the actions of NKB in the RCh are an important component of the pre-ovulatory LH surge in ewes. PMID- 25040134 TI - Validation of statistical imputation of allele-level multilocus phased genotypes from ambiguous HLA assignments. AB - Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match((r)) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with average recall >76% when imputing HLA alleles from registry data. We simulated ambiguity generated by several HLA genotyping methods to evaluate the imputation performance on several levels of typing resolution. On average, imputation percent recall of allele-level HLA haplotypes was >95% for allele-level typing, >92% for intermediate resolution typing and >58% for serology (low-resolution) typing. Thus, allele-level HLA assignments can be imputed through the application of a set of statistical and population genetics inferences and with knowledge of haplotype frequencies and self-identified race and ethnicities. PMID- 25040135 TI - Relationship between Two Types of Coil Packing Densities Relative to Aneurysm Size. AB - BACKGROUND AND PURPOSE: Coil packing density (PD) can be calculated via a formula (PDF ) or software (PDS ). Two types of PD can be different from each other for same aneurysm. This study aimed to evaluate the interobserver agreement and relationships between the 2 types of PD relative to aneurysm size. METHODS: Consecutive 420 saccular aneurysms were treated with coiling. PD (PDF , [coil volume]/[volume calculated by formula] and PDS, [coil volume]/[volume measured by software]) was calculated and prospectively recorded. Interobserver agreement was evaluated between PDF and PDS . Additionally, the relationships between PDF and PDS relative to aneurysm size were subsequently analyzed. RESULTS: Interobserver agreement for PDF and PDS was excellent (Intraclass correlation coefficient, PDF ; 0.967 and PDS ; 0.998). The ratio of PDF and PDS was greater for smaller aneurysms and converged toward 1.0 as the maximum dimension (DM ) of aneurysm increased. Compared with PDS , PDF was overestimated by a mean of 28% for DM < 5 mm, by 17% for 5 mm <= DM < 10 mm, and by 9% for DM >= 10 mm (P < 0.01). CONCLUSIONS: Interobserver agreement for PDF and PDS was excellent. However, PDF was overestimated in smaller aneurysms and converged to PDS as aneurysm size increased. PMID- 25040136 TI - Normal variation in cortical osteocyte lacunar parameters in healthy young males. AB - The most abundant cell in bone, osteocytes form an interconnected system upon which the regulation of healthy bone relies. Although the complete nature of the role of osteocytes has yet to be defined, they are generally accepted to play a part in the sensing of load and the initiation of damage repair. A previous study conducted by our group identified variation of up to 30% in osteocyte lacunar density and morphological parameters between regions of a single cross-section of human femoral shaft; that study, however, was limited to a single individual. The aim of the current study was to determine whether this pattern consistently occurs in healthy young male femora. Anterior, posterior, medial and lateral blocks were prepared from the proximal femoral shaft of seven males and synchrotron radiation micro-CT imaged. Average lacunar densities (+/- SD) from the anterior, posterior, medial and lateral regions were 23 394 +/- 1705, 30 180 +/- 4860, 35 946 +/- 5990 and 29 678 +/- 6081 lacunae per mm(3) of bone tissue, respectively. These values were significantly different between the anterior and both the medial and posterior regions (P < 0.05). The density of the combined anterior and posterior regions was also significantly lower (P = 0.006) than the density of the combined medial and lateral regions. Although no difference was found in predominant orientation, shape differences were found; with the combined anterior-posterior regions having lacunae that were significantly more elongated and less flat than the combined medial-lateral values (P < 0.001). As expected, in this larger study, there was a dramatic difference in lacunar density between the medial and anterior region (up to ~ 54%). The study clearly demonstrates that the high variation seen in osteocyte lacunar density as well as other lacunar parameters, noted in a number of biomechanical, age and pathology studies, are well within the range of normal variation; however, the reasons for and consequences of this variation remain unclear. Lacunar parameters including abundance and shape are being increasingly incorporated into computational modeling of bone biology and this paper represents a more comprehensive description of normal healthy lacunae. PMID- 25040137 TI - Review of quantitative surveys of the length and stability of MTBE, TBA, and benzene plumes in groundwater at UST sites. AB - Quantitative information regarding the length and stability condition of groundwater plumes of benzene, methyl tert-butyl ether (MTBE), and tert-butyl alcohol (TBA) has been compiled from thousands of underground storage tank (UST) sites in the United States where gasoline fuel releases have occurred. This paper presents a review and summary of 13 published scientific surveys, of which 10 address benzene and/or MTBE plumes only, and 3 address benzene, MTBE, and TBA plumes. These data show the observed lengths of benzene and MTBE plumes to be relatively consistent among various regions and hydrogeologic settings, with median lengths at a delineation limit of 10 ug/L falling into relatively narrow ranges from 101 to 185 feet for benzene and 110 to 178 feet for MTBE. The observed statistical distributions of MTBE and benzene plumes show the two plume types to be of comparable lengths, with 90th percentile MTBE plume lengths moderately exceeding benzene plume lengths by 16% at a 10-ug/L delineation limit (400 feet vs. 345 feet) and 25% at a 5-ug/L delineation limit (530 feet vs. 425 feet). Stability analyses for benzene and MTBE plumes found 94 and 93% of these plumes, respectively, to be in a nonexpanding condition, and over 91% of individual monitoring wells to exhibit nonincreasing concentration trends. Three published studies addressing TBA found TBA plumes to be of comparable length to MTBE and benzene plumes, with 86% of wells in one study showing nonincreasing concentration trends. PMID- 25040138 TI - K+ retention in leaf mesophyll, an overlooked component of salinity tolerance mechanism: a case study for barley. AB - Plant salinity tolerance is a physiologically complex trait, with numerous mechanisms contributing to it. In this work, we show that the ability of leaf mesophyll to retain K(+) represents an important and essentially overlooked component of a salinity tolerance mechanism. The strong positive correlation between mesophyll K(+) retention ability under saline conditions (quantified by the magnitude of NaCl-induced K(+) efflux from mesophyll) and the overall salinity tolerance (relative fresh weight and/or survival or damage under salinity stress) was found while screening 46 barley (Hordeum vulgare L.) genotypes contrasting in their salinity tolerance. Genotypes with intrinsically higher leaf K(+) content under control conditions were found to possess better K(+) retention ability under salinity and, hence, overall higher tolerance. Contrary to previous reports for barley roots, K(+) retention in mesophyll was not associated with an increased H(+) -pumping in tolerant varieties but instead correlated negatively with this trait. These findings are explained by the fact that increased H(+) extrusion may be needed to charge balance the activity and provide the driving force for the high affinity HAK/KUP K(+) transporters required to restore cytosolic K(+) homeostasis in salt-sensitive genotypes. PMID- 25040139 TI - The effect of implant diameter on osseointegration utilizing simplified drilling protocols. AB - OBJECTIVES: To observe and to compare histologically and histomorphometrically, the combined effect of drilling sequence and implant diameter in vivo. MATERIAL AND METHODS: A total of 72 alumina-blasted and acid-etched Ti-6Al-4V implants with three different diameters (3.75, 4.2, and 5 mm, n = 24 for each group) were placed in the right and left tibiae of 12 beagle dogs. Within the same diameter group, half of the implants were inserted after a simplified drilling procedure (pilot drill + final diameter drill) on one tibia and the other half were placed using the conventional drilling procedure on the other tibia. After 1 week, half of the animals (n = 6) were sacrificed, and the other half was sacrificed after 5 weeks (n = 6). The retrieved bone-implant samples were subjected to non decalcified histologic sectioning, and the bone-to-implant contact (BIC) and the bone area fraction occupancy (BAFO) were analyzed. Primary statistical analysis used a mixed model analysis of variance with significance level set at P < 0.05. RESULTS: Histologic observation showed that at 1 week, immature woven bone formed in vicinity of the implant, whereas at 5 weeks, the woven bone was replaced by lamellar bone, which formed in proximity with the implant. Histomorphometrically, the simplified technique was associated with significantly greater BIC and BAFO after 1 week. Differences between techniques were not longer apparent after 5 weeks, but BAFO was inversely and significantly associated with implant diameter at that time. CONCLUSIONS: The simplified technique did not impair either early or late bone formation for any tested implant diameter; however, wider diameters were associated with less bone formation at longer healing times for both techniques. PMID- 25040140 TI - Basal plasma concentrations of routine variables and packed cell volume in clinically healthy adult small-sized dogs: effect of breed, body weight, age, and gender, and establishment of reference intervals. AB - BACKGROUND: Plasma variables may be affected by breed or body weight (BW). Small sized dogs are very common, but no specific reference intervals (RI) are used. OBJECTIVES: The primary objective of this prospective study was to assess the potential effect of breed, BW, age, and sex on routine plasma analytes and packed cell volume (PCV) in small-sized dogs. A secondary objective was to establish RI in this small-sized population. METHODS: Blood was sampled under standardized conditions from healthy dogs. PCV and 15 routine plasma variables were measured at the same laboratory. Effects of breed, BW, age, and sex were tested using a general linear model. The procedure recommended by the Clinical and Laboratory Standards Institute was used to establish RI. RESULTS: In this study, 154 healthy dogs from 7 breeds were prospectively included. Although a significant effect of breed, BW, sex, or age was evidenced for most variables (except plasma sodium, phosphates, and triglycerides), it was considered as clinically irrelevant. More strikingly, the percentage of values in the reference sample group under the lower limit of the laboratory's RI ranged from 3.8% to 76.6% for 9 variables, and those higher than the upper limit of the laboratory's RI ranged from 4.5% to 9.7% for 7 variables. For example, the RI for creatinine in small-sized dogs was 45-90 MUmol/L (vs 54-144 MUmol/L for the general dog population). CONCLUSION: Specific RI should be considered for PCV and selected plasma variables in small-sized dogs. PMID- 25040141 TI - ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and management of hypoglycemia in children and adolescents with diabetes. PMID- 25040142 TI - Community reintegration of stroke survivors: the effect of a community navigation intervention. AB - AIM: The overall aim of the proposed study is to examine a newly implemented navigation intervention intended to support stroke survivors' community integration during the first year following hospital discharge in four regions of Ontario, Canada. BACKGROUND: Stroke is a leading cause of disability worldwide. Stroke survivors living in the community require regular, ongoing follow-up to assess recovery, prevent deterioration and maximize health outcomes. Internationally published evidence, often conducted in large urban centres, suggests that community reintegration services are an important component of the continuum of care for stroke survivors. This evidence, however, often does not address the particular challenges inherent in smaller urban and rural contexts. DESIGN: The design of this 2-year mixed-method study will use cohort and focused ethnography. METHODS: The three stages of this study include: (1) collection of quantitative data to profile the health status, support and extent of community reintegration of stroke survivors; (2) collection of qualitative data from stroke survivors and their care partners about community reintegration and navigation; and following triangulation of findings (3) knowledge translation activities. This study was ethically approved by the academic Research Ethics Board and clinical Research Ethics Board (Sudbury, Ontario) and funded by the Ontario Stroke Network (Canada). DISCUSSION: Results will describe experiences and outcomes of a community navigation intervention. Engagement of multiple stakeholders has the potential to develop a shared understanding of community reintegration and generate evidence informed recommendations for service enhancement at critical points in stroke recovery to support survivor and community well-being. PMID- 25040143 TI - Pre-emptive epidural analgesia improves post-operative pain and immune function in patients undergoing thoracotomy. AB - BACKGROUND: Pre-emptive analgesia may relieve post-operative pain. However, its effects on immune function of patients undergoing thoracotomy are still unclear. Therefore, we investigated effects of pre-emptive epidural analgesia on post operative pain and immune function in patients undergoing thoracotomy. METHODS: Ninety patients undergoing thoracotomy were randomized equally into three groups. Group A (control) only received patient-controlled epidural analgesia (PCEA). Group B (routine) was given 0.125% ropivacaine 6 mL 30 min after surgery, then PCEA. Group C (pre-emptive) received 0.125% ropivacaine 6 mL 30 min before skin incision and every 60 min during surgery, then PCEA. Visual analogue scale scores and cytokine levels were the main outcomes. Secondary outcomes included analgesic demands, side effects and hospital stays. RESULTS: Post-operative visual analogue scale scores were decreased in group C compared with group B, and that of group B were lower than in group A (P < 0.05). Compared with group B, protein and mRNA expressions of tumour necrosis factor-alpha, interleukin (IL)-6 and IL-8 were decreased, and that of IL-4 were increased in group C (P = 0.002~0.049). Both analgesic demands and the incidences of nausea/vomiting and hypotension were lower in group C compared with group B (P = 0.01~0.037). Hospital stays were shorter in group C compared with group B (P = 0.045). CONCLUSIONS: These findings suggest that pre-emptive epidural analgesia can produce better analgesia effects, with less analgesic demands and side effects, and attenuate the surgery-induced immune alterations, and improve the post-operative recovery in patients undergoing thoracotomy. PMID- 25040144 TI - Serum 1,3-beta-d-glucan for antifungal treatment stratification at the intensive care unit and the influence of surgery. AB - The purpose of this study was to evaluate a preemptive approach with serum 1,3 beta-d-glucan (BDG) as a marker for treatment stratification of systemic antifungal (AF) therapy in patients with clinical suspected invasive fungal infections (IFI) at intensive care units (ICU), and the impact of surgical procedures. A total of 66 ICU patients with clinical suspected IFI were included in this retrospective analysis. Serum BDG testing was performed prior to initiation of AF treatment and in addition to routine diagnostic measures. Based on the BDG results the initial clinical decision whether or not to start systemic AF therapy was re-evaluated. Impact of surgical procedures on clinical utility of serum BDG was evaluated in a sub-group of 25 patients who had undergone surgical procedures prior to BDG evaluation. BDG test results led to discontinuation of AF therapy in 13 patients, and initiation of AF therapy in seven patients. In 46 patients the clinical decision was confirmed by BDG. The majority of suspected, probable and proven IFI cases (10/13, 77%) was predicted by the test. BDG testing turned out positive in 9/25 (36%) of patients that had undergone recent surgery and levels correlated with clinical findings. Serum BDG evaluation seems to be a promising tool to guide AF therapy in ICU patients even after recent surgical procedures. PMID- 25040145 TI - Regional variation in prevalence and healthcare utilization due to epilepsy in Sweden. AB - OBJECTIVE: To estimate the regional differences in the prevalence of epilepsy and the associated costs due to inpatient and outpatient care and anti-epileptic drug (AED) utilization for the years 2005 and 2011 in Sweden. METHODS: Region-specific estimates of the prevalence of epilepsy were obtained using a method based on a linkage of the healthcare and pharmaceutical registries and the cause of death registry. Regional cost components were estimated using registry data by region on inpatient and outpatient care utilization, AED sales, and mortality. Per patient utilization and monetary costs were calculated. RESULTS: Estimated prevalence of epilepsy varied substantially across the regions in 2011, from 0.76% in Jamtland to 1.08% in Gotland. The national prevalence was 0.88%. The average number of hospitalizations per patient and year decreased at the national level between 2005 and 2011. At the national level, the per-patient specialized care (outpatient) utilization also decreased between 2005 and 2011. However, at the regional level, the decrease was not uniform, and in some counties, the per patient utilization increased during the period studied. The per-patient utilization of AEDs increased in all counties, except Kronoberg, between 2005 and 2011. Moreover, between-region differences in healthcare and AED utilization, and significant differences between regions and national averages were revealed. Similarly, regional per-patient costs were shown to deviate from the national average in 13 of 21 regions. CONCLUSIONS: There is significant variation in the prevalence of epilepsy and the provision of health care for patients with epilepsy across the different regions of Sweden. PMID- 25040146 TI - A randomized clinical trial to determine the effect of angiotensin inhibitors reduction on creatinine clearance and haemoglobin in heart failure patients with chronic kidney disease and anaemia. AB - BACKGROUND: Chronic kidney disease is a common comorbidity in elderly patients with heart failure. Evidence supports the use of angiotensin inhibitors for patients with heart failure. However, there is little evidence with which to assess the risk and benefits of this treatment in elderly patients with renal dysfunction. OBJECTIVE: To determine the efficacy and safety of angiotensin inhibitor reduction in patients with heart failure, chronic kidney disease and anaemia. STUDY DESIGN: Open randomized controlled clinical trial. SETTING: Complexo Hospitalario Universitario A Coruna (Spain). PATIENTS: Patients >= 50 years old, with heart failure, haemoglobin (Hb) < 12 mg/dl and creatinine clearance <60 ml/min/1.73 m(2) admitted to hospital, in treatment with angiotensin inhibitors. Informed consent and Ethical Review Board approval were obtained. INTERVENTION: A 50% reduction of angiotensin inhibitor dose of the basal treatment on admission (n = 30) in the intervention group. Control group (n = 16) with the standard basal dose. MAIN OUTCOME MEASURE: Primary outcome was difference in Hb (gr/dl), creatinine clearance (ml/min/1.73 m(2) ) and protein C (mg/dl) between admission and 1-3 months after discharge. Secondary outcome was survival at 6-12 months after discharge. RESULTS: Patients in the intervention group experienced an improvement in Hb (10.62-11.47 g/dl), creatinine clearance (32.5 ml/min/1.73 m(2) to 42.9 ml/min/1.73 m(2) ), and a decrease in creatinine levels (1.98-1.68 mg/dl) and protein C (3.23 mg/dl to 1.37 mg/dl). There were no significant differences in these variables in the control group. Survival at 6 and 12 months in the intervention and control group was 86.7% vs. 75% and 69.3% vs. 50%, respectively. CONCLUSION: The reduction of the dose of angiotensin inhibitors in the intervention group resulted in an improvement in anaemia and kidney function, decreased protein C and an increased survival rate. TRIAL REGISTRATION: EudraCT: 2008-008480-10. PMID- 25040147 TI - The role of lipocalin-2 in liver regeneration. AB - BACKGROUND & AIMS: Various immune mediators such as interleukin-6 (IL-6) have been implicated in the process of liver regeneration. Lipocalin-2 (LCN2) has been recently characterized as a prototypic immune mediator produced by various cell types being involved mainly in host defence. In addition, numerous studies have demonstrated its clinical value as a biomarker. This study aimed at defining the role of LCN2 in liver regeneration. METHODS: We studied LCN2 expression in wild type mice in a model of partial hepatectomy (PH). Furthermore, we evaluated liver regeneration after PH in LCN-deficient mice compared to littermate controls. Serum levels of LCN2 were assessed in a small group of patients undergoing hepatic resection. RESULTS: LCN2 is dramatically induced in livers and sera of wild-type mice after PH, whereas liver LCN2-receptor expression was decreased. Sham operations did not affect hepatic and serum LCN2 expression. Although LCN2 deficient mice exhibited increased baseline liver expression indices, LCN2 deficient mice did not differ from wild-type mice with respect to hepatic proliferation suggesting that this molecule is not involved in hepatic repair. Only serum IL-1beta levels were slightly lower in LCN(-/-) mice, whereas IL-6 serum levels did not differ between various tested animal groups. In humans undergoing hepatic resection, LCN2 levels increased significantly within 24 h following surgery. CONCLUSIONS: LCN2, although massively induced in mice after PH, is not relevant in murine hepatic regeneration. Further, human studies have to define whether LCN2 could evolve as biomarker after liver surgery. PMID- 25040148 TI - A comparison of three scales for measuring pain in children with cognitive impairment. AB - AIM: Pain is a neglected problem in children with cognitive impairments, and few studies compare the clinical use of specific pain scales. We compared the Non Communicating Children's Pain Checklist Postoperative Version (NCCPC-PV), the Echelle Douleur Enfant San Salvador (DESS) and the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS). The first two were developed for children with cognitive impairment, and the third is a more general pain scale. METHODS: Two external observers and the child's caregiver assessed 40 children with cognitive impairment for pain levels. We assessed inter-rater agreement, correlation, dependence on knowledge of the child's behaviour, simplicity and adequacy in pain rating according to the caregiver for all three scales. RESULTS: The correlation between the NCCPC-PV and the DESS was strong (Spearman correlation coefficient = 0.76) and better than between each scale and the CHEOPS. Although the DESS showed better inter-rater agreement, it was more dependent on familiarity with the child and was judged more difficult to use by all observers. The NCCPC-PV was the easiest use and the most appropriate for rating the child's pain. CONCLUSION: The NCCPC-PV was the easiest to use for pain assessment in cognitively impaired children and should be adopted in clinical settings. PMID- 25040149 TI - Peginterferon-alfa mono-therapy in the treatment of acute hepatitis C in HIV infection. AB - The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal treatment outcome in HIV co infected individuals. Cohort study of 105 HIV-infected patients with AHC infection from five centres in two European countries was carried out. Choice of treatment with pegIFN-alfa alone (group 1; n = 36) or pegIFN-alfa and ribavirin (RBV) (group 2; n = 69) was at the discretion of the investigator. Outcome was evaluated as RVR and SVR. Fisher's exact and Mann Whitney U tests were used for statistical analysis. All patients were male, median age was 39 years, main route of transmission MSM (91%). In 69% of patients, clinical signs of acute hepatic infection were missing, dominant HCV genotypes were 1 (64%) and 4 (16%) and mean baseline HCV-RNA was 3.559.085 IU/mL. 60% received HAART and CD4 cell count was 469/mm(3) . Overall SVR rate was 64.8% (68/105). SVR was reached in 69% of treated patients in group 1 and in 63% of treated patients in group 2 (P = 0.67) while RVR was seen in 61% and 49%, respectively (P = 0.35). Interestingly, by univariate analysis, SVR rates in group 1 were significantly higher in patients initiating therapy within 4 weeks of AHC diagnosis compared to patients initiating therapy within 5-36 weeks after diagnosis (P = 0.03). PegIFN-alfa alone or in combination with ribavirin results in similar response rates in HIV infected patients with AHC. In particular, when treatment is initiated within 4 weeks of diagnosis, pegIFN mono-therapy might be sufficient to allow for an optimal treatment response. PMID- 25040150 TI - Systems biology approaches to enhance our understanding of drug hypersensitivity reactions. AB - Hypersensitivity drug reactions (HDRs) encompass a wide spectrum of unpredictable clinical entities. They represent an important health problem, affecting people of all ages, and lead to a large strain on the public health system. Here, we summarize experiments that use high-throughput genomics technologies to investigate HDRs. We also introduce the field of systems biology as a relatively recent discipline concerned with the integration and analysis of high-throughput data sets such as DNA microarrays and next-generation sequencing data. We describe previous studies that have applied systems biology techniques to related fields such as allergy and asthma. Finally, we present a number of potential applications of systems biology to the study of HDRs, in order to make the reader aware of the types of analyses that can be performed and the insights that can be gained through their application. PMID- 25040151 TI - Crusted scabies is associated with increased IL-17 secretion by skin T cells. AB - Scabies is an ectoparasitic infestation by the mite Sarcoptes scabiei. Although commonly self-limiting, a fraction of patients develop severely debilitating crusted scabies. The immune mechanisms underlying the development of crusted scabies are unclear, and undertaking longitudinal infection studies in humans is difficult. We utilized a porcine model to compare cellular immune responses in peripheral blood and skin of pigs with different clinical manifestations of scabies (n = 12), and in uninfected controls (n = 6). Although clinical symptoms were not evident until at least 4 weeks post-infestation, the numbers of peripheral IFNgamma-secreting CD4(+) T cells and gammadelta T cells increased in infected pigs from week 1 post-infestation. gammadelta T cells remained increased in the blood at week 15 post-infestation. At week 15, skin cell infiltrates from pigs with crusted scabies had significantly higher CD8(+) T cell, gammadelta T cell and IL-17(+) cell numbers than those with ordinary scabies. Peripheral IL-17 levels were not increased, suggesting that localized skin IL-17-secreting T cells may play a critical role in the pathogenesis of crusted scabies development. Given the potential of anti-IL-17 immunotherapy demonstrated for other inflammatory skin diseases, this study may provide a novel therapeutic avenue for patients with recurrent crusted scabies. PMID- 25040152 TI - A novel extracellular protease of Vibrio mimicus that mediates maturation of an endogenous hemolysin. AB - Vibrio mimicus, a human pathogen that causes gastroenteritis, produces an enterotoxic hemolysin as a virulence factor. The hemolysin is secreted extracellularly as an inactive protoxin and converted to a mature toxin through removal of the N-terminal propeptide, which comprises 151 amino acid residues. In this study, a novel protease having the trypsin-like substrate specificity was purified from the bacterial culture supernatant. The N-terminal amino acid sequence of the purified protein was identical with putative trypsin VMD27150 of V. mimicus strain VM573. The purified protease was found to cause maturation of the protoxin by cleavage of the Arg(151)-Ser(152) bond. Deletion of the protease gene resulted in increased amounts of the protoxin in the culture supernatant. In addition, expression of the hemolysin and protease genes was detected during the logarithmic growth phase. These findings indicate that the protease purified may mediate maturation of the hemolysin. PMID- 25040153 TI - Pump-assisted total arch replacement using an in situ stent graft fenestration technique. AB - We describe an endovascular technique using in situ stent graft fenestration and pump assist to repair a pseudoaneurysm of the transverse arch following previous ascending aortic and transverse arch replacements. PMID- 25040154 TI - Evidence-based medicine use in pharmacy practice: a cross-sectional survey. AB - RATIONALE, AIMS AND OBJECTIVES: This study aimed to evaluate the awareness, attitude, knowledge and use of evidence-based medicine (EBM) among pharmacists in Jordan. METHODS: A cross-sectional self-reported survey was conducted on 122 pharmacists (both hospital and community) who were asked to fill a validated structured questionnaire. RESULTS: The participants showed a positive attitude towards EBM; more than 80% thought that EBM improves patient care, improves quick knowledge update, helps to unify the quality of care provided, is a good educational tool and a convenient source of advice. But despite this positive attitude, pharmacists showed partial understanding of the technical terms used in EBM; also they relied on their own judgment, medical representatives and standard textbooks in making their decision, resources that can no longer be considered sufficiently updated and/or evidence based. Patient overload, lack of personal time and limited access to EBM sources were the most commonly identified barrier to practicing EBM. Also this study suggest that pharmacist's experience is negatively associated with EBM knowledge score (Spearman's rho value -0.187, P value 0.04). CONCLUSIONS: In spite of the positive attitude towards EBM, this study showed numerous personal and institutional barriers towards implementing EBM in Jordan, which necessitate immediate action by all health care decision makers to formulate a national plan to overcome such barriers, and to further investigate the evidence that teaching, learning and daily application of EBM in practice can improve the quality of care and reduce the cost. PMID- 25040155 TI - Plant-available inorganic nutrient levels are increased in rice-derived distillery effluents inoculated with microbes. AB - AIMS: The purpose of this study was to assess the effects of microbes on plant available inorganic nutrients and a phytohormone in rice-derived distillery effluents. METHODS AND RESULTS: The effects of 37 microbial strains on the components of distillery effluents were investigated. Inoculation of several Aspergillus and Bacillus strains resulted in accumulation of a large quantity of ammonium nitrogen (NH4-N; 774 +/- 490 and 1059 +/- 463 mg l(-1), respectively) in the effluent. However, a decrease in the liquid phase during Aspergillus incubation suggested the requirement for additional treatment of the solid residue, whereas the growth of Bacillus subtilis was inhibited by the acidic conditions in the raw distillery effluent. Interestingly, Aspergillus caelatus, Aspergillus oryzae and Aspergillus tamarii yielded greater increases in nitrate concentrations (30-39 mg l(-1)). Colorimetric and gas chromatography-mass spectrometry analyses revealed that Wickerhamomyces strains generated 7-26 mg l( 1) of indole-3-acetic acid (IAA) when the effluent pH was adjusted to 7.0. CONCLUSIONS: Inoculation of several Aspergillus and Bacillus strains into distillery effluents resulted in the production of a large quantity of NH4-N. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information that will facilitate the bioconversion of distillery effluent into fast-acting liquid fertilizers. PMID- 25040156 TI - Neural correlates of endogenous attention, exogenous attention and inhibition of return in touch. AB - Selective attention helps process the myriad of information constantly touching our body. Both endogenous and exogenous mechanisms are relied upon to effectively process this information; however, it is unclear how they relate in the sense of touch. In three tasks we contrasted endogenous and exogenous event-related potential (ERP) and behavioural effects. Unilateral tactile cues were followed by a tactile target at the same or opposite hand. Clear behavioural effects showed facilitation of expected targets both when the cue predicted targets at the same (endogenous predictive task) and opposite hand (endogenous counter-predictive task), and these effects also correlated with ERP effects of endogenous attention. In an exogenous task, where the cue was non-informative, inhibition of return (IOR) was observed. The electrophysiological results demonstrated early effects of exogenous attention followed by later endogenous attention modulations. These effects were independent in both the endogenous predictive and exogenous tasks. However, voluntarily directing attention away from a cued body part influenced the early exogenous marker (N80). This suggests that the two mechanisms are interdependent, at least when the task requires more demanding shifts of attention. The early marker of exogenous tactile attention, the N80, was not directly related to IOR, which may suggest that exogenous attention and IOR are not necessarily two sides of the same coin. This study adds valuable new insight into how we process and select information presented to our body, showing both independent and interdependent effects of endogenous and exogenous attention in touch. PMID- 25040157 TI - Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment. AB - BACKGROUND: IGF1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, and microcephaly. OBJECTIVE: To identify and characterize IGF1R gene variations in a cohort of 28 Argentinean children suspected of having IGF-1 insensitivity, who were selected on the basis of the association of pre/postnatal growth failure and microcephaly. METHODS: The coding sequence and flanking intronic regions of IGF1R gene were amplified and directly sequenced. Functional characterization was performed by two in vitro assays: 1) [Methyl-(3) H] thymidine incorporation into DNA in fibroblast cell primary cultures from patients and controls treated with IGF-1 for 16-24 h. 2) PI3K/Akt pathway was evaluated with phospho-Akt (Ser473) STAR ELISA Kit (Millipore) in fibroblast cultures from patients and controls stimulated with IGF 1 for 10 min. Prepubertal clinical and GH-IGF-1 axis evaluation was followed up. RESULTS: We identified three novel heterozygous missense mutations in three unrelated patients, de novo p.Arg1256Ser, de novo p.Asn359Tyr and p.Tyr865Cys. In control cells, proliferation assay showed that IGF-1 significantly induced DNA synthesis at 20 h and Akt phosphorylation assay that it significantly stimulated phosphorylation after 10 min (P < 0.05 by anova and Bonferroni Tests). However, no significant increase was observed in any of the three patient fibroblasts in both functional studies. GH therapy growth response in two patients was inconsistent. CONCLUSION: These variations led to failure of the IGF1R function causing pre- and postnatal growth retardation and microcephaly. Microcephaly should be considered in the evaluation of SGA patients, because it seems to favour the frequency of detection of IGF1R mutations. PMID- 25040158 TI - The complement system and its role in the pathogenesis of periodontitis: current concepts. AB - Periodontitis is a highly prevalent inflammatory disease in tooth supporting tissues, induced by bacteria growing in a biofilm on tooth surfaces. Components of the complement system are present in the periodontal tissue and the system is activated in periodontitis. Continuous complement activation and modulation by bacteria within the biofilm in periodontal pockets, however, may enhance local tissue destruction, providing the biofilm with both essential nutrients and space to grow. A more profound understanding of the mechanisms involved in complement derived tissue degradation may facilitate the development of new treatment concepts for periodontitis. Further studies on the role of complement in periodontitis pathogenesis may also contribute to the understanding of why some individuals fail to resolve periodontitis. Here, we review evidence that links complement to the pathogenesis of periodontitis with an emphasis on interaction of complement with bacteria from periodontitis-associated biofilm. PMID- 25040159 TI - Some clinical factors affecting quality of the response to ustekinumab for psoriasis. AB - Ustekinumab has demonstrated efficacy for psoriasis. However, it is known that approximately 30% of patients have shown insufficient response. The aim of the current study is to clarify the specific clinical factors that could be associated with response to ustekinumab treatment. We reviewed the medical records of all patients who were treated with ustekinumab. The Psoriasis Area and Severity Index (PASI) score was calculated, and the efficacy was evaluated at week 0 and week 16. The relationship between clinical efficacy and the patients' background was investigated. The patients, who showed a <74% reduction in the PASI score, were classified as insufficient-responders. A total of 74 patients (average 60.3 years old, male to female ratio 54:20) were examined retrospectively. Eighteen patients were identified as insufficient-responders. Each of the factors, body weight (BW) over 80 kg, body mass index (BMI) over 25, or smoking habit over 20 cigarettes/day showed a higher proportion of insufficient-responders compared with responders, although the difference was not statistically significant. Patients with previous exposure to biologics showed a significantly lower response to the treatment. Furthermore, a statistical difference was identified between patients with none of these factors and patients with some of these factors. Our data suggest that some factors, such as high BW, high BMI, a smoking habit over 20 cigarettes/day, or exposure previous treatment with biologics are likely to affect the quality of the response to ustekinumab. Therefore, these factors need to be taken into account when ustekinumab is administrated. PMID- 25040160 TI - Leprosy in Brazil and its association with characteristics of municipalities: ecological study, 2009-2011. AB - OBJECTIVE: To analyse the ecological association between the demographic and socio-economic characteristics of the Brazilian municipalities and average leprosy incidence rate in the period 2009-2011. METHODS: An ecological study taking the Brazilian municipalities as its units of analysis. The local empirical Bayes estimation method was used to obtain smoothed incidence rates (SIR) for leprosy. The mean, median, first quartile (Q1) and third quartile (Q3) of the SIR were calculated per 100 000 inhabitants. Hierarchical log-linear negative binomial regression models were used to estimate the incidence rate ratios (IRR). RESULTS: In the period 2009-2011, the average SIR of leprosy in Brazil was 20.2 per 100 000 inhabitants, and the median incidence rate among municipalities was 9.1 per 100 000 inhabitants. Significantly higher adjusted IRR were identified for large municipalities (IRR = 1.67) compared to small municipalities, as well as in municipalities with higher illiteracy rates (IRR = 2.15), more urbanised municipalities (IRR = 1.53), those with greater social inequality as per the Gini index (IRR = 1.26), high percentage of households with inadequate sanitation (IRR = 1.63), higher average number of people per room (IRR = 1.41), high proportions of Family Health Programme coverage (IRR = 1.29), high percentage of household contacts investigated (IRR = 2.30) and those with percentage of cases with grade 2 disability considered to be the medium (IRR = 1.26). CONCLUSIONS: In this study, SIR was significantly associated with municipalities with low socio economic status. Disease control activities need to be focused on these municipalities, and investments need to be made in improving the population's living conditions. PMID- 25040163 TI - Emotion regulation strategies in preschool children. AB - This study investigated the development of emotion regulation strategies as reflected in the narratives of children between the ages of 3 and 6 years. An experimental procedure based on story completion tasks was devised to elicit the emotion-related narratives of 69 preschool children. Coding of the narratives led to the observation of different emotion regulation strategies: Behavioural strategies, social support, and cognitive reappraisal. Several significant gender and age differences were identified in the use of these strategies. In addition, verbal skills, non-verbal intelligence, and emotion comprehension were found to be associated with use of the observed emotion regulation strategies, although only at specific ages. PMID- 25040161 TI - Pathogen evolution and the immunological niche. AB - Host immunity is a major driver of pathogen evolution and thus a major determinant of pathogen diversity. Explanations for pathogen diversity traditionally assume simple interactions between pathogens and the immune system, a view encapsulated by the susceptible-infected-recovered (SIR) model. However, there is growing evidence that the complexity of many host-pathogen interactions is dynamically important. This revised perspective requires broadening the definition of a pathogen's immunological phenotype, or what can be thought of as its immunological niche. After reviewing evidence that interactions between pathogens and host immunity drive much of pathogen evolution, I introduce the concept of a pathogen's immunological phenotype. Models that depart from the SIR paradigm demonstrate the utility of this perspective and show that it is particularly useful in understanding vaccine-induced evolution. This paper highlights questions in immunology, evolution, and ecology that must be answered to advance theories of pathogen diversity. PMID- 25040164 TI - Effect of a food supplementation and psychosocial stimulation trial for severely malnourished children on the level of maternal depressive symptoms in Bangladesh. AB - BACKGROUND: Maternal depression is associated with poor child development and growth in low-income countries. This paper evaluates the effect of a community based trial providing psychosocial stimulation and food supplements to severely malnourished children on maternal depressive symptoms in Bangladesh. METHODS: Severely underweight (weight-for-age Z-score < -3) hospitalized children aged 6 24 months (n = 507), were randomly assigned to: psychosocial stimulation (PS), food supplementation (FS), PS+FS, clinic control (CC) and hospital control (CH) at discharge. PS included play sessions with children and parental counselling to mothers during fortnightly follow-up visit at community clinics, conducted by trained play leaders for 6 months. FS involved cereal-based supplements (150-300 kcal/day) for 3 months. All groups received medical care, micronutrient supplements and growth monitoring. We used Bayley scales, Home Observation for Measurement of Environment (HOME) inventory and a parenting questionnaire to assess child development, home stimulation and mothers' child-rearing practices, respectively. We assessed mothers' depressive symptoms using a modified version of Centre for Epidemiologic Studies Depression Scale at baseline and at 6 months post intervention. RESULTS: Maternal depressive symptoms were significantly lower in the CH group at baseline (P = 0.014). After 6 months of intervention there was no significant effect of intervention after adjusting for baseline scores and all possible confounders. Maternal depressive symptoms were higher among poorer (P = 0.06), older (P = 0.057) and less educated (P = 0.019) mothers, who were housewives (P = 0.053), and whose husbands had more unstable jobs (P = 0.058). At 6 months post intervention, children's cognitive (P = 0.045) and motor (P = 0.075) development, HOME (P = 0.012) and mother's parenting score (P = 0.057) were higher among mothers with lower depressive symptoms. CONCLUSION: The study did not show a significant effect of the intervention on the level of maternal depressive symptoms. Interventions with higher intensity and/or of longer duration focusing directly on maternal psychosocial functioning are probably needed to reduce maternal depressive symptoms. PMID- 25040165 TI - Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of p62/sequestosome-1. AB - Autophagy is a homeostatic process that is important for degrading protein aggregates, nutrient deposits, dysfunctional organelles and several signaling molecules. p62/sequestosome-1 is a protein that binds to several autophagy substrates, such as ubiquitinated proteins, damaged mitochondria and signaling molecules such as an Nrf2 inhibitor Keap1, promoting their autophagic degradation. Sestrin2, a stress-inducible protein, has recently been shown to bind to p62 and promote autophagic degradation of such p62 targets. Because Sestrin2 is a metabolic regulator that suppresses diverse age- and obesity associated pathologies, the autophagy-controlling function of Sestrin2 may be important for its other physiological functions. However, the molecular mechanism of how Sestrin2 can promote clearance of p62-associated proteins has been unclear. Here we show that Sestrin2 physically associates with Unc-51-like protein kinase 1 (ULK1) and p62 to form a complex in which both Sestrin2 and p62 become phosphorylated by ULK1 at multiple sites. Ser403 of p62, whose phosphorylation is known to promote autophagic degradation of p62 and its targets, is among the sites phosphorylated by ULK1. ULK1-mediated p62 phosphorylation was facilitated by Sestrin2 in cells as well as in in vitro kinase assays. Consistent with this finding, oligomycin-induced energy deprivation, which strongly activates ULK1, provoked a robust Ser403 phosphorylation of p62 in wild-type mouse embryonic fibroblasts. However, in ULK1/2- and Sestrin2-deficient mouse embryonic fibroblasts, oligomycin-induced p62 phosphorylation was dramatically attenuated, suggesting that endogenous Sestrin2-ULK1/2 mainly mediates p62 phosphorylation in response to energetic stress. Taken together, this study identifies ULK1 as a new p62 Ser403 kinase and establishes Sestrin2 as a promoter of ULK1-mediated p62 phosphorylation. PMID- 25040166 TI - A specific Toll-like receptor profile on T lymphocytes and values of monocytes correlate with bacterial, fungal, and cytomegalovirus infections in the early period of allogeneic stem cell transplantation. AB - BACKGROUND: Bacterial, fungal, and viral infections often affect non-relapse mortality after allogeneic stem cell transplantation (alloSCT). Recovery from infections depends on a balanced integration between innate and adaptive immune responses. In this complex interplay, a key role is played by Toll-like receptors (TLRs), which are sensors of pathogen-associated molecular patterns. To our knowledge, no previous study deals with both expression and function of all human TLRs together, in relation to infections in the setting of alloSCT. METHODS: We prospectively evaluated 9 TLRs by flow cytometry on T lymphocytes and monocytes of 35 patients in relation to infectious events from day +30 to day +120. Tumor necrois factor-alpha, interleukin-4, interferon-gamma, and monocyte chemoattractant protein-1 induction upon TLR activation was assessed by enzyme linked immunosorbent assay on cell supernatants. RESULTS: In multivariate Cox regression analysis, levels of TLR-9 expression on T lymphocytes (P = 0.01) and values of natural killer cells (P = 0.01) correlated negatively with bacterial infections, whereas cytomegalovirus (CMV) infection resulted as a positive predictor. We observed a trend for negative correlation between TLR-7 levels on T lymphocytes and fungal infections (P = 0.07). Values of monocytes were negatively associated with CMV infection (P = 0.03), whereas levels of TLR-5 on T lymphocytes were positive predictors (P = 0.01). Age (P = 0.03) and bacterial infections (P = 0.006) negatively influenced overall survival. Monocyte values were positive predictors of survival (P = 0.003). CONCLUSIONS: Bacterial, fungal, and CMV infections were associated with a different expression of some TLRs on T lymphocytes. The protective role of TLR-7 and TLR-9 seemed dominant over other TLRs involved in recognizing fungi and bacteria. We also observed an atypical involvement of TLR-5 in CMV infection. The dominant and atypical role of some TLRs could depend on their pleiotropic functions and the changing inflammatory environment of transplanted patients. A specific TLR profile and an adequate count of monocytes could improve survival, promoting an effective control of infections, and balanced immune responses. If our findings will be confirmed by further studies, these immunological variables could be useful as parameters to predict susceptibility to infections. PMID- 25040167 TI - Wavelets: on the virtues and applications of the mathematical microscope. AB - The paper provides a short introduction to wavelets and discusses their main applications in microscopy and biological imaging. PMID- 25040168 TI - Analgesic efficacy of pre-operative stellate ganglion block on postoperative pain relief: a randomised controlled trial. AB - We undertook a randomised, double-blind, placebo-controlled study to compare the analgesic efficacy of pre-operative stellate ganglion block on postoperative pain relief after upper limb orthopaedic surgery. Patients were administered a 3-ml injection during ultrasound-guided stellate ganglion block; 15 patients received lidocaine 2% and 15 patients received 0.9% saline. Following the block, all patients received standardised general anaesthesia. Postoperative analgesia included regular intravenous diclofenac, paracetamol and patient-controlled analgesia with tramadol for 24 h. Patients were observed at 0, 2, 4, 6, 8, 12 and 24 h after surgery for tramadol consumption, cardiovascular variables and visual analogue scale pain scores at rest and on movement. The mean (SD) hourly tramadol consumption was significantly reduced in the lidocaine group compared with the saline group at 4 h (8.0 (10.1) mg vs 28.0 (12.6) mg, respectively; p = 0.001), 6 h (5.3 (10.8) mg vs 17.3 (12.7) mg, respectively; p = 0.013) and 8 h (5.3 (11.8) mg vs 21.3 (9.1) mg, respectively; p = 0.001). The cumulative 24-h tramadol consumption was 97.3 (16.6) mg in the lidocaine group and 150.6 (26.0) mg in the saline group (p = 0.001). There were significant differences in the pain visual analogue scale at rest at two time points; at 4 h the median (IQR [range]) visual analogue scale scores were 4 (4-6 [2-8]) in the lidocaine group and 5 (4-6 [2-7]) in the saline group (p = 0.03), and at 6 h visual analogue scale scores were 3 (3 4 [3-6]) and 4 (4-6 [2-7]), respectively (p = 0.04). Pain visual analogue scale on movement was lower in the lidocaine group at all time intervals compared with the saline group, but this did not reach statistical significance. The present study has demonstrated a postoperative tramadol-sparing and analgesic effect of pre-operative stellate ganglion block in patients undergoing upper limb orthopaedic surgery under general anaesthesia. PMID- 25040169 TI - Resistance to oxidative stress shows low heritability and high common environmental variance in a wild bird. AB - Oxidative stress was recently demonstrated to affect several fitness-related traits and is now well recognized to shape animal life-history evolution. However, very little is known about how much resistance to oxidative stress is determined by genetic and environmental effects and hence about its potential for evolution, especially in wild populations. In addition, our knowledge of phenotypic sexual dimorphism and cross-sex genetic correlations in resistance to oxidative stress remains extremely limited despite important evolutionary implications. In free-living great tits (Parus major), we quantified heritability, common environmental effect, sexual dimorphism and cross-sex genetic correlation in offspring resistance to oxidative stress by performing a split-nest cross-fostering experiment where 155 broods were split, and all siblings (n = 791) translocated and raised in two other nests. Resistance to oxidative stress was measured as both oxidative damage to lipids and erythrocyte resistance to a controlled free-radical attack. Both measurements of oxidative stress showed low additive genetic variances, high common environmental effects and phenotypic sexual dimorphism with males showing a higher resistance to oxidative stress. Cross-sex genetic correlations were not different from unity, and we found no substantial heritability in resistance to oxidative stress at adult age measured on 39 individuals that recruited the subsequent year. Our study shows that individual ability to resist to oxidative stress is primarily influenced by the common environment and has a low heritability with a consequent low potential for evolution, at least at an early stage of life. PMID- 25040170 TI - Trends in cerebral palsy survival: are health measures really making a difference? PMID- 25040171 TI - Pazopanib for recurrent extraosseous Ewing's sarcoma of the retroperitoneum. PMID- 25040172 TI - Oculomotor executive function abnormalities with increased tic severity in Tourette syndrome. AB - BACKGROUND: Reports conflict as to whether Tourette syndrome (TS) confers deficits in executive function. This study's aim was to evaluate executive function in youths with TS using oculomotor tasks while controlling for confounds of tic severity, age, medication, and severity of comorbid disorders. METHOD: Four saccade tasks requiring the executive functions of response generation, response inhibition, and working memory (prosaccade, antisaccade, 0-back, and 1 back) were administered. Twenty youths with TS and low tic severity (TS-low), nineteen with TS and moderate tic severity (TS-moderate), and 29 typically developing control subjects (Controls) completed the oculomotor tasks. RESULTS: There were small differences across groups in the prosaccade task. Controlling for any small sensorimotor differences, TS-moderate subjects had significantly higher error rates than Controls and TS-low subjects in the 0-back and 1-back tasks. In the 1-back task, these patients also took longer to respond than Controls or TS-low subjects. CONCLUSIONS: In a highly controlled design, the findings demonstrate for the first time that increased tic severity in TS is associated with impaired response inhibition and impaired working memory and that these executive function deficits cannot be accounted for by differences in age, medication or comorbid symptom severity. PMID- 25040173 TI - A TALEN-based specific transcript knock-down of PIWIL2 suppresses cell growth in HepG2 tumor cell. AB - OBJECTIVES: PIWIL2 is widely expressed in various tumours and implicated in playing a role in tumourigenesis. For a more thorough study of PIWIL2 functions in tumour cells, we aimed to establish PIWIL2-specific transcript knock down/knockout HepG2 cell lines using transcription activator-like effector nuclease (TALEN) technology. Furthermore, we proposed to use the cell models to explore PIWIL2 functions in TGF-beta signalling in HepG2 cells. HepG2s are human hepatocellular carcinoma cells. MATERIALS AND METHODS: We established PIWIL2 knock-down or knock-out cell lines in HepG2 using TALEN technology. Next, we sought to use the cell line models to investigate effects of full length PIWIL2 specific transcripts in cell proliferation induced by TGF-beta. RESULTS: First, we established PIWIL2-specific transcript mono-allele and bi-allele knockout HepG2 cell lines. By using the cell line models, we found that specific transcript knockdown of full length PIWIL2 can suppress cell proliferation, while ectopic expression of PIWIL2 enhanced proliferation of HepG2 by suppressing the TGF-beta pathway. Furthermore, we demonstrated that PIWIL2 can interact with HSP90 to prevent formation of HSP90-TbetaR complexes, which promote degradation of TbetaRs. CONCLUSIONS: Taken together, our study revealed critical negative regulation of TGF-beta signalling by PIWIL2 in HepG2 tumour cells, and provided an effective strategy to study specific gene transcript functions in cells. PMID- 25040174 TI - Retracing the evolutionary history of Nothofagus in its geo-climatic context: new developments in the emerging field of phylogeology. AB - Phylogeographic studies have made a significant contribution to the interpretation of genetic lineage distribution in response to climate changes, such as during glaciation events of the Neogene. However, the effects of ancient landscapes associated with global sea level rises, tectonic processes, and climatology driving lineage evolution have been largely overlooked. These effects can be tested in widespread lineages of cold-tolerant species that have endured cooling, and thus, phylogeographic patterns may reflect large-scale processes that were not reset by the ice ages. We hereby combine geological evidence from marine sedimentary basins, Andean orogeny, and climatology with molecular dating and statistical phylogeography to infer how geological and climatic processes affected the distribution of lineages in cold-tolerant Nothofagus species during the Cenozoic. A total of 239 populations along the entire range of all species within the genus Nothofagus (N. antarctica, N. betuloides, N. dombeyi, N. nitida, and N. pumilio) were sampled and analyzed by sequencing three non-coding regions of the chloroplast. We found 30 chloroplast DNA haplotypes that were geographically structured. Molecular dating calibrated with fossils revealed that ancestral lineages appeared in Eocene/Oligocene, whereas most divergences took place during the Miocene; in turn, Bayesian skyline plots showed that population expansion occurred in the Early Pleistocene (1.5-1 million years ago). Lineage divergence from all wide-ranging Nothofagus was spatially and temporally concordant with episodic marine transgressions and warmer times in Patagonia during Eocene/Miocene Epochs. Long-lasting stable raised areas preserved haplotype diversity throughout Patagonia, from where cold-tolerant taxa expanded their ranges during pre-Quaternary times. The detailed study of such ancient divergences is novel and allows us to infer the effects of geological processes on distribution patterns of ancient lineages, that is, phylogeology. PMID- 25040176 TI - The startup culture of conservation entrepreneurship. PMID- 25040175 TI - Aspirin therapy in venous malformation: a retrospective cohort study of benefits, side effects, and patient experiences. AB - Venous malformations (VMs) are often painful and may enlarge over time. Chronic coagulopathy is common in VMs and may contribute to phleboliths and potentially to disease progression. Few studies have examined the effects of anticoagulation on VMs and to our knowledge none have examined the use of aspirin therapy. A survey was administered to patients and parents of patients with VMs who attended the University of California at San Francisco Vascular Anomalies Center over a 4 year period (2008-2012) to whom aspirin had been recommended. They were surveyed regarding whether they were taking aspirin and, if yes, whether aspirin had resulted in any appreciable benefit. Sixty-five letters were sent to potential subjects: 38 participated and 27 declined to participate or could not be contacted. Twenty-eight of the 38 had begun aspirin and 22 reported current use. Seventeen reported some benefit, including less aching (n = 2), less shooting pain (n = 15), less fullness and swelling (n = 13), and shrinking of the VM (n = 1). Discontinuation of aspirin was associated with worsening VM symptoms in five of six patients. Side effects were reported in 6 of 28 patients, including five episodes of minor bleeding or excessive bruising and one of nausea and vomiting. This study suggests that aspirin may be a beneficial treatment for VM, with a reduction in pain and soft tissue swelling and an acceptable side-effect profile, but the retrospective nature of the study and the small size of the cohort limited our conclusions. Larger prospective studies of aspirin for VM using clinical and laboratory outcome measures are needed to confirm these observations. PMID- 25040177 TI - Reply to Lutrin: decision-making in colorectal surgery. PMID- 25040178 TI - Merkel cell carcinoma: is this a true carcinoma? AB - Recent years have brought an enhanced understanding of Merkel cell carcinoma (MCC) biology, especially with regard to the Merkel cell polyoma virus as a causative agent. Differences between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative MCC in morphology; gene expression, miRNA profiles and prognosis have been reported. Origin of MCC is controversial. Presence of neurosecretory granules has suggested that these carcinomas originate from one of the neurocrest derivatives, most probably Merkel cells; the name Merkel cell carcinoma is now widely accepted. Expression of PGP 9.5, chromogranin A and several neuropeptides, initially regarded as specific markers for neural and neuroendocrine cells, has recently been shown in a subset of lymphomas. MCC commonly expresses terminal deoxynucleotidyl transferase and PAX5. Their co expression under physiologic circumstances is restricted to pro/pre-B cells and pre-B cells. These findings lead to the hypothesis by zur Hausen et al. that MCC originates from early B cells. This review was intended to critically appraise zur Hausen's hypothesis and discuss the possibility that MCC is a heterogenous entity with distinct subtypes. PMID- 25040179 TI - Relationship between genuine and pseudohalitosis and social anxiety disorder. AB - Halitosis is described as offensive breath caused by various factors such as periodontal diseases, bacterial coating of tongue, systemic disorders and different types of foods. Pseudohalitosis is a situation that patients complain of oral malodor even though they do not have offensive odour. The purpose of this study was to compare the relationships between social anxiety estimations and both pseudohalitosis and genuine halitosis cases. Liebowitz Social Anxiety Scale (LSAS) and questionnaire regarding halitosis were applied to 100 participants. Halitosis was determined using organoleptic method, gas chromatography and portable sulphur monitor. anova test and 2-tailed Spearman's rank-order correlation coefficient were used to determine the differences and relations between groups. With reference to LSAS, 62% of participants had anxiety. Among these patients, 98% had genuine halitosis (P < 0.05). The mean measurements of VSC values were 248.65 ppm in halimeter, 298.02 ppm of H2 S, 95.33 ppm of CH3 SH and 47.00 ppm of (CH3 )2 S in gas chromatography. Halitosis was present in 90% of participants, and it was absent in 10% by organoleptic assessment. There was a significant correlation between organoleptic and halimeter measurements. Moreover, statistically significant relationship was detected between anxiety and halitosis. Genuine halitosis patients exhibit social anxiety, so it can be said that there is a causal relationship between halitosis and anxiety. Comparison of the results of objective measurements (sulphur monitor, gas chromatography, organoleptic method) was statistically significant; therefore, it can be said that these methods can be used in diagnosis of halitosis with high accuracy. PMID- 25040180 TI - Clindamycin phosphate 1.2%-benzoyl peroxide 3.0% fixed-dose combination gel has an effective and acceptable safety and tolerability profile for the treatment of acne vulgaris in Japanese patients: a phase III, multicentre, randomised, single blinded, active-controlled, parallel-group study. AB - BACKGROUND: A topical fixed-dose clindamycin phosphate 1.2% and benzoyl peroxide 3.0% combination gel (CLNP/BPO 3%) is known to be effective and safe in white people with acne. OBJECTIVES: To evaluate the efficacy and safety of CLNP/BPO 3.0% topically applied once or twice daily vs. CLNP twice daily in Japanese patients with acne. METHODS: Eight hundred patients were randomized to receive CLNP/BPO 3.0% once daily, CLNP/BPO 3.0% twice daily or CLNP twice daily for 12 weeks. Primary endpoints were absolute change in number of total lesions (TLs) from baseline to week 12 to demonstrate the superiority of CLNP/BPO 3.0% twice daily and noninferiority of CLNP/BPO 3.0% once daily vs. CLNP twice daily. Secondary endpoints were absolute and percentage changes in TLs, inflammatory lesions (ILs), noninflammatory lesions (non-ILs) and Investigator's Static Global Assessment (ISGA) score. Safety assessments included adverse events (AEs), laboratory tests, vital signs and local skin tolerability. RESULTS: Change in TL counts from baseline to week 12 for CLNP/BPO 3.0% twice daily was superior to CLNP twice daily (difference -11.0; P < 0.01); CLNP/BPO 3.0% once daily was not inferior to CLNP twice daily (difference -10.3; P < 0.01). Absolute and percentage reductions in TL, IL and non-IL counts and ISGA score were greater for CLNP/BPO 3.0% once or twice daily than for CLNP twice daily with significant differences seen from early on. Most AEs were mild or moderate. The incidence of adverse drug reactions was higher for CLNP/BPO 3.0% once (24.0%) or twice (35.1%) daily than for CLNP twice daily (9.0%). CONCLUSIONS: Compared with CLNP twice daily, CLNP/BPO 3.0% once daily was more effective and CLNP/BPO 3.0% twice daily at least as effective, with an early onset of action and an acceptable safety and tolerability profile in Japanese patients. PMID- 25040181 TI - Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia. AB - This study was conducted to investigate the possibility that TP53 mRNA is variably expressed in chronic lymphocytic leukaemia (CLL) and that under expression is associated with TP53 dysfunction and adverse outcome. Although TP53 mRNA levels did indeed vary among the 104 CLL samples examined, this variability resulted primarily from over-expression of TP53 mRNA in 18 samples, all of which lacked TP53 deletion/mutation. These patients had higher lymphocyte counts and shorter overall and treatment-free survival times compared to cases with low TP53 mRNA expression and no TP53 deletion/mutation. Furthermore, TP53 mRNA levels did not correlate with levels of TP53 protein or its transcriptional target CDKN1A. We speculated that the adverse outcome associated with TP53 mRNA over-expression might reflect variation in levels of MIR15A and MIR16-1, which are encoded on chromosome 13q14 and target TP53 and some oncogenes including BCL2. In keeping with our hypothesis, 13q14 copy number and levels of MIR15A/MIR16-1 correlated positively with one another but negatively with levels of TP53 mRNA and BCL2 mRNA. Our findings support a model in which loss of MIR15A/MIR16-1 at chromosome 13q14 results in adverse outcome due to de-repression of oncogenes such as BCL2, and up-regulation of TP53 mRNA as a bystander effect. PMID- 25040182 TI - Neuropsychological follow-up at school age of children with asymmetric ventricles or unilateral ventriculomegaly identified in utero. AB - OBJECTIVE: To examine the long-term neuropsychological outcome of children with a prenatal diagnosis of asymmetric ventricles or unilateral ventriculomegaly. DESIGN: A clinic-based neuropsychological study. SETTING: Paediatric neurology clinic. POPULATION: Thirty-three of 41 children, previously assessed at kindergarten age, with asymmetric ventricles or unilateral ventriculomegaly identified in utero, were recruited at school age for a neuropsychological follow up. METHODS: All children, 9-11 years of age, underwent a battery of neuropsychological tests and the parents completed behavioural rating questionnaires. MAIN OUTCOME MEASURES: Results of the neuropsychological assessment and parents' questionnaires. RESULTS: There were no significant differences between children diagnosed with either asymmetric ventricles or unilateral ventriculomegaly in most parameters relative to the general population; the full-scale IQ scores were 103.13 +/- 12.43 and 103.56 +/- 10.5, respectively. A significantly lower performance was found only on one measure of attention among the unilateral ventriculomegaly group and on writing speed tasks among the asymmetric ventricles group. Both study groups showed significantly higher scores than expected in the normal population on a verbal fluency test. Comparison of both groups combined with the normative population yielded significantly lower scores only in attention tests. Yet, the clinical population showed significantly higher scores on writing accuracy, processing speed and verbal fluency and lower rates of executive dysfunction. CONCLUSIONS: Asymmetric ventricles or unilateral ventriculomegaly identified in utero does not appear to affect long-term mental development and school achievements. Further prospective research on a larger sample is needed in order to confirm our findings. PMID- 25040183 TI - Investigating goal conflict as a source of mixed emotions. AB - This research investigated whether (1) the experience of mixed emotions is a consequence of activating conflicting goals and (2) mixed emotions are distinct from emotional conflict. A preliminary experiment (Study 1, N = 35) showed that an elicited goal conflict predicted more mixed emotions than a condition where the same goals were not in conflict. The second experiment was based on naturally occurring goal activation (Study 2, N = 57). This illustrated that mixed emotions were experienced more following conflicting goals compared with a facilitating goals condition-on both a direct self-report measure of mixed emotions and a minimum index measure. The results also showed that mixed emotions were different to emotional conflict. Overall, goal conflict was found to be a source of mixed emotions, and it is feasible that such states have a role in resolving personal dilemmas. PMID- 25040184 TI - Severe hyperthermia, hypernatremia, and early postoperative death after transethmoidal cavitron ultrasonic surgical aspirator (CUSA)-assisted diencephalic mass removal in 4 dogs and 2 cats. AB - OBJECTIVE: To report clinical findings including severe hyperthermia and hypernatremia after transethmoidal Cavitron ultrasonic surgical aspirator (CUSA) assisted diencephalic mass removal. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 4) and 2 cats. METHODS: Medical records (1997-2003) of dogs and cats that had transethmoidal CUSA-assisted diencephalic mass removal were reviewed. Retrieved data were: history, signalment, blood work, neurologic examination findings, MRI results, histopathology, postoperative complications, pre- and postoperative medical therapy, and outcome. RESULTS: Tumor types included: meningioma (n = 3), choroid plexus papilloma (1), astrocytoma (1), and pituitary macroadenoma (1). Median onset of hyperthermia was 3.5 hours (range: 1 6 hours) after extubation; median high temperature at onset was 40.3 degrees C, (range: 39.6-41.7 degrees C). Median onset of hypernatremia (median, 172 mmol/L; range: 168-196 mmol/L) was 4.5 hours (range: 1-9 hours) after extubation. Median time of death after hyperthermia was 10.5 hours (range: 6-13 hours) and after extubation was 13.5 hours (range: 11-15 hours). CONCLUSIONS: Transethmoidal CUSA assisted diencephalic mass removal is associated with early postoperative hyperthermia, hypernatremia, and death, and cannot be recommended. PMID- 25040185 TI - Driving habits and risk factors for traffic accidents among sleep apnea patients- a European multi-centre cohort study. AB - Obstructive sleep apnea is associated with increased motor vehicle accident risk, and improved detection of patients at risk is of importance. The present study addresses potential risk factors in the European Sleep Apnea Database and includes patients with suspected obstructive sleep apnea [n = 8476, age 51.5 (12.5) years, body mass index 31.0 (6.6) kg m(-2) , 82.4% driver's licence holders]. Driving distance (km year(-1) ), driver's licence type, sleep apnea severity, sleepiness and comorbidities were assessed. Previously validated risk factors for accident history: Epworth Sleepiness Scale >=16; habitual sleep time <=5 h; use of hypnotics; and driving >=15 000 km year(-1) were analysed across European regions. At least one risk factor was identified in male and female drivers, 68.75 and 51.3%, respectively. The occurrence of the risk factors was similar across Europe, with only a lower rate in the eastern region (P = 0.001). The mean number of risk factors increased across classes of sleep apnea severity. Frequent driving was prevalent [14.0 (interquartile range 8.0-20.0) * 10(3) km year(-1) ] and 32.7% of drivers had severe obstructive sleep apnea [apnea hypopnea index 50.3 (38.8-66.0) n h(-1) ]. Obesity, shorter sleep time and younger age were associated with increased traffic exposure (P <= 0.03). In conclusion, the risk factors associated with accident history were common among European patients with suspected obstructive sleep apnea, but varied between geographical regions. There was a weak covariation between occurrence of risk factors and clinically determined apnea severity but frequent driving, a strong risk factor for accidents, was over-represented. Systematic evaluation of accident-related risk factors is important to detect sleep apnea patients at risk for motor vehicle accidents. PMID- 25040186 TI - Identifying a rapid bolus dose of dexmedetomidine (ED50) with acceptable hemodynamic outcomes in children. AB - BACKGROUND: Dexmedetomidine is a highly sensitive, specific alpha2 adrenoceptor agonist with anxiolytic, sedative, and analgesic effects. Administration is recommended as a loading dose infused over 10 min. Clinical experience and a previous study suggested a shorter time frame might be used without causing adverse hemodynamic effects. OBJECTIVE: To determine the dexmedetomidine dose that can be given as a rapid 5 s bolus to healthy children during total intravenous anesthesia (TIVA) without causing significant hemodynamic effects. METHODS: ASA I-II children, aged 5-9 years, having elective surgery under TIVA were recruited. The up-and-down sequential study design was employed to determine the effective dose of dexmedetomidine, starting at 0.3 mcg.kg(-1) with 0.1 mcg.kg(-1) intervals, which caused no hemodynamic response in half the subjects (ED50). Positive responses were defined as mean blood pressure (MAP) and/or heart rate (HR) changes >=30% from baseline. Three parametric estimators and one nonparametric estimator were used to determine the ED50. RESULTS: Twenty-one subjects with median age 7.1 (range 5.4-9.5) years and median weight 23.6 (range 16.2-36.7) kg were recruited. A maximum median HR decrease of 20 b.min(-1) occurred at 50 s and a maximum median MAP increase of 12.5 mmHg occurred at 100 s after bolus dose administration. Fifteen subjects (71%) had a HR <60 b.min(-1) while one subject had a HR <40 b.min(-1) (minimum 35 b.min(-1)) for 60 s following the dexmedetomidine bolus. Four estimators led to an ED50 estimate for dexmedetomidine of 0.49 mcg.kg(-1) [95% CI 0.26-0.80 mcg.kg(-1)]. CONCLUSION: The ED50 of dexmedetomidine administered over 5 s without significant hemodynamic compromise is 0.49 mcg.kg(-1). Further work is needed to determine the 'safe' (ED5 or less) and effective dose for desired perioperative clinical outcomes. PMID- 25040187 TI - Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts. AB - The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5-/-/CD8-/- recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2-/- allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2-/- versus WT allografts. Consequently, A/J.CCL2-/- allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL 1beta and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR. PMID- 25040188 TI - Novel approach for analysis of bronchoalveolar lavage fluid (BALF) using HPLC QTOF-MS-based lipidomics: lipid levels in asthmatics and corticosteroid-treated asthmatic patients. AB - To better understand the respiratory lipid phenotypes of asthma, we developed a novel method for lipid profiling of bronchoalveolar lavage fluid (BALF) using HPLC-QTOF-MS with an internal spectral library and high-throughput lipid identifying software. The method was applied to BALF from 38 asthmatic patients (18 patients with nonsteroid treated bronchial asthma [NSBA] and 20 patients with steroid treated bronchial asthma [SBA]) and 13 healthy subjects (NC). We identified 69 lipids, which were categorized into one of six lipid classes: lysophosphatidylcholine (LPC), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), sphingomyelin (SM) and triglyceride (TG). Compared with the NC group, the individual quantity levels of the six classes of lipids were significantly higher in the NSBA subjects. In the SBA subjects, the PC, PG, PS, SM, and TG levels were similar to the levels observed in the NC group. Using differentially expressed lipid species (p value < 0.05, FDR < 0.1 and VIP score of PLS-DA > 1), 34 lipid biomarker candidates with high prediction performance between asthmatics and controls were identified (AUROC > 0.9). These novel findings revealed specific characteristics of lipid phenotypes in asthmatic patients and suggested the importance of future research on the relationship between lipid levels and asthma. PMID- 25040189 TI - Effect of okra cell wall and polysaccharide on physical properties and stability of ice cream. AB - Stabilizers are used in ice cream to increase mix viscosity, promote smooth texture, and improve frozen stability. In this study, the effects of varying concentrations (0.00%, 0.15%, 0.30%, and 0.45%) of okra cell wall (OKW) and its corresponding water-soluble polysaccharide (OKP) on the physical characteristics of ice cream were determined. Ice cream mix viscosity was measured as well as overrun, meltdown, and consumer acceptability. Ice recrystallization was determined after ice cream was subjected to temperature cycling in the range of 10 to -20 degrees C for 10 cycles. Mix viscosity increased significantly as the concentrations of OKW and OKP increased. The addition of either OKW or OKP at 0.15% to 0.45% significantly improved the melting resistance of ice cream. OKW and OKP at 0.15% did not affect sensory perception score for flavor, texture, and overall liking of the ice cream. OKW and OKP (0.15%) reduced ice crystal growth to 107% and 87%, respectively, as compared to 132% for the control (0.00%). Thus, our results suggested the potential use of OKW and OKP at 0.15% as a stabilizer to control ice cream quality and retard ice recrystallization. OKP, however, at 0.15% exhibited greater effect on viscosity increase and on ice recrystallization inhibition than OKW. PMID- 25040190 TI - Management of breast papillary lesions diagnosed in ultrasound-guided vacuum assisted and core needle biopsies. AB - AIMS: To assess the outcome of breast papillary lesions diagnosed by ultrasound guided core needle biopsy (CB) or vacuum-assisted 'mammotome' biopsy (MT), the accuracy of these diagnoses, and whether it is justified not to undertake surgical excision of non-malignant papillary lesions so diagnosed. METHODS AND RESULTS: Among 3219 (MT, 2195; CB, 1024) breast biopsies spanning 5 years, 185 (5.7%) papillary lesions [MT, 162 (88%); CB, 23 (12%)] were identified. Of these, 142 cases (77%; MT/CB, 125/17) were benign, 24 (13%, 23/1) were atypical, and 19 (10%; 14/5) were malignant. Of the 142 benign cases, 114 had imaging follow-up (FU) (FU period 2-81 months); 17 of 114 cases were excised, and four were malignant (3.5%) (FU period 4-57 months). Of the 24 atypical cases (23 had FU), 19 were excised: six were benign (32%) and 13 malignant (68%). The remaining four cases were considered to be non-malignant (FU period 7-54 months). CONCLUSIONS: Benign papillary lesions diagnosed by MT or CB might not require immediate excision, but should receive imaging FU for at least 5 years. Excision should be performed in cases showing changes in imaging features, as the possibilities of carcinoma coexisting with papilloma or carcinoma developing from papilloma cannot be excluded, as illustrated by the 4% upgrade rate at excision in this study. PMID- 25040191 TI - Clinical feasibility of exercise-based A-V interval optimization for cardiac resynchronization: a pilot study. AB - BACKGROUND: One-third of eligible patients fail to respond to cardiac resynchronization therapy (CRT). Current methods to "optimize" the atrio ventricular (A-V) interval are performed at rest, which may limit its efficacy during daily activities. We hypothesized that low-intensity cardiopulmonary exercise testing (CPX) could identify the most favorable physiologic combination of specific gas exchange parameters reflecting pulmonary blood flow or cardiac output, stroke volume, and left atrial pressure to guide determination of the optimal A-V interval. METHODS: We assessed relative feasibility of determining the optimal A-V interval by three methods in 17 patients who underwent optimization of CRT: (1) resting echocardiographic optimization (the Ritter method), (2) resting electrical optimization (intrinsic A-V interval and QRS duration), and (3) during low-intensity, steady-state CPX. Five sequential, incremental A-V intervals were programmed in each method. Assessment of cardiopulmonary stability and potential influence on the CPX-based method were assessed. RESULTS: CPX and determination of a physiological optimal A-V interval was successfully completed in 94.1% of patients, slightly higher than the resting echo-based approach (88.2%). There was a wide variation in the optimal A-V delay determined by each method. There was no observed cardiopulmonary instability or impact of the implant procedure that affected determination of the CPX-based optimized A-V interval. CONCLUSIONS: Determining optimized A-V intervals by CPX is feasible. Proposed mechanisms explaining this finding and long-term impact require further study. PMID- 25040192 TI - Patients' preferences and health utility assessment with SF-6D and EQ-5D in patients with chronic hepatitis C treated with sofosbuvir regimens. AB - BACKGROUND: Health utilities measure patients' preferences for a health state. AIM: To assess health utilities for sofosbuvir-containing therapy for chronic hepatitis C. METHODS: The SF-6D utility scores were derived from the SF-36 instrument administered at baseline, during and post-treatment to participants of the previously reported clinical trials of sofosbuvir. EQ-5D utility scores were also approximated from the SF-36 using a regression model. RESULTS: Nine hundred and ninety-four patients were enrolled. Baseline SF-6D and EQ-5D scores were 0.66 +/- 0.13 and 0.71 +/- 0.22, respectively (the POSITRON trial), 0.71 +/- 0.16 and 0.76 +/- 0.23 (FISSION), 0.70 +/- 0.14 and 0.75 +/- 0.22 (FUSION), 0.72 +/- 0.15 and 0.79 +/- 0.22 (NEUTRINO). In all studies, SF-6D and EQ-5D scores were highly correlated with each other. (r = 0.83-0.87, P < 0.0001). After 12 weeks, patients receiving sofosbuvir + ribavirin (POSITRON) had similar utility scores to placebo (P > 0.05). Patients receiving 12 and 16 weeks of sofosbuvir + ribavirin (FUSION) had similar utility scores (P > 0.05). In FISSION, patients receiving sofosbuvir + ribavirin had significantly better utilities compared to patients receiving interferon + ribavirin (P < 0.001). Patients receiving sofosbuvir + ribavirin + interferon (NEUTRINO) had a decrease in utilities during treatment (SF-6D: from 0.72 to 0.62, EQ-5D: 0.79 to 0.65; P < 0.0001) similar to that observed in patients receiving pegylated interferon + ribavirin for 24 weeks in FISSION (0.72 to 0.62 and 0.77 to 0.65, respectively, P < 0.0001). After 12 weeks post treatment, patients with SVR (FUSION) had improvement in SF-6D (+0.026 from baseline, P = 0.013) and EQ-5D (+0.043, P = 0.013). In multivariate analyses, baseline depression, anxiety, fatigue, insomnia and treatment-related anaemia were the most consistent predictors of utilities. CONCLUSIONS: Patients' health utilities are minimally impacted by sofosbuvir + ribavirin treatment, as compared to interferon-based, therapy regardless of treatment duration. Clinical trials' numbers: NCT01542788 (POSITRON), NCT01497366 (FISSION), NCT01604850 (FUSION), NCT01641640 (NEUTRINO). PMID- 25040193 TI - Getting the whole picture: adding patient-reported outcomes to adjuvant endocrine treatment evaluation in premenopausal breast cancer patients. PMID- 25040194 TI - Ptolemeba n. gen., a novel genus of hartmannellid amoebae (Tubulinea, Amoebozoa); with an emphasis on the taxonomy of Saccamoeba. AB - Hartmannellid amoebae are an unnatural assemblage of amoeboid organisms that are morphologically difficult to discern from one another. In molecular phylogenetic trees of the nuclear-encoded small subunit rDNA, they occupy at least five lineages within Tubulinea, a well-supported clade in Amoebozoa. The polyphyletic nature of the hartmannellids has led to many taxonomic problems, in particular paraphyletic genera. Recent taxonomic revisions have alleviated some of the problems. However, the genus Saccamoeba is paraphyletic and is still in need of revision as it currently occupies two distinct lineages. Here, we report a new clade on the tree of Tubulinea, which we infer represents a novel genus that we name Ptolemeba n. gen. This genus subsumes a clade of hartmannellid amoebae that were previously considered in the genus Saccamoeba, but whose mitochondrial morphology is distinct from Saccamoeba. In accordance with previous research, we formalize the clade as distinct from Saccamoeba. Transmission electron microscopy of our isolates illustrate that both molecularly discrete species can be further differentiated by their unique mitochondrial cristal morphology. PMID- 25040195 TI - Central nervous system prophylaxis in patients with diffuse large B cell lymphoma, are we treating ourselves? A response to the recent BCSH Guideline - response to Griffin et al. PMID- 25040196 TI - A second-generation genetic linkage map for bighead carp (Aristichthys nobilis) based on microsatellite markers. AB - Bighead carp (Aristichthys nobilis) is an important aquaculture fish worldwide. Genetic linkage maps for the species were previously reported, but map resolution remained to be improved. In this study, a second-generation genetic linkage map was constructed for bighead carp through a pseudo-testcross strategy using interspecific hybrids between bighead carp and silver carp. Of the 754 microsatellites genotyped in two interspecific mapping families (with 77 progenies for each family), 659 markers were assigned to 24 linkage groups, which were equal to the chromosome numbers of the haploid genome. The consensus map spanned 1917.3 cM covering 92.8% of the estimated bighead carp genome with an average marker interval of 2.9 cM. The length of linkage groups ranged from 52.2 to 133.5 cM with an average of 79.9 cM. The number of markers per linkage group varied from 11 to 55 with an average of 27.5 per linkage group. Normality tests on interval distances of the map showed a non-normal marker distribution; however, significant correlation was found between the length of linkage group and the number of markers below the 0.01 significance level (two-tailed). The length of the female map was 1.12 times that of the male map, and the average recombination ratio of female to male was 1.10:1. Visual inspection showed that distorted markers gathered in some linkage groups and in certain regions of the male and female maps. This well-defined genetic linkage map will provide a basic framework for further genome mapping of quantitative traits, comparative mapping and marker-assisted breeding in bighead carp. PMID- 25040197 TI - Iliopsoas abscess as a complication of tunneled jugular vein catheterization in a hemodialysis patient. AB - Iliopsoas abscess is a rare complication in hemodialysis patients that is mainly due to adjacent catheterization, local acupuncture, discitis, and bacteremia. Herein, we report a 47-year-old woman undergoing regular hemodialysis via a catheter in the internal jugular vein who presented with low back pain and dyspnea. A heart murmur suggested the presence of catheter-related endocarditis, and this was confirmed by an echocardiogram and a blood culture of methicillin resistant Staphylococcus aureus. A computed tomography indicated a pulmonary embolism and an incidental finding of iliopsoas abscess. Following surgical intervention and intravenous daptomycin, the patient experienced full recovery and a return to usual activities. This case indicates that an iliopsoas abscess can be related to a jugular vein catheter, which is apparently facilitated by infective endocarditis. The possibility of iliopsoas abscess should be considered when a hemodialysis patient presents with severe low back pain, even when there is no history of adjacent mechanical intervention. PMID- 25040198 TI - Novel Ala94Thr mutation of keratin 14 in epidermolysis bullosa simplex. PMID- 25040199 TI - Correlation between Migraine Severity and Cholesterol Levels. AB - INTRODUCTION: Several studies have documented increased cardiovascular risk factors, particularly hypercholesterolemia, in the migraine population with respect to controls. However, no studies have investigated the possible relationship between headache severity parameters and lipid serum levels. METHODS: This study evaluated the lipid asset in 52 migraine patients (17 with and 36 without aura) before and after treatment with drugs for migraine prophylaxis for 3 months. RESULTS: High frequency (HF, >= 8/month) and intensity (HI, >= 5 Numeric Rating Score) vs. low frequency (LF, < 8/month) and intensity (LI, < 5) of crises were associated with significantly higher cholesterol levels, both total (TC, HF vs. LF, P < 0.0001; HI vs. LI, P < 0.0001) and LDL (LDL-c, HF vs. LF, P < 0.0001, and HI vs. LI, P < 0.0001). In treated patients, a significant decrease in number and intensity of crises was associated with a significant reduction of TC and LDL-c (P < 0.001). A direct linear correlation was also found between frequency and intensity of crises and lipid levels (TC/frequency, P < 0.0001; TC/intensity, P < 0.0001; LDL-c/frequency, P < 0.0001; LDL-c/intensity, P < 0.0001). No significant difference was found in the evaluated parameters for the subgroups of patients with and without aura. DISCUSSION: This study shows a significant positive association between migraine frequency and intensity with total and LDL cholesterol, demonstrating for the first time a significant reduction of these lipid parameters after migraine prophylaxis. However, in view of the retrospective design of the study and the small population size, these results should be considered as preliminary, to be confirmed by future prospective controlled trials. PMID- 25040200 TI - Discovery and characterization of pseudocyclic cystine-knot alpha-amylase inhibitors with high resistance to heat and proteolytic degradation. AB - Obesity and type 2 diabetes are chronic metabolic diseases, and those affected could benefit from the use of alpha-amylase inhibitors to manage starch intake. The pseudocyclics, wrightides Wr-AI1 to Wr-AI3, isolated from an Apocynaceae plant show promise for further development as orally active alpha-amylase inhibitors. These linear peptides retain the stability known for cystine-knot peptides in the presence of harsh treatment. They are resistant to heat treatment and endopeptidase and exopeptidase degradation, which is characteristic of cyclic cystine-knot peptides. Our NMR and crystallography analysis also showed that wrightides, which are currently the smallest proteinaceous alpha-amylase inhibitors reported, contain the backbone-twisting cis-proline, which is preceded by a nonaromatic residue rather than a conventional aromatic residue. The modeled structure and a molecular dynamics study of Wr-AI1 in complex with yellow mealworm alpha-amylase suggested that, despite having a similar structure and cystine-knot fold, the knottin-type alpha-amylase inhibitors may bind to insect alpha-amylase via a different set of interactions. Finally, we showed that the precursors of pseudocyclic cystine-knot alpha-amylase inhibitors and their biosynthesis in plants follow a secretory protein synthesis pathway. Together, our findings provide insights for the use of the pseudocyclic alpha-amylase inhibitors as useful leads for the development of orally active peptidyl bioactives, as well as an alternative scaffold for cyclic peptides for engineering metabolically stable human alpha-amylase inhibitors. PMID- 25040201 TI - Ilium pressure ulcer with pathognomonic wound deformity: the "cliff phenomenon". PMID- 25040202 TI - Divergence in plant and microbial allocation strategies explains continental patterns in microbial allocation and biogeochemical fluxes. AB - Allocation trade-offs shape ecological and biogeochemical phenomena at local to global scale. Plant allocation strategies drive major changes in ecosystem carbon cycling. Microbial allocation to enzymes that decompose carbon vs. organic nutrients may similarly affect ecosystem carbon cycling. Current solutions to this allocation problem prioritise stoichiometric tradeoffs implemented in plant ecology. These solutions may not maximise microbial growth and fitness under all conditions, because organic nutrients are also a significant carbon resource for microbes. I created multiple allocation frameworks and simulated microbial growth using a microbial explicit biogeochemical model. I demonstrate that prioritising stoichiometric trade-offs does not optimise microbial allocation, while exploiting organic nutrients as carbon resources does. Analysis of continental scale enzyme data supports the allocation patterns predicted by this framework, and modelling suggests large deviations in soil C loss based on which strategy is implemented. Therefore, understanding microbial allocation strategies will likely improve our understanding of carbon cycling and climate. PMID- 25040203 TI - Learning peer review: Is jumping into the "deep end" the best approach? PMID- 25040204 TI - Uncontrolled hypertension in Uganda: a comparative cross-sectional study. AB - In a community survey, 4432 persons aged 15 years and older in two districts in Uganda were studied. Blood pressure was measured and predictors for subtypes of uncontrolled hypertension (HTN) were assessed using bivariate and multivariate logistic regression modeling. Prevalence of uncontrolled HTN was 20.2% and the subgroups of isolated systolic HTN (ISH), isolated diastolic HTN (IDH), and systolic-diastolic HTN (SDH) were 7.2%, 4.2%, and 8.8%, respectively. No difference was observed between the sexes. For all HTN subtypes, middle (35-49 years) and older age (50+) groups had a higher prevalence compared with younger subjects (15-34 years) (all P<.001). IDH prevalence in older age was not higher compared with younger age (P=.417). After multivariate analysis, middle age predicted all subtypes of HTN and old age predicted ISH and SDH. Alcohol consumption predicted IDH and SDH. Uncontrolled HTN in this population increases in the order IDH, ISH, and SDH, with more than 1 in 5 having uncontrolled HTN. PMID- 25040205 TI - Use and interpretation of test scores from limited cognitive test batteries: how g + Gc can equal g. AB - Single scores from limited and unbalanced test batteries of cognitive ability can be ambiguous to interpret theoretically. In this study, a limited verbally and knowledge-loaded cognitive test battery, from applicants to the Swedish police academies (N = 1,344), was examined to provide foundations for the use and interpretation of test scores. Three measurement models were compared: one single factor model and two bifactor models, which decomposed the variance of the battery into orthogonal components. The models were evaluated by fit indices and omega coefficients, and then applied to the prediction of academic performance. The overall prediction of all models was similar, although specific abilities also were found to provide substantial predictive validity over and above general intelligence (g). The findings provide support for the use of single scores in applied settings (selection), but suggest that it may be more appropriate to interpret such scores as composites of substantive components, and not just as measures of g. PMID- 25040206 TI - Attention and ageing: Measuring effects of involuntary and voluntary orienting in isolation and in combination. AB - The cueing paradigm provides an established method for eliciting involuntary and voluntary attention shifts. Involuntary orienting is traditionally measured with non-predictive peripheral cues and voluntary orienting with predictive central arrows. Recent studies with young adults have established that predictive central arrows trigger a combination of involuntary and voluntary orienting, raising the possibility that previous studies - including those with older adults - misinterpreted their findings with central arrow cues as isolating the effects of voluntary attention. The present experiment applied different cueing conditions that measured involuntary orienting, voluntary orienting, and involuntary and voluntary orienting in combination in older adults. The results show that past studies of voluntary orienting in older adults confound involuntary and voluntary orienting. Cueing effects in a condition that for the first time isolated voluntary orienting (predictive number cues) with older adults were significant, and comparable to effects for younger adults, demonstrating that older adults successfully utilize cues to direct their spatial attention strategically. A similar normal pattern of orienting was observed for involuntary orienting. Our study provides a methodology that can be applied effectively to isolate and investigate the effects of age on voluntary and involuntary attention. PMID- 25040207 TI - Necrotrophic effector-triggered susceptibility (NETS) underlies the barley Pyrenophora teres f. teres interaction specific to chromosome 6H. AB - Barley net form net blotch (NFNB), caused by the necrotrophic fungus Pyrenophora teres f. teres, is a destructive foliar disease in barley-growing regions worldwide. Little is known about the genetic and molecular basis of this pathosystem. Here, we identified a small secreted proteinaceous necrotrophic effector (NE), designated PttNE1, from intercellular wash fluids of the susceptible barley line Hector after inoculation with P. teres f. teres isolate 0 1. Using a barley recombinant inbred line (RIL) population developed from a cross between the sensitive/susceptible line Hector and the insensitive/resistant line NDB 112 (HN population), sensitivity to PttNE1, which we have named SPN1, mapped to a common resistance/susceptibility region on barley chromosome 6H. PttNE1-SPN1 interaction accounted for 31% of the disease variation when the HN population was inoculated with the 0-1 isolate. Strong accumulation of hydrogen peroxide and increased levels of electrolyte leakage were associated with the susceptible reaction, but not the resistant reaction. In addition, the HN RIL population was evaluated for its reactions to 10 geographically diverse P. teres f. teres isolates. Quantitative trait locus (QTL) mapping led to the identification of at least 10 genomic regions associated with disease, with chromosomes 3H and 6H harbouring major QTLs for resistance/susceptibility. SPN1 was associated with all the 6H QTLs, except one. Collectively, this information indicates that the barley P. teres f. teres pathosystem follows, at least partially, an NE-triggered susceptibility (NETS) model that has been described in other necrotrophic fungal disease systems, especially in the Dothideomycete class of fungi. PMID- 25040208 TI - Rectal neuroendocrine tumor. PMID- 25040209 TI - Increased severity of post-endoscopic retrograde cholangiopancreatography complications in the elderly: an issue to be addressed. PMID- 25040210 TI - Endoscopic management of benign biliary stricture: should we treat more aggressively? PMID- 25040211 TI - Nursing leadership in the face of change. PMID- 25040212 TI - Mechanical restraint in psychiatry: preventive factors in theory and practice. A Danish-Norwegian association study. AB - PURPOSE: To examine how potential mechanical restraint preventive factors in hospitals are associated with the frequency of mechanical restraint episodes. DESIGN AND METHODS: This study employed a retrospective association design, and linear regression was used to assess the associations. FINDINGS: Three mechanical restraint preventive factors were significantly associated with low rates of mechanical restraint use: mandatory review (exp[B] = .36, p < .01), patient involvement (exp[B] = .42, p < .01), and no crowding (exp[B] = .54, p < .01). PRACTICE IMPLICATIONS: None of the three mechanical restraint preventive factors presented any adverse effects; therefore, units should seriously consider implementing these measures. PMID- 25040213 TI - A narratology of postpartum psychosis in an Orthodox Jewish woman. AB - PURPOSE: The purpose of this study was to understand the experience of postpartum psychosis in an Orthodox Jewish woman. DESIGN AND METHODS: A case-based narratology using an unstructured interview was conducted to facilitate the telling of her story. FINDINGS: While the nurses were unable to recognize her symptoms in the hospital, her family members were also unable to recognize escalating symptoms once she returned home, until she became a danger to herself. PRACTICE IMPLICATIONS: Better recognition of symptoms, empathetic connections, cultural appreciation of faith-based rituals and their effect on patient isolation, and education of families and nursing staff may be vital components to successful recovery from postpartum psychosis. PMID- 25040214 TI - Therapeutic relationships from the psychiatric nurses' perspectives: an interpretative phenomenological study. AB - PURPOSE: The aim of the present study was to explore the attributes of the therapeutic relationship from the perspective of psychiatric nurses in the United Arab Emirates. DESIGN AND METHODS: Interpretive phenomenology formed the framework of the study. Data were collected through unstructured recorded interviews with 17 nurses. FINDINGS: Study findings revealed that nurses emphasized the importance of the therapeutic relationship. The analysis resulted in four main themes and nine subthemes. The main themes were: provision of physical care, conveying safety and security, protection, and companionship. PRACTICE IMPLICATIONS: Psychiatric nurses can internalize these themes in their practice to improve client outcomes. These themes need to be emphasized in psychiatric mental health nursing courses as well as in nursing management in the orientation of new clinical psychiatric nurses. PMID- 25040216 TI - Feasibility of the Montreal Cognitive Assessment in acute stroke patients. AB - BACKGROUND AND PURPOSE: Cognitive deficits are common following stroke. Cognitive function in the acute stroke setting is a predictive factor for mid-term outcome. The Montreal Cognitive Assessment (MoCA) is a screening tool for cognitive impairment. The feasibility of MoCA in the acute phase of stroke was evaluated and factors predictive of cognitive impairment were determined. METHODS: In this prospective, single-centre, explorative and observational study consecutive patients with ischaemic (IS) or haemorrhagic (ICH) stroke were enrolled between March 2011 and September 2012. The routine work-up for each patient encompassed assessment of cardiovascular risk factors, the National Institutes of Health Stroke Scale (NIHSS) and the pre-morbid modified Rankin Scale (mRS) score. Cognitive performance was measured using the German version of the MoCA within the first days of admission. A MoCA score of <26 was considered to indicate cognitive impairment. RESULTS: Between March 2011 and September 2012 a total of 842 patients with IS (89.0%) and ICH (11.0%) were enrolled in our study. MoCA was feasible in 678/842 patients (80.5%). Factors independently associated with non feasibility were stroke severity (NIHSS), pre-morbid functional status (mRS), age and lower educational level. Mean MoCA was 21.4 (SD 5.7). A total of 498/678 (73.5%) patients appeared cognitively impaired (<26/30). Independent predictive factors for a lower MoCA score were age, educational level, stroke severity (NIHSS) and pre-morbid functional status (mRS). CONCLUSIONS: In the acute phase of stroke, MoCA is feasible in about 80% of eligible patients. At this stage, MoCA identifies a cognitive impairment in 75% of patients. PMID- 25040215 TI - Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: from ampicillin plus gentamicin to ampicillin plus ceftriaxone. AB - The aim of this study was to assess changes in antibiotic resistance, epidemiology and outcome among patients with Enterococcus faecalis infective endocarditis (EFIE) and to compare the efficacy and safety of the combination of ampicillin and gentamicin (A+G) with that of ampicillin plus ceftriaxone (A+C). The study was a retrospective analysis of a prospective cohort of EFIE patients treated in our centre from 1997 to 2011. Thirty patients were initially treated with A+G (ampicillin 2 g/4 h and gentamicin 3 mg/kg/day) and 39 with A+C (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) for 4-6 weeks. Increased rates of high-level aminoglycoside resistance (HLAR; gentamicin MIC >=512 mg/L, streptomycin MIC >=1024 mg/L or both) were observed in recent years (24% in 1997 2006 and 49% in 2007-2011; p 0.03). The use of A+C increased over time: 1997 2001, 4/18 (22%); 2002-2006, 5/16 (31%); 2007-2011, 30/35 (86%) (p <0.001). Renal failure developed in 65% of the A+G group and in 34% of the A+C group (p 0.014). Thirteen patients (43%) in the A+G group had to discontinue treatment, whereas only one patient (3%) treated with A+C had to discontinue treatment (p <0.001). Only development of heart failure and previous chronic renal failure were independently associated with 1-year mortality, while the individual antibiotic regimen (A+C vs. A+G) did not affect outcome (OR, 0.7; 95% CI, 0.2-2.2; p 0.549). Our study shows that the prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with A+C is safer than A+G, with similar clinical outcomes, although the sample size is too small to draw firm conclusions. Randomized controlled studies are needed to confirm these results. PMID- 25040217 TI - Temperature profiles of different cooling methods in porcine pancreas procurement. AB - Porcine islet xenotransplantation is a promising alternative to human islet allotransplantation. Porcine pancreas cooling needs to be optimized to reduce the warm ischemia time (WIT) following donation after cardiac death, which is associated with poorer islet isolation outcomes. This study examines the effect of four different cooling Methods on core porcine pancreas temperature (n = 24) and histopathology (n = 16). All Methods involved surface cooling with crushed ice and chilled irrigation. Method A, which is the standard for porcine pancreas procurement, used only surface cooling. Method B involved an intravascular flush with cold solution through the pancreas arterial system. Method C involved an intraductal infusion with cold solution through the major pancreatic duct, and Method D combined all three cooling Methods. Surface cooling alone (Method A) gradually decreased core pancreas temperature to <10 degrees C after 30 min. Using an intravascular flush (Method B) improved cooling during the entire duration of procurement, but incorporating an intraductal infusion (Method C) rapidly reduced core temperature 15-20 degrees C within the first 2 min of cooling. Combining all methods (Method D) was the most effective at rapidly reducing temperature and providing sustained cooling throughout the duration of procurement, although the recorded WIT was not different between Methods (P = 0.36). Histological scores were different between the cooling Methods (P = 0.02) and the worst with Method A. There were differences in histological scores between Methods A and C (P = 0.02) and Methods A and D (P = 0.02), but not between Methods C and D (P = 0.95), which may highlight the importance of early cooling using an intraductal infusion. In conclusion, surface cooling alone cannot rapidly cool large (porcine or human) pancreata. Additional cooling with an intravascular flush and intraductal infusion results in improved core porcine pancreas temperature profiles during procurement and histopathology scores. These data may also have implications on human pancreas procurement as use of an intraductal infusion is not common practice. PMID- 25040219 TI - Measurement of the S-adenosyl methionine (SAMe) content in a range of commercial veterinary SAMe supplements. AB - OBJECTIVES: To measure the percentage of the stated amount of S-adenosyl methionine present in a range of commercially available S-adenosyl methionine supplements for veterinary use. METHOD: Sixty-four samples of products containing S-adenosyl methionine marketed to support liver function were obtained from five manufacturers via three commercial wholesalers. The amount of S-adenosyl methionine in each product was measured using high-pressure liquid chromatography. RESULTS: There were greater than threefold variation in the percentage of measured S-adenosyl methionine compared to the stated amount on the packaging which was significantly (P < 0 . 001) related to the product group being measured. CLINICAL SIGNIFICANCE: Differences in received dose of S-adenosyl methionine between different products were marked and this could have a profound influence on studies that evaluate any variation in absorption of S-adenosyl methionine between different product formulations, the effectiveness of S adenosyl methionine-based products in clinical cases or when translating the results of studies that have used a specific S-adenosyl methionine product to those produced by a different manufacturer. PMID- 25040218 TI - HIV stigma and unprotected sex among PLWH in KwaZulu-Natal, South Africa: a longitudinal exploration of mediating mechanisms. AB - Social and structural factors including HIV stigma are theorized to drive global disparities in HIV prevalence. This study tests whether HIV self-stigma, or experiences of stigma at the individual level, is associated with engagement in unprotected sex among people living with HIV (PLWH) in KwaZulu-Natal, South Africa, where 37.4% of adults are living with HIV compared with 0.8% worldwide. It further explores whether depressive symptoms, HIV status disclosure to sex partners, and/or condom use attitudes mediate potential associations between HIV self-stigma and unprotected sex. Participants, including 924 PLWH, were recruited from primary care clinics and completed baseline, 6-, 12-, and 18-month survey assessments between 2008 and 2011. Hierarchical linear modeling analyses were used to examine longitudinal within-subjects associations between HIV self stigma, mediators, and unprotected sex with both HIV-negative/unknown and HIV positive partners. Results demonstrate that HIV self-stigma was prospectively associated with greater likelihood of unprotected sex with HIV-negative/unknown partners. None of the variables explored significantly mediated this association. HIV self-stigma was also prospectively associated with greater likelihood of unprotected sex with HIV-positive partners via the mediators of greater depressive symptoms and more negative condom use attitudes. The current study suggests that HIV self-stigma undermines HIV secondary prevention and care efforts among PLWH in KwaZulu-Natal. It is therefore critical to address HIV stigma at the social/structural level to reduce HIV self-stigma at the individual level and ultimately curb global disparities in HIV prevalence. In the absence of widespread social/structural change, interventions that treat depressive symptoms and encourage more positive condom use attitudes despite the existence of HIV stigma may buffer associations between HIV self-stigma and unprotected sex with HIV-positive partners among PLWH in KwaZulu-Natal. PMID- 25040220 TI - Hemoglobin a1c in the ESRD population: status report. PMID- 25040222 TI - Delayed bedtime due to screen time in schoolchildren: importance of area deprivation. AB - BACKGROUND: Sleep duration is an important predictor of obesity and health. This study evaluated the association between late bedtime and screen time, and the role of geographical deprivation in English schoolchildren. METHODS: We collected bedtime and waking time, screen time, sociodemographic data and measured body mass index in a cross-section of 1332 11-15-year-old schoolchildren (45.7% female) participating in the East of England healthy heart study. Logistic regression was used to determine the likelihood of late bedtime in schoolchildren with different screen time and from a different geographic location. Mean differences were assessed either on ANOVA or t-test. RESULTS: Approximately 42% of boys went to bed late at night compared with 37% of girls. When compared to those with <2 h of daily screen time, schoolchildren with 2-4 h of screen time were more likely [odds ratio (OR) = 1.50, 95% confidence interval (CI): 1.07 2.09] to go to bed late at night while those with >4 h of daily screen time were most likely to go to sleep late at night (OR, 1.97; 95%CI: 1.34-2.89). Late bedtime was associated with deprivation in schoolchildren. CONCLUSIONS: High screen time and deprivation may explain lateness in bedtime in English schoolchildren. This explanation may vary according to area deprivation and geographic location. Family-centered interventions and parental support are important to reduce screen time, late bedtime and increase sleep duration. PMID- 25040221 TI - The structure and specificity of the type III secretion system effector NleC suggest a DNA mimicry mechanism of substrate recognition. AB - Many pathogenic bacteria utilize the type III secretion system (T3SS) to translocate effector proteins directly into host cells, facilitating colonization. In enterohemmorhagic Escherichia coli (EHEC), a subset of T3SS effectors is essential for suppression of the inflammatory response in hosts, including humans. Identified as a zinc protease that cleaves NF-kappaB transcription factors, NleC is one such effector. Here, we investigate NleC substrate specificity, showing that four residues around the cleavage site in the DNA-binding loop of the NF-kappaB subunit RelA strongly influence the cleavage rate. Class I NF-kappaB subunit p50 is cleaved at a reduced rate consistent with conservation of only three of these four residues. However, peptides containing 10 residues on each side of the scissile bond were not efficiently cleaved by NleC, indicating that elements distal from the cleavage site are also important for substrate recognition. We present the crystal structure of NleC and show that it mimics DNA structurally and electrostatically. Consistent with this model, mutation of phosphate-mimicking residues in NleC reduces the level of RelA cleavage. We propose that global recognition of NF-kappaB subunits by DNA mimicry combined with a high sequence selectivity for the cleavage site results in exquisite NleC substrate specificity. The structure also shows that despite undetectable similarity of its sequence to those of other Zn(2+) proteases beyond its conserved HExxH Zn(2+)-binding motif, NleC is a member of the Zincin protease superfamily, albeit divergent from its structural homologues. In particular, NleC displays a modified Psi-loop motif that may be important for folding and refolding requirements implicit in T3SS translocation. PMID- 25040223 TI - Unlocking the secondary gene-pool of barley with next-generation sequencing. AB - Crop wild relatives (CWR) provide an important source of allelic diversity for any given crop plant species for counteracting the erosion of genetic diversity caused by domestication and elite breeding bottlenecks. Hordeum bulbosum L. is representing the secondary gene pool of the genus Hordeum. It has been used as a source of genetic introgressions for improving elite barley germplasm (Hordeum vulgare L.). However, genetic introgressions from H. bulbosum have yet not been broadly applied, due to a lack of suitable molecular tools for locating, characterizing, and decreasing by recombination and marker-assisted backcrossing the size of introgressed segments. We applied next-generation sequencing (NGS) based strategies for unlocking genetic diversity of three diploid introgression lines of cultivated barley containing chromosomal segments of its close relative H. bulbosum. Firstly, exome capture-based (re)-sequencing revealed large numbers of single nucleotide polymorphisms (SNPs) enabling the precise allocation of H. bulbosum introgressions. This SNP resource was further exploited by designing a custom multiplex SNP genotyping assay. Secondly, two-enzyme-based genotyping-by sequencing (GBS) was employed to allocate the introgressed H. bulbosum segments and to genotype a mapping population. Both methods provided fast and reliable detection and mapping of the introgressed segments and enabled the identification of recombinant plants. Thus, the utilization of H. bulbosum as a resource of natural genetic diversity in barley crop improvement will be greatly facilitated by these tools in the future. PMID- 25040224 TI - Guidance for peptide vaccines for the treatment of cancer. AB - Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area. PMID- 25040226 TI - Cost savings from palliative care teams and guidance for a financially viable palliative care program. AB - OBJECTIVES: To quantify the cost savings of palliative care (PC) and identify differences in savings according to team structure, patient diagnosis, and timing of consult. DATA SOURCES: Hospital administrative records on all inpatient stays at five hospital campuses from January 2009 through June 2012. STUDY DESIGN: The analysis matched PC patients to non-PC patients (separately by discharge status) using propensity score methods. Weighted generalized linear model regressions of hospital costs were estimated for the matched groups. DATA COLLECTION: Data were restricted to patients at least 18 years old with inpatient stays of between 7 and 30 days. Variables available included patient demographics, primary and secondary diagnoses, hospital costs incurred for the inpatient stay, and when/if the patient had a PC consult. PRINCIPAL FINDINGS: We found overall cost savings from PC of $3,426 per patient for those dying in the hospital. No significant cost savings were found for patients discharged alive; however, significant cost savings for patients discharged alive could be achieved for certain diagnoses, PC team structures, or if consults occurred within 10 days of admission. CONCLUSIONS: Appropriately selected and timed PC consults with physician and RN involvement can help ensure a financially viable PC program via cost savings to the hospital. PMID- 25040228 TI - Phenotypically matched vs. traditional screen method for preparing red blood cell units in patients with abnormal placentation: a decision analysis approach. AB - BACKGROUND: Patients with abnormal placentation are hospitalized approximately 21 days prior to scheduled delivery due to risk of peri-partum bleeding. It is required to have at least one red blood cell (RBC) unit ready throughout hospitalization. This can be accomplished by performing a type and cross (T&C) every 72 h (traditional method) or providing phenotypically matched RBC units (alternative method). METHODS: A Markov-based model was created to compare the cost-benefits between these two methods. A patient either undergoes the traditional or alternative method. If the patient already made an antibody and/or has rare phenotypes requiring frozen RBC unit at admission, then she can only enter the traditional method. All patients receive a T&C at the end of the 21st day in order to prepare RBC units for scheduled delivery. Model parameters are derived from literature and institutional experiences. RESULTS: Simulation was run for modelling of the 21-day hospitalization of each patient. The expected cost per RBC unit of the traditional method is significantly higher than the alternative method (876.59 vs. 608.32 USD, P-value <0.01). For each RBC unit, 4.85 h of technician working time is saved by the alternative method. However, to be cost-beneficial, the alternative method should be used only if the total cost of a RBC unit is <857.67 USD. CONCLUSION: Our model demonstrated that preparing phenotypically matched RBC units at admission is more cost-beneficial comparing to the traditional method of T&C every 72 h if the cost for the matched unit is <857.67 USD. PMID- 25040229 TI - Network analysis reveals that bacteria and fungi form modules that correlate independently with soil parameters. AB - Network and multivariate statistical analyses were performed to determine interactions between bacterial and fungal community terminal restriction length polymorphisms as well as soil properties in paired woodland and pasture sites. Canonical correspondence analysis (CCA) revealed that shifts in woodland community composition correlated with soil dissolved organic carbon, while changes in pasture community composition correlated with moisture, nitrogen and phosphorus. Weighted correlation network analysis detected two distinct microbial modules per land use. Bacterial and fungal ribotypes did not group separately, rather all modules comprised of both bacterial and fungal ribotypes. Woodland modules had a similar fungal : bacterial ribotype ratio, while in the pasture, one module was fungal dominated. There was no correspondence between pasture and woodland modules in their ribotype composition. The modules had different relationships to soil variables, and these contrasts were not detected without the use of network analysis. This study demonstrated that fungi and bacteria, components of the soil microbial communities usually treated as separate functional groups as in a CCA approach, were co-correlated and formed distinct associations in these adjacent habitats. Understanding these distinct modular associations may shed more light on their niche space in the soil environment, and allow a more realistic description of soil microbial ecology and function. PMID- 25040227 TI - Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics. AB - Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID- 25040230 TI - High arterial pulse wave velocity is a risk factor for falls in community dwelling older people. AB - OBJECTIVES: To examine whether arterial stiffness is a risk factor for falls in community-dwelling older people. DESIGN: Prospective cohort study. SETTING: Community population, Sydney, Australia. PARTICIPANTS: Community-dwelling older adults (mean age 79.8+/-4.4, 52.2% female; N=481). MEASUREMENTS: Carotid-femoral pulse wave velocity (PWV) was measured in the supine position after lying for 10 minutes. Demographic, medical, and medication characteristics and levels of physical activity were obtained in clinical interviews and questionnaires, and falls were recorded with monthly falls diaries for 12 months. RESULTS: Participants in the top quintile of PWV (high PWV) were more likely to have higher seated systolic blood pressure (SBP) and heart rate, unsatisfactory control of blood pressure, diabetes mellitus, and lower physical activity levels. These participants were also more likely to be male and taking cardiovascular medications. Of the 473 participants available for follow-up, 212 (44.8%) reported one or more falls. In modified Poisson regression analyses, high PWV was a risk factor for falls (relative risk=1.37, 95% confidence interval=1.06-1.78) after adjusting for use of psychotropic and cardiovascular medications, age, sex, body mass index, seated SBP, heart rate, and diabetes status. CONCLUSION: In community-dwelling older people, high PWV (as a measure of arterial stiffness) was a risk factor for falls after adjusting for potential demographic, anthropometric, disease, and medication confounders. Further research is required to investigate mediators for this association and the effect of lowering arterial stiffness on falls in older people. PMID- 25040231 TI - A new human leukocyte antigen class I allele: HLA-A*11:125. AB - HLA-A*11:125 allele differs from A*11:01:01 by one nucleotide substitution at nt 140 from T to C. PMID- 25040232 TI - Is the fastest MRI a hologram? AB - Real-time MR imaging might exert a profound influence on neuroscience in the future by enabling the direct visualization of neuronal interactions. At this time, however, all practical embodiments of MRI require at least some degree of gradient encoding, and this in turn sets a lower limit of about 100 ms for volume acquisition. A novel formulation of MRI is proposed here which is given the acronym ULTRA (Unlimited Trains of Radio Acquisitions). In the preferred embodiment ULTRA is completely free of gradient reversals, which allows for signal acquisition from the entire object volume simultaneously. This permits a rate of signal acquisition that is increased hundreds of times compared with existing techniques, with full 3-D imaging in as little as one millisecond. The proposed detector now resembles a holographic recording. PMID- 25040233 TI - Characteristics of femorotibial joint geometry in the trochlear dysplastic femur. AB - The medial and lateral tibia plateau geometry has been linked with the severity of trochlear dysplasia. The aim of the present study was to evaluate the tibial slope and the femoral posterior condylar offset in a cohort of consecutive subjects with a trochlear dysplastic femur to investigate whether the condylar offset correlates with, and thus potentially compensates for, tibial slope asymmetry. Magnetic resonance imaging was used to assess the severity of trochlear dysplasia as well as the tibial slope and posterior offset of the femoral condyles separately for the medial and lateral compartment of the knee joint in 98 subjects with a trochlear dysplastic femur and 88 control subjects. A significant positive correlation was found for the medial tibial slope and the medial posterior condylar offset in the study group (r(2) = 0.1566; P < 0.001). This relationship was significant for all subtypes of trochlear dysplasia and was most pronounced in the severe trochlear dysplastic femur (Dejour type D) (r(2) = 0.3734; P = 0.04). No correlation was found for the lateral condylar offset and the lateral tibial slope in the study group or for the condylar offset and the tibial slope on both sides in the control group. The positive correlation between the medial femoral condylar offset and the medial tibial slope, that is, a greater degree of the medial tibial slope indicated a larger offset of the medial femoral condyle, appears to represent a general anthropomorphic characteristic of distal femur geometry in patients with a trochlear dysplastic femur. PMID- 25040234 TI - Outcomes of invitational and opportunistic oral cancer screening initiatives in Oporto, Portugal. AB - OBJECTIVE: To assess the utility of oral cancer screening for the early detection of oral potentially malignant disorders (OPMDs) and oral cancer (OC) in a population of Oporto city. MATERIAL AND METHODS: We conducted an OC screening program in the city of Oporto between 2010 and 2011 using two methodologies of population recruitment: Volunteers attending an OC screening day recruited via a mass media campaign; and OC screening during dental visits to a public hospital in the Oporto City. Participants' socio-demographic information and life-style habits were ascertained by interviewers, and an oral mucosal examination (screen) was conducted by previously trained and calibrated group of 20 screeners. RESULTS: A total of 727 individuals (277 males and 450 females) with a mean age of 54 years (range 18-94) were screened. During screening, we detected 22 OPMDs: 13 (59.1%) oral leukoplakias and 9 (40.9%) cases with oral lichen planus. No erythroplakias were detected. In addition, two oral carcinomas were detected, both in the T1 stages of the disease. All screen positives attended a specialist clinic following referral to confirm their diagnoses. A randomly selected sample among negative screens was also examined to assess any false negatives. The sensitivity was 96% and specificity was 98%. Significantly more positive cases were found among older individuals (>=54 years) (P = 0.045). CONCLUSION: Screening data suggest that new cancers and OPMDs can be detected by invitational and opportunistic screening and offer a platform to raise the awareness and knowledge on this cancer in the Portuguese population. PMID- 25040235 TI - Parameter Estimation for Groundwater Models under Uncertain Irrigation Data. AB - The success of modeling groundwater is strongly influenced by the accuracy of the model parameters that are used to characterize the subsurface system. However, the presence of uncertainty and possibly bias in groundwater model source/sink terms may lead to biased estimates of model parameters and model predictions when the standard regression-based inverse modeling techniques are used. This study first quantifies the levels of bias in groundwater model parameters and predictions due to the presence of errors in irrigation data. Then, a new inverse modeling technique called input uncertainty weighted least-squares (IUWLS) is presented for unbiased estimation of the parameters when pumping and other source/sink data are uncertain. The approach uses the concept of generalized least-squares method with the weight of the objective function depending on the level of pumping uncertainty and iteratively adjusted during the parameter optimization process. We have conducted both analytical and numerical experiments, using irrigation pumping data from the Republican River Basin in Nebraska, to evaluate the performance of ordinary least-squares (OLS) and IUWLS calibration methods under different levels of uncertainty of irrigation data and calibration conditions. The result from the OLS method shows the presence of statistically significant (p < 0.05) bias in estimated parameters and model predictions that persist despite calibrating the models to different calibration data and sample sizes. However, by directly accounting for the irrigation pumping uncertainties during the calibration procedures, the proposed IUWLS is able to minimize the bias effectively without adding significant computational burden to the calibration processes. PMID- 25040236 TI - Identification of mRNA-like non-coding RNAs and validation of a mighty one named MAR in Panax ginseng. AB - Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in plants. However, little is known about lncRNAs in Panax ginseng C. A. Meyer, an economically significant medicinal plant species. A total of 3,688 mRNA like non-coding RNAs (mlncRNAs), a class of lncRNAs, were identified in P. ginseng. Approximately 40% of the identified mlncRNAs were processed into small RNAs, implying their regulatory roles via small RNA-mediated mechanisms. Eleven miRNA-generating mlncRNAs also produced siRNAs, suggesting the coordinated production of miRNAs and siRNAs in P. ginseng. The mlncRNA-derived small RNAs might be 21-, 22-, or 24-nt phased and could be generated from both or only one strand of mlncRNAs, or from super long hairpin structures. A full-length mlncRNA, termed MAR (multiple-function-associated mlncRNA), was cloned. It generated the most abundant siRNAs. The MAR siRNAs were predominantly 24-nt and some of them were distributed in a phased pattern. A total of 228 targets were predicted for 71 MAR siRNAs. Degradome sequencing validated 68 predicted targets involved in diverse metabolic pathways, suggesting the significance of MAR in P. ginseng. Consistently, MAR was detected in all tissues analyzed and responded to methyl jasmonate (MeJA) treatment. It sheds light on the function of mlncRNAs in plants. PMID- 25040237 TI - Complete digital workflow for the production of implant-supported single-unit monolithic crowns. AB - OBJECTIVES: The aim of this case series was to introduce a complete digital workflow for the production of monolithic implant crowns. MATERIAL AND METHODS: Six patients were treated with implant-supported crowns made of resin nano ceramic (RNC). Starting with an intraoral optical scan (IOS), and following a CAD/CAM process, the monolithic crowns were bonded either to a novel prefabricated titanium abutment base (group A) or to a CAD/CAM-generated individualized titanium abutment (group B) in premolar or molar sites on a soft tissue level dental implant. Economic analyses included clinical and laboratory steps. An esthetic evaluation was performed to compare the two abutment-crown combinations. RESULTS: None of the digitally constructed RNC crowns required any clinical adaptation. Overall mean work time calculations revealed obvious differences for group A (65.3 min) compared with group B (86.5 min). Esthetic analysis demonstrated a more favorable outcome for the prefabricated bonding bases. CONCLUSIONS: Prefabricated or individualized abutments on monolithic RNC crowns using CAD/CAM technology in a model-free workflow seem to provide a feasible and streamlined treatment approach for single-edentulous space rehabilitation in the posterior region. However, RNC as full-contour material has to be considered experimental, and further large-scale clinical investigations with long-term follow-up observation are necessary. PMID- 25040238 TI - The relation between awareness of personal resources and metabolic control in children and adolescents with type 1 diabetes. AB - INTRODUCTION: The study aims to elucidate whether awareness of personal resources, such as positive attributions and beliefs or social support, affects metabolic control in children and adolescents with type 1 diabetes. In addition, it will be determined to what extent metabolic control is influenced by concordance between children and parents regarding awareness of resources and the parents' ability to adopt their children's perspective. Also, the children's wishes particularly in relation to their illness will be investigated, as well as the kind of advice they would offer to fellow patients. METHODS: Seventy-eight children/adolescents with type 1 diabetes completed the Essen Resource Inventory for Children and Adolescents including personal, social, structural, and migration-specific resources. In addition, children/adolescents and their parents completed a systemic-oriented, diabetes-specific resource questionnaire in order to explore the parents' ability to adopt their children's perspective. RESULTS: Resources such as body awareness and open-minded attitude to the disease were associated with metabolic control. Particularly, resources associated to a migration background were found to be inversely correlated with hemoglobin A1c (HbA1c) value. Moreover, it was shown that the parents' ability to adopt their children's perspective was associated with improved metabolic control. Children advising fellow patients to accept the disease showed the best HbA1c value. DISCUSSION: This data identified specific modifiable factors related to metabolic control that can be addressed during counseling of pediatric patients. Also the parents' ability for adopting their child's perspective was identified as a relevant factor which should be considered during clinical counseling of young type 1 diabetes patients. PMID- 25040239 TI - The meaning of recovery in a regional mental health service: an action research study. AB - AIM: To explore the meaning of the term recovery to people with experience providing and receiving mental health services. BACKGROUND: Internationally, governments have proposed recovery-oriented mental health policy. In practice, people managing mental health difficulties struggle to recover, self-manage, or improve their quality of life. Mental health services increasingly provide acutely focused and poorly coordinated services to people experiencing mental health difficulties, with self-management, wellness and recovery overlooked. DESIGN: A cooperative enquiry, action research design guided the study. Participants were people with experience of mental health difficulties from consumer, carer and clinician perspectives. METHOD: Data were collected between August 2012-July 2013. Analysis was conducted using an iterative process for the duration of the study. A thematic network was developed that reflected key organizing themes. RESULTS: The overarching theme developed from the participants' group discussions, reflections, actions and observations was recovery as an ongoing quest in life. This global theme was constructed from five organizing themes: 'finding meaning', 'an invisible disability', 'empowerment and agency' 'connection' and 'the passage of time'. CONCLUSION: Participatory approaches support the inclusion of lived experience perspectives. Structured processes are needed to bring different perspectives together to find solutions, through dialogue, and acknowledge the barriers to participation that people who use mental health services experience. The lack of integration of lived experience perspectives demonstrates forms of discrimination that inhibit consumer participation and prevent the recovery-oriented transformation required in mental health systems. PMID- 25040240 TI - Telehealth in paediatric orthopaedic surgery in Queensland: a 10-year review. AB - BACKGROUND: Telemedicine is a patient consultation method commonly available to patients in rural and remote areas throughout Australia. Its use in paediatric orthopaedics has been rarely described. The primary aim of this study was to identify the patient cohort accessing the orthopaedic paediatric telehealth service through the Royal Children's Hospital Queensland, so as to better allocate this resource. The secondary aims were to identify the orthopaedic conditions the patients utilizing this service suffered and to follow-up on treatment outcomes to potentially assess clinical benefit. METHOD: A retrospective review of prospectively collected data of paediatric orthopaedic patients consulted using telehealth at the Royal Children's Hospital, Queensland over a 10-year period between January 2004 and September 2012 was conducted. RESULTS: One hundred and twenty-six patient records were assessed with a mean age of 6 years. Results showed that 40% of patients seen using telehealth in paediatric orthopaedics had documented cerebral palsy, an intellectual disability or congenital syndrome. Common paediatric orthopaedic conditions were seen, with lower limb malalignment being the most common presenting complaint. About 58% of patients were seen exclusively via telehealth and did not require in-person consultation or operative therapy. CONCLUSION: We found that the orthopaedic telepaedriatic consultation service at the Royal Children's Hospital reviewed a large proportion of patients with a known disability. We believe there is a role for telehealth medicine for all patients; however, we propose that even greater benefit can be obtained from telehealth consultation in patients with a disability where the cost and inconvenience of patient transport is considerably increased. PMID- 25040242 TI - The teratogenicity of the newer antiepileptic drugs - an update. AB - OBJECTIVE: To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate. MATERIALS AND METHODS: Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester. RESULTS: Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure. CONCLUSIONS: Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be. PMID- 25040241 TI - Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies. AB - As invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti-fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995-2003) and E2, (2004-2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while 'other' dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90-day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti-fungal therapy has not improved survival. PMID- 25040243 TI - Lateral epicondylitis treatment: international survey of surgeons' preferences and literature review. AB - BACKGROUND: Lateral epicondylitis (LE) is a common cause of elbow pain. Despite a relatively high prevalence and morbidity, there is still no single effective ('gold standard') treatment for LE. We hypothesised that a surgeon's experience, country of origin and area of expertise would influence choices concerning patient management. The purpose of this survey was to describe the current trends and common practices in treating LE worldwide. MATERIAL AND METHODS: A total of 291 orthopaedic surgeons of 12 subspecialties from 57 countries were surveyed on their choice of LE treatment modalities. Their preferences were analysed according to country of origin, field of expertise and seniority. The results were compared with current published level-1 evidence. RESULTS: The most popular modalities of treatment among all of the surveyed orthopaedic surgeons were non steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid (CS) injection (38% of recommendations each). The most popular Modalities of treatment among the hand surgeons was NSAIDs (48%) and CS injection (30%). There was no significant difference in recommendations based on geography, seniority or specialisation (i.e., hand surgeons among others). CONCLUSIONS: Neither geography, seniority nor medical specialty affects surgeons' preferences in the treatment of LE. There appears to be little correlation between scientific evidence and therapeutic choices for managing LE. LEVEL OF EVIDENCE: Level V, Study. PMID- 25040244 TI - Antiviral therapy (pegylated interferon and ribavirin) of hepatitis C in dialysis patients: meta-analysis of clinical studies. AB - Information on the antiviral treatment (pegylated interferon plus ribavirin) of chronic infection by hepatitis C virus (HCV) in patients on long-term dialysis is extremely limited. We evaluated the efficacy and safety of combination antiviral therapy (pegylated interferon plus ribavirin) in patients on long-term dialysis with chronic hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical studies. The primary outcome was sustained virological response (SVR) (as a measure of efficacy); the secondary outcome was dropout rate (as a measure of tolerability). We used the random-effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses. We identified eleven clinical studies (287 unique patients), two of them being controlled clinical trials. The summary estimate for SVR and dropout rate was 0.60 (95% Confidence Intervals, 0.47; 0.71) and 0.18 (95% CI, 0.08; 0.35), respectively; studies being heterogeneous with regard to both the outcomes. Stratified analysis reported a higher SVR rate in controlled trials, 0.86 (95% CI, 0.27; 0.99). The most common sources of dropout were anaemia (11/46 = 23%) and infections (6/46 = 13%). Meta-regression analysis showed a detrimental impact of HCV genotype 1 (P = 0.036) and dropout (P = 0.0001) rate upon the frequency of SVR. Antiviral therapy based on pegylated interferon plus ribavirin for HCV gives encouraging results in terms of efficacy and safety among patients on long-term dialysis; such approach should be considered the current standard of care for HCV-infected individuals on regular dialysis. PMID- 25040245 TI - Confounders in the detection of minimal hepatic encephalopathy: a neuropsychological and quantified EEG study. AB - BACKGROUND & AIMS: Chronic alcohol misuse, HCV infection and cirrhosis may cause cognitive alterations. The aim of the present study was to assess the influence of alcohol misuse, HCV infection and cirrhosis per se on the neuropsychological and electroencephalogram (EEG) profile and to evaluate the role of alcohol misuse and HCV infections as potential confounding factors in the detection of minimal hepatic encephalopathy. METHODS: A comprehensive neuropsychological profile and EEG spectral parameters were obtained in six age-matched groups of 30 subjects each: (i) HCV-related hepatitis without cirrhosis, (ii) chronic alcohol abusers, (iii) patients with HCV-related cirrhosis, (iv) alcohol-related cirrhosis, (v) cirrhosis not related to alcohol or HCV and (vi) healthy subjects. Cirrhotic patients were matched for MELD score. RESULTS: The factor 'cirrhosis' was associated with low Phonemic Verbal Fluency (PVF) and Difference between Trail Making Test B and A (TMT) (B-A) (P < 0.001). Chronic alcohol misuse was associated with low PVF, TMT (B-A), Memory with Interference Task at 10 (ITM 10) and 30 s (ITM 30) (all P < 0.05). An interaction was found between the factors 'cirrhosis', 'alcohol misuse' and tests (P < 0.01). HCV hepatitis reduced ITM 10 (P < 0.05), but no interaction was found between 'cirrhosis', 'HCV infection' and tests (P = 0.14). The EEG parameters were mainly influenced by 'cirrhosis' (P < 0.05), and EEG alterations were more pronounced in patients with alcoholic cirrhosis (P = 0.04). CONCLUSIONS: Cirrhosis per se, chronic alcohol misuse and HCV infection were found to be associated with cognitive dysfunction. In patients with cirrhosis, the interaction with alcohol misuse further impinged on brain dysfunction. PMID- 25040246 TI - Orthodontic widening of the palate may provide a cure for selected children with therapy-resistant enuresis. AB - AIM: According to a number of small case series, orthodontic treatment may have anti-enuretic effects. Thus, we evaluated whether widening of the palate can alleviate enuresis and whether prognostic information can be gained from examining children's nocturnal respiration and nasal airway dimensions. METHODS: Children with therapy-resistant enuresis underwent polysomnography, focusing on nocturnal respiration, and had their nasal airways examined. Rapid maxillary expansion was performed, widening the maxilla by approximately 0.5 cm. The dental appliance was removed after 6 months. Enuresis frequency was evaluated four times: at baseline, with the orthodontic apparatus in situ, after completed maxillary expansion and 1 year post-treatment. RESULTS: Of the 34 children recruited, one dropped out due to oral discomfort. The numbers of wet nights per week on the four assessment occasions were 5.48 +/- 1.48, 5.12 +/- 1.73, 3.09 +/- 2.49 and 2.63 +/- 2.81; p < 0.001. The proportions of responders, intermediate responders and non-responders during treatment were 21.2%, 27.3% and 51.5%, respectively. Responders were found to have a lower enuresis frequency at baseline (p = 0.001) and to have larger nasal airway dimensions (p = 0.01). CONCLUSION: Orthodontic widening of the palate may be curative in a subgroup of children with therapy-resistant enuresis. PMID- 25040247 TI - IL-17 stimulates the production of the inflammatory chemokines IL-6 and IL-8 in human dental pulp fibroblasts. AB - AIM: To investigate IL-17 expression in human pulpitis and to study the effects of IL-17 on the secretion of the chemokines IL-6 and IL-8 and the related signalling pathways. METHODOLOGY: Samples of human dental pulp tissue were obtained from healthy controls and patients with pulpitis. Cytokine IL-17 messenger RNA (mRNA) expression in the pulp tissue was detected by real-time polymerase chain reaction. In addition, human dental pulp fibroblasts (HDPFs) were stimulated with IL-17. Production of IL-6 and IL-8 was determined by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Aspects of the nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) signalling pathways were examined by Western blot analysis. RESULT: Increased levels of IL-17 mRNA were found in inflamed dental pulp tissue (pulpitis). Stimulation of dental pulp tissue with IL-17 induced the production of IL-6 and IL-8 in a dose-dependent manner. In addition, IL-17 stimulation resulted in rapid activation of nuclear factor-kappaB (NF-kappaB), phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) in HDPFs. CONCLUSION: IL-17 may participate in pulp tissue inflammation through chemokine production and NF-kappaB and MAPKs signalling pathways. PMID- 25040248 TI - Antigen itself antibody: an alternative one-step immunoassay for measuring the anti-idiotypic antibody titer. AB - Immunoassay designs rely on the great specificity of antibodies and a suitable marker that facilitates generation of a quantitative signal. Currently, there is no reliable method for measuring the titers of an anti-idiotypic antibody. Our initial attempt to measure titers of mouse anti-idiotypic antibody after idiotypic vaccination with HM-1 killer toxin neutralizing monoclonal antibody (nmAb-KT) failed. Because the injected antigen, nmAb-KT, is a mouse IgG, using a commercial antibody to measure the antibody titer always gave a false positive signal against control mouse serum antibody in parallel with the antigen-treated immunized serum antibodies. To get a reliable and clearly differentiable signal by ELISA, idiotypic antigen was labeled with HRP and HRP-conjugated-nmAb-KT used to measure the antibody titers in the antigen-treated mice. Compared with control mice, signals were found in high anti-nmAb-KT IgG responses in test mice; however, untreated control mice had a significant amount of purified non-specific IgG. This method is amenable to long read lengths and will likely enable anti idiotypic antibody titer measurement in a more specific and cost effective way without requiring commercial antibody. PMID- 25040249 TI - Limited antigenic variation in the Trypanosoma cruzi candidate vaccine antigen TSA-1. AB - Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi) is one of the most important neglected tropical diseases in the Western Hemisphere. The toxicities and limited efficacies of current antitrypanosomal drugs have prompted a search for alternative technologies such as a therapeutic vaccine comprised of T. cruzi antigens, including a recombinant antigen encoding the N-terminal 65 kDa portion of Trypomastigote surface antigen-1 (TSA-1). With at least six known genetically distinct T. cruzi lineages, variability between the different lineages poses a unique challenge for the development of broadly effective therapeutic vaccine. The variability across the major lineages in the current vaccine candidate antigen TSA-1 has not previously been addressed. To assess the variation in TSA-1, we cloned and sequenced TSA-1 from several different T. cruzi strains representing three of the most clinically relevant lineages. Analysis of the different alleles showed limited variation in TSA-1 across the different strains and fit with the current theory for the evolution of the different lineages. Additionally, minimal variation in known antigenic epitopes for the HLA A 02 allele suggests that interlineage variation in TSA-1 would not impair the range and efficacy of a vaccine containing TSA-1. PMID- 25040250 TI - The "free" right internal thoracic artery: a versatile and durable conduit. AB - BACKGROUND: Despite its potential advantages, the right internal thoracic artery (RITA) is used as a conduit in only 4% of coronary revascularizations. To broaden its application, we frequently use the RITA as a free graft. In this study, we review our experience with the RITA as an in situ and free graft. METHODS: We reviewed the perioperative outcomes and angiographic patency rates of 479 consecutive patients who underwent RITA grafting between January 1987 and December 2011. RESULTS: The RITA was harvested free (FRITA) in 380 patients (79%) and in situ in 99 (21%). The predominant target for the in situ RITA was the right coronary system (79%). The predominant targets for the FRITA were divided between the right (54%) and left coronary systems (46%). There was no perioperative mortality. Mean follow-up was 10 years. Perioperative complications included myocardial infarction (0.4%), sternal nonunions (0.4%), and reoperation for hemorrhage (0.6%). Coronary angiograms were performed in symptomatic patients (17%) after a median of seven years. FRITA patency rates at five, 10, and 15 years were 100%, 95%, and 95%, respectively, comparable to the left internal thoracic artery patency rates and superior to those of saphenous vein graft. Survival rates of FRITA patients at 10, 15, and 20 years were 92%, 89%, and 76%, respectively. CONCLUSION: The FRITA graft reaches all distal coronary vessels and is associated with excellent patency and survival rates. Its application in coronary revascularization vastly expands the benefits of internal thoracic artery grafting. PMID- 25040251 TI - The role of non-invasive biomarkers in detecting acute respiratory effects of traffic-related air pollution. AB - The role of non-invasive methods in the investigation of acute effects of traffic related air pollution is not clearly established. We evaluated the usefulness of non-invasive biomarkers in detecting acute air pollution effects according to the age of participants, the disease status, their sensitivity compared with lung function tests and their specificity for a type of pollutant. Search terms lead to 535 titles, among them 128 had potentially relevant abstracts. Sixtynine full papers were reviewed, while 59 articles were excluded as they did not meet the selection criteria. Methods used to assess short-term effects of air pollution included analysis of nasal lavage (NAL) for the upper airways, and induced sputum (IS), exhaled breath condensate (EBC) and exhaled nitric oxide (FeNO) for central and lower airways. There is strong evidence that FeNO evaluation is useful independently from subject age, while IS analysis is suitable almost for adults. Biomarker changes are generally observed upon pollutant exposure irrespective of the disease status of the participants. None of the biomarkers identified are specific for a type of pollutant exposure. Based on experimental exposure studies, there is moderate evidence that IS analysis is more sensitive than lung function tests, whereas this is not the case for biomarkers obtained by NAL or EBC. Cells and some cytokines (IL-6, IL-8 and myeloperoxidase) have been measured both in the upper respiratory tract (NAL) and in the lower airways (IS). Overall, the response to traffic exposure seems different in the two compartments. In conclusion, this survey of current literature displays the complexity of this research field, highlights the significance of short-term studies on traffic pollution and gives important tips when planning studies to detect acute respiratory effects of air pollution in a non-invasive way. PMID- 25040252 TI - Synthesizing complex data on functional decline in older people using partial least squares (PLS) analysis. AB - RATIONALE, AIMS AND OBJECTIVES: Declining capacity to function safely and independently in the community is a manifestation of ageing. Multiple measures are used to define and predict functional decline. This paper explores the use of partial least squares (PLS) analysis to understand the interaction between overtime measures of functional decline. METHODS: Comprehensive information was captured on individuals aged 65+ who presented at a large metropolitan Australian hospital Emergency Department (ED) for a complaint, which did not result in a hospital admission. They were followed-up by telephone 1 and 3 months, post-ED discharge. Information was collected each time on home situations (living alone, using community services, using a gait aid and having a formal carer), recent falls, hospitalizations and instrumental activities of daily living (IADLs). PLS analysis was applied to identify overtime relationships between measures. RESULTS: Valid information was provided by 147 individuals at all three time points. The eight individual IADL items clustered clearly around physical, mental or combined mental and physical IADLs. These clusters were strongly related to increased use of community supports, gait aid and carer, and living alone. The relationship was less convincingly for hospitalizations, and falls were not explained well. CONCLUSION: PLS analysis offers a novel and comprehensive way of analysing complex health data, which allows sense to be made of relationships over a 3-month period. This analysis provides a better understanding of declining function over time, than could be provided by current health modelling methods. PMID- 25040253 TI - Decontamination of a BSL3 laboratory by hydrogen peroxide fumigation using three different surrogates for Bacillus anthracis spores. AB - AIMS: Two independent trials investigated the decontamination of a BSL3 laboratory using vaporous hydrogen peroxide and compared the effect on spores of Bacillus cereus, Bacillus subtilis and Bacillus thuringiensis as surrogates for Bacillus anthracis spores, while spores of Geobacillus stearothermophilus served as control. METHODS AND RESULTS: Carriers containing 1.0 * 10(6) spores were placed at various locations within the laboratory before fumigation with hydrogen peroxide following a previously validated protocol. Afterwards, carriers were monitored by plating out samples on agar and observing enrichment in nutrient medium for up to 14 days. Three months later, the experiment was repeated and results were compared. On 98 of 102 carriers, no viable spores could be detected after decontamination, while the remaining four carriers exhibited growth of CFU only after enrichment for several days. Reduction factors between 4.0 and 6.0 log levels could be reached. CONCLUSIONS: A validated decontamination of a laboratory with hydrogen peroxide represents an effective alternative to fumigation with formaldehyde. Spores of B. cereus seem to be more resistant than those of G. stearothermophilus. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study provide important results in the field of hydrogen peroxide decontamination when analysing the effect on spores other than those of G. stearothermophilus. PMID- 25040254 TI - Global emergency medicine: a review of the literature from 2013. AB - OBJECTIVES: The Global Emergency Medicine Literature Review (GEMLR) conducts an annual search of peer-reviewed and grey literature relevant to global emergency medicine (EM) to identify, review, and disseminate the most important new research in this field to a worldwide audience of academics and clinical practitioners. METHODS: This year 8,768 articles written in six languages were identified by our search. These articles were distributed among 22 reviewers for initial screening based on their relevance to the field of global EM. An additional two reviewers searched the grey literature. A total of 434 articles were deemed appropriate by at least one reviewer and approved by an editor for formal scoring of overall quality and importance. RESULTS: Of the 434 articles that met our predetermined inclusion criteria, 65% were categorized as emergency care in resource-limited settings, 18% as EM development, and 17% as disaster and humanitarian response. A total of 24 articles received scores of 18 or higher and were selected for formal summary and critique. Interrater reliability for two reviewers using our scoring system was good, with an intraclass correlation coefficient of 0.63 (95% confidence interval = 0.55 to 0.69). Infectious diseases, trauma, and the diagnosis and treatment of diseases common in resource limited settings represented the majority of articles selected for final review. CONCLUSIONS: In 2013, there were more emergency care in resource-limited settings articles, while the number of disaster and humanitarian response articles decreased, when compared to the 2012 review. However, the distribution of articles selected for full review did not change significantly. As in prior years, the majority of articles focused on infectious diseases, as well as trauma and injury prevention. PMID- 25040255 TI - The control of complex finger movements by directional information flow between mesial frontocentral areas and the primary motor cortex. AB - Complex movements require the interplay of local activation and interareal communication of sensorimotor brain regions. This is reflected in a decrease of task-related spectral power over the sensorimotor cortices and an increase in functional connectivity predominantly in the upper alpha band in the electroencephalogram (EEG). In the present study, directionality of information flow was investigated using EEG recordings to gain better understanding about the network architecture underlying the performance of complex sequential finger movements. This was assessed by means of Granger causality-derived directed transfer function (DTF). As DTF measures the influence one signal exerts on another based on a time lag between them, it allows implications to be drawn on causal relationships. To reveal causal connections between brain regions that are specifically modulated by task complexity, we contrasted the performance of right handed sequential finger movements of different complexities (simple, scale, complex) that were either pre-learned (memorized) or novel instructed. A complexity-dependent increase in information flow from mesial frontocentral to the left motor cortex and, less pronounced, also to the right motor cortex specifically in the upper alpha range was found. Effective coupling during sequences of high complexity was larger for memorized sequences compared with novel sequences (P = 0.0037). These findings further support the role of mesial frontocentral areas in directing the primary motor cortex in the process of orchestrating complex movements and in particular learned sequences. PMID- 25040256 TI - Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor beta. AB - OBJECTIVE: The syndrome of resistance to thyroid hormone (RTH) is caused by a mutation of TH receptor beta (TRbeta) in 80% of cases. Patients without mutation (non-TR-RTH) may have a biochemical pattern that is difficult to differentiate from that of pituitary TSH-secreting adenoma (TSHoma). Herein, we report a large monocentric series of RTH focusing on patients with non-TR-RTH, to evaluate possible clinical or biochemical parameters able to distinguish them from TSHoma. DESIGN AND PATIENTS: We retrospectively reviewed the data of 99 consecutive patients with inappropriate TSH secretion (IST) syndrome referred to our Department between 1983 and 2011, identifying 68 patients with RTH and 31 patients with TSHomas. MEASUREMENTS: Patient records were reviewed for the main clinical, biochemical and imaging characteristics. RESULTS: Of our 68 patients with RTH, 16 (23.5%) did not show a TRbeta mutation and did not have affected family members. Of these 16 patients, three developed a TSHoma, during follow-up. To distinguish non-TR-RTH from TSHoma, we identified appropriate cut-off values for the main biochemical parameters that demonstrated the greatest sensitivity and specificity (T3 suppression test, alpha-subunit/TSH molar ratio, alpha subunit assay and TRH test) and we calculated the probability for each patient to develop a TSHoma. CONCLUSIONS: The application of the identified cut-offs could become a very useful tool in the challenging differential diagnosis between sporadic non-TR-RTH and TSHoma. It would then be possible to select the patients at higher risk of developing a TSHoma and therefore needing a closer follow-up. PMID- 25040258 TI - Biologics are more potent than other treatment modalities for improvement of quality of life in psoriasis patients. AB - Although mental health is hampered in various skin disorders, few studies regarding anxiety in psoriasis patients are available, and specifically, no evaluation exists between mental health and psoriasis severity or the patients' quality of life. To examine the relation between mental health, psoriasis severity and patient's quality of life, 119 psoriasis vulgaris patients were assessed for anxiety using the General Health Questionnaire (GHQ)-30. Psoriasis area and severity index (PASI) and Dermatological Life Quality Index (DLQI) scores were also measured. The average total GHQ-30 score was significantly decreased from 4.41 to 2.11 (52.2% decrease) in biologics-treated patients. That of patients treated with other systemic agents decreased from 4.36 to 3.32 (23.9% decrease) and that of those treated with topical agents from 4.21 to 3.48 (17.3% decrease). In the biologics-treated group five of the six categories of GHQ-30, i.e., general illness, somatic symptoms, sleep disturbance, social dysfunction, and anxiety and dysphoria, were significantly decreased after the treatment. In contrast, in the other systemic treatment and topical treatment groups, three of the six categories, general illness, somatic symptoms, and sleep disturbance were significantly decreased. There was a significant correlation between GHQ-30 and DLQI, but not with PASI. The psoriasis patients show impaired mental health and among various treatment modalities biologics are superior to other systemic or topical treatments for improving the defective mental state. PMID- 25040257 TI - Crystal structure of active site mutant of antileukemic L-asparaginase reveals conserved zinc-binding site. AB - The periplasmic enzyme l-asparaginase type II from Escherichia coli (EcAII) converts l-asparagine to l-aspartate and ammonia. EcAII is an important drug in the treatment of childhood acute lymphoblastic leukemia, the most common malignancy in children. Leukemic blast cells lack the ability to synthesize l asparagine and rely on other sources of l-asparagine for protein synthesis. EcAII injections deplete extracellular levels of l-asparagine, disrupting protein synthesis and inducing apoptosis in the malignant cells. The detailed mechanism of l-asparaginase catalytic action, the molecular mechanisms of its anticancer activity and the side effects associated with the treatment, including resistance to therapy, are not fully understood despite over 40 years of research. Here, we present X-ray structures of EcAII with an active site mutation, D90E, in three crystal forms. The region of the mutation is well ordered, allowing precise functional analysis of the consequences of the replacement of Asp90. In all three structures, the mutant protein exhibits an open conformation of the active site. In one of the structures, a zinc cation has been detected. The zinc cation is coordinated in a region of the protein that is implicated in the immunological response to EcAII treatment. A combined sequence-structure analysis of bacterial type l-asparaginases reveals that the metal coordination may play a role in the response to asparaginase treatment. The observation of a zinc-binding site in antileukemic l-asparaginases provides new insight, with consequences for acute lymphoblastic leukemia therapy. DATABASES: The atomic coordinates of the monoclinic, orthorhombic and trigonal forms of the D90E mutant of Escherichia coli type II asparaginase have been deposited with the RCSB PDB with accession codes 1JAZ, 1JJA and 1IHD, respectively. ENZYMES: EC 3.5.1.1, l-asparagine amidohydrolase, l-asparaginase; EC 3.5.1.38, l-glutamine (l-asparagine) amidohydrolase, glutaminase-asparaginase; EC 6.3.5.6, l-aspartyl-tRNA(Asn) : l glutamine amido-ligase (ADP-forming), asparaginyl-tRNA synthase (glutamine hydrolysing). PMID- 25040259 TI - Household use of insecticide consumer products in a dengue-endemic area in Mexico. AB - OBJECTIVES: To evaluate the household use of insecticide consumer products to kill mosquitoes and other insect pests, as well as the expenditures for using these products, in a dengue-endemic area of Mexico. METHODS: A questionnaire was administered to 441 households in Merida City and other communities in Yucatan to assess household use of insecticide consumer products. RESULTS: A total of 86.6% of surveyed households took action to kill insect pests with consumer products. The most commonly used product types were insecticide aerosol spray cans (73.6%), electric plug-in insecticide emitters (37.4%) and mosquito coils (28.3%). Mosquitoes were targeted by 89.7% of households using insecticide aerosol spray cans and >99% of households using electric plug-in insecticide emitters or mosquito coils. Products were used daily or every 2 days in most of the households for insecticide aerosol spray cans (61.4%), electric plug-in insecticide emitters (76.2%) and mosquito coils (82.1%). For all products used to kill insect pests, the median annual estimated expenditure per household that took action was 408 Mexican pesos ($MXN), which corresponded to approximately 31 $US. These numbers are suggestive of an annual market in excess of 75 million $MXN (>5.7 million $US) for Merida City alone. CONCLUSION: Mosquitoes threaten human health and are major nuisances in homes in the study area in Mexico. Households were found to have taken vigorous action to kill mosquitoes and other insect pests and spent substantial amounts of money on insecticide consumer products. PMID- 25040260 TI - Alternate scoring of the Bayley-III improves prediction of performance on Griffiths Mental Development Scales before school entry in preschoolers with developmental concerns. AB - BACKGROUND: The Bayley-III is widely used as an assessment tool in young children; however, its standard composite scores appear to under-estimate delay, severe and profound delay cannot be identified, and the lack of an overall score makes it difficult to compare results with later assessments. AIMS: To explore the use of Bayley-III quotient subtest and average scores, compared with composite subtest and average scores for both clinical and research purposes, comparing their ability to predict performance on the Griffiths Mental Development Scales (Griffiths) before school entry. METHOD: One hundred preschoolers referred for a diagnosis were assessed on the Bayley-III before 3.5 years. They were reassessed before school entry on the Griffiths. Composite and quotient scores were calculated and their ability to predict outcome compared across the score range. RESULTS: Averaging the three subscale quotient scores (Bayley-AQS) gave a similar mean score for this sample (61.1, SD 16.2) as for the Griffiths general quotient (Griffiths-GQ) (61.1, SD 19.6). The average composite scores (Bayley-ACS) had a significantly higher mean (74.2, SD 12.1). Correlations between the average scores on the Bayley-III and the Griffiths-GQ (0.8) were at least as strong as any of the individual subscale scores. Kappa coefficients showed that Bayley-AQS was superior to Bayley-ACS for predicting moderate and severe delay. Average change in scores was -0.1 for Bayley-AQS, and -13.2 for Bayley-ACS. Improvement in category of delay was seen in 28% of children using Bayley-AQS, and deterioration in 22%. In contrast, 5% improvement was seen using Bayley-ACS, and 65% deterioration. CONCLUSIONS: The three directly assessed subscales of the Bayley-III can be averaged to give an overall score. Bayley-AQS are a better measure of development in young children with delay than Bayley-ACS, and most children maintain their developmental classification using this method of scoring when re-assessed before school entry. PMID- 25040261 TI - Quantitative analysis of classical and new putative periodontal pathogens in subgingival biofilm: a case-control study. AB - BACKGROUND AND OBJECTIVES: A number of species/phylotypes have been newly implicated as putative periopathogens. The objective of this study was to explore associations among classical and new pathogens in subgingival biofilm and to assess their relative importance to chronic periodontitis. MATERIAL AND METHODS: Pooled subgingival biofilm samples were obtained from 40 patients with chronic periodontitis and 40 healthy controls. Taqman q-PCR assays were used to determine the absolute and relative counts of Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Parvimonas micra, Filifactor alocis, oral Synergistetes and oral TM7s. Microbial associations were assessed using cluster analysis. Different statistical models were used to explore associations between microbial parameters and periodontitis. RESULTS: The median log and relative counts were lowest for TM7s (4.4 and 0.0016%, respectively) and highest for oral Synergistetes (7.2 and 1.4%, respectively). Oral Synergistetes clustered strongly with the red complex, particularly T. forsythia (100% rescaled similarity). All species/phylotypes except TM7s were significantly associated with periodontitis (Mann-Whitney test; p <= 0.005). However, P. gingivalis and F. alocis lost association after adjusting for confounders (ordinal regression). In receiving operator characteristic curve analysis, the log counts of oral Synergistetes were the best markers of periodontitis (82.5% sensitivity and specificity), followed by those of T. forsythia, P. micra and T. denticola. In prediction analysis, however, P. micra was the only microbial predictor of periodontal parameters. CONCLUSIONS: Oral Synergistetes are presented here as new members of the red complex, with relative importance to periodontitis exceeding that of the classical members. P. micra is shown as an important periodontal pathogen warranting more attention. PMID- 25040263 TI - Cerebral trypanosomiasis in a renal transplant recipient. AB - Chagas disease is a lifelong, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi. The main form of disease transmission is vector borne, but vertical transmission, such as by organ transplantation from a chronically infected donor, is also possible. The brain tumor-like form can occur years after infection and has been described in patients with acquired immunodeficiency syndrome, and in a very few cases in transplant recipients. We describe the case of a kidney transplant patient who was human immunodeficiency virus negative and infected with T. cruzi, and developed cerebral trypanosomiasis that was successfully treated with benznidazole at 7 mg/kg/day for 60 days. The risk of Chagas disease transmission should not be underestimated in renal transplant patients, even in non-endemic areas. Chagas disease can present as a tumor-like brain lesion, very difficult to differentiate from other opportunistic infectious or neoplastic processes. Frequent monitoring for T. cruzi infection is essential to promptly implement treatment, which, in our patient, proved to be effective and safe. PMID- 25040262 TI - Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas. AB - The majority of pediatric low-grade gliomas (LGGs) are characterized by constitutive activation of the mitogen-activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion. Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon 15-9 KIAA1549-BRAF fusion. SNP array analysis of case 2, a possible dysembryoplastic neuroepithelial tumor (DNT), revealed a 2.6 Mb deletion, which included the 5' end of BRAF and extended to the 3' end of FAM131B. In case 3, deletions involving BRAF and FAM131B were observed in both a primary and a recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9. The presence of fusion transcripts in these three LGGs highlights the utility of SNP array analysis to identify deletions that are suggestive of fusion proteins. BRAF fusions can result from multiple non-overlapping deletions, suggesting various complex mechanisms of formation. PMID- 25040265 TI - Women in medicine and leadership. PMID- 25040264 TI - A role for exocyst in maturation and bactericidal function of staphylococci containing endothelial cell phagosomes. AB - Bacteria that invade human endothelial cells can be efficiently eliminated in phagolysosomes. We investigated the role of vesicle tethering exocyst complex in maturation and function of endothelial cell phagosomes harbouring staphylococci or latex beads. Exocyst complex proteins (Sec5, -8, -10, Exo70) together with recycling endosome marker Rab11 were detected in vesicles that dynamically interacted and seemingly fused with endothelial cell phagosomes. Knockdown of exocyst proteins Sec8 and Exo70 inhibited the accumulation of Rab11-positive vesicles at the phagosomes. Furthermore, knockdown of exocyst proteins and Rab11 greatly reduced acidification of phagosomes and significantly diminished the elimination of invaded staphylococci in endothelial cells. The inhibitory effect of Exo70 knockdown on bacterial elimination could be rescued by constitutively active Rab11-Q70L. Our data suggest that exocyst complex controls the interaction of recycling endocytic vesicles with phagosomes and this process is involved in maturation and functioning of the phagosomes in endothelial cells. PMID- 25040266 TI - Pharmaceutical industry regulation: does the UK take the easy way out? PMID- 25040268 TI - Inpatient glucocorticoid use: beneficence vs non-maleficence. PMID- 25040269 TI - Inpatient management of diabetes in adults: safety and good practice. PMID- 25040270 TI - Hyperprolactinaemia and psychotropics: endocrine effects and treatment. PMID- 25040271 TI - Diagnosing coeliac disease in children. AB - Small bowel biopsies and histology had been the gold standard for diagnosis of coeliac disease, an immune-mediated systemic disorder. European guidelines recommend that in certain symptomatic patients, coeliac disease can be diagnosed without small bowel biopsies. A gluten-free diet is the only method of managing coeliac disease. PMID- 25040272 TI - New fungal diagnostics. PMID- 25040273 TI - Why 'parity of esteem' for mental health is every hospital doctor's concern. PMID- 25040274 TI - The role of emotion in effective clinical leadership and compassionate care. PMID- 25040276 TI - Cost and value analyses in medical education: common errors to avoid. PMID- 25040275 TI - Improving emergency department management of paediatric clavicle fractures: a complete audit cycle. AB - A protocol was devised to address the issue of unnecessary attendance at fracture clinic by children who have a fracture of the clavicle that is deemed to be uncomplicated. For the purposes of this protocol, the clavicle was divided into three zones. Fractures of the middle clavicle for which displacement was minimal, heal quickly in the majority of cases, without the need for follow up. As a result these children can be discharged provided the parents are adequately advised. This article outlines a study which investigated the effectiveness of the protocol. The study found that implementation of the protocol reduced unnecessary attendance at clinic from 85% (47/55) to 17% (4/23). This resulted in cost savings to the trust and reduced the pressure on staff working in busy fracture clinics. PMID- 25040277 TI - Sir Francis Laking: doctor to three British monarchs. PMID- 25040278 TI - A woman with hypertrichosis. PMID- 25040279 TI - Acquired haemophilia A as a cause of recurrent bleeding episodes in the elderly. PMID- 25040280 TI - Iatrogenic calcinosis cutis following a neonatal extravasation injury. PMID- 25040282 TI - CARDIO4 mnemonic for diagnosing Kawasaki disease. PMID- 25040284 TI - Antiseptic solutions for central neuraxial blockade: which concentration of chlorhexidine to use? PMID- 25040285 TI - Intrathecal treatment of anti-N-Methyl-D-aspartate receptor encephalitis in children. AB - Anti-NDMA receptor (NMDAR) encephalitis is an auto-immune condition. There is no uniformly agreed treatment strategy for the disorder in children. We report the use of intrathecal treatment with methotrexate and methylprednisolone in three children (one male, two females, age 10y, 11y, and 14y) with anti-NMDAR encephalitis, who did not respond to steroids, plasmapheresis, or rituximab. There was significant clinical improvement and stabilization of the anti-NMDAR antibody titers in cerebrospinal fluid (CSF) and blood in two patients. In the third patient, although anti-NMDAR antibody titers in CSF decreased, clinical recovery was less satisfactory. Intrathecal treatment with methotrexate and methylprednisolone seems to be a promising alternative treatment for some paediatric cases of resistant anti-NMDAR encephalitis. PMID- 25040286 TI - Spatiotemporal patterns and risk factors for lead exposure in endangered California condors during 15 years of reintroduction. AB - Large-scale poisoning events are common to scavenging bird species that forage communally, many of which are in decline. To reduce the threat of poisoning and compensate for other persistent threats, management, including supplemental feeding, is ongoing for many reintroduced and endangered vulture populations. Through a longitudinal study of lead exposure in California condors (Gymnogyps californianus), we illustrate the conservation challenges inherent in reintroduction of an endangered species to the wild when pervasive threats have not been eliminated. We evaluated population-wide patterns in blood lead levels from 1997 to 2011 and assessed a broad range of putative demographic, behavioral, and environmental risk factors for elevated lead exposure among reintroduced California condors in California (United States). We also assessed the effectiveness of lead ammunition regulations within the condor's range in California by comparing condor blood lead levels before and after implementation of the regulations. Lead exposure was a pervasive threat to California condors despite recent regulations limiting lead ammunition use. In addition, condor lead levels significantly increased as age and independence from intensive management increased, including increasing time spent away from managed release sites, and decreasing reliance on food provisions. Greater independence among an increasing number of reintroduced condors has therefore elevated the population's risk of lead exposure and limited the effectiveness of lead reduction efforts to date. Our findings highlight the challenges of restoring endangered vulture populations as they mature and become less reliant on management actions necessary to compensate for persistent threats. PMID- 25040287 TI - Clinical spectrum of capillary malformation-arteriovenous malformation syndrome presenting to a pediatric dermatology practice: a retrospective study. AB - Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder caused by RASA1 mutations. The prevalence and phenotypic spectrum are unknown. Evaluation of patients with multiple CMs is challenging because associated AVMs can be life threatening. The objective of this study was to describe the clinical characteristics of children presenting with features of CM-AVM to an academic pediatric dermatology practice. After institutional review board approval was received, a retrospective chart review was performed of patients presenting between 2009 and 2012 with features of CM AVM. We report nine cases. Presenting symptoms ranged from extensive vascular stains and cardiac failure to CMs noted incidentally during routine skin examination. All demonstrated multiple CMs, two had Parkes Weber syndrome, and two had multiple infantile hemangiomas. Seven patients had family histories of multiple CMs; three had family histories of large, atypical CMs. Six had personal or family histories of AVMs. Genetic evaluation was recommended for all and was pursued by six families; four RASA1 mutations were identified, including one de novo. Consultations with neurology, cardiology, and orthopedics were recommended. Most patients (89%) have not required treatment to date. CM-AVM is an underrecognized condition with a wide clinical spectrum that often presents in childhood. Further evaluation may be indicated in patients with multiple CMs. This study is limited by its small and retrospective nature. PMID- 25040288 TI - A multiaxis device for in-focus manipulation of objects under a dissecting microscope. AB - An inexpensive specimen holder for objects under a dissecting microscope is described which allows arbitrary orientation and rotation of the object within the visual field and focal plane of the microscope. Based on a spherical cap upon a magnet, this apparatus is easy to construct and permits single-handed manipulation of the specimen from some distance. Precise positioning is demonstrated for halteres of Drosophila under up to 120* magnification. Because of the restricted field of view and depth of focus of a dissecting microscope, it is often difficult to position tiny objects under study in varying orientation, especially if the specimen must simultaneously be dissected with forceps, microscissors or needles. The problem is solved most conveniently with a specimen holder based on a spherical cap which is held by a strong magnet on a steel ring. The specimen tilts vertically in any direction by up to 70 degrees and-even in oblique orientation-rotates through 360 degrees around the sphere's centre in the focal plane. By help of an interleaved plastic foil in a ring carrier, these movements can be controlled unimanually from outside the visual field. PMID- 25040289 TI - Male hypogonadism and metabolic syndrome. AB - The role of androgens in cardiovascular disease is still controversial in men. In this study, we investigated metabolic disorders in Tunisian hypogonadal men compared with healthy controls. Forty hypogonadal men and 80 control subjects were enrolled. Patients with a history of pre-existing panhypopituitarism, thyroid dysfunction or inflammatory disease were excluded. Glycaemia, glycated haemoglobin (HbA1c), high-sensitive C-reactive protein (hsCRP), lipid profile, insulin, testosterone and gonadotrophins were measured. Insulin resistance was assessed by homoeostasis model assessment of insulin resistance (Homa IR). Waist circumference, body mass index and blood pressure were significantly higher in patients compared with controls. Glycemia, HbA1c, fasting serum insulin and Homa IR were significantly increased among hypogonadal men. In univariate analysis, testosterone levels were inversely correlated with body mass index, waist circumference, blood pressure, glycaemia, HbA1C, insulin, Homa IR and hsCRP. In multivariate analysis including all significant variables, initial testosterone level was the only independent risk factor for developing dyslipidaemia. With logistic regression, male hypogonadism was an independent risk factor for MS (P < 0.001). We conclude that low testosterone level plays a central role in the development of metabolic syndrome. Further prospective data are required to establish the causative link. PMID- 25040290 TI - IGF-I regulates the age-dependent signaling peptide humanin. AB - Aging is influenced by endocrine pathways including the growth hormone/insulin like growth factor-1 (GH/IGF) axis. Mitochondrial function has also been linked to the aging process, but the relevant mitochondrial signals mediating the effects of mitochondria are poorly understood. Humanin is a novel signaling peptide that acts as a potent regulator of cellular stress responses and protects from a variety of in vitro and in vivo toxic and metabolic insults. The circulating levels of humanin decline with age in mice and humans. Here, we demonstrate a negative correlation between the activity of the GH-IGF axis and the levels of humanin, as well as a positive correlation between humanin and lifespan in mouse models with altered GH/IGF-I axis. Long-lived, GH-deficient Ames mice displayed elevated humanin levels, while short-lived GH-transgenic mice have reduced humanin levels. Furthermore, treatment with GH or IGF-I reduced circulating humanin levels in both mice and human subjects. Our results indicate that GH and IGF are potent regulators of humanin levels and that humanin levels correlate with lifespan in mice. This suggests that humanin represents a circulating mitochondrial signal that participates in modulating the aging process, adding a coordinated mitochondrial element to the endocrine regulation of aging. PMID- 25040291 TI - Birth weight as an independent predictor of ADHD symptoms: a within-twin pair analysis. AB - BACKGROUND: Studies have found an association between low birth weight and ADHD, but the nature of this relation is unclear. First, it is uncertain whether birth weight is associated with both of the ADHD dimensions, inattentiveness and hyperactivity-impulsivity. Second, it remains uncertain whether the association between birth weight and ADHD symptom severity is confounded by familial factors. METHOD: Parents of all Swedish 9- and 12-year-old twins born between 1992 and 2000 were interviewed for DSM-IV inattentive and hyperactive-impulsive ADHD symptoms by the Autism - Tics, AD/HD and other Comorbidities (A-TAC) inventory (N = 21,775 twins). Birth weight was collected prospectively through the Medical Birth Registry. We used a within-twin pair design to control for genetic and shared environmental factors. RESULTS: Reduced birth weight was significantly associated with a mean increase in total ADHD (beta = -.42; 95% CI: -.53, -.30), inattentive (beta = -.26; 95% CI: -.33, -.19), and hyperactive-impulsive (beta = .16; 95% CI: -.22, -.10) symptom severity. These results imply that a change of one kilogram of birth weight corresponded to parents rating their child nearly one unit higher (going from "no" to "yes, to some extent" on a given symptom) on the total ADHD scale. These associations remained within pairs of MZ and DZ twins, and were also present when restricting the analyses to full term births. CONCLUSIONS: There is an independent association between low birth weight and all forms of ADHD symptoms, even after controlling for all environmental and genetic confounds shared within twin pairs. These results indicate that fetal growth restriction (as reflected in birth weight differences within twin pairs) and/or the environmental factors which influence it is in the casual pathway leading to ADHD. PMID- 25040292 TI - Overexpression of artemisinic aldehyde Delta11 (13) reductase gene-enhanced artemisinin and its relative metabolite biosynthesis in transgenic Artemisia annua L. AB - Artemisinic aldehyde Delta11 (13) reductase (DBR2) is the checkpoint enzyme catalyzing artemisinic aldehyde to form dihydroartemisinic aldehyde directly involved in artemisinin biosynthetic pathway. In the present study, DBR2 was employed to engineer the biosynthetic pathway of artemisinin in transgenic plants of Artemisia annua L. Seven independent transgenic plants of A. annua with DBR2 overexpression driven by the cauliflower mosaic virus 35S promoter were obtained by Agrobacterium-mediated genetic transformation and confirmed by genomic PCR. The results of real-time qPCR analysis showed that the expression levels of DBR2 gene in all the seven transgenic lines were significantly higher than in nontransgenic control. The high-performance liquid chromatography analysis of artemisinin and its relative metabolites demonstrated that the contents of artemisinin and its direct precursor dihydroartemisinic acid were remarkably increased in the transgenic plants of A. annua with DBR2 overexpression. Interestingly, it was also found that the contents of arteannuin B and its direct precursor artemisinic acid in the branch pathway competing against artemisinin biosynthesis were also improved in DBR2-overexpressed A. annua plants. The transgenic results in the present study indicated that DBR2 is a useful structural gene in engineering the artemisinin biosynthetic pathway to develop genetically modified A. annua with the higher yield of artemisinin. PMID- 25040293 TI - Thulium laser (RevoLix) vaporesection versus vapoenucleation with morcellator (Piranha) for the treatment of benign prostatic obstruction: a propensity-matched multicenter analysis. AB - OBJECTIVES: To compare the efficacy and safety of vaporesection without a morcellator, and vapoenucleation with a morcellator in thulium laser prostatectomy for the treatment of benign prostatic obstruction. METHODS: Between March 2010 and January 2013, 405 patients underwent thulium:yttrium-aluminium garnet laser prostatectomy. Among these patients, 150 patients who underwent thulium:yttrium-aluminium-garnet laser prostatectomy without a morcellator (n = 75) or with a morcellator (n = 75) were analyzed in a propensity matching study. Outcome measures included International Prostate Symptom Score, quality of life score, maximum flow rate, postvoid residual, total operating time, laser time and resected tissue weight. RESULTS: No significant differences were noted between the thulium:yttrium-aluminium-garnet laser prostatectomy without a morcellator and thulium:yttrium-aluminium-garnet laser prostatectomy with a morcellator groups, including the prostate volume (50.3 vs 51.9 mL) and postoperative prostate volume (22.4 vs 18.7 mL). However, there were differences between the groups in total operating time (72.8 vs 61.0 min, P = 0.023) and laser activating time (24.5 vs 19.9 min, P = 0.037). Thulium:yttrium-aluminium-garnet laser prostatectomy with a morcellator showed greater resected tissue volume than thulium:yttrium-aluminium-garnet laser prostatectomy without a morcellator (9.0 vs 18.2 g, P = 0.029). There were also significant differences in total retrieval efficiency (1.14 vs 1.67 g/min, P = 0.031). There were no significant differences in improvement of International Prostate Symptom Score, quality of life scores and urodynamic findings between the two groups, except for the International Prostate Symptom Score (11.2 vs 7.3, P = 0.028) at 6 weeks after surgery. CONCLUSION: Thulium:yttrium-aluminium-garnet laser prostatectomy with a morcellator provides superior reduction of prostate volume and better short-term clinical outcomes than thulium:yttrium-aluminium-garnet laser prostatectomy without a morcellator in the treatment of patients with benign prostatic obstruction. Furthermore, thulium:yttrium-aluminium-garnet laser prostatectomy with a morcellator can offer a shorter operative time. PMID- 25040294 TI - Kono-S anastomosis for Crohn's disease: narrative - a video vignette. PMID- 25040295 TI - Invasive placebo revisited. PMID- 25040296 TI - The role of the 595-nm pulsed dye laser in treating superficial basal cell carcinoma: outcome of a double-blind randomized placebo-controlled trial. AB - BACKGROUND: Pulsed dye laser (PDL) treatments have been suggested to be a safe and effective therapeutic approach for treating basal cell carcinomas (BCCs). However, robust supporting evidence is lacking due to inconsistent design of available studies. OBJECTIVES: To evaluate PDL efficacy and safety in treating superficial BCC (sBCC) at low-risk anatomical sites in an evidence-based study setting. MATERIALS AND METHODS: Thirty-nine patients (27 men and 12 women, 75.9 +/- 10 years) with a total of 100 sBCCs were randomized to receive PDL treatment (wavelength 595 nm; fluence 8 J cm(-2) ; pulse duration 0.5 ms; spot size 10 mm) or sham treatment. The primary endpoint was complete clinical and histological remission of the tumour at 6-month follow-up; the secondary endpoints were the evaluation of side-effects and pain as well as patient satisfaction. RESULTS: The primary endpoint showed significant superiority of the laser group to the sham group (P < 0.0001). Complete remission was achieved in 44 of 56 cases (78.6%) in the laser and in two of 44 cases (4.5%) in the sham treatment arm. The main adverse events in the laser group were crusts, hyper- and hypopigmentation. An average of 72% of patients stated at the individual sessions that they were 'satisfied' with the laser treatment, whereas 25% were 'very satisfied'. CONCLUSIONS: PDL is an effective and safe method for treating sBCC. However, the occurrence of persistent dyspigmentation still limits the potential for excellent cosmetic outcomes. PMID- 25040297 TI - The role of serum erythropoietin level and JAK2 V617F allele burden in the diagnosis of polycythaemia vera. AB - Low serum erythropoietin (EPO) is a minor criterion of Polycythaemia Vera (PV) but its diagnostic usefulness relies on studies performed before the discovery of JAK2 V617F mutation. The objective of the present study was to evaluate the diagnostic accuracy of serum EPO and JAK2 V617F allele burden as markers of PV as well as the combination of different diagnostic criteria in 287 patients (99 with PV, 137 with Essential Thrombocythaemia and 51 with non-clonal erythrocytosis). Low EPO showed good diagnostic accuracy as a marker for PV, with the area under the curve (AUC) of the chemiluminescent-enhanced enzyme immunoassay (CEIA) being better than that of radioimmunoassay (RIA) (0.87 and 0.76 for CEIA and RIA, respectively). JAK2 V617F quantification displayed an excellent diagnostic accuracy, with an AUC of 0.95. A haematocrit >52% (males) or >48% (females) plus the presence of the JAK2 V617F mutation had a sensitivity and specificity of 79% and 97%, respectively. Adding low EPO or the JAK2 V617F allele burden did not improve the diagnostic accuracy for PV whereas the inclusion of both improved the sensitivity up to 83% and maintaining 96% specificity. Haematocrit and qualitative JAK2 V617F mutation allow a reliable diagnosis of PV. Incorporation of EPO and/or JAK2 V617F mutant load does not improve the diagnostic accuracy. PMID- 25040298 TI - Propositional speech in unselected stroke: The effect of genre and external support. AB - Distinguished from nominal language, propositional language generation refers to the spontaneous and voluntary aspect of language that introduces novel concepts to a specific context. Propositional language can be impaired in a range of neurological disorders, including stroke, despite well-preserved nominal language. Although external support can increase speech rate in patients with reduced propositional speech, no specific investigation of propositional speech has been carried out in unselected stroke patients. The current study investigated propositional language in an unselected post-acute stroke group (N = 18) with mild cognitive impairment and prominent executive dysfunction, but without significant aphasia. Specifically, we investigated whether genre or external support affected the number of words, sentences, and novel ideas produced, compared to healthy controls (N = 27). Results showed that discourse genre was not associated with differential performances. By contrast, speech quantity increased without external support although, for stroke patients, speech novelty decreased. Overall, the novelty deficit in unselected stroke patients highlights the importance of assessing cognition and propositional speech. Our findings suggest that for stroke patients with mild cognitive deficits, including executive dysfunction, introducing external support improved speech quality but not quantity. Implications for both assessment and rehabilitation of social communication are discussed. PMID- 25040299 TI - Long-term efficacy of a 0.07% cetylpyridinium chloride mouth rinse in relation to plaque and gingivitis: a 6-month randomized, vehicle-controlled clinical trial. AB - OBJECTIVE: To evaluate the effectiveness of 0.07% cetylpyridinium chloride (CPC) mouth rinse for reduction of gingival inflammation and inhibition of plaque compared to a vehicle control (VC) mouth rinse over a 6-month period. MATERIALS & METHODS: Participants (n = 62) used their randomly assigned product as adjunct to toothbrushing. Bleeding, plaque and staining scores were assessed at baseline, 3 and 6 months. Plaque and saliva samples were taken at each assessment monitoring possible shifts in the composition of the microbiota. RESULTS: A significant difference (P = 0.002) in favour of the CPC mouth rinse, with respect to plaque scores, was found. Bleeding scores at 6 months were not significantly different (P = 0.089). However, when correcting for baseline values, a tendency towards a significant difference in bleeding scores at end trail was observed in favour of the CPC mouth rinse (P = 0.061). Regarding staining at 3 and 6 months, a small but significant difference (8.6% and 10.4%, respectively) (P < 0.0001) was observed with lower scores for the VC group. There was a significant reduction in total anaerobic count in the CPC group at 6 months (P < 0.05). The ratio of aerobes/anaerobes was markedly increased at 3 months, especially in the CPC group. No further differences were observed between groups at 6 months. CONCLUSIONS: The use of 0.07% CPC mouth rinse was significantly more effective in reducing plaque scores than the vehicle control. Bleeding scores were not different at 6 months. The test product was well accepted and did not cause any serious clinical side effects or negatively affected the microbiota. PMID- 25040300 TI - Pathological phenotypes and in vivo DNA cleavage by unrestrained activity of a phosphorothioate-based restriction system in Salmonella. AB - Prokaryotes protect their genomes from foreign DNA with a diversity of defence mechanisms, including a widespread restriction-modification (R-M) system involving phosphorothioate (PT) modification of the DNA backbone. Unlike classical R-M systems, highly partial PT modification of consensus motifs in bacterial genomes suggests an unusual mechanism of PT-dependent restriction. In Salmonella enterica, PT modification is mediated by four genes dptB-E, while restriction involves additional three genes dptF-H. Here, we performed a series of studies to characterize the PT-dependent restriction, and found that it presented several features distinct with traditional R-M systems. The presence of restriction genes in a PT-deficient mutant was not lethal, but instead resulted in several pathological phenotypes. Subsequent transcriptional profiling revealed the expression of > 600 genes was affected by restriction enzymes in cells lacking PT, including induction of bacteriophage, SOS response and DNA repair related genes. These transcriptional responses are consistent with the observation that restriction enzymes caused extensive DNA cleavage in the absence of PT modifications in vivo. However, overexpression of restriction genes was lethal to the host in spite of the presence PT modifications. These results point to an unusual mechanism of PT-dependent DNA cleavage by restriction enzymes in the face of partial PT modification. PMID- 25040301 TI - Anesthetic management of patients with Joubert syndrome: a retrospective analysis of a single-institutional case series. AB - OBJECTIVE: To analyze the anesthetic techniques used for sedation during magnetic resonance imaging (MRI) study of patients with Joubert syndrome (JS) and assess the safety and efficacy of these anesthetic regimens in these children. BACKGROUND: Joubert syndrome is a rare neurological disorder with significant anesthetic implications. This study describes the anesthetic management of children with JS undergoing MRI study with different anesthetic agents and implications of various anesthetic techniques in these patients. MATERIALS AND METHODS: The records of ten patients with JS undergoing MRI study with different anesthetic techniques were retrospectively reviewed over the last 5 years. RESULTS: The patients were aged between 6 months and 21 years. The most commonly used sedation technique involved use of alpha-2 agonists, and this technique had least complications such as apnea and patient movement during imaging. None of the patients had postanesthetic respiratory problems, although one patient receiving propofol had apnea and desaturation on induction requiring airway intervention. CONCLUSION: Alpha-2 agonist based anesthetic technique appears to be most suitable for sedation during MRI study in patients with JS with respect to adverse events and outcome. PMID- 25040302 TI - The role of vulnerability in stress-related insomnia, social support and coping styles on incidence and persistence of insomnia. AB - Individuals who are more prone to experience situational insomnia under stressful conditions may also be at greater risk to develop subsequent insomnia. While cross-sectional data exist on the link between sleep reactivity (heightened vulnerability to stress-related insomnia) and insomnia, limited data exist on its predictive value. The aim of the study was to evaluate prospectively whether sleep reactivity was associated with increased risk of incident and persistent insomnia in a population-based sample of good sleepers. Social support and coping styles were also investigated as potential moderators. Participants were 1449 adults (Mage = 47.4 years, standard deviation = 15.1; 41.2% male) without insomnia at baseline and evaluated four times over 3 years. Sleep reactivity was measured using the Ford Insomnia Response to Stress Test (FIRST). Additional measures included depressive symptoms, the frequency and perceived impact of stressful life events, social support and coping styles. After controlling for prior sleep history, depressive symptoms, arousal predisposition, stressful life events and perceived impact, individuals with higher sleep reactivity had an odds ratio (OR) of 1.56 [95% confidence interval (CI): 1.13-2.16], 1.41 (95% CI: 0.87 2.30) and 2.02 (95% CI: 1.30-3.15) of developing insomnia symptoms, syndrome and persistent insomnia, respectively. Social support and coping styles did not moderate these associations. Results suggest that heightened vulnerability to insomnia is associated with an increased risk of developing new-onset subsyndromal and persistent insomnia in good sleepers. Knowledge of premorbid differences is important to identify at-risk individuals, as this may help to develop more targeted prevention and intervention strategies for insomnia. PMID- 25040303 TI - Diagnostic accuracy of portable instrumental devices to measure sleep bruxism: a systematic literature review of polysomnographic studies. AB - This study systematically reviews the sleep bruxism (SB) literature published in the MEDLINE and Scopus databases to answer the following question: What is the validity of the different portable instrumental devices that have been proposed to measure SB if compared with polysomnographic (PSG) recordings assumed as the gold standard? Four clinical studies on humans, assessing the diagnostic accuracy of portable instrumental approaches (i.e. Bitestrip, electromyography (EMG) telemetry recordings and Bruxoff) with respect to PSG, were included in the review. Methodological shortcomings were identified by QUADAS-2 quality assessment. Findings showed contrasting results and supported only in part the validity of the described diagnostic devices with respect to PSG. The positive predictive value (PPV) of the Bitestrip device was 59-100%, with a sensitivity of 71-84.2%, whilst EMG-telemetry recordings had an unacceptable rate of false positive findings (76.9%), counterbalanced by an almost perfect sensitivity (98.8%). The Bruxoff device had the highest accuracy values, showing an excellent agreement with PSG for both manual (area under ROC = 0.98) and automatic scoring (0.96) options as well as for the simultaneous recording of events with respect to PSG (0.89-0.91). It can be concluded that the available information on the validity of portable instrumental diagnostic approaches with respect to PSG recordings is still scarce and not solid enough to support any non-PSG technique's employ as a stand-alone diagnostic method in the research setting, with the possible exception of the Bruxoff device that needs to be further confirmed with future investigations. PMID- 25040304 TI - Partially hydrolyzed soy protein shows enhanced transport of amino acids compared to nonhydrolyzed protein across an intestinal epithelial cell monolayer. AB - Consumption of protein hydrolysates has been proposed to stimulate muscle anabolism more than intact (nonhydrolyzed) proteins via accelerated delivery of amino acids for muscle protein synthesis (MPS). We evaluated whether the rate of amino acid uptake and transport across intestinal cells was enhanced for soy protein hydrolysates versus nonhydrolyzed soy protein. Intact and partially hydrolyzed proteins were subject to simulated gut digestion and applied to the apical surface of Caco-2 monolayers. Basolateral media was harvested after 3 h and quantitatively analyzed for free amino acids using ion-exchange chromatography and comparison to an included reference standard. Basolateral concentrations of all amino acids were higher (mean 32%) for hydrolyzed versus nonhydrolyzed protein with the greatest differences in histidine, lysine, and valine. Scale-up production of the soy protein hydrolysate did not diminish its enhanced absorption properties. These data support the hypothesis that hydrolyzed soy protein may provide dietary amino acids that are more rapidly transported across the intestinal epithelium versus intact soy protein. This would be important under conditions where rapid and increased levels of amino acids are needed such as in the stimulation of MPS. PMID- 25040305 TI - Decoding the s-nitrosoproteomic atlas in individualized human colorectal cancer tissues using a label-free quantitation strategy. AB - The abnormal S-nitrosylation induced by the overexpression and activation of inducible nitric oxide synthase (iNOS) modulates many human diseases, such as inflammation and cancer. To delineate the pathophysiological S-nitrosoproteome in cancer patients, we report an individualized S-nitrosoproteomic strategy with a label-free method for the site-specific quantification of S-nitrosylation in paired tumor and adjacent normal tissues from 11 patients with colorectal cancer (CRC). This study provides not only the first endogenous human S-nitrosoproteomic atlas but also the first individualized human tissue analysis, identifying 174 S nitrosylation sites in 94 proteins. Fourteen novel S-nitrosylation sites with a high frequency of elevated levels in 11 individual patients were identified. An individualized S-nitrosylation quantitation analysis revealed that the detected changes in S-nitrosylation were regulated by both the expression level and the more dramatic post-translational S-nitrosylation of the targeted proteins, such as thioredoxin, annexin A4, and peroxiredoxin-4. These endogenous S-nitrosylated proteins illustrate the network of inflammation/cancer-related and redox reactions mediated by various S-nitrosylation sources, including iNOS, transnitrosylase, or iron-sulfur centers. Given the demonstrated sensitivity of individualized tissue analysis, this label-free approach may facilitate the study of the vastly under-represented S-nitrosoproteome and enable a better understanding of the effect of endogenous S-nitrosylation in cancer. PMID- 25040306 TI - Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning. AB - Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20-40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20-min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30- or 40-min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30-min WIT and Cs solution displayed complete recovery, while hearts exposed to 40-min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20-min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with <=30-min WIT may be suitable for transplantation and warrant assessment in a transplant model. PMID- 25040307 TI - Fetal death and preterm birth associated with maternal influenza vaccination: systematic review. AB - BACKGROUND: Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently. OBJECTIVES: To review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. SEARCH STRATEGY: We searched bibliographic databases from inception to April 2014. SELECTION CRITERIA: Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data from studies meeting the inclusion criteria. MAIN RESULTS: We included one randomised clinical trial and 26 observational studies. Meta analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56-0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at >=20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta-regression did not explain the moderate between-study heterogeneity (I(2) = 57%). AUTHORS' CONCLUSIONS: Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness. PMID- 25040308 TI - Shared decision-making in medical encounters regarding breast cancer treatment: the contribution of methodological triangulation. AB - The aim of this study on shared decision-making in the doctor-patient encounter about surgical treatment for early-stage breast cancer, conducted in a regional cancer centre in France, was to further the understanding of patient perceptions on shared decision-making. The study used methodological triangulation to collect data (both quantitative and qualitative) about patient preferences in the context of a clinical consultation in which surgeons followed a shared decision-making protocol. Data were analysed from a multi-disciplinary research perspective (social psychology and health economics). The triangulated data collection methods were questionnaires (n = 132), longitudinal interviews (n = 47) and observations of consultations (n = 26). Methodological triangulation revealed levels of divergence and complementarity between qualitative and quantitative results that suggest new perspectives on the three inter-related notions of decision-making, participation and information. Patients' responses revealed important differences between shared decision-making and participation per se. The authors note that subjecting patients to a normative behavioural model of shared decision-making in an era when paradigms of medical authority are shifting may undermine the patient's quest for what he or she believes is a more important right: a guarantee of the best care available. PMID- 25040309 TI - Medical infrared imaging (thermography) of type I thoracolumbar disk disease in chondrodystrophic dogs. AB - OBJECTIVE: To: (1) determine the success of medical infrared imaging (MII) in identifying dogs with TLIVDD, (2) compare MII localization with magnetic resonance imaging (MRI) results and surgical findings, and (3) determine if the MII pattern returns to that of normal dogs 10 weeks after decompression surgery. STUDY DESIGN: Prospective case series. ANIMALS: Chondrodystrophic dogs (n = 58) with Type I TLIVDD and 14 chondrodystrophic dogs with no evidence of TLIVDD. METHODS: Complete neurologic examination, MII, and MRI studies were performed on all dogs. Dogs with type I TLIVDD had decompressive surgery and follow-up MII was performed at 10 weeks. Pattern analysis software was used to differentiate between clinical and control dogs, and statistical analysis using anatomic regions of interest on the dorsal views were used to determine lesion location. Recheck MII results were compared with control and pre-surgical images. RESULTS: Computer recognition pattern analysis was 90% successful in differentiating normal dogs from dogs affected by TLIVDD and 97% successful in identifying the abnormal intervertebral disc space in dogs with TLIVDD. Statistical comparisons of the ROI mean temperature were unable to determine the location of the disc herniation. Recheck MII patterns did not normalize and more closely resembled the clinical group. CONCLUSIONS: MII was 90% successful differentiating between normal dogs and 97% successful in identifying the abnormal intervertebral disc space in dogs with TLIVDD. Abnormal intervertebral disc space localization using ROI mean temperature analysis was not successful. MII patterns 10 weeks after surgery do not normalize. PMID- 25040310 TI - Chemoprevention of photocarcinogenesis by lycopene. AB - This review focuses on the photoprotection conferred by lycopene, one of the most potent anti-oxidants. Lycopene has been recently proposed to play a critical role on anticarcinogenic action at different levels. The photoprotective properties of lycopene remain contradictory. Some studies point out a positive and others a negative effect in both in vitro and in vivo models. Currently, researchers recognise that crucial gaps exist in understanding the role of carotenoids as effective modulators of apoptosis, cell cycle dynamics and/or of their in vivo behaviour as cellular anti-oxidants. The development of novel therapeutic strategies for skin disorders depends on our understanding of the molecular mechanism of UV damage on skin cells. The use of several effective phytocompounds, including lycopene, working through preventive and/or corrective pathways in the cell, may be an approach for reducing UV-B-generated damage. PMID- 25040311 TI - Outcome and management of pacemaker-induced superior vena cava syndrome. AB - BACKGROUND: We aimed to determine the long-term outcomes of percutaneous lead extraction and stent placement in patients with pacemaker-induced superior vena cava (SVC) syndrome. METHODS: The study retrospectively screened patients who underwent lead extraction followed by central vein stent implantation at Mayo Clinic (Rochester, MN, USA), from January 2005 to December 2012, to identify the patients with pacemaker-induced SVC syndrome. Demographic, clinical, and follow up characteristics of those patients were collected from electronic medical records. RESULTS: Six cases were identified. The mean (standard deviation) age was 56 (15) years (male, 67%). All patients had permanent dual-chamber pacemakers, with a mean 11-year history of pacemaker placement. The entire device system was explanted in five patients; one patient had a 21-year-old pacemaker lead that could not be removed. Eight stents were implanted in six patients: five patients had one stent, one patient had three. A new pacemaker system was reimplanted through the stented vein in five patients. Technical success was achieved in all patients, without any complication. Symptoms rapidly resolved in all patients after stent deployment. The mean follow-up duration was 48 months (range, 10-100 months). Three patients remained symptom free. Reintervention with percutaneous balloon venoplasty was successful in three patients with symptom recurrence. CONCLUSION: Percutaneous stent implantation after lead removal followed by reimplantation of leads is a feasible alternative therapy for pacemaker-induced SVC syndrome, although some cases may require repeat intervention. PMID- 25040312 TI - Pseudomesotheliomatous small-cell neuroendocrine carcinoma of the lung with calretinin expression. PMID- 25040313 TI - Dental student perception and assessment of their clinical knowledge in educating patients about preventive dentistry. AB - In today's dental school curricula, an increasing amount of time is dedicated to technological advances, and preventive dentistry topics may not be adequately addressed. Freshman (D1) students participated in a new Introduction to Preventive Dentistry course, which consisted of didactic lectures, active learning breakout sessions and case-based studies. The goal of this study was to determine if D1 dental students completing the course had a better knowledge and comfort level with basic preventive dentistry concepts and caries risk assessment than the upcoming graduating senior dental students. Following the completion of the course, D1 students were administered a survey that assessed their comfort level describing preventive dentistry topics to patients. This was immediately followed by an unannounced examination over the same topics. Senior (D4) students, who had not taken a formal course, reported statistically significant higher comfort levels than D1 students. However, the D4s scored significantly lower in all of the examination areas than the D1 students. Higher scores in D1s may have been due to recent exposure to the course material. However, the basic nature of the content-specific questions should be easily answered by novice practitioners educating their patients on oral disease prevention. As the current data shows lower content-specific scores of basic preventive dentistry knowledge amongst graduating D4 students, this may indicate a need for more guidance and education of students during the patient care. This study showed that implementation of a formalised course for D1 students can successfully ameliorate deficiencies in knowledge of preventive dentistry topics. PMID- 25040314 TI - Presence and content of kynurenic acid in animal feed. AB - Kynurenic acid (KYNA) was found to be an antagonist of iontropic glutamate receptors and alpha7 nicotinic acetylcholine receptors. Furthermore, it was documented that KYNA is an agonist of G-protein coupled GPR35 receptors which are mainly present in the gastrointestinal tract. It was also found that KYNA is present in the gastrointestinal tract and that its concentration gradually increases along it. The origin of KYNA in the gastrointestinal tract is not known. Both might be synthesized from tryptophan in it or absorbed from food and other dietary products. Therefore, the aim of the study was to investigate the concentration of KYNA in animal feed. The results indicate that the highest concentration of KYNA was found in animal feeds intended for livestock. The lower amount of KYNA was detected in animal feeds for fish. Interestingly, the lowest amount of KYNA was found in dog and cat feeds. Furthermore, an analysis of KYNA content in animal food ingredients was conducted. The concentration of KYNA found in one of the ingredients - rapeseed meal - was several times higher in comparison to animal feeds studied. The content of KYNA in the remaining feed ingredients tested was significantly lower. This is the first report on the concentration of KYNA in animal feeds. There is a need for further detailed analysis leading to establishing a set of guidelines for animal feeding. PMID- 25040315 TI - The impact of type 2 diabetes and obesity on the long-term outcomes of more than 85 000 liver transplant recipients in the US. AB - BACKGROUND: Type 2 diabetes is known to negatively impact the outcome of chronic liver disease. AIM: To evaluate the impact of diabetes on the outcomes of liver transplants (LT). METHODS: Study cohort included adults (>18 years) who received LT in the US between 1994 and 2013 (The Scientific Registry of Transplant Recipients). Pre- and post-transplant diabetes was recorded in patients with mortality follow-up. RESULTS: We included 85 194 liver transplant recipients. Of those, 11.2% had history of pre-transplant diabetes. The most common indications for liver transplant were hepatitis C (36.4%), alcohol-related liver disease (20.6%), primary liver malignancy of unspecified aetiology (14.7%), cryptogenic cirrhosis (8.0%), hepatitis B (4.6%) and non-alcoholic steatohepatitis (3.9%). A total of 96.5% transplants were from deceased donors, and 7.9% donors had history of diabetes. During an average 6.5 years of follow-up, 31.3% recipients died and 8.8% had a graft failure. In multivariate survival analysis [at least 5 years of cohort follow-up (N = 35 870)], after adjustment for age, ethnicity, insurance type, history of chronic diseases, HCV infection and noncompliance, independent predictors of recipient mortality included the presence of pre-transplant diabetes [adjusted hazard ratio (95%CI) = 1.21 (1.12-1.30)] and developing diabetes post-transplant [1.06 (1.02-1.11)]. Donor's history of diabetes was also independently associated with higher mortality [1.10 (1.02-1.19)]. Furthermore, donor's history of diabetes was also associated with an increased the risk of liver graft failure [1.35 (1.24-1.47)]. CONCLUSIONS: Presence of type 2 diabetes pre- and post-transplant, as well as presence of type 2 diabetes in the donors, are all associated with an increased risk of adverse post-transplant outcomes. PMID- 25040316 TI - Intensive postoperative surveillance using chest CT and bone scan in patients with locally advanced breast cancer. PMID- 25040317 TI - Severe haemolytic anaemia with erythrophagocytosis following the bite of a brown recluse spider. PMID- 25040318 TI - Evidence for gene duplication and allelic codominance (not hierarchical dominance) at the mating-type locus of the ciliate, Euplotes crassus. AB - The high-multiple mating system of Euplotes crassus is known to be controlled by multiple alleles segregating at a single locus and manifesting relationships of hierarchical dominance, so that heterozygous cells would produce a single mating type substance (pheromone). In strain L-2D, now known to be homozygous at the mating-type locus, we previously identified two pheromones (Ec-alpha and Ec-1) characterized by significant variations in their amino acid sequences and structure of their macronuclear coding genes. In this study, pheromones and macronuclear coding genes have been analyzed in strain POR-73 characterized by a heterozygous genotype and strong mating compatibility with L-2D strain. It was found that POR-73 cells contain three distinct pheromone coding genes and, accordingly, secrete three distinct pheromones. One pheromone revealed structural identity in amino acid sequence and macronuclear coding gene to the Ec-alpha pheromone of L-2D cells. The other two pheromones were shown to be new and were designated Ec-2 and Ec-3 to denote their structural homology with the Ec-1 pheromone of L-2D cells. We interpreted these results as evidence of a phenomenon of gene duplication at the E. crassus mating-type locus, and lack of hierarchical dominance in the expression of the macronuclear pheromone genes in cells with heterozygous genotypes. PMID- 25040319 TI - Goltz syndrome and PORCN mosaicism. AB - Goltz syndrome, also known as focal dermal hypoplasia, is characterized primarily by ectodermal and mesodermal defects. Manifestations include cutis aplasia, dermal hypoplasia, papillomas, chorioretinal colobomas, absent/dysplastic teeth, and skeletal anomalies. Goltz syndrome is an X-linked disorder due to mutations in PORCN, with a predominance of females affected. Germline mutations in PORCN are thought to result in embryonically lethality in males. We present a boy with a phenotype consistent with Goltz syndrome with low-level mosaicism for a novel mutation in PORCN from peripheral blood (c.956dupA; p.Asn320GlufsX99). PMID- 25040320 TI - Linkage disequilibrium over short physical distances measured in sheep using a high-density SNP chip. AB - The extent of linkage disequilibrium (LD) between genetic loci has implications for both association studies and the accuracy of genomic prediction. To characterise the persistence of LD in diverse sheep breeds, two SNP genotyping platforms were used. First, existing SNP genotypes from 63 breeds obtained using the ovine SNP50 BeadChip (49,034 loci) were used to estimate LD decay in populations with contrasting levels of genetic diversity. Given the paucity of marker pairs separated by short physical distances on the SNP50 BeadChip, genotyping was subsequently performed for four breeds using the recently developed ovine HD BeadChip that assays approximately 600,000 SNPs with an average genomic spacing of 5 kb. This facilitated a highly accurate estimate of LD over short genomic distances (<30 kb) and revealed LD varies considerably between sheep breeds. Further, sheep appear to contain generally lower levels of LD than do other domestic species, likely a reflection of aspects of their past population history. PMID- 25040321 TI - The Efficacy of Propofol vs. Subcutaneous Sumatriptan for Treatment of Acute Migraine Headaches in the Emergency Department: A Double-Blinded Clinical Trial. AB - BACKGROUND: In this double-blinded, randomized trial, we hypothesized that propofol is as effective as sumatriptan in treating acute migraine headaches, with better control of nausea and vomiting, and fewer side effects. METHODS: Ninety cases of acute migraine attack admitted to the emergency department were randomly allocated into two treatment groups: (1) 6 mg of sumatriptan subcutaneously or (2) propofol injected intravenously in 30 to 40 mg boluses, followed by 10 to 20 mg intermittent bolus doses to sedate the patients to Ramsey score of 3 to 4. Headache severity was assessed using an 11-point visual analog scale before treatment and 30 minutes, 1 hour, and 2 hours after treatment. Accompanying symptoms, improvement in headache, and the need for anti-emetic therapy were also assessed. RESULTS: A total of 91 patients were enrolled in this study. One patient in the sumatriptan group was excluded due to severe chest tightness, and 90 patients were included in the final analysis. Pain intensity was significantly lower in the propofol group 30 minutes after treatment (P = 0.001); however, after 1 and 2 hours, there were no significant differences between the groups. The need for anti-emetic therapy and the recurrence of symptoms were significantly lower in the propofol group (P = 0.045 and P = 0.001, respectively). CONCLUSION: Propofol is equally suitable as sumatriptan for the acute treatment of migraine headaches in an emergency department setting. Moreover, the use of propofol avoids some of the adverse side effects of sumatriptan while providing better control of nausea and vomiting. PMID- 25040323 TI - Spanning the globe--an international collaboration over 10 361 miles. PMID- 25040322 TI - Association between depression and inflammatory/anti-inflammatory cytokines in chronic kidney disease and end-stage renal disease patients: a review of literature. AB - Depression is a common psychiatric disorder in patients with advanced chronic kidney diseases (CKDs). Strong correlation has been reported between depression and patients' morbidity and mortality among dialysis patients. On the contrary, chronic inflammation may be a major contributor to morbidity and mortality in these patients. Elevated plasma levels of proinflammatory cytokines, especially C reactive protein and interleukin (IL)-6, have been correlated with cardiovascular events, hospitalization, and all-cause and cardiovascular-associated mortality in dialysis patients. Studies suggested that inflammation-mediated atherosclerotic cardiovascular diseases are the possible reasons for depression-induced mortality among patients without renal diseases. Several studies found significant elevations in circulating levels of proinflammatory cytokines, particularly IL-6 and tumor necrosis factor-alpha, in patients with major depression. Furthermore, depressive mood and behaviors, including sadness and suicidal ideation, were observed in patients who received repeated injections of recombinant cytokines. A thorough literature review indicates that while depressive symptoms and elevated inflammatory cytokine levels coexist in CKD and dialysis patients, their association is uncertain. Depression seems to be more associated with elevated serum levels of IL-6 than other cytokines in these patients. Further studies are needed to clarify the possibility of a causal relationship between inflammation and depressive symptoms in CKD and dialysis patients. PMID- 25040325 TI - The effectiveness of a twice-daily skin-moisturising regimen for reducing the incidence of skin tears. AB - A cluster randomised controlled trial was conducted to evaluate the effectiveness of a twice-daily moisturising regimen as compared to 'usual' skin care for reducing skin tear incidence. Aged care residents from 14 Western Australian facilities (980 beds) were invited to participate. The facilities were sorted into pairs and matched in terms of bed numbers and whether they provided high or low care. One facility from each matched pair was randomised to the intervention group. Consenting residents in an intervention facility received a twice-daily application of a commercially available, standardised pH neutral, perfume-free moisturiser on their extremities. Residents in the control facilities received ad hoc or no standardised skin-moisturising regimen. Participant numbers were sufficient to detect a 5% difference in incidence rate between the two groups with 80% power and a significance level of P = 0.05, and the inter-cluster correlation coefficient was 0.034. Data were collected over 6 months. A total of 1396 skin tears on 424 residents were recorded during the study. In the intervention group, the average monthly incidence rate was 5.76 per 1000 occupied bed days as compared to 10.57 in the control group. The application of moisturiser twice daily reduced the incidence of skin tears by almost 50% in residents living in aged care facilities. PMID- 25040327 TI - Vandetanib-associated alopecia areata in a patient with metastatic medullary thyroid cancer. PMID- 25040328 TI - Density of insect-pollinated grassland plants decreases with increasing surrounding land-use intensity. AB - Pollinator declines have raised concerns about the persistence of plant species that depend on insect pollination, in particular by bees, for their reproduction. The impact of pollinator declines remains unknown for species-rich plant communities found in temperate seminatural grasslands. We investigated effects of land-use intensity in the surrounding landscape on the distribution of plant traits related to insect pollination in 239 European seminatural grasslands. Increasing arable land use in the surrounding landscape consistently reduced the density of plants depending on bee and insect pollination. Similarly, the relative abundance of bee-pollination-dependent plants increased with higher proportions of non-arable agricultural land (e.g. permanent grassland). This was paralleled by an overall increase in bee abundance and diversity. By isolating the impact of the surrounding landscape from effects of local habitat quality, we show for the first time that grassland plants dependent on insect pollination are particularly susceptible to increasing land-use intensity in the landscape. PMID- 25040329 TI - Development of a measure to assess healthcare providers' implementation of patient-centered care. AB - BACKGROUND: Patient-centered care (PCC) is a vaguely defined element of high quality care, which precludes its consistent and precise operationalization. A conceptualization of PCC was derived from the literature and guided the development of an instrument to assess implementation of PCC by healthcare providers. The items of the instrument capture specific activities that reflect three components of PCC: holistic, collaborative, and responsive care. This paper reports on the measure's content and construct validity and reliability. METHODS: Content validity was evaluated in a sample of 11 nurse practitioners who rated the relevance of each items' content in reflecting the respective component of PCC. The content validity index (CVI) was estimated. Construct validity and internal consistency reliability were examined in a survey of 149 nurse practitioners employed in acute care institutions, using factor analysis and the KR-20 coefficient, respectively. RESULTS: The CVIs were 100% for the three subscales assessing the holistic, collaborative, and responsive care components of PCC. The items in each subscale loaded on one factor. The KR-20 coefficients were .66, .70, and .42, respectively. Overall, the majority (>70%) of respondents indicated performance of the activities comprising the three components of PCC. LINKING EVIDENCE TO ACTION: The PCC measure demonstrated acceptable psychometric properties. The low variance in responses, which is anticipated for instruments assessing fidelity of intervention implementation, accounts for the low reliability coefficients. Additional testing of the measure's psychometric properties in different groups of healthcare providers is warranted. The measure can be used to monitor healthcare providers' implementation of PCC in their usual practice. PMID- 25040330 TI - Swedish pupils' suggested coping strategies if cyberbullied: differences related to age and gender. AB - The aim of this study was to investigate the coping strategies that Swedish 10 and 12 year-olds (N = 694) suggested they would use if they were cyberbullied, with a special focus on whether there are differences in these strategies related to age and gender. The most commonly suggested coping strategy was telling someone, especially parents and teachers (70.5%). Surprisingly few of the pupils reported that they would tell a friend (2.6%). Differences in suggested coping strategies were found related to age and gender. Findings are discussed in relation to the Swedish sociocultural context as well as in relation to the implications for prevention strategies against cyberbullying. PMID- 25040331 TI - High blood pressure: why prevention and control are urgent and important: a 2014 fact sheet from the World Hypertension League and the International Society of Hypertension. PMID- 25040333 TI - Contribution of the drought tolerance-related stress-responsive NAC1 transcription factor to resistance of barley to Ramularia leaf spot. AB - NAC proteins are plant transcription factors that are involved in tolerance to abiotic and biotic stresses, as well as in many developmental processes. Stress responsive NAC1 (SNAC1) transcription factor is involved in drought tolerance in barley and rice, but has not been shown previously to have a role in disease resistance. Transgenic over-expression of HvSNAC1 in barley cv. Golden Promise reduced the severity of Ramularia leaf spot (RLS), caused by the fungus Ramularia collo-cygni, but had no effect on disease symptoms caused by Fusarium culmorum, Oculimacula yallundae (eyespot), Blumeria graminis f. sp. hordei (powdery mildew) or Magnaporthe oryzae (blast). The HvSNAC1 transcript was weakly induced in the RLS-susceptible cv. Golden Promise during the latter stages of R. collo-cygni symptom development when infected leaves were senescing. Potential mechanisms controlling HvSNAC1-mediated resistance to RLS were investigated. Gene expression analysis revealed no difference in the constitutive levels of antioxidant transcripts in either of the over-expression lines compared with cv. Golden Promise, nor was any difference in stomatal conductance or sensitivity to reactive oxygen species-induced cell death observed. Over-expression of HvSNAC1 delayed dark-induced leaf senescence. It is proposed that mechanisms controlled by HvSNAC1 that are involved in tolerance to abiotic stress and that inhibit senescence also confer resistance to R. collo-cygni and suppress RLS symptoms. This provides further evidence for an association between abiotic stress and senescence in barley and the development of RLS. PMID- 25040334 TI - The patient's perspective on "providing structure" in psychiatric inpatient care: an interview study. AB - PURPOSE: To gain insight into the patients' experiences on providing structure (PS) as a nursing intervention during psychiatric inpatient care. DESIGN AND METHOD: Interviews were conducted with patients (n = 17) from two inpatient wards within a mental healthcare organization. For data analysis, a qualitative coding process was followed. FINDINGS: The patients' expectations for PS were described. One expectation seemed to reflect key concern: the need to maintain autonomy. PRACTICAL IMPLICATIONS: The study reveals the patients' views about PS. When the importance of PS is mentioned, nurses can refer to our description of PS. We were able to further stipulate the required activities of PS and provide for an adapted definition of PS. PMID- 25040335 TI - The hidden epidemic of Escherichia coli. PMID- 25040336 TI - Outcomes of intravenous tissue plasminogen activator for acute ischaemic stroke in HIV-infected adults. AB - BACKGROUND AND PURPOSE: To our knowledge there are no studies reporting the use and short-term outcomes of intravenous tissue plasminogen activator (IV-TPA) for the treatment of acute ischaemic stroke (AIS) in people living with HIV. METHODS: The US Nationwide Inpatient Sample (NIS) (2006-2010) was searched for HIV infected AIS patients treated with IV-TPA. RESULTS: In the NIS, 2.2% (62/2877) of HIV-infected AIS cases were thrombolyzed with IV-TPA (median age 52 years, range 27-78, 32% female, 22% Caucasian) vs. 2.1% (19 335/937 896) of HIV-uninfected cases (median age 72 years, range 17-102 years, 50% female, 74% Caucasian; P = 0.77). There were more deaths in HIV-infected versus uninfected patients with stroke (220/2877, 7.6% vs. 49 089/937 547, 5.2%, P < 0.001) but no difference in the proportion of deaths amongst IV-TPA-treated patients. The age- and sex adjusted odds ratio for death following IV-TPA administration in HIV-infected versus uninfected patients was 2.26 (95% CI 1.12, 4.58), but the interaction on mortality between HIV and IV-TPA use was not statistically significant, indicating no difference in risk of in-hospital death by HIV serostatus with IV TPA use. A higher number of HIV-infected patients remained in hospital versus died or were discharged at both 10 and 30 days (P < 0.01 at 10 and 30 days). No difference in the proportion of intracerebral hemorrhage in the two groups was found (P = 0.362). CONCLUSIONS: The in-hospital mortality is higher amongst HIV infected AIS patients than HIV-uninfected patients. However, the risk of death amongst HIV-infected patients treated with IV-TPA is similar to HIV-uninfected groups. PMID- 25040338 TI - Alcohol and drug use outcomes among vulnerable women living with HIV: results from the Western Cape Women's Health CoOp. AB - Alcohol and other drug use can negatively affect adherence to and retention in antiretroviral therapy (ART) among people living with HIV/AIDS. Yet, there are few brief interventions that reduce these behaviors among this population. This article presents the findings from a randomized field experiment that assessed the effects of a woman-focused intervention (the Women's Health CoOp [WHC]) on reducing alcohol and other drug use among vulnerable women in Cape Town, South Africa. The analyses were limited to 84 women living with HIV who reported drinking alcohol at baseline. Because of the small sample size, analyses were performed using an exact logistic regression procedure. At 12-month follow-up, women in the WHC arm were more likely to be abstinent from alcohol (odds ratio [OR] = 3.61; 95% confidence intervals [CI] = 1.23, 11.70; p = 0.016) and somewhat more likely to test negative for other drugs (OR = 3.07; 95% CI = 0.83, 12.31; p = 0.105), compared with women in the comparison arms. This study provides preliminary evidence of the efficacy of a brief, woman-focused intervention in reducing alcohol and other drug use among vulnerable women living with HIV and it has implications for HIV treatment. PMID- 25040337 TI - A review of piscine islet xenotransplantation using wild-type tilapia donors and the production of transgenic tilapia expressing a "humanized" tilapia insulin. AB - Most islet xenotransplantation laboratories have focused on porcine islets, which are both costly and difficult to isolate. Teleost (bony) fish, such as tilapia, possess macroscopically visible distinct islet organs called Brockmann bodies which can be inexpensively harvested. When transplanted into diabetic nude mice, tilapia islets maintain long-term normoglycemia and provide human-like glucose tolerance profiles. Like porcine islets, when transplanted into euthymic mice, they are rejected in a CD4 T-cell-dependent manner. However, unlike pigs, tilapia are so phylogenetically primitive that their cells do not express alpha(1,3)Gal and, because tilapia are highly evolved to live in warm stagnant waters nearly devoid of dissolved oxygen, their islet cells are exceedingly resistant to hypoxia, making them ideal for transplantation within encapsulation devices. Encapsulation, especially when combined with co-stimulatory blockade, markedly prolongs tilapia islet xenograft survival in small animal recipients, and a collaborator has shown function in diabetic cynomolgus monkeys. In anticipation of preclinical xenotransplantation studies, we have extensively characterized tilapia islets (morphology, embryologic development, cell biology, peptides, etc.) and their regulation of glucose homeostasis. Because tilapia insulin differs structurally from human insulin by 17 amino acids, we have produced transgenic tilapia whose islets stably express physiological levels of humanized insulin and have now bred these to homozygosity. These transgenic fish can serve as a platform for further development into a cell therapy product for diabetes. PMID- 25040339 TI - Blood concentrations of D- and L-lactate in healthy rabbits. AB - OBJECTIVES: To determine whole blood and serum concentrations of l-lactate and serum concentrations of d-lactate in healthy rabbits and compare three methods of analysis for l-lactate measurement. METHODS: Prospective study using 25 rabbits. Concentrations of whole blood l-lactate were measured using a portable analyser and a blood gas analyser. The remainder of the sample was allowed to clot for centrifugation. Serum was stored at -20 degrees C for determination of l- and d- lactate by high-performance liquid chromatography. RESULTS: d-lactate values by high-performance liquid chromatography were 0 . 17 +/- 0 . 08 mmol/L. l-lactate values were 5 . 1 (+/-2 . 1) mmol/L by high-performance liquid chromatography, 6 . 9 (+/-2 . 7) mmol/L with the portable analyser and 7 . 1 (+/-1 . 6) mmol/L with the blood gas analyser. No significant difference (P > 0 . 05) was found between the two analysers. Significant difference existed between serum l-lactate values obtained by high-performance liquid chromatography and the whole blood values obtained with the blood gas analyser (P < 0 . 01) and portable analyser (P < 0 . 05). CLINICAL SIGNIFICANCE: Serum concentrations of d-lactate in healthy rabbits are in the range of those of other mammals. l-lactate values in healthy rabbits are higher compared with other mammals. Good correlation was found between the portable and blood gas analysers for whole blood l-lactate measurement in healthy rabbits. PMID- 25040340 TI - Endotoxemia in end-stage kidney disease. AB - Chronic unexplained inflammation remains a prevalent and clinically significant problem for patients with end-stage kidney disease (ESKD), especially in the dialysis population. The causes of persistent inflammation are likely to be multifactorial, but the underlying mechanisms remain to be elucidated. Endotoxins are reported to play a significant role in the pathogenesis of inflammation in patients with ESKD. However, blood endotoxin measurement with the Limulus amoebocyte lysate (LAL) assay is difficult with current detection systems. The reported degree and prevalence of endotoxemia varies in the literature. There are questions as to whether endotoxemia is truly present; whether the varied findings are due to methodological issues with the LAL assay and whether any endotoxemia that might be present plays a role in chronic inflammation frequently observed in ESKD patients. This review will discuss the challenges of accurate blood endotoxin detection, the potential source of blood endotoxins, and the significance of endotoxemia to patient with ESKD. PMID- 25040342 TI - Changing face and clinical features of celiac disease in children. AB - BACKGROUND: The aim of this study was to analyze and compare the epidemiological and presenting features, clinical patterns, and complications of celiac disease (CD) in children. METHODS: The clinical charts of children with CD were retrospectively analyzed. Data for children who presented during the first time period (January 2005-October 2008; group 1) were compared to those of children who presented during the second time period (November 2008-April 2012; group 2). RESULTS: Group 1 and 2 consisted of 96 and 95 children, respectively. There were no differences in gender distribution, weight, or height z-scores between the two groups. Mean age at the time of diagnosis in group 2 (9.3 +/- 4.5 years) was significantly higher than in group 1 (6.9 +/- 3.9 years; P < 0.001). Non classical presentation was more frequent in group 2 (P = 0.01). Associated disorders were observed in 49 children (25.7%) overall. There were significantly more children with type 1 diabetes mellitus in group 2 (P = 0.030). In all, 11 patients (5.8%) were overweight (either obese or at risk of obesity) at presentation. Isolated short stature was the presenting feature in 15 children (7.9%) overall, but was more frequently observed in group 2 (P = 0.003). In total, 15 patients (7.9%) presented with refractory iron deficiency anemia; the frequency was similar in both groups. Dual-energy X-ray absorptiometry was performed in 102 patients, and 82 (80.4%) had metabolic bone disease (MBD). CONCLUSION: The mode of presentation and clinical features of CD in childhood continue to change. Of note, a substantial percentage of patients were overweight at presentation. MBD is a frequent complication, necessitating routine evaluation. PMID- 25040343 TI - New wind in the sails: improving the agronomic value of crop plants through RNAi mediated gene silencing. AB - RNA interference (RNAi) has emerged as a powerful genetic tool for scientific research over the past several years. It has been utilized not only in fundamental research for the assessment of gene function, but also in various fields of applied research, such as human and veterinary medicine and agriculture. In plants, RNAi strategies have the potential to allow manipulation of various aspects of food quality and nutritional content. In addition, the demonstration that agricultural pests, such as insects and nematodes, can be killed by exogenously supplied RNAi targeting their essential genes has raised the possibility that plant predation can be controlled by lethal RNAi signals generated in planta. Indeed, recent evidence argues that this strategy, called host-induced gene silencing (HIGS), is effective against sucking insects and nematodes; it also has been shown to compromise the growth and development of pathogenic fungi, as well as bacteria and viruses, on their plant hosts. Here, we review recent studies that reveal the enormous potential RNAi strategies hold not only for improving the nutritive value and safety of the food supply, but also for providing an environmentally friendly mechanism for plant protection. PMID- 25040344 TI - Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance. AB - Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory. PMID- 25040346 TI - Microchimerism in the transfused obstetric population. AB - Microchimerism (MC), the coexistence of allogeneic populations of cells within a host, is well described in pregnancy and blood transfusion. To date, transfusion associated MC (TA-MC) appears unique to patients transfused after severe traumatic injury. We sought to determine whether transfusion in the peripartum period results in enduring, high-level TA-MC. We conducted a prospective cohort study of 22 women who were newly transfused within 48 h of delivery. Two subjects showed evidence of transient TA-MC; however, MC was not detected at 6 weeks and 6 months. The negative findings suggest that enduring TA-MC does not occur in this population. PMID- 25040347 TI - Colour difference of subcutaneous fat and palmar fat pad in open carpal tunnel release. AB - BACKGROUND: Carpal tunnel syndrome is the most common compression neuropathy of the extremity. The most frequent occurring post-operative complication of open carpal tunnel release is the incomplete release of the transverse carpal ligament. A constant pad of palmar fat pad has been found to provide a reliable indicator of the distal extent of the surgical decompression of the transverse carpal ligament. We investigated the colour difference between subcutaneous fat and palmar fat pad. METHODS: This is a prospective case series of 15 patients undergoing open carpal tunnel release. Digital images of the patients' subcutaneous and palmar fat were taken. The colour of each type of fat was described in a device independent, objective manner using the CIELab colour space. The colour difference was measured using DeltaE, the Euclidean distance between the CIELab coordinates of the colours. Wilcoxon signed-rank test was used to compare colour character differences between subcutaneous and palmar fat. The colour difference, DeltaE, was assessed and reported with 95% confidence intervals (CI). RESULTS: There is a visually detectable colour difference between subcutaneous and palmar fat. The minimum DeltaE was 4.45. The mean DeltaE was 13.03 (95% CI 9.79-16.27). The palmar fat pad is more yellow than the subcutaneous fat (P = 0.002). CONCLUSIONS: Our findings can assist in the identification of the palmar fat pad to ensure safer and a complete release of the transverse carpal ligament in carpal tunnel release. PMID- 25040348 TI - The multifaceted roles of the interspecies signalling molecule indole in Agrobacterium tumefaciens. AB - Bacteria utilize signal molecules to ensure their survival in environmental niches, and indole is an interspecies and interkingdom signalling molecule, which is widespread in the natural environment. In this study, we sought to identify novel roles of indole in soil-borne bacterium Agrobacterium tumefaciens. Agrobacterium tumefaciens was found not to synthesize indole and to degrade it rapidly. The addition of exogenous indole dose-dependently inhibited A. tumefaciens growth and decreased its motility. Surprisingly, indole markedly increased A. tumefaciens biofilm formation on polystyrene, glass and nylon membrane surfaces and enhanced its antibiotic tolerance. Transcriptional analysis showed that indole markedly up-regulated several biofilm-related (celA, cheA, exoR, phoB, flgE, fliR and motA), stress-related genes (clpB, dnaK, gsp, gyrB, marR and soxR) and efflux genes (emrA, norM, and Atu2551) in A. tumefaciens, which partially explained the increased biofilm formation and antibiotic tolerance. In contrast, the plant auxin indole-3-acetic acid did not affect biofilm formation, antibiotic tolerance or gene expression. Interestingly, indole was found to exhibit several similarities with antibiotics, as it inhibited the growth of non-indole-producing bacteria, whereas these bacteria countered its effects by rapidly degrading indole, and by enhancing biofilm formation and antibiotic tolerance. PMID- 25040349 TI - Improving women's health locally and globally. PMID- 25040350 TI - The regulatory network mediated by circadian clock genes is related to heterosis in rice. AB - Exploitation of heterosis in rice (Oryza sativa L.) has contributed greatly to global food security. In this study, we generated three sets of reciprocal F1 hybrids of indica and japonica subspecies to evaluate the relationship between yield heterosis and the circadian clock. There were no differences in trait performance or heterosis between the reciprocal hybrids, indicating no maternal effects on heterosis. The indica-indica and indica-japonica reciprocal F1 hybrids exhibited pronounced heterosis for chlorophyll and starch content in leaves and for grain yield/biomass. In contrast, the japonica-japonica F1 hybrids showed low heterosis. The three circadian clock genes investigated expressed in an above high-parent pattern (AHP) at seedling stage in all the hybrids. The five genes downstream of the circadian clock, and involved in chlorophyll and starch metabolic pathways, were expressed in AHP in hybrids with strong better-parent heterosis (BPH). Similarly, three of these five genes in the japonica-japonica F1 hybrids showing low BPH were expressed in positive overdominance, but the other two genes were expressed in additive or negative overdominance. These results indicated that the expression patterns of circadian clock genes and their downstream genes are associated with heterosis, which suggests that the circadian rhythm pathway may be related to heterosis in rice. PMID- 25040351 TI - A novel HLA-C allele, C*08:01:10 was identified in a Chinese leukemia patient. AB - HLA-C*08:01:10 differs from HLA-C*08:01:01 by a single non-coding change at nucleotide 339 G>A. PMID- 25040352 TI - Fluctuations of the anthropometric indices and mortality of patients with incident heart failure: a prospective study in the community. AB - BACKGROUND: The relationship between the fluctuations of the anthropometric indices (AIs) and the prognosis of patients with incident heart failure (HF) in a population-based cohort is unknown. AIMS: To assess the relationship between the fluctuations of the AIs, body mass index (BMI), waist hip ratio (WHR), and weight height ratio (WHeR) and the prognosis of patients with incident HF. METHODS: Anthropometric indices were prospectively measured in a 10-year population-based study of 6492 patients with incident HF (GAMIC cohort). 4530 patients (66.7%) died, during a mean follow-up of 72.7 +/- 14.2 months. A time-updated analysis of the changes of the AIs was performed to assess their association with mortality and morbidity (hospitalisations and visits). RESULTS: Patients with incident HF presenting >= 5% decrease or >= 7% increase of the AIs have an increased mortality [HR >= 1.65 (1.52-2.34) or HR >= 1.71 (1.58-1.85), respectively, p < 0.001]. Mortality risk increased >= 1.43-fold (p = -0.0003) for each 10% change in the AIs. There was an accelerated pattern of reduction in the AIs in the 6 months prior to death, and an accelerated increase in the AIs in the 3 months prior to hospitalisation. These observations were independent of the aetiology (ischaemic vs. non-ischaemic), the type of HF (systolic vs. non-systolic), and other predictors of mortality. CONCLUSIONS: Time-updated changes (increase or decrease) of the AIs, BMI, WHR and weight height ratio are independently associated with the mortality of patients with incident HF. PMID- 25040353 TI - Prognostic value of a qualitative brain MRI scoring system after cardiac arrest. AB - BACKGROUND AND PURPOSE: To develop a qualitative brain magnetic resonance imaging (MRI) scoring system for comatose cardiac arrest patients that can be used in clinical practice. METHODS: Consecutive comatose postcardiac arrest patients were prospectively enrolled. Routine MR brain sequences were scored by two independent blinded experts. Predefined brain regions were qualitatively scored on the fluid attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences according to the severity of the abnormality on a scale from 0 to 4. The mean score of the raters was used. Poor outcome was defined as death or vegetative state at 6 months. RESULTS: Sixty-eight patients with 88 brain MRI scans were included. Median time from the arrest to the initial MRI was 77 hours (IQR 58-144 hours). At 100% specificity, the "cortex score" performed best in predicting unfavorable outcome with a sensitivity of 55%-60% (95% CI 41-74) depending on time window selection. When comparing the "cortex score" with historically used predictors for poor outcome, MRI improved the sensitivity for poor outcome over conventional predictors by 27% at 100% specificity. CONCLUSIONS: A qualitative MRI scoring system helps assess hypoxic-ischemic brain injury severity following cardiac arrest and may provide useful prognostic information in comatose cardiac arrest patients. PMID- 25040354 TI - Early, delayed, or late single implant placement: 10-year results from a randomized controlled clinical trial. AB - AIM: The aim of this study was to present the 10-year clinical and radiographic data from a RCT on single-tooth implants placed early, delayed, or late after tooth extraction. MATERIALS AND METHODS: Sixty-three patients were randomly allocated to three groups and received an implant on average 10 days (Ea), 3 months (De), or 17 months (La) after tooth extraction. Second-stage surgery was performed after 3 months of submerged healing; metal-ceramic crowns were cemented after one additional month. Standardized periapical radiographs were taken 1 week after implant placement (TP), 1 week (TC) and 1-1.5 year (T1) after crown delivery, and 10 years after implant placement (T10). Pocket depth (PD) and bleeding on probing were registered during controls (TC - T10). RESULTS: Two Ea and one De implants failed to osseointegrate. Seven patients (4 Ea, 1 De, and 2 La) were not available at T10 . No significant differences were found among groups regarding implant survival or radiographic peri-implant marginal bone levels (Ea: 1.15 +/- 0.77; De: 1.53 +/- 1.06; La: 1.42 +/- 1.07) at T10 . Similarly, no differences were observed among groups in the number of implants with PD >= 5 mm (Ea: 29%; De: 35%; La: 44%) or the average depth of the sites with PD >= 5 mm (Ea: 5.4 +/- 0.7; De: 6.1 +/- 1.4; La: 5.4 +/- 0.5) at T10 . Peri implant mucositis was found in 70% of the cases; peri-implantitis was diagnosed only in two implants (1 De, 1 La) corresponding to 4.3%. CONCLUSION: Single-tooth implants placed early or delayed after tooth extraction show high survival rates and limited peri-implant marginal bone resorption or biological complications, similar to what is observed with implants placed according to the conventional (late) protocol. PMID- 25040355 TI - Dental use and expenditures for older uninsured Americans: the simulated impact of expanded coverage. AB - OBJECTIVE: To determine if providing dental insurance to older Americans would close the current gaps in dental use and expenditure between insured and uninsured older Americans. DATA SOURCES/STUDY SETTING: We used data from the 2008 Health and Retirement Survey (HRS) supplemented by data from the 2006 Medical Expenditure Panel Survey (MEPS). STUDY DESIGN: We compared the simulated dental use and expenditures rates of newly insured persons against the corresponding rates for those previously insured. DATA COLLECTION/EXTRACTION METHODS: The HRS is a nationally representative survey administered by the Institute for Social Research (ISR). The MEPS is a nationally representative household survey sponsored by the Agency for Healthcare Research and Quality (AHRQ). PRINCIPAL FINDINGS: We found that expanding dental coverage to older uninsured Americans would close previous gaps in dental use and expense between uninsured and insured noninstitutionalized Americans 55 years and older. CONCLUSIONS: Providing dental coverage to previously uninsured older adults would produce estimated monthly costs net of markups for administrative costs that comport closely to current market rates. Estimates also suggest that the total cost of providing dental coverage targeted specifically to nonusers of dental care may be less than similar costs for prior users. PMID- 25040356 TI - Limitations of the use of environmental tracers to infer groundwater age. AB - Apparent ages obtained from the measured concentrations of environmental tracers have the potential to inform recharge rates, flow rates, and assist in the calibration of groundwater models. A number of studies have investigated sources of error in the relationships between the apparent ages, and the age assumed by models to relate this quantity to an aquifer property (e.g., recharge). These studies have also provided a number of techniques for correcting the known biases of apparent ages. In this paper, we review some of the concepts of age bias. We then demonstrate this bias through the use on four numerical examples, and assess the accuracy of correction methods in overcoming this bias. We examine this for CFCs, SF6, 3H/3He, 39Ar, and 14C. We demonstrate that in our four simple steady state aquifer examples, bias occurs for a wide range of environmental tracers and flow configurations. When applying correction methods, we found that the values obtained are limited by the model assumptions. Models accounting for exchange with aquitards represent whole mobile zones and not discrete well screens. Mean transit times (comparable to mean ages) obtained from lumped parameter models deviate from actual values as the assumed distribution varies from the actual distribution. Methods that use multiple tracer ages are limited to ranges where both tracers report apparent ages. Our findings suggest that the incorporation of environmental tracer data into the understanding of groundwater systems requires approaches such as the direct use of concentrations, or the simulation of full age distributions. PMID- 25040357 TI - A case of invasive pulmonary infection caused by novel species of Perenniporia. AB - Perenniporia species, members of basidiomycetes, are known as decay fungi from wood of hardwood tree species. The clinical significance of these non-sporulating fungi from respiratory tract specimens is unknown. They have frequently been discarded as contaminants. There was only one case report of pulmonary fungal ball with positive culture for a Perenniporia species. We report herein a case of invasive pulmonary infection caused by the novel species of Perenniporia in a 44 year-old woman with active systemic lupus erythematosus who was successfully treated with voriconazole. PMID- 25040359 TI - High expression of the histone demethylase LSD1 associates with cancer cell proliferation and unfavorable prognosis in tongue cancer. AB - BACKGROUND: The histone lysine-specific demethylase (LSD1) is a key chromatin modifier mediating the demethylation of both H3K4me1/me2 and H3K9 me1/me2. Recently, its deregulation has been implicated in the initiation and progression of various cancers. The aim of this study was to investigate the expression pattern of LSD1 in tongue squamous cell carcinoma (SCC) and determine its prognostic significance in predicting patients' prognosis. METHODS: LSD1 expression was examined by RT-PCR and western blotting in three tongue cancer cell lines and by immunohistochemistry in 63 primary tongue SCC specimens with detailed clinical, pathological, and follow-up data. Its associations with various clinicopathological parameters, Ki-67 expression, and patients' survival were further assessed. RESULTS: Upregulated LSD1 expression was observed in tongue cancer cells and a major fraction of tongue SCC samples. Overexpression of LSD1 significantly associated with tumor size (P = 0.0357), pathological grade (P = 0.0323), Ki-67 abundance (P = 0.0148), and reduced overall and disease-free survival (Kaplan-Meier analysis, P = 0.0351, 0.0479, respectively). The Cox regression survival analyses identified LSD1 as an important independent predictor for patients' overall survival. CONCLUSION: Our data indicate that aberrant LSD1 overexpression associates with key clinicopathological features and unfavorable prognosis in patients with tongue cancer. LSD1 might play critical roles during tongue tumorigenesis and represent a novel biomarker and potential therapeutic target for this malignancy. PMID- 25040358 TI - Neuroanatomical distribution of mechanoreceptors in the human cadaveric shoulder capsule and labrum. AB - The distribution, location, and spatial arrangement of mechanoreceptors are important for neural signal conciseness and accuracy in proprioceptive information required to maintain functional joint stability. The glenohumeral joint capsule and labrum are mechanoreceptor-containing tissues for which the distribution of mechanoreceptors has not been determined despite the importance of these tissues in stabilizing the shoulder. More recently, it has been shown that damage to articular mechanoreceptors can result in proprioceptive deficits that may lead to recurrent instability. Awareness of mechanoreceptor distribution in the glenohumeral joint capsule and labrum may allow preservation of the mechanoreceptors during surgical treatment for shoulder instability, and in turn retain the joint's proprioceptive integrity. For this reason, we sought to develop a neuroanatomical map of the mechanoreceptors within the capsule and labrum. We postulated that the mechanoreceptors in these tissues are distributed in a unique pattern, with mechanoreceptor-scarce regions that may be more appropriate for surgical dissection. We determined the neuroanatomical distribution of mechanoreceptors and their associated fascicles in the capsule and labrum from eight human cadaver shoulder pairs using our improved gold chloride staining technique and light microscopy. A distribution pattern was consistently observed in the capsule and labrum from which we derived a neuroanatomical map. Both tissues demonstrated mechanoreceptor-dense and -scarce regions that may be considered during surgical treatment for instability. Capsular fascicles were located in the subsynovial layer, whereas labral fascicles were concentrated in the peri-core zone. The capsular fascicles presented as a lattice network and with a plexiform appearance. Fascicles within the labrum resembled a cable structure with the fascicles running in parallel. Our findings contribute to the neuroanatomical knowledge of the two glenohumeral joint stabilizers, namely, capsule and labrum, primarily involved in the onset of shoulder instability and recurrent instability. Neuroanatomical knowledge of articular mechanoreceptors is important for (i) developing a topographical map that reflects correspondence between the joint and surrounding musculature, (ii) understanding proprioceptive deficits that are only partially restored post surgical and post rehabilitative treatment, and (iii) gaining further knowledge about articular mechanoreceptors. PMID- 25040360 TI - Measurement of salivary adiponectin concentrations in dogs. AB - BACKGROUND: Measurement of salivary adiponectin could improve understanding of this adipokine's physiology, and its role in various clinical conditions. OBJECTIVES: The purpose of the study was to evaluate the utility of a human adiponectin ELISA kit for measurement of salivary adiponectin in dogs, to compare serum and salivary adiponectin concentrations in a healthy dog population, and to evaluate possible effects of tooth-cleaning on serum and salivary adiponectin concentrations in dogs. METHODS: For analytical validation, precision, accuracy, and lower limit of quantification of the assay were determined with saliva samples. In addition, adiponectin concentrations were quantified in serum and saliva samples from 24 healthy dogs, and from 7 dogs with mild gingivitis before and after a tooth-cleaning procedure. RESULTS: The validation assays for salivary adiponectin had all coefficients of variation <15%, and recovery ranged from 85% to 120%. In the linearity test, interference was observed when measuring adiponectin in saliva, but this was solved by diluting samples 1:4. In healthy dogs, salivary and serum adiponectin concentrations were positively correlated (r = .650; P = .009). After the tooth-cleaning procedure, salivary adiponectin concentration increased on day 0 (P = .004), but by day 14, concentrations were less than prior to the procedure (P = .041). CONCLUSIONS: The human adiponectin ELISA kit can be used for precise and accurate salivary adiponectin measurement in dogs. Salivary adiponectin increased 24 hours after tooth-cleaning, possibly due to acute inflammation or adiponectin leakage from the blood after gingival trauma. PMID- 25040361 TI - Improving medication management competency of clinical trainees in geriatrics. AB - The authors hypothesized that an interprofessional workshop would improve geriatrics trainees' medication management. The workshop was based on a needs assessment and comprised an interactive session with pharmacists on managing medications in elderly adults. Participants were trainees in their geriatrics rotation at a tertiary care medical center. Trainees completed a medication appropriateness survey for three patients, one of which was their own. After the workshop, trainees reviewed medications of the three patients. Trainees completed online surveys after their rotation and 3 months later. Of 95 trainees rotating through geriatrics, 76 (80%) attended the workshop and completed the worksheet. Trainees' scores on reviewing medication lists improved significantly, from 6.7+/ 2.3 to 7.7+/-2.0 out of 11 for standardized patient 1 (P<.001) and from 5.7+/-1.8 to 6.4+/-1.5 out of 11 for standardized patient 2 (P=.009). Trainees' scores on their own patients' lists also improved significantly, from 5.6+/-1.5 to 6.6+/ 1.5 out of 10 (P<.001). After the workshop, 95% (71/75) planned to change the medication regimen of the patient they presented, and 93% (68/73) planned to change other patients' medications based on information learned during the workshop. Three months later, 35% (12/34) had made changes to the regimen of the patient they discussed during the workshop, and 71% (15/21) had made changes to other patients' regimens. Seventy-eight percent (18/23) rated the workshop as the top nonclinical experience of their geriatrics rotation. In conclusion, this interprofessional medication management workshop improved trainees' ability to perform medication reviews accurately and led to change in self-reported prescribing behavior. PMID- 25040362 TI - Citrulline concentration in routinely collected neonatal dried blood spots cannot be used to predict necrotising enterocolitis. AB - AIM: Low citrulline concentration is a marker of low functional enterocyte mass, which may predispose neonates to necrotising enterocolitis (NEC). We hypothesised that citrulline could be used to assess the NEC risk that could not be accounted for by gestational age and birthweight. This study investigated whether citrulline concentrations routinely measured in neonatal dried blood spots (DBS) could predict NEC. METHODS: We used national Danish registries to retrospectively identify all 361 babies born between 2003 and 2009 who were diagnosed with NEC and had a valid citrulline concentration measured from a DBS sample. The control group comprised 1083 healthy newborns, with three controls for every newborn with NEC, matched for birthweight and gestational age. RESULTS: Neonatal dried blood spots were collected between 2 and 21 days of life, with a median of 8 days. The results showed that NEC was not associated with low citrulline concentration, either in a direct comparison between the NEC and control groups or in a multivariate logistic regression (p = 0.73). CONCLUSION: The findings of this study show that the citrulline concentrations found in routine DBS samples between 2003 and 2009 did not predict NEC in newborn babies. PMID- 25040363 TI - Perceived therapist genuineness predicts therapeutic alliance in cognitive behavioural therapy for psychosis. AB - OBJECTIVES: The quality of therapeutic alliance is a consistent and stable predictor of therapy outcome. Recent studies have shown therapist characteristics to be relevant predictors of the alliance in psychological therapies in general. However, little is known about the specific therapist characteristics that explain differences in therapeutic alliance in cognitive behavioural therapy for psychosis (CBTp). The aim of this study was to identify relevant therapist characteristics that predict early therapeutic alliance in CBTp. DESIGN AND METHODS: Forty-eight patients with a DSM-IV diagnosis of a psychotic disorder participating in a CBTp trial and 11 therapists were included in the analysis. Therapist characteristics as perceived by the patients (empathy, genuineness, positive regard, competence, and convincingness) were assessed at baseline. Alliance was assessed after the fifth therapy session. Data were analyzed using bivariate correlations and multivariate hierarchic regression analysis. RESULTS: All therapist characteristics were positively associated with patient-rated alliance. Patient characteristics were not significantly associated with alliance and did not predict alliance in the multivariate analysis. Regression analysis revealed therapist genuineness and competence to significantly predict higher patient-rated alliance. CONCLUSIONS: Our results suggest that perceived therapist genuineness is the most relevant predictor of patient-rated therapeutic alliance in CBTp. Future trials using control samples with other mental disorders could clarify whether this finding is specific to CBTp. Therapist training concepts for increasing beneficial therapist qualities are needed. PRACTITIONER POINTS: The patients' perception of the therapist as empathic, genuine, accepting, competent and convincing is associated with therapeutic alliance in CBTp. Perceived therapist genuineness and competence are the most relevant predictors of patient rated therapeutic alliance. Training and supervision should focus on increasing basic therapist qualities. Limitations of this study include homogeneity of therapists, small sample size, and lack of a control group. PMID- 25040364 TI - Working with older people with multiple long-term conditions: a qualitative exploration of nurses' experiences. AB - AIMS: (1) to generate in-depth insights into how nurses are working with older people with multiple long term conditions; (2) to gain an understanding of how nurses perceive professional patient navigation; and (3) to explore the barriers and facilitators to nurses adopting a navigation role in the context of Primary Health Care practice. BACKGROUND: Internationally, Primary Health Care has been identified as the main navigation point for older people with multiple long term conditions. Navigation models have been developed in cancer care but there is a lack of research in the context of Primary Care. There is also little evidence about the extent to which current work patterns of nurses providing care for this patient group fit with professional patient navigation models. DESIGN: A descriptive exploratory qualitative study. METHODS: Semi-structured audio recorded telephone interviews were conducted in 2012 with nurses in New Zealand who were working with older people with multiple long term conditions (n = 42) Interviews were transcribed verbatim and entered into Nvivo 9 for thematic analysis. FINDINGS: The key themes represent patterns of nursing work as; system work, relationship work and patient work. While nurses lacked a coherent understanding of patient navigation as a concept, the way they worked had some elements in common with professional navigation models. CONCLUSION: Further research involving older people in co-designing patient navigation approaches in Primary Health Care is needed to inform these types of service development and translate action from existing health policy. PMID- 25040365 TI - Characterization of Stenotrophomonas acidaminiphila NCW-702 biofilm for implication in the degradation of polycyclic aromatic hydrocarbons. AB - AIMS: Biofilm formation and polycyclic aromatic hydrocarbons (PAHs) degradation by a marine bacterium Stenotrophomonas acidaminihila NCW-702 was investigated. METHODS AND RESULTS: The biofilm structure was studied by confocal laser scanning microscopy (CLSM). Both planktonic and biofilm cultures were used for PAHs (phenanthrene and pyrene) degradation. In 7 days, Sten. acidaminiphila biofilm culture efficiently degraded 71.1 +/- 3.1% and 40.2 +/- 2.4% of phenanthrene and pyrene, respectively, whereas 38.7 +/- 2.5% of phenanthrene and 29.7 +/- 1% of pyrene degradation was observed in planktonic culture. The presence of phenolic intermediates in the culture supernatant during degradation process was evaluated by Folin-Ciocalteu reagent. The average thickness and diffusion distance of Sten. acidaminiphila NCW-702 biofilm was found to be 23.94 +/- 2.62 MUm and 2.68 +/- 0.7 MUm, respectively. Bacterial biofilms have numerous metabolic features that aid in the degradation of hydrophobic organic pollutants. CONCLUSIONS: Biofilm of Sten. acidaminiphila NCW-702 was able to degrade PAHs more efficiently as compared to planktonic cells. The findings support the efficacy of biofilms over planktonic culture in bioremediation applications. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides a constructive application of bacterial biofilms for the bioremediation of hydrophobic organic contaminants. The biofilm mode remediation process has the advantage of reusability of bacterial biomass and is also a low cost process as compared to cell immobilization techniques. PMID- 25040366 TI - Borrowed philosophy: bedside physicalism and the need for a sui generis metaphysic of medicine. AB - The character of medicine has changed over the last 100 years such that medicine is more interested in diseases than the people who suffer from them. Despite notable efforts to address this, the medical humanities do not challenge doctors' fundamental view of the world. Students adopt a metaphysic of physicalism during basic science training that gets carried into medical training. While necessary for medical science, physicalism is insufficient for clinical care. Physicalism offers no foundation for the sine qua non of medicine, the doctor-patient relationship. The character of medicine will not see a renewed interest in humanity until educators address the insufficiency of physicalism for clinical care, and clinicians partner with experts in the humanities to build a sui generis philosophy of medicine. PMID- 25040367 TI - Retraction. Immunological properties reveal the monovalent and bivalent recombinant dengue virus-like particles as candidate vaccine for dengue. PMID- 25040368 TI - MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Sorafenib is the standard of care in advanced hepatocellular carcinoma (HCC), however no criteria have been established to select patients likely to benefit from this therapy. In this study, we evaluated the predictive role of microRNAs (miRNAs) in this setting of patients. METHODS: We profiled 522 miRNA in a series of 26 HCC patients treated with sorafenib (training set) and validated the results in an independent series of 58 patients (validation set). Formalin-fixed paraffin-embedded tumour and cirrhotic liver biopsies were used for RNA extraction and miRNAs profiling with TaqMan Arrays technology. Statistical analyses were used to correlate miRNA levels with clinical outcome, including time to progression (TTP), progression free (PFS), and overall survival. Cell viability and cell motility of HuH-7 or HepG2 HCC cells were tested in vitro after transfection with specific miRNA precursor, inhibitor or controls and sorafenib treatment. RESULTS: Six miRNAs were significantly associated with clinical variables in the training set and only miR-425-3p could be further validated. Higher levels of miR-425-3p were associated with longer TTP and PFS (P = 0.0008; HR = 0.4; 95% CI = 0.2-0.7 and P = 0.007; HR = 0.5; 95% CI = 0.3-0.9 respectively). Multivariate analysis confirmed the predictive significance of miR-425-3p. Furthermore, an association between increased miR-425 3p, cell death and reduced cell motility was defined in vitro in HCC cell lines treated with sorafenib. CONCLUSIONS: Assessment of miR-425-3p levels in liver biopsies could help in stratifying patients with advanced HCC for sorafenib treatment. These promising results need to be confirmed in a large prospective study. PMID- 25040369 TI - Polycystic ovary syndrome and anti-Mullerian hormone: role of insulin resistance, androgens, obesity and gonadotrophins. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder associated with insulin resistance, hyperandrogenism, obesity, altered gonadotrophin release and anovulatory infertility. Anti-Mullerian hormone (AMH) has been proposed as a marker of ovarian function and fertility. Across a cohort of lean and overweight women with and without PCOS, we investigated the association of AMH with insulin resistance and body composition using gold standard measures. A secondary aim was to examine whether AMH was useful to determine PCOS status. DESIGN: Cross-sectional study. PATIENTS: A total of 22 lean and 21 overweight women with PCOS and 19 lean and 16 overweight non-PCOS healthy controls were recruited. PCOS was diagnosed based on the Rotterdam criteria. MEASUREMENTS: Euglycaemic-hyperinsulinaemic clamp for assessing insulin resistance, dual energy X-ray absorptiometry and computed tomography for assessing adiposity, and blood sampling for the assessment of androgens, gonadotrophins and AMH. RESULTS: Anti-Mullerian hormone levels were increased in women with PCOS (P <0.001) regardless of adiposity, with this increase associated with testosterone (P <0.001) rather than insulin resistance (P = 0.79), adiposity (P = 0.98) or gonadotrophins. In assessing the ability of AMH to predict PCOS, a value of 30 pmol/l or higher indicated 79% of women with PCOS were correctly identified as having the condition. CONCLUSION: Anti-Mullerian hormone appears primarily related to androgen status suggesting a direct and predominant role of androgens in the pathophysiology of reproductive dysfunction in PCOS. As AMH reflects PCOS status, it may also be useful in PCOS diagnosis. PMID- 25040371 TI - Measures of test performance for high-risk HPV tests and triage cytology and the importance of follow-up of women with positive test results. PMID- 25040372 TI - Sensitivity of cytology and HPV testing. PMID- 25040373 TI - Introduction: Brain science in the 21st century: clinical controversies and ethical and legal implications. PMID- 25040374 TI - Causes and consequences of sports concussion. AB - Concussion in sports is a topic that is receiving increasing amounts of publicity and attention. Increasing recognition of concussion as well as improving understanding of the short- and long-term physiologic effects of concussion have resulted in widespread legislation governing the recognition and treatment of sports concussion. The increasing amount of medical research in the field and oftentimes subjective symptoms of concussion leave many ethical questions to be answered. PMID- 25040375 TI - Concussion in the National Football League: viewpoint of an elite player. AB - Chronic traumatic encephalopathy resulting from head hits and concussions is an unfortunate illness that has affected numerous football players, especially in the National Football League. Many of my fellow players suffer from this problem, and many have died prematurely because of it. I make some suggestions for improving the situation for retired and current players. PMID- 25040376 TI - Prevention of stroke in sickle cell anemia. AB - The risk of stroke for a child with SCD is many times greater than that of a healthy child without SCD or heart disease. There is a technique that allows the identification of the children with SCD who have high risk even within this relatively high-risk group. And there is a highly effective preventive treatment. While this would on the surface appear to be a straightforward medical decision, it is not. One must weigh the benefits of preventing permanent brain damage against the risks of infection from transfused blood, iron overload, which is the result of the frequent transfusions, and rare transfusion reactions. PMID- 25040377 TI - Treating pain in sickle cell disease with opioids: clinical advances, ethical pitfalls. AB - This article explores the ethical principles of prescribing in Sickle Cell Disease. The first two sections of the article provide detailed scientific justification for the last section of the manuscript, which explores and discusses the ethical principles. PMID- 25040378 TI - Post-traumatic stress disorder: ethical and legal relevance to the criminal justice system. AB - Post-Traumatic Stress Disorder is a major public health concern in both civilian and military populations, across race, age, gender, and socio-economic status. While PTSD has been around for centuries by some name or another, its definition and description also continue to evolve. Within the last few years, the American Psychological Association has published the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, which includes some major changes in the diagnostic criteria for PTSD. Recent data on epidemiology, etiological theories, and empirically supported methods of treatment, as well as implications for legal processes and criminal justice system personnel, are discussed. PMID- 25040379 TI - The role of PTSD in adjudicating violent crimes. AB - PTSD was formalized as a diagnosis by the American Psychiatric Association in 1980 with the publication of the Diagnostic and Statistical Manual of Mental Disorders (DSM), 3rd edition. Since that time, the diagnosis has been widely utilized in the courts including the use in criminal proceedings. PTSD may play a role in the assessment of violent crimes both as a possible contributing factor in the perpetrators as well as a consequence in the victims. There are a number of ethical and clinical considerations in the use of this diagnosis. Importantly, the diagnostic criteria have changed to a degree with subsequent editions of the DSM. This may have an impact on the interpretation of past legal judgments. Moreover, extensive psychiatric comorbidity may complicate the clinical picture, e.g., mood disorders, substance use disorders, or psychosis. The diagnosis of PTSD is still based on clinical, largely subjective criteria, e.g., biological markers are not yet utilized. As such, there may not be consistent agreement about the diagnosis among experts. This paper summarizes some of these relevant issues in adjudicating violent crimes. PMID- 25040380 TI - PTSD in active combat soldiers: to treat or not to treat. AB - In this paper, we consider ethical issues related to the treatment of posttraumatic stress disorder (PTSD) in combat zones, via exposure therapy. Exposure-oriented interventions are the most well-researched behavioral treatments for PTSD, and rigorous studies across contexts, populations, and research groups provide robust evidence that exposure therapy for PTSD is effective and can be widely disseminated. Clinical procedures for Prolonged Exposure therapy, a manualized exposure-oriented protocol for PTSD, are reviewed, and we illustrate the potential benefits, as well as the potential difficulties, associated with providing this treatment in combat zones. Several ethical considerations are identified: (1) Assuming successful treatment, is it ethical to send individuals with a known risk of developing PTSD back into combat? (2) If treatment is unsuccessful in theater (perhaps due to the confounding factor of ongoing danger), could that impact treatment effectiveness for soldiers who attempt therapy again post-deployment? (3) If the military finds combat-zone treatment effective and useful in maintaining an efficient work force, will treatment become mandatory for those diagnosed with PTSD? (4) What unintended consequences might be associated with large-scale dissemination of exposure therapy in or near combat, outside of mental health care infrastructures? (5) How would genetic variations known to be associated with PTSD risk influence decisions regarding who receives treatment or returns to combat? We conclude with a review of the personal and societal costs associated with not providing evidence-based PTSD treatments wherever possible. PMID- 25040381 TI - Glioblastoma: background, standard treatment paradigms, and supportive care considerations. AB - Glioblastoma is a brain tumor condition marked by rapid neurological and clinical demise, resulting in disproportionate disability for those affected. Caring for this group of patients is complex, intense, multidisciplinary in nature, and fraught with the need for expensive treatments, surveillance imaging, physician follow-up, and rehabilitative, psychological, and social support interventions. Few of these patients return to the workforce for any meaningful time frame, and because of the enormity of the financial burden that patients, their caregivers, and society face, utilization reviews become the focus of ethical scrutiny. PMID- 25040382 TI - Is it reasonable to deny older patients treatment for glioblastoma? AB - Is it ever fair to limit treatment for diseases like glioblastoma for which prognosis is poor? Because resources are finite and health care spending limits the other possible uses for those resources, limiting access to an intervention that does not generate benefits is ethically sound. Ignoring the balance of benefits and burdens associated with treatment ignores opportunity costs and leads us to treat some lives as more valuable than others. Although it is ethically sound to set limits on medical care, I argue that biological age is a poor criterion for allocating resources. PMID- 25040383 TI - A framework for analyzing the ethics of disclosing genetic research findings. AB - Whether researchers have an obligation to disclose secondary genetic research findings, and, if so, in what circumstances, remains a matter of heated debate. This paper suggests that much of this confusion is definitional or conceptual in nature. That is, there is significant variability in the way that threshold terms and concepts such as "incidental," "analytic validity," "clinical validity," "clinical relevance," "clinical utility," "clinical significance," and "actionability," are used in the literature, which is impeding efforts to clarify the scope of an obligation to return findings. This paper analyzes the definitional muddle underlying the debate about returning genetic research findings, first, to explain the range of definitions being used in this debate. We go on to propose that, underlying all the seeming confusion and disagreement, three central and widely agreed upon concepts are at work in this debate - validity, value, and volition. Refocusing attention on these core concepts, and their appropriate conceptualizations, can produce a more productive debate regarding the return of genetic research findings. PMID- 25040384 TI - A systematic review of state and manufacturer physician payment disclosure websites: implications for implementation of the Sunshine Act. AB - Under the Physician Payment Sunshine Act (PPSA), payments to physicians from pharmaceutical, biologics, and medical device manufacturers will be disclosed on a national, publicly available website. To inform the development of the federal website, we evaluated 21 existing state and industry disclosure websites. The presentation formats and language used suggest that industry websites are aimed at patient audiences whereas state websites are structured to transmit data to researchers and guide compliance officers. These findings raise questions about the intended audience and aims of the PPSA disclosure database and expected outcomes of the law. Based on our evaluation, we offer recommendations for the national website and discuss implications of this policy for the health care system. PMID- 25040385 TI - Genomic research with the newly dead: a crossroads for ethics and policy. AB - Recent advances in next generation sequencing along with high hopes for genomic medicine have inspired interest in genomic research with the newly dead. However, applicable law does not adequately determine ethical or policy responses to such research. In this paper we propose that such research stands at a crossroads between other more established biomedical clinical and research practices. In addressing the ethical and policy issues raised by a particular research project within our institution comparatively with these other practices, we illustrate the moral significance of paying careful heed to where one looks for guidance in responding to ethical questions raised by a novel endeavor. PMID- 25040386 TI - Risk disclosure and the recruitment of oocyte donors: are advertisers telling the full story? AB - This study analyzes 435 oocyte donor recruitment advertisements to assess whether entities recruiting donors of oocytes to be used for in vitro fertilization (IVF) procedures include a disclosure of risks associated with the donation process in their advertisements. Such disclosure is required by the self-regulatory guidelines of the American Society for Reproductive Medicine (ASRM) and by law in California for advertisements placed in the state. We find very low rates of risk disclosure across entity types and regulatory regimes, although risk disclosure is more common in advertisements placed by entities subject to ASRM's self regulatory guidelines. Advertisements placed in California are more likely to include risk disclosure, but disclosure rates are still quite low. California based entities advertising outside the state are more likely to include risk disclosure than non-California entities, suggesting that California's law may have a modest "halo effect." Our results suggest that there is a significant ethical and policy problem with the status quo in light of the known and unknown risks of oocyte donation and the importance of risk disclosure to informed consent in the context of oocyte donation. PMID- 25040387 TI - Toward a jurisprudence of drug regulation. AB - Efforts to foster transparency in biopharmaceutical regulation are well underway: drug manufacturers are, for example, legally required to register clinical trials and share research results in the United States and Europe. Recently, the policy conversation has shifted toward the disclosure of clinical trial data, not just trial designs and basic results. Here, I argue that clinical trial registration and disclosure of clinical trial data are necessary but insufficient. There is also a need to ensure that regulatory decisions that flow from clinical trials - whether positive (i.e., product approvals) or negative (i.e., abandoned products, product refusals, and withdrawals) - are open to outside scrutiny. Further, a jurisprudence of drug regulation is needed. I develop two arguments motivated by (1) innovation concerns and (2) the value of good governance in support of openly publishing all final decisions for approved, abandoned, refused, and withdrawn products. After articulating why greater transparency in regulatory decision making is needed, I distil four essential features of a jurisprudence of drug regulation that prescribe policy changes in terms not only of the transparency of regulatory outcomes and the underlying reasoning, but also regulatory organization. PMID- 25040388 TI - Currents in contemporary bioethics. Extending the minimum necessary standard to uses and disclosures for treatment. PMID- 25040389 TI - Active shooters in health care settings: prevention and response through law and policy. PMID- 25040392 TI - Manipulating duckweed through genome duplication. AB - Significant inter- and intraspecific genetic variation exists in duckweed, thus the potential for genome plasticity and manipulation is high. Polyploidy is recognised as a major mechanism of adaptation and speciation in plants. We produced several genome-duplicated lines of Landoltia punctata (Spirodela oligorrhiza) from both whole plants and regenerating explants using a colchicine based cocktail. These lines stably maintained an enlarged frond and root morphology. DNA ploidy levels determined by florescence-activated cell sorting indicated genome duplication. Line A4 was analysed after 75 biomass doublings. Frond area, fresh and dry weights, rhizoid number and length were significantly increased versus wild type, while the growth rate was unchanged. This resulted in accumulation of biomass 17-20% faster in the A4 plants. We sought to determine if specific differences in gene products are found in the genome duplicated lines. Non-targeted ultra performance LC-quadrupole time of flight mass spectrometry was employed to compare some of the lines and the wild type to seek identification of up-regulated metabolites. We putatively identified differential metabolites in Line A65 as caffeoyl hexoses. The combination of directed genome duplication and metabolic profiling might offer a path for producing stable gene expression, leading to altered production of secondary metabolites. PMID- 25040391 TI - Management of treatment-naive chronic hepatitis C genotype 1 patients: a cost effectiveness analysis of treatment options. AB - New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost effectiveness analysis of boceprevir (BOC)- and telaprevir (TVR)-based triple therapy according to different patients' selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1-F4 fibrosis, (ii) only F2-F4 and (iii) only F3-F4. For each strategy, TVR interleukin-28B-guided (IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio (ICER) for F1-F4 strategy relative to F3-F4 was ?5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and ?7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1-F4 strategy relative to F3-F4 was ?1 818 679 (TVR IL28B-guided) and ?1 866 437 (BOC RVR-guided) per end-stage liver disease or death (ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization. PMID- 25040393 TI - Increased burst-firing of ventral tegmental area dopaminergic neurons in D-amino acid oxidase knockout mice in vivo. AB - d-Amino acid oxidase (DAO) degrades the N-methyl-d-aspartate (NMDA) receptor co agonist d-serine, and is implicated in schizophrenia as a risk gene and therapeutic target. In schizophrenia, the critical neurochemical abnormality affects dopamine, but to date there is little evidence that DAO impacts on the dopamine system. To address this issue, we measured the electrophysiological properties of dopaminergic (DA) and non-DA neurons in the ventral tegmental area (VTA) of anaesthetised DAO knockout (DAO(-/-) ) and DAO heterozygote (DAO(+/-) ) mice as compared with their wild-type (DAO(+/+) ) littermates. Genotype was confirmed at the protein level by western blotting and immunohistochemistry. One hundred and thirty-nine VTA neurons were recorded in total, and juxtacellular labelling of a subset revealed that neurons immunopositive for tyrosine hydroxylase had DA-like electrophysiological properties that were distinct from those of neurons that were tyrosine hydroxylase-immunonegative. In DAO(-/-) mice, approximately twice as many DA-like neurons fired in a bursting pattern than in DAO(+/-) or DAO(+/+) mice, but other electrophysiological properties did not differ between genotypes. In contrast, non-DA-like neurons had a lower firing rate in DAO(-/-) mice than in DAO(+/-) or DAO(+/+) mice. These data provide the first direct evidence that DAO modulates VTA DA neuron activity, which is of interest for understanding both the glutamatergic regulation of dopamine function and the therapeutic potential of DAO inhibitors. The increased DA neuron burst firing probably reflects increased availability of d-serine at VTA NMDA receptors, but the site, mechanism and mediation of the effect requires further investigation, and may include both direct and indirect processes. PMID- 25040394 TI - Right atrial volume reduction for severely impaired pulmonary function. AB - We report a patient with giant right atrium and severe pulmonary dysfunction who underwent successful surgical volume reduction with significant improvement of pulmonary function studies. PMID- 25040396 TI - A conceptual approach to managing severe traumatic brain injury in a time of uncertainty. AB - Current controversies in the literature suggest that a reassessment of the current management of severe traumatic brain injury (sTBI) is necessary. This article presents a conceptual framework toward individualizing sTBI treatment with respect to targeting thresholds and strategies on the basis of known physiologic processes and available monitors. Intracranial pressure (ICP) is modeled as an epiphenomenon of cerebral compliance and herniation tendency, as well as cerebral ischemia. By combining serial neurological examinations, imaging studies, and ICP measurements (values, trends, and area-under-the-curve calculations) over time, evidence can be accrued on the necessity of maintaining ICP at a given threshold in the realm of physical changes in the brain. Similarly, by collecting and trending clinical, imaging, and monitoring data on the status of cerebral blood flow, the balance of oxygen consumption and delivery, and the status of cerebral static pressure autoregulation, and analyzing them with respect to measured parameters, such as blood pressure, ICP, and cerebral perfusion pressure, one can attempt to fine-tune these variables as well. Such individualization of management optimizes the possibility of successfully treating demonstrated pathophysiological processes while avoiding unnecessary interventions and treatment toxicity. Monitor values must not be seen as targets but rather as indicators of targetable pathology. PMID- 25040395 TI - A rapid and rational approach to generating isomorphous heavy-atom phasing derivatives. AB - In attempts to replace the conventional trial-and-error heavy-atom derivative search method with a rational approach, we previously defined heavy metal compound reactivity against peptide ligands. Here, we assembled a composite pH- and buffer-dependent peptide reactivity profile for each heavy metal compound to guide rational heavy-atom derivative search. When knowledge of the best-reacting heavy-atom compound is combined with mass spectrometry assisted derivatization, and with a quick-soak method to optimize phasing, it is likely that the traditional heavy-atom compounds could meet the demand of modern high-throughput X-ray crystallography. As an example, we applied this rational heavy-atom phasing approach to determine a previously unknown mouse serum amyloid A2 crystal structure. PMID- 25040397 TI - Fibroelastolytic papulosis of the neck treated with topical tretinoin. PMID- 25040399 TI - Assessing the economic burden of illness for tuberculosis patients in Benin: determinants and consequences of catastrophic health expenditures and inequities. AB - OBJECTIVES: To inform policy-making, we measured the risk, causes and consequences of catastrophic expenditures for tuberculosis and investigated potential inequities. METHODS: Between August 2008 and February 2009, a cross sectional study was conducted among all (245) smear-positive pulmonary tuberculosis patients of six health districts from southern Benin. A standardised survey questionnaire covered the period of time elapsing from onset of tuberculosis symptoms to completion of treatment. Total direct cost exceeding the conventional 10% threshold of annual income was defined as catastrophic and used as principal outcome in a multivariable logistic regression. A sensitivity analysis was performed while varying the thresholds. RESULTS: A pure gradient of direct costs of tuberculosis in relation to income was observed. Incidence (78.1%) and intensity (14.8%) of catastrophic expenditure were high; varying thresholds was insensitive to the intensity. Incurring catastrophic expenditure was independently associated with lower- and middle-income quintiles (adjusted odd ratio (aOR) = 36.2, 95% CI [12.3-106.3] and aOR = 6.4 [2.8-14.6]), adverse pre-diagnosis stage (aOR = 5.4 [2.2-13.3]) and less education (aOR = 4.1[1.9 8.7]). Households incurred important days lost due to TB, indebtedness (37.1%), dissaving (51.0%) and other coping strategies (52.7%). CONCLUSIONS: Catastrophic direct costs and substantial indirect and coping costs may persist under the 'free' tuberculosis diagnosis and treatment strategy, as well as inequities in financial hardship. PMID- 25040400 TI - Quantifying oral inflammatory load: oral neutrophil counts in periodontal health and disease. AB - BACKGROUND AND OBJECTIVE: Neutrophils are the primary white blood cells that are recruited to fight the initial phases of microbial infections. While healthy norms have been determined for circulating blood neutrophil counts in order to identify patients with suspected systemic infections, the levels of oral neutrophils (oPMNs) in oral health and in the presence of periodontal diseases have not been described. It is important to address this deficiency in our knowledge as neutrophils are the primary immune cell present in the crevicular fluid and oral environment and previous work has suggested that they may be good indicators of overall oral inflammation and periodontal disease severity. The objective of this study was to measure oPMN counts obtained in a standardized oral rinse from healthy patients and from those with chronic periodontal disease in order to determine if oPMN levels have clinical relevance as markers of periodontal inflammation. A parallel goal of this investigation was to introduce the concept of 'oral inflammatory load', which constitutes the inflammatory burden experienced by the body as a consequence of oral inflammatory disease. MATERIAL AND METHODS: Periodontal examinations of patients with a healthy periodontium and chronic periodontal disease were performed (n = 124). Two standardized consecutive saline rinses of 30 s each were collected before patient examination and instrumentation. Neutrophils were quantified in the rinse samples and correlated with the clinical parameters and periodontal diagnosis. RESULTS: Average oPMN counts were determined for healthy patients and for those with mild, moderate and severe chronic periodontal diseases. A statistically significant correlation was found between oPMN counts and deep periodontal probing, sites with bleeding on probing and overall severity of periodontal disease. CONCLUSIONS: oPMN counts obtained through a 30-s oral rinse are a good marker of oral inflammatory load and correlate with measures of periodontal disease severity. PMID- 25040398 TI - Cardiac alternans and intracellular calcium cycling. AB - Cardiac alternans refers to a condition in which there is a periodic beat-to-beat oscillation in electrical activity and the strength of cardiac muscle contraction at a constant heart rate. Clinically, cardiac alternans occurs in settings that are typical for cardiac arrhythmias and has been causally linked to these conditions. At the cellular level, alternans is defined as beat-to-beat alternations in contraction amplitude (mechanical alternans), action potential duration (APD; electrical or APD alternans) and Ca(2+) transient amplitude (Ca(2+) alternans). The cause of alternans is multifactorial; however, alternans always originate from disturbances of the bidirectional coupling between membrane voltage (Vm ) and intracellular calcium ([Ca(2+) ]i ). Bidirectional coupling refers to the fact that, in cardiac cells, Vm depolarization and the generation of action potentials cause the elevation of [Ca(2+) ]i that is required for contraction (a process referred to as excitation-contraction coupling); conversely, changes of [Ca(2+) ]i control Vm because important membrane currents are Ca(2+) dependent. Evidence is mounting that alternans is ultimately caused by disturbances of cellular Ca(2+) signalling. Herein we review how two key factors of cardiac cellular Ca(2+) cycling, namely the release of Ca(2+) from internal stores and the capability of clearing the cytosol from Ca(2+) after each beat, determine the conditions under which alternans occurs. The contributions from key Ca(2+) -handling proteins (i.e. surface membrane channels, ion pumps and transporters and internal Ca(2+) release channels) are discussed. PMID- 25040402 TI - Successful hyperbaric oxygen therapy for refractory BK virus-associated hemorrhagic cystitis after cord blood transplantation. AB - BK virus-associated hemorrhagic cystitis (BKV-HC) is a common and major cause of morbidity in recipients of allogeneic hematopoietic stem cell transplantation. A 32-year-old woman developed severe BKV-HC on day 24 after cord blood transplantation (CBT). Despite supportive therapies - such as hyperhydration, forced diuresis, and urinary catheterization - macroscopic hematuria and bladder irritation persisted for over a month. Hyperbaric oxygen (HBO) therapy at 2.1 atmospheres for 90 min per day was started on day 64 after CBT. Macroscopic hematuria resolved within a week, and microscopic hematuria was no longer detectable within 2 weeks. Hematuria did not recur after 11 sessions of HBO therapy, and no significant side effects were observed during or after treatment. HBO therapy could thus be useful in controlling refractory BKV-HC after CBT. PMID- 25040401 TI - Amyloid-abeta Peptide in olfactory mucosa and mesenchymal stromal cells of mild cognitive impairment and Alzheimer's disease patients. AB - Patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) might develop olfactory dysfunction that correlates with progression of disease. Alteration of olfactory neuroepithelium associated with MCI may be useful as predictor of cognitive decline. Biomarkers with higher sensitivity and specificity would allow to understand the biological progression of the pathology in association with the clinical course of the disease. In this study, magnetic resonance images, apolipoprotein E (ApoE) load, Olfactory Connecticut test and Montreal Cognitive Assessment (MoCA) indices were obtained from noncognitive impaired (NCI), MCI and AD patients. We established a culture of patient-derived olfactory stromal cells from biopsies of olfactory mucosa (OM) to test whether biological properties of mesenchymal stromal cells (MSC) are concurrent with MCI and AD psychophysical pathology. We determined the expression of amyloid Abeta peptides in the neuroepithelium of tissue sections from MCI and AD, as well as in cultured cells of OM. Reduced migration and proliferation of stromal (CD90(+) ) cells in MCI and AD with respect to NCI patients was determined. A higher proportion of anosmic MCI and AD cases were concurrent with the ApoE epsilon4 allele. In summary, dysmetabolism of amyloid was concurrent with migration and proliferation impairment of patient-derived stem cells. PMID- 25040403 TI - Immuno- and correlative light microscopy-electron tomography methods for 3D protein localization in yeast. AB - Compartmentalization of eukaryotic cells is created and maintained through membrane rearrangements that include membrane transport and organelle biogenesis. Three-dimensional reconstructions with nanoscale resolution in combination with protein localization are essential for an accurate molecular dissection of these processes. The yeast Saccharomyces cerevisiae is a key model system for identifying genes and characterizing pathways essential for the organization of cellular ultrastructures. Electron microscopy studies of yeast, however, have been hampered by the presence of a cell wall that obstructs penetration of resins and cryoprotectants, and by the protein dense cytoplasm, which obscures the membrane details. Here we present an immuno-electron tomography (IET) method, which allows the determination of protein distribution patterns on reconstructed organelles from yeast. In addition, we extend this IET approach into a correlative light microscopy-electron tomography procedure where structures positive for a specific protein localized through a fluorescent signal are resolved in 3D. These new investigative tools for yeast will help to advance our understanding of the endomembrane system organization in eukaryotic cells. PMID- 25040404 TI - Improving hospital care for patients with intellectual disabilities. PMID- 25040406 TI - Ultrasound of the gall bladder and biliary tree: part 1. PMID- 25040407 TI - Ultrasound of the gall bladder and biliary tree: part 2. PMID- 25040408 TI - Bile duct injury following laparoscopic cholecystectomy. PMID- 25040409 TI - Cervical spine injury associated with facial trauma. PMID- 25040410 TI - Psychological disturbance associated with recurrent abnormal nocturnal events. PMID- 25040411 TI - Quality of patient information in the acute surgical admission: a prospective audit. PMID- 25040412 TI - Echocardiography training for non-cardiologists. PMID- 25040413 TI - The cutting edge of general surgery 50 years ago. PMID- 25040414 TI - Spontaneous haemopneumothorax secondary to an aberrant lateral thoracic artery tear. PMID- 25040415 TI - Vitamin B12 deficiency presenting with solid food aversion and global developmental delay in a child. PMID- 25040416 TI - A guide to slit lamps: make your own. PMID- 25040418 TI - Should a child with an upper respiratory tract infection have elective surgery? PMID- 25040419 TI - Dysmorphic features and developmental outcome of 2-year-old children. AB - AIM: The aim of this study was to assess the associations between dysmorphic features and neurological, mental, psychomotor, and behavioural development in order to improve our understanding of aetiological pathways leading to minor developmental problems. METHOD: In our cross-sectional study, 272 generally healthy 2-year-olds (143 males, 129 females; median gestational age 39 weeks, [range 30-43wks]), born after a parental history of subfertility either with or without fertility treatment, were examined. Dysmorphic features were classified as abnormalities (clinically relevant or not), minor anomalies, or common variants according to Merks' classification system. Hempel's neurological assessment resulted in a neurological optimality score (NOS) and fluency score. Mental and psychomotor development were assessed with the Dutch version of the Bayley Scales of Infant Development and behavioural development with the Achenbach Child Behaviour Checklist. RESULTS: Of the different types of dysmorphic feature, clinically relevant abnormalities were most strongly associated with a lower NOS (difference -2.53, 95% confidence interval [CI] -4.23 to -0.83) and fluency score (difference -0.62, 95% CI -1.1 to -0.15). The presence of one or more abnormalities (clinically relevant or not) or one or more common variants was significantly associated with a lower NOS, and the presence of three or more minor anomalies was associated with lower fluency scores. Dysmorphic features were not associated with mental, psychomotor, or behavioural development. INTERPRETATION: As dysmorphic features originate during the first trimester of pregnancy, the association between dysmorphic features and minor alterations in neurodevelopment may suggest an early ontogenetic origin of subtle neurological deviations. PMID- 25040420 TI - The impact of insurance instability on health service utilization: does non metropolitan residence make a difference? AB - PURPOSE: Discontinuous and no health insurance are major barriers to health care utilization. This paper examines if nonmetropolitan versus metropolitan residence is associated with differences in health care utilization in the face of insurance instability. METHODS: A cross-sectional analysis of adults aged 18-64 years was conducted using the 2006-2010 Medical Expenditure Panel Survey data set (N = 61,039). Negative binomial regression was used to model measures of health service utilization (emergency room [ER] visits, inpatient discharges, office based visits, dental care visits, prescriptions filled, home health visits) as functions of insurance continuity, adjusted for sociodemographic and health related covariates. Models were stratified by metropolitan versus nonmetropolitan residence. FINDINGS: Health insurance continuity was significantly associated with several measures of health service utilization, including more ER visits for individuals with gaps in health insurance (IRR [incident risk ratio] = 1.29; 95% CI: 1.16-1.42) and fewer inpatient discharges for individuals without insurance (IRR = 0.50; 95% CI: 0.43-0.57) when compared with individuals with continuous insurance. Individuals who were discontinuously insured or uninsured had significantly fewer office-based visits. They also had significantly fewer dental visits, prescription fills, and home health visits; moreover, the magnitudes of these associations were generally significantly greater for residents of nonmetropolitan areas. CONCLUSIONS: Insurance instability is associated with higher use of emergency services and reduced use of nonhospital health care services. Residents of nonmetropolitan areas with unstable or no insurance coverage may be at particular risk for reduced access and use of some health services relative to their counterparts living in metropolitan areas. PMID- 25040421 TI - Examining the efficacy and safety of squaric acid therapy for treatment of recalcitrant warts in children. AB - The objective of the study was to determine the safety and efficacy of squaric acid dibutyl ester (SADBE) therapy on the treatment of recalcitrant warts in children. This retrospective chart review examined 72 patients treated using SADBE from July 2002 to December 2012. Patients were followed for 6 months to 11 years. Patients were treated at a pediatric dermatology outpatient clinic at the University of North Carolina at Chapel Hill. Seventy-two children with verrucae who failed initial treatment for warts were selected for the study. Full long term follow-up was obtained in 48 patients. Four patients discontinued the use of SADBE because of adverse effects. The primary study outcome was efficacy of SADBE treatment. Adverse effects, dosages administered, type of wart, other cutaneous disease present, and level of immunosuppression were measured. Forty of 48 (83%) patients in whom treatment outcomes could be obtained reported complete resolution of their warts. Seventy percent of patients used a maximum concentration of 0.4% SADBE and 60% of patients reported no adverse effects. The majority of patients treated with SADBE reported complete resolution of warts. Most patients reported no adverse effects even while receiving doses as high as 2% daily. This study shows that SADBE is a safe and effective treatment for recalcitrant warts in children. PMID- 25040423 TI - Large volume cryoprotectant-free vitrification: an alternative to conventional cryopreservation for human spermatozoa. AB - Vitrification is a simple and cost-effective method for the storage of human spermatozoa without the use of conventional cryoprotectants, by plunging the sperm suspension directly into liquid nitrogen. As a result, solidification of living cells without the formation of ice crystals is achieved during cooling. This study aimed to compare cryoprotectant-free vitrification to conventional cryopreservation protocols. Semen samples (n = 35) were collected from patients seeking diagnostic assistance at the Reproductive and Endocrine Unit at Steve Biko Academic Hospital. Samples were processed using a discontinuous density gradient centrifugation method. Washed samples were split into two aliquots and cryopreserved either by means of cryoprotectant-free vitrification (sucrose + 1% albumin) or conventional slow freezing (TEST-yolk buffer). Post-thawing, the sperm motion parameters, mitochondrial membrane potential (Deltapsim) and DNA fragmentation were compared between the two groups. No significant differences were observed in the sperm motility parameters (P > 0.05). Significantly higher percentages of Deltapsim (11.99% +/- 4.326% versus 6.58% +/- 1.026%; P < 0.001) and lower percentages of DNA fragmentation (2.79% +/- 1.017% versus 3.86% +/- 1.38%; P < 0.01) were observed when comparing cryoprotectant-free vitrification to conventional cryopreservation. Cryoprotectant-free vitrification is a rapid and promising alternative to conventional methods resulting in good-quality spermatozoa post-thaw. PMID- 25040424 TI - Variants of the IL-10 gene associate with muscle strength in elderly from rural Africa: a candidate gene study. AB - Recently, it has been shown that the capacity of the innate immune system to produce cytokines relates to skeletal muscle mass and strength in older persons. The interleukin-10 (IL-10) gene regulates the production capacities of IL-10 and tumour necrosis factor-alpha (TNF-alpha). In rural Ghana, IL-10 gene variants associated with different production capacities of IL-10 and TNF-alpha are enriched compared with Caucasian populations. In this setting, we explored the association between these gene variants and muscle strength. Among 554 Ghanaians aged 50 years and older, we determined 20 single nucleotide polymorphisms in the IL-10 gene, production capacities of IL-10 and TNF-alpha in whole blood upon stimulation with lipopolysaccharide (LPS) and handgrip strength as a proxy for skeletal muscle strength. We distinguished pro-inflammatory haplotypes associated with low IL-10 production capacity and anti-inflammatory haplotypes with high IL 10 production capacity. We found that distinct haplotypes of the IL-10 gene associated with handgrip strength. A pro-inflammatory haplotype with a population frequency of 43.2% was associated with higher handgrip strength (P = 0.015). An anti-inflammatory haplotype with a population frequency of 7.9% was associated with lower handgrip strength (P = 0.006). In conclusion, variants of the IL-10 gene contributing to a pro-inflammatory cytokine response associate with higher muscle strength, whereas those with anti-inflammatory response associate with lower muscle strength. Future research needs to elucidate whether these effects of variation in the IL-10 gene are exerted directly through its role in the repair of muscle tissue or indirectly through its role in the defence against infectious diseases. PMID- 25040425 TI - Description of a new cryptic, shallow-water tonguefish (Pleuronectiformes: Cynoglossidae: Symphurus) from the western North Pacific Ocean. AB - Combined results based on morphological characters and analyses of partial sequences of the 16s rRNA and coI genes confirm the validity of a new, cryptic, symphurine tonguefish from the western North Pacific Ocean. Symphurus leucochilus n. sp., a diminutive species reaching sizes to c. 67 mm standard length, is described from nine specimens that were collected from fish-landing ports and from trawls made at c. 150 m off Taiwan and Japan. Symphurus leucochilus shares many similar features with those of Symphurus microrhynchus and that of several undescribed species that are morphologically similar to S. microrhynchus. Symphurus leucochilus has also been misidentified as Symphurus orientalis in fish collections because of shared similarities in some aspects of their morphology. The new species differs from all congeners by the following combination of meristic, morphological and pigmentation features: a predominant 1-2-2-2-2 pattern of interdigitation of proximal dorsal-fin pterygiophores and neural spines; 12 caudal-fin rays; 89-92 dorsal-fin rays; 76-80 anal-fin rays; 49-51 total vertebrae; four hypurals; 75-83 longitudinal scale rows; 32-35 transverse scales; 15-17 scale rows on the head posterior to the lower orbit; absence of a fleshy ridge on the ocular-side lower jaw and a membranous connection between the anterior nostril and lower part of the eye; a narrow interorbital space and dorsal-fin origin anterior to the vertical through the anterior margin of the upper eye; absence of both dermal spots at bases of anterior dorsal-fin rays and melanophores on the isthmus; uniformly yellow to light-brown ocular-side colouration without bands; dorsal and anal fins with alternating series of dark rectangular blotches and unpigmented areas; a uniform white blind side and a bluish-black peritoneum. Despite overall similarities in morphology between S. leucochilus and S. orientalis, as well as between two of the nominal species morphologically similar to S. microrhynchus, analyses of partial 16s rRNA and coI gene sequences show that S. leucochilus, S. orientalis and the two other nominal species represent three distinct lineages within the genus Symphurus. PMID- 25040427 TI - Performance comparisons in major uro-oncological surgeries between the USA and Japan. AB - OBJECTIVES: To elucidate the differences in clinical practice between the USA and Japan in major types of uro-oncological surgery by a head-to-head comparison of national databases in the two countries. METHODS: We compared variations in surgical modality, length of stay, total charges, caseload centralization, transfusion incidence, and in-hospital mortality between the two countries for four major types of uro-oncological surgery (radical prostatectomy, radical cystectomy, nephrectomy and nephroureterectomy) in 2011. Additionally, the chronological changes in surgical modalities were investigated for 2009-11. The national estimates were based on data from the Japanese Diagnosis Procedure Combination database and the US National Inpatient Sample. RESULTS: For radical prostatectomy, radical cystectomy, nephrectomy and nephroureterectomy, minimally invasive surgery accounted for 24.2% versus 70.2%, 0% versus 14.0%, 50.7% versus 30.7% and 50.2% versus 30.5%, respectively, in Japan versus the USA in 2011. Although minimally-invasive surgery has become increasingly frequent in both countries, the major procedures were robot-assisted surgery in the USA and laparoscopic surgery in Japan. The USA was generally characterized by a slightly younger age at operation, far higher hospital volume, a shorter length of stay, higher charges and less use of transfusion than Japan. CONCLUSIONS: The findings suggest substantial differences between the USA and Japan regarding clinical practices in uro-oncological surgery. Standing at the beginning of robotic surgery era in Japan, the precise recognition of these differences will aid a proper understanding of clinical practices. PMID- 25040426 TI - Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies. AB - Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95, and synaptotagmin levels. Conditioned media from TSP-1 over-expressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types, also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE. Defective release of astrocytic factors may impair synaptic integrity in chronic hepatic encephalopathy. We found a reduction in the release of the astrocytic matricellular proteins thrombospondin-1 (TSP-1) in ammonia-treated astrocytes; such reduction was associated with a decrease in synaptic proteins caused by conditioned media from ammonia-treated astrocytes. Exposure of neurons to CM from ammonia-treated astrocytes, in which TSP-1 is over-expressed, reversed (by approx 75%) the reduction in synaptic proteins. NF-kB = nuclear factor kappa B; PSD95 = post-synaptic density protein 95; ONS = oxidative/nitrative stress. PMID- 25040428 TI - Re: Ratios derived from an array of standard haematological indices predict the oncological outcome in colon cancer. PMID- 25040429 TI - Assessing the validity, responsiveness and meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis suppurativa treatment. AB - BACKGROUND: Quantification of disease severity supports the development of evidence-based treatments. Assessments to capture clinical improvement in hidradenitis suppurativa (HS) can be improved. OBJECTIVES: This study aimed to validate the Hidradenitis Suppurativa Clinical Response (HiSCR), which is defined as a >= 50% reduction in inflammatory lesion count (sum of abscesses and inflammatory nodules, AN), and no increase in abscesses or draining fistulas in HS when compared with baseline as a meaningful clinical endpoint for HS treatment. METHODS: Patients with >= 3 ANs at baseline in a Phase II adalimumab trial for HS were included for analysis. HiSCR achievers vs. nonachievers were assessed at week 16 and week 52. Criteria measures included physician-rated assessments [Hurley stage, modified Sartorius score (MSS), and HS Physician's Global Assessment] and patient-reported outcomes (PROs: visual analogue pain scale, Dermatology Life Quality Index, and Work Productivity and Activity Impairment questionnaire). Test-retest reliability, convergent validity, responsiveness and predictive validity of HiSCR, and its meaningfulness to patients were assessed. RESULTS: Among 138 eligible study participants, the majority were female (69.6%) with a mean age of 36.7 years. The mean (median) MSS was 125.2 (85.5) at baseline. Test-retest reliability of the AN count was 0.91. HiSCR was significantly correlated with improvements in all physician-rated and PRO measures (Spearman's rho between -0.61 and -0.27, all P < 0.001). Improvements of all PROs in HiSCR achievers exceeded the respective meaningful improvement thresholds. CONCLUSIONS: In patients with HS with >= 3 ANs, HiSCR achievers had significant improvements in physician-rated and patient-reported HS disease severity and impact. HiSCR is a valid and meaningful endpoint for assessing HS treatment effectiveness in controlling inflammatory manifestations in this population. PMID- 25040430 TI - Evaluation of the Sherlock 3CG Tip Confirmation System on peripherally inserted central catheter malposition rates. AB - Peripherally inserted central catheters are often positioned blindly in the central circulation, and this may result in high malposition rates, especially in critically ill patients. Recently, a new technology has been introduced (Sherlock 3CG Tip Positioning System) that uses an electro-magnetic system to guide positioning in the superior vena cava, and then intra-cavity ECG to guide positioning at the cavo-atrial junction. In this observational study, we investigated how the Sherlock 3CG Tip Positioning System would affect peripherally inserted central catheter malposition rates, defined using a post insertion chest radiograph, in critically ill patients. A total of 239 catheters positioned using the Sherlock 3CG Tip Positioning System were analysed. When an adequate position was defined as low superior vena cava or cavo-atrial junction, 134 catheters (56.1%; 95% CI 50-62%) were malpositioned. When an adequate position was defined as mid/low superior vena cava, cavo-atrial junction or high right atrium (<= 2 cm from cavo-atrial junction), 49 (20.5%; 95% CI 16-26%) catheters were malpositioned. These malposition rates are significantly lower than our own historical data, which used a 'blind' anthropometric technique to guide peripherally inserted central catheter insertion. PMID- 25040431 TI - Dental hygienists' perception of preparation and use for ultrasonic instrumentation. AB - OBJECTIVES: Ultrasonic scaling technology has evolved dramatically providing greater clinical utility subgingivally including instrumentation of light deposits and biofilm disruption. It is unknown whether dental hygiene curriculum has kept pace with the progression and reflects current applications. The first part of this two-part study aimed to determine new dental hygiene graduates' use and perceptions of preparedness in ultrasonic instrumentation. Part 2 investigates ultrasonic curriculum from the programme director perspective and will be reported on in a subsequent paper. METHOD: Part 1 of the study surveys recently graduated Canadian dental hygienists about their use and perceptions of preparedness with ultrasonic instruments through an electronic questionnaire developed for this study. RESULTS: Participants reported using ultrasonics about half of their instrumentation time predominantly with magnetostrictive technology. Use focussed on heavier deposits with straight, slim inserts. Subjects were generally satisfied with ultrasonic education and felt reasonably well prepared in using ultrasonics. Higher levels of perceived preparedness were most associated with graduates from the 3-year diploma programme, whereas graduates from 18-month programmes were associated with greater levels of confidence in using ultrasonics. Confidence with ultrasonics did not have an effect on subsequent use - mostly all participants increased use once in practice. An earlier introduction and more practice time in school were both associated with increased feelings of preparation and confidence. CONCLUSIONS: New dental hygiene graduates perceive greater preparedness, confidence and use of ultrasonic instrumentation within a more traditional paradigm. In addition, the results indicate a potential incorrect and/or inappropriate application of current technology. PMID- 25040433 TI - Tablet-based Interactive Distraction (TBID) vs oral midazolam to minimize perioperative anxiety in pediatric patients: a noninferiority randomized trial. AB - INTRODUCTION: Perioperative anxiety is a common and undesirable outcome in pediatric surgical patients. The use of interactive tools to minimize perioperative anxiety is vastly understudied. The main objective of the current investigation was to compare the effects of a tablet-based interactive distraction (TBID) tool to oral midazolam on perioperative anxiety. We hypothesized that the TBID tool was not inferior to midazolam to reduce perioperative anxiety. METHODS: 108 children, ages 1-11 years, presenting for outpatient surgical procedures were prospectively randomized to oral midazolam (0.5 mg.kg(-1); 20 mg max) or TBID. The primary outcome was the change in anxiety level from baseline to parental separation and anesthetic induction. Other data collected included emergence delirium, parental satisfaction, time-to-PACU discharge, and posthospitalization behavior. RESULTS: The mean difference (95% CI) in the increase of anxiety at parental separation between the TBID and the midazolam group was -9 (-2.6 to -16.4), P = 0.006, demonstrating superiority to midazolam group (one-sided P = 0.003). For children 2-11 years, the mean difference (95% CI) in anxiety at induction was significant between the TBID and midazolam groups, -14.0 (-6.1 to -22.0), P < 0.001. The median (IQR) time-to-PACU discharge was 111 (75-197) min in the midazolam group and 87 (55-137) min in the TBID group, P = 0.03. Decreased emergence delirium and increased parental satisfaction were also observed in the TBID group. CONCLUSIONS: A TBID tool reduces perioperative anxiety, emergence delirium, and time-to-discharge and increases parental satisfaction when compared to midazolam in pediatric patients undergoing ambulatory surgery. PMID- 25040432 TI - Social competence following pediatric stroke: contributions of brain insult and family environment. AB - Limited information is available regarding predictors of psychosocial difficulties in children following stroke. This study aimed to (i) compare social competence of children with arterial ischemic stroke (AIS) to those with chronic illness and healthy controls and (ii) investigate the contribution of stroke pathology, neurological outcome and environment. Thirty-six children with AIS > 12 months prior to recruitment were compared with children with chronic illness (asthma) (n = 15) and healthy controls (n = 43). Children underwent intellectual assessment, and children and parents completed questionnaires to assess social competence. Children with AIS underwent MRI scan and neurological evaluation. Child AIS was associated with poorer social adjustment and participation, and children with AIS were rated as having more social problems than controls. Lesion volume was not associated with social outcome, but subcortical stroke was linked to reduced social participation and younger stroke onset predicted better social interaction and higher self-esteem. Family function was the sole predictor of social adjustment. Findings highlight the risk of social impairment following pediatric stroke, with both stroke and environmental factors influencing children's social competence in the chronic stages of recovery. They indicate the potential for intervention targeting support at the family level. PMID- 25040434 TI - HrtBA and menaquinones control haem homeostasis in Lactococcus lactis. AB - Lactococcus lactis is a fermenting Gram-positive bacterium widely used for production of dairy products. Lacking haem biosynthesis genes, L. lactis can still shift to an energetically favourable respiratory metabolism by activating a terminal cytochrome bd oxidase when haem is added to an aerated culture. Haem intracellular homeostasis is mediated by the hrtRBA operon encoding the conserved membrane HrtBA haem efflux permease and the unique intracellular haem sensor and regulator, HrtR. Here we report that membrane-associated menaquinones (MK) favour the accumulation of reduced haem in membranes. An oxidative environment, provided by oxygen, prevents and reverses haemin reduction by MK and thus limits haem accumulation in membranes. HrtBA counteracts MK-dependent membrane retention of excess haem in membrane, suggesting direct efflux from this compartment. Moreover, both HrtBA and MK-mediated reduction have a strong impact on haem intracellular pools, as determined via HrtR haem sensor induction, suggesting that intracellular haem acquisition is controlled at the membrane level without the need for dedicated import systems. Our conclusions lead to a new hypothesis of haem acquisition and regulation in which HrtBA and the bacterial membrane have central roles in L. lactis. PMID- 25040436 TI - Systematic review and recommendations for nonodontogenic toothache. AB - Nonodontogenic toothache is a painful condition that occurs in the absence of a clinically evident cause in the teeth or periodontal tissues. The purpose of this review is to improve the accuracy of diagnosis and the quality of dental treatment regarding nonodontogenic toothache. Electronic databases were searched to gather scientific evidence regarding related primary disorders and the management of nonodontogenic toothache. We evaluated the level of available evidence in scientific literature. There are a number of possible causes of nonodontogenic toothache and they should be treated. Nonodontogenic toothache can be categorised into eight groups according to primary disorders as follows: 1) myofascial pain referred to tooth/teeth, 2) neuropathic toothache, 3) idiopathic toothache, 4) neurovascular toothache, 5) sinus pain referred to tooth/teeth, 6) cardiac pain referred to tooth/teeth, 7) psychogenic toothache or toothache of psychosocial origin and 8) toothache caused by various other disorders. We concluded that unnecessary dental treatment should be avoided. PMID- 25040435 TI - Sleep duration is associated with white matter hyperintensity volume in older adults: the Northern Manhattan Study. AB - Self-reports of long or short sleep durations have indicated an association with cardiovascular morbidity and mortality, but there are limited data evaluating their association with white matter hyperintensity volume (WMHV), a marker of cerebral small vessel disease. We conducted a cross-sectional analysis of self reported sleep duration to test for a correlation with white matter hyperintensities, measured by quantitative magnetic resonance imaging (MRI), in the Northern Manhattan Study. We used multivariable linear regression models to assess associations between both short (<6 h) and long (>=9 h) sleep durations and log-transformed WMHV, adjusting for demographic, behavioural and vascular risk factors. A total of 1244 participants, mean age 70 +/- 9 years, 61% women and 68% Hispanics were analysed with magnetic resonance brain imaging and self reported sleep duration. Short sleep was reported by 23% (n = 293) and long sleep by 10% (n = 121) of the sample. Long sleep (beta = 0.178; P = 0.035), but not short sleep (beta = -0.053; P = 0.357), was associated with greater log-WMHV in fully adjusted models. We observed an interaction between sleep duration, diabetes mellitus and log-WMHV (P = 0.07). In fully adjusted models, stratified analysis showed that long sleep duration was associated with greater WMHV only in those with diabetes (beta = 0.78; P = 0.0314), but not in those without diabetes (beta = 0.022; P = 0.2), whereas short sleep was not associated with white matter hyperintensities in those with or without diabetes. In conclusion, long sleep duration was associated with a greater burden of white matter lesions in this stroke-free urban sample. The association was seen mainly among those with diabetes mellitus. PMID- 25040437 TI - Fatal Cleistanthus collinus toxicity: a case report and review of literature. AB - Cleistanthus collinus is an extremely toxic plant poison. We report a case of suicidal ingestion of boiled water decoction of C. collinus where the patient presented with abdominal pain and giddiness. There was persistent metabolic acidosis and fluctuation in the level of serum potassium. The ECG changes indicated a probable myocardial injury with conduction abnormality. At autopsy, the viscera were found to be congested. The toxins were detected in the viscera and blood by TLC and HPLC. Cleistanthin A and B, collinusin, and diphyllin are the principal toxic constituents of the plant. Consumption of a boiled decoction of leaves is highly toxic and, medical management of patients is mainly supportive because the molecular mechanisms of toxin action are unknown. In the recent years, C. collinus has created a considerable amount of interest because of its complex metabolites and their cytotoxic activities. Through this study, the authors have tried to highlight different properties pertaining to C. collinus. PMID- 25040438 TI - MRSA and VRE colonization in solid organ transplantation: a meta-analysis of published studies. AB - The burden of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococcus (VRE) colonization among the increasing number of solid organ transplant patients has not been systematically explored. We searched PubMed and EMBASE for pertinent articles, performed a meta-analysis of prevalence across eligible studies and estimated the risk of ensuing MRSA or VRE infections relative to colonization status. We stratified effects in the pretransplant and posttransplant period. Twenty-three studies were considered eligible. Seventeen out of 23 (74%) referred to liver transplants. Before transplantation, the pooled prevalence estimate for MRSA and VRE was 8.5% (95% confidence interval [CI] 3.2 15.8) and 11.9% (95% CI 6.8-18.2), respectively. MRSA estimate was influenced by small studies and was lower (4.0%; 95% CI 0.4-10.2) across large studies (>200 patients). After transplantation, the prevalence estimates were 9.4% (95% CI 3.0 18.5) for MRSA and 16.2% (95% CI 10.7-22.6) for VRE. Pretransplant as well as posttransplant MRSA colonization significantly increased the risk for MRSA infections (pooled risk ratio [RR] 5.51; 95% CI 2.36-12.90 and RR 10.56; 95% CI 5.58-19.95, respectively). Pretransplant and posttransplant VRE colonization were also associated with significant risk of VRE infection (RR 6.65; 95% CI 2.54 17.41 and RR 7.93; 95% CI 2.36-26.67, respectively). Solid organ transplantation is a high-risk setting for MRSA and VRE colonization, and carrier state is associated with infection. Upgraded focus in prevention and eradication strategies is warranted. PMID- 25040439 TI - The prevalence of pre-eclampsia in migrant relative to native Norwegian women: a population-based study. AB - OBJECTIVE: To compare the prevalence of pre-eclampsia in migrant women with Norwegian women, and to study the prevalence of pre-eclampsia by length of residence in Norway. DESIGN: Observational study. SETTING: The Medical Birth Registry of Norway. POPULATION: All Norwegian, Pakistani, Vietnamese, Somali, Sri Lankan, Filipino, Iraqi, Thai and Afghan women who gave birth after 20 weeks of gestation during the period 1986-2005 in Norway. METHODS: The prevalence of pre eclampsia was calculated by country of birth. The association of country of birth and length of residence in Norway with pre-eclampsia was estimated as the odds ratio (OR) with 95% confidence interval (CI), using Norwegian women as a reference. We made adjustments for maternal age, parity, multifetal pregnancy, year of delivery and maternal diabetes in multivariable analysis. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Migrant women had a lower prevalence of pre eclampsia than Norwegian women (2.7% versus 3.7%, P < 0.001). Vietnamese (OR, 0.36; CI, 0.29-0.45), Afghan (OR, 0.52; CI, 0.30-0.90) and Thai (OR, 0.57; CI, 0.45-0.73) women had the lowest risk of pre-eclampsia relative to Norwegian women. Adjustment for the variables above or separate analyses for nulliparous women did not change the estimates notably. Using Norwegian women as the reference, the risk of pre-eclampsia increased by length of residence for migrant women: adjusted OR of 0.64 (0.59-0.70) at <5 years and 0.91 (0.84-0.99) at >=5 years of residence. CONCLUSIONS: The risk of pre-eclampsia was lower in migrants relative to Norwegian women, but increased by length of residence in Norway. PMID- 25040440 TI - Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. AB - BACKGROUND: Although warfarin and other vitamin K antagonists (VKAs) are the most widely used oral anticoagulants for the prevention and treatment of thromboembolic events, a number of factors hamper their manageability, the most important being the inter-individual variability of the therapeutic dose requirement. Following the discovery of the influence of CYP2C9 and VKORC1 polymorphisms on VKA dose requirements, there has been interest in genotype guided VKA dosing in order to reduce the risk of over-anticoagulation at the time of therapy initiation and hence the risk of bleeding, particularly prominent during the early days of treatment. To assess the impact on clinical outcomes of pharmacogenetic testing for initial VKA dosing, we have performed a systematic review and meta-analysis of the literature. METHODS: MEDLINE, EMBASE and Cochrane databases were searched up to March 2014. Only randomized controlled trials comparing genotype-guided vs. clinically-guided warfarin dosing were included. RESULTS: Nine trials including 2812 patients met the inclusion criteria and were pooled for meta-analytical evaluation. Risk of bias, assessed according to the Cochrane methodology, showed a low risk for the majority of domains analyzed in the included trials. A statistically significant reduction in the risk ratio (RR) for developing major bleeding events was observed in the pharmacogenetic-guided group compared with the control group (RR = 0.47; 95% CI, 0.23-0.96; P = 0.040). CONCLUSIONS: The results of this meta-analysis show that genotype-guided initial VKA dosing is able to reduce serious bleeding events by approximately 50% compared with clinically-guided dosing approaches. PMID- 25040441 TI - A preliminary study of silver sodium zirconium phosphate polyurethane foam wound dressing on wounds of the distal aspect of the forelimb in horses. AB - OBJECTIVE: To determine if application of silver sodium zirconium phosphate polyurethane semi-occlusive foam (SPF) dressing would improve measures of wound healing and decrease bacterial contamination compared with a non-adherent, absorbent dressing applied to wounds created on the distal aspect of the equine limb. STUDY DESIGN: Controlled randomized experimental study. ANIMALS: Adult Quarter Horse and Thoroughbred horses (n = 5). METHODS: One 6.25 cm(2) wound was created on the dorsomedial aspect of the proximal metacarpus on each forelimb. A SPF dressing was applied to 1 randomly assigned limb as a treatment and a non adherent, absorbent dressing was applied to the opposite limb as control. Bandages were changed every 3 days for 60 days. Granulation tissue was scored every 3 days, wound area measured every 6 days, and wound bed was cultured every 12 days. RESULTS: SPF-treatment wounds had significantly decreased wound area and decreased granulation tissue scores when evaluated <30 days and over the 60 day study, although complete wound healing times were not significantly different. Bacteria were cultured from all wounds at varying times throughout the study. CONCLUSIONS: The SPF wound dressing improved some measures of wound healing compared with the control dressing, most significantly during the first 30 days. This suggests that the SPF wound dressing may be useful in the early management of wounds on the equine lower limb. Further studies using the SPF dressing are needed to characterize the temporal and cellular effects on wound healing and evaluate this dressing in a clinical environment. PMID- 25040442 TI - Talking about sex with health professionals: the experience of people with cancer and their partners. AB - Changes to sexuality can be one of the most difficult aspects of life following cancer. This study examines the experience of discussing sexuality post cancer with health care professionals (HCPs), from the perspective of women and men with cancer (PWC), and their partners (PPWC), across a range of cancer types. A total of 657 PWC (535 women, 122 men) and 148 PPWC (87 women, 61 men) completed a survey containing closed and open-ended items, analysed by analysis of variance and thematic analysis. Discussions about sexuality with a HCP were more likely to be reported by men (68%) compared to women PWC (43%), and by women (47%) compared to men PPWC (28%), as well as by those with a sexual or reproductive cancer. Men PWC and women PPWC were most likely to want to discuss sexuality with a HCP, with men PWC and PPWC reporting highest levels of satisfaction with such discussions. Open-ended responses revealed dissatisfaction with the unwillingness of HCPs to discuss sexuality, unhappiness with the nature of such discussion, and positive accounts of discussions about sexuality with HCPs. These findings lend support to the notion that people with cancer and their partners may have unmet sexual information and support needs. PMID- 25040443 TI - Microbe driven T-helper cell differentiation: lessons from Candida albicans and Staphylococcus aureus. AB - T-helper cells integrate signals from their T-cell receptor, co-stimulatory molecules and cytokine receptors to polarize into effector T-helper subsets with specialized functions in antigen clearance or tolerance. To this end, antigen presenting cells and the local microenvironment tailor effector T-helper cells to respond appropriately to microbial challenges. These challenges comprise protection from pathogens on the one hand and tolerance for the commensal microbiota on the other hand. To accomplish these complex tasks, the host immune system needs to be highly specialized and stringently regulated. In this viewpoint article, we will concentrate on how microbes shape human T-helper cell responses and how this could relate to the emergence of chronic inflammatory diseases. Understanding the intricate communication between adaptive immunity and microbes will be important for the rational design of novel immunomodulatory therapies and also for anticipating infectious complications upon therapeutic intervention with cytokine depleting therapies, such as biologicals in dermatology. PMID- 25040444 TI - Adults with congenital heart disease: at long last, guidelines for arrhythmia management. PMID- 25040446 TI - Evaluation of the appreciation of virtual teeth with and without pathology. AB - AIM: Virtual teeth with and without tooth pathology have been developed for use in a virtual learning environment in dental education. The objective of this study was to evaluate the appearance of these virtual teeth for use in dental education and to compare them with contemporary educational models, such as plastic teeth (Frasaco GmbH) and extracted human teeth. MATERIAL AND METHODS: Six sets of photographs representing six different teeth were shown to dentists, teachers (dentists) and dental students (bachelor's and master's degree students). Each set consisted of 15 pictures showing five views of the extracted human tooth, the similar virtual tooth and the plastic tooth. The five views represented the mesial, distal, occlusal, buccal and lingual surfaces. The virtual tooth was the same as the extracted tooth (scanned with a cone beam CT, coloured and edited in ColorMapEditor((r)) ), and the plastic tooth presented the best possible match to the extracted tooth. The participants were asked to rate the appearance of the virtual teeth (overall and in terms of caries, restoration and colours), whether the virtual or plastic teeth resembled the extracted teeth better and from which teeth they expected to learn the most (extracted, virtual or plastic). RESULTS: Each group of participants found that the virtual teeth resembled the extracted teeth more than they resembled the plastic teeth; 71% of the participants expected to learn more from the virtual teeth than from the plastic teeth. CONCLUSION: The results show that the appearance of the virtual teeth was considered more realistic than the appearance of the plastic teeth. The expectation was that the learning opportunities of the virtual teeth are better than of the plastic teeth. PMID- 25040445 TI - Maspin expression patterns differ in the invasive versus lepidic growth pattern of pulmonary adenocarcinoma. AB - AIMS: To test whether changes in the subcellular localization of maspin parallel morphological progression in pulmonary adenocarcinoma, we compared its expression between lepidic and invasive growth patterns. METHODS: Applying immunohistochemistry, we compared maspin expression in lepidic and invasive growth patterns occurring in different tumours (series #1, n = 86) as well as within the same tumour and in the same section (series #2, n = 29). RESULTS: In both series, the lepidic growth pattern (n = 45) was significantly associated with nuclear maspin, while the invasive (n = 70) with combined nuclear and cytoplasmic maspin (P < 0.05). In the second series, transition from a lepidic to an invasive pattern in the same tumour was associated predominantly with a shift respectively from a nuclear to a combined nuclear and cytoplasmic maspin (15/29) or preservation of nuclear expression (8/29). A shift from nuclear maspin to negative expression (3/29) or other patterns (3/29) were also observed. CONCLUSIONS: Nuclear maspin is a typical but not exclusive feature of the lepidic growth pattern of pulmonary adenocarcinoma, whereas combined nuclear and cytoplasmic maspin characterizes invasion. These data show that changes of expression and subcellular localization of maspin may constitute an important biological end point of tumour progression and aid in the classification of lung adenocarcinoma. PMID- 25040447 TI - A randomized clinical trial of a financial education intervention with nicotine replacement therapy (NRT) for low socio-economic status Australian smokers: a study protocol. AB - BACKGROUND AND AIMS: Reducing smoking prevalence among smokers from low socio economic status (SES) is a preventative health priority. Financial stress (e.g. shortage of money or inability to pay bills) may be a major barrier to quitting smoking. This study evaluates the efficacy of a financial education and support programme coupled with pharmacotherapy at improving cessation rates at 8-month follow-up among Australian low SES smokers (people receiving a government pension or allowance). DESIGN: A two-group parallel block randomized (ratio 1 : 1) open label clinical trial (RCT) with allocation concealment will be conducted. Allocation will be concealed to interviewers at data collection-points. SETTING: The study will be conducted primarily by telephone with baseline, follow-up interviews and telephone-based support sessions. Nicotine replacement therapy (NRT) delivery will be mail-based. PARTICIPANTS: Daily smokers who are interested in quitting smoking and are currently in receipt of government benefits (n = 1046) will be recruited through study advertisements placed in newspapers, posters placed in government social assistance agencies and Quitline telephone based cessation support services. After completion of a baseline computer assisted telephone interview, participants will be allocated randomly to control or intervention group using a permuted block approach. INTERVENTION AND COMPARATOR: Participants in both groups will receive 8 weeks of free combination NRT plus Quitline support. Participants in the intervention group will also receive four telephone-delivered financial education and support sessions. MEASUREMENTS: The primary outcome measure will be prolonged abstinence (at 8 month follow-up) assessed using Russell Standard criteria and biochemically verified (urine cotinine). COMMENTS: This is the first intervention study to evaluate the potential of co-managing financial stress as a means of enhancing smokers' capacity to quit smoking. Such an intervention may provide a scalable intervention to help low SES smokers to quit. PMID- 25040448 TI - Variations in protein and fat contents and their fractions in milk from two species fed different forages. AB - This study aimed at determining the variations in milk constituents which could be varied by feed and animal species. To achieve this goal, two groups of homoparity Baladi cows and Egyptian buffaloes (n = 20 per species) were used. Each group was divided into two subgroups (n = 10): subgroup I received legume forage (Egyptian clover) and subgroup II received grass forage (sorghum forage). All experimental animals were fed the diet consisting of concentrate, forage and rice straw as 50, 25 and 25% of dry matter intake respectively. Milk samples were taken for analysis. The trial lasted until the 3rd month of parturition. The main results indicated that lactating cattle fed legume forage significantly (p <= 0.01) had more content of casein nitrogen (513 mg/100 ml milk), lower content of glutamic acid (23.56 g/100 g milk protein) and more content of cis-9, trans-11 18:2 conjugated linoleic acid (CLA) (0.77 g/100 g milk fat) compared with 433, 26.67 and 0.53, respectively, for cattle fed grass forage. With regard to the species effect, results showed that buffalo milk appeared to contain significantly higher (p <= 0.01) contents of casein nitrogen, phenylalanine, glutamic and arachidonic acid compared with cow's milk. However, the latter was significantly (p <= 0.01) more in the cis-9, trans-11CLA (0.59 g/100 g milk fat) than that in buffalo milk (0.47 g/100 g milk fat). The results revealed that not only forage type played a critical role in determining the variations of milk nitrogen distribution, milk amino acids and fatty acids but also animal species had a significant effect on these parameters. PMID- 25040449 TI - Cytomegalovirus infection in immunocompetent wheezy infants: the diagnostic value of CMV PCR in bronchoalveolar lavage fluid. AB - WHAT IS KNOWN AND OBJECTIVE: Cytomegalovirus (CMV) pneumonitis in immunocompetent hosts is uncommon but is being recognized more frequently, particularly when presenting as severe viral pneumonia. The objective of this study was to examine lower respiratory tract CMV infection in immunocompetent wheezy infants, based on polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) fluid, to compare CMV PCR results in BAL and in blood samples and to evaluate the benefits of antiviral ganciclovir therapy in these patients. METHODS: Retrospective review of the records of patients referred to our tertiary care hospital between January 2000 and July 2010 who had unexplained persistent wheezing and underwent fibreoptic flexible bronchoscopy (FFB). RESULTS AND DISCUSSION: Fibreoptic flexible bronchoscopy was applied to 102 infants with persistent wheezing and diffuse interstitial infiltration on radiological investigations; so CMV PCR in BAL fluid was performed. CMV PCR in BAL fluid was positive in 51 patients. Retrospectively, we had access to the files of 25 of these patients. The mean CMV PCR in BAL fluid was 334 840 copies/mL. Only eight patients had CMV PCR positivity in their blood samples (mean: 2026.3 copies/mL). There was not a relationship between BAL and blood CMV PCR values based on Spearman's correlation analysis (r = -0.008). Fourteen patients had severe respiratory symptoms and received ganciclovir therapy. Twelve of them fully recovered. WHAT IS NEW AND CONCLUSION: Bronchoalveolar lavage fluid CMV PCR was superior to blood CMV PCR in diagnosing lower respiratory tract infections caused by CMV in immunocompetent infants. Ganciclovir therapy may be effective in selected immunocompetent wheezy infants with CMV PCR positivity in BAL fluid. PMID- 25040450 TI - 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low grade B-cell lymphomas, including bulky disease. AB - (90) Y-ibritumomab-tiuxetan ((90) YIT) was used as a first-line therapy for patients with early-stage follicular lymphoma (FL) or marginal zone B-cell lymphoma (MZL). Thirty-one patients were treated, with an overall 3-month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow-up of 56 months, ten patients (32%) had disease relapse or progression. The progression-free rates at 3 and 5 years were lower in males, patients with FL, stage II disease and non-bulky disease, although they did not reach statistical significance. Grade 3-4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. (90) YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early-stage low-grade B-cell lymphomas. Bulky disease did not adversely affect tumour response. PMID- 25040451 TI - Enterocytozoon bieneusi genotypes in yaks (Bos grunniens) and their public health potential. AB - Enterocytozoon bieneusi, the most frequently diagnosed microsporidian species in humans, is also identified in a wide range of animals. To date, few data are available on E. bieneusi in yaks (Bos grunniens). In this study, we examined the occurrence and genotype identity of E. bieneusi in yaks in four counties in Qinghai Province of China. Of 327 fecal specimens examined by nested PCR analysis of the ribosomal internal transcribed spacer, 23 (7.0%) were E. bieneusi positive. DNA sequence analysis of the PCR products revealed the presence of five distinct genotypes: three Group 2 genotypes previously reported in cattle as well as humans (BEB4, I and J) and two novel genotypes (CHN11 and CHN12) belonging to the large zoonotic group (Group 1). Data of the study suggest that these animals could be potential reservoirs for human E. bieneusi infection. PMID- 25040452 TI - Sun protection in a pill: the photoprotective properties of Polypodium leucotomos extract. AB - BACKGROUND: Physical blocks (i.e. wearing appropriate clothing), exposure avoidance, and the use of sunscreens are the main methods of photoprotection currently used. However, phytochemical and natural botanical extracts such as polypodium leucotomos, a tropical fern found in Central and South America, demonstrate a strong potential as adjuncts to sunscreen protection. METHOD: A review of the literature was performed focusing on the photoprotective properties of PL extracts, including antioxidant, immunoregulatory, anti-inflammatory and antitumorigenic effects in the context of sunburn, photodermatoses, chronic skin damage, photoaging, and skin cancer. RESULTS: PL supplementation acts at a molecular and cellular level to enhance endogenous antioxidant systems and inhibit generation of reactive oxygen species, thus decreasing UV-mediated oxidative DNA mutations. PL has also been shown to accelerate removal of UV induced photoproducts, highlighting its anti-carcinogenic role. By reducing UV induced inflammatory responses and inhibiting extracellular matrix remodeling, PL demonstrates some protective effects against photoaging and PUVA induced phototoxicity. CONCLUSION: The use of a systemic protective agent would provide significant advantages such as a more uniform coverage over the total body surface area, regardless of individual factors such as potency of the creams, amount applied, sweating, or bathing. Oral administration of PL extracts and its favorable safety profile could have significant implications in the prevention of skin cancer. PMID- 25040453 TI - SNPQC--an R pipeline for quality control of Illumina SNP genotyping array data. AB - In genome-wide association studies, quality control (QC) of genotypes is important to avoid spurious results. It is also important to maintain long-term data integrity, particularly in settings with ongoing genotyping (e.g. estimation of genomic breeding values). Here we discuss SNPQc, a fully automated pipeline to perform QC analyses of Illumina SNP array data. It applies a wide range of common quality metrics with user-defined filtering thresholds to generate a comprehensive QC report and a filtered dataset, including a genomic relationship matrix, ready for further downstream analyses which make it amenable for integration in high-throughput environments. SNPQC also builds a database to store genotypic, phenotypic and quality metrics to ensure data integrity and the option of integrating more samples from subsequent runs. The program is generic across species and array designs, providing a convenient interface between the genotyping laboratory and downstream genome-wide association study or genomic prediction. PMID- 25040454 TI - Who is using long-acting reversible contraceptive methods? Findings from nine low fertility countries. AB - CONTEXT: Long-acting reversible contraceptive (LARC) methods-IUDs and implants are more effective than other reversible methods, yet are little used in the United States. Examining which U.S. women use LARC methods and how they differ from users in other low-fertility countries may help point the way toward increasing use. METHODS: Data from married or cohabiting women participating in the National Survey of Family Growth (2008-2010) and in eight countries' Generations and Gender Programme surveys (2004-2010) were used in bivariate and multinomial logistic regression analyses examining LARC use within each setting. RESULTS: The proportion of contraceptive use accounted for by LARC methods was generally greater in Europe (10-32%) than in the United States (10%) and Australia (7%). Compared with LARC use among comparable groups in other countries, use was particularly low among U.S. women who were married, were aged 40-44 or had had three or more children, yet was comparatively high among 18-24 year-olds. Among U.S. women, those aged 35-39 or 40-44 were more likely than 18 29-year-olds to rely on sterilization rather than on LARC methods (odds ratios, 3.0 and 10.7, respectively), those who had had three or more children were more likely to do so than were those who had had none or one (4.9), and women who had completed college were less likely than those who had not finished high school to do so (0.4). CONCLUSIONS: Certain subgroups of U.S. women may benefit from the reversibility and effectiveness of LARC methods. PMID- 25040455 TI - Color-matching strategies for non-vital discolored teeth: part 1. Laboratory ceramic veneer fabrication solutions. AB - The following is a case report exemplifying the restorative and esthetic correction of a discolored stump shade of a non-vital tooth maxillary left central incisor tooth. Treatment options are non-vital bleaching of the root canal-treated tooth or esthetic restoration through an understanding of color and layered ceramics, where the latter was employed. Proper shade communication as well as additional facial tooth preparation and reduction are key clinical requirements in order to allow the ceramist adequate room to affect a color change without sacrificing translucency or vitality of the definitive restorations. CLINICAL SIGNIFICANCE: Esthetic restorative correction of a discolored stump tooth shade can be managed with an understanding of color, shade communication, proper tooth preparation, and ceramic layering techniques. PMID- 25040456 TI - Hybrid songbirds employ intermediate routes in a migratory divide. AB - Migratory divides are contact zones between populations that use different routes to navigate around unsuitable areas on seasonal migration. Hybrids in divides have been predicted to employ intermediate and potentially inferior routes. We provide the first direct test of this hypothesis, using light-level geolocators to track birds breeding in a hybrid zone between Swainson's thrushes in western Canada. Compared to parental forms, hybrids exhibited increased variability in their migratory routes, with some using intermediate routes that crossed arid and mountainous regions, and some using the same routes as one parental group on fall migration and the other on spring migration. Hybrids also tended to use geographically intermediate wintering sites. Analysis of genetic variation across the hybrid zone suggests moderately strong selection against hybrids. These results indicate that seasonal migratory behaviour might be a source of selection against hybrids, supporting a possible role for migration in speciation. PMID- 25040457 TI - An interesting case of oedema and ulceration in red areas of tattoo. PMID- 25040458 TI - Insect bite-like reaction in association with chronic lymphocytic leukemia. PMID- 25040459 TI - Degree of extraversion and physiological responses to physical pain and sadness. AB - Extraversion is a personality frequently discussed as one of the strongest and most consistent factors that relates to individual subjective wellbeing. The goal of this study was to better understand how people with varying degrees of extraversion psychologically and physiologically respond differently to unpleasant circumstances. Emotional responses (e.g., levels of intensity, valence, and arousal) were assessed in determining the sensitivity level to negative stimuli that were specifically designed to provoke physical pain and sadness emotion. Physiological changes (e.g., heart rate (HR), blood volume pulse (BVP), and respiratory sinus arrhythmia (RSA)) were also measured during pain and sadness to observe sympathetic and parasympathetic activities. Our results showed that the degree of extraversion was associated with less unpleasant responses to sadness, less HR responses to both pain and sadness, and greater RSA responses to sadness. The findings suggest that the lower HR reactivity to painful and sad situations and greater RSA reactivity to sad situations in extraversion could be possibly due to increased parasympathetic activity. Additionally, enhanced parasympathetic activity to negative situations may explain an important mechanism underlying the positive connection between extraversion and subjective wellbeing. PMID- 25040460 TI - Evidence-based stillbirth prevention strategies: combining empirical and theoretical paradigms to inform health planning and decision-making. AB - INTRODUCTION: A global health project undertaken in Qatar on the Arabian Peninsula immersed undergraduate nursing students in hands-on learning to address the question: What strategies are effective in preventing stillbirth? Worldwide stillbirth estimates of 2.6 million per year and the high rate in the Eastern Mediterranean Region of 27 per 1,000 total live births provided the stimulus for this inquiry. METHODS: We used a dual empirical and theoretical approach that combined the principles of evidence-based practice and population health planning. Students were assisted to translate pre-appraised literature based on the 6S hierarchical pyramid of evidence. The PRECEDE-PROCEED (P-P) model served as an organizing template to assemble data extracted from the appraisal of 21 systematic literature reviews +/- meta-analyses, 2 synopses of synthesized reports, and 9 individual studies summarizing stillbirth prevention strategies in low, middle, and high income countries. Consistent with elements of the P-P model, stillbirth prevention strategies were classified as social, epidemiological, educational, ecological, administrative, or policy. RESULTS: Ten recommendations with clear evidence of effectiveness in preventing stillbirth in low, middle, or high income countries were identified. Several other promising interventions were identified with weak, uncertain, or inconclusive evidence. These require further rigorous testing. LINKING EVIDENCE TO ACTION: Two complementary paradigms--evidence-based practice and an ecological population health program planning model--helped baccalaureate nursing students transfer research evidence into useable knowledge for practice. They learned the importance of comprehensive assessments and evidence-informed interventions. The multidimensional elements of the P-P model sensitized students to the complex interrelated factors influencing stillbirth and its prevention. PMID- 25040461 TI - Multiorgan transplantation from a deceased donor with intravascular diffuse large B-cell lymphoma: transmission of the disease and results of treatment. AB - This report presents the transplantation of two kidneys and the liver from a deceased donor with suspected autoimmune encephalomeningitis (ADEM). Due to an atypical post-transplantation clinical course, the transplanted kidneys were biopsied and this disclosed diffuse large B-cell (DLBC) lymphoma of the intravascular type in each kidney. The same malignancy was found in the postmortem donor brain examination. The renal allografts from the two recipients were removed: despite every effort, one patient died, while chemotherapy was successful in the second. No malignancy was observed in the liver transplant recipient, who received prophylactic chemotherapy. These cases highlight the occasional failure of organ donor disease screening and the consequent unforeseen complications. PMID- 25040462 TI - Treating concurrent chronic low back pain and depression with low-dose venlafaxine: an initial identification of "easy-to-use" clinical predictors of early response. AB - OBJECTIVE: Depression and chronic low back pain (CLBP) are both frequent and commonly comorbid in older adults seeking primary care. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine may be effective in treating comorbid depression and CLBP. For patients with comorbid depression and CLBP, our goal was to identify "easy-to-use" early clinical variables associated with response to 6 weeks of low-dose venlafaxine pharmacotherapy that could be used to construct a clinically useful predictive model in future studies. METHODS: We report data from the first 140 patients completing phase 1 of the Addressing Depression and Pain Together clinical trial. Patients aged >=60 with concurrent depression and CLBP received 6 weeks of open-label venlafaxine 150 mg/day and supportive management. Using univariate and multivariate methods, we examined a variety of clinical predictors and their association with response to both depression and CLBP; change in depression; and change in pain scores at 6 weeks. RESULTS: About 26.4% of patients responded for both depression and pain with venlafaxine. Early improvement in pain at 2 weeks predicted improved response rates (P = 0.027). Similarly, positive changes in depression and pain at 2 weeks independently predicted continued improvement at 6 weeks in depression and pain, respectively (P < 0.001). CONCLUSIONS: An important minority of patients benefitted from 6 weeks of venlafaxine 150 mg/day. Early improvement in depression and pain at 2 weeks may predict continued improvement at week 6. Future studies must examine whether patients who have a poor initial response may benefit from increasing the SNRI dose, switching, or augmenting with other treatments after 2 weeks of pharmacotherapy. PMID- 25040463 TI - Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. AB - Clostridium difficile infections (CDIs) are frequent in hospitals, but also seem to increase in the community. Here, we aim to determine the incidence of CDI in general practice and to evaluate current testing algorithms for CDI. Three Dutch laboratories tested all unformed faeces (12,714) for C. difficile when diagnostic testing (for any enteric pathogen) was requested by a general practitioner (GP). Additionally, a nested case-control study was initiated, including 152 CDI patients and 304 age and sex-matched controls. Patients were compared using weighted multivariable logistic regression. One hundred and ninety-four samples (1.5%) were positive for C. difficile (incidence 0.67/10,000 patient years). This incidence was comparable to that of Salmonella spp. Compared with diarrhoeal controls, CDI was associated with more severe complaints, underlying diseases, antibiotic use and prior hospitalization. In our study, GPs requested a test for C. difficile in 7% of the stool samples, thereby detecting 40% of all CDIs. Dutch national recommendations advise testing for C. difficile when prior antibiotic use or hospitalization is present (18% of samples). If these recommendations were followed, 61% of all CDIs would have been detected. In conclusion, C. difficile is relatively frequent in general practice. Currently, testing for C. difficile is rare and only 40% of CDI in general practice is detected. Following recommendations that are based on traditional risk factors for CDI, would improve detection of CDI. PMID- 25040464 TI - A pleiotropic drug resistance transporter is involved in reduced sensitivity to multiple fungicide classes in Sclerotinia homoeocarpa (F.T. Bennett). AB - Dollar spot, caused by Sclerotinia homoeocarpa, is a prevalent turfgrass disease, and the fungus exhibits widespread fungicide resistance in North America. In a previous study, an ABC-G transporter, ShatrD, was associated with practical field resistance to demethylation inhibitor (DMI) fungicides. Mining of ABC-G transporters, also known as pleiotropic drug resistance (PDR) transporters, from RNA-Seq data gave an assortment of transcripts, several with high sequence similarity to functionally characterized transporters from Botrytis cinerea, and others with closest blastx hits from Aspergillus and Monilinia. In addition to ShatrD, another PDR transporter showed significant over-expression in replicated RNA-Seq data, and in a collection of field-resistant isolates, as measured by quantitative polymerase chain reaction. These isolates also showed reduced sensitivity to unrelated fungicide classes. Using a yeast complementation system, we sought to test the hypothesis that this PDR transporter effluxes DMI as well as chemically unrelated fungicides. The transporter (ShPDR1) was cloned into the Gal1 expression vector and transformed into a yeast PDR transporter deletion mutant, AD12345678. Complementation assays indicated that ShPDR1 complemented the mutant in the presence of propiconazole (DMI), iprodione (dicarboximide) and boscalid (SDHI, succinate dehydrogenase inhibitor). Our results indicate that the over-expression of ShPDR1 is correlated with practical field resistance to DMI fungicides and reduced sensitivity to dicarboximide and SDHI fungicides. These findings highlight the potential for the eventual development of a multidrug resistance phenotype in this pathogen. In addition, this study presents a pipeline for the discovery and validation of fungicide resistance genes using de novo next-generation sequencing and molecular biology techniques in an unsequenced plant pathogenic fungus. PMID- 25040465 TI - "I know you don't know I know..." children use second-order false-belief reasoning for peer coordination. AB - Numerous studies have investigated children's abilities to attribute mental states, but few have examined their ability to recruit these abilities in social interactions. Here, 6-year-olds (N = 104) were tested on whether they can use first- and second-order false-belief understanding to coordinate with peers. Children adjusted their decisions in a coordination game in response to either their partner's erroneous belief or their partner's erroneous belief about their own belief-a result that contrasts with previous findings on the use of higher order "theory of mind" (TOM) reasoning at this age. Six-year-olds are thus able to use their higher order TOM capacities for peer coordination, which marks an important achievement in becoming competent social collaborators. PMID- 25040466 TI - Psychological and cognitive impairment of long-term migrators to high altitudes and the relationship to physiological and biochemical changes. AB - BACKGROUND AND PURPOSE: The present study aimed to examine how long-term migration to high-altitude regions affects mentality and cognition, and the correlation with various physiological and biochemical changes. METHODS: The WHO Neurobehavioral Core Test Battery, Raven's Standard Progressive Matrices (RSPM) and Pittsburgh Sleep Quality Index questionnaire were used to assess 141 young male subjects who lived in plain regions and 217 young male subjects who had migrated to a 4500 m high-altitude region and lived there for 1-5 years. Arterial oxyhemoglobin saturation, cerebral tissue oxygenation indices (TOIs), serum S100B and brain-derived neurotrophic factor (BDNF) were also measured. RESULTS: Long term migrators to a high-altitude region exhibited exacerbated mood disorders, retarded color discrimination ability, decreased visual memory capacity, and impaired perceptual motor skill and motion stability. In addition, the migrators exhibited lower RSPM scores and lower sleep quality. Further analyses revealed significant correlations between sleep quality and cerebral TOIs, mood and sleep quality, mood and certain cognitive functions, mood and serum BDNF levels, and RSPM scores and serum S100B levels. CONCLUSIONS: Long-term living at high altitudes causes significant impairment of psychological and cognitive function. Cerebral hypoxic extent, sleep quality and biochemical dysfunction are major influencing factors. PMID- 25040469 TI - Extended proximal trochleoplasty for the correction of bidirectional patellar luxation in seven Pomeranian dogs. AB - Seven Pomeranians with bidirectional patellar luxation (BPL) were prospectively studied regarding aetiology and results of a new surgical technique. Radiographic evaluation of the ratio between patellar ligament length and patellar bone length revealed no differences between Pomeranians with bidirectional patellar luxation and healthy stifle joints. Functional rather than anatomic patella alta might be associated with bidirectional patellar luxation in Pomeranians. The surgical outcome of extended proximal trochleoplasty was good-to-excellent in 87.5% of the stifles and all dogs achieved functional recovery. There was only minimal radiographic progression of osteophyte formation at 48 weeks after surgery. To the authors' knowledge, this is the first report on bidirectional patellar luxation in small breed dogs and its successful surgical treatment. PMID- 25040467 TI - Lung xenotransplantation: recent progress and current status. AB - Xenotransplantation has undergone important progress in controlling initial hyperacute rejection in many preclinical models, with some cell, tissue, and organ xenografts advancing toward clinical trials. However, acute injury, driven primarily by innate immune and inflammatory responses, continues to limit results in lung xenograft models. The purpose of this article is to review the current status of lung xenotransplantation--including the seemingly unique challenges posed by this organ-and summarize proven and emerging means of overcoming acute lung xenograft injury. PMID- 25040470 TI - Scoring system for the prediction of severe acute pancreatitis in children. AB - BACKGROUND: The lack of an accurate scoring system for pediatric acute pancreatitis could cause delays in appropriate clinical management and increase the risk of progressive life-threatening complications. We investigated a modified Ministry of Health, Labour and Welfare of Japan (JPN) scoring system that uses pediatric systemic inflammatory response syndrome (SIRS) score, age, and weight to establish a more useful scoring system for children. METHODS: A retrospective chart review was conducted of pediatric patients with acute pancreatitis who were admitted to Juntendo University Hospital between 1985 and 2011. The sensitivity, specificity, and positive and negative predictive values of the pediatric JPN scoring system were calculated and then compared with those of previously developed scoring systems. RESULTS: The patient group consisted of 145 patients (88 girls, 57 boys). The pediatric JPN score had greater sensitivity (80%) than the Ranson (60%), modified Glasgow (50%), and DeBanto (60%) scores. The specificity was 96% for the pediatric JPN score, 94% for the Ranson score, 99% for the modified Glasgow score, and 86% for the DeBanto score. CONCLUSION: The pediatric JPN score can be used to predict severe acute pancreatitis during the initial medical assessment. PMID- 25040468 TI - Evidence for the prevention and treatment of stroke in dialysis patients. AB - The risks of both ischemic and hemorrhagic stroke are particularly high in dialysis patients of any age and outcomes are poor. It is therefore important to identify strategies that safely minimize stroke risk in this population. Observational studies have been unable to clarify the relative importance of traditional stroke risk factors such as blood pressure and cholesterol in those on dialysis, and are affected by biases that usually make them an inappropriate source of data on which to base therapeutic decisions. Well-conducted randomized trials are not susceptible to such biases and can reliably investigate the causal nature of the association between a potential risk factor and the outcome of interest. However, dialysis patients have been under-represented in the cardiovascular trials which have proven net benefit of commonly used preventative treatments (e.g., antihypertensive treatments, low-dose aspirin, carotid revascularization, and thromboprophylaxis for atrial fibrillation), and there remains uncertainty about safety and efficacy of many of these treatments in this high-risk population. Moreover, the efficacy of renal-specific therapies that might reduce cardiovascular risk, such as modulators of mineral and bone disorder, online hemodiafiltration, and daily (nocturnal) hemodialysis, have not been tested in adequately powered trials. Recent trials have also demonstrated how widespread current practices could be causing stroke. Therefore, it is important that reliable information on the prevention and treatment of stroke (and other cardiovascular disease) in dialysis patients is generated by performing large-scale randomized trials of many current and future treatments. PMID- 25040471 TI - Ataxia telangiectasia: more variation at clinical and cellular levels. AB - Ataxia telangiectasia (A-T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by auto(trans)phosphorylation in response to DNA double strand breaks and leads to the activation of cell cycle checkpoints and either DNA repair or apoptosis as part of the cellular response to DNA damage. The allelic heterogeneity in A-T is striking. While the majority of mutations are truncating, leading to instability and loss of the ATM protein from the allele, a significant proportion of patients carry one of a small number of mutations that are either missense or leaky splice site mutations resulting in retention of some ATM with activity. The allelic heterogeneity in ATM, therefore, results in an equally striking clinical heterogeneity. There is also locus heterogeneity because mutation of the MRE11 gene can cause an obvious A-T like disorder both clinically and also at the cellular level and mutation of the RNF168 gene results in a much milder clinical phenotype, neurologically, with the major clinical feature being an immunological defect. PMID- 25040472 TI - No clear evidence that exergames can prevent obesity. PMID- 25040473 TI - Response to letter: no clear evidence that exergames can prevent obesity. PMID- 25040475 TI - Rectal perforation following transanal irrigation. PMID- 25040474 TI - Genetic characterization and genotyping of hepatitis B virus (HBV) isolates from donors with an occult HBV infection. AB - BACKGROUND AND OBJECTIVES: Screening of Thai blood donors has resulted in the detection of donors with an occult HBV infection (OBI), where HBsAg is undetectable, but hepatitis B virus (HBV) DNA is present in serum in low concentrations. This study was designed to determine whether the occurrence of OBI in donors was linked to the HBV genotype and possibly to mutations in the surface (S) and core (C) gene regions. MATERIALS AND METHODS: Mutations in the S and C gene regions in 48 Thai donors with OBI were mapped by sequencing. Genotyping was determined with the INNO-LiPA test and by phylogenetic analysis of sequences from the S and C genes. RESULTS: The majority of OBI samples were genotype C (81.3%) with 6.3% of samples being genotype B. In addition, two genotype I isolates were identified. Mutations in the S region (100%) were found especially in loop 1 of the major hydrophilic loop (MHL) at positions I110L, T114S, T126I and S113T, whereas mutations in the C region (65%) were within the basal core promoter region (position A1762T/G1764A) and precore region (position G1896A). CONCLUSION: The majority of OBI samples were HBV genotype C, although genotype I, which is newly emerging in Thailand, was also detected. The study demonstrated that OBI was probably not associated with a particular HBV genotype or with certain mutations in the S and C gene regions. However, mutations in the C gene region which could potentially impair viral replication and HBsAg production and potentially lead to OBI were identified. PMID- 25040476 TI - FgSKN7 and FgATF1 have overlapping functions in ascosporogenesis, pathogenesis and stress responses in Fusarium graminearum. AB - Fusarium head blight caused by Fusarium graminearum is one of the most destructive diseases of wheat and barley. Deoxynivalenol (DON) produced by the pathogen is an important mycotoxins and virulence factor. Because oxidative burst is a common defense response and reactive oxygen species (ROS) induces DON production, in this study, we characterized functional relationships of three stress-related transcription factor genes FgAP1, FgATF1 and FgSKN7. Although all of them played a role in tolerance to oxidative stress, deletion of FgAP1 or FgATF1 had no significant effect on DON production. In contrast, Fgskn7 mutants were reduced in DON production and defective in H2 O2 -induced TRI gene expression. The Fgap1 mutant had no detectable phenotype other than increased sensitivity to H2 O2 and Fgap1 Fgatf1 and Fgap1 Fgskn7 mutants lacked additional or more severe phenotypes than the single mutants. The Fgatf1, but not Fgskn7, mutant was significantly reduced in virulence and delayed in ascospore release. The Fgskn7 Fgatf1 double mutant had more severe defects in growth, conidiation and virulence than the Fgatf1 or Fgskn7 mutant. Instead of producing four-celled ascospores, it formed eight small, single-celled ascospores in each ascus. Therefore, FgSKN7 and FgATF1 must have overlapping functions in intracellular ROS signalling for growth, development and pathogenesis in F. graminearum. PMID- 25040477 TI - Regulation of pepc gene expression in Anabaena sp. PCC 7120 and its effects on cyclic electron flow around photosystem I and tolerances to environmental stresses. AB - Since pepc gene encoding phosphoenolpyruvate carboxylase (PEPCase) has been cloned from Anabaena sp. PCC 7120 and other cyanobacteria, the effects of pepc gene expression on photosynthesis have not been reported yet. In this study, we constructed mutants containing either upregulated (forward) or downregulated (reverse) pepc gene in Anabaena sp. PCC 7120. Results from real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and enzymatic analysis showed that PEPCase activity was significantly reduced in the reverse mutant compared with the wild type, and that of the forward mutant was obviously increased. Interestingly, the net photosynthesis in both the reverse mutant and the forward mutant were higher than that of the wild type, but dark respiration was decreased only in the reverse mutant. The absorbance changes of P700 upon saturation pulse showed the photosystem I (PSI) activity was inhibited, as reflected by Y(I), and Y(NA) was elevated, and dark reduction of P700(+) was stimulated, indicating enhanced cyclic electron flow (CEF) around PSI in the reverse mutant. Additionally, the reverse mutant photosynthesis was higher than that of the wild type in low temperature, low and high pH, and high salinity, and this implies increased tolerance in the reverse mutant through downregulated pepc gene. PMID- 25040478 TI - Identification of two novel alleles HLA-A*11:133 and A*11:02:05 by polymerase chain reaction sequence-based typing. AB - HLA-A*11:113 shows one nucleotide difference from HLA-A*11:01:01: HLA-A*11:02:05 shows a single nucleotide difference from HLA-A*11:02:01. PMID- 25040479 TI - Lower free testosterone level is correlated with left ventricular diastolic dysfunction in asymptomatic middle-aged men with type 2 diabetes mellitus. AB - AIMS: Low testosterone (T) level is associated with cardiovascular risk factors. However, the relationship between T level and heart function in asymptomatic men with type 2 diabetes mellitus (T2DM) is unknown. METHODS: A total of 325 men were recruited who had no history, symptoms, or signs of heart disease. RESULTS: T2DM had significantly lower free T (FT) levels than those with normal glucose metabolism (NGM) (428 +/- 38 pmol/l vs. 444 +/- 38 pmol/l, p = 0.0002), and had an increased risk of LVDD (66.1% vs. 31.8%). There was a significant difference in FT level between subjects with and without LVDD among those with T2DM (421 +/- 37 pmol/l vs. 442 +/- 40 pmol/l, p = 0.0007), but not among those with NGM (439 +/- 37 pmol/l vs. 447 +/- 39 pmol/l, p = 0.247) or in the group overall (426 +/- 38 pmol/l vs. 445 +/- 38 pmol/l, p = 0.156). Lower FT level was significantly associated with LVDD [univariate odds ratio (OR) = 0.63, p = 0.032; multivariate OR = 0.71, p = 0.039]. Receiver operating characteristic curve analysis of the usefulness of FT level for predicting LVDD showed an area under the curve (AUC) of 0.85 for T2DM (p < 0.001) and 0.66 for NGM (p < 0.05). FT level had a high predictive value for LVDD in T2DM (83% for FT < 414 pmol/l), but a low predictive value in NGM (61% for FT < 423 pmol/l). Comparison of the AUCs showed that FT level was more strongly correlated with LVDD in T2DM than in NGM. CONCLUSIONS: Lower FT level is correlated with LVDD in asymptomatic middle-aged men with T2DM. PMID- 25040480 TI - Utility of the exercise electrocardiogram testing in sudden cardiac death risk stratification. AB - BACKGROUND: Sudden cardiac death (SCD) remains a major public health problem. Current established criteria identifying those at risk of sudden arrhythmic death, and likely to benefit from implantable cardioverter defibrillators (ICDs), are neither sensitive nor specific. Exercise electrocardiogram (ECG) testing was traditionally used for information concerning patients' symptoms, exercise capacity, cardiovascular function, myocardial ischemia detection, and hemodynamic responses during activity in patients with hypertrophic cardiomyopathy. METHODS: We conducted a systematic review of MEDLINE on the utility of exercise ECG testing in SCD risk stratification. RESULTS: Exercise testing can unmask suspected primary electrical diseases in certain patients (catecholaminergic polymorphic ventricular tachycardia or concealed long QT syndrome) and can be effectively utilized to risk stratify patients at an increased (such as early repolarization syndrome and Brugada syndrome) or decreased risk of SCD, such as the loss of preexcitation on exercise testing in asymptomatic Wolff-Parkinson White syndrome. CONCLUSIONS: Exercise ECG testing helps in SCD risk stratification in patients with and without arrhythmogenic hereditary syndromes. PMID- 25040481 TI - Effect of flecainide on T-wave alternans in Andersen-Tawil syndrome. PMID- 25040482 TI - Response to baranchuk et Al. PMID- 25040483 TI - Parturitional injury of the head and neck. AB - Parturitional injuries refer to injuries sustained during and secondary to fetal delivery. The skull, brain, and head and neck regions are frequently involved. Accurate differentiation and classification of the various injuries is essential for treatment, prognosis, and parental counseling. In this review, we discuss the various "bumps and lumps" that maybe encountered along the neonatal skull as well as the most frequent calvarial and intracranial parturitional injuries. In addition, a short discussion of the most common head and neck, facial, and spinal lesions is included. Various mimickers and risk factors are also presented. PMID- 25040484 TI - In vitro assessment of artifacts induced by titanium, titanium-zirconium and zirconium dioxide implants in cone-beam computed tomography. AB - AIM: The aim of this study was to test whether or not the intensity of artifacts around implants in cone-beam computed tomography (CBCT) differs between titanium, titanium-zirconium and zirconium dioxide implants. MATERIALS AND METHODS: Twenty models of a human mandible, each containing one implant in the single-tooth gap position 45, were cast in dental stone. Five test models were produced for each of the following implant types: titanium 4.1 mm diameter (Ti4.1 ), titanium 3.3 mm diameter (Ti3.3 ), titanium-zirconium 3.3 mm diameter (TiZr3.3 ) and zirconium dioxide 3.5-4.5 mm diameter (ZrO3.5-4.5 ) implants. For control purposes, three models without implants were produced. Each model was scanned using a CBCT device. Gray values (GV) were recorded at eight circumferential positions around the implants at 0.5 mm, 1 mm and 2 mm from the implant surface (GVT est ). GV were assessed in the corresponding volumes of interest (VOI) in the control models without implants (GVC ontrol ). Differences of gray values (DeltaGV) between GVT est and GVC ontrol were calculated as percentages. One-way ANOVA and post hoc tests were applied to detect differences between implant types. RESULTS: Mean DeltaGV for ZrO3.5-4.5 presented the highest absolute values, generally followed by TiZr3.3 , Ti4.1 and Ti3.3 implants. The differences of DeltaGV between ZrO3.5-4.5 and the remaining groups were statistically significant in the majority of the VOI (P <= 0.0167). DeltaGV for TiZr3.3 , Ti4.1 and Ti3.3 implants did not differ significantly in the most VOI. For all implant types, DeltaGV showed positive values buccally, mesio-buccally, lingually and disto-lingually, whereas negative values were detected mesially and distally. CONCLUSIONS: Zirconium dioxide implants generate significantly more artifacts as compared to titanium and titanium-zirconium implants. The intensity of artifacts around zirconium dioxide implants exhibited in average the threefold in comparison with titanium implants. PMID- 25040485 TI - The early effects of Medicare's mandatory hospital pay-for-performance program. AB - OBJECTIVE: To evaluate the impact of hospital value-based purchasing (HVBP) on clinical quality and patient experience during its initial implementation period (July 2011-March 2012). DATA SOURCES: Hospital-level clinical quality and patient experience data from Hospital Compare from up to 5 years before and three quarters after HVBP was initiated. STUDY DESIGN: Acute care hospitals were exposed to HVBP by mandate while critical access hospitals and hospitals located in Maryland were not exposed. We performed a difference-in-differences analysis, comparing performance on 12 incentivized clinical process and 8 incentivized patient experience measures between hospitals exposed to the program and a matched comparison group of nonexposed hospitals. We also evaluated whether hospitals that were ultimately exposed to HVBP may have anticipated the program by improving quality in advance of its introduction. PRINCIPAL FINDINGS: Difference-in-differences estimates indicated that hospitals that were exposed to HVBP did not show greater improvement for either the clinical process or patient experience measures during the program's first implementation period. Estimates from our preferred specification showed that HVBP was associated with a 0.51 percentage point reduction in composite quality for the clinical process measures (p > .10, 95 percent CI: -1.37, 0.34) and a 0.30 percentage point reduction in composite quality for the patient experience measures (p > .10, 95 percent CI: 0.79, 0.19). We found some evidence that hospitals improved performance on clinical process measures prior to the start of HVBP, but no evidence of this phenomenon for the patient experience measures. CONCLUSIONS: The timing of the financial incentives in HVBP was not associated with improved quality of care. It is unclear whether improvement for the clinical process measures prior to the start of HVBP was driven by the expectation of the program or was the result of other factors. PMID- 25040486 TI - Complete forelimb myology of the basal theropod dinosaur Tawa hallae based on a novel robust muscle reconstruction method. AB - The forelimbs of nonavian theropod dinosaurs have been the subject of considerable study and speculation due to their varied morphology and role in the evolution of flight. Although many studies on the functional morphology of a limb require an understanding of its musculature, comparatively little is known about the forelimb myology of theropods and other bipedal dinosaurs. Previous phylogenetically based myological reconstructions have been limited to the shoulder, restricting their utility in analyses of whole-limb function. The antebrachial and manual musculature in particular have remained largely unstudied due to uncertain muscular homologies in archosaurs. Through analysis of the musculature of extant taxa in a robust statistical framework, this study presents new hypotheses of homology for the distal limb musculature of archosaurs and provides the first complete reconstruction of dinosaurian forelimb musculature, including the antebrachial and intrinsic manual muscles. Data on the forelimb myology of a broad sample of extant birds, crocodylians, lizards, and turtles were analyzed using maximum likelihood ancestral state reconstruction and examined together with the osteology of the early theropod Tawa hallae from the Late Triassic of New Mexico to formulate a complete plesiomorphic myology for the theropod forelimb. Comparisons with previous reconstructions show that the shoulder musculature of basal theropods is more similar to that of basal ornithischians and sauropodomorphs than to that of dromaeosaurids. Greater development of the supracoracoideus and deltoideus musculature in theropods over other bipedal dinosaurs correlates with stronger movements of the forelimb at the shoulder and an emphasis on apprehension of relatively large prey. This emphasis is further supported by the morphology of the antebrachium and the intrinsic manual musculature, which exhibit a high degree of excursion and a robust morphology well-suited for powerful digital flexion. The forelimb myology of Tawa established here helps infer the ancestral conformation of the forelimb musculature and the osteological correlates of major muscle groups in early theropods. These data are critical for investigations addressing questions relating to the evolution of specialized forelimb function across Theropoda. PMID- 25040487 TI - Fear of recurrence: results of a randomized trial of relapse detection in schizophrenia. AB - OBJECTIVE: We aimed to develop and establish the reliability and validity of a measure of Fear of Recurrence, measuring cognitive appraisals of relapse rather than standard early signs of relapse. We also aimed to establish the sensitivity and specificity to relapse. METHOD: Participants diagnosed with schizophrenia or a related disorder were randomized to one of two early signs monitoring conditions, using either the Early Signs Scale or the Fear of Recurrence Scale (FoRSe). Participants were followed up for 6-months or until relapse. RESULTS: A total of 169 participants were randomized to Standard (n = 86) or FoRSe (n = 83) monitoring. We found good evidence supporting reliability and validity of the FoRSe. In addition, a cut-off point of >= 5 was associated with an optimal sensitivity in both Standard (n = 26:79%, 95% CI = 62-89) and FoRSe (n = 18:72%, 95% CI = 52-86) monitoring. However, this degree of sensitivity was associated with a lower specificity in Standard (n = 30:35%, 96% CI = 23-50) and FoRSe (n = 25:46%, 95% CI = 32-60). Finally, Fear of Relapse was a significant predictor of time to relapse [Exp(beta) = 1.20, 95% CI = 1.01-1.42, p < .05]. CONCLUSION: The study provides evidence that Fear of Recurrence may be an important clinical construct linked to increased risk of relapse and poorer emotional recovery in people diagnosed with schizophrenia. PRACTITIONER POINTS: Monitoring Fear of Recurrence is as sensitive to relapse detection as monitoring early signs alone. Greater Fear of Relapse was associated with shorter duration to actual relapse. Fear of recurrence may be an important clinical feature linked to poorer emotional recovery and increased risk of relapse. Fear of Recurrence may be an important focus of psychological therapy to promote emotional recovery and prevention of relapse. PMID- 25040488 TI - Effects of freezing on tissue factor activity in a thromboelastography assay. AB - BACKGROUND: Human recombinant tissue factor (TF) can be used to activate viscoelastic coagulation assays. Although the package insert indicates that TF should not be frozen, published scientific data are not available. Ability to store frozen aliquots of TF would increase laboratory efficiency and decrease costs associated with performing TF-activated assays. OBJECTIVE: The objectives of this study were to determine the effects of freezing and storage time on TF's ability to activate commercially available quality control material in thromboelastography (TEG). METHODS: TF was diluted and frozen at -20 degrees C and -70 degrees C for 72 hours, one week, 2 weeks, 3 months, and 6 months, and used for TEG after thawing. TF activation of control material was also assessed after TF storage at room temperature for 0, 24, and 48 hours. Time to fibrin formation (R), rate of clot formation (K and angle alpha), and clot strength (MA) were measured, and ANOVA used to identify differences. RESULTS: There were no significant differences in mean alpha and MA regardless of storage time or temperature. Means for R were not significantly increased at any time point after storage at room temperature or -70 degrees C, but significant increases in mean R were observed after storage at -20 degrees C starting after one week and continuing up to 6 months. CONCLUSION: TF can be stored at room temperature for at least 48 hours, stored at -20 degrees C for 72 hours, and stored at -70 degrees C for up to 6 months without significant loss of activity for TEG. PMID- 25040489 TI - Portal vein arterialization: 'enjoy' it responsibly. PMID- 25040491 TI - Staying in the game: the 10-step approach to sustaining geriatrics education in hospitalists and subspecialty providers. AB - Geriatrics as a field has been fortunate to have the support of several philanthropic organizations to advance geriatrics education and training in the past two decades. Awardees of such grants were presented with unparalleled opportunities to develop new and innovative educational initiatives affecting learners at multiple levels and in multiple disciplines and specialties. The lessons learned from the Donald W. Reynolds Foundation initiatives about effect and sustainability are invaluable to the ongoing strategic development of geriatrics nationally. This article highlights successful educational initiatives developed at four institutions with past and current Donald W. Reynolds Foundation funding. Following an ice hockey playbook, this article identifies 10 strategies and initiatives to "stay in the geriatrics game" by training hospitalists and subspecialty providers. The authors' collective experience suggests that geriatrics educational initiatives can not only influence provider education, but also improve the care of older adults in multiple settings. PMID- 25040492 TI - The effectiveness and cost-effectiveness of clinical nurse specialists in outpatient roles: a systematic review. AB - RATIONALE, AIMS AND OBJECTIVES: Increasing numbers of clinical nurse specialists (CNSs) are working in outpatient settings. The objective of this paper is to describe a systematic review of randomized controlled trials (RCTs) evaluating the cost-effectiveness of CNSs delivering outpatient care in alternative or complementary provider roles. METHODS: We searched CINAHL, MEDLINE, EMBASE and seven other electronic databases, 1980 to July 2012 and hand-searched bibliographies and key journals. RCTs that evaluated formally trained CNSs and health system outcomes were included. Study quality was assessed using the Cochrane risk of bias tool and the Quality of Health Economic Studies instrument. We used the Grading of Recommendations Assessment, Development and Evaluation to assess quality of evidence for individual outcomes. RESULTS: Eleven RCTs, four evaluating alternative provider (n = 683 participants) and seven evaluating complementary provider roles (n = 1464 participants), were identified. Results of the alternative provider RCTs (low-to-moderate quality evidence) were fairly consistent across study populations with similar patient outcomes to usual care, some evidence of reduced resource use and costs, and two economic analyses (one fair and one high quality) favouring CNS care. Results of the complementary provider RCTs (low-to-moderate quality evidence) were also fairly consistent across study populations with similar or improved patient outcomes and mostly similar health system outcomes when compared with usual care; however, the economic analyses were weak. CONCLUSIONS: Low-to-moderate quality evidence supports the effectiveness and two fair-to-high quality economic analyses support the cost-effectiveness of outpatient alternative provider CNSs. Low-to-moderate quality evidence supports the effectiveness of outpatient complementary provider CNSs; however, robust economic evaluations are needed to address cost effectiveness. PMID- 25040493 TI - A Simple Analytical Formula for the Leakage Flux Through a Perforated Aquitard. AB - In this methods note, we present a simple analytical formula to quantify the steady-state leakage flux (Q) over a perforated aquitard. The flux depends on the aquitard thickness (D), the radius of the perforation (R), the hydraulic conductivity of the material inside the perforation (kfill ), the conductivities of the overlying and underlying aquifers (k1 and k2 , respectively), and the head difference between the two aquifers (DeltaH): [Formula: see text]. This equation assumes an aquitard separating two homogeneous and infinite aquifers (R ? aquifer thickness) in which radial flow to and from the perforation occurs, with no other recharge or discharge boundaries near the perforation. The flux through a perforation in a hypothetical case study with D = 10 m, k1 = 10 m/d, k2 = 20 m/d, R = 0.072 m, and DeltaH = 1 m ranges between less than 1 mL/d if the hole is backfilled with bentonite (k(fill ) = 10(-4) m/d), to several liters per day if the perforation is backfilled with sand from the overlying aquifer (k(fill) = 10 m/d), to several m(3) /d if the perforation forms an open conduit (k(fill) = 10(5) m/d). The leakage fluxes calculated with this model agree well with those calculated using a numerical model (MODFLOW). PMID- 25040494 TI - Lung metastases from differentiated thyroid carcinoma: prognostic factors related to remission and disease-free survival. AB - OBJECTIVE: Distant metastases, although rare, account for maximum disease-related mortality in differentiated thyroid cancer (DTC). Lungs and bones are the most frequent sites of metastases. We sought to identify the prognostic factors in adult DTC patients presenting with pulmonary metastases at initial diagnosis. DESIGN: Retrospective cohort study. PATIENTS: From the medical records of 4370 patients, 200 patients aged more than 21 years who were identified to have pulmonary metastases at the time of diagnosis were included in the analysis. RESULTS: The sites of metastases were lungs alone in 133 (67%) patients, and additional sites in remaining 67 (33%) patients were as follows: bones in 59, liver in 4, brain in 2 and both bone and liver in two patients. During the mean follow-up of 61 months (range, 12-312 months), 76 patients achieved remission, 121 (60.5%) patients had biochemically and/or structurally persistent disease and three patients showed disease progression. Multivariate analysis revealed presence of macro-nodular (chest X-ray positive) pulmonary metastases and concomitant skeletal metastases as independent factors decreasing the likelihood of remission. Of the 76 patients with remission, 16 (21%) developed subsequent recurrence. Patient age >45 years and follicular histopathology were independently associated with greater hazards of developing recurrence. CONCLUSION: This study suggests that the patients with macro-nodular lung metastases and/or concomitant skeletal metastases have reduced odds of achieving remission. Moreover, significant number of patients recur even after complete remission with RAI treatment, hence strict surveillance is recommended especially in patients with age >45 years and/or with follicular histology of DTC. PMID- 25040495 TI - Preterm born 9-year-olds have elevated IGF-1 and low prolactin, but levels vary with behavioural and eating disorders. AB - AIM: This study examined the relationship between hypothalamic-associated hormones and behavioural and eating disorders in children with low birthweight. METHODS: We included 100 children (mean age 9.7 years): 39 were born preterm at <32 gestational weeks, 28 were full-term, but small for gestational age, and 33 were full-term controls. Behavioural histories were analysed, together with fasting blood samples of leptin, insulin, insulin-like growth factor-1 (IGF-I), prolactin, glucagon and cortisol. RESULTS: Preterm children had lower prolactin (p = 0.01) and higher IGF-I than controls (p < 0.05, adjusted for confounders), despite being significantly shorter than the predicted target height (p < 0.001). More preterm children displayed behavioural disorders (38% versus 10%, p < 0.001) and eating disorders (26% versus 8%, p < 0.05) than full-term children. These disorders were associated with lower leptin (p < 0.01), insulin (p < 0.05) and IGF-I (p < 0.05), but correlations between these hormones and leptin were similar among the groups. Combined behavioural and eating disorders were only observed in preterm children, who were also the shortest in height. CONCLUSION: Behavioural and eating disorders among preterm children were associated with low leptin, insulin and IGF-1. Low prolactin in all preterm children indicated an increased dopaminergic tonus, which might inhibit body weight incrementation. This raises speculation about IGF-I receptor insensitivity. PMID- 25040497 TI - In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization? AB - BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is one of the standard treatments recommended for intermediate stage hepatocellular carcinoma (HCC). At the same time, only little is known about the use of radioembolization with Yttrium-90 microspheres (TARE Y-90) for this subset of patients. To perform comparative analysis between both locoregional therapies in intermediate HCCs. Primary endpoint was overall survival (OS), while safety, response rate and time to-progression (TTP) were considered as secondary endpoints. METHODS: We collected data of 86 HCC patients in two university hospitals at which conventional TACE with doxorubicin or TARE Y-90 using glass microspheres were performed. The median observation period was 10 months. Patients were followed up for signs of toxicity and response. They underwent imaging analysis at baseline and follow-up at regular time intervals. RESULTS: Eighty-six HCC patients with intermediate stage B (BCLC) were treated with either TACE (n = 42) or TARE Y-90 (n = 44). Despite a higher tumour burden in the TARE Y-90 group, the median OS (TACE: 18 months vs. TARE Y-90: 16.4 months) and the median TTP (TACE: 6.8 months vs. TARE Y-90: 13.3 months) were not statistically different. The number of treatment sessions, the average rate of treatment sessions per patient, total hospitalization time and rate of adverse events were significantly higher in the TACE cohort. CONCLUSION: In intermediate HCC stage patients, both treatments resulted in similar survival probabilities despite more advanced disease in the TARE Y-90 group. Still, TARE Y-90 was better tolerated and associated with less hospitalization and treatment sessions. PMID- 25040496 TI - Association between human papilloma virus/Epstein-Barr virus coinfection and oral carcinogenesis. AB - BACKGROUND: The recent epidemic of head and neck squamous cell carcinomas associated with human papilloma virus (HPV) has not addressed its association with lymphoid tissue in the oropharynx or the potential role of Epstein-Barr virus (EBV)/HPV coinfection. METHODS: The prevalence of HPV and EBV infection/coinfection and CD21 mRNA expression were determined in normal and cancerous tissues from the oropharynx using in situ hybridization (ISH), p16, and quantitative reverse transcriptase PCR (qRT-PCR). The effects of coinfection on tumorigenicity were evaluated using proliferation and invasion assays. RESULTS: Normal oropharynx, tonsil, non-cancer base of tongue (BOT), and BOT from sleep apnea patients demonstrated EBV positivity ranging from 7% to 36% depending on the site and methods of detection used (qRT-PCR or ISH). Among non-malignant BOT samples, HPV positivity was noted only in 20%. The percent of tonsil and BOT cancers positive for HPV (up to 63% and 80%, respectively) or coinfected with HPV/EBV (up to 25% and 70%, respectively) were both significantly associated with cancer status. Notably, HPV/EBV coinfection was observed only in malignant tissue originating in lymphoid-rich oropharynx sites (tonsil, BOT). CD21 mRNA (the major EBV attachment receptor) was detected in tonsil and BOT epithelium, but not in soft-palate epithelium. Coinfected cell lines showed a significant increase in invasiveness (P < 0.01). CONCLUSIONS: There is a high prevalence of HPV/EBV infection and coinfection in BOT and tonsil cancers, possibly reflecting their origins in lymphoid-rich tissue. In vitro, cells modeling coinfection have an increased invasive potential. PMID- 25040498 TI - Cyberbullying: implications for the psychiatric nurse practitioner. AB - PURPOSE: The purpose of this article is to inform and educate psychiatric nurse practitioners about the pervasiveness of the rapidly increasing problem of cyberbullying. REVIEW OF LITERATURE: As more children and adolescents obtain access to the Internet, mobile devices, and social networking sites, the exposure to bullying in the virtual format increases. Cyberbullying is a growing public health concern and can affect mental health and school performance. Cyberbullying often results in a range of psychiatric symptoms and has been linked to suicide attempts and completions. CONCLUSIONS: The psychiatric nurse practitioner is uniquely prepared to provide a range of interventions for patients, families, and communities who have experienced cyberbullying. PMID- 25040499 TI - Induction of interleukin-1beta by activated microglia is a prerequisite for immunologically induced fatigue. AB - We previously reported that an intraperitoneal (i.p.) injection of synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly-I:C), produced prolonged fatigue in rats, which might serve as a model for chronic fatigue syndrome. The poly-I:C-induced fatigue was associated with serotonin transporter (5-HTT) overexpression in the prefrontal cortex (PFC), a brain region that has been suggested to be critical for fatigue sensation. In the present study, we demonstrated that microglial activation in the PFC was important for poly-I:C induced fatigue in rats, as pretreatment with minocycline, an inhibitor of microglial activation, prevented the decrease in running wheel activity. Poly-I:C injection increased the microglial interleukin (IL)-1beta expression in the PFC. An intracerebroventricular (i.c.v.) injection of IL-1beta neutralising antibody limited the poly-I:C-induced decrease in activity, whereas IL-1beta (i.c.v.) reduced the activity in a dose-dependent manner. 5-HTT expression was enhanced by IL-1beta in primary cultured astrocytes but not in microglia. Poly-I:C injection (i.p.) caused an increase in 5-HTT expression in astrocytes in the PFC of the rat, which was inhibited by pretreatment with minocycline (i.p.) and rat recombinant IL-1 receptor antagonist (i.c.v.). Poly-I:C injection (i.p.) led to a breakdown of the blood-brain barrier and enhanced Toll-like receptor 3 signaling in the brain. Furthermore, direct application of poly-I:C enhanced IL-1beta expression in primary microglia. We therefore propose that poly-I:C-induced microglial activation, which may be at least partly caused by a direct action of poly-I:C, enhances IL-1beta expression. Then, IL-1beta induces 5-HTT expression in astrocytes, resulting in the immunologically induced fatigue. PMID- 25040500 TI - Engineering large viral DNA genomes using the CRISPR-Cas9 system. AB - Manipulation of viral genomes is essential for studying viral gene function and utilizing viruses for therapy. Several techniques for viral genome engineering have been developed. Homologous recombination in virus-infected cells has traditionally been used to edit viral genomes; however, the frequency of the expected recombination is quite low. Alternatively, large viral genomes have been edited using a bacterial artificial chromosome (BAC) plasmid system. However, cloning of large viral genomes into BAC plasmids is both laborious and time consuming. In addition, because it is possible for insertion into the viral genome of drug selection markers or parts of BAC plasmids to affect viral function, artificial genes sometimes need to be removed from edited viruses. Herpes simplex virus (HSV), a common DNA virus with a genome length of 152 kbp, causes labialis, genital herpes and encephalitis. Mutant HSV is a candidate for oncotherapy, in which HSV is used to kill tumor cells. In this study, the clustered regularly interspaced short palindromic repeat-Cas9 system was used to very efficiently engineer HSV without inserting artificial genes into viral genomes. Not only gene-ablated HSV but also gene knock-in HSV were generated using this method. Furthermore, selection with phenotypes of edited genes promotes the isolation efficiencies of expectedly mutated viral clones. Because our method can be applied to other DNA viruses such as Epstein-Barr virus, cytomegaloviruses, vaccinia virus and baculovirus, our system will be useful for studying various types of viruses, including clinical isolates. PMID- 25040501 TI - Pollen transfer efficiency and its effect on inflorescence size in deceptive pollination strategies. AB - Pollination systems differ in pollen transfer efficiency, a variable that may influence the evolution of flower number. Here we apply a comparative approach to examine the link between pollen transfer efficiency and the evolution of inflorescence size in food and sexually deceptive orchids. We examined pollination performance in nine food-deceptive, and eight sexually deceptive orchids by recording pollen removal and deposition in the field. We calculated correlations between reproductive success and flower number (as a proxy for resources allocated during reproductive process), and directional selection differentials were estimated on flower number for four species. Results indicate that sexually deceptive species experience decreased pollen loss compared to food deceptive species. Despite producing fewer flowers, sexually deceptive species attained levels of overall pollination success (through male and female function) similar to food-deceptive species. Furthermore, a positive correlation between flower number and pollination success was observed in food-deceptive species, but this correlation was not detected in sexually deceptive species. Directional selection differentials for flower number were significantly higher in food compared to sexually deceptive species. We suggest that pollination systems with more efficient pollen transfer and no correlation between pollination success and number of flowers produced, such as sexual deception, may allow the production of inflorescences with fewer flowers that permit the plant to allocate fewer resources to floral displays and, at the same time, limit transpiration. This strategy can be particularly important for ecological success in Mediterranean water-deprived habitats, and might explain the high frequency of sexually deceptive species in these specialised ecosystems. PMID- 25040502 TI - Reconstruction of the right atrium and superior vena cava with extracellular matrix. AB - We describe our technique for reconstructing the free right atrial wall and superior vena cava using CorMatrix (CorMatrix Alpharetta, GA, USA) extracellular matrix following resection of a large leiomyosarcoma. PMID- 25040503 TI - Hypertension and hypertensive cardiomyopathy in patients with a relapse-free history of phaeochromocytoma. AB - BACKGROUND: In patients with a relapse-free history of phaeochromocytoma/paraganglioma (PCC/PGL), persistent hypertension has been reported, but has not been well characterized. METHODS: In 28 patients [mean age 54.5 (26-81) years] with a relapse-free history of PCC/PGLs, we prospectively analysed resting, supine blood pressure (BP), ambulatory BP, echocardiography, exercise testing, metabolic parameters and retrospectively collected data from the time of diagnosis (baseline). Echocardiographic measures were compared to healthy (n = 28) and hypertensive controls (n = 15). RESULTS: Median follow-up was 6 [1-16] years. Three patients had normal office and ambulatory BP and three patients had only increased office BP. Fifty-four per cent of patients had a blunted circadian rhythm. Comparing normal, hypertensive and PCC/PGL patients, we found significant differences in end-diastolic septal thickness (8.8 +/- 0.2, 13.8 +/- 0.4, 10.0 +/- 0.3 mm, P < 0.05), septal basal thickness (9.0 +/- 0.3, 15.9 +/- 0.5, 11.2 +/- 0.4 mm, P < 0.05) and left ventricular mass (143 +/- 8, 255 +/- 19, 169 +/- 9 g, P < 0.05). In five patients, seven major cardiovascular events were observed. Compared to baseline, no significant difference was found in systolic (140 +/- 35 vs 137 +/- 18 mmHg) and diastolic (85 +/- 18 vs 83 +/- 10 mmHg) BP. An increase or a decrease in BP (>10 mmHg) was found in 36% and 39% of patients, respectively. The number of antihypertensive drugs had not changed [1 (0-3) vs 1 (0-4)]. Fewer patients received insulin (1 vs 3) or oral antiglycaemic drugs (2 vs 7). CONCLUSION: Our data indicate that hypertension persists after removal of PCG/PGL in a substantial proportion of patients. Hypertensive heart disease is common, and cardiovascular events are frequent in patients with a history of PCC/PGL. PMID- 25040504 TI - Interferon-ribavirin therapy induces serum antibodies determining 'rods and rings' pattern in hepatitis C patients. AB - A cytoplasmic antigen associated to inosine-5'-monophosphatedehydrogenase 2 eliciting specific antibodies (antirods and rings, RR) has been identified in patients with chronic hepatitis C who were exposed to pegylated interferon (PI) and ribavirin (RBV). The significance of anti-RR in these patients merits to be investigated. Sera from 88 chronic hepatitis C virus (HCV)-infected patients undergoing PI-RBV therapy were analysed for the presence of RR pattern by indirect immunofluorescence on HEp-2 substrate (Inova Diagnostics, San Diego, CA, USA). Anti-RR antibodies developed de novo in 32 patients independently of any demographic and virological feature, but with a significant association with cumulative exposure to PI-RBV (P = 0.0089; chi-square test). RR pattern was significantly more frequent in relapsers than in patients achieving sustained virological response (56% vs 30%; P = 0.0282, chi-square test). Anti-RR titre ranged from 1:80 to 1:1280, but significantly declined following treatment cessation. Anti-RR develop de novo in a substantial proportion of patients exposed to PI-RBV in relation to the duration of treatment exposure. Further investigations are necessary to unravel the mechanisms leading to the formation of these autoantibodies. PMID- 25040505 TI - The newly characterized Pl-jun is specifically expressed in skeletogenic cells of the Paracentrotus lividus sea urchin embryo. AB - Growing evidence suggests that the transcription factors belonging to the Jun family are involved in many important cellular events, such as the control of bone development in mammalians. We have characterized, for the first time, a member of the Jun family from embryos of the sea urchin Paracentrotus lividus. The Pl-jun protein sequence includes all the functional domains characteristic of members of the Jun family (i.e. the basic leucine zipper, the basic DNA-binding and the c-Jun N-terminal kinase docking-like domains), which are evolutionarily conserved. Moreover, all the key serine and threonine residues, which are phosphorylation targets for different kinases necessary for jun activation, appear to be well preserved. A model of the monomeric protein provides a simulation of the three-dimensional structure and shows the potential sites for dimerization and DNA binding. Pl-jun mRNA is expressed in the unfertilized egg and throughout sea urchin embryo development. As the development proceeds, Pl-jun mRNA becomes exclusively expressed in the skeletogenic cells. Intriguingly, these cells contain significant amounts of the phosphorylated active protein entirely localized into their nuclei. These findings strengthen our hypothesis that suggests an active role for Pl-jun in skeletogenic cells, thus indicating that this transcription factor is a novel component of the gene regulatory networks controlling skeletogenesis. Database: Nucleotide sequence data have been deposited in the EMBL databases under the accession number: HE817756. PMID- 25040506 TI - Fine- and coarse-filter conservation strategies in a time of climate change. AB - As species adapt to a changing climate, so too must humans adapt to a new conservation landscape. Classical frameworks have distinguished between fine- and coarse-filter conservation strategies, focusing on conserving either the species or the landscapes, respectively, that together define extant biodiversity. Adapting this framework for climate change, conservationists are using fine filter strategies to assess species vulnerability and prioritize the most vulnerable species for conservation actions. Coarse-filter strategies seek to conserve either key sites as determined by natural elements unaffected by climate change, or sites with low climate velocity that are expected to be refugia for climate-displaced species. Novel approaches combine coarse- and fine-scale approaches--for example, prioritizing species within pretargeted landscapes--and accommodate the difficult reality of multiple interacting stressors. By taking a diversified approach to conservation actions and decisions, conservationists can hedge against uncertainty, take advantage of new methods and information, and tailor actions to the unique needs and limitations of places, thereby ensuring that the biodiversity show will go on. PMID- 25040507 TI - The importance of economic, social and cultural capital in understanding health inequalities: using a Bourdieu-based approach in research on physical and mental health perceptions. AB - In this article we adopt a Bourdieu-based approach to study social inequalities in perceptions of mental and physical health. Most research takes into account the impact of economic or social capital on health inequalities. Bourdieu, however, distinguishes between three forms of capital that can determine peoples' social position: economic, social and cultural capital. Health research examining the effects of cultural capital is scarce. By simultaneously considering and modelling indicators of each of Bourdieu's forms of capital, we further the understanding of the dynamics of health inequalities. Using data from a large scale representative survey (N = 1825) in Flanders, Belgium, we find that each of the forms of capital has a net effect on perceptions of physical and mental health, which persists after controlling for the other forms of capital and for the effects of other correlates of perceived health. The only exception is that the cultural capital indicators are not related to mental health. These results confirm the value of a Bourdieu-based approach and indicate the need to consider economic, social and cultural capital to obtain a better understanding of social inequality in health. PMID- 25040508 TI - Transepidermal growth in disseminated Fusarium infection. PMID- 25040509 TI - Nurses' Empowerment Scale for ICU patients' families: an instrument development study. AB - BACKGROUND: Family members provide essential support for ICU patients, contributing to their mental and physical recovery. Empowering ICU patients' families may help them overcome inadequacies and meet their own and patients' acknowledged needs. Nursing should understand and address patients' families' empowerment status. AIMS AND OBJECTIVES: To develop a tool, the Nurses' Empowerment Scale for Intensive Care Unit (ICU) Patients' Families (NESIPF), to help ICU nursing staff assess the empowerment status of patients' families. DESIGN: Four-phase instrument development study. METHODS: A 19-item instrument was initially generated based on literature review and interviews with family members of ICU patients. The Delphi research method was applied to gain expert opinion and consensus via rounds of questionnaires. A panel of 27 experts experienced in critical care medicine, nursing and psychology participated in two Delphi rounds and their input helped formulate an 18-item pretest instrument. Families of 20 patients were recruited to examine instrument readability. After a 2-week interval, another 20 patients' families were recruited to examine test retest reliability. Two hundred questionnaires were then administered and analysed to examine the instrument's construct validity, criterion-related validity and internal consistency. RESULTS: Expert authority coefficients of two Delphi rounds reached 0.89 and 0.91. Kendall' W coefficients of 0.113 (P < 0.001) in round 1 and 0.220 (P < 0.001) in round 2 indicated slight to fair agreement among experts. Content validity index (CVI) reached 1.0 for 12 items; the CVI for item 13 was <0.7 so it was excluded. Cronbach's alpha coefficient was 0.92, indicating acceptable internal consistency reliability. The coefficient of internal consistency of each dimension was 0.717-0.921. The Pearson correlation coefficient >0.9 (P < 0.05) showed an acceptable test-retest reliability. CONCLUSIONS: The instrument has acceptable reliability and validity and can assess the empowerment status of families of critically ill patients. RELEVANCE TO CLINICAL PRACTICE: Knowledge of families' empowerment status may help to address their psychological needs and their ability to provide family support. PMID- 25040511 TI - Care of the dying: priorities for the future. PMID- 25040510 TI - Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour? AB - AIMS: The main goal of the study was to describe the pharmacokinetics of maternal zidovudine (ZDV) administration during pregnancy and labour and to evaluate their impact on fetal concentrations and exposures. METHODS: A total of 195 HIV infected pregnant and non-pregnant women aged 16-59 years were included and 273 maternal and 79 cord blood ZDV concentrations were collected. A population pharmacokinetic model was developed to describe ZDV concentrations as a function of time in the mother and the fetus. Fetal exposures resulting from maternal oral administration and infusion were estimated and compared with therapeutic exposures (3-5 mg l(-1) h) and to exposure providing higher risk of toxicity (>8.4 mg l(-1) h). Different protocols for ZDV administration during labour were simulated. RESULTS: The median fetal exposure and the percentage of children with values above 8.4 mg l(-1) h were 3.20 mg l(-1) h and 0% after maternal oral administration, respectively, and 9.71 mg l(-1) h and 51% after maternal infusion during labour. Two options were considered to reduce fetal exposure during labour: (i) maternal infusion rates could be 1 mg kg(-1) h(-1) during 1 h followed by 0.5 mg kg(-1) h(-1) and (ii) the mother could only take oral ZDV every 5 h from start of labour until delivery with her neonate having their first ZDV dose as soon as possible after birth. CONCLUSIONS: Zidovudine exposures are very important during labour and during the first days of a neonate's life. Maternal ZDV dose should be reduced in addition to the neonate doses reduction already proposed. PMID- 25040512 TI - Equipping tomorrow's doctors for the patients of today. PMID- 25040515 TI - Advances in SPECT in evaluating coronary disease. AB - Myocardial perfusion scintigraphy is the longest established of the functional imaging investigations for patients with known or suspected coronary artery disease. This article describes recent technical and clinical advances that are ensuring that the technique remains relevant some 40 years after its first introduction. PMID- 25040516 TI - Three-dimensional echocardiography and structural heart interventions. AB - This article looks at the role of three-dimensional echocardiography in the anatomical assessment of cardiac structures, how this complements standard methods of assessing structural cardiac lesions and the advantages of three dimensional echocardiography in peri-procedural guidance in the cardiac catheterization laboratory. PMID- 25040517 TI - Heart muscle disease and cardiovascular magnetic resonance imaging. AB - This article introduces the reader to the different types of heart muscle disease which are commonly encountered in clinical practice. It then discusses cardiovascular magnetic resonance and explains how it can help in the work up of these diverse conditions. PMID- 25040518 TI - Management of nausea and vomiting in palliative care. AB - Nausea and vomiting are common symptoms in palliative care and can be highly distressing to patients. This review discusses the mechanisms by which nausea and vomiting are triggered, using case studies to highlight the most common scenarios and how to manage these. PMID- 25040519 TI - The use of Google Drive in clinical audit. AB - Audit is an important aspect of clinical governance and of the training of health care professionals. Conventional methods of audit data collection can be time consuming and inefficient. This article suggests a novel technique of using Google Drive, with adherence to the Caldicott principles, to facilitate data collection in both local and multicentre audits. PMID- 25040520 TI - Quantifying the challenges of specialty training: the 2013 British Junior Cardiologists' Association survey. AB - The British Junior Cardiologists' Association surveyed members to analyse their perception and experience of training. Cardiology trainees perceive significant limitations with the current training structure. This article gives suggestions which could lead to improvements in training and patient care. PMID- 25040522 TI - Pneumatosis cystoides intestinalis with pneumoperitoneum in a renal transplant patient. PMID- 25040523 TI - POEMS syndrome: a challenging diagnosis of a rare disease. PMID- 25040524 TI - Rasmussen's aneurysm. PMID- 25040525 TI - Diagnosis of lymphangioleiomyomatosis in a 75-year-old woman. PMID- 25040526 TI - Transverse melanonychia. PMID- 25040528 TI - Inter-professional training to enhance surgical safety: are we missing an opportunity? PMID- 25040529 TI - Current topics in medicine a century ago. PMID- 25040531 TI - Life as a house surgeon in the first year of the NHS. PMID- 25040532 TI - Use of suxamethonium in open eye injuries: a dilemma with explosive consequences. PMID- 25040533 TI - The actin-bundling protein L-plastin: a novel local inflammatory marker associated with periodontitis. AB - BACKGROUND AND OBJECTIVE: L-plastin, an actin-bundling protein, is exclusively expressed in leukocytes and plays a crucial role in immune-mediated events. Periodontitis is a common infectious inflammatory disease that destroys the tooth supporting tissues. Recent findings using proteomic technologies have demonstrated that L-plastin is one of the few molecules consistently present in the inflammatory exudate of the gingiva in periodontal disease, but not in health. Therefore, this study aimed to investigate in detail the local and systemic role of this molecule in different forms of periodontitis. MATERIAL AND METHODS: A total of 61 subjects who met the inclusion/exclusion criteria were recruited, including 21 with chronic periodontitis, 20 generalized aggressive periodontitis and 20 nonperiodontitis control subjects. Gingival tissue biopsies, gingival crevicular fluid, as well as serum and saliva, were obtained. Immunohistochemistry and quantitative real-time PCR were employed to evaluate the localization and mRNA expression, respectively, of L-plastin. L-plastin levels in gingival crevicular fluid, saliva and serum were measured using ELISA. Statistical analysis was performed using nonparametric methods. RESULTS: Subjects with chronic periodontitis and generalized aggressive periodontitis exhibited significantly higher tissue L-plastin gene expression and gingival crevicular fluid levels than did subjects in the control group but there was no significant difference between the two forms of periodontitis. Within gingival tissue, L plastin was confined to the inflammatory infiltrate. There was no statistically significant difference between serum and salivary L-plastin levels among the three study groups. CONCLUSION: The elevated gingival tissue expression and gingival crevicular fluid levels of L-plastin in both forms of periodontitis may denote the localized involvement of this novel molecule in the pathogenesis of the disease. PMID- 25040534 TI - Distance as a predictor of treatment attendance in a family based pediatric weight management program in rural areas. AB - PURPOSE: The primary aim of this study was to determine whether demographic variables and distance to treatment were significant predictors of treatment attendance in a family based healthy lifestyle intervention program held in rural counties. METHODS: Two hundred forty-nine children aged 8-12 who were overweight or obese and their parents participated in a 21-session healthy lifestyle intervention. Measures were obtained at baseline, and attendance included the number of the first core 12 sessions attended. Hierarchical linear regression analyses were conducted to identify variables that significantly predicted treatment attendance, and exploratory moderation analyses were conducted to examine if demographic variables moderated effects of distance to treatment site predicting group attendance. FINDINGS: Results support significant inverse relationships between distance to treatment and treatment attendance. Additionally, parents' marriage status significantly moderated the relationship between distance to treatment and treatment attendance. CONCLUSIONS: These results expand the literature to a rural sample and indicate the importance of marital status for treatment attendance. Knowledge of these barriers to treatment provides information to tailor interventions to improve attendance in the future. Possible strategies include addressing cultural norms, providing resources to overcome time and travel barriers, and implementing e-health interventions. PMID- 25040535 TI - The effect of shelter on welfare of juvenile Atlantic salmon Salmo salar reared under a feed restriction regimen. AB - This study investigated whether shelter (presence or absence) affected the frequency of fin damage in Atlantic salmon Salmo salar exposed to feed restrictions (0.73 or 0.33% of body mass day(-1) ). The presence of shelter had a positive effect on the pectoral fins at both feed ration levels and on the dorsal fin at the higher ration level but it had a negative effect on survival. The reduced feed rations resulted in fish of the same size and nutritional status as wild fish. The provision of shelter has potential to mitigate the negative effects of feed restrictions on fin quality, but the optimal shelter design requires some additional investigation. PMID- 25040536 TI - Early and sustained activation of autophagy in degenerating axons after spinal cord injury. AB - Axonal degeneration is one of the initial steps in many neurological disorders and has been associated with increased autophagic activity. Although there are increasing data on the regulation of autophagy proteins in the neuronal soma after spinal cord injury (SCI), their characterization in the axon is scarce. Here, we examined the regulation of autophagy during axonal degeneration in a rat model of SCI following a lesion at Th 8. We analyzed the morphological and ultrastructural changes in injured axons by immunohistochemical evaluation of autophagy-related proteins and electron microscopy at different time points following SCI. The expression of ULK1, Atg7 and Atg5 in damaged axons was rapidly upregulated within hours after SCI. The number of axonal LC3-positive autophagosomes was also rapidly increased after SCI and remained at an increased level for up to 6 weeks. Ultrastructural analysis showed early signs of axonal degeneration and increased autophagy. In conclusion, we show that autophagy is increased early and for a sustained period in degenerating axons after SCI and that it might be an important executive step involved in axonal degeneration. Therefore, autophagy may represent a promising target for future therapeutic interventions in the treatment of axonal degeneration in traumatic central nervous system disorders. PMID- 25040537 TI - Longitudinal trajectories of behavior problems and social competence in children with new onset epilepsy. AB - AIM: To characterize the prospective trajectory of parent-reported behavior and social competence problems in children with new or recent onset epilepsy from diagnosis to 5 to 6 years after diagnosis compared to healthy control participants. METHOD: Thirty-five children (21 males, 14 females; mean age 14y 1mo [SD 3y 4mo] range 8-18y) with new/recent onset idiopathic generalized (IGE) and 34 children with localization-related epilepsies (LRE; 19 males, 15 females; mean age 10y 8mo [SD 2y 2mo] range 8-18y) underwent behavioral assessment (Child Behavior Checklist) at baseline, 2 years, and 5 to 6 years after diagnosis. The assessment comprised the summary scales Total Behavior Problems Internalizing Problems, Externalizing Problems, and Total Competence. Sixty-two children with normal development served as comparison participants. Analyses were based on random effects regression modeling comparing trajectories with respect to time since epilepsy diagnosis among groups. RESULTS: Differences in parent-reported behavioral problems between LRE and IGE syndrome groups and healthy comparison participants were detectable at or near the time of diagnosis and remained either stable (competence) or tended to abate (behavior problems) over the ensuing 5 to 6 years without evidence of progressive worsening. These trends were evident for both LRE and IGE groups, with no differences between them. INTERPRETATION: Behavior and competence problems in children with LRE and IGE are not characterized by progressive worsening over a 5- to 6-year period. Behavioral problems are present near the time of diagnosis and tend to abate over time, with competence problems being more persistent across serial assessments, and present in both LRE and IGE groups. PMID- 25040538 TI - Interorganelle trafficking of lipids: preface for the thematic review series. PMID- 25040539 TI - An atypical case of bullous systemic lupus erythematosus in a 16-year-old boy. AB - Bullous systemic lupus erythematosus (BSLE) is a rare autoimmune subepidermal blistering disease with a female predominance characterized as an acute vesicobullous eruption in patients with systemic lupus erythematosus (SLE). Here we report a case of BSLE in a 16-year-old boy that does not adhere to the criteria originally established and suggest a new outlook on this condition. PMID- 25040540 TI - Nationwide survey of urogenital tuberculosis in Japan. AB - OBJECTIVES: To determine current epidemiology and treatment patterns of urogenital tuberculosis in Japan. METHODS: A questionnaire was sent to the urological departments of 1203 Japanese hospitals. Clinical data was reviewed retrospectively; no time range was specified. RESULTS: Of the 1203 hospitals, 399 returned questionnaires with information about 355 urogenital tuberculosis patients. Of the 399, 153 institutions reported at least one patient, and 201 patients were identified between 2000 and 2007. Infections were located in the kidneys (n = 242), ureter (n = 96), bladder (n = 100), epididymis or testes (n = 81) and prostate (n = 9). CONCLUSIONS: Urogenital tuberculosis is rare in Japan, but patients do exist, and we should not ignore them. PMID- 25040541 TI - A systematic review and meta-regression analysis of mivacurium for tracheal intubation. AB - We systematically reviewed factors associated with intubation conditions in randomised controlled trials of mivacurium, using random-effects meta-regression analysis. We included 29 studies of 1050 healthy participants. Four factors explained 72.9% of the variation in the probability of excellent intubation conditions: mivacurium dose, 24.4%; opioid use, 29.9%; time to intubation and age together, 18.6%. The odds ratio (95% CI) for excellent intubation was 3.14 (1.65 5.73) for doubling the mivacurium dose, 5.99 (2.14-15.18) for adding opioids to the intubation sequence, and 6.55 (6.01-7.74) for increasing the delay between mivacurium injection and airway insertion from 1 to 2 min in subjects aged 25 years and 2.17 (2.01-2.69) for subjects aged 70 years, p < 0.001 for all. We conclude that good conditions for tracheal intubation are more likely by delaying laryngoscopy after injecting a higher dose of mivacurium with an opioid, particularly in older people. PMID- 25040543 TI - Influence of interleukin-6 gene polymorphisms in epicardial adipose tissue and coronary artery calcification in patients with psoriasis. PMID- 25040542 TI - Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs. AB - MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142 3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR 223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women. PMID- 25040544 TI - Comparative effect of fluoride, essential oil and chlorhexidine mouth rinses on dental plaque and gingivitis in patients with and without dental caries: a randomized controlled trial. AB - OBJECTIVES: The objective of this study was to compare the effectiveness of fluoride, essential oil (EO) and chlorhexidine (CHX)-containing mouth rinses on dental plaque and gingivitis and to compare their relative efficacy in patients with and without dental caries. MATERIAL AND METHODS: A randomized, controlled, double- blind, crossover clinical trial was conducted for a period of 8 weeks. Thiry-six qualifying subjects, aged 12-44 years, were included in the study. Subjects were divided into caries and caries-free groups and were randomly assigned to one of the following mouth rinse groups: fluoride; EO; CHX and saline as negative control. Subjects used their respective mouth rinse for a period of 7 days each with 1-week wash-out periods. Primary efficacy variables were Quigley Hein plaque index (PI) and Loe and Silness gingival index. RESULTS: Fluoride and CHX mouth rinses showed significant reduction in plaque after use of mouth rinses (P < 0.05). However, no significant differences were observed with respect to each other in reducing gingivitis (P > 0.05). Further significant differences were found in reducing plaque and gingivitis in caries-free subjects in comparison to those with caries (P < 0.05). CONCLUSION: All the three mouth rinses significantly reduced plaque accumulation and gingivitis especially in caries-free subjects in comparison to those with caries, and amongst the three, fluoride and CHX proved to be more effective than EO mouth rinse. PMID- 25040545 TI - Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. AB - BACKGROUND: Recurrent Clostridium difficile infection (CDI) represents a significant burden on the healthcare system and is associated with poor outcomes in hematopoietic stem cell transplant (HSCT) patients. Data are limited evaluating recurrence rates and risk factors for recurrence in HSCT patients. METHODS: HSCT patients who developed CDI between January 2010 and December 2012 were divided into 2 groups: non-recurrent CDI (nrCDI) and recurrent CDI (rCDI). Risk factors for rCDI were compared between groups. Rate of recurrence in HSCT patients was compared to that in other hospitalized patients. RESULTS: CDI was diagnosed in 95 of 711 HSCT patients (22 rCDI and 73 nrCDI). Recurrence rates were similar in HSCT patients compared with other hospitalized patients (23.2% vs. 22.9%, P > 0.99). Patients in the rCDI group developed the index case of CDI significantly earlier than the nrCDI group (3.5 days vs. 7.0 days after transplant, P = 0.05). On univariate analysis, patients with rCDI were more likely to have prior history of CDI and neutropenia at the time of the index CDI case. Neutropenia at the time of the index CDI case was the only independent predictor of rCDI (78.8 vs. 34.8%, P = 0.006) on multivariate analysis. CONCLUSIONS: The rate of rCDI was similar between HSCT and other hospitalized patients, and the majority of patients developed the index case of CDI within a week of transplantation. Neutropenia at the index CDI case may be associated with increased rates of rCDI. PMID- 25040546 TI - The Neuroplastin adhesion molecules: key regulators of neuronal plasticity and synaptic function. AB - The Neuroplastins Np65 and Np55 are neuronal and synapse-enriched immunoglobulin superfamily molecules that play important roles in a number of key neuronal and synaptic functions including, for Np65, cell adhesion. In this review we focus on the physiological roles of the Neuroplastins in promoting neurite outgrowth, regulating the structure and function of both inhibitory and excitatory synapses in brain, and in neuronal and synaptic plasticity. We discuss the underlying molecular and cellular mechanisms by which the Neuroplastins exert their physiological effects and how these are dependent upon the structural features of Np65 and Np55, which enable them to bind to a diverse range of protein partners. In turn this enables the Neuroplastins to interact with a number of key neuronal signalling cascades. These include: binding to and activation of the fibroblast growth factor receptor; Np65 trans-homophilic binding leading to activation of p38 MAPK and internalization of glutamate (GluR1) receptor subunits; acting as accessory proteins for monocarboxylate transporters, thus affecting neuronal energy supply, and binding to GABAA alpha1, 2 and 5 subunits, thus regulating the composition and localization of GABAA receptors. An emerging theme is the role of the Neuroplastins in regulating the trafficking and subcellular localization of specific binding partners. We also discuss the involvement of Neuroplastins in a number of pathophysiological conditions, including ischaemia, schizophrenia and breast cancer and the role of a single nucleotide polymorphism in the human Neuroplastin (NPTN) gene locus in impairment of cortical development and cognitive functions. Neuroplastins are neuronal cell adhesion molecules, which induce neurite outgrowth and play important roles in synaptic maturation and plasticity. This review summarizes the functional implications of Neuroplastins for correct synaptic membrane protein localization, neuronal energy supply, expression of LTP and LTD, animal and human behaviour, and pathophysiology and disease. It focuses particularly on Neuroplastin binding partners and signalling mechanisms, and proposes perspectives for future research on these important immunoglobulin superfamily members. PMID- 25040547 TI - Response to MacDermid et al. PMID- 25040548 TI - Radiosensitization of glioblastoma cells using a histone deacetylase inhibitor (SAHA) comparing carbon ions with X-rays. AB - PURPOSE: Prognosis for patients with glioblastoma (GBM) remains poor, and new treatments are needed. Here we used a combination of two novel treatment modalities: Carbon ions and a histone deacetylase inhibitor (HDACi). We compared these to conventional X-rays, measuring the increased effectiveness of carbon ions as well as radiosensitization using HDACi. MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA) was used at a non-toxic concentration of 0.5 MUM in combination with 85 keV MUm(-1) carbon ions, and 250 kVp X-rays for comparison. Effects were assayed using clonogenic survival, gammaH2AX foci repair kinetics and measuring chromatin decondensation. RESULTS: Dose toxicity curves showed that human GBM LN18 cells were more sensitive to SAHA compared to U251 cells at higher doses, but there was little effect at low doses. When combined with radiation, clonogenic assays showed that the Sensitizer Enhancement Ratio with carbon ions at 50% survival (SER(50)) was about 1.2 and 1.5 for LN18 and U251, respectively, but was similar for X-rays at about 1.3. The repair half-life of gammaH2AX foci was slower for cells treated with SAHA and was most noticeable in U251 cells treated with carbon ions where after 24 h, more than double the number of foci remained in comparison to the untreated cells. Hoechst fluorescent dye incorporation into the nucleus showed significant chromatin decondensation and density homogenization with SAHA treatment for both cell lines. CONCLUSION: Our results suggest a vital role of histone deacetylases (HDAC) in the modulation of DNA damage response and support the use of SAHA for the treatment of GBM through the combination with heavy ion therapy. PMID- 25040549 TI - Combined nitrogen, hexane, and benzene adsorption characterization of pores and surfaces of lyophobic mesoporous silicas. AB - For lyophobic porous surfaces, structural analysis by vapor adsorption is complicated due to weak adsorbate-adsorbent interactions and limited wetting of the pores (nonzero contact angles). To investigate further, adsorption isotherms of three distinct adsorbates (nitrogen - 77 K, n-hexane and benzene - 298 K) were studied for SBA-15 ordered mesoporous silica where the surface was functionalized with lyophobic perfluoroalkyl groups (C6F13 termini). The results demonstrated a clear advantage of the combined use of the adsorption isotherms of less surface sensitive (nitrogen) and more surface sensitive (hydrocarbons) adsorbates. The adsorption of nitrogen provided basic structural characteristics like surface area, pore volume, and pore size distribution, while the isotherms of benzene and n-hexane were used to characterize wetting (contact angles) and surface energy of the C6F13 surfaces within the pores. For the first time, the statistical film thickness for nitrogen, benzene, and n-hexane are being reported for the adsorption on fluorinated surfaces, thereby providing critical data for the pore size and the contact angle determination of the lyophobic materials. PMID- 25040551 TI - Does breathing type influence electromyographic activity of obligatory and accessory respiratory muscles? AB - Craniomandibular electromyographic (EMG) studies frequently include several parameters, e.g. resting, chewing and tooth-clenching. EMG activity during these parameters has been recorded in the elevator muscles, but little is known about the respiratory muscles. The aim of this study was to compare EMG activity in obligatory and accessory respiratory muscles between subjects with different breathing types. Forty male subjects were classified according to their breathing type into two groups of 20 each: costo-diaphragmatic breathing type and upper costal breathing type. Bipolar surface electrodes were placed on the sternocleidomastoid, diaphragm, external intercostal and latissimus dorsi muscles. EMG activity was recorded during the following tasks: (i) normal quiet breathing, (ii) maximal voluntary clenching in intercuspal position, (iii) natural rate chewing until swallowing threshold, (iv) short-time chewing. Diaphragm EMG activity was significantly higher in the upper costal breathing type than in the costo-diaphragmatic breathing type in all tasks (P < 0.05). External intercostal EMG activity was significantly higher in the upper costal breathing type than in the costo-diaphragmatic breathing type in tasks 3 and 4 (P < 0.05). Sternocleidomastoid and latissimus dorsi EMG activity did not show significant differences between breathing types in the tasks studied (P > 0.05). The significantly higher EMG activity observed in subjects with upper costal breathing than in the costo-diaphragmatic breathing type suggests that there could be differences in motor unit recruitment strategies depending on the breathing type. This may be an expression of the adaptive capability of muscle chains in subjects who clinically have a different thoraco-abdominal expansion during inspiration at rest. PMID- 25040552 TI - Cytosolic iron-sulphur protein assembly is functionally conserved and essential in procyclic and bloodstream Trypanosoma brucei. AB - Cytosolic and nuclear iron-sulphur (Fe/S) proteins include essential components involved in protein translation, DNA synthesis and DNA repair. In yeast and human cells, assembly of their Fe/S cofactor is accomplished by the CIA (cytosolic iron sulphur protein assembly) machinery comprised of some 10 proteins. To investigate the extent of conservation of the CIA pathway, we examined its importance in the early-branching eukaryote Trypanosoma brucei that encodes all known CIA factors. Upon RNAi-mediated ablation of individual, early-acting CIA proteins, no major defects were observed in both procyclic and bloodstream stages. In contrast, parallel depletion of two CIA components was lethal, and severely diminished cytosolic aconitase activity lending support for a direct role of the CIA proteins in cytosolic Fe/S protein biogenesis. In support of this conclusion, the T. brucei CIA proteins complemented the growth defects of their respective yeast CIA depletion mutants. Finally, the T. brucei CIA factor Tah18 was characterized as a flavoprotein, while its binding partner Dre2 functions as a Fe/S protein. Together, our results demonstrate the essential and conserved function of the CIA pathway in cytosolic Fe/S protein assembly in both developmental stages of this representative of supergroup Excavata. PMID- 25040553 TI - Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial. AB - The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first-ever ischaemic stroke and moderate-severe obstructive sleep apnea (OSA) with an apnea-hypopnea index (AHI) >=20 events h(-1) during a 5-year follow-up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event-free survival analysis were performed after 5-year follow-up using the Kaplan-Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log-rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event-free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log-rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long-term survival in ischaemic stroke patients and moderate-severe OSA. PMID- 25040554 TI - Intraoperative apnea in children after buffered 5% povidone-iodine site sterilization for strabismus surgery. AB - BACKGROUND: Presurgical preparation for ocular surgery typically utilizes a buffered 5% povidone-iodine preparation solution. It was our observation that a significant number of spontaneously ventilating patients under sevoflurane anesthesia would become apneic upon ophthalmic instillation of this solution. This study was performed to confirm or refute this observation and to determine whether there were any patient variables that might predict this phenomenon. METHODS: After Institutional Review Board (IRB) approval, thirty pediatric patients scheduled for strabismus surgery were enrolled. Anesthesia was induced and maintained with sevoflurane via laryngeal mask airway, and all patients were breathing spontaneously. All patients received preoperative sedation with oral midazolam (0.5 kg.kg(-1), maximum 12 mg). Presurgical preparation was performed with saline wash followed by instillation of buffered 5% povidone-iodine solution. Respiratory rate was recorded at the time of surgical preparation. Apnea was defined as lack of respiratory effort for 20 s or greater. RESULTS: Data from twenty-eight children (ages 1.4-11 years) were ultimately recorded. Fifteen of the twenty-eight patients developed apnea (median duration 40, IQR 37, range 20-262 s) at the time of surgical site preparation. CONCLUSIONS: Apnea at the time of ocular preparation with buffered 5% povidone-iodine solution is common. The precise mechanism of this response is unknown. PMID- 25040555 TI - Scanning electron microscope analysis of gunshot defects to bone: an underutilized source of information on ballistic trauma. AB - Recent years have seen increasing involvement by forensic anthropologists in the interpretation of skeletal trauma. With regard to ballistic injuries, there is now a large literature detailing gross features of such trauma; however, less attention has been given to microscopic characteristics. This article presents analysis of experimentally induced gunshot trauma in animal bone (Bos taurus scapulae) using full metal jacket (FMJ), soft point (SP), and captive bolt projectiles. The results were examined using scanning electron microscopy (SEM). Additional analysis was conducted on a purported parietal gunshot lesion in a human cranial specimen. A range of features was observed in these samples suggesting that fibrolamellar bone response to projectile impact is analogous to that observed in synthetic composite laminates. The results indicate that direction of bullet travel can be discerned microscopically even when it is ambiguous on gross examination. It was also possible to distinguish SP from FMJ lesions. SEM analysis is therefore recommended as a previously underexploited tool in the analysis of ballistic trauma. PMID- 25040556 TI - Should the individual preterm birth risk be incorporated into the embryo transfer policy in in vitro fertilisation? A decision analysis. AB - OBJECTIVE: To assess by proof of principle whether the individual risk for preterm birth (PTB) should be incorporated into the embryo transfer policy in in vitro fertilisation (IVF). DESIGN AND SETTING: A theoretical decision analysis. METHODS AND MAIN OUTCOME MEASURES: A decision tree was built to compare the consequences of different chances of PTB on the outcome of single embryo transfer (SET) or double embryo transfer (DET) in patients with different prognosis of conception. Based on patient characteristics, three scenarios of prognosis of conception were considered and the consequences of SET and DET were calculated for different chances of PTB in these groups. The primary outcome was the health of the children born. Sensitivity analyses were performed for both prognosis for conception and chances of PTB. RESULTS: In women with good fertility prospects, one IVF cycle with DET increases the ongoing pregnancy rate (OPR) from 29 to 39% compared with SET, whereas the chances of poor neonatal outcome in these extra pregnancies range from 1.4 to 11% per pregnancy depending on the individual PTB risk. However, for women with poor fertility prospects, DET increases the OPR from 8 to 11% with minimal additional poor neonatal outcome, ranging from 0.3 to 4.0% per pregnancy for women with a low or high PTB risk, respectively. Our findings were robust in multiple sensitivity analyses. CONCLUSION: In an IVF programme, the optimal embryo transfer strategy is dependent on the singleton and multiple pregnancy chances of a woman, but also on her PTB risk. In women with low PTB risk, DET increases the OPR for a small additional risk of neonatal complications. Our analysis pleads for a tailored management strategy, taking into account the personalised prognosis for (multiple) pregnancy and PTB. PMID- 25040557 TI - Laparoscopic kidney transplant by extra peritoneal approach: the safe transition from laboratory to the clinic. AB - The aim of this study is to develop a novel laparoscopic surgery by extra peritoneal approach for kidney transplant and pave the way of safe transition from laboratory to the clinic. The study was established to explore the feasibility and safety of human laparoscopic kidney transplant. The experiment was first conducted on the deceased animals, then live animals and human cavader before human kidney transplant was approved. The study patient was a 49-year-old male who received the kidney for laparoscopic kidney transplant by extra peritoneal approach. The control patient received the contralateral kidney for open kidney transplant. The estimated blood loss was minimal during surgery. Both kidneys experienced delayed graft function but the kidneys started function on Day 6 postoperation. The analgesia consumption was significantly less in the study patient. There is no surgical complication during 6-month follow-up. This study has developed a new technique for laparoscopic kidney transplant by extra peritoneal approach. It has retained the advantages of open kidney transplant, which allows the graft located in the extra-peritoneal space without violating peritoneum. This study has also paved the way of safe transition for a novel laparoscopic surgery from laboratory to the clinic. PMID- 25040558 TI - Kidney disease and risk of venous thromboembolism: a nationwide population-based case-control study. AB - BACKGROUND: Chronic kidney disease is associated with hemostatic derangements, including both procoagulant activity and platelet dysfunction, which may influence the risk of venous thromboembolism. However, data associating kidney disease with risk of venous thromboembolism are sparse. OBJECTIVES: We examined whether kidney disease is associated with increased risk of venous thromboembolism. METHODS: We conducted this nationwide case-control study using data from medical databases. We included 128,096 patients with a hospital diagnosis of VTE in Denmark between 1980 and 2010 (54,473 had pulmonary embolism and 73,623 had deep venous thrombosis only) and 642,426 age- and gender-matched population controls based on risk-set sampling. We identified all previous hospital diagnoses of kidney disease, including nephrotic syndrome, glomerulonephritis without nephrotic syndrome, hypertensive nephropathy, chronic pyelonephritis/interstitial nephritis, polycystic kidney disease, diabetic nephropathy, or other kidney diseases. We used conditional logistic regression models to compute odds ratios (ORs) for venous thromboembolism with adjustment for potential confounders. RESULTS: Kidney disease was associated with an adjusted OR for venous thromboembolism ranging from 1.41 (95% CI, 1.22-1.63) for hypertensive nephropathy to 2.89 (95% CI, 2.26-3.69) for patients with nephrotic syndrome. The association was strongest within the first 3 months after a diagnosis of chronic kidney disease (adjusted OR for nephrotic syndrome = 23.23; 95% CI, 8.58-62.89), gradually declining thereafter. The risk, however, remained elevated for more than 5 years, especially in patients with nephrotic syndrome and glomerulonephritis. CONCLUSIONS: Kidney diseases, in particular nephrotic syndrome and glomerulonephritis, were associated with an increased risk of venous thromboembolism. PMID- 25040560 TI - 'Upgrading' psoriasis responsibly. AB - Psoriasis is a 'pacemaker' in dermatology. Substantial progress has been made regarding our understanding of its pathophysiology and genetic background, fuelling developments in cutaneous biology in general. Besides, the clinical perspective on psoriasis is currently changing, taking into consideration comorbidity and the systemic dimensions of this seemingly organ-specific inflammation. The availability of drugs exhibiting fewer contraindications and improved long-term safety opened a discussion around replacing a relatively limited (regarding both objectives and duration) 'therapeutic' by a much broader 'management' approach when it comes to treating psoriasis as a systemic disease. The question arises whether this 'upgrade' is warranted. PMID- 25040559 TI - Determination of the psychiatric symptoms and psychological resilience levels of hematopoietic stem cell transplant patients and their relatives. AB - This study was performed to evaluate psychiatric symptoms and resilience levels of the hematopoietic stem cell transplant patients and their relatives. The study enrolled 51 patients and 45 relatives undergoing bone marrow transplantation. Data were collected using Personal Information Form, Brief Symptom Inventory and Resilience Scale for Adults. Psychiatric symptoms of both patients and their relatives were negatively associated with resilience levels. Patients and their relatives with a higher degree of resilience showed a lower degree of psychiatric symptoms. The study results demonstrate that haematopoietic stem cell transplantation is a process that affects patients as well as their families. We suggest that patients and their family members be evaluated for psychiatric symptoms by nurses during this process and resilience level of patients be increased by helping them improve their coping and problem-solving skills for adaptation throughout the process. PMID- 25040561 TI - Reimplanting previously infected device in the same patient: a clever way to provide essential therapy. PMID- 25040562 TI - Workplace abuse narratives from dentistry, nursing, pharmacy and physiotherapy students: a multi-school qualitative study. AB - INTRODUCTION: Previous healthcare student abuse research typically employs quantitative surveys that fail to explore contributory factors for abuse and students' action in the face of abuse. Following a recent qualitative study of medical students' abuse narratives, the current study explores dental, nursing, pharmacy and physiotherapy students' abuse narratives to better understand healthcare workplace abuse. METHODS: We conducted three individual and 11 group interviews with 69 healthcare students in three Universities to elicit professionalism dilemma narratives. Of 226 professionalism dilemmas elicited, 79 were coded as student abuse. Secondary-level thematic analysis of the abuse narratives addressed the following questions: What types of abuse experiences do healthcare students narrate? What factors do they cite as contributing to abuse and their responses to abuse? RESULTS: Healthcare students reported mostly covert abuse in their narratives. Although narrators described individual, relational, work and organisational factors contributing to abuse, they mostly cited factors relating to perpetrators. Most participants stated that they acted in the face of their abuse, and they mostly cited factors relating to themselves for acting. Students who did nothing in the face of abuse typically cited the perpetrator recipient relationship as the main contributory factor. DISCUSSION: There are many similarities across the narratives of the five healthcare student groups, suggesting that complex interactional/organisational factors are all-important when considering how abuse is perpetuated within the healthcare workplace. Although some organisational factors may be difficult to change, we recommend that educational initiatives are a key starting point to tackle healthcare workplace abuse. PMID- 25040563 TI - The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity. AB - WHAT IS KNOWN AND OBJECTIVE: A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28 joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. RESULTS AND DISCUSSION: A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0.84 vs. -1.15, P = 0.446) nor with cessation of leflunomide treatment due to side effects (P = 0.433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. WHAT IS NEW AND CONCLUSION: This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA. PMID- 25040564 TI - Intestinal metaplasia in Barrett's oesophagus may be an epiphenomenon rather than a preneoplastic condition, and CDX2-positive cardiac-type epithelium is associated with minute Barrett's tumour. AB - AIMS: Although intestinal-type epithelium in Barrett's oesophagus has been traditionally recognized as having a distinct malignant potential, whether this also holds true for cardiac-type epithelium remains controversial. The aim of this study was to identify a type of epithelium that is highly associated with Barrett's tumour. METHODS AND RESULTS: We analysed tumours and the corresponding background mucosa with special regard to tumour size in 40 cases of superficial Barrett's tumour by using immunohistochemical staining for CDX2, CD10, MUC2, MUC5AC, and MUC6. Intestinal metaplasia in tumour-adjacent mucosa was not associated with tumour size, but was significantly correlated with the extent of Barrett's oesophagus (P < 0.001). The majority (69.2%, 9/13) of small tumours (<=10 mm) had no intestinal metaplasia in adjacent non-neoplastic mucosae. Minute (<=5 mm) tumours were significantly associated with a gastric immunophenotype (P < 0.001). Purely gastric-immunophenotype tumour cells expressed CDX2, and cardiac type epithelium adjacent to small tumours also showed low-level CDX2 expression. CONCLUSIONS: Our data suggest that intestinal metaplasia in Barrett's oesophagus is an epiphenomenon rather than a preneoplastic condition, and that CDX2-positive cardiac-type epithelium is highly associated with minute Barrett's tumour. Further prospective studies are needed to evaluate the risk of malignancy of cardiac-type epithelium with regard to sub-morphological intestinalization. PMID- 25040565 TI - Impacts of dietary fat level and saturation when feeding distillers grains to high producing dairy cows. AB - This experiment was conducted to determine whether increasing the net energy (NEL ) of a total mixed ration (TMR) with mainly unsaturated fat from corn distillers dried grains with solubles (DDGS) vs. rumen inert (RI)-saturated fat has similar impacts on animal performance. The experiment was an incomplete Youden square with three treatments and four 28-days periods, completed on a large commercial dairy using three early lactation pens each with approximately 380 multiparity cows. The TMR for all treatments was the same, except for 150 g/kg dry matter (DM) of each TMR which contained 90 g/kg high-protein DDGS (HPDDGS) and 60 g/kg beet pulp (i.e. low-fat control diet; LFC); 150 g/kg DDGS (i.e. high-fat diet with unsaturated fat; HFU); or 111 g/kg HPDDGS, 20 g/kg beet pulp and 19 g/kg RI fat (i.e. high-fat diet with saturated fat; HFS). The DM intake was highest (p < 0.05) for HFU-fed cows. Milk, fat and true protein yields, as well as milk energy output, were higher (p < 0.01) when cows were fed HFS vs. HFU and LFC diets. Milk true protein concentration was lowest (p < 0.01) for HFS-fed cows, but milk fat % was lowest (p < 0.01) for HFU and highest (p < 0.01) for HFS-fed cows. There were numerous differences (p < 0.01) in milk fatty acid levels amongst diets. The increase in body condition score was lowest (p < 0.01) for LFC. Whole tract digestibility of acid detergent fibre was lower (p < 0.01) for LFC vs. HFS cows, and fat digestion was lowest (p < 0.01) for LFC-fed cows. This DDGS, high in unsaturated fatty acids, was fed at high levels (i.e. 152 g/kg DM) with little impact on animal performance vs. a lower fat control diet, although addition of an RI-saturated fat to create a diet with a similarly higher fat level resulted in higher animal productivity. PMID- 25040566 TI - Molecular phylogeny of an Indian population of Kleinstyla dorsicirrata (Foissner, 1982) Foissner et al., 2002. comb. nov. (Hypotrichia, Oxytrichidae): an oxytrichid with incomplete dorsal kinety fragmentation. AB - Kleinstyla dorsicirrata (Foissner, 1982) Foissner et al., 2002. comb. nov. (basionym: Gastrostyla dorsicirrata) is a slightly flexible oxytrichid, measuring about 88-115 * 27-46 MUm in life and possesses cortical granules. Kleinstyla dorsicirrata is the only oxytrichid known so far with incompletely fragmented dorsal kinety. Morphological and morphogenetic data recognise K. dorsicirrata as nonstylonychine oxytrichid. Molecular phylogeny of an Indian population was inferred using 18S rRNA gene sequences and was examined with respect to oxytrichids exhibiting variation in dorsal kinety fragmentation. Kleinstyla dorsicirrata clusters with Oxytricha lanceolata; this proximity is quite significant as both show deviation from typical oxytrichid fragmentation of dorsal kinety. Molecular phylogeny of Indian population confirms its nonstylonychine oxytrichid status. PMID- 25040567 TI - Bilateral renal infiltration as the initial presentation of multiple myeloma. PMID- 25040568 TI - Menstrual irregularities, fertility status, and ovarian function in female patients with leprosy in India. AB - BACKGROUND: Gonadal involvement in males in lepromatous leprosy is not uncommon, but there is a paucity of literature on the involvement of gonads in female patients with leprosy. This study was undertaken to determine if there is any menstrual dysfunction, alteration in fertility status and circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and estradiol in female patients with paucibacillary (PB) and multibacillary (MB) leprosy. MATERIALS AND METHODS: In a cross-sectional study, 229 patients with leprosy (79 with PB leprosy and 150 with MB leprosy) and 100 age-matched non-leprosy controls were evaluated for menstrual function, fertility status, and circulating sex hormones. RESULTS: Twenty percent of patients with MB leprosy had menstrual irregularities post-dating the onset of leprosy in comparison to 6.3% patients with PB leprosy, and this difference was statistically significant (P < 0.001). However, the fertility profile of patients with PB leprosy was comparable to that of patients with MB leprosy (P > 0.05). A significantly higher number of patients with MB leprosy (9.3%) had elevation of circulating FSH, LH, and prolactin vis-a vis patients with PB leprosy (1.3%), and this difference was statistically significant (P < 0.05). Similarly, the mean levels of LH, FSH, and prolactin were significantly elevated in patients with MB leprosy vis-a-vis patients with PB leprosy and controls (P < 0.05). CONCLUSIONS: Multibacillary leprosy may be associated with menstrual irregularities and elevation of gonadotropin hormones, indicating an ovarian dysfunction. PMID- 25040569 TI - Zooming in on size distribution patterns underlying species coexistence in Baltic Sea phytoplankton. AB - Scale is a key to determining which processes drive community structure. We analyse size distributions of phytoplankton to determine time scales at which we can observe either fixed environmental characteristics underlying communities structure or competition-driven size distributions. Using multiple statistical tests, we characterise size distributions of phytoplankton from 20-year time series in two sites of the Baltic Sea. At large temporal scales (5-20 years), size distributions are unimodal, indicating that fundamental barriers to existence are here subtler than in other systems. Frequency distributions of the average size of the species weighted by biovolume are multimodal over large time scales, although this is the product of often unimodal short-term (<1 year) patterns. Our study represents a much-needed structured, high-resolution analysis of phytoplankton size distributions, revealing that short-term analyses are necessary to determine if, and how, competition shapes them. Our results provide a stepping-stone on which to further investigate the intricacies of competition and coexistence. PMID- 25040570 TI - A facile means for the identification of indolic compounds from plant tissues. AB - The bulk of indole-3-acetic acid (IAA) in plants is found in the form of conjugated molecules, yet past research on identifying these compounds has largely relied on methods that were both laborious and inefficient. Using recent advances in analytical instrumentation, we have developed a simple yet powerful liquid chromatography-mass spectrometry (LC-MS)-based method for the facile characterization of the small IAA conjugate profile of plants. The method uses the well-known quinolinium ion (m/z 130.0651) generated in MS processes as a signature with high mass accuracy that can be used to screen plant extracts for indolic compounds, including IAA conjugates. We reinvestigated Glycine max (soybean) for its indoles and found indole-3-acetyl-trytophan (IA-Trp) in addition to the already known indole-3-acetyl-aspartic acid (IA-Asp) and indole-3 acetyl-glutamic acid (IA-Glu) conjugates. Surprisingly, several organic acid conjugates of tryptophan were also discovered, many of which have not been reported in planta before. These compounds may have important physiological roles in tryptophan metabolism, which in turn can affect human nutrition. We also demonstrated the general applicability of this method by identifying indolic compounds in different plant tissues of diverse phylogenetic origins. It involves minimal sample preparation but can work in conjunction with sample enrichment techniques. This method enables quick screening of IAA conjugates in both previously characterized as well as uncharacterized species, and facilitates the identification of indolic compounds in general. PMID- 25040571 TI - SCAD and JERD: a confluence of excellence in esthetics. PMID- 25040572 TI - Growth factor therapy in patients with partial-thickness burns: a systematic review and meta-analysis. AB - Growth factor (GF) therapy has shown promise in treating a variety of refractory wounds. However, evidence supporting its routine use in burn injury remains uncertain. We performed this systematic review and meta-analysis assessing randomised controlled trials (RCTs) to investigate efficacy and safety of GFs in the management of partial-thickness burns. Electronic searches were conducted in PubMed and the Cochrane databases. Endpoint results analysed included wound healing and scar formation. Thirteen studies comprising a total of 1924 participants with 2130 wounds (1131 GF receiving patients versus 999 controls) were identified and included, evaluating the effect of fibroblast growth factor (FGF), epidermal growth factor (EGF) and granulocyte macrophage-colony stimulating factor (GM-CSF) on partial-thickness burns. Topical application of these agents significantly reduced healing time by 5.02 (95% confidence interval, 2.62 to 7.42), 3.12 (95% CI, 1.11 to 5.13) and 5.1 (95% CI, 4.02 to 6.18) days, respectively, compared with standard wound care alone. In addition, scar improvement following therapy with FGF and EGF was evident in terms of pigmentation, pliability, height and vascularity. No significant increase in adverse events was observed in patients receiving GFs. These results suggested that GF therapy could be an effective and safe add-on to standard wound care for partial-thickness burns. High-quality, adequately powered trials are needed to further confirm the conclusion. PMID- 25040574 TI - Quality improvement and evidence-based practice change projects and the institutional review board: is approval necessary? PMID- 25040575 TI - Home nurses and patient depression. Attitudes, competences and the effects of a minimal intervention. AB - AIM: To explore attitudes and confidence in professional competence of home nurses concerning depression and to evaluate the capacity of a minimal intervention in helping home nurses to detect depression in patients and their family caregivers. BACKGROUND: Long-term ill patients have an elevated risk to develop comorbid depression, as do their family caregivers. However, most primary care providers have little training to detect patients at risk. A minimal intervention to help home nurses detect symptoms of depression was therefore evaluated. DESIGN: Quasi-experimental field study with pre-measures, postmeasures and follow-up measures. METHODS: From the Fall of 2012-Spring of 2013, home nurses (N = 92) in three regions in Antwerp (Belgium) were assigned to a 1-hour intervention (consisting of information, skill training and discussion; N = 63) or to a control condition (N = 29). The Depression Attitude Questionnaire and the Morris Confidence Scale were completed before the intervention and 3 and 7 months afterwards. For 3 months, the number of detections of depression in patients in each region was monitored. FINDINGS: No significant changes were found in attitude or confidence in professional competences, except for a decline in the role attitude for home nurses in the intervention group. Home nurses who followed the intervention did detect significantly more depressed patients compared with controls. CONCLUSION: These findings suggest that a minimal intervention can allow home nurses to be more responsive to symptoms of depression in patients and their family caregivers. The implications of these findings are discussed and suggestions for future research are made. PMID- 25040576 TI - Epidural blood patch in leukemia patient: a case report. AB - OBJECTIVE: We present a case of a patient with acute lymphoblastic leukemia (ALL) undergoing an epidural blood patch (EBP) for post-puncture dural headaches despite the risks of spreading cancer cells to the epidural space. SETTING AND PATIENT: A 46-year-old male with a history of adult T-cell ALL presented with persistent positional headache and neutropenic fever 2 weeks after receiving multiple intrathecal methotrexate treatments. His symptoms were consistent with post-dural puncture headache. The patient underwent an EBP and experienced complete pain relief following the procedure. He had no evidence of central nervous system involvement of ALL on his last evaluation 3 months following the blood patch. CONCLUSION: Post-dural puncture headache due to intrathecal administration of chemotherapy agents becomes increasingly recognized, and there are an increasing number of requests to anesthesiologists for EBP. A major concern in the patient population with hematological malignancies is the possibility of neuroaxial seeding of malignancies. Therein, flow cytometry was implemented to screen for blast cells in the circulating blood. Careful analysis and minimization of this potential risk is required to ensure the safety of the EBP in this specific patient population. PMID- 25040577 TI - The relationship between contraceptive features preferred by young women and interest in IUDs: an exploratory analysis. AB - CONTEXT: Little research has examined the relationship between women's preferences of contraceptive features and their interest in IUD use. Given high levels of contraceptive discontinuation and dissatisfaction, a better understanding of contraceptive preferences may support women in finding their optimal method and meeting their family planning goals. METHODS: Data from 382 heterosexual women aged 18-29 were collected via a 2012 Internet survey. Chi square tests and multivariate, multinomial logistic regression models were used to examine relationships between contraceptive features preferred by women and their interest in IUD use. RESULTS: Forty-eight percent of women reported being unsure whether they would ever use an IUD; 20% were interested in using one, and 32% were not. In multivariate analyses, characteristics of a contraceptive method found positively associated with IUD interest were the method's not interfering with sexual pleasure (relative risk ratio, 3.4), being 99% effective without user action (2.5) and being effective for up to five years without any user action (3.8). Women who preferred a method that they could see or that would allow them to resume fertility immediately after discontinuation were less likely than those who did not to be interested in using rather than not using an IUD (0.4-0.5). CONCLUSIONS: The findings of this exploratory analysis indicate that women value a multitude of contraceptive features, which may have implications for their interest in using an IUD. Future research should consider the ways that women's contraceptive preferences can be incorporated into contraceptive counseling. PMID- 25040578 TI - Eruptive vellus hair cysts: an original case occurring in twins. PMID- 25040579 TI - Proteomics for the diagnosis of thyroid lesions: preliminary report. AB - OBJECTIVE: Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a unique proteomic technology that explores the spatial distribution of biomolecules directly in situ, thus integrating molecular and morphological information. The possibility of correlating distribution maps of multiple analyses with cytological features makes it an ideal research tool for discovering new diagnostic markers. A previous study showed that MALDI-IMS could help discrimination between different types of thyroid lesions, especially papillary thyroid carcinoma (PTC); the present feasibility study on ex vivo fine needle aspiration (FNA) smears describes its potential in detecting new proteomic targets of other thyroid lesions (follicular lesions, medullary carcinoma). METHODS: MALDI-IMS was conducted on ex vivo FNAs obtained from surgical specimens and corresponding in vivo samples. Differences between proteomic profiles of different thyroid lesions were compared. RESULTS: Comparing the protein profiles of hyperplastic nodules obtained from three different patients with each other, and with a new PTC, showed a high degree of concordance, indicating good reproducibility of the IMS technology on cytological samples, suggesting its potential as a tool for biomarker discovery. Furthermore, comparison of the average proteomic profiles of hyperplastic nodules with a Hurthle cell adenoma revealed significant differences, underlying the capability of MALDI-IMS to distinguish between different thyroid lesions. Finally, the proteomic profile of medullary thyroid carcinoma was also characterized. CONCLUSIONS: Our results confirmed the possible role of MALDI-IMS in the search for diagnostic targets of PTC and follicular lesions, which could be applied in larger trials aimed at the identification of proteins, convertible to cost-effective diagnostic tools such as immunohistochemistry. These tests could be used to analyse in vivo cytological smears, improving the preoperative diagnosis of indeterminate thyroid nodules. PMID- 25040580 TI - Association between brain activation (fMRI), cognition and school performance in extremely preterm and term born children. AB - The purpose of the study was to investigate a possible association between brain activation in functional magnetic resonance imaging scans, cognition and school performance in extremely preterm children and term born controls. Twenty eight preterm and 28 term born children were scanned while performing a working memory/selective attention task, and school results from national standardized tests were collected. Brain activation maps reflected difference in cognitive skills but not in school performance. Differences in brain activation were found between children born preterm and at term, and between high and low performers in cognitive tests. However, the differences were located in different brain areas. The implication may be that lack of cognitive skills does not alone explain low performance due to prematurity. PMID- 25040581 TI - Comparison of percutaneous transhepatic biliary drainage and endoscopic biliary drainage in the management of malignant biliary tract obstruction: a meta analysis. AB - BACKGROUND AND AIM: To compare percutaneous transhepatic biliary drainage (PTBD) and endoscopic biliary drainage (EBD) for management of malignant biliary tract obstruction (MBTO). METHODS: PubMed, Google Scholar, and the Cochrane database were searched to 31 December 2013. Main outcome measurements were therapeutic success rate, 30-day mortality rate, overall complications, cholangitis, and pancreatitis. RESULTS: Eight studies (five retrospective and three randomized controlled trials) were included in the meta-analysis with a total of 692 participants. Combined odds ratio (OR) = 2.18 revealed no significant difference in therapeutic success between PTBD and EBD (95% confidence interval [CI] = 0.73 6.47, P = 0.162). However, after excluding two studies that appeared to be outliers, PTBD exhibited a better therapeutic success rate than EBD (pooled OR = 4.45, 95% CI = 2.68-7.40, P < 0.001). Patients who underwent PTBD were 0.55 times as likely to have cholangitis as those who underwent EBD, whereas the overall complication rate, pancreatitis rate, and 30-day mortality were similar between the two procedures. CONCLUSIONS: PTBD may be associated with a better therapeutic success rate and lower incidence of cholangitis than EBD, but the overall complication rate, pancreatitis rate, and 30-day mortality of the two procedures are similar. PMID- 25040582 TI - Where culture takes hold: "overimitation" and its flexible deployment in Western, Aboriginal, and Bushmen children. AB - Children often "overimitate," comprehensively copying others' actions despite manifest perceptual cues to their causal ineffectuality. The inflexibility of this behavior renders its adaptive significance difficult to apprehend. This study explored the boundaries of overimitation in 3- to 6-year-old children of three distinct cultures: Westernized, urban Australians (N = 64 in Experiment 1; N = 19 in Experiment 2) and remote communities of South African Bushmen (N = 64) and Australian Aborigines (N = 19). Children overimitated at high frequency in all communities and generalized what they had learned about techniques and object affordances from one object to another. Overimitation thus provides a powerful means of acquiring and flexibly deploying cultural knowledge. The potency of such social learning was also documented compared to opportunities for exploration and practice. PMID- 25040583 TI - Validity of self-reported vaccination status among French healthcare students. AB - Data on validity of self-reported vaccinations are scarce. This study, performed on healthcare students in Paris (France), aimed to evaluate this validity for occupational vaccinations. The validity of self-reported vaccination status was compared with written information. A total of 432 students were enrolled. Sensitivity rates for BCG, hepatitis B and measles were over 74%. For diphtheria tetanus-polio and pertussis, sensitivity was below 50%. Specificity was between 70 and 95% for dTP-pertussis, and below 35% for all others. Overall, the validity of self-reported information was low, meaning that checking medical records remains the preferable strategy for assessing immunization status. PMID- 25040584 TI - Pelizaeus-Merzbacher disease: cellular pathogenesis and pharmacologic therapy. AB - Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy that causes severe dysmyelination in the central nervous system in infancy and early childhood. Many previous studies showed that various proteolipid protein 1 (plp1) mutations, including duplications, point mutations, and deletions, lead to oligodendrocyte dysfunction in patients with PMD. PMD onset and clinical severity range widely, depending on the type of plp1 mutation. Patients with PMD exhibit a delayed mental and physical development phenotype, but specific pharmacological therapy and clinical treatment for PMD are not yet well established. This review describes PMD pathology and establishment of new clinical treatment for PMD. These findings support the development of a new therapy for PMD and these treatments may improve the quality of life in patients with PMD. PMID- 25040585 TI - Evolution of donor-specific antibodies (DSA) and incidence of de novo DSA in solid organ transplant recipients after switch to everolimus alone or associated with low dose of calcineurin inhibitors. AB - BACKGROUND: Everolimus (EVR) is used in organ transplantation to minimize calcineurin inhibitors (CNI). Some studies pointed out an increase in rejection and de novo donor-specific antibodies (DSA) incidence in kidney transplant patients after switch to EVR and CNI withdrawal. The aims of our study were to determine the evolution of anti-HLA antibodies and the incidence of de novo DSA in transplant recipients after conversion to EVR. METHODS: Heart, lung, kidney, and liver transplant recipients were included in a retrospective, monocentric case-control study. Anti-HLA antibodies were identified at transplantation, pre switch, and at three, six, and 12 months post-switch. RESULTS: Conversion to EVR was performed about six yr after the transplant, and low-dose CNI was maintained in 60% of patients. We found no statistical difference for rejection, evolution of preformed anti-HLA antibodies or de novo DSA, after conversion to EVR or not. Incidence of anti-class II DSA tended to increase at month 12 whatever the immunosuppressive regimen. CONCLUSIONS: Late conversion to EVR appears to be safe and to not modify the natural evolution of anti-HLA antibodies in organ transplantation. As 60% of patients received EVR and low doses of CNI, it seems that such combinations could be used with a good outcome. PMID- 25040586 TI - Effect of thrombus size on recanalization by bridging intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: Thrombus length has been reported as an important predictor of successful recanalization by intravenous thrombolysis but its influence on bridging thrombolysis has not been investigated yet. The effect of thrombus length on recanalization rates evaluated by catheter angiography early after intravenous bridging thrombolysis was analyzed. METHODS: Ninety-six consecutive patients with acute cerebral artery occlusion were included. Occlusion site and thrombus length on initial computed tomography angiography or magnetic resonance angiography were related to recanalization after intravenous bridging thrombolysis on the initial series of catheter angiography. RESULTS: Eleven of 96 patients (11.5%) showed successful recanalization (TICI 2a, 2b or 3) after intravenous bridging thrombolysis. Mean thrombus length in these patients was 10.8 mm as opposed to 15.6 mm in patients without successful recanalization. No thrombus longer than 16 mm showed complete recanalization. Binary logistic regression demonstrated a significant influence of thrombus length on probability of recanalization (odds ratio 0.78, 95% confidence interval 0.65-0.95; P = 0.014). CONCLUSIONS: Thrombus length is a significant predictor of recanalization rates after bridging thrombolysis. Overall recanalization rate within the time frame until interventional treatment is started was 11.5% after bridging thrombolysis. PMID- 25040587 TI - Identification of a novel HLA-B*51 allele, HLA-B*51:144, in a Chinese individual. AB - The novel HLA-B*51:144 allele shows one nucleotide difference from B*51:02:02 in exon 3. PMID- 25040588 TI - What is the value of adding Medicare data in estimating VA hospital readmission rates? AB - OBJECTIVE: To determine the effects of including diagnostic and utilization data from a secondary payer on readmission rates and hospital profiles. DATA SOURCES/STUDY SETTING: Veterans Health Administration (VA) and Medicare inpatient and outpatient administrative data for veterans discharged from 153 VA hospitals during FY 2008-2010 with a principal diagnosis of acute myocardial infarction, heart failure, or pneumonia. STUDY DESIGN: We estimated hospital-level risk standardized readmission rates derived using VA data only. We then used data from both VA and Medicare to reestimate readmission rates and compared hospital profiles using two methods: Hospital Compare and the CMS implementation of the Hospital Readmissions Reduction Program (HRRP). DATA COLLECTION/EXTRACTION METHODS: Retrospective data analysis using VA hospital discharge and outpatient data matched with Medicare fee-for-service claims by scrambled Social Security numbers. PRINCIPAL FINDINGS: Less than 2 percent of hospitals in any cohort were classified discordantly by the Hospital Compare method when using VA-only compared with VA/Medicare data. In contrast, using the HRRP method, 13 percent of hospitals had differences in whether they were flagged as having excessive readmission rates in at least one cohort. CONCLUSIONS: Inclusion of secondary payer data may cause changes in hospital profiles, depending on the methodology used. An assessment of readmission rates should include, to the extent possible, all available information about patients' utilization of care. PMID- 25040589 TI - Critical appraisal of biomarkers of dietary intake and nutritional status in patients undergoing dialysis. PMID- 25040590 TI - Combined alcohol and energy drink use: hedonistic motives, adenosine, and alcohol dependence. AB - Consumption of alcohol mixed with energy drinks (AmED) has been associated with both short- and long-term risks beyond those observed with alcohol alone. AmED use has been associated with heavy episodic (binge) drinking, risky behaviors, and risk of alcohol dependence. Laboratory research has demonstrated that AmED beverages lead to greater motivation to drink versus the same amount of alcohol consumed alone. However, the reason consumers find AmED beverages particularly appealing has been unclear. A recent report by Droste and colleagues (Alcohol Clin Exp Res 2014; 38:2087-2095) is the first study to investigate motivations related to AmED consumption and to determine which motives predict AmED consumption patterns, experience of drinking-related harms, and risk of alcohol dependence. The findings of this study significantly enhance our understanding of why AmED consumption is related to the risk of alcohol dependence and change our understanding of why consumers choose AmED beverages. The authors report that hedonistic motives strongly predicted AmED use and the harms associated with use. While intoxication-reduction motives predicted self-reported accidents and injuries, these motives did not predict AmED consumption patterns and risk of dependence. The risk of alcohol dependence may arise from repeated experiences when drinking alcohol is more pleasurable when energy drinks are consumed with the alcohol. This commentary will focus on why energy drinks might increase the rewarding properties of alcohol in social drinkers. In addition, discussion is provided explaining why more research on the neurotransmitter, adenosine, may actually inform us about the mechanisms contributing to the development of alcohol dependence. PMID- 25040591 TI - Nicotinic acid supplementation in the context of alcoholic liver injury: friend or foe? AB - Li and colleagues (2014) in this issue report that dietary nicotinic acid (NA) supplementation ameliorates ethanol-induced hepatic steatosis, but a deficiency does not worsen injury induced by alcohol alone. The authors further present some mechanistic insights into the protective role of NA supplementation. Results of this and other previous studies in the context of alcoholic liver injury raise one important question as to what should be an adequate dose of NA that will provide the maximum benefit to hepatic and extrahepatic tissues and with minimum adverse effects. PMID- 25040592 TI - Advanced diagnostic imaging and surgical treatment of an odontogenic retromasseteric abscess in a guinea pig. AB - A two-year-old guinea pig presented for difficulty chewing. Examination and diagnostic imaging, including computed tomography and magnetic resonance, revealed an odontogenic retromasseteric abscess associated with a mandibular cheek tooth. Treatment included removal of the abscess and marsupialisation of the surgical site for repeated debridement and healing by second intention. Unique features of this case included the use of advanced diagnostic imaging and utilisation of marsupialisation for surgical correction. PMID- 25040593 TI - Regression of fragmented QRS complex: a marker of electrical reverse remodeling in cardiac resynchronization therapy. AB - BACKGROUND: Fragmented QRS (fQRS) marks inhomogeneous activation and asynchronous cardiac contraction. It has been proved that cardiac resynchronization therapy (CRT) could reverse geometrical remodeling as well as correct electrical dyssynchrony. We aimed to investigate whether fQRS changed corresponding to the therapeutic response to CRT. METHODS: Patients who underwent de novo CRT implantation previously and had >=1 follow-up between August 2012 and September 2013 in our hospital were investigated. Intrinsic electrocardiogram was recorded and fQRS in any lead was calculated. Response to CRT was defined as absolute improvement in left ventricular ejection fraction by >=10% or by improvement >1 New York Heart Association class and without heart failure hospitalization. RESULTS: A total of 75 patients (48 male, mean ages, 61 +/- 9 years) were included in this study. At a median follow-up of 13 months, 57 patients had response to CRT. Responders had narrowed QRS (from 167 +/- 23 ms to 158 +/- 19 ms, P = 0.003) and reduced fQRS post-CRT. Nonresponders had QRS prolonging (from 151 +/- 26 ms to 168 +/- 16 ms, P = 0.033) and increase in fQRS. Eleven of 12 patients with reduced fQRS were responders and 8 of 12 with increased fQRS were nonresponders. Both changes in QRS and fQRS correlated strongly with CRT response (r = 0.389, P = 0.001 and r = 0.403, P = 0.000, respectively). Reduction of fQRS in >=1 leads had high specificity (95%) in association to responders, though in low sensitivity (19%). CONCLUSIONS: The changes in fQRS associated with therapeutic response to CRT. Regression of fQRS could be a maker of electrical reverse remodeling following CRT. PMID- 25040594 TI - Amino acid substitution in P3 of Soybean mosaic virus to convert avirulence to virulence on Rsv4-genotype soybean is influenced by the genetic composition of P3. AB - The modification of avirulence factors of plant viruses by one or more amino acid substitutions converts avirulence to virulence on hosts containing resistance genes. Limited experimental studies have been conducted on avirulence/virulence factors of plant viruses, in particular those of potyviruses, to determine whether avirulence/virulence sites are conserved among strains. In this study, the Soybean mosaic virus (SMV)-Rsv4 pathosystem was exploited to determine whether: (i) avirulence/virulence determinants of SMV reside exclusively on P3 regardless of virus strain; and (ii) the sites residing on P3 and crucial for avirulence/virulence of isolates belonging to strain G2 are also involved in virulence of avirulent isolates belonging to strain G7. The results confirm that avirulence/virulence determinants of SMV on Rsv4-genotype soybean reside exclusively on P3. Furthermore, the data show that sites involved in the virulence of SMV on Rsv4-genotype soybean vary among strains, with the genetic composition of P3 playing a crucial role. PMID- 25040595 TI - Diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient mapping for diagnosing infectious spondylodiscitis: a preliminary study. AB - BACKGROUND AND PURPOSE: Though diffusion-weighted (DW) magnetic resonance imaging (MRI) is useful for diagnosing many pathologies, its use in infectious spondylodiscitis is unclear. We aimed to evaluate the use of DW MRI and apparent diffusion coefficient (ADC) mapping for the diagnosis of infectious spondylodiscitis. METHODS: In this retrospective study, 17 patients with confirmed infectious spondylodiscitis were matched by age and level of infected disc with 17 patients with degenerative disc disease (DDD) and 17 healthy controls. All patients received conventional MRI and diffusion-weighted imaging (DWI) in the same imaging session. ADC values of the 3 groups of patients were compared. RESULTS: The mean age of each group was 67.4 +/- 11.6 years. The mean ADCs of the normal control, DDD, and infectious spondylodiscitis groups were 1.76 +/- 0.19 * 10(-3) , 1.12 +/- 0.22 * 10(-3) , and 1.27 +/- 0.38 * 10(-3) mm2 /second, respectively. The ADCs of the DDD and infectious spondylodiscitis groups were both significantly lower than that of the normal control group (both, P < 0.001). CONCLUSION: These data suggest that DWI/ADC MRI may be useful in the early diagnosis of infectious spondylodiscitis. PMID- 25040596 TI - Postoperative lower gastrointestinal haemorrhage following bowel resection. PMID- 25040597 TI - The prevalence of metabolically healthy obesity: a systematic review and critical evaluation of the definitions used. AB - We performed a systematic review of the prevalence of metabolically healthy obesity (MHO). Medline, Web of Science and EMBASE were searched for original articles from inception to November 2013. Only prospective and cross-sectional studies were included. After screening 478 titles, we selected 55 publications, of which 27 were population-based studies and were used in the narrative synthesis. From the 27 studies, we identified 30 definitions of metabolic health, mainly based on four criteria: blood pressure, high-density lipoprotein cholesterol, triglycerides and plasma glucose. Body mass index >=30 kg m(-2) was the main indicator used to define obesity (74% of the studies). Overall, MHO prevalence ranged between 6% and 75%. In the studies that stratified the analysis by sex, prevalence was higher in women (seven out of nine studies) and in younger ages (all four studies). One-third of the studies (n = 9) reported the response rate. Of these, four reported a response rate of >=70% and they showed MHO prevalence estimates between 10% and 51%. The heterogeneity of MHO prevalence estimates described in this paper strengthens calls for the urgent need for a commonly established metabolic health definition. PMID- 25040598 TI - Plasma free triiodothyronine (fT3) levels in baboons undergoing pig organ transplantation: relevance to early recovery of organ function. PMID- 25040599 TI - Serving the underserved: creating a low-cost sunscreen with natural ingredients for humanitarian medical trips to the developing world. PMID- 25040600 TI - Sexual risk behaviour and donor deferral in Europe. AB - One of the most controversial policies in blood transfusion worldwide is the permanent deferral from donating blood of men with sexual contacts to other men (MSM). This policy was implemented for safety reasons as sex between men is known to be a high risk factor for acquiring severe infectious diseases transmissible by blood transfusion. Sexual contacts among heterosexual persons may hold similar risks but a clear-cut discrimination between different individual risks is impossible. Nevertheless, the current blood donor deferral periods defined by European Union (EU) legislation depend on a distinction of different grades of risk with respect to sexual behaviour. Under the aegis of the Steering Committee on Blood Transfusion (CD-P-TS) of the Council of Europe (CoE), an international working group evaluated epidemiological and behavioural data, modelling studies on residual risk and spread of infections, and studies on adherence to donor selection criteria. The aim was to distinguish sexual behaviour of different risk categories. It was concluded, that existing data confirm that MSM and commercial sex workers (CSW) are groups at high risk. Any further grading lacks a scientific data base. Modelling studies indicate that adherence to deferral policies is of major relevance suggesting that good donor adherence may outweigh the small negative effects on blood safety postulated for changing from permanent to temporary deferral periods for high risk sexual behaviours. The fact that a considerable percentage of donors are MSM - despite the permanent deferral policy - demonstrates the need to increase donor understanding and adherence. PMID- 25040601 TI - The ecosystem approach to fisheries: management at the dynamic interface between biodiversity conservation and sustainable use. AB - The emergence of an ecosystem approach to fisheries (EAF) was characterized by the adoption of objectives for maintaining ecosystem health alongside those for fisheries. The EAF was expected to meet some aspirations for biodiversity conservation, but health was principally linked to sustainable use rather than lower levels of human impact. Consequently, while policies including EAF concepts identified objectives for fisheries management and biodiversity conservation, the wording often reflected unresolved societal and political debates about objectives and gave imprecise guidance on addressing inevitable trade-offs. Despite scientific progress in making trade-offs and consequences explicit, there remain substantial differences in interpretations of acceptable impact, responses to uncertainty and risk, and the use of management measures by groups accountable for fisheries management and biodiversity conservation. Within and among nations and regions, these differences are influenced by the contribution of fisheries, aquaculture, farming, and trade to food security, consumers' options, and other social, economic, and environmental factors. Notwithstanding, mutual understanding of the motivations and norms of fisheries management and biodiversity conservation groups is increasing, and interactions between these groups have likely supported more progress toward meeting their stated objectives than would have otherwise been achievable. PMID- 25040602 TI - Characterization of large deletions in the DHCR7 gene. AB - Pathogenic variants in the DHCR7 gene cause Smith-Lemli-Opitz syndrome (SLOS), a defect of cholesterol biosynthesis resulting in an autosomal recessive congenital metabolic malformation disorder. In approximately 4% of patients, the second mutation remains unidentified. In this study, 12 SLOS patients diagnosed clinically and/or by elevated 7-dehydrocholesterol (7-DHC) have been investigated by customized multiplex ligation-dependent probe amplification (MLPA) analysis, because only one DHCR7 sequence variant has been detected. Two unrelated patients of this cohort carry different large deletions in the DHCR7 gene. One patient showed a deletion of exons 3-6. The second patient has a deletion of exons 1 and 2 (non-coding) and lacks the major part of the promoter. These two patients show typical clinical and biochemical phenotypes of SLOS. Second disease-causing mutations are p.(Arg352Trp) and p.(Thr93Met), respectively. Deletion breakpoints were characterized successfully in both cases. Such large deletions are rare in the DHCR7 gene but will resolve some of the patients in whom a second mutation has not been detected. PMID- 25040603 TI - Measurement of Natural Losses of LNAPL Using CO2 Traps. AB - Efflux of CO2 above releases of petroleum light nonaqueous phase liquids (LNAPLs) has emerged as a critical parameter for resolving natural losses of LNAPLs and managing LNAPL sites. Current approaches for resolving CO2 efflux include gradient, flux chamber, and mass balance methods. Herein a new method for measuring CO2 efflux above LNAPL bodies, referred to as CO2 traps, is introduced. CO2 traps involve an upper and a lower solid phase sorbent elements that convert CO2 gas into solid phase carbonates. The sorbent is placed in an open vertical section of 10 cm ID polyvinyl chloride (PVC) pipe located at grade. The lower sorbent element captures CO2 released from the subsurface via diffusion and advection. The upper sorbent element prevents atmospheric CO2 from reaching the lower sorbent element. CO2 traps provide integral measurement of CO2 efflux based over the period of deployment, typically 2 to 4 weeks. Favorable attributes of CO2 traps include simplicity, generation of integral (time averaged) measurement, and a simple means of capturing CO2 for carbon isotope analysis. Results from open and closed laboratory experiments indicate that CO2 traps quantitatively capture CO2 . Results from the deployment of 23 CO2 traps at a former refinery indicate natural loss rates of LNAPL (measured in the fall, likely concurrent with high soil temperatures and consequently high degradation rates) ranging from 13,400 to 130,000 liters per hectare per year (L/Ha/year). A set of field triplicates indicates a coefficient of variation of 18% (resulting from local spatial variations and issues with measurement accuracy). PMID- 25040604 TI - Personal view: Hormones and depression in women. AB - Depression is more common in women, occurring at times of hormonal fluctuations as premenstrual depression, postnatal depression and perimenopausal depression. These are all related to changes in hormone levels and constitute the diagnosis of reproductive depression. There is a risk that severe premenstrual depression can be misdiagnosed as bipolar disorder and that women will be started on inappropriate antidepressants or mood-stabilizing therapy. The most effective treatment for severe premenstrual syndrome is by suppression of ovulation and suppression of the cyclical hormonal changes by transdermal estrogens or by GnRH analogs. Postnatal depression is more common in women with a history of premenstrual depression and also responds to transdermal estrogens. Transdermal testosterone gel can be also used in women who suffer loss of energy and loss of libido which may be due to the inappropriate prescription of antidepressants. There is also a role for the Mirena IUS and laparoscopic hysterectomy and oophorectomy in women who are progestogen-intolerant. The hormonal causation of certain common types of depression in women and the successful treatment by estrogens should be understood by psychiatrists and gynecologists. PMID- 25040605 TI - Healing of Bio-Oss(r) grafted marginal gaps at implants placed into fresh extraction sockets of incisor teeth in dogs: a study on the effect of submerged vs. non-submerged healing. AB - OBJECTIVES: To evaluate the effect of submerged vs. non-submerged (NS) protocols in healing outcomes of grafted marginal defects of immediate implants. MATERIALS AND METHODS: The second maxillary incisors were extracted bilaterally in six greyhound dogs. Bone level reduced diameter implants were installed into the extraction sockets leaving orofacial gaps of 2 mm wide. Defects were filled with Bio-Oss((r)) and covered with Bio-Gide((r)). On the one side, the flap was advanced to fully submerge the implant, and on the other, the flap was sutured to allow NS healing. After 3 months of healing, the dogs were sacrificed and block biopsies were obtained to perform histological and morphometric analysis. RESULTS: All implants were clinically healthy and well integrated into bone. In the majority of the specimens, the original bone in the coronal 2-3 mm of the buccal crest had completely resorbed and was replaced by a regenerated bone wall consisting of Bio-Oss((r)) particles surrounded by newly formed bone. Horizontal and vertical resorption of the buccal bone resulted in >=1 mm exposure of the implant surface in one-third of implants. Minor differences existed in some aspects of hard tissue healing between submerged and NS. CONCLUSION: There was very little difference in healing outcomes as well as modelling of the facial bone wall between the submerged and NS protocols in relation to immediate implant placement in this dog model. PMID- 25040606 TI - Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog. AB - BACKGROUND: Hemophilia A is an X-linked disorder caused by a deficiency in coagulation factor VIII. Over 2300 unique mutations in the gene-encoding factor VIII have been documented in people, but limited information is known in dogs. An 11-week-old male Boxer and a 5-year-old male German Shepherd were diagnosed with hemophilia A based on diminished factor VIII activity. OBJECTIVE: The purpose of the study was to identify genetic mutations associated with hemophilia A in both dogs. METHODS: Genomic DNA was isolated from EDTA blood samples from the affected German Shepherd and Boxer, the Boxer's dam, 3 female siblings, and one asymptomatic male sibling. Primers were designed in noncoding regions to amplify the 26 exons of the factor VIII gene via PCR. RESULTS: The affected Boxer sequence revealed a single nucleotide change, cytosine to guanine, at nucleotide position 1412 (1412C>G) in exon 10. The change is predicted to result in the substitution of arginine for proline at amino acid 471 (P471R) in the A2 domain of factor VIII. The dam and female siblings were carriers, the male sibling did not have the mutation. The German Shepherd dog had a single nucleotide change of a guanine to adenine at position 1643 (1643G>A) in exon 11, predicting the substitution of tyrosine for cysteine at amino acid 548 (C548Y) in the A2 domain. CONCLUSIONS: Here we document 2 mutations associated with canine hemophilia A associated with < 1% factor VIII activity, similar to that in people. Another related Boxer with the P471R mutation was later identified. PMID- 25040607 TI - An evidence-based program to improve analgesic practice and pain outcomes in residential aged care facilities. AB - Pain is common in individuals living in residential aged care facilities (RACFs), and a number of obstacles have been identified as recurring barriers to adequate pain management. To address this, the Australian Pain Society developed 27 recommendations for comprehensive good practice in the identification, assessment, and management of pain. This study reviewed preexisting pain management practice at five Australian RACFs and identified changes needed to implement the recommendations and then implemented an evidence-based program that aimed to facilitate better pain management. The program involved staff training and education and revised in-house pain-management procedures. Reviews occurred before and after the program and included the assessment of 282 residents for analgesic use and pain status. Analgesic use improved after the program (P<.001), with a decrease in residents receiving no analgesics (from 15% to 6%) and an increase in residents receiving around-the-clock plus as-needed analgesics (from 24% to 43%). There were improvements in pain relief for residents with scores indicative of pain, with Abbey pain scale (P=.005), Pain Assessment in Advanced Dementia Scale (P=.001), and Non-communicative Patient's Pain Assessment Instrument scale (P<.001) scores all improving. Although physical function declined as expected, Medical Outcomes Study 36-item Short-Form Survey bodily pain scores also showed improvement (P=.001). Better evidence-based practice and outcomes in RACFs can be achieved with appropriate training and education. Investing resources in the aged care workforce using this program improved analgesic practice and pain relief in participating sites. Further attention to the continued targeted pain management training of aged care staff is likely to improve pain-focused care for residents. PMID- 25040608 TI - Professor MJT FitzGerald (1929-2014). PMID- 25040610 TI - Reply to the letter regarding 'A systematic review of hospitalization resulting from medicine related problems in adult patients'. PMID- 25040611 TI - New prophylaxis methods for adverse events of uterine compression sutures: removing compression threads. PMID- 25040609 TI - Heterogeneity in ess transcriptional organization and variable contribution of the Ess/Type VII protein secretion system to virulence across closely related Staphylocccus aureus strains. AB - The Type VII protein secretion system, found in Gram-positive bacteria, secretes small proteins, containing a conserved W-x-G amino acid sequence motif, to the growth medium. Staphylococcus aureus has a conserved Type VII secretion system, termed Ess, which is dispensable for laboratory growth but required for virulence. In this study we show that there are unexpected differences in the organization of the ess gene cluster between closely related strains of S. aureus. We further show that in laboratory growth medium different strains of S. aureus secrete the EsxA and EsxC substrate proteins at different growth points, and that the Ess system in strain Newman is inactive under these conditions. Systematic deletion analysis in S. aureus RN6390 is consistent with the EsaA, EsaB, EssA, EssB, EssC and EsxA proteins comprising core components of the secretion machinery in this strain. Finally we demonstrate that the Ess secretion machinery of two S. aureus strains, RN6390 and COL, is important for nasal colonization and virulence in the murine lung pneumonia model. Surprisingly, however, the secretion system plays no role in the virulence of strain SA113 under the same conditions. PMID- 25040612 TI - Human papillomavirus vaccine awareness, uptake, and parental and health care provider communication among 11- to 18-year-old adolescents in a rural Appalachian Ohio county in the United States. AB - PURPOSE: This study examined human papillomavirus (HPV) vaccine awareness and uptake, and communication with a parent and/or a health care provider among 11- to 18-year-old male and female adolescents in an Appalachian Ohio county. METHODS: Five questions regarding the HPV vaccine were added to the 2012 Youth Risk Behavior Surveillance System (YRBSS) surveys administered to middle and high school students in the county. The YRBSS surveys are school-based, anonymous, and voluntary. The questions added were about vaccine awareness and uptake, and communication with a parent or health care provider about the vaccine. RESULTS: Of the 1,299 participants, 51.9% were male and 90.3% were white. Overall, 49.2%, 23.5%, 19.2%, and 24.6%, respectively, reported vaccine awareness, uptake of at least 1 dose of the HPV vaccine, communication with a parent, and communication with a health care provider. Females and adolescents >= 15 years were significantly more likely to report awareness, uptake, and parental and provider communication than males and adolescents <= 14 years. Adolescents receiving any dose of the vaccine were significantly more likely to have had a parent (OR: 3.74; 95% CI: 2.30-6.06) or a health care provider (OR: 10.91; 95% CI: 6.42-18.6) discuss the vaccine than those who had not received any dose. CONCLUSIONS: Despite the strong link between parental and health care provider communication and HPV vaccine uptake, the levels of communication remain low in this Appalachian population. These findings suggest the need for public health education programs targeting the health care providers, the parents, and the adolescents to improve awareness, knowledge, and HPV vaccine uptake. PMID- 25040613 TI - Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled randomized trial. AB - BACKGROUND: Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to moderate persistent asthma. METHODS: A 24-week, multicenter, randomized, placebo controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged >=12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1 ) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. RESULTS: Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: -55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. CONCLUSIONS: FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP. PMID- 25040614 TI - Surgical outcomes of total anomalous pulmonary venous connection repair: a 22 year experience. AB - BACKGROUND: Total anomalous pulmonary venous connection (TAPVC) is a rare congenital heart disease (CHD), whose surgical repair is associated with high mortality and reoperation rates. We sought to identify predictors of early and late outcomes. METHODS: Data from medical records of patients who underwent surgical repair for TAPVC from 1989 to 2012 were included. The patients were divided in two groups, according to absence or presence of associated major CHDs. RESULTS: Forty-six patients were included (M/F: 26/20, median age 26 days, interquartile range 15 to 59, median weight 3.350 kg, interquartile range 1800 to 4470). Anatomic types of TAPVC were: supracardiac in 48%, intracardiac in 20%, infracardiac in 20%, and mixed in 12%; TAPVC was obstructive in 33%; TAPVC was isolated in 63%, complex in 37%. Single ventricle physiology was present in 11 patients, heterotaxy in eight patients. Overall operative mortality was 19.6% (9/46): 6.9% in isolated TAPVC, 41.2% in complex type (p-value: 0.002). It was associated with low weight at intervention (<3 kg, p = 0.027), single ventricle physiology (p = 0.047), and aortic cross-clamp time >60 minutes (p = 0.097). At a median follow-up of 2.97 years (range 43 days to 22 years, 91% complete), there were nine late deaths (24.3%); 15 patients (40.5%) had major events (including late death). Multivariate analysis of event-free survival showed worse outcome in the complex group (p = 0.001). CONCLUSION: Surgical mortality and morbidity remain consistent in patients with TAPVC and associated major CHD, while the isolated type shows excellent outcomes. Pulmonary vein obstruction is a rare but highly lethal complication. doi: 10.1111/jocs.12399 (J Card Surg 2014;29:678 685). PMID- 25040615 TI - Primary mucinous carcinoma of the skin on the breast with lymph node metastasis. PMID- 25040616 TI - Gastrointestinal: Bouveret's syndrome. PMID- 25040617 TI - Gastrointestinal: Strongyloides stercoralis infestation. PMID- 25040618 TI - Gastrointestinal: gastric outlet obstruction and air pancreatogram in the setting of recurrent acute pancreatitis. PMID- 25040619 TI - Hepatobiliary and pancreatic: traumatic neuroma of the ampulla of Vater. PMID- 25040620 TI - Hepatobiliary and pancreatic: coexisting cancers: Hepatic neuroendocrine carcinomas with gall bladder adenocarcinoma. PMID- 25040621 TI - Post-hepatectomy haemorrhage: a single-centre experience. AB - OBJECTIVES: This study aimed to explore the incidence and causes of intra abdominal haemorrhage after hepatectomy, indications for re-exploration, and factors affecting occurrence. METHODS: Clinical data for 77 patients (0.2% of 32 856 hepatectomy patients) submitted to re-exploration for haemorrhage following hepatectomy for primary liver cancer (PLC) from 2001 to 2010 were retrospectively reviewed and analysed for postoperative complications, potential site and cause of bleeding. RESULTS: The median interval between hepatectomy and re-exploration was 23 h in the 77 patients (range: 1 h to 11 days). Re-exploration occurred within 24 h after hepatectomy in 64 patients (83.1%), and within 8 h in 37 patients (48.1%). The most common anatomic site of intra-abdominal haemorrhage was the cut surface of the liver (n = 51, 66.2%), followed by the perihepatic ligaments (n = 19, 24.7%), the splenic fossa (n = 7, 9.1%), the diaphragm (n = 6, 7.8%), the retroperitonium (n = 6, 7.8%), the right adrenal gland (n = 3, 3.9%), and the gallbladder bed (n = 2, 2.6%). The most common form of bleeding was oozing. Early haemorrhage (at <= 24 h) was most likely to occur in the form of venous bleeding or oozing from the cut surface of the liver. Rates of 5-year overall and disease-free survival in the 77 patients were 22.1% and 3.9%, respectively. CONCLUSIONS: Re-exploration for haemorrhage following hepatectomy for PLC is a rare event. Haemorrhage occurs predominantly at the cut parenchymal surface. Early return to the operating room is vital and perioperative survival is common in this high-risk group. PMID- 25040622 TI - Proline-serine-threonine phosphatase interacting protein 1 inhibition of T-cell receptor signaling depends on its SH3 domain. AB - Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) is an adaptor protein associated with the cytoskeleton that is mainly expressed in hematopoietic cells. Mutations in PSTPIP1 cause the rare autoinflammatory disease called pyogenic arthritis, pyoderma gangrenosum, and acne. We carried out this study to further our knowledge on PSTPIP1 function in T cells, particularly in relation to the phosphatase lymphoid phosphatase (LYP), which is involved in several autoimmune diseases. LYP-PSTPIP1 binding occurs through the C-terminal homology domain of LYP and the F-BAR domain of PSTPIP1. PSTPIP1 inhibits T-cell activation upon T-cell receptor (TCR) and CD28 engagement, regardless of CD2 costimulation. This function of PSTPIP1 depends on the presence of an intact SH3 domain rather than on the F-BAR domain, indicating that ligands of the F-BAR domain, such as the PEST phosphatases LYP and PTP-PEST, are not critical for its negative regulatory role in TCR signaling. Additionally, PSTPIP1 mutations that cause the pyogenic arthritis, pyoderma gangrenosum and acne syndrome do not affect PSTPIP1 function in T-cell activation through the TCR. PMID- 25040623 TI - Discovery of a bifunctional acyltransferase responsible for ornithine lipid synthesis in Serratia proteamaculans. AB - Ornithine lipids (OLs) are phosphorus-free membrane lipids that can be formed by many bacteria but that are absent from archaea and eukaryotes. A function for OLs in stress conditions and in host-bacteria interactions has been shown in some bacteria. Some bacterial species have been described that can form OLs, but lack the known genes (olsBA) involved in its biosynthesis, which implied the existence of a second pathway. Here we describe the bifunctional protein OlsF from Serratia proteamaculans involved in OL formation. Expression of OlsF and its homologue from Flavobacterium johnsoniae in Escherichia coli causes OL formation. Deletion of OlsF in S. proteamaculans caused the absence of OL formation. Homologues of OlsF are widely distributed among gamma-, delta- and epsilon-Proteobacteria and in the Cytophaga-Flavobacterium-Bacteroidetes group of bacteria, including several well-studied pathogens for which the presence of OLs has not been suspected, such as for example Vibrio cholerae and Klebsiella pneumonia. Using genomic data, we predict that about 50% of bacterial species can form OLs. PMID- 25040624 TI - A practice change initiative to improve the provision of enteral nutrition to intensive care patients. AB - AIM: To describe a practice change initiative that improved the provision of enteral nutrition (EN) to patients in a New Zealand tertiary intensive care unit (ICU). METHODS: The project reviewed and summarized EN literature, amended local policy, and an evidence-based EN delivery algorithm was developed. The EN practice change initiative was implemented and evaluated. Data was collected and analyzed in a pre-audit (2009) and a post-audit (2013). RESULTS: Comparison of the pre-audit (N = 25) and the post-audit (N = 40) data demonstrated improvements in three areas of EN delivery. The commencement of early EN within 24 h of admission was evident for a large proportion of patients in both 2009 and 2013 audits. There was a large reduction in time between the two audits for both ICU admission to achievement of EN goal rate (M = 57.71 h versus M = 33.79 h, p = 0.006) and also for EN commencement to achievement of EN goal rate (M = 31.65 h versus M = 10.15 h, p = 0.000). The volume of prescribed EN delivered on days 2, 4 and 6 was greater in the 2013 audit in comparison to the 2009 audit. Staff compliance with adhering to the EN policy and algorithm improved from 46% in 2009, to 95% in 2013. CONCLUSIONS: The practice change has significantly improved the practice delivery of EN for patients in the local ICU resulting in optimal care. RELEVANCE TO CLINICAL PRACTICE: Malnutrition is highly prevalent among intensive care patients. Strategies and initiatives that improve the delivery of enteral nutrition to the critical care population is therefore vitally important. This article describing such an initiative is thus highly relevant to all health care professionals delivering enteral nutrition in intensive and critical care units. PMID- 25040625 TI - Long-term outcome of hand-assisted laparoscopic radical nephrectomy for T1 renal cell carcinoma. AB - OBJECTIVES: To investigate the long-term outcomes of hand-assisted laparoscopic radical nephrectomy compared with those of open nephrectomy. METHODS: Hand assisted laparoscopic radical nephrectomy was carried out in 132 patients with T1 renal cell carcinoma (between November 1999 and November 2008). Their outcomes were compared with those of 61 patients treated with open nephrectomy. The durations of follow up were 6-121 months (median 65 months) and 7-146 months (median 84 months) in the hand-assisted laparoscopic radical nephrectomy and open nephrectomy groups, respectively. RESULTS: The 7-year recurrence-free rates were 88.5 and 85.6% in the hand-assisted laparoscopic radical nephrectomy and open nephrectomy groups, respectively, showing no significant difference between the two groups. The 7-year cancer-specific survival rates were 92.3 and 91.4% in the hand-assisted laparoscopic radical nephrectomy and open nephrectomy groups, respectively, showing no significant difference between the two groups. Also, the 10-year recurrence-free rates were 85.4 and 78.1% in the hand-assisted laparoscopic radical nephrectomy and open nephrectomy groups, respectively. When changes in the recurrence-free rate were analyzed using the Kaplan-Meier method, no significant difference was observed between the two groups. The 10-year cancer specific survival rates were 91.8 and 87.9% for hand-assisted laparoscopic radical nephrectomy and open nephrectomy, respectively, showing no significant difference between the groups. CONCLUSIONS: Hand-assisted laparoscopic radical nephrectomy might be comparable with open nephrectomy with regard to long-term cancer control. PMID- 25040626 TI - Missing in action: inclusion and exclusion in the first days of AIDS in The Netherlands. AB - Approaches combining social and political theory with ontology have rarely been utilised in the evaluation of decision-making processes. Drawing on such an approach clarifies the questions that still need to be asked about the policy response to HIV/AIDS in The Netherlands in the early 1980s. The initial response in The Netherlands is internationally regarded as an example of successful cooperation between public authorities, health organisations, blood banks and the gay movement. In comparison with other countries, deeply dividing social conflicts as well as dramatic medical disasters were avoided. This image, however, is misleading. Although it was on a smaller scale than the disasters with contaminated blood products in other countries, The Netherlands had their blood scandal too. A reconstruction of this episode offers the opportunity to evaluate the role objects are granted in theories of institutionalisation and to critically examine the procedural notion of politics in actor network theory. The aim of the article is to show that analyses of decision-making processes under conditions of uncertainty ought to engage more carefully with processes of exclusion and the transformative role of objects. PMID- 25040627 TI - Effects of laryngoscope handle light source on the light intensity from disposable laryngoscope blades. AB - A bench-top study was performed to assess the effects of different laryngoscope handles on the light intensity delivered from disposable metal or plastic laryngoscope blades. The light intensity from both the handle light sources themselves and the combined handle and laryngoscope blade sets was measured using a custom-designed testing system and light meter. Five samples of each disposable blade type were tested and compared with a standard re-usable stainless steel blade using three different handle/light sources (Vital Signs LED, Heine 2.5 V Xenon and 3.5 V Xenon). The light intensity delivered by the disposable blades ranged from 790 to 3846 lux for the different handle types. Overall, the 3.5 V Heine handle delivered the highest light output (p < 0.007) in comparison with the other handles. For the disposable blades, the overall light output was significantly higher from the plastic than the metal blades (p < 0.001). PMID- 25040628 TI - The replicometer is broken: telomeres activate cellular senescence in response to genotoxic stresses. AB - Telomeres, the ends of our linear chromosomes, can function as 'replicometers', capable of counting cell division cycles as they progressively erode with every round of DNA replication. Once they are critically short, telomeres become dysfunctional and consequently activate a proliferative arrest called replicative senescence. For many years, telomeres were thought to be autonomous structures, largely isolated from cell intrinsic and extrinsic signals, whose function is to prevent limitless cellular proliferation, a characteristic of most cancer cells. It is becoming increasingly evident, however, that telomeres not only count cell divisions, but also function as sensors of genotoxic stresses to stop cell cycle progression prematurely and long before cells would have entered replicative senescence. This stable growth arrest, triggered by dysfunctional telomeres that are not necessarily critically short, likely evolved as a tumor-suppressing mechanism as it prevents proliferation of cells that are at risk for acquiring potentially hazardous and transforming mutations both in vitro and in vivo. Here, we review studies supporting the concept that telomeres are important cellular structures whose function not only is to count cell divisions, but also to act as molecular switches that can rapidly stop cell cycle progression permanently in response to a variety of stresses, including oncogenic signals. PMID- 25040629 TI - Nail involvement as a predictor of concomitant psoriatic arthritis in patients with psoriasis. AB - BACKGROUND: Patients with psoriatic arthritis (PsA) suffer from increased burden of disease and impairments in quality of life. Early detection and treatment of PsA could contribute to the prevention of clinical and radiological progression. OBJECTIVES: To analyse the predictive value of clinical and patient-reported outcomes for concomitant PsA in a population-based cohort of patients with psoriasis. METHODS: We performed a retrospective analysis of data from three independent national cross-sectional studies on health care in psoriasis and PsA, conducted in Germany in the years 2005, 2007 and 2008. Patients with psoriasis were included in the study by dermatologists (n = 3520) and via the German patient advocacy group for psoriasis (n = 2449). In all studies, psoriasis history, clinical findings, PsA, nail involvement, health care and patient reported outcomes were collected with standardized questionnaires. RESULTS: In the regression model on 4146 patients the strongest predictors for concomitant PsA were nail involvement [odds ratio (OR) 2.93, 95% confidence interval (CI) 2.51-3.42, P < 0.001] and inpatient hospital treatment (OR 1.63, 95% CI 1.38 1.93, P < 0.001). By contrast, scalp involvement was not a significant predictor. CONCLUSIONS: Patients with psoriasis seen by dermatologists and those in patient advocacy groups show clinical indicators of PsA, the most predictive being nail disease. In practice, a comprehensive assessment of clinical findings associated with PsA is needed. PMID- 25040631 TI - From the editors: our paper (first) anniversary and launching Epilepsia's new look. PMID- 25040632 TI - Proceedings of the 12th Biennial Meeting of the Asian-Pacific Society for Neurochemistry, 23-26 August, 2014, Kaohsiung, Taiwan. PMID- 25040630 TI - Alpha-7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress, and brain injury in mice with ischemic stroke and bone fracture. AB - Bone fracture at the acute stage of stroke exacerbates stroke injury by increasing neuroinflammation. We hypothesize that activation of alpha-7 nicotinic acetylcholine receptor (alpha-7 nAchR) attenuates neuroinflammation and oxidative stress, and reduces brain injury in mice with bone fracture and stroke. Permanent middle cerebral artery occlusion (pMCAO) was performed in C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0.8 mg/kg PHA 568487 (PHA, alpha-7 nAchR-specific agonist), 6 mg/kg methyllycaconitine (alpha-7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Behavior was tested 3 days after pMCAO. Neuronal injury, CD68(+) , M1 (pro-inflammatory) and M2 (anti inflammatory) microglia/macrophages, phosphorylated p65 component of nuclear factor kappa b in microglia/macrophages, oxidative and anti-oxidant gene expression were quantified. Compared to saline-treated mice, PHA-treated mice performed better in behavioral tests, had fewer apoptotic neurons (NeuN(+) TUNEL(+) ), fewer CD68(+) and M1 macrophages, and more M2 macrophages. PHA increased anti-oxidant gene expression and decreased oxidative stress and phosphorylation of nuclear factor kappa b p65. Methyllycaconitine had the opposite effects. Our data indicate that alpha-7 nAchR agonist treatment reduces neuroinflammation and oxidative stress, which are associated with reduced brain injury in mice with ischemic stroke plus tibia fracture. Bone fracture at the acute stage of stroke exacerbates neuroinflammation, oxidative stress, and brain injury, and our study has shown that the alpha-7 nAchR agonist, PHA (PHA 568487), attenuates neuroinflammation, oxidative stress, and brain injury in mice with stroke and bone fracture. Hence, PHA could provide an opportunity to develop a new strategy to reduce brain injury in patients suffering from stroke and bone fracture. PMID- 25040633 TI - Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients are at high risk of invasive pneumococcal disease (IPD). We investigated the incidence and risk factors of IPD in alloHSCT recipients from 4 regional transplant centers over an 11-year period. This study aimed to inform future improvements in post-transplant care. METHODS: We conducted a retrospective nested 1:2 case-control study in patients aged >=18 years who underwent alloHSCT between 2001 and 2011 in 4 major allogeneic transplant centers. Controls were matched with IPD cases on the basis of conditioning intensity and donor relationship (related or unrelated). Demographics and clinical characteristics of cases and controls were summarized. Univariate analysis of risk factors in matched case-control sets, and multivariate conditional logistic regression to control for confounding, were performed. RESULTS: In 23 alloHSCT recipients, 26 IPD episodes were identified. The cumulative incidence over 11 years was 2.3% (95% confidence interval [CI] 1.45 3.15) and the incidence density 956 per 100,000 transplant years of follow-up (95% CI 580-1321). Multivariate risk factor analysis and backwards elimination showed a significant positive association between mycophenolate mofetil (MMF), hyposplenism/asplenia, and IPD, whereas trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was associated with lower odds of IPD cases. Of alloHSCT recipients with IPD, 38.5% required intensive care, and, of deaths documented in cases over the period of review, 30% were attributable to IPD. Serotypes causing IPD matched currently available vaccines in 15/22 (68.1%) episodes. CONCLUSIONS: The incidence of IPD in alloHSCT recipients is an important cause of morbidity and mortality, with rates of disease being many fold higher than the general population. Patients with evidence of hyposplenism/asplenia define a high-risk group in the alloHSCT population for IPD, and the independent association with IPD and MMF in the adjusted model from this study requires further evaluation. The occurrence of post-transplant IPD may be reduced by measures such as vaccination with both 13 valent and 23-valent pneumococcal vaccines. TMP/SMX prophylaxis for the prevention of PJP may offer incidental protection against IPD in alloHSCT recipients. PMID- 25040634 TI - Antifibrotic effects of luteolin on hepatic stellate cells and liver fibrosis by targeting AKT/mTOR/p70S6K and TGFbeta/Smad signalling pathways. AB - BACKGROUND & AIMS: Luteolin has been reported to exert antifibrogenic effects in CCl4 -induced hepatic fibrosis in mice. However, limited information is available on the cellular and molecular events responsible for this effect. This study focused on the action of luteolin on hepatic stellate cells (HSCs) and the relevant signalling molecules and pathways as well as the antifibrotic efficacy in multiple models of fibrosis. METHODS: The in vitro effect of luteolin on rat HSCs and HSC-T6 cells was assessed using proliferation assays, invasion chamber, quantitative real-time PCR analysis and Western blotting. The in vivo effect of luteolin on progression of fibrosis was assessed in three experimental rat models induced by CCl4 , dimethylnitrosamine (DMN) and bile duct ligation (BDL). RESULTS: Luteolin inhibited proliferation, migration, collagen synthesis as well as expression of fibrosis-related genes in the activated HSCs and HSC-T6 cells stimulated with or without transforming growth factor-beta1(TGFbeta1) or platelet derived growth factor (PDGF). Luteolin induced HSC apoptosis associated with the increased caspase 3 activity and p53 expression, and induced G1 arrest with the decreased expression of bcl-2, Cyclin E and p-Cdk-2. Moreover, luteolin significantly inhibited PDGF and TGFbeta1-simulated phosphorylation of AKT and Smad pathway. In vivo study showed that luteolin administration markedly alleviated hepatic fibrosis along with reduced elevations of alanine aminotransferase and aspartate aminotransferase. HSCs were found to undergo apoptosis and decreased expression of p-Smad2 and p-AKT in luteolin-treated animals. CONCLUSIONS: This study demonstrates that luteolin prevents the progression of liver fibrosis through multiple mechanisms and indicates that luteolin has potential for effective treatment of liver fibrosis. PMID- 25040635 TI - A comparative immunohistochemistry study of diagnostic tools in salivary gland tumors: usefulness of mammaglobin, gross cystic disease fluid protein 15, and p63 cytoplasmic staining for the diagnosis of mammary analog secretory carcinoma? AB - BACKGROUND: Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. METHODS: A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. RESULTS: Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. CONCLUSION: Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement. PMID- 25040636 TI - Patients' antibiotic knowledge: a trial assessing the impact of verbal education. AB - OBJECTIVES: The purpose of this study was to assess the effectiveness of involving community pharmacy staff in patient education about antibiotic resistance, thus improving antibiotic knowledge. METHODS: Thirty-four patients presenting a valid antibiotic script for dispensing at three community pharmacies in regional New South Wales, Australia were randomly allocated by ballot draw to an intervention group or control group. Those in the intervention group were provided with verbal education based on an Australian National Prescribing Service patient leaflet regarding antibiotics. KEY FINDINGS: This paper presents pilot data indicating that there was a significant increase in antibiotic knowledge determined approximately 1 month after receiving verbal antibiotic education (33.3 +/- 40.8) as compared with patients not receiving verbal antibiotic education (-5.1 +/- 23.0), t (18.9) = 2.957, P = 0.008. CONCLUSIONS: This study has shown that verbal education, provided within a community pharmacy, regarding antibiotics improved patients' knowledge about antibiotics and provides evidence for the critical role of pharmacy staff in patient education. PMID- 25040642 TI - Ebola and Marburg virus diseases in Africa: increased risk of outbreaks in previously unaffected areas? AB - Filoviral hemorrhagic fever (FHF) is caused by ebolaviruses and marburgviruses, which both belong to the family Filoviridae. Egyptian fruit bats (Rousettus aegyptiacus) are the most likely natural reservoir for marburgviruses and entry into caves and mines that they stay in has often been associated with outbreaks of MVD. On the other hand, the natural reservoir for ebola viruses remains elusive; however, handling of wild animal carcasses has been associated with some outbreaks of EVD. In the last two decades, there has been an increase in the incidence of FHF outbreaks in Africa, some being caused by a newly found virus and some occurring in previously unaffected areas such as Guinea, Liberia and Sierra Leone, in which the most recent EVD outbreak occurred in 2014. Indeed, the predicted geographic distribution of filoviruses and their potential reservoirs in Africa includes many countries in which FHF has not been reported. To minimize the risk of virus dissemination in previously unaffected areas, there is a need for increased investment in health infrastructure in African countries, policies to facilitate collaboration between health authorities from different countries, implementation of outbreak control measures by relevant multi-disciplinary teams and education of the populations at risk. PMID- 25040637 TI - AP-1A controls secretory granule biogenesis and trafficking of membrane secretory granule proteins. AB - The adaptor protein 1A complex (AP-1A) transports cargo between the trans-Golgi network (TGN) and endosomes. In professional secretory cells, AP-1A also retrieves material from immature secretory granules (SGs). The role of AP-1A in SG biogenesis was explored using AtT-20 corticotrope tumor cells expressing reduced levels of the AP-1A MU1A subunit. A twofold reduction in MU1A resulted in a decrease in TGN cisternae and immature SGs and the appearance of regulated secretory pathway components in non-condensing SGs. Although basal secretion of endogenous SG proteins was unaffected, secretagogue-stimulated release was halved. The reduced MU1A levels interfered with the normal trafficking of carboxypeptidase D (CPD) and peptidylglycine alpha-amidating monooxygenase-1 (PAM 1), integral membrane enzymes that enter immature SGs. The non-condensing SGs contained POMC products and PAM-1, but not CPD. Based on metabolic labeling and secretion experiments, the cleavage of newly synthesized PAM-1 into PHM was unaltered, but PHM basal secretion was increased in sh-MU1A PAM-1 cells. Despite lacking a canonical AP-1A binding motif, yeast two-hybrid studies demonstrated an interaction between the PAM-1 cytosolic domain and AP-1A. Coimmunoprecipitation experiments with PAM-1 mutants revealed an influence of the luminal domains of PAM-1 on this interaction. Thus, AP-1A is crucial for normal SG biogenesis, function and composition. PMID- 25040643 TI - The efficacy, safety and acceptability of medical termination of pregnancy provided by standard care by doctors or by nurse-midwives: a randomised controlled equivalence trial. AB - OBJECTIVE: To assess nurse-midwife provision of early medical termination of pregnancy (TOP) in a high-resource setting where ultrasound examination for dating of pregnancy is part of the protocol. DESIGN: Randomised controlled equivalence trial. SETTING: Out-patient family planning unit at a university hospital. POPULATION: Women seeking early medical TOP. METHODS: A total of 1180 women were randomised, without any prior examination, to counselling, examination, and treatment by either nurse-midwife or gynaecologist. Ultrasound was performed in all cases by the allocated provider. MAIN OUTCOME MEASURES: The primary outcome was efficacy, defined as the successful completion of TOP without need for vacuum aspiration. Secondary outcomes were safety, defined as need for hospitalisation or blood transfusion, and acceptability, defined as preferred provider were the women to have a medical TOP in the future. RESULTS: A total of 481 women in the nurse-midwife group and 457 women in the doctor group were available for the final analysis. The effectiveness of provision of medical TOP by nurse-midwife providers was superior to that provided by doctors (risk difference 1.6%, 95% confidence interval 0.2-3.0%, which was within the set margin of equivalence). There were no significant differences in safety parameters. Women examined and counselled by a nurse-midwife were significantly more likely (P < 0.001, 95% confidence interval 0.308-0.394) to prefer seeing a nurse-midwife for the consultation were they to have another medical TOP in the future. CONCLUSIONS: These findings show that nurse-midwife provision of early medical TOP in a high-resource setting, where ultrasound is part of the protocol, is effective, and can be safely implemented with high acceptability among women. PMID- 25040644 TI - Hepatitis A virus in the Middle East and North Africa region: a new challenge. AB - During the past three decades, a gradual shift in the age of infection with hepatitis A virus (HAV) from early childhood to adulthood has been observed. There is a general lack of updated data on HAV burden of disease, incidence and age-specific seroprevalence in countries of the Middle East and North Africa (MENA) region. The aim of this article is to review the published data on anti HAV seroprevalence, an important tool to monitor infections rates, in countries of the MENA region and associated risk factors including water and socioeconomic data when available. Data on anti-HAV seroprevalence were found for 12 of 25 MENA countries. We show that MENA countries, similar to other areas in the world, have a clear shift in HAV incidence with a decline among young age groups and an increase among adults and older individuals. This would likely be associated with increased morbidity and increased risks of outbreaks among younger age groups. Consequently, the continuous surveillance of hepatitis A cases and the inclusion of hepatitis A vaccine in the expanded immunization programmes are needed in countries of the MENA. PMID- 25040646 TI - THE NURSES' FORM OF ORGANIZATIONAL COMMUNICATION: WHAT IS THE ROLE OF GOSSIP? AB - Abstract Background: Gossip is important for managers to control it and to use it to create positive effects that help organizations to attain their goals. Objectives/Aim: The study utilised a descriptive model to determine how nurses use gossip as an informal communication channel in organizational communication. Method: Nurses working in 4 hospitals within a city in the eastern part of Turkey form the population of the study whereas nurses who agreed to participate in the study form the sample. Among these hospitals, two of them serve under the Ministry of Health while two serve under a university; diagnosis, treatment and rehabilitation services in any field are provided in each of these hospitals. The researchers developed a questionnaire for data collection after examining the literature. The approval of the ethical committees and written official permissions were obtained for the study. Data were acquired from 264 out of 420 nurses in total. Data were collected between June and September 2011. The response rate to the data collection tool was 62.8%. Subsequently, data were analyzed by frequency and percentage distribution tests with SPSS for Windows 17.0. Results: This study determined that nurses uses gossip most frequently about working conditions to share information face-to-face when they feel angry. Conclusion: The study concluded that nurses use gossip as an informal communication style in their institutions. PMID- 25040645 TI - Defending plasma T3 is a biological priority. AB - Triiodothyronine (T3), the active form of thyroid hormone is produced predominantly outside the thyroid parenchyma secondary to peripheral tissue deiodination of thyroxine (T4), with <20% being secreted directly from the thyroid. In healthy individuals, plasma T3 is regulated by the negative feedback loop of the hypothalamus-pituitary-thyroid axis and by homoeostatic changes in deiodinase expression. Therefore, with the exception of a minimal circadian rhythmicity, serum T3 levels are stable over long periods of time. Studies in rodents indicate that different levels of genetic disruption of the feedback mechanism and deiodinase system are met with increase in serum T4 and thyroid stimulating hormone (TSH) levels, while serum T3 levels remain stable. These findings have focused attention on serum T3 levels in patients with thyroid disease, with important clinical implications affecting therapeutic goals and choice of therapy for patients with hypothyroidism. Although monotherapy with levothyroxine is the standard of care for hypothyroidism, not all patients normalize serum T3 levels with many advocating for combination therapy with levothyroxine and liothyronine. The latter could be relevant for a significant number of patients that remain symptomatic on monotherapy with levothyroxine, despite normalization of serum TSH levels. PMID- 25040647 TI - Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). AB - OBJECTIVE: The aim of this study was to determine the extent of drug interactions affecting levothyroxine, using study drugs often co-administered to patients on long-term levothyroxine therapy. DESIGN: A retrospective population analysis linking biochemistry and prescription data between 1 January 1993 and 31 December 2012 was used. PATIENTS: The study population was Tayside residents prescribed levothyroxine on at least three occasions, within a six-month period, prior to the start of a study drug. Individuals acted as their own controls pre- and postinitiation of study drug. Overall, 10 999 patients (mean age 58 years, 82% female) being treated with thyroxine were included in the study. MEASUREMENTS: Changes in TSH following initiation of study drug. RESULTS: Iron, calcium, proton pump inhibitors and oestrogen all increased serum TSH concentration: an increase of 0.22 mU/l (P < 0.001), 0.27 mU/l (P < 0.001), 0.12 mU/l (P < 0.01), and 0.08 mU/l (P < 0.007), respectively. For these four study drugs, there was a clinically significant increase of over 5 mU/l in serum TSH, in 7.5%, 4.4%, 5.6% and 4.3% patients, respectively. There was a decrease of 0.17 mU/l (P-value 0.01) in the TSH concentration for those patients on statins. The TSH decreased by 5 mU/l in 3.7% of patients. There was no effect with H2 receptor antagonists or glucocorticoids. CONCLUSION: This large population-based study demonstrates significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, statins and oestrogens. These drugs may reduce the effectiveness of levothyroxine, and patients' TSH concentrations should be carefully monitored. PMID- 25040648 TI - Effect of tongue position on masseter and temporalis electromyographic activity during swallowing and maximal voluntary clenching: a cross-sectional study. AB - The purpose of this study was to measure and compare the tonic electromyographic (EMG) activity of the temporalis and masseter muscles following placement of the tongue either on the palate or in the floor of the mouth during swallowing and maximal voluntary clenching (MVC). Thirty healthy dental students with natural dentition and bilateral molar support, between the ages of 18 and 22, with no prior history of oro-facial injury, or current or past pain in the jaw, mouth or tongue participated in the study. Tonic masseter and temporalis EMG activities were recorded using surface electrodes. Subjects were instructed to passively place the tongue either on the anterior hard palate or in the floor of the mouth during swallowing and MVC. At each tongue position, the resulting EMG was recorded. During swallowing, no significant difference in EMG activity was found either for the masseter (P-value = 0.1592) or the temporalis (P-value = 0.0546) muscles, regardless of the tongue position. During MVC, there was a statistically significant difference for both the masseter (P-value = 0.0016) and the temporalis (P-value = 0.0277) muscles with lower levels recorded with the tongue in the floor of the mouth. This study found that in normal, pain-free subjects, placing the tongue in the floor of the mouth significantly reduces masticatory muscle activity during MVC. Thus, it may be considered as a possible therapeutic option to decrease masticatory muscle activity; however, further research is needed in patients with oro-facial pain. PMID- 25040649 TI - Dehydrin expression in seeds and maturation drying: a paradigm change. AB - Dehydrins are well known for being expressed in leaves during the course of developmental processes as well as under drought stress, being part of the protective machinery. Moreover, in seed physiology, dehydrins are classified as late embryogenesis-related proteins (LEA protein), where they are thought to be responsible for persistence and longevity of seeds. Although both topics are a focus of modern plant biology, a direct linkage between these both areas is generally lacking. Based on an alignment of the chain of events, this paper will help to generate understanding that the occurrence of dehydrins in maturing seeds and leaves suffering drought stress is part of the same basic principle: basic principle: dehydrins are expressed in response to water shortage. Unfortunately, the related developmental process in seeds, i.e. maturation drying, has not been adequately considered as a part of this process. As a corresponding implication, the chain of events must be adjusted: the differences in dehydrin expression in orthodox, intermediate and recalcitrant seeds could be directly attributed to the occurrence or absence of maturation drying. The differences in dehydrin expression in orthodox, intermediate and recalcitrant seeds, and thus the differences in longevity, could be attributed to the occurrence or absence of a maturation drying. PMID- 25040650 TI - Validated age, growth and maturity of the bonnethead Sphyrna tiburo in the western North Atlantic Ocean. AB - The age, growth and maturity of bonnetheads Sphyrna tiburo inhabiting the estuarine and coastal waters of the western North Atlantic Ocean (WNA) from Onslow Bay, North Carolina, south to West Palm Beach, Florida, were examined. Vertebrae were collected and aged from 329 females and 217 males ranging in size from 262 to 1043 mm and 245 to 825 mm fork length, LF , respectively. Sex specific von Bertalanffy growth curves were fitted to length-at-age data. Female von Bertalanffy parameters were Linfinity = 1036 mm LF , k = 0.18, t0 = -1.64 and L0 = 272 mm LF . Males reached a smaller theoretical asymptotic length and had a higher growth coefficient (Linfinity = 782 mm LF , k = 0.29, t0 = -1.43 and L0 = 266 mm LF ). Maximum observed age was 17.9 years for females and 16.0 years for males. Annual deposition of growth increments was verified by marginal increment analysis and validated for age classes 2.5+ to 10.5+ years through recapture of 13 oxytetracycline-injected specimens at liberty in the wild for 1-4 years. Length (LF50 ) and age (A50 ) at 50% maturity were 819 mm and 6.7 years for females, and 618 mm and 3.9 years for males. Both female and male S. tiburo in the WNA had a significantly higher maximum observed age, LF50 , A50 and Linfinity , and a significantly lower k and estimated L0 than evident in the Gulf of Mexico (GOM). These significant differences in life-history parameters, as well as evidence from tagging and genetic studies, suggest that S. tiburo in the WNA and GOM should be considered separate stocks. PMID- 25040651 TI - Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy. AB - AIM: Eosinophils are potent proinflammatory cells that are involved in the pathogenesis of ulcerative colitis (UC). We evaluated the infiltration of eosinophils into the lamina propria in patients with active and inactive ulcerative colitis (UC) and investigated its clinical significance, among other variables, in predicting the outcome of medical treatment in active disease. METHOD: We studied colorectal biopsy specimens from 18 UC patients with disease in long-standing remission, from 22 patients with active disease who responded to therapy (12 with complete response and 10 with partial response) and from 10 patients who were nonresponders. Demographic information was obtained at baseline, and clinical, endoscopic and laboratory data were obtained at baseline and 12 weeks post-treatment. We evaluated five histological features: mucosal ulceration; mucosal erosions; crypt abscesses; cryptitis; and eosinophilic infiltration of the lamina propria. The severity of these lesions was graded as: none or minimal; mild; moderate; or severe. Statistical analyses were performed between responders and nonresponders for differences in demographic, clinical, laboratory, endoscopic and histological parameters. RESULTS: Laboratory, endoscopic and histological parameters were significantly improved after treatment only in the complete responders group. Analyses of baseline data revealed no significant differences in parameters between complete or partial responders and nonresponders, except for a less severe eosinophilic infiltration of lamina propria in complete responders (P < 0.05). Multiple logistic regression analysis showed that severe eosinophilic infiltration in colonic biopsies was the most significant predictor of poor response to medical therapy. CONCLUSION: Assessing the severity of eosinophilic infiltration in the lamina propria of colonic biopsies in patients with ulcerative colitis could be a valuable predictive tool of response to medical therapy. PMID- 25040652 TI - Significance chasing in research practice: causes, consequences and possible solutions. AB - BACKGROUND AND AIMS: The low reproducibility of findings within the scientific literature is a growing concern. This may be due to many findings being false positives which, in turn, can misdirect research effort and waste money. METHODS: We review factors that may contribute to poor study reproducibility and an excess of 'significant' findings within the published literature. Specifically, we consider the influence of current incentive structures and the impact of these on research practices. RESULTS: The prevalence of false positives within the literature may be attributable to a number of questionable research practices, ranging from the relatively innocent and minor (e.g. unplanned post-hoc tests) to the calculated and serious (e.g. fabrication of data). These practices may be driven by current incentive structures (e.g. pressure to publish), alongside the preferential emphasis placed by journals on novelty over veracity. There are a number of potential solutions to poor reproducibility, such as new publishing formats that emphasize the research question and study design, rather than the results obtained. This has the potential to minimize significance chasing and non publication of null findings. CONCLUSIONS: Significance chasing, questionable research practices and poor study reproducibility are the unfortunate consequence of a 'publish or perish' culture and a preference among journals for novel findings. It is likely that top-down change implemented by those with the ability to modify current incentive structure (e.g. funders and journals) will be required to address problems of poor reproducibility. PMID- 25040653 TI - Job satisfaction and perceived future roles of Malaysian dental therapists: findings from a national survey. AB - OBJECTIVE: To assess Malaysian dental therapists' perceptions of their job satisfaction and future roles. METHODS: A nationwide postal survey involving all Malaysian dental therapists who met the inclusion criteria (n = 1726). RESULTS: The response rate was 76.8%. All respondents were females; mean age 35.4 years (SD = 8.4). Majority were married (85.5%) and more than one-half had a working experience of <10 years (56.1%). Majority worked in community dental service (94.3%) and in urban areas (61.7%). Overall, they were highly satisfied with most aspects of their career. However, they were least satisfied with administrative workload (58.1%), career advancement opportunities (51.9%) and remuneration package; specifically income (45.2%), allowances (45.2%) and non-commensurate between pay and performance (44.0%). Majority perceived their role as very important in routine clinical tasks such as examination and diagnosis, preventive treatment, extraction of deciduous teeth and oral health promotion. However, fewer than one-half consider complex treatment such as placement of preformed crowns on deciduous teeth (37.1%) and extraction of permanent teeth (37.2%) as very important tasks. CONCLUSION: Majority expressed high career satisfaction with most aspects of their employment but expressed low satisfaction in remuneration, lack of career advancement opportunities and administrative tasks. We conclude that most Malaysian dental therapists have positive perceptions of their current roles but do not favour wider expansion of their roles. These findings imply that there was a need to develop a more attractive career pathway for therapists to ensure sustainability of effective primary oral healthcare delivery system for Malaysia's children. PMID- 25040654 TI - Study of spatial relationship of phrenic nerves with cardiac structures relevant to electrophysiologic interventions. AB - BACKGROUND: Pulmonary vein (PV) isolation with catheter ablation in treating atrial fibrillation carries the risk of injury to phrenic nerve (PN). Left PN (LPN) stimulation continues to be one of the common complications of transvenous left ventricular lead placement during cardiac resynchronization therapy (CRT). METHODS AND RESULTS: In 30 formalin-fixed cadavers, spatial relationship of PNs with PV ostia, left atrial appendage (LAA), and cardiac veins was observed. Segmental location of LPN and cardiac vein crossover was also noted. Right and left PNs coursed abutting the ostium of right superior and left superior PVs in five (16.6%) and one (3.33%) cases, respectively. LPN coursed along the lateral surface of LAA in 20 (66.66%) cases and behind LAA in one (3.33%) case. Out of 18 (60%) cases having two cardiac veins draining free wall of left ventricle (LV) and suitable for CRT lead placement, both cardiac veins were crossed by LPN in two (6.66%) cases. LPN-cardiac vein crossover was located in midlateral segment in 10 (33.3%) cases; mid posterolateral segment in five (16.7%) cases; apical lateral segment and apical posterolateral segment in three (10.0%) cases each. CONCLUSION: PN is highly susceptible to either injury during catheter ablation or stimulation with LV pacing in certain critical locations. Detailed knowledge of spatial relationship of PNs with cardiac structures could help minimize inadvertent complications during these transcatheter electrophysiological procedures. PMID- 25040655 TI - Effect of a tunnel-structured beta-tricalcium phosphate graft material on periodontal regeneration: a pilot study in a canine one-wall intrabony defect model. AB - BACKGROUND AND OBJECTIVE: Tissue regeneration is affected by the porosity, chemical properties and geometric structure of graft materials. Regeneration of severe periodontal defects, such as one-wall intrabony defects, is difficult because of reduced tissue support, and bone grafts are commonly used in such cases. In the present study, a tunnel-structured beta-tricalcium phosphate (tunnel beta-TCP) graft material designed to stimulate bone formation was fabricated. The objective of this pilot study was to evaluate the effect of this graft material on periodontal regeneration in one-wall intrabony defects in dogs. MATERIAL AND METHODS: Six male beagle dogs were used in this study. First, the mandibular second and third incisors were extracted. Experimental surgery was performed 12 wk after tooth extraction. Bilateral 4 * 8 mm (width * depth) one wall intrabony defects were created in the mesial side of the mandibular canines. At the experimental sites, the defects were filled with tunnel beta-TCP, whereas the control defects were left empty. Twelve weeks after surgery, qualitative and quantitative histological analyses were performed. RESULTS: There were no signs of clinical inflammation 12 wk after surgery. Coronal extension indicative of new bone formation was higher at the experimental sites than at the control sites, although the differences between both the sites in the newly formed cementum and connective tissue attachment were not significant. Newly formed periodontal ligament and cementum-like tissue were evident along the root surface at the experimental sites. The inner surface of the tunnels was partially resorbed and replaced with new bone. New blood vessels were observed inside the lumens of tunnel beta-TCP. CONCLUSION: Tunnel beta-TCP serves as a scaffold for new bone formation in one-wall intrabony defects. PMID- 25040656 TI - Relationship between primary colorectal tumour and location of colorectal liver metastases. AB - BACKGROUND: There is conflicting evidence regarding whether streamlining of blood flow within the portal vein influences the anatomical distribution of colorectal liver metastases (CRLM). This study assesses the relationship between primary tumour location and metastases location. METHODS: Patients were identified using a prospectively maintained database, and those with known site of primary colorectal tumour and hemiliver involvement were included. Site of metastases and segments affected were confirmed via review of the radiology reports. The location of primary colonic tumour was confirmed via review of clinical correspondence letters. RESULTS: A total of 2364 metastases were identified in 891 patients. Of these, 379 metastases were in the right lobe and 156 in the left lobe, with 356 having bilobar disease. There was no significant relationship between the distribution of CRLM and the site of primary disease (left colon versus right colon) (P = 0.819). However, when the segmental location of the metastases was considered, there is a statistically significant difference between the number of right-sided CRLM compared with left-sided CRLM (P < 0.001). CONCLUSIONS: Right-sided CRLM is more likely regardless of the primary location. Portal streaming may have an effect, although the natural anatomical 'angulation', particularly of the left portal vein branch is more likely to play a role. PMID- 25040657 TI - Wheat germ agglutinin as a counterstain for immunofluorescence studies of equine hoof lamellae. AB - Equine laminitis is a common, painful, debilitating condition of the hoof that is a leading cause of disability in horses, often necessitating euthanasia. The equine hoof represents an extreme evolutionary adaptation of an epidermal structure homologous to the human or murine nail units. Immunohistochemistry is frequently utilized in the study of the pathophysiology of laminitis. The complex, multilayered, extensively interdigitated epidermal-dermal lamellar interface renders precise interpretation of immunofluorescence localization difficult, especially when effective technique and reagents render non-reactive tissues completely dark. Fluorescent-conjugated wheat germ agglutinin (WGA) selectively labels dermal extracellular matrix fibres and epidermal cell membranes in tissue sections of horse hoof lamellae, is compatible with indirect immunofluorescence and augments interpretation of indirect immunofluorescence antigen localization. The current report details the use of WGA as a rapid, simple, economical counterstain for immunofluorescence studies of the equine hoof and may have application to other complex epidermal tissue structures. PMID- 25040658 TI - Efficient decoration of nanoparticles intended for intracellular drug targeting with targeting residues, as revealed by a new indirect analytical approach. AB - In our previous studies, we developed a nanodrug delivery system (nano-DDS) based on poly(lactic-co-glycolic acid) PLGA nanoparticles encapsulating antigenic peptide and fluorescent marker and 3-stage approach for its decoration with peptide targeting residues. The objectives of this study were (a) to develop methods for quantitative analysis of efficiency of individual conjugation steps and (b) to determine, based on these methods, the efficiency of our 3-stage approach of nano-DDS decoration. We prepared antigenic peptide-loaded PLGA-based nano-DDSs and sequentially decorated them with specific residues using carbodiimide and Click (azide-alkyne Huisgen cycloaddition using copper(I) catalysis) reactions. The extent of cargo encapsulation and release kinetics were analyzed using HPLC-based and colorimetric analytical methods. The efficiency of residue conjugation to the nano-DDSs was analyzed using FTIR spectroscopy and by quantifying the unreacted residues in the reaction mixture (i.e., by indirect analysis of reaction efficiencies). We revealed that copper, the catalyst of the Click reactions, formed complexes with unreacted targeting residues and interfered with the analysis of their conjugation efficiency. We used penicillamine (a chelator) to disrupt these complexes, and to recover the unreacted residues. Quantitative analysis revealed that 28,800-34,000 targeting residues (corresponding to 11-13 nm(2) surface area per residue) had been conjugated to a single nano-DDS using our 3-stage decoration approach, which is much higher than previously reported conjugation efficiencies. We conclude that the applied analytical tools allow quantitative analysis of nano-DDSs and the efficiency of their conjugation with targeting residues. The 3-stage decoration approach resulted in dense conjugation of nano-DDSs with targeting residues. The present decoration and analytical approaches can be effectively applied to other types of delivery systems and other targeting residues. PMID- 25040659 TI - A novel flow-based assay reveals discrepancies in ADAMTS-13 inhibitor assessment as compared with a conventional clinical static assay. AB - BACKGROUND: Several static Bethesda-type assays are routinely used to determine ADAMTS-13-neutralizing autoantibodies in acquired thrombotic thrombocytopenic purpura (TTP), but the inhibitory activity of these antibodies has not been thoroughly evaluated under the more physiologic condition of flow. OBJECTIVES: We investigated whether ADAMTS-13 inhibitor assessment with the FRETS-VWF73 assay is predictive for evaluation under flow. METHODS: Anti-ADAMTS-13 autoantibodies were purified from patients with acquired TTP by chromatography involving an ADAMTS-13 affinity matrix and/or protein G. ADAMTS-13 activity was measured with the FRETS VWF73 assay and a novel flow assay determining the ADAMTS-13-mediated decrease in platelet aggregate surface coverage, caused by perfusion of a suspension containing platelets, erythrocytes and von Willebrand factor (VWF) over a surface coated with extracellular matrix components. The neutralizing activities of ADAMTS-13 inhibitors were compared under static conditions and under flow by use of the two assays. RESULTS: The suitability of the flow-based ADAMTS-13 activity assay for quantification of ADAMTS-13 inhibitors could be demonstrated by reversibility of the ADAMTS-13-dependent decrease in surface coverage upon addition of goat ADAMTS-13 antiserum. Testing the neutralizing activity of purified autoantibodies from six patients in the flow assay according to their FRETS-VWF73-based inhibitor titers gave rise to vastly different inhibitory effects, indicating a discrepancy in inhibitor assessment between static and flow conditions. CONCLUSIONS: Anti-ADAMTS-13 autoantibodies may show inhibitory properties in vivo that are not consistent with the ADAMTS-13 inhibitor levels determined in routine static assays, possibly because certain epitopes are selectively exposed under shear. Consequently, the course of disease and treatment efficacy may vary among TTP patients, despite common inhibitor titers. PMID- 25040661 TI - Govinda s. Visvesvara: a tribute. PMID- 25040662 TI - Epidemiological link between wheat allergy and exposure to hydrolyzed wheat protein in facial soap. AB - BACKGROUND: Recent studies have highlighted the importance of extra-intestinal routes of sensitization to food-related allergens as the cause of epidemics of food allergy. Instances of Japanese women developing food allergy to wheat after exposure to hydrolyzed wheat protein (HWP) present in facial soap have been reported. However, the epidemiologic impact of these ingredients as a cause of food allergy has not been well studied. METHODS: To clarify the epidemiological relationship between food allergy to wheat and contact exposure to HWP, a case control study of Japanese women aged 20-54 years with self-reported wheat allergy (WA) (cases, n = 157) and age-matched control subjects without WA (controls, n = 449) was performed using a large-scale Web-based research panel. Subjects answered a Web-based questionnaire regarding the use of skin and hair care products, as well as other possible risk factors. RESULTS: Current use of an HWP containing facial soap (Cha no Shizuku; Yuka) was significantly associated with an increased risk of WA (adjusted odds ratio, 2.6; 95% confidence interval, 1.2 5.7; frequencies of current use in cases and controls; 11% and 6%, respectively). Use of Cha no Shizuku was more common in subjects with more recent-onset WA, implying that this soap may have contributed to the recent epidemic of WA. CONCLUSIONS: An epidemiological relationship between WA and contact exposure to HWP has been documented. This study implicates a possible role of contact exposure to food-derived protein hydrolysates as a risk factor for the development of food allergy manifesting itself as anaphylaxis. PMID- 25040660 TI - Testing the role of preBotzinger Complex somatostatin neurons in respiratory and vocal behaviors. AB - Identifying neurons essential for the generation of breathing and related behaviors such as vocalisation is an important question for human health. The targeted loss of preBotzinger Complex (preBotC) glutamatergic neurons, including those that express high levels of somatostatin protein (SST neurons), eliminates normal breathing in adult rats. Whether preBotC SST neurons represent a functionally specialised population is unknown. We tested the effects on respiratory and vocal behaviors of eliminating SST neuron glutamate release by Cre-Lox-mediated genetic ablation of the vesicular glutamate transporter 2 (VGlut2). We found the targeted loss of VGlut2 in SST neurons had no effect on viability in vivo, or on respiratory period or responses to neurokinin 1 or MU opioid receptor agonists in vitro. We then compared medullary SST peptide expression in mice with that of two species that share extreme respiratory environments but produce either high or low frequency vocalisations. In the Mexican free-tailed bat, SST peptide-expressing neurons extended beyond the preBotC to the caudal pole of the VII motor nucleus. In the naked mole-rat, however, SST-positive neurons were absent from the ventrolateral medulla. We then analysed isolation vocalisations from SST-Cre;VGlut2(F/F) mice and found a significant prolongation of the pauses between syllables during vocalisation but no change in vocalisation number. These data suggest that glutamate release from preBotC SST neurons is not essential for breathing but play a species- and behavior-dependent role in modulating respiratory networks. They further suggest that the neural network generating respiration is capable of extensive plasticity given sufficient time. PMID- 25040663 TI - A rare complication of cesarean delivery: iliopsoas abscess. PMID- 25040664 TI - Systemic mastocytosis emerging after azacitidine treatment of refractory anaemia with excess blasts type 2. PMID- 25040665 TI - Significance of time awake for predicting pilots' fatigue on short-haul flights: implications for flight duty time regulations. AB - European regulations restrict the duration of the maximum daily flight duty period for pilots as a function of the duty start time and the number of scheduled flights. However, late duty end times that may include long times awake are not specifically regulated. In this study, fatigue levels in pilots finishing their duty late at night (00:00-01:59 hour) were analysed and compared with pilots starting their duty early (05:00-06:59 hour). Fatigue levels of 40 commercial short-haul pilots were studied during a total of 188 flight duty periods, of which 87 started early and 22 finished late. Pilots used a small handheld computer to maintain a duty and sleep log, and to indicate fatigue levels immediately after each flight. Sleep logs were checked with actigraphy. Pilots on late-finishing flight duty periods were more fatigued at the end of their duty than pilots on early-starting flight duty periods, despite the fact that preceding sleep duration was longer by 1.1 h. Linear mixed-model regression identified time awake as a preeminent factor predicting fatigue. Workload had a minor effect. Pilots on late-finishing flight duty periods were awake longer by an average of 5.5 h (6.6 versus 1.1 h) before commencing their duty than pilots who started early in the morning. Late-finishing flights were associated with long times awake at a time when the circadian system stops promoting alertness, and an increased, previously underestimated fatigue risk. Based on these findings, flight duty limitations should consider not only duty start time, but also the time of the final landing. PMID- 25040666 TI - Correlates of gait speed in advanced knee osteoarthritis. AB - OBJECTIVE: This study aims to evaluate correlates of gait speed, a measure of disability, in older adults with advanced knee osteoarthritis (OA) and chronic pain. DESIGN/SETTING/SUBJECTS/METHODS: Baseline data were analyzed from a clinical trial of 190 participants aged >50 with advanced knee OA (according to clinical and radiographic American College of Rheumatology criteria) and chronic pain. Data included 4-meter gait speed, quality of life (Short Form Health Survey 36 global health subscale), knee pain (Western Ontario and McMasters Universities Osteoarthritis Index [WOMAC]), depressive symptoms (Center for Epidemiologic Studies Depression Scale), coping strategies (catastrophizing subscale and Cognitive Strategies Questionnaire), self-efficacy (Athritis Self-efficacy Scale [ASES]), comorbidity (Cumulative Illness Rating Scale), analgesic use, and pain comorbidities (location, frequency, and intensity). A multivariable regression model was used to investigate these variables as they relate to gait speed. RESULTS: In the univariate analysis, the following variables were associated with gait speed: knee pain (per WOMAC), age, depressive symptoms, global health, catastrophizing, ASES function and other, comorbidity, and opioid use (all P values <0.05). In the fully adjusted multivariate model, controlling for knee pain, significant associations between gait speed and age (beta = -0.006; P < 0.001), ASES function (beta = 0.003; P < 0.001), and opioid use (beta = -0.082; P = 0.009) persisted. The correlation between opioid dose and gait speed (among opioid users) was not statistically significant (r = 0.04; P = 0.81). CONCLUSION: In a cross-sectional study of older adults with advanced knee OA and chronic pain, we found that age, arthritis function self-efficacy, and opioid use (but not dose) were significantly associated with decreased gait speed. PMID- 25040667 TI - Clinical usefulness of a short-type, prototype single-balloon enteroscope for endoscopic retrograde cholangiopancreatography in patients with altered gastrointestinal anatomy: preliminary experiences. AB - BACKGROUND AND AIM: A limited number of endoscopic retrograde cholangiopancreatography (ERCP) accessories are compatible with the conventional single-balloon enteroscope (SBE) because of the latter's dimensions. The aim of the present study was to assess the utility of a prototype SBE that has a shorter working length and a wider channel than the conventional SBE. METHODS: ERCP procedures carried out between January 2012 and July 2013 using the short SBE prototype were reconstructions such as Billroth II (B-II), post-gastrectomy with Roux-en-Y (RY-G), and post-choledochojejunostomy with Roux-en-Y (RY-CJ). We retrospectively analyzed the rate of reaching the blind end of the intestine, the diagnostic success rate, the interventional success rate, and the frequency of related complications. RESULTS: Twenty-seven ERCP procedures on 18 patients analyzed comprised two B-II, 15 RY-G, and 10 RY-CJ reconstructions. With a mean procedure time of 56 min (range 40-150 min), the rate of reaching the blind end, the diagnostic success rate, and the interventional success rate were 24/27 (89%), 20/27 (74%), and 19/27 (70%), respectively. There were no major ERCP related complications in any patient. CONCLUSIONS: The prototype short-type SBE appears safe and effective for use in ERCP, and is compatible with conventional endoscopy accessories. PMID- 25040668 TI - Developments in pediatric liver transplantation since implementation of the new allocation rules in Eurotransplant. AB - Liver allocation in the Eurotransplant (ET) region has changed from a waiting time to an urgency-based system using the model of end-stage liver disease (MELD) score in 2006. To allow timely transplantation, pediatric recipients are allocated by an assigned pediatric MELD independent of severity of illness. Consequences for children listed at our center were evaluated by retrospective analysis of all primary pediatric liver transplantation (LTX) from deceased donors between 2002 and 2010 (110 LTX before/50 LTX after new allocation). Of 50 children transplanted in the MELD era, 17 (34%) underwent LTX with a high-urgent status that was real in five patients (median lab MELD 22, waiting time five d) and assigned in 12 patients (lab MELD 7, waiting time 35 d). Thirty-three children received a liver by their assigned pediatric MELD (lab MELD 15, waiting time 255 d). Waiting time in the two periods was similar, whereas the wait-list mortality decreased (from about four children/yr to about one child/yr). One- and three-yr patient survival showed no significant difference (94.5/97.7%; p = 0.385) as did one- and three-yr graft survival (80.7/75.2%; and 86.5/82%; p = 0.436 before/after). Introduction of a MELD-based allocation system in ET with assignment of a granted score for pediatric recipients has led to a clear priorization of children resulting in a low wait-list mortality and good clinical outcome. PMID- 25040669 TI - Inflammatory and oxidative biomarkers of disease severity in dogs with parvoviral enteritis. AB - OBJECTIVES: To study changes in serum C-reactive protein, haptoglobin, ceruloplasmin and albumin concentration, total anti-oxidant capacity and paraoxonase-1 and butyrylcholinesterase activity in dogs with parvoviral enteritis of different degrees of clinical severity. METHODS: Prospective study of 9 healthy and 43 dogs with parvoviral enteritis that were classified into mildly, moderately and affected groups. RESULTS: Dogs with parvoviral enteritis had a significant increase in C-reactive protein compared with healthy dogs, with an increase of higher magnitude in animals with more severe clinical signs. All dogs with parvoviral enteritis had a significant increase in haptoglobin concentration compared with healthy dogs, but with no difference according to disease severity. There was a decrease in paraoxonase-1 activity in parvoviral enteritis. CLINICAL SIGNIFICANCE: Major increases of C-reactive protein concentrations in dogs with parvoviral enteritis are a marker of disease severity. In addition, higher values for anti-oxidants in severe cases compared with mild and moderate cases suggest a possible compensatory anti-oxidant mechanism. PMID- 25040670 TI - Obituary: Bryan Clarke. PMID- 25040671 TI - Developmental integration in a functional unit: deciphering processes from adult dental morphology. AB - The evolution of mammalian dentition is constrained by functional necessity and by the non-independence of morphological structures. Efficient chewing implies coherent tooth coordination from development to motion, involving covariation patterns (integration) within dental parts. Using geometric morphometrics, we investigate the modular organization of the highly derived vole dentition. Integration patterns between and within the upper and lower molar rows are analyzed to identify potential modules and their origins (functional and developmental). Results support an integrated adult dentition pattern for both developmental and functional aspects. The integration patterns between opposing molar pairs suggest a transient role for the second upper and lower molars during the chewing motion. Upper and lower molar rows form coherent units but the relative integration of molar pairs is in contradiction with existing developmental models. Emphasis on the first three cusps to grow leads to a very different integration pattern, which would be congruent with developmental models. The early developmental architecture of traits is masked by later stages of growth, but may still be deciphered from the adult phenotype, if careful attention is paid to relevant features. PMID- 25040672 TI - Will smaller plates lead to smaller waists? A systematic review and meta-analysis of the effect that experimental manipulation of dishware size has on energy consumption. AB - It has been suggested that providing consumers with smaller dishware may prove an effective way of helping people eat less and preventing weight gain, but experimental evidence supporting this has been mixed. The objective of the present work was to examine the current evidence base for whether experimentally manipulated differences in dishware size influence food consumption. We systematically reviewed studies that experimentally manipulated the dishware size participants served themselves at a meal with and measured subsequent food intake. We used inverse variance meta-analysis, calculating the standardized mean difference (SMD) in food intake between smaller and larger dishware size conditions. Nine experiments from eight publications were eligible for inclusion. The majority of experiments found no significance difference in food intake when participants ate from smaller vs. larger dishware. With all available data included, analysis indicated a marginal effect of dishware size on food intake, with larger dishware size associated with greater intake. However, this effect was small and there was a large amount of heterogeneity across studies (SMD: 0.18, 95% confidence interval: -0.35, 0.00, I(2) = 77%). Evidence to date does not show that dishware size has a consistent effect on food intake, so recommendations surrounding the use of smaller plates/dishware to improve public health may be premature. PMID- 25040673 TI - A novel device for target controlled administration and reflection of desflurane- the MirusTM. AB - The AnacondaTM system is used to deliver inhalational sedation in the intensive care unit in mainland Europe. The new MirusTM system also uses a reflector like the Anaconda; however, it also identifies end-tidal concentrations from the gas flow, injects anaesthetics during early inspiration, controls anaesthetic concentrations automatically, and can be used with desflurane, which is not possible using the Anaconda. We tested the Mirus with desflurane in the laboratory. Compared with an external gas monitor, the bias (two standard deviations) of the end-tidal concentration was 0.11 (0.29)% volume. In addition, automatic control was reasonable and maximum concentration delivered was 10.2%, which was deemed to be sufficient for clinical use. Efficiency was > 80% and was also deemed to be acceptable, but only when delivering a low concentration of desflurane (<= 1.8%). By modifying the reflector, we improved efficiency up to a concentration of 3.6%. The Mirus appears to be a promising new device for long term sedation with desflurane on the intensive care unit, but efficiency must be improved before routine clinical use becomes affordable. PMID- 25040674 TI - Cutaneous adverse events in patients treated with BRAF inhibitor-based therapies for metastatic melanoma for longer than 52 weeks. AB - BACKGROUND: BRAF inhibitor-based therapies have been shown to induce cutaneous toxicities, with onset generally in the first 8-26 weeks of therapy. OBJECTIVES: To determine whether cutaneous toxicities persist in patients who have remained on BRAF inhibitor-based therapies for longer than 52 weeks, and therefore whether ongoing dermatology assessment is required. METHODS: All patients treated with the BRAF inhibitors vemurafenib or dabrafenib or combination BRAF inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor therapy at Westmead Hospital, Sydney, Australia underwent regular dermatological assessments for the duration of therapy. All patients enrolled in a clinical trial, and 18% of patients in the compassionate access scheme underwent a baseline assessment prior to commencement of therapy and every 4-8 weeks thereafter. Patients' adverse events were recorded in a specific database. RESULTS: Patients continued to develop cutaneous adverse events after 52 weeks of continuous therapy. Patients on single-agent BRAF inhibitor therapy suffered from Grover disease (45%), plantar hyperkeratosis (45%), verrucal keratosis (18%) and even cutaneous squamous cell carcinoma (16%). The most frequent adverse event seen in patients in the combination BRAF and MEK inhibitor group was an acneiform eruption (40%). CONCLUSIONS: Patients on BRAF inhibitor-based therapies need to continue to have regular dermatological follow-up independent of the duration of their therapy. PMID- 25040675 TI - Pathways to care: how superdiversity shapes the need for navigational assistance. AB - The recently developed sociological concept of superdiversity provides a potentially interesting and useful way of developing an understanding of life in contemporary Europe. Here we report on research based on individual narratives about access to health care, as described by a range of people from very different sociocultural backgrounds in four European countries. This article notes the frequent appearance in first-person narratives of the need for navigational assistance in the form of knowledge, cultural competence and orientation that facilitate the identification and use of pathways to health care. Our dataset of 24 semi-structured interviews suggests that, in the context of needing health care, the feeling of being a 'stranger in a strange land' is common in people from a wide range of backgrounds. In social settings characterised by transnationalism and cultural heterogeneity, it is important to understand the need for navigational assistance, particularly at times of uncertainty, in the design and delivery of health services. The relationship between the inhabitants of contemporary Europe and the healthcare systems available in the places where they live is dominated by both complexity and contingency - and this is the cultural field in which navigation operates. PMID- 25040676 TI - Treatment of gout in a renal transplant patient leading to severe thrombocytopenia. AB - WHAT IS KNOWN AND OBJECTIVE: Allopurinol (AP) inhibits the xanthine oxidase, which may indirectly lead to myelotoxicity when used in combination with azathioprine (AZA). CASE SUMMARY: A 79-year-old female developed symptomatic thrombocytopenia after combination therapy with AZA (75 mg/day) and AP (100 mg/day) - after AP had been stopped. Concentrations of the myelotoxic 6 thioguanine-nucleotides metabolite of AZA were increased. Thrombocyte counts normalized within 8 days of discontinuation of AZA. WHAT IS NEW AND CONCLUSION: The effect of a drug interaction in a patient with decreased elimination capacity may take several weeks to become apparent and may in fact do so even after the drug has been stopped. Concurrent AZA and AP therapy demands cautious use. PMID- 25040678 TI - Norovirus disease today. PMID- 25040677 TI - Carotid MRI Detection of Intraplaque Hemorrhage at 3T and 1.5T. AB - BACKGROUND AND PURPOSE: Carotid intraplaque hemorrhage leads to plaque progression and ischemic events. Detection can be accomplished with 3T T1w sequences, but may be limited by false-positive lipid/necrosis. The purpose of this study was threefold: (1) to determine if magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) detects intraplaque hemorrhage versus lipid/necrosis; (2) if 3T MPRAGE image quality is retained at 1.5T; and (3) to determine observer agreement. METHODS: MPRAGE positive areas were compared to hemorrhage and lipid/necrosis areas from 100 carotid endarterectomy slides in 12 subjects using multivariable linear regression. Image quality was determined between 3T and 1.5T in 716 carotid arteries using t-tests and multivariable linear regression. Kappa analysis was used to determine agreement. RESULTS: Intraplaque hemorrhage, not lipid/necrosis, was a significant predictor of MPRAGE positive area before and after adjusting for confounders (slope = .52 vs. .51, P < .001). Image quality at 3T was slightly lower than 1.5T (mean 3.87 vs. 4.34, P < .0001). 3T image quality remained slightly decreased before and after adjusting for confounders (slope = -.46 vs. -.41, P < .001). Kappa values for inter /intraobserver agreement were .807/.919 at 3T and .803/.871 at 1.5T. CONCLUSIONS: Carotid MPRAGE detects intraplaque hemorrhage, not lipid/necrosis. 3T image quality was retained at 1.5T with very good observer agreement. PMID- 25040679 TI - Comparing the effects of nebivolol and dexpanthenol on wound healing: an experimental study. AB - Wound healing is a dynamic, interactive process that is initiated in response to injury. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. The aim of this study was to compare the effects of dexpanthenol, a molecule that is widely used for improving wound healing, and nebivolol, a molecule that increases nitric oxide release, on wound healing. A total of 30 rats were divided into three equal groups (n = 10). A linear 2 cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 5% nebivolol cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21(st) day, all wounds were excised and histologically evaluated. The wound healing rates of the dexpanthenol and nebivolol groups were higher than those of the control group (P < 0.05). However, the wound healing rates of the dexpanthenol and nebivolol groups were not significantly different. Nebivolol and dexpanthenol have comparable effects on wound healing. PMID- 25040680 TI - Factors explaining variability in health literacy outcomes of public health nursing clients. AB - OBJECTIVES: To evaluate variability in health literacy outcomes due to home visiting (HV) program components including PHN, Intervention, and Client. DESIGN AND SAMPLE: A comparative, correlational study evaluated PHN home visiting program data that included PHNs (N = 16); Interventions (N = 21,634); and Clients (N = 141). Client age ranged from 14 to 46 (median = 21, mean = 22.8, SD = 6.65). Clients were predominately White (75.9%), not married (84.4%), and female (99.3%). PHNS documented care using electronic health records (EHR) and the Omaha System. MEASURES: The outcome of interest was health literacy benchmark attainment (adequate knowledge) operationalized by Omaha System Problem Rating Scale for Outcomes Knowledge scores averaged across problems. INTERVENTION: Program of individually tailored, evidence-based HV interventions provided by PHNs. RESULTS: There were 233 different interventions for 22 problems. Knowledge benchmark was attained by 16.3% of clients. Four factors explained variance in reaching the knowledge benchmark: Client (51%), Problem (17%), Intervention (16%), and PHN (16%). CONCLUSIONS: The PHN and intervention tailoring are actionable components of HV programs that explain variability in health literacy outcomes. Further research should examine effects of training on PHN relationship skills and intervention tailoring to optimize outcomes of evidence-based PHN HV programs, and to evaluate whether improving health literacy may subsequently improve client problems. PMID- 25040681 TI - Statistical and scientific inference. PMID- 25040682 TI - HLA similarities indicate shared genetic risk in 21-hydroxylase autoantibody positive South African and United States Addison's disease. AB - Genetic similarities between patients from the United States and South African (SA) Addison's Disease (AD) strengthen evidence for genetic association. SA-AD (n = 73), SA healthy controls (N = 78), and US-AD patients (N = 83) were genotyped for DQA1, DQB1, DRB1, and HLA-B alleles. Serum was tested for the quantity of 21OH-AA and IFNalpha-AA at the Barbara Davis Center. Although not as profound as in US-AD, in SA-AD 21OH-AA + subjects the predominantly associated risk haplotypes were DRB1*0301-DQB1*0201 (DR3), DRB1*04xx-DQB1*0302 (DR4), and the combined DR3/4 genotype. DQB1*0302 associated DRB1*04xx haplotypes conferred higher risk than those DRB1*04xx haplotypes associated with other DQB1 alleles. We found negative association in 21OH-AA + SA-AD for DQA1*0201-DQB1*0202 and DQA1*0101-DQB1*0501 vs SA controls, and positive association for DQA1*0401 DQB1*0402 vs US-AD. Apart from the class II DR3 haplotype, HLA-B8 did not have an independent effect; however together DR3 and HLA-B8 conferred the highest risk vs 21OH-AA negative SA-AD and SA-controls. HLA-B7 (often with DR4) conferred novel risk in 21OH-AA + SA-AD vs controls. This study represents the first comparison between South African and United States AD populations utilizing genotyping and serology performed at the same center. SA-AD and US-AD 21OH-AA + patients share common HLA risk haplotypes including DR4 (with HLA-B7) and DR3 (with HLA-B8), strengthening previously described HLA associations and implicating similar genetic etiology. PMID- 25040683 TI - It's the talk: a study of involvement initiatives in secure mental health settings. AB - BACKGROUND: A study of involvement initiatives within secure mental health services across one UK region, where these have been organized to reflect alliances between staff and service users. There is little previous relevant international research, but constraints upon effective involvement have been noted. OBJECTIVE: To explore and evaluate involvement initiatives in secure mental health settings. DESIGN: A case study design with thematic analysis of qualitative interviews and focus groups. SETTING AND PARTICIPANTS: Data collection was carried out between October 2011 and February 2012 with 139 staff and service users drawn from a variety of secure mental health settings. FINDINGS: Our analysis offers four broad themes, titled: safety and security first?; bringing it all back home; it picks you up; it's the talk. The quality of dialogue between staff and services users was deemed of prime importance. Features of secure environments could constrain communication, and the best examples of empowerment took place in non-secure settings. DISCUSSION: Key aspects of communication and setting sustain involvement. These features are discussed with reference to Jurgen Habermas's work on communicative action and deliberative democracy. CONCLUSIONS: Involvement initiatives with service users resident in secure hospitals can be organized to good effect and the active role of commissioners is crucial. Positive outcomes are optimized when care is taken over the social space where involvement takes place and the process of involvement is appreciated by participants. Concerns over risk management are influential in staff support. This is germane to innovative thinking about practice and policy in this field. PMID- 25040684 TI - Editorial Comment from Dr Kaag and Dr Raman to Obesity and prognosis in muscle invasive bladder cancer: the continuing controversy. PMID- 25040685 TI - Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort. AB - Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine. PMID- 25040686 TI - A qualitative analysis of approaches to contraceptive counseling. AB - CONTEXT: Underuse and inconsistent use of contraceptives contribute to the continued high rate of unintended pregnancy in the United States. High-quality interaction between patient and provider about contraception is associated with improved contraceptive use, yet little is known about how providers support patients in the decision-making process. METHODS: A random sample of 50 family planning visits by patients in the San Francisco Bay Area was selected from a larger sample of 342 audio-recorded visits to six clinics between 2009 and 2012. In qualitative analysis guided by grounded theory techniques, transcripts were assessed to determine counseling approaches and patterns in the use of these approaches. RESULTS: Providers employed three counseling approaches: foreclosed (in 48% of visits), characterized by discussion of few contraceptive methods and method selection by the patient with no involvement from the provider; informed choice (30%), characterized by detailed description of multiple methods, but little or no interaction between the patient and the provider; and shared decision making (22%), characterized by the provider's interactive and responsive participation with the patient in method selection. Use of these approaches varied by patient's age: Women 25 or younger experienced the foreclosed approach more often than older women, and patients older than 35 were far more likely than their younger counterparts to experience the shared decision-making approach. CONCLUSIONS: Most visits did not include interactive engagement between the patient and the provider. Contraceptive counseling interventions should encourage providers to responsively engage with patients of all ages to better meet their contraceptive needs. PMID- 25040687 TI - Comparative analysis of assays for detection of cell-mediated immunity toward cytomegalovirus and M. tuberculosis in samples from deceased organ donors. AB - Cell-mediated immunity assays could be valuable for risk assessment of organ donors, but no data exist on their feasibility in deceased donors. In this study, 105 deceased donors (52.3 +/- 16.9 years) were screened at the time of organ procurement. Pathogen-specific stimulation was performed using a cytomegalovirus (CMV) lysate, tuberculin (purified protein derivative [PPD]) and soluble Mycobacterium tuberculosis-specific ESAT-6/CFP-10 proteins in combination with an in-house fluorescence-activated cell sorting (FACS) assay or commercial assay formats (QuantiFERON-CMV/TB for ELISA, T-SPOT.TB for ELISPOT). CMV-IgG antibody titers were determined as gold standard for CMV infection; 51.4% of samples were CMV seropositive. Indeterminate results were observed in 47.6% of ELISA, 12.5% of FACS and 0% of ELISPOT assays. Agreement with serology was highest for FACS (95.6%, kappa = 0.91), followed by ELISPOT (84.0%, kappa = 0.68) and ELISA (80.0%, kappa = 0.60). Agreement between ELISA and serology increased if the CMV lysate was used as stimulus (96.7%, kappa = 0.92). Among the T cell assays, agreement between ELISPOT and FACS was highest (kappa = 0.70). PPD-positive results among valid samples differed between assays (26.5% for ELISA, 23.1% for FACS and 50.5% for ELISPOT); 2.0% were QuantiFERON-TB positive, 3.3% were ESAT 6/CFP-10-positive in FACS and 13.4% were positive in the T-SPOT.TB assay. In conclusion, cellular immunity may be analyzed from samples of deceased donors, although the assays differ in the rate of positivity and indeterminate results. PMID- 25040688 TI - Micro-evolution of the hepatitis B virus genome in hepatitis B e-antigen-positive carriers: comparison of genotypes B and C at various immune stages. AB - BACKGROUND AND AIM: Patients with hepatitis B virus (HBV) genotype B infection experience hepatitis B e-antigen (HBeAg) seroconversion at an earlier stage than do patients with genotype C infection. Therefore, this study investigated whether the differential phenotypes are related to HBV genomic evolution. METHODS: Thirty three HBeAg-positive patients with a mean follow-up of 3.1 years were enrolled: 16 at the immune tolerance stage (group I) and 17 at the immune clearance stage (group II). The evolution rates of paired viral genomes at enrollment and at the final follow-up in the full-length genome (MUf), nonoverlapping regions (synonymous [MUs] and nonsynonymous [MUa]), and overlapping regions (MU) were calculated. The evolution rates were then compared according to serum alanine aminotransferase (ALT) levels and HBV genotype. RESULTS: The overall MUf evolution rate was lower in group I than in group II (1.4 * 10(-5) +/- 3.3 * 10( 5) vs 1.2 * 10(-3) +/- 1.2 * 10(-3) nucleotide substitution/site/year, P < 0.001). We observed similar results for the MUs, MUa, and MU evolution rates. All evolution parameters were comparable between genotypes B and C. We determined a positive correlation between MUa/y and the area under the average ALT time curve in genotype B (R(2) = 0.6935, P < 0.0001), but not in genotype C (R(2) = 0.1606, P = 0.124). CONCLUSION: The evolution rate of the HBV genome is higher at the immune clearance stage than at the immune tolerance stage. Host immune selection might play a role in triggering evolution of genotype B. PMID- 25040689 TI - The role of the area postrema in the anorectic effects of amylin and salmon calcitonin: behavioral and neuronal phenotyping. AB - Amylin reduces meal size by activating noradrenergic neurons in the area postrema (AP). Neurons in the AP also mediate the eating-inhibitory effects of salmon calcitonin (sCT), a potent amylin agonist, but the phenotypes of the neurons mediating its effect are unknown. Here we investigated whether sCT activates similar neuronal populations to amylin, and if its anorectic properties also depend on AP function. Male rats underwent AP lesion (APX) or sham surgery. Meal patterns were analysed under ad libitum and post-deprivation conditions. The importance of the AP in mediating the anorectic action of sCT was examined in feeding experiments of dose-response effects of sCT in APX vs. sham rats. The effect of sCT to induce Fos expression was compared between surgery groups, and relative to amylin. The phenotype of Fos-expressing neurons in the brainstem was examined by testing for the co-expression of dopamine beta hydroxylase (DBH) or tryptophan hydroxylase (TPH). By measuring the apposition of vesicular glutamate transporter-2 (VGLUT2)-positive boutons, potential glutamatergic input to amylin- and sCT-activated AP neurons was compared. Similar to amylin, an intact AP was necessary for sCT to reduce eating. Further, co-expression between Fos activation and DBH after amylin or sCT did not differ markedly, while co-localization of Fos and TPH was minor. Approximately 95% of neurons expressing Fos and DBH after amylin or sCT treatment were closely apposed to VGLUT2-positive boutons. Our study suggests that the hindbrain pathways engaged by amylin and sCT share many similarities, including the mediation by AP neurons. PMID- 25040690 TI - Clinical application of autologous fibroblast cell culture in gingival recession treatment. AB - BACKGROUND AND OBJECTIVE: Gingival recession is defined as soft and hard tissue displacement resulting in root surface exposure. The optimal outcome of gingival recession treatment is complete, predictable and long-lasting root coverage with a significant level of tissue regeneration. Tissue engineering, which applies active regeneration principles, presents the contemporary treatment approach in the restitution and regeneration of lost tissues. The objective of the present study was to evaluate and compare the clinical results of application of an autologous fibroblast cell culture (AFCC) on a collagen matrix and a connective tissue graft (CTG) placed under a coronally advanced flap (CAF), in the treatment of single and multiple gingival recessions. MATERIAL AND METHODS: Eighteen patients from the Department of Periodontology, School of Dentistry, University of Belgrade, were randomly enrolled in this study. Inclusion criteria were the bilateral presence of Miller Class I or II single or multiple maxillary gingival recessions. A split-mouth design was used in the study. The experimental group was treated with AFCC on a collagen scaffold, which was placed under a CAF. The control group received a combination of CTG and CAF. Clinical parameters such as gingival recession coverage, keratinized tissue width, clinical attachment level and gingival index were recorded at baseline and at 12 mo postoperatively. The oral hygiene level was assessed by plaque index evaluation. Postoperative healing was evaluated through the healing index, recorded 1, 2 and 3 wk postoperatively. The final esthetic outcome was assessed using the mean root coverage esthetic score (RES). RESULTS: Statistically significant improvement of all parameters assessed was found compared with baseline. A statistically significant difference between groups was observed only in keratinized tissue width. Greater keratinized tissue width is still obtained with the use of CTG. Regarding the tissue-healing results, no statistically significant difference was achieved. The RES results were similar for both groups. CONCLUSIONS: Within the limitations of the present study, both procedures proved to be efficient in gingival recession treatment. AFCC, as a novel tissue-engineering concept and living cell-based therapy, proved to be a reliable and successful treatment concept. PMID- 25040692 TI - Report on Third International Intensive Aftercare Conference in Norrkoping, Sweden. AB - The third international conference on intensive care unit (ICU) diaries and intensive aftercare took place in Norrkoping, Sweden, on 28 November 2013. The conference was organized by Carl Backman and colleagues, Vrinnevi Hospital and NOFI, and represented by Sissell Storli. More than 100 clinicians from across Europe and the USA attended the conference. PMID- 25040691 TI - Personality and adolescent pregnancy outcomes. AB - AIMS: To examine the relationship between personality, pregnancy and birth outcomes in adolescents. BACKGROUND: Personality has been shown to be a strong predictor of many health outcomes. Adolescents who become pregnant have worse birth outcomes than adults. DESIGN: Cross-sectional study using data from the National Longitudinal Study of Adolescent Health (baseline, 1994-1995; follow-up, 2007-2008). METHODS: The study sample was 6529 girls, 820 of whom reported on pregnancy outcomes for a teenage birth. Personality data were taken from the Mini International Personality Item Pool personality tool, which measures the five factor personality traits of neuroticism, conscientiousness, intellect/imagination, extraversion and agreeableness. Logistic regression was used to predict teen pregnancy and linear regression was used to predict birth weight and gestational age with adjustment for confounders and stratification by race. RESULTS: Agreeableness and intellect/imagination were associated with a reduced likelihood of becoming pregnant as an adolescent, while neuroticism, conscientiousness and extraversion were all associated with an increased likelihood of becoming pregnant. Higher neuroticism was associated with lower birth weight and gestational age among Black girls, but not non-Black. Conscientiousness was associated with lower gestational age among non-Black girls. No relationships were found with extraversion or agreeableness and birth outcomes. Receiving late or no prenatal care was associated with higher intellect/imagination. CONCLUSIONS: Personality is understudied with respect to pregnancy and birth outcomes compared with other health outcomes. Such research could help professionals and clinicians design and target programmes that best fit the characteristics of the population most likely to need them, such as those with high neuroticism. PMID- 25040693 TI - Volumetric bone mineral density and bone geometry assessed by peripheral quantitative computed tomography in women with differentiated thyroid cancer under TSH suppression. AB - OBJECTIVE: TSH suppression therapy in patients with differentiated thyroid cancer (DTC) has been associated with adverse effects on areal bone mineral density (aBMD) only in postmenopausal women. The purpose of study was to examine the effect of TSH suppression therapy on skeletal integrity using peripheral quantitative computed tomography (pQCT) at the radius and tibia in pre- and postmenopausal women with DTC and controls. STUDY DESIGN AND PATIENTS: Subjects included 80 women with DTC (40 pre- and 40 postmenopausal) and 89 (29 and 60, respectively) controls. pQCT was performed at the radius and tibia, Dual-energy X ray absorptiometry (DXA) at the hip and lumbar spine, while samples were taken for calciotropic hormones and bone markers. RESULTS: No differences were observed concerning aBMD by DXA. In premenopausal women, there were no significant differences concerning vBMD, while cortical thickness was higher at the radius in patients with DTC (P < 0.01) compared with controls. In postmenopausal women with DTC trabecular bone mineral content (BMC), area and vBMD were lower at the radius (all P < 0.05), while at the tibia trabecular BMC and vBMD were lower at the mixed transition zone (14% from the distal end, P < 0.05) compared with controls. Cortical thickness was lower at the radius (P < 0.01) in postmenopausal patients compared with controls. Serum CTX was higher in postmenopausal women with DCT (P < 0.01), while in premenopausal patients, parathyroid hormone (PTH) was lower (P = 0.01) compared with controls. CONCLUSIONS: TSH suppression therapy is associated with higher bone resorption only in postmenopausal women; this adversely affects trabecular and cortical bone properties especially at nonweight bearing sites such as the radius. PMID- 25040694 TI - Population structure and temporal maintenance of the multihost fungal pathogen Botrytis cinerea: causes and implications for disease management. AB - Understanding the causes of population subdivision is of fundamental importance, as studying barriers to gene flow between populations may reveal key aspects of the process of adaptive divergence and, for pathogens, may help forecasting disease emergence and implementing sound management strategies. Here, we investigated population subdivision in the multihost fungus Botrytis cinerea based on comprehensive multiyear sampling on different hosts in three French regions. Analyses revealed a weak association between population structure and geography, but a clear differentiation according to the host plant of origin. This was consistent with adaptation to hosts, but the distribution of inferred genetic clusters and the frequency of admixed individuals indicated a lack of strict host specificity. Differentiation between individuals collected in the greenhouse (on Solanum) and outdoor (on Vitis and Rubus) was stronger than that observed between individuals from the two outdoor hosts, probably reflecting an additional isolating effect associated with the cropping system. Three genetic clusters coexisted on Vitis but did not persist over time. Linkage disequilibrium analysis indicated that outdoor populations were regularly recombining, whereas clonality was predominant in the greenhouse. Our findings open up new perspectives for disease control by managing plant debris in outdoor conditions and reinforcing prophylactic measures indoor. PMID- 25040695 TI - Structural analysis of human soluble adenylyl cyclase and crystal structures of its nucleotide complexes-implications for cyclase catalysis and evolution. AB - The ubiquitous second messenger cAMP regulates a wide array of functions, from bacterial transcription to mammalian memory. It is synthesized by six evolutionarily distinct adenylyl cyclase (AC) families. In mammals, there are two AC types: nine transmembrane ACs (tmACs) and one soluble AC (sAC). Both AC types belong to the widespread cyclase class III, which has members in numerous organisms from archaeons to mammals. Class III also contains all known guanylyl cyclases (GCs), which synthesize the cAMP-related messenger cGMP in many eukaryotes and possibly some prokaryotes. Among mammalian ACs, sAC is uniquely regulated by bicarbonate, and has been proposed to be more closely related to a bacterial AC subfamily than to mammalian ACs, on the basis of sequence comparisons. Here, we used crystal structures of human sAC catalytic domains to analyze its relationships with other class III ACs and GCs, and to study its substrate selection mechanisms. Structural comparisons revealed a similarity within an sAC-like subfamily but no family-specific structure elements, and an unexpected sAC similarity to eukaryotic GCs and a potential bacterial GC. We further solved novel crystal structures of sAC catalytic domains in complex with a substrate analog, unprocessed ATP substrate, and product after soaking with ATP or GTP. The structures show a novel ATP-binding conformation, and suggest mechanisms for substrate association and recognition. Our results could explain the limited substrate specificity of sAC, suggest how specificity is increased in other cyclases, and indicate evolutionary relationships among class III enzymes, with sAC being close to a putative 'ancestor' cyclase. DATABASE: Coordinates and structure factors for the novel sAC-cat structures described have been deposited with the Worldwide PDB (www.pdb.org): ApCpp soak (entry 4usu), ATP + Ca(2+) soak (entry 4usv), GTP + Mg(2+) soak (entry 4ust), ATP soak (entry 4usw). PMID- 25040696 TI - Rapidly growing non-tuberculous mycobacterial infection in a renal transplant patient after alemtuzumab induction. AB - Renal transplant recipients are at high risk of developing opportunistic infections particularly in the first 6 months after transplantation. Organisms causing such infections include rapidly growing non-tuberculous mycobacteria (NTM). Lymphocytes have a central role in combating mycobacterial infections. The use of lymphocyte-depleting agents, such as alemtuzumab, in the renal transplant population has increased in recent years. A case of multifocal osteomyelitis caused by one of the NTM, Mycobacterium chelonae, in a renal transplant recipient, after alemtuzumab induction, is presented. PMID- 25040697 TI - Delays in time to surgery for minorities with temporal lobe epilepsy. AB - OBJECTIVES: To determine whether adult minority patients with medically refractory temporal lobe epilepsy (TLE) experience significantly longer times to anterior temporal lobectomy (ATL) following presurgical evaluation. METHODS: A retrospective cohort study of 223 adult patients with epilepsy (PWE) and unilateral mesial temporal sclerosis who completed presurgical evaluation in the epilepsy monitoring unit at University of California, San Francisco, between January 1, 1993 and December 31, 2010, with follow-up through December 31, 2012. Log-rank test was performed for Kaplan-Meier survival curves of time to ATL stratified by race/ethnicity and by limited English proficiency (LEP). Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards and Weibull modeling. RESULTS: African Americans (AAs) and Asian/Pacific Islanders (Asian/PIs) experienced significantly longer times to surgery than whites in Kaplan-Meier plots (log-rank test p = 0.02 and p = 0.005, respectively). AAs and Asian/PIs also had longer times to surgery after adjusting for frailty, LEP, sex, age, mesial temporal sclerosis (MTS) laterality, and nonconcordant ictal electroencephalography (EEG) (adjusted HR = 0.22, p = 0.006; adjusted HR = 0.25, p = 0.003, respectively). Patients with LEP experienced significantly longer times to surgery than patients proficient in English (log rank test p = 0.0085; adjusted HR = 0.48, p = 0.041). In Cox modeling, nonconcordant ictal EEG studies (adjusted HR = 0.47, p = 0.01), left-sided MTS (adjusted HR = 0.69, p = 0.023), and female sex (adjusted HR = 0.72, p = 0.048) were risk factors for longer times to surgery. SIGNIFICANCE: AA and Asian/PI patients as well as those with LEP have significantly longer times to ATL following presurgical evaluation. Future studies should be aimed at identifying the source of these disparities and developing targeted interventions to address them. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 25040698 TI - In vitro color evaluation of esthetic coatings for metallic dental implants and implant prosthetic appliances. AB - OBJECTIVES: The aim of this study was to characterize the optical properties of newly developed esthetic coatings for metallic implants and components for an improved peri-implant soft tissue appearance. MATERIAL AND METHODS: Pig maxillae (n = 6) were used for the in vitro color evaluation of coated and uncoated samples. Three different coating systems (Ti-ZrO(2), Ti-Al-ZrO(2), and Ti-Ag ZrO(2)) were deposited on titanium substrates, which exhibited different roughness (polished, machined, and sand-blasted) and interference colors (pink, yellow, and white). Spectrophotometric measurements were made of samples below three different mucosa thicknesses (1 mm, 2 mm, and 3 mm) and titanium served as negative control. Color difference DeltaE was calculated using DeltaL, Deltaa, and Deltab values for each sample (in total 30 samples). RESULTS: DeltaE values were significantly above the threshold value of 3.70 for sand-blasted Ti and Ti ZrO(2) samples when tested below 1 mm thick soft tissue, hence resulted in a dark appearance of the soft tissues. In contrast, Ti-Al-ZrO(2) and Ti-Ag-ZrO(2) samples showed significant DeltaL values below 1 mm, which indicates a brightening of the covering tissue. In general, DeltaE values decreased with increasing thickness of the tissue. At 3 mm thick tissue, DeltaE values were significantly below 3.70 for Ti-Al-ZrO(2) and Ti-Ag-ZrO(2) samples. The preferable substrate surface should be machined due increased color brightness, good soft tissue integration and improved adhesion between coating and substrates. Improvement of the optical appearance of the metal was achieved with the coating systems Ti-Al-ZrO(2) and Ti-Ag-ZrO(2). Darkening effects could not be observed for these systems, and partially light brightening of the tissue was observed. Advantageous colors were suggested to be pink and yellow. PMID- 25040699 TI - Cross-sectional associations of acylation stimulating protein (ASP) and adipose tissue gene expression with estradiol and progesterone in pre- and postmenopausal women. AB - OBJECTIVE: Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP). DESIGN, PATIENTS AND MEASUREMENTS: In 392 women with wide age (18-69 years) and body size (BMI: 17 to 90 kg/m(2) ) ranges, fasting plasma levels of ASP, ovarian hormones, glucose, adiponectin and lipids/apolipoproteins were assessed, along with determination of metabolic syndrome (MS) features. Gene expression of C3 (ASP precursor) and related receptors C5L2, C3aR and C5aR in subcutaneous and omental adipose tissues was measured in a subset. RESULTS: Acylation stimulating protein correlated negatively with concentrations of estradiol (P < 0.0001), adiponectin (P < 0.001) and apolipoprotein A1 (P < 0.001) and positively with apolipoprotein B levels (P < 0.001), systolic blood pressure (P < 0.001), waist circumference (P < 0.001), and triglyceride concentrations (P < 0.01). In age-matched groups of lean, overweight, metabolically healthy obese (MHO) and obese with metabolic syndrome (MSO), there was a stepwise increase in ASP levels (P < 0.001) while concentrations of adiponectin (P < 0.0001) and estradiol (P < 0.001) but not those of progesterone decreased. Progesterone but not estradiol levels correlated positively with C3 gene expression in omental adipose tissue (P < 0.05) and negatively with C5L2 expression in both omental (P < 0.01) and subcutaneous (P < 0.05) adipose tissues. CONCLUSION: Our results are consistent with the concept that sex hormones differentially influence circulating ASP and adipose tissue gene expression of its related proteins in a depot-specific manner. ASP may play a role in the regulation of regional fat metabolism through interactions with sex hormones in women. PMID- 25040700 TI - Accelerated differentiation of melanocyte stem cells contributes to the formation of hyperpigmented maculae. AB - It has been reported that the abnormal regulation of melanocyte stem cells (McSCs) causes hair greying; however, little is known about the role of McSCs in skin hyperpigmentation such as solar lentigines (SLs). To investigate the involvement of McSCs in SLs, the canonical Wnt signalling pathway that triggers the differentiation of McSCs was analysed in UVB-induced delayed hyperpigmented maculae in mice and human SL lesions. After inducing hyperpigmented maculae on dorsal skin of F1 mice of HR-1* HR/De, which was formed long after repeated UVB irradiation, the epidermal Wnt1 expression and the number of nuclear beta-catenin positive McSCs were increased as compared to non-irradiated control mice. Furthermore, the expression of dopachrome tautomerase (Dct), a downstream target of beta-catenin, was significantly upregulated in McSCs of UVB-irradiated mice. The Wnt1 expression and the number of nuclear beta-catenin-positive McSCs were also higher in human SL lesions than in normal skin. Recombinant Wnt1 protein induced melanocyte-related genes including Dct in early-passage normal human melanocytes (NHEMs), an in vitro McSC model. These results demonstrate that the canonical Wnt signalling pathway is activated in SL lesions and strongly suggest that the accelerated differentiation of McSCs is involved in SL pathogenesis. PMID- 25040701 TI - Atypical giant axonal neuropathy arising from a homozygous mutation by uniparental isodisomy. PMID- 25040702 TI - Optimizing clinical outcomes resulting from glucose-lowering therapies in type 2 diabetes: increased confidence about the DPP-4 inhibitors and continued concerns regarding sulphonylureas and exogenous insulin. PMID- 25040703 TI - Is recurrent miscarriage a useful clinical concept? AB - Many treatments have been used to increase the chances of an ongoing pregnancy after recurrent miscarriage (RM). Yet no clear evidence for an effective intervention has been found. Therefore, the clinical concept RM should be reconsidered. Both the statistical and clinical bases for RM are poor. If the individual risk is taken into account, then simple calculations explain the observed frequency of RM. Most miscarriages, either sporadic or recurrent, are abnormal in construction or development. Although some risk factors for miscarriage have been identified, such as age and number of previous miscarriages, the importance of other factors remains uncertain. RM has a favorable prognosis: the cumulative live birth rate is usually over 90% after two or three more attempts. So maternal systemic pathology does not seem to play a major role in the cause of RM. Little benefit can be expected from any intervention aimed at increasing the chance of a live birth. RM does not appear to be a real pathological entity that requires a special explanation. Moral support should replace medical interventions in most cases. PMID- 25040704 TI - Measurement of pain and anthropometric parameters in women with chronic pelvic pain. AB - RATIONALE, AIMS AND OBJECTIVES: To analyse anthropometric parameters, clinical pain and experimental pain in women with chronic pelvic pain (CPP). METHODS: Ninety-one women with a clinical diagnosis of CPP, mean age of 40.03 +/- 9.97 years, submitted to anthropometric evaluation based on body mass index (BMI) and percent body fat (%BF) using bioimpedance body composition monitor; pain intensity was determined by visual analogue scale (VAS), numerical categorical scale (NCS) and McGill Pain Questionnaire; experimental pain was determined by transcutaneous electrical nerve stimulation (TENS), and anxiety and depression symptoms were determined by the Hospital Anxiety and Depression scale. RESULTS: A total of 54.8% of the women showed %BF >32 risk of disease associated with obesity. Regarding the anthropometric data, a statistically significant difference was observed between groups for both BMI and %BF (P<0.0001). In the analysis of pain intensity by the VAS, NCS and total McGill, there was no significant difference between the groups, and experimental pain by TENS revealed significant difference only between the normal weight and overweight groups (P=0.0154). The results of anxiety symptoms were above the cut-off point in all groups, with no significant difference between them (P=0.3710). The depression symptoms were below the cut-off point in the normal weight group and above the cut-off point in the overweight and obese groups, 9.469(4.501) and 9.741(4.848), respectively, with no significant difference between them (P=0.6476). CONCLUSION: Evaluation of anthropometric parameters and pain measurements can be applied in clinical practice, making a contribution to the diagnosis and influencing the choice of a more effective treatment for women with CPP. PMID- 25040705 TI - Intrapartum monitoring with cardiotocography and ST-waveform analysis in breech presentation: an observational study. AB - OBJECTIVE: To determine the electrocardiographic performance and neonatal outcome of pregnancies with breech presentation and planned vaginal delivery monitored with ST-waveform analysis (STAN). DESIGN: Prospective observational study. SETTING: University hospital, Norway; 2004-2008. POPULATION: Singleton pregnancies with a gestational age above 35 + 6 weeks, breech presentation, selected for vaginal delivery and monitored with STAN. METHODS: Common clinical guidelines for STAN monitoring were used. An experienced neonatologist graded the symptoms of neonatal encephalopathy. The outcome was compared with STAN-monitored high-risk deliveries in a vertex presentation (n = 5569) using logistic regression analysis. MAIN OUTCOME MEASURE: Frequency of ST events, indications of intervention for fetal distress, and neonatal morbidity and mortality. RESULTS: Breech presentation occurred in 750 of 23,219 (3.2%) deliveries, 625 (83%) of which were selected for vaginal delivery. Intrapartum monitoring by STAN was performed in 433 (69%). Compared with vertex presentations, fetuses in breech presentation had a lower risk of baseline T/QRS rise during labour [odds ratio (OR) = 0.7, 95% confidence interval (95% CI) = 0.7-0.9, P = 0.003] and a higher risk for intervention as a result of preterminal cardiotocogram (OR = 2.9, 95% CI = 1.6-5.9, P = 0.001). The risks of perinatal mortality (OR = 1.8, 95% CI = 0.2 15, P = 0.6), cord metabolic acidosis (OR = 0.8, 95% CI = 0.2-3.2, P = 0.7) and moderate or severe neonatal encephalopathy (OR = 1.8, 95% CI = 0.5-6.2, P = 0.3) did not differ significantly between breech and vertex deliveries. CONCLUSION: STAN can be used for the surveillance of breech presentations selected for vaginal delivery with an acceptable neonatal outcome. The electrocardiogram (ECG) pattern during labour varies with the fetal presentation. PMID- 25040706 TI - Barriers to weight-related health behaviours: a qualitative comparison of the socioecological conditions between pregnant and post-partum low-income women. AB - The association between socioecological factors and poor health outcomes for low income women and their children has been the focus of disparities research for several decades. This research compares the socioecological conditions among low income women from pregnancy to post-partum and highlights the factors that make weight management increasingly difficult after delivery. As part of the formative research for an online health intervention, group and individual interviews were conducted with low-income pregnant and post-partum women. Five pregnancy group interviews (n = 15 women), five post-partum group interviews (n = 23 women) and seven individual interviews with a total of 45 participants were conducted in Rochester, New York. All interviews were audio-recorded. The constant comparative method was used to code interview notes and identify emergent themes. Subjects faced many challenges that affected their attitudes, beliefs and their ability to maintain or improve healthy weight behaviours. These included unemployment, relationship issues, minimal social support, lack of education, limited health care access, pre-existing medical conditions and neighbourhood disadvantage. Compared with pregnant women, post-partum women faced additional difficulties, such as child illnesses and custody issues. The most striking differences between pregnancy and post-partum related to the family's medical problems and greater environmental constraints. Many factors detracted from women's capacity to engage in healthy weight behaviours post-partum, including challenges present prior to delivery, challenges present prior to delivery that worsen after delivery, and new challenges that begin after delivery. These additional post-partum challenges need to be considered in designing programmes, policies and interventions that promote healthy weight. PMID- 25040707 TI - Sturge-Weber Syndrome Is Associated with Cortical Dysplasia ILAE Type IIIc and Excessive Hypertrophic Pyramidal Neurons in Brain Resections for Intractable Epilepsy. AB - Sturge-Weber syndrome (SWS) is a rare syndrome characterized by capillary-venous malformations involving skin and brain. Many patients with SWS also suffer from drug-resistant epilepsy. We retrospectively studied a series of six SWS patients with epilepsy and extensive neurosurgical resections. At time of surgery, the patients' age ranged from 11 to 35 years (with a mean of 20.2 years). All surgical specimens were well preserved, which allowed a systematic microscopical inspection utilizing the 2011 ILAE classification for focal cortical dysplasia (FCD). Neuropathology revealed dysmorphic-like neurons with hypertrophic cell bodies reminiscent to those described for FCD type IIa in all cases. However, gross architectural abnormalities of neocortical layering typical for FCD type IIa were missing, and we propose to classify this pattern as FCD ILAE type IIIc. In addition, our patients with earliest seizure onset also showed polymicrogyria (PMG; n = 4). The ictal onset zones were identified in all patients by subdural electrodes, and these areas always showed histopathological evidence for FCD type IIIc. Four out of five patients had favorable seizure control after surgery with a mean follow-up period of 1.7 years. We concluded from our study that FCD type IIIc and PMG are frequently associated findings in SWS. FCD type IIIc may play a major epileptogenic role in SWS and complete resection of the associated FCD should be considered a prognostic key factor to achieve seizure control. PMID- 25040709 TI - Pitfalls of patch testing with glucosides. PMID- 25040708 TI - Monoracial and biracial children: effects of racial identity saliency on social learning and social preferences. AB - Children prefer learning from, and affiliating with, their racial in-group but those preferences may vary for biracial children. Monoracial (White, Black, Asian) and biracial (Black/White, Asian/White) children (N = 246, 3-8 years) had their racial identity primed. In a learning preferences task, participants determined the function of a novel object after watching adults (White, Black, and Asian) demonstrate its uses. In the social preferences task, participants saw pairs of children (White, Black, and Asian) and chose with whom they most wanted to socially affiliate. Biracial children showed flexibility in racial identification during learning and social tasks. However, minority-primed biracial children were not more likely than monoracial minorities to socially affiliate with primed racial in-group members, indicating their in-group preferences are contextually based. PMID- 25040710 TI - Nickel release from white gold. PMID- 25040711 TI - Sofa dermatitis caused by methylisothiazolinone in a leather-care product. PMID- 25040712 TI - Systemic allergic dermatitis caused by cobalt and cobalt toxicity from a metal on a metal hip replacement. PMID- 25040713 TI - Glove-related hand urticaria caused by disposable gloves in healthcare workers. PMID- 25040714 TI - Severe allergic contact dermatitis caused by a rubber glove coated with a moisturizer. PMID- 25040715 TI - Contact urticaria and contact sensitization to yucca (Yucca gigantea Lem.) in a plant keeper. PMID- 25040716 TI - Occupational contact dermatitis caused by sodium cocoamphopropionate in a liquid soap used in fast-food restaurants. PMID- 25040717 TI - Contact urticaria syndrome caused by direct hair dyes in a hairdresser. PMID- 25040718 TI - Protein contact dermatitis caused by fishing bait in a patient with contact urticaria caused by shrimp. PMID- 25040719 TI - Granular cell tumours of the colorectum: histopathological and immunohistochemical evaluation of 30 cases. AB - AIMS: Granular cell tumours (GCTs) are uncommon in the gastrointestinal tract, particularly in the colorectum. Herein, we report a series of 30 colorectal GCTs and discuss the properties of colorectal GCTs based on histopathological and immunohistochemical studies. METHODS AND RESULTS: Searching the surgical pathology files identified 30 cases of colorectal GCTs for 2005-2013. A broad panel of antibodies including neural and macrophage markers were used for immunohistochemical evaluation. Colorectal GCTs predominantly involved the right colon and showed increased nuclear atypia including nuclear pleomorphism and nuclear spindling. All 24 cases with mucosal tumour components had infiltrative growth patterns within the mucosa. In all available cases, diffuse strong immunopositivity was observed for S100 and SOX10 of schwannian differentiation markers, as well as for CD68. Other neuronal lineage markers, including CD56, neuron-specific enolase, nestin, and synaptophysin showed consistently high expression rates. The immunohistochemical results are suggestive for a neural origin of GCTs. CONCLUSION: Histopathological and immunohistochemical features of colorectal GCTs were delineated in this large series of 30 colorectal GCTs. Although the incidence of GCTs is relatively low, clinicians and pathologists need to be aware of GCT in the differential diagnosis. PMID- 25040721 TI - Effective hemostasis for rupture of gastric exposed aneurysm with over-the-scope clip (with video). PMID- 25040722 TI - College law enforcement and security department responses to alcohol-related incidents: a national study. AB - BACKGROUND: Campus police and security personnel are often the first to respond to alcohol-related incidents on campus. The purpose of this study is to examine how campus law enforcement and security respond to alcohol-related incidents, and how consequences and communication differ based on characteristics of the incident. METHODS: Directors of campus police/security from 343 colleges across the United States completed a survey regarding usual practice following serious, underage, and less serious alcohol incidents on and off campus. RESULTS: Campus law enforcement and security most commonly reported contacting campus officials. A minority reported issuing citations and referring students to the health center. Enforcement actions were more commonly reported for serious and underage incidents than for less serious incidents. Large (vs. small) colleges, public (vs. private) colleges, and those located in small (vs. large) towns more consistently reported taking actions against drinkers. CONCLUSIONS: Understanding how campus police and security respond to alcohol-related incidents is essential for reducing alcohol-related problems on college campuses. PMID- 25040723 TI - A new tool for coding and interpreting injuries in fatal airplane crashes: the crash injury pattern assessment tool application to the Air France Flight AF447 disaster (Rio de Janeiro-Paris), 1st of June 2009. AB - For investigation of air disasters, crash reconstruction is obtained using data from flight recorders, physical evidence from the site, and injuries patterns of the victims. This article describes a new software, Crash Injury Pattern Assessment Tool (CIPAT), to code and analyze injuries. The coding system was derived from the Abbreviated Injury Score (AIS). Scores were created corresponding to the amount of energy required causing the trauma (ER), and the software was developed to compute summary variables related to the position (assigned seat) of victims. A dataset was built from the postmortem examination of 154/228 victims of the Air France disaster (June 2009), recovered from the Atlantic Ocean after a complex and difficult task at a depth of 12790 ft. The use of CIPAT allowed to precise cause and circumstances of deaths and confirmed major dynamics parameters of the crash event established by the French Civil Aviation Safety Investigation Authority. PMID- 25040724 TI - Neurodisability perspectives. PMID- 25040720 TI - Ciliopathies: the trafficking connection. AB - The primary cilium (PC) is a very dynamic hair-like membrane structure that assembles/disassembles in a cell-cycle-dependent manner and is present in almost every cell type. Despite being continuous with the plasma membrane, a diffusion barrier located at the ciliary base confers the PC properties of a separate organelle with very specific characteristics and membrane composition. Therefore, vesicle trafficking is the major process by which components are acquired for cilium formation and maintenance. In fact, a system of specific sorting signals controls the right of cargo admission into the cilia. Disruption to the ciliary structure or its function leads to multiorgan diseases known as ciliopathies. These illnesses arise from a spectrum of mutations in any of the more than 50 loci linked to these conditions. Therefore, it is not surprising that symptom variability (specific manifestations and severity) among and within ciliopathies appears to be an emerging characteristic. Nevertheless, one can speculate that mutations occurring in genes whose products contribute to the overall vesicle trafficking to the PC (i.e. affecting cilia assembly) will lead to more severe symptoms, whereas those involved in the transport of specific cargoes will result in milder phenotypes. In this review, we summarize the trafficking mechanisms to the cilia and also provide a description of the trafficking defects observed in some ciliopathies which can be correlated to the severity of the pathology. PMID- 25040725 TI - Analysis of dopaminergic neuronal dysfunction in genetic and toxin-induced models of Parkinson's disease in Drosophila. AB - Drosophila melanogaster has contributed significantly to the understanding of disease mechanisms in Parkinson's disease (PD) as it is one of the very few PD model organisms that allow the study of age-dependent behavioral defects, physiology and histology, and genetic interactions among different PD-related genes. However, there have been contradictory results from a number of recent reports regarding the loss of dopaminergic neurons in different PD fly models. In an attempt to re-evaluate and clarify this issue, we have examined three different genetic (alpha-synuclein, Pink1, parkin) and two toxin-based (rotenone and paraquat) models of the disease for neuronal cell loss. Our results showed no dopaminergic neuronal loss in all models tested. Despite this surprising result, we found additional phenotypes showing the dysfunctional status of the dopaminergic neurons in most of the models analyzed. A common feature found in most models is a quantifiable decrease in the fluorescence of a green-fluorescent protein reporter gene in dopaminergic neurons that correlates well with other phenotypes found for these models and can be reliably used as a hallmark of the neurodegenerative process when modeling diseases affecting the dopaminergic system in Drosophila. Analyzing three genetic and two toxin-based Drosophila models of Parkinson's disease (PD) through green fluorescent protein reporter and alpha-tyrosine hydroxylase staining, we have found the number of dopaminergic neurons to remain unchanged. Despite the lack of neuronal loss, we have detected a remarkable decrease in a reporter green-fluorescent protein (GFP) signal in dopaminergic neurons, suggesting an abnormal neuronal status that correlates with the phenotypes associated with those PD fly models. PMID- 25040726 TI - Longitudinal analysis of VP7 gene of group A human rotavirus G2P[4] strains circulating in the pre-vaccine era in Sapporo, Japan from 1991 to 2011. AB - Sequence analysis of the VP7 gene in 23 group A human rotavirus G2P[4] strains obtained during 1991-2011, that is, the pre-vaccine era, in Sapporo, Japan showed considerable genetic diversity, mainly in variable regions. Recent G2P[4] epidemic strains were located in sublineage IVa with a distinctive substitution of D96N. This study provides background data on the genetic variability of G2P[4] rotavirus-VP7 gene prior to the widespread use of rotavirus vaccines in Japan. PMID- 25040727 TI - Numerical Analysis of Thermal Remediation in 3D Field-Scale Fractured Geologic Media. AB - Thermal methods are promising for remediating fractured geologic media contaminated with volatile organic compounds, and the success of this process depends on the coupled heat transfer, multiphase flow, and thermodynamics. This study analyzed field-scale removal of trichloroethylene (TCE) and heat transfer behavior in boiling fractured geologic media using the multiple interacting continua method. This method can resolve local gradients in the matrix and is less computationally demanding than alternative methods like discrete fracture matrix models. A 2D axisymmetric model was used to simulate a single element of symmetry in a repeated pattern of extraction wells inside a large heated zone and evaluate effects of parameter sensitivity on contaminant recovery. The results showed that the removal of TCE increased with matrix permeability, and the removal rate was more sensitive to matrix permeability than any other parameter. Increasing fracture density promoted TCE removal, especially when the matrix permeability was low (e.g., <10(-17) m(2)). A 3D model was used to simulate an entire treatment zone and the surrounding groundwater in fractured material, with the interaction between them being considered. Boiling was initiated in the center of the upper part of the heated region and expanded toward the boundaries. This boiling process resulted in a large increase in the TCE removal rate and spread of TCE to the vadose zone and the peripheries of the heated zone. The incorporation of extraction wells helped control the contaminant from migrating to far regions. After 22 d, more than 99.3% of TCE mass was recovered in the simulation. PMID- 25040728 TI - Unusual presentation of testicular torsion in an elderly man. PMID- 25040729 TI - Using root form to improve our understanding of root function. PMID- 25040730 TI - The role of preadaptations or evolutionary novelties for the evolution of sexually deceptive orchids. PMID- 25040731 TI - Using magnetic resonance imaging to diagnose neonatal seizures. PMID- 25040732 TI - Cost-effectiveness analysis of early vs. late autologous stem cell transplantation in multiple myeloma. AB - BACKGROUND: Autologous stem cell transplant (ASCT) is the current standard of care for most patients with multiple myeloma (MM) who are transplant eligible, yet the timing of ASCT is disputed due to a similar overall (OS) and progression free survival with an early ASCT (eASCT) or a delayed ASCT (dASCT) approach. OBJECTIVE: We developed a decision analytic model to perform cost-effectiveness analysis of the two commonly used treatment strategies for MM. METHODS: Data on disease progression and treatment effectiveness came from 2001 to 2008 cohort treated at the Mayo Clinic and from published studies. Cost analysis was performed from a third-party payer perspective. RESULTS: The Consumer Price Index adjusted 2012 costs of eASCT and dASCT were $249 236 and $262 610, respectively. eASCT cohort had a benefit of 1.96 quality-adjusted life years (QALYs), 0.23 QALYs more than dASCT, implying that eASCT is preferred (dominant) over dASCT. The most critical variables in one-way sensitivity analysis were treatment related mortality and OS associated with eASCT strategy. CONCLUSIONS: We conclude that eASCT could potentially be a relatively cost-effective treatment option for appropriate patients with MM, and these results would help patients, providers, and payers in decision making for timing of ASCT. PMID- 25040733 TI - Comparable cytological features between cells processed as either wet mount or conventional cytospins. AB - OBJECTIVE: Microfluidics represents a novel approach for the processing of pathological biopsy specimens. It represents an enabling platform between traditional morphology-driven pathology diagnostics and future sequencing technologies. Microfluidics requires the dissociation of cells from tissue, but the evaluation of these cells still lies within the domain of pathology, specifically cytopathology. The dissociated cells, however, require supravital staining and examination under wet mount conditions as part of their processing in a microfluidic platform. These conditions are vastly different from current approaches for cytopathological specimen preparation. No studies to date have compared the cytological characteristics of cells between these two different conditions. METHODS: Slivers of different types of unfixed tissue were procured and the cells were dissociated. The cells were recovered and separated for processing either by staining with a supravital dye and examination under wet mount conditions or by conventional preparatory methods and staining by the Papanicolaou method. RESULTS: Obvious differences existed in the tinctorial hue between similar cells stained by the two different methods; however, there were no significant differences in the features between the matched cells. Some cells in the wet mount preparations existed in three-dimensional balls, reducing the quality of the images relative to cells flattened to the slide by the cytospin method. CONCLUSIONS: Cells stained with a supravital stain and examined in a wet mount environment appear to be cytologically similar to cells prepared by conventional methods. Long-established criteria for the evaluation of cells prepared by established protocols can therefore be extended and applied to cells viewed within a microfluidic platform. PMID- 25040734 TI - Sequential allergen desensitization of basophils is non-specific and may involve p38 MAPK. AB - BACKGROUND: Sequential allergen desensitization provides temporary tolerance for allergic patients. We adapted a clinical protocol to desensitize human blood basophils ex vivo and investigated the mechanism and allergen specificity. METHODS: We included 28 adult, grass allergic subjects. The optimal, activating allergen concentration was determined by measuring activated CD63(+) CD193(+) SS(Low) basophils in a basophil activation test with 8 log-dilutions of grass allergen. Basophils in whole blood were desensitized by incubation with twofold to 2.5-fold increasing allergen doses in 10 steps starting at 1 : 1000 of the optimal dose. Involvement of p38 mitogen-activated protein kinase (MAPK) was assessed after 3 min of allergen stimulation (n = 7). Allergen specificity was investigated by desensitizing cells from multi-allergic subjects with grass allergen and challenging with optimal doses of grass, birch, recombinant house dust mite (rDer p2) allergen or anti-IgE (n = 10). RESULTS: Desensitization reduced the fraction of blood basophils responding to challenge with an optimal allergen dose from a median (IQR) 81.0% (66.3-88.8) to 35.4% (19.8-47.1, P < 0.0001). CD63 MFI expression was reduced from 68 248 (29 336-92 001) to 30 496 (14 046-46 179, P < 0.0001). Basophils from multi-allergic subjects were desensitized with grass allergen. Challenge with grass allergen resulted in 39.6% activation (15.8-58.3). An unrelated challenge (birch, rDer p2 or anti-IgE) resulted in 53.4% activation (30.8-66.8, P = 0.16 compared with grass). Desensitization reduced p38 MAPK phosphorylation from a median 48.1% (15.6-92.8) to 26.1% (7.4-71.2, P = 0.047) and correlated with decrease in CD63 upregulation (n = 7, r > 0.79, P < 0.05). CONCLUSION: Desensitization attenuated basophil response rapidly and non-specifically at a stage before p38 MAPK phosphorylation. PMID- 25040735 TI - A detailed appraisal of mesocolic lymphangiology--an immunohistochemical and stereological analysis. AB - Inadequate resection of the adjoining mesentery is associated with adverse outcome for colon cancer. Disruption of the integrity of the mesenteric lymphatic package has been implicated in this, though not proven. Recent studies have determined mesenteric anatomy and histology and now provide an opportunity to determine accurately the distribution of lymphatic vessels. The aim of this study was to characterise the distribution of the lymphatic vessels (LV) within the small intestinal and colonic mesentery, and in Toldt's fascia, which lies between the mesocolon and underlying retroperitoneum. Mesenteric samples were harvested from 12 human cadavers. Samples were taken from the small bowel mesentery, ascending, transverse, descending mesocolon and from both apposed and non-apposed portions of the mesosigmoid. Serial sections were stained immunohistochemically with monoclonal antibody D2-40 (podoplanin), and Masson's Trichrome. Lymphatic vessel (LV) density and radius of diffusion were determined using a stereological approach. A lymphatic network was embedded within the mesenteric connective tissue lattice throughout each mesenteric region. LV were identifiable within the submesothelial connective tissue where they measured 10.2 +/- 4.1 MUm in diameter and had an average radius of diffusion of 174.72 +/- 97.68 MUm. Unexpectedly, LV were identified in Toldt's fascia, where they measured 4.3 +/- 3.1 MUm in diameter and had a radius of diffusion of 165.12 +/- 66.26 MUm. This is the first study systematically to determine and quantify the distribution of lymphatic vessels within the mesenteric organ and to demonstrate the presence of such vessels within Toldt's fascia. A rich lymphatic network occupies all levels of the mesenteric connective tissue lattice. Within the latter, they are found within 0.1 mm of peritonealised mesenteric surfaces and are separated by an average distance of 0.17 mm and may be particularly vulnerable during surgery. PMID- 25040737 TI - The relationship of Prohepcidin levels with anemia and inflammatory markers in non-diabetic uremic patients: a controlled study. AB - INTRODUCTION: Hepcidin, a small peptide hormone synthesized in the liver, plays central role in regulation of iron metabolism. Hepcidin generation in chronic kidney disease (CKD) is dependent on iron status, anemia, inflammation, and hypoxia and erythropoietin levels. In our study, the relationship between Prohepcidin levels and inflammation and iron indices in non-diabetic uremic patients was investigated. METHODS: This study has a cross-sectional design which includes four groups: Non-diabetic 21 patients with stage 4 CKD (predialysis), 20 hemodialysis (HD) and 21 peritoneal dialysis (PD) patients and 17 healthy volunteers as the control group. Complete blood count, iron, total iron binding capacity (TIBC), ferritin, high-sensitive C-reactive protein (hsCRP), fibrinogen, parathyroid hormone, interleukin (IL)-6 and Prohepcidin levels were recorded. RESULTS: Serum Prohepcidin levels in the predialysis, HD, PD and the control groups were 119.6 +/- 45.1 ng/mL, 140.2 +/- 41.8 ng/mL, 148.2 +/- 35.0 ng/mL and 93.8 +/- 21.9 ng/mL, respectively (p < 0.001). Prohepcidin was positively correlated with urea (r = 0.345, p = 0.002), creatinine (r = 0.465, p < 0.001), phosphorus (r = 0.253, p = 0.025), hsCRP (r = 0.275, p = 0.019), duration of dialysis treatment (r = 0.443, p < 0.001), fibrinogen (r = 0.467, p < 0.001) and IL-6 (r = 0.615, p < 0.001) levels. A negative correlation was detected between Prohepcidin levels and albumin (r = -0.286, p < 0.001), TIBC (r = -0.573, p < 0.001), GFR (r = -0.473, p < 0.001), hemoglobin (r = -0.351, p = 0.002) and hematocrit (r = -0.342, p = 0.002) levels. DISCUSSION: Prohepcidin levels increase with deepening anemia and show positive correlation with inflammatory markers. Therapeutic interventions regarding Prohepcidin action on inflammatory status may play a role in the treatment of anemia due to inflammation. Functional iron deficiency is frequent in uremic patients. It may be beneficial to measure Prohepcidin level together with ferritin among these patients. PMID- 25040736 TI - SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence. AB - The inactivation of plasminogen activator inhibitor-1 (PAI-1) has been shown to exert beneficial effects in age-related vascular diseases. Limited information is available on the molecular mechanisms regarding the negatively regulated expression of PAI-1 in the vascular system. In this study, we observed an inverse correlation between SIRT1, a class III histone deacetylase, and PAI-1 expression in human atherosclerotic plaques and the aortas of old mice, suggesting that internal negative regulation exists between SIRT1 and PAI-1. SIRT1 overexpression reversed the increased PAI-1 expression in senescent human umbilical vein endothelial cells (HUVECs) and aortas of old mice, accompanied by decreased SA beta-gal activity in vitro and improved endothelial function and reduced arterial stiffness in vivo. Moreover, the SIRT1-mediated inhibition of PAI-1 expression exerted an antisenescence effect in HUVECs. Furthermore, we demonstrated that SIRT1 is able to bind to the PAI-1 promoter, resulting in a decrease in the acetylation of histone H4 lysine 16 (H4K16) on the PAI-1 promoter region. Thus, our findings suggest that the SIRT1-mediated epigenetic inhibition of PAI-1 expression exerts a protective effect in vascular endothelial senescence. PMID- 25040738 TI - miRNA in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Despite improvements in HCC therapy, the prognosis for HCC patients remains poor due to a high incidence of recurrence. An improved understanding of the pathogenesis of HCC development would facilitate the development of more effective outcomes for the diagnosis and treatment of HCC at earlier stages. miRNA are small, endogenous, non-coding, ssRNA that are 21-30 nucleotides in length and modulate the expression of various target genes at the post transcriptional and translational levels. Aberrant expression of miRNA is common in various human malignancies and modulates cancer-associated genomic regions or fragile sites. As for the relationship between miRNA and HCC, several studies have demonstrated that the aberrant expression of specific miRNA can be detected in HCC cells and tissues. However, little is known about the mechanisms of miRNA related cell proliferation and development. In this review, we summarize the central and potential roles of miRNA in the pathogenesis of HCC and elucidate new possibilities that may be useful as diagnostic and prognostic markers, as well as novel therapeutic targets in HCC. PMID- 25040739 TI - Prevention of tea-induced extrinsic tooth stain. AB - OBJECTIVES: The objectives of this study were to determine whether the addition of milk to tea reduces the ability of tea to stain extracted human teeth and, if so, to ascertain the component of milk that is responsible for milk's stain reducing properties. METHODS: Extracted human teeth were immersed in a tea solution, with the addition of 2% milk, 5.26% lactose, 2.7% casein or 10% fat free milk for 24 h at 37 degrees C. A dental spectrophotometer (VITA Easyshade Compact) was used to evaluate the colour of the teeth both before and after immersion in the tea solutions. Commission internationale de l'eclairage (CIE) L*a*b* colour space values were recorded, and the change in colour (DeltaE*) was calculated. A two-tailed t-test or one-way analysis of variance (anova) was used to determine whether there were statistical differences between groups. RESULTS: Milk significantly reduces the ability of tea to stain teeth (P = 0.0225), specifically in the L* and a* dimensions (P = 0.0182 and P = 0.0124, respectively) of the colour sphere. Casein, which makes up 80% of the protein content in bovine milk, is the component of milk that is responsible for significantly reducing tea's ability to stain teeth (P < 0.0001). CONCLUSIONS: The addition of milk to tea significantly reduces the tea's ability to stain teeth. Casein was determined to be the component of milk that is responsible for preventing tea-induced staining of teeth to a similar order of magnitude that can be obtained by vital bleaching treatments. PMID- 25040740 TI - Identification of HLA-A2-restricted immunogenic peptides derived from a xenogenic porcine major histocompatibility complex. AB - BACKGROUND: Little information is available regarding the precise swine leukocyte antigen (SLA)-derived immunogenic peptides that are presented in the context of human HLA molecules. Here, we identified SLA-derived immunogenic peptides that are presented in association with human HLA-A2 molecule. METHODS: The SLA-derived peptides that bind to HLA-A*0201, a representative of the A2 supertype, were predicted using a computer-assisted algorithm. The candidate peptides were synthesized, and the stabilities of complexes formed between peptides and HLA A*0201 were compared using major histocompatibility complex (MHC) stabilization assays. The cytotoxic T lymphocyte (CTL)-inducing activity of the selected peptides was examined in HLA-A*0201-transgenic mice. RESULTS: Among 15 candidate peptides synthesized, two peptides, peptide-35 (YLGPDGLLL) and peptide-43 (TLICHVDSI), were selected to have high affinity and stability with HLA-A*0201. Examination of the CTL-inducing activity of the two peptides in HLA-A*0201 transgenic mice showed that immunization with peptide-35, but not peptide-43, elicited potent CD8-specific CTL responses. The Peptide-35 is present in non polymorphic alpha2 domains of 34 SLA-1 alleles, 18 SLA-2 alleles, and 1 SLA-3 allele. CONCLUSION: This study identifies an immunogenic HLA-A*0201-restricted epitope derived from the SLA, which may be valuable for the development of epitope-specific immunoregulation strategies. PMID- 25040741 TI - The ward round: what it is and what it can be. PMID- 25040742 TI - Limb-girdle muscle weakness. PMID- 25040743 TI - Imaging in colorectal cancer. PMID- 25040745 TI - Editorial: probiotics and IBS - where are we now? PMID- 25040744 TI - Kruppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells. AB - We previously reported that hypoxia-induced MDR in gastric cancer (GC) cells is hypoxia-inducible factor-1 (HIF-1)-dependent. However, the exact mechanisms are still unknown. Our previous study revealed that Kruppel-like factor 8 (KLF8), a novel transcription factor, was associated with malignant phenotype in GC cells. KLF8 is overexpressed in clear cell renal carcinoma lacking von Hippel-Lindau protein function, which resulted in HIF-1 stabilization. Given this association, we hypothesized that KLF8 contributed to hypoxia-induced MDR in GC cells. Initial experiments revealed that hypoxia could increase KLF8 and HIF-1alpha expressions in GC cells, and KLF8 levels in GC drug-resistant cell lines were higher than in parental cell lines. Subsequent experiments showed that in normoxia, exogenous KLF8 could promote the MDR phenotype; however, blocking KLF8 expression could effectively reverse the MDR phenotype induced by hypoxia. Overexpressed KLF8 increased resistance-associated gene MDR1 mRNA levels, Bcl-2 and P-gp protein levels, and decreased Bax and caspase-3 protein levels in GC cells, and knockout KLF8 reversed these effects. Dual luciferase reporter and ChIP assays showed that KLF8 could promote MDR1 transcriptional activity by combining with KLF8 binding sites located in the upstream of MDR1 transcriptional start site. These results suggest that KLF8 is involved in hypoxia-induced MDR through inhibiting apoptosis and increasing the drug release rate by directly regulating MDR1 transcription. PMID- 25040746 TI - Letter: proton pump inhibitors, GERD and oesophageal adenocarcinoma. PMID- 25040747 TI - Letter: proton pump inhibitors, GERD and oesophageal adenocarcinoma - authors' reply. PMID- 25040748 TI - Letter: faecal calprotectin and lactoferrin - accurate biomarkers in post operative Crohn's disease? PMID- 25040749 TI - Letter: biological therapies are effective for prevention of post-operative Crohn's disease recurrence. PMID- 25040751 TI - Letter: renal effects of tenofovir in adefovir dipivoxil-experienced HBV patients. PMID- 25040750 TI - Letter: faecal calprotectin and lactoferrin - accurate biomarkers in post operative Crohn's disease - authors' reply. Letter: biologic therapies are effective for prevention of post-operative Crohn's disease recurrence - authors' reply. PMID- 25040752 TI - Numerical representations and intuitions of probabilities at 12 months. AB - Recent research shows that preverbal infants can reason about single-case probabilities without relying on observed frequencies, adapting their predictions to relevant dynamic parameters of the situation (Teglas, Vul, Girotto, Gonzalez, Tenenbaum & Bonatti, ; Teglas, Girotto, Gonzalez & Bonatti, ). Here we show that intuitions of probabilities may derive from the ability to represent a limited number of possibilities. After watching a scene containing moving objects of two ensembles, 12-month-olds looked longer at an unlikely than at a likely single case outcome when the objects were within the parallel individuation range. However, they did not do so when the scene contained the same ratio between ensembles but a larger number of objects. At the same time, they could form rational expectations about single-case outcomes in scenes containing the same large number of objects when they could exploit subtle physical parameters induced by the objects' movements and their spatial configuration. Our findings demonstrate that at early stages of development the mental representations involved in probability estimations of future individual situations are powerful and sophisticated, but at the same time they depend on infants' overall cognitive architecture, being constrained by the numerical representations spontaneously induced by the situations. PMID- 25040753 TI - Accelerated idioventricular rhythm unmasking the brugada electrocardiographic pattern. AB - It has recently been reported that a high-degree right bundle branch block (RBBB) may conceal the electrocardiographic manifestations of the Brugada ECG pattern. An 82-year-old with recent onset palpitations was seen in clinic. The resting ECG showed sinus rhythm, high-degree RBBB, and an irregular idioventricular rhythm. Some fusion beats between sinus rhythm and idioventricular rhythm occurred spontaneously depicting incomplete RBBB pattern and a clear cut elevation of the ST-segment was unveiled, giving rise to a suspicious Brugada ECG pattern. The mechanisms and implications of these findings are discussed. PMID- 25040755 TI - Development and evaluation of a screening tool to identify people with diabetes at increased risk of medication problems relating to hypoglycaemia and medication non-adherence. AB - Abstract Aims: To develop and evaluate a screening tool to identify people with diabetes at increased risk of medication problems relating to hypoglycaemia and medication non-adherence. Methods: A retrospective audit of attendances at a diabetes outpatient clinic at a public, teaching hospital over a 16-month period was conducted. Logistic regression was undertaken to examine risk factors associated with medication problems relating to hypoglycaemia and medication non adherence and the most predictive set of factors comprise the Diabetes Medication Risk Screening Tool. Evaluating the tool involved assessing sensitivity and specificity, positive and negative predictive values, cut-off scores, inter-rater reliability, and content validity. Results: The Diabetes Medication Risk Screening Tool comprises seven predictive factors: age, living alone, English language, mental and behavioural problems, comorbidity index score, number of medications prescribed, and number of high-risk medications prescribed. The tool has 76.5% sensitivity, 59.5% specificity, and has a 65.1% positive predictive value, and a 71.8% negative predictive value. A score of 27 or more out of 62 was associated with high-risk of a medication problem. The inter-rater reliability of the tool was high (kappa = 0.79, 95% CI 0.75 - 0.84) and the content validity index was 99.4%. Conclusion: The Diabetes Medication Risk Screening Tool has good psychometric properties and can proactively identify people with diabetes at greatest risk of medication problems relating to hypoglycaemia and medication non adherence. PMID- 25040754 TI - Comparison of acoustic and impedance methods with mask capnometry to assess respiration rate in obese patients recovering from general anaesthesia. AB - Respiratory depression, a potentially serious complication after general anaesthesia, can be detected promptly by close monitoring of both oxygen saturation and respiratory rate. Obese patients have morphological changes that may impair the reliability of monitoring devices. In this study, respiration rate was simultaneously recorded every second for up to 60 min using a computer in 30 adult obese patients (body mass index >= 35 kg.m(-2)), by three methods: acoustic; thoracic impedance; and capnometry via a facemask (Capnomask, reference method). Of the 99,771 data triplets collected, only 85,520 (86%) were included; 12,021 (84%) were not studied due to failure of capnometry and 2240 (16%) due to failure of the acoustic method. Compared with capnometry, bias was similar using both the acoustic method and impedance (-0.3 bpm vs. -0.6 bpm, respectively, p = 0.09), but limits of agreement were narrower for the acoustic method (+/-3.5 bpm vs. +/-5.3 bpm, respectively, p = 0.0008). The proportion of respiration rate values obtained with the acoustic method and impedance that differed by at least 10% or 20% for more than 15 s were 11% vs. 23% and 2% vs. 6%, respectively (p = 0.0009 for both comparisons). The acoustic sensor was well tolerated, while the facemask was pulled off on several occasions by four (13%) agitated patients. In obese patients requiring close monitoring of respiration rate, the acoustic method may be more precise than thoracic impedance and better tolerated than capnometry with a facemask. PMID- 25040756 TI - The addition of tramadol to the standard of i.v. acetaminophen and morphine infusion for postoperative analgesia in neonates offers no clinical benefit: a randomized placebo-controlled trial. AB - BACKGROUND: Tramadol is used following neonatal cardiac and general surgery. However, its ability to opioid-spare or facilitate earlier extubation in postoperative neonates is unquantified. OBJECTIVE: This randomized placebo controlled trial aimed to assess whether tramadol's addition to standard analgesia resulted in earlier extubation or reduced analgesic/sedative requirements in postsurgical neonates. METHODS: Neonates born >=32 weeks postmenstrual age received either tramadol [T] 2 mg.kg(-1) or placebo [P] 6 hourly for up to 5 days postthoracoabdominal surgery in addition to morphine (commenced at 20 mcg.kg(-1) .h(-1)) and 6-hourly i.v. acetaminophen. Time to extubation, morphine and midazolam amounts, hourly pain scores, and seizure activity were compared using an intention-to-treat and per-protocol analysis. RESULTS: Seventy-one neonates participated. Median survival time to extubation was similar between the groups (T 67 h [95% CI 51, 84] vs P 52 h [95%CI 43, 65]; P = 0.4), and similar numbers were extubated by 96 h (T 69% vs P 77%; difference 8%, 95%CI -28, 13%). Morphine and midazolam exposure was similar, with low pain scores in both groups (mean percentage of time with a pain score >5/20 during the 5 days: T 13% vs P 11%, difference in means 2.8 [95% CI -1.8, 7.6], P = 0.20). Most participants had normal cranial ultrasounds (T 86% vs P 86%); no seizures occurred clinically or electroencephalographically. CONCLUSION: Tramadol's addition to standard analgesia in this small group of postsurgical neonates did not appear to have any positive effect on time to extubation, morphine or midazolam exposure, or pain scores. This questions the benefit of tramadol for postsurgical neonates. Importantly, no seizures occurred in these ill neonates who may potentially be at greater risk of tramadol toxicity compared with adults. PMID- 25040757 TI - Au transport in catalyst coarsening and Si nanowire formation. AB - The motion of Au between AuSi liquid eutectic droplets, both before and during vapor-liquid-solid growth, is important in controlling tapering and diameter uniformity in Si nanowires. We measure the kinetics of coarsening of AuSi droplets on Si(001) and Si(111), quantifying the size evolution of droplets during annealing in ultrahigh vacuum using in situ transmission electron microscopy. For individual droplets, we show that coarsening kinetics are modified when disilane or oxygen is added: coarsening rates increase in the presence of disilane but decrease in oxygen. Matching droplet size measurements on Si(001) with coarsening models confirms that Au transport is driven by capillary forces and that the kinetic coefficients depend on the gas environment present. We suggest that the gas effects are qualitatively similar whether transport is attachment limited or diffusion limited. These results provide insight into manipulating nanowire morphologies for advanced device fabrication. PMID- 25040758 TI - Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88 dependent and interleukin-1-dependent pathway. AB - BACKGROUND: Several attempts to establish a model in mice that reflects nickel allergy in humans have been made. Most models use intradermal injection of nickel in combination with adjuvant to induce nickel allergy. However, such models poorly reflect induction of nickel allergy following long-lasting epicutaneous exposure to nickel. OBJECTIVE: To develop a mouse model reflecting nickel allergy in humans induced by epicutaneous exposure to nickel, and to investigate the mechanisms involved in such allergic responses. METHODS: Mice were exposed to NiCl2 on the dorsal side of the ears. Inflammation was evaluated by the swelling and cell infiltration of the ears. T cell responses were determined as numbers of CD4+ and CD8+ T cells in the draining lymph nodes. Localization of nickel was examined by dimethylglyoxime staining. RESULTS: Epicutaneous exposure to nickel results in prolonged localization of nickel in the epidermis, and induces nickel allergy in mice. The allergic response to nickel following epicutaneous exposure is MyD88-dependent and interleukin (IL)-1 receptor-dependent, but independent of toll-like receptor (TLR)-4. CONCLUSION: This new model for nickel allergy that reflects epicutaneous exposure to nickel in humans shows that nickel allergy is dependent on MyD88 and IL-1 receptor signalling, but independent of TLR4. PMID- 25040760 TI - Editorial: Defining, profiling and locating older people: an inner city Afro Caribbean experience. PMID- 25040759 TI - Cutaneous lesions of Kikuchi's disease: evolution of histopathological findings. AB - We report a 38-year-old male patient who presented with cutaneous lesions mimicking widespread discoid lupus erythematosus with high-grade fever, arthralgia and lymphadenopathy. Additional lymph node and skin biopsies, however, revealed karyorrhectic debris without neutrophils and numerous CD68-positive cells, a characteristic finding of Kikuchi's disease (KD). Comparing skin biopsies on different occasions, we could see different forms of histopathology. The histopathology of skin lesions of KD may vary during the clinical course, which may reflect the stage of the disease. PMID- 25040761 TI - Sexuality of postinfarction patients: diagnosis, results and nursing intervention. AB - AIMS AND OBJECTIVES: To identify the main nursing diagnosis and to analyse and select the appropriate outcomes and interventions for postinfarction patients. BACKGROUND: After a cardiac event, few patients resume their sexual life with the same intensity and frequency they used to have, and some patients do not even do it. Doubtful and insecure reactions are observed in both patients/partners and health professionals. These behaviours are frequently taboos and preconceptions about sexuality which are still taken as real among us. DESIGN: Exploratory study. METHODS: Integrative literature review with online search on the Virtual Health Library (BVS) and websites. The most relevant diagnosis in the general literature was compared with International Classification for Nursing Practice and North-American International Nursing Diagnosis Association. The outcomes were selected from Nursing Outcome Classification, and the interventions and activities were based on the general literature and Nursing Intervention Classification. RESULTS: Sexual dysfunction was the most relevant diagnosis described in the general literature. The characteristics and related factors were specified in patient's/their partner's verbalisation of the physical difficulties in having sexual activity and in their social and emotional reactions to the disease and to the prescribed medicine. The selected priority results were sexuality and knowledge on sexuality. The counselling intervention was chosen as the most appropriate. CONCLUSION: It was possible to get to the wide understanding of the sexual dysfunction as a nursing diagnosis expressed in the daily routine of the care to the postinfarction patient. Its identification requires knowledge and abilities to acknowledge its characteristics and related factors, which served as support for selection of outcomes, interventions and nursing activities. RELEVANCE TO CLINICAL PRACTICE: Association between diagnosis, outcomes, interventions and nursing activities established for the postinfarction patient is strategic so as to guide the nurses who operate in the cardiovascular area and may contribute towards refinement of the nursing classifications. PMID- 25040762 TI - Commentary on Levett-Jones T and Lathlean J (2009) The Ascent to Competence conceptual framework: an outcome of a study of belongingness. Journal of Clinical Nursing 18, 2870-2879. PMID- 25040763 TI - Commentary on Horsburgh D and Ross J (2013) Care and compassion: experiences of newly qualified staff nurses. Journal of Clinical Nursing 22, 1124-1132. PMID- 25040764 TI - Can mobile technology improve treatment of chronic pain? PMID- 25040765 TI - Response to Letter to the Editor: Are Bovine-Derived Bone Graft Materials Safe? PMID- 25040766 TI - Gingival bleeding on probing: relationship to change in periodontal pocket depth and effect of sodium hypochlorite oral rinse. AB - BACKGROUND AND OBJECTIVE: This study evaluated the potential of gingival bleeding on probing to serve as a predictor of future periodontal breakdown. It also assessed the ability of 0.25% sodium hypochlorite twice-a-week oral rinse to convert periodontal pockets showing bleeding on probing to nonbleeding sites. MATERIAL AND METHODS: The study was performed as a randomized, single-blinded, clinical trial in parallel groups. Seven periodontitis patients rinsed twice weekly for 3 mo with 15 mL of a fresh solution of 0.25% sodium hypochlorite, and five periodontitis patients rinsed with water. The 12 study patients received no subgingival or supragingival scaling. Clorox((r)) Regular-Bleach was the source of sodium hypochlorite. At baseline and 3-mo visits, gingival bleeding was assessed within 30 s after probing to full pocket depth using an approximate force of 0.75 N. RESULTS: A total of 470 (38%) of 1230 periodontal pockets in the bleach-rinse group revealed bleeding on probing at the initial visit but not at the 3-mo visit; only 71 (9%) of 828 pockets in the control group became bleeding negative during the study (p < 0.001). Bleeding on probing in 4- to 7-mm-deep pockets decreased by 53% in the bleach-rinse group but increased by 6% in the water-rinse group (p < 0.001). Ninety-seven pockets showed depth increases of >= 2 mm after 3 mo: 60 (62%) of those pockets exhibited bleeding on probing at both the initial and the 3-mo visits; 24 (25%) bled at only one of the two visits; and 13 (13%) never demonstrated gingival bleeding (p < 0.001). CONCLUSIONS: Persistent gingival bleeding on probing was associated with an increased risk for periodontal breakdown, and the absence of gingival bleeding seemed to be a useful, although not perfect, indicator of disease stability. Twice-weekly oral rinsing with dilute bleach (0.25% sodium hypochlorite) produced a significant reduction in bleeding on probing, even in deep unscaled pockets. Sodium hypochlorite constitutes a valuable antiseptic in periodontal self-care. PMID- 25040767 TI - Post-introduction observation of transcatheter aortic valve implantation in Galicia (Spain). AB - RATIONALE, AIMS AND OBJECTIVES: Transcatheter aortic valve implantation constitutes an example of a technology introduced into the Galician Health Care System basket and subjected to a post-introduction observational study after coverage. This paper aims to describe the process and results of this experience, illustrating the main challenges and opportunities in using these studies for supporting decision making. METHODS: The study protocol was developed by a multidisciplinary team consisting of experts from the Galician HTA Agency (avalia t), interventional cardiologists and cardiac surgeons. Together they agreed on the information that was relevant and feasible for collection, and planned the study design, data collection and analysis of results. RESULTS: During the 1-year recruitment period, 94 patients underwent percutaneous aortic valve replacement in the three authorized centres. Implantation rate and prosthesis models differed substantially across the centres. Overall, procedural success rate was 96.8% and hospital mortality was 7.4%. Complications during post-surgical admission were recorded in 40.4% of patients. Moderate residual aortic regurgitation was observed in 10% of patients, and the procedure was associated with a stroke rate of 3.3% at 30 days and 5.3% at 1 year. CONCLUSIONS: Post-introduction observation has made it feasible to determine the use of this procedure within the SERGAS context and has enabled the assessment of performance in real-life conditions. The proposed strategic actions and interventions have been drawn up based upon the collective judgement of a group of experienced professionals, and have served to establish recommendations on further research that would be required to optimize health benefits. PMID- 25040768 TI - Mixed-methods study identifies key strategies for improving infant and young child feeding practices in a highly stunted rural indigenous population in Guatemala. AB - Guatemala's rural indigenous population suffers from one of the highest rates of chronic child malnutrition (stunting) in the world. Successfully addressing stunting requires defining the barriers to and opportunities for new behaviour change initiatives. We undertook a mixed-methods assessment of feeding practices and food purchasing behaviours around infants and young children aged 6-36 months in two rural indigenous Guatemalan communities. We found that most caregivers were aware only of acute forms of child malnutrition and that they greatly underestimated the local prevalence of malnutrition. Despite moderate adherence to exclusive breastfeeding and timing of complementary food introduction, diets had poor diversity and inadequate meal frequency. Furthermore, perceptions of food insecurity were high even in the presence of land ownership and agricultural production. Although fortified foods were highly valued, they were considered expensive. At the same time, proportionally equivalent amounts of money were spent on junk foods or other processed foods by most participants. Biological mothers often lacked autonomy for food purchasing and nutritional decisions because of the power exerted by husbands and paternal grandmothers. Our findings suggest several creative and community-based programming initiatives including education about the acute vs. chronic malnutrition distinction, engaging landowners in discussions about domestic food consumption, engaging with caregivers to redirect funds towards fortified foods rather than junk food purchases and directing behaviour-change initiatives towards all household stakeholders. PMID- 25040769 TI - Effect of sorghum grain supplementation on glucose metabolism in cattle and sheep fed temperate pasture. AB - The aim of this work was to evaluate the effect of sorghum grain supplementation on plasma glucose, insulin and glucagon concentrations, and hepatic mRNA concentrations of insulin receptor (INSR), pyruvate carboxylase (PC), and phosphoenolpyruvate carboxykinase (PCK1) mRNA and their association with nutrient intake, digestion and rumen volatile fatty acids (VFA) in cattle and sheep fed a fresh temperate pasture. Twelve Hereford * Aberdeen Angus heifers and 12 Corriedale * Milchschaf wethers in positive energy balance were assigned within each species to one of two treatments (n = 6 per treatment within specie): non supplemented or supplemented with sorghum grain at 15 g/kg of their body weight (BW). Supplemented cattle had greater plasma glucose concentrations, decreased plasma glucagon concentrations and tended to have greater plasma insulin and insulin-to-glucagon ratio than non-supplemented ones. Hepatic expression of INSR and PC mRNA did not differ between treatments but PCK1 mRNA was less in supplemented than non-supplemented cattle. Supplemented sheep tended to have greater plasma glucagon concentrations than non-supplemented ones. Plasma glucose, insulin, insulin-to-glucagon ratio, and hepatic expression of INSR and PC mRNA did not differ between treatments, but PCK1 mRNA was less in supplemented than non-supplemented sheep. The inclusion of sorghum grain in the diet decreased PCK1 mRNA but did not affect PC mRNA in both species; these effects were associated with changes in glucose and endocrine profiles in cattle but not in sheep. Results would suggest that sorghum grain supplementation of animals in positive energy balance (cattle and sheep) fed a fresh temperate pasture would modify hepatic metabolism to prioritize the use of propionate as a gluconeogenic precursor. PMID- 25040770 TI - An overview of the role of society and risk in xenotransplantation. AB - BACKGROUND: Over time, the notion of public has evolved. While the concept of public was initially conceived of as a single undifferentiated entity, the common understanding is now that a variety of differentiated, multifaceted and multiple public(s) can be constructed for different purposes. This is equally true in xenotransplantation; the literature shows how different kind of publics can be introduced as relevant. The paper explores the notion of public and the contemporary participatory procedures as participatory rights for citizens in decisions concerning technoscience and society. Its perspective, thus, is normative; namely, it aims at understanding how the political role of citizens is changing in democratic societies where matters of innovation are concerned. It is focused on xenotransplantation whose connections with public discourse and practices are quite paradigmatic among new emerging biomedical technologies, due to its peculiar risks. METHODS AND RESULTS: The paper reviews the historical background of risk communication and public involvement in science-based decision making and provides an overview of the current roles and meanings of deliberative procedures in xenotransplantation. After a short discussion of the history of the social implementation of xenotransplantation, the construction of the different publics dealing with this biomedical technology is briefly analysed. Publics have been firstly conceived of as objects of research, which has looked at them to quantify people's positive and negative attitudes towards xenotransplantation. Further developments have led to the notion of the public as composed of citizens, empowered as subjects of decisions. In both Canadian and Australian consultations, citizens were engaged in a complex learning process aimed at committing them to a decision. Despite the fact both public consultations represented important forms of experimental democracy, they were still focused on seeking consensus and assessing compliance from citizens. New Zealand is the most recent example of public consultation in xenotransplantation. Likewise, several public consultations have recently been launched by the European Commission on Advanced Therapies. Unlike in the Canadian and Australian cases, the latter initiatives aimed to reach only certain parts of the population, and the overall consultations were prepared to seek approval. CONCLUSIONS: Several categories of individuals may be interesting and interested publics in xenotransplantation. This is a field in which the importance of the potential risks that xenotransplants pose to society has been widely discussed. The point is that publics should not only be educated about the risk but should be given an opportunity to participate actively in the decision about whether and under what conditions they are exposed to the risk. Likewise, the boundaries between surveys, consultations and collection of advice may be blurred in actual practices. The hope remains that all different instruments either to collect or disseminate knowledge, and to explore new tools of governance may help connect science and policy to society in deeper and more complex ways. The next step points to a different meaning of public participation. It is shifting from participation as mere consensus and risk acceptance, to public engagement as a form of shared responsibility for risk control and regulatory decision-making. PMID- 25040771 TI - Translation of obesity practice guidelines: interprofessional perspectives regarding the impact of public health nurse system-level intervention. AB - OBJECTIVE: The purpose of the study was to investigate the perceptions of administrators and clinicians regarding a public health facilitated collaborative supporting the translation into practice of the Institute for Clinical Systems Improvement (ICSI) Adult Obesity Guideline. DESIGN AND SAMPLE: This qualitative study was conducted with 10 health care organizations participating in a voluntary, interprofessional obesity management collaborative. A purposive sample of 39 participants included two to three clinicians and an administrator from each organization. Interview analysis focused on how the intervention affected participants and their practices. RESULTS: Four themes described participant experiences of obesity guideline translation: (1) a shift from powerlessness to positive motivation, (2) heightened awareness coupled with improved capacity to respond, (3) personal ownership and use of creativity, and (4) a sense of the importance of increased interprofessional collaboration. CONCLUSIONS: The investigation of interprofessional perspectives illuminates the feelings and perceptions of clinician and administrator participants regarding obesity practice guideline translation. These themes suggest that positive motivation, improved capacity, personal creative ownership, and interprofessional collaboration may be conducive to successful evidence-based obesity guideline implementation. Further research is needed to evaluate these findings relative to translating the ICSI obesity guideline and other guidelines into practice in diverse clinical settings. PMID- 25040772 TI - Prognostic features in mucoepidermoid carcinoma of major salivary glands with emphasis on tumour histologic grading. AB - AIMS: To compare the different grading systems of mucoepidermoid carcinoma (MEC) and identify the most reliable and objective histopathologic features predictive of outcome. METHODS AND RESULTS: Seventy-two cases diagnosed as MEC were subjected to a meticulous histopathologic re-review. 20 of 72 (28%) cases were originally misdiagnosed as MEC including 16 as high grade (HG). Among the 52 confirmed MEC, median follow up (FU) was 59 months. Mitosis (>=4/10 High Power Fields), necrosis, pleomorphism, focal keratinization, desmoplasia, and lymph node metastasis were associated with adverse disease specific survival (DSS) and recurrence free survival (RFS) (P < 0.002). In all grading systems, low and intermediate grade had similar DSS and RFS but much better outcome than HG (P < 0.007). All patients with tumour harboring low mitotic rate and no necrosis did not recur except for one patient with a positive margin. All cases with high mitotic rate and necrosis died or recurred. CONCLUSIONS: The majority of previously diagnosed HG MEC cases are misclassified. There is no difference in outcome between low and intermediate grade in all grading schemes. Consideration should be given to stratify MEC based on relatively objective criteria such as mitosis and necrosis. PMID- 25040773 TI - Towards safer and appropriate application of endoscopic submucosal dissection for T1 colorectal carcinoma as total excisional biopsy: future perspectives. AB - According to the Japanese Society for Cancer of the Colon and Rectum Guidelines 2014 for the Treatment of Colorectal Cancer, cases with T1 colorectal carcinoma should be considered for additional colectomy with lymph node dissection when histologically complete en bloc resection is endoscopically carried out and when one of the four risk factors listed below is present. These four risk factors are: (i) submucosal (SM) invasion depth >=1000 MUm; (ii) positive vascular invasion; (iii) poorly differentiated adenocarcinoma, signet ring cell carcinoma, or mucinous carcinoma; and (iv) grade 2/3 budding at the deepest part of SM invasion. However, the probability of lymph node metastasis is extremely low if none of these risk factors are present, with the exception of SM invasion depth >=1000 MUm. Consequently, it is assumed that there will be an increasing number of cases where no additional surgery is done, or cases of moderate invasive carcinoma in which endoscopic treatment is carried out to achieve an excisional biopsy, for which complete resection is applicable. In these cases, the preoperative diagnosis, resection techniques such as endoscopic submucosal dissection, features of resected specimens, and the accuracy of pathological diagnosis are all extremely important. PMID- 25040774 TI - Validity of pre-eclampsia registration in the medical birth registry of norway for women participating in the norwegian mother and child cohort study, 1999 2010. AB - BACKGROUND: The Norwegian Mother and Child Cohort Study (MoBa), a prospective population-based pregnancy cohort, is a valuable database for studying causes of pre-eclampsia. Pre-eclampsia data in MoBa come from the Medical Birth Registry of Norway (MBRN); thus, we wanted to study the validity of MBRN pre-eclampsia registration for MoBa women. METHODS: We selected all MoBa pregnancies with pre eclampsia registered in the MBRN (n = 4081) and a random control group (n = 2000) without pre-eclampsia registrations. After excluding two delivery units not participating in MoBa and one no longer operating, units were asked to provide copies of antenatal charts with blood pressure and urinary measurements from all antenatal visits during pregnancy, and hospital discharge codes from the delivery stay. We received data for 5340 pregnancies delivered 1999-2010 (87% of all eligible). We calculated positive predictive value (PPV), and sensitivity and specificity of MBRN registration, using hypertension and proteinuria on the antenatal charts and/or hospital discharge codes indicating pre-eclampsia as gold standard. RESULTS: Overall PPV was 83.9% [95% CI 82.7, 85.1] and was higher when women were primiparous, or delivered preterm or low birthweight infants. Severe pre-eclampsia in the MBRN was found to be a true severe pre-eclampsia in 70% of cases. Extrapolating to the total MoBa population, the estimated sensitivity was low - 43.0% (38.7, 48.2) - while specificity was high - 99.2% (99.2, 99.3). False negative cases seemed to have mild forms of pre-eclampsia. CONCLUSIONS: PPV and specificity of pre-eclampsia registration in the MBRN during 1999-2010 was satisfactory, while sensitivity was low. PMID- 25040775 TI - Telomere shortening over 6 years is associated with increased subclinical carotid vascular damage and worse cardiovascular prognosis in the general population. AB - INTRODUCTION: Leucocyte telomere length (LTL) is an important determinant of telomere function and cellular replicative capacity. The aim of the present study was to examine prospectively the associations between telomere shortening (TS) and both the progression of atherosclerosis and the incidence of cardiovascular events (CVEs). MATERIALS AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction to determine the ratio of telomere length to single-copy gene (T/S) in 768 subjects (462 female and 306 male) enrolled in a large general population survey [the Progressione della Lesione Intimale Carotidea (PLIC study)]. Common carotid artery intima-media thickness was determined at baseline and after 6 years of follow-up, and the associations between TS and the progression of atherosclerosis and incidence of CVEs were evaluated. RESULTS: Mean LTL was 1.25 +/- 0.92 T/S (median 1.14) at baseline and 0.70 +/- 0.37 T/S (median 0.70) after 6 years of follow-up. Median 6-year LTL change was -0.46 T/S [interquartile range (IQR) -0.57 to 1.06], equating to 0.078 T/S [IQR(-0.092 to 0.176)] per year. Of note, telomere lengthening occurred in 30.4% of subjects. After adjustment for classical cardiovascular disease (CVD) risk factors (age, gender, smoking, physical activity, alcohol consumption, systolic blood pressure, glucose levels, lipid profile and therapies), TS was associated with incident subclinical carotid vascular damage [hazard ratio (HR) 5.19, 95% confidence interval (CI) 1.20-22.4, P = 0.028]. Finally, subjects in whom LTL shortened over time showed an increased risk of incident CVE, compared to those in whom LTL lengthened (HR 1.69, CI 1.02-2.78, P = 0.041). CONCLUSION: These data indicate that TS is associated with increased risk of subclinical carotid vascular damage and increased incidence of CVEs beyond CVD risk factors in the general population, whereas LTL lengthening is protective. PMID- 25040776 TI - Do the same traffic rules apply? Directional chromosome segregation by SpoIIIE and FtsK. AB - Over a decade of studies have tackled the question of how FtsK/SpoIIIE translocases establish and maintain directional DNA translocation during chromosome segregation in bacteria. FtsK/SpoIIIE translocases move DNA in a highly processive, directional manner, where directionality is facilitated by sequences on the substrate DNA molecules that are being transported. In recent years, structural, biochemical, single-molecule and high-resolution microscopic studies have provided new insight into the mechanistic details of directional DNA segregation. Out of this body of work, a series of models have emerged and, ultimately, yielded two seemingly opposing models: the loading model and the target search model. We review these recent mechanistic insights into directional DNA movement and discuss the data that may serve to unite these suggested models, as well as propose future directions that may ultimately solve the debate. PMID- 25040777 TI - Fetal head-symphysis distance and mode of delivery in the second stage of labor. AB - OBJECTIVE: To evaluate whether the fetal head-symphysis distance measured by three-dimensional transperineal ultrasound during the active second stage predicts operative delivery. DESIGN: Prospective observational study. SETTING: University hospital, Bologna, Italy. POPULATION: Seventy-one nulliparous women at term in active second stage of labor. METHODS: We acquired a series of sonographic volumes at the beginning of the active second stage (T1) and every 20 min thereafter (T2, T3, T4, T5, T6) until delivery. All volumes were retrospectively analyzed and head-symphysis distance was measured for each acquisition. We compared head-symphysis distance between women with spontaneous vaginal delivery and those with operative delivery. Receiver operator characteristic curves were constructed to estimate the accuracy of head-symphysis distance in the prediction of operative delivery. Logistic regression was used to identify independent variables associated with operative delivery. MAIN OUTCOME MEASURES: Operative delivery (vacuum or cesarean). RESULTS: Of the women included, 81.7% had a spontaneous vaginal delivery and 18.3% underwent operative delivery. Women with spontaneous vaginal delivery had shorter head-symphysis distance than women in the operative delivery group at T1 (p < 0.001), T2 (p < 0.001) and T3 (p = 0.025), whereas no significant differences were recorded thereafter. Receiver operator characteristic curves revealed accuracy values of 81.0%, 87.9% and 77.6% in the prediction of operative delivery at T1, T2 and T3, respectively. At multivariate logistic regression head-symphysis distance and epidural analgesia were the only independent predictors of operative delivery among ultrasonographic, maternal and intrapartum variables. CONCLUSIONS: Ultrasonographic measurement of head-symphysis distance in the second stage of labor can be used to predict operative delivery. PMID- 25040778 TI - Gate control: guard cell regulation by microbial stress. AB - Terrestrial plants rely on stomata, small pores in the leaf surface, for photosynthetic gas exchange and transpiration of water. The stomata, formed by a pair of guard cells, dynamically increase and decrease their volume to control the pore size in response to environmental cues. Stresses can trigger similar or opposing movements: for example, drought induces closure of stomata, whereas many pathogens exploit stomata and cause them to open to facilitate entry into plant tissues. The latter is an active process as stomatal closure is part of the plant's immune response. Stomatal research has contributed much to clarify the signalling pathways of abiotic stress, but guard cell signalling in response to microbes is a relatively new area of research. In this article, we discuss present knowledge of stomatal regulation in response to microbes and highlight common points of convergence, and differences, compared to stomatal regulation by abiotic stresses. We also expand on the mechanisms by which pathogens manipulate these processes to promote disease, for example by delivering effectors to inhibit closure or trigger opening of stomata. The study of pathogen effectors in stomatal manipulation will aid our understanding of guard cell signalling. PMID- 25040779 TI - When first language is not first: an functional magnetic resonance imaging investigation of the neural basis of diglossia in Arabic. AB - In Arabic, the language used for everyday conversation ('spoken Arabic' - SA) differs markedly from literary Arabic (LA), which is used for written communication and formal functions. This fact raises questions regarding the cognitive status of the two varieties and their processing in the brain. Previous studies using auditory stimuli suggested that LA is processed by Arabic native speakers as a second language. The current study examined this issue in the visual modality. Functional magnetic resonance imaging (fMRI) responses were collected while Arabic-Hebrew bilinguals performed a semantic categorization task on visually presented words in LA, SA and Hebrew. Performance on LA was better than SA and Hebrew, which did not differ from each other. Activation in SA was stronger than in LA in left inferior frontal, precentral, parietal and occipito temporal regions, and stronger than in Hebrew in left precentral and parietal regions. Activation in SA was also less lateralized than activation for LA and Hebrew, which did not differ from each other in terms of lateralization, though activation for Hebrew was more extensive in both hemispheres than activation for LA. Altogether, these results indicate an advantage for LA in the current study, presumably due to participants' proficiency in reading in this language. Stronger activation for SA appears to be due to the relative unfamiliarity of written word forms in SA, which could also explain differences in performance between the two languages. However, the stronger activation observed in the left parietal cortex may also reflect stronger associations among words in SA. PMID- 25040780 TI - Achondroplasia and brain stem dysfunction. PMID- 25040781 TI - Residents' willingness-to-pay for attributes of rural health care facilities. AB - CONTEXT: As today's rural hospitals have struggled with financial sustainability for the past 2 decades, it is critical to understand their value relative to alternatives, such as rural health clinics and private practices. PURPOSE: To estimate the willingness-to-pay for specific attributes of rural health care facilities in rural Kentucky to determine which services and operational characteristics are most valued by rural residents. METHODOLOGY: We fitted choice experiment data from 769 respondents in 10 rural Kentucky counties to a conditional logit model and used the results to estimate willingness-to-pay for attributes in several categories, including hours open, types of insurance accepted, and availability of health care professionals and specialized care. FINDINGS: Acceptance of Medicaid/Medicare with use of a sliding fee scale versus acceptance of only private insurance was the most valued attribute. Presence of full diagnostic services, an emergency room, and 24-hour/7-day-per-week access were also highly valued. Conversely, the presence of specialized care, such as physical therapy, cancer care, or dialysis, was not valued. In total, respondents were willing to pay $225 more annually to support a hospital relative to a rural health clinic. CONCLUSION: Rural Kentuckians value the services, convenience, and security that rural hospitals offer, though they are not willing to pay more for specialized care that may be available in larger medical treatment centers. The results also inform which attributes might be added to existing rural health facilities to make them more valuable to local residents. PMID- 25040782 TI - Reducing the strain of dermatological surgery. PMID- 25040783 TI - Multicentric reticulohistiocytosis misdiagnosed as rheumatoid arthritis. PMID- 25040784 TI - Reducing occupational sedentary time: a systematic review and meta-analysis of evidence on activity-permissive workstations. AB - Excessive sedentary time is detrimentally linked to obesity, type 2 diabetes, cardiovascular disease and premature mortality. Studies have been investigating the use of activity-permissive workstations to reduce sedentary time in office workers, a highly sedentary target group. This review systematically summarizes the evidence for activity-permissive workstations on sedentary time, health-risk biomarkers, work performance and feasibility indicators in office workplaces. In July 2013, a literature search identified 38 relevant peer-reviewed publications. Key findings were independently extracted by two researchers. The average intervention effect on sedentary time was calculated via meta-analysis. In total, 984 participants across 19 field-based trials and 19 laboratory investigations were included, with sample sizes ranging from n = 2 to 66 per study. Sedentary time, health-risk biomarkers and work performance indicators were reported in 13, 23 and 23 studies, respectively. The pooled effect size from the meta-analysis was -77 min of sedentary time/8-h workday (95% confidence interval = -120, -35 min). Non-significant changes were reported for most health- and work-related outcomes. Studies with acceptability measures reported predominantly positive feedback. Findings suggest that activity-permissive workstations can be effective to reduce occupational sedentary time, without compromising work performance. Larger and longer-term randomized-controlled trials are needed to understand the sustainability of the sedentary time reductions and their longer-term impacts on health- and work-related outcomes. PMID- 25040785 TI - mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. AB - The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (mTOR) kinase is important in growth, disease, and aging and is present in the mTORC1 and mTORC2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of mTORC1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about mTORC2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. mTORC2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK-1 kinase, but current data on SGK-1 and lifespan seem to be conflicting. Here, by analyzing the mTORC2 component Rictor (RICT-1), we show that mTORC2 modulates longevity by activating SGK-1 in two pathways that affect lifespan oppositely. RICT-1/mTORC2 limits longevity by directing SGK-1 to inhibit the stress-response transcription factor SKN-1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN-1 and lifespan. In addition, RICT-1/mTORC2 functions in neurons in an SGK-1-mediated pathway that increases lifespan at lower temperatures. RICT-1/mTORC2 and SGK-1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK-1 and aging, show that the bacterial microenvironment influences SKN-1/Nrf, mTORC2 functions, and aging, and identify two longevity-related mTORC2 functions that involve SGK-regulated responses to environmental cues. PMID- 25040786 TI - The role of personal and key resources in the family-to-work enrichment process. AB - Based on the work-home resources model, the aim of the present research was to test a process model of family-to-work enrichment by examining whether self efficacy (i.e., personal resource) mediates the relationship between support from one's family and work engagement. Further, it was assumed that positive affectivity (i.e., key resource) moderates the relation between family support and self-efficacy. Using an occupationally heterogeneous sample of Slovenian employees (n = 738), we found support for a mediating effect of self-efficacy as well as for the moderating role of positive affectivity. In general, our results broaden the understanding of work-family enrichment processes and provide support for the work-home resources model. In addition, they point to the relevant role of personal and key resources in work-family interactions. PMID- 25040787 TI - Is Nox4 a key regulator of the activated state of fibroblasts in systemic sclerosis? AB - The family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases consists of phagocytic gp91(phox) and six-related isoforms. Recent evidence indicates that the NADPH oxidase isoform Nox4 controls vascular, renal and pulmonary injury. We propose that Nox4 is an intrinsic regulator of the activated state of dermal fibroblasts in systemic sclerosis (SSc). Profibrotic cytokines on the one hand and antifibrogenic factors such as alpha-melanocyte-stimulating hormone on the other hand may target Nox4 as an intracellular nodal point. Via increased or decreased generation of reactive oxygen species and/or hydrogen peroxide, Nox4 could orchestrate collagen synthesis, differentiation of dermal fibroblasts into a profibrotic myofibroblast phenotype and thus dermal fibrosis. Confirmation of this hypothesis will have important consequences in our understanding of the activated state of dermal fibroblasts in SSc. Based on the availability of clinically useful Nox4 inhibitors, novel antifibrotic therapies of SSc can be envisioned. PMID- 25040788 TI - Training preschoolers on first-order false belief understanding: transfer on advanced ToM skills and metamemory. AB - This study investigated the relation between theory of mind (ToM) and metamemory knowledge using a training methodology. Sixty-two 4- to 5-year-old children were recruited and randomly assigned to one of two training conditions: A first-order false belief (ToM) and a control condition. Intervention and control groups were equivalent at pretest for age, parents' education, verbal ability, inhibition, and ToM. Results showed that after the intervention children in the ToM group improved in their first-order false belief understanding significantly more than children in the control condition. Crucially, the positive effect of the ToM intervention was stable over 2 months and generalized to more complex ToM tasks and metamemory. PMID- 25040789 TI - Combining animal movements and behavioural data to detect behavioural states. AB - Animal movement paths show variation in space caused by qualitative shifts in behaviours. I present a method that (1) uses both movement path data and ancillary sensor data to detect natural breakpoints in animal behaviour and (2) groups these segments into different behavioural states. The method can also combine analyses of different path segments or paths from different individuals. It does not assume any underlying movement mechanism. I give an example with simulated data. I also show the effects of random variation, # of states and # of segments on this method. I present a case study of a fisher movement path spanning 8 days, which shows four distinct behavioural states divided into 28 path segments when only turning angles and speed were considered. When accelerometer data were added, the analysis shows seven distinct behavioural states divided into 41 path segments. PMID- 25040790 TI - Norovirus infection in immunocompromised hosts. AB - Acute gastroenteritis caused by noroviruses often has a duration of 2-3 days and is characteristically self-limiting. In contrast, chronic infection caused by noroviruses in immunocompromised individuals can last from weeks to years, making clinical management difficult. The mechanisms by which noroviruses establish persistent infection, and the role of immunocompromised hosts as a reservoir for noroviruses in the general human population, are not known. However, study of this patient cohort may lead to new insights into norovirus biology and approaches to treatment. PMID- 25040791 TI - Clinical utility of complement biomarkers in the diagnosis and treatment of acute thrombotic microangiopathies. PMID- 25040792 TI - Ultrasound in preoperative evaluation for dialysis-access placement. AB - US vessel mapping for vascular access creation has evolved as standard practice in the preoperative evaluation of an ESRD patient. The best yield from this technology is when it is used to compliment physical examination and viewed in realtime by the operating physician. It is important to evaluate both arterial and venous systems during vessel mapping. While minimum diameters have been associated with an increased chance of maturation of an AV access, the quality of the vessel wall also plays an important role in maturation. US has a distinct advantage of being a noninvasive modality that can evaluate both structural and functional aspects of vessels that play an important role in access maturation. PMID- 25040793 TI - The mini-mental state examination, clinical factors, and motor vehicle crash risk. AB - OBJECTIVES: To examine the association between Mini-Mental State Examination (MMSE) score and motor vehicle crash (MVC) risk in a large cohort of community dwelling participants with cardiovascular disease (CVD) or diabetes mellitus. DESIGN: Prospective observational study. SETTING: Participants enrolled in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease clinical trial, which included individuals aged 55 and older with CVD or diabetes mellitus. PARTICIPANTS: Totally 17,538 frequent drivers (defined as driving at least once per week) who had completed a baseline MMSE. MEASUREMENTS: Involvement in a MVC as the driver. RESULTS: Baseline MMSE score was divided into four categories: 30, 27-29, 24-26, and <24. The median MMSE score was 29 (interquartile range 27-30), and 726 (4.1%) has a MMSE score of less than 24 at baseline. After a mean follow-up of 4.5 years, 1,068 (6.1%) participants were drivers in a MVC. Lower scores were not associated with future MVCs (MMSE score 29-27, hazard ratio (HR)=1.06, 95% confidence interval (CI)=0.93 1.22); MMSE score 26-24, HR=0.96, 95% CI=0.78-1.19; MMSE score<24, HR=0.72, 95% CI=0.50-1.05) on multivariable analysis. A MVC within the previous 2 years (HR=2.68, 95% CI=2.29-3.13) was the strongest predictor of future MVCs. Other clinical factors associated with greater MVC risk were depression, falls within the previous year, sleep apnea, and lower baseline systolic blood pressure. CONCLUSION: In a population of frequent drivers, the MMSE does not predict MVCs. Other clinical factors have a stronger association with MVC risk. PMID- 25040794 TI - TET2 as an epigenetic master regulator for normal and malignant hematopoiesis. AB - DNA methylation is one of the critical epigenetic modifications regulating various cellular processes such as differentiation or proliferation, and its dysregulation leads to disordered stem cell function or cellular transformation. The ten-eleven translocation (TET) gene family, initially found as a chromosomal translocation partner in leukemia, turned out to be a key enzyme for DNA demethylation. TET genes hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, which is then converted to unmodified cytosine through multiple mechanisms. Somatic mutations of the TET2 gene were reported in a variety of human hematological malignancies such as leukemia, myelodysplastic syndrome, and malignant lymphoma, suggesting a critical role for TET2 in hematopoiesis. The importance of the TET-mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (IDH1) and IDH2 in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2-hydroxyglutarate. Studies using mouse models revealed that TET2 is critical for the function of hematopoietic stem cells, and disruption of TET2 results in the expansion of multipotent as well as myeloid progenitors, leading to the accumulation of premalignant clones. In addition to cytosine demethylation, TET proteins are involved in chromatin modifications and other cellular processes through the interaction with O-linked beta-N-acetylglucosamine transferase. In summary, TET2 is a critical regulator for hematopoietic stem cell homeostasis whose functional impairment leads to hematological malignancies. Future studies will uncover the whole picture of epigenetic and signaling networks wired with TET2, which will help to develop ways to intervene in cellular pathways dysregulated by TET2 mutations. PMID- 25040795 TI - Lymphadenectomy with radical cystectomy at an Australian tertiary referral institution: time trends and impact on oncological outcomes. AB - BACKGROUND: Lymph node dissection (LND) with radical cystectomy (RC) for surgical treatment of invasive urothelial carcinoma of the bladder can improve staging and has possible therapeutic benefit. The aim of this study was to assess utilization and extent of LND with RC at our institution and determine its impact on oncological outcomes. METHODS: Using surgical databases and hospital coding, clinical and histopathological characteristics of 87 patients who underwent RC at Austin Health between 2004 and 2011 were retrospectively analysed. Associations of predictor variables with LND use and lymph node (LN) status were analysed using logistic regression. Survival analyses were undertaken using Cox proportional hazard models. RESULTS: Fifty-eight (65.9%) patients underwent LND, with a clear trend over time in the proportion of patients undergoing LND (three of seven in 2004 up to 10 of 10 in 2011, P < 0.001) and the median (range) of LN yield from five (2-19) in 2004 to 18 (7-35) in 2011 (P < 0.001). Year of treatment was the only significant predictor (univariately and multivariately) of a patient undergoing LND. Multivariately, a significant association with nodal metastases was found for cN stage and planned extent of LND preoperatively, and pT stage postoperatively. LN status was associated significantly with recurrence free survival with best outcomes in patients who were node-negative on a pelvic LND. A similar trend was seen for cancer-specific survival (P = 0.053). CONCLUSIONS: Over the study period, there was an increase in the use of pelvic LND and LN numbers retrieved during RC. LN status appears to impact on recurrence free survival, and possibly cancer-specific survival. PMID- 25040796 TI - Determinants of number-specific recall error of last menstrual period: a retrospective cohort study. AB - OBJECTIVE: To assess the digit preference for last menstrual period (LMP) dates, associated determinants and impact on obstetric outcome. DESIGN: Retrospective cohort study. SETTING: University medical centre (the Netherlands). POPULATION: Cohort of 24 665 LMP records and a subgroup of 4630 cases with known crown-rump length (CRL) measurement, and obstetric outcome. METHODS: Digit preference was determined by comparing the observed to expected counts of each day. Associated determinants were identified by multivariate regression analysis. Differences in obstetric outcome between LMP and CRL dating were analysed. MAIN OUTCOME MEASURES: (Non)deprived neighbourhood, cycle irregularity, certainty of LMP date, maternal age, smoking, body mass index, parity and ultrasound investigator. Preterm and post-term delivery. RESULTS: LMP digit preference for the first [odds ratio (OR), 1.28; 95% confidence interval (95% CI), 1.20-1.36], fifth (OR, 1.10; 95% CI, 1.03-1.17), 10th (OR, 1.17; 95% CI, 1.09-1.25), 15th (OR, 1.31; 95% CI, 1.23-1.40), 20th (OR, 1.22; 95% CI, 1.15-1.30) and 25th (OR, 1.08; 95% CI, 1.01 1.15) days of the month occurred more often than expected. Digit preference occurred more frequently in women living in a deprived neighbourhood (OR, 1.21; 95% CI, 1.06-1.39), with uncertain LMP (OR, 2.03; 95% CI, 1.63-2.52) or irregular cycle (OR, 1.24; 95% CI, 1.06-1.44). More post-term (>=42 weeks) deliveries (OR, 1.27; 95% CI, 1.05-1.54) were observed in LMP dating. This effect was larger in women with a digit preference (OR, 1.56; 95% CI, 1.03-2.37). CONCLUSIONS: LMP digit preference occurs more often in women living in deprived neighbourhoods, with uncertain LMP or an irregular cycle. LMP-dated pregnancies are associated with more post-term pregnancies. PMID- 25040797 TI - Encephalitis caused by human herpesvirus-6B in pancreas-after-kidney transplantation. AB - Human herpesvirus-6 (HHV-6) is a common pathogen among children, classically presenting with fever and rash that resolves without specific therapy. HHV-6 can be reactivated in the immunosuppressed patient. After bone marrow and solid organ transplantation, HHV-6 has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, myelitis, hepatitis, pneumonitis, and bone marrow suppression. However, HHV-6 encephalitis after pancreatic transplant has rarely been reported. Early diagnosis and treatment of HHV-6 encephalitis may be important for affected patients. We report the case of a 53 year-old pancreas-after-kidney transplant recipient who initially presented with high fever and confusion 3 weeks after operation. We managed to save the patient's life and preserve the pancreas graft function. We also review previously reported cases of HHV-6B encephalitis in solid organ transplant recipients. PMID- 25040798 TI - Ephrin-A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia. AB - Increasing evidence indicates that the Eph receptors and their ephrin ligands are involved in the regulation of interactions between neurons and astrocytes. Moreover, astrocytic ephrin-A3 reverse signaling mediated by EphA4 receptors is necessary for controlling the abundance of glial glutamate transporters. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. In the present study, we found that the EphA4 receptor and its ephrin-A3 ligand, which were distributed in neurons and astrocytes, respectively, in the hippocampus showed a coincident up regulation of protein expression in the early stage of ischemia. Application of clustered EphA4 decreased the expressions of astrocytic glutamate transporters together with astrocytic glutamate uptake capacity through activating ephrin-A3 reverse signaling. In consequence, neuronal loss was aggravated in the CA1 region of the hippocampus accompanied by impaired hippocampus-dependent spatial memory when clustered EphA4 treatment was administered prior to transient global ischemia. These findings indicate that EphA4-mediated ephrin-A3 reverse signaling is a crucial mechanism for astrocytes to control glial glutamate transporters and prevent glutamate excitotoxicity under pathological conditions. Astrocytic ephrin A3 reverse signaling mediated by EphA4 receptor is necessary for controlling the abundance of glial glutamate transporters under physiological conditions. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. We found EphA4-mediated ephrin-A3 reverse signaling to be a crucial mechanism for astrocytes to control glial glutamate transporters and protect hippocampal neurons from glutamate excitotoxicity under ischemic conditions, this cascade representing a potential therapeutic target for stroke. PMID- 25040800 TI - Sisyphean evolution in Darwin's finches. AB - The trajectory of speciation involves geographic isolation of ancestral populations followed by divergence by natural selection, genetic drift or sexual selection. Once started, the process may experience fits and starts, as sometimes diverging populations intermittently reconnect. In theory populations might cycle between stages of differentiation and never attain species status, a process we refer to as Sisyphean evolution. We argue that the six putative ground finch species (genus Geospiza) of the Galapagos Islands represent a dramatic example of Sisyphean evolution that has been confused with the standard model of speciation. The dynamic environment of the Galapagos, closely spaced islands, and frequent dispersal and introgression have prevented the completion of the speciation process. We suggest that morphological clusters represent locally adapted ecomorphs, which might mimic, and have been confused with, species, but these ecomorphs do not form separate gene pools and are ephemeral in space and time. Thus the pattern of morphological, behavioural and genetic variation supports recognition of a single species of Geospiza, which we suggest should be recognized as Darwin's ground finch (Geospiza magnirostris). We argue that instead of providing an icon of insular speciation and adaptive radiation, which is featured in nearly every textbook on evolutionary biology, Darwin's ground finch represents a potentially more interesting phenomenon, one of transient morphs trapped in an unpredictable cycle of Sisyphean evolution. Instead of revealing details of the origin of species, the mechanisms underlying the transient occurrence of ecomorphs provide one of the best illustrations of the antagonistic effects of natural selection and introgression. PMID- 25040799 TI - Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis. Tranexamic acid (TA) has been widely used in the treatment of these severe bleeds but with no properly designed trial. OBJECTIVES: To demonstrate the efficacy of TA in epistaxis in HHT patients and to explore its safety of use. PATIENTS/METHODS: A randomized, placebo-controlled, double-blind, cross-over trial was conducted. Participants were randomized to receive TA (3 g a day) then placebo or the opposite sequence. The main analysis compared intra-individual mean duration of epistaxis under TA vs. placebo on a log scale. The primary outcome was the mean duration of epistaxis per month, assessed with specific grids to be completed by participants. The number of epistaxis episodes was recorded as a secondary outcome. RESULTS: A total of 118 randomized patients contributed to the statistical analysis. The mean duration of epistaxis per month was significantly shorter with TA than placebo (0.19 on the log scale; SD = 0.07; P = 0.005), corresponding to a decrease of 17.3% (15.7 min) in the duration of epistaxis per month (CI 95%, 5.5-27.6). The median number of epistaxis episodes per month was 22.1 episodes in the placebo arm vs. 23.3 episodes in the TA arm. No thrombophlebitis was observed. CONCLUSIONS: In the ATERO study, we demonstrated a significant decrease in the duration of epistaxis in HHT patients taking TA. No safety issues were recorded in our cohort of patients. PMID- 25040801 TI - Hypericum perforatum hydroxyalkylpyrone synthase involved in sporopollenin biosynthesis--phylogeny, site-directed mutagenesis, and expression in nonanther tissues. AB - Anther-specific chalcone synthase-like enzyme (ASCL), an ancient plant type III polyketide synthase, is involved in the biosynthesis of sporopollenin, the stable biopolymer found in the exine layer of the wall of a spore or pollen grain. The gene encoding polyketide synthase 1 from Hypericum perforatum (HpPKS1) was previously shown to be expressed mainly in young flower buds, but also in leaves and other tissues at lower levels. Angiosperm ASCLs, identified by sequence and phylogenetic analyses, are divided into two sister clades, the Ala-clade and the Val-clade, and HpPKS1 belongs to the Ala-clade. Recombinant HpPKS1 produced triketide and, to a lesser extent, tetraketide alkylpyrones from medium-chain (C6) to very long-chain (C24) fatty acyl-CoA substrates. Like other ASCLs, HpPKS1 also preferred hydroxyl fatty acyl-CoA esters over the analogous unsubstituted fatty acyl-CoA esters. To study the structural basis of the substrate preference, mutants of Ala200 and Ala215 at the putative active site and Arg202 and Asp211 at the modeled acyl-binding tunnel were constructed. The A200T/A215Q mutant accepted decanoyl-CoA, a poor substrate for the wild-type enzyme, possibly because of active site constriction by bulkier substitutions. The substrate preference of the A215V and A200T/A215Q mutants shifted toward nonhydroxylated, medium-chain to long-chain fatty acyl-CoA substrates. The R202L/D211V double mutant was selective for acyl-CoA with chain lengths of C16-C18, and showed a diminished preference for the hydroxylated acyl-CoA substrates. Transient upregulation by abscisic acid and downregulation by jasmonic acid and wounding suggested that HpPKS1, and possibly other Ala-clade ASCLs, may be involved in the biosynthesis of minor cell wall components in nonanther tissues. PMID- 25040805 TI - Effects of a comprehensive cardiac rehabilitation program in patients with coronary heart disease in Korea. AB - The purpose of this study was to develop a comprehensive cardiac rehabilitation program that considered patients' learning needs and cultural context, and to identify the impact of this program on patients with coronary heart disease in Korea. We employed a quasi-experimental design to evaluate the effects of the developed program in 61 patients with coronary heart disease. The experimental group received education, counseling, educational materials, and telephone follow ups by cardiac nurses for six months. Results showed that participants of the program exhibited reduced body mass index and waist circumference as well as improved left ventricular diastolic function and cardiac disease-related quality of life. There was no significant difference between the groups with the rate of recurring symptoms or cardiac events. This comprehensive cardiac rehabilitation program safely and effectively improved body composition, cardiac function, and quality of life in patients with coronary heart disease. PMID- 25040806 TI - Per-oral endoscopic myotomy: emerging indications and evolving techniques. AB - Esophageal achalasia is a benign esophageal motility disorder resulting from an impaired relaxation of the lower esophageal sphincter. The principles of treatment involve disruption of the sphincter at the esophagogastric junction. Treatment techniques include balloon dilatation, botulinum toxin injection, and surgical myotomy. In 2008, per-oral endoscopic myotomy (POEM) was introduced by Inoue et al. as an endoscopic myotomy with no skin incision. The procedure has been well accepted and widely applied owing to its minimal invasiveness and high cure rates. Moreover, there have been discussions on wider indications for POEM and new technical developments have been reported. The present article reviews the historical background and present status of POEM, as well as future prospects for its application in the treatment of esophageal achalasia. PMID- 25040807 TI - Factors associated with long-term outcome of endoscopic thoracic sympathectomy for palmar hyperhidrosis: a questionnaire survey in a cohort of French patients. PMID- 25040810 TI - Pseudotumor cerebri pathophysiology: the likely role of aldosterone. PMID- 25040808 TI - Multiple domains of tetanus toxin direct entry into primary neurons. AB - Tetanus toxin elicits spastic paralysis by cleaving VAMP-2 to inhibit neurotransmitter release in inhibitory neurons of the central nervous system. As the retrograde transport of tetanus neurotoxin (TeNT) from endosomes has been described, the initial steps that define how TeNT initiates trafficking to the retrograde system are undefined. This study examines TeNT entry into primary cultured cortical neurons by total internal reflection fluorescence (TIRF) microscopy. The initial association of TeNT with the plasma membrane was dependent upon ganglioside binding, but segregated from synaptophysin1 (Syp1), a synaptic vesicle (SV) protein. TeNT entry was unaffected by membrane depolarization and independent of SV cycling, whereas entry of the receptor binding domain of TeNT (HCR/T) was stimulated by membrane depolarization and inhibited by blocking SV cycling. Measurement of the incidence of colocalization showed that TeNT segregated from Syp1, whereas HCR/T colocalized with Syp1. These studies show that while the HCR defines the initial association of TeNT with the cell membrane, regions outside the HCR define how TeNT enters neurons independent of SV cycling. This provides a basis for the unique entry of botulinum toxin and tetanus toxin into neurons. PMID- 25040811 TI - Figure reversal: "A tale of two systems: cardiac cephalalgia vs. migrainous thoracalgia". PMID- 25040812 TI - A critical re-evaluation of migraine trigger site decompression surgery. PMID- 25040813 TI - Transient global amnesia as a presenting aura or epilepsy? PMID- 25040814 TI - Response to "transient global amnesia as a presenting aura or epilepsy?". PMID- 25040815 TI - Migraine and cardiovascular disease. PMID- 25040818 TI - The case for invasive placebo - is the devil in the detail? PMID- 25040819 TI - Split liver transplantation using Hemiliver graft in the MELD era: a single center experience in the United States. AB - Under the "sickest first" Model for End-Stage Liver Disease (MELD) allocation, livers amenable to splitting are most often allocated to patients unsuitable for split liver transplantation (SLT). Our experience with SLT using hemilivers was reviewed. From April 2004 to June 2012, we used 25 lobar grafts (10 left lobes and 15 right lobes) for adult-sized recipients. Twelve recipients were transplanted with primary offers, and 13 were transplanted with leftover grafts. Six grafts were shared with other centers. The data were compared with matched whole liver grafts (n = 121). In 92% of donors, the livers were split in situ. Hemiliver recipients with severe portal hypertension had a greater graft-to recipient weight ratio than those without severe portal hypertension (1.96% vs. 1.40%, p < 0.05). Hemiliver recipients experienced biliary complications more frequently (32.0% vs. 10.7%, p = 0.01); however, the 5-year graft survival for hemilivers was comparable to whole livers (80.0% vs. 81.5%, p = 0.43). The secondary recipients with leftover grafts did not have increased incidences of graft failure (p = 0.99) or surgical complications (p = 0.43) compared to the primary recipients. In conclusion, while routine application is still controversial due to various challenges, hemiliver SLT can achieve excellent outcomes under the MELD allocation. PMID- 25040820 TI - Revisiting TP53 Mutations and Immunohistochemistry--A Comparative Study in 157 Diffuse Gliomas. AB - The association between p53 immunohistochemistry and TP53 mutation status has been controversial. The present study aims to re-evaluate the efficacy of p53 immunohistochemistry to predict the mutational status of TP53. A total of 157 diffuse gliomas (World Health Organization grades II-IV) were assessed by exon-by exon DNA sequencing from exon 4 through 10 of TP53 using frozen tissue samples. Immunohistochemistry with a p53 antibody (DO-7) on paired formalin-fixed paraffin embedded materials was assessed for the extent and intensity of reactivity in all cases. A total of 72 mutations were detected in 66 samples. They included 60 missense mutations, five nonsense mutations, four deletions and three alterations in the splicing sites. A receiver operating characteristic curve analysis revealed that strong p53 immunoreactivity in more than 10% of cells provided the most accurate prediction of mutation. Using this cutoff value, 52 of 55 immunopositive cases harbored a mutation, whereas only 14 of 102 immunonegative cases showed mutations, sensitivity and specificity being 78.8% and 96.7%. Tumors with frameshift mutations frequently showed negative immunostaining. Staining interpretation by an independent observer yielded comparable accuracy. We thus propose p53 immunohistochemistry as a moderately sensitive and highly specific marker to predict TP53 mutation. PMID- 25040821 TI - Natural products in Glycyrrhiza glabra (licorice) rhizome imaged at the cellular level by atmospheric pressure matrix-assisted laser desorption/ionization tandem mass spectrometry imaging. AB - The rhizome of Glycyrrhiza glabra (licorice) was analyzed by high-resolution mass spectrometry imaging and tandem mass spectrometry imaging. An atmospheric pressure matrix-assisted laser desorption/ionization imaging ion source was combined with an orbital trapping mass spectrometer in order to obtain high resolution imaging in mass and space. Sections of the rhizome were imaged with a spatial resolution of 10 MUm in the positive ion mode, and a large number of secondary metabolites were localized and identified based on their accurate mass and MS/MS fragmentation patterns. Major tissue-specific metabolites, including free flavonoids, flavonoid glycosides and saponins, were successfully detected and visualized in images, showing their distributions at the cellular level. The analytical power of the technique was tested in the imaging of two isobaric licorice saponins with a mass difference of only 0.02 Da. With a mass resolving power of 140 000 and a bin width of 5 ppm in the image processing, the two compounds were well resolved in full-scan mode, and appeared with different distributions in the tissue sections. The identities of the compounds and their distributions were validated in a subsequent MS/MS imaging experiment, thereby confirming their identities and excluding possible analyte interference. The use of high spatial resolution, high mass resolution and tandem mass spectrometry in imaging experiments provides significant information about the biosynthetic pathway of flavonoids and saponins in legume species, combing the spatially resolved chemical information with morphological details at the microscopic level. Furthermore, the technique offers a scheme capable of high-throughput profiling of metabolites in plant tissues. PMID- 25040822 TI - Simple and robust monitoring of ethanol fermentations by capillary electrophoresis. AB - Free-solution capillary electrophoresis (CE), or capillary zone electrophoresis, with direct UV detection was used for the first time for the determination of mono- and disaccharides, sugar alcohols, and ethanol in fermentation broths. Sample preparation proved to be minimal: no derivatization or specific sample purification was needed. The CE conditions can be adapted to the type of fermentation by simply altering the background electrolyte (BGE). KOH (130 mM) or NaOH (130 mM) as the BGE led to the fastest analysis time when monitoring simple fermentations. A mixture of 65 mM NaOH and 65 mM LiOH led to a 19% improvement in resolution for a complex mixture of carbohydrates. Quantification of a simple carbohydrate fermentation by CE showed values in close agreement with that of high-performance anion exchange chromatography and high-performance liquid chromatography (HPLC) on a cation exchange resin. For complex fermentations, quantification of carbohydrates by HPLC and CE led to similar results, whereas CE requires an injection volume of only 10-20 nL. Analysis of an ethanol fermentation of hydrolyzed plant fiber demonstrated the robustness of the separation and detection of carbohydrates, as well as ethanol. Ethanol determination is achieved by coupling the CE method to pressure mobilization, using the same instrument and the same sample. PMID- 25040823 TI - Impact of structural valve deterioration on outcomes in the cryopreserved mitral homograft valve. AB - OBJECTIVE: This study examines the outcomes of the cryopreserved mitral homograft in 110 patients prospectively followed with clinical, echocardiographic and structural valve deterioration (SVD) assessments. METHODS: The etiology of mitral disease was: rheumatic disease (n = 70), endocarditis (n = 33), and others (n = 7). There were 31 partial homografts and 79 total homografts. Mitro-aortic homograft valve replacement was performed in 29 cases. RESULTS: Mean follow-up was 9.8 +/- 6.3 years (up to 19.2 years). There were seven early (<3 months) and 13 late deaths. There have been nine early (<3 months) and 24 late reoperations. Postoperatively, nine patients had endocarditis and six had an ischemic event. As compared to baseline, follow-up echocardiography showed progression of MR grade (from 0.4 to 1.3 p < 0.001) with stenosis (elevated gradient: from 3.9 to 7.0 mmHg p < 0.001 and decreased valve area: from 2.3 to 1.7 cm(2) p < 0.001). The proportion of freedom from SVD was 90%, 76%, and 65% at five years, 10 years, and 15 years, respectively. SVD was more frequent in pregnant patients (p = 0.016 vs. no pregnancy) and in patients with a ring smaller than 30 mm. Stenosis related to SVD was more pronounced for age <40 years and ring size 30 mm. Mitral-aortic homograft valve replacement was the preferred choice in complex infective endocarditis. Pathological analysis of the explanted homografts almost invariably showed dense fibrosis with calcification and no cellularity. CONCLUSION: Mitral homografts have early echocardiographic results similar to those of valve repair. SVD produced mixed stenosis with insufficiency and its incidence was comparable to that of bioprosthetic SVD. An improvement in the preservation mode of valvular homografts is warranted. PMID- 25040824 TI - Click-chemistry tagging of proteins in living cells: new possibilities for microbial (meta) proteomics. PMID- 25040825 TI - Hematocrit distribution and tissue oxygenation in large microcirculatory networks. AB - OBJECTIVE: Oxygen tension in the brain is controlled by the microcirculatory supply of RBC, but the effect of non-Newtonian blood flow rheology on tissue oxygenation is not well characterized. This study assesses different biphasic blood flow models for predicting tissue oxygen tension as a function of microcirculatory hemodynamics. METHODS: Two existing plasma-skimming laws are compared against measured RBC distributions in rat and hamster microcirculatory networks. A novel biphasic blood flow model is introduced. The computational models predict tissue oxygenation in the mesentery, cremaster muscle, and the human secondary cortex. RESULTS: This investigation shows deficiencies in prior models, including inconsistent plasma-skimming trends and insufficient oxygen perfusion due to the high prevalence (33%) of RBC-free microvessels. Our novel method yields physiologically sound RBC distributions and tissue oxygen tensions within one standard deviation of experimental measurements. CONCLUSIONS: A simple, novel biphasic blood flow model is introduced with equal or better predictive power when applied to historic raw data sets. It can overcome limitations of prior models pertaining to trifurcations, anastomoses, and loops. This new plasma-skimming law eases the computations of bulk blood flow and hematocrit fields in large microcirculatory networks and converges faster than prior procedures. PMID- 25040826 TI - Predictors of successful cardioversion with vernakalant in patients with recent onset atrial fibrillation. AB - BACKGROUND: Vernakalant is a novel atrial-selective antiarrhythmic drug able to convert recent-onset atrial fibrillation (AF) with reportedly low proarrhythmic risk. Successful cardioversion predictors are largely unknown. We sought to evaluate clinical and electrocardiographic predictors of cardioversion of recent onset AF with vernakalant. METHODS: Consecutive patients with AF <=48 hours admitted for cardioversion with vernakalant (n = 113, median age 62 years, 69 male) were included. Sinus rhythm (SR) within 90 minutes after infusion start was considered to be successful cardioversion. Predictive values of demographics, concomitant therapy, comorbidities, and electrocardiographic parameters were assessed. Atrial fibrillatory rate (AFR), exponential decay, and mean fibrillatory wave amplitude were measured from surface ECG using QRST cancellation and time-frequency analysis. RESULTS: Cardioversion was achieved in 66% of patients. Conversion rate was higher in women than in men (80% vs 58%, P = 0.02) while none of other clinical characteristics, including index AF episode duration, could predict SR restoration. Female gender was predictive of vernakalant's effect in logistic regression analysis (OR = 2.82 95%CI 1.18-6.76, P = 0.020). There was no difference in AFR (350 +/- 60 vs 348 +/- 62 fibrillations per minute [fpm], P = 0.893), mean fibrillatory wave amplitude (86 +/- 33 vs 88 +/- 67 MUV, P = 0.852), or exponential decay (1.30 +/- 0.42 vs 1.35 +/- 0.42, P = 0.376) between responders and nonresponders. CONCLUSIONS: Female gender is associated with a higher rate of SR restoration using intravenous (i.v.) vernakalant for recent-onset AF. ECG-derived indices of AF organization, which previous studies associated with effect of rhythm control interventions, did not predict vernakalant's effect. PMID- 25040827 TI - Structural determination of an N-glycan moiety attached to the prothoracicotropic hormone from the silkmoth Bombyx mori. AB - The predominant structure of the N-glycan on the prothoracicotropic hormone (PTTH) isolated from 1.8 million adult heads of silkmoths was determined to be Manalpha1-6Manbeta1-4GlcNAcbeta1-4(Fucalpha1-6)GlcNAc-OH, which is identical to that of the baculovirus-expressed recombinant PTTH. An ecdysis progression assay demonstrated that N-glycosylated PTTH exhibited a slightly higher activity than the recombinant PTTH without N-glycosylation produced by an Escherichia coli expression system. PMID- 25040828 TI - Ultrasonic Assessment of Mucosal Thickness around Implants: Validity, Reproducibility, and Stability of Connective Tissue Grafts at the Buccal Aspect. AB - PURPOSE: (1) To assess validity and reproducibility of mucosal thickness (MT) registration by means of an ultrasonic device and (2) to determine the MT stability of connective tissue grafts (CTGs) when applied at the buccal aspect of single implants demonstrating alveolar process deficiency. MATERIALS AND METHODS: For the validity assessment, four human cadaver edentulous maxillae were used to determine MT at 100 different sites. Soft tissue thickness as recorded with the ultrasonic device was compared with MT as registered with Micro-CT (UGent, Ghent, Belgium), taking the latter as gold standard. For the reproducibility assessment, 50 duplicate ultrasonic registrations were used. For the clinical part, 10 non smoking patients with a single implant were included. All demonstrated alveolar process deficiency and had been provided with a provisional screw-retained crown at the time of inclusion. Following an intrasulcular incision at the buccal aspect, a CTG was inserted to thicken soft tissues. MT was assessed at t0 (before CTG), t1 (immediately after CTG), t2 (suture removal), t3 (permanent crown installation), and t4 (9 months after CTG). RESULTS: There was a strong correlation between ultrasonic and Micro-CT measurements (r = 0.89, p < .001). However, the former significantly underrated MT by 0.13 mm (p = .030). There was a strong correlation between duplicate ultrasonic recordings (r = 0.99, p < .001). Seven females and three males were included in the clinical study with a mean age of 52. MT significantly increased by 0.92 mm between t0 and t1 (p = .005). Between t3 and t4, there was a slight, yet significant decrease of 0.15 mm (p = .047). CONCLUSION: The ultrasonic device can be used as a non-invasive, reliable, and reproducible method to evaluate MT. Using this technology around single implants demonstrated that CTG may substantially thicken the peri-implant mucosa with acceptable stability over a 9-month period. PMID- 25040829 TI - Epidural analgesia in labour and risk of caesarean delivery. AB - BACKGROUND: A Cochrane Systematic Review of randomised controlled trials of epidural analgesia compared with other or no analgesia in labour reported no overall increased risk of caesarean delivery. However, many trials were affected by substantial non-compliance, and there are concerns about the external validity of some trials for contemporary maternity populations. We aimed to explore the association between epidural analgesia in labour and caesarean delivery in clinical practice and compare with findings from randomised controlled trials. METHODS: Population-based cohort of pregnant women (n = 210 708) without major obstetrical complications who delivered a singleton live infant in hospitals in New South Wales, Australia, 2007-10. Data were obtained from linked, validated population-based data collections. Propensity score matching was used to examine the association between epidural analgesia in labour and caesarean delivery. RESULTS: Epidural analgesia in labour was used by a third (31.5%, n = 66 317) of the women, and 9.8% (n = 20 531) had a caesarean delivery. Epidural analgesia in labour was associated with increased risk of caesarean delivery {risk ratio [RR] 2.5, [95% confidence interval (CI) 2.5, 2.6]}. The association with epidural analgesia in labour was higher for caesarean delivery for failure to progress {RR 3.0, [95% CI 2.9, 3.0]} than for caesarean delivery for fetal distress {RR 1.9, [95% CI 1.8, 2.0]}. CONCLUSIONS: Epidural analgesia in labour is associated with caesarean delivery in a large maternity population. Population-based studies contribute important data about obstetrical care, when research settings and participants may not represent the clinical settings or broader population in which obstetrical interventions in labour are applied. PMID- 25040831 TI - Improvement of the diagnostic accuracy of MRA with subtraction technique in cerebral vasospasm. AB - PURPOSE: Vasospasm has been considered the most severe acute complication after subarachnoid hemorrhage (SAH). MRA is not considered ideal for detecting cerebral vasospasm because of background including the hemorrhage. The aim of this study is to evaluate the efficacy of Subtraction MRA (SMRA) by comparing it to that of conventional MRA (CMRA) for diagnosis of cerebral vasospasm. METHODS: Arteries were assigned to one of three categories based on the degree of MRA diagnostic quality of vasospasm (quality score): 0, bad ... 2, good. Furthermore each artery was assigned to one of four categories based on the degree of vasospasm severity (SV score): 0, no vasospasm ... 3, severe. The value of the difference between DSA-SV score and MRA-SV score was defined as the DIF score. CMRA and SMRA were compared for each arterial region with regard to quality score and DIF score. RESULTS: The average CMRA and SMRA quality score were 1.46 and 1.79; the difference was statistically significant. The average CMRA and SMRA DIF score were 1.08 and .60; the difference was statistically significant. CONCLUSIONS: Diagnosis of cerebral vasospasm is more accurate by SMRA than by CMRA. The advantages are its noninvasive nature and its ability to detect cerebral vasospasm. PMID- 25040832 TI - Epidermal UV-A absorbance and whole-leaf flavonoid composition in pea respond more to solar blue light than to solar UV radiation. AB - Plants synthesize phenolic compounds in response to certain environmental signals or stresses. One large group of phenolics, flavonoids, is considered particularly responsive to ultraviolet (UV) radiation. However, here we demonstrate that solar blue light stimulates flavonoid biosynthesis in the absence of UV-A and UV-B radiation. We grew pea plants (Pisum sativum cv. Meteor) outdoors, in Finland during the summer, under five types of filters differing in their spectral transmittance. These filters were used to (1) attenuate UV-B; (2) attenuate UV-B and UV-A < 370 nm; (3) attenuate UV-B and UV-A; (4) attenuate UV-B, UV-A and blue light; and (5) as a control not attenuating these wavebands. Attenuation of blue light significantly reduced the flavonoid content in leaf adaxial epidermis and reduced the whole-leaf concentrations of quercetin derivatives relative to kaempferol derivatives. In contrast, UV-B responses were not significant. These results show that pea plants regulate epidermal UV-A absorbance and accumulation of individual flavonoids by perceiving complex radiation signals that extend into the visible region of the solar spectrum. Furthermore, solar blue light instead of solar UV-B radiation can be the main regulator of phenolic compound accumulation in plants that germinate and develop outdoors. PMID- 25040830 TI - The ins and outs of bacterial iron metabolism. AB - Iron is a critical nutrient for the growth and survival of most bacterial species. Accordingly, much attention has been paid to the mechanisms by which host organisms sequester iron from invading bacteria and how bacteria acquire iron from their environment. However, under oxidative stress conditions such as those encountered within phagocytic cells during the host immune response, iron is released from proteins and can act as a catalyst for Fenton chemistry to produce cytotoxic reactive oxygen species. The transitory efflux of free intracellular iron may be beneficial to bacteria under such conditions. The recent discovery of putative iron efflux transporters in Salmonella enterica serovar Typhimurium is discussed in the context of cellular iron homeostasis. PMID- 25040833 TI - From egg to hatchling: preferential retention of fatty acid biomarkers in young of-the-year Port Jackson sharks Heterodontus portusjacksoni. AB - The muscle and liver fatty acid composition of young-of-the-year (YOY) Port Jackson sharks Heterodontus portusjacksoni were investigated to determine the effects of a known dietary lipid source v. maternal input as demonstrated by egg yolk fatty acid profiles. Ten Heterodontus portusjacksoni egg yolks were collected in situ and compared with four hatched H. portusjacksoni fed a known diet in a controlled feeding experiment of 185 days. This study demonstrated that fatty acids are probably conservatively transferred from egg yolks to YOY H. portusjacksoni, while diet did not have a large effect on the fatty acid composition of the liver or muscle. PMID- 25040834 TI - Fear of falling: association between the Modified Falls Efficacy Scale, in hospital falls and hospital length of stay. AB - RATIONALE, AIMS AND OBJECTIVES: Falls in hospital are costly and may impact psychologically on fallers causing them to avoid mobilization, thereby affecting recovery rate and hospital length of stay. The study aim was to investigate the relationships between fear of falling, falls risk, in-hospital falls and hospital length of stay. METHOD: A convenience sample (n=141) of patients from a large tertiary hospital was recruited. Data were collected over 6 months using the Modified Falls Efficacy Scale (MFES) on ward admission, prior to discharge, and in the event of a fall. RESULTS: A third of the sample (n=44) was admitted to hospital following a fall. The majority (65%) was categorized as medium falls risk. Twenty-five participants sustained a total of 30 falls during their hospital admission of which 13 sustained a total of 15 falls on the study wards. The mean admission MFES score was 5.5, which increased to 6.1 on hospital discharge. Fallers scored significantly lower admission MFES scores than non fallers (P=0.003). Receiver-operating curve analysis indicated that admission MFES score was a 'fair' predictor of sustaining a fall (area under curve=0.71, P=0.013). With a cut-off score of 5, admission MFES sensitivity was 77% and specificity was 55%. Study ward fallers had significantly longer hospital length of stay (49 days) than non-fallers (27 days; P=0.037). Furthermore, regardless of whether the participant was a faller or not, significantly longer hospital stay was associated with an admission MFES score of less than 5. CONCLUSIONS: An admission MFES score of less than 5 is an effective predictor of patient falls and is associated with a significantly longer hospital length of stay. PMID- 25040835 TI - Impact of third- and fourth-degree perineal tears at first birth on subsequent pregnancy outcomes: a cohort study. AB - OBJECTIVE: To investigate, among women who have had a third- or fourth-degree perineal tear, the mode of delivery in subsequent pregnancies as well as the recurrence rate of third- or fourth-degree tears. DESIGN: A retrospective cohort study of deliveries using a national administrative database. SETTING: The English National Health Service between 1 April 2004 and 31 March 2012. POPULATION: A total of 639,402 primiparous women who had a singleton, term, vaginal live birth between April 2004 and March 2011, and a second birth before April 2012. METHODS: Multivariable logistic regression models were used to estimate odds ratios, adjusted for other risk factors. MAIN OUTCOME MEASURES: Mode of delivery and recurrence of tears at second birth. RESULTS: The rate of elective caesarean at second birth was 24.2% for women with a third- or fourth degree tear at first birth, and 1.5% for women without (adjusted odds ratio, aOR 18.3, 95% confidence interval, 95% CI 16.4-20.4). Among women who had a vaginal delivery at second birth, the rate of third- or fourth-degree tears was 7.2% for women with a third- or fourth-degree tear at first birth, compared with 1.3% for women without (aOR 5.5, 95% CI 5.2-5.9). CONCLUSIONS: The risk of a severe perineal tear is increased five-fold in women who had a third- or fourth-degree tear in their first delivery. This increased risk should be taken into account when decisions about mode of delivery are made. PMID- 25040836 TI - Changes in the expression of epidermal differentiation markers at sites where cultured epithelial autografts were transplanted onto wounds from burn scar excision. AB - This study investigated the recovery process during which grafted cultured epithelium formed normal epidermis. The subjects were 18 patients whose burn scars were excised at a depth not exposing the fat layer and who subsequently received cultured epithelial autografts. A total of 24 samples were obtained from the grafted sites: 6 samples within 6 weeks (stage 1), 5 samples after 6 weeks and within 6 months (stage 2), 6 samples after 6 months and within 18 months (stage 3) and 7 samples beyond 18 months (stage 4) after transplantation. These samples were stained for monoclonal antibodies against filaggrin, transglutaminase (TG), cytokeratin 6 and involucrin. Their expressions were examined in the epidermis. The expression patterns were classified using a six grade scale. The grades of filaggrin and TG were significantly higher at stage 3 and 4 compared with stage 1. There was a marginally significant increase in the grade of cytokeratin 6 at stage 3 and it was significantly higher at stage 4 compared with stage 1. These results showed that wound healing continued at a molecular level until the end of stage 3. The recovery of involucrin was delayed compared with that of other markers. TG and involucrin are thought to be regulated independently at the grafted sites. PMID- 25040837 TI - Experiences of municipal public health nurses following Japan's earthquake, tsunami, and nuclear disaster. AB - OBJECTIVE: The purpose of this study was to explore the experiences of municipal public health nurses in the wake of the March 2011 massive earthquake and tsunami and resulting nuclear accident in Fukushima, Japan, from the time of the disaster until December 2013. DESIGN AND SAMPLE: Thirty-two public health nurses working in three cities in Fukushima prefecture were divided into four focus groups and took part in interviews, which were analyzed using a qualitative descriptive method. RESULTS: Two major themes were extracted: (1) experiences of difficulties and dilemmas, and (2) professional challenges and the meaning of excellence as a public health nurse. Subjects recounted their experiences based on the timeline of events. The process of overcoming various dilemmas--between prescribed roles and actual needs on the ground, being both civil servants and private citizens with families, and having to be publicly accountable while lacking adequate information--caused participants to reexamine the meaning of excellence in the practice of public health. CONCLUSION: The strenuous and complex demands of extended disaster management caused subjects to grow professionally. Helping them process their emotions should also help these nurses give focus to their posttraumatic growth, and strengthen their sense of professionalism. PMID- 25040838 TI - Predictors and permanency of cardiac conduction disorders and necessity of pacing after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) with the Medtronic CoreValve bioprosthesis (CoreValve Inc., Irvine, CA, USA) is associated with a high incidence of new-onset left bundle branch block (LBBB) and cardiac conduction disorders (CCDs) requiring permanent pacemaker (PPM) implantation. Our objective was to investigate the predictors and permanency of CCDs after TAVI and specifically to evaluate the necessity for pacing. METHODS: In this single-center study, we included patients who underwent TAVI with the Medtronic-CoreValve bioprosthesis. Electrocardiographic evaluation was performed pre- and post-TAVI and at follow-up. Pacemaker follow-up data were obtained and analyzed. RESULTS: We included 121 patients (age 81 +/- 8 years). LBBB developed in 47 patients, for which prosthesis size (26 mm; odds ratio [OR]: 4.1, 95% confidence interval [CI]: 1.32-12.34, P = 0.01) and prosthesis depth (OR: 1.3, 95% CI: 1.09-1.57, P = 0.004) were independent predictors. In 19%, this new-onset LBBB was temporary. Requirement for a PPM occurred in 23 patients, for which mitral annular calcification (MAC; OR: 1.3, 95% CI: 1.05-1.56, P = 0.02) and preexisting right bundle branch block (RBBB; OR: 8.5, 95%CI: 1.61-44.91, P = 0.01) were independent predictors. At follow-up, 52% of the patients were continuously paced, but 22% of the patients had adequate atrioventricular conduction without the necessity for pacing. In the other 26% of the patients there was intermittent pacing. CONCLUSION: There is a high incidence of new-onset LBBB and PPM implantation following TAVI with a Medtronic-CoreValve bioprosthesis. Prosthesis depth and size were predictors for new LBBB, while MAC and preexistent RBBB were predictors for PPM implantation. In approximately one fifth of the patients, new-onset LBBB and the necessity for pacing are only temporary. PMID- 25040839 TI - Judges' views of child sexual abuse: evaluating beliefs against research findings in a Finnish sample. AB - Beliefs impact our decision-making and different professionals have been shown to have beliefs about child sexual abuse (CSA) that do not coincide with scientific findings. In the present study, judges' beliefs regarding CSA were explored. Finnish judges (N = 104) answered a questionnaire about CSA related issues as well as questions regarding their professional experience of CSA cases. The judges held both correct and incorrect beliefs; while their CSA prevalence estimates were rather well in line with research findings, half of the participants estimated that no professionals use suggestive methods when interviewing children and more than 40% thought suggestive methods can be useful when trying to get a child to tell about real events. Judges correctly assumed symptoms cannot be used to assess a CSA case, however, the majority thought play observations were appropriate means for evaluating such suspicions. Experience seemed to lead to more confidence in their own expertise but not in an actual increase in knowledge, namely, judges thought themselves more expert when more experienced although their expertise as measured by the questionnaire did not improve. Overall, the judges had both correct and erroneous beliefs but while experience did not improve the situation, gaining information about CSA did. More research about the beliefs of judges and how such beliefs impact legal decision making is needed. PMID- 25040840 TI - A dose-response study of caudal dexmedetomidine with ropivacaine in pediatric day care patients undergoing lower abdominal and perineal surgeries: a randomized controlled trial. AB - OBJECTIVES: This randomized double-blind study was conducted to evaluate the analgesic efficacy and safety of addition of three different doses of dexmedetomidine in caudal ropivacaine compared with plain ropivacaine for postoperative analgesia in pediatric day care patients. METHODS: Eighty children of American Society of Anesthesiologists grade I-II, aged 1-8 years, undergoing lower abdominal and perineal surgery were included. Children were randomly allocated into four groups. Group 1 received 0.2% plain ropivacaine 0.75 ml.kg( 1), while group 2, 3, and 4 received dexmedetomidine 0.5, 1.0, and 1.5 MUg.kg( 1), respectively, along with 0.2% ropivacaine 0.75 ml.kg(-1). Anesthesia was induced and maintained with sevoflurane and 50% N2O in oxygen. Children were observed for postoperative pain, nausea-vomiting, agitation, sedation, and adverse effects. Rescue analgesia was provided with oral paracetamol. RESULTS: Postoperative analgesia was significantly prolonged in all dexmedetomidine groups as compared to plain ropivacaine group (P < 0.001). All patients in the plain ropivacaine group required rescue analgesia within first 6 postoperative hours, while none in the other three groups. None of the patients showed delayed anesthetic emergence. Four patients in the plain ropivacaine group developed agitation, while none in the dexmedetomidine groups. Patients receiving dexmedetomidine 1.5 MUg.kg(-1) were more sedated as compared to the other groups (P < 0.01), but it did not delay discharge of the patients. CONCLUSIONS: All three doses of caudal dexmedetomidine appear to be effective for preventing postoperative pain in pediatric day care patients. Caudal dexmedetomidine used in these doses seems to be safe for day care surgery. PMID- 25040841 TI - Radiofrequency ablation combined with chemolipiodolization in a porcine liver: Comparison of the pharmacokinetic analysis with cisplatin powder and miriplatin. AB - AIM: To compare the pharmacokinetics of radiofrequency (RF) ablation with chemolipiodolization using cisplatin (CDDP) powder and miriplatin (MPT) in a porcine liver. METHODS: Twelve pigs were divided equally into four groups. After each CDDP powder-lipiodol suspension (n = 6; groups A and B) or MPT-lipiodol suspension (n = 6; groups C and D) was injected into the lateral left artery, one RF ablation was performed at the lateral left lobe of each pig. Six pigs (groups A and C) were killed on the same day as treatment, whereas the other pigs (groups B and D) were killed 7 days after the treatment. The platinum concentrations in venous blood were assayed at 15, 60 and 120 min, and 7 days after treatment. The platinum concentrations in the ablated area and the surrounding liver were also examined. RESULTS: Plasma platinum concentrations of the CDDP group peaked at 15 min, and then gradually diminished over time (MUg units), while plasma platinum levels in the MPT group gradually increased over time (ng units). Liver tissue platinum concentrations of the CDDP group were significantly lower in non ablative areas than in ablated areas at days 0 and 7, while liver concentrations of the MPT group were significantly higher in non-ablative areas than in ablated areas at day 7. CONCLUSION: MPT may be a suitable chemotherapeutic agent to stagnate platinum in the surrounding liver. PMID- 25040842 TI - Exploration of the relationship between parent/guardian sociodemographics, intention, and knowledge and the oral health status of their children/wards enrolled in a Central Florida Head Start Program. AB - OBJECTIVE: The purpose of this study was to identify possible relationships between parent/guardian sociodemographics, intention, knowledge, and the oral health status of their child/ward. Intention includes three factors as defined in the Theory of Planned Behavior: attitudes, subjective norms and perceived control, and oral health status was measured by decayed, missing and filled teeth (dmft) scores. METHODS: A convenience sample of parent/guardian with child/ward with age of three to five (n = 181 dyads) enrolled in a Head Start program in the state of Florida participated. A cross-sectional observational study comprised of two components, parent/guardian questionnaire and an oral health status form for recording dmft scores of participating child/ward was employed. RESULTS: Parent/guardian race/ethnicity and years of education were significantly related to dmft of child/ward. The highest rates of severe early childhood caries (ECC) were found in child/ward whose parent/guardian is Hispanic and parent/guardian with less than a high school education. Multivariate regression analysis found that increased education level of parent/guardian was significantly associated with lower dmft in this population. No significant relationship was found between parent/guardian self-reported intention (attitudes, subjective norms and perceived control), knowledge and dmft scores of the child/ward. CONCLUSION: Researchers have called for greater attention to the impact of parental influences in the aetiology of ECC. Results from this study were consistent with current studies where parent/guardian race/ethnicity and educational level served as predictors of oral health status of children. In this study population, parent/guardian intention and knowledge were not shown to significantly impact the oral health status of their child/ward. PMID- 25040843 TI - Functional analysis of the fractalkine gene promoter in human aortic smooth muscle cells exposed to proinflammatory conditions. AB - Fractalkine (Fk) and its receptor CX3C receptor 1 contribute effectively to the atherosclerotic process, mediating the recruitment of leukocytes and promoting the interactions between monocytes/macrophages and smooth muscle cells (SMCs). As Fk expression is significantly increased in SMCs during atherogenesis, we aimed to uncover the detailed molecular mechanisms of transcriptional regulation of the Fk gene. For this purpose, we cloned and characterized the human Fk promoter, and studied the specific roles of different transcription factors in its regulation in human aortic SMCs activated by interferon-gamma. In silico analysis of the Fk promoter indicated the presence of binding sites for various inflammatory modulators, such as nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription (STAT)1/STAT3, and activator protein-1. Using a luciferase reporter plasmid, we identified a 2046-bp region spanning the transcriptional start point of the Fk gene, which has strong constitutive promoter activity in SMCs. The effects of interferon-gamma on both Fk reporter activity and endogenous transcription were abolished by silencing NF-kappaB, STAT1, and STAT3. Transient overexpression of p65/NF-kappaB and STAT1/STAT3 increased Fk promoter activity, whereas c-Jun/activator protein-1 overexpression had no effect. The results obtained with chromatin immunoprecipitation assays revealed the existence of physical interactions of p65 and STAT1/STAT3 with the predicted elements of the Fk promoter. Moreover, Fk-promoted monocyte chemotaxis was dependent on the janus kinase-STAT pathway. Investigation of the detailed molecular mechanisms by cloning and characterizing potential transcriptional response elements has identified the Fk regulatory mechanism in activated human SMCs. PMID- 25040844 TI - Patch test study of 90 patients with tattoo reactions: negative outcome of allergy patch test to baseline batteries and culprit inks suggests allergen(s) are generated in the skin through haptenization. AB - BACKGROUND: Tattoo reactions, especially in red tattoos, are often suggested as allergic in nature, however, systematic evaluation by patch testing has not performed in the past. OBJECTIVE: To report the results of patch testing in 90 patients with non-infectious chronic tattoo reactions. MATERIALS/METHODS: From 2009 to 2013 at the 'Tattoo Clinic', Department of Dermatology, Bispebjerg University Hospital, 90 patients were patch tested with batteries of baseline allergens, disperse dyes/textile allergens, and a selection of tattoo ink stock products, which, according to case observations, were problematic, supplemented with individual culprit inks when accessible. RESULTS: Patients with reactions to the tattoo colour red, the most predominant colour associated with skin reactions, showed negative patch test results with common allergens. Outcomes were also negative in patients who had experienced concomitant reactions in another hitherto tolerated tattoo of the same colour as the problematic tattoo. DISCUSSION/CONCLUSION: The allergen or allergens responsible for tattoo reactions are not present directly in tattoo ink stock products. This is despite the fact that clinical histories suggest that the vast majority of clinical reactions, especially reactions to red and red nuances, are likely to be allergic events caused by the injected inks. We suggest that the responsible allergen results from a complicated and slow process of haptenization, which may even include photochemical cleavage of red azo pigment. PMID- 25040845 TI - Pain and decreased cognitive function negatively impact physical functioning in older adults with knee osteoarthritis. AB - OBJECTIVE: We hypothesized that among community-dwelling older adults without dementia with advanced chronic knee osteoarthritis (OA) pain: 1) higher levels of self-reported pain would be associated with decreased executive cognitive function and decreased physical function; and 2) decreased cognitive function would be associated with decreased physical function. METHODS: Substudy on 79 older adults who were participants in a Veterans Affairs clinical trial of periosteal stimulation therapy for advanced painful knee OA. Participants were >= 60 years, had radiographic evidence of Kellgren-Lawrence 3 or 4 knee OA on a standing anterior-posterior X-ray, had pain of at least moderate intensity and of at least 3 months' duration, and knee pain severity greater than pain severity in other parts of the body. Measures included computerized cognitive tests of executive function, pain, and physical function (gait speed and stair climbing). RESULTS: As pain scores worsened, gait speed and stair climbing worsened (P = 0.007 and P = 0.035, respectively). Lower performance on the executive function tests was also significantly associated with decreased gait speed and stair climbing (P = 0.002 and P = 0.014, respectively). We did not find a significant relationship between pain and cognitive function. We explored the relationship between pain and physical function adjusted for executive functioning and found that pain was no longer associated with gait speed (P = 0.06). CONCLUSION: Worse pain scores and executive function scores were associated with worse physical function in older adults with painful knee OA. This suggests that slower gait speed in patients could be an indication to clinicians to monitor their patient's cognitive function. Executive function in particular affected the relationship between gait speed and pain, suggesting a possible mediating relationship. PMID- 25040846 TI - Asymmetrical cortical vessel sign on susceptibility-weighted imaging: a novel imaging marker for early neurological deterioration and unfavorable prognosis. AB - BACKGROUND AND PURPOSE: Susceptibility-weighted imaging (SWI) is a high spatial resolution technique that can indirectly demonstrate increased cerebral oxygen extraction. Our aim was to assess whether asymmetric cortical vessel sign (ACVS) on SWI could be associated with early neurological deterioration (END) as well as 90-day unfavorable outcome in patients with acute ischaemic stroke. MATERIALS AND METHODS: Consecutive patients with acute middle cerebral artery (MCA) territory infarction were prospectively enrolled. ACVS was defined as more and/or larger vessels with greater signal loss than those in the opposite hemisphere on minimum intensity projection of SWI. The neurofunctional fluctuation during acute phase as well as 90-day outcomes were assessed. A National Institutes of Health Stroke Scale increment >=2 points and >=4 points despite standard treatment in the first 72 h after admission was defined as END2 and END4, respectively. RESULTS: In all, 572 patients were finally enrolled. ACVS on SWI was present in 39 (6.8%) subjects. Multivariate analysis indicated that ACVS is an independent predictor for END2 [odds ratio (OR) 4.47, 95% confidence interval (CI) 1.99-10.05) and END4 (OR 4.24, 95% CI 1.94-9.23). Furthermore, ACVS also correlates with 90-day unfavorable outcome defined as a modified Rankin Scale score >1 point (OR 2.93, 95% CI 1.15-7.48). Both positive and negative predictive values of ACVS for END2, END4 and 90-day prognosis were reasonable and both could be slightly enhanced as long as patients with contralateral artery stenosis or occlusion were excluded. CONCLUSION: In patients with MCA territory acute ischaemic stroke, especially in those without contralateral internal carotid artery/MCA stenosis or occlusion, ACVS might be considered as a neuroimaging predictor for END and unfavorable prognosis. PMID- 25040847 TI - Proteomics profiling of keratocystic odontogenic tumours reveals AIDA as novel biomarker candidate. AB - BACKGROUND: Keratocystic odontogenic tumour (KCOT) is a benign, yet aggressive odontogenic tumour. Herein, proteome analysis of KCOT lesions in comparison with control patient-matched tissue unaffected by the disease and with inflammatory odontogenic cysts, namely radicular cysts is presented. METHODS: For the proteomics profiling, two complementary proteomics techniques MALDI-MS/MS and LC ESI-MS/MS were employed. Potential candidate biomarkers were validated by immunohistochemistry. RESULTS: More than 43 proteins were found to be differentially expressed or up-regulated in KCOT lesions in comparison with patient-matched unaffected oral mucosa. These proteins bear important biological functions and are involved in cell proliferation, cytoskeletal re-organization, transcription, cellular motility and apoptosis. In particular, a number of differentially expressed proteins participate in autocrine regulation and signalization within JNK and p38 MAPK signalling pathways. CONCLUSIONS: Immunohistochemical validation of chosen putative biomarkers revealed axin interaction partner and dorsalization-antagonist (AIDA), known as a protein that blocks activation of JNK signalling pathway, as a differential biomarker for KCOT lesions on an independent cohort of KCOT tissue samples in comparison with most prevalent intra-oseal lesions inflammatory odontogenic cysts. PMID- 25040848 TI - Surge capacity: analysis of census fluctuations to estimate the number of intensive care unit beds needed. AB - OBJECTIVE: To compare methods of characterizing intensive care unit (ICU) bed use and estimate the number of beds needed. STUDY SETTING: Three geographic regions in the Canadian province of Manitoba. STUDY DESIGN: Retrospective analysis of population-based data from April 1, 2000, to March 31, 2007. METHODS: We compared three methods to estimate ICU bed requirements. Method 1 analyzed yearly patient days. Methods 2 and 3 analyzed day-to-day fluctuations in patient census; these differed by whether each hospital needed to independently fulfill its own demand or this resource was shared across hospitals. PRINCIPAL FINDINGS: Three main findings were as follows: (1) estimates based on yearly average usage generally underestimated the number of beds needed compared to analysis of fluctuations in census, especially in the smaller regions where underestimation ranged 25-58 percent; (2) 4-29 percent fewer beds were needed if it was acceptable for demand to exceed supply 18 days/year, versus 4 days/year; and (3) 13-36 percent fewer beds were needed if hospitals within a region could effectively share ICU beds. CONCLUSIONS: Compared to using yearly averages, analyzing day-to-day fluctuations in patient census gives a more accurate picture of ICU bed use. Failing to provide adequate "surge capacity" can lead to demand that frequently and severely exceeds supply. PMID- 25040849 TI - Editorial Comment to Contemporary minimally-invasive extended pelvic lymph node dissection for prostate cancer before curative radiotherapy: prospective standardized analysis of complications. PMID- 25040850 TI - Expressing concern and writing it down: an experimental study investigating transfer of information at nursing handover. AB - AIMS: To examine the effects of two factors on the transmission of clinical information at nursing handover. These factors were: (i) an affective statement expressing concern about the information; and (ii) verbal reference to a written summary of the information. BACKGROUND: Quality of communication at patient handover is inconsistent, compromising patient safety. Little is known about the nuances of communication that lead to effective handovers. Furthermore, effective information transmission during handovers is seldom evaluated using experimental research designs. DESIGN: A randomized, single-blind, controlled experiment. METHODS: Postanaesthesia care unit or surgical ward nurses and final-year nursing students were randomly assigned to watch one of four versions of a video-recorded handover. In each version, one piece of information was presented as either a simple statement (control), with an affective qualifier, with a written summary of the information, or with both an affective qualifier and a written summary. Primary outcome was assessed by questionnaire following a task directing attention away from the handover. Data were collected July-October, 2013 and analysed using 2 * 2 anova. RESULTS: A total of 157 nurses participated. Successful transmission of the clinical information did not significantly differ across the experimental conditions. Subgroup analysis revealed significantly higher transmission success among more experienced nurses when the affective statement was present compared to when it was absent (Kruskal-Wallis P = 0.002). CONCLUSIONS: Expressing concern about information or directing attention to written notes may not improve information transfer at handover. However, affective qualifiers may have differential receiver-specific influences on information retention. PMID- 25040851 TI - Does the prior application of the field kit bullet hole testing kit 3 on a suspected bullet hole bias the analysis of atomic absorption spectrophotometry? AB - Forensic ballistics is the study of bullet trajectory and consists of determining gunshot residue (GSR) to identify bullet holes. Among several highly sensitive methods, atomic absorption spectrophotometry (AAS) is employed to analyze GSR in the laboratory. However, it is sometimes necessary to identify bullet holes immediately at a crime scene. The purpose of this examination was to determine whether the use of the field test Bullet Hole Testing Kit 3 (BTK3) on a suspected bullet hole would influence the outcome of AAS-analysis: Three commonly encountered firearms (Glock17, Tokarev, and Colt) were fired at skin, wood, and cloth. AAS-analysis was performed with and without previous BTK3 application. The results clearly indicate that there is no significant interaction on the grounds of BTK3 use (BTK3 vs. no-BTK3 [kit_nokit] [Pb: p = 0.1309; Sb: p = 0.9111], material*kit_nokit [Pb: p = 0.5960; Sb: p = 0.9930], distance*kit_nokit [Pb: p = 0.4014; Sb: p = 0.9184], and firearm type*kit_nokit [Pb: p = 0.9662; Sb: p = 0.9885]); hence, applying this field kit does not falsify later AAS outcomes. PMID- 25040852 TI - The oncogenic role of androgen receptors in promoting the growth of oral squamous cell carcinoma cells. AB - OBJECTIVES: The aims of this study were to examine the expression of androgen receptors (AR) in oral squamous cell carcinoma (OSCC) cells and tumors and to determine the role of AR in regulating OSCC cell growth. MATERIALS AND METHODS: Four OSCC cell lines were used for analyzing AR expression and transcriptional activity. The effects of AR knockdown on the growth and tumorigenicity of OSCC cells were examined. A series of 11 benign, 22 premalignant, and 21 malignant lesions of the oral cavity were used for analyzing AR expression. RESULTS: OSCC cells expressed AR proteins with differential activities. Stimulation of AR by dihydrotestosterone in OSCC cells caused an increase in cyclin D1 expression and promoted cell growth, whereas treatment with bicalutamide led to decreased cyclin D1 expression and inhibited cell growth. Knockdown of AR expression in OSCC cells resulted in decreased proliferation, increased apoptosis, and inhibited tumorigenicity. Results from immunohistochemical studies showed that AR immunoreactivity was found in 27% (3/11) of benign lesions, while 68% (15/22) of premalignant and 67% (14/21) of malignant lesions showed positive AR staining. CONCLUSION: Our data suggest that OSCC cells express functional AR proteins which are critical for promoting cell growth and causing malignant disease. PMID- 25040853 TI - Recurrent miscarriage is a useful and valid clinical concept. AB - Although epidemiological, clinical and biochemical risk factors are known for recurrent miscarriage (RM), the etiology is mainly unknown. Two main hypotheses dominate: that RM is mainly caused by aneuploid conceptions and other conception errors and that the recurrence rate is explained by the combination of chance and increased risk, or that maternal endocrinological, thrombophilic or immunological abnormalities play a main role in causing loss of euploid conceptions. Believers of the former hypothesis advocate that management of RM should be conservative and that the spontaneous prognosis is very favorable. Believers of the latter hypothesis think that treatments aimed at the woman may improve pregnancy outcome, but that testing of such treatments in randomized controlled trials is needed. In this article in favor of RM being a specific and useful clinical concept, arguments are advanced that a significant subset of RM patients exhibit a poor spontaneous prognosis and should be offered relevant investigations, close surveillance during pregnancy, and treatment, preferably as part of randomized controlled trials. PMID- 25040854 TI - Will the wound-healing field earn its wings? AB - In a recently published issue of Experimental Dermatology, Dr. Nuria Paricio and colleagues review recent advances using the fruit fly, Drosophila melanogaster, as a wound-healing model. They describe many of the advantages of the fly model for gene discovery and functional analysis, highlighting its particular strengths and limitations for studies of wound healing. This commentary assumes that dermatologist-scientists and fly wound-healing researchers share a common field wide goal of discovering all of the clinically relevant wound-healing genes and understanding in molecular detail how those genes work. We ask: how can we cooperate to achieve this shared goal? PMID- 25040855 TI - Gut microbes of mammalian herbivores facilitate intake of plant toxins. AB - The foraging ecology of mammalian herbivores is strongly shaped by plant secondary compounds (PSCs) that defend plants against herbivory. Conventional wisdom holds that gut microbes facilitate the ingestion of toxic plants; however, this notion lacks empirical evidence. We investigated the gut microbiota of desert woodrats (Neotoma lepida), some populations of which specialise on highly toxic creosote bush (Larrea tridentata). Here, we demonstrate that gut microbes are crucial in allowing herbivores to consume toxic plants. Creosote toxins altered the population structure of the gut microbiome to facilitate an increase in abundance of genes that metabolise toxic compounds. In addition, woodrats were unable to consume creosote toxins after the microbiota was disrupted with antibiotics. Last, ingestion of toxins by naive hosts was increased through microbial transplants from experienced donors. These results demonstrate that microbes can enhance the ability of hosts to consume PSCs and therefore expand the dietary niche breadth of mammalian herbivores. PMID- 25040856 TI - Impact of obesity on complications after resection for rectal cancer. AB - AIM: The prevalence of obesity in Australia is high and increasing, with associated serious negative effects on health. The technical complexity of rectal cancer surgery is exacerbated in obese patients, which may compromise outcomes. The aim of this study was to examine the association between obesity and complications after resection of rectal cancer. METHOD: Data were drawn from a comprehensive prospective registry of rectal cancer resections performed from 2007 to 2011 by members of the colorectal surgical unit in a tertiary referral hospital and in a single private hospital with which they were affiliated. RESULTS: Of 255 patients who had a resection for rectal cancer during the study period, 95 (37%) were classified as obese on the basis of a body mass index (BMI) >= 30 kg/m(2) . Among 24 postoperative complications the only significant differences for obese patients were higher rates of wound complications (16% vs 8%, P = 0.038), small bowel obstruction (4% vs 0%, P = 0.019) and prolonged ileus (18% vs 8%, P = 0.011). The total number of complications did not differ significantly between obese and nonobese patients, and there was no difference between obese and nonobese patients in the rates of reoperation and postoperative death. CONCLUSION: This study did not support an association between obesity and early postoperative complications after resection of rectal cancer. PMID- 25040857 TI - 'Seeing me through my memories': a grounded theory study on using reminiscence with people with dementia living in long-term care. AB - AIMS AND OBJECTIVES: To understand people with dementia, staff and relatives perspectives on reminiscence, its impact on their lives and experience of care and care giving. BACKGROUND: The quality of life of people with dementia living in long-term care is an important question for providers and policymakers. Reminiscence is thought to have potential for increasing resident-staff interaction, thereby contributing to enhanced personhood for people with dementia. Relatively little is known about the effects of reminiscence on people with dementia or staff. DESIGN: This is a grounded theory study. This design was chosen because of its focus on understanding people's behaviour, interaction and response to events. METHODS: In-depth interviews were conducted with residents with dementia (n = 11), relatives (n = 5), healthcare assistants (n = 10), nurses (n = 9) and nurse managers (n = 3). RESULTS: Reminiscence enabled staff to see and know the person beneath the dementia. It acted as ... a key revealing the person to staff, enabling them to engage with the person with dementia in a different way. Knowing the person enabled staff to understand (through the lens of the person's past) and sometimes to accommodate the person's current behaviour. CONCLUSION: The theory of 'seeing me (through my memories)' was generated from the data. This theory explains that through reminiscing and engaging with the person with dementia, staff begin to see the person (their personhood) through the mirror of their memories. RELEVANCE TO CLINICAL PRACTICE: This study found that reminiscence enhanced the experience of living in long-term care for residents with dementia and working in long-term care settings for staff. PMID- 25040858 TI - The use of a nerve stimulator for intraoperative stimulation of individual nerves of the brachial plexus. PMID- 25040859 TI - A momentous day for palliative care. PMID- 25040860 TI - Does the Belgian law legalising euthanasia for minors really address the needs of life-limited children? PMID- 25040861 TI - Hospice: a safe place to suffer. A reflection 25 years on. PMID- 25040862 TI - Death awareness, feelings of uncertainty, and hope in advanced lung cancer patients: can they coexist? AB - Patients diagnosed with stage-IV lung cancer are forced to quickly transition from a cancer-free and perhaps healthy life to one of serious illness, uncertainty, and anticipation of a premature death. Health professionals may be too quick to label the patient as being in denial if they hope for healing. Hope may not be lost when reality is accepted. Studies have investigated what it is like to live with awareness of impending death. Using a patient case study this paper discusses the concepts of death awareness, uncertainty, and hope. The aim is to provide a deeper understanding of how these seemingly antithetical emotions can coexist to the benefit of the patient, and to provide clinicians with practical considerations for supporting patients' hope throughout their terminal illness. PMID- 25040863 TI - The challenges of providing palliative care for people with intellectual disabilities: a literature review. AB - People with intellectual disabilities are often marginalised from mainstream health-care services because of the complexities of their disability. They are under-referred to specialist palliative care owing to a limited understanding of its role and little collaborative working. Furthermore, professionals caring for people with intellectual disabilities and palliative care services often lack knowledge about and confidence in their ability to meet the needs of people with an intellectual disability who require palliative care. This literature review explores the challenges of providing palliative care for people with intellectual disability. It highlights that training requirements need to be effectively identified, referrals between professional groups made, and the perspectives of patients understood to overcome the marginalisation of people with intellectual disability. There is a need for ongoing staff development focusing on staff confidence, collaborative working between professionals, and the empowerment of people with intellectual disability to be involved in decisions about their end of-life care. Further research is needed to examine the most effective way of capturing the perspectives of those with intellectual disability and of enabling people with intellectual disability to access and engage with health surveillance, cancer screening, and palliative care services. PMID- 25040864 TI - Final-year nursing undergraduates' understandings of palliative care: a qualitative study in Wales, UK. AB - BACKGROUND: With worldwide population ageing and the increasing prevalence of chronic conditions, government policies promoting palliative care, and evidence of disparate or even blurred conceptions of palliative care, it is important for educators and practitioners who support undergraduate nurses to establish how these students conceptualise palliative care. Today's students are tomorrow's nurses, and their understanding will shape the ways in which palliative care is integrated into their professional practice. AIM: The aim of this work was to explore nursing undergraduates' understandings of palliative care. METHODS: As part of a larger qualitative study of palliative care for people with advanced dementia, 11 final-year adult-field nursing undergraduates' understandings of palliative care were explored through in-depth individual interviews. The data was subject to thematic content analysis. FINDINGS: The analysis revealed that the participants were cognisant of the broad scope of palliative care. Moreover, they valued and appreciated compassionate comfort care and emotional support. However, their understanding was rather superficial and focused on the imminently dying phase. CONCLUSION: The findings are positive as they indicate that the participants appreciated and valued compassionate person- and family-centred care. However, they also illuminate where undergraduate nurse education could be further enhanced. PMID- 25040865 TI - Nurses' professional autonomy and attitudes toward caring for dying patients in South-East Iran. AB - BACKGROUND: Nurses in Iran have been found to have less professional autonomy than nurses in Western countries. Professional autonomy is important, affecting nurses' caring behaviour and attitudes. AIM: This study aimed to examine the correlation between the professional autonomy of oncology and intensive care unit (ICU) nurses in the south-east of Iran and their attitudes toward the care of dying patients. METHODS: 155 oncology and ICU nurses in three hospitals supervised by Kerman University of Medical Sciences completed the Frommelt Attitude Toward Care of the Dying (FATCOD) and Pankratz Nursing Questionnaire (PNQ) tools during April-June 2013. RESULTS: The participants had a neutral to moderately positive mean attitude toward caring for dying patients (mean=3.18+/ 0.37 out of 5) and moderate professional autonomy (mean=3.08+/-0.33 out of 5). There was a significant positive correlation between total scores on professional autonomy and total scores on attitudes toward caring for dying patients. There was also a significant positive correlation between the PNQ subscale of 'patients' rights' and attitudes toward caring for dying patients. CONCLUSIONS: Autonomy could be an important component of nurses' attitudes toward caring for dying patients. To improve nurses' autonomy, nursing education in end-of-life care in Iran must be improved. Other factors relating to autonomy and attitudes specific to the Iranian context should also be considered. PMID- 25040866 TI - Do patients and carers find separate palliative care clinic consultations acceptable? A pilot study. AB - BACKGROUND: As differing patient and carer information needs have been reported, and in light of changing health-system priorities and issues identified in a self assessment study, a specialist palliative care service established an interdisciplinary psychosocial assessment clinic to separately assess patient and carer needs. AIM: To determine the acceptability of the separate assessment to patients and carers. METHOD: Patients with a high functional score and who were deemed well enough to manage an appointment were invited to attend the clinic. Consent to follow-up was obtained. Patient and carer satisfaction surveys were developed based on existing tools. Questionnaires were posted out with a pre-paid reply envelope to patients and carers. Data from completed surveys was entered into a data management system and frequency analysis completed. A secondary analysis of the comments was undertaken. FINDINGS: The clinic was attended by 41 patients and 37 carers between September 2011 and the end of February 2012. There was a 46% response rate, with 24 questionnaires returned from both the patient and their carer, 6 from patients only, and 6 from carers only (2 of whom were bereaved). The opportunity for privacy to discuss their own fears and concerns related to the illness was appreciated by 94% of the patients and 83% of the carers. CONCLUSION: This initial pilot data shows patient and carer satisfaction with this clinic model. Further qualitative data would provide more information on the patient and carer experiences of the clinic. PMID- 25040869 TI - Mutations in IDH1 and IDH2 are not present in sporadic ovarian sex cord-stromal tumours. PMID- 25040870 TI - Does walking speed mediate the association between visual impairment and self report of mobility disability? The Salisbury Eye Evaluation Study. AB - OBJECTIVES: To determine whether performance speeds mediate the association between visual impairment and self-reported mobility disability over an 8-year period. DESIGN: Longitudinal analysis. SETTING: Salisbury, Maryland. PARTICIPANTS: Salisbury Eye Evaluation Study participants aged 65 and older (N=2,520). MEASUREMENTS: Visual impairment was defined as best-corrected visual acuity worse than 20/40 in the better-seeing eye or visual field less than 20 degrees . Self-reported mobility disability on three tasks was assessed: walking up stairs, walking down stairs, and walking 150 feet. Performance speed on three similar tasks was measured: walking up steps (steps/s), walking down steps (steps/s), and walking 4 m (m/s). RESULTS: For each year of observation, the odds of reporting mobility disability was significantly greater for participants who were visually impaired (VI) than for those who were not (NVI) (odds ratio (OR) difficulty walking up steps=1.58, 95% confidence interval (CI)=1.32-1.89; OR difficulty walking down steps=1.90, 95% CI=1.59-2.28; OR difficulty walking 150 feet=2.11, 95% CI=1.77-2.51). Once performance speed on a similar mobility task was included in the models, VI participants were no longer more likely to report mobility disability than those who were NVI (OR difficulty walking up steps=0.84, 95% CI=0.65-1.11; OR difficulty walking down steps=0.96, 95% CI=0.74-1.24; OR difficulty walking 150 feet=1.22, 95% CI=0.98-1.50). CONCLUSION: Slower performance speed in VI individuals largely accounted for the difference in the odds of reporting mobility disability, suggesting that VI older adults walk slower and are therefore more likely to report mobility disability than those who are NVI. Improving mobility performance in older adults with visual impairment may minimize the perception of mobility disability. PMID- 25040871 TI - RAPSTROMTM first-in-man study long-term results of a biodegradable polymer sustained-release sirolimus-eluting stent in de novo coronary stenoses. AB - BACKGROUND: Durable polymers used for first-generation drug-eluting stents (DES) potentially contribute to persistent inflammation and late DES thrombosis. We report the first real-life human experience with the rapamycin-eluting biodegradable polymer-coated Rapstrom stent. METHODS: All consecutive patients with single de novo native coronary stenosis (<30 mm and between 2.5 and 4.0 mm) were enrolled. Major adverse cardiac events (MACE) at 1 year (cardiac death, myocardial infarction [Q and non-Q], or ischemia-driven target lesion revascularization) were the primary end-point. RESULTS: A total of 123 patients were enrolled. The stent was implanted without complications in all patients, and no MACE were recorded at 30 days. At 12-month follow-up 9 patients (7.3%) experienced a MACE and 4 (3.2%) required a target lesion revascularization, while 1 (1%) stent thrombosis was recorded. A planned angiographic follow-up (FU) was performed in 73 patients (59%) at 9.4 +/- 2.6 months following the index procedure. In-stent late loss was 0.16 +/- 0.09 mm, and in-segment late loss was 0.18 +/- 0.8 mm. CONCLUSION: The Rapstrom biodegradable polymer rapamycin-eluting stent appeared safe and efficacious in this first real-life human experience, due to a low late lumen loss. Larger randomized studies are required to confirm these preliminary results. PMID- 25040872 TI - Lessons in biostatistics: inferences and conjectures about average and conditional treatment effects in randomized trials and observational studies. PMID- 25040873 TI - Below-knee cast immobilization and the risk of venous thrombosis: results from a large population-based case-control study. AB - BACKGROUND: From the available evidence, the risk of venous thrombosis in patients with below-knee cast immobilization remains unclear. OBJECTIVES: To estimate the risk of venous thrombosis after below-knee cast immobilization and to identify high-risk groups. PATIENTS AND METHODS: We used data from a large population-based case-control study (MEGA study) on the etiology of venous thrombosis (4418 cases; 6149 controls). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and adjusted for age, sex, body mass index, and regular exercise. Absolute risks were estimated from the ORs. RESULTS: One hundred and thirty-four patients and 23 controls had below-knee plaster cast immobilization in the year before the index date, resulting in an eight-fold increased risk (OR 8.3 [95% CI 5.3-12.9]). Traumatic indications led to a higher risk than non-traumatic indications: OR 12.7 (95% CI 6.6-24.6) vs. OR 7.6 (95% CI 0.9-66.4). An additionally increased risk was found for combinations with genetic or acquired risk factors: oral contraceptives (OR 18.2 [95% CI 6.2-53.4]); obesity (OR 17.2 [95% CI 5.4-55.2]); factor V Leiden, factor II 20210A mutation, and/or non-O blood group (OR 23.0 [95% CI 11.5-46.0]); all for a period of 1 year. Ninety per cent of the events occurred in the first 3 months after cast application. This led to a 56-fold increased risk (OR 56.3 [95% CI 17.9-177.3]) in this period. CONCLUSIONS: Below-knee cast immobilization strongly increases the risk of venous thrombosis. We found distinct differences in intrinsic risk between individuals with respect to indication for cast immobilization and the presence of genetic or acquired risk factors. PMID- 25040874 TI - Images of post-pneumonectomy syndrome: progressive mediastinal displacement causing bronchial narrowing by stretching. PMID- 25040875 TI - Sense of meaning in work and risk of burnout among medical professionals. PMID- 25040876 TI - Oral health of Australian Indigenous children compared to non-Indigenous children enrolled in school dental services. PMID- 25040877 TI - Predictive value of a fragmented QRS complex in patients undergoing primary angioplasty for ST elevation myocardial infarction. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic value of fragmented QRS (fQRS) on electrocardiography (ECG) patients with acute ST-segment elevation in myocardial infarction (STEMI), who are undergoing primary percutaneous coronary intervention (PCI). METHODS: We prospectively enrolled 414 consecutive STEMI patients (mean age of 55.2 +/- 12.2 years old, range of 26-91 years old) undergoing primary PCI. The study patients were divided into two groups according to the presence or absence of fQRS as shown by ECG in the first 48 hours. The presence of fQRS group was defined as fQRS(+) (n = 91), and the absence of fQRS group was defined as the fQRS(-) (n = 323) group. Clinical characteristics and the one-year outcome of the primary PCI were analyzed. RESULTS: The patients in the fQRS(+) group were older (mean age 60.7 +/- 12.5 vs. 53.6 +/- 11.6 years old, P < 0.001). Higher one-year all-cause mortality rates were observed in the fQRS group upon ECG (23.1% vs. 2.5%, P < 0.001, respectively). When using the Cox multivariate analysis, the presence of fQRS on the ECG was found to be a powerful independent predictor of one-year all-cause mortality (hazard ratio: 5.24, 95% confidence interval: 1.43-19.2, P = 0.01). CONCLUSIONS: These results suggest that the presence of fQRS on ECG was associated with an increased in-hospital cardiovascular mortality, and one-year all-cause mortality in patients with STEMI who are under primary PCI. PMID- 25040878 TI - Quality of life of patients with 46,XX and 46,XY disorders of sex development. AB - Disorders of sex development (DSD) result from abnormalities in the complex process of sex determination and differentiation. An important consideration to guide the assignment of social sex in newborns with ambiguous genitalia is the quality of life (QoL) of these patients in adulthood. The rarity of most DSD conditions makes it difficult to conduct a long-term follow-up of affected patients through adulthood. This review of papers on the QoL of DSD patients evaluated in developing and developed countries by qualitative and quantitative instruments revealed a large spectrum of QoL, ranging from very poor to similar to, or even better than, the normal population. A more adequate QoL was found in patients from tertiary centres, indicating that the medical care of DSD patients should be multidisciplinary and carried out by specialized teams. PMID- 25040879 TI - Adolescent alcohol abuse and adverse adult outcomes: evaluating confounds with drinking-discordant twins. AB - BACKGROUND: Adolescent alcohol abuse is associated with adverse outcomes in early adulthood, but differences in familial status and structure and household and community environments correlate with both adolescent drinking and adverse adult outcomes and may explain their association. We studied drinking-discordant twin pairs to evaluate such confounds to ask: Will between-family associations replicate in within-family comparisons? METHODS: With longitudinal data from >3,000 Finnish twins, we associated drinking problems at age 181/2 with 13 outcomes assessed at age 25; included were sustained substance abuse, poor health, physical symptoms, early coital debut, multiple sexual partners, life dissatisfaction, truncated education, and financial problems. We assessed associations among twins as individuals with linear regression adjusted for correlated observations; within-family analyses of discordant twin pairs followed, comparing paired means for adult outcomes among co-twins discordant for adolescent problem drinking. Defining discordance by extreme scores on self reported problem drinking at age 181/2 permitted parallel analyses of twins as individuals and discordant twin pairs. Alternate definitions of pair-wise discordance and difference score correlations across the entire twin sample yielded supplementary analyses. RESULTS: All individual associations were highly significant for all definitions of discordance we employed. Depending on definitions of discordance, 11 to 13 comparisons of all drinking-discordant twin pairs and 3 to 6 comparisons of discordant monozygotic (MZ) twin pairs replicated between-family associations. For most outcomes, effect size attenuated from individual-level analysis to that within discordant MZ twin pairs providing evidence of partial confounding in associations reported in earlier research. The exception was the General Health Questionnaire (GHQ); at age 25, GHQ-12 had equivalent associations with age 181/2 Rutgers Alcohol Problem Index across all comparisons. CONCLUSIONS: Our analyses control for shared family background, and, partly or fully, for shared genes, to yield within-family replications and more compelling evidence than previously available that adolescent alcohol abuse disrupts transitions into early adulthood. PMID- 25040880 TI - Impact of body mass index on incidence of febrile neutropenia and treatment related mortality in United States veterans with diffuse large B-cell lymphoma receiving rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. PMID- 25040881 TI - State selective pumping reveals spin-relaxation pathways in CdSe quantum dots. AB - The band-edge exciton in elongated CdSe nanocrystals is composed of an upper and lower manifold associated with heavy and light holes in which the energy separation is sensitive to the nanocrystal shape. Using resonant photoluminescence excitation, we probe the upper heavy hole exciton manifold and find rapid relaxation to the lower light hole manifold on a 5 ps time scale. State selective excitation allows the preparation of single quantum states in this system. We used this to map the hole spin relaxation pathways between the fine structure sublevels, which have energy splittings incommensurate with either optical or acoustic phonon energies. This reveals a hitherto unexpected hole spin relaxation channel in these materials. PMID- 25040882 TI - Achieving patient-centred care: the potential and challenge of the patient-as professional role. AB - BACKGROUND: The patient-as-professional concept acknowledges the expert participation of patients in interprofessional teams, including their contributions to managing and coordinating their care. However, little is known about experiences and perspectives of these teams. OBJECTIVE: To investigate (i) patients' and carers' experiences of actively engaging in interprofessional care by enacting the patient-as-professional role and (ii) clinicians' perspectives of this involvement. DESIGN, SETTING AND PARTICIPANTS: A two-phased qualitative study. In Phase 1, people with chronic disease (n = 50) and their carers (n = 5) participated in interviews and focus groups. Phase 2 involved interviews with clinicians (n = 14). Data were analysed thematically. FINDINGS: Patients and carers described the characteristics of the role (knowing about the condition, questioning clinicians, coordinating care, using a support network, engaging an advocate and being proactive), as well as factors that influence its performance (the patient-clinician partnership, benefits, barriers and applicability). However, both patients and carers, and clinicians cautioned that not all patients might desire this level of involvement. Clinicians were also concerned that not all patients have the required knowledge for this role, and those who do are time consuming. When describing the inclusion of the patient-as-professional, clinicians highlighted the patient and clinician's roles, the importance of the clinician-patient relationship and ramifications of the role. CONCLUSION: Support exists for the patient-as-professional role. The characteristics and influencing factors identified in this study could guide patient engagement with the interprofessional team and support clinicians to provide patient-centred care. Recognition of the role has the potential to improve health-care delivery by promoting patient-centred care. PMID- 25040883 TI - In comparison with nitrate nutrition, ammonium nutrition increases growth of the frostbite1 Arabidopsis mutant. AB - Ammonium nutrition inhibits the growth of many plant species, including Arabidopsis thaliana. The toxicity of ammonium is associated with changes in the cellular redox state. The cellular oxidant/antioxidant balance is controlled by mitochondrial electron transport chain. In this study, we analysed the redox metabolism of frostbite1 (fro1) plants, which lack mitochondrial respiratory chain complex I. Surprisingly, the growth of fro1 plants increased under ammonium nutrition. Ammonium nutrition increased the reduction level of pyridine nucleotides in the leaves of wild-type plants, but not in the leaves of fro1 mutant plants. The observed higher activities of type II NADH dehydrogenases and cytochrome c oxidase in the mitochondrial electron transport chain may improve the energy metabolism of fro1 plants grown on ammonium. Additionally, the observed changes in reactive oxygen species (ROS) metabolism in the apoplast may be important for determining the growth of fro1 under ammonium nutrition. Moreover, bioinformatic analyses showed that the gene expression changes in fro1 plants significantly overlap with the changes previously observed in plants with a modified apoplastic pH. Overall, the results suggest a pronounced connection between the mitochondrial redox system and the apoplastic pH and ROS levels, which may modify cell wall plasticity and influence growth. PMID- 25040884 TI - iSlide: a 'big picture' interactive teledermatopathology e-learning system. AB - BACKGROUND: Dermatopathology training is often limited by facilities and a dearth of specialists. Advancements in information and communication technologies have made possible the adoption of innovative learning techniques, especially in places where specialists are lacking. OBJECTIVES: To implement and evaluate the performance of the iSlide system, which is an interactive dermatopathology training platform (http://scope.tmu.edu.tw/islide2/). METHODS: Fifty-two cases representing a variety of dermatopathology conditions and complications were used to set up the iSlide system, and virtual slides of these cases were produced. Medical students from the Dermatology Department of Taipei Medical University were taught to use the system. Performance of the system was evaluated and validated using questionnaires, the first comprising 20 questions and the second a shorter, six-question telephone-based survey on 15 of the 96 interns. Twenty cases prepared by the iSlide system were also presented at an international dermatopathology conference and evaluated by conference participants. RESULTS: Ninety-six students and 72 experts participated in the study. Ninety-two per cent of the students and 98% of the experts found the iSlide system to be a useful tool for learning dermatopathology. Of these, 82% of the students and 63% of the experts felt that iSlide was easy to use. CONCLUSIONS: iSlide is useful for dermatopathology. As only 82% of the student evaluators and 63% of the expert evaluators found the system easy to use, further work has to be done to improve the iSlide interface to make the system more user friendly. PMID- 25040885 TI - Mitotic Index is an Independent Predictor of Recurrence-Free Survival in Meningioma. AB - While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within-grade heterogeneity with respect to recurrence-free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on hematoxylin and eosin sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment, we evaluated 363 meningiomas with phospho histone H3 (Ser10) and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grade I (n = 268), grade II (n = 84) and grade III (n = 11) tumors were 1, 4 and 12. Classification and regression tree analysis to categorize cut-offs identified three subgroups defined by mitotic indices of 0-2, 3-4 and >=5, which on univariate analysis were associated with RFS (P < 0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (P < 0.01) after adjustment for Simpson grade, WHO grade and MIB-1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and grade II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification. PMID- 25040886 TI - Prediagnostic serum levels of inflammatory biomarkers are correlated with future development of lung and esophageal cancer. AB - This study tests the hypothesis that prediagnostic serum levels of 20 cancer associated inflammatory biomarkers correlate directly with future development of head and neck, esophageal, and lung cancers in a high-risk prospective cohort. This is a nested case-control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 21 cytokines, chemokines, and inflammatory molecules using Luminex technology in serum samples collected 2 or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank sum test, odds ratios, receiver operating characteristic areas of discrimination, and multivariate analysis. Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including interleukin-1Ralpha (IL-1Ra; 35.9), interferon alpha2 (IFN-a2; 34.0), fibroblast growth factor-2 (FGF-2; 17.4), and granulocyte/macrophage colony-stimulating factor (GM-CSF; 17.4). The same pattern was observed among future lung cancer cases for G-CSF (27.7), GM-CSF (13.3), and tumor necrosis factor-alpha (TNF-a; 8.6). By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development. This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients 2 or more years before cancer diagnosis. PMID- 25040887 TI - Molecular mechanism of allosteric modulation at GPCRs: insight from a binding kinetics study at the human A1 adenosine receptor. AB - BACKGROUND AND PURPOSE: Many GPCRs can be allosterically modulated by small molecule ligands. This modulation is best understood in terms of the kinetics of the ligand-receptor interaction. However, many current kinetic assays require at least the (radio)labelling of the orthosteric ligand, which is impractical for studying a range of ligands. Here, we describe the application of a so-called competition association assay at the adenosine A1 receptor for this purpose. EXPERIMENTAL APPROACH: We used a competition association assay to examine the binding kinetics of several unlabelled orthosteric agonists of the A1 receptor in the absence or presence of two allosteric modulators. We also tested three bitopic ligands, in which an orthosteric and an allosteric pharmacophore were covalently linked with different spacer lengths. The relevance of the competition association assay for the binding kinetics of the bitopic ligands was also explored by analysing simulated data. KEY RESULTS: The binding kinetics of an unlabelled orthosteric ligand were affected by the addition of an allosteric modulator and such effects were probe- and concentration-dependent. Covalently linking the orthosteric and allosteric pharmacophores into one bitopic molecule had a substantial effect on the overall on- or off-rate. CONCLUSION AND IMPLICATIONS: The competition association assay is a useful tool for exploring the allosteric modulation of the human adenosine A1 receptor. This assay may have general applicability to study allosteric modulation at other GPCRs as well. PMID- 25040888 TI - Strontium hydroxyapatite in situ gel-forming system - a new approach for minimally invasive bone augmentation. AB - OBJECTIVES: To achieve ideal functional and aesthetic requirements, ridge augmentation is often required before dental implant placement. Bone augmentation (especially vertical), which normally consists of complex and invasive surgeries, still remains challenge. This study seeks to investigate the feasibility of an injectable in situ gel-forming system containing strontium hydroxyapatite (SrHA) and alginate for minimally invasive bone augmentation in a rat calvarial model. MATERIAL AND METHODS: SrHA-alginate solution was prepared by mixing SrHA powder with alginate solution (20 mg/mL) to the final concentration of 0.5% (w/v). Each animal received a 200-MUL single subperiosteal injection of either SrHA-alginate solution or alginate solution. The new bone formation was assessed at 0, 4, and 8 weeks histologically and radiologically. RESULTS: The SrHA-alginate solution materials could form solid gel once injected. As such, no sutures were required to close the injection site. Significantly greater amount of new bone formation was observed in the SrHA-alginate group compared with the alginate group both by micro-CT and by histological section. The newly formed bone in the SrHA-alginate group originated both from the underlying original bone and from the elevated periosteum. A 2.3-fold increase of the vertical bone height was observed in the SrHA-alginate group compared with 1.3-fold increase in the alginate group. CONCLUSIONS: Rat calvarial bone augmentation was achieved by a single subperiosteal injection of SrHA-alginate solution without any administration of stem cells or growth factors. The in situ gel-forming material may hold potential therapeutic benefits for local bone augmentation in a minimally invasive manner. PMID- 25040889 TI - Fearful faces drive gaze-cueing and threat bias effects in children on the lookout for danger. AB - Most developmental studies of face emotion processing show faces in isolation, in the absence of any broader context. Here we investigate two types of interactions between expression and threat contexts. First, in adults, following of another person's direction of social attention is increased when that person shows fear and the context requires vigilance for danger. We investigate whether this also occurs in children. Using a Posner-style eye-gaze cueing paradigm, we tested whether children would show greater gaze-cueing from fearful than happy expressions when the task was to be vigilant for possible dangerous animals. Testing across the 8-12-year-old age range, we found this fear priority effect was absent in the youngest children but developed to reach adult levels in the oldest children. However, even the oldest children were unable to sustain fear prioritization when the onset of the target was delayed. Second, we addressed the development of 'threat bias' - namely faster identification of dangerous animals than safe animals - in the social context provided by expressive faces. In our non-anxious samples (i.e. with typical-population levels of anxiety), adults showed a threat bias regardless of the expression or looking direction of the just-seen cue face whereas 8-12-year-olds only showed a threat bias when the just seen cue face displayed fear. Overall, the results argue that some, but not all, aspects of expression-context interactions are mature by 12 years of age. PMID- 25040890 TI - Poor appointment-keeping behaviour among repeat blood donors and its relationship to the intent to donate again. AB - BACKGROUND AND OBJECTIVES: Anecdotal evidence suggests that missed donation appointments among repeat whole-blood donors are associated with decreased likelihood of future blood donation. This study sought to examine the relationship between missed donation appointments and intention to donate again among repeat whole-blood donors and to examine whether demographic variables are related to appointment-keeping behaviour. METHODS: During the period February June 2013, telephone interviews were conducted with repeat donors who either did not show up for or cancelled their donation appointments on the day of the appointment. We asked them whether or not they wanted to schedule appointments for subsequent donations. RESULTS: Rates of missed donation appointments varied by age, but not gender. Although a statistically significant difference between male and female donors was not found with regard to willingness to donate again, female donors were more likely than male donors to call and cancel their appointment. Finally, compared with repeat donors who called and cancelled their appointment, no-show donors were 2.5 times less likely to schedule appointments for subsequent donations (P < 0.001). CONCLUSION: The results demonstrate that poor appointment-keeping behaviour, and in particular no-show behaviour, is significantly associated with decreased likelihood of future blood donation among repeat whole-blood donors. PMID- 25040891 TI - Identifying benefits and barriers to respite for carers of children with complex health needs: A qualitative study. AB - Abstract Background: Increasing numbers of children with complex health needs are being cared for in their own homes. Caring for a child with complex health needs is an enormous task for a family and so access to suitable respite is critical for the wellbeing of all members of the family. Aim: The aim of this study was to explore the concept of 'suitable' respite from the perspective of the carer and whether suitable respite is currently available. Method: A qualitative descriptive approach was used. Five people who acted as a carer for a child with complex health agreeing to participate in the study. Semi-structured interviews were conducted in the home of the carers and interview data analyses with a thematic analysis. Results: This study identified some of the barriers and enablers for families when accessing respite services for children with complex health needs. Carers describe optimal respite for these children to be similar to a family home with suitable facilities, equipment and activities for children. Flexible respite services and enthusiastic competent staff were considered very important by the family carers. Conclusion: Further research is needed to better understand the complexities of care for CWCHN and to identify effective strategies to support family carers. PMID- 25040892 TI - Joint hypermobility and headache: understanding the glue that binds the two together--part 1. AB - BACKGROUND: Heritable connective tissue disorders (HCTD) present with a wide array of findings, including headache. Because of their unusual substrate, headaches in HCTD can derive from both common and uncommon circumstances. METHODS: Literature review. RESULTS: Ehlers-Danlos hypermobile type can be recognized by multiple joint findings and its tendency to progress to a multisystem chronic pain syndrome. Ehlers-Danlos classic type also manifests joint laxity and similar pain complaints, but is differentiated by its skin laxity and fragility. Ehlers-Danlos vascular type presents the most severe risk due to blood vessel and hollow organ rupture. Marfan syndrome demonstrates skeletal abnormalities, lens dislocations, and aortic root dilation that can result in dissection. CONCLUSIONS: In a headache patient, recognizing the presence of an HCTD improves the strategy for diagnosis and management. A brief review of findings related to joints, skin, and arteries may prompt further investigation into the HCTDs. PMID- 25040893 TI - Hydrophobic cavity formed by oligopeptide for doxorubicin delivery based on dendritic poly(L-lysine). AB - To deliver anti-cancer drugs to tumors, a hydrophobic cavity was prepared in the dendritic molecule, dendritic poly(L-lysine) of sixth generation (KG6), which was used as a drug carrier. The dendritic molecule was modified with polyethylene glycol (PEG)-linked hydrophobic penta-phenylalanine or penta-alanine. The hydrophobic cavity was formed between the KG6 and PEG chains. The penta phenylalanine peptide was better in encapsulating doxorubicin (DOX) in the cavity compared with penta-alanine. The loaded DOX was slowly released from the cavity, and it depended on pH. After intravenous injection, the DOX-loaded dendrimers accumulated in the tumor by the enhanced permeability and retention effect, and showed significant suppression of tumor growth without loss of body weight. These results indicate that hydrophobic oligopeptides can be used for forming a hydrophobic cavity in a dendritic molecule for delivery of anti-cancer drugs to tumor sites. PMID- 25040894 TI - Prophylactic antibiotic regimen and dental implant failure: a meta-analysis. AB - The aim of this meta-analysis was to investigate whether there are any positive effects of prophylactic antibiotic regimen on implant failure rates and post operative infection when performing dental implant treatment in healthy individuals. An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomised or not. The search strategy resulted in 14 publications. The I(2) statistic was used to express the percentage of the total variation across studies due to heterogeneity. The inverse variance method was used with a fixed- or random-effects model, depending on the heterogeneity. The estimates of relative effect were expressed in risk ratio (RR) with 95% confidence interval. Six studies were judged to be at high risk of bias, whereas one study was considered at moderate risk, and six studies were considered at low risk of bias. The test for overall effect showed that the difference between the procedures (use versus non-use of antibiotics) significantly affected the implant failure rates (P = 0.0002), with a RR of 0.55 (95% CI 0.41-0.75). The number needed to treat (NNT) to prevent one patient having an implant failure was 50 (95% CI 33 100). There were no apparent significant effects of prophylactic antibiotics on the occurrence of post-operative infections in healthy patients receiving implants (P = 0.520). A sensitivity analysis did not reveal difference when studies judged as having high risk of bias were not considered. The results have to be interpreted with caution due to the presence of several confounding factors in the included studies. PMID- 25040895 TI - Burden of HIV and hepatitis C co-infection: the changing epidemiology of hepatitis C in HIV-infected patients in France. AB - BACKGROUND & AIMS: To better evaluate the HIV-HCV co-infection burden in the context of new effective HCV treatment. METHODS: We reviewed all the epidemiological data available on HCV-related disease in HIV-infected patients in France. Sources of data have been selected using the following criteria: (i) prospective cohorts or cross-sectional surveys; (ii) conducted at a national level; (iii) in the HIV-infected population; (iv) able to identify HCV co infection and chronic active hepatitis C (HCV RNA positive); and (v) conducted during the period 2003-2012. RESULTS: The overall prevalence of HIV-HCV co infection has decreased from 22-24% to 16-18%. This prevalence decreased from 93% to 87% among injecting drug users while it increased from 4% to 6% among men who have sex with men. The characteristics of patients have changed: decrease in the proportion of patients with chronic active hepatitis C (HCV RNA positive) from 77% to 63% and in the genotypes 2 and 3 HCV infection; increase in the proportion of HCV genotype 1 (from 45-50% to 58%) and genotype 4 (from 15% to 22%). The proportion of patients treated with highly active antiretroviral therapy increased from 76% to 95%, with higher rates of undetectable HIV viral load (47% in 2004 vs. 85% in 2012). CONCLUSION: The decreasing prevalence and the change in patients profile in HIV-HCV co-infection underline the importance of continuing efforts to educate physicians and patients. This should increase the benefit of viral risk reduction policies and increase the access of co-infected patients to HCV treatment. PMID- 25040896 TI - PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. AB - BACKGROUND AND AIM: Lifestyle modification is the cornerstone for the management of nonalcoholic fatty liver disease (NAFLD), and patatin-like phospholipase 3 (PNPLA3) is one of the most important genetic determinants of NAFLD. We aimed to investigate the effect of PNPLA3 gene polymorphism on the response to lifestyle modification in NAFLD patients. METHODS: This was a post-hoc analysis of a randomized controlled trial on a lifestyle modification program in community NAFLD patients. The PNPLA3 rs738409 gene polymorphism was correlated with changes in metabolic profile and intrahepatic triglyceride content (IHTG) as measured by proton magnetic resonance spectroscopy. RESULTS: One hundred and fifty-four patients were equally randomized into the intervention and control groups. The presence of G allele was associated with greater reduction in IHTG (CC: 3.7 +/- 5.2%, CG: 6.5 +/- 3.6%), and GG: 11.3 +/- 8.8% (Spearman's correlation, 0.34; P = 0.002), body weight (P = 0.030), waist-to-hip ratio (P = 0.024), total cholesterol (P = 0.031), and low-density lipoprotein cholesterol (P = 0.009) in the intervention group. In contrast, PNPLA3 polymorphism had no impact on IHTG changes in the control group. By multivariable analysis, PNPLA3 genotype and body mass index (BMI) change were independently associated with IHTG reduction in the intervention group. Only BMI change was associated with IHTG reduction in the control group. CONCLUSION: Although the PNPLA3 rs738409 GG genotype confers a higher risk of NAFLD, these patients are more sensitive to the beneficial effects of lifestyle modification and should be encouraged to do so. PMID- 25040897 TI - Social networks of people with mild intellectual disabilities: characteristics, satisfaction, wishes and quality of life. AB - BACKGROUND: A supportive social network is crucial for facilitating social inclusion, which can, in turn, contribute to the quality of life (QOL) for people with intellectual disabilities (ID). In this study, we investigate how people with mild ID perceive their social networks and which network characteristics relate to satisfaction with the network and perceived QOL. METHOD: Data were gathered from 33 young adults with a mild to borderline ID using structured questionnaires: the MSNA to map the social network, the IDQOL-16 to assess QOL, and a questionnaire to determine satisfaction and wishes with regard to the social network. RESULTS: The majority of the participants (73.1%) were satisfied with their social networks. Improvement in the area of strengthening existing ties (e.g. more frequent contact, better contact) was desired as opposed to expansion of the network. Affection--especially towards family and professionals- was most strongly related to perceived QOL. It appears to be essential that relatives live in the same town, can frequently meet up and provide both emotional and practical support. CONCLUSIONS: The significance of family and the importance of high-quality interpersonal relationships between professional and client in the lives of young adults with ID cannot be overestimated. Although measures of satisfaction and wishes can have limitations, in actual practice it is considered useful to assess the opinions of clients with respect to their social networks. Interventions can then be tailored to the needs and wishes of the persons themselves. PMID- 25040898 TI - Efficacy of motivational enhancement therapy on alcohol use disorders in patients with chronic hepatitis C: a randomized controlled trial. AB - AIMS: To determine the efficacy of motivational enhancement therapy (MET) on alcohol use in patients with the hepatitis C virus (HCV) and an alcohol use disorder (AUD). DESIGN: Randomized, single-blind, controlled trial comparing MET to a control education condition with 6-month follow-up. SETTING: Patients were recruited from hepatitis clinics at the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care Systems, USA. PARTICIPANTS AND INTERVENTION: Patients with HCV, an AUD and continued alcohol use (n = 139) were randomized to receive either MET (n = 70) or a control education condition (n = 69) over 3 months. MEASUREMENTS: Data were self-reported percentage of days abstinent from alcohol and number of standard alcohol drinks per week 6 months after randomization. FINDINGS: At baseline, subjects in MET had 34.98% days abstinent, which increased to 73.15% at 6 months compared to 34.63 and 59.49% for the control condition. Multi-level models examined changes in alcohol consumption between MET and control groups. Results showed a significant increase in percentage of days abstinent overall (F(1120.4) = 28.04, P < 0.001) and a significant group * time effect (F(1119.9) = 5.23, P = 0.024) with the MET group showing a greater increase in percentage of days abstinent at 6 months compared with the education control condition. There were no significant differences between groups for drinks per week. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. CONCLUSION: Motivational enhancement therapy (MET) appears to increase the percentage of days abstinent in patients with chronic hepatitis C, alcohol use disorders and ongoing alcohol use. PMID- 25040899 TI - Tolerance to egg proteins in egg-sensitized infants without previous consumption. AB - BACKGROUND: Egg-sensitized infants who have never eaten egg may react at first ingestion. We sought to determine the association between skin prick test (SPT) and specific IgE (sIgE) to egg proteins (EP) and oral food challenge (OFC) outcomes to find cut-off points which can diagnose egg allergy. METHODS: One hundred and fifty-four infants up to 18 months, with cow's milk allergy (CMA) and/or atopic dermatitis (AD) without previous egg consumption, were recruited. SPT to EP were performed. If it was positive, sIgE was performed. If positive SPT and/or sIgE (n = 94), OFC was performed between 12 and 18 months. Receiver operating characteristic (ROC) curves were plotted, and the outcome of the OFC was related to SPT and sIgE. The cut-off points with the best diagnostic accuracy were found. RESULTS: Ninety-four patients were sensitized to egg (69%) and 60 nonsensitized (31%). Of the sensitized, 27 tolerated cooked (CE) and raw egg (RE) (28.7%). Sixty-seven were allergic (71.3%): 29 reacted to CE, seven to egg yolk (EY) and 22 to egg white (EW) and 38 reacted to RE. 69.2% tolerated CE. EW SPT and ovalbumin (OVA) sIgE have the best area under the curve (AUC). The higher positive predictive values (PPV) were obtained for EW SPT and EW sIgE. CONCLUSIONS: In egg-sensitized infants with EW SPT >=8 mm and/or EW sIgE >=8.36 KU/l, egg diagnostic OFC can be avoided as there is 94% probability of becoming positive. In the other patients, OFC should be performed safely and early to avoid unnecessary diets. PMID- 25040900 TI - Delayed-type hypersensitivity to 6-methyl-prednisolone sodium succinate. PMID- 25040901 TI - An observational study of how patients are identified before medication administrations in medical and surgical wards. AB - The aims of this study were to clarify how a patient's identity was verified before the administration of medication in medical and surgical wards in a hospital, as well as to study the association between patient identification and the registered nurse's work experience, observed interruptions, and distractions. The study material was collected during April and May 2012 in two surgical and two medical wards in one university hospital in Finland, using a direct, structured observation method. A total of 32 registered nurses were observed while they administered 1058 medications to 122 patients. Patients were not identified at all in 66.8% (n = 707) of medication administrations. Patient identifications were made more often by nurses with shorter work experience in the nursing profession or in the wards (4 years or less), or if distractions existed during medication administration. According to the results, patient identification was not adequately conducted. There is a need for education and change in the culture of medication processes and nursing practice. PMID- 25040902 TI - Towards evidence-based management of delivery following previous obstetric anal sphincter injury. PMID- 25040903 TI - Eng2 is a component of a dynamic protein complex required for endocytic uptake in fission yeast. AB - Eng2 is a glucanase required for spore release, although it is also expressed during vegetative growth, suggesting that it might play other cellular functions. Its homology to the Saccharomyces cerevisiae Acf2 protein, previously shown to promote actin polymerization at endocytic sites in vitro, prompted us to investigate its role in endocytosis. Interestingly, depletion of Eng2 caused profound defects in endocytic uptake, which were not due to the absence of its glucanase activity. Analysis of the dynamics of endocytic proteins by fluorescence microscopy in the eng2Delta strain unveiled a previously undescribed phenotype, in which assembly of the Arp2/3 complex appeared uncoupled from the internalization of the endocytic coat and resulted in a fission defect. Strikingly also, we found that Eng2-GFP dynamics did not match the pattern of other endocytic proteins. Eng2-GFP localized to bright cytosolic spots that moved around the cellular poles and occasionally contacted assembling endocytic patches just before recruitment of Wsp1, the Schizosaccharomyces pombe WASP. Interestingly, Csh3-YFP, a WASP-interacting protein, interacted with Eng2 by co immunoprecipitation and was recruited to Eng2 in bright cytosolic spots. Altogether, our work defines a novel endocytic functional module, which probably couples the endocytic coat to the actin module. PMID- 25040904 TI - Multi-gene silencing in Arabidopsis: a collection of artificial microRNAs targeting groups of paralogs encoding transcription factors. AB - Functional redundancy often hampers the analysis of gene families. To overcome this difficulty, we constructed Arabidopsis thaliana lines that expressed artificial microRNAs designed to simultaneously target two to six paralogous genes encoding members of transcription factor families. Of the 576 genes that we chose as targets, only 122 had already been functionally studied at some level. As a simple indicator of the inhibitory effects of our amiRNAs on their targets, we examined the amiRNA-expressing transgenic lines for morphological phenotypes at the rosette stage. Of 338 transgenes tested, 21 caused a visible morphological phenotype in leaves, a proportion that is much higher than that expected as a result of insertional mutagenesis. Also, our collection probably represents many other mutant phenotypes, not just those in leaves. This robust, versatile method enables functional examination of redundant transcription factor paralogs, and is particularly useful for genes that occur in tandem. PMID- 25040905 TI - The Xanthomonas campestris effector protein XopDXcc8004 triggers plant disease tolerance by targeting DELLA proteins. AB - Plants protect themselves from the harmful effects of pathogens by resistance and tolerance. Disease resistance, which eliminates pathogens, can be modulated by bacterial type III effectors. Little is known about whether disease tolerance, which sustains host fitness with a given pathogen burden, is regulated by effectors. Here, we examined the effects of the Xanthomonas effector protein XopDXcc8004 on plant disease defenses by constructing knockout and complemented Xanthomonas strains, and performing inoculation studies in radish (Raphanus sativus L. var. radiculus XiaoJinZhong) and Arabidopsis plants. XopDXcc8004 suppresses disease symptoms without changing bacterial titers in infected leaves. In Arabidopsis, XopDXcc8004 delays the hormone gibberellin (GA)-mediated degradation of RGA (repressor of ga1-3), one of five DELLA proteins that repress GA signaling and promote plant tolerance under biotic and abiotic stresses. The ERF-associated amphiphilic repression (EAR) motif-containing region of XopDXcc8004 interacts with the DELLA domain of RGA and might interfere with the GA-induced binding of GID1, a GA receptor, to RGA. The EAR motif was found to be present in a number of plant transcriptional regulators. Thus, our data suggest that bacterial pathogens might have evolved effectors, which probably mimic host components, to initiate disease tolerance and enhance their survival. PMID- 25040906 TI - Oil extraction from algae: A comparative approach. AB - In this article, various methods including soxhlet, Bligh & Dyer (B&D), and ultrasonic-assisted B&D were investigated for the extraction of lipid from algal species Chlorella vulgaris. Relative polarity/water content and impolar per polar ratios of solvents were considered to optimize the relative proportions of each triplicate agent by applying the response surface method (RSM). It was found that for soxhlet, hexane-methanol (54-46%, respectively) with total lipid extraction of 14.65% and chloroform-methanol (54-46%, respectively) with the extraction of 19.87% lipid were the best set of triplicate where further addition of acetone to the first group and ethanol to the second group did not contributed to further extraction. In B&D, however, chloroform-methanol-water (50%-35%-15%, respectively) reached the all-time maximum of 24%. Osmotic shock as well as ultrasonication contributed to 3.52% of further extraction, which is considered to promote the total yield up to almost 15%. From the growth data and fatty acid analysis, the applied method was assessed to be appropriate for biodiesel production with regard to selectivity and extraction yield. PMID- 25040907 TI - Single-cause attribution in a multifactorial world: cerebral palsy attributed to or associated with congenital cytomegalovirus? PMID- 25040909 TI - Primary complete repair of interrupted aortic arch with associated lesions in infants. AB - OBJECTIVE: Interrupted aortic arch (IAA) is a complicated congenital heart disease requiring an individualized management strategy. We reported the results for surgical repair of IAA with associated anomalies. METHODS: This was a retrospective review of 119 patients undergoing one-stage biventricular repair of IAA with associated lesions at the median age of 18 days (range, 3 to 90) between 2000 and 2013. End-to-side anastomosis with patch augmentation was adopted in all patients. Left ventricular outflow tract obstruction (LVOTO) procedure was performed in 23 patients. Selective cerebral perfusion was used in 55 patients (46%). RESULTS: IAA types were A in 92 patients (77%) and B in 27 (23%). Associated anomalies were multiple including noncomplex lesions in 91 (76%) and complex lesions in 28 (24%). Mean follow-up was 98.7 +/- 74.2 months. Follow-up was 80% completed. There were 19 in-hospital and six late deaths. The overall actuarial survival including early mortality was 84% at 30 day, 81% at five years, and 79% at 10 and 13 years. Cox proportional hazard model was used to determine risk factors for death: presence of complex lesions (p = 0.005), critical aortic valve stenosis (AVS) (p = 0.016), and long cardiopulmonary bypass (CPB) duration (p = 0.036). Eighteen patients required re-intervention, including 16 for subsequent LVOTO and two for arch restenosis. CONCLUSIONS: Single-stage repair using end-to-side anastomosis with patch augmentation is an effective approach for infants with IAA. PMID- 25040910 TI - MRI-guided breast needle core biopsies: pathologic features of newly diagnosed malignancies. AB - Magnetic resonance imaging (MRI) of the breast is used for select groups of patients. MRI-guided breast core needle biopsies performed over a 3-year period were retrospectively reviewed to determine the incidence and types of cancers found and to correlate the cancers with the MRI findings and the indication for the study. Patients were stratified based on indication for MRI examination including, evaluation of disease extent in patients with current ipsilateral carcinoma, surveillance for recurrence of prior ipsilateral carcinoma, as a problem-solving method and for screening high-risk patients. The high-risk screening group included those with family history (with or without germline mutations), prior chest wall radiation, and contralateral breast carcinoma (current or prior). Four-hundred and forty-five biopsies were performed on 386 patients. The majority of biopsies (79%) were benign. Biopsies demonstrating ductal carcinoma in situ (DCIS) and invasive carcinoma were more likely to present as nonmass-like and mass-forming enhancements respectively, but with only 52% specificity. The highest rate of malignancy (44%) was seen in the least frequently biopsied patient group (n = 25), those with prior ipsilateral carcinoma. Conversely, the most frequently biopsied group (n = 283), the high risk screening group, demonstrated the lowest malignancy rate (16%). Within this group, most malignant cases were invasive carcinomas (n = 27), 67% of which were small (<=1 cm), well or moderately differentiated with a good prognostic receptor profile (estrogen receptor positive, human epidermal growth factor receptor 2 negative), and lacked nodal macrometastases. The remaining malignant cases in the high-risk screening group were DCIS with or without microinvasion (n = 18), 78% of which demonstrated high nuclear grade. Overall, enhancement pattern did not correlate with the likelihood of or type of malignancy. The most common types of carcinomas identified by screening were small estrogen receptor positive invasive tumors and high grade DCIS. PMID- 25040911 TI - Effect of dietary Schizochytrium microalga oil and fish oil on plasma cholesterol level in rats. AB - The purpose of the study was to test the hypothesis that the dietary oils with different content of n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) affect plasma lipid level in rats in a different degree. The diets with 6% of fish oil (FO) and Schizochytrium microalga oil (SchO; EPA+DHA content in the diets 9.5 + 12.3 and 2.6 + 29.5% of the sum of total fatty acids, respectively) were used; the diet with 6% of safflower oil (high content of n-6 PUFA linoleic acid, 65.5%; EPA+DHA content 0.7 + 0.9%) was used as a control. The difference between FO and SchO was established only in the case of plasma triacylglycerol (TAG) level: plasma TAG of the FO-fed rats did not differ from the control rats (p > 0.05), while SchO decreased (p < 0.05) plasma TAG to 46% of the control. On the other hand, FO and SchO decreased (p < 0.05) total plasma cholesterol (TC) in rats in the same extent, to 73% of the control. Regarding the underlying mechanisms for the TC decrease, both SchO and FO up regulated hepatic Insig-1 gene (181 and 133% of the control; p < 0.05), which tended (p = 0.15 and p = 0.19 respectively) to decrease the amount of hepatic nSREBP-2 protein (61 and 66% of the control). However, neither SchO nor FO influenced hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase gene expression (p > 0.05); SchO (but not FO) increased (p < 0.05) low-density lipoprotein receptor mRNA in the liver. It was concluded that the decrease of total plasma cholesterol might be caused by an increased cholesterol uptake from plasma into the cells (in the case of SchO), but also by other (in the present study not tested) mechanisms. PMID- 25040912 TI - MicroRNA-302b-inhibited E2F3 transcription factor is related to all trans retinoic acid-induced glioma cell apoptosis. AB - All-trans retinoic acid (ATRA), a derivative of retinoid, is involved in the onset of differentiation and apoptosis in a wide variety of normal and cancer cells. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression. Several miRNAs were identified to participate in ATRA-mediated cell differentiation. However, no studies have demonstrated whether miRNA can enhance ATRA cytotoxicity, thereby resulting in cell apoptosis. This study investigated the effects of ATRA-mediated miRNA expression in activating apoptotic pathways in glioblastoma. First, we found that high-dose ATRA treatment significantly reduced cell viability, caspase-dependent apoptosis, endoplasmic reticular (ER) stress activation, and intracellular reactive oxygen species accumulation. From microarray data, miR-302b was analyzed as a putative downstream regulator upon ATRA treatment. Furthermore, we found that ATRA up-regulated miR-302b expression in a dose- and time-dependent manner through retinoic acid receptor alpha mediated pathway. Overexpression and knockdown of miR-302b significantly influenced ATRA-mediated cytotoxicity. E2F3, an important transcriptional regulator of glioma proliferation, was validated to be a direct target gene of miR-302b. The miR-302b-reduced E2F3 levels were also identified to be associated with ATRA-mediated glioma cell death. These results emphasize that an ATRA mediated miR-302b network may provide novel therapeutic strategies for glioblastoma therapy. We propose that high-dose all-trans retinoic acid (ATRA) treatment, a derivative of retinoid, significantly induces glioblastoma cell apoptosis via caspase-dependent apoptosis, endoplasmic reticular (ER) stress, and intracellular reactive oxygen species (ROS) accumulation. The miR-302b overexpression enhanced by ATRA-mediated retinoic acid receptor (RAR)alpha pathway was also identified. The E2F3 repression, a novel target gene of miR 302b, was involved in ATRA-induced glioblastoma cell cytotoxicity. PMID- 25040913 TI - Why U.S. epilepsy hospital stays rose in 2006. AB - OBJECTIVE: We observed a substantial increase in age-adjusted hospitalization rates in the United States National Hospital Discharge Survey data from 1996 to 2010. We aimed to assess reasons for this increase. METHODS: The National Hospital Discharge Survey collected data on a national sample of short-term hospital stays in nonfederal hospitals. We determined epilepsy-related discharge diagnoses by age, gender, and region using weighted analysis, and estimated age adjusted rates and annual percent changes using regression analysis. We also looked at epilepsy as the principal discharge diagnosis in the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project. RESULTS: In the United States, on average, nearly 110,000 more admissions were reported each year with epilepsy as the principal discharge diagnosis in 2006-2010 than in 1996 2005, a 2.7-fold increase in hospitalization rates from epilepsy. During this period, there were more hospitalizations with principal discharge diagnosis of epilepsy not otherwise specified, and among older patients. The number of discharges with seizure not otherwise specified dropped dramatically after 2006, and was more evident among pediatric patients. The age-adjusted rates of hospital stays combining discharges with any mention of epilepsy (345.XX) or seizures unspecified (780.39) in seven discharge diagnoses, were similar in 1996-2005 and 2006-2010. SIGNIFICANCE: We postulate that the excess in hospitalizations with epilepsy as first discharge diagnosis in 2006-2010 in the United States was related to the changes in coding in 2006. Any use of U.S. hospital discharge data with epilepsy-related diagnosis after that date will require further validation. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 25040914 TI - Severe folliculitis with secondary impetiginization in the scalp of a woman treated with panitumumab. PMID- 25040915 TI - Migration and reproductive biology of Mugil liza (Teleostei: Mugilidae) in south Brazil. AB - The mullet Mugil liza occurs along the Atlantic coast of South America from Venezuela to Argentina, but 95% of the commercial catch is collected from south Brazil between Sao Paulo and Argentina. Mugil liza is a single spawner with oocyte development occurring synchronously in two groups. Spawning happens in marine areas and occurs after migration. The reproductive migration occurs from Argentina (38 degrees S) to the southern Brazilian states (24-26 degrees S) from April to July, with peak spawning in June between northern Santa Catarina and Parana. The presence of hyaline oocytes was associated with high salinity and sea surface temperatures of 19-21 degrees C, and followed the seasonal northward displacement of these oceanographic conditions. The average size at first maturity (Lm ) for both sexes was 408.3 mm total length, LT . Males (Lm = 400.1) matured earlier than females (Lm = 421.9 mm). Fecundity ranged from 818,992 to 2,869,767 oocytes (mean = 1,624,551) in fish that were between 426 and 660 mm LT . PMID- 25040916 TI - Interactions between the stratum corneum and topically applied products: regulatory, instrumental and formulation issues with focus on moisturizers. AB - Virtually everyone in Europe will use at least one cosmetic product every day. The extensive use of cosmetics and results from measurements of quality of life in patients with skin diseases demonstrate the importance of a healthy skin. The skin is not only a barrier against desiccation and intrusion of harmful materials, but also an organ of social communication, where dry, scaly, rough stratum corneum is unappealing to touch, inducing anxiety and depression. Knowledge about the skin biochemistry and the use of noninvasive instruments facilitate the development of topical products and quantification of their effects. The presentation of the products and mode of action determine the regulatory demands and the approval process, as they can fall into different regulatory entities, such as cosmetics, medicinal products, medical devices and as other chemical products. The majority of the topical products on the market are regulated as cosmetics. For example, facial skin care and daily moisturizing routines are frequently used. However, despite visible relief of dryness symptoms, some products are reported to result in deterioration of the skin barrier function. New clinical outcomes show important clinical differences between formulations and the relapse of eczema. In a worst case scenario, treatment with a moisturizing cream may increase the risks of eczema and asthma. In the present overview, product presentations and mode of actions are reflected against the regulatory demands in Europe. The regulations are continuously revisited and new guidelines are being implemented, such as the new cosmetic regulation with advice on testing and responsible marketing. PMID- 25040917 TI - Urinary corticoid concentrations measured by 5 different immunoassays and gas chromatography-mass spectrometry in healthy dogs and dogs with hypercortisolism at home and in the hospital. AB - BACKGROUND: Determination of the urinary corticoid-to-creatinine ratio (UCCR) is an important screening test in the diagnosis of hypercortisolism (HC). However, urinary cortisol metabolites interfere with cortisol measurement in immunoassays, leading to decreased specificity. Gas chromatography-mass spectrometry (GC-MS) is considered the gold standard for steroid hormone analysis, because it provides a high level of selectivity and accuracy. OBJECTIVES: To prospectively compare the UCCR of healthy dogs and dogs with HC determined by 5 different immunoassays and by GC-MS and to evaluate the influence of veterinary care on UCCR. ANIMALS: Twenty healthy dogs; 18 dogs with HC. METHODS: Urine was collected in the hospital and again after 6 days at home. Three chemiluminescence immunoassays (Access 2, Beckmann; Immulite 2000, DPC Siemens, with and without trichloromethane extraction) and 2 RIAs (Utrecht in house; Access Beckmann) were used. GC-MS analyses were performed with Agilent 6890N/5973N. Urinary corticoid concentrations were related to urinary creatinine concentrations. RESULTS: Immunoassay results were significantly higher compared to GC-MS results. Evaluation of bias plots and clinical assessment made on the basis of the assay results of each dog indicated substantial disagreement among the assays. Sensitivity varied from 37.5 to 75% and with selected assays was lower in samples from day 6 compared to day 0. GC-MS was not superior to the immunoassays in discriminating healthy from HC dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Considerable variation must be anticipated comparing different urinary cortisol assays. Establishing an assay- and laboratory-specific reference range is critical when using UCCR. PMID- 25040918 TI - Clinical anatomy of the maxillary nerve block in pediatric patients. AB - BACKGROUND: Anatomical landmarks in children are mostly extrapolated from studies in adults. Despite this, complex regional anesthetic procedures are frequently performed on pediatric patients. Sophisticated imaging techniques are available but the exact position, course and/or relationships of the structures are best understood with appropriate anatomical dissections. Maxillary nerve blocks are being used for peri-operative analgesia after cleft palate repair in infants. However, the best approach for blocking the maxillary nerve in pediatric patients has yet to be established. OBJECTIVE: To determine the best approach for blocking the maxillary nerve within the pterygopalatine fossa. METHODS: In an attempt to define an optimal approach for maxillary nerve block in this age group three approaches were simulated and compared on 10 dried pediatric skulls as well as 30 dissected pediatric cadavers. The needle course, including depth and angles, to block the maxillary nerve, as it exits the skull at the foramen rotundum within the pterygopalatine fossa, was measured and compared. Two groups were studied: Group 1 consisted of skulls and cadavers of neonates (0-28 days after birth) and Group 2 consisted of skulls and cadavers from 28 days to 1 year after birth. RESULTS: No statistically significant difference (P > 0.05) was found between the left and right side of each skull or cadaver. Only technique B, the suprazygomatic approach from the frontozygomatic angle towards the pterygopalatine fossa, exhibited no statistical significance (P > 0.05) when other measurements made on the skulls and cadavers were compared. Technique A, a suprazygomatic approach from the midpoint on the lateral border of the orbit, as well as technique C, an infrazygomatic approach with an entry at a point on a vertical line extending along the lateral orbit wall, showed statistical significant differences when measurements of the skulls and cadavers were compared. CONCLUSIONS: On the basis of these findings technique B produces the most consistent data for age groups 1 and 2 and supports the clinical findings recently reported. PMID- 25040919 TI - Systematic identification of tRNAome and its dynamics in Lactococcus lactis. AB - Transfer RNAs (tRNAs) through their abundance and modification pattern significantly influence protein translation. Here, we present a systematic analysis of the tRNAome of Lactococcus lactis. Using the next-generation sequencing approach, we identified 40 tRNAs which carry 16 different post transcriptional modifications as revealed by mass spectrometry analysis. While small modifications are located in the tRNA body, hypermodified nucleotides are mainly present in the anticodon loop, which through wobbling expand the decoding potential of the tRNAs. Using tRNA-based microarrays, we also determined the dynamics in tRNA abundance upon changes in the growth rate and heterologous protein overexpression stress. With a fourfold increase in the growth rate, the relative abundance of tRNAs cognate to low abundance codons decrease, while the tRNAs cognate to major codons remain mostly unchanged. Significant changes in the tRNA abundances are observed upon protein overexpression stress, which does not correlate with the codon usage of the overexpressed gene but rather reflects the altered expression of housekeeping genes. PMID- 25040920 TI - Release of E. coli D21g with transients in water content. AB - Transients in water content are well-known to mobilize microorganisms that are retained in the vadose zone. However, there is no consensus on the relative importance of drainage and imbibition events on microorganism release. To overcome this limitation, we have systematically studied the release of Escherichia coli D21g during cycles of drainage and imbibition under various solution chemistry and initial conditions. Results from these column studies revealed the influence of imbibition and drainage on D21g release. In particular, imbibition efficiently released cells from the air-water interface (AWI) that were initially retained under steady-state unsaturated conditions by expansion of water films and destruction of the AWI. Conversely, significant release and transport of cells during drainage only occurred below a critical water saturation (water film thickness). In this case, a fraction of the cells that were initially retained on the solid-water interface (SWI) partitioned into the mobile aqueous phase and the AWI as the receding water film thickness decreased during drainage. The efficiency of cell release from the SWI during drainage was much less than for the AWI during imbibition. Cycles of drainage and imbibition removed cells from the SWI and the AWI, respectively. However, the peak concentration and amount of cells that were released increased with the number of retained cells and the amount of drainage and imbibition, and decreased with the number of drainage and imbibition cycles. Release of cells during drainage and imbibition was found to be more pronounced in the presence of a weak secondary minimum when the ionic strength (IS) was 5 mM NaCl. Increases in the solution IS decreased the influence of water transients on release, especially during drainage. Complete recovery of the retained cells could be achieved using both IS reduction and cycles of drainage and imbibition, even when the cells were retained under favorable attachment conditions. In general, cell release was more pronounced with transients in water content than transients in IS when the IS >= 5 mM. PMID- 25040921 TI - The impact of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction on pancreatic fistula after pancreaticoduodenectomy: meta-analysis of randomized controlled trials. AB - BACKGROUND: Pancreatic fistula (PF) remains a common source of morbidity following pancreaticoduodenectomy (PD). Despite numerous studies, the optimal method of pancreatic remnant reconstruction is controversial. This study examines the hypothesis that pancreaticogastrostomy (PG) is associated with a lower risk for PF after PD compared with pancreaticojejunostomy (PJ). METHODS: Five electronic databases and the grey literature were searched for randomized controlled trials (RCTs) comparing PJ and PG after PD. Two reviewers independently selected studies, extracted data and assessed methodology. The primary outcome was the occurrence of PF of International Study Group on Pancreatic Fistula (ISGPF) Grade B or C. RESULTS: Four RCTs including 676 patients were included. Pancreaticogastrostomy reduced the risk for PF [relative risk (RR) 0.41, 95% confidence interval (CI) 0.21-0.62] without any difference between high- and low-risk patients. Absolute risk reduction for PF was 4% (95% CI 2.4-5.6) in low-risk patients compared with 10% (95% CI 6.5-14.8) in high-risk patients undergoing PG rather than PJ. The strength of evidence for PF outcome was moderate according to the GRADE classification. CONCLUSIONS: Reconstruction by PG decreases the rate of PF in comparison with PJ. Surgeons should consider reconstructing the pancreatic remnant following PD with PG, particularly in patients at high risk for PF. PMID- 25040922 TI - Attachment-related biases in adolescents' memory. AB - Attachment theorists propose that individuals' internal working models influence their social information processing. This study explored links between attachment representations and social information processing by examining adolescents' (n = 189; Mage = 16.5 years) attachment-related memory biases. Participants completed laboratory tasks assessing memory for (a) emotionally salient childhood events, (b) adjectives describing their parents, and (c) generalized parent-related characteristics not specific to their own parents. As expected, dismissing attachment (assessed using the Adult Attachment Interview) was linked across tasks to a deactivating strategy in which memory for emotional childhood events and attachment-relevant stimuli was reduced. In contrast, evidence that preoccupied attachment was linked to a hyperactivating strategy in which memory was heightened emerged only in relation to emotional childhood events. PMID- 25040923 TI - Antibiotic resistance: a geopolitical issue. AB - Antimicrobial resistance (AMR), associated with a lack of new antibiotics, is a major threat. Some countries have been able to contain resistance, but in most countries the numbers of antibiotic-resistant bacteria continue to increase, along with antibiotic consumption by humans and animals. AMR is a global issue, and concerns all decision-makers worldwide. Some initiatives have been undertaken in the last 15 years, in particular by the WHO, the European Centre for Disease Prevention and Control, and the CDC, but those initiatives were partial and poorly implemented, without coordination. Very recently, some important initiatives have been implemented by the WHO. Since 2009, a US and European joint task force, the Trans-Atlantic Task Force on Antibiotic Resistance, has been working on common recommendations. At a national level, some important initiatives have been implemented, in particular in European countries and in the USA. The Chennai declaration, in India, is also a good example of a multidisciplinary and national initiative that was highly political. Finally, several non-governmental non-profit organizations are also very active, and have helped to raise awareness about the problem of AMR. In the future, this global issue will need political involvement and strong cooperation between countries and between international agencies. PMID- 25040924 TI - Loss of liver transplant surgeons into alternate career paths: how to overcome? PMID- 25040925 TI - Letter: incidence rates of Barrett's oesophagus and oesophageal adenocarcinoma in the UK and the Netherlands. PMID- 25040926 TI - Letter: incidence rates of Barrett's oesophagus and oesophageal adenocarcinoma in UK and the Netherlands - authors' reply. PMID- 25040927 TI - Letter: calcineurin inhibitor level reduction during treatment with sofosbuvir in liver transplanted patients. PMID- 25040928 TI - Letter: tenofovir is associated with higher probability of acute kidney injury compared with entecavir. PMID- 25040929 TI - Who coined the term radix entomolaris? PMID- 25040930 TI - Utility of a new reusable clip device for endoscopic treatment. AB - BACKGROUND AND AIM: Existing reusable endoscopic clip devices have some problems regarding opening the device and precise control of clip application. The aim of the present study was to evaluate reusable clip devices for endoscopic treatment. METHODS: Ability to close a large defect and grip force were evaluated using ex vivo porcine colon. We assessed clip loading and opening in a non-clinical setting and describe the resulting learning curve. To evaluate clinical utility, data for clip application in 72 post-endoscopic mucosal resection (EMR) defects in 40 patients were retrospectively analyzed. RESULTS: There was no difference in the ability to close a 20-mm full-thickness defect and the grip force comparing the new clip device (ZEOCLIP(r)) and a previously used reusable clip device (EZClip(r)). Although the time to load the ZEOCLIP was almost same as the EZClip, the time to open the ZEOCLIP was significantly shorter than the EZClip (P < 0.001). Opening width of the ZEOCLIP was significantly wider than the EZClip (P < 0.05). We successfully accomplished closure of post-EMR defects by clip application in 72 lesions using ZEOCLIP. Reopening/repositioning and restoring it to the working channel were more frequently carried out in a non-easy location than in an easy location (11/35 [31%] vs 4/37 [11%], P = 0.030; and 21/35 [60%] vs 1/37 [3%], P < 0.001, respectively). CONCLUSIONS: ZEOCLIP is more quickly and easily opened to its maximum width compared with EZClip, and is feasible for clip application after EMR. PMID- 25040931 TI - Measurement of liver stiffness as a non-invasive method for diagnosis of non alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the major causes of liver disease worldwide. To detect early stages of NAFLD and start treatment or to monitor the changes in trials of new drugs, non-invasive diagnostic methods are needed, such as biochemical markers or liver stiffness measurement (LSM). LSM with transient elastography (TE) and acoustic radiation force impulse (ARFI) has been shown to be useful in NAFLD, although the cut-off values have varied among reports. Magnetic resonance elastography and real-time tissue elastography also can be useful for the diagnosis of NAFLD, although the number of studies is limited. Fibrosis is absent in 8-40% of patients with non-alcoholic steatohepatitis (NASH), making it difficult to diagnose NASH by LSM because LSM is usually associated with fibrotic stage. The presence of inflammation or hepatocyte ballooning may affect LSM and aid the diagnosis of NASH without fibrosis. However, obesity significantly increases the failure of LSM and its interference is more conspicuous in TE than in ARFI. The newly implemented XL probe of TE has overcome the difficulty to some degree. Nonetheless, the effects of obesity, hepatocyte ballooning, steatosis and inflammation on LSM values have not yet been adequately investigated, although they are likely to affect LSM values. Further studies are needed to establish the clinical utility of LSM in NAFLD. PMID- 25040932 TI - Collapsin response-mediator protein 5 (CRMP5) phosphorylation at threonine 516 regulates neurite outgrowth inhibition. AB - The collapsin response-mediator proteins (CRMPs) are multifunctional proteins highly expressed during brain development but down-regulated in the adult brain. They are involved in axon guidance and neurite outgrowth signalling. Among these, the intensively studied CRMP2 has been identified as an important actor in axon outgrowth, this activity being correlated with the reorganisation of cytoskeletal proteins via the phosphorylation state of CRMP2. Another member, CRMP5, restricts the growth-promotional effects of CRMP2 by inhibiting dendrite outgrowth at early developmental stages. This inhibition occurs when CRMP5 binds to tubulin and the microtubule-associated protein MAP2, but the role of CRMP5 phosphorylation is still unknown. Here, we have studied the role of CRMP5 phosphorylation by mutational analysis. Using non-phosphorylatable truncated constructs of CRMP5 we have demonstrated that, among the four previously identified CRMP5 phosphorylation sites (T509, T514, T516 and S534), only the phosphorylation at T516 residue was needed for neurite outgrowth inhibition in PC12 cells and in cultured C57BL/6J mouse hippocampal neurons. Indeed, the expression of the CRMP5 non-phosphorylated form induced a loss of function of CRMP5 and the mutant mimicking the phosphorylated form induced the growth inhibition function seen in wildtype CRMP5. The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway. The findings provide new insights into the mechanisms underlying neurite outgrowth. PMID- 25040933 TI - Dorsal muscle group area and surgical outcomes in liver transplantation. AB - INTRODUCTION: Better measures of liver transplant risk stratification are needed. Our previous work noted a strong relationship between psoas muscle area and survival following liver transplantation. The dorsal muscle group is easier to measure, but it is unclear if they are also correlated with surgical outcomes. METHODS: Our study population included liver transplant recipients with a preoperative CT scan. Cross-sectional areas of the dorsal muscle group at the T12 vertebral level were measured. The primary outcomes for this study were one- and five-yr mortality and one-yr complications. The relationship between dorsal muscle group area and post-transplantation outcome was assessed using univariate and multivariate techniques. RESULTS: Dorsal muscle group area measurements were strongly associated with psoas area (r = 0.72; p < 0.001). Postoperative outcome was observed from 325 patients. Multivariate logistic regression revealed dorsal muscle group area to be a significant predictor of one-yr mortality (odds ratio [OR] = 0.53, p = 0.001), five-yr mortality (OR = 0.53, p < 0.001), and one-yr complications (OR = 0.67, p = 0.007). CONCLUSION: Larger dorsal muscle group muscle size is associated with improved post-transplantation outcomes. The muscle is easier to measure and may represent a clinically relevant postoperative risk factor. PMID- 25040934 TI - Everolimus in heart transplantation: does it finally have a home? AB - This editorial approves the use of everolimus to wean calcineurin inhibitors (by 7-11 weeks postoperative) as safe and effective with improved first-year renal function and reduced intimal thickness by intravascular ultrasound. See article by Andreassen et al on page 1828. PMID- 25040935 TI - PIM-1 modulates cellular senescence and links IL-6 signaling to heterochromatin formation. AB - Cellular senescence is a stable state of proliferative arrest that provides a barrier against malignant transformation and contributes to the antitumor activity of certain chemotherapies. Unexpectedly, we found that the expression of proto-oncogene PIM-1, which can promote tumorigenesis, is induced at transcriptional level during senescence. Inhibition of PIM-1 alleviated both replicative and oncogene-induced senescence. Conversely, ectopic expression of PIM-1 resulted in premature senescence. We also revealed that PIM-1 interacts with and phosphorylates heterochromatin protein 1gamma (HP1gamma) on Ser93. This PIM-1-mediated HP1gamma phosphorylation enhanced HP1gamma's capacity to bind to H3K9me3, resulting in heterochromatin formation and suppression of proliferative genes, such as CCNA2 and PCNA. Analysis of the mechanism underlying the up regulation of PIM-1 expression during senescence demonstrated that IL-6, a critical regulator of cellular senescence, is responsible for PIM-1 induction. Our study demonstrated that PIM-1 is a key component of the senescence machinery that contributes to heterochromatin formation. More importantly, we demonstrated that PIM-1 is also a direct target of IL-6/STAT3 signaling and mediates cytokine induced cellular senescence. PMID- 25040937 TI - Does Special Care Dentistry undergraduate teaching improve dental student attitudes towards people with disabilities? AB - INTRODUCTION: Undergraduate dental curricula increasingly aim to address student attitudes towards people with disabilities. This study reports the effectiveness of a comprehensive, blended learning Special Care Dentistry undergraduate programme to change attitudes towards people with disabilities. METHODS: A validated psychometric instrument (ATDP-Form 0) was given as a course evaluation to third-year dental students in the Dublin Dental University Hospital over 3 years from 2010 to 2013, immediately before and after the delivery of a brief comprehensive curriculum in Special Care Dentistry. RESULTS: From a population of 109 students, 100 (91.7%) pre-test and 83 (76.1%) retest responses were analysed. Mean score before the course, for all years, was 74.8 (SD = 14.7), compared with 76.8 (SD = 14.0) for all years after the course. CONCLUSIONS: Dental students in our study had neither particularly positive, or negative attitudes towards people with disabilities. There was no statistically significant difference in student attitudes before and after the educational intervention. This study, therefore, shows that a comprehensive undergraduate blended learning module, which aimed to improve attitudes towards people with disabilities, did not do so, using the described measures within the selected timeframe. PMID- 25040936 TI - Prolonged localized photosensitivity following allergic and photo-aggravated contact dermatitis from etofenamate. PMID- 25040938 TI - The influence of educational level and oral hygiene behaviours on DMFT index and CPITN index in an adult Italian population: an epidemiological study. AB - OBJECTIVES: To estimate the influence of educational level and oral hygiene behaviours on the prevalence and severity of dental caries and periodontal disease in an adult Italian population attending the Oral Hygiene department of a public Dental Clinic. METHODS: Dental caries was diagnosed according to the World Health Organization criteria. The DMFT index (decayed, missing, filled tooth) was used to record the dental caries' experience. The periodontal status was assessed using the community periodontal index of treatment needs (CPITN). Questionnaires on educational level and oral hygiene behaviours were also collected. RESULTS: A total of 350 patients were enrolled. The mean DMFT value reported was 4.37 +/- 3.06, and higher values were observed for male patients (P < 0.05). Increased CPITN scores and DMFT values were significantly correlated with lower level of education (P < 0.05). Subjects of high educational status showed significantly better oral hygiene habits (P < 0.05). CONCLUSIONS: The oral health status, in terms of periodontal disease and dental caries, appears correlated with patients' educational level. PMID- 25040939 TI - In Vitro Assessment with the Infrared Thermometer of Temperature Differences Generated During Implant Site Preparation: The Traditional Technique Versus the Single-Drill Technique. AB - PURPOSE: To assess in vitro, using an infrared (IR) thermometer, temperature changes generated at implant sites by osteotomies involving two different drilling methods (with multiple drills versus only one) and to measure the influence of irrigation on the temperature variation. MATERIALS AND METHODS: Forty bone samples (from bovine rib) were divided into two groups of 20. Osteotomies were performed in group A with four drills, using the standard method (Leone Dental Implant System, final diameter 3.5 mm), and in group B with a single drill (Zero1 Drill, Leone Dental Implant System 3.5 mm diameter). In each group, half of the osteotomies were performed with irrigation (subgroups A1 and B1) and the other half without irrigation (subgroups A2 and B2). Two osteotomies were performed on each sample, using four different-sized drills according to the standard technique on one side and using a single drill on the other side. The starting temperature (T0 ) and the maximum temperature (Tmax ) reached in the bone were measured. Comparisons of DeltaT were drawn between subgroups A1 and B1 and between subgroups A2 and B2. The data were analyzed using Student's t-test (with 95% confidence interval). RESULTS: The mean difference identified between the temperature produced with the last drill used in the traditional technique and that produced with the single drill was 0.3150 +/- 1.0194 degrees C when irrigation was used (group A1 vs group B1; not statistically significant). The mean difference between the temperature produced with the last drill of the traditional technique and that produced with the single drill was -0.3526 +/- 0.5232 degrees C when irrigation was not used (group A2 vs group B2; statistically significant). CONCLUSIONS: The single-drill method induced a significantly greater variation in temperature than the traditional method, but only when irrigation was used; without any irrigation, the difference in the temperature variation generated by the two methods was not statistically significant. In any case, bone heating during the osteotomy never exceeded 2 degrees C and was clinically irrelevant, as thermal damage to bone has only been reported in the literature for temperatures beyond 47 degrees C persisting for more than one minute. PMID- 25040940 TI - Bacillus subtilis attachment to Aspergillus niger hyphae results in mutually altered metabolism. AB - Interaction between microbes affects the growth, metabolism and differentiation of members of the microbial community. While direct and indirect competition, like antagonism and nutrient consumption have a negative effect on the interacting members of the population, microbes have also evolved in nature not only to fight, but in some cases to adapt to or support each other, while increasing the fitness of the community. The presence of bacteria and fungi in soil results in various interactions including mutualism. Bacilli attach to the plant root and form complex communities in the rhizosphere. Bacillus subtilis, when grown in the presence of Aspergillus niger, interacts similarly with the fungus, by attaching and growing on the hyphae. Based on data obtained in a dual transcriptome experiment, we suggest that both fungi and bacteria alter their metabolism during this interaction. Interestingly, the transcription of genes related to the antifungal and putative antibacterial defence mechanism of B. subtilis and A. niger, respectively, are decreased upon attachment of bacteria to the mycelia. Analysis of the culture supernatant suggests that surfactin production by B. subtilis was reduced when the bacterium was co-cultivated with the fungus. Our experiments provide new insights into the interaction between a bacterium and a fungus. PMID- 25040941 TI - Refeeding enteroclysis as an alternative to parenteral nutrition for enteric fistula. AB - AIM: Refeeding enteroclysis is one method of giving artificial nutritional support to patients with enterocutaneous fistula. This study compares the results of this technique with parenteral nutrition or nutrition given via a proximal stoma. METHOD: All patients admitted to our intestinal failure unit with a proximal enteric fistula and managed with refeeding enteroclysis over a 4-year period were included and compared with a matched group of patients managed without using this technique. RESULTS: Twenty patients (15 men) with a proximal enteric fistula received chyme refeeding down the distal limb of the fistula. This was established at a mean of 14 days after admission to the unit and total parenteral nutrition could be weaned off by 20 days. The mean output from the proximal limb was 1800 ml and the mean volume refed down the distal limb was 1220 ml per day. Additional enteric feed was given to 12 patients. No patient was given pharmacological agents to delay gastrointestinal transit or additional intravenous water and electrolyte for most of the time after refeeding was established. There were no complications or deaths related to chyme refeeding. CONCLUSION: Refeeding enteroclysis is feasible in selected patients with a proximal enteric fistula or stoma. Adequate nutrition, water and electrolyte balance can be achieved without resorting to parenteral infusions. PMID- 25040942 TI - Readability of product ingredient labels can be improved by simple means: an experimental study. AB - BACKGROUND: Ingredient labels on products used by consumers and workers every day, such as food, cosmetics, and detergents, can be difficult to read and understand. OBJECTIVE: To assess whether typographical design and ordering of ingredients can improve the readability of product ingredient labels. METHODS: The study subjects (n = 16) had to search for two target ingredients in 30 cosmetic product labels and three alternative formats of each. Outcome measures were completion time (reading speed), recognition rate, eye movements, task load and subjective rating when the reading of ingredient labels was assessed by video recording, an eye tracking device, and questionnaires. RESULTS: The completion time was significantly lower (p < 0.001) when subjects were reading all alternative formats than when they were reading the original. The recognition rate was generally high, and improved slightly with the alternative formats. The eye movement measures confirmed that the alternative formats were easier to read than the original product labels. Mental and physical demand and effort were significantly lower (p < 0.036) and experience rating was higher (p < 0.042) for the alternative formats. There were also differences between the alternative formats. CONCLUSIONS: Simple adjustments in the design of product ingredient labels would significantly improve their readability, benefiting the many allergic individuals and others in their daily struggle to avoid harmful or unwanted exposure. PMID- 25040943 TI - Daptomycin in solid organ transplantation: consideration of dosage adjustments in renal impairment. PMID- 25040944 TI - Carcinogenic polycyclic aromatic hydrocarbons: an analysis of screening values, guidelines, and standards in the Northeast. AB - Risk-based, background, and laboratory quantitation limit-derived standards for carcinogenic polycyclic aromatic hydrocarbons (cPAHs) in residential and nonresidential soils vary across the northeast region of the United States. The magnitude and extent of this variation, however, have not been systematically studied. This article examines the technical basis and methodology used by eight northeastern states in the development of risk-based screening values, guidelines, and standards for cPAHs in soils. Exposure pathways, human receptors, algorithms, and input variables used by each state in the calculation of acceptable human health risks are identified and reviewed within the context of environmental policy and regulatory impacts. Emphasis is placed on a comparative analysis of multipathway exposures (incidental ingestion, dermal contact, and particulate inhalation) and key science-policy decisions that have led to the promulgation and adoption of different exposure criteria for cPAHs in the Northeast. More than 425 data points and 20 distinct exposure factors across eight state programs, 18 age subgroups, six activity scenarios, and three exposure pathways were systematically evaluated. Risk-based values for one state varied either above or below risk-based, background or laboratory quantitation limit-derived standards of another state for the same cPAH and receptor. Standards for cPAHs in soils were found to differ significantly across the northeast region--in some cases, by one or two orders of magnitude. While interstate differences can be expected to persist, future changes in federal guidance could mean a shift in risk drivers, compliance status, or calculated cumulative risks for individual properties impacted by PAH releases. PMID- 25040945 TI - The amino acid response to a mixed meal in patients with type 2 diabetes: effect of sitagliptin treatment. AB - AIMS: Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of alpha-hydroxybutyrate (alpha-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and alpha-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment. METHODS: Forty-seven T2D patients [56 +/- 7 years, body mass index (BMI) 29.9 +/- 4.2 kg/m(2) ] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). RESULTS: During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l . h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l . h, p = 0.05]. Fasting alpha-HB was higher [7.5(2.7) vs. 5.9(1.3) ug/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) ug/ml . h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 +/- 16 vs. 35 +/- 10 mEq/l . h, p = 0.005). Compared to placebo, both BCAA [ 6.4(21.1) vs. 0.0(48.0) mmol/l . h, p = 0.01] and alpha-HB increments [-114(250) vs. 114(428) ug/ml . h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and alpha-HB were reciprocally related to changes in insulin sensitivity (rho = -0.37 and -0.43, p <= 0.01). CONCLUSIONS: T2D is associated with a hyperaminoacidaemic response to MTT, which circulating alpha-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and alpha-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that alpha HB is a readout of metabolic overload. PMID- 25040946 TI - Atrial fibrillation: an observational study with outpatients. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia with serious clinical consequences in the absence of treatment. However, there are limited data on the treatment of these patients in Argentina. The objective was to describe the therapeutic management of patients with nonacute AF by Argentinean cardiologists and to determine the incidence of clinical events after 12 months follow-up. METHODS: The Atrial Fibrillation study in Argentina (FARAON) was an observational, descriptive, prospective, national, and multicentric study that included outpatients with AF, followed for 12 months. The study included 38 sites in Argentina. Each researcher included the first 10 patients who met the inclusion criteria of being over 21 and also being an AF carrier documented by electrocardiogram or Holter within 12 months prior to or at the time of enrollment. RESULTS: A total of 373 patients were included, mean age 70 +/- 11.5 years, 40% women; 65% had AF rhythm at the time of inclusion, 57% had permanent AF, and 56% were asymptomatic. At the time of enrollment, 40% of physicians opted for rhythm control strategy. beta-blockers and amiodarone were the most used drugs. Patients with rhythm control drugs had higher success rate than those with frequency control drug therapy (80% vs 57%). CONCLUSION: Cardiologists in Argentina receive patients with AF that are mostly permanent AF. More than half of the patients are asymptomatic. They opt primarily by controlling the pace. When choosing antiarrhythmic drugs, nearly half of them indicated amiodarone. PMID- 25040947 TI - A laboratory comparison between two liquid skin barrier products. AB - Exposure of skin to friction and moisture is detrimental to skin health. The purpose of this experimental study was to investigate the ability of a cyanoacrylate polymer film to protect human skin against moisture and abrasion. A secondary purpose of this study was to compare this cyanoacrylate material to a traditional barrier film. Twelve healthy subjects participated in the wash-off resistance test to determine the percentage of dye that was left on the skin after repeated washing. Ten subjects participated in the abrasion test. Transepidermal water loss (TEWL) was measured before and after abrasion to determine the level of skin damage, as high water loss seen post-abrasion is indicative of skin damage post-abrasion. Skin treated with cyanoacrylate had significantly more dye remaining than sites treated with traditional film barrier or control sites. The change in TEWL was statistically lower for cyanoacrylate treated areas. PMID- 25040948 TI - The design and methods of genetic studies on acute and chronic postoperative pain in patients after total knee replacement. AB - OBJECTIVE: Total knee replacement (TKR) is the treatment option of choice for the millions of individuals whose osteoarthritis pain can no longer be managed through non-invasive methods. Over 500,000 TKRs are performed annually in the United States. Although most patients report improvement in pain and functioning following TKR, up to 30% report persistent pain that interferes with daily function. However, the reasons for poor outcomes are not clear. To best determine which patients are at risk for pain post TKR, a detailed and comprehensive approach is needed. In this article, we present the methodology of a study designed to identify a set of genetic, proteomic, clinical, demographic, psychosocial, and psychophysical risk factors for severe acute and chronic pain post TKR. DESIGN: Prospective longitudinal observational study. SETTING: University Hospital System. SUBJECTS: Patients scheduled for unilateral TKR with a target number of 150. METHODS: Prior to surgery, we collect demographic, psychosocial, and pain data. Biological data, including blood samples for genetic analyses, and serum, urine, and joint fluid for cytokine assessment are collected intraoperatively. Pain assessments as well as medication use are collected during each of the three days postsurgery. Additionally, pain and psychosocial information is collected 6 and 12 months following surgery. CONCLUSIONS: This study, for the first time, captures the information on both genetic and "environmental" risk factors for acute and chronic pain post-TKR and has the potential to lead to the next step-multicenter large-scale studies on predictors and biomarkers of poor TKR outcomes as well as on tailored interventions and personalized medicine approaches for those at risk. PMID- 25040950 TI - Dissection of additive, epistatic effect and QTL * environment interaction of quantitative trait loci for sheath blight resistance in rice. AB - A recombinant inbred line (RIL) population from a cross between 'HH1B' and 'RSB02' (a deep-water rice variety with resistance to sheath blight) was planted in two locations for four different growing seasons. Seven traits were used to evaluate the disease severity, namely disease rating (DR), lesion length (LL), lesion height (LH), relative lesion length (RLL), relative lesion height (RLH), plant height (PH) and heading date (HD). Based on a linkage map of 163 simple sequence repeat (SSR) markers, a total of 37 QTLs were mapped on nine chromosomes. Additionally, 32 epistatic QTLs were identified, distributed on all the 12 chromosomes. The contribution of a single QTL's additive and epistatic effect was of low magnitude for most cases (from 0.39% to 24.62%). Among QTL * environment interaction test, 28 additive QTLs and six pairs of epistatic interactions were involved. Correlation analysis showed that DR had significant positive correlations with LL, RLL and RLH, but had a negative correlation with PH, two of six QTLs controlling DR were mapped in the same chromosome regions as the QTLs controlling PH. The alleles which can enhance disease resistance and increase PH are from the resistant parent 'RSB02', indicating that PH has certain effect on sheath blight resistance in the present study. PMID- 25040949 TI - The R-factor gap in macromolecular crystallography: an untapped potential for insights on accurate structures. AB - In macromolecular crystallography, the agreement between observed and predicted structure factors (Rcryst and Rfree ) is seldom better than 20%. This is much larger than the estimate of experimental error (Rmerge ). The difference between Rcryst and Rmerge is the R-factor gap. There is no such gap in small-molecule crystallography, for which calculated structure factors are generally considered more accurate than the experimental measurements. Perhaps the true noise level of macromolecular data is higher than expected? Or is the gap caused by inaccurate phases that trap refined models in local minima? By generating simulated diffraction patterns using the program MLFSOM, and including every conceivable source of experimental error, we show that neither is the case. Processing our simulated data yielded values that were indistinguishable from those of real data for all crystallographic statistics except the final Rcryst and Rfree . These values decreased to 3.8% and 5.5% for simulated data, suggesting that the reason for high R-factors in macromolecular crystallography is neither experimental error nor phase bias, but rather an underlying inadequacy in the models used to explain our observations. The present inability to accurately represent the entire macromolecule with both its flexibility and its protein-solvent interface may be improved by synergies between small-angle X-ray scattering, computational chemistry and crystallography. The exciting implication of our finding is that macromolecular data contain substantial hidden and untapped potential to resolve ambiguities in the true nature of the nanoscale, a task that the second century of crystallography promises to fulfill. DATABASE: Coordinates and structure factors for the real data have been submitted to the Protein Data Bank under accession 4tws. PMID- 25040951 TI - Assessment of non-technical skills in the operating room--one assessment tool per specialty? PMID- 25040952 TI - Vitamin D deficiency in anesthesia department caregivers at the end of winter. AB - BACKGROUND: To test whether the vitamin D status of anesthesia department caregivers practicing at high Northern latitudes is compatible with current recommendations, the 25-hydroxyvitamin D (25(OH)D) levels of caregivers at hospitals in Iceland (64 degrees 08' N) and in Wisconsin (43 degrees 07' N) were compared at the end of winter. METHODS: Anesthesia department faculty and resident physicians, non-physician anesthetists, and critical care nurses completed a questionnaire, and provided blood samples for analysis of 25(OH)D by reverse-phase high performance liquid chromatography. RESULTS: One hundred and six participants in Iceland and 124 participants in Wisconsin were enrolled. No difference in mean serum 25(OH)D levels between Iceland [70.53 nmol/l, standard deviation (SD) 30.87 nmol/l] and Wisconsin (70.0 nmol/l, SD 30.0 nmol/l) was observed. In Iceland and Wisconsin, 25(OH)D levels below 25 nmol/l were observed in 4.7% and 4.0%, below 50 nmol/l in 34.9% and 25.0%, and below 75 nmol/l in 56.6% and 61.3% of caregivers, respectively. CONCLUSIONS: 25(OH)D levels below the 50 nmol/l (20 ng/ml) threshold recommended by the Institute of Medicine and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and below the 75 nmol/l (30 ng/ml) threshold recommended by The Endocrine Society, are highly prevalent among anesthesia caregivers working at two Northern hospitals at the end of winter who may otherwise not meet criteria to be tested. Anesthesia and critical care providers may wish to determine their 25(OH)D levels and use effective, safe, and low cost supplementation to target a 25(OH)D level compatible with optimal health. PMID- 25040954 TI - Mental health in Swedish children living in joint physical custody and their parents' life satisfaction: a cross-sectional study. AB - This study compared the psychological symptoms of 129 children in joint physical custody with children in single care and nuclear families, using a nationally representative 2011 survey of 1,297 Swedish children aged between four and 18 years. The outcome measure was the Strengths and Difficulties Questionnaire (SDQ) and its association with three dimensions of parental life satisfaction was investigated. Linear regression analyses showed higher SDQ-scores for children in joint physical custody (B = 1.4, p < 0.001) and single care (B = 2.2, p < 0.001) than in nuclear families, after adjustment for socio-demographic variables. The estimates decreased to 1.1 and 1.3, respectively, after being adjusted for parental life satisfaction ( p < 0.01). Our findings confirm previous research that showed lower symptom scores for children in nuclear families than children in single care and joint physical custody. Parental life satisfaction should be investigated further as a possible explanation of differences in symptom load between children in different living arrangements. PMID- 25040956 TI - The time has come to consider neonatal outcomes when designing embryo transfer policies. PMID- 25040955 TI - Osteoimmunology in orthodontic tooth movement. AB - The skeletal and immune systems share a multitude of regulatory molecules, including cytokines, receptors, signaling molecules, and signaling transducers, thereby mutually influencing each other. In recent years, several novel insights have been attained that have enhanced our current understanding of the detailed mechanisms of osteoimmunology. In orthodontic tooth movement, immune responses mediated by periodontal tissue under mechanical force induce the generation of inflammatory responses with consequent alveolar bone resorption, and many regulators are involved in this process. In this review, we take a closer look at the cellular/molecular mechanisms and signaling involved in osteoimmunology and at relevant research progress in the context of the field of orthodontic tooth movement. PMID- 25040958 TI - Updated meta-analysis of the association between CYP2E1 RsaI/PstI polymorphisms and lung cancer risk in Chinese population. AB - BACKGROUND: A number of studies have reported relationships of CYP2E1 RsaI/PstI polymorphisms with susceptibility to lung cancer in Chinese population. However, the epidemiologic results have been conflictive rather than conclusive. The purpose of this study was to address the associations of CYP2E1 RsaI/PstI polymorphisms with lung cancer risk in Chinese population comprehensively. MATERIALS AND METHODS: Systematic searches were conducted in the PubMed, Science Direct, Elsevier, CNKI and Chinese Biomedical Literature Databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of association. RESULTS: Overall, we observed a decreased lung cancer risk among subjects carrying CYP2E1 RsaI/PstI c1/ c2 and c1/c2+c2/c2 genotypes (OR=0.76, 95%CI: 0.64-0.90 and OR=0.78, 95%CI: 0.66-0.93, respectively), as compared with subjects carrying the c1/c1 genotype. In subgroup analysis, we observed a decreased lung cancer risk among c1/c2 carriers in hospital-based studies (OR=0.81, 95%CI: 0.68-0.98) and among carriers with c1/ c2 and c1/c2+c2/c2 genotypes in population-based studies(OR=0.57, 95%CI: 0.42-0.79 and OR=0.58, 95%CI: 0.43-0.79, respectively), as compared with subjects carrying the c1/c1 genotype. Limiting the analysis to studies with controls in Hardy-Weinberg equilibrium (HWE), we similarly observed a decreased lung cancer risk among c1/c2 and c1/c2+c2/c2 carriers (OR=0.73, 95%CI: 0.60-0.88 and OR=0.73, 95%CI: 0.60 0.88, respectively), as compared with c1/c1. CONCLUSIONS: Our results suggested that CYP2E1 RsaI/PstI c1/c2 and c1/c2+c2/c2 variants might be a protective factor for developing lung cancer in Chinese population. Further well-designed studies with larger sample size are required to verify our findings. PMID- 25040957 TI - Fatigue and quality of life in women treated for various types of gynaecological cancers: a cross-sectional study. AB - AIMS AND OBJECTIVES: To examine the prevalence of cancer-related fatigue in women treated for various types of gynaecological cancers and, for these cancers, to assess fatigue in relation to distress, health-related quality of life, demography and treatment characteristics. BACKGROUND: Advances in treatment of cancer have improved the likelihood of survival. Consequently, there are a growing number of patients who become survivors after cancer and who face side effects even years after treatment. One of the most frequently reported side effects across all types and stages of the disease is cancer-related fatigue. DESIGN: A descriptive cross-sectional study. METHODS: One hundred and twenty women treated for gynaecological cancers who were participants in an intervention study were included. Fatigue, psychological distress, health-related QoL and demographics were assessed by questionnaires. Disease and treatment characteristics were extracted from medical records. RESULTS: Cancer-related fatigue was reported in 53% of the women treated for gynaecological cancers, with a higher proportion in the group of cervical cancer, followed by ovarian cancer. Younger participants reported fatigue more frequently than older participants. When adjusting for age, the type of cancer a woman experiences was shown to have little impact on her risk of experiencing fatigue. The participants with fatigue reported higher levels of anxiety and depression than participants without fatigue. There was a relationship between fatigue and quality of life as measured by SF-36 domains. CONCLUSION: The findings underscore the importance of screening for fatigue, patient education and symptom management. This should be included in a standard procedure during treatment and follow-up. Both somatic and psychological aspects of fatigue should be emphasised. RELEVANCE TO CLINICAL PRACTICE: The findings imply the need for health personnel to have focus on fatigue during the entire cancer trajectory of women after gynaecological cancers, as well as the need for screening, information, guidance and symptom management. PMID- 25040959 TI - Feasibility of computed tomography colonography as a diagnostic procedure in colon cancer screening in India. AB - Computed Tomography Colonography (CTC) is a medical imaging technology used in identifying polyps and colon cancer masses in the large intestine. The technique has evolved a great deal since its invention and has become a routine diagnostic procedure in Western countries due to its non invasiveness and ease of use. The objective of our study was to explore the possibility of CTC application in Indian hospitals. This paper gives an overview of the procedure and its commercial viability. The explanation begins with the domain aspects from gastroenterologist perspective, the new way of thinking in polyp classification, the technical components of CTC procedure, and how engineering solutions have helped clinicians in solving the complexities involved in colon diagnosis. The colon cancer statistics in India and the results of single institution study we carried out with retrospective data is explained. By considering the increasing number of patients developing colon malignancies, the practicality of CTC in Indian hospitals is discussed. This paper does not reveal any technical aspects (algorithms) of engineering solutions implemented in CTC. PMID- 25040960 TI - Anti cancer effects of Cnidium officinale Makino extract mediated through apoptosis and cell cycle arrest in the HT-29 human colorectal cancer cell line. AB - The anti cancer properties and underlying cell death mechanisms induced by an extract of the roots of Cnidium officinale Makino (COM) were investigated. An ethanolic extract of COM inhibited proliferation of human colon cancer cells (HT 29) with both dose- and time-dependence. Analysis of the cell cycle after treatment of HT-29 cells with various concentrations of COM showed reduction of cellular proliferation via G1 phase arrest. Apoptotic effects of COM and Western blotting both revealed that COM extract dose-dependently increased the expression of p53, p21,Bax and caspase-3. Anti-apoptotic factor Bcl-2 expression was down regulated as well as those of cyclin D1 and CDK4. These data suggest that COM has anti cancer properties by inducing apoptosis and cell cycle arrest in HT-29 cells and could have possible therapeutic potential against human colon adenocarcinoma. PMID- 25040961 TI - IOTA simple rules in differentiating between benign and malignant ovarian tumors. AB - BACKGROUND: To evaluate the diagnostic performance of IOTA simple rules in differentiating between benign and malignant ovarian tumors. MATERIALS AND METHODS: A study of diagnostic performance was conducted on women scheduled for elective surgery due to ovarian masses between March 2007 and March 2012. All patients underwent ultrasound examination for IOTA simple rules within 24 hours of surgery. All examinations were performed by the authors, who had no any clinical information of the patients, to differentiate between benign and malignant adnexal masses using IOTA simple rules. Gold standard diagnosis was based on pathological or operative findings. RESULTS: A total of 398 adnexal masses, in 376 women, were available for analysis. Of them, the IOTA simple rules could be applied in 319 (80.1%) including 212 (66.5%) benign tumors and 107 (33.6%) malignant tumors. The simple rules yielded inconclusive results in 79 (19.9%) masses. In the 319 masses for which the IOTA simple rules could be applied, sensitivity was 82.9% and specificity 95.3%. CONCLUSIONS: The IOTA simple rules have high diagnostic performance in differentiating between benign and malignant adnexal masses. Nevertheless, inconclusive results are relatively common. PMID- 25040962 TI - Cervical cytological screening results of 8,495 cases in Turkey--common inflammation but infrequent epithelial cell abnormalities? AB - BACKGROUND: Cervical cancer is the ninth most common cancer among females in Turkey. Cervical smear is a routine screening test used for the detection of cervical abnormalities and also it detects certain infections of the cervix. OBJECTIVE: To analyze cervical smear results of our clinic in order to determine most frequent pathology of the women in North Eastern Anatolia Region of Turkey. MATERIALS AND METHODS: In a retrospective study design, 8,495 cervical cytology cases diagnosed at the Pathology Department of the Regional Education and Research Hospital in Erzurum over the last one and half years extending from August 2012 to December 2013 were investigated. RESULTS: The most common diagnosis was found to be inflammation, 65.5 % (5,566 out of 8,495), and the least was squamous epithelial abnormalities 0.2% (13 out of 8,495). There was some variation among the three pathologists regarding diagnosis but findings for the latter. CONCLUSIONS: Regular cervical smear tests are one of the most important strategies in early diagnosis of cervical cancer but there are conflicting data regarding the prevalence of epithelial cell abnormalities in Turkey, and the reasons of this should be investigated. PMID- 25040963 TI - Health economics evaluation of a gastric cancer early detection and treatment program in China. AB - OBJECTIVE: To use health economics methodology to assess the screening program on gastric cancer in Zhuanghe, China, so as to provide the basis for health decision on expanding the program of early detection and treatment. MATERIALS AND METHODS: The expense of an early detection and treatment program for gastric cancer in patients found by screening, and also costs of traditional treatment in a hospital of Zhuanghe were assessed. Three major techniques of medical economics, namely cost-effective analysis (CEA), cost-benefit analysis (CBA) and cost utility analysis (CUA), were used to assess the screening program. RESULTS: RESULTS from CEA showed that investing every 25, 235 Yuan on screening program in Zhuanghe area, one gastric cancer patient could be saved. Data from CUA showed that it was cost 1, 370 Yuan per QALY saved. RESULTS from CBA showed that: the total cost was 1,945,206 Yuan with a benefit as 8,669,709 Yuan and an CBR of 4.46. CONCLUSIONS: The early detection and treatment program of gastric cancer appears economic and society-beneficial. We suggest that it should be carry out in more high risk areas for gastric cancer. PMID- 25040964 TI - Down-regulation of miRNA-452 is associated with adriamycin-resistance in breast cancer cells. AB - Adriamycin (ADR) is an important chemotherapeutic agent frequently used in treatment of breast cancer. However, resistance to ADR results in treatment failure in many patients. Recent studies have indicated that microRNAs (miRNAs) may play an important role in such drug-resistance. In the present study, microRNA-452 (miR-452) was found to be significantly down-regulated in adriamycin resistant MCF-7 cells (MCF-7/ADR) compared with the parental MCF-7 cells by miRNA microarray and real-time quantitative PCR (RT-qPCR). MiR-452 mimics and inhibitors partially changed the adriamycin-resistance of breast cancer cells, as also confirmed by apoptosis assay. In exploring the potential mechanisms of miR 452 in the adriamycin-resistance of breast cancer cells, bioinformatics analysis, RT-qPCR and Western blotting showed that dysregulation of miR-452 played an important role in the acquired adriamycin-resistance of breast cancer, maybe at least in part via targeting insulin-like growth factor-1 receptor (IGF-1R). PMID- 25040965 TI - Cost effective analysis of recall methods for cervical cancer screening in Selangor--results from a prospective randomized controlled trial. AB - Cervical cancer screening in Malaysia is by opportunistic Pap smear which contributes to the low uptake rate. To overcome this, a pilot project called the SIPPS program (translated as information system of Pap smear program) had been introduced whereby women aged 20-65 years old are invited for Pap smear and receive recall to repeat the test. This study aimed at determining which recall method is most cost-effective in getting women to repeat Pap smear. A randomised control trial was conducted where one thousand women were recalled for repeat smear either by registered letter, phone messages, phone call or the usual postal letter. The total cost applied for cost-effectiveness analysis includes the cost of sending letter for first invitation, cost of the recall method and cost of two Pap smears. Cost-effective analysis (CEA) of Pap smear uptake by each recall method was then performed. The uptake of Pap smear by postal letter, registered letters, SMS and phone calls were 18.8%, 20.0%, 21.6% and 34.4%, respectively (p<0.05). The CER for the recall method was lowest by phone call compared to other interventions; RM 69.18 (SD RM 0.14) compared to RM 106.53 (SD RM 0.13), RM 134.02 (SD RM 0.15) and RM 136.38 (SD RM 0.11) for SMS, registered letter and letter, respectively. ICER showed that it is most cost saving if the usual method of recall by postal letter be changed to recall by phone call. The possibility of letter as a recall for repeat Pap smear to reach the women is higher compared to sending SMS or making phone call. However, getting women to do repeat Pap smear is better with phone call which allows direct communication. Despite the high cost of the phone call as a recall method for repeat Pap smear, it is the most cost-effective method compared to others. PMID- 25040966 TI - Chronic exposure to chlorophenol related compounds in the pesticide production workplace and lung cancer: a meta-analysis. AB - BACKGROUND: Chlorophenols (CPs) and related phenoxyacetic acids (PAs) are pesticide groups contaminated with highly toxic 2, 3, 7, 8-tetrachlorodibenzo-p dioxin (TCDD) during production. PAs and CPs exposure is associated with risk of cancer, but the situation regarding lung cancer has not been clearly defined. We proposed a meta-analysis of published researches to evaluate relationship between chronic exposure to PAs and CPs in pesticide production workplaces and the risk of lung cancer. MATERIALS AND METHODS: After searching PubMed, Scopus, Scholar Google, Web of Sciences until August 2013, the association between chronic PAs and CPs exposure in production workplace and lung cancer was studied in 15 cohort studies. The standardized mortality rate (SMR) and 95% confidence intervals (CI) were collected from the papers. We used random or fixed-effects models, Egger test, funnel plot and meta regression in our analysis. RESULTS: Five papers with six reports were included in the final analysis. The standardized mortality rate for lung cancer from the random model was 1.18 (95% CI: 1.03-1.35, p=0.014) with moderate heterogeneity. Publication bias was not found for included studies in meta-analysis (p=0.9). CONCLUSIONS: Our findings has strengthen the evidence of lung cancer from chronic exposure to chlorophenol related compounds (PAs, CPs). PMID- 25040967 TI - Lobaplatin-TACE combined with radioactive 125I seed implantation for treatment of primary hepatocellular carcinoma. AB - AIM: To investigate the efficacy and safety of lobaplatin-transcatheter arterial chemoembolization (TACE) combined with radioactive 125I seed implantation in treatment of primary hepatocellular carcinoma (HCC). METHODS: 75 patients with primary HCC were enrolled in the study, among them 43 receiving lobaplatin- TACE (TACE group) and 32 lobaplatin-TACE combined with 125I seed implantation (TACE+125I group). After treatment, the local remission rates and postoperative complications of two groups were compared using the Pearson Chi-square test. Overall survival in the two groups was calculated using Kaplan-Meier survival curves and the differences were tested using Log-rank test. RESULTS: There were 7 cases of complete response (CR), 13 of partial response (PR), 6 of stable disease (SD) and 17 of progressive disease (PD) in the TACE group, with 13 cases of CR, 9 of PR, 5 of SD and 5 of PD in the TACE+125I group. The disease control rates of TACE and TACE+125I group were 60.5% (26/43) and 84.4% (27/32), respectively, with a significant difference between them (P < 0.05). The survival rates at 6, 12 and 18 months in the TACE group were 100.0%, 81.8% and 50.0%, respectively, and those in TACE+125I group were 100.0%, 93.8% and 65.6%. The mean survival times in the TACE and TACE+125I groups were 19.5 and 22.9 months, respectively. There was a significant difference in the overall survival rate between two groups (P < 0.05). No serious complications were encountered in either group. CONCLUSION: Lobaplatin-TACE combined with 125I seed implantation is favorable and safe for treatment of primary HCC. PMID- 25040968 TI - Recreational physical activity and risk of ovarian cancer: a meta-analysis. AB - Our aim was to access the association between recreational physical activity (RPA) and risk of ovarian cancer (OC). The studies were retrieved from the PubMed and Embase databases up to February 20th, 2014. Risk ratios (OR) and 95% confidence intervals (CI) were used to estimate effect sizes. Random-effects or fixed-effects models were used to pool the data. The trim and fill method was applied for sensitivity analysis. Begg's rank correlation test and Egger's regression asymmetry test were employed to assess the publication bias. A total of 6 studies (435398 participants including 2983 OC patients) were included in this meta-analysis. The overall estimate indicated that there was weakly inverse association between RPA and OC risk (RR=0.90, 95%CI: 0.72-1.12, p=0.335). Meanwhile, for prospective cohort studies, a result consistent with the overall estimate was obtained (RR=1.12, 95% CI: 0.88-1.42, p=0.356). However, for case control studies, the pooled estimate of RR was 0.76 (95%CI: 0.64-0.90, p=0.002), indicating a clear significant association between RPA and OC risk. In addition, the sensitivity analysis indicated a significant link between RPA and risk of OC after removing Lahmann's study (RR=0.80, 95% CI: 0.68-0.93, p=0.004). No significant publication bias was found (Begg's test: p=1.00; Egger's test: p=0.817). In conclusion, our meta-analysis indicated a weakly inverse relationship between RPA and the occurrence of OC. PMID- 25040969 TI - Characteristics of Hodgkin lymphoma in a defined group of Iranian pediatric patients. AB - This study was conducted to describe the characteristics of Hodgkin lymphoma in Iranian children. In a referral center for pediatric oncology (Mofid Hospital) in Tehran, patient data over a 10-year period were retrieved and recorded accordingly. Among 82 cases, 73.2% were male, 26.8% were female, and 70.7% were 5 9 years old. About 40% of patients were in stage III and 42.7% had systemic signs. Cervical nodes were commonly involved (91.5%). The most frequent histological subtype was mixed cellularity. The main hematological features were anemia (47.6%), lymphopenia (20.7%), and eosinophilia (8.7%). Survival rate was 72%, and 8.4% of patients were deceased. A 3% recurrence rate was observed in our patients. A significant relationship was found between the stage of disease and systemic signs (P<0.0005, chi2). Despite diagnosis of Hodgkin lymphoma in many children in Iran being made in higher stages, the mortality rate is relatively low. PMID- 25040970 TI - Stereotactic vacuum-assisted core biopsy results for non-palpable breast lesions. AB - BACKGROUND: The increase in breast cancer awareness and widespread use of mammographic screening has led to an increased detection of (non-palpable) breast cancers that cannot be discovered through physical examination. One of the methods used in the diagnosis of these cancers is vacuum-assisted core biopsy, which prevents a considerable number of patients from undergoing surgical procedures. The aim of this study was to present the results of stereotactic vacuum-assisted core biopsy for suspicious breast lesions. MATERIALS AND METHODS: Files were retrospectively scanned and data on demographic, radiological and pathological findings were recorded for patients who underwent stereotactic vacuum-assisted core biopsy due to suspicious mammographic findings at the Interventional Radiology Centre of the Florence Nightingale Hospital between January 2010, and April 2013. Statistical analysis was carried out using Pearson's Chi-square, continuity correction, and Fisher's exact tests. RESULTS: The mean age of the patients was 47 years (range: 36-70). Biopsies were performed due to BIRADS 3 lesions in 8 patients, BIRADS 4 lesions in 77 patients, and BIRADS 5 lesions in 3 patients. Mammography elucidated clusters of microcalcifications in 73 patients (83%) and focal lesions (asymmetrical density, distortion) in 15 patients (17%). In terms of complications, 1 patient had a hematoma, and 2 patients had ecchymoses (3/88; 3.3%). The histopathologic results revealed benign lesions in 63 patients (71.6%) and malignant lesions in 25 patients (28.4%). The mean duration of the procedure was 37 minutes (range: 18 55). Although all of the BIRADS 3 lesions were benign, 22 (28.6%) of the BIRADS 4 lesions and all of the BIRADS 5 lesions were malignant. Among the malignant cases, 80% were in situ, and 20% were invasive carcinomas. These patients underwent surgery. CONCLUSIONS: In cases where non-palpable breast lesions are considered to be suspicious in mammography scans, the vacuum-assisted core biopsy method provides an accurate histopathologic diagnosis thus preventing a significant number of patients undergoing unnecessary surgical procedures. PMID- 25040971 TI - MicroRNAs as promising biomarkers for tumor-staging: evaluation of MiR21 MiR155 MiR29a and MiR92a in predicting tumor stage of rectal cancer. AB - OBJECTIVE: In this study, tumor-stage predictive abilities of miR21, miR155, miR29a and miR92a were evaluated in rectal cancer (RC). METHODS: Expression of miR21, miR155, miR29a and miR92a was detected and quantitated in tumor tissue and in adjacent normal tissue from 40 patients by TaqMan MicroRNA assay. RESULTS: Significant overexpression of miR21, miR155, miR29a and miR92a was observed in RC tissues. While high expression of miR21, miR155 and miR29a in N1-2 and C-D stages presented a potential correlation with N and Duke stages, partial correlation analysis suggested that only miR155 rather than miR21 and miR29a played a greater influencing role. Receiver operating characteristics (ROC) curve analysis showed that miR155 could discriminate N0 from N1-2 with 85.0% sensitivity and 85.0% specificity, N2 from N0-1 with 90.0% sensitivity and 96.7% specificity, and C-D stage from A-B stage with 81.0% sensitivity and 84.2% specificity. CONCLUSIONS: Increase in expression of miR155 might represent a novel predictor for RC N and Dukes staging. PMID- 25040972 TI - Tumor-derived transforming growth factor-beta is critical for tumor progression and evasion from immune surveillance. AB - Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-beta(TGF-beta) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-beta produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-beta in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-beta using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ Treg cells, and consequently enhanced IFN-gamma production by CTLs. Knockdown of tumor-derived TGF-beta also significantly reduced the conversion of naive CD4+ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-beta suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-beta is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF beta may serve as a potential therapeutic approach for cancer. PMID- 25040974 TI - Survival outcomes of liver metastasectomy in colorectal cancer cases: a single center analysis in Turkey. AB - BACKGROUND: The purpose of this study was to analyze our series of liver resections for metastatic colorectal carcinoma (mCRC) to determine prognostic factors affecting survival and to evaluate the potential roles of neoadjuvant or adjuvant chemotherapy. MATERIALS AND METHODS: Ninety-nine patients who underwent metastasectomy for liver metastases due to colorectal cancer at the Department of Medical Oncology, 9 Eylul University Hospital between 1996 and 2010 were evaluated in this study. The patients were followed through July 2013. Demographic, perioperative, laboratory, radiological and chemotherapy as well as survival data were obtained by retrospective chart review. RESULTS: In 47 (47.5%) patients, liver metastases were unresectable at initial evaluation; the remaining 52 (52.5%) patients exhibited resectable liver metastases. Simultaneous hepatic resection was applied to 52 (35.4%) patients with synchronous metastasis, whereas 5 (64.5%) patients underwent hepatic resection after neoadjuvant chemotherapy. Forty-two patients with metachronous metastasis underwent hepatic resection following neoadjuvant chemotherapy. R0 resection was obtained in 79 (79.8%) patients. A second hepatectomy was performed in 22 (23.2%) patients. Adjuvant chemotherapy was given to 85 (85.9%) patients after metastasectomy. The median disease-free and overall survivals after initial metastasectomy were 12 and 37 months, respectively, the 1-year, 3-year and 5-year disease-free survival (DFS) and overall survival (OS) rates being 46.5%, 24.3% and 17.9%and 92.3%, 59.0% and 39.0%, respectively. On multivariate analysis, the primary tumor site, tumor differentiation, resection margin and DFS were independent factors predicting better overall survival. CONCLUSIONS: In selected cases, hepatic metastasectomy for mCRC to the liver can result in long-term survival. Neoadjuvant chemotherapy did not exert a positive effect on DFS or OS. Adjuvant chemotherapy also did not appear to impact DFS and OS. PMID- 25040973 TI - Lack of association between fingernail selenium and thyroid cancer risk: a case control study in French Polynesia. AB - BACKGROUND: Numerous studies have suggested that selenium deficiency may be associated with an increased risk for several types of cancer, but few have focused on thyroid cancer. MATERIALS AND METHODS: We examined the association between post-diagnostic fingernail selenium levels and differentiated thyroid cancer risk in a French Polynesian matched case-control study. Conditional logistic regression models were used to estimate odds ratios and 95% confidence intervals. RESULTS: The median selenium concentration among controls was 0.76 MUg/g. Significantly, we found no association between fingernail selenium levels and thyroid cancer risk after conditioning on year of birth and sex and additionally adjusting for date of birth (highest versus lowest quartile: odds ratio=1.12, 95% confidence interval: 0.66-1.90; p-trend=0.30). After additional adjustment for other covariates, this association remained non-significant (p trend=0.60). When restricting the analysis to thyroid cancer of 10 mm or more, selenium in nails was non-significantly positively linked to thyroid cancer risk (p-trend=0.09). Although no significant interaction was evidenced between iodine in nails and selenium in nails effect (p=0.70), a non-significant (p-trend =0.10) positive association between selenium and thyroid cancer risk was seen in patients with less than 3 ppm of iodine in nails. The highest fingernail selenium concentration in French Polynesia was in the Marquises Islands (M=0.87 MUg/g) and in the Tuamotu-Gambier Archipelago (M=0.86 MUg/g). CONCLUSIONS: Our results do not support, among individuals with sufficient levels of selenium, that greater long-term exposure to selenium may reduce thyroid cancer risk. Because these findings are based on post-diagnostic measures, studies with prediagnostic selenium are needed for corroboration. PMID- 25040975 TI - Emodin-provoked oxidative stress induces apoptosis in human colon cancer HCT116 cells through a p53-mitochondrial apoptotic pathway. AB - Emodin, a natural anthraquinone isolated from the traditional Chinese medicine Radix rhizoma Rhei, can induce apoptosis in many kinds of cancer cells. This study demonstrated that emodin induces apoptosis in human colon cancer HCT116 cells by provoking oxidative stress, which subsequently triggers a p53 mitochondrial apoptotic pathway. Emodin induced mitochondrial transmembrane potential loss, increase in Bax and decrease in Bcl-2 expression and mitochondrial translocation and release of cytochrome c to cytosol in HCT116 cells. In response to emodin-treatment, ROS increased rapidly, and subsequently p53 was overexpressed. Pretreatment with the antioxidant NAC diminished apoptosis and p53 overexpression induced by emodin. Transfecting p53 siRNA also attenuated apoptosis induced by emodin, Bax expression and mitochondrial translocation being reduced compared to treatment with emodin alone. Taken together, these results indicate that ROS is a trigger of emodin-induced apoptosis in HCT116 cells, and p53 expression increases under oxidative stress, leading to Bax-mediated mitochondrial apoptosis. PMID- 25040976 TI - Susceptibility of lung cancer with polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 genotypes in the population of Inner Mongolia region. AB - BACKGROUND: To study the relationship of susceptibility to lung cancer with the gene polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1, GSTP1 and smoking status in Han and Mongolian populations of Inner Mongolia, an autonomous region of China. MATERIALS AND METHODS: PCR-RFLP, allele-specific and multiplex PCR were employed to identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case control study of 322 lung cancer patients diagnosed by bronchoscopy and 456 controls free of malignancy. RESULTS: There is a significant difference in genotypic frequency of GSTT1 of healthy Mongolian and Han subjects. A statistically prominent association was found between CYP1A1 Msp1 (vt/vt) (OR=4.055, 95%CI:2.107-7.578, p=0.000), GSTM1 (-) (OR=2.290, 95%CI:1.467-3.573, p=0.000) and lung cancer in Mongolians. Similarly, in the Han population, CYP1A1 Msp1 (vt/vt) (OR=3.194, 95%CI:1.893-5.390, p=0.000) and GSTM1 (-) (OR=1.884, 95%CI:1.284-2.762, p=0.001) carriers also had an elevated risk of lung cancer. The smokers were more susceptible to lung cancer 2.144 fold and 1.631 fold than non-smokers in Mongolian and Han populations, respectively. The smokers who carried with CYP1A1 Msp1 (wt/vt+vt/vt), exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) respectively were found all to have a high risk of lung cancer. CONCLUSIONS: CYP1A1 Msp1 (vt/ vt) and GSTM1 (-) are risk factors of lung cancer in Han and Mongolian population in the Inner Mongolia region. The smokers with CYP1A1 Msp1 (wt/vt+vt/vt), CYP1A1 exon7 (Val/Val+Ile /Val), GSTM1 ( ), GSTM3 (AB+BB), and GSTT1 (-) genotypes, respectively, are at elevated risk of lung cancer. PMID- 25040977 TI - Treatment outcomes of gemcitabine in refractory or recurrent epithelial ovarian cancer patients. AB - BACKGROUND: To study the response rate (RR), progression-free survival (PFS) and toxicity profiles of recurrent epithelial ovarian cancer (EOC) patients treated with gemcitabine. MATERIALS AND METHODS: Recurrent EOC patients who were treated with gemcitabine between January 2000 and December 2013 at the Department of Obstetrics and Gynecology, Faculty of Medicine Vajira Hospital were identified and medical records were reviewed. Clinico-pathological features including data of gemcitabine treatment, response and toxicity were collected. RESULTS: We identified 43 EOC patients who had gemcitabine treatment. All except one patient who did not receive any adjuvant treatment, had received platinum-based chemotherapy. Among these 42 patients, 31.0% had refractory cancer to first-line chemotherapy while 69.0% had recurrence with 48.8% being platinum- sensitive. The total cycles of gemcitabine used were 203 (median 4, range 2-9 cycles). Overall RR was 11.6%: 19% in platinum-sensitive vs 4.5% in platinum-resistant groups (p=0.158) and 42.9% in the patients having gemcitabine together with platinum vs 5.6% using gemcitabine alone (P=0.024). Median PFS was 3.6 months (95% confidence interval [CI], 2.73-4.49 months): 8.1 months (95% CI, 2.73-4.49 months) in combination regimen vs 3.2 months (95% CI, 2.01-4.42 months) in single regimen (p=0.077) and 8.1 months (95% CI, 4.73-11.48 months) with the gemcitabine combination vs 2.7 months (95% CI, 1.98-3.38 months) by single gemcitabine in platinum sensitive patients (P=0.007). Common toxicities were hematologic which were well tolerated and manageable. CONCLUSIONS: Gemcitabine has modest activity in pre-treated EOC. A combination regimen had higher activity than single agent in platinum sensitive patients with a significant improvement in RR and PFS. PMID- 25040978 TI - Fruit and vegetable intake in relation to prostate cancer in Iranian men: a case control study. AB - BACKGROUND: Findings of epidemiologic studies on the relationship between fruit and vegetable consumption and prostate cancer (PCa) risk have been inconclusive. We therefore examined the association between intake of fruits and vegetables and PCa risk in Iran. MATERIALS AND METHODS: In this hospital based, case-control study, a total of 50 patients with PCa and 100 controls underwent face-to-face interviews. Regression analysis was used to examine the relation between fruit and vegetable intake and PCa risk. RESULTS: A protective independent effect was observed for the highest tertile of total fruit and vegetable (OR: 0.33, CI: 0.04 0.30, p value<0.001), total fruit (OR: 0.30, CI: 0.06-0.4, p value=0.03) and total vegetable (OR: 0.31, CI: 0.02-0.21, p value<0.001) consumption. Within the group of fruits, a significant inverse association was observed for apple and pomegranate (p trends were 0.01 and 0.016, respectively). In the vegetable group, a significant inverse association was observed for tomatoes (p trend<0.001) and cabbage (p trend=0.021). CONCLUSIONS: The results of the present study suggested that fruits and vegetable intake might be negatively associated with PCa risk. PMID- 25040979 TI - No association between traffic density and risk of childhood leukemia: a meta analysis. AB - BACKGROUND: While many studies have concluded that local traffic density is positively associated with childhood leukemia, the results are inconsistent. We therefore performed a meta-analysis to assess the relationship between traffic density and the risk of childhood leukemia. METHODS: A systematic literature review was carried out using PubMed, EMBASE, and the Cochrane Library from January 1979 to December 2013. We selected and assessed journal articles evaluating the relationship between local traffic density and the risk of leukemia in children. The analysis was carried out using STATA version 12.0. RESULTS: A total of 11 articles, including 12 estimates of effect, were included in our meta-analysis. The summary effect size from the random-effects model, expressed as an odds ratio, was 1.03 (95% CI: 0.98-1.09, p=0.002). No significant association between traffic density and the risk of childhood leukemia was found. Similar conclusions were found on subgroup analysis. CONCLUSIONS: The results of our meta-analysis suggested no association between traffic density and the risk of childhood leukemia. This implies that living in close proximity to roads with heavy traffic may not increase the risk of childhood leukemia. However, further high-quality prospective trials are needed to support these results. PMID- 25040980 TI - Combined effects methylation of FHIT, RASSF1A and RARbeta genes on non-small cell lung cancer in the Chinese population. AB - Epigenetic modifications of tumour suppressor genes are involved in all kinds of human cancer. Aberrant promoter methylation is also considered to play an essential role in development of lung cancer, but the pathogenesis remains unclear.We collected the data of 112 subjects, including 56 diagnosed patients with lung cancer and 56 controls without cancer. Methylation of the FHIT, RASSF1A and RAR-beta genes in DNA from all samples and the corresponding gene methylation status were assessed using the methylation-specific polymerase chain reaction (PCR, MSP). The results showed that the total frequency of separate gene methylation was significantly higher in lung cancer compared with controls (33.9 85.7 vs 0 %) (p<0.01).Similar outcomes were obtained from the aberrant methylation of combinations of any two or three genes (p<0.01). There was a tendency that the frequency of combinations of any two or three genes was higher in stage I+II than that in stage III+IV with lung cancer. However, no significant difference was found across various clinical stages and clinic pathological gradings of lung cancer (p>0.05).These observations suggest that there is a significant association of promoter methylation of individual genes with lung cancer risk, and that aberrant methylation of combination of any two or three genes may be associated with clinical stage in lung cancer patients and involved in the initiation of lung cancer tumorigenesis. Methylation of FHIT, RASSF1A and RARbeta genes may be related to progression of lung oncogenesis. PMID- 25040981 TI - Clinico-pathological patterns and survival outcome of colorectal cancer in young patients: western Saudi Arabia experience. AB - BACKGROUND: The prognosis of young colorectal cancer (CRC) patients has been addressed by several studies but with contradictory results. The aim of the present study was to evaluate the clinico-pathological features of young Saudi patients with CRC in addition to displaying their survival outcome. MATERIALS AND METHODS: In this retrospective study, young CRC patients (<= 40 years) diagnosed between 2007 and 2011 from 4 centres in western Saudi Arabia, were included. Clinico-pathological features, tumor markers, dates of disease relapse and death were collected. Survival parameters were compared with those of older Saudi patients, reported in previous studies. RESULTS: One hundred and sixteen young patients with CRC were identified (32.2% rectal, 67.8% colon). Some 44% were metastatic while 32.7% had stage III at diagnosis. Patients with grade 3 tumors made up 29.4% of the total while 49.5% had positive lymphovascular invasion (LVI), 56% had a lymph node (LN) ratio >= 0.2 and 40.2% were K-ras mutant. Median disease-free survival (DFS) and overall survival (OS) in non-metastatic cases were 22.8 and 49.6 months respectively with better median DFS in K-ras wild compared to mutant patients (28.5 vs 20.9 months, p=0.005). In metastatic cases, median OS was 19.5 months. These survival outcomes are inferior compared to those of older Saudi patients reported in prior studies. CONCLUSIONS: Young CRC patients present more commonly with advanced stage and a high incidence of adverse prognostic factors such as LVI and high LN ratio. Young CRC patients seem to have worse survival compared to older Saudi patients. PMID- 25040982 TI - Evaluation of the Atlas Helicobacter pylori stool antigen test for diagnosis of infection in adult patients. AB - BACKGROUND: Helicobacter pylori (H. pylori) is one of the most important causes of dyspepsia and gastric cancer and diagnosis can be made by invasive or non invasive methods. The Atlas Helicobacter pylori antigen test is a new rapid non invasive method which is simple to conduct. The aim of this study was to determine its sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. MATERIALS AND METHODS: This prospective study was conducted between July 2012 and December 2013. Stool samples of 59 dyspeptic patients who underwent upper endoscopy were evaluated for H. pylori stool antigen. RESULTS: From the 59 patients who participated in this study, there were 36 (61%) males and 23 (39%) females. H. pylori was diagnosed in 24 (40.7%) gastric biopsies, 22 (91.7 %) of these being positive for the Atlas H. pylori antigen test. The sensitivity, specificity, PPV, NPV and accuracy were 91.7%, 100%, 100%, 94.6% and 96.6% respectively. CONCLUSIONS: The Atlas H. pylori antigen test is a new non-invasive method which is simple to perform and avails reliable results in a few minutes. Thus it can be the best option for the diagnosis of H. pylori infection due to its high sensitivity and specificity. PMID- 25040983 TI - RTN4 3'-UTR insertion/deletion polymorphism and susceptibility to non-small cell lung cancer in Chinese Han population. AB - Nogo protein, encoded by gene reticulon-4 (RTN4), includes three major isoforms by different splicing, named Nogo-A Nogo-B and Nogo-C. Nogo proteins play an important role in the apoptosis of cells, especially in tumor cells. RTN4 single nucleotide polymorphisms (SNPs) can influence the efficiency of transcription and translation thus being related with an individual's predisposition to cancer. The CAA insertion/deletion polymorphism (rs34917480) within RTN4 3'-UTR has been reported to be associated with many cancer types. In order to investigate the relationship between this polymorphism and susceptibility to non-small cell lung cancer (NSCLC) in the Chinese population, we conducted the present case-control study including 411 NSCLC patients and 471 unrelated healthy controls. The genotype distributions were significantly different between cases and controls (p=0.014). We found that the del allele could significantly increase NSCLC risk (ins/ins vs ins/del: p=0.007, OR 1.46, 95%CI=1.11-1.93; dominant model: p=0.004, OR 1.47, 95%CI=1.13-1.92 and allele model: p=0.008, OR 1.35, 95%CI=1.08-1.67). This association was stronger in participants over 60 years old, males and smokers. We therefore conclude that the CAA insertion/deletion polymorphism (rs34917480) contributes to non-small cell lung cancer risk in Chinese population. Age, sex and environmental exposure are also related to carcinogenic effects of rs34917480. PMID- 25040984 TI - Inhaled formaldehyde induces bone marrow toxicity via oxidative stress in exposed mice. AB - Formaldehyde (FA) is an economically important chemical, and has been found to cause various types of toxic damage to the body. Formaldehyde-induced toxic damage involves reactive oxygen species (ROS) that trigger subsequent toxic effects and inflammatory responses, which may increase risk of cancer. Therefore, in the present study, we aimed to investigate the possible toxic mechanism in bone marrow caused by formaldehyde. In accordance with the principle of randomization, the mice were divided into four groups of 6 mice per group. One group was exposed to ambient air and the other three groups were exposed to different concentrations of formaldehyde (20, 40, 80 mg/m3) for 15 days in the respective inhalation chambers, 2h a day. At the end of the 15-day experimental period, all mice were killed. Bone marrow cells were obtained. Some of those were used for the determination of blood cell numbers, bone marrow karyote numbers, CFU-F, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content; others were used for the determination of mitochondrial membrane potential (MMP), cell cycle and Bcl-2, Bax, CytC protein expression. WBC and PLT numbers in median and high dose groups were obvious reduced, but there was no change on RBC numbers. There was also reduced numbers of bone marrow karyotes and CFU-F in the high dose group. SOD activity was decreased, but MDA content was increased. MMP and Bcl-2 expression were decreased with increasing formaldehyde concentration, while expression of Bax and Cyt C was increased. We also observed change in cell cycling, and found that there was S phase arrest in the high dose group. Our study suggested that a certain concentration of formaldehyde could have toxic effects on the hematopoietic system, with oxidative stress as a critical effect. PMID- 25040985 TI - CT based 3-dimensional treatment planning of intracavitary brachytherapy for cancer of the cervix: comparison between dose-volume histograms and ICRU point doses to the rectum and bladder. AB - BACKGROUND: CT based brachytherapy allows 3-dimensional (3D) assessment of organs at risk (OAR) doses with dose volume histograms (DVHs). The purpose of this study was to compare computed tomography (CT) based volumetric calculations and International Commission on Radiation Units and Measurements (ICRU) reference point estimates of radiation doses to the bladder and rectum in patients with carcinoma of the cervix treated with high-dose-rate (HDR) intracavitary brachytherapy (ICBT). MATERIALS AND METHODS: Between March 2011 and May 2012, 20 patients were treated with 55 fractions of brachytherapy using tandem and ovoids and underwent post-implant CT scans. The external beam radiotherapy (EBRT) dose was 48.6 Gy in 27 fractions. HDR brachytherapy was delivered to a dose of 21 Gy in three fractions. The ICRU bladder and rectum point doses along with 4 additional rectal points were recorded. The maximum dose (DMax) to rectum was the highest recorded dose at one of these five points. Using the HDR plus 2.6 brachytherapy treatment planning system, the bladder and rectum were retrospectively contoured on the 55 CT datasets. The DVHs for rectum and bladder were calculated and the minimum doses to the highest irradiated 2cc area of rectum and bladder were recorded (D2cc) for all individual fractions. The mean D2cc of rectum was compared to the means of ICRU rectal point and rectal DMax using the Student's t-test. The mean D2cc of bladder was compared with the mean ICRU bladder point using the same statistical test .The total dose, combining EBRT and HDR brachytherapy, were biologically normalized to the conventional 2 Gy/fraction using the linear-quadratic model. (alpha/beta value of 10 Gy for target, 3 Gy for organs at risk). RESULTS: The total prescribed dose was 77.5 Gy alpha/beta10. The mean dose to the rectum was 4.58 +/- 1.22 Gy for D 2cc, 3.76 +/ 0.65 Gy at D ICRU and 4.75 +/- 1.01 Gy at DMax. The mean rectal D 2cc dose differed significantly from the mean dose calculated at the ICRU reference point (p<0.005); the mean difference was 0.82 Gy (0.48 -1.19 Gy). The mean EQD2 was 68.52 +/- 7.24 Gy alpha/beta3 for D 2cc, 61.71 +/- 2.77 Gy alpha/beta3 at D ICRU and 69.24 +/- 6.02 Gy alpha/beta3 at DMax. The mean ratio of D 2cc rectum to D ICRU rectum was 1.25 and the mean ratio of D 2cc rectum to DMax rectum was 0.98 for all individual fractions. The mean dose to the bladder was 6.00 +/- 1.90 Gy for D 2cc and 5.10 +/- 2.03 Gy at D ICRU. However, the mean D 2cc dose did not differ significantly from the mean dose calculated at the ICRU reference point (p=0.307); the mean difference was 0.90 Gy (0.49-1.25 Gy). The mean EQD2 was 81.85 +/- 13.03 Gy alpha/beta3 for D 2cc and 74.11 +/- 19.39 Gy alpha/beta3 at D ICRU. The mean ratio of D 2cc bladder to D ICRU bladder was 1.24. In the majority of applications, the maximum dose point was not the ICRU point. On average, the rectum received 77% and bladder received 92% of the prescribed dose. CONCLUSIONS: OARs doses assessed by DVH criteria were higher than ICRU point doses. Our data suggest that the estimated dose to the ICRU bladder point may be a reasonable surrogate for the D 2cc and rectal DMax for D 2cc. However, the dose to the ICRU rectal point does not appear to be a reasonable surrogate for the D 2cc. PMID- 25040986 TI - Copayment policy effects on healthcare spending and utilization by Korean lung cancer patients at end of life: a retrospective cohort design 2003-2012. AB - BACKGROUND: In Korea, the National Health Insurance program has initiated various copayment policies over a decade in order to alleviate patient financial burden. This study investigated healthcare spending and utilization in the last 12 months of life among patients who died with lung cancer by various copayment policy windows. MATERIALS AND METHODS: We performed a retrospective cohort study using nationwide lung cancer health insurance claims data from 2002 to 2012. We used descriptive and multivariate methods to compare spending measured by total costs, payer costs, copayments, and utilization (measured by length of stay or outpatient days). Using 1,4417,380 individual health insurance claims (inpatients: 673,122, outpatients: 744,258), we obtained aggregated healthcare spending and utilization of 155,273 individual patient (131,494 inpatient and 103,855 outpatient) records. RESULTS: National spending and utilization is growing, with a significant portion of inpatient healthcare spending and utilization occurring during the end-of-life period. Specifically, inpatients were more likely to have more spending and utilization as they got close to death. As coverage expanded, copayments decreased, but overall costs increased due to increased utilization. The trends were the same in both inpatient and outpatient services. Multivariate analysis confirmed the associations. CONCLUSIONS: We found evidence of the higher end of life healthcare spending and utilizations in lung cancer patients occurring as coverage expanded. The practice pattern within a hospital might be influenced by coverage policies. Health policy makers should consider initiating various health policies since these influence the long-term outcomes of service performance and overall healthcare spending and utilization. PMID- 25040987 TI - MEKK3 and survivin expression in cervical cancer: association with clinicopathological factors and prognosis. AB - Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important protein kinase and a member of the MAPK family, which regulates cellular responses to environmental stress and serves as key integration points along the signal transduction cascade that not only link diverse extracellular stimuli to subsequent signaling molecules but also amplify the initiating signals to ultimately activate effector molecules and induce cell proliferation, differentiation and survival. To explore the relationship between MEKK3 and cell apoptosis, clinicopathology and prognosis, we characterize the expression of MEKK3 and survivin in cervical cancer. MEKK3 and survivin expression was measured by RT-PCR and Western blotting of fresh surgical resections from 30 cases of cervical cancer and 25 cases of chronic cervicitis. Protein expression was detected by tissue microarray and immunochemistry (En Vision) in 107 cases of cervical cancer, 86 cases of cervical intraepithelial neoplasia (CIN), and 35 cases of chronic cervicitis. Expression patterns were analyzed for their association with clinicopathological factors and prognosis in cervical cancer. Expression of MEKK3 and survivin mRNA was significantly higher in cervical cancer than in the controls (p<0.05). MEKK3 and survivin expression differed significantly between cervical carcinoma, CIN, and cervicitis (p<0.05) and correlated with clinical stage, infiltration depth, and lymph node metastasis (p<0.05). MEKK3 expression was positively correlated with survivin (p<0.05). Kaplan-Meier survival analysis showed that MEKK3 and survivin expression, lymph node metastasis, depth of invasion, and FIGO stage reduce cumulative survival. Cox multivariate regression analysis showed that MEKK3, survivin, and clinical staging are independent prognostic factors in cervical cancer (p<0.05). Expression of MEKK3 and survivin are significantly increased in cervical cancer, their overexpression participating in the occurrence and development of cervical cancer, with protein expression and clinical staging acting as independent prognostic factors for patients with cervical cancer. PMID- 25040988 TI - The MDM2 SNP309T>G polymorphism increases bladder cancer risk among Caucasians: a meta-analysis. AB - Published studies have evaluated associations between the MDM2 SNP309T>G polymorphism and bladder cancer susceptibility. However, these generated inconsistent results. The aim of the present investigation was to quantify the strength of association between MDM2 SNP309T>G polymorphism and bladder cancer risk by conducting a meta-analysis. We searched PubMed and Embase for related studies that had been published in English before April 1, 2014 and associations were assessed by summarizing the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Five case-control studies with a total of 972 cases and 1,012 controls were finally identified to be eligible for the meta-analysis. Overall, the results indicated that there was no significant association between the MDM2 SNP309T>G polymorphism and bladder cancer risk (for the allele model G vs. T: OR=1.08, 95% CI 0.85-1.36, p=0.54; for the co-dominant model GG vs. TT: OR=1.20, 95% CI 0.74-1.93, p=0.46; for the dominant model GG+GT vs. TT: OR=0.98, 95% CI 0.80-1.20, p=0.83; for the recessive model GG vs. GT+TT: OR=1.20, 95% CI 0.83-1.74, p=0.33). However, on subgroup analysis by ethnicity, significant associations were found in Caucasians in three models (for the allele model G vs. T: OR=1.41, 95% CI 1.10-1.81, p=0.006; for the co-dominant model GG vs. TT: OR=2.16, 95% CI 1.28-3.63, p=0.004; for the recessive model GG vs. GT+TT: OR=2.06, 95% CI 1.31-3.22, p=0.002). In summary, the present meta-analysis provides evidence that the genotype for the MDM2 SNP309T>G polymorphism may be associated with genetic susceptibility to bladder cancer among Caucasians. PMID- 25040989 TI - Quality of life by stage of cervical cancer among Malaysian patients. AB - Stage of cervical cancer may adversely affect the quality of life (QOL) among patients. The objective of this study was to predict the QOL among cervical cancer patients by the stage of their cancer. A cross-sectional study from September 2012 until January 2013 was conducted among cervical cancer patients who completed treatment. All patients completed a interviewer-guided questionnaire comprising four sections: (A) socio- demographic data, (B) medical history, (C) QOL measured by general health status questionnaire (QLQ-30) and (D) cervical cancer specific module CX-24 (EORTC) was used to measured patient's functional, symptom scale and their global health status. Results showed that global health status, emotional functioning and pain score were higher in stage III cervical cancer patients while role functioning was higher in stage I cervical cancer patients. Patients with stage IV cancer have a lower mean score in global health status (adjusted b-22.0, 95 CI% -35.6, -8.49) and emotional functioning (adjusted b -22.5, 95 CI% -38.1, -6.69) while stage III had lower mean score in role functioning (adjusted b -14.3, 95 CI% -25.4, -3.21) but higher mean score in pain (adjusted b 22.1, 95 CI% 8.56, 35.7). In conclusion, stage III and IV cervical cancers mainly affect the QOL of cervical cancer patients. Focus should be given to these subgroups to help in improving the QOL. PMID- 25040990 TI - Associations between quality of life and marital status in cancer patients and survivors. AB - BACKGROUND: The cancer survival rate in Korea has substantially increased, necessitating the management of not only patients with cancer but also longer term survivors. Although the divorce rate has drastically increased in Korea, there is not sufficient research regarding the relationship between changes in marital status and quality of life (QOL) in cancer patients and survivors. Thus, we aimed to examine the relationship between marital status and QOL in such cases. MATERIALS AND METHODS: This study was performed using the Community Health Survey of 2008 administered by the Korea Centers for Disease Control and Prevention (N=169,328). We used t-tests and Chi-square tests to compare demographic variables between men and women, and analysis of variance (ANOVA) to compare QOL scores among comparison groups. We also performed a multilevel analysis on the relationship between QOL and marital status while accounting for provincial differences. RESULTS: Decline of EuroQOL five dimensions (EQ-5D) in single patients with cancer was greater than in any other marital status group, but there was no statistically significant decline in survivors of cancer with regard to marital status. In the general population, the decline of EQ-5D was higher among single people than married people. Using the EuroQOL visual analog scale (EQ-VAS), single people had higher values than those of other marital status among both patients with cancer and survivors of cancer. In the general population, EQ-VAS values were higher for single people compared to married people. CONCLUSIONS: There may be a significant relationship between marital status and QOL in cancer patients and survivors. Policy interventions to manage patients with cancer who experience a decline in QOL as well as marital problems should be conducted. PMID- 25040991 TI - Salt processed food and gastric cancer in a Chinese population. AB - To investigate the association between salt processed food and gastric cancer, a hospital based case-control study was conducted in a high risk area of China. One hundred and seven newly diagnosed cases with histological confirmation of gastric cancer and 209 controls were recruited. Information on dietary intake was collected with a validated food frequency questionnaire. Unconditional logistic regression was applied to estimate the odds ratios with adjustment for other potential confounders. Comparing the high intake group with never consumption of salt processed foods, salted meat, pickled vegetables and preserved vegetables were significantly associated with increased risk of gastric cancer. Meanwhile, salt taste preference in diet showed a dose-response relationship with gastric cancer. Our results suggest that consumption of salted meat, pickled and preserved vegetables, are positively associated with gastric cancer. Reduction of salt and salt processed food in diets might be one practical measure to preventing gastric cancer. PMID- 25040992 TI - Geographic distribution and epidemiology of lung cancer during 2011 in Zhejiang province of China. AB - BACKGROUND: To explore etiology for providing scientific clues for the prevention of lung cancer. MATERIALS AND METHODS: Data for lung cancer incidence and meteorological geographic factors from 25 counties in Zhejiang province of China during 2011 were studied. Stepwise multiple regression and correlation analysis were performed to analyze the geographic distribution and epidemiology of lung cancer. RESULTS: 8,291 new cases (5,998 in males and 2,293 females) of lung cancer during 2011 in Zhejiang province were reported in the 25 studied counties. Reported and standardized incidence rates for lung cancer were 58.0 and 47.0 per 100,000 population, respectively. The incidence of lung cancer increased with age. Geographic distribution analysis shows that the standardized incidence rates of lung cancer in northeastern Zhejiang province were higher than in the southwestern part, such as in Nanhu, Fuyang, Wuxing and Yuyao counties, where the rates were more than 50 per 100,000 population. In the southwestern Zhejiang province, for instance, in Yueqing, Xianju and Jiande counties, the standardized incidence rates of lung cancer were lower than 37 per 100,000 population. Spearman correlation tests showed that forest coverage rate, air quality index (AQI), and annual precipitation level are associated with the incidence of lung cancer. CONCLUSIONS: Lung cancer in Zhejiang province shows obvious regional differences. High incidence appears associated with low forest coverage rate, poor air quality and low annual precipitation. Therefore, increasing the forest coverage rate and controlling air pollution may play an important role in lung cancer prevention. PMID- 25040993 TI - Side effects of chemotherapy among cancer patients in a Malaysian General Hospital: experiences, perceptions and informational needs from clinical pharmacists. AB - BACKGROUND: This study aimed to assess the most common physical side effects experienced by local chemotherapy patients. Their perceptions of these side effects and informational needs from clinical pharmacists were also evaluated. MATERIALS AND METHODS: This was a single-center, cross-sectional study. A face-to face interview guided by a structured questionnaire with cancer patients admitted to receive repeated cycles of chemotherapy was conducted. Information collected included chemotherapy-related side effects after last chemotherapy experience, the most worrisome side effects, the side effects overlooked by healthcare professionals and the preferred method, amount and source of receiving related information. RESULTS: Of 99 patients recruited, 90 participated in this survey (response rate: 90.9%). The majority were in the age range of 45-64 years (73.3%) and female (93.3%). Seventy-five (83.3%) and seventy-one (78.9%) experienced nausea and vomiting, respectively. Both symptoms were selected as two of the most worrisome side effects (16.7% vs. 33.3%). Other common and worrisome side effects were hair loss and loss of appetite. Symptoms caused by peripheral neuropathies were perceived as the major symptoms being overlooked (6.7%). Most patients demanded information about side effects (60.0%) and they would like to receive as much information as possible (86.7%). Oral conversation (83.3%) remained as the preferred method and the clinical pharmacist was preferred by 46.7% of patients as the educator in this aspect. CONCLUSIONS: The high prevalence of chemotherapy related side effects among local patients is of concern. Findings of their perceptions and informational needs may serve as a valuable guide for clinical pharmacists to help in side effect management in Malaysia. PMID- 25040994 TI - Luteolin-loaded phytosomes sensitize human breast carcinoma MDA-MB 231 cells to doxorubicin by suppressing Nrf2 mediated signalling. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as a transcription factor that controls mechanisms of cellular defense response by regulation of three classes of genes, including endogenous antioxidants, phase II detoxifying enzymes and transporters. Previous studies have revealed roles of Nrf2 in resistance to chemotherapeutic agents and high level expression of Nrf2 has been found in many types of cancer. At physiological concentrations, luteolin as a flavonoid compound can inhibit Nrf2 and sensitize cancer cells to chemotherapeutic agents. We reported luteolin loaded in phytosomes as an advanced nanoparticle carrier sensitized MDA-MB 231 cells to doxorubicin. In this study, we prepared nano phytosomes of luteolin to enhance the bioavailability of luteolin and improve passive targeting in breast cancer cells. Our results showed that co- treatment of cells with nano particles containing luteolin and doxorubicin resulted in the highest percentage cell death in MDA-MB 231 cells (p<0.05). Furthermore, luteolin-loaded nanoparticles reduced Nrf2 gene expression at the mRNA level in cells to a greater extent than luteolin alone (p<0.05). Similarly, expression of downstream genes for Nrf2 including Ho1 and MDR1 were reduced significantly (p<0.05). Inhibition of Nrf-2 expression caused a marked increase in cancer cell death (p<0.05). Taken together, these results suggest that phytosome technology can improve the efficacy of chemotherapy by overcoming resistance and enhancing permeability of cancer cells to chemical agents and may thus be considered as a potential delivery system to improve therapeutic protocols for cancer patients. PMID- 25040995 TI - Association between three eNOS polymorphisms and cancer risk: a meta-analysis. AB - Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may influence the risk of cancer, but the results are still debatable. Therefore, we performed a systematic review to provide a more complete picture and conducted a meta analysis to derive a precise estimation. We searched PubMed, EMBASE, EBSCO, Google Scholar and China National Knowledge Infrastructure (CNKI) databases until April 2014 to identify eligible studies. Thirty-one studies with cancer patients and controls were included in the meta-analysis. Overall, the polled analysis revealed that the T-786C polymorphism was significantly associated with increased cancer risk under multiple genetic models (C vs T: OR=1.135, 95%CI=1.048-1.228; CC vs TT: OR=1.278, 95%CI=1.045- 1.562; TC vs TT: OR=1.136, 95%CI=1.023-1.261; CC+TC vs TT: OR=1.159, 95%CI=1.047-1.281; CC vs TC+TT: OR=1.204, 95%CI= 1.003 1.447). G894T was associated with significant risk for females (TT vs GG: OR=1.414, 95%CI=1.056-1.892; TT vs GT+GG: OR=1.356, 95%CI=1.108-1.661) and for breast cancer (T vs G: OR=1.097, 95%CI=1.001-1.203; TT vs GG: OR=1.346, 95%CI=1.012-1.789; TT vs GT+GG: OR=1.269, 95%CI=1.028-1.566). Increased susceptibility was revealed for prostate cancer with 4a/b (ba vs bb: OR=1.338, 95%CI=1.013-1.768; aa+ba vs bb: OR=1.474, 95%CI=1.002-2.170). This meta-analysis indicated that the eNOS T-786C polymorphism is associated with elevated cancer risk; the G894T polymorphism contributes to susceptibility to breast cancer and cancer generally in females; and the 4a/b polymorphism may be associated with prostate cancer risk. PMID- 25040996 TI - Construction of a protein-protein interaction network for chronic myelocytic leukemia and pathway prediction of molecular complexes. AB - BACKGROUND: Chronic myelocytic leukemia is a disease that threatens both adults and children. Great progress has been achieved in treatment but protein-protein interaction networks underlining chronic myelocytic leukemia are less known. OBJECTIVE: To develop a protein-protein interaction network for chronic myelocytic leukemia based on gene expression and to predict biological pathways underlying molecular complexes in the network. MATERIALS AND METHODS: Genes involved in chronic myelocytic leukemia were selected from OMIM database. Literature mining was performed by Agilent Literature Search plugin and a protein protein interaction network of chronic myelocytic leukemia was established by Cytoscape. The molecular complexes in the network were detected by Clusterviz plugin and pathway enrichment of molecular complexes were performed by DAVID online. RESULTS AND DISCUSSION: There are seventy-nine chronic myelocytic leukemia genes in the Mendelian Inheritance In Man Database. The protein-protein interaction network of chronic myelocytic leukemia contained 638 nodes, 1830 edges and perhaps 5 molecular complexes. Among them, complex 1 is involved in pathways that are related to cytokine secretion, cytokine-receptor binding, cytokine receptor signaling, while complex 3 is related to biological behavior of tumors which can provide the bioinformatic foundation for further understanding the mechanisms of chronic myelocytic leukemia. PMID- 25040997 TI - Comparison between early and late onset breast cancer in Pakistani women undergoing breast conservative therapy: is there any difference? AB - BACKGROUND: Early onset breast cancer is associated with poor outcomes but variable results have been reported. It is a significant problem in Pakistani women but remains under reported. Breast conservation plays an important role in surgical management of this younger patient group. The objective of this study was to determine the outcome of breast conservative therapy in patients with early onset breast cancer in our population and compare it with their older counterparts. MATERIALS AND METHODS: A review of patients with invasive breast cancer who underwent breast conservation surgery at Shaukat Khanum Cancer Hospital from 1997 to 2009 was performed. Patients were divided into two groups i.e. Group I age <= 40 and Group II >40 years. A total of 401 patients with breast cancer were identified in Group I and 405 patients in Group II. Demographics, histopathological findings and receptor status of the two groups were compared. The Chi square test was used for categorical variables. Outcome was assessed on basis of 10 year locoregional recurrence free survival (LRRFS), disease free survival (DFS) and overall survival (OS) . For survival analysis Kaplan Meier curves were used and significance was determined using the Log rank test. Cox regression was applied for multivariate analysis. RESULTS: Median follow up was 4.31 (0.1-15.5) years. Median age at presentation was 34.6 years (17-40) and 51.9 years (41-82) for the two groups. Groups were significantly different from each other with respect to grade, receptor status, tumor stage and use of neoadjuvant therapy. No significant difference was present between the two groups for estimated 10 year LRRFS (86% vs 95%) (p=0.1), DFS (70% vs 70%) (p=0.5) and OS (75% vs 63%) (p=0.1). On multivariate analysis, tumor stage was an independent predictor of LRRFS, DFS and OS. CONCLUSIONS: Early onset breast cancer is associated with a distinct biology but does not lead to poorer outcomes in our population. PMID- 25040998 TI - Recurrence risk and prognostic parameters in stage I rectal cancers. AB - BACKGROUND: The standard therapy for stage I rectum cancer is surgical resection. Currently, there is no strong evidence to suggest that any type of adjuvant therapy is beneficial. The risks of local relapse and distant metastasis are higher in rectal tumors. Therefore, while there is no clearly defined absolute indication for adjuvant therapy in lymph node negative colon cancers, rectum tumors that are T3N0 and higher require adjuvant treatment. Due to the more aggressive nature of rectal cancers, we explored the clinical and pathologic factors that could predict the risk of relapse in Stage I (T1-T2) disease and whether there was any progression-free survival benefit to adjuvant therapy. MATERIALS AND METHODS: This multicenter study was carried out by the Anatolian Society of Medical Oncology. A total of 178 patients with rectal cancers who underwent curative surgery between January 1994 and August 2012 in 13 centers were included in the study. Patient demographics, including survival data and tumor characteristics were obtained from medical charts. RESULTS: The median age was 58 years (range 26-85 years). Most tumors were well or moderately differentiated. For adjuvant treatment, 13 patients (7.3%) received radiotherapy alone, 12 patients (6.7%) received chemotherapy alone and 15 patients (8.4%) were given chemoradiotherapy. Median follow up was 29 months (3-225 months). Some 42 patients (23.6%) had relapse during follow up; 30 with local recurrence (71.4%) whereas 12 (28.6%) were distant metastases. Among the patients, 5-year DFS was 64% and OS was 82%. Mucinous histology and receiving adjuvant therapy were found to have statistically insignificant correlations with relapse and survival. CONCLUSIONS: In our retrospective analysis, approximately one quarter of patients exhibited either local or systemic relapse. The rates of relapse were slightly higher in the patients who had no adjuvant therapy. There may thus be a role for adjuvant therapy in high-risk stage I rectal tumors. PMID- 25040999 TI - Meta-analysis of six randomized control trials of chemotherapy plus anti-HER monoclonal antibody for advanced gastric and gastroesophageal cancer. AB - BACKGROUND: A meta-analysis was performed to examine the benefit/risk ratio for the addition of anti- HER MoAbs to chemotherapy in patients with advanced gastric and gastroesophageal cancer from six randomized phase II/III trials. MATERIALS AND METHODS: We searched relative trials from Pubmed, EMBASE, Cochrane library databases, China National Knowledge Infrastructure databases, Google Scholar and the NIH ClinicalTrials. Primary outcomes were overall response rate (ORR), progression-free survival (PFS), overall survival (OS). Secondary outcomes were toxicities. All analyses were performed using STATA 12.0. RESULTS: This meta analysis included six randomized controlled trials (RCTs) with 2, 297 patients and we demonstrated that the anti-HER MoAbs arm did have a positive effect on ORR in the anti-HER MoAbs arm (OR 1.28, 95% CI 1.00-1.64, p=0.01). There was an increasing benefit regarding OS (HR 0.74, 95% CI 0.60-0.88, p<0.05) and PFS (HR 0.72, 95% CI 0.60-0.84, p<0.05) in the anti-HER2 subgroup, but a reduction of OS (HR 1.11, 95% CI 0.87-1.36, p<0.05) and PFS (HR 1.13, 95% CI 0.98 -1.28, P<0.05) in anti-EGFR subgroup. Some grade 3-4 toxicity had a significantly higher incidence in the anti-HER MoAbs arm. There was no significant publication bias for all endpoints. CONCLUSIONS: The addition of trstuzumab MoAb to chemotherapy for gastric and gastroesophageal cancer significantly improved outcome of OS and PFS endpoints, while other MoAbs led to no improvement in results. Some adverse events were increased in anti-HER MoAbs arm compared with the control. PMID- 25041000 TI - Use of an artificial neural network to predict risk factors of nosocomial infection in lung cancer patients. AB - Statistical methods to analyze and predict the related risk factors of nosocomial infection in lung cancer patients are various, but the results are inconsistent. A total of 609 patients with lung cancer were enrolled to allow factor comparison using Student's t-test or the Mann-Whitney test or the Chi-square test. Variables that were significantly related to the presence of nosocomial infection were selected as candidates for input into the final ANN model. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the performance of the artificial neural network (ANN) model and logistic regression (LR) model. The prevalence of nosocomial infection from lung cancer in this entire study population was 20.1% (165/609), nosocomial infections occurring in sputum specimens (85.5%), followed by blood (6.73%), urine (6.0%) and pleural effusions (1.82%). It was shown that long term hospitalization (>= 22 days, P= 0.000), poor clinical stage (IIIb and IV stage, P=0.002), older age (>= 61 year old, P=0.023), and use the hormones were linked to nosocomial infection and the ANN model consisted of these four factors .The artificial neural network model with variables consisting of age, clinical stage, time of hospitalization, and use of hormones should be useful for predicting nosocomial infection in lung cancer cases. PMID- 25041001 TI - Roles of sonography and hysteroscopy in the detection of premalignant and malignant polyps in women presenting with postmenopausal bleeding and thickened endometrium. AB - BACKGROUND: To assess the role of sonographic endometrial thickness and hysteroscopic polyp size in predicting premalignant and malignant polyps in postmenopausal women. MATERIALS AND METHODS: A total of 328 postmenopausal women with abnormal uterine bleeding and thickened endometrium underwent operative hysteroscopy due to detection of endometrial polyps were included in this retrospective study. Preoperative endometrial thickness measured by transvaginal ultrasonography and polyp size on hysteroscopy were noted. Hysteroscopic resection with histology was performed for endometrial polyps. Endometrial thickness and polyp size were evaluated on the basis of final diagnosis established by histologic examination. Receiver operator characteristic curves were calculated to assess the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of endometrial thickness and polyp size for detecting premalignant and malignant polyps. RESULTS: Premalignant and malignant polyps were identified in 26 (7.9%) of cases. Sonographic measurement showed a greater endometrial thickness in cases of premalignant and malignant polyps when compared to benign polyps. On surgical hysteroscopy, premalignant and malignant polyps were also larger. Endometrial thickness demonstrated a sensitivity of 53.8%, specificity of 85.8%, PPV of 24.6% and NPV of 95.6% at a cut-off limit of 11.5 mm with diagnostic accuracy of 83.2%. Polyp size has a diagnostic accuracy of 94.8% with a sensitivity of 92.3%, specificity of 95.0%, PPV of 61.5% and NPV of 99.3% at a cut-off point of 19.5mm. CONCLUSIONS: Endometrial thickness measured by transvaginal ultrasonography is not sufficient in predicting premalignant and malignant endometrial polyps in postmenopausal women with abnormal uterine bleeding and thickened endometrium. Polyp size on hysteroscopy is a more accurate parameter, because of better sensitivity and specificity. However, while polyp size >= 19.5mm seems to have a great accuracy for predicting premalignancy and malignancy, histologic evaluation is still necessary to exclude premalignant and malignant polyps. PMID- 25041002 TI - Feasibility and safety of robotic surgery for gynecologic cancers. AB - BACKGROUND: To determine surgical outcomes, perioperative complications, and patient outcomes in gynecologic cancer patients undergoing robotic surgery. MATERIALS AND METHODS: Surgical outcomes, including docking time, total operative time, console time, estimated blood loss (EBL), conversion rate and perioperative complications were retrospectively reviewed in 30 gynecologic cancer patients undergoing robotic surgery. Patient outcomes included recovery time and patient satisfaction, as scored by a visual analogue scale (VAS) from 0-10. RESULTS: The operations included 24 hysterectomies with pelvic lymphadenectomy (PLD) and/or para-aortic lymphadenectomy, four radical hysterectomies with PLD, and two radical trachelectomies with PLD. Mean docking time was 12.8 +/- 9.7 min, total operative time was 345.5 +/- 85.0 min, and console time was 281.9 +/- 78.6 min. These times were decreased in the second half of the cases. There was no conversion rate. Three intraoperative complications, including one external iliac artery injury, one bladder injury, and one massive bleeding requiring blood transfusion were reported. Postoperative complications occurred in eight patients, most were minor. Only one patient had port herniation that required reoperation. Mean hospital stay was 3.5 +/- 1.7 days, and recovery time was 14.2 +/- 8.1 days. Two-thirds of patients felt very satisfied and one-third felt satisfied; the mean satisfaction score was 9.4 +0.9. Two patients with stage III endometrial cancer developed isolated port site metastasis at five and 13 months postoperatively. CONCLUSIONS: Robotic surgery for gynecologic cancer appears to be feasible, with acceptable perioperative complication rate, fast recovery time and high patient satisfaction. PMID- 25041003 TI - Lymph node ratio is an independent prognostic factor in node positive rectal cancer patients treated with preoperative chemoradiotherapy followed by curative resection. AB - BACKGROUND: The lymph node ratio (LNR) has been shown to be an important prognostic factor for colorectal cancer. However, studies focusing on the prognostic impact of LNR in rectal cancer patients who received neoadjuvant chemoradiotherapy (CRT) followed by curative resection have been limited. The aim of this study was to investigate LNR in rectal cancer patients who received neoadjuvant chemoradiotherapy (CRT) followed by curative resection. MATERIALS AND METHODS: A total of 131 consecutive rectal cancer patients who underwent neoadjuvant CRT and total mesorectal excision were included in this study. Patients were divided into two groups according to the LNR (<= 0.2 [n=86], >0.2 [n=45]) to evaluate the prognostic effect on overall survival (OS) and disease free survival (DFS). RESULTS: The median number of retrieved and metastatic lymph node (LN) was 14 (range 1-48) and 2 (range 1-10), respectively. The median LNR was 0.154 (range 0.04-1.0). In multivariate analysis, LNR was shown to be an independent prognostic factor for both overall survival (hazard ratio[HR]= 3.778; 95% confidence interval [CI] 1.741-8.198; p=0.001) and disease-free survival (HR=3.637; 95%CI 1.838- 7.195; p<0.001). Increased LNR was significantly associated with worse OS and DFS in patients with <12 harvested LNs, and as well as in those >= 12 harvested LNs (p<0.05). In addition, LNR had a prognostic impact on both OS and DFS in patients with N1 staging (p<0.001). CONCLUSIONS: LNR is an independent prognostic factor in ypN-positive rectal cancer patients, both in patients with <12 harvested LNs, and as well as in those >= 12 harvested LNs. LNR provides better prognostic value than pN staging. Therefore, it should be used as an additional prognostic indicator in ypN-positive rectal cancer patients. PMID- 25041004 TI - Risk of lymph node metastases from early gastric cancer in relation to depth of invasion: experience in a single institution. AB - BACKGROUND: An accurate assessment of potential lymph node metastasis is important for the appropriate treatment of early gastric cancers. Therefore, this study analyzed predictive factors associated with lymph node metastasis and identified differences between mucosal and submucosal gastric cancers. MATERIALS AND METHODS: A total of 518 early gastric cancer patients who underwent radical gastrectomy were reviewed in this study. Clinicopathological features were analyzed to identify predictive factors for lymph node metastasis. RESULTS: The rate of lymph node metastasis in early gastric cancer was 15.3% overall, 3.3% for mucosal cancer, and 23.5% for submucosal cancer. Using univariate analysis, risk factors for lymph node metastasis were identified as tumor location, tumor size, depth of tumor invasion, histological type and lymphovascular invasion. Multivariate analysis revealed that tumor size >2 cm, submucosal invasion, undifferentiated tumors and lymphovascular invasion were independent risk factors for lymph node metastasis. When the carcinomas were confined to the mucosal layer, tumor size showed a significant correlation with lymph node metastasis. On the other hand, histological type and lymphovascular invasion were associated with lymph node metastasis in submucosal carcinomas. CONCLUSIONS: Tumor size >2 cm, submucosal tumor, undifferentiated tumor and lymphovascular invasion are predictive factors for lymph node metastasis in early gastric cancer. Risk factors are quite different depending on depth of tumor invasion. Endoscopic treatment might be possible in highly selective cases. PMID- 25041005 TI - Comparison of quality of life of Turkish breast cancer patients receiving breast conserving surgery or modified radical mastectomy. AB - PURPOSE: The aim of this study was to investigate the differences in quality of life in patients who received breast conserving surgery (BCS) or modified radical mastectomy (MRM) for breast cancer. MATERIALS AND METHODS: A total of 100 women with breast cancer who underwent either BCS or MRM between September 2011 and April 2012 at a private health center and completed their chemotherapy and radiation therapy cycles were included in the study. To assess the quality of life, we used a demographic questionnaire, the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Quality of Life assessment in Breast Cancer (EORTC QLQ-BR23). RESULTS: Using QLQ-C30, we found that patients who underwent BCS had better functional status and fewer symptoms than patients who underwent MRM. In QLQ-BR23, independent factors improving the functional scales were BCS, higher level of education and marital status (married); independent factors improving symptoms were BCS, higher level of education, younger age and low and normal body mass index (BMI). In QLQ-C30, independent factors affecting the functional and symptom scales were only BCS and higher level of education. CONCLUSIONS: We determined that patients who received BCS had better functional status and less frequent symptoms than patients who underwent MRM. PMID- 25041006 TI - Carbohydrate antigen 19-9 levels associated with pathological responses to preoperative chemoradiotherapy in rectal cancer. AB - PURPOSE: To investigate whether pretreatment serum carbohydrate antigen 19-9 (CA 19-9) levels are associated with pathological responses to preoperative chemoradiotherapy (CRT) in patients with rectal cancer. MATERIALS AND METHODS: In total, 260 patients with locally advanced rectal cancer (cT3-4NanyM0) who underwent preoperative CRT and radical surgery were analyzed retrospectively. CRT consisted of 50.4 Gy pelvic radiotherapy and concurrent chemotherapy. Radical surgery was performed at a median of 7 weeks after CRT completion. Pathological CRT response criteria included downstaging (ypStage 0-I) and ypT0-1. A discrimination threshold of CA 19-9 level was determined using a receiver operating characteristics analysis. RESULTS: The median CA 19-9 level was 8.0 (1.0-648.0) U/mL. Downstaging occurred in 94 (36.2%) patients and ypT0-1 in 50 (19.2%). The calculated optimal threshold CA 19-9 level was 10.2 U/mL for downstaging and 9.0 U/mL for ypT0-1. On multivariate analysis, CA 19-9 (<= 9.0 U/mL) was significantly associated with downstaging (odds ratio, 2.089; 95% confidence interval, 1.189-3.669; P=0.010) or ypT0-1 (OR, 2.207; 95%CI, 1.079 4.512; P=0.030), independent of clinical stage or carcinoembryonic antigen. CONCLUSIONS: This study firstly showed a significant association of pretreatment serum CA 19-9 levels with pathological CRT responses of rectal cancer. The CA 19 9 level is suggested to be valuable in predicting CRT responses of rectal cancer cases before treatment. PMID- 25041007 TI - Impact of a clinical pathway on hospital costs, length of stay and early outcomes after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: A clinical pathway (CP) can standardize and improve perioperative care for a number of interventions. In hepatic surgery, however, pertinent evidence is very limited. This study was conducted to implement a CP for hepatocellular carcinoma (HCC) patients undergoing hepatectomy, and to evaluate its effects on hospital costs, length of hospital stay (LOHS) and early clinical outcomes. MATERIALS AND METHODS: Medical records for HCC patients undergoing hepatectomy were retrospectively reviewed before implementation of a CP (the non CP group) from March 2012 to August 2012. This information was compared with the data collected prospectively from patients after implementation of the CP (the CP group) between September 2012 and April 2013. Hospital costs, LOHS and early clinical outcomes were evaluated and compared between groups. RESULTS: There were no significant differences in terms of patient clinical characteristics between the two groups. For clinical outcome measures, no significant differences were found in postoperative complications, mortality and readmission rate. The hospital costs were significantly reduced from 24,844 RMB in the non-CP group to 19,761 RMB in the CP group (p<0.01). In addition, patients of the CP group also had shorter LOHS compared with the non-CP group (8.3 versus 12.3 days, p<0.001). CONCLUSIONS: The CP proved to be an effective approach to minimize hospital costs and LOHS with hepatectomy for HCC without compromising patient care. PMID- 25041008 TI - Seniors have a better learning curve for laparoscopic colorectal cancer resection. AB - PURPOSE: This study was designed to evaluate the outcomes of laparoscopic colorectal resection in a period of learning curve completed by surgeons with different experience and aptitudes with a view to making clear whether seniors had a better learning curve compared with juniors. METHODS: From May 2010 to August 2012, the first twenty patients underwent laparoscopic colorectal resection completed by each surgeon were selected for analysis retrospectively. A total of 240 patients treated by 5 seniors and 7 juniors were divided into the senior group (n=100) and the junior group (n=140). The short-term outcomes of laparoscopic surgery of the two groups were compared. RESULTS: The mean numbers of lymph nodes harvested were 21.2 +/- 11.0 in the senior group and 17.3 +/- 11.5 in the junior group (p=0.010); The mean operative times were 187.9 +/- 60.0 min as compared to 231.3 +/- 55.7 min (p=0.006), and blood loss values were 177.0 +/- 100.7 ml and 234.0 +/- 185 ml, respectively (p=0.001); Conversion rate in the senior group was obviously lower than in the junior group (10.0% vs 20.7%, p=0.027) and the mean time to passing of first flatus were 3.3 +/- 0.9 and 3.8 +/ 0.9 days (p=0.001). For low rectal cancer, the sphincter preserving rates were 68.7% and 35.3% (p=0.027). CONCLUSIONS: Seniors could perform laparoscopic colorectal resection with relatively better oncological outcomes and quicker recovery, and seniors could master the laparoscopic skill more easily and quickly. Seniors had a better learning curve for laparoscopic colorectal cancer resection compared to juniors. PMID- 25041009 TI - Awareness of risk factors for cancer among Omani adults--a community based study. AB - BACKGROUND: Cancer is the leading cause of mortality around the world. However, the majority of cancers occur as a result of modifiable risk factors; hence public awareness of cancer risk factors is crucial to reduce the incidence. The objective of this study was to identify the level of public awareness of cancer risk factors among the adult Omani population. MATERIALS AND METHODS: A community based survey using the Cancer Awareness Measure (CAM) questionnaire was conducted in three areas of Oman to measure public awareness of cancer risk factors. Omani adults aged 18 years and above were invited to participate in the study. SPPSS (ver.20) was used to analyse the data. RESULTS: A total of 384 participated from 500 invited individuals (response rate =77%). The majority of respondents agreed that smoking cigarettes (320, 83.3%), passive smoking (279, 72.7%) and excessive drinking of alcohol (265, 69%) are risks factors for cancer. However, fewer respondents agreed that eating less fruit and vegetables (83, 21.6%), eating more red or processed meat (116, 30.2%), being overweight (BMI>25) (123, 32%), doing less physical exercise (119, 31%), being over 70 years old (72, 18.8%), having a close relative with cancer (134, 34.9%), infection with human papilloma virus (HPV) (117, 30.5%) and getting frequent sunburn during childhood (149, 38.8%) are risk factors for cancer. A significant association was found between participant responses and their educational level. The higher the educational level, the more likely that respondents identified cancer risk factors including smoking (p<0.0005), passive smoking (p= 0.007), excessive drinking of alcohol (p<0.0005), eating less fruit and vegetables (p= 0.001) and infection with HPV (p<0.0005). CONCLUSIONS: The majority of respondents in this study in Oman were not aware of the common risk factors for cancer. It may be possible to reduce the incidence of cancers in Oman by developing strategies to educate the public about these risk factors. PMID- 25041010 TI - Additive properties of crude, age specific and age adjusted rates for cancer incidence and mortality. AB - BACKGROUND: In National Cancer Registry Programme (NCRP) reports, various rates are routinely provided for 50 cancer sites of males and 54 cancer sites of females. Very often, depending on our interest, we wish to see these rates for group of cancers like head and neck cancers, oral cancers, and reproductive cancers. In such a situation, the desired rates are calculated independently from the actual data and reported. The question is can we derive the rates for groups of cancers from the published reports when the data is provided only for the individual sites? OBJECTIVE: In the present paper, an attempt is made to explore the mathematical properties of various rates to derive them directly for the group of cancer sites from the published data when the rates are provided only for the individual sites. SOURCE OF DATA: The cancer incidence data collected by two urban Population Based Cancer Registries (PBCRs), under the network of NCRP for the period of 2006-08 was considered for the study purposes. The Registries included were: Bangalore and Bhopal. RESULTS: In the present communication, we have shown that the crude rate (CR), age specific rates and age-adjuste rates (AAR) all possess additive properties. This means, given the above rates for individual sites, the above rates can be calculated for groups of sites by simply adding them. In terms of formula it can be stated that CR(Site1+Site2+++ SiteN) = CR(Site1)+CR(Site2) +++ CR(SiteN). This formula holds good for age specific rates as well as for AAR. This property facilitates the calculation of various rates for defined groups of cancers by simply adding the above rates for individual sites from which they are made up. PMID- 25041011 TI - Metabolomics investigation of cutaneous T cell lymphoma based on UHPLC-QTOF/MS. AB - OBJECTIVES: The identification of cutaneous T cell lymphoma (CTCL) biomarkers may serve as a predictor of disease progression and treatment response. The aim of this study was to map potential biomarkers in CTCL plasma. DESIGN AND METHODS: Plasma metabolic perturbations between CTCL cases and healthy individuals were investigated using metabolomics and ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). RESULTS: Principal component analysis (PCA) of the spectra showed clear metabolic changes between the two groups. Thirty six potential biomarkers associated with CTCL were found. CONCLUSIONS: Based on PCA, several biomarkers were determined and further identified by LC/MS/MS analysis. All of these could be potential early markers of CTCL. In addition, we established that heparin as anticoagulant has better pre treatment results than EDTA with the UHPLC-QTOF/MS approach. PMID- 25041012 TI - Risk factors for endometrial hyperplasia concomitant endometrial polyps in pre- and post-menopausal women. AB - PURPOSE: To evaluate the risk factors for endometrial hyperplasia concomitant endometrial polyps in pre- and post-menopausal women. MATERIALS AND METHODS: A total of 203 patients undergoing endometrial sampling before hysterectomy were evaluated in this retrospective study. Data recorded were age, gravidity, parity, body mass index (BMI: weight(kg)/height(m)2), endometrial thickness (ET), menopausal status, presence of adenomyosis and diabetes mellitus. RESULTS: Endometrial hyperplasia and polyps were detected in 13 patients. There were statistically significant differences in terms of age, menopausal status, morbid obesity and diabetes mellitus (p<0.005). Logistic regression demonstrated that menopausal status and presence of diabetes mellitus were independent risk factors. CONCLUSIONS: According to the current study; menopause and diabetes mellitus are strong risk factors for the presence of concomitant endometrial polyps and endometrial hyperplasia. PMID- 25041013 TI - Evaluation of stapled versus hand-sewn techniques for colo- rectal anastomosis after low anterior resection of mid-rectal carcinoma: a study on 50 patients. AB - AIM: To evaluate the outcome of stapled versus sutured colo-rectal anastomosis after low anterior resection of mid-rectal carcinoma. PATIENTS AND METHODS: A prospective study of fifty patients who underwent colo-rectal anastomosis following low anterior resection (LAR) of T2 mid-rectal cancers at the Egyptian National Cancer Institute during the time period from June 2010 to June 2013 was conducted. Classification was into two groups; a stapled anastomosis group I (25 patients) and a hand-sewn anastomosis group II (25 patients). All operations are evaluated regarding intra-operative complications such as anastomotic line bleeding, visceral injuries or major blood loss. The anastomotic time and operative time are documented for each operation. All patients are evaluated post operatively for anastomotic leakage (AL), wound infection and ileus. RESULTS: The distance of the tumor from the anal verge was 9.6 +/- 2.0 cm in group I and 9.9 +/- 2.4 cm in group II. The mean operative time was 191.5 +/- 16.2 min in the stapled group and 208 +/- 18.6 min in the sutured group (p=0.002). The mean anastomotic times were 9.0 +/- 1.9 min and 19.7 +/- 12.2 min (p=0.001). Anastomotic leakage developed in three (12.0%) patients in the stapled group and in four (16.0%) patients in the sutured group (p=1.000). Post-operative ileus was observed in 3 patients in group I and one patient in group II. Wound infection developed in three (12.0%) patients in the stapled group and four (16.0%) patients in the sutured group (p=1.000). CONCLUSION: Colo-rectal anastomosis after low anterior resection for mid rectal carcinoma can be conducted safely either by stapling or hand-sewn techniques; however the stapling technique showed shorter anastomotic and operative times with no significant advantages regarding intra- or post-operative complications or hospital stay. PMID- 25041014 TI - Cecropin suppresses human hepatocellular carcinoma BEL- 7402 cell growth and survival in vivo without side-toxicity. AB - Conventional chemotherapy against hepatocellular carcinoma typically causes various side effects. Our previous study showed that cecropin of Musca domestica can induce apoptosis in human hepatocellular carcinoma BEL-7402 cells in vitro. However, whether cecropin inhibits BEL-7402 cell in vivo and the question of possible side effects remained undentified. The present study confirmed tumor inhibitory effects of cecropin in vivo, and furthermore strongly suggested that cecropin cytotoxicity in BEL-7402 cells in vivo may be mainly derived from its pro-apoptotic action. Specifically, we found that cecropin exerted no obvious side effects in tumor-bearing mice as it had no significant hematoxicity as well as visceral toxicity. Therefore, cecropin may be a potential candidate for further investigation as an antitumor agent against hepatocellular carcinoma. PMID- 25041015 TI - Effects of PLCE1 gene silencing by RNA interference on cell cycling and apoptosis in esophageal carcinoma cells. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most malignancies with a poor prognosis. The phospholipase C? gene (PLCE1) encodes a novel ras-related protein effector mediating the effects of R-Ras on the actin cytoskeleton and membrane protrusion. However, molecular mechanisms pertinent to ESCC are unclear. We therefore designed PLCE1-special small interfering RNA and transfected to esophageal squamous cell (EC) 9706 cells to investigate the effects of PLCE1 gene silencing on the cell cycle and apoptosis of ESCC and indicate its important role in the development of ESCC. Esophageal cancer tissue specimens and normal esophageal mucosa were obtained and assayed by immunohistochemical staining to confirm overexpression of PLCE1 in neoplasias. Fluorescence microscopy was used to examine transfection efficiency, while the result of PLCE1 silencing was examined by reverse transcription (RT-PCR). Flow cytometry and annexin V apoptosis assays were used to assess the cell cycle and apoptosis, respectively. Expression of cyclin D1 and caspase-3 was detected by Western-blotting. The level of PLCE1 protein in esophageal cancer tissue was significantly higher than that in normal tissue. After transfection, the expression of PLCE1 mRNA in EC 9706 was significantly reduced, compared with the control group. Furthermore, flow cytometry results suggested that the PLCE1 gene silencing arrested the cell cycle in the G0/G1 phase; apoptosis was significantly higher than in the negative control group and mock group. PLCE1 gene silencing by RNAi resulted in decreased expression of cyclin D1 and increased expression of caspase-3. Our study suggests that PLCE1 may be an oncogene and play an important role in esophageal carcinogenesis through regulating proteins which control cell cycling and apoptosis. PMID- 25041016 TI - An interleukin-6 receptor polymorphism is associated with opisthorchiasis-linked cholangiocarcinoma risk in Thailand. AB - The cholangiocarcinoma (CCA) is a relatively rare cancer worldwide but it is highly prevalent in Thailand where the liver fluke, Opisthorchis viverrini is endemic. There are reports that interleukin 6 (IL-6) may play an important role in the pathogenesis of opisthorchiasis associated CCA. Functionally, IL-6 can act on target cells through its receptor, IL-6R, and IL-6R polymorphisms may affect the functional activity of IL-6 leading to susceptibility to cholangiocarcinogenesis. Therefore, we assessed the association of the 48892 A/C (Asp358Ala) polymorphism in exon 9 of the IL-6R gene in 79 CCA cases compared to 80 healthy controls using the PCR- RFLP technique. The results showed significant differences between CCA cases and controls in overall genotype (p=0.001) and allele frequencies (p=0.0002). Chi-square for trend test revealed a significant association between genotype and CCA susceptibility (p=0.0002). The odds ratios (ORs) for genotype were 0.283 (95% CI=0.131-0.605, AC vs. AA; p=0.0003) and 0.206 (95% CI=0.196-1.245, CC vs. AA; p=0.0416), the OR for alleles was 0.347 (95% CI=0.187-0.633, allele C vs. allele A; p=0.0002) and that for the carrier C variant was 0.272 (95% CI=0.130-0.564; p=0.0001). This study demonstrated a close association between an IL-6R polymorphism, specifically higher A allele, and cholangiocarcinoma. PMID- 25041017 TI - High frequency of TP53 but not K-ras gene mutations in Bolivian patients with gallbladder cancer. AB - Although genetic characteristics are considered to be a factor influencing the geographic variation in the prevalence of gallbladder cancer (GBC), they have not been well studied in Bolivia, which has a high prevalence rate of GBC. The purpose of this study was to examine the frequency of TP53 and K-ras mutations in Bolivian patients with GBC and to compare them with our previous data obtained in other high-GBC-prevalence countries, namely Japan, Chile, and Hungary. DNA was extracted from cancer sites in paraffin-embedded tissue from 36 patients using a microdissection technique. TP53 mutations at exons 5 to 8 and K-ras mutations at codons 12, 13 and 61 were examined using direct sequencing techniques. The data obtained were compared with those in the other high-GBC-prevalence countries. Of the 36 patients, 18 (50.0%) had a TP53 mutation (one mutation in each of 17 patients and three mutations in one patient), and only one (2.8%) had a K-ras mutation. Of the 20 TP53 mutations, 12 were of the transition type (60.0%). This rate was significantly lower than that in Chile (12/12, P<0.05). In addition, three mutations were of the CpG transition type (15.0%), which is a feature of endogenous mutation. All three were found in the hot spot region of the TP53 gene. In contrast, G:C to T:A transversion was found in Bolivia, suggesting the presence of exogenous carcinogens. Our findings suggest that the development of GBC in Bolivia is associated with both exogenous carcinogens and endogenous mechanisms. The identification of an environmental risk factor for GBC is needed to confirm these findings. PMID- 25041018 TI - Saponins from Rubus parvifolius L. induce apoptosis in human chronic myeloid leukemia cells through AMPK activation and STAT3 inhibition. AB - BACKGROUND: Saponins are a major active component for the traditional Chinese medicine, Rubus parvifolius L., which has shown clear antitumor activities. However, the specific effects and mechanisms of saponins of Rubus parvifolius L. (SRP) remain unclear with regard to human chronic myeloid leukemia cells. The aim of this study was to investigate inhibition of proliferation and apoptosis induction effects of SRP in K562 cells and further elucidate its regulatory mechanisms. MATERIALS AND METHODS: K562 cells were treated with different concentrations of SRP and MTT assays were performed to determine cell viability. Apoptosis induction by SRP was determined with FACS and DAPI staining analysis. Western blotting was used to detect expression of apoptosis and survival related genes. Specific inhibitors were added to confirm roles of STAT3 and AMPK pathways in SRP induction of apoptosis. RESULTS: Our results indicated that SRP exhibited obvious inhibitory effects on the growth of K562 cells, and significantly induced apoptosis. Cleavage of pro-apoptotic proteins was dramatically increased after SRP exposure. SRP treatment also increased the activities of AMPK and JNK pathways, and inhibited the phosphorylation expression level of STAT3 in K562 cells. Inhibition of the AMPK pathway blocked the activation of JNK by SRP, indicating that SRP regulated the expression of JNK dependent on the AMPK pathway. Furthermore, inhibition of the latter significantly conferred resistance to SRP pro- apoptotic activity, suggesting involvement of the AMPK pathway in induction of apoptosis. Pretreatment with a STAT3 inhibitor also augmented SRP induced growth inhibition and cell apoptosis, further confirming roles of the STAT3 pathway after SRP treatment. CONCLUSIONS: Our results demonstrated that SRP induce cell apoptosis through AMPK activation and STAT3 inhibition in K562 cells. This suggests the possibility of further developing SRP as an alternative treatment option, or perhaps using it as adjuvant chemotherapeutic agent for chronic myeloid leukemia therapy. PMID- 25041019 TI - MiR-421 regulates apoptosis of BGC-823 gastric cancer cells by targeting caspase 3. AB - MicroRNAs might act as oncogenes or tumor suppressors in cancer. Recent studies have shown that miR-421 is up-regulated in human gastric cancer. Here, we found that miR-421 was over-expressed in gastric cancer tissues and cell lines. Bioinformatics analysis predicted that the caspase-3 gene was a target of miR 421. Caspase-3 was negatively regulated by miR-421 at the post-transcriptional level. Bax and Bcl-2 were also regulated by miR-421. Moreover, tumor necrosis factor receptor-I and -II, death receptors in the apoptosis pathway, were up regulated by miR-421. The over-expression of miR-421 promoted gastric cancer cell growth and inhibited apoptosis of the BGC-823 gastric cancer cell line. These observations indicate that miR-421 acts as a tumor promoter by targeting the caspase-3 gene and preventing apoptosis of gastric cancer cells through inhibition of caspase-3 expression. These findings contribute to our understanding of the functions of miR-421 in gastric cancer. PMID- 25041020 TI - Knowledge, acceptance, and willingness to pay for human papilloma virus (HPV) vaccination among female parents in Thailand. AB - BACKGROUND: This study aimed to examine the level of knowledge, attitude, acceptance, and willingness to pay (WTP) for HPV vaccination among female parents of girls aged 12-15 years in Thailand. MATERIALS AND METHODS: A cross-sectional survey was conducted in eight schools across Bangkok. RESULTS: Of 1,200 questionnaires sent out, a total of 861 questionnaires were received. Knowledge regarding the HPV vaccine among parents was quite low. Only half of the parents knew about the link between HPV and cervical cancer while one-third of them knew that the vaccine should be administered to the children before they become sexually active. Nevertheless, vaccine acceptance was high if it was offered for free: 76.9% for the bivalent and 74.4% for the quadrivalent vaccine. The proportion of respondents who were willing to copay for the vaccine if it was not totally free was also high, ranging from 68.9% for the bivalent to 67.3% for the quadrivalent vaccine. No significant difference between bivalent and quadrivalent vaccines in terms of prevalence of acceptance and willingness to pay was found. About one-third of the participants, who were willing to copay for the vaccine if it was not offered for free, indicated that they would copay less than 500 baht (30 baht = approx US$1) for three doses of bivalent vaccine. CONCLUSIONS: Substantial effort should be made to educate parents prior to introduction of a national HPV vaccination program. In terms of acceptance, either bivalent or quadrivalent vaccines can be recommended. PMID- 25041021 TI - Situation analysis of existing facilities for screening, treatment and prevention of cervical cancer in hospitals/primary health centers of Delhi-NCR region, India. AB - Cervical cancer, the second most common malignancy all over the world, is associated with HPV infection. In a developing country like India, lack of early detection and treatment facilities is the main cause for its high burden. Therefore, through our study we e tried to present the current scenario of existing facilities for the detection and treatment of cervical cancer in hospitals and primary health centers (PHCs) of Delhi-NCR region. Data were collected from 312 healthcare facilities including public and private hospitals and PHCs of all nine districts from Delhi-NCR region. Healthcare providers including gynecologists, medical officers, women health care providers and paramedical staff were interviewed, using a questionnaire; the facilities for screening, diagnosing, and treating cervical cancer in each institution were recorded, using a previously designed checklist. Our study has shown that the basic facilities for the detection and treatment of cervical cancer are abhorrently lacking in Public hospitals and PHCs as compared to the Private hospitals in Delhi-NCR region. This study demonstrates that there is an urgent need for more investment in the diagnosis and treatment of cervical cancer facilities in public and rural healthcare facilities of Delhi-NCR region. PMID- 25041022 TI - Clinical and prognostic significance of SOX11 in breast cancer. AB - Recently, the transcription factor SOX11 has gained extensive attention as a diagnostic marker in a series of cancers. However, to date, the possible roles of SOX11 in breast cancer has not been investigated. In this study, immunohistochemical staining for SOX11 was performed for 116 cases of breast cancer. Nuclear SOX11 was observed in 42 (36.2%) and cytoplasmic SOX11 in 52 (44.8%) of breast cancer samples. Moreover, high expression of cytoplasmic and nuclear SOX11 was associated with clinicopathological factors, including earlier tumor grade, absence of lymph node metastasis and smaller tumor size. Kaplan Meier survival curves demonstrated high nuclear SOX11 expression to be associated with more prolonged overall survival than those with low expression and it could be an independent predictor of survival for breast cancer patients. It is worthwhile to note that cytoplasmic SOX11 was not correlated with prognosis of breast cancer patients. These data suggest the possibility that nuclear SOX11 could be as a potential target for breast cancer therapy. PMID- 25041023 TI - Clinical value of real time elastography in patients with unexplained cervical lymphadenopathy: quantitative evaluation. AB - Ultrasonography is non-invasive and can give useful clues in the diagnosis of cervical lymphadenopathy, However, differential diagnosis is difficult in some situations even combined with color Doppler imaging. The present study was conducted to evaluate the clinical value of real time elastography in patients with unexplained cervical lymphadenopathy using a quantitative method. From May 2011 to February 2012, 39 enlarged lymph nodes from 39 patients with unexplained cervical lymphadenopathy were assessed. All the patients were examined by both B mode ultrasound, color Doppler flow imaging and elastography. The method of analyzing elasto-graphic data was the calculation of the 10 parametres ("mean", "sd", "area%", "com", "kur", "ske", "con", "ent", "idm", "asm") offered by the software integrated into the Hitachi system. The findings were then correlated with the definitive tissue diagnosis obtained by lymph node dissection or biopsy. Final histology revealed 10 cases of metastatic lymph nodes, 11 cases of lymphoma, 12 cases of tuberculosis and 6 cases of nonspecific lymphadenitis. The significant distinguishing features for conventional ultrasound were the maximum short diameter (p=0.007) and absent of echogenic hilum (p=0.0293). The diagnostic accuracy was 43.6% (17/39 cases) and there were 17 patients with equivocal diagnosis. For elastography, "mean" (p=0.003), "area%" (p=0.009), "kurt" (p=0.0291), "skew" (p=0.014) and "cont" (p=0.012) demonstrated significant differences between groups. With 9 of the 17 patients with previous equivocal diagnoses (52.9%) definite and correct diagnoses could be obtained. The diagnostic accuracy for conventional ultrasound combined elastography was 69.2% (27/39 cases). There were differences in the diagnostic sensitivity of the two methods (p=0.0224). Ultrasound combined with elastography demonstrated higher rates of conclusive and accurate diagnoses in patients with unexplained cervical lymphadenopathy than conventional ultrasound. The quantitative program showed good correlation with the pathology of different lymph node diseases. PMID- 25041024 TI - Efficacy of taxane-based regimens in a first-line setting for recurrent and/or metastatic Chinese patients with esophageal cancer. AB - OBJECTIVE: To compare the efficacy of taxane-based regimens in the first line setting retrospectively in Chinese patients with recurrent and/or metastatic esophageal cancer. METHODS: We analyzed 102 recurrent and/or metastatic esophageal cancer patients who received taxanes-based regimens in a first-line setting from January 2009 to December 2013. Sixteen (15.7%) patients were administered Nab-PTX based chemotherapy and 86 patients (84.3%) received paclitaxel (PTX) or docetaxel (DTX) based chemotherapy. Patients in the PTX/DTX group could be further divided into TP (71 patients) and TPF (15 patients) groups. RESULTS: The objective response rate (ORR) of all patients was 20.6%, and the disease control rate (DCR) was 67.6%. The median overall survival (OS) was 10.5 months (95% CI 10.1-16.4) and the median progression-free survival (PFS) was 6.04 months (95% CI 5.09-7.91). The DCR was higher in the TPF group than the TP group (93.3% vs. 59.1%; p = 0.015 ). There were no significant differences in ORR, OS, and PFS among Nab-PTX, TPF and TP groups. CONCLUSIONS: The three regimens of Nab-PTX based, TP and TPF proved active in a first line setting of Chinese patients with recurrent and/or metastatic esophageal cancer, and should thus be regarded as alternative treatments. PMID- 25041025 TI - Coaxing cancer pro-apoptoticity: an approach blending therapeutic miRNAs and dietary phytochemicals. PMID- 25041026 TI - Standardized descriptive method for the anthropological evaluation of pediatric skull fractures. AB - The literature pertaining to pediatric skull fracture is primarily clinically based and thus motivated by the need for effective assessment of both fracture characteristics (type, frequency, location, and mechanics) and context (severity of injury, associated soft tissue damage, and prognosis). From a strictly descriptive standpoint, these schemas employ overlapping levels of detail that confound the nonclinical description of fractures in the forensic context. For this reason, application of these schemas in the forensic anthropological interpretation of skull fractures is inappropriate. We argue that forensic anthropological interpretation of skull fractures requires a standard classification system that reflects fracture morphology alone, and we suggest a three-stepped classification system that conveys increasing detail with each additional step. A retrospective application of the method to a sample of 31 children aged 1 month to 2 years demonstrated its efficacy in the description of pediatric skull fractures. PMID- 25041027 TI - Therapeutic targeting of tumor-associated macrophages and microglia in glioblastoma. PMID- 25041028 TI - Could targeting secretory leukocyte protease inhibitor be an effective therapeutic option to prevent infections in acute liver failure? PMID- 25041031 TI - Skin disruption is associated with indomethacin-induced small intestinal injury in mice. AB - One mechanism by which non-steroidal anti-inflammatory drugs (NSAIDs) cause intestinal injury is by inducing matrix metalloproteinases (MMPs) that degrade and remodel the extracellular matrix. In addition to the intestinal mucosa, MMPs are expressed in the skin and can be activated by mast cell-secreted tryptase. We therefore investigated whether intestinal injury resulting from treatment with the NSAID indomethacin induced MMPs in the skin of mice and caused an associated disruption of skin function. Hairless mice and mast cell-deficient mice were administered indomethacin, after which damage to the jejuna and skin was assessed with immunohistochemistry and Western blotting. The plasma concentration of inflammatory mediators was assessed to evaluate potential pathways for signalling skin disruption in response to intestinal injury. In hairless mice with intestinal injury, transepidermal water loss (TEWL) was higher and skin hydration was lower than in control mice. The expression levels of mast cells, tryptase, MMP-1 and MMP-9 were also increased, with concurrent degradation of types I and IV collagen. In contrast, no changes in skin TEWL or skin hydration were observed in mast cell-deficient mice with indomethacin-induced intestinal injury. In all mice evaluated, the plasma concentrations of IgE, IgA, histamine and TNF-alpha were increased in response to indomethacin treatment. Skin disruption was strongly associated with indomethacin-induced small intestinal injury, and the activation of mast cells and induction of tryptase, MMP-1 and MMP-9 are critical to this association. PMID- 25041033 TI - Electrocardiographic indicators of excitability in horses for predicting recovery quality after general anaesthesia. AB - OBJECTIVE: To determine whether preoperative electrocardiographic measurements linked to sympathetic nervous activity could be used to predict recovery quality after general anaesthesia in horses. STUDY DESIGN: Prospective, clinical study. ANIMALS: Eighteen adult client-owned horses. METHODS: The electrocardiogram (ECG) was recorded presurgery in horses under three standard conditions: stabled unattended; with a groom whilst being led along a standard course; alone in the induction box. After surgery, each animal's recovery quality was scored by eight experienced anaesthetists or technicians using Donaldson's scoring system (2000). The digitized ECG recordings were analyzed for T-wave morphology, mean heart rate (HR), HR variability (HRV) and HRV derivatives including mean R-R interval, standard deviation of normal intervals (SDNN) and the root mean square of successive intervals (RMSSD), low (LF) and high frequency (HF) activity and the LF/HF ratio in both fast Fourier transformed and autoregressive spectra. Correlations between ECG variables and recovery score were examined using Spearman's rank correlation. RESULTS: There was no significant correlation between preanaesthetic ECG measurements and recovery quality. CONCLUSIONS: Predictions of recovery quality after general anaesthesia in horses cannot be based on preanaesthetic ECG variables. CLINICAL RELEVANCE: Measures other than those based on the ECG should be investigated as predictors of recovery quality. PMID- 25041030 TI - Engineering alpha-fetoprotein-based gene vaccines to prevent and treat hepatocellular carcinoma: review and future prospects. AB - Activation of a patient's immune system offers an attractive approach to prevent and treat hepatocellular carcinoma (HCC). However, the antitumor efficacy of current HCC vaccines was weak owing to insufficient immune activation of targeting self/tumor antigens. We recently found that epitope-optimized alpha fetoprotein effectively activated CD8 T cells and generated potent antitumor effects in the carcinogen-induced autochthonous HCC mouse model. We predict that the same antigen engineering approach of epitope-optimization will enable us to develop effective human vaccines to prevent HCC recurrence after liver resection. The engineered human HCC vaccines may also allow us to identify high-affinity T cell receptors and antibodies that can be used to reprogram T cells to treat HCC tumors via adoptive transfer. PMID- 25041032 TI - Association between hearing impairment and lower levels of physical activity in older adults. AB - OBJECTIVES: To determine whether hearing impairment, highly prevalent in older adults, is associated with activity levels. DESIGN: Cross-sectional. SETTING: National Health and Nutritional Examination Survey (2005-06). PARTICIPANTS: Individuals aged 70 and older who completed audiometric testing and whose physical activity was assessed subjectively using questionnaires and objectively using body-worn accelerometers (N=706). MEASUREMENTS: Hearing impairment was defined according to the speech-frequency (0.5-4 kHz) pure-tone average in the better-hearing ear (normal <25.0 dB, mild 25.0-39.9 dB, moderate or greater >=40 dB). Main outcome measures were self-reported leisure time physical activity and accelerometer-measured physical activity. Both were quantified using minutes of moderate-intensity physical activity and categorized as inactive, insufficiently active, or sufficiently active. Ordinal logistic regression analyses were conducted and adjusted for demographic and cardiovascular risk factors. RESULTS: Individuals with moderate or greater hearing impairment had greater odds than those with normal hearing of being in a lower category of physical activity as measured according to self-report (OR=1.59, 95% CI=1.11-2.28) and accelerometry (OR=1.70, 95% CI=0.99-2.91). Mild hearing impairment was not associated with level of physical activity. CONCLUSION: Moderate or greater hearing impairment in older adults is associated with lower levels of physical activity independent of demographic and cardiovascular risk factors. Future research is needed to investigate the basis of this association and whether hearing rehabilitative interventions could affect physical activity in older adults. PMID- 25041034 TI - A cut-off value of basal serum calcitonin for detecting macroscopic medullary thyroid carcinoma. AB - OBJECTIVE: Serum calcitonin (CT) level is used to detect medullary thyroid carcinoma (MTC), but the cut-off level is unclear. We aimed at identifying the optimal cut-off value of basal serum CT levels for detecting MTC. DESIGN AND PATIENTS: We retrospectively enrolled patients with hypercalcitoninemia (>=2.9 pmol/l) who had undergone thyroid ultrasonography (US) and subsequent work-up between 2001 and 2013 at Asan Medical Center. We divided patients into four groups: proven MTC (group 1, n = 93), pathologically proven non-MTC after surgery (group 2, n = 57), benign single nodule by cytology (group 3, n = 68) and patients without nodules on US (group 4, n = 24). MEASUREMENT: Basal serum CT levels were evaluated. RESULTS: The median CT level of group 1 (119.5 pmol/l) was significantly higher than those of other groups (4.0, 3.8 and 3.8 pmol/l, P < 0.001). When we adopted 19.0 pmol/l of CT level as a cut-off value, the sensitivity, specificity, and positive and negative predictive values were 77.4%, 98.7%, 97.3% and 87.8%, respectively. When we compared 29.2 pmol/l (100 pg/ml) and 19.0 pmol/l (65 pg/ml) as cut-off values, 19.0 pmol/l was more sensitive and accurate than 29.2 pmol/l. Factors associated with hypercalcitoninemia in non-MTC groups were autoimmune thyroiditis, chronic kidney disease, proton pump inhibitors and other malignancies. Serum CT levels tended to decrease spontaneously in non-MTC groups. CONCLUSION: Basal serum CT levels higher than 19.0 pmol/l can be a useful cut-off value for detecting macroscopic MTC, even though values below 19.0 pmol/l cannot exclude the presence of MTC like small volume MTC or premalignant C-cell hyperplasia. PMID- 25041035 TI - Simultaneous irradiation with different wavelengths of ultraviolet light has synergistic bactericidal effect on Vibrio parahaemolyticus. AB - Ultraviolet (UV) irradiation is an increasingly used method of water disinfection. UV rays can be classified by wavelength into UVA (320-400 nm), UVB (280-320 nm), and UVC (<280 nm). We previously developed UVA sterilization equipment with a UVA light-emitting diode (LED). The aim of this study was to establish a new water disinfection procedure using the combined irradiation of the UVA-LED and another UV wavelength. An oxidative DNA product, 8-hydroxy-2' deoxyguanosine (8-OHdG), increased after irradiation by UVA-LED alone, and the level of cyclobutane pyrimidine dimers (CPDs) was increased by UVC alone in Vibrio parahaemolyticus. Although sequential irradiation of UVA-LED and UVC induced additional bactericidal effects, simultaneous irradiation with UVA-LED and UVC-induced bactericidal synergistic effects. The 8-OHdG and CPDs production showed no differences between sequential and simultaneous irradiation. Interestingly, the recovery of CPDs was delayed by simultaneous irradiation. The synergistic effect was absent in SOS response-deficient mutants, such as the recA and lexA strains. Because recA- and lexA-mediated SOS responses have crucial roles in a DNA repair pathway, the synergistic bactericidal effect produced by the simultaneous irradiation could depend on the suppression of the CPDs repair. The simultaneous irradiation of UVA-LED and UVC is a candidate new procedure for effective water disinfection. PMID- 25041036 TI - Effect of intracoronary nitroprusside in preventing no reflow phenomenon during primary percutaneous coronary intervention: a meta-analysis. AB - BACKGROUND: Adjunctive therapy with intracoronary nitroprusside (NTP) in primary percutaneous coronary intervention (PPCI) had controversial benefits in patients with ST segment elevation myocardial infarction (STEMI). OBJECTIVES: To evaluate the effect of intracoronary NTP on no reflow phenomenon (NR) and clinical outcomes in STEMI patients undergoing PPCI. METHODS: We searched the following databases without language or time limitation in January 2014: PubMed, EMBASE, CENTRAL, ISI Web of Science, and CNKI. Trials compared the effect of intracoronary NTP with control group (placebo or no NTP treatment) on NR in STEMI patients undergoing PPCI enrolled for analyzing. RESULTS: A total of 7 trials involving 781 patients were included into this meta-analysis. Intracoronary NTP significantly reduced the incidence of thrombolysis in myocardial infarction (TIMI) flow grade (TFG) <=2 (RR: 0.47, 95% CI: 0.30-0.73, P = 0.001); the corrected TIMI frame count (CTFC) (WMD: -5.28, 95% CI: -6.79 to 3.78, P = 0.000) increased the events of myocardial blush grade (MBG) >=2 (RR: 1.12, 95% CI: 1.01 1.24, P = 0.038), and reduced the incidence of major adverse cardiac events (MACE) (RR: 0.43, 95% CI: 0.27-0.70, P = 0.001). Although the events of the complete ST segment resolution (STR) did not reach statistical significance, there was a trend indicating improvement in the intracoronary NTP group (RR: 1.143, 95% CI: 0.97-1.34, P = 0.101). CONCLUSIONS: Intracoronary NTP can significantly reduce the incidence of angiographic NR during PPCI, as well as the incidence of MACE. It seems to be a promising adjunctive therapy for NR during PPCI. PMID- 25041037 TI - Bayesian design of superiority clinical trials for recurrent events data with applications to bleeding and transfusion events in myelodyplastic syndrome. AB - In many biomedical studies, patients may experience the same type of recurrent event repeatedly over time, such as bleeding, multiple infections and disease. In this article, we propose a Bayesian design to a pivotal clinical trial in which lower risk myelodysplastic syndromes (MDS) patients are treated with MDS disease modifying therapies. One of the key study objectives is to demonstrate the investigational product (treatment) effect on reduction of platelet transfusion and bleeding events while receiving MDS therapies. In this context, we propose a new Bayesian approach for the design of superiority clinical trials using recurrent events frailty regression models. Historical recurrent events data from an already completed phase 2 trial are incorporated into the Bayesian design via the partial borrowing power prior of Ibrahim et al. (2012, Biometrics 68, 578 586). An efficient Gibbs sampling algorithm, a predictive data generation algorithm, and a simulation-based algorithm are developed for sampling from the fitting posterior distribution, generating the predictive recurrent events data, and computing various design quantities such as the type I error rate and power, respectively. An extensive simulation study is conducted to compare the proposed method to the existing frequentist methods and to investigate various operating characteristics of the proposed design. PMID- 25041038 TI - Unifying elemental stoichiometry and metabolic theory in predicting species abundances. AB - While metabolic theory predicts variance in population density within communities depending on population average body masses, the ecological stoichiometry concept relates density variation across communities to varying resource stoichiometry. Using a data set including biomass densities of 4959 populations of soil invertebrates across 48 forest sites we combined these two frameworks. We analyzed how the scaling of biomass densities with population-averaged body masses systematically interacts with stoichiometric variables. Simplified analyses employing either only body masses or only resource stoichiometry are highly context sensitive and yield variable and often misleading results. Our findings provide strong evidence that analyses of ecological state variables should integrate allometric and stoichiometric variables to explain deviations from predicted allometric scaling and avoid erroneous conclusions. In consequence, our study provides an important step towards unifying two prominent ecological theories, metabolic theory and ecological stoichiometry. PMID- 25041039 TI - In memoriam: Eduardo Dei-Cas (1945-2014). PMID- 25041040 TI - Equivalent survival and improved preservation of renal function after distal ureterectomy compared with nephroureterectomy in patients with urothelial carcinoma of the distal ureter: a propensity score-matched multicenter study. AB - OBJECTIVES: To investigate the oncological and functional outcome of distal ureterectomy compared with nephroureterectomy in the management of distal ureteral urothelial carcinoma. METHODS: Using a database including upper urinary tract urothelial carcinoma patients (n = 1329), 282 patients were identified with urothelial carcinoma localized in the distal ureter on clinical evaluation. To adjust for potential baseline differences between groups, 43 patients undergoing distal ureterectomy were matched with 86 patients undergoing nephroureterectomy using propensity scoring. Cox regression models tested the effect of surgery type on recurrence-free survival and cancer-specific survival. Estimated glomerular filtration rate was measured before and after surgery. RESULTS: The median follow up period was 50 months. There were no significant differences in 5-year recurrence-free survival and cancer-specific survival rates between the distal ureterectomy and nephroureterectomy groups (P = 0.22 and P = 0.70, respectively). Multivariate analysis showed that surgery type was not associated with recurrence free survival and cancer-specific survival (P = 0.90 and P = 0.28, respectively). In the subanalysis, recurrence-free survival and cancer-specific survival in the distal ureterectomy group were equivalent to those of the nephroureterectomy group in both pTa-1 and pT2-4 patients. Renal function was better preserved in the distal ureterectomy group than in the nephroureterectomy group (rate of change in estimated glomerular filtration rate 2% vs -20%; P < 0.001). CONCLUSIONS: The oncological outcome of distal ureterectomy is comparable with that of nephroureterectomy in distal ureteral urothelial carcinoma patients, and distal ureterectomy provides better preservation of renal function. Distal ureterectomy would be feasible for carefully selected patients with distal ureteral urothelial carcinoma. PMID- 25041041 TI - Relation between blood pressure and mortality risk in an older population: role of chronological and biological age. AB - BACKGROUND: The relation between high blood pressure (BP) and mortality risk in older individuals (above 65 years of age) is still debated. Some data suggest that this relation is inverted in certain subgroups of (biologically) older individuals. We therefore investigated whether the association between BP and mortality is dependent on chronological age and on physical and cognitive function as indicators of biological age. METHODS: The relationship between BP and all-cause mortality was investigated in 1466 older participants (aged 65 years and older; mean age 75.8 years) of the Longitudinal Ageing Study Amsterdam using multiple adjusted Cox proportional hazard models. Analyses were stratified for age, gait speed and mini mental state examination score. RESULTS: A total of 1008 participants died after a median (range) follow-up of 10.6 (0.2; 15.9) years. Low diastolic blood pressure (DBP) was associated with an increased all cause mortality risk: hazard ratio (HR) of low DBP (<=70 mmHg) compared to normal DBP (71-90 mmHg) was 1.36 [95% confidence interval (CI) 1.15; 1.61]. This relation was particularly strong in the oldest old (individuals aged >80 years) and in those who had lower levels of both physical and cognitive functioning: HRs (95% CIs) of low versus normal DBP were 1.58 (1.26; 1.98) and 1.45 (1.18; 1.77), respectively. CONCLUSION: In a large population-based cohort of older adults, low DBP was associated with an increased all-cause mortality risk, especially in the oldest old and in biologically old individuals. PMID- 25041042 TI - Distinct claudin expression characterizes BRCA1-related breast cancer. AB - AIMS: Members of the claudin family are involved in cancer progression and are differentially expressed in subtypes of breast cancer. Breast cancers in BRCA1 germ line mutation carriers have distinct clinicopathological characteristics. Biomarkers that discriminate between BRCA1-related and sporadic breast cancer cases are needed to improve early identification of mutation carriers. In this study we evaluated protein expression of five major claudins in BRCA1-related breast cancers in comparison with sporadic controls. METHODS AND RESULTS: Forty breast cancers in BRCA1 mutation carriers and 40 age-matched sporadic breast cancers were immunohistochemically stained for claudins 1, 3, 4, 6 and 7. Total intratumoural expression levels were compared to those in the surrounding normal tissue. In addition, subcellular claudin expression was scored. Higher overexpression rates were observed for all five claudins in BRCA1-related breast cancers when compared to sporadic controls. In multivariate analysis, overexpression of claudin 3, 4, and 7 was mainly dependent on ER-status, whereas overexpression of claudin 6 and high membranous expression of claudin 1 were independent of other characteristics. CONCLUSIONS: BRCA1-related breast cancers are characterized by frequent overexpression of claudins. Especially claudin 1 and 6 expression may help to discriminate mutation carriers from sporadic breast cancer cases. PMID- 25041043 TI - Hospital pharmacy services in the Pacific Island countries. AB - RATIONALE, AIMS AND OBJECTIVES: Non-communicable diseases have become an increasing problem in the Pacific Island countries (PICs). With the medical supply system often attached to hospitals in PICs, the training of hospital pharmacy staff has become increasingly important. This study aimed to explore hospital pharmacy services in the PICs using these validated surveys (BS26-27 and BS28-31 surveys) focusing upon hospital pharmacists' influence on prescribing and quality use of medicines. METHOD: The BS26-27 and BS28-31 surveys were distributed online to pharmacy directors in hospitals in the PICs in 2011 and 2013, respectively. Surveys were made available in both English and French. RESULTS: In total, data from 55 hospitals were received (77% of the hospital sample in PICs) for either the BS26-27 or BS28-31 survey. From the responses received, 97% (36/37) of hospitals had a formulary, with 81% (26/32) of hospitals having a Pharmacy and Therapeutics (P&T) committee. Furthermore, 67% (24/36) of respondents stated that they provided some sort of clinical pharmacy service. On average, hospitals had two pharmacists involved in clinical pharmacy services. In BS28-31, over 75% (n=27) of respondents believed having a strong relationship with other health care professionals, having effective communication skills and taking professional responsibility for the medicines prescribed as 'mostly' or 'strongly' facilitating clinical services. CONCLUSIONS: Hospital pharmacists' participation on P&T committee and clinical services is common in the PICs. Such services enhance medication selection and reduce wastage. Although there are still too few hospital pharmacists in PICs, additional support aimed at enhancing their team building and communication skills will allow them to expand their roles and continue to improve patient health outcomes. PMID- 25041045 TI - The story of diabetes and hypertension: bad companions with internecine mission on the left atrium. PMID- 25041047 TI - Behcet's disease, echocardiographers, and cardiac surgeons: together is better. AB - Behcet's disease is an inflammatory disorder of unknown etiology, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Many abnormal echocardiographic findings have been previously reported in patients with Behcet's disease. Some of these; namely, aortic root dilation, aortic valve regurgitation, intracardiac thrombi, and pulmonary artery aneurysm may precede other manifestations of the disease and occasionally require surgical intervention for proper management. Compared to patients without Behcet's disease, management of these complications in patients with the disease is challenging and requires different treatment strategies. If diagnosis of Behcet's disease is missed prior to surgical intervention, higher incidence of surgical failure, recurrence, and even higher postoperative mortality may occur. In this review, the author discusses these major cardiac complications of Behcet's disease. PMID- 25041048 TI - Papillary fibroelastoma of the pulmonary valve-a systematic review: advantages of live/real time three-dimensional transthoracic and transesophageal echocardiography. PMID- 25041049 TI - Reply: To PMID 24128270. PMID- 25041053 TI - Excellence, quality and limitations of the NICE venous thromboembolism score tool: how can it be improved? PMID- 25041052 TI - Phase I/II trial of 2-weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807). AB - We carried out a phase I/II trial of adding 2-weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2-weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2-weekly docetaxel (30 mg/m(2) [dose level (DL)1] or 40 mg/m(2) [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed-dose CF (80 mg/m(2) cisplatin, day 1; 800 mg/m(2) fluorouracil, days 1-5) repeated every 4 weeks. The primary endpoint was dose-limiting toxicity (DLT) in phase I and central peer review-based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty-two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48-75%); median overall survival and progression-free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment-related death in one patient. The 2-weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737. PMID- 25041054 TI - HIGH PATIENT SATISFACTION WITH NURSE PRACTITIONER DELIVERED SERVICES AT TWO HEALTH CENTRES IN URBAN JAMAICA. AB - Abstract Background: Nurse practitioners are playing an increasing role in the delivery of primary healthcare. Patient satisfaction with their services patients is an important factor to the expansion of their role in the health services. Objective: To explore the level of patient satisfaction with nurse practitioner delivered services at two health centres in urban Jamaica. Method: A cross sectional survey of 120 adult clients (age >=18 years old) seen by Nurse Practitioner at a Type 3 or Type 5 health centre in Kingston, Jamaica was conducted using a modified self-administered Nurse Practitioner Satisfaction Survey questionnaire. Data were analyzed using SPSS(r) version 18 for Windows(r). Results: The study achieved response rate of 91.6% (n=120). The majority were females (77%) with an average age of 40 +/- 16 years. Most (63%) were from the Type 5 health centre and the rest (37%) were from a Type 3 facility. The mean general satisfaction score was 81 out of a possible 90 and 83% of the respondents reported they were very satisfied with another 17% expressing that they were satisfied with the nurse practitioner services at both facilities. No respondent was dissatisfied. The mean satisfaction score was significantly higher among respondents 40 years and older than that of their younger counterparts. Socio demographic and organization characteristics were not associated with the mean satisfaction score. Conclusions: A high level of satisfaction exists among patients seen by nurse practitioners at two facilities in Kingston, Jamaica. This may represent an opportunity for expanded role of Nurse practitioners in the delivery of primary in Jamaica. PMID- 25041055 TI - Rates of inbreeding and genetic diversity in Iranian Holstein cattle. AB - The accumulation of inbreeding and the loss of genetic diversity is a potential problem in Holstein dairy cattle. The goal of this study was to estimate inbreeding levels and other measures of genetic diversity, using pedigree information from Iranian Holstein cattle. Edited pedigree included 1,048,572 animals. The average number of discrete generation equivalents and pedigree completeness index reached 13.4 and 90%, respectively. The rate of inbreeding was 0.3% per year. Effective number of founders, founder genomes, non-founders and ancestors of animals born between 2003 and 2011 were 503, 15.6, 16.1 and 25.7, respectively. It was proven that the unequal founder contributions as well as bottlenecks and genetic drift were important reasons for the loss of genetic diversity in the population. The top 10 ancestors with the highest marginal genetic contributions to animals born between 2003 and 2011 and with the highest contributions to inbreeding were 48.20% and 63.94%, respectively. Analyses revealed that the most important cause of genetic diversity loss was genetic drift accumulated over non-founder generations, which occurred due to small effective population size. Therefore, it seems that managing selection and mating decisions are controlling future co-ancestry and inbreeding, which would lead to better handling of the effective population size. PMID- 25041056 TI - A new twist on old ideas: how sitting reorients crawlers. AB - Traditionally, crawling and sitting are considered distinct motor behaviors with different postures and functions. Ten- to 12-month-old infants were observed in the laboratory or in their homes while being coaxed to crawl continuously over long, straight walkways (Study 1; N = 20) and during spontaneous crawling during free play (Study 2; N = 20). In every context, infants stopped crawling to sit 3 6 times per minute. Transitions from crawling to sitting frequently turned infants' bodies away from the direction of heading; subsequent transitions back to crawling were offset by as much as 180 degrees from the original direction of heading. Apparently, body reorientations result from the biomechanics of transitioning between crawling and sitting. Findings indicate that sustained, linear crawling is likely an epiphenomenon of how gait is studied in standard paradigms. Postural transitions between crawling and sitting are ubiquitous and can represent a functional unit of action. These transitions and the accompanying body reorientations likely have cascading effects for infants' exploration, visual perception, and spatial cognition. PMID- 25041057 TI - Mouse models of intracranial aneurysm. AB - Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-alpha, the renin-angiotensin system and the beta-estrogen receptor. An agreed clear, precise and reproducible definition of what constitutes an aneurysm in the models would assist in their use to better understand the pathology of intracranial aneurysm and applying findings to patients. PMID- 25041058 TI - Meditation for migraines: a pilot randomized controlled trial. AB - OBJECTIVE: Our objective was to assess the safety, feasibility, and effects of the standardized 8-week mindfulness-based stress reduction (MBSR) course in adults with migraines. BACKGROUND: Stress is a well-known trigger for headaches. Research supports the general benefits of mind/body interventions for migraines, but there are few rigorous studies supporting the use of specific standardized interventions. MBSR is a standardized 8-week mind/body intervention that teaches mindfulness meditation/yoga. Preliminary research has shown MBSR to be effective for chronic pain syndromes, but it has not been evaluated for migraines. METHODS: We conducted a randomized controlled trial with 19 episodic migraineurs randomized to either MBSR (n = 10) or usual care (n = 9). Our primary outcome was change in migraine frequency from baseline to initial follow-up. Secondary outcomes included change in headache severity, duration, self-efficacy, perceived stress, migraine-related disability/impact, anxiety, depression, mindfulness, and quality of life from baseline to initial follow-up. RESULTS: MBSR was safe (no adverse events), with 0% dropout and excellent adherence (daily meditation average: 34 +/- 11 minutes, range 16-50 minutes/day). Median class attendance from 9 classes (including retreat day) was 8 (range [3, 9]); average class attendance was 6.7 +/- 2.5. MBSR participants had 1.4 fewer migraines/month (MBSR: 3.5 to 1.0 vs control: 1.2 to 0 migraines/month, 95% confidence interval CI [-4.6, 1.8], P = .38), an effect that did not reach statistical significance in this pilot sample. Headaches were less severe, although not significantly so ( 1.3 points/headache on 0-10 scale, [-2.3, 0.09], P = .053) and shorter (-2.9 hours/headache, [-4.6, -0.02], P = .043) vs control. Migraine Disability Assessment and Headache Impact Test-6 dropped in MBSR vs control (-12.6, [-22.0, 1.0], P = .017 and -4.8, [-11.0, -1.0], P = .043, respectively). Self-efficacy and mindfulness improved in MBSR vs control (13.2 [1.0, 30.0], P = .035 and 13.1 [3.0, 26.0], P = .035 respectively). CONCLUSIONS: MBSR is safe and feasible for adults with migraines. Although the small sample size of this pilot trial did not provide power to detect statistically significant changes in migraine frequency or severity, secondary outcomes demonstrated this intervention had a beneficial effect on headache duration, disability, self-efficacy, and mindfulness. Future studies with larger sample sizes are warranted to further evaluate this intervention for adults with migraines. This study was prospectively registered (ClinicalTrials.gov identifier NCT01545466). PMID- 25041059 TI - Critical assessment of the systematic review on hospitalization resulting from medicine related problems. PMID- 25041060 TI - Twenty-five million liters of blood into the sewer. AB - Laboratory medicine has evolved tremendously but not so much to the individual patient's benefit as far as the volume of blood samples is concerned. It can be calculated that with the current collection methods and the small amounts of blood or serum required by modern laboratory analyzers in the Western world alone each 25 million liter of patients' blood is thrown into waste containers. That is four times more than the total volume of blood that is transfused each year. And this is not a trivial issue, as studies show that many patients develop 'hospital acquired anemia' due to blood collection and this is associated with an adverse outcome. It is time that collection methods for blood samples are adapted to the much smaller volumes that are required by new generation laboratory analyzers, in particular for vulnerable groups, such as hematology or oncology patients, critically ill patients, or children. PMID- 25041061 TI - Personality in remitted major depressive disorder with single and recurrent episodes assessed with the Temperament and Character Inventory. AB - AIM: Previous studies consistently reported increased harm avoidance (HA) assessed with the Temperament and Character Inventory (TCI) in patients with major depressive disorder (MDD). However, such findings may have been related with depression severity and number of depressive episodes. The aims of the present study were twofold: to examine TCI personality profile in remitted MDD (DSM-IV) patients and to compare TCI personality between MDD patients with single episode (SGL-MDD) and those with recurrent episodes (REC-MDD) in order to elucidate personality profile associated with recurrence. METHODS: TCI was administered to 86 outpatients with remitted SGL-MDD (12 male and 17 female patients; mean age 43.2 +/- 12.1 years) and REC-MDD (26 male and 31 female patients; 40.3 +/- 11.6 years), and 529 healthy controls (225 men and 304 women; 43.4 +/- 15.5 years), matched for age, sex and education years. Logistic regression analyses were performed in which single/recurrent episodes of depression were the dependent variable and age, sex, age of onset, family history of psychiatric disease and TCI scores were entered as possible predictors. RESULTS: The remitted MDD patients had significantly higher scores on HA (P < 0.001) and lower scores on self-directedness (P < 0.001), compared with the controls. HA (P = 0.03), its subscore, fatigability (P = 0.03), and family history of psychiatric disease were found to be positive predictors for recurrence. CONCLUSION: There are differences in personality profile between remitted MDD patients and controls, and between remitted REC-MDD and SGL-MDD patients, suggesting that they are trait markers. HA and fatigability might be useful to assess risk for recurrence of depression. PMID- 25041062 TI - Human papillomavirus evaluation of vemurafenib-induced skin epithelial tumors: a case series. PMID- 25041063 TI - The assessment of relationship between fragmented QRS complex and left ventricular wall motion score index in patients with ST elevation myocardial infarction who underwent primary percutaneous coronary intervention. AB - OBJECTIVES: Fragmented QRS (fQRS) has been found to be associated with high mortality and arrhythmic events in acute coronary syndromes. Regional systolic function using wall motion score index (WMSI) is an alternative to left ventricular ejection fraction (LVEF) for the assessment of left ventricular systolic function. The aim of this study was to investigate the relation between the presence of fQRS on admission electrocardiogram (ECG) and WMSI in ST elevation myocardial infarction (STEMI) underwent primary coronary intervention (PCI). The in-hospital and long-term prognostic significance of persistent fQRS was also evaluated. METHODS: In this retrospective study, 542 patients with a diagnose of STEMI underwent primary PCI were included. Study patients were divided into two groups according to the presence (n = 153) or absence (n = 389) of a fQRS on admission ECG. RESULTS: WMSI was found to be significantly higher in fQRS(+) group compared to the fQRS(-) group (P < 0.001). In multivariete analysis, WMSI was found to be an independent predictor of fQRS, and fQRS was inversely associated with LVEF. The in-hospital reinfarction (P = 0.003), MACE (P = 0.024), intraaortic balloon pump use (P = 0.014), and advanced heart failure (P < 0.001) were found to be significantly more frequent in the fQRS(+) group. The presence of fQRS on admission was found to be associated with an increase in long term cardiovascular mortality (P = 0.028), and long-term all-cause mortality (P = 0.022). CONCLUSION: WMSI was significantly related with the presence of the fQRS, which reflects the linking between impairment of regional left ventricular systolic function and the presence of severe myocardial injury in STEMI. PMID- 25041064 TI - Single incision and reduced port laparoscopic low anterior resection for rectal cancer: initial experience in 96 cases. AB - BACKGROUND: Although a single incision laparoscopic (SIL) technique has been used increasingly in colorectal surgery, there are only a few reports on the clinical availability of this approach coupled with low anterior resection (SIL-LAR) for colorectal cancers. We report here 96 consecutive cases of SIL-LAR and reduced port LAR cases, of which the initial approach was SIL. METHODS: This is a retrospective review of prospectively collected data of SIL-LAR cases performed by a single surgeon in Samsung Medical Center between June 2011 and June 2012. RESULTS: Out of 96 cases, 28 were finished as 'pure' SIL-LAR. Sixty-four cases were performed with one additional port, and four needed two more ports. There was no open conversion. The median duration of operation was 165 min. Proximal and distal resection margins were negative in all cases. Circumferential resection margins were positive in four cases. The median duration of postoperative stay was 7 days and the complication rate was 20%. There were six cases of anastomosis leakage (6%). CONCLUSION: The SIL-LAR technique can be applied safely with the optional use of an additional port. One additional port in the right suprapubic area is useful for obtaining a secure distal division and a safe total mesorectal excision, especially in patients with lower lesions or history of neoadjuvant chemoradiation. PMID- 25041065 TI - Vitamin D and white matter abnormalities in older adults: a cross-sectional neuroimaging study. AB - BACKGROUND AND PURPOSE: Morphological brain changes related to hypovitaminosis D have been poorly studied. In particular, the age-related decrease in vitamin D concentrations may explain the onset of white matter abnormalities (WMA) in older adults. Our objectives were (i) to investigate whether there was an association between serum 25-hydroxyvitamin D (25OHD) concentration and the grade of WMA in older adults and (ii) to determine whether the location of WMA was associated with 25OHD concentration. METHODS: One hundred and thirty-three Caucasian older community-dwellers with no clinical hydrocephalus (mean 71.6 +/- 5.6 years; 43.6% female) received a blood test and a magnetic resonance imaging scan of the brain. The grades of total, periventricular and deep WMA were scored using semiquantitative visual rating scales from T2-weighted fluid-attenuated inversion recovery images. The association of WMA with as-measured and deseasonalized 25OHD concentrations was evaluated with the following covariates: age, gender, body mass index, use of anti-vascular drugs, number of comorbidities, impaired mobility, education level, Mini-Mental State Examination score, medial temporal lobe atrophy, serum concentrations of calcium, thyroid-stimulating hormone and vitamin B12, and estimated glomerular filtration rate. RESULTS: Both as-measured and deseasonalized serum 25OHD concentrations were found to be inversely associated with the grade of total WMA (adjusted beta = -0.32, P = 0.027), specifically with periventricular WMA (adjusted beta = -0.15, P = 0.009) but not with deep WMA (adjusted beta = -0.12, P = 0.090). Similarly, participants with 25OHD concentration <75 nM had on average a 33% higher grade of periventricular WMA than those with 25OHD >=75 nM (P = 0.024). No difference in average grade was found for deep WMA (P = 0.949). CONCLUSIONS: Lower serum 25OHD concentration was associated with higher grade of WMA, particularly periventricular WMA. These findings provide a scientific basis for vitamin D replacement trials. PMID- 25041066 TI - Association between infant swimming and rhinovirus-induced wheezing. AB - AIM: Infant swimming has been considered as a risk factor for wheezing, but the role that respiratory viruses play is unclear. We explored the effects of infant swimming on the risk of all wheezing illnesses and wheezing associated with rhinoviruses. METHODS: We followed up a birth cohort of 1827 children until 17 months of age, collecting data on infant swimming, other risk factors and physician-diagnosed bronchiolitis or recurrent wheezing. Viral diagnostics were performed in a subset of children with all respiratory tract infections. RESULTS: Data on infant swimming were obtained for 1038 children, with viral follow-up for 635 children. At least one wheezing illness was documented in 45/469 (9.6%) swimming children versus 39/569 (6.9%) nonswimming children (p = 0.11), and rhinoviruses were associated with wheezing in 11/296 (3.7%) swimming children versus 4/339 (1.2%) nonswimming children (p = 0.04). In adjusted logistic regression analyses, swimming had an odds ratio of 1.71 (p = 0.05) for bronchiolitis and 3.57 (p = 0.06) for rhinovirus-associated wheezing. An association between infant swimming and rhinovirus-associated wheezing was detected for children with atopic eczema (p = 0.006). CONCLUSION: There may be a link between infant swimming and rhinovirus-induced wheezing illnesses in atopic infants. PMID- 25041067 TI - How does solar ultraviolet-B radiation improve drought tolerance of silver birch (Betula pendula Roth.) seedlings? AB - We hypothesized that solar ultraviolet (UV) radiation would protect silver birch seedlings from the detrimental effects of water stress through a coordinated suite of trait responses, including morphological acclimation, improved control of water loss through gas exchange and hydraulic sufficiency. To better understand how this synergetic interaction works, plants were grown in an experiment under nine treatment combinations attenuating ultraviolet-A and ultraviolet-B (UVB) from solar radiation together with differential watering to create water-deficit conditions. In seedlings under water deficit, UV attenuation reduced height growth, leaf production and leaf length compared with seedlings receiving the full spectrum of solar radiation, whereas the growth and morphology of well-watered seedlings was largely unaffected by UV attenuation. There was an interactive effect of the treatment combination on water relations, which was more apparent as a change in the water potential at which leaves wilted or plants died than through differences in gas exchange. This suggests that changes occur in the cell wall elastic modulus or accumulation of osmolites in cells under UVB. Overall, the strong negative effects of water deficit are partially ameliorated by solar UV radiation, whereas well-watered silver birch seedlings are slightly disadvantaged by the solar UV radiation they receive. PMID- 25041069 TI - The effect of energy drinks on the urge to drink alcohol in young adults. AB - BACKGROUND: Recently, Marczinski and colleagues (2013) showed that energy drinks combined with alcohol augment a person's desire to drink more alcohol relative to drinking alcohol alone. The current study replicates the findings of Marczinski and colleagues (2013) using a robust measure of alcohol craving. METHODS: Seventy five participants aged 18 to 30 years were assigned to an alcohol only or alcohol+energy drink condition in a double-blind randomized pre- versus posttest experiment. Participants received a cocktail containing either 60 ml of vodka and a Red Bull((r)) Silver Edition energy drink (alcohol+energy drink condition) or 60 ml of vodka with a soda water vehicle (alcohol-only condition); both cocktails contained 200 ml of fruit drink. The primary outcome measure was the Alcohol Urge Questionnaire taken at pretest and at 20 minutes (posttest). Other measures taken at posttest were the Biphasic Alcohol Effects Questionnaire, the Drug Effects Questionnaire, and breath alcohol concentration (BAC). RESULTS: The alcohol+energy drink condition showed a greater pre- versus posttest increase in urge to drink alcohol compared with the alcohol-only condition (B = 3.24, p = 0.021, d = 0.44). Participants in the alcohol+energy drink condition had significantly higher ratings on liking the cocktail and wanting to drink more of the cocktail, and lower BACs, than the alcohol-only condition. When examined at specific BACs, the effect of the energy drink on the pre- to posttest increase in urge to drink was largest and only significant at BACs of 0.04-0.05 (cf. < 0.04 g/dl).There were no significant differences in stimulation, sedation, feeling the effects of the cocktail, or feeling high. CONCLUSIONS: Combining energy drinks with alcohol increased the urge to drink alcohol relative to drinking alcohol alone. More research is needed to understand what factors mediate this effect and whether it increases subsequent alcohol consumption. PMID- 25041070 TI - Male labour migration, spousal communication, and STI treatment in Armenia. AB - This study aims to add to the scant research on the association between labour migration and sexually transmitted infections (STIs). It builds upon earlier findings suggesting that left-behind migrants' wives tend to have higher risks of contracting STIs than women married to non-migrants. Using data from a 2007 survey in rural Armenia, a post-Soviet patriarchal setting with high levels of seasonal male migration and high rates of STIs, we examine how migration influences spousal communication about STIs, and how this communication, in turn, affects women's use of medical care for STI-like symptoms. The results of random intercept logistic regression models show that migrants' wives were significantly more likely to talk about STI-related risks with their husbands than were non migrants' wives. However, among women reporting STI-like symptoms in 12 months before the survey, migrants' wives were less likely to have talked to their husbands about these symptoms. We also find that women married to migrants were less likely to seek professional care for their STI-like symptoms than those married to non-migrants, but this association was moderated by women's communication about these symptoms with their spouses. PMID- 25041068 TI - Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-beta1/Smad2/3 signalling. AB - BACKGROUND AND PURPOSE: Chronic hepatic inflammation results in liver fibrosis. As effective anti-fibrogenic agents are lacking, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate with anti-inflammatory and anti-apoptotic properties for tis effects on hepatic fibrogenesis. EXPERIMENTAL APPROACH: To stimulate fibrogenesis, LX2 hepatic stellate cells were cultured with conditioned medium from CL48 liver cells after exposure to stress-inducing conditions - methionine-choline-deficient (MCD) medium or TNFalpha/cycloheximide (CHX) - with or without UDCA-LPE preincubation. Anti-fibrogenic effects of UDCA-LPE were further studied in CL48 and LX2 cells and in primary human hepatic stellate cells (HHStec) directly exposed to TGF-beta1. To test UDCA-LPE in vivo, C57BL/6 mice were fed a MCD diet for 11 weeks followed by 30 mg.kg(-1) UDCA-LPE 3* per week for 2.5 weeks. KEY RESULTS: Expression of alpha-smooth muscle actin (alpha-SMA), alpha1-collagen, vimentin and TGF-beta1 was down-regulated by up to 93% by UDCA-LPE in LX-2 cells cultured with conditioned medium. Also, UDCA-LPE inhibited Smad3 phosphorylation in CL48 cells incubated with MCD medium or TNFalpha/CHX and in LX2 cells exposed to conditioned medium. UDCA-LPE also decreased phosphorylated Smad3 and Smad2 directly induced by TGF-beta1. Inhibition of TGF-beta1/Smad2/3 signalling with down-regulation of target genes was confirmed in HHStec. In vivo, UDCA-LPE decreased hepatic alpha-SMA, alpha1-collagen and TGF-beta1 expression and markedly lowered alpha-SMA protein and collagen deposition in MCD mice. CONCLUSIONS AND IMPLICATIONS: By blocking TGF-beta1/Smad2/3 signalling, UDCA-LPE suppressed key mediators of hepatic fibrogenesis. Thus, UDCA-LPE could be suitable for prevention of fibrotic progression of chronic liver disease. PMID- 25041071 TI - The impact of DECISION+2 on patient intention to engage in shared decision making: secondary analysis of a multicentre clustered randomized trial. AB - BACKGROUND: Training health professionals in shared decision making (SDM) may influence their patients' intention to engage in SDM. OBJECTIVE: To assess the impact of DECISION+2, a SDM training programme for family physicians about the use of antibiotics to treat acute respiratory infections (ARIs), on their patients' intention to engage in SDM in future consultations. DESIGN: Secondary analysis of a multicentre clustered randomized trial. SETTING AND PARTICIPANTS: Three hundred and fifty-nine patients consulting family physicians about an ARI in nine family practice teaching units (FPTUs). INTERVENTION: DECISION+2 (two hour online tutorial, two-hour workshop, and decision support tools) was offered in the experimental group (five FPTUs, 162 physicians, 181 patients). Usual care was provided in the control group (four FPTUs, 108 physicians, 178 patients). OUTCOME MEASURE: Change in patients' intention scores (range -3 to +3) between pre- and post-consultation. RESULTS: The mean +/- SD [median] scores of intention to engage in SDM were high in both study groups before consultation (DECISION+2 group: 1.4 +/- 1.0 [1.7]; control group: 1.5 +/- 1.1 [1.7]) and increased in both groups after consultation (DECISION+2 group: 2.1 +/- 1.1 [2.7]; control group: 1.9 +/- 1.2 [2.3]). Change of intention, classified as either increased, stable or decreased, was not statistically associated with the exposure to the DECISION+2 programme after adjusting for the cluster design (proportional odds ratio = 1.5; 95% confidence interval = 0.8-3.0). CONCLUSION: DECISION+2 had no significant impact on patients' intention to engage in SDM for choosing to use antibiotics or not to treat an ARI in future consultations. Patient-targeted interventions may be necessary to achieve this purpose. PMID- 25041072 TI - Fresh extraction socket: spontaneous healing vs. immediate implant placement. AB - AIM: To evaluate the impact that immediate implant placement may have on bone remodelling in comparison with adjacent sockets left to heal spontaneously. MATERIALS AND METHODS: In a beagle dog model (N = 16 dogs), mandibular premolars were extracted, and implants were placed in each distal socket (test) with the corresponding mesial site left to heal undisturbed (control). Healing was assessed measuring both the vertical distance between buccal and lingual crest (B'L') and the width of buccal and lingual walls at different levels. Five healing periods were evaluated. Differences between means for each variable and for each healing period between test and control were compared (Kruskal-Wallis test; Friedman test). RESULTS: At 2 and 8 weeks of healing, the B'L' distance revealed significant higher values at test compared to control sites, being this difference three times higher at the end of the study (P < 0.05). In the test group, the width of the crest was reduced between baseline (0.37 [0.04]) and 8 weeks healing (0.13 [0.64]), demonstrating a 62% reduction of the initial width. These differences were not observed in the control group. CONCLUSIONS: Immediate implant placement into fresh extraction sockets may jeopardize the vertical bone remodelling of the socket. Furthermore, a tendency towards greater buccal horizontal resorption was observed in the most coronal aspect of the buccal bone crest. PMID- 25041073 TI - Campylobacter lari in a platelet donation: an unexpected finding. PMID- 25041074 TI - Primary sclerosing cholangitis increases the risk for pancreatitis after endoscopic retrograde cholangiopancreatography. AB - BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) have an increased risk for adverse events following endoscopic retrograde cholangiopancreatography (ERCP), mainly caused by bacterial cholangitis. The risk of pancreatitis is less examined. Therefore, our aim was to study adverse events following ERCP and to evaluate if PSC is a risk factor for pancreatitis. METHODS: Data were collected through a Swedish nationwide quality registry comprising fifty-one Swedish ERCP centres. The final study cohort consisted of 8932 adults who had undergone ERCP from 1 January 2007 to 31 December 2009. A total of 141 patients had PSC. Variables of importance for adverse events were entered into a multivariate logistic regression model for risk factor analysis. RESULTS: The following adverse events were increased in PSC as compared with non-PSC patients: overall (18.4% vs. 7.3%), pancreatitis (7.8% vs. 3.2%, P = 0.002), cholangitis (7.1% vs. 2.1%, P < 0.001) and per-operative extravasation of contrast (5.7% vs. 0.7%, P < 0.001). PSC was shown to be an independent risk factor for all of these adverse events: pancreatitis, OR 2.02 (95% CI, 1.04-3.92), cholangitis, OR 2.88 (95% CI, 1.47-5.65), and extravasation of contrast, OR 5.84 (95% CI, 2.24-15.23). CONCLUSION: The rate of adverse events overall following ERCP in PSC is 18% and PEP occurs in 8%. PSC is an independent risk factor for PEP and the risk is doubled. These findings underline the importance of a careful selection of PSC patients eligible for ERCP as well as a need for high competence of the treating team. PMID- 25041075 TI - Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1. AB - BACKGROUND: Programmed death-1 (PD-1) costimulation acts as a negative regulator of T-cell responses to allografts. However, the role of the PD-1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T-cell responses to porcine transfectants overexpressing PD-Ligand1 (L23 PD-L1 cells) are remarkably weak. In this report, we asked whether the PD-1/PD-L1 pathway has the potential to diminish xenogeneic immune responses also in vivo. METHODS: L23-PD-L1 or mock transfected control cells (L23-GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney-infiltrating rat leukocytes and the induction of anti-pig antibodies were monitored in grafted animals. RESULTS: Assessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23-PD-L1 or L23-GFP control cells. However, the level of MHC class-II molecules was reduced on macrophages responding to L23 PD-L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23-PD-L1 cells. In addition, the titers of induced anti-pig antibodies were significantly lower in rats grafted with L23-PD L1 cells. CONCLUSIONS: These data suggest that signals triggered by PD-1-PD-L1 interaction interfere with activation pathways involved in the induction of cellular and antibody-mediated immune responses to xenografts in vivo. Targeting of PD-1 and/or PD-L1 may be a promising approach for immune modulation after xenotransplantation. PMID- 25041076 TI - Severe hepatic injury associated with different statins in patients with chronic liver disease: a nationwide population-based cohort study. AB - BACKGROUND AND AIM: The hepatotoxicity of statins in patients with chronic liver diseases remains unclear. In this study, we aimed to estimate the risk of severe hepatic injury associated with different statins in patients with chronic liver disease. METHODS: A nationwide population-based cohort study was conducted by analyzing the Taiwan National Health Insurance database. A total of 37,929 subjects with chronic liver disease who started statin therapy were identified during the period of January 1, 2005 to December 31, 2009. Outcome was defined as hospitalization due to liver injury. RESULTS: During a total of 118,772 person years of follow-up, 912 incident cases of hospitalization due to hepatic injury are identified. The incidence rate was 2.95, 2.49, 2.92, 1.94, 2.65, and 2.52 per 100,000 person-days for atorvastatin, lovastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin initiators, respectively. Overall, there was no difference in the incidence associated with different statins. However, when each statin was further categorized to high (? 0.5 defined daily dose) or low (< 0.5 defined daily dose) mean daily dose, only high-dose atorvastatin was significantly associated with increased risk of hospitalization due to hepatic injury (hazard ratio, 1.62; 95% confidence interval, 1.29, 2.03) as compared with low-dose atorvastatin. CONCLUSION: The overall incidence of hospitalization due to severe hepatic injury was low among statin initiators with chronic liver disease. Only high-dose atorvastatin was associated with increased risk. PMID- 25041077 TI - Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing. AB - OBJECTIVE: To establish and utilize a Next-Generation Sequencing (NGS)-based strategy to screen for maturity onset diabetes of the young (MODY) gene mutations in subjects with early-onset diabetes. PATIENTS AND METHODS: Maturity onset diabetes of the young (MODY) genetic testing was carried out in 80 subjects of Asian Indian origin with young onset diabetes to identify mutations in a comprehensive panel of ten MODY genes. A novel multiplex polymerase chain reaction (PCR)-based target enrichment was established, followed by NGS on the Ion Torrent Personal Genome Machine (PGM). All the mutations and rare variants were confirmed by Sanger sequencing. RESULTS: We identified mutations in 11 (19%) of the 56 clinically diagnosed MODY subjects and seven of these mutations were novel. The identified mutations include p.H241Q, p.E59Q, c.-162G>A 5' UTR in NEUROD1, p.V169I cosegregating with c.493-4G>A and c.493-20C>T, p.E271K in HNF4A, p.A501S in HNF1A, p.E440X in GCK, p.V177M in PDX1, p.L92F in HNF1B and p.R31L in PAX4 genes. Interestingly, two patients with NEUROD1 mutation were also positive for the p.E224K mutation in PDX1 gene. These patients with coexisting NEUROD1 PDX1 mutations showed a marked reduction in glucose-induced insulin secretion. All 24 subjects who had not met the clinical criteria of MODY were negative for the mutations. To the best of our knowledge, this is the first report of PDX1, HNF1B, NEUROD1 and PAX4 mutations from India. CONCLUSIONS: Multiplex PCR coupled with NGS provides a rapid, cost-effective and accurate method for comprehensive parallelized genetic testing of MODY. When compared to earlier reports, we have identified a higher frequency and a novel digenic mutation pattern involving NEUROD1 and PDX1 genes. PMID- 25041078 TI - The cytotoxicity and cellular stress by temperature-fabricated polyshaped gold nanoparticles using marine macroalgae, Padina gymnospora. AB - Bioreduction of metal ions for the synthesis of stable nanoparticles (NPs) in physiological environment has been a great challenge in the field of nanotechnology and its application. In the present study, well-defined biofunctionalized gold nanoparticles (AuNPs) were developed following a biomimetic approach for an enhanced anticancer activity. The fucoxanthins-capped crystalline AuNPs showed a particle size of 14 nm. The temperature-mediated biosynthesized NPs were characterized by UV-vis, dynamic light scattering, high resolution transmission electron microscopy, and energy-dispersive X-ray spectroscopy. The cytotoxicity of the NPs was analyzed on liver (HepG2) and lung (A549) cancerous cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay infers that the biofunctionalized polyshaped AuNPs synthesized with an aqueous macroalgae extract showed a satisfactory anticancer effect on the cell lines, as evaluated by changes in cell morphology, cell viability, and metabolic activity. An altered cellular function and the morphology of cancer cell lines suggest a potential for in vivo application of AuNPs and the need to understand the interactions between nanomaterials, biomolecules, and cellular components. With continued improvements, these NPs may prove to be potential drug delivery vehicles for cancer therapy. PMID- 25041079 TI - Casein-specific IL-4- and IL-13-secreting T cells: a tool to implement diagnosis of cow's milk allergy. AB - BACKGROUND: Cow's milk allergy (CMA) is a frequent food allergy in young children. The oral food challenge is the gold standard for diagnosis, and there is currently no reliable biological test. Our aim was to evaluate the diagnostic potential of a functional assay quantifying allergen-specific Th2 cells in CMA children. METHODS: A total of 29 children aged 2.8-10.5 years underwent a double blind, placebo-controlled food challenge (DBPCFC) to cow's milk. Blood was collected before performing the DBPCFC, and peripheral mononuclear cells were cultured in an 18-h ELISpot assay with casein, alpha-lactalbumin, or beta lactoglobulin. Numbers of antigen-specific IL-4- and IL-13-secreting lymphocytes and serum-specific IgE, IgG4, and total IgE levels were assessed. Receiver operating characteristic (ROC) curves were generated. RESULTS: A total of 17 (59%) children reacted to cow's milk and were therefore considered as allergic to cow's milk (CMA). The mean number of casein-specific IL-4- and IL-13-secreting T cells was higher in CMA than in non-CMA children (P = 0.009, 0.004, respectively). Moreover, it was inversely correlated with the cumulative dose of cow's milk tolerated (P = 0.003, 0.0009, respectively). ROC curve of combined IL 4 and IL-13 analysis showed an area under the curve of 0.98 (95% CI 0.90-1.06). For a cutoff of 10 IL-4- and 12 IL-13-secreting T cells, sensitivity and negative predictive value were 100%. CONCLUSIONS: Enumeration of casein-specific IL-4- and IL-13-secreting T cells appears a promising tool to improve diagnosis and, if confirmed in larger studies, could permit less frequent use of the oral food challenge. PMID- 25041080 TI - PIKfyve inhibition interferes with phagosome and endosome maturation in macrophages. AB - Macrophages eliminate pathogens and cell debris through phagocytosis, a process by which particulate matter is engulfed and sequestered into a phagosome. Nascent phagosomes are innocuous organelles resembling the plasma membrane. However, through a maturation process, phagosomes are quickly remodeled by fusion with endosomes and lysosomes to form the phagolysosome. Phagolysosomes are highly acidic and degradative leading to particle decomposition. Phagosome maturation is intimately dependent on the endosomal pathway, during which diverse cargoes are sorted for recycling to the plasma membrane or for degradation in lysosomes. Not surprisingly, various regulators of the endosomal pathway are also required for phagosome maturation, including phosphatidylinositol-3-phosphate, an early endosomal regulator. However, phosphatidylinositol-3-phosphate can be modified by the lipid kinase PIKfyve into phosphatidylinositol-3,5-bisphosphate, which controls late endosome/lysosome functions. The role of phosphatidylinositol-3,5 bisphosphate in macrophages and phagosome maturation remains basically unexplored. Using Fcgamma receptor-mediated phagocytosis as a model, we describe our research showing that inhibition of PIKfyve hindered certain steps of phagosome maturation. In particular, PIKfyve antagonists delayed removal of phosphatidylinositol-3-phosphate and reduced acquisition of LAMP1 and cathepsin D, both common lysosomal proteins. Consistent with this, the degradative capacity of phagosomes was reduced but phagosomes appeared to still acidify. We also showed that trafficking to lysosomes and their degradative capacity was reduced by PIKfyve inhibition. Overall, we provide evidence that PIKfyve, likely through phosphatidylinositol-3,5-bisphosphate synthesis, plays a significant role in endolysosomal and phagosome maturation in macrophages. PMID- 25041081 TI - Recent trends in cerebral palsy survival. Part II: individual survival prognosis. AB - AIM: The aim of the study was to determine survival probabilities and life expectancies for individuals with cerebral palsy based on data collected over a 28-year period in California. METHOD: We identified all individuals with cerebral palsy, aged 4 years or older, who were clients of the California Department of Developmental Services between 1983 and 2010. Kaplan-Meier survival curves were constructed for 4-year-old children, and the estimated survival probabilities were adjusted to reflect trends in mortality by calendar year. For persons aged 15, 30, 45, and 60 years, separate Poisson regression models were used to estimate age-, sex-, and disability-specific mortality rates. These mortality rates were adjusted to reflect trends of improved survival, and life expectancies were obtained using life table methods. RESULTS: The sample comprised 16,440, 14,609, 11,735, 7023, and 2375 persons at ages 4, 15, 30, 45, and 60 years, respectively. In 1983, 50% of 4-year-old children who did not lift their heads in the prone position and were tube fed lived to age 10.9 years. By 2010, the median age at death had increased to 17.1 years. In ambulatory children the probability of survival to adulthood did not change by more than 1%. Life expectancies for adolescents and adults were lower for those with more severe limitations in motor function and feeding skills, and decreased with advancing age. Life expectancies for tube-fed adolescents and adults increased by 1 to 3 years, depending on age and pattern of disability, over the course of the study period. INTERPRETATION: Over the past three decades in California there have been significant improvements in the survival of children with very severe disabilities. There have also been improvements to the life expectancy of tube-fed adults, though to a lesser extent than in children. PMID- 25041082 TI - Do patients prefer mesh or anterior colporrhaphy for primary correction of anterior vaginal wall prolapse: a labelled discrete choice experiment. AB - OBJECTIVE: We investigated patients' preferences for anterior colporrhaphy or mesh surgery as surgical correction of anterior vaginal wall prolapse. DESIGN: Labelled discrete choice experiment. SETTING: Three Dutch teaching hospitals. POPULATION: Women with anterior vaginal wall prolapse Pelvic Organ Prolapse Quantification stage 2 or more, indicated for anterior colporrhaphy (n = 100). METHODS: Discrete choice experiments are an attribute-based survey method for measuring preferences. In this experiment, women were asked to choose between two treatment scenarios, mesh surgery or anterior colporrhaphy. These surgical treatments differed in four treatment attributes: (i) recurrence rate, (ii) exposure rate, (iii) infection rate, (iv) dyspareunia. Data were analysed using a multinomial logit model. MAIN OUTCOME MEASURES: Women's preferences for anterior colporrhaphy or mesh surgery for the repair of vaginal wall prolapse. RESULTS: All treatment attributes, i.e. recurrence, exposure, infection and dyspareunia, proved to be significant in the woman's decision to choose mesh surgery (P < 0.001), while only two attributes out of three, recurrence and infection, were significant for anterior colporrhaphy (P < 0.001). The relative importance data showed that with regards to the four statistically significant attributes for mesh, dyspareunia was the most important attribute, and of the two significant attributes for anterior colporrhaphy, the risk of infection. Based on the attributes and levels in our discrete choice experiment, anterior colporrhaphy was preferred in 74% as a primary correction of anterior vaginal wall prolapse, followed by a preference for mesh in 26% of all choices. CONCLUSION: This study showed that next to the risk of recurrence, other aspects like risk of infection, dyspareunia and exposure play a role in the woman's preference for a surgical treatment. In addition, our results indicate that anterior colporrhaphy is preferred in the majority of the choices, followed by a preference for mesh surgery in a quarter of all choice sets. However, these results represent the average preference of a sample of women and cannot be taken as the preference of each individual. In the medical decision-making context, information from the current study should be personalised to fit patient's unique circumstances. For patients to construct their own, individual preferences, they should be well informed about the existence and magnitude of the potential benefits and risks related to either anterior colporrhaphy or mesh surgery. PMID- 25041083 TI - Surgical management with CO2 laser for pseudosyndactyly in recessive dystrophic epidermolysis bullosa. PMID- 25041084 TI - Do doctors' smoking habits influence their smoking cessation practices? A systematic review and meta-analysis. AB - AIMS: To assess the association between doctors' smoking status and the use of the '5As' of smoking cessation. METHODS: A systematic search of 11 databases covering English and Spanish language publications since 1996 was undertaken. Studies were included if they reported doctors' smoking status (current, former or never smoker) and rates of practising any of the 5As of smoking cessation (Ask; Advise; Assess; Assist; and Arrange). Frequencies and proportions were extracted from individual papers and risk ratios (RR) were calculated. A random effects meta-analysis model was used to assess the effect of the doctor's personal smoking history. Covariate effects were explored using meta-regression for three pre-specified study characteristics: doctors' role, smoking prevalence of the sample and study quality. RESULTS: Twenty studies were included in this systematic review. The RR of always asking patients about their smoking was not associated significantly with doctors' smoking status [RR = 0.98; 95% confidence interval (CI) = 0.94-1.02; P = 0.378; I(2) = 0.00%; 10 studies]. Meta-analysis suggested that doctors who were current smokers had a 17% increased risk of not advising their patients to quit compared with never-smokers (RR = 0.83; 95% CI = 0.77-0.90; P < 0.000; I(2) = 82.14%; 14 studies). However, high levels of heterogeneity were found that were not explained by the meta-regression. Regarding assisting patients to quit, never smokers were more likely to counsel than current smokers (RR = 0.92; 95% CI = 0.85-0.99; P = 0.036; I(2) = 0.00%; three studies) but less likely to make a referral (RR = 1.40; 95% CI = 1.09-1.79; P = 0.009; I(2) = 0.00%; five studies). No statistically significant differences were found in arranging future contact by smoking status (RR = 0.80; 95% CI = 0.52-1.23; P = 0.315; I(2) = 47.03%; four studies). CONCLUSIONS: Smoking status of doctors may affect their delivery of smoking cessation treatments to patients, with smokers being less likely than non-smokers or ex-smokers to advise and counsel their patients to quit but more likely to refer them to smoking cessation programmes. PMID- 25041085 TI - High-resolution time-resolved imaging of in vitro Arabidopsis rosette growth. AB - Although quantitative characterization of growth phenotypes is of key importance for the understanding of essential networks driving plant growth, the majority of growth-related genes are still being identified based on qualitative visual observations and/or single-endpoint quantitative measurements. We developed an in vitro growth imaging system (IGIS) to perform time-resolved analysis of rosette growth. In this system, Arabidopsis plants are grown in Petri dishes mounted on a rotating disk, and images of each plate are taken on an hourly basis. Automated image analysis was developed in order to obtain several growth-related parameters, such as projected rosette area, rosette relative growth rate, compactness and stockiness, over time. To illustrate the use of the platform and the resulting data, we present the results for the growth response of Col-0 plants subjected to three mild stress conditions. Although the reduction in rosette area was relatively similar at 19 days after stratification, the time lapse analysis demonstrated that plants react differently to salt, osmotic and oxidative stress. The rosette area was altered at various time points during development, and leaf movement and shape parameters were also affected differently. We also used the IGIS to analyze in detail the growth behavior of mutants with enhanced leaf size. Analysis of several growth-related parameters over time in these mutants revealed several specificities in growth behavior, underlining the high complexity of leaf growth coordination. These results demonstrate that time-resolved imaging of in vitro rosette growth generates a better understanding of growth phenotypes than endpoint measurements. PMID- 25041086 TI - A novel Arabidopsis CHITIN ELICITOR RECEPTOR KINASE 1 (CERK1) mutant with enhanced pathogen-induced cell death and altered receptor processing. AB - Plants detect pathogens by sensing microbe-associated molecular patterns (MAMPs) through pattern recognition receptors. Pattern recognition receptor complexes also have roles in cell death control, but the underlying mechanisms are poorly understood. Here, we report isolation of cerk1-4, a novel mutant allele of the Arabidopsis chitin receptor CERK1 with enhanced defense responses. We identified cerk1-4 in a forward genetic screen with barley powdery mildew and consequently characterized it by pathogen assays, mutant crosses and analysis of defense pathways. CERK1 and CERK1-4 proteins were analyzed biochemically. The cerk1-4 mutation causes an amino acid exchange in the CERK1 ectodomain. Mutant plants maintain chitin signaling capacity but exhibit hyper-inducible salicylic acid concentrations and deregulated cell death upon pathogen challenge. In contrast to chitin signaling, the cerk1-4 phenotype does not require kinase activity and is conferred by the N-terminal part of the receptor. CERK1 undergoes ectodomain shedding, a well-known process in animal cell surface proteins. Wild-type plants contain the full-length CERK1 receptor protein as well as a soluble form of the CERK1 ectodomain, whereas cerk1-4 plants lack the N-terminal shedding product. Our work suggests that CERK1 may have a chitin-independent role in cell death control and is the first report of ectodomain shedding in plants. PMID- 25041087 TI - Transperineal prostate biopsy: template-guided or freehand? PMID- 25041088 TI - Norms of the Attitudes Toward Intellectual Disability Questionnaire. AB - BACKGROUND: The Attitudes Toward Intellectual Disability Questionnaire (ATTID) has demonstrated good psychometric qualities for measuring the attitudes of different groups of adults in the general population toward intellectual disability (ID). A significant advantage of the ATTID is that it addresses the concept of attitudes using a three-dimensional model (affective, cognitive and behavioural). To our knowledge, there are no normative data published regarding attitudes toward ID on general population-based samples. METHODS: The sample of 1605 men and women was stratified to be representative of the general adult population of Quebec. The ATTID was administered by phone interview through an independent survey firm. RESULTS: Normative data are presented as percentile scores associated with the raw score of the ATTID by gender and age categories. Analysis of the variance yielded significant differences in attitude by gender and age. The directions and the strength of these associations vary according to each of the five factors used to define attitudes. CONCLUSION: These norms will provide an essential tool to compare different groups and assess the effectiveness of various public campaigns to encourage more positive attitudes towards persons with ID. These norms would also allow international comparisons. PMID- 25041089 TI - Use of mechanical circulatory support devices in end-stage heart failure patients. AB - BACKGROUND: Mechanical circulatory support (MCS) is the standard therapy for the management of acute or chronic end-stage heart failure. We report on our two center experience with MCS therapy. METHODS: Between January 2000 and December 2012, 116 adult patients (mean age 56.8 +/- 9.9 years, range: 31 to 76 years) were primarily supported on temporary or long-term ventricular assist devices (VADs) or total artificial hearts (TAHs) at our institutions. Temporary extracorporeal radial VAD support was established in 50 patients (43.1%) (Group A) whereas 66 (56.8%) patients received long-term paracorporeal and intracorporeal VAD or TAH (Group B). LVAD support was established in 63 patients (54.3%), with BVAD/TAH support in 29 (25%). A temporary CentriMag was the only device adopted as an isolated RVAD support, being placed in 24 patients (20.6%). RESULTS: In Group A, the overall mean support time was 10.2 +/- 6.6 days (range: 3 to 43 days) and the overall success rate was 55.1% (27 patients). The mean LVAD support time was 357 +/- 352.3 days (range: 1 to 902 days) in Group B and 98 +/- 82.6 days (range: 8 to 832 days) in BVAD/TAH patients, with success rates of 72.5% (37 patients) and 46.6% (seven patients), respectively. The heart transplantation (Htx) rate for both groups combined was 25.8% (n = 30). The overall one- and five-year survival rates after Htx were 73.3% and 60%, respectively. CONCLUSIONS: When a decision to treat with VAD or TAH is made early, either modality can be used as an alternative to Htx, affording comparable early to mid-term outcomes. PMID- 25041090 TI - The effects of ADL on recovery of swallowing function in stroke patients after acute phase. AB - This study aimed to examine the association between the degree of recovery from dysphagia and changes in functional independence measure (FIM) items in stroke patients after acute phase by conducting a historical cohort study, because none explains the effects of activities of daily living (ADL) on recovery of swallowing function. Study patients included hospitalised stroke patients after acute phase in whom dysphagia was confirmed (n = 72). Change in nutritional intake method score was examined for association with age, days from stroke onset to admission, length of hospital stay and change in FIM score. Moreover, to examine characteristics of patients who were removed from tube feeding, all patients who required tube feeding at the time of admission were divided into two groups comprising those who required tube feeding at discharge and those who did not. A significant and positive association was observed between change in nutritional intake method and FIM for all items other than self-care of bathing, locomotion of stairs and problem solving. Patients who were removed from tube feeding were significantly younger than those who required tube feeding at the time of discharge (P < 0.041) and also showed significantly higher FIM scores for transfer and all cognitive FIM items at the time of admission (P < 0.05). This study demonstrated that nutritional intake methods improve in conjunction with FIM improvements in patients with dysphagia following the acute phase of stroke. Our results suggest that the age and cognitive function may influence the recovery of patient ability of oral intake. PMID- 25041091 TI - Chitosan and its oligosaccharide derivatives (chito-oligosaccharides) as feed supplements in poultry and swine nutrition. AB - Chitosan is a non-toxic polyglucosamine, widespread in nature, which is deacetylated to varying degrees form of chitin, a component of exoskeleton of shrimps, crabs and insects. Because chitosan contains reactive functional groups, that is, amino acids and hydroxyl groups, it is characterised by antimicrobial, anti-inflammatory, anti-oxidative, antitumor, immunostimulatory and hypocholesterolemic properties when fed as dietary additive for farm animals. This article reviews and discusses the results of studies on the effects of dietary chitosan and its oligosaccharide derivatives on performance and metabolic response in poultry and pigs, that is, haematological, biochemical and immunological blood characteristics, microbiological profile of intestines, intestinal morphology and digestibility of nutrients, as well as on the quality of meat and eggs. The results of most of the experiments presented in this review indicate that chitosan used as a feed additive for poultry and pigs has some beneficial, biological effects, including immunomodulatory, anti-oxidative, antimicrobial and hypocholesterolemic properties. These properties of chitosan, unlike many other kinds of feed additives, were often reflected in improved growth performance (body weight gain and/or feed conversion ratio) of young animals, that is, broiler chickens and weaned pigs. PMID- 25041092 TI - First experience using contrast-enhanced ultrasound to evaluate vascularisation of acellular dermal matrices after implant-based breast reconstruction. AB - Acellular dermal matrices (ADM) have been used frequently in therapeutic and prophylactic breast procedures. To date there have been no reports on vascularisation of ADMs and formation of tissue around them as seen with modern non-invasive imaging techniques such as contrast-enhanced ultrasound (CEUS). In this case series, we used CEUS to investigate the features of ADM in relation to vascular ingrowth and scaffold for "new" tissue formation. This is a retrospective evaluation of patients who underwent successful skin- and nipple sparing mastectomy (SSM, NSM) with immediate IBBR using ADM from May 31, 2010, through December 28, 2012. Over a 24-month period, 16 patients, with an average age of 44 years (range 27-70 years), were evaluated with CEUS. No contrast agent allergies or side effects were reported for the ultrasound examination. After contrast agent injection (1-18 months postoperatively), homogeneous normal enhancement in the ADM and peripheral region with physiological tissue formation was seen in all patients. In this small study, the most obvious contribution of CEUS is the in vivo evaluation of vascular ingrowth and tissue formation after IBBR with ADM after follow-up of 1-18 months postoperatively. LEVEL OF EVIDENCE III: Retrospective cohort or comparative study; case-control study; or systematic review of these studies. PMID- 25041093 TI - Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. AB - Immunization is increasingly recognized as a suitable therapeutic avenue for the treatment of neurological diseases such as Alzheimer's disease and other tauopathies. Tau is a key molecular player in these conditions and therefore represents an attractive target for passive immunization approaches. We performed such an approach in two independent tau transgenic mouse models of tauopathy, K369I tau transgenic K3 and P301L tau transgenic pR5 mice. The antibodies we used were either specific for full-length tau or tau phosphorylated at serine 404 (pS404), a residue that forms part of the paired helical filament (PHF)-1 phosphoepitope that characterizes tau neurofibrillary tangles in tauopathies. Although both pS404 antibodies had a similar affinity, they differed in isotype, and only passive immunization with the IgG2a/kappa pS404-specific antibody resulted in a lower tangle burden and reduced phosphorylation of tau at the PHF1 epitope in K3 mice. In pR5 mice, the same antibody led to a reduced phosphorylation of the pS422 and PHF1 epitopes of tau. In addition, histological sections of the hippocampal dentate gyrus of the immunized pR5 mice displayed reduced pS422 staining intensities. These results show that passive immunization targeting tau can modulate aspects of tau pathology in tau transgenic mouse models, in an antibody isotype-specific manner. We show that passive immunization targeting the pathological phosphorylation site pS404 on human tau with a monoclonal IgG2a/kappa, but not a IgG1/kappa antibody, reduced hyperphosphorylation of tau and tangle burden in two independent mouse models of tau pathology. This shows that both specificity and isotype of phospho-tau (p tau)-specific antibodies are important for therapeutically ameliorating tau pathology. PMID- 25041094 TI - Assessment of partial-mouth periodontal examination protocols for periodontitis surveillance. AB - OBJECTIVE: To evaluate bias associated with nine identified partial-mouth periodontal examination (PMPE) protocols in estimating periodontitis prevalence using the periodontitis case definition given by the Centers of Disease Control and Prevention and American Academy of Periodontology (CDC/AAP). MATERIAL AND METHODS: Prevalence from full-mouth examination was determined in a sample of 3667 adults >=30 years old from the National Health and Nutrition Examination Survey (NHANES) 2009-2010. Prevalence, absolute bias, relative bias, sensitivity and inflation factor were derived for these protocols according to the CDC/AAP definition and half-reduced CDC/AAP definition as <=50% of sites were measured. RESULTS: Bias in moderate and severe periodontitis prevalence ranged between 11.1 52.5% and 27.1-76.3% for full-mouth mesiobuccal-distolingual protocol and half mouth mesiobuccal protocol respectively; according to the CDC/AAP definition. With half-reduced CDC/AAP definition, half-mouth four sites protocol provided small absolute bias (3.2%) and relative bias (9.3%) for the estimates of moderate periodontitis prevalence; corresponding biases for severe periodontitis were 1.2% and -10.2%. CONCLUSION: Periodontitis prevalence can be estimated with limited bias when a half-mouth four sites protocol and a half-reduced CDC/AAP case definition are used in combination. PMID- 25041095 TI - Yield of epileptiform electroencephalogram abnormalities in incident unprovoked seizures: a population-based study. AB - OBJECTIVE: The yield of epileptiform abnormalities in serial electroencephalography (EEG) studies has not been addressed in a population-based setting for subjects with incident epilepsy or a single unprovoked seizure, raising the possibility of methodologic limitations such as selection bias. Our aim was to address these limitations by assessing the yield and predictors of epileptiform abnormalities for the first and subsequent EEG recording in a study of incident epilepsy or single unprovoked seizure in Rochester, Minnesota. METHODS: We used the resources of the Rochester Epidemiology Project to identify all 619 residents of Rochester, Minnesota, born in 1920 or later with a diagnosis of incident epilepsy (n = 478) or single unprovoked seizure (n = 141) between 1960 and 1994, who had at least one EEG study. Information on all EEG studies and their results was obtained by comprehensive review of medical records. RESULTS: Among subjects with epilepsy, the cumulative yield of epileptiform abnormalities was 53% after the first EEG study and 72% after the third. Among subjects with a single unprovoked seizure, the cumulative yield was 39% after the first EEG study and 68% after the third. Young age at diagnosis and idiopathic etiology were risk factors for finding epileptiform abnormalities across all EEG recordings. SIGNIFICANCE: Although the cumulative yield of epileptiform abnormalities increases over successive EEG recordings, there is a decrease in the increment for each additional EEG study after the first EEG study. This is most evident in incident epilepsy and in younger subjects. Clinically it may be worthwhile to consider that the probability of finding an epileptiform abnormality after the third nonepileptiform EEG recording is low. PMID- 25041096 TI - Examination of fine-scale spatial-temporal overlap and segregation between two closely related congeners Gadus morhua and Gadus ogac in coastal Newfoundland. AB - The spatial and temporal movement patterns of sympatric juvenile Atlantic cod Gadus morhua and Greenland cod Gadus ogac were studied using high-resolution radio-acoustic positioning in a coastal area of Newfoundland during the summers of 2009 and 2010. A total of 20 fish (10 G. ogac and 10 G. morhua) were equipped with acoustic transmitters and monitored for periods up to 23 days. Most fishes showed high site fidelity with mean residence times of 12.4 (G. morhua) and 14.4 days (G. ogac). A few individuals showed a transient use of the study area, ranging distances up to c. 4 km. Mean daily home ranges [95% kernel utilization distributions (KUDs)] and core activity areas were significantly larger for G. morhua (3.8 and 0.5 ha) than for G. ogac (2.7 and 0.3 ha). Home ranges were not related to total length (LT ) for G. morhua but showed a weak positive relationship for G. ogac. Gadus morhua occupied larger areas during the day while G. ogac occupied slightly larger areas at night. Mean rates of movement for G. ogac and G. morhua ranged from 0.83 to 1.24 and 0.76 to 1.76 LT s(-1) , respectively, and were highest during crepuscular periods. Overall, G. morhua were wider ranging, moved at faster rates and were active throughout the diel cycle compared to G. ogac of the same size. It is suggested that differential use of space and activity periods plays an important role in the successful coexistence of these two species. PMID- 25041097 TI - Genetic epidemiology of tooth agenesis in Japan: a population- and family-based study. AB - Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% [95% confidence interval (CI): 6.1-7.7%] and 0.1% (95% CI: 0.04-0.3%), respectively, and sibling recurrence risk of these were 24.5% (95% CI: 13.8 38.3%) and 43.8% (95% CI: 26.4-62.3%), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides. PMID- 25041098 TI - Vitiligo masks malignant acanthosis nigricans in a woman with ovarian cancer. PMID- 25041099 TI - Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies. AB - Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed. PMID- 25041100 TI - Detection of small amounts of human adenoviruses in stools: comparison of a new immuno real-time PCR assay with classical tools. AB - The detection of low virus concentrations in biological matrices, especially stool samples, is facing significant limitations as far as common diagnostic methods (enzyme-linked-immunosorbent assay (ELISA) or quantitative real-time PCR (qPCR)) are considered. Here the development of a new immuno real-time PCR (iPCR) is described and its performance in the detection of human adenoviruses (HAdVs) in spiked stools is compared with those of ELISA and qPCR assays. For the iPCR, detection of the sandwich formed by the complexation of capture antibody-antigen detection antibody was performed by qPCR thanks to the substitution of peroxydase by a chimeric DNA. This modification increased the detection sensitivity 200-fold compared to ELISA. The direct qPCR results revealed that only 0.3-9.5% of the spiked HAdV were detectable, resulting from important losses of DNA occurring at the extraction step. This step was not necessary in the iPCR workflow, avoiding this drawback. The losses of viral particles occurred at the elution step from the stool only. The recovery rate of the iPCR was thus better and ranged between 21 and 54%. As a result, iPCR enabled the detection of lower virus concentrations in stool samples compared to those detected by ELISA and qPCR. The iPCR could be considered as a 'hyper sensitive ELISA' for early detection of HAdV infections, especially in the case of immunocompromised patients after haematopoietic stem cell transplant. PMID- 25041101 TI - Continuous flow using an entrainer and t-piece vs drawover apparatus for inhalational induction of anesthesia in children. AB - BACKGROUND: Inhalational induction in children is easiest to perform with the Ayres t-piece & bag (Mapleson F). Drawover anesthesia systems may be used but have not been studied. The aim of this study was to examine the quality of induction of anesthesia in children comparing a continuous flow system using the Farman entrainer and the pediatric t-piece, to a pediatric drawover system. METHODS: We conducted a randomized controlled trial in accordance with departmental and institutional standards with 60 subjects who received inhalational induction using either apparatus. RESULTS: There was no evidence of a difference in the median Sp02 between the two methods (P = 0.626) neither was there a difference between the method of induction regarding abdominal distension (P = 0.348) or restraint (P = 0.186). Induction time using the pediatric drawover apparatus 240 (range 115-605) seconds was significantly greater than the Farman entrainer/t-piece 146 (range 65-535) seconds (P < 0.05). CONCLUSIONS: We consider that this difference is unlikely to be clinically significant in many cases; however, the increased speed using the entrainer and t-piece may sometimes confer an advantage. PMID- 25041102 TI - Peripheral and central venous blood glucose concentrations in dogs and cats with acute arterial thromboembolism. AB - BACKGROUND: Acute limb paralysis because of arterial thromboembolism (ATE) occurs in cats and less commonly in dogs. ATE is diagnosed based on physical examination findings and, occasionally, advanced imaging. HYPOTHESIS/OBJECTIVES: Peripheral, affected limb venous glucose concentration is decreased in ATE, whereas its systemic concentration is within or above reference interval. ANIMALS: Client owned cats and dogs were divided into 3 respective groups: acute limb paralysis because of ATE (22 cats and 9 dogs); acute limb paralysis secondary to orthopedic or neurologic conditions (nonambulatory controls; 10 cats and 11 dogs); ambulatory animals presented because of various diseases (ambulatory controls; 10 cats and 9 dogs). METHODS: Prospective observational, clinical study. Systemic and local (affected limb) blood glucose concentrations were measured. Their absolute and relative differences (DeltaGlu and %DeltaGlu, respectively) were compared among groups. RESULTS: DeltaGlu and %DeltaGlu were significantly higher in the ATE cats and dogs groups, compared to both of their respective controls (P < .0001 and P < .001, respectively). No significant differences were observed between the control groups. Receiver operator characteristics analysis of DeltaGlu and %DeltaGlu as predictors of ATE had area under the curve of 0.96 and 0.99 in cats, respectively, and 1.00 and 1.00, in dogs, respectively. DeltaGlu cutoffs of 30 mg/dL and 16 mg/dL, in cats and dogs, respectively, corresponded to sensitivity and specificity of 100% and 90% in cats, respectively, and 100% in dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: DeltaGlu and %DeltaGlu are accurate, readily available, diagnostic markers of acute ATE in paralyzed cats and dogs. PMID- 25041103 TI - Flagellar biosynthesis exerts temporal regulation of secretion of specific Campylobacter jejuni colonization and virulence determinants. AB - The Campylobacter jejuni flagellum exports both proteins that form the flagellar organelle for swimming motility and colonization and virulence factors that promote commensal colonization of the avian intestinal tract or invasion of human intestinal cells respectively. We explored how the C. jejuni flagellum is a versatile secretory organelle by examining molecular determinants that allow colonization and virulence factors to exploit the flagellum for their own secretion. Flagellar biogenesis was observed to exert temporal control of secretion of these proteins, indicating that a bolus of secretion of colonization and virulence factors occurs during hook biogenesis with filament polymerization itself reducing secretion of these factors. Furthermore, we found that intramolecular and intermolecular requirements for flagellar-dependent secretion of these proteins were most reminiscent to those for flagellin secretion. Importantly, we discovered that secretion of one colonization and virulence factor, CiaI, was not required for invasion of human colonic cells, which counters previous hypotheses for how this protein functions during invasion. Instead, secretion of CiaI was essential for C. jejuni to facilitate commensal colonization of the natural avian host. Our work provides insight into the versatility of the bacterial flagellum as a secretory machine that can export proteins promoting diverse biological processes. PMID- 25041104 TI - Cost effectiveness after a pancreaticoduodenectomy: bolstering the volume argument. AB - BACKGROUND: The cost implication of variability in pancreatic surgery is not well described. It was hypothesized that for a pancreaticoduodenectomy (PD), lower volume centres demonstrate worse peri-operative outcomes at higher costs. METHODS: From 2009-2011, 9883 patients undergoing a PD were identified from the University HealthSystems Consortium (UHC) database and stratified into quintiles by annual hospital case volume. A decision analytic model was constructed to assess cost effectiveness. Total direct cost data were based on Medicare cost/charge ratios and included readmission costs when applicable. RESULTS: The lowest volume centres demonstrated a higher peri-operative mortality rate (3.5% versus 1.3%, P < 0.001) compared with the highest volume centres. When both index and readmission costs were considered, the per-patient total direct cost at the lowest volume centres was $23,005, or 10.9% (i.e. $2263 per case) more than at the highest volume centres. One-way sensitivity analyses adjusting for peri operative mortality (1.3% at all centres) did not materially change the cost effectiveness analysis. Differences in cost were largely recognized in the index admission; readmission costs were similar across quintiles. CONCLUSIONS: For PD, low volume centres have higher peri-operative mortality rates and 10.9% higher cost per patient. Performance of PD at higher volume centres can lead to both better outcomes and substantial cost savings. PMID- 25041105 TI - From flexibility to constraint: the contrastive use of lexical tone in early word learning. AB - Infants must develop both flexibility and constraint in their interpretation of acceptable word forms. The current experiments examined the development of infants' lexical interpretation of non-native variations in pitch contour. Fourteen-, 17-, and 19-month-olds (Experiments 1 and 2, N = 72) heard labels for two novel objects; labels contained the same syllable produced with distinct pitch contours (Mandarin lexical tones). The youngest infants learned the label object mappings, but the older groups did not, despite being able to discriminate pitch differences in an object-free task (Experiment 3, N = 14). Results indicate that 14-month-olds remain flexible regarding what sounds make meaningful distinctions between words. By 17-19 months, experience with a nontonal native language constrains infants' interpretation of lexical tone. PMID- 25041107 TI - Zinc in house dust: speciation, bioaccessibility, and impact of humidity. AB - Indoor exposures to metals arise from a wide variety of indoor and outdoor sources. This study investigates the impact of humid indoor conditions on the bioaccessibility of Zn in dust, and the transformation of Zn species during weathering. House dust samples were subjected to an oxygenated, highly humid atmosphere in a closed chamber for 4 to 5 months. Zinc bioaccessibility before and after the experiment was determined using a simulated gastric acid extraction. Bulk and micro X-ray absorption structure (XAS) spectroscopy was used to speciate Zn in dust. Exposure to humid conditions led to a significant increase in Zn bioaccessibility in all samples, which was due to a redistribution of Zn from inorganic forms toward the organic pools such as Zn adsorbed on humates. ZnO readily dissolved under humid conditions, whereas ZnS persisted in the dust. Elevated humidity in indoor microenvironments may sustain higher Zn bioaccessibility in settled dust compared to drier conditions, and part of this change may be related to fungal growth in humid dust. These results help to explain the greater bioaccessibility of certain metals in house dust compared to soils. PMID- 25041106 TI - Leukemia inhibitor factor promotes functional recovery and oligodendrocyte survival in rat models of focal ischemia. AB - Human umbilical cord blood (HUCB) cells have shown efficacy in rodent models of focal ischemia and in vitro systems that recapitulate stroke conditions. One potential mechanism of protection is through secretion of soluble factors that protect neurons and oligodendrocytes (OLs) from oxidative stress. To overcome practical issues with cellular therapies, identification of soluble factors released by HUCB and other stem cells may pave the way for treatment modalities that are safer for a larger percentage of stroke patients. Among these soluble factors is leukemia inhibitory factor (LIF), a cytokine that exerts pleiotropic effects on cell survival. Here, data show that LIF effectively reduced infarct volume, reduced white matter injury and improved functional outcomes when administered to rats following permanent middle cerebral artery occlusion. To further explore downstream signaling, primary oligodendrocyte cultures were exposed to oxygen-glucose deprivation to mimic stroke conditions. LIF significantly reduced lactate dehydrogenase release from OLs, reduced superoxide dismutase activity and induced peroxiredoxin 4 (Prdx4) transcript. Additionally, the protective and antioxidant capacity of LIF was negated by both Akt inhibition and co-incubation with Prdx4-neutralising antibodies, establishing a role for the Akt signaling pathway and Prdx4-mediated antioxidation in LIF protection. PMID- 25041108 TI - The effects of caffeine on wound healing. AB - The purine alkaloid caffeine is a major component of many beverages such as coffee and tea. Caffeine and its metabolites theobromine and xanthine have been shown to have antioxidant properties. Caffeine can also act as adenosine-receptor antagonist. Although it has been shown that adenosine and antioxidants promote wound healing, the effect of caffeine on wound healing is currently unknown. To investigate the effects of caffeine on processes involved in epithelialisation, we used primary human keratinocytes, HaCaT cell line and ex vivo model of human skin. First, we tested the effects of caffeine on cell proliferation, differentiation, adhesion and migration, processes essential for normal wound epithelialisation and closure. We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) proliferation assay to test the effects of seven different caffeine doses ranging from 0.1 to 5 mM. We found that caffeine restricted cell proliferation of keratinocytes in a dose-dependent manner. Furthermore, scratch wound assays performed on keratinocyte monolayers indicated dose-dependent delays in cell migration. Interestingly, adhesion and differentiation remained unaffected in monolayer cultures treated with various doses of caffeine. Using a human ex vivo wound healing model, we tested topical application of caffeine and found that it impedes epithelialisation, confirming in vitro data. We conclude that caffeine, which is known to have antioxidant properties, impedes keratinocyte proliferation and migration, suggesting that it may have an inhibitory effect on wound healing and epithelialisation. Therefore, our findings are more in support of a role for caffeine as adenosine-receptor antagonist that would negate the effect of adenosine in promoting wound healing. PMID- 25041109 TI - Outcomes of adult liver re-transplant patients in the model for end-stage liver disease era: is it time to reconsider its indications? AB - OBJECTIVE: To better understand the outcomes and utility of liver re transplantation in non-hepatitis C patients, we sought to identify predictors that impact post-transplant patient and graft survival comparing primary liver transplant patients to those receiving subsequent allografts. METHODS: We conducted a retrospective cohort analysis using the United Network for Organ Sharing database from February 2002 through December 2012, including non hepatitis C infected adults (18 yr and older) who underwent primary and repeat liver transplantation. Patient and graft survival were compared between the two groups using the Kaplan-Meier estimator. Cox proportional hazards models were constructed to evaluate variables associated with both patient and graft survival. RESULTS: We identified 33 176 primary transplant recipients and 2710 re transplants. Re-transplantation patients were more likely to be on dialysis prior to transplant (18% vs. 10%), hospitalized (26% vs. 16%), in the intensive care unit (ICU) (34% vs. 13%), on a ventilator (17% vs. 3%), and had higher model for end-stage liver disease (MELD) score (27 vs. 21). Re-transplants also received livers with a lower donor risk index (DRI) (1.57 vs. 1.64). We estimated an adjusted hazard ratio (HR) of 1.7 for patient survival (95% CI: 1.56-1.84) and 1.61 (95% CI: 1.5-1.73) for graft survival. CONCLUSIONS: Liver re-transplantation in non-hepatitis C patients, although life saving, has significantly inferior patient and graft survival compared to primary liver transplantation. Higher quality grafts are used inefficiently in a sicker patient population, suggesting that a more optimal strategy may include restricting their use to patients who obtain a longer term benefit. PMID- 25041110 TI - Dental students' reflective habits: is there a relation with their academic achievements? AB - INTRODUCTION: Reflection is regarded as an important and essential component of healthcare professionals' education and practice. This cross-sectional study aimed to explore the levels of reflection habits of dental students and clinical and PhD postgraduate trainees and to establish the relationship between students' reflection and their academic performance. MATERIALS AND METHODS: A total of 324 subjects (208 females, 56% >=23 years of age) from King's College London Dental Institute, consisting of 281 undergraduate and 43 postgraduate trainees, responded to the invitation to participate and completed an online self-reported Reflection Questionnaire; this assesses two levels of non-reflective actions (Habitual Action and Understanding) and two levels of reflective actions (Reflection and Critical Reflection). Reflection results were compared amongst different cohorts and correlated with students' academic performance. RESULTS: Reflection Questionnaire mean scores were 10.7 for Habitual Action, 17.3 for Understanding, 17.0 for Reflection and 14.4 for Critical Reflection, with significant differences between cohorts of undergraduate students, clinical postgraduates and PhD trainees. Reflection and Critical Reflection mean scores were higher as students climbed courses. Further, those >=24 years of age and those with previous university degrees demonstrated higher reflective habits, whilst there was no gender difference. Additionally, the assessment programme methods correlated differently to the Reflection Questionnaire scores. DISCUSSION: The Reflection Questionnaire's internal reliability was acceptable. The most common approaches used by both students and trainees were Understanding and Reflection, whilst those with high Understanding scores also tended to have good Reflective scores. Further, multiple choice questions encouraged students to 'understand', whilst ill-defined problems, such as those from essays to clinical reasoning cases, increased this to the reflection scale. CONCLUSION: To foster reflective thinking, tutoring should primarily be focused on younger students (<=23 years old) and those without a previous university degree. Further, a wide variety of assessment methods is suggested to stimulate different reflective constructs. PMID- 25041111 TI - Comparison of adrenaline auto-injector devices: ease of use and ability to recall use. AB - BACKGROUND: A limited number of adrenaline auto-injectors are currently available. Epipen and Anapen are available in Australia, New Zealand, UK and parts of Europe and Asia. Few studies have compared the performance of these devices. OBJECTIVE: To compare the intuitiveness of use of these devices. A secondary aim was to compare the ability to recall the use of each device after a period of 3 months. METHOD: A random sample of 100 subjects naive to both the EpiPen and Anapen were recruited from staff and families attending Royal Children's Hospital, Melbourne Australia. Subjects were randomized to Anapen (n = 53) or EpiPen (n = 47) and asked to demonstrate use of a 'trainer' device (i) prior to and (ii) after receiving training in its correct use. A subset (n = 32) participated in a follow-up study to evaluate (iii) the ability to recall correct use of each device. RESULTS: Most subjects correctly demonstrated all steps in use of the EpiPen and Anapen both prior to (89% vs. 79%, p = 0.17) and after training on use (100% vs. 100%). However, after 3 months, significantly more participants correctly demonstrated use of EpiPen (87%) compared to Anapen (35%) (p = 0.003) and critical errors that would likely result in failure to administer adrenaline were more common with Anapen (59% vs. 13%, p = 0.01). CONCLUSION: Most study participants correctly demonstrated the use of both devices without prior training. There was greater attrition in correct use of Anapen compared to EpiPen over time. Critical errors in administration were more likely with Anapen than EpiPen. PMID- 25041112 TI - Autologus bone marrow stem cells in atrophic acne scars: A pilot study. AB - BACKGROUND: Acne scar is a very distressing and difficult problem for physicians and patients. Management of cutaneous scarring from acne can be challenging and confusing. The available modalities may be effective, having considerable morbidity and long downtime. Besides, they may not have the same efficacy in different skin types or acne scar types. OBJECTIVE: To evaluate the short-term safety and efficacy of autologous bone marrow (BM) stem cells (SCs) in treating atrophic acne scars. METHODS: Fourteen patients with moderate to severe atrophic acne scars were included. All patients were subjected to single session of autologous BMSCs therapy. Each patient received 5 MUg/kg/day granulocyte colony stimulating factor (G-CSF) as a single subcutaneous dose for 2 successive days before BM aspiration. The SC-containing solution was injected under each scar intradermally. The scars of the patients were clinically assessed both qualitatively and quantitatively before and after 6 months. The patients were given a preformed questionnaire Cardiff acne disability index (CADI) before and after treatment. RESULTS: After 6 months of the injection, there was significant improvement in the qualitative grading, quantitative grading and CADI scores. All types of scars showed significant improvement. No significant adverse effects were reported in any patient. CONCLUSION: Autologous BMSCs seem to be a safe and effective treatment option for the management of all types of atrophic facial acne scars. PMID- 25041113 TI - Do you make the correct management strategy on CO2 laser in treating divided nevus of the eyelid? PMID- 25041114 TI - Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases. AB - AIM: To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis. METHODS: MPA areas under the concentration-time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0 ) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed. RESULTS: In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l(-1) (IQR 0.9-2.1 mg l(-1)) vs. 2.95 mg l(-1) (IQR 1.38-3.73 mg l(-1)) for SLE (P = 0.048) and 1.55 mg l(-1) (IQR 0.98-2.18 mg l(-1)) vs. 3 mg l(-1) (IQR 2.2-4.4 mg l(-1)) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5-3 mg l(-1) was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 >= 2.5-3 mg l( 1) at inclusion had better clinical outcomes during the 12 months following PK assessment. CONCLUSION: Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose. PMID- 25041115 TI - The loss of a shared lifetime: a qualitative study exploring spouses' experiences of losing couplehood with their partner with dementia living in institutional care. AB - AIMS AND OBJECTIVES: To explore and describe spouses' experiences of losing couplehood with their dementia-afflicted partner living in institutional care. BACKGROUND: Despite the losses and experiences of discontinuity due to the cognitive decline caused by dementia, the feelings of belonging and reciprocity in close relationships are still crucial to many couples. However, these experiences of spouses with partners living in institutional care are not well documented and are thus the focus of this study. DESIGN: A constructivist grounded theory approach was used to capture the relational processes described by the spouses. METHODS: Conversational interviews were conducted with n = 10 spouses of dementia-afflicted persons living in institutional care. Data were analysed using the constant comparative method. RESULTS: The spouses' experiences of losing couplehood were primarily connected to separation from the partner and the sense of being alone. They were also related to the loss of the shared past and future. However, these experiences did not seem to be constant; short glimpses of connectedness, reciprocity and interdependence contributed to a feeling of couplehood, although these were only momentary. CONCLUSIONS: The spouses' experiences of losing couplehood were dynamic and were related to the couple's entire life. The spouses wavered between senses of loss and belonging to couplehood, depending on the conditions characterising the moment. RELEVANCE TO CLINICAL PRACTICE: Healthcare personnel must recognise the severity of some spouses' experiences of losing couplehood and be aware of how these experiences can fluctuate and be situation dependent. PMID- 25041116 TI - Analysis of novel mutations in BRCA1 in Iranian families with breast cancer. AB - In Iran and the rest of the world, breast cancer (BC) is the most common malignancy in women. Familial history and age are significant risk factors for the development of this disease in Iran. Most hereditary BCs are associated with inherited mutations in the BRCA1 and BRCA2 genes. Some recent studies demonstrated that BRCA1 mutations are seen in high-risk women with family histories of BC. In this report we investigated all BRCA1 exons from 40 female patients with family histories of BC and one BC twin, and report a novel mutation in this gene in one patient. As controls, BRCA1 exons from 100 normal women and the BC-free twin of the BC twin were also examined for this mutation. None of the women in the normal group harbored the mutation. Whether this variation is specific for the Iranian population or for special subgroups remains to be determined. PMID- 25041117 TI - Global population structure and demographic history of the grey seal. AB - Although the grey seal Halichoerus grypus is one of the most familiar and intensively studied of all pinniped species, its global population structure remains to be elucidated. Little is also known about how the species as a whole may have historically responded to climate-driven changes in habitat availability and anthropogenic exploitation. We therefore analysed samples from over 1500 individuals collected from 22 colonies spanning the Western and Eastern Atlantic and the Baltic Sea regions, represented by 350 bp of the mitochondrial hypervariable region and up to nine microsatellites. Strong population structure was observed at both types of marker, and highly asymmetrical patterns of gene flow were also inferred, with the Orkney Islands being identified as a source of emigrants to other areas in the Eastern Atlantic. The Baltic and Eastern Atlantic regions were estimated to have diverged a little over 10 000 years ago, consistent with the last proposed isolation of the Baltic Sea. Approximate Bayesian computation also identified genetic signals consistent with postglacial population expansion across much of the species range, suggesting that grey seals are highly responsive to changes in habitat availability. PMID- 25041118 TI - Metabolomic analysis indicates a pivotal role of the hepatotoxin microcystin in high light adaptation of Microcystis. AB - Microcystis is a freshwater cyanobacterium frequently forming nuisance blooms in the summer months. The genus belongs to the predominant producers of the potent hepatotoxin microcystin. The success of Microcystis and its remarkable resistance to high light conditions are not well understood. Here, we have compared the metabolic response of Microcystis aeruginosa PCC7806, its microcystin-deficient DeltamcyB mutant (Mut) and the cyanobacterial model organism Synechocystis PCC6803 to high light exposure of 250 MUmol photons m(-2) s(-1) using GC/MS based metabolomics. Microcystis wild type and Mut show pronounced differences in their metabolic reprogramming upon high light. Seventeen per cent of the detected metabolites showed significant differences between the two genotypes after high light exposure. Whereas the microcystin-producing wild type shows a faster accumulation of glycolate upon high light illumination, loss of microcystin leads to an accumulation of general stress markers such as trehalose and sucrose. The study further uncovers differences in the high light adaptation of the bloom forming cyanobacterium Microcystis and the model cyanobacterium Synechocystis. Most notably, Microcystis invests more into carbon reserves such as glycogen after high light exposure. Our data shed new light on the lifestyle of bloom forming cyanobacteria, the role of the widespread toxin microcystin and the metabolic diversity of cyanobacteria. PMID- 25041119 TI - Radioisotope cisternography in spontaneous CSF leaks: interpretations and misinterpretations. AB - A broadening of the clinical and imaging features of the spontaneous cerebrospinal fluid (CSF) leaks is now well recognized, far beyond what was thought only two decades ago. This has resulted in increasing number of patients with atypical and unusual features who, not unexpectedly, are directed to headache specialists and tertiary referral centers. In many cases, obviously the fundamental question of presence or absence of CSF leak will need to be addressed prior to proceeding with further and often more involved, more invasive, and more costly diagnostic and therapeutic considerations. Radioisotope cisternography often proves to be very helpful in these situations by demonstrating reliable, although indirect, evidences of CSF leak while it is less helpful in directly identifying the exact site of the CSF leakage. In this overview article, the expectations from and the limitations of this diagnostic method are described along with some personal observations in the past 25 years. PMID- 25041120 TI - Belatacept: is there BENEFIT for liver transplantation too? AB - The results of the multicenter belatacept liver transplant trial disappoint with respect to safety and efficacy, and new approaches will be required before this agent plays a role in liver transplant immunosuppression. See article by Klintmalm et al on page 1817. PMID- 25041121 TI - Single-incision laparoscopic subtotal colectomy through ileostomy site for ulcerative colitis - a video vignette. PMID- 25041122 TI - Liver stiffness measured by acoustic radiation force impulse elastography reflects the severity of liver damage and prognosis in patients with acute liver failure. AB - AIM: We measured liver stiffness (LS) in patients with acute liver failure (ALF) using acoustic radiation force impulse (ARFI) elastography and investigated the usefulness of measuring LS for predicting the prognosis of ALF patients. METHODS: From April 2010 to December 2013, we evaluated 63 patients with acute liver disease. The subjects included 41 patients with acute hepatitis (AH), 16 patients with severe AH (SAH), who had no hepatic encephalopathy despite plasma prothrombin time of 40% or less, and six patients with fulminant hepatitis (FH) diagnosed according to the criteria of the Japanese Study Group. The relationships among shear wave velocity (SWV), clinical diagnosis, liver function tests and prognosis were evaluated. Receiver-operator curve (ROC) analysis was performed to investigate whether ARFI elastography exhibits potential usefulness for the prediction of FH. RESULTS: The mean SWV on admission were 1.98 +/- 0.55, 2.61 +/- 0.58 and 3.66 +/- 0.86 m/s in the AH, SAH and FH groups, respectively. The SWV was significantly higher in the FH group than in the other groups (P < 0.001), and in the SAH group than in the AH group (P = 0.002). The area under the ROC for predicting FH was 0.924 (sensitivity, 83.3%; specificity, 93.0%). The SWV was significantly increased in non-survivors, while remaining decreased in survivors (P = 0.002). CONCLUSION: The SWV measured by ARFI elastography reflects severity of liver damage, and serial changes in SWV predict the prognosis of ALF patients. The SWV is an early and precise biomarker of FH. PMID- 25041123 TI - Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4. AB - OBJECTIVE: Valproic acid (VPA), a mood stabilizer used for treating bipolar disorder (BD), uncompetitively inhibits acylation of arachidonic acid (AA) by recombinant AA-selective acyl-CoA synthetase 4 (Acsl4) at an enzyme inhibition constant (Ki ) of 25 mM. Inhibition may account for VPA's ability to reduce AA turnover in brain phospholipids of unanesthetized rats and to be therapeutic in BD. However, VPA is teratogenic. We tested whether valnoctamide (VCD), a non teratogenic amide derivative of a VPA chiral isomer, which had antimanic potency in a phase III BD trial, also inhibits recombinant Acsl4. METHODS: Rat Acsl4-flag protein was expressed in Escherichia coli. We used Michaelis-Menten kinetics to characterize and quantify the ability of VCD to inhibit conversion of AA to AA CoA by recombinant Acsl4 in vitro. RESULTS: Acsl4-mediated activation of AA to AA CoA by Acsl4 was inhibited uncompetitively by VCD, with a Ki of 6.38 mM. CONCLUSIONS: VCD's ability to uncompetitively inhibit AA activation to AA-CoA by Acsl4, at a lower Ki than VPA, suggests that, like VPA, VCD may reduce AA turnover in rat brain phospholipids. If so, VCD and other non-teratogenic Acsl4 inhibitors might be considered further for treating BD. PMID- 25041124 TI - Hepatic abscesses in five outdoor-housed rhesus macaques (Macaca mulatta). AB - Hepatic abscesses are uncommon in non-human primates and usually occur as multifocal microabscesses originating from bacteremia. Necropsy, histopathology, and bacterial cultures were performed on five subadult to adult female rhesus macaques (Macaca mulatta) that died spontaneously. Necropsy findings included cavitating abscesses in the right central liver lobe of all five animals, with intralesional plant material in four animals. This is the first report of cavitating hepatic abscesses with intralesional plant material in non-human primates. PMID- 25041125 TI - Metformin and the risk of head and neck cancer: a case-control analysis. AB - AIMS: Metformin use has been associated with a decreased risk of some cancers, although data on head and neck cancer (HNC) are scarce. We explored the relation between the use of antidiabetic drugs and the risk of HNC. METHODS: We conducted a case-control analysis in the UK-based Clinical Practice Research Datalink (CPRD) of people with incident HNC between 1995 and 2013 below the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice and number of years of active history in the CPRD prior to the index date. Other potential confounders including body mass index (BMI), smoking, alcohol consumption and comorbidities were also evaluated. The final analyses were adjusted for BMI, smoking and diabetes mellitus (or diabetes duration in a sensitivity analysis). Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Use of metformin was neither associated with a statistically significant altered risk of HNC overall (1-29 prescriptions: adjusted OR 0.87, 95% CI 0.61-1.24 and >= 30 prescriptions adjusted OR 0.80, 95% CI 0.53-1.22), nor was long-term use of sulphonylureas (adjusted OR 0.87, 95% CI 0.59-1.30), or any insulin use (adjusted OR 0.92, 95% CI 0.63-1.35). However, we found a (statistically non-significant) decreased risk of laryngeal cancer associated with long-term metformin use (adjusted OR 0.41, 95% CI 0.17-1.03). CONCLUSIONS: In this population-based study, the use of antidiabetic drugs was not associated with a materially altered risk of HNC. Our data suggest a protective effect of long-term metformin use for laryngeal cancer. PMID- 25041126 TI - Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice. AB - Nrf1 (NF-E2-related factor 1) is a basic region leucine zipper-type transcription factor belonging to the CNC (cap-'n'-collar) family. Major pathophysiological contribution of Nrf1 remains unclear. As single nucleotide polymorphism rs3764400 in 5'-flanking region of NRF1 gene appears to associate with obesity, in this study, we focused on the Nrf1 function on metabolism. We found that the risk C allele of rs3764400 increased NRF1 gene transcriptional activity compared with the T allele in hepatoma cell lines. Therefore, we newly established Nrf1 transgenic (Nrf1-Tg) mouse lines and examined roles that Nrf1 plays on the obesity and metabolism. Unexpectedly, Nrf1 over-expression repressed bodyweight gain in both lean and diet-induced obesity mice. Of note, Nrf1-Tg mice showed rise in blood glucose levels; Nrf1 strongly reduced glucose infusion rate in euglycemic-hyperinsulinemic clamp test and increased blood glucose levels in insulin tolerance test, indicating that Nrf1 induces insulin resistance in mice. Nrf1 repressed insulin-regulated glycolysis-related gene expression and gave rise to loss of glucose-6-phosphate and fructose-6-phosphate contents in liver. Consistently, Nrf1 heterozygote improved impaired glucose regulations in diet induced obesity model. These results showed that Nrf1 contributes to metabolic regulation, which gain-of-function develops diabetes mellitus in mice. PMID- 25041127 TI - Impacts of breeder loss on social structure, reproduction and population growth in a social canid. AB - The importance of individuals to the dynamics of populations may depend on reproductive status, especially for species with complex social structure. Loss of reproductive individuals in socially complex species could disproportionately affect population dynamics by destabilizing social structure and reducing population growth. Alternatively, compensatory mechanisms such as rapid replacement of breeders may result in little disruption. The impact of breeder loss on the population dynamics of social species remains poorly understood. We evaluated the effect of breeder loss on social stability, recruitment and population growth of grey wolves (Canis lupus) in Denali National Park and Preserve, Alaska using a 26-year dataset of 387 radiocollared wolves. Harvest of breeding wolves is a highly contentious conservation and management issue worldwide, with unknown population-level consequences. Breeder loss preceded 77% of cases (n = 53) of pack dissolution from 1986 to 2012. Packs were more likely to dissolve if a female or both breeders were lost and pack size was small. Harvest of breeders increased the probability of pack dissolution, likely because the timing of harvest coincided with the breeding season of wolves. Rates of denning and successful recruitment were uniformly high for packs that did not experience breeder loss; however, packs that lost breeders exhibited lower denning and recruitment rates. Breeder mortality and pack dissolution had no significant effects on immediate or longer term population dynamics. Our results indicate the importance of breeding individuals is context dependent. The impact of breeder loss on social group persistence, reproduction and population growth may be greatest when average group sizes are small and mortality occurs during the breeding season. This study highlights the importance of reproductive individuals in maintaining group cohesion in social species, but at the population level socially complex species may be resilient to disruption and harvest through strong compensatory mechanisms. PMID- 25041128 TI - Suppression of vascular endothelial growth factor abrogates the immunosuppressive capability of murine gastric cancer cells and elicits antitumor immunity. AB - The mechanisms underlying immune evasion by gastric cancer have not been well described due to a lack of gastric tumor models in immunocompetent mice. In the current study, we found that supernatants from MFC cells, a murine gastric cancer line, inhibited the lipopolysaccharide (LPS) induced maturation and cross presentation of bone-marrow-derived dendritic cells (BMDCs). Moreover, MFC tumor derived factors markedly altered the cytokine profiles of BMDCs, leading to a trend of increased levels of interleukin 4 (IL4), IL6, IL23 and transforming growth factor beta, as well as decreased levels of tumor necrosis factor alpha. qPCR and ELISA revealed that MFC cells expressed a high level of vascular endothelial growth factor (VEGF). Downregulating VEGF expression abrogated the inhibitory effect of MFC-derived factors on the maturation and cross-presentation of BMDCs. In addition, VEGF knockdown greatly impaired the tumorigenicity of MFC cells in immunocompetent mice. Compared with parental MFC tumors, VEGF-low MFC tumors grew much more slowly and the survival of tumor-inoculated mice was significantly improved. More importantly, mice rejecting inoculated VEGF-low MFC tumor cells gained resistance to re-challenged parental tumors, which was attributed to an antitumor immunity response against parental MFC tumors. These results reveal an immunosuppressive role for VEGF in murine gastric cancer. PMID- 25041129 TI - Radiocarbon analysis of human remains: a review of forensic applications. AB - Radiocarbon analysis of organic materials, with the comparison of values with those of the post-1950 modern bomb curve, has proven useful in forensic science to help evaluate the antiquity of evidence. Applications are particularly helpful in the study of human remains, especially with those displaying advanced decomposition of soft tissues. Radiocarbon analysis can reveal if the remains relate to the modern, post-1950 era and if so, also provide information needed to evaluate the death and birth date. Sample selection and interpretation of results must be guided by knowledge of the formation and remodeling of different human tissues, as well as contextual information and the approximate age at death of the individual represented. Dental enamel does not remodel and thus captures dietary radiocarbon values at the time of juvenile formation. Most other human tissues do remodel but at differing rates and therefore collectively offer key information relative to the estimation of the death date. PMID- 25041131 TI - Prototype holder adequately supports the overtube in balloon-assisted endoscopic submucosal dissection. PMID- 25041130 TI - The thrifty psychiatric phenotype. PMID- 25041132 TI - Failure of total hip implants: metals and metal release in 52 cases. AB - BACKGROUND: The pathogenesis of total joint replacement failure is multifactorial. One hypothesis suggests that corrosion and wear of alloys result in metal ion release, which may then cause sensitization and even implant failure, owing to the acquired immune reactivity. OBJECTIVES: To assess cobalt, nickel and chromium(VI) release from, and the metal composition of, failed metal on-ethylene total hip replacements. MATERIALS/METHODS: Implant components from 52 revision cases were evaluated with spot tests for free nickel, cobalt, and chromium (VI) ions. Implant composition was determined with X-ray fluorescence spectroscopy, and information on the reason for revision and complications in relation to surgery was collected from the medical charts when possible (72%). For 10 implants, corrosion was further characterized with scanning electron microscopy. RESULTS: We detected cobalt release from three of 38 removed femoral heads and from one of 24 femoral stems. Nickel release was detected from one of 24 femoral stems. No chromium(VI) release was detected. CONCLUSIONS: We found that cobalt and nickel were released from some failed total hip arthroplasties, and corrosion was frequently observed. Metal ions and particles corroded from metal-on-polyethylene may play a role in the complex aetiopathology of implant failure. PMID- 25041133 TI - Niche construction initiates the evolution of mutualistic interactions. AB - Niche construction theory explains how organisms' niche modifications may feed back to affect their evolutionary trajectories. In theory, the evolution of other species accessing the same modified niche may also be affected. We propose that this niche construction may be a general mechanism driving the evolution of mutualisms. Drosophilid flies benefit from accessing yeast-infested fruits, but the consequences of this interaction for yeasts are unknown. We reveal high levels of variation among strains of Saccharomyces cerevisiae in their ability to modify fruits and attract Drosophila simulans. More attractive yeasts are dispersed more frequently, both in the lab and in the field, and flies associated with more attractive yeasts have higher fecundity. Although there may be multiple natural yeast and fly species interactions, our controlled assays in the lab and field provide evidence of a mutualistic interaction, facilitated by the yeast's niche modification. PMID- 25041134 TI - Sinus Width Analysis and New Classification with Clinical Implications for Augmentation. AB - PURPOSE: To measure the distances between the medial and lateral sinus wall (sinus width [SW]) at different levels on cone beam computed tomography (CBCT) and apply those SW values to formulate a new sinus classification. MATERIALS AND METHODS: Edentulous sites adjacent to maxillary sinuses with inadequate residual bone height (RBH) were included from the CBCT database. SW was measured at the heights of 1, 3, 5, 7, and 9 mm from the sinus floor. Mean SW was stratified into different groups by RBH, study sites (first and second premolars and molars), and measurement levels. Statistical analyses were conducted with commercially available software (IBM SPSS Statistics 19, SPSS Inc., Chicago, IL, USA). RESULTS: A total 186 patients (mean age 50.4 years) with 267 edentulous sites were included. Mean SW was wider at molar sites, higher measurement levels, and sites with less RBH. Narrow, average, or wide sinuses were classified based on the 33rd and 67th percentile SW values at 1-, 5-, and 9-mm measurement levels, respectively. CONCLUSIONS: SW at different levels relating to sinus floor elevation was measured. The proposed classification could contribute to estimate the difficulty of sinus augmentation, useful for the selection of surgical approaches. Further studies are required to testify its clinical implications. PMID- 25041135 TI - Orofacial functional impairments among patients following stroke: a systematic review. AB - OBJECTIVES: The objective of this study was to review orofacial functional impairments among patients following stroke, including objective and subjective assessment. METHODS: A structured search strategy was applied to three electronic databases (Pubmed, Embase, and Web of Science) to identify effective papers. Relevant data regarding subjects, method, outcomes, and key findings were extracted from the effective papers and the results were summarized. RESULTS: The initial search yielded 5227 papers, and 18 effective papers (Kappa: 0.971) were in accordance with the inclusion criteria. The patients with stroke consistently showed a decreased lip force, salivary flow rate, and chewing performance compared with the healthy controls. Due to equivocal results gained from the effective papers, the qualitative assessments regarding whether there was any change in masticatory force on the affected side and oral health-related quality of life were inconclusive. CONCLUSIONS: Existing evidence highlights a number of compromised orofacial functions experienced by patients following stroke. These impairments appear to be sustained, with spontaneous recovery unlikely to occur. While rehabilitative approaches may have the potential to improve orofacial function and quality of life following stroke, there is currently a lack of evidence-based interventions available to inform the development of comprehensive rehabilitation protocols. PMID- 25041136 TI - OPERA: responses to peginterferon and ribavirin therapy in a subgroup of interferon-naive patients with HIV/HCV genotype 2/3 co-infection in Italy. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) genotype 3 (G3) is common among HIV/HCV co-infected individuals and associated with moderate sustained virological response (SVR) rates with pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy, while G2 is less frequent and associated with higher SVR. To determine SVR and other response rates, identify SVR predictors and analyse differences between G2 and G3 with PEG-IFN/RBV in a large HIV/HCV G2/3 patient population. METHODS: This subgroup analysis of the prospective, observational OPERA (Optimized Pegylated interferon Efficacy and anti-Retroviral Approach) study was conducted between 2005 and 2011 in Italy in PEG-IFN/RBV-naive HIV/HCV patients. The primary efficacy endpoint was SVR rate (HCV RNA <50 IU/ml or undetectable 24 weeks after end-of-treatment). RESULTS: Five hundred and fifty six HCV G2/3 patients (G2 n = 60; G3 n = 496) were treated with PEG-IFN alfa-2a 180 MUg/week or PEG-IFN alfa-2b 1.5 MUg/kg, + RBV 13.6 +/- 2.3 (mean +/- SD) mg/kg/day for median 47 (26-54) weeks. SVR rates were 57.7%, 68.3% and 56.5% for G2/3, G2 and G3 respectively) and RVR rates were 53.2%, 57.1% and 45.8% respectively. Independent SVR predictors were undetectable baseline HIV RNA [adjusted odds ratio (AOR), 2.64; 95% CI: 1.523-4.565, P = 0.0005], age (AOR 0.95 per year; 95% CI: 0.908-0.994, P = 0.0258) and anti-HCV treatment duration (AOR 1.034 per week; 95% CI: 1.013-1.057, P = 0.0019). CONCLUSIONS: Undetectable HIV RNA, longer anti-HCV treatment adherence and younger age were independent SVR predictors in treatment-naive HIV/HCV G2/3 patients receiving PEG-IFN/RBV. Suppressing HIV RNA replication before anti-HCV therapy and increasing adherence to PEG-IFN/RBV treatment SVR rates may improve SVR. PMID- 25041137 TI - Oral health-related resources - a salutogenic perspective on Swedish 19-year olds. AB - The aim was to explore health-oriented resources among 19-year-olds and, specifically, how these resources interact with oral health-related attitudes and behaviour. To represent individuals with various psychosocial environments and socioeconomic areas, the participants were selected from different geographical locations of the Public Dental Service clinics in the county of Jonkoping, Sweden. A structured questionnaire was distributed, including the instrument 'sense of coherence', for description of the study group, followed by a semi structured thematized interview. The qualitative method used for sampling and analyses was grounded theory. Data sampling and analysis were performed in parallel procedures and ended up in a sample of ten informants (five women). In the analysis of interview data, a core category was identified, 'Resources of Wealth and Balance in Life - a Foundation for Healthy Choices', describing the central meaning of the informants' perceptions of resources with an essential beneficial impact on oral health. The core category was built on five themes, which in turn had various subthemes, describing different dimensions of resources interacting with beneficial oral health-related attitudes and behaviour: 'Security-building Resources and Support', 'Driving force and Motivation', 'Maturity and Insight', 'Health Awareness' and 'Environmental influences.' The results elucidate personal and environmental health-oriented resources with influence on oral health-related attitudes and behaviours of young individuals. Such beneficial recourses should be recognized by dental personnel to promote oral health. PMID- 25041138 TI - Psychopathic Sexuality: The Thin Line Between Fantasy and Reality. AB - In two studies, we explored the relations between psychopathic traits and sexual fantasy content. In Study 1, we rated content themes in the fantasy narratives of 195 men and women recruited at a Canadian university. In Study 2, we administered a sexual fantasy questionnaire to a sample of 355 Canadian undergraduate students. In Study 1, we found that psychopathic traits predicted themes of anonymous, uncommitted, and nonromantic sexual activity after controlling for participant sex. In Study 2, we found that psychopathy added to the prediction of self-reported engagement in unrestricted, dominant, submissive, deviant, and adventurous sexual activity, even after controlling for participant sex and level of fantasizing about that activity. Furthermore, an interaction between psychopathy and level of fantasizing was observed for unrestricted and deviant sexual behavior, such that participants who reported high levels of fantasizing about these sexual themes were more likely to engage in that behavior if they also reported high levels of psychopathic traits. These findings suggest that psychopathy is related not only to interest in particular sexual behaviors, but also to whether individuals will translate these fantasized behaviors into reality. PMID- 25041139 TI - Graft vasculopathy in the skin of a human hand allograft: implications for diagnosis of rejection of vascularized composite allografts. AB - Whereas vascularized composite allografts often undergo acute rejections early in the postgraft period, rejection manifesting with severe vascular changes (graft vasculopathy) has only been observed on three occasions in humans. We report a hand-allografted patient who developed severe rejection following discontinuation of the immunosuppressive treatment. It manifested clinically with erythematous maculopapules on the skin and pathologically with graft vasculopathy that affected both large vessels and smaller cutaneous ones. The observation that graft vasculopathy can affect skin vessels shows that it is amenable to diagnosis with usual skin biopsy as recommended for the follow-up of these allografts. Graft vasculopathy developing in the setting of vascularized composite allografts likely represents chronic rejection due to under-immunosuppression and, if confirmed, should be included in a future update of the Banff classification of vascularized composite allograft rejection. PMID- 25041140 TI - A qualitative study of traditional healing practices among American Indians with chronic pain. AB - OBJECTIVE: Although chronic pain is prevalent among American Indian (AI) populations, the use of traditional healing practices has not been widely investigated. The aim of this qualitative study was to solicit information from adult AIs with chronic pain regarding use of traditional health practices (THPs) for chronic pain and pain reduction. DESIGN: Prospective qualitative design. SETTING: The Min No Aya Win Human Services Center, Fond du Lac Band Reservation in Cloquet, MN, and the Center for American Indian Resources, Duluth, MN. PATIENTS: The cohort included 21 (10 women and 11 men) AI patients with chronic pain. INTERVENTION: A semi-structured interview guide was developed, and audiotaped interviews were conducted with all patients. OUTCOME MEASURE: Audiotaped interviews were transcribed, and thematic analysis strategies were used to identify core concepts and categories for coding interview data. A qualitative software analysis program was used to facilitate data coding. RESULTS: A range of THP were described including smudging (burning sage), sweat lodge (ceremonial sauna), sema (ceremonial tobacco), feasting (strengthening process), pipes (ceremonial herb and tobacco), storytelling (nonhierarchical environment for verbal communication), and contact with a traditional healer (elder spiritual leader). The majority of individuals from the Reservation described prior exposure to THP; however, the majority of urban individuals reported limited exposure. Although the majority of individuals endorsed inclusion of THP in ambulatory-based pain treatment programs, recommendations for inclusion of specific practices were not systematically identified. CONCLUSIONS: The findings of this qualitative study suggest AIs from this tribal community utilize THP, but which specific THPs should be included in an ambulatory-based pain treatment program will require further research. PMID- 25041142 TI - Testosterone and mortality. AB - Epidemiological studies have found that men with low or low normal endogenous testosterone are at an increased risk of mortality than those with higher levels. Cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone. Cancer and respiratory deaths in some of the studies are also significantly more prevalent. Disease-specific studies have identified that there are higher mortality rates in men with cardiovascular, respiratory and renal diseases, type 2 diabetes and cancer with low testosterone. Obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease and inflammatory disorders are all associated with an increased prevalence of testosterone deficiency. Two major questions that arise from these findings are (1) is testosterone deficiency directly involved in the pathogenesis of these conditions and/or a contributory factor impairing the body's natural defences or is it merely a biomarker of ill health and the severity of underlying disease process? (2) Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival? This review will discuss the current state of knowledge and discuss whether or not there are any answers to either of these questions. There is convincing evidence that low testosterone is a biomarker for disease severity and mortality. Testosterone deficiency is associated with adverse effects on certain cardiovascular risk factors that when combined could potentially promote atherosclerosis. The issue of whether or not testosterone replacement therapy improves outcomes is controversial. Two retrospective studies in men with diagnosed hypogonadism with or without type 2 diabetes have reported significantly improved survival. PMID- 25041141 TI - Gaviscon Double Action Liquid (antacid & alginate) is more effective than antacid in controlling post-prandial oesophageal acid exposure in GERD patients: a double blind crossover study. AB - BACKGROUND: Recent studies have shown that Gaviscon Double Action Liquid (a combination alginate-antacid) administered post-prandially co-localises with the acid pocket, the 'reservoir' for post-prandial acid reflux. AIM: To compare the effectiveness of Gaviscon Double Action Liquid to an equivalent strength antacid without alginate in controlling post-prandial acid reflux in GERD patients. METHODS: Fourteen GERD patients undertook two 3.5-h high-resolution manometry/pH impedance studies during which they ate a standardised meal. In a double-blinded randomised crossover design they then took Gaviscon or CVS brand antacid, each with ~18 mmol/L acid neutralising capacity. The primary outcome was distal oesophageal acid exposure; secondary outcomes were number of reflux events, proximal extent of reflux, nadir pH of the refluxate, mechanism of reflux and reflux symptoms scored with a validated instrument. RESULTS: Ten patients completed the study. Gaviscon studies had significantly less distal oesophageal acid exposure and greater nadir refluxate pH in the 30-150 min post-prandial period than antacid studies. There were no differences in the number of reflux events (acid or weakly acidic) or the number of proximal reflux events (15-17 cm above the LES) with either study medication. CONCLUSIONS: Gaviscon Double Action Liquid is more effective than an antacid without alginate in controlling post prandial oesophageal acid exposure. However, the number and spatial distribution of reflux events within the oesophagus are similar. This suggests that Gaviscon main effectiveness relates to its co-localisation with and displacement/neutralisation of the post-prandial acid pocket, rather than preventing reflux. PMID- 25041143 TI - Do inflammatory pathways drive melanomagenesis? AB - Inflammatory pathways serve to protect the host and promote tissue healing/repair; however, over-activation or dysregulation can be pathological with unintended consequences including malignant progression. A correlation between inflammation and cancer has been well established, and anti-inflammatory medications have been shown to be chemopreventive in certain malignancies. Data are now becoming available that outline an inflammatory pathway that may have a critical role in melanomagenesis. ATP-regulated membrane channels/receptors P2X7 and PANX1 have been directly implicated in melanoma tumor growth. Among other potential effects, opening of the P2X7/PANX1 channel results in activation of the NALP3 inflammasome, which in turn leads to caspase-1 activation and increased levels of activated IL-1beta. Elevated levels of caspase-1 and IL-1beta have been correlated with melanoma progression, and inhibitors of the inflammasome, caspase and IL-1beta activity have all been shown to inhibit melanoma growth. Among many other potential actions, IL-1beta increases cyclooxygenase-2 expression leading to local increases in inflammatory mediators such as prostaglandin E2 (PGE2). Anti-inflammatory medications targeting the end of this pathway have had positive results for certain cancers but overall remain mixed for melanoma. A better understanding of the pathways and appropriate intervention points may help direct future therapies. In this viewpoint, we will review data and attempt to model an inflammatory pathway that may be critical for melanomagenesis and propose future directions for exploration. PMID- 25041145 TI - Life cycle of Cystoisospora felis (Coccidia: Apicomplexa) in cats and mice. AB - Cystoisospora felis is a ubiquitous apicomplexan protozoon of cats. The endogenous development of C. felis was studied in cats after feeding them infected mice. For this, five newborn cats were killed at 24, 48, 72, 96, and 120 h after having been fed mesenteric lymph nodes and spleens of mice that were inoculated with C. felis sporulated sporocysts. Asexual and sexual development occurred in enterocytes throughout the villi of the small intestine. The number of asexual generations was not determined with certainty, but there were different sized merozoites. At 24 h, merogony was seen only in the duodenum and the jejunum. Beginning at 48 h, the entire small intestine was parasitized. At 24 h, meronts contained 1-4 zoites, and at 48 h up to 12 zoites. Beginning with 72 h, the ileum was more heavily parasitized than the jejunum. At 96 and 120 h, meronts contained many zoites in various stages of development; some divided by endodyogeny. The multiplication was asynchronous, thus both immature multinucleated meronts and mature merozoites were seen in the same parasitophorous vacuole. Gametogony occurred between 96 and 120 h, and oocysts were present at 120 h. For the study of the development of C. felis in murine tissues, mice were killed from day 1 to 720 d after having been fed 10(5) sporocysts, and their tissues were examined for the parasites microscopically, and by bioassay in cats. The following conclusions were drawn. (1) Cystoisospora felis most frequently invaded the mesenteric lymph nodes of mice and remained there for at least 23 mo. (2) It also invaded the spleen, liver, brain, lung, and skeletal muscle of mice, but division was not seen based on microscopical examination. (3) This species could not be passed from mouse to mouse. PMID- 25041144 TI - Metabolites related to gut bacterial metabolism, peroxisome proliferator activated receptor-alpha activation, and insulin sensitivity are associated with physical function in functionally-limited older adults. AB - Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6-month change in serum mass spectrometry-obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6-month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400-m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally-limited older adults (SPPB <= 10; 70-85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p-cresol sulfate, 3-indoxyl sulfate, serotonin, N-methylproline, hydrocinnamate, dimethylglycine, trans-urocanate, valerate) that are altered in response to peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation (alpha-hydroxyisocaproate, alpha-hydroxyisovalerate, 2-hydroxy-3 methylvalerate, indolelactate, serotonin, 2-hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5-dodecenoate, myristoleate, palmitoleate; gamma-glutamylamino acids: gamma-glutamylglutamine, gamma glutamylalanine, gamma-glutamylmethionine, gamma-glutamyltyrosine; branched-chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6-month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR-alpha activation, and insulin sensitivity may be involved in mechanisms that underlie physical function in functionally-limited older adults. PMID- 25041146 TI - Getting to know the unknown. PMID- 25041147 TI - Going from A to B: the safety of incompatible group A plasma for emergency release in trauma and massive transfusion patients. PMID- 25041148 TI - Staphylococcus aureus sepsis from one cocomponent of a "triple" apheresis platelet donation. PMID- 25041149 TI - Donor criteria for men who have sex with men: a Canadian perspective. PMID- 25041150 TI - Current patterns of use in therapeutic apheresis: a metropolitan center experience. PMID- 25041151 TI - Successful pulmonary thromboendarterectomy in a patient with sickle cell disease treated with a single preoperative red blood cell exchange. PMID- 25041152 TI - Integrated coagulation consultation for transfusion medicine. PMID- 25041153 TI - Implications of legalized recreational marijuana on the United States blood supply. PMID- 25041154 TI - The effect of 30-Gy X-ray irradiation on platelets washed with M-sol additive solution. PMID- 25041155 TI - Exacerbation of pulmonic regurgitation by diastolic tricuspid regurgitation. AB - Few cases of diastolic mitral regurgitation (MR) and tricuspid regurgitation (TR) have been reported in the world literature. We report the case of a 63-year-old woman admitted for syncope, with a permanent pacemaker following complete heart block. Echocardiography revealed that the timing of the diastolic TR (and noted MR) coincided with the second phase of the pulmonic insufficiency (PI) jet. The respirometer revealed that the diastolic TR and the second phase of the PI are highly sensitive to respiration (attenuated with inspiration and exacerbated with expiration). The uniqueness of this case is the rare occurrence of the exacerbation of PI as the result of diastolic TR. PMID- 25041156 TI - Renal sympathetic denervation for treatment of resistant hypertension: Egyptian experience. AB - BACKGROUND: Among the Egyptian population with essential hypertension, a minority are under control (systolic pressure <140 mmHg and diastolic pressure <90 mmHg), despite the use of multiple antihypertensive medications. In this article, we describe our experience with percutaneous treatment using renal artery radiofrequency (RF) ablation. OBJECTIVES: To evaluate the feasibility, efficacy, and safety of catheter-based radiofrequency renal sympathetic denervation for treatment of resistant hypertension in Egyptian patients. METHODS: Patients with essential hypertension unresponsive to at least 3 types of antihypertensive medical therapy (baseline office systolic blood pressure >=160 mmHg) (n = 55) were enrolled between February 2012 and June 2013 and received percutaneous RF ablation. Patients were followed up for 6 months after treatment to detect any change in office-based measurement of blood pressure. Urine and blood samples were taken to evaluate the effects on renal function. RESULTS: A reduction of mean office blood pressure was seen from 174/103 +/- 9/5 mmHg at baseline to 150/91 +/- 8/5 mmHg at 6 months follow-up (P = 0.001). Also, we noted a significant decrease in plasma renin activity (3.66 +/- 0.64 vs. 3.37 +/- 0.47 ng/mL per hour; P = 0.003), and there were no periprocedural complications, no adverse events, and no change in renal function during the follow-up period. Also, no change was noted in the number of medications after 6 months (3.95 +/- 1.64 vs. 3.67 +/- 0.72; P = 0.27). CONCLUSION: In this observational study, catheter-based renal denervation causes sustained blood pressure reduction in patients with resistant hypertension, without serious adverse events. PMID- 25041157 TI - Kelps feature systemic defense responses: insights into the evolution of innate immunity in multicellular eukaryotes. AB - Brown algae are one of the few eukaryotic lineages that have evolved complex multicellularity, together with Opisthokonts (animals, fungi) and Plantae (land plants, green and red algae). In these three lineages, biotic stresses induce similar local defense reactions. Animals and land plants also feature a systemic immune response, protecting the whole organism after an attack on one of its parts. However, the occurrence of systemic defenses has never been investigated in brown algae. We elicited selected parts of the kelp Laminaria digitata and monitored distant, nonchallenged areas of the same individual for subsequent defense reactions. A systemic reaction was detected following elicitation on a distant area, including an oxidative response, an increase in haloperoxidase activities and a stronger resistance against herbivory. Based on experiments with pharmacological inhibitors, the liberation of free fatty acids is proposed to play a key role in systemic signaling, reminiscent of what is known in land plants. This study is the first report, outside the phyla of Opisthokonts and Plantae, of an intraorganism communication leading to defense reactions. These findings indicate that systemic immunity emerged independently at least three times, as a consequence of convergent evolution in multicellular eukaryotic lineages. PMID- 25041158 TI - Stromal miR-21 is more important than miR-21 of tumour cells for the progression of gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is a common cancer globally. miRNA-21 (miR-21) appears to be important in the tumourigenesis of almost all types of human cancer. However its precise localization in GC has yet to be clarified. We thus examined miR-21 localization in GC and revealed its clinicopathological importance. METHODS: Tissue arrays of 469 GCs from 454 patients were examined for miR-21 using in situ hybridization (ISH). The positivity was evaluated separately in tumour cells and stromal cells. Conventional sections of 10 GCs were also stained. Eight cases were examined by quantitative RT-PCR (qRT-PCR). RESULTS: miR 21 was highly expressed in tumour cells of 44% of cases and in cancer stroma of 51% of cases. miR-21 of tumour cells was not related to clinicopathological factors, whereas stromal miR-21 was related to many factors including tumour stage, size, and nodal metastasis. Stromal miR-21 gradually increased during tumour progression. ISH of whole sections showed stronger stromal positivity in invasive areas with desmoplastic reaction. Cancer stroma also showed higher miR 21 expression than tumour and non-tumourous tissue in the qRT-PCR study. CONCLUSION: Stromal miR-21 is closely related to tumour progression in GC. Stromal miR-21 of tumours might be a target of treatment. PMID- 25041160 TI - Cbc2p, Upf3p and eIF4G are components of the DRN (Degradation of mRNA in the Nucleus) in Saccharomyces cerevisiae. AB - Messenger RNAs retained in the nucleus of Saccharomyces cerevisiae are subjected to a degradation system designated DRN (Degradation of mRNA in the Nucleus) that is dependent on the nuclear mRNA cap-binding protein, Cbc1p, as well as nuclear exosome component Rrp6p, a 3' to 5' exoribonuclease. DRN has been shown to act on RNAs preferentially retained in the nucleus, such as: (1) global mRNAs in export defective nup116-Delta mutant strains at the restrictive temperature; (2) a certain class of normal mRNAs called special mRNAs (e.g. IMP3 and YLR194c mRNAs); and (3) mutant mRNAs for example, lys2-187 and cyc1-512. In this study, we further identify three novel components of DRN (Cbc2p, Upf3p and Tif4631p) by employing a genetic screen and by considering proteins/factors that interact with Cbc1p. Participation of these components in DRN was confirmed by demonstrating that null alleles of these genes resulted in stabilization of the rapid decay of global mRNAs in the export defective nup116-Delta strain and of representative special mRNAs. Depletion of Tif4632p, an isoform of Tif4631p, also exhibited a partial impairment of DRN function and is therefore also considered to play a functional role in DRN. These findings clearly establish that CBC2, UPF3, and TIF4631/32 gene products participate in DRN function. PMID- 25041161 TI - Using inter-institutional practice variation to understand the risks and benefits of routine labour induction at 41(+0) weeks. AB - OBJECTIVE: To evaluate the risks and benefits of routine labour induction at 41(+0) weeks' gestation for mother and newborn. DESIGN: Population-based retrospective cohort study of inter-institutional variation in labour induction practices for women at or beyond 41(+0) weeks' gestation. POPULATION: Women in British Columbia, Canada, who remained pregnant >=41(+0) weeks and delivered at one of the province's 42 hospitals with >50 annual deliveries, 2008-2012 (n = 14,627). METHODS: The proportion of women remaining pregnant a week or more past the expected delivery date who were induced at 41(+0) or 41(+1) weeks' gestation for an indication of 'post-dates' was calculated for each institution. We used instrumental variable analysis (using the institutional rate of labour induction at 41(+0) weeks as the instrument) to estimate the effect of labour induction on maternal and neonatal health outcomes. MAIN OUTCOME MEASURES: Caesarean delivery, instrumental delivery, post-partum haemorrhage, 3rd or 4th degree lacerations, macrosomia, neonatal intensive care unit admission, and 5-minute Apgar score <7. RESULTS: Institutional rates of labour induction at 41(+0) weeks ranged from 14.3 to 46%. Institutions with higher (>=30%) and average (20-29.9%) induction rates did not have significantly different rates of caesarean delivery, instrumental delivery, or other maternal or neonatal outcomes than institutions with lower induction rates (<20%). Instrumental variable analyses also demonstrated no significantly increased (or decreased) risk of caesarean delivery (0.69 excess cases per 100 pregnancies [95% CI -10.1, 11.5]), instrumental delivery (8.9 per 100 [95% CI -2.3, 20.2]), or other maternal or neonatal outcomes in women who were induced (versus not induced). CONCLUSIONS: Within the current range of clinical practice, there was no evidence that differential use of routine induction at 41(+0) weeks affected maternal or neonatal health outcomes. PMID- 25041163 TI - The patient experience of a Peripherally Inserted Central Catheter (PICC): a qualitative descriptive study. AB - Abstract Aim: To investigate the patient experience of PICC insertion, the significance of arm choice and the impact of the device on activities of daily living. Background: Arm choice for PICC insertion is often determined by PICC nurses with little input from consumers. There are few studies that have investigated the patient experience of living with a PICC and none that have examined the impact of arm choice from the consumer's perspective. Method: Participants were recruited in a hospital whilst they waited for PICC insertion. A purposeful sampling approach was used to select participants based on diagnosis types. Semistructured telephone interviews were conducted November 2012-August 2013. Transcripts of the interviews were analysed using thematic analysis. Findings: Ten participants were interviewed. Four themes were identified: (i) apprehension/ adaptation/ acceptance, (ii) impact of treatment, (iii) asking questions (trusting doctors) and (iv) freedom. Although initially apprehensive, participants adapted to the PICC and came to accept that the device allowed convenient access for treatment. This allowed them the freedom to receive treatment at home. The use of the dominant or non-dominant arm for PICC insertion had marginal impact on activities of daily living for participants. Auxiliary factors such as the infusion pump had a significant impact for those who received outpatient treatment. For those participants who did not understand the procedure, many did not seek clarification and trusted medical and nursing staff to make decisions for them. Conclusion: Nurses should involve consumers in clinical decision-making and provide individualised information and support that facilitates adaptation for patients living with a PICC. PMID- 25041164 TI - Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. AB - BACKGROUND: Chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) can be used for palliative treatment of malignant pheochromocytoma and paraganglioma. However, the precise effect of this chemotherapeutic regimen on tumour volume is unclear. The main objective of this study was to perform a systematic review and meta-analysis assessing the effect of chemotherapy with CVD on tumour volume in patients with malignant paraganglioma/pheochromocytoma. METHODS: A literature search was performed in October 2013 to identify potentially relevant studies. Main outcomes were the pooled percentages of complete response, partial response and stable disease after chemotherapy with CVD. A meta-analysis was performed with an exact likelihood approach using a logistic regression. Pooled percentages with 95% confidence intervals (CI) were reported. RESULTS: Four studies concerning a total of 50 patients with malignant paraganglioma/pheochromocytoma reported on treatment with a combination of CVD chemotherapy. A meta-analysis of the effect of chemotherapy on tumour volume showed pooled percentages of complete response, partial response and stable disease of, respectively, 4% (95% CI: 1%-15%), 37%(95% CI: 25%-51%) and 14% (95% CI: 7%-27%). Only two studies concerning a total of 35 patients assessed the response on catecholamine excess; pooled percentages for complete, partial and stable hormonal response were 14% (95% CI: 6%-30%), 40% (95% CI: 25%-57%) and 20% (95% CI: 10%-36%), respectively. Duration of response was also reported in only two studies with a median duration of response of 20 months and 40 months. CONCLUSIONS: Data on the effects of a combination of CVD chemotherapy on malignant paraganglioma/pheochromocytoma suggest that a partial response concerning tumour volume can be achieved in about 37% of patients and a partial response on catecholamine excess in about 40% of patients. However, in the included studies, the protocol when to initiate treatment was not well described. Therefore, it cannot be excluded that the reported effect of chemotherapy on tumour volume reflects the natural course of the disease, at least partially. PMID- 25041165 TI - The dorsal raphe nucleus is integral to negative prediction errors in Pavlovian fear. AB - Prediction errors are central to modern learning theories. While brain regions contributing to reward prediction errors have been uncovered, the sources of aversive prediction errors remain largely unknown. Here we used probabilistic and deterministic reinforcement procedures, followed by extinction, to examine the contribution of the dorsal raphe nucleus to negative, aversive prediction errors in Pavlovian fear. Rats with dorsal raphe lesions were able to acquire fear and reduce fear to a non-reinforced deterministic cue. However, dorsal raphe lesions impaired the reduction of fear to a probabilistic cue and fear extinction to a deterministic cue, both of which involve the use of negative prediction errors. The results point to an integral role for the dorsal raphe nucleus in negative prediction error signaling in Pavlovian fear. PMID- 25041166 TI - Quality of psychopharmacological medication prescribing and mortality in Medicare beneficiaries in nursing homes. AB - OBJECTIVES: To examine the influence of quality measures of psychopharmacological medication (PPM) prescribing on all-cause mortality in a Medicare long-stay nursing home (NH) population. DESIGN: Longitudinal. SETTING: 2007-09 Medicare data linked to Minimum Data Set 2.0 files. PARTICIPANTS: Four new-user cohorts of residents initiating antipsychotic (n=13,105), antidepressant (n=14,251), anxiolytic and sedative-hypnotic (n=10,789), and any PPM (n=14,568) medication. MEASUREMENTS: Three measures of PPM prescribing quality were assessed monthly with a 6-month look-back: evidence of appropriate indication, dose (modified standardized daily dose (mSDD); below (<1), at (1), and above (>1) recommended geriatric dose), and duration of therapy (DOT; <=30, 31-60, 61-90, 91-180 days from medication initiation). Complementary log-log models with quality measures as time-dependent variables were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. RESULTS: Appropriate use of antidepressants, anxiolytics and sedative-hypnotics, and any PPMs, as evidenced by appropriate indications, was significantly associated with lower mortality risk (HRantidepressants=0.81, 95% CI=0.76-0.86; HRanxiolytics and sedative hypnotics=0.81, 0.75-0.88; HRPPM=0.89, 0.83-0.95). Antipsychotic and anxiolytic and sedative-hypnotic users with a mSDD of less than 1 had lower mortality risk than those with a mSDD greater than 1, whereas a protective effect was observed in antidepressant users with a mSDD greater than 1. In all four cohorts, those with a DOT of 91 to 180 days had lower mortality than those with a DOT of 1 month or less; the lower risk of mortality was detected after antipsychotic use for 31 days or longer. CONCLUSION: Optimal PPM prescribing quality, as measured by indication and duration, is associated with low mortality. The benefit related to drug dosage varied by therapeutic class. When prescribing PPMs to NH residents, providers should consider not only drug choice, but also dose and duration of prescribed regimens. PMID- 25041167 TI - Analysis of an Arabidopsis heat-sensitive mutant reveals that chlorophyll synthase is involved in reutilization of chlorophyllide during chlorophyll turnover. AB - Chlorophylls, the most abundant pigments in the photosynthetic apparatus, are constantly turned over as a result of the degradation and replacement of the damage-prone reaction center D1 protein of photosystem II. Results from isotope labeling experiments suggest that chlorophylls are recycled by reutilization of chlorophyllide and phytol, but the underlying mechanism is unclear. In this study, by characterization of a heat-sensitive Arabidopsis mutant we provide evidence of a salvage pathway for chlorophyllide a. A missense mutation in CHLOROPHYLL SYNTHASE (CHLG) was identified and confirmed to be responsible for a light-dependent, heat-induced cotyledon bleaching phenotype. Following heat treatment, mutant (chlg-1) but not wild-type seedlings accumulated a substantial level of chlorophyllide a, which resulted in a surge of phototoxic singlet oxygen. Immunoblot analysis suggested that the mutation destabilized the chlorophyll synthase proteins and caused a conditional blockage of esterification of chlorophyllide a after heat stress. Accumulation of chlorophyllide a after heat treatment occurred during recovery in the dark in the light-grown but not the etiolated seedlings, suggesting that the accumulated chlorophyllides were not derived from de novo biosynthesis but from de-esterification of the existing chlorophylls. Further analysis of the triple mutant harboring the CHLG mutant allele and null mutations of CHLOROPHYLLASE1 (CLH1) and CLH2 indicated that the known chlorophyllases are not responsible for the accumulation of chlorophyllide a in chlg-1. Taken together, our results show that chlorophyll synthase acts in a salvage pathway for chlorophyll biosynthesis by re-esterifying the chlorophyllide a produced during chlorophyll turnover. PMID- 25041168 TI - A methodology for risk analysis based on hybrid Bayesian networks: application to the regasification system of liquefied natural gas onboard a floating storage and regasification unit. AB - This article presents an iterative six-step risk analysis methodology based on hybrid Bayesian networks (BNs). In typical risk analysis, systems are usually modeled as discrete and Boolean variables with constant failure rates via fault trees. Nevertheless, in many cases, it is not possible to perform an efficient analysis using only discrete and Boolean variables. The approach put forward by the proposed methodology makes use of BNs and incorporates recent developments that facilitate the use of continuous variables whose values may have any probability distributions. Thus, this approach makes the methodology particularly useful in cases where the available data for quantification of hazardous events probabilities are scarce or nonexistent, there is dependence among events, or when nonbinary events are involved. The methodology is applied to the risk analysis of a regasification system of liquefied natural gas (LNG) on board an FSRU (floating, storage, and regasification unit). LNG is becoming an important energy source option and the world's capacity to produce LNG is surging. Large reserves of natural gas exist worldwide, particularly in areas where the resources exceed the demand. Thus, this natural gas is liquefied for shipping and the storage and regasification process usually occurs at onshore plants. However, a new option for LNG storage and regasification has been proposed: the FSRU. As very few FSRUs have been put into operation, relevant failure data on FSRU systems are scarce. The results show the usefulness of the proposed methodology for cases where the risk analysis must be performed under considerable uncertainty. PMID- 25041169 TI - Prediction of Parturition Time in Queens using Radiography and Ultrasonography. AB - This study investigated the prediction of parturition in queens, as well as the effects of the queens' age and weight and the litter size on the accuracy of the prediction. A prospective study was performed in 24 purebred queens of 11 different breeds, all in normal body condition, using radiographic and ultrasonographic measurements of foetal femoral length (FL) and biparietal diameter (BPD) of foetal skull that apply to different breeds. Pregnant queens with aborted or malformed foetuses were excluded. The examinations were performed up to three times during the second half of pregnancy; litter size was obtained with radiography, and FL and BPD measurements were taken of each foetus using both radiography and ultrasonography. The maximal FL and the transversal BPD were recorded for each foetus. Radiography showed the number of foetuses accurately but did not allow accurate prediction of time of parturition. However, ultrasonography did establish the best predictive model according to the data with the FL. This model corresponded to the formula Y = 37.864 - 0.193 * FL + 1.227 * W - 0.615 * LS - 0.832 * A using the FL (10(-1) mm), litter size (LS, number of foetuses per queen) and maternal parameters (weight (W, kg) and age (A, years)). Time to parturition correlated positively with the queen's weight and negatively with her age (P < 0.01). The ultrasonographic FL associated with pregnancy and maternal factors appeared to be an accurate model to predict parturition. PMID- 25041170 TI - An explained variance-based genetic risk score associated with gestational diabetes antecedent and with progression to pre-diabetes and type 2 diabetes: a cohort study. AB - OBJECTIVE: To determine whether an explained-variance genetic risk score (GRS), with 36 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes (T2D), is also associated with gestational diabetes mellitus (GDM), and with the progression to pre-diabetes and T2D among women with prior GDM. DESIGN: A cohort study. SETTING: Clinical investigation unit of Laval University, Quebec, Canada. POPULATION: A cohort of 214 women with prior GDM and 82 controls recruited between 2009 and 2012. METHODS: Associations between the GRS and GDM. MAIN OUTCOMES MEASURES: GDM and prevalence of pre-diabetes and T2D. RESULTS: Women with prior GDM had a higher GRS compared with controls (38.6 +/- 3.9, 95% CI 38.1-39.1, versus 37.4 +/- 3.2, 95% CI 36.7-38.1; P < 0.0001). In women with prior GDM, the explained-variance GRS was higher for pre-diabetic women compared with women who remained normoglucotolerant at testing (1.21 +/- 0.18, 95% CI 1.18 1.23, versus 1.17 +/- 0.15, 95% CI 1.13-1.20; P < 0.0001). Similarly, women with T2D had a higher explained-variance GRS compared with women with prior GDM who remained normoglucotolerant (1.20 +/- 0.18, 95% CI 1.14-1.25, versus 1.17 +/- 0.17, 95% CI 1.13-1.20; P < 0.0001). The predictive effects of the explained variance GRS, age, and body mass index (BMI), or the additive effects of the three variables, were tested for pre-diabetes and T2D. We observed an area under the curve of 0.6269 (95% CI 0.5638-0.6901) for age and BMI, and adding the explained-variance GRS into the model increased the area to 0.6672 (95% CI 0.6064 0.7281) for the prediction of pre-diabetes. CONCLUSIONS: An explained-variance GRS is associated with both GDM and progression to pre-diabetes and T2D in women with prior GDM. PMID- 25041171 TI - Increased Meningeal T and Plasma Cell Infiltration is Associated with Early Subpial Cortical Demyelination in Common Marmosets with Experimental Autoimmune Encephalomyelitis. AB - Subpial cortical demyelination (SCD) accounts for the greatest proportion of demyelinated cortex in multiple sclerosis (MS). SCD is already found in biopsy cases with early MS and in marmosets with experimental autoimmune encephalomyelitis (EAE), but the pathogenesis of SCD is not well understood. The objective of this study was to investigate whether and, if so, which meningeal inflammatory cells were associated with early SCD in marmosets with EAE. Immunohistochemistry was performed to analyze brain samples from eight control animals and eight marmosets immunized with myelin oligodendrocyte glycoprotein. Meningeal T, B and plasma cells were quantified adjacent to SCD, normal-appearing EAE cortex (NAC) and control marmoset cortex. SCD areas appeared mostly hypocellular with low-grade microglial activation. In marmosets with EAE, meninges adjacent to SCD showed significantly increased T cells paralleled by elevated plasma cells, but unaltered B cell numbers compared with NAC. The elevation of meningeal T and plasma cells was a specific finding topographically associated with SCD, as the meninges overlying NAC displayed similarly low T, B and plasma cell numbers as control cortex. These findings suggest that local meningeal T and plasma cell infiltration contributes to the pathogenesis of SCD in marmosets with EAE. PMID- 25041172 TI - Effects of the 2004 postgraduate training program on the interprefectural distribution of psychiatrists in Japan. AB - AIMS: After a new postgraduate training program was launched by the Ministry of Health, Labour, and Welfare in 2004, concern regarding the maldistribution of physicians has increased in Japan. This study aimed to assess the interprefectural distribution of psychiatrists in Japan before and after the start of the new postgraduate training program. METHODS: Our data included nine time points: 1996, 1998, 2000, 2002, 2004, 2006, 2008, 2010 and 2012. The Gini coefficient (GC) was calculated using prefectures as the study unit to assess whether the interprefectural distribution of psychiatrists significantly changed in relation to the population and area of prefectures. The effect of the new postgraduate training program on the GC of psychiatrist distribution was assessed by estimating the interaction between year and period (before or after the postgraduate training program) using a general linear model analysis. RESULTS: The total number of psychiatrists increased from 10,093 to 14,733 over the observed period. The general linear model showed a significant interaction between the year and the period for the GC based on the number of psychiatrists per 100 km(2) , whereas no interaction was found for the GC based on the number of psychiatrists per 100,000 population. CONCLUSIONS: The interprefectural distribution of psychiatrists per 100 km(2) worsened after the launch of the new training program; this result may reflect the adverse impact of the training program. Further observation is needed to explore how this difference in the interprefectural distribution of psychiatrists affects the mental health status of the population. PMID- 25041174 TI - Duplication cyst of the appendix: a proposal for modification of the Cave Wallbridge classification. PMID- 25041173 TI - A moderating role for gender in racial/ethnic disparities in alcohol services utilization: results from the 2000 to 2010 national alcohol surveys. AB - BACKGROUND: Few nationally representative studies have examined racial/ethnic disparities in alcohol services utilization. Further, little is known about whether racial/ethnic disparities generalize across genders, and what factors account for these disparities. Thus, we aimed to describe the combined impact of race/ethnicity and gender on alcohol services utilization, and to explore the roles for social influence factors in explaining racial/ethnic and gender disparities. METHODS: Data were pooled across the 2000, 2005, and 2010 National Alcohol Surveys. Outcomes included lifetime utilization of any services, specialty alcohol treatment, and Alcoholics Anonymous. Social influence factors were assessed as lifetime social pressures (i.e., pressures from a partner, friends, and/or family), legal consequences, and work-related consequences. Core analyses included only those with a lifetime alcohol use disorder (AUD). RESULTS: Analyses revealed a pattern of lower services utilization among Latinos and Blacks (vs. Whites) and women (vs. men); further, race-by-gender interactions revealed that Black-White differences were limited to women, and provided some evidence of stronger Latino-White disparities among women (vs. men). Illustrating these patterns, among women, only 2.5% of Latinas and 3.4% of Blacks with a lifetime AUD accessed specialty treatment, versus 6.7% of Whites; among men, corresponding figures were 6.8% for Latinos, 12.2% for Blacks, and 10.1% for Whites. Racial/ethnic differences were typically robust (or stronger) when controlling for demographics and AUD severity. Evidence did not support a role for measured social influence factors in racial/ethnic disparities, but did suggest that these factors contribute to gender disparities, particularly among Whites and Blacks. CONCLUSIONS: Findings for substantial Latino-White and Black White disparities, especially among women, highlight the need for continuing research on explanatory factors and the development of appropriate interventions. Meanwhile, our evidence for persistent gender disparities and for social influence factors as drivers of these disparities tentatively suggests a need for intensified outreach to female heavy drinkers. PMID- 25041175 TI - Nerve growth factor inhibits osmotic swelling of rat retinal glial (Muller) and bipolar cells by inducing glial cytokine release. AB - Osmotic swelling of neurons and glial cells contributes to the development of retinal edema and neurodegeneration. We show that nerve growth factor (NGF) inhibits the swelling of glial (Muller) and bipolar cells in rat retinal slices induced by barium-containing hypoosmotic solution. NGF also reduced Muller and bipolar cell swelling in the post-ischemic retina. On the other hand, NGF prevented the swelling of freshly isolated Muller cells, but not of isolated bipolar cells, suggesting that NGF induces a release of factors from Muller cells that inhibit bipolar cell swelling in retinal slices. The inhibitory effect of NGF on Muller cell swelling was mediated by activation of TrkA (the receptor tyrosine kinase A), but not p75(NTR) , and was prevented by blockers of metabotropic glutamate, P2Y1 , adenosine A1 , and fibroblast growth factor receptors. Basic fibroblast growth factor fully inhibited the swelling of freshly isolated Muller cells, but only partially the swelling of isolated bipolar cells. In addition, glial cell line-derived neurotrophic factor and transforming growth factor-beta1, but not epidermal growth factor and platelet-derived growth factor, reduced the swelling of bipolar cells. Both Muller and bipolar cells displayed TrkA immunoreactivity, while Muller cells were also immunostained for p75(NTR) and NGF. The data suggest that the neuroprotective effect of NGF in the retina is in part mediated by prevention of the cytotoxic glial and bipolar cell swelling. Cytotoxic cell swelling contributes to retinal neurodegeneration. Nerve growth factor (NGF) inhibits the osmotic swelling of glial cells by acting at TrkA, release of bFGF, and opening of K(+) and Cl(-) channels. The NGF-induced glial release of cytokines like bFGF inhibits the osmotic swelling of bipolar cells, suggesting that the neuroprotective effect of NGF is in part mediated by prevention of cytotoxic cell swelling. PMID- 25041177 TI - Physical changes in specimens of five species of Cyprinidae preserved in ethanol and frozen. AB - Preservation in 30% ethanol and freezing to a temperature of -20 +/- 2 degrees C is an appropriate method for measurement of fish eggs, larvae and juveniles. Egg diameter of the common carp Cyprinus carpio increased insignificantly by 1.32% after preservation compared with live size. The total length (LT ) of 1 day post hatching (dph) larvae as well as the standard length (LS) of 16 dph larvae of C. carpio increased significantly (2.95 and 1.50%, respectively) after preservation. Egg diameter as well as the LT of 1 dph larvae of barbel Barbus barbus increased significantly after preservation, by 1.74 and 1.96%, respectively over their original size. The standard length (LS ) of 14 dph larvae of B. barbus as well as juveniles of B. barbus, crucian carp Carassius carassius, common nase Chondrostoma nasus and tench Tinca tinca decreased significantly after preservation (-0.56 to -5.54%), whereas their body mass increased significantly (11.46-18.57%). Preserved eggs of C. carpio and B. barbus were hard, round and transparent. The larvae and juveniles of examined fishes, preserved in frozen ethanol, were straight, flexible and easily measurable after 60 days. Integrity of body surface and fins, as well as preservation of colours were much better in larvae or juveniles frozen and thawed only once than in specimens frozen and thawed thrice. Cooling in 30% ethanol to a temperature of 6 +/- 2 degrees C and freezing in water to a temperature of -20 +/- 2 degrees C are not appropriate preservation methods for eggs and larvae of C. carpio (1 and 16 dph). PMID- 25041176 TI - Contralateral interictal spikes are related to tapetum damage in left temporal lobe epilepsy. AB - OBJECTIVE: In temporal lobe epilepsy (TLE), the epileptogenic focus is focal and unilateral in the majority of patients. A key characteristic of focal TLE is the presence of subclinical epileptiform activity in both the ictal and contralateral "healthy" hemisphere. Such interictal activity is clinically important, as it may reflect the spread of pathology, potentially leading to secondary epileptogenesis. The role played by white matter pathways in this process is unknown. METHODS: We compared three interhemispheric white matter tracts (anterior commissure, fornix, and tapetum) to determine the pathway most associated with the presence of contralateral interictal spikes. Forty patients with unilateral left or right TLE were categorized based on the presence or absence of contralateral interictal spikes. Analyses of variance (ANOVAs) were run on diffusion properties from each tract. RESULTS: The analyses revealed that patients with left TLE and with bilateral interictal spikes had lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the tapetum. Patients with right TLE did not show this effect. No significant associations with bilateral activity were observed for the other tracts. Blood oxygen level-dependent (BOLD) functional connectivity data revealed that homotopic lateral, not mesial, temporal areas were reliably correlated in bilateral patients, independent of ictal side. SIGNIFICANCE: Our results indicate that, among the tracts investigated, only the tapetum was associated with contralateral epileptiform activity, implicating this structure in seizures and possible secondary epileptogenesis. We describe two mechanisms that might explain this association (the interruption of inhibitory signals or the toxic effect of carrying epileptiform signals toward the healthy hemisphere), but also acknowledge other rival factors that may be at work. We also report that patients with TLE with bilateral spikes had increased lateral bitemporal lobe connectivity. Our current results can be seen as bringing together important functional and structural data to elucidate the basis of contralateral interictal activity in focal, unilateral epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 25041178 TI - Surface morphology analysis of dental implants following insertion into bone using scanning electron microscopy: a pilot study. AB - BACKGROUND: Dental implants have become essential in reconstructive dentistry. Primary healing is determined by the design of their surface. The aim of this pilot study has been to investigate whether the morphology of the sandblasted and acid-etched (SLA((r)) ) surface remains unaffected after the insertion process into human bone. MATERIALS AND METHODS: Two edentulous-atrophied human jaw specimens were used. Six brand new Straumann Standard RN implants with an SLA((r)) surface and having a diameter of 3.3 mm and a length of 12 mm were inserted. Another two implants of the same type, but not inserted into bone, served as a reference. After explantation, the four implants were cleaned in an ultrasonic bath and two were left uncleaned. All eight implants were inspected by SEM for qualitative surface changes. RESULTS: All four implants showed relevant changes of the topography at the apical thread flanks. The non-cleaned implants showed an almost complete coverage of the surface by a honeycomb-like structure, consistent with bone residues. The reference implants showed no changes. DISCUSSION: The results indicate that, for the osseointegration of dental implants, subtractive modifications of implant surfaces are less important than the reestablishment of the destroyed TiO2 layer. Further studies of other implant surfaces are required to verify the present results. PMID- 25041179 TI - Usefulness of T(peak) -T(end) interval to distinguish arrhythmogenic right ventricular cardiomyopathy from idiopathic right ventricular outflow tract tachycardia. AB - BACKGROUND: The two predominant etiologies of right ventricular tachycardia (VT) are arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic VT arising from the right ventricular outflow tract (RVOT). Discrimination between these two entities is critical, as their prognoses and therapeutic options differ. The Tpeak -Tend (Tpe) interval reflects the transmural repolarization dispersion and its prolongation is associated with high mortality. METHODS: We compared the sinus rhythm electrocardiogram (ECG) of 43 patients (24 male, 43 +/- 16 years) with VT originating from right ventricle. Five patients under antiarrhythmic drug therapy were excluded. Tpe interval was measured in each precordial leads and compared among patients with ARVC and RVOT-VT. RESULTS: Twenty-five patients (16 male, 42 +/- 16 years) met the Task Force criteria for the diagnosis of ARVC, and 13 patients (seven male, 45 +/- 14 years) had idiopathic RVOT tachycardia. Patients with ARVC had significantly prolonged Tpe intervals in all precordial leads compared to patients with idiopathic RVOT VT (137.1 +/- 32.6 ms vs 93.8 +/- 16.9 ms; P < 0.001 in V1, 133.2 +/- 35.5 ms vs 104.7 +/- 16.9 ms; P = 0.01 in V2, 125.7 +/- 31.5 ms vs 99.1 +/- 19.6 ms; P = 0.09 in V3, 121.9 +/- 26.5 ms vs 92.3 +/- 19.7 ms; P = 0.001 in V4, 123.1 +/- 26.5 ms vs 99.5 +/- 20:1 ms; P = 0.04 in V5 and 126.9 +/- 32.2 ms vs 89 +/- 11.3 ms; P < 0.001 in V6, respectively). For the diagnosis of ARVC, Tpe cut-off value of 97 ms in V1 had 84% sensitivity and 62% specificity (area under curve = 0.880). CONCLUSION: In patients with VT of RV origin, the prolonged Tpe interval in sinus rhythm electrocardiogram supports the diagnosis of ARVC. PMID- 25041180 TI - Semi-xenotransplantation: the regenerative medicine-based approach to immunosuppression-free transplantation and to meet the organ demand. AB - Although xenografts have always held immeasurable potential as an inexhaustible source of donor organs, immunological barriers and physiological incompatibility have proved to be formidable obstacles to clinical utility. An exciting, new regenerative medicine-based approach termed "semi-xenotransplantation" (SX) seeks to overcome these obstacles by combining the availability and reproducibility of animal organs with the biocompatibility and functionality of human allografts. Compared to conventional xenotransplantation wherein the whole organ is animal derived, SX grafts are cleansed of their antigenic cellular compartment to produce whole-organ extracellular matrix scaffolds that retain their innate structure and vascular channels. These scaffolds are then repopulated with recipient or donor human stem cells to generate biocompatible semi-xenografts with the structure and function of native human organs. While numerous hurdles must be still overcome in order for SX to become a viable treatment option for end-stage organ failure, the immense potential of SX for meeting the urgent needs for a new source of organs and immunosuppression-free transplantation justifies the interest that the transplant community is committing to the field. PMID- 25041181 TI - Distinct characteristics of OxyR2, a new OxyR-type regulator, ensuring expression of Peroxiredoxin 2 detoxifying low levels of hydrogen peroxide in Vibrio vulnificus. AB - Two peroxiredoxins, Prx1 and Prx2, were previously identified in Vibrio vulnificus. Besides OxyR1, a homologue of Escherichia coli OxyR (EcOxyR), OxyR2 that shares low homology with EcOxyR was first identified in V. vulnificus. OxyR2 activated prx2 during aerobic growth, while OxyR1 activated prx1 only when exposed to exogenous H2O2. OxyR2 was oxidized to form a reversible C206 to C215 disulphide bond by sensing low levels of H2O2, which were insufficient to oxidize OxyR1, and only the oxidized OxyR2 activated prx2. OxyR25CA, in which all cysteine residues except for C206 and C215 were replaced with alanines, and its mutants, OxyR25CA-C206S and OxyR25CA-C215S, were constructed. OxyR25CA and OxyR25CA-C215S directly bound to a specific binding sequence centred at -56.5 from the prx2 transcription start site, albeit with different binding affinities. The binding sequence consisted of four ATCGnt elements spaced by a helical turn and aligned in the twofold dyad symmetry, suggesting that OxyR2 binds DNA as a tetramer. OxyR25CA-C206S also directly bound to DNA comprising more extended sequences, indicating that oxidized and reduced OxyR2 adopt different conformational states, leading to altered DNA contacts. The oxyR2 mutation reduced cytotoxicity and growth during infection, indicating that OxyR2 is essential for the pathogenesis of V. vulnificus. PMID- 25041182 TI - Effects of doxycycline on clinical, microbiological and immunological parameters in well-controlled diabetes type-2 patients with periodontal disease: a randomized, controlled clinical trial. AB - AIM: To evaluate the clinical, microbiological and immunological effects of systemic doxycycline as an adjunct to scaling and root planing (SRP) in chronic periodontitis patients with well-controlled type 2 diabetes. MATERIALS AND METHODS: Sixty-six patients compliant to oral hygiene (Hygiene Index <20%) allocated to either a test (systemic doxycycline for 21 days) or a control (placebo) group participated in the present randomized controlled trial (RCT). Clinical assessments were recorded at baseline, 3 and 6 months after therapy and included clinical attachment level (CAL), set as the primary outcome of the study, probing pocket depth (PPD), recession (RE) and bleeding on probing (BOP). At the same time points, counts of 15 subgingival species were evaluated by "checkerboard" DNA-DNA hybridization, gingival crevicular fluid samples were analysed for matrix metalloproteinase-8 (MMP-8) by ELISA and HbA1c levels were determined. Comparisons between and within groups were performed by non parametric tests (Mann-Whitney, Wilcoxon signed-ranks and z-test for proportions with Bonferroni corrections) at the 0.05 level. RESULTS: No major differences were noticed in clinical and microbiological parameters of periodontal disease or levels of MMP-8 between the two groups. CONCLUSIONS: Adjunctive systemic doxycycline does not seem to significantly enhance the effects of SRP in well controlled diabetes type 2 patients. PMID- 25041183 TI - Insight into yeast: A study model of lipid metabolism and terpenoid biosynthesis. AB - With the development of transcriptomics, metabolomics, proteomics, and mathematical modeling, yeast Saccharomyces cerevisiae is recently considered as a model studying strain by biologists who try to reveal the mystery of microorganic metabolism or develop heterologous pharmaceutical and economic products. Among S. cerevisiae metabolic research, lipid metabolism always attracts great interest because of its dominant role in cell physiology. Related researchers have developed multiple functions from cell membrane component such as adjustment to changing environment and impact on protein folding. Nowadays, many common human diseases such as diabetes mellitus, Alzheimer's disease, obesity, and atherosclerosis are related to lipid metabolism, which makes the study of lipids a desperate need. In addition to lipid metabolism, the study of the native mevalonic acid (MVA) pathway in S. cerevisiae has increased exponentially because of its huge potential to produce economically important products terpenoids. With the progress of technology in gene engineering and metabolic engineering, more and more biosynthetic pathways will be developed and put into industrial application. PMID- 25041184 TI - Red blood cells of sickle cell disease patients exhibit abnormally high abundance of N-methyl D-aspartate receptors mediating excessive calcium uptake. AB - Recently we showed that N-methyl D-aspartate receptors (NMDARs) are expressed in erythroid precursors (EPCs) and present in the circulating red blood cells (RBCs) of healthy humans, regulating intracellular Ca(2+) in these cells. This study focuses on investigating the possible role of NMDARs in abnormally high Ca(2+) permeability in the RBCs of patients with sickle cell disease (SCD). Protein levels of the NMDAR subunits in the EPCs of SCD patients did not differ from those in EPCs of healthy humans. However, the number and activity of the NMDARs in circulating SCD-RBCs was substantially up-regulated, being particularly high during haemolytic crises. The number of active NMDARs correlated negatively with haematocrit and haemoglobin levels in the blood of SCD patients. Calcium uptake via these non-selective cation channels was induced by RBC treatment with glycine, glutamate and homocysteine and was facilitated by de-oxygenation of SCD RBCs. Oxidative stress and RBC dehydration followed receptor stimulation and Ca(2+) uptake. Inhibition of the NMDARs with an antagonist memantine caused re hydration and largely prevented hypoxia-induced sickling. The EPCs of SCD patients showed higher tolerance to memantine than those of healthy subjects. Consequently, NMDARs in the RBCs of SCD patients appear to be an attractive target for pharmacological intervention. PMID- 25041186 TI - Two-year-old children but not domestic dogs understand communicative intentions without language, gestures, or gaze. AB - Infants can see someone pointing to one of two buckets and infer that the toy they are seeking is hidden inside. Great apes do not succeed in this task, but, surprisingly, domestic dogs do. However, whether children and dogs understand these communicative acts in the same way is not yet known. To test this possibility, an experimenter did not point, look, or extend any part of her body towards either bucket, but instead lifted and shook one via a centrally pulled rope. She did this either intentionally or accidentally, and did or did not address her act to the subject using ostensive cues. Young 2-year-old children but not dogs understood the experimenter's act in intentional conditions. While ostensive pulling of the rope made no difference to children's success, it actually hindered dogs' performance. We conclude that while human children may be capable of inferring communicative intent from a wide variety actions, so long as these actions are performed intentionally, dogs are likely to be less flexible in this respect. Their understanding of communicative intention may be more dependent upon bodily markers of communicative intent, including gaze, orientation, extended limbs, and vocalizations. This may be because humans have come under selective pressure to develop skills for communicating with absent interlocutors - where bodily co-presence is not possible. PMID- 25041185 TI - Celastrol protects ischaemic myocardium through a heat shock response with up regulation of haeme oxygenase-1. AB - BACKGROUND AND PURPOSE: Celastrol, a triterpene from plants, has been used in traditional oriental medicine to treat various diseases. Here, we investigated the cardioprotective effects of celastrol against ischaemia. EXPERIMENTAL APPROACH: Protective pathways induced by celastrol were investigated in hypoxic cultures of H9c2 rat cardiomyoblasts and in a rat model of myocardial infarction, assessed with echocardiographic and histological analysis. KEY RESULTS: In H9c2 cells, celastrol triggered reactive oxygen species (ROS) formation within minutes, induced nuclear translocation of the transcription factor heat shock factor 1 (HSF1) resulting in a heat shock response (HSR) leading to increased expression of heat shock proteins (HSPs). ROS scavenger N-acetylcysteine reduced expression of HSP70 and HSP32 (haeme oxygenase-1, HO-1). Celastrol improved H9c2 survival under hypoxic stress, and functional analysis revealed HSF1 and HO-1 as key effectors of the HSR, induced by celastrol, in promoting cytoprotection. In the rat ischaemic myocardium, celastrol treatment improved cardiac function and reduced adverse left ventricular remodelling at 14 days. Celastrol triggered expression of cardioprotective HO-1 and inhibited fibrosis and infarct size. In the peri-infarct area, celastrol reduced myofibroblast and macrophage infiltration, while attenuating up-regulation of TGF-beta and collagen genes. CONCLUSIONS AND IMPLICATIONS: Celastrol treatment induced an HSR through activation of HSF1 with up-regulation of HO-1 as the key effector, promoting cardiomyocyte survival, reduction of injury and adverse remodelling with preservation of cardiac function. Celastrol may represent a novel potent pharmacological cardioprotective agent mimicking ischaemic conditioning that could have a valuable impact in the treatment of myocardial infarction. PMID- 25041187 TI - Editorial comment to prevalence of lower urinary tract symptoms, overactive bladder and urinary incontinence in western Turkey: results of a population-based survey. PMID- 25041189 TI - Most individuals with either segmental or non-segmental vitiligo display evidence of bilateral cochlear dysfunction. AB - BACKGROUND: Vitiligo has been classified clinically into segmental vitiligo (SV) and nonsegmental vitiligo (NSV) and may also be associated with audiological abnormalities. OBJECTIVES: We examined cochlear function in ears of individuals with SV and NSV, including subjects with facial and nonfacial lesions, and in patients who have SV with unilateral facial involvement. METHODS: This study included 25 patients with SV and 28 patients with NSV. Fifteen age- and sex matched healthy individuals served as controls. Cochlear function was studied using the distortion product otoacoustic emissions (DPOAEs). Data were analysed using SPSS. RESULTS: Sixty-four ears (60%) of patients with vitiligo had cochlear dysfunction while the control group exhibited no abnormalities. On comparing the cochlear dysfunction of patients with SV with patients with NSV, no statistically significant difference was found. The ears on both sides, affected and unaffected by vitiligo, in patients with SV showed cochlear dysfunction with no statistically significant difference in DPOAE. To determine the effect of the lesion side on cochlear function, we compared DPOAE amplitude using Student's t test. The comparisons included NSV of the face vs. NSV on other areas, NSV of the face vs. SV of the face and SV of the face vs. SV of other areas. No statistically significant difference was found in these comparisons. CONCLUSIONS: Bilateral cochlear dysfunction is common in both NSV and SV and does not reflect the appearance of vitiligo in the skin. Our results underscore the important role of melanocytes and melanin in cochlear function, and suggest that the cochlear abnormalities in SV point to the presence of additional nonsegmental pathophysiological events underlying all forms of vitiligo. PMID- 25041188 TI - Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice. AB - BACKGROUND: The resolution of deep vein thrombosis requires an inflammatory response and mobilization of proteases, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), to degrade the thrombus and remodel the injured vein wall. Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor (serpin) with unique immunosuppressive and cell survival properties that was originally identified as an inhibitor of uPA. OBJECTIVE: To investigate the role of PAI-2 in venous thrombus formation and resolution. METHODS: Venous thrombus resolution was compared in wild-type C57BL/6, PAI-2(-/-) , and PAI-1(-/-) mice using the stasis model of deep vein thrombosis. Formed thrombi were harvested, thrombus weights were recorded, and tissue was analyzed for uPA and MMP activities, PAI-1 expression, and the nature of inflammatory cell infiltration. RESULTS: We found that the absence of PAI-2 enhanced venous thrombus resolution, while thrombus formation was unaffected. Enhanced venous thrombus resolution in PAI-2(-/-) mice was associated with increased uPA activity and reduced levels of PAI-1, with no significant effect on MMP-2 and -9 activities. PAI-1 deficiency resulted in an increase in thrombus resolution similar to PAI-2 deficiency, but additionally reduced venous thrombus formation and altered MMP activity. PAI-2-deficient thrombi had increased levels of the neutrophil chemoattractant CXCL2, which was associated with early enhanced neutrophil recruitment. CONCLUSIONS: These data identify PAI-2 as a novel regulator of venous thrombus resolution, which modulates several pathways involving both inflammatory and uPA activity mechanisms, distinct from PAI-1. Further examination of these pathways may lead to potential therapeutic prospects in accelerating thrombus resolution. PMID- 25041191 TI - Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy. AB - BACKGROUND AND PURPOSE: Subcutaneous immunoglobulin (SCIG) is superior to placebo treatment for maintenance of muscle strength during 12 weeks in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The present study evaluated whether SCIG preserves muscle strength for 1 year in an open-label follow-up study. METHODS: Seventeen responders to intravenous immunoglobulin (IVIG) who had participated in the previous study of SCIG versus placebo in CIDP were included. After one IVIG infusion 2 weeks prior to baseline, all continued on SCIG treatment at weekly equal dosage and were evaluated after 3, 6 and 12 months. Primary end-points were changes in muscle strength evaluated by isokinetic dynamometry in four affected muscle groups and a composite score of muscle performance and function tests, including Medical Research Council (MRC) score, grip strength, 40-m walking test (40-MWT) and nine-hole peg test (9-HPT). Secondary end-points were changes of each of the listed parameters at each time point as well as an overall disability sum score (ODSS). RESULTS: The dose of SCIG was significantly unaltered during the follow-up period. Overall the isokinetic dynamometry value increased by 7.2% (P = 0.033) and after 3, 6 and 12 months by 5.7%, 8.2% and 6.8% (ns). The overall composite score at all time intervals and for each interval remained unchanged. Amongst the secondary parameters the MRC score increased significantly by 1.7% (P = 0.007), whereas grip strength, 40-MWT, 9-HPT and ODSS remained unchanged. CONCLUSION: SCIG preserves muscle strength and functional ability in patients with CIDP who previously responded to IVIG. SCIG should be considered as an alternative in long term treatment of CIDP patients. PMID- 25041190 TI - Adolescent alcohol use: a reflection of national drinking patterns and policy? AB - AIMS: To analyse how adolescent drunkenness and frequency of drinking were associated with adult drinking patterns and alcohol control policies. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional survey data on 13- and 15-year-olds in 37 countries who participated in the Health Behaviour in School-Aged Children (HBSC) Study in 2010 (n = 144 788) were linked to national-level indicators on alcohol control policies and adult drinking patterns. MEASUREMENTS: Outcome measures were self-reported weekly drinking and life-time drunkenness (drunk once or more). Data were analysed using multi-level logistic regression models. FINDINGS: In the mutually adjusted models, adolescent drunkenness was associated significantly with high adult alcohol consumption [odds ratio (OR) = 3.15 among boys, 95% confidence interval (CI) = 2.13-4.64, OR girls = 2.44, CI = 1.57-3.80] and risky drinking patterns in the adult population (OR boys = 2.02, CI = 1.33 3.05, OR girls = 1.61, CI = 1.18-2.18). The level of abstainers in the adult population was also associated significantly with girls' drunkenness; a 10% increase in the number of abstainers in a country reduced the odds of drunkenness with 21% (OR = 0.79, CI = 0.68-0.90). Weekly drinking was associated significantly with weak restrictions on availability (OR boys = 2.82, CI = 1.74 4.54, OR girls = 2.00, CI = 1.15-3.46) and advertising (OR boys = 1.56, CI = 1.02 2.40, OR girls = 1.79, CI = 1.10-2.94). CONCLUSIONS: Comparing data cross nationally, high levels of adult alcohol consumption and limited alcohol control policies are associated with high levels of alcohol use among adolescents. PMID- 25041192 TI - Rhinovirus bronchiolitis: to be or not to be? PMID- 25041193 TI - Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis. AB - OBJECTIVE: To investigate transient receptor potential vanilloid 4 (TRPV4) expression in bladder afferents and study the effect of TRPV4 and TRPV1 antagonists, alone and in combination, in bladder hyperactivity and pain induced by cystitis. MATERIAL AND METHODS: TRPV4 expression in bladder afferents was analysed by immunohistochemistry in L6 dorsal root ganglia (DRG), labelled by fluorogold injected in the urinary bladder. TRPV4 and TRPV1 co-expression was also investigated in L6 DRG neurones of control rats and in rats with lipopolysaccharide (LPS)-induced cystitis. The effect of TRPV4 antagonist RN1734 and TRPV1 antagonist SB366791 on bladder hyperactivity and pain induced by cystitis was assessed by cystometry and visceral pain behaviour tests, respectively. RESULTS: TRPV4 is expressed in sensory neurones that innervate the urinary bladder. TRPV4-positive bladder afferents represent a different population than the TRPV1-expressing bladder afferents, as their co-localisation was minimal in control and inflamed rats. While low doses of RN1734 and SB366791 (176.7 ng/kg and 143.9 ng/kg, respectively) had no effect on bladder activity, the co-administration of the two totally reversed bladder hyperactivity induced by LPS. In these same doses, the antagonists partially reversed bladder pain behaviour induced by cystitis. CONCLUSIONS: TRPV4 and TRPV1 are present in different bladder afferent populations. The synergistic activity of antagonists for these receptors in very low doses may offer the opportunity to treat lower urinary tract symptoms while minimising the potential side-effects of each drug. PMID- 25041194 TI - Involvement of chlororespiration in chilling stress in the tropical species Spathiphyllum wallisii. AB - Spathiphyllum wallisii plants were used to study the effect of chilling stress under high illumination on photosynthesis and chlororespiration. Leaves showed different responses that depended on root temperature. When stem, but not root, was chilled, photosystem II (PSII) was strongly photoinhibited. However, when the whole plant was chilled, the maximal quantum yield of PSII decreased only slightly below the normal values and cyclic electron transport was stimulated. Changes were also observed in the chlororespiration enzymes and PGR5. In whole plants chilled under high illumination, the amounts of NADH dehydrogenase (NDH) complex and plastid terminal oxidase (PTOX) remained similar to control and increased when only stem was chilled. In contrast, the amount of PGR5 polypeptide was higher in plants when both root and stem were chilled than in plants in which only stem was chilled. The results indicated that the contribution of chlororespiration to regulating photosynthetic electron flow is not relevant when the whole plant is chilled under high light, and that another pathway, such as cyclic electron flow involving PGR5 polypeptide, may be more important. However, when PSII activity is strongly photoinhibited in plants in which only stem is chilled, chlororespiration, together with other routes of electron input to the electron transfer chain, is probably essential. PMID- 25041195 TI - Supporting economically disadvantaged tobacco users to help them stop: time to review priorities? PMID- 25041196 TI - Vice ratchets. PMID- 25041197 TI - New evidence on the tenuous state of evidence-based drug policy. PMID- 25041198 TI - Widening the debate on the drug policy ratchet: response to commentaries. PMID- 25041199 TI - Legislative strategies other than legalizing illicit opioids may help to reduce overdose fatalities. PMID- 25041200 TI - Commentary on Garbutt et al. (2014): Can we predict who benefits from naltrexone in the treatment of alcohol dependence? PMID- 25041201 TI - Commentary on Schwalbe et al. (2014): Two wishes for the future of motivational interviewing-workshops with fewer learning targets and sustainable coaching. PMID- 25041202 TI - Commentary on Degenhardt et al. (2014): Access to opioid substitution therapy in prison is not enough-the crucial role of post-release retention in preventing drug-related harms. PMID- 25041203 TI - Commentary on Degenhardt et al. (2014): Regional variation in the global burden of disease attributable to opioid dependence-where do the data come from and does population size matter? PMID- 25041204 TI - Response to Hser et al. (2014): The necessity for more and better data on the global epidemiology of opioid dependence. PMID- 25041205 TI - Commentary on Ort et al. (2014): What next to deliver on the promise of large scale sewage-based drug epidemiology? PMID- 25041206 TI - Inaccuracies in editorial by Babor & Miller. PMID- 25041207 TI - Response to Babor & Miller editorial 'McCarthyism, conflict of interest and Addiction's new transparency declaration procedures'. PMID- 25041208 TI - Reply to Conibear (2014). PMID- 25041211 TI - Shiitake dermatitis demonstrating Koebner phenomenon. PMID- 25041212 TI - Cervical assessment in women with hysteroscopic uterine septum resection: a retrospective cohort study. AB - OBJECTIVE: To estimate whether cervical length measured by transvaginal ultrasonography in women with a history of hysteroscopic uterine septum resection predicts spontaneous preterm birth <35 weeks' gestation. METHODS: This retrospective cohort study compared women who had undergone hysteroscopic metroplasty, and were subsequently pregnant with singleton gestations delivered January 2003 to December 2012, to a low-risk control group. Transvaginal ultrasonographic cervical lengths were measured 16-30 weeks' gestation. The primary outcome was spontaneous preterm birth <35 weeks' gestation and the primary exposure variable of interest was cervical length. RESULTS: Women with a uterine septum resected (N = 24) had a shorter cervical length (2.90 cm) than the low-risk control group (N = 141, 4.31 cm, p < 0.0001); and were more likely to have a cervical length <3.0 cm (41.7% versus 1.4%, p < 0.0001), <2.5 cm (33.3% versus 0%, p < 0.0001), <2.0 cm (16.7% versus 0%, p < 0.0001) and <1.5 cm (12.5% versus 0%, p = 0.003). Women with septum resected were more likely to receive corticosteroids (33.3% versus 11.3%, p = 0.010), but were not more likely to have a spontaneous preterm birth <35 weeks (4.2% versus 0.7%, p = 0.27). There were no differences noted in secondary outcomes including neonatal morbidity. CONCLUSION: Pregnant women with a history of a hysteroscopic uterine septum resection have shorter cervical lengths than low-risk controls but may not be at a higher risk of spontaneous preterm birth <35 weeks' gestation. Further research with a larger sample size is needed to evaluate this group of women to determine if transvaginal ultrasonographic cervical length assessment is of benefit. PMID- 25041213 TI - Rare case of transfusion-transmitted hepatitis E from the blood of a donor infected with the hepatitis E virus genotype 3 indigenous to Japan: Viral dynamics from onset to recovery. AB - AIM: The transfusion transmission of hepatitis E can occur even in non-endemic areas in the world as autochthonous hepatitis E has been increasingly reported in developed countries where the hepatitis E virus (HEV) is not prevalent. We investigated the post-transfusion transmission of hepatitis E in a patient by molecularly confirming its presence, and characterized the viral kinetics of HEV in this case. METHODS: A Japanese man underwent re-thoracotomy for hemostasis followed by platelet transfusion. After the transfusion, the blood donor was found to be HEV positive. The donated blood was re-examined and was found to contain HEV. Throughout the prospective follow up of the patient, we analyzed the viral kinetics, chronological anti-HEV antibody level changes and disease progression during the entire course of HEV infection from transfusion until the end of viremia. RESULTS: Sequence analysis of the strains isolated from both the donor and the patient who contracted acute hepatitis E showed an identical match for 326 nucleotides in open reading frame 1. Two strains belonged to HEV genotype 3 indigenous to Japan. CONCLUSION: To the best of our knowledge, this is the first detailed report on the entire natural course of hepatitis E from viral transmission, then clearance, to replication preceding liver injury caused by HEV genotype 3, which is responsible for autochthonous infection in developed countries. The findings provide valuable insights into the mechanism of the transfusion transmission of HEV and subsequent viral dynamics. PMID- 25041214 TI - Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England. AB - AIM: The aim of this study was to investigate whether children in England with narcolepsy who received the ASO3 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix) differed clinically from unvaccinated patients. METHOD: A retrospective review was conducted in children with narcolepsy diagnosed by sleep centres and paediatric neurologists in 16 English hospitals. The inclusion criteria were patient age 4 to 18 years, onset of narcolepsy after January 2008, and diagnosis by the time of the key data-gathering visit in 2011. Clinical data came from hospital notes and general practitioner questionnaires. An expert panel validated the diagnoses. RESULTS: Seventy-five patients with narcolepsy were identified (43 males, 32 females; mean age at onset 10y 4mo, range 3-18y). Of these patients, 11 received the Pandemrix vaccine before narcolepsy onset. On first presentation, there were more frequent reports of cataplexy, among other features, in vaccinated than in unvaccinated patients (82% vs 55%), but only excessive weight gain (55% vs 20%) was significantly more frequent (p=0.03). Facial hypotonia (p=0.03) and tongue protrusion (p=0.01) were eventually seen more frequently in vaccinated children. When considering patients diagnosed within a year of onset, vaccinated children were not diagnosed more rapidly than unvaccinated children. INTERPRETATION: Some symptoms and signs of narcolepsy were more frequently reported in Pandemrix-vaccinated patients. There was no evidence of the more rapid diagnosis in vaccinated patients that has been reported in Finland and Sweden. PMID- 25041215 TI - Digestive physiology of captive giant anteaters (Myrmecophaga tridactyla): determinants of faecal dry matter content. AB - Giant anteaters (Myrmecophaga tridactyla) are specialized insectivores and consume mainly ants and termites in the wild. In captivity, giant anteaters are either fed a complete diet, or a combination of a domestic carnivore diet with leaf eater pellets, or a traditional gruel-type diet. Soft faeces are a frequently encountered problem with this type of feeding. In the present study, we analysed diet and faeces composition, calculated digestibility and measured mean retention time on various diets in eight giant anteaters (total of n = 64 experiments). The results suggest that the digestive physiology of giant anteaters is similar to that of domestic dogs and cats in terms of nutrient digestibility and digesta retention. When testing correlations between faecal dry matter content and other variables, no relationship with dietary crude fibre content or mean digesta retention time could be detected. However, acid insoluble ash intake was significantly and positively correlated with faecal dry matter content. The amount of acid insoluble ash excreted with the faeces was higher than that ingested with the diet offered, indicating that the giant anteaters ingested soil from their enclosure of up to 93 g per day. This finding is consistent with observation of faeces of wild giant anteaters that contain soil or sand most likely due to indiscriminate feeding. It also corresponds to reports that indigestible materials such as peat, soil, chitin or cellulose contribute to a firmer faecal consistency in various carnivore species. Therefore, offering giant anteaters the opportunity to voluntarily ingest soil from their enclosure might be beneficial. PMID- 25041216 TI - S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents. AB - OBJECTIVE: To determine the potency ratio between S-ketamine and racemic ketamine as inductive agents for achieving tracheal intubation in dogs. STUDY DESIGN: Prospective, randomized, 'blinded', clinical trial conducted in two consecutive phases. ANIMALS: 112 client-owned dogs (ASA I or II). METHODS: All animals were premedicated with intramuscular acepromazine (0.02 mg kg(-1)) and methadone (0.2 mg kg(-1)). In phase 1, midazolam (0.2 mg kg(-1)) with either 3 mg kg(-1) of racemic ketamine (group K) or 1.5 mg kg(-1) of S-ketamine (group S) was administered IV, for induction of anaesthesia and intubation. Up to two additional doses of racemic (1.5 mg kg(-1)) or S-ketamine (0.75 mg kg(-1)) were administered if required. In phase 2, midazolam (0.2 mg kg(-1)) with 1 mg kg(-1) of either racemic ketamine (group K) or S-ketamine (group S) was injected and followed by a continuous infusion (1 mg kg minute(-1)) of each respective drug. Differences between groups were statistically analyzed via t-test, Fisher exact test and ANOVA for repeated measures. RESULTS: Demographics and quality and duration of premedication, induction and intubation were comparable among groups. During phase 1 it was possible to achieve tracheal intubation after a single dose in more dogs in group K (n = 25) than in group S (n = 16) (p = 0.046). A dose of 3 mg kg(-1) S-ketamine allowed tracheal intubation in the same number of dogs as 4.5 mg kg(-1) of racemic ketamine. The estimated potency ratio was 1.5:1. During phase 2, the total dose (mean +/- SD) of S-ketamine (4.02 +/-1.56 mg kg(-1)) and racemic ketamine (4.01 +/- 1.42) required for tracheal intubation was similar. CONCLUSION AND CLINICAL RELEVANCE: Racemic and S-ketamine provide a similar quality of anaesthetic induction and intubation. S-ketamine is not twice as potent as racemic ketamine and, if infused, the potency ratio is 1:1. PMID- 25041217 TI - Serum levels of matrix metalloproteinase-13 in patients with eosinophilic fasciitis. AB - Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family, has been implicated in the pathogenesis of connective tissue diseases characterized by extracellular matrix remodeling. Since serum MMP-13 levels reflect disease severity of systemic sclerosis and localized scleroderma, we evaluated the clinical significance of serum MMP-13 levels in eosinophilic fasciitis (EF). All the EF patients had serum MMP-13 levels lower than the mean - 2SD of healthy controls. Serum MMP-13 levels were also significantly decreased in EF patients compared with diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, and generalized morphea patients. Although serum MMP-13 levels did not reflect any clinical and serological features of EF, these results indicate that MMP-13 may be involved in the development of this disease. PMID- 25041218 TI - Transesophageal echocardiography as the sole guidance for occlusion of patent ductus arteriosus using a canine ductal occluder in dogs. AB - BACKGROUND: Transcatheter occlusion of patent ductus arteriosus (PDA) is usually performed by fluoroscopy alone or together with transesophageal echocardiography (TEE). Transthoracic echocardiography (TTE) guidance has been used for deployment of Amplatz Canine Ductal Occluder (ACDO), but sometimes is limited by suboptimal acoustic windows. Transesophageal echocardiography can overcome such issues and provides higher image resolution at the level of the great vessels. OBJECTIVES: To determine if TEE without fluoroscopy could be used to successfully perform ductal occlusion for the treatment of PDA in dogs. ANIMALS: Twenty client-owned dogs with PDA. METHODS: A prospective consecutive case series of PDA occlusion was performed using only TEE guidance. Dogs were positioned in right lateral recumbency and the TEE probe was positioned to visualize the descending aorta, PDA, and pulmonary artery. The guide wire, long introducer sheath, and ACDO were imaged by TEE to direct deployment. RESULTS: Ductal occlusion was performed successfully without need for fluoroscopy and without complications in 19 dogs. One dog required a second larger ACDO because of embolization of the first device 18 hours after positioning. CONCLUSIONS AND CLINICAL IMPORTANCE: We have demonstrated that TEE monitoring without concurrent fluoroscopy can guide each step of transcatheter ACDO embolization thereby providing an alternate method of visualization for this procedure. Use of TEE alone can reduce radiation exposure or is an option when fluoroscopy is not available, and, therefore, should be evaluated in a larger case series to better assess procedural failure rates. PMID- 25041219 TI - Changes in students' perceptions of their dental education environment. AB - OBJECTIVES: To examine the 'Expected' and 'Actual' educational environment experienced by a cohort of Bachelor of Dental Surgery (BDS) students at the University of Otago's Faculty of Dentistry using the Dundee Ready Educational Environment Measure (DREEM). METHODS: Cohort members were asked to complete five DREEM surveys over the four-year BDS programme. Student expectations at the beginning of their first year were assessed using a modified version of the DREEM questionnaire, while following (standard) DREEM questionnaires at the end of each professional year addressed students' 'Actual' perception of the educational environment. RESULTS: Sixty-six students (99%) completed at least one questionnaire. Overall, the BDS students' perceptions of their educational environment tended to be positive and students identified both perceived strengths and weaknesses in the BDS programme. However, more negative than positive shifts were reported between the 'Expected' and 'Actual' individual DREEM individual items, suggesting that BDS students initially expected more from their educational environment than they actually experienced. Individual DREEM outcomes undergoing negative and positive shifts differed over the years and varied in number. These may be explained, in part, by changes in the curriculum focus from year to year. CONCLUSION: The students' changing DREEM responses over time revealed anticipated and perceived strengths and weaknesses of the BDS curriculum, as well as shifts in students' perceptions in response to curricular changes. However, our findings highlight the potential usefulness for dental education of a measure for use that takes the unique aspects of the dental education environment into account. PMID- 25041221 TI - Getting the magnitude right. PMID- 25041220 TI - Repeated stereotactic ablative radiotherapy using CyberKnife for patients with hepatocellular carcinoma. AB - BACKGROUND AND AIM: This study aimed to evaluate the outcomes and toxicities of repeated stereotactic ablative radiotherapy (SABR) in hepatocellular carcinoma (HCC). METHODS: Fourteen HCC patients with local recurrence (18 lesions) after liver SABR received repeated radiotherapy with SABR using CyberKnife. No patients experienced radiation-induced liver disease after the first SABR course. The median first SABR dose was 41 Gy (range, 34-60 Gy); the median second SABR dose, 40 Gy (range, 25-50 Gy); and the median interval, 12.9 months. Local recurrence was divided into in-field recurrence and out-field recurrence. RESULTS: Objective responses were observed in 11 tumors (61.1%), including five tumors (27.8%) with complete responses. Intrahepatic out-field failure was the main cause of treatment failure (7 of 14 patients). In-field failure had developed in 1 of 18 tumors (5.6%), resulting in a 2-year in-field failure-free rate of 88.2%. The median time to progression was 14.0 months, with 1- and 2-year progression-free survival rates of 68.6% and 42.9%, respectively. One- and two-year overall survival rates were 76% and 59.1%, respectively. Of the 14 patients, one developed radiation-induced liver disease and three showed progression of the Child-Turcotte-Pugh class after the second SABR course. Other toxicities were generally mild and tolerable. CONCLUSION: Repeated SABR in selected HCC patients is feasible with acceptable toxicity. PMID- 25041222 TI - Prospective study of effects of endogenous estrogens on myocardial no-reflow risk in postmenopausal women with acute myocardial infarction. AB - The relationship between endogenous estrogens and cardiovascular disease in menopausal women remains poorly understood. Studies examining the relationship have yielded conflicting results. Therefore, we performed this study to prospectively assess the effects of endogenous estrogen on the risk of myocardial no-reflow in postmenopausal women with ST-elevation myocardial infarction (STEMI). Consecutive 100 postmenopausal women diagnosed with STEMI and who had undergone emergence percutaneous coronary intervention (PCI) were included in this study. Blood samples were obtained before PCI and assayed for endogenous sex hormones. Logistic regression models were developed with adjustment for confounders. Compared with normal-reflow group, the circulating levels of estrone, estradiol, sex hormone binding globulin (SHBG), and hypersensitive C reaction protein (Hs-CRP) were significantly higher in the no-reflow group (P < 0.05). In univariable logistic regression models, lesion length, reference luminal diameter, thrombus score >= 4, and the levels of estrone, estradiol, and SHBG were all found to be positively associated with the risk of no-reflow (P < 0.05). After adjusting for these factors, thrombus score >= 4 (OR = 4.994, CI 1.987-10.518; P = 0.035), SHBG (OR = 0.800, CI 0.341-0.983; P = 0.047), and estradiol levels (OR 4.091, CI 1.105-8.582; P = 0.046) continued to demonstrate strong positive associations with the risk of no-reflow. Our data showed that high circulating levels of endogenous estrogens have a positive and statistically significant relationship with no-reflow in postmenopausal women with STEMI. It has been suggested that estrogens may have a potential detrimental effect on myocardial no-reflow. However, our results need to be confirmed in a larger population. PMID- 25041223 TI - Heterogeneity of breast cancer clinical characteristics and outcome in US black women--effect of place of birth. AB - Breast cancer mortality in black women is disproportionately high; reasons for this phenomenon are still unclear. In addition to socioeconomic factors, the biology of the tumor may play a role. We analyzed 1,097 incident invasive breast cancer cases diagnosed between 2000 and 2010 in black US women from Long Island and Brooklyn. Thirty-five percent of women had an estrogen receptor (ER) negative tumor, 46% a progesterone receptor (PR) negative tumor. ER, PR negative tumors were diagnosed at an earlier age (55.8 versus 55.3 years), at a later stage (p = 0.06), were larger in size (p = 0.04), and more frequently treated with neo adjuvant chemotherapy (p = 0.06) than ER, PR positive tumors. Determinants of shorter survival were: ER, PR negativity (HR: 2.2, 95% CI: 1.4-3.4), age, and stage at diagnosis (HR: 2.0; 95% CI: 1.5-2.7). ER, PR negative breast cancer born outside of the US experienced a significantly worse survival than ER, PR negative women who were born in the US. ER, PR negative tumors in black women born outside the US, mainly in the Caribbean, are biologically more aggressive than the same size and age-matched tumors in black women born in the US. Our study suggests that environmental exposures in the country of origin may impact on host cancer interactions and cancer outcome. PMID- 25041224 TI - Evaluation of i-gel(TM) airway in children: a meta-analysis. AB - BACKGROUND: I-gel(TM) is a relatively newer addition in the pediatric anesthesia practice. Its comparison with the other laryngeal mask airway repor-ted a wide range of results. Randomized controlled trials where i-gel(TM) has been compared with other laryngeal masks (laryngeal mask airway ProSeal(TM) and laryngeal mask airway Classic(TM) ) in children for airway management device during general anesthesia has been included in this meta-analysis. METHODS: PubMed and Central Register of Clinical Trials of the Cochrane Collaboration for eligible controlled trials using following search words: 'i-gel', 'i-gel laryngeal mask airway', 'i gel children', 'i-gel paediatric' until February 15, 2014. A total nine prospective randomized controlled trials have been included in this meta analysis. RESULTS: Pooled analyses have found that i-gel(TM) provided significantly higher oropharyngeal leak pressure than laryngeal mask airway ProSeal(TM) [496 participants, mean difference 2.07 cm H2 O, 95% CI 0.52-3.62; P = 0.009] and a similar leak in comparison with laryngeal mask airway Classic(TM) [355 participants, mean difference 1.73 cm H2 O, 95% CI -0.04, 3.51 cm H2 O; P =0.06]. No difference was found in first insertion success rate and ease of insertion between i-gel(TM) , laryngeal mask airway ProSeal(TM) , and laryngeal mask airway Classic(TM) . Ease of gastric tube insertion is similar between i gel(TM) and laryngeal mask airway ProSeal(TM) . Reported complications are infrequent and similar in all three devices. CONCLUSION: We conclude that i gel(TM) is an effective alternative of the commonly used laryngeal mask airway ProSeal(TM) and laryngeal mask airway Classic(TM) in children for airway management during general anesthesia. PMID- 25041225 TI - Ribosomal protein S6 is hyperactivated and differentially phosphorylated in epidermal lesions of patients with psoriasis and atopic dermatitis. AB - BACKGROUND: The ribosomal protein S6 is part of the translation machinery and is activated by phosphorylation via the mammalian target of rapamycin pathway, which is activated in psoriatic skin. OBJECTIVES: To investigate which S6 sites are phosphorylated in psoriasis and atopic dermatitis (AD), and to study whether S6 phosphorylation is associated with inflammation and/or keratinocyte hyperproliferation. METHODS: Healthy skin and skin lesions of patients with psoriasis and AD were investigated by immunostaining using antibodies that stain proliferating cells, leucocytes and distinct phosphorylated sites of S6. RESULTS: All psoriasis and AD lesions revealed abnormal S6 phosphorylation in the epidermis. The extent of S6 phosphorylation was diverse, generally stronger in psoriasis and correlated, in both diseases, with inflammation. S6 showed differential phosphorylation in distinct epidermal layers, which was most pronounced in hyperproliferative regions. CONCLUSIONS: Differential S6 phosphorylation may have a role in abnormal keratinocyte proliferation/differentiation. PMID- 25041226 TI - Microcirculation of skeletal muscle adapts differently to a resistive exercise intervention with and without superimposed whole-body vibrations. AB - Whole-body vibration (WBV) training is commonly practiced and may enhance peripheral blood flow. Here, we investigated muscle morphology and acute microcirculatory responses before and after a 6-week resistive exercise training intervention without (RE) or with (RVE) simultaneous whole-body vibrations (20 Hz, 6 mm peak-to-peak amplitude) in 26 healthy men in a randomized, controlled parallel-design study. Total haemoglobin (tHb) and tissue oxygenation index (TOI) were measured in gastrocnemius muscle (GM) with near-infrared spectroscopy (NIRS). Whole-body oxygen consumption (VO2 ) was measured via spirometry, and skeletal muscle morphology was determined in soleus (SOL) muscle biopsies. Our data reveal that exercise-induced muscle deoxygenation both before and after 6 weeks training was similar in RE and RVE (P = 0.76), although VO2 was 20% higher in the RVE group (P < 0.001). The RVE group showed a 14%-point increase in reactive hyperaemia (P = 0.007) and a 27% increase in blood volume (P < 0.01) in GM after 6 weeks of training. The number of capillaries around fibres was increased by 15% after 6 weeks training in both groups (P < 0.001) with no specific effect of superimposed WBV (P = 0.61). Neither of the training regimens induced fibre hypertrophy in SOL. The present findings suggest an increased blood volume and vasodilator response in GM as an adaptation to long-term RVE, which was not observed after RE alone. We conclude that RVE training enhances vasodilation of small arterioles and possibly capillaries. This effect might be advantageous for muscle thermoregulation and the delivery of oxygen and nutrients to exercising muscle and removal of carbon dioxide and metabolites. PMID- 25041228 TI - Characteristics of the electrocardiogram in patients with continuous-flow left ventricular assist devices. AB - BACKGROUND: Electrocardiograms (ECGs) are routinely obtained in patients with advanced congestive heart failure (CHF) before and after surgical implantation with a left-ventricular assist device (LVAD). As the number of patients with CHF is increasing, it is necessary to characterize the changes present in the ECG of patients with LVADs. METHODS: ECGs of 43 patients pre- and postimplantation of a HeartMate II LVAD were compared to characterize the presence of an LVAD using the following six criteria (LVADS2 ): low limb-lead voltage, ventricular pacing, artifact (electrical), duration of the QRS > 120 milliseconds, ST-elevation in the lateral leads, and splintering of the QRS complex. Additionally, 50 ECGs of non-LVAD patients coded as "lateral myocardial infarction (MI)" and 50 ECGs coded as "ventricular pacing" were chosen at random and scored. Odds ratios were calculated using Fisher's exact test. Logistic regression models were built to predict the presence of an LVAD in all patients. RESULTS: Univariate analysis of the pre- and post-LVAD ECGs confirmed that all criteria except the "Duration of QRS > 120 milliseconds" characterized the ECG of a patient with an LVAD. Electrical artifact and low limb-lead voltage yielded the greatest association with an LVAD-ECG. CONCLUSIONS: The ECG of a patient with end-stage CHF significantly changes with LVAD implantation. The LVADS2 criteria provide a framework towards characterizing and establishing a new baseline of the ECG in a patient with a continuous-flow LVAD. PMID- 25041227 TI - Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. AB - In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3-6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7-11 weeks and everolimus exposure increased (6-10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean +/- SD: 79.8 +/- 17.7 mL/min/1.73 m2 vs. 61.5 +/- 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7-11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome. PMID- 25041229 TI - Endoscopic ultrasound as an adjunctive evaluation in patients with esophageal motor disorders subtyped by high-resolution manometry. AB - BACKGROUND: Esophageal motor disorders are a heterogeneous group of conditions identified by esophageal manometry that lead to esophageal dysfunction. The aim of this study was to assess the clinical utility of endoscopic ultrasound (EUS) in the further evaluation of patients with esophageal motor disorders categorized using the updated Chicago Classification. METHODS: We performed a retrospective, single center study of 62 patients with esophageal motor disorders categorized according to the Chicago Classification. All patients underwent standard radial endosonography to assess for extra-esophageal findings or alternative explanations for esophageal outflow obstruction. Secondary outcomes included esophageal wall thickness among the different patient subsets within the Chicago Classification. KEY RESULTS: EUS identified 9/62 (15%) clinically relevant findings that altered patient management and explained the etiology of esophageal outflow obstruction. We further identified substantial variability in esophageal wall thickness in a proportion of patients including some with a significantly thickened non-muscular layer. CONCLUSIONS & INFERENCES: EUS findings are clinically relevant in a significant number of patients with motor disorders and can alter clinical management. Variability in esophageal wall thickness of the muscularis propria and non-muscular layers identified by EUS may also explain the observed variability in response to standard therapies for achalasia. PMID- 25041230 TI - Entrustable professional activities for gastroenterology fellowship training. PMID- 25041231 TI - Societal economic benefits associated with an extended-release opioid with abuse deterrent technology in the United States. PMID- 25041232 TI - Cellular changes associated with the acclimation of the intertidal sea anemone Actinia tenebrosa to ultraviolet radiation. AB - To assess the relative importance of long- and short-term cellular defense mechanisms in seasonally UV-R-acclimated Actinia tenebrosa (Anthozoa, Actiniidae), individuals were exposed to summer doses of PAR, UV-A, UV-B and enhanced UV-B (20%) for a period of 4 days. Mycosporine-like amino acids (MAAs) and cyclobutane pyrimidine dimer (CPD) concentrations were quantified, while oxidative damage to lipids and proteins, and the activities or levels of the antioxidant enzymes SOD, CAT, GR, GPOX and total glutathione were determined. Our results show that summer UV-R-acclimated individuals had a higher UV-R tolerance, with no significant increases in CPDs levels, than winter-acclimated sea anemones possibly due to higher MAA concentrations. Summer-acclimated individuals showed increased lipid and protein oxidation and GPOX activity only when they were exposed to UV-B at 20% above ambient UV-R levels. In contrast, winter-acclimated sea anemones showed elevated levels of oxidative damage, GPOX and SOD activities after exposure to UV-A or UV-B at ambient and elevated levels. Thus, this study indicates that long-term UV-R acclimation mechanisms such as the accumulation of MAAs could be more important than short-term increases in antioxidant defenses with respect to reducing indirect UV-R damage in intertidal sea anemones. PMID- 25041233 TI - Progressive microcephaly is caused by compound-heterozygous mutations in QARS. AB - Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures Zhang et al. (2014) The American Journal of Human Genetics;94(4):547-558. PMID- 25041234 TI - Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease. AB - INTRODUCTION: Ranolazine reduces the Na-dependent calcium overload via inhibition of the late sodium current, improving diastolic tone and oxygen handling during myocardial ischemia. In patients with angina, evidence of myocardial ischemia, but no obstructive coronary artery disease (CAD), abnormal coronary autoregulation plays a key role. Transthoracic Doppler-derived coronary flow reserve (CFR) is an index of coronary arterial reactivity and decreases in both microvascular dysfunction and coronary artery stenosis. The aim of this study was to assess the effect of ranolazine on CFR in this group of patient. METHODS: Fifty-eight (39M, 19F) patients with angina and evidence of myocardial ischemia, but no obstructive CAD, were enrolled in a double-blind, placebo-controlled trial. Participants were assigned to ranolazine (29) or placebo (29) for 8 weeks (up to 500 mg twice a day). CFR was determined as the ratio of hyperemic, induced by intravenous dypiridamole administration, to baseline diastolic coronary flow velocity. CFR was assessed before and after 8-week therapy. RESULTS: CFR was successfully performed in all patients. There were no significant differences in baseline characteristics and CFR between ranolazine and placebo group. After 8 weeks CFR significantly increased in ranolazine group (2.54 +/- 0.44 vs. 1.91 +/- 0.31; P = 0.005) but not in placebo group (1.99 +/- 0.32 vs. 1.94 +/- 0.29; P = ns). No patient dropped out during 8 weeks therapy. Side effects were similar in both groups. CONCLUSIONS: Ranolazine is able to improve CFR in these patients. This is probably due to improvement in abnormal coronary autoregulation, both reducing baseline diastolic coronary flow velocity and increasing hyperemic diastolic coronary flow velocity. PMID- 25041235 TI - Therapeutic potential of Pirfenidone for treating equine corneal scarring. AB - OBJECTIVE: To evaluate the safety and efficacy of Pirfenidone (PFD) in the treatment of equine corneal fibrosis using an in vitro model. METHODS: Healthy donor equine corneas were collected and used to generate primary equine corneal fibroblasts (ECFs) by growing cultures in minimal essential medium supplemented with 10% fetal bovine serum. Equine corneal myofibroblasts (ECMs), used as a model of equine corneal fibrosis, were produced by growing ECF cultures in serum free medium containing transforming growth factor beta1 (1 ng/mL). Trypan blue viability assays and changes in ECF morphology were utilized to determine the optimal PFD dose for this in vitro model. Trypan blue viability, phase-contrast microscopy, and TUNEL assays were used to evaluate the cytotoxicity of PFD. Scratch and MTT assays were used to evaluate the effect of PFD on cellular migration and proliferation. Real-time PCR, immunoblot analysis, and immunocytochemistry were employed to determine the efficacy of PFD to inhibit ECM formation in vitro. RESULTS: Topical PFD application at 200 MUg/mL successfully decreased alphaSMA expression when compared to the TGFbeta1 only treatment group (P < 0.01). PFD application <= 200 MUg/mL did not affect ECF phenotype or cellular viability and did not result in significant cytotoxicity. CONCLUSIONS: Pirfenidone safely and effectively inhibits TGFbeta1-induced equine corneal fibrosis in vitro. In vivo studies are warranted. PMID- 25041236 TI - Three missense mutations found in the KEL gene lead to K(mod) or K0 red blood cell phenotypes. AB - BACKGROUND: The KEL gene is highly polymorphic. It presents two major alleles, KEL1(K) and KEL2(k), but a variety of mutations give rise to weakened (K(mod) phenotype) or lack (K0 phenotype) of Kell antigen expression. Recently, the use of advanced DNA-based techniques has greatly increased our understanding of the Kell blood group system. STUDY DESIGN AND METHODS: Three blood samples that had shown discordant results between the serologic and molecular typing for k were investigated by DNA sequencing. Two of these samples were also subjected to studies of adsorption and elution. RESULTS: After sequencing the whole KEL gene, we found three new missense mutations: c.455A>G (p.Tyr152Cys) at Exon 5, c.2111A>C (p.Pro704His) at Exon 19, and c.1726G>C (p.Gly576Arg) at Exon 16. So far, no known clinical implications are associated with these mutations. Further investigation by adsorption and elution methods has defined that c.455A>G and c.1726G>C resulted in K0 phenotype, while c.2111A>C encoded a K(mod) phenotype. CONCLUSION: Molecular investigation is an important complement to routine serologic analyses of Kell antigens. Discrepancies between genotype and phenotype may reveal the presence of K(mod) or K0 phenotypes. Our description of three new KEL alleles suggests a role for a wider diagnostic approach to typing of the Kell system. PMID- 25041238 TI - Chlorine-35 solid-state NMR spectroscopy as an indirect probe of germanium oxidation state and coordination environment in germanium chlorides. AB - Due to the prevalence of Ge-Cl bonds in germanium chemistry and the inherent challenges of germanium-73 NMR spectroscopy, chlorine-35 NMR spectroscopy was investigated as an indirect method of characterization for these ubiquitous and useful compounds. Chlorine-35 NMR parameters were correlated with structural metrics as well as the oxidation state of germanium. PMID- 25041239 TI - Nucleic acid sensing and beyond: virtues and vices of high-mobility group box 1. AB - High-mobility group box 1 (HMGB1) was first described as an architectural chromatin-binding protein. Today, a wealth of evidence indicates that this protein is very versatile and serves an amazing assortment of roles in the nucleus, cytoplasm and extracellular milieu. As a result, HMGB1 is fast becoming recognized as a key regulator of protective and pathological immune responses. Whilst acknowledging the many functions of HMGB1 and its family members, we focus this review on their role as broad effectors of immune responses mediated by nucleic acids. In addition, we touch upon the recent progress in determining the in vivo role of HMGB1 as revealed by the study of mice conditionally null for the Hmgb1 gene. PMID- 25041240 TI - Endocannabinoid modulation by FAAH and monoacylglycerol lipase within the analgesic circuitry of the periaqueductal grey. AB - BACKGROUND AND PURPOSE: Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids and the inhibitors of their degradation are largely unknown within this pain-modulating region. EXPERIMENTAL APPROACH: In vitro electrophysiological recordings were conducted from PAG neurons in rat midbrain slices. The effects of the major endocannabinoids and their degradation inhibitors on inhibitory GABAergic synaptic transmission were examined. KEY RESULTS: Exogenous application of the endocannabinoid, anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), produced a reduction in inhibitory GABAergic transmission in PAG neurons. This AEA-induced suppression of inhibition was enhanced by the fatty acid amide hydrolase (FAAH) inhibitor, URB597, whereas a 2 AG-induced suppression of inhibition was unmasked by the monoacylglycerol lipase (MGL) inhibitor, JZL184. In addition, application of the CB1 receptor antagonist, AM251, facilitated the basal GABAergic transmission in the presence of URB597 and JZL184, which was further enhanced by the dual FAAH/MGL inhibitor, JZL195. CONCLUSIONS AND IMPLICATIONS: Our results indicate that AEA and 2-AG act via disinhibition within the PAG, a cellular action consistent with analgesia. These actions of AEA and 2-AG are tightly regulated by their respective degradative enzymes, FAAH and MGL. Furthermore, individual or combined inhibition of FAAH and/or MGL enhanced tonic disinhibition within the PAG. Therefore, the current findings support the therapeutic potential of FAAH and MGL inhibitors as a novel pharmacotherapy for pain. PMID- 25041241 TI - Is there an association between root architecture and mycorrhizal growth response? AB - The symbiosis between arbuscular mycorrhizal (AM) fungi and plants is evolutionarily widespread. The response of plant growth to inoculation by these fungi (mycorrhizal growth response; MGR) is highly variable, ranging from positive to negative. Some of this variation is hypothesized to be associated with root structure and function. Specifically, species with a coarse root architecture, and thus a limited intrinsic capacity to absorb soil nutrients, are expected to derive the greatest growth benefit from inoculation with AM fungi. To test this hypothesis, previously published literature and phylogenetic information were combined in a meta-analysis to examine the magnitude and direction of relationships among several root architectural traits and MGR. Published studies differed in the magnitude and direction of relationships between root architecture and MGR. However, when combined, the overall relationship between MGR and allocation to roots, root diameter, root hair length and root hair density did not differ significantly from zero. These findings indicate that possessing coarse roots is not necessarily a predictor of plant growth response to AM fungal colonization. Root architecture is therefore unlikely to limit the evolution of variation in MGR. PMID- 25041242 TI - Contribution of noncommunicable diseases to medical admissions of elderly adults in Africa: a prospective, cross-sectional study in Nigeria, Sudan, and Tanzania. AB - OBJECTIVES: To describe the nature of geriatric medical admissions to teaching hospitals in three countries in Africa (Nigeria, Sudan, Tanzania) and compare them with data from the United Kingdom. DESIGN: Cross-sectional cohort study. SETTING: Federal Medical Centre, Idi-Aba, Abeokuta, Nigeria; Soba University Hospital, Khartoum, Sudan; Kilimanjaro Christian Medical Centre, Moshi, Tanzania; and North Tyneside General Hospital, North Shields, United Kingdom. PARTICIPANTS: All people aged 60 and older urgently medically admitted from March 1 to August 31, 2012. MEASUREMENTS: Data were collected regarding age, sex, date of admission, length of stay, diagnoses, medication, date of discharge or death, and discharge destination. RESULTS: In Africa, noncommunicable diseases (NCDs) accounted for 81.0% (n=708) of admissions (n=874), and tuberculosis, malaria, and the human immunodeficiency virus and acquired immunodeficiency syndrome accounted for 4.6% (n=40). Cerebrovascular accident (n=224, 25.6%) was the most common reason for admission, followed by cardiac or circulatory dysfunction (n=150, 17.2%). Rates of hypertension were remarkably similar in the United Kingdom (45.8%) and Africa (40.2%). CONCLUSIONS: In the elderly population, the predicted increased burden of NCDs on health services in Africa appears to have occurred. Greater awareness and some reallocation of resources toward NCDs may be required if the burden of such diseases is to be reduced. PMID- 25041243 TI - The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta analysis of 16,786 subjects. AB - OBJECTIVES: The aim of this study was to evaluate the association of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism with bipolar disorder in (i) a meta-analysis and (ii) a case-control study in a Mexican population. We also investigated the possible association of this polymorphism with clinical features. METHODS: We performed a keyword search of the PubMed and Web of Science databases. A total of 22 studies that have investigated the association of Val66Met (rs6265) with bipolar disorder were selected for inclusion and combined with random effects meta-analysis, using allelic, additive, dominant, and recessive models. Finally, the single nucleotide polymorphism (rs6265) Val66Met in the BDNF gene was genotyped and compared between 139 patients with bipolar disorder and 141 healthy volunteers in a Mexican population. RESULTS: The pooled results from the meta-analysis (9,349 cases and 7,437 controls) did not show a significant association in any of the models. The same results were obtained in our case-control study when analyzing the distribution of the genotypic frequencies of the Val66Met polymorphism in patients with bipolar disorder. However, when we analyzed the association between rs6265 and lifetime history of suicidal behavior, we found an association between genotype Val-Val and suicide attempt (p = 0.02). CONCLUSIONS: Although the present study has some limitations, the results indicate a lack of association between the Val66Met polymorphism and bipolar disorder. However, in our case-control study in a Mexican population, the Val66Met polymorphism was associated with suicidal behavior in patients with bipolar disorder. Nevertheless, it is important to consider potential interactions of the BDNF gene, the environment, and different inheritance patterns, when carrying out future genetic studies with larger samples. PMID- 25041244 TI - Adherence to UK national guidance for discharge information: an audit in primary care. AB - AIMS: Poor communication of clinical information between healthcare settings is associated with patient harm. In 2008, the UK National Prescribing Centre (NPC) issued guidance regarding the minimum information to be communicated upon hospital discharge. This study evaluates the extent of adherence to this guidance and identifies predictors of adherence. METHODS: This was an audit of discharge summaries received by medical practices in one UK primary care trust of patients hospitalized for 24 h or longer. Each discharge summary was scored against the applicable NPC criteria which were organized into: 'patient, admission and discharge', 'medicine' and 'therapy change' information. RESULTS: Of 3444 discharge summaries audited, 2421 (70.3%) were from two teaching hospitals and 906 (26.3%) from three district hospitals. Unplanned admissions accounted for 2168 (63.0%) of the audit sample and 74.6% (2570) of discharge summaries were electronic. Mean (95% CI) adherence to the total NPC minimum dataset was 71.7% [70.2, 73.2]. Adherence to patient, admission and discharge information was 77.3% (95% CI 77.0, 77.7), 67.2% (95% CI 66.3, 68.2) for medicine information and 48.9% (95% CI 47.5, 50.3) for therapy change information. Allergy status, co morbidities, medication history and rationale for therapy change were the most frequent omissions. Predictors of adherence included quality of the discharge template, electronic discharge summaries and smaller numbers of prescribed medicines. CONCLUSIONS: Despite clear guidance regarding the content of discharge information, omissions are frequent. Adherence to the NPC minimum dataset might be improved by using comprehensive electronic discharge templates and implementation of effective medicines reconciliation at both sides of the health interface. PMID- 25041245 TI - Regulatory gene networks that shape the development of adaptive phenotypic plasticity in a cichlid fish. AB - Phenotypic plasticity is the ability of organisms with a given genotype to develop different phenotypes according to environmental stimuli, resulting in individuals that are better adapted to local conditions. In spite of their ecological importance, the developmental regulatory networks underlying plastic phenotypes often remain uncharacterized. We examined the regulatory basis of diet induced plasticity in the lower pharyngeal jaw (LPJ) of the cichlid fish Astatoreochromis alluaudi, a model species in the study of adaptive plasticity. Through raising juvenile A. alluaudi on either a hard or soft diet (hard-shelled or pulverized snails) for between 1 and 8 months, we gained insight into the temporal regulation of 19 previously identified candidate genes during the early stages of plasticity development. Plasticity in LPJ morphology was first detected between 3 and 5 months of diet treatment. The candidate genes, belonging to various functional categories, displayed dynamic expression patterns that consistently preceded the onset of morphological divergence and putatively contribute to the initiation of the plastic phenotypes. Within functional categories, we observed striking co-expression, and transcription factor binding site analysis was used to examine the prospective basis of their coregulation. We propose a regulatory network of LPJ plasticity in cichlids, presenting evidence for regulatory crosstalk between bone and muscle tissues, which putatively facilitates the development of this highly integrated trait. Through incorporating a developmental time-course into a phenotypic plasticity study, we have identified an interconnected, environmentally responsive regulatory network that shapes the development of plasticity in a key innovation of East African cichlids. PMID- 25041246 TI - Residents with mild cognitive decline and family members report health students 'enhance capacity of care' and bring 'a new breath of life' in two aged care facilities in Tasmania. AB - BACKGROUND: Care provided by student doctors and nurses is well received by patients in hospital and primary care settings. Whether the same is true for aged care residents of nursing homes with mild cognitive decline and their family members is unknown. OBJECTIVE: To investigate the perspectives of aged care residents with mild cognitive decline and their family members on interdisciplinary student placements in two residential aged care facilities (RACF) in Tasmania. DESIGN, SETTING AND PARTICIPANTS: A mixed methods design was employed with both qualitative and quantitative data collected. All participants were interviewed and completed a questionnaire on residents' quality of life, during or after a period of student placements in each facility (October November, 2012). Qualitative data were coded for themes following a grounded theory approach, and quantitative data were analysed using SPSS. RESULTS: Twenty one participants (13 residents and 8 family members) were recruited. Four themes were identified from the qualitative data and included (i) increased social interaction and facility vibrancy; (ii) community service and personal development, (iii) vulnerability and sensitivity (learning to care) and (iv) increased capacity and the confidence of enhanced care. Residents' quality of life was reported to be mostly good in the presence of the students, despite their high care needs. CONCLUSION: Residents with mild cognitive decline and their family members perceive a wide array of benefits of student provided care in RACFs including increased social interaction. Future quantitative research should focus on whether changes in care occur for residents as a result of student involvement. PMID- 25041247 TI - 'Planning ahead' among community-dwelling older people from culturally and linguistically diverse background: a cross-sectional survey. AB - AIMS AND OBJECTIVES: To explore preparedness of end-of-life care planning among community-dwelling older persons of culturally and linguistically diverse background. BACKGROUND: To improve end-of-life care through advance care planning, the key concept 'Planning ahead' has been promoted in Australia. However, since the introduction of the model in 2008, it is not known whether 'Planning Ahead' practice by older people from culturally and linguistically diverse backgrounds has improved. DESIGN: A cross-sectional survey. METHODS: A total of 453 community older adults (65+) who attended 17 day care centres in a region were invited to participate in the study. A total of 229 people completed the survey with a response rate of 50.5%. The questions relevant to this study include: (1) awareness of enduring guardian, advance care directive and advance care planning, (2) the preference for substitute decision-makers and (3) the challenges experienced with advance care planning. RESULTS: Awareness of advance care planning was low, and completion of advance care directive was very low. 37.5% of Anglo Celtic group had an enduring guardian, compared with 15.5, 24.1 and 13.3% from Mediterranean, Eastern European and Asia/Pacific group, respectively. Children were the most preferred substitute decision-makers more for Asia/Pacific group than Anglo Celtic, Mediterranean and Eastern Europeans. The various difficulties experienced included being time-consuming, difficult to understand terms and forms, and do not know how to do it. CONCLUSION: Regardless of cultural and ethnic backgrounds, a low level of 'Planning ahead' practices was apparent because of a lack of understanding of the concept, the forms and the processes involved. The gap identified between the existing legal/ethical frameworks and the preferences of older people as substitute decision-makers adds new knowledge for further discussion. RELEVANCE TO CLINICAL PRACTICE: Nursing professionals are provided with an opportunity to improve their practice to meet the needs of older persons and their families in planning ahead for future treatment options. PMID- 25041248 TI - The Ephrin receptor EphA4 restricts axonal sprouting and enhances branching in the injured mouse optic nerve. AB - The lack of axonal regeneration in the adult central nervous system is in part attributable to the presence of inhibitory molecules present in the environment of injured axons such as the myelin-associated proteins Nogo-A and MAG and the repulsive guidance molecules Ephrins, Netrins and Semaphorins. In the present study, we hypothesized that EphA4 and one of its potential binding partners EphrinA3 may participate in the inhibition of adult axon regeneration in the model of adult mouse optic nerve injury. Axonal regeneration was analysed in three dimensions after tissue clearing of EphA4 knockout (KO), EphrinA3 KO and wild-type (WT) optic nerves. By immunohistochemistry, EphA4 was highly expressed in Muller glia endfeet in the retina and in astrocytes in the retina and the optic nerve, while EphrinA3 was present in retinal ganglion cells and oligodendrocytes. Optic nerve crush did not cause expression changes. Significantly more axons grew in the crushed optic nerve of EphA4 KO mice than in WT or EphrinA3 KO animals. Single axon analysis revealed that EphA4 KO axons were less prone to form aberrant branching than axons in the other mouse groups. The expression of growth-associated proteins Sprr1a and Gap-43 did not vary between EphA4 KO and WT retinae. However, glial fibrillary acidic protein-expressing astrocytes were withdrawn from the perilesional area in EphA4 KO, suggesting that gliosis down-regulation may locally contribute to improve axonal growth at the injury site. In summary, our three-dimensional analysis of injured mouse optic nerves reveals beneficial effects of EphA4 ablation on the intensity and the pattern of optic nerve axon regeneration. PMID- 25041250 TI - Interpregnancy interval and gestation at the next birth--is there a racial difference? PMID- 25041252 TI - Clinical and Radiographic Evaluation of Marginal Bone Changes around Platform Switching Implants Placed in Crestal or Subcrestal Positions: A Randomized Controlled Clinical Trial. AB - BACKGROUND: It has been reported in many articles that marginal bone resorptions are prevented by platform-switching design. However, what occurs when these implants are placed in the apical position is not completely known. PURPOSE: This report describes a randomized controlled clinical trial study that aims to test the hypothesis that less resorption will occur when platform-switching implants are placed 1 mm below bone level. MATERIALS AND METHODS: A total of 56 randomly selected implants were inserted bilaterally, either 1 mm below bone level (test group, 28 implants) or at bone level (control group, 28 implants) of the patients' posterior regions. Marginal bone resorptions were examined through periapical radiographies taken with the parallel technique at the time of crown cementation and the third, sixth, 12th, and 36th months after prosthetic loading. The modified plaque index, gingival index, bleeding on probing, and probing depths were used for follow-up periodontal care of the implants. RESULTS: After 3 years, the mean radiographic vertical bone loss in the control group was significantly lower than in the test group (0.56 +/- 0.35 mm and 1.21 +/- 1.05 mm, respectively) (p < .01). In terms of periodontal indexes, there were no statistically significant differences between the two groups (p > .05). No peri implantitis or peri-implant mucositis was observed around the test or control implants. CONCLUSIONS: More marginal bone resorptions occurred after the third year of loading in implants placed 1 mm below bone level. However, the resorptions did not reach the implants thread. In the control group, the first bone implant contact was placed under the level of the first threads. Therefore, the present randomized clinical trial confirmed the hypothesis that placing platform-switching implants 1 mm below bone level reduced marginal bone loss. It can be noted that to reduce resorption, platform-switching implants should be placed below bone level. PMID- 25041251 TI - Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling. AB - This study was designed to determine whether treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Wild-type and GTP cyclohydrolase I (GTPCH-I)-deficient hph1 mice were administered EPO (1000 U/kg/day, s.c., 3 days). Cerebral microvessels of hph1 mice demonstrated reduced tetrahydrobiopterin (BH4) bioavailability, increased production of superoxide anions and impaired endothelial NO signaling. Treatment of hph1 mice with EPO attenuated the levels of 7,8-dihydrobiopterin, the oxidized product of BH4, and significantly increased the ratio of BH4 to 7,8-dihydrobiopterin. Moreover, EPO decreased the levels of superoxide anions and increased NO bioavailability in cerebral microvessels of hph1 mice. Attenuated oxidation of BH4 and inhibition of endothelial NO synthase uncoupling were explained by the increased expression of antioxidant proteins, manganese superoxide dismutase, and catalase. The protective effects of EPO observed in cerebral microvessels of hph1 mice were also observed in GTPCH-I siRNA-treated human brain microvascular endothelial cells exposed to EPO (1 U/mL or 10 U/mL; 3 days). Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of BH4 and endothelial NO in the cerebral microvascular endothelium. We demonstrate that treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of tetrahydrobiopterin (BH4) and endothelial nitric oxide. PMID- 25041253 TI - Headache and spontaneous glabellar ecchymosis: more than a self-injury behavior? PMID- 25041254 TI - Measurement of thirst in chronic heart failure- a review. AB - Abstract Background: Thirst is a bothersome symptom of chronic heart failure (CHF) which impacts adversely on quality of life. Despite this, limited work has been done to investigate thirst as a symptom or to develop reliable and valid measures of thirst in CHF. The purpose of this manuscript is to establish which tools have been used in research to measure thirst in CHF. Methods: Medline, PubMed, CINAHL, and Scopus were searched using following key words thirst, heart failure, measure, scale, randomised controlled trials and multicentre studies. Results: The search discovered 37 studies of which 6 studies met the inclusion criteria. One study was a research abstract and five were full- text studies. To date, there are only three measurement tools utilised in studies examining thirst in CHF patients (Visual Analogue Scale, Numeric Rating Scale and Thirst Distress Scale). Conclusion: Thirst in CHF is measured in a non- systematic way. In recent studies, the VAS has been used to measure thirst intensity. While this measurement tool is very easy and quick to administer, using a uni-dimensional tool in conjunction with a multi-dimensional tool may be beneficial to capture all dimensions of thirst. In order to manage thirst efficiently, consistent measurement of thirst in CHF is vital. PMID- 25041255 TI - Novel gene identified in an exome-wide association study of tanning dependence. AB - Growing evidence suggests that some individuals may exhibit symptoms of dependence to ultraviolet light, a known carcinogen, in the context of tanning. Genetic associations with tanning dependence (TD) have not yet been explored. We conducted an exome-wide association study in 79 individuals who exhibited symptoms of TD and 213 individuals with volitional exposure to ultraviolet light, but who were not TD based on three TD scales. A total of 300 000 mostly exomic single nucleotide polymorphisms primarily in coding regions were assessed using an Affymetrix Axiom array. We performed a gene burden test with Bonferroni correction for the number of genes examined (P < 0.05/14 904 = 3.36 * 10(-6) ). One gene, patched domain containing 2 (PTCHD2), yielded a statistically significant P-value of 2.5 * 10(-6) (OR = 0.27) with fewer individuals classified as TD having a minor allele at this locus. These results require replication, but are the first to support a specific genetic association with TD. PMID- 25041256 TI - The British Nursing Index and CINAHL: a comparison of journal title coverage and the implications for information professionals. AB - OBJECTIVES: This paper compares the journal coverage of the British Nursing Index (BNI) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). The main objectives are to assess whether BNI is a useful source of UK publications and to consider the implications for information professionals. METHODS: Lists of the journals indexed in BNI and CINAHL, CINAHL Plus and CINAHL Complete were compared. The date coverage and article entry date of a selection of UK nursing journals were also compared. RESULTS: One hundred and fifty-nine journals are uniquely indexed in BNI compared with the basic version of CINAHL. Eighty-one journals are uniquely indexed in BNI compared with all versions of CINAHL. Fifty-one of these journals are UK publications. Most of the selected UK nursing journals have earlier start and entry dates in CINAHL than BNI. CONCLUSION: BNI is smaller than CINAHL, and BNI indexes a relatively small number of unique journals. An information professional with access to CINAHL Plus or CINAHL Complete could reasonably not search BNI for a nursing topic, particularly if the topic is not UK specific. UK nursing research is more likely to benefit from using BNI, although the acquisition of BNI by ProQuest could impact this finding. PMID- 25041257 TI - Risk factors of symptomatic NSAID-induced small intestinal injury and diaphragm disease. AB - BACKGROUND: The aetiology for nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal injuries has not been well characterised. AIM: To determine the risk factors of symptomatic NSAID-induced small intestinal injuries, including diaphragm disease. METHODS: Of the 1262 symptomatic patients who underwent videocapsule endoscopy and/or double-balloon enteroscopy, 156 consecutive patients were verified as having taken NSAIDs. Their CYP2C9*2, *3 and *13 single nucleotide polymorphisms (SNPs) were determined by allelic discrimination with Taqman 5'-nuclease assays. RESULTS: Of the 156 NSAIDs users, 31 patients (20%) were diagnosed with NSAID-induced small intestinal injury. Multivariate analysis indicated that the presence of comorbidities and the use of oxicams (meloxicam, ampiroxicam and lornoxicam) or diclofenac were associated with an increased risk of NSAID-induced small intestinal injury (adjusted OR: 2.97, 95% CI: 1.05-8.41, P = 0.041 and adjusted OR: 7.05, 95% CI: 2.04-24.40, P = 0.002, respectively). The combination of aspirin and non-aspirin NSAID was more damaging than aspirin alone. Age, sex, concomitant use of proton pump inhibitors, indications for NSAIDs use, duration of NSAIDs use and CYP2C9*2, *3 and *13SNPs were unrelated. The use of meloxicam and CYP2C9*3SNPs were significantly associated with an increased risk for diaphragm disease (adjusted OR: 183.75, 95% CI: 21.34-1582.38; P < 0.0001 and adjusted OR: 12.94, 95% CI: 1.55-108.36, P = 0.018, respectively). CONCLUSION: The use of specific NSAIDs and the factors interfering with NSAIDs metabolism might associate with small intestinal injury, especially with diaphragm disease. PMID- 25041258 TI - Histomorphometric study of the goat stomach during prenatal development. AB - The aim of this study was to perform a morphometric analysis of the different structural tissue layers of the goat stomach to study their prenatal growth from mathematical models fitted to these morphometric data. A total of 90 embryos and fetuses were used, from the early stages of prenatal life until birth. The growth rate of the gastric wall was slower than that of body length; rumen was the stomach compartment displaying slowest growth. In the three non-glandular compartments, the epithelial layer grew faster than the gastric wall itself, while the growth rate of the abomasal epithelium declined in the early stages of development. A decline in growth rate was also observed for the lamina propria and submucosa in rumen and reticulum from the early embryonic stages, whereas in omasum and abomasum these layers continued to grow as gestation progressed. The tunica muscularis displayed consistent growth in all compartments, growing faster than the gastric wall. Serosa thickness increased as gestation progressed, displaying a decline in growth-rate only in the omasum. In conclusion, the dynamics of gastric wall growth were governed by the growth rate of each of the component tissue layers. PMID- 25041259 TI - Morphology of three species of Amphileptus (Protozoa, Ciliophora, Pleurostomatida) from the South China Sea, with note on phylogeny of A. dragescoi sp. n. AB - Two new and one problematic species of pleurostomatids, Amphileptus dragescoi sp. n., A. wilberti sp. n., and A. marinus from coastal areas of the South China Sea, are described based on observations of live and protargol-impregnated specimens. Amphileptus dragescoi is different from its congeners by the presence of an apical group of extrusomes and the possession of 12-15 right and five left somatic kineties, two macronuclear nodules, and a single terminally positioned contractile vacuole. Amphileptus wilberti is diagnosed by oval or pyriform body, 15-19 right and seven or eight left somatic kineties, extrusomes arranged only in anterior portion of oral slit, usually three ventrally located contractile vacuoles, and two macronuclear nodules. Amphileptus marinus (Kahl, 1931) Song et al., 2004 is redescribed and its diagnosis is improved. One isolate which was misidentified as A. marinus by Song et al. (2004) is believed to represent an unknown form, named here as Amphileptus songi sp. n. Phylogenetic analyses of the SSU rDNA sequences indicate that the genus Amphileptus is paraphyletic, but its monophyly is not rejected by statistical tree topology tests. PMID- 25041260 TI - On the Cornea of Healthy Merino Sheep: A Detailed Ex Vivo Confocal, Histological and Ultrastructural Study. AB - Our study performed qualitative and quantitative studies on the corneal ultrastructure of healthy female Merino sheep of ages 4 months and 6 years old from the Argentinean Pampa. The corneas were evaluated using ex vivo laser scanning confocal microscopy, light microscopy and transmission electron microscopy. Those studies allowed us to obtain detailed images of the corneal layers as well as quantitative data of the cellular and sub-basal nerve densities in the cornea from sheep of different ages. The density of the corneal cells was significantly different in the anterior versus the posterior epithelium and stroma. Moreover, the density of the epithelial, stromal cells and endothelial cells, as well as the sub-basal nerve density were significantly lower in adult than in young animals. Our work provided a wide-ranging description of the corneal ultrastructure of healthy female Merino sheep, which adds to the current knowledge about the ophthalmological aspects of this species and undoubtedly benefits veterinarians. PMID- 25041261 TI - A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study). AB - The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 * 10(9) /l and <=50 * 10(9) /l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 * 10(9) /l) or partial response (PR; platelet count >50 * 10(9) /l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 * 10(9) /l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m(2) four-dose schedule in relapsed/chronic ITP. PMID- 25041262 TI - Prosthetic reconstruction of a patient with an acquired nasal defect using extraoral implants and a CAD/CAM copy-milled bar. AB - Traditionally, patients with maxillofacial defects have been challenging to treat. A multitude of challenges associated with maxillofacial prosthetic treatment are not typically seen with patients who need conventional prosthodontic treatment. These types of patients generally require replacement of significant amounts of hard and soft tissues than do conventional prosthodontic patients. Most maxillofacial patients also warrant more emotional support than do conventional prosthodontic patients. Successful maxillofacial prosthetics still need to embrace the traditional goals of prosthodontic treatment: stability, support, retention, and esthetics. It is unlikely that a maxillofacial prosthesis will exactly duplicate the anatomy and function of missing or damaged structures. Although craniofacial implants (CFI's) have lower cumulative survival rates (CSR's) than intraoral endosseous implants, osseointegrated CFI's have proven to be significant adjuncts to improving retention of maxillofacial prostheses. However, CSR's of CFI's have been reported to be lower than CSR's for intraoral endosseous implants. Lately, computer-assisted design and computer-assisted machining (CAD/CAM) has been used in dentistry to facilitate fabrication of implant-supported frameworks. CAD/CAM protocols have numerous advantages over conventional casting techniques, including improved accuracy and biocompatibility, and decreased costs. The purpose of this paper is to review the literature on cumulative survival rates (CSR's) reported for CFI's and to illustrate the treatment of a maxillofacial patient using CFI's and a CAD/CAM copy-milled framework for retention and support of a nasal prosthesis. PMID- 25041263 TI - Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. AB - BACKGROUND: Ketamine and dexmedetomidine are increasingly used in combination in pediatric patients. This study examined the hypothesis that dexmedetomidine attenuated ketamine-induced neurotoxicity. METHODS: Neonatal rats were randomly divided into four groups (n=10, male 5, female 5). Group S+S received an equal volume of normal saline intraperitoneally and subcutaneously at an interval of 5 min. Group K+S received an intraperitoneal injection of 75 mg/kg ketamine followed by subcutaneous injection of normal saline 5 min later. Group S+D were given subcutaneously 25 MUg/kg dexmedetomidine 5 min after injection of normal saline. Group K+D received a subcutaneous injection of 25 MUg/kg dexmedetomidine 5 min after ketamine injection. The above drugs were given once daily for 3 days. Neuronal apoptosis in the CA1 region and the dentate gyrus of rats was examined by transferase dUTP nick end labeling (TUNEL) assays. Learning and memory abilities of 2-month old rats were examined by Morris water maze test. The results were analyzed by analysis of variance. RESULTS: The percentage of TUNEL positive cells in group K+S (CA1, 49.0+/-9.46 and dentate gyrus, 49.4+/-5.41) was markedly higher than that in group K+D (CA1, 37.2+/-5.54 and dentate gyrus, 35.2+/-5.06) (F=5.49, P<0.05 and F=13.51, P<0.001, respectively). Group K+S took significantly longer time and swimming distance to find the hidden platform on the fourth and fifth training days than group K+D (P<0.05). Moreover, group K+D spent considerably more time in the target quadrant than group K+S (P<0.05). Dexmedetomidine alone caused a small but statistically insignificant increase in neuronal apoptosis of the CA1 region and the dentate gyrus of neonatal rats compared with normal saline. CONCLUSION: In conclusion, ketamine caused neuroapoptosis and impaired brain functions in the developing rat brain which can be effectively attenuated by dexmedetomidine. Dexmedetomidine alone was not neurotoxic to the developing brain. PMID- 25041264 TI - Causal learning from probabilistic events in 24-month-olds: an action measure. AB - How do young children learn about causal structure in an uncertain and variable world? We tested whether they can use observed probabilistic information to solve causal learning problems. In two experiments, 24-month-olds observed an adult produce a probabilistic pattern of causal evidence. The toddlers then were given an opportunity to design their own intervention. In Experiment 1, toddlers saw one object bring about an effect with a higher probability than a second object. In Experiment 2, the frequency of the effect was held constant, though its probability differed. After observing the probabilistic evidence, toddlers in both experiments chose to act on the object that was more likely to produce the effect. The results demonstrate that toddlers can learn about cause and effect without trial-and-error or linguistic instruction on the task, simply by observing the probabilistic patterns of evidence resulting from the imperfect actions of other social agents. Such observational causal learning from probabilistic displays supports human children's rapid cultural learning. PMID- 25041265 TI - The role of peri-hepatic drain placement in liver surgery: a prospective analysis. AB - BACKGROUND: The standard use of an intra-operative perihepatic drain (IPD) in liver surgery is controversial and mainly supported by retrospective data. The aim of this study was to evaluate the role of IPD in liver surgery. METHODS: All patients included in a previous, randomized trial were analysed to determine the association between IPD placement, post-operative complications (PC) and treatment. A multivariate analysis identified predictive factors of PC. RESULTS: One hundred and ninety-nine patients were included in the final analysis of which 114 (57%) had colorectal liver metastases. IPD (n = 87, 44%) was associated with pre-operative biliary instrumentation (P = 0.023), intra-operative bleeding (P < 0.011), Pringle's manoeuver(P < 0.001) and extent of resection (P = 0.001). Seventy-seven (39%) patients had a PC, which was associated with pre-operative biliary instrumentation (P = 0.048), extent of resection (P = 0.002) and a blood transfusion (P = 0.001). Patients with IPD had a higher rate of high-grade PC (25% versus 12%, P = 0.008). Nineteen patients (9.5%) developed a post-operative collection [IPD (n = 10, 11.5%) vs. no drains (n = 9, 8%), P = 0.470]. Seven (8%) patients treated with and 9(8%) without a IPD needed a second drain after surgery, P = 1. Resection of >=3 segments was the only independent factor associated with PC [odds ratio (OR) = 2, P = 0.025, 95% confidence interval (CI) 1.1-3.7]. DISCUSSION: In spite of preferential IPD use in patients with more complex tumours/resections, IPD did not decrease the rate of PC, collections and the need for a percutaneous post-operative drain. IPD should be reserved for exceptional circumstances in liver surgery. PMID- 25041266 TI - Benign glandular downgrowth in gastric neuroendocrine neoplasms: a potential mimic of composite tumour. AB - AIMS: We have observed glandular downgrowth in some gastric neuroendocrine tumours (NETs), in which nonneoplastic appearing gastric glands are admixed with submucosal neuroendocrine nests, that could potentially be confused with composite tumours. METHODS AND RESULTS: We reviewed 68 gastric NETs with at least submucosal invasion, and evaluated associations between glandular downgrowth, clinical parameters (age, gender, NET setting) and tumour characteristics (size, depth of invasion, grade). Controls included 45 duodenal NETs. Glandular downgrowth was present in 28 (41%) gastric NETs but only 2 (4.4%) duodenal NETs (P < 0.0001). It was not related to age, gender, hypergastrinemia (downgrowth present in 43% of NETs arising in autoimmune gastritis, 41% of Zollinger-Ellison syndrome, 36% of sporadic NETs), tumour size, depth of invasion, or grade. Glandular downgrowth was confined to the submucosa even though 12 (18%) gastric NETs invaded muscularis propria. Submucosal gastric glands (pyloric type in 79%, intestinal in 50%, fundic in 29%) showed metaplastic changes similar to overlying mucosa, were usually mitotically inactive (64% of cases lacked mitotic figures), were geographically restricted to the NET, and never metastasized. CONCLUSIONS: Our findings support the frequent occurrence and nonneoplastic nature of glandular downgrowth in gastric NETs, which should not be mistaken for composite tumours. PMID- 25041267 TI - Multiplexing with three-primer PCR for rapid and economical microsatellite validation. AB - The next generation sequencing revolution has enabled rapid discovery of genetic markers, however, development of fully functioning new markers still requires a long and costly process of marker validation. This study reports a rapid and economical approach for the validation and deployment of polymorphic microsatellite markers obtained from a 454 pyrosequencing library of Atlantic cod, Gadus morhua, Linnaeus 1758. Primers were designed from raw reads to amplify specific amplicon size ranges, allowing effective PCR multiplexing. Multiplexing was combined with a three-primer PCR approach using four universal tails to label amplicons with separate fluorochromes. A total of 192 primer pairs were tested, resulting in 73 polymorphic markers. Of these, 55 loci were combined in six multiplex panels each containing between six and eleven markers. Variability of the loci was assessed on G. morhua from the Celtic Sea (n = 46) and the Scotian Shelf (n = 46), two locations that have shown genetic differentiation in previous studies. Multilocus F(ST) between the two samples was estimated at 0.067 (P = 0.001). After three loci potentially under selection were excluded, the global F(ST) was estimated at 0.043 (P = 0.001). Our technique combines three-primer and multiplex PCR techniques, allowing simultaneous screening and validation of relatively large numbers of microsatellite loci. PMID- 25041268 TI - Keeping surveys valid, reliable, and useful: a tutorial. AB - This tutorial focuses on how to produce reliable and generalizable data from random-digit-dialing (RDD) landline and cell phone surveys. The article notes that RDD response rates have declined and explores the impact of this pronounced decline. The tutorial addresses order, response mode, and many other biases, sample size, cooperation and response rates, weighting, and hybrid designs-all using examples from risk analysis to illustrate the key points. The article ends with a brief review of the advantages and disadvantages of major Internet and paper surveys tools, and how these can be molded and sometimes combined in repeated, longitudinal, and other designs to answer questions about risk preferences and perceptions. PMID- 25041269 TI - Visualization of the antegrade fast and slow pathway inputs in patients with slow fast atrioventricular nodal reentrant tachycardia. AB - INTRODUCTION: Mapping of the antegrade fast pathway (A-FP) exact sites and antegrade slow pathway (A-SP) input locations has not been well described. METHODS: In 56 patients with slow-fast atrioventricular nodal reentrant tachycardia (SF-AVNRT), pacing during sinus rhythm and entrainment pacing during SF-AVNRT were performed at various sites in the triangle of Koch and coronary sinus (CS) to identify the A-FP and A-SP inputs. User-defined three-dimensional electro-anatomical mapping of the stimulus-His potential (St-H) interval and anatomical location was performed. The A-FP input was defined as the site of the shortest St-H interval, and A-SP input as the site of the shortest St-H interval and with a postpacing-interval equal to the tachycardia cycle length. The locations of the A-FP and A-SP inputs were mapped as a ratio of the distance between the His bundle (HB) and CS orifice (CSO), and the HB-CSO axis was divided into three zones: superior-, mid-, and inferior septum. The distance between the A-SP and A-FP inputs was calculated using the distance from each input to the HB and HB-CSO axis. RESULTS: Only 30 patients were included in this study because the A-SP mapping failed in 26. The A-SP input was distributed to the superior septum in four, mid- or inferior septum in 25, and CS in one. An A-SP input which was located less than 10 mm from the A-FP input was observed in one of four patients with a superior septum A-SP. CONCLUSIONS: An A-SP input at the superior septum seemed to be a potential risk for atrioventricular nodal injury during ablation. PMID- 25041270 TI - The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. AB - BACKGROUND: Nonclassical congenital adrenal hyperplasia (NC-CAH) is caused by mutations of the CYP21A2 gene. The clinical manifestations and hormonal derangements of NC-CAH are quite variable. OBJECTIVES: (i) To define the phenotype and its relation to genotype according to gender and age and (ii) to evaluate the validity of currently applied hormonal criteria for establishing the diagnosis of NC-CAH. PATIENTS AND METHODS: The clinical, hormonal and molecular data of 280 subjects (235 female) with NC-CAH and a median age of 17.6 years were analysed. CYP21A2 genotyping was performed in all subjects. RESULTS: The majority of females aged less than 8 years presented with premature pubarche (88.3%), while those older than 8 presented with a polycystic ovary-like phenotype (63.2%). A total of 7.7% of the females and 51.1% of the males were asymptomatic at the time of diagnosis. In the total group, 50.4% of the subjects were compound heterozygotes for one classical (C) and one nonclassical (NC) mutation, while 46% of the alleles studied carried the p.V281L mutation. Basal 17OHP values were below 6 nm (2 ng/ml) in 2.1% of the subjects with NC-CAH, but none had peak 17OHP values post-ACTH lower than 30 nm (10 ng/ml). CONCLUSIONS: NC-CAH has a variable phenotype depending on the age, gender and the presence of a classical mutation. A peak cut-off value of 17OHP post-ACTH lower than 30 nm excludes the diagnosis of NC-CAH, whereas basal 17OHP <6 nm may represent a false-negative result. A significant number of patients harboured a classical mutation, a finding which requires genotyping of the partner for genetic counselling. PMID- 25041271 TI - Anastomosing haemangioma of kidney: a rare subtype of vascular tumour of the kidney mimicking angiosarcoma. PMID- 25041272 TI - Arabidopsis CPL4 is an essential C-terminal domain phosphatase that suppresses xenobiotic stress responses. AB - Eukaryotic gene expression is both promoted and inhibited by the reversible phosphorylation of the C-terminal domain of RNA polymerase II (pol II CTD). More than 20 Arabidopsis genes encode CTD phosphatase homologs, including four CTD phosphatase-like (CPL) family members. Although in vitro CTD phosphatase activity has been established for some CPLs, none have been shown to be involved in the phosphoregulation of pol II in vivo. Here we report that CPL4 is a CTD phosphatase essential for the viability of Arabidopsis thaliana. Mass spectrometry analysis identified the pol II subunits RPB1, RPB2 and RPB3 in the affinity-purified CPL4 complex. CPL4 dephosphorylates both Ser2- and Ser5-PO(4) of the CTD in vitro, with a preference for Ser2-PO(4). Arabidopsis plants overexpressing CPL4 accumulated hypophosphorylated pol II, whereas RNA interference-mediated silencing of CPL4 promoted hyperphosphorylation of pol II. A D128A mutation in the conserved DXDXT motif of the CPL4 catalytic domain resulted in a dominant negative form of CPL4, the overexpression of which inhibited transgene expression in transient assays. Inhibition was abolished by truncation of the phosphoprotein-binding Breast Cancer 1 C-terminal domain of CPL4, suggesting that both catalytic function and protein-protein interaction are essential for CPL4-mediated regulation of gene expression. We were unable to recover a homozygous cpl4 mutant, probably due to the zygotic lethality of this mutation. The reduction in CPL4 levels in CPL4(RNAi) plants increased transcript levels of a suite of herbicide/xenobiotic-responsive genes and improved herbicide tolerance, thus suggesting an additional role for CPL4 as a negative regulator of the xenobiotic detoxification pathway. PMID- 25041273 TI - A clinical prospective study on alveolar bone augmentation and dental implant success in patients with type 2 diabetes. AB - OBJECTIVES: The objective of this prospective, controlled clinical study was to determine the outcomes of dental implant therapy with staged guided bone regeneration procedures in patients with type 2 diabetes. PATIENTS AND METHODS: Twenty-four patients were included in the study. Half of the patients were diagnosed with type 2 diabetes mellitus (group 1) while the other half (group 2) of the patients consisted of patients without diabetes. The edentulous maxillary anterior/premolar regions with sufficient vertical height but inadequate horizontal width were treated with staged guided bone regeneration technique and with one or two implant-supported fixed restorations. The patients were followed up at least for 12 months. The parameters that were evaluated were radiographic evaluations on CBCT images and periapical radiographs, histomorphometric analysis, resonance frequency analysis (RFA) and wound-healing parameters. The data were analyzed statistically. RESULTS: A total of 43 implants were placed in 24 patients (22 implants in group 1 and 21 implants in group 2). The survival rates of implants were 100% for both groups. The success rate of implants was 95% for group 1 and 100% for group 2. None of the parameters including CBCT findings, RFA values, success rates and wound-healing scores showed a significant difference between the two groups. CONCLUSION: Staged guided bone regeneration is a feasible augmentation procedure for the treatment of horizontal bone deficiencies of the maxillary anterior/premolar regions in well-controlled type 2 diabetic patients. PMID- 25041274 TI - Humoral immune response as predictor of recurrence in Clostridium difficile infection. AB - Low serum concentrations of antibodies directed against the toxins TcdA and TcdB have been associated with a higher risk of recurrence of Clostridium difficile infection (CDI) after successful antibiotic treatment. However, there are conflicting reports. Herein, we compared serum levels of antibodies of patients with a single episode of CDI with those of patients who subsequently suffered a recurrence. We used a serum bank from patients who received an experimental whey protein product following successful antibiotic treatment for CDI. We determined levels of IgA and IgG directed against TcdA, TcdB and non-toxin cell surface antigens in serum collected directly and 3 weeks after completing a 10-day course of antibiotic treatment for CDI. We also developed an objective flow cytometry based assay to determine the proportion of cells exhibiting cytopathic effect after exposure to TcdB. Using this method, we measured the TcdB-neutralizing capacity of sera. We compared the results for patients without a subsequent recurrence with those of patients who suffered a recurrence within 60 days after completing the antibiotic treatment. Advanced age, comorbidity other than immunocompromised state and low serum levels of anti-TcdA and anti-TcdB antibodies were associated with recurrence, whereas serum levels of antibodies directed against cell surface antigens were not. Serum TcdB-neutralizing capacity, which correlated only weakly with serum IgG anti-TcdB, was not significantly associated with recurrence. PMID- 25041275 TI - Insulin glargine metabolite 21(A) -Gly-human insulin (M1) is the principal component circulating in the plasma of young children with type 1 diabetes: results from the PRESCHOOL study. AB - BACKGROUND AND AIMS: Insulin glargine metabolite 21(A) -Gly-human insulin (M1) is the principal component circulating in plasma of adults with type 1 diabetes. The objective of this study was to confirm this finding in young children and to rule out accumulation of parent insulin glargine. DESIGN AND METHODS: Children with type 1 diabetes from the PRESCHOOL study, aged 2-6 yr, were treated with insulin glargine for 24 wk (n = 62). Blood samples were drawn at weeks 1, 2, and 4 approximately 24 h after the last dose and analyzed for glargine, M1, and Thr(30B) -des-M1 (M2) using immunoaffinity purification and liquid chromatography with mass spectrometry. The lower limit of quantification was 33 pmol/L for all analytes. RESULTS: M1 was the principal active component circulating in plasma. Mean (SD) plasma Ctrough values were 101 (138), 80 (122), and 79 (102) pmol/L following glargine doses of 0.33 (0.02), 0.34 (0.02), and 0.38 (0.03) U/kg at weeks 1, 2, and 4, respectively. Parent insulin glargine and M2 concentrations were below the level of quantification. These results are in line with those observed in adults and indicate no accumulation of the parent compound in this patient population. CONCLUSION: In young children with type 1 diabetes, the principal component circulating in plasma after subcutaneous injection of insulin glargine is M1, the pharmacologically active component. No accumulation of the parent insulin glargine was observed. These data provide additional evidence on the safety profile of insulin glargine in young children (Clinical trial identifier: NCT00993473). PMID- 25041276 TI - Mechanosensitive channels Msy1 and Msy2 are required for maintaining organelle integrity upon hypoosmotic shock in Schizosaccharomyces pombe. AB - The mechanosensitive channels, Mys1 and Msy2, in fission yeast are localized in the endoplasmic reticulum membrane and control cytoplasmic Ca(2+) levels in the hypoosmotic response. We here investigated changes in organellar structures with hypoosmotic shock using transmission electron microscopy. While msy1(-) and msy2( ) single mutant cells developed a number of swollen vacuoles following hypoosmotic shock, similar to wild-type cells, msy1(-) msy2(-) double mutant cells only had two abnormally large vacuoles and cracks between the inner and outer nuclear membranes. These results suggest that Msy1 and Msy2 may be involved in maintaining vacuole integrity and protecting the nuclear envelope upon hypoosmotic shock and also that these two channels are functionally complementary. PMID- 25041277 TI - Tramadol can selectively manage moderate pain in children following European advice limiting codeine use. AB - The European Medicine Agency recommendations limiting codeine use in children have created a void in managing moderate pain. We review the evidence on the pharmacokinetic, pharmacodynamic and safety profile of tramadol, a possible substitute for codeine. CONCLUSION: Tramadol appears to be safe in both paediatric inpatients and outpatients. It may be appropriate to limit the current use of tramadol to monitored settings in children with risk factors for respiratory depression, subject to further safety evidence. PMID- 25041278 TI - Development and characterization of an equine skin-equivalent model. AB - BACKGROUND: There is increasing interest in the biological and pathological study of equine skin owing to the high prevalence of cutaneous diseases in horses. However, knowledge of equine skin cell biology and cultures is limited by the low number of in vitro studies in the literature. HYPOTHESIS/OBJECTIVES: The objective of the study was to develop and characterize an in vitro equine skin equivalent. METHODS: Cultures of pure equine keratinocytes and dermal fibroblasts were obtained by enzymatic digestion of skin biopsies. Fibroblasts were embedded into type I collagen matrices to obtain dermal scaffolds, the surface of which was seeded with keratinocytes. The three-dimensional cultures were exposed to the air-liquid interface to enable epidermal stratification. RESULTS: After 14 days in air-exposed conditions, histological analysis showed that keratinocytes underwent differentiation into a multilayered epidermis. Immunohistochemical studies revealed the expression of epidermal cytokeratin in keratinocytes, whereas vimentin was expressed in dermal fibroblasts, as expected in equine skin. Immunostaining of Ki67 showed proliferative keratinocytes in the stratum basale. A continuous basement membrane at the dermo-epidermal junction was also detected immunohistochemically through the expression of its major components (type IV collagen and laminin 5). Ultrastructural analysis by electron microscopy showed desmosomes located among keratinocytes in all layers and hemidesmosomes among the basal keratinocytes and lamina densa. CONCLUSIONS AND CLINICAL IMPORTANCE: This study reports, for the first time, the development of an in vitro equine skin equivalent model that resembles equine skin morphologically, immunohistochemically and ultrastructurally. PMID- 25041279 TI - A case of toxic shock due to clandestine abortion by misoprostol self administration. AB - Maternal mortality and morbidity are the leading causes of death and illness, respectively, among women of reproductive age in many countries throughout the world. Of all maternal deaths, those related to unsafe abortions are the most widely underestimated, but they are also the most largely preventable. Medical abortion is a safe and reliable method for termination of a pregnancy in early gestation, although it is important to be aware of signs and symptoms of severe infection and toxic shock syndrome after the medical termination of pregnancy; case studies in literature are rarely fatal events. We report the first case of septic shock syndrome following a clandestine pregnancy termination with a misoprostol-only regimen (12 tablets 200 MUg each). Autopsy findings and histopathological examination proved that the woman died from septic shock. This case suggests to improve the forensic investigations in case of unsafe, often clandestine, abortion is suspected. PMID- 25041280 TI - Distinct bacterial assemblages reside at different depths in Arctic multiyear sea ice. AB - Bacterial communities in Arctic sea ice play an important role in the regulation of nutrient and energy dynamics in the Arctic Ocean. Sea ice has vertical gradients in temperature, brine salinity and volume, and light and UV levels. Multiyear ice (MYI) has at least two distinct ice layers: old fresh ice with limited permeability, and new saline ice, and may also include a surface melt pond layer. Here, we determine whether bacterial communities (1) differ with ice depth due to strong physical and chemical gradients, (2) are relatively homogenous within a layer, but differ between layers, or (3) do not vary with ice depth. Cores of MYI off northern Ellesmere Island, NU, Canada, were subsectioned in 30-cm intervals, and the bacterial assemblage structure was characterized using 16S rRNA gene pyrotag sequencing. Assemblages clustered into three distinct groups: top (0-30 cm); middle (30-150 cm); and bottom (150-236 cm). These layers correspond to the occurrence of refrozen melt pond ice, at least 2-year-old ice, and newly grown first-year ice at the bottom of the ice sheet, respectively. Thus, MYI houses multiple distinct bacterial assemblages, and in situ conditions appear to play a less important role in structuring microbial assemblages than the age or conditions of the ice at the time of formation. PMID- 25041281 TI - Professor Lanjuan Li to join Artificial Organs as Co-Editor, Asian Region. PMID- 25041282 TI - Minimally invasive off-pump left ventricular assist device exchange: anterolateral thoracotomy. AB - The new generation of left ventricular assist devices has enabled minimally invasive surgical procedures. Herein we present a novel technique of left ventricular assist device exchange through a left-sided anterolateral thoracotomy. PMID- 25041284 TI - Diel growth patterns of young soybean (Glycine max) leaflets are synchronous throughout different positions on a plant. AB - Leaf growth is controlled by various internal and external factors. Leaves of dicotyledonous plants show pronounced diel (24 h) growth patterns that are controlled by the circadian clock. To date, it is still uncertain whether diel leaf growth patterns remain constant throughout the development of a plant. In this study, we followed growth from the primary leaves to leaflets of the seventh trifoliate leaf of soybean (Glycine max) on the same plants with a recently developed imaging-based method under controlled conditions and at a high temporal resolution. We found that all leaflets displayed a consistent diel growth pattern with maximum growth towards the end of the night. In some leaves, growth maxima occurred somewhat later - at dawn - as long as the leaves were still in a very early developmental stage. Yet, overall, diel growth patterns of leaves from different positions within the canopy were highly synchronous. Therefore, the diel growth pattern of any leaf at a given point in time is representative for the overall diel growth pattern of the plant leaf canopy and a deviation from the normal diel growth pattern can indicate that the plant is currently facing stress. PMID- 25041285 TI - The impact of oxaliplatin-based chemotherapy for colorectal cancer on the autonomous nervous system. AB - BACKGROUND: The oxaliplatin (OmicronChiAlpha)-based regimens FOLFOX and XELOX can cause peripheral neuropathy. It is unknown if OmicronChiAlpha, alone or in combination regimens, affects the Autonomous Nervous System (ANS). Accordingly, we evaluated the impact of OmicronChiAlpha-based chemotherapy on the ANS. METHODS: We enrolled 36 patients with colorectal cancer, treated with adjuvant mFOLFOX6 or XELOX chemotherapy, and 22 healthy volunteers. For the assessment of ANS function, participants completed a questionnaire and underwent neurophysiological examination at three time points (baseline, 3-4 months and 6-8 months after the first chemotherapy cycle). ANS testing included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (ratio 30/15) and Sympathetic Skin Response (SSR). RESULTS: The values of the 30/15 ratio were significantly reduced at the two time point assessments compared to baseline (Wilcoxon signed ranks test, both P < 0.001), while patients had more often diastolic OH at the 6-8 month evaluation compared to baseline (P = 0.039). In contrast, SSR was not affected. The incidence of positive responses in the questionnaire assessing the subjective impact of symptoms attributable to ANS dysfunction was higher at the two time points compared to baseline (P = 0.036 and P = 0.020). CONCLUSIONS: Oxaliplatin based chemotherapy is associated with significant effects on the adrenergic cardiovascular reaction and the parasympathetic heart innervation, whereas SSR remains untouched. PMID- 25041286 TI - Tactile sensory and pain thresholds in the face and tongue of subjects asymptomatic for oro-facial pain and headache. AB - The aim of this study was to examine the tactile sensory and pain thresholds in the face, tongue, hand and finger of subjects asymptomatic for pain. Sixteen healthy volunteers (eight men and eight women, mean age 35.7 years, range 27-41) participated. Using Semmes-Weinstein monofilaments, the tactile detection threshold (TDT) and the filament-prick pain detection threshold (FPT) were measured at five sites: on the cheek skin (CS), tongue tip (TT), palm side of the thenar skin (TS), dorsum of the hand (DH) and the finger tip (FT). The difference between the tactile sensory and pain threshold (FPT-TDT) was also calculated. Both for the TDT and FPT, TT and DH had the lowest and highest values, respectively. As for the FPT-TDT, there were no significant differences among the measurement sites. As the difference between FPT and TDT (FPT-TDT) is known to be an important consideration in interpreting QST (quantitative sensory testing) data and can be altered by neuropathology, taking the FPT-TDT as a new parameter in addition to the TDT and FPT separately would be useful for case-control studies on oro-facial pain patients with trigeminal neuralgia, atypical facial pain/atypical odontalgia and burning mouth syndrome/glossodynia. PMID- 25041287 TI - High spatial resolution of distribution and interconnections between Fe- and N redox processes in profundal lake sediments. AB - The Fe and N biogeochemical cycles play key roles in freshwater environments. We aimed to determine the spatial positioning and interconnections of the N and Fe cycles in profundal lake sediments. The gradients of O2, NO3(-), NH4(+), pH, Eh, Fe(II) and Fe(III) were determined and the distribution of microorganisms was assessed by most probable numbers and quantitative polymerase chain reaction. The redox zones could be divided into an oxic zone (0-8 mm), where microaerophiles (Gallionellaceae) were most abundant at a depth of 7 mm. This was followed by a denitrification zone (6-12 mm), where NO3(-)-dependent Fe(II) oxidizers and organoheterotrophic denitrifiers both reduce nitrate. Lastly, an iron redox transition zone was identified at 12.5-22.5 mm. Fe(III) was most abundant above this zone while Fe(II) was most abundant beneath. The high abundance of poorly crystalline iron suggested iron cycling. The Fe and N cycles are biologically connected through nitrate-reducing Fe(II) oxidizers and chemically by NOx(-) species formed during denitrification, which can chemically oxidize Fe(II). This study combines high resolution chemical, molecular and microbiological data to pinpoint sedimentary redox zones in which Fe is cycled between Fe(II) and Fe(III) and where Fe and N-redox processes interact. PMID- 25041288 TI - Robot-assisted laparoscopic high-intensity focused ultrasound for focal therapy of prostate: novel approach. PMID- 25041289 TI - Triphenylguanidine, a new (old?) rubber accelerator detected in surgical gloves that may cause allergic contact dermatitis. AB - BACKGROUND: Rubber accelerators are common contact allergens in healthcare personnel, owing to exposures from medical gloves. OBJECTIVES: To analyse glove extracts used for patch testing for the presence of guanidine-type accelerators, and to describe the results of patch testing with triphenylguanidine (TPG) in 2 cases of contact allergy and with TPG added to the rubber series. MATERIALS AND METHODS: Gas chromatography-mass spectrometry and liquid chromatography with ultraviolet detection were used for analysis of glove extracts. Patch tests were performed with guanidine accelerators detected in the extracts. RESULTS: TPG, an accelerator not previously reported as being present in rubber gloves, was found in the glove extracts. Patch testing with TPG showed relevant contact allergic reactions in patients with hand dermatitis caused by rubber gloves. CONCLUSIONS: Chemical analysis of extracts for patch testing is important in the identification of new possible allergens. In this case, a rubber accelerator previously not reported as a possible contact allergen was found in extracts of surgical gloves. PMID- 25041290 TI - The embryogenesis of the equine femorotibial joint: The equine interzone. AB - REASONS FOR PERFORMING STUDY: Articular cartilage regeneration is the focus and goal of considerable research effort. Since articular chondrocytes descend from a distinct cohort of progenitor cells located in embryonic nascent joints (interzones), establishing the timing of equine interzone formation is an essential first step towards understanding equine joint and articular cartilage development. OBJECTIVES: To establish the time frame during which the equine femorotibial interzone forms. STUDY DESIGN: Descriptive anatomical study. METHODS: Equine embryos were harvested at 37 (E37), 40, 42, 45, 50 and 65 days' gestation. The femorotibial interzone was examined using high-resolution episcopic microscopy of E37, E42, E45, E50 and E65. Additional histology and collagen-II-immunohistochemistry were performed on E42. RESULTS: At E37, the femorotibial interzone is first visible as a uniform layer, while at E42 the interzone is fully formed and consists of 3 morphologically distinct layers. The first evidence of cavitation was seen at E45. At E50, the cruciate ligaments were well formed and by E65, joint formation appeared complete. CONCLUSIONS: The embryogenesis of the equine femorotibial joint is similar to the developmental timeline of stage-matched human and murine embryos. Further studies looking at interzone formation on a cellular and molecular level may further our understanding of the intricate developmental patterns and pathways of articular cartilage development. PMID- 25041291 TI - Addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis: a randomized double-blind placebo-controlled trial. AB - BACKGROUND: Fumaric acid esters (FAEs) are considered an effective and safe long term treatment for psoriasis. However, 30-40% of patients need to discontinue FAE treatment due to intolerable adverse events. OBJECTIVES: To assess whether the addition of cetirizine, an oral histamine-1 receptor antagonist, to FAEs would reduce the incidence of adverse events. METHODS: In a randomized, double-blind, placebo-controlled trial, patients with psoriasis with a Psoriasis Area and Severity Index >= 10 starting an FAE up to a dose of dimethylfumarate 720 mg per day were randomized 1 : 1 to receive either additional cetirizine 10 mg once daily (n = 25) or placebo (n = 25) for 12 weeks. Randomization and treatment allocation were done at our hospital trial pharmacy. Primary outcomes were the incidence of adverse events and the proportion of patients discontinuing treatment. RESULTS: Fifty patients (33 male, 17 female; median age 44 years) were enrolled. Addition of cetirizine did not reduce the incidence of adverse events compared with placebo (84% vs. 84%, P = 1.00). The types of adverse events were not different between the cetirizine and placebo groups, the most common being gastrointestinal complaints (68% vs. 64%) and flushes (60% vs. 48%). The proportion of patients discontinuing treatment was not statistically different between the cetirizine and placebo groups (24% vs. 32%, P = 0.53). CONCLUSIONS: Addition of oral cetirizine 10 mg once daily to FAE treatment did not reduce adverse events in patients with psoriasis during the first 12 weeks of treatment. The mechanisms underlying FAE-induced gastrointestinal and flushing symptoms likely involve mediators other than histamine. PMID- 25041292 TI - Writing well. PMID- 25041293 TI - Enterovirus 71 outbreak in Northern Sydney, 2013: case series and initial response. AB - AIM: Enteroviruses are a common cause of childhood disease which may manifest in a variety of ways. Enterovirus 71 (EV71) is a subtype of enterovirus which can cause meningoencephalomyelitis resulting in neurological sequelae including lethargy, weakness, ataxia, sleep myoclonus, urinary retention and, in severe cases, cardiorespiratory collapse due to neurogenic pulmonary oedema. EV71 was responsible for outbreaks in South East Asia in 1997-1998, in Western Australia in 1999 and in Sydney in 2000-2001. In 2013, we are experiencing another EV71 outbreak in Sydney. This study describes the discovery of a new outbreak in Sydney's Northern Beaches, the clinical findings as well as the public health response. METHODS: Thirty-seven children in total presented with presumed EV71 to the Northern Beaches Health Service from December 2012 to April 2013. Most children presented with a prodrome lasting 2-7 days prior to seeking medical attention. Sleep myoclonus was a common presenting sign occurring in 65%. Neurological signs were subtle in the majority of children and were at times missed by clinicians on a child's first presentation. Forty-six per cent of children who presented to Northern Beaches Health Service during this outbreak required a transfer to a tertiary paediatric centre for more intensive care. RESULTS: The public health investigation was important in establishing that the disease was widespread throughout the community and not as a result to exposure to a single child care setting. Identification of risk factors enabled more targeted communication to medical practitioners, child care centres and parents within the local community. CONCLUSIONS: EV71 is in Australia and all clinicians seeing children in primary, secondary and tertiary care centres need to be aware of the disease, the subtle nature of initial symptoms and the potentially devastating consequences. PMID- 25041298 TI - An expanding rash. PMID- 25041299 TI - The curious case of ileocolic intussusception. PMID- 25041300 TI - Chromosomal microarray testing in children: experience from a New Zealand secondary care hospital. PMID- 25041301 TI - Cross-border promotion of formula milk in Lao People's Democratic Republic and opportunities for breastfeeding promotion. PMID- 25041302 TI - Spinal muscular atrophy-1 and gastrostomy. PMID- 25041304 TI - Combined anti-cholinergic and short-acting beta-agonist therapy reduces hospital admissions for acute asthma. PMID- 25041305 TI - Occupational allergy to flowers: immunoblot analysis of allergens in freesia, gerbera and chrysanthemum pollen. AB - High exposure to pollen from ornamental flowers can induce an IgE-mediated occupational allergy in florists and horticulture workers. We investigated IgE binding antigens in chrysanthemum, freesia and gerbera pollen by immunoblot analysis and analysed the cross-reactivity of these pollen with birch, grass and mugwort pollen. In immunoblots with chrysanthemum pollen, major IgE-binding structures were seen with a molecular weight (MW) of approximately 25, 45 and 65 kD. In the immunoblots with freesia pollen, IgE from freesia pollen was directed against two proteins with an MW of approximately 15 kD. Most sera showed IgE binding to an approximately 15 kD band in gerbera pollen; with some sera additional bands were seen in the range of 30-50 kD. IgE binding to chrysanthemum pollen was inhibited by mugwort pollen only, whereas IgE binding to freesia pollen was suppressed by birch, grass and mugwort pollen. The inhibitory activity of birch and grass pollen extract on IgE binding to gerbera pollen extract was serum dependent and ranged from no inhibition to complete inhibition. Occupational exposure to many different flowers induced IgE against all three types of pollen. Exposure in greenhouses to gerbera flowers elicited mainly IgE against gerbera pollen. Mugwort pollen extract inhibited IgE binding to pollen from all three flowers. PMID- 25041307 TI - Diagnostic accuracy of magnetic resonance imaging (MRI) prostate imaging reporting and data system (PI-RADS) scoring in a transperineal prostate biopsy setting. AB - OBJECTIVES: To determine the sensitivity and specificity of multiparametric magnetic resonance imaging (mpMRI) for significant prostate cancer with transperineal sector biopsy (TPSB) as the reference standard. PATIENTS AND METHODS: The study included consecutive patients who presented for TPSB between July 2012 and November 2013 after mpMRI (T2- and diffusion-weighted images, 1.5 Tesla scanner, 8-channel body coil). A specialist uro-radiologist, blinded to clinical details, assigned qualitative prostate imaging reporting and data system (PI-RADS) scores on a Likert-type scale, denoting the likelihood of significant prostate cancer as follows: 1, highly unlikely; 3, equivocal; and 5, highly likely. TPSBs sampled 24-40 cores (depending on prostate size) per patient. Significant prostate cancer was defined as the presence of Gleason pattern 4 or cancer core length >=6 mm. RESULTS: A total of 201 patients were included in the analysis. Indications were: a previous negative transrectal biopsy with continued suspicion of prostate cancer (n = 103); primary biopsy (n = 83); and active surveillance (n = 15). Patients' mean (+/-sd) age, prostate-specific antigen and prostate volumes were 65 (+/-7) years, 12.8 (+/-12.4) ng/mL and 62 (+/-36) mL, respectively. Overall, biopsies were benign, clinically insignificant and clinically significant in 124 (62%), 20 (10%) and 57 (28%) patients, respectively. Two of 88 men with a PI-RADS score of 1 or 2 had significant prostate cancer, giving a sensitivity of 97% (95% confidence interval [CI] 87-99) and a specificity of 60% (95% CI 51-68) at this threshold. Receiver-operator curve analysis gave an area under the curve of 0.89 (95% CI 0.82-0.92). The negative predictive value of a PI-RADS score of <=2 for clinically significant prostate cancer was 97.7% CONCLUSION: We found that PI-RADS scoring performs well as a predictor for biopsy outcome and could be used in the decision-making process for prostate biopsy. PMID- 25041309 TI - From incontinence associated dermatitis to pressure ulcers. PMID- 25041308 TI - Structure and interactions of the Bacillus subtilis sporulation inhibitor of DNA replication, SirA, with domain I of DnaA. AB - Chromosome copy number in cells is controlled so that the frequency of initiation of DNA replication matches that of cell division. In bacteria, this is achieved through regulation of the interaction between the initiator protein DnaA and specific DNA elements arrayed at the origin of replication. DnaA assembles at the origin and promotes DNA unwinding and the assembly of a replication initiation complex. SirA is a DnaA-interacting protein that inhibits initiation of replication in diploid Bacillus subtilis cells committed to the developmental pathway leading to formation of a dormant spore. Here we present the crystal structure of SirA in complex with the N-terminal domain of DnaA revealing a heterodimeric complex. The interacting surfaces of both proteins are alpha helical with predominantly apolar side-chains packing in a hydrophobic interface. Site-directed mutagenesis experiments confirm the importance of this interface for the interaction of the two proteins in vitro and in vivo. Localization of GFP SirA indicates that the protein accumulates at the replisome in sporulating cells, likely through a direct interaction with DnaA. The SirA interacting surface of DnaA corresponds closely to the HobA-interacting surface of DnaA from Helicobacter pylori even though HobA is an activator of DnaA and SirA is an inhibitor. PMID- 25041310 TI - The effect of a ceramide-containing dressing in preventing pressure ulcers. AB - OBJECTIVE: To evaluate the effect of a ceramide-containing dressing (Remois Pad(r)) on preventing pressure ulcers. METHOD: A total of 32 patients (64 samples) with a Braden Scale score of 16 or less in intensive care units were enrolled to have the dressing applied for an experimental bilateral comparison study. The dressing was randomly applied to the right or left greater trochanter for 7 days. Incidence of nonblanching erythema and the water-holding capacity of the skin were measured on the third day and seventh day after intervention. RESULTS: On the third day after intervention, nonblanching erythema was not apparent in either the experimental or the control groups. On the seventh day, one (3.3%) and four (13.3%) cases of nonblanching erythema were observed in the experimental group and the control group, respectively; however, the difference was not statistically significant. The water-retaining capacity of the skin on the third and seventh days after the intervention was significantly higher than that of the control group. CONCLUSION: The data collected from this study gave no evidence that a ceramide-containing dressing had an effect on preventing pressure ulcers in the greater trochanter area. DECLARATION OF INTEREST: There were no external sources of funding for this study. The authors have no conflicts of interest to declare. PMID- 25041311 TI - A novel approach to reconstruct a large full thickness abdominal wall defect: successful treatment with MatriDerm(r) and Split. AB - OBJECTIVE: Reconstruction of large abdominal wall defects is a challenging procedure, often contraindicated in critically ill patients, with high incidences of complications. We present a case of a patient with a large abdominal wall defect who had reconstruction with MatriDerm(r) (an engineered dermal template) and split thickness skin grafting (SSG) as an alternative to reconstruction with myo- or fascio-cutaneous flaps. Successful wound closure was achieved with a single technique, while providing a robust reconstruction and an interface between skin and underlying viscera, should further surgery be necessary. PMID- 25041312 TI - The Fitzpatrick skin type scale: a reliability and validity study in women undergoing radiation therapy for breast cancer. AB - OBJECTIVE: This study aimed to evaluate the internal consistency reliability and construct validity of the Fitzpatrick Skin Type Scale during radiation therapy in a cohort of women receiving treatment for breast cancer. METHOD: The assessment of the scale was performed as a nested study within a randomised controlled trial of two creams used for radiation therapy skin care for breast cancer patients. The sample consisted of 244 female patients undergoing radiation therapy for breast cancer. Participants completed a modified version of the Fitzpatrick Skin Type Scale. RESULTS: Internal consistency as measured by Cronbach's alpha was 0.505, 0.829 and 0.339 for the Genetic Disposition, Sun Exposure and Tanning Habits subscales respectively. Only the Sun Exposure subscale surpassed the 0.70 cut-off, indicating good internal consistency. Maximum likelihood factor analysis with promax rotation method confirmed the a priori factor structure for the Sun Exposure subscale as well as providing evidence of construct validity for this subscale. Analysis for the other two subscales highlighted issues with internal reliability and construct validity suggesting that not all items on each subscale truly measure the intended trait. CONCLUSION: The study findings support reliability and validity of the Sun Exposure subscale of the Fitzpatrick Skin Type Scale in a convenience sample of women receiving radiation therapy for cancer. Despite limitations with two of the three subscales, this tool continues to be used in clinical practice. PMID- 25041313 TI - Pressure ulcer risk assessment and prevention: what difference does a risk scale make? A comparison between Norway and Ireland. AB - OBJECTIVE: To explore similarities and differences in nurses' views on risk assessment practices and preventive care activities in a context where patients' risk of developing pressure ulcers is assessed using clinical judgment (Norway) and a context where patients' risk of developing pressure ulcers is assessed using a formal structured risk assessment combined with clinical judgement (Ireland). METHOD: A descriptive, qualitative design was employed across two different care settings with a total of 14 health care workers, nine from Norway and five from Ireland. RESULTS: Regardless of whether risk assessment was undertaken using clinical judgment or formal structured risk assessment, identified risk factors, at risk patients and appropriate preventive initiatives discussed by participant were similar across care settings. Furthermore, risk assessment did not necessarily result in the planning and implementation of appropriate pressure ulcer prevention initiatives. Thus, in this instance, use of a formal risk assessment tool does not seem to make any difference to the planning, initiation and evaluation of pressure ulcer prevention strategies. CONCLUSION: Regardless of the method of risk assessment, patients at risk of developing pressure ulcers are detected, suggesting that the practice of risk assessment should be re-evaluated. Moreover, appropriate preventive interventions were described. However, the missing link between risk assessment and documented care planning is of concern and barriers to appropriate pressure ulcer documentation should be explored further. DECLARATION OF INTEREST: This work is partly funded by a research grant from the Norwegian Nurses Organisation (NNO) (Norsk Sykepleierforbund NSF) in 2012. The authors have no conflict of interest to declare. PMID- 25041315 TI - Life with r(20)-Ring chromosome 20 syndrome. PMID- 25041314 TI - Characterization of acid and non-acid glycosphingolipids of porcine heart valve cusps as potential immune targets in biological heart valve grafts. AB - BACKGROUND: Although xenotransplantation of vascularized organs/cells has not yet reached the clinic, glutaraldehyde-treated bioprosthetic heart valves (BHV), derived from porcine or bovine tissues, are today used for clinical replacement of diseased heart valves. However, the durability of these valve cusps is limited partly due to the onset of immune responses to the grafts. The xenoantigen determinant Galalpha3Gal- and corresponding anti-Gal antibodies have been postulated to in part contribute to BHV damage. However, the presence of other non-Gal carbohydrate antigen determinants as well as the immune response to these non-Gal antigens and the inflammatory response generated by their interaction with the immune system has not been studied. In this study, we have isolated and structurally characterized both non-acid and acid glycosphingolipids from naive porcine aortic and pulmonary valve cusps. METHODS: Total non-acid and acid glycosphingolipids were isolated from porcine aortic and pulmonalis valve cusps of 20 animals. Glycosphingolipid components were structurally characterized by thin-layer chromatography, liquid chromatography-mass spectrometry and binding of monoclonal antibodies and lectins. RESULTS: The non-acid glycosphingolipids were characterized as globotetraosylceramide, H-type 2 pentaosylceramide, fucosyl gangliotetraosylceramide, and Galalpha3neolactotetraosylceramide. The acid glycosphingolipid fractions had both sulfatide and gangliosides (GM3, GM2, GM1, fucosyl-GM1, GD3 and GD1a), and all gangliosides contained N-acetyl-neuraminic acid. Significantly, the N-glycolyl-neuraminic acid (NeuGc) variant, a major component in many pig organs and to which humans can develop antibodies, was not detected among the gangliosides. CONCLUSIONS: Pig valve cusps contain several complex lipid-bound carbohydrate structures that may be targets for the human immune system. Notable, the NeuGc determinant was absent in the cusp gangliosides. This work forms a platform for further characterizing the antibody reactivity of patients with porcine-derived BHV. PMID- 25041316 TI - The burden of premature opioid-related mortality. AB - BACKGROUND AND AIMS: The burden of premature mortality due to opioid-related death has not been fully characterized. We calculated temporal trends in the proportion of deaths attributable to opioids and estimated years of potential life lost (YLL) due to opioid-related mortality in Ontario, Canada. DESIGN: Cross sectional study. SETTING: Ontario, Canada. PARTICIPANTS: Individuals who died of opioid-related causes between January 1991 and December 2010. MEASUREMENTS: We used the Registered Persons Database and data abstracted from the Office of the Chief Coroner to measure annual rates of opioid-related mortality. The proportion of all deaths related to opioids was determined by age group in each of 1992, 2001 and 2010. The YLL due to opioid-related mortality were estimated, applying the life expectancy estimates for the Ontario population. FINDINGS: We reviewed 5935 opioid-related deaths in Ontario between 1991 and 2010. The overall rate of opioid-related mortality increased by 242% between 1991 (12.2 per 1 000 000 Ontarians) and 2010 (41.6 per 1 000 000 Ontarians; P < 0.0001). Similarly, the annual YLL due to premature opioid-related death increased threefold, from 7006 years (1.3 years per 1000 population) in 1992 to 21 927 years (3.3 years per 1000 population) in 2010. The proportion of deaths attributable to opioids increased significantly over time within each age group (P < 0.05). By 2010, nearly one of every eight deaths (12.1%) among individuals aged 25-34 years was opioid-related. CONCLUSIONS: Rates of opioid-related deaths are increasing rapidly in Ontario, Canada, and are concentrated among the young, leading to a substantial burden of disease. PMID- 25041317 TI - Critical swimming speeds of wild-caught sand-smelt Atherina presbyter larvae. AB - Swimming abilities of wild-caught sand-smelt Atherina presbyter larvae were assessed as critical swimming speed (Ucrit ) throughout ontogeny. The mean Ucrit increased with size, ranging from 3.6 to 18.7 cm s(-1) , over the size range of 6.6-21.0 mm LT . This indicates that at hatching A. presbyter larvae, far from being passive floaters, are already capable of active behaviours, which may influence their dispersal patterns. PMID- 25041318 TI - Funding emergency care: Australian style. AB - The ongoing challenge for ED leaders is to remain abreast of system-wide changes that impact on the day-to-day management of their departments. Changes to the funding model creates another layer of complexity and this introductory paper serves as the beginning of a discussion about the way in which EDs are funded and how this can and will impact on business decisions, models of care and resource allocation within Australian EDs. Furthermore it is evident that any funding model today will mature and change with time, and moves are afoot to refine and contextualise ED funding over the medium term. This perspective seeks to provide a basis of understanding for our current and future funding arrangements in Australian EDs. PMID- 25041319 TI - Dilemmas of allergy diagnosis in perioperative anaphylaxis. PMID- 25041320 TI - Associations of retinal oximetry in persons with diabetes. AB - BACKGROUND: There are limited data available on the variables that might affect retinal vessel oxygen saturation (SO2) in diabetes. Therefore, the aim of this study is to assess factors associated with retinal oximetry values in persons with diabetes. DESIGN: Clinic-based cross-sectional study. PARTICIPANTS: Fifty eight persons with diabetes aged 18+ years, recruited from the University of Melbourne, the Royal Victorian Eye and Ear Hospital, and St. Vincent's Hospital (Melbourne), Australia. METHODS: Retinal oximetry was performed using the oximetry module of the Vesselmap system (Imedos UG, Jena, Germany) in 92 diabetic eyes. Generalized estimating equation models were used to estimate the associations between candidate variables (age; gender; retinal capillary flow; duration of diabetes; hypertension; smoking status; presence of diabetic retinopathy [DR]; glycated haemoglobin; triglyceride; total cholesterol; finger SO2 and ocular perfusion pressure) with retinal oximetry measures. MAIN OUTCOME MEASURE: Arteriolar SO2, venular SO2 and the arterio-venous (A-V) difference. RESULTS: Of the candidate factors assessed, only the presence of DR was significantly associated with increased venular SO2 and decreased A-V difference in unadjusted analyses. In models adjusting for age and gender and significant variables from unadjusted analyses, compared with no DR, the presence of DR was significantly associated with greater retinal venular SO2 values (beta = 3.65%, 95% confidence interval: 0.67-6.63%) and decreased A-V difference (beta = -2.00%, 95% confidence interval: -3.46 to -0.53%). CONCLUSION: In patients with diabetes, eyes with DR were associated with increased venular SO2 and decreased A-V difference compared with eyes without DR, suggesting an altered metabolic state in DR. PMID- 25041321 TI - Determination of some blood and seminal plasma ions in the beluga, Huso huso (Linnaeus, 1758). AB - Blood and seminal plasma ionic parameters are essential for monitoring health status, detecting illnesses, fish stock conservation and development of artificial propagation methods via extender improvement. In this study, comparison of blood and seminal plasma ionic parameters in beluga, Huso huso (30 45 kg, 1-2 m, n = 10), was made. The results obtained show that Na(+) (82.54 +/- 5.46), Cl(-) (15.95 +/- 0.72) and K(+) (3.57 +/- 0.15) were predominant ions in the seminal plasma (as mM). Blood ionic values (as mM) were determined for Na(+) (110.2 +/- 1.26), K(+) (3.77 +/- 0.081), Cl(-) (60.12 +/- 1.5), Ca(2+) (2.05 +/- 0.35) and Mg(2+) (1.9 +/- 0.16). Results of the comparison between ionic parameters of seminal and blood plasma indicated that the concentrations of all parameters of blood plasma with the exception of K(+) were significantly (p < 0.05) higher than those of seminal plasma. PMID- 25041322 TI - Disseminated carcinomatosis of the bone marrow originating from hepatocellular carcinoma. A case report. AB - A 50-year-old male patient was admitted to the hospital for persistent high fever and back pain. He was diagnosed with hepatocellular carcinoma (HCC), bone marrow metastasis and disseminated intravascular coagulation (DIC). Despite the diagnosis and treatment, the general condition deteriorated rapidly and he died of cerebral hemorrhage associated with generalized bleeding tendency. Autopsy showed multiple HCC in the liver and systemic metastasis including bone marrow. The case describes a rare complication of HCC with disseminated carcinomatosis of the bone marrow (DCBM) complicated with DIC, with rapid deterioration and death. This is the first case of DCBM from HCC. Physicians need to be aware of DCBM in patients with HCC. PMID- 25041323 TI - Topographical relationship of the greater palatine artery and the palatal spine. Significance for periodontal surgery. AB - AIM: The aims of this study were to (1) identify the branching pattern and course of the greater palatine artery (GPA), (2) carry out a morphological analysis of the palatal bony prominence that divides the medial and lateral grooves and (3) characterize the topographical relationships between these two structures. METHODS: Thirty-six hemimaxillae were studied with the aid of a surgical microscope to elucidate the GPA. A further 25 dry skulls were examined to establish the morphology of the palatal spine. RESULTS: The most common GPA branching pattern was type I (41.7%, 15 sides), which gave off the medial and canine branches after the bony prominence. The distances from the CEJ to the lateral branch of the GPA were 9.04 +/- 2.93 mm (canine), 11.12 +/- 1.89 mm (first premolar), 13.51 +/- 2.08 mm (second premolar), 13.76 +/- 2.86 mm (first molar) and 13.91 +/- 2.20 mm (second molar). The palatal spine was frequently observed as the bony prominence (66.3%, 57 sides), and was located at 6.49 +/- 1.76 mm from the greater palatine foramen, with a length of 10.42 +/- 2.45 mm. There was no a correlation between the bony prominence shape and the GPA branching pattern. CONCLUSIONS: These results could provide the reference data regarding the topography of the GPA for periodontal surgery. PMID- 25041324 TI - Failure of heterogeneous amyloid-enhancing factor in geriatric squirrel monkeys (Saimiri boliviensis). AB - BACKGROUND: Cross-species transmission of AA amyloidosis between primates and other animals has not been previously reported. METHODS: Eight geriatric squirrel monkeys were intravenously administered chimpanzee, bovine, or chicken amyloid fibrils and simultaneously received inflammatory stimulation. RESULTS: AA amyloid deposition was not detected in any of the monkeys histopathologically or immunohistochemically. CONCLUSIONS: These results suggest that heterogeneous AA amyloidosis may not be easily transmitted into primates. PMID- 25041325 TI - Nerve stimulator-guided sciatic-femoral nerve block in raptors undergoing surgical treatment of pododermatitis. AB - OBJECTIVE: To describe the nerve stimulator-guided sciatic-femoral nerve block in raptors undergoing surgical treatment of pododermatitis. STUDY DESIGN: Prospective clinical trial. ANIMALS: Five captive raptors (Falco peregrinus) aged 6.7 +/- 1.3 years. METHODS: Anaesthesia was induced and maintained with isoflurane in oxygen. The sciatic-femoral nerve block was performed with 2% lidocaine (0.05 mL kg(-1) per nerve) as the sole intra-operative analgesic treatment. Intraoperative physiological variables were recorded every 10 minutes from endotracheal intubation until the end of anaesthesia. Assessment of intraoperative nociception was based on changes in physiological variables above baseline values, while evaluation of postoperative pain relied on species specific behavioural indicators. RESULTS: The sciatic-femoral nerve block was feasible in raptors and the motor responses following electrical stimulation of both nerves were consistent with those reported in mammalian species. During surgery no rescue analgesia was required. The anaesthesia plane was stable and cardiorespiratory variables did not increase significantly in response to surgical stimulation. Iatrogenic complications, namely nerve damage and local anaesthetic toxicity, did not occur. Recovery was smooth and uneventful. The duration (mean +/- SD) of the analgesic effect provided by the nerve block was 130 +/- 20 minutes. CONCLUSION AND CLINICAL RELEVANCE: The sciatic-femoral nerve block as described in dogs and rabbits can be performed in raptors as well. Further clinical trials with a control groups are required to better investigate the analgesic efficacy and the safety of this technique in raptors. PMID- 25041326 TI - CT-guided chemonucleolysis combined with psoas compartment block in lumbar disc herniation: a randomized controlled study. AB - OBJECTIVES: The study was designed to evaluate the effectiveness of the combination of chemonucleolysis and psoas compartment block (PCB) for the treatment of lumbar disc herniations (LDHs) and to explore the role of PCB in managing postoperative pain of collagenase injection. METHODS: Two groups of patients (N = 192) were treated in different ways, respectively. Group A (N = 95) was treated with chemonucleolysis only (the injection of oxygen-ozone combined with collagenase into the lumbar disc and the epidural space); group B (N = 97) was treated with chemonucleolysis and PCB. After the treatment, the patients were followed-up, and the therapeutic effect was assessed at 1 week, 1 month, 3 months, and 6 months by the relative pain reduction, visual analog scale (VAS) pain scores, and the Oswestry Disability Index (ODI) scores. RESULTS: In group A, treatment success rate was 64.2% (61 of 95), 82.1% (78 of 95), 84.2% (80 of 95), and 86.3% (82 of 95) at 1 week, 1 month, 3 months, and 6 months, respectively. In group B, treatment success rate was 86.5% (84 of 97), 89.6% (87 of 97), 93.8% (91 of 97), and 91.7% (89 of 97) at 1 week, 1 month, 3 months, and 6 months, respectively. There was statistically significant difference in outcome between two groups at 1 week, but there were no statistically significant difference in outcome between two groups at 1 month, 3 months, and 6 months. VAS scores and ODI were significantly decreased in both group A and group B, when compared with the baseline values in the same group at all points of follow-up. Group B produced a significant reduction in the VAS scores and ODI when compared with group A at: 1 week, 1-month, 3-month, 6-month follow-up. CONCLUSIONS: Computer tomography (CT) guided chemonucleolysis combined with PCB leads to rapid pain relief, fewer postoperative pain of collagenase injection happen, and should be regarded as a useful treatment for the management of LDH. PMID- 25041327 TI - The ImmuKnow assay--does it really put us in the know about the immune system? PMID- 25041328 TI - Treatment strategies to treat antibody-mediated rejection and to reduce donor specific antibodies. PMID- 25041329 TI - Hepatic venous reconstruction as the stake of the liver: technical note and thoughts. PMID- 25041330 TI - Waiting for transplant: physical, psychosocial, and nutritional status considerations for pediatric candidates and implications for care. AB - The waiting period for an organ transplant has been described as a time of tremendous uncertainty and vulnerability, posing unique challenges and stressors for pediatric transplant candidates and their families. It has been identified as the most stressful stage of the transplant journey, yet little attention has been given to the physical, psychological, or social impact of the waiting period in the literature. In this review, we discuss the physical, nutritional, and psychosocial implications of the waiting period for child and adolescent transplant candidates and the impact on their parents and siblings. We identify areas for future research and provide recommendations for clinical practice to support children, adolescents, and families during the waiting period. PMID- 25041331 TI - The use of bi-planar tissue expanders to augment abdominal domain in a pediatric intestinal transplant recipient. AB - Intestinal transplantation is a well-accepted treatment for SBS. However, patients with SBS often have decreased abdominal capacity, which makes size matching of donor organs more difficult, thus decreasing organ availability. Reported approaches for addressing this problem include surgically reducing the graft size, leaving an open abdomen for a prolonged period, and cotransplanting rectus fascia as a non-vascularized allograft. Each approach has significant disadvantages. There has been one previous report of tissue expanders used intra abdominally and two reports of subcutaneous use to increase intra-abdominal capacity prior to transplantation. We report the first use of bi-planar expander placement for this purpose. In our case, a two-yr-old male child with SBS due to malrotation was treated with tissue expanders 10 months prior to intestinal transplantation, thus allowing transplantation of a larger graft with the ability to close the abdomen safely. There were no complications, and the patient is now doing well and tolerating diet off PN. The use of tissue expanders prior to intestinal transplantation is a promising approach for such patients and avoids the morbidity associated with other approaches. This approach requires a multidisciplinary effort by gastroenterology, transplant surgery, and plastic surgery teams. PMID- 25041332 TI - Array CGH-based analysis of post-transplant plasmacytic hyperplasia reveals 'intact genomes' arguing against categorizing it as part of the post-transplant lymphoproliferative disease spectrum. PMID- 25041333 TI - The efficacy of long-term psychodynamic psychotherapy, fluoxetine and their combination in the outpatient treatment of depression. AB - OBJECTIVE: There are few randomized controlled trials examining the efficacy of long-term psychodynamic psychotherapy (LTPP) in depression treatment. LTPP was compared with fluoxetine treatment and their combination; METHODS: 272 depressed patients (aged 26-34, 72% with a first episode of depression) were randomized to receive LTPP (one session/week), fluoxetine treatment (20-60 mg/day) or their combination for 24 months. Beck Depression Inventory (BDI) was the outcome measure. The psychotherapy was not manualized and the treatment took place under real-life conditions in an outpatient psychiatric clinic. RESULTS: Intention-to treat analyses indicated that all the treatments were associated with significant reductions in the BDI scores (mean reduction of 18.88 BDI points). Furthermore, LTPP and combination therapy were more effective in reducing BDI scores than fluoxetine alone (22.08 and 22.04 vs. 12.53 BDI points). CONCLUSIONS: LTPP, pharmacological treatment with fluoxetine and their combination are effective in reducing symptoms of patients with moderate depression. LTPP and combined treatment were more effective compared to fluoxetine alone. These findings have implications for patients with depression who may benefit from long-term psychotherapy or combined treatment, or for depressed patients who do not wish to take medications such as fluoxetine. PMID- 25041334 TI - Skin photoprotection and consumption of coffee and polyphenols in healthy middle aged Japanese females. AB - BACKGROUND: Reactive oxygen species are known to mediate skin photoaging, which results in the formation of pigmented spots and wrinkles. Coffee is the largest source of polyphenols, which supplies a large number of antioxidants in one's daily life. However, little is known about how much coffee and polyphenol consumption influences skin health. In this study, a cross-sectional survey of the diet, environmental factors, and skin conditions was conducted in healthy Japanese females to explore the influence of coffee and polyphenol consumption on skin conditions. MATERIALS AND METHODS: Non-smoking, healthy female subjects with moderate sun exposure in their daily lives were recruited for this study (n = 131, age range: 30-60 years old) and recorded their food and beverage intake and life circumstances using questionnaires. The skin water content, transepidermal water loss, and elasticity were measured on the cheek of each subject using non invasive methods: a Corneometer, a Tewameter, and a Cutometer, respectively. Wrinkles and pigmented spots were evaluated using digital photograph images. RESULTS: Consumption of coffee and total polyphenols from all sources and from coffee showed a statistically significant correlation towards a decrease in pigmented spot scores (P < 0.05). Subjects with high total polyphenol consumption from coffee or chlorogenic acids (the third tertile group) showed the lowest score of ultraviolet pigmented spots (P < 0.05). CONCLUSION: Coffee and polyphenol consumption was associated with low facial pigmented spots in Japanese middle-aged females. We speculated that coffee helps protect human skin from photoaging, and polyphenols, including chlorogenic acids, may contribute to the decreased hyperpigmentation of pigmented spots. PMID- 25041335 TI - Trichoderma reesei XYN VI--a novel appendage-dependent eukaryotic glucuronoxylan hydrolase. AB - Expression of a Trichoderma reesei gene coding for a putative GH30 xylanase in Aspergillus oryzae led to isolation and purification of a novel xylanase exhibiting catalytic properties different from those of the previously characterized GH30 xylanase XYN IV of T. reesei. The novel enzyme, named XYN VI, exhibited catalytic properties similar to appendage-dependent GH30 glucuronoxylanases previously recognized only in bacteria. XYN VI showed high specific activity only on xylans or xylooligosaccharides containing 4-O-methyl-D glucuronic acid or D-glucuronic acid side substituents. The cleavage of the main chain takes place primarily at the second glycosidic linkage from the branch towards the reducing end of the polysaccharides or aldouronic acids. These catalytic properties resemble bacterial GH30 glucuronoxylanases, although the recognition of the uronic acid side chains by XYN VI is apparently based on interaction of the substrate with other amino acids. Moreover, in contrast to bacterial enzymes, XYN VI is also capable of slower but significant cleavage of unsubstituted parts of xylan and acidic xylooligosaccharides. The data point to a great catalytic diversity of xylanases produced by the most extensively studied cellulolytic fungus. PMID- 25041336 TI - If you want to be good, start early. PMID- 25041337 TI - Esophageal adenocarcinoma with white opaque substance observed by magnifying endoscopy with narrow band imaging. AB - White opaque substance (WOS) is observed in the gastric neoplasia of 0-IIa type using magnifying endoscopy with narrow band imaging (NBI-ME). Colonic and duodenal neoplasms with WOS have also been reported. Immunohistochemical examination with adipophilin reveals WOS in gastric neoplasms as lipid droplets, and WOS is specific for neoplasm with intestinal or gastrointestinal phenotype. We herein report a case of adenocarcinoma of the esophagogastric junction with WOS. A male patient in his sixties was found by esophagogastroduodenoscopy to have an esophageal elevated lesion. NBI-ME showed whitish deposits that looked similar to WOS in gastric neoplasms. The patient underwent endoscopic submucosal dissection and the lesion was resected in a single piece. This tumor had diffuse positivity for adipophilin and gastrointestinal phenotype. PMID- 25041339 TI - Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. AB - This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42-48%) versus tacrolimus groups (15-38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15-34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated. PMID- 25041340 TI - Age as a moderator of the secular trend for grip strength in Canada and the United States. AB - PURPOSE: To determine whether grip strength changed on average over recent decades at each of two age levels (children and adolescents versus adults) in Canada and the US. METHODS: For each sex, weighted least squares regression analyses were performed on mean grip strength values as reported in studies conducted from the 1960s onwards. RESULTS: Grip strength did not change significantly as a function of year tested in children and adolescents, whereas it declined as a negatively accelerated function of year tested in adults. CONCLUSION: The results are contrary to what might be expected given that body weight has increased in both countries in recent decades and given that grip strength has been found to be positively correlated with body weight. It is suggested that there was a concurrent change in a factor that operated to counteract the effect of increased body weight on grip strength, a prime candidate being a decrease in levels of serum vitamin D. It is also suggested that the secular decline in adult grip strength can be explained by a factor that affects muscular function but which has a long latency period, a prime candidate here being obesity history. PMID- 25041341 TI - Safety profile of a divided dose of propranolol for heart rate in children with infantile haemangioma during 16 weeks of treatment. AB - BACKGROUND: Although propranolol has been accepted as a first-line drug for infantile haemangioma (IH), no study has systematically characterized changes in heart rates during long-term propranolol treatment. OBJECTIVES: To evaluate the influence of a divided dose of propranolol on heart rates in patients with IH. METHODS: A prospective study was conducted from January 2009 to December 2013. All patients with IH were administered propranolol at 0.67 mg kg(-1) per day as a single dose on days 1 and 2, gradually increased to the full dose (2 mg kg(-1) per day) on day 5, which was given in three divided doses. Heart rates were recorded before treatment and were closely monitored during treatment. Heart rates in controls were monitored once a week. RESULTS: All heart rates monitored during treatment were found to be within the normal range. Fluctuations in heart rates were observed after every dose from the first day to the first dose of the sixth day; however, from the second dose of the sixth day onwards, no significant differences in heart rates were observed after each dose on successive days. During the second week of drug therapy, no significant differences in heart rates were observed at 1 h after the first dose (P = 1.00). Also, no significant differences (P = 0.73) in heart rates were observed between patients and controls at 1 h after the first dose on Mondays from week 1 to 16 of treatment. CONCLUSIONS: A three-times-daily dosing regimen of propranolol had no significant sustained effects on heart rates in subjects with IH. PMID- 25041342 TI - Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China. AB - BACKGROUND & AIMS: Several genome-wide association studies have revealed that HLA DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. METHODS: A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. RESULTS: HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46-0.82; rs9277535, OR = 0.56, 95% CI = 0.41-0.75; rs7453920, OR = 0.64, 95%CI = 0.47-0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24-0.96; rs9277535, OR = 0.43, 95% CI = 0.20-0.91; rs7453920, OR = 0.62, 95% CI = 0.39-0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58-0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P < 0.05), and a lower prevalence of HBV infection as previously reported. CONCLUSIONS: HLA-DP/DQ but not IL-28B polymorphisms correlate with HBV natural clearance, irrespective of race, and HLA DP/DQ would be causative genes attributing to varying prevalence in different regions. STAT4 rs7574865 seemed to be population specific in Tibetans and it might synergistically interact with virus contributing to disease progression. PMID- 25041343 TI - Prediction of long-term outcome by measurement of serum concentration of cardiac troponins in critically ill dogs with systemic inflammation. AB - BACKGROUND: Myocardial injury, detected by cardiac troponin I and T (cTnI and cTnT), has been associated with long-term death in the noncardiac human intensive care unit (ICU). HYPOTHESIS: Presence of myocardial injury predicts 1-year case fatality in critically ill dogs with systemic inflammation. ANIMALS: Thirty-eight dogs with evidence of systemic inflammation and no primary cardiac disease. METHODS: Prospective cohort study. In dogs admitted to the ICU with evidence of systemic inflammation, blood samples were obtained at ICU admission for measurement of cTnI and cTnT, and cTnI was measured once daily during ICU hospitalization. Receiver operating characteristic (ROC) curves were used to examine prognostic capacity of admission cTnI, admission cTnT, and peak cTnI concentrations. RESULTS: One-year case fatality rate was 47% (18/38 dogs). Admission cTnI concentrations were (median [range]) 0.48 [0.004-141.50] ng/mL, and peak cTnI concentrations were 1.21 [0.021-141.50] ng/mL. Admission cTnT concentrations were 15 [<13-3744] ng/L. For each marker, non-survivors had significantly higher concentrations than survivors (P = .0082-.038). ROC analyses revealed areas under curves [95% CI] of 0.707 [0.537-0.843] for peak cTnI and 0.739 [0.571-0.867] for admission cTnT, respectively. At the optimal cut-off, concentrations were 1.17 ng/mL (peak cTnI) and 23 ng/L (admission cTnT), sensitivities were 72% and 72%, and specificities were 70% and 80%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: While peak cTnI and admission cTnT are significantly related to 1-year case fatality in critically ill dogs with systemic inflammation, low sensitivities and specificities prevent their prediction of long-term outcome in individual patients. Troponins might play a role in identification of dogs at long-term risk of death. PMID- 25041344 TI - Clinical role of Notch signaling pathway in intraductal papillary mucinous neoplasm of the pancreas. AB - BACKGROUND AND AIM: This study was performed to elucidate the expression of the Notch signaling pathway and its correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs). It is incontrovertible that regulatory T cells (Tregs) play an important role in tumor immunity. However, the whole mechanism of control of peripheral Tregs remains unclear. It is also known that the Notch signaling pathway is involved in Treg suppressor function. Moreover, IPMNs have a high malignant potential. METHODS: Peripheral blood samples and resected specimens from 18 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, and anti-Notch2 intracellular domain antibody staining) and compared in terms of clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. RESULTS: Disease-free survival was significantly worse in the Notch1 high-expression group (P = 0.023). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P = 0.012; Notch2-intracellular domain, P = 0.036). Jagged1 expression was significantly higher in IPMC than in IPMA (P < 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P < 0.01). CONCLUSIONS: Notch signaling, especially Jagged1 expression, reflects IPMN aggressiveness. Our data may suggest that the Notch signaling pathway is a key pathway that determines IPMN pathological aggressiveness and reflects the peripheral Treg population. PMID- 25041345 TI - Blood transfusion in patients treated with surgery for necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a common surgical emergency in premature infants and has high morbidity and mortality. Intraoperative treatment with fluid and transfusions may be difficult. OBJECTIVES: We evaluated risk factors for patients who needed transfusion with packed red blood cells during surgery for necrotizing enterocolitis with bowel resection. METHODS: Retrospective medical and anesthetic record review of 206 patients who had necrotizing enterocolitis during 10 years at a pediatric referral center. RESULTS: In the 206 patients who had necrotizing enterocolitis, 88 patients (43%) had exploratory laparotomy, 67 with bowel resection. Of these, 50 needed transfusion of packed red blood cells in comparison with 17 who did not. Upon univariate analyses, patients who received packed red blood cells during surgery had significantly longer mean duration of surgery, lower preoperative hemoglobin and hematocrit, higher postoperative hemoglobin and hematocrit, more platelet transfusions, and greater estimated blood loss than patients who did not receive packed red blood cells during surgery. A binary logistic regression procedure revealed that the need for preoperative hemoglobin was found to be a significant risk factor for transfusion of packed red blood cells (odds ratio = 0.55; 95%CI = 0.36-0.84; P = 0.001). CONCLUSION: Patients having necrotizing enterocolitis with bowel resection are more likely to need preoperative transfusion with packed red blood cells, which may be more necessary when surgery is longer, preoperative hematocrit is lower, and estimated blood loss is higher. PMID- 25041346 TI - The impact of methadone maintenance therapy on hepatitis C incidence among illicit drug users. AB - AIMS: To determine the relationship between methadone maintenance therapy (MMT) and hepatitis C (HCV) seroconversion among illicit drug users. DESIGN: A generalized estimating equation model assuming a binomial distribution and a logit-link function was used to examine for a possible protective effect of MMT use on HCV incidence. SETTING: Data from three prospective cohort studies of illicit drug users in Vancouver, Canada between 1996 and 2012. PARTICIPANTS: A total of 1004 HCV antibody-negative illicit drug users stratified by exposure to MMT. MEASUREMENTS: Baseline and semi-annual HCV antibody testing and standardized interviewer-administered questionnaire soliciting self-reported data relating to drug use patterns, risk behaviors, detailed socio-demographic data and status of active participation in an MMT program. FINDINGS: One hundred and eighty-four HCV seroconversions were observed for an HCV incidence density of 6.32 [95% confidence interval (CI) = 5.44-7.31] per 100 person-years. After adjusting for potential confounders, MMT exposure was protective against HCV seroconversion [adjusted odds ratio (AOR) = 0.47; 95% CI = 0.29-0.76]. In subanalyses, a dose response protective effect of increasing MMT exposure on HCV incidence (AOR = 0.87; 95% CI = 0.78-0.97) per increasing 6-month period exposed to MMT was observed. CONCLUSION: Participation in methadone maintenance treatment appears to be highly protective against hepatitis C incidence among illicit drug users. There appears to be a dose-response protective effect of increasing methadone exposure on hepatitis C incidence. PMID- 25041347 TI - The cytidine deaminase signature HxE(x)n CxxC of DYW1 binds zinc and is necessary for RNA editing of ndhD-1. AB - In flowering plants, RNA editing involves deamination of specific cytidines to uridines in both mitochondrial and chloroplast transcripts. Pentatricopeptide repeat (PPR) proteins and multiple organellar RNA editing factor (MORF) proteins have been shown to be involved in RNA editing but none have been shown to possess cytidine deaminase activity. The DYW domain of some PPR proteins contains a highly conserved signature resembling the zinc-binding active site motif of known nucleotide deaminases. We modified these highly conserved amino acids in the DYW motif of DYW1, an editing factor required for editing of the ndhD-1 site in Arabidopsis chloroplasts. We demonstrate that several amino acids of this signature motif are required for RNA editing in vivo and for zinc binding in vitro. We conclude that the DYW domain of DYW1 has features in common with cytidine deaminases, reinforcing the hypothesis that this domain forms part of the active enzyme that carries out RNA editing in plants. PMID- 25041348 TI - Risperidone for non-psychotic disorders in paediatric patients: which child is to benefit? PMID- 25041349 TI - Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1): implications for GLP-1 measurements in clinical studies. AB - AIMS: To evaluate the performances of commercially available glucagon-like peptide-1 (GLP-1) assays and the implications for clinical studies. METHODS: Known concentrations (5-300 pmol/l) of synthetic GLP-1 isoforms (GLP-1 1-36NH2, 7 36NH2, 9-36NH2, 1-37, 7-37 and 9-37) were added to the matrix (assay buffer) supplied with 10 different kits and to human plasma, and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations. Endogenous GLP-1 levels in clinical samples were assessed using three commercial kits. RESULTS: The USCN LIFE assay detected none of the GLP-1 isoforms. The active GLP-1 enzyme-linked immunosorbent assays (ELISAs) from Millipore and DRG appeared identical and were specific for intact GLP-1 in buffer and plasma. The Meso Scale Discovery (MSD) total GLP-1 kit detected all six GLP-1 isoforms, although recovery of non-active forms was incomplete, especially in plasma. Millipore total GLP-1 ELISA kit detected all isoforms in buffer, but mainly amidated forms in plasma. The Alpco, Phoenix and Bio-Rad kits detected only amidated GLP-1, but the Alpco kit had a limited measurement range (30 pmol/l), the Phoenix kit had incomplete recovery in plasma and the Bio-Rad kit was insensitive (detection limit in plasma 40 pmol/l). The pattern of postprandial GLP-1 responses in clinical samples was similar between the kits tested, but the absolute concentrations measured varied. CONCLUSIONS: The specificity and sensitivity of commercially available kits for the analysis of GLP-1 levels vary considerably. This should be taken into account when selecting which assay to use and when comparing data from different studies. PMID- 25041350 TI - Renovating Situation Taxonomies: Exploring the Construction and Content of Fundamental Motive Situation Types. AB - The present work demonstrates a method for constructing theoretically based situational classifications and exploring their behavioral implications. Fundamental motives theory (FMT; Kenrick, Griskevicius, Neuberg, & Schaller, 2010; Kenrick, Neuberg, Griskevicius, Becker, & Schaller, 2010) proposes that humans have evolved seven specific social motives that would be differentially evoked by different situations. Experts in FMT used the Riverside Situational Q sort (RSQ) to describe prototypic motive-relevant situations and the Riverside Behavioral Q-sort (RBQ) to construct templates representing predictions of how people would behave in them. A sample of 201 undergraduate participants used the RSQ to describe situations they had experienced within the past 24 hours, and they described their behavior in each situation using the RBQ. For both the RSQ and RBQ, self-protection and disease avoidance templates were highly similar to each other and different from mate-seeking and affiliation templates. Participants more often reported experiencing situations similar to the mate seeking, affiliation, and kin care templates and less often reported experiencing situations similar to the self-protection and disease avoidance templates. Participants' reported behavior was consistent with expectations from FMT. This study illustrates how relations between situations and behavior can be illuminated through the use of theoretically derived templates. PMID- 25041351 TI - Chemical and biological mechanisms of pathogen reduction technologies. AB - Within the last decade new technologies have been developed and implemented which employ light, often in the presence of a photosensitizer, to inactivate pathogens that reside in human blood products for the purpose of transfusion. These pathogen reduction technologies attempt to find the proper balance between pathogen kill and cell quality. Each system utilizes various chemistries that not only impact which pathogens they can inactivate and how, but also how the treatments affect the plasma and cellular proteins and to what degree. This paper aims to present the various chemical mechanisms for pathogen reduction in transfusion medicine that are currently practiced or in development. PMID- 25041353 TI - Circular muscle contraction in the mice rectum plays a key role in morphine induced constipation. AB - BACKGROUND: Although opioids induce intestinal muscle contraction and provoke constipation, the intestinal region(s) that contribute to the constipation have remained unclear. We report here a region-specific response of intestinal muscle contraction to morphine and its correlation with in vivo constipation. METHODS: Regions of mice small and large intestines were dissected histologically and circular muscle contractile responses were measured using isometric transducers. Bead expulsion assays were performed to assess in vivo constipation. KEY RESULTS: The strongest contraction in response to morphine was detected in the rectum. The distal and transverse colon also showed strong contractions, whereas weak responses were detected in the proximal colon, jejunum, and ileum. Regarding the sustainability of muscle contractions during morphine exposure, prolonged waves were detected only in the rectum, while the waves diminished gradually in other regions. To identify the mechanism(s) underlying this difference, we focused on nitric oxide synthase (NOS). In the distal colon, decreased contraction during morphine exposure was recovered by application of a NOS inhibitor (L-NAME), while a NOS substrate (L-arginine) enhanced contractile degradation. In contrast L-NAME and L-arginine modestly affected the sustained contraction in the rectum. To confirm the correlation with constipation, beads were inserted into the transverse colon, distal colon, or rectum after morphine administration and expulsion times were examined. Beads tended to stop at the rectum even when inserted in the deeper colonic regions. CONCLUSIONS & INFERENCES: The rectum showed the greatest response to morphine in both in vitro and in vivo analyses, therefore it may play a key role for opioid-induced constipation. PMID- 25041354 TI - Prognostic significance of survivin in breast cancer: meta-analysis. AB - Survivin, an inhibitor of apoptosis protein, is a potentially prognostic factor and therapeutic target in breast carcinoma, but no consensus exists based on heterogeneous data. The aim of this present study is to clarify the prognostic relevance of survivin in breast cancer patients. Relevant articles were screened in PubMed and EMBASE databases. Patients' clinical characteristics, overall survival (OS), disease/recurrence-free survival (DFS/RFS) and positive expressed survivin rates were extracted for further analysis. Statistics extracted from Kaplan-Meier survival curves were calculated indirectly with methods developed by Parmar, Williamson, and Tierney. Multivariate Cox hazard regression analysis data were used directly in Stata 11.0. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to evaluate the prognostic role of survivin in breast cancer. Online literature search identified 23 articles containing 3,259 breast cancer patients. Our meta-analysis of all included studies about survival outcomes showed positive correlation between poor prognosis and survivin expression. Pooled HRs (95% CIs) for OS and DFS/RFS were 1.37 (1.12-1.68) and 1.34 (1.02-1.76), respectively. Subgroup analyses considering methods used to detect survivin (immunohistochemistry or not) and localization of survivin (whole, nuclear or cytoplasm of the cell) were also conducted, and all the above analyses supported the stability of the prognostic role of survivin. In addition, our study revealed a significant association between survivin expression and lymph node metastasis (OR: 2.74; 95% CI: 1.27-5.93) or stage of breast cancer (OR: 2.01; 95% CI: 1.29-3.13). Positive expression of survivin demonstrated a significantly higher risk of recurrence and decreased OS rates in breast cancer. PMID- 25041355 TI - Development of a multiplex PCR assay for rapid and simultaneous detection of four genera of fish pathogenic bacteria. AB - Species of genus Aeromonas, Vibrio, Edwardsiella and Streptococcus are the most common fish pathogenic bacteria that cause economically devastating losses in aquaculture. A multiplex polymerase chain reaction (mPCR) was developed for the simultaneous detection and differentiation of the four genera of fish pathogenic bacteria. Through the use of genus-specific primers instead of species-specific ones, the current mPCR covered much more target bacterial species compared with previously reported species-specific mPCR methods. The specificity of the four putative genus-specific primers was validated experimentally while used exclusively (uniplex PCR) or combined (mPCR) against bacterial genomic DNA templates of the target bacteria and nontarget bacteria. The PCR amplicons for the following genera were obtained as expected: Aeromonas (875 bp), Vibrio (524 bp), Edwardsiella (302 bp) and Streptococcus (197 bp), and the fragments could be separated clearly on the agarose gel electrophoresis. The mPCR did not produce nonspecific amplification products when used to amplify 21 nontarget species of bacteria. The mPCR detection limits for each target bacterial genera were 50 colony-forming units (CFU) in pure culture and 100 CFU in fish tissue samples. In conclusion, the mPCR assay was proven to be a powerful alternative to the conventional culture-based method, given its rapid, specific, sensitive and reliable detection of target pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: The fish pathogenic bacteria of genus Aeromonas, Vibrio, Edwardsiella and Streptococcus frequently cause severe outbreaks of diseases in cultured fish, and the genus-specific multiplex PCR assay developed in this study can detect the bacteria of the four genera when present in the samples either alone or mixed. The mPCR assay is expected to identify the causative agents more efficiently than uniplex PCR or species-specific multiplex PCR for clinical diagnosis, resulting in the earlier implementation of control measures. This mPCR assay provides a rapid, specific and sensitive tool for the detection or identification of common fish pathogenic bacteria in aquaculture practice. PMID- 25041356 TI - Switching patients from clopidogrel to prasugrel in acute coronary syndrome: impact of the clopidogrel loading dose on platelet reactivity. AB - OBJECTIVES: The present study aimed to assess the pharmacodynamic response of a prasugrel 60-mg loading dose (LD) alone compared with prasugrel 60 mg added to clopidogrel 600 mg. BACKGROUND: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) commonly receive a clopidogrel LD prior to angiography. Switching these patients to prasugrel may be desirable because higher platelet inhibition is expected. METHODS: In this open label, multicenter, nonrandomized trial, 75 patients were categorized into 2 treatment strategies: Those who received a clopidogrel 600-mg LD and received a reloading dose of prasugrel 60 mg (clopidogrel/prasugrel group) and those who did not receive a clopidogrel LD and received a prasugrel 60-mg LD (prasugrel group). Platelet reactivity was assessed using VerifyNow P2Y12 reaction units (PRU) and Platelet Reactivity Index vasodilator-stimulated phosphoprotein phosphorylation (PRI-VASP) at 3 different times: at the sheath insertion prior to prasugrel LD, 4 hours after prasugrel LD, and at discharge. RESULTS: Four hours after prasugrel LD, platelet reactivity did not differ between the clopidogrel/prasugrel group and the prasugrel group according to the VerifyNow assay (median PRU 23 [5-71] vs. 54 [5-91], respectively; P = 0.18) and the VASP assay (median PRI 8.67 [4.51 16.85] versus 8.03 [4.82-21.72], respectively; P = 1.0). No significant differences in PRU and PRI were observed at discharge. Few bleeding events were reported without any significant differences between the 2 groups. CONCLUSIONS: Platelet reactivity with prasugrel 60 mg added to a clopidogrel 600-mg LD was not significantly different compared with prasugrel 60 mg alone in ACS patients undergoing PCI. PMID- 25041352 TI - Heart failure and Alzheimer's disease. AB - It has recently been proposed that heart failure is a risk factor for Alzheimer's disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer's disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed. PMID- 25041357 TI - Serum 25-hydroxyvitamin D concentrations in dogs - correlation with health and cancer risk. AB - 25-hydroxyvitamin D (25(OH)D) is important in bone health as well as many diseases including cancer. Supplementation may increase responsiveness of cancer cells to chemotherapy. Serum 25(OH)D, intact parathyroid hormone (iPTH) and canine C-reactive protein (c-CRP) were measured in healthy dogs and dogs with haemoabdomen. Regression analysis determined optimal 25(OH)D concentrations. In healthy dogs (n = 282), mean iPTH concentrations correlated inversely (r(2) = 0.88, P < 0.001) to 25(OH)D concentrations. Variation in both iPTH and c-CRP plateaued at 25(OH)D concentrations of 100-120 ng mL(-1) . Haemoabdomen dogs (n = 63, 43 malignant and 20 benign) had 25(OH)D concentrations ranging from 19.4 to >150 ng mL(-1) . Relative risk of cancer increased with decreasing 25(OH)D concentrations [RR = 3.9 for 25(OH)D below 40 ng mL(-1) (P = 0.0001)]. Serum 25(OH)D concentrations in dogs vary widely, and are influenced by dietary VitD content. Serum vitD measurement can identify dogs for which supplementation may improve health and response to cancer therapy. PMID- 25041358 TI - Ethnic variations in cervical cytokine concentrations and vaginal flora during pregnancy. AB - PROBLEM: Pregnancy-mediated changes in immunity may influence risk of HIV-1 acquisition. This risk appears greatest among non-Caucasian women. METHOD OF STUDY: Pregnant women with low risk of immune disruption were enrolled in a prospective observational cohort. Study visits occurred each trimester and postpartum. Semi-quantitative vaginal cultures and concentrations of cervical cytokines were compared between Caucasian and non-Caucasian women. RESULTS: In the second trimester, non-Caucasian women were more likely to be colonized with Gardnerella vaginalis (62% versus 25%, P = 0.02) and non-pigmented anaerobic gram negative rods (43% versus 8%, P = 0.01). Mycoplasma hominis was more frequently isolated in non-Caucasian women throughout the second (29% versus 4%, P = 0.03) and third trimesters (35% versus 6%, P = 0.04). Non-Caucasian women had higher median interleukin (IL)-10 concentrations throughout the second (128 pg/mL versus 7 pg/mL, P = 0.05) and third trimesters (224 pg/mL versus 7 pg/mL, P = 0.05). CONCLUSION: Non-Caucasian women experienced a greater diversity of microorganisms and increased IL-10 in the second and third trimesters. PMID- 25041359 TI - Aortic valve stenosis planimetry by means of three-dimensional transesophageal echocardiography in the real clinical setting: feasibility, reliability and systematic deviations. AB - AIMS: To assess the feasibility and reliability of aortic valve area (AVA) planimetry by means of three-dimensional transesophageal echocardiography (3DTEE) as compared with the transthoracic echocardiogram (TTE) calculation of AVA, to determine the systematic deviations between measurements, and to describe the distribution of mean systolic in relation with 3DTEE anatomical AVA. METHODS AND RESULTS: Three hundred seven patients with aortic valve stenosis (AVS) underwent both TTE and 3DTEE for AVA measurement by means of the continuity equation and direct anatomical planimetry, respectively. AVA planimetry was achieved in 282 (91.9%) of patients. Severity of the aortic valve calcification was independently associated with a poorer performance of planimetry. Intraclass correlation coefficient yielded a 0.848 (95% CI: 0.807-0.879) value. 3DTEE rendered a mild constant underestimation of AVA in comparison with TTE. Severe aortic stenosis according to the area criterion (<1 cm(2) ) despite mean systolic gradient below 40 mm Hg was detected in 37.6% of the study population, and in 33.7% of the subset of patients with preserved left ventricular ejection fraction. CONCLUSIONS: Reliability of AVA planimetry by 3DTEE in comparison with the calculation by TTE is good, but 3DTEE underestimates slightly the measurement. Feasibility of the technique is good but independently affected by valvular calcification. Inconsistent classification of AVS severity as graded by AVA or mean systolic gradient is observed in the overall population and in patients with preserved systolic function. PMID- 25041360 TI - A case of mucocutaneous leishmaniasis diagnosed by serology. AB - A 43-year-old Japanese Bolivian male had been suffering from a right leg ulcer after an insect bite during his residence in Bolivia. The ulcer healed after herbal medicine treatment. Ten years later, the patient had symptoms of nasal obstruction, nasal bleeding, and pharyngodynia, which were accompanied by a destructive ulcer with surrounding erythema involving the right nostril apex and columella. Papillary, irregular mucosal lesions were seen on the soft palate. Giemsa staining and polymerase chain reaction (PCR) using biopsy specimens of the papillary mucosal lesions on the soft palate failed to identify Leishmania parasites. However, the IgG antibody test was positive for Leishmania (Leishmania) donovani, and the dot enzyme-linked immunosorbent assay (dot-ELISA) using five Leishmania antigens L. (L.) mexicana, L. (L.) amazonensis, Leishmania (Viannia) guyanensis, L. (V.) braziliensis, and L. (V.) panamensis was positive. Combined, the findings suggested mucocutaneous leishmaniasis. Treatment with liposomal amphotericin B was started but was soon terminated because of palpitation, epigastralgia and facial flushing. It is sometimes difficult to identify the parasites in lesions of mucocutaneous leishmaniasis and serological tests are useful for such occasions. PMID- 25041361 TI - Polypharmacy and potentially inappropriate medication use in older adults with cancer undergoing chemotherapy: effect on chemotherapy-related toxicity and hospitalization during treatment. AB - OBJECTIVES: To evaluate the prevalence of polypharmacy and potentially inappropriate medication (PIM) use and the association between these and chemotherapy-related adverse events in older adults with cancer undergoing chemotherapy. DESIGN: Secondary analysis of prospectively collected data. SETTING: Outpatient oncology clinics in seven academic medical centers. PARTICIPANTS: Adults aged 65 and older with cancer undergoing chemotherapy. MEASUREMENTS: Measures included number of daily medications (polypharmacy); PIM use based on three indices (Beers, Zhan, and Drugs to Avoid in the Elderly criteria), and use of six "high risk" medication classes for adverse drug events (anticoagulants, antiplatelet agents, opioids, insulin, oral hypoglycemics, antiarrhythmics). Using multivariate logistic regression, the relations were evaluated between these criteria and Grade 3 to 5 chemotherapy-related toxicity and between these criteria and hospitalization during chemotherapy. RESULTS: Participants (N=500; mean age 73, 61% Stage IV disease) took a mean of 5+/-4 daily medications (range 0-23). PIM use was common (up to 29% according to Beers criteria). No association was found between number of daily medications (reference 0-3 medications) and toxicity (4-9 medications, odds ratio (OR)=1.34, 95% confidence interval (CI)=0.92-1.97; >=10 medications, OR=0.82, 95% CI=0.45 1.49) or hospitalization (>=4 medications, OR=1.34, 95% CI=0.82-2.18, P=.24). There was also no association between PIM use and toxicity (P=.93) or hospitalization (P=.98). No medication class was associated with either outcome. CONCLUSIONS: Polypharmacy and PIM use were common but were not associated with chemotherapy-related toxicity or hospitalization in older adults with cancer. PMID- 25041362 TI - Rational design of CXCR4 specific antibodies with elongated CDRs. AB - The bovine antibody (BLV1H12) which has an ultralong heavy chain complementarity determining region 3 (CDRH3) provides a novel scaffold for antibody engineering. By substituting the extended CDRH3 of BLV1H12 with modified CXCR4 binding peptides that adopt a beta-hairpin conformation, we generated antibodies specifically targeting the ligand binding pocket of CXCR4 receptor. These engineered antibodies selectively bind to CXCR4 expressing cells with binding affinities in the low nanomolar range. In addition, they inhibit SDF-1-dependent signal transduction and cell migration in a transwell assay. Finally, we also demonstrate that a similar strategy can be applied to other CDRs and show that a CDRH2-peptide fusion binds CXCR4 with a K(d) of 0.9 nM. This work illustrates the versatility of scaffold-based antibody engineering and could greatly expand the antibody functional repertoire in the future. PMID- 25041363 TI - Activation-induced cytidine deaminase regulates activity-dependent BDNF expression in post-mitotic cortical neurons. AB - Activity-dependent gene expression depends, in part, on transcriptional regulation that is coordinated by rapid changes in the chromatin landscape as well as the covalent modification of DNA. Here we demonstrate that the expression of brain-derived neurotrophic factor (BDNF), a gene that is critically involved in neural plasticity and subject to epigenetic regulation, is regulated by the RNA/DNA editing enzyme, activation-induced cytidine deaminase (AID). Similar to previous reports, we observed an activity-dependent induction of BDNF exon IV mRNA expression, which correlated with a reduction in DNA methylation within the BDNF P4 promoter. Lentiviral-mediated knockdown of AID disrupted these effects and inhibited BDNF exon IV mRNA expression, an effect that was associated with decreased cAMP response element-binding protein occupancy within the BDNF P4 promoter. Thus, together with other epigenetic mechanisms, AID plays a key role in regulating activity-dependent BDNF expression in post-mitotic cortical neurons. PMID- 25041364 TI - Suppression of the TGF-beta1-induced protein expression of SNAI1 and N-cadherin by miR-199a. AB - MicroRNA miR-199a is clustered with miR-214 on chromosome 1 and its expression is up-regulated by various factors that are associated with epithelial-to mesenchymal transition (EMT), such as a transcriptional repressor Twist1 and transforming growth factor (TGF)-beta. miR-199a is either up-regulated or down regulated in a variety of cancers, although EMT is associated with the progression of cancer. We found here that miR-199a suppressed the translation of SNAI1, a transcriptional repressor that plays a role in EMT, by targeting the sequence within the 3'UTR of the SNAI1 mRNA, and reduced the protein level of SNAI1. miR-199a increased the protein level of claudin-1 in both the TGF-beta1 treated and -untreated cells at least partly by decreasing the protein level of SNAI1, a transcriptional repressor for claudin-1. In addition, miR-199a targeted the sequence within the 3'UTR of the N-cadherin mRNA and suppressed the TGF-beta1 induced increase in the protein level of N-cadherin in a manner independent of SNAI1. These results indicate that miR-199a suppresses the TGF-beta1-induced protein expression of SNAI1 and N-cadherin. PMID- 25041365 TI - A case report of different degrees of the left anterior, septal and posterior fascicular branch block. AB - We present a rare case of various conduction defects involving the left anterior, septal, and posterior branch in one patient. The different degrees of block of anterior, septal, and posterior fascicular of the left bundle branch indicate pathological changes in left ventricle. However, the values of this electrocardiographic presentation indicating the left ventricular function still need more investigations. PMID- 25041366 TI - A registry of HLA-typed donors for production of virus-specific CD4 and CD8 T lymphocytes for adoptive reconstitution of immune-compromised patients. AB - BACKGROUND: Virus-specific CD4 and CD8 T lymphocytes from HLA-matched donors are effective for treatment and prophylaxis of viral infections in immune-compromised recipients of hematopoietic stem cell transplant recipients. Adoptive immune reconstitution is based on selection of specific T cells or on generation of specific T-cell lines from the graft donor. Unfortunately, the graft donor is not always immune to the relevant pathogen or the graft donor may not be available (registry-derived or cord blood donors). STUDY DESIGN AND METHODS: Since the possibility of using T cells from a third-party subject is now established, we screened potential donors for T-cell responses against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, the viruses most frequently targeted by adoptive immune reconstitution. Specific T-cell responses against viral antigens were analyzed in 111 donors using a miniaturized interferon-gamma release assay. RESULTS: Responders to CMV were 64%, to EBV 40%, and to adenovirus 51%. Simultaneous responders to the three viruses were 49%. CMV-specific CD4 and CD8 T cell lines could be generated from 11 of 12 donors defined as positive responders according to the T-cell assay. CONCLUSIONS: These data demonstrate that a large fraction of volunteers can be recruited in a donor registry for selection or expansion of virus specific T cells and that our T-cell assay predicts the donors' ability to give rise to established T-cell lines endowed with proliferative potential and effector function for adoptive immune reconstitution. PMID- 25041368 TI - Development of tear production and intraocular pressure in healthy canine neonates. AB - OBJECTIVE: The aim of this study was to investigate the development of aqueous tear production and intraocular pressure in healthy canine neonates between 2 and 12 weeks of age. ANIMALS: One litter, consisting of 8 healthy Beagle dogs--four males and four females-was used. PROCEDURES: Between the age of 2 and 12 weeks, tear production and intraocular pressure were measured weekly in both eyes. Tear production was measured by Schirmer tear test, before (STT1) and after (STT2) topical anesthesia and drying of the conjunctival sac. Intraocular pressure (IOP) was measured using a rebound tonometer. As no significant differences existed between left and right eye measurements (STT1, STT2, and IOP) at all time points, only right eye measurements were further analyzed. RESULTS: STT1, STT2, and IOP values increased significantly until the age of 9 weeks for STT1, until the age of 10 weeks for STT2, and until the age of 6 weeks and again between 10 and 11 weeks of age for IOP. IOP decreased significantly between 11 and 12 weeks of age. There were no significant differences in STT1, STT2, and IOP between males and females, except for IOP at 10 and 12 weeks of age. No significant correlation was demonstrated between body weight and STT1 or STT2. CONCLUSIONS: STT1, STT2, and IOP values increased significantly in the first weeks after birth. The results of this study indicate that separate reference values for tear production and intraocular pressure need to be established for neonatal dogs. PMID- 25041367 TI - TRPC6 regulates cell cycle progression by modulating membrane potential in bone marrow stromal cells. AB - BACKGROUND AND PURPOSE: Ca(2+) influx is important for cell cycle progression, but the mechanisms involved seem to vary. We investigated the potential roles of transient receptor potential (TRP) channels and store-operated Ca(2+) entry (SOCE)-related molecules STIM (stromal interaction molecule)/Orai in the cell cycle progression of rat bone marrow stromal cells (BMSCs), a reliable therapeutic resource for regenerative medicine. EXPERIMENTAL APPROACH: PCR and immunoblot analyses were used to examine mRNA and protein levels, fluorescence imaging and patch clamping for Ca(2+) influx and membrane potential measurements, and flow cytometry for cell cycle analysis. KEY RESULTS: Cell cycle synchronization of BMSCs revealed S phase-specific enhancement of TRPC1, STIM and Orai mRNA and protein expression. In contrast, TRPC6 expression decreased in the S phase and increased in the G1 phase. Resting membrane potential (RMP) of BMSCs was most negative and positive in the S and G1 phases, respectively, and was accompanied by an enhancement and attenuation of SOCE respectively. Chemically depolarizing/hyperpolarizing the membrane erased these differences in SOCE magnitude during the cell cycle. siRNA knockdown of TRPC6 produced a negative shift in RMP, increased SOCE and caused redistribution of BMSCs with increased populations in the S and G2 /M phases and accumulation of cyclins A2 and B1. A low concentration of Gd(3+) (1 MUM) suppressed BMSC proliferation at its concentration to inhibit SOC channels relatively specifically. CONCLUSIONS AND IMPLICATIONS: TRPC6, by changing the membrane potential, plays a pivotal role in controlling the SOCE magnitude, which is critical for cell cycle progression of BMSCs. This finding provides a new therapeutic strategy for regulating BMSC proliferation. PMID- 25041371 TI - Changes of metabolic parameters during electroconvulsive treatment of schizophrenia: Preliminary results. PMID- 25041372 TI - Systematic review: the association between eosinophilic oesophagitis and coeliac disease. AB - BACKGROUND: The relationship between eosinophilic oesophagitis (EoE) and coeliac disease (CD) remains controversial, with studies yielding varied results. AIM: To systematically review the evidence of a possible association between both diseases. METHODS: Electronic searches were performed with keywords relating to EoE and CD in the MEDLINE, EMBASE and SCOPUS databases. Summary estimates were calculated. A random-effects model was used depending on heterogeneity (I(2) ). Publication bias was assessed with the aid of funnel plot analysis, along with the Begg-Mazumdar, Harbord and Egger tests. RESULTS: The search yielded 197 references; 30 were included in the quantitative summary, with most of these presenting methodological inconsistencies. Significant publication bias in favour of short studies reporting positive associations between both diseases was documented. The prevalence of EoE in CD ranged from 0% to 10.7% (I(2) = 78.9%). Prevalence of CD in EoE varied between 0.16% and 57.1% (I(2) = 89%). One high quality, prospective, randomly selected, population-based study documented a 1.1% prevalence of CD, with no patients presenting EoE. Clinical and methodological heterogeneity hindered the performance of quantitative summaries for prevalence data. A gluten-free diet was effective in achieving histological remission of EoE in 32.1% of coeliac patients (95% confidence interval, 14.9-52.2%; I(2) = 52.2%), which was similar to that expected for wheat elimination in EoE patients. CONCLUSIONS: While a lack of valid studies prevents us from completely ruling out a true association between EoE and CD, currently available evidence does not support this hypothesis. Indeed, the only epidemiological study with sufficient validity points to the independence of both diseases. PMID- 25041370 TI - Short-term effects of a modified Alt-RAMEC protocol for early treatment of Class III malocclusion: a controlled study. AB - OBJECTIVES: To assess the effects of a modified alternate rapid maxillary expansion and constriction (Alt-RAMEC) protocol in combination with facemask (FM) in Class III growing patients. SETTING AND SAMPLE POPULATION: Thirty one Class III patients (17 males, 14 females) were treated with a modified Alt-RAMEC/FM protocol at the Department of Orthodontics of the University of Florence. MATERIAL AND METHODS: All patients were evaluated at the beginning (T1, mean age 6.4 +/- 0.8 years) and at the end of orthopedic therapy (T2, mean age 8.1 +/- 0.9 years), and they were compared to a matched sample of 31 Class III patients (16 males and 15 females) treated with rapid maxillary expansion and facemask (RME/FM) and to a matched control group of 21 subjects (9 males and 12 females) with untreated Class III malocclusion. The three groups were compared with anova with Benjamini-Hochberg correction for multiple tests. RESULTS: Both the Alt RAMEC/FM and the RME/FM protocols showed significantly favorable effects leading to correction of the Class III malocclusion. The Alt-RAMEC/FM protocol produced a more effective advancement of the maxilla (SNA +1.2 degrees ) and greater intermaxillary changes (ANB +1.7 degrees ) vs. the RME/FM protocol. No significant differences were recorded as for mandibular skeletal changes and vertical skeletal relationships. CONCLUSION: The Alt-RAMEC/FM protocol induced more favorable skeletal short-term effects compared with RME/FM therapy in Class III growing patients. PMID- 25041369 TI - Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3(+) regulatory T cells. AB - Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg ) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8(+) T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-betaRII) mice to recombination-activating gene (Rag)1(-/-) recipients. We then used this robust established adoptive transfer system and co-transferred CD8(+) T cells from dnTGF-betaRII mice with either C57BL/6 or dnTGF-betaRII forkhead box protein 3 (FoxP3(+) ) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-betaRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versus dnTGF-betaRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-betaRII mice. Our data reflect the therapeutic potential of wild-type CD4(+) FoxP3(+) Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC. PMID- 25041373 TI - Genetic structure of an introduced paper wasp, Polistes chinensis antennalis (Hymenoptera, Vespidae) in New Zealand. AB - Several eusocial wasps are prominent invaders to remote islands. The paper wasp Polistes chinensis antennalis is native to East Asia, was introduced to New Zealand in 1979 and has expanded its distribution there. This provides an excellent opportunity to examine the impacts of an initial bottleneck and subsequent expansion on genetic structure. We analysed and compared the genetic population structures of the native (Japan and South Korea) and invasive New Zealand populations. Although 94% of individuals had shared haplotypes detected across both populations, the remaining 6% had private haplotypes identified in only one of the three countries. The genetic variation at microsatellite loci was lower in New Zealand than in native countries, and the genetic structure in New Zealand was clearly distinct from that in its native range. Higher frequencies of diploid-male- and triploid-female-producing colonies were detected in New Zealand than in the native countries, showing the reduction in genetic variation via a genetic bottleneck. At least two independent introductions were suggested, and the putative source regions for New Zealand were assigned as Kanto (central island) and Kyushu (south island) in Japan. Serial founder events following the initial introduction were also indicated. The estimated dispersal distance between mother and daughter in New Zealand was twice that in Japan. Thus, the introduction history of P. chinensis antennalis in New Zealand is probably the result of at least two independent introductions, passing through a bottleneck during introduction, followed by population expansion from the point of introduction. PMID- 25041374 TI - A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC. PMID- 25041375 TI - Parathyroid hormone-related peptide and the hair cycle - is it the agonists or the antagonists that cause hair growth? AB - While the effects of PTHrP have been studied for almost 20 years, most of these studies have focused on effects on the termination of the anagen phase, giving an incomplete picture of the overall effect of PTHrP on the hair cycle. PTHrP was determined in several experimental models to promote transition of hair follicles from anagen to catagen phase, which by itself would suggest that PTHrP blockade might prolong the anagen phase and promote hair growth. However, clinical trials with topically applied PTHrP antagonists have been disappointing, leading to a reconsideration of this model. Additional studies performed in mouse models where hair follicles are damaged (alopecia areata, chemotherapy-induced alopecia) suggest that PTHrP has effects early in the hair cycle as well, promoting hair follicles' entry into anagen phase and initiates the hair cycle. While the mechanism of this has yet to be elucidated, it may involve activation of the Wnt pathway. Thus, the overall effect of PTHrP is to stimulate and accelerate the hair cycle, and in the more clinically relevant models of hair loss where hair follicles have been damaged or become quiescent, it is the agonists, not the antagonists, which would be expected to promote hair growth. PMID- 25041376 TI - An exploration of the practice of restricting a child's movement in hospital: a factorial survey. AB - AIMS AND OBJECTIVES: To identify the reported predictors of the practice of restricting a child for a clinical procedure in hospital. BACKGROUND: Previous work in this area is dominated by discussion papers and suggestions for addressing the issue of restriction. This is the first study to explore reported predictors of this practice with a view to implementing change based on research findings. DESIGN: A factorial survey was developed, which incorporated the use of vignettes with various scenarios. The factorial design enabled exploration of the interaction of multiple factors on the practice of restriction. METHODS: One hundred and sixty-six nurses caring for children were each sent 10 vignettes and asked to rate their likelihood to restrict a child based on the vignettes. A total of 105 nurses responded to the survey, representing a response rate of 63%. Hierarchical linear regression was used to identify reported predictors of restriction. RESULTS: Nurses were more likely to restrict a child if they had prior instruction on safe holding, if there was no play therapist available, if the nurse was a registered general nurse with no other registration qualification, if the child required cannulation or if the child was less than five years of age. CONCLUSION: This study identified predictors of restriction from the perspective of practicing nurses; the evidence needs to be used in developing clinical guidelines and in multidisciplinary education. RELEVANCE TO CLINICAL PRACTICE: There is a need to move from any presumption of restriction towards more critical consideration of the individual requirements of the child. There is a need to increase the numbers of nurses receiving specialist training on the care of a child in hospital. The importance of a well-resourced play therapy service is supported, and there is a need for multidisciplinary work to explore alternatives to restriction. PMID- 25041377 TI - A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF 05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01). AB - AIMS: The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed. METHODS: In this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg(-1) intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria. RESULTS: Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax , AUC (0 , t last) and AUC(0,infinity) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term 'pyrexia' was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA). CONCLUSIONS: This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. PMID- 25041378 TI - Predictors of Alveolar Process Remodeling Following Ridge Preservation in High Risk Patients. AB - PURPOSE: (1) To clinically evaluate horizontal remodeling of the alveolar process (hard and soft tissues) following ridge preservation in high-risk patients and (2) to identify predictors of such remodeling. MATERIALS AND METHODS: Periodontally healthy nonsmoking patients with a failing tooth in the anterior maxilla (15-25) were selected for a prospective case series. All were in need of a single implant and demonstrated high risk for aesthetic complications given an incomplete buccal bone wall and/or thin-scalloped gingival biotype. Following flapless tooth extraction, ridge preservation was performed using one or more collagen-enriched, bovine-derived block grafts (Geistlich Bio-Oss(r) Collagen(r) 100 mg, Geistlich Pharma AG, Wolhusen, Switzerland) without the additional use of membranes or soft tissue grafts. The change in buccopalatal dimension of the alveolar process between baseline (prior to tooth extraction) and 4 months was assessed on the basis of superimposed occlusal slides. Regression analysis was performed to identify predictors of alveolar process remodeling. RESULTS: Forty two patients (21 females, 21 males; mean age 38) met the selection criteria and consented to the treatment. Mean alveolar process remodeling was 14% (SD 7, range 4-30) with minimal remodeling (<= 10%) in 16 patients (38%) and advanced remodeling (>20%) in 10 patients (24%). A single implant could be installed in all subjects without additional guided bone regeneration. Connective tissue grafting was performed later on in the treatment for aesthetic purposes, hereby compensating for tissue loss at the buccal aspect. Predictors of alveolar process remodeling were tooth location (central incisors and cuspids > laterals incisors and premolars), tooth abscess (p = .025), and buccal bone loss (p = .035). CONCLUSION: Alveolar process remodeling seems inevitable yet acceptable following ridge preservation in high-risk patients. Proper case selection may reduce the incidence of advanced remodeling. PMID- 25041379 TI - Region-specific dysregulation of glycogen synthase kinase-3beta and beta-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia. AB - OBJECTIVES: There is both direct and indirect evidence suggesting abnormalities of glycogen synthase kinase (GSK)-3beta and beta-catenin, two important components of the Wingless-type (Wnt) signaling pathway, in the pathophysiology of bipolar illness and possibly schizophrenia (SZ). In order to further clarify the role of the Wnt signaling pathway in the pathophysiology of bipolar disorder (BP) and SZ, we studied GSK-3beta and beta-catenin in the postmortem brains of subjects with these disorders. METHODS: We determined the protein expression of GSK-3beta, phosphorylated form at serine 9 position (pGSK-3-ser-9), and beta catenin using the western blot technique, and mRNA using the quantitative polymerase chain reaction (qPCR) method, in the dorsolateral prefrontal cortex (DLPFC), cingulate gyrus (CG), and temporal cortex (TEMP) obtained from 19 subjects with BP, 20 subjects with SZ, and 20 normal control (NC) subjects. RESULTS: We found that the protein expression of GSK-3beta, pGSK-3beta-ser-9, and beta-catenin was significantly decreased in the DLPFC and TEMP, but not in the CG, of subjects with BP compared with NC subjects. The mRNA expression of GSK 3beta and beta-catenin was significantly decreased in the DLPFC and TEMP, but not in the CG, of subjects with BP compared with NC subjects. There were no significant differences in the protein or mRNA expression of GSK-3beta, pGSK 3beta-ser-9, or beta-catenin between subjects with SZ and NC subjects in any of the brain areas studied. CONCLUSIONS: These studies show region-specific abnormalities of both protein and mRNA expression of GSK-3beta and beta-catenin in postmortem brains of subjects with BP but not subjects with SZ. Thus, abnormalities of the Wnt signaling pathway may be associated with the pathophysiology of bipolar illness. PMID- 25041380 TI - Sarcomatoid carcinoma of the prostate: ERG fluorescence in-situ hybridization confirms epithelial origin. PMID- 25041381 TI - Does preoperative urodynamics improve outcomes for women undergoing surgery for stress urinary incontinence? A systematic review and meta-analysis. AB - BACKGROUND: Urodynamics is widely used in the investigation of urinary incontinence. The existing evidence questions its add-on value in improving the outcome of surgical treatment for stress urinary incontinence (SUI). OBJECTIVES: To compare the surgical outcomes in women with SUI or stress-predominant mixed urinary incontinence (MUI) based on urodynamic diagnoses compared with diagnoses based on office evaluation without urodynamics. SEARCH STRATEGY: We searched Cochrane, MedLine, Embase, CINAHL, LILACS, metaRegister of Controlled Trials (mRCT) and Google Scholar databases from inception until March 2013. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing surgical outcomes in women investigated by urodynamics and women who had office evaluation only. DATA COLLECTION AND ANALYSIS: Two independent reviewers (S.R. and P.L.) extracted the data and analysed it using review manager (revman) 5.2 software. MAIN RESULTS: Of the 388 articles identified, only four RCTs met our criteria. The data from one study are as yet unpublished. In the other three RCTs, the women with SUI or stress-predominant MUI were randomised either to office evaluation and urodynamics (n = 388) or to office evaluation only (n = 387). There was no statistical difference in the risk ratio (RR) of subjective cure in the two groups (RR 1.02, 95%CI 0.90-1.15, P = 0.79, I(2) = 45%), objective cure (RR 1.01, 95%CI 0.93-1.11, P = 0.28, I(2) = 20%) or complications such as voiding dysfunction (RR 1.54, 95%CI 0.61-3.89, P = 0.27, I(2) = 18%) or urinary urgency (RR 0.80, 95%CI 0.28-2.3, P = 0.19, I(2) = 40%). AUTHORS' CONCLUSIONS: In women undergoing primary surgery for SUI or stress-predominant MUI without voiding difficulties, urodynamics does not improve outcomes - as long as the women undergo careful office evaluation. PMID- 25041382 TI - Assessment of deep tissue hyperalgesia in the groin - a method comparison of electrical vs. pressure stimulation. AB - BACKGROUND: Deep pain complaints are more frequent than cutaneous in post surgical patients, and a prevalent finding in quantitative sensory testing studies. However, the preferred assessment method - pressure algometry - is indirect and tissue unspecific, hindering advances in treatment and preventive strategies. Thus, there is a need for development of methods with direct stimulation of suspected hyperalgesic tissues to identify the peripheral origin of nociceptive input. METHODS: We compared the reliability of an ultrasound guided needle stimulation protocol of electrical detection and pain thresholds to pressure algometry, by performing identical test-retest sequences 10 days apart, in deep tissues in the groin region. Electrical stimulation was performed by five up-and-down staircase series of single impulses of 0.04 ms duration, starting from 0 mA in increments of 0.2 mA until a threshold was reached and descending until sensation was lost. Method reliability was assessed by Bland-Altman plots, descriptive statistics, coefficients of variance and intraclass correlation coefficients. RESULTS: The electrical stimulation method was comparable to pressure algometry regarding 10 days test-retest repeatability, but with superior same-day reliability for electrical stimulation (P < 0.05). Between-subject variance rather than within-subject variance was the main source for test variation. There were no systematic differences in electrical thresholds across tissues and locations (P > 0.05). CONCLUSION: The presented tissue-specific direct deep tissue electrical stimulation technique has equal or superior reliability compared with the indirect tissue-unspecific stimulation by pressure algometry. This method may facilitate advances in mechanism based preventive and treatment strategies in acute and chronic post-surgical pain states. PMID- 25041383 TI - Effects of a hydrogel patch on denture-related traumatic ulcers; an exploratory study. AB - PURPOSE: The aim of this exploratory study was to evaluate the effects of hydrogel patch wound dressing on healing time and pain level of denture-related lesions of the oral mucosa in edentulous individuals. MATERIALS AND METHODS: Twenty-three adults with newly fabricated complete sets of dentures who subsequently developed at least two ulcerative lesions related to their complete dentures were included in the study. For each participant, the smaller lesion (control lesion) was allocated to usual care, that is, adjustment of the denture's margins, whereas the larger lesion (test lesion) was assigned to receive usual care plus application of a hydrogel patch. In the latter, a patch was applied directly on the affected area three times within the first 24 hours, followed by application of three additional patches, namely one during each of the following 3 days. Participants were monitored until complete healing of all ulcers. The primary outcome measures were changes since baseline in each lesion's greatest dimension at days 1 and 7, as well as improvement in ulcer-related pain experienced. RESULTS: Participants were on average about 70 years old, about half were women, and just over 40% had type 2 diabetes. Lesions treated with the hydrogel patch extended between 4.3 and 10.2 mm (mean 7.1 mm) in their greatest dimension, and the smaller lesions receiving usual care were initially 4 mm on average, ranging from 2.0 to 7.0 mm. The hydrogel patch lesions attained 25% to 75% reductions in their greatest lesion extent from baseline to days 1 and 7, respectively, compared to 10% and just over 50% reduction in the lesions that received usual care. Healing rates were similar in patients with and without diabetes. The participants reported significant improvement in pain level 1 day following treatment initiation for 30% of the control lesions, compared to 65% of the lesions treated with the hydrogel patch. CONCLUSIONS: The results of this exploratory study suggest that application of hydrogel patches may represent a novel, effective treatment for accelerating the healing process and pain reduction in mucosal lesions associated with complete dentures also in people with type 2 diabetes; however, larger studies need to confirm these findings. PMID- 25041384 TI - Addressing quality in endocrine care. PMID- 25041385 TI - Small group learning: graduate health students' views of challenges and benefits. AB - Abstract Background: For health care professionals, particularly nurses, the need to work productively and efficiently in small groups is a crucial skill required to meet the challenges of the contemporary health-care environment. Small group work is an educational technique that is used extensively in nurse education. The advantage of group work includes facilitation of deep, active and collaborative learning. However, small group work can be problematic and present challenges for students. Many of the challenges occur because group work necessitates the coming together of collections of individuals, each with their own personalities and sets of experiences. Aim: This study aimed to identify challenges and benefits associated with small group work and to explore options for retaining the positive aspects of group work while reducing or eliminating the aspects the students experienced as negative. Method: Online survey; thematic analysis. Results: Over all, students experienced a range of challenges that necessitated the development of problem-solving strategies. However, they were able to elucidate some enjoyable and positive aspects of group work. Implications for teaching and learning are drawn from this study. Conclusion: The ability to work effectively in small groups and teams is essential for all health care workers in the contemporary health environment. Findings of this study highlight the need for educators to explore novel and effective ways in which to engage nurses in group work. PMID- 25041386 TI - Qualified doctor and medical students' use of resources for accessing information: what is used and why? AB - BACKGROUND: Learning to access information using resources such as books and search engines is an important and fast changing challenge for doctors and medical students. Many resources exist to support evidence-based clinical decision-making, but a wide range of factors influences their use. OBJECTIVE: To explore qualified doctor and medical students' use of resources for accessing information and to determine what is used and why. METHODS: A stratified sample of 46 participants was recruited in Devon, UK. Participants kept a self-report diary of resources used over a week. The diaries were then used to stimulate recall within a semi-structured interview. Diary data were collated into tables of resource use. Qualitative data from the interviews were transcribed verbatim and thematically analysed. RESULTS: Many resources were used by participants but typically for a short duration of time. Categories of reasons for accessing resources were 'to check', 'to learn' and 'to demonstrate'. The two main factors influencing choice of information resource were 'ease of access' and 'quality of information'. Students accessed more information, for a longer duration. DISCUSSION & CONCLUSION: Resources must be quick to use, easy to access and tailored to the different purposes that they serve for qualified doctors and medical students. PMID- 25041387 TI - Ventricular Tracking of Atrial Flutter in a Patient with Complete Atrioventricular Block: Is it the Device's Fault? PMID- 25041388 TI - Tuning the developing brain to emotional body expressions. AB - Reading others' emotional body expressions is an essential social skill. Adults readily recognize emotions from body movements. However, it is unclear when in development infants become sensitive to bodily expressed emotions. We examined event-related brain potentials (ERPs) in 4- and 8-month-old infants in response to point-light displays (PLDs) of happy and fearful body expressions presented in two orientations (upright and inverted). The ERP results revealed that 8-month olds but not 4-month-olds respond sensitively to the orientation and the emotion of the dynamic expressions. Specifically, 8-month-olds showed (i) an early (200 400 ms) orientation-sensitive positivity over frontal and central electrodes, and (ii) a late (700-1100 ms) emotion-sensitive positivity over temporal and parietal electrodes in the right hemisphere. These findings suggest that orientation sensitive and emotion-sensitive brain processes, distinct in timing and topography, develop between 4 and 8 months of age. PMID- 25041399 TI - Abstracts of the 50th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 25-27 August, 2014, Melbourne, Australia. PMID- 25041400 TI - Appendicitis caused by gelatin-based haemostatic agent. PMID- 25041401 TI - Lupus anticoagulant testing and anticoagulation do not mix: quantitation of discrepant results and potential approaches to reduce false positives. PMID- 25041389 TI - Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand. AB - LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, (ii) > 100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (Ki > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [(3) H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15 min at 37 degrees C) and binds with high affinity to both human (Kd = 0.06 +/- 0.01 nM) and rat (Kd = 0.2 +/- 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [(3) H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [(3) H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype. PMID- 25041402 TI - The prevalence of isolated growth hormone deficiency among children of short stature in Jordan and its relationship with consanguinity. AB - OBJECTIVE: The prevalence of isolated growth hormone deficiency (IGHD) among short-statured children in Jordan, where consanguineous marriage (CM) is common, is unknown. No studies have investigated the relationship between degrees of consanguinity and IGHD. This study aimed to determine the prevalence of IGHD among short-statured children referred to a university hospital in Jordan and its relationship with different degrees of consanguinity. DESIGN: We conducted a 24 month cross-sectional observational trial at an outpatient tertiary care center in Amman, Jordan. PATIENTS: We obtained detailed family histories, medical evaluations and laboratory tests for 94 short-statured children (50 boys and 44 girls aged 6-16 years). MEASUREMENTS: Complete and partial GHD were defined as peak GH responses of 5 and 7 MUg/l (15 and 21 mIU/l) [IRMA/DiaSorin(r)], respectively, in both exercise and insulin tolerance tests. RESULTS: GHD was diagnosed in 69.1% of the short children, including 86% (43/50) of the children of consanguineous parents (83.3%, 93.8% and 81.8% of children of first cousins, first cousins once removed and second cousins, respectively) and 50% (20/44) of the children of nonconsanguineous parents (P = 0.039, 0.002 and 0.013, respectively). However, there was no statistically significant difference in the prevalence of small pituitary MRI between GH-deficient children of consanguineous parents and those of nonconsanguineous parents (28.6% vs 13.6%, P = 0.3). CONCLUSIONS: The prevalence of IGHD among referred short children in Jordan was exceptionally high and significantly higher in the children of CM. In countries where CM is common, preconception counselling and rigorous surveillance for GHD in short children may be indicated. PMID- 25041403 TI - A combined chemical and enzymatic method to determine quantitatively the polysaccharide components in the cell wall of yeasts. AB - A reliable method to determine cell wall polysaccharides composition in yeast is presented, which combines acid and enzymatic hydrolysis. Sulphuric acid treatment is used to determine mannans, whereas specific hydrolytic enzymes are employed in a two sequential steps to quantify chitin and the proportion of beta-(1,3) and beta-(1,6)-glucan in the total beta-glucan of the cell wall. In the first step, chitin and beta-(1,3)-glucan were hydrolysed into their corresponding monomers N acetylglucosamine and glucose, respectively, by the combined action of a chitinase from Streptomyces griseus and a pure preparation of endo/exo-beta-(1,3) glucanase from Trichoderma species. This step was followed by addition of recombinant endo-beta-(1,6)-glucanase from Trichoderma harzianum with beta glucosidase from Aspergillus niger to hydrolyse the remaining beta-glucan. This latter component corresponded to a highly branched beta-(1,6)-glucan that contained about 75-80% of linear beta-(1,6)-glucose linked units as deduced from periodate oxidation. We validated this novel method by showing that the content of beta-(1,3), beta-(1,6)-glucan or chitin was dramatically decreased in yeast mutants defective in the biosynthesis of these cell wall components. Moreover, we found that heat shock at 42 degrees C in Saccharomyces cerevisiae and treatment of this yeast species and Candida albicans with the antifungal drug caspofungin resulted in 2- to 3-fold increase of chitin and in a reduction of beta-(1,3) glucan accompanied by an increase of beta-(1,6)-glucan, whereas ethanol stress had apparently no effect on yeast cell wall composition. PMID- 25041404 TI - Predicting recurrence patterns after resection of hepatocellular cancer. AB - BACKGROUND: The reliable prediction of hepatocellular carcinoma (HCC) recurrence patterns potentially allows for the prioritization of patients for liver resection (LR) or transplantation. OBJECTIVES: The aim of this study was to analyse clinicopathological factors and preoperative Milan criteria (MC) status in predicting patterns of HCC recurrence. METHODS: During 1992-2012, 320 patients undergoing LR for HCC were categorized preoperatively as being within or beyond the MC, as were recurrences. RESULTS: After a median follow-up of 47 months, 183 patients developed recurrence, giving a 5-year cumulative incidence of recurrence of 62.5%. Patients with preoperative disease within the MC had better survival outcomes than those with preoperative disease beyond the MC (median survival: 102 months versus 45 months; P < 0.001). Overall, 31% of patients had preoperative disease within the MC and 69% had preoperative disease beyond the MC. Estimated rates of recurrence-free survival at 5 years were 61.8% for all patients and 53.8% for patients with initial beyond-MC status. Independent factors for recurrence beyond-MC status included preoperative disease beyond the MC, the presence of microsatellite or multiple tumours and lymphovascular invasion (all: P < 0.001). A clinical risk score was used to predict survival and the likelihood of recurrence beyond the MC; patients with scores of 0, 1, 2 and 3 had 5- year incidence of recurring beyond-MC of 9.0%, 29.5%, 48.8% and 75.4%, respectively (P < 0.0001). CONCLUSIONS: Regardless of initial MC status, at 5 years the majority of patients remained disease-free or experienced recurrence within the MC after LR, and thus were potentially eligible for salvage transplantation (ST). Incorporating clinicopathological parameters into the MC allows for better risk stratification, which improves the selection of patients for ST and identifies patients in need of closer surveillance. PMID- 25041406 TI - Quantitative trait loci mapping of metal concentrations in leaves of the maize IBM population. AB - Characterizing concentrations of several beneficiary and toxic metals in maize leaves is of importance for ionomic studies and for silage production. The intermated B73 * Mo17 maize population (IBM) was evaluated for concentrations of eight metals (cadmium - Cd, copper - Cu, iron - Fe, potassium - K, magnesium - Mg, manganese - Mn, strontium - Sr and zinc - Zn) in ear-leaf to map quantitative trait loci (QTL) with 2161 molecular markers across the genome. QTL analysis revealed nine significant QTLs for concentrations of Cd, Cu, Fe, K, Mg and Sr combined over two environments. Median resolution for the QTL interval was less than 1 cM on a regular F2 map, which is a big improvement compared with the prior mapping (8 cM). The highest LOD scores of 15.52 and 15.31 were detected for K and Cd concentrations, respectively, explaining more than 20 percent of the phenotypic variance. No QTLs were found to be colocalized. QTL mapping in the IBM population did not confirm our earlier QTL results demonstrating considerable QTL *genetic background interaction. The only exception is confirmation of the major QTL for Cd accumulation on chromosome 2. Our results could facilitate further genetic and physical mapping of genes for metal accumulation in maize. PMID- 25041405 TI - Atomic force microscopic imaging of Acanthamoeba castellanii and Balamuthia mandrillaris trophozoites and cysts. AB - Light microscopy and electron microscopy have been successfully used in the study of microbes, as well as free-living protists. Unlike light microscopy, which enables us to observe living organisms or the electron microscope which provides a two-dimensional image, atomic force microscopy provides a three-dimensional surface profile. Here, we observed two free-living amoebae, Acanthamoeba castellanii and Balamuthia mandrillaris under the phase contrast inverted microscope, transmission electron microscope and atomic force microscope. Although light microscopy was of lower magnification, it revealed functional biology of live amoebae such as motility and osmoregulation using contractile vacuoles of the trophozoite stage, but it is of limited value in defining the cyst stage. In contrast, transmission electron microscopy showed significantly greater magnification and resolution to reveal the ultra-structural features of trophozoites and cysts including intracellular organelles and cyst wall characteristics but it only produced a snapshot in time of a dead amoeba cell. Atomic force microscopy produced three-dimensional images providing detailed topographic description of shape and surface, phase imaging measuring boundary stiffness, and amplitude measurements including width, height and length of A. castellanii and B. mandrillaris trophozoites and cysts. These results demonstrate the importance of the application of various microscopic methods in the biological and structural characterization of the whole cell, ultra-structural features, as well as surface components and cytoskeleton of protist pathogens. PMID- 25041408 TI - A computational framework for prime implicants identification in noncoherent dynamic systems. AB - Dynamic reliability methods aim at complementing the capability of traditional static approaches (e.g., event trees [ETs] and fault trees [FTs]) by accounting for the system dynamic behavior and its interactions with the system state transition process. For this, the system dynamics is here described by a time dependent model that includes the dependencies with the stochastic transition events. In this article, we present a novel computational framework for dynamic reliability analysis whose objectives are i) accounting for discrete stochastic transition events and ii) identifying the prime implicants (PIs) of the dynamic system. The framework entails adopting a multiple-valued logic (MVL) to consider stochastic transitions at discretized times. Then, PIs are originally identified by a differential evolution (DE) algorithm that looks for the optimal MVL solution of a covering problem formulated for MVL accident scenarios. For testing the feasibility of the framework, a dynamic noncoherent system composed of five components that can fail at discretized times has been analyzed, showing the applicability of the framework to practical cases. PMID- 25041409 TI - A hydrologic retention system and water quality monitoring program for a human decomposition research facility: concept and design. AB - Forensic taphonomy is an essential research field; however, the decomposition of human cadavers at forensic science facilities may lead to nutrient loading and the introduction of unique biological compounds to adjacent areas. The infrastructure of a water retention system may provide a mechanism for the biogeochemical processing and retention of nutrients and compounds, ensuring the control of runoff from forensic facilities. This work provides a proof of concept for a hydrologic retention system and an autonomous water quality monitoring program designed to mitigate runoff from The Southeast Texas Applied Forensic Science (STAFS) Facility. Water samples collected along a sample transect were analyzed for total phosphorous, total nitrogen, NO3-, NO2-, NH4, F(-), and Cl(-). Preliminary water quality analyses confirm the overall effectiveness of the water retention system. These results are discussed with relation to how this infrastructure can be expanded upon to monitor additional, more novel, byproducts of forensic science research facilities. PMID- 25041407 TI - Longitudinal association between television watching and computer use and risk markers in diabetes in the SEARCH for Diabetes in Youth Study. AB - BACKGROUND: The study provides evidence of the longitudinal association between screen time with hemoglobin A1c (HbA1c) and cardiovascular risk markers among youth with type 1 diabetes (T1D) and type 2 diabetes (T2D). OBJECTIVE: To examine the longitudinal relationship of screen time with HbA1c and serum lipids among youth with diabetes. SUBJECTS: Youth with T1D and T2D. METHODS: We followed up 1049 youth (>=10 yr old) with recently diagnosed T1D and T2D participating in the SEARCH for Diabetes in Youth Study. RESULTS: Increased television watching on weekdays and during the week over time was associated with larger increases in HbA1c among youth with T1D and T2D (p-value <0.05). Among youth with T1D, significant longitudinal associations were observed between television watching and TG (p-value <0.05) (week days and whole week), and low-density lipoprotein cholesterol (LDL-c, p-value <0.05) (whole week). For example, for youth who watched 1 h of television per weekday at the outset and 3 h per weekday 5 yr later, the longitudinal model predicted greater absolute increases in HbA1c (2.19% for T1D and 2.16% for T2D); whereas for youth who watched television 3 h per weekday at the outset and 1 h per weekday 5 yr later, the model predicted lesser absolute increases in HbA1c (2.08% for T1D and 1.06% for T2D). CONCLUSIONS: Youth with T2D who increased their television watching over time vs. those who decreased it had larger increases in HbA1c over 5 yr. Youth with T1D who increased their television watching over time had increases in LDL-c, TG, and to a lesser extent HbA1c. PMID- 25041410 TI - The female reproductive cycle of the neotropical snake Atractus pantostictus (Fernandes and Puorto, 1993) from south-eastern Brazil. AB - Data on reproductive activity of fossorial species are limited because the specimens are difficult to be observed and captured. Here in, we present the reproductive cycle of female Atractus pantostictus, a fossorial neotropical species, and the sexual maturity of males and females in south-eastern Brazil. The female reproductive cycle of A. pantostictus is seasonal, with vitellogenic follicles being found from September to April and eggs in November, February, March and April with the number varying between two and four. Spermatozoa were found in the lumen of the glandular and non-glandular uterus in females collected during the rainy season. Sperm storage tubules were found in the posterior infundibulum of the females, where the storage of sperm occurs for a short time. The storage may occur because mating and ovulation are dissociated. PMID- 25041411 TI - Dynamic, high precision targeting of growth modulating agents is able to trigger pollen tube growth reorientation. AB - The pollen tube is the most rapidly growing cell in the plant kingdom and has the function to deliver the sperm cells for fertilization. The growing tip region of the cell behaves in a chemotropic manner to respond to the guidance cues emitted by the pistil and the female gametophyte, but how it perceives and responds to these directional triggers is virtually unknown. Quantitative assessment of chemotropic behavior can greatly be enhanced by the administration of pharmacological or other biologically active agents at subcellular precision, which is a technical challenge when the target area moves as it grows. We developed a laminar flow based microfluidic device that allows for continuous administration of two different solutions with a movable interface that permits the dynamic targeting of the growing pollen tube apex over prolonged periods of time. Asymmetric administration of calcium revealed that rather than following the highest calcium concentration as would be expected with simple chemotropic behavior, the pollen tube of Camellia targets an optimal concentration suggesting the presence of two superimposed mechanisms. Subcellular application of pectin methyl esterase (PME), an enzyme that modifies the growth behavior by rigidifying the pollen tube cell wall, caused the tube to turn away from the agent - providing important evidence for a previously proposed conceptual model of the growth mechanism. PMID- 25041412 TI - In vivo long-term effects of retinoic acid exposure in utero on induced tumours in adult mouse skin. AB - BACKGROUND: Retinoic acid (RA) and its analogues (retinoids) are promising agents in skin cancer prevention following either topical application or oral administration. However, long-term in vivo effects of RA on chemically induced hyperplastic epidermal foci in adult mouse skin have also been described, casting some doubt with regard to its chemopreventive activity. HYPOTHESIS/OBJECTIVES: To characterize chemically induced skin tumours and to investigate the in vivo long term action and preventive effect of RA on adult mouse skin carcinogenesis. ANIMALS: Fifty-six adult Naval Medical Research Institute mice, exposed (n = 28) or not exposed (n = 28) to RA in utero. METHODS: Mice were treated with a standard two-stage skin carcinogenesis protocol, which included an initiating application of 7,12-dimethylbenz(a)anthracene followed by promotion with 12-O tetradecanoylphorbol 13-acetate. RESULTS: Retinoic acid administered to pregnant mice showed a long-term inhibitory action on cell differentiation and development of chemically induced tumours on the adult skin of their offspring, as well as a stimulatory effect on cell proliferation and expression of an early marker of malignant progression (keratin 13). CONCLUSIONS AND CLINICAL IMPORTANCE: The results suggest that RA exposure in utero confers long-lasting effects on adult mouse skin carcinogenesis. These include chemopreventive activity (reduced number of tumours), as well as enhancement of squamous papilloma progression, which appears to be due to enhanced keratinocyte proliferation and suppression of epidermal maturation. The clinical significance of these findings is not known for other routes of RA administration at this time. PMID- 25041413 TI - Available web-based dental implants information for patients. How good is it? AB - BACKGROUND: Massive use of the Internet for health issues has raised concerns about the quality of the information available and about consumers' ability to tell "good" from "bad" information. PURPOSE: To assess the quality of patient addressed, dental implants-related websites in terms of reliability, accessibility, usability and readability. MATERIALS AND METHODS: Two search engines (Google and Yahoo) were used in this study. The first 100 sites, as listed by each engine, were considered for the study. Each site was categorised and analysed for quality using the DISCERN and the LIDA instruments. The Flesch Kinkaid Reading Grade Level (FKRGL) and the Flesh Reading Ease Score (FRES) were used to assess legibility. RESULTS: After applying the inclusion and exclusion criteria, 32 single websites entered the study. The median score for the DISCERN instrument (3 [2-3]) indicated serious or potentially important shortcoming in the quality of the information obtained. LIDA scores showed modest percentages for accessibility (79.36 [74.60-85.31]) and intermediate for usability (59.20 (50.46-68.51)) and reliability (55.55 [45.37-66.66]). Legibility indices reached scores within the range of difficult to read (FRES = 51.72 [38.70-55.27]); FKRGL = 12.76 [10.07-14.87]). CONCLUSIONS: Available e-health information on dental implants in English language is difficult to read for the average patient and poor in terms of quality. PMID- 25041414 TI - Icons in paediatrics: Arvo Henrik Ylppo (1887-1992). PMID- 25041415 TI - Numerical model of dog mast cell tumor treated by electrochemotherapy. AB - Electrochemotherapy is a combination of high electric field and anticancer drugs. The treatment basis is electroporation or electropermeabilization of the cell membrane. Electroporation is a threshold phenomenon and, for efficient treatment, an adequate local distribution of electric field within the treated tissue is important. When this local electric field is not enough, there is a regrown tumor cell; however, if it is stronger than necessary, permanent damage to the tissue occurs. In the treatment of dogs, electrochemotherapy is not yet an established treatment for mast cell tumor in veterinary medicine, although there are studies showing evidence of its effectiveness. In this study, we examined electrochemotherapy of dog mast cell tumor with numerical simulation of local electric field distribution. The experimental result was used to validate the numerical models. The effect of tumor position and tissue thickness (tumor in different parts of dog body) was investigated using plate electrodes. Our results demonstrated that the electrochemotherapy is efficient and flexible, and even when the tumor extends into the subcutis, the treatment with plate electrode eliminated the tumor cells. This result suggests that electrochemotherapy is a suitable method to treat mast cell tumors in dog. PMID- 25041416 TI - Genetic analysis of twinning rate and milk yield using a threshold-linear model in Japanese Holsteins. AB - The objective of this study was to estimate genetic parameters and breeding values for the twinning rate of the first three parities (T1, T2 and T3) and 305 day milk yield in first lactation (MY), using a four-trait threshold-linear animal model in Japanese Holsteins. Data contained 1 323 946 cows calving between 1990 and 2007. Twinning was treated as a binary character: 'single' or 'twin or more'. Reported T1, T2 and T3 were 0.70%, 2.87%, and 3.73%, respectively. Individual 305-day milk yield was computed using a multiple trait prediction for cows with at least eight test-day records. (Co)variance components were estimated via Gibbs sampling for randomly sampled subsets. Posterior means of heritabilities for T1, T2 and T3 were 0.11, 0.16 and 0.14, respectively. Genetic correlations between parities were 0.92 or greater. Genetic correlations of MY with twinning rate were not 'significant' (i.e. their 95% highest probability density intervals contained zeros). Multiple births at different parities were considered as the same genetic trait. The average evaluations of T1 (T2) for sires born before 1991 was 0.48% (2.25%) compared with a mean of 0.76% (3.37%) for sires born after 1992. A recent increase in the reported twinning rate reflects the positive genetic trend for sires in Japanese Holsteins. PMID- 25041417 TI - Coordination between water transport capacity, biomass growth, metabolic scaling and species stature in co-occurring shrub and tree species. AB - The significance of xylem function and metabolic scaling theory begins from the idea that water transport is strongly coupled to growth rate. At the same time, coordination of water transport and growth seemingly should differ between plant functional types. We evaluated the relationships between water transport, growth and species stature in six species of co-occurring trees and shrubs. Within species, a strong proportionality between plant hydraulic conductance (K), sap flow (Q) and shoot biomass growth (G) was generally supported. Across species, however, trees grew more for a given K or Q than shrubs, indicating greater growth-based water-use efficiency (WUE) in trees. Trees also showed slower decline in relative growth rate (RGR) than shrubs, equivalent to a steeper G by mass (M) scaling exponent in trees (0.77-0.98). The K and Q by M scaling exponents were common across all species (0.80, 0.82), suggesting that the steeper G scaling in trees reflects a size-dependent increase in their growth based WUE. The common K and Q by M exponents were statistically consistent with the 0.75 of ideal scaling theory. A model based upon xylem anatomy and branching architecture consistently predicted the observed K by M scaling exponents but only when deviations from ideal symmetric branching were incorporated. PMID- 25041418 TI - Synchronous dynamics and correlations between bacteria and phytoplankton in a subtropical drinking water reservoir. AB - Both phytoplankton and bacteria are key and abundant components of aquatic ecosystems and play pivotal roles in maintaining ecosystem structure and function. However, the extent to which phytoplankton community succession influences changes in bacterial community composition (BCC) is largely unknown. In this study, we evaluated the correlations between bacteria and phytoplankton communities and determined the relative contribution of phytoplankton community succession to temporal variation of BCC in a subtropical drinking water reservoir (Tingxi Reservoir, southeast China). Bacterial communities were investigated by quantitative PCR and 454 pyrosequencing of 16S rRNA genes, while phytoplankton communities were analyzed by light microscopy. A remarkable seasonal succession from Cyanophyta to Bacillariophyta was observed during the study period, and this succession can accurately predict the distribution and abundance of the bacterial OTUs based on the discriminant function analysis. Association networks revealed that 38 of the 46 abundant bacterial OTUs exhibited significant correlations with phytoplankton. More interestingly, the positive correlations dominated the associated network, which may suggest that facilitative correlations between phytoplankton and bacteria are more important than inhibitory correlations in the Tingxi Reservoir. In addition, some bacterial OTUs were closely correlated with the dynamics of Microcystis, and they were affiliated with the divisions Acidobacteria, Actinobacteria, and Proteobacteria. Structural equation model showed that succession of phytoplankton community explained the largest part of temporal variation in BCC. Therefore, our data suggest that the distinct succession of phytoplankton community may mediate the temporal dynamics of bacterial community in the Tingxi Reservoir. PMID- 25041419 TI - Clinical outcome of deep brain stimulation for dystonia: constant-current or constant-voltage stimulation? A non-randomized study. AB - BACKGROUND AND PURPOSE: Bilateral globus pallidus deep brain stimulation (GPi DBS) represents an effective and relatively safe therapy for different forms of refractory dystonia. The aim of this study was to assess, retrospectively, the effect of two different stimulation settings during GPi-DBS in 22 patients affected by primary generalized or multi-segmental dystonia. METHODS: Thirteen patients were stimulated using a voltage-controlled setting whilst in the other nine patients a current-controlled setting was used. Clinical features were evaluated for each patient at baseline, 6 months and 12 months after surgery by means of the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Globus pallidus deep brain stimulation was effective in all patients. However, comparing constant current and constant-voltage stimulation, a better outcome was found in the current-controlled group during the last 6 months of follow-up. CONCLUSIONS: Current-controlled stimulation is effective during GPi-DBS for primary dystonia and it could be a better choice than voltage-controlled stimulation over long term follow-up. PMID- 25041420 TI - Region-specific regulation of the serotonin 2A receptor expression in development and ageing in post mortem human brain. AB - AIMS: The serotonin 2A receptor (HTR2A) is widely expressed in the brain and involved in the modulation of fear, mood, anxiety and other symptoms. HTR2A and HTR2A gene variations are implicated in depression, schizophrenia, anxiety and obsessive-compulsive disorder. To understand HTR2A signalling changes in psychiatric or neurodegenerative disorders, its normal pattern of brain expression and region specificity during development and ageing needs to be clarified. The aim of the present study was to assess HTR2A expression through developmental and ageing stages in six brain regions in post mortem human brain samples from individuals with no clinical or neuropathological evidence of neuropsychiatric disorders and to investigate the interaction with the rs6311 HTR2A promoter polymorphism. METHODS: DNA, RNA and protein were isolated from post mortem brain samples including six regions (frontal cortex, striatum, amygdala, thalamus, brain stem and cerebellum) from 55 individuals. HTR2A mRNA levels were assessed using quantitative real-time RT-PCR and HTR2A protein levels - with Western blot. The rs6311 HTR2A polymorphism was analysed with genotyping. RESULTS: We found that HTR2A mRNA and protein levels are differentially regulated with age in different brain regions studied, but are not affected by gender. Significant changes in HTR2A expression with age were found in frontal cortex, amygdala, thalamus, brain stem and cerebellum. CONCLUSIONS: Our results show plasticity and region specificity of HTR2A expression regulation in human brain with age, which may be important for the interaction with other neurotransmitter systems and for the occurrence of developmental periods with increased vulnerability to neuropsychiatric or neurodegenerative disorders. PMID- 25041421 TI - Toxin YafQ increases persister cell formation by reducing indole signalling. AB - Persister cells survive antibiotic and other environmental stresses by slowing metabolism. Since toxins of toxin/antitoxin (TA) systems have been postulated to be responsible for persister cell formation, we investigated the influence of toxin YafQ of the YafQ/DinJ Escherichia coli TA system on persister cell formation. Under stress, YafQ alters metabolism by cleaving transcripts with in frame 5'-AAA-G/A-3' sites. Production of YafQ increased persister cell formation with multiple antibiotics, and by investigating changes in protein expression, we found that YafQ reduced tryptophanase levels (TnaA mRNA has 16 putative YafQ cleavage sites). Consistently, TnaA mRNA levels were also reduced by YafQ. Tryptophanase is activated in the stationary phase by the stationary-phase sigma factor RpoS, which was also reduced dramatically upon production of YafQ. Tryptophanase converts tryptophan into indole, and as expected, indole levels were reduced by the production of YafQ. Corroborating the effect of YafQ on persistence, addition of indole reduced persistence. Furthermore, persistence increased upon deleting tnaA, and persistence decreased upon adding tryptophan to the medium to increase indole levels. Also, YafQ production had a much smaller effect on persistence in a strain unable to produce indole. Therefore, YafQ increases persistence by reducing indole, and TA systems are related to cell signalling. PMID- 25041422 TI - Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer? AB - OBJECTIVES: To determine whether oncological outcomes are improved in prostate cancer patients by using a multidisciplinary strategy as compared with a standard clinic paradigm, and whether time to treatment is delayed when using a multidisciplinary approach. METHODS: We retrospectively analyzed patients who were evaluated and pursued radical prostatectomy as primary treatment, by the same surgeons, in the prostate cancer multidisciplinary clinic (n = 194) and standard urology clinic (n = 741) at Duke University Medical Center from 2005 to 2009. Comparisons of baseline characteristics were examined using rank sum and chi(2) -tests. Differences in time to radical prostatectomy and oncological outcomes were evaluated using multivariate linear and Cox regression, respectively. RESULTS: A greater proportion of high-risk patients (D'Amico criteria) were evaluated at the multidisciplinary clinic compared with the urology clinic (23.2% vs 15.6%, P = 0.014). Mean-adjusted time from biopsy to radical prostatectomy was shorter for multidisciplinary clinic patients (85.6 vs 96.8 days, P = 0.006). After a median follow up of 21 months, no significant difference was found between the multidisciplinary clinic and urology clinic in the risk of biochemical recurrence after radical prostatectomy, whether controlling for clinical (hazard ratio 0.71, P = 0.249) or pathological variables (hazard ratio 0.75, P = 0.349). CONCLUSIONS: Despite higher-risk disease, men evaluated using the multidisciplinary approach have similar oncological outcomes compared with men undergoing standard evaluation. Furthermore, time to radical prostatectomy is not delayed by the multidisciplinary management of these patients. PMID- 25041423 TI - Occupational contact dermatitis in blue-collar workers: results from a multicentre study from the Danish Contact Dermatitis Group (2003-2012). AB - BACKGROUND: Blue-collar workers have a high risk of occupational contact dermatitis, but epidemiological studies are scarce. OBJECTIVES: To investigate allergic contact dermatitis in blue-collar workers with dermatitis registered by the Danish Contact Dermatitis Group. METHODS: A retrospective analysis of patch test data from 1471 blue-collar workers and 1471 matched controls tested between 2003 and 2012 was performed. A logistic regression was used to test for associations. RESULTS: The blue-collar workers often had occupational hand dermatitis (p < 0.001). Atopic dermatitis was less commonly observed among blue collar workers (19.6%) than among controls (23.9%) (p = 0.005). Allergens with a statistically significant association with the occupational group of blue-collar workers were epoxy resins, methyldibromo glutaronitrile, 2-bromo-2-nitro-1,3 propanediol, potassium dichromate, and methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI). The following occupations were additionally identified as risk factors for contact sensitization to MCI/MI and MI, epoxy resins, and potassium dichromate, respectively: painting, construction work, and tile setting/terrazzo work. CONCLUSION: Contact allergy is a major problem among blue-collar workers. The data indicate a healthy worker effect among blue-collar workers diagnosed with dermatitis, as blue-collar workers were diagnosed significantly less often with atopic dermatitis than were controls. PMID- 25041424 TI - Empyema of the nasal conchal bulla as a cause of chronic unilateral nasal discharge in the horse: 10 cases (2013-2014). AB - REASONS FOR PERFORMING STUDY: Empyema of the nasal conchal bullae has recently been identified in horses suffering from chronic unilateral nasal discharge. The diagnosis and management of such cases has not been reported previously. OBJECTIVES: To describe the diagnosis and treatment of cases suffering from empyema of the nasal conchal bullae and report the frequency of diagnosis from a population of horses referred for head computed tomography (CT). STUDY DESIGN: Retrospective case review. METHODS: Records from cases diagnosed with nasal conchal bulla disease using CT were reviewed. RESULTS: Abnormalities of the nasal conchal bullae were identified by CT in 10 cases (8 ventral conchal bulla, 2 dorsal conchal bulla), from 102 equine head CT examinations. Eight cases were subsequently treated at the study clinic, 7 of which had concurrent paranasal sinus disease. In 3 cases, fenestration of the ventral conchal bulla per nasum facilitated drainage and clearance of empyema. CONCLUSIONS: Disease of the conchal bullae should be considered as a potential cause of chronic unilateral nasal discharge in horses. Clearance of empyema within these bullae is unlikely to occur through lavage of the paranasal sinuses alone. Where necessary, fenestration of the bulla allows physical removal of infected material. PMID- 25041425 TI - Retrospective review of dog bite injuries in children presenting to a South Australian tertiary children's hospital emergency department. AB - AIM: To describe the characteristics, circumstances and consequences of dog bite injuries in children in order to inform the discourse concerning preventative approaches. METHOD: A retrospective review of children presenting to the emergency department (ED) of the Women's and Children's Hospital (WCH) in South Australia between the years 2009 and 2011 was performed. RESULTS: A total of 277 children presented to the WCH with dog bite injuries between 2009 and 2011. Of those, 141(51.0%) were referred for admission. Injury rates were highest in those aged 0-4, declining thereafter with age. In the 0-4 year age group, 89.5% of children presented after being bitten by a familiar dog with 92.5% occurring at home. The head/neck region constituted the most common location for injuries. We found that 67.5% of dog bite injuries were provoked and occurred between the child and a familiar dog (78.0%). Dogs from the bull terrier group (20.0%) and Jack Russell Terriers (11.0%) were the two most documented breeds. Almost half of the children presenting during the specified timeframe required at least one operation under a general anaesthetic. Two children were referred to a psychologist for management of post-traumatic stress. CONCLUSION: Dog bite injuries are common in children and often require admission for inpatient care. This presents as a significant public health burden. For this reason, prevention initiatives need to be implemented on an ongoing basis. PMID- 25041426 TI - Evaluation of immune response elicited by inulin as an adjuvant with filarial antigens in mice model. AB - Filariasis caused by infectious parasitic nematodes has been identified as the second leading source of permanent and long-term disability in Sub-Saharan Africa, Asia and Latin America. Several vaccine candidates were identified from infective third-stage larvae (L3) which involves in the critical transition from arthropod to human. Hitherto studies of these antigens in combination with alum adjuvant have shown to elicit its characteristic Th2 responses. Inulin is a safe, non-toxic adjuvant that principally stimulates the innate immune response through the alternative complement pathway. In the present study, the immune response elicited by inulin and alum as adjuvants were compared with filarial antigens from different aetiological agents: secreted larval acidic protein 1 (SLAP1) from Onchocerca volvulus and venom allergen homologue (VAH) from Brugia malayi as single or as cocktail vaccines in mice model. The study revealed that inulin can induce better humoral response against these antigens than alum adjuvant. Antibody isotyping disclosed inulin's ability to elevate the levels of IgG2a and IgG3 antibodies which mediates in complement-dependent cytotoxicity and antibody dependent cell-mediated cytotoxicity (ADCC), respectively, in mice. Splenocyte analysis showed that T cells prestimulated with inulin have higher stimulation index (P < 0.05) than alum except for BmVAH antigen. In vitro ADCC assay showed that inulin formulation had induced higher cytotoxicity with filarial antigens (as single P < 0.01 and as cocktail P < 0.05, respectively) than alum. The results had confirmed the capability of inulin to deplete the levels of Treg and brought a balance in Th1/Th2 arms against filarial antigens in mice. PMID- 25041427 TI - Failure of corn trypsin inhibitor to affect the thrombin generation assay in plasma from severe hemophiliacs. AB - BACKGROUND: The thrombin generation assay (TGA) is an important global coagulation assay; however, it suffers from the lack of preanalytical standardization. The addition of corn trypsin inhibitor (CTI) to blood collection tubes before TGA has been previously advocated to block the contact activation pathway. Emerging data, however, suggest that CTI may only be necessary when minimal tissue factor (TF) concentrations < 1 pmol are used. OBJECTIVES: To determine whether blood collection tubes containing CTI influenced TGA parameters. METHODS: This cross-sectional, observational study performed the TGA using TF 1 pmol L(-1) in 15 healthy volunteers, 14 severely factor VIII (FVIII) deficient patients, and 15 severely FVIII-deficient patients with documented FVIII inhibitors. TGA was conducted using blood tubes that contained CTI 33 MUg mL(-1) and no CTI. RESULTS: CTI markedly reduced peak thrombin (P = 0.002) and endogenous thrombin potential (P < 0.001) in the healthy volunteers but had no significant effect on TGA parameters in severely FVIII-deficient patients or those with inhibitors. CONCLUSIONS: This lack of effect raises additional questions regarding the need for CTI as a preanalytical addition to blood collection tubes during TGA in severe hemophiliacs, particularly when activating samples with TF 1 pmol L(-1) . PMID- 25041428 TI - Plant-driven genome selection of arbuscular mycorrhizal fungi. PMID- 25041429 TI - Tuning transcription of nutrient utilization genes to catabolic rate promotes growth in a gut bacterium. AB - Cells respond to nutrient availability by expressing nutrient catabolic genes. We report that the regulator controlling utilization of chondroitin sulphate (CS) in the mammalian gut symbiont Bacteroides thetaiotaomicron is activated by an intermediate in CS breakdown rather than CS itself. We determine that the rate determining enzyme in CS breakdown is responsible for degrading this intermediate and establish that the levels of the enzyme increase 100-fold, whereas those of the regulator remain constant upon exposure to CS. Because enzyme and regulator compete for the intermediate, B. thetaiotaomicron tunes transcription of CS utilization genes to CS catabolic rate. This tuning results in a transient increase in CS utilization transcripts upon exposure to excess CS. Constitutive expression of the rate-determining enzyme hindered activation of CS utilization genes and growth on CS. An analogous mechanism regulates heparin utilization genes, suggesting that the identified strategy aids B. thetaiotaomicron in the competitive gut environment. PMID- 25041430 TI - The use of a dermal substitute for simultaneous flap delay and donor site coverage in two cases. AB - OBJECTIVE: Lower extremity traumatic wounds can be difficult to treat owing to limb ischaemia and large zones of injury. Often, muscle or fasciocutaneous flaps are used in the presence of severe open orthopaedic injuries with soft tissue defects. Sometimes local flaps may be the preferred or only option, but may not tolerate being rotated or advanced owing to resulting flap ischaemia. One well studied technique that can increase the survival of various flaps involves the delay phenomenon. METHOD: In these case reports, Integra Dermal Regeneration template was used to simultaneously create delayed flaps and to cover the wound and flap donor site so that the donor site could be skin grafted at the time of flap inset. RESULTS: These cases demonstrate that use of Integra can enhance the delay phenomenon while simultaneously providing coverage of soft tissue defects in preparation for ultimately insetting delayed flaps and better covering donor areas. CONCLUSION: This technique may be applicable to many different flaps in many different anatomic locations and should be considered an option when reconstructing complicated wounds. DECLARATION OF INTEREST: none. PMID- 25041431 TI - A comparison of two total contact cast constructs with variable body mass. AB - OBJECTIVE: There is a growing body of evidence implicating obesity as having a negative effect on the development and treatment of diabetic foot disease. The aim of this study was to increase the body of knowledge on the effects of obesity on foot function, specifically as it relates to peak plantar pressures in the total contact cast (TCC). Our investigational objectives were to compare the effect of two different TCC designs on mean peak plantar pressures, and to evaluate the efficacy of two TCC constructs with increasing body mass. METHOD: The primary outcome measure was mean peak plantar pressure in the heel, midfoot, forefoot and first metatarsal as measured with an in-shoe pressure measurement system. The variables were patient weight (from 'normal' body mass index (BMI) to 'overweight', 'obese' and 'morbidly obese') and the TCC construct (with both a standard and alternate cast design). The standard TCC is considered the gold standard for off-loading of the diabetic foot. The alternate TCC was designed to use the essential offloading component of the traditional TCC, namely the total contact leg section, with use of an open cell polyurethane foam to transfer load from the foot to the lower leg, thereby offloading the foot by suspending it within a padded fiberglass walking cast. RESULTS: We did not observe statistically significant differences in mean peak plantar pressures in any plantar foot anatomic area or with any body mass between the two TCC designs. CONCLUSION: Based on the results, we concluded that the alternate TCC design provides another viable TCC construct option for practitioners working with the neuropathic foot. This investigation also provides specific data on changes that occur in peak plantar pressures with use of the total contact cast and variable BMIs. DECLARATION OF INTEREST: none. PMID- 25041432 TI - An immunosufficient murine model for the study of human islets. AB - For the sake of therapy of diabetes, it is critical to understand human beta cell function in detail in health and disease. Current studies of human beta cell physiology in vivo are mostly limited to immunodeficient mouse models, which possess significant technical limitations. This study aimed to create a new model for the study of human islets through induction of transplant tolerance in immunosufficient mice. B6 diabetic mice were transplanted with human islets and treated with anti-CD45RB. To assess whether anti-CD45RB-induced transplant tolerance requires B cells, B6 recipients received additional anti-CD20 or B6MUMT /- mice were used. For some anti-CD45RB-treated B6MUMT-/- mice, additional anti CD25 mAb was applied at the early or late stage post-transplant. Immunohistology was performed to show the Foxp3 cells in grafted anti-CD45RB/anti-CD20-treated Foxp3-GFP B6 mice. The results showed that anti-CD45RB alone allowed indefinite graft survival in 26.6% of B6 mice, however 100% of xenografts were accepted in mice treated simultaneously with anti-CD20, and 88.9% of xenografts accepted in anti-CD45RB-treated MUMT-/- mice. These MUMT-/- mice accepted the islets from another human donor but rejected the islets from baboon. Additional administration of anti-CD25 mAb at the time of transplantation resulted in 100% rejection, whereas 40% of grafts were rejected while the antibody was administrated at days 60 post-transplant. Immunohistologic examination showed Foxp3+ cells accumulated around grafts. We conclude that induction of tolerance to human islets in an immunosufficient mouse model could be generated by targeting murine CD45RB and CD20. This new system will facilitate study of human islets and accelerate the dissection of the critical mechanisms underlying islet health in human disease. PMID- 25041433 TI - Modulation of NADPH oxidase activity by known uraemic retention solutes. AB - BACKGROUND: Uraemia and cardiovascular disease appear to be associated with an increased oxidative burden. One of the key players in the genesis of reactive oxygen species (ROS) is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Based on initial experiments demonstrating a decreased inhibitory effect on NADPH oxidase activity in the presence of plasma from patients with CKD-5D after dialysis compared with before dialysis, we investigated the effect of 48 known and commercially available uraemic retention solutes on the enzymatic activity of NADPH oxidase. METHODS: Mononuclear leucocytes isolated from buffy coats of healthy volunteers were isolated, lysed and incubated with NADH in the presence of plasma from healthy controls and patients with CKD-5D. Furthermore, the leucocytes were lysed and incubated in the presence of uraemic retention solute of interest and diphenyleneiodonium chloride (DPI), an inhibitor of NADPH oxidase. The effect on enzymatic activity of NADPH oxidase was quantified within an incubation time of 120 min. RESULTS: Thirty-nine of the 48 uraemic retention solutes tested had a significant decreasing effect on NADPH oxidase activity. Oxalate has been characterized as the strongest inhibitor of NADPH oxidase (90% of DPI inhibition). Surprisingly, none of the uraemic retention solutes we investigated was found to increase NADPH oxidase activity. Furthermore, plasma from patients with CKD-5D before dialysis caused significantly higher inhibitory effect on NADPH oxidase activity compared with plasma from healthy subjects. However, this effect was significantly decreased in plasma from patients with CKD 5D after dialysis. CONCLUSIONS: The results of this study show that uraemic retention solutes modulated the activity of the NADPH oxidase. The results of this study might be the basis for the development of inhibitors applicable as drug in the situation of increased oxidative stress. PMID- 25041434 TI - Molecular and morphological variation in saddled fathead sculpins (Psychrolutidae: Cottunculus) of the north-east Atlantic Ocean, with a synonymy of three species. AB - On the basis of 104 individuals of Cottunculus from the Norwegian coast, the Barents Sea, Svalbard and north-east Greenland waters, this paper evaluates the descriptive taxonomic characters of three species Cottunculus sadko, Cottunculus microps and Cottunculus konstantinovi and links the character variation to genetic characterizations. Eleven morphological characters used as diagnostic characters in the original descriptions of these species were analysed in pair wise character comparisons. All characters show cross-species traits when in combination with each other, and all individuals show traits of more than one of the species. Partial cytochrome oxidase c subunit I (coI) gene sequences from 21 individuals, covering the morphological variation among the specimens, show little variation among the individuals. From these results, it is concluded that the descriptive characters do not support the maintenance of more than one species. It is recommended that C. microps remains the name for this species, with C. sadko and C. konstantinovi as junior synonyms. PMID- 25041435 TI - A case of stump appendicitis. PMID- 25041436 TI - Screening phenotypically normal Caucasian Australians for the lysyl oxidase-like 1 gene. PMID- 25041437 TI - Vitiligo nonsurgical treatment: a review of latest treatment researches. AB - Vitiligo is a common depigmenting acquired disorder affecting about 1-2% of the world population, regardless of race, ethnic background, or gender. It is characterized by the appearance of milky white maculae because of a loss of melanocytes. The disfiguring nature of vitiligo causes high psychosocial morbidity. This is especially pronounced in populations with darker skin tone, likely because of the marked contrast. A variety of nonsurgical treatment regimens are currently employed in vitiligo. We reviewed the latest studies carried out on different nonsurgical treatment modalities used in vitiligo. All nonsurgical treatment aid to repigment or depigmentation the skin, however, many of them require a prolonged treatment course and may yield minimal results as well as carry unwanted side effects. There is a need for further research into the causes of vitiligo and into discovering better treatments. PMID- 25041438 TI - Detailed characterization of Act d 12 and Act d 13 from kiwi seeds: implication in IgE cross-reactivity with peanut and tree nuts. AB - BACKGROUND: Act d 12 (11S globulin) and Act d 13 (2S albumin) are two novel relevant allergens from kiwi seeds that might be useful to improve the diagnostic sensitivity and the management of kiwifruit-allergic patients. OBJECTIVE: To perform a comprehensive structural and immunological characterization of purified Act d 12 and Act d 13 from kiwi seeds. METHODS: Sera from 55 well-defined kiwifruit-allergic patients were used. Act d 12 and Act d 13 were purified by chromatographic procedures. Circular dichroism, mass spectrometry, concanavalin A detection, immunoblotting, enzyme-linked immunosorbent assays, basophil activation tests, and IgE-inhibition experiments were used. RESULTS: Act d 12 and Act d 13 were purified from kiwi seeds to homogeneity by combining size exclusion, ion-exchange, and RP-HPLC chromatographies. Both purified allergens preserve the structural integrity and display typical features of their homologous counterparts from the 11S globulin and 2S albumin protein families, respectively. These allergens are released from kiwi seeds after oral and gastric digestion of whole kiwifruit, demonstrating their bioavailability after ingestion. The allergens retain the capacity to bind serum IgE from kiwifruit allergic patients, induce IgE cross-linking in effector-circulating basophils, and display in vitro IgE cross-reactivity with homologous counterparts from peanut and tree nuts. CONCLUSION: Purified Act d 12 and Act d 13 from kiwi seeds are well-defined molecules involved in in vitro IgE cross-reactivity with peanut and tree nuts. Their inclusion in component-resolved diagnosis of kiwifruit allergy might well contribute to improve the diagnostic sensitivity and the management of kiwifruit-allergic patients. PMID- 25041440 TI - Goniometric evaluation of both forelimbs and hind limbs in two species of Neotropical monkeys. AB - BACKGROUND: The aim of this study was to evaluate the goniometric measurements of the forelimb and hind limb joints in two species of Neotropical primates maintained in captivity. METHODS: Eighteen intact monkeys organized into two groups were studied: Group 1-9 brown howlers (Alouatta fusca), and Group 2-9 tufted capuchins (Sapajus apella). RESULTS: Significant differences were observed in the maximum flexion of the shoulder, elbow, carpus, stifle, and tarsus (G1>G2); maximum extension and abduction of the shoulder (G1G2) and adduction (G1G2). The ROM was significantly different in all joints: shoulder (G1G2), hip (G1>G2), stifle (G14 mm were subject to subgingival air polishing (test side) or ultrasonic debridement (control side). The primary endpoint was presence/absence of PD >4 mm after 12 months. RESULTS: Totally 6918 sites were monitored at baseline, 457 of them had a PD >4 mm (range 5-9 mm). The number of pockets >4 mm per subject, PD and bleeding on probing were significantly lower at month 12. Differences between test and control were not significant. There was a significant difference in favour of air-polishing for the perception of pain/discomfort. Differences of frequencies at >1000 and >100,000 cells/ml of six microorganisms between baseline and month 12 were not significant. At month 12, test sites were less frequently positive for Aggregatibacter actinomycetemcomitans at >1000 cells/ml than controls, and counts never exceeded 100,000 cells/ml. CONCLUSIONS: Repeated subgingival air-polishing reduced the number of pockets >4 mm similar to ultrasonic debridement. It was safe and induced less pain. PMID- 25041442 TI - Health care experiences when pain and substance use disorder coexist: "just because i'm an addict doesn't mean i don't have pain". AB - OBJECTIVE: To report the health care experiences of 34 individuals with coexisting substance use disorder (SUD) and chronic pain. DESIGN: Narrative inquiry qualitative study of 90-minute interviews. SETTING: Midwest metropolitan methadone clinic. SUBJECTS: All individuals had SUD and were treated for SUD with methadone. They all self-identified as having pain longer than 6 months. METHODS: This qualitative design allowed exploration of how participants made sense of events related to living with SUD and chronic pain. Narrative inquiry gives a consistent story from the participants' perspective, and researchers can perform additional analysis using the storyline. Thematic analysis occurred of their health care experiences. RESULTS: Results revealed that participants 1) spoke about how they used deception to obtain opioids when their drug cravings were out of control; 2) were disturbed by health care providers having little understanding or ability to help them with their painful condition; 3) felt they wanted to abuse opioids again when receiving poor treatment by the health care team; 4) related what went well in their health care to help them maintain their sobriety; and 5) recommended improvements on health care interventions that included effective treatment of pain. CONCLUSIONS: Coexisting chronic pain and SUD create unique health care needs by mutually activating and potentiating the other. There are very few comparable studies exploring the experiences of individuals when pain and SUD coexist. The health care team can better develop treatment plans and test interventions sensitive to their unique needs when they understand the experiences of this population. PMID- 25041443 TI - Upregulation of alpha-enolase in acute rejection of cardiac transplant in rat model: implications for the secretion of interleukin-17. AB - Acute allograft rejection remains a major problem in solid organ transplantation. The enzyme alpha-enolase has been shown to induce an immune response in cardiac transplantation. In this study, we investigated the role of alpha-enolase in acute allograft rejection in a rat model of heart transplantation. Hearts from either (WF: RT1(u) ) or (Lew: RT1(1) ) rats were transplanted into (Lew: RT1(1) ) rats. No rejection occurred in the isograft group, for which the median survival time was >168 days, whereas the median survival time of the allograft group was significantly less at 10 +/- 2.1 days (n = 8 per group, p < 0.001). Increased inflammation was observed in allografts, including increased alpha-enolase expression and increased numbers of infiltrating CD4(+) T cells (p < 0.05). By immunohistochemical staining, we confirmed that alpha-enolase was expressed not only in myocardial cells but also in the infiltrating lymphocytes. However, on the fifth day after transplantation, alpha-enolase expression was no longer observed in the lymphocytes (n = 3, p < 0.001). In contrast, no lymphocytes were found in isografts after transplantation (n = 3, p < 0.001). alpha-enolase expression was increased in lymphocytes, which are implicated in the acute rejection of cardiac transplants. Intragraft alpha-enolase inhibition may be useful as an adjuvant therapy to systemic immunosuppression in heart transplantation. PMID- 25041445 TI - Comparisons of gene expression in normal, lesional, and non-lesional psoriatic skin using DNA microarray techniques. AB - OBJECTIVES: This study was designed to explore the pathogenesis of psoriasis and to identify potential bio-targets. Genome array technology was used to analyze the gene expression profiles of lesional and non-lesional psoriatic skin samples and normal skin samples. METHODS: Gene expression profile GSE14905 was downloaded from the Gene Expression Omnibus (GEO) database. This included skin biopsy samples from normal healthy donors (n = 21), lesional skin biopsy samples from psoriasis patients (n = 33), and non-lesional skin biopsy samples from psoriasis patients (n = 28). Differentially expressed genes (DEGs) were identified using the Limma package in R language. Functions of specific DEGs were predicted by Gene Ontology (GO) enrichment analysis. A protein-protein interaction network was constructed to display the interactions among common DEGs. Finally, DAVID and WebGestalt were used to achieve a functional analysis of common DEGs. RESULTS: Totals of 1020, 562, and 643 genes, respectively, were identified as being differentially expressed in normal versus lesional, normal versus non-lesional, and lesional versus non-lesional samples. The specific DEGs in the three groups were enriched for several GO terms, including mitotic cell cycle, immune response, and response to organic matter. The 40 common DEGs in the three groups may be involved in the defense response pathway in the development of psoriasis. Furthermore, three genes (RGS1, SOCS3, and NAMPT) may play key roles in distinguishing lesional and non-lesional tissues from normal tissues, and 10 genes (PTRRC, ALDH1A3, SAMSA1, C15orf48, ZC3H12A, SOD2, IL8, LTF, RHCG, and IL7R) may play key roles in distinguishing non-lesional from normal and lesional samples. CONCLUSIONS: These genes may be considered as potential diagnostic markers and targets of therapeutics in psoriasis. PMID- 25041444 TI - Antinociceptive effect of buprenorphine and evaluation of the nociceptive withdrawal reflex in foals. AB - OBJECTIVE: To elicit and evaluate the NWR (nociceptive withdrawal reflex) in 2 and 11 day old foals, to investigate if buprenorphine causes antinociception and determine if the NWR response changes with increasing age. The effect of buprenorphine on behaviour was also evaluated. STUDY DESIGN: Prospective, experimental cross-over trial. ANIMALS: Nine Norwegian Fjord research foals. METHODS: Buprenorphine, 10 MUg kg(-1) was administered intramuscularly (IM) to the same foal at 2 days and at 11 days of age. The NWR and the effect of buprenorphine were evaluated by electromyograms recorded from the left deltoid muscle following electrical stimulation of the left lateral palmar nerve at the level of the pastern. Mentation, locomotor activity and respiratory rate were recorded before and after buprenorphine administration. RESULTS: We were able to evoke the NWR and temporal summation in foals using this model. Buprenorphine decreased the root mean square amplitude following single electrical stimulation (p < 0.001) in both age groups, and increased the NWR threshold following single electrical stimulation in 2 day old foals (p = 0.0012). Repeated electrical stimulation at 2 Hz was more effective to elicit temporal summation compared to 5 Hz (p < 0.001). No effect of age upon the NWR threshold was found (p = 0.34). Sedation when left undisturbed (11 occasions), increased locomotor activity when handled (9 occasions) and tachypnea (13 occasions) were common side-effects of buprenorphine. CONCLUSION AND CLINICAL RELEVANCE: These findings indicate that buprenorphine has antinociceptive effect in foals. Opioid side effects often recognized in adult horses also occur in foals. PMID- 25041446 TI - Total hepatectomy, pancreatoduodenectomy, and living donor liver transplantation using innovative vascular reconstruction for unresectable cholangiocarcinoma. PMID- 25041447 TI - Primary B-cell lymphoma developing at epicardial pacemaker lead site. PMID- 25041448 TI - Double-balloon enteroscopy for choledochojejunal anastomotic stenosis after hepato-biliary-pancreatic operation. AB - BACKGROUND AND AIM: There have been few reports on the success rate of balloon dilation and stent deployment using endoscopic retrograde cholangiopancreatography by double-balloon enteroscopy (DBE-ERCP) or on the follow-up period after stent removal in patients with a reconstructed digestive tract and stenosis of choledochojejunal anastomosis. The present study was designed to evaluate the usefulness of DBE-ERCP in patients with a reconstructed digestive tract and stenosis of choledochojejunal anastomosis. METHODS: Forty four patients with stenosis of choledochojejunal anastomosis underwent DBE-ERCP at Okayama University Hospital between April 2008 and January 2012 (107 procedures). Rates of reaching choledochojejunal anastomosis, stent deployment, and restenosis after stent removal were retrospectively evaluated. RESULTS: Insertion of DBE into the choledochojejunal anastomotic site succeeded in 38 of 44 patients (86.4%), and anastomotic dilation and stent deployment succeeded in 36 of 44 patients (81.8%). In 32 of 44 patients (72.7%), their anastomotic stenoses were improved, and they achieved stent removal. After stent removal, restenosis of choledochojejunal anastomosis was detected in seven of 32 patients; however, the resolution of restenosis was achieved in all seven of those patients. CONCLUSION: Dilation of choledochojejunal anastomosis combined with stent deployment using DBE-ERCP seems to be a viable first-line treatment for patients with stenosis of choledochojejunal anastomosis. PMID- 25041449 TI - Giant cell arteritis. AB - Giant cell arteritis (GCA) is a medium and large-vessel vasculitis, which is an important cause of secondary headache in older adults. While GCA has a classic presentation occurring after the age of 50, atypical presentations (eg, fever of unknown origin, cough, low or normal erythrocyte sedimentation rate) may lead to a delay in diagnosis. The topography of vascular involvement has implications for disease-related complications, which can result in neurologic disease at multiple levels of the nervous system. The most feared complication, vision loss, fortunately becomes uncommon after initiation of corticosteroids. Corticosteroid treatment should not be withheld while waiting the results of a temporal artery biopsy (TAB), which remains the gold standard for GCA diagnosis. Newer diagnostic modalities, including ultrasound, magnetic resonance imaging, and positron emission tomography can play an important role in directing treatment in cases with negative TAB. After successful control of the disorder, patients should be gradually tapered off corticosteroids, with careful monitoring using both clinical and laboratory parameters to assess for relapse. Corticosteroid-related treatment complications are not uncommon in GCA. There is mixed evidence for use of adjunct corticosteroid-sparing agents (eg, methotrexate), although these should be initiated in the setting of corticosteroid-related morbidity and/or cases with frequent relapse. PMID- 25041450 TI - Response to letter regarding article entitled "Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure". PMID- 25041451 TI - Why does the gut synthesize glucocorticoids? AB - Glucocorticoids (GC) are steroid hormones with important implications in the treatment of various inflammatory and autoimmune diseases. At the same time GC are known to have numerous side-effects. Endogenous GC are predominantly produced by the adrenal glands, and adrenal-derived GC serve important functions in the regulation of development, metabolism, and immune regulation. The last two decades of research have led to the identification of numerous alternative sources of extra-adrenal GC synthesis. Among other tissues the intestine and lung are capable of locally producing considerable amounts of immunoregulatory GC. This local steroidogenesis in these mucosal tissues appears to be regulated by transcription factors and mediators different from those in the adrenals, likely reflecting an adaptation to the local requirements and conditions. Here we summarize the current knowledge about the extra-adrenal GC synthesis in the mucosal tissues, with special emphasis on the intestinal epithelium, and its implication on the regulation of immune homeostasis and inflammatory processes. PMID- 25041452 TI - Intravenous transplantation of bone marrow mesenchymal stem cells could effectively promote vascularization and skin regeneration in mechanically stretched skin. AB - BACKGROUND: Skin expansion is a procedure that stimulates and promotes skin regeneration by applying continuous mechanical stretching. However, the outcome of treatment is limited by the skin's instinctive regeneration capacity. OBJECTIVES: To evaluate the impact of intravenous transplantation of bone marrow mesenchymal stem cells (MSCs) on expanded skin regeneration. METHODS: MSCs from luciferase-Tg Lewis rats were transplanted into a rat tissue expansion model and tracked in vivo by luminescence imaging. At the end of 21 days of skin expansion, the expanded skin was harvested and skin regeneration was evaluated by inflation volume, skin area and thickness. Counting of capillaries and vascular endothelial cell growth factor (VEGF) expression analysis were conducted to assess the impact of MSCs on expanded skin vascularization. RESULTS: Samples of the skin expansion model from the MSC group were observed to have a significantly higher inflation volume and greater expanded skin area than those from the control group at the end of 21 days' follow-up. In vivo tracing results showed that MSCs were recruited by mechanical stretch and migrated to expanded skin. Migrated MSCs promoted skin vascularization by secreting VEGF and differentiating into CD31+ endothelial cells. Skin sections from the MSC group had a significant advantage in thickness and proliferating cell count, indicating that MSCs effectively enhanced expanded skin regeneration. CONCLUSIONS: Intravenous transplantation of MSCs could effectively promote expanded skin regeneration. Transplanted MSCs could be recruited by mechanical stretch and subsequent migration to expanded skin. Engrafted MSCs could contribute to vascularization and cell proliferation. PMID- 25041454 TI - The relative position of femoral artery and vein in children under general anesthesia--an ultrasound-guided observational study. AB - BACKGROUND: Femoral artery overlaps femoral vein by varying degrees distal to the inguinal ligament, which may result in difficult venous access and also increases the risk of arterial puncture. OBJECTIVE: To study the size of femoral vessels and the degree of overlap in children undergoing anesthesia using ultrasound at 1 and 3 cm distal to inguinal ligament. METHODS: A prospective observational study, 84 children aged <7 years were recruited in six different age groups. An experienced anesthetist identified the femoral vessels and their overlap using ultrasound at two fixed points distal to the inguinal ligament. We also evaluated the correlation of skin puncture site marked as per Advanced Paediatric Life support (APLS) guidance using landmark technique with the ultrasound location of femoral vein beneath the same site. RESULTS: The percentage of children with overlap of femoral vein by femoral artery increases from 5% to 60% as we move distal to the inguinal ligament. At 3 cm distal to inguinal ligament, the incidence of any degree of overlap was statistically significant (P < 0.05) in children <5 years. In 80% of children, the femoral vein was located by ultrasound beneath the skin puncture site as recommended by APLS guidelines. CONCLUSION: A significant increase in femoral vein overlap occurs as we move distal to the inguinal ligament. There is one in five chance of failure to locate femoral vein by landmark technique. In children <2 years, a high approach to femoral vein cannulation under ultrasound guidance is recommended. PMID- 25041453 TI - Parallel testing of plasma iron and fibrinogen concentrations to detect systemic inflammation in hospitalized horses. AB - OBJECTIVES: To determine if plasma iron concentration is different between horses with and without systemic inflammation (SI) and to assess the accuracy for the detection of SI by assaying plasma iron and fibrinogen concentrations, individually or combined. To assess the prognostic value of plasma iron concentration and to describe the progression of plasma iron and fibrinogen concentrations during hospital follow-up, and its relation to SI and survival. DESIGN: Prospective observational study evaluating plasma iron and fibrinogen. SETTING: University veterinary teaching hospital. ANIMALS: Equine patients greater than 30 days of age. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma iron and fibrinogen concentration was prospectively determined in hospitalized horses. Horses were classified into 2 groups: SI and non-SI. Horses were also classified according to clinical outcome. A group of control healthy horses was also included. A total of 135 horses were included in the study. Plasma iron concentration was significantly lower and fibrinogen concentration was higher in the SI group. Nonsurvivors had a mean plasma fibrinogen concentration significantly higher than survivors. The combination of plasma iron and fibrinogen has a high degree of specificity, sensitivity, and accuracy for the detection of SI in horses. Follow-up measurements were obtained in 48 horses. Surviving horses normalized plasma iron concentration during follow-up examination whereas nonsurviving horses had persistently low plasma iron concentrations. CONCLUSIONS: Plasma iron concentration alone is an accurate marker of SI in hospitalized horses. Alteration of both plasma iron and fibrinogen concentrations improves the specificity and positive predictive value for diagnosis of SI. Alteration of either one of both increases sensitivity and negative predictive value. Surviving horses normalized plasma iron concentrations during follow-up period. The combination of plasma iron and fibrinogen concentrations may help in the detection of SI. Follow-up of plasma iron concentrations may provide useful prognostic information. PMID- 25041455 TI - 100 years of blood purification in poisoning: closing the gap between anecdotal care and evidence-based therapy. PMID- 25041458 TI - Serological markers associated with disease behavior and response to anti-tumor necrosis factor therapy in ulcerative colitis. AB - BACKGROUND AND AIM: Information is limited on the relationship between serological markers and disease behavior and anti-tumor necrosis factor-alpha (anti-TNF) therapy response in ulcerative colitis (UC). This study aimed to determine the association between serological markers and unfavorable UC behavior defined as need for colectomy or UC-related hospitalization. The association between serological markers and requirement for and outcome of anti-TNF therapy was also evaluated. METHODS: Two hundred thirty patients were studied. Requirement for colectomy, UC-related hospitalization, and anti-TNF therapy were documented. Response to anti-TNF therapy at 1 year and rates of therapy discontinuation were recorded. Titers of perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs), anti-Saccharomyces cerevisiae antibody (ASCA), and antibody to Escherichia Coli outer membrane porin (anti-OmpC) were determined. Antibody reference ranges were used to dichotomize subjects into seropositive and seronegative groups. Where multiple tests were performed, P-values were Bonferroni corrected (pcorr). RESULTS: Extensive colitis was associated with requirement for colectomy and UC-related hospitalization, HR 7.7 (95% confidence interval [CI] 1.9-32.2) pcorr = 0.03 and HR 2.7 (95% CI 1.5-4.6), pcorr = 0.006, respectively. No serological variable was associated with unfavorable UC behavior. Anti-OmpC positivity was associated with a lack of response to anti-TNF therapy at 1 year (odds ratio 0.14 [95% CI 0.03-0.60], pcorr = 0.04) and increased likelihood of therapy discontinuation (HR 2.2 [95% CI 1.1-4.7], P = 0.03). CONCLUSION: Extensive colitis is associated with unfavorable disease course in UC. Anti-OmpC holds promise as a biomarker of anti-TNF therapy response in UC; however, prospective studies are required before it can be incorporated into routine clinical practice. PMID- 25041460 TI - Shkedy Rabani et al. reply. PMID- 25041459 TI - Is smoking cessation associated with worse comorbid substance use outcomes among homeless adults? AB - BACKGROUND AND AIMS: Smoking prevalence among homeless adults is exceedingly high, and high rates of comorbid substance use are among the barriers to abstinence experienced by this group. The extent to which smoking cessation might engender an escalation in comorbid substance use could be a concern prohibiting treatment provision and engagement. This study examined whether smoking abstinence status was associated with alcohol and substance use at 26 weeks post randomization among homeless smokers in a smoking cessation trial. DESIGN: The current study was a secondary analysis of randomized smoking cessation intervention trial data. SETTING: The parent study was conducted in the Minneapolis/St Paul area of Minnesota, USA. PARTICIPANTS: Participants were 427 homeless adult smokers interested in quitting smoking. MEASUREMENTS: Covariates collected at baseline included alcohol, cocaine, marijuana/hashish, heroin and 'any' drug use, age, sex, race/ethnicity, education, tobacco dependence, length of time homeless and treatment group. Biochemically verified smoking abstinence and self-reported alcohol and substance use were collected at 26 weeks post randomization. FINDINGS: Smoking abstinence was associated with fewer drinking days (P = 0.03), fewer drinks consumed on drinking days (P = 0.01), and lower odds of heavy drinking (P = 0.05), but not with differences in the number of days of cocaine, marijuana/hashish, heroin or any drug use. CONCLUSIONS: In homeless smokers, achieving smoking abstinence may be associated with a reduction in alcohol consumption but appears not to be associated with a substantial change in other drug use. PMID- 25041461 TI - The endocannabinoid system is altered in the post-mortem prefrontal cortex of alcoholic subjects. AB - There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non-suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non-alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences in CB1 mRNA relative expression among the four experimental groups. Conversely, our results showed an increase in CB1 receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 +/- 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels of MAGL activity, regardless of the cause of death. A significant decrease in the active form of ERK and CREB levels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for the ECS in the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease. PMID- 25041462 TI - Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. AB - AIMS: Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes. METHODS: We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables. RESULTS: We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy. CONCLUSIONS: Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern. PMID- 25041463 TI - miR-22 regulates expression of oncogenic neuro-epithelial transforming gene 1, NET1. AB - MicroRNAs control cellular processes by regulating expression of their target genes. Here we report that neuro-epithelial transforming gene 1 (NET1) is a target of tumor suppressor microRNA 22 (miR-22). miR-22 is downregulated in peripheral blood mononuclear cells derived from chronic myeloid leukemia (CML) patients and in CML cell line K562. NET1 was identified as one of the targets of miR-22 using both in vitro and in vivo experiments. Either mutations or naturally occurring single-nucleotide polymorphisms in NET1 3'-UTR that map at the miR-22 binding site were found to affect binding of miR-22 to NET1 mRNA. Over expression of NET1 in K562 cells resulted in increased proliferation. However decreased proliferation and alteration in cell cycle were observed on either overexpression of miR-22 or knockdown of NET1 expression respectively. We also found that overexpression of miR-22 or NET1 knockdown inhibits actin fiber formation, probably by downregulation of NET1 as NET1 knockdown also resulted in depletion of actin fiber formation. We suggest that the oncogenic properties of CML cells are probably due to deregulated expression of NET1 as a result of altered expression of miR-22. PMID- 25041464 TI - The Stability of Social Desirability: A Latent Change Analysis. AB - Social desirability has been shown to be stable in samples with higher school education. However, little is known about the stability of social desirability in more heterogeneous samples differing in school education. This study aimed to investigate the stability of social desirability and which factors predict interindividual differences in intraindividual change. As part of a randomized controlled trial, 1,243 job seekers with unhealthy alcohol use were systematically recruited at three job agencies. A total of 1,094 individuals (87.8%) participated in at least one of two follow-ups (6 and 15 months after baseline) and constitute this study's sample. The Social Desirability Scale-17 was applied. Two latent change models were conducted: Model 1 tested for interindividual differences in intraindividual change of social desirability between both follow-ups; Model 2 included possible predictors (age, sex, education, current employment status) of interindividual differences in intraindividual change. Model 1 revealed a significant decrease of social desirability over time. Model 2 revealed school education to be the only significant predictor of change. These findings indicate that stability of social desirability may depend on school education. It may not be as stable in individuals with higher school education as in individuals with lower education. PMID- 25041466 TI - Sun protection provided by regulation school uniforms in Australian schools: an opportunity to improve personal sun protection during childhood. AB - Childhood sun exposure is linked to excessive pigmented mole development and melanoma risk. Clothing provides a physical barrier, protecting skin from ultraviolet radiation (UVR). Extending sleeves to elbow length and shorts to knee length has been shown to significantly reduce mole acquisition in preschoolers from tropical Queensland. We used publicly available uniform images and guidelines from primary schools in Townsville (latitude 19.25 degrees S, n = 43 schools), Cairns (16.87 degrees S, n = 46) and the Atherton Tablelands (17.26 degrees S, n = 23) in tropical Australia to objectively determine the body surface proportion covered by regulation school uniforms. Uniforms of nongovernment, large (>=800 students), urban, educationally advantaged schools with comprehensive sun protection policies covered more skin than those of government schools (63.2% vs 62.0%; P < 0.001), smaller schools (63.4% vs 62.3%; P = 0.009), rural (62.7% vs 61.9%; P = 0.002) and educationally disadvantaged schools (62.8% vs 62.3%; P < 0.001) with underdeveloped sun protection policies (62.8% vs 62.2%; P = 0.002). Overall, SunSmart and non-SunSmart school uniforms covered identical body surface proportions (62.4%, P = 0.084). Although wearing regulation school uniforms is mandatory at most Australian primary schools, this opportunity to improve children's sun protection is largely overlooked. Recent evidence suggests that even encouraging minor alterations to school uniforms (e.g. slightly longer sleeves/dresses/skirts/shorts) to increase skin coverage may reduce mole acquisition and melanoma risk, especially in high-risk populations. PMID- 25041465 TI - Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis. AB - BACKGROUND: There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC. METHODS: Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer. KEY RESULTS: Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types. CONCLUSIONS & INFERENCES: Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages. PMID- 25041467 TI - Steroid plus antiviral treatment for Bell's palsy. AB - OBJECTIVES: The effectiveness of antiviral agents for the treatment of Bell's palsy is uncertain. We evaluated whether a steroid with an antiviral agent (S + A group) provided better recovery outcomes than a steroid alone (S group) in patients with Bell's palsy. SUBJECTS AND DESIGN: A total of 1342 patients diagnosed with Bell's palsy who visited the Kyung Hee Medical Center in Seoul, Korea, from 2002 to 2012 were included in this study. Patients in the S + A group were treated with prednisolone and antiviral agents (n = 569) and those in the S group with prednisolone alone (n = 773). Outcomes were measured using the House Brackmann (HB) scale according to age, initial disease severity, electroneurography (ENoG) findings and underlying comorbidities. RESULTS: The rate of recovery (HB grades I and II) with initially severe Bell's palsy (HB grades V and VI) was higher in the S + A than in the S group (P = 0.001). However, the rates of recovery were similar with initially moderate palsy (HB grades II-IV) (P = 0.502). In patients classified according to age and ENoG determined severity of palsy, the overall recovery rate was higher in the S + A than in the S group, but the differences were not statistically significant (P > 0.05 for both). The recovery rate without diabetes mellitus (DM) and hypertension (HTN) was higher in the S + A group than in the S group (P = 0.031). But in the patients with HTN and DM, the difference in recovery rates between the S + A and S groups was not statistically significant (P = 0.805). CONCLUSIONS: Treatment with a steroid plus antiviral agent resulted in significantly higher recovery rates than steroid therapy alone in patients with initially severe Bell's palsy and without either HTN or DM, and a nonsignificant trend towards higher recovery rates in all patients with Bell's palsy in this study. Antiviral agents may therefore help in the treatment of Bell's palsy. PMID- 25041468 TI - The prevalence, severity, and impact of breast pain in the general population. AB - Breast pain has been investigated in clinical populations; however we have yet to understand the prevalence and severity of this condition in the general population to determine whether more should be done to minimize the impact of this condition on women's quality of life. Therefore, this study investigated the prevalence, severity, and impact of breast pain on quality of life and factors associated with breast pain in a normal population sample. 1,659 females (34.1 +/ 13.2 years) completed the Breast Pain Questionnaire online, providing information on demographics, duration, frequency, and severity of breast pain, its association with the menstrual cycle, relieving, and aggravating factors and the impact on quality of life. Over half the sample (51.5%) experienced breast pain, with a severity similar to that reported in clinical populations. There was a higher prevalence of breast pain in older participants, larger breasted participants and those who were less fit and active. Of symptomatic participants, 41% and 35% reported breast pain affecting quality of life measures of sex and sleep and 10% of symptomatic participants had sufferer for over half their lives. The results of this study suggest that breast pain is a significant issue within the general population and yet this is the first study to investigate it. It is concluded that this condition warrants increased investigation, awareness, and treatment. The reported relationship between breast pain and fitness/activity levels may offer an alternative treatment in the form of exercise intervention strategies to reduce breast pain. PMID- 25041469 TI - Secondary biliary cholestasis promotes testicular macrophage infiltration and autophagy in rats. AB - PROBLEM: Cholestasis can cause translocation of gut bacteria, and endotoxemia, and systemic inflammation. Now, little is known about the effects of cholestasis on the testicular inflammation and autophagy. METHODS: A rat biliary cholestasis model caused by common bile duct ligation (CBDL), together with biliary decompression (choledochoduodenostomy), was used. RESULTS: The magnitude of MCP-1 expression and CD68(+) macrophage infiltration within testes was progressively up regulated in rats along with increasing duration of CBDL and was maintained at relatively high level in rats with biliary decompression. The large up-regulation of testicular ATG-12, LC3II, and autophagic vacuoles was found with the extending duration of CBDL and kept at 5 weeks following biliary decompression. The autophagic contents were a large accumulation of mitophagy in testes in rats with CBDL, and cytosol components in rats with biliary decompression. CONCLUSION: Secondary biliary cholestasis can promote inflammatory reaction and the activation of mitophagy and autophagy in testes. PMID- 25041470 TI - Of mice and men: olfactory neuroblastoma among animals and humans. AB - Olfactory neuroblastoma (ONB) is a rare tumour of nasal cavity and paranasal sinuses that arises from the olfactory neuroepithelium and has unpredictable clinical course. As the sense of smell is phylogenetically one of the first senses and olfactory neuroepithelium is evolutionary conserved with striking similarities among different species, we performed an extensive analysis of the literature in order to evaluate the similarities and differences between animals and humans on the clinical, morphological, immunohistochemical, ultrastructural and molecular level. Our analysis revealed that ONB was reported mainly in mammals and showed striking similarities to human ONB. These observations provide rationale for introduction of therapy modalities used in humans into the veterinary medicine. Animal models of neuroblastoma should be considered for the preclinical studies evaluating novel therapies for ONB. PMID- 25041471 TI - The effect of age on right ventricular diastolic function in healthy subjects undergoing treadmill exercise test. AB - OBJECTIVE: There is an increasing interest for the value of right ventricle (RV) in predicting exercise tolerance and prognosis in cardiovascular disease. However, there is relatively few data evaluating the effect of age on RV diastolic filling velocities during rest or exercise in healthy subjects. METHODS: A total of 54 healthy subjects were enrolled in this study. Patients were divided into 2 groups according to their age: Group 1 (<=45-years-old) and Group 2 (>45-years-old). A treadmill exercise test was performed using modified Bruce protocol. Conventional pulsed-wave Doppler and tissue Doppler velocities were obtained both at rest and immediately after the end of exercise, respectively. RESULTS: In the overall analysis, tricuspid flow Doppler analysis showed a significant increase in A-wave velocity, less marked rise in E-wave velocity, decreased E/A ratio and decreased E-wave deceleration time (EDT) with exercise. Tissue Doppler analysis revealed increased Aa velocity, decreased in Ea/Aa ratio and IVRT. No significant change was observed in Ea velocity and E/Ea ratio with exercise. Although diastolic velocities changed significantly with exercise, systolic velocities did not. Cardiac response to exercise differed slightly in the older subjects compared to younger ones. The older subjects were more likely to have a reduced mean rate of RV filling for the second half of diastole from baseline to peak exercise. CONCLUSION: To distinguish normal physiological changes due to aging from those of pathologic conditions may provide benefits while evaluating patients with known or suspected cardiovascular disease. PMID- 25041472 TI - Case of leukemia cutis showing asymmetrical linear distribution suggestive of Koebner's phenomenon. PMID- 25041474 TI - 2-Pyridonate tantalum complexes for the intermolecular hydroaminoalkylation of sterically demanding alkenes. AB - The design and synthesis of a mixed 2-pyridonate-Ta(NMe2)3Cl complex for the direct C-H alkylation adjacent to nitrogen in unprotected secondary amines are reported. The hydroaminoalkylation of sterically demanding internal alkenes gives the direct, catalytic formation of C(sp(3))-C(sp(3)) bonds. Substrate scope investigations reveal key strategies for further catalyst development efforts in this 100% atom-economic synthesis of alpha-alkylated amines. PMID- 25041473 TI - Abbreviated care-process quality indicator sets linked with survival and functional status benefit in older adults under ambulatory care. AB - OBJECTIVES: To identify subsets of ambulatory care (outpatient only) quality indicators (QIs) associated with better survival and physical function outcomes. DESIGN: Observational cohort study. SETTING: Pooled data from the Assessing Care of Vulnerable Elders (ACOVE)-1 study, which measured quality of care using 140 care-process QIs, and the subsequent ACOVE-2 study, which reduced the QIs to 69 ambulatory care QIs. PARTICIPANTS: Older adults receiving ambulatory care (N=1,015). MEASUREMENTS: To prioritize and reduce the QIs into subsets, an expert panel rated each of 69 ambulatory care QIs for the strength of the link between process and benefit, defined as direct trial evidence on older adults or high expectation of benefit if a trial were conducted in older adults. This resulted in three reduced QI sets, reflecting their intended benefit: 17 QIs for survival (ACOVE Quality for Survival (AQS)-17), five QIs to preserve function (AQF-5), and 16 QIs to improve quality-of-life related to physical health and symptoms (AQQ 16). Whether AQS-17 would predict 3-year survival was first tested in 1,015 pooled ACOVE-1 and ACOVE-2 participants. Second, whether AQF-5 (n=74) and AQQ-16 (n=359) would predict change in the Physical Component Summary (PCS) score of the Medical Outcomes Study 12-item Short-Form Survey at 1 year was tested in the ACOVE-2 cohort. Control variables were age, function-based vulnerability, and comorbidity. RESULTS: Each 20-percentage-point increment in AQS-17 was associated with survival (hazard ratio (HR)=0.83, P=.01) up to 500 days but not thereafter. AQF-5, but not AQQ-16, predicted 1-year improvement in PCS score (1.13-points per 20%-point increment in AQF-5, P=.02). CONCLUSION: Subsets of care processes can be linked with outcomes important to older adults. The AQS-17 and AQF-5 are potential tools for improving ambulatory care of older adults. PMID- 25041475 TI - Top-down inputs from the olfactory cortex in the postprandial period promote elimination of granule cells in the olfactory bulb. AB - Elimination of granule cells (GCs) in the olfactory bulb (OB) is not a continual event but is promoted during a short time window in the postprandial period, typically with postprandial sleep. However, the neuronal mechanisms for the enhanced GC elimination during the postprandial period are not understood. Here, we addressed the question of whether top-down inputs of centrifugal axons from the olfactory cortex (OC) during the postprandial period are involved in the enhanced GC elimination in the OB. Electrical stimulation of centrifugal axons from the OC of anesthetized mice increased GC apoptosis. Furthermore, pharmacological suppression of top-down inputs from the OC to the OB during the postprandial period of freely behaving mice by gamma-aminobutyric acid (GABA)A receptor agonist injection in the OC significantly decreased GC apoptosis. Remarkable apoptotic GC elimination in the sensory-deprived OB was also suppressed by pharmacological blockade of top-down inputs. These results indicate that top-down inputs from the OC to the OB during the postprandial period are the crucial signal promoting GC elimination, and suggest that the life and death decision of GCs in the OB is determined by the interplay between bottom-up sensory inputs from the external world and top-down inputs from the OC. PMID- 25041476 TI - Computing volume potentials for noninvasive imaging of cardiac excitation. AB - BACKGROUND: In noninvasive imaging of cardiac excitation, the use of body surface potentials (BSP) rather than body volume potentials (BVP) has been favored due to enhanced computational efficiency and reduced modeling effort. Nowadays, increased computational power and the availability of open source software enable the calculation of BVP for clinical purposes. In order to illustrate the possible advantages of this approach, the explanatory power of BVP is investigated using a rectangular tank filled with an electrolytic conductor and a patient specific three dimensional model. METHODS: MRI images of the tank and of a patient were obtained in three orthogonal directions using a turbo spin echo MRI sequence. MRI images were segmented in three dimensional using custom written software. Gmsh software was used for mesh generation. BVP were computed using a transfer matrix and FEniCS software. RESULTS: The solution for 240,000 nodes, corresponding to a resolution of 5 mm throughout the thorax volume, was computed in 3 minutes. The tank experiment revealed that an increased electrode surface renders the position of the 4 V equipotential plane insensitive to mesh cell size and reduces simulated deviations. In the patient-specific model, the impact of assigning a different conductivity to lung tissue on the distribution of volume potentials could be visualized. CONCLUSION: Generation of high quality volume meshes and computation of BVP with a resolution of 5 mm is feasible using generally available software and hardware. Estimation of BVP may lead to an improved understanding of the genesis of BSP and sources of local inaccuracies. PMID- 25041477 TI - Weight loss maintenance: an agenda for health psychology. PMID- 25041480 TI - Interaction of lectin pathway of complement-activating pattern recognition molecules with mycobacteria. AB - We have demonstrated that mannose-binding lectin (MBL) recognizes various slow growing, pathogenic mycobacteria [Mycobacterium tuberculosis (MTB), M. bovis, M. kansasii, M. gordonae] as well as non-pathogenic M. smegmatis. Recognition resulted in activation of the lectin pathway (LP) of complement and an enhancement of phagocytosis (shown for M. tuberculosis). Although MBL may be considered the main factor activating the LP upon recognition of mycobacteria, involvement of ficolins has also to be considered. Interaction of ficolin-3 with M. tuberculosis, M. bovis and M. kansasii, and ficolin-1 with M. tuberculosis and M. bovis was shown for the first time. Binding of recombinant MBL or ficolin-3 to MTB H37 Rv led to the agglutination of bacteria and promoted their phagocytosis, but little effect was apparent with ficolin-1 or ficolin-2. Data from Western blots suggest mannosylated lipoarabinomannan (ManLAM) to be one of the main cell components of slow-growing mycobacteria, involved in LP activation. However, the LP was also activated by other cell fractions. Results presented here supplement considerably the data concerning the ability of complement-activating lectins to interact with mycobacteria. Ficolins (especially ficolin-3) might influence host response to infection and thus have clinical significance, at least as disease modifiers. PMID- 25041481 TI - Embedded earring back mistaken for ear lobe keloid in an eight-year-old girl. PMID- 25041478 TI - Macrophages clear refrigerator storage-damaged red blood cells and subsequently secrete cytokines in vivo, but not in vitro, in a murine model. AB - BACKGROUND: In mice, refrigerator-stored red blood cells (RBCs) are cleared by extravascular hemolysis and induce cytokine production. To enhance understanding of this phenomenon, we sought to model it in vitro. STUDY DESIGN AND METHODS: Ingestion of refrigerator-stored murine RBCs and subsequent cytokine production were studied using J774A.1 mouse macrophage cells and primary murine splenic macrophages. Wild-type and Ccl2-GFP reporter mice were used for RBC clearance in vivo. RESULTS: Although J774A.1 cells and primary macrophages preferentially ingested refrigerator-stored RBCs in vitro, compared to freshly isolated RBCs, neither produced increased cytokines after erythrophagocytosis. In contrast, phagocytosis of refrigerator-stored RBCs in vivo induced increases in circulating monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC) and correspondingly increased mRNA levels in mouse spleen and liver. In the spleen, these were predominantly expressed by CD11b+ cells. Using Ccl2-GFP reporter mice, the predominant splenic population responsible for MCP-1 mRNA production was tissue-resident macrophages (i.e., CD45+, CD11b+, F4/80+, Ly6c+, and CD11c(low) cells). CONCLUSION: J774A.1 cells and primary macrophages selectively ingested refrigerator-stored RBCs by phagocytosis. Although cytokine expression was not enhanced, this approach could be used to identify the relevant receptor-ligand combination(s). In contrast, cytokine levels increased after phagocytosis of refrigerator-stored RBCs in vivo. These were primarily cleared in the liver and spleen, which demonstrated increased MCP-1 and KC mRNA expression. Finally, in mouse spleen, tissue-resident macrophages were predominantly involved in MCP-1 mRNA production. The differences between cytokine production in vitro and in vivo are not yet well understood. PMID- 25041482 TI - National strategy for suicide prevention in Japan: impact of a national fund on progress of developing systems for suicide prevention and implementing initiatives among local authorities. AB - AIM: In Japan, the Cabinet Office released the 'General Principles of Suicide Prevention Policy' in 2007 and suggested nine initiatives. In 2009, a national fund was launched to help prefectures (the administrative divisions of Japan) and local authorities implement five categories of suicide-prevention programs. This paper examines the impact of the national fund on the establishment of the systems for suicide prevention and the implementation of these initiatives among local authorities. METHODS: The present study included 1385 local authorities (79.5%) from all 47 prefectures that responded to the cross-sectional questionnaire survey. RESULTS: Improved suicide-prevention systems and the implementation of nine initiatives in April 2013 were observed among 265 local authorities (19.1%) that implemented 'Training of community service providers' and 'Public awareness campaigns'; 178 local authorities (12.9%) that implemented 'Face-to-face counseling', 'Training of community service providers' and 'Public awareness campaigns'; and 324 local authorities (23.4%) that implemented 'Trauma informed policies and practices'. There was no significant difference in suicide prevention systems and the implementation of nine initiatives between 203 local authorities (14.7%) that implemented only 'Public awareness campaigns' and 231 local authorities (16.7%) that did not implement any suicide-prevention programs. CONCLUSION: The results of our study suggest that the national fund promoted the establishment of community systems for suicide prevention and helped implement initiatives among local authorities. The national suicide-prevention strategy in Japan should explore a standard package of programs to guide community suicide prevention efforts with a sustained workforce among local authorities. PMID- 25041479 TI - Nicotinic acetylcholine receptors control acetylcholine and noradrenaline release in the rodent habenulo-interpeduncular complex. AB - BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nACh receptors) play a central role in the habenulo-interpeduncular system. We studied nicotine-induced release of NA and ACh in the habenula and interpeduncular nucleus (IPN). EXPERIMENTAL APPROACH: The habenula and IPN were loaded with [(3) H]-choline or [(3) H]-NA and placed in superfusion chambers. [(3) H]-ACh release was also stimulated using nicotinic agonists, electrical pulses and elevated [KCl]o in hippocampal and cortical slices from rats, wild-type mice and mice lacking alpha5, alpha7, beta2, or beta4 nACh receptor subunits. Finally, we analysed nACh receptor subtypes in the IPN using immunoprecipitation. KEY RESULTS: Nicotine induced release of [(3) H]-ACh in the IPN of rats and mice. This release was calcium-dependent but not blocked by tetrodotoxin (TTX); moreover, [(3) H]-ACh release was abolished in beta4-knockout mice but was unaffected in beta2- and alpha5-knockout mice. In contrast, nicotine-induced release of [(3) H]-NA in the IPN and habenula was blocked by TTX and reduced in both beta2-knockout and beta4 knockout mice, and dose-response curves were right-shifted in alpha5-knockout mice. Although electrical stimuli triggered the release of both transmitters, [(3) H]-ACh release required more pulses delivered at a higher frequency. CONCLUSIONS AND IMPLICATIONS: Our results confirm previous findings that beta4 containing nACh receptors are critical for [(3) H]-ACh release in the mouse IPN. Experiments using alpha5-knockout mice also revealed that unlike in the hippocampus, nicotine-induced [(3) H]-NA release in the habenulo-interpeduncular system is altered in this knockout model. As alpha5-containing nACh receptors play a key role in nicotine intake, our results add NA to the list of transmitters involved in this mechanism. PMID- 25041483 TI - Soil fungal communities of grasslands are environmentally structured at a regional scale in the Alps. AB - Studying patterns of species distributions along elevation gradients is frequently used to identify the primary factors that determine the distribution, diversity and assembly of species. However, despite their crucial role in ecosystem functioning, our understanding of the distribution of below-ground fungi is still limited, calling for more comprehensive studies of fungal biogeography along environmental gradients at various scales (from regional to global). Here, we investigated the richness of taxa of soil fungi and their phylogenetic diversity across a wide range of grassland types along a 2800 m elevation gradient at a large number of sites (213), stratified across a region of the Western Swiss Alps (700 km(2)). We used 454 pyrosequencing to obtain fungal sequences that were clustered into operational taxonomic units (OTUs). The OTU diversity-area relationship revealed uneven distribution of fungal taxa across the study area (i.e. not all taxa are everywhere) and fine-scale spatial clustering. Fungal richness and phylogenetic diversity were found to be higher in lower temperatures and higher moisture conditions. Climatic and soil characteristics as well as plant community composition were related to OTU alpha, beta and phylogenetic diversity, with distinct fungal lineages suggesting distinct ecological tolerances. Soil fungi, thus, show lineage-specific biogeographic patterns, even at a regional scale, and follow environmental determinism, mediated by interactions with plants. PMID- 25041485 TI - Diffuse disseminated lichenoid-type cutaneous sarcoidosis mimicking erythroderma. PMID- 25041486 TI - The pharmacokinetics, pharmacodynamics and safety of oral doses of ilaprazole 10, 20 and 40 mg and esomeprazole 40 mg in healthy subjects: a randomised, open-label crossover study. AB - BACKGROUND: Ilaprazole, a proton pump inhibitor (PPI) currently in clinical use, may provide improved acid suppression vs. other PPIs. AIM: To compare the pharmacodynamic and pharmacokinetic profiles of ilaprazole and esomeprazole. METHODS: A phase 1, randomised, open-label, single-centre, 4-period crossover study was conducted in 40 healthy volunteers. Ilaprazole 10, 20 or 40 mg or esomeprazole 40 mg was administered once daily for 5 days with >=5-day washout intervals. Pharmacokinetic blood samples and intragastric pH measurements were collected at scheduled timepoints for 24 h after dosing on Days 1 and 5. RESULTS: Esomeprazole 40 mg provided significantly better pH control during the initial hours (0-4 h) after a single dose, but ilaprazole (particularly 20 and 40 mg) provided significantly better pH control for the entire 24-h period and during evening and overnight hours after single and multiple doses. Increasing ilaprazole doses resulted in dose-proportional increases in peak plasma concentration and area under the plasma concentration vs. time curve following single and multiple doses. Ilaprazole was safe and generally well tolerated; an unexpectedly high incidence of allergic eye and skin reactions were observed but were not specific to any dosing regimen. Plasma gastrin concentrations did not increase proportionately with increasing ilaprazole dose. CONCLUSIONS: Ilaprazole provided significantly better pH control over 24 h and during evening and overnight hours compared with esomeprazole in healthy volunteers, which may translate to greater relief of night-time heartburn in the clinical setting for patients with gastric acid-related disorders. PMID- 25041487 TI - Melanoma-derived IL-1 converts vascular endothelium to a proinflammatory and procoagulatory phenotype via NFkappaB activation. AB - Spreading of melanoma is associated with efficient extravasation of circulating tumor cells from the vascular system into distant target organs. This process is accompanied and supported by proinflammatory and procoagulatory conditions. In this study, we analysed the ability of human melanoma cell lines to activate endothelial cells (ECs) in vitro. Some melanoma cells, that is, MV3, were shown to trigger an prompt calcium-flux-dependent, procoagulatory endothelial response that was accompanied by luminal release of ultra-large von Willebrand factor (ULVWF) fibres that were immobilized to the endothelial surface layer. In contrast to MV3-derived supernatant, prolonged treatment of ECs with WM9-derived supernatant mediated a pronounced activation of nuclear factor kappa B (NFkappaB). NFkappaB activation in ECs was dependent on both IL-1alpha and IL 1beta secreted from melanoma cells. Melanoma-derived IL-1 mediated an upregulation of proinflammatory cytokines IL-6 and IL-8, the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the procoagulatory tissue factor (TF) in ECs. Our data show that melanoma cells activate ECs either directly and within seconds or by an IL-1-mediated NFkappaB activation. Both pathways of EC activation convert the regular repressive function of ECs on inflammation and coagulation to a proinflammatory and procoagulatory surface that supports tumor progression. PMID- 25041488 TI - Suffering and transition strategies in adult patients attending a chronic pain management programme. AB - AIMS AND OBJECTIVES: To develop a deeper understanding of suffering and useful transition strategies in patients after participation in a chronic pain management programme. BACKGROUND: Chronic pain is a complex, multifaceted, individual experience. Limitations in patients' ability to perform their usual activities, as well as social isolation, are frequently reported. This condition may include a state of suffering that leads to challenges with transitions, for which support, guidance and achievement of useful strategies are needed. DESIGN: Qualitative study with a descriptive and explorative design from a phenomenological perspective. METHODS: A phenomenological-hermeneutic approach was used to analyse interviews with 12 participants in a group-based cognitive behavioural therapy management programme. RESULTS: Suffering from chronic pain means handling difficult thoughts and feelings. Expression of these thoughts and feelings through group support and therapeutic writing alleviates suffering. In addition, new perspectives through active involvement in the cognitive behavioural therapy programme indicate a transition towards adaptation to the chronic pain situation. CONCLUSION: Qualitative analysis of participation in a cognitive-behavioural therapy programme deepens our understanding of both patient suffering and helpful transition strategies towards adaptation. Group participation in the programme appeared to be useful in improving patients' ability to handle challenging experiences with transitions. It is essential that the patients play an active role in adaptive transitions by developing new perspectives and insight. RELEVANCE TO CLINICAL PRACTICE: It is an important activity for nurses or other healthcare workers to assist in the transition process so that the patient can take an active role to achieve alleviation. Focus on transition conditions seems to be helpful because it considers the factors that might facilitate successful transitions towards optimal adaptation. PMID- 25041489 TI - Four-Millimeter-Long Posterior-Mandible Implants: 5-Year Outcomes of a Prospective Multicenter Study. AB - BACKGROUND: There is lack of evidence on long-term success of short dental implants in reduced alveolar bone. PURPOSE: In this prospective 5-year study, survival and marginal bone loss of 4-mm implants, which supported fixed dental prostheses (FDPs) in severely resorbed posterior mandibles, were evaluated. MATERIAL AND METHODS: In 28 patients, evaluation of 86 osseointegrated 4-mm-long implants, which supported a 3- or a 4-unit FDP by crown splinting without the use of pontics or cantilevers, was performed over a 5-year period. RESULTS: Three subjects dropped out for non-study reasons: one subject had her three implants removed after 1 year and two subjects died (six implants). Five implants in three subjects were lost between 3 and 5 years. Twenty-four subjects and 71 implants were active at the 5-year follow-up (92.2% survival). After 1 year, significant (p < .001) mean (standard error of the mean [SEM]) 0.44-mm (0.05) marginal bone loss occurred. At 2, 3, and 5 years, mean (SEM) bone loss of 0.57 mm (0.06), 0.55 mm (0.07), and 0.53 mm (0.08) occurred, respectively (no significant change after 1 year). At 5 years, average plaque levels were 13.3%; 69% of the implants were plaque free. On average, mucosal bleeding occurred at 8.1% of the implants. During 5 years, two subjects experienced uncomplicated bridge loosening. No other complications occurred during the study. CONCLUSION: Four-millimeter implants can support FDPs in severely resorbed posterior mandibles for 5 years with healthy peri-implant conditions. PMID- 25041490 TI - Rosai-Dorfman disease of the genito-urinary tract: analysis of six cases from the testis and kidney. AB - AIMS: Rosai-Dorfman disease (RDD) commonly occurs in lymph nodes, but it can also affect the genitourinary (GU) system. In a search of GU RDD, we identified three cases involving the testis and three the kidney. METHODS AND RESULTS: The mean age was 52.4 (35-76) years. Tumour sizes were 3.6 cm on average (1.5-4.3) for testicular cases and 15.5 cm for the renal case treated by nephrectomy. All renal cases showed typical morphology similar to nodal RDD with scattered foci of lymphocytic aggregation. In contrast, all three testicular cases had an evenly distributed lymphocyte and plasma cell infiltration with entrapment of Sertoli only seminiferous tubules. In all six cases, immunohistochemistry (IHC) for S100 showed strong reactivity in the lesional histiocytes and highlighted the hallmark emperipolesis. One testicular case had pleural and pericardial effusions but resolved after removal of the RDD lesion. Another renal case subsequently involved bone and then lung over a 3-year period. CONCLUSIONS: RDD involving the GU system is rare with it most commonly involving the kidney followed by testis. Our three renal cases were similar in morphology to typical nodal RDD. The testicular cases had a somewhat different histological picture and needed IHC for S100 to verify the diagnosis. PMID- 25041491 TI - Umbilical cord prolapse--progress! PMID- 25041492 TI - miR-520c-3p with therapeutic potential in hepatocellular carcinoma. PMID- 25041493 TI - Reduced activities of phospholipases A2 in platelets of drug-naive bipolar disorder patients. AB - OBJECTIVE: Phospholipases A2 (PLA2 ) comprise a family of hydrolytic enzymes that cleave membrane phospholipids and play a key role in cellular homeostasis. Alterations in enzymatic activity have been hypothesized in bipolar disorder (BD). Recent studies suggest that PLA2 activity in platelets may reflect PLA2 activity in the brain. The aim of this study was to determine PLA2 activity in platelets of BD patients. METHODS: We determined the activity of PLA2 subtypes [extracellular, calcium-dependent PLA2 (sPLA2 ), intracellular, calcium-dependent PLA2 (cPLA2 ), and intracellular, calcium-independent PLA2 (iPLA2 )] by a radioenzymatic method in platelets from 20 patients with BD (15 drug-naive and five drug-free) and from 16 age- and gender-matched healthy controls. RESULTS: We found that iPLA2 , cPLA2 , and sPLA2 activities were lower in drug-naive patients with BD when compared to the control group (p = 0.017, p < 0.001, and p < 0.001, respectively). CONCLUSIONS: Reduced PLA2 activity at the early stage of BD may disrupt brain function and increase the risk for the disease. Moreover, epidemiological studies show that patients with BD have a fivefold increased risk for developing Alzheimer's disease. Because patients with Alzheimer's disease also have reduced PLA2 activity, the present finding of reduced PLA2 in the BD group may be related to the risk factor for these individuals developing Alzheimer's disease in advanced age. PMID- 25041494 TI - Safety, local tolerability and pharmacokinetics of ceftaroline fosamil administered in a reduced infusion volume. AB - AIMS: The standard dose of ceftaroline fosamil for patients with normal renal function is 600 mg diluted in 250 ml by 60 min intravenous infusion every 12 h. This two part phase I trial (NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50 ml and 250 ml infusions, and pharmacokinetics following single administrations of each infusion volume. METHODS: Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600 mg and placebo infusions in each arm (50 ml then 250 ml or vice versa) every 12 h for 72 h, with a >= 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores >=2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50 ml and 250 ml ceftaroline fosamil 600 mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24 h. RESULTS: In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50 ml or 250 ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50 ml and 250 ml infusions in part B. CONCLUSIONS: No new safety concerns were identified for ceftaroline fosamil 600 mg 50 ml compared with 250 ml. These findings suggest infusion volumes down to 50 ml may be used in patients with fluid intake restrictions. PMID- 25041495 TI - Continuous wound infiltration with ropivacaine for analgesia after caesarean section: a randomised, placebo-controlled trial. AB - BACKGROUND: We evaluated the analgesic effect of ropivacaine infiltration into the surgical wound after caesarean section. METHODS: In a double-blind trial, 67 patients who were scheduled for caesarean section under spinal anaesthesia were randomly assigned to receive either 0.75% ropivacaine or placebo (NaCl 0.9%) through a multi-orifice catheter that was placed into the surgical wound, between the muscle fascia and the subcutaneous tissue. The study drug was administered as a bolus of 10 ml at the end of the operation, followed by an infusion at 2 ml/h for 48 h. All patients were also given paracetamol and ibuprofen. The primary outcome was the total amount of rescue oxycodone needed during the first 48 h post-operatively. Secondary outcomes included pain and patient satisfaction scores. Analyses were according to intention to treat. RESULTS: The mean (+/- standard deviation) amount of oxycodone administered during the first 48 h was 47.5 +/- 20.9 mg in the ropivacaine group and 57.8 +/- 29.4 mg in the placebo group (95% confidence interval for the difference between means, -22.8-2.2 mg; P = 0.10). There were no differences between the groups in pain scores or in patient satisfaction scores. CONCLUSION: Continuous wound infiltration with ropivacaine did not decrease the need for opioids and had no impact on pain scores or patient satisfaction after caesarean section. PMID- 25041496 TI - Self-adhesive resin cements: a clinical review. AB - PURPOSE: To review the performance of self-adhesive luting agents to determine their clinical evidence. MATERIALS AND METHODS: In March 2013, we conducted a literature search by means of PubMed and manually searched German and English medical journals using general search terms (e.g., "self-adhesive resin cements"), detailed search terms (e.g., clinical study "self-adhesive resin cement"), and brand name search terms (clinical study AND "brand name of the cement"). The resulting lists of articles were manually searched for clinical studies. Because of the low number of relevant articles, we decided to broaden our search by including in vitro studies based on a thermal cycling and mechanical loading (TCML) design. RESULTS: The search using the six general search terms yielded a list with over 100 studies with only 13 in vivo studies and 6 in vitro studies based on a TCML design. The other studies either did not comply with the requirements or were not in vitro studies based on a TCML design. Two more in vivo studies could be added after the brand name search. Altogether, 15 in vivo studies and 6 in vitro studies were included in our analysis. CONCLUSION: Because of the low number of studies available, the clinical evidence of self-adhesive luting agents cannot be assessed in a sufficient manner. PMID- 25041497 TI - Commentary. PMID- 25041498 TI - ACTH stimulation test in patients with type 1 diabetes and recurrent severe hypoglycaemia. PMID- 25041499 TI - Assessment of vaccination-related information for consumers available on Facebook. AB - OBJECTIVES: To assess the magnitude, interest, purpose and validity of vaccination-related information on Facebook and to determine whether information varies by site viewpoint. METHODS: The 10 largest vaccination-focused Facebook pages, groups and places in each category were identified and classified by viewpoint (i.e. anti-, pro-, neutral) and purpose. Number of members, posts per week, likes, comments and shares per post were recorded. Posts were assessed for concordance with CDC and FDA recommendations. RESULTS: Of 30 sites, 43% (n = 13) were anti-vaccination, 7% (n = 2) neutral and 50% (n = 15) pro-vaccination. Most sites were most popular with American users. Median members were similar between anti-vaccination (2703 members, range 337-33 631 members) and pro-vaccination sites (2142 members, range 456-61,565 members, P = 0.262); however, anti vaccination sites accumulated more posts per week by authors (median 15 vs. 3, P = 0.031) and members (median 33 vs. 1, P < 0.001). Pro-vaccination sites more commonly had commercial purpose (53% [n = 8] vs. 8% [n = 1], P = 0.02). Anti vaccination sites more commonly gave medical advice (54% [n = 7] vs. 0%, P = 0.004). Overall, 48% (n = 22) of author posts were concordant with regulatory recommendations; concordance was more common on pro-vaccination sites (78% [n = 21] vs. 5% [n = 1], P = 0.0002). CONCLUSION: Vaccination-related information is prevalent on Facebook regardless of viewpoint; however, anti-vaccination information generates more interest. Anti-vaccination sites were likely to provide medical advice and disagree with regulatory bodies. PMID- 25041500 TI - Trigeminal rhythm during ventricular pacing in a patient with ventricular preexcitation: what is the mechanism? PMID- 25041501 TI - Brain serotonin synthesis in MDMA (ecstasy) polydrug users: an alpha-[(11) C]methyl-l-tryptophan study. AB - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[(11) C]methyl-l-tryptophan ((11) C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional (11) C-AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized (11) C-AMT trapping in pre-frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized (11) C-AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized (11) C-AMT trapping in the brainstem and pre-frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre-existing 5 HT alterations pre-disposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms. PMID- 25041503 TI - Burden of stroke in Egypt: current status and opportunities. AB - Middle East and North Africa (MENA) countries have a diversity of populations with similar life style, dietary habits, and vascular risk factors that may influence stroke risk, prevalence, types, and disease burden. Egypt is the most populated nation in the Middle East with an estimated 85.5 million people. In Egypt, according to recent estimates, the overall prevalence rate of stroke is high with a crude prevalence rate of 963/100,000 inhabitants. In spite of disease burden, yet there is a huge evidence practice gap. The recommended treatments for ischemic stroke that are guideline include systematic supportive care in a stroke unit or stroke center is still deficient. In addition, the frequency of thrombolysis in Egypt is very low for many reasons; the major one is that the health insurance system is not covering thrombolysis therapy in nonprivate sectors so patients must cover the costs using their own personal savings; otherwise, they will not receive treatment. Another important factor is the pronounced delay in prehospital and in hospital management of acute stroke. Improvement of stroke care in Egypt should be achieved through multi and interdisciplinary approach including public awareness, physicians' education, and synergistic approach to stroke care with Emergency Medical System. PMID- 25041502 TI - The N400 and the fourth grade shift. AB - While behavioral and educational data characterize a fourth grade shift in reading development, neuroscience evidence is relatively lacking. We used the N400 component of the event-related potential waveform to investigate the development of single word processing across the upper elementary years, in comparison to adult readers. We presented third graders, fourth graders, fifth graders, and college students with a well-controlled list of real words, pseudowords, letter strings, false font strings, and animal name targets. Words and pseudowords elicited similar N400s across groups. False font strings elicited N400s similar to words and letter strings in the three groups of children, but not in college students. The pattern of findings suggests relatively adult-like semantic and phonological processing by third grade, but a long developmental time course, beyond fifth grade, for orthographic processing in this context. Thus, the amplitude of the N400 elicited by various word-like stimuli does not reflect some sort of shift or discontinuity in word processing around the fourth grade. However, the results do suggest different developmental time courses for the processes that contribute to automatic single word reading and the integrative N400. PMID- 25041504 TI - Polymorphisms in oxidative stress pathway genes and risk of diabetic nephropathy in South Indian type 2 diabetic patients. AB - AIM: Diabetic nephropathy (DN), a common microvascular complication of type 2 diabetes mellitus (T2DM) is polygenic, with a vast array of genes contributing to disease susceptibility. Accordingly, we explored the association between DN and six polymorphisms in oxidative stress related genes, namely eNOS, p22phox subunit of NAD(P)H oxidase, PARP-1 and XRCC1 in South Indian T2DM subjects. METHODS: The study included 155 T2DM subjects with DN and 162 T2DM patients with no evidence of DN. The selected polymorphisms were genotyped by polymerase chain reaction and Taqman allele discrimination assay. RESULTS: No significant difference was observed in the genotype and allele distribution of eNOS -786T > C, intron 4a4b, p22phox 242C > T and XRCC1 Arg399Gln polymorphisms between T2DM groups with and without DN. Contrastingly, there appeared to be a significant association of eNOS 894G > T and PARP-1 Val762Ala polymorphisms with DN wherein, the presence of 894T allele was associated with an enhanced risk for DN [P = 0.005; OR = 1.78 (1.17 2.7)], while the 762Ala allele seemed to confer significant protection against DN [P = 0.02; OR = 0.59 (0.37-0.92)]. Multiple logistic regression analysis revealed a significant and independent association of eNOS 894G > T, PARP-1 Val762Ala polymorphisms and hypertension with DN in T2DM individuals. CONCLUSIONS: eNOS 894G > T and PARP-1 Val762Ala polymorphisms appeared to associate significantly with DN, with the former contributing to an enhanced risk and the latter to a reduced susceptibility to DN in South Indian T2DM individuals. PMID- 25041505 TI - Regular automated red cell exchange transfusion in the management of pulmonary hypertension in sickle cell disease. PMID- 25041506 TI - Prophylactic octreotide for pancreatoduodenectomy: more harm than good? AB - BACKGROUND: Most accrued evidence regarding prophylactic octreotide for a pancreatoduodenectomy (PD) predates the advent of the International Study Group of Pancreatic Fistula (ISGPF) classification system for a post-operative pancreatic fistula (POPF), and its efficacy in the setting of high POPF risk is unknown. The Fistula Risk Score (FRS) predicts the risk and impact of a clinically relevant (CR)-POPF and can be useful in assessing the impact of octreotide in scenarios of risk. METHODS: From 2001-2013, 1018 PDs were performed at four institutions, with octreotide administered at the surgeon's discretion. The FRS was used to analyse the occurrence and burden of POPF across various risk scenarios. RESULTS: Overall, 391 patients (38.4%) received octreotide. A CR-POPF occurred more often when octreotide was used (21.0% versus 7.0%; P < 0.001), especially when there was advanced FRS risk. Octreotide administration also correlated with an increased hospital stay (mean: 13 versus 11 days; P < 0.001). Regression analysis, controlling for FRS risk, demonstrated that octreotide increases the risk for CR-POPF development. CONCLUSION: This multi-institutional study, using ISGPF criteria, evaluates POPF development across the entire risk spectrum. Octreotide appears to confer no benefit in preventing a CR-POPF, and may even potentiate CR-POPF development in the presence of risk factors. This analysis suggests octreotide should not be utilized as a POPF mitigation strategy. PMID- 25041507 TI - Saccharomyces eubayanus and Saccharomyces uvarum associated with the fermentation of Araucaria araucana seeds in Patagonia. AB - Mudai is a traditional fermented beverage, made from the seeds of the Araucaria araucana tree by Mapuche communities. The main goal of the present study was to identify and characterize the yeast microbiota responsible of Mudai fermentation as well as from A. araucana seeds and bark from different locations in Northern Patagonia. Only Hanseniaspora uvarum and a commercial bakery strain of Saccharomyces cerevisiae were isolated from Mudai and all Saccharomyces isolates recovered from A. araucana seed and bark samples belonged to the cryotolerant species Saccharomyces eubayanus and Saccharomyces uvarum. These two species were already reported in Nothofagus trees from Patagonia; however, this is the first time that they were isolated from A. araucana, which extends their ecological distribution. The presence of these species in A. araucana seeds and bark samples, led us to postulate a potential role for them as the original yeasts responsible for the elaboration of Mudai before the introduction of commercial S. cerevisiae cultures. The molecular and genetic characterization of the S. uvarum and S. eubayanus isolates and their comparison with European S. uvarum strains and S. eubayanus hybrids (S. bayanus and S. pastorianus), allowed their ecology and evolution us to be examined. PMID- 25041508 TI - Molecular and morphometric characteristics of Ceratomyxa hamour n. sp. (Myxosporea: Bivalvulida) infecting the gallbladder of the orange-spotted grouper Epinephelus coioides from the Arabian Gulf, Saudi Arabia. AB - Ceratomyxa hamour n. sp. was found to infect the gallbladder of the orange spotted grouper, Epinephelus coioides located off the Saudi Arabian coast of the Arabian Gulf. The infection was reported as a free-floating spore in the bile, and pseudoplasmodia were not observed. Mature spores were crescent-shaped and measured on average 7 MUm in length and 16 MUm in thickness. The polar capsule, meanwhile, had length to width measurements of 4 MUm and 3 MUm on average. A periodical survey was conducted throughout a sampling period between December 2012 and December 2013, with the results showing that the parasite was present throughout the year with a mean prevalence of 32.6%. The objective of this study was to characterize this new species based on its morphological and molecular differences from previously described species. Molecular analysis based on the partial sequence of the SSU rDNA gene, showed the highest similarity (97.8%) to Ceratomyxa buri, reported in the cultured yellow tail Seriola quinqueradiata in Japan. Indeed, C. buri and the new species described here formed an individual cluster with a high degree of bootstrap support. This is the first reported species of genus Ceratomyxa from the Arabian Gulf fishes off Saudi Arabia. PMID- 25041509 TI - ISPAD Clinical Practice Consensus Guidelines 2014. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. PMID- 25041510 TI - The impact of mega-catastrophes on insurers: an exposure-based analysis of the U.S. homeowners' insurance market. AB - Insurance is a key risk-sharing mechanism that protects citizens and governments from the losses caused by natural catastrophes. Given the increase in the frequency and intensity of natural catastrophes over recent years, this article analyzes the performance effects of mega-catastrophes for U.S. insurance firms using a measure of market expectations. Specifically, we analyze the share price losses of insurance firms in response to catastrophe events to ascertain whether mega-catastrophes significantly damage the performance of insurers and whether different types of mega-catastrophes have different impacts. The main message from our analysis is that the impact of mega-catastrophes on insurers has not been too damaging. While the exact impact of catastrophes depends on the nature of the event and the degree of competition within the relevant insurance market (less competition allows insurers to recoup catastrophe losses through adjustments to premiums), our overall results suggest that U.S. insurance firms can adequately manage the risks and costs of mega-catastrophes. From a public policy perspective, our results show that insurance provides a robust means of sharing catastrophe losses to help reduce the financial consequences of a catastrophe event. PMID- 25041511 TI - Impact of plaque accumulation on the osseointegration of titanium-zirconium alloy and titanium implants. A histological and immunohistochemical analysis. AB - OBJECTIVES: To evaluate the impact of plaque accumulation on osseointegration at surface enhanced modified hydrophilic titanium-zirconium (TiZr) alloy and titanium (Ti) implants. MATERIALS AND METHODS: TiZr and Ti implants with a sand blasted, acid etched, and chemically modified endosseous and a machined (M) transmucosal portion were bilaterally (i.e., one implant type on each side) inserted in the maxilla of six foxhounds. In a split-mouth design, experimental mucositis was induced at one randomly assigned side (NPC), while the contralateral side received mechanical plaque removal three times per week (PC). After 16 weeks, tissue biopsies were processed for histological (primary outcome: bone-to-implant contact [BIC]) and immunohistochemical (CD68) analysis. RESULTS: Mean BIC values varied between 81.96% (TiZrM) and 88.72% (TiM) in the NPC group, and between 87.88% (TiM) and 92.69% (TiZrM) in the PC group. Even though BIC values tended to be lower within the endosseous coronal compartment at NPC sites, within group (NPC vs. PC) comparisons failed to reach statistical significance at both types of implants. These non-BIC areas were not associated with any CD68 positive cells. CONCLUSIONS: Osseointegration of both TiZrM and TiM implants was not influenced by plaque accumulation in this experimental model. PMID- 25041512 TI - Understanding alcohol and other drug use during the event. PMID- 25041513 TI - A comparative study of blood alcohol concentrations in Australian night-time entertainment districts. AB - INTRODUCTION AND AIMS: There is little research describing how intoxication levels change throughout the night in entertainment districts. This research aims to describe levels of alcohol intoxication across multiple Australian metropolitan and regional nightlife districts. DESIGN AND METHODS: This study was conducted in the night-time entertainment districts of three metropolitan cities (Sydney, Melbourne and Perth) and two regional cities (Wollongong and Geelong) in Australia. Data collection occurred approximately fortnightly in each city on a Friday or Saturday night between 8 pm and 5 am. Brief structured interviews (3-10 min) and breathalyser tests were undertaken in busy thoroughfares over six months. RESULTS: Of the 7037 individuals approached to participate in the study, 6998 [61.8% male, mean age 24.89 years (standard deviation 6.37; range 18-73)] agreed to be interviewed. There was a linear increase in blood alcohol concentration (BAC) levels throughout the night. Post hoc testing revealed significantly more highly intoxicated participants (i.e. BAC above 0.10 mg of alcohol per 100 mL of blood) after midnight (P < 0.05). The overall mean BAC was 0.06 mg/100 mL. Men were more intoxicated than women earlier in the night, but gender differences disappeared by 3 am. There was no age differences in intoxication earlier in the night, but after midnight, patrons over the age of 21 showed increasing BAC levels. DISCUSSION AND CONCLUSIONS: There is a consistent trend across the cities of high to very high levels of intoxication later in the night, with trends after midnight being significantly different to those before. PMID- 25041514 TI - Underrepresentation of heroin involvement in unintentional drug overdose deaths in Allegheny County, PA. AB - Drugs contributing to overdose deaths are listed on death certificates, but their validity is rarely studied. To assess the accuracy of "morphine" and "codeine" listings on death certificates for unintentional overdose deaths in Allegheny County, PA, investigative and laboratory reports were reviewed. Deaths were reclassified as heroin-related if documentation showed 6-monoacetylmorphine in blood or urine, "stamp bags" or drug paraphernalia at scene, history of heroin use, or track marks. Deaths were considered morphine-related if notes indicated morphine use, prescription, or morphine at scene, or codeine-related if the codeine blood level exceeded morphine. Of 112 deaths with morphine but not heroin listed on the death certificate, 74 met heroin criteria and 21 morphine criteria. Of 20 deaths with both morphine and heroin listed, only one met morphine criteria. Of 34 deaths with codeine listed, only five were attributed to codeine. Consideration of patient history, death scene evidence, and expanded toxicology testing may improve the accuracy of death certificate drug listings. PMID- 25041516 TI - Rapid evolution of reproductive isolation between incipient outcrossing and selfing Clarkia species. AB - A major goal of speciation research is to understand the processes involved in the earliest stages of the evolution of reproductive isolation (RI). One important challenge has been to identify systems where lineages have very recently diverged and opportunities for hybridization are present. We conducted a comprehensive examination of the components of RI across the life cycle of two subspecies of Clarkia xantiana, which diverged recently (ca. 65,000 bp). One subspecies is primarily outcrossing, but self-compatible, whereas the other is primarily selfing. The subspecies co-occur in a zone of sympatry but hybrids are rarely observed. Premating barriers resulted in nearly complete isolation in both subspecies with flowering time and pollinator preference (for the outcrosser over the selfer) as the strongest barriers. We found that the outcrosser had consistently more competitive pollen, facilitating hybridization in one direction, but no evidence for pollen-pistil interactions as an isolating barrier. Surprisingly, postzygotic isolation was detected at the stage of hybrid seed development, but in no subsequent life stages. This crossing barrier was asymmetric with crosses from the selfer to outcrosser most frequently failing. Collectively, the results provide evidence for rapid evolution of multiple premating and postzygotic barriers despite a very recent divergence time. PMID- 25041515 TI - RCN1/OsABCG5, an ATP-binding cassette (ABC) transporter, is required for hypodermal suberization of roots in rice (Oryza sativa). AB - Suberin is a complex polymer composed of aliphatic and phenolic compounds. It is a constituent of apoplastic plant interfaces. In many plant species, including rice (Oryza sativa), the hypodermis in the outer part of roots forms a suberized cell wall (the Casparian strip and/or suberin lamellae), which inhibits the flow of water and ions and protects against pathogens. To date, there is no genetic evidence that suberin forms an apoplastic transport barrier in the hypodermis. We discovered that a rice reduced culm number1 (rcn1) mutant could not develop roots longer than 100 mm in waterlogged soil. The mutated gene encoded an ATP-binding cassette (ABC) transporter named RCN1/OsABCG5. RCN1/OsABCG5 gene expression in the wild type was increased in most hypodermal and some endodermal roots cells under stagnant deoxygenated conditions. A GFP-RCN1/OsABCG5 fusion protein localized at the plasma membrane of the wild type. Under stagnant deoxygenated conditions, well suberized hypodermis developed in wild types but not in rcn1 mutants. Under stagnant deoxygenated conditions, apoplastic tracers (periodic acid and berberine) were blocked at the hypodermis in the wild type but not in rcn1, indicating that the apoplastic barrier in the mutant was impaired. The amount of the major aliphatic suberin monomers originating from C(28) and C(30) fatty acids or omega-OH fatty acids was much lower in rcn1 than in the wild type. These findings suggest that RCN1/OsABCG5 has a role in the suberization of the hypodermis of rice roots, which contributes to formation of the apoplastic barrier. PMID- 25041517 TI - Early predictors of severe acetaminophen-induced hepatotoxicity in a paediatric population referred to a tertiary paediatric department. AB - AIM: The data on severe acetaminophen-induced hepatotoxicity in children are very limited. This study explored the dose-response relationship between ingested acetaminophen and hepatotoxicity, the early biochemical and clinical predictors of hepatotoxicity, the impact of early N-acetylcysteine treatment on hepatotoxicity and the incidence of nephrotoxicity. METHODS: We carried out a retrospective case study on 25 children aged 11-16 years with severe acetaminophen poisoning. RESULTS: Initial biochemical parameters predicted hepatotoxicity, defined as the maximum levels of the international normalised ratio (INR) and alanine aminotransferase (ALT). Significant relationships were found between: (1) the maximal INR and, for example, the initial bilirubin (p = 0.0003) and initial phosphate (p = 0.003), (2) the maximal ALT and, for example, the initial INR (p = 0.0003) and initial creatinine (p = 0.002), (3) the number of prehospital vomiting episodes and, for example, the maximal INR (p = 0.013) and maximum ALT (p = 0.0005) and (4) the time of N-acetylcysteine initiation and, for example, maximum ALT (p = 0.001) and maximum gamma-glutamyl transferase (GGT) (p = 0.007). The incidence of nephrotoxicity was 12%. There was no significant relationship between the amount of ingested acetaminophen and the degree of hepatotoxicity. CONCLUSION: Paediatric patients at increased risk of severe hepatotoxicity were identified by early biochemical parameters, prehospital vomiting episodes and latency time before N-acetylcysteine initiation. PMID- 25041518 TI - Hemodialysis-specific factors associated with salivary flow rates. AB - The saliva is important to maintain the integrity of tissues and teeth, besides having microbial activity. Hemodialysis (HD) patients usually have reduced salivary flow rate (SFR) and are exposed to all its associated complications. The aim of the present study was to identify HD-related factors associated with reduced SFR. A cross-sectional study was performed with maintenance HD patients. Stimulated whole saliva was collected before and after HD. Xerostomia was assessed through the validated xerostomia inventory and thirst through the dialysis thirst inventory. Parameters of dental health status were obtained by the decayed, missed, and filled teeth index and community periodontal index. One hundred twenty-eight patients (66 males) participated in this study. Stimulated SFR before HD was 0.38 +/- 0.28 mL/min. In univariate analysis and after adjusting for several factors, serum urea before HD session, serum intact parathormone (iPTH), calcium-phosphorus product (Ca*Pi), serum ferritin, and number of medications were negatively correlated with SFR in univariate analysis. Moreover, patients taking sevelamer had reduced SFR in comparison with those not receiving it (SFR 0.32 +/- 0.19 vs. 0.44 +/- 0.23 mL/min, P = 0.003). At multivariate analysis, including dialysis and nondialysis-related factors, age, elevated pre-HD serum urea, higher Ca*Pi product, higher iPTH, and sevelamer use remained as factors that were independently associated with a reduced SFR. After dialysis, there was a significant increment in SFR (0.39 +/- 0.28 vs. 0.60 +/- 0.34 mL/min, P < 0.001). Several HD-related features were associated with reduced SFR, including serum urea, sevelamer use, and bone and mineral disorders markers. PMID- 25041519 TI - Genetic variability of Lizard canary breed inferred from pedigree analysis. AB - The genealogical data of 471 (whole population: WP) Lizard canaries of an Italian breeder were analyzed to evaluate the genetic variability of the breed. The reference population (RP) comprised 346 living reproductive birds. Average generation interval was 1.61 +/- 0.718 for males and 1.72 +/- 0.863 for females. The average value of inbreeding (F) and relatedness (AR) in the RP were 15.83% and 22.63%, while the average increase in inbreeding was estimated to be 6.71% per generation (effective population size = 7.49). The results showed the need to reduce the level of inbreeding which would result in significant loss of genetic variation and in significant inbreeding depression. PMID- 25041520 TI - Somatosensory system hyperexcitability in alternating hemiplegia of childhood. AB - BACKGROUND AND PURPOSE: Alternating hemiplegia of childhood (AHC) is a rare neurological disease characterized by recurrent paroxysmal attacks of hemiplegia. The aim of the study was to assess the recovery cycle of the somatosensory evoked potentials (SEPs) in a group of AHC patients. METHODS: Seven AHC patients and 10 control age-matched subjects (CS) were recruited. Right and left median nerve SEPs were recorded. The somatosensory system excitability was assessed by calculating the SEP changes after paired electrical stimuli. All patients were studied during the interictal phase, whilst four patients were studied also during the ictal phase. RESULTS: In AHC patients during the interictal phase, the amplitudes of the cervical N13 and of the cortical N20, P24 and N30 responses showed a faster recovery than in CS. In AHC patients during the ictal phase, the cortical N20 recovery cycle was prolonged compared with the interictal phase. CONCLUSIONS: A shortened SEP recovery cycle in AHC during the interictal phase suggests multilevel somatosensory system hyperexcitability in AHC. A partial recovery of this phenomenon during the ictal phase possibly reflects a functional reset of the somatosensory system. Overall, there is a disinhibition of the somatosensory system in AHC, a functional change of brain function associated with a possible involvement of the Na(+) /K(+) channels. This abnormality and its partial recovery during the attacks might be linked to the pathophysiological and genetic mechanisms of the disease. PMID- 25041521 TI - Host-dependent differences in abundance, composition and host range of cyanophages from the Red Sea. AB - Cyanobacteria coexist in the oceans with a wealth of phages that infect them. While numerous studies have investigated Synechococcus phages, much less data are available for Prochlorococcus phages. Furthermore, little is known about cyanophage composition. Here, we examined the abundance and relative composition of cyanophages on six cyanobacterial hosts in samples collected during spring and summer from the Red Sea. Maximal abundances found on Synechococcus of 35 000 phages/ml are within ranges found previously, whereas the 24 000 phages/ml found on Prochlorococcus are approximately 10-fold higher than previous findings. T7 like, T4-like and 'unknown' phages were isolated on all hosts, including many T4 like phages on high-light adapted Prochlorococcus strains, whereas TIM5-like phages were found only on Synechococcus. Large differences in cyanophage abundance and composition were found for different hosts on the same sampling date, as well as for the same host on different dates, with few predictable patterns discerned. Host range analyses showed that T7-like and TIM5-like phages were quite host-specific, whereas the breadth of hosts for T4-like phages was related to host type: those isolated on high-light adapted Prochlorococcus were considerably more host-specific than those on low-light adapted Prochlorococcus or Synechococcus. These host-related differences likely contribute to the complexity of host-phage interactions in the oceans. PMID- 25041522 TI - Micturition associated with painless lacrimation. PMID- 25041523 TI - Host-cell specificity and transcytosis of nontoxic nonhemagglutinin protein of botulinum neurotoxin serotype D. AB - Serotype D botulinum toxin (BoNT) complex (TC), a causative agent of foodborne botulism in animals, traverses the gastrointestinal tract and circulation, eventually becoming localized in neuromuscular junctions, where the serotype D BoNT cleaves SNARE substrate synaptobrevin II involved in neurotransmitter release. During this process, BoNT must pass through cells, thus from the intestinal lumen to the cells of the intestinal tract and blood vessels. The botulinum TC is formed by association of the BoNT with at least one nontoxic protein, which may be a nontoxic nonhemagglutinin (NTNHA). In this work, we examined the binding and transcytosis of serotype D NTNHA protein in epithelial and endothelial cells to clarify the role played by the protein in toxin delivery. Our studies showed that NTNHA bound to and transcytosed across rat intestinal epithelial (IEC-6) and bovine aortic endothelial (BAEC) cells. While NTNHA also bound to canine renal (MDCK) or human colon carcinoma (Caco-2) cells, but it did not traverse across MDCK or Caco-2 cells. Such specificity of NTNHA protein transcytosis may explain why only some animals are sensitive to botulinum toxin. The sensitivity depends on the toxin serotype in play, and the route of toxin delivery. PMID- 25041524 TI - Charting a research agenda for understanding the epidemiology of food allergy in adults in Europe. PMID- 25041525 TI - Global Allergy Forum and Second Davos Declaration 2013 Allergy: Barriers to cure- challenges and actions to be taken. PMID- 25041526 TI - Characterisation of the faecal metabolome and microbiome of Thoroughbred racehorses. AB - REASONS FOR PERFORMING STUDY: The intestinal bacterial community of the horse is a key determinant of intestinal and whole body health. Understanding the bacterial community structure and function is an important foundation for studies of intestinal health and disease. OBJECTIVES: To describe the faecal bacterial community and volatile organic compounds (VOCs) of the faecal metabolome of healthy Thoroughbred racehorses and to characterise responses to dietary supplementation with amylase-rich malt extract. STUDY DESIGN: Intervention study. METHODS: Faecal samples were collected noninvasively before and 6 weeks after supplementation in 8 privately owned Thoroughbred racehorses in active race training. Faecal metabolome was characterised using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS), with spectral analysis performed using AMDIS and compared against the NIST database. Taxonomic description of the faecal microbiota was achieved using error-corrected 454 pyrosequencing data from 16S rRNA gene amplicons. RESULTS: The faecal metabolome of our study population was dominated by organic acids, alcohols and ketones. We identified 81 different VOCs only 28 of which were present in >50% of samples indicating functional diversity. Faecal VOC profiles differed between first and second sampling point, some VOCs being significantly reduced post supplementation, consistent with a marked response to dietary amylase-rich malt extract. Faecal microbiota was characterised as highly diverse; samples demonstrated verifiable diversity in the range 1200-3000 operational taxonomic units (OTUs) per individual. The methods used also describe high levels of infrequent, low abundance OTUs. Faecal microbial community structure was found to be different following dietary supplementation. Differences in several low abundance bacterial taxa were detected and also some evidence of interhorse variation in response. CONCLUSIONS: The volatile faecal metabolome of Thoroughbred racehorses is dominated by organic acids, alcohols and ketones; this study demonstrates that dietary supplementation with amylase-rich malt extract may significantly alter the profile of VOCs. The faecal microbiome is highly diverse, dominated by Firmicutes and Bacteroidetes. Small but significant changes in microbial community structure were detected following dietary supplementation. This study describes the faecal metabolome and microbiome of healthy Thoroughbred racehorses against which future studies of disease and dietary intervention can be benchmarked. PMID- 25041527 TI - Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. AB - Epstein-Barr Virus (EBV) is present in the neoplastic cells of around 20-30% of patients with Hodgkin Lymphoma (HL). Although, an immunosuppressive environment is currently described in HL patients, little is known concerning the regulatory mechanism induced by EBV proteins expression in tumour cells. This study aimed to investigate an association between regulatory Type 1 cells (Tr1) and EBV tissue positivity in HL patients. Transcriptomic analysis of both EBV-positive and EBV negative tumours showed that EBV infection increased gene expression of Tr1 related markers (ITGA2, ITGB2, LAG3) and associated-immunosuppressive cytokines (IL10). This up-regulation was associated with an over-expression of several chemokine markers known to attract T-helper type 2 (Th2) and regulatory T cells thus contributing to immune suppression. This Tr1 cells recruitment in EBV positive HL was confirmed by immunohistochemical analysis of frozen nodes biopsies and by flow cytometric analysis of peripheral blood mononuclear cells of EBV-positive patients. Additionally, we showed that IL10 production was significantly enhanced in tumours and blood of EBV-positive HL patients. Our results propose a new model in which EBV can recruit Tr1 cells to the nodes' microenvironment, suggesting that the expression of EBV proteins in tumour cells could enable the escape of EBV-infected tumour cells from the virus-specific CTL response. PMID- 25041528 TI - Associations between mindfulness and panic symptoms among young adults with asthma. AB - Despite the well-documented associations between panic psychopathology and asthma, there has been a dearth of empirical work examining factors that may reduce the negative effects of panic for individuals with asthma. Thus, the goal of the present study was to examine the role of mindfulness skills (i.e. observe, describe, acting with awareness, nonjudgment, and nonreactivity) in symptoms of panic psychopathology (i.e. panic symptoms, anxiety sensitivity, and body vigilance). Participants were young adults with asthma (n = 56; 30.4% male, Mage = 19.5 years, SD = 2.7) who completed online self-report measures for course credit. After controlling for the effects of asthma control and negative affectivity, greater use of the mindfulness skill of acting with awareness, relative to the other mindfulness skills, significantly predicted fewer panic symptoms and decreased anxiety sensitivity. The skill of observing approached statistical significance in terms of predicting increased body vigilance and anxiety sensitivity. These finding suggest that targeting the skill of acting with awareness may be a novel way to decrease panic symptomatology among individuals with asthma. PMID- 25041529 TI - Looking for coeliac disease in children with type 1 diabetes mellitus. AB - AIM: To establish how clinicians in New Zealand (NZ) approach screening for and management of coeliac disease (CD) in type 1 diabetes mellitus (T1DM) in their paediatric patients. METHODS: All clinicians caring for children under 15 years with T1DM in NZ in 2010 were asked to complete an online survey detailing their personal and departmental approach to diagnosing and managing patients with CD and T1DM. RESULTS: Thirty-four from 37 clinicians responded to the survey. Most clinicians in NZ have a protocol for screening for CD in T1DM, and 25/34 respondents will screen for CD at diagnosis of T1DM. Those who do not screen will use symptoms, growth and hypoglycaemia as indicators to test. All use anti-tissue transglutaminase to screen for CD, and 32/34 use biopsy-proven CD as a criterion for commencing gluten-free diet (GFD). Nearly all consultants will still advise a GFD in symptom-free CD and will try to encourage the patients to adopt a GFD if they initially decline. CONCLUSIONS: Most clinicians in NZ screen for CD, but there is a wide variation in practice. PMID- 25041530 TI - Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target. AB - AIM: Levels of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) are robustly increased in spinal muscular atrophy (SMA) patient fibroblasts and mouse models. We therefore wanted to establish whether changes in UCHL1 contribute directly to disease pathogenesis, and to assess whether pharmacological inhibition of UCHL1 represents a viable therapeutic option for SMA. METHODS: SMA mice and control littermates received a pharmacological UCHL1 inhibitor (LDN-57444) or DMSO vehicle. Survival and weight were monitored daily, a righting test of motor performance was performed, and motor neurone loss, muscle fibre atrophy and neuromuscular junction pathology were all quantified. Ubiquitin-like modifier activating enzyme 1 (Uba1) was then pharmacologically inhibited in neurones in vitro to examine the relationship between Uba1 levels and UCHL1 in SMA. RESULTS: Pharmacological inhibition of UCHL1 failed to improve survival, motor symptoms or neuromuscular pathology in SMA mice and actually precipitated the onset of weight loss. LDN-57444 treatment significantly decreased spinal cord mono-ubiquitin levels, further exacerbating ubiquitination defects in SMA mice. Pharmacological inhibition of Uba1, levels of which are robustly reduced in SMA, was sufficient to induce accumulation of UCHL1 in primary neuronal cultures. CONCLUSION: Pharmacological inhibition of UCHL1 exacerbates rather than ameliorates disease symptoms in a mouse model of SMA. Thus, pharmacological inhibition of UCHL1 is not a viable therapeutic target for SMA. Moreover, increased levels of UCHL1 in SMA likely represent a downstream consequence of decreased Uba1 levels, indicative of an attempted supportive compensatory response to defects in ubiquitin homeostasis caused by low levels of SMN protein. PMID- 25041531 TI - Association of single nucleotide polymorphisms in the IL27 gene with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is one of the autoimmune diseases, where different polymorphisms in cytokine genes play a pathogenic role. Interleukin 27 (IL-27) is a novel pro-/anti-inflammatory cytokine, an excellent candidate for chronic inflammatory disease studies. The aim of the study was to identify polymorphisms in the IL-27 gene and their possible association with susceptibility to and severity of RA. Two hundred and seventy-four patients with RA and of 295 healthy individuals were examined for -924A/G and 4730T/C IL27 gene polymorphisms using PCR-RFLP method and TaqMan SNP genotyping assay, respectively. Haplotype frequencies of IL-27 polymorphisms were estimated using SHEsis platform. Frequencies of the -924GG genotype and the -924G allele were statistically higher in RA patients comparing with the healthy control group (P = 0.008 and P = 0.004, respectively). Overall, strong LD was observed between the IL27 gene -924A/G and 4730 T/C polymorphisms (D' = 0.613, r2 = 0.199). From four possible haplotypes, frequencies of two (CA and CG) showed significant differences between both examined groups (respectively: P < 0.001 and P = 0.001062). The genotype phenotype analysis showed significant association between the IL-27 4730 T/C polymorphism and HAQ score and means value of the ESR, additionally they revealed that individuals with the polymorphic allele -924G had more advanced disease than wild-type allele carriers. Present findings indicated that IL27 -924A/G polymorphism may be involved in susceptibility to RA in the Polish population. PMID- 25041532 TI - Coagulation function and mechanisms in various clinical phenotypes of patients with acquired factor V inhibitors. AB - BACKGROUND: The clinical phenotype of individuals with acquired factor V (A-FV) inhibitors varies from asymptomatic (non-B group) to life-threatening bleeding (B group), but the mechanism(s) underlying this variation in hemorrhagic phenotype are poorly understood. OBJECTIVE: To investigate coagulation mechanistically in a range of patients with A-FV antibodies. METHODS AND RESULTS: Ten cases of A-FV inhibitors in the non-B (n = 5) and B groups (n = 5) were studied. Thrombin generation assays in these plasmas revealed little thrombin generation, despite similar FV activity levels in both groups. However, prothrombin time-based clot waveform analysis revealed that the clot times were significantly prolonged and the maximum velocity and acceleration of coagulation were lower in the B group than in the non-B group, suggesting that this technique might be useful for predicting and monitoring hemorrhagic symptoms. A-FV inhibitors from the non-B group recognized predominantly the FV heavy chain, whereas those from the B group recognized the light chain. Purified anti-FV autoantibodies (autoAbs) from the B group inhibited FV binding to phospholipid by 60-90%, whereas there was little effect on this reaction in the non-B group. In addition, anti-FV autoAbs from the non-B group impaired the activated protein C (APC) cofactor activity of FV in FVIIIa inactivation mechanisms, and delayed APC-catalyzed cleavage of FVa at Arg306, but not at Arg506, indicating the presence of APC resistance in the non-B group. CONCLUSIONS: The results suggest that the different hemorrhagic phenotypes in A-FV inhibitors depend on the specific epitope of anti-FV autoAbs, and appear to be associated with an imbalance of procoagulant and anticoagulant function. PMID- 25041533 TI - NilD CRISPR RNA contributes to Xenorhabdus nematophila colonization of symbiotic host nematodes. AB - The bacterium Xenorhabdus nematophila is a mutualist of entomopathogenic Steinernema carpocapsae nematodes and facilitates infection of insect hosts. X. nematophila colonizes the intestine of S. carpocapsae which carries it between insects. In the X. nematophila colonization-defective mutant nilD6::Tn5, the transposon is inserted in a region lacking obvious coding potential. We demonstrate that the transposon disrupts expression of a single CRISPR RNA, NilD RNA. A variant NilD RNA also is expressed by X. nematophila strains from S. anatoliense and S. websteri nematodes. Only nilD from the S. carpocapsae strain of X. nematophila rescued the colonization defect of the nilD6::Tn5 mutant, and this mutant was defective in colonizing all three nematode host species. NilD expression depends on the presence of the associated Cas6e but not Cas3, components of the Type I-E CRISPR-associated machinery. While cas6e deletion in the complemented strain abolished nematode colonization, its disruption in the wild-type parent did not. Likewise, nilD deletion in the parental strain did not impact colonization of the nematode, revealing that the requirement for NilD is evident only in certain genetic backgrounds. Our data demonstrate that NilD RNA is conditionally necessary for mutualistic host colonization and suggest that it functions to regulate endogenous gene expression. PMID- 25041534 TI - Xenotransplantation literature update, May-June 2014. PMID- 25041535 TI - Effectiveness of individual-focused interventions to prevent chronic disease. AB - BACKGROUND: The burden of chronic disease is projected to assume crisis proportions in most parts of the world by the middle of the century, focusing attention on the need for preventive interventions. We identify and review published research on primary prevention individual-level interventions in current practice and describe and discuss the limitations of the current evidence. The report facilitates prioritizing a research agenda for potential interventions that might be investigated within cohort studies. MATERIALS AND METHODS: This study is a rapid review. Computerized database searches (PubMed and EMBASE) were performed in October 2012 to identify articles on primary prevention interventions that are directed at the individual level. Potentially, relevant International Agency of Research on Cancer handbooks and monographs were also reviewed. The review includes articles reported in English on the efficacy or effectiveness of a preventive intervention in an adult population. It excludes articles on alcohol or tobacco smoking. RESULTS: Many chronic disease interventions directed at individuals report a protective effect in the short term and some evidence for the efficacy of chemoprevention in chronic disease prevention exists. Evidence these effects persist in the longer term is inconsistent. CONCLUSIONS: There are currently only limited evidence-based preventions for most chronic diseases, for which a summary is available in Table A1 (see Appendix B). Most individual-level intervention research studies have been conducted using case-control designs and some small, randomized studies. There are fewer impediments to lifestyle modifications when compared to prevention using chemoprevention and vaccination or other methods of prevention of persistent infection. PMID- 25041536 TI - Harmonization of quantitative BCR-ABL measurements using the secondary reference material anchored to the WHO primary standards. PMID- 25041537 TI - Effect of curing agents on the oxidative and nitrosative damage to meat proteins during processing of fermented sausages. AB - The effect of increasing concentrations of curing agents, ascorbate (0, 250, and 500 ppm), and nitrite (0, 75, and 150 ppm), on the oxidative and nitrosative damage to proteins during processing of fermented sausages was studied. The potential influence of these reactions on color and texture of the fermented sausages was also addressed. Nitrite had a pro-oxidant effect on tryptophan depletion and promoted the formation of protein carbonyls and Schiff bases. The nitration degree in the fermented sausages was also dependent on nitrite concentration. On the other hand, ascorbate acted as an efficient inhibitor of the oxidative and nitrosative damage to meat proteins. As expected, nitrite clearly favored the formation of the cured red color and ascorbate acted as an enhancer of color formation. Nitrite content was positively correlated with hardness. The chemistry behind the action of nitrite and ascorbate on muscle proteins during meat fermentation is thoroughly discussed. The results suggest that ascorbate (500 ppm) may be required to compensate the pro-oxidant impact of nitrite on meat proteins. PRACTICAL APPLICATION: This study provides insight on the action of curing agents on meat proteins during processing of fermented sausages. This chemistry background provides understanding of the potential influence of the oxidative and nitrosative damage to proteins on the quality of processed muscle foods. The study provides novel information on the impact of the combination of nitrite and ascorbate on the chemical deterioration of proteins and the influence on particular quality traits of fermented sausages. These data may be of interest for the design of cured muscle foods of enhanced quality. PMID- 25041538 TI - Optimized aqueous extraction of saponins from bitter melon for production of a saponin-enriched bitter melon powder. AB - Bitter melon, Momordica charantia L. (Cucurbitaceae), aqueous extracts are proposed to have health-promoting properties due to their content of saponins and their antioxidant activity. However, the optimal conditions for the aqueous extraction of saponins from bitter melon and the effects of spray drying have not been established. Therefore, this study aimed to optimize the aqueous extraction of the saponins from bitter melon, using response surface methodology, prepare a powder using spray drying, and compare the powder's physical properties, components, and antioxidant capacity with aqueous and ethanol freeze-dried bitter melon powders and a commercial powder. The optimal aqueous extraction conditions were determined to be 40 degrees C for 15 min and the water-to-sample ratio was chosen to be 20:1 mL/g. For many of its physical properties, components, and antioxidant capacity, the aqueous spray-dried powder was comparable to the aqueous and ethanol freeze-dried bitter melon powders and the commercial powder. The optimal conditions for the aqueous extraction of saponins from bitter melon followed by spray drying gave a high quality powder in terms of saponins and antioxidant activity. PRACTICAL APPLICATION: This study highlights that bitter melon is a rich source of saponin compounds and their associated antioxidant activities, which may provide health benefits. The findings of the current study will help with the development of extraction and drying technologies for the preparation of a saponin-enriched powdered extract from bitter melon. The powdered extract may have potential as a nutraceutical supplement or as a value added ingredient for incorporation into functional foods. PMID- 25041539 TI - Fucosylated chondroitin sulfate from sea cucumber improves insulin sensitivity via activation of PI3K/PKB pathway. AB - This study was to investigate the effects of fucosylated chondroitin sulfate (CHS) from sea cucumber on insulin sensitivity in skeletal muscle of type 2 diabetic mice induced by a high-fat high-sucrose diet (HFSD). CHS supplementation for 19 wk significantly improved insulin sensitivity by 20%, and reduced blood glucose and insulin levels. Western blotting assay showed that CHS significantly increased insulin-stimulated glucose transporter 4 (GLUT4) translocation to 1.7 fold, phosphorylation of phosphoinositide 3-kinase (PI3K) at p85 to 5.0-fold, protein kinase B (PKB) at Ser473 to 1.5-fold, and Thr308 to 1.6-fold in skeletal muscle. However, PI3K, PKB, and GLUT4 total proteins expression were unchangeable. In addition, qRT-PCR analysis proved that the insulin signaling was activated by CHS treatment, showing the increased mRNA expressions of glucose uptake-related key genes. It indicated that CHS improved insulin sensitivity by activation of PI3K/PKB signaling in skeletal muscle of type 2 diabetic mice. Identification of potential mechanism by which CHS increased insulin sensitivity might provide a new functional food or pharmaceutical application of sea cucumber. PMID- 25041540 TI - Stereospecificity of ginsenoside Rg3 in the promotion of cellular immunity in hepatoma H22-bearing mice. AB - Previous investigations have demonstrated that ginsenoside Rg3 (Rg3) has many actions including antitumor, antioxidative, and immunomodulatory effects. However, Rg3 exists as 2 stereoisomeric pairs, 20(S)-ginsenoside Rg3 [20(S)-Rg3] and 20(R)-ginsenoside Rg3 [20(R)-Rg3], which have disparate pharmacological actions because of their different chemical structures. In this study, the 2 epimers were compared for their effects on the growth of hepatocellular carcinoma H22 transplanted tumors and the immune function of H22-bearing mice. In vivo efficacy study showed that the growth of H22 transplanted tumors was significantly inhibited when treated with 20(S)-Rg3 and 20(R)-Rg3 (P < 0.05), and the inhibition rate of tumor growth was 23.6% and 40.9%, respectively. Furthermore, the cellular immunity of H22-bearing mice was remarkably enhanced after Rg3 treatment (P < 0.05), which may be due to stimulation of ConA-induced lymphocyte proliferation and augmentation of Th1-type cytokines interleukin-2 and interferon-gamma levels in mice. Interestingly, the effects of 20(R)-Rg3 were significantly greater than those of the S-form (P < 0.05). Taken together, these results indicate that Rg3 inhibits H22 tumor growth in vivo at least partly by improving the host's cellular immunity in a stereospecific manner, and 20(R)-Rg3 is more potent for treating cancers or other immune-mediated diseases clinically. PMID- 25041542 TI - Seventy-five years of IFT: the Journal of Food Science Education. PMID- 25041544 TI - Busted! Management of paediatric upper limb fractures: not all that it's cracked up to be. AB - OBJECTIVE: The primary objective was to assess use of splinting prior to X-ray in paediatric ED patients with deformed upper limb fractures. Secondary objectives were to evaluate pharmaceutical analgesia use and the impact of demographic, hospital and clinical variables on splint and analgesia provision. METHODS: A retrospective study of 1407 paediatric ED patients who received upper limb X rays. The records of those with fractures requiring manipulation were identified, and reviewed for data on demographics, mode of arrival, triage category, site of fracture, clinician seniority, pain scoring, splint application and analgesic use. RESULTS: Two hundred and twelve patients had fractures requiring manipulation. Of these, 47 (22%) had a splint applied prior to X-ray and 161 (76%) of patients were prescribed analgesia in the first hour after presentation. A triage category 1 or 2 and arrival by ambulance predicted for splint application. Children with higher recorded pain scores were more likely to receive any analgesia in the first hour (91% with a pain score >=7 compared with 62% with pain score of <=6, P < 0.001), and more likely to receive strong analgesia (59% vs 13%, P < 0.001). Those triaged to category 1 or 2 were more likely to receive analgesia in the first hour (P < 0.001). CONCLUSIONS: This study identified significant shortcomings in ED management of children with deformed upper limb fractures. Only a minority were splinted prior to X-ray, and a quarter did not receive any analgesia in the first hour after presentation. Future study should investigate methods to improve ED management of these patients. PMID- 25041545 TI - Noonan syndrome with bilateral acute angle-closure. PMID- 25041546 TI - Scoping meta-review: introducing a new methodology. AB - For researchers, policymakers, and practitioners facing a new field, undertaking a systematic review can typically present a challenge due to the enormous number of relevant papers. A scoping review is a method suggested for addressing this dilemma; however, scoping reviews present their own challenges. This paper introduces the "scoping meta-review" (SMR) for expanding current methodologies and is based on our experiences in mapping the field of consumer engagement in healthcare. During this process, we developed the novel SMR method. An SMR combines aspects of a scoping review and a meta-review to establish an evidence based map of a field. Similar to a scoping review, an SMR offers a practical and flexible methodology. However, unlike in a traditional scoping review, only systematic reviews are included. Stages of the SMR include: undertaking a preliminary nonsystematic review; building a search strategy; interrogating academic literature databases; classifying and excluding studies based on titles and abstracts; saving the refined database of references; revising the search strategy; selecting and reviewing the full text papers; and thematically analyzing the selected texts and writing the report. The main benefit of an SMR is to map a new field based on high-level evidence provided by systematic reviews. PMID- 25041547 TI - Assessment of topical versus oral ivermectin as a treatment for head lice. AB - Many medications are available for treatment of pediculosis capitis including ivermectin. Our aim is to compare the efficacy and safety of topical versus oral ivermectin in treatment of pediculosis capitis. Sixty-two patients with proved head lice infestation were included and divided into group I (31 patients; received single topical application of 1% ivermectin) and group II (31 patients; received single dose of oral ivermectin). Treatment was repeated after 1 week for nonresponders. At 1 week after treatment, the eradication rates and improvement of pruritus were significantly higher among patients who received topical than oral ivermectin. When a second treatment, topical or oral, was given to nonresponders, the cure rates of infestation and pruritus was 100% and 97% among patients treated with topical and oral ivermectin, respectively with no significant difference between the two groups. This study suggests that both topical and oral ivermectin demonstrate high efficacy and tolerability in treatment of pediculosis capitis. However, a single treatment with topical ivermectin provides significantly higher cure of infestation and faster relief of pruritus than oral ivermectin. In addition, whether topical or oral ivermectin is used to treat head lice, a second dose is required in some cases to ensure complete eradication. PMID- 25041548 TI - Interaction between amino acids on the performances of individually housed piglets. AB - Dietary branched-chain amino acid and tryptophan concentrations have been associated with effects on daily feed intake; this study is an extension of that research. We evaluated eight dietary treatments in a Latin square cross-over design with 32 female piglets during 8 weeks (9.9 +/- 0.6 kg to 44.9 +/- 2.9 kg, mean +/- SD). Treatments differed in dietary standardized ileal digestible leucine (10.8 and 21.3 g/kg), valine (7.0 and 7.8 g/kg), isoleucine (6.0 or 7.3 g/kg) and tryptophan (2.0 and 2.5 g/kg) content. A longitudinal model was fitted with the level of valine, leucine, isoleucine, tryptophan and the interactions leucine * tryptophan, valine * leucine, isoleucine * tryptophan as fixed effects. Increasing the dietary leucine content decreased feed intake (-169 g/day) and daily gain (-168 g/day) of the pigs and impaired the feed conversion ratio (+0.49 g/g) (p < 0.01 for all parameters). Adding valine to the high leucine diet counteracted the feed intake reduction partially, while effects on daily gain and feed conversion ratio were largely counteracted by adding extra valine. The positive effect on feed conversion ratio diminished over time (p = 0.001 for age * valine). Adding extra tryptophan to the high leucine diet tended to negatively affect daily gain (p = 0.081) and feed conversion ratio (p = 0.074). Adding extra dietary isoleucine together with extra valine did not further counteract the negative effects of excess dietary leucine. The present results confirmed that, with excess leucine, extra valine benefits performance. Further adding extra tryptophan or isoleucine did not improve performances. PMID- 25041549 TI - Increased risk of peanut allergy in infants of Asian-born parents compared to those of Australian-born parents. AB - BACKGROUND: Asian infants appear to be over-represented among patients with clinical food allergy in Australia, but this has not been formally examined at the population level. Any difference in prevalence according to parental country of birth may be secondary to modifiable lifestyle factors. We aimed to quantify (i) differences in the prevalence of peanut allergy by parental country of birth and (ii) contribution of measured environmental exposures to these differences. METHODS: The population-based HealthNuts study in Melbourne, Australia, screened 5276 infants (74% participation) with skin prick tests and sensitized infants underwent food challenge. Of these, 535 had a parent born in East Asia and 574 in UK/Europe. Associations between parents' country of birth and offspring peanut allergy were examined using multiple logistic regression. RESULTS: Compared to infants with two Australian-born parents, peanut allergy was more common among infants with parent/s born in East Asia (OR 3.4, 95% CI 2.2-5.1) but not those with parent/s born in the UK/Europe (OR 0.8, 95% CI 0.4-1.5). Paradoxically rates of allergic disease were lower among Asian parents. A higher prevalence of eczema among infants of Asian parents explained around 30% of the increase in peanut allergy, while differences in dog ownership explained around 18%. CONCLUSIONS: The high peanut allergy prevalence among infants of Asian-born parents appears to have occurred in a single generation and was not present among infants with parents migrating from other countries, suggesting gene-environment interactions are important. The role of eczema and microbial exposure in food allergy prevention warrants exploration. PMID- 25041550 TI - The effect of periodontal therapy on cardiovascular risk markers: a 6-month randomized clinical trial. AB - AIM: To determine the influence of non-surgical mechanical periodontal treatment on inflammatory markers related to risk for cardiovascular disease. MATERIAL AND METHODS: A total of 64 patients with severe chronic periodontitis was randomly subjected to immediately periodontal treatment (test group, n = 32) or delayed periodontal treatment, without treatment during the study period (control group, n = 32). Clinical periodontal and laboratory examinations were performed at baseline (T0), 2 months (T2), and 6 months (T6) after the initial examinations (Control group) or completion of periodontal treatment (Test group). RESULTS: After 2 months of periodontal treatment there was a significant reduction of erythrocyte sedimentation rate (ESR) and triglycerides (p = 0.002, p = 0.004, respectively) in the test group. Median values of C-reactive protein, ESR, total cholesterol, and triglycerides were reduced after 6 month of periodontal treatment in the test group (p < 0.001, p < 0.001, p < 0.001, and p = 0.015, respectively). CONCLUSIONS: The non-surgical periodontal treatment was effective in reducing the levels of systemic inflammation markers and improved the lipid profile in subjects with severe chronic periodontitis. PMID- 25041551 TI - Diagnostic and therapeutic pitfalls in considering chronic pain as a disease. PMID- 25041552 TI - Association of Veterinary Anaesthetists--the beginnings. PMID- 25041553 TI - Romiplostim treatment allows for platelet transfusion-free liver transplantation in pediatric thrombocytopenic patient with primary sclerosing cholangitis. AB - Thrombocytopenia is a major risk factor for cirrhotic liver disease. Patients with thrombocytopenia may have esophageal or gastric varices secondary to portal hypertension, leading to variceal bleeding which exposes the liver to further damage. Here, we present a female pediatric patient with PSC and CD, whose progressive thrombocytopenia was successfully controlled by romiplostim, a TPO receptor agonist. The patient developed bloody diarrhea at four yr of age, and was subsequently diagnosed with PSC and CD when seven yr old. While CD was well controlled by immunomodulators, the patient's thrombocytopenia gradually progressed resulting in petechiae (platelet count of 11 * 10(9) /L) when she was 10 yr and four months old. She responded poorly to immunoglobulin and corticosteroids. Weekly subcutaneous injection of romiplostim was therefore initiated, and platelet counts were maintained over at 50 * 10(9) /L. She was able to undergo successful LDLT without platelet transfusion seven months after the initiation of romiplostim. Romiplostim was not required after LDLT with improved platelet counts. This case report suggests that romiplostim may be effective in the treatment of thrombocytopenic children with liver cirrhosis and portal hypertension, and in eliminating the need for platelet transfusion during the peri-transplant period. PMID- 25041554 TI - Incidence and mortality of bullous pemphigoid in north-east Poland (Podlaskie Province), 1999-2012: a retrospective bicentric cohort study. AB - BACKGROUND: Bullous pemphigoid (BP) is the most frequently encountered autoimmune blistering disorder, affecting mainly elderly population. The aim of the study was to assess the incidence of BP in Podlaskie Province (north-east Poland) in 1999-2012, socio-demographic characteristics and mortality of patients with BP. METHODS: The number of newly diagnosed (in two regional hospitals) cases of BP per million inhabitants of the province in consecutive years was calculated and analysis of age, sex, and residency of patients performed. RESULTS: A total of 122 cases of BP were diagnosed (in 52 males and 70 females). The average annual incidence was 7.38 +/- 3.51 per million inhabitants: 5.70 +/- 4.16 and 9.26 +/- 4.40 in urban and rural areas, P < 0.05, respectively, and had an increasing trend over the period analyzed. Age of patients with BP was 74.18 +/- 12.12. The incidence among men and women over 75 years of age was 86.67 +/- 61.39 and 51.49 +/- 41.44, P < 0.05, respectively. The 1-year mortality of patients was 32.35 and 18.42% (P < 0.05) in men and women, respectively. Overall mortality was 36.11%. CONCLUSIONS: The incidence of BP in Podlaskie Province is almost twice as high among residents of rural than urban areas, and in males than females in advanced age. The results suggest that the incidence of BP will be increasing in an aging society, as will its impact on the quality of life of the population. PMID- 25041555 TI - Successful management of six pregnancies resulting in live births after simultaneous pancreas kidney transplantation: a single-center experience. PMID- 25041556 TI - Cardiac function recovery following LVAD implantation and bariatric surgery in a morbidly obese patient. AB - We present a morbidly obese 44-year-old female who underwent Thoratec HeartMate II left ventricular assist device implantation. The patient subsequently underwent laparoscopic sleeve gastrectomy and removal of the LVAD following improvement in her cardiac function. PMID- 25041557 TI - Whipple's disease involving the eye, the brain, the heart and the gut diagnosed through the eye. PMID- 25041558 TI - Role of left ventricular assist devices in assessment of patients for combined heart-kidney transplantation. PMID- 25041559 TI - Postexercise rehydration with beer impairs fluid retention, reaction time, and balance. AB - Beer is promoted by popular media as a good choice for rehydration, but there is limited support for the claim. To assess the effect of beer alcohol on rehydration and motor control, 11 young (24.4 +/- 3.7 years old) males of legal drinking age were dehydrated to 2.12% +/- 0.20% body mass (mean +/- SD) by exercising in a climatic chamber (31.7 +/- 1.6 degrees C, 55.0% +/- 8.3% relative humidity) on 3 different days, 1 week apart, and rehydrated with 100% of their sweat loss using water (WATER), 4.6% alcohol beer (BEER), or low-alcohol beer (LAB), in random order. Urine output, blood alcohol content (BAC), reaction time (RT), and balance (as measured by center of pressure velocity (VCoP)) were measured every 30 min over 3 h and compared via 2-way, repeated-measures analyses of variance (ANOVAs). After consuming ~1.6 L in 1 h, urine output was greater for BEER (1218 +/- 279 mL) than for LAB (745 +/- 313 mL, p = 0.007) and WATER (774 +/ 304 mL, p = 0.043). BAC remained at 0 with WATER and LAB; with BEER, BAC reached 0.857 g/L (95% confidence intervals [0.752, 0.963]) immediately postrehydration. RT was longer for BEER (0.314 +/- 0.039 s) than for LAB (0.294 +/- 0.034 s, p = 0.009), but was no different from WATER (0.293 +/- 0.049 s, p = 0.077). VCoPx was significantly higher for BEER (0.0284 +/- 0.0020 m/s) compared with LAB (0.0233 +/- 0.0010 m/s) or WATER (0.0238 +/- 0.0010 m/s) (p = 0.022), but VCoPy was not different among beverages. In conclusion, rehydration with BEER resulted in higher diuresis, slower RT, and impaired VCoP than rehydration with LAB or WATER. PMID- 25041560 TI - Utility of radiotherapy for treatment of basal cell carcinoma: a review. AB - Radiotherapy is an available treatment for management of basal cell carcinoma (BCC). This study aims to analyse the published literature about radiotherapy in treatment of BCC. A focus of this study will be to compare the dosing regimens adopted in these studies. A search of the Medline database was conducted from 1984 to August 2013. Search terms used were 'basal cell carcinoma', 'radiotherapy', 'epithelial skin cancer' and 'external irradiation'. Fourteen studies on the use of radiotherapy for BCC were included. Seven studies included only cases of BCC, while six studies also included patients treated for squamous cell carcinoma. The overall cure rates ranged from 79.2% to 100%. More than 90% of the patients reported good or excellent aesthetic outcome from radiotherapy (three studies). There was a wide variation in the total dose and dose per fraction of radiotherapy used. Nine studies utilized dosing regimens within the recommended guidelines of the National Comprehensive Cancer Network. There are a limited number of high-quality prospective studies of radiotherapy for BCC. Based on the available evidence, radiotherapy provides a high rate of local control with low rates of complications that are comparable with surgery. PMID- 25041561 TI - Mechanical ventilation and management of an adult horse with presumptive botulism. AB - OBJECTIVE: To describe the clinical course, management, and outcome of a horse with a presumptive diagnosis of botulism treated with long-term mechanical ventilation. CASE SUMMARY: A 6-year-old Quarter Horse gelding with a history of esophageal obstruction was evaluated for progressive tetraparesis. Generalized and progressive skeletal muscle weakness characterized by recumbency, decreased tongue, tail, eyelid, and anal tone, and respiratory failure was observed. Anticholinergic signs including decreased salivation, xerophthalmia, and ileus were also noted. A presumptive diagnosis of botulism was made, although mouse inoculation and spore identification testing were negative. Pentavalent botulism antitoxin was administered on Day 3. The horse was maintained on a water mattress and was managed with mechanical ventilation for 2 weeks. Complications encountered included necrotic rhinitis, intertrigo, decubital ulceration, jugular and cephalic vein thrombophlebitis, corneal ulceration, and transient ventricular tachycardia. The horse showed marked improvement in skeletal muscle strength and parasympathetic nervous system function, allowing it to be successfully weaned from the ventilator but suffered large colon volvulus on Day 21 and was euthanized. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first report of successful weaning from long-term mechanical ventilation and management of recumbency using a water mattress in an adult horse with presumptive botulism. PMID- 25041563 TI - Cardiac stress testing in patients with end-stage renal disease. PMID- 25041562 TI - Genetic variation in personality traits explains genetic overlap between borderline personality features and substance use disorders. AB - AIMS: To examine the genetic overlap between borderline personality features (BPF) and substance use disorders (SUDs) and the extent to which variation in personality traits contributes to this covariance. DESIGN: Genetic structural equation modelling was used to partition the variance in and covariance between personality traits, BPF and SUDs into additive genetic, shared and individual specific environmental factors. SETTING: All participants were registered with the Australian Twin Registry. PARTICIPANTS: A total of 3127 Australian adult twins participated in the study. MEASUREMENTS: Diagnoses of DSM-IV alcohol and cannabis abuse/dependence (AAD; CAD) and nicotine dependence (ND) were derived via computer-assisted telephone interview. BPF and five-factor model personality traits were derived via self-report questionnaires. FINDINGS: Personality traits, BPF and substance use disorders were partially influenced by genetic factors with heritability estimates ranging from 0.38 (neuroticism; 95% confidence interval: 0.30-0.45) to 0.78 (CAD; 95% confidence interval: 0.67-0.86). Genetic and individual-specific environmental correlations between BPF and SUDs ranged from 0.33 to 0.56 (95% CI = 0.19-0.74) and 0.19-0.32 (95% CI = 0.06-0.43), respectively. Overall, there was substantial support for genetic influences that were specific to AAD, ND and CAD (30.76-68.60%). Finally, genetic variation in personality traits was responsible for 11.46% (extraversion for CAD) to 59.30% (neuroticism for AAD) of the correlation between BPF and SUDs. CONCLUSIONS: Both genetic and individual-specific environmental factors contribute to comorbidity between borderline personality features and substance use disorders. A substantial proportion of this comorbidity can be attributed to variation in normal personality traits, particularly neuroticism. PMID- 25041564 TI - Mosapride treatment for functional dyspepsia: a meta-analysis. AB - BACKGROUND AND AIM: The aim of this study was to assess the therapeutic effect of mosapride in patients with functional dyspepsia (FD). METHODS: Randomized controlled trials (RCTs) of mosapride for the treatment of FD performed between 2002 and 2013 were identified from databases. Symptom response rates were extracted and analyzed using risk ratios (RRs). A random effect model was applied based on Higgins I(2) tests. Publication bias was evaluated using a funnel plot, Egger's test, trim and fill, and the rank correlation test. RESULTS: In total, 13 RCTs, which included 1091 mosapride-treated patients and 1129 control patients (on placebo or other drugs), were identified and analyzed. Overall, mosapride showed an RR of 0.999 (95% confidence interval [CI]: 0.869-1.150, P = 0.992) for improving global efficacy or symptom-based scores. In a sensitivity analysis of the high-quality RCTs, mosapride showed an RR of 1.114 (95% CI: 1.011-1.227, P = 0.029). However, in the studies using the Rome III criteria for the diagnosis of FD, mosapride showed an RR of 0.906 (95% CI: 0.807-1.016, P = 0.092). In the studies having funding source, mosapride showed an RR of 1.131 (95% CI: 1.028 1.244, P = 0.012), whereas an RR of 0.966 (95% CI: 0.896-1.042, P = 0.367) was observed in the studies without funding source. Publication bias was not detected. CONCLUSION: In this analysis, we could not find a significant effect of mosapride on FD. Inconsistent diagnostic criteria for FD and different assessment outcomes are causes of heterogeneity. Further studies using common validated outcomes or questionnaires and high-quality RCTs will elucidate the real effect of this medication on FD. PMID- 25041565 TI - Early identification and intervention in cerebral palsy. AB - Infants with possible cerebral palsy (CP) are commonly assumed to benefit from early diagnosis and early intervention, but substantial evidence for this is lacking. There is no consensus in the literature on a definition of 'early', but this review focuses on interventions initiated within the first 6 months after term age. We cover basic neuroscience, arguing for a beneficial effect of early intervention, and discuss why clinical research to support this convincingly is lacking. We argue that infants offered early intervention in future clinical studies must be identified carefully, and that the intervention should be focused on infants showing early signs of CP to determine an effect of treatment. Such signs may be efficiently detected by a combination of neuroimaging and the General Movements Assessment. We propose a research agenda directed at large scale identification of infants showing early signs of CP and testing of high intensity, early interventions. PMID- 25041566 TI - Expression of cytokines on the iris of patients with neovascular glaucoma. AB - PURPOSE: To determine the expression levels of cytokines, including growth factors, inflammatory cytokines, and cell migration associated factors on the iris from subjects with neovascular glaucoma (NVG). METHODS: After receiving formal consent from 12 subjects with NVG secondary to proliferative diabetic retinopathy and 12 subjects with primary open angle glaucoma (POAG), trabeculectomy was performed and iris specimens were collected during the surgery. Each subject with NVG received intravitreal injection of bevacizumab 1 week prior to the surgery. The mRNA level of vascular endothelial growth factor, basic fibroblastic growth factor, placental-induced growth factor, interleukin-2, interleukin 6, tumour necrosis factor alpha, intercellular adhesion molecule 1 (ICAM-1) and integrin subunit alphaV were determined by real-time polymerase chain reaction. The mRNA levels were compared between the two groups. RESULTS: The mRNA levels of all inflammatory cytokines and integrin subunit alphaV were significantly increased in the NVG group compared with POAG controls. However, the mRNA level of growth factors and ICAM-1 did not show any difference between the two groups. CONCLUSIONS: Inflammatory process maybe an important cause of iris neovascularization in subjects with NVG in addition to growth factors alone. Further studies should focus on the effect of growth factors in different phases in the pathogenesis of NVG. PMID- 25041567 TI - Sevelamer in a diabetologist's perspective: a phosphate-binding resin with glucose-lowering potential. AB - Sevelamer is a calcium-free and metal-free phosphate-binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid-lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These 'novel' effects are most probably derived from the bile acid-binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose-lowering effect of the drug. PMID- 25041569 TI - Rubisco Accumulation Factor 1 from Thermosynechococcus elongatus participates in the final stages of ribulose-1,5-bisphosphate carboxylase/oxygenase assembly in Escherichia coli cells and in vitro. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) biosynthesis is a multi step process in which specific chaperones are involved. Recently, a novel polypeptide, Rubisco Accumulation Factor 1 (RAF1), has been identified as a protein that is necessary for proper assembly of this enzyme in maize cells (Zea mays). However, neither its specific function nor its mode of action have as yet been determined. The results presented here show that the prokaryotic homolog of RAF1 from Thermosynechococcus elongatus is expressed in cyanobacterial cells and interacts with a large Rubisco subunit (RbcL). Using a heterologous expression system, it was demonstrated that this protein promotes Rubisco assembly in Escherichia coli cells. Moreover, when co-expressed with RbcL alone, a stable RbcL-RAF1 complex is formed. Molecular mass determination for this Rubisco assembly intermediate by size-exclusion chromatography coupled with multi-angle light scattering indicates that it consists of an RbcL dimer and two RAF1 molecules. A purified RbcL-RAF1 complex dissociated upon addition of a small Rubisco subunit (RbcS), leading to formation of the active holoenzyme. Moreover, titration of the octameric (RbcL8) core of Rubisco with RAF1 results in disassembly of such a stucture and creation of an RbcL-RAF1 intermediate. The results presented here are the first attempt to elucidate the role of cyanobacterial Rubisco Accumulation Factor 1 in the Rubisco biosynthesis process. PMID- 25041568 TI - Specific interaction between Mycobacterium tuberculosis lipoprotein-derived peptides and target cells inhibits mycobacterial entry in vitro. AB - Tuberculosis (TB) continues being one of the diseases having the greatest mortality rates around the world, 8.7 million cases having been reported in 2011. An efficient vaccine against TB having a great impact on public health is an urgent need. Usually, selecting antigens for vaccines has been based on proteins having immunogenic properties for patients suffering TB and having had promising results in mice and non-human primates. Our approach has been based on a functional approach involving the pathogen-host interaction in the search for antigens to be included in designing an efficient, minimal, subunit-based anti-TB vaccine. This means that Mycobacterium tuberculosis has mainly been involved in studies and that lipoproteins represent an important kind of protein on the cell envelope which can also contribute towards this pathogen's virulence. This study has assessed the expression of four lipoproteins from M. tuberculosis H37Rv, that is, Rv1411c (LprG), Rv1911c (LppC), Rv2270 (LppN) and Rv3763 (LpqH), and the possible biological activity of peptides derived from these. Five peptides were found for these proteins which had high specific binding to both alveolar A549 epithelial cells and U937 monocyte-derived macrophages which were able to significantly inhibit mycobacterial entry to these cells in vitro. PMID- 25041570 TI - The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals. AB - Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment. PMID- 25041571 TI - Functional Neuroscience of Psychopathic Personality in Adults. AB - Psychopathy is a personality disorder that involves a constellation of traits including callous-unemotionality, manipulativeness, and impulsiveness. Here we review recent advances in the research of functional neural correlates of psychopathic personality traits in adults. We first provide a concise overview of functional neuroimaging findings in clinical samples diagnosed with the PCL-R. We then review studies with community samples that have focused on how individual differences in psychopathic traits (variously measured) relate to individual differences in brain function. Where appropriate, we draw parallels between the findings from these studies and those with clinical samples. Extant data suggest that individuals with high levels of psychopathic traits show lower activity in affect-processing brain areas to emotional/salient stimuli, and that attenuated activity may be dependent on the precise content of the task. They also seem to show higher activity in regions typically associated with reward processing and cognitive control in tasks involving moral processing, decision making, and reward. Furthermore, affective-interpersonal and lifestyle-antisocial facets of psychopathy appear to be associated with different patterns of atypical neural activity. Neuroimaging findings from community samples typically mirror those observed in clinical samples, and largely support the notion that psychopathy is a dimensional construct. PMID- 25041572 TI - Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea-predominant IBS. AB - BACKGROUND: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional gastrointestinal (GI) disorder, defined by the presence of loose stools and abdominal pain. In search for a novel anti-IBS-D therapy, here we investigated the nociceptin receptor (NOP)-dependent effects in the GI tract. METHODS: A novel potent and selective NOP agonist SCH 221510 was used in the study. The effect of NOP activation on mouse intestinal motility was characterized in vitro and in vivo, in physiological conditions and in animal models of hypermotility and diarrhea. Well-established mouse models of visceral pain were used to characterize the antinociceptive effect of the NOP activation. To provide additional evidence that the endogenous nociceptin system is a relevant target for IBS, NOP expression and nociceptin levels were quantified in serum and colonic biopsies from IBS-D patients. KEY RESULTS: SCH 221510 produced a potent NOP-mediated inhibitory effect on mouse intestinal motility in vitro and in vivo in physiological conditions. The NOP agonist displayed an antidiarrheal and analgesic action after oral administration in animal models mimicking the symptoms of IBS-D. Studies on human samples revealed a strong decrease in endogenous nociceptin system expression in IBS-D patients compared with healthy controls. CONCLUSIONS & INFERENCES: Collectively, mouse and human data suggest that the endogenous nociceptin system is involved in IBS-D and may become a target for anti-IBS-D treatments using potent and selective synthetic NOP agonists. PMID- 25041574 TI - Observation of in vivo morphologic changes after carbon dioxide ablative fractional laser in a mouse model using noninvasive imaging modalities and comparison with histologic examination. AB - Ablative fractional carbon dioxide (CO2) lasers have been widely used for several types of cosmetic dermatosis. A number of previous studies have evaluated this technique in animals or human beings by observing morphologic changes using an invasive modality such as skin biopsy. In this study, we assessed in vivo skin changes after CO2 ablative fractional laser treatment in a mouse model using noninvasive imaging modalities (Folliscope((r)) and Visioscan 98((r))), and each results was compared with data from histologic examination. An ablative fractional CO2 laser was applied with different pulse energy between 7 to 35 mJ/microspot. As results of above methods, we also confirmed that the CO2 ablative fractional laser generated injuries with increasing width and depth with increasing pulse energy. Although numerous papers have described application of this laser in vivo skin specimens, our study evaluated the feasibility of using relative noninvasive imaging modalities for assessing the outcome of laser ablation. Based on our data, we suggest that these technologies may be useful alternative modalities for assessing laser ablation that are easier to perform and less invasive than skin biopsy. PMID- 25041573 TI - Case report: failure under azithromycin treatment in a case of bacteremia due to Salmonella enterica Paratyphi A. AB - BACKGROUND: Limited information is available regarding the clinical efficacy of azithromycin for the treatment of enteric fever due to fluoroquinolone-resistant Salmonella Typhi and Salmonella Paratyphi among travelers returning to their home countries. CASE PRESENTATION: We report a case of a 52-year-old Japanese man who returned from India, who developed a fever of 39 degrees C with no accompanying symptoms 10 days after returning to Japan from a 1-month business trip to Delhi, India. His blood culture results were positive for Salmonella Paratyphi A. He was treated with 14 days of ceftriaxone, after which he remained afebrile for 18 days before his body temperature again rose to 39 degrees C with no apparent symptoms. He was then empirically given 500 mg of azithromycin, but experienced clinical and microbiological failure of azithromycin treatment for enteric fever due to Salmonella Paratyphi A. However, the minimum inhibitory concentration (MIC) of azithromycin was not elevated (8 mg/L). He was again given ceftriaxone for 14 days with no signs of recurrence during the follow-up. CONCLUSION: There are limited data available for the treatment of enteric fever using azithromycin in travelers from developed countries who are not immune to the disease, and thus, careful follow-up is necessary. In our case, the low azithromycin dose might have contributed the treatment failure. Additional clinical data are needed to determine the rate of success, MIC, and contributing factors for success and/or failure of azithromycin treatment for both Salmonella Typhi and Salmonella Paratyphi infections. PMID- 25041575 TI - Family history of type 2 diabetes increases the risk of both obesity and its complications: is type 2 diabetes a disease of inappropriate lipid storage? AB - OBJECTIVES: The aim of this study was to characterize diabetes risk in relation to amount and distribution of body fat (environmental factors) and genetic risk defined as having first-degree (FH1) or second-degree relatives with diabetes. DESIGN: We analysed the METSIM population of 10 197 middle-aged, randomly selected men. At baseline, information about family history of diabetes was registered and all individuals underwent extensive phenotyping. A follow-up study was conducted after 6 years. The metabolic consequences of increased visceral versus subcutaneous fat were characterized in a separate cohort of 158 healthy men (the Kuopio Cohort of the EUGENE2 study). RESULTS: At baseline, individuals with a family history of diabetes (FH+) had approximately a twofold increase in the prevalence of type 2 diabetes compared with individuals without a family history of the disease (FH-) (18.0% vs. 9.9%; P = 1.3 * 10(-31) ). FH1 individuals were more commonly overweight and obese compared with FH- (69.2% vs. 64.8%; P = 1.3 * 10(-4) ) and, for a given body mass index, showed an increased risk profile for both type 2 diabetes and cardiovascular disease as well as a greater susceptibility to the negative consequences of increased body fat also when nonobese. Subgroup analyses indicated that the metabolic consequences were due primarily to increased ectopic/visceral fat rather than subcutaneous fat. The increased risk profile in FH+ individuals was not altered by adjusting for 43 major diabetes risk genes. CONCLUSIONS: Family history of type 2 diabetes (particularly FH1) is associated with both increased risk of becoming overweight/obese and with a greater susceptibility to the negative consequences of increasing body fat, probably as a consequence of an increased propensity to accumulate ectopic (nonsubcutaneous) fat. PMID- 25041577 TI - Behavioral migraine management modifies behavioral and cognitive coping in people with migraine. AB - OBJECTIVE: This is a secondary analysis of a randomized clinical trial which aims to examine changes in cognitive and behavioral responses to migraine with cognitive behavioral treatment for migraine, preventive medication for migraine, and their combination, and the relationship between these changes and reductions in migraine-related disability. BACKGROUND: Cognitive behavioral treatment is thought to reduce migraine-related disability through modifying maladaptive cognitive and behavioral responses to migraine. METHODS: Two hundred thirty-two people with migraine who did not respond to 5 weeks of optimized acute therapy were randomized into a 2 (beta-blocker vs placebo) X 2 (behavioral migraine management [BMM] vs no BMM) treatment design. Participants received BMM and/or beta-blocker dose adjustment for 4 months, and were followed for an additional 12 months. Participants completed measures of catastrophizing, behavioral coping, and migraine-related disability throughout the study. RESULTS: Compared to drug therapy only, BMM demonstrated larger decreases in catastrophizing scores (19.16 to 9.89 vs 16.78 to 11.84, P < .001) and increases in number of positive coping strategies (proactive: 1.09 to 1.90 vs 1.16 to 1.09, P < .001; anticipatory: 0.19 to 0.69 vs 0.10 to 0.08, P < .001; migraine management: 0.14 to 0.36 vs 0.04 to 0.04, P < .001) at the end of the follow-up period. Decreases in catastrophizing were associated with a larger BMM effect on migraine-related disability (P = .036). CONCLUSIONS: This study demonstrated that BMM modified important cognitive and behavioral factors postulated to be mechanisms of cognitive behavioral treatments for migraine. PMID- 25041576 TI - Effect of proteases against biofilms of Staphylococcus aureus and Staphylococcus epidermidis. AB - Biofilms play a key role in bacterial resistance against antibacterial agents-an issue that causes multiple problems in medical fields, particularly with Staphylococcus biofilms that colonize medical indwelling devices. The literature reports several anti-biofilm strategies that have been applied in medicine. Disrupting the biofilm formation process creates new sites open to colonization by treatment-generated planktonic bacteria, so efforts have turned to focus on strategies to prevent and control the initial Staphylococci adhesion. Here, we investigated the preventive activities of three commercial proteases (Flavourzyme, Neutrase and Alcalase) against biofilm formation by two Staphylococcus strains. Some proteolytic extracts revealed interesting results with Staphylococcus epidermidis and Staphylococcus aureus aureus biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY: Three proteases were tested against Staphylococcus aureus and Staphylococcus epidermidis biofilms in standard conditions. The Flavourzyme containing a mix of Aspergillus orizae endo- and exoproteases demonstrated significant efficacy against Staph. epidermidis biofilm formation. These results could prove valuable in the effort to develop simple anti-biofilm methods. PMID- 25041578 TI - Localized crystal-storing histiocytosis presenting as a breast nodule: an unusual presentation of a rare entity. AB - Crystal-storing histiocytosis (CSH) is a rare disorder associated with crystalline immunoglobulin deposition in the cytoplasm of histiocytes and is usually associated with lymphoproliferative or plasma cell disorders (LP-PCD) that express monoclonal immunoglobulin. Localized CSH without underlying LP-PCD are extremely rare. We report a case of localized CSH in breast which was an unexpected difficult diagnosis. The awareness of this entity is of importance to delineate it morphologically from other common differential diagnosis and enable appropriate management. To date, this is the first case of localized CSH reported in breast in a patient with no known history of LP-PCD. PMID- 25041579 TI - The CD200-tolerance signaling molecule associated with pregnancy success is present in patients with early-stage breast cancer but does not favor nodal metastasis. AB - PROBLEM: The CD200-tolerance signaling molecule prevents pregnancy failure and is also expressed by a wide variety of malignant tumors. The effect of CD200 mRNA expression on progression of human tumors has been variable. METHOD OF STUDY: A cross-sectional study was performed to examine the correlation between CD200 protein expression in the primary tumors from postoperative Stage I-IIIA human breast cancer and the likelihood of regional lymph node metastasis. RESULTS: Fifty-eight percentage of patients had strong CD200(+) tumor staining (71% of Stage I and 53% Stage II-IIIA). Strong staining was associated with large T2-3 primary tumors compared to T1 tumors (64 versus 50%) and T2-3 N(+) versus T1 N(-) tumors (70 versus 63%), but this was not statistically significant. Nodal metastases were not more frequent in patients with strong CD200(+) staining (57% compared to 58% for weak/negative staining cases), and the metastatic tumor cells in regional lymph nodes were often CD200(-) when the primary tumor was CD200(+). CONCLUSION: CD200 expression by early-stage human breast cancer cells in primary tumors did not correlate with increased regional lymph node metastasis. PMID- 25041580 TI - Safety of intrathecal administration of cytosine arabinoside and methotrexate in dogs and cats. AB - The objective of the study was to retrospectively evaluate the short-term safety of intrathecal administration of cytosine arabinoside alone or in combination with methotrexate in dogs and cats. One hundred and twelve dogs and eight cats admitted between September 2008 and December 2013, diagnosed with suspected inflammatory (meningoencephalomyelitis of unknown aetiology) or neoplastic disease affecting brain or spinal cord and treated with an intrathecal administration of cytosine arabinoside alone or in combination with methotrexate were included in the study. Recorded information regarding possible adverse events during administration while recovering from anaesthesia and during hospitalization period were evaluated. The results showed that one patient developed generalized tonic-clonic seizure activity after administration of cytosine arabinoside and methotrexate during recovery from anaesthesia, however responded to intravenous administration of diazepam. On the base of our results we can conclude that intrathecal administration of cytosine arabinoside alone or in combination with methotrexate is a safe procedure in dogs and cats. PMID- 25041581 TI - Effect of remote ischemic postconditioning on left ventricular mechanics. AB - BACKGROUND: Remote ischemic postconditioning (RIPC) decreases infarct size and prevents left ventricular (LV) remodeling in patients with myocardial infarction. However, there is no study that evaluates the effect of RIPC on LV mechanics assessed by speckle tracking echocardiography. Therefore, we aimed to test the effects of RIPC on LV deformation parameters such as strain, strain rate, rotation, and twist in healthy subjects. METHODS: The study group consisted of 22 healthy subjects. To test the effects of RIPC, 3 cycles of reperfusion followed by ischemia (each lasting 10 or 30 seconds) were applied immediately after 20 minutes of nondominant arm ischemia. Transthoracic echocardiography (TTE) was obtained at baseline and repeated 30 minutes after the completion of these cycles. In TTE images, apical 4-3-2 chamber longitudinal strain (LS)/strain rate, basal and apical circumferential strain/strain rate, and rotational parameters, such as basal rotation, apical rotation, and LV twist, were recorded. RESULTS: Apical 4-3-2 chamber LS and apical circumferential strain/strain rate measurements were comparable before and after RIPC, whereas basal circumferential strain was significantly decreased after RIPC (-23 +/- 3.4 vs. -18.9 +/- 6.9, P = 0.017). After RIPC, apical rotation was significantly increased (11.6 +/- 3.7 vs. 16.7 +/- 4.0, P < 0.001) and basal rotation was significantly decreased (-6.1 +/- 2.1 vs. -4.7 +/- 2.4, P = 0.03).Consequently, net LV twist was significantly increased (17.4 +/- 4.5 vs. 21.7 +/- 4.7). CONCLUSIONS: We proposed that RIPC affects the rotational mechanics of the heart rather than longitudinal mechanics. These results might give new insights into understanding the favorable effects of the post- conditioning. PMID- 25041582 TI - Staphylococcal scalded skin syndrome in an immunocompetent adult, clinically mimicking toxic epidermal necrolysis. PMID- 25041583 TI - Cognitive function, behavioral problems, and physical function in long-term care insurance beneficiaries with dementia in South Korea: comparison of home care and institutional care services. AB - OBJECTIVES: To examine, in beneficiaries with long-term care (LTC) insurance (LTCI) with dementia in Korea, changes in cognitive function, behavioral symptoms, and physical function over time in relation to LTCI service type and to determine the 2-year effects of service type on those health outcomes. DESIGN: Secondary analyses of the existing LTCI data set from 2008 to 2010. SETTING: South Korea. PARTICIPANTS: LTCI beneficiaries with dementia aged 65 and older (N=31,319). Participants were divided according to the service type that they were receiving home care (HC), institutional care (IC), and combined care (CC). MEASUREMENTS: A LTC approval checklist was used to determine the level of LTCI coverage of each participant and to assess cognitive function, behavioral symptoms, and physical function. Linear mixed models and multiple regression models were used. RESULTS: There were significant differences in cognitive function, behavioral symptoms, and physical function at baseline between individuals receiving the three service types (P<.001) and overall improvements in those outcomes over 2 years in the three groups (P<.001). After limiting the sample to those who had received LTCI services for the full 2 years (2008-2010) and adjusting for baseline characteristics, individuals receiving HC were more likely to have better cognitive and physical function than those receiving IC or CC but were likely to have more behavioral symptoms 2 years after the LTCI enrollment (P<.001). CONCLUSION: LTCI service type (HC, IC, CC) predicted cognitive function, behavioral symptoms, and physical function at 2-year follow up in beneficiaries with dementia. Further research is necessary to examine the effect of LTC services on health outcomes in a longer observational cohort. PMID- 25041584 TI - Beyond directed ortho metalation: Ru-catalyzed CAr-O activation/cross-coupling reaction by amide chelation. AB - Disclosed is a new, catalytic, and general methodology for the chemical synthesis of biaryl, heterobiaryl, and polyaryl molecules by the cross-coupling of o methoxybenzamides with aryl boroneopentylates. The reaction is based on the activation of the unreactive C-OMe bond by the proximate amide directing group using catalytic RuH2(CO)(PPh3)3 conditions. A one-step, base-free coupling process is thereby established that has the potential to supersede the useful two step directed ortho metalation/cross-coupling reaction involving cryogenic temperature and strong base conditions. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, minimum waste, and convenient scale-up make these reactions suitable for industrial applications. PMID- 25041585 TI - Right ventricular electrical and mechanical synchronization by properly timed septal pacing in a patient with right bundle branch block and first degree AV block--a case report. AB - We present a case of near-normalization of the QRS by septal pacing in a patient with dual-chamber pacemaker and underlying complete right bundle branch block and first degree atrioventricular block. The right ventricular mechanical synchronization suggested by the ECG was validated as such by strain echo. To the best of our knowledge, this is the first time it has been shown that the narrowing of the QRS corresponds to mechanical synchronization in a case of this seldom-recognized phenomenon. PMID- 25041586 TI - Measles and rubella vaccination coverage in Haiti, 2012: progress towards verifying and challenges to maintaining measles and rubella elimination. AB - OBJECTIVES: We conducted a nationwide survey to assess measles containing vaccine (MCV) coverage among children aged 1-9 years in Haiti and identify factors associated with vaccination before and during the 2012 nationwide supplementary immunisation activities (SIA). METHODS: Haiti was stratified into five geographic regions (Metropolitan Port-au-Prince, North, Centre, South and West), 40 clusters were randomly selected in each region, and 35 households were selected per cluster. RESULTS: Among the 7000 visited households, 75.8% had at least one child aged 1-9 years; of these, 5279 (99.5%) households consented to participate in the survey. Of 9883 children enrolled, 91% received MCV before and/or during the SIA; 31% received MR for the first time during the SIA, and 50.7% received two doses of MCV (one before and one during the 2012 SIA). Among the 1685 unvaccinated children during the SIA, the primary reason of non-vaccination was caregivers not being aware of the SIA (31.0%). Children aged 1-4 years had significantly lower MR SIA coverage than those aged 5-9 years (79.5% vs. 84.8%) (P < 0.0001). A higher proportion of children living in the West (12.3%) and Centre (11.2%) regions had never been vaccinated than in other regions (4.8-9.1%). Awareness, educational level of the mother and region were significantly associated with MR vaccination during and before the SIA (P < 0.001). CONCLUSIONS: The 2012 SIA successfully increased MR coverage; however, to maintain measles and rubella elimination, coverage needs to be further increased among children aged 1-4 years and in regions with lower coverage. PMID- 25041587 TI - A systematic study of single-nucleotide polymorphisms in the A4GALT gene suggests a molecular genetic basis for the P1/P2 blood groups. AB - BACKGROUND: The molecular mechanism for the formation of the P1/P2 blood groups remains unsolved. It has been shown that the P1/P2 polymorphism is connected to the different A4GALT gene expression levels in P1 and P2 red blood cells. STUDY DESIGN AND METHODS: The present investigation conducted a pilot investigation that involved the detailed and stepwise screening of single-nucleotide polymorphisms (SNPs) in the A4GALT gene, followed by a larger-scale association study. The transcription-inducing activity by the different genotypes of SNPs was analyzed using reporter assays. RESULTS: A total of 416 different SNP sites in the A4GALT genes from four P1 and four P2 individuals were analyzed in the pilot investigation, and 11 SNP sites, distributed in the A4GALT Intron 1 region, exhibited an association with the P1/P2 phenotypes. In the follow-up association study, the genotypes at the 11 SNPs of a total of 338 individuals across four different ethnic populations were determined, and the results show that two SNPs, rs2143918 and rs5751348, are consistently associated with the P1/P2 phenotypes. Reporter assays demonstrated significantly higher transcription-inducing activity by the SNPs bearing the P(1)-allele genotype than by the SNPs bearing the P(2) allele genotype and that the difference in transcriptional activity was determined by the different genotypes at SNP rs5751348. CONCLUSION: The results of this investigation demonstrate a consistent association of A4GALT SNPs rs2143918 and rs5751348 with the P1/P2 phenotypes and suggest that SNP rs5751348 may lead to allelic variations in A4GALT gene expression and consequently leads to the formation of the P1/P2 phenotypes. PMID- 25041588 TI - Environmental drivers of soil microbial community distribution at the Koiliaris Critical Zone Observatory. AB - Data on soil microbial community distribution at large scales are limited despite the important information that could be drawn with regard to their function and the influence of environmental factors on nutrient cycling and ecosystem services. This study investigates the distribution of Archaea, Bacteria and Fungi as well as the dominant bacterial phyla (Acidobacteria, Actinobacteria, Bacteroidetes, Firmicutes), and classes of Proteobacteria (Alpha- and Betaproteobacteria) across the Koiliaris watershed by qPCR and associate them with environmental variables. Predictive maps of microorganisms distribution at watershed scale were generated by co-kriging, using the most significant predictors. Our findings showed that 31-79% of the spatial variation in microbial taxa abundance could be explained by the parameters measured, with total organic carbon and pH being identified as the most important. Moreover, strong correlations were set between microbial groups and their inclusion on variance explanation improved the prediction power of the models. The spatial autocorrelation of microbial groups ranged from 309 to 2.226 m, and geographic distance, by itself, could explain a high proportion of their variation. Our findings shed light on the factors shaping microbial communities at a high taxonomic level and provide evidence for ecological coherence and syntrophic interactions at the watershed scale. PMID- 25041589 TI - High-frequency oscillation in early adult respiratory distress syndrome. PMID- 25041591 TI - Regression of a basal cell carcinoma infiltrating the brain after vismodegib therapy. PMID- 25041590 TI - The effect of cell death in the initiation of lupus nephritis. AB - Cell death and the release of chromatin have been demonstrated to activate the immune system producing autoantibodies against nuclear antigens in patients with systemic lupus erythematosus (SLE). Apoptosis, necrosis, necroptosis, secondary necrosis, autophagy and the clearance of dying cells by phagocytosis are processes believed to have a role in tolerance avoidance, activation of autoimmune lymphocytes and tissue damage by effector cells. The released chromatin not only activates the immune system; it also acts as antigen for the autoantibodies produced, including anti-dsDNA antibodies. The subsequent immune complex formed is deposited within the basement membranes and the mesangial matrix of glomeruli. This may be considered as an initiating event in lupus nephritis. The origin of the released chromatin is still debated, and the possible mechanisms and cell sources are discussed in this study. PMID- 25041593 TI - Electrical impedance tomography: so close to touching the holy grail. AB - Electrical impedance tomography is a new technology giving us lung imaging that may allow lung function to be monitored at the bedside. Several applications have been studied to guide mechanical ventilation at the bedside with electrical impedance tomography. Positive end-expiratory pressure trials guided by electrical impedance tomography are relevant in terms of recruited volume or homogeneity of the lung. Tidal impedance variation is a new parameter of electrical impedance tomography that may help physicians with ventilator settings in acute respiratory distress syndrome patients. This parameter is able to identify the onset of overdistention in the nondependent part and recruitment in the dependent part. Electrical impedance tomography presents a big step forward in mechanical ventilation. PMID- 25041592 TI - Treatment for infections with carbapenem-resistant Enterobacteriaceae: what options do we still have? AB - The global spread of carbapenem-resistant Enterobacteriaceae (CRE) is increasingly becoming a major challenge in clinical and public health settings. To date, the treatment for serious CRE infections remains difficult. The intelligent use of antimicrobials and effective infection control strategies is crucial to prevent further CRE spread. Early consultation with experts in the treatment of infections with multidrug-resistant organisms is valuable in patient management. This brief review will focus on the current, yet limited, treatment options for CRE infections. PMID- 25041597 TI - Rhabdomyomatous mesenchymal hamartoma: case report and literature review. PMID- 25041596 TI - Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study. AB - BACKGROUND: Breath testing is becoming an important diagnostic method to evaluate many disease states. In the light of rising healthcare costs, is important to develop a simple non-invasive tool to potentially identify paediatric patients who need endoscopy for suspected inflammatory bowel disease (IBD). AIM: To analyse exhaled volatile organic compounds (VOCs) and investigate the presence of a unique breath patterns to differentiate paediatric patients with (IBD) from healthy controls. METHODS: A cross-sectional, single-centre study included paediatric IBD patients and healthy controls (age range, 5-21 years). The diagnosis of IBD was confirmed by endoscopic, histological and radiographic data. Exhaled breath was collected and analysed using a selective ion flow tube mass spectroscopy (SIFT-MS) to identify new markers or patterns of IBD. RESULTS: One hundred and seventeen patients (62 with IBD and 55 healthy controls) were included in the study. Linear discriminant analysis and principle component analysis of mass scanning ion peak data demonstrated 21 pre-selected VOCs correctly classify patients with IBD or as healthy controls; P < 0.0001. Multivariable logistic regression analysis further showed three specific VOCs (1 octene, 1-decene, (E)-2-nonene) had excellent accuracy for predicting the presence of IBD with an area under the curve (AUC) of 0.96 (95% CI: 0.93-0.99). No significant difference in VOCs was found between patients with Crohn's disease or ulcerative colitis, and no significant correlation was seen with disease activity. CONCLUSION: These pilot data support the hypothesis that a unique breathprint potentially exists for paediatric IBD in the exhaled metabolome. PMID- 25041598 TI - Hindering and buffering factors for parental sleep in neonatal care. A phenomenographic study. AB - AIMS AND OBJECTIVES: To explore and describe how parents of preterm and/or sick infants in neonatal care perceive their sleep. BACKGROUND: Parents experience many stressful situations when their newborn infant is preterm and/or sick. This affects bonding. By developing more family-centred care units with single-family rooms, parents are given the opportunity to stay and care for their newborn infant(s) 24 hours a day. Lack of sleep may affect new parents' ability to cope with the many challenges they face on a daily basis. DESIGN: A phenomenographic study with an inductive and exploratory design. METHODS: Semi-structured interviews were conducted with twelve parents of infants in neonatal care between January-March 2012. To describe variations in perception of the phenomenon, data were analysed using phenomenography. FINDINGS: Four descriptive categories were identified within the phenomenon sleep in parents of preterm and/or sick infants in neonatal care: impact of stress on sleep; how the environment affects sleep; keeping the family together improves sleep; and, how parents manage and prevent tiredness. CONCLUSION: Anxiety, uncertainty and powerlessness have a negative influence on sleep. This can be decreased by continuous information, guidance and practical support. Skin-to-skin care was perceived as a stress-reducing factor that improved relaxation and sleep and should be encouraged by the nurse. The parents also mentioned the importance of being together. Having a private place where they could relax and take care of themselves and their newborn infant improved sleep. It was also desirable to involve older siblings in order to decrease feelings of loneliness, sadness and isolation. RELEVANCE FOR CLINICAL PRACTICE: Improved parental sleep in neonatal care may help the families cope with the situation and facilitate problem-solving, emotional regulation and the transition to parenthood. PMID- 25041599 TI - Unconventional Implant Placement Part III: Implant Placement Encroaching upon Residual Roots - A Report of Six Cases. AB - BACKGROUND: When a residual root is found in the way of a planned implant placement, invasive surgery is usually performed in order to remove it. Consequently, implant therapy is rendered more complex and lengthy. PURPOSE: We present 6 cases treated according to an unconventional protocol in which invasive surgery was avoided by allowing the implants to encroach upon the residual roots in order to permit a prosthetically driven surgery. MATERIALS AND METHODS: Six patients were treated with 7 implants placed through a residual root (4 in the mandible and 3 in the maxilla). The residual roots had to be clinically and radiographically asymptomatic and covered by bone or healthy gingiva. The radiographic follow-up ranged from 20 months to 9 years. RESULTS: Healing was uneventful. Implants were clinically stable, and radiographic examination did not show any unusual feature at the root-implant interface. CONCLUSION: Several types of new implant-tissue interfaces were created in addition to the classical implant-bone interface, but this did not seem to jeopardize implant integration. Reports of more cases with a longer follow-up are needed before this protocol can be endorsed for routine application. Nonetheless, if confirmed as acceptable, this protocol might open intriguing possibilities; it might also lead to revision of one of the leading concepts in dental implantology. PMID- 25041600 TI - Percutaneous renal tumour biopsy. AB - The use of percutaneous renal tumour biopsy (RTB) as a diagnostic tool for the histological characterization of renal masses has increased dramatically within the last 30 years. This increased utilization has paralleled advances in imaging techniques and an evolving knowledge of the clinical value of nephron sparing surgery. Improved biopsy techniques using image guidance, coupled with the use of smaller gauge needles has led to a decrease in complication rates. Reports from series containing a large number of cases have shown the non-diagnostic rate of RTB to range from 4% to 21%. Re-biopsy has been shown to reduce this rate, while the use of molecular markers further improves diagnostic sensitivity. In parallel with refinements of the biopsy procedure, there has been a rapid expansion in our understanding of the complexity of renal cell neoplasia. The 2013 Vancouver Classification is the current classification for renal tumours, and contains five additional entities recognized as novel forms of renal malignancy. The diagnosis of tumour morphotype on RTB is usually achievable on routine histology; however, immunohistochemical studies may be of assistance in difficult cases. The morphology of the main tumour subtypes, based upon the Vancouver Classification, is described and differentiating features are discussed. PMID- 25041602 TI - A novel template for reporting pre-hospital major incident medical management. PMID- 25041601 TI - Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct. AB - In the past, there has been a perception that ethical and practical problems limit the opportunities for research in neonates. This perception is no longer appropriate. It is now clear that research about the medicines used in neonates is an ethical requirement. It is possible to conduct high quality research in neonates if the research team adapt to the characteristics of this population. Good practice involves respecting the specific needs of newborn babies and their families by adopting relevant approaches to study design, recruitment, pharmacokinetic studies and safety assessment. Neonatal units have a unique culture that requires careful development in a research setting. Clinical investigators need to recognize the clinical and ethical imperative to conduct rigorous research. Industry needs to engage with neonatal networks early in the process of drug development, preferably before contacting regulatory agencies. Follow-up over 3-5 years is essential for the evaluation of medicines in neonates and explicit funding for this is required for the assessment of the benefit and risk of treatments given to sick newborn babies. The views of parents must be central to the development of studies and the research agenda. Ethical and practical problems are no longer barriers to research in neonates. The current challenges are to disseminate good practice and maximize capacity in order to meet the need for research among newborn babies. PMID- 25041603 TI - DNA methylation and expression of KCNQ3 in bipolar disorder. AB - OBJECTIVES: Accumulating evidence implicates the potassium voltage-gated channel, KQT-like subfamily, member 2 and 3 (KCNQ2 and KCNQ3) genes in the etiology of bipolar disorder (BPD). Reduced KCNQ2 or KCNQ3 gene expression might lead to a loss of inhibitory M-current and an increase in neuronal hyperexcitability in disease. The goal of the present study was to evaluate epigenetic and gene expression associations of the KCNQ2 and KCNQ3 genes with BPD. METHODS: DNA methylation and gene expression levels of alternative transcripts of KCNQ2 and KCNQ3 capable of binding the ankyrin G (ANK3) gene were evaluated using bisulfite pyrosequencing and the quantitative real-time polymerase chain reaction in the postmortem prefrontal cortex of subjects with BPD and matched controls from the McLean Hospital. Replication analyses of DNA methylation findings were performed using prefrontal cortical DNA obtained from the Stanley Medical Research Institute. RESULTS: Significantly lower expression was observed in KCNQ3, but not KCNQ2. DNA methylation analysis of CpGs within an alternative exonic region of KCNQ3 exon 11 demonstrated significantly lower methylation in BPD, and correlated significantly with KCNQ3 mRNA levels. Lower KCNQ3 exon 11 DNA methylation was observed in the Stanley Medical Research Institute replication cohort, although only after correcting for mood stabilizer status. Mood stabilizer treatment in rats resulted in a slight DNA methylation increase at the syntenic KCNQ3 exon 11 region, which subsequent analyses suggested could be the result of alterations in neuronal proportion. CONCLUSION: The results of the present study suggest that epigenetic alterations in the KCNQ3 gene may be important in the etiopathogenesis of BPD and highlight the importance of controlling for medication and cellular composition-induced heterogeneity in psychiatric studies of the brain. PMID- 25041604 TI - Pediatric medication administration errors and workflow following implementation of a bar code medication administration system. AB - Direct observation was used to detect medication errors and Bar Code Medication Administration (BCMA) workarounds on two pediatric units and one neonatal unit at UCSF Benioff Children's Hospital. The study (1) measured the frequency of nursing medication administration-related errors, (2) characterized the types of medication errors, (3) assessed compliance with the institution's six medication administration safety processes, and (4) identified observed workarounds following BCMA implementation. The results of the direct observation were compared to medication administration-related incident reports (IRs) for the same period. The frequency of medication errors was 5% for the three units. Compliance with the process measures was achieved 86% of the time (range 23-100%). Seven medication administration-related IRs were submitted during the same observation period. Three BCMA workarounds were identified; (1) failure to visually confirm patient's identification, (2) failure to compare the medication to the electronic medication administration record at least twice before administration, and (3) charting administration of medication before actual administration. The direct observation methodology identified a low frequency of medication administration errors (MAEs) consistent with post-BCMA implementation. The incident reporting system identified different MAEs than direct observation suggesting that both methods should be used to better characterize the scope of MAEs. PMID- 25041605 TI - Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia. AB - Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed. PMID- 25041606 TI - A meta-analysis of prevalence estimates and moderators of low bone mass in people with schizophrenia. AB - OBJECTIVE: To assess the prevalence and moderators of low bone mass, osteopenia and osteoporosis in schizophrenia patients. METHOD: Major electronic databases were searched from inception till December 2013 for studies reporting the prevalence of low bone mass (osteopenia + osteoporosis = primary outcome), osteopenia or osteoporosis in schizophrenia patients. Two independent authors completed methodological appraisal and extracted data. A random effects meta analysis was utilized. RESULTS: Nineteen studies were included (n = 3038 with schizophrenia; 59.2% male; age 24.5-58.9 years). The overall prevalence of low bone mass was 51.7% (95% CI = 43.1-60.3%); 40.0% (CI = 34.7-45.4%) had osteopenia and 13.2% (CI = 7.8-21.6%) had osteoporosis. Compared with controls, schizophrenia patients had significantly increased risk of low bone mass (OR = 1.9, CI = 1.30-2.77, P < 0.001, n = 1872) and osteoporosis (OR = 2.86, CI = 1.27 6.42, P = 0.01, n = 1824), but not osteopenia (OR = 1.33, CI = 0.934-1.90, P = 0.1, n = 1862). In an exploratory regression analysis, older age (P = 0.004) moderated low bone mass, while older age (P < 0.0001) and male sex (P < 0.0001) moderated osteoporosis. The subgroup analyses demonstrated high heterogeneity, but low bone mass was less prevalent in North America (35.5%, CI = 26.6-45.2%) than Europe (53.6%, CI = 38.0-68.5%) and Asia (58.4%, CI = 48.4-67.7%), and in mixed in-/out-patients (32.9%, CI = 49.6-70.1%) vs. in-patients (60.3%, CI = 49.6 70.1%). CONCLUSION: Reduced bone mass (especially osteoporosis) is significantly more common in people with schizophrenia than controls. PMID- 25041607 TI - The role of the health information professional. AB - This virtual issue has been published to mark the CILIP Health Libraries Group 2014 Conference, taking place in Oxford on 24th and 25th July 2014. The issue's theme is to highlight the key role of the health information professional and it shines a spotlight on professional expertise, demonstrating what we can share and learn from each other. It comprises a collection of articles published in the Health Information and Libraries Journal during the last 2 years but is very much about looking forward. The articles selected embrace three main themes: new ways of working; acquiring new skills and competencies; and fine-tuning existing skills and practices. The virtual issue mirrors the format of the regular journal, namely a review article, six original articles and the three regular features, covering Dissertations into Practice, International Perspectives and Initiatives and Learning and Teaching in Action. All articles included in this virtual issue are available free online. PMID- 25041608 TI - Atrioventricular block reproduced during atrial threshold testing: what is the mechanism? PMID- 25041609 TI - Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases. AB - We performed an external and multicentric validation of the nomogram and prognostic index (PI) proposed by the MD Anderson Cancer Center to prognostically stratify chronic lymphocytic leukaemia (CLL) patients in 1502 CLL cases. All six parameters involved in the nomogram and PI (age, sex, absolute lymphocyte count, number of lymph node groups, Rai stage and beta2-microglobulin) were independently associated with survival. The nomogram was accurate in predicting survival (c-index = 0.82). According to the PI, 38.7% of patients were at low risk, 58.3% at intermediate-risk and 3% at high-risk. The estimated median survival times were: not reached for low-risk, 13.4 years for intermediate-risk and 3.4 years for high-risk. The estimated median and 5-year survival by PI were similar to those originally reported. The PI remained a predictor of survival when analysis was limited to 847 Rai stage 0 (P < 0.0001) and 151 clinical monoclonal B-cell lymphocytosis (cMBL) cases (P = 0.033). Finally, the PI allowed prediction of time to therapy in all patients (P < 0.0001), in Rai 0 (P < 0.0001) and in cMBL cases (P = 0.044). Our results confirm the ability of the PI to predict prognosis, even in early stage disease cases. The study also extended the utility of the PI to cMBL cases. PMID- 25041610 TI - Prevalence of vertebral artery origin stenosis in a multirace-ethnic posterior circulation stroke cohort: Miami Stroke Registry (MIAMISR). AB - BACKGROUND: Vertebral artery origin stenosis is an important etiology for stroke in the posterior circulation. Data from the Oxford Vascular Study and New England Registry show a prevalence of vertebral artery origin disease of 26-32%. These populations are largely comprised of Caucasians. The prevalence of vertebral artery origin disease in multirace-ethnic stroke population is unknown. AIM: The study aims to assess the prevalence of vertebral artery origin stenosis in a multirace population with posterior circulation stroke. DESIGN/METHODS: The Miami Stroke Registry is a prospective registry which offers enrollment to consecutive patients admitted with a diagnosis of stroke/transient ischemic attack. Baseline demographics, vascular risk factors, and stroke topography in the posterior circulation were analyzed. All vascular imaging studies were reviewed for the presence of vertebral artery origin stenosis, and stroke etiology was adjudicated by TOAST classification. RESULTS: Mean age of the population was 63 +/- 13 years; 149 (70%) were men. Among cases, 123 were Hispanic (58%), almost one third 70 (32%) were of African descent, and 15 (7%) were white. The most common stroke etiology was small vessel occlusion (27%), followed by large artery intracranial disease 25% (posterior cerebral arteries, basilar and vertebral arteries), cardioembolic 19%, and cryptogenic 16%. Vertebral artery origin stenosis/occlusion was present in 28 (13.1%) patients, of whom only 2 (0.9%) were bilateral; it was attributed as the direct cause of stroke in 11 (5.2%) patients. CONCLUSIONS: We found a lower prevalence of vertebral artery origin stenosis in a predominately non-white population with posterior circulation stroke than previously reported. Vertebral artery origin stenosis was a direct cause of posterior circulation stroke in only 5.2% of patients. PMID- 25041611 TI - Tumour biology of colorectal liver metastasis is a more important factor in survival than surgical margin clearance in the era of modern chemotherapy regimens. AB - BACKGROUND: The aim of the authors was to reassess the impact of a positive surgical margin (R1) after a liver resection for colorectal liver metastases (CLMs) on survival in the era of modern chemotherapy, through their own experience and a literature review. METHODS: Inclusion criteria were: R1 or R0 resection with no local treatment modalities, extra-hepatic metastases or other cancer. RESULTS: Among 337 patients operated between 2000 and 2010, 273 patients were eligible (214 R0/59 R1). The mean follow-up was 43 +/- 29 months. Compared with a R0 resection, a R1 resection offered a lower 5-year overall (39.1% versus 54.2%, P = 0.010), disease-free (15.2% versus 31.1%, P = 0.021) and progression free (i.e. time to the first non-curable recurrence; 33.1% versus 47.3%, P = 0.033) survival rates. Metastases in the R1 group were more numerous, larger and more frequently synchronous. Independent factors of poor survival were: number, size and short-time interval of CLM occurrence, N status, rectal primary, absence of adjuvant chemotherapy, but not a R1 resection. With the more-systematic administration of chemotherapy since 2005, the intergroup difference in progression-free survival disappeared (P = 0.264). CONCLUSION: A R1 resection had no prognostic value per se but reflected a more severe disease. The recent change in the prognostic value of a R1 resection may be linked to the beneficial effect of chemotherapy. PMID- 25041612 TI - A comparative study on glycerol metabolism to erythritol and citric acid in Yarrowia lipolytica yeast cells. AB - Citric acid and erythritol biosynthesis from pure and crude glycerol by three acetate-negative mutants of Yarrowia lipolytica yeast was investigated in batch cultures in a wide pH range (3.0-6.5). Citric acid biosynthesis was the most effective at pH 5.0-5.5 in the case of Wratislavia 1.31 and Wratislavia AWG7. With a decreasing pH value, the direction of biosynthesis changed into erythritol synthesis accompanied by low production of citric acid. Pathways of glycerol conversion into erythritol and citric acid were investigated in Wratislavia K1 cells. Enzymatic activity was compared in cultures run at pH 3.0 and 4.5, that is, under conditions promoting the production of erythritol and citric acid, respectively. The effect of pH value (3.0 and 4.5) and NaCl presence on the extracellular production and intracellular accumulation of citric acid and erythritol was compared as well. Low pH and NaCl resulted in diminished activity of glycerol kinase, whereas such conditions stimulated the activity of glycerol-3 phosphate dehydrogenase. The presence of NaCl strongly influenced enzymes activity - the effective erythritol production was correlated with a high activity of transketolase and erythrose reductase. Therefore, presented results confirmed that transketolase and erythrose reductase are involved in the overproduction of erythritol in the cells of Y. lipolytica yeast. PMID- 25041613 TI - Deterioration, improvement of kidney function over time and determinants in the Cape Town Bellville South cohort. AB - AIM: The aim of the present study was to assess the trajectories of glomerular filtration rate (GFR) and determinants of change during a 3-year period in free living mixed-ancestry South Africans. METHODS: In all 320 (78.1% women) adults, aged 56.2 years, from Cape Town were examined in 2008 and 2011. Estimated glomerular filtration rate (eGFR) was based on the Modification of Diet in Renal Disease model; and staging of eGFR used the National Kidney Foundation's classification. RESULTS: Mean eGFR (mL/min per 1.73 m2) was 68.6 at baseline and eGFR stages were: > 90 (9.4%), 60-90 (58.7%), 30-60 (28.1%) and < 30 (0.9%). eGFR increased by 8 mL/min during follow-up, reflecting variable trajectories by baseline eGFR stages, sex, hypertension and glucose tolerance (all P-interaction <= 0.012). Movements across eGFR stages during follow-up favoured improvement in 113 participants (35.3%), and worsened in 23 (7.2%). In adjusted multinomial logistic regressions, men had a 72% (43-86%) lower chance of improvement, while each mmHg higher systolic blood pressure conferred a 7% (3-11%) risk of deterioration. Equivalent for each 1% HbA1c was 30% (8-56%). Participants with glucose intolerance had 102% (3-297%) higher chances of improvement than diabetics. CONCLUSION: Variable trajectories of eGFR with time were observed in this cohort, reflecting the effects of modifiable risk factors such as hypertension and dysglycaemia. PMID- 25041614 TI - The effect of haptens on protein-carrier immunogenicity. AB - The immune response against hapten is T-cell-dependent, and so requires the uptake, processing and presentation of peptides on MHC class II molecules by antigen-presenting cells to the specific T cell. Some haptens, following conjugation to the available free amines on the surface of the carrier protein, can reduce its immunogenicity. The purpose of this study was to explore the mechanism by which this occurs. Four proteins were tested as carriers and six molecules were used as haptens. The immune response to the carrier proteins was reduced > 100-fold by some of the haptens (termed carrier immunogenicity reducing haptens--CIRH), whereas other haptens did not influence the protein immunogenicity (carrier immunogenicity non-reducing haptens--nCIRH). Conjugation of the protein to a CIRH affected protein degradation by lysosomal cathepsins, leading to the generation of peptides that differ in length and sequence from those derived from the same native protein or that protein modified with nCIRH. Injection of CIRH-conjugated protein into mice induced an increase in the population of regulatory T cells. The results of this study provide a putative mechanism of action for the reduction of immune response to haptenated proteins. PMID- 25041615 TI - Ankle range of motion vs. venous ulcer healing rate: a complex relationship. PMID- 25041617 TI - Amniotic membrane: new concepts for an old dressing. AB - The amniotic membrane is the innermost layer of fetal membranes that surrounds and protects the embryo. The amniotic epithelial cells are a rich source for biologically active factors known to promote cell proliferation and differentiation. Therefore, the amniotic membrane is considered to be an attractive wound dressing material. Despite a large number of publications reporting anti-inflammatory, bacteriostatic, reepithelializing, and scar preventing properties of amniotic membrane, not all the molecular mechanisms underlying the beneficial actions of the amniotic membrane dressing have been fully elucidated. This review summarizes current knowledge on the properties of the amniotic membrane and its various clinical applications. It includes an overview of the main biologically active factors that may be responsible for the observed clinical effects of amnion dressings. This issue is briefly discussed in the context of the role of amnion processing and inter- and intradonor variations between amniotic membrane specimens. Finally, future directions for the use of amnion derivatives in wound care are indicated. PMID- 25041616 TI - Costs of burn care: a systematic review. AB - Burn care is traditionally considered expensive care. However, detailed information about the costs of burn care is scarce despite the increased need for this information and the enhanced focus on healthcare cost control. In this study, economic literature on burn care was systematically reviewed to examine the problem of burn-related costs. Cost or economic evaluation studies on burn care that had been published in international peer-reviewed journals from 1950 to 2012 were identified. The methodology of these articles was critically appraised by two reviewers, and cost results were extracted. A total of 156 studies met the inclusion criteria. Nearly all of the studies were cost studies (n = 153) with a healthcare perspective (n = 139) from high-income countries (n = 127). Hospital charges were often used as a proxy for costs (n = 44). Three studies were cost effectiveness analyses. The mean total healthcare cost per burn patient in high income countries was $88,218 (range $704-$717,306; median $44,024). A wide variety of methodological approaches and cost prices was found. We recommend that cost studies and economic evaluations employ a standard approach to improve the quality and harmonization of economic evaluation studies, optimize comparability, and improve insight into burn care costs and efficiency. PMID- 25041618 TI - Internet-based survey on current practice for evaluation, prevention, and treatment of scars, hypertrophic scars, and keloids. AB - No universally accepted standard for evaluation, prevention, and treatment of scars, hypertrophic scars, and keloids exists. Following development of a questionnaire, we performed a closed Web-based survey among burn centers. Server based data collection was performed over 4 weeks and closed thereafter. The poll revealed emerging new treatment schemes, but the majority of participants adhered to evaluation (Patient and Observer Scar Assessment Scale, Matching Assessment of Scars and Photographs, Vancouver Scar Scale, two-dimensional photography) and prevention (silicone gel sheets and compression garments) strategies that were in line with the currently available recommendations from the literature. We noted a low penetration for the use of objective evaluation tools in our poll and detected differences in surgical approaches to keloids. Based on the results of our survey and the power of currently available clinical recommendations, we expect future guidelines to gain more evidence-based power, especially when more high-quality clinical trials with objective evaluation support, clearly defined disease entities, and therapeutic outcome factors have become available. PMID- 25041619 TI - The effect of ankle range of motion on venous ulcer healing rates. AB - Limitation of ankle movement may contribute to calf muscle pump failure, which is thought to contribute to venous leg ulcer formation, which affects nearly 1 million Americans. We therefore wished to study ankle movement in patients with venous leg ulcers and its effect on healing. Using goniometry, we measured baseline ankle range of motion in venous leg ulcer patients from a Phase 2 dose finding study of an allogeneic living cell bioformulation. Two hundred twenty seven patients were enrolled in four active treatment groups and one standard care control group, all receiving compression therapy. Goniometry data from a control group of 49 patients without venous disease, from a previous study, was used for comparison. We found patients with active venous leg ulcers had significantly reduced ankle range of motion compared with the control group (p = 0.001). After 12 weeks of therapy, baseline ankle range of motion was not associated with healing, as there was no significant difference between healed and nonhealed groups, suggesting that ankle range of motion is not important in venous leg ulcer healing or, more likely, is overcome by compression. However, patients with venous ulcers located on the leg (as opposed to the ankle) had significantly higher ankle range of motion for plantar flexion and inversion (p = 0.021 and p = 0.034, respectively) and improved healing with both cell bioformulation and standard care (p = 0.011), suggesting that wound location is an important variable for ankle range of motion as well as for healing outcomes. PMID- 25041620 TI - Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: a randomized double-blinded controlled trial. AB - The healing process in diabetic foot ulcer (DFU) is hindered by factors such as chronic inflammation, defects in fibroblast function, poor angiogenesis, and lack of cell migration. Recombinant human epidermal growth factor (rhEGF) has been shown to enhance extracellular matrix formation, cellular proliferation, and angiogenesis. Therefore, intralesional application of rhEGF in DFU could accelerate wound healing. Our objective was to determine the efficacy and safety of rhEGF in patients with DFU. A randomized, double-blinded, placebo-controlled study was conducted comparing a thrice-per-week intralesional application of rhEGF (75 MUg) or placebo in patients with DFU for 8 weeks. The number of completely healed ulcers, size, and wound bed characteristics were evaluated to determine the efficacy of rhEGF. Adverse events were recorded and analyzed to establish its safety. A total of 34 patients were recruited for the study. After three dropouts, we were able to follow and analyze 16 patients in the placebo group and 15 patients in the rhEGF study to the end of the trial. Baseline testing showed that both groups were similar. Compared to the placebo group, more ulcers achieved complete healing in the rhEGF group (rhEGF, n = 4; placebo, n = 0; p = 0.033); ulcers in the rhEGF group decreased in area size (12.5 cm2 [rhEGF] vs. 5.2 cm2 [placebo]; p = 0.049); and more epithelial islands in the wound bed were present (28% vs. 3%; p = 0.025). Mild transitory dizziness was the only side effect that was more frequently noted in the rhEGF group. Our results showed that in patients with DFU who received standard care, intralesional rhEGF application resulted in complete healing in more patients, promoted the epithelialization of the wound bed, and significantly reduced the area of the DFU treated. Therefore, rhEGF resulted in better outcomes for patients suffering from DFU. PMID- 25041622 TI - Supplementation with olive oil, but not fish oil, improves cutaneous wound healing in stressed mice. AB - Supplementation with olive and fish oils reverses the effects of stress on behavioral activities and adrenal activation. However, previous studies have not shown whether supplementation with olive and fish oil could inhibit the effects of stress on cutaneous wound healing. Thus, this study investigated the effects of supplementation with fish or olive oil on cutaneous healing in stressed mice. Mice were subjected to rotational stress and treated with olive or fish oil daily until euthanasia. An excisional lesion was created on each mouse, and 14 days later, the lesions were analyzed. In addition, murine skin fibroblasts were exposed to elevated epinephrine levels plus olive oil, and fibroblast activity was evaluated. In the in vivo studies, administration of olive oil, but not fish oil, inhibited stress-induced reduction in wound contraction, reepithelialization, hydroxyproline levels, and blood vessel density. Stress induced increases in vascular endothelial growth factor expression and the numbers of macrophages and neutrophils were reversed only by olive oil. Both oils reversed stress-induced increase in catecholamine levels and oxidative damage. In in vitro studies, olive oil treatment reversed the reduction in fibroblast migration and collagen deposition and the increase in lipid peroxidation induced by epinephrine. In conclusion, supplementation with olive oil, but not fish oil, improves cutaneous wound healing in chronically stressed mice. PMID- 25041623 TI - To what extent does the reporting behavior of the media regarding a celebrity suicide influence subsequent suicides in South Korea? AB - This study investigated the nature of media coverage of a national entertainer's suicide and its impact on subsequent suicides. After the celebrity suicide, the number of suicide-related articles reported surged around 80 times in the week after the suicide compared with the week prior. Many articles (37.1%) violated several critical items on the World Health Organization suicide reporting guidelines, like containing a detailed suicide method. Most gender and age subgroups were at significantly higher risk of suicide during the 4 weeks after the celebrity suicide. Results imply that massive and noncompliant media coverage of a celebrity suicide can cause a large-scale copycat effect. PMID- 25041621 TI - Hyaluronan enhances wound repair and increases collagen III in aged dermal wounds. AB - Age-related changes in the extracellular matrix contribute to delayed wound repair in aging. Hyaluronan, a linear nonsulfated glycosaminoglycan, promotes synthesis and assembly of key extracellular matrix components, such as the interstitial collagens, during wound healing. The biological effects of hyaluronan are mediated, in part, by hyaluronan size. We have previously determined that dermal wounds in aged mice, relative to young mice, have deficits in the generation of lower molecular weight hyaluronan (defined as <300 kDa). Here, we tested the effect of exogenous hyaluronan of 2, 250, or 1,000 kDa sizes on full-thickness excisional wounds in aged mice. Only wounds treated with 250 kDa hyaluronan (HA250) were significantly improved over wounds that received carrier (water) alone. Treatment with HA250 was associated with increased expression of transcripts for the hyaluronan receptors CD44 and RHAMM, as well as collagens III and I. Analyses of dermal protein content by mass spectrometry and Western blotting confirmed significantly increased expression of collagen III in wounds treated with HA250 relative to control wounds. In summary, we find that HA250 improves wound repair and increases the synthesis of collagen III in aged dermal wounds. PMID- 25041624 TI - Cost estimation of single-implant treatment in the periodontally healthy patient after 16-22 years of follow-up. AB - BACKGROUND: Costs for single-implant treatment are mostly described for the initial treatment. Information on the additional cost related to aftercare is scarce. OBJECTIVE: To make an estimation of complication costs of single implants in periodontally healthy patients after 16-22 years and to compare costs for various prosthetic designs. MATERIALS AND METHODS: Patients with a single implant were recalled for a clinical examination and file investigation. Prosthetic designs included single-tooth (ST) and CeraOne (CO) abutments supporting a porcelain-fused-to-metal (PFM), all-ceramic (CER), or gold-acrylic (ACR) crown. Costs related to failures or technical, biologic, and aesthetic complications were retrieved from patient's records. Total and yearly additional complication costs were calculated as a percentage relative to the initial cost. Chair time needed to solve the complication was recorded and prosthetic designs were compared by Kruskal-Wallis tests. RESULTS: Fifty patients with 59 surviving implants were clinically investigated. Additional complication costs after a mean follow-up of 18.5 years amounted to 23% (range 0-110%) of the initial treatment cost. In total, 39% of implants presented with no costs, whereas 22% and 8% encountered additional costs over 50% and 75%, respectively. In 2%, the complication costs exceeded the initial cost. The mean yearly additional cost was 1.2% (range 0-6%) and mean complication time per implant was 67 min (range 0-345 min). Differences between prosthetic designs (CO, ST-PFM, ST-ACR) were statistically significant for total cost (P = 0.011), yearly cost (P = 0.023), and time (P = 0.023). Pairwise comparison revealed significant lower costs for CO compared with ST-ACR reconstructions. CONCLUSION: Patients should be informed about additional costs related to complications with single implants. The mean additional cost spent on complications was almost one-quarter of the initial treatment price. A majority of implants presented with lower additional costs, whereas the highest complication costs were related to a smaller group with 22% of the implants needing more than half of the initial cost for complication management. Expenses were significantly different for various prosthetic designs. PMID- 25041625 TI - A scenario-based evaluation of the Middle East respiratory syndrome coronavirus and the Hajj. AB - Between April 2012 and June 2014, 820 laboratory-confirmed cases of the Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported in the Arabian Peninsula, Europe, North Africa, Southeast Asia, the Middle East, and the United States. The observed epidemiology is different to SARS, which showed a classic epidemic curve and was over in eight months. The much longer persistence of MERS-CoV in the population, with a lower reproductive number, some evidence of human-to-human transmission but an otherwise sporadic pattern, is difficult to explain. Using available epidemiological data, we implemented mathematical models to explore the transmission dynamics of MERS-CoV in the context of mass gatherings such as the Hajj pilgrimage, and found a discrepancy between the observed and expected epidemiology. The fact that no epidemic occurred in returning Hajj pilgrims in either 2012 or 2013 contradicts the long persistence of the virus in human populations. The explanations for this discrepancy include an ongoing, repeated nonhuman/sporadic source, a large proportion of undetected or unreported human-to-human cases, or a combination of the two. Furthermore, MERS-CoV is occurring in a region that is a major global transport hub and hosts significant mass gatherings, making it imperative to understand the source and means of the yet unexplained and puzzling ongoing persistence of the virus in the human population. PMID- 25041626 TI - Effectiveness of femur bone indexes to segregate wild from captive minks, Mustela vison, and forensic implications for small mammals. AB - Utilization of free-living populations of endangered wildlife species is usually strictly prohibited or restricted. Farming of endangered species can provide products that are in demand as a countermeasure. A novel forensic issue arises because it becomes necessary to discriminate the origin of given wildlife products. We tested the effectiveness of five measurements and four indexes of femur bone using farmed minks (n = 40) and escapees (n = 32). Results showed all measurements, namely body mass (L(f)), body length (M(f)), femur mass (V(f)), femur length (M(b)), and femur volume (L(b)), were highly discriminatory. However, they are susceptible to the influence of nutrition level and sex. Femur length index (I(fl)), femur linear density (D(l)), and femur volume density (D(v)) eliminated the influence of level of nutrition and were highly effective. However, I(fl) and D(l) were influenced by sex (p = 0.000). Because D(v) was not influenced by sex (p = 0.683) and was highly effective, it was the preferred index. PMID- 25041627 TI - Antagonistic roles of abscisic acid and cytokinin during response to nitrogen depletion in oleaginous microalga Nannochloropsis oceanica expand the evolutionary breadth of phytohormone function. AB - The origin of phytohormones is poorly understood, and their physiological roles in microalgae remain elusive. Genome comparison of photosynthetic autotrophic eukaryotes has revealed that the biosynthetic pathways of abscisic acid (ABA) and cytokinins (CKs) emerged in unicellular algae. While ABA and CK degradation mechanisms emerged broadly in algal lineages, complete vascular plant-type conjugation pathways emerged prior to the rise of Streptophyta. In microalgae, a complete set of proteins from the canonical ABA and CK sensing and signaling pathways is not essential, but individual components are present, suggesting stepwise recruitment of phytohormone signaling components. In the oleaginous eustigmatophyte Nannochloropsis oceanica IMET1, UHPLC-MS/MS detected a wide array of plant hormones, despite a phytohormone profile that is very distinct from that of flowering plants. Time-series transcriptional analysis during nitrogen depletion revealed activation of the ABA biosynthetic pathway and antagonistic transcription of CK biosynthetic genes. Correspondingly, the ABA level increases while the dominant bioactive CK forms decrease. Moreover, exogenous CKs stimulate cell-cycle progression while exogenous ABA acts as both an algal growth repressor and a positive regulator in response to stresses. The presence of such functional flowering plant-like phytohormone signaling systems in Nannochloropsis sp. suggests a much earlier origin of phytohormone biosynthesis and degradation than previously believed, and supports the presence in microalgae of as yet unknown conjugation and sensing/signaling systems that may be exploited for microalgal feedstock development. PMID- 25041628 TI - Do we need heparin coating for extracorporeal membrane oxygenation? New concepts and controversial positions about coating surfaces of extracorporeal circuits. AB - Blood contact with surfaces of the extracorporeal circuit provokes the activation of the coagulation system. To improve biocompatibility of the extracorporeal circuit without increasing the risk of bleeding, coatings of artificial surfaces were designed; many of them involve the use of heparin. Data in the literature show that heparin-induced thrombocytopenia is a major issue in the extracorporeal membrane oxygenation scenario, and no relevant benefits have been shown comparing heparin and no-heparin coating. PMID- 25041629 TI - Fossils and a large molecular phylogeny show that the evolution of species richness, generic diversity, and turnover rates are disconnected. AB - The magnitude and extent of global change during the Cenozoic is remarkable, yet the impacts of these global changes on the biodiversity and evolutionary dynamics of species diversification remain poorly understood. To investigate this question, we combine paleontological and neontological data for the angiosperm order Fagales, an ecologically important clade of about 1370 species of trees with an exceptional fossil record. We show differences in patterns of accumulation of generic diversity, species richness, and turnover rates for Fagales. Generic diversity evolved rapidly since the Late Cretaceous and peaked during the Eocene or Oligocene. Turnover rates were high during periods of extreme global climate change, but relatively low when the climate remained stable. Species richness accumulated gradually throughout the Cenozoic, possibly at an accelerated pace after the Middle Miocene. Species diversification occurred in new environments: Quercoids radiating in Oligocene subtropical seasonally arid habitats, Casuarinaceae in Australian pyrophytic biomes, and Betula in Late Neogene holarctic habitats. These radiations were counterbalanced by regional extinctions in Late Neogene mesic warm-temperate forests. Thus, the overall diversification at species level is linked to regional radiations of clades with appropriate ecologies exploiting newly available habitats. PMID- 25041630 TI - Rebuttal note to the letter to the editor by Agostoni and Zocchi. PMID- 25041631 TI - Multiple sclerosis clinical course and cardiovascular disease risk - Swedish cohort study. AB - BACKGROUND AND PURPOSE: Cardiovascular disease (CVD) risk amongst multiple sclerosis (MS) patients appears raised, but few studies have examined CVD risk amongst an unselected MS patient group. MS course may be relevant for CVD risk. Our aim was to assess CVD risk and variation by course in MS patients. METHODS: The Multiple Sclerosis Register identified 7667 patients who received an MS diagnosis between 1964 and 2005. They were matched by age, period, region and sex with 76 045 members of the general population without MS using Swedish registers. Poisson regression compared the two cohorts to estimate the relative risk for CVD, overall, as well as grouped and individual CVD diagnoses. RESULTS: MS patients had an increased adjusted relative risk (with 95% confidence intervals; number of MS cohort events) for CVD of 1.31 (1.22-1.41; n = 847), with some variation by course: relapsing-remitting 1.38 (1.17-1.62; n = 168); secondary progressive 1.30 (1.18-1.53; n = 405) and primary progressive 1.15 (0.93-1.41; n = 108). The association for the relapsing-remitting course was not significant after excluding the first year of follow-up. Overall incidence rates per 1000 person-years for CVD are 11.8 (11.06-12.66) for the MS cohort and 8.8 (8.60-9.05) for the non-MS cohort. The most pronounced association was for deep vein thrombosis: relapsing-remitting 2.16 (1.21-3.87; n = 14), secondary progressive 3.41 (2.45-4.75; n = 52) and primary progressive 3.57 (1.95-6.56; n = 15). MS was associated with ischaemic stroke but largely during the first year of follow-up. MS was associated with a decreased relative risk for angina pectoris and atrial fibrillation. CONCLUSIONS: There is a significantly increased relative risk for CVD in MS, particularly for venous thromboembolic disorders in progressive MS, suggesting immobility as a possible factor. An increased frequency of ischaemic stroke in MS is most probably due to surveillance bias resulting from diagnostic investigations for MS. There is no increased relative risk for ischaemic heart disease in MS and atrial fibrillation appears to be less common than amongst the general population. PMID- 25041632 TI - Microbiology of sugar-rich environments: diversity, ecology and system constraints. AB - Microbial habitats that contain an excess of carbohydrate in the form of sugar are widespread in the microbial biosphere. Depending on the type of sugar, prevailing water activity and other substances present, sugar-rich environments can be highly dynamic or relatively stable, osmotically stressful, and/or destabilizing for macromolecular systems, and can thereby strongly impact the microbial ecology. Here, we review the microbiology of different high-sugar habitats, including their microbial diversity and physicochemical parameters, which act to impact microbial community assembly and constrain the ecosystem. Saturated sugar beet juice and floral nectar are used as case studies to explore the differences between the microbial ecologies of low and higher water-activity habitats respectively. Nectar is a paradigm of an open, dynamic and biodiverse habitat populated by many microbial taxa, often yeasts and bacteria such as, amongst many others, Metschnikowia spp. and Acinetobacter spp., respectively. By contrast, thick juice is a relatively stable, species-poor habitat and is typically dominated by a single, xerotolerant bacterium (Tetragenococcus halophilus). A number of high-sugar habitats contain chaotropic solutes (e.g. ethyl acetate, phenols, ethanol, fructose and glycerol) and hydrophobic stressors (e.g. ethyl octanoate, hexane, octanol and isoamyl acetate), all of which can induce chaotropicity-mediated stresses that inhibit or prevent multiplication of microbes. Additionally, temperature, pH, nutrition, microbial dispersion and habitat history can determine or constrain the microbiology of high-sugar milieux. Findings are discussed in relation to a number of unanswered scientific questions. PMID- 25041633 TI - Prospective evaluation of automatized PF4/heparin immunoassays HemosIL HIT-ab (PF4-H) for the diagnosis of heparin-induced thrombocytopenia. AB - INTRODUCTION: Recently, rapid immunoassays have been developed to allow the detection of antibodies anti-PF4/heparin. In this prospective study, we evaluated the performances of a automatized immunoassay (HemosIL HIT-Ab) in comparison with an ELISA (Zymutest HIA IgG) used for the diagnosis of heparin-induced thrombocytopenia (HIT) in association with the 4T's score. METHODS: According to the 4T's score, samples with score <=3 had no further analysis. Two immunological assays Zymutest HIA IgG and HemosIL HIT-Ab were performed in samples with score >=4. In patients with at least one positive immunological assay or two negative immunological assays but with high-pretest probability (4T's score >=6), HIT was screened by one functional assay using washed platelets. RESULTS: The sensitivities of both assays were excellent and comparable (100%). The specificity was 92.3% for ELISA and 91.2% for HemosIL HIT-Ab. The analysis of the operating characteristics showed that both assays have almost identical ROCs (AUROC, 0.9951 and 0.9853, respectively, for ELISA and HemosIL HIT-Ab) and the calculating of the kappa coefficient revealed a good agreement (0.67). CONCLUSION: Performance characteristics of the HemosIL HIT-Ab are comparable to the Zymutest HIA IgG. The HemosIL HIT-Ab can be used in association with the 4T's score to rule out HIT. PMID- 25041634 TI - The assessment of the T102C polymorphism of the 5HT2a receptor gene, 3723G/A polymorphism of the NMDA receptor 3A subunit gene (GRIN3A) and 421C/A polymorphism of the NMDA receptor 2B subunit gene (GRIN2B) among cardiac surgery patients with and without delirium. AB - OBJECTIVE: The studies regarding the role of genes polymorphism in development of postoperative delirium are extremely rare. Therefore, we investigated the potential association of polymorphism in 5HT2a receptor gene and N-methyl-d aspartate (NMDA) receptor 3A and 2B subunits genes with postoperative delirium. METHOD: We conducted a prospective, nested, case-control study. For analysis, 3723 G/A (rs3739722) polymorphism in the GRIN3A gene, 421 C/A (rs3764028) polymorphism in the GRIN2B gene and T102C (rs6313) polymorphism in the 5HT2A gene were selected. RESULTS: Genetic analysis confirmed that there were significant differences in genotype frequencies for 3723 G/A between delirium patients and controls. No other significant associations were observed. Moreover, according to the multivariate conditional logistic regression analysis the presence of AG haplotype of GRIN3A gene was independently associated with postoperative delirium. CONCLUSIONS: These findings suggest that the genetic variations of NR3A subunit of NMDA receptor may be a predisposing factor to delirium among the Polish population of cardiac surgery patients. PMID- 25041635 TI - Glaring need for new studies of antidepressants in cancer care. PMID- 25041636 TI - Olfactory reference syndrome: a still open nosological and treatment debate. AB - OBJECTIVE: The objective was to report a case of olfactory reference syndrome (ORS) with several co-occurring disorders and to discuss ORS differential diagnoses, diagnostic criteria and classification. METHOD: Case report. RESULTS: A 37-year-old married woman presented overvalued ideas of having bad breath since adolescence. She met current diagnostic criteria for social anxiety disorder, specific phobia, obsessive-compulsive disorder, generalized anxiety disorder, body dysmorphic disorder and major depressive disorder. ORS similarities and differences with some related disorders are discussed. CONCLUSION: Further studies regarding symptoms, biomarkers and outcomes are needed to fully disentangle ORS from existing depressive, anxiety and obsessive-compulsive spectrum disorders. PMID- 25041637 TI - miR-106b is overexpressed in medulloblastomas and interacts directly with PTEN. AB - AIMS: MicroRNAs (miRNAs) are an abundant group of small non-coding RNAs that have been implicated in tumorigenesis. They regulate expression of target genes by complementary base pairing. The purposes of this study were to delineate miR-106b expression in medulloblastoma (MB) and to explore its functional contributions to MB pathogenesis. METHODS: We analysed expression of miR-106b in 32 MB samples by quantitative RT-PCR. We applied gain- and loss-of-function strategies to delineate the functional roles of miR-106b in MB. Luciferase reporter assay was conducted to confirm target gene of miR-106b. RESULTS: Expression of miR-106b was overexpressed in MB, and was significantly associated with its host gene MCM7 (P = 0.020). Transfection of miR-106b inhibitor in MB cell lines markedly reduced cell proliferation, migration and invasion potential, and tumour sphere formation. Cell cycle analysis indicated that miR-106b inhibition induced G1 arrest and apoptosis. The cell cycle regulators, p21 and cyclin D1, and apoptotic marker cleaved PARP were differentially expressed in miR-106b inhibitor transfected cells. PTEN was identified as a direct target gene of miR-106b. Luciferase reporter assay confirmed miR-106b directly interacted with the 3' UTR of PTEN. We found miR-106b directly targeted PTEN at transcriptional and translational levels. Immunohistochemistry revealed a trend between PTEN and miR 106b in MB tumours (P = 0.07). CONCLUSIONS: These data suggested the upregulation of miR-106b in MB and the involvement of miR-106b in MB biology. PMID- 25041638 TI - Contraceptive pills and thrombosis: effects of the French crisis on prescriptions and consequences for medicine agencies. AB - The higher risk of venous thromboembolism with 3rd and 4th- generations combined oral contraceptives compared to 2nd generation triggered a media crisis in France. Exposure to 3rd or 4th-generation combined oral contraceptives led to an annual excess of around 100 premature deaths in Europe. In the absence of any demonstrated additional benefit of these combined oral contraceptives, measures were taken to decrease exposure of women to this illegitimate excess of risk. As a consequence, this crisis saw a 45% decrease in the prescription of 3rd and 4th generations combined oral contraceptives, without adverse consequences. PMID- 25041639 TI - Do we have a workable clinical protocol for differentiating lympho-hematopoietic stem cells from the source of embryonic stem cells and induced pluripotent stem cells in culture? AB - In recent years, many researchers are focusing on deriving lympho-hematopoietic stem cells (L-HSC) from human embryonic stem cells (ESC) and/or induced pluripotent stem cells (iPSC) in culture as alternative sources for transplantation. Two protocols are available for research purposes: mouse stroma cell line coculture system and embryoid bodies (EBs) suspension culture system. However, due to the lack of human stroma cell line, which could support the derivation of L-HSC in culture, the generation of therapeutic lympho hematopoietic cells for clinical purpose can only be achieved using EBs suspension culture system. In this short communication/review, the results of EBs suspension culture system using mouse and human ESC/iPSC are summarized and the potential clinical application is discussed. PMID- 25041640 TI - In situ identification of the synthrophic protein fermentative Coprothermobacter spp. involved in the thermophilic anaerobic digestion process. AB - Thermophilic bacteria have recently attracted great attention because of their potential application in improving different biochemical processes such as anaerobic digestion of various substrates, wastewater treatment or hydrogen production. In this study we report on the design of a specific 16S rRNA-targeted oligonucleotide probe for detecting members of Coprothermobacter genus characterized by a strong protease activity to degrade proteins and peptides. The newly designed CTH485 probe and helper probes hCTH429 and hCTH439 were optimized for use in fluorescence in situ hybridization (FISH) on thermophilic anaerobic sludge samples. In situ probing revealed that thermo-adaptive mechanisms shaping the 16S rRNA gene may affect the identification of thermophilic microorganisms. The novel developed FISH probe extends the possibility to study the widespread thermophilic syntrophic interaction of Coprothermobacter spp. with hydrogenotrophic methanogenic archaea, whose establishment is a great benefit for the whole anaerobic system. PMID- 25041641 TI - Chronic kidney disease and perioperative outcomes in urological oncological surgery. AB - OBJECTIVES: To evaluate baseline renal dysfunction among patients undergoing urological oncological surgery and its impact on early postoperative outcomes. METHODS: Between 2005 and 2011, patients who underwent minimally-invasive or open radical prostatectomy, partial nephrectomy and radical nephrectomy, or open radical cystectomy, respectively, were identified in the National Surgical Quality Improvement Program dataset. Preoperative kidney function was assessed using estimated glomerular filtration rate and staged according to National Kidney Foundation definitions. Multivariable logistic regression was used to model the association between preoperative renal function and the risk of 30-day mortality and major complications. Furthermore the impact of chronic kidney disease on operation time and length of hospital stay was assessed. RESULTS: Overall, 13,168 patients underwent radical prostatectomy (65.4%), partial nephrectomy (10.7%) and radical nephrectomy (16.1%) and radical cystectomy (7.8%), respectively; 50.1% of evaluable patients had reduced kidney function (chronic kidney disease II), and a further 12.6, 0.7 and 0.9% were respectively classified into chronic kidney disease stages III, IV, and V. Chronic kidney disease was an independent predictor of 30-day major postoperative complications (chronic kidney disease III: odds ratio 1.61, P < 0.001; chronic kidney disease IV: odds ratio 2.24, P = 0.01), of transfusions (chronic kidney disease III: odds ratio 2.14, P < 0001), of prolonged length of stay (chronic kidney disease III: odds ratio 2.61, P < 0.001; chronic kidney disease IV: odds ratio 3.37, P < 0.001; and chronic kidney disease V: odds ratio 1.68; P = 0.03) and of 30-day mortality (chronic kidney disease III: odds ratio 4.15, P = 0.01; chronic kidney disease IV: odds ratio 10.10, P = 0.003; and chronic kidney disease V: odds ratio 17.07, P < 0.001) compared with patients with no kidney disease. CONCLUSIONS: Renal dysfunction might be underrecognized in patients undergoing urological cancer surgery. Chronic kidney disease stages III, IV and V are independent predictors for poor 30-day postoperative outcomes. PMID- 25041642 TI - Impact of fat and selected profiles of fatty acids contained in the colostrum and milk of sows of native breeds on piglet rearing. AB - The aim of this study was to evaluate the effect of the level of fat and selected fatty acids found in the milk of sows on the rearing of native breed piglets. Simultaneously, in order to improve the accuracy of the performed analyses, atomic absorption spectrometry was employed in the applied analytic methodology. The experimental animal material comprised 60 sows of the indigenous White Zlotnicka breed. Colostrum and milk were collected on the first and 14th days of lactation. In all, 240 samples were collected. The following parameters were determined in the course of the experiment: number and weight of piglets, body weight gains as well as deaths of piglets. A total of 1270 born piglets was subjected to investigations. The performed experiments demonstrated that, with the progress of the lactation period, the content of fat and saturated fatty acids (SFA) turned out to be statistically significant and showed a growing tendency. Fat increased by about 2% and palmitic acid (C16:0) increased most, that is by 5%. Linolic (C18:2) and linolenic (C18:3) acids revealed decreasing trends. Irrespective of the day of lactation, the level of unsaturated fatty acids (UFA) determined in sows' colostrum and milk was higher in comparison with that of SFA, and the UFA to SFA ratio ranged from 1.84% to 1.33%. Proportions of n-6 to n-3 fatty acids were determined at the level of about 1.6:1.0 in the colostrum and 1.3:10 in milk. The highest daily body weight gains were recorded in the case of piglets derived from sows with the highest fat level - 294 g, while in the case of stearic acid (C18:0), the smaller its concentration in the colostrum and milk of the experimental sows, the better body weight gains of piglets - 262 g. At the same time, stearic acid (C18:0) was found to exert a statistically significant effect on piglet mortality at the level of P <= 0.05. Its highest concentration caused the highest proportion of deaths among piglets - 16.23%. The performed analysis of correlations that occurred between fat, fatty acids and traits associated with piglet rearing confirmed that linolic acid (C18:2; n-6) was highly significantly correlated with piglets' body weights (r = 0.456**) and was negatively correlated with piglets' deaths (r = -0.312). On the other hand, fat revealed correlation with body weight gains of piglets (r = 0.333*_ and a negative correlation with deaths of piglets (r = -0344*). Recapitulating, the results of the performed experiments revealed that differences in the levels of fat and fatty acids found in sows' colostrum and milk influenced results of piglet rearing. Together with the increase in the content of fat and UFA in sows' colostrum and milk, piglets were characterized by the best body weight, growth rate, as well as by small mortality. PMID- 25041643 TI - [Organizational culture of the Spanish National Health Care System. Results within the framework of Foro Gerendia]. PMID- 25041644 TI - All preclinical trials should be registered in advance in an online registry. PMID- 25041645 TI - Habitat-based polymorphism is common in stream fishes. AB - Morphological differences (size and shape) across habitats are common in lake fish where differences relate to two dominant contrasting habitats: the pelagic and littoral habitat. Repeated occurrence of littoral and pelagic morphs across multiple populations of several lake fish species has been considered as important evidence that polymorphism is adaptive in these systems. It has been suggested that these habitat-based polymorphic differences are due to the temporal stability of the differences between littoral and pelagic habitats. Although streams are spatially heterogeneous, they are also more temporally dynamic than lakes and it is still an open question whether streams provide the environmental conditions that promote habitat-based polymorphism. We tested whether fish from riffle, run and pool habitats, respectively, differed consistently in their morphology. Our test compared patterns of morphological variation (size and shape) in 10 fish species from the three stream habitat types in 36 separate streams distributed across three watersheds. For most species, body size and shape (after controlling for body size) differed across riffle, run and pool habitats. Unlike many lake species, the nature of these differences was not consistent across species, possibly because these species use these habitat types in different ways. Our results suggest that habitat-based polymorphism is an important feature also in stream fishes despite the fact that streams are temporally variable in contrast to lake systems. Future research is required to assess whether the patterns of habitat-based polymorphism encountered in streams have a genetic basis or they are simply the result of within generation phenotypic plasticity. PMID- 25041646 TI - How is paediatric chronic fatigue syndrome/myalgic encephalomyelitis diagnosed and managed by paediatricians? An Australian Paediatric Research Network Study. AB - AIM: The diagnosis and management of paediatric chronic fatigue syndrome/myalgic encepnalomyelitis (CFS/ME) represent ongoing challenges for paediatricians. A better understanding of current approaches at a national level is important in informing where research and education could improve treatment outcomes. We aimed to examine current diagnosis and management practices for CFS/ME by Australian paediatricians. METHOD: An online survey was sent to members of the Australian Paediatric Research Network. The primary outcomes of interest included diagnostic criteria used, medical investigations and management practices in paediatric CFS/ME. RESULTS: One hundred seventy-eight (41%) of 430 eligible paediatricians responded, with 70 of the 178 (39%) reporting that they diagnose and manage CFS/ME as part of their practice. Medical investigations used for diagnosis were variable. Conditions that more than half of the paediatricians reported as commonly co-occurring (i.e. present in >50% of cases) included somatisation disorders, anxiety, depression and fibromyalgia. There was wide variation in behavioural and pharmacological management strategies but most paediatricians commonly engaged a school teacher, physiotherapist and/or psychologist as part of their management. CONCLUSION: The diagnostic and management practices of paediatricians for CFS/ME within Australia vary widely. This likely reflects a paucity of paediatric-specific guidelines, together with limited evidence to guide best practice and limited training in this area. There is a need for guidance and education for the diagnosis and management of paediatric CFS/ME in Australia. PMID- 25041648 TI - Review article: Maxillofacial emergencies: dentoalveolar and temporomandibular joint trauma. AB - Dentoalveolar trauma and dislocations of the temporomandibular joint are common reasons for patients to present to EDs in Australia. The majority of medical practitioners receive very little formal training in the management of these injuries and might not have ready access to dental services out of hours for advice. This article focuses on the emergency assessment, triage and non specialist management of dentoalveolar trauma and injuries to the temporomandibular joint. PMID- 25041649 TI - Mechanisms of benzalkonium chloride toxicity in a human trabecular meshwork cell line and the protective role of preservative-free tafluprost. AB - BACKGROUND: Benzalkonium chloride (BAK) is a controversial ophthalmic preservative because of its prominent side-effect profile. In this study, we examined the mechanism of BAK toxicity in human trabecular meshwork cells (HTMC) and compared the effects of BAK with tafluprost free acid, which is an active form of tafluprost commercially available in a preservative-free formulation. METHODS: Primary HTMC were treated with different BAK concentrations over various exposure times. Cell viability was quantified using the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenol tetrazolium bromide assay, and apoptosis was measured by enzyme linked immunosorbent assay. The cell viability of primary HTMC exposed to various concentrations and times of tafluprost free acid was also determined. Cells were treated with BAK and tafluprost free acid for 30 min at 37 degrees C, and cell viability was again assessed. The effect of BAK on the gap junction protein Connexin-43 (Cx43) expression was subsequently examined. RESULTS: BAK treatment resulted in a dose- and time-dependent decline in cell viability. Apoptosis increased following BAK treatment. Tafluprost-free acid treatment did not significantly affect cell viability. Tafluprost co-treatment with BAK resulted in an increase in cell viability as compared with BAK treatment alone. BAK treatment upregulated Cx43 expression in HTMC. CONCLUSIONS: These results demonstrate that BAK is harmful to the health of cultured HTMC. Tafluprost is both safe and cytoprotective against BAK for these HTMC. The effect of tafluprost on the gap junctions of the HTM should be further investigated. PMID- 25041650 TI - Initial external validation of REGRESS in public health graduate students. AB - Linear regression is typically taught as a second and potentially last required (bio)statistics course for Public Health and Clinical and Translational Science students. There has been much research on the attitudes of students toward basic biostatistics, but there has not been much assessing students' understanding of critical regression topics. The REGRESS (REsearch on Global Regression Expectations in StatisticS) quiz developed at Mayo Clinic utilizes 27 questions to assess understanding for simple and multiple linear regression. We performed an initial external validation of this tool with 117 University of Michigan public health students. We compare the results of pre- and postcourse quiz scores from the Michigan cohort to scores of Mayo medical students and professional statisticians. University of Michigan students performed higher than Mayo students on the precourse quiz due to previous related coursework, but did not perform as high postcourse indicating the need for course modification. In the Michigan cohort, REGRESS scores improved by a mean (standard deviation) of 4.6 (3.4), p < 0.0001. Our results support the use of the REGRESS quiz as a learning tool for students and an evaluation tool to identify topics for curricular improvement for teachers, while we highlight future directions of research. PMID- 25041651 TI - Inter-rater agreement in the diagnosis of mucositis and peri-implantitis. AB - AIM: The objective was to assess the inter-rater agreement in the diagnosis of mucositis and peri-implantitis. MATERIAL AND METHODS: Adult patients with >= 1 dental implant were eligible. Three operators examined the patients. One examiner allocated the patients to three groups of nine as follows: nine implants with peri-implantitis, nine implants with mucositis, and 9 implants with healthy mucosa. Each examiner recorded on all 27 patients (one implant per patient) recessions, probing depth, bleeding on probing, suppuration, keratinized tissue depth and bone loss, leading to a final diagnosis of mucositis, peri-implantitis or healthy mucosa. Examiners were independent and blinded to each other. RESULTS: Fleiss k-statistic with quadratic weight in the diagnosis of peri-implantitis and mucositis was 0.66 [CI95%: 0.45-0.87]. A complete agreement was obtained only in 14 cases (52%). Fleiss k-statistics in bleeding on probing and bone loss were respectively 0.31 [CI95%: 0.20-0.41] and 0.70 [CI95%: 0.45-0.94]. Intra-class correlation coefficients for recession, probing depth and keratinized tissue depth were respectively 0.69 [CI95%: 0.62-0.75], 0.54 [CI95%: 0.44-0.63] and 0.56 [CI95%: 0.27-0.77]. CONCLUSIONS: The inter-rater agreement in the diagnosis of peri-implant disease was qualified as merely good. This could also be due in part to the unclear definition of peri-implantitis and mucositis. PMID- 25041652 TI - Application to proteomics to understand and modify meat quality. AB - The use of proteomics in the field of meat science has gained in robustness and accuracy. This is consistent with the genomic and bioinformatic tools. Its application to sensorial and technological meat quality traits is discussed as well as the emergence of sanitary and nutritional issue which will grow in a next future. PMID- 25041653 TI - Red meats: time for a paradigm shift in dietary advice. AB - Recent evidence suggests dietary advice to limit red meat is unnecessarily restrictive and may have unintended health consequences. As nutrient-rich high quality protein foods, red meats can play an important role in helping people meet their essential nutrient needs. Yet dietary advice to limit red meat remains standard in many developed countries, even though red meat intakes appear to be within current guidelines. Meanwhile, energy intakes from processed foods have increased dramatically at the expense of nutrient-rich foods, such as red meat. Research suggests these food trends are associated with the growing burden of obesity and associated diseases in recent decades. It is time for dietary advice that emphasizes the value of unprocessed red meat as part of a healthy balanced diet. PMID- 25041654 TI - Improving beef color stability: practical strategies and underlying mechanisms. AB - This paper overviewed the current literature on strategies to improve beef color and attempted to logically explain the fundamental mechanisms involved. Surface color and its stability are critical traits governing the marketability of fresh beef when sold, whereas internal cooked color is utilized as an indicator for doneness at the point of consumption. A multitude of exogenous and endogenous factors interact with the redox biochemistry of myoglobin in post-mortem skeletal muscles. The scientific principles of these biomolecular interactions are applied by the meat industry as interventions for pre-harvest (i.e. diet, animal management) and post-harvest (i.e. packaging, aging, antioxidants) strategies to improve color stability in fresh and cooked beef. Current research suggests that the effects of several of these strategies are specific to type of animal, feeding regimen, packaging system, and muscle source. Meat scientists should explore novel ways to manipulate these factors using a biosystems approach to achieve improved beef color stability, satisfy consumer perception, and increase market profitability. PMID- 25041655 TI - 'Trafficking' or 'personal use': do people who regularly inject drugs understand Australian drug trafficking laws? AB - INTRODUCTION AND AIMS: Legal thresholds for drug trafficking, over which possession of an illicit drug is deemed 'trafficking' as opposed to 'personal use', are employed in all Australian states and territories excepting Queensland. In this paper, we explore the extent to which people who regularly inject drugs understand such laws. DESIGN AND METHODS: Participants from the seven affected states/territories in the 2012 Illicit Drug Reporting System (n = 823) were asked about their legal knowledge of trafficking thresholds: whether, if arrested, quantity possessed would affect legal action taken; and the quantities of heroin, methamphetamine, cocaine and cannabis that would constitute an offence of supply. Data were compared against the actual laws to identify the accuracy of knowledge by drug type and state, and sociodemographics, use and purchasing patterns related to knowledge. RESULTS: Most Illicit Drug Reporting System participants (77%) correctly said that quantity possessed would affect charge received. However, only 55.8% nominated any specific quantity that would constitute an offence of supply, and of those 22.6% nominated a wrong quantity, namely a quantity that was larger than the actual quantity for supply (this varied by state and drug). DISCUSSION AND CONCLUSIONS: People who regularly inject drugs have significant gaps in knowledge about Australian legal thresholds for drug trafficking, particularly regarding the actual threshold quantities. This suggests that there may be a need to improve education for this population. Necessity for accurate knowledge would also be lessened by better design of Australian drug trafficking laws. PMID- 25041656 TI - Contact sensitizer 2,4-dinitrochlorobenzene is a highly potent human TRPA1 agonist. AB - 2,4-Dinitrochlorobenzene (DNCB) is widely used in human clinical studies and in experimental animal studies to evoke allergic contact dermatitis. 2,4 Dinitrochlorobenzene is a potent immunogen capable of inducing contact sensitization in all humans exposed. However, the mechanism by which DNCB evokes such symptoms is presently unknown. TRPA1 is a nonselective cation channel that is expressed in peptidergic sensory neurons and fibroblasts. TRPA1 activation was recently implicated in the pathophysiology of atopic dermatitis especially in transducing cutaneous itch signals. Here, we test the hypothesis that DNCB acts as a TRPA1 agonist and thereby evokes allergic symptoms. We found that DNCB activates human TRPA1 dose dependently in FLIPR experiments with an EC50 of 167 nM, an effect that was fully blocked by selective TRPA1 antagonists Chembridge 5861528 and A-967079. Similarly, DNCB activated nonselective TRPA1 current in patch clamp studies. Neutralization of 3 critical cysteines in TRPA1 resulted in a loss of DNCB agonism. PMID- 25041657 TI - Optimization of homogenization-evaporation process for lycopene nanoemulsion production and its beverage applications. AB - Lycopene is a natural antioxidant which has several health benefits. Undesirable oxidation of lycopene compromises its health benefits and also affects the sensory quality of food products containing lycopene. Health benefits associated with lycopene in food preparations can be enhanced by preventing its degradation by incorporating it into the oil phase of an oil-in-water nanoemulsion. In this study, lycopene nanoemulsions were prepared from a low-concentration lycopene extract using an emulsification-evaporation technique. The effects of the concentrations of the lycopene extract (0.015 to 0.085 mg/mL) and emulsifier (0.3 to 0.7 mg/mL), and the number of homogenization cycles (2 to 4) on the droplet size, emulsification efficiency (EE), and nanoemulsion stability were investigated and optimized by statistical analysis using a Box-Behnken design. Regression analysis was used to determine the 2nd-order polynomial model relationship of independent and dependent variables, with multiple regression coefficients (R(2)) of 0.924, 0.933, and 0.872, for the droplet size, EE, and nanoemulsion stability, respectively. Analysis of variance showed that the lycopene extract concentration has the most significant effect on all the response variables. Response surface methodology predicted that a formulation containing 0.085 mg/mL of lycopene extract and 0.7 mg/mL of emulsifier, subjected to 3 homogenization cycles, is optimal for achieving the smallest droplet size, greatest emulsion stability, and acceptable EE. The observed responses were in agreement with the predicted values of the optimized formulation. This study provided important information about the statistical design of lycopene nanoemulsion preparation. PMID- 25041658 TI - The importance of planetary rotation period for ocean heat transport. AB - The climate and, hence, potential habitability of a planet crucially depends on how its atmospheric and ocean circulation transports heat from warmer to cooler regions. However, previous studies of planetary climate have concentrated on modeling the dynamics of atmospheres, while dramatically simplifying the treatment of oceans, which neglects or misrepresents the effect of the ocean in the total heat transport. Even the majority of studies with a dynamic ocean have used a simple so-called aquaplanet that has no continental barriers, which is a configuration that dramatically changes the ocean dynamics. Here, the significance of the response of poleward ocean heat transport to planetary rotation period is shown with a simple meridional barrier--the simplest representation of any continental configuration. The poleward ocean heat transport increases significantly as the planetary rotation period is increased. The peak heat transport more than doubles when the rotation period is increased by a factor of ten. There are also significant changes to ocean temperature at depth, with implications for the carbon cycle. There is strong agreement between the model results and a scale analysis of the governing equations. This result highlights the importance of both planetary rotation period and the ocean circulation when considering planetary habitability. PMID- 25041659 TI - Immunohistochemical study on localization of serotonin immunoreactive cells in the gastrointestinal tract of the European catfish (Silurus glanis, L.). AB - In this study, it was aimed to identify the distribution of serotonin immunoreactive cells within the gastrointestinal tract (GIT) of European catfish (Silurus glanis). For this purpose, the tissue samples were taken from the stomach (cardia, fundus and pylorus region) and intestine (anterior, middle and posterior region). They were examined by applying the avidin-biotin immunoperoxidase method. The serotonin containing immunoreactive cells are presented in all regions of the GIT. It was determined to be localized generally in different distribution within the stomachs and intestines of S. glanis. It was found that the most intensive regions of immunoreactive cells were the cardia stomach and posterior of intestine. PMID- 25041660 TI - Pulmonary function following allogeneic stem cell transplantation in childhood: a retrospective cohort study of 51 patients. AB - HSCT is associated with a high risk of late morbidity. The aim of this study was to evaluate the frequency, time frame, risk factors, and possible etiology of pulmonary dysfunction following allogeneic HSCT in childhood. We evaluated the pulmonary function of 51 HSCT patients (>6 yr), by including FVC and FEV1 values prior to (baseline) and annually up to five yr after HSCT. A Cox proportional hazards model was used to analyze the risk factors for a pulmonary event. Over half (59%) of the patients developed pulmonary dysfunction, mainly consisting of restrictive abnormalities. Acute GvHD (HR 4.31, 95% CI 1.47-12.63), chronic GvHD (HR 10.20, 95% CI 2.42-43.03), and an abnormal baseline pulmonary function (HR 4.82, 95% CI 1.02-22.84) were associated with post-transplant dysfunction. FEV1 (p < 0.001) and FVC (p < 0.001) declined significantly by 12 months after HSCT and both remained below the pre-HSCT level at up to four yr post-transplantation. HSCT in childhood is associated with early and persistent restrictive impairment of pulmonary function. Patients with extensive chronic GvHD are particularly vulnerable to severe pulmonary dysfunction. Scheduled pulmonary function testing is warranted as part of the follow-up of survivors of HSCT in childhood. PMID- 25041661 TI - Art in clinical teaching. PMID- 25041662 TI - Art-mediated peer-to-peer learning of empathy. AB - BACKGROUND: Making experiential art in a clinical clerkship offers opportunities for students to gain self-awareness and enhance their empathic understanding of patients. The student-created art can be further used as teaching material for other students. CONTEXT: The graduating class of 2012 from Ajou University School of Medicine in South Korea was interested in learning about medical humanities initiatives at the Li Ka Shing Faculty of Medicine, University of Hong Kong (HKU), and made an educational visit in May 2012. INNOVATION: As part of the core family medicine curriculum, third-year HKU medical students created poetry and art based on their experiences witnessing patients in pain and suffering. Twenty of the artworks and accompanying reflective writing were chosen for an exhibition. The visiting students viewed the exhibit and created their own art based on their emotional response to one piece selected from the exhibit. IMPLICATIONS: The combination of viewing art made by their peers and creating art in response resulted in empathic understanding of patient pain and suffering, and an appreciation of holistic care and the value of the doctor-patient relationship. Medical student-generated artwork has the potential to educate both students and professionals on humanistic aspects of medical care. PMID- 25041663 TI - The One Minute Wonder Network. AB - BACKGROUND: The European Working Time Directive has had a well-documented impact on training, and therefore educational opportunities should be maximised. The clinical day has frequent short, routine pauses that could allow for brief bites of medical education. The One Minute Wonder Network was developed to take advantage of these pauses, and has created an additional educational opportunity within the normal working day. INNOVATION: One Minute Wonders (OMW) are focused educational displays that contain information that can be read and absorbed in just 1 minute. They are displayed on boards located where teams regularly briefly wait and experience dead time. The board topics change weekly and feature clinical topics related to the department. Written displays are shared between board hosts through the project website, enabling many departments to freely benefit from each OMW and the educational resource. IMPLICATIONS: The network of OMW boards has expanded across several specialties in addition to emergency medicine, and has been welcomed by trainees. There is now a large archive of OMWs available to share. CONCLUSION: One Minute Wonder boards are a novel opportunity for the education and training of an entire multidisciplinary team. PMID- 25041664 TI - Remember how it feels to be a student? AB - BACKGROUND: Students' education in their clinical placements is often supervised by practising clinicians. Most health care professional programmes provide workshops and short courses to train clinicians for supervising student learning. CONTEXT: Although clinical educators are often expert clinicians with extensive years of clinical experience, they are not necessarily expert educators. The lack of educational experience can lead to clinical educators having difficulty relating to the student experience, and subsequent difficulty in planning a meaningful and effective learning experience. INNOVATION: We incorporated Kolb's model of experiential learning into the curriculum of a workshop that is regularly offered by the local university for training physical therapy educators. Using this model, participants had to feel and think like a student by putting themselves in a student's role. Over 3 years (2009-2011), 302 participants attended the workshop. Participants were asked to fill out a survey after the workshop to evaluate the incorporation of Kolb's model into the curriculum. After the workshop, participants reported a high level of satisfaction with the workshop (9.2/10), as well as a 50 per cent increase in their readiness and comfort in planning and supervising student learning. IMPLICATIONS: Kolb's model is a highly adaptable model that can be used effectively in the training of clinical educators. The experiential approach of this model enables educators to understand 'how it feels to be a student' and carry that understanding forward into planning learning experiences for their own students. PMID- 25041665 TI - Pedagogical and professional compromises by medical teachers in hospitals. AB - AIM: Following research about workplace constraints reducing the effectiveness of teaching and the motivation to teach, this study sought to understand how medical teachers in hospitals respond to the institutional context for their teaching of medical students. METHODS: Through purposive sampling, younger and older male and female teachers in a range of medical and surgical paediatrics subspecialties participated in this qualitative study. We drew on ethnographic methods in interviews so that answers to the questions came from the teachers' own emphases. The systematic coding and categorising procedures used in the inductive analysis of the interview transcripts reflect the constant comparison approach of grounded theory, locating features, patterns and conceptual categories. RESULTS: We identified four main concepts: teachers' goals and motivations; their approaches to teaching; teachers' preferences; and, finally, as discussed in this article, the teachers' perceptions of contextual and institutional pressures in hospital based medical teaching and related compromises. The teachers perceive constraints resulting from the various mismatches that they experience, a loss of autonomy, and the paucity of acknowledgement and resources. They suggest that the compromises they make in response are both pedagogical and institutional. CONCLUSION: We conclude that professional development is not enough to address these issues: the conditions for medical teaching and teachers in hospitals require workplace responses to enable a more productive connection between the students, curriculum and pedagogy. In particular, teachers' responsibilities in teaching and curriculum development need to be acknowledged, and practising teachers need to be supported and included in the education mission. PMID- 25041667 TI - Leadership training for registrars on ward rounds. AB - BACKGROUND: The post-take ward round (PTWR) provides formal consultant review of acutely unwell patients admitted to hospital, yet specialist medical registrars, the consultants of tomorrow, receive little to no formal training in this area. There is an expectation that 'on the job' experience will provide sufficient preparation for this important aspect of clinical leadership. METHODS: We aimed to seek the opinions of medical registrars on the use of a structured considerative checklist and learning-by-example approach in PTWR leadership training, assessing whether this model influences current and future practice. This was studied through a questionnaire-based survey of medical registrars working in Worthing Hospital from 2009 to 2011. RESULTS: Eighteen of 25 registrars (72%) across a range of specialties returned questionnaires. Although a third of respondents had spent time considering how they conduct ward rounds, none had received formal training, with most feeling that ward round skills were acquired 'on the job' from observation and experience of those conducted by senior colleagues. Exposure to the considerative checklist changed thinking in 94 per cent and changed practice in 88 per cent. Common positive themes included enhanced pre-ward round preparation, the importance of inclusion and communication, and the need for structure (facilitated by physical or mental checklist). Seventeen of 18 participants felt that this training would influence their consultant practice. DISCUSSION: Trainees respond positively to participation in a structured PTWR using a considerative checklist as a model of good practice, leading to changes in their current and future practice, and could be considered as a training tool. PMID- 25041666 TI - A mentorship programme for final-year students. AB - BACKGROUND: Current mentorship programmes in the UK tend to focus predominantly on junior medical students; however, final-year medical students may encounter significant academic and personal pressures. We established a mentoring scheme to provide individualised support for final-year students from a junior doctor mentor. The objectives of this study were to assess the benefits of the scheme and identify areas for future improvement. METHODS: Final-year students at Great Western Hospital in Swindon (n = 34) were allocated a junior doctor mentor at the start of their attachment. At the end of the 3-month placement, students and mentors provided feedback on their experiences of the mentoring scheme. In total, 24 students and eight doctors returned completed questionnaires. Qualitative analyses were performed using the constant comparison method, and descriptive statistical analyses were performed on the numerical data. RESULTS: Key benefits for students were improved confidence, academic support, increased enjoyment and sense of belonging during their final year. Mentors valued the opportunity to gain teaching experience. All doctors and 96 per cent of students would recommend the scheme to a friend. Possible improvements include an introductory lecture alongside the handbook and a bank of 'reserve' mentors to stand-in when a mentor is away. DISCUSSION: The mentorship programme was a valuable addition to the final-year experience, with benefits for students and mentors alike. We will be continuing this programme in the future, and would recommend the adoption of mentorship schemes for other final-year cohorts. PMID- 25041668 TI - Reflection and feedback in ambulatory education. AB - BACKGROUND: It has been argued that the best method of acquiring clinical reasoning is through seeing new out-patients. The purpose of this interventional study was to establish a clinical clerkship course for Japanese medical students in an out-patient care setting, with multiple opportunities for reflective practice and improving the clinical reasoning abilities of the students. The effectiveness of the course was also examined. METHODS: Students performed examinations of new patients and made diagnostic decisions in 20 minutes. They presented their case using the SNAPPS (Summarize the case, Narrow the differential, Analyze the differential, Probe the preceptor, Plan management, and Select an issue for self directed learning) method, and this was followed by feedback from faculty members using the 1-minute preceptor method and a mini clinical evaluation exercise (mini-CEX). Students' clinical reasoning abilities were assessed by the objective structured clinical examination (OSCE) and the script concordance test (SCT). Students' written comments and responses to an interview about the course were also analysed. Cross-sectional data were examined by comparing individual OSCE and SCT scores, and the multiple-choice question examination (MCQ) completed by students who did and did not participate in this project. RESULTS: Students in the programme had higher scores on the mini-CEX in all areas. The SCT and OSCE scores were also significantly higher than the scores for the control group. Students' comments about the course, which provided an opportunity for daily reflection, were positive. DISCUSSION: Students rapidly acquired clinical reasoning skills through reflective practice. Students also demonstrated motivation to learn through the examination of new patients. The clinical clerkship programme with multiple opportunities for reflective practice in an out-patient care setting substantially improved the clinical reasoning abilities of medical students. PMID- 25041669 TI - Teaching final-year medical students in a paediatric ambulatory care unit. AB - BACKGROUND: The importance of community-based ambulatory experiences for medical students has been emphasised in the past few decades. Although such teaching programmes are assumed to be better for medical students, there is little evidence comparing the out-patient and in-patient experiences in student education. OBJECTIVE: We carried out a study to compare the educational experiences between two in-patient and out-patient clinical units. METHODS: Over a 12-week paediatric clerkship, 38 senior medical students attending the paediatric ward were divided into two groups. One group attended a 15-day paediatric out-patient clinic while the other group attended the in-patient programme. RESULTS: Those who took part in the out-patient clinic programme obtained better scores in a test on common paediatric ambulatory problems when compared with the students who exclusively attended the in-patient teaching programme. The former group all agreed that this ambulatory paediatric course was a beneficial learning experience and consistent with their future career needs. PMID- 25041670 TI - Minimal supervision out-patient clinical teaching. AB - BACKGROUND: Minimal faculty member supervision of students refers to a method of instruction in which the patient-student encounter is not directly supervised by a faculty member, and presents a feasible solution in clinical teaching. It is unclear, however, how such practices are perceived by patients and how they affect student learning. CONTEXT: We aimed to assess patient and medical student perceptions of clinical teaching with minimal faculty member supervision. Questionnaires focusing on the perception of students' performance were administered to patients pre- and post-consultation. Students' self-perceptions on their performance were obtained using a questionnaire at the end of the consultation. INNOVATION: Before encounters with students, 22 per cent of the 95 patients were not sure if they would feel comfortable or trust the students; after the consultation, almost all felt comfortable (97%) and relied on the students (99%). The 81 students surveyed agreed that instruction with minimal faculty member supervision encouraged their participation and engagement (86%). They expressed interest in knowing patients' opinions about their performance (94%), and they felt comfortable about being assessed by the patients (86%). IMPLICATIONS: The minimal faculty member supervision model was well accepted by patients. Responses from the final-year students support the use of assessments that incorporate feedback from patients in their overall clinical evaluations. PMID- 25041671 TI - Clinical supervisors and cultural competence. AB - OBJECTIVE: To investigate how clinical supervisors of junior doctors provide feedback and assessment on cultural competence, one of several professionalism skills outlined in the Australian Curriculum Framework for Junior Doctors. METHODS: Twenty clinical supervisors were recruited to a qualitative study in a regional hospital in Queensland, Australia. Data from semi-structured interviews (June-August 2011) were thematically analysed. RESULTS: Interviews revealed that cultural competence was interpreted by the supervising clinicians as a vague concept, and that junior doctors were not assessed in this area. Additional themes related to the cultural competence of junior doctors, as reported by their supervisors, included: limited direct supervision of, and feedback to, junior doctors; variations in approaches to assessment; clinicians' communication focuses on clinical aspects of disease process; perceived lack of cultural diversity among staff and patients; acceptance of laypersons as English interpreters; language barriers with international medical graduates; and patients' low levels of health literacy. CONCLUSION: Supervisors were unable to define cultural competence in ways that enable them to apply the concept to clinical training for junior doctors. Specific training in cultural competence, and guidelines for its assessment, is therefore recommended for clinical supervisors and junior doctors to improve their approaches to patient care and health outcomes. PMID- 25041672 TI - Assessing non-technical skills on the delivery suite: a pilot study. AB - BACKGROUND: The importance of non-technical skills (NTS) is a growing area for training and assessment in medicine. Currently there is little formal assessment of these skills in obstetrics and gynaecology. CONTEXT: Non-technical Skills for Surgeons (NOTSS) is perhaps the most psychometrically robust tool for assessing individual NTS in the surgical environment. It has previously been evaluated in our specialty alongside objective structured assessments of technical skills, with promising results. INNOVATION: By removing rankings, NOTSS was adapted for use as a formative feedback tool. This article describes the subsequent Royal College of Obstetricians and Gynaecologists (RCOG) usability pilot of the adapted version of NOTSS in the real delivery suite environment using minimally trained assessors. Twenty-six trainee evaluations and 25 trainer evaluations were completed after 55 assessments. IMPLICATIONS: The number of assessments and evaluations completed was disappointing. However, NOTSS appears promising as a formative NTS assessment tool for use on the delivery suite. Overall satisfaction with NOTSS was high (an average score of 4.5 on a scale of 1-5 for trainers and trainees). Both trainers and trainees consider that it is accep and straightforward to deliver, and that the form takes an average of 10 minutes to complete, including time for feedback (range 5-20 min). There will be considerable challenges to achieving the successful implementation of the NOTSS tool, and its inclusion in the RCOG training matrix: primarily, in training those using it to recognise the behaviours under observation and to give feedback appropriately, and also engaging trainees, although they obviously appreciated the NOTSS process when used. PMID- 25041673 TI - Electronic management of practice assessment data. AB - BACKGROUND: The assessment of a practising physician's performance may be conducted for various reasons, including licensure. In response to a request from the College of Physicians and Surgeons of Manitoba (CPSM), the Division of Continuing Professional Development in the Faculty of Medicine, University of Manitoba, has established a practice-based assessment programme - the Manitoba Practice Assessment Program (MPAP) - as the College needed a method to evaluate the competence and performance of physicians on the conditional register. CONTEXT: Using a multifaceted approach and CanMEDS as a guiding framework, a variety of practice-based assessment surveys and tools were developed and piloted. Because of the challenge of collating data, the MPAP team needed a computerised solution to manage the data and assessment process. INNOVATION: Over a 2-year period, a customised web-based forms and information management system was designed, developed, tested and implemented. The secure and robust system allows the MPAP team to create assessment surveys and tools in which each item is mapped to Canadian Medical Education Directives for Specialists (CanMEDS) roles and competencies. Reports can be auto-generated, summarising a physician's performance on specific competencies and roles. Overall, the system allows the MPAP team to effectively manage all aspects of the assessment programme. IMPLICATIONS: Throughout all stages of design to implementation, a variety of lessons were learned that can be shared with those considering building their own customised web-based system. The key to success is active involvement in all stages of the process! PMID- 25041674 TI - Simulation training for geriatric medicine. AB - BACKGROUND: Geriatric medicine encompasses a diverse nature of medical, social and ethical challenges, and requires a multidimensional, interdisciplinary approach. Recent reports have highlighted failings in the care of the elderly, and it is therefore vital that specialist trainees in geriatric medicine are afforded opportunities to develop their skills in managing this complex patient population. Simulation has been widely adopted as a teaching tool in medicine; however, its use in geriatric medicine to date has involved primarily role-play or discrete clinical skills training. This article outlines the development of a bespoke, multimodal, simulation course for specialist trainees in geriatric medicine. METHODS: A 1-day multimodal and interprofessional simulation course was created specifically for specialist trainees in geriatric medicine, using six curriculum-mapped scenarios in which the patient perspective was central to the teaching objectives. Various simulation techniques were used, including high fidelity human patient manikins, patient actors, with integrated clinical skills using part-task trainers, and role-play exercises. Debriefs by trained faculty members were completed after each scenario. RESULTS: Twenty-six candidates attended four similar courses in 2012. Quantitative analysis of pre- and post course questionnaires revealed an improvement of self-reported confidence in managing geriatric scenarios (Z = 4.1; p < 0.001), and thematic analysis of candidate feedback was supportive of simulation as a useful teaching tool, with reported benefits for both technical and non-technical skills. DISCUSSION: Simulation is an exciting and novel method of delivering teaching for specialist trainees in geriatric medicine. This teaching modality could be integrated into the training curriculum for geriatric medicine, to allow a wider application. PMID- 25041675 TI - The other side of the hospital bed. PMID- 25041676 TI - Starved of teaching in the Emergency Department: inspiration for change. PMID- 25041677 TI - Cutting edge: teaching future surgeons. PMID- 25041678 TI - Vulnerability and the beginner's mind. PMID- 25041680 TI - Medical athletes and musicians: their perspectives on feedback. PMID- 25041681 TI - What do medical students value in their classroom teachers? PMID- 25041683 TI - Attitudes towards workplace-based assessments. PMID- 25041684 TI - Response: maximising the learning afforded by supervised learning events. PMID- 25041685 TI - Prescribing under pressure. PMID- 25041686 TI - Intravenous sufentanil-midazolam versus sevoflurane anaesthesia in medetomidine pre-medicated Himalayan rabbits undergoing ovariohysterectomy. AB - OBJECTIVE: To compare physiological effects of sufentanil-midazolam with sevoflurane for surgical anaesthesia in medetomidine premedicated rabbits. STUDY DESIGN: Prospective, randomized controlled experimental study. ANIMALS: Eighteen female Himalayan rabbits, weight 2.1 +/- 0.1 kg. METHODS: Premedication with 0.1 mg kg(-1) medetomidine and 5 mg kg(-1) carprofen subcutaneously, was followed by intravenous anaesthetic induction with sufentanil (2.3 MUg mL(-1)) and midazolam (0.45 mg mL(-1)). After endotracheal intubation, anaesthesia was maintained with sufentanil-midazolam (n = 9) or sevoflurane (n = 9). Ovariohysterectomy was performed. Intermittent positive pressure ventilation was performed as required. Physiological variables were studied perioperatively. Group means of physiologic data were generated for different anaesthetic periods. Data were compared for changes from sedation, and between groups by anova. Post-operatively, 0.05 mg kg( 1) buprenorphine was administered once and 5 mg kg(-1) carprofen once daily for 2 3 days. Rabbits were examined and weighed daily until one week after surgery. RESULTS: Smooth induction of anaesthesia was achieved within 5 minutes. Sufentanil and midazolam doses were 0.5 MUg kg(-1) and 0.1 mg kg(-1), during induction and 3.9 MUg kg(-1) hour(-1) and 0.8 mg kg(-1) hour(-1) during surgery, respectively. End-tidal sevoflurane concentration was 2.1% during surgery. Assisted ventilation was required in nine rabbits receiving sufentanil-midazolam and four receiving sevoflurane. There were no differences between groups in physiologic data other than arterial carbon dioxide. In rabbits receiving sevoflurane, mean arterial pressure decreased pre-surgical intervention, heart rate increased 25% during and after surgery and body weight decreased 4% post operatively. Post-operative problems sometimes resulted from catheterization of the ear artery. CONCLUSION: Sevoflurane and sufentanil-midazolam provided surgical anaesthesia of similar quality. Arterial blood pressure was sustained during sufentanil-midazolam anaesthesia and rabbits receiving sevoflurane lost body weight following ovariohysterectomy. Mechanical ventilation was required with both anaesthetic regimens. CLINICAL RELEVANCE: Anaesthesia with sufentanil midazolam in medetomidine premedicated healthy rabbits is useful in the clinical and the research setting, as an alternative to sevoflurane. PMID- 25041687 TI - Parieto-motor cortical dysfunction in primary cervical dystonia. AB - BACKGROUND: Dystonia is considered as a motor network disorder involving the dysfunction of the posterior parietal cortex, a region involved in preparing and executing reaching movements. OBJECTIVE/HYPOTHESIS: We used transcranial magnetic stimulation to test the hypothesis that cervical dystonic patients may have a disrupted parieto-motor connectivity. METHODS: We enrolled 14 patients with primary cervical dystonia and 14 controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right posterior parietal cortex and the right primary motor area. Changes in the amplitudes of motor evoked potential were analyzed as an index of parieto-motor effective connectivity. Patients and healthy subjects were also evaluated with a reaching task. Reaction and movement times were measured. RESULTS: In healthy subjects, but not in dystonic patients, there was a facilitation of motor evoked potential amplitudes when the conditioning parietal stimulus preceded the test stimulus applied over the primary motor area by 4 ms. Reaction and movement times were significantly slower in patients than in controls. In dystonic patients, the relative strength of parieto-motor connectivity correlated with movement times. CONCLUSIONS: Parieto motor cortical connectivity is impaired in cervical dystonic patients. This neurophysiological trait is associated with slower reaching movements. PMID- 25041688 TI - Recent cocaine use is a significant risk factor for sudden cardiovascular death in 15-49-year-old subjects: a forensic case-control study. AB - AIMS: The aims of the present study were to: (i) evaluate the prevalence of recent cocaine use in adolescents and young adults who had died by sudden cardiovascular death (SCVD); (ii) assess if recent cocaine use was associated with an increased risk of SCVD; and (iii) determine the demographic, clinical pathological and toxicological characteristics of SCVD related to recent cocaine use. DESIGN: This was a case-control autopsy-based observational retrospective study. SETTING/CASES: Cases were all SCVD in individuals aged between 15 and 49 years during the period ranging from 1 January 2003 to 31 December 2009, with autopsies performed in Biscay, Spain. Medico-legal sudden deaths not due to cardiovascular diseases (SnoCVD) were used as the control group. In all deaths a complete autopsy and toxicological and histopathological studies were carried out. Recent cocaine use was considered when cocaine and/or benzoylecgonine were detected in blood. MEASUREMENTS: The risk for SCVD according to demographic variables (sex and age), cardiovascular risk factors (obesity, hypertension, diabetes and smoking) and toxicological variables (opioids, benzodiazepines, amphetamines, cannabis and alcohol) was analysed using three logistic regression models. We also estimated the prevalence of recent cocaine use in the general population aged 15-49 years based on the projection of population surveys. FINDINGS: Recent cocaine use was significantly higher in the SCVD group (27 of 311 subjects, 9%) than in the SnoCVD group (three of 126 subjects, 2%). In a full logistic regression controlling for all recorded covariates, the main risk factor for SCVD was recent cocaine use (odds ratio 4.10; 95% confidence interval 1.12 15.0). Compared with the estimated data in the general population, the prevalence of recent cocaine use was 13-58 times higher in people with SCVD. CONCLUSIONS: Recent cocaine use is associated significantly with an increased risk for sudden cardiovascular death in people aged 15-49 years. PMID- 25041689 TI - Lichen scrofulosorum caused by Mycobacterium leprae: first report. AB - BACKGROUND: Tuberculides are skin lesions caused by the hematogeneous dissemination of Mycobacterium tuberculosis. Bacilli are rapidly destroyed in the skin and are thus neither visible histologically nor identifiable by culture. Diagnosis depends on previous knowledge of systemic and/or cutaneous tuberculosis. Lichen scrofulosorum (LS), the most uncommon variant of tuberculid, is usually associated with M. tuberculosis infection of lymph nodes or bone but was also reported in association with other mycobacterioses. OBJECTIVES: We report a case of LS in a patient with M. leprae infection. METHODS: In 2008, a 51 year-old woman from the Philippines was diagnosed with tuberculoid leprosy and treated. In 2010 the leprosy was considered to have been cured, and treatment was stopped. In 2011 the patient presented with lesions on the trunk and legs. Biopsy specimens were obtained for histopathologic examination and DNA detection for polymerase chain reaction (PCR). RESULTS: Histopathology in the biopsy from the trunk revealed the dermis to be diffusely occupied by granulomas with perineural and periadnexal disposition. Granulomas were composed of epithelioid cells and lymphocytes. Fite-Faraco staining revealed a few solid acid-fast bacilli within nerve fascicles. Reinfection or the re-reactivation of multibacillary borderline tuberculoid leprosy was diagnosed. Histopathology in the biopsy taken from the leg showed superficial, well-formed granulomas in the vicinity of hair follicles and sweat ducts. No acid-fast bacilli were seen. Analysis by PCR revealed M. leprae DNA in specimens from both the leg and trunk. The clinical features of the papular eruption and the histopathologic findings and concomitant mycobacterial infection with M. leprae led to a diagnosis of LS. Treatment was commenced with dapsone 100 mg/day, clofazimine 50 mg/day and 300 mg/month, and rifampicin 600 mg/day. The lichenoid eruption on the legs disappeared at one month of therapy, whereas the other skin lesions resolved in one year leaving residual hypochromic macules. CONCLUSIONS: Infection with M. leprae may cause LS. The use of PCR in skin biopsies from granulomatous dermatitis of unknown origin can help to identify the responsible agents. PMID- 25041690 TI - Helicobacter pylori vacuolating cytotoxin induces apoptosis via activation of endoplasmic reticulum stress in dendritic cells. AB - BACKGROUND AND AIM: Dendritic cells (DCs) are observed on the Helicobacter pylori infected gastric mucosa. DCs generally play an important role in the regulation of inflammation. Although stimulation of gastric epithelial cells with H. pylori vacuolating cytotoxin (VacA) has been reported to induce apoptosis and endoplasmic reticulum (ER) stress, the effects of VacA on the DC apoptotic response have not been well elucidated. This study was conducted to investigate the role of H. pylori VacA on the apoptotic process and ER stress in DCs. METHODS: Murine and human DCs were generated from specific pathogen-free C57BL/6 mice and human peripheral blood mononuclear cells, respectively. DCs were incubated with purified VacA, after which Bax activation, cytochrome c release, and DNA fragmentation for apoptosis were measured by fluorescent microscopy, immunoblot, and ELISA. ER stress-related molecules such as GRP78 and CHOP were analyzed by immunoblot. RESULTS: Treatment of DCs with purified H. pylori VacA resulted in the induction of apoptosis. DC stimulation with VacA led to the translocation of cytoplasmic Bax to mitochondria and cytochrome c release from mitochondria. H. pylori VacA induced signals for ER stress early during the stimulation process in DCs. Furthermore, suppression of ER stress resulted in a significant inhibition of the VacA-induced apoptosis in DCs. CONCLUSION: These results suggest that ER stress is critical for regulation of DC apoptotic process in response to VacA stimulation. PMID- 25041691 TI - Costs and benefits of pneumatic collection in three specific New York City cases. AB - Truck-based collection of municipal solid waste imposes significant negative externalities on cities and constrains the efficiency of separate collection of recyclables and organics and of unit-price-based waste-reduction systems. In recent decades, hundreds of municipal-scale pneumatic collection systems have been installed in Europe and Asia. Relatively few prior studies have compared the economic or environmental impacts of these systems to those of truck collection. A critical factor to consider when making this comparison is the extent to which the findings reflect the specific geographic, demographic, and operational characteristics of the systems considered. This paper is based on three case studies that consider the specific characteristics of three locations, comparing pneumatic systems with conventional collection on the basis of actual waste tonnages, composition, sources, collection routes, truck trips, and facility locations. In one case, alternative upgrades to an existing pneumatic system are compared to a potential truck-collection operation. In the other cases, existing truck operations are compared to proposed pneumatic systems which, to reduce capital costs, would be installed without new trenching or tunneling through the use of existing linear infrastructure. For the two proposed retrofit pneumatic systems, up to 48,000 truck kilometers travelled would be avoided and energy use would be reduced by up to 60% at an incremental cost of up to $400,000 USD per year over the total operating-plus-capital cost of conventional collection. In the location where a greenfield pneumatic system is already in operation, truck collection would be both less expensive and more energy-efficient than pneumatic collection. The results demonstrate that local geographic, demographic, and operational conditions play a decisive role in determining whether pneumatic collection will reduce energy requirements, produce more or fewer greenhouse gas emissions, and cost more or less over the long-term. These findings point to the local factors that will determine the relative economic and environmental costs and benefits in specific situations. PMID- 25041692 TI - Impact of donor age on survival after heart transplantation: an analysis of the United Network for Organ Sharing (UNOS) registry. AB - BACKGROUND: Data are limited regarding the influence of donor age on outcomes after heart transplantation. We sought to determine if advanced donor age is associated with differences in survival after heart transplantation and how this compares to waitlist survival. METHODS: All adult heart transplants from 2000 to 2012 were identified using the United Network for Organ Sharing database. Donors were stratified into four age groups: 18-39 (reference group), 40-49, 50-54, and 55 and above. Propensity scoring was used to compare status IA waitlist patients who did not undergo transplantation with IA recipients who received hearts from advanced age donors. The primary outcome of interest was recipient survival and this was analyzed with multivariate Cox regression analysis and the Kaplan-Meier method. RESULTS: A total of 22,960 adult heart transplant recipients were identified. Recipients of hearts from all three older donor groups had significantly increased risk of mortality (HR, 1.187-1.426, all p < 0.001) compared to recipients from donors age 18 to 39. Additionally, propensity-matched status IA patients managed medically without transplantation had significantly worse adjusted survival than status IA recipients who received hearts from older donors age >=55 (HR, 1.362, p < 0.001). CONCLUSIONS: Compared to donors aged 18 39, age 40 and above is associated with worse adjusted recipient survival in heart transplantation. This survival difference becomes more pronounced as age increases to above 55. However, the survival rate among status IA patients who receive hearts from advanced age donors (>=55) is significantly better compared to similar status IA patients who are managed without transplantation. PMID- 25041693 TI - Determination and validation of volume to be instilled for standardized intra abdominal pressure measurement in dogs. AB - OBJECTIVES: The objectives of this study were to determine (1) most appropriate volume of saline to be infused into the bladder prior to intra-abdominal pressure (IAP) measurement, (2) to determine if a difference exists between IAP measurements before and after abdominal surgery, and (3) to assess the variability in IAP measurements associated with different saline volumes. DESIGN: Prospective study. SETTING: University teaching hospital. ANIMALS: Fifteen female research dogs, 7 undergoing ovariohysterectomy (OHE), and 8 undergoing laparoscopy. INTERVENTIONS: All dogs had urinary catheters placed and 4 consecutive IAP measurements measured using a different volume of instilled saline (0.25, 0.5, 1, and 2 mL/kg) at baseline. Measurements were repeated intraoperatively in laparoscopy dogs and postoperatively in OHE dogs. MEASUREMENTS AND MAIN RESULTS: For both groups of dogs, the volume infused into the bladder significantly affected IAP measurement. An instilled volume of 1 mL/kg of saline produced the best correlation (R(2) = 0.44, P = 0.04) between IAP measurement and laparoscopic insufflator pressure. The mean (+/-SD) preoperative IAP (cmH2 O) using 1 mL/kg instilled saline was 7.9 +/- 1.4 and 9.6 +/-1.9 for laparoscopy and OHE dogs, respectively. There was no difference in IAP before and after surgery in the dogs undergoing an OHE (P = 0.58). The volume of saline instilled into the bladder significantly affected the IAP (P = 0.0028). CONCLUSIONS: One milliliter per kilogram instilled saline is recommended for standardized IAP pressure measurement in dogs. IAP in clinically normal dogs was not affected by abdominal surgery. PMID- 25041694 TI - The paradox of bardoxolone methyl: a call for every witness on the stand? AB - People with type 2 diabetes and chronic kidney disease (CKD) remain an extremely vulnerable population with increased cardiovascular morbidity, mortality and mounting societal costs. As such, any effort to improve their dismal outcome is heavily supported. Yet, most drugs fail to replicate the promising signals of early experiments in humans in large and methodologically sound trials. As a recent example, an independent data and safety committee advised the termination of a phase 3 trial due to excessive cardiovascular disease and especially heart failure in patients allocated to the antioxidant synthetic triterpenoid bardoxolone methyl versus placebo. We evaluate the reasons why this outcome in hindsight was possibly not totally unexpected and develop a mechanistic model that shows that the consistent drop in serum magnesium concentration in patients exposed to bardoxolone methyl might have contributed to the development of heart failure. As such, this trial, despite its negative outcome, might provide additional pieces of the puzzle enabling us to get a better grip on diseases that share increased inflammation and oxidative stress, such as type 2 diabetes, metabolic syndrome, heart failure and CKD. PMID- 25041695 TI - Experiences obtaining insurance after live kidney donation. AB - The impact of kidney donation on the ability to change or initiate health or life insurance following donation is unknown. To quantify this risk, we surveyed 1046 individuals who donated a kidney at our center between 1970 and 2011. Participants were asked whether they changed or initiated health or life insurance after donation, and if they had any difficulty doing so. Among 395 donors who changed or initiated health insurance after donation, 27 (7%) reported difficulty; among those who reported difficulty, 15 were denied altogether, 12 were charged a higher premium and 8 were told they had a preexisting condition because they were kidney donors. Among 186 donors who changed or initiated life insurance after donation, 46 (25%) reported difficulty; among those who reported difficulty, 23 were denied altogether, 27 were charged a higher premium and 17 were told they had a preexisting condition because they were kidney donors. In this single-center study, a high proportion of kidney donors reported difficulty changing or initiating insurance, particularly life insurance. These practices by insurers create unnecessary burden and stress for those choosing to donate and could negatively impact the likelihood of live kidney donation among those considering donation. PMID- 25041696 TI - Ophthalmological findings in 10-year-old full-term children--a population-based study. AB - PURPOSE: To determine different ophthalmological parameters in 10-year-old, healthy, full-term children in Stockholm County, Sweden. METHODS: Two hundred and seventeen children were included in the study. Best-corrected distance and near visual acuities (VA) were measured using logMAR charts. Cycloplegic retinoscopy was performed, and spherical equivalent and astigmatism were determined. Examination of ocular movement and cover test for distance and near were performed. Stereopsis was assessed with the TNO test, and contrast sensitivity with the Vistech test. The Royal Air Force rule was used for assessing accommodation, and near point of convergence was measured with the Lang fixation stick. Ophthalmoscopy was performed through dilated pupils. RESULTS: Eighty-two per cent of the children had a distance VA of -0.1 logMAR (1.3 Snellen acuity) or better. None of the children were visually impaired [VA>0.6 logMAR (<0.3 Snellen acuity)]. Ninety-three per cent had a near VA of -0.1 logMAR (1.25 Snellen acuity) or better. Mean spherical equivalent was 0.6 D. Eight (3.6%) children had hypermetropia (>=+2 D), and 17 (7.8%) were myopic (<=-0.5 D). Nine (4.1%) children had an astigmatism>=1 D, and two (0.9%) had anisometropia of >=1 D. Manifest strabismus was found in seven (3.2%) children, five of whom had exotropia. Heterophoria for distance and/or near was found in 80.2% of the children. In children without manifest strabismus, stereopsis>60 seconds of arc was found in five (2.4%). Three (1.4%) of 215 children had contrast sensitivity below normal limits. Binocular median near point of accommodation was 14 D, and median near point of convergence 6 cm. CONCLUSION: Knowledge of various visual functions in normally developing children is crucial to be able to draw conclusions from ophthalmological examinations in children with eye diseases. This population-based study describes different ophthalmological parameters in full-term ten-year-old children. The material can be used as a control when examining children of similar ages with various ophthalmological conditions, such as groups of children with specific neurological or retinal diseases, and syndromes. PMID- 25041697 TI - What the devil is in your phytomedicine? Exploring species substitution in Harpagophytum through chemometric modeling of 1H-NMR and UHPLC-MS datasets. AB - Harpagophytum procumbens (Pedaliaceae) and its close taxonomical ally Harpagophytum zeyheri, indigenous to southern Africa, are being harvested for exportation to Europe where phytomedicines are developed to treat inflammation related disorders. The phytochemical variation within and between natural populations of H. procumbens (n=241) and H. zeyheri (n=107) was explored using proton nuclear magnetic resonance ((1)H-NMR) and ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) in combination with multivariate data analysis methods. The UHPLC-MS results revealed significant variation in the harpagoside content: H. procumbens (0.17-4.37%); H. zeyheri (0.00-3.07%). Only 41% of the H. procumbens samples and 17% of the H. zeyheri samples met the pharmacopoeial specification of ?1.2%. Both principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA) indicated separation based on species (UHPLC-MS data OPLS-DA model statistics: R(2)X=0.258, R(2)Y (cum)=0.957 and Q(2)(cum)=0.934; (1)H-NMR data OPLS-DA model statistics: R(2)X=0.830, R(2)Y=0.865 (cum) and Q(2)(cum)=0.829). It was concluded that two species are not chemically equivalent and should not be used interchangeably. PMID- 25041698 TI - Age-dependent changes from allylphenol to prenylated benzoic acid production in Piper gaudichaudianum Kunth. AB - HPLC-DAD and principal component analysis (PCA) of the (1)H NMR spectrum of crude plant extracts showed high chemical variability among seedlings and adult organs of Piper gaudichaudianum. While gaudichaudianic acid was the major compound in the adult leaves, apiole and dillapiole were the major compounds in their seedling leaves. By the 15th month of seedling growth, the levels of apiole and dillapiole decreased and gaudichaudianic acid appeared along with two compounds, biosynthetically related to gaudichaudianic acid. PMID- 25041699 TI - Complement and blood-brain barrier integrity. AB - The blood-brain barrier (BBB) is structurally unique and regulates what is transported into and out of the brain, thereby maintaining brain homeostasis. In inflammatory settings the BBB becomes leaky, regulation of transport is lost and neuronal function goes awry. It is caused by a number of mediators such as complement activation products, processes and networks going haywire, the exact cellular and molecular mechanisms of which remain an enigma. Complement activation byproduct, C5a signaling through its G-protein coupled receptor C5aR1/CD88 increased BBB permeability in neuroinflammatory disease settings in vivo. Studies in brain endothelial cells in vitro demonstrated that the C5a/C5aR1 signaling occurred through the NF-kappaB pathway and altered miRNA in these cells. Inhibition or deletion of C5aR1 was protective in brain, both in vivo and in vitro revealing their potential as possible effective therapeutic targets. Although, this is a field where progress has been made, yet a lot remains to be done due to a number of limitations. This review will deal with the advances in the experimental models, technology and the underlying mechanisms causing the BBB pathology, with an emphasis on the complement proteins and their downstream mechanisms. PMID- 25041700 TI - Heritability of anterior chamber depth and axial length: a population-based twin study among 66 to 79-year old female twins. PMID- 25041701 TI - Too much to bear: endoscopic palliation of a duodenal fistula. PMID- 25041702 TI - Biodegradation of sulfosulphuron in agricultural soil by Trichoderma sp. AB - Sulfosulphuron-degrading fungus was isolated by enrichment technique from the sulfosulphuron-contaminated soil of wheat rhizosphere. To assess the biodegradation potential of isolated Trichoderma sp., minimal potato dextrose agar broth with different levels of sulfosulphuron (up to 2 g l(-1) ) was evaluated in the growth and biotransformation experiments. ESI LC-MS/MS analysis revealed the presence of degradation products 2-amino-4,6-dimethoxypyrimidine (I) and 2-ethylsulfonyl imidazo{1,2-a} pyridine-3-sulfonamide-2-ethylsulfonyl imidazo{1,2-a} pyridine-3-sulfonamide (II) indicating the cleavage of the urea bridge and the presence of the by-product N-(4,6-dimethoxypyrimidin-2-yl)urea (III) indicating the degradation of sulfonylamide linkage. Two other metabolites, N-(4,6-dimethoxypyrimidin-2-yl)-N'-hydroxyurea (IV) and N, N'-bis(4,6 dimethoxypyrimidin-2-yl)urea (V), were also identified. From the previous reports, it was found that the degradation of sulfonyl urea herbicides took place through the chemical degradation of the sulfonylurea bridge followed by microbial degradation. During this investigation, Trichoderma sp. grew well with and degraded sulfosulphuron via both the decarboxylation on the sulphonyl urea bridge and the hydrolytic cleavage of the sulfonylamide linkage as demonstrated by the formation of metabolites. Trichoderma is nonphytopathogenic in nature, and some species of it restrict the growth of soil-dwelling phytopathogens. Therefore, it is a promising candidate for the decontamination of soil from sulfosulphuron residues. SIGNIFICANCE AND IMPACT OF THE STUDY: The degradation of sulfosulphuron by any individual fungus is being reported for the first time. Trichoderma sp. isolated from wheat-rhizospheric soil could survive in minimal broth rich in sulfosulphuron. Previous reports have described the complete degradation of any sulfonyl urea herbicides by micro-organisms only after the pH-dependent chemical hydrolysis of the sulfonyl urea bridge of the herbicide. This study demonstrates the novel result that the Trichoderma sp. utilized the sulfosulphuron as a sole carbon source and degraded it by cleaving sulfonyl urea bridge and sulfonylamide linkage. Thus, the application of Trichoderma sp., which is nonphytopathogenic, has the potential to decontaminate agricultural soil from sulfosulphuron load. PMID- 25041703 TI - Evaluation of major membrane protein-I as a serodiagnostic tool of pauci bacillary leprosy. AB - We have previously shown that the serodiagnosis using major membrane protein-II (MMP-II) is quite efficient in diagnosing leprosy. However, the detection rate of pauci-bacillary (PB) leprosy patients is still low. In this study, we examined the usefulness of major membrane protein-I (MMP-I) from Mycobacterium leprae. The MMP-I-based serodiagnosis did not show significantly high detection rate. However, when the mixture of MMP-I and MMP-II antigens was used, we detected 94.4% of multi-bacillary leprosy and 39.7% of PB patients. There were little correlation between the titers of anti-MMP-I antibodies (Abs) and that of anti MMP-II Abs in PB patients' sera. Ten out of 46 MMP-II-negative PB leprosy patients were MMP-I positive, so that the detection rate of PB leprosy patient increased from 39.7% to 53.8% by taking either test positive strategy. We concluded that MMP-I can complement the MMP-II-based serodiagnosis of leprosy. PMID- 25041704 TI - Intestinal decontamination of multidrug-resistant Klebsiella pneumoniae after recurrent infections in an immunocompromised host. AB - Multidrug-resistant (MDR) Enterobacteriaceae infections are associated with increased morbidity. We describe a 20-year-old hematopoietic cell transplantation recipient with recurrent MDR Klebsiella pneumoniae infection, prolonged intestinal colonization, and subsequent intestinal decontamination. Further study should evaluate stool surveillance, molecular typing, and fecal microbiota transplantation for patients with intestinal MDR Enterobacteriaceae carriage. PMID- 25041705 TI - Emergency department hospitalization volume and mortality in the United States. AB - STUDY OBJECTIVE: Although numerous studies have demonstrated a relationship between higher volume and improved outcomes in the delivery of health services, it has not been extensively explored in the emergency department (ED) setting. Therefore, we seek to examine the association between ED hospitalization volume and mortality for common high-risk conditions. METHODS: Using data from the Nationwide Inpatient Sample, a national sample of hospital discharges, we evaluated mortality overall and for 8 different diagnoses between 2005 and 2009 (total admissions 17.55 million). These conditions were chosen because they are frequent (in the top 25 of all ED hospitalizations) and high risk (> 3% observed mortality). EDs were excluded from analysis if they did not have at least 1,000 total annual admissions and 30 disease-specific cases. EDs were then placed into quintiles based on hospitalized volume. Regression techniques were used to describe the relationship between volume (number of hospitalized ED patients per year) and both subsequent early inpatient mortality (within 2 days of admission) and overall mortality, adjusted for patient and hospital characteristics. RESULTS: Mortality decreased as volume increased overall and for all diagnoses, but the relative importance of volume varied, depending on the condition. Absolute differences in adjusted mortality rates between very high-volume EDs and very low-volume EDs ranged from -5.6% for sepsis (95% confidence interval [CI] 6.5% to -4.7%) to -0.2% for pneumonia (95% CI -0.6% to 0.1%). Overall, this difference was -0.4% (95% CI -0.6% to -0.3%). A similar pattern was observed when early hospital deaths were evaluated. CONCLUSION: Patients have a lower likelihood of inhospital death if admitted through high-volume EDs. PMID- 25041706 TI - Autophagy inhibition in early but not in later stages prevents 3T3-L1 differentiation: Effect on mitochondrial remodeling. AB - Autophagy is essential for successful white adipocyte differentiation but the data regarding the timing and relevance of autophagy action during different phases of adipogenesis are limited. We subjected 3T3-L1 preadipocytes to a standard differentiation protocol and inhibited the autophagy within time-limited periods (days 0-2; 2-4; 4-6; 6-8) by asparagine or 3-methyladenine. In the normal course of events, both autophagy flux and the mRNA expression of autophagy related genes (Atg5, Atg12, Atg16, beclin 1) is most intensive at the beginning of differentiation (days 0-4) and then declines. The initiation of differentiation is associated with a 50% reduction of the mitochondrial copy number on day 2 followed by rapid mitochondrial biogenesis. Preadipocytes and differentiated adipocytes differ in the mRNA expression of genes involved in electron transport (Nufsd1, Sdhb, Uqcrc1); ATP synthesis (ATP5b); fatty acid metabolism (CPT1b, Acadl); mitochondrial transporters (Hspa9, Slc25A1) and the TCA cycle (Pcx, Mdh2) as well as citrate synthase activity. Autophagy inhibition during the first two days of differentiation blocked both phenotype changes (lipid accumulation) and the gene expression pattern, while having no or only a marginal effect over any other time period. Similarly, autophagy inhibition between days 0-2 inhibited mitotic clonal expansion as well as mitochondrial network remodeling. In conclusion, we found that autophagy is essential and most active during an initial stage of adipocyte differentiation but it is dispensable during its later stages. We propose that the degradation of preadipocyte cytoplasmic structures, predominantly mitochondria, is an important function of autophagy during this phase and its absence prevents remodeling of the mitochondrial gene expression pattern and mitochondrial network organization. PMID- 25041707 TI - [50 years Swiss Society of Radiobiology and Medical Physics]. PMID- 25041708 TI - Acoustic Radiation Force Impulse (ARFI) and Transient Elastography (TE) for evaluation of liver fibrosis in HIV-HCV co-infected patients. AB - BACKGROUND: Transient elastography (TE) is widely used for non-invasive assessment of liver fibrosis in HIV-HCV co-infected patients. TE, however, cannot determine liver morphology. Acoustic radiation force impulse (ARFI) imaging is a novel procedure enabling assessment of liver fibrosis during a conventional ultrasonographic examination. This study evaluated the correlation between liver fibrosis measurements by TE and ARFI. METHODS: Each of 46 HIV-HCV patients underwent both ARFI and TE within 6 months. Patients were evaluated by the "equivalent METAVIR" scoring system, using previously established cut-off values. Agreements between the ARFI and TE scores were estimated by Kappa coefficients, with Kappa values >=0.40, >=0.60, and >=0.80 defined as moderate, good and very good agreement, respectively. RESULTS: ARFI and TE yielded "Equivalent Metavir" fibrosis scores of F1 in 26 and 31 patients, respectively; F2 in nine and seven, respectively; F3 in three and two, respectively; and F4 in eight and six, respectively. The two methods showed very good agreement in predicting overall stages [Kappa = 0.82] and for F >=3 [Kappa = 0.80] and moderate agreement in predicting significant fibrosis F >=2 [Kappa = 0.50]. Morphologic ultrasound analysis concomitant to ARFI detected two hepatocarcinomas. CONCLUSIONS: ARFI showed promising results in the non-invasive assessment of liver fibrosis in HIV HCV patients, with liver fibrosis staging similar to that of TE. Moreover, ARFI can assess morphology and fibrosis during the same session. PMID- 25041709 TI - The influence of seizure frequency on anterograde and remote memory in mesial temporal lobe epilepsy. AB - PURPOSE: Seizure frequency, although considered as an important factor in memory impairment in mesial temporal epilepsy (mTLE), is mostly confounded with other clinical variables, making it unclear to what extent recurrent seizures actually interfere with memory. The present study focuses on the influence of seizure frequency, studied as a main variable, on anterograde and remote memory. METHODS: Seventy-one patients with unilateral mTLE were divided into two subgroups, as a function of their seizure frequency (monthly versus weekly seizures). Other seizure-related variables were controlled, namely, lateralisation and type of lesion, age at onset, years of ongoing seizures, etiologic factors, and number of AED. A comprehensive neuropsychological examination, including anterograde memory (verbal and non verbal recognition memory and free recall) tasks together with a large range of tests exploring different domains of remote memory, was carried out. RESULTS: Despite similar results on IQ, executive functions and attention, the low seizure-frequency group performed significantly better than the high seizure-frequency group on anterograde memory tests. Loss of autobiographical episodes and public-events memory, concomitant with spared personal semantic knowledge, was observed in both patient groups compared with healthy subjects. A worsening effect of high seizure frequency was recorded for autobiographical incidents and news-events memory, but unexpectedly, not for memory for famous people. CONCLUSION: The study of seizure frequency as the main variable leads us to suggest that high seizure frequency, itself, potentiates the effects of mesial temporal lobe damage on episodic memory deficits. PMID- 25041710 TI - Identification and characterization of D-xylose reductase involved in pentose catabolism of the zygomycetous fungus Rhizomucor pusillus. AB - Rhizomucor pusillus NBRC 4578 efficiently produces ethanol from lignocellulosic biomass because of its ability to ferment not only d-glucose, but also d-xylose. When the strain was cultivated on d-xylose, ethanol was gradually formed in the culture medium with a decrease in d-xylose and the simultaneous accumulation of xylitol, which suggested that the strain catabolized d-xylose with d-xylose reductase (XR) and xylitol dehydrogenase (XDH). XR (RpXR) was purified to homogeneity from the crude extract prepared from the mycelia of the strain grown on d-xylose. The purified enzyme was found to be NADPH-dependent and prefer pentoses such as d-xylose, d-ribose, and l-arabinose as substrates. Isolation of the genomic DNA and cDNA of the xyl1 gene encoding RpXR revealed that the gene was interrupted by two introns and the exon of the gene encoded a protein composed of 322 amino acids with a Mr of 36,724. Phylogenetic analysis showed that RpXR is more related to 4-dihydromethyltrisporate dehydrogenases from Mucoraseae fungi rather than the previously reported fungal XRs. Quantitative real-time PCR indicated that transcription of the xyl1 gene was marked in the presence of d-xylose and l-arabinose, but was week in the presence of d-glucose. These biochemical and expression analyses suggest that RpXR is involved in the catabolism of l-arabinose as well as d-xylose. This is the first report of the purification, characterization, and gene cloning of XR from zygomycetous fungi. PMID- 25041711 TI - In vitro selection of a photoresponsive peptide aptamer to glutathione immobilized microbeads. AB - Photoresponsive peptide aptamer to glutathione-immobilized microbeads was in vitro selected using ribosome display incorporated with tRNA carrying an amino acid coupled with an azobenzene. PMID- 25041712 TI - Breast papilloma without atypia and risk of breast carcinoma. AB - The incidence of asymptomatic papilloma has increased with the rising popularity of core needle biopsy for breast lesions. In this study, the risk of benign papilloma without atypia for subsequent breast carcinoma during follow-up was evaluated. From January 2000 to December 2010, among 39,461 women with breast ultrasonography, 37,847 women with benign papilloma on biopsy or excision, with benign diseases on biopsy, and with only ultrasonography performed were recruited. Women with concurrent or prior high-risk lesions (atypia, phyllodes tumor, or lobular neoplasm) or malignancies, or with a follow-up period of less than 12 months were excluded. The eligible 12,302 women were classified into three groups; papilloma (n = 265, patients with benign papilloma without atypia at excision), benign (n = 3,066, patients with benign results other than high risk results on core needle biopsy), and ultrasonography (n = 8,971, patients who underwent ultrasonography only without biopsy or surgery). The relative risks (RRs) of the papilloma and benign groups were calculated with intervals of 2 years using the Poisson regression analysis with age, family history, follow-up period, and breast parenchymal density being adjusted, and the ultrasonography group was used as a reference. The RR of the papilloma group was 4.8 (95% confidence interval [CI], 2.5-9.0), significantly higher than 1.5 (95% CI, 1.0 2.1) of the benign group. In the first 2 years, the RR of the papilloma group was 5.2 (95% CI, 2.2-12.6) but it dropped to 2.2 (95% CI, 0.5-9.2) during the next 2 years. Afterward, the RR increased over time although statistical significance was not achieved. Benign papilloma without atypia increased breast cancer risk fivefold when the ultrasonography group was used as a reference, higher than other benign lesions. PMID- 25041714 TI - Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review. AB - BACKGROUND: Ototoxicity is a known side effect of combined radiation therapy and cisplatin chemotherapy for the treatment of medulloblastoma. The delivery of an involved field boost by intensity modulated radiation therapy (IMRT) may reduce the dose to the inner ear when compared with conventional radiotherapy. The dose of cisplatin may also affect the risk of ototoxicity. A retrospective study was performed to evaluate the impact of involved field boost using IMRT and cisplatin dose on the rate of ototoxicity. METHODS: Data from 41 medulloblastoma patients treated with IMRT were collected. Overall and disease-free survival rates were calculated by Kaplan-Meier method Hearing function was graded according to toxicity criteria of Pediatric Oncology Group (POG). Doses to inner ear and total cisplatin dose were correlated with hearing function by univariate and multivariate data analysis. RESULTS: After a mean follow-up of 44 months (range: 14 to 72 months), 37 patients remained alive, with two recurrences, both in spine with CSF involvement, resulting in a disease free-survival and overall survival of 85.2% and 90.2%, respectively.Seven patients (17%) experienced POG Grade 3 or 4 toxicity. Cisplatin dose was a significant factor for hearing loss in univariate analysis (p < 0.03). In multivariate analysis, median dose to inner ear was significantly associated with hearing loss (p < 0.01). POG grade 3 and 4 toxicity were uncommon with median doses to the inner ear bellow 42 Gy (p < 0.05) and total cisplatin dose of less than 375 mg/m2 (p < 0.01). CONCLUSIONS: IMRT leads to a low rate of severe ototoxicity. Median radiation dose to auditory apparatus should be kept below 42 Gy. Cisplatin doses should not exceed 375 mg/m2. PMID- 25041715 TI - Unusual conduction disorder: left posterior fascicular block + left septal fascicular block. AB - A 44-year-old man with aortic valve insufficiency and stenosis underwent aortic valve replacement depicting interesting ECG changes. This unique case is discussed, contributing to the understanding of a trifascicular left intraventricular conduction system. PMID- 25041716 TI - Outcomes of a nurse-managed service for stable HIV-positive patients in a large South African public sector antiretroviral therapy programme. AB - OBJECTIVES: Models of care utilizing task shifting and decentralization are needed to support growing ART programmes. We compared patient outcomes between a doctor-managed clinic and a nurse-managed down-referral site in Cape Town, South Africa. METHODS: Analysis included all adults who initiated ART between 2002 and 2011 within a large public sector ART service. Stable patients were eligible for down-referral. Outcomes [mortality, loss to follow-up (LTFU), virologic failure] were compared under different models of care using proportional hazards models with time-dependent covariates. RESULTS: Five thousand seven hundred and forty six patients initiated ART and over 5 years 41% (n = 2341) were down-referred; the median time on ART before down-referral was 1.6 years (interquartile range, 0.9-2.6). The nurse-managed down-referral site reported lower crude rates of mortality, LTFU and virologic failure compared with the doctor-managed clinic. After adjustment, there was no difference in the risk of mortality or virologic failure by model of care. However, patients who were down-referred were more likely to be LTFU than those retained at the doctor-managed site (adjusted hazard ratio, 1.36; 95% CI, 1.09-1.69). Increased levels of LTFU in the nurse-managed vs. doctor-managed service were observed in subgroups of male patients, those with advanced disease at initiation and those who started ART in the early years of the programme. CONCLUSION: Reorganization of ART maintenance by down-referral to nurse-managed services is associated with programme outcomes similar to those achieved using doctor-driven primary care services. Further research is necessary to identify optimal models of care to support long-term retention of patients on ART in resource-limited settings. PMID- 25041717 TI - Characterization of Pythium oligandrum populations that colonize the rhizosphere of vines from the Bordeaux region. AB - This study focused on one oomycete, Pythium oligandrum, well-known for its plant protection abilities, which thrives in microbial environment where bacteria and fungal communities are also present. The genetic structures and dynamics of fungal and bacterial communities were studied in three Bordeaux subregions with various types of soil, using single-strand conformation polymorphism. The structure of the fungal communities colonizing the rhizosphere of vines planted in sandy-stony soils was markedly different from that those planted in silty and sandy soils; such differences were not observed for bacteria. In our 2-year experiment, the roots of all the vine samples were also colonized by echinulated oospore Pythium species, with P. oligandrum predominating. Cytochrome oxidase I and tubulin gene sequencings showed that P. oligandrum strains clustered into three groups. Based on elicitin-like genes coding for proteins able to induce plant resistance, six populations were identified. However, none of these groups was assigned to a particular subregion of Bordeaux vineyards, suggesting that these factors do not shape the genetic structure of P. oligandrum populations. Results showed that different types of rootstock and weeding management both influence root colonization by P. oligandrum. These results should prove particularly useful in improving the management of potentially plant-protective microorganisms. PMID- 25041719 TI - Theoretical elucidation of the origins of substituent and strain effects on the rates of Diels-Alder reactions of 1,2,4,5-tetrazines. AB - The Diels-Alder reactions of seven 1,2,4,5-tetrazines with unstrained and strained alkenes and alkynes were studied with quantum mechanical calculations (M06-2X density functional theory) and analyzed with the distortion/interaction model. The higher reactivities of alkenes compared to alkynes in the Diels-Alder reactions with tetrazines arise from the differences in both interaction and distortion energies. Alkenes have HOMO energies higher than those of alkynes and therefore stronger interaction energies in inverse-electron-demand Diels-Alder reactions with tetrazines. We have also found that the energies to distort alkenes into the Diels-Alder transition-state geometries are smaller than for alkynes in these reactions. The strained dienophiles, trans-cyclooctene and cyclooctyne, are much more reactive than unstrained trans-2-butene and 2-butyne, because they are predistorted toward the Diels-Alder transition structures. The reactivities of substituted tetrazines correlate with the electron-withdrawing abilities of the substituents. Electron-withdrawing groups lower the LUMO+1 of tetrazines, resulting in stronger interactions with the HOMO of dienophiles. Moreover, electron-withdrawing substituents destabilize the tetrazines, and this leads to smaller distortion energies in the Diels-Alder transition states. PMID- 25041718 TI - Continuous glucose control in the ICU: report of a 2013 round table meeting. AB - Achieving adequate glucose control in critically ill patients is a complex but important part of optimal patient management. Until relatively recently, intermittent measurements of blood glucose have been the only means of monitoring blood glucose levels. With growing interest in the possible beneficial effects of continuous over intermittent monitoring and the development of several continuous glucose monitoring (CGM) systems, a round table conference was convened to discuss and, where possible, reach consensus on the various aspects related to glucose monitoring and management using these systems. In this report, we discuss the advantages and limitations of the different types of devices available, the potential advantages of continuous over intermittent testing, the relative importance of trend and point accuracy, the standards necessary for reporting results in clinical trials and for recognition by official bodies, and the changes that may be needed in current glucose management protocols as a result of a move towards increased use of CGM. We close with a list of the research priorities in this field, which will be necessary if CGM is to become a routine part of daily practice in the management of critically ill patients. PMID- 25041720 TI - Tight glycemic control in the ICU - is the earth flat? AB - Tight glycemic control in the ICU has been shown to reduce mortality in some but not all prospective randomized control trials. Confounding the interpretation of these studies are differences in how the control was achieved and underlying incidence of hypoglycemia, which can be expected to be affected by the introduction of continuous glucose monitoring (CGM). In this issue of Critical Care, a consensus panel provides a list of the research priorities they believe are needed for CGM to become routine practice in the ICU. We reflect on these recommendations and consider the implications for using CGM today. PMID- 25041721 TI - Is the neutrophil a 'prima donna' in the procoagulant process during sepsis? AB - Activation of the coagulation system is a fundamental host defense mechanism. Microorganisms that have invaded the body are trapped and disposed of in clots. Monocytes/macrophages are widely accepted as the main players in the procoagulant process; however, recent evidence suggests that neutrophils also play important roles. Tissue factor, which initiates the extrinsic coagulation cascade, is reportedly expressed on the surface of neutrophils, as well as on microparticles derived from neutrophils. Neutrophil extracellular traps (NETs) are another source of tissue factor. The components of NETs, such as DNA, histones, and granule proteins, also provide procoagulant activities. For instance, DNA initiates the intrinsic pathway, histones are a strong generator of thrombin, and granule proteins such as neutrophil elastase, cathepsin G and myeloperoxidase contribute to the suppression of the anticoagulation systems. Although understanding of the mechanisms that are involved in coagulation/fibrinolysis in sepsis has gradually progressed, the impact of neutrophils on thrombogenicity during sepsis remains to be addressed. Since the importance of the connection between coagulation and inflammation is advocated nowadays, further research on neutrophils is required. PMID- 25041722 TI - Alzheimer and platelets: low-density platelet populations reveal increased serotonin content in Alzheimer type dementia. AB - INTRODUCTION: Alzheimer's disease (AD) is a progressive form of dementia characterized by an increase in the toxic substance beta-amyloid in the brain. Platelets display a substantial heterogeneity with respect to density. They further contain a substantial amount of beta-amyloid precursor protein. Platelets take up and store serotonin (5-HT) that plays an important role in the pathogenesis of severe depression. The current study aims to investigate platelet serotonin content in different platelet density populations. MATERIAL AND METHODS: The study involved 8 patients (age 70+/-8 (SD) years) (3 females/5 males) with moderate AD. 6 healthy elderly subjects (age 66+/-9 (SD) years) (3 females/3 males) served as controls. The platelet population was divided into 17 subpopulations according to density, using a linear PercollTM gradient. Platelets were counted in all fractions. After cell lysis an ELISA technique was employed to determine the 5-HT content in each platelet subfraction. RESULTS: The two study groups did not differ significantly regarding platelet distribution in the gradients, but AD sufferers have a significantly higher 5-HT content (p<0.05) in the lighter platelet populations. DISCUSSION: AD-type dementia proved to be associated with lighter platelets containing more 5-HT. It is possible that platelets from AD patients release less 5-HT. It is speculated that AD synapses are affected in a manner comparable to platelets, which could explain why 5-HT reuptake inhibitors are less effective in AD dementia. PMID- 25041723 TI - Clinical features of 58 Japanese patients with mosaic neurofibromatosis 1. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutation in the NF1 tumor-suppressor gene, and may sometimes manifest in a mosaic form. "Segmental NF1" is generally assumed to be the result of somatic mosaicism for a NF1 mutation, and patients with mosaic NF1 have typical features of NF1 limited to specific body segments. The clinical features of 58 patients (42 females and 16 males; aged 1-69 years; mean age, 23.4 years) with mosaic NF1 seen at the Jikei University Hospital during 2004-2007 and at the Jikei University Daisan Hospital during 2007-2011, were retrospectively studied. Somatic or gonosomal mosaicism was not investigated. Patients were classified into four groups: (i) pigmentary changes (cafe-au-lait spots and freckling) only (n = 32); (ii) neurofibromas only (n = 5); (iii) neurofibromas and pigmentary changes (n = 13); and (iv) solitary plexiform neurofibromas (n = 8). The area of involvement was variable. The majority of patients were asymptomatic, except patients with plexiform neurofibromas who presented most commonly with pain or tenderness. Lisch nodules were rarely seen. Only four of our 58 patients (6.9%) had specific NF1 complications, including language delay (n = 1) and bone deformity (n = 3). Two patients were ascertained through their children with generalized NF1. Patients with mosaic NF1 are at low risk of developing disease-associated complications, except patients with plexiform neurofibromas. However, they need to be aware of the small risk of having a child with generalized NF1. PMID- 25041724 TI - Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis. AB - BACKGROUND: Accurate and reproducible measurement of expression of pro inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements. AIM: To validate methods for measuring changes in gene expression in colonic biopsy samples. METHODS: Twelve colonic biopsies were obtained from each of six healthy controls, six patients with inactive UC and seven patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active vs. inactive UC was calculated using a linear mixed effect model. RESULTS: mRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, three rectal biopsies from two to four patients are required to detect changes in gene expression corresponding to active vs. inactive UC to achieve a power of 80% with an alpha of 0.05. CONCLUSION: Our data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing, and assessment of clinical activity and response to therapy in ulcerative colitis. PMID- 25041725 TI - Antioxidative effects and percutaneous absorption of five polyphenols. AB - A new strategy was designed to evaluate the antioxidant effectiveness of five topically applied polyphenols following skin penetration profiles. The antioxidants were the following polyphenol derivatives: epicatechin, resveratrol, rutin, quercetin, and trolox, which was used as the reference antioxidant. The hydrophilic/lipophilic character of these compounds was evaluated, and their antioxidant activity was measured by the DPPH method. The percutaneous absorption of these polyphenols was obtained by an in vitro methodology using porcine skin biopsies. This methodology involves the quantification of the antioxidants present in each specific skin layer to evaluate antioxidant effectiveness. The antioxidant activity in each skin layer was also determined by the DPPH method. The results indicated that lipophilic antioxidants (epicatechin, resveratrol, quercetin, and trolox) penetrated deeper into the skin layers, whereas a more hydrophilic compound, rutin, remained on the skin surface. The antioxidant evaluation of each skin compartment suggested that resveratrol and rutin were the most effective topically applied compounds in view of their antioxidant activity and their skin penetration profile. PMID- 25041726 TI - Coronal plane spinal malalignment and Parkinson's disease: prevalence and associations with disease severity. AB - BACKGROUND CONTEXT: Parkinson's disease (PD) is a progressive degenerative disorder of the central nervous system. Patients with PD often present with abnormal posturing. PURPOSE: To investigate coronal plane deformities in patients with PD, and to evaluate the correlation between clinical features, coronal parameters related to spine alignment, and disease severity. STUDY DESIGN: A cross-sectional study. PATIENT SAMPLE: Eighty-nine patients with PD and 89 controls were included. OUTCOME MEASURES: A medical history was collected from the medical records. METHODS: This study was a prospective assessment of consecutive patients with PD. Clinical and demographic parameters were collected from medical records and outpatient interviews. Full-length standing anteroposterior and lateral spine radiographs were used to assess the spinal parameters. The threshold for scoliosis was set at a 10 degrees Cobb angle, and the curve type was classified using Schwab classification. RESULTS: A total of 178 patients (89 in PD and 89 in control groups) were included. Scoliosis was identified in 27 patients (30%) and 22 controls (p=.502). However, coronal imbalance was more common in patients with PD than in controls (11 vs. 0 patients, p=.001). Scoliosis was more common in women than in men (male:female=8:19, p=.04). Back pain was more common in patients with scoliosis than in those without scoliosis (14 of 27 vs. 17 of 62, p=.036). Schwab Type IV (thoracolumbar major) was the most common type of scoliosis in patients with PD and Type V (lumbar major) was the most common type in controls. With adjustment for patient age and gender, multiple linear regression analysis revealed that severity of PD (Unified Parkinson's Disease Rating Scale, p=.037) and magnitude of global coronal malalignment (p=.003) were associated with the scoliosis Cobb angle (p=.037, B=0.139). Direction of scoliosis and side of global coronal malalignment were not significantly correlated with the laterality of predominant PD symptoms (p>.05). CONCLUSIONS: Global coronal malalignment is more prevalent in patients with PD than in controls. Greater severity of PD was significantly associated with greater magnitude of scoliosis Cobb angle, even after adjusting for the effects of patient age and gender. However, direction of scoliosis and side of global coronal malalignment were not significantly associated with the dominant laterality of PD symptoms. PMID- 25041727 TI - Epidemiologic, functional, and oncologic outcome analysis of spinal sarcomas treated surgically at a single institution over 10 years. AB - BACKGROUND CONTEXT: Spinal sarcomas are aggressive tumors that originate from the cells of mesechymal origin, specifically fat, cartilage, bone, and muscle. They are high-grade lesions, and treatment of spinal sarcomas can involve chemotherapy, radiation therapy, and surgery. In the appendicular skeleton, sarcomas are often treated with amputation, however, in the spinal column, surgical resection poses a unique set of challenges. PURPOSE: To better understand the optimal treatment regimens and the impact of en bloc or intralesional resection on patient outcome. STUDY DESIGN: A cohort of 25 sarcoma patients treated at a single medical institution between 2002 and 2012 was reviewed. PATIENT SAMPLE AND OUTCOME MEASURES: Patients were classified by tumor type for subgroup analysis, including chondrosarcoma, osteosarcoma, and other malignant spinal sarcomas. Demographic data for review included patient age, tumor type, tumor location, surgery type, exposure to chemotherapy, and radiation therapy. METHODS: Survival statistics and Kaplan-Meier curves were calculated using GraphPad Prism 5.0. The threshold for statistical significance was set at p<.05. Unpaired, two-tailed, equal variance t tests were performed for statistical analyses in Microsoft Excel 2010. RESULTS: Twenty-five patients with spinal sarcomas were treated over the 10-year period. Diagnosis included chondrosarcoma (n=9), osteosarcoma (n=4), and other sarcomas (n=12). Mean age at the time of diagnosis was 42 years. Pain was present at the time of diagnosis in 92% patients. Median survival after surgery was 59.5 months for chondrosarcoma, undefined for other sarcomas, and 16.8 months for osteosarcoma. Median survival after en bloc resection was undefined. Median survival after intralesional resection was 17.8 months. The difference in median survival between en bloc and intralesional resection was statistically significant (p=.049). CONCLUSIONS: The authors report the largest cohort of patients with spinal sarcoma. Median survival in this cohort was the longest for patients with sarcomas of varying pathologies. Median survival was longer for chondrosarcoma. En bloc resection demonstrated a survival advantage over intralesional resection. Long-term follow up is needed for patients with spinal sarcoma to establish definitive survival data. PMID- 25041728 TI - Necrobiotic features in both cutaneous and lymph node lesions in a patient with interstitial mycosis fungoides. PMID- 25041729 TI - Human absorption, distribution, metabolism and excretion properties of drug molecules: a plethora of approaches. AB - Human radiolabel studies are traditionally conducted to provide a definitive understanding of the human absorption, distribution, metabolism and excretion (ADME) properties of a drug. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical ADME and pharmacokinetic (PK) information. These include microdose and microtracer approaches using accelerator mass spectrometry, and the identification and quantification of metabolites in samples from classical human PK studies using technologies suitable for non-radiolabelled drug molecules, namely liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. These recently developed approaches are described here together with relevant examples primarily from experiences gained in support of drug development projects at GlaxoSmithKline. The advantages of these study designs together with their limitations are described. We also discuss special considerations which should be made for a successful outcome to these new approaches and also to the more traditional human radiolabel study in order to maximize knowledge around the human ADME properties of drug molecules. PMID- 25041730 TI - Mutant huntingtin replaces Gab1 and interacts with C-terminal SH3 domain of growth factor receptor binding protein 2 (Grb2). AB - Huntington's disease (HD) is caused due to expansion of CAG repeats in the gene huntingtin (Htt). Adaptor protein Grb2, involved in Ras-MAP kinase pathway, is a known interactor of Htt. Mutant Htt-Grb2 interaction reduces Ras-MAPK signaling in HD models. In normal cells Grb2 forms Grb2-Sos1-Gab1 complex through its N-SH3 and C-SH3 domains respectively, essential for sustained activation of Ras. We found that C-SH3 of Grb2 mediates the interaction with mutant Htt and this interaction being stronger could replace Gab1, with mutant Htt becoming the preferred partner. This would have immense effect on downstream signaling events. PMID- 25041731 TI - Transformation and removal of arsenic in groundwater by sequential anodic oxidation and electrocoagulation. AB - Oxidation of As(III) to As(V) is generally essential for the efficient remediation of As(III)-contaminated groundwater. The performance and mechanisms of As(III) oxidation by an as-synthesized active anode, SnO2 loaded onto Ti-based TiO2 nanotubes (Ti/TiO2NTs/Sb-SnO2), were investigated. The subsequent removal of total arsenic by electrocoagulation (EC) was further tested. The Ti/TiO2NTs/Sb SnO2 anode showed a high and lasting electrochemical activity for As(III) oxidation. 6.67MUM As(III) in synthetic groundwater was completely oxidized to As(V) within 60min at 50mA. Direct electron transfer was mainly responsible at the current below 30mA, while hydroxyl radicals contributed increasingly with the increase in the current above 30mA. As(III) oxidation was moderately inhibited by the presence of bicarbonate (20mM), while was dramatically increased with increasing the concentration of chloride (0-10mM). After the complete oxidation of As(III) to As(V), total arsenic was efficiently removed by EC in the same reactor by reversing electrode polarity. The removal efficiency increased with increasing the current but decreased by the presence of phosphate and silica. Anodic oxidation represents an effective pretreatment approach to increasing EC removal of As(III) in groundwater under O2-limited conditions. PMID- 25041732 TI - Adsorption and transport of polymaleic acid on Callovo-Oxfordian clay stone: batch and transport experiments. AB - Dissolved Organic Matter (DOM) can affect the mobility of radionuclides in pore water of clay-rich geological formations, such as those intended to be used for nuclear waste disposal. The present work studies the adsorption and transport properties of a polycarboxylic acid, polymaleic acid (PMA, Mw=1.9kDa), on Callovo Oxfordian argillite samples (COx). Even though this molecule is rather different from the natural organic matter found in clay rock, the study of its retention properties on both dispersed and intact samples allows assessing to which extent organic acids may undergo sorption under natural conditions (pH7) and what could be the impact on their mobility. PMA sorption and desorption were investigated in dispersed systems. The degree of sorption was measured after 1, 8 and 21days and for a range of PMA initial concentrations from 4.5*10(-7) to 1.4*10(-3)mol.L(-1). The reversibility of the sorption process was estimated by desorption experiments performed after the sorption experiments. At the sorption steady state, the sorption was described by a two-site Langmuir model. A total sorption capacity of COx for PMA was found to be 1.01*10(-2) mol.kg(-1) distributed on two sorption sites, one weak and one strong. The desorption of PMA was incomplete, independently of the duration of the sorption phase. The amount of desorbable PMA even appeared to decrease for sorption phases from 1 to 21days. To describe the apparent desorption hysteresis, two conceptual models were applied. The two-box diffusion model accounted for intraparticle diffusion and more generally for nonequilibrium processes. The two-box first-order non-reversible model accounted for a first-order non-reversible sorption and more generally for kinetically controlled irreversible sorption processes. The use of the two models revealed that desorption hysteresis was not the result of nonequilibrium processes but was due to irreversible sorption. Irreversible sorption on the strong site was completed after 1day and represented 96% of the total sorption on this site. On the weak site the irreversible uptake was slower and completed only after 16days but it also dominated the sorption. 85% of the PMA sorbed on the weak site was not desorbable after 21days of sorption. The migration of PMA was studied by applying a hydraulic gradient to a clay core inserted in a stainless steel cell. Breakthrough of polymaleic acid, simulated with a 1D transport model including the two-box first-order non-reversible model, revealed that the mobility of PMA was limited by the same set of reversible/irreversible interactions as observed in the dispersed system. However, to describe efficiently the transport, the total sorption capacity had to be reduced to 33% of the capacity estimated in batch experiments. The irreversible sorption on the weak site was also slower in the intact sample than in the crushed sample. Geometrical constraints would therefore affect both the accessibility to the sorption sites and the kinetics of the irreversible sorption process. PMID- 25041733 TI - Nitrate attenuation potential of hypersaline lake sediments in central Spain: flow-through and batch experiments. AB - Complex lacustrine systems, such as hypersaline lakes located in endorheic basins, are exposed to nitrate (NO3(-)) pollution. An excellent example of these lakes is the hypersaline lake located in the Petrola basin (central Spain), where the lake acts as a sink for NO3(-) from agricultural activities and from sewage from the surrounding area. To better understand the role of the organic carbon (Corg) deposited in the bottom sediment in promoting denitrification, a four stage flow-through experiment (FTR) and batch experiments using lake bottom sediment were performed. The chemical, multi-isotopic and kinetic characterization of the outflow showed that the intrinsic NO3(-) attenuation potential of the lake bottom sediment was able to remove 95% of the NO3(-) input over 296days under different flow conditions. The NO3(-) attenuation was mainly linked with denitrification but some dissimilatory nitrate reduction to ammonium was observed at early days favored by the high C/N ratio and salinity. Sulfate reduction could be neither confirmed nor discarded during the experiments because the sediment leaching masked the chemical and isotopic signatures of this reaction. The average nitrogen reduction rate (NRR) obtained was 1.25mmold(-1)kg( 1) and was independent of the flow rate employed. The amount of reactive Corg from the bottom sediment consumed during denitrification was 28.8mmol, representing approximately 10% of the total Corg of the sediment (1.2%). Denitrification was produced coupled with an increase in the isotopic composition of both delta(15)N and delta(18)O. The isotopic fractionations (epsilon of (15)N NO3(-) and (18)O-NO3(-)) produced during denitrification were calculated using batch and vertical profile samples. The results were -14.70/00 for epsilonN and 14.50/00 for epsilonO. PMID- 25041734 TI - The relation between X chromosome parental origin and aortic stiffness in patients with Turner's syndrome: role of hypertension and antihypertensive drugs. PMID- 25041735 TI - Acceptance and commitment therapy for anxiety and OCD spectrum disorders: an empirical review. AB - A fair amount of research exists on acceptance and commitment therapy (ACT) as a model and a treatment for anxiety disorders and OCD spectrum disorders; this paper offers a quantitative account of this research. A meta-analysis is presented examining the relationship between psychological flexibility, measured by versions of the Acceptance and Action Questionnaire (AAQ and AAQ-II) and measures of anxiety. Meta-analytic results showed positive and significant relationships between the AAQ and general measures of anxiety as well as disorder specific measures. Additionally, all outcome data to date on ACT for anxiety and OCD spectrum disorders are reviewed, as are data on mediation and moderation within ACT. Preliminary meta-analytic results show that ACT is equally effective as manualized treatments such as cognitive behavioral therapy. Future directions and limitations of the research are discussed. PMID- 25041736 TI - Cost of stroke in low and middle income countries: a systematic review. AB - BACKGROUND: There is limited information available from low and middle-income countries regarding the cost of stroke treatment. Hence, we aimed to review the costs of stroke in low and middle-income countries. SUMMARY OF REVIEW: The literature search was done using databases: PubMed/Medline, Ovid, EconLit and Google Scholar from 1966 until January 2014 using key words 'economic impact of stroke', 'cost of illness in low and middle income countries' and 'cost of stroke'. With these key words, 10/184 articles were retained for this review. The cost data were converted to 2013 currency values using a web-based tool (CCEMG EPPI-centre cost converter). Most of the included studies were conducted in Asia. The design of these studies was retrospective and conducted predominantly in multicenter private hospitals. The highest mean direct medical cost of stroke was US$ 8424 in Nigeria. The lowest mean cost of stroke was in Senegal (US$ 416). The average length of hospital stay was longest (20 days) in China. The main predictors of higher costs appeared to be due to differences in length of stay and stroke severity. CONCLUSION: Costs of stroke are variable because of heterogeneous healthcare systems prevailing in low and middle-income countries. Length of hospital stay and stroke severity appear to be the main predictors of cost. Understanding the costs of stroke in low and middle-income countries is important. However, the evidence remains limited because there is a lack of standardized research. Future research should focus on using a uniform method across low and middle-income countries for estimating the costs of stroke. PMID- 25041737 TI - Recent applications of synthetic biology tools for yeast metabolic engineering. AB - The last 20 years of metabolic engineering has enabled bio-based production of fuels and chemicals from renewable carbon sources using cost-effective bioprocesses. Much of this work has been accomplished using engineered microorganisms that act as chemical factories. Although the time required to engineer microbial chemical factories has steadily decreased, improvement is still needed. Through the development of synthetic biology tools for key microbial hosts, it should be possible to further decrease the development times and improve the reliability of the resulting microorganism. Together with continuous decreases in price and improvements in DNA synthesis, assembly and sequencing, synthetic biology tools will rationalize time-consuming strain engineering, improve control of metabolic fluxes, and diversify screening assays for cellular metabolism. This review outlines some recently developed synthetic biology tools and their application to improve production of chemicals and fuels in yeast. Finally, we provide a perspective for the challenges that lie ahead. PMID- 25041738 TI - Ratio of hepatic arterial flow to recipient body weight predicts biliary complications after deceased donor liver transplantation. AB - OBJECTIVES: Adequate hepatic arterial (HA) flow to the bile duct is essential in liver transplantation. This study was conducted to determine if the ratio of directly measured HA flow to weight is related to the occurrence of biliary complications after deceased donor liver transplantation. METHODS: A retrospective review of 2684 liver transplants carried out over a 25-year period was performed using data sourced from a prospectively maintained database. Rates of biliary complications (biliary leaks, anastomotic and non-anastomotic strictures) were compared between two groups of patients with HA flow by body weight of, respectively, <5 ml/min/kg (n = 884) and >=5 ml/min/kg (n = 1800). RESULTS: Patients with a lower ratio of HA flow to weight had higher body weight (92 kg versus 76 kg; P < 0.001) and lower HA flow (350 ml/min versus 550 ml/min; P < 0.001). A lower ratio of HA flow to weight was associated with higher rates of biliary complications at 2 months, 6 months and 12 months (19.8%, 28.2% and 31.9% versus 14.8%, 22.4% and 25.8%, respectively; P < 0.001). CONCLUSIONS: A ratio of HA flow to weight of < 5 ml/min/kg is associated with higher rates of biliary complications. This ratio may be a useful parameter for application in the prevention and early detection of biliary complications. PMID- 25041739 TI - Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-beta signalling pathway. AB - The Notch signalling pathway is involved in multiple cellular processes and has been recently indicated to modulate the host immune response. However, the role of the Notch pathway in dengue virus (DENV) infection remains unknown. Our study has screened the expression profile of Notch receptors, ligands and target genes in human monocytes, macrophages and dendritic cells in response to DENV infection. The real-time PCR data showed that Notch ligand Dll1 was significantly induced in DENV-infected monocytes; and receptor Notch4, ligands Dll1 and Dll4, and target Hes1 were dramatically enhanced in DENV-infected macrophages and dendritic cells. In macrophages, induction of Dll1 and Dll4 mediated by DENV2 was increased by treatment with interferon-beta (IFN-beta), and was impaired by neutralization of IFN-beta. The DENV-induced Dll1 and Dll4 expression level was decreased by silencing key innate immune molecules, including Toll-like receptor 3 (TLR3), MyD88, RIG-I and IPS-I. In IFN-receptor-depleted macrophages, the Dll1 and Dll4 induction was significantly alleviated. Functionally, activation of Notch signalling by Dll1 in CD4(+) T cells enhanced the expression of a T helper type 1 (Th1) cytokine IFN-gamma, while Notch activation in macrophages had no direct effect on replication of DENV. Our data revealed that the expressions of Notch ligands in antigen-presenting cells were differentially induced by DENV via innate immune signalling, which is important for Th1/Th2 differentiation during adaptive immune response. PMID- 25041740 TI - Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. AB - Venous leg ulcers (VLUs) are one of the most prevalent types of chronic wounds. The aim of this study was to determine the safety and dose-response efficacy of the human synthetic peptide LL-37 in the treatment of hard-to-heal VLUs. This first-in-man trial included 34 participants with VLUs and comprised a 3-week, open-label, run-in period on placebo, followed by a 4-week randomized double blind treatment phase with twice weekly applications of LL-37 (0.5, 1.6, or 3.2 mg/mL) or placebo, and a 4-week follow-up. The healing rate constants for 0.5 and 1.6 mg/mL of LL-37 were approximately six- and threefold higher than for placebo (p = 0.003 for 0.5 mg/mL and p = 0.088 for 1.6 mg/mL). Square-root transformed wound area data showed improved healing for the 0.5 and 1.6 mg/mL dose groups compared with pretreatment values (p < 0.001 and p = 0.011, respectively). Consistently, treatment with the two lower doses markedly decreased the mean ulcer area (68% for 0.5 mg/mL and 50% for 1.6 mg/mL groups). No difference in healing was observed between the groups receiving 3.2 mg/mL of LL-37 and placebo. There were no safety concerns regarding local or systemic adverse events. In conclusion, topical treatment with LL-37 for chronic leg ulcers was safe and well tolerated with the marked effect on healing predictors at the two lower doses warranting further investigations. PMID- 25041741 TI - [Drop in the bucket. Introductory commentary for Paola Bucci: Plans for the chapter on mental disorders of ICD-11: Synopsis for WPA constituencies]. PMID- 25041742 TI - Plans for the chapter on mental disorders of ICD-11: a synopsis for WPA constituencies. PMID- 25041743 TI - Gender interactions in the recognition of emotions and conduct symptoms in adolescents. AB - BACKGROUND: According to literature data, impairment in the recognition of emotions might be related to antisocial developmental pathway. In the present study, the relationship between gender-specific interaction of emotion recognition and conduct symptoms were studied in non-clinical adolescents. METHODS: After informed consent, 29 boys and 24 girls (13-16 years, 14 +/- 0.1 years) participated in the study. The parent version of the Strengths and Difficulties Questionnaire was used to assess behavioral problems. The recognition of basic emotions was analyzed according to both the gender of the participants and the gender of the stimulus faces via the "Facial Expressions of Emotion- Stimuli and Tests". RESULTS: Girls were significantly better than boys in the recognition of disgust, irrespective from the gender of the stimulus faces, albeit both genders were significantly better in the recognition of disgust in the case of male stimulus faces compared to female stimulus faces. Both boys and girls were significantly better in the recognition of sadness in the case of female stimulus faces compared to male stimulus faces. There was no gender effect (neither participant nor stimulus faces) in the recognition of other emotions. Conduct scores in boys were inversely correlated with the recognition of fear in male stimulus faces (R=-0.439, p<0.05) and with overall emotion recognition in male stimulus faces (R=-0.558, p<0.01). In girls, conduct scores were shown a tendency for positive correlation with disgust recognition in female stimulus faces (R=0.376, p<0.07). CONCLUSIONS: A gender-specific interaction between the recognition of emotions and antisocial developmentalpathway is suggested. PMID- 25041744 TI - [Fear of the dark in adolescence and emerging adulthood: general model, gender and age differences]. AB - INTRODUCTION: In our study we investigated fear of the dark in adolescence and emerging adulthood. First, we define fear and anxiety, which constitute together fear of the dark. We present the cognitive and interactionist models of fear, individual differences that affect the formation and maintenance of fear and the developmental aspects of this topic. The aim of our study was to map the phenomenon in adolescence and emerging adulthood, with respect to gender and age differences, and individual factors that affect the genesis of fear of the dark. METHODS: 83 secondary school (34 females) and 57 university students (29 females) filled our survey package. To measure the frequency of fear of the dark we used a self-developed scale. Our subjects also reported about the content and origin of their fears, and coping strategies applied against these fears. Individual differences were operationalized as trait anxiety, dysfunctional attitudes and self-esteem. RESULTS: 71 per cent of respondents reported to have experienced fear of dark at least rarely. Women - compared to men - indicated imagination as source of their fears, and were more likely to use avoidance, attention detraction and social support as coping. University students - compared to secondary school students - reported negative information as origin of their fears, and preferred avoidance as a mode of coping with them. Contents of fear showed no significant difference between either genders or age groups. In a pathway model we found that gender had a direct effect on the frequency of fear of the dark. Dysfunctional attitudes affected the frequency of fear via trait anxiety and low selfesteem. CONCLUSIONS: Fear of the dark effects a significant proportion of adolescents and emerging adults even in a non-clinical sample. Our results confirm and supplement former results concerning gender and age differences. The pathway model could prove to be an important empirical base for the treatment of fears and anxieties. PMID- 25041745 TI - [Investigation of the compulsive and impulsive behavioral addictions among adolescents]. AB - INTRODUCTION: Recently there has been an increase in the number of studies focusing on behavioral addictions. The aim of our research was to examine the behavioral addictions among adolescents and prove their connection with emotion regulation difficulties. Based on the compulsive-impulsive spectrum approach of addictions we hypothesized that the compulsive and impulsive forms of eating disorders (binge eating, emotional eating and restriction) - despite their various symptom structure - share a common motive, i.e. the emotion regulation deficit. METHODS: Our participants were high-school students (n = 272) between the age of 16 and 17 (128 males and 144 females, mean age: 16,8). We used the impulse- and emotion control subscales on the emotional stability dimension of the Big Five Questionnaire (BFQ), the Three Factor Eating Questionnaire (TFEQ R21), the Hungarian Problematic Internet Use Questionnaire (PIH-K) and the Difficulties in Emotion Regulation Scale (DERS). RESULTS: We found a strong connection between the uncontrolled eating and the problematic internet use (r = 0,404; p < 0,05). As expected, the individuals' skill of emotion regulation and their impulsiveness are both strongly correlated to these impulsive disorders (see Table 1.) Interestingly the cognitive restriction (r=0,073; p>0,05) and emotional eating (r=0,061; p>0,05) did not correlate with emotion regulation difficulties. There was a connection between the emotional eating and the emotion (r=-0,264; p<0,05) and impulse control deficit (r=-0,142; p<0,05), however. CONCLUSION: On the basis of these results we argue that the impulsive behavior of the adolescents (binge eating, problematic internet use) is determined by their impulsivity and their emotion regulation strategy. However, a compulsive behavior such as the cognitive restraint is regarded as a much more conscious and healthy behavior, the core feature of the emotional eating is also assumes a high anxiety level. PMID- 25041746 TI - [Verbal fluency tasks I. Investigation of the Hungarian version of the letter fluency task between 5 and 89 years of age]. AB - The letter fluency task is a widely used neuropsychological instrument to assess language and executive functions. We investigated the Hungarian version of the letter fluency task across lifespan, between 5 and 89 years of age (N=562). In the letter fluency task the participants are asked to generate as many words as possible in 1 minute that began with letter K, T or A. We obtained the next classical scores from the fluency task: number of words, number of perseverations, errors and more complex scores like number of clusters, cluster size, total switches and cluster switches. We found partly different developmental trajectories for these indices. Sex differences in performance were more prominent in younger ages. The analysis of the classical and complex indices of the Hungarian letter fluency task presented in our study can help in the investigation of normal and disrupted executive functions in the case of psychiatric and neurological disorders. PMID- 25041747 TI - [Verbal fluency tasks II. Investigation of the Hungarian version of the semantic fluency task between 5 and 89 years of age]. AB - The semantic fluency task is a widely used neuropsychological tool to assess lexico-semantic and executive functions related to fronto-temporal circuits. We investigated the Hungarian version of the semantic fluency task across lifespan, between 5 and 89 years of age (N=562). In the semantic fluency task the participants are asked to generate as many words as possible in 1 minute in a given category (animals, fruits, supermarket products). We analyzed classical scores such as number of words, perseverations and errors. Moreover we evaluated complex indices such as number of clusters, cluster size, total switches and cluster switches. We present the age-related and sex differences in the above mentioned indices. This tool pack could help in a more detailed characterization of cognitive functions in psychiatric and neurological disorders. PMID- 25041748 TI - [Minor physical anomalies in the relatives of schizophrenia patients. A systematic review of the literature]. AB - Minor physical anomalies are mild, clinically and cosmetically insignificant errors of morphogenesis which have a prenatal origin and may bear major informational value for diagnostic, prognostic and epidemiological purposes. Since both the central nervous system and the skin are derived from the same ectodermal tissue in utero, minor physical anomalies can be external markers of abnormal brain development and they appear more commonly in neurodevelopmental disorders. Recently studies were published on the prevalence of minor physical anomalies in the relatives of patients with schizophrenia. In a systematic review of literature 11 studies were identified with mixed results. We suppose that the differentiation of minor malformations and phenogenetic variants can help to clarify the minor anomaly profile as a potential endophenotype in schizophrenia. PMID- 25041749 TI - [Treatment of tardive syndromes]. AB - Tardive syndromes associated with dopamine-receptor blocking agents have heterogeneous appearance. The treatment of tardive dyskinesia, dystonia, myoclonus, tourettism, tremor and akathisia is challenging for both psychiatrists and neurologists. Lack of randomized and controlled examinations for many routinely applied clinical therapeutic options make the development of clinical guidelines difficult. The present review article summarizes the available evidence for the treatment of tardive syndromes. According to the treatment guideline published by the American Academy of Neurology in 2013, the usage of clonazepam, ginkgo biloba, amantadine and tetrabenazine has enough evidence to draw conclusions. Although lowering or stopping the eliciting agent, changing to atypical antipsychotics, and adding anticholinergics are widely used techniques, there are no convincing controlled studies available to support their efficacy. The usage of Vitamin E, levetiracetam, propranolol, botulinum toxin and deep brain stimulation may be promising treatment options in the future. PMID- 25041750 TI - [Compairing investigation of the stereotypes concerning doctors and psychotherapists]. AB - In this study the stereotypes about psychotherapists and medical doctors were examined. 172 personality traits were selected and dimensions were created, that was grouped by three professions (engineers, physicians, psychotherapists). The research questionnaire contained 45 contrary personality dimensions, which was rated to the previous three professions. After the screening criteria, 101 persons were included in the statistical analysis. Analyses of the variance filtered out 20 of the 45 dimensions in which the professions did not differ and 25 profession-specific dimensions remained in the study. In these dimension, the doctors and the psychotherapists (with the exception of introversion extroversion) were significantly different. Dimensional factor analysis was carried out by the dimensions of doctors and psychotherapists and it listed the dimensions to 3-3 factors. The first profile of the medical doctor released a picture of a doctor who has magical expectations of the patients, the second profile is distant, technocratic doctors, and the third is a pleasant human characteristics of medical images. The first factor of the psychotherapist is the humanistic therapist, the second profile is the cold, analytic therapist's image and the third is the image of a professional scientist. 2-2 factors are correlated, and the third ones in the trust / distrust towards the helpers are also connected. A hypothesis testing was carried out that people with own psychotherapy experiences and without own psychotherapeutic experience significantly differed: people with own psychotherapy experiences evaluated the psychotherapists significantly more imaginative, but in the other dimension there were no difference. Finally, we compared the assessments of the psychotherapists by men and women: women found them significantly more respectful, more scientific and more accurate workers, than the men did. PMID- 25041751 TI - Learning to manipulate and categorize in human and artificial agents. AB - This study investigates the acquisition of integrated object manipulation and categorization abilities through a series of experiments in which human adults and artificial agents were asked to learn to manipulate two-dimensional objects that varied in shape, color, weight, and color intensity. The analysis of the obtained results and the comparison of the behavior displayed by human and artificial agents allowed us to identify the key role played by features affecting the agent/environment interaction, the relation between category and action development, and the role of cognitive biases originating from previous knowledge. PMID- 25041752 TI - Rediscovering black phosphorus as an anisotropic layered material for optoelectronics and electronics. AB - Graphene and transition metal dichalcogenides (TMDCs) are the two major types of layered materials under intensive investigation. However, the zero-bandgap nature of graphene and the relatively low mobility in TMDCs limit their applications. Here we reintroduce black phosphorus (BP), the most stable allotrope of phosphorus with strong intrinsic in-plane anisotropy, to the layered-material family. For 15-nm-thick BP, we measure a Hall mobility of 1,000 and 600 cm(2)V( 1)s(-1) for holes along the light (x) and heavy (y) effective mass directions at 120 K. BP thin films also exhibit large and anisotropic in-plane optical conductivity from 2 to 5 MUm. Field-effect transistors using 5 nm BP along x direction exhibit an on-off current ratio exceeding 10(5), a field-effect mobility of 205 cm(2)V(-1)s(-1), and good current saturation characteristics all at room temperature. BP shows great potential for thin-film electronics, infrared optoelectronics and novel devices in which anisotropic properties are desirable. PMID- 25041753 TI - Fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration. AB - Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations. PMID- 25041754 TI - A compliant, banded outflow cannula for decreased afterload sensitivity of rotary right ventricular assist devices. AB - Biventricular support with dual rotary ventricular assist devices (VADs) has been implemented clinically with restriction of the right VAD (RVAD) outflow cannula to artificially increase afterload and, therefore, operate within recommended design speed ranges. However, the low preload and high afterload sensitivity of these devices increase the susceptibility of suction events. Active control systems are prone to sensor drift or inaccurate inferred (sensor-less) data, therefore an alternative solution may be of benefit. This study presents the in vitro evaluation of a compliant outflow cannula designed to passively decrease the afterload sensitivity of rotary RVADs and minimize left-sided suction events. A one-way fluid-structure interaction model was initially used to produce a design with suitable flow dynamics and radial deformation. The resultant geometry was cast with different initial cross-sectional restrictions and concentrations of a softening diluent before evaluation in a mock circulation loop. Pulmonary vascular resistance (PVR) was increased from 50 dyne s/cm(5) until left-sided suction events occurred with each compliant cannula and a rigid, 4.5 mm diameter outflow cannula for comparison. Early suction events (PVR ~ 300 dyne s/cm(5) ) were observed with the rigid outflow cannula. Addition of the compliant section with an initial 3 mm diameter restriction and 10% diluent expanded the outflow restriction as PVR increased, thus increasing RVAD flow rate and preventing left sided suction events at PVR levels beyond 1000 dyne s/cm(5) . Therefore, the compliant, restricted outflow cannula provided a passive control system to assist in the prevention of suction events with rotary biventricular support while maintaining pump speeds within normal ranges of operation. PMID- 25041755 TI - Hybridization, natural selection, and evolution of reproductive isolation: a 25 years survey of an artificial sympatric area between two mosquito sibling species of the Aedes mariae complex. AB - Natural selection can act against maladaptive hybridization between co-occurring divergent populations leading to evolution of reproductive isolation among them. A critical unanswered question about this process that provides a basis for the theory of speciation by reinforcement, is whether natural selection can cause hybridization rates to evolve to zero. Here, we investigated this issue in two sibling mosquitoes species, Aedes mariae and Aedes zammitii, that show postmating reproductive isolation (F1 males sterile) and partial premating isolation (different height of mating swarms) that could be reinforced by natural selection against hybridization. In 1986, we created an artificial sympatric area between the two species and sampled about 20,000 individuals over the following 25 years. Between 1986 and 2011, the composition of mating swarms and the hybridization rate between the two species were investigated across time in the sympatric area. Our results showed that A. mariae and A. zammitii have not completed reproductive isolation since their first contact in the artificial sympatric area. We have discussed the relative role of factors such as time of contact, gene flow, strength of natural selection, and biological mechanisms causing prezygotic isolation to explain the observed results. PMID- 25041756 TI - Augmented endothelial-specific L-arginine transport prevents obesity-induced hypertension. AB - AIM: Hypertension is a major clinical complication of obesity. Our previous studies show that abnormal uptake of the nitric oxide precursor L-arginine, via the cationic amino acid transporter-1 (CAT1), contributes to endothelial dysfunction in cardiovascular disease. In this study, we tested the hypothesis that abnormal L-arginine transport may be a key mediator of obesity-induced hypertension. METHODS: Mean arterial pressure (MAP) was monitored by telemetry in conscious wild-type (WT; n = 13) mice, and transgenic mice with endothelial specific overexpression of CAT1 (CAT+; n = 14) fed a normal or a high fat diet for 20 weeks. Renal angiotensin II (Ang II), CAT1 mRNA and plasma nitrate/nitrite levels were then quantified. In conjunction, plasma nitrate/nitrite levels were assessed in obese normotensive (n = 15) and obese hypertensive subjects (n = 15). RESULTS: Both genotypes of mice developed obesity when fed a high fat diet (P <= 0.002). Fat fed WT mice had 13% greater MAP and 78% greater renal Ang II content, 42% lesser renal CAT1 mRNA levels and 42% lesser plasma nitrate/nitrite levels, than WT mice fed a normal fat diet (P <= 0.02). In contrast, none of these variables were significantly altered by high fat feeding in CAT+ mice (P >= 0.36). Plasma nitrate/nitrite levels were 17% less in obese hypertensives compared with obese normotensives (P = 0.02). CONCLUSION: Collectively, these data indicate that obesity-induced down-regulation of CAT1 expression and subsequent reduced bioavailability of nitric oxide may contribute to the development of obesity-induced hypertension. PMID- 25041757 TI - The dipole moment of the spin density as a local indicator for phase transitions. AB - The intra-atomic magnetic dipole moment - frequently called ?Tz? term - plays an important role in the determination of spin magnetic moments by x-ray absorption spectroscopy for systems with nonspherical spin density distributions. In this work, we present the dipole moment as a sensitive monitor to changes in the electronic structure in the vicinity of a phase transiton. In particular, we studied the dipole moment at the Fe(2+) and Fe(3+) sites of magnetite as an indicator for the Verwey transition by a combination of x-ray magnetic circular dichroism and density functional theory. Our experimental results prove that there exists a local change in the electronic structure at temperatures above the Verwey transition correlated to the known spin reorientation. Furthermore, it is shown that measurement of the dipole moment is a powerful tool to observe this transition in small magnetite nanoparticles for which it is usually screened by blocking effects in classical magnetometry. PMID- 25041758 TI - Evidence of concurrent local adaptation and high phenotypic plasticity in a polar microeukaryote. AB - Here we investigated whether there is evidence of local adaptation in strains of an ancestrally marine dinoflagellate to the lacustrine environment they now inhabit (optimal genotypes) and/or if they have evolved phenotypic plasticity (a range of phenotypes). Eleven strains of Polarella glacialis were isolated and cultured from three different environments: the polar seas, a hyposaline and a hypersaline Antarctic lake. Local adaptation was tested by comparing growth rates of lacustrine and marine strains at their own and reciprocal site conditions. To determine phenotypic plasticity, we measured the reaction norm for salinity. We found evidence of both, limited local adaptation and higher phenotypic plasticity in lacustrine strains when compared with marine ancestors. At extreme high salinities, local lake strains outperformed other strains, and at extreme low salinities, strains from the hyposaline lake outperformed all other strains. The data suggest that lake populations may have evolved higher phenotypic plasticity in the lake habitats compared with the sea, presumably due to the high temporal variability in salinity in the lacustrine systems. Moreover, the interval of salinity tolerance differed between strains from the hyposaline and hypersaline lakes, indicating local adaptation promoted by different salinity. PMID- 25041759 TI - Thrombolysis in patients with prior stroke within the last 3 months. AB - BACKGROUND AND PURPOSE: Patients with prior stroke within 3 months have been mostly excluded from randomized thrombolysis trials mainly because of the fear of an increased rate of symptomatic intracerebral hemorrhage (sICH). The aim of this study was to compare baseline characteristics and clinical outcome of thrombolyzed patients who had a previous stroke within the last 3 months with those not fulfilling this criterion (comparison group). METHODS: In all, 1217 patients were included in our analysis (42.2% women, mean age 68.8 +/- 14.4 years). RESULTS: Patients with previous stroke within the last 3 months (17/1.4%) had more often a basilar artery occlusion (41.2% vs. 10.8%) and less frequently a modified Rankin scale (mRS) score 0-1 prior to index stroke (88.2% vs. 97.3%) and a higher mean time lapse from symptom onset to thrombolysis (321 min vs. 262 min) than those in the comparison group. Stroke severity was not different between the two groups. Rates of sICH were 11.8% vs. 6%. None of the sICHs and only one asymptomatic intracerebral hemorrhage occurred in the region of the former infarct. At 3 months, favorable outcome (mRS <= 2) in patients with previous stroke within 3 months was 29.4% (vs. 48.9%) and mortality 41.2% (vs. 22.7%). CONCLUSIONS: In patients with prior stroke within the last 3 months, none of the sICHs and only one asymptomatic intracerebral hemorrhage occurred in the region of the former infarct. The high mortality was influenced by four patients, who died until discharge due to acute major index stroke. It is reasonable to include these patients in randomized clinical trials and registries to assess further their thrombolysis benefit-risk ratio. PMID- 25041760 TI - Single sST2 protein measurement predicts adverse outcomes at 1-year follow-up in patients with chronic heart failure. AB - INTRODUCTION: sST2 protein is a new biomarker. Its prognostic value in chronic heart failure (CHF) is still unclear. OBJECTIVES: The aim of the study was to evaluate the value of sST2 protein in patients with CHF during 1-year follow-up after hospitalization for prediction of adverse events: cardiovascular death, rehospitalization, an increase in diuretic doses, and/or worsening of the New York Heart Association functional class, defined as the composite endpoint. PATIENTS AND METHODS: The study involved 145 consecutive patients (mean age, 62.16 +/-11.25 y; men, 82.76%) with left ventricular (LV) ejection fraction of 30% or less and symptomatic CHF. We analyzed clinical and biochemical data along with the serum concentrations of N-terminal pro-B-type natriuretic peptide (NT proBNP) and sST2. The optimal cut-off points for significant predictors of the composite endpoint were determined using receiver operating characteristi c curves. RESULTS: Patients with elevated levels of sST2 and NT-proBNP had more than a 4-fold higher risk of composite endpoint (odds ratio [OR], 4.033; 95%CI, 1.540-10.559) compared with patients in whom both biomarkers were below the cut off points. The C-statistic for predicting the composite endpoint was improved when both biomarkers were incorporated into the model (C-statistic, 0.692; P = 0.0001) compared with an individual analysis for NT-proBNP (C-statistic, 0.606; P = 0.009) and sST2 (C-statistic, 0.613; P = 0.003). Moreover, after the addition of sST2 to NT-proBNP, the continuous net reclassification improvement index (OR, 0.256; 95% CI, 0.090-0.401; P = 0.007) and the integrated discrimination improvement index (OR, 0.104; 95% CI 0.011-0.221; P = 0.007) significantly improved. CONCLUSIONS: A single measurement of sST2 levels on admission in patients with poor LV systolic function and stable CHF is useful in short-term risk stratification and, in combination with NT-proBNP, it could be more useful in identifying patients with unfavorable c ourse of CHF. PMID- 25041761 TI - The role of PFA-100 measurement in preoperative screening in total knee arthroplasty patients with perioperative replacement of cyclooxygenase-2 inhibitor. PMID- 25041762 TI - Familial polyglucosan body myopathy with unusual phenotype. PMID- 25041763 TI - The atmospheric oxidation mechanism of 1,2,4-trimethylbenzene initiated by OH radicals. AB - The atmospheric oxidation mechanism of 1,2,4-trimethylbenzene (1,2,4-TMB) initiated by OH radicals is investigated using quantum chemistry calculations at M06-2X and ROCBS-QB3 levels. The calculations show that the initiation of the reaction is dominated by OH addition to C1, C3 and C5 to form 1,2,4-TMB-OH adducts R1, R3, and R5 with branching ratios of 0.22, 0.19, and 0.38, respectively, using ROCBS-QB3 energies. In the troposphere, the adducts react with O2 by irreversible H-abstraction to form phenolic compounds and by reversible addition to TMB-OH-O2 peroxy radicals, which will cyclize to bicyclic radicals, similar to those in benzene, toluene, and xylenes. The bicyclic radicals can further recombine with O2 to generate bicyclic peroxy and alkoxyl radicals. The bicyclic alkoxyl radicals would break the ring directly to form 1,2 dicarbonyl products and unsaturated 1,4-dicarbonyl co-products, or undergo another cyclization to form an epoxy group, followed by the ring-breakage to form 1,2-dicarbonyl products and epoxy-1,4-dicarbonyl co-products. The predicted yields of products agree reasonably with the previous experimental measurements, while considerable discrepancies also exist for the yields of nitrates, biacetyl, 4-oxo-2-pentenal, and butenedial, etc. Our mechanism also predicts a new type of epoxy-1,4-dicarbonyl compounds with a total yield of ~0.32. The epoxy-1,4 dicarbonyl compounds have not been suggested or reported in previous studies. PMID- 25041764 TI - The role of substrate pre-stretch in post-wrinkling bifurcations. AB - When a stiff film on a soft substrate is compressed, the surface of the film forms wrinkles, with tunable wavelengths and amplitudes that enable a variety of applications. As the compressive strain increases, the film undergoes post wrinkling bifurcations, leading to period doubling and eventually to formation of localized folds or ridges. Here we study the post-wrinkling bifurcations in films on pre-stretched substrates. Through a combination of experiments and simulations, we demonstrate that pre-stretched substrates not only show substantial shifts in the critical strain for the onset of post-wrinkling bifurcations, but also exhibit qualitatively different post-wrinkled states. In particular, we report on the stabilization of wrinkles in films on pre-tensioned substrates and the emergence of 'chaotic' morphologies in films on pre-compressed substrates. PMID- 25041765 TI - A combined small-angle X-ray and neutron scattering study of the structure of purified soluble gastrointestinal mucins. AB - The structures of purified soluble porcine gastric (Muc5ac) and duodenal (Muc2) mucin solutions at neutral and acidic pH were examined using small-angle X-ray scattering and small-angle neutron scattering experiments. We provide evidence for the morphology of the network above the semidilute overlap concentration and above the entanglement concentration. Furthermore, we investigated the gelation of both types of mucin solutions in response to a reduction in pH, where we observed the formation of large-scale heterogeneities within the polymer solutions, typical of microphase-separated gels. The concentration dependence of the inhomogeneity length scale (Xi) and the amplitude of the excess scattering intensity [I(ex) (0)] are consistent with previously studied gelled synthetic polymeric systems. The persistence lengths of the chains were found to be similar for both Muc5ac and Muc2 from Kratky plots of the neutron data (8 +/- 2 nm). PMID- 25041766 TI - Individual and species-specific traits explain niche size and functional role in spiders as generalist predators. AB - The function of a predator within a community is greatly based on its trophic niche, that is the number and the strength of feeding links. In generalist predators, which feed on a wide range of prey, the size and position of the trophic niche is likely determined by traits such as hunting mode, the stratum they occur in, their body size and age. We used stable isotope analyses ((13)C and (15)N) to measure the trophic niche size of nine spider species within a forest hedge community and tested for species traits and individual traits that influence stable isotope enrichment, niche size and resource use. The spiders Enoplognatha, Philodromus, Floronia, and Heliophanus had large isotopic niches, which correspond to a more generalistic feeding behaviour. In contrast, Araneus, Metellina and Agelena, as top predators in the system, had rather narrow niches. We found a negative correlation between trophic position and niche size. Differences in trophic position in spiders were explained by body size, hunting modes and stratum, while niche size was influenced by hunting mode. In Philodromus, the size of the trophic niche increased significantly with age. Fitting spiders to functional groups according to their mean body size, hunting mode and their habitat domain resulted in largely separated niches, which indicates that these traits are meaningful for separating functional entities in spiders. Functional groups based on habitat domain (stratum) caught the essential functional differences between the species with species higher up in the vegetation feeding on flying insects and herb and ground species also preying on forest floor decomposers. Interestingly, we found a gradient from large species using a higher habitat domain and having a smaller niche to smaller species foraging closer to the ground and having a larger niche. This shows that even within generalist predators, such as spiders, there is a gradient of specialism that can be predicted by functional traits. PMID- 25041767 TI - A brick in the wall. PMID- 25041768 TI - Mortality from common drug interactions systems, knowledge and clinical reasoning to optimise prescribing. PMID- 25041769 TI - Interferon-gamma release assays and the diagnosis of tuberculosis: have they found their place? AB - Tuberculosis (TB) remains an important issue in Australia with more than 85% of active cases contributed by overseas-born persons. Other risk groups include older Australians who acquired TB in the past and indigenous people. Immune suppression is an emerging risk factor for TB, particularly due to the expanding group of conditions for which potent immunosuppressive therapies is now used. Screening for latent TB is recommended in many risk groups including recent contacts of those with transmissible TB, those undergoing immune suppressive therapy, recently arrived refugees or migrants from high-risk countries and indigenous people with high rates of TB in the local community. Interferon-gamma release assay (IGRA) has now been available for several years for the diagnosis of latent TB. It is now used in many clinical situations, and despite the rapid rate of new publications, there are still gaps in our knowledge. This paper reviews the current role of interferon-gamma release assay in various situations, to determine its place in current practice and to explore where uncertainties exist. PMID- 25041770 TI - Rhabdomyolysis in association with simvastatin and dosage increment in clarithromycin. AB - Clarithromycin is the most documented cytochrome P450 3A4 (CYP3A4) inhibitor to cause an adverse interaction with simvastatin. This particular case is of interest as rhabdomyolysis only occurred after an increase in the dose of clarithromycin. The patient developed raised cardiac biomarkers without any obvious cardiac issues, a phenomenon that has been linked to rhabdomyolysis previously. To date, there has been no reported effect of rhabdomyolysis on the structure and function of cardiac muscle. Clinicians need to be aware of prescribing concomitant medications that increase the risk of myopathy or inhibit the CYP3A4 enzyme. Our case suggests that troponin elevation could be associated with statin induced rhabdomyolysis, which may warrant further studies. PMID- 25041771 TI - Vancomycin-associated drug reaction with eosinophilia and systemic symptoms syndrome. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially life-threatening multi-system disorder characterised by the delayed onset of fever, rash and internal organ involvement following the administration of a drug. We report three definite cases of vancomycin-associated DRESS syndrome occurring and review the literature regarding this syndrome. PMID- 25041772 TI - Eltrombopag for resistant immune thrombocytopenia secondary to chronic lymphocytic leukaemia. AB - Autoimmune manifestations are a common occurrence with chronic lymphocytic leukaemia (CLL). We describe a case of CLL-associated immune thrombocytopenia (ITP) that had a loss of response to standard treatment for ITP. The thrombopoeitin receptor agonist, eltrombopag, was successfully used preoperatively to increase the platelet count to a safer level, in this instance to facilitate laparoscopic splenectomy. PMID- 25041773 TI - Novel finding of carbamazepine induced gall bladder granulomatous vasculitis. AB - We report a 63-year-old male patient who presented with eosinophilic granulomatous vasculitis of the gall bladder secondary to carbamazepine drug therapy. Following commencement of carbamazepine for treatment of partial seizures, the patient developed an allergic cutaneous drug rash. He continued to take carbamazepine postdischarge despite cessation by the treating team. He represented 7 weeks later with acute pancreatitis and cholecystis. Gall bladder histopathology showed a granulomatous vasculitis. PMID- 25041774 TI - Clinical judgement and the emotions. AB - The basic emotions are more important in decision making than we think. So we need to be aware of them and look not just for rationality in our clinical judgements but rational judgements that 'feel' right. PMID- 25041775 TI - Severe haemosiderin pigmentation after intravenous iron infusion. PMID- 25041776 TI - A novel hepatitis B virus S gene insertion associated with reduced humoral immunity and diagnostic escape. PMID- 25041777 TI - Acute viral encephalitis co-existing with fulminant hepatitis caused by Epstein Barr virus. PMID- 25041778 TI - Successful pregnancy in ventilatory failure due to campomelic dysplasia with severe kyphoscoliosis. PMID- 25041779 TI - Author reply: To PMID 24621289. PMID- 25041780 TI - Flawed peer-review process. PMID- 25041783 TI - Circulating endothelial cells as a biomarker in non-small cell lung cancer patients: correlation with clinical outcome. AB - BACKGROUND: Circulating endothelial cells (CECs) have been proposed as a biomarker for the assessment of patients with solid tumors. However, few data are available in non-small cell lung cancer (NSCLC). We therefore analyzed the clinical significance of CECs in newly diagnosed NSCLC patients. In addition, we tried to determine the prognostic value of CECs in NSCLC. METHODS: In this prospective study, 151 newly diagnosed NSCLC patients and 25 healthy volunteers were included. Furthermore, 25 patients with a partial response (n=15) or stable disease (n=10) after treatment were evaluated at recurrence with a mean follow-up of 117 days (range: 47-364 days). CECs were counted using magnetic beads coupled to a specific antibody against CD146. RESULTS: The pre-treatment CEC count was significantly higher in patients with all histological subtypes of NSCLC than in healthy volunteers (p<0.0001). High baseline CEC counts were significantly correlated with advanced clinical stages (p=0.026), weight loss (p=0.03), and poorly differentiated NSCLC (p=0.02). The amount of CECs increased significantly at recurrence compared with their amount after treatment in 20/21 assessable patients (p=0.0001). Nevertheless, there was no significant correlation between baseline CEC count and median duration of progression-free survival (p=0.402). CONCLUSIONS: Increased CEC counts were present in patients with newly diagnosed NSCLC compared with healthy subjects. Elevated levels of baseline CECs correlated with high-risk factors in NSCLC. In addition, increased CEC count during follow up seems to be correlated with recurrence in NSCLC patients. PMID- 25041782 TI - Epigenetic changes of TIMP-3, GSTP-1 and 14-3-3 sigma genes as indication of status of chronic inflammation and cancer. AB - OBJECTIVES: This study aimed to compare the epigenetic changes via hypermethylation status of TIMP-3, GSTP-1 and 14-3-3sigma genes, between healthy subjects and patients with reversible chronic inflammatory disease, and between healthy subjects and patients with irreversible malignant disease, to highlight the genetic changes that occur in the progression from an inflammatory condition to irreversible genetic changes commonly observed in cancer patients. METHODS: DNA was extracted from the blood of 680 healthy subjects, and tissues and blood of 110 patients with chronic inflammation disease of the gums, as well as neoplastic tissues of 108 breast cancer patients. Methylation-specific polymerase chain reaction (PCR) for TIMP-3, GSTP-1 and 14-3-3sigma was performed, and hypermethylation status was analyzed and compared between the 3 groups. RESULTS: The hypermethylation frequencies of TIMP-3 and GSTP-1 of reversible chronic inflammatory gum disease and the control group were similar, but both were significantly lower than those for malignant disease patients (p<0.0001). The methylation frequency of 14-3-3sigma in chronic inflammatory gum disease was higher than in the cancer and control groups (p<0.0001). The methylation of CpG islands in TIMP-3 and GSTP-1 in chronic inflammation patients occurred as frequently as in the control group, but less frequently than in breast cancer patients. However, the epigenetic silencing of 14-3-3sigma occurred more frequently in the chronic inflammation group than in cancer patients and healthy controls. CONCLUSIONS: The epigenetic silencing of 14-3-3sigma might be essential for chronic inflammatory gum disease. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to cancer. PMID- 25041784 TI - HER2 as a predictive factor for successful neoadjuvant anthracycline chemotherapy of locally advanced and early breast cancer. AB - OBJECTIVE: The aim of this study was to look for predictive and prognostic factors in anthracycline-based neoadjuvant chemotherapy. METHODS: Three hundred and nine patients with early-stage or locally advanced breast cancer were enrolled in this study and preoperatively treated with neoadjuvant chemotherapies in intense dose-dense (cyclophosphamide + epirubicin) or conventional (paclitaxel + epirubicin) regimens. Outcome parameters included overall objective response rate, as well as factors for determining pathological features influencing the efficacy of chemotherapy, such as estrogen receptor, progesterone receptor, and HER2 status, Eastern Cooperative Oncology Group (ECOG) score, tumor size, tumor inflammation, and lymph node metastasis. RESULTS: The overall pathological complete response (pCR) rate was 14.3%, and the main factor affecting the efficacy of chemotherapy was HER2 expression. The pCR rate was significantly higher for patients with HER2 overexpression, compared with patients with low HER2 expression (27.5% vs. 9.6%, p<0.001). The recurrence risk for patients with pCR decreased 1.12-fold compared with patients without pCR (5-year disease-free survival [DFS]: 81.8% vs. 65.7%, p=0.038). Patients in the HER2 overexpression subgroup benefited more from pCR than those in the HER2 low expression group (5 year DFS: 86.4% vs. 62.1%, p=0.049). CONCLUSION: HER2 overexpression in primary tumors might be a predictive marker for good efficacy of anthracycline-based neoadjuvant chemotherapy. The pCR is a suitable prognostic factor, even for patients with HER2 overexpression. PMID- 25041785 TI - Tumor microvasculature characteristics studied by image analysis: histologically driven angiogenic profile. AB - Angiogenesis, a hallmark of cancer, has been studied to be a potential marker for diagnosis, prognosis and therapy in breast cancer. To evaluate tumor angiogenesis, histological assessment has been a common approach and counting tumor microvessels after visualizing them by immunohistochemistry has been in use for a long time. With recent advances in digital pathology and image analysis, other characteristics of tumor vasculature can also be evaluated. In this article we briefly review the potentials of image analysis in assessing tumor microvessel morphologically that might be helpful in defining a better angiogenesis marker than other common markers like vessel count. PMID- 25041786 TI - Acute myeloid leukemia impairs natural killer cells through the formation of a deficient cytotoxic immunological synapse. AB - Acute myeloid leukemia (AML) cells are killed by allogeneic NK cells. However, autologous NK cells from AML patients express decreased levels of activating receptors, and show reduced cytotoxicity. Here, we investigated how interactions between NK and AML cells might cause loss of NK-cell activity in patients. Our results show that AML cell lines and primary blasts alter the NK-cell phenotype, reducing their cytotoxic potential upon prolonged contact. Downregulation of NK cell-activating receptors was contact-dependent and correlated with conjugate formation. Time-lapse imaging of HL60 AML cell line and NK-cell interactions showed a high proportion of noncytolytic contacts. Studies of NK-cell immunological synapses revealed a defect in lytic synapse formation. Namely, despite correct F-actin and LFA-1 recruitment, polarization of lytic granules toward primary blasts or AML cell lines was reduced. The NK-AML cell line synapses showed impairment of CD3zeta recruitment. Attempts to correct these synapse defects by cytokine stimulation of NK cells improved conjugate formation, but not granule polarization. Pretreatment of AML cell lines with the immunomodulating molecule lenalidomide significantly enhanced granule polarization. We speculate that combining immunomodulatory drugs and cytokines could increase AML cell sensitivity to autologous NK cells and reinforce the activity of allogeneic NK cells in adoptive immunotherapy. PMID- 25041787 TI - Expression pattern of vascular endothelial growth factor in canine folliculogenesis and its effect on the growth and development of follicles after ovarian organ culture. AB - In this study, the expressions of VEGF in dog follicles were detected by immunohistochemistry and the effects of VEGF treatment on the primordial to primary follicle transition and on subsequent follicle progression were examined using a dog ovary organ culture system. The frozen-thawed canine ovarian follicles within slices of ovarian cortical tissue were cultured for 7 and 14 days in presence or absence of VEGF. After culture, the ovaries were fixed, sectioned, stained and counted for morphologic analysis. The results showed that VEGF was expressed in the theca cells of antral follicles and in the granulosa cells nearest the oocyte in preantral follicle but not in granulosa cells of primordial and primary follicles; however, the VEGF protein was expressed in CL. After in vitro culture, VEGF caused a decrease in the number of primordial follicles and concomitant increase in the number of primary follicles that showed growth initiation and reached the secondary and preantral stages of development after 7 and 14 days. Follicular viability was also improved in the presence of VEGF after 7 and 14 days in culture. In conclusion, treatment with VEGF was found to promote the activation of primordial follicle development that could provide an alternative approach to stimulate early follicle development in dogs. PMID- 25041788 TI - Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells. AB - BACKGROUND: Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. OBJECTIVE: To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. METHODS: Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments. RESULTS: S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. CONCLUSION: S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma. PMID- 25041789 TI - Maintaining high activity levels in sedentary adults with a reinforcement thinning schedule. AB - Physical inactivity is a leading cause of mortality. Reinforcement interventions appear to be useful for increasing activity and preventing adverse consequences of sedentary lifestyles. This study evaluated a reinforcement-thinning schedule for maintaining high activity levels. Sedentary adults (N = 77) were given pedometers and encouraged to walk >=10,000 steps per day. Initially, all participants earned rewards for each day they walked >=10,000 steps. Subsequently, 61 participants were randomized to a monitoring-only condition or a monitoring-plus-reinforcement-thinning condition, in which frequencies of monitoring and reinforcing walking decreased over 12 weeks. The mean (+/- SD) percentage of participants in the monitoring-plus-reinforcement-thinning condition who met walking goals was 83% +/- 24% and was 55% +/- 31% for participants in the monitoring-only condition, p < .001. Thus, monitoring plus reinforcement thinning maintained high rates of walking when it was in effect; however, groups did not differ at a 24-week follow-up. Monitoring plus reinforcement thinning, nevertheless, hold potential to extend benefits of reinforcement interventions at low costs. PMID- 25041790 TI - Reproductive and menstrual factors and risk of differentiated thyroid carcinoma: the EPIC study. AB - Differentiated thyroid carcinoma (TC) is threefold more common in women than in men and, therefore, a role of female hormones in the etiology of differentiated TC has been suggested. We assessed these hypotheses in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 345,157 women (mean age 51) followed for an average of 11 years, 508 differentiated TC cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No significant associations were observed between differentiated TC risk and number of pregnancies, breast feeding, menopausal status, and age at menarche and at menopause. Significant associations were found with history of infertility problems (HR 1.70; 95% CI 1.12-2.60), a recent pregnancy (HR for <= 5 vs. >5 years before recruitment 3.87; 95% CI 1.43-10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95% CI 1.41-3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95% CI 0.25-0.92) and duration of OC use (HR for >= 9 vs. <= 1 year: 0.66; 95% CI: 0.50 0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR = 1.30, 95% CI 1.02-1.67), but this was not significant after adjustment for type of menopause (HR = 1.22, 95% CI 0.95-1.57). Overall, our findings do not support a strong role of reproductive and menstrual factors, and female hormone use in the etiology of differentiated TC. The few observed associations may be real or accounted for by increased surveillance in women who had infertility problems, recent pregnancies or underwent surgical menopause. PMID- 25041793 TI - Safety and feasibility of granulocyte colony-stimulating factor (G-CSF) primed bone marrow (BM) using three days of G-CSF priming as stem cell source for pediatric allogeneic BM transplantation. AB - There are limited data on the optimal dosing and schedule of G-CSF priming prior to BM harvest. We evaluated the safety and efficacy of three days of G-CSF of primed BM from related pediatric donors. Forty-five children were treated. All donors received 5 MUg/kg per day of G-CSF as a single subcutaneous injection for three consecutive days prior to the BM harvest. The median age of the donors was seven yr (range, 0.8-18) and no donor experienced major adverse events related to G-CSF administration. The median age for the recipients was five yr (0.3-16 yr). Thirty-five patients had non-malignant disorders. The median dose of nucleated (TNC) and CD34+, CD3 cells infused per recipient weight was 5.4 * 10(8) /kg (range, 0.61-17), 4.7 * 10(6) /kg (range, 1.6-19), and 43.8 * 10(6) /kg (range, 1.8-95), respectively. All patients achieved neutrophil and platelets engraftment, at a median of 15 (range, 10-22) and 23 days (range, 13-111), respectively. At a median follow up of 60 months (range 12-100), the estimated five yr overall and EFS was 91% and 80%, respectively. Collection of BM following three days of G-CSF priming from pediatric donors is safe and results in high TNC and CD34+ cell yield. PMID- 25041791 TI - Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). AB - BACKGROUND: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC. PMID- 25041794 TI - Neuroprotection against degeneration of sk-N-mc cells using neuron growth factor encapsulated liposomes with surface cereport and transferrin. AB - Liposomes with Cereport (RMP-7) and transferrin (Tf) (RMP-7/Tf/liposomes) were employed to target the blood-brain barrier (BBB) and to inhibit the degeneration of neurons insulted with fibrillar beta-amyloid peptide 1-42 (Abeta1-42). Neuron growth factor (NGF)-encapsulated RMP-7/Tf/liposomes (RMP-7/Tf/NGF-liposomes) were used to permeate a monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes (HAs) and to treat Abeta1-42 -attacked SK N-MC cells. An increase in RMT-7 concentration increased the particle size, zeta potential, propidium iodide (PI) permeability, and NGF permeability, but decreased the cross-linking efficiency of RMT-7, viability of HBMECs and HAs, and transendothelial electrical resistance (TEER). In addition, an increase in Tf concentration enhanced the particle size, viability of HBMECs, HAs, and SK-N-MC cells, PI permeability, and NGF permeability, but reduced the zeta potential, cross-linking efficiency of RMT-7 and Tf, and TEER. RMP-7/Tf/NGF-liposomes can transport NGF across the BBB and improve the neuroprotection for Alzheimer's disease therapy in preclinical trials. PMID- 25041792 TI - Target- and input-dependent organization of AMPA and NMDA receptors in synaptic connections of the cochlear nucleus. AB - We examined the synaptic structure, quantity, and distribution of alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-type glutamate receptors (AMPARs and NMDARs, respectively) in rat cochlear nuclei by a highly sensitive freeze-fracture replica labeling technique. Four excitatory synapses formed by two distinct inputs, auditory nerve (AN) and parallel fibers (PF), on different cell types were analyzed. These excitatory synapse types included AN synapses on bushy cells (AN-BC synapses) and fusiform cells (AN-FC synapses) and PF synapses on FC (PF-FC synapses) and cartwheel cell spines (PF-CwC synapses). Immunogold labeling revealed differences in synaptic structure as well as AMPAR and NMDAR number and/or density in both AN and PF synapses, indicating a target-dependent organization. The immunogold receptor labeling also identified differences in the synaptic organization of FCs based on AN or PF connections, indicating an input-dependent organization in FCs. Among the four excitatory synapse types, the AN-BC synapses were the smallest and had the most densely packed intramembrane particles (IMPs), whereas the PF-CwC synapses were the largest and had sparsely packed IMPs. All four synapse types showed positive correlations between the IMP-cluster area and the AMPAR number, indicating a common intrasynapse-type relationship for glutamatergic synapses. Immunogold particles for AMPARs were distributed over the entire area of individual AN synapses; PF synapses often showed synaptic areas devoid of labeling. The gold-labeling for NMDARs occurred in a mosaic fashion, with less positive correlations between the IMP-cluster area and the NMDAR number. Our observations reveal target- and input-dependent features in the structure, number, and organization of AMPARs and NMDARs in AN and PF synapses. PMID- 25041795 TI - Aortic coarctation repair in neonates with intracardiac defects: the importance of preservation of the lesser curvature of the aortic arch. AB - BACKGROUND AND AIM: The aim of this study was to evaluate the mid-term outcomes of a strategy for repair of coarctation of the aorta (CoA) and hypoplastic aortic arch (HAA) with a modified, extended end-to-end repair that preserves the lesser curvature of the aortic arch in neonates with intracardiac defects. METHODS: We studied 21 neonates who underwent CoA repair and remote intracardiac repair (2000 2013). Fifteen patients had HAA, and six patients had no HAA. Follow-up ranged from 0.4 to 12.8 years (median, 7.5 years), and all patients underwent cardiac catheterization and blood pressure measurement in both the arms and legs. RESULTS: The overall median age at the time of CoA repair was seven days and the median age at the time of intracardiac defect repair was 18.6 months. There were no hospital deaths and one case had recoarctation (4.8%). The overall mean pressure gradient at the latest follow-up was 3.4 +/- 5.7 mmHg. Critical deformation of arch geometry was not found. No patient had hypertension or an abnormal arm-leg gradient. There was no difference in the cardiac catheterization data or blood pressure between patients with and without HAA. CONCLUSIONS: A modified, extended end-to-end repair for CoA and HAA resulted in a low rate of recoarctation, no operative mortality, maintenance of a smooth rounded arch, and normal blood pressures in the arms and legs during mid-term follow-up. These results suggest that this technique may be acceptable for repair of CoA and HAA in neonates with intracardiac defects. PMID- 25041796 TI - Assessment of cluster yield components by image analysis. AB - BACKGROUND: Berry weight, berry number and cluster weight are key parameters for yield estimation for wine and tablegrape industry. Current yield prediction methods are destructive, labour-demanding and time-consuming. In this work, a new methodology, based on image analysis was developed to determine cluster yield components in a fast and inexpensive way. RESULTS: Clusters of seven different red varieties of grapevine (Vitis vinifera L.) were photographed under laboratory conditions and their cluster yield components manually determined after image acquisition. Two algorithms based on the Canny and the logarithmic image processing approaches were tested to find the contours of the berries in the images prior to berry detection performed by means of the Hough Transform. Results were obtained in two ways: by analysing either a single image of the cluster or using four images per cluster from different orientations. The best results (R(2) between 69% and 95% in berry detection and between 65% and 97% in cluster weight estimation) were achieved using four images and the Canny algorithm. The model's capability based on image analysis to predict berry weight was 84%. CONCLUSION: The new and low-cost methodology presented here enabled the assessment of cluster yield components, saving time and providing inexpensive information in comparison with current manual methods. PMID- 25041797 TI - Retention, fatigue, burnout and job satisfaction: new aspects and challenges. PMID- 25041798 TI - Turnover of regulated nurses in long-term care facilities. AB - AIMS: To describe the relationship between nursing staff turnover in long-term care (LTC) homes and organisational factors consisting of leadership practices and behaviours, supervisory support, burnout, job satisfaction and work environment satisfaction. BACKGROUND: The turnover of regulated nursing staff [Registered Nurses (RNs) and Registered Practical Nurses (RPNs)] in LTC facilities is a pervasive problem, but there is a scarcity of research examining this issue in Canada. METHODS: The study was conceptualized using a Stress Process model. Distinct surveys were distributed to administrators to measure organisational factors and to regulated nurses to measure personal and job related sources of stress and workplace support. In total, 324 surveys were used in the linear regression analysis to examine factors associated with high turnover rates. RESULTS: Higher leadership practice scores were associated with lower nursing turnover; a one score increase in leadership correlated with a 49% decrease in nursing turnover. A significant inverse relationship between leadership turnover and nurse turnover was found: the higher the administrator turnover the lower the nurse turnover rate. CONCLUSION: Leadership practices and administrator turnover are significant in influencing regulated nurse turnover in LTC. IMPLICATIONS FOR NURSING MANAGEMENT: Long-term care facilities may want to focus on building good leadership and communication as an upstream method to minimize nurse turnover. PMID- 25041799 TI - Why are they leaving? Causes of actual turnover in the Danish eldercare services. AB - AIM: To investigate reasons for actual turnover among eldercare staff and to investigate changes in job design that could prevent turnover. BACKGROUND: Many Western countries have difficulties in recruiting healthcare staff to provide care for an ageing population. Knowledge on the causes of turnover among healthcare staff is therefore important. METHOD: In a prospective cohort study (n = 7025) baseline characteristics were compared for employees who respectively quit, retired and worked in eldercare at follow-up. Additionally, a survey was conducted among those employees who left their jobs during follow-up. RESULTS: Employees who quit their jobs (n = 461) primarily stated that psychosocial work conditions caused them to quit, whereas retirees (n = 265) primarily stated reasons related to health and physical job demands. Improvements in the time available for the contact with the elderly, increased skill discretion and improved social relations could prompt employees to reconsider quitting or retiring. CONCLUSION: Work in eldercare has some 'core' aspects that appear desirable to employees who quit or retired. Building on those aspects offers a strategy for enhanced recruitment potential. IMPACT FOR NURSING MANAGEMENT: To reduce turnover managers should improve psychosocial work conditions in eldercare and ensure that physical demands do not exceed the capacities of employees. PMID- 25041800 TI - The impact of shift work on nurses' job stress, sleep quality and self-perceived health status. AB - AIM: The aim of this study was to describe the current state of nurses' shift work in Taiwan and how it affects nurses' stress, sleep quality and self perceived health status. BACKGROUND: To enable the provision of 24-hour patient care, nurses need to work various shifts. Long-term shift work significantly affects nurses' overall physical and mental health. METHOD: Nurses from four Chiayi County district hospitals in Taiwan (n = 266) participated in this cross sectional study from August to September 2010. Demographics, work schedule forms, a stress checklist, a sleep-quality measure and a health-status measure were used to collect data. Independent t-test, one-way anova, Pearson's r, and hierarchical regression were applied for analysis. RESULTS: The results showed that regardless of the amount of shift work they performed, nurses reported moderate job stress, poor sleep quality and moderate self-perceived health. The following significant relationships were observed: job stress was inversely related to sleep quality, which was directly related to self-perceived health status. CONCLUSION AND IMPLICATIONS FOR NURSING MANAGEMENT: Hospital managers need to ensure more healthy shift work scheduling in order to improve nurses' clinical performance and personal health status, thereby also improving the quality of patient care. PMID- 25041801 TI - The influence of perceived stress on work-family conflict and mental health: the moderating effect of person-environment fit. AB - AIM: This study examines whether higher perceived stress among female hospital workers can result in more serious work-family conflict (WFC) and poorer mental health, and also identifies the role that person-environment (P-E) fit plays in moderating these relationships. BACKGROUND: Female hospital workers with higher perceived stress tend to report greater WFC and worse mental health than others with less perceived stress. A better fit between a person and her environment may lead to lower perceived stress. As a result, she may experience less WFC and better mental health. METHODS: This study adopts a longitudinal design with 273 participants, all of whom are employed by hospitals in Taiwan. All hypotheses are tested using hierarchical regression analyses. RESULTS: The results show that perceived stress is an effective predictor of WFC and mental health status, whereas the P-E fit can moderate these relationships. CONCLUSION: Hospitals should pay more attention to the negative effects of perceived high stress on the WFC levels and mental health of their female employees. The P-E fit can buffer effectively the impact of perceived stress on both WFC and mental health. IMPLICATIONS FOR NURSING MANAGEMENT: If hospitals can adopt appropriate human resource management practices as well as monitor and manage the P-E fit continuously, they can better help their employees to fit into the overall hospital environment. PMID- 25041802 TI - Factors related to burnout among Chinese female hospital nurses: cross-sectional survey in Liaoning Province of China. AB - AIM: To explore the factors associated with burnout among female hospital nurses in China. BACKGROUND: Burnout has been a major concern in the field of occupational health, and yet there has been little research exploring the factors related to burnout among Chinese nurses. Exploring the factors associated with burnout is important in improving nurses' health and the quality of health care services in China. METHODS: The study population consisted of 1845 female hospital nurses in the Liaoning Province of China. Burnout was measured using the Chinese version of the Maslach Burnout Inventory-General Survey; occupational stress was measured using the Chinese versions of the Job Content Questionnaire and Effort-Reward Imbalance Questionnaire. A general linear regression model was applied to analyse the factors associated with burnout. RESULTS: Mean scores (+/ SD) were 11.74 (7.14) for emotional exhaustion, 7.12 (5.67) for cynicism and 23.34 (9.60) for self-efficacy. Strong extrinsic effort was the most powerful predictor of emotional exhaustion and cynicism; strong psychological job demands were the most robust predictor of low self-efficacy. CONCLUSION: The findings suggest that occupational stress was strongly related to burnout among female hospital nurses in China. IMPLICATIONS FOR NURSING MANAGEMENT: Occupational stress was identified as the most robust predictor of burnout among Chinese female hospital nurses. Reducing burnout among nurses working in China may require health education, health promotion and occupational training programmes aimed at improving work situations and reducing occupational stress. PMID- 25041803 TI - Does participative leadership reduce the onset of mobbing risk among nurse working teams? AB - AIMS: To evaluate the advancement of knowledge on the impact of an empowering leadership style on the risk of mobbing behaviour among nurse working teams. The secondary aim was to evaluate, along with leadership style, the contribution of other organisational- and individual-related mobbing predictors. BACKGROUND: The style of leadership in reducing the onset of mobbing risk in nurse working teams still remains a matter of discussion. Nurse working teams are particularly affected by mobbing and studies exploring individual and organisational inhibiting/modulating factors are needed. METHODS: An empirical study involving 175 nurses of various public hospital corporations in northern Italy. Data were collected via structured and anonymous questionnaires and analysed through a logistic regression. RESULTS: Organisational, individual and participative leadership variables explained 33.5% (P < 0.01) of variance in the onset of mobbing. Two predictive factors emerged: a participative leadership enacted by nursing managers and the nursing shortage as perceived by clinical nurses. Results confirmed that the contribution made by a participative leadership style in attenuating the onset of mobbing risk in working teams was significant. CONCLUSIONS AND IMPLICATIONS FOR NURSING MANAGEMENT: A participative leadership style adopted by the nurse manager allows for the reduction of tensions in nurse working teams. However, mobbing remains a multifaceted phenomenon that is difficult to capture in its entirety and the leadership style cannot be considered as a panacea for resolving this problem in nurse working teams. PMID- 25041804 TI - Job satisfaction among public health nurses: a national survey. AB - BACKGROUND: Despite increasing interest in nurses' job satisfaction relatively few studies have investigated job satisfaction among public health nurses. AIM: To establish current level of job satisfaction among public health nurses and identify the main contributing variables/factors to job satisfaction among this population. DESIGN: Quantitative descriptive design. A simple random sample of 1000 public health nurses was conducted yielding a response rate of 35.1% (n = 351). Data was collected using the Index of Work Satisfaction Questionnaire. Descriptive and inferential statistics were deployed. RESULTS: Low levels of job satisfaction among public health nurses emerged. Professional status, interaction and autonomy contributed most to job satisfaction while pay and task-related activities contributed least. Age and tenure were the only biographic factors that correlated significantly with job satisfaction. CONCLUSION: Public health nurse managers/leaders need to find creative ways of improving the factors that contribute to job satisfaction and address robustly those factors that result in low job satisfaction. IMPLICATIONS FOR NURSING MANAGEMENT: The critical issue for public health nurse managers is to determine how job satisfaction can be improved. Greater collaboration and consultation between managers and public health nurses can be regarded as a useful way to begin this process, especially if contemporary nursing is to embrace a responsive approach within the profession. PMID- 25041805 TI - Job satisfaction among nursing personnel in Hong Kong: a questionnaire survey. AB - AIMS: To investigate the perceived importance and actual level of job satisfaction among enrolled nurses (ENs), registered nurses (RNs), specialty nurses (SNs) and nurse managers (NMs) in Hong Kong. BACKGROUND: In the past, few studies have been conducted to investigate job satisfaction among different groups of nursing personnel. METHODS: This was a cross-sectional study. Stamps and Piedmonte's Index of Work Satisfaction (IWS) Scale was used to measure the level of job satisfaction. RESULTS: Six hundred and seventy-two nursing personnel from two large hospitals participated in this study. Discrepancies were found between the perceived importance and the actual satisfaction of job components among nursing personnel. The level of job satisfaction varied by position (F3,668 = 28.83, P < 0.001). Tukey's post-hoc tests further indicated that RNs had the lowest job satisfaction. The IWS scores for ENs, RNs, SNs and NMs were 12.3, 11.2, 12.5 and 13, respectively. Each group shared and had its own unique factors associated with its job satisfaction. CONCLUSION: The perceived importance and actual satisfaction with the six job components among nursing personnel varied by position. IMPLICATIONS FOR NURSING MANAGEMENT: Administrators should be aware that strategies to improve job satisfaction should be specific to job titles. No single strategy is appropriate for all nursing personnel. PMID- 25041806 TI - Tribute to Professor Melanie Jasper, editor-in-chief of the Journal of Nursing Management. PMID- 25041807 TI - Turbinate-septal suture for middle turbinate medialization: a prospective randomized trial. AB - OBJECTIVES/HYPOTHESIS: One of the primary goals of endoscopic sinus surgery (ESS) is to create widely patent paranasal sinus ostia, but lateralization of the middle turbinate (MT) after ESS can obstruct otherwise patent ethmoid and maxillary sinuses. The aim of this study was to evaluate the effectiveness of turbinate-septal suturing in preventing lateralization of the MT. STUDY DESIGN: A prospective, randomized, blinded controlled study. METHODS: The study was performed in 120 patients who had undergone ESS. The patients were randomized to receive nasal (group A) or turbinate-septal suture plus nasal packing (group B). Postoperative lateralization of the MT and synechia formation were assessed as the primary outcome 3 months post-ESS. The Lund-Kennedy Scores at 1 week, 2 week, and 1 month after ESS were assessed as the secondary outcomes. RESULTS: A total of 120 patients were enrolled (60 patients in each group). Group B had a significantly lower rate of MT lateralization compared to group A after 3 months of surgery (6 of 120 sides vs. 19 of 120 sides; P < 0.01). Synechia formation rates in groups B were also significantly lower than those in group A (4 of 120 sides vs. 13 of 120 sides; P = 0.023). CONCLUSION: Middle turbinate-septal suturing medialization during ESS is an effective method for preventing lateralization of the MT. PMID- 25041808 TI - Possible delayed respiratory depression following intrathecal injection of morphine and bupivacaine in an alpaca. AB - OBJECTIVE: To describe general anesthesia and successful treatment of an alpaca, which developed respiratory arrest 2 hours after intrathecal injection of morphine and bupivacaine. CASE SUMMARY: A 10-day-old female alpaca weighing 7.3 kg was presented to our hospital with a fractured right tibia. The cria was anesthetized to repair the fracture with a dynamic compression plate. Anesthesia was induced with IV propofol and maintained with sevoflurane in 100% oxygen. Prior to the start of surgery the alpaca received an unintended intrathecal injection of 0.6 mL of a solution of 0.5 mg morphine (0.068 mg/kg) and 1.5 mg bupivacaine (0.2 mg/kg), after an attempted lumbo-sacral epidural. The alpaca developed respiratory arrest 120 minutes after the intrathecal injection was administered. Adequate hemoglobin-oxygen saturation was maintained despite minimal intermittent manual ventilation, but marked hypercapnia developed (PaCO2 of 17.3 KPa [130 mm Hg]). Delayed respiratory depression resulting from cephalad migration of intrathecal morphine was suspected. Ventilation was supported until the end of surgery when sevoflurane was discontinued. The trachea remained intubated, 100% oxygen was supplied, and ventilation was supported at 2-4 breaths/min for the next 60 minutes, but no attempts to breathe spontaneously were detected. Intravenous naloxone (0.3 mg [0.04 mg/kg]) was administered slowly to effect until adequate spontaneous ventilation and full consciousness returned. The anesthetic recovery of the alpaca was rapid and uneventful after the opioid antagonist was given. NEW INFORMATION PROVIDED: Delayed respiratory depression is a potential complication after intrathecal administration of morphine. Careful dose-adjustment may reduce the risk, and close monitoring will result in early detection and treatment of this complication. PMID- 25041809 TI - Central serous chorioretinopathy and bright light: authors reply. PMID- 25041810 TI - Sonography of the first metatarsophalangeal joint and sonographically guided intraarticular injection of corticosteroid in acute gout attack. AB - OBJECTIVE: The aims of this study were to identify the characteristic ultrasound (US) findings of the first metatarsophalangeal joint (MTPJ1) in acute gout attack and to evaluate the efficacy and safety of US-guided intraarticular corticosteroid injection of the MTPJ1. METHODS: We enrolled 21 patients with acute gout attack involving the MTPJ1 unilaterally. US evaluation of each affected MTPJ1 was compared with radiographic features. US-guided intraarticular corticosteroid (0.5 ml [20 mg] of triamcinolone mixed with 0.5 ml of 2% lidocaine) was injected into the affected MTPJ1s. Pain, general disability, and walking disability were assessed at baseline, 24 hours, 48 hours, and 7 days after injection with visual analog scales. RESULTS: The characteristic US findings of MTPJ1 were erosion, joint effusion, synovial hypertrophy, tophus-like lesion, double contour, hyperechoic spots, and increased power Doppler signal in acute gout attack. US was more sensitive than conventional radiograph in detecting erosion and tophus-like lesion. The reductions of mean visual analog scale scores in pain, general disability, and walking disability were 48 mm (SD, 27), 35 mm (SD, 26) and 39 mm (SD, 26), respectively, 48 hours after US-guided intraarticular corticosteroid injection. There were no adverse events. CONCLUSIONS: US is a sensitive tool to evaluate joint abnormality of the MTPJ1 in acute gout attack and US-guided intraarticular corticosteroid injection to this joint is effective and safe. PMID- 25041811 TI - Population pharmacokinetics of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens. AB - ABT-384 is a potent and selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (HSD-1). The pharmacokinetics of ABT-384 was evaluated in healthy volunteers in single-dose (1, 8, 20, 50, 120 and 240 mg) and multiple dose studies (1, 2, 4, 8, 20, 30 and 100 mg once daily). Less than dose proportional pharmacokinetics of ABT-384 was observed when ABT-384 was administered at single doses lower than 8 mg. This nonlinear phenomenon disappeared after repeated doses. The dose-normalized plasma concentration-time curves superposed across all dose groups on day 7, but not on day 1. This phenomenon cannot be explained by the half-life of ABT-384. Based on available data, the nonlinearity is likely due to binding of ABT-384 to a high-affinity-low capacity site, such that this interaction was reflected in ABT-384 pharmacokinetics. To characterize the pharmacokinetics of ABT-384, a population pharmacokinetic model for ABT-384 was constructed. The model provided reasonable fitting for both single- and multiple-dose data. Further investigation is warranted to evaluate the disposition of ABT-384 at low doses using a larger number of subjects. The constructed model would be useful in predicting ABT-384 concentrations at different doses and guiding the selection of dosing regimens in further clinical trials. PMID- 25041812 TI - Can prenatal screening reduce the adverse obstetric outcomes related to abnormal placentation? PMID- 25041813 TI - Neuropsychological study of amyotrophic lateral sclerosis and parkinsonism dementia complex in Kii peninsula, Japan. AB - BACKGROUND: The Kii peninsula of Japan is one of the foci of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in the world. The purpose of this study is to clarify the neuropsychological features of the patients with ALS/PDC of the Kii peninsula (Kii ALS/PDC). METHODS: The medical interview was done on 13 patients with Kii ALS/PDC, 12 patients with Alzheimer's disease, 10 patients with progressive supranuclear palsy, 10 patients with frontotemporal lobar degeneration and 10 patients with dementia with Lewy bodies. These patients and their carer/spouse were asked to report any history of abulia-apathy, hallucination, personality change and other variety of symptoms. Patients also underwent brain magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and neuropsychological tests comprising the Mini Mental State Examination, Raven's Colored Progressive Matrices, verbal fluency, and Paired Associate Word Learning Test and some of them were assessed with the Frontal Assessment Battery (FAB). RESULTS: All patients with Kii ALS/PDC had cognitive dysfunction including abulia-apathy, bradyphrenia, hallucination, decrease of extraversion, disorientation, and delayed reaction time. Brain MRI showed atrophy of the frontal and/or temporal lobes, and SPECT revealed a decrease in cerebral blood flow of the frontal and/or temporal lobes in all patients with Kii ALS/PDC. Disorientation, difficulty in word recall, delayed reaction time, and low FAB score were recognized in Kii ALS/PDC patients with cognitive dysfunction. CONCLUSIONS: The core neuropsychological features of the patients with Kii ALS/PDC were characterized by marked abulia-apathy, bradyphrenia, and hallucination. PMID- 25041814 TI - Response to an expanding role of biomarkers in acute aortic syndromes. PMID- 25041815 TI - Application of temperature-correlated mobility theory for optimizing the MEKC separation of the main lignans from Schisandra Chinensis Fructus and its prescription Yuye Decoction. AB - The present work shows the application of the temperature-correlated mobility theory for the optimization of the separation and peak alignment of the main lignans from water extracts of traditional Chinese medicine Schisandra Chinensis Fructus as well as its prescription Yuye Decoction (Jade Fluid Decoction; YYD). This is the first application of this theory for MEKC separations, and the data presentation allows a much easier peak tracking and thereby identification of the analytes. Most interestingly, the data obtained and presented in the mobility scale at 298 K, show that Schisantherin A, which is easily mistaken as one of the analytes using traditional time scale, was actually not detected in Schisandra Chinensis Fructus and Yuye Decoction (Jade Fluid Decoction) water extracts. This proves the value of the temperature-correlated mobility scale for method optimization of complex samples. Thus, in the temperature-correlated mobility scale, the optimization of the system conditions for the MEKC separations can easily be achieved by correcting for viscosity changes. Also, the influence of the operating temperature can be monitored in a more distinct way. PMID- 25041816 TI - Single-neuron axonal pathfinding under geometric guidance: low-dose-methylmercury developmental neurotoxicity test. AB - Because the nervous system is most vulnerable to toxicants during development, there is a crucial need for a highly sensitive developmental-neurotoxicity-test model to detect potential toxicants at low doses. We developed a lab-on-chip wherein single-neuron axonal pathfinding under geometric guidance was created using soft lithography and laser cell-micropatterning techniques. After coating the surface with L1, an axon-specific member of the Ig family of cell adhesion molecules (CAMs), and optimizing microunit geometric parameters, we introduced low-dose methylmercury, a well-known, environmentally significant neurotoxicant, in the shared medium. Its developmental neurotoxicity was evaluated using a novel axonal pathfinding assay including axonal turning and branching rates at turning points in this model. Compared to the conventional neurite-outgrowth assay, this model's detection threshold for low-dose methylmercury was 10-fold more sensitive at comparable exposure durations. These preliminary results support study of developmental effects of known and potential neurotoxicants on axon pathfinding. This novel assay model would be useful to study neuronal disease mechanisms at the single-cell level. To our knowledge, the potential of methylmercury chloride to cause acute in vitro developmental neurotoxicity (DNT) at such a low dosage has not been reported. This is the first DNT test model with high reproducibility to use single-neuron axonal pathfinding under precise geometric guidance. PMID- 25041818 TI - Intramammary infusion of an Enterococcus faecium SF68 preparation promoted the involution of drying off Holstein cows partly related to neutrophil-associated matrix metalloproteinase 9. AB - A problem for dairy cows following milk stasis is to cope with a high risk of intramammary infection and there is a need to initiate an extensive renewal of secretory modules in mammary glands so that milk production in next lactation may be optimized. We recently reported that ultrasonicated Enterococcus faecium SF68 (SF68) is compatible with cow mammary glands and an enhancer of innate immunity during the immediate post-milk stasis period. The current study further examines the concomitant effect of ultrasonicated SF68 on mammary tissue remodeling. Four Holstein cows each received intramammary infusions of regular antibiotic dry-cow formula (positive control) and two different doses of SF68 in different quarters. Analyses of individual quarter secretion samples showed faster neutrophil infiltration, earlier modifications in protein composition, including caseins and lactoferrins, as well as more prompt elevation of the specific unit of 92-kDa matrix metalloproteinase 9 (MMP9) in SF68-infused quarters compared to the positive controls. Intramammary infusion of ultrasonicated SF68 seems able to accelerate the regression of mammary synthetic capacity and potentiate the breakdown of glandular extracellular matrix, indicating a more efficient mammary gland involution. Correlation analyses imply that the ability of ultrasonicated SF68 to induce faster neutrophil chemotaxis and the associated MMP9 release is partly responsible. PMID- 25041817 TI - Functional characterization of breast cancer using pathway profiles. AB - BACKGROUND: The molecular characteristics of human diseases are often represented by a list of genes termed "signature genes". A significant challenge facing this approach is that of reproducibility: signatures developed on a set of patients may fail to perform well on different sets of patients. As diseases are resulted from perturbed cellular functions, irrespective of the particular genes that contribute to the function, it may be more appropriate to characterize diseases based on these perturbed cellular functions. METHODS: We proposed a profile-based approach to characterize a disease using a binary vector whose elements indicate whether a given function is perturbed based on the enrichment analysis of expression data between normal and tumor tissues. Using breast cancer and its four primary clinically relevant subtypes as examples, this approach is evaluated based on the reproducibility, accuracy and resolution of the resulting pathway profiles. RESULTS: Pathway profiles for breast cancer and its subtypes are constructed based on data obtained from microarray and RNA-Seq data sets provided by The Cancer Genome Atlas (TCGA), and an additional microarray data set provided by The European Genome-phenome Archive (EGA). An average reproducibility of 68% is achieved between different data sets (TCGA microarray vs. EGA microarray data) and 67% average reproducibility is achieved between different technologies (TCGA microarray vs. TCGA RNA-Seq data). Among the enriched pathways, 74% of them are known to be associated with breast cancer or other cancers. About 40% of the identified pathways are enriched in all four subtypes, with 4, 2, 4, and 7 pathways enriched only in luminal A, luminal B, triple-negative, and HER2+ subtypes, respectively. Comparison of profiles between subtypes, as well as other diseases, shows that luminal A and luminal B subtypes are more similar to the HER2+ subtype than to the triple-negative subtype, and subtypes of breast cancer are more likely to be closer to each other than to other diseases. CONCLUSIONS: Our results demonstrate that pathway profiles can successfully characterize both common and distinct functional characteristics of four subtypes of breast cancer and other related diseases, with acceptable reproducibility, high accuracy and reasonable resolution. PMID- 25041819 TI - Coagulopathy following major trauma hemorrhage: lytic, lethal and a lack of fibrinogen. AB - Trauma-induced coagulopathy (TIC) is present soon after injury and is associated with increased transfusion requirements and worse outcomes. The pathophysiological mechanisms, which result in the widespread derangements of hemostasis following major trauma hemorrhage, are as yet not fully defined. Profound activation of fibrinolytic pathways and fibrinogen depletion appear to be fundamental processes in the development of TIC and offer potential therapeutic targets. Collaborative and multi-disciplinary scientific study is thus a research priority in order to characterize the primary drivers of TIC and develop targeted and efficacious treatment strategies. PMID- 25041820 TI - Special issue: Biofilms. PMID- 25041823 TI - Causal diagrams and multivariate analysis I: a quiver full of arrows. AB - How do we know which variables we should include in our multivariate analyses? What role does each variable play in our understanding of the analysis? In this article I begin a discussion of these issues and describe 2 different types of studies for which this problem must be handled in different ways. PMID- 25041825 TI - Detection of lipopolysaccharide induced inflammatory responses in RAW264.7 macrophages using atomic force microscope. AB - In recent years, LPS activated RAW264.7 cells are widely used as an in vitro inflammatory model for the screen of effective anti-inflammation drugs and the investigation of exact anti-inflammation mechanism of these drugs. But up to now, there are few data about the effect of LPS on the morphology, especially on the membrane ultrastructure and bio-mechanical properties of RAW264.7 macrophages. In this work, the topographical and biophysical changes of RAW264.7 macrophages upon LPS stimulation are detected by high resolution atomic force microscopy (AFM). The AFM results suggested that LPS activated RAW264.7 macrophages changed to be much bigger than control cells with some holes emerged on cell surface. The size of membrane protein clusters and the roughness of membrane significantly increased after LPS exposure. In addition, the AFM force measurement results demonstrated that LPS stimulation increased the adhesion force of RAW264.7 macrophages, and also increased the stiffness of RAW264.7 macrophages, which were attributed to the re-distribution of intracellular F-actin structures induced by LPS. These findings suggested that LPS stimulation could also induce the pathophysiological changes of RAW264.7 macrophages, which would benefit our understanding of the inflammatory processes in macrophages upon pathogen stimulation at nano-scale. PMID- 25041824 TI - Integrative genomic and transcriptomic characterization of papillary carcinomas of the breast. AB - Papillary carcinoma (PC) is a rare type of breast cancer, which comprises three histologic subtypes: encapsulated PC (EPC), solid PC (SPC) and invasive PC (IPC). Microarray-based gene expression and Affymetrix SNP 6.0 gene copy number profiling, and RNA-sequencing revealed that PCs are luminal breast cancers that display transcriptomic profiles distinct from those of grade- and estrogen receptor (ER)-matched invasive ductal carcinomas of no special type (IDC-NSTs), and that the papillary histologic pattern is unlikely to be underpinned by a highly recurrent expressed fusion gene or a highly recurrent expressed mutation. Despite displaying similar patterns of gene copy number alterations, significant differences in the transcriptomic profiles of EPCs, SPCs and IPCs were found, and may account for their different histologic features. PMID- 25041826 TI - Interfacial microstructure and growth mechanism of Al4C3 in Grf/Al composites fabricated by liquid pressure method. AB - In this study, Grf/Al composite was fabricated by liquid pressure method. The diffusion layer and the nucleation and growth of Al4C3 were observed at the interface of Grf/Al composites by TEM and HRTEM. The growth mechanism of Al4C3 was analyzed in detail by crystallography theory. It was found that Al4C3 had no phase relations with the carbon fiber. (0001) layer of Al4C3 was parallel with main growth direction. Both the diffusion layer at the interface and crystal structure of Al4C3 affected the shape of Al4C3. At a certain position, Al4C3 could connect two fibers when the fibers were close to each other. PMID- 25041827 TI - The gigapixel image concept for graphic SEM documentation. Applications in archeological use-wear studies. AB - In this paper, we propose a specific procedure to create gigapixel-like images from SEM (scanning electron microscope) micrographs. This methodology allows intensive SEM observations to be made for those disciplines that require of large surfaces to be analyzed at different scales once the SEM sessions have been completed (e.g., stone tools use-wear studies). This is also a very useful resource for academic purposes or as a support for collaborative studies, thus reducing the number of live observation sessions and the associated expense. PMID- 25041828 TI - Automated microscopic image analysis for leukocytes identification: a survey. AB - Automatic quantification and classification of leukocytes in microscopic images are of paramount importance in the perspective of disease identification, its progress and drugs development. Extracting numerical values of leukocytes from microscopic images of blood or tissue sections represents a tricky challenge. Research efforts in quantification of these cells include normalization of images, segmentation of its nuclei and cytoplasm followed by their classification. However, there are several related problems viz., coarse background, overlapped nuclei, conversion of 3-D nuclei into 2-D nuclei etc. In this review, we have categorized, evaluated, and discussed recently developed methods for leukocyte identification. After reviewing these methods and finding their constraints, a future research perspective has been presented. Further, the challenges faced by the pathologists with respect to these problems are also discussed. PMID- 25041829 TI - Microstructural investigation of stress-assisted alpha"-alpha' phase transformation in cold-rolled Ti-7.5Mo alloy. AB - The present study investigated the microstructure and stress-assisted alpha" alpha' phase transformation of a solution-treated Ti-7.5Mo alloy being cold rolled with a series of different thickness reductions using transmission electron microscopic (TEM) and electron backscatter diffraction (EBSD) techniques. The EBSD/IPF results indicated a substantially random texture in ST sample. When the alloy was mildly cold-rolled, a texture toward <101-0> preferred orientation was established, which gradually shifted toward <21-1-0> with increased reduction in thickness. The TEM results indicated that substantially all fine platelets in the solution-treated (ST) sample had an orthorhombic alpha" phase, and that a stress-assisted alpha"-to-alpha' phase transformation took place when the alloy was cold-rolled, confirming the XRD results. In the mildly rolled (CR20) sample, the existence of alpha' phase could be easily identified, indicating that the stresses involved in the mild rolling process were sufficient to initiate the alpha"-alpha' phase transition. On the other hand, in the heavily rolled (CR80) sample, the presence of residual alpha" phase was still observed throughout the sample, indicating that the alpha"-to-alpha' phase transition was never complete even after a severe cold rolling process. The SAD analysis indicated an orientation relationship, alpha(')(12-10)//alpha(")(202-) and alpha' [0001]//alpha" [020], existing between the two phases. PMID- 25041830 TI - Etoposide interferes with the process of chromatin condensation during alga Chara vulgaris spermiogenesis. AB - DNA topoisomerase II plays an essential role in animal spermiogenesis, where changes of chromatin structure are connected with appearance of transient DNA breaks. Such topo II activity can be curtailed by inhibitors such as etoposide and suramine. The aim of the present study was to investigate, for the first time, the effect of etoposide on spermatid chromatin remodeling in the green alga Chara vulgaris. This inhibitor prolonged the early spermiogenesis stages and blocked the formation of the phosphorylated form of histone H2AX at stages VI VII. The lack of transient DSBs at these stages impairs the elimination of supercoils containing nucleosomes which lead to disturbances in nucleoprotein exchange and the pattern of spermatid chromatin fibrils at stages VI-VIII. Immunofluorescent and ultrastructural observations revealed that during C. vulgaris spermiogenesis topo II played an important role similar to that in mammals. Some corresponding features had been pointed out before, the present studies showed further similarities. PMID- 25041831 TI - Immunodetection of type I acidic keratins associated to periderm granules during the transition of cornification from embryonic to definitive chick epidermis. AB - The change in the modality of cornification from embryonic to definitive epidermis in the chick has been studied using immunocytochemistry and electron microscopy to show that the initial soft cornification based on an acidic type I alpha-keratin transits to a definitive hard cornification based on beta-proteins in the claw, scales and feathers. The first two periderm layers contain acidic keratins associated with periderm granules and participate in a mild form of cornification before shedding of the periderm. The transition from embryonic to adult cornification is best seen in the transitional layers of the claw where numerous periderm granules merge with packets or bundles of corneous beta proteins. This process is hardly seen in scale and feathers where periderm granules remain most in the periderm or in the feather sheath. Periderm granules disappear in corneocytes generated underneath the periderm in scales or in the transitional layer in claws and are replaced by beta-proteins associated to other types of acidic alpha-keratins. This process produces a mechanically resistant corneous material underneath the softer periderm, adapted to terrestrial demand for mechanical protection in scales and in the dorsal part of the claw, the unguis. In the ventral part of the claw, the sub-unguis, scarce or no beta proteins are accumulated resulting in a softer corneous layer. The study indicates that specific alpha-keratins form the cytoskeletal framework of definitive corneocytes in claws, scales and feathers, and that specialized corneous beta-proteins are deposited over this framework to produce epidermal layers with higher mechanical resistance. PMID- 25041832 TI - Quantitative and ultrastructural changes in the haemocytes of Spodoptera littoralis (Boisd.) treated individually or in combination with Spodoptera littoralis multicapsid nucleopolyhedrovirus (SpliMNPV) and azadirachtin. AB - The total haemocyte count (THC) and the possible ultrastructural alterations induced in the haemocytes of the fourth larval instars of the Egyptian cotton leafworm, Spodoptera littoralis (Boisd.) (Lepidoptera: Noctuidae), 96 h post feeding on a semi-synthetic diet, treated with the LC50 of Spodoptera littoralis multicapsid nucleopolyhedrovirus (SpliMNPV) and the LC50 of azadirachtin alone, and the LC25 of SpliMNPV combined with the LC25 of azadirachtin were studied and compared to the control. Single treatment with the virus and azadirachtin or combined treatment significantly decreased the THC compared to the control. There are five types of haemocytes in S. littoralis: prohaemocytes, plasmatocytes, granulocytes, spherulocytes and oenocytoids. The most common symptoms in granulocytes and plasmatocytes, the main affected cell types, due to viral infection were the presence of virogenic stroma, peripheral dispersion of the chromatin and disappearance of the nucleoli. However, the most common symptoms in these two types of haemocytes due to treatment with azadirachtin were the presence of rough endoplasmic reticulum filled with fibrous materials, due to probably apoptosis, in their cisternae and disorganization of mitochondria (looped, vacuolated and swollen). In addition, the cytoplasm of granulocytes was vacuolated with the appearance of autophagic lysosomes, while plasmatocytes showed ruptured cell membrane and folded nuclear envelope. Combined treatment with the NPV and azadirachtin induced the same pathological changes which were recorded from individual treatment with the virus or azadirachtin to the same haemocytes. It can be concluded that the change in the THC and ultrastructure of granulocytes and plasmatocytes may affect the cellular-mediated immune response in S. littoralis. Moreover, it seems likely that mitochondria were the target site of azadirachtin, as they were affected in both granulocytes and plasmatocytes treated with azadirachtin alone or in combination with SpliMNPV. PMID- 25041833 TI - New method development in prehistoric stone tool research: evaluating use duration and data analysis protocols. AB - Lithic microwear is a research field of prehistoric stone tool (lithic) analysis that has been developed with the aim to identify how stone tools were used. It has been shown that laser scanning confocal microscopy has the potential to be a useful quantitative tool in the study of prehistoric stone tool function. In this paper, two important lines of inquiry are investigated: (1) whether the texture of worn surfaces is constant under varying durations of tool use, and (2) the development of rapid objective data analysis protocols. This study reports on the attempt to further develop these areas of study and results in a better understanding of the complexities underlying the development of flexible analytical algorithms for surface analysis. The results show that when sampling is optimised, surface texture may be linked to contact material type, independent of use duration. Further research is needed to validate this finding and test an expanded range of contact materials. The use of automated analytical protocols has shown promise but is only reliable if sampling location and scale are defined. Results suggest that the sampling protocol reports on the degree of worn surface invasiveness, complicating the ability to investigate duration related textural characterisation. PMID- 25041834 TI - Intestinal anisakidosis: histopathological findings and differential diagnosis. AB - Anisakidosis is a human zoonotic disease caused by the ingestion of raw or undercooked or not adequately salted, pickled, or smoked fish containing larval nematodes of the Anisakis species. The incidence of this infection is higher in geographical zones with traditional consumption of raw fish. However, in the last years, prevalence raised in low risk zones due to the increase popularity of Asian cuisine. According to where the larvae settle in the gastrointestinal tract, anisakidosis may have different clinical symptoms. In particular, intestinal anisakidosis may mimic several surgical conditions, including appendicitis, ileitis, diverticulitis or inflammatory bowel disease. For this reason, diagnosis is often histopathological. In the present paper, we describe the clinico-pathological findings of six novel cases of intestinal anisakidosis occurred in southern Italy, and provide clues for the differential diagnosis toward Crohn's disease and eosinophilic enteritis, which have similar histopathological characteristics. Awareness of the existence of intestinal anisakidosis may facilitate its recognition and correct diagnosis, which is of fundamental importance for appropriate therapeutic approach. PMID- 25041835 TI - Association of CD98, integrin beta1, integrin beta3 and Fak with the progression and liver metastases of colorectal cancer. AB - CD98-mediated beta1 and beta3 integrins activation can induce Fak phosphorylation which eventually promotes cell survival, proliferation, and migration. We evaluated the expression of CD98, integrin beta1, integrin beta3 and Fak in 45 cases of matched colorectal cancer (CRC) and liver metastases as well as 35 cases of CRC without liver metastases. There was a gradual increase of the expression of CD98, integrin beta1, integrin beta3 and Fak as tumor progressed from normal colon to carcinoma to budding tumor cells at the invasive front and to liver metastases. The expression of CD98 and integrin beta1 in CRC with liver metastases was significantly higher than that in CRC without liver metastases. Furthermore, for those liver metastases with desmoplastic growth pattern, expression of CD98, integrin beta1, integrin beta3 and Fak at the metastases center was as strong as that at the metastases periphery. For those liver metastases with pushing or replacement growth patterns, more intense expression of these markers was found at the metastases center than the periphery. Overexpression of CD98, integrin beta1, integrin beta3 and Fak is associated with the progression and liver metastases of CRC. Overexpression of these markers in liver metastases requires direct contact between tumor cells and the stroma. PMID- 25041836 TI - Expression patterns of SDF1/CXCR4 in human invasive breast carcinoma and adjacent normal stroma: correlation with tumor clinicopathological parameters and patient survival. AB - SDF-1/CXCR4 axis is involved in various steps of breast tumorigenesis such as tumor growth, angiogenesis and metastasis. The goal of the present study is to demonstrate in detail the immunohistochemical distribution of SDF-1 and CXCR4 in invasive breast carcinomas and identify possible correlation of their expression patterns with clinicopathological parameters and patients survival. We investigated the immunoexpression of CXCR4 and SDF1 in 76 invasive breast carcinomas. Both SDF-1 and CXCR4 had statistically significant higher expression in carcinomas compared with adjacent normal breast tissue. Furthermore the expression of CXCR4 in intratumoral fibroblasts had a positive correlation with overall and disease-free survival, while SDF1 membranous immunopositivity in normal breast epithelial cells was a risk factor for relapse. In addition, expression of SDF1 in fibroblasts of normal breast tissue was positively associated with tumor grade. Overall, our results suggest that the differential expression of CXCR4 in intratumoral stroma and SDF1 in adjacent normal mammary cells may predict clinical outcome in breast cancer patients. PMID- 25041837 TI - Immunohistochemical expression of HBME-1 and galectin-3 in the differential diagnosis of follicular-derived thyroid nodules. AB - BACKGROUND: Thyroid nodules are common among adults with only a small percentage being malignant and histologically mimic benign nodules. Accurate diagnosis of these thyroid nodules is critical for the proper clinical management. The determination of malignancy in follicular patterned thyroid lesions is based on postoperative histological findings. Therefore, affected patients are referred for surgery, although only 10% will have a final diagnosis of malignancy. The aim of this study was to investigate the ability of two immunohistochemical (IHC) markers; galectin-3 and Hector Battifora mesothelial-1 (HBME-1) individually or in combination, to distinguish between benign (non-neoplastic and neoplastic) and malignant (follicular and papillary carcinomas) thyroid lesions removed by surgical resection. METHODS: We investigated the immunoexpression of galectin-3 and HBME-1 in 50 cases of benign and malignant thyroid nodules. The benign group included 13 cases of thyroid nodular goiter (NG) and 9 cases of follicular adenoma (FA). The malignant group included 5 cases of follicular thyroid carcinomas (FC), 18 cases of classic papillary thyroid carcinoma and 5 cases of follicular variant papillary carcinoma (FVPC). RESULTS: The staining results showed that malignant tumors expressed galectin-3 and HBME-1 significantly more than benign nodules. The sensitivity of these markers for the distinction between benign and malignant lesions ranged from 89.3% to 92.9%. Co-expression of galectin-3 and HBME-1 was seen in 82.1% of carcinomas, but in none of the benign nodules. Immunoexpression was usually diffuse in malignant tumors, and focal in the benign lesions. CONCLUSION: Our findings indicate that these immunohistochemical markers are significantly more expressed in malignant tumors compared to benign lesions and may be of additional diagnostic value when combined with routine histology. Galectin-3 has higher sensitivity and specificity of immunoexpression in thyroid malignancy than HBME-1, and the combined use of galectin-3 and HBME-1 can increase the specificity of immunoexpression in malignant tumors. PMID- 25041838 TI - Expression of focal adhesion kinase in uveal melanoma and the effects of Hsp90 inhibition by 17-AAG. AB - INTRODUCTION: Focal adhesion kinase (FAK) is implicated in tumor progression and metastatic cascade, and has been shown to be overexpressed in a variety of human cancers. However, the role of FAK in human uveal melanoma (UM) is not well defined. The purpose of this study was to evaluate the expression of FAK in UM tumors and normal eyes, and to determine the effect of Hsp90 inhibition on FAK expression in UM cells. METHODS: FAK expression was assessed in 39 UM specimens, FAK[pY397] expression was assessed in 51 UM specimens, and both FAK and FAK[pY397] expression were assessed in 20 normal eyes. The expression of FAK and FAK[pY397] was detected by Western blot in five UM cell lines after treatment with 10 MUmol/L of 17-AAG. RESULTS: FAK was positive in 87.2% and FAK[pY397] in 90% of UM specimens. Low FAK expression was detected in non-tumor structures and in normal eyes. The cell lines with the most proliferative, invasive phenotype (92.1, SP6.5 and MKT-BR) displayed high expression of FAK[pY397], and the levels of FAK and FAK[pY397] were decreased in the presence of 17-AAG starting with 24 h of exposure. CONCLUSION: FAK and FAK[pY397] were overexpressed in human UM tumors compared to normal ocular tissue and high levels of FAK[pY397] were seen in the most aggressive UM cell lines. Hsp90 inhibition led to downregulation of FAK expression. We propose a role for FAK in the pathogenesis of UM. Future studies are needed to explore the use of Hsp90 inhibitors as a feasible approach for modulating FAK in UM. PMID- 25041839 TI - Gastroprotective effect of taurine zinc solid dispersions against absolute ethanol-induced gastric lesions is mediated by enhancement of antioxidant activity and endogenous PGE2 production and attenuation of NO production. AB - Zinc plays a key role in maintaining gastric mucosal integrity, while alcohol dependency can lead to low zinc status. Complexes containing zinc have been reported to have better ability to protect gastric mucosa than the compounds alone. In this study, taurine zinc [Zn(NH3CH2CH2SO3)2] solid dispersions (SDs) were synthesized and investigated in an ethanol-induced ulcer model in rats. Gastric ulcer index; gastric mucosa malondialdehyde (MDA) level, glutathione (GSH) content, superoxide dismutase (SOD) activity and prostaglandin E2 (PGE2) production; and serum nitric oxide (NO) were assessed and histological analysis of the gastric mucosa tissue was performed. Taurine zinc (100, 200 mg/kg) SDs protected rat gastric mucosa from ethanol-induced injury. Moreover, the gastroprotective effect of taurine zinc SDs was accompanied by a decrease in serum NO and significant increase in gastric prostaglandin E2 (PGE2). When indomethacin, a non-selective COX inhibitor was administered before the last dose of taurine zinc, the gastroprotective effect of taurine zinc was weakened. Furthermore, taurine zinc (200 mg/kg) SDs protected against ulceration more significantly than the same dose of taurine alone, suggesting a synergistic effect between taurine and zinc. These results indicate taurine zinc protects the gastric mucosa against ethanol-induced damage by elevating antioxidants, decreasing lipid peroxidation and inhibiting the production of nitric oxide. The gastroprotective effect of taurine zinc was also partially mediated by endogenous PGE2 production. PMID- 25041840 TI - Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. AB - Autophagy is a lysosomal degradation pathway, which is essential for cell survival, proliferation, differentiation and homeostasis. It is well known that beta-amyloid (Abeta) aggregation is one of key characteristics for Alzheimer's disease (AD), which triggers a complex pathological cascade, leading to neurodegeneration. Recent studies have shown that Abeta peptide is generated from amyloid beta precursor protein (APP) during autophagic turnover of APP-rich organelles by autophagy. Abeta generation during normal autophagy is subsequently degraded by lysosomes. Curcumin, a nature plant extraction, has been reported to inhibit the generation and deposition of Abeta; however, the underlying mechanisms are not fully understood yet. In the present study, we reported that curcumin treatment not only attenuated cognitive impairment detected by Morris water maze test, but also inhibited the generation of Abeta investigated by immunohistochemistry in APP/PS1 double transgenic AD mice. Moreover, curcumin induced autophagy in the mice, evidenced by LC3 immunofluorescence analysis and western blot assays on LC3. Furthermore, we found that curcumin significantly decreased the expression of Phosphatidylinositol 3-Kinase (PI3K), phosphorylated Akt and rapamycin (mTOR) at protein levels, respectively. Taken together, our data suggests that curcumin inhibits Abeta generation and induces of autophagy by downregulating PI3K/Akt/mTOR signaling pathway, and further shows a neuroprotective effect. Meanwhile curcumin might be a candidate neuroprotective agent for AD patients treatment by inducing autophagy. PMID- 25041841 TI - Beneficial effects of houttuynin on ventricular remodeling induced by coronary artery ligation in rats. AB - To examine the effects of houttuynin on ventricular remodeling induced by coronary artery ligation in rats and the underlying mechanisms. A rat model of ventricular remodeling was established by left coronary artery ligation (CAL). Rats were randomly divided into four groups: CAL control, CAL plus 40 mg/kg captopril, CAL plus 100 mg/kg houttuynin and sham-operated control. The rats were administered intragastrically with the corresponding drugs or distilled water for 7 weeks. At the end of the experiment, the left ventricular weight index (LVWI) and heart weight index (HWI) were determined. Myocardium tissue was stained with hematoxylin and eosin or picric acid/Sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of angiotensin I (Ang I), angiotensin II (Ang II), aldosterone (ALD) and endothelin 1 (ET-1) in myocardium or serum were detected by radioimmunoassay. The hydroxyproline (Hyp) concentration was measured by alkali hydrolysis. Ultraviolet spectrophotometry was used to determine glutathione peroxidase (GSH-Px) and catalase (CAT) activities in serum. Houttuynin significantly diminished LVWI and HWI, decreased Ang I, Ang II, ALD, ET-1 and Hyp concentrations in myocardium or serum, increased NO concentration and GSH-Px, CAT activities after 7 weeks of treatment. Houttuynin could also reduce cardiomyocyte cross-section area and collagen deposition. Houttuynin attenuates ventricular remodeling in coronary artery ligation rats by restricting the excessive activation of rennin angiotensin-aldosterone system (RAAS) and the peroxidation. PMID- 25041842 TI - Adenosine A1 receptor antagonist, L-97-1, improves survival and protects the kidney in a rat model of cecal ligation and puncture induced sepsis. AB - Previously it was reported that combining antibiotics with L-97-1, an adenosine A1 receptor antagonist, significantly improves survival and blocks acute lung injury induced by Yersinia pestis CO 99 in a rat model of pneumonic plague. In the current studies using a conscious rat model of cecal ligation and puncture (CLP) sepsis, L-97-1 was administered in daily intravenous infusions in combination with antibiotics to simulate the use of L-97-1 as an anti-sepsis therapeutic in the clinical setting. In these studies, when administered at 12 h following CLP, in combination with broad spectrum antibiotics, ceftriaxone and clindamycin, L-97-1 improves 7 day (d) survival [25%, 35%, and 75% for L-97-1 (10 mg/kg/h, 12.5 mg/kg/h, and 15 mg/kg/h, respectively) versus (vs.) 25% for antibiotics alone] in a dose-dependent manner. The addition of L-97-1, 15 mg/kg/h to antibiotics significantly increased 7 d survival following CLP compared to therapy with either antibiotics alone (P=0.002) or L-97-1 at 15 mg/kg/h alone (P<0.001) and was not significantly different than survival in sham CLP animals (Log-rank (Mantel-Cox) test with Bonferroni's correction for multiple comparisons). Moreover, in these studies, in combination with antibiotics L-97-1 dose-dependently protects the kidney, significantly improving renal function at 24 h post CLP at 10 mg/kg/h (P<0.001), 12.5 mg/kg/h (P<0.0001), and 15 mg/kg/h (P<0.0001) vs. antibiotics alone (ANOVA followed by Tukey's post-hoc test for pair-wise comparisons). The results of these studies support efficacy for L-97-1 as an anti-sepsis therapeutic. PMID- 25041843 TI - Sharks modulate their escape behavior in response to predator size, speed and approach orientation. AB - Escape responses are often critical for surviving predator-prey interactions. Nevertheless, little is known about how predator size, speed and approach orientation impact escape performance, especially in larger prey that are primarily viewed as predators. We used realistic shark models to examine how altering predatory behavior and morphology (size, speed and approach orientation) influences escape behavior and performance in Squalus acanthias, a shark that is preyed upon by apex marine predators. Predator models induced C-start escape responses, and increasing the size and speed of the models triggered a more intense response (increased escape turning rate and acceleration). In addition, increased predator size resulted in greater responsiveness from the sharks. Among the responses, predator approach orientation had the most significant impact on escapes, such that the head-on approach, as compared to the tail-on approach, induced greater reaction distances and increased escape turning rate, speed and acceleration. Thus, the anterior binocular vision in sharks renders them less effective at detecting predators approaching from behind. However, it appears that sharks compensate by performing high-intensity escapes, likely induced by the lateral line system, or by a sudden visual flash of the predator entering their field of view. Our study reveals key aspects of escape behavior in sharks, highlighting the modulation of performance in response to predator approach. PMID- 25041844 TI - Cereal byproducts have prebiotic potential in mice fed a high-fat diet. AB - Barley husks, rye bran, and a fiber residue from oat milk production were processed by heat pretreatment, various separation steps, and treatment with an endoxylanase in order to improve the prebiotic potential of these cereal byproducts. Metabolic functions were intended to improve along with improved microbial activity. The products obtained were included in a high-fat mouse diet so that all diets contained 5% dietary fiber. In addition, high-fat and low-fat controls as well as partially hydrolyzed guar gum were included in the study. The soluble fiber product obtained from rye bran caused a significant increase in the bifidobacteria (log copies of 16S rRNA genes; median (25-75 percentile): 6.38 (6.04-6.66) and 7.47 (7.30-7.74), respectively; p < 0.001) in parallel with a tendency of increased production of propionic acid and indications of improved metabolic function compared with high-fat fed control mice. The oat-derived product caused an increase in the pool of cecal propionic (from 0.62 +/- 0.12 to 0.94 +/- 0.08) and butyric acid (from 0.38 +/- 0.04 to 0.60 +/- 0.04) compared with the high-fat control, and it caused a significant increase in lactobacilli (log copies of 16S rRNA genes; median (25-75 percentile): 6.83 (6.65-7.53) and 8.04 (7.86-8.33), respectively; p < 0.01) in the cecal mucosa. However, no changes in measured metabolic parameters were observed by either oat or barley products. PMID- 25041845 TI - PKM2 depletion induces the compensation of glutaminolysis through beta-catenin/c Myc pathway in tumor cells. AB - The metabolic activity in cancer cells primarily rely on aerobic glycolysis. Besides glycolysis, some tumor cells also exhibit excessive addition to glutamine, which constitutes an advantage for tumor growth. M2-type pyruvate kinase (PKM2) plays a pivotal role in sustaining aerobic glycolysis, pentose phosphate pathway and serine synthesis pathway. However, the participation of PKM2 in glutaminolysis is little to be known. Here we demonstrated that PKM2 depletion could provoke glutamine metabolism by enhancing the beta-catenin signaling pathway and consequently promoting its downstream c-Myc-mediated glutamine metabolism in colon cancer cells. Treatment with 2-deoxy-d-glucose (2 DG), a glycolytic inhibitor, got consistent results with the above. In addition, the dimeric form of PKM2, which lacks the pyruvate kinase activities, plays a critical role in regulating beta-catenin. Moreover, we found that overexpression of PKM2 negatively regulated beta-catenin through miR-200a. These insights supply evidence that glutaminolysis plays a compensatory role for cell survival upon glucose metabolism impaired. PMID- 25041846 TI - Differential roles of ATF-2 in survival and DNA repair contributing to radioresistance induced by autocrine soluble factors in A549 lung cancer cells. AB - Radioresistance is one of the obstacles to the effective radiotherapy for non small cell lung cancer. Soluble factors in the tumour microenvironment are often implicated in radioresistance but the underpinning mechanism(s) remain largely elusive. We herein studied the wholesome effect of autocrine cytokines and growth factors in the form of self-conditioned medium (CM) on the radiosensitivity of A549 cells. A549 cells grown in CM exhibited radioresistance which was associated with increased survival and DNA repair. CM induced pro-survival pathways through increased intracellular cAMP and phosphorylation of JNK and p38. Downstream to JNK/p38 signalling, ATF-2 phosphorylated at Thr69/71 was accompanied with its increased transcriptional activity in CM treated cells. Pre-treatment with cAMP inhibitor and silencing of ATF-2 abrogated the CM-induced survival. Interestingly, in cells treated with CM followed by radiation, ATF-2 was found to be switched over from transcription factor to DNA damage response protein. In CM treated cells, after gamma-radiation p-ATF-2(Thr69/71) and subsequently the transcriptional activity of ATF-2 were declined with simultaneous rise in p-ATF 2(Ser490/498). Immunoprecipitation/immunoblotting and inhibitor studies showed that phosphorylation of ATF-2 at Ser490/498 was mediated by ATM. Moreover, p-ATF 2(Ser490/498) was found to be co-localised with gamma-H2AX in DNA repair foci in CM-treated cells. The DNA repair activity of ATF-2 was assisted with higher activity MRN complex in cells grown in CM. Our study revealed that, autocrine soluble factors regulate dual but differential role of ATF-2 as a transcription factor or DNA repair protein, which collectively culminate in radioresistance of A549 cells. PMID- 25041847 TI - Cytoplasmic salt bridge formation in integrin alphavbeta3 stabilizes its inactive state affecting integrin-mediated cell biological effects. AB - Heterodimeric integrin receptors are mediators of cell adhesion, motility, invasion, proliferation, and survival. By this, they are crucially involved in (tumor) cell biological behavior. Integrins trigger signals bidirectionally across cell membranes: by outside-in, following binding of protein ligands of the extracellular matrix, and by inside-out, where proteins are recruited to beta integrin cytoplasmic tails resulting in conformational changes leading to increased integrin binding affinity and integrin activation. Computational modeling and experimental/mutational approaches imply that associations of integrin transmembrane domains stabilize the low-affinity integrin state. Moreover, a cytoplasmic interchain salt bridge is discussed to contribute to a tight clasp of the alpha/beta-membrane-proximal regions; however, its existence and physiological relevance for integrin activation are still a controversial issue. In order to further elucidate the functional role of salt bridge formation, we designed mutants of the tumor biologically relevant integrin alphavbeta3 by mutually exchanging the salt bridge forming amino acid residues on each chain (alphavR995D and beta3D723R). Following transfection of human ovarian cancer cells with different combinations of wild type and mutated integrin chains, we showed that loss of salt bridge formation strengthened alphavbeta3 mediated adhesion to vitronectin, provoked recruitment of cytoskeletal proteins, such as talin, and induced integrin signaling, ultimately resulting in enhanced cell migration, proliferation, and activation of integrin-related signaling molecules. These data support the notion of a functional relevance of integrin cytoplasmic salt bridge disruption during integrin activation. PMID- 25041848 TI - Trace metals in blood and urine of newborn/mother pairs, adolescents and adults of the Flemish population (2007-2011). AB - The Flemish Centre for Environment and Health started with human biomonitoring in 2002 (FLEHS I: 2002-2006). The main goal of the second human biomonitoring cycle (FLEHS II: 2007-2011), was to determine mean values for a large number of pollutants in a representative sample of the general Flemish population. Values for Cd and Pb were updated, and a group of previously undetermined metals and metalloids (As, Mn, Cu and Tl) were included in some of the age groups. In this human biomonitoring program, three different age groups of the general Flemish population were monitored: 255 newborns and their mothers, 210 adolescents aged 14-15, and 204 adults between 20 and 40 years old. Trace elements were determined in cord blood and maternal blood of the mothers, in blood and urine of adolescents and in urine of adults. Determinants of life-style and personal factors were taken into account. The levels of trace elements in cord blood and maternal blood were for most elements at the lower end of the range found in literature. For Pb, As and Tl, a strong correlation (respectively r=0.43, 0.55 and 0.33; p<0.05) was found between levels in cord blood (respectively 8.6, 0.54 and 0.017 MUg/L) and maternal blood (11.1, 0.64 and 0.028 MUg/L), indicating that they are transported via the placenta from mother to fetus. The levels found in the adolescents and adults were compared with results from international biomonitoring studies, and were found to be in the same ranges. With the exception of Pb, all trace elements increased with increasing age group population. Finally, the results also showed that the levels of Cd and Pb in blood for this campaign (e.g. for Pb 8.6 and 14.8 MUg/L in neonates and adolescents respectively) were lower compared to the first campaign (e.g. for Pb 14.7 and 21.7 MUg/L in neonates and adolescents respectively), indicating a decrease over time. However, differences in sampling strategies might partially explain this observed trend. PMID- 25041849 TI - Randomized trial of narrow-band versus white-light cystoscopy for restaging (second-look) transurethral resection of bladder tumors. AB - Narrow-band imaging (NBI) cystoscopy detects more bladder tumors than standard white-light imaging (WLI) cystoscopy, but it is unclear whether NBI improves transurethral resection (TUR) of bladder tumors. This study compares 2-yr recurrence-free survival (RFS) of patients with non-muscle-invasive bladder tumors following restaging TUR using NBI or WLI cystoscopy. Patients were randomized 1:1 to undergo NBI-assisted TUR (NBI-TUR) or WLI-assisted TUR (WLI TUR). The main outcome was number of patients free of tumor recurrence after 2-yr follow-up and 2-yr RFS times. Of 254 patients, 127 underwent NBI-TUR and 127 had WLI-TUR. Within 2 yr, 22% of the patients in the NBI-TUR group recurred compared with 33% after WLI-TUR (p=0.05). The mean RFS time was 22 mo (95% confidence interval [CI], 20-23) for the NBI-TUR group versus 19 mo (95% CI, 18-21) for the WLI-TUR group (p=0.02). Limitations are that this was a single-surgeon study and that a 20% difference in the number of patients free of recurrence was not achieved, suggesting the study was underpowered. In addition, observer bias may have contributed to results because NBI-TUR was performed after both WLI and NBI cystoscopy was used to inspect the bladder. Although the results suggest reduced recurrence rates and improved RFS times after restaging NBI-TUR compared with WLI TUR, a larger study is needed. PATIENT SUMMARY: Narrow-band imaging enhances visibility of bladder tumors over conventional white-light cystoscopy. This report compares transurethral resection of bladder tumors using narrow-band cystoscopy with white-light cystoscopy. The results show that narrow-band cystoscopy improves surgical removal of bladder tumors, which reduces the frequency of early and later tumor recurrences. PMID- 25041850 TI - A novel robotic system for single-port urologic surgery: first clinical investigation. AB - BACKGROUND: The idea of performing a laparoscopic procedure through a single abdominal incision was conceived with the aim of expediting postoperative recovery. OBJECTIVE: To determine the clinical feasibility and safety of single port urologic procedures by using a novel robotic surgical system. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective institutional review board approved, Innovation, Development, Exploration, Assessment, Long-term Study (IDEAL) phase 1 study. After enrollment, patients underwent a major urologic robotic single-port procedure over a 3-wk period in July 2010. The patients were followed for 3 yr postoperatively. INTERVENTION: Different types of urologic surgeries were performed using the da Vinci SP Surgical System. This system is intended to provide the same core clinical capabilities as the existing multiport da Vinci system, except that three articulating endoscopic instruments and an articulating endoscopic camera are inserted into the patient through a single robotic port. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcomes were the technical feasibility of the procedures (as measured by the rate of conversions) and the safety of the procedures (as measured by the incidence of perioperative complications). Secondary end points consisted of evaluating other key surgical perioperative outcomes as well as midterm functional and oncologic outcomes. RESULTS AND LIMITATIONS: A total of 19 patients were enrolled in the study. Eleven of them underwent radical prostatectomy; eight subjects underwent nephrectomy procedures (partial nephrectomy, four; radical nephrectomy, two; and simple nephrectomy, two). There were no conversions to alternative surgical approaches. Overall, two major (Clavien grade 3b) postoperative complications were observed in the radical prostatectomy group and none in the nephrectomy group. At 1-yr follow-up, one radical prostatectomy patient experienced biochemical recurrence, which was successfully treated with salvage radiation therapy. The median warm ischemia time for three of the partial nephrectomies was 38 min. At 3-yr follow-up all patients presented a preserved renal function; none had tumor recurrence. Study limitations include the small sample and the lack of a control group. CONCLUSIONS: We describe the first clinical application of a novel robotic platform specifically designed for single-port urologic surgery. Major urologic procedures were successfully completed without conversions. Further assessment is warranted to corroborate these promising findings. PATIENT SUMMARY: A novel purpose-built robotic system enables surgeons to perform safely and effectively a variety of major urologic procedures through a single small abdominal incision. TRIAL REGISTRATION: The study was registered on www.ClinicalTrials.gov (NCT02136121). PMID- 25041851 TI - Regulators should better leverage effectiveness standards to enhance drug value. AB - Regulators show some flexibility in the evidentiary standards of effectiveness that must be demonstrated for a drug prior to its market authorization. Adopting a more formal framework for when and how effectiveness standards should vary would improve the therapeutic value of new medicines at the time of market entry. We identify three factors-the number and effectiveness of existing treatment alternatives, magnitude of unmet need, and expected clinical application-to guide the effectiveness threshold for a given therapy. Using these factors, regulators should actively guide sponsors regarding appropriate comparators and end points in pivotal trials, as well as determining the size and characteristics of the patient populations enrolled. PMID- 25041852 TI - [The importance of intraoperative transesophageal echocardiography in the surgical decision in cardiac surgery]. AB - OBJECTIVE: To determine the importance of intraoperative transesophageal echocardiography (IOTEE) in the surgical decision in patients undergoing cardiac surgery. PATIENTS AND METHOD: Prospective observational study of patients undergoing cardiac surgery from January 2009 to May 2012, which was monitored with IOTEE by the anesthesiologist in charge. The data collected were: 1) type of surgery; 2) preoperative echocardiographic diagnosis (baseline ECHO); 3) echocardiographic diagnosis before entering cardiopulmonary bypass (CPB) (pre-CPB IOTEE); 4) any differences between the baseline ECHO and the pre-CPB IOTEE (new pre-CPB finding) and whether these differences modified the planned surgery, and 5) echocardiographic diagnosis after disconnection of CPB (unexpected post-CPB finding) and whether these post-CPB echocardiographic findings led to reinstating it. The software program SPSS((r)) was used for data analysis. RESULTS: The total number of patients studied was 1,273. Monitoring with IOTEE showed "new pre-CPB" findings in 98 patients (7.7%), and 43.8% of these led to a change in the scheduled surgery. Of these findings, the most frequent were abnormalities of the mitral valve that had not been diagnosed, and which led to a replacement or repair that had not been scheduled. The incidence of "unexpected post-CPB findings" was 6.2% (79 patients), and 46.8% of those required reinstating the CPB and modifying the surgery performed. The failed valve repairs and dysfunctional valve prostheses were the main causes that led to re-entry into CPB. In the remaining 42 patients, with "unexpected post-CPB findings", there were no changes in the surgical procedure as the echocardiographic findings were not considered to be significant enough to re-establish CPB and revise or change the surgical procedure. CONCLUSION: Intraoperative monitoring with IOTEE by the anesthesiologist during surgery provides important information before and after the CPB that resulted in modifying surgical management. PMID- 25041853 TI - A rapid and sensitive LC-MS/MS method for the determination of Pulsatilla saponin D in rat plasma and its application in a rat pharmacokinetic and bioavailability study. AB - A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of Pulsatilla saponin D, a potential antitumor constituent isolated from Pulsatilla chinensis in rat plasma. Rat plasma samples were pretreated by protein precipitation with methanol. The method validation was performed in accordance with US Food and Drug Administration guidelines and the results met the acceptance criteria. The method was successfully applied to assess the pharmacokinetics and oral bioavailability of Pulsatilla saponin D in rats. PMID- 25041854 TI - The onset of heat-induced testicular calcification in mice: involvement of the telomeric locus on chromosome 1. AB - Spermatocytes of MRL/MpJ mice are more heat resistant than those of C57BL/6 mice in experimental cryptorchidism. This phenotype depends in part on the locus at the 81-cM region of MRL/MpJ-type chromosome 1 (Chr 1). To evaluate the function of this locus, we examined pathological changes in mouse testes resulting from transient scrotal heat stress. Immediately after scrotal heat stress, meiosis progression and blood-testis barrier integrity were preserved in MRL/MpJ but not in C57BL/6 mice, nor in a C57BL/6-based congenic strain carrying the MRL/MpJ derived Chr 1 locus (B6.MRLc1). Testicular damage was severe in the weeks after scrotal heat stress in all three strains; however, testicular calcification was observed only in C57BL/6 and MRL/MpJ mice (initially as nanocrystals in mitochondria of degenerating germ cells). In testes, expression of gremlin 2, a bone morphogenetic protein antagonist encoded on Chr 1, was markedly higher in B6.MRLc1 than in C57BL/6 or MRL/MpJ mice. Furthermore, gremlin-2 and bone morphogenetic protein 2 mRNA levels in heated testes correlated negatively and positively, respectively, with calcification. Thus, although the MRL/MpJ-derived locus on Chr 1 may play a pivotal role in recovery from heat-induced testicular damage, especially via inhibition of calcification, MRL/MpJ mice have a precipitating factor for testicular calcification and heat shock-resistant factors that reside outside the 81-cM region of Chr 1. PMID- 25041855 TI - Fatty acid binding protein 7 regulates phagocytosis and cytokine production in Kupffer cells during liver injury. AB - Kupffer cells (KCs) are involved in the progression of liver diseases such as hepatitis and liver cancer. Several members of the fatty acid binding proteins (FABPs) are expressed by tissue macrophages, and FABP7 is localized only in KCs. To clarify the role of FABP7 in the regulation of KC function, we evaluated pathological changes of Fabp7 knockout mice during carbon tetrachloride-induced liver injury. During liver injury in Fabp7 knockout mice, serum liver enzymes were increased, cytokine expression (tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and transforming growth factor-beta) was decreased in the liver, and the number of KCs in the liver necrotic area was significantly decreased. Interestingly, in the FABP7-deficient KCs, phagocytosis of apoptotic cells was impaired, and expression of the scavenger receptor CD36 was markedly decreased. In chronic liver injury, Fabp7 knockout mice showed less fibrogenic response to carbon tetrachloride compared with wild-type mice. Taken together, FABP7 is involved in the liver injury process through its regulation of KC phagocytic activity and cytokine production. Such modulation of KC function by FABP7 may provide a novel therapeutic approach to the treatment of liver diseases. PMID- 25041856 TI - TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors. AB - Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53 germline mutation who developed peripheral schwannomas also carried the MSH4 germline mutation, and in addition, a germline mutation of the LATS1 gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1 gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4 mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53 and LATS1 germline mutations. PMID- 25041857 TI - Arsenophonus insect symbionts are commonly infected with APSE, a bacteriophage involved in protective symbiosis. AB - Insects commonly have intimate associations with maternally inherited bacterial symbionts. While many inherited symbionts are not essential for host survival, they often act as conditional mutualists, conferring protection against certain environmental stresses. The defensive symbiont Hamiltonella defensa which protects aphids against attacks by parasitoid wasps is one of these conditional mutualists. The protection afforded by Hamiltonella depends on the presence of a lysogenic bacteriophage, called APSE, encoding homologs of toxins that are suspected to target wasp cells. In this study, an important diversity of APSE variants is reported from another heritable symbiont, Arsenophonus, which is exceptionally widespread in insects. APSE was found in association with two thirds of the Arsenophonus strains examined and from a variety of insect groups such as aphids, white flies, parasitoid wasps, triatomine bugs, louse flies, and bat flies. No APSE was, however, found from Arsenophonus relatives such as the recently described Aschnera chinzeii and ALO-3 endosymbionts. Phylogenetic investigations revealed that APSE has a long evolutionary history in heritable symbionts, being secondarily acquired by Hamiltonella through lateral transfer from Arsenophonus. Overall, this highlights the role of lateral transfer as a major evolutionary process shaping the emergence of defensive symbiosis in heritable bacteria. PMID- 25041858 TI - Modeling the determinants of Medicaid home care payments for children with special health care needs: A structural equation model approach. AB - BACKGROUND: The management of children with special needs can be very challenging and expensive. OBJECTIVE: To examine direct and indirect cost drivers of home care expenditures for this vulnerable and expensive population. METHODS: We retrospectively assessed secondary data on children, ages 4-20, receiving Medicaid Personal Care Services (PCS) (n = 2760). A structural equation model assessed direct and indirect effects of several child characteristics, clinical conditions and functional measures on Medicaid home care payments. RESULTS: The mean age of children was 12.1 years and approximately 60% were female. Almost half of all subjects reported mild, moderate or severe ID diagnosis. The mean ADL score was 5.27 and about 60% of subjects received some type of rehabilitation services. Caseworkers authorized an average of 25.5 h of PCS support per week. The SEM revealed three groups of costs drivers: indirect, direct and direct + indirect. Cognitive problems, health impairments, and age affect expenditures, but they operate completely through other variables. Other elements accumulate effects (externalizing behaviors, PCS hours, and rehabilitation) and send them on a single path to the dependent variable. A few elements exhibit a relatively complex position in the model by having both significant direct and indirect effects on home care expenditures - medical conditions, intellectual disability, region, and ADL function. CONCLUSIONS: The most important drivers of home care expenditures are variables that have both meaningful direct and indirect effects. The only one of these factors that may be within the sphere of policy change is the difference among costs in different regions. PMID- 25041859 TI - Escalation to weekly dosing recaptures response in adalimumab-treated patients with moderately to severely active ulcerative colitis. AB - BACKGROUND: Patients with moderately to severely active ulcerative colitis occasionally do not respond to or lose initial response to maintenance dosing of anti-TNF therapy. AIM: To report the efficacy of escalation from every other week (EOW) to weekly adalimumab dosing in patients from the clinical trial ULTRA 2 (NCT00408629), by week 8 response (i.e. response after adalimumab induction therapy). METHODS: Week 52 remission, response, and mucosal healing rates were assessed in ULTRA 2 adalimumab-randomised patients who escalated to weekly dosing. Patients were stratified by week 8 response per partial Mayo score. Kaplan-Meier and logistic regression analyses estimated time to weekly dosing and defined predictors of escalation to weekly dosing, respectively. Adverse events were reported for patients receiving open-label adalimumab. RESULTS: The rate of escalation to weekly dosing was 16.3% (20/123) for week 8 responders and 38.4% (48/125) for week 8 nonresponders. Week 52 remission, response and mucosal healing rates with weekly dosing were 20%, 45%, and 45% for week 8 responders and 2.1%, 25% and 29.2% for nonresponders, respectively (NRI). The median time to weekly dosing was 288 days for week 8 nonresponders and not estimable for responders. Prior anti-TNF use was a significant predictor of escalation to weekly dosing. Treatment-emergent adverse event rates were similar for patients receiving open-label EOW or weekly adalimumab. CONCLUSIONS: Escalation to weekly adalimumab dosing demonstrated clinical benefits for patients who lost response to therapy and may be beneficial for patients not initially responding to induction therapy. No new safety risks were identified with weekly dosing. PMID- 25041860 TI - Heterologous expression and functional characterization of a novel cellulose disruptive protein LeEXP2 from Lycopersicum esculentum. AB - There has been little research reported on the synergism of plant expansins in cellulose hydrolysis because of the difficulty of heterologous expression. In this study, the expansin gene LeExp2 of Lycopersicum esculentum was expressed for the first time in Pichia pastoris to identify its function in vitro. The optimal expression level was obtained by adding PMSF and a commercial protease inhibitor, and the maximum expression level was 70.9 mg/L. The affinity-purified LeEXP2 displayed cellulose-weakening activity and synergism with cellulase, and the reducing sugar yield in the reaction mixture with LeEXP2 was 1.4-9.8-fold that of control. The optimum pH and temperature for reducing-sugar liberation by LeEXP2 and endoglucanase were pH 4.8 and 50 degrees C. Cu(2+) and Fe(2+) notably increased the synergistic activity of LeEXP2, and Co(2+) enhanced the activity of endoglucanase but failed to improve synergism. LeEXP2 exhibited a high level of robustness to reagents and heat, indicating its potential application for cellulose decomposition. LeEXP2 preferentially bound to cellulose over lignin, and the binding capability to given substrates was not related to the crystallinity. This is the first study to characterize the functional role of LeEXP2 in cellulose degradation. PMID- 25041861 TI - Intractable proctitis in a 46-year-old man. PMID- 25041862 TI - Intestinal secretory mechanisms in irritable bowel syndrome-diarrhea. AB - Although diarrhea is the predominant bowel dysfunction in as many as one-third of patients with irritable bowel syndrome (IBS), it is unclear whether there is a specific disorder of intestinal fluid or electrolyte secretion in IBS. Diarrhea is generally considered a result of accelerated colonic transit in patients with IBS. Although a primary secretory diathesis has not been well-documented in patients with IBS with diarrhea (IBS-D), several mechanisms that could potentially contribute to intestinal secretion have been reported. Some of these mechanisms also influence motor and secretory dysfunctions that contribute to the pathophysiology of IBS-D. We review the evidence supporting secretion in IBS-D caused by peptides and amines produced by enteroendocrine cells or submucosal neurons, enterocyte secretory processes, and intraluminal factors (bile acids and short-chain fatty acids). Understanding these mechanisms and developing clinical methods for their identification could improve management of patients with IBS-D. PMID- 25041863 TI - Outcomes of patients with chronic hepatitis B who do not meet criteria for antiviral treatment at presentation. AB - BACKGROUND & AIMS: The availability of potent, well-tolerated, oral antivirals with low rates of resistance has led many experts to recommend liberalizing indications for the treatment of chronic hepatitis B (CHB). This study sought to determine the rate of transitions to an active phase of infection, the frequency of treatment initiation, and the clinical outcomes of patients with CHB who did not meet treatment criteria at presentation. METHODS: We reviewed medical records of patients with CHB, seen in the liver clinics at the University of Michigan Health System from 1999 through 2010, who did not receive antiviral treatment within 6 months of presentation. We collected data on transitions between different phases of CHB, hepatitis B e antigen (HBeAg) seroconversion, loss of hepatitis B surface antigen (HBsAg), and the development of hepatocellular carcinoma (HCC). Data analyses were censored or truncated at the time of treatment initiation or development of an outcome. RESULTS: Of the 234 patients analyzed, 52.1% were men (median age, 35 y), 72.2% were Asian, and 81.2% were HBeAg-negative. During a median follow-up period of 51 months, 19.2% of patients transitioned to a more active disease phase and 18.8% started antiviral therapy. Of the 44 HBeAg-positive patients, 4 patients (9%) had spontaneous HBeAg seroconversion. Nine HBeAg-negative patients but none of the HBeAg-positive patients lost HBsAg. The cumulative probability of HBsAg loss among HBeAg negative patients was 1% at year 5 and 21% by year 10. No patients had flares of icteric hepatitis or hepatic decompensation. None of the HBeAg-positive patients developed HCC, whereas 2 HBeAg-negative patients developed HCC. CONCLUSIONS: Careful monitoring of patients with CHB who did not meet treatment criteria at presentation permits timely initiation of treatment, with a low risk of adverse clinical outcomes, based on a retrospective study with a median follow-up period of 4.3 years. These findings indicate that current guidelines for initiating treatment are appropriate. PMID- 25041864 TI - A rule for determining risk of colorectal cancer in patients with inflammatory bowel disease. AB - BACKGROUND & AIMS: Surveillance guidelines for inflammatory bowel disease associated colorectal cancer (IBD-CRC) are based on findings from retrospective studies. We aimed to create and validate a prediction rule to assist clinicians in identifying patients with IBD who are at low and high risk for CRC. METHODS: We performed a retrospective case-control study of 2 cohorts of patients from tertiary care centers (the University Hospital of Leuven, Belgium, and 7 University Medical Centers in The Netherlands). Multivariate Cox regression was used to select independent risk factors for CRC in the Leuven cohort. Based on their regression coefficients (beta), we created a rule to predict risk for CRC. In validation studies, the predictive strength was tested by C-statistic analysis and then validated externally in the Dutch cohort. RESULTS: In total, we identified 50 patients with IBD-CRC (cases) and 136 patients with IBD without CRC (controls) in Leuven, and 138 cases and 206 controls in the Dutch cohort. From the Leuven cohort we created the CRC risk prediction rule based on 4 risk factors: IBD-type ulcerative colitis (beta = 1.2), primary sclerosing cholangitis (beta = 1.1), extent of colonic disease >=50% (beta = 1.1), and postinflammatory polyps (beta = 0.8). The prediction rule consisted of a total score for each individual patient calculated from the presence or absence of these 4 risk factors. For example, a score of 13 represented patients who had extensive Crohn's disease without PSC or postinflammatory polyps, who had a 15% likelihood of CRC in the Leuven cohort and a 24% likelihood of CRC in the Dutch cohort. Scores of 0, 13, 23, 27, and 37 represented patients with Crohn's disease, and scores 15, 25, 28, 38, 42, and 52 represented patients with ulcerative colitis. The total score per patient had a C-statistic of 0.75. In the Dutch cohort this score had a C-statistic of 0.67. CONCLUSIONS: Ulcerative colitis, primary sclerosing cholangitis, disease extent >=50%, and postinflammatory polyps were found to determine risk for CRC in patients with IBD. A surveillance guideline that incorporates the relative weights of these risk profiles would identify patients at risk for CRC more accurately than algorithms in current guidelines. PMID- 25041865 TI - Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. AB - BACKGROUND & AIMS: Crohn's disease and ulcerative colitis are associated with an increased risk of colorectal cancer (CRC). Surveillance colonoscopy is recommended at 2- to 3-year intervals beginning 8 years after diagnosis of inflammatory bowel disease (IBD). However, there have been no reports of whether colonoscopy examination reduces the risk for CRC in patients with IBD. METHODS: In a retrospective study, we analyzed data from 6823 patients with IBD (2764 with a recent colonoscopy, 4059 without a recent colonoscopy) seen and followed up for at least 3 years at 2 tertiary referral hospitals in Boston, Massachusetts. The primary outcome was diagnosis of CRC. We examined the proportion of patients undergoing a colonoscopy within 36 months before a diagnosis of CRC or at the end of the follow-up period, excluding colonoscopies performed within 6 months before a diagnosis of CRC, to avoid inclusion of prevalent cancers. Multivariate logistic regression was performed, adjusting for plausible confounders. RESULTS: A total of 154 patients developed CRC. The incidence of CRC among patients without a recent colonoscopy (2.7%) was significantly higher than among patients with a recent colonoscopy (1.6%) (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39-0.80). This difference persisted in multivariate analysis (OR, 0.65; 95% CI, 0.45-0.93) and was robust when adjusted for a range of assumptions in sensitivity analyses. Among patients with CRC, a colonoscopy within 6 to 36 months before diagnosis was associated with a reduced mortality rate (OR, 0.34; 95% CI, 0.12-0.95). CONCLUSIONS: Recent colonoscopy (within 36 months) is associated with a reduced incidence of CRC in patients with IBD, and lower mortality rates in those diagnosed with CRC. PMID- 25041867 TI - Gastric explosion induced by argon plasma coagulation and prevention strategies. AB - We describe the occurrence of an iatrogenic explosion induced by argon plasma coagulation in a 70-year-old man undergoing gastroscopy. Combustible gases in the stomach may have been released by bacterial overgrowth as a result of partial gastric outlet obstruction (caused by a gastric tumor) and reduced acidity (from proton pump inhibitor therapy). We propose a stepwise process during upper endoscopy to prevent this devastating complication, comprising aspiration, preinsufflation with CO2, and then coagulation. PMID- 25041866 TI - Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes. AB - BACKGROUND & AIMS: Acute hyperglycemia delays gastric emptying in patients with diabetes. However, it is not clear whether improved control of glycemia affects gastric emptying in these patients. We investigated whether overnight and short term (6 mo) improvements in control of glycemia affect gastric emptying. METHODS: We studied 30 patients with poorly controlled type 2 diabetes (level of glycosylated hemoglobin, >9%). We measured gastric emptying using the [(13)C] Spirulina platensis breath test on the patients' first visit (visit 1), after overnight administration of insulin or saline, 1 week later (visit 2), and 6 months after intensive therapy for diabetes. We also measured fasting and postprandial plasma levels of C-peptide, glucagon-like peptide 1, and amylin, as well as autonomic functions. RESULTS: At visit 1, gastric emptying was normal in 10 patients, delayed in 14, and accelerated in 6; 6 patients had gastrointestinal symptoms; vagal dysfunction was associated with delayed gastric emptying (P < .05). Higher fasting blood levels of glucose were associated with shorter half times of gastric emptying (thalf) at visits 1 (r = -0.46; P = .01) and 2 (r = 0.43; P = .02). Although blood levels of glucose were lower after administration of insulin (132 +/- 7 mg/dL) than saline (211 +/- 15 mg/dL; P = .0002), gastric emptying thalf was not lower after administration of insulin, compared with saline. After 6 months of intensive therapy, levels of glycosylated hemoglobin decreased from 10.6% +/- 0.3% to 9% +/- 0.4% (P = .0003), but gastric emptying thalf did not change (92 +/- 8 min before, 92 +/- 7 min after). Gastric emptying did not correlate with plasma levels of glucagon-like peptide 1 and amylin. CONCLUSIONS: Two-thirds of patients with poorly controlled type 2 diabetes have mostly asymptomatic yet abnormal gastric emptying. Higher fasting blood levels of glucose are associated with faster gastric emptying. Overnight and sustained (6 mo) improvements in glycemic control do not affect gastric emptying. PMID- 25041868 TI - Intensive therapy induces contralateral white matter changes in chronic stroke patients with Broca's aphasia. AB - Using a pre-post design, eleven chronic stroke patients with large left hemisphere lesions and nonfluent aphasia underwent diffusion tensor imaging and language testing before and after receiving 15 weeks of an intensive intonation based speech therapy. This treated patient group was compared to an untreated patient group (n=9) scanned twice over a similar time period. Our results showed that the treated group, but not the untreated group, had reductions in fractional anisotropy in the white matter underlying the right inferior frontal gyrus (IFG, pars opercularis and pars triangularis), the right posterior superior temporal gyrus, and the right posterior cingulum. Furthermore, we found that greater improvements in speech production were associated with greater reductions in FA in the right IFG (pars opercularis). Thus, our findings showed that an intensive rehabilitation program for patients with nonfluent aphasia led to structural changes in the right hemisphere, which correlated with improvements in speech production. PMID- 25041869 TI - Effects of factor Xa on the expression of proteins in femoral arteries from type 2 diabetic patients. AB - AIM: Further to its pivotal role in haemostasis, factor Xa (FXa) promotes effects on the vascular wall. The purpose of the study was to evaluate if FXa modifies the expression level of energy metabolism and oxidative stress-related proteins in femoral arteries obtained from type 2 diabetic patients with end-stage vasculopathy. METHODS: Femoral arteries were obtained from 12 type 2 diabetic patients who underwent leg amputation. Segments from the femoral arteries were incubated in vitro alone and in the presence of 25 nmol l(-1) FXa and 25 nmol l( 1) FXa + 50 nmol l(-1) rivaroxaban. RESULTS: In the femoral arteries, FXa increased triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase isotype 1 expression but decreased pyruvate dehydrogenase expression. These facts were accompanied by an increased content of acetyl-CoA. Aconitase activity was reduced in FXa-incubated femoral arteries as compared with control. Moreover, FXa increased the protein expression level of oxidative stress-related proteins which was accompanied by an increased malonyldialdehyde arterial content. The FXa inhibitor, rivaroxaban, failed to prevent the reduced expression of pyruvate dehydrogenase induced by FXa but reduced acetyl-CoA content and reverted the decreased aconitase activity observed with FXa alone. Rivaroxaban + FXa but not FXa alone increased the expression level of carnitine palmitoyltransferase I and II, two mitochondrial long chain fatty acid transporters. Rivaroxaban also prevented the increased expression of oxidative stress-related proteins induced by FXa alone. CONCLUSIONS: In femoral isolated arteries from type 2 diabetic patients with end-stage vasculopathy, FXa promoted disruption of the aerobic mitochondrial metabolism. Rivaroxaban prevented such effects and even seemed to favour long chain fatty acid transport into mitochondria. PMID- 25041871 TI - Co-occurrence of malignant acanthosis nigricans and the Leser-Trelat sign in a patient with hepatocellular carcinoma. PMID- 25041870 TI - Baseline characteristics and treatment response of patients from the Philippines in the CHIMES study. AB - BACKGROUND: The CHIMES Study compared MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 h. Sites from the Philippines randomized 504 of 1099 (46%) patients in the study. We aimed to define the patient characteristics and treatment responses in this subgroup to better plan future trials. METHODS: The CHIMES dataset was used to compare the baseline characteristics, time from stroke onset to study treatment initiation, and treatment responses to MLC601 between patients recruited from Philippines and the rest of the cohort. Treatment effect was analyzed using end-points at month 3 as described in the primary publication, that is, modified Rankin Score, National Institutes of Health Stroke Scale, and Barthel Index. RESULTS: The Philippine cohort was younger, had more women, worse baseline National Institutes of Health Stroke Scale, and longer time delay from stroke onset to study treatment compared with the rest of the cohort. Age (P = 0.003), baseline National Institutes of Health Stroke Scale (P < 0.001), and stroke onset to study treatment initiation (P = 0.016) were predictors of modified Rankin Score at three-months. Primary analysis of modified Rankin Score shift was in favor of MLC601 (adjusted odds ratio 1.41, 95% confidence interval 1.01-1.96). Secondary analyses were likewise in favor of MLC601 for modified Rankin Score dichotomy 0-1, improvement in National Institutes of Health Stroke Scale (total and motor scores), and Barthel Index. CONCLUSIONS: The treatment effects in the Philippine cohort were in favor of MLC601. This may be due to inclusion of more patients with predictors of poorer outcome. PMID- 25041872 TI - Electroacupuncture and A-317491 depress the transmission of pain on primary afferent mediated by the P2X3 receptor in rats with chronic neuropathic pain states. AB - P2X is a family of ligand-gated ion channels that act through adenosine ATP. The P2X3 receptor plays a key role in the transmission of neuropathic pain at peripheral and spinal sites. Electroacupuncture (EA) has been used to treat neuropathic pain effectively. To determine the role of EA in neuropathic pain mediated through the P2X3 receptor in dorsal root ganglion neurons and the spinal cord, a chronic constriction injury (CCI) model was used. Sprague-Dawley rats were divided into four groups: sham CCI, CCI, CCI plus contralateral EA, and CCI plus ipsilateral EA. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded. Furthermore, the expression of the P2X3 receptor was evaluated through Western blotting and immunofluorescence. The effects of EA and A-317491 were investigated through the whole-cell patch-clamp method and intrathecal administration. Our results show that the MWT and TWL of EA groups were higher than those in the CCI group, whereas the expression of the P2X3 receptor was lower than that in the CCI group. However, no significant difference was detected between the two EA groups. EA depressed the currents created by ATP and the upregulation of the P2X3 receptor in CCI rats. Additionally, EA was more potent in reducing mechanical allodynia and thermal hyperalgesia when combined with A-317491 through intrathecal administration. These results show that both contralateral and ipsilateral EA might inhibit the primary afferent transmission of neuropathic pain induced through the P2X3 receptor. In addition, EA and A-317491 might have an additive effect in inhibiting the transmission of pain mediated by the P2X3 receptor. PMID- 25041873 TI - Is continuous adductor canal block better than continuous femoral nerve block after total knee arthroplasty? Effect on ambulation ability, early functional recovery and pain control: a randomized controlled trial. AB - Total knee arthroplasty is associated with intense, early post-operative pain. Femoral nerve block is known to provide optimal pain relief but reduces the strength of the quadriceps muscle and associated with the risk of falling. Adductor canal block is almost pure sensory blockade with minimal effect on quadriceps muscle strength. We prospectively randomized 100 patients in two groups' continuous adductor and femoral block group. Ambulation ability (Timed up go, 10-m walk, 30 s chair test), time to active SLR, quadsticks, staircase competency, ambulation distance was significantly better (P value < 0.001) in adductor canal group whereas pain scores, opioid consumption showed no significant difference. Adductor canal block provided better ambulation and early functional recovery but without superior analgesia than femoral nerve block post TKA. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25041874 TI - Non-oncologic total femoral arthroplasty: retrospective review. AB - Total femoral arthroplasty (TFA) is an option to amputation in the setting of excessive bones loss during revision total hip and knee arthroplasty. Twenty non oncologic TFAs with a minimum of 2years follow-up were retrospectively reviewed. The average clinical follow-up was 73+/-49months. The incidence of new infection was 25% (5/20), while the overall infection rate was 35% (7/20). The incidence of primary hip instability was 10% (2/20), while the overall instability rate was 25% (5/20). Six patients (30%) required revision. The average pre-operative HHS was 30.2+/-13.1. The average post-operative HHS was 65.3+/-16.9. TFA is a viable alternative to amputation in non-oncologic patients with massive femoral bone deficiency. However, TFA performed poorly in the setting of infection and instability. PMID- 25041876 TI - Effects of aerobic, resistance and balance training in adults with intellectual disabilities. AB - Adults with intellectual disability (ID) have decreased cardiovascular fitness and strength present with lower rates of physical activity (PA), and often have balance and functional impairments. The purpose of this study was to investigate the effect of a combined PA program (CPAP) utilizing aerobic, strength and balance training on cardiovascular fitness, strength, balance and functional measures in a controlled clinical trial. Adults with mild to moderate ID were assigned into either the intervention group (IG; n=37) or the control group (CG; n=29). The IG trained 3 day/week, 1 h/day over 14 weeks, while the CG did not participate in any exercise program. Cardiovascular fitness, strength, balance, flexibility and functional ability were assessed pre-post training. The IG increased cardiovascular fitness (26.8 vs. 29.3 ml kg(-1) min(-1)), handgrip strength (19.2 vs. 21.9 kg), leg strength, and balance following the training period (p<.05). Body weight (70.1 vs. 68.1 kg) and body mass index (27.4 vs. 26.6 kg m(-2)) decreased (p<.05) in the IG group. The CG showed no changes in any parameter. These data suggest a combined aerobic, strength and balance exercise training program is beneficial among individuals with ID. PMID- 25041875 TI - Evidence of health risks associated with prolonged standing at work and intervention effectiveness. AB - PURPOSE: Prolonged standing at work has been shown to be associated with a number of potentially serious health outcomes, such as lower back and leg pain, cardiovascular problems, fatigue, discomfort, and pregnancy-related health outcomes. Recent studies have been conducted examining the relationship between these health outcomes and the amount of time spent standing while on the job. The purpose of this article was to provide a review of the health risks and interventions for workers and employers that are involved in occupations requiring prolonged standing. A brief review of recommendations by governmental and professional organizations for hours of prolonged standing is also included. FINDINGS: Based on our review of the literature, there seems to be ample evidence showing that prolonged standing at work leads to adverse health outcomes. Review of the literature also supports the conclusion that certain interventions are effective in reducing the hazards associated with prolonged standing. Suggested interventions include the use of floor mats, sit-stand workstations/chairs, shoes, shoe inserts and hosiery or stockings. Studies could be improved by using more precise definitions of prolonged standing (e.g., duration, movement restrictions, and type of work), better measurement of the health outcomes, and more rigorous study protocols. CONCLUSION AND CLINICAL RELEVANCE: Use of interventions and following suggested guidelines on hours of standing from governmental and professional organizations should reduce the health risks from prolonged standing. PMID- 25041877 TI - Functional variables of challenging behavior in individuals with intellectual disabilities. AB - Research suggests that different types of challenging behavior (CB) may be maintained by different contingencies of reinforcement. In this study, we examined functional variables for nine types of CB (physical aggression, verbal aggression, self-injury, tantrums, non-compliance, property destruction, disruptive behavior, stereotypes and inappropriate verbal behavior) in 300 people with intellectual disabilities. The Questions About Behavioral Function (QABF) instrument was administered to 183 direct care staff members to assess a total of 328 challenging behaviors. Results of non-parametric analyses distinguished significant differences across behavioral functions. CBs associated with each subscale of the QABF were identified. Results were consistent with previous research, stereotypic behavior was scored significantly higher across the non social functions measured by the QABF, whereas other types of CB (such as aggressive behavior) were scored significantly higher across social functions. The results of this study extend the literature on this issue, and implications for future research and direct care professionals are discussed. PMID- 25041878 TI - Evolved Saccharomyces cerevisiae wine strains with enhanced glutathione production obtained by an evolution-based strategy. AB - In winemaking, the application of glutathione (GSH) has been the subject of ever growing interest because of its important role in limiting must and wine oxidation and in protecting various aromatic compounds. Glutathione concentration in wine is highly variable, involving as it does several factors from must, through alcoholic fermentation, to yeast strain activity. Consequently, the development of new wine yeast strains able to improve flavor stability is in great demand. To generate evolved Saccharomyces cerevisiae strains with enhanced GSH production, we have applied an evolution-based strategy that combines the sexual recombination of spores with the application of molybdate, which is toxic for the cells at high concentration, as specific selective pressure. Eight molybdate-resistant strains were selected and further screened for GSH production in synthetic grape must and in microvinification assay. By this nongenetically modified strategy, we obtained two evolved strains, Mo21T2-5 and Mo21T2-12, both able to enhance GSH content in wine with an increase of 100% and 36%, respectively, compared with the parental strain 21T2, and 120% and 50% compared with initial GSH content in the must. PMID- 25041879 TI - Pancreatic fistulae after pancreatic resections for neuroendocrine tumours compared with resections for other lesions. AB - BACKGROUND: Resection for pancreatic neuroendocrine tumours (PNET) is suggested to be associated with an increased risk of a post-operative pancreatic fistula (POPF). The aim of this study was to describe morbidity after resections for PNET, focusing on POPF. Outcomes were compared with resections for other lesions. METHODS: Patients undergoing an elective pancreatic resection during a 12-year period were retrospectively analysed. Morbidity was defined according to the International Study Group of Pancreatic Surgery (ISGPS) definitions. RESULTS: Eighty-eight out of 832 patients (10.6%) underwent a resection for PNET. Atypical pancreatic resections (enucleation and central pancreatectomy) and distal pancreatectomies were more frequently performed for PNET. The POPF rate was 22.7% in patients operated for PNET compared with 17.2% in other patients (P = 0.200). In univariate analysis, body mass index (BMI), pancreatic duct diameter, somatostatin analogue administration, type of resection and type of pathology were associated with a POPF. In multivariate analysis, BMI, a pancreatic duct diameter <3 mm and central pancreatectomy remained independent risk factors [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.22-3.07 and OR 3.04, 95% CI 1.05 8.82, respectively]. CONCLUSIONS: High rates of POPF were found in patients operated for PNET. However, this was mainly owing to the fact that atypical resections, known to be associated with a higher fistula rate, were performed more frequently in these patients. PMID- 25041880 TI - First-line treatment of 102 chronic myeloid leukemia patients with imatinib: a long-term single institution analysis. AB - Imatinib mesylate radically changed the natural history of chronic myeloid leukemia (CML). The recent availability of alternative tyrosine kinase inhibitors (TKIs) renders the clinical management of CML more complex. In this article, we summarize our long-term single institution experience. From 2003 to 2012, 102 patients with newly diagnosed chronic phase CML were referred to our institution and treated with imatinib mesylate as first-line therapy. All patients were followed inside a dedicated CML clinic. At 1 year, 82/95 patients (86.3%) achieved complete cytogenetic response (CCyR) using a treatment performed analysis (TPA); when using an intention to treat analysis, 85/102 patients (83.3%) obtained CCyR. At 3 months, 58 patients (64.4% TPA) obtained a BCR-ABL transcripts level <10%. A major molecular response (MMR) was obtained by 38% and 53% of patients at 1 and 2 years. Twenty patients (19.6%) discontinued treatment with imatinib; six of them did so in the initial 2 years of treatment (4 for resistance and 2 for adverse events). We observed seven deaths (6.86%). Overall survival (OS) at 6 years is 95.1% (95% C.I. 90-100%) and is not different from that of the general population. No patient experienced progression of disease (95% C.I.: 0-3%). Our results suggest that patient management is a crucial point to obtain a successful therapeutic outcome: at 1 year CCyR and MMR rates are similar to the results obtained with second generation TKIs and OS is not different from that of the general population. PMID- 25041881 TI - Arthroscopic management of anterior instability of the shoulder. AB - BACKGROUND: The aim of all shoulder joint stabilization surgery is to prevent further dislocation and restore anatomical continuity of the capsule-labral complex to the anterior and inferior edge of the glenoid. In this study, the authors analyzed the results of arthroscopic stabilization techniques using the method of suture anchors in patients with recurrent anterior shoulder instability. MATERIAL AND METHODS: During the reporting period they performed surgery on 91 patients with anterior shoulder instability using the method of MITEK GII suture anchors and BIO ANCHOR . The group consisted of 19 women and 72 men with a mean age of 28.6 years (range 16-70 years). RESULTS: In the preoperative evaluation, the mean Rowe score was 37.1 (range 15-55). Postoperatively there was a significant increase (p < 0.000) in the score analysed using Rowe with a mean of 87.4 (range 45-100). When analyzing the results of operations, they evaluated the function as excellent in 65 patients (71.4 %) and 14 patients (15.4 %) were evaluated as good function. A satisfactory function was observed in 12 patients (13.2 %). For five patients, there was recurrence of instability of the shoulders. CONCLUSIONS: Arthroscopic stabilization of post-traumatic shoulder instability using the suture anchor technique is the optimal solution for anterior shoulder instability. In conjunction with comprehensive treatment and subsequent rehabilitation an early return to the preoperative activities can be achieved with a reduction of residual restriction of shoulder movement. PMID- 25041882 TI - Evaluation of treatment outcomes of periprosthetic femoral fractures after hip replacement surgery. AB - BACKGROUND: The aim of this paper is to evaluate treatment outcomes of periprosthetic femoral fractures (PFFs) after total hip arthroplasty (THA). MATERIAL AND METHODS: The study group consisted of 119 patients (125 procedures) with PFFs, including 101 patients (105 procedures) with intraoperative fractures and 20 with postoperative fractures. Intraoperative PFFs occurred in 84 primary arthroplasties and in 21 revision arthroplasties. The control group comprised 390 patients (408 procedures) without PFFs. The Harris Hip Score (HHS) questionnaire was used to evaluate the influence of the fracture and its type according to the Vancouver classification and the treatment method on the patients' clinical status. RESULTS: No statistically significant differences were found between HHS scores of patients with intraoperative PFFs and patients without fractures or between the group of patients after revision THA performed due to a late PFF and patients reoperated on for other reasons. Trendelenburg's sign was positive more frequently in patients with an intraoperative PFF after revision THA than in those after primary THA (p=0.006). The small size of the subgroups studied did not make possible a reliable analysis of PFF treatment outcomes for given types of fractures according to the Vancouver classification and their respective treatment methods. CONCLUSIONS: 1. Treatment outcomes of intraoperative PFFs are satisfactory despite the use of simple fixation methods, as opposed to poor treatment outcomes of postoperative fractures, whose stabilization required the use of complicated surgical methods. 2. The results did not allow for determining the influence of the type of fracture according to the Vancouver classification and the treatment method on the clinical condition of patients after PFF treatment. PMID- 25041883 TI - Cemented reconstruction of acetabular ceiling using the vertebroplasty set in treatment of metastatic lesions. AB - INTRODUCTION: The number of patients suffering from malignant tumors with bony metastases has been increasing. Surgery makes it possible to preserve physical function and decrease pain. Safe and efficient techniques for filling cancer related bone defects within the pelvis are still being searched for. MATERIAL AND METHODS: A total of 13 patients with cancer metastases to the acetabular ceiling area in the hip were operated on using vertebroplasty sets in the Oncological Orthopedics Department in Brzozow in the years 2010-2013. A percutaneous approach was employed in 4 patients, while in 9 the surgery was combined with acetabulofemoral joint resection and arthroplasty. Patient qualification for the treatment took into account the size and shape of the bone defect as determined per computed tomography. Pain intensity (VAS scale) and gait efficiency were evaluated before and after the treatment. RESULTS: All patients reported a distinct decrease in pain intensity. All of them started to ambulate and loading the joint did not aggravate the symptoms. No thrombo-embolic or infectious complications were observed. The mobility of the operated joints was good. CONCLUSIONS: The filling of lytic bone defects in the acetabular ceiling area determines walking efficiency and reduced pain intensity. Surgical procedures take a long time, are complicated and associated with a high risk of complications. Percutaneous administration of bone cement may be an alternative solution in patients with an intact cortical bone layer. The literature data indicate good outcomes of this approach, with a minimal number of complications. Acetabuloplasty with bone cement is a safe and effective treatment method in the case of cancer metastases to the acetabular ceiling area. PMID- 25041884 TI - Analysis of problems in the daily functioning of patients after hip arthroplasty. AB - BACKGROUND: Awareness of functional status of patients after arthroplasty helps therapists to select suitable topics of education that will enable the patients to continue rehabilitation on their own and improve the quality of life among hip joint prosthesis recipients. MATERIAL AND METHODS: The study involved a group of 60 patients (41 men and 19 women) after arthroplasty who were hospitalised in medical rehabilitation wards of Lodz hospitals. The average age of the patients was 65.0+/-11.2 years (65.4+/-11.5 years among women and 63.9+/-10.8 years among men). The functional status of the patients was assessed using the modified Rankin Scale (mRS) for self-evaluation of disability, Barthel Index (BI) to determine the degree of independence in performance of daily living activities and a survey prepared by the authors. RESULTS: The degree of disability of the study subjects may be assessed as moderate (mRS score: 2.8 overall, 2.6 for women and 3.1 for men). The distributions of disability scores indicate a clinically significant difference in the assessment of disability level between women and men. The functional status of patients with regard to performance of daily living activities was evaluated as moderately severe (BI: 77.7+/-18.2 overall, 76.8+/ 17.2 for women, 79.5+/-16.6 for men). The women after hip arthroplasty assessed their ability to dress and undress as significantly poorer than the men did. CONCLUSIONS: 1. The patients assessed their functional status as moderate disability. 2. The study participants faced the most serious problems with bathing, walking up and down stairs, grooming, and dressing and undressing. 3. The women assessed their ability to dress and undress as significantly poorer than the men did. 4. Physiotherapists and nurses were indicated as the main sources of education. PMID- 25041885 TI - Assessment of the influence of body composition on bone mass in children and adolescents based on a functional analysis of the muscle-bone relationship. AB - BACKGROUND: The functional model of skeletal development considers the mechanical factor to be the most important skeletal modulant. The aim of the study was a functional analysis of the bone-muscle relationship in children with low and normal bone mass. MATERIAL AND METHODS: The study involved 149 children with low and 99 children with normal bone mass (control group). All patients underwent a densitometry examination (DXA). Low bone mass was diagnosed if the Z-score was below <1.01. Means and standard deviations of parameters required for the functional analysis according to Jaworski and Pludowski were calculated. RESULTS: The study found lower mean values of Z-scores for all parameters in children with low bone mass as compared to the control group. Children with low bone mass had lower content of adipose and muscle tissue and a marked deficit of muscle tissue with regard to height (which according to mechanostat theory leads to lower muscle-generated strain on bones). This group of children had also lower TBBMC/LBM Z-scores, which indicates greater fracture susceptibility. CONCLUSIONS: 1. Functional analysis, which showed associations between bone and muscle tissues, can be useful for diagnosing and monitoring skeletal system disorders as well as making therapeutic decisions.2. The study emphasizes the role of proper nutrition and physical activities, which contribute to proper body composition, in the prevention of bone mineralization disorders in childhood and adolescence. 3. The study showed the inadequacy of the classic reference ranges used in interpreting DXA data in children and demonstrated the usefulness of continuous variables for that purpose. PMID- 25041886 TI - Patients with spinal cord damage due to uncertain/unknown etiology: the CP phenomenon (confusion and perplexity). Case reports. AB - Usually, most of the clients who are referred to departments of rehabilitation medicine, bear firm and sound diagnoses. We describe herewith 10 patients who developed spinal cord pathologies due to unknown or uncertain etiologies. We would like to share our thoughts with the readers. PMID- 25041887 TI - Total hip arthroplasty in HIV-seropositive patients--case study and review of literature. AB - Hip arthroplasty is widely used in the treatment of osteoarthritis, especially in patients with steroid-induced osteonecrosis of the femoral head. However, this procedure in HIV-seropositive patients has not been described in the Polish literature and is not considered a standard treatment. This paper presents a case study of an HIV-seropositive patient who underwent hip arthroplasty for steroid induced avascular necrosis of the femoral head without significant complications. Based on this case, we propose an approach to the management of this group of patients. PMID- 25041888 TI - Complex dislocation of the second metacarpophalangeal joint. Case report. AB - Dislocation of the second metacarpophalangeal joint is a rare injury and despite trivial symptoms generally requires operative treatment. We present a case of complex dislocation treated operatively from a volar approach. This approach allows good visualization and repair of the volar plate. K-wire stabilization for 3 weeks was enough to avoid joint instability and did not limit the range of motion. PMID- 25041889 TI - Physiotherapy in pauciarticular juvenile idiopathic arthritis. Case study. AB - Juvenile idiopathic arthritis (JIA) is the most common arthropathy of childhood and adolescence. This term encompasses a group of chronic systemic inflammatory diseases of the connective tissue which cause arthritis in patients under 16 years of age lasting at least 6 weeks. The authors presented the characteristic features of physiotherapy based on functional examination results on the basis of two cases of girls with pauciarticular JIA treated according to an established pharmacological regimen. Physiotherapy should be introduced at an early stage of the disease. Kinesiotherapy preceded by history-taking and a functional examination of the patient, has to focus on both primary and secondary joint lesions. PMID- 25041890 TI - Assessment of gait after bilateral hip replacement. Case study. AB - Total hip arthroplasty (THA) is one of the most effective methods of treatment of severe hip osteoarthritis (HOA). In many cases pathological gait patterns persist despite properly conducted surgery and disturb the normal wear of the artificial joint surfaces. The aim of the study was to conduct functional and biomechanical assessment of gait in a patient after bilateral THA due to severe degenerative changes in the hip. The assessment focused on the gait parameters which significantly deviate from a normal gait pattern at various stages of treatment. Physiotherapeutic assessment of the patient included measurements of the range of motion in lower limb joints, the Timed Up and Go test, and pain assessment. Biomechanical assessment involved measurements of spatiotemporal gait parameters and the dynamic range of motion using BTS Smart-E motion analysis system. Although clinical examinations after both the first and second procedure suggested recovery of the patient's physical function, biomechanical assessment of her gait after the second procedure indicated the presence of deviations from a normal gait pattern. Secondary to a limited range of internal/external hip rotation, extension, and abduction, corresponding indices were still in the pathological range. PMID- 25041891 TI - Chronically unreduced posterior dislocation of the elbow. AB - BACKGROUND: Chronically unreduced posterior dislocation of the elbow is a complex and difficult problem for the surgeon and its treatment significantly influences future functional performance of the patient. There are few reports in the literature regarding chronically unreduced dislocations, and most of them are based on observations of individual patients. MATERIAL AND METHODS: A total of 9 patients with chronically unreduced posterior dislocations of the elbow were treated in the Department of Orthopaedics and Traumatology between 2004 and 2012. The mean time between injury and reduction was 5.6 weeks. Eight of the patients had a concomitant fracture of the radial head, 5 had a fracture of the coronoid process, and 8 demonstrated significant damage to the lateral collateral ligament complex. All patients were qualified for surgical reduction of the dislocation, and then, after a maximum of 2 weeks of immobilization in a plaster cast, the patients were referred for intensive physiotherapy. Stability, range of motion and elbow function according to the MEPI score were evaluated during follow-up visits. RESULTS: Elbow instability did not occur in any of the patients during the follow-up. Complications in our patients included a posttraumatic contracture of the elbow, periarticular ossifications and loosening of the radial head endoprosthesis. CONCLUSIONS: Recommendations for the management of these difficult cases are formulated. PMID- 25041892 TI - The effect of the Kinesio Taping method on spinal motion and physiological spinal curvatures. Literature review. AB - BACKGROUND: The Kinesiology Taping / Kinesio Taping (KT) method has become more and more popular in recent years. Many studies have been developed to demonstrate the application of this method in numerous fields of medicine. Despite its continuous development, several issues pertaining to the legitimacy of its application and mechanisms of its operation still need to be addressed. The aim of this study is to analyse the available literature in terms of the effect of KT on the spinal motion and physiological spinal curvatures. This study is based on a method of analysing bibliographic databases such as: SPORTDiscus, Medline, ScienceDirect, EBSCOhost, and Google Scholar. RESULTS AND CONCLUSIONS: There were found seven research articles that observe the criteria of this study's aim. Four of those research articles were devoted to the motion of the lumbar spinal segment, the other two discussed the motion of the cervical spinal segment and one of them concentrated on the lumbar lordosis. None of those research articles included any information on negative effect of this method. The effect of KT on assessed parameters is barely noticeable. Therefore, it is necessary to conduct further research in respect of the effect of the Kinesiology Taping method on the spinal motion and physiological spinal curvatures. PMID- 25041893 TI - [Principles of prevention of venous thromboembolism in orthopedics and traumatology (updated on 02/18/2014)]. PMID- 25041894 TI - Microhabitat differences impact phylogeographic concordance of codistributed species: genomic evidence in montane sedges (Carex L.) from the Rocky Mountains. AB - By selecting codistributed, closely related montane sedges from the Rocky Mountains that are similar in virtually all respects but one-their microhabitat affinities-we test predictions about how patterns of genetic variation are expected to differ between Carex nova, an inhabitant of wetlands, and Carex chalciolepis, an inhabitant of drier meadows, slopes, and ridges. Although contemporary populations of the taxa are similarly isolated, the distribution of glacial moraines suggests that their past population connectedness would have differed. Sampling of codistributed population pairs from different mountain ranges combined with the resolution provided by over 24,000 single nucleotide polymorphism loci supports microhabitat-mediated differences in the sedges' patterns of genetic variation that are consistent with their predicted differences in the degree of isolation of ancestral source populations. Our results highlight how microhabitat preferences may interact with glaciations to produce fundamental differences in the past distributions of presently codistributed species. We discuss the implications of these findings for generalizing the impacts of climate-induced distributional shifts for communities, as well as for the prospects of gaining insights about species specific deterministic processes, not just deterministic community-level responses, from comparative phylogeographic study. PMID- 25041895 TI - Up-regulation of fibroblast growth factor (FGF) 9 expression and FGF-WNT/beta catenin signaling in laser-induced wound healing. AB - Fibroblast growth factor (FGF) 9 is secreted by both mesothelial and epithelial cells, and plays important roles in organ development and wound healing via WNT/beta-catenin signaling. The aim of this study was to evaluate FGF9 expression and FGF-WNT/beta-catenin signaling during wound healing of the skin. We investigated FGF9 expression and FGF-WNT/beta-catenin signaling after laser ablation of mouse skin and adult human skin, as well as in cultured normal human epidermal keratinocytes (NHEKs) upon stimulation with recombinant human (rh) FGF9 and rh-transforming growth factor (TGF)-beta1. Our results showed that laser ablation of both mouse skin and human skin leads to marked overexpression of FGF9 and FGF9 mRNA. Control NHEKs constitutively expressed FGF9, WNT7b, WNT2, and beta catenin, but did not show Snail or FGF receptor (FGFR) 2 expression. We also found that FGFR2 was significantly induced in NHEKs by rhFGF9 stimulation, and observed that FGFR2 expression was slightly up-regulated on particular days during the wound healing process after ablative laser therapy. Both WNT7b and WNT2 showed up-regulated protein expression during the laser-induced wound healing process in mouse skin; moreover, we discerned that the stimulatory effect of rhFGF9 and rhTGF-beta1 activates WNT/beta-catenin signaling via WNT7b in cultured NHEKs. Our data indicated that rhFGF9 and/or rhTGF-beta1 up-regulate FGFR2, WNT7b, and beta-catenin, but not FGF9 and Snail; pretreatment with rh dickkopf-1 significantly inhibited the up-regulation of FGFR2, WNT7b, and beta catenin. Our results suggested that FGF9 and FGF-WNT/beta-catenin signaling may play important roles in ablative laser-induced wound healing processes. PMID- 25041896 TI - Ecotoxicity of benzo[a]pyrene assessed by soil microbial indicators. AB - The ecotoxicity of benzo[a]pyrene (BaP) to soil microorganisms was evaluated using the following microbial indicators: soil microbial biomass, respiration, nitrification, and Shannon index. Two soil types, udic ferrosols and aquic cambisols, were amended with 0 mg/kg, 1 mg/kg, 10 mg/kg, 100 mg/kg, 500 mg/kg, or 1000 mg/kg BaP; incubated at 25 degrees C; and tested on days 28, 60, and 180. The Shannon index was extremely insensitive to BaP. Microbial biomass and respiration could not be classified as sensitive indicators because of their relatively high 10% effect concentration (EC10) values. Nitrification was the most sensitive indicator in both soils and could be the preferred microbial indicator for testing the ecotoxicity of BaP. Higher toxicity of BaP was exhibited in udic ferrosols than in aquic cambisols, and the ecotoxicity of BaP decreased with incubation time. Extending the 28-d incubation time, which is suggested in the International Organization for Standardization and Organisation for Economic Co-operation and Development guidelines, to 60 d was recommended for future microbial toxicity tests of BaP. On day 28, the EC10 values for microbial biomass, respiration, and nitrification were 71 mg/kg, 43 mg/kg, and 3.4 mg/kg in aquic cambisols and 51 mg/kg, 22 mg/kg, and 1.3 mg/kg in udic ferrosols, respectively. On day 60, these values were 106 mg/kg, 59 mg/kg, and 19 mg/kg in aquic cambisols and 77 mg/kg, 40 mg/kg, and 6.9 mg/kg in udic ferrosols. These values could be used in combination to derive ecotoxicological soil screening levels of BaP. PMID- 25041897 TI - Development of simple equations for effective screening of spurious hemolysis in whole-blood specimens. AB - INTRODUCTION: We aimed to identify simple but reliable indices for effective screening of spurious hemolysis in whole-blood specimens. METHODS: Thirteen inpatient whole-blood samples were divided in two aliquots. The former was left untreated, whereas the latter was mechanically hemolyzed by forced aspiration with an insulin syringe. All aliquots were tested on Siemens Advia 2120 and Sysmex XE-2100. The hemolysis index (HI) was also assessed in centrifuged plasma. RESULTS: The mechanical hemolysis generated a 4-40% decrease in red blood cells (RBCs). A statistically significant decrease was observed for hematocrit (Ht) and mean corpuscular volume (MCV), whereas mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet count were increased. The values of hemoglobin (Hb) and white blood cells remained substantially unchanged. Two specific equations ([Ht/Hb] * ?MCV and [Ht/Hb] * 100) were developed. Both equations displayed an area under the curve of >=0.99 for identifying spurious hemolysis, much greater than that of both RBC ghosts and immature platelet fraction. A highly significant correlation was also observed between results of these equations and percentage reduction in RBCs or HI increase. CONCLUSION: Provided that these results will be confirmed in further studies, these equations may provide a reliable means for screening spurious hemolysis in whole-blood samples. PMID- 25041898 TI - Acute necrotizing pancreatitis complicated by severe hemorrhage from the celiac trunk into walled-off pancreatic necrosis. PMID- 25041899 TI - High-efficiency translational bypassing of non-coding nucleotides specified by mRNA structure and nascent peptide. AB - The gene product 60 (gp60) of bacteriophage T4 is synthesized as a single polypeptide chain from a discontinuous reading frame as a result of bypassing of a non-coding mRNA region of 50 nucleotides by the ribosome. To identify the minimum set of signals required for bypassing, we recapitulated efficient translational bypassing in an in vitro reconstituted translation system from Escherichia coli. We find that the signals, which promote efficient and accurate bypassing, are specified by the gene 60 mRNA sequence. Systematic analysis of the mRNA suggests unexpected contributions of sequences upstream and downstream of the non-coding gap region as well as of the nascent peptide. During bypassing, ribosomes glide forward on the mRNA track in a processive way. Gliding may have a role not only for gp60 synthesis, but also during regular mRNA translation for reading frame selection during initiation or tRNA translocation during elongation. PMID- 25041900 TI - Framework-flexibility driven selective sorption of p-xylene over other isomers by a dynamic metal-organic framework. AB - Chemical separation has great importance in industrial applications. Separation of xylene isomers still prevails to be one of the most important challenges in chemical industry, due to the large amount of commercial use of p-xylene in the production of beverage bottles, fibers and films. A novel Zn(II)-based dynamic coordination framework based on flexible ether-linkage, exhibiting selective adsorption of p-Xylene over its congener C8-alkyl aromatic isomers at ambient conditions is reported. Notably, no dynamic structure based MOF compound is known in the literature which shows clear preference of p-xylene over other isomers. This type of framework-breathing and guest-induced reversible solid-state structural transformations with unique adsorption selectivity can be exploited purposefully to develop smart functional host materials capable of industrially important chemical separations. PMID- 25041901 TI - Selective renal vasoconstriction, exaggerated natriuresis and excretion rates of exosomic proteins in essential hypertension. AB - AIM: In essential hypertension (EH), the regulation of renal sodium excretion is aberrant. We hypothesized that in mild EH, (i) abnormal dynamics of plasma renin concentration (PRC) and atrial natriuretic peptide (ANP) are responsible for the exaggerated natriuresis, and (ii) exosomic protein patterns reflect the renal tubular abnormality involved in the dysregulation of sodium excretion. METHODS: After 2-week drug washout and 4-day diet, systemic and renal hemodynamics, cardio renal hormones, glomerular filtration and renal excretion were studied in male patients during saline loading (SL). Excretion rates of exosome-related urinary proteins including apical membrane transporters were determined by proteomics based methods. RESULTS: In patients, baseline renal vascular conductance was reduced (-44%, P < 0.001), but non-renal vascular conductances were normal while PRC was reduced and ANP elevated (both P < 0.01). SL induced exaggerated natriuresis and reduced PRC (P < 0.01), at normal suppression rate. SL increased arterial pressure in patients (+11 mmHg, P < 0.001), but not in controls; however, during time control, patients showed identical increases (+10 mmHg, P < 0.005) apparently dissociating arterial pressure from natriuresis. At baseline, excretion rates of 438 proteins ranged from 0.07 to 49.8 pmol (mmol creatinine)( 1); 12 proteins were found in all subjects, and 21 proteins were found in two or more patients, but not in controls. In patients, the excretion rate of retinoic acid-induced gene 2 protein was reduced, and excretion rates of other proteins showed increased variances compatible with pathophysiological and clinical applicability. CONCLUSION: Essential hypertension patients exhibit selective renal vasoconstriction and individually varying excretion rates of several exosome-related proteins. Hormonal changes, rather than arterial pressure, seem to cause exaggeration of natriuresis. PMID- 25041902 TI - Ceramide center stage in progressive myoclonus epilepsies. PMID- 25041904 TI - LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. AB - To improve standardization and consensus regarding performance, interpreting, and reporting computed tomography (CT) and magnetic resonance imaging (MRI) examinations of the liver in patients at risk for hepatocellular carcinoma (HCC), LI-RADS (Liver Imaging Reporting and Data System) was launched in March 2011 and adopted by many clinical practices throughout the world. LI-RADS categorizes nodules recognized at CT or MRI, in patients at high risk of HCC, as definitively benign, probably benign, intermediate probability of being HCC, probably HCC, and definitively HCC (corresponding to LI-RADS categories 1-5). The LI-RADS Management Working Group, consisting of internationally recognized medical and surgical experts on HCC management, as well as radiologists involved in the development of LI-RADS, was convened to evaluate management implications related to radiological categorization of the estimated probability that a lesion will be ultimately diagnosed as HCC. In this commentary, we briefly review LI-RADS and the initial consensus of the LI-RADS Management Working Group reached during its deliberations in 2013. We then focus on initial discordance of LI-RADS with American Association for the Study of Liver Diseases and Organ Procurement Transplant Network guidelines, the basis for these differences, and how they are being addressed going forward to optimize reporting of CT and MRI findings in patients at risk for HCC and to increase consensus throughout the international community of physicians involved in the diagnosis and treatment of HCC. PMID- 25041903 TI - TARV: tree-based analysis of rare variants identifying risk modifying variants in CTNNA2 and CNTNAP2 for alcohol addiction. AB - Since the development of next generation sequencing (NGS) technology, researchers have been extending their efforts on genome-wide association studies (GWAS) from common variants to rare variants to find the missing inheritance. Although various statistical methods have been proposed to analyze rare variants data, they generally face difficulties for complex disease models involving multiple genes. In this paper, we propose a tree-based analysis of rare variants (TARV) that adopts a nonparametric disease model and is capable of exploring gene-gene interactions. We found that TARV outperforms the sequence kernel association test (SKAT) in most of our simulation scenarios, and by notable margins in some cases. By applying TARV to the study of addiction: genetics and environment (SAGE) data, we successfully detected gene CTNNA2 and its 43 specific variants that increase the risk of alcoholism in women, with an odds ratio (OR) of 1.94. This gene has not been detected in the SAGE data. Post hoc literature search also supports the role of CTNNA2 as a likely risk gene for alcohol addiction. In addition, we also detected a plausible protective gene CNTNAP2, whose 97 rare variants can reduce the risk of alcoholism in women, with an OR of 0.55. These findings suggest that TARV can be effective in dissecting genetic variants for complex diseases using rare variants data. PMID- 25041905 TI - Bone mineral density and donor age are not predictive of femoral ring allograft bone mechanical strength. AB - While metal or plastic interbody spinal fusion devices are manufactured to appropriate mechanical standards, mechanical properties of commercially prepared structural allograft bone remain relatively unassessed. Robust models predicting compressive load to failure of structural allograft bone based on easily measured variables would be useful. Three hundred twenty seven femoral rings from 34 cadaver femora were tested to failure in axial compression. Predictive variables included age, gender, bone mineral density (BMD), position along femoral shaft, maximum/minimum wall thickness, outer/inner diameter, and area. We used support vector regression and 10-fold cross-validation to develop robust nonlinear predictive models for load to failure. Model performance was measured by the root mean-squared-deviation (RMSD) and correlation coefficients (r). A polynomial model using all variables had RMSD = 7.92, r = 0.84, indicating excellent performance. A model using all variables except BMD was essentially unchanged (RMSD = 8.12, r = 0.83). Eliminating both age and BMD produced a model with RMSD = 8.41, r = 0.82, again essentially unchanged. Compressive strength of structural allograft bone can be estimated using easily measured geometric parameters, without including BMD or age. As DEXA is costly and cumbersome, and setting upper age-limits for potential donors reduces the supply, our results may prove helpful to increase the quality and availability of structural allograft. PMID- 25041906 TI - No association between multiple sclerosis and periodontitis after adjusting for smoking habits. AB - BACKGROUND AND PURPOSE: Periodontitis has been reported to be associated with several systemic disorders, and recently a possible relationship with multiple sclerosis (MS) was suggested. The aim of the present study was to investigate the association between periodontitis and MS in a Norwegian cohort. METHODS: A case control study in 756 MS patients and 1090 controls was conducted, and logistic regression analysis, adjusting for age, gender, place of residence, mononucleosis and smoking, was performed to investigate the association between MS and periodontitis. RESULTS: In the unadjusted analysis a higher prevalence of periodontitis was seen in MS patients, but this difference was not statistically significant after adjusting for the covariates. CONCLUSIONS: The previously suggested association between MS and periodontitis is not supported in this study. Our results underline the importance of adjusting for relevant covariates in epidemiological research. PMID- 25041907 TI - Calculations in apheresis. AB - It's important to work smoothly with your apheresis equipment when you are an apheresis nurse. Attention should be paid to your donor/patient and the product you're collecting. It gives additional value to your work when you are able to calculate the efficiency of your procedures. You must be capable to obtain an optimal product without putting your donor/patient at risk. Not only the total blood volume (TBV) of the donor/patient plays an important role, but also specific blood values influence the apheresis procedure. Therefore, not all donors/patients should be addressed in the same way. Calculation of TBV, extracorporeal volume, and total plasma volume is needed. Many issues determine your procedure time. By knowing the collection efficiency (CE) of your apheresis machine, you can calculate the number of blood volumes to be processed to obtain specific results. You can calculate whether you need one procedure to obtain specific results or more. It's not always needed to process 3* the TBV. In this way, it can be avoided that the donor/patient is needless long connected to the apheresis device. By calculating the CE of each device, you can also compare the various devices for quality control reasons, but also nurses/operators. PMID- 25041908 TI - Human cytomegalovirus and primary intracranial tumours: frequency of tumour infection and lack of correlation with systemic immune anti-viral responses. AB - AIMS: Human cytomegalovirus (HCMV) is a ubiquitous beta human herpesvirus able to influence infected cell survival and proliferation and to modulate the host immune response. As there is accumulating evidence that HCMV is detected in primary intracranial astrocytic tumours, in this study we looked for the presence of HCMV in intracranial tumours and tried to correlate this eventual presence with the anti-HCMV systemic immunoreactivity and with the detection of HCMV in peripheral blood. METHODS: In this study, we analysed 43 glioblastomas (GBM), 14 oligodendrogliomas (OL) and 20 meningiomas (MG) by immunofluorescence (IF) targeting HCMV immediate early antigen (IE1) and by nested PCR (nPCR) amplifying HCMV glycoprotein B (gB). RESULTS: Detection of IE1 by IF showed the presence of HCMV in 70% of GBM, 57% of OL and 85% of MG, in contrast to gB nPCR, which detected HCMV in only 50% of GBM, 38% of OL and 46% of MG. Unexpectedly, HCMV DNA and antigens were detected within GBM, OL and MG of patients that exhibit negative viral serology. More surprisingly, PCR on the peripheral blood did not detect HCMV in patients with a HCMV-positive tumour. CONCLUSIONS: Our results are in agreement with previous observations demonstrating HCMV in glial tumours and highlight the presence of HCMV in meningiomas. We also showed that anti-HCMV specific systemic immunoreactivity and detection of HCMV in peripheral blood are not predictive of HCMV presence in primary intracranial tumours. PMID- 25041909 TI - A prevalence survey of intravascular catheter use in a general hospital. AB - PURPOSE: Survey of intravascular catheter management is an essential step in the control and prevention of catheter-related infection. In recent years, most surveillance studies only included catheters from intensive care units (ICUs). Data regarding the level of care and adherence to international guidelines in a whole general institution are scarce. Our objective was to evaluate the care situation of intravascular catheters in our adult units of a General Hospital. METHODS: We surveyed adults hospitalized in non-psychiatric/maternity wards. In a week, a nurse visited all the adult hospitalized patients. Data were registered in a protocol that included variables, such as no. of catheters, location of catheter, type of catheter, date of placement and the need of an indication of each catheter in the visit day. RESULTS: We included in the study a total of 753 adult patients. Of them, 653 (86.7%) had one or more inserted catheters at the moment of the study visit (total: 797 catheters). Of all the catheters, 144 (18.0%) were central venous catheters and 653 (81.9%) were peripheral lines. The hospitalization units where the patients were admitted were ICU, 52 (6.9%); and non-ICU, 601 (92.0%). There were 183 (22.9%) catheters with no need to remain in place in the day of the study. Overall, we found 464 (71.0%) patients with one or more opportunities for catheter care improvement. CONCLUSIONS: A rapid survey of the care situation of intravascular catheters is feasible and easy to do with our methodology. The data show great opportunity for improvement, mainly in the non ICU areas. PMID- 25041910 TI - A case of critical hand ischemia treated by balloon angioplasty in a dialysis patient with an occluded ulnar artery. PMID- 25041911 TI - Factors affecting the frequency of vascular access via intraosseous cannulation performed by paramedics in Johannesburg. AB - PURPOSE: In an emergency, the administration of fluids and medications remains a vital component of patient care. Although this is usually achieved via an intravenous line, intraosseous (IO) cannulation is accepted as a useful alternative for the administration of fluids and medications in situations where intravenous cannulation is difficult or impossible. Despite this, IO cannulation appeared to be infrequently performed by paramedics in Johannesburg (JHB). This study investigated factors that may be affecting the frequency with which IO cannulation is performed by paramedics in JHB. METHODS: A qualitative design was utilized making use of one-on-one interviews with 12 purposefully selected operational paramedics from emergency medical services in JHB. The interviews were recorded and transcribed. Introspective analysis and interpretive phenomenological analysis were conducted to identify emerging themes and patterns. RESULTS: IO cannulation is infrequently performed by paramedics in JHB. Factors identified that reduce the likelihood of the procedure being performed included "Negative Perceptions Relating to the Procedure"; "Practitioner Success at Intravenous Cannulation"; "Close Proximity of Hospitals"; "Patient Profile, Presentation and Case Load"; "Lack of Appropriate Equipment"; and "Lack of Appropriate Training." CONCLUSION: Procedures are more inclined to move from the in-hospital to the prehospital environment if they are seen to be commonly performed, safe and effective. It would appear that paramedics infrequently witness IO cannulation being performed in emergency departments. This together with a lack of appropriate equipment, training and retraining including the perceived invasiveness and pain associated with the procedure appears to be dissuading paramedics from regularly performing IO cannulation. PMID- 25041912 TI - A dedicated protocol and environment for central venous catheter removal in pediatric patients affected by onco-hematological diseases. AB - PURPOSE: The removal of long-term central venous catheters (CVCs) is not performed according to evidence-based guidelines, thus conveying the message that it is a procedure of secondary importance. Our study aims at comparing the experience at Bambino Gesu Pediatric Hospital before and after the implementation of a dedicated protocol and the identification of a specific area to perform such a procedure under the so-called nonoperating room anesthesia (NORA). METHODS: Starting on January 1, 2010, an appropriate protocol regarding long-term CVC removal was applied. Then, data from all patients who underwent CVC removal under NORA regimen were compared with patients who have undergone the same procedure before the beginning of such protocol in terms of complication rate, duration of procedure, and costs. RESULTS: Between January 2010 and December 2012, 266 patients were evaluated for long-term CVC removal under a NORA regimen. Of these, 194 underwent the procedure. In the period from January 2007 to December 2009, 60 out of 82 patients scheduled for elective removal of long-term CVC in the operating theatre were eligible for this study. Median procedure time was 7 min for removal in NORA and 10 min for the operating theatre (p=0.016); no complications occurred. CONCLUSION: Long-term CVC removal is an often-neglected procedure, carrying a small, but definite rate of complications. Our study shows that CVC removal performed in NORA regimen is safe and feasible, also allowing multiple procedures in the same session with prompt management of possible complications and reduction of the anxiety and pain associated with the procedure. PMID- 25041913 TI - Bilateral central vein stenosis: options for dialysis access and renal replacement therapy when all upper extremity access possibilities have been lost. AB - PURPOSE: Patients with bilateral central vein stenosis present a unique challenge: treatment options are limited, largely unproven and associated with reputedly poor outcomes. Our aim was to compare patency rates of different access and renal replacement treatment (RRT) modalities in patients with bilateral central vein stenosis/occlusion. MATERIAL AND METHODS: Data on all patients presenting to a tertiary referral vascular access centre with end-stage vascular access (defined by bilateral central vein stenosis/occlusion with loss of upper limb access) over a 5-year period were included. 3, 6 and 12-month patencies of translumbar catheters (TLs), tunnelled femoral catheters (Fem), native long saphenous vein loops (SV), prosthetic mid-thigh loop grafts (ThGr), peritoneal dialysis (PD), and expedited donation after cardiac death (DCD) cadaveric renal transplants (Tx) via local allocation policies were compared using log-rank test. Kaplan-Meier survival analysis was used to estimate long-term access survival. RESULTS: One hundred forty-six vascular access modalities were attempted in 62 patients (62 Fem, 25 TL, 15 SV, 25 ThGr, 8 PD, 11 Tx). Median follow-up was 876+/ 57 days. Three, 6 and 12-month primary-assisted patencies for each modality were as follows: Fem: 75.4%, 60% and 28%; TL: 88%, 65% and 50%; SV: 87.5%, 60% and 44.6%; ThGr: 64%, 38% and 23.5%; PD: 62.5%, 62.5% and 50%; Tx: 72.7%, 72.7% and 72.7%. SV had better secondary patency at 900 days (76.9%) than ThGr (49.2%) or Fem (35.8%) (p<0.01). No patients died as a result of loss of access. CONCLUSION: Patients with bilateral central vein stenosis often require more than one vascular access modality to achieve a "personal access solution." Native long saphenous vein loops provided the best long-term patency. Expedited renal transplantation with priority local allocation of DCD organs to patients with precarious vascular access provides a potential solution to this difficult problem. PMID- 25041914 TI - Misplaced central venous catheter in the vertebral artery: endovascular treatment of foreseen hemorrhage during catheter withdrawal. AB - PURPOSE: We report on the endovascular management of hemorrhage with stent-graft due to a misplaced central venous catheter in the vertebral artery (VA) during percutaneous internal jugular vein catheterization in a child. METHODS: A 16-year old female was presented with the diagnosis of familial Mediterranean fever related chronic renal insufficiency. An attempt was made to place a central venous catheter via the right internal jugular vein without image guidance and the patient experienced dyspnea and pain at the catheter insertion site. Computerized tomography (CT) showed hemorrhage in the cervical region and upper mediastinum, also reformatted images showed that the catheter was passing through the proximal part of the VA and terminating in the right mediastinum. The catheter was removed during manual compression under angio-flouroscopic monitoring and ongoing extravasation was observed. A stent-graft was placed to the bleeding site of the VA. RESULTS: Angiography immediately after the stent graft placement revealed complete disappearance of extravasation and patency of vertebral and subclavian arteries. CONCLUSION: Central venous catheterization (CVC) is not a risk-free procedure and arterial injuries are in a wide spectrum from a simple puncture to rupture of the artery. Inadvertent VA cannulation is a rare and serious complication necessitating prompt diagnosis and early treatment. If an arterial injury with a large-caliber catheter occurs, endovascular treatment with stent-graft seems to be a safe and effective option in terms of achieving hemostasis and preserving arterial patency. Recent findings suggest that endovascular management of inadvertent cervical arterial injury secondary to CVC seems to be the safest strategy. PMID- 25041915 TI - Do we need navigation systems in the vascular access practice? A case of peripherally inserted central catheter malposition. PMID- 25041916 TI - Percutaneous transluminal angioplasty for central venous disease in dialysis patients: influence on cardiac function. AB - PURPOSE: Increased vascular access flow after percutaneous transluminal angioplasty (PTA) for central venous stenosis and occlusion (central venous disease, CVD) can affect cardiac function in hemodialysis (HD) patients. We evaluated the cardiac function, etiology, and treatment in HD patients with CVD. METHODS: HD patients with CVD treated by PTA between June 2006 and February 2013 were studied. RESULTS: Of the 26 patients, 22 had left arteriovenous fistulas (AVFs), 1 left arteriovenous graft (AVG), 2 right AVFs, and 1 right AVG. CVD sites were the left brachiocephalic vein (LBCV; n=13), left subclavian vein (LSCV; n=7), both LBCV and LSCV (n=3), right BCV (n=2), and right SCV (n=1). Computed tomography findings indicated a high extrinsic compression rate for the LBCV (91%) and LSCV (50%). The success rate of PTA was 96%. The primary patency rates at 3, 6, 9, and 12 months were 81%, 73%, 65%, and 57%, respectively. The post-PTA brachial artery flow volume was significantly increased compared with the pre-PTA volume (1306 vs. 957 ml/min; p=0.005). The post-PTA left ventricular ejection fraction and expiration inferior vena cava diameter were the same as the pre-PTA values (57% versus 60%, p=0.2 and 17 versus 17 mm, p=0.9, respectively). CONCLUSIONS: Our findings suggest that increased vascular access flow after PTA for CVD has no relation to cardiac function. PMID- 25041917 TI - The eternal tale of dialysis access vessels and restenosis: are drug-eluting balloons the solution? AB - In dialysis access fistulas and grafts, percutaneous transluminal angioplasty (PTA) is frequently followed by restenosis development, which results in repeated periodical re-interventions. The technique of drug-eluting balloon (DEB) angioplasty has shown promising results in the treatment of femoropopliteal arteriosclerotic lesions. In contrast to arteriosclerotic arteries, dialysis access vessels host unfavorable hemodynamics due to the direct conduction of high pressure fluid into a low-pressure system. Hence, the beneficial effect of DEB angioplasty may be limited in this system. However, a first prospective randomized trial on 40 patients with arteriovenous fistula or graft stenoses exhibited a significantly higher 6-month primary patency of the treated lesions after DEB angioplasty than after uncoated balloon angioplasty. Despite such a positive reference, general recommendations regarding the value of DEBs in dialysis access vessels cannot be considered as serious unless large randomized controlled trials have been performed. PMID- 25041918 TI - Intra-arterial treatment for subcutaneous or intramuscular bleeding in extremities with arteriovenous fistula. PMID- 25041919 TI - Iatrogenesis imperfecta: stroke caused by accidental carotid artery catheterization. AB - PURPOSE: Central venous catheterization is a commonly used procedure to gain access to the central circulation. Although ultrasound guidance decreases the complication rates, arterial puncture may still occur. Failure to recognize this early may lead to devastating complications such as thrombosis and embolic stroke. We discuss the factors associated with increased risk of arterial puncture, techniques to detect them early and the management of established carotid artery cannulation. METHODS: We report a case of internal jugular catheterization complicated by carotid artery puncture leading to embolic stroke. RESULT: Arterial catheterization in the patient went unrecognized for 2 days. During this period, the patient developed catheter-related thrombus in the carotid artery, ultimately resulting in embolic stroke. Emergent open surgical repair of the vessels with thrombectomy was performed. CONCLUSION: Even with ultrasound-guided central venous catheterization, it is essential to remain vigilant for the early detection of vascular complications. Clinical suspicion combined with diagnostic modalities such as chest radiograph, transduction and manometry can increase the detection rates. PMID- 25041920 TI - Retrograde femoral vein catheter insertion. A new approach for challenging hemodialysis vascular access. AB - INTRODUCTION: Venous catheters provide access for hemodialysis (HD) when patients do not have functioning access device. Obstruction of jugular, femoral or even external iliac vessels further depletes options. Subclavian approach is prohibited. Catheterization of inferior vena cava requires specialized equipment and skills. PURPOSE: The purpose is to assess a new lifesaving HD vascular access approach for patients with nonfunctioning access device in the ordinary sites. This entails insertion of a retrograde temporary HD catheter in the superficial femoral vein, directing the catheter distally, toward the foot. MATERIALS AND METHODS: We included six end-stage renal disease (ESRD) patients retrospectively who are on regular renal replacement therapy and need urgent HD with nonfunctioning access device in the ordinary sites. RESULTS: Successful insertion of six retrograde femoral vein catheters in the superficial femoral vein. The mean catheter days were 2.5+/-0.5 days with one patient having 26 catheter days. The mean blood pump speed was 230.0+/-44.7 mL/min. Urea reduction ratio and Kt/V at 3 hours HD session were 47% and 1.5, respectively, which increased with increasing session duration. The ultrafiltration volume was 2-3 L/session which increased up to 6 L/session in case of using slow low-efficiency dialysis. No major complications were observed during insertion or the postinsertion period except thigh pain in one patient and exit site infection in the case of long duration. CONCLUSIONS: This is a newly applied lifesaving HD vascular access approach for selected ESRD patients with no available HD vascular access at the ordinary sites with accepted HD adequacy. It needs more evaluation and more studies. PMID- 25041921 TI - Fractures of totally implantable central venous ports: more than fortuity. A three-year single center experience. AB - PURPOSE: Totally implantable venous access devices (Ports) represent the mainstay for infusion therapy in patients undergoing chemotherapy, total parenteral nutrition and/or long-term antibiotic treatment. Amongst mechanical complications, lesions of the catheter wall represent a rare but potentially severe condition. We report our experience with the accidental detection of catheter ruptures in a series of ports removed for complication or for end of use. METHODS: All ports removed from January 2011 to June 2013 were considered. All removed ports had been inserted according to a standardized protocol including ultrasound-guided percutaneous venipuncture (out-of-plane or in-plane approaches) and electrocardiogram-guided positioning of the tip. Once removed, each catheter was checked by inspection and saline instillation in order to evaluate the integrity of the device itself and rule out possible ruptures. RESULTS: In over 338 removed ports, 12 Groshong catheters out of 65 (18.5%) had evidence of partial rupture of the catheter wall. Amongst considered variables, "out-of-plane" approach and type of port (silicon, closed tip with Groshong valve) were the only ones significantly associated with catheter ruptures (p=0.0003 and 0.0008, respectively). We could detect no evidence of rupture in any silicon open-ended catheter (Celsite ports) or in any catheter inserted by "in-plane" approach to the vein. CONCLUSIONS: The actual advantage of using port connected with Groshong silicon catheters should be questioned, since apparently they are more fragile than standard catheters. Furthermore, ultrasound-guided "out-of-plane" puncture of the internal jugular vein should be discouraged. PMID- 25041922 TI - The use of 8-cm 22G Seldinger catheters for intravenous access in children with cystic fibrosis. AB - PURPOSE: Long intravenous catheters are an effective and economical choice of vascular access for intravenous antibiotic therapy in children with cystic fibrosis (CF). This prospective audit assesses the use of Vygon Leaderflex 22G * 8 cm catheters in an Australian tertiary centre. Key outcomes included catheter lifespan, ability to complete antibiotic therapy and complication rates. METHODS: All paediatric patients admitted with infective exacerbations of CF lung disease for 18 months between 2012 and 2013 were prospectively included. Data were analysed using t-tests and Fisher exact test. RESULTS: A total of 40 successful catheter insertions for 20 patients during 32 admissions were identified. The mean duration of the catheters was 10.08 days (median 9.5, SD=5.0). Of the 32 admissions, antibiotic therapy was completed with long catheters in 78% of cases (n=25) and with a single catheter in 48% (n=19). Rates of local complications were high, but there were no serious adverse outcomes. CONCLUSION: Although limited by a small sample size, the results from this study are promising and suggest that 8 cm long catheters are a safe, effective and economical alternative to peripherally inserted central catheters (PICCs) in treating pulmonary exacerbations in children with CF. PMID- 25041923 TI - bPeaks: a bioinformatics tool to detect transcription factor binding sites from ChIPseq data in yeasts and other organisms with small genomes. AB - Peak calling is a critical step in ChIPseq data analysis. Choosing the correct algorithm as well as optimized parameters for a specific biological system is an essential task. In this article, we present an original peak-calling method (bPeaks) specifically designed to detect transcription factor (TF) binding sites in small eukaryotic genomes, such as in yeasts. As TF interactions with DNA are strong and generate high binding signals, bPeaks uses simple parameters to compare the sequences (reads) obtained from the immunoprecipitation (IP) with those from the control DNA (input). Because yeasts have small genomes (<20 Mb), our program has the advantage of using ChIPseq information at the single nucleotide level and can explore, in a reasonable computational time, results obtained with different sets of parameter values. Graphical outputs and text files are provided to rapidly assess the relevance of the detected peaks. Taking advantage of the simple promoter structure in yeasts, additional functions were implemented in bPeaks to automatically assign the peaks to promoter regions and retrieve peak coordinates on the DNA sequence for further predictions of regulatory motifs, enriched in the list of peaks. Applications of the bPeaks program to three different ChIPseq datasets from Saccharomyces cerevisiae, Candida albicans and Candida glabrata are presented. Each time, bPeaks allowed us to correctly predict the DNA binding sequence of the studied TF and provided relevant lists of peaks. The bioinformatics tool bPeaks is freely distributed to academic users. Supplementary data, together with detailed tutorials, are available online: http://bpeaks.gene-networks.net. PMID- 25041924 TI - High-frequency oscillations in Parkinson's disease: spatial distribution and clinical relevance. AB - The pathophysiology of Parkinson's disease (PD) has been related to excessive beta band oscillations in the basal ganglia. Recent recordings from the subthalamic nucleus of PD patients showed that beta oscillations show strong cross-frequency coupling with high-frequency oscillations (>200 Hz). However, little is known about the characteristics and functional properties of these oscillations. We studied the spatial distribution of high-frequency oscillations and their relation to PD motor symptoms. We included 10 PD patients in medication OFF who underwent implantation of deep brain stimulation (DBS) electrodes. Intraoperative five-channel microelectrode recordings were performed at 9 to 10 recording sites within the subthalamic nucleus and its immediate surroundings. We found a focal spatial distribution of high-frequency oscillations with highest power 2 mm below the dorsolateral border of the subthalamic nucleus. Within the subthalamic nucleus, power peaked slightly anterior to the DBS target site. In addition, contralateral akinesia/rigidity scores were negatively correlated with high-frequency oscillation power. Our results demonstrate a focal origin of high frequency oscillations within the subthalamic nucleus and provide further evidence for their functional association with motor state. PMID- 25041925 TI - Grader learning effect and reproducibility of Doppler Spectral-Domain Optical Coherence Tomography derived retinal blood flow measurements. AB - PURPOSE: To investigate grader learning effect and to quantify intergrader reproducibility of Doppler Spectral-Domain Optical Coherence Tomography (SD-OCT) derived retinal blood flow measurements. METHODS: Fifteen healthy young subjects (mean age 28.44; SD 3 years) underwent Doppler SD-OCT scans of one eye using the circumpapillary double circular scan protocol of the Optovue RTVue by one of two experienced operators. One trained (i.e. having undergone certification) and one novice (i.e. preliminary training comprising five standard practice data sets) individual then graded a standardized set of scans, consisting of 15 data sets (session 1) using custom Doppler Optical Coherence Tomography of Retinal Circulation (DOCTORC) software. One week later (session 2), the novice grader underwent further training by grading an additional 15 practice data sets and then both graders subsequently regraded the original 15 data sets. RESULTS: Measurements achieved by a novice grader during session 1 showed a trend to be higher in terms of total retinal venous blood flow (TRBF) and also to be significantly (p = 0.03) higher for venous area, compared with a trained grader. Session 2 results were not significantly different for either grader. The mean TRBF for session 2 for the trained and novice grader was 45.29 +/- 9.28 MUl/min and 44.39 +/- 7.36 MUl/min, respectively. The coefficient of repeatability (COR) of session 2 TRBF values between the trained and novice grader was 8.09 MUl/min. CONCLUSIONS: There is a grader learning effect which impacts the venous area measurements. Reproducible and repeatable retinal blood flow measurements were achieved among trained graders using DOCTORC software. PMID- 25041926 TI - 3D hydrodynamic focusing microfluidics for emerging sensing technologies. AB - While the physics behind laminar flows has been studied for 200 years, understanding of how to use parallel flows to augment the capabilities of microfluidic systems has been a subject of study primarily over the last decade. The use of one flow to focus another within a microfluidic channel has graduated from a two-dimensional to a three-dimensional process and the design principles are only now becoming established. This review explores the underlying principles for hydrodynamic focusing in three dimensions (3D) using miscible fluids and the application of these principles for creation of biosensors, separation of cells and particles for sample manipulation, and fabrication of materials that could be used for biosensors. Where sufficient information is available, the practicality of devices implementing fluid flows directed in 3D is evaluated and the advantages and limitations of 3D hydrodynamic focusing for the particular application are highlighted. PMID- 25041927 TI - Potato leaf extract and its component, alpha-solanine, exert similar impacts on development and oxidative stress in Galleria mellonella L. AB - Plants synthesize a broad range of secondary metabolites that act as natural defenses against plant pathogens and herbivores. Among these, potato plants produce glycoalkaloids (GAs). In this study, we analyzed the effects of the dried extract of fresh potato leaves (EPL) on the biological parameters of the lepidopteran, Galleria mellonella (L.) and compared its activity to one of the main EPL components, the GA alpha-solanine. Wax moth larvae were reared from first instar on a diet supplemented with three concentrations of EPL or alpha solanine. Both EPL and alpha-solanine affected survivorship, fecundity, and fertility of G. mellonella to approximately the same extent. We evaluated the effect of EPL and alpha-solanine on oxidative stress in midgut and fat body by measuring malondialdehyde (MDA) and protein carbonyl (PCO) contents, both biomarkers of oxidative damage. We evaluated glutathione S-transferase (GST) activity, a detoxifying enzyme acting in prevention of oxidative damage. EPL and alpha-solanine altered MDA and PCO concentrations and GST activity in fat body and midgut. We infer that the influence of EPL on G. mellonella is not enhanced by synergistic effects of the totality of potato leaf components compared to alpha-solanine alone. PMID- 25041928 TI - Teaching central line placement: no clear window. PMID- 25041929 TI - Micronucleus formation in human keratinocytes is dependent on radiation quality and tissue architecture. AB - The cytokinesis-block micronucleus (MN) assay was used to assess the genotoxicity of low doses of different types of space radiation. Normal human primary keratinocytes and immortalized keratinocytes grown in 2D monolayers each were exposed to graded doses of 0.3 or 1.0 GeV/n silicon ions or similar energies of iron ions. The frequencies of induced MN were determined and compared to gamma ray data. RBE(max) values ranged from 1.6 to 3.9 for primary keratinocytes and from 2.4 to 6.3 for immortalized keratinocytes. At low radiation doses <= 0.4 Gy, 0.3 GeV/n iron ions were the most effective at inducing MN in normal keratinocytes. An "over-kill effect" was observed for 0.3 GeV/n iron ions at higher doses, wherein 1.0 GeV/n iron ions were most efficient in inducing MN. In immortalized keratinocytes, 0.3 GeV/n iron ions produced MN with greater frequency than 1.0 GeV/n iron ions, except at the highest dose tested. MN formation was higher in immortalized keratinocytes than in normal keratinocytes for all doses and radiation qualities investigated. MN induction was also assessed in human keratinocytes cultured in 3D to simulate the complex architecture of human skin. RBE values for MN formation in 3D were reduced for normal keratinocytes exposed to iron ions, but were elevated for immortalized keratinocytes. Overall, MN induction was significantly lower in keratinocytes cultured in 3D than in 2D. Together, the results suggest that tissue architecture and immortalization status modulate the genotoxic response to space radiation, perhaps via alterations in DNA repair fidelity. PMID- 25041930 TI - Sexual dysfunction at the onset of type 2 diabetes: the interplay of depression, hormonal and cardiovascular factors. AB - INTRODUCTION: Several data have emphasized the importance of early diagnosis of erectile dysfunction (ED) and meticulous cardiovascular investigation in the type 2 diabetic mellitus (T2DM) patients. AIM: To estimate the prevalence of ED and its associated determinants in a sample of male patients with new or recently diagnosed T2DM. METHODS: The SUBITO-DE study is an observational, multicenter, prospective study involving 27 Italian diabetes centers. Male patients recently diagnosed with T2DM were consecutively interviewed by their attending physician at the diabetes care centers and asked whether they had experienced a change in their sexual function or found it unsatisfactory. Those responding positively were then invited to participate in the study. MAIN OUTCOME MEASURE: Several hormonal and biochemical parameters were studied. RESULTS: A nonselected series of 1,503 patients was interviewed, 499 of which (mean age, 58.8 +/- 8.8 years) entered the study, yielding a final enrolment rate of 33.3%. ED was classified as mild in 19.4%, mild-to-moderate in 15.4%, moderate in 10.4%, and severe in 21.6% of patients, respectively. In addition, premature ejaculation, delayed ejaculation, and hypoactive sexual desire (HSD) were comorbid in 28.3%, 32.9%, and 58.4%, respectively. Finally, hypogonadism, showed an estimated prevalence of almost 20%. Both organic (at least one chronic DM-associated complication) and psychological factors (severe depressive symptoms) increased the risk of ED. Severe depressive symptoms were also associated with ejaculatory problems, HSD, and hypogonadism. CONCLUSIONS: A high prevalence of sexual dysfunction in men with recently diagnosed T2DM was detected. Early diagnosis of ED could help prevent emotional and physical discomfort in men and aid in identifying reversible cardiovascular risk factors. Screening of sexual dysfunction should become a part of routine care in the management of T2DM patients. PMID- 25041931 TI - The correlation between the vestibulo-ocular reflex and multi-focal ocular correction: implications for vestibular compensation. AB - PURPOSE: An accurate vestibulo-ocular reflex is important for gaze stability, and is adaptable through modification, based on stable and repeated vestibular and visual feedback. The optical power of eye glasses changes the ocular rotation needed to view an object due to the prismatic effect. Depending on the diopter of a lens, eyes have to rotate through fewer or more degrees to correct for refractive change. We aim to determine how multifocal lenses, such as progressives, affect needed ocular rotation and ocular gain based on location of the lens in which an object is viewed. Differing ocular gains within the same field of vision will create non-stable visual feedback possibly delaying vestibular recovery. METHODS AND MATERIALS: Needed ocular rotation, and ocular gain to view an object 30 degrees lateral to midline were calculated across different points in the vertical axis of a representative progressive lens. RESULTS: In a progressive lens with superior correction of +1 D and inferior correction of +5.5 D, needed ocular rotation to view an object 30 degrees lateral to midline would differ by 4.015 degrees , with difference in ocular gain of 0.1336, indicating a 13.027% change in ocular gain, based on superior verse inferior viewing. CONCLUSIONS: Progressive lenses have variable areas of VOR gain. This lack of consistent vestibulo-visual feedback may lead to prolonged compensation time in patients with vestibular injury. PMID- 25041932 TI - Is MESNA an effective drug preventing recurrence of cholesteatoma after surgical treatment? PMID- 25041933 TI - Cranial fasciitis: a rare pediatric non-neoplastic lesion with 14-year follow up. AB - Cranial fasciitis is a fibroblastic lesion found in the cranium of children three weeks to six years of age. It most commonly manifests as a solitary, rapid growing mass on the scalp with frequent involvement of underlying bone and occasional intracranial expansion. Patients with cranial fasciitis may present with a wide range of associated symptoms. Otologic symptoms such as otalgia, otorrhea, hearing loss and middle ear effusion are not frequently encountered. We present a case of cranial fasciitis with intracranial involvement and associated otologic symptoms in a four year old boy with subsequent follow up 14 years later. PMID- 25041934 TI - Investigation of continuous changes in the electric-field-induced electronic state in Bi(1-x)Ca(x)FeO(3-delta). AB - Amongst the most interesting phenomena in correlated oxide systems are the doping driven competitions between energetically similar ground states found in, e.g., high-Tc superconductors and colossal magnetoresistance manganites. It has recently been reported that doped multiferroics also exhibit this generic concept of phase competition. Here, we employ photoelectron emission microscopy (PEEM) to demonstrate evidence of systematic changes in the electronic structure of Bi(1 x)Ca(x)FeO(3-delta) treated by electrically controlled hole carrier doping, the outcome of which clearly correlates with the local modulation of electronic conductivity observed in the same material. PMID- 25041935 TI - Ventilation during extracorporeal membrane oxygenation for adult respiratory distress syndrome. PMID- 25041937 TI - Posture alters human resting-state. AB - Neuroimaging is ubiquitous; however, neuroimagers seldom investigate the putative impact of posture on brain activity. Whereas participants in most psychological experiments sit upright, many prominent neuroimaging techniques (e.g., functional magnetic resonance imaging (fMRI)) require participants to lie supine. Such postural discrepancies may hold important implications for brain function in general and for fMRI in particular. We directly investigated the effect of posture on spontaneous brain dynamics by recording scalp electrical activity in four orthostatic conditions (lying supine, inclined at 45 degrees , sitting upright, and standing erect). Here we show that upright versus supine posture increases widespread high-frequency oscillatory activity. Our electroencephalographic findings highlight the importance of posture as a determinant in neuroimaging. When generalizing supine imaging results to ecological human cognition, therefore, cognitive neuroscientists would benefit from considering the influence of posture on brain dynamics. PMID- 25041936 TI - Elevated depressive symptoms enhance reflexive but not reflective auditory category learning. AB - In vision an extensive literature supports the existence of competitive dual processing systems of category learning that are grounded in neuroscience and are partially-dissociable. The reflective system is prefrontally-mediated and uses working memory and executive attention to develop and test rules for classifying in an explicit fashion. The reflexive system is striatally-mediated and operates by implicitly associating perception with actions that lead to reinforcement. Although categorization is fundamental to auditory processing, little is known about the learning systems that mediate auditory categorization and even less is known about the effects of individual difference in the relative efficiency of the two learning systems. Previous studies have shown that individuals with elevated depressive symptoms show deficits in reflective processing. We exploit this finding to test critical predictions of the dual-learning systems model in audition. Specifically, we examine the extent to which the two systems are dissociable and competitive. We predicted that elevated depressive symptoms would lead to reflective-optimal learning deficits but reflexive-optimal learning advantages. Because natural speech category learning is reflexive in nature, we made the prediction that elevated depressive symptoms would lead to superior speech learning. In support of our predictions, individuals with elevated depressive symptoms showed a deficit in reflective-optimal auditory category learning, but an advantage in reflexive-optimal auditory category learning. In addition, individuals with elevated depressive symptoms showed an advantage in learning a non-native speech category structure. Computational modeling suggested that the elevated depressive symptom advantage was due to faster, more accurate, and more frequent use of reflexive category learning strategies in individuals with elevated depressive symptoms. The implications of this work for dual-process approach to auditory learning and depression are discussed. PMID- 25041938 TI - Acute heart transplant graft failure in association with hyperosmolar hyperglycemia state. AB - We report a 38-year-old male with end-stage ischemic cardiomyopathy requiring left ventricular assist device placement, followed by orthotopic heart transplantation, who presented 18 months post-orthotopic heart transplant with acute graft failure with estimated left ventricular ejection fraction of 5% to 10%, in association with a glucose level of 550 mg/dL, and hemoglobin A1C of 13.8% and a negative pathology for a graft cellular and humoral rejection and no vasculaopthy. His left ventricular ejection fraction improved significantly to 40% to 45% within three days of optimal glucose control. PMID- 25041939 TI - Relative EBV antibody concentrations and cost of standard IVIG and CMV-IVIG for PTLD prophylaxis in solid organ transplant patients. AB - Some centers prefer CMV-IVIG over IVIG for the prophylaxis of EBV-related PTLD in solid organ transplant patients. Our objective was to compare the relative dose related EBV ELISA antibody concentrations and cost of standard IVIG and CMV-IVIG. The concentration of EBV IgG to VCA was analyzed via ELISA in four lots of IVIG and four lots of CMV-IVIG. Relative EBV ELISA antibody concentrations and cost were compared assuming an IVIG dose of 0.5 gm/kg and CMV-IVIG dose of 0.15 gm/kg in a 50-kg patient. The price of IVIG was $70/gm and CMV-IVIG $430/gm. IVIG contains the same EBV antibody concentrations (20 790 ELISA antibody units/mL) than CMV-IVIG (17 430 ELISA antibody units/mL, p > 0.2) in the four lots of each product sampled. When factoring in the dosing scheme for a 50-kg patient, IVIG contains two times more EBV antibody than CMV-IVIG. Yet, CMV-IVIG is 1.8 times more expensive than IVIG ($3225 vs. $1750). In the four lots of each product sampled, IVIG contains more EBV antibodies and costs less than CMV-IVIG when factoring in the dosing scheme. Studies are needed to determine whether there is clinical efficacy of immunoglobulin products for EBV-related PTLD prophylaxis. PMID- 25041940 TI - Intact globe inflation testing of changes in scleral mechanics in myopia and recovery. AB - The purpose of this study was to examine the effects of myopia-inducing and myopia recovery conditions on the scleral biomechanics of enucleated eyes of young chicks. Enucleated eyes from 5-day old chicks, with fiducial markers attached at 5 locations on the external sclera, were placed in a custom-built chamber filled with phosphate-buffered saline, and subjected to controlled increments in intraocular pressure (IOP). IOP was initially ramped from 15 to 100 mmHg and then maintained at 100 mmHg for one hour, with eyes photographed at a rate of 0.1 Hz over the same period. There were two experimental groups, one in which chicks were monocularly form deprived for four days to induce myopia, and the other in which chicks were allowed two days of recovery from myopia induced by two days of form deprivation. For all chicks, the contralateral (fellow) eyes served as controls. Myopic eyes showed less initial deformation relative to their fellows, while no difference was recorded between recovering eyes and their fellows over the same time frame. With exposure to sustained elevated pressure, eyes in all groups displayed time-dependent changes in creep behavior, which included a linear region of secondary, steady creep. The creep deformation of myopic eyes was significantly higher than that of their fellows, consistent with results of previous studies using uniaxial loading of scleral strips. When allowed only 2 days to recover from induced myopia, previously myopic eyes continued to show increased creep deformation. Compared to results reported in studies involving scleral strips, our whole globe testing yielded higher values for creep rate. Whole globe inflation testing provides a viable, less anatomically disruptive and readily adaptable method for investigating scleral biomechanics than uniaxial tensile strip testing. Furthermore, our results suggest that elastic stretching does not contribute to the increased axial elongation underlying myopia in young chick eyes. They also confirm the very limited involvement of the sclera in the early recovery from myopia, reflecting the well documented lag in scleral versus choroidal recovery responses. PMID- 25041942 TI - A metabonomic study of adjuvant-induced arthritis in rats using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Rheumatoid arthritis (RA) is a chronic systemic inflammatory and autoimmune disease accompanied by the destruction and deformities of joints. Adjuvant induced arthritis (AIA) is one of the excellent animal models of RA used to understand disease pathogenesis and screen potential drugs. In this paper, a urinary metabonomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) has been established to investigate the disease progression of AIA and find potential biomarkers of secondary inflammation in AIA rats. 24 potential biomarkers were identified, including xanthurenic acid, kynurenic acid, 4-pyridoxic acid, and phenylalanine, which revealed that tryptophan metabolism, phenylalanine metabolism, gut microbiota metabolism and energy metabolism were disturbed in AIA rats. These potential biomarkers and their corresponding pathways are helpful to further understand the mechanisms of AIA and pathogenesis of RA. This study demonstrates that metabonomics based on UPLC-Q-TOF-MS is a powerful methodology to analyze the underlying disease pathogenesis. PMID- 25041941 TI - Vinpocetine inhibits amyloid-beta induced activation of NF-kappaB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells. AB - Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Abeta) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-kappaB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-kappaBeta. ARPE19/NF-kappaB-luciferase reporter cells treated with Abeta demonstrated enhanced NF-kappaB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-kappaB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1beta, IL-18, and TNF-alpha in the RPE of adult rats that received intraocular Alphabeta, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3alpha, IL-6, IL-1alpha, IL-1beta, IL-18, and TNF-alpha in vinpocetine treated animals. These results suggest that the NF-kappaB pathway is activated by Abeta in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1beta and IL-18. NF-kappaB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use. PMID- 25041943 TI - Wolbachia strain wAlbB confers both fitness costs and benefit on Anopheles stephensi. AB - BACKGROUND: Wolbachia is a maternally transmitted intracellular bacterium that is estimated to infect up to 65% of insect species, but it is not naturally present in Anopheles malaria vectors. Wolbachia-based strategies for malaria vector control can be developed either through population replacement to reduce vectorial capacity or through population suppression to reduce the mosquito population. We have previously generated An. stephensi mosquitoes carrying a stable wAlbB Wolbachia infection and have demonstrated their ability to invade wild-type laboratory populations and confer resistance to Plasmodium on these populations. METHODS: We assessed wAlbB-associated fitness by comparing the female fecundity, immature development and survivorship, body size, male mating competiveness, and adult longevity of the infected An. stephensi to that of wild type mosquitoes. RESULTS: We found that wAlbB reduced female fecundity and caused a minor decrease in male mating competiveness. We also observed that wAlbB increased the life span of both male and female mosquitoes when they were maintained solely on sugar meals; however, there was no impact on the life span of blood-fed females. In addition, wAlbB did not influence either immature development and survivorship or adult body sizes. CONCLUSIONS: These results provide significant support for developing Wolbachia-based strategies for malaria vector control. PMID- 25041944 TI - Hypothesis: brain size and skull shape as criteria for a new hominin family tree. AB - Today, gorillas and chimpanzees live in tropical forests, where acid soils do not favor fossilization. It is thus widely believed that there are no fossils of chimpanzees or gorillas. However, four teeth of a 0.5-million-year (Ma)-old chimpanzee were discovered in the rift valley of Kenya (McBrearty and Jablonski, 2005), and a handful of teeth of a 10-Ma-old gorilla-like creature were found in Ethiopia (Suwa et al., 2007), close to the major sites of Homo discoveries. These discoveries indicate that chimpanzees and gorillas once shared their range with early Homo. However, the thousands of hominin fossils discovered in the past century have all been attributed to the Homo line. Thus far, our family tree looks like a bush with many dead-branches. If one admits the possibility that the australopithecines can also be the ancestors of African great apes, one can place Paranthropus on the side of gorilla ancestors and divide the remaining Australopithecus based on the brain size into the two main lines of humans and chimpanzees, thereby resulting in a coherent family tree. PMID- 25041946 TI - Elastography in predicting preterm delivery in asymptomatic, low-risk women: a prospective observational study. AB - BACKGROUND: Despite the efforts to decrease the rate of preterm birth, preterm delivery is still the main cause of neonatal morbidity and mortality. Identifying patients threatened with preterm delivery remains one of the main obstetric challenges. The aim of this study was to estimate the potential value of elastographic evaluation of internal cervical os stiffness at 18-22 weeks of pregnancy in low risk, asymptomatic women in the prediction of spontaneous preterm delivery. METHODS: This prospective observational study included 333 low risk, asymptomatic women presenting for the routine second trimester ultrasound scan according to the Polish Gynecological Society recommendation between 18-22 weeks of pregnancy. Ultrasound examinations of the cervix were performed transvaginally. The following data were recorded: elastographic color assessment of the internal os and ultrasound cervical length at 18-22 and 30 weeks of pregnancy; maternal age; obstetrical history; presence of cervical funneling at 30 weeks of pregnancy; gestational age at birth. Elastographic assessment of the internal os was performed using a color map: red (soft), yellow (medium soft), blue (medium hard) and purple (hard). If two colors were visible in the region of the internal os, the softer option was noted. Statistical analysis was performed using Statistica software (version 10, Statsoft Poland) using the following tests: chi square test to compare frequency of preterm deliveries in various categories of internal os assessment and Spearman correlation test to determine the correlation between elastographic assessment and cervical shortening. To determine the cut off category of internal os elastography assessment in selecting high preterm delivery risk patients we have calculated the sensivity, specifity, negative predictive value and positive predictive value. RESULTS: The number of preterm deliveries (<37 weeks of pregnancy) was significantly higher in the red and yellow groups, than in the blue and purple groups. The sensivity, specifity, NPV and PPV for both red and yellow internal os assessment in predicting preterm delivery were 85.7%, 97.6%, 98.3% and 81.1% respectively. CONCLUSIONS: Elastographic assessment of the internal cervical os at 18-22 weeks of pregnancy may identify patients with high risk of preterm delivery in low risk, asymptomatic women. PMID- 25041947 TI - A postmortem study to compare agonist and antagonist 5-HT1A receptor-binding sites in Alzheimer's disease. AB - AIMS: Positron emission tomography (PET) imaging using 5-HT1A receptor radioligands shows a decreased expression of this serotonin receptor in the hippocampus of patients with Alzheimer's disease (AD) at advanced stages. However, previous 5-HT1A receptor radioligands used in human imaging were antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the functional state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radioligand, which binds selectively to the functional state of the receptors, with the PET imaging obtained using an antagonist radioligand would therefore provide original information on 5-HT1A receptor impairment during AD. METHODS: Quantitative autoradiography using (18) F-F15599 and (18) F-MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of 18 patients with AD. RESULTS: Functional 5-HT1A receptors, labeled by (18) F-F15599, represented ~35% of total receptors, as estimated by (18) F-MPPF labeling. (18) F F15599 binding decreased in dentate gyrus of patients with AD, as indicated by Braak's stages. In contrast, binding of (18) F-MPPF was statistically unchanged. CONCLUSION: These in vitro results support testing the concept of functional PET imaging using agonist radioligands in clinical studies. PMID- 25041948 TI - Biosynthesis of the 4-methyloxazoline-containing nonribosomal peptides, JBIR-34 and -35, in Streptomyces sp. Sp080513GE-23. AB - JBIR-34 and -35 produced by Streptomyces sp. Sp080513GE-23 are nonribosomal peptides that possess an unusual 4-methyloxazoline moiety. Through draft genome sequencing, cosmid cloning, and gene disruption, the JBIR-34 and -35 biosynthesis gene cluster (fmo cluster) was identified; it encodes 20 proteins including five nonribosomal peptide synthetases (NRPSs). Disruption of one of these NRPS genes (fmoA3) resulted in no JBIR-34 and -35 production and accumulation of 6-chloro-4 hydroxyindole-3-carboxylic acid. Stable isotope-feeding experiments indicated that the methyl group of the methyloxazoline ring is derived from alanine rather than methionine. A recombinant FmoH protein, a glycine/serine hydroxymethyltransferase homolog, catalyzed conversion of alpha-methyl-l-serine into d-alanine (the reverse reaction of alpha-methyl-l-serine synthesis catalyzed by FmoH in vivo). Taken together, we concluded that alpha-methyl-l-serine synthesized from d-alanine is incorporated into JBIR-34 and -35 to form the 4 methyloxazoline moiety. We also propose the biosynthesis pathway of JBIR-34 and 35. PMID- 25041949 TI - Simple and highly efficient chiral dopant molecules possessing both rod- and arch like units. AB - A simple chiral dopant molecule (R)-1 with both rod- and arch-like units was prepared, and extremely large helical twisting powers (+123 to +228 MUm(-1)) in nematic liquid crystal phases were achieved. We have demonstrated that the introduction of an arch-like unit in addition to rod-like units is highly effective in controlling the helical molecular alignment. As an application of the dopant, induction of blue phases by addition of a small amount of it was achieved. PMID- 25041950 TI - Response to copper of Acidithiobacillus ferrooxidans ATCC 23270 grown in elemental sulfur. AB - The response of Acidithiobacillus ferrooxidans ATCC 23270 to copper was analyzed in sulfur-grown cells by using quantitative proteomics. Forty-seven proteins showed altered levels in cells grown in the presence of 50 mM copper sulfate. Of these proteins, 24 were up-regulated and 23 down-regulated. As seen before in ferrous iron-grown cells, there was a notorious up-regulation of RND-type Cus systems and different RND-type efflux pumps, indicating that these proteins are very important in copper resistance. Copper also triggered the down-regulation of the major outer membrane porin of A. ferrooxidans in sulfur-grown bacteria, suggesting they respond to the metal by decreasing the influx of cations into the cell. On the contrary, copper in sulfur-grown cells caused an overexpression of putative TadA and TadB proteins known to be essential for biofilm formation in bacteria. Surprisingly, sulfur-grown microorganisms showed increased levels of proteins related with energy generation (rus and petII operons) in the presence of copper. Although rus operon is overexpressed mainly in cells grown in ferrous iron, the up-regulation of rusticyanin in sulfur indicates a possible role for this protein in copper resistance as well. Finally, copper response in A. ferrooxidans appears to be influenced by the substrate being oxidized by the microorganism. PMID- 25041951 TI - Evidence-based evaluation of the thyroid nodule. AB - This article reviews the most current literature on thyroid nodule evaluation, with particular attention to the problem of the incidentally identified thyroid nodule. Although traditional risk factors for thyroid cancer, such as age, gender, and familial syndromes, are still important, the manner in which a thyroid nodule comes to attention is of great importance these days when considering how to proceed in a workup. Most thyroid nodules today are discovered through radiologic imaging tests performed for other reasons. This article covers the key considerations that are vital in balancing the risks and benefits of thyroid nodule workup and treatment. PMID- 25041952 TI - Thyroid cytology. AB - This article covers, in a comprehensive way, thyroid cytopathology. The Bethesda System for Reporting Thyroid Cytology is reviewed, with emphasis on the atypical and indeterminate diagnostic categories. Immunohistochemistry stains and molecular tests panels applicable to cytology specimens are described. PMID- 25041953 TI - Clinician-performed thyroid ultrasound. AB - This article is intended to demystify the process for those with a potential interest in acquiring ultrasound skills. It is not intended to be a comprehensive review of head and neck ultrasound but, rather, is focused on the bare minimum requirements and considerations involved in clinician-performed ultrasound. The article covers the initial diagnosis and the unparalleled usefulness of ultrasound for surgical planning just before incision. Further readings are listed at the end of the article to direct the reader to some excellent texts to help build confidence and experience. PMID- 25041954 TI - Clinician-performed thyroid ultrasound-guided fine-needle aspiration. AB - Fine needle aspiration biopsy (FNA) is the key step in selecting most patients with thyroid nodules for or against surgery. Accurate acquisition of cytologic samples from suspicious lesions is achieved by adding ultrasound guidance to optimize targeting as well as to enable sampling from nonpalpable lesions. This article discusses the indications, variations, and technical details of ultrasound-guided FNA. PMID- 25041955 TI - Surgical diagnosis: frozen section and the extent of surgery. AB - This article outlines features of the biology of well differentiated thyroid cancer, and how these impact on systems of risk prediction. It covers salient points that the surgeon should consider from the clinical history and examination in the office, and outlines the procedures available for surgical management of thyroid cancer. The article then examines the choices that face thyroid surgeons both in relation to planning primary thyroid surgery and the approach to regional lymphadenectomy. In addition, key findings in the operating room are discussed in relation to their impact on decision making. Long-term outcomes are presented for patients following surgery. PMID- 25041956 TI - Contemporary surgical techniques. AB - Recent technologic advances have engendered alternative and innovative approaches to thyroid surgery aimed at reducing cosmetic sequelae. Minimally invasive techniques via small anterior cervical incisions hidden in natural skin creases and remote access approaches that eliminate anterior neck incisions entirely have emerged as viable options for patients who regard cosmesis as a priority. The safe application of these techniques to both benign and malignant thyroid disease has been evaluated. PMID- 25041957 TI - Management of the neck in thyroid cancer. AB - The management of regional lymph nodes in thyroid carcinoma is guided by preoperative evaluation, histologic subtype, and often a consideration of data for potential benefit and morbidity of a neck dissection. The goal of lymphadenectomy is complete surgical resection of grossly evident metastatic disease and the removal of regional lymph node groups at highest risk for microscopic disease. Surgery should achieve disease eradication but preserve voice, airway, swallowing, and parathyroid function. This article discusses recommendations for addressing cervical lymph nodes in thyroid carcinoma, discusses current literature regarding the common histologic subtype (papillary carcinoma), and details our operative approach. PMID- 25041959 TI - Clinical diagnostic gene expression thyroid testing. AB - Thyroid fine-needle aspiration biopsies are cytologically indeterminate in 15% to 30% of cases. When cytologically indeterminate thyroid nodules undergo diagnostic surgery, approximately three-quarters prove to be histologically benign. A negative predictive value of more than or equal to 94% for the Afirma Gene Expression Classifier (GEC) is achieved for indeterminate nodules. Most Afirma GEC benign nodules can be clinically observed, as suggested by the National Comprehensive Cancer Network Thyroid Carcinoma Guideline. More than half of the benign nodules with indeterminate cytology (Bethesda categories III/IV) can be identified as GEC benign and removed from the surgical pool to prevent unnecessary diagnostic surgery. PMID- 25041958 TI - Clinical application of molecular testing of fine-needle aspiration specimens in thyroid nodules. AB - Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Thyroid cancer is typically diagnosed during the evaluation of thyroid nodules. Although most thyroid nodules are benign, the challenge is to accurately and effectively identify malignant nodules. Understanding of genetic pathways involved in thyroid carcinogenesis has improved, and molecular testing techniques have become widespread and cost-efficient. Routine testing for somatic mutations and rearrangements that are commonly found in thyroid cancer can augment current diagnostic testing algorithms for thyroid nodules, and can provide preoperative prognostic information that helps to optimize initial patient management. PMID- 25041960 TI - The prognostic implications from molecular testing of thyroid cancer. AB - Thyroid cancer is the most common endocrine malignancy and its incidence has increased over the past few decades. Most patients with thyroid cancer have an excellent prognosis, but there is a 15% recurrence rate within 10 years after initial treatment and mortality is possible. To date, there are no prospective, well-defined data supporting the use of molecular markers alone to decide the extent of treatment of patients with thyroid cancer or to predict the individual prognosis of these patients. Molecular markers are promising in the development of new targeted therapies particularly for radioiodine-refractory and unresectable thyroid cancers. PMID- 25041961 TI - Decision making for diagnosis and management: algorithms from experts for molecular testing. AB - Cases are presented in light of the current diagnostic and therapeutic trends in management of thyroid nodules and well-differentiated cancers. Demographic, historical, and population-based risk factors are used to risk stratify cases. Ultrasonographic features and other imaging are discussed with regard to appropriateness of utilization and impact on management. The role of traditional cytologic and histopathologic analysis with fine-needle aspiration and intraoperative frozen sections is discussed, including diagnostic nuances and limitations. The emerging role of biomarkers such as Braf are evaluated regarding their role in contemporary assessment of thyroid nodules by reviewing practical cases. PMID- 25041962 TI - Thyroid cancer: current diagnosis, management, and prognostication. PMID- 25041963 TI - Physical activity temporal trends among children and adolescents. AB - OBJECTIVES: It is particularly important to measure trends in physical activity to identify specific contexts where physical activity may have declined and can be targeted for intervention. The aim of this review was to summarize overall physical activity trends based on objectively measured physical activity as well as trends in specific contexts (active transport, organized sport, school physical education and school play periods) using self- or proxy-reported physical activity. DESIGN: A comprehensive literature search was completed to identify articles on the specific contexts of physical activity for inclusion in this review. METHODS: Journal articles for inclusion in this narrative review were sourced from the various databases and reference lists. Most studies in this review employed self-report or proxy-report methodologies. RESULTS: There is limited research on temporal trends in children's and adolescents' physical activity. The few studies that employ objective measures to assess trends in physical activity indicate little change has occurred in the last 20 years. Other studies that employed self-report methods indicate organized sport trends are somewhat inconsistent across countries, however most studies reported an increase in participation. Within the limited physical education trend studies, inconsistent trends were noted. There have been consistent declines in active transport, particularly cycling. Few studies have investigated trends in physical activity and sedentary behaviour during school play periods, highlighting a need for further research. CONCLUSIONS: Mixed results and inconsistent magnitudes of change were identified when exploring trends in different contexts of physical activity for children and adolescents over the last few decades. Taken overall, there is little evidence for a decrease in children's and adolescents' physical activity, although consistent declines in active transport highlight this context as a suitable intervention target. PMID- 25041964 TI - Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2. OBJECTIVE: We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population. METHODS: We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations. RESULTS: We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available. CONCLUSION: In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D. PMID- 25041965 TI - ST-segment deviation behavior during acute myocardial ischemia in opposite ventricular regions: observations in the intact and perfused heart. AB - BACKGROUND: Acute myocardial ischemia in opposite regions may attenuate ST segment changes, but whether this effect is expressed differently in extracardiac compared to direct intramyocardial recordings is not well known. OBJECTIVE: The purpose of this study was to characterize ST-segment changes induced by opposite ischemic regions in intact and isolated perfused pig hearts. METHODS: Left anterior descending (LAD) and right coronary arteries (RCA) were occluded in 7 closed chest pigs and in 5 isolated pig hearts. ST-segment changes were analyzed in 12-lead ECG and in local extracellular electrograms. RESULTS: Isolated LAD or RCA occlusion induced maximal ST-segment elevation in leads V4 (0.84 +/- 0.30 mV, P = .003) and III (0.16 +/- 0.11 mV, P = .04), respectively. RCA occlusion also induced reciprocal ST-segment depression maximal in lead V4 (-0.40 +/- 0.16 mV, P = .005). Simultaneous LAD and RCA occlusion reduced ST-segment elevation by about 60% and blunted reciprocal ST-segment changes. Reperfusion of 1 of the 2 occluded arteries induced immediate regional reversion of ST-segment elevation with concurrent beat-to-beat re-elevation in the opposite ischemic region and reappearance of reciprocal ST-segment changes. In the isolated heart, single LAD or RCA ligature induced regional transmural ST-segment elevation that was maximal in endocardial electrograms with no appreciable reciprocal ST-segment depression. Simultaneous LAD and RCA ligature reduced ST-segment elevation by about 30% with no appreciable re-elevation after 1-vessel selective reperfusion. CONCLUSION: Acute myocardial ischemia in opposite ventricular regions attenuated ST-segment elevation and blunted reciprocal depression in conventional ECG leads but not in direct local myocardial electrograms. PMID- 25041966 TI - A formidable "TASK": tipping the balance in favor of rhythm control for the management of atrial fibrillation. PMID- 25041967 TI - Etienne-Arthur Louis Fallot and his tetralogy. AB - Etienne-Arthur Louis Fallot (1850-1911) is one of the most significant medical figures of the 19th century with an eponymous congenital cardiac malformation. His initial account of the four anatomical features making up his tetralogy proved remarkably significant in the progression of clinical descriptions of the lesions producing cyanotic congenital cardiac disease. Although subsequently the cause of appreciable controversy, the accuracy of his initial descriptions underscore the current diagnostic and therapeutic approach to the malformation now known uniformly as tetralogy of Fallot. PMID- 25041975 TI - Multimodality imaging of the postpartum or posttermination uterus: evaluation using ultrasound, computed tomography, and magnetic resonance imaging. AB - Postpartum and posttermination complications are common causes of morbidity and mortality in women of reproductive age. These complications can be broadly categorized into vascular, infectious, surgical, and neoplastic etiologies, or are due to ectopic implantation of placental or endometrial tissue. Causes of postpartum vascular complications include retained products of conception, arteriovenous malformation, and pseudoaneurysm. Infectious entities include endometritis, abscess, wound cellulitis, and pelvic septic thrombophlebitis. Postsurgical complications include uterine scar dehiscence, bladder flap hematoma, and subfascial hematoma. Neoplastic complications include the spectrum of gestational trophoblastic neoplasms. Ectopic tissue implantation complications include abnormal placentation and uterine scar endometriosis. Imaging is essential for diagnosis, and radiologists must be familiar with and aware of these entities so that accurate treatment and management can be obtained. In this review, we illustrate the imaging findings of common postpartum and posttermination complications on ultrasound, computed tomography, and magnetic resonance imaging. PMID- 25041977 TI - Adrenomedullin: a vasodilator to treat sepsis? AB - Adrenomedullin is a vasodilatory polypeptide with pleiotropic effects secreted by various organs. Adrenomedullin is produced first as a prepropeptide, and then cleaved into mature adrenomedullin and mid-regional proadrenomedullin. Whereas levels of the latter have been shown to correlate with severity of sepsis and carry prognostic value, adrenomedullin plays a role in vascular tone homeostasis. In the previous issue of Critical Care, the infusion of exogenous adrenomedullin is suggested to protect against increased lung endothelial permeability and end organ dysfunction in a model of pneumococcal pneumonia in mechanically ventilated mice, possibly by stabilizing vascular endothelia. Since adrenomedullin is a strong vasodilatory molecule, further studies are needed to evaluate its potential as a future treatment of sepsis. PMID- 25041976 TI - Rapid dissolution of switchgrass in 1-butyl-3-methylimidazolium chloride by ultrasonication. AB - The utilization of ultrasonics to rapidly dissolve switchgrass in ionic liquid, 1 butyl-3-methylimidazolium chloride ([Bmim][Cl]) was evaluated in this work. The objective of the study focused on determining the effects of various ultrasonic conditions on the recovery of carbohydrate from biomass, lignin removal, and enzymatic hydrolysis. Dried ground switchgrass was added to ionic liquid, then sonicated at a frequency of 20kHz. The experiments were conducted using a catenoidal horn at varying amplitudes of 96MUm, 128MUm, and 160MUm and sonication times of 2, 3, and 4min. Similarly, ground switchgrass was dissolved in ionic liquid assisted by conventional heat treatment at 130 degrees C for 12 and 24h. The results showed good delignification results of 53% for the 24h heat pretreated samples and of 50.8% for ultrasonic assisted samples at 160MUm amplitude and 4min. Even in the presence of lignin in the recovered biopolymer, both of heat treated and ultrasonicated samples obtained 100% glucan digestibility after only 3h of enzymatic hydrolysis. Heat pretreated samples exhibited 44-59% lower xylan digestibility compared to ultrasonic pretreated samples (160MUm amplitude and 4min sonication time). Scanning electron microscope images displayed significant changes in biomass structure from intact and crystalline of the untreated biomass to disintegrated and amorphous of the treated biomass (heat treated and ultrasonicated). With increasing ultrasonic amplitude the carbohydrate recovery decreased. Also, more than 50% of the hemicellulose fraction was lost during biomass recovery. Overall, it was concluded that ultrasonication was a promising technology to enhance dissolution of lignocellulose in ionic liquid. PMID- 25041978 TI - Coronary artery disease detected by coronary computed tomography angiography in adult survivors of childhood Hodgkin lymphoma. AB - BACKGROUND: Survivors of Hodgkin lymphoma (HL) have significant cardiovascular risk and require long-term surveillance. The current study assessed the prevalence of coronary artery disease (CAD) by coronary computed tomography angiography (CCTA) in adult survivors of childhood HL. METHODS: Thirty-one survivors of HL, 13 of whom (42%) were treated with radiotherapy (RT) only and 18 of whom (58%) were treated with multimodal therapy, underwent CCTA, echocardiography, electrocardiography (ECG), and treadmill stress testing. Obstructive CAD was defined as >=50% occlusion of the left main or >=70% occlusion of the left anterior descending, left circumflex, or right coronary arteries on CCTA. Echocardiograms with resting wall motion abnormalities or an ejection fraction <50%; ECGs with Q waves, ST abnormalities without Q waves, or T wave abnormalities without Q waves; and a J-point depression of >=1 mm with a horizontal or downsloping ST segment on stress testing were considered abnormal. RESULTS: The prevalence of disease in participants (median age, 40 years [range, 26 years-55 years]; median time from cancer diagnosis, 24 years [range, 17 years 39 years]) was 39%, with 39 plaques detected among 12 survivors. Three participants (10%) treated with RT only had 4 obstructive lesions; 9 patients (29%; 5 of whom were treated with RT only and 4 of whom were treated with multimodal therapy) had nonobstructive lesions. Approximately 15% of lesions involved the left main, 21% involved the proximal left anterior descending, 18% involved the proximal right coronary, and 13% involved the proximal left circumflex arteries. Of the 12 participants found to have CAD by CCTA, 7 had a positive ECG, 1 had a positive echocardiogram, and 1 had a positive stress test. CONCLUSIONS: CCTA identified CAD in a substantial percentage of survivors of HL and may be an effective screening modality for this population. PMID- 25041979 TI - An absolute method for determination of misalignment of an immersion ultrasonic transducer. AB - An absolute methodology has been developed for quantification of misalignment of an ultrasonic transducer using a corner-cube retroreflector. The amplitude based and the time of flight (TOF) based C-scans of the reflector are obtained for various misalignments of the transducer. At zero degree orientation of the transducer, the vertical positions of the maximum amplitude and the minimum TOF in the C-scan coincide. At any other orientation of the transducer with the horizontal plane, there is a vertical shift in the position of the maximum amplitude with respect to the minimum TOF. The position of the minimum (TOF) remains the same irrespective of the orientation of the transducer and hence is used as a reference for any misalignment of the transducer. With the measurement of the vertical shift and the horizontal distance between the transducer and the vertex of the reflector, the misalignment of the transducer is quantified. Based on the methodology developed in the present study, retroreflectors are placed in the Indian 500MWe Prototype Fast Breeder Reactor for assessment of the orientation of the ultrasonic transducer prior to the under-sodium ultrasonic scanning for detection of any protrusion of the subassemblies. PMID- 25041980 TI - Influence of nesting shell size on brightness longevity and resistance to ultrasound-induced dissolution during enhanced B-mode contrast imaging. AB - This study aims to bridge the gap between transport mechanisms of an improved ultrasound contrast agent (UCA) and its resulting behavior in a clinical imaging study. Phospholipid-shelled microbubbles nested within the aqueous core of a polymer microcapsule are examined for their use and feasibility as an improved UCA. The nested formulation provides contrast comparable to traditional formulations, specifically an SF6 microbubble coated by a DSPC PEG-3000 monolayer, with the advantage that contrast persists at least nine times longer in a mock clinical, in vitro setting. The effectiveness of the sample was measured using a contrast ratio in units of decibels (dB) which compares the brightness of the nested microbubbles to a reference value of a phantom tissue mimic. During a 40min imaging study, six nesting formulations with average outer capsule diameters of 1.95, 2.53, 5.55, 9.95, 14.95, and 20.51MUm reached final contrast ratio values of 0.25, 2.35, 3.68, 4.51, 5.93, and 8.00dB, respectively. The starting contrast ratio in each case was approximately 8dB and accounts for the brightness attributed to the nesting shell. As compared with empty microcapsules (no microbubbles nested within), enhancement of the initial contrast ratio increased systematically with decreasing microcapsule size. The time required to reach a steady state in the temporal contrast ratio profile also varied with microcapsule diameter and was found to be 420s for each of the four smallest shell diameters and 210s and 150s, respectively, for the largest two shell diameters. All nested formulations were longer-lived and gave higher final contrast ratios than a control sample comprising un-nested, but otherwise equivalent, microbubbles. Specifically, the contrast ratio of the un-nested microbubbles decreased to a negative value after 4min of continuous ultrasound exposure with complete disappearance of the microbubbles after 15min whereas all nested formulations maintained positive contrast ratio values for the duration of the 40min trial. The results are consistent with two distinct stages of gas transport: in the first stage, passive diffusion occurs under ambient conditions across the microbubble monolayer within the first few minutes after formulation until the aqueous interior of the microcapsule is saturated with gas; in the second stage ultrasound drives additional gas dissolution even further due to pressure modulation. It is important to understand the chemistry and transport mechanisms of this contrast agent under the influence of ultrasound to attain better perspicacity for enhanced applications in imaging. Results from this study will facilitate future preclinical studies and clinical applications of nested microbubbles for therapeutic and diagnostic imaging. PMID- 25041981 TI - Abstracts of the ISPD 18th International Conference on Prenatal Diagnosis and Therapy, 20-23 July, 2014, Brisbane, Australia. PMID- 25041982 TI - Enhanced bacterial tumor delivery by modulating the EPR effect and therapeutic potential of Lactobacillus casei. AB - Bacteria of micrometer size could accumulate in tumor based on enhanced permeability and retention (EPR) effect. We report here Lactobacillus casei (L. casei), a nonpathogenic facultatively anaerobic bacterium, preferentially accumulated in tumor tissues after intravenously (i.v.) injection; at 24 h, live bacteria were found more in the tumor, whereas the bacteria in normal tissues including the liver and spleen were cleared rapidly. The tumor-selective accumulation and growth of L. casei is probably due to the EPR effect and the hypoxic tumor environment. Moreover, the bacterial tumor delivery was significantly increased by a nitric oxide (NO) donor nitroglycerin (NG, 10-70 times) and an angiotensin II converting enzyme inhibitor, enalapril (6-18 times). Consequently significant suppression of tumor growth was found in a colon cancer C26 model, and more remarkable antitumor effect was achieved when L. casei was combined with NG, probably by modulating the host nonspecific immune responses; tumor necrosis factor-alpha significantly increased in tumor after the treatment, as well as NO synthase activity and myleoperoxidase activity. These findings suggest the potential of L. casei as a candidate for targeted bacterial antitumor therapy, especially in combine with NG or other vascular mediators. PMID- 25041983 TI - Effectiveness of a standardized education process for tracheostomy care. AB - OBJECTIVES/HYPOTHESIS: Evaluate the effectiveness of an educational curriculum on general tracheostomy care principles and determine the effect of this educational curriculum on the level of provider comfort with tracheostomy care. STUDY DESIGN: Cross-sectional questionnaire in an academic medical center. MATERIALS AND METHODS: A 25-question multiple choice and true/false quiz was given to nonotolaryngology health care providers (nurses and physicians) who routinely provide tracheostomy care. This was followed by an education module, and the quiz was repeated. Participants were also asked to rate their level of comfort (0-100 point scale) managing a tracheostomy before and after the module. A 6-month follow-up assessment was also obtained. RESULTS: A total of 94 health care providers participated in the education module (50 physicians, 37 nurses, 7 fourth-year medical students). The average number of correct answers increased by 3.1 (P < 0.001). The level of confidence in tracheostomy care improved by 18.8 points (P < 0.001). At the 6-month assessment, there was still a significant improvement in the number of correct questions and level of confidence when compared to preeducation values (P < 0.02 for both). There was no significant change in the 6-month values when compared to the posteducation values. CONCLUSIONS: A standardized education module for tracheostomy care teaching resulted in significant increases in provider knowledge and confidence. Standardization of tracheostomy education and care is essential in academic hospital medical centers where multiple specialties may be performing tracheostomies and health care providers frequently change. LEVEL OF EVIDENCE: N/A. PMID- 25041984 TI - Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder. AB - Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype. PMID- 25041985 TI - Expression profile of neurotransmitter receptor and regulatory genes in the prefrontal cortex of spontaneously hypertensive rats: relevance to neuropsychiatric disorders. AB - The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study several behavioral, pathophysiological and pharmacological aspects of schizophrenia and attention-deficit/hyperactivity disorder. To further understand the genetic underpinnings of this model, our primary goal in this study was to compare the gene expression profile of neurotransmitter receptors and regulators in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of SHR and Wistar rats (control group). In addition, we investigated DNA methylation pattern of promoter region of the genes differentially expressed. We performed gene expression analysis using a PCRarray technology, which simultaneously measures the expression of 84 genes related to neurotransmission. Four genes were significantly downregulated in the PFC of SHR compared to Wistar rats (Gad2, Chrnb4, Slc5a7, and Qrfpr) and none in nucleus accumbens. Gad2 and Qrfpr have CpG islands in their promoter region. For both, the promoter region was hypomethylated in SHR group, and probably this mechanism is not related with the downregulation of these genes. In summary, we identified genes that are downregulated in the PFC of SHR, and might be related to the behavioral abnormalities exhibited by this strain. PMID- 25041986 TI - The natural history of asymptomatic severe carotid artery stenosis. AB - BACKGROUND: Although level 1 evidence supports carotid endarterectomy (CEA) for stroke prevention in patients with asymptomatic severe carotid artery stenosis (ASCAS; >70%), medical therapy alone has been promulgated by some as equally effective. The goal of this study was to determine the natural history of medically treated patients with ASCAS. METHODS: Patients with ASCAS from 2005 to 2006 were identified in a health network database. Patients were included if the initial therapeutic plan involved medical therapy alone (usually because of comorbidities or patient preference). Study end points included: ipsilateral neurologic symptoms (INS) of transient ischemic attack and/or stroke, death, and INS and/or death. RESULTS: There were 126 carotid arteries identified in 115 patients. Using standard duplex velocity criteria, 88 (70%) had severe (70%-89%) and 38 (30%) had very severe stenoses (VSS; 90%-99%). The average age was 73.5 years, demographic characteristics included: 66% hypertension, 64% coronary artery disease, 30% diabetes, 5% chronic kidney disease (CKD), and 86% were taking a statin drug (28% had a low-density lipoprotein level <100 mg/dL). There were 31 patients (24.6%) who developed INS during a mean follow-up of 27 months; most (23 of 31; 74%) occurred within 12 months of the initial duplex ultrasound examination; 14 (45%) were strokes. The 5-year actuarial freedom from INS was 70.1 +/- 5%. Multivariate predictors of INS included: VSS (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.56-6.76; P = .002), CKD (HR, 6.25; 95% CI, 2.05-19.2; P = .001), and age (HR, 0.94; 95% CI, 0.91-0.98; P = .001). There were 41 patients (33%) who underwent eventual carotid revascularization (32 CEA, nine stent); 23 of 41 (56%) were performed for INS and 18 (44%) for plaque progression. Overall 5-year actuarial survival was 69.8% +/- 4.1%. Multivariate predictors of death included: age (HR, 1.06; 95% CI, 1.03-1.1; P = .0001), chronic obstructive pulmonary disease (HR, 1.92; 95% CI, 1.08-3.41; P = .03), and diabetes (HR, 5.08; 95% CI, 2.86-9.01; P < .0001). The 5-year actuarial freedom from INS and/or death was 54 +/- 4.4%. Multivariate predictors of INS and/or death were: VSS (HR, 1.98; 95% CI, 1.22-3.23; P = .006), CKD (HR, 5.46; 95% CI, 2.12-14.08; P = .0004), and diabetes (HR, 2.6; 95% CI, 1.59-4.24; P = .0001). Statin use was not protective against INS or death in this cohort. CONCLUSIONS: Medically managed patients with ASCAS develop INS early, especially in patients with VSS. Medical therapy with aspirin and statins failed to control ASCAS, thus validating the role of CEA in these patients as promulgated in multiple current treatment guidelines. PMID- 25041987 TI - Open repair of adult aortic coarctation mostly by a resection and graft replacement technique. AB - BACKGROUND: We report on our experience with treatment of adults requiring de novo or redo open aortic coarctation repair mostly by a resection and interposition graft technique. METHODS: We retrospectively reviewed all patients older than 16 years requiring open repair of aortic coarctation. Indications for repair, operative details, and outcomes were analyzed. RESULTS: Between 1996 and 2011, we treated 29 adult aortic coarctation patients with open repair. The mean age was 42 years (range, 17-69 years), and there were 15 men. Nine patients had previous repair with recurrence; the remaining 20 had native coarctation. Thoracic aortic aneurysms were present in 22 patients (76%), ranging in size from 3.0 to 9.6 cm (mean, 4.8 cm). Four patients had intercostal artery aneurysms (range, 1.0-2.5 cm), four had left subclavian artery aneurysms, and four had ascending/arch aneurysms. The most common repair was resection of aortic coarctation with interposition graft replacement (93%). Two patients without aneurysm had bypasses from the proximal descending thoracic aorta to the infrarenal aorta without aortic resection. There was no in-hospital mortality, stroke, or paraplegia. Long-term survival was 89% during a median follow-up of 81 months (interquartile range, 47-118 months), with no patient requiring reoperation on the repaired segment. CONCLUSIONS: Open repair of native and recurrent adult aortic coarctation has acceptable morbidity and low mortality. Especially in patients with concomitant aneurysm, resection with interposition graft replacement provides a safe and durable repair option. PMID- 25041988 TI - Discussion. PMID- 25041989 TI - Patient compliance limits the efforts of quality improvement initiatives on arteriovenous fistula maturation. AB - OBJECTIVE: Our institutional quality-improvement (QI) initiative instituted a well-defined office follow-up schedule after arteriovenous fistula (AVF) creation, including an office visit within 30 days, fistulogram within 40 days, if indicated, and a second office visit within 55 days. In addition, a patient liaison contacted patients and dialysis units to improve follow-up. The purpose of this study was to determine the effect of the QI initiative on patient compliance and overall time to AVF permission to cannulate. METHODS: We performed a retrospective review of patients undergoing first-time radiocephalic, brachiocephalic, and basilic vein transposition creation before the QI initiative (pre-QI group: January to April 2012) and during the QI period (QI group: January to April 2013). Categoric data were compared using chi(2) analysis, and nominal data were compared using the Student t-test. RESULTS: We reviewed 198 first-time AVF creations in patients (57% male) with a mean age of 61 years. Demographics and comorbidities between the pre-QI and QI groups were similar. Compliance with the first 30-day postoperative appointment increased significantly after the QI initiative, from 48% in the pre-QI group to 65% in the QI group (P = .015). Yet, the QI initiative did not maintain an effect on the subsequent follow-up checkpoints. No statistical difference was identified for compliance with fistulogram within 40 days of access creation (pre-QI, 12% vs QI, 25%; P = .093) or for compliance with the 55-day postoperative appointment (pre-QI, 33% vs QI, 23%; P = .457). Both checkpoints demonstrated a very high noncompliance rate. Accordingly, the mean time to permission to cannulate was 88 days for both the pre-QI and QI groups, with a failure to mature rate of 22% for the pre-QI group and 21% for the QI group (P = .816). CONCLUSIONS: The QI initiative significantly increased the number of patients complying with the first 30-day follow-up appointment after AVF access creation. However, patient compliance with a timely fistulogram and the second follow-up appointment was poor and not influenced by the QI initiative, limiting the functional effect of the QI initiative on the time to AVF permission to cannulate. PMID- 25041990 TI - Attenuation of early atherosclerotic lesions by immunotolerance with beta2 glycoprotein I and the immunomodulatory effectors interleukin 2 and 10 in a murine model. AB - OBJECTIVE: This study assessed the effect of cellular and humoral autoimmune response inhibition after immunization with beta2-glycoprotein I (beta2-GPI) and the effect of immunomodulation with interleukin (IL)-2 and IL-10 in the development of early atherosclerotic vascular lesion in a murine model. Atherosclerosis is increasingly considered a chronic inflammatory disease with pathogenic autoimmune processes. Regulatory T cells, and their cytokines, have been implicated in the inhibition of the development of atherosclerotic lesions and involved in the immunologic tolerance induction. METHODS: Eight-week-old male C57BL6 LDL-receptor deficient (LDLR(-/-)) mice were fed a cholesterol-rich (2.8%), high-saturated-fat (82%) diet for a week and divided in five groups. The groups received the following intravenous immunizations: group I (control group): one dose of 5 MUg beta2-GPI; group II: 5 MUg beta2-GPI I and 1 MUg IL-2; group III: 5 MUg beta2-GPI and 0.75 MUg of IL-10; and group IV: 5 MUg beta2-GPI, 1 MUg IL-2, and 0.75 MUg IL-10. The aortas of the mice were assessed 8 weeks after inoculation to determine the aortic lesion size and composition in all groups. RESULTS: beta2-GPI immunization attenuated the early atherosclerotic lesions development compared with the control group (P = .001). Macroscopic and histologic aortic atherosclerotic lesions were significantly decreased in the IL 2 and IL-10-treated groups in beta2-GPI-tolerant mice compared with the beta2-GPI tolerant group without cytokine injection (P = .001). The association of both cytokines did not provoke a major inhibition in the atherosclerosis development when compared with groups injected with the two cytokines separately. CONCLUSIONS: The immunotolerance induction against beta2-GPI attenuates the development of atherosclerosis lesions in an animal model, enhanced by downregulation of the cellular and humoral autoimmune response provoked by IL-2 and IL-10. PMID- 25041991 TI - Vitrification of mouse preantral follicles versus slow freezing: Morphological and apoptosis evaluation. AB - The aim of this study was evaluation of survivability, maturation rate and apoptotic gene expression of preantral follicles after vitrification and slow freezing technique. Normal mouse preantral follicles were randomly divided into three experimental groups. In the control group, follicles were cultured immediately; in the vitrification and slow freezing groups, follicles were cultured after vitrification-warming and slow freezing-thawing procedures. Follicular viability was assessed by using 0.4% trypan blue, and molecular evaluation of messenger RNA levels of apoptosis-related genes was performed by the semi-quantitative RT-PCR method after 3 h of culture. Oocyte maturation rates were also evaluated on day 14 of culture. Survival and maturation rate in the slow freezing group were significantly lower than those in control and vitrification groups (P <= 0.05). Although there was no difference in Survivin expression among the three experimental groups, Bcl-2 expression was significantly lower in the slow freezing group compared to the other groups (P <= 0.05). The expression of Bax, P53, Fas and Bax/Bcl-2 ratio in the slow freezing group was significantly higher than control and vitrification groups (P <= 0.05). Preantral follicle vitrification seems to be better than slow freezing as seen in the survival, maturation and expression rates of apoptotic gene variants. PMID- 25041992 TI - Expert witness blinding strategies to mitigate bias in radiology malpractice cases: a comprehensive review of the literature. AB - Like all physicians, radiologists in the United States are subject to frequent and costly medical malpractice claims. Legal scholars and physicians concur that the US civil justice system is neither precise nor accurate in determining whether malpractice has truly occurred in cases in which claims are made. Sometimes, this inaccuracy is driven by biases inherent in medical expert-witness opinions. For example, expert-witness testimony involving "missed" radiology findings can be negatively affected by several cognitive biases, such as contextual bias, hindsight bias, and outcome bias. Biases inherent in the US legal system, such as selection bias, compensation bias, and affiliation bias, also play important roles. Fortunately, many of these biases can be significantly mitigated or eliminated through the use of appropriate blinding techniques. This paper reviews the major works on expert-witness blinding in the legal scholarship and the radiology professional literature. Its purpose is to acquaint the reader with the evidence that unblinded expert-witness testimony is tainted by multiple sources of bias and to examine proposed strategies for addressing these biases through blinding. PMID- 25041993 TI - Admission high serum sodium is not associated with increased intensive care unit mortality risk in respiratory patients. AB - BACKGROUND: Because increased serum osmolarity may be lung protective, we hypothesized that increased mortality associated with increased serum sodium would be ameliorated in critically ill patients with an acute respiratory diagnosis. METHODS: Data collected within the first 24 hours of intensive care unit (ICU) admission were accessed using ANZICS CORE database. From January 2000 to December 2010, 436,209 patients were assessed. Predefined subgroups including patients with acute respiratory diagnoses were examined. The effect of serum sodium on ICU mortality was assessed with analysis adjusted for illness severity and year of admission. Results are presented as odds ratio (95% confidence interval) referenced against a serum sodium range of 135 to 144.9 mmol/L. RESULTS: Overall ICU mortality was increased at each extreme of dysnatremia (U shaped relationship). A similar trend was found in various subgroups, with the exception of patients with respiratory diagnoses where ICU mortality was not influenced by high serum sodium (odds ratio, 1.3 [0.7-1.2]) and was different from other patient groups (P<.01). Any adverse associations with hypernatremia in respiratory patients were confined to those with arterial pressure of oxygen (PaO2)/fraction of inspired oxygen (Fio2) ratios of greater than 200. CONCLUSION: High admission serum sodium is associated with increased odds for ICU death, except in respiratory patients. PMID- 25041995 TI - Identification of metabolites of gardenin A in rats by combination of high performance liquid chromatography with linear ion trap-Orbitrap mass spectrometer based on multiple data processing techniques. AB - Gardenin A is one of the less abundant hydroxylated polymethoxyflavonoids (OH PMFs) in nature, and has many potential significant health benefits. In the present study, an efficient strategy was established using high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer to profile the in vivo metabolic fate of gardenin A in rat plasma and various tissues. First, an online LC-MS(n) data acquisition method was developed to trace all the probable metabolites. Second, a combination of offline data processing methods including extracted ion chromatography and multiple mass defect filters was employed to screen the common and uncommon metabolites from the background noise and endogenous components. Finally, structures of the metabolites were elucidated based on an accurate mass measurement, the diagnostic product ions of PMFs, and relevant drug biotransformation knowledge. Based on the proposed strategy, a total of 26 metabolites were observed and characterized. The results indicate that some biotransformations, such as methylation, demethoxylation, demethylation, glucuronide conjugation, sulfate conjugation and their composite reactions, have been discovered for OH-PMFs. Moreover, some diagnostic biotransformation pathways are summarized. Overall, this study gives us a first insight into the in vivo metabolism of gardenin A. The study also provides a practical strategy for rapidly screening and identifying metabolites, which can be widely applied for the other biotransformations. PMID- 25041994 TI - Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304). AB - BACKGROUND: Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS: The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS: There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06). CONCLUSIONS: Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU. PMID- 25041996 TI - Identification and analysis of the salt tolerant property of AHL lactonase (AiiATSAWB ) of Bacillus species. AB - Bacterial biofilms communicate by a process called Quorum Sensing. Gram negative bacterial pathogens specifically talk through the production, detection, and response to the signal or autoinducer called Acyl Homoserine Lactones. Bacterial lactonases are important AHL hydrolysing or quorum quenching enzymes. The present study deals with ten endospore forming gram positive isolates of the saltern soil. Preliminary screening for Quorum Quenching activity with the QS Inhibition indicator strain Chromobacterium violaceum ATCC 12472, showed positive activity in four isolates namely TS2, TS16, TSAWB, and TS53B. AHL lactonase (AiiA) specific primers amplified Acyl Homoserine Lactone lactonase gene in the TSAWB genome alone. Phylogenetic relationship of the identified AiiATSAWB confirmed its evolutionary relationship with bacterial AiiA like AHL lactonase of the metallo beta-lactamase super family. Our in vitro AHL hydrolysis assay under wide percentage (0-5) of salt solutions with TSAWB isolate and also its intracellular soluble protein fraction showed halotolerant AHL hydrolysis ability of the AiiATSAWB enzyme. In silico determination of putative tertiary structure, the ESBRI derived conserved salt bridges, aminoacid residue characterization with high mole percent of acidic and hydrophobic residues reaffirmed the halotolerant ability of the enzyme. So we propound the future use of purified AiiATSAWB , as hypertonic suspension for inhalation to substitute the action of inactivated host's paraoxonase in treating Pseudomonas aeruginosa infection in cystic fibrosis patients. PMID- 25041997 TI - Design and validation of a 3D virtual reality desktop system for sonographic length and volume measurements in early pregnancy evaluation. AB - PURPOSE: To design and validate a desktop virtual reality (VR) system, for presentation and assessment of volumetric data, based on commercially off-the shelf hardware as an alternative to a fully immersive CAVE-like I-Space VR system. METHODS: We designed a desktop VR system, using a three-dimensional (3D) monitor and a six degrees-of-freedom tracking system. A personal computer uses the V-Scope (Erasmus MC, Rotterdam, The Netherlands) volume-rendering application, developed for the I-Space, to create a hologram of volumetric data. Inter- and intraobserver reliability for crown-rump length and embryonic volume measurements are investigated using Bland-Altman plots and intraclass correlation coefficients. Time required for the measurements was recorded. RESULTS: Comparing the I-Space and the desktop VR system, the mean difference for crown-rump length is -0.34% (limits of agreement -2.58-1.89, +/-2.24%) and for embryonic volume 0.92% (limits of agreement -6.97-5.13, +/-6.05%). Intra- and interobserver intraclass correlation coefficients of the desktop VR system were all >0.99. Measurement times were longer on the desktop VR system compared with the I-Space, but the differences were not statistically significant. CONCLUSIONS: A user friendly desktop VR system can be put together using commercially off-the-shelf hardware at an acceptable price. This system provides a valid and reliable method for embryonic length and volume measurements and can be used in clinical practice. PMID- 25041998 TI - Suppression in mice of immunosurveillance against PEGylated liposomes by encapsulated doxorubicin. AB - PEGylated liposomes (PEG-lip) can escape from recognition by immune system and show a longer half-life in the blood than non-PEGylated liposomes. In this study, we investigated the influence of injected PEG-lip encapsulating doxorubicin (PEG lip-DOX) on the biodistribution of subsequently injected PEG-lip in mice. PEG-lip DOX, free doxorubicin or empty PEG-lip were initially injected into BALB/c mice via a tail vein, and 3days later [(3)H]-labeled PEG-lip ([(3)H] PEG-lip) were injected into these same mice. At 24h after the injection, the distribution of [(3)H] PEG-lip in the liver and spleen was significantly reduced in the PEG-lip DOX group compared with that in the free doxorubicin or PEG-lip group. Consequently, the plasma concentration of [(3)H] PEG-lip was significantly elevated by the pretreatment with PEG-lip-DOX. Altered pharmacokinetics was observed at least until 72h after the injection of [(3)H] PEG-lip. The influence of the injected PEG-lip-DOX on the pharmacokinetics of the subsequently injected [(3)H] PEG-lip was clearly observed from 1 to 14days, and slightly observed on days 21 and 28, after the injection of the PEG-lip-DOX. Flow cytometric analysis showed that the number of liver Kupffer cells was significantly reduced after the treatment with PEG-lip-DOX. On the other hand, a similar alteration in the distribution of the subsequently injected [(3)H] PEG-lip was observed in immunodeficient mice such as BALB/c nu/nu and severe combined immunodeficiency (SCID) mice. These findings suggest that immune cells including liver Kupffer cells responsible for recognizing PEG-lip were selectively damaged by the encapsulated doxorubicin in PEG-lip injected initially, which damage led to prolongation of the half-life of subsequently injected [(3)H] PEG-lip in the blood. PMID- 25041999 TI - sTRAIL coupled to liposomes improves its pharmacokinetic profile and overcomes neuroblastoma tumour resistance in combination with Bortezomib. AB - Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer cell specific molecule exerting remarkable anti-tumour activities against paediatric malignancies both in vitro and in preclinical settings. However, due to its too fast elimination and to the undesired related side effects, the improvement of sTRAIL in vivo bioavailability and the specific delivery to the tumour is mandatory for increasing its therapeutic efficacy. In this manuscript, we developed an innovative pegylated liposomal formulation carrying the sTRAIL at the outer surface (sTRAIL-SL) with the intent to improve its serum half-life and increase its efficacy in vivo, while reducing side effects. Furthermore, the possibility to combine sTRAIL-SL with the proteasome inhibitor Bortezomib (BTZ) was investigated, being BTZ able to sensitize tumour cells toward TRAIL-induced apoptosis. We demonstrated that sTRAIL preserved and improved its anti-tumour activity when coupled to nanocarriers. Moreover, sTRAIL-SL ameliorated its PK profile in blood allowing sTRAIL to exert a more potent anti-tumour activity, which led, upon BTZ priming, to a statistically significant enhanced life spans in two models of sTRAIL-resistant NB-bearing mice. Finally, mechanistic studies indicated that the combination of sTRAIL with BTZ sensitized sTRAIL-resistant NB tumour cells to sTRAIL-induced cell death, both in vitro and in vivo, through the Akt/GSK3/beta-catenin axis-dependent mechanism. In conclusion, our results suggest that sTRAIL-SL might be an efficient vehicle for sTRAIL delivery and that its use in clinic, in combination with BTZ, might represent an adjuvant strategy for the treatment of stage IV, sTRAIL-resistant, NB patients. PMID- 25042000 TI - Electrospun tecophilic/gelatin nanofibers with potential for small diameter blood vessel tissue engineering. AB - Tissue engineering techniques particularly using electrospun scaffolds have been intensively used in recent years for the development of small diameter vascular grafts. However, the development of a completely successful scaffold that fulfills multiple requirements to guarantee complete vascular regeneration remains challenging. In this study, a hydrophilic and compliant polyurethane namely Tecophilic (TP) blended with gelatin (gel) at a weight ratio of 70:30 (TP(70)/gel(30)) was electrospun to fabricate a tubular composite scaffold with biomechanical properties closely simulating those of native blood vessels. Hydrophilic properties of the composite scaffold induced non-thrombogenicity while the incorporation of gelatin molecules within the scaffold greatly improved the capacity of the scaffold to serve as an adhesive substrate for vascular smooth muscle cells (SMCs), in comparison to pure TP. Preservation of the contractile phenotype of SMCs seeded on electrospun TP(70)/gel(30) was yet another promising feature of this scaffold. The nanostructured TP(70)/gel(30) demonstrated potential feasibility toward functioning as a vascular graft. PMID- 25042001 TI - GMCSF-armed vaccinia virus induces an antitumor immune response. AB - Oncolytic Western Reserve strain vaccinia virus selective for epidermal growth factor receptor pathway mutations and tumor-associated hypermetabolism was armed with human granulocyte-macrophage colony-stimulating factor (GMCSF) and a tdTomato fluorophore. As the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we used immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semipermissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene-carrying viruses was similar to unarmed virus. The hGMCSF-encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific antitumor immunity was also shown by ex vivo co-culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF-virus-treated tumors. These findings help clarify the mechanism of action of GMCSF-armed vaccinia viruses undergoing clinical trials. PMID- 25042002 TI - The clinical spectrum of isolated peripheral motor dysfunction. AB - INTRODUCTION: Isolated peripheral motor dysfunction due to lower motor neuron or peripheral nerve disorders presents an interesting challenge to clinicians because of the diverse differential diagnosis with a broad range of prognoses. METHODS: We retrospectively reviewed clinical data of adults who presented over 12 years with muscle weakness, atrophy, or fasciculations, but without hyperreflexia or sensory involvement. RESULTS: In 119 patients, 52% had a motor neuron disease (MND), 13% had immune neuropathies, 11% had genetic neuronopathies, 10% had residual or post-polio syndrome, 5% had benign fasciculation, 1% had an infectious etiology, and 8% were not given a final diagnosis. Only MND patients had cognitive dysfunction or frontal release signs. Bulbar and respiratory symptoms virtually excluded consideration of immune neuropathy. CONCLUSIONS: Only half of the patients were diagnosed with MND. A significant minority have treatable conditions. Cognitive involvement, frontal release signs, and bulbar or respiratory symptoms are strongly suggestive of MND. PMID- 25042003 TI - In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc). AB - To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4 dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 MUM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 MUM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between beta2 and alpha2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc). PMID- 25042004 TI - Probing homodimer formation of epidermal growth factor receptor by selective crosslinking. AB - Ligand binding promotes conformational rearrangement of the epidermal growth factor receptor (EGFR) leading to receptor autophosphorylation and downstream signaling. However, transient interactions between unstimulated EGFR molecules on the cell surface are not fully understood. In this report, we describe the investigation of homodimer formation of EGFR by means of an SNAP-tag based selective crosslinking approach (S-CROSS). EGFR homodimers were selectively captured in living cells and utilized for analysis of protein receptor interactions on the plasma membrane and ligand-induced activation. We showed that EGFR forms homodimers in unstimulated cells with efficiencies similar to those seen in cells treated with the epidermal growth factor ligand (EGF) supporting the existence of constitutive transient receptor-receptor interactions. EGFR crosslinked homodimers displayed a substantially increase in kinase activation upon ligand stimulation. Interestingly, in unstimulated cells the levels of spontaneous phosphorylation were found to correlate with the yields of the crosslinked homodimers species. In addition, we demonstrated that this crosslinking approach can be applied to interrogate the effect of small molecule inhibitors on receptor dimerization and kinase activity. Our crosslinking assay provides a new tool to dissect ligand-independent dimerization and activation mechanisms of receptor tyrosine kinases, many of which are important anticancer drug targets. PMID- 25042005 TI - Deoxyribonuclease inhibitors. AB - Deoxyribonucleases (DNases) are a class of enzymes able to catalyze DNA hydrolysis. DNases play important roles in cell function, while DNase inhibitors control or modify their activities. This review focuses on DNase inhibitors. Some DNase inhibitors have been isolated from various natural sources, such as humans, animals (beef, calf, rabbit and rat), plants (Nicotiana tabacum), and microorganisms (some Streptomyces and Adenovirus species, Micromonospora echinospora and Escherichia coli), while others have been obtained by chemical synthesis. They differ in chemical structure (various proteins, nucleotides, anthracycline and aminoglycoside antibiotics, synthetic organic and inorganic compounds) and mechanism of action (forming complexes with DNases or DNA). Some of the inhibitors are specific toward only one type of DNase, while others are active towards two or more. Physico-chemical properties of DNase inhibitors are calculated using the Molinspiration tool and most of them meet all criteria for good solubility and permeability. DNase inhibitors may be used as pharmaceuticals for preventing, monitoring and treating various diseases. PMID- 25042006 TI - Nanoscale investigation on Pseudomonas aeruginosa biofilm formed on porous silicon using atomic force microscopy. AB - Colonization of surfaces by bacterial cells results in the formation of biofilms. There is a need to study the factors that are important for formation of biofilms since biofilms have been implicated in the failure of semiconductor devices and implants. In the present study, the adhesion force of biofilms (formed by Pseudomonas aeruginosa) on porous silicon substrates of varying surface roughness was quantified using atomic force microscopy (AFM). The experiments were carried out to quantify the effect of surface roughness on the adhesion force of biofilm. The results show that the adhesion force increased from 1.5 +/- 0.5 to 13.2 +/- 0.9 nN with increase in the surface roughness of silicon substrate. The results suggest that the adhesion force of biofilm is affected by surface roughness of substrate. PMID- 25042007 TI - Highly sensitive gas sensor by the LaAlO3 /SrTiO3 heterostructure with Pd nanoparticle surface modulation. AB - The palladium nanoparticle (Pd NP)-decorated LaAlO3 /SrTiO3 (LAO/STO) heterostructure is for the first time used as a hydrogen-gas sensor with very high sensitivity and workability at room temperature. The outstanding gas-sensing properties are due to the Pd NPs' catalytic effect to different gases, resulting in charge coupling between the gas molecules and the two-dimensional electron gas (2DEG) through the Pd NPs by either a direct charge exchange or a change of the electron affinity. These results provide insight into the emerging properties at LAO/STO interfaces. PMID- 25042008 TI - Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T cell immunity associated with control of viral load. AB - Efforts aimed at restoring robust immune responses limiting human immunodeficiency virus (HIV)-1 replication therapeutically are warranted. We report that vaccination with dendritic cells generated ex vivo and loaded with HIV lipopeptides in patients (n = 19) on antiretroviral therapy was well tolerated and immunogenic. Vaccination increased: (i) the breadth of the immune response from 1 (1-3) to 4 (2-5) peptide-pool responses/patient (p = 0.009); (ii) the frequency of functional T cells (producing at least two cytokines among IFN gamma, TNF-alpha, and IL-2) from 0.026 to 0.32% (p = 0.002) and from 0.26 to 0.35% (p = 0.005) for CD4(+) and CD8(+) T cells, respectively; and (iii) the breadth of cytokines secreted by PBMCs upon antigen exposure, including IL-2, IFN gamma, IL-21, IL-17, and IL-13. Fifty percent of patients experienced a maximum of viral load (VL) 1 log10 lower than the other half following antiretroviral treatment interruption. An inverse correlation was found between the maximum of VL and the frequency of polyfunctional CD4(+) T cells (p = 0.007), production of IL-2 (p = 0.006), IFN-gamma (p = 0.01), IL-21 (p = 0.006), and IL-13 (p = 0.001). These results suggest an association between vaccine responses and a better control of viral replication. These findings will help in the development of strategies for a functional cure for HIV infection. PMID- 25042009 TI - Injury prevention among friends: the benefits of school connectedness. AB - Unsafe road behaviors, violence and alcohol use, are primary contributors to adolescent injury. Research suggests that adolescents look out for their friends and engage in protective behavior to reduce others' risk-taking and that school connectedness is associated with reduced injury-risks. This study examined the role of school connectedness in willingness to protect and prevent friends from involvement in alcohol use, fights and unlicensed driving. Surveys were completed at two time points, six months apart, by 545 13-14 year olds from seven Australian high schools. Females were significantly more likely than males to report willingness to protect their friends. School connectedness significantly and positively predicted willingness to protect across all three injury-risk behaviors, after accounting for sex and own involvement in injury-risk behaviors. School connectedness may therefore be an important factor to target in school based prevention programs, both to reduce adolescents' own injury-risk behavior and to increase injury prevention among friends. PMID- 25042010 TI - In-gel equilibration for improved protein retention in 2DE-based proteomic workflows. AB - The 2DE is a powerful proteomic technique, with excellent protein separation capabilities where intact proteins are spatially separated by pI and molecular weight. 2DE is commonly used in conjunction with MS to identify proteins of interest. Current 2DE workflow requires several manual processing steps that can lead to experimental variability and sample loss. One such step is the transition between first dimension IEF and second-dimension SDS-PAGE, which requires exchanging denaturants and the reduction and alkylation of proteins. This in solution-based equilibration step has been shown to be rather inefficient, losing up to 30% of the original starting material through diffusion effects. We have developed a refinement of this equilibration step using agarose stacking gels poured on top of the second-dimension SDS-PAGE gel, referred to as in-gel equilibration. We show that in-gel equilibration is effective at reduction and alkylation in SDS-PAGE gels. Quantification of whole-cell extracts separated on 2DE gels shows that in-gel equilibration increases protein retention, decreased intergel variability, and simplifies 2DE workflow. PMID- 25042013 TI - A new class of homogeneous visible-light photocatalysts: molecular cerium vanadium oxide clusters. AB - The first systematic access to molecular cerium vanadium oxides is presented. A family of structurally related, di-cerium-functionalized vanadium oxide clusters and their use as visible-light-driven photooxidation catalysts is reported. Comparative analyses show that photocatalytic activity is controlled by the cluster architecture. Increased photoreactivity of the cerium vanadium oxides in the visible range compared with nonfunctionalized vanadates is observed. Based on the recent discovery of the first molecular cerium vanadate cluster, (nBu4 N)2 [(Ce(dmso)3 )2 V12 O33 Cl]?2 DMSO (1), two new di-cerium-containing vanadium oxide clusters [(Ce(dmso)4 )2 V11 O30 Cl]?DMSO (2) and [(Ce(nmp)4 )2 V12 O32 Cl]?NMP?Me2 CO (3; NMP=N-methyl-2-pyrrolidone) were obtained by using a novel fragmentation and reassembly route. Pentagonal building units {(V)M5 } (M=V, Ce) reminiscent of "Muller-type" pentagons are observed in 2 and 3. Compounds 1-3 feature high visible-light photooxidative activity, and quantum efficiencies >10 % for indigo photooxidation are observed. Photocatalytic performance increases in the order 1<3<2. Mechanistic studies show that the irradiation wavelength and the presence of oxygen strongly affect photoreactivity. Initial findings suggest that the photooxidation mechanism proceeds by intermediate formation of hydroxyl radicals. The findings open new avenues for the bottom-up design of sunlight driven photocatalysts. PMID- 25042015 TI - Silylative coupling versus metathesis--efficient methods for the synthesis of difunctionalized double-decker silsesquioxane derivatives. AB - A series of functionalized dialkenylsilsesquioxanes were obtained by efficient and highly stereoselective silylative coupling and cross-metathesis of divinylsubstituted double-decker silsesquioxanes (DDSQ-2SiVi) with substituted styrenes and other olefins. Both reactions proceed highly stereoselectively and lead to nearly quantitative formation of E isomers. The optimized reaction conditions for styrene were adopted for successful silylative coupling polycondensation of DDSQ-2SiVi with 1,4-divinylbenzene yielding stereoregular cooligomer containing double-decker (silsesquioxyl-silylene)-vinylene-phenylene units. PMID- 25042014 TI - Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation induced cognitive damage. AB - In our previous studies, we found that a single ultralow dose of tetrahydrocannabinol (THC; 0.002 mg/kg, three to four orders of magnitude lower than the conventional doses) protects the brain from different insults that cause cognitive deficits. Because various insults may trigger a neuroinflammatory response that leads to secondary damage to the brain, the current study tested whether this extremely low dose of THC could protect the brain from inflammation induced cognitive deficits. Mice received a single injection of THC (0.002 mg/kg) 48 hr before or 1-7 days after treatment with lipopolysccharide (LPS; 10 mg/kg) and were examined with the object recognition test 3 weeks later. LPS caused long lasting cognitive deficits, whereas the application of THC before or after LPS protected the mice from this LPS-induced damage. The protective effect of THC was blocked by the cannabinoid (CB) 1 receptor antagonist SR14176A but not by the CB2 receptor antagonist SR141528 and was mimicked by the CB1 agonist ACEA but not by the CB2 agonist HU308. The protective effect of THC was also blocked by pretreatment with GW9662, indicating the involvement of peroxisome proliferator activated receptor-gamma. Biochemical examination of the brain revealed a long term (at least 7 weeks) elevation of the prostaglandin-producing enzyme cyclooxygenase-2 in the hippocampus and in the frontal cortex following the injection of LPS. Pretreatment with the extremely low dose of THC tended to attenuate this elevation. Our results suggest that an ultralow dose of THC that lacks any psychotrophic activity protects the brain from neuroinflammation induced cognitive damage and might be used as an effective drug for the treatment of neuroinflammatory conditions, including neurodegenerative diseases. PMID- 25042016 TI - Sub acute gastric residuals elimination change project. AB - PURPOSE: The practice of checking gastric residual volumes (GRV) for patients receiving enteral tube feedings has long been a tradition in nursing based on the concern that large residuals would increase the risk of aspiration and pneumonia. However, a review of the literature suggests that the practice of checking GRV is not a reliable method for assessing risk for aspiration. We conducted a study in our adult Sub Acute Unit to determine whether it was necessary to continue routine monitoring of GRV. METHOD: A retrospective chart review was conducted that included 15 patients who had received G-tube enteral feedings as their primary source of nutrition for a period of 1 year. FINDINGS: Over 10,000 GRV were reviewed, with no instance of aspiration or pneumonia found. CONCLUSIONS AND CLINICAL RELEVANCE: This resulted in the decision to change our facility's policy, eliminating routine GRV checks, saving over 3 hours of nursing time per patient, per week with no deleterious effects. PMID- 25042017 TI - [Topical anesthesia in flexible nasofibrolaryngoscopy]. AB - INTRODUCTION: The emergence of flexible nasofibrolaryngoscopy in recent decades has facilitated the development of Otolaryngology and the nasofibrolaryngoscope has become an essential diagnostic tool for the otolaryngologist. However, its use is not without discomfort for the patient, which is why various options for topical anaesthesia have been proposed during the development of the technique. MATERIAL AND METHODS: This was a prospective, double blind, crossover study in patients with no history of nasal disease, through which we compared the use of topical anaesthetic (Lidocaine) + epinephrine, oxymetazoline and placebo. Using a visual analogue scale, the degree of discomfort was assessed during each scan. RESULTS: We evaluated 18 patients, 10 women (55.6%) and 8 men (44.4%), with a mean age of 28+/-4 years. The degree of disturbance generated by the scan with the application of lidocaine-epinephrine was 1.94; with oxymetazoline it was 3.78, and with placebo, 4.61. When the lidocaine-epinephrine solution was compared with oxymetazoline, there was a statistical significance in favour of lidocaine-epinephrine (P<0.05). When we compared the use of lidocaine-epinephrine with the placebo, the result was also statistically significant in favour of lidocaine-epinephrine (P<0.05). CONCLUSIONS: In this study we demonstrated that using lidocaine associated with epinephrine as a topical anaesthetic prior to flexible nasofibrolaryngoscopy decreases pain and feeling of discomfort for the patient. Consequently, we can recommend the use of topical nasal anaesthesia when performing this exploration. PMID- 25042019 TI - Understanding long-term unmet needs in Australian survivors of stroke. AB - BACKGROUND: Limited data exist on the long-term needs of community-dwelling stroke survivors. We aimed to describe factors associated with the extent to which needs were met in Australian survivors of stroke. METHOD: Multifaceted strategies were used to obtain a national sample. Adults 12+ months poststroke and living in the community participated. Needs were assessed over the domains of health, everyday living, work, leisure, social support, and finances. Multivariable negative-binomial and logistic regression were used. RESULTS: Seven hundred sixty-five survivors completed surveys. Most (84%) reported having needs that were not being fully met (median 4 of 20, Q1, Q3: 1, 9). Variations occurred based on age, residential location, time since stroke, and disability level. Multivariable results showed that having fatigue, cognition or emotional problems, decreasing age, and increased disability were associated with increasing numbers of needs not being fully met (P < 0.001). Factors associated with needs not being fully met were as follows: (1) greater disability (adjusted odds ratio: 3.4, 95% confidence interval: 1.9, 6.0) and fatigue problems (adjusted odds ratio: 2.0, 95% confidence interval: 1.1, 3.4) (health domain); (2) greater disability (adjusted odds ratio: 7.0, 95% confidence interval: 3.0, 17.0) and being one to two-years poststroke (adjusted odds ratio: 3.4, 95% confidence interval: 1.5, 7.8) (work domain); and (3) increased disability (adjusted odds ratio: 3.8, 95% confidence interval: 2.2, 6.5) and memory problems (adjusted odds ratio: 2.1, 95% confidence interval: 1.0, 4.2) (leisure domain). CONCLUSION: The extent to which long-term needs were met was influenced by a variety of factors, particularly age, disability levels, and residential location. Changes need to be made to the way and extent to which survivors are supported following stroke. PMID- 25042018 TI - Silent cerebral infarction, income, and grade retention among students with sickle cell anemia. AB - Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia. PMID- 25042020 TI - Switching of single-molecule magnetic properties of TbIII -porphyrin double decker complexes and observation of their supramolecular structures on a carbon surface. AB - Double-decker complexes based on single-molecule magnets (SMMs) are a class of highly promising molecules for applications in molecular spintronics, wherein control of both the ligand oxidative states and the 2D supramolecular structure on carbon materials is of great importance. This study focuses on the synthesis and study of 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP)-Tb(III) double-decker complexes with different electronic structures comprising protonated, anionic, and radical forms. Magnetic susceptibility measurements revealed that only the anionic and radical forms of the OEP-Tb(III) double-decker complexes exhibited SMM properties. The barrier heights for magnetic moment reversal were estimated to be 207 and 215 cm(-1) for the anionic and radical forms, respectively. Scanning tunneling microscopy (STM) investigations revealed that these OEP Tb(III) complexes form well-ordered monolayers upon simple dropcasting from dilute dichloromethane solutions. All three complexes form an isomorphic pseudo hexagonal 2D pattern, regardless of the differences in the electronic structures of their porphyrin-Tb cores. This finding is of interest for SMM technology as ultrathin films of these materials undergoing chemical transformations will not require any detrimental reorganization. Finally, we demonstrate self-assembly of the protonated 5,15-bisdodecylporphyrin (BDP)-Tb(III) double-decker complex as an example of successful supramolecular design to achieve controlled alignment of SMM-active sites. PMID- 25042021 TI - Effect of the addition of soy flour on sensory quality of extrusion and conventionally cooked cassava complementary porridges. AB - BACKGROUND: The sensory properties of the usual conventionally cooked cassava porridge consumed in some regions of Africa and porridges consisting of composited cassava and either defatted or full fat soy flour, with or without extrusion cooking, were evaluated to better understand consumers' acceptance. The composited and extruded porridges have superior nutritional quality and added convenience value in the case of extrusion cooked products. RESULTS: Extrusion cooking allowed preparation of porridges with 25% solids content (compared with 10% for conventional cooking) with a viscosity suitable for consumption by infants. Compositing and extrusion cooking reduced the apparent negative sensory attributes of high viscosity, stickiness, translucency, jelly-like appearance and bland flavour that characterise conventionally cooked cassava porridge while increasing slimy appearance of the porridge. The caramel aroma and overall flavour of all extrusion cooked porridges was more intense, with more toasted nutty flavour and aftertaste compared to the corresponding conventionally cooked porridges. Slightly more consumers preferred the conventionally cooked cassava soy flour porridges. CONCLUSIONS: Compositing cassava flour with full-fat or defatted soy flour and extrusion cooking change the appearance and flavour of porridges while improving the textural properties for better mastication and swallowing by infants. Hedonic adjustment to the changed sensory properties of the porridges in comparison to what mothers and caregivers are used to (conventionally cooked cassava only porridges) is required to ensure acceptance. PMID- 25042022 TI - Effect of environmental exposure to cigarette smoke on blood pressure in 24-hour ambulatory blood pressure monitoring in patients with essential hypertension. AB - INTRODUCTION: A relationship between environmental exposure to cigarette smoke and blood pressure has not been well-established. OBJECTIVES: The aim of the study was to evaluate the effects of environmental exposure to cigarette smoke on blood pressure (BP) in patients with essential hypertension. PATIENTS AND METHODS: The study involved 39 nonsmoking patients with essential hypertension treated with hypotensive agents and environmentally exposed to cigarette smoke (group 1) and 39 nonsmoking patients with essential hypertension treated with hypotensive agents and not exposed to cigarette smoke (group 2). The following variables of 24-hour ambulatory BP monitoring (ABPM) were measured: systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) during 24-hour ABPM, and, separately, for the period of daily activity and night rest. RESULTS: In group 1, the mean values of 24-hour SBP, DBP, MAP, and PP, daytime SBP, DBP, MAP, and PP, and nighttime SBP, MAP, and PP were significantly higher than those in group 2. Statistically significant positive linear correlations were demonstrated between the mean time of daily exposure (expressed in hours) to cigarette smoke and 24-hour MAP and PP (r = 0.52 and r = 0.48, respectively, P <0.05). Advanced age, higher low-density lipoprotein cholesterol and glucose concentrations, and environmental exposure to cigarette smoke were independent factors of elevated 24-hour PP in the study group. CONCLUSIONS: In patients with essential hypertension, environmental exposure to cigarette smoke may result in elevated BP values in 24-hour ABPM. PMID- 25042023 TI - Redox divergent synthesis of fawcettimine-type Lycopodium alkaloids. AB - A new approach for synthesis of fawcettimine-type Lycopodium alkaloids is described. A divergent strategy was achieved by applying stereoselective Diels Alder reaction followed by redox-controlled elaboration. Eventually, (-)-8 deoxyserratinine, (+)-fawcettimine, (-)-lycopoclavamine-A, (-)-serratine, (-) lycopoclavamine-B and (-)-serratanidine were successfully accessed. PMID- 25042024 TI - Laser speckle contrast imaging of Raynaud phenomenon. PMID- 25042025 TI - Nucleic acids and smart materials: advanced building blocks for logic systems. AB - Logic gates can convert input signals into a defined output signal, which is the fundamental basis of computing. Inspired by molecular switching from one state to another under an external stimulus, molecular logic gates are explored extensively and recognized as an alternative to traditional silicon-based computing. Among various building blocks of molecular logic gates, nucleic acid attracts special attention owing to its specific recognition abilities and structural features. Functional materials with unique physical and chemical properties offer significant advantages and are used in many fields. The integration of nucleic acids and functional materials is expected to bring about several new phenomena. In this Progress Report, recent progress in the construction of logic gates by combining the properties of a range of smart materials with nucleic acids is introduced. According to the structural characteristics and composition, functional materials are categorized into three classes: polymers, noble-metal nanomaterials, and inorganic nanomaterials. Furthermore, the unsolved problems and future challenges in the construction of logic gates are discussed. It is hoped that broader interests in introducing new smart materials into the field are inspired and tangible applications for these constructs are found. PMID- 25042026 TI - Rituximab and intermediate-purity plasma-derived factor VIII concentrate (Koate(r)) as adjuncts to therapeutic plasma exchange for thrombotic thrombocytopenic purpura in patients with an ADAMTS13 inhibitor. AB - Thrombotic thrombocytopenic purpura (TTP) results from a congenital or acquired deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13. The disease can be fatal and hence treatment should be initiated promptly. Therapeutic plasma exchange (TPE) remains the standard treatment along with adjunct therapies including steroids and immunosuppressive drugs. Addition of rituximab to TPE has been shown to be beneficial in refractory/relapsing TTP; however, TPE results in removal of rituximab from the circulation requiring more frequent dosing of rituximab to achieve a favorable outcome. The intermediate purity plasma-derived Factor VIII concentrate (FVIII) Koate(r) contains the highest amount of ADAMTS13 activity yet reported and has been used successfully in treating congenital TTP. Here we report our experience with addition of this FVIII concentrate to rituximab, corticosteroids and TPE in three TTP patients with an ADAMTS13 inhibitor to permit withholding TPE for 48 h after rituximab infusion. PMID- 25042027 TI - Central hydrogen sulphide mediates ventilatory responses to hypercapnia in adult conscious rats. AB - AIM: Hydrogen sulphide (H2S) is endogenously produced and plays an important role as a modulator of neuronal functions; however, its modulatory role in the central CO2 chemoreception is unknown. The aim of the present study was to assess the role of endogenously produced H2S in the ventilatory response to hypercapnia in adult conscious rats. METHODS: Cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) inhibitors (aminooxyacetate: AOA and propargylglycine: PAG respectively) and a H2S donor (sodium sulphide: Na2S) were microinjected into the fourth ventricle (4V). Ventilation (V(E)), oxygen consumption (VO2) and body temperature were recorded before (room air) and during a 30-min CO2 exposure (hypercapnia, 7% CO2). Endogenous H2S levels were measured in the nucleus tractus solitarius (NTS). RESULTS: Microinjection of Na2S (H2S donor), AOA (CBS inhibitor) or PAG (CSE inhibitor) did not affect baseline of the measured variables compared to control group (vehicle). In all experimental groups, hypercapnia elicited an increase in V(E). However, AOA microinjection, but not PAG, attenuated the ventilatory response to hypercapnia (P < 0.05), whereas Na2S elicited a slight, not significant, enhancement. Moreover, endogenous H2S levels were found higher in the NTS after hypercapnia (P < 0.05) compared to room air (normoxia) condition. CONCLUSION: There are a few reports on the role of gaseous transmitters in the control of breathing. Importantly, the present data suggest that endogenous H2S via the CBS-H2S pathway mediates the ventilatory response to hypercapnia playing an excitatory role. PMID- 25042028 TI - Outcome of kidney transplants for adults with hemolytic uremic syndrome in the U.S.: a ten-year database analysis. AB - BACKGROUND: There is currently no large study of the U.S. transplant registry comparing the outcome of kidney transplantation for adults with and without hemolytic uremic syndrome (HUS). To date, information on the outcome of transplants for HUS in the U.S. is derived from single or combined-centers studies, but none has been of a nationwide scope. MATERIAL AND METHODS: We retrospectively studied a US registry for the outcome of 323 kidney transplants in adults with HUS and of 121,311 transplants in adults with other renal diseases during the period 1999-2009. We analyzed patient, over-all, and death-censored graft survival in the 5 years following transplantation using Kaplan-Meir curves and Cox hazard models. RESULTS: In the 5 years following kidney transplantation, patient mortality was not significantly different [Hazard Ratio (HR) 1.27, 95% Confidence Interval (CI) 0.78-2.08], but death-censored graft loss was twice as common (HR 2.05, 95% CI 1.53-2.73) for allograft recipients whose native kidney disease was HUS compared to other transplant recipients. The subgroup (n=40 cases) with post-transplant HUS recurrence had a 5-year graft loss rate 5 times that of the subgroup (n=283 cases) without HUS-recurrence (graft survival 14.7% vs.77.4%, log rank 116.5; p<0.001). CONCLUSIONS: In the largest US series to date of kidney transplants for adults with HUS, 5-year patient survival was not different, but graft outcome was inferior in recipients whose native renal disease were HUS compared to recipients with other kidney diseases. Native kidney HUS is associated with a 2-fold increased risk of death-censored graft loss after kidney transplantation. PMID- 25042029 TI - Indoor air characterization of various microenvironments in the Arctic. The case of Tromso, Norway. AB - The present pilot study monitored for the first time volatile organic compounds (VOCs) and aerosols in domestic and occupational microenvironments in the Arctic Region. Differences between the two categories of samples are noted with domestic environments exhibiting higher concentrations of VOCs (total VOCs ranging between 106 and 584 MUg m(-3)), while total particulate matter was highest in workplace non-office environments (ranging between 132 and 284 MUg m(-3)). The terpenes were the most abundant class of VOCs, while a variety of other compounds exhibited 100% frequency of occurrence (i.e. naphthalene, D5-volatile methyl siloxane). Compared to results from other studies/regions, the concentrations of VOCs are considered as relatively low. Based on the results and the knowledge of the typical characteristics of the Arctic lifestyle, some important sources are identified. As this is the first study that deals with indoor air quality in the coldest region globally, it is expected that it will trigger the interest of Authorities to proceed to more detailed studies. PMID- 25042030 TI - Commentary on nephropathy and longitudinal studies of diabetes, and dioxins, furans, and dioxin-like PCBs. PMID- 25042031 TI - Evaluation of carbon nanotubes network toxicity in zebrafish (Danio rerio) model. AB - This is a detailed in vivo study of the biological response to carbon nanotubes network as probed by the zebrafish model. First, we prepared pristine carbon nanotubes (CNTs) by methanol chemical vapor deposition in the presence of Mn and Co as catalysts, followed by purification in acid, which furnished curved tubes with diameters lying between 10 and 130 nm. The CNT network consisted of pristine CNTs dispersed in water in the presence of a surfactant. The CNT network pellets corresponded to agglomerated multi-walled CNTs with an average diameter of about 500 nm. Although the same pristine CNTs had been previously found to exert genotoxic effects in vitro, here we verified that the CNT network was not genotoxic in vivo. Indeed, Raman spectroscopy and microscopy conducted in the intestine of the zebrafish revealed complete clearance of the CNT network as well as minimal disturbances, such as aneurysms, hyperemia, and reversible inflammatory focus in the zebrafish gills. PMID- 25042033 TI - Investigating the spill-over hypothesis: analysis of the association between local inflammatory markers in sputum and systemic inflammatory mediators in plasma. AB - Exposure to air pollutants represents a risk factor not only for respiratory diseases and lung cancer, but also for cardiometabolic diseases. It has been hypothesised that local inflammation in the lung and systemic subclinical inflammation are linked by impaired lung function and the spill-over of proinflammatory factors from the lung into the circulation which could act as intermediaries between environmental exposures and disease risk. We wanted to investigate whether local and systemic inflammatory markers are associated, which would support the spill-over hypothesis. Sputum and plasma samples were obtained from 257 women of the German SALIA cohort. We performed immunoassays to measure multiple biomarkers of airway inflammation in sputum as well as cytokines, chemokines and soluble adhesion molecules in plasma. Correlations were calculated and adjusted for potentially confounding variables. Even though several significant associations were detected between inflammatory mediators in sputum and plasma, correlation coefficients were rather low ranging from r>=-0.20 to r<=0.20. Comparatively stronger associations were observed between nitrite, eosinophil cationic protein, leukotrienes C/D/E4 and interleukin-8 in sputum. Notably, correlations were positive with all proinflammatory biomarkers and interleukin-1 receptor antagonist in plasma, whereas negative correlations were observed with the anti-inflammatory adipokine adiponectin. In conclusion, local inflammation in the lung and systemic subclinical inflammation appear mainly independently regulated in elderly women from the general population. Although we found multiple significant correlations between inflammatory biomarkers in sputum and plasma, our results do not provide clear support for the spill-over hypothesis. PMID- 25042034 TI - Low serum zinc is associated with elevated risk of cadmium nephrotoxicity. AB - BACKGROUND: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available. OBJECTIVE: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium mediated renal dysfunction in humans. METHODS: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011-2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m(2) and/or the urinary albumin to-creatinine ratio surpassed 2.5 in men and 3.5mg/mmol in women. RESULTS: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 MUg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09-4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13-3.69) than their low cadmium (<0.18 MUg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39-8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01). CONCLUSIONS: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity. PMID- 25042032 TI - Growth in Inuit children exposed to polychlorinated biphenyls and lead during fetal development and childhood. AB - BACKGROUND: Because of their geographical location and traditional lifestyle, Canadian Inuit children are highly exposed to polychlorinated biphenyls (PCBs) and lead (Pb), environmental contaminants that are thought to affect fetal and child growth. We examined the associations of these exposures with the fetal and postnatal growth of Inuit children. METHODS: We conducted a prospective cohort study among Inuit from Nunavik (Arctic Quebec). Mothers were recruited at their first prenatal visit; children (n=290) were evaluated at birth and at 8-14 years of age. Concentrations of PCB 153 and Pb were determined in umbilical cord and child blood. Weight, height and head circumference were measured at birth and during childhood. RESULTS: Cord blood PCB 153 concentrations were not associated with anthropometric measurements at birth or school age, but child blood PCB 153 concentrations were associated with reduced weight, height and head circumference during childhood. There was no association between cord Pb levels and anthropometric outcomes at birth, but cord blood Pb was related to smaller height and shows a tendency of a smaller head circumference during childhood. INTERPRETATION: Our results suggest that chronic exposure to PCBs during childhood is negatively associated with skeletal growth and weight, while prenatal Pb exposure is related to reduced growth during childhood. This study is the first to link prenatal Pb exposure to poorer growth in school-age children. PMID- 25042035 TI - Genotoxic and mutagenic potential of nitramines. AB - Climate change is one of the major challenges in the world today. To reduce the amount of CO2 released into the atmosphere, CO2 at major sources, such as power plants, can be captured. Use of aqueous amine solutions is one of the most promising methods for this purpose. However, concerns have been raised regarding its impacts on human health and the environment due to the degradation products, such as nitrosamines and nitramines that may be produced during the CO2 capture process. While several toxicity studies have been performed investigating nitrosamines, little is known about the toxic potential of nitramines. In this study a preliminary screening was performed of the genotoxic and mutagenic potential of nitramines most likely produced during amine based CO2 capture; dimethylnitramine (DMA-NO2), methylnitramine (MA-NO2), ethanolnitramine (MEA NO2), 2-methyl-2-(nitramino)-1-propanol (AMP-NO2) and piperazine nitramine (PZ NO2), by the Bacterial Reverse Mutation (Ames) Test, the Cytokinesis Block Micronucleus (CBMN) Assay and the in vitro Single-Cell Gel Electrophoresis (Comet) Assay. MA-NO2 and MEA-NO2 showed mutagenic potential in the Ames test and a weak genotoxic response in the CBMN Assay. AMP-NO2 and PZ-NO2 significantly increased the amount of DNA strand breaks; however, the level of breaks was below background. Most previous studies on nitramines have been performed on DMA-NO2, which in this study appeared to be the least potent nitramine. Our results indicate that it is important to investigate other nitramines that are more likely to be produced during CO2 capture, to ensure that the risk is realistically evaluated. PMID- 25042037 TI - Ni(II)-Schiff base complex as an enzyme inhibitor of hen egg white lysozyme: a crystallographic and spectroscopic study. AB - The engineering of protein-small molecule interactions becomes imperative today to recognize the essential biochemical processes in living systems. Here we have investigated the interaction between hen egg white lysozyme (HEWL) and a newly synthesized small, simple nickel Schiff base complex (NSC) {(N(1)E,N(2)E) N(1),N(2)-bis(pyridine-2-ylmethylene)propane-1,2-diaminenickel(II)} using different spectroscopic techniques. We attempted to determine the exact site of the interaction by crystallography. Absorption spectroscopy reveals that the interaction occurs through the ground state. The complex can quench the intrinsic fluorescence of HEWL through a static quenching method. The fluorescence quenching study along with the determination of thermodynamic parameters reveal that NSC binds HEWL spontaneously with moderate binding affinity. The results have also identified that the spontaneity of this enthalpy guided interaction is mainly governed by some H-bonding and hydrophobic interactions which are also indicated by the crystallographic analyses. Moreover, the crystallographic study shows that NSC makes its way into the active site enzyme cavity of HEWL forming a single covalent adduct between Ni(2+) and the oxygen of the active site Asp 52. The possibility of inhibiting the catalytic activity of HEWL by inclusion of NSC in the enzyme active site observed from crystallographic analyses has also been confirmed by enzyme kinetics experiments. PMID- 25042036 TI - Noninvasive molecular fingerprinting of host-microbiome interactions in neonates. AB - The early postnatal period is a critical window for intestinal and immune maturation. Intestinal development and microbiome diversity and composition differ between breast- (BF) and formula-fed (FF) infants. Mechanistic examination into host-microbe relationships in healthy infants has been hindered by ethical constraints surrounding tissue biopsies. Thus, a statistically rigorous analytical framework to simultaneously examine both host and microbial responses to dietary/environmental factors using exfoliated intestinal epithelial cells was developed. Differential expression of ~1200 genes, including genes regulating intestinal proliferation, differentiation and barrier function, was observed between BF and FF term infants. Canonical correlation analysis uncovered a relationship between microbiome virulence genes and host immunity and defense genes. Lastly, exfoliated cells from preterm and term infants were compared. Pathways associated with immune cell function and inflammation were up-regulated in preterm, whereas cell growth-related genes were up-regulated in the term infants. Thus, coordinate measurement of the transcriptomes of exfoliated epithelial cells and microbiome allows inquiry into mutualistic host-microbe interactions in the infant, which can be used to prospectively study gut development or, retrospectively, to identify potential triggers of disease in banked samples. PMID- 25042038 TI - Telestroke a viable option to improve stroke care in India. AB - In India, stroke care services are not well developed. There is a need to explore alternative options to tackle the rising burden of stroke. Telemedicine has been used by the Indian Space Research Organization (ISRO) to meet the needs of remote hospitals in India. The telemedicine network implemented by ISRO in 2001 presently stretches to around 100 hospitals all over the country, with 78 remote/rural/district health centers connected to 22 specialty hospitals in major cities, thus providing treatment to more than 25 000 patients, which includes stroke patients. Telemedicine is currently used in India for diagnosing stroke patients, subtyping stroke as ischemic or hemorrhagic, and treating accordingly. However, a dedicated telestroke system for providing acute stroke care is needed. Keeping in mind India's flourishing technology sector and leading communication networks, the hub-and-spoke model could work out really well in the upcoming years. Until then, simpler alternatives like smartphones, online data transfer, and new mobile applications like WhatsApp could be used. Telestroke facilities could increase the pool of patients eligible for thrombolysis. But this primary aim of telestroke can be achieved in India only if thrombolysis and imaging techniques are made available at all levels of health care. PMID- 25042039 TI - Purkinje cell loss in essential tremor. PMID- 25042040 TI - The same answer using a simpler method: diagnosis in dysferlin muscle disease. PMID- 25042041 TI - Ultra-sensitive optical oxygen sensors for characterization of nearly anoxic systems. AB - Oxygen quantification in trace amounts is essential in many fields of science and technology. Optical oxygen sensors proved invaluable tools for oxygen measurements in a broad concentration range, but until now neither optical nor electrochemical oxygen sensors were able to quantify oxygen in the sub-nanomolar concentration range. Herein we present new optical oxygen-sensing materials with unmatched sensitivity. They rely on the combination of ultra-long decaying (several 100 ms lifetime) phosphorescent boron- and aluminium-chelates, and highly oxygen-permeable and chemically stable perfluorinated polymers. The sensitivity of the new sensors is improved up to 20-fold compared with state-of the-art analogues. The limits of detection are as low as 5 p.p.b., volume in gas phase under atmospheric pressure or 7 pM in solution. The sensors enable completely new applications for monitoring of oxygen in previously inaccessible concentration ranges. PMID- 25042042 TI - vanI: a novel D-Ala-D-Lac vancomycin resistance gene cluster found in Desulfitobacterium hafniense. AB - The glycopeptide vancomycin was until recently considered a drug of last resort against Gram-positive bacteria. Increasing numbers of bacteria, however, are found to carry genes that confer resistance to this antibiotic. So far, 10 different vancomycin resistance clusters have been described. A chromosomal vancomycin resistance gene cluster was previously described for the anaerobic Desulfitobacterium hafniense Y51. We demonstrate that this gene cluster, characterized by its d-Ala-d-Lac ligase-encoding vanI gene, is present in all strains of D. hafniense, D. chlororespirans and some strains of Desulfosporosinus spp. This gene cluster was not found in vancomycin-sensitive Desulfitobacterium or Desulfosporosinus spp., and we show that this antibiotic resistance can be exploited as an intrinsic selection marker for Desulfitobacterium hafniense and D. chlororespirans. The gene cluster containing vanI is phylogenetically only distantly related with those described from soil and gut bacteria, but clusters instead with vancomycin resistance genes found within the phylum Actinobacteria that include several vancomycin-producing bacteria. It lacks a vanH homologue, encoding a D-lactate dehydrogenase, previously thought to always be present within vancomycin resistance gene clusters. The location of vanH outside the resistance gene cluster likely hinders horizontal gene transfer. Hence, the vancomycin resistance cluster in D. hafniense should be regarded a novel one that we here designated vanI after its unique d-Ala-d-Lac ligase. PMID- 25042043 TI - Recent advances in capillary electrochromatography using molecularly imprinted polymers. AB - There is an increased and continuous need for developing new methods for the separation and quantification of an increasing number of analytes in the environmental, pharmaceutical, pharmacological, and toxicological sciences. CEC is still withholding its popularity, representing a viable alternative to the more conventional techniques (HPLC, GC) due to the numerous advantages, such as, low sample/reagent volumes, high separation efficiencies, hybrid separation principle, etc. One particular promising direction in CEC is the use of molecularly imprinted polymers (MIPs) as stationary phases. They are usually immobilized in the capillary column as a continuous polymeric monolith or as a thin polymer coating attached to the capillary's inner wall. Another emerging trend is the use of MIPs in the form of nanoparticles as a pseudostationary phase. This review discusses the recent developments (2011-2013) in finding the optimal polymerization mixture and the suitable MIP format that should be employed in CEC separations. The most important applications of MIPs in CEC technique are also highlighted. PMID- 25042044 TI - Restoration of the central slip in congenital form of boutonniere deformity: case report. AB - We present a case of a congenital form of a boutonniere deformity involving both little fingers with a poorly differentiated extensor mechanism and the absence of the tendinous attachment on the dorsal aspect of the middle phalanx. This complex deformity was evaluated histologically followed by successful reconstruction of the central slip. PMID- 25042045 TI - The clinical anatomy of the inferior vena cava: a review of common congenital anomalies and considerations for clinicians. AB - Anomalies in the course and drainage of the Inferior Vena Cava (IVC) may complicate normal functioning, correct diagnosis, and therapeutic interventions within the abdomen. Development of the IVC occurs during the 4th to 8th week of gestation, and due to its developmental complexity, there are many opportunities for malformations to occur. Although most IVC anomalies are clinically silent and are usually discovered incidentally on abdominal imaging, aberrations may be responsible for formation of thrombosis, back pain, and anomalous circulation of blood to the heart. In this review, we will discuss the most common variations and abnormalities of the IVC, which include the posterior cardinal veins, the subcardinal veins, the supracardinal veins, persistent left IVC, IVC duplication, situs inversus, left retroaortic renal vein, left circumaortic renal collar, scimitar syndrome, and IVC agenesis. For each abnormality outlined above, we aim to discuss relevant embryology and potential clinical significance with regards to presentation, diagnosis, and treatment as is important for radiologists, surgeons, and clinicians in current clinical practice. PMID- 25042046 TI - Effects of supplementation with dietary green tea polyphenols on parasite resistance and acute phase protein response to Haemonchus contortus infection in lambs. AB - The objective of this study was to determine the effects of supplementation with dietary green tea polyphenols (GTPs) on parasite resistance and acute phase protein (APP) response to Haemonchus contortus infection in lambs. Thirty male Ujumqin lambs were randomly assigned to five treatment groups for an 8-week feeding period. Treatments included: (1) uninfected as control, (2) infected but not given GTP (INFGTP0) and (3)-(5) infected and fed 2, 4, or 6g GTP/kg feed (dry matter basis; INFGTP2, INFGTP4, and INFGTP6, respectively). Fecal and blood samples were collected to determine fecal egg count (FEC), packed cell volume (PCV), and APP concentrations. Live weight was measured once every 2 weeks. At the end of the feeding period, lambs were slaughtered to determine the adult H. contortus burden. The results demonstrated interaction effects between treatment and sampling time on the average daily gain (ADG; P=0.0005), FEC (P<0.0001), PCV (P=0.0005), and concentrations of serum amyloid A (SAA), haptoglobin (Hp), lipopolysaccharide binding protein (LBP), and alpha1-acid glycoprotein (alpha1AGP) (P<0.0001). From days 0 to 56, the ADG values for all infected lambs were lower than that of uninfected lambs, but the ADG values for all GTP-fed lambs were higher than that of INFGTP0 lambs, especially from days 28 to 42. The FECs of all GTP-fed lambs were higher than those of uninfected lambs but lower than that of INFGTP0 lambs. The PCVs of all infected lambs were lower than those of uninfected lambs, but PCV increased with increasing amounts of GTP supplementation. Furthermore, supplementation with different concentrations of GTP significantly reduced the numbers of adult H. contortus, including both males and females (P<0.0001), and the H. contortus burden in INFGTP6 lambs was reduced to uninfected levels. Overall, the SAA, Hp, LBP, and alpha1AGP concentrations of all infected lambs were higher than those of uninfected lambs from days 0 to 56. Two peaks in expression were observed from days 0 to 3 and at day 28, and APP concentrations of all GTP-fed lambs were lower than those of INFGTP0 lambs, except for SAA in INFGTP6 lambs. In conclusion, quantitative measurements of APP responses to H. contortus infection provide valuable diagnostic information for monitoring infection progression and treatment responses in lambs. An appropriate dose of dietary GTP supplementation can increase host resistance by reducing H. contortus burden and weight loss and suppressing blood APP expression. PMID- 25042047 TI - A degradation study of cefepime hydrochloride in solutions under various stress conditions by TLC-densitometry. AB - A rapid, accurate and sensitive thin-layer chromatography (TLC) method with densitometric detection has been developed and validated for the determination of cefepime in pharmaceuticals. Chromatographic separation was achieved on a silica gel TLC F254 plates with a mobile phase consisting of ethanol-2-propanol-glacial acetic acid 99.5%-water (4:4:1:3, v/v). Densitometric detection was carried out at wavelength of 266 nm in reflectance/absorbance mode. The validation of the method was found to be satisfactory with high accuracy (from 99.24 to 101.37%) and precision (RSD from 0.06 to 0.36%). Additionally, the stability of cefepime in solution was investigated, including the effect of pH, temperature and incubation time. Favorable retention parameters (Rf , Rs, alpha) were obtained under the developed conditions, which guaranteed good separation of the studied components. The degradation process of cefepime hydrochloride was described by kinetic and thermodynamic parameters (k, t0.1 , t0.5 and Ea ). Moreover, the chemical properties of degradation products were characterized by the Rf values, absorption spectra, HPLC-MS/MS and TLC-densitometry analysis. As the method could effectively separate the active substance from its main degradation product (1 methylpyrrolidine), it can be employed as a method to indicate the stability of this drug. PMID- 25042048 TI - Modeling enzymatic hydrolysis of lignocellulosic substrates using fluorescent confocal microscopy II: pretreated biomass. AB - In this study, we extend imaging and modeling work that was done in Part I of this report for a pure cellulose substrate (filter paper) to more industrially relevant substrates (untreated and pretreated hardwood and switchgrass). Using confocal fluorescence microscopy, we are able to track both the structure of the biomass particle via its autofluorescence, and bound enzyme from a commercial cellulase cocktail supplemented with a small fraction of fluorescently labeled Trichoderma reseii Cel7A. Imaging was performed throughout hydrolysis at temperatures relevant to industrial processing (50 degrees C). Enzyme bound predominantly to areas with low autofluorescence, where structure loss and lignin removal had occurred during pretreatment; this confirms the importance of these processes for successful hydrolysis. The overall shape of both untreated and pretreated hardwood and switchgrass particles showed little change during enzymatic hydrolysis beyond a drop in autofluorescence intensity. The permanence of shape along with a relatively constant bound enzyme signal throughout hydrolysis was similar to observations previously made for filter paper, and was consistent with a modeling geometry of a hollowing out cylinder with widening pores represented as infinite slits. Modeling estimates of available surface areas for pretreated biomass were consistent with previously reported experimental results. PMID- 25042049 TI - Risk prediction of hepatocellular carcinoma in patients with cirrhosis: the ADRESS-HCC risk model. AB - BACKGROUND: All patients with cirrhosis are at risk of developing hepatocellular carcinoma (HCC). This risk is not uniform because other patient-related factors influence the risk of HCC. The objective of the current study was to develop an HCC risk prediction model to estimate the 1-year probability of HCC to assist with patient counseling. METHODS: Between 2002 and 2011, a cohort of 34,932 patients with cirrhosis was identified from a national liver transplantation waitlist database from the United States. Cox proportional hazards regression methods were used to develop and validate a risk prediction model for incident HCC. In the validation cohort, discrimination and calibration of the model was examined. External validation was conducted using patients with cirrhosis who were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study. RESULTS: HCC developed in 1960 patients (5.6%) during a median follow-up of 1.3 years (interquartile range, 0.47 years-2.83 years). Six baseline clinical variables, including age, diabetes, race, etiology of cirrhosis, sex, and severity (ADRESS) of liver dysfunction were independently associated with HCC and were used to develop the ADRESS-HCC risk model. C-indices in the derivation and internal validation cohorts were 0.704 and 0.691, respectively. In the validation cohort, the predicted cumulative incidence of HCC by the ADRESS-HCC model closely matched the observed data. In patients with cirrhosis in the HALT-C cohort, the model stratified patients correctly according to the risk of developing HCC within 5 years. CONCLUSIONS: The ADRESS-HCC risk model is a useful tool for predicting the 1-year risk of HCC among patients with cirrhosis. PMID- 25042051 TI - Professionalizing midwifery: exploring medically imagined labor rooms in rural Rajasthan. AB - In India, globalized flows of biomedical discourse like evidence-based delivery practices (EBDs) and new technologies are reshaping the field of reproductive health care. As iterations of evidence-based medicine shift, non-governmental organizations (NGOs) increasingly act as distributive agents for biomedical projects that equate modernized health care spaces and provider-care techniques with a marked improvement in the safety of birth outcomes. In this article, I examine how particular local iterations of EBDs are distributed to skilled birth attendants (SBAs) who have become sites for globalized projects aimed at reshaping their professional designation. I draw on data collected through in depth ethnographic interviews with SBAs practicing in health centers around southern Rajasthan to explore the dynamics and tensions surrounding the professionalization of midwives and the increasing promotion of EBDs in institutional labor rooms. PMID- 25042050 TI - A brief overview of amyloids and Alzheimer's disease. AB - Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with a number of presently incurable diseases such as Alzheimer's and Parkinson's disease. Millions of people worldwide suffer from amyloid diseases. This review summarizes the unique cross-beta structure of amyloid fibrils, morphological variations, the kinetics of amyloid fibril formation, and the cytotoxic effects of these fibrils and oligomers. Alzheimer's disease is also explored as an example of an amyloid disease to show the various approaches to treat these amyloid diseases. Finally, this review investigates the nanotechnological and biological applications of amyloid fibrils; as well as a summary of the typical biological pathways involved in the disposal of amyloid fibrils and their precursors. PMID- 25042052 TI - Risk of breast cancer following fertility treatment--a registry based cohort study of parous women in Norway. AB - Despite increasing numbers of women availing themselves of assisted reproductive technology (ART), effects on cancer risk remain unresolved. Given hormonal exposures, breast cancer risk is of particular concern. The aim of this study is to investigate breast cancer risk amongst women giving birth following ART as compared to that amongst women who gave birth without ART. Data on all women who gave birth in Norway with or without ART, between 1984 and 2010 were obtained from the Medical Birth Registry of Norway (MBRN). 808,834 women eligible for study were linked to the Cancer Registry of Norway. Cox proportional models computed hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer between the two groups, adjusting for age, parity, age at first birth, calendar period and region of residence. In total, 8,037 women were diagnosed with breast cancer during the study period, 138 ART women and 7,899 unexposed. Total follow up time was 12,401,121 person-years (median 16.0); median age at entry was 32.5 years (range 18.6-49.9) for ART women and 26.3 (range 10.5-54.6) for unexposed. Women exposed to ART had an elevated risk of breast cancer (adjusted HR 1.20, 95% CI 1.01-1.42). Subgroup analyses gave an HR of 1.30 (95% CI 1.07-1.57) for women treated with IVF and 1.35 (95 % CI 1.07-1.71) for women with follow-up >10 years, compared with controls. Our findings of increased risk in the study population warrant continued monitoring of women treated with ART as this population advances into more typical cancer age ranges. PMID- 25042053 TI - Origin of giant viruses from smaller DNA viruses not from a fourth domain of cellular life. AB - The numerous and diverse eukaryotic viruses with large double-stranded DNA genomes that at least partially reproduce in the cytoplasm of infected cells apparently evolved from a single virus ancestor. This major group of viruses is known as Nucleocytoplasmic Large DNA Viruses (NCLDV) or the proposed order Megavirales. Among the "Megavirales", there are three groups of giant viruses with genomes exceeding 500kb, namely Mimiviruses, Pithoviruses, and Pandoraviruses that hold the current record of viral genome size, about 2.5Mb. Phylogenetic analysis of conserved, ancestral NLCDV genes clearly shows that these three groups of giant viruses have three distinct origins within the "Megavirales". The Mimiviruses constitute a distinct family that is distantly related to Phycodnaviridae, Pandoraviruses originate from a common ancestor with Coccolithoviruses within the Phycodnaviridae family, and Pithoviruses are related to Iridoviridae and Marseilleviridae. Maximum likelihood reconstruction of gene gain and loss events during the evolution of the "Megavirales" indicates that each group of giant viruses evolved from viruses with substantially smaller and simpler gene repertoires. Initial phylogenetic analysis of universal genes, such as translation system components, encoded by some giant viruses, in particular Mimiviruses, has led to the hypothesis that giant viruses descend from a fourth, probably extinct domain of cellular life. The results of our comprehensive phylogenomic analysis of giant viruses refute the fourth domain hypothesis and instead indicate that the universal genes have been independently acquired by different giant viruses from their eukaryotic hosts. PMID- 25042055 TI - Encapsulation of antigen-loaded silica nanoparticles into microparticles for intradermal powder injection. AB - Epidermal powder immunisation (EPI) is being investigated as a promising needle free delivery methods for vaccination. The objective of this work was to prepare a nanoparticles-in-microparticles (nano-in-micro) system, integrating the advantages of nanoparticles and microparticles into one vaccine delivery system for epidermal powder immunisation. Cationic mesoporous silica nanoparticles (MSNP NH2) were prepared and loaded with ovalbumin as a model antigen. Loading was driven by electrostatic interactions. Ovalbumin-loaded silica nanoparticles were subsequently formulated into sugar-based microparticles by spray-freeze-drying. The obtained microparticles meet the size requirement for EPI. Confocal microscopy was used to demonstrate that the nanoparticles are homogeneously distributed in the microparticles. Furthermore, the silica nanoparticles in the dry microparticles can be re-dispersed in aqueous solution showing no aggregation. The recovered ovalbumin shows integrity compared to native ovalbumin. The present nano-in-micro system allows (1) nanoparticles to be immobilized and finely distributed in microparticles, (2) microparticle formation and (3) re-dispersion of nanoparticles without subsequent aggregation. The nanoparticles inside microparticles can (1) adsorb proteins to cationic shell/surface voids in spray-dried products without detriment to ovalbumin stability, (2) deliver antigens in nano-sized modes to allow recognition by the immune system. PMID- 25042056 TI - UV-cured, platinum-free, soft poly(dimethylsiloxane) networks. AB - To overcome the drawbacks exhibited by platinum-catalyzed curing of silicones, photoinitiated thiol-ene cross-linking of high-molecular-weight poly(dimethylsiloxane) (PDMS) prepolymers has been investigated as a pathway to novel soft PDMS networks, based on commercially available starting materials was developed. Through a fast and efficient two-step cross-linking reaction highly flexible PDMS elastomers were prepared. PMID- 25042054 TI - Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. AB - The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+ M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We evaluated the ability of WFA+-M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+-M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA+-M2BP, and the response to interferon (IFN) therapy. Serum WFA+-M2BP levels were significantly increased according to the progression of liver fibrosis stage (P<0.001). In each distinctive stage of fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+-M2BP. Multivariate analysis identified age>57 years, F4, AFP>20 ng/mL, WFA+-M2BP >=4, and WFA+-M2BP 1-4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time-dependent areas under the receiver operating characteristic curve demonstrated that the WFA+-M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP. CONCLUSION: WFA+-M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy. PMID- 25042057 TI - Thermolysin damages animal life through degradation of plasma proteins enhanced by rapid cleavage of serpins and activation of proteases. AB - Thermolysin, a metallopeptidase secreted by pathogenic microbes, is concluded as an important virulence factor due to cleaving purified host proteins in vitro. Using the silkworm Bombyx mori as a model system, we found that thermolysin injection into larvae induces the destruction of the coagulation response and the activation of hemolymph melanization, which results in larval death. Thermolysin triggers the rapid degradation of insect and mammalian plasma proteins at a level that is considerably greater than expected in vitro and/or in vivo. To more specifically explore the mechanism, thermolysin-induced changes to key proteins belonging to the insect melanization pathway were assessed as a window for observing plasma protein cleavage. The application of thermolysin induced the rapid cleavage of the melanization negative regulator serpin-3, but did not directly activate the melanization rate-limiting enzyme prophenoloxidase (PPO) or the terminal serine proteases responsible for PPO activation. Terminal serine proteases of melanization are activated indirectly after thermolysin exposure. We hypothesize that thermolysin induces the rapid degradation of serpins and the activation of proteases directly or indirectly, boosting uncontrolled plasma protein degradation in insects and mammalians. PMID- 25042058 TI - Synthesis of prenyl- and geranyl-substituted carbazole alkaloids by DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a]carbazoles. AB - The DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2 a]carbazoles provides a direct access to a broad range of prenyl- and geranyl substituted carbazoles. Formation of a pyran ring followed by reductive ring opening represents a new method for the introduction of prenyl and geranyl groups. In the course of the present work, we achieved the first total syntheses of the following eight carbazole alkaloids: clauraila-E, 7-hydroxyheptaphylline, 7-methoxyheptaphylline, mukoenine-B (clausenatine-A), mukoenine-A (girinimbilol), mahanimbinol (mahanimbilol), euchrestine-A, and isomurrayafoline-B. PMID- 25042060 TI - Abstracts of the 44th Annual Meeting of the International Continence Society (ICS) 20-24 October, 2014, Rio de Janeiro, Brazil. PMID- 25042059 TI - Estimating heritability of drug-induced liver injury from common variants and implications for future study designs. AB - Recent genome-wide association studies identified certain human leukocyote antigen (HLA) alleles as the major risk factors of drug-induced liver injuries (DILI). While these alleles often cause large relative risk, their predictive values are quite low due to low prevalence of idiosyncratic DILI. Finding additional risk factors is important for precision medicine. However, optimal design of further genetic studies is hindered by uncertain overall heritability of DILI. This is a common problem for low-prevalence pharmacological traits, since it is difficult to obtain clinical outcome data in families. Here we estimated the heritability (h(2)) of DILI from case-control genome-wide single nucleotide polymorphism data using a method based on random effect models. We estimated the proportion of h(2) captured by common SNPs for DILI to be between 0.3 and 0.5. For co-amoxiclav induced DILI, chromosome 6 explained part of the heritability, indicating additional contributions from common variants yet to be found. We performed simulations to assess the robustness of the h(2) estimate with limited sample size under low prevelance, a condition typical to studies on idiosyncratic pharmacological traits. Our findings suggest that common variants outside of HLA contribute to DILI susceptability; therefore, it is valuable to conduct further GWAS with expanded case collection. PMID- 25042061 TI - Direct trifluoromethylthiolation of alcohols under mild reaction conditions: conversion of R-OH into R-SCF3. AB - A direct process for the trifluoromethylthiolation of allylic and benzylic alcohols under mild conditions has been developed. A wide range of free alcohols underwent nucleophilic substitution in the presence of stable CuSCF3 and BF3 ?Et2O to give the corresponding products in good to excellent yields. PMID- 25042062 TI - Does the CT improve inter- and intra-observer agreement for the AO, Fernandez and Universal classification systems for distal radius fractures? AB - INTRODUCTION: Distal radius fractures are very common upper limb injuries irrespective of the patient's age. The aim of our study is to evaluate the reliability of the three systems that are often used for their classification (AO - Arbeitsgemeinschaft fur Osteosynthesefragen/Association for the Study of Internal Fixation, Fernandez and Universal) and to assess the need for computed tomography (CT) scan to improve inter- and intra-observer agreement. MATERIALS AND METHODS: Five orthopaedic surgeons and two hand surgeons classified radiographs and CT scans of 26 patients using the Fernandez, AO and Universal systems. All data were recorded using MS Excel and Kappa statistics were performed to determine inter- and intra-observer agreement and to evaluate the role of CT scan. RESULTS: Fair-to-moderate inter-observer agreement was noted with the use of X-rays for all classification systems. Intra-observer reproducibility did not improve with the addition of CT scans, especially for the senior hand surgeons. CONCLUSIONS: The agreement rates observed in the present study show that currently there is no classification system that is fully reproducible. Adequate experience is required for the assessment and treatment of these injuries. CT scan should be requested only by experienced hand surgeons in order to help guide treatment, as it does not significantly improve inter- and intra-observer agreement for all classification systems. PMID- 25042063 TI - A clinical evaluation of alternative fixation techniques for medial malleolus fractures. AB - BACKGROUND: Medial malleolus fractures have traditionally been managed using partially threaded screws and/or Kirschner wire fixation. Using these conventional techniques, a non-union rate of as high as 20% has been reported. In addition too many patients complaining of prominent hardware as a source of pain post-fixation. This study was designed to assess the outcomes of medial malleolar fixation using a headless compression screw in terms of union rate, the need for hardware removal, and pain over the hardware site. SETTING: Saint Louis University and Mercy Medical Center, Level 1 Trauma Centers, St. Louis, MO. METHODS: After IRB approval, we used billing records to identify all patients with ankle fractures involving the medial malleolus. Medical records and radiographs were reviewed to identify patients with medial malleolar fractures treated with headless compression screw fixation. Our inclusion criteria included follow-up until full weight bearing and a healed fracture. Follow-up clinical records and radiographs were reviewed to determine union, complication rate and perception of pain over the site of medial malleolus fixation. Sixty-four ankles were fixed via headless compression screws and 44 had adequate follow-up for additional evaluation. RESULTS: Seven patients had isolated medial malleolar fractures, 23 patients had bimalleolar fractures, and 14 patients had trimalleolar fractures. One patient (2%) required hardware removal due to cellulitis. One patient (2%) had a delayed union, which healed without additional intervention. Ten patients (23%) reported mild discomfort to palpation over the medial malleolus. The median follow-up was 35 weeks (range: 12-208 weeks). There were no screw removals for painful hardware and no cases of non-union. CONCLUSIONS: Headless compression screws provide effective compression of medial malleolus fractures and result in good clinical outcomes. The headless compression screw is a beneficial alternative to the conventional methods of medial malleolus fixation. PMID- 25042064 TI - Results of the 2014 survey of the American Alliance of Academic Chief Residents in Radiology. AB - RATIONALE AND OBJECTIVES: The American Alliance of Academic Chief Residents in Radiology (A3CR2) conducts an annual survey of chief residents in accredited radiology programs in North America. The survey serves as a tool for observing trends and disseminating ideas among radiology programs. MATERIALS AND METHODS: An online survey conducted through the SurveyMonkey Web site was distributed to chief residents from 187 Accreditation Council on Graduate Medical Education (ACGME)-accredited radiology training programs. A variety of multiple-choice and free-response questions were designed to gather information about residency program details, benefits, chief resident responsibilities, call, preparations for the recent American Board of Radiology Core Examination, implementation of selectives (mini-fellowships), fellowships, health care economics and the job market, and ACGME milestones. RESULTS: Among those surveyed, 212 unique responses from 136 programs were provided, yielding a 73% response rate. Data were compared to historical data from prior surveys dating back through 2002. CONCLUSIONS: Programs are increasingly providing 24-hour sonographer coverage, full day routine services on weekends, and 24-hour attending radiologist coverage. The new American Board of Radiology examination format and schedule has driven many changes, including when chief residents serve, board preparation and review, and how the final year of residency training is structured. Despite facing many changes, there is slightly more optimism among chief residents regarding their future job prospects. PMID- 25042065 TI - Structure-performance correlations of organic dyes with an electron-deficient diphenylquinoxaline moiety for dye-sensitized solar cells. AB - The high performances of dye-sensitized solar cells (DSSCs) based on seven new dyes are disclosed. Herein, the synthesis and electrochemical and photophysical properties of a series of intentionally designed dipolar organic dyes and their application in DSSCs are reported. The molecular structures of the seven organic dyes are composed of a triphenylamine group as an electron donor, a cyanoacrylic acid as an electron acceptor, and an electron-deficient diphenylquinoxaline moiety integrated in the pi-conjugated spacer between the electron donor and acceptor moieties. The DSSCs based on the dye DJ104 gave the best overall cell performance of 8.06 %; the efficiency of the DSSC based on the standard N719 dye under the same experimental conditions was 8.82 %. The spectral coverage of incident photon-to-electron conversion efficiencies extends to the onset at the near-infrared region due to strong internal charge-transfer transition as well as the effect of electron-deficient diphenylquinoxaline to lower the energy gap in these organic dyes. A combined tetraphenyl segment as a hydrophobic barrier in these organic dyes effectively slows down the charge recombination from TiO2 to the electrolyte and boosts the photovoltage, comparable to their Ru(II) counterparts. Detailed spectroscopic studies have revealed the dye structure-cell performance correlations, to allow future design of efficient light-harvesting organic dyes. PMID- 25042066 TI - The use of dialectical behavior therapy skills training as stand-alone treatment: a systematic review of the treatment outcome literature. AB - OBJECTIVE: Dialectical behavior therapy (DBT) skills training is currently being administered as stand-alone treatment across a variety of clinical settings, serving diverse client populations. However, there is little empirical support for this use. METHOD: In this systematic review, we identified 17 trials employing a treatment that included DBT skills training in the absence of the other DBT modalities. RESULTS: While the literature reviewed provides preliminary evidence of the utility of DBT skills training to address a range of mental health and behavioral problems, methodological limitations of published studies preclude us from drawing strong conclusions about the efficacy of skills training as a stand-alone treatment. CONCLUSION: We present an overview of the implementation of DBT skills training across clinical settings and populations. We found preliminary evidence supporting the use of DBT skills training as a method of addressing a range of behaviors. We provide recommendations for future research. PMID- 25042067 TI - Patients with T+/low NK+ IL-2 receptor gamma chain deficiency have differentially impaired cytokine signaling resulting in severe combined immunodeficiency. AB - X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor gamma-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-45 cells/uL, 23% of samples would have been deferred from testing, resulting in decreased cost, improved efficiency, and reduction in the need for unnecessary testing without a negative impact on clinical care. PMID- 25042071 TI - Exploratory assessment of CD4+ T lymphocytes in brown hares (Lepus europeus) using a cross-reactive anti-rabbit CD4 antibody. AB - In lagomorphs, lymphocyte subset distributions and the importance of CD4(+) T cell levels has so far only been considered in the frame of rabbit disease models. In this study, the first assessment of CD4(+) T lymphocytes in peripheral blood cells in brown hares (Lepus europaeus L., 1758), a further leporid species using a cross-reactive rabbit anti-CD4 antibody in flow cytometry, is presented. In addition, the entire coding region of the hare CD4 gene (1380 bp) coding for a polypeptide of 459 amino acids has been sequenced. Using generalized least squares fitting by maximum likelihood (GLS) test, significantly (p=0.0095) higher CD4(+) T cell frequencies in males than in females and significantly (p=0.0001) higher frequencies for leverets (younger than 2 months of age) than for subadult and adult (older than 7 months of age) individuals were detected. No significant age influence, however, was found for subadult and adult hares. The study is particularly meant to provide a first step in establishing a toolbox for the assessment of the immune response in this leporid species. PMID- 25042072 TI - Physical performance and radiographic and clinical vertebral fractures in older men. AB - In men, the association between poor physical performance and likelihood of incident vertebral fractures is unknown. Using data from the MrOS study (N = 5958), we describe the association between baseline physical performance (walking speed, grip strength, leg power, repeat chair stands, narrow walk [dynamic balance]) and incidence of radiographic and clinical vertebral fractures. At baseline and follow-up an average of 4.6 years later, radiographic vertebral fractures were assessed using semiquantitative (SQ) scoring on lateral thoracic and lumbar radiographs. Logistic regression modeled the association between physical performance and incident radiographic vertebral fractures (change in SQ grade >=1 from baseline to follow-up). Every 4 months after baseline, participants self-reported fractures; clinical vertebral fractures were confirmed by centralized radiologist review of the baseline study radiograph and community acquired spine images. Proportional hazards regression modeled the association between physical performance with incident clinical vertebral fractures. Multivariate models were adjusted for age, bone mineral density (BMD, by dual energy X-ray absorptiometry [DXA]), clinical center, race, smoking, height, weight, history of falls, activity level, and comorbid medical conditions; physical performance was analyzed as quartiles. Of 4332 men with baseline and repeat radiographs, 192 (4.4%) had an incident radiographic vertebral fracture. With the exception of walking speed, poorer performance on repeat chair stands, leg power, narrow walk, and grip strength were each associated in a graded manner with an increased risk of incident radiographic vertebral fracture (p for trend across quartiles <0.001). In addition, men with performance in the worst quartile on three or more exams had an increased risk of radiographic fracture (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.33-2.45) compared with men with better performance on all exams. Clinical vertebral fracture (n =149 of 5813, 2.6%) was not consistently associated with physical performance. We conclude that poorer physical performance is associated with an increased risk of incident radiographic (but not clinical) vertebral fracture in older men. PMID- 25042073 TI - Comparing the effectiveness of metagenomics and metabarcoding for diet analysis of a leaf-feeding monkey (Pygathrix nemaeus). AB - Faecal samples are of great value as a non-invasive means to gather information on the genetics, distribution, demography, diet and parasite infestation of endangered species. Direct shotgun sequencing of faecal DNA could give information on these simultaneously, but this approach is largely untested. Here, we used two faecal samples to characterize the diet of two red-shanked doucs langurs (Pygathrix nemaeus) that were fed known foliage, fruits, vegetables and cereals. Illumina HiSeq produced ~74 and 67 million paired reads for these samples, of which ~ 10,000 (0.014%) and ~ 44,000 (0.066%), respectively, were of chloroplast origin. Sequences were matched against a database of available chloroplast 'barcodes' for angiosperms. The results were compared with 'metabarcoding' using PCR amplification of the P6 loop of trnL. Metagenomics identified seven and nine of the likely 16 diet plants while six and five were identified by metabarcoding. Metabarcoding produced thousands of reads consistent with the known diet, but the barcodes were too short to identify several plant species to genus. Metagenomics utilized multiple, longer barcodes that combined had greater power of identification. However, rare diet items were not recovered. Read numbers for diet species in metagenomic and metabarcoding data were correlated, indicating that both are useful for determining relative sequence abundance. Metagenomic reads were uniformly distributed across the chloroplast genomes; thus, if chloroplast genomes were used as reference, the precision of identifications and species recovery would improve further. Metagenomics also recovered the host mitochondrial genome and numerous intestinal parasite sequences in addition to generating data useful for characterizing the microbiome. PMID- 25042074 TI - DNA damage following pulmonary exposure by instillation to low doses of carbon black (Printex 90) nanoparticles in mice. AB - We previously observed genotoxic effects of carbon black nanoparticles at low doses relative to the Danish Occupational Exposure Limit (3.5 mg/m(3)). Furthermore, DNA damage occurred in broncho-alveolar lavage (BAL) cells in the absence of inflammation, indicating that inflammation is not required for the genotoxic effects of carbon black. In this study, we investigated inflammatory and acute phase response in addition to genotoxic effects occurring following exposure to nanoparticulate carbon black (NPCB) at even lower doses. C57BL/6JBomTac mice were examined 1, 3, and 28 days after a single instillation of 0.67, 2, 6, and 162 ug Printex 90 NPCB and vehicle. Cellular composition and protein concentration was evaluated in BAL fluid as markers of inflammatory response and cell damage. DNA strand breaks in BAL cells, lung, and liver tissue were assessed using the alkaline comet assay. The pulmonary acute phase response was analyzed by Saa3 mRNA real-time quantitative PCR. Instillation of the low doses of NPCB induced a slight neutrophil influx one day after exposure. Pulmonary exposure to small doses of NPCB caused an increase in DNA strand breaks in BAL cells and lung tissue measured using the comet assay. We interpret the increased DNA strand breaks occurring following these low exposure doses of NPCB as DNA damage caused by primary genotoxicity in the absence of substantial inflammation, cell damage, and acute phase response. PMID- 25042075 TI - Polonium-210 in marine mussels (bivalve molluscs) inhabiting the southern coast of India. AB - The present study focused on the determination of the alpha-emitter, (210)Po, in two species of marine mussels (bivalve molluscs) commonly available in the southern coastal region of India. The brown mussel, Perna indica was collected from the west coast and the green mussel, Perna viridis from the east coast. The concentration of (210)Po was related to the allometry (length of shell, wet/dry weight of shell/soft tissue) of the mussels and significant results were found. The study period focused on three seasons namely, pre-monsoon, monsoon and post monsoon for a 1-year period (2010-2011). The results revealed higher activity levels in smaller-sized mussels compared to larger ones. Marked variation in (210)Po activity concentration was noted in the whole-body soft tissues between seasons and sampling site (p < 0.05). The dose rate assessment for mussels was performed using the ERICA Assessment tool. The chronic exposure to mussels due to (210)Po was found to be lesser than the global benchmark dose rate of 10 MUGy h( 1). The effective ingestion dose to adults who intake mussels was estimated to be in the range 5.1-34.9 MUSv y(-1). The measurement contributes to the furthering of knowledge of (210)Po, since no data exist in this region. PMID- 25042076 TI - Radiocesium distribution in sugi (Cryptomeria japonica) in eastern Japan: translocation from needles to pollen. AB - We assessed the radiocesium contamination of sugi (Cryptomeria japonica) forests in eastern Japan from November 2012 to February 2013, including 80 sites in Fukushima and 35 sites in other regions (Tohoku and Kanto-Koshinetsu), by measuring the (137)Cs concentrations in needles of different ages, male flowers, and pollen. Over a wide geographic area, needles that were present at the time of the Fukushima Dai-ichi Nuclear Power Plant accident contained much higher (137)Cs concentrations than needles that emerged after the accident. This result, together with visual analysis of (137)Cs distribution using autoradiography, indicated that some of the (137)Cs derived from direct fallout remained on the surface of the older needles. Since we also detected (137)Cs in younger needles and male flowers, we concluded that (137)Cs was translocated toward the tips of sugi needles. The (137)Cs concentration in male flowers was higher than and positively correlated with that in the currently growing (2012) needles. Also, a positive relationship was observed between the (137)Cs concentration of male flowers and pollen, and they were found to be nearly identical (137)Cs concentration. These results indicate the occurrence of acropetal translocation of (137)Cs from old needles to young needles, male flowers and pollen. However, the results as related to (137)Cs concentration in the needles of three different ages differed from the results of similar studies conducted more than 4 y after the Chernobyl accident. This suggests that, 2 y after the Fukushima Dai-ichi NPP accident, the distribution of (137)Cs in the sugi forests has not yet reached a steady state. PMID- 25042077 TI - When ultrasound-guided catheterization is useless: back to landmarks! PMID- 25042078 TI - Detection of ischemic penumbra using combined perfusion and T2* oxygen challenge imaging. AB - BACKGROUND: Acute ischemic stroke is common and disabling, but there remains a paucity of acute treatment options and available treatment (thrombolysis) is underutilized. Advanced brain imaging, designed to identify viable hypoperfused tissue (penumbra), could target treatment to a wider population. Existing magnetic resonance imaging and computed tomography-based technologies are not widely used pending validation in ongoing clinical trials. T2* oxygen challenge magnetic resonance imaging, by providing a more direct readout of tissue viability, has the potential to identify more patients likely to benefit from thrombolysis - irrespective of time from stroke onset - and patients within and beyond the 4.5 h thrombolysis treatment window who are unlikely to benefit and are at an increased risk of hemorrhage. AIMS: This study employs serial multimodal imaging and voxel-based analysis to develop optimal data processing for T2* oxygen challenge penumbra assessment. Tissue in the ischemic hemisphere is compartmentalized into penumbra, ischemic core, or normal using T2* oxygen challenge (single threshold) or T2* oxygen challenge plus cerebral blood flow (dual threshold) data. Penumbra defined by perfusion imaging/apparent diffusion coefficient mismatch (dual threshold) is included for comparison. METHODS: Permanent middle cerebral artery occlusion was induced in male Sprague-Dawley rats (n = 6) prior to serial multimodal imaging: T2* oxygen challenge, diffusion weighted and perfusion imaging (cerebral blood flow using arterial spin labeling). RESULTS: Across the different methods evaluated, T2* oxygen challenge combined with perfusion imaging most closely predicted 24 h infarct volume. Penumbra volume declined from one to four-hours post-stroke: mean +/- SD, 77 +/- 44 to 49 +/- 37 mm(3) (single T2* oxygen challenge-based threshold); 55 +/- 41 to 37 +/- 12 mm(3) (dual T2* oxygen challenge/cerebral blood flow); 84 +/- 64 to 42 +/- 18 mm(3) (dual cerebral blood flow/apparent diffusion coefficient), as ischemic core grew: 155 +/- 37 to 211 +/- 36 mm(3) (single apparent diffusion coefficient threshold); 178 +/- 56 to 205 +/- 33 mm(3) (dual T2* oxygen challenge/cerebral blood flow); 139 +/- 30 to 168 +/- 38 mm(3) (dual cerebral blood flow/apparent diffusion coefficient). There was evidence of further lesion growth beyond four-hours (T2-defined edema-corrected infarct, 231 +/- 19 mm(3) ). CONCLUSIONS: In conclusion, T2* oxygen challenge combined with perfusion imaging has advantages over alternative magnetic resonance imaging techniques for penumbra detection by providing serial assessment of available penumbra based on tissue viability. PMID- 25042079 TI - Targeted treatment of migrating partial seizures of infancy with quinidine. AB - Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically resistant to treatment. The most common cause is a gain of function mutation in the potassium channel KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate drug for treatment of this condition. We report the case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was correlated with a marked reduction in seizure frequency and improved psychomotor development. PMID- 25042080 TI - Heterobimetallic s-block hydrides by sigma-bond metathesis. AB - Reactions between PhSiH3 and alkali-metal diamidoalkylmagnesiates ([M{N(SiMe3)2}2MgBu], M = Li, Na, K) provide either selective alkyl metathesis or the formation of polyhydride aggregates contingent upon the identity of the Group 1 metal. In the case of [M{N(SiMe3)2}2MgBu], this reactivity results in a structurally unprecedented dodecametallic decahydride cluster species. PMID- 25042081 TI - Fundamentals on new capillaries inspired by photonic crystal fibers as optofluidic separation systems in CE. AB - Two prototypes of microstructured capillaries (MSCs) were designed, manufactured, and used to carry out different experiments. MSC-1 consisted of six holes of ~28 MUm id whereas MSC-2 consisted of 85 holes of ~7.7 MUm id. A fundamental study on the hydrodynamic injection through a commercial CE equipment was conducted. Experimental times to flush specific volumes were approximately three times larger than the theoretical values. Then, the detection of starch was carried out by using the MSCs and conventional capillaries, and the electropherograms were compared on the basis of analytical parameters employed in CE. An improvement in peak asymmetry was obtained for the MSC-1 compared to the conventional capillaries. S/N was one order of magnitude increased with the MSC, improving ten times the sensitivity. Considering this advantage, the separation and detection of nitrostarch was performed as a first application of the MSC-1. Minimal sample amounts of nitrostarch (1.7 MUg) were detected. Results present a real interest in forensics since this substance had not been previously detected through CE, leading to new investigations in the design of new capillaries capable of enhancing CE performance. PMID- 25042082 TI - Commentary to: exercise training decreases fasting insulin levels and improves insulin resistance in children and adolescents. PMID- 25042083 TI - Wear and metallographic analysis of WaveOne and reciproc NiTi instruments before and after three uses in root canals. AB - Reciprocating instruments made from M-wire alloy have been proposed to reduce the risk of fracture. No information is available on the surface alteration after single and multiple uses in root canals. Two reciprocating NiTi instruments were used on extracted teeth up to three times. ESEM/EDS analysis was conducted to determine defects, alterations, and wear features of the apical third of instruments and metallographic analysis was performed on the cross-section of new and used instruments to compare alloy properties. Topography of apical portion was evaluated by AFM before and after uses. Extracted single-rooted teeth were divided into two groups and instrumented according to the manufacturer's recommendations with: (A) WaveOne Primary and (B) Reciproc R25. Each group was divided into three subgroups according to the number of canals instrumented: 1, 2, and 3, respectively. Chi square test was performed to verify homogeneity of defects distribution and GLM to evaluate the differences of RMS at baseline and after use for both groups (alpha level 0.05). No instrument fractured and no spiral distortions were observed under optical microscope even when the number of uses increased. Not significant differences were found for WaveOne and Reciproc. Blades presented a wrapped portion in WaveOne group and a more symmetrical feature in Reciproc group. Metallographic analysis revealed in both groups the presence of twinned martensitic grains with isolated flat austenitic areas. Both instruments demonstrated limited alteration, such as tip deformation and wear. This study confirmed the safe clinical use of both instruments for shaping multi rooted teeth. PMID- 25042084 TI - A reliable multiplex genotyping assay for HCV using a suspension bead array. AB - The genotyping of the hepatitis C virus (HCV) plays an important role in the treatment of HCV because genotype determination has recently been incorporated into the treatment guidelines for HCV infections. Most current genotyping methods are unable to detect mixed genotypes from two or more HCV infections. We therefore developed a multiplex genotyping assay to determine HCV genotypes using a bead array. Synthetic plasmids, genotype panels and standards were used to verify the target-specific primer (TSP) design in the assay, and the results indicated that discrimination efforts using 10 TSPs in a single reaction were extremely successful. Thirty-five specimens were then tested to evaluate the assay performance, and the results were highly consistent with those of direct sequencing, supporting the reliability of the assay. Moreover, the results from samples with mixed HCV genotypes revealed that the method is capable of detecting two different genotypes within a sample. Furthermore, the specificity evaluation results suggested that the assay could correctly identify HCV in HCV/human immunodeficiency virus (HIV) co-infected patients. This genotyping platform enables the simultaneous detection and identification of more than one genotype in a same sample and is able to test 96 samples simultaneously. It could therefore provide a rapid, efficient and reliable method of determining HCV genotypes in the future. PMID- 25042085 TI - Screening the mechanical stability of Escherichia coli biofilms through exposure to external, hydrodynamic shear forces. AB - The desire to attain a deeper understanding of the fundamental aspects governing the mechanical properties of biofilms has become more prominent in recent years. This has largely been due to the realization that these sessile microbial communities often withstand environments where hydrodynamic turbulence and shearing forces are considerable. In the present study, Escherichia coli K-12 was used as a model system to develop a laboratory technique that can be used to quickly screen the mechanical integrity or stability of laboratory cultivated bacterial biofilms when exposed to such external, hydrodynamic shear forces. The screening method utilizes a custom-built, automated water jetting apparatus to generate and precisely apply a pressurized stream of water directly to biofilms cultured in multi-well plates. An optimized set of water jetting parameters was determined to resolve subtle to moderate differences in the mechanical stability of isogenic strains of E. coli K-12 as a function of percent biofilm removal. Mutations in both flagella biosynthesis (fliA) and acetate metabolism (ackA and ackA pta) were shown to impair the mechanical integrity of 24-h biofilms, while a "housekeeping" strain deficient in arginine metabolism (argD) exhibited a mechanical stability profile comparable to the parent strain. PMID- 25042086 TI - Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients. AB - Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion-weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7-22 years; mean, 12 years) and 11 typically developing age-matched participants (age range, 8-23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel-based morphometry, whereas tract-based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral-postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum-localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early-stage white matter motor pathway degeneration within young patients. PMID- 25042087 TI - Increased risk of colorectal neoplasia among family members of patients with colorectal cancer: a population-based study in Utah. AB - BACKGROUND & AIMS: Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis. METHODS: We performed a case-control study of Utah residents, 50-80 years old, who underwent colonoscopy from 1995 through 2009. Index cases (exposed to colonoscopy) were colonoscopy patients with a CRC diagnosis. Age- and sex-matched individuals, unexposed to colonoscopy (controls) were selected to form the comparison groups for determining risk in relatives. Colonoscopy results were linked to cancer and pedigree information from the Utah Population Database to investigate familial aggregation of colorectal neoplasia using Cox regression analysis. RESULTS: Of 126,936 patients who underwent a colonoscopy, 3804 were diagnosed with CRC and defined the index cases. FDRs had an increased risk of CRC (hazard rate ratio [HRR], 1.79; 95% confidence interval [CI],1.59-2.03), as did second-degree relatives (HRR, 1.32; 95% CI, 1.19-1.47) and first cousins (HRR, 1.15; 95% CI, 1.07-1.25), compared with relatives of controls. This risk was greater for FDRs when index patients developed CRC at younger than age 60 years (HRR, 2.11; 95% CI, 1.70-2.63), compared with older than age 60 years (HRR, 1.77; 95% CI, 1.58 1.99). The risk of adenomas (HRR, 1.82; 95% CI, 1.66-2.00) and adenomas with villous histology (HRR, 2.43; 95% CI, 1.96-3.01) also were increased in FDRs. Three percent of CRCs in FDRs would have been missed if the current guidelines, which stratify screening recommendations by the age of the proband, were strictly followed. CONCLUSIONS: FDRs, second-degree relatives, and first cousins of patients who undergo colonoscopy and are found to have CRC have a significant increase in the risk of colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and families. PMID- 25042088 TI - Improving the nutritional quality of charitable meals for homeless and vulnerable adults. A case study of food provision by a food aid organisation in the UK. AB - The prevalence of homelessness in the UK is rising, and demand for food aid through charitable meal services has increased. Charitable services make a substantial contribution to the food and nutrient intake of vulnerable people, and thus offer a platform for dietary improvement. This study examined food provision by a large charitable organisation in a major UK city. It had several objectives: Firstly to quantify nutritional composition of breakfast and lunch meals, secondly to understand factors that influence the composition of menus and meals, and thirdly to determine whether, within the context of these influences, improvements to the menu would be possible and whether these would be acceptable to clients. Mixed methods of ethnography, semi-structured interviews, quantitative nutrient analysis, recipe adaptation and taste tests were employed. The research team worked as volunteers in the organisation for a 3-week period and interviews were held with the kitchen staff. Food choice was recorded for 189 clients at breakfast and 251 clients at lunch over a 5-day period and nutrient content of these meals was estimated. Meals were weighted towards fat and sugar energy. Energy, potassium, calcium, vitamin C, vitamin A, zinc and magnesium content of meals were below Dietary Reference Value (DRV) targets for at least 20% of breakfast and lunch meals. Such inadequacies may be addressed by the addition of simple foods to the breakfast menu and adaptation of lunchtime recipes. Twelve lunchtime dishes were proposed and eight of these were seemingly acceptable to clients in taste testing. Barriers to provision of healthier meals include budget, food donations and acceptability of meals. PMID- 25042089 TI - Lower energy intake following consumption of Hi-oleic and regular peanuts compared with iso-energetic consumption of potato crisps. AB - Snack foods can contribute a high proportion of energy intake to the diet. Peanuts are a snack food rich in unsaturated fatty acids, protein and fibre which have demonstrated satiety effects and may reduce total energy intake, despite their high energy density. This study examined the effects of consuming Hi-oleic (oleic acid ~75% of total fatty acids) peanuts and regular peanuts (oleic acid ~50% and higher in polyunsaturated fatty acids) compared with a high carbohydrate snack (potato crisps) on satiety and subsequent energy intake. Using a triple crossover study design, 24 participants (61 +/- 1 years) consumed iso-energetic amounts (56-84 g) of Hi-oleic or regular peanuts or (60-90 g) potato crisps after an overnight fast. Hunger and satiety were assessed at baseline, 30, 60, 120 and 180 minutes following snack consumption using visual analogue scales, after which a cold buffet meal was freely consumed and energy intake measured. The same snack was consumed on 3 subsequent days with energy intake assessed from dietary records. This protocol was repeated weekly with each snack food. Total energy intake was lower following consumption of Hi-oleic and regular peanuts compared with crisps, both acutely during the buffet meal (-21%; p<.001 and -17%; p< .01) and over the 4 days (-11%; p< .001 and -9%; p< .01). Despite these reductions in energy intake, no differences in perceived satiety were observed. The findings suggest peanuts may be a preferred snack food to include in the diet for maintaining a healthy weight. PMID- 25042090 TI - Sucrose esters increase drug penetration, but do not inhibit p-glycoprotein in caco-2 intestinal epithelial cells. AB - Sucrose fatty acid esters are increasingly used as excipients in pharmaceutical products, but few data are available on their toxicity profile, mode of action, and efficacy on intestinal epithelial models. Three water-soluble sucrose esters, palmitate (P-1695), myristate (M-1695), laurate (D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40, were tested on Caco-2 cells. Caco-2 monolayers formed a good barrier as reflected by high transepithelial resistance and positive immunostaining for junctional proteins claudin-1, ZO-1, and beta-catenin. Sucrose esters in nontoxic concentrations significantly reduced resistance and impedance, and increased permeability for atenolol, fluorescein, vinblastine, and rhodamine 123 in Caco-2 monolayers. No visible opening of the tight junctions was induced by sucrose esters assessed by immunohistochemistry and electron microscopy, but some alterations were seen in the structure of filamentous actin microfilaments. Sucrose esters fluidized the plasma membrane and enhanced the accumulation of efflux transporter ligands rhodamine 123 and calcein AM in epithelial cells, but did not inhibit the P-glycoprotein (P-gp) mediated calcein AM accumulation in MES-SA/Dx5 cell line. These data indicate that in addition to their dissolution-increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes without inhibiting P-gp. PMID- 25042091 TI - Production of an anthocyanin-rich food colourant from Thymus moroderi and its application in foods. AB - BACKGROUND: Anthocyanins and other polyphenols from flowers and bracts of Thymus sp. are studied. An anthocyanin-rich food colourant with interesting high antioxidant activity from Thymus moroderi has been obtained, and applied to colour foods. RESULTS: Anthocyanins and other polyphenols from T. moroderi and another five Thymus sp. were extracted in methanol/hydrochloric acid 0.1 mol L( 1) (50/50, v/v) 2 h stirring at 50 degrees C. They were identified and quantified by HPLC-PDA-MS and UHPLC-PDA-fluorescence, as total individual polyphenols. Total polyphenols were also determined. Flowers had higher anthocyanins and other polyphenols concentrations than bracts; for example, total polyphenols content of T. moroderi were 131.58 and 61.98 g GAE kg(-1) vegetal tissue, respectively. A liquid concentrated colourant was obtained from T. moroderi using water/citric acid as solvent. It was characterised and compared with other two commercial anthocyanin-rich food colourants from red grape skin and red carrot (colour strength of 1.7 and 3.6 AU, respectively). T. moroderi colourant had 1.2 AU colour strength, and high storage stability (>97.1% remaining colour after 110 days at 4 degrees C). It showed a higher polyphenols content than commercial colourants. Its antioxidant activity was 0.707 mmol Trolox eq. g(-1) plant dry weight, 69.5 times higher than red carrot. The three colourants were applied to colour yogurts, giving pinky tonalities. The colour did not change evidently (DeltaE*(ab) < 3) when stored under refrigeration during 1 month. CONCLUSIONS: T. moroderi can be a source of anthocyanin-rich food colourant (E-163) with both high polyphenols content and high antioxidant activity. This colourant gives a stable colour to a yogurt during 1 month. These results expand the use of natural colourants. PMID- 25042093 TI - Pain in hereditary neuropathy with liability to pressure palsy: an association with fibromyalgia syndrome? AB - INTRODUCTION: This study characterizes the nature of pain in hereditary neuropathy with liability to pressure palsy (HNPP). METHODS: This retrospective study was performed to assess duration, nature, location, and intensity of pain on initial presentation of subjects with HNPP, including the degree and type of analgesic medication use and electrodiagnostic characteristics. Subjects who met the American College of Rheumatology criteria for fibromyalgia syndrome (FMS) were also identified. RESULTS: Of 32 HNPP subjects, 24 (75%) had symptoms of pain, and 4 (12%) had pain as an initial symptom. Of subjects who described pain, 9 (28%) reported only musculoskeletal pain, 10 (31%) only neuropathic pain, and 5 (16%) both musculoskeletal and neuropathic pain. All 9 subjects with only musculoskeletal pain met criteria for FMS. CONCLUSIONS: Neuropathic and musculoskeletal pain occur commonly in HNPP and may be a presenting symptom. Additionally, HNPP with predominantly musculoskeletal pain may meet criteria for FMS and potentially delay the diagnosis. PMID- 25042092 TI - HUCBCs increase angiopoietin 1 and induce neurorestorative effects after stroke in T1DM rats. AB - BACKGROUND AND PURPOSE: We investigated the neurorestorative effects and underlying mechanisms of stroke treatment with human umbilical cord blood cells (HUCBCs) in Type one diabetes mellitus (T1DM) rats. METHODS: Type one diabetes mellitus rats were subjected to middle cerebral artery occlusion (MCAo) and 24 h later were treated with: (1) phosphate-buffered-saline; (2) HUCBCs. Brain endothelial cells (MBECs) were cultured and capillary tube formation was measured. RESULTS: Human umbilical cord blood cells treatment significantly improved functional outcome and promoted white matter (WM) remodeling, as identified by Bielschowsky silver, Luxol fast blue and SMI-31 expression, increased oligodendrocyte progenitor cell and oligodendrocyte density after stroke in T1DM rats. HUCBC also promoted vascular remodeling, evident from enhanced vascular and arterial density and increased artery diameter, and decreased blood-brain barrier leakage. HUCBC treatment also increased Angiopoietin-1 and decreased receptor for advanced glycation end-products (RAGE) expression compared to T1DM-MCAo control. In vitro analysis of MBECs demonstrated that Ang1 inversely regulated RAGE expression. HUCBC and Ang1 significantly increased capillary tube formation and decreased inflammatory factor expression, while anti-Ang1 attenuated HUCBC-induced tube formation and antiinflammatory effects. CONCLUSION: Human umbilical cord blood cells is an effective neurorestorative therapy in T1DM-MCAo rats and the enhanced vascular and WM remodeling and associated functional recovery after stroke may be attributed to increasing Angiopoietin-1 and decreasing RAGE. PMID- 25042094 TI - Novel methods of instruction in ACL injury prevention programs, a systematic review. AB - Anterior cruciate ligament (ACL) injury prevention programs have been successful in the short term. Motor learning strategies with an internal focus (IF) to body movements have traditionally been utilized, but may be less suitable than an external focus (EF) for the acquisition and control of complex motor skills required for sport. To investigate the available literature and provide an overview of the effect of IF and EF instructions on jump landing technique. Systematic searches were conducted in PubMed (1966 to May 2014), CINAHL (1981 to May 2014) and PsycInfo (1989 to May 2014). A priori defined inclusion criteria were: (i) full text; (ii) published in English, German or Dutch; (iii) healthy adult subjects (mean age >=18 years); (iv) jump and landing performance tested and (v) study used comparison between an EF and IF. Performance (jump height and distance) and technique (kinematics and kinetics) were the primary outcome variables of interest. Nine papers were included. Significant better motor performance and movement technique was found with an EF compared to an IF. Considering the beneficial results in the included studies when utilizing an EF, it is suggested to implement these strategies into ACL injury prevention programs. PMID- 25042095 TI - Application of fasciocutaneous V-Y advancement flap in primary and recurrent sacrococcygeal pilonidal sinus disease. AB - BACKGROUND: Pilonidal sinus disease is a common disease of young adults, which most frequently occurs in the sacrococcygeal region on the skin's midline. Various procedures, ranging from simple incision and curettage to complex flaps for natal cleft obliteration, have been described in the literature. MATERIAL/METHODS: We aimed to present the dermographic characters, post-operative complications, length of stay in hospital, time of return to daily activities, and recurrence rates of the patients in which we applied sinus excision and fasciocutaneous V-Y advancement flap due to primary complicated or recurrent sacrococcygeal pilonidal sinus disease. RESULTS: Patients with primary complicated and recurrent pilonidal sinus received a fasciocutaneous V-Y advancement flap in the general surgery service of our hospital. Eleven patients had recurrent disease. Thirty-seven patients received a unilateral V-Y flap and 8 patients received a bilateral V-Y flap. None of the patients had post-operative flap necrosis or wound opening. Two of the patients had a self-draining simple seroma and 3 of the patients had delayed wound healing in the perianal region of the incision, which was treated with dressing. The mean time required to return to daily activities was 7 days, and return to work took 17 days. In the mean 25 month follow-ups of the patients, no recurrences were detected. CONCLUSIONS: We think that fasciocutaneous V-Y advancement flap is an easily learned and practicable method that reduces the recurrences in the patients with primary complicated and recurrent pilonidal sinus, length of stay in hospital, and time to return to daily activities and work in the post-operative period. PMID- 25042098 TI - Fast automatic myocardial segmentation in 4D cine CMR datasets. AB - A novel automatic 3D+time left ventricle (LV) segmentation framework is proposed for cardiac magnetic resonance (CMR) datasets. The proposed framework consists of three conceptual blocks to delineate both endo and epicardial contours throughout the cardiac cycle: (1) an automatic 2D mid-ventricular initialization and segmentation; (2) an automatic stack initialization followed by a 3D segmentation at the end-diastolic phase; and (3) a tracking procedure. Hereto, we propose to adapt the recent B-spline Explicit Active Surfaces (BEAS) framework to the properties of CMR images by integrating dedicated energy terms. Moreover, we extend the coupled BEAS formalism towards its application in 3D MR data by adapting it to a cylindrical space suited to deal with the topology of the image data. Furthermore, a fast stack initialization method is presented for efficient initialization and to enforce consistent cylindrical topology. Finally, we make use of an anatomically constrained optical flow method for temporal tracking of the LV surface. The proposed framework has been validated on 45 CMR datasets taken from the 2009 MICCAI LV segmentation challenge. Results show the robustness, efficiency and competitiveness of the proposed method both in terms of accuracy and computational load. PMID- 25042099 TI - New frontiers and challenges in silicon chemistry: ISOS XVII in Berlin. PMID- 25042097 TI - The ever-expanding role of asymmetric covalent organocatalysis in scalable, natural product synthesis. AB - Following the turn of the millennium, the role of asymmetric covalent organocatalysis has developed into a scalable, synthetic paradigm galvanizing the synthetic community toward utilization of these methods toward more practical, metal-free syntheses of natural products. A myriad of reports on asymmetric organocatalytic modes of substrate activation relying on small, exclusively organic molecules are delineating what has now become the multifaceted field of organocatalysis. In covalent catalysis, the catalyst and substrate combine to first form a covalent, activated intermediate that enters the catalytic cycle. Following asymmetric bond formation, the chiral catalyst is recycled through hydrolysis or displacement by a pendant group on the newly formed product. Amine- and phosphine-based organocatalysts are the most common examples that have led to a vast array of reaction types. This Highlight provides a brief overview of covalent modes of organocatalysis and applications of scalable versions of these methods applied to the total synthesis of natural products including examples from our own laboratory. PMID- 25042102 TI - Identification of constrained peptidomimetic chemotypes as HIV protease inhibitors. AB - Small-molecule peptidomimetic inhibitors that already showed activity towards Secreted aspartic protease 2 as anti-Candida agents are herein presented as candidate HIV protease inhibitors. A library of 6,8-dioxa-3-azabicyclo[3.2.1] octane peptidomimetic scaffolds was screened towards HIV protease, resulting in the identification of hit compounds possessing IC50 in the sub-micromolar range, and showing the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues. PMID- 25042103 TI - Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles. AB - Bacteria assume distinct lifestyles during the planktonic and biofilm modes of growth. Increased levels of the intracellular messenger c-di-GMP determine the transition from planktonic to biofilm growth, while a reduction causes biofilm dispersal. It is generally assumed that cells dispersed from biofilms immediately go into the planktonic growth phase. Here we use single-nucleotide resolution transcriptomic analysis to show that the physiology of dispersed cells from Pseudomonas aeruginosa biofilms is highly different from those of planktonic and biofilm cells. In dispersed cells, the expression of the small regulatory RNAs RsmY and RsmZ is downregulated, whereas secretion genes are induced. Dispersed cells are highly virulent against macrophages and Caenorhabditis elegans compared with planktonic cells. In addition, they are highly sensitive towards iron stress, and the combination of a biofilm-dispersing agent, an iron chelator and tobramycin efficiently reduces the survival of the dispersed cells. PMID- 25042104 TI - Relationship between nighttime vital sign assessments and acute care transfers in the rehabilitation inpatient. AB - PURPOSE: To investigate the role of nighttime vital sign assessment in predicting acute care transfers (ACT) from inpatient rehabilitation. DESIGN: Retrospective chart review. METHODS: Fifty patients unexpectedly discharged to acute care underwent chart review to determine details of each ACT. FINDINGS: Seven of 50 ACT possessed new vital sign abnormalities at the 11 pm vital sign assessment the night before ACT. None of these seven underwent ACT during the night shift the abnormalities were detected. Two of 50 ACT were transferred between 11 pm and 6:59 am; both demonstrating normal vital sign at the 11 pm assessment. During study period, an estimated 5,607 11 pm vital sign assessments were performed. CONCLUSIONS: Nighttime vital sign assessments do not seem to be a good screening tool for clinical instability in the rehabilitation hospital. CLINICAL RELEVANCE: Eliminating sleep disturbance is important to the rehabilitation inpatient as inadequate sleep hinders physical performance. Tailoring vital sign monitoring to fit patents' clinical presentation may benefit this population. PMID- 25042105 TI - What is the best imaging modality in evaluating patients with unilateral pulsatile tinnitus? PMID- 25042106 TI - Linear and fast hydrogel glucose sensor materials enabled by volume resetting agents. AB - A volume resetting agent is incorporated into a boronic acid functionalized hydrogel containing an embedded photonic crystal, yielding a glucose sensor material with a linear and fast response, minimal hysteresis, and good stability under simulated physiological conditions. The hydrogel can be tuned to modulate both the sensitivity and kinetics. PMID- 25042108 TI - Extreme environments. PMID- 25042107 TI - [Addition to the exchange between Doctor Vercoustre and Professor Levy [editorial and forum JGOBR 2014; 43 (6): 409-10 et 411-12], where it is a question of choosing the route of delivery...]. PMID- 25042109 TI - Synthesis of Indolyldiketopiperazines with NBS. AB - Two series of indolyldiketopiperazines were synthesized starting from methyl 1 substituted-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate hydrochlorides via N bromo-succinimide (NBS) as an important reagent. All eight compounds were characterized by nuclear magnetic resonance (NMR) and elemental analysis. Furthermore, the mechanisms of NBS-reacted rearrangements are also discussed. PMID- 25042110 TI - HPLC-ELSD determination of kanamycin B in the presence of kanamycin A in fermentation broth. AB - A novel method for the direct determination of kanamycin B in the presence of kanamycin A in fermentation broth using high performance liquid chromatography with evaporative light scattering detector (HPLC-ELSD) was developed. An Agilent Technologies C18 column was utilized, evaporation temperature of 40 degrees C and nitrogen pressure of 3.5 bar, the optimized mobile phase was water-acetonitrile (65:35, v/v), containing 11.6 mm heptafluorobutyric acid (isocratic elution with flow rate of 0.5 mL/min) with the gain 11. Kanamycin B was eluted at 5.6 min with an asymmetry factor of 1.827. The method showed good linearity over the concentration range of 0.05 to 0.80 mg/mL for the kanamycin B (r(2) = 0.9987). The intra-day and inter-day coefficients of variation obtained from kanamycin B were less than 4.3%. Mean recovery of kanamycin B from spiked fermentation broth was 95%. The developed method was applied to the determination of kanamycin B without any interference from other constituents in the fermentation broth. This method offers simple, rapid and quantitative detection of kanamycin B. PMID- 25042111 TI - Impulsivity: mechanisms, moderators and implications for addictive behaviors. PMID- 25042112 TI - Anti-inflammatory effects of ginsenosides Rg5 , Rz1 , and Rk1 : inhibition of TNF alpha-induced NF-kappaB, COX-2, and iNOS transcriptional expression. AB - In the course of this experiment on the anti-inflammatory effect of ginsenosides, protopanaxdiol ginsenosides have shown inhibition activities in inflammatory responses: NF-kappaB, COX-2, and iNOS were induced by TNF-alpha. The responses of this experiment were evaluated by NF-kappaB-luciferase assay and RT-PCR experiment of COX-2 and iNOS genes. The NF-kappaB expressions were inhibited by ginsenosides Rd, Rg5 , Rz1 , and Rk1 in a dose-dependent manner. The IC50 values were 3.47, 0.61, 0.63, and 0.75 MUM, respectively. Particularly, ginsenosides Rg5 , Rz1 , and Rk1 as converted ginsenosides from primary protopanaxdiol ginsenosidess significantly inhibited COX-2 and iNOS gene expression. These inhibition levels were similar to sulfasalazine as reference material. PMID- 25042113 TI - Gene expression analysis in patients with traumatic anterior shoulder instability suggests deregulation of collagen genes. AB - Shoulder dislocation occurs in 1-2% of the population. Capsular deformation is a key factor in shoulder dislocation; however, little is known about capsule biology. We evaluated, for the first time in literature, the expression of COL1A1, COL1A2, COL3A1 and COL5A1 in the antero-inferior, antero-superior and posterior regions of the glenohumeral capsule of 31 patients with anterior shoulder instability and eight controls. The expression of collagen genes was evaluated by quantitative reverse transcription-PCR. The expression of COL1A1, COL3A1 and the ratio of COL1A1/COL1A2 were increased in all three portions of the capsule in patients compared to controls (p < 0.05). COL1A2 expression was upregulated in the antero-superior and posterior sites of the capsule of patients (p < 0.05). The ratio of COL1A2/COL3A1 expression was reduced in capsule antero inferior and posterior sites of patients compared to controls (p < 0.05). In the capsule antero-inferior site of patients, the ratios of COL1A1/COL5A1, CO1A2/COL5A1 and COL3A1/COL5A1 expression were increased (p < 0.05). In patients, COL1A1/COL5A1 was also increased in the posterior site (p < 0.05). We found deregulated expression of collagen genes across the capsule of shoulder instability patients. These molecular alterations may lead to modifications of collagen fibril structure and impairment of the healing process, possibly with a role in capsular deformation. PMID- 25042115 TI - Revisiting therapeutic hypothermia for severe traumatic brain injury... again. AB - Improved understanding of the molecular mechanisms of secondary brain injury has informed the optimum depth and duration of cooling and led to increased clinical interest in the therapeutic moderate hypothermia for severe traumatic brain injury over the past two decades. Although several large multi-center clinical trials have not found a treatment effect, multiple single-center trials have, and a recent meta-analysis by Crossley and colleagues now finds that the cumulative findings of those single-center trials dilute the multi-center trial results and show an overall reduction in mortality and poor outcomes associated with cooling. The need for consistent support of key physiologic parameters during cooling is emphasized by this finding. PMID- 25042114 TI - Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes. AB - Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology. PMID- 25042116 TI - Migration of inorganic ions from the leachate of the Rio das Ostras landfill: a comparison of three different configurations of protective barriers. AB - Batch tests and diffusion tests were performed to analyze the efficiency of a protective barrier in a landfill consisting of compacted soil with 10% bentonite compared to the results obtained for only compacted soil and for compacted soil covered with a 1-mm-thick HDPE geomembrane; the soil and leachate were collected from the Rio das Ostras Landfill in Rio de Janeiro, Brazil. The diffusion tests were performed for periods of 3, 10 and 60 days. After the test period, the soil pore water was analyzed and the profiles for chloride, potassium and ammonium were determined along a 6-cm soil depth. The results of the batch tests performed to define sorption parameters were used to adjust the profiles obtained in the diffusion cell experiment by applying an ion transfer model between the interstitial solution and the soil particles. The MPHMTP model (Multi Phase Heat and Mass Transfer Program), which is based upon the solution of the transport equations of the ionic contaminants, was used to solve the inverse problem of simultaneously determining the effective diffusion coefficients. The results of the experimental tests and of the model simulation confirmed that the compacted soil with 10% bentonite was moderately efficient in the retention of chloride, potassium and ammonium ions compared to the configurations of compacted soil with a geomembrane and compacted soil alone, representing a solution that is technically feasible and requires potentially lower costs for implementation in landfills. PMID- 25042118 TI - Modeling enzymatic hydrolysis of lignocellulosic substrates using confocal fluorescence microscopy I: filter paper cellulose. AB - Enzymatic hydrolysis is one of the critical steps in depolymerizing lignocellulosic biomass into fermentable sugars for further upgrading into fuels and/or chemicals. However, many studies still rely on empirical trends to optimize enzymatic reactions. An improved understanding of enzymatic hydrolysis could allow research efforts to follow a rational design guided by an appropriate theoretical framework. In this study, we present a method to image cellulosic substrates with complex three-dimensional structure, such as filter paper, undergoing hydrolysis under conditions relevant to industrial saccharification processes (i.e., temperature of 50 degrees C, using commercial cellulolytic cocktails). Fluorescence intensities resulting from confocal images were used to estimate parameters for a diffusion and reaction model. Furthermore, the observation of a relatively constant bound enzyme fluorescence signal throughout hydrolysis supported our modeling assumption regarding the structure of biomass during hydrolysis. The observed behavior suggests that pore evolution can be modeled as widening of infinitely long slits. The resulting model accurately predicts the concentrations of soluble carbohydrates obtained from independent saccharification experiments conducted in bulk, demonstrating its relevance to biomass conversion work. PMID- 25042117 TI - Variation in treatment associated with life expectancy in a population-based cohort of men with early-stage prostate cancer. AB - BACKGROUND: Men with major comorbidities are at risk for overtreatment of prostate cancer due to uncertainty regarding their life expectancy. We sought to characterize life expectancy and treatment in a population-based cohort of men with differing ages and comorbidity burdens at diagnosis. METHODS: We sampled 96,032 men aged >=66 years with early-stage prostate cancer who had Gleason scores <=7 and were diagnosed during 1991 to 2007 from the Surveillance, Epidemiology, and End Results-Medicare database. We calculated cumulative incidence of other-cause mortality and determined treatment patterns among subgroups defined by age and Charlson comorbidity index scores. RESULTS: Overall, life expectancy was <10 years (10-year other-cause mortality rate, >50%) for 50,049 of 96,032 men (52%). Life expectancy differed by age and comorbidity score and was <10 years for men ages 66 to 69 years with Charlson scores >=2, for men ages 70 to 74 years with Charlson scores >=1, and for all men ages 75 to 79 years and >=80 years. Among those who had a life expectancy <10 years, treatment was aggressive (surgery, radiation, or brachytherapy) for 68% of men aged 66 to 69 years, 69% of men aged 70 to 74 years, 57% of men aged 75 to 79 years, and 24% of men aged >=80 years. Among these men, aggressive treatment was predominantly radiation therapy (50%, 53%, 63%, and 69%, respectively) and less frequently was surgery (30%, 25%, 13%, and 9%, respectively). Multivariate models revealed little variation in the probability of aggressive treatment by comorbidity status within age subgroups despite substantial differences in mortality. CONCLUSIONS: Men aged <80 years at diagnosis who have life expectancies <10 years often receive aggressive treatment for low-risk and intermediate-risk prostate cancer, mostly with radiation therapy. PMID- 25042119 TI - Colorectal cancer mortality among Hispanics in California: differences by neighborhood socioeconomic status and nativity. AB - BACKGROUND: Socioeconomic status (SES) plays an important role in colorectal cancer (CRC) mortality, although the independent and joint effects with nativity and neighborhood factors have yet to be evaluated. METHODS: With nearly one-third of all US Hispanics residing in California, the authors obtained information from the California Cancer Registry to examine the associations between neighborhood SES and mortality in all 33,146 Hispanic individuals diagnosed with CRC from 1988 through 2010, with a particular focus on associations among US-born and foreign born Hispanics. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CI) for overall and CRC-specific mortality. RESULTS: Hispanics residing in lower SES neighborhoods demonstrated a higher rate of overall and CRC-specific mortality than those residing in high SES neighborhoods (SES quintile 1[low] vs quintile 5 [high]: HR, 1.15 [95% CI, 1.05 1.26] and HR, 1.16 [95% CI, 1.03-1.30], respectively). Nativity modified the associations between SES and mortality (P for interaction, .02 for overall and P for interaction, .01 for CRC-specific mortality) such that the SES associations were observed only among US-born (P for trend < .01 for overall and CRC-specific mortality) but not among foreign-born Hispanics. CONCLUSIONS: Neighborhood SES demonstrates significant differential effects on overall and CRC-specific mortality between US-born and foreign-born Hispanics. Future efforts should investigate the underlying contextual and individual-level factors that could account for these differential associations by nativity. PMID- 25042120 TI - Molecular determinants of tetramerization in the KcsA cytoplasmic domain. AB - The cytoplasmic C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is an amphiphilic domain that forms a helical bundle with four fold symmetry mediated by hydrophobic and electrostatic interactions. Previously we have established that a CTD-derived 34-residue peptide associates into a tetramer in a pH-dependent manner (Kamnesky et al., JMB 2012;418:237-247). Here we further investigate the molecular determinants of tetramer formation in the CTD by characterizing the kinetics of monomer-tetramer equilibrium for 10 alanine mutants using NMR, sedimentation equilibrium (SE) and molecular dynamics simulation. NMR and SE concur in finding single-residue contributions to tetramer stability to be in the 0.5 to 3.5 kcal/mol range. Hydrophobic interactions between residues lining the tetramer core generally contributed more to formation of tetramer than electrostatic interactions between residues R147, D149 and E152. In particular, alanine replacement of residue R147, a key contributor to inter subunit salt bridges, resulted in only a minor effect on tetramer dissociation. Mutations outside of the inter-subunit interface also influenced tetramer stability by affecting the tetramerization on-rate, possibly by changing the inherent helical propensity of the peptide. These findings are interpreted in the context of established paradigms of protein-protein interactions and protein folding, and lay the groundwork for further studies of the CTD in full-length KcsA channels. PMID- 25042121 TI - Patterns of circulating tumor cells identified by CEP8, CK and CD45 in pancreatic cancer. AB - To improve the identification for CTCs with weak or negative CK and diploid CTCs in pancreatic cancer, we combined immune-staining of CK, CD45, DAPI and fluorescence in situ hybridization with the centromere of chromosome 8 (CEP8) probe method. CTCs in 3.75 mL of blood were depleted for CD45 positive cells with anti-CD45 antibodies and identified by combining CK, CD45, DAPI and CEP8 in 61 cases including 22 pancreatic cancers, 3 borderline pancreatic solid pseudopapillary tumors, 6 pancreatic benign tumors, and 30 healthy individuals. We found that enriched cells could be classified into 5 patterns: CK+CD45 DAPI+CEP8=2 (2 hybridization signals), CK+CD45-DAPI+CEP8>2 (>2 hybridization signals), CK-CD45-DAPI+CEP8>2, CK-CD45-DAPI+CEP8=2, and CK+/-CD45+DAPI+CEP8=2 or >2. Among 22 pancreatic cancers, CK+CD45-DAPI+CEP8=2 and CK+CD45-DAPI+CEP8>2 patterns were identified in two cases, and CK-CD45- DAPI+CEP8>2 pattern was identified in 16 cases. CK-CD45-DAPI+CEP8=2 and CK+/-CD45+DAPI+CEP8=2 or >2 patterns were detected in pancreatic cancers, other pancreatic diseases and healthy individuals. Among the five patterns, CK+CD45-DAPI+CEP8=2, CK+CD45 DAPI+CEP8>2 and CK-CD45-DAPI+CEP8>2 were considered as CTCs, while CK-CD45 DAPI+CEP8=2 and CK+/-CD45+DAPI+CEP8=2 or >2 were considered as indeterminate cells. When the cutoff value was set as 2 cells/3.75 mL based on ROC curve, the sensitivity and specificity in the diagnosis of pancreatic cancer was 68.18 and 94.87%, respectively. Dynamically monitoring CTCs changes prior to and after surgery in pancreatic patients revealed that CTCs count decreased in 3 days after surgery, but increased in 10 days after surgery in most patients. During our one and a half year follow-up, CTCs positive patients showed metastasis and worse survival rate. PMID- 25042123 TI - Endovascular treatment for ruptured abdominal aortic aneurysm. AB - BACKGROUND: An abdominal aortic aneurysm (AAA) (pathological enlargement of the aorta) can develop in both men and women as they grow older. It is most commonly seen in men over the age of 65 years. Progressive aneurysm enlargement can lead to rupture and massive internal bleeding, a fatal event unless timely repair can be achieved. Despite improvements in perioperative care, mortality remains high (approximately 50%) after conventional open surgical repair. A newer minimally invasive technique, endovascular aneurysm repair (EVAR), has been shown to reduce early morbidity and mortality as compared to conventional open surgery for planned AAA repair. Emergency endovascular aneurysm repair (eEVAR) has been used successfully to treat ruptured abdominal aortic aneurysm (RAAA), proving that it is feasible in selected patients. However, it is not yet known if eEVAR will lead to significant improvements in outcomes for these patients or indeed if it can replace conventional open repair as the preferred treatment for this lethal condition. OBJECTIVES: To assess the advantages and disadvantages of emergency endovascular aneurysm repair (eEVAR) in comparison with conventional open surgical repair for the treatment of ruptured abdominal aortic aneurysm (RAAA). This will be determined by the effect on short-term mortality, major complication rates, aneurysm exclusion, and late complications when compared with the effects in patients who have had conventional open repair of RAAA. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co ordinator searched the Specialised Register (last searched February 2014) and CENTRAL (2014, Issue 2). Reference lists of relevant publications were also checked. SELECTION CRITERIA: Randomised controlled trials in which patients with a clinically or radiologically diagnosed RAAA were randomly allocated to eEVAR or conventional open surgical repair. DATA COLLECTION AND ANALYSIS: Studies identified for potential inclusion were independently assessed for eligibility by at least two review authors. Data extraction and quality assessment were also completed independently by two review authors. Disagreements were resolved through discussion. Meta-analysis was performed using fixed-effect models with odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous data and mean differences with 95% CIs for continuous data. MAIN RESULTS: Three randomised controlled trials were included in this review. A total of 761 patients with a clinical or radiological diagnosis of RAAA were randomised to receive either eEVAR or open surgical repair. Overall risk of bias was low but one study did not adequately report random sequence generation, putting it at risk of selection bias, two studies did not report on outcomes identified in their protocol, indicating reporting bias, and one study was underpowered. There was no clear evidence to support a difference between the two interventions on 30-day (or in hospital) mortality, OR of 0.91 (95% CI 0.67 to 1.22; P = 0.52). The 30-day complications included myocardial infarction, stroke, composite cardiac complications, renal complications, severe bowel ischaemia, spinal cord ischaemia, re-operation, amputation, and respiratory failure. Individual complication outcomes were reported in only one or two studies and therefore no robust conclusion can currently be drawn. For complication outcomes that did include at least two studies in the meta-analysis there was no clear evidence to support a difference between eEVAR and open repair. Six-month outcomes were evaluated in only a single study, which included mortality and re-operation, with no clear evidence of a difference between the interventions and no overall association. Cost per patient was only evaluated in a single study and therefore no overall associations can currently be derived. AUTHORS' CONCLUSIONS: The conclusions of this review are currently limited by the paucity of data. From the data available there is no difference in the outcomes evaluated in this review between eEVAR and open repair, specifically 30-day mortality. Not enough information was provided for complications in order to make a well informed conclusion at this time. Long-term data are lacking for both survival and late complications. More high quality, randomised controlled trials comparing eEVAR and open repair for the treatment of RAAA are needed in order to better understand if one method is superior to the other, or if there is no difference between the methods on relevant outcomes. PMID- 25042124 TI - Sentiments analysis at conceptual level making use of the Narrative Knowledge Representation Language. AB - This paper illustrates some of the knowledge representation structures and inference procedures proper to a high-level, fully implemented conceptual language, NKRL (Narrative Knowledge Representation Language). The aim is to show how these tools can be used to deal, in a sentiment analysis/opinion mining context, with some common types of human (and non-human) "behaviors". These behaviors correspond, in particular, to the concrete, mutual relationships among human and non-human characters that can be expressed under the form of non fictional and real-time "narratives" (i.e., as logically and temporally structured sequences of "elementary events"). PMID- 25042122 TI - CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis. AB - There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5(+) CD4(+) Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. CONCLUSION: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches. PMID- 25042126 TI - Veterinary journal editors meet in Croatia. PMID- 25042127 TI - Synthesis, characterization, self-assembly, gelation, morphology and computational studies of alkynylgold(III) complexes of 2,6-bis(benzimidazol-2' yl)pyridine derivatives. AB - A novel class of alkynylgold(III) complexes of the dianionic ligands derived from 2,6-bis(benzimidazol-2'-yl)pyridine (H2bzimpy) derivatives has been synthesized and characterized. The structure of one of the complexes has also been determined by X-ray crystallography. Electronic absorption studies showed low-energy absorption bands at 378-466 nm, which are tentatively assigned as metal-perturbed pi-pi* intraligand transitions of the bzimpy(2-) ligands. A computational study has been performed to provide further insights into the nature of the electronic transitions for this class of complexes. One of the complexes has been found to show gelation properties, driven by pi-pi and hydrophobic-hydrophobic interactions. This complex exhibited concentration- and temperature-dependent (1)H NMR spectra. The morphology of the gel has been characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). PMID- 25042128 TI - Two major cuticular proteins are required for assembly of horizontal laminae and vertical pore canals in rigid cuticle of Tribolium castaneum. AB - The insect exoskeleton is composed of cuticle primarily formed from structural cuticular proteins (CPs) and the polysaccharide chitin. Two CPs, TcCPR27 and TcCPR18, are major proteins present in the elytron (highly sclerotized and pigmented modified forewing) as well as the pronotum (dorsal sclerite of the prothorax) and ventral abdominal cuticle of the red flour beetle, Tribolium castaneum. Both CPs belong to the CPR family, which includes proteins that have an amino acid sequence motif known as the Rebers & Riddiford (R&R) consensus sequence. Injection of double-stranded RNA (dsRNA) for TcCPR27 and TcCPR18 resulted in insects with shorter, wrinkled, warped and less rigid elytra than those from control insects. To gain a more comprehensive understanding of the roles of CPs in cuticle assembly, we analyzed for the precise localization of TcCPR27 and the ultrastructural architecture of cuticle in TcCPR27- and TcCPR18 deficient elytra. Transmission electron microscopic analysis combined with immunodetection using gold-labeled secondary antibody revealed that TcCPR27 is present in dorsal elytral procuticle both in the horizontal laminae and in vertical pore canals. dsRNA-mediated RNA interference (RNAi) of TcCPR27 resulted in abnormal electron-lucent laminae and pore canals in elytra except for the boundary between these two structures in which electron-dense molecule(s) apparently accumulated. Insects subjected to RNAi for TcCPR18 also had disorganized laminae and pore canals in the procuticle of elytra. Similar ultrastructural defects were also observed in other body wall regions with rigid cuticle such as the thorax and legs of adult T. castaneum. TcCPR27 and TcCPR18 are required for proper formation of the horizontal chitinous laminae and vertical pore canals that are critical for formation and stabilization of rigid adult cuticle. PMID- 25042129 TI - Parasitization by Scleroderma guani influences expression of superoxide dismutase genes in Tenebrio molitor. AB - Superoxide dismutase (SOD) is an antioxidant enzyme involved in detoxifying reactive oxygen species. In this study, we identified genes encoding the extracellular and intracellular copper-zinc SODs (ecCuZnSOD and icCuZnSOD) and a manganese SOD (MnSOD) in the yellow mealworm beetle, Tenebrio molitor. The cDNAs for ecCuZnSOD, icCuZnSOD, and MnSOD, respectively, encode 24.55, 15.81, and 23.14 kDa polypeptides, which possess structural features typical of other insect SODs. They showed 20-94% identity to other known SOD sequences from Bombyx mori, Musca domestica, Nasonia vitripennis, Pediculus humanus corporis, and Tribolium castaneum. Expression of these genes was analyzed in selected tissues and developmental stages, and following exposure to Escherichia coli and parasitization by Scleroderma guani. We recorded expression of all three SODs in cuticle, fat body, and hemocytes and in the major developmental stages. Relatively higher expressions were detected in late-instar larvae and pupae, compared to other developmental stages. Transcriptional levels were upregulated following bacterial infection. Analysis of pupae parasitized by S. guani revealed that expression of T. molitor SOD genes was significantly induced following parasitization. We infer that these genes act in immune response and in host parasitoid interactions. PMID- 25042130 TI - Impulse control disorders in frontotemporal dementia: spectrum of symptoms and response to treatment. AB - OBJECTIVE: To describe a patient with behavioral variant frontotemporal dementia (bvFTD) presenting with impulse control disorders (ICDs) which responded to fluvoxamine and topiramate. CASE REPORT: A 64-year-old woman was affected by several ICDs. At disease onset, she suffered from impulsive smoking and overeating which caused a body weight increase of 20 kg in 6 months. Later on she manifested binge-eating behavior and skin-picking compulsion. Presence of progressive frontal cognitive impairment (Mini Mental State Examination 24/30) and evidence of hypoperfusion of the anterior cingulate and dorsolateral frontal cortex with brain single-photon emission computed tomography scan contributed to the diagnosis of bvFTD. Use of combination treatment with selective serotonin reuptake inhibitor drugs and topiramate improved all these symptoms. CONCLUSION: This case extends the clinical phenotype of repetitive and compulsive habits in bvFTD to encompass symptoms suggestive of ICDs. It is proposed that fluvoxamine and topiramate may be considered as treatment options in these conditions. PMID- 25042131 TI - Meniscal suturing versus screw fixation for treatment of osteochondritis dissecans: clinical and magnetic resonance imaging results. AB - PURPOSE: The purpose of this study was to compare meniscal stabilization alone with screw fixation in restoring subjective and objective knee function and structural cartilage integrity in skeletally immature patients with osteochondritis dissecans (OCD) of the knee. METHODS: This study comprised 28 patients (32 knees) with magnetic resonance imaging (MRI)-confirmed OCD. Unstable menisci were treated with either stabilization (15 patients, 16 knees) or screw fixation (13 patients, 16 knees; control group). Patients were assessed by functional scoring (Hughston, International Knee Documentation Committee [IKDC]) and MRI for a minimum follow-up period of 2.5 years. RESULTS: In the meniscus stabilization group, the Hughston score improved from 1.4 to 3.8 (P < .01). There was improvement in the IKDC grade, from grade C preoperatively to grade A in 14 knees and grade B in 2 (P < .01). Of 16 knees, 15 had complete defect resolution on MRI by 1 year. There were 3 complications: 1 wound infection, 1 case of trauma requiring reoperation, and 1 revision because of treatment failure at 6 months. In the screw fixation group, the Hughston score improved from 1.4 to 3.6 (P < .01). There was a significant improvement in IKDC grade, from grade C preoperatively to grade A in 11 knees and grade B in 5 (P < .01). At 2 years postoperatively, no differences in these variables were found between the groups. CONCLUSIONS: Meniscal suturing alone for the treatment of an OCD of the knee shows good or excellent results in terms of clinical scoring and MRI assessment at almost 3 years' follow-up. The results are comparable with those of screw fixation but with a faster recovery in the postoperative course. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25042132 TI - Electrically tunable graphene plasmonic quasicrystal metasurfaces for transformation optics. AB - The past few years have witnessed tremendous achievements of transformation optics applied to metallic plasmonic systems. Due to the poor tunability of metals, however, the ultimate control over surface plasmons remains a challenge. Here we propose a new type of graphene plasmonic (GP) metasurfaces by shaping the dielectrics underneath monolayer graphene into specific photonic crystals. The radial and axial gradient-index (GRIN) lenses are implemented to demonstrate the feasibility and versatility of the proposal. It is found that the designed GP GRIN lenses work perfectly well for focusing, collimating, and guiding the GP waves. Especially, they exhibit excellent performances in the THz regime as diverse as ultra-small focusing spot (lambda0/60) and broadband electrical tunability. The proposed method offers potential opportunities in exploiting active transformational plasmonic elements operating at THz frequencies. PMID- 25042133 TI - Small cycloalkane (CN)2C-C(CN)2 structures are highly directional non-covalent carbon-bond donors. AB - High-level calculations (RI-MP2/def2-TZVP) disclosed that the sigma-hole in between two C atoms of cycloalkane X2 C?CX2 structures (X=F, CN) is increasingly exposed with decreasing ring size. The interacting energy of complexes of F(-) , HO(-) , N=C(-) , and H2 CO with cyclopropane and cyclobutane X2 C?CX2 derivatives was calculated. For X=F, these energies are small to positive, while for X=CN they are all negative, ranging from -6.8 to -42.3 kcal mol(-1) . These finding are corroborated by a thorough statistical survey of the Cambridge Structural Database (CSD). No clear evidence could be found in support of non-covalent carbon bonding between electron-rich atoms (El.R.) and F2 C?CF2 structures. In marked contrast, El.R.???(CN)2 C?C(CN)2 interactions are abundant and highly directional. Based on these findings, the hydrophobic electrophilic bowl formed by 1,1',2,2'-tetracyano cyclopropane or cyclobutane derivatives is proposed as a new and synthetically accessible supramolecular synthon. PMID- 25042134 TI - Vacuum extraction enhances rhPDGF-BB immobilization on nanotubes to improve implant osseointegration in ovariectomized rats. AB - Nanotube morphology has been previously applied to improve osseointegration in osteoporosis, but the osteogenic capability of the technique requires further improvements. This study aimed to investigate the effects of vacuum extraction on the loading of rhPDGF-BB on nanotube arrays as well as its effects on the osseointegration of ovariectomized (OVX) rats. More rhPDGF-BB protein particles aggregated on the nanotube surface and into the nanotube after vacuum extraction for 10 min. The immobilized protein could be slowly released for at least 14 days and still kept its biological activity. In vitro, the immobilized rhPDGF-BB enhanced cell adhesion, proliferation and osteogenic differentiation. In vivo, more rhPDGF-BB immobilized on the nanotube surface also promoted the osseointegration. These results suggest that the enhanced immobilization of rhPDGF-BB on nanotube arrays can potentially be used in the future as an implant surface modification strategy in dental and orthopedic applications in osteoporotic patients. FROM THE CLINICAL EDITOR: This study presents convincing evidence that enhanced immobilization of recombinant human PDGF-BB protein particles on nanotubes lead to improved osteogenic differentiation in an experimental system. When used as a surface modification strategy for dental or orthopedic implants, this method was able to promote osseointegration even in an osteoporotic animal model, raising the likelihood for potential future clinical applications. PMID- 25042136 TI - Best practice in the use of onabotulinumtoxinA (BOTOX(r)) to optimize patient outcomes in overactive bladder. PMID- 25042135 TI - Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes - an immunohistochemical study. AB - BACKGROUND: It is largely accepted that specific immunological parameters in solid malignancies are associated with patient's prognosis. Recently a correlation of macrophage polarization with histomorphological parameters could also be shown in oral squamous cell carcinoma (oscc). The observed tumor derived peripheral immune tolerance could be associated with the macrophage polarization in regional tumor draining lymph nodes.So far there are no studies analyzing the macrophage polarization in cervical lymph nodes of oscc patients. In the present study we aimed to correlate macrophage polarization in different anatomical lymph node compartments of patients diagnosed with oscc with histopathologic parameters of the primary tumor (T-, N-, L-, V-, Pn-status, grading). METHODS: Tumor free (n = 37) and metastatic (n = 17) lymph nodes of T1 and T2 oscc patients were processed for immunohistochemistry to detect CD68, CD11c, CD163 and MRC1 positive cells. Samples were digitized using whole slide imaging and the number of cells expressing the aforementioned markers in the region of interest quantitatively analyzed. RESULTS: The malignancy of the primary tumor (defined by T-, L-, Pn status, grading) correlated with the lymph node macrophage polarization. L1 and Pn1 tumor cases displayed a significantly (p < 0.05) decreased M1 and increased M2 polarization in the sinus of the lymph nodes. G3 cases presented a significantly (p < 0.05) increased M2 polarization in the sinus compared to G2 cases. T2 tumors had significantly (p < 0.05) increased M2 polarization in the interfollicular zone of regional lymph nodes compared to T1 tumors. Metastatic and non-metastatic lymph nodes did not differ regarding their macrophage polarization. CONCLUSIONS: The current study revealed for the first time an influence of oscc on the macrophage polarization in regional lymph nodes. Markers of malignant behavior in the primary tumor were associated with a shift of macrophage polarization in lymph nodes from the anti-tumoral M1 type to the tumor promoting M2 type. As tumor free and metastatic lymph nodes did not differ in terms of their macrophage polarization pattern, there must be other factors influencing the location for lymph node metastasis formation. PMID- 25042137 TI - Chapter 3: Molecular basis for the therapeutic effectiveness of botulinum neurotoxin type A. AB - The utility of botulinum neurotoxin type A (BoNT/A) for treating overactive muscles and endocrine glands is attributable to a unique conflation of properties honed to exploit and inactivate synaptic transmission. Specific, high-affinity coincident binding to gangliosides plus an intraluminal loop of synaptic vesicle protein 2 (SV2) by the heavy chain (HC) of BoNT/A confers selectivity for presynaptic nerve terminals and subsequent uptake by endocytosis. Upon vesicle acidification, the HC forms a channel for transmembrane transfer of the light chain to the cytosol, as observed by single channel recordings. The light chain is a Zn(2+) -dependent endoprotease that cleaves and inactivates SNAP-25, thereby blocking exocytotic release of transmitters, a discovery that revealed the pivotal role of the latter in synaptic vesicle fusion. A di-leucine motif in BoNT/A light chain stabilizes this protease, contributing to its longevity inside nerves. The ubiquity of SV2 and SNAP-25 has prompted re-evaluation of the nerve types susceptible to BoNT/A. In urology, there is emerging evidence that BoNT/A blocks neuropeptide release from afferent nerves, exocytosis of acetylcholine and purines from efferent nerves, and possibly ATP release from the urothelium. Suppression by BoNT/A of the surface expression of nociceptor channels on bladder afferents might also contribute to its improvement of urological sensory symptoms. PMID- 25042138 TI - Chapter 1: The conditions of neurogenic detrusor overactivity and overactive bladder. AB - Overactive bladder (OAB) is a symptom syndrome consisting of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence (UUI), in the absence of a causative infection or pathological conditions. The prevalence of OAB is approximately 11-19% in both men and women, and leads to a significant negative effect on a patient's health-related quality of life (HRQOL). OAB is also associated with comorbidities such as urinary tract infection (UTI) and an increased risk of falls. Following behavioral therapy, anticholinergic agents are commonly prescribed, but these often fail because of lack of efficacy and/or poor tolerability. Evaluation of treatment success in OAB should include pre-defined, patient-centered goals. Patients for whom oral therapy has failed to meet such goals may be considered refractory to oral therapy and candidates for minimally invasive therapy. Neurogenic detrusor overactivity (NDO) is a bladder dysfunction frequently observed in patients with conditions such as multiple sclerosis (MS) and spinal cord injury (SCI). Increased storage pressure can put the upper urinary tract at risk of deterioration and reducing this risk is a primary aim of therapy. Urinary incontinence (UI) is reported by approximately 50% of MS patients, and most SCI patients will develop some bladder dysfunction. NDO leads to a negative impact on HRQOL, independent of the impact of the primary condition. NDO patients in whom oral therapy has failed to normalize storage pressure may be considered refractory and are candidates for minimally invasive therapy. PMID- 25042139 TI - Chapter 4: Guidelines for the diagnosis and treatment of overactive bladder (OAB) and neurogenic detrusor overactivity (NDO). AB - This chapter focuses on the position of botulinum toxin type A in the treatment pathway for overactive bladder (OAB) and neurogenic lower urinary tract dysfunction associated with neurogenic detrusor overactivity (NDO), and the recommendations of the major international guideline groups. Recommendations of different guideline groups may vary, especially when evidence is weak, often because of differences in methodology and panel composition. Relevant guidelines from the European Association of Urology, American Urological Association, and the UK National Institute for Care and Clinical Excellence were reviewed, and the recommendations that form the basis of the treatment algorithms have been discussed. Any differences between guidelines have been highlighted and special emphasis made on the position of botulinum toxin type A in these pathways. In all the reviewed guidelines, botulinum toxin type A is recommended, alongside sacral nerve neuromodulation, to treat OAB and NDO in patients who have failed oral therapy. The evidence base is consistent, but further evidence is required regarding optimal dosing regimens and injection technique. PMID- 25042140 TI - Chapter 5: Clinical data in neurogenic detrusor overactivity (NDO) and overactive bladder (OAB). AB - Following use of botulinum toxin in the 1980s for the treatment of detrusor sphincter dyssynergia in patients with spinal cord injury (SCI), the potential therapeutic value of this neurotoxin in urology has been the subject of much interest. The DIGNITY (Double-blind InvestiGation of purified Neurotoxin complex In neurogenic deTrusor overactivitY) clinical research program aimed to compare onabotulinumtoxinA with placebo in terms of efficacy and safety in patients with neurogenic detrusor overactivity (NDO) due to SCI or multiple sclerosis. The EMBARK clinical research program mirrored these aims in patients with overactive bladder with urinary incontinence (UI). Each program comprised two phase III, randomized, placebo-controlled studies. In all four trials, primary efficacy endpoints were met, and significant benefits of onabotulinumtoxinA versus placebo were demonstrated across a range of secondary endpoints, including measures of health-related quality of life. The most common adverse event across both programs was urinary tract infection. Interim analyses of data from ongoing long term extensions to these phase III trials have provided promising evidence for the efficacy of repeated injections. While further investigation is recommended to enrich the dataset, the available evidence indicates that onabotulinumtoxinA provides an effective treatment option for these two populations, which were previously considered very difficult to treat. PMID- 25042141 TI - Chapter 6: Practical aspects of administration of onabotulinumtoxinA. AB - Candidates for onabotulinumtoxinA are generally patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) whose disease is inadequately controlled with behavioral therapy and oral medication. All patients must be willing and able to perform clean intermittent catheterization (CIC). Before the decision to administer onabotulinumtoxinA is made, the clinician should provide counseling to the patient regarding the agent's indications, proposed benefits, risks, and mode of administration. The patient should be aware that onabotulinumtoxinA takes effect after approximately 1-2 weeks and usually lasts for 4-10 months, after which repeat injections will be necessary to maintain effect. Patient preparation may include pre-treatment antibiotics and withdrawal of antiplatelet therapy or anticoagulants. Preparation of the product involves reconstitution in sterile saline and dilution according to the planned dose. Local anesthesia (e.g., bladder instillation of lidocaine) is usually administered, although general anesthesia may be used in certain cases. The injections are performed using a flexible or rigid cystoscope, and the procedure takes approximately 15 min. The initial follow-up visit occurs within 7-14 days, when evidence of adverse effects, including urinary retention, can be evaluated. Repeat injections can be scheduled as needed, but not sooner than 3 months. Currently, the total dose of onabotulinumtoxinA should not exceed 360 U in a 3 month period for all indications, including those outside the urinary tract (i.e., cosmetic, ophthalmologic, etc.). Overall, onabotulinumtoxinA is effective, generally well tolerated, safe, and is relatively simple to provide. PMID- 25042142 TI - Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder". AB - It is now clearly recognized that the function of the lower urinary tract represents a complex interaction between the bladder and its outlet, acting under the control of the central nervous system. While in the past attention has principally focused on the motor (efferent) control of the bladder, sensory (afferent) innervation is now known to be an important therapeutic target. This change in emphasis is strongly supported by both basic science and clinical evidence demonstrating the efficacy of therapy directed at the afferent system. This chapter summarizes the neurophysiological control mechanism that underpins normal lower urinary tract function, emphasizing the importance of the afferent system as a potential therapeutic target. PMID- 25042144 TI - General facile approach to transition-metal oxides with highly uniform mesoporosity and their application as adsorbents for heavy-metal-ion sequestration. AB - Mesoporous powders of transition-metal oxides, TiO2, ZrO2, HfO2, Nb2O5, and Ta2O5, pure from organic impurities were produced by a rapid single-step thermohydrolytic approach. The obtained materials display an impressively large active surface area and sharp pore-size distribution, being composed of partially coalesced uniform nanoparticles with crystalline cores and amorphous shells. They reveal extremely high adsorption capacity in removal of Cr(VI) anions from solutions (25.8 for TiO2, 73.0 for ZrO2, and 74.7 mg g(-1) for Nb2O5 in relation to the Cr2O7(2-) anion), making them very attractive as adsorbents in water remediation applications. The difference in adsorption capacities for the studied oxides may be explained by variation in surface hydration and surface-charge distribution. PMID- 25042143 TI - Pseudo-random center placement O-space imaging for improved incoherence compressed sensing parallel MRI. AB - PURPOSE: Nonlinear spatial encoding magnetic (SEM) field strategies such as O space imaging have previously reported dispersed artifacts during accelerated scans. Compressed sensing (CS) has shown a sparsity-promoting convex program allows image reconstruction from a reduced data set when using the appropriate sampling. The development of a pseudo-random center placement (CP) O-space CS approach optimizes incoherence through SEM field modulation to reconstruct an image with reduced error. THEORY AND METHODS: The incoherence parameter determines the sparsity levels for which CS is valid and the related transform point spread function measures the maximum interference for a single point. The O space acquisition is optimized for CS by perturbing the Z(2) strength within 30% of the nominal value and demonstrated on a human 3T scanner. RESULTS: Pseudo random CP O-space imaging is shown to improve incoherence between the sensing and sparse domains. Images indicate pseudo-random CP O-space has reduced mean squared error compared with a typical linear SEM field acquisition method. CONCLUSION: Pseudo-random CP O-space imaging, with a nonlinear SEM field designed for CS, is shown to reduce mean squared error of images at high acceleration over linear encoding methods for a 2D slice when using an eight channel circumferential receiver array for parallel imaging. PMID- 25042145 TI - A cross-sectional survey on gender-based violence and mental health among female urban refugees and asylum seekers in Kampala, Uganda. AB - OBJECTIVE: To assess gender-based violence and mental health outcomes among a population of female urban refugees and asylum seekers. METHODS: In a questionnaire-based, cross-sectional study conducted in 2010 in Kampala, Uganda, a study team interviewed a stratified random sample of female refugees and asylum seekers aged 15-59 years from the Democratic Republic of Congo and Somalia. Questionnaires were used to collect information about recent and lifetime exposure to sexual and physical violence, and symptoms of depression and post traumatic stress disorder (PTSD). RESULTS: Among the 500 women selected, 117 (23.4%) completed interviews. The weighted lifetime prevalences of experiencing any (physical and/or sexual) violence, physical violence, and sexual violence were 77.5% (95% CI 66.6-88.4), 76.2% (95% CI 65.2-87.2), and 63.3% (95% CI 51.2 75.4), respectively. Lifetime history of physical violence was associated with PTSD symptoms (P<0.001), as was lifetime history of sexual violence (P=0.014). Overall, 112 women had symptoms of depression (weighted prevalence 92.0; 95% CI 83.9-100) and 83 had PTSD symptoms (weighted prevalence 71.1; 95% CI 59.9-82.4). CONCLUSION: Prevalences of violence, depression, and PTSD symptoms among female urban refugees in Kampala are high. Additional services and increased availability of psychosocial programs for refugees are needed. PMID- 25042146 TI - Maternal obesity and rate of cesarean delivery in Djibouti. AB - OBJECTIVE: To calculate the prevalence of maternal obesity and to determine the relation between obesity and cesarean delivery in an urban hospital in Djibouti. METHODS: In an observational cohort study, all women who had a live birth or stillbirth between October 2012 and November 2013 were considered for inclusion. Body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) was calculated throughout pregnancy, and women with a BMI of at least 30.0 were deemed to be obese. Multivariate logistic regression analyses were used to evaluate the relation between cesarean and obesity. RESULTS: Overall, 100 (24.8%) of 404 women were obese before 14 weeks of pregnancy, as were 112 (25.2%) of 445 before 22 weeks, and 200 (43.2%) of 463 at delivery. Obesity before 22 weeks was associated with a 127% excess risk of cesarean delivery (adjusted odds ratio 2.27; 95% CI 1.07-4.82; P=0.032). Similar trends were found when the analyses were limited to the subgroup of women without a previous cesarean delivery or primiparae. CONCLUSION: Prevalence of maternal obesity is high in Djibouti City and is related to an excess risk of cesarean delivery, even after controlling for a range of medical and socioeconomic variables. PMID- 25042148 TI - Relationship between molecular stacking and optical properties of 9,10-bis((4-N,N dialkylamino)styryl) anthracene crystals: the cooperation of excitonic and dipolar coupling. AB - Five 9,10-bis((4-N,N-dialkylamino)styryl) anthracene derivatives (DSA-C1-DSA-C7) with different length alkyl chains were synthesized. They showed the same color in dilute solutions but different colors in crystals. The absorption, photoluminescence, and fluorescence decay indicate that there exist both excitonic and dipolar coupling in crystals of DSA-C1-DSA-C7. X-ray crystallographic analysis revealed that all the crystals belong to the triclinic space group P1 with one molecule per unit cell and that the molecules in every crystal have the identical orientation. This offers ideal samples to investigate the impact of the molecular stacking on the optical properties of the crystals. For the first time, the cooperation of excitonic and dipolar coupling has been comprehensively studied, and the contribution to the spectral shift from the excitonic and dipolar couplings quantitatively obtained. The experiments of amplified spontaneous emission (ASE) together with measurements of the quantum efficiency further confirmed this interpretation. The results suggest that the excitonic and dipolar couplings between the adjacent molecules are both important and jointly induce the spectral shifts of the crystals. PMID- 25042147 TI - Fetal myocardial calcifications and non-compaction: a shared etiology? PMID- 25042149 TI - Rumination and emotions in nonsuicidal self-injury and eating disorder behaviors: a preliminary test of the emotional cascade model. AB - OBJECTIVE: This study examined relations between repeated rumination trials and emotions in nonsuicidal self-injury (NSSI) and eating disorder behaviors (EDBs) within the context of the emotional cascade model (Selby, Anestis, & Joiner, 2008). METHOD: Rumination was repeatedly induced in 342 university students (79.2% female, Mage = 18.61, standard error = .08); negative and positive emotions were reported after each rumination trial. Repeated measures analyses of variance were used to examine the relations between NSSI and EDB history and changes in emotions. RESULTS: NSSI history associated with greater initial increases in negative emotions, whereas EDB history associated with greater initial decreases in positive emotions. Baseline negative emotional states and trait emotion regulation mediated the relation between NSSI/EDB history and emotional states after rumination. CONCLUSION: Although NSSI and EDBs share similarities in emotion dysregulation, differences also exist. Both emotion dysregulation and maladaptive cognitive processes should be targeted in treatment for NSSI and EDBs. PMID- 25042150 TI - QST-FST comparisons with unbalanced half-sib designs. AB - QST , a measure of quantitative genetic differentiation among populations, is an index that can suggest local adaptation if QST for a trait is sufficiently larger than the mean FST of neutral genetic markers. A previous method by Whitlock and Guillaume derived a simulation resampling approach to statistically test for a difference between QST and FST , but that method is limited to balanced data sets with offspring related as half-sibs through shared fathers. We extend this approach (i) to allow for a model more suitable for some plant populations or breeding designs in which offspring are related through mothers (assuming independent fathers for each offspring; half-sibs by dam); and (ii) by explicitly allowing for unbalanced data sets. The resulting approach is made available through the R package QstFstComp. PMID- 25042151 TI - OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis. AB - BACKGROUND: Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1 targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic beta-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor. METHODS: We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008. RESULTS: In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first. CONCLUSION: This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent. PMID- 25042152 TI - Abiraterone acetate in metastatic castration-resistant prostate cancer: a retrospective review of the Princess Margaret experience of (I) low dose abiraterone and (II) prior ketoconazole. AB - INTRODUCTION: Abiraterone (AA) is a CYP17 inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). Data suggest similar pharmacokinetics of 250-500 mg of AA with high-fat meals ('low-dose') and 1000 mg in the fasting state ('full-dose'). Ketoconazole (KT) is a less potent CYP17 inhibitor previously widely used in mCRPC. OBJECTIVE: To study outcomes of men with mCRPC treated with low-dose AA and/or with prior exposure to KT. PATIENTS AND METHODS: Retrospective chart review of all men treated with AA at the Princess Margaret Cancer Centre between November 2009 and March 2013. Outcome measures were prostate-specific antigen response rate (PSA-RR), biochemical progression-free survival (bPFS), treatment duration and overall survival (OS). Associations between AA dose or prior KT and outcomes were assessed using chi square test for PSA-RR and log-rank test for bPFS, treatment duration and OS. RESULTS: In total, 111 men who received AA were evaluable, of which 21 received low-dose AA and 23 received prior KT. There was a non-significant difference in PSA-RR (43% versus 32%, p=0.37), but no significant differences in median bPFS, median treatment duration and median OS (18.7 versus 16.6 months, p=0.25) in the full and low-dose cohorts respectively, and for those who received prior KT or not (PSA-RR 48% versus 38%, p=0.4; median OS 24.2 versus 16.5 months, p=0.066, respectively). CONCLUSIONS: Low-dose AA or prior KT treatment were not associated with poorer outcome in men with mCRPC treated with AA. These observations may have implications for drug sequencing and dose in resource-limited settings. PMID- 25042153 TI - A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibits dysregulated methylation in rheumatoid arthritis Treg cells. AB - Treg-cell function is compromised in rheumatoid arthritis (RA). As the master regulator of Treg cells, FOXP3 controls development and suppressive function. Stable Treg-cell FOXP3 expression is epigenetically regulated; constitutive expression requires a demethylated Treg-specific demethylated region. Here, we hypothesised that methylation of the FOXP3 locus is altered in Treg cells of established RA patients. Methylation analysis of key regulatory regions in the FOXP3 locus was performed on Treg cells from RA patients and healthy controls. The FOXP3 Treg-specific demethylated region and proximal promoter displayed comparable methylation profiles in RA and healthy-donor Treg cells. We identified a novel differentially methylated region (DMR) upstream of the FOXP3 promoter, with enhancer activity sensitive to methylation-induced silencing. In RA Treg cells we observed significantly reduced DMR methylation and lower DNA methyltransferase (DNMT1/3A) expression compared with healthy Treg cells. Furthermore, DMR methylation negatively correlated with FOXP3 mRNA expression, and Treg cells isolated from rheumatoid factor negative RA patients were found to express significantly higher levels of FOXP3 than Treg cells from RhF-positive patients, with an associated decrease in DMR methylation. In conclusion, the novel DMR is involved in the regulation of Treg-cell FOXP3 expression, but this regulation is lost post-transcriptionally in RA Treg cells. PMID- 25042154 TI - PHEX 3'-UTR c.*231A>G near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets. AB - Heritable forms of hypophosphatemic rickets (HR) include X-linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, DMP1 or ENPP1, and activating mutations in FGF23, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel single-base change near the polyadenylation (pA) signal in the 3'-UTR of PHEX was identified in XLH by other investigators. This c.*231A > G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 3'-UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3' UTR region showed the c.*231A > G mutation in four unrelated boys. Then, among an additional 22 of our 72 "sporadic" XLH patients, one boy and one girl were found to have the 3'-UTR defect, totaling six patients. Among these 52 sporadic XLH patients with PHEX analysis, 36 were girls and 16 were boys; ie, a ~2:1 gender ratio consistent with XLH. However, finding five boys and only one girl with this 3'-UTR mutation presented an unexplained gender bias (p = 0.02). Haplotyping for the five boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their six mothers had been studied clinically and biochemically (three radiologically). Remarkably, the seemingly unaffected mothers of four of these boys carried the 3'-UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, PHEX c.*231A > G can masquerade as sporadic or X-linked recessive HR. PMID- 25042155 TI - Early detection of abnormal left ventricular relaxation in acute myocardial ischemia with a quadratic model. AB - AIMS: The time constant of left ventricular (LV) relaxation derived from a monoexponential model is widely used as an index of LV relaxation rate, although this model does not reflect the non-uniformity of ventricular relaxation. This study investigates whether the relaxation curve can be better fitted with a "quadratic" model than with the "conventional" monoexponential model and if changes in the LV relaxation waveform due to acute myocardial ischemia could be better detected with the quadratic model. METHODS AND RESULTS: Isovolumic relaxation was assessed with quadratic and conventional models during acute myocardial ischemia performed in 6 anesthetized pigs. Mathematical development indicates that one parameter (Tq) of the quadratic model reflects the rate of LV relaxation, while the second parameter (K) modifies the shape of the relaxation curve. Analysis of experimental data obtained in anesthetized pigs showed that the shape of LV relaxation consistently deviates from the conventional monoexponential decay. During the early phase of acute myocardial ischemia, the rate and non-uniformity of LV relaxation, assessed with the quadratic function, were significantly enhanced. Tq increased by 16% (p<0.001) and K increased by 12% (p<0.001) within 30 and 60 min, respectively, after left anterior descending (LAD) coronary artery occlusion. However, no significant changes were observed with the conventional monoexponential decay within 60 min of ischemia. CONCLUSIONS: The quadratic model better fits LV isovolumic relaxation than the monoexponential model and can detect early changes in relaxation due to acute myocardial ischemia that are not detectable with conventional methods. PMID- 25042157 TI - Influenza A(H1N1)pdm09 resistance and cross-decreased susceptibility to oseltamivir and zanamivir antiviral drugs. AB - Neuraminidase inhibitors (NAIs) oseltamivir and zanamivir are currently the only effective antiviral drugs available worldwide for the management of influenza. The potential development of resistance is continually threatening their use, rationalizing and highlighting the need for a close and sustained evaluation of virus susceptibility. This study aimed to analyze and characterize the phenotypic and genotypic NAIs susceptibility profiles of A(H1N1)pdm09 viruses circulating in Portugal from 2009 to 2010/2011. A total of 144 cases of A(H1N1)pdm09 virus infection from community and hospitalized patients were studied, including three suspected cases of clinical resistance to oseltamivir. Oseltamivir resistance was confirmed for two of the suspected cases. Neuraminidase (NA) H275Y resistant marker was found in viruses from both cases but for one it was only present in 26.2% of virus population, raising questions about the minimal percentage of resistant virus that should be considered relevant. Cross-decreased susceptibility to oseltamivir and zanamivir (2-4 IC50 fold-change) was detected on viruses from two potentially linked community patients from 2009. Both viruses harbored the NA I223V mutation. NA Y155H mutation was found in 18 statistical non outlier viruses from 2009, having no impact on virus susceptibility. The mutations at NA N369K and V241I may have contributed to the significantly higher baseline IC50 value obtained to oseltamivir for 2010/2011 viruses, compared to viruses from the pandemic period. These results may contribute to a better understanding of the relationship between phenotype and genotype, which is currently challenging, and to the global assessment of A(H1N1)pdm09 virus susceptibility profile and baseline level to NAIs. PMID- 25042156 TI - Exploiting pre-rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis. AB - Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene. PMID- 25042158 TI - Recent advances in transition metal complexes and light-management engineering in organic optoelectronic devices. AB - Two of the recent major research topics in optoelectronic devices are discussed: the development of new organic materials (both molecular and polymeric) for the active layer of organic optoelectronic devices (particularly organic light emitting diodes (OLEDs)), and light management, including light extraction for OLEDs and light trapping for organic solar cells (OSCs). In the first section, recent developments of phosphorescent transition metal complexes for OLEDs in the past 3-4 years are reviewed. The discussion is focused on the development of metal complexes based on iridium, platinum, and a few other transition metals. In the second part, different light-management strategies in the design of OLEDs with improved light extraction, and of OSCs with improved light trapping is discussed. PMID- 25042161 TI - Use of harmonic scalpel in sphincter pharyngoplasty. PMID- 25042160 TI - Tau reduction prevents disease in a mouse model of Dravet syndrome. AB - OBJECTIVE: Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies. METHODS: We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav 1.1. We genetically deleted 1 or 2 Tau alleles in mice carrying an Nav 1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, electroencephalographic recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays. RESULTS: Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance. INTERPRETATION: Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies. PMID- 25042159 TI - iPad technology for home rehabilitation after stroke (iHOME): a proof-of-concept randomized trial. AB - BACKGROUND: Tablets are a novel line of computers controlled by a multitouch screen. Fine motor movements are captured on the tablet computer through electrical fields and can be qualitatively and quantitatively assessed. Evidence is limited on tablet use for stroke rehabilitation. METHODS: iHOME is an investigator-initiated randomized controlled pilot trial with a single-blinded outcome assessment. The intervention consists of iPad use (investigational group) vs. usual care (control group) among patients receiving conventional outpatient rehabilitation. Eligibility includes aged 18-85 years who experienced a mild ischemic or hemorrhagic stroke (as diagnosed on neuroimaging and determined by the Chedoke-McMaster score >=3. The STROKE REHAB(r) software for the iPad was specifically designed for patients with fine motor weakness and/or neglect. Of the total 30 patients, 20 will be in iHOME Acute (enrolled within three-months of stroke onset) and 10 patients in iHOME Chronic (enrolled more than six-months from onset). OUTCOME MEASURES: The primary feasibility outcome is the proportion of the scheduled iPad time used (more than 70% (>=140 mins) of the total 'dose' of intervention intended will be considered successful). Efficacy in fine motor movements will be assessed using the nine-hole peg test; time to magnify and pop the balloons in the iPad software application, and improvement in Wolf Motor Function Test. CONCLUSIONS: iHOME is a randomized controlled trial assessing the feasibility, safety, and efficacy of tablet technology for home use in stroke rehabilitation. The results of this study will serve as the basis for a larger multicenter trial. PMID- 25042162 TI - Characterization of the complete mitochondrial genome of Chilo auricilius and comparison with three other rice stem borers. AB - The mitogenome of Chilo auricilius (Lepidoptera: Pyraloidea: Crambidae) was a circular molecule made up of 15,367 bp. Sesamia inferens, Chilo suppressalis, Tryporyza incertulas, and C. auricilius, are closely related, well known rice stem borers that are widely distributed in the main rice-growing regions of China. The gene order and orientation of all four stem borers were similar to that of other insect mitogenomes. Among the four stem borers, all AT contents were below 83%, while all AT contents of tRNA genes were above 80%. The genomes were compact, with only 121-257 bp of non-coding intergenic spacer. There are 56 or 62-bp overlapping nucleotides in Crambidae moths, but were only 25-bp overlapping nucleotides in the noctuid moth S. inferens. There was a conserved motif 'ATACTAAA' between trnS2 (UCN) and nad1 in Crambidae moths, but this same region was 'ATCATA' in the noctuid S. inferens. And there was a 6-bp motif 'ATGATAA' of overlapping nucleotides, which was conserved in Lepidoptera, and a 14-bp motif 'TAAGCTATTTAAAT' conserved in the three Crambidae moths (C. suppressalis, C. auricilius and T. incertulas), but not in the noctuid. Finally, there were no stem-and-loop structures in the two Chilo moths. PMID- 25042163 TI - Multilocus sequence evaluation for differentiating species of the trematode Family Gastrothylacidae, with a note on the utility of mitochondrial COI motifs in species identification. AB - Amphistomiasis, a neglected trematode infectious disease of ruminants, is caused by numerous species of amphistomes belonging to six families under the Superfamily Paramphistomoidea. In the present study, four frequently used DNA markers, viz. nuclear ribosomal 28S (D1-D3 regions), 18S and ITS2 and mitochondrial COI genes, as well as sequence motifs from these genes were evaluated for their utility in species characterization of members of the amphistomes' Family Gastrothylacidae commonly prevailing in Northeast India. In sequence and phylogenetic analyses the COI gene turned out to be the most useful marker in identifying the gastrothylacid species, with the exception of Gastrothylax crumenifer, which showed a high degree of intraspecific variations among its isolates. The sequence analysis data also showed the ITS2 region to be effective for interspecies characterization, though the 28S and 18S genes were found unsuitable for the purpose. On the other hand, sequence motif analysis data revealed the motifs from the COI gene to be highly conserved and specific for their target species which allowed accurate in silico identification of the gastrothylacid species irrespective of their intraspecific differences. We propose the use of COI motifs generated in the study as a potential tool for identification of these species. PMID- 25042165 TI - Use of three-dimensional power Doppler sonography in the diagnosis of uterine arteriovenous malformation and follow-up after uterine artery embolization: Case report and brief review of literature. AB - Arteriovenous malformations (AVM) of the uterus can cause life-threatening hemorrhage. Unexplained, heavy vaginal bleeding in a reproductive age woman should raise suspicion for an AVM. Here a 37-year-old woman had increasingly severe vaginal bleeding for 15 days. Serum beta-hCG was elevated. Two-dimensional transvaginal ultrasound suggested retained products of conception. Before dilation and curettage (D&C), color Doppler and three-dimensional (3D) power Doppler demonstrated findings indicative of uterine AVM. A bilateral uterine artery embolization was performed without complications. Three months after uterine artery embolization, 3D power Doppler ultrasonography found complete resolution of the AVM. This case illustrates the importance of assessing both gray-scale and 3D power Doppler, and the ability of postprocedure Doppler to assess resolution. PMID- 25042164 TI - Albumin administration in the acutely ill: what is new and where next? AB - Albumin solutions have been used worldwide for the treatment of critically ill patients since they became commercially available in the 1940s. However, their use has become the subject of criticism and debate in more recent years. Importantly, all fluid solutions have potential benefits and drawbacks. Large multicenter randomized studies have provided valuable data regarding the safety of albumin solutions, and have begun to clarify which groups of patients are most likely to benefit from their use. However, many questions remain related to where exactly albumin fits within our fluid choices. Here, we briefly summarize some of the physiology and history of albumin use in intensive care before offering some evidence-based guidance for albumin use in critically ill patients. PMID- 25042166 TI - Imbalance between protective (adiponectin) and prothrombotic (Plasminogen Activator Inhibitor-1) adipokines in metabolic syndrome. AB - AIMS: The metabolic syndrome (MS) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Visceral adipose tissue actively produces a variety of adipokines that interact in various obesity related disorders such as metabolic syndrome, diabetes mellitus and heart diseases. Adiponectin has protective role in the vascular physiology while Plasminogen Activator Inhibitor-1 (PAI-1) has a prothrombotic and consequent deleterious effect on the endothelium. We attempted to assess the putative imbalance if any between these two mediators in subjects with metabolic syndrome in the Indian context. MATERIALS AND METHODS: We enrolled 50 diagnosed case of metabolic syndrome as per International Diabetes Federation (IDF) criteria and 50 healthy volunteers as control. Clinical evaluation included anthropometric, routine biochemical analysis as well as adiponectin and PAI-1 measurement. RESULT: Subject with MS had significantly lower adiponectin (9.8+/ 1.0 vs 16+/-1.1 MUg/ml) and higher PAI-1 (232+/-87 vs 185+/-96 ng/ml). A statistically significant correlation was observed between adiponectin and HDL levels (r=0.388, p=0.005). CONCLUSION: Subjects with MS have lower adiponectin and higher PAI-1 levels as compared to controls. The subsequent tilt toward a more prothrombotic and pro inflammatory milieu in the vascular endothelium may be pathognomonic of metabolic syndrome. This understanding of the still undiscovered subtle vascular alterations may help in the better management of obesity and MS. PMID- 25042167 TI - Double-injection capillary electrophoresis for the identification of analytes. AB - This paper presents a new approach for identifying analytes by CE. The compound to be identified is analyzed together with the corresponding reference standard during a double injection capillary electrophoretic run. The inter-plug distance is regulated by applying an electrical field over the capillary for a predetermined time period (t(PE)). The migration time of an analyte being exposed to the partial electrophoresis was calculated from the partial migration time (t(mig(p))) as described in this paper. The identification is based on the closeness of agreement between the calculated migration time (t(mig(c))) and observed migration time (t(mig)) of the reference standard. The validity of the derived equations was checked by analyzing several substances such as caffeine, melamine, acetyl salicylic acid, paracetamol, ibuprofen, metoprolol, naproxen, somatropin, several insulin analogs, as well as different pharmaceutical and natural products. The migration time ratios for the identified solutes varied between 0.996 and 1.006 (i.e., 1.001 +/- 0.005), indicating good agreement between the observed and calculated migration times. PMID- 25042168 TI - Multifunctional inorganic nanocontainers for DNA and drug delivery into living cells. AB - The design and synthesis of multifunctional nanomaterials could lead to applications relevant for biomedicine. Manufacturing porous particles to make them able to carry bioactive molecules into living cells represents a substantial goal towards the development of powerful tools for nanomedicine. This work describes a first example of using zeolite-L crystals as multifunctional nanocontainers to simultaneously deliver DNA oligonucleotides and organic molecules into living cells. Multifunctional zeolite-L was prepared by filling the pore system with guest molecules, whilst DNA was adsorbed electrostatically on their surface. The release kinetics of DNA and of the guest molecules into living cells was studied to prove the multiple-drug-delivery ability of the system. The localization of all the components in different cellular compartments was followed. The presented system may be a prototype for the development of novel nanoparticles for drug delivery and gene therapy. PMID- 25042169 TI - Management practices and forage quality affecting the contamination of milk with anaerobic spore-forming bacteria. AB - BACKGROUND: Anaerobic spore-forming bacteria (ASFB) in milk derive from the farm environment, and the use of silages and management practices are the main responsible of milk ASFB contamination. The aim of this study was to evaluate the relationships between feeding, milking routine and cow hygiene and milk and Grana Padano cheese (produced with and without lysozyme) ASFB contamination. RESULTS: The study involved 23 dairy farms. ASFB in corn silage were on average 2.34 +/- 0.87 log10 MPN g(-1). For grass, Italian ryegrass and alfalfa, ASFB (log10 MPN g( 1)) were numerically higher for silages (3.22) than hays (2.85). The use of corn silages of high quality (high lactic and acetic acids concentrations) decreased the milk ASFB contamination, whilst the use of herbage silages did not affect it. The presence (>40%) of cows with dirty udders increased the ASFB contamination of milk, while forestripping had a positive effect (-9% ASFB). Ripened Grana Padano had an ASFB count below the analytical limit; Clostridium tyrobutyricum DNA was found only in wheels produced without lysozyme, which also showed late blowing. CONCLUSION: The factors increasing milk spore contamination were corn silage quality, cow udder hygiene and inadequate milking routine. Late blowing was present only in cheeses without lysozyme. PMID- 25042170 TI - A simple strategy for the generation of multi-copy Pichia pastoris with the efficient expression of mannanase. AB - Pichia pastoris expression system was widely used for producing heterologous proteins. Some researches revealed that the increase in the copy number could improve the expression of foreign genes in P. pastoris. Hundreds or thousands of antibiotic-resistance recombinants need to be screened because the frequency of multiple gene insertion events is very low in P. pastoris. The traditional method of constructing multi-copy gene is complicated, tedious, and full of randomness. Here, we developed a rapid method for constructing multi-copy Pichia expression vectors harboring mannanase gene. The developed strategy is easy to manipulate genetically and can precisely generate plasmids with a certain copy number of heterologous gene. The average mannanase activities of recombinants randomly chosen from two-, four-, and six-copy recombinant libraries were 1.7-, 2.2-, and 1.3-folds, respectively, of that from single-copy recombinant library. The result revealed that the strategy could effectively improve the expression of foreign proteins in P. pastoris. PMID- 25042175 TI - Identifying local co-regulation relationships in gene expression data. AB - Identifying interesting relationships between pairs of genes, presented over some of experimental conditions in gene expression data set, is useful for discovering novel functional gene interactions. In this paper, we introduce a new method for id entifying L ocal C o-regulation R elationships (IdLCR). These local relationships describe the behaviors of pairwise genes, which are either up- or down-regulated throughout the identified condition subset. IdLCR firstly detects the pairwise gene-gene relationships taking functional forms and the condition subsets by using a regression spline model. Then it measures the relationships using a penalized Pearson correlation and ranks the responding gene pairs by their scores. By this way, those relationships without clearly biological interpretations can be filtered out and the local co-regulation relationships can be obtained. In the simulation data sets, ten different functional relationships are embedded. Applying IdLCR to these data sets, the results show its ability to identify functional relationships and the condition subsets. For micro-array and RNA-seq gene expression data, IdLCR can identify novel biological relationships which are different from those uncovered by IFGR and MINE. PMID- 25042176 TI - Mucosal melanoma: an update. AB - Mucosal melanoma is a rare melanoma subtype that differs from the cutaneous form of the tumor in its biology, clinical manifestations, and management. Diagnosis is usually late due to a lack of early or specific signs and the location of lesions in areas that are difficult to access on physical examination. Surgical excision is the treatment of choice for localized disease. The value of sentinel lymph node biopsy and lymphadenectomy is still unclear. Radiotherapy can be used as adjuvant therapy for the control of local disease. c-KIT mutations are more common than in other types of melanoma and this has led to significant advances in the use of imatinib for the treatment of metastatic mucosal melanoma. PMID- 25042177 TI - Focal hand dystonia: using brain stimulation to probe network interactions and brain plasticity. PMID- 25042178 TI - Apoptosis induced by Pseudomonas aeruginosa: a lonely killer? PMID- 25042179 TI - D-serine-induced inactivation of NMDA receptors in cultured rat hippocampal neurons expressing NR2A subunits is Ca2+-dependent. AB - AIMS: Our previous studies indicate that glycine can inhibit N-methyl-D-aspartate receptor (NMDAR) responses induced by high concentrations of NMDA in rat hippocampal neurons. The present study was designed to observe whether D-serine induces inactivation of NMDARs in cultured rat hippocampal neurons and to investigate the underlying mechanisms of this effect. METHODS: Cell culture, whole-cell patch-clamp electrophysiology, Ca(2+) imaging, immunohistochemistry, and Western blot analysis were used. RESULTS: We found that the peak current and Ca(2+) influx evoked by 30 MUM NMDA were increased by co-application of D-serine, but those evoked by 300 MUM NMDA were reduced dose-dependently by co-application of D-serine. However, the inhibitory effect of D-serine on NMDAR responses was reversed by ZnCl2 (30 nM), an inhibitor of the NR2A subunit, but was less influenced by ifenprodil (10 MUM), an NR2B inhibitor. In addition, the inhibitory effect of D-serine was not detected in young hippocampal neurons that expressed less of the NR2A subunits and reversed in the presence of 10 mM BAPTA. CONCLUSIONS: D-serine can also induce inactivation of NMDARs, the NR2A subunit is required for the induction of this effect, and this inactivation is Ca(2+) dependent in nature. This action of D-serine is hypothesized to play a neuroprotective role upon a sustained large glutamate insult to the brain. PMID- 25042180 TI - Inhibition of chemokine-like factor 1 protects against focal cerebral ischemia through the promotion of energy metabolism and anti-apoptotic effect. AB - Chemokine-like factor 1 (CKLF1) is a novel C-C chemokine, and plays important roles in immune response and brain development. In previous study, we have found that the expression of CKLF1 increased after focal cerebral ischemia and inhibition of CKLF1 using antagonist C19 peptide protected against cerebral ischemia. However, few studies have focused on the role of CKLF1 on neuronal apoptosis. The objective of present study is to investigate the role of CKLF1 on neuronal apoptosis by applying anti-CKLF1 antibodies in rat focal cerebral ischemia and reperfusion model. Antibodies against CKLF1 was applied to the right cerebral ventricle immediately after transient middle cerebral artery occlusion (MCAO), and infarct volume, neurological score, glucose metabolism and apoptosis related protein were measured. Treatment with anti-CKLF1 antibody decreased infarct volume and neurological score, and inhibited neuronal apoptosis in a dose dependent manner at 24h after reperfusion. Anti-CKLF1 antibody also reduced the level of phosphorylation of Akt (P-Akt), and led to decrease of pro-apoptotic protein Bcl-2 associated X protein (Bax) and increase of anti-apoptotic protein B cell lymphoma-2 protein (Bcl-2) and the ratio of Bcl-2/Bax, and inhibited caspase 3 at last. In addition, positron emission tomography (PET) indicated that anti CKLF1 antibody increased glucose metabolism in ischemic hemisphere. These results suggest that CKLF1 is associated with neuronal apoptosis after cerebral ischemia and reperfusion. Neutralization of CKLF1 with antibodies shows neuroprotective effects against cerebral ischemia, which may be involved in inhibition of Akt pathway, regulation of apoptosis-related protein expression, and improvement glucose metabolism in ischemic hemisphere. Therefore, CKLF1 may be a novel target for the treatment of stroke. PMID- 25042181 TI - Porcine blood and surrogate markers do not prove benefit of aDabi-Fab. PMID- 25042183 TI - [Expansion of indications for total replacement of thoracoabdominal aorta]. AB - Experience of surgical treatment of 111 patients with thoracoabdominal aorta aneurysm are presented in the article. All patients were operated in terms 2007 to December 2011 in the department of aortic surgery of acad. B.V. Petrovskogo RSCS of RAMS. All patients were divided into 3 groups. Thoracoabdominal aorta prosthetics from isthmus to bifurcation was performed in 10 patients of the first group. It was done descending thoracic aorta prosthetics in the second group (72 patients). The third group (29 patients) had suprarenal aorta prosthetics. The groups were comparable with respect to initial severity of underlying and concomitant diseases. Hemorrhage was 6242+/-3040, 2666+/-1590 and 2962+/-1547 ml respectively. Liver and renal failure developed in 10, 7 and 24% of cases respectively (p<0.05). Respiratory failure developed in 40, 33 and 27.6% of cases. Mortality was 10, 7 and 13.8% respectively. It was concluded about comparable treatment outcomes regardless of the amount of reconstruction. It is necessary to develop the techniques improving surgical treatment results and decreasing postoperative complications frequency. PMID- 25042184 TI - [Efficiency of bioprosthesis in case of axillary-femoral bypass in patients with high operative risk]. AB - It was analyzed the treatment results of 60 male patients with critical limb ischemia in case of atherosclerotic lesions of the aorta-iliac segment and severe somatic diseases. All patients were divided into 2 groups. Every group consisted 30 patients. The first group included axillary-femoral bypass by using of synthetic polytetrafluoroethylene prosthesis. The second group - by using of bioprosthesis of bull's internal thoracic arteries. Using of bioprosthesis allows to reduce early postoperative complications in intermediate postoperative period on 13.3%, late bypass thrombosis on 30%. Also there was elongation of average time of bypasses functioning in 1.8 times. Physical health was increased on 12.8%, mental - on 9.1%. PMID- 25042185 TI - [Complex ultrasonic study of parathyroids in diagnostic and surgical treatment of primary hyperparathyroidism]. AB - Primary hyperparathyroidism is the most common disease in Russian Federation, cured by endocrine surgeons. Health status after surgical correction of primary hyperparathyroidism depends on availability of screening hypercalciemia, which is still absent in our country. Another problem is a model of surgical management of primary hyperparathyroidism (frozen section, intraoperative monitoring of parathyroid hormone, gamma-detection and so on). Although minimally invasive parathyroidectomy has become the only method of treatment in many countries, it is still crucial to identify and accurately localize parathyroid glands before bilateral neck exploration surgery. The diagnostic efficacy of the various imaging techniques is still the subject of current debate. The usefulness of preoperative parathyroid imaging with both dual scintigraphy-single-photon emission computed tomography (SPECT) Tc 99m and high-resolution ultrasonography (US) was studied in 92 patients undergoing operations for primary hyperparathyroidism. The accuracy of "integrated" ultrasonography ("check-up US", "target US" after SPECT) and "intraoperative US") of parathyroid glands was 92.9%, sensitivity - 91% and positive predictive value - 94%. This study supports an algorithm of obtaining "integrated" ultrasonography as the initial and in most cases the only preoperative localization tests for patients with primary hyperparathyroidism. PMID- 25042186 TI - [Evaluation of long-term results of surgical treatment of thyroid's diseases]. AB - It was analyzed the surgical treatment results of thyroid's diseases in 462 patients in terms 1-15 years. Relapse of the disease was defined in 39.4% of cases after organ-preserving operations. Relapse formation was through 5-10 years after surgery. There were nodes up to 1 cm in diameter after hemistrumectomy and maximum subtotal resection of thyroid. Large nodes more than 3 cm in diameter were after subtotal resection of thyroid. Good results after interstitial laser photocoagulation were achieved in all patients, after sclerotherapy - in 89.5% of cases. An average degree of node reduction after laser destruction was 55.5+/ 3.0%, after sclerotherapy - 49.7+/-_5.6%. PMID- 25042187 TI - [Diagnosis and treatment of cervicothoracic injuries]. AB - It analyzed the diagnosis and treatment results of 123 patients with cervicothoracic injuries for 21 years. The frequency of cervicothoracic injuries among all patients with cervical injuries was 5.7%. Preoperative and postoperative diagnosis included radial and endoscopic methods. The complications rate was 43.6%. The most severe complications were observed in patients with delayed diagnosis of trachea and esophagus injuries. PMID- 25042188 TI - [Laparoscopic herniorrhaphy in children]. AB - It was described the results of endosurgical treatment different technique of 170 children of both sexes aged 4 months to 14 years. Children had inguinal hernia. There were unilateral hernia in 148 patients and bilateral hernia in 22 patients. It was used such interventions as laparoscopic herniotomy with hernial sac extirpation (6 operations), laparoscopic suturing of deep inguinal ring (22 operations), dual-port laparoscopic extraperitoneal herniorrhaphy (46 operations), original single-port laparoscopic extraperitoneal herniorrhaphy (118 operations). The minimum duration of the operation (4.5-7.5 minutes) was observed in the last group. These patients did not need postoperative anesthesia. Relapse was detected in 2 (1.1%) cases. Developed single-port laparoscopic extraperitoneal herniorrhaphy may be alternative in children with inguinal hernia. PMID- 25042189 TI - [Modern approach to diagnosis and treatment of acute mesenteric ischemia]. AB - It was proposed the medical and diagnostic tactic in patients with acute mesenteric ischemia on basis of efficiency results of modern laboratory markers and instrumental methods. Positive laboratory D-dimer-test with computed tomography of abdominal organs or abdominal aorta and its branches CT-angiography led to diagnose thrombosis or embolism of mesenteric arteries at early terms and to reduce preoperative period. The authors presented the variant of isolated endovascular intervention in case of superior mesenteric artery thrombosis. This technique may be regarded as the method of choice in the treatment of patients with acute mesenteric ischemia. PMID- 25042182 TI - Ataluren treatment of patients with nonsense mutation dystrophinopathy. AB - INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males >= 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Delta=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. PMID- 25042191 TI - [Laparoscopic subtotal colectomy with mesorectumectomy in case of Hirschsprung's disease in adults]. AB - Hirschsprung's disease in adults is a rare pathology. It was suggested the new method of Hirschsprung's disease surgical treatment in adults: distal subtotal colectomy, mesorectumectomy, appendectomy with ceco-anal anastomosis. The successful experience of laparoscopic subtotal colectomy, mesorectumectomy for this pathology is described in the article. PMID- 25042190 TI - [State of duodenal patency in patients with postgastrectomy syndromes]. AB - It was analyzed the examination and treatment results of 100 patients who underwent resection of stomach by Billroth-I in case of peptic ulcer. Chronic disorders of duodenal patency were diagnosed in 86% of patients. The main role of chronic disorders of duodenal patency in postgastrectomy syndromes development was proved. There were a combination of reflux gastritis with dumping syndrome in 66.3% of patients, a combination of reflux gastritis with recurrent ulcer in 8.1% of patients. Correction of chronic disorders of duodenal patency is necessary stage in conservative and surgical treatment of postgastrectomy syndromes. PMID- 25042192 TI - [Surgical treatment of humerus condylar fracture]. AB - 55 patients with intra-articular condyles fractures of humerus were operated in terms 1998 to 2013 year in the Clinic of Traumatology and Orthopedics of the Presidential Administration. All patients were operated by using of perosseous osteosynthesis method with external fixing device design A.I. Gorodnichenko. Indications for osteosynthesis were open and closed fractures of C1,2,3 types accordingly to AO Classification. Closed, atraumatic and reliable fixation of bone fragments intensifies patients faster, improves their life quality, decreases time of hospitalization and minimizes complications rate. Fractures consolidation was achieved in all cases. It was observed such complications as soft tissue inflammatory around shafts in 4 (7.3%) observations. Long-term results were studied in 51 (92.7%) patients including 9 (17.6%) patients with excellent results, 24 (47.1%) patients with good results and 18 (35.3%) patients with satisfactory results. It was not detected unsatisfactory results. The method permits early reconstructive treatment of patients and improves functional results in case of condyles fractures. This preserves active moving function of damaged elbow from the first day after operation and during all period of treatment. PMID- 25042193 TI - [Treatment of purulent wounds by using of negative pressure]. AB - It was analyzed the results of wounds treatment complicated by surgical infection. An apparatus for creating negative pressure VivanoTec/S042 was used for this in 74 patients. Types of surgical interventions depended on phase of inflammatory process and severity of clinical manifestations. It was done 153 operations. Surgical management of infected wounds, necrectomy were performed. As the relief of inflammatory process repeated surgical management with plasty by using of local tissue was done. Short-term good anatomical results were achieved in 97% of patients. Good functional result was marked in all patients. Wound healing occurred at the optimum time. PMID- 25042194 TI - [Treatment of acute deep vein thrombosis with new oral anticoagulant rivaroxaban: the first experience]. AB - The aim of the study was to make a preliminary assessment of the efficacy and safety of acute deep vein thrombosis (DVT) prolonged treatment with new oral anticoagulant rivaroxaban. Materials and methods. It was a prospective observational study included patents with instrumentally verified DVT admitted to the Department of Vascular Surgery of the Clinical Hospital n.1 President's Administration of Russian Federation. All patients were administrated to the initial treatment with low-molecular weight heparins during first 24-48 hours followed by overlapped therapy with vitamin-K-antagonists. Patients who rejected a standard therapy were offered an alternative oral anticoagulant rivaroxaban: 15 mg bid during first 3 weeks followed by 20 mg qd. The duration of therapy varied from 3 to 12 month and more depend on localization and clinical provocation of the thrombosis. The dynamic control was performed on 3rd, 6th, 9th and 12th month. The endpoints of the study were recurrent DVT verified with duplex ultrasound or pulmonary embolism (PE) and hemorrhagic complications. In the study were enrolled 30 patients aged 27-87 years (mean age - 59.0+/-16.8), 13 men and 17 women who had from 0 to 6 individual risk factors (average - 2.4+/-1.6). In 33.3% cases DVT was clinically provoked and in 66.7% - unprovoked. Results. There were no recurrent DVT or PE observed. Cumulative rate of bleeding was 13.3% (95% CI: 1.2-25.5%): 6.65% (95% CI: 1.8-21.3%) - minor bleeding , that did not need drug withdrawal or extra visit to the doctor, and 6.65% (95% CI: 1.8-21.3%) - clinically significant bleeding, that needed an unscheduled visit to the doctor, the temporary interruption of the therapy or medical intervention. Major bleeding were not identified. Bleeding were presented as hematuria, petechial skin hemorrhages and epistaxis. Conclusion. The study demonstrates feasibility and safety of the new oral anticoagulant rivaroxaban application in the prolonged treatment of acute DVT. PMID- 25042195 TI - [Medical and diagnostic tactics in case of iatrogenic injury of common bile duct]. PMID- 25042196 TI - [Cholecystectomy from mini-laparotomic access by using of special retractor illuminator]. PMID- 25042197 TI - [Treatment of patient with femur chronic medullary osteomyelitis and foreign bodies in the medullary canal]. PMID- 25042198 TI - Time-dependent effects of hydrophobic amine-containing drugs on lysosome structure and biogenesis in cultured human fibroblasts. AB - Many weakly basic amine-containing drugs are known to be extensively sequestered in acidic lysosomes by an ion trapping-type mechanism. The entrapment of drugs in lysosomes has been shown to influence drug activity, cancer cell selectivity, and pharmacokinetics and can cause the hyperaccumulation of various lipids associated with lysosomes. In this work, we have investigated the prolonged time-dependent effects of drugs on lysosomal properties. We have evaluated two amine-containing drugs with intermediate (propranolol) and high (halofantrine) relative degrees of lipophilicity. Interestingly, the cellular accumulation kinetics of these drugs exhibited a biphasic characteristic at therapeutically relevant exposure levels with an initial apparent steady-state occurring at 2 days followed by a second stage of enhanced accumulation. We provide evidence that this secondary drug accumulation coincides with the nuclear localization of transcription factor EB, a master regulator of lysosome biogenesis, and the appearance of an increased number of smaller and lipid-laden lysosomes. Collectively, these results show that hydrophobic lysosomotropic drugs can induce their own cellular accumulation in a time-dependent fashion and that this is associated with an expanded lysosomal volume. These results have important therapeutic implications and may help to explain sources of variability in drug pharmacokinetic distribution and elimination properties observed in vivo. PMID- 25042200 TI - Exploiting interleukin 6 in multicentric Castleman's disease. PMID- 25042199 TI - Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. METHODS: We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS: We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34.0%, 95% CI 11.1-54.8, p=0.0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1 1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION: Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING: Janssen Research & Development. PMID- 25042201 TI - A treatment for activated B-cell-like DLBCL? PMID- 25042203 TI - Localized crystallization of enantiomeric organic compounds on chiral micro patterns from various organic solutions. AB - The controlled crystallization of enantiomers of an organic compound (a cyclic phosphoric acid derivative) on templated micro-patterned functionalised surfaces is demonstrated. Areas where a complementary chiral thiol has been located were effective heterogeneous nucleation centres when a solution of the compound is evaporated slowly. Various organic solvents were employed, which present a challenge with respect to other examples when water is used. The solvent and the crystallization method have an important influence on the crystal growth of these compounds. When chloroform was employed, well-defined crystals grow away from the surface, whereas crystals grow in the plane from solutions in isopropanol. In both cases, nucleation is confined to the polar patterned regions of the surface, and for isopropanol growth is largely limited within the pattern, which shows the importance of surface chemistry for nucleation and growth. The apparent dependence on the enantiomer used in the latter case could imply stereo differentiation as a result of short-range interactions (the templating monolayer is disordered, even at the nanometre scale). The size of the pattern of chiral monolayer also determines the outcome of the crystallization; 5 MUm dots are most effective. Despite the low surface tension of the samples (relative to the high surface tension of water), differential solvation of the polar and hydrophobic layers of the solvents allows crystallization in the polar regions of the monolayer, therefore the polarity of the regions in which heterogeneous nucleation takes place is indeed very important. Despite the complex nature of the crystallization process, these results are an important step towards to the use of patterned surfaces for heterogeneous selective nucleation of enantiomers. PMID- 25042202 TI - Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20 positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. AB - BACKGROUND: Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non Hodgkin lymphoma. METHODS: In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20 positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. FINDINGS: From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. INTERPRETATION: Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. FUNDING: Janssen. PMID- 25042204 TI - Influences of different hysterectomy techniques on patients' postoperative sexual function and quality of life. AB - INTRODUCTION: Hysterectomy ranks among the most frequently performed gynecological surgical procedures. At the time of operation, the majority of patients are premenopausal and sexually active. Hence, detailed counseling about the effects of hysterectomy on postoperative sexuality and quality of life can be regarded as an integral part of preoperative counseling. However, available data on these subjects are limited and contradictory. AIM: The aim of this study was to assess quality of life and sexuality following three common hysterectomy procedures-total laparoscopic hysterectomy (TLH), supracervical laparoscopic hysterectomy (SLH), and vaginal hysterectomy (VH)-in premenopausal patients using the European Quality of Life Five-Dimension Scale (EQ-5D) and Female Sexual Function Index (FSFI). MAIN OUTCOME MEASURES: Preoperative and postoperative EQ 5D and FSFI scores were compared using the Wilcoxon signed-rank test. Kruskal Wallis analysis and Mann-Whitney U-test with post hoc Bonferroni correction were used to assess differences among the three subgroups. METHODS: All premenopausal patients who underwent TLH, SLH, or VH without adnexectomy due to benign uterine disorders between April 2011 and June 2013 at the Department of Gynaecology and Obstetrics of Saarland University Hospital were enrolled in this observational cohort study. Sexuality and quality of life status were assessed preoperatively and 6 months postoperatively using two standardized validated questionnaires: the FSFI, a multidimensional, self-reported instrument for the assessment of female sexual function, and the EQ-5D, a standardized, validated instrument to measure an individual's health status. RESULTS: Of 402 eligible patients, 237 completed the study. Patient characteristics and preoperative FSFI and EQ-5D scores did not differ among the three hysterectomy subgroups. Postoperative FSFI and EQ-5D scores were significantly higher (P <= 0.01) than preoperative scores for all procedures but did not differ among the groups. CONCLUSIONS: In this cohort of premenopausal women, hysterectomy without adnexectomy performed due to benign uterine pathologies had significant positive effects on postoperative sexual function and quality of life, regardless of the surgical technique used. PMID- 25042206 TI - Simple fabrication of flexible electrodes with high metal-oxide content: electrospun reduced tungsten oxide/carbon nanofibers for lithium ion battery applications. AB - A one-step and mass-production synthetic route for a flexible reduced tungsten oxide-carbon composite nanofiber (WO(x)-C-NF) film is demonstrated via an electrospinning technique. The WO(x)-C-NF film exhibits unprecedented high content of metal-oxides (~ 80 wt%) and good flexibility (the tensile strength of the specimen was 6.13 MPa) without the use of flexible support materials like CNTs or graphene. The WO(x)-C-NF film is directly used as an anode in a lithium ion battery (LIB). Compared with previously reported tungsten oxide electrodes, the WO(x)-C-NF film exhibits high reversible capacity (481 mA h g(-1)total electrode), stable cycle, and improved rate performance, without the use of additive carbon, a polymeric binder and a current collector. Moreover, control electrodes fabricated by conventional processes support the positive effects of both the freestanding electrode and metal-oxide embedded carbon 1-D nanofiber structure. PMID- 25042205 TI - Recent insights into the evolution of innate viral sensing in animals. AB - The evolution of viral sensors is likely to be shaped by the constraint imposed through high conservation of viral Pathogen-Associated Molecular Patterns (PAMPs), and by the potential for 'arms race' coevolution with more rapidly evolving viral proteins. Here we review the recent progress made in understanding the evolutionary history of two types of viral sensor, RNA helicases and Toll like receptors. We find differences both in their rates of evolution, and in the levels of positive selection they experience. We suggest that positive selection has been the primary driver of the rapid evolution of the RNA helicases, while selective constraint has been a stronger influence shaping the slow evolution of the Toll-like receptors. PMID- 25042207 TI - Stabilizing colloidal crystals by leveraging void distributions. AB - Colloids often crystallize into polymorphic structures, which are only separated by marginal differences in free energy. Due to this fact, the face-centred cubic and hexagonal close-packed hard-sphere morphologies, for example, usually crystallize simultaneously from a supersaturated solution. The resulting lack of long-range order in these polymorphic structures has been a significant barrier to the widespread application of these crystals in, for instance, photonic bandgap materials. Here, we report a simple method to stabilize one out of two competing polymorphs by exploiting the fact that they have significantly different spatial distributions of voids. We use a variety of polymeric additives whose geometries can be tuned such that their entropy loss, which is related to crystal void symmetries, is different in the two competing polymorphs. This, in turn, controls which polymorph is most thermodynamically stable, providing a generalizable means to stabilize a selected crystal polymorph from a suite of competing structures. PMID- 25042208 TI - Widespread occurrence of neonicotinoid insecticides in streams in a high corn and soybean producing region, USA. AB - Neonicotinoid insecticides are of environmental concern, but little is known about their occurrence in surface water. An area of intense corn and soybean production in the Midwestern United States was chosen to study this issue because of the high agricultural use of neonicotinoids via both seed treatments and other forms of application. Water samples were collected from nine stream sites during the 2013 growing season. The results for the 79 water samples documented similar patterns among sites for both frequency of detection and concentration (maximum:median) with clothianidin (75%, 257 ng/L:8.2 ng/L) > thiamethoxam (47%, 185 ng/L:<2 ng/L) > imidacloprid (23%, 42.7 ng/L: <2 ng/L). Neonicotinoids were detected at all nine sites sampled even though the basin areas spanned four orders of magnitude. Temporal patterns in concentrations reveal pulses of neonicotinoids associated with rainfall events during crop planting, suggesting seed treatments as their likely source. PMID- 25042209 TI - Identifying Risk Factors for Elder Falls in Geriatric Rehabilitation in Israel. AB - PURPOSE: To identify risk factors for elder falls in a geriatric rehabilitation center in Israel. DESIGN: Retrospective chart review study. METHODS: Four hundred and twelve medical records of inpatients in geriatric rehabilitation were retrospectively analyzed to compare between elders who sustained falls and those who did not. FINDINGS: Of elders hospitalized during this year, 14% sustained falls. Fallers included a high proportion of males, with little comorbidity, not obese, and cardiovascular patients. Falls occurred frequently during patients' first week at the facility, mostly during the daytime. The falls occurred frequently in patients' rooms, and a common scenario was a fall during transition. CONCLUSIONS: The research findings single out patients who are allegedly at a lower risk of falls than more complex patients. CLINICAL RELEVANCE: Caregivers in geriatric rehabilitation settings should pay attention to patients who are allegedly at a lower risk of falls than more complex patients, and to cardiovascular patients in particular. PMID- 25042210 TI - The nonrecurrent laryngeal nerve: anatomic and electrophysiologic algorithm for reliable identification. AB - OBJECTIVES/HYPOTHESIS: The recurrent laryngeal nerve (RLN) intraoperative monitoring (IONM) provides a new functional dynamic that adds to visual identification of the RLN to optimize its intraoperative management. Intraoperative monitoring has been applied to the initial identification of the RLN. We now apply IONM to the identification of the nonrecurrent laryngeal nerve (NRLN) and provide electrophysiologic and anatomic parameters to facilitate this technique of neural identification for the NRLN, which is at increased risk of injury during thyroid surgery. STUDY DESIGN: Retrospective. METHODS: A study of cases of the NRLN from consecutive thyroid surgeries with IONM was conducted. Preoperative and postoperative laryngoscopy was documented in all cases. RESULTS: Ten right-sided nerves (0.6%) were identified as NRLN. One hundred percent of NRLNs had documented normal preoperative and postoperative laryngeal function. Distal and proximal vagal nerve stimulation points that allowed for the electrophysiologic prediction of a nonrecurrence in all patients were identified. Electrophysiological normative parameters of NRLN were compared to those of the normal right RLN and right vagus nerves. CONCLUSION: Nonrecurrent laryngeal nerve is present in 0.6% of patients undergoing thyroid surgery. Intraoperative monitoring involving vagal stimulation at the defined distal and proximal points provides reliable electrophysiologic intraoperative verification of the presence of the NRLN. Three anatomical subtypes of right NRLN are noted that enable early identification of the NRLN. In conjunction with detailed knowledge of the NRLN anatomic pathways, they also may be helpful in preventing injury to the NRLN, which has been shown to be at higher risk during thyroid surgery. We provide an anatomic and electrophysiologic algorithm for reliable identification of the NRLN. LEVEL OF EVIDENCE: 4. PMID- 25042211 TI - Elastomeric thermal interface materials with high through-plane thermal conductivity from carbon fiber fillers vertically aligned by electrostatic flocking. AB - Electrostatic flocking is applied to create an array of aligned carbon fibers from which an elastomeric thermal interface material (TIM) can be fabricated with a high through-plane thermal conductivity of 23.3 W/mK. A high thermal conductivity can be achieved with a significantly low filler level (13.2 wt%). As a result, this material retains the intrinsic properties of the matrix, i.e., elastomeric behavior. PMID- 25042212 TI - Self-efficacy and acceptance of cravings to smoke underlie the effectiveness of quitline counseling for smoking cessation. AB - BACKGROUND: Few studies have examined why smoking cessation interventions are effective. The aim of this study was to examine the mediating processes underlying the effectiveness of cessation counseling administered by the Dutch national quitline. METHODS: Data were used of a two-arm randomized controlled trial in which smoking parents, who were recruited through primary schools in The Netherlands, received either quitline cessation counseling (n=256) or a self-help brochure (n=256). The endpoint was 6-months prolonged abstinence at 12-months follow-up, with 86.7% outcome data retention. Putative psychological mediators of treatment effectiveness included smoking-related cognitions (positive smoking outcome expectancies, self-efficacy), emotions (negative affect, perceived stress, depressive symptoms), and smoking cue coping methods (avoidance coping, acceptance coping) assessed at 3-months post-measurement. RESULTS: Quitline cessation counseling significantly decreased positive smoking outcome expectancies and negative affect and increased self-efficacy to refrain from smoking, avoidance of external cues to smoking, and acceptance of internal cues to smoking compared to self-help material. Increased self-efficacy to refrain from smoking in stressful and tempting situations (p<.001) and increased acceptance of cravings to smoke (p<.001) significantly mediated the effect of quitline cessation counseling on prolonged abstinence at 12-months follow-up (explained variance: 25.1%). CONCLUSIONS: Self-efficacy to refrain from smoking and acceptance of cravings represent an important source of therapeutic change in smoking cessation counseling. PMID- 25042213 TI - Effect of a primary care based brief intervention trial among risky drug users on health-related quality of life. AB - BACKGROUND: Improvement in quality of life (QOL) is a long term goal of drug treatment. Although some brief interventions have been found to reduce illicit drug use, no trial among adult risky (moderate non-dependent) drug users has tested effects on health-related quality of life. METHODS: A single-blind randomized controlled trial of patients enrolled from February 2011 to November 2012 was conducted in waiting rooms of five federally qualified health centers. 413 adult primary care patients were identified as risky drug users using the WHO ASSIST and 334 (81% response; 171 intervention, 163 control) consented to participate in the trial. Three-month follow-ups were completed by 261 patients (78%). Intervention patients received the QUIT intervention of brief clinician advice and up to two drug-use health telephone sessions. The control group received usual care and information on cancer screening. Outcomes were three month changes in the Short Form Health Survey (SF-12) mental health component summary score (MCS) and physical health component summary score (PCS). RESULTS: The average treatment effect (ATE) was non-significant for MCS (0.2 points, p value=0.87) and marginally significant for PCS (1.7 points, p-value=0.08). The average treatment effect on the treated (ATT) was 0.1 (p-value=0.93) for MCS and 1.9 (p-value=0.056) for PCS. The effect on PCS was stronger at higher (above median) baseline number of drug use days: ATE=2.7, p-value=0.04; ATT=3.21, p value=0.02. CONCLUSIONS: The trial found a marginally significant effect on improvement in PCS, and significant and stronger effect on the SF-12 physical component among patients with greater frequency of initial drug use. PMID- 25042215 TI - Net reclassification improvement and integrated discrimination improvement require calibrated models: relevance from a marker and model perspective. PMID- 25042214 TI - Taking a life course approach to studying substance use treatment among a community cohort of African American substance users. AB - BACKGROUND: Life course theory emphasizes the need to examine a wide variety of distal factors along with proximal factors, longitudinally. Yet research on who obtains substance use treatment is generally cross-sectional and limited to examining developmentally proximal factors (e.g., substance use severity) and demographic factors. METHODS: To investigate treatment within a life-course framework, we studied 522 drug and/or alcohol users from a community cohort of African Americans followed prospectively from age 6. Developmentally distal factors of childhood and adolescent social behavior, family environment, academic achievement, mental health, and substance use along with the key proximal factors of substance use severity and socioeconomic status were examined using regression analyses to assess their impact on obtaining adult substance use treatment. RESULTS: One-fifth of the study population obtained treatment for substance use by age 32 (20.5%). Although adult socioeconomic status was not associated with substance use treatment in adulthood in the multivariable model, the proximal factor of substance use severity was a strong predictor of obtaining substance use treatment, as expected. After including several developmentally distal factors in the model, childhood aggression also had an independent effect on adult substance use treatment, above and beyond substance use severity. CONCLUSIONS: These findings emphasize the importance of using a life course framework when exploring predictors of treatment; early life characteristics are important influences beyond the more proximal factors in adulthood. Research should continue to take a life course approach to better understand pathways to substance use treatment. PMID- 25042216 TI - Calibration of models is not sufficient to justify NRI. PMID- 25042217 TI - HIV: science and stigma. PMID- 25042218 TI - Europe's responsibility to refugees: health beyond borders. PMID- 25042219 TI - Rare diseases in children: towards better and fairer treatment. PMID- 25042220 TI - Towards a cure for HIV--are we making progress? PMID- 25042221 TI - Antiretroviral therapy: stubborn limitations persist. PMID- 25042222 TI - Bending the curve: maximising impact with focused HIV prevention. PMID- 25042224 TI - Sharon Lewin: guiding us towards a cure for HIV. PMID- 25042225 TI - Treatment of adolescents with anorexia nervosa. PMID- 25042226 TI - Why primary health-care interventions for intimate partner violence do not work. PMID- 25042227 TI - Treatment of adolescents with anorexia nervosa--authors' reply. PMID- 25042228 TI - Interventions for people with schizophrenia and their caregivers in India. PMID- 25042229 TI - Interventions for people with schizophrenia and their caregivers in India- authors' reply. PMID- 25042230 TI - Preoperative chemotherapy for non-small-cell lung cancer. PMID- 25042231 TI - Standardised packaging and tobacco-industry-funded research. PMID- 25042232 TI - Preoperative chemotherapy for non-small-cell lung cancer--authors' reply. PMID- 25042233 TI - Hypertension in populations of different ethnic origins. PMID- 25042235 TI - Maximising the effect of combination HIV prevention through prioritisation of the people and places in greatest need: a modelling study. AB - BACKGROUND: Epidemiological data show substantial variation in the risk of HIV infection between communities within African countries. We hypothesised that focusing appropriate interventions on geographies and key populations at high risk of HIV infection could improve the effect of investments in the HIV response. METHODS: With use of Kenya as a case study, we developed a mathematical model that described the spatiotemporal evolution of the HIV epidemic and that incorporated the demographic, behavioural, and programmatic differences across subnational units. Modelled interventions (male circumcision, behaviour change communication, early antiretoviral therapy, and pre-exposure prophylaxis) could be provided to different population groups according to their risk behaviours or their location. For a given national budget, we compared the effect of a uniform intervention strategy, in which the same complement of interventions is provided across the country, with a focused strategy that tailors the set of interventions and amount of resources allocated to the local epidemiological conditions. FINDINGS: A uniformly distributed combination of HIV prevention interventions could reduce the total number of new HIV infections by 40% during a 15-year period. With no additional spending, this effect could be increased by 14% during the 15 years-almost 100,000 extra infections, and result in 33% fewer new HIV infections occurring every year by the end of the period if the focused approach is used to tailor resource allocation to reflect patterns in local epidemiology. The cumulative difference in new infections during the 15-year projection period depends on total budget and costs of interventions, and could be as great as 150,000 (a cumulative difference as great as 22%) under different assumptions about the unit costs of intervention. INTERPRETATION: The focused approach achieves greater effect than the uniform approach despite exactly the same investment. Through prioritisation of the people and locations at greatest risk of infection, and adaption of the interventions to reflect the local epidemiological context, the focused approach could substantially increase the efficiency and effectiveness of investments in HIV prevention. FUNDING: The Bill & Melinda Gates Foundation and UNAIDS. PMID- 25042236 TI - A 48-year-old woman with panic attacks. PMID- 25042237 TI - Is muscle hypertrophy following resistance exercise regulated by truncated splice variants of PGC-1alpha? PMID- 25042238 TI - Chiral dirhodium(II) carboxylates and carboxamidates as effective chemzymes in asymmetric synthesis of three-membered carbocycles. AB - In this review the recent advances in the utilization of two of the most important classes of dirhodium(II) paddlewheel complexes, dirhodium(II) carboxylates and carboxamidates, as chemzymes in inter- and intramolecular asymmetric cyclopropanation, as well as cyclopropenation reactions are discussed. PMID- 25042239 TI - Simultaneous determination of oleanolic acid, ursolic acid, quercetin and apigenin in Swertia mussotii Franch by capillary zone electrophoresis with running buffer modifier. AB - The method of capillary zone electrophoresis (CZE) with direct UV detection was developed for the determination of oleanolic acid, ursolic acid, quercetin and apigenin. and then for the first time successfully applied to the analysis of four analytes in Swertia mussotii Franch and its preparations. Various factors affecting the CZE procedure were investigated and optimized, and the optimal conditions were: 50 * 10(-3) mol/L borate-phosphate buffer (pH 9.5) with 5.0 * 10(-3) mol/L beta-cyclodextrin, 15 kV separation voltage, 20 degrees C column temperature, 250 nm detection wavelength and 5 s electrokinetic injection time (voltage 20 psi). Under the conditions, oleanolic acid, ursolic acid, quercetin and apigenin could be determined within the test ranges with a good correlation coefficient (r(2) > 0.9991). The limits of detection for conditions, oleanolic acid, ursolic acid, quercetin and apigenin were 0.3415, 0.2003, 0.0062 and 0.2538 ug/mL, respectively, and the intra- and inter-day relative standard deviations were no more than 4.72%. This procedure provided a convenient, sensitive and accurate method for simultaneous determination of oleanolic acid, ursolic acid, quercetin and apigenin in S. mussotii Franch. PMID- 25042240 TI - An overview of the nutritional value of beef and lamb meat from South America. AB - The southern region of South America, a subtropical and temperate zone, is an important region for the production of beef and lamb meat, which is mainly produced in extensive pasture-based systems. Because of its content in highly valuable nutrients such as iron, zinc, selenium, fatty acids, and vitamins, meat is a unique and necessary food for the human diet in order to secure a long and healthy life, without nutritional deficiencies. Beef and lamb production systems based on temperate or tropical grasslands show interesting and, in some cases, a differential content in minerals, fatty acids and vitamins. This review deals with the distinctive aspects of the nutritional quality of beef and lamb meat produced in this region in terms of nutritional composition and the bioavailability of key nutrients related to its contribution for a healthy diet for all ages. PMID- 25042241 TI - Use of mild irradiation doses to control pathogenic bacteria on meat trimmings for production of patties aiming at provoking minimal changes in quality attributes. AB - The objectives of the present work were to assess the use of moderate doses of gamma irradiation (2 to 5 kGy) and to reduce the risk of pathogen presence without altering the quality attributes of bovine trimmings and of patties made of irradiated trimmings. Microbiological indicators (coliforms, Pseudomonas spp and mesophilic aerobic counts), physicochemical indicators (pH, color and tiobarbituric acid) and sensory changes were evaluated during storage. 5 kGy irradiation doses slightly increased off flavors in patties. Two pathogenic markers (Listeria monocytogenes and Escherichia coli O157:H7) were inoculated at high or low loads to trimming samples which were subsequently irradiated and lethality curves were obtained. Provided that using irradiation doses <=2.5 kGy are used, reductions of 2 log CFU/g of L. monocytogenes and 5 log CFU/g of E. coli O157:H7 are expected. It seems reasonable to suppose that irradiation can be successfully employed to improve the safety of frozen trimmings when initial pathogenic bacteria burdens are not extremely high. PMID- 25042242 TI - Can proline-rich polypeptide complex mimic the effect of nerve growth factor? AB - Naturally occurring compounds that can act as prosurvival factors and neurite formation stimulants in the conditions of reduced neurotrophins production are important both in neuronal protection and therapy of neurodegenerative disorders. Therefore, the role of proline-rich polypeptide complex (PRP) and its nonapeptide fragment (NP) in the promotion of pheochromocytoma cell line (PC12) survival and neurite outgrowth pathway is presented. It was shown that PRP/NP did not affect the neuronal nitric oxide synthase (nNOS) at the transcriptional and protein level. However, the activity of nNOS and intracellular nitric oxide (NO) concentration was markedly increased after treatment of PC12 cells with peptides. This reaction was inhibited by L-NAME-nNOS inhibitor. It was shown that PRP and NP induce the soluble guanylyl cyclase to release higher amount of cyclic GMP (cGMP), and subsequently, the increased phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1/2) is observed. This effect was abolished by both U0126 (inhibitor of ERK1/2) and also by L-NAME. Reduction of ERK1/2 activity observed in the presence of nNOS inhibitor suggests that its activation is NO dependent. The presented results shed some light on the mechanism of action of PRP complex. PRP and NP can activate NO/cGMP/ERK1/2 signaling pathway, similarly to nerve growth factor (NGF). The prosurvival action and short fibers formation suggest the role of PRP and NP in neuroprotection and the initiation of neuritogenesis. They can also participate in the amplification of signals controlling the survival and differentiation of neurons effect when the deficit of NGF takes place. PMID- 25042243 TI - [Hepatitis induced by glatiramer acetate]. PMID- 25042244 TI - Uptake and effects of a mixture of widely used therapeutic drugs in Eruca sativa L. and Zea mays L. plants. AB - Pharmaceutically active compounds (PACs) are continuously dispersed into the environment due to human and veterinary use, giving rise to their potential accumulation in edible plants. In this study, Eruca sativa L. and Zea mays L. were selected to determine the potential uptake and accumulation of eight different PACs (Salbutamol, Atenolol, Lincomycin, Cyclophosphamide, Carbamazepine, Bezafibrate, Ofloxacin and Ranitidine) designed for human use. To mimic environmental conditions, the plants were grown in pots and irrigated with water spiked with a mixture of PACs at concentrations found in Italian wastewaters and rivers. Moreover, 10* and 100* concentrations of these pharmaceuticals were also tested. The presence of the pharmaceuticals was tested in the edible parts of the plants, namely leaves for E. sativa and grains for Z. mays. Quantification was performed by liquid chromatography mass spectroscopy (LC/MS/MS). In the grains of 100* treated Z. mays, only atenolol, lincomycin and carbamazepine were above the limit of detection (LOD). At the same concentration in E. sativa plants the uptake of all PACs was >LOD. Lincomycin and oflaxacin were above the limit of quantitation in all conditions tested in E. sativa. The results suggest that uptake of some pharmaceuticals from the soil may indeed be a potential transport route to plants and that these environmental pollutants can reach different edible parts of the selected crops. Measurements of the concentrations of these pharmaceuticals in plant materials were used to model potential adult human exposure to these compounds. The results indicate that under the current experimental conditions, crops exposed to the selected pharmaceutical mixture would not have any negative effects on human health. Moreover, no significant differences in the growth of E. sativa or Z. mays plants irrigated with PAC-spiked vs. non-spiked water were observed. PMID- 25042245 TI - Quantification of Salmonella Typhi in water and sediments by molecular-beacon based qPCR. AB - A molecular-beacon based qPCR assay targeting staG gene was designed for specific detection and quantification of S. Typhi and validated against water and sediment samples collected from the river Ganga, Yamuna and their confluence on two days during Mahakumbha mela 2012-2013 (a) 18 December, 2012: before six major religious holy dips (Makar Sankranti, Paush Poornima, Mauni Amavasya, Basant Panchami, Maghi Poornima and Mahashivratri) (b) 10 February, 2013: after the holy dip was taken by over 3,00,00,000 devotees led by ascetics of Hindu sects at Sangam on 'Mauni Amavasya' (the most auspicious day of ritualistic mass bathing). The assay could detect linearly lowest 1 genomic equivalent per qPCR and is highly sensitive and selective for S. Typhi detection in presence of non specific DNA from other bacterial strains including S. Paratyphi A and S. Typhimurium. It has been observed that water and sediment samples exhibit S. Typhi. The mass holy dip by devotees significantly affected the water and sediment quality by enhancing the number of S. Typhi in the study area. The qPCR developed in the study might be helpful in planning the intervention and prevention strategies for control of enteric fever outbreaks in endemic regions. PMID- 25042246 TI - Prediction of gas/particle partition quotients of Polybrominated Diphenyl Ethers (PBDEs) in north temperate zone air: an empirical approach. AB - Gas/particle (G/P) partitioning process is an important factor governing the transport and fate of chemicals in the atmosphere. Based on a large dataset of more than 700 pairs of air samples in gaseous and particulate phases with a wide ambient temperature range of 60 degrees C from -22 degrees C to +38 degrees C obtained from our Chinese POPs Soil and Air Monitoring Program, Phase 2 (China SAMP-II), we investigated G/P partitioning behavior of polybrominated diphenyl ether (PBDEs) in Chinese air. We derived for the first time empirical equations to predict the values of slopes and intercepts for both subcooled-liquid-vapor pressure (PL)-based and octanol-air-partition-coefficient (KOA)-based models as functions of temperature, and thus predicted partition quotient (KP) without assuming an equilibrium status and free of artifacts. These equations have been successfully applied to predict the values of KP for PBDEs in air of China and other countries in the north temperate zone (NTZ) and also at an Arctic site in East Greenland, and our results matched the monitoring data well at background, rural, urban, and suburban sites, but not at e-waste sites due to the unpredictable PBDE emissions at these sites. Our equations predicted that the ranges of slopes were 0.02-0.82 for logKP-logKOA plots and -0.82 to -0.02 for logKP-logPL plots at temperatures ranged of 60 degrees C from -22 degrees C to +38 degrees C. Our new KOA-based equation was compared with the Harner-Bidleman equation that was derived at a condition of equilibrium, and the results indicated that our new equation has a better performance than the Harner-Bidleman equation in describing G/P partitioning behavior of PBDEs in air as functions of logKOA. We also found for the first time that the G/P partitioning of PBDE congeners would become saturated in the particulate phase respect to the gas phase if the ambient temperature is low enough. A criterion to classify the equilibrium and nonequilibrium status for PBDEs was also established using logKOA. The study presented in this paper provides a useful tool for environmental scientists in both monitoring and modeling research on G/P partitioning behavior for PBDEs in air. PMID- 25042247 TI - Physiological and biochemical responses of Chlorella vulgaris to Congo red. AB - Extensive use of synthetic dyes in many industrial applications releases large volumes of wastewater. Wastewaters from dying industries are considered hazardous and require careful treatment prior to discharge into receiving water bodies. Dyes can affect photosynthetic activities of aquatic flora and decrease dissolved oxygen in water. The aim of this study was to evaluate the effect of Congo red on growth and metabolic activity of Chlorella vulgaris after 96h exposure. Exposure of the microalga to Congo red reduced growth rate, photosynthesis and respiration. Analysis of chlorophyll a fluorescence emission showed that the donor side of photosystem II was affected at high concentrations of Congo red. The quantum yield for electron transport (phiEo), the electron transport rate (ETR) and the performance index (PI) also decreased. The reduction in the ability to absorb and use the quantum energy increased non-photochemical (NPQ) mechanisms for thermal dissipation. Overall, Congo red affects growth and metabolic activity in photosynthetic organisms in aquatic environments. PMID- 25042248 TI - Soil fluoride spiking effects on olive trees (Olea europaea L. cv. Chemlali). AB - A pot experiment under open air conditions was carried out to investigate the uptake, accumulation and toxicity effects of fluoride in olive trees (Olea europaea L.) grown in a soil spiked with inorganic sodium fluoride (NaF). Six different levels (0, 20, 40, 60, 80 and 100mM NaF) of soil spiking were applied through NaF to irrigation water. At the end of the experiment, total fluoride content in soil was 20 and 1770mgFkg(-1) soil in control and 100mM NaF treatments, respectively. The comparative distribution of fluoride partitioning among the different olive tree parts showed that the roots accumulated the most fluoride and olive fruits were minimally affected by soil NaF spiking as they had the lowest fluoride content. In fact, total fluoride concentration varied between 12 and 1070ugFg(-1) in roots, between 9 and 570ugFg(-1) in shoots, between 12 and 290ugFg(-1) in leaves, and between 10 and 29ugFg(-1) in fruits, respectively for control and 100mM NaF treatments. Indeed, the fluoride accumulation pattern showed the following distribution: roots>shoots>leaves>fruits. On the other hand, fluoride toxicity symptoms such as leaf necrosis and leaf drop appeared only in highly spiked soils (60, 80 and 100mM NaF). PMID- 25042249 TI - Photodegradation of organophosphorus pesticides in honey medium. AB - Honey can be polluted due to environmental pollution and misuse of beekeeping practices. In the present study, photodegradation experiments of organophosphorus pesticides (coumaphos, methyl parathion and fenitrothion) in honey medium were conducted using Atlas Suntest simulator CPS+ as a sunlight producer. Photodegradation experiments were conducted under three different intensities as 250W/m(2), 500W/m(2) and 750W/m(2) to evaluate the impact of sunlight intensity on removal of OPs in honey medium. Significant decreases of three OPs' concentrations were observed. Coumaphos showed the highest degradability, reaching a degradation percentage of 90 percent within 15min. After 1h irradiation, residual percentages of coumaphos were 6.62 percent for 250W/m(2), 3.48 percent for 500W/m(2) and 2.98 percent for 750W/m(2), respectively. Methyl parathion and fenitrothion also could be removed through photodegradation efficiently. After 1h irradiation, the residual percentages of methyl parathion and fenitrothion under 750W/m(2) sunlight irradiation were 26.89 percent and 16.70 percent, respectively. Intensity of sunlight showed a positive impact on removal of OPs in honey medium. The higher intensity, the lower residual percentage. Photodegradation of three OPs fitted well with pseudo-first order kinetics. Half-lives calculated from pseudo-first order kinetics were 17.61min (250W/m(2)), 16.67min (500W/m(2)) and 17.58min (750W/m(2)) for coumaphos, 57.62min (250W/m(2)), 34.13min (500W/m(2)) and 31.69min (750W/m(2)) for methyl parathion and 144.70min (250W/m(2)), 95.47min (500W/m(2)) and 22.57min (750W/m(2)) for fenitrothion, respectively. Most of the three OPs could dissipate in a short time under sunlight irradiation. Photodegradation could be accepted as an appropriate method for the removal of OPs in honey medium. PMID- 25042250 TI - Contaminants as habitat disturbers: PAH-driven drift by Andean paramo stream insects. AB - Contaminants can behave as toxicants, when toxic effects are observed in organisms, as well as habitat disturbers and fragmentors, by triggering avoidance responses and generating less- or uninhabited zones. Drift by stream insects has long been considered a mechanism to avoid contamination by moving to most favorable habitats. Given that exploration and transportation of crude oil represent a threat for surrounding ecosystems, the key goal of the present study was to assess the ability of autochthonous groups of aquatic insects from the Ecuadorian paramo streams to avoid by drift different concentrations of polycyclic aromatic hydrocarbons (PAH) contained in the soluble fraction of locally transported crude oil. In the laboratory, different groups of insects were exposed to PAH for 12h. Three different assays, which varied in taxa and origin of the organisms, concentrations of PAH (0.6-38.8ugL(-1)), and environment settings (different levels of refuge and flow) were performed. For Anomalocosmoecus palugillensis (Limnephilidae), drift was a major cause of population decline in low concentration treatments but at higher concentrations mortality dominated. PAH was highly lethal, even at lower concentrations, for Chironomidae, Grypopterygidae (Claudioperla sp.) and Hydrobiosidae (Atopsyche sp.), and, therefore, no conclusion about drift can be drawn for these insects. Contamination by PAH showed to be a threat for benthic aquatic insects from Ecuadorian paramo streams as it can cause a population decline due to avoidance by drift and mortality. PMID- 25042251 TI - 3D-isotropic high-resolution morphological imaging and quantitative T2 mapping as biomarkers for gender related differences after matrix-associated autologous chondrocyte transplantation (MACT). AB - The aim of this study was to determine in vivo high-resolution morphological and biochemical gender related differences in cartilage repair tissue (MACT). Forty patients were examined clinically and by MR scans at 3T-MRI (coronal 3D True-FISP sequence for morphologic assessment and multi-echo spin-echo T2-mapping for biochemical assessment of healthy cartilage and MACT cartilage). Mean T2 values in repair tissue in the deep zone showed significantly shorter T2 times in females (p = 0.009, female 43.5 +/- 9.8 vs. male 48.2 +/- 7.7 ms). The superficial zone showed higher T2 values than the deep zone in both the groups (female 48.5 +/- 9.8, males 52.6 +/- 11.0 ms) without significant difference between female and male patients. Native control cartilage showed no statistically significant differences for T2 between females and males. The subdivisions "structure of the repair tissue" and "subchondral bone" of the MOCART score showed statistically significant differences between females and males (p = 0.026 and p = 0.007) as well as the Lysholm score (p = 0.03). Our investigations revealed differences between female and male patients after MACT of the knee in clinical outcome and advanced morphological and biochemical MRI. The presented imaging biomarkers can depict subtle changes after cartilage regeneration procedures and might help to understand gender related differences after cartilage repair procedures. PMID- 25042253 TI - Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7 carboxamides as oral PI3Kbeta inhibitors, useful as antiplatelet agents. AB - Optimization of AZD6482 (2), the first antiplatelet PI3Kbeta inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kalpha to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kbeta inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance. PMID- 25042234 TI - Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. AB - BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals. PMID- 25042254 TI - Novel inhibitors of human histone deacetylases: design, synthesis and bioactivity of 3-alkenoylcoumarines. AB - Histone deacetylases (HDACs) are well-established, promising targets for anticancer therapy due to their critical role in cancer development. Accordingly, an increasing number of HDAC inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a large panel of chemical structures was described including coumarin-containing molecules. In this study, we described synthesis and biological activity of new coumarin-based derivatives as HDAC inhibitors. Among eight derivatives, three compounds showed HDAC inhibitory activities and antitumor activities against leukemia cell lines without affecting the viability of peripheral blood mononuclear cells from healthy donors. PMID- 25042255 TI - Design and synthesis of phenolic hydrazide hydrazones as potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors. AB - Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes responsible for catalyzing the formation and degradation of poly(ADP ribose) (PAR) polymers, respectively. Activation of PARP has been shown to be involved in cell death induced by genotoxic stimuli. On the other hand, genetic disruption of PARG also leads to increased level of cell death by accumulation of PAR. Unlike PARP, where significant medicinal effort has been expended to identify potent inhibitors, PARG has been insufficiently investigated as a molecular therapeutic target. In this study, we report the design, synthesis, and biological evaluation of phenolic hydrazide hydrazones as potent PARG inhibitors. Compounds 3d, 3e, 5d, 5e, 8a, 8b and 8c showed their ability to inhibit the catalytic activity of PARG in vitro with IC50 values of 1.0, 2.1, 3.1, 3.2, 3.1, 2.8 and 1.6 MUM, respectively. PMID- 25042257 TI - Overtreatment of men with early-stage prostate cancer and limited life expectancy. PMID- 25042258 TI - Application of bioreactor design principles and multivariate analysis for development of cell culture scale down models. AB - A bench scale cell culture model representative of manufacturing scale (2,000 L) was developed based on oxygen mass transfer principles, for a CHO-based process producing a recombinant human protein. Cell culture performance differences across scales are characterized most often by sub-optimal performance in manufacturing scale bioreactors. By contrast in this study, reduced growth rates were observed at bench scale during the initial model development. Bioreactor models based on power per unit volume (P/V), volumetric mass transfer coefficient (kL a), and oxygen transfer rate (OTR) were evaluated to address this scale performance difference. Lower viable cell densities observed for the P/V model were attributed to higher sparge rates and reduced oxygen mass transfer efficiency (kL a) of the small scale hole spargers. Increasing the sparger kL a by decreasing the pore size resulted in a further decrease in growth at bench scale. Due to sensitivity of the cell line to gas sparge rate and bubble size that was revealed by the P/V and kL a models, an OTR model based on oxygen enrichment and increased P/V was selected that generated endpoint sparge rates representative of 2,000 L scale. This final bench scale model generated similar growth rates as manufacturing. In order to take into account other routinely monitored process parameters besides growth, a multivariate statistical approach was applied to demonstrate validity of the small scale model. After the model was selected based on univariate and multivariate analysis, product quality was generated and verified to fall within the 95% confidence limit of the multivariate model. PMID- 25042256 TI - Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction. AB - We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232. PMID- 25042259 TI - Loss of LKB1 in high-grade endometrial carcinoma: LKB1 is a novel transcriptional target of p53. AB - BACKGROUND: Liver kinase B1 (LKB1) is a serine/threonine kinase that functions as a tumor suppressor and regulates cell polarity, proliferation, and metabolism. Mutations in LKB1 are associated with Peutz-Jeghers syndrome as well as sporadic cervical and lung cancers. Although LKB1-null mice develop invasive endometrial cancers, the role and regulation of LKB1 in the pathogenesis of human endometrial cancer are not well defined and are the focus of these studies. METHODS: LKB1 protein and messenger RNA (mRNA) expression levels were evaluated in high-grade and low-grade endometrioid endometrial cancer (EEC) and cell lines by reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and immunohistochemistry. Mutational and promoter analyses of the LKB1 gene (serine/threonine kinase 11 [STK11]) were performed to identify the mechanisms that contribute to the loss of LKB1 in high-grade EEC. RESULTS: Analysis of the LKB1 gene in low-grade and high-grade EECs revealed no genetic mutations, suggesting that alterations in LKB1 transcription may be responsible for LKB1 protein loss in high-grade EEC. Analysis of the LKB1 promoter revealed 4 putative tumor protein 53 (p53) binding sites. Quantitative chromatin immunoprecipitation demonstrated that p53 bound directly to 1 of these sites and increased LKB1 promoter activity 140-fold. LKB1 promoter activity, mRNA, and protein levels were suppressed after silencing of p53 with small interfering RNA and were elevated in cells that overexpressed p53. Levels of p53 mRNA and protein expression were decreased in high-grade EEC and were positively correlated with LKB1 protein levels (Spearman correlation, r=0.601; P<.001). CONCLUSIONS: LKB1 is a direct transcriptional target of p53. The loss of wild-type p53 in high-grade EEC may contribute to the LKB1 loss observed in these more aggressive tumors. PMID- 25042260 TI - System review and meta-analysis on photodynamic therapy in central serous chorioretinopathy. AB - PURPOSE: To evaluate the effect of photodynamic therapy (PDT) on central serous chorioretinopathy (CSC) compared with laser therapy and intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs, and to find the maximum treatment effect with minimal dose and fluence of PDT. METHODS: A systematic electronic search was conducted in Feb 2013 in PubMed, Embase, ISI Web of Knowledge and the Cochrane library. The main outcome factors were compared in best-corrected visual acuity (BCVA), central macular thickness (CMT) and resolution of subretinal fluid (SRF). Meta-analysis was performed when it is appropriate. The comparisons were designed into four groups: group 1, PDT versus laser photocoagulation; group 2, PDT versus intravitreal injection of anti-VEGF drugs; group 3, half-dose verteporfin PDT versus placebo; group 4, half-fluence PDT versus full-fluence PDT. RESULTS: We retrieved nine reports of studies including a total of 319 patients. In group 1, the summary result indicated that PDT was superior in resolution of SRF (p = 0.005) than laser photocoagulation. In group 2, PDT could resolute SRF (p = 0.007) and decrease CMT (p = 0.002) more rapidly than intravitreal injection of anti-VEGF drugs. In group 3, half-dose PDT was effective in improving BCVA (p < 0.00001), decreasing CMT (p = 0.001) and resolving SRF (p < 0.001). In group 4, half-fluence PDT was effective and could significantly decrease the hypoxic damage which was caused by PDT (p < 0.001). CONCLUSION: PDT is a promising therapy for CSC patients and the parameters of PDT can be adjusted to obtain the maximum treatment effect with minimal adverse effects. PMID- 25042261 TI - Imaging for interventional cardiologists: the sine qua non condition. PMID- 25042262 TI - Measurements matters: the case for 3D MSCT software for aortic annulus quantification. PMID- 25042263 TI - Hybrid intravascular imaging: the key for a holistic evaluation of plaque pathology. PMID- 25042264 TI - Sustained progress through continuity: a new presidential criss-cross. PMID- 25042265 TI - Unexpected calcification after direct intravascular injection of autologous bone marrow-derived cells in a chronic total occlusion model. AB - AIMS: Patients with symptomatic chronic total occlusions (CTO) remain a therapeutic challenge. Enhancement of intraluminal neovascularisation by pro angiogenic therapies has been proposed as a new strategy to improve percutaneous revascularisation. The aim of this study was to investigate the effects of intraluminal injection of bone marrow-derived cells (BMC) into experimental CTO. METHODS AND RESULTS: CTO were created in the femoral arteries of 43 New Zealand White rabbits using the thrombin injection model. At 12 weeks following CTO creation, 33 rabbits were injected with either cultured BMC (n=19) or control DMEM alone (n=14) directly into the CTO. Ten rabbits were used for cell tracking (seven BMC and three control). BMC labelled with fluorescent Qdot(r) nanocrystals were identified in the CTO up to one week after injection. Animals were sacrificed at three to five weeks post-treatment and arterial samples were excised for micro-CT imaging and histologic morphometric analysis. There was a significant but modest increase in neovascularisation in BMC-treated arteries compared to controls (7.47+/-4.75% vs. 4.35+/-2.97%, p<0.05). However, unexpected intravascular calcification was only detected within the CTO in BMC cell treated arteries. Western blot for conditioned medium from BMC showed up-regulation of osteogenic proteins (BMP-2 and -7). CONCLUSIONS: Although direct delivery of BMC into CTO increases neovascularisation, undesirable vascular calcification will limit this therapeutic approach. PMID- 25042266 TI - A randomised comparison of transradial and transfemoral approach for carotid artery stenting: RADCAR (RADial access for CARotid artery stenting) study. AB - AIMS: Limited data exist on radial access in carotid artery stenting. This multicentre prospective randomised study was performed to compare the outcome and complication rates of transradial and transfemoral carotid artery stenting. METHODS AND RESULTS: The clinical and angiographic data of 260 consecutive patients with high risk for carotid endarterectomy, treated between 2010 and 2012 by carotid stenting with cerebral protection, were evaluated. Patients were randomised to transradial (n=130) or transfemoral (n=130) groups and several parameters were evaluated. Primary combined endpoint: major adverse cardiac and cerebral events, rate of access-site complications. Secondary endpoints: angiographic outcome of the procedure, fluoroscopy time and X-ray dose, procedural time, crossover rate to another puncture site and hospitalisation in days. Procedural success was achieved in all 260 patients (100%), the crossover rate was 10% in the TR and 1.5% in the TF group (p<0.05). A major access-site complication was encountered in one patient (0.9%) in the TR group and in one patient (0.8%) in the TF group (p=ns). The incidence of major adverse cardiac and cerebral events was 0.9% in the TR and 0.8% in the TF group (p=ns). Procedure time (1,620 [1,230-2,100] vs. 1,500 [1,080-2,100] sec, p=ns) and fluoroscopy time (540 [411-735] vs. 501 [378-702] sec, p=ns) were not significantly different, but the radiation dose was significantly higher in the TR group (195 [129-274] vs. 148 [102-237] Gy*cm2, p<0.05) by per-protocol analysis. Hospitalisation days were significantly lower in the TR group (1.17+/-0.40 vs. 1.25+/-0.45, p<0.05). By intention-to-treat analysis there was a significantly higher radiation dose in the TR group (195 [130-288] vs. 150 [104-241], p<0.05), but no difference in major events (0.9 vs. 0.8, p=ns) and length of hospitalisation in days (1.4+/-2.6 vs. 1.25+/-0.45, p=ns). CONCLUSIONS: The transradial approach for carotid artery stenting is safe and efficacious; however, the crossover rate is higher with transradial access. There are no differences in the total procedure duration and fluoroscopy time between the two approaches but the radiation dose is significantly higher in the radial group, and the hospitalisation is shorter with the use of transradial access by per-protocol analysis. By evaluating the patient data according to intention-to-treat analysis we found no difference in major adverse events and hospitalisation. In both groups, vascular complications rarely occurred. PMID- 25042267 TI - Renal sympathetic denervation suppresses ventricular substrate remodelling in a canine high-rate pacing model. AB - AIMS: This study sought to assess whether renal sympathetic denervation (RSD) could suppress ventricular substrate remodelling and attenuate heart failure (HF) progression. METHODS AND RESULTS: Nineteen dogs were randomised into three groups - seven sham-operated controls, six with right ventricular pacing to induce HF, and six with RSD followed eight weeks later by pacing induction of HF. Haemodynamic variables were monitored at baseline and after HF. Levels of ventricular interstitial fibrosis, BNP, Ang II, aldosterone and TGF-beta were measured. All the dogs in the HF and HF+RSD groups showed increased left and right ventricular diastolic dimensions, but the dogs in the HF+RSD group had a higher left ventricular ejection fraction (LVEF) than the HF dogs (0.42+/-0.05 vs. 0.35+/-0.04, p<0.01). Compared with the dogs with HF alone, the HF+RSD dogs had lower left ventricular end-diastolic pressure (LVEDP) (3.3+/-1.6 vs. 25+/-3.7 mmHg, p<0.01) and less fibrous tissue. The levels of BNP, Ang II, aldosterone and TGF-beta expression in ventricular tissue were higher in the HF dogs than in the sham-operated and HF+RSD dogs. CONCLUSIONS: RSD suppressed ventricular substrate remodelling induced by long-term rapid ventricular pacing. PMID- 25042268 TI - Tools and Techniques - Clinical: the inner curve technique for implantation of the Direct Flow Medical(r) transcatheter aortic valve. PMID- 25042269 TI - How should I treat a patient with an entrapped infected permanent pacemaker lead? PMID- 25042270 TI - Will this trial change my practice? TASTE - a randomised registry on thrombus aspiration in primary PCI with a 30-day endpoint. PMID- 25042271 TI - Will this trial change my practice? ACCOAST - early loading with a novel P2Y12 inhibitor in patients with an acute coronary syndrome. PMID- 25042272 TI - Will this trial change my practice? PRAMI - treatment of bystander coronary lesions in patients undergoing primary PCI for acute STEMI. PMID- 25042273 TI - Resveratrol protects against homocysteine-induced cell damage via cell stress response in neuroblastoma cells. AB - Recent findings underscore that some natural compounds are responsible for specific biochemical effects, i.e., the activation of redox-sensitive intracellular pathways and modulation of different stress proteins, such as heat shock proteins and sirtuins. Resveratrol, a natural polyphenol widely present in plants, has been shown to display various beneficial effects, including neuroprotection, in several pathological conditions. In the present study, by using differentiated SH-SY5Y neuroblastoma cells, we investigated the potential protective effects of resveratrol against homocysteine-induced neurotoxicity. We observed that homocysteine (100 uM) decreased cell viability while at the same time significantly increasing intracellular reactive oxygen species and DNA fragmentation. Cell pretreatment with resveratrol concentrations ranging from 1 to 5 uM elicited protective effects through the reduction of oxidative stress and genotoxic damage. In addition, we observed that resveratrol produced significant changes in the expression of both Hsp70 and sirtuin 1 (SIRT1). After homocysteine treatment in the presence of resveratrol, SIRT1 protein was found abundantly not only in the cytosol but also in the nucleus, as demonstrated by confocal laser scanning microscopy. The results of this study suggest that resveratrol is a potential protective agent against homocysteine-induced neurotoxicity and that beneficial effects are accompanied by changes in cell stress response. Taken together, these features contribute to our knowledge of underlying mechanisms involved in resveratrol-induced cell survival. PMID- 25042274 TI - 1H NMR studies of binary and ternary dapsone supramolecular complexes with different drug carriers: EPC liposome, SBE-beta-CD and beta-CD. AB - Binary and ternary systems composed of dapsone, sulfobutylether-beta-cyclodextrin (SBE-beta-CD), beta-CD and egg phosphatidylcholine (EPC) were evaluated using 1D ROESY, saturation transfer difference NMR and diffusion experiments (DOSY) revealing the binary complexes Dap/beta-CD (K(a) 1396 l mol(-1)), Dap/SBE-beta-CD (K(a) 246 l mol(-1)), Dap/EPC (K(a) 84 l mol(-1)) and the ternary complex Dap/beta-CD/EPC (K(a) 18 l mol(-1)) in which dapsone is more soluble. PMID- 25042275 TI - A comparison between QM/MM and QM/QM based fitting of condensed-phase atomic polarizabilities. AB - Recently we reported a combined QM/MM approach to estimate condensed-phase values of atomic polarizabilities for use in (bio)molecular simulation. The setup relies on a MM treatment of the solvent when determining atomic polarizabilities to describe the response of a QM described solute to its external electric field. In this work, we study the effect of using alternative descriptions of the solvent molecules when evaluating atomic polarizabilities of a methanol solute. In a first step, we show that solute polarizabilities are not significantly affected upon substantially increasing the MM dipole moments towards values that are typically reported in literature for water solvent molecules. Subsequently, solute polarization is evaluated in the presence of a QM described solvent (using the frozen-density embedding method). In the latter case, lower oxygen polarizabilities were obtained than when using MM point charges to describe the solvent, due to introduction of Pauli-repulsion effects. PMID- 25042276 TI - Viewing rate and reference ranges for papillary muscle areas of the fetal heart using four-dimensional ultrasound in the rendering mode. AB - OBJECTIVES: The aims of this study were to assess the viewing rate and determine reference ranges for the papillary muscle areas in the fetal atrio-ventricular valves using four-dimensional (4D) ultrasound and spatio-temporal image correlation (STIC) in the rendering mode. METHODS: This cross-sectional prospective study included 310 4D STIC volume data sets of normal fetuses between 18 weeks 0 day and 34 weeks 0 day of gestation. The papillary muscles were antero lateral (MPAL) and postero-medial (MPPM) to the mitral valve and antero-superior (MPAS), inferior (MPI) and septal (MPS) to the tricuspid valve. Polynomial regressions were built to determine the reference ranges, and adjustments were made using the determination coefficient (R(2) ). To assess inter-observer reproducibility, the intra-class correlation coefficient (ICC) was used. RESULTS: Identification of the papillary muscles was possible in 89.3% patients. The best fit regression equations between papillary muscle areas and gestational age were second degree. The inter-observer reproducibility was good (ICC: 0.98 to MPAS, 0.97 to MPI, 0.98 to MPS, 0.98 to MPAL and 0.97 to MPPM). CONCLUSIONS: Identification of the papillary muscles of the fetal valves was possible in most of the 4D STIC volume data sets, enabling the determination of reference ranges using the rendering mode. The reference ranges for the papillary muscle areas were determined. PMID- 25042281 TI - Multilevel competing risks in the evaluation of nosocomial infections: time to move on from proportional hazards and even from hazards altogether. AB - A competing risk is an event (for example, death in the ICU) that hinders the occurrence of an event of interest (for example, nosocomial infection in the ICU) and it is a common issue in many critical care studies. Not accounting for a competing event may affect how results related to a primary event of interest are interpreted. In the previous issue of Critical Care, Wolkewitz and colleagues extended traditional models for competing risks to include random effects as a means to quantify heterogeneity among ICUs. Reported results from their analyses based on cause-specific hazards and on sub-hazards of the cumulative incidence function were indicative of lack of proportionality of these hazards over time. Here, we argue that proportionality of hazards can be problematic in competing risk problems and analyses must consider time by covariate interactions as a default. Moreover, since hazards in competing risks make it difficult to disentangle the effects of frequency and timing of the competing events, their interpretation can be murky. Use of mixtures of flexible and succinct parametric time-to-event models for competing risks permits disentanglement of the frequency and timing at the price of requiring stronger data and a higher number of parameters. We used data from a clinical trial on fluid management strategies for patients with acute respiratory distress syndrome to support our recommendations. PMID- 25042282 TI - Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort. AB - Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring serum levels of Se and Selenoprotein P (SePP) and examined the association with CRC risk in a nested case-control design (966 CRC cases; 966 matched controls) within the European Prospective Investigation into Cancer and Nutrition. Se was measured by total reflection X-ray fluorescence and SePP by immunoluminometric sandwich assay. Multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Respective mean Se and SePP levels were 84.0 MUg/L and 4.3 mg/L in cases and 85.6 MUg/L and 4.4 mg/L in controls. Higher Se concentrations were associated with a non-significant lower CRC risk (IRR = 0.92, 95% CI: 0.82 1.03 per 25 MUg/L increase). However, sub-group analyses by sex showed a statistically significant association for women (p(trend) = 0.032; per 25 MUg/L Se increase, IRR = 0.83, 95% CI: 0.70-0.97) but not for men. Higher SePP concentrations were inversely associated with CRC risk (p(trend) = 0.009; per 0.806 mg/L increase, IRR = 0.89, 95% CI: 0.82-0.98) with the association more apparent in women (p(trend) = 0.004; IRR = 0.82, 95% CI: 0.72-0.94 per 0.806 mg/L increase) than men (p(trend) = 0.485; IRR = 0.98, 95% CI: 0.86-1.12 per 0.806 mg/L increase). The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women. PMID- 25042284 TI - Hypoglycemia after gastric bypass: an old problem resurfaces. PMID- 25042283 TI - Superior survival using living donors and donor-recipient matching using a novel living donor risk index. AB - The deceased-donor organ supply in the U.S. has not been able to keep pace with the increasing demand for liver transplantation. We examined national Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 2002-2012 to assess whether living donor liver transplantation (LDLT) has surpassed deceased donor liver transplantation (DDLT) as a superior method of transplantation, and used donor and recipient characteristics to develop a risk score to optimize donor and recipient selection for LDLT. From 2002-2012, there were 2,103 LDLTs and 46,674 DDLTs that met the inclusion criteria. The unadjusted 3-year graft survival for DDLTs was 75.5% (95% confidence interval [CI]: 75.1-76.0%) compared with 78.9% (95% CI: 76.9-80.8%; P<0.001) for LDLTs that were performed at experienced centers (>15 LDLTs), with substantial improvement in LDLT graft survival over time. In multivariate models, LDLT recipients transplanted at experienced centers with either autoimmune hepatitis or cholestatic liver disease had significantly lower risks of graft failure (hazard ratio [HR]: 0.56, 95% CI: 0.37-0.84 and HR: 0.76, 95% CI: 0.63 0.92, respectively). An LDLT risk score that included both donor and recipient variables facilitated stratification of LDLT recipients into high, intermediate, and low-risk groups, with predicted 3-year graft survival ranging from >87% in the lowest risk group to <74% in the highest risk group. CONCLUSION: Current posttransplant outcomes for LDLT are equivalent, if not superior, to DDLT when performed at experienced centers. An LDLT risk score can be used to optimize LDLT outcomes and provides objective selection criteria for donor selection in LDLT. PMID- 25042285 TI - Sup-ER orthosis: an innovative treatment for infants with birth related brachial plexus injury. AB - Impairments in active and passive range of upper extremity supination and shoulder external rotation are common sequelae for children with delayed recovery from birth related brachial plexus injury. Orthotic intervention may complement traditional treatment strategies commonly employed in the newborn period. These authors describe their custom fabricated orthosis designed to balance shoulder growth and muscular function, and improve prognosis of long term functional outcomes for children with birth related brachial plexus injury. - Victoria Priganc, PhD, OTR, CHT, CLT, Practice Forum Editor. PMID- 25042286 TI - A thorny question: the taxonomic identity of the Pirro Nord cervical vertebrae revisited. AB - The past geographic distribution of the genus Theropithecus (Primates: Cercopithecidae) is mainly restricted to Africa. Outside that continent, the earliest reported records of this genus consist of a calcaneus of cf. Theropithecus sp. from 'Ubeidiya (Israel, 1.6-1.2 Ma [millions of years ago]), as well as three associated cervical vertebrae from Pirro Nord (Italy, 1.7-1.3 Ma) attributed to Theropithecus sp. The attribution of the Pirro Nord vertebrae to this genus has been disputed on morphometric grounds, although their assignment to a large-bodied cercopithecid has remained undisputed. Here we report unpublished cervical vertebral specimens with a similar morphology and, given their significance for the paleobiogeography of Theropithecus (purportedly representing its earliest European record), we re-evaluate their taxonomic attribution. In particular, we reconsider the possibility that they belong to another non-primate mammal recorded at this site. Based on both qualitative and metric morphological comparisons, we strongly favor an alternative attribution of the cervical vertebrae from Pirro Nord to the large porcupine Hystrix refossa, which is widely documented at the site by both dentognathic and other postcranial remains. We therefore conclude that the dispersal of Theropithecus out of Africa before ca. 1 Ma (when it is recorded by dental remains from Cueva Victoria, Spain) is currently based only on the calcaneus from 'Ubeidiya tentatively attributed to this genus. PMID- 25042287 TI - Variations in size, shape and asymmetries of the third frontal convolution in hominids: paleoneurological implications for hominin evolution and the origin of language. AB - The study of brain structural asymmetries as anatomical substrates of functional asymmetries in extant humans, great apes, and fossil hominins is of major importance in understanding the structural basis of modern human cognition. We propose methods to quantify the variation in size, shape and bilateral asymmetries of the third frontal convolution (or posterior inferior frontal gyrus) among recent modern humans, bonobos and chimpanzees, and fossil hominins using actual and virtual endocasts. These methodological improvements are necessary to extend previous qualitative studies of these features. We demonstrate both an absolute and relative bilateral increase in the size of the third frontal convolution in width and length between Pan species, as well as in hominins. We also observed a global bilateral increase in the size of the third frontal convolution across all species during hominin evolution, but also non allometric intra-group variations independent of brain size within the fossil samples. Finally, our results show that the commonly accepted leftward asymmetry of Broca's cap is biased by qualitative observation of individual specimens. The trend during hominin evolution seems to be a reduction in size on the left compared with the right side, and also a clearer definition of the area. The third frontal convolution considered as a whole projects more laterally and antero-posteriorly in the right hemisphere. As a result, the left 'Broca's cap' looks more globular and better defined. Our results also suggest that the pattern of brain asymmetries is similar between Pan paniscus and hominins, leaving the gradient of the degree of asymmetry as the only relevant structural parameter. As the anatomical substrate related to brain asymmetry has been present since the appearance of the hominin lineage, it is not possible to prove a direct relationship between the extent of variations in the size, shape, and asymmetries of the third frontal convolution and the origin of language in hominins. PMID- 25042288 TI - Atomic force microscopy of novel zeolitic materials prepared by top-down synthesis and ADOR mechanism. AB - Top-down synthesis of 2D materials from a parent 3D zeolite with subsequent post synthetic modification is an interesting method for synthesis of new materials. Assembly, disassembly, organisation, reassembly (ADOR) processes towards novel materials based on the zeolite UTL are now established. Herein, we present the first study of these materials by atomic force microscopy (AFM). AFM was used to monitor the ADOR process through observation of the changes in crystal surface and step height of the products. UTL surfaces were generally complex and contained grain boundaries and low-angle intergrowths, in addition to regular terraces. Hydrolysis of UTL to IPC-1P did not have adverse effects on the surfaces as compared to UTL. The layers remained intact after intercalation and calcination forming novel materials IPC-2 and IPC-4. Measured step heights gave good correlation with the X-ray diffraction determined d200 -spacing in these materials. However, swelling gave rise to significant changes to the surface topography, with significantly less regular terrace shapes. The pillared material yielded the roughest surface with ill-defined surface features. The results support a mechanism for the majority of these materials in which the UTL layers remain intact during the ADOR process as opposed to dissolving and recrystallising during each step. PMID- 25042289 TI - The MCP-8 gene and its possible association with resistance to Streptococcus agalactiae in tilapia. AB - Mast cell proteases play an important role in the regulation of the immune response. We identified the cDNA of the mast cell protease 8 (MCP-8) gene and analyzed its genomic structure in tilapia. The ORF of the MCP-8 was 768 bp, encoding 255 amino acids. Quantitative real-time PCR revealed that the MCP-8 gene was expressed predominantly in spleen, moderately in liver, blood, brain, gill, intestine, skin, and weakly expressed in kidney, muscle and eye. After a challenge with Streptococcus agalactiae, the gene was induced significantly (p < 0.05) in intestine, kidney, spleen and liver. Furthermore, we identified five single nucleotide polymorphisms (SNPs) in the MCP-8 gene and found that three SNPs were significantly associated (p < 0.05) with resistance against S. agalactiae. However, we found no association between four SNPs and growth traits (p > 0.05). These results suggest that the MCP-8 gene play an important role in the resistance to S. agalactiae in tilapia. The SNP markers in the MCP-8 gene associated with the resistance to the bacterial pathogen may facilitate selection of tilapia resistant to the bacterial disease. PMID- 25042291 TI - Bilateral whole lung lavage in pulmonary alveolar proteinosis--a retrospective study. AB - Whole lung lavage (WLL) is the gold standard technique for the treatment of Pulmonary Alveolar Proteinosis (PAP). In this paper we evaluated and discuss bilateral WLL, namely the procedure work-up and the therapeutic efficacy. Six bilateral WLL performed through a careful adherence to a modified Royal Brompton Hospital (London) technique were carried out without major complications and were associated with clinical and functional improvement of the PAP patients submitted to this procedure. As there are benefits in terms of time, patient comfort and cost effectiveness compared to unilateral WLL, associated with the efficacy and safety observed, bilateral WLL seems to be a suitable first choice for therapeutic lavage in PAP patients. PMID- 25042290 TI - Effect of providing conditional economic compensation on uptake of voluntary medical male circumcision in Kenya: a randomized clinical trial. AB - IMPORTANCE: Novel strategies are needed to increase the uptake of voluntary medical male circumcision (VMMC) in sub-Saharan Africa and enhance the effectiveness of male circumcision as an HIV prevention strategy. OBJECTIVE: To determine whether small economic incentives could increase circumcision prevalence by addressing reported economic barriers to VMMC and behavioral factors such as present-biased decision making. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted between June 22, 2013, and February 4, 2014, among 1504 uncircumcised men aged 25 to 49 years in Nyanza region, Kenya. VMMC services were provided free of charge and participants were randomized to 1 of 3 intervention groups or a control group. INTERVENTIONS: Participants in the 3 intervention groups received varying amounts of compensation conditional on undergoing circumcision at 1 of 9 study clinics within 2 months of enrollment. Compensation took the form of food vouchers worth 200 Kenya shillings (~ US $2.50), 700 Kenya shillings (~ US $8.75), or 1200 Kenya shillings (~ US $15.00), which reflected a portion of transportation costs and lost wages associated with getting circumcised. The control group received no compensation. MAIN OUTCOMES AND MEASURES: VMMC uptake within 2 months. RESULTS: Analysis of data for 1502 participants with complete data showed that VMMC uptake within 2 months was higher in the US $8.75 group (6.6%; 95% CI, 4.3%-9.5% [25 of 381]) and the US $15.00 group (9.0%; 95% CI, 6.3%-12.4% [34 of 377]) than in the US $2.50 group (1.9%; 95% CI, 0.8%-3.8% [7 of 374]) and the control group (1.6%; 95% CI, 0.6%-3.5% [6 of 370]). In logistic regression analysis, the US $8.75 group had significantly higher VMMC uptake than the control group (adjusted odds ratio [AOR] 4.3; 95% CI, 1.7-10.7), as did the US $15.00 group (AOR 6.2; 95% CI, 2.6-15.0). Effect sizes for the US $8.75 and US $15.00 groups did not differ significantly (P = .20). CONCLUSIONS AND RELEVANCE: Among uncircumcised men in Kenya, compensation in the form of food vouchers worth approximately US $8.75 or US $15.00, compared with lesser or no compensation, resulted in a modest increase in the prevalence of circumcision after 2 months. The effects of more intense promotion or longer implementation require further investigation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01857700. PMID- 25042292 TI - The linear interplay of intrinsic and extrinsic noises ensures a high accuracy of cell fate selection in budding yeast. AB - To gain insights into the mechanisms of cell fate decision in a noisy environment, the effects of intrinsic and extrinsic noises on cell fate are explored at the single cell level. Specifically, we theoretically define the impulse of Cln1/2 as an indication of cell fates. The strong dependence between the impulse of Cln1/2 and cell fates is exhibited. Based on the simulation results, we illustrate that increasing intrinsic fluctuations causes the parallel shift of the separation ratio of Whi5P but that increasing extrinsic fluctuations leads to the mixture of different cell fates. Our quantitative study also suggests that the strengths of intrinsic and extrinsic noises around an approximate linear model can ensure a high accuracy of cell fate selection. Furthermore, this study demonstrates that the selection of cell fates is an entropy-decreasing process. In addition, we reveal that cell fates are significantly correlated with the range of entropy decreases. PMID- 25042293 TI - Cloning and expression analysis of G-protein Galphaq subunit and Gbeta1 subunit from Bemisia tabaci Gennadius (Homoptera: Aleyrodidae). AB - The heterotrimeric G proteins play an essential role in a wide variety of signal transduction pathways, mediating the process of chemical signals from the environment in all higher eukaryotic organisms. In this article, two G-protein subunit genes encoding Galphaq and Gbeta1 were cloned from Bemisia tabaci Gennadius. The full-length cDNA sequence of BtGalphaq consisted of 2,336 bp with an ORF of 1,062 bp encoding 353 amino acids and BtGbeta1 had a full length of 1,942 bp with an ORF of 1,023 nucleotides encoding 340 amino acids. The amino acid sequences of BtGalphaq and BtGbeta1 from B. tabaci B biotype were identical to those from the Q biotype. Phylogenetic analysis identified G protein alpha and beta subunit families from insects based on their amino acid sequences. The expression patterns of BtGalphaq and BtGbeta1 at different development stages and in different body regions were analyzed by real-time quantitative PCR and Western blot. The results show that BtGalphaq and BtGbeta1 are neither developmental stage-specific nor tissue-specific. The transcript levels of BtGalphaq in the B biotype are similar to that in the Q biotype, the transcript levels of BtGbeta1 at egg, first instar and pupae in B biotype were significantly higher than that in Q biotype. The transcript levels of BtGalphaq and BtGbeta1 in the head were significantly higher than those in thorax and abdomen indicating that they are involved in nervous system and sensory functions. PMID- 25042294 TI - 2,6-Diphospha-s-indacene-1,3,5,7(2 H,6 H)-tetraone: a phosphorus analogue of aromatic diimides with the minimal core exhibiting high electron-accepting ability. AB - Phosphorus analogues of pyrromellitic diimides (PyDIs), which represent a family of privileged electron-accepting organic compounds, have been successfully synthesized as novel electron-accepting pi-conjugated molecules. Investigation into their physicochemical properties uncovered their prominent electron accepting abilities over the corresponding PyDI. Furthermore, theoretical studies revealed the significant contribution of sigma*-pi* hyperconjugation in stabilizing the LUMO+1. PMID- 25042295 TI - A multiplex PCR to differentiate the two sibling species of mosquitoes Ochlerotatus detritus and Oc. coluzzii and evidence for further genetic heterogeneity within the Detritus complex. AB - Internal transcribed spacer regions of ribosomal DNA were sequenced, and species specific primers were designed to simplify the identification of two morphologically similar species of the Detritus complex, Ochlerotatus detritus and Ochlerotatuscoluzzii. Each newly designed primer was able to amplify a species-specific fragment with a different size. Samples from France and Germany were successfully tested. This new tool prompts for bio-ecological studies to refine basic knowledge on the bionomics of this species complex, towards a better control and prevention of ensuing nuisances. Moreover, ITS2 sequencing revealed the existence of (1) two distinct haplotypes of Oc. detritus that are sympatric and widely distributed along the French Atlantic and Mediterranean littorals and (2) a specific haplotype in mosquitoes sampled from Tunisia, raising the question of the taxonomic status of this North-African population. PMID- 25042296 TI - Multispecies acute toxicity evaluation of wastewaters from different treatment stages in a coking wastewater-treatment plant. AB - Coking wastewater contributes approximately 5% of the total discharge volume of industrial wastewaters every year in China. The toxicity of coking wastewater to aquatic organisms is still unknown. The authors evaluated the toxicity of wastewater from different treatment stages in a coking wastewater treatment plant, South China, using 5 test species belonging to different trophic levels: luminous bacteria, green alga, a crustacean, duckweed, and zebrafish embryos. The raw influent displayed the highest toxicity to the test species, with toxic units ranging from 16.2 to 1176. The toxicity in the wastewater was then gradually removed by sequential primary treatment, biological fluidized-bed treatment, and secondary clarifier treatment. The toxic unit of the final effluent was reduced to 2.26 for the green alga (Pseudokirchneriella subcapitata) and to 0 for the other 4 organisms. Quantitative analysis of metals and polycyclic aromatic hydrocarbons (PAHs) and qualitative scanning by gas chromatography-mass spectrometry showed the presence of a variety of pollutants in the coking wastewaters. Multivariate statistical analysis revealed that the toxicity in the coking wastewater was correlated to the chemical oxygen demand, total nitrogen, ammonia nitrogen, volatile phenols, sulfide, metals (Cr, As, Sb, Hg, Pb, and Ni), and SigmaPAHs. Based on the results, it is required to set a safety emission limit value for the discharge of coking wastewater to protect aquatic organisms in the receiving water bodies. PMID- 25042297 TI - Relative lens vault in subjects with angle closure. AB - BACKGROUND: The purpose of this study was to investigate the association of a novel biometric parameter, relative lens vault (LV), with primary angle-closure (PAC) and primary angle-closure glaucoma (PACG). METHODS: We evaluated 101 subjects with PAC (G) and 101 normal subjects that were age- and gender-matched. Based on anterior-segment optical coherence tomography scans, and using customized software, the anterior vault (AV) and LV were measured. They were defined as the maximum distances between the horizontal line connecting the two scleral spurs and the posterior corneal surface and anterior lens surface, respectively. The relative LV was calculated by dividing the LV by the AV. RESULTS: Significant differences between PAC (G) eyes and normal eyes were found in the LV (1.06 +/- 0.41 vs. 0.36 +/- 0.37 mm, P < 0.001), relative LV (0.34 +/- 0.23 vs. 0.11 +/- 0.25, P < 0.001), and axial length (22.96 +/- 0.94 vs. 24.02 +/ 1.33 mm, P < 0.001). However, the two groups' values of the AV relative to those of axial length were quite similar (both 0.14 +/- 0.03, P = 0.91). The relative LV values distinguished between PAC (G) eyes and normal eyes better than the LV values (area under the receiver operator characteristic curve: 0.97 vs. 0.92, P = 0.032). CONCLUSIONS: Our results suggest that relative dimensions of the eyeball's anterior portion in PAC (G) eyes might be within the normal range. And the value of LV relative to that of the AV (i.e., the relative LV) is more closely related to PAC (G) than is the absolute value of LV. PMID- 25042298 TI - Sphincter electromyography in diabetes mellitus and multiple system atrophy. AB - AIMS: Abnormalities of external anal sphincter electromyography (EAS-EMG) characterize multiple system atrophy (MSA) and focal cauda equina or conus medullaris lesions. This study is designed to determine whether and how diabetic polyneuropathy (DPN) affects EAS as compared to the abnormalities seen in MSA. METHODS: We conducted multi-motor unit potential (MUP) analysis of EAS in 22 healthy controls, 32 diabetes mellitus (DM) patients without neuropathy, 38 DPN patients, and 68 MSA patients. RESULTS: DPN patients had a significant (P < 0.01) increase in MUP mean duration, mean amplitude, percentage of long duration MUPs, and satellite rate, but to a lesser extent than MSA. Mean duration and satellite rate showed the least overlap among different groups in individual value distributions. CONCLUSIONS: Compared with MSA, DPN affects EAS to a lesser degree as judged by neurogenic MUP abnormalities in EMG. Mean duration and satellite rate may serve as the most discriminating aspects in MUP analysis of EAS. PMID- 25042299 TI - Magnetic anisotropy of mononuclear Ni(II) complexes: on the importance of structural diversity and the structural distortions. AB - Mononuclear Ni(II) complexes are particularly attractive in the area of single molecule magnets as the axial zero-field splitting (D) for the Ni(II) complexes is in the range of -200 to +200 cm(-1) . Despite this advantage, very little is known on the origin of anisotropy across various coordination ligands, coordination numbers, and particularly what factors influence the D parameter in these complexes. To answer some of these questions, herein we have undertaken a detailed study of a series of mononuclear Ni(II) complexes with ab initio calculations. Our results demonstrate that three prominent spin-conserved low lying d-d transitions contribute significantly to the D value. Variation in the sign and the magnitude of D values are found to correlate to the specific structural distortions. Apart from the metal-ligand bond lengths, two different parameters, namely, Deltaalpha and Deltabeta, which are correlated to the cis angles present in the coordination environment, are found to significantly influence the axial D values. Developed magneto-structural D correlations suggest that the D values can be enhanced significantly by fine tuning the structural distortion in the coordination environment. Calculations performed on a series of Ni(II) models with coordination numbers two to six unfold an interesting observation-the D parameter increases significantly upon a reduction in coordination number compared with a reference octahedral coordination. Besides, if high symmetry is maintained, even larger coordination numbers yield large D values. PMID- 25042301 TI - Can we describe what we do? PMID- 25042300 TI - Low-level 45,X/46,XX mosaicism is not associated with congenital heart disease and thoracic aorta dilatation:prospective magnetic resonance imaging and ultrasound study. AB - OBJECTIVE: To establish the prevalence of risk factors for aortic dissection, such as bicuspid aortic valve, aortic coarctation and ascending aorta dilatation, in women with low-level 45,X/46,XX mosaicism undergoing an in-vitro fertilization (IVF) procedure. METHODS: The study group comprised 25 women with low-level 45,X/46,XX mosaicism (ranging from 3.3% to 10.0%) who were referred to two reproductive medicine units between 2009 and 2013 because of infertility and who underwent subsequent karyotyping. In accordance with the recommendation of the Practice Committee of the American Society for Reproductive Medicine for patients with Turner syndrome (TS), prior to the IVF procedure, all women underwent careful cardiovascular screening for congenital heart disease and thoracic aorta dilatation, including standard cardiac examination, echocardiography and non contrast cardiac magnetic resonance imaging. Aortic size index (ASI, diameter of the ascending aorta normalized to body surface area) and the prevalence of coarctation of the aorta and of bicuspid aortic valve were compared with findings previously reported in women with TS and the general population. RESULTS: Bicuspid aortic valve without any stenosis or regurgitation was found in one woman in the study group with low-level 45,X/46,XX mosaicism, a statistically significantly lower prevalence of bicuspid aortic valve than that reported in women with TS. Aortic coarctation was not identified in any individual. The ASI was below the 95th percentile in all cases and the mean value was significantly lower than the mean reference values for both the general population and women with TS. CONCLUSION: Compared with the general population, the prevalence of risk factors for aortic dissection was not found to be higher in women with low-level 45,X/46,XX mosaicism without any noticeable features except infertility. PMID- 25042302 TI - Massage therapy plus topical analgesic is more effective than massage alone for hand arthritis pain. AB - METHODS: 20 adults were randomly assigned to a massage therapy or a massage therapy plus a topical analgesic application group. Both groups received a weekly massage from a therapist and were taught self-massage (same procedure) to be done by each participant once daily over a four-week period. RESULTS: The massage plus topical analgesic group as compared to the massage group had greater improvement in hand function as measured by a digital hand exerciser following the first session and across the four-week period. That group also had a greater increase in perceived grip strength and a greater decrease in hand pain, depressed mood and sleep disturbances over the four-week period. Massage therapy has been effective for several pain syndromes including migraine headaches (Lawle and Cameron, 2006)), lower back pain (Hsieh et al., 2004), fibromyalgia (Kalichman, 2010), neck and shoulder pain (Kong et al., 2013), carpal tunnel syndrome (Elliott and Burkett, 2013), and pain related to upper limb arthritis (Field et al., 2013). The purpose of the current study was to determine whether applying a topical analgesic following massage might be more effective than massage alone in treating pain associated with hand arthritis. PMID- 25042303 TI - Analysis of activities in the daily lives of older adults exposed to the Pilates Method. AB - OBJECTIVE: The objective of this study was to analyse the Pilates Method (PM) to assess whether it can help to improve the performance of activities that older adults undertake in their daily lives. METHOD: this is a pre-post experimental study with a convenience sample consisting of 22 women, aged from 65 to 74 years. Data collection was divided into three stages: 1) the Battery Test of Daily Life Activities for Physically Independent Elderly (BTDLAPIE); 2) 12 weeks of Pilates training, with 50-minute sessions twice a week; 3) Repetition of all BTDLAPIE tests. We used the Student t test for paired samples and the level of significance was considered to be <=0.05. CONCLUSION: After the study group had been exposed to 12 weeks of training with the PM, it took them less time to perform the activities of their daily lives. However, we suggest that other controlled studies are needed in order to understand these outcomes more fully. PMID- 25042304 TI - Feasibility and outcomes of a classical Pilates program on lower extremity strength, posture, balance, gait, and quality of life in someone with impairments due to a stroke. AB - Pilates is a method that can potentially be used for stroke rehabilitation to address impairments in gait, balance, strength, and posture. The purpose of this case report was to document the feasibility of using Pilates and to describe outcomes of a 9-month program on lower extremity strength, balance, posture, gait, and quality of life in an individual with stroke. The participant was taught Pilates exercises up to two times per week for nine months in addition to traditional rehabilitation in the United States. Outcomes were assessed using the Berg Balance Scale (BBS), Stroke Impact Scale (SIS), GAITRite System((r)), 5 repetition sit-to-stand test (STST), and flexicurve. Improvements were found in balance, lower extremity strength, and quality of life. Posture and gait speed remained the same. While these changes cannot be specifically attributed to the intervention, Pilates may have added to his overall rehabilitation program and with some modifications was feasible to use in someone with a stroke. PMID- 25042305 TI - The effect of Pilates based exercise on mobility, postural stability, and balance in order to decrease fall risk in older adults. AB - Falls are a common problem in older adults. Impaired balance, mobility and postural stability are risk factors for falling. Limited research has been performed on Pilates exercise and the ability to decrease fall risk. In this quasi-experimental study, 35 adults (61-87 years old) participated in an 8-week Pilates based exercise program. Blind examiners conducted the Timed Up and Go (TUG), Forward Reach Test, and Turn 180 Test before and after the intervention. Number of falls, perception of Pilates, and fear of falling was also recorded. Thirty-two (91.4%) participants completed post-test measures. Significant improvements were seen in the TUG (p <0.001) and Turn 180 Test (p = 0.002). Improvements were also demonstrated in the Forward Reach Test (p = 0.049). A positive perception of the Pilates program and decreased fear of falling was shown. Results suggest a Pilates based exercise program may be effective in improving balance, mobility and postural stability to decrease fall risk. PMID- 25042306 TI - Biomechanical assessment of human posture: a literature review. AB - INTRODUCTION: Postural deviations have been linked to a series of different kinds of pain and dysfunction. However, posture is not an easy subject to study, mainly because postural assessments are still scientifically inaccurate, such as photography, or expensive, such as MRI, whereas others, such as X-ray, involve radiation problems. The aim of this literature review was to search for new scientific methods for assessing posture and to discuss which among both new and old methods are best for scientific and clinical objectives. MATERIALS AND METHODS: The Medline and Lilacs databases were searched for the period 2003 to 2013 with the use of the following keywords: "posture" and "postural." RESULTS: A total of 452 articles that assessed posture in some way were found. Twenty-two articles were selected, and 11 relevant types of technologies were described. DISCUSSION: The relevant technologies discussed were force plate; pictures; goniometers, inclinometers, tape, and other devices; 3D analysis; 3D X-ray; sensors; electromyography; Kinect; magnetic resonance imaging; 4D computed tomography; and infrared. CONCLUSION: There is enough technology to make a very good quantitative evaluation possible. For example, the 3D MRI or the 4D CT can register static and dynamic posture. Other cheaper solutions may use combined and synchronized equipments. However, these synchronizations still require validation. PMID- 25042307 TI - A 12-week medical exercise therapy program leads to significant improvement in knee function after degenerative meniscectomy: a randomized controlled trial with one year follow-up. AB - There is no consensus in the postoperative rehabilitation regimen for patients who have undergone surgery for medial meniscus damage. The aim of this study was to examine whether it is necessary to undergo postoperative physiotherapy treatment these patients. A prospective randomized controlled clinical trial was performed. 42 participants (26 males, 16 women) were randomly assigned into an exercise group (EG) (n = 22) or a control group (CG) (n = 20). Prognostic variables were similar between the groups at baseline. The EG achieved significantly better outcome effects than the CG at pain (VAS reduced 1.9 in TG and 0.6 in CG, p < 0.01) and function (KOOS decreased 18.0 in TG and only 6.5 in CG, p < 0.01) during the 12 week intervention period. The results after a 12 month follow-up indicated the same results as at posttest 3 months postoperatively. In patients with surgery for degenerative meniscus damage, postoperative medical exercise therapy - as a model of physiotherapy - is an efficient treatment alternative compared to no systematic rehabilitation. PMID- 25042308 TI - The effects of isometric contraction of shoulder muscles on cervical multifidus muscle dimensions in healthy office workers. AB - It is argued that cervical multifidus muscles (CMM) are responsible for providing neck stability. However, whether they are actually activated during the tasks performed by the upper extremities to the neck is still unknown. Therefore, the aim of this study was to examine the effects of isometric contraction of shoulder muscles on the dimensions of CMM. Twenty three healthy males voluntarily participated in this study. Ultrasonography imaging of CMM was conducted at rest and at 25%, 50%, 75%, and 100% of maximal voluntary contraction of shoulder muscles in 6 directions of shoulder movements. Anterior-posterior dimension (APD), lateral dimension (LD), shape ratio and multiplied linear dimension (MLD) of cervical multifidus were measured. The APD of CMM was increased while LD and shape ratio were decreased by shoulder muscles contraction (P < 0.01). PMID- 25042309 TI - The effect of dry needling for myofascial trigger points in the neck and shoulders: a systematic review and meta-analysis. AB - BACKGROUND: and purpose: The aim of this systematic review with meta-analysis is to determine the effect of dry needling in the treatment of MTrPs. METHODS: Searches were performed using the electronic databases AMED, EBM reviews, Embase, and Ovid MEDLINE (all from database inception-February 2012). STUDY SELECTION: Randomized controlled trials (RCTs) were included if they compared dry needling with another form of treatment or placebo and included pain intensity as an outcome. DATA EXTRACTION: Two blinded reviewers independently screened the articles, scored their methodological quality and extracted data. QUALITY ASSESSMENT: Physiotherapy Evidence Database (PEDro) quality scale and the Cochrane risk of bias tool were used. RESULTS: Four RCTs compared dry needling to lidocaine and one RCT compared dry needling to placebo. Meta-analyses of dry needling revealed no significant difference between dry needling and lidocaine immediately after treatment standardized mean difference (SMD) 0.41 (95%CI -0.15 to 0.97), at one month (SMD -1.46; 95% CI -2.04 to 4.96) and three to six months (SMD -0.28; 95% CI -0.63 to 0.07). DISCUSSION: Although not significant in the meta-analyses, there were interesting patterns favoring lidocaine immediately after treatment and dry needling at three to six months. PMID- 25042310 TI - The effects of selected asanas in Iyengar yoga on flexibility: pilot study. AB - In recent years the practice of yoga has gained popularity as a form of physical fitness and exercise, and has been said to improve strength and flexibility. The main objective of this research project was to evaluate the effects of a six week Iyengar yoga intervention on flexibility. N = 16 low to moderately active females (52.37 +/- 7.79 years) attended Iyengar yoga practice for a total of 6 weeks, consisting of one 90 min session per week. Lumbar and hamstring flexibility were assessed pre and post-intervention using a standard sit and reach test. The results show a significant increase in flexibility, indicating 6 weeks of single session yoga training may be effective in increasing erector spinae and hamstring flexibility. This is important when considering that much of the population find it difficult to attend more than one session a week into their training schedule. PMID- 25042311 TI - Kinesiologic taping and muscular activity: a myofascial hypothesis and a randomised, blinded trial on healthy individuals. AB - BACKGROUND: During recent years scientific research has demonstrated a growing interest in elastic and anaelastics adhesive taping techniques. However, only a few studies investigating the principles behind the effects of taping. At present, the action mechanisms of kinesiology taping remain speculative. OBJECTIVES: To investigate the effects of taping application on the tone of the pectoralis major muscle at rest, in absence of any relevant pathologies. METHODS AND MEASURES: The study involved a prospective, randomised and blinded clinical trial on healthy individuals and a repeated measures study design. Two different taping techniques (facilitatory and inhibitory) were applied over the pectoralis major of 24 healthy volunteers. The outcome measure was passive range of motion of external rotation of the glenohumeral joint. RESULTS: Facilitatory taping significatively enhanced the activity of the underlying muscle. Results showed a negative correlation between facilitatory taping application and the contralateral pectoralis major length, indicating a possible effect on the muscle tone of areas outside the site of direct application. The inhibitory taping application did not produce significant results. CONCLUSIONS: effects on ipsilateral and contralateral muscle physiology could be interpreted through the initial hypothesis of taping inducing changes in fascial stiffness. These could be transmitted along the continuing system. Further studies are needed to inform the possible uses of taping in clinical practice. PMID- 25042312 TI - Stroke-related motor outcome measures: do they quantify the neurophysiological aspects of upper extremity recovery? AB - Various stroke rehabilitation outcome measures are used in clinical and research practice. Severe upper extremity paresis serves as a challenge for the selection of an appropriate outcome measure. No single measure is universally acceptable and sufficient to record the minute clinically important changes. The objectives of the present review were to explore the stroke-specific upper extremity motor outcome measures and to better understand those measures' ability to quantify upper extremity motor recovery. Seven outcome measures were selected for this review. The criteria used to select outcome measures for this review included performance-based tools that assessed the upper extremity's voluntary motor control and outcome measures which had been used for the past 10 years. A critical review that referred to motor recovery stages and volitional control was performed. The upper extremity components of each measure were compared with the neurophysiological aspects of recovery (Brunnstrom Recovery Stages) and analyzed for their clinical relevance. The concepts of minimal detectable change and minimal clinically important difference were also considered while examining the outcome measures. The findings of this review reveal that there were very few measures available to precisely assess the upper extremity motor components and volitional control. Most of the measures are functional and performance-based. Only Fugl-Meyer Assessment was found to explore the individual joint motor control as per the sequential recovery stages. Further, there is a need to develop stroke-specific upper extremity outcome measures. Scoring criteria of the acceptable measures may be modified to discern precise and progressive, but clinically significant motor changes. PMID- 25042313 TI - A comparison of two formulas of topical menthol on vascular responses and perceived intensity prior to and follow a bout of maximum voluntary muscular contractions (MVMCs). AB - The purpose of this study was to compare the vascular responses in the brachial artery and perceived intensity of two different formulas of topical menthol gels prior to and following a bout of maximum voluntary muscular contractions (MVMCs). 18 adults completed the same protocol on different days using blinded topical menthol gels (Old Formula and New Formula). Heart rate, brachial artery blood flow (ml/min), vessel diameter and reported intensity of sensation were measured at baseline (T1), at 5 min after application of the gel to the upper arm (T2), and immediately following five MVMCs hand grips (T3). The New Formula exhibited a significant decline in blood flow (-22.6%) between T1 and T2 which was not different than the nonsignificant declines under the Old Formula 1 (-21.8%). Both formulas resulted in a significant increase in perceived intensity of sensation between T1 and T2. Blood flow increased significantly with the New Formula (488%) between T2 and T3 and nonsignificantly with the Old Formula (355%). PMID- 25042314 TI - The chronicity of myogenous temporomandibular disorder changes the skin temperature over the anterior temporalis muscle. AB - The aim of the present study was to investigate the correlation between the chronicity of myogenous temporomandibular disorder (TMD) and skin temperature over the masseter and anterior temporalis muscles. A blind, cross-sectional study was carried out involving 30 women with myogenous TMD, aged 18-40 years (mean of 23.60 +/- 5.12 years). The volunteers were recruited from the university community. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) was used for the diagnosis of TMD and the determination of chronicity. The volunteers were also submitted to infrared thermography to measure absolute skin temperature over the masseter and anterior temporalis muscles and determine their temperature asymmetries. A significant association was found between duration of TMD and temperature asymmetry of the anterior temporalis muscle (rs = 0.224, p = 0.034). The present findings demonstrate that chronicity of myogenous TMD changes the skin temperature over the anterior temporalis muscle. PMID- 25042315 TI - Assessment of type of bite and vertical dimension of occlusion in children and adolescents with temporomandibular disorder. AB - The aim of the present study was determine the type of bite and abnormalities in the vertical dimension of occlusion (VDO) among children and adolescents with temporomandibular disorder (TMD). The Helkimo index was employed for the diagnostic investigation of TMD. A clinical examination was performed for the determination of occlusion. The VDO was measured using a digital caliper. Fisher's exact text was used to determine associations between type of bite, gender and TMD. The Student's t-test was used to compare age and VDO by gender. The significance level was set to 5% or corresponding p-value. Children and adolescents with anterior open bite were 1.2-fold more likely to develop TMD in comparison to those without any type of malocclusion. The same was found for those with posterior crossbite and mixed malocclusion. A statistically significant association was found between the VDO and age in both genders. TMD affected 68.85% of the sample. No correlation was found between malocclusion, VDO and TMD in the sample. The present findings suggest that individuals with malocclusion are more prone to TMD. Therefore, it is important to evaluate all variables capable of influencing the harmony of the stomatognathic system for an effective diagnosis of TMD and malocclusion. PMID- 25042316 TI - Why are there so many discussions about the nomenclature of fasciae? PMID- 25042317 TI - The fascia debate. PMID- 25042318 TI - Langevin's response to Stecco's fascial nomenclature editorial. PMID- 25042319 TI - Myers' response to Stecco's fascial nomenclature editorial. PMID- 25042320 TI - Schleip & Klingler's response to Stecco's fascial nomenclature editorial. PMID- 25042321 TI - Tozzi's response to Stecco's fascial nomenclature editorial. PMID- 25042322 TI - Surface electromyographic recordings after passive and active motion along the posterior myofascial kinematic chain in healthy male subjects. AB - OBJECTIVE: To map the association of muscle activations along the superficial back line (SBL) using separate conditions of active range of motion with and without resistance and passive range of motion. METHOD: Using surface electromyography, electrodes were placed at specific points along the SBL. Twenty healthy adult males (aged 25.35 +/- 1.24 years and body mass index 23.78 +/- 2.12) underwent five test conditions. Conditions 1-3 involved passive movement, active movement and active movement against maximum isometric resistance (IR) of the right gastrocnemius and conditions 4 and 5 involved neck extension without and with isometric resistance from prone position. RESULTS: Passive and active motion without resistance found no significant (p > 0.05) correlations at any electrodes. Maximum IR yielded significant (p < 0.05) correlations with medium to very strong correlations at almost all electrodes. Neck extension without and with resistance showed significant medium to very strong correlations though the posterior superior iliac spine and right hamstring, respectively. CONCLUSION: Results demonstrated significant associations between the test condition muscle activations and muscle activations along the contiguous SBL. Thus, showing a need for a complete evaluation of the SBL in patients suffering from myofascial pain at all locations along it. PMID- 25042323 TI - Case study: could ultrasound and elastography visualized densified areas inside the deep fascia? AB - Many manual techniques describe palpable changes in the subcutaneous tissue. Many manual therapists have perceived palpable tissue stiffness and how it changes after treatment. No clear demonstration exists of the presence of specific alterations in the subcutaneous tissue and even less a visualization of their changes following manual therapy. This case study visualizes by ultrasound and elastography an alteration of the deep fascia in a 40-year-old male with subacute pain in the calf area. Ultrasound and elastography permits visualization of gliding, echogenicity and elasticity of deep fascia and their changes, after manual therapy (Fascial Manipulation((c))). This study suggests the possible use of the ultrasound and elastography to furnish a more objective picture of the "sensations" that are commonly reported by manual therapists, and which supports clinicians in the diagnosis of the myofascial pain. PMID- 25042324 TI - Are movement screens relevant for Pilates, circus or dance? PMID- 25042325 TI - The Double Knee Swing Test - a practical example of The Performance Matrix Movement Screen. AB - Movement screens have been suggested as an appropriate tool to identify 'uncontrolled movement' within the human neuromusculoskeletal system. Movement screens test the Central Nervous System along with the muscular system, for their combined ability to successfully control low threshold forces, such as those affecting posture and alignment, or, high threshold forces, such as those requiring muscular strength to control. Further information such as the identification of an anatomical site and direction of a potential uncontrolled movement can be elicited by this type of testing. This paper describes a low threshold, movement screen test, designed to be part of a battery of tests, which when used as a whole, can identify injury risk or factors affecting performance limitations. The testing is suggested to be a suitable assessment tool for Pilates Teachers working in a rehabilitative environment. PMID- 25042327 TI - Comparison of group motor control training versus individual training for people suffering from back pain. AB - This study investigated the effects of "motor-control training" (MCT) using the model of deficits in the activation of transversus abdominis (TrA) in people with recurrent back pain. The purpose of this investigation was to establish whether MCT - implemented within a new group intervention (experimental group) - is able to produce results similar to those of a conventional intervention applied individually (control group) to people suffering from back pain. Using the form of an experimental pre-post-test design, the study consisted of an experimental group (N = 18, mean age M = 45.2; SD = 18.4; 9 ?, 9 ?) and a comparison group (N = 13; age = 56.6; SD = 18.5; 6 ?, 7 ?). The training covered a period of six weeks, with two training sessions per week. The amount of training was the same in both groups. Aside from the same extent of training, the participants in the experimental group completed training content in the group interventions identical to that completed by the comparison group in the individual treatments. To clarify: The difference between the two groups was that the participants in the individual-therapy control group received individual feedback on their exercise performance and correction notes from the instructor. This degree of individual attention was not given within the group therapy. The selective activation of the M. transversus abdominis (TrA) was the main focus of the intervention, with the intent of improving its stabilising corset function, especially within the lumbar region, via increased tension of the thoracolumbar fascia. To record the progress of both groups, the anterolateral abdominal muscle recruitment of the M. transversus abdominis (TrA) was measured as a main influencing factor for anterolateral stabilisation of the spine. For measurements of muscle recruitment, rehabilitative ultrasound imaging (M-TurboTM SonoSite((r)) Erlangen in B-Mode) according to Whittaker (2007) was used. Furthermore, the relationship between pain relief and the development of muscle recruitment was evaluated. Finally, the possible pain relief and the improvement of daily routine disruptions were assessed via the visual analogous scale (VAS) and the Oswestry Disability Questionnaire (ODI) (Mannion et al., 2006a,b). Both forms of intervention produced significant improvements in abdominal muscle control and pain (p < 0.003; p < 0.007). However, according to Cohen (1988), the effect sizes could be classified as a low to medium effect advantage on the part of the individual treatment (d < 0.5). Nevertheless, there were no statistically significant differences between individual and group interventions for the measured parameters, indicating that the group interventions can be considered more efficient because more patients were helped at the same time with similar effort. This result provides new and valuable insights for doctors, sports medicine specialists and physiotherapists, as well as for the sponsors of prescribed treatments, and it confirms the usefulness of integrating the new form of intervention into existing multimodal back therapy training concepts. PMID- 25042326 TI - Comparison of spine motion and trunk muscle activity between abdominal hollowing and abdominal bracing maneuvers during prone hip extension. AB - The aim of this study was to examine the effects of lumbopelvic stabilization maneuvers on spine motion and trunk muscle activity during prone hip extension (PHE). In this study, 14 healthy male volunteers (mean age, 21.2 +/- 2.6 years) were instructed to perform PHE without any maneuvers (control), with abdominal hollowing (AH), and with abdominal bracing (AB). Surface electromyography data were collected from the trunk muscles and the lumbopelvic motion was measured. Lumbar extension and anterior pelvic tilt degree were significantly lower in the AH and AB than in the control condition during PHE (p < 0.001). Lumbar extension and anterior pelvic tilt degree did not differ significantly between the AH and AB (p > 0.05). Global muscle group activity such as external obliques was lower in the AH than in the AB. These findings suggest that PHE with AH effectively minimizes unwanted lumbopelvic motion which does not result in global muscle activation. PMID- 25042328 TI - The teeter. PMID- 25042329 TI - Sarcomere length organization as a design for cooperative function amongst all lumbar spine muscles. AB - The functional design of spine muscles in part dictates their role in moving, loading, and stabilizing the lumbar spine. There have been numerous studies that have examined the isolated properties of these individual muscles. Understanding how these muscles interact and work together, necessary for the prediction of muscle function, spine loading, and stability, is lacking. The objective of this study was to measure sarcomere lengths of lumbar muscles in a neutral cadaveric position and predict the sarcomere operating ranges of these muscles throughout full ranges of spine movements. Sarcomere lengths of seven lumbar muscles in each of seven cadaveric donors were measured using laser diffraction. Using published anatomical coordinate data, superior muscle attachment sites were rotated about each intervertebral joint and the total change in muscle length was used to predict sarcomere length operating ranges. The extensor muscles had short sarcomere lengths in a neutral spine posture and there were no statistically significant differences between extensor muscles. The quadratus lumborum was the only muscle with sarcomere lengths that were optimal for force production in a neutral spine position, and the psoas muscles had the longest lengths in this position. During modeled flexion the extensor, quadratus lumborum, and intertransversarii muscles lengthened so that all muscles operated in the approximate same location on the descending limb of the force-length relationship. The intrinsic properties of lumbar muscles are designed to complement each other. The extensor muscles are all designed to produce maximum force in a mid-flexed posture, and all muscles are designed to operate at similar locations of the force-length relationship at full spine flexion. PMID- 25042330 TI - Mechanical properties vary for different regions of the finger extensor apparatus. AB - The extensor apparatus, an aponeurosis that covers the dorsal side of each finger, transmits force from a number of musculotendons to the phalanges. Multiple tendons integrate directly into the structure at different sites and the extensor apparatus attaches to the phalanges at multiple points. Thus, prediction of the force distribution within the extensor apparatus, or hood, and the transmission to the phalanges is challenging, especially as knowledge of the underlying mechanical properties of the tissue is limited. We undertook quantification of some of these properties through material testing of cadaver specimens. We punched samples at specified locations from 19 extensor hood specimens. Material testing was performed to failure for each sample with a custom material testing device. Testing revealed significant differences in ultimate load, ultimate strain, thickness, and tangent modulus along the length of the extensor hood. Specifically, thickness, ultimate load, and ultimate strain were greater in the more proximal sections of the extensor hood, while the tangent modulus was greater in the more distal sections. The variations in mechanical properties within the hood may impact prediction of force transmission and, thus, should be considered when modeling the action of the extensor apparatus. Across the extensor hood, tangent modulus values were substantially smaller than values reported for other soft tissues, such as the Achilles tendon and knee ligaments, while ultimate strains were much greater. Thus, the tissue in the extensor apparatus seems to have greater elasticity, which should be modeled accordingly. PMID- 25042331 TI - Impact of hybrid rooms with image fusion on radiation exposure during endovascular aortic repair. AB - OBJECTIVE: To evaluate exposure to radiation during endovascular aneurysm repair (EVAR) performed with intraoperative guidance by preoperative computed tomographic angiogram fusion. METHODS: All consecutive patients who underwent standard bifurcated (BIF) or thoracic (THO), and complex fenestrated (FEN) or branched (BR) EVAR were prospectively enrolled. Indirect dose-area product (DAP), fluoroscopy time (FT), and contrast medium volume were recorded. These data were compared with a previously published prospective EVAR cohort of 301 patients and to other literature. Direct DAP and peak skin dose were measured with radiochromic films. Results are expressed as median (interquartile range). RESULTS: From December 2012 to July 2013, 102 patients underwent standard (56.8%) or complex (43.2%) EVAR. The indirect DAP (Gy.cm(2)) was as follows: BIF 12.2 (8.7-19.9); THO 26.0 (11.9-34.9); FEN 43.7 (24.7-57.5); and BR 47.4 (37.2-108.2). The FT (min) was as follows: BIF 10.6 (9.1-14.7); THO 8.9 (6.0-10.5); FEN 30.7 (20.2-40.5); and BR 39.5 (34.8-51.6). The contrast medium volume (mL) was as follows: BIF 59.0 (50.0-75.0); THO 80.0 (50.0-100.0); FEN 105.0 (70.0-136.0); and BR 120.0 (100.0-170.0). When compared with a previous cohort, there was a significant reduction in DAP during BIF, FEN, and BR procedures, and a significant reduction of iodinated contrast volume during FEN and BR procedures. There was also a significant reduction in DAP during BIF procedures when compared with the literature (p < .01). DAP measurement on radiochromic films was strongly correlated with indirect DAP values (r(2) = .93). CONCLUSION: The exposure of patients and operators to radiation is significantly reduced by routine use of image fusion during standard and complex EVAR. PMID- 25042332 TI - Type II endoleak: conservative management is a safe strategy. AB - OBJECTIVE: Type II endoleak is the most common complication after endovascular abdominal aortic aneurysm repair (EVAR); however, its natural history is unclear. The aim of this study was to examine the incidence and outcomes of type II endoleak, at a single institution after EVAR. METHODS: A total of 904 consecutive patients who underwent EVAR between September 1995 and July 2013 at a single centre were entered onto a prospective database. All patients were followed up by duplex ultrasound (DUSS). Patients who developed type II endoleak were compared for preoperative demographics, mortality, and sac expansion. RESULTS: A total of 175(19%) patients developed type II endoleak over a median follow-up of 3.6 years (1.5-5.9 years); 54% of type II endoleaks spontaneously resolved within 6 months (0.25-1.2 years). No difference was found in preoperative demographics or choice of endograft between the two groups. Survival was significantly higher in the group with type II endoleak (94.1% vs. 85.6%; p = .01) and this effect was most pronounced in those with late type II endoleaks (97.7% vs. 85.6% p = .004). No difference was seen in aneurysm-related mortality or rate of type I endoleak between the two groups. Freedom from sac expansion (>5 mm from preoperative diameter) was significantly lower in the group of patients with type II endoleak (82.5% vs. 93.2%, p = .0001); however, at a threshold of >10 mm from preoperative diameter no difference was seen. CONCLUSIONS: Patients with isolated type II endoleak demonstrate equivalent aneurysm-related mortality and an improved survival. PMID- 25042333 TI - Eaton's reagent-mediated domino pi-cationic arylations of aromatic carboxylic acids to Iasi-red polymethoxylated polycyclic aromatic hydrocarbons: products with unprecedented biological activities as tubulin polymerization inhibitors. AB - A rapid domino pi-cationic arylation of aromatic carboxylic acids, mediated by Eaton's reagent, has been developed for the synthesis of Iasi-red polymethoxylated polycyclic aromatic hydrocarbons (PAHs). This route is currently the easiest method to obtain such popular PAH compounds, which bear in addition numerous methoxy groups. The domino process was generalized, the structure of the obtained red products and the mechanism of their formations were elucidated, and some of their photophysical properties were determined. Newly synthesized polymethoxylated-PAHs were tested for their interaction with tubulin polymerization as well as for their cytotoxicity on a panel of NCI-60 human cancer cell lines. Interestingly, one of these rubicene derivatives exhibited remarkable cytotoxicity in vitro, including inhibition of leukemia, colon, melanoma, CNS, and ovarian cancer cell lines with GI50 values in the low nanomolar range (GI50 < 10 nM). PMID- 25042334 TI - Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity. AB - Foxp3 specifies the Treg cell lineage and is indispensable for immune tolerance. Accordingly, rare Foxp3 mutations cause lethal autoimmunity. The mechanisms precipitating more prevalent human autoimmune diseases are poorly understood, but involve a combination of genetic and environmental factors. Many autoimmune diseases associate with a partial Treg-cell dysfunction, yet mouse models reflecting such complex pathophysiological processes are rare. Around 95% of Foxp3(+) Treg cells can be specifically depleted in bacterial artifical chromosome (BAC)-transgenic Depletion of REGulatory T cells (DEREG) mice through diphtheria toxin (DT) treatment. However, Treg-cell depletion fails to cause autoimmunity in adult DEREG mice for unclear reasons. By crossing Foxp3(GFP) knock-in mice to DEREG mice, we introduced additional genetic susceptibility that does not affect untreated mice. Strikingly, DT treatment of DEREG * Foxp3(GFP) mice rapidly causes autoimmunity characterized by blepharitis, tissue damage, and autoantibody production. This inflammatory disease is associated with augmented T cell activation, increased Th2 cytokine production and myeloproliferation, and is caused by defective Treg-cell homeostasis, preventing few DT-insensitive Treg cells from repopulating the niche after Treg-cell depletion. Our study provides important insights into self-tolerance. We further highlight DEREG * Foxp3(GFP) mice as a model to investigate the role of environmental factors in precipitating autoimmunity. This may help to better understand and treat human autoimmunity. PMID- 25042335 TI - DNA barcoding gap: reliable species identification over morphological and geographical scales. AB - The philosophical basis and utility of DNA barcoding have been a subject of numerous debates. While most literature embraces it, some studies continue to question its use in dipterans, butterflies and marine gastropods. Here, we explore the utility of DNA barcoding in identifying spider species that vary in taxonomic affiliation, morphological diagnosibility and geographic distribution. Our first test searched for a 'barcoding gap' by comparing intra- and interspecific means, medians and overlap in more than 75,000 computed Kimura 2 parameter (K2P) genetic distances in three families. Our second test compared K2P distances of congeneric species with high vs. low morphological distinctness in 20 genera of 11 families. Our third test explored the effect of enlarging geographical sampling area at a continental scale on genetic variability in DNA barcodes within 20 species of nine families. Our results generally point towards a high utility of DNA barcodes in identifying spider species. However, the size of the barcoding gap strongly depends on taxonomic groups and practices. It is becoming critical to define the barcoding gap statistically more consistently and to document its variation over taxonomic scales. Our results support models of independent patterns of morphological and molecular evolution by showing that DNA barcodes are effective in species identification regardless of their morphological diagnosibility. We also show that DNA barcodes represent an effective tool for identifying spider species over geographic scales, yet their variation contains useful biogeographic information. PMID- 25042337 TI - Synthesis, characterization, antifungal evaluation and 3D-QSAR study of phenylhydrazine substituted tetronic acid derivatives. AB - A series of 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H,5H) diones were designed and prepared using two synthetic routes. Their structures were confirmed by FT-IR, (1)H NMR, (13)C NMR, MS, elemental analysis and single crystal X-ray diffraction. Their bioactivity was evaluated against Botrytis cinerea in vitro. Most target compounds exhibited remarkable antifungal activity. Two compounds 7f and 7h were highly effective and their EC50 values were 0.241 MUg/mL and 0.167 MUg/mL, respectively, close to that of the control drug procymidone. 3D-QSAR studies of CoMFA and CoMSIA were carried out. Models with good predictive ability were generated with the cross validated q(2) values for CoMFA and CoMSIA being 0.565 and 0.823. Conventional r(2) values were 0.983 and 0.945, respectively. The results provided a practical tool for guiding the design and synthesis of novel and more potent tetronic acid derivatives containing substituted phenylhydrazine moiety. PMID- 25042338 TI - Study on one-pot four-component synthesis of 9-aryl-hexahydro-acridine-1,8-diones using SiO2-I as a new heterogeneous catalyst and their anticancer activity. AB - A simple, efficient and cost-effective method for the synthesis of 9-aryl hexahydro-acridine-1,8-diones by a one-pot four-component cyclocondensation of dimedone, aromatic aldehydes and ammonium acetate as a nitrogen source in the presence of a new heterogeneous catalyst silica iodide (SiO2-I) in EtOH at 80 degrees C is described. SiO2-I was subjected to SEM-EDX and found to have iodo group bound to the catalyst. Some of the prepared acridine-diones were found to exhibit promising anti-cancer activity against HepG2 and MCF-7 cell lines. PMID- 25042341 TI - Relation between freezing of gait and frontal function in Parkinson's disease. AB - INTRODUCTION: Freezing of gait (FOG) is a common symptom of Parkinson's disease (PD). Although the pathophysiological mechanism of FOG is unknown, previous studies have suggested that frontal dysfunction is associated with FOG. The Behavioral Assessment of the Dysexecutive Syndrome (BADS) battery, which is wide ranging neurological battery composed of six subtests, evaluates frontal function and is more sensitive to executive dysfunction (ED) than other tools in PD patients. This is the first study to assess the relation between FOG in the 'on' state and frontal dysfunction evaluated using BADS. METHODS: Subjects were 65 patients with PD. Multiple logistic regression analysis was used to compare the age-controlled standardized BADS score, age, disease duration, Hoehn and Yahr (HY) stage, levodopa-equivalent daily dose, and Mini-Mental State Examination (MMSE) score across patients with FOG (n = 43) and patients without FOG (n = 22). Score on each of the six BADS subtests were compared across patients with and without FOG using the Mann-Whitney U test. RESULTS: Multiple logistic regression analysis revealed that FOG was related to lower age-controlled standardized BADS score (P = 0.022) and higher HY stage (P = 0.009) but not to disease duration, levodopa equivalent daily dose, or MMSE score. Among the six BADS subtests, score on the Zoo Map Test, which evaluates problem solving and planning, was lower in patients with FOG than in patients without FOG. CONCLUSION: These results support a relation between on-state FOG and frontal dysfunction in PD patients. PMID- 25042339 TI - Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - Using physicochemical property-driven optimization, twelve new diarylaniline compounds (DAANs) (7a-h, 11a-b and 12a-b) were designed and synthesized. Among them, compounds 12a-b not only showed high potency (EC50 0.96-4.92 nM) against both wild-type and drug-resistant viral strains with the lowest fold change (FC 0.91 and 5.13), but also displayed acceptable drug-like properties based on aqueous solubility and lipophilicity (LE>0.3, LLE>5, LELP<10). The correlations between potency and physicochemical properties of these DAAN analogues are also described. Compounds 12a-b merit further development as potent clinical trial candidates against AIDS. PMID- 25042340 TI - Thrombospondin-1 regulates bone homeostasis through effects on bone matrix integrity and nitric oxide signaling in osteoclasts. AB - Thrombospondin-1 (TSP1), an endogenous antiangiogenic, is a widely expressed secreted ligand with roles in migration, adhesion, and proliferation and is a target for new therapeutics. While TSP1 is present in the bone matrix and several TSP1 receptors play roles in bone biology, the role of TSP1 in bone remodeling has not been fully elucidated. Bone turnover is characterized by coordinated activity of bone-forming osteoblasts (OB) and bone-resorbing osteoclasts (OC). TSP1-/- mice had increased bone mass and increased cortical bone size and thickness compared to wild type (WT). However, despite increased size, TSP1-/- femurs showed less resistance to bending than expected, indicative of diminished bone quality and a bone material defect. Additionally, we found that TSP1 deficiency resulted in decreased OC activity in vivo and reduced OC differentiation. TSP1 was critical during early osteoclastogenesis, and TSP1 deficiency resulted in a substantial overexpression of inducible nitric oxide synthase (iNOS). Importantly, administration of a NOS inhibitor rescued the OC function defects of TSP1-/- mice in vivo. To investigate the role of bone-derived TSP1 in osteoclastogenesis, we found that WT pre-OCs had defective iNOS expression when cultured on TSP1-/- bone compared to WT bone, suggesting that TSP1 in bone plays a critical role in iNOS signaling during OC development. These data implicate a new role for TSP1 in bone homeostasis with roles in maintaining bone matrix integrity and regulating OC formation. It will be critical to monitor bone health of patients administered TSP1-pathway directed therapeutics in clinical use and under development. PMID- 25042342 TI - Restless legs syndrome in patients with sequelae of poliomyelitis. AB - BACKGROUND: No studies have examined the association between RLS and the sequelae of poliomyelitis (PM). We studied the frequency and severity of RLS in a group of consecutive patients with the sequelae of poliomyelitis (PM) and the effect of treatment with dopaminergic drugs. METHODS: A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS rating scale. Information on sex, age, age at onset, site affected by PM, disease duration of PM, and history of post-polio syndrome (pPS) was obtained in a cohort of 52 PM patients. RESULT: The mean age was 55.9 +/- 6.5 years; 39 patients had post-polio syndrome (75%). RLS was diagnosed in 21 (40.4%) patients. Sixteen of the 21 patients (76.2%) with RLS had pPS, which was similar to the non RLS group (74.2% patients with pPS). RLS symptoms were very severe in 5 patients, severe in 13, moderate in 2 and mild in 1. Nineteen of the 21 patients with RLS had symptoms predominantly in the more affected lower limb (90% of patients). Sixteen patients received dopaminergic agonist treatment with a significant reduction in their scores on the RLS severity scale from 28.3 +/- 4.7 to 6.9 +/- 7.3 (p < 0.001). DISCUSSION: RLS occurs frequently in patients with PM, both in those with and without pPS, and responds well to treatment with dopaminergic drugs. PMID- 25042343 TI - De novo acute myeloid leukemia with 20-29% blasts is less aggressive than acute myeloid leukemia with >=30% blasts in older adults: a Bone Marrow Pathology Group study. AB - It is controversial whether acute myeloid leukemia (AML) patients with 20-29% bone marrow (BM) blasts, formerly referred to as refractory anemia with excess blasts in transformation (RAEBT), should be considered AML or myelodysplastic syndrome (MDS) for the purposes of treatment and prognostication. We retrospectively studied 571 de novo AML in patients aged >50 years, including 142 RAEBT and 429 with >=30% blasts (AML30), as well as 151 patients with 10-19% BM blasts (RAEB2). RAEBT patients were older and had lower white blood count, but higher hemoglobin, platelet count, and karyotype risk scores compared to AML30, while these features were similar to RAEB2. FLT3 and NPM1 mutations and monocytic morphology occurred more commonly in AML30 than in RAEBT. RAEBT patients were treated less often with induction therapy than AML30, whereas allogeneic stem cell transplant frequency was similar. The median and 4-year OS of RAEBT patients were longer than those of AML30 patients (20.5 vs 12.0 months and 28.6% vs 20.4%, respectively, P = 0.003); this difference in OS was manifested in patients in the intermediate UKMRC karyotype risk group, whereas OS of RAEBT patients and AML30 patients in the adverse karyotype risk group were not significantly different. Multivariable analysis showed that RAEBT (P < 0.0001), hemoglobin (P = 0.005), UKMRC karyotype risk group (P = 0.002), normal BM karyotype (P = 0.004), treatment with induction therapy (P < 0.0001), and stem cell transplant (P < 0.0001) were associated with longer OS. Our findings favor considering de novo RAEBT as a favorable prognostic subgroup of AML. PMID- 25042344 TI - Comparison of clinical manifestations, outcomes and cerebrospinal fluid findings between herpes simplex type 1 and type 2 central nervous system infections in adults. AB - In previous reports on the viral causes of central nervous system (CNS) infections, it has been generally recognized that HSV-1 is a major cause of encephalitis, while HSV-2 is the predominant cause of aseptic meningitis in adults. To examine this matter, the clinical characteristics in the two types of HSV CNS infections were investigated. In a retrospective cohort study which included all adult patients (>=16 years) between January 1999 and December 2013 in a 2,700-bed tertiary care hospital, all the patients in whom PCR of the CSF for HSV was positive were identified. Ninety-five patients with positive CSF PCR results for HSV were included, 21 with HSV-1 and 74 with HSV-2. Many patients with HSV-1 had encephalitis (13/21, 61.9%), whereas most patients with HSV-2 had meningitis (62/74, 83.8%). However, HSV-1 and HSV-2 accounted for similar proportion of patients with HSV encephalitis (13/25, 52.0% vs. 12/25, 48.0%). Neurological sequelae were more frequent among patients with HSV-1 (9/21, 42.9% vs. 6/74, 8.1%; P = 0.001). The present study suggests that HSV-2 is not only a major cause of aseptic meningitis, but also it may cause serious manifestation as HSV-1 encephalitis in adults. PMID- 25042345 TI - Quality of life after surgical decompression for space-occupying middle cerebral artery infarction: systematic review. AB - BACKGROUND AND PURPOSE: In patients with space-occupying middle cerebral artery infarction, surgical decompression strongly reduces risk of death and increases the chance of a favorable outcome. This comes at the expense of an increase in the risk of survival with (moderately) severe disability. We assessed quality of life, depression, and caregiver burden in these patients. SUMMARY OF REVIEW: We systematically reviewed the literature by searching MEDLINE, EMBASE, and PsycINFO up to March 2014. We included randomized controlled trials, cohort studies, case control studies, and case series with quality of life, depression, or caregiver burden as primary or secondary outcome. Seventeen articles reporting on 459 patients were included. At final follow-up at 7 to 51 months, 1344 patients (30%) had died, and 34 (11%) were lost to follow up. Data on 291 patients were available, of whom 81 of 213 survivors (39%) achieved good functional outcome at final follow-up (modified Rankin Scale <= 3). Mean quality of life was 46% to 67% of the best possible score when based on questionnaires or visual analogue scales. At final follow-up, 143 of 189 patients (76%) would in retrospect again choose for surgical decompression. Severe depressive symptoms were present in 14 of 113 patients (16%). Three studies investigated caregiver burden and reported substantial burden. Patients more than 60 years old had a lower quality of life in comparison with younger patients. CONCLUSIONS: Most patients treated with surgical decompression for space-occupying infarction have a reasonable quality of life at long-term follow-up and are satisfied with the treatment received. Severe depressive symptoms are uncommon. PMID- 25042346 TI - State of the art of single-walled carbon nanotube synthesis on surfaces. AB - Single-walled carbon nanotubes (SWNTs) directly synthesized on surfaces are promising building blocks for nanoelectronics. The structures and the arrangement of the SWNTs on surfaces determine the quality and density of the fabricated nanoelectronics, implying the importance of structure controlled growth of SWNTs on surfaces. This review summarizes the recent research status in controlling the orientation, length, density, diameter, metallicity, and chirality of SWNTs directly synthesized on surfaces by chemical vapor deposition, together with a session presenting the characterization method of the chirality of SWNTs. Finally, the remaining major challenges are discussed and future research directions are proposed. PMID- 25042347 TI - Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling. AB - The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-beta1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-beta pathway. TGF-beta1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-beta1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-beta1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF beta1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. PMID- 25042348 TI - Low- and high-frequency oscillations reveal distinct absence seizure networks. AB - OBJECTIVE: The aim of this study was to determine the frequency-dependent, spatiotemporal involvement of corticothalamic networks to the generation of absence seizures. METHODS: Magnetoencephalography recordings were obtained in 12 subjects (44 seizures) with untreated childhood absence seizures. Time-frequency analysis of each seizure was performed to determine bandwidths with significant power at ictal onset. Source localization was then completed to determine brain regions contributing to generalized spike and wave discharges seen on electroencephalogram. RESULTS: Significant power in the time-frequency analysis was seen within 1 to 20Hz, 20 to 70Hz, and 70 to 150Hz bandwidths. Source localization revealed that sources localized to the frontal cortex similarly for the low- and gamma-frequency bandwidths, whereas at the low-frequency bandwidth (3-20Hz) significantly more sources localized to the parietal cortex (odds ratio [OR] = 16.7). Cortical sources within the high-frequency oscillation (HFO) bandwidth (70-150Hz) localized primarily to the frontal region compared to the parietal (OR = 7.32) or temporal (OR = 2.78) areas. INTERPRETATION: Neuromagnetic activity within frontal and parietal cortical regions provides further confirmation of hemodynamic changes reported using functional magnetic resonance imaging that have been associated with absence seizures. The frequency-dependent nature of these networks has not previously been reported, and the presence of HFOs during absence seizures is a novel finding. Co-occurring frontal and parietal corticothalamic networks may interact to produce a pathological state that contributes to the generation of spike and wave discharges. The clinical and pathophysiological implications of HFOs within the frontal cortical region are unclear and should be further investigated. PMID- 25042349 TI - The development of a rubric for peer assessment of individual teamwork skills in undergraduate midwifery students. AB - BACKGROUND: Poor teamwork is cited as one of the major root causes of adverse events in healthcare. Bullying, resulting in illness for staff, is an expression of poor teamwork skills. Despite this knowledge, poor teamwork persists in healthcare and teamwork skills are rarely the focus of teaching and assessment in undergraduate health courses. AIM: To develop and implement an assessment tool for use in facilitating midwifery students' learning of teamwork skills. METHODS: This paper describes how the TeamUP rubric tool was developed. A review of the literature found no research reports on how to teach and assess health students' teamwork skills in standing teams. The literature, however, gives guidance about how university educators should evaluate individual students using peer assessment. The developmental processes of the rubric were grounded in the theoretical literature and feminist collaborative conversations. The rubric incorporates five domains of teamwork skills: Fostering a Team Climate; Project Planning; Facilitating Teams; Managing Conflict and Quality Individual Contribution. The process and outcomes of student and academic content validation are described. CONCLUSION: The TeamUP rubric is useful for articulating, teaching and assessing teamwork skills for health professional students. The TeamUP rubric is a robust, theoretically grounded model that defines and details effective teamwork skills and related behaviours. If these skills are mastered, we predict that graduates will be more effective in teams. Our assumption is that graduates, empowered by having these skills, are more likely to manage conflict effectively and less likely to engage in bullying behaviours. PMID- 25042350 TI - Axis ring fractures due to simulated head impacts. AB - BACKGROUND: We investigated mechanisms of axis ring fractures due to simulated head impacts. METHODS: Our model consisted of a human upper cervical spine specimen (occiput through C3) mounted to a surrogate torso mass on a sled and carrying a surrogate head. We divided 13 specimens into 3 groups based upon head impact location: upper forehead in the midline, upper lateral side of the forehead, and upper lateral side of the head. Post-impact fluoroscopy and anatomical dissection documented the injuries. Average occurrence times of the peak loads and accelerations were statistically compared (P<0.05) using ANOVA and Bonferroni pair-wise post-hoc tests. FINDINGS: Of the 13 upper cervical spines tested, 5 specimens sustained axis ring fractures with the most common mechanism being impact to the upper left lateral side of the forehead. The first local force peaks at the impact barrier and neck and all peak head accelerations occurred between 18.0 and 22.8 ms, significantly earlier than the absolute force peaks. The average peak neck loads reached 1761.2N and the axis ring fractures occurred within 50 ms. INTERPRETATION: We observed asymmetrical fractures of the axis ring including fractures of the superior and inferior facets, laminae, posterior wall of the vertebral body, pars interarticularis, and pedicles. The fracture patterns were related to the morphology of the axis as a transitional vertebra of the upper cervical spine. Understanding the mechanisms of axis ring fractures may help in choosing the optimal reduction technique and stabilization method based upon the specific fracture pattern. PMID- 25042351 TI - Clinical and sonographic parameters at mid-trimester and the risk of cesarean delivery in low-risk nulliparas. AB - BACKGROUND: To examine the potential clinical and sonographic parameters at mid trimester that predict the risk of intrapartum cesarean delivery at term among low-risk nulliparas. METHODS: This prospective study recruited nulliparas with singleton low-risk pregnancies at 20.0-24.0 weeks. Sonographic measurement of the cervical length and fetal biometry was performed. The data collected at enrollment included maternal age, measured weight at first prenatal visit to the hospital, current weight, height, fetal biometric parameters, and cervical length. A multivariate analysis was conducted, with control for known intra- and postpartum confounding factors associated with cesarean delivery, including sex of the fetus. RESULTS: Based on multivariate analyses of 652 women, of all variables at mid-trimester, only maternal height was significantly associated with increased risk of cesarean delivery (61, 9.4%), whereas for intra- or postpartum variables, induction of labor, epidural analgesia, male gender, and nightshift delivery showed statistically significant association with the risk of cesarean delivery. CONCLUSIONS: Maternal height and fetal gender, as measured at mid-trimester, are potential independent predictors for the risk of intrapartum cesarean delivery at term in low-risk nulliparas; however, sonographic measurements of the cervical length, fetal biometric ratio, maternal age, and current weight at mid-trimester were not predictive of cesarean delivery at term. (c) 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:235-242, 2015. PMID- 25042353 TI - Detection of S-adenosylhomocysteine and methylation index in blood by capillary electrophoresis. AB - This work proposes an approach to the direct analysis of S-adenosylhomocysteine (SAH) and the methylation index in blood using CE with UV detection (CE-UV). After application of meglumine postinjection, we achieved SAH in-capillary preconcentration in the HClO4 extracts of erythrocytes, which improved the detection limit (S/N = 3) of SAH up to 3 fmol or 180 nmol/L at the injection volume of 50 nL, taking into account the sample dilution rate. CE-UV was carried out in 30 mM glycine and 45 mmol/L HCl (pH ~1.8) at 17 kV in a capillary 48 cm in length and 50 MUm id. Accuracy of the technique was 101% and reproducibility was about 12%. PMID- 25042354 TI - Study on reducing antigenic response and IgE-binding inhibitions of four milk proteins of Lactobacillus casei 1134. AB - BACKGROUND: Cow's milk allergy has aroused public concern. The aim of this study was to investigate the effects of fermentation by Lactobacillus casei 1134 on the antigenicity and allergenicity (IgE-binding inhibitions) of milk proteins. The effects of pH value on the antigenicity and allergenicity of four milk proteins (alpha-lactalbumin, beta-lactoglobulin, alpha-casein and beta-casein) were examined by indirect competitive enzyme-linked immunosorbent assay. The free amino acids which were produced in the fermentation process were analysed and the proteolysis of milk proteins was detected. RESULTS: Fermentation by L. casei 1134 could significantly reduce the antigenicity and allergenicity of the four proteins in reconstituted milk. The allergenicity of milk proteins was further reduced in the process of simulated gastrointestinal digestion. Moreover, we could deduce that one of the potential factors of antigenicity was lactic acid with the comparison of the antigenicity of the four proteins between L. casei 1134 fermented milk and lactic acid milk at different pH values. CONCLUSION: There are many factors which can affect the milk proteins allergen, including lactic acid and proteolytic enzymes. PMID- 25042352 TI - Increased expression of stress inducible protein 1 in glioma-associated microglia/macrophages. AB - Factors released by glioma-associated microglia/macrophages (GAMs) play an important role in the growth and infiltration of tumors. We have previously demonstrated that the co-chaperone stress-inducible protein 1 (STI1) secreted by microglia promotes proliferation and migration of human glioblastoma (GBM) cell lines in vitro. In the present study, in order to investigate the role of STI1 in a physiological context, we used a glioma model to evaluate STI1 expression in vivo. Here, we demonstrate that STI1 expression in both the tumor and in the infiltrating GAMs and lymphocytes significantly increased with tumor progression. Interestingly, high expression of STI1 was observed in macrophages and lymphocytes that infiltrated brain tumors, whereas STI1 expression in the circulating blood monocytes and lymphocytes remained unchanged. Our results correlate, for the first time, the expression of STI1 and glioma progression, and suggest that STI1 expression in GAMs and infiltrating lymphocytes is modulated by the brain tumor microenvironment. PMID- 25042355 TI - Mycoplasma hyorhinis induces proinflammatory responses in mice lymphocytes. AB - Mycoplasmas are frequent contaminants of cultured cells, leading to alterations in cellular gene expression, protein synthesis, signal transduction, and metabolic pathways. Mycoplasma hyorhinis, the major contaminant of tissue cultures, has been implicated in a variety of diseases in swine. Most human and animal mycoplasmas remain attached to the surface of epithelial cells. Nonetheless, we have recently shown that M. hyorhinis is able to invade nonphagocytic melanoma cells. In the present study, we show by confocal laser scanning microscopy, that by exposing mice splenocytes to intact M. hyorhinis, intracellular mycoplasmas were detected. Mycoplasmal components were not detected within splenocytes after exposure to heat inactivated M. hyorhinis or to a purified M. hyorhinis lipoprotein (LPP) fraction. However, incubation of the splenocytes with intact M. hyorhinis cells, heat inactivated cells or M. hyorhinis LPP fraction induced accelerated cell proliferation and the secretion of interferon gamma and interleukin 17. Thus, M. hyorhinis and its LPPs can be added to the list of infectious agents causing direct stimulation of proinflammatory responses by mammalian lymphocytes. PMID- 25042356 TI - Stereoselective hydrodehalogenation via a radical-based mechanism involving T shaped chiral nickel(I) pincer complexes. AB - We herein report the catalytic enantioselective hydrodehalogenation based on the interplay of a chiral molecular nickel(I)/nickel(II)hydride system. Prochiral geminal dihalogenides are dehalogenated via a secondary configurationally unstable, potentially metal-stabilized radical intermediate. In a subsequent step, the liberated radical is then trapped by the nickel(II) hydrido complex, present in a large excess under the catalytic conditions, which in turn induces the enantioselectivity during the hydrogen atom transfer onto the radical intermediate. These new chiral nickel(I) complexes were found to catalyze the asymmetric hydrodehalogenation of geminal dihalogenides with moderate to good enantiomeric excess values using LiEt3 BH as reductant. The main side product generally observed is the dehalogenated alkene, whereas the hydrodehalogenation of the chiral monohalogen compound occurred much more slowly despite the large excess of reductant. PMID- 25042357 TI - Aggression on haemodialysis units: a mixed method study. AB - BACKGROUND: Aggression on haemodialysis units is a growing problem internationally that has received little research attention to date. Aggressive behaviour by patients or their relatives can compromise the safety and well-being of staff and other patients sharing a haemodialysis session. OBJECTIVES: The objectives of the study were twofold: First, to identify the prevalance and nature of aggression on haemodialysis units; and second, to investigate factors that contribute to aggressive behaviour on haemodialysis units. DESIGN AND METHODS: A cross-sectional, sequential mixed method research design was adopted, with two research methods utilised. Incidents of aggressive behaviour were recorded over a 12-month period, using a renal version of the Staff Observation Aggression Scale. Six months after the incident data collection had commenced, semi-structured qualitative interviews were conducted with 29 multidisciplinary members of staff. RESULTS: Over 12 months, 74 aggressive incidents were recorded. The majority of incidents involved verbal aggression, and the perpetrators were a minority of patients, relatives and staff. Two patients were responsible for 38% of all incidents; both patients had mental health problems. Distinct temporal patterns to the aggressive behaviour were observed according to the day of the week and time of day. CONCLUSION: This study demonstrates that aggression is a significant problem on haemodialysis units, with verbal aggression most prevalent. The temporal patterns to aggression observed are related to the uniqueness of the haemodialysis setting, with a distinctly different treatment environment compared with other healthcare settings. PMID- 25042358 TI - Reply: the FM/AM world is shaping the future of deep brain stimulation. PMID- 25042359 TI - Seventy day safety assessment of an orally ingested, l-glutamine-containing oat and yeast supplement for horses. AB - We describe a safety assessment of an oral supplement designed to nutritionally support the gastrointestinal system of horses. The supplement comprised a mixture of essential (l-threonine) and conditionally essential (l-glutamine) amino acids, polar lipids, oat bran rich in beta glucans and yeast extract. Young (1-2years) horses of both sexes were allocated to control (n=7) and treatment groups (n=7) and studied for 9weeks. Horses in the treatment group received the supplement daily for 8weeks. After 8weeks of supplementation, horses were studied for one additional week. Outcome measures included body mass, weight gain, results of clinical examination, hematology and plasma chemistry. There were no adverse events associated with supplementation and horses in both groups showed normal weight gain, clinical signs, hematology and chemistry. l-Glutamine, which is not yet listed as GRAS, was considered with respect to its potential for nutritional support and safety when ingested orally. It is concluded that this oral supplement, when ingested by horses at twice the recommended daily level, was safe and does not pose a health risk when used in accordance with good feeding practice. PMID- 25042360 TI - Considerations for non-clinical safety studies of therapeutic peptide vaccines. AB - Guidelines for non-clinical studies of prophylactic vaccines against infectious diseases have been published widely, but similar guidelines for therapeutic vaccines, and especially therapeutic peptide vaccines, have yet to be established. The approach to non-clinical safety studies required for therapeutic vaccines differs from that for prophylactic vaccines due to differences in the risk-benefit balance and the mechanisms of action. We propose the following guidelines for non-clinical safety studies for therapeutic peptide vaccines. (i) Since the main safety concern is related to the immune response that might occur at normal sites that express a target antigen, identification of these possible target sites using in silico human expression data is important. (ii) Due to the strong dependence on HLA, it is not feasible to replicate immune responses in animals. Thus, the required non-clinical safety studies are characterized as those detecting off-target toxicity rather than on-target toxicity. PMID- 25042361 TI - Combined EXAFS and DFT structure calculations provide structural insights into the 1:1 multi-histidine complexes of Cu(II) , Cu(I) , and Zn(II) with the tandem octarepeats of the mammalian prion protein. AB - The metal-coordinating properties of the prion protein (PrP) have been the subject of intense focus and debate since the first reports of its interaction with copper just before the turn of the century. The picture of metal coordination to PrP has been improved and refined over the past decade, but structural details of the various metal coordination modes have not been fully elucidated in some cases. In the present study, we have employed X-ray absorption near-edge spectroscopy as well as extended X-ray absorption fine structure (EXAFS) spectroscopy to structurally characterize the dominant 1:1 coordination modes for Cu(II) , Cu(I) , and Zn(II) with an N-terminal fragment of PrP. The PrP fragment corresponds to four tandem repeats representative of the mammalian octarepeat domain, designated as OR4 , which is also the most studied PrP fragment for metal interactions, making our findings applicable to a large body of previous work. Density functional theory (DFT) calculations have provided additional structural and thermodynamic data, and candidate structures have been used to inform EXAFS data analysis. The optimized geometries from DFT calculations have been used to identify potential coordination complexes for multi-histidine coordination of Cu(II) , Cu(I) , and Zn(II) in an aqueous medium, modelled using 4-methylimidazole to represent the histidine side chain. Through a combination of in silico coordination chemistry as well as rigorous EXAFS curve fitting, using full multiple scattering on candidate structures derived from DFT calculations, we have characterized the predominant coordination modes for the 1:1 complexes of Cu(II) , Cu(I) , and Zn(II) with the OR4 peptide at pH 7.4 at atomic resolution, which are best represented as square-planar [Cu(II) (His)4 ](2+) , digonal [Cu(I) (His)2 ](+) , and tetrahedral [Zn(II) (His)3 (OH2 )](2+) , respectively. PMID- 25042362 TI - Inflammatory interference of memory formation. AB - CD8+ memory T cells are critical for immunity against intracellular pathogens. Epidemiological evidence demonstrates that bystander infection can impact immune responses to co-infection or vaccination. A recent paper in Immunity demonstrates that persistent bystander inflammation can negatively impact CD8+ T cell effector to memory transition and protection from subsequent infection. PMID- 25042363 TI - Antibacterial activity of two-dimensional MoS2 sheets. AB - Graphene-like two-dimensional materials (2DMats) show application potential in optoelectronics and biomedicine due to their unique properties. However, environmental and biological influences of these 2DMats remain to be unveiled. Here we reported the antibacterial activity of two-dimensional (2D) chemically exfoliated MoS2 (ce-MoS2) sheets. We found that the antibacterial activity of ce MoS2 sheets was much more potent than that of the raw MoS2 powders used for the synthesis of ce-MoS2 sheets possibly due to the 2D planar structure (high specific surface area) and higher conductivity of the ce-MoS2. We investigated the antibacterial mechanisms of the ce-MoS2 sheets and proposed their antibacterial pathways. We found that the ce-MoS2 sheets could produce reactive oxygen species (ROS), different from a previous report on graphene-based materials. Particularly, the oxidation capacity of the ce-MoS2 sheets toward glutathione oxidation showed a time and concentration dependent trend, which is fully consistent with the antibacterial behaviour of the ce-MoS2 sheets. The results suggest that antimicrobial behaviors were attributable to both membrane and oxidation stress. The antibacterial pathways include MoS2-bacteria contact induced membrane stress, superoxide anion (O2(-) induced ROS production by the ce MoS2, and the ensuing superoxide anion-independent oxidation. Our study thus indicates that the tailoring of the dimension of nanomaterials and their electronic properties would manipulate antibacterial activity. PMID- 25042364 TI - Prospective study of muscle cramps in Charcot-Marie-tooth disease. AB - INTRODUCTION: This study aims to assess the frequency, location, severity, duration, and fluctuation over time of muscle cramps in Charcot-Marie-Tooth disease (CMT). METHODS: Inherited Neuropathies Consortium Contact Registry participants recorded the occurrence and characteristics of muscle cramps using an 11-question survey administered 3 times over 8 weeks. RESULTS: A total of 110 adult patients with CMT completed the survey. Weekly cramp frequency was 9.3 (SD 12.3), and 23% had daily muscle cramps. Twenty-two percent reported a significant impact on quality of life. Over 8 weeks, the daily frequency and severity of muscle cramps did not change significantly. CONCLUSIONS: Patients with CMT have muscle cramps that vary little over an 8-week period, and they may interfere with quality of life. These data may be useful in the planning of clinical trials of agents to treat adults with CMT-associated muscle cramps. PMID- 25042365 TI - [Intraoperative combined spectroscopy (optical biopsy) of cerebral gliomas]. AB - Clinical studies have revealed high selectivity of 5-ALA-induced protoporphyrin IX accumulation in different brain tumors. Modern methods of evaluation of tissues visible fluorescence are based on the qualitative analysis of the images. Up-to-date methods of combined spectral analysis allow fulfilling the intraoperative quantitative evaluation of the protoporphyrin IX content, as well as the scattering and absorption properties of a tissue. This paper presents a new method of the simultaneous analysis of hemoglobin concentration in oxygenated and reduced forms, tumor marker concentration (5-ALA-induced PP IX) and a new way to analyze the changes in the scattering properties of the tissues. The method is implemented by splitting the visible spectrum into intervals where hemoglobin and protoporphyrin IX have the characteristic peaks of absorption and fluorescence. The present method shows the dependence of the fluorescence index from the tumor grade. Combined spectroscopy (optical biopsy) can detect the differences between the subtypes of gliomas that are similar in the protoporphyrin IX fluorescence index. This method complements and enhances the diagnostic capabilities of spectroscopy, which is particularly important in the non-fluorescent glioma surgery. PMID- 25042366 TI - [Orbitosphenopetroclival meningeomas: clinical and topographic features and results of combined treatment]. AB - The aim of the study was to access clinical and topographic features of orbitosphenopetroclival meningeomas and the results of surgical and combined treatment in patients with meningeaomas of that location. Orbitosphenopetroclival meningeomas comprise a peculiar group of tumors and are the result of infiltrative sphenopetroclival meningeomas progression, when the latter extend into the orbit and temporal fossa. Development of neurosurgery, use modern approaches and adjuvant therapies such as stereotaxic radiosurgery and radiotherapy in the past years markedly improve treatment results in these patients. However, difficulties in treatment strategy choice remain. One attempting to excise a tumor radically encounters with the risk of damage to critically important neurovascular structures. When a tumor is excised partially the risk of complication dwindles, however risk of relapse increases. Palliative surgery improve patients' quality of life. Radiosurgery and irradiation of residual tumors allow to establish control on a tumor growth. MATERIAL AND METHODS: Twenty three patients were studied, of them 20 received surcery, 9 - stereotaxic irradiation, 5 - conventional irradiation. The follow-up interval comprised 8-84 months (median 37 months). RESULTS: Manifestations of orbitosphenopetroclival meningeomas are combined from signs and symptoms of cranioorbital and petroclival meningeomas, and in many patients include signs of skull base external surface involvemevt, marked cosmetic deficits and psychological distress. Orbitosphenopetroclival meningeomas originate from cavernous sinus and medial parts of sphenoid bone wings. During its progression a tumor extends onto orbit and onto clivus, and then onto infratemporal and sphenopalatine fossae, nasopharynx and posterior cranial fossa. CONCLUSION: If a residual tumor is present patients with orbitosphenopetroclival meningeomas should undergo adjuvant irradiation after the first surgery. PMID- 25042367 TI - [Analysis of the neurological status and functional outcome after facial nerve neuroplasctics using accessory nerve]. AB - AIM: to assess effectiveness of mimic muscles rehabilitation after cross neuroplastics using accessory nerve (AN) by neurological scales estimating functional outcome. MATERIAL AND METHODS: During 1998-2010 20 patients underwent cross neuroplastics of facial nerve (FN) by a main trunk of AN. The average follow-up was 4.65 years (1-10 years). At baseline all patients had total function loss of FN after excision of acoustic neuroma. The interval between function loss and surgery was 1-6 months (4.7 months in average). Patients were within age range 37-73 years (51.8 years in average). Each patient was accessed by clinical scales House-Brackmann Facial Grading Systems (HB) and Yanagihara system (YS) for estimation of the extent of mimic paresis. Sunnybrook Facial Grading scale (SFG) was used to assess facial symmetry and synkineses. Self assessment questionnaire Facial Disability Index (FDI) was also used. Original questionnaire, Shoulder Disability Index (SDI), including 4 questions was used for self-assessment of a denervated shoulder segment (maximum 100 degrees). RESULTS: 4 patients (20%) recovered up to HB II, 11 (55%) - up to HB III and 5 (25%) - up to HB IV-V. Average degree by YS was 27.5+/-4.06, average SFG was 71.1+/-9.38. Average degree by self-assessment (FDI) was 143.75+/- 22,82, and average SDI was 69.06+/- 22.16. All acquired data was statistically analyzed and compared. Strong correlation (r= -0.72, p< 0.001) was found between magnitudes of HB, YS and SFG after surgery, and between total FDI and SDI (r=0.56, p<0.001). CONCLUSION: Results of cross neuroplastics of FN using AN are compatible with those in other neuroplastic techniques and improve patients' quality of life. This procedure is acceptable for rehabilitation of FN function after surgery of skull base. The main problem of assessment of mimic muscles is subjectivism, that is why clinical scales and self-assessment questionnaires have to be used. After cross neuroplastics denervated segment of shoulder should be assessed by the specialized scale. PMID- 25042368 TI - [A comprehensive study of early outcome (at the time of discharge from the hospital) after lumber discectomy for degenerative spine disease]. AB - AIM: To find out early outcomes after lumbar discectomy in patients with degenerative spine disease at discharge (10-12 days after surgery) from the hospital. METHODS: The study was performed on 50 patients who have undergone lumbar discectomy for degenerative disc/spine disease in their pre- and post operative stages of treatment. The study included 50 patients, taking into account both anamnesis and postoperative follow-up data. The outcomes were evaluated using modified Oswestry Disability Index (ODI), Visual Analogue Scale (VAS) and location of pain. RESULTS: The study group consisted of 50 patients who completed the questionnaire in the pre- and post-operative period. The mean age of the patients was 50.0+/-2.1 years (male-27, female-23). The questionnaire contained questions about severity of pain (VAS), pain tolerance, well-being, walking, standing, sitting and sleeping. The data was compared in the pre- and post-operative stage, differences were evaluated using paired 't' test. There was a significant difference pain severity, walking, standing and sleeping among pre- and post-operative patients. Forty two percent of patients noted significant reduction of pain in the post-operative period. 48% of patients showed normalization of sleep without analgesics and hypnotics. About 72% of patients on the onset of the disease noted pain in both back and leg, and 6% had only low back pain, at the pre-operative stage. 52% of patients had no pain soon after surgery. CONCLUSION: The majority of patients noted an improvement - rapid reduction of pain and restoration of sleep without analgesics and hypnotics in the post-operative period. PMID- 25042369 TI - [Intraparenchymal brainstem schwannomas: report of three cases and literature review]. AB - We report three patients with intraparenchymal brainstem schwannomas that were confirmed by surgery and pathological examination: tumors originated from the midbrain parenchyma, the dorsal aspect of the pontomedullary junction and the medulla oblongata respectively. Two of the presented patients differed in age of disease presentation which may reflect different mechanisms of tumor development according to the current views on origin of intraparenchymal schwannomas. One of the cases illustrates treatment of non-communicating hydrocephalus associated with ventricular tumors by preventive stenting of the cerebrospinal fluid pathways. PMID- 25042370 TI - [The first experience of skull base defect reconstruction using pedicled buccal fat pad after endoscopic endonasal resection of a craniofacial tumor]. AB - BACKGROUND: Buccal fat pad (BFP) is widely used in maxillofacial surgery for closure of oroantral and oronasal defects. V.A. Cherekaev et al. were the first who described application of pedicled BFP flap in reconstruction of anterior and middle skull base defects. This article focuses on a novel surgical technique - plastic closure of craniobasal defects via endonasal endoscopic approach. MATERIAL AND METHODS: We present a case of 12-year old male patient with advanced juvenile angiofibroma who was operated endoscopically using biportal transnasal transantral approach. After removal of the tumor the defect of anterior cavernous sinus was reconstructed by translocated pedicled BFP flap supported by balloon catheter. RESULTS: No postoperative complications such as cerebrospinal fluid nasal leakage were observed after withdrawal of balloon-catheter on the 4th day after surgery. The same day the patient was discharged in good condition. CONCLUSION: The proposed technique is promising and advantageous as part of complex multilayer skull base defect reconstruction after resection of extra intracranial mass lesions due to preserved vascular supply of BFP flap. The method is safe and associated with extremely low risk of complications. We hope that the described flap will be appreciated and will take its place within the range of plastic materials for reconstruction of skull base defects in endoscopic endonasal approach. PMID- 25042371 TI - [Glioneuronal tumor with neuropil-like islands in a neonate]. AB - Glioneuronal tumor with neuropil-like islands - GTNI is a rare histopatological subtype of anaplastic astrocytoma. English-language literature contains only 43 observations, among them only 4 observations in children up to 18 years. Neuropil is an eosinophilic stained a cellular foci of tumor tissue. These cells demonstrate less proliferation activity than prevailing glial component, which is characterized by a high degree of atypia - Gr III according to WHO classification. Single reports about verification of the glioneuronal tumor with neuropil-like islands in children are supplemented with an observation of the case with tumor, located in lateral ventricular in infant with the onset of hypertension symptoms at the age of 11 months. The potential for complete removal of these tumors despite its large size and young age of the child is presented. However, the prognosis in infants with GTNI despite completeness of removal and chemotherapy might be extremely unfavorable - in case of intraventricular localization progression in the form of tumor implantation on ventricular ependyma is possible. PMID- 25042372 TI - [Working results of the electronic "on-line" version of the Spine Registry for Degenerative Lumbar Spine Diseases and study of its synchronization capacity with the electronic case history]. AB - AIM: To assess the results of use of lumbar spine on-line registry in 2012 (IV quarter). MATERIAL AND METHODS: The Burdenko Neurosurgery Institute of the Russian Academy of Medical Sciences (RAMS) and the System Analysis Institute of the Russian Academy of Sciences (RAS) have developed an electronic "on-line" portal of the Spine Registry for Degenerative Lumbar Spine Diseases. The data on 1295 retrospective and 145 prospective patients who underwent treatment in Burdenko Neurosurgery Institute, the "AXIS" clinic, Medical Centre of the Bank of Russia, "Marina Spine Clinic" LA, USA and in the Neurosurgery department of Research Institute of Traumatology and Orthopedics, Nizhny Novgorod were analyzed. Since May 2012 to the present time outcomes of 1295 (retrospective group) and 145 (prospective group) patients with Degenerative Lumbar Spine Diseases, which underwent treatment from 2002 to 2012 were entered into online registry and subsequently analyzed. The current study has revealed two problems that need to be discussed. First problem is that the archived information is not sufficient for data base update. The second problem is low activity of many physicians in inputting data into the register. We believe that the solution of these problems lies in the plane of synchronization of on-line registry with electronic medical records. This synchronization between registry and online records will allow studying their joint work. If found to be successful after the development of the other sections of the register they will be added to an already running version as provided by the principles of its work - scalability and extesibility. The results of this work will be profile of vertebrological version of electronic medical records. In the future it could be used in clinics dealing with spine disorders. RESULTS: Since May 2012 the outcomes of 1295 (retrospective group) and 145 (prospective group) patients with Degenerative Lumbar Spine Diseases, who were operated on in Burdenko Neurosurgery Institute (Moscow, Russia), minimally invasive spinal surgery clinic "AXIS" (Moscow, Russia), Medical Centre of The Bank of Russia (Moscow, Russia), "Marina Spine Clinic" (LA, USA) and Neurosurgery department of Research Institute of Traumatology and Orthopedics (Nizhny Novgorod, Russia) from 2002 to 2012 were analyzed. The perspective of this work is development of other parts of spine registry (for cervical and thoracic spine) and improving the outcome assessment process in Russian spinal surgery clinics. PMID- 25042373 TI - [Microsurgical selective neurotomy in treatment of the focal spastic syndromes of the different etiology]. AB - OBJECT: To estimate the effectiveness of selective peripheral neurotomy (SPN) in the treatment of local botuloresistant spastic disorders. METHODS: 20 SPNs were performed in 18 patients with spastic disorders. In 11 cases we performed SPN of the nervus obturatorius, in 5 - tibialis, in 3 - musculocutaneous, in 1 - radialis. The results of surgical treatment were estimated by the Ashworth scale and GMFM-88. These data was statistically processed. RESULTS: There was a significant decrease of spasticity in most cases: from 4,02+/-0,52 points before surgery to 1,86+/-0,63 points after surgery (p<0,001). In 11 cases we observed significant improvement in motor functions: from 50,7+/-12,92% before surgery to 54,9+/-13,6% after surgery (p<0,001). CONCLUSION: SPN is an effective procedure which leads to significant reduction of spasticity, improvement in movement range motor functions in patients with spastic disorders. PMID- 25042374 TI - Inflammation biomarkers and delirium in critically ill patients: new insights? AB - The pathophysiological mechanism of the serious and frequently occurring disorder delirium is poorly understood. Inflammation and sepsis are known risk factors for ICU delirium and therefore these patients are highly susceptible to delirium. Several studies have been performed to determine which cytokines are most associated with delirium but the results are inconclusive. Also, new biomarkers associated with brain dysfunction and cognitive impairment are still recognized and need to be studied to determine their relation with delirium. In this commentary we address some limitations concerning an interesting new study that warrants directions for future studies. PMID- 25042375 TI - Rational design of atomic-layer-deposited LiFePO4 as a high-performance cathode for lithium-ion batteries. AB - Atomic layer deposition is successfully applied to synthesize lithium iron phosphate in a layer-by-layer manner by using self-limiting surface reactions. The lithium iron phosphate exhibits high power density, excellent rate capability, and ultra-long lifetime, showing great potential for vehicular lithium batteries and 3D all-solid-state microbatteries. PMID- 25042376 TI - High-mobility transport anisotropy and linear dichroism in few-layer black phosphorus. AB - Two-dimensional crystals are emerging materials for nanoelectronics. Development of the field requires candidate systems with both a high carrier mobility and, in contrast to graphene, a sufficiently large electronic bandgap. Here we present a detailed theoretical investigation of the atomic and electronic structure of few layer black phosphorus (BP) to predict its electrical and optical properties. This system has a direct bandgap, tunable from 1.51 eV for a monolayer to 0.59 eV for a five-layer sample. We predict that the mobilities are hole-dominated, rather high and highly anisotropic. The monolayer is exceptional in having an extremely high hole mobility (of order 10,000 cm(2) V(-1) s(-1)) and anomalous elastic properties which reverse the anisotropy. Light absorption spectra indicate linear dichroism between perpendicular in-plane directions, which allows optical determination of the crystalline orientation and optical activation of the anisotropic transport properties. These results make few-layer BP a promising candidate for future electronics. PMID- 25042377 TI - Factors Associated with Reported Infection and Lymphedema Symptoms among Individuals with Extremity Lymphedema. AB - PURPOSE: This study aimed to examine factors associated with reported infection and symptoms among individuals with extremity lymphedema. DESIGN: A cross sectional study was used. METHODS: Data were collected from a survey supported by the National Lymphedema Network from March 2006 through January 2010. A total of 1837 participants reported having extremity lymphedema. Logistic regression analyses were used. FINDINGS: Factors associated with reported infection among individuals with extremity lymphedema included male gender, decreased annual household income, decreased self-care, self-report of heaviness, and lower extremity as opposed to upper extremity. Factors associated with symptoms included infection, decreased self-care, lower knowledge level of self-care, decreased annual household income, and presence of secondary lower extremity lymphedema. CONCLUSIONS/CLINICAL RELEVANCE: Select factors of income, self-care status, and site of lymphedema were associated with increased occurrence of infection and symptoms among individuals with extremity lymphedema. Longitudinal studies are needed to identify risk factors contributing to infections and symptoms in individuals with lymphedema. PMID- 25042378 TI - Attitudes toward professionalism education in Otolaryngology-Head and Neck Surgery residency programs. AB - OBJECTIVES/HYPOTHESIS: Resident professionalism development is important for physician training and patient care. Meaningful professionalism curriculum requires collaboration between learners and educators. We aimed to better understand attitudes of Otolaryngology-Head and Neck Surgery (OHNS) program directors (PDs) and residents toward professionalism education. STUDY DESIGN: Prospective survey. METHODS: We identified contemporary methods of professionalism evaluation and education and formulated questions to assess attitudes toward professionalism education. Surveys were electronically distributed to 104 PDs who were asked to forward a separate survey to residents. RESULTS: The resident survey was completed by 110 OHNS residents, and the PD survey was completed by 33 OHNS PDs. The majority of residents (78%) and faculty (84%) believed professionalism could be taught. Role modeling (93%) and morbidity and mortality conference (90%) were the most common methods of education. Faculty questionnaires (100%) and nursing/ancillary staff questionnaires (93%) were the most common methods of resident evaluation. The majority of residents considered faculty mentoring (66%) and small group discussions (56%) to be useful methods for teaching professionalism, whereas only 14% considered formal lectures useful. Residents valued questionnaires by faculty (98%), medical staff (97%), and patients (94%) for professionalism evaluation. CONCLUSION: We are the first to study OHNS residents and PDs attitudes toward professionalism evaluation and education. Residents value mentoring programs and small group sessions rather than formal didactics and value evaluation from multiple sources. Programs should consider incorporating these specific educational and evaluative methods into their professionalism curricula. LEVEL OF EVIDENCE: N/A. PMID- 25042379 TI - Understanding men's attributions of why they ejaculate before desired: an internet study. AB - INTRODUCTION: Recent developments in the study of men's sexual response have raised significant issues related to the definition and diagnosis of premature ejaculation (PE). AIM: We wanted to understand men's perceived reasons for "ejaculating before they wanted," whether they selected attributions from the same broad category when allowed to endorse multiple reasons, and whether younger and older cohorts differed in their attributions. METHODS: A subsample of 376 men who indicated that they "ejaculated before they wanted" was drawn from a larger pool of 1,249 men participating in an online survey on men's sexual health. This subsample responded to a number of items regarding their ejaculatory patterns, including two questions listing 10 possible self-reported attributions/reasons for their quick ejaculation--one item allowed respondents to endorse multiple reasons, the other limited the response to the most important reason. MAIN OUTCOME MEASURES: The primary outcome measure was men's attributions for ejaculating before desired, with choices from 10 possible pretested reasons. In addition, concordance across attributions was determined, that is, if a man responded to one category, was he also likely to select another category? RESULTS: Men who met the ejaculatory latency criterion for PE were generally no different from those who did not. Overall, when required to select the most important attribution, most men identified a specific issue with "lack of self efficacy" (lack of control or aroused too quickly). Few respondents identified erection loss, partner issues, or medical/medication concerns as the reason--and these patterns were independent of age. Concordance was high across self-efficacy attributions but low across other attributions. CONCLUSIONS: Most men who complain of ejaculating before desired attribute this response to problems with self-efficacy. Only a small percent of men identified other possible reasons for their quick ejaculation. Such findings have implications for both the diagnostic process and definitional language for PE. PMID- 25042380 TI - A combined network model for membrane fouling. AB - Membrane fouling during particle filtration occurs through a variety of mechanisms, including internal pore clogging by contaminants, coverage of pore entrances, and deposition on the membrane surface. Each of these fouling mechanisms results in a decline in the observed flow rate over time, and the decrease in filtration efficiency can be characterized by a unique signature formed by plotting the volumetric flux, Q^, as a function of the total volume of fluid processed, V^. When membrane fouling takes place via any one of these mechanisms independently the Q^V^ signature is always convex downwards for filtration under a constant transmembrane pressure. However, in many such filtration scenarios, the fouling mechanisms are inherently coupled and the resulting signature is more difficult to interpret. For instance, blocking of a pore entrance will be exacerbated by the internal clogging of a pore, while the deposition of a layer of contaminants is more likely once the pores have been covered by particulates. As a result, the experimentally observed Q^V^ signature can vary dramatically from the canonical convex-downwards graph, revealing features that are not captured by existing continuum models. In a range of industrially relevant cases we observe a concave-downwardsQ^V^ signature, indicative of a fouling rate that becomes more severe with time. We derive a network model for membrane fouling that accounts for the inter-relation between fouling mechanisms and demonstrate the impact on the Q^V^ signature. Our formulation recovers the behaviour of existing models when the mechanisms are treated independently, but also elucidates the concave-downward Q^V^ signature for multiple interactive fouling mechanisms. The resulting model enables post experiment analysis to identify the dominant fouling modality at each stage, and is able to provide insight into selecting appropriate operating regimes. PMID- 25042381 TI - Reliability and validity of the Leuven Perceptual Organization Screening Test (L POST). AB - Neuropsychological tests of visual perception mostly assess high-level processes like object recognition. Object recognition, however, relies on distinct mid level processes of perceptual organization that are only implicitly tested in classical tests. Furthermore, the psychometric properties of the existing instruments are limited. To fill this gap, the Leuven perceptual organization screening test (L-POST) was developed, in which a wide range of mid-level phenomena are measured in 15 subtests. In this study, we evaluated reliability and validity of the L-POST. Performance on the test is evaluated relative to a norm sample of more than 1,500 healthy control participants. Cronbach's alpha of the norm sample and test-retest correlations for 20 patients provide evidence for adequate reliability of L-POST performance. The convergent and discriminant validity of the test was assessed in 40 brain-damaged patients, whose performance on the L-POST was compared with standard clinical tests of visual perception and other measures of cognitive function. The L-POST showed high sensitivity to visual dysfunction and decreased performance was specific to visual problems. In conclusion, the L-POST is a reliable and valid screening test for perceptual organization. It offers a useful online tool for researchers and clinicians to get a broader overview of the mid-level processes that are preserved or disrupted in a given patient. PMID- 25042382 TI - Pure invasive micropapillary carcinoma of the male breast: report of a rare case with C-MYC amplification. AB - Male breast cancer is rare. The most common histological subtypes include invasive carcinoma "of no special type" and papillary carcinoma. Other variants, including pure micropapillary carcinoma, have been described as well but are extremely rare. Pure micropapillary carcinoma has been recently characterized by a C-MYC gene amplification in women. We report here, occurring in a 73-year-old man, the first case of pure micropapillary carcinoma with amplification of the C MYC gene. PMID- 25042383 TI - Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer. AB - Amplification or deletion of the topoisomerase IIalpha (TOP2A) gene in breast cancer has been related with responsiveness to anthracyclines-based chemotherapy. The purpose of this study was to evaluate the predictive value of TOP2A gene for the efficacy of neo-adjuvant anthracycline in a population with locally advanced breast cancer. Sixty-two patients were included, and the status of TOP2A gene was determined by in situ hybridization method. Treatment efficacy was determined by clinical and pathological response and overall survival. TOP2A gene alterations were found in 22.6% (21.0% of cases with amplification and 1.6% with deletion), and these tumors were biologically more aggressive, with higher nuclear grade, more frequently with HER2 amplification and inflammatory type. Also in these tumors response to chemotherapy appeared to be increased. There was a higher clinical and pathological response rate (complete pathological response of 21.4% vs. 8.3%), a trend toward longer progression-free survival (82.51 vs. 63.12 months) and a trend to increased overall survival (92.08 months; 95% CI 82.81 101.35 vs. 73.40 months; 95% CI 63.44-83.36; p=0.113). These results corroborate that the TOP2A gene alterations may play an important role in determining anthracycline sensitivity in breast cancer. PMID- 25042384 TI - ERCC1 expression and tumor regression predict survival in esophageal squamous cell carcinoma patients receiving combined trimodality therapy. AB - PURPOSE: Combined trimodality therapy with neoadjuvant chemoradiation followed by surgery has shown promising results for locally advanced operable esophageal cancer. DNA repair proteins may affect treatment efficacy through repairing DNA damage induced by chemotherapy and radiation therapy. We evaluated the associations of XRCC1, ERCC1 and MGMT expression with histopathologic response and survival in patients with locally advanced operable esophageal squamous cell carcinoma (ESCC) who received neoadjuvant chemoradiation. METHODS: Paraffin embedded pre-treatment tissue samples, collected by endoscopic biopsy from patients treated with cisplatin-based neoadjuvant chemoradiation followed by surgery, were immunohistochemically stained for XRCC1, ERCC1 and MGMT expression. RESULTS: Of the 44 patients, major histopathologic response was noted in 26 (59.1%) patients. 68.8% of patients with ERCC1-negative tumors had major histopathologic response, compared to 53.6% of those who expressed positive ERCC1, though the difference was not statistically significant (P=0.361). The patients with ERCC1-negative tumor presented much better overall survival than those positive for ERCC1 expression (P=0.018). Patients with major histopathologic response had a 3-year survival rate of 96.2% versus those with minor response, with a 3-year survival rate of 41.5% (P=0.000). Multivariate analysis showed that ERCC1 expression and histopathologic response were independent predictive factors of overall survival in patients with locally advanced operable ESCC receiving neoadjuvant chemoradiation. CONCLUSION: Patients with ERCC1-negative tumors show a benefit from neoadjuvant chemoradiation, ERCC1 expression and tumor regression are useful predictive markers in patients with locally advanced operable ESCC receiving neoadjuvant chemoradiation followed by surgery. PMID- 25042385 TI - CEACAM5 has different expression patterns in gastric non-neoplastic and neoplastic lesions and cytoplasmic staining is a marker for evaluation of tumor progression in gastric adenocarcinoma. AB - OBJECTIVE: The aim of this study was to investigate the expression patterns of CEACAM5 in non-neoplastic and neoplastic gastric lesions, as well as its application in the differential diagnosis and its relationship with tumor progression. METHODS: CEACAM5 expression was detected by immunohistochemical staining in the serial sections of the gastric neoplastic and non-neoplastic lesions. The impacts of CEACAM5 expression patterns on tumor progression were evaluated by statistics, the clinical and pathological data included sex, age, tumor extension, lymph node involvement and tumor staging. RESULTS: There was no CEACAM5 expression in normal gastric epithelial cells. In hyperplastic polyps, CEACAM5 was expressed with apical membranous staining in the hyperplastic and prolonged gastric pit adjacent to the surface. Intestinal metaplasia (IM) expressed CEACAM5 mainly with membranous pattern, and some cases showed membranous staining mixed with cytoplasmic staining. GIN expressed CEACAM5 mainly with membranous staining, but the mixed staining of cytoplasmic and membranous patterns increased, and especially in the high grade GIN, cytoplasmic staining of CEACAM5 began to occur. Compared with IM and GIN, CEACAM5 expression patterns of hyperplastic polyp showed a significant difference (P=0.000). IM, low grade GIN and the whole GIN showed no significant difference in CEACAM5 expression patterns (P=0.355), but IM and high grade GIN showed a significant difference (P=0.027). There was a significant difference between low and high grade GIN (P=0.002). GIN and well-differentiated carcinomas showed no significant difference (P=0.070), but low grade GIN and well differentiated carcinomas showed a significant difference (P=0.006). In gastric adenocarcinomas, CEACAM5 expression patterns showed a significant difference in tumor grading (P=0.010) and Lauren classification (P=0.001). In histological grading, well differentiated carcinomas showed more membranous staining than moderately and poorly differentiated, and more cytoplasmic CEACAM5 staining was detected in moderately and poorly differentiated carcinomas. Similar to that, in Lauren classification, intestinal carcinomas showed more membranous staining, and diffuse carcinomas showed more cytoplasmic staining. Moreover, CEACAM5 expression patterns showed a significant difference in tumor extension (P=0.012), lymph node involvement (P=0.015) and tumor staging (P=0.002), suggesting that CEACAM5 should be involved in tumor progression. In advanced carcinomas, CEACAM5 was expressed with more cytoplasmic staining regardless of the histological classification. CONCLUSION: CEACAM5 had different expression patterns in gastric non-neoplastic and neoplastic lesions. The CEACAM5 expression patterns were associated with tumor progression. Membranous staining of CEACAM5 might be a marker of premalignancy in gastric lesions, and cytoplasmic CEACAM5 might enhance tumor invasion and migration and be an evaluated marker for progressive and advanced gastric cancer. Also, it might be useful for the differential diagnosis of gastric premalignant lesions. PMID- 25042386 TI - Pseudoperforation: an uncommon histologic phenomenon in prurigo misleading for the diagnosis of reactive perforating collagenosis. AB - Prurigo is a common skin condition characterized by vigorous scratching. Although ulceration is not uncommon in prurigo, a perforating-like lesion was not previously reported. In this study we described series of cases of prurigo with perforating-like lesions and discussed its relation to acquired perforating dermatoses. The study included 32 cases, during the period from 2008 to 2013. Clinical data and histological features were recorded and analyzed. The study included 78.1% males and 21.9% females with a mean age of 39.3 +/- 5.61 years. History of insect bite was evident in 28.1%, hepatitis C virus infection in 46.9%, and diabetes mellitus in 9.4% of patients. Histologically, well developed lesions showed full thickness epidermal degeneration overlay by a cup-shaped crater. The contents of the crater included collagen and elastic fibers, bacterial colonies, inflammatory cells and necrotic keratin. The dermis showed non-altered collagen, increased vascularity and mixed inflammatory infiltrate. We believe that this pseudoperforation process is a secondary response to vigorous scratching in prurigo patients and not a primary mechanism as occurred in perforating dermatoses. The absence of altered collagen, the presence of full thickness epidermal necrosis and concomitant elimination of elastic fibers are significant histologic clues for differentiation between both conditions. PMID- 25042387 TI - T-cell/histiocyte-rich large B-cell lymphoma with zonal expansion of fibroblastic reticulum cells and infiltration by a subpopulation of myeloperoxidase positive histiocytes. PMID- 25042388 TI - The association of the cribriform pattern with outcome for prostatic adenocarcinomas. AB - With the revision of the Gleason system at the 2005 International Society of Urological Pathology Consensus Conference, there was consensus that most cribriform glands should be classified as pattern 4. There is now increased understanding that invasive cribriform carcinoma is a relatively aggressive disease. This study was based on 233 radical prostatectomy (RP) specimens collected at the Department of Pathology, Umraniye Education and Research Hospital, from 2006 to 2013. We assessed the cribriform foci associated with the more definitive patterns 3, 4, and 5 elsewhere on the RP specimens and evaluated the association of the presence of cribriform pattern (CP) with biochemical prostate-specific antigen recurrence (BPR). In Cox regression model, taking into account the Gleason score (GS), pathologic stage, surgical margin (SM) status, presence of a CP, and preoperative prostate-specific antigen (PSA), a positive SM, and the presence of a CP were independent predictors of BPR after RP. We observed BPR more frequently in GS 3+3 cases with a CP than in those without a CP (p=0.008). There was no significant difference in BPR status for cases with GS 3+4, 4+3, 4+5, and 5+4 when the patients were stratified by the presence of a CP. On the basis of these data, we suggest that the classification of CP into Gleason pattern 4 has value in predicting BPR status after RP. However, as many of these modifications are empirical and supported by only a few studies, long-term follow up studies with clinical endpoints are necessary to validate these recommendations. PMID- 25042389 TI - Ab initio electronic circular dichroism of fullerenes, single-walled carbon nanotubes, and ligand-protected metal nanoparticles. AB - The versatility and applicability of a time-perturbed density functional method implemented within the SIESTA program package to calculate electronic circular dichroism of diverse nanoparticles is discussed. Results for nanostructures, such as fullerenes, single-wall carbon nanotubes, as well as metallic nanoparticles composed of up to hundreds of atoms were examined by comparison with previously reported experimental and theoretical results. In all cases, the calculated electronic circular dichroism shows very good consistency with other calculations, and a remarkable agreement with experiments. It is concluded that such a high-level method provides theoretical support for the quantification, understanding, and prediction of chirality and its measurement in nanostructures. It is expected that this information would be useful to motivate further experimental studies and interpretation of optical activity in terms of electronic circular dichroism in novel nanostructures. PMID- 25042390 TI - Investigating the prediction ability of survival models based on both clinical and omics data: two case studies. AB - In biomedical literature, numerous prediction models for clinical outcomes have been developed based either on clinical data or, more recently, on high throughput molecular data (omics data). Prediction models based on both types of data, however, are less common, although some recent studies suggest that a suitable combination of clinical and molecular information may lead to models with better predictive abilities. This is probably due to the fact that it is not straightforward to combine data with different characteristics and dimensions (poorly characterized high-dimensional omics data, well-investigated low dimensional clinical data). In this paper, we analyze two publicly available datasets related to breast cancer and neuroblastoma, respectively, in order to show some possible ways to combine clinical and omics data into a prediction model of time-to-event outcome. Different strategies and statistical methods are exploited. The results are compared and discussed according to different criteria, including the discriminative ability of the models, computed on a validation dataset. PMID- 25042391 TI - Multicentre evaluation of the INTERPRET decision support system 2.0 for brain tumour classification. AB - In a previous study, we have shown the added value of (1) H MRS for the neuroradiological characterisation of adult human brain tumours. In that study, several methods of MRS analysis were used, and a software program, the International Network for Pattern Recognition of Tumours Using Magnetic Resonance Decision Support System 1.0 (INTERPRET DSS 1.0), with a short-TE classifier, provided the best results. Since then, the DSS evolved into a version 2.0 that contains an additional long-TE classifier. This study has two objectives. First, to determine whether clinicians with no experience of spectroscopy are comparable with spectroscopists in the use of the system, when only minimum training in the use of the system was given. Second, to assess whether or not a version with another TE is better than the initial version. We undertook a second study with the same cases and nine evaluators to assess whether the diagnostic accuracy of DSS 2.0 was comparable with the values obtained with DSS 1.0. In the second study, the analysis protocol was flexible in comparison with the first one to mimic a clinical environment. In the present study, on average, each case required 5.4 min by neuroradiologists and 9 min by spectroscopists for evaluation. Most classes and superclasses of tumours gave the same results as with DSS 1.0, except for astrocytomas of World Health Organization (WHO) grade III, in which performance measured as the area under the curve (AUC) decreased: AUC = 0.87 (0.72-1.02) with DSS 1.0 and AUC = 0.62 (0.55-0.70) with DSS 2.0. When analysing the performance of radiologists and spectroscopists with respect to DSS 1.0, the results were the same for most classes. Having data with two TEs instead of one did not affect the results of the evaluation. PMID- 25042392 TI - Simultaneous determination of plasma creatinine, uric acid, kynurenine and tryptophan by high-performance liquid chromatography: method validation and in application to the assessment of renal function. AB - A high-performance liquid chromatography with ultraviolet detection method has been developed for the simultaneous determination of a set of reliable markers of renal function, including creatinine, uric acid, kynurenine and tryptophan in plasma. Separation was achieved by an Agilent HC-C18 (2) analytical column. Gradient elution and programmed wavelength detection allowed the method to be used to analyze these compounds by just one injection. The total run time was 25 min with all peaks of interest being eluted within 13 min. Good linear responses were found with correlation coefficient >0.999 for all analytes within the concentration range of the relevant levels. The recovery was: creatinine, 101 +/- 1%; uric acid, 94.9 +/- 3.7%; kynurenine, 100 +/- 2%; and tryptophan, 92.6 +/- 2.9%. Coefficients of variation within-run and between-run of all analytes were <=2.4%. The limit of detection of the method was: creatinine, 0.1 umol/L; uric acid, 0.05 umol/L; kynurenine, 0.02 umol/L; and tryptophan, 1 umol/L. The developed method could be employed as a useful tool for the detection of chronic kidney disease, even at an early stage. PMID- 25042393 TI - Poverty and transitions in health in later life. AB - Using a sample of Europeans aged 50+ from 12 countries in the Survey of Health, Ageing and Retirement in Europe (SHARE), we analyse the role of poor material conditions as a determinant of changes in health over a four- to five-year period. We find that poverty defined with respect to relative income has no effect on changes in health. However, broader measures of poor material conditions, such as subjective poverty or low wealth, significantly increase the probability of transition to poor health among the healthy and reduce the chance of recovery from poor health over the time interval analysed. In addition to this, the subjective measure of poverty has a significant effect on mortality, increasing it by 65% among men and by 68% among those aged 50-64. Material conditions affect health among older people. We suggest that if attempts to reduce poverty in later life and corresponding policy targets are to focus on the relevant measures, they should take into account broader definitions of poverty than those based only on relative incomes. PMID- 25042395 TI - Changes of density distribution of the subchondral bone plate after supramalleolar osteotomy for valgus ankle osteoarthritis. AB - CT-osteoabsorptiometry (CT-OAM) has been used to visualize subchondral bone plate density distribution regarding to its mineralization. The purpose of this study was to display and analyze the density distribution of the subchondral bone plate before and after supramalleolar realignment osteotomies. We retrospectively analysed pre- and postoperative CT images of nine consecutive patients with post traumatic unilateral valgus ankle OA. The distribution charts of CT-OAM scans were quantitatively analyzed for subchondral bone plate density distribution. VAS for pain and the Tegner activity scale were used to assess clinical outcome. At a mean follow-up of 20 +/- 5.6 months (range 13-27), we observed a significant pre- to postoperative decrease of the mean high-density area ratio in tibia (lateral and posterior area) (p <= 0.05) and the talus (lateral area) (p <= 0.05). Pairwise comparison between the pre- and postoperative mineralization at the articular surface showed a significant decrease of the high-density area ratio for the tibia and the talus. The VAS decreased from 6.2 +/- 0.9 pre- to 2.8 +/- 0.9 postoperatively (p = 0.027), and the Tegner score inclined from 4.5 +/- 1.1 preoperatively to 5.3 +/- 0.7 after surgery (p = 0.082). The tibial and talar subchondral bone plate density, regarding to its mineralization, decreased after supramalleolar medial closing wedge osteotomy in patients with valgus ankle OA. The results of this study suggest that realignment surgery may decrease peak bone density areas corresponding to the alignment correction and contribute to a homogenization of the subchondral bone plate mineralization. PMID- 25042394 TI - Hepatitis B virus infection and vaccine-induced immunity in Madrid (Spain). AB - OBJECTIVE: To estimate the prevalence of hepatitis B virus (HBV) infection and vaccine-induced immunity in the region of Madrid, and to analyze their evolution over time. METHODS: An observational, analytical, cross-sectional study was carried out in the population aged 16-80 years between 2008 and 2009. This was the last of four seroprevalence surveys in the region of Madrid. The prevalence of HBV infection and vaccine-induced immunity was estimated using multivariate logistic models and were compared with the prevalences in the 1989, 1993 and 1999 surveys. RESULTS: In the population aged 16-80 years, the prevalence of HBV infection was 11.0% (95% CI: 9.8-12.3) and that of chronic infection was 0.7% (95% CI: 0.5-1.1). The prevalence of vaccine-induced immunity in the population aged 16-20 years was 73.0% (95% CI: 70.0-76.0). Compared with previous surveys, there was a decrease in the prevalence of HBV infection. CONCLUSIONS: Based on the prevalence of chronic infection (<1%), Madrid is a region with low HBV endemicity. Preventive strategies against HBV should especially target the immigrant population. PMID- 25042396 TI - Substance use disorder and its effects on outcomes in men with advanced-stage prostate cancer. AB - BACKGROUND: Substance use disorder in patients with cancer has implications for outcomes. The objective of this study was to analyze the effects of the type and timing of substance use on outcomes in elderly Medicare recipients with advanced prostate cancer. METHODS: This was an observational cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from 2000 to 2009. Among men who were diagnosed with advanced prostate cancer between 2001 and 2004, we identified those who had a claim for substance use disorder in the year before cancer diagnosis, 1 year after cancer diagnosis, and an additional 4 years after diagnosis. The outcomes investigated were use of health services, costs, and mortality. RESULTS: The prevalence of substance use disorder was 10.6%. The category drug psychoses and related had greater odds of inpatient hospitalizations (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-2.8), outpatient hospital visits (OR, 2.6; 95% CI, 1.9-3.6), and emergency room visits (OR, 1.7; 95% CI, 1.2-2.4). Substance use disorder in the follow-up phase was associated with greater odds of inpatient hospitalizations (OR, 2.0; 95% CI, 1.8 2.2), outpatient hospital visits (OR, 2.0; 95% CI, 1.7-2.4), and emergency room visits (OR, 1.7; 95% CI, 1.5-2.1). Compared with men who did not have substance use disorder, those in the category drug psychoses and related had 70% higher costs, and those who had substance use disorder during the follow-up phase had 60% higher costs. The hazard of all-cause mortality was highest for patients in the drug psychoses and related category (hazard ratio, 1.3; 95% CI, 1.1-1.7) and the substance use disorder in treatment phase category (hazard ratio, 1.5; 95% CI, 1.3-1.7). CONCLUSIONS: The intersection of advanced prostate cancer and substance use disorder may adversely affect outcomes. Incorporating substance use screening and treatments into prostate cancer care guidelines and coordination of care is desirable. PMID- 25042397 TI - Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers. AB - Disease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1(G93A) transgenic mice), congenital myasthenic syndrome (AChE knockout mice and Musk(V789M/-) mutant mice), Schwartz-Jampel syndrome (Hspg2(C1532YNEO/C1532YNEO) mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1(G93A), Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz Jampel syndrome and nerve injury. PMID- 25042399 TI - Preliminary evidence of neuropeptides involvement in keratoconus. PMID- 25042398 TI - Augmented Berlin-Frankfurt-Munster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). AB - BACKGROUND: Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Munster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen. METHODS: Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes. RESULTS: The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged <=21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively. CONCLUSIONS: ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD. PMID- 25042400 TI - Modeling the nutrient removal process in aerobic granular sludge system by coupling the reactor- and granule-scale models. AB - We developed a model for nutrient removal in an aerobic granular sludge system. This model can quantitatively describe the start-up of the system by coupling a model for studying the population dynamics of the granules in the reactor (reactor-scale model) and a model for studying the microbial community structure in the granules (granule-scale model). The reactor-scale model is used for simulation for 10 days from the start, during which the granule size is relatively small; the granule-scale model is used after Day 10. The present approach proposes the output data of the reactor-scale model after 10 days as initial conditions for the granule-scale model. The constructed model satisfactorily describes experimental data in various spatial and temporal scales, which were obtained in this study by performing the anaerobic-aerobic anoxic cycles using a sequencing batch reactor. Simulations using this model quantitatively predicted that the stability of nutrient removal process depended largely on the dissolved oxygen (DO) concentration, and the DO setpoint adaptation could improve the nutrient removal performance. PMID- 25042401 TI - Cannulation in extracorporeal membrane oxygenation. PMID- 25042402 TI - Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. PMID- 25042403 TI - Dexamethasone reduces brain cell apoptosis and inhibits inflammatory response in rats with intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) is associated with high rates of mortality and morbidity. Thus, the identification of novel therapeutic agents for preventing strokes and attenuating poststroke brain damage is crucial. Dexamethasone (DEX) is used clinically to reduce edema formation in patients with spinal cord injury and brain tumors. In this study, we sought to elucidate the effects of DEX treatment on apoptosis and inflammation following ICH in rats. A high dose of DEX (15 mg/kg) was administered immediately following ICH induction and again 3 days later. The inflammatory and apoptotic responses in the rat brains were evaluated by using hematoxylin-eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, Nissl, and neurofilament-H staining. Levels of phosphorylated neurofilaments and apoptosis-related proteins such as B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), caspase-3, and P53 were analyzed by Western blotting. This study shows that rats without ICH that received DEX treatment had a fourfold higher expression of Bcl-2 than sham operated rats. ICH causes an increase in Bax, cleaved caspase-3, and P53 proteins from 4 hr to 7 days following ICH induction. In comparison with the ICH rats, the ICH/DEX rats showed significantly decreased apoptotic cell death and increased neuron survival and maintained neurofilament integrity in the perihematomal region. DEX increased the Bcl-2/Bax ratio and lowered the expression of cleaved caspase-3 at 12 hr and 5 days. The ICH rats were accompanied by activation of the inflammatory response, and DEX treatment modulated the expression of a variety of cell types and then decreased ICH-induced apoptosis. PMID- 25042404 TI - Nme family of proteins--clues from simple animals. AB - Nucleoside-diphosphate kinases (Nme/Nm23/NDPK) are evolutionarily conserved enzymes involved in many biological processes in vertebrates. The biochemical mechanisms of these processes are still largely unknown. The Nme family consists of ten members in humans of which Nme1/2 have been extensively studied in the context of carcinogenesis, especially metastasis formation. Lately, it has been proven that the majority of genes linked to human diseases were already present in species distantly related to humans. Most of cancer-related protein domains appeared during the two main evolutionary transitions-the emergence of unicellular eukaryotes and the transition to multicellular metazoans. In spite of these recent insights, current knowledge about cancer and status of cancer related genes in simple animals is limited. One possible way of studying human diseases relies on analyzing genes/proteins that cause a certain disease by using model organism that represent the evolutionary level at which these genes have emerged. Therefore, basal metazoans are ideal model organisms for gaining a clearer picture how characteristics and functions of Nme genes changed in the transition to multicellularity and increasing complexity in animals, giving us exciting new evidence of their possible functions in potential pathological conditions in humans. PMID- 25042405 TI - Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis. AB - The pathogenesis of diffuse large B-cell lymphomas (DLBCL) is only partly understood. We analyzed 148 DLBCL by single nucleotide polymorphism (SNP)-chips to characterize genomic imbalances. Seventy-nine cases were of the germinal center B-cell like (GCB) type of DLBCL, 49 of the activated B-cell like (ABC) subtype and 20 were unclassified DLBCL. Twenty-four regions of recurrent genomic gains and 38 regions of recurrent genomic losses were identified over the whole cohort, with a median of 25 imbalances per case for ABC-DLBCL and 19 per case for GCB-DLBCL. Several recurrent copy number changes showed differential frequencies in the GCB- and ABC-DLBCL subgroups, including gains of HDAC7A predominantly in GCB-DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 predominantly in ABC DLBCL (35%), hinting at disparate pathogenetic mechanisms in these entities. Correlating gene expression and copy number revealed a strong gene dosage effect in all tumors, with 34% of probesets showing a concordant expression change in affected regions. Two new potential tumor suppressor genes emerging from the analysis, CASP3 and IL5RA, were sequenced in ten and 16 candidate cases, respectively. However, no mutations were found, pointing to a potential haploinsufficiency effect of these genes, considering their reduced expression in cases with deletions. Our study thus describes differences and similarities in the landscape of genomic aberrations in the DLBCL subgroups in a large collection of cases, confirming already known targets, but also discovering novel copy number changes with possible pathogenetic relevance. PMID- 25042406 TI - Dual thermo- and pH-responsive zwitterionic sulfobataine copolymers for oral delivery system. AB - A novel oral delivery system consisting of thermoresponsive zwitterionic poly(sulfobetaine methacrylate) (PSBMA) and pH-responsive poly(2 (diisopropylamino)ethyl methacrylate) (PDPA) is synthesized via free radical polymerization. This copolymer can self-aggregate into nanoparticles via electrostatic attraction between ammonium cation and sulfo-anion of PSBMA and successfully encapsulate anticancer drug, curcumin (CUR), with highest loading content of 2.6% in the P(SBMA-co-DPA) nanoparticles. The stimuli-responsive phase transition behaviors of P(SBMA-co-DPA) copolymers at different pH buffer solution show pH-dependent upper critical solution temperature (UCST) attributed to the influence of protonation/deprotonation of the pH-responsive DPA segments. Through the delicate adjustment of the PSBMA/PDPA molar ratios, the stimuli-responsive phase transition could be suitable for physiological environment. The kinetic drug release profiles demonstrate that P(SBMA-co-DPA) nanoparticles have the potential as oral delivery carriers due to their effective release of entrapped drugs in the stimulated intestinal fluid and preventing the deterioration of drug in stimulated gastric fluid. PMID- 25042407 TI - Novel transition-metal (M=Cr, Mo, W, Fe) carbonyl complexes with bis(guanidinato)silicon(II) ligands. AB - The donor-stabilized silylene 2 (the first bis(guanidinato)silicon(II) complex) reacts with the transition-metal carbonyl complexes [M(CO)6 ] (M=Cr, Mo, W) to form the respective silylene complexes 7-10. In the reactions with [M(CO)6 ] (M=Cr, Mo, W), the bis(guanidinato)silicon(II) complex 2 behaves totally different compared with the analogous bis(amidinato)silicon(II) complex 1, which reacts with [M(CO)6 ] as a nucleophile to replace only one of the six carbonyl groups. In contrast, the reaction of 2 leads to the novel spirocyclic compounds 7 9 that contain a four-membered SiN2 C ring and a five-membered MSiN2 C ring with a M?Si and M?N bond (nucleophilic substitution of two carbonyl groups). Compounds 7-10 were characterized by elemental analyses (C, H, N), crystal structure analyses, and NMR spectroscopic studies in the solid state and in solution. PMID- 25042408 TI - Thrombosis of torcular herophili: diagnosis, prenatal management, and outcome. AB - OBJECTIVES: The objective of this article is to describe and assess prenatal imaging findings, fetal and postnatal outcomes of thrombosis of torcular herophili, and to determine diagnostic features, pathophysiology, prognosis, and optimal management. METHODS: Over a decade, we compiled the largest single-center retrospective study of outcomes. Fetal magnetic resonance imaging (MRI) was used to confirm the sonographic suspicion and monitor thrombosis of torcular herophili. We noted prenatal and postnatal imaging specifications, pregnancy outcomes, and clinical and radiological pediatric monitoring. Analysis of findings and review of the literature allowed us to define prognostic factors. RESULTS: In eight cases of prenatal diagnosis of thrombosis of torcular herophili, MRI outcomes were specific. There were five deliveries at full term, two terminations of pregnancy, and one fetal demise in utero. Neonates had a good clinical and radiological outcome. Factors of poor prognosis were deep venous sinus thrombosis, enduring mass effect, brain parenchymal injury, and heart failure related to dural arteriovenous shunt. CONCLUSION: Among dural sinus malformations, thrombosis of torcular herophili with or without extension at the posterior segment of the longitudinal sinus frequently has a good prognosis. It is urgent to wait because the prognosis can only be ascertained over time by means of ultrasound scan and MRI monitoring. PMID- 25042409 TI - Reply: To PMID 24002724. PMID- 25042410 TI - Percutaneous mitral valve repair preserves right ventricular function. AB - BACKGROUND: Chronic mitral regurgitation (MR) often leads to diminished right ventricular (RV) function due to long-standing pressure and volume overload. Surgical intervention often adds to the preexisting RV dysfunction. Percutaneous mitral valve (MV) repair can reduce MR, but to what extent this affects the right ventricle is unknown. METHODS: Consecutive patients scheduled for percutaneous MV repair using the MitraClip system underwent transthoracic echocardiography at baseline and at 1- and 6-month follow-up. RV systolic function was evaluated using five echocardiographic parameters. RV afterload was evaluated using systolic pulmonary arterial pressure and the mean MV pressure gradient. Residual MR was defined as grade >= 3 and mitral stenosis (MS) as a mean MV pressure gradient >= 5 mm Hg. RESULTS: Sixty-eight patients (52% men; mean age, 75 +/- 10 years) were included. Six months after MitraClip implantation, there were no significant changes in any of the RV parameters. MR decreased (P < .01) and the mean MV pressure gradient increased during follow-up (2.3 +/- 1.4 mm Hg at baseline vs 4.5 +/- 2.7 mm Hg at 6 months, P < .01). Patients with both residual MR and MS 6 months after MitraClip implantation showed significantly higher systolic pulmonary arterial pressure values (P < .01) and lower New York Heart Association functional classes (P < .01) compared with patients without residual MR or MS. CONCLUSIONS: Percutaneous MV repair, in contrast to surgical repair or replacement, does not negatively affect RV function. After repair, RV afterload and New York Heart Association functional class are improved in the case of successful repair but adversely affected in the presence of both residual MR and MS. PMID- 25042411 TI - Echocardiography: profiling of the athlete's heart. AB - Cardiovascular physiologic remodeling associated with athleticism may mimic many of the features of genetic and acquired heart disease. The most pervasive dilemma is distinguishing between normal and abnormal physiologic remodeling in an athlete's heart. Imaging examinations, such as magnetic resonance imaging and computed tomography, which focus predominantly on anatomy, and electrocardiography, which monitors electrical components, do not simultaneously evaluate cardiac anatomy and physiology. Despite nonlinear anatomic and electrical remodeling, the athlete's heart retains normal or supernormal myocyte function, whereas a diseased heart has various degrees of pathophysiology. Echocardiography is the only cost-effective, validated imaging modality that is widely available and capable of simultaneously quantifying variable anatomic and physiologic features. Doppler echocardiography substantially redefines the understanding of normal remodeling from preemergent and overt disease. PMID- 25042412 TI - 'To prone or not to prone' in severe ARDS: questions answered, but others remain. PMID- 25042413 TI - Comparison of the dielectric and NMR results for liquid crystals: dynamic aspects. AB - Critical analysis of the results of studies of molecular rotational dynamics in liquid crystalline substances with the aid of the dielectric spectroscopy (DS) and nuclear magnetic resonance (NMR) is given. Both methods are known to be sensitive to different aspects of molecular rotations: the polarization vector and the relaxation time tau(DS) in the case of DS, a tensor describing a nuclear interaction and the correlation time tau(NMR) for NMR method. Furthermore, both methods provide correlation functions with different rank values. A common basis for the comparison between tau(DS) and tau(NMR) is postulated. Several examples of the temperature dependence of the correlation times coming from the two spectroscopic methods are presented. Qualitative agreements of the correlation times were achieved in most cases. PMID- 25042414 TI - Lessons from an acupuncture teaching clinic: patient characteristics and pain management effectiveness. AB - OBJECTIVES: To understand the following about patients using an acupuncture teaching clinic: (1) sociodemographic characteristics and main complaints and (2) self-reported level of patient-centered outcomes regarding pain management. METHODS/DESIGN: Retrospective chart review. SUBJECTS: A total of 458 new patients at NESA clinic during October 1, 2009 to July 31, 2010 were enrolled in the study. INTERVENTIONS: A variety of styles of Oriental medicine, primarily Chinese and Japanese style acupuncture and also heat treatments (MOXA or heat lamps) and Tui Na (Asia bodywork). RESULTS: Results from Objective 1 were descriptive (n = 421). Objective 2 focused on the 59 patients from the larger sample who completed both an initial and a follow-up Measure Your Medical Outcome Profile (MYMOP) form and who used acupuncture for pain management of (1) diseases of the musculoskeletal system and/or connective tissue or (2) migraine/headache. Both the symptom severity and activity of daily living/well-being scales of the MYMOP showed over 15.8% improvement from baseline to at least six weeks of treatment: 28.6% for Symptom 1, 19.4% for Symptom 2, 35.7% for activities of daily living, and 25.0% for well-being. The relative majority for each sociodemographic trait investigated were as follows: female, about 40 years old, white, not Hispanic or Latino, married, highly educated, and employed. Most patients were confident in acupuncture treatment. Out of the 421 acupuncture patients, 68.2% wanted acupuncture in order to manage pain. Overall, 20.6% of the patients (59, N = 287) who used acupuncture for pain management for diseases of the musculoskeletal system and/or connective tissue or migraine or headache completed the sixth-week follow-up MYMOP form. Of these patients, 57.6% (34, N = 59) returned during week 6 of the semester for acupuncture treatment and reported clinical improvement in at least one MYMOP severity score, and no score got worse. CONCLUSIONS: The information about sociodemographic characteristic and patient-centered outcomes of pain management can be used for service provision, future study planning, and marketing. Future studies should address the low follow-up rate, the quality of self-reported clinic data, and the reasons that patients chose acupuncture treatments and teaching clinics. PMID- 25042415 TI - Current anthropogenic pressures on agro-ecological protected coastal wetlands. AB - Coastal wetlands are areas that suffer from great pressure. Much of it is due to the rapid development of the surrounding artificial landscapes, where socio economic factors lead to alterations in the nearby environment, affecting the quality of natural and agricultural systems. This work analyses interconnections among landscapes under the hypothesis that urban-artificial impacts could be detected on soils and waters of an agro-ecological protected area, L'Albufera de Valencia Natural Park, located in the vicinity of the City of Valencia, Spain. The methodological framework developed addresses two types of anthropogenic pressure: (1) direct, due to artificialisation of soil covers that cause soil sealing, and (2) indirect, which are related to water flows coming from urban populations through sewage and irrigation systems and which, ultimately, will be identified by the presence of emerging pharmaceutical contaminants in waters of the protected area. For soil sealing, a methodology based on temporal comparison of two digital layers for the years 1991 and 2011, applying Geographical Information Systems and landscapes metrics, was applied. To determine presence of emerging contaminants, 21 water samples within the Natural Park were analysed applying liquid chromatography tandem mass spectrometry for the detection of 17 pharmaceutical compounds. Results showed that both processes are present in the Natural Park, with a clear geographical pattern. Soil sealing and presence of pharmaceuticals are more intensive in the northern part of the study area. This is related to population density (detection of pharmaceuticals) and land cover conversion from agricultural and natural surfaces to artificial ones (soil sealing). PMID- 25042416 TI - Invertebrate community responses to emerging water pollutants in Iberian river basins. AB - Chemical pollution is one of the greatest threats to freshwater ecosystems, especially in Mediterranean watersheds, characterized by periodical low flows that may exacerbate chemical exposure. Different groups of emerging pollutants have been detected in these basins during the last decade. This study aims to identify the relationships between the presence and levels of prioritary and emerging pollutants (pesticides, pharmaceutical active compounds--PhACs, Endocrine Disrupting Compounds EDCs and Perfluorinated Compounds--PFCs) and the invertebrate community in four Mediterranean basins: the Ebro, the Llobregat, the Jucar and the Guadalquivir. Structural (species composition and density) and functional (catalase activity of the tricopteran Hydropsyche exocellata and the feeding activity of the cladoceran Daphnia magna) variables were analyzed to determine which of the pollutants would greatly influence invertebrate responses. EDCs and conductivity, followed by PhACs, were the most important variables explaining the invertebrate density changes in the studied basins, showing a gradient of urban and industrial pollutions. Despite this general pattern observed in the four studied basins - impoverishment of species diversity and abundance change with pollution - some basins maintained certain differences. In the case of the Llobregat River, analgesics and anti-inflammatories were the significant pollutants explaining the invertebrate community distribution. In the Jucar River, fungicides were the main group of pollutants that were determining the structure of the invertebrate community. Functional biomarkers tended to decrease downstream in the four basins. Two groups of pollutants appeared to be significant predictors of the catalase activity in the model: EDCs and PhACs. This study provides evidence that the information given by functional biomarkers may complement the results found for the structural community descriptors, and allowed us to detect two emerging contaminant groups that are mainly affecting the invertebrate community in these basins. PMID- 25042418 TI - Influence of surface properties of zinc oxide nanoparticles on their cytotoxicity. AB - The toxicity of nanoparticles (NPs) depends on several factors including size, shape, surface properties and chemical nature of the NPs. The release of toxic ions due to the dissolution of NPs is another important factor. In addition, impurities or reaction products from synthesis procedures on the NP surfaces may contribute to the toxicity. Zinc oxide nanoparticles (ZnO NPs) are one of the unique NPs showing toxicity through all of these mentioned factors. In this study, we demonstrate that the treatment of the ZnO NPs with hydrogen peroxide (H2O2) alters the surface properties of the ZnO NPs by decomposing organic impurities remained from synthesis procedures. The changes on the surface chemistry and properties of the ZnO NPs influence their behavior in cell culture media and the NPs-cell interactions. Finally, a decrease in the cytotoxicity of H2O2 treated ZnO NPs is observed on HDF and A549 cells through the decrease of the membrane damage and oxidative stress. PMID- 25042417 TI - Performance assessment of nitrate leaching models for highly vulnerable soils used in low-input farming based on lysimeter data. AB - The agricultural sector faces the challenge of ensuring food security without an excessive burden on the environment. Simulation models provide excellent instruments for researchers to gain more insight into relevant processes and best agricultural practices and provide tools for planners for decision making support. The extent to which models are capable of reliable extrapolation and prediction is important for exploring new farming systems or assessing the impacts of future land and climate changes. A performance assessment was conducted by testing six detailed state-of-the-art models for simulation of nitrate leaching (ARMOSA, COUPMODEL, DAISY, EPIC, SIMWASER/STOTRASIM, SWAP/ANIMO) for lysimeter data of the Wagna experimental field station in Eastern Austria, where the soil is highly vulnerable to nitrate leaching. Three consecutive phases were distinguished to gain insight in the predictive power of the models: 1) a blind test for 2005-2008 in which only soil hydraulic characteristics, meteorological data and information about the agricultural management were accessible; 2) a calibration for the same period in which essential information on field observations was additionally available to the modellers; and 3) a validation for 2009-2011 with the corresponding type of data available as for the blind test. A set of statistical metrics (mean absolute error, root mean squared error, index of agreement, model efficiency, root relative squared error, Pearson's linear correlation coefficient) was applied for testing the results and comparing the models. None of the models performed good for all of the statistical metrics. Models designed for nitrate leaching in high-input farming systems had difficulties in accurately predicting leaching in low-input farming systems that are strongly influenced by the retention of nitrogen in catch crops and nitrogen fixation by legumes. An accurate calibration does not guarantee a good predictive power of the model. Nevertheless all models were able to identify years and crops with high- and low-leaching rates. PMID- 25042419 TI - Predictors of adverse events among patients undergoing primary percutaneous coronary intervention: insights from a pooled analysis of the COMFORTABLE AMI and EXAMINATION trials. AB - AIMS: The aim of this study was to identify predictors of adverse events among patients with ST-elevation myocardial infarction (STEMI) undergoing contemporary primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Individual data of 2,655 patients from two primary PCI trials (EXAMINATION, N=1,504; COMFORTABLE AMI, N=1,161) with identical endpoint definitions and event adjudication were pooled. Predictors of all-cause death or any reinfarction and definite stent thrombosis (ST) and target lesion revascularisation (TLR) outcomes at one year were identified by multivariable Cox regression analysis. Killip class III or IV was the strongest predictor of all-cause death or any reinfarction (OR 5.11, 95% CI: 2.48-10.52), definite ST (OR 7.74, 95% CI: 2.87 20.93), and TLR (OR 2.88, 95% CI: 1.17-7.06). Impaired left ventricular ejection fraction (OR 4.77, 95% CI: 2.10-10.82), final TIMI flow 0-2 (OR 1.93, 95% CI: 1.05-3.54), arterial hypertension (OR 1.69, 95% CI: 1.11-2.59), age (OR 1.68, 95% CI: 1.41-2.01), and peak CK (OR 1.25, 95% CI: 1.02-1.54) were independent predictors of all-cause death or any reinfarction. Allocation to treatment with DES was an independent predictor of a lower risk of definite ST (OR 0.35, 95% CI: 0.16-0.74) and any TLR (OR 0.34, 95% CI: 0.21-0.54). CONCLUSIONS: Killip class remains the strongest predictor of all-cause death or any reinfarction among STEMI patients undergoing primary PCI. DES use independently predicts a lower risk of TLR and definite ST compared with BMS. The COMFORTABLE AMI trial is registered at: http://www.clinicaltrials.gov/ct2/show/NCT00962416. The EXAMINATION trial is registered at: http://www.clinicaltrials.gov/ct2/show/NCT00828087. PMID- 25042420 TI - Evaluation of proximal protection devices during carotid artery stenting as the first choice for embolic protection. AB - AIMS: To assess the use of proximal protection devices in consecutive patients as the preferred means of cerebral embolic protection for primary carotid stenting. METHODS AND RESULTS: This was a prospective single-centre study to evaluate the technical and clinical success of proximal protection devices as the first choice for embolic protection in symptomatic (>=50%) and asymptomatic (>=70%) carotid stenosis. Proximal protection devices were used for embolic protection in 124 consecutive patients. No patients were excluded for anatomical reasons. The GORE Flow Reversal System (W.L. Gore, Flagstaff, AZ, USA) was used in 92 patients, and the Mo.Ma Ultra device (Medtronic, Minneapolis, MN, USA) in 32 patients. Follow up duration was 30 days. Mean age was 71+/-8 years. Seventy-five percent of patients were male (n=93). Twenty-six of 124 (21%) treated stenoses were symptomatic. Technical success was achieved in 122 of 124 cases (98%). Due to anatomical conditions, in two patients flow reversal could not be established. In both cases additional distal filter devices were used. Carotid stenting was successful in 124 lesions (100%). Ten patients (8.1%) had contraindications to flow reversal (three high-grade ostial stenoses of the external carotid artery, seven contralateral occlusions of the internal carotid artery) in none of whom complications occurred. There were no procedural neurologic events. Within 30 days of follow-up, one patient had an ischaemic stroke (on day 11). CONCLUSIONS: Proximal protection is a safe method as the first choice for embolic protection. It can be used with a high rate of technical success. PMID- 25042421 TI - Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-EU registry. AB - AIMS: Clinical data on the early and midterm outcomes of bioresorbable vascular scaffolds (BVS) in routine clinical practice are limited. To fill this gap, we report on the early and midterm clinical outcomes of PCI with everolimus-eluting BVS from the large multicentre GHOST-EU registry. METHODS AND RESULTS: Between November 2011 and January 2014, 1,189 patients underwent percutaneous coronary intervention with one or more BVS (Absorb BVS; Abbott Vascular, Santa Clara, CA, USA) at 10 European centres. The primary outcome of interest was target lesion failure (TLF), defined as the combination of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularisation (TLR). A total of 1,731 Absorb BVS were implanted at a mean of 12.3+/-3.4 atm. Technical success was achieved in 99.7% of cases. TLF was recorded in 67 of 1,189 patients at a median of 109 (interquartile range 8-227) days after implantation. The cumulative incidence of TLF was 2.2% at 30 days and 4.4% at six months. The annualised rate of TLF was 10.1%. At six months, the rate of cardiac death was 1.0%, target vessel myocardial infarction was 2.0%, TLR was 2.5%, and target vessel revascularisation was 4.0%. Diabetes mellitus was the only independent predictor of TLF (hazard ratio 2.41, 95% confidence interval: 1.28-4.53; p=0.006). The cumulative incidence of definite/probable scaffold thrombosis was 1.5% at 30 days and 2.1% at six months, with 16 of 23 cases occurring within 30 days. CONCLUSIONS: "Real-world" outcomes of BVS showed acceptable rates of TLF at six months, although the rates of early and midterm scaffold thrombosis, mostly clustered within 30 days, were not negligible. PMID- 25042422 TI - Maximizing shoulder function after accessory nerve injury and neck dissection surgery: A multicenter randomized controlled trial. AB - BACKGROUND: Shoulder pain and dysfunction after neck dissection may result from injury to the accessory nerve. The effect of early physical therapy in the form of intensive scapular strengthening exercises is unknown. METHODS: A total of 59 neck dissection participants were prospectively recruited for this study. Participants were randomly assigned to either the intervention group (n = 32), consisting of progressive scapular strengthening exercises for 12 weeks, or the control group (n = 29). Blinded assessment occurred at baseline, and at 3, 6, and 12 months. RESULTS: Three-month data were collected on 52 participants/53 shoulders. Per-protocol analysis demonstrated that the intervention group had statistically significantly higher active shoulder abduction at 3 months compared to the control group (+26.6 degrees ; 95% confidence interval [CI] 7.28-45.95; p = .007). CONCLUSION: The intervention is a favorable treatment for maximizing shoulder abduction in the short term. The effect of the intervention compared to usual care is uncertain in the longer term. PMID- 25042423 TI - Older adults' reporting of specific sedentary behaviors: validity and reliability. AB - BACKGROUND: Previous questionnaires targeting older adults' sedentary time have underestimated total sedentary time, possibly by not including all relevant specific sedentary behaviors. The current study aimed to investigate the criterion validity and test-retest reliability of a new questionnaire assessing a comprehensive set of sedentary behaviors. Additionally, we examined whether the criterion validity of the questionnaire differed according to age, gender and educational level. METHODS: A sample of home-dwelling Belgian older adults (>64 years, n = 508) completed a newly-developed questionnaire assessing twelve specific sedentary behaviors and wore an accelerometer for seven consecutive days as criterion measure. A subsample (n = 28) completed the questionnaire a second time to examine test-retest reliability. Data collection occurred between September 2010 and October 2012. RESULTS: Correlational analyses examining self reported total sitting time and accelerometer-derived sedentary time yielded a Spearman's rho of 0.30. Using the Bland-Altman regression procedure, self reported total sitting time underestimated accelerometer-derived sedentary time by -82 minutes/day for a participant with an average level of sedentary time (539 minutes/day). Corresponding 95% limits of agreement were wide (-364, 200 minutes/day). Better, but still not ideal, validity findings were observed in the younger, male and tertiary-educated subgroups. Acceptable test-retest reliability (ICC > 0.70) was found for total sitting time, TV viewing, computer use, and driving a car. CONCLUSION: Validity for older adults' self-reported total sitting time against accelerometer-derived sedentary time was not strong, but comparable to previous studies. However, underestimation of total sedentary time was lower compared to previous studies, possibly explained by the inclusion of additional specific sedentary behaviors. Further research is needed to develop self-report tools and objective criterion measures that accurately measure engagement in (specific) sedentary behavior(s) among different subgroups of the older population. PMID- 25042424 TI - Accurate in silico identification of species-specific acetylation sites by integrating protein sequence-derived and functional features. AB - Lysine acetylation is a reversible post-translational modification, playing an important role in cytokine signaling, transcriptional regulation, and apoptosis. To fully understand acetylation mechanisms, identification of substrates and specific acetylation sites is crucial. Experimental identification is often time consuming and expensive. Alternative bioinformatics methods are cost-effective and can be used in a high-throughput manner to generate relatively precise predictions. Here we develop a method termed as SSPKA for species-specific lysine acetylation prediction, using random forest classifiers that combine sequence derived and functional features with two-step feature selection. Feature importance analysis indicates functional features, applied for lysine acetylation site prediction for the first time, significantly improve the predictive performance. We apply the SSPKA model to screen the entire human proteome and identify many high-confidence putative substrates that are not previously identified. The results along with the implemented Java tool, serve as useful resources to elucidate the mechanism of lysine acetylation and facilitate hypothesis-driven experimental design and validation. PMID- 25042425 TI - The intentionality bias in schizophrenia. AB - The tendency to over-interpret events of daily life as resulting from voluntary or intentional actions is one of the key aspects of schizophrenia with persecutory delusions. Here, we ask whether this characteristic may emerge from the abnormal activity of a basic cognitive process found in healthy adults and children: the intentionality bias, which refers to the implicit and automatic inclination to interpret human actions as intentional (Rosset, 2008, Cognition 108, 771-780). In our experiment, patients with schizophrenia and healthy controls were shown sentences describing human actions in various linguistic contexts, and were asked to indicate whether the action was intentional or not. The results indicated that people with schizophrenia exhibited a striking bias to over attribute intentionality regardless of linguistic context, contrary to healthy controls who did not exhibit such a general intentionality bias. Moreover, this study provides some insight into the cognitive mechanisms underlying this bias: an inability to inhibit the automatic attribution of intentionality. PMID- 25042426 TI - Minocycline alleviates behavioral deficits and inhibits microglial activation in the offspring of pregnant mice after administration of polyriboinosinic polyribocytidilic acid. AB - Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. Activation of microglia is a key event in the reaction of the cerebral immune system to pathological changes. It can be hypothesized that microglia contribute to the neuropathology of schizophrenia. In this study, at embryonic day (ED) 9 pregnant mice were treated with intraperitoneal injection of polyriboinosinic polyribocytidilic acid (Poly I:C) at a single dose of 20 mg/kg. At postnatal day 42, descendants were treated with minocycline (40 mg/kg) or saline for consecutive 14 days. Behavioral changes (locomotor activity, social interaction, and prepulse inhibition) were examined and the number of microglia was assessed after the treatment. The adult offspring exposed to Poly I:C at ED 9 showed behavioral changes (hyperlocomotion, deficits in social interaction and prepulse inhibition) and significant microglial activation in these brain areas (hippocampus, thalamus, and cerebral cortex) compared to those in saline-injected group. Moreover, minocycline attenuated the behavioral deficits and inhibited the activated microglia. These findings suggest that maternal infection may contribute to microglial activation in the offspring. In addition, the effect of minocycline in this immune model may be related to the inhibition of microglial activation. PMID- 25042427 TI - Physiological efects of paichongding applied to rice on the Nilaparvata lugens (Sta l), the brown planthopper. AB - Nilaparvata lugens (Stal) is a major rice pest in Asia. Paichongding is a novel neonicotinoid insecticide developed in 2008. The effects of this insecticide on the activity of detoxification enzymes of N. lugens and on rice resistance to the pest were examined in the laboratory. The results showed that paichongding could significantly decrease the acetylcholinesterase and GSHs transferase activities of N. lugens. The variation tendency of mixed function oxidase (MFO) activity was similar with that of the esterase. After 12 h treatment, there was no significance between the treatment and control. However, the activities of MFO and esterase increased after 24 and 48 h treatment, which suggested that MFO and esterase may play an important role in the detoxification of paichongding for N. lugens. Our results also demonstrated that treated with paichongding, damage levels of rice plants were significantly lower than those of control plants except 15 days after treatment. Compared with the control, injury indices decreased 70.22, 49.12, 34.44, and 23.23% at 3 , 6 , 9, and 12 days after paichongding treatment, respectively. The laboratory results suggested that paichongding may be effective for the control of brown planthopper. PMID- 25042428 TI - Ultrasonographic measurement of fetal growth parameters over three successive pregnancies in a captive Malayan tapir (Tapirus indicus). AB - This study was conducted to establish representative curves that allow evaluation of fetal growth and estimation of gestational age from measurement of fetal structures by ultrasound in Malayan tapirs (Tapirus indicus). Three pregnancies (i.e. 3 fetuses) were examined in one female Malayan tapir. Transabdominal ultrasonographic examination was performed without anesthesia from 79 +/- 8 days to 281 +/- 48 days (mean +/- S.D.) post mating. To assess fetal growth attempts were made to measure biparietal diameter (BPD), head length (HL), thorax diameter A (TDA), thorax height A (THA), thorax diameter B (TDB), thorax height B (THB), abdomen diameter (AD), abdomen height (AH), humerus length (HUL) and Crown rump length (CRL). The value of each parameter as an estimator of gestational age was assessed by ease of observation and the length of time the parameter was measurable throughout gestation. The most precise predictors for gestational age in this study were BPD and CRL (weeks 10-20 of gestation), as well as AD and AH (weeks 14-43 of gestation). The parameters TDB, THB and HUL (weeks 15-41 of gestation) gave almost as good predictions. Fetal viability was assessed by identifying a fetal heartbeat and movement. All pregnancies resulted in normal deliveries and healthy offspring. The ultrasound examination was well tolerated by the female. The gestation lengths (399 +/- 3 days) were within reported ranges. The serial transabdominal ultrasound, without the need for anesthesia, was an effective method to evaluate fetal growth, development and well being in a Malayan tapir. PMID- 25042429 TI - Foreword: Primary care for refugee children. PMID- 25042430 TI - Primary health care for refugees--introduction. PMID- 25042431 TI - Nutrition for refugee children: risks, screening, and treatment. AB - Pediatric refugees are at an increased risk for growth and nutritional deficits. As more children are resettled to the United States, it is important to screen appropriately in order to identify any growth or nutritional issues. Resettled refugee children continue to be at risk for both over- and undernutrition, therefore culturally appropriate education and counseling should be provided to improve long-term health. PMID- 25042432 TI - Strategies in infectious disease prevention and management among US-bound refugee children. AB - For multiple reasons, including exposure to violence or trauma, nutritional deficiencies, and an inconsistent medical infrastructure, refugee children are at an increased risk for many infectious diseases. Among these are tuberculosis, malaria, helminthic infections, and neglected tropical diseases. Our purposes are to review the US Centers for Disease Control and Prevention's pre-departure program of testing and presumptive therapy for these infections and to review the possible presentations, symptomatology, diagnostic tools, and recommended therapies, if necessary, upon arrival to the US. An understanding of these non endemic infections, their diagnosis, and their management will improve the domestic medical exam and help to ease the transition for newly arrived immigrant children, their families, and their receiving communities. PMID- 25042433 TI - Refugee children and their families: supporting psychological well-being and positive adaptation following migration. AB - The support of refugee children and their families is a worldwide concern. This article will highlight models of mental health care for refugee children and their families, focusing on collaborative care with primary care providers. Case vignettes are provided to illustrate how collaborative care can support refugee children's psychological well-being and positive adaptation following migration. PMID- 25042434 TI - Chirality and polarity in the f-block borates M4[B16O26(OH)4(H2O)3Cl4] (M = Sm, Eu, Gd, Pu, Am, Cm, and Cf). AB - The reactions of trivalent lanthanides and actinides with molten boric acid in high chloride concentrations result in the formation of M4[B16O26(OH)4(H2O)3Cl4] (M = Sm, Eu, Gd, Pu, Am, Cm, Cf). This cubic structure type is remarkably complex and displays both chirality and polarity. The polymeric borate network forms helical features that are linked via two different types of nine-coordinate f element environments. The f-f transitions are unusually intense and result in dark coloration of these compounds with actinides. PMID- 25042435 TI - Vibrational spectrum and gas-phase structure of disulfur dinitride (S2N2). AB - Gas-phase FTIR spectra of the nu6 (B-type) and the nu4 (C-type) fundamental bands of S2 N2 (D2h ) were recorded with a resolution of <=0.004 cm(-1) and the vibrational spectrum of S2 N2 (D2h ) in solid Ar has been revisited. All IR active fundamentals and four combination bands were assigned in excellent agreement with calculated values from anharmonic VPT2 and VCI theory based on (explicitly correlated) coupled-cluster surfaces. Accurate experimental vibrational ground- and excited-state rotational constants of (32) S2 (14) N2 are obtained from a rovibrational analysis of the nu6 and nu4 fundamental bands, and precise zero-point average rz (Rz (SN)=1.647694(95) A, alphaz (NSN)=91.1125(33) degrees ) and semi-experimental equilibrium structures (Re (SN)=1.64182(33) A, alphae (NSN)=91.0716(93) degrees ) of S2 N2 have been established. These are compared to the solid-state structure of S2 N2 and structural properties of related sulfur nitrogen compounds and to results of ab initio structure calculations. PMID- 25042436 TI - Separation of enantiomers on chiral stationary phase based on chicken alpha1-acid glycoprotein: effect of silica particle diameters on column performance. AB - The effects of silica particle diameters on performances of chicken alpha1-acid glycoprotein (c-AGP)-immobilized silica particle columns were investigated. c-AGP was immobilized onto aminopropyl silica particles, whose nominal particle diameters were 5, 3 and 2.1 MUm, activated with N,N'-disuccinimidyl carbonate. The retention factor (k), enantioseparation factor (alpha), resolution (Rs) and height equivalent to a theoretical plate (H) of solutes on three c-AGP columns were evaluated using a mixture of phosphate buffer and organic modifier as a mobile phase in LC. There were not so much differences in their k and alpha values among three c-AGP columns, while their Rs values were in the order of 2.1 MUm>3 MUm>5 MUm silica particles and their H values were in the reversed order. Since three c-AGP columns gave almost the same enantioseparation factors for solutes, their highest Rs and lowest H values on a c-AGP-immobilized column prepared with 2.1-MUm silica particles came from its highest column efficiency among there c-AGP columns. These results suggest that 2.1-MUm silica particles could be useful for the preparation of c-AGP- or protein-based CSPs. PMID- 25042437 TI - Click synthesis of glucose-functionalized hydrophilic magnetic mesoporous nanoparticles for highly selective enrichment of glycopeptides and glycans. AB - Selective enrichment of glycopeptides from complex biological samples is essential for MS-based glycoproteomics, but challenges still remain. In this work, glucose-functionalized magnetic mesoporous nanoparticles (MMNs), which hold the attractive features of well-defined core/shell structure, high specific surface area (324m(2)/g), narrow pore size distribution (2.2nm) and high magnetic responsivity (69.1emug(-1)), were synthesized via click chemistry and applied to enrich glycopeptides and glycans. Taking advantages of the size-exclusive effect of mesopore against proteins and the hydrophilic interaction between glycans and glucose, the hydrophilic MMNs possessed high selectivity for glycopeptides at the digested mixtures of horseradish peroxidase (HRP), myoglobin and beta-casein at molar ratio of 1:1:10, large enrichment capacity (as high as 250mg/g), high sensitivity (50fmol), excellent speed (5min for enrichment) and high recovery of glycopeptides (as high as 94.6%). Additionally, the MMNs exhibited excellent performance in enrichment of N-linked glycans from the digested human serum that are made up of peptides, large proteins and other compounds. These outstanding features will give the hydrophilic MMNs high benefit for MS analysis of low abundance glycopeptides/glycans. PMID- 25042438 TI - Enantioselective high performance liquid chromatography and supercritical fluid chromatography separation of spirocyclic terpenoid flavor compounds. AB - Chiral spirocyclic terpenoids are abundant natural flavors with significant impact particularly on the food industry. Chromatographic methods for analytical and preparative separation of these compounds are therefore of high interest to natural product chemists in academia and industry. Gas chromatography on chiral stationary phases is currently the standard method for the separation of volatile terpenoids, limiting the scale to analytical quantities. We report herein high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) protocols for the chiral separation of several racemic spirocyclic terpenoids such as the important flavors theaspirane and vitispirane. A screening of mobile phases and 16 commercially available chiral stationary phases (CSPs) largely based on polysaccharides led to identification of protocols for the separation of all terpenoids tested. SFC methods were found to be particularly useful for the separation of these spirocyclic flavors due to the volatility and low polarity of the compounds. The reported chiral HPLC and SFC protocols are scalable alternatives to gas chromatographic separations of volatile terpenoid flavors. PMID- 25042439 TI - Recognitive nano-thin-film composite beads for the enantiomeric resolution of the metastatic breast cancer drug aminoglutethimide. AB - Straightforward crushing and sieving bulk polymeric R-aminoglutethimide-imprinted materials were prepared by classical free radical polymerization, whereas nano thin walled grafted imprinted materials were prepared using RAFT mediated control polymerization technique. A stoichiometric non-covalent approach based on a triply hydrogen bonding functional monomer-template 1:1 complex (K=599mol(-1)L( 1)) led to chiral selectors far outperforming previously used selectors for resolving this racemate. The recognitive materials produced here (enantioselectivity factors, alpha~10) also have no match within the previously reported enantioselective imprinted polymers (alpha 1.2-4.5). We here demonstrate a potentially generic solution to produce good quality grafted MIPs for templates interacting by hydrogen bonding alone, relying on solvent polarity tuning, significantly extending the range of templates compatible with this format. PMID- 25042440 TI - Fast and "green" method for the analytical monitoring of haloketones in treated water. AB - Several groups of organic compounds have emerged as being particularly relevant as environmental pollutants, including disinfection by-products (DBPs). Haloketones (HKs), which belong to the unregulated volatile fraction of DBPs, have become a priority because of their occurrence in drinking water at concentrations below 1MUg/L. The absence of a comprehensive method for HKs has led to the development of the first method for determining fourteen of these species. In an effort to miniaturise, this study develops a micro liquid-liquid extraction (MLLE) method adapted from EPA Method 551.1. In this method practically, the whole extract (50MUL) was injected into a programmed temperature vaporiser-gas chromatography-mass spectrometer in order to improve sensitivity. The method was validated by comparing it to EPA Method 551.1 and showed relevant advantages such as: lower sample pH (1.5), higher aqueous/organic volume ratio (60), lower solvent consumption (200MUL) and fast and cost-saving operation. The MLLE method achieved detection limits ranging from 6 to 60ng/L (except for 1,1,3 tribromo-3-chloroacetone, 120ng/L) with satisfactory precision (RSD, ~6%) and high recoveries (95-99%). An evaluation was carried out of the influence of various dechlorinating agents as well as of the sample pH on the stability of the fourteen HKs in treated water. To ensure the HKs integrity for at least 1 week during storage at 4 degrees C, the samples were acidified at pH ~1.5, which coincides with the sample pH required for MLLE. The green method was applied to the speciation of fourteen HKs in tap and swimming pool waters, where one and seven chlorinated species, respectively, were found. The concentration of 1.1 dichloroacetone in swimming pool water increased ~25 times in relation to tap water. PMID- 25042441 TI - Multi-allergen detection in food by micro high-performance liquid chromatography coupled to a dual cell linear ion trap mass spectrometry. AB - There is a raising demand for sensitive and high throughput MS based methods for screening purposes especially tailored to the detection of allergen contaminants in different food commodities. A challenging issue is represented by complex food matrices where the antibody-based kits commercially available might encounter objective limitations consequently to epitope masking phenomena due to a multitude of interfering compounds arising from the matrix. The performance of a method duly optimized for the extraction and simultaneous detection of soy, egg and milk allergens in a cookie food matrix by microHPLC-ESI-MS/MS, is herein reported. Thanks to the innovative configuration and the versatility shown by the dual cell linear ion trap MS used, the most intense and reliable peptide markers were first identified by untargeted survey experiment, and subsequently employed to design an ad hoc multi-target SRM method, based on the most intense transitions recorded for each selected precursor peptide. A sample extraction and purification protocol was optimized also including an additional step based on sonication, which resulted in a considerable improvement in the detection of milk allergen peptides. Data DependentTM Acquisition scheme allowed to fill out a tentative list of potential peptide markers, which were further filtered upon fulfilling specific requirements. A total of eleven peptides were monitored simultaneously for confirmation purposes of each allergenic contaminant and the two most sensitive peptide markers/protein were selected in order to retrieve quantitative information. Relevant LODs were found to range from 0.1MUg/g for milk to 0.3MUg/g for egg and 2MUg/g for soy. PMID- 25042442 TI - Fast-multivariate optimization of chiral separations in capillary electrophoresis: anticipative strategies. AB - The design of experiments (DOE) is a good option for rationally limiting the number of experiments required to achieve the enantioresolution (Rs) of a chiral compound in capillary electrophoresis. In some cases, the modeled Rs after DOE analysis can be unsatisfactory, maybe because the range of the explored factors (DOE domain) was not the adequate. In these cases, anticipative strategies can be an alternative to the repetition of the process (e.g. a new DOE), to save time and money. In this work, multiple linear regression (MLR)-steepest ascent and a new anticipative strategy based on a multiple response-partial least squares model (called PLS2-prediction) are examined as post-DOE strategies to anticipate new experimental conditions providing satisfactory Rs values. The new anticipative strategy allows to include the analysis time (At) and uncertainty limits into the decision making process. To demonstrate their efficiency, the chiral separation of hexaconazole and penconazole, as model compounds, is studied using highly sulfated-beta-cyclodextrin (HS-beta-CD) in electrokinetic chromatography (EKC). Box-Behnken DOE for three factors (background electrolyte pH, separation temperature and HS-beta-CD concentration) and two responses (Rs and At) is used. Using commercially available software, the whole modeling and anticipative process is automatic, simple and requires minimal skills from the researcher. Both strategies studied have proven to successfully anticipate Rs values close to the experimental ones for EKC conditions outside the DOE domain for the two model compounds. The results in this work suggest that PLS2 prediction approach could be the strategy of choice to obtain secure anticipations in EKC. PMID- 25042443 TI - The advantage of mixed-mode separation in the first dimension of comprehensive two-dimensional liquid-chromatography. AB - Comprehensive two-dimension liquid chromatography (LC*LC) has exhibited its powerful ability to separate complex samples. However, the use of a single chromatographic mode in 1st dimension has been limited to the separation of components by their individual characteristics, such as hydrophobicity, ionic properties etc. The use of mixed-mode stationary phases has revealed opportunities to combine different retention mechanisms. In this respect, stationary phases featuring both RP-like hydrophobic and ion-exchange interactive sites promise great versatility in retaining both polar and more apolar ionic and non-ionic compounds. We have therefore developed an LC*LC system based on mixed mode (strong anion exchange and reversed phase) in the first dimension and a C18 phase in the second dimension. The system has been evaluated with standard compounds and applied for the separation of white wine and Chinese Herbal Medicine (CHM). The mixed-mode system SAX-PFP*C18 results in a better separation than a single mode system such as SAX*C18 or PFP*C18. Although little improvement in orthogonality (0.91 instead 0.86) is achieved with SAX*C18, the mixed-mode SAX PFP*C18 gives a much larger effective peak distribution area in the analysis of e. g. white wine. But the analysis of aqueous extracts of CHM (Hdyotis diffusa and Scutellaria barbata) with SAX-PFP*RP leads to a very long analysis time because of strong hydrophobic interactions with the PFP column. Thus, the system was changed by using a cyano phase instead of a PFP phase. The improved SAX CN*C18 system shows a better peak distribution and more importantly a reasonable analysis time. PMID- 25042444 TI - Prevalence of pelvic adhesions on ultrasound examination in women with a history of Cesarean section. AB - OBJECTIVES: To investigate the prevalence and location of pelvic adhesions in women with a history of Cesarean section and to identify risk factors for their formation and symptoms associated with their presence. METHODS: This was a prospective observational study of women in whom one or more Cesarean sections had been performed > 12 months previously and who attended for a gynecological ultrasound examination. In all women, both transvaginal and transabdominal scans were performed in order to identify the presence of pelvic adhesions. Medical and surgical history was recorded and a structured questionnaire was used to enquire about any history of pelvic pain and urinary symptoms. RESULTS: A total of 308 women were recruited into the study. On ultrasound examination, 139 (45.1% (95% CI, 39.7-50.7%)) women showed evidence of adhesions within the pelvis. Adhesions in the vesicouterine pouch were the most common and were found in a total of 79 (25.6% (95% CI, 20.7-30.5%)) women. In women with a history of no surgery other than Cesarean section(s) (n = 220), an increasing number of Cesarean sections (odds ratio (OR) 3.4 (95% CI, 2.1-5.5)) and a postoperative wound infection (OR 11.7 (95% CI, 3.5-39.5)) increased the likelihood of adhesions developing in the anterior pelvic compartment. There was a significant association between the presence of anterior compartment adhesions and chronic pelvic pain. Multivariable logistic regression analysis identified anterior abdominal wall adhesions (OR 2.4 (95% CI, 1.0-5.9)) and any adhesions present on ultrasound scan (OR 2.6 (95% CI, 1.2-5.7)) as independent predictors of chronic pelvic pain. CONCLUSIONS: Pelvic adhesions are present in more than a third of women with a history of Cesarean section and they are associated with chronic pelvic pain. PMID- 25042446 TI - Implicit false-belief processing in the human brain. AB - Eye-movement patterns in 'Sally-Anne' tasks reflect humans' ability to implicitly process the mental states of others, particularly false-beliefs - a key theory of mind (ToM) operation. It has recently been proposed that an efficient ToM system, which operates in the absence of awareness (implicit ToM, iToM), subserves the analysis of belief-like states. This contrasts to consciously available belief processing, performed by the explicit ToM system (eToM). The frontal, temporal and parietal cortices are engaged when humans explicitly 'mentalize' about others' beliefs. However, the neural underpinnings of implicit false-belief processing and the extent to which they draw on networks involved in explicit general-belief processing are unknown. Here, participants watched 'Sally-Anne' movies while fMRI and eye-tracking measures were acquired simultaneously. Participants displayed eye-movements consistent with implicit false-belief processing. After independently localizing the brain areas involved in explicit general-belief processing, only the left anterior superior temporal sulcus and precuneus revealed greater blood-oxygen-level-dependent activity for false- relative to true-belief trials in our iToM paradigm. No such difference was found for the right temporal-parietal junction despite significant activity in this area. These findings fractionate brain regions that are associated with explicit general ToM reasoning and false-belief processing in the absence of awareness. PMID- 25042445 TI - Hierarchical feature representation and multimodal fusion with deep learning for AD/MCI diagnosis. AB - For the last decade, it has been shown that neuroimaging can be a potential tool for the diagnosis of Alzheimer's Disease (AD) and its prodromal stage, Mild Cognitive Impairment (MCI), and also fusion of different modalities can further provide the complementary information to enhance diagnostic accuracy. Here, we focus on the problems of both feature representation and fusion of multimodal information from Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). To our best knowledge, the previous methods in the literature mostly used hand-crafted features such as cortical thickness, gray matter densities from MRI, or voxel intensities from PET, and then combined these multimodal features by simply concatenating into a long vector or transforming into a higher-dimensional kernel space. In this paper, we propose a novel method for a high-level latent and shared feature representation from neuroimaging modalities via deep learning. Specifically, we use Deep Boltzmann Machine (DBM)(2), a deep network with a restricted Boltzmann machine as a building block, to find a latent hierarchical feature representation from a 3D patch, and then devise a systematic method for a joint feature representation from the paired patches of MRI and PET with a multimodal DBM. To validate the effectiveness of the proposed method, we performed experiments on ADNI dataset and compared with the state-of-the-art methods. In three binary classification problems of AD vs. healthy Normal Control (NC), MCI vs. NC, and MCI converter vs. MCI non-converter, we obtained the maximal accuracies of 95.35%, 85.67%, and 74.58%, respectively, outperforming the competing methods. By visual inspection of the trained model, we observed that the proposed method could hierarchically discover the complex latent patterns inherent in both MRI and PET. PMID- 25042447 TI - Interregional alpha-band synchrony supports temporal cross-modal integration. AB - In a continuously changing environment, time is a key property that tells us whether information from the different senses belongs together. Yet, little is known about how the brain integrates temporal information across sensory modalities. Using high-density EEG combined with a novel psychometric timing task in which human subjects evaluated durations of audiovisual stimuli, we show that the strength of alpha-band (8-12 Hz) phase synchrony between localizer-defined auditory and visual regions depended on cross-modal attention: during encoding of a constant 500 ms standard interval, audiovisual alpha synchrony decreased when subjects attended audition while ignoring vision, compared to when they attended both modalities. In addition, alpha connectivity during a variable target interval predicted the degree to which auditory stimulus duration biased time estimation while attending vision. This cross-modal interference effect was estimated using a hierarchical Bayesian model of a psychometric function that also provided an estimate of each individual's tendency to exhibit attention lapses. This lapse rate, in turn, was predicted by single-trial estimates of the stability of interregional alpha synchrony: when attending to both modalities, trials with greater stability in patterns of connectivity were characterized by reduced contamination by lapses. Together, these results provide new insights into a functional role of the coupling of alpha phase dynamics between sensory cortices in integrating cross-modal information over time. PMID- 25042448 TI - A new class of tunable dendritic diphosphine ligands: synthesis and applications in the Ru-catalyzed asymmetric hydrogenation of functionalized ketones. AB - A series of tunable G0-G3 dendritic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) ligands was prepared by attaching polyaryl ether dendrons onto the four phenyl rings on the P atoms. Their ruthenium complexes were employed in the asymmetric hydrogenation of beta-ketoesters, alpha-ketoesters, and alpha ketoamides to reveal the effects of dendron size on the catalytic properties. The second- and third-generation catalysts exhibited excellent enantioselectivities, which are remarkably higher than those obtained from the small molecular catalysts and the first-generation catalyst. Molecular modeling indicates that the incorporation of bulky dendritic wedges can influence the steric environments around the metal center. In addition, the ruthenium catalyst bearing a second generation dendritic ligand could be recycled and reused seven times without any obvious decrease in enantioselectivity. PMID- 25042449 TI - Transducer hygiene: comparison of procedures for decontamination of ultrasound transducers and their use in clinical practice. AB - BACKGROUND: To determine whether current hygiene practices are appropriate during sonographic examinations. METHODS: Five major hospitals in Sweden were investigated with a survey. At each hospital, the departments corresponding to the main types of sonographic examination were chosen. Personnel who were responsible for or acquainted with the local hygiene procedures completed a standardardized questionnaire. RESULTS: The surveys were completed by 25 departments, where the total number of sonographic examinations was approximately 20,000 per month. For transvaginal and transrectal sonographic examinations, the most common method for decontamination of the transducer was barrier protection during the procedure followed by cleansing with alcohol. Latex was the predominant cover material, but one department used polyethylene gloves, and another department used nitrile gloves. Both of these involved transvaginal ultrasonography. In transcutaneous examinations, all hospitals were using alcohol and paper or cloth for decontamination at a minimum. Transesophageal examinations were carried out without barrier protection, and decontamination was performed with an alkylating substance. CONCLUSIONS: The hygiene practices appear to be appropriate at most hospitals, but there is a prevalence of transducer cover materials of unacceptable permeability, as well as use of gloves on transducers despite insufficient evidence of safety. PMID- 25042450 TI - Comparative effects of antihypertensive drugs on stroke outcome in China. AB - BACKGROUND: Antihypertensive drugs are useful in the prevention of stroke; however, much debate surrounds which class of agent provides the most benefit post-stroke. AIMS: The aim of this study was to examine the impact of different classes of antihypertensive agent on stroke outcome using data from the ChinaQUEST study, a prospective, hospital-based stroke registry undertaken across 62 hospitals in China. METHODS: Logistic regression analysis was used to determine the comparative associations of different antihypertensive medications when initiated in-hospital post-stroke on the following poor outcomes in stroke survivors at three- and 12 months post-stroke: (1) death and dependency, based on modified Rankin Scale scores 3-5; (2) death; and (3) dependency. RESULTS: Of the 6416 patients with baseline data, 3986 (62%) were on at least one antihypertensive agent. After adjustment for baseline characteristics and concomitant therapies, there were no differences in outcomes between therapies at three- and 12 months, but at 12 months, calcium channel blocker use was associated with reduced risks of death/dependency (odds ratio 0.78, P = 0.001) and death (odds ratio 0.66, P < 0.001). In addition, angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use was associated with reduced risk of death (odds ratio 0.76, P = 0.009), whereas both beta-blockers and diuretics were shown to increase the risk of death/dependency and death but had no effect on the risk of dependency. CONCLUSION: This study suggests that early initiation of calcium channel blockers is associated with improved outcome after stroke. Further randomized studies are warranted to confirm these findings and to delineate differential beneficial effects of antihypertensive therapy in stroke prevention. PMID- 25042451 TI - Endothelin 1 gene as a modifier in dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a myocardial disease of unknown etiology with left ventricular dilatation and impaired myocardial contractility leading to heart failure. It is considered to be a multifactorial disorder with the interplay of both genetic and environmental factors. One of the possible genes implicated in DCM is endothelin 1 (EDN1). The genetic variants of EDN1 may be involved in the pathophysiology of DCM hence the entire EDN1 gene was screened to examine for the possible genotypic associations with DCM. A total of 115 DCM patients and 250 control subjects were included in the present study. PCR based SSCP analysis was carried out followed by commercial sequencing. Screening of EDN1 revealed two common and two rare polymorphisms. Allelic and genotypic frequencies were estimated in patient and control groups by appropriate statistical tests. The heterozygotes of insertion variation (+138A) were found to exhibit four-fold increase risk to DCM (OR=4.12, 95% CI 2.10-8.08; p=0.0001). The two rare variants (G>A transition (rs150035515) at c.90 and C>T transition (rs149399492) at c.119) observed in the present study were found to be unique in DCM. The secondary mRNA structures of these variations were found to have less free energy than wild type. The haplotype analysis revealed 4A-T to be risk haplotype for DCM (OR 5.90, 95% CI 2.29-15.25, p=0.0001). In conclusion, EDN1 polymorphisms (+138A, A30A, T40I) appear to play a significant role in the pathogenesis of DCM, as they influence the stability of protein. The increased EDN1 production may lead to constriction of coronary arteries, reducing coronary blood flow which may in turn increase the load on left ventricle, impairing contractility of the heart resulting in a DCM phenotype, an end stage of heart failure. PMID- 25042452 TI - Deletion of CDY1b copy of Y chromosome CDY1 gene is a risk factor of male infertility in Tunisian men. AB - The relationship between male infertility and microdeletions in the Y chromosome that remove multiple genes varies among countries and populations. The aim of this study was to investigate the different types of Chromodomain protein, Y linked 1 (CDY1) gene deletions and their effect on male infertility and spermatogenesis in Tunisian men. A total of 241 infertile men with different spermatogenic impairments and 115 fertile men were included in this study. We determined the prevalence of CDY1a and CDY1b copy deletions by PCR-RFLP using PvuII as restriction endonuclease. RESULTS: Among the 356 Tunisian individuals, 93.25% had the two copies (CDY1a and CDY1b) of CDY gene (91.2% in infertile patients and 97.3% in fertile men). We also found that deletion of CDY1b was significantly more frequent in infertile patients (azoo/oligospermic and normospermic) than in fertile men (7% vs 1.7% respectively; p value=0.02). However, deletion of CDY1a copy was very rare, and was detected in only one fertile man and four normospermic infertile patients. Our findings showed that deletion of CDY1b copy gene is a significant risk factor for male infertility independent of sperm concentration, whereas deletion of CDY1a gene seems to have no effect on fertility in the Tunisian population. PMID- 25042453 TI - Complete chloroplast genome sequences of Praxelis (Eupatorium catarium Veldkamp), an important invasive species. AB - Praxelis (Eupatorium catarium Veldkamp) is a new hazardous invasive plant species that has caused serious economic losses and environmental damage in the Northern hemisphere tropical and subtropical regions. Although previous studies focused on detecting the biological characteristics of this plant to prevent its expansion, little effort has been made to understand the impact of Praxelis on the ecosystem in an evolutionary process. The genetic information of Praxelis is required for further phylogenetic identification and evolutionary studies. Here, we report the complete Praxelis chloroplast (cp) genome sequence. The Praxelis chloroplast genome is 151,410 bp in length including a small single-copy region (18,547 bp) and a large single-copy region (85,311 bp) separated by a pair of inverted repeats (IRs; 23,776 bp). The genome contains 85 unique and 18 duplicated genes in the IR region. The gene content and organization are similar to other Asteraceae tribe cp genomes. We also analyzed the whole cp genome sequence, repeat structure, codon usage, contraction of the IR and gene structure/organization features between native and invasive Asteraceae plants, in order to understand the evolution of organelle genomes between native and invasive Asteraceae. Comparative analysis identified the 14 markers containing greater than 2% parsimony-informative characters, indicating that they are potential informative markers for barcoding and phylogenetic analysis. Moreover, a sister relationship between Praxelis and seven other species in Asteraceae was found based on phylogenetic analysis of 28 protein-coding sequences. Complete cp genome information is useful for plant phylogenetic and evolutionary studies within this invasive species and also within the Asteraceae family. PMID- 25042454 TI - Complete mitochondrial genome of Malaysian Mahseer (Tor tambroides). AB - This is the first documentation of the complete mitochondrial genome sequence of the Malaysian Mahseer, Tor tambroides. The 16,690 bp mitogenome with GenBank accession number JX444718 contains 13 protein genes, 22 tRNAs, two rRNAs, and a noncoding control region (D-loop) as is typical of most vertebrates. The phylogenomic reconstruction of this newly generated data with 21 Cypriniformes GenBank accession ID concurs with the recognized status of T. tambroides within the subfamily Cyprininae. This is in agreement with previous hypotheses based on morphological and partial mitochondrial analyses. PMID- 25042456 TI - Targeting EMT in cancer: opportunities for pharmacological intervention. AB - The spread of cancer cells to distant organs represents a major clinical challenge in the treatment of cancer. Epithelial-mesenchymal transition (EMT) has emerged as a key regulator of metastasis in some cancers by conferring an invasive phenotype. As well as facilitating metastasis, EMT is thought to generate cancer stem cells and contribute to therapy resistance. Therefore, the EMT pathway is of great therapeutic interest in the treatment of cancer and could be targeted either to prevent tumor dissemination in patients at high risk of developing metastatic lesions or to eradicate existing metastatic cancer cells in patients with more advanced disease. In this review, we discuss approaches for the design of EMT-based therapies in cancer, summarize evidence for some of the proposed EMT targets, and review the potential advantages and pitfalls of each approach. PMID- 25042457 TI - What is pharmacological 'affinity'? Relevance to biased agonism and antagonism. AB - The differences between affinity measurements made in binding studies and those relevant to receptor function are described. There are theoretical and practical reasons for not utilizing binding data and, in terms of the quantification of signaling bias, it is unnecessary to do so. Finally, the allosteric control of ligand affinity through receptor-signaling protein interaction is discussed within the context of biased antagonism. In this regard, it is shown that both the bias and relative efficacy of a ligand are essential data for fully predicting biased effects in vivo. PMID- 25042458 TI - Ten real-time PCR assays for detection of fish predation at the community level in the San Francisco Estuary-Delta. AB - The effect of predation on native fish by introduced species in the San Francisco Estuary-Delta (SFE) has not been thoroughly studied despite its potential to impact species abundances. Species-specific quantitative PCR (qPCR) is an accurate method for identifying species from exogenous DNA samples. Quantitative PCR assays can be used for detecting prey in gut contents or faeces, discriminating between cryptic species, or detecting rare aquatic species. We designed ten TaqMan qPCR assays for fish species from the SFE watershed most likely to be affected by non-native piscivores. The assays designed are highly specific, producing no signal from co-occurring or related species, and sensitive, with a limit of detection between 3.2 and 0.013 pg/MUL of target DNA. These assays will be used in conjunction with a high-throughput qPCR platform to compare predation rates between native and non-native piscivores and assess the impacts of predation in the system. PMID- 25042460 TI - Comparison of objective Bayes factors for variable selection in parametric regression models for survival analysis. AB - This paper considers the problem of selecting a set of regressors when the response variable is distributed according to a specified parametric model and observations are censored. Under a Bayesian perspective, the most widely used tools are Bayes factors (BFs), which are undefined when improper priors are used. In order to overcome this issue, fractional (FBF) and intrinsic (IBF) BFs have become common tools for model selection. Both depend on the size, Nt , of a minimal training sample (MTS), while the IBF also depends on the specific MTS used. In the case of regression with censored data, the definition of an MTS is problematic because only uncensored data allow to turn the improper prior into a proper posterior and also because full exploration of the space of the MTSs, which includes also censored observations, is needed to avoid bias in model selection. To address this concern, a sequential MTS was proposed, but it has the drawback of an increase of the number of possible MTSs as Nt becomes random. For this reason, we explore the behaviour of the FBF, contextualizing its definition to censored data. We show that these are consistent, providing also the corresponding fractional prior. Finally, a large simulation study and an application to real data are used to compare IBF, FBF and the well-known Bayesian information criterion. PMID- 25042459 TI - Structural and mechanical repair of diffuse damage in cortical bone in vivo. AB - Physiological wear and tear causes bone microdamage at several hierarchical levels, and these have different biological consequences. Bone remodeling is widely held to be the mechanism by which bone microdamage is repaired. However, recent studies showed that unlike typical linear microcracks, small crack damage, the clusters of submicron-sized matrix cracks also known as diffuse damage (Dif.Dx), does not activate remodeling. Thus, the fate of diffuse damage in vivo is not known. To examine this, we induced selectively Dif.Dx in rat ulnae in vivo by using end-load ulnar bending creep model. Changes in damage content were assessed by histomorphometry and mechanical testing immediately after loading (ie, acute loaded) or at 14 days after damage induction (ie, survival ulnae). Dif.Dx area was markedly reduced over the 14-day survival period after loading (p < 0.02). We did not observe any intracortical resorption, and there was no increase in cortical bone area in survival ulnae. The reduction in whole bone stiffness in acute loaded ulnae was restored to baseline levels in survival ulnae (p > 0.6). Microindentation studies showed that Dif.Dx caused a highly localized reduction in elastic modulus in diffuse damage regions of the ulnar cortex. Moduli in these previously damaged bone areas were restored to control values by 14 days after loading. Our current findings indicate that small crack damage in bone can be repaired without bone remodeling, and they suggest that alternative repair mechanisms exist in bone to deal with submicron-sized matrix cracks. Those mechanisms are currently unknown and further investigations are needed to elucidate the mechanisms by which this direct repair occurs. PMID- 25042461 TI - Enantiomeric separation by microchip electrophoresis using bovine serum albumin conjugated magnetic core-shell Fe3 O4 @Au nanocomposites as stationary phase. AB - In this work, a novel enantioselective MCE was developed employing BSA-conjugated Fe3 O4 @Au nanoparticles (Fe3 O4 @Au NPs) as stationary phase. Fe3 O4 @Au NPs with high magnetic responsively, excellent solubility, and high dispersibility in water were prepared through a sonochemical synthesis strategy. BSA was then immobilized onto the Fe3 O4 @Au NPs surfaces through the well-developed interaction between Au NPs and amine groups of BSA to form Fe3 O4 @Au NPs-BSA conjugates, which were then locally packed into PDMS microchannels with the help of magnets. The resultant Fe3 O4 @Au NPs-BSA conjugates not only have the magnetism of Fe3 O4 NPs that make them easily manipulated by an external magnetic field, but also have the larger surface and excellent biocompatibility of Au shell, which can incorporate much more biomolecules and well maintain their biological activity. In addition, the successful BSA decorations endowed Fe3 O4 @Au NPs-BSA conjugates with pH-tunable water solubility related to the pI of BSA (pI 4.7) and led to enhanced stability against high ionic strength. Compared with the native PDMS microchannel, the modified surfaces exhibited more stable and suppressed electroosmotic mobility, and less nonspecific adsorption toward analytes. Successful separation of chiral amino acids (tryptophan and threonine) and ofloxacin enantiomers demonstrate that the constructed MCE columns own ideal enantioselectivity. The results are expected to open up a new possibility for high-throughput screening of enantiomers with protein targets as well as a new application of magnetic NPs. PMID- 25042462 TI - Gold-catalyzed oxa-Povarov reactions for the synthesis of highly substituted dihydrobenzopyrans from diaryloxymethylarenes and olefins. AB - Oxa-Povarov reactions involving readily available diaryloxymethylarenes and aryl substituted alkenes are reported. Their [4+2] cycloadditions were efficiently catalyzed by IPrAuSbF6 (IPr=1,3-bis(diisopropylphenyl)imidazol-2-ylidene) with high diastereoselectivity. Product analysis revealed that the reactions likely proceed by a stepwise ionic mechanism, because both E- and Z-configured beta methylstyrene gave the same cycloadducts in the same proportions. PMID- 25042463 TI - A 3D mathematical model to predict spinal joint and hip joint force for trans tibial amputees with different SACH foot pylon adjustments. AB - A solid-ankle cushioned heel (SACH) foot is a non-joint foot without natural ankle function. Trans-tibial amputees may occur toe scuffing in the late swing phase due to a lack of active dorsiflexion. To address this problem, clinical guidelines suggests shortening the pylon to produce a smooth gait. However, this causes a leg length discrepancy, induces asymmetry in the hip joint, and causes an overload of L5/S1 joint force. Therefore, this study aimed to investigate the influence of different prosthesis pylons on the hip joint and L5/S1 joint forces. Ten subjects were recruited using leg length for normalisation. Four different pylon reductions (0%, 1%, 2%, and 3%) were used for gait analysis. A Vicon system and force plates were used to collect kinematic data and ground reaction force, respectively. The software package MATLAB was used to create a mathematical model for evaluating the symmetry and force of the hip joint and the low back force of the L5/S1 joint. The model was validated by the correlation coefficient (CC=0.947) and root mean square (RMS=0.028 BW). The model estimated that the 1% group had a symmetrical hip joint force and a lower L5/S1 joint force in the vertical direction. This study indicates that a 1% pylon shortening on a SACH prosthesis is appropriate for a trans-tibial amputee. PMID- 25042464 TI - Autophagy and mitophagy interplay in melanoma progression. AB - Autophagy, or self-eating, is the most extensively studied lysosomal degradation pathway for the recycling of obsolete or damaged cytoplasmic materials, including proteins and organelles. Although this pathway was initially thought to function as trafficking system for 'in bulk' degradation by the lysosomes of cytoplasmic material, it is now widely appreciated that cargo selection by the autophagic machinery is a major process underlying the cytoprotective or--possibly--pro death functions ascribed to this catabolic process. Indeed increasing evidence suggests that in mammalian cells the removal of dysfunctional or aged mitochondria occurs through a selective degradation pathway known as 'mitophagy'. Due to the crucial role of mitochondria in energy metabolism, redox control and cell survival/death decision, deregulated mitophagy can potentially impact a variety of crucial cell autonomous and non-autonomous processes. Accumulating evidence indicates that during malignant transformation aggressive cancers hijack autophagy to preserve energy fitness and to acquire the plasticity required to adapt to the hostile microenvironment. However, whether and how mitophagy contributes to carcinogenesis, which pathways regulate this process in the cancer cells and how cancer cell-mitophagy impacts and modifies the tumor microenvironment and therapeutic responses, remain largely unanswered issues. In this review, we discuss novel paradigms and pathways regulating mitophagy in mammalian cells and the impact this process might have on one of the most dreadful human malignancies, melanoma. PMID- 25042465 TI - Dynamics of HCV RNA levels during acute hepatitis C virus infection. AB - Understanding viral dynamics during acute hepatitis C virus (HCV) infection can provide important insights into immunopathogenesis and guide early treatment. The aim of this study was to investigate the dynamics of HCV RNA and alanine transaminase (ALT) levels during recent HCV infection in the Australian Trial in Acute Hepatitis C (ATAHC). ATAHC was a prospective study of the natural history of recently acquired HCV infection. Longitudinal HCV RNA and ALT levels were compared among individuals with persistent infection and spontaneous clearance. Among those with HCV persistence (n = 104) and HCV clearance (n = 30), median HCV RNA (5.2 vs. 4.1 log IU/ml, respectively) and ALT levels (779 vs. 1,765 IU/L, respectively) were high during month two following infection, and then declined during months three and four in both groups. Among those with HCV persistence, median HCV RNA was 2.9 log IU/ml during months four, increased to 5.5 log IU/ml during month five, and remained subsequently relatively stable. Among those with HCV clearance, median HCV RNA was undetectable by month five. Median HCV RNA levels were comparable between individuals with HCV persistence and HCV clearance during month three following infection (3.2 vs. 3.5 log IU/ml, respectively; P = 0.935), but markedly different during month five (5.5 vs. 1.0 log IU/ml, respectively; P < 0.001). In conclusion, dynamics of HCV RNA levels in those with HCV clearance and HCV persistence diverged between months three and five following infection, with the latter time-point being potentially useful for commencing early treatment. PMID- 25042466 TI - Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms. An European Leukemia Net study. AB - To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN-CVT) to 87 with MPN and other venous thrombosis (group MPN-VT) and 178 with MPN and no thrombosis (group MPN-NoT) matched by sex, age at diagnosis of MPN (+/-5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN-CVT and MPN-VT than in MPN-NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow-up period (6.1 vs. 10.3 years, P = 0.019), a higher long-term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN-CVT than in MPN-VT group (8.8% and 4.2% patient years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05-3.72 and 2.09, 1.09-4.00, respectively). PMID- 25042467 TI - Vanillin analog--vanillyl mandelic acid, a novel specific inhibitor of snake venom 5'-nucleotidase. AB - Snake venom 5'-nucleotidase (5'NUC) plays a very important role in envenomation strategies; however, apart from its modulation of hemostatic functions, its other pharmacological effects are not yet well characterized. Several studies have used specific inhibitors of enzyme toxins as a biochemical or pharmacological tool to characterize or establish its mechanism of action. We report here for the first time vanillin mandelic acid (VMA), an analog of vanillin, to potentially, selectively, and specifically inhibit venom 5'NUC activity among other enzymes present in venoms. VMA is much more potent in inhibiting 5'NUC activity than vanillyl acid (VA). The experimental results obtained are in good agreement with the in silico molecular docking interaction data. Both VA and VMA are competitive inhibitors as evident by the inhibition-relieving effect upon increasing the substrate concentration. VMA also dose-dependently inhibited the anticoagulant effect in Naja naja venom. In this study, we report novel non-nucleoside specific inhibitors of snake venom 5'NUC and experimentally demonstrate their involvement in the anticoagulant activity of N. naja venom. Hence, we hypothesize that VMA can be used as a molecular tool to evaluate the role of 5'NUC in snake envenomation and to develop prototypes and lead compounds with potential therapeutic applications against snake bites. PMID- 25042468 TI - Acute coagulopathy in trauma: with or without shock? That is the question. PMID- 25042469 TI - Stereoselective reduction of C-20 ketone of vitamin D CD-ring and a new synthetic approach to maxacalcitol. AB - Stereoselective reduction of C-20 ketone of vitamin D CD-ring precursor using Corey's CBS reagents, (R)-(+)-2-methyl-CBS-oxazaborolidine and (S)-(-)-2-methyl CBS-oxazaborolidine, led to the (20S)-alcohol 5 and (20R)-epimer 4 in approximately 17:1 selectivity. A new synthetic approach to the 22-oxa-25-hydroxy Grundmann's ketone 11 was developed through the Williamson etherification of (20S)-alcohol 5 with 1-bromomethyl-2,2-dimethyloxirane, followed by regioselective reductive epoxide ring opening with LiAlH4, the removal of the silyl protecting group by TBAF, and the environmentally benign TEMPO-mediated oxidation using inexpensive Oxone as a co-oxidizing agent. The preparation of drug maxacalcitol was achieved on gram scale by the convergent Lythgoe coupling via Wittig-Horner reaction of the A-ring phosphine oxide synthon with the CD-ring fragment. PMID- 25042470 TI - Peer group normalization and urine to blood context in steroid metabolomics: the case of CAH and obesity. AB - Traditional interpretation of GC-MS output involved the semi-quantitative estimation of outstanding low or high specific metabolites and the ratio between metabolites. Here, we utilize a systems biology approach to steroid metabolomics of a complex steroid-related disorder, using an all-inclusive analysis of the steroidal pathway in the form of a subject steroidal fingerprint and disease signature, providing novel methods of normalization and visualization. The study compares 324 normal children to pure enzymatic deficiency in 27 untreated 21 hydroxylase CAH patients and to complex disease in 70 children with obesity. Steroid profiles were created by quantitative data generated by GC-MS analyses. A novel peer-group normalization method defined each individual subject's control group in a multi-dimensional space of metadata parameters. Classical steroid pathway visualization was enhanced by adding urinary end-product sub-nodes and by color coding of semi-quantitative metabolic concentrations and enzymatic activities. Unbiased automated data analysis confirmed the common knowledge for CAH - the inferred 17-hydroxyprogesterone was up-regulated and the inferred 21 hydroxylase enzyme activity was down-regulated. In childhood obesity, we observe a general decrease of both glucocorticoid and mineralocorticoid metabolites, increased androgens, up-regulation of 17,20-lyase, 17-OHase and 11beta-HSD1 activity and down-regulation of 21-OHase enzymatic activity. Our study proved novel normalization and visualization techniques are to be useful in identifying subject fingerprint and disease signature in enzymatic deficiency and insufficiency, while demonstrating hypothesis generation in a complex disease such as childhood obesity. PMID- 25042472 TI - Steroid sulfatase mediated growth Sof human MG-63 pre-osteoblastic cells. AB - Estrogen plays an important role in maintaining bone density. Postmenopausal women have low plasma estrogen, but have high levels of conjugated steroids, particularly estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS). Conversion of these precursors to active estrogens may help maintain bone density in postmenopausal women. The enzyme steroid sulfatase (STS) converts sulfated steroids into active forms in peripheral tissues. STS occurs in bone, but little is known about its role in bone function. In this study, we investigated STS activity and expression in the human MG-63 pre-osteoblastic cell line. We also tested whether sulfated steroids can stimulate growth of these cells. MG-63 cells and microsomes both possessed STS activity, which was blocked by the STS inhibitors EMATE and 667 Coumate. Further evidence for STS in these cells was provided by RT-PCR, using STS specific primers, which resulted in cDNA products of the predicted size. We then tested for growth of MG-63 cells in the presence of estradiol-17beta, E1S and DHEAS. All three steroids stimulated MG-63 cell growth in a steroid-free basal medium. We also tested whether the cell growth induced by sulfated steroids could be blocked using a STS inhibitor (667 Coumate) or using an estrogen receptor blocker (ICI 182,780). Both compounds inhibited E1S induced cell growth, indicating that E1S stimulates MG-63 cell growth through a mechanism involving both STS and the estrogen receptor. Finally, we demonstrated using RT-PCR that MG-63 cells contain mRNA for both estrogen receptor alpha and estrogen receptor beta. Our data reveal that STS is present in human pre osteoblastic bone cells and that it can influence bone cell growth by converting inactive sulfated steroids to estrogenic forms that act via estrogen receptor alpha or beta. PMID- 25042471 TI - Steroidal sapogenins and glycosides from the fibrous roots of Polygonatum odoratum with inhibitory effect on tissue factor (TF) procoagulant activity. AB - Six new spirostane glycosides (1-6), named polygodosides A-F, one new furostanol glycoside, polygodoside G (7), one new cholestane glycoside, polygodoside H (8), and one new steroidal sapogenin, polygodosin A (9), together with thirteen known compounds (10-22) were isolated from a 90% MeOH extract of the fibrous roots of Polygonatum odoratum (Mill.) Druce. The structures of new compounds were elucidated by extensive 1D and 2D NMR spectroscopic analyses and mass spectrometry. The effects on TF procoagulant activity in THP-1 cells were tested for most of the compounds. PMID- 25042474 TI - Interim FDG PET/CT for predicting the outcome in patients with head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: The study aimed to investigate the prognostic effects of interim (18) fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT) during definitive radiotherapy (RT) or chemoradiotherapy (CRT) in patients with head and neck cancer. STUDY DESIGN: This is a prospectively treatment study. METHODS: The pretreatment and interim PET/CT images of 51 patients with advanced pharyngeal cancers receiving definitive RT/CRT were evaluated prospectively. The interim PET/CT images were taken at a cumulative RT dose ranging from 41.4 to 46.8 Gy. The maximum standardized uptake value (SUVm) of the interim PET/CT and the reduction ratio of the SUVm (SRR) between the two images were measured. The differences between patients with or without local failures were examined using the Mann-Whitney test. Overall survival (OS), disease-free survival (DFS), and primary and nodal relapse-free survival rates were calculated using the Kaplan-Meier method. Independent prognosticators were identified using Cox regression analysis. RESULTS: After a median follow-up duration of 23 months, a higher interim SUVm was associated with local failures. Conducting a multivariate analysis revealed that a SUVmax reduction ratio of primary tumor (SRR-P) < 0.64 was associated with the inferior OS (hazard ratio 2.64; P =0.035) and DFS (hazard ratio 2.33; P = 0.045). Patients who had tumors with an SRR-P < 0.64 had a considerably lower 2-year OS and DFS compared with those who had SRR-P >= 0.64 (47% vs. 66%; 41% vs. 64%). CONCLUSION: A higher interim SUVm was associated with local recurrence. In addition, patients with a lower SRR-P should be considered to be at risk of primary failure. LEVEL OF EVIDENCE: 4. PMID- 25042475 TI - Intraoperative floppy iris and prevalence of intraoperative complications: results from ophthalmic surgery outcomes database. PMID- 25042473 TI - CSF1 overexpression has pleiotropic effects on microglia in vivo. AB - Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 overexpressing mice have increased microglial proliferation and increased microglial numbers compared with controls. Treatment with PLX3397, a small molecule inhibitor of the CSF1 receptor CSF1R and related kinases, decreases microglial numbers by promoting microglial apoptosis in both CSF1 overexpressing and control mice. Microglia in CSF1 overexpressing mice exhibit gene expression profiles indicating that they are not basally M1 or M2 polarized, but they do have defects in inducing expression of certain genes in response to the inflammatory stimulus lipopolysaccharide. These results indicate that the CSF1 overexpression observed in CNS pathologies likely has pleiotropic influences on microglia. Furthermore, small molecule inhibition of CSF1R has the potential to reverse CSF1-driven microglial accumulation that is frequently observed in CNS pathologies, but can also promote apoptosis of normal microglia. PMID- 25042476 TI - Questionnaire for child gastro-esophageal reflux disease. PMID- 25042477 TI - The optimal timing of enterostomy closure in preterm infants. PMID- 25042478 TI - Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid rich necrotic cores in hypercholesterolemic mice. AB - Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF kappaB-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis. PMID- 25042480 TI - An error taxonomy system for analysis of haemodialysis incidents. AB - OBJECTIVES: This paper describes the development of a haemodialysis error taxonomy system for analysing incidents and predicting the safety status of a dialysis organisation. METHODS: The error taxonomy system was developed by adapting an error taxonomy system which assumed no specific specialty to haemodialysis situations. Its application was conducted with 1,909 incident reports collected from two dialysis facilities in Japan. RESULTS: Over 70% of haemodialysis incidents were reported as problems or complications related to dialyser, circuit, medication and setting of dialysis condition. Approximately 70% of errors took place immediately before and after the four hours of haemodialysis therapy. Error types most frequently made in the dialysis unit were omission and qualitative errors. Failures or complications classified to staff human factors, communication, task and organisational factors were found in most dialysis incidents. Device/equipment/materials, medicine and clinical documents were most likely to be involved in errors. Haemodialysis nurses were involved in more incidents related to medicine and documents, whereas dialysis technologists made more errors with device/equipment/materials. CONCLUSIONS: This error taxonomy system is able to investigate incidents and adverse events occurring in the dialysis setting but is also able to estimate safety-related status of an organisation, such as reporting culture. PMID- 25042479 TI - Wine evolution and spatial distribution of oxygen during storage in high-density polyethylene tanks. AB - BACKGROUND: Porous plastic tanks are permeable to oxygen due to the nature of the polymers with which they are manufactured. In the wine industry, these types of tanks are used mainly for storing wine surpluses. Lately, their use in combination with oak pieces has also been proposed as an alternative to mimic traditional barrel ageing. RESULTS: In this study, the spatial distribution of dissolved oxygen in a wine-like model solution, and the oxygen transfer rate (OTR) of high-density polyethylene tanks (HDPE), was analysed by means of a non invasive opto-luminescence detector. Also, the chemical and sensory evolution of red wine, treated with oak pieces, and stored in HDPE tanks was examined and compared against traditional oak barrel ageing. The average OTR calculated for these tanks was within the commonly accepted amounts reported for new barrels. With regards to wine evolution, a number of compositional and sensory differences were observed between the wines aged in oak barrels and those stored in HDPE tanks with oak barrel alternatives. CONCLUSION: The use of HDPE tanks in combination with oak wood alternatives is a viable alternative too for ageing wine. PMID- 25042481 TI - Hormonal and surgical treatment in trans-women with BRCA1 mutations: a controversial topic. AB - INTRODUCTION: Male-to-female transgender persons (trans-women) receive livelong cross-sex hormonal treatment in order to induce and maintain secondary female characteristics. One of the concerns of long-term estrogen treatment is the induction of carcinomas of estrogen-sensitive tissues such as the breast. BRCA1 mutations have been shown to account for a large proportion of inherited predispositions to breast cancer. AIM: The aim of this case report is to discuss the hormonal and surgical options in the treatment of trans-women with a genetic predisposition for breast cancer. METHOD: We describe a case of a trans-woman who was found to be a carrier of a BRCA1 mutation. RESULTS: The patient underwent a breast augmentation. She refused a prophylactic mastectomy followed by a primary breast reconstruction. She also underwent a vaginoplasty and a bilateral castration. Androgen blocking treatment was stopped after surgery; estradiol treatment however was continued. CONCLUSIONS: This case points to the importance of routine investigation of family history in trans-women. Trans-women with BRCA mutations should be carefully monitored and if cancers develop, this should be reported. Follow-up should be according to the guidelines for breast cancer screening in biological women, and the guidelines for prostate cancer and colon cancer screening in men. PMID- 25042482 TI - Whole-tree seasonal nitrogen uptake and partitioning in adult Fagus sylvatica L. and Picea abies L. [Karst.] trees exposed to elevated ground-level ozone. AB - The effect of long-term exposure of twice-ambient O(3) (2 * O(3)) on whole-tree nitrogen (N) uptake and partitioning of adult beech and spruce was studied in a mixed forest stand, SE-Germany. N uptake as (15)N tracer and N pools were calculated using N concentrations and biomass of tree compartments. Whole-tree N uptake tended to be lower under 2 * O(3) in both species compared to trees under ambient O(3) (1 * O(3)). Internal partitioning in beech showed significantly higher allocation of new N to roots, with mycorrhizal root tips and fine roots together receiving about 17% of new N (2 * O(3)) versus 7% (1 * O(3)). Conversely, in spruce, N allocation to roots was decreased under 2 * O(3). These contrasting effects on belowground N partitioning and pool sizes, being largely consistent with the pattern of N concentrations, suggest enhanced N demand and consumption of stored N with higher relevance for tree-internal N cycling in beech than in spruce. PMID- 25042483 TI - [Complex types of vertigo: diagnostic possibilities]. AB - OBJECTIVE: To study diagnostic possibilities of a complex vestibular examination of patients with hard curable vertigo. MATERIAL AND METHODS: We studied 312 patients with complex types of vertigo. Neurologic and othoneurologic examination and some audio- and vestibulometry tests were carried out. RESULTS: The high frequency of comorbid lesions of the vestibular analyzer and coordination system was identified. CONCLUSION: Diagnostic and therapeutic approaches to hard curable vertigo are discussed. PMID- 25042484 TI - [Clinical and genetic markers of chronic cerebral ischemia]. AB - OBJECTIVE: To study the effectiveness of common neuropsychological tests for the verification of the diagnosis of cerebral ischemia (CE) and a role of polymorphisms in SERT, ApoE and BDNF genes in its development. MATERIAL AND METHODS: We studied 272 inpatients, aged from 37 to 70 years, with CE of the first stage (58 patients), CE of the second stage (121 patients) and CE of the third stage (93 patients). A set of neuropsychological tests, as well as biochemical and molecular-genetic studies were performed. RESULTS AND CONCLUSION: Reitan test was the most effective test for the diagnosis of cognitive impairment. The results of the Clock Drawing Test and MMSE were correlated with the disease severity but did not distinguish between the first and second stages of CE. Arterial hypertension and stenosing atherosclerosis of brain vessels were significant predictors of CE. SERT gene was a marker of the CE risk in men. The genotype SS was associated with the risk of CE with early age-at-onset. No association of ApoE and BDNF genes with CE was found. PMID- 25042485 TI - [Risk of manifestation of endogenous psychosis in patients with nonpsychotic mental disorders of juvenile age]. AB - OBJECTIVE: To identify people at high risk of endogenous psychosis in patients of juvenile age with nonpsychotic mental disorders. MATERIAL AND METHODS: Authors examine 49 patients of juvenile age with symptoms of nonpsychotic mental disorders (ICD-10 diagnoses of mood disorder, personality disorder or schizotypal disorder). RESULTS: In all cases, symptoms related to signs of the premorbid stage of endogenous psychosis (schizophrenia and schizoaffective psychosis) were identified. After psychopharmacological treatment, an incomplete (<30%) reduction of psychopathological disorders recorded at admission was found in 24.5% of patients. Based on the response of patients to treatment, family history (having a first-degree relative with psychosis) and the diagnosis of mental disorder, it was singled out "high-risk" (20.4% patients) and "ultra-high risk" (18.4%) states for psychosis. CONCLUSION: In light of these findings, the necessity of a longitude prospective study of these patients and pharmacological interventions in outpatient conditions is discussed. PMID- 25042486 TI - [Tempo-rhythmic correction of gait in Parkinson's disease]. AB - OBJECTIVE: To evaluate the effectiveness of the method of tempo-rhythmic correction (TRC) of gait on slowing of the disease progression in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Authors have used the device to determine step-speed performance parameters, method TRC of gait, a quality of life questionnaire (PDQ-39). RESULTS: The method of TRC improved gait and quality of life in patients with Parkinson's disease, reduced the pharmacoeconomic cost of treatment. CONCLUSION: A neuroprotective effect of the method of TRC may take place due to increasing the interval between PD stages, more recent emergence of new symptoms. PMID- 25042488 TI - [Melatonin and pain]. AB - OBJECTIVE: To study analgesic possibilities of melatonin. MATERIAL AND METHODS: A study included 120 patients, aged from 40 to 65 years, with low back pain. Duration of illness was not less than 12 weeks, the VAS score was >3. Patients were stratified into 4 groups (2 pairs of comparison). In the first pair, patients of the main group (n=31) received a chondroprotector ARTRA with the addition of melaxen (melatonin in dose 3 mg) and patients of the control group (n=29) received only ARTRA. In the second pair, patients of the control group (n=30) were treated with ARTRA and diclofenac and patients of the main group (n=30) received additionally melaxen. Treatment efficacy was assessed after 3 months for the first pair and after 1 month for the second pair. RESULTS: A significant reduction in pain intensity at both resting state and movement was noted in main groups compared to controls. CONCLUSION: Due to its therapeutic efficacy and good tolerability, melatonin may be regarded as a drug of choice in the complex treatment of chronic pain syndromes. Possible analgesic properties of melatonin and their mechanisms are discussed. PMID- 25042487 TI - [The possibilities of increasing of efficacy of treatment in patients with dorsalgia]. AB - OBJECTIVE: An influence of L-lysine aescinat on decrease of pain syndrome and normalization of movement's functions. MATERIAL AND METHODS. 220 patients with dorsalgia has been studied. To asses treatment efficacy the Huskisson's visual analog scale, multidimensional verbal and color test of pain and the modified Waddel's scale were used. RESULTS AND CONCLUSION: The results of the study revealed that the use of L-lysine aescinat promotes considerable acceleration of process of regression of a pain syndrome and the efficacious rehabilitation of movements and plays a significant role in faster and expressed knocking over of a radicular syndrome. PMID- 25042489 TI - [Tanakan in the treatment of cognitive and autonomic impairments and headache in young patients]. AB - OBJECTIVE: To determine the efficacy and tolerability of tanakan in the treatment of memory and attention impairments in young patients. MATERIAL AND METHODS: We studied 30 outpatients (24 women and 6 men, mean age 33,5+/-7,5 years) with headache, memory and attention impairments and decrease in mental working capacity. Treatment duration was 90 days. Patients received tanakan in dose 40 mg 3 times per day to restore cognitive function. The study design included 4 visits during which patients completed questionnaires and scales. RESULTS: All patients reported positive changes in mood, memory, information learning and working capacity. Headaches of tension decreased by 50%, vertigo and noise in ears became less intense, autonomic disturbances practically disappeared. No effect on the frequency of migrainous attacks was found. CONCLUSION: Tanakan is effective and safe for symptomatic therapy of cognitive impairment in any age, including young patients. PMID- 25042490 TI - [Dynamics of the extracranial blood flow in patients after posterior fossa surgery in sitting position]. AB - OBJECTIVE: To study the brachiocephalic blood flow in patients after posterior fossa surgery in sitting position. MATERIAL AND METHODS: We examined 60 patients (44 women and 16 men, mean age from 46.45+/-13.2 years) after the surgery of neurinomas and meningiomas. The study of neurological symptoms and cerebral blood flow as well as computed tomography of the brain were performed. RESULTS AND CONCLUSION: No changes in the extracranial blood flow were found in patients without pneumocephalus or with a small amount of air in the intracranial cavity. Pneumocephalus decreased the linear velocity of the blood flow in the postoperative period. A trend towards the restoration of the blood flow along the inner carotid artery on both sides up to the preoperative level was found in patients with common pneumocephalus 24-48h after the surgery. PMID- 25042491 TI - [Pathogenetic mechanisms of demyelinating diseases of the central nervous system in children]. AB - OBJECTIVE: To study cerebrospinal fluid and protein indices characterizing the permeability of the hematoencephalitic barrier and intrathecal immunoglobulin synthesis in children with different course and outcome of demyelinating diseases of the central nervous system. MATERIAL AND METHODS: We examined 72 children with demyelinating diseases of the central nervous system and 16 children of a control group (without neuroinfections). RESULTS: Differences in the concentration of myelin basic protein, immunoglobulin G, albumin and immunoglobulin indices in the cerebrospinal fluid were determined depending on acute, prolonged, chronic course of disseminated encephalitis and multiple sclerosis in children. The maximum value of the immunoglobulin index and the intrathecal immunoglobulin synthesis index was identified in multiple sclerosis. The correlations of cerebrospinal fluid indicators and protein factors in the acute period of demyelinating diseases and the formation of neurologic deficiency in the disease outcome were determined that can be used for prognostic purpose. CONCLUSION: The alterations in the indices obtained in this study can be included in the algorithm of laboratory examination. The results prove the involvement of various mechanisms in the pathogenesis of demyelinating diseases of the central nervous system in children. PMID- 25042492 TI - [Effect of valproic acid on SMN protein level in peripheral blood mononuclear cells of patients with spinal muscular atrophy and different SMN2 copy numbers]. AB - OBJECTIVE: Spinal muscular atrophy (SMA) is currently untreatable hereditary disorder caused by few types of mutations in the SMN1 gene and respective lack of gene's product - survival motor neuron protein (SMN). Last decade studies have shown that phenotype of the disorder is substantially influenced by copy numbers of homologous SMN2 gene; also, an ability of valproic acid to increase the level of SMN in vitro and in vivo has been shown. We investigated an effect of valproic acid on SMN level in peripheral blood mononuclear cells derived from patients with SMA and their parents and sought for possible predictors for treatment efficacy. MATERIAL AND METHODS: We examined 10 children with SMA and 6 their parents as heterozygous carriers of the mutation using appropriate molecular genetic techniques. Valproic acid was prescribed in 20mg/kg/day during 2 weeks. RESULTS AND CONCLUSION: There were no correlation between baseline SMN level and SMN2 copy number; both of the markers do not predict SMN level after the treatment with valproic acid. However, all of patients responded to valproic acid treatment with different grades of SMN level increase. Strong intrafamilial correlation was found for the SMN/Beta2-microglobulin ratio. PMID- 25042493 TI - [The comparative pattern of neuromidin and magnetic stimulation influence on neuroplasticity in experimental traumatic neuropathy]. AB - OBJECTIVE: Traumatic neuropathies are among the most actual problems in neurology due to the severe neurological deficit in most cases and poor prognosis of recovery. We evaluated the effect of ipidacrin (cholinesterase inhibitor) and magnetic stimulation on neuroplastic axonal changes after experimental neurotmesis of rat's sciatic nerve. MATERIAL AND METHODS: Animals (20 rats) were stratified into 3 groups. There was no treatment in the control group; in the second -group experimental animals underwent 3-5 min daily rhythmic magnetic stimulation (0,8-1T, 3 Hz) The third group of animals received intramuscular 0,035 mg of ipidacrin daily within 1 month. RESULTS AND CONCLUSIONS: Based on the received data on the restoration of myelin, axons, myelin nodes structure and lemmocyte ultrastructure), we have concluded that both magnetic stimulation and ipidacrin can trigger restorative and compensative processes in traumatic neuropathies. PMID- 25042494 TI - [An analysis of epidemiological indices of stroke based on the data of a regional population register from 2009 to 2012]. AB - OBJECTIVE: To study the dynamics of basic epidemiological sex- and age-related indices in the Russian Federation for 2009-2012. MATERIAL AND METHODS. The regions (administrative units, cities or city regions) with the population from 100 000 to 200 000 people were selected. The total population was 10 373 279 people. The indices were evaluated using the uniform method developed by the National stroke association. RESULTS: Incidence and fatality in men and women older than 25 years and able-bodied people (25-59 years) was analyzed using European standards. CONCLUSIONS: The incidence of stroke decreased regardless of sex and age from 2010 to 2012. There was a trend towards the decrease in fatality in men and women older than 25 years. Incidence and fatality were lower in women compared to men. PMID- 25042495 TI - [Cognitive functions in patients with chronic heart failure]. AB - OBJECTIVE: To evaluate cognitive functions in patients with different stages of chronic heart failure (CHF) and different degrees of stenosis of precerebral arteries. MATERIAL AND METHODS: Authors examined 148 patients with CHF and 21 patients without CHF (controls). Neuropsychological assessment (NINDS-Canadian Stroke Standards - 30 minutes protocol), ultrasound scanning of the main cranial arteries and transcranial dopplerography and echocardiogram were made. RESULTS AND CONCLUSION: Patients with CHF more frequently had combined (multifocal) cognitive impairment. Patients with systolic heart failure performed significantly worse on neuropsychological tests, in particular, functional domains within the frontal lobes and "executive" dysfunction, than those with diastolic heart failure. Cognitive impairment in patients with CHF was associated with the lower left ventricular ejection fraction and deterioration in indices of diastolic function but not with carotid artery stenosis. PMID- 25042496 TI - [Clinical characteristics of hypertensive encephalopathy in the perimenopausal period]. AB - OBJECTIVES: To study correlations between symptoms of hypertensive encephalopathy (HE), structural MRI changes of the brain and affective disorders in the perimenopausal period. MATERIALS AND METHODS: A study included 150 women who have been through natural menopause (group 1) and 100 women in the premenopausal (group 2). Somatic and neurological examination, MRI and psychometric scales for anxiety and depression were used. RESULTS AND CONCLUSIONS: Women with hypertensive encephalopathy in the postmenopausal period had signs of persistent psycho-emotional disorders (higher anxiety, depression of different severity) combined with structural changes in the brain, with their severity increasing with the progression of HE. PMID- 25042497 TI - [Primary progressive aphasias]. AB - Primary progressive aphasias (PPA) is a heterogeneous group of neurodegenerative disorders related to focal degenerations of the brain which are characterized by continuous loss of speech. According to the Classification developed by the International body of experts, 3 main variants of PPA are singled out: agrammatic, logopenic and semantic. This stratification is based on the differences in clinical features of speech defect, neuroimaging and pathomorphological data. The search for treatment strategies is related with putative neurochemical deficit but the results of clinical trials on the efficacy of different drugs remain unequivocal. PMID- 25042498 TI - [Confusion (delirium) in elderly patients of a general hospital]. AB - Objective. Confusion in elderly patients is an urgent problem due to its high frequency both in psychiatric hospitals and general clinics. Authors studied the frequency of confusion, the psychopathological structure of these conditions and risk factors for their development in old age in elderly patients of a multiprofile hospital. Material and methods. 187 elderly patients (over 65 years old) were examined using psychopathological method, computed tomography (CT and MRI). Epidemiological evaluation of the cohort was performed as well. Results and conclusion. The frequency of confusion was 2.8% of the total number of inpatients (n=6788). Several psychopathological variants of confusion were singled out: delirious confusion (37.9%), amentia syndrome 18.7%, confabulation confusion (11.8%) and undifferentiated exogenous-organic psychosis (31.6%). The following factors were shown to increase the risk of confusion: the age above 85 years old, previous diagnosis of dementia or encephalopathy, comorbid pneumonia or urological infections. Confusion was most frequent in therapeutic and neurological departments. PMID- 25042499 TI - [Comparative efficacy and safety of antidepressant mono- and multimodal therapy in elderly patients with depression (a clinical experience in a psychogeriatric hospital)]. AB - Objective. A comparative evaluation of the efficacy and safety of a multimodal antidepressant therapy with venlafaxine plus cerebrolysin and monotherapy with the same antidepressant for the treatment of depression in elderly patients in a psychiatric hospital. Material and methods. Two groups of patients (20 patients in each group), aged 60 years and older (60 to 79 years), were studied. The groups were matched for demographic and clinical (severity of depressive episode) characteristics. Patients of the first group were treated with venlafaxine in dose 75-150 mg twice a day. Patients of the second group received additionally 20 intravenous infusions of cerebrolysin (20.0 ml in 100 ml isotonic sodium chloride solution). Results. Therapeutic effect of antidepressant therapy (56 days) was characterized by a good balanced profile in relation to symptoms of depression, anxiety and apathy in both groups. However, the use of multimodal therapy allowed to get the more rapid response and more pronounced therapeutic effect compared to monotherapy with the same antidepressant, as well as to reduce adverse events. Conclusion. The results obtained allow to recommend multimodal antidepressant therapy with venlafaxine and cerebrolysin for using in hospital practice to achieve a more rapid therapeutic response, reduce the risk of adverse effects of antidepressants and shorten a period of hospitalization. PMID- 25042500 TI - [Clinical, neuropsychological and neuroimaging features of patients with mixed dementia]. AB - Objective. Mixed dementia (MD), characterized by a combination of Alzheimer's disease (AD) and cerebrovascular disease, is one of the most common and, at the same time, poorly diagnosed forms of dementia in the elderly. The aim of our study was to investigate features of AD with its combination with cerebrovascular disease on the basis of clinical, neuropsychological and neuroimaging data. Material and methods. Authors examined 79 patients with dementia: 30 patients with AD, 33 patients with MD and 16 patients with vascular dementia. Patients with MD were older, had more often frontal gait disorders (48.5%), postural instability (45%), pseudobulbar syndrome (60%). Results and conclusion. The neuropsychological profile of patients with MD had mixed amnestic-dysexecutive character and, depending on the severity of vascular pathology, in some cases was closer to AD and in others to vascular dementia. A negative effect of vascular risk factors on medial temporal atrophy was found. Neuroimaging changes in MD were correlated with clinical manifestations. Proposed approaches to the diagnosis of MD help to determine more precisely the main directions of the treatment of patients and predict the course of the disease. PMID- 25042501 TI - [Clinical evaluation of Parkinson's disease progression]. AB - Objective. We conducted a prospective study on the dynamics of clinical progression of motor and non-motor impairments in PD from 2009 to 2012. Material and methods. We examined 136 patients with Parkinson's disease, 77 men and 59 women, mean age 63.2+/-10.4 years, disease duration 7.5+/-3.8 years, including 50 (36.8%) patients at the mild stage of disease, 67 (49.3%) patients at the moderate stage and 19 (13.9%) patients at the advanced stage. Evaluation of progression was carried out annually using part III UPDRS: an annual increase of 9 scores or more indicated the fast progression; from 5 to 8 scores - moderate progression; up to 4 scores - slow progression. Results. Eighty-five patients (62.5%) had slow progression, 39 patients (27.1%) had moderate progression and 12 patients (10.4%) had fast progression. Conclusion. Older age, severity of axial movement disorders, cognitive impairment and motor fluctuations, orthostatic hypotension and psychotic disorders (hallucinations) predicted the fast progression. PMID- 25042502 TI - [Freezing of gait in patients with Parkinson's disease]. AB - Objective. Freezing of gait (FOG) are the brief episodes of voluntary movement blocks in Parkinson's disease and other variants of parkinsonism, which limit patient's mobility and decrease quality of life. Pathogenesis of FOG is still unclear. Authors studied characteristics of FOG in different stages of PD. Material and methods. Seventy patients were examined using different scales for assessment of clinical features. We measured the length, speed and cadence of gait and carried out a kinematic analysis of movements and stabilometry. Results and conclusion. FOG were found in 34.3% patients with PD, most of them were in advanced and late stages. FOG in off-periods were observed in 2/3 patients treated with levodopa, 1/3 of patients did not relate FOG with the periods of levodopa action. Turn and start FOG were noted more often. In patients with FOG, there were more expressed Parkinson's signs, especially axial symptoms, and more frequent urination disorders. The reduced speed of gait and asymmetry of gait were found as well. The kinematic analysis of gait revealed a correlation between the frequency of FOG and periods of support (and double support). PMID- 25042503 TI - [Mental disorders of cognitive and non-cognitive spectrum in the elderly caregivers of the patients with Alzheimer's disease]. AB - OBJECTIVE: To study the structure and prevalence of cognitive and non-cognitive mental disorders in the elderly caregivers of the patients with Alzheimer's disease (AD). MATERIAL AND METHODS: We compared two groups of people: 59 caregivers living with AD patients who were not their blood relatives (group 1) and 20 first-degree relatives of AD patients who lived separately and were not caregivers (group 2). RESULTS: In group 1, the frequency of depression was 35,2% and in group 20,0% (p<0,05). Behavioral and psychotic disorders in the patient, in particular, excitement, anxiety, sleep disorders, irritability and apathy, were risk factors of depression in caregivers. Mild cognitive impairment was identified in 16% in group 1 and in 10% in group 2 (p<0,05). CONCLUSION: Caregiving to the patient with AD is a risk factor for depression disorders in the old age. People who are at risk need special medical, social and psychological care. PMID- 25042504 TI - [A comparative study of the efficacy of deep brain stimulation of the subthalamic nucleus and pharmacological treatment in advanced Parkinson's disease]. AB - Objective. To assess the clinical efficacy of deep brain stimulation (DBS STN) of the subthalamic nucleus in patients with Parkinson's disease (PD) compared to pharmacological treatment. Material and methods. DBS STN was applied to 22 patients (mean age 53.2 years, mean disease duration 9,6 years). The control group included 28 patients (mean age 54.2 years, mean disease duration 9,6 years) with PD who received pharmacological treatment. Patients were examined in OFF medication and ON-medication conditions at 3, 6, 9, 12, 24, 36 months. The Unified Parkinson's Disease Rating Scale (UPDRS) part II, III, IV, the Hoehn and Yahr scale, the Schwab and England Scale, PDQ-39, the Hamilton Rating Scale for depression and the Spielberger Anxiety Scale were administered. All patients had motor fluctuations and dyskinesias. Results and conclusion. We demonstrated that DBS STN improved UPDRS II, III scores, reduced dyskinesias and motor fluctuations. After surgery, dopaminergic therapy was reduced by approximately 54.5%. In the control group, levodopa dose was increased by 20.5% to 36th month. PMID- 25042505 TI - [The efficacy of piribedyl in chronic vascular encephalopathy with mild cognitive impairment]. AB - OBJECTIVE: Cognitive impairment is a main symptom of chronic vascular encephalopathy (CVE) that impact the severity of illness. Symptomatic treatment is needed for the improvement of cognitive functions and quality of life. We studied the efficacy of piribedyl in patients with severe CVE. MATERIAL AND METHODS: Thirty-six patients with mild cognitive impairment who met diagnostic criteria for CVE were enrolled. Patients were stratified into 3 groups: two groups received piribedyl in dose 50 mg per day during 3 months as monotherapy (group 1) or in the combination with ginkgo biloba in dose 240 mg per day (group 2). RESULTS AND CONCLUSION: Piribedyl reduced cognitive impairment and improved quality of life. Comorbid affective disorders can predict the effect of piribedyl on cognitive impairment in CVE. The similar efficacy of piribedyl was noted for monotherapy and in combination with ginkgo biloba. PMID- 25042506 TI - [Possibilities using prolonged release dopamine receptor agonists in elderly and old age]. AB - Treatment efficacy of Parkinson's disease has been essentially improved due to the introduction of dopamine receptors agonists to clinical practice. However, these drugs are not recommended to patients over 70 years because of the high probability of side-effects that significantly reduce therapeutic opportunities in elderly patients. It is known, that many dopaminergic side-effects are due to unstable and high peak concentrations of drugs. Application of prolonged forms of dopamine receptors agonists, and careful selection of elderly patients, allows to use these drugs as safely, as in patients of middle age. This fact has been proved by several clinical trials. Criteria for selection of elderly patients for treatment with dopamine receptors agonists are: the absence of severe cognitive disturbances, REM-sleep behavioral disorders, orthostatic hypotension, frequent falling and decompensated somatic diseases. PMID- 25042507 TI - [REM sleep behavior disorders in Parkinson's disease]. AB - The article presents a literature review on REM sleep behavior disorder (RBD). The loss of REM atonia of sleep, such that patients act out the contents of their dreams, is described. The most important implication of research into this area is that patients with idiopathic RBD are at very high risk of developing synuclein-mediated neurodegenerative disease (Parkinson's disease, dementia with Lewy bodies and multiple system atrophy), with risk estimates that approximate 40 65% at 10 years. Thus, RBD is a reliable marker of prodromal synucleinopathy that open possibilities for neuroprotective therapy. PMID- 25042508 TI - [Methods of rehabilitation in Parkinson's disease]. AB - The review of literature addresses the problems of rehabilitation in Parkinson's disease (PD). In the last decade, evidence of effectiveness of training balance and gait for increasing mobility and activities of daily living in PD patients has been demonstrated. In addition, the data on the possible impact of the training on launching and strengthening of mechanisms of neuroprotection and neuroplasticity in PD has been proved. All this facts indicate the importance of rehabilitation in PD in the early stage of the disease. However, despite a large number of studies, there are many open questions in the choice of a rehabilitation program with the use of different methodology, duration and frequency of training, performance assessment. Follow-up studies are warranted to develop common practical guidelines for the rehabilitation of patients with PD. PMID- 25042509 TI - [Cerebral amyloid angiopathy]. AB - Cerebral amyloid angiopathy (CAA) is characterized by the deposition of Beta amyloid protein in the media and adventitia of small arteries and capillaries. It may be an independent disease, but is often combined with Alzheimer's disease (AD). This review will discuss up-to-date understanding of the pathophysiology, clinical manifestations of CAA, its diagnosis with neuroimaging and biomarkers. Cerebral microbleeds (CMBs) may be considered as neuroimaging markers of AD and CAA. The clinical significance of CAA is defined by the risk of intracerebral hemorrhages during thrombolytic therapy and warfarin therapy in patients with acute myocardial infarction, pulmonary embolism, ischemic stroke. PMID- 25042510 TI - [New approaches to diagnosis and treatment of Parkinson's disease (an overview of abstracts of the World Congress "Parkinsonism and other movement disorders"]. PMID- 25042511 TI - The effect of kiwifruit (Actinidia deliciosa) cysteine protease actinidin on the occludin tight junction network in T84 intestinal epithelial cells. AB - Actinidin, a kiwifruit cysteine protease, is a marker allergen for genuine sensitization to this food allergen source. Inhalatory cysteine proteases have the capacity for disruption of tight junctions (TJs) enhancing the permeability of the bronchial epithelium. No such properties have been reported for allergenic food proteases so far. The aim was to determine the effect of actinidin on the integrity of T84 monolayers by evaluating its action on the TJ protein occludin. Immunoblot and immunofluorescence were employed for the detection of occludin protein alterations. Gene expression was evaluated by RT-PCR. Breach of occludin network was assessed by measuring transepithelial resistance, blue dextran leakage and passage of allergens from the apical to basolateral compartment. Actinidin exerted direct proteolytic cleavage of occludin; no alteration of occludin gene expression was detected. There was a reduction of occludin staining upon actinidin treatment as a consequence of its degradation and dispersion within the membrane. There was an increase in permeability of the T84 monolayer resulting in reduced transepithelial resistance, blue dextran leakage and passage of allergens actinidin and thaumatin-like protein from the apical to basolateral compartment. Opening of TJs by actinidin may increase intestinal permeability and contribute to the process of sensitization in kiwifruit allergy. PMID- 25042512 TI - Exposure assessment approach through mycotoxin/creatinine ratio evaluation in urine by GC-MS/MS. AB - In this pilot survey human urine samples were analyzed for presence of 15 mycotoxins and some of their metabolites using a novel urinary multi-mycotoxin GC MS/MS method following salting-out liquid-liquid extraction. Fifty-four urine samples from children and adults residents in Valencia were analyzed for presence of urinary mycotoxin and expressed in gram of creatinine. Three out of 15 mycotoxins were detected namely, HT-2 toxin, nivalenol and deoxynivalenol (DON). 37 samples showed quantifiable values of mycotoxins. Co-occurrence of these contaminants was also observed in 20.4% of assayed samples. DON was the most frequently detected mycotoxin (68.5%) with mean levels of 23.3 MUg/g creatinine (range: 2.8-69.1 MUg/g creatinine). The levels of urinary DON were used to carry out an exposure assessment approach. 8.1% of total subjects were estimated to exceed the DON provisional maximum tolerable daily intake (PMTDI) (1 MUg/kg b.w.). Two out of 9 exposed children exceeded the DON PMTDI thus, making them the most exposed based on the urinary results. PMID- 25042513 TI - Cancer risk due to contamination: consideration from market basket survey in Qatar. PMID- 25042514 TI - Protection of centre spin coherence by dynamic nuclear spin polarization in diamond. AB - We experimentally investigate the protection of electron spin coherence of a nitrogen-vacancy (NV) centre in diamond by dynamic nuclear spin polarization (DNP). The electron spin decoherence of an NV centre is caused by the magnetic field fluctuation of the (13)C nuclear spin bath, which contributes large thermal fluctuation to the centre electron spin when it is in an equilibrium state at room temperature. To address this issue, we continuously transfer the angular momentum from electron spin to nuclear spins, and pump the nuclear spin bath to a polarized state under the Hartmann-Hahn condition. The bath polarization effect is verified by the observation of prolongation of the electron spin coherence time (T). Optimal conditions for the DNP process, including the pumping pulse duration and repeat numbers, are proposed by numerical simulation and confirmed by experiment. We also studied the depolarization effect of laser pulses. Our results provide a new route for quantum information processing and quantum simulation using the polarized nuclear spin bath. PMID- 25042515 TI - Size matters! On the way to ionic liquid systems without ion pairing. AB - Several, partly new, ionic liquids (ILs) containing imidazolium and ammonium cations as well as the medium-sized [NTf2 ](-) (0.230 nm(3) ; Tf=CF3 SO3 (-) ) and the large [Al(hfip)4 ](-) (0.581 nm(3) ; hfip=OC(H)(CF3 )2 ) anions were synthesized and characterized. Their temperature-dependent viscosities and conductivities between 25 and 80 degrees C showed typical Vogel-Fulcher-Tammann (VFT) behavior. Ion-specific self-diffusion constants were measured at room temperature by pulsed-gradient stimulated-echo (PGSTE) NMR experiments. In general, self-diffusion constants of both cations and anions in [Al(hfip)4 ](-) based ILs were higher than in [NTf2 ](-) -based ILs. Ionicities were calculated from self-diffusion constants and measured bulk conductivities, and showed that [Al(hfip)4 ](-) -based ILs yield higher ionicities than their [NTf2 ](-) analogues, the former of which reach values of virtually 100 % in some cases.From these observations it was concluded that [Al(hfip)4 ](-) -based ILs come close to systems without any interactions, and this hypothesis is underlined with a Hirshfeld analysis. Additionally, a robust, modified Marcus theory quantitatively accounted for the differences between the two anions and yielded a minimum of the activation energy for ion movement at an anion diameter of slightly greater than 1 nm, which fits almost perfectly the size of [Al(hfip)4 ](-) . Shallow Coulomb potential wells are responsible for the high mobility of ILs with such anions. PMID- 25042516 TI - Alfred Jaretzki III, MD. PMID- 25042517 TI - Genetic variations are associated with lymph node metastasis in colorectal cancer patients. AB - BACKGROUND AND OBJECTIVES: Regional lymph nodes (LNs) are believed to be a first line barrier against tumor metastasis. However, it remains unclear whether underlying genetic factors exist and affect LN metastasis risk. We therefore evaluated inherited risk variants using single nucleotide polymorphisms (SNPs) in pathological T3 colorectal cancer patients in the absence or presence of LN metastasis. METHODS: The study population comprised 629 retrospectively collected colorectal cancer samples between 2000 and 2009 in a single hospital, including 273 patients with LN metastasis and 355 control subjects without LN metastasis. We analyzed 87 SNPs in genes that are associated with susceptibility to carcinogenesis or metastasis in colorectal or other cancers. RESULTS: Only 11 SNPs were found to have significant genotype distribution differences between the cases and controls. The average number of risk alleles carried by patients with LN metastasis was 7 (6.6 +/- 1.4; range 2-10), which was significantly higher than the 6 risk alleles that were carried on average by patients without LN metastasis (6.0 +/- 1.6; range 0-10; P < 0.001). CONCLUSIONS: Certain SNPs can increase genetic susceptibility to LN metastasis. As the number of risk alleles increases, the risk of LN metastasis also increases, although the difference is subtle. PMID- 25042518 TI - Lipid tail protrusions mediate the insertion of nanoparticles into model cell membranes. AB - Recent work has demonstrated that charged gold nanoparticles (AuNPs) protected by an amphiphilic organic monolayer can spontaneously insert into the core of lipid bilayers to minimize the exposure of hydrophobic surface area to water. However, the kinetic pathway to reach the thermodynamically stable transmembrane configuration is unknown. Here, we use unbiased atomistic simulations to show the pathway by which AuNPs spontaneously insert into bilayers and confirm the results experimentally on supported lipid bilayers. The critical step during this process is hydrophobic-hydrophobic contact between the core of the bilayer and the monolayer of the AuNP that requires the stochastic protrusion of an aliphatic lipid tail into solution. This last phenomenon is enhanced in the presence of high bilayer curvature and closely resembles the putative pre-stalk transition state for vesicle fusion. To the best of our knowledge, this work provides the first demonstration of vesicle fusion-like behaviour in an amphiphilic nanoparticle system. PMID- 25042519 TI - Diabetes self-management support for patients with low health literacy: Perceptions of patients and providers. AB - BACKGROUND: The aim of the present study was to explore perceptions and strategies of health care providers regarding diabetes self-management support for patients with low health literacy (LHL), and to compare their self-management support with the needs of patients with LHL and type 2 diabetes. This study serves as a problem analysis for systematic intervention development to improve diabetes self-management among patients with LHL. METHODS: This qualitative study used in-depth interviews with general practitioners (n = 4), nurse practitioners (n = 5), and patients with LHL (n = 31). The results of the interviews with health care providers guided the patient interviews. In addition, we observed 10 general practice consultations. RESULTS: Providers described patients with LHL as uninvolved and less motivated patients who do not understand self-management. Their main strategy to improve self-management was to provide standard information on a repeated basis. Patients with LHL seemed to have a different view of diabetes self-management than their providers. Most demonstrated a low awareness of what self-management involves, but did not express needing more information. They reported several practical barriers to self-management, although they seemed reluctant to use the information provided to overcome them. CONCLUSIONS: Providing and repeating information does not fit the needs of patients with LHL regarding diabetes self-management support. Health care providers do not seem to have the insight or the tools to systematically support diabetes self-management in this group. Systematic intervention development with a focus on skills-based approaches rather than cognition development may improve diabetes self-management support of patients with LHL. PMID- 25042520 TI - Designing multi-branched gold nanoechinus for NIR light activated dual modal photodynamic and photothermal therapy in the second biological window. AB - Gold nanoechinus can sensitize the formation of singlet oxygen in the first and the second near-infra red (NIR) biological windows and exert in vivo dual modal photodynamic and photothermal therapeutic effects (PDT and PTT) to destruct the tumors completely. This is the first literature example of the destruction of tumors in NIR window II induced by dual modal nanomaterial-mediated photodynamic and photothermal therapy (NmPDT & NmPTT). PMID- 25042521 TI - Inhibitory effect of apocynin on methylglyoxal-mediated glycation in osteoblastic MC3T3-E1 cells. AB - Methylglyoxal (MG), a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress or inflammation. The present study investigated the effects of apocynin on the mechanisms associated with MG toxicity in osteoblastic MC3T3-E1 cells. Pretreatment of MC3T3-E1 cells with apocynin prevented the MG-induced protein glycation and formation of intracellular reactive oxygen species and mitochondrial superoxide in MC3T3-E1 cells. In addition, apocynin increased glutathione levels and restored the activity of glyoxalase I inhibited by MG. These findings suggest that apocynin provide a protective action against MG-induced cell damage by reducing oxidative stress and by increasing the MG detoxification system. Apocynin treatment decreased the levels of proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6 induced by MG. Additionally, the nitric oxide level reduced by MG was significantly increased by apocynin. These findings indicate that apocynin might exert its therapeutic effects via upregulation of glyoxalase system and antioxidant activity. Taken together, apocynin may prove to be an effective treatment for diabetic osteopathy. PMID- 25042523 TI - Functional and radiographic consideration of lower limb malalignment in children and adolescents with idiopathic genu valgum. AB - Three-dimensional gait analysis is capable of assessing dynamic load characteristics and the resulting compensatory effects of lower limb malalignment, which are generally not reflected in static imaging. This study determined differences in gait parameters in the frontal and transverse plane between patients and controls in order to identify compensatory mechanisms, and to correlate radiographic measurements and gait parameters in a consecutive series of children with idiopathic genu valgum. Thirty-three patients (mean age 12.3 years) were retrospectively reviewed and compared to a healthy control group. Children with genu valgum demonstrated significantly decreased internal knee valgus moments, shifting into varus moments. Furthermore, significantly different transverse plane gait patterns (decreased external knee rotation, increased external hip rotation) were observed. These patterns showed a relevant influence on the frontal knee moments, with knee rotation and foot progression angle showing the highest predictive value for changes and possible compensation of frontal knee moments. The correlation between commonly used radiographic measurements (i.e., mechanical axis deviation) and findings of the gait analysis was only low. Besides showing decreased internal knee valgus moments, our results suggest that considerable compensatory gait mechanisms may be present in children with idiopathic genu valgum to reduce joint loading. PMID- 25042522 TI - Rehabilitation versus Nursing Home Nurses' Low Back and Neck-Shoulder Complaints. AB - PURPOSE: To compare the prevalence of those complaints in nurses working in rehabilitation departments and nursing homes, and to evaluate factors associated with them. DESIGN: A cross-sectional study in rehabilitation and in nursing home departments. METHODS: Data were obtained from questionnaires relating to basic demographics, prevalence of musculoskeletal complaints, potentially harmful positions and actions and job satisfaction. FINDINGS: Multivariate analyses demonstrated higher work-related musculoskeletal complaints for nurses in rehabilitation than nursing home nurses (p=.012 for low back pain; p<.001 for neck-shoulder pain). Trunk bending, static posture, repetitive tasks, and recognition of superiors were associated with low back pain. Freedom to choose work techniques and degree of diversity at work were associated with neck shoulder pain. CONCLUSIONS: Differences between the nurse groups as to work tasks might be a reason for differences in musculoskeletal complaints. Further comparisons between nurses working in different fields might reveal more accurate potential risk factors for work-related musculoskeletal complaints. CLINICAL RELEVANCE: Instruction for static/awkward posture avoidance, by using mechanical aids and designing a friendlier environment, should be part of a nursing staff injury prevention strategy. PMID- 25042524 TI - Trends and variations in the use of adjuvant therapy for patients with head and neck cancer. AB - BACKGROUND: The National Comprehensive Cancer Network guidelines recommend that patients with surgically resected head and neck cancers that have adverse pathologic features should receive adjuvant therapy in the form of radiotherapy (RT) or chemoradiation (CRT). To the authors' knowledge, the current study is the first analysis of temporal trends and use patterns of adjuvant therapy for these patients. METHODS: Patients with head and neck cancer and adverse pathologic features were identified in the National Cancer Data Base (1998-2011). Data were analyzed using chi-square, Student t, and log-rank tests; multivariate logistic regression; and Cox multivariate regression. RESULTS: A total of 73,088 patients were identified: 41.5% had received adjuvant RT, 33.5% had received adjuvant CRT, and 25.0% did not receive any adjuvant therapy. From 1998 to 2011, the increase in the use of adjuvant CRT was greatest for patients with oral cavity (6-fold) and laryngeal (5-fold) cancers. Multivariate analysis demonstrated that Medicare/Medicaid insurance (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.01-1.11), distance >=34 miles from the cancer center (OR, 1.66; 95% CI, 1.59-1.74), and academic (OR, 1.26; 95% CI, 1.20-1.31) and high-volume (OR, 1.10; 95% CI, 1.05-1.15) centers were independently associated with patients not receiving adjuvant therapy. Receipt of adjuvant therapy was found to be independently associated with improved overall survival (hazard ratio, 0.84; 95% CI, 0.81-0.86). CONCLUSIONS: Approximately 25% of patients are not receiving National Comprehensive Cancer Network guideline-directed adjuvant therapy. Patient-level and hospital-level factors are associated with variations in the receipt of adjuvant therapy. Further evaluation of these differences in practice patterns is needed to standardize practice and potentially improve the quality of care. Cancer 2014;120:3353-3360. (c) 2014 American Cancer Society. PMID- 25042525 TI - Rh2 (S-1,2-NTTL)4 : A novel Rh2 (S-PTTL)4 analog with lower ligand symmetry for asymmetric synthesis of chiral cyclopropylphosphonates. AB - A new series of dirhodium(II) tetracarboxylate was derived from N-1,2-naphthaloyl (S)-amino acid ligands. In terms of enantioselectivity, Rh2 (S-1,2-NTTL)4 () derived from N-1,2-naphthaloyl-(S)-tert-leucine, was the best-performing catalyst among the new series in the enantioselective synthesis of cyclopropylphosphonate derivatives (up to >99% enantiomeric excess). A predictive model was proposed to justify the observed high enantiomeric induction exhibited by Rh2 (S-1,2-NTTL)4 with donor-acceptor phosphonate carbenoids. PMID- 25042526 TI - Synthesis of meso-pyrrole-substituted 22-oxacorroles by a "3+2" approach. AB - Unsymmetrical 22-oxacorrole containing two aryl groups and one pyrrole group at the meso position was synthesized by condensing one equivalent of 16 oxatripyrrane with one equivalent of meso aryl dipyromethane under mild acid catalyzed conditions followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4 benzoquinone (DDQ). This [3+2] condensation approach was expected to yield meso free 25-oxasmaragdyrin but unexpectedly afforded unsymmetrical meso-pyrrole substituted 22-oxacorrole. We demonstrated the versatility of the reaction by synthesizing four new meso-pyrrole-substituted 22-oxacorroles. The reactivity of alpha-position of meso-pyrrole was tested by carrying out various functionalization reactions such as bromination, formylation, and nitration and obtained the functionalized meso-pyrrole-substituted 22-oxacorroles in decent yields. The X-ray structure obtained for one of the functionalized meso-pyrrole substituted 22-oxacorrole revealed that the macrocycle was nearly planar and the meso-pyrrole was in the perpendicular orientation with respect to the macrocyclic plane. The meso-pyrrole-substituted 22-oxacorroles absorb strongly in 400-700 nm region with one strong Soret band and four weak Q bands. The 22-oxacorroles are strongly fluorescent and showed emission maxima at ~650 nm with decent quantum yields and singlet-state lifetimes. The 22-oxacorroles are redox-active and exhibited three irreversible oxidations and one or two reversible reduction(s). A preliminary biological study indicated that meso-pyrrole corroles are biocompatible. PMID- 25042527 TI - A severe equine herpesvirus type 1 (EHV-1) abortion outbreak caused by a neuropathogenic strain at a breeding farm in northern Germany. AB - A particularly severe equine herpesvirus type 1 (EHV-1) abortion outbreak occurred at a breeding farm in northern Germany. Sixteen of 25 pregnant mares that had received regular vaccination using an inactivated vaccine aborted and two gave birth to weak non-viable foals in a span of three months, with 89% of cases occurring within 40 days after the initial abortion case. Virological examinations revealed the presence of EHV-1 in all cases of abortion and serological follow-up in mares confirmed recent infection. Molecular studies identified a neuropathogenic variant (Pol/ORF30 A2254 to G2254) that belonged to geographical group 4 of EHV-1 isolates. The abortion outbreak was preceded by a case of mild ataxia of unknown cause in a mare that aborted four months after the ataxic episode. Although vaccination of pregnant mares did not prevent abortion, good EHV-1 immune status of the population at the time of outbreak may have had an impact in the failure of manifestation of the neurological form of the disease. PMID- 25042528 TI - Molecular epidemiology of H9N2 influenza viruses in Northern Europe. AB - Low pathogenic avian influenza viruses are maintained in wild bird populations throughout the world. Avian influenza viruses are characterized by their efficient ability to reassort and adapt, which enables them to cross the species barrier and enhances their zoonotic potential. Influenza viruses of the H9N2 subtype appear endemic among poultry in Eurasia. They usually exist as low pathogenic strains and circulate between wild bird populations, poultry and birds sold at live bird markets. Direct transmission of H9N2 viruses, with receptor specificities similar to human influenza strains, to pigs and humans has been reported on several occasions. H9N2 virus was first encountered in Finland in 2009, during routine screening of hunted wild waterfowl. The next year, H9N2 influenza viruses were isolated from wild birds on four occasions, including once from a farmed mallard. We have investigated the relationship between the reared and wild bird isolates by sequencing the hemagglutinin and the neuraminidase genes of the Finnish H9N2 viruses. Nucleotide sequence comparison and phylogenetic analyses indicate that H9N2 was transmitted from wild birds to reared birds in 2010, and that highly identical strains have been circulating in Europe during the last few years. PMID- 25042529 TI - Sheep as an important source of E. coli O157/O157:H7 in Turkey. AB - Escherichia coli O157:H7 is a globally important foodborne pathogen and has been mainly associated with cattle as the reservoir. However, accumulating data shows the importance of sheep as an E. coli O157:H7 vehicle. The presence of E. coli O157/O157:H7 in recto-anal mucosal swap and carcass sponge samples of 100 sheep brought to the slaughterhouse in Kirikkale were analyzed over a year. Molecular characteristics (stx1, stx2, eaeA, hly, lpfA1-3, espA, eae-alpha1, eae-alpha2, eae-beta, eae-beta1, eae-beta2, eae-gamma1, eae-gamma2/theta, stx1c, stx1d, stx2c, stx2d, stx2e, stx2f, stx2g, blaampC, tet(A), tet(B), tet(C), tet(D), tet(E), tet(G), sul1, sul2, floR, cmlA, strA, strB and aadA) of 79 isolates were determined and minimum inhibitory concentrations of 20 different antibiotics were investigated. E. coli O157/O157:H7 was found in 18% of sheep included in the study and was more prevalent in yearlings than lambs and mature sheep, and male than female sheep, though none of the categories (season, sex or age range) had significant effect on prevalence. Furthermore, Shiga-toxigenic E. coli (STEC) O157:H7 was determined in 2% and 8% of sheep feces and carcasses, respectively. Additionally, lpfA1-3 and eae-gamma1 were detected in all isolates. None of the isolates showed resistance against investigated antibiotics, even though 4 sorbitol fermenting E. coli O157 isolates were positive for tet(A), sul1 and aadA. This is the first study in Turkey that reveals the potential public health risk due to the contamination of sheep carcasses with potentially highly pathogenic STEC O157:H7 strains. PMID- 25042531 TI - Setting the research agenda for ENT, hearing and balance: the GENERATE project. PMID- 25042532 TI - The 'dizzy child': a 12-minute consultation. PMID- 25042533 TI - Re: An analysis of emerging antimicrobial resistance in an ENT outpatient department: a comparison of three hundred and forty-nine swabs taken in 2007 with five hundred and seventy-four swabs in 2012. PMID- 25042534 TI - Brain not processing: is finding a role for BNP in sepsis like fitting a square peg into a round hole? AB - Since its introduction to the intensive care setting a decade ago, B-type natriuretic peptide has been the focus of studies in different areas (in particular, sepsis). With this biomarker, as with many newly identified biomarkers, its diagnostic performance was pursued initially and then its ability to predict outcomes. Despite all the efforts, results have not been consistent and the applications of B-type natriuretic peptide in the intensive care setting remain by and large academic. Will such studies one day become clinical practice? Or are we too obsessed with finding a place for every biomarker? PMID- 25042535 TI - Extent and mechanisms of brominated flame retardant emissions from waste soft furnishings and fabrics: A critical review. AB - Use of brominated flame retardants (BFRs) in soft furnishings has occurred for over thirty years with the phase out of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) only relatively recently begun. As products treated with BFRs reach the end of their lifecycle they enter the waste stream, thereby constituting an important and increasing reservoir of these chemicals. This review highlights the dearth of data on the extent and potential mechanisms of BFR emissions from waste soft furnishings. However, insights into what may occur are provided by scrutiny of the larger (though still incomplete) database related to BFR emissions from electronic waste (e-waste). In many countries, municipal landfills have historically been the primary disposal method of waste consumer products and therefore represent a substantial reservoir of BFRs. Published data for BFR emissions to both air and water from landfill and other waste disposal routes are collated, presented and reviewed. Reported concentrations of PBDEs in landfill leachate range considerably from <1ngL(-1) to 133,000ngSigmaPBDEL(-1). In addition to direct migration of BFRs from waste materials; there is evidence that some higher brominated flame retardants are able to undergo degradation and debromination during waste treatment, that in some instances may lead to the formation of more toxic and bioavailable compounds. We propose that waste soft furnishings be treated with the same concern as e-waste, given its potential as a reservoir and source of environmental contamination with BFRs. PMID- 25042536 TI - Assessing the hydration free energy of a homologous series of polyols with classical and quantum mechanical solvation models. AB - Molecular dynamics (MD) simulations associated with the thermodynamic integration (TI) scheme and the polarizable continuum model (PCM) in combination with the SMD solvation model were used to study the hydration free energy of the homologous series of polyols, C(n)H(n+2)(OH)n (1 <= n <= 7). Both solvation models predict a nonlinear behavior for the hydration free energy with the increase of the number of hydroxyl groups. This study also indicates that there is a sizable solute polarization in aqueous solution and that the inclusion of the polarization effect is important for a reliable description of the free energy differences considered here. PMID- 25042537 TI - Volcano-like behavior of Au-Pd core-shell nanoparticles in the selective oxidation of alcohols. AB - Gold-palladium (AuPd) nanoparticles have shown significantly enhanced activity relative to monometallic Au and Pd catalysts. Knowledge of composition and metal domain distributions is crucial to understanding activity and selectivity, but these parameters are difficult to ascertain in catalytic experiments that have primarily been devoted to equimolar nanoparticles. Here, we report AuPd nanoparticles of varying Au:Pd molar ratios that were prepared by a seed growth method. The selective oxidation of benzyl alcohol was used as a model reaction to study catalytic activity and selectivity changes that occurred after varying the composition of Pd in bimetallic catalysts. We observed a remarkable increase in catalytic conversion when using a 10:1 Au:Pd molar ratio. This composition corresponds to the amount of Pd necessary to cover the existing Au cores with a monolayer of Pd as a full-shell cluster. The key to increased catalytic activity derives from the balance between the number of active sites and the ease of product desorption. According to density functional theory calculations, both parameters are extremely sensitive to the Pd content resulting in the volcano like activity observed. PMID- 25042538 TI - Application of 3-dimensional printing in hand surgery for production of a novel bone reduction clamp. AB - Three-dimensional printing is being rapidly incorporated in the medical field to produce external prosthetics for improved cosmesis and fabricated molds to aid in presurgical planning. Biomedically engineered products from 3-dimensional printers are also utilized as implantable devices for knee arthroplasty, airway orthoses, and other surgical procedures. Although at first expensive and conceptually difficult to construct, 3-dimensional printing is now becoming more affordable and widely accessible. In hand surgery, like many other specialties, new or customized instruments would be desirable; however, the overall production cost restricts their development. We are presenting our step-by-step experience in creating a bone reduction clamp for finger fractures using 3-dimensional printing technology. Using free, downloadable software, a 3-dimensional model of a bone reduction clamp for hand fractures was created based on the senior author's (M.V.M.) specific design, previous experience, and preferences for fracture fixation. Once deemed satisfactory, the computer files were sent to a 3 dimensional printing company for the production of the prototypes. Multiple plastic prototypes were made and adjusted, affording a fast, low-cost working model of the proposed clamp. Once a workable design was obtained, a printing company produced the surgical clamp prototype directly from the 3-dimensional model represented in the computer files. This prototype was used in the operating room, meeting the expectations of the surgeon. Three-dimensional printing is affordable and offers the benefits of reducing production time and nurturing innovations in hand surgery. This article presents a step-by-step description of our design process using online software programs and 3-dimensional printing services. As medical technology advances, it is important that hand surgeons remain aware of available resources, are knowledgeable about how the process works, and are able to take advantage of opportunities in order to advance the field. PMID- 25042539 TI - Desmoid tumors of the upper extremity. AB - PURPOSE: To determine the outcomes of surgical excision with or without adjuvant treatment in the management of desmoid tumors of the upper extremity. METHODS: We retrospectively reviewed 52 patients with a histologically confirmed desmoid tumor in the upper extremity that was managed surgically. All patients presented between 1970 and 2011 and had a minimum 2-year follow-up. RESULTS: There were 25 males and 27 females with an average age of 37 +/- 17 years. The most common location was the shoulder (n = 27). The most common symptom was a painful mass (n = 30). Average tumor size was 189 +/- 371 cm(3). Negative margins (wide or marginal resection) were achieved in 43 patients. The 5-year disease-free interval was 57%. Patients with recurrence were younger than those without (31 vs 43 y). Postoperative radiotherapy increased the time to recurrence (2.6 vs 1.6 y) but ultimate disease-free interval at 5 years was similar in patients who did and did not receive radiotherapy. Compared with the preoperative evaluation, there was a significant reduction in patients reporting moderate or severe pain postoperatively. CONCLUSIONS: Desmoid tumors are locally aggressive fibrous tumors. Recurrence after surgical excision of a desmoid tumor in the upper extremity is common, especially in younger patients. Adjuvant radiation therapy tended to increase time to recurrence but not rate of recurrence. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25042540 TI - Glioma grading using apparent diffusion coefficient map: application of histogram analysis based on automatic segmentation. AB - The accurate diagnosis of glioma subtypes is critical for appropriate treatment, but conventional histopathologic diagnosis often exhibits significant intra observer variability and sampling error. The aim of this study was to investigate whether histogram analysis using an automatically segmented region of interest (ROI), excluding cystic or necrotic portions, could improve the differentiation between low-grade and high-grade gliomas. Thirty-two patients (nine low-grade and 23 high-grade gliomas) were included in this retrospective investigation. The outer boundaries of the entire tumors were manually drawn in each section of the contrast-enhanced T1 -weighted MR images. We excluded cystic or necrotic portions from the entire tumor volume. The histogram analyses were performed within the ROI on normalized apparent diffusion coefficient (ADC) maps. To evaluate the contribution of the proposed method to glioma grading, we compared the area under the receiver operating characteristic (ROC) curves. We found that an ROI excluding cystic or necrotic portions was more useful for glioma grading than was an entire tumor ROI. In the case of the fifth percentile values of the normalized ADC histogram, the area under the ROC curve for the tumor ROIs excluding cystic or necrotic portions was significantly higher than that for the entire tumor ROIs (p < 0.005). The automatic segmentation of a cystic or necrotic area probably improves the ability to differentiate between high- and low-grade gliomas on an ADC map. PMID- 25042541 TI - Reply: To PMID 23787765. PMID- 25042543 TI - The politics of tuberculosis and HIV service integration in Ghana. AB - The need to integrate TB/HIV control programmes has become critical due to the comorbidity regarding these diseases and the need to optimise the use of resources. In developing countries such as Ghana, where public health interventions depend on donor funds, the integration of the two programmes has become more urgent. This paper explores stakeholders' views on the integration of TB/HIV control programmes in Ghana within the remits of contingency theory. With 31 purposively selected informants from four regions, semi-structured interviews and observations were conducted between March and May 2012, and the data collected were analysed using the inductive approach. The results showed both support for and opposition to integration, as well as some of the avoidable challenges inherent in combining TB/HIV control. While those who supported integration based their arguments on clinical synergies and the need to promote the efficient use of resources, those who opposed integration cited the potential increase in workload, the clinical complications associated with joint management, the potential for a leadership crisis, and the "smaller the better" propositions to support their stance. Although a policy on TB/HIV integration exists, inadequate 'political will' from the top management of both programmes has trickled down to lower levels, which has stifled progress towards the comprehensive management of TB/HIV and particularly leading to weak data collection and management structures and unsatisfactory administration of co trimoxazole for co-infected patients. It is our view that the leadership of both programmes show an increased commitment to protocols involving the integration of TB/HIV, followed by a commitment to addressing the 'fears' of frontline service providers to encourage confidence in the process of service integration. PMID- 25042542 TI - Use of a small molecule cell cycle inhibitor to control cell growth and improve specific productivity and product quality of recombinant proteins in CHO cell cultures. AB - The continued need to improve therapeutic recombinant protein productivity has led to ongoing assessment of appropriate strategies in the biopharmaceutical industry to establish robust processes with optimized critical variables, that is, viable cell density (VCD) and specific productivity (product per cell, qP). Even though high VCD is a positive factor for titer, uncontrolled proliferation beyond a certain cell mass is also undesirable. To enable efficient process development to achieve consistent and predictable growth arrest while maintaining VCD, as well as improving qP, without negative impacts on product quality from clone to clone, we identified an approach that directly targets the cell cycle G1 checkpoint by selectively inhibiting the function of cyclin dependent kinases (CDK) 4/6 with a small molecule compound. Results from studies on multiple recombinant Chinese hamster ovary (CHO) cell lines demonstrate that the selective inhibitor can mediate a complete and sustained G0/G1 arrest without impacting G2/M phase. Cell proliferation is consistently and rapidly controlled in all recombinant cell lines at one concentration of this inhibitor throughout the production processes with specific productivities increased up to 110 pg/cell/day. Additionally, the product quality attributes of the mAb, with regard to high molecular weight (HMW) and glycan profile, are not negatively impacted. In fact, high mannose is decreased after treatment, which is in contrast to other established growth control methods such as reducing culture temperature. Microarray analysis showed major differences in expression of regulatory genes of the glycosylation and cell cycle signaling pathways between these different growth control methods. Overall, our observations showed that cell cycle arrest by directly targeting CDK4/6 using selective inhibitor compound can be utilized consistently and rapidly to optimize process parameters, such as cell growth, qP, and glycosylation profile in recombinant antibody production cultures. PMID- 25042544 TI - The social life of health records: understanding families' experiences of autism. AB - Outside of the epidemiological surveillance studies of autism prevalence, health records of children diagnosed with autism have not been sufficiently examined, yet they provide an important lens for showing how autism diagnosis, services and interventions are negotiated, coordinated and choreographed by families and practitioners across multiple settings. This article provides a multifaceted understanding of these processes from an ethnographic and discourse analytic perspective that reveals structural and interactional phenomena contributing to disparities in autism diagnosis and services. We consider health records as dualistic, material-discursive artifacts that are socio-interactionally co constructed and variably interpreted, contested and utilized across home, school and clinic contexts. We chronicle several families' experiences of their children's autism diagnoses and interventions and describe ways in which health records are socially constructed, curated and placed in the middle of clinical encounters. We show how the parents in our study draw upon health records' material-discursive properties to display epistemic authority, expertise and knowledge in interactions with healthcare and school professionals involved in authorizing and planning their children's care. We describe how the parents experience the health records' clinical portrayals of their children and themselves, and how the parents' portrayals of their children are tacitly ratified or negated in the health records. The data include health record reviews, narrative interviews with parents and practitioners, and clinical observations. These data were collected between October 2009 and August 2012 as part of a larger study on disparities in autism diagnosis, interventions and services experienced by African American children with autism and their families living in Los Angeles County, California. Our analysis reveals the central role of health records in maintaining continuity of an autism diagnosis, interventions and services. This article contributes to enhanced professional awareness, parent professional partnerships, and equity in the provision of healthcare and human services related to autism. PMID- 25042545 TI - Bacterial cellulose nanopaper as reinforcement for polylactide composites: renewable thermoplastic NanoPaPreg. AB - Bacterial cellulose (BC) is often regarded as a prime candidate nano reinforcement for the production of renewable nanocomposites. However, the mechanical performance of most BC nanocomposites is often inferior compared with commercially available polylactide (PLLA). Here, the manufacturing concept of paper-based laminates is used, i.e., "PaPreg," to produce BC nanopaper reinforced PLLA, which has been called "nanoPaPreg" by the authors. It is demon-strated that high-performance nanoPaPreg (vf = 65 vol%) with a tensile modulus and strength of 6.9 +/- 0.5 GPa and 125 +/- 10 MPa, respectively, can be fabricated. It is also shown that the tensile properties of nanoPaPreg are predominantly governed by the mechanical performance of BC nanopaper instead of the individual BC nanofibers, due to difficulties impregnating the dense nanofibrous BC network. PMID- 25042546 TI - Students' perceptions of practice assessment in the skills laboratory: an evaluation study of OSCAs with immediate feedback. AB - Assessment of clinical skills is fundamental to undergraduate nursing programmes. However, enabling assessment to be a good learning experience as well is a challenge to nurse educators. The study presented here presents the change from using an objective structured clinical examination (OSCE) for summative assessment (with feedback given to students after results had gone to the examination board--6 weeks after the OSCE) to one with immediate feedback. Because the previous OSCEs were universally disliked by students, for reasons that included absence of immediate feedback, in making this change the university re-branded the OSCE as an objective structured clinical assessment (OSCA) with immediate feedback provided to students. A survey was undertaken to measure student engagement with the OSCA, its value and impact, and its sustainability from the students' perspectives. There is little in the literature about student engagement with OSCEs and sustainability. Findings show that the OSCA with immediate feedback was perceived positively by students, was valued with regard to a number of factors, had a positively impact on student learning and confidence and was felt to be a form of assessment that this university should continue to use. PMID- 25042547 TI - Measuring biomarkers of acute kidney injury during renal replacement therapy: wisdom or folly? AB - Early data are now appearing relating to the measurement of biomarkers of acute kidney injury during renal replacement therapy. These data go some way in describing the clearance of these molecules during renal support. Understanding the potential clearance, or otherwise, of these proteins may lead to directing our therapies in the future particularly with regard to cessation of renal support. We describe a recent study which has provided data that may aid in addressing this issue. PMID- 25042548 TI - Mother recognition and preference after neonatal amygdala lesions in rhesus macaques (Macaca mulatta) raised in a semi-naturalistic environment. AB - Attachment to the caregiver, typically the biological mother, is crucial to young mammals' socio-emotional development. Although studies in nonprimate species suggest that the amygdala regulates social preference and attachment development, its role in primate filial attachment development has been little investigated and has produced mixed results. This study assessed the effects of neonatal amygdala- (Neo-A, N = 16) and sham- (Neo-C, N = 12) lesions on mother recognition and discrimination in macaques raised in species-typical social groups. Neonatal amygdalectomy did not affect social discriminative abilities and mother preference at 3 and 6 months of age, strongly suggesting that the amygdala is not involved in the cognitive processes underlying the development of filial attachment at least when the amygdala damage occurred after the third to fourth weeks of age. Nevertheless, as compared to sham-operated controls, amygdalectomized infants initiated physical contact with their mothers less frequently. The findings are discussed in relation to the known contribution of the amygdala to filial attachment in both rodents and humans. PMID- 25042549 TI - MG132, a proteasome inhibitor, enhances LDL uptake in HepG2 cells in vitro by regulating LDLR and PCSK9 expression. AB - AIM: Expression of liver low-density lipoprotein receptor (LDLR), a determinant regulator in cholesterol homeostasis, is tightly controlled at multiple levels. The aim of this study was to examine whether proteasome inhibition could affect LDLR expression and LDL uptake in liver cells in vitro. METHODS: HepG2 cells were examined. Real-time PCR and Western blot analysis were used to determine the mRNA and protein levels, respectively. DiI-LDL uptake assay was used to quantify the LDLR function. Luciferase assay system was used to detect the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9, a major protein mediating LDLR degradation) promoter. Specific siRNAs were used to verify the involvement of PCSK9. RESULTS: Treatment of HepG2 cells with the specific proteasome inhibitor MG132 (0.03-3 MUmol/L) dose-dependently increased LDLR mRNA and protein levels, as well as LDL uptake. Short-term treatment with MG132 (0.3 MUmol/L, up to 8 h) significantly increased both LDLR mRNA and protein levels in HepG2 cells, which was blocked by the specific PKC inhibitors GF 109203X, Go 6983 or staurosporine. In contrast, a longer treatment with MG132 (0.3 MUmol/L, 24 h) did not change LDLR mRNA, but markedly increased LDLR protein by reducing PCSK9 mediated lysosome LDLR degradation. Furthermore, MG132 time-dependently suppressed PCSK9 expression in the HepG2 cells through a SREBP-1c related pathway. Combined treatment with MG132 (0.3 MUmol/L) and pravastatin (5 MUmol/L) strongly promoted LDLR expression and LDL uptake in HepG2 cells, and blocked the upregulation of PCSK9 caused by pravastatin alone. CONCLUSION: Inhibition of proteasome by MG132 in HepG2 cells plays dual roles in LDLR and PCSK9 expression, and exerts a beneficial effect on cholesterol homeostasis. PMID- 25042550 TI - Sedentary behavior and blood pressure control among osteoarthritis initiative participants. AB - OBJECTIVE: To examine the association between sedentary behavior and blood pressure (BP) among Osteoarthritis Initiative (OAI) participants. DESIGN: We conducted a cross-sectional analysis of the OAI 48-month visit participants whose physical activity was measured using accelerometers. Participants were classified into four quartiles according to the percentage of wear time that was sedentary (<100 activity counts per min). Users of antihypertensive medications or non steroidal anti-inflammatory drugs (NSAIDs) were excluded. Our main outcomes were systolic and diastolic blood pressures (SBP and DBP) and "elevated BP" defined as BP >= 130/85 mm Hg. RESULTS: For this study cohort (N = 707), mean BP was 121.4 +/- 15.6/74.7 +/- 9.5 mm Hg and 33% had elevated BP. SBP had a graded association with increased sedentary time (P for trend = 0.02). The most sedentary quartile had 4.26 mm Hg higher SBP (95% confidence interval (CI), 0.69-7.82; P = 0.02) than the least sedentary quartile, adjusting for age, moderate-to-vigorous (MV) physical activity, and other demographic and health factors. The probability of having elevated BP significantly increased in higher sedentary quartiles (P for trend = 0.046). There were no significant findings for DBP. CONCLUSION: A strong graded association was demonstrated between sedentary behavior and increased SBP and elevated BP, independent of time spent in MV physical activity. Reducing daily sedentary time may lead to improvement in BP and reduction in cardiovascular risk. PMID- 25042551 TI - Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway. AB - OBJECTIVE: Bisphosphonates are commonly used anti-osteoporotic drugs which have controversial effects on joint diseases including osteoarthritis. Certain bisphosphonates have been shown to have anabolic effects on cartilage which could have important ramifications for their proposed effects in vivo; however, the underlying mechanisms are poorly understood. Thus, the purpose of this study was to characterize the effects of clodronate on primary articular chondrocyte metabolism and to determine the underlying signaling pathways responsible. DESIGN: The effects of clodronate and pamidronate on extracellular matrix (ECM) biosynthesis, accumulation and MMP-13 activity were observed in high density, 3D cultures of bovine articular chondrocytes for up to 4 weeks were evaluated. Mechanisms were delineated by measuring intracellular Ca(2+) signaling and the effects of pharmacologic inhibition of the purinergic receptor pathway. RESULTS: Clodronate (100 MUM) induced an anabolic effect (increased biosynthesis by 13 14%) which resulted in an 89-90% increase in ECM accumulation after 4 weeks of culture and without an associated effect on matrix turn-over. Stimulation by clodronate resulted in a 3.3-fold increase in Ca(2+) signaling and pharmacological inhibitor experiments suggested that the anabolic effects exerted by clodronate are transduced through the purinergic receptor pathway. CONCLUSIONS: These findings support the previous notion that certain bisphosphonates may be useful as adjunctive therapies to potentially ameliorate progression of cartilage degeneration and improve arthritis management. PMID- 25042552 TI - Determinants of revision and functional outcome following unicompartmental knee replacement. AB - OBJECTIVE: Unicompartmental Knee Replacement (UKR) has important advantages over total knee replacement (TKR) but has a higher revision rate. Outcomes vary between centres, suggesting that risk factors for revision may be modifiable with changes to patient selection or operative technique. The objective of this study was to determine factors affecting revision, patient-reported outcome and satisfaction following UKR. METHOD: 25,982 cases from three national databases were analysed. Multilevel multivariable regression models were used to examine the effect of patient and surgical factors on implant survival, patient-reported outcome and satisfaction at 6 months and 8 years following UKR. RESULTS: Of the 25,982 cases, 3862 (14.9%) had pre-operative and 6-month Oxford Knee Scores (OKS). Eight-year survival was 89.1% (95% confidence intervals (CI) 88.3-89.9). OKS increased from 21.9 (SD 7.6) to 37.5 (SD 9.5). Age (Hazard ratio (HR) 0.96 (95% CI 0.96-0.97) per year), male gender (HR 0.86 (95% CI 0.76-0.96)), unit size (HR 0.92 (95% CI 0.86-0.97) per case up to 40 cases/year) and operating surgeon grade (HR 0.78 (95% CI 0.67-0.91) if consultant) predicted improved implant survival. Older patients (>= 75 years), and those with lower deprivation levels had superior OKS and satisfaction (adjusted mean difference 0.14 (95% CI 0.09 0.20) points per year of age and 0.93 (95% CI 0.60-1.27) per quintile of deprivation). Ethnicity, anxiety and co-morbidities also affected patient reported outcome. CONCLUSIONS: This study has identified important predictors of revision and patient-reported outcome following UKR. Older patients, who are least likely to be offered UKR, may derive the greatest benefits. Improved understanding of these factors may improve the long-term outcomes of UKR. PMID- 25042553 TI - Bone mineral density and association of osteoarthritis with fracture risk. AB - OBJECTIVE: High body mass index (BMI) is associated with increased risk of osteoarthritis (OA) and reduced risk of fragility fracture. However, the relationship between fragility fracture and OA remained unclear. This study sought to investigate the effect of bone mineral density (BMD) in the OA-fracture relationship. METHODS: Data from 2412 women and 1452 men aged >45 years in the Dubbo Osteoporosis Epidemiology Study (DOES) were analyzed. Individuals have been followed for up to 22 years (median: 7.5 years; range: 0.1-22 years). Femoral neck BMD (FNBMD) and lumbar spine BMD (LSBMD) was measured by dual energy X-ray absorptiometry (DXA) (GE LUNAR, Madison, WI). The presence of OA was ascertained at baseline by self-reported diagnosis. The incidence of low-trauma fracture was ascertained from X-ray reports. RESULTS: Overall, 29% of women and 26% of men had reported a diagnosis of OA. Fracture risk was significantly higher in women with OA than those without OA (Hazard ratio (HR) = 1.50; 95% confidence interval (CI), 1.28-1.76). However, the association was mainly observed in women with osteopenic BMD (HR = 1.74; 95% CI, 1.38-2.17) and normal-BMD (HR = 1.50; 95% CI, 1.06-2.13) and not in those with osteoporosis. Further analysis revealed that osteopenic women with OA had significant increase in risk of vertebral (HR = 1.85; 95% CI, 1.24-2.75) and limb fracture (HR = 2.49; 95% CI, 1.77-3.48), but not in hip fracture. In men, no comparable relationship was found before and after adjustment for covariates. CONCLUSION: Women with OA have an increased risk of fragility fracture, and the risk was mainly observed in non-osteoporotic group. PMID- 25042554 TI - Improved heterogeneous electron transfer kinetics of fluorinated graphene derivatives. AB - Though graphitic carbons are commercially available for various electrochemical processes, their performance is limited in terms of various electrochemical activities. Recent experiments on layered carbon materials, such as graphene, demonstrated an augmented performance of these systems in all electrochemical activities due to their unique electronic properties, enhanced surface area, structure and chemical stabilities. Moreover, flexibility in controlling electronic, as well as electrochemical activities by heteroatom doping brings further leverage in their practical use. Here, we study the electron transfer kinetics of fluorinated graphene derivatives, known as fluorinated graphene oxide (FGO) and its reduced form, RFGO. Enhanced electron transfer kinetics (heterogeneous electron transfer (HET)) is observed from these fluorinated systems in comparison to their undoped systems such as graphene oxide (GO) and reduced GO. A detailed study has been conducted using standard redox probes and biomolecules revealing the enhanced electro-catalytic activities of FGO and RFGO, and electron transfer rates are simulated theoretically. This study reveals that fluorine not only induces defects in graphitic lattice leading to an enhanced HET process but also can modify the electronic structure of graphene surface. PMID- 25042555 TI - [Weight loss and abdominal pain in a 58-year-old-man]. PMID- 25042556 TI - Statistical challenges of high-dimensional methylation data. AB - With the fast growing field of epigenetics comes the need to better understand the intricacies of DNA methylation data analysis. High-throughput profiling using techniques, such as Illumina's BeadArray assay, enable the quantitative assessment of methylation. Challenges arise from the fact that resulting methylation levels (so-called beta values) are proportions between 0 and 1, often from an asymmetric, bimodal distribution with peaks close to 0 and 1. Therefore, the majority of standard statistical approaches do not apply. The logit transformation into so-called M-values is a common approach to circumvent this problem and aims to allow the use of common statistical methods. However, it can be observed that the transformation from beta to M-values does not necessarily result in an approximately homoscedastic distribution. Often, bimodality, asymmetry and heteroscedasticity are conserved even after transformation. We give an overview and discussion of methods suggested in the recent years that attempt to address the characteristics of methylation data in univariate screening settings. In order to identify 'differential' methylation with respect to covariates of interest while adjusting for confounders, we compare parametric methods, such as linear and beta regression, and nonparametric methods, such as rank-based regression. Our goal is to sensitise researchers to the challenges and issues that arise from this type of data as well as to present possible solutions. PMID- 25042557 TI - Reactive oxygen species-dependent JNK downregulated olaquindox-induced autophagy in HepG2 cells. AB - Autophagy plays an important role in response to intracellular and extracellular stress to sustain cell survival. However, dysregulated or excessive autophagy may lead to cell death, known as "type II programmed cell death," and it is closely associated with apoptosis. In our previous study, we proposed that olaquindox induced apoptosis of HepG2 cells through a caspase-9 dependent mitochondrial pathway. In this study, we investigated autophagy induced by olaquindox and explored the crosstalk between apoptosis and autophagy in olaquindox-treated HepG2 cells. Olaquindox-induced autophagy was demonstrated by the accumulation of monodansylcadervarine, as well as elevated expression of autophagy-related MAP LC3 and Beclin 1 proteins. The autophagy inhibitor 3-methyladenine significantly increased the apoptotic rate induced by olaquindox, which was correlated with increased ratio of Bax/Bcl-2. The further studies showed that olaquindox increased the levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L cysteine (NAC) effectively blocked the accumulation of ROS but failed to block autophagy. Moreover, olaquindox induced the activation of c-Jun N-terminal protein kinase (JNK), and JNK inhibitor SP600125 failed to block autophagy. Instead, olaquindox-induced autophagy was enhanced by NAC or SP600125. Meanwhile, JNK activation was remarkably blocked by NAC, indicating that ROS may be the upstream signaling molecules of JNK activation and involved in the negative regulation of olaquindox-induced autophagy. These results suggest that olaquindox induces autophagy in HepG2 cells and that olaquindox-induced apoptosis can be enhanced by 3-methyladenine. Olaquindox-induced autophagy in HepG2 cells is upregulated by Beclin 1 but downregulated by ROS-dependent JNK. PMID- 25042558 TI - Design, synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors. AB - A series of thienopyridinone derivatives was designed and synthesized as inhibitors of checkpoint kinase 1 (Chk1). Most of them exhibited moderate to good Chk1 inhibitory activities. Among them, compounds 8q, 8t, and 8w with excellent Chk1 inhibitory activities (IC50 values of 4.05, 6.23, and 2.33nM, respectively) displayed strong synergistic effects with melphalan, a DNA-damaging agent in the cell-based assay. Further kinase profiling indicated that compound 8t was highly selective against CDK2/cyclinA, Aurora A, and PKC. PMID- 25042559 TI - Recent advances in biocatalyst discovery, development and applications. AB - Enzymes catalyze a wide range of biotransformations and have a great potential as environmentally friendly alternatives to classical chemical catalysts in various industrial applications. Recently, advanced techniques and strategies in enzyme discovery and engineering have led to the significant expansion of the quantity and functional diversity of biocatalysts, which has further allowed broader uses of biocatalysts in new processes, especially those traditionally enabled only by chemical catalysts. Here we highlight some of these recent advances with the focus on new approaches in biocatalyst discovery and development, and discuss new applications of selected biocatalysts including transaminases, cytochrome P450s, and Baeyer-Villiger monooxygenases. PMID- 25042560 TI - Click approach to the discovery of 1,2,3-triazolylsalicylamides as potent Aurora kinase inhibitors. AB - A series of 1,2,3-triazolylsalicylamide derivatives has been developed from the antiproliferative agent 7 and was evaluated for their Aurora kinase inhibitory activity. The novel 1,2,3-triazolylsalicylamide scaffold could be readily assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition, allowing rapid access to the structurally diverse analogues. The synthesized 1,2,3 triazolylsalicylamide derivatives revealed a significant Aurora kinase inhibitory activity. In particular, 8g inhibited Aurora A with IC50 values of 0.37MUM. The critical role of phenolic -OH in the binding was confirmed by a molecular modeling study. PMID- 25042561 TI - Alterations in insulin-signaling and coagulation pathways in platelets during hyperglycemia-hyperinsulinemia in healthy non-diabetic subject. AB - INTRODUCTION: Diabetes mellitus (DM) is a prothrombotic and proinflammatory state. Hyperglycemia (HG) is encountered even in patients without DM. We have shown that combined HG and hyperinsulinemia (HI) in healthy non-diabetic subjects increased circulating tissue factor (TF) and thrombin generation. To understand the changes in platelet and monocyte pathways induced by combined HG and HI in healthy non-diabetic state, we performed whole genome expression profiling of leukocyte-depleted platelets and monocytes before and after 24 hours of combined HG (glucose ~200mg/dL) and HI by glucose infusion clamp in a healthy non-diabetic subject. RESULTS: We defined time-dependent differential mRNA expression (24 versus 0 hour fold change (FC) >= 2) common to platelets and monocytes. Ingenuity Pathways Analysis revealed alterations in canonical insulin receptor signaling and coagulation pathways. A preliminary group of 9 differentially expressed genes was selected for qRT-PCR confirmation. Platelet 24 hour sample was compared to the 0 hour sample plus 4 controls. Five transcripts in platelets and 6 in monocytes were confirmed. Platelet GSK3B and PTPN1 were upregulated, and STXBP4 was downregulated in insulin signaling, and F3 and TFPI were upregulated in coagulation pathways. Monocyte, PIK3C3, PTPN11 and TFPI were downregulated. Platelet GSKbeta3 and PTPN11 protein and TF antigen in platelets and monocytes was increased. CONCLUSIONS: Even in non-diabetic state, HG+HI for 24 hours induces changes in platelets and monocytes. They suggest downregulation of insulin signaling and upregulation of TF. Further studies are needed to elucidate cellular alterations leading to the prothrombotic and proinflammatory state in DM. PMID- 25042562 TI - Suppression of angiogenic response in local vein wall is associated with reduced thrombus resolution. AB - INTRODUCTION: The formation of new vascular channels within and around venous thrombus contributes to its resolution. Neovascularisation arising from the surrounding vein may facilitate this process. Treatment of cancer patients with anti-angiogenic agents can lead to increased incidence of venous thromboembolic events, but the effect of these agents on the processes that govern thrombus resolution are unclear. The aim of this study was to determine the effect of anti angiogenic treatment with 2-methoxyestradiol (2ME) on (i) angiogenic response in the thrombosed vein and (ii) venous thrombus resolution. MATERIALS AND METHODS: Venous thrombus was induced in the inferior vena cava (IVC) of 36 adult male BALB/C mice. Thrombosed mice received either the anti-angiogenic agent, 2ME (150 mg/kg/day, i/p), or vehicle control (n=18/group). In the thrombosed IVC of both groups: hypoxia-inducible factor (HIF) 1alpha, and its angiogenic targets, vascular endothelial growth factor (VEGF) and placental growth factor (PLGF), were quantified using enzyme-linked immunosorbent assays at days 1 and 10 post thrombus induction (n=6/group); and inflammatory cell content, cell proliferation, and vein recanalisation were quantified using immunostaining and image analysis at day 10 (n=6/group). RESULTS: In the IVC of mice treated with 2ME compared with control: HIF1alpha (P<0.005 and P<0.02), VEGF (P<0.005 and P<0.02), and PLGF levels (P<0.01 and P<0.001) were reduced at days 1 and 10 post thrombus induction respectively, and macrophage content (P<0.005), neutrophil content (P<0.01), vein recanalistion (P<0.05), and thrombus resolution (P<0.001) were also reduced at day 10. CONCLUSIONS: Anti-angiogenic treatment with 2ME supressed the HIF1-mediated angiogenic drive in local vein wall and attenuated venous thrombus resolution. The potential pro-thrombotic effect of anti angiogenic agents should be carefully considered when managing venous thromboembolic events in cancer patients. PMID- 25042563 TI - Hippo-YAP signaling pathway: A new paradigm for cancer therapy. AB - In the past decades, the Hippo signaling pathway has been delineated and shown to play multiple roles in the control of organ size in both Drosophila and mammals. In mammals, the Hippo pathway is a kinase cascade leading from Mst1/2 to YAP and its paralog TAZ. Several studies have demonstrated that YAP/TAZ is a candidate oncogene and that other members of the Hippo pathway are tumor suppressive genes. The dysregulation of the Hippo pathway has been observed in a variety of cancers. This review chronicles the recent progress in elucidating the function of Hippo signaling in tumorigenesis and provide a rich source of potential targets for cancer therapy. PMID- 25042564 TI - Prediction of early- and late-onset pregnancy-induced hypertension using placental volume on three-dimensional ultrasound and uterine artery Doppler. AB - OBJECTIVES: To determine whether uterine artery (UtA) Doppler findings and three dimensional (3D) ultrasound measurement of placental volume during the first trimester allowed prediction of early- and late-onset pregnancy-induced hypertension (early PIH and late PIH). METHODS: Subjects with singleton pregnancy who underwent an ultrasound scan at 11-13 weeks' gestation and delivered between 2011 and 2013 were enrolled prospectively into the study. The UtA Doppler indices and placental volume on 3D ultrasound at 11-13 weeks' gestation in cases that developed early PIH (< 34 weeks) or PIH later in pregnancy (>= 34 weeks) were compared with values in unaffected pregnancies. RESULTS: Ten cases of early PIH, 67 cases of late PIH and 1285 unaffected pregnancies were analyzed. The UtA pulsatility index (PI) was higher in cases of early PIH than that in unaffected pregnancies (median, 2.35 vs. 1.79; P = 0.043) but did not differ between cases of late PIH and unaffected pregnancies. Placental volume was smaller in cases of early PIH than that in unaffected pregnancies (median, 43 cm3 vs. 62 cm(3) ; P = 0.003) but did not differ between cases of late PIH and unaffected pregnancies. The area under the receiver-operating characteristics curve for the prediction of early PIH, by combining UtA-PI and placental volume, was 0.832 (95% CI, 0.742 0.921), with this combination providing a detection rate for early PIH of 67.5% for a 5% false-positive rate. CONCLUSIONS: High UtA-PI and small placental volume were observed more often in cases of early PIH compared with unaffected pregnancies, but not in cases of late PIH. These results may indicate that there are differences in pathophysiology between early PIH and late PIH. PMID- 25042565 TI - Biochar-manure compost in conjunction with pyroligneous solution alleviated salt stress and improved leaf bioactivity of maize in a saline soil from central China: a 2-year field experiment. AB - BACKGROUND: Salinity is a major stress threatening crop production in dry lands. A 2-year field experiment was conducted to assess the potential of a biochar product to alleviate salt-stress to a maize crop in a saline soil. The soil was amended with a compost at 12 t ha(-1) of wheat straw biochar and poultry manure compost (BPC), and a diluted pyroligneous solution (PS) at 0.15 t ha(-1) (BPC PS). Changes in soil salinity and plant performance, leaf bioactivity were examined in the first (BPC-PS1) and second (BPC-PS2) year following a single amendment. RESULTS: While soil salinity significantly decreased, there were large increases in leaf area index, plant performance, and maize grain yield, with a considerable decrease in leaf electrolyte leakage when grown in amendments. Maize leaf sap nitrogen, phosphorus and potassium increased while sodium and chloride decreased, leaf bioactivity related to osmotic stress was significantly improved following the treatments. These effects were generally greater in the second than in the first year. CONCLUSION: A combined amendment of crop straw biochar with manure compost plus pyroligneous solution could help combat salinity stress to maize and improve productivity in saline croplands in arid/semi-arid regions threatened increasingly by global climate change. PMID- 25042566 TI - The relationship between unspecific s-IgA and dental caries: a systematic review and meta-analysis. AB - OBJECTIVES: This systematic review and meta-analysis is focused on evaluating the possible association of s-IgA levels and dental caries. DATA: The inclusion criteria comprised the clinical investigations with case and control groups, a caries diagnostic method, and evaluation of unspecific s-IgA concentration by using tests for both groups in humans, healthy subjects, and with statistical analyses. Quality assessment and data extraction of the included articles were performed. Meta-analysis of pooled data was performed through RevMan software after a sensitivity analysis. SOURCES: An electronic and manual search was performed in PubMed, ISI Web of Science, Scopus, Cochrane Library, and Lilacs, with a supplemental hand search of the references of retrieved articles. STUDY SELECTION: From 314 abstracts, 14 fulfilled the inclusion criteria. After reading the full articles, one of them was excluded due to the lack of a control group. Seven studies were included in the meta-analysis, and the heterogeneity among the studies (I(2)) was 41%. The pooled meta-analysis demonstrated higher levels of s IgA in the caries active group (p<0.00001) than in the control group with a mean difference and confidence interval of 0.27 [0.17-0.38]. CONCLUSIONS: Based on these findings, there is evidence that supports the presence of increased s-IgA levels in caries-active subjects. CLINICAL SIGNIFICANCE: Dental caries is a multifactorial disease that comprehends intrinsic and extrinsic factors. The risk factors and events related to dental caries are overlooked in the literature. Additionally, it is also important to understand the host response against this disorder. Since the studies are contradictory in this field, we conducted a systematic review followed by meta-analysis to present the immunological host response evidence-based. PMID- 25042567 TI - Targeted detection of mammalian species using carrion fly-derived DNA. AB - DNA analysis from carrion flies (iDNA analysis) has recently been promoted as a powerful tool for cost- and time-efficient monitoring of wildlife. While originally applied to identify any mammalian species present in an area, it should also allow for targeted detection of species and individuals. Using carrion flies captured in the Tai National Park, Cote d'Ivoire, we assessed this possibility by (i) screening carrion fly DNA extracts with nonspecific and species-specific PCR systems, respectively, targeting mitochondrial DNA (mtDNA) fragments of any mammal or of Jentink's duiker (Cephalophus jentinki), three colobine monkeys (subfamily Colobinae) and sooty mangabey (Cercocebus atys); and (ii) genotyping carrion fly extracts containing sooty mangabey mtDNA. In comparison with the nonspecific PCR assay, the use of specific PCRs increased the frequency of detection of target species up to threefold. Detection rates partially reflected relative abundances of target species in the area. Amplification of seven microsatellite loci from carrion flies positive for sooty mangabey mtDNA yielded an average PCR success of 46%, showing that the identification of individuals is, to some extent, possible. Regression analysis of microsatellite PCR success and mtDNA concentration revealed that, among all carrion flies analysed for this study, 1% contained amounts of mammal mtDNA sufficient to attempt genotyping with potentially high success. We conclude that carrion fly-derived DNA analysis represents a promising tool for targeted monitoring of mammals in their natural habitat. PMID- 25042569 TI - Fe-N decorated hybrids of CNTs grown on hierarchically porous carbon for high performance oxygen reduction. AB - An Fe-N-decorated hybrid material of carbon nanotubes (CNTs) grown in situ from porous carbon microblocks is designed and constructed. This material successfully combines the desirable merits for oxygen reduction reaction (ORR), such as highly active Fe-N species, good conductivity, large pore size, and sufficient surface area. These structural advantages give this low-priced material an outstanding catalytic performance for ORR closely comparable with Pt/C of the same quantity. PMID- 25042568 TI - Pharmacists' influences on prescribing: validating a clinical pharmacy services survey in the Western Pacific Region. AB - BACKGROUND: Hospital pharmacists around the world are becoming increasingly involved in promoting the responsible use of medicines through clinical pharmacy services. This is reflected in the Basel Statements developed by the International Pharmaceutical Federation Hospital Pharmacy Section, particularly the theme 'Influences on Prescribing.' Some countries, particularly in Asia, are currently establishing clinical pharmacy services and would benefit from identification of facilitators. OBJECTIVES: To validate a survey exploring clinical pharmacy services focusing on pharmacists' influences on prescribing, based on Basel Statements 28-31, and the factors that affect their implementation in the Western Pacific Region (WPR). METHODS: Content and face validity of the survey (BS28-31) was established. This resulted in the BS28-31 consisting of 20 questions, which included a Clinical Pharmacy Services Facilitators (CPSF) scale (25 items) to measure respondents' perceptions of facilitators of clinical pharmacy services. The BS28-31 was emailed to hospital pharmacy directors in the WPR. The survey was made available in English, Japanese, Chinese, Vietnamese, Lao, Khmer, French and Mongolian. Principal components and internal consistency analyses were conducted to assess the reliability and construct validity of the CPSF scale. RESULTS: The final survey was sent to a total of 2525 hospital pharmacy directors in the WPR of which 726 were returned from 31 nations yielding a response rate of 29%. Two items in the scale were removed due to low communalities (0.22 and 0.16). The resulting 23 item scale produced a parsimonious two-factor solution, divided into internal (e.g. individual pharmacist traits and pharmacy departmental structure/resources) and environmental facilitators (e.g. government support, patient and physician expectations). This two factor solution explained 51.5% of the variance. In addition, the Cronbach's alpha for the internal and environmental subscales were 0.94 and 0.78 respectively. CONCLUSION: The BS28-31 survey was found to be a reliable and valid instrument for assessing hospital pharmacy directors' perceptions of clinical pharmacy services regarding pharmacists' influences on prescribing and their facilitators in the WPR. PMID- 25042570 TI - Pharmacokinetic comparisons by UPLC-MS/MS of isomer paeoniflorin and albiflorin after oral administration decoctions of single-herb Radix Paeoniae Alba and Zengmian Yiliu prescription to rats. AB - Zengmian Yiliu (ZMYL), a traditional Chinese formula, is designed to improve clinical efficacy and reduce adverse effects in combination with cisplatin in ovarian cancer chemotherapy. In ZMYL, Radix Paeoniae Alba (RPA, made from root of Paeonia lactiflora Pall.) acts as an adjunctive drug in cancer treatment by ameliorating side effects induced by radio- and chemotherapy. The pharmacokinetics differences between isomer albiflorin and paeoniflorin, the main components of RPA, after oral administration decoction of single-herb RPA and ZMYL were compared using a sensitive and accurate UPLC-MS/MS. The results indicate that there are statistically significant differences between the pharmacokinetic parameters: decreasing area under the plasma concentration-time curve (AUC), maximum concentration (Cmax ), elimination rate constant (Ke ) and increasing apparent volume of distribution (Vd ) and clearance (CL) for albiflorin, increasing distribution half-life (T1/2d ) and decreasing elimination half-life (T1/2e ), distribution rate constant (Kd ) and absorption rate constant (Ka ) for paeoniflorin in the ZMYL group compared with the single-herb RPA group. In comparison with albiflorin, the pharmacokinetic parameters of paeoniflorin included significantly increasing mean residence time (MRT) and Vd , decreasing CL and Ke in the single-herb RPA group and increasing MRT and T1/2d and decreasing CL, Ke and Kd in the ZMYL group. Both paeoniflorin and albiflorin are more likely, as the main active ingredients in RPA and ZMYL, to play a variety of pharmacological effects, and herb-herb interactions occur, resulting in different pharmacokinetics of albiflorin and paeoniflorin in RPA and ZMYL. PMID- 25042571 TI - A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment. AB - Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERalpha and ERbeta, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERalpha and ERbeta transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface. PMID- 25042572 TI - Feasibility and reproducibility of diffusion-weighted magnetic resonance imaging of the fetal brain in twin-twin transfusion syndrome. AB - OBJECTIVE: The aim of this study is to test the feasibility and reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) evaluations of the fetal brains in cases of twin-twin transfusion syndrome (TTTS). METHOD: From May 2011 to June 2012, 24 patients with severe TTTS underwent MRI scans for evaluation of the fetal brains. Datasets were analyzed offline on axial DW images and apparent diffusion coefficient (ADC) maps by two radiologists. The subjective evaluation was described as the absence or presence of water diffusion restriction. The objective evaluation was performed by the placement of 20-mm(2) circular regions of interest on the DW image and ADC maps. Subjective interobserver agreement was assessed by the kappa correlation coefficient. Objective intraobserver and interobserver agreements were assessed by proportionate Bland-Altman tests. RESULTS: Seventy-four DW-MRI scans were performed. Sixty of them (81.1%) were considered to be of good quality. Agreement between the radiologists was 100% for the absence or presence of diffusion restriction of water. For both intraobserver and interobserver agreement of ADC measurements, proportionate Bland-Altman tests showed average percentage differences of less than 1.5% and 95% CI of less than 18% for all sites evaluated. CONCLUSION: Our data demonstrate that DW-MRI evaluation of the fetal brain in TTTS is feasible and reproducible. PMID- 25042573 TI - The mitochondrial genome in aging and senescence. AB - Aging is characterized by a progressive decline in organism functions due to the impairment of all organs. The deterioration of both proliferative tissues in liver, skin and the vascular system, as well as of largely post-mitotic organs, such as the heart and brain could be attributed at least in part to cell senescence. In this review we examine the role of mitochondrial dysfunction and mtDNA mutations in cell aging and senescence. Specifically, we address how p53 and telomerase reverse transcriptase (TERT) activity switch their roles from cytoprotective to detrimental and also examine the role of microRNAs in cell aging. The proposed role of Reactive Oxygen Species (ROS), both as mutating agents and as signalling molecules, underlying these processes is also described. PMID- 25042574 TI - PET-positive extralimbic presentation of anti-glutamic acid decarboxylase antibody-associated encephalitis. AB - Anti-glutamic acid decarboxylase (GAD) antibody-associated autoimmune encephalitis has been reported mostly as limbic encephalitis. Only few cases with extralimbic involvement are reported with limited investigation. Here, we report an extensive investigation with MRI, PET, and pathological examination. A 66-year old Japanese female with a history of hypothyroidism, colon cancer, pheochromocytoma, and thymoma-associated myasthenia gravis presented with generalised tonic-clonic seizures. MRI showed multiple hyperintense lesions and PET showed hypermetabolic lesions in the brain. Biopsy showed non-specific gliosis, microglial proliferation, and perivascular lymphohistiocytic infiltrates. Various neuronal antibodies were negative, except for anti-GAD antibody. Anti-GAD antibody-associated encephalitis is an increasingly recognised CNS disease. Pathophysiology of this encephalitis is unclear. While PET showed hypermetabolic lesions, the biopsy showed non-specific changes. The treatments may include immunosuppressants, IVIg, and plasma exchange. One should consider to measure this antibody, in addition to others, when autoimmune encephalitis is suspected [Published with video sequences] . PMID- 25042575 TI - External validation of a model to predict locoregional failure after radical cystectomy. PMID- 25042576 TI - What causes grief in dementia caregivers? AB - Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world. Most AD patients become dependent on their relatives, i.e. family caregivers. Providing care to a person with AD influences caregiver's life and leads to feelings of grief, which often precede caregiver depression. The purpose of the article was to evaluate the Meuser and Marwit Caregiver Grief Inventory (MM-CGI-50) for use in Polish family caregivers and to find out determinants of grief of family caregivers of AD individuals living in Poland. A sample of 151 spouse and adult child caregivers of community-dwelling AD patients (95 females and 56 males) was interviewed to determine the influence of such factors as caregiver's age, gender, family relation to the care recipient (CR) and caregiving-related changes in caregiver's working time, leisure time and material status to find out the impact of caregiving role on intensity of caregiver grief. Caregiver grief was measured by means of MM-CGI-50. Additionally, carers were administered a questionnaire including patient's and caregiver's demographics. Also, CR's dementia assessment was informant-based and determined with investigator-administered clinical dementia rating (CDR) scale. Of all analyzed factors, only caregiver's informant dementia rating significantly influenced caregiver grief. To conclude, the effect of caregiver's age, gender, family relation to the CR and caregiving-related changes in caregiver's working time; leisure time and material status could not be found. To add, MM-CGI-50 can be effectively used to assess grief in Polish family caregivers of AD patients. PMID- 25042577 TI - Super-resolution fluorescence imaging to study cardiac biophysics: alpha-actinin distribution and Z-disk topologies in optically thick cardiac tissue slices. AB - A major motivation for the use of super-resolution imaging methods in the investigation of cardiac biophysics has been the insight from biophysical considerations and detailed mathematical modeling that the spatial structure and protein organisation at the scale of nanometres can have enormous implications for calcium signalling in cardiac muscle. We illustrate the use of dSTORM based super-resolution in optically thick (~10 MUm) tissue slices of rat ventricular tissue to visualize proteins at the cardiac Z-disk and compare those images with confocal (diffraction-limited) as well as electron microscopy (EM) data which still provides a benchmark in terms of resolution. alpha-actinin is an abundant protein target that effectively defines the Z-disk in striated muscle and provides a reference structure for other proteins at the Z-line and the transverse tubules. Using super-resolution imaging alpha-actinin labelling provides very detailed outlines of the contractile machinery which we have used to study the properties of Z-disks and the distribution of alpha-actinin itself. We determined the local diameters of the myo-fibrillar and non-myofibrillar space using alpha-actinin labelling. Comparison between confocal and super-resolution based myofibrillar masks suggested that super-resolution data was able to segment myofibrils accurately while confocal approaches were not always able to distinguish neighbouring myofibrillar bundles which resulted in overestimated diameters. The increased resolution of super-resolution methods provides qualitatively new information to improve our understanding of cardiac biophysics. Nevertheless, conventional diffraction-limited imaging still has an important role to play which we illustrate with correlative confocal and super-resolution data. PMID- 25042578 TI - Oncoplastic surgery in breast conservation: a prospective evaluation of the patients, techniques, and oncologic outcomes. AB - BACKGROUND: The oncologic efficacy of breast-conserving therapies has been established in recent decades. Oncoplastic breast surgery (OBS), as a leap forward in breast conservation, offers concomitant techniques of oncologic and plastic surgeries that grant better esthetic results. The outcomes of our oncoplastic surgeries from 2007 to 2012 are reported. METHODS: A series of 258 cases with breast masses (18 benign and 240 carcinomas) were operated on by OBS techniques and prospectively followed. Neoadjuvant and adjuvant oncologic treatments were also delivered as indicated. RESULTS: Free margins were obtained in 95% of cancer patients. During the 26 months of follow-up, local recurrence happened in 7 (2.9%) patients, of which 1 underwent oncologic therapies and 6 underwent completion mastectomy. Complications postponed adjuvant therapies in 3 (1.2%) patients. Postsurgically, metastases were diagnosed in 8 (3.3%) patients. Two patients (.8%) died of cancer. CONCLUSIONS: Outcomes of OBS are oncologically acceptable with low frequencies of positive margins and recurrence, while cosmetic results are much improved by OBS. PMID- 25042579 TI - The effect of body mass index on outcome in total hip arthroplasty: early analysis from the New Zealand Joint Registry. AB - This study assessed the early outcomes of total hip arthroplasty compared with body mass index (BMI). 5357 hip arthroplasties were evaluated. Oxford Scores, revision for any reason and other factors including American Society of Anaesthesiology scores, length of surgery and cementation of components were analyzed. Both a high and a low BMI predicted for worse Oxford Hip Scores. Obese and morbidly obese patients had significantly lower six month Oxford Scores than healthy patients, the lowest survival, were younger than all other groups and had greater proportions with fully un-cemented prostheses. At this early stage, the results show that outcome and early revision are statistically and clinically poorer for obese patients. PMID- 25042580 TI - Immune memory response induced in vitro by recombinant hepatitis B surface antigen challenge 13-18 years after primary vaccination. AB - The question of whether booster doses are required to maintain long-term protection against hepatitis B virus (HBV) after primary vaccination remains to be determined. Thus, the aim of this study was to evaluate the immune memory responses to hepatitis B surface antigen (HBsAg) challenge in vaccinated individuals through an in vitro-specific stimulation assay. Peripheral blood mononuclear cells (4 * 10(6) cells/ml) were stimulated with 50 ng/ml of recombinant HBsAg. In vitro anamnestic antibody responses, as shown by detection of high avidity antibody in culture supernatants, were found 13-18 years after primary vaccination and were not correlated with serum antibodies (r = -0.177; P = 0.377). In addition, the findings from this study indicate that immune memory against hepatitis B was well preserved in 40.0% and 60.0% of vaccinees with anti HBs levels less than 10 IU/L or lacking serum antibodies altogether, respectively. In conclusion, the data suggest the presence of immunological memory in vaccinated individuals, including those who showed anti-HBs <10 IU/L or undetectable antibody. PMID- 25042582 TI - Stereospecific (5) JHortho,OMe couplings in methoxyindoles, methoxycoumarins, and methoxyflavones. AB - Long-range coupling constants (5) JHortho,OMe were measured in series of methoxyindoles, methoxycoumarins, and methoxyflavones by the modified J doubling in the frequency domain method. The COSY and NOESY spectra revealed the coupling of the -OMe group with a specific proton at the ortho position and its preferred conformation. Homonuclear (1) H-(1) H couplings were confirmed by irradiation of the -OMe signal. Density functional theory calculations of (5) JHortho,OMe using the modified aug-cc-pVTZ basis set evidenced that the Fermi contact term shows good agreement with the experimental J values. Accurate chemical shift and coupling constant values followed after iterative quantum mechanical spectral analysis using the PERCH software. PMID- 25042581 TI - Orbitofrontal activation restores insight lost after cocaine use. AB - Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use. PMID- 25042583 TI - In vivo imaging of spinal cord atrophy in neuroinflammatory diseases. AB - OBJECTIVE: Spinal cord atrophy is prominent in chronic progressive neurologic diseases such as human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Here we compared the spinal cord cross-sectional area (SCCSA) in HAM/TSP and MS patients to that of healthy volunteers (HVs). METHODS: SCCSA and clinical disability scores were measured in 18 HAM/TSP patients, 4 asymptomatic carriers (ACs) of HTLV-1, 18 MS patients, and 10 HVs from a 3T magnetic resonance imaging. SCCSA measured in patients and ACs were compared to that of HVs and correlated with disability scores. RESULTS: The entire spinal cord in HAM/TSP patients was thin compared to HVs, whereas only the cervical cord in MS patients was thinner than in HVs (p < 0.0001). In HAM/TSP patients, SCCSA extensively correlated with Ambulation Index, whereas only the cervical cord correlated with disease duration (p < 0.05). In MS patients, the SCCSA extensively correlated with Scripps Neurologic Rating Score and the Expanded Disability Status Scale (p < 0.05). One of the 4 ACs showed atrophy in a pattern similar to HAM/TSP. INTERPRETATION: These results are in accordance with the findings that whereas over half of all lesions in an MS cord are seen in the upper cervical cord, most of the pathology in HAM/TSP is seen in the thoracolumbar cord, which in turn may be responsible for the more extensive cord atrophy seen in HAM/TSP. An imaging marker such as SCCSA might serve as a surrogate endpoint in clinical trials, especially to assess the neuroprotective impact of various therapies. PMID- 25042584 TI - Phylogenomic analysis of spiders reveals nonmonophyly of orb weavers. AB - Spiders constitute one of the most successful clades of terrestrial predators. Their extraordinary diversity, paralleled only by some insects and mites, is often attributed to the use of silk, and, in one of the largest lineages, to stereotyped behaviors for building foraging webs of remarkable biomechanical properties. However, our understanding of higher-level spider relationships is poor and is largely based on morphology. Prior molecular efforts have focused on a handful of genes but have provided little resolution to key questions such as the origin of the orb weavers. We apply a next-generation sequencing approach to resolve spider phylogeny, examining the relationships among its major lineages. We further explore possible pitfalls in phylogenomic reconstruction, including missing data, unequal rates of evolution, and others. Analyses of multiple data sets all agree on the basic structure of the spider tree and all reject the long accepted monophyly of Orbiculariae, by placing the cribellate orb weavers (Deinopoidea) with other groups and not with the ecribellate orb weavers (Araneoidea). These results imply independent origins for the two types of orb webs (cribellate and ecribellate) or a much more ancestral origin of the orb web with subsequent loss in the so-called RTA clade. Either alternative demands a major reevaluation of our current understanding of the spider evolutionary chronicle. PMID- 25042585 TI - Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. AB - BACKGROUND: Excitatory synapses in the CNS are highly dynamic structures that can show activity-dependent remodeling and stabilization in response to learning and memory. Synapses are enveloped with intricate processes of astrocytes known as perisynaptic astrocytic processes (PAPs). PAPs are motile structures displaying rapid actin-dependent movements and are characterized by Ca(2+) elevations in response to neuronal activity. Despite a debated implication in synaptic plasticity, the role of both Ca(2+) events in astrocytes and PAP morphological dynamics remain unclear. RESULTS: In the hippocampus, we found that PAPs show extensive structural plasticity that is regulated by synaptic activity through astrocytic metabotropic glutamate receptors and intracellular calcium signaling. Synaptic activation that induces long-term potentiation caused a transient PAP motility increase leading to an enhanced astrocytic coverage of the synapse. Selective activation of calcium signals in individual PAPs using exogenous metabotropic receptor expression and two-photon uncaging reproduced these effects and enhanced spine stability. In vivo imaging in the somatosensory cortex of adult mice revealed that increased neuronal activity through whisker stimulation similarly elevates PAP movement. This in vivo PAP motility correlated with spine coverage and was predictive of spine stability. CONCLUSIONS: This study identifies a novel bidirectional interaction between synapses and astrocytes, in which synaptic activity and synaptic potentiation regulate PAP structural plasticity, which in turn determines the fate of the synapse. This mechanism may represent an important contribution of astrocytes to learning and memory processes. PMID- 25042586 TI - Crossmodal comparisons of signal components allow for relative-distance assessment. AB - Animals have multiple senses through which they detect their surroundings and often integrate sensory information across different modalities to generate perceptions. Animal communication, likewise, often consists of signals containing stimuli processed by different senses. Stimuli with different physical forms (i.e., from different sensory modalities) travel at different speeds. As a consequence, multimodal stimuli simultaneously emitted at a source can arrive at a receiver at different times. Such differences in arrival time can provide unique information about the distance to the source. Male tungara frogs (Physalaemus pustulosus) call from ponds to attract females and to repel males. Production of the sound incidentally creates ripples on the water surface, providing a multimodal cue. We tested whether male frogs attend to distance dependent cues created by a calling rival and whether their response depends on crossmodal comparisons. In a first experiment, we showed distance-dependent changes in vocal behavior: males responded more strongly with decreasing distance to a mimicked rival. In a second experiment, we showed that males can discriminate between relatively near and far rivals by using a combination of unimodal cues, specifically amplitude changes of sound and water waves, as well as crossmodal differences in arrival time. Our data reveal that animals can compare the arrival time of simultaneously emitted multimodal cues to obtain information on relative distance to a source. We speculate that communicative benefits from crossmodal comparison may have been an important driver of the evolution of elaborate multimodal displays. PMID- 25042587 TI - Mechanical role of actin dynamics in the rheology of the Golgi complex and in Golgi-associated trafficking events. AB - BACKGROUND: In vitro studies have shown that physical parameters, such as membrane curvature, tension, and composition, influence the budding and fission of transport intermediates. Endocytosis in living cells also appears to be regulated by the mechanical load experienced by the plasma membrane. In contrast, how these parameters affect intracellular membrane trafficking in living cells is not known. To address this question, we investigate here the impact of a mechanical stress on the organization of the Golgi complex and on the formation of transport intermediates from the Golgi complex. RESULTS: Using confocal microscopy, we visualize the deformation of Rab6-positive Golgi membranes applied by an internalized microsphere trapped in optical tweezers and simultaneously measure the corresponding forces. Our results show that the force necessary to deform Golgi membranes drops when actin dynamics is altered and correlates with myosin II activity. We also show that the applied stress has a long-range effect on Golgi membranes, perturbs the dynamics of Golgi-associated actin, and induces a sharp decrease in the formation of Rab6-positive vesicles from the Golgi complex as well as tubulation of Golgi membranes. CONCLUSIONS: We suggest that acto-myosin contractility strongly contributes to the local rigidity of the Golgi complex and regulates the mechanics of the Golgi complex to control intracellular membrane trafficking. PMID- 25042588 TI - Impaired associative learning with food rewards in obese women. AB - Obesity is a major epidemic in many parts of the world. One of the main factors contributing to obesity is overconsumption of high-fat and high-calorie food, which is driven by the rewarding properties of these types of food. Previous studies have suggested that dysfunction in reward circuits may be associated with overeating and obesity. The nature of this dysfunction, however, is still unknown. Here, we demonstrate impairment in reward-based associative learning specific to food in obese women. Normal-weight and obese participants performed an appetitive reversal learning task in which they had to learn and modify cue reward associations. To test whether any learning deficits were specific to food reward or were more general, we used a between-subject design in which half of the participants received food reward and the other half received money reward. Our results reveal a marked difference in associative learning between normal weight and obese women when food was used as reward. Importantly, no learning deficits were observed with money reward. Multiple regression analyses also established a robust negative association between body mass index and learning performance in the food domain in female participants. Interestingly, such impairment was not observed in obese men. These findings suggest that obesity may be linked to impaired reward-based associative learning and that this impairment may be specific to the food domain. PMID- 25042589 TI - Behavioral analysis of cuttlefish traveling waves and its implications for neural control. AB - Traveling waves (from action potential propagation to swimming body motions or intestinal peristalsis) are ubiquitous phenomena in biological systems and yet are diverse in form, function, and mechanism. An interesting such phenomenon occurs in cephalopod skin, in the form of moving pigmentation patterns called "passing clouds". These dynamic pigmentation patterns result from the coordinated activation of large chromatophore arrays. Here, we introduce a new model system for the study of passing clouds, Metasepia tullbergi, in which wave displays are very frequent and thus amenable to laboratory investigations. The mantle of Metasepia contains four main regions of wave travel, each supporting a different propagation direction. The four regions are not always active simultaneously, but those that are show synchronized activity and maintain a constant wavelength and a period-independent duty cycle, despite a large range of possible periods (from 1.5 s to 10 s). The wave patterns can be superposed on a variety of other ongoing textural and chromatic patterns of the skin. Finally, a traveling wave can even disappear transiently and reappear in a different position ("blink"), revealing ongoing but invisible propagation. Our findings provide useful clues about classes of likely mechanisms for the generation and propagation of these traveling waves. They rule out wave propagation mechanisms based on delayed excitation from a pacemaker but are consistent with two other alternatives, such as coupled arrays of central pattern generators and dynamic attractors on a network with circular topology. PMID- 25042590 TI - Drosophila learn opposing components of a compound food stimulus. AB - Dopaminergic neurons provide value signals in mammals and insects. During Drosophila olfactory learning, distinct subsets of dopaminergic neurons appear to assign either positive or negative value to odor representations in mushroom body neurons. However, it is not known how flies evaluate substances that have mixed valence. Here we show that flies form short-lived aversive olfactory memories when trained with odors and sugars that are contaminated with the common insect repellent DEET. This DEET-aversive learning required the MB-MP1 dopaminergic neurons that are also required for shock learning. Moreover, differential conditioning with DEET versus shock suggests that formation of these distinct aversive olfactory memories relies on a common negatively reinforcing dopaminergic mechanism. Surprisingly, as time passed after training, the behavior of DEET-sugar-trained flies reversed from conditioned odor avoidance into odor approach. In addition, flies that were compromised for reward learning exhibited a more robust and longer-lived aversive-DEET memory. These data demonstrate that flies independently process the DEET and sugar components to form parallel aversive and appetitive olfactory memories, with distinct kinetics, that compete to guide learned behavior. PMID- 25042591 TI - Converging circuits mediate temperature and shock aversive olfactory conditioning in Drosophila. AB - BACKGROUND: Drosophila learn to avoid odors that are paired with aversive stimuli. Electric shock is a potent aversive stimulus that acts via dopamine neurons to elicit avoidance of the associated odor. While dopamine signaling has been demonstrated to mediate olfactory electric shock conditioning, it remains unclear how this pathway is involved in other types of behavioral reinforcement, such as in learned avoidance of odors paired with increased temperature. RESULTS: To better understand the neural mechanisms of distinct aversive reinforcement signals, we here established an olfactory temperature conditioning assay comparable to olfactory electric shock conditioning. We show that the AC neurons, which are internal thermal receptors expressing dTrpA1, are selectively required for odor-temperature but not for odor-shock memory. Furthermore, these separate sensory pathways for increased temperature and shock converge onto overlapping populations of dopamine neurons that signal aversive reinforcement. Temperature conditioning appears to require a subset of the dopamine neurons required for electric shock conditioning. CONCLUSIONS: We conclude that dopamine neurons integrate different noxious signals into a general aversive reinforcement pathway. PMID- 25042592 TI - Phylogenomics resolves a spider backbone phylogeny and rejects a prevailing paradigm for orb web evolution. AB - Spiders represent an ancient predatory lineage known for their extraordinary biomaterials, including venoms and silks. These adaptations make spiders key arthropod predators in most terrestrial ecosystems. Despite ecological, biomedical, and biomaterial importance, relationships among major spider lineages remain unresolved or poorly supported. Current working hypotheses for a spider "backbone" phylogeny are largely based on morphological evidence, as most molecular markers currently employed are generally inadequate for resolving deeper-level relationships. We present here a phylogenomic analysis of spiders including taxa representing all major spider lineages. Our robust phylogenetic hypothesis recovers some fundamental and uncontroversial spider clades, but rejects the prevailing paradigm of a monophyletic Orbiculariae, the most diverse lineage, containing orb-weaving spiders. Based on our results, the orb web either evolved much earlier than previously hypothesized and is ancestral for a majority of spiders or else it has multiple independent origins, as hypothesized by precladistic authors. Cribellate deinopoid orb weavers that use mechanically adhesive silk are more closely related to a diverse clade of mostly webless spiders than to the araneoid orb-weaving spiders that use adhesive droplet silks. The fundamental shift in our understanding of spider phylogeny proposed here has broad implications for interpreting the evolution of spiders, their remarkable biomaterials, and a key extended phenotype--the spider web. PMID- 25042593 TI - Ultraconformal contact transfer of monolayer graphene on metal to various substrates. AB - The direct transfer method of large area monolayer CVD graphene from Cu foil to various substrates such as PET, PDMS, and glass is developed using mechano electro-thermal forces based on ultraconformal contact without any metal etching process or additional carrier layers in a solid-state process. Transferred graphene presents both excellent quality (with no residues, few defects, or no folding) and remarkable mechanical and electrical stability. PMID- 25042594 TI - The parasitoid, Cotesia flavipes (Cameron) (Hymenoptera: Braconidae), influences food consumption and utilization by larval Diatraea saccharalis (F.) (Lepidoptera: Crambidae). AB - Parasitoids exploit host insects for food and other resources; they alter host development and physiology to optimize conditions to favor parasitoid development. Parasitoids influence their hosts by injecting eggs, along with a variety of substances, including venoms, polydnaviruses, ovarian fluids, and other maternal factors, into hosts. These factors induce profound changes in hosts, such as behavior, metabolism, endocrine events, and immune defense. Because endoparasitoids develop and consume tissues from within their hosts, it is reasonable to suggest that internal parasitization would also influence host food consumption and metabolism. We report on the effects of parasitism by Cotesia flavipes on the food consumption and utilization of its host, Diatraea saccharalis. Cotesia flavipes reduces the host food consumption, but parasitized larvae considered a unit with their parasitoid's attained the same final weight as the nonparasitized larvae. Nutritional indices, midgut activities of carbohydrases, and trypsin of parasitized and nonparasitized D. saccharalis were assessed. Parasitized larvae had reduced relative food consumption, metabolic and growth rates, coupled with higher efficiency for conversion of the digested, but not ingested, food into body mass. Parasitism also affected food flux through the gut and protein contents in the midgut of parasitized larvae. The activity of alpha-amylase and trehalase in parasitized host was enhanced in the first day after parasitism relative to control larvae. Saccharase activity remained unchanged during larval development. Trypsin activity was reduced from the fifth to ninth day after parasitism. We argue on the mechanisms involved in host food processing after parasitism. PMID- 25042595 TI - Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects. AB - During antibiotic treatments, active residuals reaching the colon profoundly affect the bacterial flora resulting in the emergence of resistance. To prevent these effects, we developed an enteric-coated formulated activated-charcoal based product, DAV132, meant to deliver its adsorbent to the ileum and neutralize antibiotic residues in the proximal colon. In a randomized, control, crossover study, the plasma pharmacokinetics of the probe drugs amoxicillin (500 mg) absorbed in the proximal intestine, and sulfapyridine (25 mg) metabolized from sulfasalazine in the cecum and rapidly absorbed, were compared after a single administration in 18 healthy subjects who had received DAV132, uncoated formulated activated charcoal (FAC) or water 16 and 8 hours before, concomitantly with the probe drugs, and 8 hours thereafter. The AUC0-96 h of amoxicillin was reduced by more than 70% when it was taken with FAC, but bioequivalent when it was taken with water or DAV132. By contrast, the AUC0-96 h of sulfapyridine was reduced by more than 90% when administered with either FAC or DAV132 in comparison with water. The results show that DAV132 can selectively adsorb drug compounds in the proximal colon, without interfering with drug absorption in the proximal small intestine, thereby constituting a proof of concept that DAV132 actually functions in humans. PMID- 25042596 TI - Microbial community study in newly established Qingcaosha Reservoir of Shanghai, China. AB - Qingcaosha Reservoir located at Yangtze Estuary of China is a newly constructed and one of the largest tidal reservoirs in the world, which will be an important drinking water source of Shanghai. This study aims at investigating microbial community and its shifts corresponding to different water quality during the test running period of Qingcaosha Reservoir. The results showed lower concentrations of total nitrogen (TN) and total phosphorus (TP) in the reservoir than that in Yangtze Estuary. The number of total cultivable bacteria was significantly lower in the reservoir than that of Yangtze Estuary. The denaturing gradient gel electrophoresis (DGGE) analysis showed that the dominant microbes were alpha Proteobacteria, beta-Proteobacteria, Flavobacterium, Rheinheimera, Prochlorococcus, and Synechococcus. The quantitative PCR (q-PCR) results revealed significantly higher number of cyanobacteria and Microcystis in the reservoir during summer season. In addition, bacterial abundance positively correlated with TP concentration inside the reservoir. These results indicated that Qingcaosha Reservoir had ability to reduce the TN and TP in influent and improve the water quality overall. However, it also faced the risk of potential cyanobacteria bloom and eutrophication in Qingcaosha Reservoir where phosphorus will be the nutrient limiting factor. PMID- 25042597 TI - The application of bacterial indicator phylotypes to predict shrimp health status. AB - The incidence of shrimp disease is closely associated with the microbial composition in surrounding water, but it remains uncertain whether microbial indicator phylotypes are predictive for shrimp health status (healthy or diseased). To test this idea, we combined the data from our previous works, to investigate the feasibility of indicator phylotypes as independent variables to predict the health status during a shrimp culture procedure. The results showed linearly increased dissimilarities (P<0.001) of the bacterioplankton community over time, while the communities dramatically deviated from this defined trend when disease occurred. This sudden shift in the bacterial community appears to cause severe mass mortality of the shrimps. In particular, we created a model to identify indicators that discriminated ponds with diseased shrimp populations from these with healthy shrimp populations. As a result, 13 indicative families were screened, in which seven are healthy indicator and six are diseased indictor. An improved logistic regression model additionally revealed that the occurrences of these indicator families could be predictive of the shrimp health status with a high degree of accuracy (>79 %). Overall, this study provides solid evidences that indicator phylotypes could be served as independent variables for predicting the incidences of shrimp disease. PMID- 25042598 TI - Novel chitosan-based pH-sensitive and disintegrable polyelectrolyte nanogels. AB - A novel approach to design pH-sensitive and disintegrable polyelectrolyte nanogels composed of citraconic-based N-(carboxyacyl) chitosan (polyanion) and quaternary chitosan (polycation) was reported. Firstly, the hydrolysis of citraconic-modified chitosan was monitored using fluorescamine assay and it could selectively dissociate in acidic media (e.g., pH ~5.0) due to the isomerization during the addition of citraconic anhydride to chitosan. Secondly, the self assembly behaviors of different polyelectrolyte pairs between citraconic-based chitosan and quaternary chitosan were investigated via colloidal titration assay. It was indicated that the difference in molecular weight (MW) of opposite charged polyelectrolytes played an important role on the formation of polyelectrolyte nanogels. Results showed that polyelectrolyte nanogels (ca. 300nm in size) only formed when polyanion and polycation had a very large difference in MW. The pH sensitive behavior of polyelectrolyte nanogels was comprehensively investigated by dynamic light scattering (DLS) and transmission electron microscope (TEM). The incorporation of charge-conversional citraconic-based chitosan into polyelectrolyte complexes has provided an effective approach to prepare polyelectrolyte nanogels which were very stable at neutral pH but disintegrated quickly in acidic media. PMID- 25042599 TI - Continuous positive airway pressure therapy for obstructive sleep apnea reduces interictal epileptiform discharges in adults with epilepsy. AB - Obstructive sleep apnea (OSA) is highly prevalent, affecting 25% of men and 10% of women. We recently reported a prevalence of OSA of 30% among 130 adults with epilepsy unselected for sleep disorder complaints, including 16% with moderate-to severe disease, rates that markedly exceed general population estimates. Treatment of OSA with continuous positive airway pressure (CPAP) therapy or upper airway surgery reduces seizures in many cases. A single study reported a reduction in interictal spike rate with CPAP in 6 patients with OSA. We explored the effect of CPAP therapy on spike rate in 9 adults with epilepsy and OSA. Interictal epileptiform discharges were quantified during a diagnostic polysomnogram (PSG) and a second PSG using therapeutic CPAP. Spike rates were calculated for each recording during wake and sleep stages. Continuous positive airway pressure therapy was associated with significant reductions in median (quartiles) spike rate overall (77.9 [59.7-90.7] %), in wakefulness (38.5 [0.3 55] %), and in sleep (77.7 [54.8-94.7] %) but not in REM sleep. Continuous positive airway pressure therapy also produced a significant improvement in oxygen saturation and arousals. Our work extends a single prior observation demonstrating beneficial effects of CPAP therapy on interictal EEG in patients with epilepsy with comorbid OSA and supports the hypothesis that sleep fragmentation due to OSA contributes to epileptogenicity. PMID- 25042600 TI - Gypsogenin derivatives: an unexpected class of inhibitors of cholinesterases. AB - Gypsogenin (1) was obtained by acidic hydrolysis from its saponin. While the parent compound 1 acted as a selective inhibitor for butyrylcholinesterase (from equus) possessing a moderate mixed-type inhibition of the enzyme, Ki values as low as 2.67 +/- 0.59 MUM were determined for (3beta,4alpha) 3-O-acetyl-olean-12 ene-23,28-dinitrile (11) and acetylcholinesterase (AChE, from electric eel). Thus, 11 possesses one-fifth of the inhibitory activity of the "gold standard" galantamine hydrobromide; this compound is one of the first pentacyclic triterpenoids described as a potent AChE-selective inhibitor. PMID- 25042601 TI - Association analysis of PTPN22, CTLA4 and IFIH1 genes with type 1 diabetes in Colombian families. AB - BACKGROUND: Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and interferon induced with helicase C domain 1 (IFIH1) are among the confirmed type 1 diabetes (T1D) susceptibility genes in several populations. The aim of this study was to evaluate the role of PTPN22, CTLA4, and IFIH1 gene variants in the development of T1D in a Colombian population. METHODS: Associations of PTPN22, CTLA4, and IFIH1 variants with T1D were investigated in a sample of 197 nuclear families, including 205 affected children, in the Colombian population. Three to four single nucleotide polymorphisms (SNPs) were analyzed per gene: rs2476600, rs2476601, rs1217418, and rs2488457 for PTPN22; rs1990760, rs3747517, and rs10930046 for IFIH1; and rs231775, rs3087243, and rs231779 for CTLA4. A transmission disequilibrium test was performed for the global sample, in addition to stratified analysis considering autoimmunity, age at onset, and parent of origin. Haplotypes per gene were also analyzed. RESULTS: There was no significant transmission distortion for CTLA4. Conversely, SNPs rs10930046 (IFIH1) and rs2476601 (PTPN222) exhibited significant transmission distortion of the C and T alleles, respectively, from parents to affected children (odds ratio [OR] 0.57 and 1.83, respectively). In addition, decreased transmission of the C allele for rs10930046 occurred preferentially from mothers. Stratification analysis revealed that this association was maintained in individuals who were positive for autoantibodies and in those with an age of diagnosis <5 years. CONCLUSION: The results show that IFIH1 and PTPN22 are associated with T1D in Colombian families. PMID- 25042602 TI - Encoding atlases by randomized classification forests for efficient multi-atlas label propagation. AB - We propose a method for multi-atlas label propagation (MALP) based on encoding the individual atlases by randomized classification forests. Most current approaches perform a non-linear registration between all atlases and the target image, followed by a sophisticated fusion scheme. While these approaches can achieve high accuracy, in general they do so at high computational cost. This might negatively affect the scalability to large databases and experimentation. To tackle this issue, we propose to use a small and deep classification forest to encode each atlas individually in reference to an aligned probabilistic atlas, resulting in an Atlas Forest (AF). Our classifier-based encoding differs from current MALP approaches, which represent each point in the atlas either directly as a single image/label value pair, or by a set of corresponding patches. At test time, each AF produces one probabilistic label estimate, and their fusion is done by averaging. Our scheme performs only one registration per target image, achieves good results with a simple fusion scheme, and allows for efficient experimentation. In contrast to standard forest schemes, in which each tree would be trained on all atlases, our approach retains the advantages of the standard MALP framework. The target-specific selection of atlases remains possible, and incorporation of new scans is straightforward without retraining. The evaluation on four different databases shows accuracy within the range of the state of the art at a significantly lower running time. PMID- 25042603 TI - Squamous cell carcinoma of the head and neck outside the oropharynx is rarely human papillomavirus related. AB - OBJECTIVES/HYPOTHESIS: The incidence of human papillomavirus (HPV)-driven disease beyond the oropharynx varies greatly in the reported literature. STUDY DESIGN: Case series. METHODS: Two hundred twenty-one samples were strictly classified to the subsites of oral cavity, larynx, or hypopharynx at the time of primary surgery. Formalin-fixed paraffin-embedded samples were subjected to a validated, tiered, diagnostic algorithm of p16 immunohistochemistry, high-risk HPV in situ hybridization, and quantitative polymerase chain reaction for HPV E6 DNA. An additional 60 oropharyngeal cases acted as an internal biological control. RESULTS: An incidence of 4% of HPV-driven cases was observed across the subsites outside the oropharynx compared to 70% of tumors confined within it. CONCLUSIONS: This is the first reporting of a broad range of nonoropharyngeal HPV rates using this validated diagnostic algorithm. It remains unclear whether patients with HPV driven disease originating outside the oropharynx enjoy the same survival advantage apparent in those patients with oropharyngeal squamous cell carcinomas. LEVEL OF EVIDENCE: 4 Laryngoscope, 124:2739-2744, 2014. PMID- 25042604 TI - Central serous chorioretinopathy and bright light. PMID- 25042605 TI - Randomized controlled trial of a multipronged intervention to improve blood pressure control among stroke survivors in Nigeria. AB - RATIONALE: Stroke is the second-leading cause of death in low- and middle-income countries, but use of evidence-based therapies for stroke prevention in such countries, especially those in Africa, is extremely poor. This study is designed to enhance the implementation and sustainability of secondary stroke-preventive services following hospital discharge. AIM/HYPOTHESIS: The primary study aim is to test whether a Chronic Care Model-based initiative entitled the Tailored Hospital-based Risk reduction to Impede Vascular Events after Stroke (THRIVES) significantly improves blood pressure control after stroke. DESIGN: This prospective triple-blind randomized controlled trial will include a cohort of 400 patients with a recent stroke discharged from four medical care facilities in Nigeria. The culturally sensitive, system-appropriate intervention comprises patient report cards, phone text messaging, an educational video, and coordination of posthospitalization care. STUDY OUTCOMES: The primary outcome is improvement of blood pressure control. Secondary endpoints include control of other stroke risk factors, medication adherence, functional status, and quality of life. We will also perform a cost analysis of THRIVES from the viewpoint of government policy-makers. DISCUSSION: We anticipate that a successful intervention will serve as a scalable model of effective postdischarge chronic blood pressure management for stroke in sub-Saharan Africa and possibly for other symptomatic cardiovascular disease entities in the region. PMID- 25042606 TI - Falls and Use of Assistive Devices in Stroke Patients with Hemiparesis: Association with Balance Ability and Fall Efficacy. AB - PURPOSE: This study investigates balance ability and the fall efficacy with regard to the experiences of stroke patients with hemiparesis. METHODS: The experience of falling, the use of assistive devices, and each disease-related characteristic were assessed using face-to-face interviews and a self-reported questionnaire. The Berg Balance Scale and Fall Efficacy Scale were used to measure balance ability and confidence. RESULTS: The fall efficacy was significantly lower in participants who had experienced falls than those who had not. The participants who used assistive devices exhibited low balance ability and fall efficacy compared to those who did not use assistive devices. CONCLUSIONS: Stroke patients with fall experience and walking aids might be considered at increased risk of falling. CLINICAL RELEVANCE: Preventive measures for individuals using walking aids may be beneficial in reducing the fall rate of community-dwelling stroke patients. PMID- 25042607 TI - Phylogenetic clustering of hepatitis C virus among people who inject drugs in Vancouver, Canada. AB - Little is known about factors associated with hepatitis C virus (HCV) transmission among people who inject drugs (PWID). Phylogenetic clustering and associated factors were evaluated among PWID in Vancouver, Canada. Data were derived from the Vancouver Injection Drug Users Study. Participants who were HCV antibody-positive at enrolment and those with HCV antibody seroconversion during follow-up (1996 to 2012) were tested for HCV RNA and sequenced (Core-E2 region). Phylogenetic trees were inferred using maximum likelihood analysis and clusters were identified using ClusterPicker (90% bootstrap threshold, 0.05 genetic distance threshold). Factors associated with clustering were assessed using logistic regression. Among 655 eligible participants, HCV genotype prevalence was: G1a: 48% (n=313), G1b: 6% (n=41), G2a: 3% (n=20), G2b: 7% (n=46), G3a: 33% (n=213), G4a: <1% (n=4), G6a: 1% (n=8), G6e: <1% (n=1), and unclassifiable: 1% (n=9). The mean age was 36 years, 162 (25%) were female, and 164 (25%) were HIV+. Among 501 participants with HCV G1a and G3a, 31% (n=156) were in a pair/cluster. Factors independently associated with phylogenetic clustering included: age <40 (versus age>=40, adjusted odds ratio [AOR]=1.64; 95% confidence interval [CI] 1.03, 2.63), human immunodeficiency virus (HIV) infection (AOR=1.82; 95% CI 1.18, 2.81), HCV seroconversion (AOR=3.05; 95% CI 1.40, 6.66), and recent syringe borrowing (AOR 1.59; 95% CI 1.07, 2.36). CONCLUSION: In this sample of PWID, one third demonstrated phylogenetic clustering. Factors independently associated with phylogenetic clustering included younger age, recent HCV seroconversion, prevalent HIV infection, and recent syringe borrowing. Strategies to enhance the delivery of prevention and/or treatment strategies to those with HIV and recent HCV seroconversion should be explored, given an increased likelihood of HCV transmission in these subpopulations. PMID- 25042609 TI - Disupersilylperoxo radical anion [tBu3 SiOOSitBu3 ](?-) : an intermediate of supersilanide oxidation. AB - In the oxidative process of the supersilanide anion [SitBu3 ](-) , radical species are generated. The continuous wave (cw)-EPR spectrum of the reaction solution of Na[SitBu3 ] with O2 revealed a signal, which could be characterized as disupersilylperoxo radical anion [tBu3 SiOOSitBu3 ](?-) affected by sodium ions though ion-pair formation. A mechanism is suggested for the oxidative process of supersilanide, which in a further step can be helpful in a better understanding of the oxidation process of isoelectronic phosphanes. PMID- 25042608 TI - GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at 'freeze-all strategy'. AB - A case is reported of early onset ovarian hyperstimulation syndrome (OHSS) after gonadotrophin-releasing hormone agonist (GnRHa) trigger for final oocyte maturation in a GnRH antagonist protocol. The use of GnRHa in place of HCG as a trigger for final oocyte maturation in an antagonist IVF cycle has been proposed as a method for preventing OHSS in predicted high-responders. This approach, however, did not prevent the occurrence of OHSS in our case despite a freeze-all strategy. To the best of our knowledge, this is a possible index case of severe OHSS with GnRHa trigger for oocyte maturation without any luteal HCG rescue for a high responder, despite IVF cycle segmentation. PMID- 25042610 TI - Editorial overview: viruses and RNA interference. PMID- 25042612 TI - Rheumatic diseases and the microbiome. PMID- 25042617 TI - Kawasaki disease. PMID- 25042611 TI - The genetics of hemoglobin A2 regulation in sickle cell anemia. AB - Hemoglobin A2 , a tetramer of alpha- and delta-globin chains, comprises less than 3% of total hemoglobin in normal adults. In northern Europeans, single nucleotide polymorphisms (SNPs) in the HBS1L-MYB locus on chromosome 6q and the HBB cluster on chromosome 11p were associated with HbA2 levels. We examined the genetic basis of HbA2 variability in sickle cell anemia using genome-wide association studies. HbA2 levels were associated with SNPs in the HBS1L-MYB interval and SNPs in BCL11A. These effects are mediated by the association of these loci with gamma globin gene expression and fetal hemoglobin (HbF) levels. The association of polymorphisms downstream of the beta-globin gene (HBB) cluster on chromosome 11 with HbA2 was not mediated by HbF. In sickle cell anemia, levels of HbA2 appear to be modulated by trans-acting genes that affect HBG expression and perhaps also elements within the beta-globin gene cluster. HbA2 is expressed pancellularly and can inhibit HbS polymerization. It remains to be seen if genetic regulators of HbA2 can be exploited for therapeutic purposes. PMID- 25042618 TI - Unravelling the relationship between Raman enhancement and photocatalytic activity on single anisotropic Au microplates. AB - Anisotropic noble-metal structures are attracting increasing attention because of interesting size- and shape-dependent properties and have emerging applications in the fields of optics and catalysis. However, it remains a significant challenge to overcome chemical contributions and acquire molecular insight into the relationship between Raman enhancement and photocatalytic activity. This study gives visualized experimental evidence of the anisotropic spatial distribution of Raman signals and photocatalytic activity at the level of single nanometer-thin Au microtriangles and microhexagons. Theoretical simulations indicate an anisotropic spatial distribution and sharpness-dependent strength of the electric-field enhancement. Analysis by using statistical surface-enhanced Raman scattering (SERS) supports this view, that is, Raman enhancement is on the order of corner>edge>face for a single microplate, but SERS measurements at different depths of focus also imply a concentration-dependent feature of SERS signals, especially at the corners and edges. Similarly, the SERS signals of product molecules in plasmonic photocatalysis also exhibit asymmetrical strengths at different corners of the same microplate. However, by examining the variations in the relative intensities of the SERS peaks, the difference in the photocatalytic activities at the corners, edges, and faces has been successfully calculated and is highly consistent with electric-field simulations, thus indicating that an increased number of molecules adsorbed at specific sites does not necessarily lead to a higher conversion ratio in noble-metal photocatalysis. Our strategy weakens the assumed impact of plasmonic local heating and, to a certain extent, excludes the influence of concentration effects and chemical contributions in noble-metal photocatalysis, thus clearly profiling plasmon related characteristics. This study also promises a new research direction to understand the enhancement mechanism of SERS-active structures. PMID- 25042619 TI - Delineation of gliomas using radial metabolite indexing. AB - (1) H MRSI has demonstrated the ability to characterise and delineate brain tumours, but robust data analysis methods are still needed. In this study, we present an objective analysis method for MRSI data to delineate tumour abnormality regions. The presented method is a development of the choline-to-N acetylaspartate index (CNI), which uses perpendicular distances in a choline versus N-acetylaspartate plot as a measure of abnormality. We propose a radial CNI (rCNI) method that uses the choline to N-acetylaspartate ratio directly as an abnormality measure. To avoid problems with small or zero denominators, we perform an arctangent transformation. CNI abnormality contours were evaluated using a z-score threshold of 2 (CNI2) and 2.5 (CNI2.5) and compared with rCNI2. Simulations modelling low-grade (LGG) and high-grade (HGG) gliomas with different tissue compartments and partial volume effects suggest improved specificity of rCNI2 (LGG 92%/HGG 91%) over CNI2 (LGG 69%/HGG 69%) and CNI2.5 (LGG 74%/HGG 75%), whilst retaining a similar sensitivity to both CNI2 and CNI2.5. Our simulation results also confirm a previously reported increase in specificity of CNI2.5 over CNI2 with little penalty in sensitivity. The analysis of MRSI data acquired from 10 patients with low-grade glioma at 3 T suggests a more robust delineation of the lesions using rCNI with respect to conventional imaging compared with standard CNI. Further analysis of 29 glioma datasets acquired at 1.5 T, together with previously published estimated tumour proportions, suggests that rCNI has higher sensitivity and specificity for the identification of abnormal MRSI voxels. PMID- 25042621 TI - Ultra-small plutonium oxide nanocrystals: an innovative material in plutonium science. AB - Apart from its technological importance, plutonium (Pu) is also one of the most intriguing elements because of its non-conventional physical properties and fascinating chemistry. Those fundamental aspects are particularly interesting when dealing with the challenging study of plutonium-based nanomaterials. Here we show that ultra-small (3.2+/-0.9 nm) and highly crystalline plutonium oxide (PuO2 ) nanocrystals (NCs) can be synthesized by the thermal decomposition of plutonyl nitrate ([PuO2 (NO3 )2 ]?3 H2 O) in a highly coordinating organic medium. This is the first example reporting on the preparation of significant quantities (several tens of milligrams) of PuO2 NCs, in a controllable and reproducible manner. The structure and magnetic properties of PuO2 NCs have been characterized by a wide variety of techniques (powder X-ray diffraction (PXRD), X-ray absorption fine structure (XAFS), X-ray absorption near edge structure (XANES), TEM, IR, Raman, UV/Vis spectroscopies, and superconducting quantum interference device (SQUID) magnetometry). The current PuO2 NCs constitute an innovative material for the study of challenging problems as diverse as the transport behavior of plutonium in the environment or size and shape effects on the physics of transuranium elements. PMID- 25042622 TI - Determinants of sexual impairment in multiple sclerosis in male and female patients with lower urinary tract dysfunction: results from an Italian cross sectional study. AB - INTRODUCTION: Sexual dysfunction (SD) is prevalent in multiple sclerosis (MS) patients and affects quality of life. Furthermore, lower urinary tract dysfunction (LUTD) is common in MS patients. AIMS: This study aims to evaluate the relationship between SD, neurological disability, depression, anxiety, and urodynamic alterations in patients with MS and LUTD. METHODS: From January 2011 to September 2013, 135 consecutive patients with MS in remission phase and LUTD underwent first urodynamic examination, according to the International Continence Society criteria. Depression and anxiety were evaluated with the Hamilton Depression Scale (HAM-D) and the Hamilton Anxiety Scale (HAM-A), neurological impairment was assessed using the Expanded Disability Status Scale (EDSS), and SD was investigated with the Female Sexual Function Index (FSFI) or the International Index of Erectile Function (IIEF-15). MAIN OUTCOME MEASURES: Multivariate logistic regression analyses were carried out to identify variables for predicting female sexual dysfunction (FSD) (FSFI < 26.55), male SD (IIEF-15 < 60), or moderate-severe erectile dysfunction (IIEF-EF <= 16), after adjusting for confounding factors. RESULTS: Total IIEF-15 and all subdomains (all P < 0.01), total FSFI, FSFI-arousal, FSFI-lubrication, and FSFI-orgasm (all P < 0.05) were lower in subjects with EDSS >= 4.5. We found inverse relationship between IIEF-15 and relative subdomains with EDSS (all P < 0.01) and between FSFI and relative subdomains with EDSS (all P < 0.01), HAM-D (all P < 0.01), and HAM-A (all P < 0.01). Continuous EDSS (odds ratio [OR] = 1.54; P = 0.03) and categorical EDSS (>=4.5) (OR = 6.0; P = 0.03), HAM-D (OR = 4.74; P = 0.03), and HAM-A (OR = 4.10; P = 0.02) were significantly associated with FSD (FSFI < 26.55). Detrusor overactivity (DO) was an independent predictor of moderate-severe ED (IIEF-EF <= 16) (OR = 2.03; P < 0.01), and of FSD (OR = 9.73; P = 0.04). CONCLUSIONS: Neurological disability, depression and DO are significantly predictive of SD in MS patients, irrespective of gender. An EDSS >= 4.5 may significantly predict the presence of SD. PMID- 25042623 TI - Single-cell measurement of the uptake, intratumoral distribution and cell cycle effects of cisplatin using mass cytometry. AB - Although of fundamental importance to the treatment of cancer patients, the quantitative study of drug distribution and action in vivo at the single cell level is challenging. We used the recently-developed technique of mass cytometry to measure cisplatin uptake into individual tumor cells (Pt atoms/cell), combined with measurement of the rate of IdU incorporation into DNA (I(127) atoms/cell/min) and tumor hypoxia identified by the 2-nitroimidazole EF5 in cisplatin-treated BxPC-3 and ME-180 xenografts. Pt levels of 10(5) to 10(6) atoms/cell were obtained following a single cisplatin treatment using clinically relevant doses. Cisplatin caused cell cycle arrest in a dose- and time-dependent manner that paralleled effects in vitro, and it readily penetrated into hypoxic tumor regions. Similar levels of Pt/cell were found in xenografts treated with oxaliplatin. Mass cytometry offers the unique capability to study the cellular uptake and anticancer effects of platinum-containing drugs at the single cell level in animal models, and it has the potential for application to samples obtained from cancer patients during treatment. PMID- 25042620 TI - Early management of patients with acute heart failure: state of the art and future directions. A consensus document from the society for academic emergency medicine/heart failure society of America acute heart failure working group. AB - Heart failure (HF) afflicts nearly 6 million Americans, resulting in one million emergency department (ED) visits and over one million annual hospital discharges. An aging population and improved survival from cardiovascular diseases is expected to further increase HF prevalence. Emergency providers play a significant role in the management of patients with acute heart failure (AHF). It is crucial that emergency physicians and other providers involved in early management understand the latest developments in diagnostic testing, therapeutics and alternatives to hospitalization. Further, clinical trials must be conducted in the ED in order to improve the evidence base and drive optimal initial therapy for AHF. Should ongoing and future studies suggest early phenotype-driven therapy improves in-hospital and post-discharge outcomes, ED treatment decisions will need to evolve accordingly. The potential impact of future studies which incorporate risk-stratification into ED disposition decisions cannot be underestimated. Predictive instruments that identify a cohort of patients safe for ED discharge, while simultaneously addressing barriers to successful outpatient management, have the potential to significantly impact quality of life and resource expenditures. PMID- 25042624 TI - [Antiphospholipid syndrome and pregnancy: Obstetrical prognosis according to the type of APS]. AB - OBJECTIVE: The objective of our study was to compare treatment-based obstetrical outcomes in women with either thrombotic or obstetrical antiphospholipid syndrome (APS). MATERIALS AND METHODS: This was a historical cohort study conducted between 1998 and 2009 in 23 patients who had a total of 83 pregnancies. The syndrome was diagnosed using the 2006 Sapporo criteria. RESULTS: Thirty-one of these 83 pregnancies were valid before the diagnosis was made. A live infant was born in 22% of them, the infant being small for gestational age in 26% of cases. The fetus died in utero in a further 26% of cases. Pregnancies were subdivided into 2 groups depending on whether the initial event leading to APS diagnosis was obstetrical or thrombotic. Treatment (aspirin and low molecular weight heparin) was based on this classification: the latter was given in a curative dose for thrombotic events, in a preventive dose for obstetrical events. No fetal loss was observed when treatment was administered according to the protocol. Nevertheless, 20% of the pregnancies with obstetrical APS were complicated by smallness for gestational age and only 38% of the infants were live births. More than 87% of the thrombotic forms treated were free of complications and led to birth of a living child. CONCLUSION: Appropriate treatment appears to improve the prognosis for pregnancies in patients with APS. These patients are nevertheless at increased risk of an obstetrical event and require close monitoring, especially in obstetrical manifestations, which appear to have a poorer prognosis. Multidisciplinary follow-up by an experienced team is essential. PMID- 25042625 TI - [What's new in 2014 about anti-Mullerian hormone?]. AB - The existence of the anti-Mullerian hormone (AMH) has been postulated by Professor Alfred Jost to explain the regression of the Mullerian ducts during male sexual differentiation. Since then, AMH has been purified, its gene and specific receptor, AMHR-II have been cloned. Further, the signaling pathways were identified and it has been observed that AMH was produced by the granulosa cells of growing follicles. From the 2000s, unexpected roles of AMH have been highlighted, reactivating international research on this hormone. It is now well established that AMH plays a key role in the follicular recruitment and development. Over the past years, serum AMH measurements have been proposed as a marker of the follicular ovarian status, and a predictor of assisted reproductive cycles. AMH is also useful to assess the effectiveness of treatment of some gynecological tumors. This article is a review of the past five years advances on the regulation of the expression of AMH and its specific receptor AMHR-II in female. PMID- 25042626 TI - Covariance adjustment on propensity parameters for continuous treatment in linear models. AB - Propensity scores are widely used to control for confounding when estimating the effect of a binary treatment in observational studies. They have been generalized to ordinal and continuous treatments in the recent literature. Following the definition of propensity function and its parameterizations (called the propensity parameter in this paper) proposed by Imai and van Dyk, we explore sufficient conditions for selecting propensity parameters to control for confounding for continuous treatments in the context of regression-based adjustment in linear models. Typically, investigators make parametric assumptions about the form of the dose-response function for a continuous treatment. Such assumptions often allow the analyst to use only a subset of the propensity parameters to control confounding. When the treatment is the only predictor in the structural, that is, causal model, it is sufficient to adjust only for the propensity parameters that characterize the expectation of the treatment variable or its functional form. When the structural model includes selected baseline covariates other than the treatment variable, those baseline covariates, in addition to the propensity parameters, must also be adjusted in the model. We demonstrate these points with an example estimating the dose-response relationship for the effect of erythropoietin on hematocrit level in patients with end-stage renal disease. PMID- 25042627 TI - Perinatal outcome after prenatal diagnosis of single-ventricle cardiac defects. AB - OBJECTIVES: To investigate the perinatal outcome of cases with a prenatal diagnosis of single-ventricle cardiac defects, single ventricle being defined as a dominant right ventricle (RV) or left ventricle (LV), in which biventricular circulation was not possible. METHODS: We reviewed patients with a prenatal diagnosis of single-ventricle cardiac defects, made at one institution between 1995 and 2008. Cases diagnosed with double-inlet LV, tricuspid atresia, pulmonary atresia with intact ventricular septum and severe RV hypoplasia and those with hypoplastic left heart syndrome (HLHS) were included in the study population. Patients with HLHS were identified prenatally as being standard risk or high risk (HLHS with highly restrictive or intact atrial septum, mitral stenosis with aortic atresia and/or LV coronary artery sinusoids). Patients with an address over 200 miles from the hospital, diagnosed with heterotaxy syndrome or referred for fetal intervention, were excluded. RESULTS: We identified 312 cases of single ventricle cardiac defect (208 dominant RV; 104 dominant LV) that were diagnosed prenatally. Most (96%) patients with a dominant RV had HLHS. Among the total 312 cases there were 98 (31%) elective terminations of pregnancy (TOP), 12 (4%) cases of spontaneous fetal demise, 12 (4%) cases lost to prenatal follow-up and 190 (61%) live births. Among the 199 patients that underwent fetal echocardiography before 24 weeks' gestation, there were 97 (49%) cases of elective TOP. There was no difference in prenatal outcome between those with a dominant RV and those with a dominant LV (P = 0.98). Of the 190 live births, five received comfort care. With an average of 7 years' follow-up (to obtain data on the Fontan procedure), transplantation-free survival was lower in those with a dominant RV than in those with a dominant LV (standard-risk HLHS odds ratio (OR), 3.0 (P = 0.01); high-risk HLHS OR, 8.8 (P < 0.001)). CONCLUSIONS: The prenatal outcome of cases with single ventricle cardiac defects was similar between those with a dominant RV and those with a dominant LV, however postnatal intermediate-term survival favored those with a dominant LV. High-risk HLHS identified prenatally was associated with the lowest transplantation-free survival. PMID- 25042628 TI - Molecular diversity and hypoglycemic polypeptide-P content of Momordica charantia in different accessions and different seasons. AB - BACKGROUND: Momordica charantia (MC) has been used for treating diabetes mellitus from ancient times in Asia, Africa and South America. There are many MC accessions in local markets. Polypeptide-P as a main hypoglycemic component in MC was first studied in this experiment to illustrate the different contents in MC of different accessions and different harvesting times. RESULTS: Nineteen MC accessions collected from different regions were clustered into three groups using random amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR) molecular markers. Content of polypeptide-P in the tested MC accessions was detected by western blot (WB) method. The WB results revealed that polypeptide-P was detected in MC accessions harvested in June and July but not in September and October. Furthermore, Polypeptide-P content corresponded well with the MC accessions. CONCLUSION: Our results suggest that the MC accessions and the harvesting times or the weather during harvest play significant roles in high content of polypeptide-P. PMID- 25042629 TI - Toxicity of new emerging pollutant tris-(2,3-dibromopropyl) isocyanurate on BALB/c mice. AB - The emerging heterocyclic brominated flame retardant tris-(2,3-dibromopropyl) isocyanurate (TBC), widely used in reinforced plastics, has demonstrated toxicity to fish. However, little is known about its toxicity in rodents. This study aims to determine the effect of TBC on growth, biochemical parameters in serum, organs and related gene expression of both male and female BALB/c mice after gastro gavage administration of 0, 2, 10 and 50 mg kg-1 TBC for 28 days. Results indicated that exposure to TBC had no effects on basic growth and food intake of mice, but significantly increased serum alanine aminotransferase levels in male mice. Histopathological analyses showed that focal necrosis (2, 10 and 50 mg kg-1 TBC-exposed groups) and ballooning degeneration (10 and 50 mg kg-1 TBC-exposed groups) were found in mouse liver, whereas transmission electron microscopy revealed dose-dependent hepatocyte apoptosis, mitochondrial degeneration and endoplasmic reticulum dilation. Histopathological and ultrastructural assessments in the lung showed dose-dependent hyperplasia of pulmonary alveolar epithelium, bronchial congestion, infiltration of inflammatory cells and mitochondrial swelling following TBC exposure. Our results also indicated that mitochondria are one of the major target cytoplasmic organelles for TBC, suggesting that damage in mitochondria is one of the pathways that led to toxic effects in the liver and lung of TBC-treated groups. Moreover, TBC effectively activated the gene expression of p53 in mice liver. Our findings provide strong evidence that TBC induces significant toxicity in mice organs, especially in liver and lung, which play vital roles in detoxification and gas exchange, respectively. This research will contribute to characterize the toxic effects of TBC, which was introduced as one of the candidates for brominated flame retardant replacement. PMID- 25042631 TI - A new measure of tibiofemoral subchondral bone interactions that correlates with early cartilage damage in injured sheep. AB - We have demonstrated previously that chondral damage is associated with increased knee surface velocities following ligament and meniscus injuries in sheep. We tested the hypothesis that cartilage damage scores would correlate with a new bone surface interaction measure that captures complex changes in tibiofemoral alignment, "proximity disturbance" (PD). Six sheep underwent combined anterior cruciate and medial collateral ligament transection (ACL/MCLx), five complete lateral meniscectomy (Mx), and four sham arthrotomy (Sham). Tibiofemoral subchondral bone surfaces were modeled, and the post-operative changes in relative separation of the surfaces (i.e., "proximity") were derived from subject specific in vivo 3D stifle kinematics. Surface areas of regions of near contact were determined, and PD was calculated as the range of change in tibiofemoral proximity, divided by normalized overlapping proximity surface areas between baseline and post-operative time points. Cartilage morphology was graded at dissection. ACL/MCLx PD was significantly elevated relative to Mx and Shams, and correlated with cartilage damage (r(2) = 0.88-0.98). Although not statistically significant, Mx PD values tended to be higher than those of Shams, and correlated with cartilage damage. Results from both injury models suggest that increasing change in tibiofemoral surface alignment may be increasingly deleterious to long term cartilage health in sheep. PMID- 25042633 TI - Future directions of clinical laboratory evaluation of pregnancy. AB - In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss (RPL) or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant. New understanding leads to the concept that the activated innate response is vital for pregnancy and this can result in more effective testing and treatment to prevent an abnormal pregnancy in the future. We describe here only three such areas for future testing: one area involves sperm and semen and factors necessary for successful fertilization; another area would determine conditions for production of growth factors necessary for implantation in the uterus; finally, the last area would be to determine conditions necessary for the vascularization of the placenta and growing fetus by activated natural killer (NK) cells (combinations of killer cell immunoglobulin-like receptor (KIR) family genes with HLA-C haplotypes) that lead to capability of secreting angiogenic growth factors. These areas are novel but understanding their role in pregnancy can lead to insight into how to maintain and treat pregnancies with complicating factors. PMID- 25042635 TI - Bromolactamization: key step in the stereoselective synthesis of enantiomerically pure, cis-configured perhydropyrroloquinoxalines. AB - Compounds based on the pyrroloquinoxaline system can interact with serotonin 5 HT3 , cannabinoid CB1 , and MU-opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)-14A is presented. Introduction of the cyclohexenyl ring at the N-atom of (S)-proline derivatives 8 or methyl (S)-pyroglutamate (12) led to the N-cyclohexenyl substituted pyrrolidine derivatives 4 and 13, respectively. All attempts to cyclize the (S)-proline derivatives 4 with a basic pyrrolidine N-atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R) 13bA and (S,S)-13bB with LiO(t) Bu and NBS provided the tricyclic bromolactam (S,R,R,R)-14A with high diastereoselectivity from (S,R)-13bA, but did not transform the diastereomer (S,S)-13bB. The different behavior of the diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB is explained by different energetically favored conformations. PMID- 25042632 TI - Immunobiology of congenital cytomegalovirus infection of the central nervous system-the murine cytomegalovirus model. AB - Congenital human cytomegalovirus infection is a leading infectious cause of long term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8(+) T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed. PMID- 25042634 TI - Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells. AB - High-mobility group box (HMGB) proteins, a family of chromatin-associated nuclear proteins, play amazingly multifaceted roles in the immune system of mammals. Thus far, little is known about the nucleocytoplasmic distribution of HMGBs in teleosts. The present study systematically investigated the dynamic localization of all six HMGB proteins in Ctenopharyngodon idella kidney (CIK) cells. Under basal conditions, all HMGBs exclusively localized to the nucleus. Grass carp reovirus (GCRV), polyinosinic-polycytidylic (poly(I?C)) potassium salt and lipopolysaccharide (LPS) challenge evoked the nuclear export of HMGBs to various degrees: GCRV challenge induced the highest nuclear export of CiHMGB2b, and poly(I?C) and LPS evoked the highest nucleocytoplasmic shuttling of CiHMGB1b. Overall, the nucleocytoplasmic shuttling of CiHMGB2a and CiHMGB3b was rarely induced by these challenges. Dynamic imaging uncovered that the nucleocytoplasmic GCRV-induced relocation of CiHMGB2b occurred in cells undergoing karyotheca rupture, apoptosis or proliferation. Western blot analyses were used to examine HMGB-EGFP fusion proteins in whole cell lysates, cytosol, nuclear fractions and culture medium. Further investigation demonstrated the nuclear retention of N terminal HMG-boxes and the nucleocytoplasmic distribution of the C-terminal acidic tails. Comparative analyses of the dynamic relocation of full-length, truncated or chimeric HMGBs confirmed that the intramolecular interaction between HMG-boxes and C-tail domains mediated the nucleocytoplasmic translocation of HMGBs. These results not only provide an overall understanding of the subcellular localization of HMGBs, but also reveal the induction mechanism of the nucleocytoplasmic translocation of HMGBs by GCRV challenge, which lays a foundation for further studies on the interactions among pathogens, HMGBs and pattern recognition receptors in the innate immunity of teleosts. PMID- 25042636 TI - Autocrine/paracrine sphingosine-1-phosphate fuels proliferative and stemness qualities of glioblastoma stem cells. AB - Accumulating reports suggest that human glioblastoma contains glioma stem-like cells (GSCs) which act as key determinants driving tumor growth, angiogenesis, and contributing to therapeutic resistance. The proliferative signals involved in GSC proliferation and progression remain unclear. Using GSC lines derived from human glioblastoma specimens with different proliferative index and stemness marker expression, we assessed the hypothesis that sphingosine-1-phosphate (S1P) affects the proliferative and stemness properties of GSCs. The results of metabolic studies demonstrated that GSCs rapidly consume newly synthesized ceramide, and export S1P in the extracellular environment, both processes being enhanced in the cells exhibiting high proliferative index and stemness markers. Extracellular S1P levels reached nM concentrations in response to increased extracellular sphingosine. In addition, the presence of EGF and bFGF potentiated the constitutive capacity of GSCs to rapidly secrete newly synthesized S1P, suggesting that cooperation between S1P and these growth factors is of central importance in the maintenance and proliferation of GSCs. We also report for the first time that S1P is able to act as a proliferative and pro-stemness autocrine factor for GSCs, promoting both their cell cycle progression and stemness phenotypic profile. These results suggest for the first time that the GSC population is critically modulated by microenvironmental S1P, this bioactive lipid acting as an autocrine signal to maintain a pro-stemness environment and favoring GSC proliferation, survival and stem properties. PMID- 25042637 TI - Upconverting nanoparticles: a versatile platform for wide-field two-photon microscopy and multi-modal in vivo imaging. AB - Lanthanide-doped upconverting nanoparticles (UCNPs) have recently attracted enormous attention in the field of biological imaging owing to their unique optical properties: (1) efficient upconversion photoluminescence, which is intense enough to be detected at the single-particle level with a (nonscanning) wide-field microscope setup equipped with a continuous wave (CW) near-infrared (NIR) laser (980 nm), and (2) resistance to photoblinking and photobleaching. Moreover, the use of NIR excitation minimizes adverse photoinduced effects such as cellular photodamage and the autofluorescence background. Finally, the cytotoxicity of UCNPs is much lower than that of other nanoparticle systems. All these advantages can be exploited simultaneously without any conflicts, which enables the establishment of a novel UCNP-based platform for wide-field two photon microscopy. UCNPs are also useful for multimodal in vivo imaging because simple variations in the composition of the lattice atoms and dopant ions integrated into the particles can be easily implemented, yielding various distinct biomedical activities relevant to magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). These multiple functions embedded in a single type of UCNPs play a crucial role in precise disease diagnosis. The application of UCNPs is extended to therapeutic fields such as photodynamic and photothermal cancer therapies through advanced surface conjugation schemes. PMID- 25042638 TI - Fast, Ca2+-dependent exocytosis at nerve terminals: shortcomings of SNARE-based models. AB - Investigations over the last two decades have made major inroads in clarifying the cellular and molecular events that underlie the fast, synchronous release of neurotransmitter at nerve endings. Thus, appreciable progress has been made in establishing the structural features and biophysical properties of the calcium (Ca2+) channels that mediate the entry into nerve endings of the Ca2+ ions that trigger neurotransmitter release. It is now clear that presynaptic Ca2+ channels are regulated at many levels and the interplay of these regulatory mechanisms is just beginning to be understood. At the same time, many lines of research have converged on the conclusion that members of the synaptotagmin family serve as the primary Ca2+ sensors for the action potential-dependent release of neurotransmitter. This identification of synaptotagmins as the proteins which bind Ca2+ and initiate the exocytotic fusion of synaptic vesicles with the plasma membrane has spurred widespread efforts to reveal molecular details of synaptotagmin's action. Currently, most models propose that synaptotagmin interfaces directly or indirectly with SNARE (soluble, N-ethylmaleimide sensitive factor attachment receptors) proteins to trigger membrane fusion. However, in spite of intensive efforts, the field has not achieved consensus on the mechanism by which synaptotagmins act. Concurrently, the precise sequence of steps underlying SNARE-dependent membrane fusion remains controversial. This review considers the pros and cons of the different models of SNARE-mediated membrane fusion and concludes by discussing a novel proposal in which synaptotagmins might directly elicit membrane fusion without the intervention of SNARE proteins in this final fusion step. PMID- 25042639 TI - Biodegradable ethylene-bis(propyl)disulfide-based periodic mesoporous organosilica nanorods and nanospheres for efficient in-vitro drug delivery. AB - Periodic mesoporous organosilica nanorods and nanospheres are synthesized from 1,4-bis(triethoxysilyl)ethylene and bis(3-ethoxysilylpropyl)disulfide. The nanosystems present the long-range order of the hexagonal nanostructure. They are degraded in simulated physiological conditions. The loading and release of doxorubicin with these nanosystems are both pH dependent. These nanoparticles are endocytosed by breast cancer cells and are very efficient for doxorubicin delivery in these cells. PMID- 25042640 TI - Microscope-assisted thyroidectomy: Our experience in one hundred and twenty-one consecutive cases. PMID- 25042641 TI - A two-scale approach to electron correlation in multiconfigurational perturbation theory. AB - We present a new approach for the calculation of dynamic electron correlation effects in large molecular systems using multiconfigurational second-order perturbation theory (CASPT2). The method is restricted to cases where partitioning of the molecular system into an active site and an environment is meaningful. Only dynamic correlation effects derived from orbitals extending over the active site are included at the CASPT2 level of theory, whereas the correlation effects of the environment are retrieved at lower computational costs. For sufficiently large systems, the small errors introduced by this approximation are contrasted by the substantial savings in both storage and computational demands compared to the full CASPT2 calculation. Provided that static correlation effects are correctly taken into account for the whole system, the proposed scheme represent a hierarchical approach to the electron correlation problem, where two molecular scales are treated each by means of the most suitable level of theory. PMID- 25042644 TI - Pharmacokinetic study of five ginsenosides using a sensitive and rapid liquid chromatography-tandem mass spectrometry method following single and multiple oral administration of Shexiang Baoxin pills to rats. AB - Shexiang Baoxin pills (SBP) are a traditional Chinese medicine that are used for treating coronary heart disease. Ginsenosides are the main effective components of SBP, but a comprehensive and deep pharmacokinetic study of ginsenosides in SBP, including multiple dosing and linear or nonlinear properties, is lacking. This study was designed to investigate and compare the pharmacokinetic characteristics of ginsenosides in SBP at a single dose and in multiple doses. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of the ginsenosides Rg1, Re, Rb3, Rc and Rb1 in rat plasma. Rats were randomly assigned to receive a single dose of 4, 8 or 12 g/kg and multiple doses (4 g/kg) of SBP for 8, 15 or 22 consecutive days. The results revealed that ginsenosides, following a single oral dose of 4 or 8 g/kg, were absorbed rapidly, with a Tmax ranging from 0.250 to 1.08 h. The AUC0-t and Cmax of the ppd-type ginsenosides Rb3, Rc and Rb1 were greater than those of the ppt-type ginsenosides Rg1 and Re. Nondose-dependent exposure was observed at doses of 4-12 g/kg for all of the ginsenosides. After multiple dosing, the plasma levels of the ppt-type ginsenosides decreased, whereas those of the ppd-type ginsenosides did not change significantly. In conclusion, the LC-MS/MS method was successfully applied to investigate the pharmacokinetics of ginsenosides after single and multiple oral administrations of SBP. The ginsenosides did not accumulate after multiple dosing. The ppd-type ginsenosides displayed more favorable pharmacokinetic properties compared with the ppt-type ginsenosides. PMID- 25042645 TI - Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin. AB - Dissemination of cancer cells from primary to distant sites is a complex process; little is known about the genesis of metastatic changes during disease development. Here we show that the metastatic potential of E2F1-dependent circulating tumour cells (CTCs) relies on a novel function of the hyaluronan mediated motility receptor RHAMM. E2F1 directly up-regulates RHAMM, which in turn acts as a co-activator of E2F1 to stimulate expression of the extracellular matrix protein fibronectin. Enhanced fibronectin secretion links E2F1/RHAMM transcriptional activity to integrin-beta1-FAK signalling associated with cytoskeletal remodelling and enhanced tumour cell motility. RHAMM depletion abolishes fibronectin expression and cell transmigration across the endothelial layer in E2F1-activated cells. In a xenograft model, knock-down of E2F1 or RHAMM in metastatic cells protects the liver parenchyma of mice against extravasation of CTCs, whereas the number of transmigrated cells increases in response to E2F1 induction. Expression data from clinical tissue samples reveals high E2F1 and RHAMM levels that closely correlate with malignant progression. These findings suggest a requirement for RHAMM in late-stage metastasis by a mechanism involving cooperative stimulation of fibronectin, with a resultant tumourigenic microenvironment important for enhanced extravasation and distant organ colonization. Therefore, stimulation of the E2F1-RHAMM axis in aggressive cancer cells is of high clinical significance. Targeting RHAMM may represent a promising approach to avoid E2F1-mediated metastatic dissemination. PMID- 25042646 TI - How did the simple faint get so complicated? Syncope in 2014. PMID- 25042647 TI - Are cardiologists truly better at appropriately selecting patients for stress myocardial perfusion imaging? PMID- 25042648 TI - Catheter based inhibition of arterial calcification by bisphosphonates in an experimental atherosclerotic rabbit animal model. AB - BACKGROUND: Vascular calcification is an active process, sharing common molecular mechanisms with bone formation. Bisphosphonates are components, which inhibit calcification. The aim of the present study was to evaluate the safety and effectiveness of local delivery of the bisphosphonate zoledronate on inhibition of calcium formation in the arterial wall in an experimental animal model. METHODS: Sixteen New Zealand rabbits were placed on vitamin D enriched atherogenic diet for 3 weeks. Subsequently, all animals underwent angiography of abdominal aorta and common iliac arteries. A mixture containing 500 MUg/l zoledronate was delivered on the vascular wall of the target iliac artery, using a dedicated balloon catheter. A placebo mixture was administered on the contralateral iliac artery of each animal, which was used as control. At 28 days all animals were sacrificed. Histologic sections of each common iliac artery were stained with hematoxylin-eosin and von Kossa. Computer-assisted histomorphometry was performed for the calcium content quantification of each section from the target and the control iliac artery. RESULTS: In all animals the local delivery of zoledronate and placebo mixtures was successful and uncomplicated. The mean percentage of the calcium content of the media was higher in the control artery segments compared to the target (2.66 +/- 0.73 versus 1.08 +/- 0.62 % of the area of the media, p<0.01). CONCLUSIONS: Inhibition of vascular calcification by local catheter-based delivery of bisphosphonate zolendronic acid is effective without evident short-term complications. These finding and its potential clinical implication remain to be confirmed in human studies. PMID- 25042649 TI - Miraculous catch of a broken coronary guidewire tip in the right internal carotid artery. PMID- 25042650 TI - Breakfast consumption is not associated with hypertension until via physical fitness: East of England Healthy Hearts Study, 2006-2011. PMID- 25042651 TI - Arterial stiffness in obese populations: is it reduced by aerobic training? PMID- 25042652 TI - Comments on hypertonic saline with furosemide for the treatment of acute congestive heart failure: a systematic review and meta-analysis. PMID- 25042653 TI - Effect of smoking ban at home on adult cardiovascular health: Scottish Health Survey, 2012. PMID- 25042654 TI - DNA methylation inhibition: a novel therapeutic strategy for heart failure. PMID- 25042655 TI - Prevalence and significance of early repolarization in patients presenting with syncope. PMID- 25042656 TI - Inadequate heart rate control despite widespread use of beta-blockers in outpatients with stable CAD: findings from the international prospective CLARIFY registry. AB - BACKGROUND: To use CLARIFY, a prospective registry of patients with stable CAD (45 countries), to explore heart rate (HR) control and beta-blocker use. METHODS: We analyzed the CLARIFY population according to beta-blocker use via descriptive statistics with Pearson's chi(2) test for comparisons, as well as a multivariable stepwise model. RESULTS: Data on beta-blocker use was available for 32,914 patients, in whom HR was 68 +/- 11 bpm; patients with angina, previous myocardial infarction, and heart failure had HRs of 69 +/- 12, 68 +/- 11, and 70 +/- 12 bpm, respectively. 75% of these patients were receiving beta-blockers. Bisoprolol (34%), metoprolol tartrate (16%) or succinate (13%), atenolol (15%), and carvedilol (12%) were mostly used; mean dosages were 49%, 76%, 35%, 53%, and 45% of maximum doses, respectively. Patients aged <65 years were more likely to receive beta-blockers than patients >= 75 years (P<0.0001). Gender had no effect. Subjects with HR <= 60 bpm were more likely to be on beta-blockers than patients with HR >= 70 bpm (P<0.0001). Patients with angina, previous myocardial infarction, heart failure, and hypertension were more frequently receiving beta blockers (all P<0.0001), and those with PAD and asthma/COPD less frequently (both P<0.0001). Beta-blocker use varied according to geographical region (from 87% to 67%). CONCLUSIONS: Three-quarters of patients with stable CAD receive beta blockers. Even so, HR is insufficiently controlled in many patients, despite recent guidelines for the management of CAD. There is still much room for improvement in HR control in the management of stable CAD. PMID- 25042657 TI - Selenium contributes to myocardial injury and cardiac remodeling in heart failure. PMID- 25042658 TI - Left anterior descending coronary artery flow impaired by right ventricular apical pacing: the role of systolic dyssynchrony. AB - INTRODUCTION: Right ventricular (RV) pacing may affect myocardial perfusion and coronary blood flow; however, it remains unknown whether this is related to systolic dyssynchrony induced by RV pacing. This prospective study was aimed to assess the relationship between dyssynchrony and the changes of coronary blood flow. METHODS: Seventy patients with sinus node dysfunction were prospectively enrolled. Coronary flow was evaluated by measuring diastolic velocity time integral (VTI) and duration at the distal-portion of left anterior descending coronary artery (LAD) with transthoracic echocardiography at baseline and follow up. Systolic dyssynchrony was assessed with tissue Doppler imaging by time standard deviation to peak systolic velocity of 12 left ventricular segments (Ts SD, cutoff value >= 33 ms). RESULTS: Adequate data for analysis was available from 65 patients. At follow-up (mean follow up time: 127 +/- 45 days), LAD velocity-time integral (LAD-VTI: 12.1 +/- 4.2 vs. 10.7 +/- 4.6 cm, p<0.001) was decreased and there was deterioration of left ventricular systolic function (left ventricular ejection fraction: 65 +/- 7% vs. 62 +/- 7%). However, these changes were only detected in those with RV pacing induced systolic dyssynchrony. Significant reduction of LAD-VTI (defined as >= 5%) occurred in 34 (52%) patients which was more prevalent in those with pacing-induced systolic dyssynchrony than those without (85.3% versus 16.1%, chi(2)=31.1, p<0.001). Though similar at baseline, LAD-VTI was significantly lower in the dyssynchrony group at follow up (p<0.001). Cox-regression analysis showed that pacing-inducing systolic dyssynchrony [hazard ratio (HR): 3.62, p=0.009] and higher accumulative pacing percentage (HR: 1.02, p=0.002) were independently associated with reduction of LAD-VTI. ROC curve demonstrated that accumulative pacing percentage >= 35% was 97% sensitive and 84% specific in revealing significant reduction (area under the curve: 0.961, p<0.001). CONCLUSIONS: RV pacing induced dyssynchrony is associated with reduced coronary flow and this may account for, in part, the deleterious effect of RV pacing on ventricular function over time. PMID- 25042659 TI - Association between obesity and severity of coronary artery disease at the time of acute myocardial infarction: another piece of the puzzle in the "obesity paradox". PMID- 25042660 TI - Takotsubo syndrome as a complication of Pickering syndrome, and perhaps hypertensive emergencies. PMID- 25042661 TI - Beneficial effect of high dose statins on the vascular wall in patients with repaired aortic coarctation? AB - BACKGROUND: Carotid intima-media thickness (CIMT) is a marker for atherosclerosis. Adult post-coarctectomy patients (CoA) demonstrate an increased cardiovascular risk and increased CIMT compared to controls. This study evaluates the effect of high dose statins on the change in CIMT and cardiovascular risk. METHODS: We designed a multicenter, prospective, randomized, open label trial with blinded endpoint (PROBE design) to evaluate the effect of three year treatment with atorvastatin 80 mg on CIMT and cardiovascular risk. Primary endpoint was CIMT measured by B mode ultrasonography. Secondary endpoints were mortality and morbidity due to cardiovascular disease and serum lipids. RESULTS: 155 patients (36.3 +/- 11.8 years, 96 (62%) male) were randomized (atorvastatin=80, no treatment=75). There was no significant effect of atorvastatin on the change in CIMT (treatment effect -0.005, 95% CI, -0.039 0.029; P=0.76). A significant effect on serum cholesterol and LDL levels was found (- 0.71, 95% CI, - 1.16 to - 0.26; P = 0.002 vs - 0.66, 95% CI - 1.06 to - 0.26; P = 0.001). There was no difference in secondary outcome measures. Baseline CIMT was higher in hypertensive compared to normotensive CoA. (0.69 +/- 0.16 mm vs 0.61 +/- 0.98 mm; P=0.002). Hypertension (beta=0.043, P=0.031) was the strongest determinant CIMT. CONCLUSION: Three year treatment with atorvastatin does not lead to a reduction of CIMT and secondary outcome measures, despite a decrease in total cholesterol and LDL levels. Hypertensive CoA demonstrate the highest CIMT and the largest CIMT progression. Blood pressure control should be the main focus in CoA to decrease cardiovascular risk. PMID- 25042662 TI - Authors' responses concerning working hours, sleep duration and cardiovascular risk. PMID- 25042663 TI - Quantitative assessment of tissue prolapse on optical coherence tomography and its relation to underlying plaque morphologies and clinical outcome in patients with elective stent implantation. AB - BACKGROUND: Tissue prolapse (TP) is sometimes observed after percutaneous coronary intervention (PCI), but its clinical significance remains unclear. We investigated the relationship between TP volume on optical coherence tomography (OCT) after PCI and underlying plaque morphologies and the impact of TP on clinical outcomes. METHODS: We investigated 178 native coronary lesions with normal pre-PCI creatine kinase-myocardial band (CK-MB) values (154 lesions with stable angina; 24 with unstable angina). TP was defined as tissue extrusion from stent struts throughout the stented segments. All lesions were divided into tertiles according to TP volume. The differences in plaque morphologies and 9 month clinical outcomes were evaluated. RESULTS: TP volume was correlated with lipid arc (r=0.374, p<0.0001) and fibrous cap thickness (r=-0.254, p=0.001) at the culprit sites. The frequency of thin-cap fibroatheroma (TCFA) was higher in the largest TP tertile (>= 1.38 mm(3)) (p=0.015). In multivariate analysis, right coronary artery lesion (odds ratio [OR]: 2.779; p=0.005), lesion length (OR: 1.047; p=0.003), and TCFA (OR: 2.430; p=0.022) were related to the largest TP tertile. Lesions with post-PCI CK-MB elevation (>upper reference limit) had larger TP volume than those without (1.28 [0.48 to 3.97] vs. 0.70 [0.16 to 1.64] mm(3), p=0.007). The prevalence of cardiac events during the 9-month follow-up was not significantly different according to TP volume. CONCLUSIONS: TP volume on OCT was related to plaque morphologies and instability, and post-PCI myocardial injury, but not to worse 9-month outcomes. PMID- 25042664 TI - Reversible tachycardia mediated cardiomyopathy after radiofrequency ablation of idiopathic left ventricular tachycardia. PMID- 25042665 TI - Which number of morphological types of ventricular premature beats predicts poor prognosis in subjects with various cardiomyopathies without obstructed coronary arteries? PMID- 25042666 TI - Increased mortality after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and low ejection fraction: a meta-analysis of 6898 patients. AB - BACKGROUND: There is conflicting evidence regarding the safety and efficacy of transcatheter aortic valve implantation (TAVI) procedures in patients with severe aortic stenosis and low left ventricular ejection fraction (EF). The primary aim of this study was to determine the impact of TAVI on short- and long-term mortality in patients with low EF (EF <50%); the secondary aim was to analyze the impact of TAVI procedure on EF recovery in the same setting of patients. METHODS AND RESULTS: Twenty-six studies enrolling 6898 patients with severe aortic stenosis undergoing TAVI procedure were included in the meta-analysis and analyzed for 30-day, 6-month and 1-year all-cause and cardiovascular mortality; a further meta-analysis was also performed in patients with low EF to assess EF changes post TAVI. In low EF patients, both all-cause and cardiovascular short- and long-term mortality were significantly higher when compared to patients with normal EF (30-day-all-cause mortality: 0.13; 95% confidence interval [CI]: 0.01 to 0.25, I(2)=49.65, Q=21.85; 1-year-all-cause mortality: 0.25; 95% [CI]: 0.16 to 0.34, I(2)=25.57, Q=16.12; 30-day-cardiovascular mortality: 0.03; 95% [CI]: -0.31 to 0.36, I(2)=66.84, Q=6.03; 1-year-cardiovascular mortality: 0.29; 95% [CI]: 0.12 to 0.45, I(2)=0.00, Q=1.88). Nevertheless, in low EF patients TAVI was associated with a significant recovery of EF, which started at discharge and proceeded up to 1-year-follow-up. CONCLUSIONS: Patients with low EF severe aortic stenosis have higher mortality following TAVI compared to normal EF patients, despite a significant and sustained improvement in EF. PMID- 25042667 TI - Unusual presentation of hypothalamic hamartoma with hypersomnia in an adult patient. AB - We report a patient with polysomnography findings related to hypersomnia, as a primary presenting symptom, who was shown to have stereotypical gelastic seizures. Her cranial magnetic resonance imaging revealed a hypothalamic hamartoma in the posterior region of the hypothalamus. The patient had no previous history of gelastic seizures. We suggest that patients who present with hypersomnia should be investigated for gelastic seizures in order to avoid misdiagnosis and receive appropriate treatment. PMID- 25042668 TI - Introduction. A "neurovascular unit" approach in newborns with HIE: can we improve outcomes? PMID- 25042669 TI - Complicated pediatric subglottic granular cell tumor with extensive intraluminal and extraluminal invasion. AB - Subglottic granular cell tumors (GCT) are rare, potentially life threatening benign tumors. Complete resection is necessary, yet care must be taken to preserve laryngeal function. We present the first description of a pediatric subglottic GCT with extensive invasion beyond the confines of the subglottis to include the vocal folds and central neck. Urgent endoscopic debulking avoided tracheotomy and facilitated extubation. Later, complete resection required hemithyroidectomy, laryngofissure and partial cricotracheal resection. We conclude that endoscopic debulking is an appropriate initial treatment. Transmural extension should be suspected in tumors larger than 1cm and warn of the need for tracheal resection. PMID- 25042670 TI - Scalable antifouling reverse osmosis membranes utilizing perfluorophenyl azide photochemistry. AB - We present a method to produce anti-fouling reverse osmosis (RO) membranes that maintains the process and scalability of current RO membrane manufacturing. Utilizing perfluorophenyl azide (PFPA) photochemistry, commercial reverse osmosis membranes were dipped into an aqueous solution containing PFPA-terminated poly(ethyleneglycol) species and then exposed to ultraviolet light under ambient conditions, a process that can easily be adapted to a roll-to-roll process. Successful covalent modification of commercial reverse osmosis membranes was confirmed with attenuated total reflectance infrared spectroscopy and contact angle measurements. By employing X-ray photoelectron spectroscopy, it was determined that PFPAs undergo UV-generated nitrene addition and bind to the membrane through an aziridine linkage. After modification with the PFPA-PEG derivatives, the reverse osmosis membranes exhibit high fouling-resistance. PMID- 25042671 TI - Incidence of ano-genital and head and neck malignancies in women with a previous diagnosis of cervical intraepithelial neoplasia. AB - OBJECTIVE: The objective of this study was to determine if women with a history of Cervical Intraepithelial Neoplasia grades 2 and 3 (CIN2 and CIN3) are at increased long-term risk for developing non-cervix HPV-related malignancies. MATERIAL AND METHODS: Women diagnosed with CIN2 or CIN3 between 1980 and 2005 were identified from the British Columbia (BC) Cancer Agency Cervical Cancer Screening Program's database. These patients' records were then cross-referenced with the BC Cancer Registry for diagnosis of vulvar, vaginal, anal or head and neck (HN) cancers during the period subsequent to their diagnosis of CIN. Standardized incidence ratios (SIR) were generated according to expected rates of each cancer. RESULTS: 54,320 women with a diagnosis of CIN2 or CIN3 were identified between 1985 and 2005. The crude incidence rate for non-cervix HPV related cancers was 35.4 per 100,000 person-years (8.6 for vagina, 17.6 for vulva, 3.7 for anal canal and 5.5 for HN). The SIR was 1.9 (95% CI 1.3-2.7) for all non-cervix cancers, 6.7 (95% CI: 3.0-12.8) for vagina, 2.9 (95% CI: 1.7-4.6) for vulva, 1.8 (95% CI: 0.4-4.7) for anal canal, and 0.6 (95% CI: 0.2-1.4) for HN. There were statistically significant increases in anal cancers for years 5-9 and in HN cancers for years 0.5-5. CONCLUSION: BC women with a history of CIN2 or CIN3 are at relatively high risk of developing non-cervical HPV-related malignancies. The findings of this study suggest that interventions such as vaccination against high-risk HPV or long-term screening for these other cancers should be evaluated. PMID- 25042672 TI - A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer. AB - OBJECTIVE: To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy. METHODS: Data were analyzed and compared for all patients with stage III-IV EOC who underwent optimal primary cytoreduction (residual disease <= 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001-12/2005) or primary IV/IP chemotherapy (1/2005-7/2011). RESULTS: We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57-1.06; p=0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38-0.83; p=0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56 1.11; p=0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39-0.89; p=0.01). CONCLUSIONS: In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC. PMID- 25042673 TI - A single-nucleotide polymorphism-based approach for rapid and cost-effective genetic wolf monitoring in Europe based on noninvasively collected samples. AB - Noninvasive genetics based on microsatellite markers has become an indispensable tool for wildlife monitoring and conservation research over the past decades. However, microsatellites have several drawbacks, such as the lack of standardisation between laboratories and high error rates. Here, we propose an alternative single-nucleotide polymorphism (SNP)-based marker system for noninvasively collected samples, which promises to solve these problems. Using nanofluidic SNP genotyping technology (Fluidigm), we genotyped 158 wolf samples (tissue, scats, hairs, urine) for 192 SNP loci selected from the Affymetrix v2 Canine SNP Array. We carefully selected an optimised final set of 96 SNPs (and discarded the worse half), based on assay performance and reliability. We found rates of missing data in this SNP set of <10% and genotyping error of ~1%, which improves genotyping accuracy by nearly an order of magnitude when compared to published data for other marker types. Our approach provides a tool for rapid and cost-effective genotyping of noninvasively collected wildlife samples. The ability to standardise genotype scoring combined with low error rates promises to constitute a major technological advancement and could establish SNPs as a standard marker for future wildlife monitoring. PMID- 25042674 TI - Effect of temperature change on anammox activity. AB - Autotrophic nitrogen removal appears as a prerequisite for the implementation of energy autarchic municipal wastewater treatment plants. Whilst the application of anammox-related technologies in the side-stream is at present state of the art, the feasibility of this energy-efficient process in main-stream conditions is still under investigation. Lower operating temperatures and ammonium concentrations, together with a demand for high and stable nitrogen removal efficiency, represent the main challenges to overcome for this appealing new frontier of the wastewater treatment field. In this study, we report the short term effect of temperature on the maximum biomass specific activity of anaerobic ammonium oxidizing (anammox) bacteria as evaluated by means of batch tests. The experiments were performed on anammox biomass sampled from two full-scale reactors and two lab-scale reactors, all characterized by different reactor configurations and operating conditions. The results indicate that for the anammox conversion, the temperature dependency cannot be accurately modeled by one single Arrhenius coefficient (i.e., theta) as typically applied for other biological processes. The temperature effect is increasing at lower temperatures. Adaptation of anammox bacteria after long-term cultivation at 20 and 10 degrees C was observed. Implications for modeling and process design are finally discussed. PMID- 25042675 TI - Rapid determination of ibotenic acid and muscimol in human urine. PMID- 25042676 TI - Usefulness of presepsin (sCD14 subtype) measurements as a new marker for the diagnosis and prediction of disease severity of sepsis in the Korean population. AB - PURPOSE: Presepsin has recently emerged as a new useful sepsis marker, and our study is focused on the usefulness of presepsin as earlier detection and monitoring biomarker for sepsis comparing with other conventional biomarkers. MATERIALS AND METHODS: We compared the mean values of presepsin, procalcitonin, interleukin 6, and high-sensitivity C-reactive protein levels between infection group and noninfection group of study subjects and assessed whether the values decreased during treatment. Furthemore, we evaluated the diagnostic accuracy of presepsin in sepsis and compared the mean level of presepsin to the Acute Physiology and Chronic Health Evaluation III score and mortality rate on the 30th day. RESULTS: Mean presepsin levels were significantly different between infection group and noninfection group (1403.47 pg/mL vs 239.00 pg/mL). During treatment, mean levels of presepsin decreased significantly, and in the receiver operating characteristic curve analysis, the area under curve value of presepsin was significantly higher than that of other biomarkers. The presepsin levels did not correlate significantly with Acute Physiology and Chronic Health Evaluation III scores and mortality rates on the 30th day. CONCLUSIONS: Presepsin showed significantly higher values in infection group than in noninfection group. The diagnostic accuracy of presepsin was higher than other conventional biomarkers. For early diagnosis and treatment of bacterial sepsis, presepsin could be a more useful marker than the other markers. PMID- 25042677 TI - Hepatitis E genotype 4 virus from feces of monkeys infected experimentally can be cultured in PLC/PRF/5 cells and upregulate host interferon-inducible genes. AB - The understanding of the interaction between hepatitis E virus (HEV) and its host cells has been impeded greatly by the absence of a cell culture system. In this study, an efficient cultivation method was developed in PLC/PRF/5 cells for HEV genotype 4 from the feces of monkeys infected experimentally. Compared to minimal essential medium (MEM), mixed Dulbecco's Modified Eagle's Medium (DMEM)/M199 improved the infection efficiency of HEV in PLC/PRF/5 cells. The incubation time and temperature were set at 6 hr and 40 degrees C, respectively. Compared to a 100% ELISA positive ratio (EPR) of 1 * 10(6) copies/ml HEV inoculated flasks, the ELISA positive ratio was 100%, 75%, 37.5%, and 100% for flasks inoculated with HEV incubated for 30 min under the conditions of pH 3.0, pH 11.0, 56 degrees C and delipidation treatment, respectively. Gene expression profiles of HEV inoculated and control PLC/PRF/5 cells were assayed using a microarray. Four interferon-inducible genes, IFI27, IFI6, Mx1, and CMPK2, were up-regulated during HEV-infection. Furthermore, the replication of HEV was inhibited at 3-14 days after treatment with 500 IU/ml IFN-alpha2b. PMID- 25042678 TI - End-to-side repair for aortic arch lesions offers excellent chances to reach adulthood without reoperation. AB - BACKGROUND: The purpose of this study was to determine the rate of reinterventions from birth to adulthood after end-to-side anastomosis technique for interrupted and hypoplastic aortic arches. Multicenter data have shown that more than half of patients require arch reintervention in the 2 decades after repair. METHODS: The follow-up of 170 consecutive patients undergoing end-to-side repair through sternotomy for interrupted aortic arch (95) or coarctation (75) in one institution between 1985 and 2012 was reviewed. Associated lesions included ventricular septal defect (143) and bicuspid aortic valve (50). One-stage repair was performed in 158 patients (93%). RESULTS: There were 12 hospital deaths (7%), and 4 early arch reinterventions (2 for bronchial compression). Eleven hospital survivors (7%) were lost to follow-up. After a mean of 10 +/- 6 years, there were 9 late deaths. Eighteen-year survival was 93% (95% confidence interval: 87 to 96). Eight patients had bronchial compression, 5 during initial stay and 3 after hospital discharge; 2 of them required surgery. Eighteen-year freedom from arch reoperation was 87% (95% confidence interval: 76 to 93). An additional 10 patients underwent balloon dilation, for an 18-year freedom from reintervention (balloon dilation or surgery) of 77% (95% confidence interval: 65 to 85). At last follow-up, 24 patients (16%) had an echocardiographic gradient greater than 25 mm Hg. Blood pressure was recorded in 105 patients, and only 11 (10%) were hypertensive. CONCLUSIONS: The end-to-side anastomosis technique for repair of aortic arch lesions results in a low rate of mortality, arch reoperation, and late hypertension. The development of arch obstruction requiring balloon dilation warrants continuous follow-up of these patients. PMID- 25042679 TI - Sonographic diagnosis of ectopia cordis before 9 weeks of gestation. PMID- 25042680 TI - Extracorporeal membrane oxygenation therapy for pulmonary decompression illness. PMID- 25042681 TI - Novel diketopyrroloppyrrole random copolymers: high charge-carrier mobility from environmentally benign processing. AB - The random copolymerization between two different diketopyrrolopyrole-based conducting units represents a suitable synthetic strategy to increase the solubility of polymer semiconductors in a non-chlorinated solvent, without compromising the high charge-carrier mobility. Highly performing thin-film transistors processed from environmentally benign solvents such as tetralin are demonstrated for the first time, resulting in a mobility of greater than 5 cm(2) V(-1) s(-1). PMID- 25042682 TI - Bringing biocuration to China. AB - Biocuration involves adding value to biomedical data by the processes of standardization, quality control and information transferring (also known as data annotation). It enhances data interoperability and consistency, and is critical in translating biomedical data into scientific discovery. Although China is becoming a leading scientific data producer, biocuration is still very new to the Chinese biomedical data community. In fact, there currently lacks an equivalent acknowledged word in Chinese for the word "curation". Here we propose its Chinese translation as (Pinyin) "shen bian", based on its implied meanings taken by biomedical data community. The 8th International Biocuration Conference to be held in China (http://biocuration2015.tilsi.org) next year bears the potential to raise the general awareness in China of the significant role of biocuration in scientific discovery. However, challenges are ahead in its implementation. PMID- 25042683 TI - Meropenem in children receiving continuous renal replacement therapy: clinical trial simulations using realistic covariates. AB - Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to (1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and (2) estimate the effect of fluid overload on target attainment. Clinical trial simulations were employed to evaluate target attainment of meropenem in various age groups and degrees of fluid overload in children receiving CRRT. Pharmacokinetic parameters were extracted from published literature, and 287 patients from the prospective pediatric CRRT registry database provided realistic clinical covariates including patient weight, fluid overload, and CRRT prescription characteristics. Target attainment at 40% and 75% time above the minimum inhibitory concentration was evaluated. Clinical trial simulations demonstrated that children greater than 5 years of age achieved acceptable target attainment with a dosing regimen of 20 mg/kg every 12 hours. In children less than 5, however, increased dosing of 20 mg/kg every 8 hours was needed to optimize target attainment. Fluid overload did not affect target attainment. These in silico model predictions will need to be verified in vivo in children receiving meropenem and CRRT. PMID- 25042684 TI - Reply to external validation of a model to predict local failure after radical cystectomy. PMID- 25042685 TI - A sensitive protocol for FOXP3 epigenetic analysis in scarce human samples. PMID- 25042686 TI - Childhood cognitive development as a skill. AB - Theories view childhood development as being either driven by structural maturation of the brain or being driven by skill-learning. It is hypothesized here that working memory (WM) development during childhood is partly driven by training effects in the environment, and that similar neural mechanisms underlie training-induced plasticity and childhood development. In particular, the functional connectivity of a fronto-parietal network is suggested to be associated with WM capacity. The striatum, dopamine receptor D2 (DRD2) activity, and corticostriatal white-matter tracts, on the other hand, seem to be more important for plasticity and change of WM capacity during both training and development. In this view, the development of WM capacity during childhood partly involves the same mechanisms as skill-learning. PMID- 25042687 TI - Origins and activation of prophenoloxidases in the digestive tract of the cricket, Gryllus bimaculatus. AB - The function of Phenoloxidases (POs) in sclerotization and defense in insects is well understood, but little is known concerning their occurrence, origins, and function in the digestive tract. In Gyrllus bimaculatus gut all of the PO activity is found in the lumen of the digestive tract, and no detectible activity is found in homogenates of the gut epithelium or secretions from incubated epithelial tissues. Prophenoloxidases (PPOs) are synthesized in the hemocytes of Bombyx mori and are transported into the cuticle. It is suggested that the PPOs in the caecal lumen of G. bimaculatus likewise are synthesized in hemocytes and are transported by unknown means into the caecal lumen, where they are activated to POs by trypsin. Peristalsis transports the POs both forward into the crop and posterior within the peritrophic membrane into the hind gut. The PPOs in the hemolymph consist of a trimer (270-280 kDa) and a tetramer (340-370 kDa). The active POs in the gut lumen consist of a monomer (85-95 kDa) in addition to an activated trimer and tetramer. PMID- 25042688 TI - Pragmatic trials can be designed as optimal medical care: principles and methods of care trials. AB - OBJECTIVES: The way clinical research and care are currently separated encourages the practice of unverifiable medicine. Some pragmatic trials can be designed (1) to guide proper medical conduct in the presence of uncertainty and (2) to govern the distinction between unvalidated and validated care. METHODS: Care trials are simple randomized trials integrated into a practice they regulate in the interest of present patients. The fundamental principle guiding the design of a care trial is the protection of the patient being offered medical care that has not yet been validated. Selection criteria are inclusive, to assist most current patients confronted with the problem. The trial entails no extra tests or risks beyond what is proven beneficial. Endpoints are pre-defined, simple, valuable and resistant to bias. Follow-up visits and tests are routine. Data is collected in simple case-report forms. RESULTS: Care trials protect present patients from both unverifiable medicine and research performed for extraneous interests. They provide prudent care when evidence is lacking. They should not be obstructed by the need for separate funding, or by bureaucracy. CONCLUSION: Care trials can identify which medical alternative should be standard therapy. In the meantime, they provide optimal care in the presence of uncertainty. PMID- 25042689 TI - Type 1 diabetes-associated cognitive decline: a meta-analysis and update of the current literature. AB - BACKGROUND: Type 1 diabetes (T1D) can have a significant impact on brain structure and function, which is referred to as T1D-associated cognitive decline (T1DACD). Diabetes duration, early onset disease, and diabetes-associated complications are all proposed as factors contributing to T1DACD. However, there have been no comparisons in T1DACD between children and adults with T1D. To obtain a better insight into the occurrence and effects of T1DACD in T1D, the aim of the present meta-analysis was to investigate differences between children and adults and to analyse factors contributing T1DACD. METHODS: Two electronic databases were consulted: PubMed and ISI Web of Knowledge. Literature published up until the end of 2013 was included in the analysis. Effect sizes (Cohen's d), which are standardized differences between experimental and control groups, were calculated. RESULTS: There was a small to modest decrease in cognitive performance in T1D patients compared with non-diabetic controls. Children with T1D performed worse while testing for executive function, full intelligence quotient (IQ), and motor speed, whereas adults with T1D performed worse while testing the full, verbal and performance IQ, part of the executive function, memory, spatial memory, and motor speed. Episodes of severe hypoglycemia, chronic hyperglycemia, and age of onset can be significant factors influencing cognitive function in T1D. CONCLUSIONS: The findings in the literature suggest that T1DACD is more severe in adults than children, indicating that age and diabetes duration contribute to this T1DACD. PMID- 25042690 TI - Novel ametantrone-amsacrine related hybrids as topoisomerase IIbeta poisons and cytotoxic agents. AB - The precise definition of the structural requirements for effective topoisomerase II poisoning by drug molecules is still an elusive issue. In the attempt to better define a pharmacophoric pattern, we prepared several conjugates combining the chemical features of two well-known topoisomerase II poisons, amsacrine and ametantrone. Indeed, an appropriate fusion geometry, which entails the anthracenedione moiety of ametantrone appropriately connected to the methanesulfonamidoaniline side chain of amsacrine, elicits DNA-intercalating properties, the capacity to inhibit the human topoisomerase IIbeta isoform, and cytotoxic activity resembling that of the parent compounds. In addition, the properties of the lateral groups linked to the anthracenedione group play an important role in modulating DNA binding and cell cytotoxicity. Among the compounds tested, 10, 11, and 19 appear to be promising for further development. PMID- 25042692 TI - A novel method to measure sensory nerve conduction of the supraclavicular nerve. AB - INTRODUCTION: In this report we describe a reliable method for recording sensory nerve action potentials (SNAPs) of the supraclavicular nerve. METHODS: Supraclavicular SNAPs were recorded by placing a surface active electrode at the posterior border of the sternocleidomastoid muscle at a distance of 6 cm from the sternoclavicular joint. The nerve was stimulated at the lower border of the clavicle 4.5 cm lateral to the sternoclavicular joint. RESULTS: Supraclavicular SNAPs were recorded bilaterally from 20 healthy volunteers. Mean onset latency was 1.0 +/- 0.2 ms, and mean peak latency was 1.4 +/- 0.3 ms. Mean baseline-to peak amplitude for the SNAPs was 6.1 +/- 2.2 uV, and mean maximum conduction velocity was 59.8 +/- 6.2 m/s. The mean percentage of side-to-side difference in amplitude was 12.9 +/- 11.0%. CONCLUSIONS: Supraclavicular SNAPs could be obtained in all normal subjects. Assessment of supraclavicular nerve conduction is very useful in the diagnosis of supraclavicular neuropathy. PMID- 25042691 TI - Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. AB - Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycle Disorders Consortium, we evaluated whether treatment with NaPBA leads to a decrease in plasma BCAA levels. Our analysis shows that NaPBA use independently affects the plasma BCAA levels even after accounting for multiple confounding covariates. Moreover, NaPBA use increases the risk for BCAA deficiency. This effect of NaPBA seems specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use. Our study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications. Our results indicate that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency. On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism. PMID- 25042694 TI - The core of after death care in relation to organ donation - a grounded theory study. AB - OBJECTIVES: The aim of this study was to investigate how intensive and critical care nurses experience and deal with after death care i.e. the period from notification of a possible brain dead person, and thereby a possible organ donor, to the time of post-mortem farewell. RESEARCH METHODOLOGY: Grounded theory, based on Charmaz' framework, was used to explore what characterises the ICU-nurses concerns during the process of after death and how they handle it. Data was collected from open-ended interviews. FINDINGS: The core category: achieving a basis for organ donation through dignified and respectful care of the deceased person and the close relatives highlights the main concern of the 29 informants. This concern is categorised into four main areas: safeguarding the dignity of the deceased person, respecting the relatives, dignified and respectful care, enabling a dignified farewell. CONCLUSION: After death care requires the provision of intense, technical, medical and nursing interventions to enable organ donation from a deceased person. It is achieved by extensive nursing efforts to preserve and safeguard the dignity of and respect for the deceased person and the close relatives, within an atmosphere of peace and tranquillity. PMID- 25042693 TI - Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. AB - OBJECTIVE: Duchenne and Becker muscular dystrophies (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine whether the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). METHODS: Adults with DBMD and cardiomyopathy (ejection fraction <= 50%) were randomized to receive sildenafil (20mg 3* daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac magnetic resonance imaging. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. RESULTS: An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4 of 14) of subjects had a >=10% increase in LVESV after 6 months of sildenafil compared to 13% (1 of 8) of subjects receiving placebo. Subjects with LVESV > 120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p = 0.035). Due to the higher number of subjects worsening on sildenafil, the data and safety monitoring board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. INTERPRETATION: Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD. PMID- 25042695 TI - The biomechanical characteristics of arthroscopic tibial inlay techniques for posterior cruciate ligament reconstruction: in vitro comparison of tibial graft tunnel placement. AB - PURPOSE: The hypothesis of the present study was that the biomechanical properties of arthroscopic tibial inlay procedures depend on tibial graft bone block position. METHODS: Five paired fresh-frozen human cadaveric knee specimens were randomized to a reconstruction with quadriceps tendon placing the replicated footprint either to the more proximal margin of the remnants of the anatomical PCL fibrous attachments (group A) or to the distal margin of the anatomical PCL fibrous attachments at the edge of the posterior tibial facet to the posterior tibial cortex in level with the previous physis line (group B). The relative graft-tibia motions, post cycling pull-out failure load and failure properties of the tibia-graft fixation were measured. Cyclic displacement at 5, 500 and 1,000 cycles, stiffness and yield strength were calculated. RESULTS: The cyclic displacement at 5, 500 and 1,000 cycles measured consistently more in group A without statistically significant difference (4.11 +/- 1.37, 7.73 +/- 2.73 and 8.18 +/- 2.75 mm versus 2.81 +/- 1.33, 6.01 +/- 2.37 and 6.46 +/- 2.37 mm). Mean ultimate load to failure (564.6 +/- 212.3) and yield strength (500.2 +/- 185.9 N) were significantly higher in group B (p < 0.05). CONCLUSION: Replicating the anatomical PCL footprint at the posterior edge of the posterior tibial facet yields higher pull-out strength and less cycling loading displacement compared to a tunnel position at the centre of the posterior tibial facet. PMID- 25042696 TI - Mallampati class, obesity, and a novel airway trajectory measurement to predict difficult laryngoscopy. AB - OBJECTIVES/HYPOTHESIS: To determine whether Mallampati class correlates with Cormack-Lehane grade in obese adults, and investigate a novel airway trajectory measurement (ATM) to anticipate difficult laryngoscopy. STUDY DESIGN: Retrospective cohort plus a pilot study. METHODS: One hundred eighty-four nonobese and 160 obese adults underwent laryngoscopy. Spearman correlations, gamma coefficients (G), and Kendall's tau investigated body mass index (BMI):Mallampati, BMI: Cormack-Lehane, and Mallampati:Cormack-Lehane. A z test compared the two groups. Twenty-six volunteers had neck x-rays taken in the sniffing position to examine trajectories to the larynges (ATM). RESULTS: Positive predictive value of high Mallampati for difficult laryngoscopy was 8.57%. BMI did not correlate with Mallampati (r = 0.055 [nonobese], r = -0.056 [obese]) or Cormack-Lehane [r = -0.014 [nonobese], r = -0.022 [obese]). Among nonobese adults, gamma coefficients for BMI:Mallampati was 0.039 (P = .63), for BMI:Cormack-Lehane was 0.02 (P = .85), and for Mallampati:Cormack-Lehane was 0.43 (P = .004). Among obese adults, gamma coefficients for BMI:Mallampati was -0.127 (P = .16), for BMI:Cormack-Lehane was 0.014 (P = .88), and for Mallampati:Cormack Lehane was 0.365 (P = .01). Kendall's tau were comparable to gamma coefficients in all analyses. When comparing gamma coefficients for Mallampati:Cormack-Lehane among the nonobese and obese, z = 0.04 (P = .98). In the ATM study, only Mallampati and upper lip bite test had a significant relationship (G = 1.00, P < .001). CONCLUSIONS: Mallampati correlates poorly with Cormack-Lehane, regardless of BMI. Pilot data suggest that ATM is feasible. PMID- 25042698 TI - Perceptual narrowing: retrospect and prospect. AB - Research is reviewed demonstrating perceptual narrowing across a variety of domains. Research is also reviewed showing that the temporal window of perceptual narrowing can be extended and, in some cases, perceptual narrowing can be reversed. Research is also reviewed highlighting the neurophysiological correlates of perceptual narrowing as well as some of the individual neurophysiological differences associated with perceptual narrowing. Various methodological issues associated with perceptual narrowing are also discussed. The broader purpose of this paper, however, is to argue that the term perceptual narrowing fails to capture the dynamic nature of this perceptual process. Finally, it is argued that just as other concepts associated with experience and development are refined and modified as new evidence emerges, likewise we need to evaluate and refine how we conceptualize perceptual narrowing. PMID- 25042697 TI - Assessment of HIV testing among young methamphetamine users in Muse, Northern Shan State, Myanmar. AB - BACKGROUND: Methamphetamine (MA) use has a strong correlation with risky sexual behaviors, and thus may be triggering the growing HIV epidemic in Myanmar. Although methamphetamine use is a serious public health concern, only a few studies have examined HIV testing among young drug users. This study aimed to examine how predisposing, enabling and need factors affect HIV testing among young MA users. METHODS: A cross-sectional study was conducted from January to March 2013 in Muse city in the Northern Shan State of Myanmar. Using a respondent driven sampling method, 776 MA users aged 18-24 years were recruited. The main outcome of interest was whether participants had ever been tested for HIV. Descriptive statistics and multivariate logistic regression were applied in this study. RESULTS: Approximately 14.7% of young MA users had ever been tested for HIV. Significant positive predictors of HIV testing included predisposing factors such as being a female MA user, having had higher education, and currently living with one's spouse/sexual partner. Significant enabling factors included being employed and having ever visited NGO clinics or met NGO workers. Significant need factors were having ever been diagnosed with an STI and having ever wanted to receive help to stop drug use. CONCLUSIONS: Predisposing, enabling and need factors were significant contributors affecting uptake of HIV testing among young MA users. Integrating HIV testing into STI treatment programs, alongside general expansion of HIV testing services may be effective in increasing HIV testing uptake among young MA users. PMID- 25042699 TI - Phosphate-triggered self-assembly of N-[(Uracil-5-yl)methyl]urea: a minimalistic urea-derived hydrogelator. AB - N-[(Uracil-5-yl)methyl]urea is reported as a minimalistic low-molecular-weight hydrogelator (LMWHG). The unusual phosphate-induced assembly of this compound has been thoroughly investigated by IR, UV/Vis, and NMR spectroscopy, electron microscopy, and rheological experiments. This rare example of an anion-triggered urea-based LMWHG is the first example of a pyrimidine- and urea-containing molecule that can be forced into self-assembly in aqueous solution without additional aromatic or lipophilic groups. The gelator/phosphate ratio within the hydrogel was successfully determined by (31) P MAS NMR spectroscopy. The hydrogel exhibits a very fast and repeatable self-healing property, and remarkable G' values. The viscoelastic properties of the hydrogel can easily be tuned by variation of the phosphate ratio. PMID- 25042700 TI - Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial. AB - BACKGROUND: A prospective randomized trial was conducted to compare the impact of systemic chemotherapy versus multi-modality therapy (complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy) on overall survival (OS) in patients with gastric carcinomatosis. METHODS: Patients with measurable metastatic gastric adenocarcinoma involving the peritoneum, and resectable to "no evidence of disease" were randomized to gastrectomy, metastasectomy, HIPEC, and systemic FOLFOXIRI (GYMS arm) or FOLFOXIRI alone (SA arm). RESULTS: Seventeen patients were enrolled (16 evaluable); 7 of 9 patients in the multi-modality GYMS arm achieved complete cytoreduction (CCR0). Median OS was 11.3 months in the GYMS arm and 4.3 months in the SA arm. Four patients in the GYMS arm survived >12 months, 2 patients close to 2 years at last follow-up, and 1 patient more than 4 years, with 2 of these patients still alive. No patient in the SA arm lived beyond 11 months. All patients surviving beyond 12 months in the surgery arm achieved complete cytoreduction and had an initial Peritoneal Cancer Index (PCI) of <= 15. CONCLUSION: Maximal cytoreductive surgery combined with regional (HIPEC) and systemic chemotherapy in selected patients with gastric carcinomatosis and limited disease burden can achieve prolonged survival. PMID- 25042701 TI - A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche. AB - Despite progress in identifying the cellular composition of hematopoietic stem/progenitor cell (HSPC) niches, little is known about the molecular requirements of HSPC support. To address this issue, we used a panel of six recognized HSPC-supportive stromal lines and less-supportive counterparts originating from embryonic and adult hematopoietic sites. Through comprehensive transcriptomic meta-analyses, we identified 481 mRNAs and 17 microRNAs organized in a modular network implicated in paracrine signaling. Further inclusion of 18 additional cell strains demonstrated that this mRNA subset was predictive of HSPC support. Our gene set contains most known HSPC regulators as well as a number of unexpected ones, such as Pax9 and Ccdc80, as validated by functional studies in zebrafish embryos. In sum, our approach has identified the core molecular network required for HSPC support. These cues, along with a searchable web resource, will inform ongoing efforts to instruct HSPC ex vivo amplification and formation from pluripotent precursors. PMID- 25042702 TI - NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency. AB - Mesoderm is induced at the primitive streak (PS) and patterns subsequently into mesodermal subtypes and organ precursors. It is unclear whether mesoderm induction generates a multipotent PS progenitor or several distinct ones with restricted subtype potentials. We induced mesoderm in human pluripotent stem cells with ACTIVIN and BMP or with GSK3-beta inhibition. Both approaches induced BRACHYURY(+) mesoderm of distinct PS-like identities, which had differing patterning potential. ACTIVIN and BMP-induced mesoderm patterned into cardiac but not somitic subtypes. Conversely, PS precursors induced by GSK3-beta inhibition did not generate lateral plate and cardiac mesoderm and favored instead somitic differentiation. The mechanism of these cell fate decisions involved mutual repression of NANOG and CDX2. Although NANOG was required for cardiac specification but blocked somitic subtypes, CDX2 was required for somitic mesoderm but blocked cardiac differentiation. In sum, rather than forming a common PS progenitor, separate induction mechanisms distinguish human mesoderm subtypes. PMID- 25042703 TI - Behavioral and physiological responses in felids to exhibit construction. AB - Despite the growing body of literature examining the welfare of zoo-housed animals, little standardized work has been published on the effect of construction and environmental disruption on the physiology and behavior of affected animals. When Lincoln Park Zoo (Chicago, IL), embarked on a renovation project for its Kovler Lion House, the opportunity was taken to perform a scientific study of behavioral and physiological markers in the resident felids to determine the effect of construction and environmental disruption. Fecal samples and behavioral observations were collected on four felid species (five individuals) before, during, and after the period of construction. As a group, the average z-score for fecal glucocorticoid metabolite concentration increased during construction relative to baseline. Levels remained elevated after construction, but trended toward baseline. All individuals demonstrated a significant decrease in the frequency of pacing and time spent visible during construction. Overall activity levels also showed a significant decrease relative to baseline measures. As zoological institutions continue to recognize the importance of habitat design, construction and renovation become inevitable. It is important to be aware of the potential consequences this can have on animals in the vicinity and to work toward minimizing negative effects. One recommendation is the availability of ample retreat and hiding space for felids during disruption to their environment. PMID- 25042704 TI - Functional morphology of the bovid astragalus in relation to habitat: controlling phylogenetic signal in ecomorphology. AB - Bovid astragali are one of the most commonly preserved bones in the fossil record. Accordingly, astragali are an important target for studies seeking to predict the habitat preferences of fossil bovids based on bony anatomy. However, previous work has not tested functional hypotheses linking astragalar morphology with habitat while controlling for body size and phylogenetic signal. This article presents a functional framework relating the morphology of the bovid astragalus to habitat-specific locomotor ecology and tests four hypotheses emanating from this framework. Highly cursorial bovids living in structurally open habitats are hypothesized to differ from their less cursorial closed-habitat dwelling relatives in having (1) relatively short astragali to maintain rotational speed throughout the camming motion of the rotating astragalus, (2) a greater range of angular excursion at the hock, (3) relatively larger joint surface areas, and (4) a more pronounced "spline-and-groove" morphology promoting lateral joint stability. A diverse sample of 181 astragali from 50 extant species was scanned using a Next Engine laser scanner. Species were assigned to one of four habitat categories based on the published ecological literature. A series of 11 linear measurements and three joint surface areas were measured on each astragalus. A geometric mean body size proxy was used to size-correct the measurement data. Phylogenetic generalized least squares (PGLS) was used to test for differences between habitat categories while controlling for body size differences and phylogenetic signal. Statistically significant PGLS results support Hypotheses 1 and 2 (which are not mutually exclusive) as well as Hypothesis 3. No support was found for Hypothesis 4. These findings confirm that the morphology of the bovid astragalus is related to habitat-specific locomotor ecology, and that this relationship is statistically significant after controlling for body size and phylogeny. Thus, this study validates the use of this bone as an ecomorphological indicator. PMID- 25042705 TI - Formation of one-dimensional helical columns and excimerlike excited states by racemic quinoxaline-fused [7]carbohelicenes in the crystal. AB - A series of quinoxaline-fused [7]carbohelicenes (HeQu derivatives) was designed and synthesized to evaluate their structural and photophysical properties in the crystal state. The quinoxaline units were expected to enhance the light-emitting properties and to control the packing structures in the crystal. The electrochemical and spectroscopic properties and excited-state dynamics of these compounds were investigated in detail. The first oxidation potentials of HeQu derivatives are approximately the same as that of unsubstituted reference [7]carbohelicene (Heli), whereas their first reduction potentials are shifted to the positive by about 0.7 V. The steady-state absorption, fluorescence, and circular dichroism spectra also became redshifted compared to those of Heli. The molecular orbitals and energy levels of the HOMO and LUMO states, calculated by DFT methods, support these trends. Moreover, the absolute fluorescence quantum yields of HeQu derivatives are about four times larger than that of Heli. The structural properties of the aggregated states were analyzed by single-crystal analysis. Introduction of appropriate substituents (i.e., 4-methoxyphenyl) in the HeQu unit enabled the construction of one-dimensional helical columns of racemic HeQu derivatives in the crystal state. Helix formation is based on intracolumn pi stacking between two neighboring [7]carbohelicenes and intercolumn CH???N interaction between a nitrogen atom of a quinoxaline unit and a hydrogen atom of a helicene unit. The time-resolved fluorescence spectra of single crystals clearly showed an excimerlike delocalized excited state owing to the short distance between neighboring [7]carbohelicene units. PMID- 25042706 TI - Bacterial-induced expression of RAB18 protein in Orzya sativa salinity stress and insights into molecular interaction with GTP ligand. AB - In the present research, we have studied the inoculation effects of two root associated plant growth-promoting rhizobacteria (PGPR) in rice and provide the pieces of evidence that the inoculation of the PGPR could potentially result in inducing the expression of the salt stress-related RAB18 plant gene under varying degrees of salinity stress. The sequenced putative gene of RAB18 of Oryza sativa in this study is 740 bp long, has a content of 44.4%, and a molecular weight of 492 102.00 Da. BLAST homology patterns revealed sequence similarity with the previously sequenced RAB in model plant species. We demonstrate the mode of action of this stress-related protein by performing comparative modeling of Q10RT8 (Os03g0146000 protein, homolog of the sequenced RAB18; O. sativa subsp. japonica) using energy minimization, molecular dynamic simulations, and molecular docking of a guanosine triphosphate (GTP) ligand with the protein. The docking results indicated that Ser21, Ala22, Lys25, Asp68, Ala70, Glu73, and Arg74 are important determinant residues for functional interaction with the GTP ligand. The present research contributes to the understanding of the PGPR inoculation in salinity stress. Additionally, it provides the layout of the understanding of the molecular interactions between RAB and GTP ligand. PMID- 25042707 TI - Molecularly imprinted composite cryogels for hemoglobin depletion from human blood. AB - A molecularly imprinted composite cryogel (MICC) was prepared for depletion of hemoglobin from human blood prior to use in proteome applications. Poly(hydroxyethyl methacrylate) based MICC was prepared with high gel fraction yields up to 90%, and characterized by Fourier transform infrared spectrophotometer, scanning electron microscopy, swelling studies, flow dynamics and surface area measurements. MICC exhibited a high binding capacity and selectivity for hemoglobin in the presence of immunoglobulin G, albumin and myoglobin. MICC column was successfully applied in fast protein liquid chromatography system for selective depletion of hemoglobin for human blood. The depletion ratio was highly increased by embedding microspheres into the cryogel (93.2%). Finally, MICC can be reused many times with no apparent decrease in hemoglobin adsorption capacity. PMID- 25042708 TI - Switches of hydrogen bonds during ligand-protein association processes determine binding kinetics. AB - Revealing the processes of ligand-protein associations deepens our understanding of molecular recognition and binding kinetics. Hydrogen bonds (H-bonds) play a crucial role in optimizing ligand-protein interactions and ligand specificity. In addition to the formation of stable H-bonds in the final bound state, the formation of transient H-bonds during binding processes contributes binding kinetics that define a ligand as a fast or slow binder, which also affects drug action. However, the effect of forming the transient H-bonds on the kinetic properties is little understood. Guided by results from coarse-grained Brownian dynamics simulations, we used classical molecular dynamics simulations in an implicit solvent model and accelerated molecular dynamics simulations in explicit waters to show that the position and distribution of the H-bond donor or acceptor of a drug result in switching intermolecular and intramolecular H-bond pairs during ligand recognition processes. We studied two major types of HIV-1 protease ligands: a fast binder, xk263, and a slow binder, ritonavir. The slow association rate in ritonavir can be attributed to increased flexibility of ritonavir, which yields multistep transitions and stepwise entering patterns and the formation and breaking of complex H-bond pairs during the binding process. This model suggests the importance of conversions of spatiotemporal H-bonds during the association of ligands and proteins, which helps in designing inhibitors with preferred binding kinetics. PMID- 25042709 TI - Generation of an intrabody-based reagent suitable for imaging endogenous proliferating cell nuclear antigen in living cancer cells. AB - Intrabodies, when expressed in cells after genetic fusion to fluorescent proteins, are powerful tools to study endogenous protein dynamics inside cells. However, it remains challenging to determine the conditions for specific imaging and precise labelling of the target antigen with such intracellularly expressed antibody fragments. Here, we show that single-chain Fv (scFv) antibody fragments can be generated that specifically recognize proliferating cell nuclear antigen (PCNA) when expressed in living cancer cells. After selection by phage display, the anti-PCNA scFvs were screened in vitro after being tagged with dimeric glutathione-S-transferase. Anti-PCNA scFvs of increased avidity were further engineered by mutagenesis with sodium bisulfite and error-prone PCR, such that they were almost equivalent to conventional antibodies in in vitro assays. These intrabodies were then rendered bifunctional by fusion to a C-terminal fragment of p21 protein and could thereby readily detect PCNA bound to chromatin in cells. Finally, by linking these optimized peptide-conjugated scFvs to an enhanced green fluorescent protein, fluorescent intrabody-based reagents were obtained that allowed the fate of PCNA in living cells to be examined. The approach described may be applicable to other scFvs that can be solubly expressed in cells, and it provides a unique means to recognize endogenous proteins in living cells with high accuracy. PMID- 25042710 TI - Water-compatible silica sol-gel molecularly imprinted polymer as a potential delivery system for the controlled release of salicylic acid. AB - Molecularly imprinted polymers (MIPs) for salicylic acid were synthesized and evaluated in aqueous environments in the aim to apply them as drug delivery carriers. One organic MIP and one inorganic MIP based on the sol-gel process were synthesized. The organic MIP was prepared by radical polymerization using the stoichiometric functional monomer, 1-(4-vinylphenyl)-3-(3,5 bis(trifluoromethyl)phenyl)urea, which can establish strong electrostatic interactions with the -COOH of salicylic acid. The sol-gel MIP was prepared with 3-(aminopropyl)triethoxysilane and trimethoxyphenylsilane, as functional monomers and tetraethyl orthosilicate as the crosslinker. While the organic MIPs bound the target specifically in acetonitrile, they exhibited lower binding in the presence of water, although the imprinting factor increased under these conditions, due to reduced non-specific binding. The sol-gel MIP has a high specificity and capacity for the drug in ethanol, a solvent compatible with drug formulation and biomedical applications. In vitro release profiles of the polymers in water were evaluated, and the results were modelled by Fick's law of diffusion and the power law. Analysis shows that the release mechanism was predominantly diffusion controlled. PMID- 25042711 TI - A novel strategy for the rapid preparation and isolation of intact immune complexes from peptide mixtures. AB - The development and application of a miniaturized affinity system for the preparation and release of intact immune complexes are demonstrated. Antibodies were reversibly affinity-adsorbed on pipette tips containing protein G' and protein A, respectively. Antigen proteins were digested with proteases and peptide mixtures were exposed to attached antibodies; forming antibody-epitope complexes, that is, immune complexes. Elution with millimolar indole propionic acid (IPA)-containing buffers under neutral pH conditions allowed to effectively isolate the intact immune complexes in purified form. Size exclusion chromatography was performed to determine the integrity of the antibody-epitope complexes. Mass spectrometric analysis identified the epitope peptides in the respective SEC fractions. His-tag-containing recombinant human glucose-6 phosphate isomerase in combination with an anti-His-tag monoclonal antibody was instrumental to develop the method. Application was extended to the isolation of the intact antibody-epitope complex of a recombinant human tripartite motif 21 (rhTRIM21) auto-antigen in combination with a rabbit polyclonal anti-TRIM21 antibody. Peptide chip analysis showed that antibody-epitope binding of rhTRIM21 peptide antibody complexes was not affected by the presence of IPA in the elution buffer. By contrast, protein G' showed an ion charge structure by electrospray mass spectrometry that resembled a denatured conformation when exposed to IPA containing buffers. The advantages of this novel isolation strategy are low sample consumption and short experimental duration in addition to the direct and robust methodology that provides easy access to intact antibody-antigen complexes under neutral pH and low salt conditions for subsequent investigations. PMID- 25042714 TI - Angiogenic response pattern during normal and impaired skin flap re-integration in mice: a comparative study. AB - BACKGROUND: Distal skin flap necrosis represents a severe complication in surgery. This study investigated angiogenic responses in healthy and impaired pedicled skin flap tissue in normal and diabetic mice. METHODS: Histologic, qRT PCR, ELISA and immunoblot techniques determined expression and localization of angiogenesis-related growth factors, receptors and cell types upon skin flap re integration. RESULTS: Skin flap tissue re-integration was severely disturbed in diabetic mice. Impaired skin flap tissue lost early VEGF expression from wound margin keratinocytes and markedly reduced expression of endothelium-specific receptors Tie-2 and FLT-1. Numbers of blood vessels were reduced in impaired flaps. In addition, HIF-1alpha protein was absent from disturbed skin flap tissue. Reduced VEGF expression and the loss of epithelium in disturbed skin flaps were paralleled by the appearance of VEGF expressing inflammatory infiltrate. CONCLUSION: In summary, our data show a dysregulated spatial and temporal pattern of angiogenic processes during skin flap re-integration in diabetic mice. Our data suggest that reduced expression of angiogenic receptors in skin flap tissue might contribute to a loss of VEGF function in impaired tissue. PMID- 25042713 TI - Elevated levels of antibodies against xenobiotics in a subgroup of healthy subjects. AB - In spite of numerous research efforts, the exact etiology of autoimmune diseases remains largely unknown. Genetics and environmental factors, including xenobiotics, are believed to be involved in the induction of autoimmune disease. Some environmental chemicals, acting as haptens, can bind to a high-molecular weight carrier protein such as human serum albumin (HSA), causing the immune system to misidentify self-tissue as an invader and launch an immune response against it, leading to autoimmunity. This study aimed to examine the percentage of blood samples from healthy donors in which chemical agents mounted immune challenges and produced antibodies against HSA-bound chemicals. The levels of specific antibodies against 12 different chemicals bound to HSA were measured by ELISA in serum from 400 blood donors. We found that 10% (IgG) and 17% (IgM) of tested individuals showed significant antibody elevation against aflatoxin-HSA adduct. The percentage of elevation against the other 11 chemicals ranged from 8% to 22% (IgG) and 13% to 18% (IgM). Performance of serial dilution and inhibition of the chemical-antibody reaction by specific antigens but not by non-specific antigens were indicative of the specificity of these antibodies. Although we lack information about chemical exposure in the tested individuals, detection of antibodies against various protein adducts may indicate chronic exposure to these chemical haptens in about 20% of the tested individuals. Currently the pathological significance of these antibodies in human blood is still unclear, and this protein adduct formation could be one of the mechanisms by which environmental chemicals induce autoimmune reactivity in a significant percentage of the population. PMID- 25042715 TI - SN2 regioselectivity in the esterification of 5- and 7-membered azacycloalkane quaternary salts: a DFT study to reveal the transition state ring conformation prevailing over the ground state ring strain. AB - The nucleophilic esterification of 5- and 7-membered N-phenylcyclic ammonium salts resulted in distinctive regioselectivity, despite their comparable ring strain in the ground states relative to the corresponding cyclopentane and cycloheptane (both 25.9 kJ mol(-1)). The former underwent a selective ring opening reaction, while the latter predominantly underwent ring-emitting with concurrent ring-opening reactions. A DFT study of the model compounds revealed that the regioselection in the 5- and 7-membered azacycloalkane quaternary salts is plausibly directed by the transition state ring conformation, and not by the ground state ring strain. Remarkably, at the ring-opening transition state, the 5 membered cyclic skeletal structure expands toward the unstrained and thus less frustrated 6-membered cyclohexane conformation. On the other hand, the 7-membered counterpart expands at the ring-opening transition state toward the more frustrated 8-membered cyclooctane conformation to promote the alternative ring emitting process. PMID- 25042716 TI - ENU Mutagenesis in the Mouse. AB - This unit describes the treatment of laboratory mice with the mutagen N-ethyl-N nitrosourea (ENU) to induce very highly increased rates of mutation throughout the genome. Further, it describes several popular mating schemes designed to produce animals displaying phenotypes associated with the induced mutations. PMID- 25042717 TI - Diagnosis of lysosomal storage disorders: Gaucher disease. AB - Gaucher Disease (GD) is a progressive lysosomal storage disorder caused by deficiency of glucocerebrosidase (GBA). The clinical phenotype follows a spectrum ranging from severe early-onset to milder late-onset disease. The absence of neurological involvement defines GD type I, whereas neuronopathic features define GD type II and III. Early diagnosis may be important for timely initiation of enzyme replacement therapy to prevent disease complications, although the enzyme does not cross the blood brain barrier. Diagnosis of GD can be readily achieved by analysis of GBA in leukocytes, fibroblasts, and/or dried blood spots using fluorometric, microfluidic or mass spectrometry-based assays. Low GBA activities are typically confirmed through molecular analysis of the GBA gene. GBA analysis in dried blood spots may be attractive for high-throughput screening of at-risk individuals and/or newborn infants. The method detailed in this unit is based on GBA analysis by tandem mass spectrometry following incubation of dried blood spots with the GBA-specific substrate D-glucosyl-beta1-1'-N-dodecanoyl-D-erythro sphingosine [C12-glucocerebroside (C36H69NO8)] and internal standard N-myristoyl D-erythro-sphingosine [C14-ceramide (C32H63NO3)]. GBA activities in more than 2,000 newborn infants showed a mean of 22.0 +/- 13.8 MUmol/hr/liter (median: 19.9 MUmol/hr/liter; 95% CI: 21.41-22.59 MUmol/hr/liter). GBA activities in an adult population (n >1,200) showed generally lower enzyme activities than newborns, with a mean of 9.87 +/- 9.35 MUmol/hr/liter (median: 8.06 MUmol/hr/liter). GBA activities in ten adult patients with confirmed GD were less than 4.2 MUmol/hr/liter and in seven infants and children with GD less than 1.24 MUmol/hr/liter. This method is robust, sensitive, and suitable for high throughput analysis of hundreds of samples. PMID- 25042718 TI - Getting started with microbiome analysis: sample acquisition to bioinformatics. AB - Historically, in order to study microbes, it was necessary to grow them in the laboratory. It was clear though that many microbe communities were refractory to study because none of the members could be grown outside of their native habitat. The development of culture-independent methods to study microbiota using high throughput sequencing of the 16S ribosomal RNA gene variable regions present in all prokaryotic organisms has provided new opportunities to investigate complex microbial communities. In this unit, the process for a microbiome analysis is described. Many of the components required for this process may already exist. A pipeline is described for acquisition of samples from different sites on the human body, isolation of microbial DNA, and DNA sequencing using the Illumina MiSeq sequencing platform. Finally, a new analytical workflow for basic bioinformatics data analysis, QWRAP, is described, which can be used by clinical and basic science investigators. PMID- 25042719 TI - Digital Droplet PCR: CNV Analysis and Other Applications. AB - Digital droplet PCR (ddPCR) is an assay that combines state-of-the-art microfluidics technology with TaqMan-based PCR to achieve precise target DNA quantification at high levels of sensitivity and specificity. Because quantification is achieved without the need for standard assays in an easy to interpret, unambiguous digital readout, ddPCR is far simpler, faster, and less error prone than real-time qPCR. The basic protocol can be modified with minor adjustments to suit a wide range of applications, such as CNV analysis, rare variant detection, SNP genotyping, and transcript quantification. This unit describes the ddPCR workflow in detail for the Bio-Rad QX100 system, but the theory and data interpretation are generalizable to any ddPCR system. PMID- 25042720 TI - Quality assurance and quality control in clinical cytogenetics. AB - The goal of any clinical laboratory should be to provide patients with the most accurate test results possible. This is accomplished through various overlapping programs that continuously monitor and optimize all aspects of a test, including decisions by the laboratory to offer a test, the decision of providers to request the test, the testing itself, and the reporting of results to the referral source and patient. The levels at which test performance and accuracy can be optimized are encompassed under quality control (QC) and quality assurance (QA). The monitoring of QC and QA problems allows for the integration of these parameters into a total quality management program. This unit reviews QC and QA guidelines, in addition to discussing how to establish a quality assurance program. PMID- 25042721 TI - Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with hypophosphatemic rickets. AB - Hypophosphatemic rickets (HR) is characterized by a generalized mineralization defect. Although densitometric studies have found the patients to have an elevated bone mineral density (BMD), data on bone geometry and microstructure are scarce. The aim of this cross-sectional in vivo study was to assess bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated bone strength in adult patients with HR using high-resolution peripheral quantitative computed tomography (HR-pQCT). Twenty-nine patients (aged 19 to 79 years; 21 female, 8 male patients), 26 of whom had genetically proven X-linked HR, were matched with respect to age and sex with 29 healthy subjects. Eleven patients were currently receiving therapy with calcitriol and phosphate for a median duration of 29.1 years (12.0 to 43.0 years). Because of the disproportionate short stature in HR, the region of interest in HR-pQCT images at the distal radius and tibia were placed in a constant proportion to the entire length of the bone in both patients and healthy volunteers. In age- and weight-adjusted models, HR patients had significantly higher total bone cross-sectional areas (radius 36%, tibia 20%; both p < 0.001) with significantly higher trabecular bone areas (radius 49%, tibia 14%; both p < 0.001) compared with controls. In addition, HR patients had lower total vBMD (radius -20%, tibia -14%; both p < 0.01), cortical vBMD (radius 5%, p < 0.001), trabecular number (radius -13%, tibia -14%; both p < 0.01), and cortical thickness (radius -19%; p < 0.01) compared with controls, whereas trabecular spacing (radius 18%, tibia 23%; p < 0.01) and trabecular network inhomogeneity (radius 29%, tibia 40%; both p < 0.01) were higher. Estimated bone strength was similar between the groups. In conclusion, in patients with HR, the negative impact of lower vBMD and trabecular number on bone strength seems to be compensated by an increase in bone diameter, resulting in HR patients having normal estimates of bone strength. (c) 2014 American Society for Bone and Mineral Research. PMID- 25042722 TI - Therapeutic potential of adipose-derived stem cells-based micro-tissues in a rat model of postprostatectomy erectile dysfunction. AB - INTRODUCTION: Stem cells (SCs) show significant benefits in the treatment of postprostatectomy erectile dysfunction (ED). However, the low retention rate of the traditional single-cell strategy at the injection sites limits its therapeutic potential. AIM: This study aims to investigate the feasibility and mechanism of adipose-derived stem cells (ADSCs)-based micro-tissues (MTs) in the treatment of ED in a rat model of bilateral cavernous nerves (CNs) injury. METHODS: ADSCs labeled with 5-ethynyl-2-deoxyuridine (EdU) were used to generate MTs with hanging drop method. 10 Sprague-Dawley (SD) rats underwent sham surgery and intracavernous (IC) injection of phosphate buffer solution (PBS) (the sham group). Another 70 rats underwent bilateral CN crush and were then treated with PBS (n = 10, the crush group), dissociated ADSCs (n = 30, the ADSCs group), and MTs (n = 30, the MTs group), respectively. At day 1, 3, 7, 14 (n = 5), and 28 (n = 10) postsurgery, specimens were harvested for histology. At day 28, 10 rats in each group were examined for erectile function before tissue harvest. MAIN OUTCOME MEASURES: Light microscopy of the dynamic aggregation of the MT, immunohistologic examination of the MTs, the retention and distribution of EdU + ADSCs in the corpus cavernosum (CC), and the penis histological analyses of collagen content, Western blot of functional proteins in MTs, intracavernous pressure recording on CN electrostimulation. RESULTS: Three-day-old MTs became stable and expressed nerve growth factor, vascular endothelial growth factor, C-X C chemokine receptor type 4, Wnt5a, and collagen IV. More EdU + ADSCs retained in the CC in the MTs group than that in the ADSCs group. IC injection of MTs resulted in significant restoration of the erectile function and histopathological changes compared with the ADSCs group. CONCLUSION: IC-injected MTs resulted in a better restoration of erectile function than traditional single cell strategy. The underlying mechanisms of recovery appear to involve enhanced cellular retention in the penis and upregulation of some paracrine factors. PMID- 25042723 TI - Goldenhar syndrome presenting atypically with an additional cranial bone. PMID- 25042724 TI - Blood genomic profiling in extracranial- and intracranial atherosclerosis in ischemic stroke patients. AB - OBJECTIVE: Extracranial- and intracranial atherosclerosis (ECAS and ICAS) have been suggested to have different pathogeneses. Blood genomic profiling may identify their unique molecular signatures. METHODS: Whole gene microarray of peripheral blood was performed in 24 patients with acute ischemic stroke (ECAS, n=12; ICAS, n=12) and 12 healthy controls. Differential gene expression and gene set enrichment analysis (GSEA) were conducted. Plasma resistin levels were compared across independent samples of stroke patients with ECAS (n=39), ICAS (n=20), and small vessel disease (SVD, n=57). RESULTS: Microarray revealed that 144 and 24 transcripts were altered in ECAS and ICAS, respectively, compared to controls. All the transcripts that were differentially expressed in ICAS were also differentially expressed in ECAS. A total of 120 transcripts were differentially expressed only in ECAS. Gene sets related to immune response and protein metabolism were altered in both ECAS and ICAS, but the magnitude of gene alteration was higher in ECAS than in ICAS. Several genes of interest including RETN, IRF5, CD163, and CHST13 were more highly expressed in ECAS than in ICAS. Circulating resistin levels were elevated in independent samples of ECAS, but not in those of ICAS, compared to those of SVDs. CONCLUSIONS: ECAS showed prominent genomic alteration related to immune response compared to ICAS. Although there was no ECAS-specific gene to be identified on microarray, the level of resistin expression was high on peripheral blood in ECAS, suggesting that resistin is associated with the pathogenesis of ECAS. PMID- 25042725 TI - Lysability of fibrin clots is a potential new determinant of stroke risk in atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation increases the risk of ischemic stroke, but the risk depends on other factors as well. Present risk stratification schemes use age and co-morbidities, but not biochemical markers. We investigated the hypothesis that the formation, structure and lysability of fibrin clots are potential determinants of stroke risk in patients with atrial fibrillation. MATERIALS AND METHODS: A total of 179 patients with atrial fibrillation in stable anticoagulant treatment were included. Thirty-two had a previous ischemic stroke. We measured thrombin generation, plasma concentrations of fibrinogen and C reactive protein and analysed fibrin structure and lysability by turbidity. Fibrinolytic capacity was measured using the euglobulin fraction of plasma expressed in terms of t-PA equivalents (IU/ml). RESULTS: The patients with previous stroke had a slightly higher burden of co-morbidities compared with the remaining patients as indicated by the CHA2DS2-VASc score, but no significant differences were found regarding age, fibrinogen concentration, C-reactive protein, thrombin generation or fibrinolytic capacity. Furthermore, the patients with previous stroke had a higher mass/length ratio of fibrin fibers (5.5 vs. 5.1 x10(12) Da/cm, p=0.044) and an increased lysability (79.3 vs. 55.3%, p<0.01). CONCLUSION: The higher lysability of fibrin clots in atrial fibrillation patients with previous stroke is most likely a result of a difference in fibrin fiber properties. An increased lysability may increase the risk of embolization of clots formed in the atria, and therefore fibrin clot structure seems to be a determinant of stroke risk in atrial fibrillation. PMID- 25042726 TI - Functionally compromised FGG variant (gamma320Asp->Glu) expressed at low level in plasma fibrinogen. PMID- 25042727 TI - Genetic variations in the thrombin-activatable fibrinolysis inhibitor gene and risk of cardiovascular disease: a systematic review and meta-analysis. AB - BACKGROUND: An imbalance between coagulation and fibrinolytic system plays an important role in the pathogenesis of arterial thrombosis. It has been identified that elevated plasma thrombin-activatable fibrinolysis inhibitor (TAFI) concentration, an anti-fibrinolytic factor, is associated with an increased risk of cardiovascular disease (CVD). But the effect of genetic variations in TAFI gene on the risk of CVD is inconclusive. OBJECTIVES: To investigate the associations between two variants Ala147Thr(rs3742264) and Thr325Ile(rs1926447) in TAFI and the risk of CVD. METHODS: Systematic review and meta-analysis of eligible studies published before January 2014. Coronary heart disease(CHD) and stroke are regarded as end-points of CVD. RESULTS: A total of 18 articles including 23 studies were enrolled. Among these articles were 19 studies of Ala147Thr and 15 of Thr325Ile variants, comprising 4,977 CVD patients and 8,082 controls together with 4,890 cases and 8,311 controls, respectively. There were no significant associations between Ala147Thr variant and CVD under allele, dominant, recessive genetic models. Similar results were observed when end-point, ethnicity, sample size, genotyping method were taken into account. Likewise, meta analysis of Thr325Ile variant did not show significant associations with CVD under three genetic models. Nevertheless, in sub-analysis based on end-point, the TT(Ile/Ile) genotype was associated with a 25% higher risk of coronary heart disease(CHD) (OR=1.25, 95%CI, 1.02-1.54; P=0.03) compared with TC+CC(Thr/Ile+Thr/Thr) genotype(recessive model). CONCLUSIONS: The present meta analysis failed to confirm the influence of Ala147Thr and Thr325Ile variants on the susceptibility to CVD. However, potentially increased risk of CHD was detected in Ile325 allele carriers under recessive model. PMID- 25042728 TI - Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms. AB - INTRODUCTION: VKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance. MATERIALS AND METHODS: We sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n=260) or warfarin (n=219). RESULTS: There were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c. 1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0-35.0] vs. 42.0 [28.0-56.0] mg/week, p<0.0001; 35.0 [28.0-52.0] vs. 52.0 [35.0-70.0] mg/week, p=0.0001, respectively). Carriers of 2 and/or 3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with 1 1 carriers (35.0 [31.5-52.5] vs. 43.8 [35.0-60.2] mg/week, p=0.02; 35.0 [23.5-35.0] vs. 43.8 [35.0-60.2] mg/week, p<0.0001, respectively). Similarly, possession of G allele of GGCX c.2084+45 polymorphism was associated with lower warfarin dose (35.0 [26.3-39.2] vs. 45.5 [35.0-65.1] mg/week, p=0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084+45G>C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0-60.2] vs. 35.0 [35.0-52.5] mg/week, p=0.01; 35.0 [28.0-52.5] vs. 28.0 [28.0-42.0] mg/week, p=0.05). CONCLUSIONS: We have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084+45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe. PMID- 25042729 TI - Ranibizumab for Branch Retinal Vein Occlusion Associated Macular Edema Study (RABAMES): six-month results of a prospective randomized clinical trial. AB - PURPOSE: To compare standard-of-care grid laser photocoagulation versus intravitreal ranibizumab (IVR) versus a combination of both in the treatment of chronic (>3 months) macular oedema secondary to branch retinal vein occlusion. METHODS: Prospective, randomized, multicentre clinical trial. Thirty patients with a best-corrected visual acuity (BCVA) between 20/320 and 20/40 were randomized 1:1:1 to receive grid laser or three monthly injections of 0.5 mg IVR or both followed by 3 months of observation. RESULTS: Mean change from baseline BCVA at month 6 was +2 letters [laser; 0.04 logMAR, 95% confidence interval ( 0.17; 0.25)], +17 letters [IVR; 0.34 (0.19; 0.5)] and +6 letters [combination; 0.12 (0.01; 0.24)] (IVR versus laser p = 0.02 and IVR versus combination p = 0.02). At month 3, mean improvement in central retinal thickness (CRT) was 90.6 MUm (laser) (-18.65; 199.8), 379.5 MUm (IVR) (204.2; -554.8), and 248 MUm (167.2; -328.8) (combination) (IVR versus laser p = 0.005, laser versus combination p = 0.02). During the observation period, CRT improved in laser [37.6 MUm (-66.82; 142.0)], but deteriorated in IVR [-142.4 MUm (-247.6; -37.16)] and combination [ 171.7 MUm (-250.4; -92.96)] (laser versus IVR p = 0.01, laser versus combination p = 0.002) indicating recurrent oedema. Less laser retreatments (at 8 weeks) were required in combination group (2/10) than grid group (7/10). CONCLUSION: Six month results suggest that ranibizumab may be superior to grid laser in improving visual acuity. Grid combined with IVR neither enhanced functional and morphological improvement of IVR nor did it prevent or prolong recurrence of oedema. In IVR groups, CRT increased slowly after stopping injections, whereas improvement in visual acuity was sustained, indicating that morphological changes occur prior to functional impairment. PMID- 25042730 TI - Light-stable bis(norharmane)silver(I) compounds: synthesis, characterization and antiproliferative effects in cancer cells. AB - Four different-anion Ag(I) compounds with the ligand norharmane (9H-Pyrido[3,4 b]indole; Hnor) and having the general formula [Ag(Hnor)2](anion) (anion=ClO4(-), NO3(-) and BF4(-)) [Ag(Hnor)2(MeCN)](PF6) are reported, and studied in detail regarding their coordination mode and in vitro antiproliferative effects. X-ray structural analysis revealed that the complex with the PF6(-) anion has a MeCN solvent molecule weakly coordinated to Ag(I), making the metal coordination T shaped, while the other compounds present the classical linear Ag(I) coordination. The compounds showed certain cell growth inhibitory effects in two different cancer cell lines, with the perchlorate containing complex being the most toxic and in fact comparable to cisplatin. Notably, the compounds are stable in visible light; and the luminescence in the solid state was found to be extremely weak, whereas in MeOH solution all compounds show a moderate to weak emission band at 375 nm, when excited at 290 nm. PMID- 25042731 TI - Proton pumping by an inactive structural variant of cytochrome c oxidase. AB - The aa3-type cytochrome c oxidases (CytcOs) from e.g. Rhodobacter sphaeroides and Paracoccus denitrificans harbor two proton-transfer pathways. The K pathway is used for proton uptake upon reduction of the CytcO, while the D pathway is used after binding of O2 to the catalytic site. The aim of the present study was to determine whether or not CytcO in which the K pathway is blocked (by e.g. the Lys362Met replacement) is capable of pumping protons. The process can not be studied using conventional assays because the O2-reduction activity is too low when the K pathway is blocked. Consequently, proton pumping with a blocked K pathway has not been demonstrated directly. Here, the Lys362Met and Ser299Glu structural variants were reconstituted in liposomes and allowed to (slowly) become completely reduced. Then, the reaction with O2 was studied with MUs time resolution after flash photolysis of a blocking CO ligand bound to heme a3. The data show that with both the inactive Lys362Met and partly active Ser299Glu variants proton release occurred with the same time constants as with the wild type oxidase, i.e. ~200MUs and ~3ms, corresponding in time to formation of the ferryl and oxidized states, respectively. Thus, the data show that the K pathway is not required for proton pumping, suggesting that D and K pathways operate independently of each other after binding of O2 to the catalytic site. PMID- 25042732 TI - High metal substitution tolerance of anthrax lethal factor and characterization of its active copper-substituted analogue. AB - Anthrax lethal factor (LF) is a zinc-dependent metalloendopeptidase and a member of the gluzincin family. The current report demonstrates a high metal substitution tolerance of LF atypical of gluzincins and other zinc-dependent metalloproteases. Mn(2+), Co(2+), Ni(2+), Cu(2+) and Cd(2+) were found to reactivate the apoprotein of LF to a level either comparable to or significantly higher than that noted for the native zinc enzyme. The most active form of LF was obtained with Cu(2+), a surprising observation since most Cu(2+)-substituted zinc proteases display very low activity. Cu(2+)-substituted LF (CuLF), prepared by direct exchange and by apoprotein reconstitution methodologies, displayed a several-fold higher catalytic competence towards chromogenic and fluorogenic LF substrates than native LF. CuLF bound Cu(2+) tightly with a dissociation constant in the femtomolar range. The electron paramagnetic resonance spectrum of CuLF revealed the protein-bound metal ion to be coordinated to two nitrogen donor atoms, suggesting that Cu(2+) binds to both active site histidine residues. While ZnLF and CuLF (prepared by direct exchange) were capable of killing RAW 264.7 murine macrophage-like cells, apoLF and all metal-reconstituted apoprotein preparations failed to elicit a cytotoxic response. Competition experiments using apoLF/ZnLF mixtures demonstrated the propensity of apoLF to relieve ZnLF-induced cell death, suggesting that both protein forms can compete with each other for binding to protective antigen. The lack of cytotoxicity of apoLF and its metal reconstituted variants likely originates from structural perturbations in these proteins which might prevent their translocation into the cytoplasm. PMID- 25042733 TI - Enantioselective diamination with novel chiral hypervalent iodine catalysts. AB - Vicinal diamines constitute one the most important functional motif in organic chemistry because of its wide occurrence in a variety of biological and pharmaceutical molecules. We report an efficient metal-free, highly stereoselective intramolecular diamination using a novel chiral hypervalent iodine reagent together with its application as an efficient catalyst for the synthesis of diamines. PMID- 25042734 TI - Second solid cancers after allogeneic hematopoietic cell transplantation using reduced-intensity conditioning. AB - We examined risk of second solid cancers after allogeneic hematopoietic cell transplantation (AHCT) using reduced-intensity/nonmyeloablative conditioning (RIC/NMC). RIC/NMC recipients with leukemia/myelodysplastic syndrome (MDS) (n = 2833) and lymphoma (n = 1436) between 1995 and 2006 were included. In addition, RIC/NMC recipients 40 to 60 years of age (n = 2138) were compared with patients of the same age receiving myeloablative conditioning (MAC, n = 6428). The cumulative incidence of solid cancers was 3.35% at 10 years. There was no increase in overall cancer risk compared with the general population (leukemia/MDS: standardized incidence ratio [SIR] .99, P = 1.00; lymphoma: SIR .92, P = .75). However, risks were significantly increased in leukemia/MDS patients for cancers of lip (SIR 14.28), tonsil (SIR 8.66), oropharynx (SIR 46.70), bone (SIR 23.53), soft tissue (SIR 12.92), and vulva (SIR 18.55) and skin melanoma (SIR 3.04). Lymphoma patients had significantly higher risks of oropharyngeal cancer (SIR 67.35) and skin melanoma (SIR 3.52). Among RIC/NMC recipients, age >50 years was the only independent risk factor for solid cancers (hazard ratio [HR] 3.02, P < .001). Among patients ages 40 to 60 years, when adjusted for other factors, there was no difference in cancer risks between RIC/NMC and MAC in leukemia/MDS patients (HR .98, P = .905). In lymphoma patients, risks were lower after RIC/NMC (HR .51, P = .047). In conclusion, the overall risks of second solid cancers in RIC/NMC recipients are similar to the general population, although there is an increased risk of cancer at some sites. Studies with longer follow-up are needed to realize the complete risks of solid cancers after RIC/NMC AHCT. PMID- 25042736 TI - Incidence, risk factors, and long-term outcomes of sclerotic graft-versus-host disease after allogeneic hematopoietic cell transplantation. AB - Sclerotic chronic graft-versus-host disease (sclGVHD) is associated with significant morbidity and a poor quality of life. We reviewed 502 patients diagnosed with chronic GVHD and analyzed the incidence and risk factors of sclGVHD and long-term outcomes and immunosuppressive therapy (IST) cessation in patients with sclGVHD. With a median onset at 18 months the cumulative incidence of sclGVHD was estimated at 22.6% at 5 years (95% confidence interval, 18.6% to 26.8%). Univariate and multivariate analysis identified 2 risk factors for sclGVHD: non-T cell depletion (hazard ratio [HR] 9.09, P < .001) and peripheral blood stem cell (HR 3.87, P < .001). Overall survival (OS) at 5 years was significantly better in the sclGVHD group (88.1%) compared with the non-sclGVHD group (62.7%; P < .001), as were nonrelapse mortality (7.3% versus 21.5% at 5 years) and relapse rates (9.1% versus 19.3% at 5 years). There was no difference in the rate of IST cessation at 5 years (44.8% versus 49.9%, P = .312), but there was a trend of longer IST duration in the sclGVHD group compared with the non sclGVHD group (median 71.6 months versus 62.9 months). In conclusion, T cell depletion and graft source affect the risk of sclGVHD. SclGVHD did not adversely affect long-term outcomes or IST duration. PMID- 25042735 TI - Favorable outcomes from allogeneic and autologous stem cell transplantation for patients with transformed nonfollicular indolent lymphoma. AB - The role of allogeneic (allo-) and autologous stem cell transplantation (auto SCT) in the management of patients with transformed indolent nonfollicular non Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3 year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT. PMID- 25042737 TI - Infused autograft lymphocyte to monocyte ratio and survival in diffuse large B cell lymphoma. AB - Infused autograft absolute lymphocyte count is a prognostic factor for survival after autologous peripheral hematopoietic stem cell transplantation (APHSCT) for diffuse large B cell lymphoma (DLBCL). CD14(+) HLA-DR(low/neg) immunosuppressive monocytes affect tumor growth by suppressing host antitumor immunity. Thus, we set out to investigate if the infused autograft lymphocyte to monocyte ratio (A LMR), as a biomarker of host immunity (ie, lymphocytes) and immunosuppression (ie, monocytes), affects survival after APHSCT. From 1994 to 2012, 379 DLBCL patients who underwent APHSCT were studied. The 379 patients were randomly divided into a training set (n = 253) and a validation set (n = 126). Receiver operating characteristic and area under the curve identified an A-LMR >=1 as the best cut-off value, which was validated by the k-fold cross-validation in the training set. Multivariate analysis showed A-LMR to be an independent prognostic factor for survival in the training set. Patients with an A-LMR >= 1.0 experienced superior overall survival (OS) compared with patients with an A-LMR <1.0 (median OS: 167.2 versus 17.6 months; 5-year OS: 73% [95% confidence interval (CI), 63% to 80%] versus 30% [95% CI, 2% to 38%], P < .0001, respectively) in the training set. In the validation set, an A-LMR >= 1 showed a median OS of 181.2 months versus 19.5 months for an A-LMR <1, and 5-year OS rates of 67% (95% CI, 52% to 79%) versus 35% (95% CI, 25% to 47%), P < .0001, respectively. The A-LMR provides a platform to engineer immunocompetent autograft to improve clinical outcomes in DLBCL patients undergoing APHSCT. PMID- 25042738 TI - Noninherited maternal antigens identify acceptable HLA mismatches: benefit to patients and cost-effectiveness for cord blood banks. AB - Cord blood unit (CBU) transplantations to patients mismatched for only 1 HLA antigen, which is identical to the CBU noninherited maternal antigen (NIMA), are designated as having a 6/6 "virtual" NIMA-matched phenotype and have a prognosis similar to 6/6 inherited HLA-matched CBUs. Such virtual HLA phenotypes of CBUs can be created by replacing the inherited alleles with 1 or more NIMAs. Phenotypes of Dutch patients (n = 2020) were matched against the inherited and virtual HLA phenotypes of the National Cord Blood Program CBU file (with known NIMA, n = 6827). Inherited 6/6 matches were found for 11% of the patients. Including virtual phenotypes resulted in, overall, 19-fold more different phenotypes than were inherited, conferring 6/6 virtual matches for an additional 20% of the patients, whereas another 17% might benefit from CBUs with a 4/6 HLA match and 1 NIMA match (4/6 + 1NIMA or 5/6 virtual match). The elucidation of donors' maternal HLA phenotypes can provide significant numbers of 6/6 and 5/6 virtually matched CBUs to patients and is potentially cost effective. PMID- 25042739 TI - Venous thromboembolism risk prediction in ambulatory cancer patients: clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. AB - Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios might represent a yet unrecognized risk factor for venous thromboembolism (VTE) in cancer out patients receiving chemotherapy. Accordingly, this study was aimed at analyzing the significance of these novel markers in the risk prediction of a first VTE episode in a population representative of a general practice cohort. To this purpose, a mono-institutional cohort study was conducted to retrospectively analyze NLR and PLR in 810 consecutive cancer out-patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. Over a median follow-up of 9.2 months, VTE occurred in 6.7% of patients. Incidental VTE was diagnosed at time of restaging in 47% of cases. Median pre-chemotherapy NLR (p = 0.015) and PLR (p = 0.040) were significantly higher in patients with intermediate risk class who developed symptomatic VTE with a twofold increased VTE risk for both inflammation-based markers (NLR: p = 0.022; PLR: p = 0.037) and a worst 1-year VTE-free survival for patients with high NLR or PLR. However, only PLR (HR = 2.4, p = 0.027) confirmed to be an independent predictor of future VTE in patients in the intermediate risk class in multivariate analysis, together with ECOG performance status (HR = 3.4, p = 0.0002) and bevacizumab use (HR = 4.7, p = 0.012). We may, thus, conclude that PLR, but to a lesser extent NLR, could represent useful clinical predictors of VTE, especially in selected categories of patients such as those in the intermediate risk class in whom the assessment of PLR could allow a better risk stratification of VTE without additional costs to the national health systems. PMID- 25042740 TI - 'Ready to hit the ground running': Alumni and employer accounts of a unique part time distance learning pre-registration nurse education programme. AB - BACKGROUND: This study explored the impact of The Open University's (OU) preregistration nursing programme on students' employability, career progression and its contribution to developing the nursing workforce across the United Kingdom. Designed for healthcare support workers who are sponsored by their employers, the programme is the only part-time supported open/distance learning programme in the UK leading to registration as a nurse. The international literature reveals that relatively little is known about the impact of previous experience as a healthcare support worker on the experience of transition, employability skills and career progression. OBJECTIVES: To identify alumni and employer views of the perceived impact of the programme on employability, career progression and workforce development. DESIGN/METHOD: A qualitative design using telephone interviews which were digitally recorded, and transcribed verbatim prior to content analysis to identify recurrent themes. SETTINGS: Three geographical areas across the UK. PARTICIPANTS: Alumni (n=17) and employers (n=7). Inclusion criterion for alumni was a minimum of two years' post-qualifying experience. Inclusion criteria for employers were those that had responsibility for sponsoring students on the programme and employing them as newly qualified nurses. RESULTS: Four overarching themes were identified: transition, expectations, learning for and in practice, and flexibility. CONCLUSIONS: Alumni and employers were of the view that the programme equipped them well to meet the competencies and expectations of being a newly qualified nurse. It provided employers with a flexible route to growing their own workforce and alumni the opportunity to achieve their ambition of becoming a qualified nurse when other more conventional routes would not have been open to them. Some of them had already demonstrated career progression. Generalising results requires caution due to the small, self-selecting sample but findings suggest that a widening participation model of pre-registration nurse education for employed healthcare support workers more than adequately prepares them for the realities of professional practice. PMID- 25042741 TI - The challenge of giving written thesis feedback to nursing students. AB - Providing effective written feedback on nursing student's assignments can be a challenging task for any assessor. Additionally, as the student groups tend to become larger, written feedback is likely to gain an overall more prominent position than verbal feedback. Lack of formal training or regular discussion in the teaching faculty about the skill set needed to provide written feedback could negatively affect the students' learning abilities. In this brief paper, we discuss written feedback practices, whilst using the Bachelor of Science in Nursing thesis as an example. Our aim is to highlight the importance of an informed understanding of the impact written feedback can have on students. Creating awareness about this can facilitate the development of more strategic and successful written feedback strategies. We end by offering examples of some relatively simple strategies for improving this practice. PMID- 25042742 TI - Comparison of bullying of food-allergic versus healthy schoolchildren in Italy. PMID- 25042743 TI - Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding. PMID- 25042744 TI - Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation. AB - BACKGROUND: Schistosomiasis, a chronic helminth infection, elicits distinct immune responses within the host, ranging from an initial TH1 and subsequent TH2 phase to a regulatory state, and is associated with dampened allergic reactions within the host. OBJECTIVE: We sought to evaluate whether non-transplacental helminth infection during pregnancy alters the offspring's susceptibility to allergy. METHODS: Ovalbumin-induced allergic airway inflammation was analyzed in offspring from Schistosoma mansoni-infected mothers mated during the TH1, TH2, or regulatory phase of infection. Embryos derived from in vitro fertilized oocytes of acutely infected females were transferred into uninfected foster mice to determine the role of placental environment. The fetomaternal unit was further characterized by helminth-specific immune responses and microarray analyses. Eventually, IFN-gamma-deficient mice were infected to evaluate the role of this predominant cytokine on the offspring's allergy phenotype. RESULTS: We demonstrate that offspring from schistosome-infected mothers that were mated in the TH1 and regulatory phases, but not the TH2 immune phase, are protected against the onset of allergic airway inflammation. Interestingly, these effects were associated with distinctly altered schistosome-specific cytokine and gene expression profiles within the fetomaternal interface. Furthermore, we identified that it is not the transfer of helminth antigens but rather maternally derived IFN-gamma during the acute phase of infection that is essential for the progeny's protective immune phenotype. CONCLUSION: Overall, we present a novel immune phase dependent coherency between the maternal immune responses during schistosomiasis and the progeny's predisposition to allergy. Therefore, we propose to include helminth-mediated transmaternal immune modulation into the expanded hygiene hypothesis. PMID- 25042745 TI - Reply: To PMID 24084078. PMID- 25042747 TI - Gene silencing and related oligonucleotide therapies for TH2-promoting cytokines. PMID- 25042746 TI - Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling. AB - BACKGROUND: The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known. OBJECTIVE: To determine the role of the COX pathway and prostaglandin I2 (PGI2) signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance. METHODS: Wild-type (WT) BALB/c mice and IP knockout mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements. RESULTS: WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti tolerance effect of COX inhibition. CONCLUSION: COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and that clinical use of COX-inhibiting drugs may increase the risk of developing allergic diseases. PMID- 25042749 TI - Solid state fermentation with lactic acid bacteria to improve the nutritional quality of lupin and soya bean. AB - BACKGROUND: The ability of bacteriocin-like inhibitory substance (BLIS)-producing lactic acid bacteria (LAB) to degrade biogenic amines as well as to produce L(+) and D(-)-lactic acid during solid state fermentation (SSF) of lupin and soya bean was investigated. In addition, the protein digestibility and formation of organic acids during SSF of legume were investigated. RESULTS: Protein digestibility of fermented lupin and soya bean was found higher on average by 18.3% and 15.9%, respectively, compared to untreated samples. Tested LAB produced mainly L-lactic acid in soya bean and lupin (D/L ratio 0.38-0.42 and 0.35-0.54, respectively), while spontaneous fermentation gave almost equal amounts of both lactic acid isomers (D/L ratio 0.82-0.98 and 0.92, respectively). Tested LAB strains were able to degrade phenylethylamine, spermine and spermidine, whereas they were able to produce putrescine, histamine and tyramine. CONCLUSIONS: SSF improved lupin and soya bean protein digestibility. BLIS-producing LAB in lupin and soya bean medium produced a mixture of D- and L-lactic acid with a major excess of the latter isomer. Most toxic histamine and tyramine in fermented lupin and soya bean were found at levels lower those causing adverse health effects. Selection of biogenic amines non-producing bacteria is essential in the food industry to avoid the risk of amine formation. PMID- 25042750 TI - Understanding perceptions of stuttering among school-based speech-language pathologists: an application of attribution theory. AB - INTRODUCTION: The purpose of this study was to investigate whether attribution theory could explain speech-language pathologists (SLPs) perceptions of children with communication disorders such as stuttering. Specifically, it was determined whether perceptions of onset and offset controllability, as well as biological and non-biological attributions for communication disorders were related to willingness to help, sympathy, and anger toward children with these disorders. It was also of interest to determine if blame for stuttering was related to perceived controllability of stuttering and negative attitudes toward people who stutter (PWS). METHOD: A survey was developed to measure perceived onset and offset controllability, biological and non-biological attributions, willingness to help, sympathy, and anger toward middle school children with developmental stuttering, functional articulation disorders, and cerebral palsy. In addition, a scale was developed to measure blame and negative attitudes toward PWS in general. Surveys were mailed to 1000 school-based SLPs. Data from 330 participants were analyzed. RESULTS: Supporting the hypotheses of attribution theory, higher perceived onset and offset controllability of the disorder was linked to less willingness to help, lower sympathy, and more anger across conditions. Increased biological attributions were associated with more reported sympathy. Increased blame for stuttering was linked to higher perceived controllability of stuttering, more dislike of PWS, and more agreement with negative stereotypes about PWS. CONCLUSIONS: Educating SLPs about the variable loss of control inherent in stuttering could improve attitudes and increase understanding of PWS. Reductions in blame may facilitate feelings of sympathy and empathy for PWS and reduce environmental barriers for clients. Learning outcomes Readers should be able to: (1) identify the main principles of Weiner's attribution theory (2) identify common negative perceptions of people who stutter (3) describe how disorders of stuttering, articulation disorders, and cerebral palsy are differentiated in terms of perceived onset and offset controllability, and biological and non-biological attributions (4) describe relationships between perceived onset and offset controllability of disorders and sympathy, anger, and willingness to help. PMID- 25042748 TI - Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. AB - BACKGROUND: TH2 cells can further differentiate into dual-positive TH2/TH17 cells. The presence of dual-positive TH2/TH17 cells in the airways and their effect on asthma severity are unknown. OBJECTIVE: We sought to study dual positive TH2/TH17 cells in bronchoalveolar lavage (BAL) fluid from asthmatic patients, examine their response to glucocorticoids, and define their relevance for disease severity. METHODS: Bronchoscopy and lavage were performed in 52 asthmatic patients and 25 disease control subjects. TH2 and TH2/TH17 cells were analyzed by using multicolor flow cytometry and confocal immunofluorescence microscopy. Cytokines were assayed by means of ELISA. RESULTS: Dual-positive TH2/TH17 cells were present at a higher frequency in BAL fluid from asthmatic patients compared with numbers seen in disease control subjects. High-level IL-4 production was typically accompanied by high-level IL-17 production and coexpression of GATA3 and retinoic acid receptor-related orphan receptor gammat. Increased presence of TH2/TH17 cells was associated with increased IL-17 production in lavage fluid. TH2/TH17 cell counts and IL-17 production correlated with PC20 for methacholine, eosinophil counts, and FEV1. TH2/TH17 cells, unlike TH2 cells, were resistant to dexamethasone-induced cell death. They expressed higher levels of mitogen-activated protein-extracellular signal-regulated kinase kinase 1, a molecule that induces glucocorticoid resistance. On the basis of the dominance of BAL fluid TH2 or TH2/TH17 cells, we identified 3 subgroups of asthma: TH2(predominant), TH2/TH17(predominant), and TH2/TH17(low). The TH2/TH17(predominant) subgroup manifested the most severe form of asthma, whereas the TH2/TH17(low) subgroup had the mildest asthma. CONCLUSION: Asthma is associated with a higher frequency of dual-positive TH2/TH17 cells in BAL fluid. The TH2/TH17(predominant) subgroup of asthmatic patients manifested glucocorticoid resistance in vitro. They also had the greatest airway obstruction and hyperreactivity compared with the TH2(predominant) and TH2/TH17(low) subgroups. PMID- 25042751 TI - In utero resolution of microcystic congenital cystic adenomatoid malformation after prenatal betamethasone therapy: A report of three cases and a literature review. AB - Fetal congenital cystic adenomatoid malformation (CCAM) can progress to nonimmune hydrops, and the mortality rate of CCAM with hydrops is reported to be nearly 100%. We describe three microcystic CCAM cases in which the fetal condition improved after maternal betamethasone therapy. The median gestational age at steroid administration was 23 5/7 weeks' gestation. The CCAM decreased in size in all cases. Our series showed a 100% hydrops resolution rate (2/2) and a 100% survival rate (3/3). Our experience suggests the efficacy of betamethasone treatment on fetuses with microcystic CCAM who have fluid collection or are at risk of developing hydrops. PMID- 25042752 TI - Selenium in sepsis--substitution, supplementation or pro-oxidative bolus? PMID- 25042753 TI - How to unfasten the Spanish Stroke Belt? Andalusia chooses research. AB - Andalusia in southern Spain, one of the largest regions in the European Union, has made a profound economic and social transformation that has led to establishment of a modern universal public health care system. However, due to its high stroke mortality rates, Andalusia is still known as the 'Spanish Stroke Belt'. To fight these figures, successive initiatives culminated in the launch of the Andalusian Plan for Stroke Care, to be developed during the period of 2011 to 2014. In addition, involved professionals have hypothesized that clinical and experimental research may contribute to improving stroke care in our community. To that end, one of the leading institutes of biomedical research in Andalusia, the Institute of Biomedicine of Seville (IBiS), has selected stroke as a flagship project in the region. Moreover, Seville, the capital of Andalusia, is now conducting a fusion process of its two largest hospitals, with the potential to generate a stroke alliance that will make it one of the main stroke hospitals in Europe (>2000 cases per year). It is anticipated that this will be an excellent platform to facilitate acute-phase clinical trials and speed the translation process from basic research in IBiS laboratories to the clinical setting. Furthermore, the recently created Andalusian Neurovascular Group is ready to develop prospective, collaborative, multicenter research projects that will evaluate interventions in areas of stroke care uncertainty. If we succeed in forging a link between research and health care quality, we may succeed in lowering the incidence of stroke and related mortality in the region in a short period of time. PMID- 25042754 TI - New advances in precision medicine for hepatocellular carcinoma recurrence prediction and treatment. PMID- 25042755 TI - Synthesis and solution studies of silver(I)-assembled porphyrin coordination cages. AB - The synthesis and the characterization of two porphyrin coordination cages are reported. The design of the cage formation is based on the coordination of silver(I) ions to the pyridyl units of 3-pyridyl appended porphyrins. (1)H/(109)Ag NMR spectroscopy, and diffusion-ordered spectroscopy (DOSY) experiments demonstrate that both the free base porphyrin 2H-TPyP and the Zn porphyrin Zn-TPyP form the closed cages, [Ag4(2H-TPyP)2](4+) and [Ag4(Zn TPyP)2](4+), respectively, upon addition of two equivalents of Ag(+). The complexation processes are characterized in details by means of absorption and emission spectroscopy in diluted CH2Cl2 solutions. The data are discussed in the frame of the point-dipole exciton coupling theory; the two porphyrin monomers, in fact, experience a rigid face-to-face geometry in the cages and a weak inter porphyrin exciton coupling. An intermediate species is observed, for Zn-TPyP, in a porphyrin/Ag(+) stoichiometric ratio of about 1:0.5 and is tentatively ascribed to an oblique open form. The occurrence of a photoinduced electron-transfer reaction within the cages is excluded on the basis of the experimental outcomes and thermodynamic evaluations. Photophysical experiments evidence different reactivities of singlet and triplet excited states in the assemblies. A lower fluorescence quantum yield and triplet formation is discussed in relation to the constrained geometry of the complexes. Unusually long triplet excited state lifetimes are measured for the assemblies. PMID- 25042756 TI - Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study. AB - BACKGROUND: Efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) was inferred before licensure from an aggregate correlate of protection established for the seven-valent vaccine (PCV7). We did a postlicensure assessment of serotype-specific vaccine effectiveness and immunogenicity in England, Wales, and Northern Ireland to derive the correlates of protection for individual serotypes. METHODS: We assessed vaccine effectiveness against invasive pneumococcal disease using the indirect cohort method. We measured serotype-specific IgG concentration in infants after they were given two priming doses of PCV7 (n=126) or PCV13 (n=237) and opsonophagocytic antibody titre from a subset of these infants (n=100). We derived correlates of protection by relating percentage protection to a threshold antibody concentration achieved by an equivalent percentage of infants. We used multivariable logistic regression to estimate vaccine effectiveness and reverse cumulative distribution curves to estimate correlates of protection. FINDINGS: For the 706 cases of invasive pneumococcal disease included in the study, PCV13 vaccine effectiveness after two doses before age 12 months or one dose from 12 months was 75% (95% CI 58-84). Vaccine effectiveness was 90% (34-98) for the PCV7 serotypes and 73% (55-84) for the six additional serotypes included in PCV13. Protection was shown for four of the six additional PCV13 serotypes (vaccine effectiveness for serotype 3 was not significant and no cases of serotype 5 infection occurred during the observation period). The vaccine effectiveness for PCV13 and PCV7 was lower than predicted by the aggregate correlate of protection of 0.35 MUg/mL used during licensing. Calculated serotype-specific correlates of protection were higher than 0.35 MUg/mL for serotypes 1, 3, 7F, 19A, 19F, and lower than 0.35 MUg/mL for serotypes 6A, 6B, 18C, and 23F. Opsonophagocytic antibody titres of 1 in 8 or higher did not predict protection. INTERPRETATION: PCV13 provides significant protection for most of the vaccine serotypes. Although use of the aggregate correlate of protection of 0.35 MUg/mL has enabled the licensing of effective new PCVs, serotype-specific correlates of protection vary widely. The relation between IgG concentration after priming and long-term protection needs to be better understood. FUNDING: Public Health England and UK Department of Health Research and Development Directorate. PMID- 25042757 TI - Pneumococcal conjugate vaccination: correlates of protection. PMID- 25042758 TI - Disease mapping via negative binomial regression M-quantiles. AB - We introduce a semi-parametric approach to ecological regression for disease mapping, based on modelling the regression M-quantiles of a negative binomial variable. The proposed method is robust to outliers in the model covariates, including those due to measurement error, and can account for both spatial heterogeneity and spatial clustering. A simulation experiment based on the well known Scottish lip cancer data set is used to compare the M-quantile modelling approach with a disease mapping approach based on a random effects model. This suggests that the M-quantile approach leads to predicted relative risks with smaller root mean square error. The paper concludes with an illustrative application of the M-quantile approach, mapping low birth weight incidence data for English Local Authority Districts for the years 2005-2010. PMID- 25042759 TI - Group therapy for women with substance use disorders: results from the Women's Recovery Group Study. AB - BACKGROUND: This Stage II trial builds on a Stage I trial comparing the single gender Women's Recovery Group (WRG) to mixed-gender Group Drug Counseling (GDC) that demonstrated preliminary support for the WRG in treating women with substance use disorders. The Stage II trial aims were to (1) investigate effectiveness of the WRG relative to GDC in a sample of women heterogeneous with respect to substance of abuse and co-occurring psychiatric disorders, and (2) demonstrate the feasibility of implementing WRG in an open-enrollment group format at two sites. METHOD: In this randomized clinical trial, participants were included if they were substance dependent and had used substances within the past 60 days (n=158). Women were randomized to WRG (n=52) or GDC (n=48); men were assigned to GDC (n=58). Substance use outcomes were assessed at months 1-6 and 9. RESULTS: Women in both the WRG and GDC had reductions in mean number of substance use days during treatment (12.7 vs 13.7 day reductions for WRG and GDC, respectively) and 6 months post-treatment (10.3 vs 12.7 day reductions); however, there were no significant differences between groups. CONCLUSIONS: The WRG demonstrated comparable effectiveness to standard mixed-gender treatment (i.e., GDC) and is feasibly delivered in an open-group format typical of community treatment. It provides a manual-based group therapy with women-focused content that can be implemented in a variety of clinical settings for women who are heterogeneous with respect to their substance of abuse, other co-occurring psychiatric disorders, and life-stage. PMID- 25042760 TI - Nicotine exposure beginning in adolescence enhances the acquisition of methamphetamine self-administration, but not methamphetamine-primed reinstatement in male rats. AB - BACKGROUND: Nicotine is commonly abused in adolescence and is believed to be a "gateway" to other drugs of abuse [e.g., methamphetamine (METH)]. The relationship between early nicotine exposure and later METH use is complicated because the majority of juvenile smokers continue to use cigarettes into adulthood. Thus, the present investigation examined the individual and combined contribution of adolescent and adult nicotine exposure on METH self administration. METHODS: Forty-three male rats were pretreated with saline or nicotine (0.16 or 0.64 mg/kg, SC) from postnatal day (PD) 35-50. On PD 51, subjects were split into the following groups: SAL-SAL, 0.16-0.16, 0.16-SAL, 0.64 0.64, and 0.64-SAL. Rats were then trained to lever press for METH (0.05 mg/kg) for seven days on an FR1 and seven days on an FR3 reinforcement schedule. After acquisition training, rats underwent 14 days of extinction and were then tested for METH-induced primed reinstatement (1.0mg/kg, IP). RESULTS: Data showed that rats receiving continuous injections of the low dose of nicotine (0.16-0.16) obtained more METH infusions versus the control group (SAL-SAL) on an FR1 and FR3 schedule. In addition, rats on the FR3 schedule that received a low dose of nicotine during the adolescent period only (0.16-SAL) had more METH intake than the control group (SAL-SAL). Interestingly, the high dose of nicotine exposure had no effect on METH intake and neither nicotine dose altered METH seeking behavior. CONCLUSIONS: Low dose exposure to nicotine during adolescence enhances the reinforcing effects of METH, while heavier exposure has no effect on METH intake. PMID- 25042761 TI - Unemployment and substance outcomes in the United States 2002-2010. AB - BACKGROUND: The economic shock of 2008-2009 provided an opportunity to study the robustness of observed statistical associations between unemployment and problematic substance use. METHODS: Data from 405,000 non-institutionalized adult participants in the 2002 to 2010 U.S. National Survey on Drug Use and Health were used to compare substance outcomes among unemployed and employed persons. Association of unemployment with substance outcomes was examined for the years 2002-2004, 2005-2007, 2008, and 2009-2010, corresponding to periods prior to and after the economic downturn of 2008. Multivariate logistic regression models adjusted for age, sex, race/ethnicity, education, urban/rural residence, current DSM-IV Major Depression, and local county unemployment rates. RESULTS: Higher rates of past month tobacco and illicit drug use, heavy alcohol use, and past year drug or alcohol abuse/dependence were found among the unemployed. Markedly increased unemployment in 2009-2010 did not moderate the association between substance outcomes and employment. This association was not confounded by sex, age group, or race/ethnicity for tobacco and illicit drugs, although it varied for alcohol outcomes among 18-25 year-olds. Results based on retrospective data regarding marijuana use in the period prior to unemployment suggest its use was associated with future job loss. CONCLUSIONS: Employment status was strongly and robustly associated with problematic use of substances. Prevention and treatment interventions are warranted for a group whose employment and resulting insurance status may impair access to much needed health care. PMID- 25042762 TI - Impact of trauma symptomatology on personal networks among substance using women. AB - BACKGROUND: Interpersonal trauma poses challenges and complications to the development and maintenance of personal networks of substance using women. Few studies have examined its effects on personal network support availability and quality of relationships, limiting our understanding of the social context in which substance using women with a history of trauma are embedded. METHODS: Women with substance use disorders (SUD) who received treatment at three county-funded, women-only intensive treatment programs (N=375) were interviewed at intake and at follow ups 1, 6, and 12 months later. A network software program, EgoNet, elicited 25 network members per respondent, social support availability, and the quality of network relationship at each assessment. Trauma symptomatology was assessed with Trauma Symptom Checklist-40 at intake. RESULTS: Findings from longitudinal mixed model analyses indicated that higher levels of trauma symptomatology were associated with both a negative, critical quality and less closeness in network relationships over the 12 month study period. However, trauma symptoms were not related to the number of network members reported as providing emotional, concrete, or sobriety support. Effects of trauma symptoms on the support availability in the network and the quality of network relationships were consistent over the follow-up period. CONCLUSIONS: Findings highlight the potential role of trauma symptoms in determining the quality of relationships within personal networks among women with SUD, suggesting the need for routine mapping of network relationships throughout treatment. PMID- 25042763 TI - Investigation of DMSO-induced conformational transitions in human serum albumin using two-dimensional raman optical activity spectroscopy. AB - Recent Raman and Raman optical activity (ROA) results have demonstrated that dimethyl sulfoxide (DMSO) induces the selective conversion of alpha-helix motifs into the poly(L-proline) II (PPII) helix conformation in an array of proteins, while beta-sheets remain mostly unaffected. Human serum albumin (HSA), a highly alpha-helical protein, underwent the most dramatic changes and, therefore, was selected as a model for further investigations into the mechanism of this conformational change. Herein we report the use of two-dimensional ROA correlation analysis applying synchronous, autocorrelation, and moving windows approaches in order to understand the conformational transitions in HSA as a function of DMSO concentration. Our results indicate that the destabilization of native alpha-helix starts at DMSO concentrations as little as 20% in water (v/v), with the transition to PPII helix being complete at ~80% DMSO. These results clearly indicate that any protein preparation containing relatively low concentrations of DMSO should consider possible disruptions in alpha-helical domains. PMID- 25042765 TI - Thymosin beta4 administration enhances fracture healing in mice. AB - Thymosin beta4 (Tbeta4 ) is a regenerative peptide that we hypothesized would promote healing of fractured bone. Mice received a bilateral fibular osteotomy and were given i.p. injections of either Tbeta4 (6 mg/kg) or saline. Calluses from saline- and Tbeta4 -treated mice were analyzed for: (1) biomechanical properties and (2) composition using micro-computed tomography (uCT) and histomorphometry. Biomechanical analysis showed that Tbeta4 -treated calluses had a 41% increase in peak force to failure (p < 0.01) and were approximately 25% stiffer (p < 0.05) than saline-treated controls. uCT analysis at 21 days post fracture showed that the fractional volume of new mineralized tissue and new highly mineralized tissue were respectively 18% and 26% greater in calluses from Tbeta4 -treated mice compared to controls (p < 0.01; p < 0.05, respectively). Histomorphometry complemented the uCT data; at 21 days post-fracture, Tbeta4 treated calluses were almost 23% smaller (p < 0.05), had nearly 47% less old cortical bone (p < 0.05) and had a 31% increase in new trabecular bone area/total callus area fraction compared with controls (p < 0.05). Our finding of enhanced biomechanical properties of fractures in mice treated with Tbeta4 provides novel evidence of the therapeutic potential of this peptide for treating bone fractures. PMID- 25042764 TI - Gender differences in working memory networks: a BrainMap meta-analysis. AB - Gender differences in psychological processes have been of great interest in a variety of fields. While the majority of research in this area has focused on specific differences in relation to test performance, this study sought to determine the underlying neurofunctional differences observed during working memory, a pivotal cognitive process shown to be predictive of academic achievement and intelligence. Using the BrainMap database, we performed a meta analysis and applied activation likelihood estimation to our search set. Our results demonstrate consistent working memory networks across genders, but also provide evidence for gender-specific networks whereby females consistently activate more limbic (e.g., amygdala and hippocampus) and prefrontal structures (e.g., right inferior frontal gyrus), and males activate a distributed network inclusive of more parietal regions. These data provide a framework for future investigations using functional or effective connectivity methods to elucidate the underpinnings of gender differences in neural network recruitment during working memory tasks. PMID- 25042766 TI - Toll-like receptor 4 deficiency impairs microglial phagocytosis of degenerating axons. AB - Microglia are rapidly activated in the central nervous system (CNS) in response to a variety of injuries, including inflammation, trauma, and stroke. In addition to modulation of the innate immune response, a key function of microglia is the phagocytosis of dying cells and cellular debris, which can facilitate recovery. Despite emerging evidence that axonal debris can pose a barrier to regeneration of new axons in the CNS, little is known of the cellular and molecular mechanisms that underlie clearance of degenerating CNS axons. We utilize a custom micropatterned microfluidic system that enables robust microglial-axon co-culture to explore the role of Toll-like receptors (TLRs) in microglial phagocytosis of degenerating axons. We find that pharmacologic and genetic disruption of TLR4 blocks induction of the Type-1 interferon response and inhibits phagocytosis of axon debris in vitro. Moreover, TLR4-dependent microglial clearance of unmyelinated axon debris facilitates axon outgrowth. In vivo, microglial phagocytosis of CNS axons undergoing Wallerian degeneration in a dorsal root axotomy model is impaired in adult mice in which TLR4 has been deleted. Since purinergic receptors can influence TLR4-mediated signaling, we also explored a role for the microglia P2 receptors and found that the P2X7R contributes to microglial clearance of degenerating axons. Overall, we identify TLR4 as a key player in axonal debris clearance by microglia, thus creating a more permissive environment for axonal outgrowth. Our findings have significant implications for the development of protective and regenerative strategies for the many inflammatory, traumatic, and neurodegenerative conditions characterized by CNS axon degeneration. PMID- 25042767 TI - Giant room-temperature elastocaloric effect in ferroelectric ultrathin films. AB - Environmentally friendly ultrathin BaTiO3 capacitors can exhibit a giant stress induced elastocaloric effect without hysteresis loss or Joule heating. By combining this novel elastocaloric effect with the intrinsic electrocaloric effect, an ideal refrigeration cycle with high performance (temperature change over 10 K with a wide working-temperature window of 60 K) at room temperature is proposed for future cooling applications. PMID- 25042770 TI - Vertical components of head-shaking nystagmus in vestibular neuritis, Meniere's disease and migrainous vertigo. AB - OBJECTIVES: To describe vertical and horizontal components of head-shaking nystagmus (HSN) in various vestibular disorders. DESIGN: Retrospective case review. SETTING: Tertiary care academic referral centre. PARTICIPANTS: Head shaking nystagmus was assessed in 66 vestibular neuritis (VN) patients at acute (<7 days) and follow-up (2 months), and 65 Meniere's disease (MD) and 76 migrainous vertigo (MV) in interictal period. MAIN OUTCOME MEASURES: Head-shaking nystagmus was categorised as pure horizontal, pure vertical or mixed. Horizontal HSN was classified as monophasic or biphasic and paretic or recovery. Vertical HSN was classified as upbeat or downbeat. RESULTS: Abnormal HSN (pathologic monophasic, biphasic or delayed-peak HSN) showed different positive rates depending on the vestibular disorders and compensation (94% in acute VN; 89% in FU VN; 78% in MD; 50% in MV). Paretic HSN with the nystagmus towards the lesioned side was the most common type in VN and MD; however, recovery HSN with the nystagmus towards the intact side could be rarely observed especially in patients with MD or compensated VN. Vertical nystagmus could be combined with horizontal HSN, and upbeat HSN was observed in most (83%) of the patients with acute VN, but downbeat HSN was common in follow-up VN (83%), MD (97%) and MV (85%). Weak perverted HSN, which is assumed to be a central nystagmus, was rarely observed in MD and MV (6-9%), but not in VN. CONCLUSIONS: Head-shaking nystagmus (HSN) in horizontal plane is a valuable tool in the assessment of vestibular imbalance. Common observation of upbeat HSN in acute VN and downbeat HSN in follow-up VN, MD and MV suggests that vertical components are possibly related to the involvement of vestibular apparatus and compensation. Weak perverted HSN and delayed-peak HSN were rarely observed in MD and MV, and never observed in VN, suggesting that it is possibly related to either asymmetrically impaired vertical canals or misorientation of the velocity-storage system. PMID- 25042771 TI - The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. AB - Early gastric cancers (EGCs) precede advanced gastric cancers (AGCs), with a favourable prognosis compared to AGC. To understand the progression mechanism of EGC to AGC, it is required to disclose EGC and AGC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of nine microsatellite (MS)-unstable (MSI-H) (five EGCs and four AGCs) and eight MS-stable (MSS) gastric cancers (four EGCs and four AGCs). In the cancers, we observed well-known driver mutations (TP53, APC, PIK3CA, ARID1A, and KRAS) that were enriched in cancer-related pathways, including chromatin remodelling and tyrosine kinase activity. The MSI-H genomes harboured ten times more mutations, but were largely depleted of copy number alterations (CNAs) compared to the MSS cancers. Interestingly, EGC genomes showed a comparable level of mutations to AGC in terms of the number, sequence composition, and functional consequences (potential driver mutations and affected pathways) of mutations. Furthermore, the CNAs between EGC and AGC genomes were not significantly different in either MSI-H and MSS. Evolutionary analyses using somatic mutations and MSI as molecular clocks further identified that EGC genomes were as old as AGC genomes in both MSS and MSI-H cancers. Our results suggest that the genetic makeup for gastric cancer may already be achieved in EGC genomes and that the time required for transition to AGC may be relatively short. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful in the clinical settings for the molecular diagnosis and therapeutics of gastric cancer patients. PMID- 25042772 TI - Prevalence and potential risk factors for the occurrence of cefotaxime resistant Escherichia coli in German fattening pig farms--a cross-sectional study. AB - A cross-sectional study concerning farm prevalence and risk factors for the count of cefotaxime resistant Escherichia coli (E. coli) (CREC) positive samples per sampling group on German fattening pig farms was performed in 2011 and 2012. Altogether 48 farms in four agricultural regions in the whole of Germany were investigated. Faecal samples, boot swabs and dust samples from two sampling groups per farm were taken and supplemental data were collected using a questionnaire. On 85% of the farms, at least one sample contained cefotaxime resistant E. coli colonies. Positive samples were more frequent in faeces (61%) and boot swabs (54%) than in dust samples (11%). Relevant variables from the questionnaire were analysed in a univariable mixed effect Poisson regression model. Variables that were related to the number (risk) of positive samples per sampling group with a p-value <0.2 were entered in a multivariable model. This model was reduced to statistically significant variables via backward selection. Factors that increased the risk for positive samples involved farm management and hygienic aspects. Farms that had a separate pen for diseased pigs had a 2.8 higher mean count of positive samples (95%-CI [1.71; 4.58], p=0.001) than farms without an extra pen. The mean count was increased on farms with under-floor exhaust ventilation compared to farms with over floor ventilation (2.22 [1.43; 3.46], p=0.001) and more positive samples were observed on farms that controlled flies with toxin compared to farms that did not (1.86 [1.24; 2.78], p=0.003). It can be concluded, that CREC are wide spread on German fattening pig farms. In addition the explorative approach of the present study suggests an influence of management strategies on the occurrence of cefotaxime resistant E. coli. PMID- 25042773 TI - Longitudinal accuracy of web-based self-reported weights: results from the Hopkins POWER Trial. AB - BACKGROUND: Websites and phone apps are increasingly used to track weights during weight loss interventions, yet the longitudinal accuracy of these self-reported weights is uncertain. OBJECTIVE: Our goal was to compare the longitudinal accuracy of self-reported weights entered online during the course of a randomized weight loss trial to measurements taken in the clinic. We aimed to determine if accuracy of self-reported weight is associated with weight loss and to determine the extent of misclassification in achieving 5% weight loss when using self-reported compared to clinic weights. METHODS: This study examined the accuracy of self-reported weights recorded online among intervention participants in the Hopkins Practice-Based Opportunities for Weight Reduction (POWER) trial, a randomized trial examining the effectiveness of two lifestyle-based weight loss interventions compared to a control group among obese adult patients with at least one cardiovascular risk factor. One treatment group was offered telephonic coaching and the other group was offered in-person individual coaching and group sessions. All intervention participants (n=277) received a digital scale and were asked to track their weight weekly on a study website. Research staff used a standard protocol to measure weight in the clinic. Differences (self-reported weight - clinic weight) indicate if self-report under (-) or over (+) estimated clinic weight using the self-reported weight that was closest in time to the clinic weight and was within a window ranging from the day of the clinic visit to 7 days before the 6-month (n=225) and 24-month (n=191) clinic visits. The absolute value of the differences (absolute difference) describes the overall accuracy. RESULTS: Underestimation of self-reported weights increased significantly from 6 months (mean -0.5 kg, SD 1.0 kg) to 24 months (mean -1.1 kg, SD 2.0 kg; P=.002). The average absolute difference also increased from 6 months (mean 0.7 kg, SD 0.8 kg) to 24 months (mean 1.3, SD 1.8 kg; P<.001). Participants who achieved the study weight loss goal at 24 months (based on clinic weights) had lower absolute differences (P=.01) compared to those who did not meet this goal. At 24 months, there was 9% misclassification of weight loss goal success when using self-reported weight compared to clinic weight as an outcome. At 24 months, those with self-reported weights (n=191) had three times the weight loss compared to those (n=73) without self-reported weights (P<.001). CONCLUSIONS: Underestimation of weight increased over time and was associated with less weight loss. In addition to intervention adherence, weight loss programs should emphasize accuracy in self-reporting. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00783315; http://clinicaltrials.gov/show/NCT00783315 (Archived by WebCite at http://www.webcitation.org/6R4gDAK5K). PMID- 25042774 TI - The interactions between nerve growth factor and gonadotrophins in bovine oviduct. AB - Nerve growth factor promotes the survival and differentiation of nervous cells and is thought to play an important role in the development of reproductive tissues. The aims of this work were to detect the presence of NGF and its receptor NTRK1 in bovine oviduct samples, and to investigate the regulatory interactions between NGF/NTRK1 and gonadotrophins in bovine oviduct epithelial cells. Both transcripts and proteins of NGF and NTRK1 were detected by RT-PCR and Western blotting, and the corresponding proteins were specifically immunolocalized in oviduct epithelial cells. In addition, real-time PCR experiments revealed that the levels of NGF and NTRK1 mRNA in oviduct epithelial cells treated with exogenous FSH or LH were greater than those in negative control cells (P<0.05). Similarly, treatment with NGF significantly increased the expression of FSHR and LHR in oviduct epithelial cells via its effects on NTRK1 (P<0.05). This process was suppressed by treatment with the NTRK1 inhibitor K252alpha. We conclude that NGF/NTRK1 may have a role in regulating the function of bovine oviducts via its interactions with gonadotrophins. PMID- 25042775 TI - The impact of exogenous DNA on the structure of sperm of olive flounder (Paralichthys olivaceus). AB - Sperm-mediated gene transfer (SMGT) is a promising transgenic technology that relies on the capability of sperm to internalize exogenous DNA. In marine fish, however, the interaction between sperm and exogenous DNA appears to be deficient. Here, we demonstrated significant DNase activity in the seminal plasma of the olive flounder. When incubated with naked-DNA, the spermatozoa lost their structural integrity, including the head, mitochondria and flagellum, in an incubation time-dependent manner. However, internalization of a liposome-DNA complex resulted in the structural integrity of the spermatozoa being maintained, even when using incubation times of up to 50min. We concluded that in the olive flounder, SMGT is possible by integrating liposome-DNA complexes, rather than naked-DNA alone, into the sperm. In brief, removal of the seminal plasma and packaging the exogenous DNA were necessary for successful SMGT in the olive flounder. PMID- 25042776 TI - Microporous polymeric 3D scaffolds templated by the layer-by-layer self-assembly. AB - Polymeric scaffolds serve as valuable supports for biological cells since they offer essential features for guiding cellular organization and tissue development. The main challenges for scaffold fabrication are i) to tune an internal structure and ii) to load bio-molecules such as growth factors and control their local concentration and distribution. Here, a new approach for the design of hollow polymeric scaffolds using porous CaCO3 particles (cores) as templates is presented. The cores packed into a microfluidic channel are coated with polymers employing the layer-by-layer (LbL) technique. Subsequent core elimination at mild conditions results in formation of the scaffold composed of interconnected hollow polymer microspheres. The size of the cores determines the feature dimensions and, as a consequence, governs cellular adhesion: for 3T3 fibroblasts an optimal microsphere size is 12 MUm. By making use of the carrier properties of the porous CaCO3 cores, the microspheres are loaded with BSA as a model protein. The scaffolds developed here may also be well suited for the localized release of bio-molecules using external triggers such as IR-light. PMID- 25042777 TI - Endocannabinoid influence on partner preference in female rats. AB - The present study investigated the role of the endocannabinoid system on sexual motivation in the female rat. In Experiment 1, gonadally intact female rats were first tested for partner preference after a vehicle injection. Approximately 2 weeks later, all rats were tested again after an injection of the endocannabinoid antagonist, SR141716 (SR; also known as Rimonabant; 1.0mg/kg). During the first 10 min of each partner preference test, subjects could spend time near either a male or female stimulus animal that was placed behind a wire mesh (No-Contact). During the second 10 min of each partner preference test, subjects had unrestricted access to both stimulus animals (Contact). When the female subjects were treated with SR, they made fewer visits to either stimulus animal during the no-contact phase of the partner preference test compared to when they were treated with vehicle. In Experiment 2, ovariectomized (OVX) subjects primed with estrogen were administered SR or vehicle and tested for partner preference (Experiment 2A). Approximately 2 weeks later, the subjects from the control group were tested again after an injection of SR (Experiment 2B). In contrast to Experiment 1, treatment with SR reduced the number of visits specifically to the male stimulus during the contact phase of the test in Experiment 2. Experiment 3 tested the effects of SR on general locomotion and found no effect of SR on line crossings in an open field. Finally, in Experiment 4, OVX estrogen- and progesterone-primed subjects were administered the endocannabinoid agonist anandamide (AEA: 1.0mg/kg) or vehicle and tested for partner preference. AEA treated subjects made more visits to the male stimulus than vehicle-treated subjects during the contact phase of the test. The results of the present study suggest that the endocannabinoid system may contribute to sexual motivation in female rats by specifically altering approach behavior. PMID- 25042779 TI - A practical tutorial to set up NMR diffusometry equipment: application to liquid crystals. AB - NMR diffusometry is nowadays a well-established and powerful technique to investigate molecular translation in fluid materials. Standard NMR diffusometry approaches are based on pulsed field gradients generated by specific hardware and specially designed NMR probes. Here, we present an alternative set-up that exploits the static gradient present in the fringe field of any commercial superconducting magnet. This stray field diffusometry technique can be particularly useful to study diffusional processes in fast-relaxing and slow diffusing systems, such as thermotropic liquid crystals, ionic liquids and polymer melts. PMID- 25042778 TI - Lack of effect of a P2Y6 receptor antagonist on neuropathic pain behavior in mice. AB - Accumulating evidence indicates that various subtypes of purinergic receptors (P2X and P2Y receptor families) play an essential role in the development and the maintenance of neuropathic pain. However, there is only limited data available about the role of P2Y6 receptors in pain processing. Here we detected P2Y6 receptor immunoreactivity in primary afferent neurons of mice and observed an upregulation in response to peripheral nerve injury. However, systemic and intrathecal administration of the P2Y6 receptor antagonist MRS2578 failed to affect the injury-induced neuropathic pain behavior. Our results suggest that P2Y6 receptors, in contrast to other purinergic receptor subtypes, are not critically involved in nerve injury-induced neuropathic pain processing in mice. PMID- 25042780 TI - New evidence on treatments for varicose veins. PMID- 25042781 TI - Randomized clinical trial of isolated Roux-en-Y versus conventional reconstruction after pancreaticoduodenectomy (Br J Surg 2014; 101: 1084-1091). PMID- 25042784 TI - Optimized cell transplantation using adult rag2 mutant zebrafish. AB - Cell transplantation into adult zebrafish has lagged behind mouse models owing to the lack of immunocompromised strains. Here we have created rag2(E450fs) mutant zebrafish that have reduced numbers of functional T and B cells but are viable and fecund. Mutant fish engraft muscle, blood stem cells and various cancers. rag2(E450fs) mutant zebrafish are the first immunocompromised zebrafish model that permits robust, long-term engraftment of multiple tissues and cancer. PMID- 25042785 TI - Fast, accurate reconstruction of cell lineages from large-scale fluorescence microscopy data. AB - The comprehensive reconstruction of cell lineages in complex multicellular organisms is a central goal of developmental biology. We present an open-source computational framework for the segmentation and tracking of cell nuclei with high accuracy and speed. We demonstrate its (i) generality by reconstructing cell lineages in four-dimensional, terabyte-sized image data sets of fruit fly, zebrafish and mouse embryos acquired with three types of fluorescence microscopes, (ii) scalability by analyzing advanced stages of development with up to 20,000 cells per time point at 26,000 cells min(-1) on a single computer workstation and (iii) ease of use by adjusting only two parameters across all data sets and providing visualization and editing tools for efficient data curation. Our approach achieves on average 97.0% linkage accuracy across all species and imaging modalities. Using our system, we performed the first cell lineage reconstruction of early Drosophila melanogaster nervous system development, revealing neuroblast dynamics throughout an entire embryo. PMID- 25042786 TI - Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. AB - We report a single-cell bisulfite sequencing (scBS-seq) method that can be used to accurately measure DNA methylation at up to 48.4% of CpG sites. Embryonic stem cells grown in serum or in 2i medium displayed epigenetic heterogeneity, with '2i like' cells present in serum culture. Integration of 12 individual mouse oocyte datasets largely recapitulated the whole DNA methylome, which makes scBS-seq a versatile tool to explore DNA methylation in rare cells and heterogeneous populations. PMID- 25042787 TI - High-resolution reconstruction of the beating zebrafish heart. AB - The heart's continuous motion makes it difficult to capture high-resolution images of this organ in vivo. We developed tools based on high-speed selective plane illumination microscopy (SPIM), offering pristine views into the beating zebrafish heart. We captured three-dimensional cardiac dynamics with postacquisition synchronization of multiview movie stacks, obtained static high resolution reconstructions by briefly stopping the heart with optogenetics and resolved nonperiodic phenomena by high-speed volume scanning with a liquid lens. PMID- 25042788 TI - Current practice in the management of tetanus. AB - Tetanus is still a scourge among the under-privileged populations of the world, and unfortunately remains an important cause of death although a cheap, safe and highly efficacious vaccine is available. The rarity of the disease in some parts of the world results in newly trained physicians being unable to make a clinical diagnosis, and hampers the conduct of adequately powered randomized controlled trials. Several new and experimental pharmacological agents are being used to control the spasms in tetanus, and to combat the autonomic instability that occurs in the disease. New evidence is emerging regarding the use of antibiotics and intrathecal immunoglobulin in tetanus. It is imperative, therefore, that all physicians working in critical care should be aware of the current advances and evidence-based guidelines for management of tetanus in order to achieve the best outcomes, which Rodrigo and colleagues have reviewed in a recent issue of Critical Care. PMID- 25042789 TI - Protease inhibitor resistance mutations in untreated Brazilian patients infected with HCV: novel insights about targeted genotyping approaches. AB - Several new direct-acting antiviral (DAA) drugs are being developed or are already approved for the treatment of chronic hepatitis C virus (HCV) infection. HCV variants presenting drug-resistant phenotypes were observed both in vitro and during clinical trials. The aim of this study was to characterize amino acid changes at positions previously associated with resistance in the NS3 protease in untreated Brazilian patients infected with HCV genotypes 1a and 1b. Plasma samples from 171 untreated Brazilian patients infected with HCV were obtained from the Department of Gastroenterology of Clinics Hospital (HCFMUSP) in Sao Paulo, Brazil. Nested PCR and Sanger sequencing were used to obtain genetic information on the NS3 protein. Bioinformatics was used to confirm subtype information and analyze frequencies of resistance mutations. The results from the genotype analysis using non-NS3 targeted methods were at variance with those obtained from the NS3 protease phylogenetic analyses. It was found that 7.4% of patients infected with HCV genotype 1a showed the resistance-associated mutations V36L, T54S, Q80K, and R155K, while 5.1% of patients infected with HCV genotype 1b had the resistance-associated mutations V36L, Q41R, T54S, and D168S. Notably, codons at positions 80 and 155 differed between samples from Brazilian patient used in this study and global isolates. The present study demonstrates that genotyping methods targeting the NS3 protein showed a difference of results when compared to mainstream methodologies (INNO-LiPA and polymerase sequencing). The resistance mutations present in untreated patients infected with HCV and codon composition bias by geographical location warrant closer examination. PMID- 25042790 TI - Cutaneous T-cell lymphoma: 2014 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sezary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, and blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. Multiagent chemotherapy (e.g., CHOP) may be employed for those patients with extensive visceral involvement requiring rapid disease control. In highly selected patients, allogeneic stem cell transplantation may be considered. PMID- 25042791 TI - Validation of standard ASTM F2732 and comparison with ISO 11079 with respect to comfort temperature ratings for cold protective clothing. AB - American standard ASTM F2732 estimates the lowest environmental temperature for thermal comfort for cold weather protective clothing. International standard ISO 11079 serves the same purpose but expresses cold stress in terms of required clothing insulation for a given cold climate. The objective of this study was to validate and compare the temperature ratings using human subject tests at two levels of metabolic rates (2 and 4 MET corresponding to 116.4 and 232.8 W/m(2)). Nine young and healthy male subjects participated in the cold exposure at 3.4 and -30.6 degrees C. The results showed that both standards predict similar temperature ratings for an intrinsic clothing insulation of 1.89 clo and for 2 MET activity. The predicted temperature rating for 2 MET activity is consistent with test subjects' thermophysiological responses, perceived thermal sensation and thermal comfort. For 4 MET activity, however, the whole body responses were on the cold side, particularly the responses of the extremities. ASTM F2732 is also limited due to its omission and simplification of three climatic variables (air velocity, radiant temperature and relative humidity) and exposure time in the cold which are of practical importance. PMID- 25042792 TI - Reference ranges of fetal spleen biometric parameters and volume assessed by three-dimensional ultrasound and their applicability in spleen malformations. AB - AIM: The aims of this article are to establish three-dimensional ultrasonographic nomograms of normal fetal spleen size and to evaluate the clinical application value. METHODS: An observational, cross-sectional study was performed on 455 women with a normal singleton pregnancy between 18 and 38 weeks' gestational age (GA). Fetal spleen volume was measured using three-dimensional ultrasound equipped with virtual organ computer-aided analysis, and biometric parameters were assessed in multiplanar mode to create reference ranges to GA. Thirty cases were randomly selected to conduct reliability analyses via intraobserver and interobserver ultrasonographic measurement. Moreover, 50 cases of suspected splenic malformations were evaluated by the newly established nomograms and followed up subsequently. RESULTS: Using regression formulas, we found that fetal spleen size increased with GA. We observed strong reliability in intraobserver and interobserver volume measurements with intraclass correlation coefficients of 0.994 and 0.962. Bland-Altman analyses showed narrow limits of agreement [intraobserver: (-3.2 to 3.5)%; interobserver: (-3.2 to 4.3)%]. Of the 50 cases with suspected splenic malformations, six cases of splenomegaly and one case of splenic cyst were diagnosed. CONCLUSION: Three-dimensional ultrasound nomograms of normal fetal spleen size across a range of GA have a strong diagnostic value. Volume measurements with good reliability were optimal in clinical practice. PMID- 25042793 TI - Renal recovery after acute kidney injury: choice of initial renal replacement therapy modality still matters. AB - Renal replacement therapy can be applied either in an intermittent fashion or in a continuous fashion in severe acute kidney injury. To date, no modality has been shown to consistently improve patient survival. In the study recently reported by Sun and colleagues, continuous application of renal replacement therapy was associated with improved renal recovery, defined by lower risk of long-term need for chronic dialysis therapy. This association between nonrecovery and intermittent renal replacement therapy may be explained by a higher rate of hypotensive episodes and the lower capacity for fluid removal during the first 72 hours of therapy. Altogether, this study adds to the growing body of evidence to suggest improved likelihood of recovery of kidney function in critically ill survivors of AKI with continuous modalities for renal replacement therapy. PMID- 25042794 TI - Baclofen prevented the changes in c-Fos and brain-derived neutrophic factor expressions during mecamylamine-precipitated nicotine withdrawal in mice. AB - Previous studies from our laboratory showed that baclofen (BAC, GABAB receptor agonist) prevented the behavioral and neurochemical alterations of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying these effects, we analyzed the c-Fos and brain-derived neutrophic factor (BDNF) expression during NIC withdrawal and its prevention with BAC. Swiss-Webster mice received NIC (2.5 mg/kg, sc) four times daily, for 7 days. On the 8th day, NIC treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and the immunohistochemistry assays (c-Fos and BDNF) were performed at different anatomical levels. c-Fos expression decreased in the dentate gyrus of the hippocampus (DG) and the bed nucleus of the stria terminalis (BST), and increased in the habenular (Hb), accumbens shell (AcbSh) nuclei during NIC withdrawal. BAC re-established the modified c-Fos expression only in the DG, BST and AcbSh during NIC withdrawal. Conversely, BDNF expression decreased in the CA1 and CA3 area of the hippocampus, the Hb, and caudate putamen (CPu) during NIC withdrawal. Finally, BAC restored the decreased BDNF expression during NIC withdrawal in the CA1, CA3, Hb, and CPu. The results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in c-Fos and BDNF expression, observed in specific brain areas of NIC-withdrawn mice. PMID- 25042795 TI - Interfacial material system exhibiting superwettability. AB - Engineering the wettability of solid materials is a traditional, yet key issue in surface science and attracts tremendous interest by researchers in diverse fields. Recently, different superwetting phenomena have been discovered in both nature and experimental results. Therefore, in this review, various superwetting states, leading to a "superwettability" system, are summarized and predicted. Fundamental rules for understanding superwettability are discussed, mainly taking superhydrophobicity in air as an example. Then, some recent application progress of individual members of this "superwettability" system are introduced. Notably, several novel application fields, mainly gas, water, oil and/or other liquid environments, are presented in the following section. By combining different members of this "superwettability" system, new interfacial functions can be generated, allowing unexpected applications, such as in environmental protection, energy, green industry, and many other important domains. Finally, the future development of this interesting "superwettability" system is discussed. PMID- 25042796 TI - Interferon gamma induced by resveratrol analog, HS-1793, reverses the properties of tumor associated macrophages. AB - Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state. Tumor-associated macrophages (TAM) are a kind of alternatively activated M2 macrophage, which may contribute to tumor progression. Following our previous study to evaluate the anti-tumor effect of a synthetic resveratrol analog HS-1793, the current study demonstrated that HS 1793 treatment significantly increased IFN-gamma secreting cells in splenocytes and decreased CD206+ macrophage infiltration compared to CD68+ cells in the tumor site with a higher expression of IFN-gamma. As these results suggested that IFN gamma increased locally at the tumor sites could modulate the status of TAM, we designed an in vitro model to study macrophage morphology and functions in relation to the tumor microenvironment. Human monocytic cell line THP-1 cells stimulated with phorbol-12-myristate-13-acetate (PMA) differentiated to macrophages with M2-like phenotypes. TAM-like properties of CD206(high), CD204(high), IL-10(high), TGF-beta(high), IL-6(low), IL-12(low), VEGF(high), and MMP-9(high) and promotion of tumor cell invasion were more pronounced in M-2 polarized THP-1 macrophages generated by differentiating THP-1 cells with PMA and subsequently polarizing them with Th2 cytokines (IL-4/IL-13). Upon IFN-gamma exposure, THP-1-derived TAM changed their phenotypes to the M-1-like morphology and intracellular granular pattern with an expression of an increased level of proinflammatory and immunostimulatory cytokines and a reduced level of immunosuppressive and tumor progressive mediators. These results explain the underlying mechanism of the anti-tumor activity of HS-1793. The elevated level of IFN-gamma production after HS-1793 treatment evoked reprogramming of M-2 phenotype TAM, which efficiently countered the immunosuppressive and tumor progressive influences of TAM. PMID- 25042797 TI - Derivation of Phase 3 dosing for peginterferon lambda-1a in chronic hepatitis C, Part 2: Exposure-response analyses for efficacy and safety variables. AB - This is the second of two manuscripts detailing the pharmacodynamic derivation of peginterferon lambda-1a (Lambda) dosing and treatment durations for Phase 3 studies in hepatitis C virus (HCV) infection, based on Phase 2 data. Herein, we describe the derivation of regression models for 12-week on-treatment virologic response and safety outcomes at 120, 180, and 240 MUg Lambda with ribavirin. In patients with HCV genotypes 1 or 4, there was a significant (P = 0.024) relationship between undetectable HCV-RNA at Week 4 and Lambda exposure (AUC or Cmax ), with the largest difference between adjacent dose levels between the 180 and 120 MUg exposure ranges. Risk of Grade 3-4 aminotransferase or bilirubin elevations relative to a peginterferon alfa-2a/ribavirin control were related to Lambda exposure for all patients, and the largest increase between adjacent dose levels was seen for 240 versus 180 MUg. Anemia and neutropenia events were lower than control across all doses and exposures. Based on these data and those in our previous manuscript, Phase 3 studies will evaluate fixed 180 ug doses of Lambda in combination with ribavirin and a direct-acting antiviral for 24-48 weeks in HCV genotypes 1 or 4 or 12-24 weeks in genotypes 2 or 3. PMID- 25042798 TI - The foreign body response to the Utah Slant Electrode Array in the cat sciatic nerve. AB - As the field of neuroprosthetic research continues to grow, studies describing the foreign body reaction surrounding chronic indwelling electrodes or microelectrode arrays will be critical for assessing biocompatibility. Of particular importance is the reaction surrounding penetrating microelectrodes that are used to stimulate and record from peripheral nerves used for prosthetic control, where such studies on axially penetrating electrodes are limited. Using the Utah Slant Electrode Array and a variety of histological methods, we investigated the foreign body response to the implanted array and its surrounding silicone cuff over long indwelling periods in the cat sciatic nerve. We observed that implanted nerves were associated with increased numbers of activated macrophages at the implant site, as well as distal to the implant, at all time points examined, with the longest observation being 350 days after implantation. We found that implanted cat sciatic nerves undergo a compensatory regenerative response after the initial injury that is accompanied by shifts in nerve fiber composition toward nerve fibers of smaller diameter and evidence of axons growing around microelectrode shafts. Nerve fibers located in fascicles that were not penetrated by the array or were located more than a few hundred microns from the implant appeared normal when examined over the course of a year-long indwelling period. PMID- 25042799 TI - Prognostic factors and impact of adjuvant treatments on local and metastatic relapse of soft-tissue sarcoma patients in the competing risks setting. AB - BACKGROUND: In the medical literature many analyses of outcomes of sarcoma patients were performed without regard to the problem of "competing risks." METHODS: We analyzed local relapse-free and metastasis-free survival in a population of 3255 adult patients with a primary soft-tissue sarcoma (STS) included in the French Sarcoma Group database. Cumulative incidence of local and metastatic relapse was estimated by accounting for death as a competing event. RESULTS: On multivariate analysis, age, tumor site, histological subtype, and grade were independent adverse prognostic factors for local relapse, whereas tumor depth and size had no influence. Histological subtype, tumor depth, tumor size, and grade were independent adverse prognostic factors for metastatic relapse. Despite a higher incidence of competing deaths in patients managed with adjuvant radiotherapy than in patients not receiving radiotherapy, adjuvant radiotherapy was associated with a significant benefit in terms of local relapse free survival. Despite a similar cumulative incidence of competing deaths in patients with grade 2 and grade 3 disease, we found that the benefit of adjuvant chemotherapy was present only in patients with grade 3 and not in patients with grade 2 disease. CONCLUSIONS: In the setting of competing risks, tumor biology reflected by histological grade is a crucial predictor of local relapse, whereas tumor depth and size have poor if any influence. Grade could also predict the benefit of adjuvant chemotherapy in patients with STS. PMID- 25042800 TI - High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins. AB - TERT promoter mutations were recently discovered in melanoma by next generation sequencing. Subsequently, several malignancies including urothelial carcinoma were also found to be associated with the same TERT promoter mutations. Small cell carcinoma (SCC) of the urinary bladder is a rare subtype with an aggressive clinical course. Despite the frequent occurrence of TERT promoter mutations in urothelial carcinoma, the incidence of the mutations in SCC of the urinary bladder is unknown. In addition, as a potential molecular marker to distinguish SCC of the urinary bladder from SCC of the prostate, lung (SCLC) and other origins, this information may be clinically useful. We collected a total of 11 cases of SCC of the urinary bladder (10 cases are primary SCC of the urinary bladder; 1 case has primary SCC of the urinary bladder and liver metastasis). We also included 20 cases of SCLC, 2 cases of SCC of the prostate, 5 cases of Merkel cell carcinoma, and 6 cases of SCC from other sites (cervical, GE junction, breast, and soft tissue). In addition, 3 cases of non-neoplastic tissue from the matched SCC of bladder patient and 14 cases of benign urinary bladder were also included. All tumor sections have been examined to confirm the diagnosis and to make sure more than 20% are of tumor content. Genomic DNA was isolated from FFPE tissue and a fragment of the TERT promoter (145 bp) was amplified by PCR. The TERT promoter mutations are determined by bi-directional Sanger sequencing. All (11/11) SCC of the urinary bladder bear TERT promoter mutation C228T. Neither of SCC from all other origins nor matched non-neoplastic tissue contains the TERT promoter mutations. We demonstrated a high frequency TERT promoter mutation in SCC of the urinary bladder, but not in SCC of other origin, such as the prostate. The findings further illustrate molecular differences between SCC of the urinary bladder and SCC of other origins, despite their shared morphologic and immunophenotypic similarities. The TERT promoter mutation may be a biomarker differentiating SCC of the urinary bladder from SCC of other origins. PMID- 25042801 TI - An inducible chaperone adapts proteasome assembly to stress. AB - The proteasome is essential for the selective degradation of most cellular proteins. To survive overwhelming demands on the proteasome arising during environmental stresses, cells increase proteasome abundance. Proteasome assembly is known to be complex. How stressed cells overcome this vital challenge is unknown. In an unbiased suppressor screen aimed at rescuing the defects of a yeast Rpt6 thermosensitive proteasome mutant, we identified a protein, hereafter named Adc17, as it functions as an ATPase dedicated chaperone. Adc17 interacts with the amino terminus of Rpt6 to assist formation of the Rpt6-Rpt3 ATPase pair, an early step in proteasome assembly. Adc17 is important for cell fitness, and its absence aggravates proteasome defects. The abundance of Adc17 increases upon proteasome stresses, and its function is crucial to maintain homeostatic proteasome levels. Thus, cells have mechanisms to adjust proteasome assembly when demands increase, and Adc17 is a critical effector of this process. PMID- 25042802 TI - A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation. AB - Sox2 is a key factor for maintaining embryonic stem cell (ESS) pluripotency, but little is known about its posttranslational regulation. Here we present evidence that the precise level of Sox2 proteins in ESCs is regulated by a balanced methylation and phosphorylation switch. Set7 monomethylates Sox2 at K119, which inhibits Sox2 transcriptional activity and induces Sox2 ubiquitination and degradation. The E3 ligase WWP2 specifically interacts with K119-methylated Sox2 through its HECT domain to promote Sox2 ubiquitination. In contrast, AKT1 phosphorylates Sox2 at T118 and stabilizes Sox2 by antagonizing K119me by Set7 and vice versa. In mouse ESCs, AKT1 activity toward Sox2 is greater than that of Set7, leading to Sox2 stabilization and ESC maintenance. In early development, increased Set7 expression correlates with Sox2 downregulation and appropriate differentiation. Our study highlights the importance of a Sox2 methylation phosphorylation switch in determining ESC fate. PMID- 25042803 TI - Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. AB - Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP(+) binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in part to reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells. PMID- 25042804 TI - The Cep192-organized aurora A-Plk1 cascade is essential for centrosome cycle and bipolar spindle assembly. AB - As cells enter mitosis, the two centrosomes separate and grow dramatically, each forming a nascent spindle pole that nucleates a radial array of microtubules. Centrosome growth (and associated microtubule nucleation surge), termed maturation, involves the recruitment of pericentriolar material components via an as-yet unknown mechanism. Here, we show that Cep192 binds Aurora A and Plk1, targets them to centrosomes in a pericentrin-dependent manner, and promotes sequential activation of both kinases via T-loop phosphorylation. The Cep192 bound Plk1 then phosphorylates Cep192 at several residues to generate the attachment sites for the gamma-tubulin ring complex and, possibly, other pericentriolar material components, thus promoting their recruitment and subsequent microtubule nucleation. We further found that the Cep192-dependent Aurora A-Plk1 activity is essential for kinesin-5-mediated centrosome separation, bipolar spindle formation, and equal centrosome/centriole segregation into daughter cells. Thus, our study identifies a Cep192-organized signaling cascade that underlies both centrosome maturation and bipolar spindle assembly. PMID- 25042805 TI - Diversification of transcription factor paralogs via noncanonical modularity in C2H2 zinc finger DNA binding. AB - A major challenge in obtaining a full molecular description of evolutionary adaptation is to characterize how transcription factor (TF) DNA-binding specificity can change. To identify mechanisms of TF diversification, we performed detailed comparisons of yeast C2H2 ZF proteins with identical canonical recognition residues that are expected to bind the same DNA sequences. Unexpectedly, we found that ZF proteins can adapt to recognize new binding sites in a modular fashion whereby binding to common core sites remains unaffected. We identified two distinct mechanisms, conserved across multiple Ascomycota species, by which this molecular adaptation occurred. Our results suggest a route for TF evolution that alleviates negative pleiotropic effects by modularly gaining new binding sites. These findings expand our current understanding of ZF DNA binding and provide evidence for paralogous ZFs utilizing alternate modes of DNA binding to recognize unique sets of noncanonical binding sites. PMID- 25042807 TI - Molecular pom poms from self-assembling alpha,gamma-cyclic peptides. AB - The hierarchical self-assembly properties of a dimer-forming cyclic peptide that bears a nicotinic acid moiety to form molecular pom-pom-like structures are described. This dimeric assembly self organizes into spherical structures that can encapsulate small organic molecules owing to its porosity and it can also facilitate metal deposition on its surface directed by the pyridine moiety. PMID- 25042806 TI - An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. AB - The serine/threonine kinase LKB1 is a tumor suppressor whose loss is associated with increased metastatic potential. In an effort to define biochemical signatures of metastasis associated with LKB1 loss, we discovered that the epithelial-to-mesenchymal transition transcription factor Snail1 was uniquely upregulated upon LKB1 deficiency across cell types. The ability of LKB1 to suppress Snail1 levels was independent of AMPK but required the related kinases MARK1 and MARK4. In a screen for substrates of these kinases involved in Snail regulation, we identified the scaffolding protein DIXDC1. Similar to loss of LKB1, DIXDC1 depletion results in upregulation of Snail1 in a FAK-dependent manner, leading to increased cell invasion. MARK1 phosphorylation of DIXDC1 is required for its localization to focal adhesions and ability to suppress metastasis in mice. DIXDC1 is frequently downregulated in human cancers, which correlates with poor survival. This study defines an AMPK-independent phosphorylation cascade essential for LKB1-dependent control of metastatic behavior. PMID- 25042808 TI - Development of a genosensor for peanut allergen ARA h 2 detection and its optimization by surface response methodology. AB - A new selective electrochemical genosensor has been developed for the detection of an 86-mer DNA peanut sequence encoding part of the allergen Ara h 2 (conglutin homolog protein). The method is based on a sandwich format, which presents two advantages: it permits shortening the capture probe and avoids labeling of the target. Screen-printed gold electrodes have been used as platform for the immobilization of oligonucleotides by the well-known S-Au bond. Mixed self assembled monolayers (SAM), including thiol-modified capture probe and mercaptohexanol, were prepared to achieve an organized, homogeneous and not too compact SAM in which unspecific adsorption of the capture probe would be prevented. The optimization of the sensing phase was carried out using the Design of Experiments (DoE) approach. Traditionally, response optimization is achieved by changing the value of one factor at a time until there is no further improvement. However, DoE involves regulating the important factors so that the result becomes optimal. Optimized conditions were found to be 1.34 uM for capture probe concentration and 3.15 mM for mercaptohexanol (spacer) concentration. When the optimal conditions were employed the analytical performance of the proposed genosensor improved significantly, showing a sensitivity as high as 3 uA/nM, with a linear range from 5*10(-11) to 5*10(-8) M and a detection limit of 10 pM. PMID- 25042809 TI - Enzyme-integrated cholesterol biosensing scaffold based on in situ synthesized reduced graphene oxide and dendritic Pd nanostructure. AB - A new approach for the one-pot synthesis of reduced graphene oxide-dendritic Pd nanoparticle (rGO-nPd) hybrid material and the development of biosensing scaffold for the amperometric sensing of H2O2 and total cholesterol in human serum are described. In situ reduction of both graphene oxide (GO) and PdCl4(2-) in acidic solution was achieved with Zn to obtain rGO-nPd hybrid material. The oxygen containing functionalities of GO were reduced by the liberated atomic hydrogen in 20 min. The formal potential of Zn/Zn(2+) and PdCl4(2-)/Pd couples favor the facile reduction of PdCl4(2-). The in situ produced Pd nanoparticles behave like hydrogen sponge and increase the local concentration of atomic hydrogen. Biosensing platforms for H2O2 and cholesterol in human serum and butter sample were developed using the hybrid material. Amperometric sensing of H2O2 at 0.2 nM level without any redox mediator or enzymes in neutral pH is demonstrated. The cholesterol biosensing platform was developed by integrating cholesterol oxidase and cholesterol esterase with the hybrid material. The biosensor is highly sensitive (5.12+/-0.05 MUA/MUM cm(2)) and stable with a fast response time of 4 s; it could detect cholesterol ester as low as 0.05 uM (S/N=3). The biosensor is successfully used for the analysis of total cholesterol in human serum and butter. PMID- 25042812 TI - Relationship between metabolic syndrome and meal-induced glucagon like peptide-1 response in type 1 diabetic patients1-1. AB - BACKGROUND: Metabolic syndrome (MS) is found in approximately% 30-40% of patients with type 1 diabetes mellitus (T1DM). Meal-induced glucagon-like peptide-1 (GLP 1) secretion in T1DM patients with MS is yet to be clarified. The aim of the present study was to analyse the relationship between total fasting GLP-1 concentrations and the meal-induced GLP-1 response with MS prevalence in T1DM patients compared with lean, normal glucose tolerance (NGT), control subjects. METHODS: The study included 77 T1DM patients (61% male), 26 (34%) with MS, who had a mean age of 45.08 years, mean body mass index (BMI) of 25.42 kg/m(2) , and median diabetes duration of 21 years. Ten age-, gender, and BMI-matched NGT control subjects were also included in the study. Circulating GLP-1 concentrations ere measured before and 30 min after a meal by ELISA. The difference between the 30-min postprandial and fasting GLP-1 concentration (DeltaGLP-1) was calculated by subtracting fasting GLP-1 concentrations from postprandial GLP-1 concentrations. RESULTS: The NGT group had significantly higher total fasting, postprandial, and meal-induced GLP-1 concentrations than the T1DM groups. The T1DM patients without MS had a higher increase in circulating GLP-1 concentrations compared with the T1DM group with MS. After adjustment for age, gender, disease duration, and meal caloric value, GLP-1 response levels were inversely correlated with MS prevalence in binary logistic regression analysis. CONCLUSION: A higher meal-induced GLP-1 response is associated with lower MS prevalence, but whether GLP-1 has a protective role in MS development is yet to be determined. This may provide further insight into the implementation of GLP-1-based therapies in the T1DM population. PMID- 25042813 TI - Aryl-copper(III)-acetylides as key intermediates in Csp2-Csp model couplings under mild conditions. AB - The mechanism of copper-mediated Sonogashira couplings (so-called Stephens-Castro and Miura couplings) is not well understood and lacks clear comprehension. In this work, the reactivity of a well-defined aryl-Cu(III) species (1ClO4) with p-R phenylacetylenes (R = NO2, CF3, H) is reported and it is found that facile reductive elimination from a putative aryl-Cu(III)-acetylide species occurs at room temperature to afford the Caryl-Csp coupling species (IR), which in turn undergo an intramolecular reorganisation to afford final heterocyclic products containing 2H-isoindole (P NO2, P CF3, PHa) or 1,2-dihydroisoquinoline (PHb) substructures. Density Functional Theory (DFT) studies support the postulated reductive elimination pathway that leads to the formation of C sp2-Csp bonds and provide the clue to understand the divergent intramolecular reorganisation when p H-phenylacetylene is used. Mechanistic insights and the very mild experimental conditions to effect Caryl-Csp coupling in these model systems provide important insights for developing milder copper-catalysed Caryl-Csp coupling reactions with standard substrates in the future. PMID- 25042814 TI - Fluorescence characteristics of sodium fluorescein-rose bengal ophthalmic solution mixtures. AB - PURPOSE: To assess fluorescence emission properties of sodium fluorescein-rose bengal mixtures in buffered aqueous solution. METHODS: Solutions of sodium fluorescein (NaFl) or rose bengal (RB) or mixtures of these two chemicals were prepared over a range of dilutions in 1% NaCl with 10mM phosphate buffer to give a pH of 7.5 at room temperature. Absorbance and fluorescence spectra were recorded in 10mm path length cuvettes. RESULTS: The fluorescence emission from NaFl extends between 480 and nearly 600nm, a spectral range that is also covered by the absorbance of RB (between 500 and 580nm). With very dilute solutions of NaFl (less than 0.002%), an apparent total quenching of its fluorescence can occur in the presence of 0.01% RB, with a proportionate decrease at lower concentrations of RB. CONCLUSIONS: The presence of RB in an aqueous solution of NaFl at physiological pH appears to act in a similar way to a barrier filter, resulting in the quenching of the measurable fluorescence from NaFl. It remains to be established how substantial or significant such an effect might be if a mixture of NaFl and RB as used as part of the examination of the external eye. PMID- 25042815 TI - Forward and backward locomotion in individuals with dizziness. AB - The vestibular system plays an important role in locomotion. Individuals with vestibular pathology present with gait abnormalities, which may increase their fall frequency. Backward walking (BW) has been suggested as a predictor of falls in other patient populations; however it has not been studied in individuals with dizziness. Our aims were: (1) to investigate the differences in forward walking (FW) and BW both between and within 3 groups: Healthy controls, individuals with dizziness and vestibular pathology, and individuals with dizziness without vestibular pathology, (2) describe differences in FW and BW between individuals that have fallen and those that have not. We studied 28 healthy controls (mean 53.8 +/- 17 years), 21 individuals with pathophysiology of the vestibular system (mean 68.5 +/- 13 years), and 18 individuals without a vestibular cause for their dizziness (mean 67.4 +/- 17 years). Subjects performed 2 FW and 2 BW trials over the GAITRite walkway. Data on history of falls in the preceding year were collected. We found BW was different to FW within each group. When comparing between groups and correcting for age and gender, only BW velocity (beta=-11.390, p=0.019), cadence (beta=-8.471, p=0.021), step time (beta=0.067, p=0.007) and stride time (beta=0.137, p=0.005) were significantly affected by having dizziness, with no differences in FW characteristics. There were no differences between FW and BW between fallers and non-fallers. BW appears to be a better biomarker than FW for identifying individuals with symptoms of dizziness; though it does not appear to characterize those who fall. PMID- 25042816 TI - Vancomycin-resistant enterococci colonization among dialysis patients: a meta analysis of prevalence, risk factors, and significance. AB - BACKGROUND: Vancomycin-resistant enterococci (VRE) have become important nosocomial pathogens causing outbreaks worldwide. Patients undergoing dialysis represent a vulnerable population due to their comorbid conditions, frequent use of antibacterial agents, and frequent contact with health care settings. STUDY DESIGN: Systematic review and meta-analysis of cross-sectional studies of screening for VRE colonization. SETTING & POPULATION: Patients receiving long term dialysis treatment. SELECTION CRITERIA FOR STUDIES: We performed a systematic literature search of PubMed and EMBASE databases to identify studies performing screening for VRE colonization among dialysis patients. PREDICTOR: Region, recent use of vancomycin or other antibiotics, previous hospitalization. OUTCOMES: (1) VRE colonization and (2) rate of VRE infection among colonized and noncolonized individuals. Relative effects were expressed as ORs and 95% CIs. RESULTS: We identified 23 studies that fulfilled the inclusion criteria and provided data for 4,842 dialysis patients from 100 dialysis centers. The pooled prevalence of VRE colonization was 6.2% (95% CI, 2.8%-10.8%), with significant variability between centers. The corresponding number for North American centers was 5.2% (95% CI, 2.8%-8.2%). Recent use of any antibiotic (OR, 3.62; 95% CI, 1.22-10.75), particularly vancomycin (OR, 5.15; 95% CI, 1.56-17.02), but also use of antibiotics other than vancomycin (OR, 2.92; 95% CI, 0.99-8.55) and recent hospitalization (OR, 4.55; 95% CI, 1.93-10.74) significantly increased the possibility of a VRE-positive surveillance culture. Colonized patients had a significantly higher risk of VRE infection (OR, 21.62; 95% CI, 5.33-87.69) than their noncolonized counterparts. LIMITATIONS: In 19 of 23 studies, a low percentage of dialysis patients (<80%) consented to participate in the screening procedure. 4 of 8 studies in which patients were followed up for more than 1 month reported VRE infections and only 5 of 23 studies provided extractable data for antibiotic consumption prior to screening. CONCLUSIONS: VRE colonization is prevalent in dialysis centers. Previous antibiotic use, in particular vancomycin, and recent hospitalization are important predicting factors of colonization, whereas the risk of VRE infection is significantly higher for colonized patients. PMID- 25042817 TI - Natural history and biomarkers in hereditary sensory neuropathy type 1. AB - INTRODUCTION: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. METHODS: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. RESULTS: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14-54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = -0.8) and median motor amplitude (r2 = -0.75). CONCLUSIONS: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials. PMID- 25042818 TI - Genetic association signal near NTN4 in Tourette syndrome. AB - Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 * 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 * 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. PMID- 25042819 TI - A new kind of labyrinth-like capillary is responsible for leakage from human choroidal neovascular endothelium, as investigated by high-resolution electron microscopy. AB - PURPOSE: This study reports the clinicopathologic findings of leaky sites in pathological vessels after submacular removal of choroidal neovascular membranes (CNV). As the site that causes fluid exudation from neovascular vessels is unknown, specific attention was focused on the formation of fenestrations, cellular junctions, and morphologic alteration which can cause endothelial leakage. METHODS: Choroidal neovascular membranes of 15 patients who underwent submacular surgery for CNV were investigated. Five patients received bevacizumab treatment before surgery, and another five received photodynamic therapy before surgery. The remaining five did not receive any other treatment before surgery. All membranes were embedded for transmission electron microscopy. CNVs were analyzed for pathological cell-to-cell connections, fenestrations, or other pathological conditions which can cause leakage of plasma. RESULTS: The morphology of the newly formed blood channels was very variable, and in principle was not different in treated and untreated patients. The sources of leakage in neovascular choroidal vessels were caused by insufficient endothelial cell connections and by capillaries with microvillar projections into the vessel lumen which blocked cellular perfusion but still allowed the flow of plasma. Fenestrations were only infrequently observed. CONCLUSIONS: A newly discovered type of pathological capillary, called a labyrinth capillary, is very likely responsible for the permanent leakage of fluid. Due to the small vessel lumen, thrombocytes cannot enter these capillaries to close the leakages. Fenestrations did not appear to play a significant role in vascular leakiness. PMID- 25042820 TI - Water compatible photoarylation of amino acids and peptides. AB - A novel photoarylation of amino acids and peptides is described, which tolerates the presence of water. Irradiation of Boc-protected amino acids in the presence of N-protected 2-azidobenzimidazoles leads to selective arylation of carboxy termini or side chains. The new reaction also works for peptides. Irradiation of the nonapeptide H-SPSYVYHQF-OH also resulted in selective arylation of the tyrosine side chains, as indicated by ESI-MS/MS fragmentation. Chemo- and regioselectivity could add the title reaction to the repertoire of photoaffinity labeling methods. PMID- 25042821 TI - Revealing signal from noisy (19) F MR images by chemical shift artifact correction. AB - PURPOSE: The correction of chemical shift artifacts in MR images of fluorinated molecules with a multi-resonance spectrum is investigated. The goal is to find a deconvolution method which is capable of correcting the artifact, thereby enhancing signal-to-noise ratio (SNR) and revealing signal that vanishes in the noise in the original image. THEORY AND METHODS: Simulations for inspecting the influence of MRI acquisition parameters on the possibility to correct the artifact are performed. Artifact correction is studied on the spectrum of a perfluorocarbon compound by means of deconvolution of complex images with a measured or an optimized point spread function and by using lasso regularization. RESULTS: Distinct parameter settings for image acquisition are identified that should be avoided for successful deconvolution. With in vitro and in vivo images it is shown that the SNR of the corrected image can be increased significantly by 20-50% by a regularized deconvolution of the artifact image and (19) F signal can be revealed from noise. CONCLUSION: By deconvolution, SNR can be enhanced as compared to an image which only exploits the strongest peak of the spectrum. Thus, the limit of detection of the (19) F signal can be lowered by exciting all resonances and by means of correcting the chemical shift artifact. PMID- 25042822 TI - Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model. AB - Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology. Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria (p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum. In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events. PMID- 25042825 TI - Medawar and the immunological paradox of pregnancy: 60 years on. PMID- 25042823 TI - The utility of common surgical instruments for pediatric adenotonsillectomy. AB - OBJECTIVES/HYPOTHESIS: To evaluate the correlation between surgical instrumentation and intraoperative surgical time, postoperative hemorrhage, and associated healthcare cost for pediatric adenotonsillectomy. STUDY DESIGN: Retrospective chart analysis. METHODS: Chart data were collected from pediatric patients who underwent adenotonsillectomy from 2011 to 2013. Monopolar electrocautery, radiofrequency ablation, and PlasmaBlade instruments were compared for intraoperative surgical time and postoperative hemorrhage rate. Univariate analysis of variance (ANOVA) and chi(2) analysis was utilized to evaluate differences between instrumentation and variables. Cost analysis examining instrumentation and intraoperative anesthesia was also reviewed. RESULTS: A total of 1,280 patients who underwent adenotonsillectomy were evaluated. There was no significant overall difference in age, sex, or preoperative diagnosis identified between the three instrumentation groups. When examining the various instruments' effect on procedure time in minutes, univariate ANOVA demonstrated a significant difference overall among the three groups (F = 8.79; P < .001). Post-hoc pairwise comparisons identified significantly faster surgical times for monopolar cautery than either PlasmaBlade (P = .03) or radiofrequency ablation (P < .001). The difference in the number of patients who experienced a postoperative bleed by instrument was not statistically significant (chi(2) = 2.36; P = .31). After instrumentation expenses were added to anesthesia cost, the overall average costs by instrument and surgical time were estimated to be $30.04 for monopolar cautery, $246.95 for PlasmaBlade, and $244.32 for radiofrequency ablation. CONCLUSIONS: The ideal surgical instrumentation should be cost and time efficient with a low complication rate. Monopolar cautery was associated with a statistically significant lower intraoperative surgical time, similar postoperative hemorrhage rates, and lower operative costs when compared to radiofrequency ablation and PlasmaBlade. LEVEL OF EVIDENCE: 4. PMID- 25042831 TI - The role of the American College of Surgeons' cancer program accreditation in influencing oncologic outcomes. AB - The multidisciplinary Commission on Cancer (CoC) and National Accreditation Program for Breast Centers (NAPBC), administered by the American College of Surgeons (ACoS), defines evidence and consensus-based standards, require an operational infrastructure, collect high quality cancer data, and validate compliance with standards through external peer review. A survey of our constituents confirms a high level of agreement that accreditation is regarded as important in improving oncologic outcomes through compliance with standards that include continuous quality improvement. PMID- 25042832 TI - Evaluating the physiological and behavioral response of a male and female gorilla (Gorilla gorilla gorilla) during an introduction. AB - Prolonged stress responses can lead to infertility and death; therefore monitoring respective indicators like stress-related hormones and behaviors is an important tool in ensuring the health and well-being among zoo-housed animal populations. Changes in social structure, such as the introduction of a new conspecific, can be a source of stress. In April 2010, a sexually mature female western lowland gorilla (Gorilla gorilla gorilla) was brought to Lincoln Park Zoo (LPZ; Chicago, IL) from the Chicago Zoological Park (Brookfield, IL) for a breeding recommendation from the Gorilla Species Survival Plan. Fecal glucocorticoid metabolites (FGMs) were monitored in two gorillas prior to, during and immediately following the social introduction. Reproduction events, such ovarian cyclicity and pregnancy, were monitored using behavior and fecal progestagen metabolite (FPM; female) and fecal androgen metabolite (FAM; male) analyses. Mean (+/- standard error) FGM concentrations for the male were elevated (P = 0.002) during the introduction (20.61 +/- 0.83 ng/g) compared to the pre- and post-introduction phases (11.31 +/- 0.48 ng/g and 12.42 +/- 0.65 ng/g, respectively). For the female, mean FGM concentrations were lower (P < 0.001) during the post-introduction (17.91 +/- 1.07 ng/g) than during the pre- and introduction phases (30.50 +/- 3.42 and 27.38 +/- 1.51 ng/g, respectively). The female maintained normal FPM cyclicity throughout the study and became pregnant in the post-introduction phase. These results suggest the importance of both behavioral and physiological monitoring of zoo animals and demonstrate the potential stress that can occur during social introductions. Zoo Biol. 33:394 402, 2014. (c) 2014 Wiley Periodicals Inc. PMID- 25042833 TI - Cerenkov luminescence imaging of alphav beta6 integrin expressing tumors using (90) Y-labeled peptides. AB - Cerenkov luminescence imaging (CLI) is an emerging preclinical molecular imaging modality that tracks the radiation emitted in the visible spectrum by fast moving charged decay products of radionuclides. The aim of this study was in vitro and in vivo evaluation of the two radiotracers, (90) Y-DOTA-PEG28 -A20FMDV2 ((90) Y 1) and (90) Y-DOTA-Ahx-A20FMDV2 ((90) Y-2) (>99% radiochemical purity, 3.7 GBq/umol specific activity) for noninvasive assessment of tumors expressing the integrin alphav beta6 and their future use in tumor targeted radiotherapy. Cell binding and internalization in alphav beta6 -positive cells was (90) Y-1: 10.1 +/ 0.8%, 50.3 +/- 2.1%; (90) Y-2: 22.4 +/- 1.7%, 44.7 +/- 1.5% with <5% binding to alphav beta6 -negative control cells. Biodistribution studies showed maximum alphav beta6 -positive tumor uptake of the radiotracers at 1-h post injection (p.i.) ((90) Y-1: 0.64 +/- 0.15% ID/g; (90) Y-2: 0.34 +/- 0.11% ID/g) with high renal uptake (>25% ID/g at 24 h). Because of the lower tumor uptake and high radioactivity accumulation in kidneys (that could not be reduced by pre administration of either lysine or furosemide), the luminescence signal from the alphav beta6 -positive tumor was not clearly detectable in CLI images. The studies suggest that CLI is useful for indicating major organ uptake for both radiotracers; however, it reaches its limitation when there is low signal-to noise ratio. PMID- 25042834 TI - Highly efficient chiral resolution of DL-arginine by cocrystal formation followed by recrystallization under preferential-enrichment conditions. AB - An excellent chiral symmetry-breaking spontaneous enantiomeric resolution phenomenon, denoted preferential enrichment, was observed on recrystallization of the 1:1 cocrystal of dl-arginine and fumaric acid, which is classified as a racemic compound crystal with a high eutectic ee value (>95 %), under non equilibrium crystallization conditions. On the basis of temperature-controlled video microscopy and in situ time-resolved solid-state (13) C NMR spectroscopic studies on the crystallization process, a new mechanism of phase transition that can induce preferential enrichment is proposed. PMID- 25042835 TI - The place of evidence in the treatment of sex offenders. PMID- 25042836 TI - Improving access to psychological therapies in prisons. PMID- 25042837 TI - A feasibility study of the Reasoning and Rehabilitation Mental Health Programme (R&R2MHP) in male offenders with intellectual disability. PMID- 25042838 TI - The functional consequences of generalized joint hypermobility: a cross-sectional study. AB - BACKGROUND: Generalized Joint Hypermobility (GJH) has been found to be associated with musculoskeletal complaints and disability. For others GJH is seen as a prerequisite in order to excel in certain sports like dance. However, it remains unclear what the role is of GJH in human performance. Therefore, the purpose of the study was to establish the association between GJH and functional status and to explore the contribution of physical fitness and musculoskeletal complaints to this association. METHODS: A total of 72 female participants (mean age (SD; range): 19.6 (2.2; 17-24)) were recruited among students from the Amsterdam School of Health Professions (ASHP) (n = 36) and the Amsterdam School of Arts (ASA), Academy for dance and theater (n = 36) in Amsterdam, The Netherlands. From each participant the following data was collected: Functional status performance (self-reported Physical activity level) and capacity (walking distance and jumping capacity: side hop (SH) and square hop (SQH)), presence of GJH (Beighton score >=4), muscle strength, musculoskeletal complaints (pain and fatigue) and demographic characteristics (age and BMI). RESULTS: GJH was negatively associated with all capacity measures of functional status. Subjects with GJH had a reduced walking distance (B(SE):-75.5(10.5), p = <.0001) and jumping capacity (SH: B(SE): 10.10(5.0), p = .048, and SQH: B(SE):-11.2(5.1), p = .024) in comparison to subjects without GJH, when controlling for confounding: age, BMI and musculoskeletal complaints. In participants with GJH, functional status was not associated with performance measures. CONCLUSION: GJH was independently associated with lower walking and jumping capacity, potentially due to the compromised structural integrity of connective tissue. However, pain, fatigue and muscle strength were also important contributors to functional status. PMID- 25042839 TI - TGFbeta and BMP signaling in skeletal muscle: potential significance for muscle related disease. AB - The transforming growth factor beta (TGFbeta) superfamily comprises a large number of secreted proteins that regulate various fundamental biological processes underlying embryonic development and the postnatal regulation of many cell types and organs. Sequence similarities define two ligand subfamilies: the TGFbeta/activin subfamily and the bone morphogenetic protein (BMP) subfamily. The discovery that myostatin, a member of the TGFbeta/activin subfamily, negatively controls muscle mass attracted attention to this pathway. However, recent findings of a positive role for BMP-mediated signaling in muscle have challenged the model of how the TGFbeta network regulates skeletal muscle phenotype. This review illustrates how this complex network integrates crosstalk among members of the TGFbeta superfamily and downstream signaling elements to regulate muscle in health and disease. PMID- 25042840 TI - Renal cells exposed to cadmium in vitro and in vivo: normalizing gene expression data. AB - Cadmium (Cd) is a toxic metal with a long half-life in biological systems. This half-life is partly as a result of metallothioneins (MTs), metal-binding proteins with a high affinity for Cd. The high retention properties of the kidneys reside in proximal tubular cells that possess transport mechanisms for Cd-MT uptake, ultimately leading to more Cd accumulation. Researchers have studied MT-metal interactions using various techniques including quantitative real-time PCR (qPCR), an efficient tool for quantifying gene expression. Often a poor choice of reference genes, which is represented by their instability and condition dependency, leads to inefficient normalization of gene expression data and misinterpretations. This study demonstrates the importance of an efficient normalization strategy in toxicological research. A selection of stable reference genes was proposed in order to acquire reliable and reproducible gene quantification under metal stress using MT expression as an example. Moreover, in vitro and in vivo setups were compared to identify the influence of toxicological compounds in function of the experimental design. This study shows that glyceraldehyde-3-phosphate dehydrogenase (Gapdh), tyrosine monooxygenase/tryptophan5-monooxygenase activation-protein, zeta polypeptide (Ywhaz) and beta-actin (Actb) are the most stable reference genes in a kidney proximal tubular cell line exposed to moderate and high Cd concentrations, applied as CdCl2 . A slightly different sequence in reference gene stability was found in renal cells isolated from rats in vivo exposed to Cd. It was further shown that three reference genes are required for efficient normalization in this experimental setup. This study demonstrates the importance of an efficient normalization strategy in toxicological research. PMID- 25042843 TI - A randomized test for the conditional odds ratio of matched pairs in an inverse binomial sampling design. AB - Matched case-control paired data are commonly used to study the association between a disease and an exposure of interest. This work provides a consistent test for this association with respect to the conditional odds ratio (ORc), which is a measure of association that is also valid in prospective studies. We formulate the test from the maximum likelihood (ML) estimate of ORc by using data under inverse binomial sampling, in which individuals are selected sequentially to form matched pairs until for the first time one obtains either a prefixed number of index pairs with the case unexposed but the control exposed or with the case exposed but the control unexposed. We discuss the situation of possible early stopping. We compare numerically the performance of our procedure with a competitor proposed by Lui () in terms of type I error rate, power, average sample number (ASN) and the corresponding standard error. Our numerical study shows a gain in sample size without loss in power as compared to the competitor. Finally, we use the data taken from a case-control study on the use of X-rays and the risk of childhood acute myeloid leukemia for illustration. PMID- 25042841 TI - The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collaborative meta-analysis of randomized controlled trials. AB - Calcium supplementation, particularly with vitamin D, has been an approved public health intervention to reduce fracture risk. Enthusiasm for this intervention has been mitigated by meta-analyses suggesting that calcium supplementation with or without vitamin D increases myocardial infarction (MI) risk; however, concern has been raised over the design of these meta-analyses. We, therefore, undertook a meta-analysis of randomized controlled trials with placebo or no-treatment control groups to determine if these supplements increase all-cause mortality and coronary heart disease (CHD) risk including MI, angina pectoris and acute coronary syndrome, and chronic CHD verified by clinical review, hospital record, or death certificate in elderly women. The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were searched from January 1, 1966, to May 24, 2013, for potentially eligible studies, reference lists were checked, and trial investigators were contacted where additional unpublished data were required. The search yielded 661 potentially eligible reports of which 18 met the inclusion criteria and contributed information on 63,563 participants with 3390 CHD events and 4157 deaths. Two authors extracted the data independently with trial data combined using random-effects meta-analysis to calculate the relative risk (RR). Five trials contributed CHD events with pooled relative RR of 1.02 (95% confidence interval [CI], 0.96-1.09; p = 0.51). Seventeen trials contributed all-cause mortality data with pooled RR of 0.96 (95% CI, 0.91-1.02; p = 0.18). Heterogeneity among the trials was low for both primary outcomes (I(2) = 0%). For secondary outcomes, the RR for MI was 1.08 (95% CI, 0.92-1.26; p = 0.32), angina pectoris and acute coronary syndrome 1.09 (95% CI, 0.95-1.24; p = 0.22) and chronic CHD 0.92 (95% CI, 0.73-1.15; p = 0.46). In conclusion, current evidence does not support the hypothesis that calcium supplementation with or without vitamin D increases coronary heart disease or all cause mortality risk in elderly women. PMID- 25042844 TI - "Sexplorando": sexual practices and condom use among an internet-based sample of men and women in Puerto Rico. AB - INTRODUCTION: Despite the wealth of literature addressing sexual practices and condom use among men and women, very little data are available among Hispanic/Latino populations and in the Caribbean Region. This study adds to the existing literature on sexual practices and condom use in Puerto Rico (PR) and provides comparisons based on sex given the need for more current information on the sexual characteristics and condom use rates among understudied populations. AIM: The aim of this study was to assess the rates of sexual practices and condom use among adults, aged 21-49, in PR. METHODS: We report the prevalence of lifetime and recent (past 3 months) sexual practices by sex, as event-level condom use rates, and condom familiarity and accessibility in an online-based sample of adult men and women in PR. MAIN OUTCOME MEASURES: The main variables assessed include sociodemographic characteristics, solo and partnered sexual practices, and condom use frequencies, as well as familiarity and accessibility to male and female condoms. RESULTS: Overall, 93% of the sample reported having been sexually active (engaged in oral, vaginal, and/or anal sex) in their lifetime and 78% reported sexual practices in the past 3 months. As in other studies Hispanic/Latino populations, reported rates of anal intercourse (AI) among both men and women were relatively high. Overall, a greater proportion of men reported condom use during all sexual practices (41% vaginal intercourse (VI); 65% receptive AI; 46% insertive AI) than women (22% VI; 18% AI). CONCLUSIONS: These findings provide current sexual practice and condom use frequency rates that can aid in the understanding of the particular sexual health needs of Hispanic/Latino populations as well as of other groups in the Caribbean. It also serves for the development of future studies and sexual health promotion programs, including comprehensive sexual health care. PMID- 25042845 TI - Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. AB - OBJECTIVES: To estimate procedure-related risks of miscarriage following amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and a meta-analysis. METHODS: A search of MEDLINE, EMBASE, CINHAL and The Cochrane Library (2000-2014) was performed to review relevant citations reporting procedure-related complications of amniocentesis and CVS. Only studies reporting data on more than 1000 procedures were included in this review to minimize the effect of bias from smaller studies. Heterogeneity between studies was estimated using Cochran's Q, the I(2) statistic and Egger bias. Meta-analysis of proportions was used to derive weighted pooled estimates for the risk of miscarriage before 24 weeks' gestation. Incidence-rate difference meta-analysis was used to estimate pooled procedure-related risks. RESULTS: The weighted pooled risks of miscarriage following invasive procedures were estimated from analysis of controlled studies including 324 losses in 42 716 women who underwent amniocentesis and 207 losses in 8899 women who underwent CVS. The risk of miscarriage prior to 24 weeks in women who underwent amniocentesis and CVS was 0.81% (95% CI, 0.58-1.08%) and 2.18% (95% CI, 1.61-2.82%), respectively. The background rates of miscarriage in women from the control group that did not undergo any procedures were 0.67% (95% CI, 0.46-0.91%) for amniocentesis and 1.79% (95% CI, 0.61-3.58%) for CVS. The weighted pooled procedure-related risks of miscarriage for amniocentesis and CVS were 0.11% (95% CI, -0.04 to 0.26%) and 0.22% (95% CI, -0.71 to 1.16%), respectively. CONCLUSION: The procedure-related risks of miscarriage following amniocentesis and CVS are much lower than are currently quoted. PMID- 25042846 TI - A combination of acid lactase from Aspergillus oryzae and yogurt bacteria improves lactose digestion in lactose maldigesters synergistically: A randomized, controlled, double-blind cross-over trial. AB - BACKGROUND & AIMS: Lactose digestion can be improved in subjects with impaired or completely absent intestinal lactase activity by administration of lactase preparations and particularly of acid lactase, which is active in the stomach, or by yogurt containing live lactic acid bacteria. It is the question, if lactose digestion can be further enhanced by combining these two approaches. METHODS: We investigated in a randomised, placebo-controlled, double-blind, 5-arm crossover study on 24 lactose malabsorbers with variable degrees of lactase deficiency if different lactase preparations and freeze-dried yogurt culture affect gastrointestinal lactose digestion after consuming moderate amounts of lactose (12.5 g) by assessing hydrogen exhalation over 6 h. Furthermore, symptoms of lactose intolerance (excess gas production, abdominal pain, diarrhoea or nausea) were assessed using validated questionnaires. RESULTS: All preparations increased lactose digestion and reduced peak hydrogen exhalation by -27% (yogurt), -29/-33% (3300/9000 FCC(1) ((1) One FCC hydrolyses about 5 or 1.7-2.5 mg lactose in aquous solution or in (artificial) chyme, respectively, according to the FCC-III method of the Committee on Codex Specifications, Food and Nutrition Board, National Research Council. Food Chemicals Codex, 3rd edition. Washington, DC, National Academy Press, 1981 It cannot precisely be defined how much lactose can be hydrolysed in vivo by the consumption of a certain number of FCC units.) units acid lactase from Aspergillus oryzae) or -46%, respectively (3300 FCC units lactase plus yogurt culture combined), as compared with placebo (p < 0.001, Friedman test). The combination preparation had not only the strongest effect, but also showed the lowest variance in H(2)-exhalation values (less malabsorbers with no reduction of H(2)-exhalation) Apart from this, both the higher dose lactase and the combination preparation significantly reduced the symptoms most closely associated with H(2)-exhalation, namely flatulences and abdominal pain, respectively. CONCLUSIONS: The combined administration of freeze-dried yogurt cultures and acid lactase increases lactose digestion more than either freeze dried yogurt cultures or acid lactase alone, and more lactose malabsorbers benefited from this effect. PMID- 25042847 TI - Evaluation of quality of kefir from milk obtained from goats supplemented with a diet rich in bioactive compounds. AB - BACKGROUND: The composition of bioactive components in dairy products depends on their content in raw milk and the processing conditions. The experimental material consisted of the milk of dairy goats supplemented with 120 g d(-1) per head of false flax cake. The aim of the study was to evaluate the quality of kefir produced from goat's milk with a higher content of bioactive components resulting from supplementation of the goats' diet with false flax cake. RESULTS: The administration of false flax cake to goats had a positive effect on the fatty acid profile of the raw milk, causing an increase in the proportion of polyunsaturated fatty acids (PUFA), including conjugated linoleic acid (CLA) and n-3 fatty acids. Their increased percentage was detected in the kefir after production as well as after storage. The processing value of the harvested milk did not differ from the qualitative characteristics of milk from goats of the control group. Increasing the proportion of bioactive components in goat's milk did not result in changes in the acidity, texture, colour, flavour, aroma or consistency of the kefir obtained. CONCLUSION: Milk and kefir obtained after the administration of false flax cake to goats contain bioactive components (PUFA including CLA, n-3 and monoenic trans fatty acids) in significant amounts. Kefir from experimental goat's milk did not differ in quality from kefir made from the milk of the control group. PMID- 25042849 TI - Distinct roles of homeoproteins in brain topographic mapping and in neural circuit formation. AB - The construction of the brain is a highly regulated process, requiring coordination of various cellular and molecular mechanisms that together ensure the stability of the cerebrum architecture and functions. The mature brain is an organ that performs complex computational operations using specific sensory information from the outside world and this requires precise organization within sensory networks and a separation of sensory modalities during development. We review here the role of homeoproteins in the arealization of the brain according to sensorimotor functions, the micropartition of its cytoarchitecture, and the maturation of its sensory circuitry. One of the most interesting observation about homeoproteins in recent years concerns their ability to act both in a cell autonomous and non-cell-autonomous manner. The highlights in the present review collectively show how these two modes of action of homeoproteins confer various functions in shaping cortical maps. PMID- 25042848 TI - Necroptotic signaling in adaptive and innate immunity. AB - The vertebrate immune system is highly dependent on cell death for efficient responsiveness to microbial pathogens and oncogenically transformed cells. Cell death pathways are vital to the function of many immune cell types during innate, humoral and cellular immune responses. In addition, cell death regulation is imperative for proper adaptive immune self-tolerance and homeostasis. While apoptosis has been found to be involved in several of these roles in immunity, recent data demonstrate that alternative cell death pathways are required. Here, we describe the involvement of a programmed form of cellular necrosis called "necroptosis" in immunity. We consider the signaling pathways that promote necroptosis downstream of death receptors, type I transmembrane proteins of the tumor necrosis factor (TNF) receptor family. The involvement of necroptotic signaling through a "RIPoptosome" assembled in response to innate immune stimuli or genotoxic stress is described. We also characterize the induction of necroptosis following antigenic stimulation in T cells lacking caspase-8 or FADD function. While necroptotic signaling remains poorly understood, it is clear that this pathway is an essential component to effective vertebrate immunity. PMID- 25042850 TI - Diabetic macular oedema quantified with spectral-domain optical coherence tomography--evaluation of boundary line artefacts and the effect on retinal thickness. AB - PURPOSE: To characterize frequency, morphological cause and time-dependent change of boundary line artefacts in optical coherence tomography (OCT) examinations of centre-involved diabetic macular oedema (ciDME) patients who underwent ranibizumab treatment with 1-year follow-up and to evaluate the impact of artefacts on retinal thickness. METHODS: One hundred and fourteen patients were examined with radial scan protocol by Topcon 3D OCT at baseline, 3 and 12 months. All B scans from all visits were examined for boundary line artefacts (artefacts) and were stratified by morphological element causing artefacts including hard exudates (HE), epiretinal membranes (ERM), optical opacities and serous detachments. Boundary line artefacts were manually corrected and the corrected central subfield thickness (CST) and macular volume were compared with automated values. Data were compared with a repeatability coefficient of 25 MUm. RESULTS: Boundary line artefacts were found in 51.8% of the total 342 OCT examinations and in 25.5% of the total 2052 B scans. Morphological elements that caused artefacts in the total 2052 B scans were HE (10.6%), ERM (10.3%), optical opacities (4.4%), serous detachments (1.7%) and others (1.2%). The number of artefacts due to HE decreased significantly (p = 0.0005), and the number of artefacts due to ERM were unchanged (p = 0.087) during 12 months. In OCT examinations with artefacts caused by HE, manually corrected CST was statistically significant higher than automated value at baseline and 3 months. For ERM, manually corrected CST was statistically significant lower than automated value at baseline and 12 months. CONCLUSION: Boundary line artefacts in OCT examinations of ciDME patients using Topcon 3D OCT occur in 51.8%. In situation of boundary line artefacts in centre 1-mm area every fourth OCT examination has a change in CST beyond 25 MUm. PMID- 25042851 TI - Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family. AB - Selective ubiquitin-dependent autophagy plays a pivotal role in the elimination of protein aggregates, assemblies, or organelles and counteracts the cytotoxicity of proteins linked to neurodegenerative diseases. Following substrate ubiquitylation, the cargo is delivered to autophagosomes involving adaptors like human p62 that bind ubiquitin and the autophagosomal ubiquitin-like protein Atg8/LC3; however, whether similar pathways exist in lower eukaryotes remained unclear. Here, we identify by a screen in yeast a new class of ubiquitin-Atg8 adaptors termed CUET proteins, comprising the ubiquitin-binding CUE-domain protein Cue5 from yeast and its human homolog Tollip. Cue5 collaborates with Rsp5 ubiquitin ligase, and the corresponding yeast mutants accumulate aggregation prone proteins and are vulnerable to polyQ protein expression. Similarly, Tollip depletion causes cytotoxicity toward polyQ proteins, whereas Tollip overexpression clears human cells from Huntington's disease-linked polyQ proteins by autophagy. We thus propose that CUET proteins play a critical and ancient role in autophagic clearance of cytotoxic protein aggregates. PMID- 25042853 TI - Right bundle branch block and ventricular septal fibrosis in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Right bundle branch block (RBBB) is associated with ventricular septal fibrosis in patients with hypertrophic cardiomyopathy (HCM) after alcohol septal ablation, but little data are available in HCM patients without a history of septal ablation. METHODS: Magnetic resonance late gadolinium enhancement (LGE) was performed in 59 HCM patients with no history of alcohol septal ablation. The location and extent of LGE were examined in relation to electrocardiographic features including RBBB. RESULTS: LGE volume was higher in 7 HCM patients with RBBB (7.3+/-7.4g/cm) than in patients without RBBB (2.9+/-7.4g/cm, p=0.016). LGE volume was positively correlated to QRS duration of RBBB (correlation coefficient=0.93, p=0.023). The diagnostic value of RBBB was highly specific for the detection of LGE in the ventricular septum, with sensitivity 21% and specificity 94%. CONCLUSIONS: The presence of RBBB may be a simple marker for detecting ventricular septal fibrosis in HCM patients who had no history of alcohol septal ablation. Further studies are necessary to confirm our findings. PMID- 25042852 TI - Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions. AB - Cancer stem cells are key drivers of tumor progression and disease recurrence in multiple myeloma (MM). However, little is known about the regulation of MM stem cells. Here, we show that a population of MM cells, known as the side population (SP), exhibits stem-like properties. Cells that constitute the SP in primary MM isolates are negative or seldom expressed for CD138 and CD20 markers. In addition, the SP population contains stem cells that belong to the same lineage as the mature neoplastic plasma cells. Importantly, our data indicate that the SP and nonside population (NSP) percentages in heterogeneous MM cells are balanced, and that this balance can be achieved through a prolonged in vitro culture. Furthermore, we show that SP cells, with confirmed molecular characteristics of MM stem cells, can be regenerated from purified NSP cell populations. We also show that the percentage of SP cells can be enhanced by the hypoxic stress, which is frequently observed within MM tumors. Finally, hypoxic stress enhanced the expression of transforming growth factor beta1 (TGF-beta1) and blocking the TGF beta1 signaling pathway inhibited the NSP dedifferentiation. Taken together, these findings indicate that the balance between MM SP and NSP is regulated by environmental factors and TGF-beta1 pathway is involved in hypoxia-induced increase of SP population. Understanding the mechanisms that facilitate SP maintenance will accelerate the design of novel therapeutics aimed at controlling these cells in MM. PMID- 25042854 TI - The 1st symposium on ECG changes in left or right ventricular hypertension or hypertrophy in conditions of pressure overload. PMID- 25042855 TI - The THRIVE score predicts symptomatic intracerebral hemorrhage after intravenous tPA administration in SITS-MOST. AB - BACKGROUND: The Totaled Health Risks in Vascular Events (THRIVE) score is a clinical prediction score that predicts ischemic stroke outcomes in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute therapy. We have previously found an association between THRIVE and risk of post-tissue plasminogen activator symptomatic intracranial hemorrhage in the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator trial and risk of radiographic hemorrhage in Virtual International Stroke Trials Archive. AIMS: The study aims to validate the relationship between THRIVE and symptomatic intracranial hemorrhage among tissue plasminogen activator-treated patients in the large Safe Implementation of Thrombolysis in Stroke - Monitoring Study (SITS-MOST). METHODS: This is a retrospective analysis of the prospective SITS-MOST to examine the relationship between THRIVE and symptomatic intracranial hemorrhage after tissue plasminogen activator treatment. Symptomatic intracranial hemorrhage after tissue plasminogen activator was defined according to each of three standard definitions: the NINDS, European Cooperative Acute Stroke Study (ECASS), and Safe Implementation of Thrombolysis in Stroke (SITS) criteria. Multivariable logistic regression was used to confirm the relationship of THRIVE and individual THRIVE components with the risk of symptomatic intracranial hemorrhage and to examine the relationship of THRIVE, symptomatic intracranial hemorrhage, and functional outcome. RESULTS: The odds ratio for symptomatic intracranial hemorrhage at each increased level of THRIVE score is 1.34 (95% CI 1.27 to 1.41, P < 0.001) for symptomatic intracranial hemorrhage by NINDS criteria, 1.36 (95% CI 1.27 to 1.46, P < 0.001) for symptomatic intracranial hemorrhage by ECASS criteria, and 1.21 (95% CI 1.09 to 1.36, P < 0.001) for symptomatic intracranial hemorrhage by SITS criteria. In receiver-operator characteristics analysis, the C-statistic for THRIVE prediction of symptomatic intracranial hemorrhage was 0.65 (95% CI 0.62 to 0.67) for symptomatic intracranial hemorrhage by NINDS criteria, 0.66 (95% CI 0.63 to 0.69) for symptomatic intracranial hemorrhage by ECASS criteria, and 0.61 (95% CI 0.56 to 0.66) for symptomatic intracranial hemorrhage by SITS criteria. Each component of the THRIVE score predicts the risk of symptomatic intracranial hemorrhage, with independent impact of each component in multivariable analysis. CONCLUSIONS: The THRIVE score predicts the risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator administration. This external validation of the relationship between THRIVE and symptomatic intracranial hemorrhage in a prospective study further strengthens the role of the THRIVE score in the prediction of poststroke outcomes. PMID- 25042856 TI - Glutamine--from conditionally essential to totally dispensable? AB - Recently a large multicentre randomised controlled trial in critically ill patients reported harm to the patients given supplementary glutamine. In the original publication, no explanation was offered for why this result was obtained; a large number of studies have reported beneficial effects or no effect, but never before reported harm. These results have been commented upon in a number of communications. Now some of the authors of the multicentre randomised controlled trial present a review and meta-analysis of glutamine supplementation, and the discrepancy of results is suggested to relate to intravenous administration to patients of supplementary glutamine via parenteral nutrition or a combination of enteral and parenteral nutrition in contrast to enteral administration of supplementation or a combination of enteral and parenteral supplementation. To explain results by epidemiological means only, by combining results into a meta-analysis, is perhaps not the best way to explain mechanisms behind results. Meta-analyses are primarily hypothesis generating. Launching treatment without a solid mechanistic explanation is always risky. Glutamine supplementation of the critically ill comes into that category. Now we will all have to do our homework and try to understand whether supplementation or omission of glutamine for patients fed parenterally is a good idea or not. PMID- 25042857 TI - Prenatal diagnosis of left coronary artery to right ventricle fistula. AB - Prenatal diagnosis of a congenital coronary artery fistula between the left coronary artery and the right ventricle was established at 28 weeks of gestation. Hydrops fetalis developed during follow-up and the baby died on the first day after delivery. It is rare for coronary artery fistulas to become symptomatic during fetal life. PMID- 25042858 TI - H-aggregates of oligophenyleneethynylene (OPE)-BODIPY systems in water: guest size-dependent encapsulation mechanism and co-aggregate morphology. AB - The synthesis of a new oligophenyleneethynylene (OPE)-4,4-difluoro-4-bora-3a,4a diaza-s-indacene (BODIPY) bolaamphiphile 1 and its aqueous self-assembly are reported. Compound 1 forms H-type aggregates in aqueous and polar media, as demonstrated by UV/Vis and fluorescence experiments. Concentration-dependent (1)H NMR studies in CD3CN reveal that the BODIPY units are arranged on top of each other into pi-stacks with H-type excitonic coupling, as supported by ROESY NMR and theoretical calculations and visualized by Cryo-SEM studies. A detailed analysis of the spectral changes observed in temperature-dependent UV/Vis studies reveals that 1 self-assembles in a non-cooperative (isodesmic) fashion in water. The hydrophobic interior of these self-assembled structures can be exploited to encapsulate hydrophobic dyes, such as tetracene and anthracene. Both dyes absorb in a complementary region of the UV/Vis spectrum and are small enough to interact with the hydrophobic segments of 1. Temperature-dependent UV/Vis studies reveal that the spectral changes associated to the encapsulation mechanism of tetracene can be fitted to a Boltzmann function, and the initially flexible fibres of 1 rigidify upon guest addition. In contrast, the co-assembly of 1 and anthracene is a highly cooperative process, which suggests that a different class of (more ordered) aggregates is formed. TEM and Cryo SEM imaging show the formation of uniform spherical nanoparticles, indicating that a subtle change in the guest molecular structure induces a significant change in the encapsulation mechanism and, consequently, the aggregate morphology. PMID- 25042859 TI - Impacts of obesity and stress on neuromuscular fatigue development and associated heart rate variability. AB - OBJECTIVES: Obesity and stress are independently associated with decrements in neuromuscular functions. The present study examined the interplay of obesity and stress on neuromuscular fatigue and associated heart rate variability (HRV). METHODS: Forty-eight non-obese (18.50.05) on bursa and thymus over body wt ratios, however, chickens co-infected with REV and ALV-J had significantly lower titers than REV-infected chickens and ALV-J-infected chickens on HI antibody titers to ND and AIV-H9 after vaccination (P<0.05). These findings suggested that the co-infection of REV and ALV-J caused more serious growth retardation and immunosuppression in SPF chickens. PMID- 25042880 TI - Rhodium-catalyzed intramolecular [3+2+2] cycloadditions between alkylidenecyclopropanes, alkynes, and alkenes. AB - A Rh-catalyzed intramolecular [3+2+2] cycloaddition is reported. The cycloaddition affords synthetically relevant 5,7,5-fused tricyclic systems of type 2 from readily available dienyne precursors. The transformation takes place with moderate or good yields, high diastereoselectivity, and total chemoselectivity. PMID- 25042878 TI - EGFR expression and survival in patients given cetuximab and chemoradiation for stage III non-small cell lung cancer: a secondary analysis of RTOG 0324. AB - PURPOSE: We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab+chemoradiation for stage III non-small cell lung cancer. METHODS: Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin + paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP). RESULTS: Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n = 51) or without (n= 36) EGFR IHC data, or with (n = 45) or without (n = 42) FISH data. However, patients without IHC data had worse OS (HR = 1.63, P = 0.05), worse PFS (HR = 1.88, P = 0.008), and worse TTP [HR = 1.99, P = 0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP. CONCLUSIONS: Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials. PMID- 25042881 TI - Clinical experience with long-term acetazolamide treatment in children with nondystrophic myotonias: a three-case report. AB - BACKGROUND: Today, treatment of the nondystrophic myotonias consists of mexiletine, although care has to be taken because of the proarrhythmogenic potential of this drug. In this article, we report years of experience with the carbonic anhydrase inhibitor acetazolamide. PATIENTS: We present three children with nondystrophic myotonias. RESULTS: During acetazolamide treatment, symptoms and signs of myotonia decreased in our children. CONCLUSIONS: Based on this clinical experience and the favorable pharmacologic profile of acetazolamide, it may be a good treatment option for children with nondystrophic myotonias. PMID- 25042883 TI - Solvent vapor annealing: an efficient approach for inscribing secondary nanostructures onto electrospun fibers. AB - Solvent vapor annealing (SVA) is originally developed to attain equilibrium nanostructures from microphase-separated block polymer thin films. Interestingly, by carefully choosing a solvent vapor that can selectively mobilize the amorphous chains of a semicrystalline polymer while preserving the integrity of its crystalline structure, this study demonstrates that the SVA method can also be utilized to introduce hierarchical structures onto semicrystalline polymer-based materials. This study on electrospun poly(epsilon-caprolactone) (PCL) fibers clearly shows that acetone, a poor solvent for PCL, can effectively delocalize the amorphous chains and redeposit them onto the pre-existing crystal edges, giving rise to secondary nanostructures inscribed onto the PCL fibers. In the past decade, various fiber fabrication methods and numerous fiber products are reported. The easy one-step approach reported here provides new insight into the design and fabrication of structurally hierarchical polymeric materials. PMID- 25042884 TI - Estimation of enantiomeric impurity in piperidin-3-amine by chiral HPLC with precolumn derivatization. AB - A simple, precise, accurate, robust chiral high-performance liquid chromatographic (chiral HPLC) method was developed for estimation of (S) piperidin-3-amine (S-isomer) in (R)-piperidin-3-amine dihydrochloride (R-AMP). As AMP is a high-melting solid and nonchromophoric compound, development of a suitable chiral method is a challenging task. The proposed chiral HPLC-UV method involves a precolumn derivatization technique with para toluene sulphonyl chloride (PTSC) in the presence of a base to introduce chromophore into analytes. It utilizes chiralpak AD-H column with a simple mobile phase of 0.1% diethyl amine in ethanol with a 0.5 mL/min flow rate. Analytes were monitored by using a UV detector at 228 nm. The resolution between the two enantiomers was more than 4.0. The developed method was validated as per current International Conference on Harmonization (ICH) guidelines. PMID- 25042885 TI - Syncope paradox in the outcome of patients with pulmonary thromboembolism: short term and midterm outcome. AB - BACKGROUND AND AIM: We compare the early and midterm outcomes of pulmonary thromboembolism (PTE) in patients with and without syncope in our single-center registry. METHOD: Between December 2006 and May 2013, 351 consecutive patients (mean age = 60.21 +/- 16.91 years, 55.3% male) with confirmed acute symptomatic PTE were divided in with and without syncope groups. Groups were compared in terms of the effect of syncope on 30-day mortality and adverse events, and mortality in a median follow-up time of 16.9 months. RESULTS: From 351 patients, 39 (11.1%) had syncope and 312 (88.9%) did not. Syncope group had less frequently chest pain (30.8% vs 51.4%; P value = 0.015). Also, the rates of 30-day adverse events and mortality were 12.8% and 5.1% for the group with syncope, and 14.4% and 10.3% for the group without syncope, respectively, with no significant difference. At follow up, 65 patients died and mortality was 18.5% for 351 patients (5.1% in the group with syncope and 20.2% for the other group). After adjustment for confounding factors, the effect of syncope on 30-day adverse events and mortality remained non-significant and on the midterm mortality was significant, showing that the presence of syncope was associated with lower midterm mortality (P value = 0.038). CONCLUSION: Among PTE patients in our registry, 11.1% presented with syncope. Relationship between syncope and 30-day adverse events and mortality remained non-significant after adjustments for other factors. However, in midterm follow up, patients with syncope were significantly at decreased risk of mortality compared to those without syncope. PMID- 25042886 TI - Efficient CO2 capture and photoreduction by amine-functionalized TiO2. AB - Amine-functionalization of TiO2 nanoparticles, through a solvothermal approach, substantially increases the affinity of CO2 on TiO2 surfaces through chemisorption. This chemisorption allows for more effective activation of CO2 and charge transfer from excited TiO2 , and significantly enhances the photocatalytic rate of CO2 reduction into methane and CO. PMID- 25042887 TI - Antitumor agent cabozantinib decreases RANKL expression in osteoblastic cells and inhibits osteoclastogenesis and PTHrP-stimulated bone resorption. AB - Cabozantinib, an inhibitor of vascular endothelial growth factor and hepatocyte growth factor signaling, decreases bone lesions in patients with prostate cancer. To determine direct effects of cabozantinib on bone, resorption in neonatal mouse bone organ culture and on gene expression, proliferation, and phenotypic markers in osteoblast and osteoclast cell lines were examined. Cabozantinib, 0.3 and 3 uM, prevented PTHrP-stimulated calcium release from neonatal mouse calvaria. Since the effect on resorption could reflect effects on osteoblasts to prevent osteoclast activation, or direct inhibition of osteoclasts, responses in osteoblastic and osteoclast precursor cell lines were examined. Twenty-four-hour treatment of osteoblastic MC3T3-E1 cells with 3 uM cabozantinib decreased expression of receptor activator of NFkB ligand (RANKL) and alkaline phosphatase. Forty-eight-hour treatment of MC3T3-E1 cells with 3 uM cabozantinib inhibited cell proliferation and decreased MTT activity. Effects on alkaline phosphatase activity were biphasic, with small stimulatory effects at concentrations below 3 uM. When RAW 264.7 osteoclast precursor cells differentiated with 20 ng/ml RANKL were co-treated for 24 h with 3 uM cabozantinib, expression of RANK, TRAP, cathepsin K, alpha v or beta 3 integrin, or NFATc1 were unaffected. Five-day treatment of RANKL-treated RAW 264.7 cells with 3 uM cabozantinib decreased TRAP and MTT activity. The results suggest that the osteoblast could be the initial target, with subsequent direct and indirect effects on osteoclastogenesis leading to decreased resorption. The multiple effects of cabozantinib on the cell microenvironment of bone are consistent with its effectiveness in reducing lesions from prostate cancer metastases. PMID- 25042888 TI - Distributed feedback imprinted electrospun fiber lasers. AB - Imprinted, distributed feedback lasers are demonstrated on individual, active electrospun polymer nanofibers. In addition to advantages related to miniaturization, optical confinement and grating nanopatterning lead to a significant threshold reduction compared to conventional thin-film lasers. The possibility of imprinting arbitrary photonic crystal geometries on electrospun lasing nanofibers opens new opportunities for realizing optical circuits and chips. PMID- 25042889 TI - A genetically engineered mouse model developing rapid progressive pancreatic ductal adenocarcinoma. AB - The premalignant lesions of pancreatic cancer, pancreatic intraepithelial neoplasia (PanIN), have a high frequency of mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), and genetic alterations in the retinoblastoma (Rb)-E2 factor (E2F) and transformed 3T3 cell double minute 2 (MDM2)-p53 pathways accelerate development of pancreatic ductal adenocarcinoma. The viral oncoprotein SV40 large T antigen (TAg) can inhibit the effects of the Rb family of molecules and of p53 on these pathways, and targeted expression of TAg in mouse pancreas is associated with the development of endocrine or acinar cell tumours. In this study, to determine whether the viral oncoprotein promotes pancreatic duct carcinogenesis initiated by oncogenic KRAS, we generated mice expressing temperature-sensitive SV40 large T antigen (tsTAg) on pancreatic epithelial cells in the presence or absence of Kras(G12D) . Mice with pancreas-specific tsTAg expression developed acinar cell dysplasia by 22 weeks without PanIN formation, while mice expressing both tsTAg and Kras(G12D) developed highly aggressive adenocarcinoma with a ductal cell phenotype within a short period, and died within 3 weeks. The tumours resembled human pancreatic ductal adenocarcinoma (PDAC) at the histological level, and oncogenic Kras and tsTAg synergistically activated E2f and Sre transcription in established PDAC cell lines. These results suggest that tsTAg synergistically promotes Kras(G12D) -associated PDAC formation, and our study identifies a new mouse model of PDAC that may allow a better understanding of the mechanism of carcinogenesis in pancreatic carcinoma, which shows a catastrophic clinical course. PMID- 25042890 TI - Innocent murmurs and pediatric patients: when should the primary care provider refer? PMID- 25042891 TI - The glucose RQ-feedback control leading to improved erythromycin production by a recombinant strain Saccharopolyspora erythraea ZL1004 and its scale-up to 372 m(3) fermenter. AB - In this paper, glucose respiratory quotient (RQ)-feedback control was developed for erythromycin production with a recombinant strain Saccharopolyspora erythraea ZL1004. RQ was confirmed to be an ideal online parameter for regulating glucose feed rate. Through feeding glucose to control RQ at 0.85 during 45-100 h and 0.95 during 100-185 h, erythromycin titer and erythromycin A concentration were reached 11.88 and 8.82 g l(-1) in 50 l fermenter, which were increased by 8.3 and 6.1 % as compared to that with glucose pH-feedback control, respectively. When glucose RQ-feedback control was scaled up to 372-m(3) fermenter, erythromycin titer and erythromycin A concentration at 155 h were reached 9.12 and 7.12 g l( 1), respectively, which were 10.5 and 9.4 % higher than that with the original technology (glucose pH-feedback control). To the best of our knowledge, this is the first report on the successful application of glucose RQ-feedback control in erythromycin production, especially in 372-m(3) fermenter. PMID- 25042892 TI - An autocatalytic kinetic model for describing microbial growth during fermentation. AB - The mathematical modelling of the behaviour of microbial growth is widely desired in order to control, predict and design food and bioproduct processing, stability and safety. This work develops and proposes a new semi-empirical mathematical model, based on an autocatalytic kinetic, to describe the microbial growth through its biomass concentration. The proposed model was successfully validated using 15 microbial growth patterns, covering the three most important types of microorganisms in food and biotechnological processing (bacteria, yeasts and moulds). Its main advantages and limitations are discussed, as well as the interpretation of its parameters. It is shown that the new model can be used to describe the behaviour of microbial growth. PMID- 25042893 TI - Conversion of red-algae Gracilaria verrucosa to sugars, levulinic acid and 5 hydroxymethylfurfural. AB - This study employed a statistical methodology to investigate the optimization of conversion conditions and evaluate the reciprocal interaction of reaction factors related to the process of red-algae Gracilaria verrucosa conversion to sugars (glucose, galactose), levulinic acid and 5-hydroxymethylfurfural (5-HMF) by acidic hydrolysis. Overall, the conditions optimized for glucose formation included a higher catalyst concentration than did those for galactose, and these conditions for galactose were similar to those for 5-HMF. Levulinic acid production, meanwhile, was optimized at a higher reaction temperature, a higher catalyst concentration, and a longer reaction time than was glucose, galactose or 5-HMF production. By this approach, the optimal yields (and reaction conditions) for glucose, galactose, levulinic acid, and 5-HMF were as follows: glucose 5.29 g/L (8.46 wt%) (reaction temperature 160 degrees C, catalyst concentration 1.92%, reaction time 20 min), galactose 18.38 g/L (29.4 wt%) (160 degrees C, 1.03%, 20 min), levulinic acid 14.65 g/L (18.64 wt%) (180.9 degrees C, 2.85%, 50 min), and 5-HMF 3.74 g/L (5.98 wt%) (160.5 degrees C, 1%, 20 min). PMID- 25042894 TI - Value of clinical data and vestibular testing in a population of 101 patients with recurrent vestibulopathy. PMID- 25042895 TI - Meta-analysis of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. AB - BACKGROUND: Surgical reconstruction following pancreaticoduodenectomy (PD) is associated with significant morbidity and mortality. Because of great variability in definitions of specific complications, it remains unclear whether there is a difference in complication rates following the two commonest types of reconstruction, pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ). Published consensus definitions for postoperative pancreatic fistula (POPF) have led to a series of randomized clinical trials (RCTs) uniquely placed to address this question. METHODS: A literature search was carried out to identify all RCTs comparing postoperative complications of PG versus PJ reconstruction following PD published between January 1995 and December 2013. Pooled odds ratios (ORs) with 95 percent confidence intervals (c.i.) were calculated using fixed-effect or random-effects models. RESULTS: In total, seven RCTs with 1121 patients were included. Four of these trials applied definitions as published by the International Study Group on Pancreatic Fistula (ISGPF). Using ISGPF definitions, the incidence of POPF was lower in patients undergoing PG than in those having PJ (OR 0.50, 95 per cent c.i. 0.34 to 0.73; P < 0.001). Using definitions applied by each individual study, PG was associated with significantly lower rates of POPF (OR 0.51, 0.36 to 0.71; P < 0.001), intra-abdominal fluid collection (OR 0.50, 0.34 to 0.74; P < 0.001) and biliary fistula (OR 0.42, 0.18 to 0.93; P = 0.03) than PJ. CONCLUSION: Meta-analysis of four RCTs based on ISGPF criteria, and seven RCTs using non-standard criteria, revealed that PG reduced the incidence of POPF after PD compared with PJ. PMID- 25042896 TI - Epidemiology of diabetes mellitus, pre-diabetes, undiagnosed and uncontrolled diabetes and its predictors in general population aged 15 to 75 years: A community-based study (KERCADRS) in southeastern Iran. AB - BACKGROUND: The goal of this research was to measure the age-sex standardized prevalence of pre-diabetes (pre-DM) and diabetes (DM), and the effectiveness of diabetes management (using HbA1C as the indicator) in an urban area in Iran. METHODS: Using a randomized cluster household survey, we recruited 5900 individuals whose age ranged from 15 to 75 from Kerman for assessing coronary artery disease risk factors (KERCADRS) including diabetes. In 2010 and 2011, all of the participants were interviewed by trained staff for medical history and physical activities, and were then examined for blood pressure and anthropometric measures. Venus blood sample was also collected for fasting plasma glucose and HbA1c. RESULTS: The age-sex standardized prevalence of pre-diabetes, diagnosed and undiagnosed was 18.7%, 6.3% and 2.7%, respectively. Diabetes increased by age (from 14.7% in the 15-24 years old group to 28.4% in the 65-75 years old group), particularly after 40 years. Occasional opium users had the highest prevalence of Pre-DM (34.6%). Seventy-nine percent of the depressed and 75.5% of the anxious participants with diagnosed-DM were identified as uncontrolled-DM. More than 60% of diagnosed diabetic cases had impaired HbA1c. Overweight and obesity (adjusted odds ratio (AOR) 1.6) and low physical activity (AOR 1.5) were the most preventable risk factors associated with diabetes. CONCLUSION: Considerable prevalence of diabetes, susceptibility in progressing to diabetes and uncontrolled diabetes among individuals living in Kerman, suggested ineffective prevention and treatment of diabetes in urban areas in Iran. Successful experience regarding primary health-care in rural areas should be expanded to urban settings. PMID- 25042897 TI - The individualized neuromuscular quality of life questionnaire: cultural translation and psychometric validation for the Dutch population. AB - INTRODUCTION: In this study we describe the translation and psychometric evaluation of the Dutch Individualized Neuromuscular Quality of Life (INQoL) questionnaire. METHODS: Backward and forward translation of the questionnaire was executed, and psychometric properties were assessed on the basis of reliability and validity. RESULTS: Two hundred six patients were included in the study. Reliability analyses resulted in Cronbach alpha values of >0.70 for all subdomains. Known-group validity showed a significant correlation between INQoL scores and severity as well as age for the majority of subdomains. Item-total correlation for overall quality of life was satisfactory. Concurrent validity with the SF-36 and EQ-5D was good (range of Spearman correlation coefficients 0.43 to -0.76). CONCLUSIONS: This study resulted in a questionnaire that is appropiate for use in the Dutch-speaking population to measure quality of life among patients with a wide variety of muscle disorders. This confirms and extends data obtained in the UK, US, Italy, and Serbia. PMID- 25042898 TI - Thermal stabilisation of polymer-fullerene bulk heterojunction morphology for efficient photovoltaic solar cells. AB - A novel stable bisazide molecule that can freeze the bulk heterojunction morphology at its optimized layout by specifically bonding to fullerenes is reported. The concept is demonstrated with various polymers: fullerene derivatives systems enable highly thermally stable polymer solar cells. PMID- 25042899 TI - Executive function in the context of chronic disease prevention: theory, research and practice. AB - OBJECTIVE: To provide an overview of the nature, organization and measurement of executive function, and describe its significance for preventive medicine theory, research and practice. METHOD: A conceptual and narrative review linking the operation of executive control systems to health behavior performance and health outcomes, within the context of chronic illness prevention. RESULTS: Stronger executive function is linked with more consistent performance of a variety of health protective behaviors, less performance of health risk behaviors, and greater longevity in the existing observational research literature. These effects are not fully explained by demographic factors such as education, income and socioeconomic status, but may in some cases interact with them, or mediate their effects on other outcomes. Experimental manipulations of executive control suggest that the effect of executive function is causal, particularly in relation to the modulation of appetitive craving responses that may compete with healthy behaviors (or facilitate unhealthy behaviors). CONCLUSION: Executive function is a potentially important variable in explanatory frameworks for health behavior and health outcomes. The size of effect and its endurance remain uncertain, though the causal status of its influence on some behaviors is becoming increasingly clear. Additional understanding of the relation between executive control and demand imposed by ecological context is an important frontier for research on changing behavior to prevent disease, and may be an explanatory factor in social patterning of these same conditions. PMID- 25042900 TI - Electrochemical oligonucleotide-based biosensor for the determination of lead ion. AB - The possibility of utilization of gold electrodes modified with short guanine rich ssDNA probes for determination of Pb(2+) was examined. Interaction between guanine residues and lead ion followed by formation of G-quadruplex structures was confirmed by electrochemical impedance spectroscopy investigations. An external cationic redox label, methylene blue, was employed in voltammetric measurements for analytical signal generation. It was shown that due to the G quadruplex formation, the oligonucleotides in the recognition layer fold, which enhances the electron transfer between methylene blue and the electrode surface. The MB current signal rises proportionally to the lead ion concentration in the range from 0.05 to 1MUmol/L. The developed biosensor demonstrated high selectivity towards Pb(2+) ion, with only minor response towards interfering metal cations. The calculated limit of detection was of 34.7nmol/L. The utilization of the biosensor for Pb(2+) determination in real samples of water was also tested. PMID- 25042901 TI - Valence state parameters of all transition metal atoms in metalloproteins- development of ABEEMsigmapi fluctuating charge force field. AB - To promote accuracy of the atom-bond electronegativity equalization method (ABEEMsigmapi) fluctuating charge polarizable force fields, and extend it to include all transition metal atoms, a new parameter, the reference charge is set up in the expression of the total energy potential function. We select over 700 model molecules most of which model metalloprotein molecules that come from Protein Data Bank. We set reference charges for different apparent valence states of transition metals and calibrate the parameters of reference charges, valence state electronegativities, and valence state hardnesses for ABEEMsigmapi through linear regression and least square method. These parameters can be used to calculate charge distributions of metalloproteins containing transition metal atoms (Sc-Zn, Y-Cd, and Lu-Hg). Compared the results of ABEEMsigmapi charge distributions with those obtained by ab initio method, the quite good linear correlations of the two kinds of charge distributions are shown. The reason why the STO-3G basis set in Mulliken population analysis for the parameter calibration is specially explained in detail. Furthermore, ABEEMsigmapi method can also quickly and quite accurately calculate dipole moments of molecules. Molecular dynamics optimizations of five metalloproteins as the examples show that their structures obtained by ABEEMsigmapi fluctuating charge polarizable force field are very close to the structures optimized by the ab initio MP2/6 311G method. This means that the ABEEMsigmapi/MM can now be applied to molecular dynamics simulations of systems that contain metalloproteins with good accuracy. PMID- 25042902 TI - Aperture width of the osteomeatal complex as a predictor of successful treatment of odontogenic maxillary sinusitis. AB - Odontogenic maxillary sinusitis (OMS) is an inflammatory disease caused by the spread of dental inflammation into the sinus. The long-term administration of antibiotic medicine and/or treatment of the causative tooth are the usual initial treatments. These initial treatments are not always effective, and the reason is not well understood. The purpose of this study was to identify factors of significance that may contribute to the results of the initial treatment of OMS. Thirty-nine patients were studied, divided into two groups according to the results of initial treatment: effective or non-effective. The effective group comprised 20 patients who were cured by initial treatment. The non-effective group comprised 19 patients who required an additional operation. The duration of symptoms, spread into the other sinuses, aperture width of the osteomeatal complex (OMC) on the side of the maxillary sinus, and anatomical variations in the sinuses were compared between the groups. The only significant difference found was in the aperture width of the OMC, which was significantly narrower in the non-effective group than in the effective group. The aperture width of the OMC may be a significant predictor of the effectiveness of initial treatment of OMS. PMID- 25042903 TI - Microwave-assisted synthesis of cyclic phosphopeptide on solid support. AB - Phosphopeptides are important tools for studying intracellular signal transduction events in vitro and in vivo and are also potential drugs due to their direct competition with phosphoprotein recognition elements. Cyclization has been demonstrated to improve peptide selectivity, metabolic stability, and bioavailability. However, cyclic phosphopeptide synthesis may not be straightforward due to the sterically hindered phosphorylated side-chain amino acid derivatives. One option to overcome this hurdle is to use microwave-assisted synthesis, which has been shown to increase efficiency and reduce synthesis time. Herein, a detailed protocol is provided for synthesizing cyclic phosphopeptides using automated microwave. The overall synthesis duration was reduced and yields increased compared with a manual conventional method. This method provides a general, fast and facile way to synthesize cyclic peptides, demonstrating the synthesis of cyclic phosphorylated peptides which are known to be among the most challenging to produce. PMID- 25042904 TI - Gestational age-specific scoring systems for the prediction of coarctation of the aorta. AB - OBJECTIVES: To determine which combination of cardiac parameters provides the best prenatal prediction of coarctation of aorta (CoAo). METHODS: We selected all cases of simple cardiac asymmetry prenatally diagnosed in 2003-2013. Logistic regression was used to select the best predictors of CoAo. RESULTS: The study population included 115 fetuses. CoAo was confirmed in 52 neonates (45%). The sample was divided in two groups according to the gestational age (GA) at diagnosis: early group (EG) <=28 weeks (n = 57), and late group (LG) >28 weeks (n = 58). CoAo was confirmed in 75% and 16% of cases, respectively. GA-specific scoring systems with maximum two parameters were made, and the pairwise combination with the best diagnostic performance for each group was selected. In EG, the z-score of ascending aorta (AAo) and aortic isthmus (three vessels and trachea view) showed the best diagnostic accuracy [area under receiver-operating curve (AUC) 0.98, 95% confidence interval (CI) 0.94-1.00]. In the LG, the best results were provided by the tricuspid valve/mitral valve ratio with the main pulmonary artery/AAo ratio (AUC 0.84, 95% CI 0.67-1.00). CONCLUSIONS: Gestational age-specific scoring systems combining size-based cardiac parameters may improve the accuracy of fetal echocardiography to stratify the risk of CoAo. The objectivity and simplicity of its components may facilitate its implementation in fetal cardiology units. PMID- 25042906 TI - Effect of N-acetylarginine, a metabolite accumulated in hyperargininemia, on parameters of oxidative stress in rats: protective role of vitamins and L-NAME. AB - In the present investigation, we initially evaluated the in vitro effect of N acetylarginine on thiobarbituric acid-reactive substances (TBA-RS), total sulfhydryl content and on the activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the blood, kidney and liver of rats. Results showed that N-acetylarginine, at a concentration of 5.0 MUM, decreased the activity of CAT in erythrocytes, enhanced TBA-RS in the renal cortex, decreased CAT and SOD activities in the renal medulla and decreased CAT and increased SOD and GSH-Px activities in the liver of 60-day old rats. Furthermore, we tested the influence of the antioxidants, trolox and ascorbic acid, as well as of the N(omega) -nitro-L-arginine methyl ester (L-NAME) on the effects elicited by N-acetylarginine on the parameters tested. Antioxidants and L-NAME prevented most of the alterations caused by N acetylarginine on the oxidative stress parameters evaluated. Data indicate that oxidative stress induction is probably mediated by the generation of NO and/or ONOO(-) and other free radicals because L-NAME and antioxidants prevented the effects caused by N-acetylarginine in the blood, renal tissues and liver of rats. Our findings lend support to a potential therapeutic strategy for this condition, which may include the use of appropriate antioxidants for ameliorating the damage caused by N-acetylarginine. PMID- 25042905 TI - Developmental exposure to the organochlorine insecticide endosulfan alters expression of proteins associated with neurotransmission in the frontal cortex. AB - Exposure to environmental contaminants, such as organochlorine insecticides during critical periods of neurodevelopment has been shown to be a major contributor to several neuropsychological deficits seen in children, adolescence, and adults. Although the neurobehavioral outcomes resulting from exposure to these compounds are known the neurotransmitter circuitry and molecular targets that mediate these endpoints have not been identified. Given the importance of the frontal cortex in facilitating numerous neuropsychological processes, our current study sought to investigate the effects of developmental exposure to the organochlorine insecticide, endosulfan, on the expression of specific proteins associated with neurotransmission in the frontal cortex. Utilizing in vitro models we were able to show endosulfan reduces cell viability in IMR-32 neuroblastoma cells in addition to reducing synaptic puncta and neurite outgrowth in primary cultured neurons isolated from the frontal cortex of mice. Elaborating these findings to an in vivo model we found that developmental exposure of female mice to endosulfan during gestation and lactation elicited significant alterations to the GABAergic (GAT1, vGAT, GABAA receptor), glutamatergic (vGlut and GluN2B receptor), and dopaminergic (DAT, TH, VMAT2, and D2 receptor) neurotransmitter systems in the frontal cortex of male offspring. These findings identify damage to critical neurotransmitter circuits and proteins in the frontal cortex, which may underlie the neurobehavioral deficits observed following developmental exposure to endosulfan and other organochlorine insecticides. PMID- 25042907 TI - Searching for behavioral indicators of welfare in zoos: uncovering anticipatory behavior. AB - A current focus of zoo-based research aims to identify indicators of animal welfare. Reliable behavioral indicators of welfare are highly desirable as behavioral observation is non invasive and requires little in the way of specialized equipment and other costly resources-save for observer time. Anticipatory behavior is an indicator of an animal's sensitivity to reward and as such, it is a real-time indicator of animals' own perceptions of their well being. In fact, anticipatory behavior may generate a positive affective state and thus be at least a brief manifestation of good welfare itself. The husbandry conditions of most captive animals are such that food acquisition and other positive outcomes are highly scheduled and easily signaled. These conditions promote the development of anticipatory behavior, yet little research has either documented or interpreted this behavior in zoo and aquarium animals. This commentary suggests that anticipatory behavior could be a useful tool for assessing welfare and calls upon zoo and aquarium researchers to begin to develop this tool by describing the behavior and the circumstances that lead to its modulation. PMID- 25042908 TI - The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. AB - PCOS is one of the most common endocrine disorders affecting women and it is characterized by a combination of hyper-androgenism, chronic anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment remains to be determined. Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level. PMID- 25042909 TI - Retrotransposons in pluripotent cells: Impact and new roles in cellular plasticity. AB - Transposable Elements are pieces of DNA able to mobilize from one location to another within genomes. Although they constitute more than 50% of the human genome, they have been classified as selfish DNA, with the only mission to spread within genomes and generate more copies of themselves that will ensure their presence over generations. Despite their remarkable prevalence, only a minor group of transposable elements remain active in the human genome and can sporadically be associated with the generation of a genetic disorder due to their ongoing mobility. Most of the transposable elements identified in the human genome corresponded to fixed insertions that no longer move in genomes. As selfish DNA, transposable element insertions accumulate in cell types where genetic information can be passed to the next generation. Indeed, work from different laboratories has demonstrated that the main heritable load of TE accumulation in humans occurs during early embryogenesis. Thus, active transposable elements have a clear impact on our pluripotent genome. However, recent findings suggest that the main proportion of fixed non-mobile transposable elements might also have emerging roles in cellular plasticity. In this concise review, we provide an overview of the impact of currently active transposable elements in our pluripotent genome and further discuss new roles of transposable elements (active or not) in regulating pluripotency. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID- 25042910 TI - [Chinese experts consensus on new oral anticoagulant in the non-valvular atrial fibrillation]. PMID- 25042911 TI - [New oral anticoagulants and thromboembolism prevention in atrial fibrillation]. PMID- 25042912 TI - [Antithrombotic strategies for patients with atrial fibrillation and coronary artery disease]. PMID- 25042913 TI - [Association between thyroid dysfunction and incidence of atrial fibrillation in patients with stable angina pectoris]. AB - OBJECTIVE: To explore the correlation between incidence of atrial fibrillation (AF) and thyroid dysfunction. METHODS: Patients with stable angina pectoris with thyroid function test results hospitalized at Fuwai Hospital from 2011 Jan to 2011 Dec were included in this analysis (n = 2 541). General clinical data and related biochemical parameters were analyzed. We divided patients into 5 subgroups according to TSH levels: <0.55 mIU/L (n = 105), 0.55-2.49 mIU/L (n = 1599), 2.50-4.77 mIU/L (n = 621), 4.78-9.99 mIU/L (n = 180), >10.00 mIU/L (n = 36). RESULTS: A total of 157 patients were diagnosed with AF (6.8%). (1) Compare to stable angina pectoris patients without AF, stable angina pectoris patients with AF have older age (P < 0.001), higher proportion of female (P = 0.04), uric acid (P < 0.001), NT-proBNP (P = 0.001), larger left atrial diameter (P < 0.001), left ventricular end diastolic diameter (P < 0.001) and lower LVEF (P = 0.038), FT3(P = 0.002), TT3 (P < 0.001). (2) When TSH levels were less than 0.55,0.55 2.49, 2.50-4.77, 4.78-9.99 mIU/L and greater than 10.00 mIU/L, the incidence of AF were 7.6% (8/105) , 5.7% (91/1 599), 7.9% (49/621), 9.4% (17/180) and 22.2% (8/36), respectively. Both a high and a low TSH level were associated with an increased incidence of AF. After adjustment for common risk factor (age, gender and so on) , stepwise multiple logistic regression analysis revealed that TSH levels were significantly related with the incidence of AF. Compared to patients with TSH 0.55-2.49 mIU/L, the adjusted odds ratio of AF for TSH < 0.55, 2.50 4.77, 4.78-9.99, >10.00 mIU/L were 1.37 (95%CI 0.65-2.90, P = 0.415), 1.42 (95CI 0.99-2.04, P = 0.057), 1.73 (95%CI 1.01-2.97, P = 0.048), 4.74 (95%CI 2.10-10.69, P < 0.001), respectively. CONCLUSION: Our results show that incidence of AF increases in proportion to TSH level in patients with stable angina pectoris. PMID- 25042914 TI - [Association between CHADS2 score and long-term atrial fibrillation recurrence rate after catheter ablation]. AB - OBJECTIVE: To investigate the association between CHADS2 score and long-term ( >= 3 years) outcomes post catheter ablation in patients with atrial fibrillation (AF). METHODS: AF patients who received single catheter ablation in our hospital from January 2004 to March 2009 in our department were included and patients received regular follow-up. AF recurrence was defined as the occurrence of atrial arrhythmias (AF, atrial flutter and atrial tachycardia) recorded by electrocardiogram monitor ( >= 30 seconds) after ablation during follow-up period (after 3 months blanking period). The relationship between baseline clinical and echocardiographic characteristics and the time to recurrence during follow-up was evaluated using Cox multivariate analysis. RESULTS: A total of 280 patients who received single catheter ablation procedure were included in the study, 3 patients died and there were 50 patients lost to follow-up. A total of 227 patients with AF (163 paroxysmal and 64 non-paroxysmal ) were enrolled in the final analysis. During a median follow-up of 51 months (41-56 months), 109 patients experienced AF recurrences and the recurrence rate after catheter ablation ( >= 3 years) was 48.0% (109/227). Cox multivariate analysis showed that the high CHADS2 score (HR: 1.417, 95%CI 1.194-1.682, P < 0.001) and AF non termination during ablation (HR: 2.077, 95%CI 1.380-3.126, P = 0.043) were risk factors of AF recurrence. AF recurrence rates in the termination and non termination group were 41.0% (75/183) and 77.3% (34/44), respectively. In the AF termination group, the recurrence rates and the median recurrence free time in patients with CHADS2 score >= 3 were 80.0% (12/15) and 1 year, respectively. In the non-AF termination group, the recurrence rates in patients with CHADS2 score = 0, CHADS2 score = 1-2 and CHADS2 score >= 3 were 60.0% (6/10), 77.8% (21/27) and 100% (7/7), respectively; the median recurrence free time of patients with CHADS2 score = 0, CHADS2 score = 1-2 and CHADS2 score >= 3 were 30 months, 12 months and 6 months, respectively. CONCLUSIONS: CHADS2 score is a predictor of AF recurrences after catheter ablation. Patients with high CHADS2 score is associated with higher risk of long-term ( >= 3 years) AF recurrences. PMID- 25042915 TI - [Establishment and preliminary validation of warfarin maintenance dose algorithm in Chinese Han Population]. AB - OBJECTIVES: To establish an algorithm to predict the warfarin maintenance dose in Chinese Han population and validate the accuracy of this algorithm. METHODS: A total of 488 Chinese Han patients, hospitalized in Fuwai hospital and had a stable dose of warfarin and a target international normalized ratio (INR) of 1.5 to 3.0, were recruited. Indications for warfarin use included prosthetic heart valve, atrial fibrillation and pulmonary embolism. These patients were divided into derivation group (n = 323) and validation group (n = 165) according to the enrollment time. A warfarin maintenance dose algorithm was established based on genetic information, demographic characteristics and concomitant medications by multiple linear regression analysis in derivation group. In the validation group, we evaluated the accuracy of our algorithm by comparing the predicted dose with the actual dose. RESULTS: Our algorithm included VKORC1-1639G > A, CYP2C9*3 and CYP4F2 genotype, age, Body hight, body weight, amiodarone and digoxin use (R(2) = 0.652, P < 0.001) .In the validation group, the average predicted dose by our algorithm had no statistical difference with the actual dose [(3.51 +/- 1.03) mg vs. (3.53 +/- 1.41) mg, P = 0.779]. Our algorithm identified 100 out of 165 (60.6%) patients in the validation group, whose predicted dose of warfarin was within 20% of the actual dose, and predicted warfarin dose was underestimated in 17.6% (29/165) patients and overestimated in 21.8% (36/165) patients. CONCLUSION: Our algorithm based on VKORC1, CYP2C9 and CYP4F2 polymorphisms can help to predict the warfarin maintenance dose in Chinese Han Population. PMID- 25042916 TI - [Comparison between CHADS2 score and CHA2DS2-VASc score on assessing the risk of ischemic stroke in patients with nonvalvular atrial fibrillation]. AB - OBJECTIVE: To compare the value between CHADS2 score and CHA2DS2-VASc score on assessing the risk of ischemic stroke in patients with nonvalvular atrial fibrillation. METHODS: In this retrospective study, nonvalvular atrial fibrillation patients with acute ischemic stroke hospitalized from January 2004 to March 2013 in our department were included. CHADS2 score (range, 0-6) and CHA2DS2-VASc score (range, 0-9) before acute ischemic stroke was calculated. For both schemes, patients were also classified with scores of 0, 1 and >= 2 in low risk, intermediated-risk and high-risk categories, respectively, the difference between the two risk stratification schemes was evaluated by each category. RESULTS: A total of 599 patients [320 men, mean age (75.4 +/- 9.1) years] were collected. According to CHADS2 score, 30 (5.0%), 132 (22.0%) and 437 (73.0%) patients were classified in the low-risk, intermediated-risk and high-risk categories, respectively. The corresponding classification by CHA2DS2-VASc score was 6(1.0%), 25(4.2%) and 568 (94.8%) cases. The number of low-risk category patients (5.0% vs. 1.0%, chi(2) = 22.04, P < 0.001) and in intermediate-risk category patients (22.0% vs. 4.2%, chi(2) = 84.81, P < 0.001, Kappa = 0.075) was significantly higher in CHADS2 score group than in CHA2DS2-VASc score group, and the consistence between the two scores was poor (Kappa = 0.322). There were less patients classified in the high-risk group by CHADS2 score compared to CHA2DS2 VASc score (73.0% vs. 94.8%,chi(2) = 131.00, P < 0.001, Kappa = 0.257). CONCLUSION: Compared with CHADS2 score, CHA2DS2-VASc score is more valuable in predicting ischemic stroke for patients with nonvalvular atrial fibrillation. PMID- 25042917 TI - [Clinical features of patients with premature acute coronary syndrome]. AB - OBJECTIVE: To analyze the clinical features of patients with premature acute coronary syndrome(ACS). METHODS: Three hundreds and forty seven patients with ACS who underwent coronary angiography from January 2011 to June 2013 in our department were included in this study. Eligible patients were divided into premature group (pre-group, male < 55 years old, female < 65 years old, n = 140) and non-premature group(N-pre group, male >= 55 years old, female >= 65 years old, n = 207). The cardiovascular risk factors, coronary angiography (CAG) features, complications and in-hospital mortality were analyzed. RESULTS: Compared to N-pre group, the pre-group had a significantly higher rate of smoking [56.4% (79/140) vs. 44.4% (92/207), P < 0.05], dyslipidemia [61.4% (86/140) vs. 50.2% (104/207), P < 0.05] and positive family history of coronary artery disease [39.3% (55/140) vs. 24.6% (51/207), P < 0.01]. However, other traditional cardiovascular risk factors were less (3.03 +/- 1.28 vs. 3.91 +/- 1.30, P < 0.01). CAG identified higher incidence of one-vessel and double-vessel diseases (63.6%, 89/140) in pre-group, but the incidence of multi-vessel diseases (57.0%, 118/207) was more frequent in N-pre group . Moreover, the pre-group had a higher rate of coronary artery occlusion [45.7% (64/140) vs. 34.8% (72/207), P < 0.05]. Compared with N-pre group, the pre-group had a lower Gensini Score of CAG (46.2 +/- 33.2 vs. 60.4 +/- 37.5, P < 0.01) and a lower rate of heart failure[4.3% (6/140) vs. 11.1% (23/207), P < 0.05] during hospitalization. In-hospital mortality rate was similar between the two groups [0 vs. 1.9% (4/207), P > 0.05]. CONCLUSION: Smoking, dyslipidemia and family history of coronary artery disease are major risk factors for patients with premature ACS, these patients are more likely to have milder coronary artery stenosis and a lower incidence of heart failure compared to N-pre group. PMID- 25042918 TI - [Pulmonary arterial hypertension after operation for congenital heart disease: analysis of baseline clinical characteristics of 122 Chinese patients]. AB - OBJECTIVE: To explore the baseline clinical characteristics of patients with pulmonary arterial hypertension after operation for congenital heart disease (AO CHD-PAH) in China. METHODS: A total of 122 consecutive patients diagnosed as AO CHD-PAH in Shanghai Pulmonary Hospital from September 1, 2006 to August 31, 2011 were retrospective analyzed. RESULTS: Sixty-seven percent patients were female. The median age at procedure and diagnosis were 14.8 and 24.8 years old, respectively. The median duration from procedure of CHD to diagnosis of PAH was 7.3 years. The most frequent initial symptom (109/122, 89.3%) attributed to PAH was dyspnea on exertion. The frequent sign was accentuation of second heart sound on pulmonary valve area (113/122, 92.6%).Incidence of WHO functional PAH classes I/II was 53.3% (65/122) and mean 6 minutes walk distance was limited to (408.4 +/ 103.3) m. Borg dyspnea score was 2.0 (1.0, 3.0).Right heart catheterization demonstrated severe elevated mean pulmonary arterial pressure [(71.6 +/- 24.2) mmHg, 1 mmHg = 0.133 kPa] and pulmonary vascular resistance index [(29.1 +/- 16.0) Wood U.m(2)] in this patient cohort. Cardiac index was (2.7 +/- 0.9) L.min( 1).m(-2), 90.2% (110/122) patients received PAH-specific therapy. The majority of PAH-specific therapy was phosphodiesterase type 5 inhibitor, which is somehow different from PAH-specific therapy regimen of American-European developed countries. CONCLUSIONS: PAH-specific therapy rate is satisfactory for pulmonary arterial hypertension after operation for congenital heart disease in China and phosphodiesterase type 5 inhibitors are predominant PAH-specific medication in China. PMID- 25042919 TI - [Association between fragmented QRS complexes and imperfect ST-segment resolution in patients with ST-elevation myocardial infarction after primary percutaneous coronary intervention]. AB - OBJECTIVE: To explore the relationship between fragmented QRS complexes (fQRS) and imperfect ST-segment resolution in ST elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (p-PCI). METHODS: This study included 227 consecutive patients with STEMI who underwent p-PCI. They were divided into two groups: ECG with fQRS (n = 142) and without fQRS (n = 85). Baseline clinical characteristics,Gensini score, coronary angiography features and the rate of ST-segment resolution were compared between the two groups. RESULTS: (1) Patients with fQRS of ECG had higher cTnI, CK, CK-MB levels and Gensini score, prolonged QRS interval, lower rate of ST-segment resolution and left ventricular ejection fraction (LVEF) than in patients without fQRS (all P < 0.01 or P < 0.05). (2) Pearson correlation analysis showed that the rate of ST segment resolution (r = -0.207, P = 0.002),Gensini score (r = 0.191, P = 0.004), LVEF(r = -0.188, P = 0.006), cTnI(r = 0.172, P = 0.010), and the TIMI grade post p-PCI (r = -0.148, P = 0.028) were significantly related with the presence of fQRS. (3) Multivariate logistic regression analysis demonstrated that presence of fQRS at pre-PCI (OR = 2.908, 95%CI:1.095-7.723, P = 0.032) , the number of leads with fQRS before PCI (OR = 1.582, 95%CI:1.250-2.002, P < 0.001), and increased QRS interval (OR = 0.955, 95%CI: 0.924-0.988, P = 0.008) were independent predictors of imperfect ST-segment resolution. CONCLUSIONS: fQRS is related to imperfect ST-segment resolution in STEMI patients undergoing p-PCI.fQRS may be a useful parameter to identify the patients with severe coronary lesion, larger areas of ischemic injury and myocardial infarction as well as severe left ventricular contracted dysfunction. PMID- 25042920 TI - [Clinical features and outcome of eight patients with mediastinal and neck hematoma after transradial cardiac catheterization approach]. AB - OBJECTIVE: The clinical features of patients with mediastinal and/or neck hematoma after transradial cardiac catheterization were reviewed and analyzed to help the clinicians to recognize this complication, and try their best to avoid the complication and treat the complication properly. METHODS: A total of 8 patients with mediastinal and/or neck hematoma after right transradial cardiac catheterization in Fuwai hospital from January 1, 2005 to the end of 2012 were included in this study. Among these 8 patients, 1 patient underwent coronary angiography, 7 patients underwent percutaneous coronary intervention and drug eluting stents were successfully implanted in 6 patients. The clinical data of these patients were analyzed retrospectively. RESULTS: Super slide hydrophilic guild-wire was used in all patients. These patients felt chest pain, dyspnea and neck pain and neck or throat tightness after the procedure. CT scan was performed in all 8 patients and reviewed mediastinal hematoma, 4 patients complicated with neck hematoma, and suspicious laceration on the right subclavian artery or branch of innominate artery were found in 2 patients. Post procedure hemoglobin decrease was evidenced in all 8 patients. Anti-platelet therapy was discontinued until discharge in 2 patients, dual anti-platelet drugs were transiently discontinued or underwent dosage reduction in 4 patients, protamine was administered in 2 patients to neutralize heparin. Blood transfusion was not required, there was no stent thrombosis, and surgery was not indicated for all 8 patients. No complication was reported during follow up. CONCLUSIONS: Mediastinal and/or neck hematoma is a rare complication post transradial catheterization approach. This complication is caused by super slide guild-wire or catheter's injury of small vessels near the aortic arch or subclavian artery, especially with rough manipulation. Neck and mediastinal CT scan should be performed as early as possible for patients with suspect hematoma and prognosis is usually fine with suitable therapy. PMID- 25042921 TI - [Niflumic acid relaxes mesenteric small artery through downregulating connexin 43 expression in smooth muscle cells from spontaneously hypertensive rat]. AB - OBJECTIVE: To explore the impact of niflumic acid (NFA) on connexin 43 (Cx43) expression in smooth muscle cells of mesenteric small artery from spontaneously hypertensive rats (SHR). METHODS: Blood pressure of Wistar rats and spontaneously hypertensive rats (SHR) was measured by the tail cuff method. Relaxation and contraction of mesenteric small artery from Wistar rat and SHR were evaluated by pressure myograph system under various concentrations of NFA. Protein Cx43 expression on primary cultured mesenteric smooth muscle cells from Wistar rats and SHR was detected in the absence and presence of various NFA concentrations by Western blot. RESULTS: Phenylephrine resulted in mesenteric small arteries contraction [(193 +/- 13.5) um], while NFA (3*10(-4) mol/L) could relax the artery [(275 +/- 17.1) um]. The relaxation response in Wistar rats was significantly stronger than that in SHR (P < 0.05). Cx43 expression of the first level branch and the third branch mesenteric artery of SHR were higher than the corresponding branch vessels of Wistar rats, and the Cx43 expression of the third branches of mesenteric artery was higher than that of the first branch (F = 1 014.43, P < 0.01). Cx43 expression in primary cultured mesenteric smooth muscle cells was significantly downregulated post NFA treatment in a concentration dependent manner. CONCLUSION: In the SHR mesenteric small arteries, Cx43 may be involved in smooth muscle cells communication, thereby affecting vascular contraction and relaxation responses.NFA could downregulate the expression of Cx43 in SHR mesenteric artery vascular smooth muscle cells and induce vasodilation. PMID- 25042922 TI - [Prenatal exposure to lipolysaccharide result in expression changes of myocardial renin angiotensin system in offspring rats]. AB - OBJECTIVE: To explore expression changes of myocardial renin angiotensin system induced by prenatal exposure to lipopolysaccharide in offspring rats. METHODS: Twelve pregnant SD rats were randomly divided into three groups: LPS model group: intraperitoneal injection of LPS (0.79 mg/kg) at 8, 10, 12 days of pregnancy; control group: intraperitoneal injection of sterile saline (0.5 ml) at 8, 10, 12 days of pregnancy; LPS + PDTC group: intraperitoneal injection of LPS (0.79 mg/kg) at 8, 10, 12 days of pregnancy plus daily intraperitoneal injection of NF kappaB inhibitor -pyrrolidine dithiocarbamate (PDTC, 100 mg/kg) on day 8 to 14 pregnancy day. Protein expression of AngiotensinII(AngII) in heart was detected by immunohistochemistry; myocardial ACE,ACE2 mRNA expression was detected by real time PCR; protein expression of ACE and ACE2 in heart was detected by Western blot in offspring rats of various groups. RESULTS: Compared with control group (0.07 +/- 0.02,0.11 +/- 0.01), AngII protein levels (0.14 +/- 0.04) were significantly increased at 6 weeks (P < 0.01) and 16 weeks (0.17 +/- 0.04, P < 0.05) in offspring rats of LPS model group, which could be significantly attenuated by PDTC intervention (0.10 +/- 0.01,0.13 +/- 0.03, respectively, all P < 0.05).Similarly, myocardial ACE mRNA expression in 16 weeks offspring rats of LPS model group was significantly upregulated compared with control group (1.10 +/- 0.26 vs.0.72 +/- 0.22, P < 0.05), which was significantly attenuated by PDTC intervention (0.67 +/- 0.01, P < 0.01 vs.LPS group). Myocardial protein expression ACE2 in 16 weeks offspring rats of LPS model group was significantly downregulated compared to control group, which was slightly upregulated by PDTC intervention (P > 0.05). CONCLUSION: Pregnancy exposure to lipopolysaccharide increases myocardial ACE and AngII expression while reduces myocardial ACE2 expression in offspring rats, which might be one of the pathomechanisms of offspring hypertension. PMID- 25042923 TI - [Cardiac protective effect of the autoantibody against beta3-adrenoceptor in rats with experimental heart failure]. AB - OBJECTIVE: To explore the effect of the autoantibody against the beta3 adrenoceptor on rats with experimental heart failure. METHOD: The peptide corresponding to the sequence of beta3 adrenoceptor was synthesized to actively immunize the rats, ELISA was used to detect the serum level of autoantibody against the beta3-adrenoceptor (beta3AA). Total IgGs were extracted from the serum containing beta3AA in immunized rats. Aortic banding surgery was used to establish the heart failure model in male Wistar rats and rats were divided into the sham group (n = 8), heart failure group(n = 8),beta3AA-immunized heart failure group (HF+beta3AA, n = 8) and corresponding negative IgG-immunized heart failure group (HF+ IgG, n = 8).In 6 weeks and 8 weeks after aortic banding surgery, the serum levels of NT-pro brain natriuretic peptide (NT-proBNP) were assayed with ELISA assay and cardiac function was assessed by echocardiography. RESULTS: beta3AA was used to immunize rat with heart failure, the serum level of beta3AA was stable at 50 days post immunization. At 8 weeks after aortic banding surgery, heart failure group showed significantly increased LVEDD [(6.92 +/- 0.22) mm vs.(5.62 +/- 0.19) mm, P < 0.001], LVESD [(4.63 +/- 0.23) mm vs.(3.50 +/ 0.20) mm, P < 0.01] and IVS [(2.44 +/- 0.06) mm vs.(2.28 +/- 0.05) mm, P < 0.05], and decreased LVEF[(62.07 +/- 3.99)% vs.(79.63 +/- 3.02)%, P < 0.01] and LVFS [(31.46 +/- 3.22)% vs.(43.65 +/- 2.68) %, P < 0.05] compared with the sham group.HF+beta3AA IgG group showed decreased LVEDD [(6.07 +/- 0.30) mm vs.(6.92 +/ 0.24) mm, P < 0.05] and LVESD [(3.92 +/- 0.22) mm vs.(4.68 +/- 0.23) mm, P < 0.05], and higher LVEF [(70.29 +/- 1.78)% vs.(61.95 +/- 3.03)%, P < 0.05] and LVFS [(38.08 +/- 2.32)% vs.(30.50 +/- 1.82)%, P < 0.05] compared to the HF+ IgG group.In addition, compared with the HF+ IgG group, HF+beta3AA IgG group showed decreased serum levels of NT-proBNP [(196.43 +/- 6.56) pg/ml vs.(242.13 +/- 7.86) pg/ml, P < 0.01]. CONCLUSION: Our results demonstrate that beta3AA can improve cardiac function and reduce the serum levels of NT-proBNP in rat with heart failure. PMID- 25042924 TI - [Interleukin-17 contributes to the macrophage secretion of interleukin-27 in a murine model of viral myocarditis]. AB - OBJECTIVE: Interleukin-27 (IL-27) has been reported to reduce the levels of interleukin-17 (IL-17) and alleviate the severity of experimental autoimmune myocarditis. IL-17, an important tissue-protective cytokine in viral myocarditis (VMC), has been reported to increase synovial expression of IL-27 in rheumatoid arthritis. However, the influence of IL-17 on IL-27 expression in murine model of VMC remains unknown. METHODS: Wild-type (WT) and IL-17A-deficient (IL-17A(-/-)) mice on the BALB/c background were intraperitoneally (i.p) injected with coxsackievirus B3 (CVB3) for establishing VMC models. Cardiac tissue was obtained on day 7 after CVB3 injection. Myocardial histopathologic changes were observed by hematoxylin-eosin (HE) stained myocardial sections.Expression of IL-27 in heart and serum was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. Furthermore, splenic lymphocytes and peritoneal macrophages were purified 1 week after injection from WT mice.Isolated lymphocytes were cultured in the presence of different concentrations (0 and 25 ng/ml) of recombinant IL-17 (rIL-17) for 24 h. Macrophages were cultured with different concentrations of rIL-17 (0 and 10 ng/ml) for 48 h.IL-27 mRNA expression of cultured cells was assayed by RT-PCR, and their protein level in the culture supernatant was measured by ELISA. RESULTS: Compared with WT mice, significantly less cardiac inflammation was evidenced in the heart of IL-17A-/- mice (0.9 +/- 0.3 vs.1.9 +/- 0.5) , relative cardiac IL-27 p28 mRNA expressions (1.11 +/- 0.24 vs.3.1 +/- 0.8) and serum IL-27 protein[(72 +/- 18) pg/ml vs.(95 +/- 25) pg/ml] were also significantly lower in IL-17A-/- mice (all P < 0.05).In the culture lymphocytes, the relative mRNA (1.02 +/- 0.13 vs.1.32 +/- 0.21) and protein [(49 +/- 9) pg/ml vs.(52 +/- 11) pg/ml]expressions of IL-27 p28 and were similar post treatment with 0 and 25 ng/ml rIL-17 (all P > 0.05). Compared with 0 ng/ml rIL-17 culture with macrophages, higher relative mRNA (8.5 +/- 3.1 vs.2.2 +/- 0.7) and protein [(368 +/- 95) pg/ml vs.(150 +/- 38) pg/ml] expressions of IL-27 p28 were detected in 10 ng/ml rIL-17 group (all P < 0.05). CONCLUSION: Our data indicates that cytokine IL-17 may contribute to the secretion of IL-27 in VMC mice.Furthermore, macrophages but not lymphocytes may be the important IL-27-producing immune cells and major target cells for IL-17. Thus,IL-27 and IL-17 might be actively involved in the pathogenesis of VMC. PMID- 25042925 TI - [Effect of native aortic valve sparing aortic root reconstruction surgery on short- and long-term prognosis in Marfan syndrome patients:a meta-analysis]. AB - OBJECTIVE: This meta-analysis was performed to analyze the effect of preserving the native aortic valve on short- and long-term prognosis post aortic root reconstruction surgery for patients with Marfan syndrome. METHODS: Database including Pubmed,Embase, Cochrane library, CNKI, Wanfang,VIP and CBM were searched to collect studies comparing clinical results of valve sparing surgery with composite valve graft surgery for patients with Marfan syndrome. Study quality was assessed by Newcastle-Ottawa Scale and publication bias was assessed by visual inspection of the funnel plot together with Egger test. Clinical outcomes data was extracted from the manuscripts and analyzed with Revman 5.0 supplied by Cochrane collaboration. RESULTS: Seven clinical trials with 690 patients were included. Meta- analysis demonstrated that valve sparing surgery was associated with a lower incidence of re-exploration (RR = 0.51, 95%CI:0.29- 0.90, P < 0.05), thromboembolism (RR = 0.17, 95%CI:0.05-0.57, P < 0.01), endocarditis (RR = 0.31, 95%CI:0.11-0.94, P < 0.05) and significantly lower long term death rate (RR = 0.37, 95%CI:0.18-0.74, P < 0.01). Reoperation rate was similar between the two groups (RR = 1.07, 95%CI:0.35-3.27, P > 0.05). CONCLUSION: Valve sparing aortic root reconstruction surgery is a superior procedure to composite valve graft surgery in term of improving the short- and long-term prognosis for patients with Marfan syndrome. PMID- 25042926 TI - [A case of endovascular treatment of infrarenal aortoiliac arteriosclerosis obliterans]. PMID- 25042927 TI - [Update on anaphylaxis-induced acute coronary syndrome]. PMID- 25042928 TI - [Association between ryanodine receptor 2 with cardiovascular diseases]. PMID- 25042929 TI - [Research progress on the association between connective tissue growth factor and ventricular remodeling after acute myocardial infarction]. PMID- 25042930 TI - Vocal learning in seals, sea lions, and walruses. AB - The pinnipeds provide a variety of clues to those interested in the vocal learning capabilities of non-human animals. Observational and experimental studies of seals, sea lions, and walruses reveal elements of vocal development, contextual control, plasticity in expression and learning, and even imitation of complex sounds. Consideration of the factors that influence the expression of these capabilities informs understanding of the behavioral and structural mechanisms that support vocal learning in mammals and the evolutionary forces shaping these capabilities. PMID- 25042931 TI - Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy. AB - OBJECTIVE: Patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects by a phosphodiesterase 5 (PDE5) inhibitor (sildenafil) improves skeletal and cardiac muscle performance. Sildenafil also improves blood flow in patients with BMD. We therefore hypothesized that sildenafil would improve blood flow, maximal work capacity, and heart function in patients with BMD. METHODS: A randomized, double-blind, placebo controlled crossover design with two 4-week periods of treatment, separated by 2 week washout was used. We assessed brachial artery blood flow during maximal handgrip exercise, 6-minute walk test, maximal oxidative capacity, and life quality; cardiac function was evaluated by magnetic resonance imaging (MRI) at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 were tested with Western blotting in 5 patients. RESULTS: Sixteen patients completed all skeletal muscle evaluations, and 13 completed the cardiac MRI investigations. Sildenafil had no effect on any of the outcome parameters. No serious adverse effects were recorded. PDE5 and nNOS were deficient in 5 of 5 biopsies. INTERPRETATION: Despite positive evidence from animal models of dystrophinopathy and physiological findings in patients with BMD, this double-blind, placebo controlled clinical study showed no effect of sildenafil on blood flow, maximal work capacity, and heart function in adults with BMD. This discrepancy may be explained by a significant downregulation of PDE5 in muscle. PMID- 25042932 TI - Development of a nerve conduction technique for the recurrent laryngeal nerve. AB - OBJECTIVES/HYPOTHESIS: To develop a reliable and safe laryngeal nerve conduction technique and to obtain consistent parameters as normal reference values. STUDY DESIGN: A prospective single-arm study. METHODS: A nerve conduction test was performed on the contralateral normal side in 42 patients with unilateral vocal fold palsy. The recording was performed in the intact thyroarytenoid muscle using a monopolar needle. The electrical stimulation using a 37-mm monopolar needle was applied 3 cm below the lower margin of the cricoid cartilage, just lateral to the trachea and medial to the carotid artery, and its intensity was gradually increased until the amplitude of the electrical response reached the maximum level. The latency of the evoked muscle response was acquired at the first evoked waveform deflection from the baseline. RESULTS: The average latency of the recurrent laryngeal nerves was 1.98 +/- 0.26 ms. The latencies showed normal distribution according to the quantile-quantile plot and Kolmogorov-Smirnov test (P = .098). There was no significant difference in latencies between the right and left recurrent laryngeal nerves. Anthropometric factors including height and weight did not show any correlation with the latencies. CONCLUSIONS: We developed a reliable and safe laryngeal nerve conduction technique and obtained normal reference values for the recurrent laryngeal nerve conduction study. This laryngeal nerve conduction study can be an additional tool for detecting recurrent laryngeal nerve injury if it is performed in combination with the conventional laryngeal electromyography. LEVEL OF EVIDENCE: 4. PMID- 25042933 TI - Sexual functioning in military personnel: preliminary estimates and predictors. AB - INTRODUCTION: Although the military is a young and vigorous force, service members and veterans may experience sexual functioning problems (SFPs) as a result of military service. Sexual functioning can be impaired by physical, psychological, and social factors and can impact quality of life (QOL) and happiness. AIMS: This study aims to estimate rates and correlates of SFPs in male military personnel across demographic and psychosocial characteristics, to examine the QOL concomitants, and to evaluate barriers for treatment seeking. METHODS: This exploratory cross-sectional study was conducted using data from a larger nationwide study conducted between October 2013 and November 2013. This sample consists of 367 male active duty service members and recent veterans (military personnel) age 40 or younger. MAIN OUTCOME MEASURES: Erectile dysfunction (ED) was determined using the five-item International Index of Erectile Function, sexual dysfunction (SD) was determined using the Arizona Sexual Experiences Scale, Male, and QOL was determined using the World Health Organization Quality of Life, Brief. RESULTS: SFPs were associated with various demographic, physical, and psychosocial risk factors. The rates of SD and ED were 8.45% and 33.24%, respectively, for male military personnel aged 21-40. Those who were 36-40, nonmarried, nonwhite, and of lower educational attainment reported the highest rates of SFPs. Male military personnel with poor physical and psychosocial health presented the greatest risk for ED and SD. SFPs were associated with reduced QOL and lower happiness, and barriers for treatment were generally related to social barriers. CONCLUSIONS: SFPs in young male military personnel are an important public health concern that can severely impact QOL and happiness. PMID- 25042934 TI - Surgery for primary hyperparathyroidism. AB - In the Western world, primary hyperparathyroidism is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women. Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging. Primary hyperparathyroidism is a complex disease process that requires careful diagnosis and thoughtful medical and surgical management. The surgical management of patients with persistent or recurrent disease, inherited primary hyperparathyroidism syndromes, and parathyroid carcinoma is particularly challenging. High-quality imaging and reliable intraoperative adjuncts are critical to success. PMID- 25042935 TI - Genomic medicine and targeted therapy for solid tumors. AB - A marked paradigm shift in cancer therapy has occurred over the past 20 years. Systemic treatment has evolved from nonspecific cytotoxic chemotherapy to targeting cancer-associated pathways, profoundly changing treatment approaches in the metastatic and adjuvant settings. This review will highlight some of the major clinical advances in targeted cancer therapy in select epithelial malignancies made possible by the understanding of the molecular mechanisms driving tumor growth through genomic methods. PMID- 25042936 TI - Fetal outcome in the critically ill pregnant woman. AB - Management of the critically ill pregnant woman is complicated by potential adverse effects of both maternal illness and ICU interventions on the fetus. This paper reviews the potential risks to the fetus of maternal critical illness, including shock, hypoxemia, and fever, as well as the effects of critical care management, such as drug therapy and radiological investigations. The authors' recommended approach to management is provided. Prior publications and new data presented identify that there is insufficient information to prognosticate accurately on fetal outcome after maternal critical illness, although maternal shock, hypoxemia and early gestational age are likely significant risk factors. PMID- 25042938 TI - Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy. AB - Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure. PMID- 25042939 TI - An active recombinant cocoonase from the silkworm Bombyx mori: bleaching, degumming and sericin degrading activities. AB - BACKGROUND: Cocoonase is a serine protease produced by silk moths and used for softening the cocoons so that they can escape. Degumming is one of the important steps in silk processing. This research aimed to produce an active recombinant Bombyx mori cocoonase (BmCoc) for the silk degumming process. RESULTS: A recombinant BmCoc was successfully expressed in a Pichia pastoris system. The purified enzyme showed specific activity of 227 U mg(-1) protein, 2.4-fold purification, 95% yield and a molecular weight of 26 kDa. The enzyme exhibited optimal temperature at 40 degrees C and optimal pH at 8, and showed thermal stability at 25-45 degrees C and pH stability at 5-9. The recombinant enzyme exhibited sericin degumming ability and color bleaching characteristics, and did not affect the fibroin fiber. The enzyme also degraded sericin substrate with a product size about 30-70 kDa. CONCLUSION: In this study, we successfully produced the active recombinant BmCoc in P. pastoris with promising functions for the Thai silk degumming process, which includes degumming, sericin degrading and color bleaching activities. Our data clearly indicated that the recombinant enzyme had proteolytic activity on sericin but not on fibroin proteins. The recombinant BmCoc has proven to be suitable for numerous applications in the silk industry. PMID- 25042940 TI - Evaluation of the chiral separation ability of single-isomer cationic beta cyclodextrins in capillary electrophoresis. AB - Eight single-isomer ammonium-beta-cyclodextrin derivatives with different side chains were successfully developed as chiral selectors for the chiral separation of selected racemates in capillary electrophoresis. The number of substituted groups at N-atom as well as the alkyl chain length greatly influenced the chiral separation. With the numbers of hydroxylalkyl groups at N-atom growing, the aqueous solubility of resolving agents were distinctly decreased and chiral separation ability was also significantly reduced. The apparent complex stability constants between CDs and analytes were further determined. The best enantioseparations of hydroxyl acids was achieved with the use of mono-6(A) -(3 hydroxypropyl)-1-ammonium-beta-cyclodextrin chloride and mono-6(A) -(3 methoxypropyl)-1-ammonium-beta-cyclodextrin chloride. The nuclear magnetic resonance experiments were carried out using them with mandelic acid as guest molecules, revealing the inclusion pattern as well as electrostatic interactions and hydrogen bonding interactions as additional chiral driving force. The contribution of potential interaction sites in the sidearm could enhance the enantioseparations. PMID- 25042941 TI - VgrG, Tae, Tle, and beyond: the versatile arsenal of Type VI secretion effectors. AB - The type VI secretion system (T6SS) is a macromolecular machine that delivers protein effectors into both prokaryotic and eukaryotic cells, therefore participating in interbacterial competition and virulence. The T6SS is functionally and structurally similar to the contractile bacteriophage cell puncturing device: the contraction of a sheath-like structure is believed to propel an inner tube terminated by a spike towards target cells, allowing the delivery of effectors. In this review, we summarize recent advances in the identification and characterization of T6SS effector proteins, highlighting the broad repertoire of enzymatic activities, and discuss recent findings relating to the secretion mechanisms. PMID- 25042943 TI - Digital psychiatry in Asia. PMID- 25042942 TI - Can individual conditions during childhood mediate or moderate the long-term cognitive effects of poor economic environments at birth? AB - Recent analyses revealed that the business cycle at the time of birth influences cognitive functioning at older ages, and that those individuals born during economic boom periods on average display better cognitive functioning later in life. The current study examines the impact of childhood conditions on late-life cognitive functioning and investigates whether they mediate or moderate the effects of the business cycle at the time of birth. The underlying purpose is to find potential starting points for societal interventions that may counterbalance the negative long-term outcomes of adverse living conditions early in life. We use data from 7935 respondents at ages 60+ in eleven European countries from the first three waves of the Survey of Health, Ageing and Retirement in Europe (SHARE). The survey data was collected in 2004, 2006/07, and 2008/09. Country fixed-effects models are used to examine the impact of macro-economic deviations in the year of birth and the indicators of childhood circumstances on late-life cognitive functioning. This study shows that the effects of boom and recession periods at birth are not simply mediated or moderated by living conditions during childhood. Conditions at birth have biological long-run effects on late-life cognitive functioning. Individuals born during boom periods display signs of having better cognitive functioning later in life, whereas recessions negatively influence cognition. Furthermore, a series of childhood conditions in and of themselves influence late-life cognition. Good childhood cognition, high education as well as a high social status, favourable living arrangements, and good health have a positive impact. Policy interventions should aim at a better access to school or measures to improve the economic and social situations of disadvantaged households. PMID- 25042944 TI - Do schizophrenia patients age early? AB - The etiopathogenesis of schizophrenia is poorly understood. Within the proposed "neurodegeneration paradigm", observations have been put forth for "accelerated aging" in this disorder. This proposition is largely based on the neuroscience research that demonstrates progressive changes in brain as well as other systemic abnormalities supportive of faster aging process in patients with this disorder. In this review, we have summarized the literature related to the concept of early aging in schizophrenia. These studies include P300 abnormalities & visual motion discrimination, neuroimaging findings, telomere dynamics as well as neuropathology of related brain regions. We also propose a role of vitamin D, neuroimmunological changes and elevated oxidative stress as well as mitochondrial dysfunction in addition to the above factors with 'vitamin-D deficiency' as the central paradox. Put together, the evidence supporting early aging in schizophrenia is compelling and this requires further systematic studies. PMID- 25042945 TI - Behavioral Health Homes: an opportunity to address healthcare inequities in people with serious mental illness. AB - People with serious mental illness (SMI) face striking reductions in lifespan versus the general population, in part due to the inadequacy of healthcare systems in meeting the substantial physical health needs of this group. Integrated care, the strategic combination and coordination of behavioral health and primary care services, has been proposed as a potential healthcare service delivery solution to address these care gaps. Inspired by the primary care Patient-Centered Medical Home concept, Behavioral Health Homes bring primary care services into the community mental health center in various ways. In this paper the authors review the literature describing Behavioral Health Home interventions and highlight an integration project that provides co-located and coordinated primary care and wellness services in a community mental health center. Such approaches hold great promise for improving the health and healthcare of people with SMI. PMID- 25042946 TI - Life satisfaction and its correlates among college students in China: a test of social reference theory. AB - INTRODUCTION: To study life satisfaction and to test the role of social reference in determining the degree of life satisfaction, we examined a large sample of undergraduate students in China for the correlates of campus life satisfaction. METHODS: A questionnaire survey was administered at a university and the final sample consisted of 439 respondents aged between 17 and 24 years, from all over the country, and studying different subjects. RESULTS: It was found that freshman students tended to score higher on their life satisfaction than students in other grades and the college students' life satisfaction was positively related to female gender, self-esteem, social support, and the liberal attitudes on female gender roles, but negatively correlated with depression and suicidal ideation. CONCLUSIONS: Contrary to common beliefs, students from an urban area or from better-off families were not necessarily more satisfied with current life than those students coming from the countryside or low income families. The findings were accounted for by the social reference theory and in this case college students' campus life satisfaction is basically affected by their pre-college life quality as a reference. PMID- 25042947 TI - Risk factors associated with depressive symptoms among undergraduate students. AB - The purpose of the present study was to examine the relationship of several cognitive and emotional variables including perfectionism, rumination, and attachment quality with depressive symptoms in a sample of Iranian undergraduate students. Two hundred and ninety nine undergraduate students (144 males, 156 females) from Urmia University of Technology, Urmia University, and Urmia University of Medical Sciences participated in this study. Participants were asked to complete Tehran Multidimensional Perfectionism Scale (TMPS), Ruminative Responses Scale (RRS), Revised Adult Attachment Scale (RAAS), and Center for Epidemiologic Studies Depression Scale (CES-D). The results demonstrated that insecurity of attachment, socially prescribed perfectionism, and rumination could significantly predict the depressive symptoms in undergraduate students. Confirming predictive risk factors of depressive symptoms, results of the present study can produce an empirical basis for designing educational and health programs for people at risk. Accordingly, proper assessment of the risk factors of depressive symptoms in health care settings may provide invaluable information for prevention and management programs. PMID- 25042948 TI - Burnout among doctors in residency training in a tertiary hospital. AB - The mental health of doctors is an issue of growing concern all over the world as it frequently interplays with their professional trainings and responsibilities. This study was done to determine the pattern and correlates of burnout among 204 doctors undergoing residency training. Eligible participants were interviewed using designed questionnaire, General Health Questionnaire (GHQ-12) and Maslach Burnout Inventory (MBI). The mean age of participants was 33.44+/-4.50. Ninety three (45.6%) respondents reported burnout in the dimension of emotional exhaustion (EE), 118 (57.8%) in the dimension of depersonalization (D), and 126 (61.8%) in the dimension of reduced personal accomplishment (RPA). Factors that were significantly associated with all the dimensions of burnout were perceived heavy workload and presence of emotional distress (based on GHQ score of >=3). The perception of call duty as being not stressful was negatively predictive of burnout in the emotional exhaustion subscale (odds ratio [OR]=0.52; 95%confidence interval [CI]=0.29-0.97; p=0.03), while emotional distress was a positive predictor (OR=6.97; 95%CI=3.28-14.81; p<0.001]. Absence of doctor-to-doctor conflict negatively predicted burnout in the depersonalization subscale (OR=0.36; 95%CI=0.17-0.76); p<0.01), while older age (OR=0.66; 95%CI=0.47-0.95; p=0.03) and adequate support from the management (OR=0.45; 95%CI=0.22-0.90; p=0.02) constituted negative predictors of burnout in the reduced personal accomplishment subscale. Burnout is highly prevalent among resident doctors. Evolvement of comprehensive mental health services, training supports, conflict de escalation/resolution mechanisms, and periodic assessment are indicated to mitigate work related distress with burn out among resident doctors, while improving their productivity. PMID- 25042949 TI - Development and validation of NIMHANS screening tool for psychological problems in Indian context. AB - Screening for psychiatric morbidity helps to identify disease, enable initiation of treatment and intervention to reduce mortality and suffering from psychological problems. There is a dearth of such scales in India and South East Asia. The present work aims to develop and validate the NIMHANS screening tool for psychological problems in Indian context. 754 (229 normal subjects and 525 clinical subjects) were taken from the community and in-patient and out patient psychiatric setting of the hospital. Socio-demographic datasheet and the newly developed tool were administered on them. Split half reliability of the tool was .84. Score of 12 & 24 and above indicated presence of psychiatric distress in normal and clinical group respectively. Discriminate validity developed with sensitivity of .76 and specificity of .82. The NIMHANS screening tool for psychological problems has a utility in screening out psychiatric distress in the community. PMID- 25042950 TI - Effectiveness of group cognitive-behavioral therapy in reducing self-stigma in Japanese psychiatric patients. AB - OBJECTIVE: There is evidence that the stigma surrounding mental illness may be greater in Japan than elsewhere. However, few Japanese studies have focused on self-stigma (the internalization of social stigma), and few interventions to reduce self-stigma exist. To remedy this deficiency, we evaluated the efficacy of group cognitive-behavioral therapy (CBT) in reducing self-stigma and examined the relationship between cognitive restructuring and self-stigma. METHODS: We administered a 10-session group CBT program to 46 Japanese outpatients with anxiety and depressive symptoms (36 men, 10 women; mean age=38.57 years, SD=8.33; 20 diagnosed with mood disorders; 24 with neurotic, stress-related, or somatoform disorders; and 2 with other disorders). A pretest-posttest design was used to examine the relationship between cognitive restructuring and self-stigma. Outcomes were measured using the Japanese versions of the Devaluation Discrimination Scale, Dysfunctional Attitude Scale, Beck Depression Inventory-II, State-Trait Anxiety Inventory State-Form, and Rosenberg's Self Esteem Scale. RESULTS: Participants exhibited significant improvements in depression, anxiety, and maladjusted cognitive bias and reductions in self-stigma. Cognitive bias was significantly correlated with self-stigma. CONCLUSIONS: Group CBT is effective in improving both emotional symptoms and self-stigma in outpatients with anxiety and depressive symptoms. Reduction in self-stigma plays a mediating role in alleviating emotional symptoms and improving cognition. PMID- 25042953 TI - Development of a school-based program for adolescents at-risk for depression in India: results from a pilot study. AB - A majority of adolescents in India, who are at risk for depression, do not receive treatment or receive it when the psychopathology has become entrenched and chronic. The present pilot study was an endeavor to assess the felt needs of adolescents vis-a-vis the difficulties and stressors experienced by them. For this purpose, 300 students across three schools were screened using standardized measures. Another objective of the study was to develop and test a school-based Coping Skills Program to address adolescents at-risk for depression. Schools were sequentially assigned to intervention or control conditions; students of index (n=13) and control (n=6) groups were assessed at baseline, post-intervention, and 3 months follow-up. At post-intervention for the index group, all outcomes measures except coping skills-including depressive symptoms, negative cognitions, academic stress, and social problem-solving-showed change in the expected direction, this difference assuming significance at follow-up. The program was rated positively by students using anonymous feedback and there was low to nil perceived stigmatization. Results are discussed in the context of need for such intervention programs in India, and future scope of research involving larger samples. PMID- 25042952 TI - Cardiovascular risk factors among bipolar disorder patients admitted to an inpatient unit of a tertiary care hospital in India. AB - OBJECTIVE: The study aimed to examine the prevalence of cardiovascular risk factors in patients with bipolar disorder. METHODS: By consecutive sampling, 93 inpatients (aged >=20 years) diagnosed with bipolar disorder were evaluated for 10 year coronary heart disease (CHD) risk and 10-year cardiovascular mortality risk (CMR) on the Framingham (10-year all CHD events) function/risk equation and Systematic Coronary Risk Evaluation (SCORE) respectively. RESULTS: Ten-year CHD risk was 3.36% and 10-year CMR was estimated to be 1.73%. One tenth (10.7%) of the sample was found to have very high/high CHD risk (>=10) and 6.45% of the sample had high CMR risk (>=5). More than half (54.88%) of patients had metabolic syndrome. Compared to females, males had higher Framingham function score (4.09+/ 5.75 vs 1.59+/-1.05, U value - 634.5*, p<0.05) and had higher very high/high CHD risk (>=10) (15.1% vs 0, chi(2) 4.58, p<0.05). CONCLUSIONS: Findings of the present study suggest the presence of cardiovascular risk factors and higher rate of metabolic syndrome in patients with bipolar disorder. Considering this fact, there is an urgent need for routine screening for cardiovascular risk factors in these patients. Mental health professionals should be aware of these risks; there is need to develop preventive strategies to reduce the cardiovascular risk in this population. PMID- 25042951 TI - Clinical correlates of parametric digit-symbol substitution test in schizophrenia. AB - Processing speed deficit, ascertained by digit-symbol substitution test (DSST), is considered as a fundamental impairment in schizophrenia. Clinical correlates of processing speed abnormalities, especially using the parametric version of DSST is yet to be evaluated comprehensively. In this study, we examined schizophrenia patients (N=66) and demographically matched healthy controls (N=72) using computer-administered parametric DSST (pDSST) with fixed (pDSSTF) as well as random (pDSSTR) conditions and analysed the relationship between pDSST performance and clinical symptoms. Psychopathology was assessed using Scale for Assessment of Positive Symptoms (SAPS)/Negative Symptoms (SANS) with good inter rater reliability. In comparison with healthy controls, patients demonstrated significantly lesser number of correct responses (CN) in pDSSTF (t=8.0; p<0.001) and pDSSTR (t=7.8; p<0.001) as well as significantly prolonged reaction time in pDSSTF (t=7.1; p<0.001) and pDSSTR (t=7.0; p<0.001). The difference in CN between pDSSTF and pDSSTR [DeltaCN] was significantly lesser in patients than healthy controls (t=2.61; p=0.01). The pDSST reaction time had significant positive correlation with negative syndrome scores as well as bizarre behaviour score. Significantly greater processing speed deficits in pDSST suggest potential relational memory/visual scanning abnormalities in schizophrenia. Furthermore, pDSST deficits demonstrated a significant association with the psychopathology, especially with the various negative symptoms and bizarre behaviour. PMID- 25042954 TI - An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India. AB - Multiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N=38) and healthy subjects (N=37) from South India. Patients with schizophrenia showed trend-level (p<0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia. PMID- 25042955 TI - Mobile technology and global mental health. PMID- 25042956 TI - Internet access is NOT restricted globally to high income countries: so why are evidenced based prevention and treatment programs for mental disorders so rare? AB - Mental disorders are widespread and universal. They are frequently accompanied by considerable harmful consequences for the individual and come at a significant economic cost to a community. Yet while effective evidence based prevention and treatment exists, there are a number of barriers to access, implement and disseminate. Cognitive behavior therapy programs, such as those available at www.thiswayup.com.au are widely available using the Internet in high income countries, such as Australia. With the ubiquitous uptake of Internet users globally, it is suggested that low and middle income countries should consider ways to embrace and scale up these cost effective programs. An explanation of why and some suggestions as to how this can be done are presented. PMID- 25042957 TI - The Internet Addiction Test: assessing its psychometric properties in Bangladeshi culture. AB - There is growing importance of the Internet Addiction Test (IAT) in Internet addiction research around the world. Since the development of the IAT (Young, 1996, 1998), a number of validation studies have been done in various cultures. The aim of this study was to translate the instrument into Bangla and validate in Bangladeshi culture, a culture vulnerable to Internet addiction. A total of 177 Internet users (77 females and 100 males) participated in the study. Exploratory factor analysis (EFA) of the data from 172 participants (who provided complete responses) identified a four factor structure of the IAT with 18 items. The four factors namely 'Neglect of duty', 'Online dependence', 'Virtual fantasies', and 'Privacy and self-defense' together explained 55.68% of the total variance. Problematic (moderate/excessive) users on the IAT scored, on average, higher on each of the four IAT factors as compared to average or non-problematic (minimal) users consistently across genders. The IAT and its factors showed good internal consistency (Cronbach's alpha=.89 for the IAT, and .60-.84 for the factors), strong convergent and discriminant validity. Thus, the Bangla version IAT appears to be valid and reliable and therefore may be used in further research on Internet addiction in the country. PMID- 25042958 TI - A socio-cognitive inquiry of excessive mobile phone use. AB - OBJECTIVES: The study examined the predictive ability of selected demographic and socio-psychological characteristics in explaining excessive mobile phone use (EMPU) behavior and problematic use in a sample of university students on the basis of the social cognitive theory. METHODS: The sample consisted of 476 randomly selected university students in Tabriz, Iran. The study was cross sectional in nature. A researcher-designed questionnaire was used for the purpose of data collection. No causal inferences were drawn due to non-experimental nature of the study. RESULTS: It was found that having boyfriend/girlfriend increases the likelihood of EMPU while self-efficacy to avoid EMPU decreases it. Self-efficacy to avoid EMPU, self-regulation, observational learning, self control, and attitude toward EMPU were predictors of mobile phone problematic use. The results provided a proper fit for a conceptual model of reciprocal determinism. CONCLUSION: Although social cognitive constructs may predict mobile phone problematic use, they are not useful in predicting the behavior of EMPU. PMID- 25042959 TI - Use of mobile assessment technologies in inpatient psychiatric settings. AB - Mobile electronic devices (i.e., PDAs, cellphones) have been used successfully as part of research studies of individuals with severe mental illness living in the community. More recently, efforts have been made to incorporate such technologies into outpatient treatments. However, few attempts have been made to date to employ such mobile devices among hospitalized psychiatric patients. In this article, we evaluate the potential use of such devices in inpatient psychiatric settings using 33 hospitalized patients with schizophrenia. Employing an Experience Sampling Method approach, we provide support for the feasibility of using such devices, along with examples of potentially clinically-relevant information that can be obtained using such technologies, including assessment of fluctuations in the severity of psychotic symptoms and negative mood in relation to social context, unit location, and time of day. Following these examples, we discuss issues related to the potential use of mobile electronic devices by patients hospitalized at inpatient psychiatric settings including issues related to patients' compliance, assessment schedules, questionnaire development, confidentiality issues, as well as selection of appropriate software/hardware. Finally, we delineate some issues and areas of inquiry requiring additional research and development. PMID- 25042960 TI - Mobile health (mHealth) for mental health in Asia: objectives, strategies, and limitations. AB - Mobile technologies are transforming the way in which we interact with one another, access resources, find information, and conduct business around the world. Harnessing the capabilities of mobile technologies to support health care initiatives worldwide has developed into a new interdisciplinary field called mobile health (mHealth). In the current paper, we review the penetration of mobile technology in Asia, and consider the integration of mobile technologies into the study, diagnoses, and treatment of mental disorders in the region. We outline how mHealth programs could improve mental health literacy, provide greater access to mental health services, extend community-based outreach and engagement, support self-management of illness, and regulate medication distribution. We end with a consideration of the potential barriers and limitations of mHealth for mental health, including funding, language and literacy barriers, power supply considerations, data security, and privacy issues. PMID- 25042961 TI - Mobile health in China: current status and future development. AB - Mobile health applications offer unique opportunities for monitoring patient progress, providing education materials to patients and family members, receiving personalized prompts and support, collecting ecologically valid data, and using self-management interventions when and where they are needed. Mobile health application services to mental illness have evidenced success in Western countries. However, they are still in the initial stage of development in China. The purpose of this paper is to identify needs for mobile health in China, present major mobile health products and technology in China, introduce mobile and digital psychiatric services, and discuss ethical issues and challenges in mobile health development in a country with the largest population in the world. PMID- 25042962 TI - A synopsis of recent influential papers published in mental health journals (2012 2013) in Mainland China. AB - Research dissemination is becoming more and more global. There is, however, limitation in allowing researchers who speak a language other than Chinese to follow the research trends in China, a country with the largest population in the world. Therefore, the purpose of this review article was to introduce the current research studies conducted in Mainland China. We limited our search of publications between 2012 and 2013 from three tier one Chinese mental health journals. We identified and reviewed seven papers which were highly downloaded by Chinese readers and which had not been published in English. PMID- 25042963 TI - Mental health issues among migrant workers in Gulf Cooperation Council countries: literature review and case illustrations. AB - More than 15 million non-nationals are currently living and working in Gulf Cooperation Council (GCC) states. The majority are blue-collar or domestic workers coming from the Indian Subcontinent or South East Asia. They often work under very harsh conditions. There are reports of a high rate of psychosis and suicide among these people but no reliable data are available. To address this issue we conducted a literature search both in English and in Arabic to review the available articles on the psychological well-being of this population. Very few articles were found. We hereby review the available literature and contribute by presenting several brief vignettes to illustrate the various clinical aspects of this at risk population. We also discuss possible reasons for underreporting and underscore the need for more research in this area. PMID- 25042964 TI - Parents: a resource to promote resilience in children. PMID- 25042965 TI - Tardive movements and clozapine: the interesting association. PMID- 25042966 TI - Koro presenting as acute and transient psychosis: implications for classification. PMID- 25042967 TI - Science, art and healing: a meeting of minds. PMID- 25042968 TI - Promise and perils of digital psychiatry. PMID- 25042969 TI - Unique properties of 2 D layered titanate nanosheets as a building block for the optimization of the photocatalytic activity and photostability of TiO2-based nanohybrids. AB - In comparison with the hybridization with 0D TiO2 nanoparticle, 2D layered TiO2 nanosheets are much more effective in the improvement of the photocatalytic activity and photostability of semiconducting compounds. The 2D TiO2-Ag3PO4 nanohybrid described in this paper shows a greater decrease in the electron-hole recombination upon hybridization and a stronger chemical interaction between the components than the 0D homologue. This result confirms the benefits of 2D layered TiO2 nanosheets as a building block for efficient hybrid-type photocatalyst materials. PMID- 25042970 TI - Orientational ordering studies of fluorinated thermotropic liquid crystals by NMR spectroscopy. AB - Fluorinated calamitic thermotropic liquid crystals represent an important class of materials for high-tech applications, especially in the field of liquid crystal displays. The investigation of orientational ordering in these systems is fundamental owing to the dependence of their applications on the anisotropic nature of macroscopic optical, dielectric, and visco-elastic properties. NMR spectroscopy is the most powerful technique for studying orientational order in liquid crystalline systems at a molecular level thanks to the possibility of exploiting different anisotropic observables (chemical shift, dipolar couplings, and quadrupolar coupling) and nuclei ((2)H, (13)C, and (19)F). In this paper, the basic theory and NMR experiments useful for the investigation of orientational order on fluorinated calamitic liquid crystals are reported, and a review of the literature published on this subject is given. Finally, orientational order parameters determined by NMR data are discussed in comparison to those obtained by optical and dielectric anisotropy measurements. PMID- 25042971 TI - [Diagnosis and treatment of familial hypercholesterolemia in Spain: Consensus document]. AB - Familial hypercholesterolemia (FH) is a common genetic disorder, clinically manifested since birth, and associated with very high levels of plasma LDL cholesterol (LDL-c), xanthomas, and premature coronary heart disease. Its early detection and treatment reduces coronary morbidity and mortality. Despite effective treatment being available, FH is under-diagnosed and under-treated. Identification of index cases and cascade screening using LDL-c levels and genetic testing are the most cost-effective strategies for detecting new cases and starting early treatment. Long-term treatment with statins has decreased the vascular risk to the levels of the general population. LDL-c targets are <130mg/dL for children and young adults, <100mg/dL for adults, and <70mg/dL for adults with known coronary heart disease or diabetes. Most patients do not to reach these goals, and combined treatments with ezetimibe or other drugs may be necessary. When the goals are not achieved with the maximum tolerated drug treatment, a reduction >=50% in LDL-c levels can be acceptable. Lipoprotein apheresis can be useful in homozygous, and in treatment-resistant severe heterozygous, cases. This Consensus Paper gives recommendations on the diagnosis, screening, and treatment of FH in children and adults, and specific advice to specialists and general practitioners with the objective of improving the clinical management of these patients, in order to reduce the high burden of coronary heart disease. PMID- 25042972 TI - [Need of specific criteria for psychotherapy referral in the public health system: A proposal]. AB - This study discusses the need of specific criteria for psychotherapy referral in the public services. the use of psychotherapy as a supplement to traditional medication, and its comparison with informal methods of support, has been questioned. This study proposes the establishment of basic criteria for the integration of psychotherapy, based on an analysis of the conditions that allow it to function. It thus aims to contribute to improving the reputation and the practice conditions of psychotherapy in the public health system. PMID- 25042973 TI - [The importance of nutrition in primary care: nutrition and malnutrition risk]. PMID- 25042974 TI - [Prevalence and factors associated with peripheral artery disease in patients with type 2 diabetes mellitus in Primary Care]. AB - INTRODUCTION: Peripheral artery disease in the lower limbs (PAD) is a prevalent condition that entails high morbidity in diabetic patients; this study assesses PAD in these patients and its socio-demographic and clinic associated variables. MATERIAL AND METHODS: Descriptive study in a systematic sample of diabetic patients (DM2) aged 50-80 years, in Primary Care settings. The dependent variable was the presence of PAD diagnosed by ankle-brachial index (ABI) <= 0.9; independent variables: socio-demographic, clinical and laboratory. STATISTICS: bivariate and multiple logistic regression analyses were performed to determine the variables associated with low ABI. RESULTS: A sample of 251 patients, 52.6% women; mean age: 68.5 +/-8.5. A low ABI was detected in 18.3% (95% Confidence Interval (95% CI):13.3-23.3%), with 6 subjets (2.4%) previously diagnosed as suffering PAD. Age (OR=1.07; 95% CI: 1.02-1.12) and retinopathy (OR=2.69; 95% CI: 1.06-6.81) were associated (multiple logistic regression analysis) with ABI. CONCLUSIONS: The percentage of patients diagnosed with PAD is very low, although PAD prevalence is high among DM2 patients attending Primary Care clinics, especially in older patients and those with retinopathy. We emphasize the recommendation of performing the ABI test in this population at risk. PMID- 25042975 TI - Making blood 'Melanesian': fieldwork and isolating techniques in genetic epidemiology (1963-1976). AB - 'Isolated' populations did not exist unproblematically for life scientists to study. This article examines the practical and conceptual labour, and the historical contingencies that rendered populations legible as 'isolates' for population geneticists. Though a standard historiographical narrative tells us that population geneticists were moving from typological understandings of biological variation to processual ones, cultural variation was understood as vulnerable to homogenisation. I chart the importance that D. Carleton Gajdusek placed on isolates from his promotion of genetic epidemiology in WHO technical reports and at a Cold Spring Harbour symposium to his fieldwork routines and collection practices in a group of South Pacific islands. His fieldwork techniques combined social, cultural and historical knowledge of the research subjects in order to isolate biological descent using genealogies. Having isolated a population, Gajdusek incorporated biological materials derived from that population into broad categories of 'Melanesian' and 'race' to generate statements about the genetics of abnormal haemoglobins and malaria. Alongside an analysis of Gajdusek's practices, I present different narratives of descent, kinship and identities learned during my ethnographic work in Vanuatu. These alternatives show tacit decisions made pertaining to scale in the production of 'isolates'. PMID- 25042976 TI - The role of baseline HIV-1 RNA, drug resistance, and regimen type as determinants of response to first-line antiretroviral therapy. AB - The factors influencing virological response to first-line combined antiretroviral therapy (cART) in an Italian cohort of HIV-1-infected patients were examined. Eligible patients were those enrolled in a national prospective observational cohort (Antiretroviral Resistance Cohort Analysis), starting first line cART between 2001 and 2011 and who had at least one follow-up of HIV-1 RNA. The primary endpoint was virological success, defined as the first viral load <50 copies/ml. Time to events were analyzed by Kaplan-Meier analysis and Cox proportional hazard model. One thousand three hundred five patients met the study inclusion criteria. In a multivariable model adjusting for transmission mode, presence of transmitted drug resistance, baseline CD4(+) cell count, viral subtype, and type of NRTI backbone employed, independent predictors of virological success were higher baseline viral load (>=500,000 vs. <100,000 HR 0.52; P < 0.001), a weighted genotypic susceptibility score (wGSS) <3 (HR 0.58; P = 0.003), male sex (HR 0.76 P = 0.001), and type of initial third drug employed (integrase inhibitor vs. boosted protease inhibitors HR 3.23; P < 0.001). In the subset with HIV-1 RNA >100,000 copies/ml, virologic success was only associated with the use of integrase inhibitors in the first cART regimen. Independent predictors of immunological success were baseline CD4(+) cell count and wGSS <3. High baseline HIV-1 RNA, predicted activity of the first-line regimen based on genotypic resistance testing, gender, and use of new agents were found to predict time to achieve virological success. The type of initial nucleoside analog backbone was not found to predict virological response. PMID- 25042977 TI - Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: a meta-analysis with 1,392 participants. AB - The hypomethylating agents decitabine and azacitidine have been found to improve the outcome of patients with myelodysplastic syndrome (MDS); however, the clinical choice between them is controversial. Therefore, this meta-analysis was performed to compare the efficacy, toxicity, and survival advantage of decitabine and azacitidine in patients with MDS. Eleven trials with a total of 1392 patients with MDS (decitabine, n = 768; azacitidine, n = 624) were included for analysis. The pooled estimates of partial response, hematologic improvement, and overall response rates for azacitidine were significantly higher than for decitabine. There were no differences between these 2 drugs regarding complete response, red blood cell transfusion-independent rates, and grade 3 or 4 hematologic toxicity. When compared with best supportive care, azacitidine significantly improved overall survival (hazard ratio [HR], 0.69; 95% CI, 0.54-0.87) and time to acute myeloid leukemia transformation (HR, 0.51; 95% CI, 0.35-0.74). But these benefits were not found with decitabine. Among patients with higher risk (International Prognostic Scoring System value of 3) or older than 75 years, treatment with azacitidine was a favorable factor, whereas decitabine showed no advantage. Therefore, with higher overall response rates and better survival benefits, azacitidine is recommended as the first-line hypomethylating agent for MDS, especially in elderly patients or those with high risk. PMID- 25042978 TI - Childhood cortical porosity is related to microstructural properties of the bone muscle junction. AB - Childhood cortical porosity is attributable to giant asymmetrical drifting osteonal canals that arise predominantly along the primary-secondary bone interface (PSBI). Bone from the external iliac crest cortex of 92 subjects aged 0 to 25 years was examined histomorphometrically for differences in microstructural properties between primary and secondary bone that might account for features of drifting osteonal canals. Primary compared with secondary bone showed greater numbers of osteocyte lacunae, thinner collagen lamellae, and a scaffold of elastic perforating fibers (PFs). The greater number of osteocyte lacunae compounded by known perilacunar strain amplification and the presence of elastic PFs are expected to be associated with greater bone tissue strain in primary than in secondary bone and thus with strain gradients at the PSBI. Strain gradients may lead local osteocytes to originate resorption canals and to promote transverse drift of the resorption front into lower-strain secondary bone, thus creating giant asymmetrical drifting osteonal canals that remodel primary to secondary bone. PFs extended from muscle fibers through periosteum and primary bone to the PSBI, where they were resorbed by origination of drifting canals. Growth modeling by periosteal osteoblasts proceeds in the gaps between PFs. Through the direct connection between muscle and the PSBI via PFs, muscle forces may influence not only modeling by raising strain but also remodeling of primary to secondary bone by increasing strain gradients at the PSBI. With reduction in primary bone width after the mid-teens, numbers of drifting canals and porosity declined. Differences in microstructural properties between primary and secondary bone are expected to generate strain gradients at the PSBI that contribute to site, transverse drift, asymmetry and large size of drifting canals, and, hence, to cortical porosity. Cortical porosity in children is a physiological feature of bone growth in width. Advisability of therapeutic intervention remains to be defined. PMID- 25042979 TI - Spontaneous stepwise self-assembly of a polyoxometalate-organic hybrid into catalytically active one-dimensional anisotropic structures. AB - An inorganic-organic hybrid surfactant with a hexavanadate cluster as the polar head group was designed and observed to assemble into micelle structures, which further spontaneously coagulate into a 1D anisotropic structure in aqueous solutions. Such a hierarchical self-assembly process is driven by the cooperation of varied noncovalent interactions, including hydrophobic, electrostatic, and hydrogen-bonding interactions. The hydrophobic interaction drives the quick formation of the micelle structure; electrostatic interactions involving counterions leads to the further coagulation of the micelles into larger assemblies. This process is similar to the crystallization process, but the specific counterions and the directional hydrogen bonding lead to the 1D growth of the final assemblies. Since most of the hexavanadates are exposed to the surface, the 1D assembly with nanoscale thickness is a highly efficient heterogeneous catalyst for the oxidation of organic sulfides with appreciable recyclability. PMID- 25042980 TI - Association between specific timothy grass antigens and changes in TH1- and TH2 cell responses following specific immunotherapy. AB - BACKGROUND: Different populations of T cells are involved in the pathogenesis of allergic diseases. OBJECTIVE: We investigated changes in TH-cell populations in patients with allergies after specific immunotherapy (SIT). METHODS: PBMCs were isolated from patients with allergies who received SIT and those who did not (controls). We tested the ability of peptides from 93 timothy grass (TG) proteins to induce T-cell responses (cytokine production). We used ELISPOT and staining assays for intracellular cytokines to measure the production of IL-4, IL-5, IL 13, IFN-gamma, and IL-10. RESULTS: Compared with PBMCs from controls, PBMCs from patients who received SIT produced lower levels of TH2 cytokines on incubation with several different TG peptides. These data were used to select 20 peptides to be tested in an independent cohort of 20 patients with allergies who received SIT and 20 controls. We again observed a significant decrease in the production of TH2 cytokines, and an increase in the production of the TH1 cytokine IFN-gamma, in PBMCs from the validation groups. These changes correlated with improved symptoms after SIT. Immunization with this selected pool of peptides (or their associated antigens) could protect a substantial proportion of the population from TG allergy. CONCLUSIONS: We observed a significant decrease in the production of TH2 cytokines by PBMCs from patients who received SIT for TG allergy compared to those who did not. These changes might be used to monitor response to therapy. The decrease occurred in response to antigens that elicit little (if any) IgE responses; these antigens might be developed for use in immunotherapy. PMID- 25042981 TI - Oral immunotherapy induces IgG antibodies that act through FcgammaRIIb to suppress IgE-mediated hypersensitivity. AB - BACKGROUND: Food-induced anaphylaxis is triggered by specific IgE antibodies. Paradoxically, some subjects with significant IgE levels can ingest allergenic foods without incident. Similarly, subjects completing oral immunotherapy (OIT) tolerate food challenges despite persistent high-titer food-specific IgE. OBJECTIVE: We sought to test whether IgG antibodies induced by food immunotherapy prevent food-induced anaphylaxis and whether this occurs through the inhibitory receptor FcgammaRIIb. METHODS: Food allergy-susceptible Il4raF709 mice were enterally sensitized to ovalbumin (OVA). Similarly sensitized IgE-deficient (IgE( /-)) Il4raF709 mice, which can ingest OVA without anaphylaxis, were subjected to a high-dose enteral OVA desensitization protocol (OIT). Sera from both groups were tested for the ability to activate or inhibit bone marrow mast cells (BMMCs) exposed to allergen or to passively transfer allergy to naive hosts. In parallel experiments sera obtained from patients with peanut allergy before and after undergoing OIT were interrogated for their ability to enhance or suppress peanut induced activation in an indirect assay by using basophils from nonallergic donors. RESULTS: Il4raF709 mice exhibited strong OVA-specific IgE responses. Their sera efficiently sensitized BMMCs for activation by antigen challenge. Sera from Il4raF709/IgE(-/-) mice subjected to OVA OIT suppressed BMMC responses. This inhibition was IgG mediated and FcgammaRIIb dependent. Similarly, pre-OIT but not post-OIT sera from patients efficiently sensitized basophils for peanut-induced activation. IgG antibodies in post-OIT sera suppressed basophil activation by pre OIT sera. This inhibition was blocked by antibodies against FcgammaRII. CONCLUSION: Food-specific IgG antibodies, such as those induced during OIT, inhibit IgE-mediated reactions. Strategies that favor IgG responses might prove useful in the management of food allergy. PMID- 25042982 TI - Neutrophils in antiretroviral therapy-controlled HIV demonstrate hyperactivation associated with a specific IL-17/IL-22 environment. AB - BACKGROUND: Despite control of HIV infection under antiretroviral therapy (ART), immune T-cell activation persists in patients with controlled HIV infection, who are at higher risk of inflammatory diseases than the general population. PMNs play a key role in host defenses against invading microorganisms but also potentiate inflammatory reactions in cases of excessive or misdirected responses. OBJECTIVE: The aim of our study was to analyze PMN functions in 60 ART-treated and controlled HIV-infected patients (viral load, <20 RNA copies/mL; CD4 count, >= 350 cells/mm(3)) with (HIV[I] group) and without (HIV[NI] group) diseases related to an inflammatory process and to compare them with 22 healthy control subjects. METHODS: Flow cytometry was used to evaluate PMN functions in whole blood conditions. We studied in parallel the activation markers of T lymphocytes and monocytes and the proinflammatory cytokine environment. RESULTS: Blood samples from HIV-infected patients revealed basal PMN hyperactivation associated with deregulation of the apoptosis/necrosis equilibrium. Interestingly, this hyperactivation was greater in HIV(I) than HIV(NI) patients and contrasted with a lack of monocyte activation in both groups. The percentage of circulating cells producing IL-17 was also significantly higher in HIV-infected patients than in control subjects and was positively correlated with markers of basal PMN activation. In addition, the detection of IL-22 overproduction in HIV(NI) patients suggests that it might contribute to counteracting chronic inflammatory processes during HIV infection. CONCLUSIONS: This study thus demonstrates the presence of highly activated PMNs in HIV-infected patients receiving effective ART and the association of these cells with a specific IL-17/IL-22 environment. PMID- 25042983 TI - A new beginning! PMID- 25042984 TI - Circulating endothelial cells as markers of endothelial dysfunction during hematopoietic stem cell transplantation for pediatric primary immunodeficiency. PMID- 25042985 TI - Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. AB - BACKGROUND: The activation of plasma enzyme systems is insufficiently controlled in hereditary angioedema due to the deficiency of C1-inhibitor (C1-INH) (HAE-C1 INH). Recently, it was suggested that the ficolin-lectin pathway (ficolin-LP) might play a more dominant role than the mannose-binding lectin-lectin pathway in the pathomechanism of HAE-C1-INH. OBJECTIVE: Because the role of the ficolin-LP during edematous attacks is still enigmatic, we analyzed its activity during such episodes. METHODS: Thirty-five patients with HAE-C1-INH, who have experienced severe attacks on 106 occasions, were enrolled. We analyzed blood samples drawn during attacks, and obtained 35 samples from the same patients during symptom free periods. The serum levels of ficolin-2, ficolin-3, MASP-2, ficolin-3/MASP-2 complex, C1-INH, and C4, as well as the extent of ficolin-3-mediated terminal complement complex (FCN3-TCC) deposition, were measured using ELISA-based methods. RESULTS: Levels of MASP-2 and of the ficolin-3/MASP-2 complex were elevated (P < .0001 and .033, respectively), whereas that of FCN3-TCC was lower (P < .0001) during attacks than during the symptom-free period. During symptom free periods, FCN3-TCC deposition was significantly related to concentrations of ficolin-3 (R = 0.2778; P = .0022), antigenic C1-INH (R = 0.3152; P = .0006), and C4 (R = 0.5307; P < .0001). Both ficolin-3 and MASP-2 levels correlated inversely with the time from the onset of the attack until blood sampling. CONCLUSIONS: There is a marked heterogeneity of the pathomechanism and development of hereditary angioedema attacks in different patients. Our results suggest that the activation of the ficolin-LP may deplete the innately low level of C1-INH and thus, it may contribute to the uncontrolled activation of plasma cascade systems, and thereby to edema formation. PMID- 25042986 TI - Microstructural information from angular double-pulsed-field-gradient NMR: From model systems to nerves. AB - PURPOSE: To evaluate the ability of angular double-pulsed-field gradient (d-PFG) MR to provide microstructural information in complex phantoms and fixed nerves. METHODS: We modeled the signal in angular d-PFG MR experiments performed on phantoms of increasing complexity where the ground truth is known a priori. After analyzing the microstructural features of such phantoms the same methodology was used to study microstructural features in fixed nerves. RESULTS: We found that our modeling is able to determine with high accuracy and with very little prior knowledge the sizes and relative fractions of the restricted components as well as the fraction of the free diffusing water molecules. The same approach was used to study nerve microstructure. We found the apparent averaged axonal diameter (AAD) to be 2.3 +/- 0.2 MUm. However, here the results depended, to some extent, on the parameters used to collect the data and were affected by the diffusion time. CONCLUSION: Modeling of the angular d-PFG MR signal provides a means to obtain accurate microstructural information in complex phantoms where the ground truth is known. This approach also seems to be suitable for obtaining microstructural features in fixed nerves. Magn Reson Med 74:25-32, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25042987 TI - Sexual structures and recombination of the wheat rust fungus Puccinia striiformis on Berberis vulgaris. AB - An isolate of the basidiomycete Puccinia striiformis, which causes yellow (stripe) rust on wheat, was selfed on the newly discovered alternate host, Berberis vulgaris. This allowed a study of the segregation of molecular markers and virulence in the progeny isolates, and of the development of fungal sexual structures and spore forms. Pycnia and aecia were obtained after inoculation of B. vulgaris with basidiospores resulting from germinating teliospores from infected wheat leaves. Subsequent inoculation of wheat with aeciospores from bulked aecia resulted in 16 progeny isolates of the S1 generation. Genotyping with 42 simple sequence repeat (SSR) markers confirmed a parental origin of progeny isolates. Of the 42 analyzed loci, 15 were heterozygous in the parental isolate and 14 revealed segregation in the progenies. This resulted in 11 new multilocus genotypes (MLGs), which confirmed segregation following sexual reproduction. Additionally, parental and progeny isolates were phenotyped using a genetic stock of wheat genotypes representing 21 resistance genes. All S1 progeny isolates had virulence for 14 out of 15 loci where the parental isolate was virulent. This was consistent with the hypothesis that virulence in plant pathogens is often recessive to avirulence, i.e., only expressed in a homozygous state. Furthermore, no segregation was observed for five out of six loci, for which the parental isolate had an avirulent phenotype. The results for one of the two segregating virulence/avirulence loci suggested that the parental isolate was heterozygous with Avr alleles resulting in different but clearly avirulent phenotypes. The other locus indicated that additional genes modifying the phenotypic expression of avirulence were involved. PMID- 25042988 TI - A single blastocyst assay optimized for detecting CRISPR/Cas9 system-induced indel mutations in mice. AB - BACKGROUND: Microinjection of clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-related RNA and DNA into fertilized eggs is a novel approach for creating gene-modified mice. Blastocysts obtained just before implantation may be appropriate for testing the fidelity of CRIPSR/Cas9-mediated genome editing because they can be individually handled in vitro and obtained 3days after microinjection, thus allowing researchers to check mutations rapidly. However, it is not known whether indel mutations caused by the CRISPR/Cas9 system can be reproducibly detected in embryos. In this study, we assessed the detection of CRISPR/Cas9-induced mutations in embryos. RESULTS: T7 endonuclease I was more effective than Surveyor nuclease for detecting mutations in annealed fragments derived from 2 plasmids, which contained nearly identical sequences. Mouse fertilized eggs were microinjected with CRISPR/Cas9-related RNA/DNA to examine whether non-homologous end joining-mediated knockout and homologous recombination-mediated knockin occurred in the endogenous receptor (G protein-coupled) activity modifying protein 2 (Ramp2) gene. Individual blastocysts were lysed to obtain crude DNA solutions, which were used for polymerase chain reaction (PCR) assays. T7 endonuclease I-based PCR and sequencing analysis demonstrated that 25-100% of the embryos were knockout embryos and 7-57% of the embryos were knockin embryos. Our results also established that crude DNA from a single blastocyst was an appropriate template for Whole genome amplification and subsequent assessment by PCR and the T7 endonuclease I-based assay. CONCLUSIONS: The single blastocyst-based assay was useful for determining whether CRISPR/Cas9-mediated genome editing worked in murine embryos. PMID- 25042991 TI - Prognosis and treatment of intracranial dural arteriovenous fistulae: a systematic review and meta-analysis. AB - BACKGROUND: Dural arteriovenous fistulae can cause intracranial hemorrhage, but influences on this are unclear. SUMMARY OF REVIEW: We searched Ovid MEDLINE (from 1966), Embase (from 1980), and the Cochrane Library in September 2013 for studies of >=50 adults with dural arteriovenous fistulae describing death or intracranial hemorrhage. Of 16 studies of retrospective associations between dural arteriovenous fistulae vascular anatomy and prior mode of presentation, fistula location in the cavernous sinus was consistently associated with nonhemorrhagic modes of presentation; in five studies involving 855 patients, fistulae with retrograde leptomeningeal (cortical) venous drainage were associated with prior presentation with intracranial hemorrhage (pooled odds ratio 23.2, 95% CI 13.8 to 39.0; I(2) = 0%). Future intracranial hemorrhage during untreated clinical course was statistically significantly associated with the presence of venous varix in one study and with presentation with intracranial hemorrhage in patients with retrograde leptomeningeal venous drainage in another. In 19 observational studies of treatment of dural arteriovenous fistulae involving 2329 patients, the pooled risk of death was 1.2% (95% CI 0.6 to 1.8, I(2) = 35%), that of nonfatal intracranial haemorrhage was 0.5% (95%CI 0.2 to 0.8, I(2) = 9%), and that of nonfatal cerebral infarction was 0.7% (95% CI 0.3 to 1.4, I(2) = 52%), for a combined risk of 2.5% (95% CI 1.4 to 3.9, I(2) = 69%). CONCLUSIONS: Retrograde leptomeningeal venous drainage seems strongly associated with intracranial hemorrhage at presentation of dural arteriovenous fistula, but its association with subsequent intracranial hemorrhage is less clear. Short-term complications of dural arteriovenous fistula treatment affect 2-3% of patients in published reports. PMID- 25042992 TI - Survey of UK sonographers on the prevention of work related muscular-skeletal disorder (WRMSD). AB - BACKGROUND: To establish whether the current training of student sonographers in both academic and clinical settings is sufficient for educating about the dangers of work-related musculoskeletal disorders (WRMSDs). METHODS: A dual method of data collection was undertaken. Initially, a focus group was set up, involving a small group of practicing sonographers from a hospital in the United Kingdom, with the results of that survey being used to design a postal survey questionnaire. The questionnaire focused on ergonomics, scanning technique, training in physical techniques, personal general health, risk, stress, and task management. It was sent to seven participating universities across the United Kingdom. Approvals were obtained from the local ethics committees, the hospital Trust, and the academic institution. RESULTS: The focus group highlighted several areas in which improvements could be made in educating sonographers on the reduction of WRMSDs. The questionnaire results indicated that students are being taught about certain aspects of WRMSD prevention by both their university and clinical mentors. Respondents received training on the prevention of WRMSDs: 97% in the university setting and 81% from clinical mentors. CONCLUSIONS: Improvements need to be made in terms of educating students to perform muscle strengthening exercises during the workday; to have a system of reporting injury; to consider personal health, well-being, and stress management in the workplace; and to evaluate the ergonomics of computer workstations. PMID- 25042993 TI - Effect of stochastic resonance whole body vibration on functional performance in the frail elderly: A pilot study. AB - The aim of this pilot study was to evaluate the feasibility and the effect size of a four-week stochastic resonance whole body vibration (SR-WBV) intervention on functional performance and strength in frail elderly individuals. Twenty-seven participants have been recruited and randomly distributed in an intervention group (IG) and a sham group (SG). Primary outcomes were feasibility objectives like recruitment, compliance and safety. Secondary outcomes were short physical performance battery (SPPB), isometric maximum voluntary contraction (IMVC) and isometric rate of force development (IRFD). The intervention was feasible and safe. Furthermore it showed significant effects (p=0.035) and medium effect size (0.43) within the IG in SPPB. SR-WBV training over four weeks with frail elderly individuals is a safe intervention method. The compliance was good and SR-WBV intervention seems to improve functional performance. Further research over a longer time frame for the strength measurements (IMVC and IRFD) is needed to detect potential intervention effects in the force measurements as well. Clinical Trial register: NTC01704976. PMID- 25042994 TI - The prediction of disability by self-reported physical frailty components of the Tilburg Frailty Indicator (TFI). AB - Disability is an important health outcome for older persons; it is associated with impaired quality of life, future hospitalization, and mortality. Disability also places a high burden on health care professionals and health care systems. Disability is regarded as an adverse outcome of physical frailty. The main objective of this study was to assess the predictive validity of the eight individual self-reported components of the physical frailty subscale of the TFI for activities of daily living (ADL) and instrumental activities of daily living (IADL) disability. This longitudinal study was carried out with a sample of Dutch citizens. At baseline the sample consisted at 429 people aged 65 years and older and a subset of all respondents participated again two and a half years later (N=355, 83% response rate). The respondents completed a web-based questionnaire comprising the TFI and the Groningen Activity Restriction Scale (GARS) for measuring disability. Five components together (unintentional weakness, weakness, poor endurance, slowness, low physical activity), referring to the phenotype of Fried et al., predicted disability, even after controlling for previous disability and other background characteristics. The other three components of the physical frailty subscale of the TFI (poor balance, poor hearing, poor vision) together did not predict disability. Low physical activity predicted both total and ADL disability, and slowness both total and IADL disability. In conclusion, self-report assessment using the physical subscale of the TFI aids the prediction of future ADL and IADL disability in older persons two and a half years later. PMID- 25042995 TI - Effects of combined therapy with glipizide and Aralia root bark extract on glycemic control and lipid profiles in patients with type 2 diabetes mellitus. AB - BACKGROUND: The root bark of Aralia is a rich source of bioactive components that may improve glycemic control and lipid status. In this study, 148 patients with type 2 diabetes mellitus (T2DM) were assigned randomly to receive either glipizide alone or glipizide plus Aralia root bark extract (ARBE) for 8 weeks to test the effects of ARBE plus glipizide therapy on glycemic control and lipid profiles in these patients. RESULTS: Levels of HbA1c, fasting plasma glucose (FPG) and 2 h postprandial plasma glucose (2-h PPG) in both groups significantly decreased from baseline. Glycated hemoglobin (HbA1c) decreased marginally significantly in participants taking glipizide plus ARBE compared with the glipizide group (P = 0.06). Participants in the combination group had significant decreases in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL C), and the between-group difference achieved statistical significance for LDL-C (P = 0.04). Reduction in HbA1c in the combination group was significantly associated with changes in TC (r = 0.32; P = 0.006) and LDL-C (r = 0.34; P = 0.005), and the change in FPG was inversely correlated with LDL-C reduction (r = 0.34; P = 0.004). CONCLUSIONS: In patients with T2DM, combination therapy with glipizide and ARBE resulted in moderately lowering HbA1c and LDL-C levels compared with glipizide alone. PMID- 25042996 TI - Graphical assessment of incremental value of novel markers in prediction models: From statistical to decision analytical perspectives. AB - New markers may improve prediction of diagnostic and prognostic outcomes. We aimed to review options for graphical display and summary measures to assess the predictive value of markers over standard, readily available predictors. We illustrated various approaches using previously published data on 3264 participants from the Framingham Heart Study, where 183 developed coronary heart disease (10-year risk 5.6%). We considered performance measures for the incremental value of adding HDL cholesterol to a prediction model. An initial assessment may consider statistical significance (HR = 0.65, 95% confidence interval 0.53 to 0.80; likelihood ratio p < 0.001), and distributions of predicted risks (densities or box plots) with various summary measures. A range of decision thresholds is considered in predictiveness and receiver operating characteristic curves, where the area under the curve (AUC) increased from 0.762 to 0.774 by adding HDL. We can furthermore focus on reclassification of participants with and without an event in a reclassification graph, with the continuous net reclassification improvement (NRI) as a summary measure. When we focus on one particular decision threshold, the changes in sensitivity and specificity are central. We propose a net reclassification risk graph, which allows us to focus on the number of reclassified persons and their event rates. Summary measures include the binary AUC, the two-category NRI, and decision analytic variants such as the net benefit (NB). Various graphs and summary measures can be used to assess the incremental predictive value of a marker. Important insights for impact on decision making are provided by a simple graph for the net reclassification risk. PMID- 25042997 TI - Predictive validity of the structured assessment of violence risk in youth: A 4 year follow-up. AB - BACKGROUND: Structured violence risk assessment is an essential part of treatment planning for violent young people. The Structured Assessment of Violence Risk in Youth (SAVRY) has been shown to have good reliability and validity in a range of settings but has hardly been studied in adolescent mental health services. AIMS: This study aimed to evaluate the long-term predictive validity of the SAVRY in adolescent psychiatry settings. METHODS: In a prospective study, 200 SAVRY assessments of adolescents were acquired from psychiatric, forensic and correctional settings. Re-offending records from the Finnish National Crime Register were collected. Receiver operating curve statistics were applied. RESULTS: High SAVRY total and individual subscale scores and low values on the protective factor subscale were significantly associated with subsequent adverse outcomes, but the predictive value of the total score was weak. At the risk item level, those indicating antisocial lifestyle, absence of social support and pro social involvement were strong indicators of subsequent criminal convictions, with or without violence. The SAVRY summary risk rating was the best indicator of likelihood of being convicted of a violent crime. After allowing for sex, age, psychiatric diagnosis and treatment setting, for example, conviction for a violent crime was over nine times more likely among those young people given high SAVRY summary risk ratings. CONCLUSIONS: The SAVRY is a valid and useful method for assessing both short-term and long-term risks of violent and non-violent crime by young people in psychiatric as well as criminal justice settings, adding to a traditional risk-centred assessment approach by also indicating where future preventive treatment efforts should be targeted. The next steps should be to evaluate its role in everyday clinical practice when using the knowledge generated to inform and monitor management and treatment strategies. PMID- 25042998 TI - Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. AB - Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small molecule drugs for the treatment of brain disorders. PMID- 25042999 TI - Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. AB - The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies. PMID- 25043000 TI - Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. AB - Rheumatoid arthritis is a chronic autoinflammatory disease that affects 1-2% of the world's population and is characterized by widespread joint inflammation. Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to production of interleukin-1beta in rheumatoid arthritis is limited by the absence of suitable mouse models of the disease in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients. Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2). Here we show, however, that it crucially relies on the Nlrp3 inflammasome and interleukin-1 receptor signalling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1beta. As a result, A20-deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and interleukin-1beta secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, because deletion of Nlrp3, caspase-1 and the interleukin-1 receptor markedly protects against rheumatoid-arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis. PMID- 25043001 TI - The Get1/2 transmembrane complex is an endoplasmic-reticulum membrane protein insertase. AB - Hundreds of tail-anchored proteins, including soluble N-ethylmaleimide-sensitive factor attachment receptors (SNAREs) involved in vesicle fusion, are inserted post-translationally into the endoplasmic reticulum membrane by a dedicated protein-targeting pathway. Before insertion, the carboxy-terminal transmembrane domains of tail-anchored proteins are shielded in the cytosol by the conserved targeting factor Get3 (in yeast; TRC40 in mammals). The Get3 endoplasmic reticulum receptor comprises the cytosolic domains of the Get1/2 (WRB/CAML) transmembrane complex, which interact individually with the targeting factor to drive a conformational change that enables substrate release and, as a consequence, insertion. Because tail-anchored protein insertion is not associated with significant translocation of hydrophilic protein sequences across the membrane, it remains possible that Get1/2 cytosolic domains are sufficient to place Get3 in proximity with the endoplasmic-reticulum lipid bilayer and permit spontaneous insertion to occur. Here we use cell reporters and biochemical reconstitution to define mutations in the Get1/2 transmembrane domain that disrupt tail-anchored protein insertion without interfering with Get1/2 cytosolic domain function. These mutations reveal a novel Get1/2 insertase function, in the absence of which substrates stay bound to Get3 despite their proximity to the lipid bilayer; as a consequence, the notion of spontaneous transmembrane domain insertion is a non sequitur. Instead, the Get1/2 transmembrane domain helps to release substrates from Get3 by capturing their transmembrane domains, and these transmembrane interactions define a bona fide pre-integrated intermediate along a facilitated route for tail-anchor entry into the lipid bilayer. Our work sheds light on the fundamental point of convergence between co-translational and post translational endoplasmic-reticulum membrane protein targeting and insertion: a mechanism for reducing the ability of a targeting factor to shield its substrates enables substrate handover to a transmembrane-domain-docking site embedded in the endoplasmic-reticulum membrane. PMID- 25043002 TI - Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations. AB - The great therapeutic achievements of antibiotics have been dramatically undercut by the evolution of bacterial strategies that overcome antibiotic stress. These strategies fall into two classes. 'Resistance' makes it possible for a microorganism to grow in the constant presence of the antibiotic, provided that the concentration of the antibiotic is not too high. 'Tolerance' allows a microorganism to survive antibiotic treatment, even at high antibiotic concentrations, as long as the duration of the treatment is limited. Although both resistance and tolerance are important reasons for the failure of antibiotic treatments, the evolution of resistance is much better understood than that of tolerance. Here we followed the evolution of bacterial populations under intermittent exposure to the high concentrations of antibiotics used in the clinic and characterized the evolved strains in terms of both resistance and tolerance. We found that all strains adapted by specific genetic mutations, which became fixed in the evolved populations. By monitoring the phenotypic changes at the population and single-cell levels, we found that the first adaptive change to antibiotic stress was the development of tolerance through a major adjustment in the single-cell lag-time distribution, without a change in resistance. Strikingly, we found that the lag time of bacteria before regrowth was optimized to match the duration of the antibiotic-exposure interval. Whole genome sequencing of the evolved strains and restoration of the wild-type alleles allowed us to identify target genes involved in this antibiotic-driven phenotype: 'tolerance by lag' (tbl). Better understanding of lag-time evolution as a key determinant of the survival of bacterial populations under high antibiotic concentrations could lead to new approaches to impeding the evolution of antibiotic resistance. PMID- 25043003 TI - Genome sequencing of normal cells reveals developmental lineages and mutational processes. AB - The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree, the number of divisions that each cell has undergone and the mutational processes that have been operative. Here we describe whole genomes of clonal lines derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible. PMID- 25043004 TI - Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia. AB - Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to gamma-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL. PMID- 25043008 TI - Velocity anti-correlation of diametrically opposed galaxy satellites in the low redshift Universe. AB - Recent work has shown that the Milky Way and the Andromeda galaxies both possess the unexpected property that their dwarf satellite galaxies are aligned in thin and kinematically coherent planar structures. It is interesting to evaluate the incidence of such planar structures in the larger galactic population, because the Local Group may not be a representative environment. Here we report measurements of the velocities of pairs of diametrically opposed satellite galaxies. In the local Universe (redshift z < 0.05), we find that satellite pairs out to a distance of 150 kiloparsecs from the galactic centre are preferentially anti-correlated in their velocities (99.994 per cent confidence level), and that the distribution of galaxies in the larger-scale environment (out to distances of about 2 megaparsecs) is strongly clumped along the axis joining the inner satellite pair (>7sigma confidence). This may indicate that planes of co-rotating satellites, similar to those seen around the Andromeda galaxy, are ubiquitous, and their coherent motion suggests that they represent a substantial repository of angular momentum on scales of about 100 kiloparsecs. PMID- 25043007 TI - Tracking photon jumps with repeated quantum non-demolition parity measurements. AB - Quantum error correction is required for a practical quantum computer because of the fragile nature of quantum information. In quantum error correction, information is redundantly stored in a large quantum state space and one or more observables must be monitored to reveal the occurrence of an error, without disturbing the information encoded in an unknown quantum state. Such observables, typically multi-quantum-bit parities, must correspond to a special symmetry property inherent in the encoding scheme. Measurements of these observables, or error syndromes, must also be performed in a quantum non-demolition way (projecting without further perturbing the state) and more quickly than errors occur. Previously, quantum non-demolition measurements of quantum jumps between states of well-defined energy have been performed in systems such as trapped ions, electrons, cavity quantum electrodynamics, nitrogen-vacancy centres and superconducting quantum bits. So far, however, no fast and repeated monitoring of an error syndrome has been achieved. Here we track the quantum jumps of a possible error syndrome, namely the photon number parity of a microwave cavity, by mapping this property onto an ancilla quantum bit, whose only role is to facilitate quantum state manipulation and measurement. This quantity is just the error syndrome required in a recently proposed scheme for a hardware-efficient protected quantum memory using Schrodinger cat states (quantum superpositions of different coherent states of light) in a harmonic oscillator. We demonstrate the projective nature of this measurement onto a region of state space with well defined parity by observing the collapse of a coherent state onto even or odd cat states. The measurement is fast compared with the cavity lifetime, has a high single-shot fidelity and has a 99.8 per cent probability per single measurement of leaving the parity unchanged. In combination with the deterministic encoding of quantum information in cat states realized earlier, the quantum non-demolition parity tracking that we demonstrate represents an important step towards implementing an active system that extends the lifetime of a quantum bit. PMID- 25043005 TI - Serial time-resolved crystallography of photosystem II using a femtosecond X-ray laser. AB - Photosynthesis, a process catalysed by plants, algae and cyanobacteria converts sunlight to energy thus sustaining all higher life on Earth. Two large membrane protein complexes, photosystem I and II (PSI and PSII), act in series to catalyse the light-driven reactions in photosynthesis. PSII catalyses the light-driven water splitting process, which maintains the Earth's oxygenic atmosphere. In this process, the oxygen-evolving complex (OEC) of PSII cycles through five states, S0 to S4, in which four electrons are sequentially extracted from the OEC in four light-driven charge-separation events. Here we describe time resolved experiments on PSII nano/microcrystals from Thermosynechococcus elongatus performed with the recently developed technique of serial femtosecond crystallography. Structures have been determined from PSII in the dark S1 state and after double laser excitation (putative S3 state) at 5 and 5.5 A resolution, respectively. The results provide evidence that PSII undergoes significant conformational changes at the electron acceptor side and at the Mn4CaO5 core of the OEC. These include an elongation of the metal cluster, accompanied by changes in the protein environment, which could allow for binding of the second substrate water molecule between the more distant protruding Mn (referred to as the 'dangler' Mn) and the Mn3CaOx cubane in the S2 to S3 transition, as predicted by spectroscopic and computational studies. This work shows the great potential for time-resolved serial femtosecond crystallography for investigation of catalytic processes in biomolecules. PMID- 25043006 TI - Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. AB - Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-alpha2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-alpha2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution. PMID- 25043009 TI - Malaria: Protein-export pathway illuminated. PMID- 25043010 TI - PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes. AB - To mediate its survival and virulence, the malaria parasite Plasmodium falciparum exports hundreds of proteins into the host erythrocyte. To enter the host cell, exported proteins must cross the parasitophorous vacuolar membrane (PVM) within which the parasite resides, but the mechanism remains unclear. A putative Plasmodium translocon of exported proteins (PTEX) has been suggested to be involved for at least one class of exported proteins; however, direct functional evidence for this has been elusive. Here we show that export across the PVM requires heat shock protein 101 (HSP101), a ClpB-like AAA+ ATPase component of PTEX. Using a chaperone auto-inhibition strategy, we achieved rapid, reversible ablation of HSP101 function, resulting in a nearly complete block in export with substrates accumulating in the vacuole in both asexual and sexual parasites. Surprisingly, this block extended to all classes of exported proteins, revealing HSP101-dependent translocation across the PVM as a convergent step in the multi pathway export process. Under export-blocked conditions, association between HSP101 and other components of the PTEX complex was lost, indicating that the integrity of the complex is required for efficient protein export. Our results demonstrate an essential and universal role for HSP101 in protein export and provide strong evidence for PTEX function in protein translocation into the host cell. PMID- 25043011 TI - Crystal structure of the human COP9 signalosome. AB - Ubiquitination is a crucial cellular signalling process, and is controlled on multiple levels. Cullin-RING E3 ubiquitin ligases (CRLs) are regulated by the eight-subunit COP9 signalosome (CSN). CSN inactivates CRLs by removing their covalently attached activator, NEDD8. NEDD8 cleavage by CSN is catalysed by CSN5, a Zn(2+)-dependent isopeptidase that is inactive in isolation. Here we present the crystal structure of the entire ~350-kDa human CSN holoenzyme at 3.8 A resolution, detailing the molecular architecture of the complex. CSN has two organizational centres: a horseshoe-shaped ring created by its six proteasome lid CSN-initiation factor 3 (PCI) domain proteins, and a large bundle formed by the carboxy-terminal alpha-helices of every subunit. CSN5 and its dimerization partner, CSN6, are intricately embedded at the core of the helical bundle. In the substrate-free holoenzyme, CSN5 is autoinhibited, which precludes access to the active site. We find that neddylated CRL binding to CSN is sensed by CSN4, and communicated to CSN5 with the assistance of CSN6, resulting in activation of the deneddylase. PMID- 25043013 TI - Gene regulation: fine-tuned amplification in cells. PMID- 25043012 TI - Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. AB - In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins. PMID- 25043014 TI - A shift of thermokarst lakes from carbon sources to sinks during the Holocene epoch. AB - Thermokarst lakes formed across vast regions of Siberia and Alaska during the last deglaciation and are thought to be a net source of atmospheric methane and carbon dioxide during the Holocene epoch. However, the same thermokarst lakes can also sequester carbon, and it remains uncertain whether carbon uptake by thermokarst lakes can offset their greenhouse gas emissions. Here we use field observations of Siberian permafrost exposures, radiocarbon dating and spatial analyses to quantify Holocene carbon stocks and fluxes in lake sediments overlying thawed Pleistocene-aged permafrost. We find that carbon accumulation in deep thermokarst-lake sediments since the last deglaciation is about 1.6 times larger than the mass of Pleistocene-aged permafrost carbon released as greenhouse gases when the lakes first formed. Although methane and carbon dioxide emissions following thaw lead to immediate radiative warming, carbon uptake in peat-rich sediments occurs over millennial timescales. We assess thermokarst-lake carbon feedbacks to climate with an atmospheric perturbation model and find that thermokarst basins switched from a net radiative warming to a net cooling climate effect about 5,000 years ago. High rates of Holocene carbon accumulation in 20 lake sediments (47 +/- 10 grams of carbon per square metre per year; mean +/- standard error) were driven by thermokarst erosion and deposition of terrestrial organic matter, by nutrient release from thawing permafrost that stimulated lake productivity and by slow decomposition in cold, anoxic lake bottoms. When lakes eventually drained, permafrost formation rapidly sequestered sediment carbon. Our estimate of about 160 petagrams of Holocene organic carbon in deep lake basins of Siberia and Alaska increases the circumpolar peat carbon pool estimate for permafrost regions by over 50 per cent (ref. 6). The carbon in perennially frozen drained lake sediments may become vulnerable to mineralization as permafrost disappears, potentially negating the climate stabilization provided by thermokarst lakes during the late Holocene. PMID- 25043015 TI - The evolution of the placenta drives a shift in sexual selection in livebearing fish. AB - The evolution of the placenta from a non-placental ancestor causes a shift of maternal investment from pre- to post-fertilization, creating a venue for parent offspring conflicts during pregnancy. Theory predicts that the rise of these conflicts should drive a shift from a reliance on pre-copulatory female mate choice to polyandry in conjunction with post-zygotic mechanisms of sexual selection. This hypothesis has not yet been empirically tested. Here we apply comparative methods to test a key prediction of this hypothesis, which is that the evolution of placentation is associated with reduced pre-copulatory female mate choice. We exploit a unique quality of the livebearing fish family Poeciliidae: placentas have repeatedly evolved or been lost, creating diversity among closely related lineages in the presence or absence of placentation. We show that post-zygotic maternal provisioning by means of a placenta is associated with the absence of bright coloration, courtship behaviour and exaggerated ornamental display traits in males. Furthermore, we found that males of placental species have smaller bodies and longer genitalia, which facilitate sneak or coercive mating and, hence, circumvents female choice. Moreover, we demonstrate that post-zygotic maternal provisioning correlates with superfetation, a female reproductive adaptation that may result in polyandry through the formation of temporally overlapping, mixed-paternity litters. Our results suggest that the emergence of prenatal conflict during the evolution of the placenta correlates with a suite of phenotypic and behavioural male traits that is associated with a reduced reliance on pre-copulatory female mate choice. PMID- 25043016 TI - Processing properties of ON and OFF pathways for Drosophila motion detection. AB - The algorithms and neural circuits that process spatio-temporal changes in luminance to extract visual motion cues have been the focus of intense research. An influential model, the Hassenstein-Reichardt correlator, relies on differential temporal filtering of two spatially separated input channels, delaying one input signal with respect to the other. Motion in a particular direction causes these delayed and non-delayed luminance signals to arrive simultaneously at a subsequent processing step in the brain; these signals are then nonlinearly amplified to produce a direction-selective response. Recent work in Drosophila has identified two parallel pathways that selectively respond to either moving light or dark edges. Each of these pathways requires two critical processing steps to be applied to incoming signals: differential delay between the spatial input channels, and distinct processing of brightness increment and decrement signals. Here we demonstrate, using in vivo patch-clamp recordings, that four medulla neurons implement these two processing steps. The neurons Mi1 and Tm3 respond selectively to brightness increments, with the response of Mi1 delayed relative to Tm3. Conversely, Tm1 and Tm2 respond selectively to brightness decrements, with the response of Tm1 delayed compared with Tm2. Remarkably, constraining Hassenstein-Reichardt correlator models using these measurements produces outputs consistent with previously measured properties of motion detectors, including temporal frequency tuning and specificity for light versus dark edges. We propose that Mi1 and Tm3 perform critical processing of the delayed and non-delayed input channels of the correlator responsible for the detection of light edges, while Tm1 and Tm2 play analogous roles in the detection of moving dark edges. Our data show that specific medulla neurons possess response properties that allow them to implement the algorithmic steps that precede the correlative operation in the Hassenstein-Reichardt correlator, revealing elements of the long-sought neural substrates of motion detection in the fly. PMID- 25043017 TI - Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow microenvironment might contribute to the clinical outcomes of this common event. We previously showed that bone marrow nestin(+) mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin(+) MSCs are consistently reduced in the bone marrow of MPN patients and mice expressing the human JAK2(V617F) mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by bone marrow neural damage and Schwann cell death triggered by interleukin-1beta produced by mutant HSCs. In turn, in vivo depletion of nestin(+) cells or their production of CXCL12 expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with beta3-adrenergic agonists that restored the sympathetic regulation of nestin(+) MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukaemic stem cells. Our results demonstrate that mutant-HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets. PMID- 25043018 TI - Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. AB - In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response. PMID- 25043019 TI - Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway. AB - Programmed -1 ribosomal frameshift (-1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a -1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA-miRNA interaction suggests that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional -1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells. PMID- 25043020 TI - Topoisomerase II mediates meiotic crossover interference. AB - Spatial patterning is a ubiquitous feature of biological systems. Meiotic crossovers provide an interesting example, defined by the classic phenomenon of crossover interference. Here we identify a molecular pathway for interference by analysing crossover patterns in budding yeast. Topoisomerase II plays a central role, thus identifying a new function for this critical molecule. SUMOylation (of topoisomerase II and axis component Red1) and ubiquitin-mediated removal of SUMOylated proteins are also required. The findings support the hypothesis that crossover interference involves accumulation, relief and redistribution of mechanical stress along the protein/DNA meshwork of meiotic chromosome axes, with topoisomerase II required to adjust spatial relationships among DNA segments. PMID- 25043021 TI - DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth. AB - During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5' end to the first AUG start codon with favourable sequence context. For many mRNAs this AUG belongs to a short upstream open reading frame (uORF), and translation of the main downstream ORF requires re-initiation, an incompletely understood process. Re-initiation is thought to involve the same factors as standard initiation. It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR-MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth. PMID- 25043022 TI - A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. AB - The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (beta = 3.8 mmol l(-1), P = 2.5 * 10( 35)) and serum insulin (beta = 165 pmol l(-1), P = 1.5 * 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (beta = -0.18 mmol l( 1), P = 1.1 * 10(-6)) and fasting serum insulin (beta = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 * 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (beta = 0.43 mmol l(-1), P = 5.3 * 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations. PMID- 25043023 TI - Carbonic anhydrases, EPF2 and a novel protease mediate CO2 control of stomatal development. AB - Environmental stimuli, including elevated carbon dioxide levels, regulate stomatal development; however, the key mechanisms mediating the perception and relay of the CO2 signal to the stomatal development machinery remain elusive. To adapt CO2 intake to water loss, plants regulate the development of stomatal gas exchange pores in the aerial epidermis. A diverse range of plant species show a decrease in stomatal density in response to the continuing rise in atmospheric CO2 (ref. 4). To date, one mutant that exhibits deregulation of this CO2 controlled stomatal development response, hic (which is defective in cell-wall wax biosynthesis, ref. 5), has been identified. Here we show that recently isolated Arabidopsis thaliana beta-carbonic anhydrase double mutants (ca1 ca4) exhibit an inversion in their response to elevated CO2, showing increased stomatal development at elevated CO2 levels. We characterized the mechanisms mediating this response and identified an extracellular signalling pathway involved in the regulation of CO2-controlled stomatal development by carbonic anhydrases. RNA-seq analyses of transcripts show that the extracellular pro peptide-encoding gene EPIDERMAL PATTERNING FACTOR 2 (EPF2), but not EPF1 (ref. 9), is induced in wild-type leaves but not in ca1 ca4 mutant leaves at elevated CO2 levels. Moreover, EPF2 is essential for CO2 control of stomatal development. Using cell-wall proteomic analyses and CO2-dependent transcriptomic analyses, we identified a novel CO2-induced extracellular protease, CRSP (CO2 RESPONSE SECRETED PROTEASE), as a mediator of CO2-controlled stomatal development. Our results identify mechanisms and genes that function in the repression of stomatal development in leaves during atmospheric CO2 elevation, including the carbonic anhydrase-encoding genes CA1 and CA4 and the secreted protease CRSP, which cleaves the pro-peptide EPF2, in turn repressing stomatal development. Elucidation of these mechanisms advances the understanding of how plants perceive and relay the elevated CO2 signal and provides a framework to guide future research into how environmental challenges can modulate gas exchange in plants. PMID- 25043024 TI - Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. AB - Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1alpha (HIF1alpha). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth. PMID- 25043025 TI - Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. AB - Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state. PMID- 25043026 TI - Visualization of arrestin recruitment by a G-protein-coupled receptor. AB - G-protein-coupled receptors (GPCRs) are critically regulated by beta-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the beta2 adrenergic receptor (beta2AR)-G-protein complex, has provided novel insights into the structural basis of receptor activation. However, complementary information has been lacking on the recruitment of beta arrestins to activated GPCRs, primarily owing to challenges in obtaining stable receptor-beta-arrestin complexes for structural studies. Here we devised a strategy for forming and purifying a functional human beta2AR-beta-arrestin-1 complex that allowed us to visualize its architecture by single-particle negative stain electron microscopy and to characterize the interactions between beta2AR and beta-arrestin 1 using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and chemical crosslinking. Electron microscopy two-dimensional averages and three dimensional reconstructions reveal bimodal binding of beta-arrestin 1 to the beta2AR, involving two separate sets of interactions, one with the phosphorylated carboxy terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of crosslinked residues suggest engagement of the finger loop of beta-arrestin 1 with the seven-transmembrane core of the receptor. In contrast, focal areas of raised HDX levels indicate regions of increased dynamics in both the N and C domains of beta-arrestin 1 when coupled to the beta2AR. A molecular model of the beta2AR-beta-arrestin signalling complex was made by docking activated beta-arrestin 1 and beta2AR crystal structures into the electron microscopy map densities with constraints provided by HDX-MS and crosslinking, allowing us to obtain valuable insights into the overall architecture of a receptor-arrestin complex. The dynamic and structural information presented here provides a framework for better understanding the basis of GPCR regulation by arrestins. PMID- 25043027 TI - The alarmin IL-33 promotes regulatory T-cell function in the intestine. AB - FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF) beta1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses. PMID- 25043028 TI - Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. AB - The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci. Recent work suggested that rather than up- and downregulating selected groups of genes, Myc targets all active promoters and enhancers in the genome (a phenomenon termed 'invasion') and acts as a general amplifier of transcription. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during B-cell lymphomagenesis in mice, in cultured B cells and fibroblasts. Consistent with long-standing observations, we detected general increases in total RNA or messenger RNA copies per cell (hereby termed 'amplification') when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, although having the potential to interact with all active or poised regulatory elements in the genome, Myc does not directly act as a global transcriptional amplifier. Instead, our results indicate that Myc activates and represses transcription of discrete gene sets, leading to changes in cellular state that can in turn feed back on global RNA production and turnover. PMID- 25043029 TI - Molecular architecture and mechanism of the anaphase-promoting complex. AB - The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of the G1 phase of the cell cycle. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C-substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-electron microscopy reconstruction of a human APC/C-coactivator-substrate complex at 7.4 A resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that the coactivator promotes a profound allosteric transition involving displacement of the cullin RING catalytic subunits relative to the degron-recognition module of coactivator and APC10. This transition is accompanied by increased flexibility of the cullin RING subunits and enhanced affinity for UBCH10-ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity. PMID- 25043030 TI - Fructose-1,6-bisphosphatase opposes renal carcinoma progression. AB - Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1 associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6 bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours. PMID- 25043031 TI - Coordinated regulation of protein synthesis and degradation by mTORC1. AB - Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis. PMID- 25043032 TI - Brain structure resolves the segmental affinity of anomalocaridid appendages. AB - Despite being among the most celebrated taxa from Cambrian biotas, anomalocaridids (order Radiodonta) have provoked intense debate about their affinities within the moulting-animal clade that includes Arthropoda. Current alternatives identify anomalocaridids as either stem-group euarthropods, crown group euarthropods near the ancestry of chelicerates, or a segmented ecdysozoan lineage with convergent similarity to arthropods in appendage construction. Determining unambiguous affinities has been impeded by uncertainties about the segmental affiliation of anomalocaridid frontal appendages. These structures are variably homologized with jointed appendages of the second (deutocerebral) head segment, including antennae and 'great appendages' of Cambrian arthropods, or with the paired antenniform frontal appendages of living Onychophora and some Cambrian lobopodians. Here we describe Lyrarapax unguispinus, a new anomalocaridid from the early Cambrian Chengjiang biota, southwest China, nearly complete specimens of which preserve traces of muscles, digestive tract and brain. The traces of brain provide the first direct evidence for the segmental composition of the anomalocaridid head and its appendicular organization. Carbon rich areas in the head resolve paired pre-protocerebral ganglia at the origin of paired frontal appendages. The ganglia connect to areas indicative of a bilateral pre-oral brain that receives projections from the eyestalk neuropils and compound retina. The dorsal, segmented brain of L. unguispinus reinforces an alliance between anomalocaridids and arthropods rather than cycloneuralians. Correspondences in brain organization between anomalocaridids and Onychophora resolve pre-protocerebral ganglia, associated with pre-ocular frontal appendages, as characters of the last common ancestor of euarthropods and onychophorans. A position of Radiodonta on the euarthropod stem-lineage implies the transformation of frontal appendages to another structure in crown-group euarthropods, with gene expression and neuroanatomy providing strong evidence that the paired, pre-oral labrum is the remnant of paired frontal appendages. PMID- 25043033 TI - Visualizing the kinetic power stroke that drives proton-coupled zinc(II) transport. AB - The proton gradient is a principal energy source for respiration-dependent active transport, but the structural mechanisms of proton-coupled transport processes are poorly understood. YiiP is a proton-coupled zinc transporter found in the cytoplasmic membrane of Escherichia coli. Its transport site receives protons from water molecules that gain access to its hydrophobic environment and transduces the energy of an inward proton gradient to drive Zn(II) efflux. This membrane protein is a well-characterized member of the family of cation diffusion facilitators that occurs at all phylogenetic levels. Here we show, using X-ray mediated hydroxyl radical labelling of YiiP and mass spectrometry, that Zn(II) binding triggers a highly localized, all-or-nothing change of water accessibility to the transport site and an adjacent hydrophobic gate. Millisecond time-resolved dynamics reveal a concerted and reciprocal pattern of accessibility changes along a transmembrane helix, suggesting a rigid-body helical re-orientation linked to Zn(II) binding that triggers the closing of the hydrophobic gate. The gated water access to the transport site enables a stationary proton gradient to facilitate the conversion of zinc-binding energy to the kinetic power stroke of a vectorial zinc transport. The kinetic details provide energetic insights into a proton coupled active-transport reaction. PMID- 25043034 TI - Structural biology: Corralling a protein-degradation regulator. PMID- 25043035 TI - Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. AB - As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments. PMID- 25043036 TI - Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA. AB - Imitation switch (ISWI)-family remodelling enzymes regulate access to genomic DNA by mobilizing nucleosomes. These ATP-dependent chromatin remodellers promote heterochromatin formation and transcriptional silencing by generating regularly spaced nucleosome arrays. The nucleosome-spacing activity arises from the dependence of nucleosome translocation on the length of extranucleosomal linker DNA, but the underlying mechanism remains unclear. Here we study nucleosome remodelling by human ATP-dependent chromatin assembly and remodelling factor (ACF), an ISWI enzyme comprising a catalytic subunit, Snf2h, and an accessory subunit, Acf1 (refs 2, 11 - 13). We find that ACF senses linker DNA length through an interplay between its accessory and catalytic subunits mediated by the histone H4 tail of the nucleosome. Mutation of AutoN, an auto-inhibitory domain within Snf2h that bears sequence homology to the H4 tail, abolishes the linker length sensitivity in remodelling. Addition of exogenous H4-tail peptide or deletion of the nucleosomal H4 tail also diminishes the linker-length sensitivity. Moreover, Acf1 binds both the H4-tail peptide and DNA in an amino (N)-terminal domain dependent manner, and in the ACF-bound nucleosome, lengthening the linker DNA reduces the Acf1-H4 tail proximity. Deletion of the N terminal portion of Acf1 (or its homologue in yeast) abolishes linker-length sensitivity in remodelling and leads to severe growth defects in vivo. Taken together, our results suggest a mechanism for nucleosome spacing where linker DNA sensing by Acf1 is allosterically transmitted to Snf2h through the H4 tail of the nucleosome. For nucleosomes with short linker DNA, Acf1 preferentially binds to the H4 tail, allowing AutoN to inhibit the ATPase activity of Snf2h. As the linker DNA lengthens, Acf1 shifts its binding preference to the linker DNA, freeing the H4 tail to compete AutoN off the ATPase and thereby activating ACF. PMID- 25043037 TI - Climate science: cold carbon storage. PMID- 25043038 TI - HIV: Early treatment may not be early enough. PMID- 25043039 TI - Three-dimensional structure of human gamma-secretase. AB - The gamma-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Aberrant cleavage of the amyloid precursor protein (APP) results in aggregation of amyloid-beta, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human gamma-secretase complex at 4.5 A resolution, determined by cryo-electron-microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) from nicastrin, which sits immediately above the hollow space formed by the TM horseshoe. Intriguingly, nicastrin ECD is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA. This structure serves as an important basis for understanding the functional mechanisms of the gamma-secretase complex. PMID- 25043040 TI - Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells. AB - Stable maintenance of gene regulatory programs is essential for normal function in multicellular organisms. Epigenetic mechanisms, and DNA methylation in particular, are hypothesized to facilitate such maintenance by creating cellular memory that can be written during embryonic development and then guide cell-type specific gene expression. Here we develop new methods for quantitative inference of DNA methylation turnover rates, and show that human embryonic stem cells preserve their epigenetic state by balancing antagonistic processes that add and remove methylation marks rather than by copying epigenetic information from mother to daughter cells. In contrast, somatic cells transmit considerable epigenetic information to progenies. Paradoxically, the persistence of the somatic epigenome makes it more vulnerable to noise, since random epimutations can accumulate to massively perturb the epigenomic ground state. The rate of epigenetic perturbation depends on the genomic context, and, in particular, DNA methylation loss is coupled to late DNA replication dynamics. Epigenetic perturbation is not observed in the pluripotent state, because the rapid turnover based equilibrium continuously reinforces the canonical state. This dynamic epigenetic equilibrium also explains how the epigenome can be reprogrammed quickly and to near perfection after induced pluripotency. PMID- 25043042 TI - Molecular basis of adaptation to high soil boron in wheat landraces and elite cultivars. AB - Environmental constraints severely restrict crop yields in most production environments, and expanding the use of variation will underpin future progress in breeding. In semi-arid environments boron toxicity constrains productivity, and genetic improvement is the only effective strategy for addressing the problem. Wheat breeders have sought and used available genetic diversity from landraces to maintain yield in these environments; however, the identity of the genes at the major tolerance loci was unknown. Here we describe the identification of near identical, root-specific boron transporter genes underlying the two major-effect quantitative trait loci for boron tolerance in wheat, Bo1 and Bo4 (ref. 2). We show that tolerance to a high concentration of boron is associated with multiple genomic changes including tetraploid introgression, dispersed gene duplication, and variation in gene structure and transcript level. An allelic series was identified from a panel of bread and durum wheat cultivars and landraces originating from diverse agronomic zones. Our results demonstrate that, during selection, breeders have matched functionally different boron tolerance alleles to specific environments. The characterization of boron tolerance in wheat illustrates the power of the new wheat genomic resources to define key adaptive processes that have underpinned crop improvement. PMID- 25043041 TI - Neuropsychosocial profiles of current and future adolescent alcohol misusers. AB - A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention. PMID- 25043043 TI - PTEX is an essential nexus for protein export in malaria parasites. AB - During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol. These proteins have a variety of roles that are essential to virulence or parasite growth. There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins. One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX). Although PTEX has been linked to the export of one class of exported proteins, there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) and PEXEL-negative exported proteins (PNEPs). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target. PMID- 25043044 TI - PVT1 dependence in cancer with MYC copy-number increase. AB - 'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target. PMID- 25043045 TI - Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer. AB - Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alpha-ketoglutarate (alphaKG) to 2 hydroxyglutarate (2HG), which inhibits the activity of multiple alphaKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4alpha, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4alpha silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH driven malignancy. PMID- 25043046 TI - Equalizing excitation-inhibition ratios across visual cortical neurons. AB - The relationship between synaptic excitation and inhibition (E/I ratio), two opposing forces in the mammalian cerebral cortex, affects many cortical functions such as feature selectivity and gain. Individual pyramidal cells show stable E/I ratios in time despite fluctuating cortical activity levels. This is because when excitation increases, inhibition increases proportionally through the increased recruitment of inhibitory neurons, a phenomenon referred to as excitation inhibition balance. However, little is known about the distribution of E/I ratios across pyramidal cells. Through their highly divergent axons, inhibitory neurons indiscriminately contact most neighbouring pyramidal cells. Is inhibition homogeneously distributed or is it individually matched to the different amounts of excitation received by distinct pyramidal cells? Here we discover that pyramidal cells in layer 2/3 of mouse primary visual cortex each receive inhibition in a similar proportion to their excitation. As a consequence, E/I ratios are equalized across pyramidal cells. This matched inhibition is mediated by parvalbumin-expressing but not somatostatin-expressing inhibitory cells and results from the independent adjustment of synapses originating from individual parvalbumin-expressing cells targeting different pyramidal cells. Furthermore, this match is activity-dependent as it is disrupted by perturbing pyramidal cell activity. Thus, the equalization of E/I ratios across pyramidal cells reveals an unexpected degree of order in the spatial distribution of synaptic strengths and indicates that the relationship between the cortex's two opposing forces is stabilized not only in time but also in space. PMID- 25043048 TI - A vaccine targeting mutant IDH1 induces antitumour immunity. AB - Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours. PMID- 25043049 TI - Jet acceleration of the fast molecular outflows in the Seyfert galaxy IC 5063. AB - Massive outflows driven by active galactic nuclei are widely recognized to have a key role in the evolution of galaxies, by heating the ambient gas, expelling it from the nuclear regions, and thereby affecting the star-formation histories of the galaxy bulges. It has been proposed that the powerful jets of relativistic particles (such as electrons) launched by some active nuclei can both accelerate and heat the molecular gas, which often dominates the mass budgets of the outflows. Clear evidence for this mechanism, in the form of detailed associations between the molecular gas kinematics and features in the radio-emitting jets, has however been lacking. Here we report that the warm molecular hydrogen gas in the western radio lobe of the Seyfert galaxy IC 5063 is moving at high velocities-up to about 600 kilometres per second-relative to the galaxy disk. This suggests that the molecules have been accelerated by fast shocks driven into the interstellar medium by the expanding radio jets. These results demonstrate the general feasibility of accelerating molecular outflows in fast shocks driven by active nuclei. PMID- 25043047 TI - Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. AB - Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer. PMID- 25043050 TI - Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins. AB - Aberrant regulation of RNA stability has an important role in many disease states. Deregulated post-transcriptional modulation, such as that governed by microRNAs targeting linear sequence elements in messenger RNAs, has been implicated in the progression of many cancer types. A defining feature of RNA is its ability to fold into structures. However, the roles of structural mRNA elements in cancer progression remain unexplored. Here we performed an unbiased search for post-transcriptional modulators of mRNA stability in breast cancer by conducting whole-genome transcript stability measurements in poorly and highly metastatic isogenic human breast cancer lines. Using a computational framework that searches RNA sequence and structure space, we discovered a family of GC-rich structural cis-regulatory RNA elements, termed sRSEs for structural RNA stability elements, which are significantly overrepresented in transcripts displaying reduced stability in highly metastatic cells. By integrating computational and biochemical approaches, we identified TARBP2, a double-stranded RNA-binding protein implicated in microRNA processing, as the trans factor that binds the sRSE family and similar structural elements--collectively termed TARBP2-binding structural elements (TBSEs)--in transcripts. TARBP2 is overexpressed in metastatic cells and metastatic human breast tumours and destabilizes transcripts containing TBSEs. Endogenous TARBP2 promotes metastatic cell invasion and colonization by destabilizing amyloid precursor protein (APP) and ZNF395 transcripts, two genes previously associated with Alzheimer's and Huntington's disease, respectively. We reveal these genes to be novel metastasis suppressor genes in breast cancer. The cleavage product of APP, extracellular amyloid-alpha peptide, directly suppresses invasion while ZNF395 transcriptionally represses a pro-metastatic gene expression program. The expression levels of TARBP2, APP and ZNF395 in human breast carcinomas support their experimentally uncovered roles in metastasis. Our findings establish a non-canonical and direct role for TARBP2 in mammalian gene expression regulation and reveal that regulated RNA destabilization through protein-mediated binding of mRNA structural elements can govern cancer progression. PMID- 25043051 TI - Viral tagging reveals discrete populations in Synechococcus viral genome sequence space. AB - Microbes and their viruses drive myriad processes across ecosystems ranging from oceans and soils to bioreactors and humans. Despite this importance, microbial diversity is only now being mapped at scales relevant to nature, while the viral diversity associated with any particular host remains little researched. Here we quantify host-associated viral diversity using viral-tagged metagenomics, which links viruses to specific host cells for high-throughput screening and sequencing. In a single experiment, we screened 10(7) Pacific Ocean viruses against a single strain of Synechococcus and found that naturally occurring cyanophage genome sequence space is statistically clustered into discrete populations. These population-based, host-linked viral ecological data suggest that, for this single host and seawater sample alone, there are at least 26 double-stranded DNA viral populations with estimated relative abundances ranging from 0.06 to 18.2%. These populations include previously cultivated cyanophage and new viral types missed by decades of isolate-based studies. Nucleotide identities of homologous genes mostly varied by less than 1% within populations, even in hypervariable genome regions, and by 42-71% between populations, which provides benchmarks for viral metagenomics and genome-based viral species definitions. Together these findings showcase a new approach to viral ecology that quantitatively links objectively defined environmental viral populations, and their genomes, to their hosts. PMID- 25043052 TI - Structure of an Rrp6-RNA exosome complex bound to poly(A) RNA. AB - The eukaryotic RNA exosome processes and degrades RNA by directing substrates to the distributive or processive 3' to 5' exoribonuclease activities of Rrp6 or Rrp44, respectively. The non-catalytic nine-subunit exosome core (Exo9) features a prominent central channel. Although RNA can pass through the channel to engage Rrp44, it is not clear how RNA is directed to Rrp6 or whether Rrp6 uses the central channel. Here we report a 3.3 A crystal structure of a ten-subunit RNA exosome complex from Saccharomyces cerevisiae composed of the Exo9 core and Rrp6 bound to single-stranded poly(A) RNA. The Rrp6 catalytic domain rests on top of the Exo9 S1/KH ring above the central channel, the RNA 3' end is anchored in the Rrp6 active site, and the remaining RNA traverses the S1/KH ring in an opposite orientation to that observed in a structure of a Rrp44-containing exosome complex. Solution studies with human and yeast RNA exosome complexes suggest that the RNA path to Rrp6 is conserved and dependent on the integrity of the S1/KH ring. Although path selection to Rrp6 or Rrp44 is stochastic in vitro, the fate of a particular RNA may be determined in vivo by the manner in which cofactors present RNA to the RNA exosome. PMID- 25043053 TI - Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. AB - Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival. PMID- 25043055 TI - miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. AB - Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-beta-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers. PMID- 25043056 TI - Convergence of terrestrial plant production across global climate gradients. AB - Variation in terrestrial net primary production (NPP) with climate is thought to originate from a direct influence of temperature and precipitation on plant metabolism. However, variation in NPP may also result from an indirect influence of climate by means of plant age, stand biomass, growing season length and local adaptation. To identify the relative importance of direct and indirect climate effects, we extend metabolic scaling theory to link hypothesized climate influences with NPP, and assess hypothesized relationships using a global compilation of ecosystem woody plant biomass and production data. Notably, age and biomass explained most of the variation in production whereas temperature and precipitation explained almost none, suggesting that climate indirectly (not directly) influences production. Furthermore, our theory shows that variation in NPP is characterized by a common scaling relationship, suggesting that global change models can incorporate the mechanisms governing this relationship to improve predictions of future ecosystem function. PMID- 25043054 TI - Proteogenomic characterization of human colon and rectal cancer. AB - Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology. PMID- 25043057 TI - The long-term maintenance of a resistance polymorphism through diffuse interactions. AB - Plant resistance (R) genes are a crucial component in plant defence against pathogens. Although R genes often fail to provide durable resistance in an agricultural context, they frequently persist as long-lived balanced polymorphisms in nature. Standard theory explains the maintenance of such polymorphisms through a balance of the costs and benefits of resistance and virulence in a tightly coevolving host-pathogen pair. However, many plant pathogen interactions lack such specificity. Whether, and how, balanced polymorphisms are maintained in diffusely interacting species is unknown. Here we identify a naturally interacting R gene and effector pair in Arabidopsis thaliana and its facultative plant pathogen, Pseudomonas syringae. The protein encoded by the R gene RPS5 recognizes an AvrPphB homologue (AvrPphB2) and exhibits a balanced polymorphism that has been maintained for over 2 million years (ref. 3). Consistent with the presence of an ancient balanced polymorphism, the R gene confers a benefit when plants are infected with P. syringae carrying avrPphB2 but also incurs a large cost in the absence of infection. RPS5 alleles are maintained at intermediate frequencies in populations globally, suggesting ubiquitous selection for resistance. However, the presence of P. syringae carrying avrPphB is probably insufficient to explain the RPS5 polymorphism. First, avrPphB homologues occur at very low frequencies in P. syringae populations on A. thaliana. Second, AvrPphB only rarely confers a virulence benefit to P. syringae on A. thaliana. Instead, we find evidence that selection for RPS5 involves multiple non-homologous effectors and multiple pathogen species. These results and an associated model suggest that the R gene polymorphism in A. thaliana may not be maintained through a tightly coupled interaction involving a single coevolved R gene and effector pair. More likely, the stable polymorphism is maintained through complex and diffuse community-wide interactions. PMID- 25043058 TI - Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. AB - Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes. PMID- 25043059 TI - High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. AB - Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK 875 at 2.3 A resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40-TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca(2+) influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive like state. PMID- 25043060 TI - HIV: The mixed blessing of interferon. PMID- 25043061 TI - Enhancer loops appear stable during development and are associated with paused polymerase. AB - Developmental enhancers initiate transcription and are fundamental to our understanding of developmental networks, evolution and disease. Despite their importance, the properties governing enhancer-promoter interactions and their dynamics during embryogenesis remain unclear. At the beta-globin locus, enhancer promoter interactions appear dynamic and cell-type specific, whereas at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed. The extent to which preformed enhancer-promoter conformations exist at other, more typical, loci and how transcription is eventually triggered is unclear. Here we generated a high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis, covering two developmental stages and tissue contexts, at unprecedented resolution. Although local regulatory interactions are common, long-range interactions are highly prevalent within the compact Drosophila genome. Each enhancer contacts multiple enhancers, and promoters with similar expression, suggesting a role in their co regulation. Notably, most interactions appear unchanged between tissue context and across development, arising before gene activation, and are frequently associated with paused RNA polymerase. Our results indicate that the general topology governing enhancer contacts is conserved from flies to humans and suggest that transcription initiates from preformed enhancer-promoter loops through release of paused polymerase. PMID- 25043063 TI - Targeting the relaxin hormonal pathway in prostate cancer. AB - Targeting the androgen signalling pathway has long been the hallmark of anti hormonal therapy for prostate cancer. However, development of androgen independent prostate cancer is an inevitable outcome to therapies targeting this pathway, in part, owing to the shift from cancer dependence on androgen signalling for growth in favor of augmentation of other cellular pathways that provide proliferation-, survival- and angiogenesis-promoting signals. This review focuses on the role of the hormone relaxin in the development and progression of prostate cancer, prior to and after the onset of androgen independence, as well as its role in cancers of other reproductive tissues. As the body of literature expands, examining relaxin expression in cancerous tissues and its role in a growing number of in vitro and in vivo cancer models, our understanding of the important involvement of this hormone in cancer biology is becoming clearer. Specifically, the pleiotropic functions of relaxin affecting cell growth, angiogenesis, blood flow, cell migration and extracellular matrix remodeling are examined in the context of cancer progression. The interactions and intercepts of the intracellular signalling pathways of relaxin with the androgen pathway are explored in the context of progression of castration-resistant and androgen independent prostate cancers. We provide an overview of current anti-hormonal therapeutic treatment options for prostate cancer and delve into therapeutic approaches and development of agents aimed at specifically antagonizing relaxin signalling to curb tumor growth. We also discuss the rationale and challenges utilizing such agents as novel anti-hormonals in the clinic, and their potential to supplement current therapeutic modalities. PMID- 25043062 TI - Exonuclease-mediated degradation of nascent RNA silences genes linked to severe malaria. AB - Antigenic variation of the Plasmodium falciparum multicopy var gene family enables parasite evasion of immune destruction by host antibodies. Expression of a particular var subgroup, termed upsA, is linked to the obstruction of blood vessels in the brain and to the pathogenesis of human cerebral malaria. The mechanism determining upsA activation remains unknown. Here we show that an entirely new type of gene silencing mechanism involving an exonuclease-mediated degradation of nascent RNA controls the silencing of genes linked to severe malaria. We identify a novel chromatin-associated exoribonuclease, termed PfRNase II, that controls the silencing of upsA var genes by marking their transcription start site and intron-promoter regions leading to short-lived cryptic RNA. Parasites carrying a deficient PfRNase II gene produce full-length upsA var transcripts and intron-derived antisense long non-coding RNA. The presence of stable upsA var transcripts overcomes monoallelic expression, resulting in the simultaneous expression of both upsA and upsC type PfEMP1 proteins on the surface of individual infected red blood cells. In addition, we observe an inverse relationship between transcript levels of PfRNase II and upsA-type var genes in parasites from severe malaria patients, implying a crucial role of PfRNase II in severe malaria. Our results uncover a previously unknown type of post transcriptional gene silencing mechanism in malaria parasites with repercussions for other organisms. Additionally, the identification of RNase II as a parasite protein controlling the expression of virulence genes involved in pathogenesis in patients with severe malaria may provide new strategies for reducing malaria mortality. PMID- 25043064 TI - Time-series analysis on human brucellosis during 2004-2013 in Shandong Province, China. AB - Human brucellosis is a re-emerging bacterial anthropozoonotic disease, which remains a public health concern in China with the growing number of cases and more widespread natural foci. The purpose of this study was to short-term forecast the incidence of human brucellosis with a prediction model. We collected the annual and monthly laboratory data of confirmed cases from January 2004 to December 2013 in Shandong Diseases Reporting Information System (SDRIS). Autoregressive integrated moving average (ARIMA) model was fitted based on the monthly human brucellosis incidence from 2004 to 2013. Finally, monthly brucellosis incidences in 2014 were short-term forecasted by the obtained model. The incidence of brucellosis was increasing from 2004 to 2013. For the ARIMA (0, 2, 1) model, the white noise diagnostic check (x(2) = 5.58 P = 0.35) for residuals obtained was revealed by the optimum goodness-of-fit test. The monthly incidences that fitted by ARIMA (0, 2, 1) model were closely consistent with the real incidence from 2004 to 2013. And forecasting incidences from January 2014 to December 2014 were, respectively, 0.101, 0.118, 0.143, 0.166, 0.160, 0.172, 0.169, 0.133, 0.122, 0.105, 0.103 and 0.079 per100 000 population, with standard error 0.011-0.019 and mean absolute percentage error (MAPE) of 58.79%. PMID- 25043065 TI - Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis. AB - The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of immunoglobulin M (IgM) and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also crossreactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We used flow cytometry and enzyme linked immunospot assay (ELISPOT) to examine B-cell subsets in 59 subjects, including 28 with PBC, 13 with primary sclerosing cholangitis (PSC), and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B-cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+ CCR10low plasmablast population. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct noncirculating tissue source of xenobiotic crossreacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+ CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28. CONCLUSION: Our findings suggest a sustained rigorous B-cell response in PBC, likely activated and perpetuated by cognate autoantigen. PMID- 25043066 TI - Tranexamic acid in pediatric trauma: why not? AB - Trauma is a leading cause of death in pediatrics. Currently, no medical treatment exists to reduce mortality in the setting of pediatric trauma; however, this evidence does exist in adults. Bleeding and coagulopathy after trauma increases mortality in both adults and children. Clinical research has demonstrated a reduction in mortality with early use of tranexamic acid in adult trauma patients in both civilian and military settings. Tranexamic acid used in the perioperative setting safely reduces transfusion requirements in children. This article compares the hematologic response to trauma between children and adults, and explores the potential use of tranexamic acid in pediatric hemorrhagic trauma. PMID- 25043067 TI - Novel completed biodegradable polymer sirolimus-eluting stent versus durable polymer sirolimus-eluting stent in de novo lesions: nine-month angiographic and three-year clinical outcomes of HOPE trial. AB - BACKGROUND: Drug-eluting stents (DES) with durable polymer have significantly reduced restenosis and target vessel revascularization compared with bare metal stents. Durable polymer has been linked with persistent inflammation of vessel wall and delayed endothelial healing that may increase the risk of late and very late stent thrombosis. This study sought to evaluate the efficacy and safety of HELIOS completed biodegradable polymer sirolimus-eluting stent (SES) in de novo coronary lesions. METHODS: Totally, 287 patients with one or two de novo coronary lesions (lesion length <= 38 mm and reference vessel diameter 2.5-4.0 mm) were enrolled in the HOPE study, a prospective, multicenter, randomized, non inferiority trial. Patients were randomized to treatment either with HELIOS completed biodegradable polymer SES (n = 142) or PARTNER durable polymer SES (n = 145). The primary endpoint was angiographic in-stent late lumen loss (LLL) at 9 month follow-up. The secondary endpoint included stent thrombosis and major adverse cardiac events including cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR). RESULTS: The 9-month in-stent LLL in the HELIOS group was similar to the PARTNER group, (0.16 +/- 0.22) mm vs. (0.19 +/- 0.30) mm (P = 0.28). The difference and 95% confidence interval were -0.03 ( 0.09, 0.04), and the P value for non-inferiority <0.01. Major adverse cardiovascular event (MACE) occurred in 7.9% vs. 8.2%, MI in 2.4% vs. 3.0%, TLR in 5.5% vs. 3.0%, and stent thrombosis in 0 vs. 1.5%; and events were comparable between the HELIOS group and PARTNER group at three-year follow-up (all P > 0.05). The three-year cardiac death was lower in the HELIOS group, but with no significant difference, 0 vs. 3.0% (P = 0.12). CONCLUSIONS: In the HOPE trial, the novel completed biodegradable polymer SES HELIOS was non-inferior to the durable polymer SES PARTNER with respect to nine-month in-stent LLL in de novo coronary lesions. The incidence of other clinical endpoints was low for both of the stents in three-year follow-up. PMID- 25043068 TI - Comparative study of video-assisted thoracoscopic surgery ablation and radiofrequency catheter ablation on treating paroxysmal atrial fibrillation: a randomized, controlled short-term trial. AB - BACKGROUND: It is unclear whether the effect of video-assisted thoracoscopic surgery ablation is better than catheter ablation on paroxysmal atrial fibrillation (PAF) or not. This study aimed to compare the effects of catheter ablation and video-assisted thoracoscopic surgery ablation on PAF. METHODS: From March 2008 to March 2012, 138 consecutive patients with PAF were randomly assigned to receive either video-assisted thoracoscopic surgery ablation (thoracoscopy group, n = 66) or the traditional catheter ablation (catheter group, n = 72). RESULTS: No patient died during the study and all were successfully followed and included in analysis. There were no significant differences in clinical and echocardiographic characteristics between the two groups. All patients were evaluated at 1 week, 1 month, 3 months, 6 months, and 12 months after discharge by physical examination and related laboratory tests. Preoperative left atrium dimensions (LADs) of the recurrent AF were (47 +/- 4) mm in the thoracoscopy group and (46 +/- 8) mm in the catheter group, whereas the LADs were (40 +/- 5) and (39 +/- 9) mm, respectively, in non-recurrent PAF. CONCLUSIONS: The short-term outcome of video-assisted thoracoscopic surgery ablation is safe and effective; and the indications are wider than those for catheter ablation. The larger left atrium diameter is related to the recurrence of atrial fibrillation. PMID- 25043069 TI - Comparison of loading with maintenance dose of clopidogrel on platelet reactivity in Chinese with different CYP2C19 genotypes prior to percutaneous coronary intervention. AB - BACKGROUND: Whether two clopidogrel pretreatment strategies prior to elective percutaneous coronary intervention (PCI): a 300 mg loading dose (LD) in clopidogrel naive patients and a 75 mg maintenance dose (MD) once daily in patients on chronic clopidogrel therapy play the same role in the platelet inhibition in Chinese with different CYP2C19 genotypes remains unknown. We aim to evaluate the impact on platelet inhibition by clopidogrel pretreatment strategy and its interaction effect with CYP2C19 genotype. METHODS: Chinese patients undergoing PCI (n = 840) were assigned to 2*2 groups in the trial according to different clopidogrel pretreatment strategies (470 patients in LD, 370 patients in MD) and CYP2C19 genotypes (494 carriers of any CYP2C19 *2 or *3 loss-of function allele, 346 non-carriers). The primary outcome was platelet aggregation (PA) as measured by the 10 umol/L adenosine diphosphate induced light transmission aggregation. RESULTS: Compared with MD group, LD strategy showed a significantly higher PA-((59.22 +/- 11.67)% vs. (52.83 +/- 12.17)%, P < 0.01), similar PA difference was observed in CYP2C19 loss-of-function carriers compared with non-carriers ((59.41 +/- 10.91)% vs. (52.10 +/- 12.90)%, P < 0.01). LD patients in either the CYP2C19 loss-of-function allele carrier or non-carrier group showed a significantly higher PA compared with MD group ((61.50 +/- 10.61)% vs. (56.84 +/- 10.74)%, P < 0.01; (56.06 +/- 12.34)% vs. (46.88 +/- 11.78)%, P < 0.01, respectively). A quantitative interaction effect was observed between clopidogrel pretreatment strategy and CYP2C19 genotype (P = 0.001). CONCLUSION: The 300 mg LD strategy results in a decreased effect on platelet inhibition compared with the 75 mg MD in Chinese patients receiving clopidogrel prior to PCI, especially in the CYP2C19 2 or 3 loss-of-function allele non-carriers. (ClinicalTrials.gov number NCT01710436) PMID- 25043070 TI - Procalcitonin could be a reliable marker in differential diagnosis of post implantation syndrome and infection after percutaneous endovascular aortic repair. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is an emerging treatment modality, which has been rapidly embraced by clinicians treating thoracic aortic disease. However, the clinical manifestations of systemic inflammatory response after TEVAR as post-implantation syndrome (PIS) resemble the perioperative infection. This study aimed to evaluate changes and diagnostic value of procalcitonin (PCT) and other traditional inflammatory markers for infections after TEVAR. METHODS: We conducted a prospective clinical study that enrolled 162 consecutive aortic dissection cases, who underwent TEVAR in our institution between July 2011 and November 2012. The PCT, C-response protein (CRP), erythrocyte sedimentation rate (ESR) and blood routine examination were monitored before the operation and on days 1, 2, 3 and 5 after the operation. The diagnosis of infection was confirmed by the infection control committee with reference to Hospital Acquired Infection Diagnostic Criteria Assessment, released by the Ministry of Health of the People's Republic of China. RESULTS: Post endovascular repair of thoracic aorta, PCT changes significantly at different time points (chi(2) = 13.225, P = 0.021), without significant difference between the PIS group and the control group (0.24 +/- 0.04 vs.0.26 +/- 0.10, P = 0.804). PCT values were significantly higher in the first day after TEVAR than the preoperative levels (0.18 +/- 0.03 vs. 0.11 +/- 0.02, P < 0.001). Compared with PIS patients, the level of PCT, CRP, White blood cell (WBC) and neutrophil (NEU) in the infection patients elevated significantly (relatively chi(2) = 6.062, P = 0.048; chi(2) = 6.081, P = 0.048; chi(2) = 11.030, P = 0.004; chi(2) = 14.632, P = 0.001). According to the ROC analysis, the PCT levels in the first day after TEVAR (AUC = 0.785, P = 0.012) had better predictive values of infection than WBC, NEU CRP and ESR (AUC = 0.720, P = 0.040; AUC = 0.715, P = 0.045; AUC = 0.663, P = 0.274; AUC = 0.502, P = 0.991). The best predictive index was the changes of PCT between preoperative and postoperative (PCT), which possess AUC as 0.803 (P = 0.014). And PCT = 0.055 could be considered as an infection diagnosis cutoff value with a sensitivity of 83.3% and specificity 69.0%. CONCLUSIONS: PCT provides better diagnostic value of infection compared with other inflammatory markers. The potential applications of PCT in differential diagnosis of PIS and infection after percutaneous TEVAR deserve further studies. PMID- 25043071 TI - Interferon alpha: the salvage therapy for patients with unsatisfactory response to minimal residual disease-directed modified donor lymphocyte infusion. AB - BACKGROUND: Minimal residual disease (MRD)-directedmodified donor lymphocyte infusion (mDLI) is used to treat relapse after hematopoietic stem cell transplantation (HSCT). For patients who experience an unsatisfactory response tomDLI, relapse is usually inevitable. Therefore, we sought to evaluate the efficacy ofinterferon alpha therapy in these patients. METHODS: Regular MRD monitoring was carried out after the HSCT. The patients who were MRD-positive underwent mDLI. Patients with an unsatisfactory response to mDLI received interferon alpha therapy (3 million units, twice weekly) with regular monitoring of MRD. To ensure the immunomodulatory effects of interferon alpha, immunosuppressant treatment would be stopped before interferon alpha treatment. RESULTS: Five patients with an unsatisfactory response to mDLI treatment received interferon alpha (3 had t (8;21) chromosomal translocation acute myeloid leukemia, and 2 had common acute leukemia). They had significantly reduced or resolved MRD. Four patients developed chronic graft-versus-host disease. Two of the 5 patients reported transient fevers, and no significant bone marrow suppression was observed. All of them were in continuous complete remission after interferon a treatment. The median survival time was 469 days (range 368-948 days). CONCLUSIONS: In patients with an unsatisfactory response to MRD-directed mDLI, interferon a may directly or indirectly induce the graft-versus-leukemia effect to improve mDLI efficacy and clear MRD. PMID- 25043072 TI - Clinical curative effect analysis and predictors of prognosis in patients with temporal lobe epilepsy after anterior temporal lobectomy: results after five years. AB - BACKGROUND: Anterior temporal lobectomy (ATL) is the most common surgical treatment for temporal lobe epilepsy (TLE), although long-term prognosis is often less favorable than short-term outcomes. This study aimed to examine the outcomes of patients with TLE 5 years after undergoing ATL, and to seek possible predictors of prognosis. METHODS: We examined the clinical records of 121 patients with TLE who underwent ATL in our institution between January 2005 and December 2008. The Engel seizure classification was used to divide patients into "seizure free" and "non-seizure free" groups. Univariate and multivariate Logistic regression analyses were used to identify potential prognostic indicators, including history, clinical features of seizures, and magnetic resonance imaging (MRI) and video-electroencephalography (EEG) findings. RESULTS: The majority of patients were seizure free during the follow-up period: 71.9% 1 year after surgery; 71.6% after 2 years; 75.8% after 3 years; 78.8% after 4 years after surgery and 68.8% after 5 years. There were significant differences between seizure-free and non-seizure-free groups in terms of preoperative seizure duration, history of febrile seizures, type of seizure, and MRI and video-EEG findings (P < 0.05), but not in terms of sex, age at seizure onset, age at surgery, side of surgery, auras, family history of seizure, or history of traumatic brain injury, perinatal anoxia or intracranial infection history (P > 0.05). Multivariate Logistic regression analysis showed that a preoperative seizure duration <10 years, a history of febrile seizures, simple complex partial seizures, positive MRI findings, hippocampal sclerosis and unilateral localized video-EEG spikes predicted better outcome (P < 0.05). CONCLUSIONS: ATL appears to be an effective means of treating TLE. Patients undergoing ATL for TLE require careful and comprehensive assessment to ensure optimal outcomes and to allow patients to make informed decisions about their treatment. PMID- 25043073 TI - Comparison of symptom and risk assessment methods among patients with chronic obstructive pulmonary disease. AB - BACKGROUND: The global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (COPD) guidelines classify patients into four groups according to the number of symptoms and the level of future risk of acute exacerbation COPD (AECOPD). This study aimed to compare the results of different methods used in diagnosis of COPD and evaluate the accuracy of the assessment methods in guiding clinical practice. METHODS: A survey was conducted of 194 COPD outpatients between March and September 2012. Demographic characteristics, the number of exacerbations the patient has had within the previous 12 months, COPD assessment test (CAT), Modified British Medical Research Council (mMRC) scale, and results of the lung function tests were recorded. RESULTS: Of the 194 patients assessed, 21 had a CAT score >=10 and an mMRC grade <=1, 13 had a CAT score <10 and an mMRC grade >=2. A predicted forced expiratory volume in one second (FEV1%) of <50% with less than two acute exacerbations was observed in 39 patients, while a predicted FEV1% of >=50% was noted in 20 patients with two or more acute exacerbations. The sensitivity of a predicted FEV1% <50% in predicting the risk of AECOPD in the future was 80.9%, while that in the real number of AECOPD events recorded was 62.8%, the difference being statistically significant (P = 0.004). The sensitivity of CAT in predicting the severity of symptoms was 90%, while that of mMRC was 83.8%, and the difference was not statistically significant. CONCLUSIONS: The COPD assessment method recommended by the global initiative for chronic obstructive pulmonary disease (GOLD) 2011 is complicated and should be simplified. CAT is more comprehensive and accurate than mMRC. The lung function classification is a better tool for predicting the risk of AECOPD in the future, and the number of AECOPD can be referred to when required. PMID- 25043074 TI - Effects of pneumoperitoneum of laparoscopic cholecystectomy on the coagulation system of patients: a prospective observational study. AB - BACKGROUND: Laparoscopic cholecystectomy has been widely used in clinical practice during the recent decades; however, the effects of pneumoperitoneum and the surgery on the coagulation system are largely unknown. This clinical study aimed to observe any possible effects of pneumoperitoneum and the surgery on the coagulation system of patients. METHODS: This was a prospective observational study. The inclusion criteria included (1) patients with chronic cholecystitis and/or cholecystic polyps and (2) patients in the relief stage of acute cholecystitis. The exclusion criteria included (1) patients in the episodic stage of acute cholecystitis and those complicated with cholangiolithiasis; (2) patients with concomitant hematologic diseases, damages to the liver function, malignant tumors or immune system diseases, or patients complicated with thrombotic or hemorrhagic disorders; and (3) patients who had taken anticoagulant medication within a week before surgery. Fifty patients who were hospitalized into our department for elective laparoscopic cholecystectomy between November 2011 and February 2013 were eligible and enrolled into this study. Of the 50 patients, 22 were male and 28 female. The age of the patients ranged from 29 to 78 (mean 56.7+/-11.5) years. The surgery for each of the 50 patients was performed with the same equipment and conditions. The surgeries for all the patients were performed under general anesthesia with the patients in a 30-degree head-up tilted posture, and the pressure of pneumoperitoneum was maintained at 13 mmHg. Venous blood specimens were taken from each patient before and at the end of pneumoperitoneum (i.e., 0 hour after surgery) and at 8 hours after surgery for determination of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), thrombin time (TT), and D-dimer (DD). The results of the determinations of these parameters were compared. RESULTS: (1) All the patients recovered well without any complications. (2) The pre-pneumoperitoneum values of the parameters of coagulation had normalized. (3) The PT values slightly increased (P > 0.05) at the end of pneumoperitoneum (i.e., 0 hour after surgery) and decreased by 0.5 seconds at 8 hours after surgery as compared to the pre-pneumoperitoneum values (P < 0.05). (4) APTT at 0 and 8 hours decreased by 1.4 seconds (P > 0.05) and 3.7 seconds (P < 0.05) respectively as compared to pre pneumoperitoneum values, while the difference between the APTT values at 0 and 8 hours after surgery was not statistically significant (P > 0.05). (5) FIB determined at 0 hour post-operation increased by 0.1 g/L as compared to pre pneumoperitoneum values (P > 0.05); however, the FIB values at 8 hours after operation increased by 1.2 g/L as compared to the pre-pneumoperitoneum values (P < 0.05), and increased by 1.1 g/L as compared to 0 hour post-operation (P < 0.05). (6) The TT values obtained at 0 and 8 hours post-operation were not significantly different as compared to the pre-pneumoperitoneum values (P > 0.05). (7) The DD values gradually increased after operation; as compared to pre pneumoperitoneum values, DD at 0 and 8 hours after operation increased by 210.8 ng/ml and 525.9 ng/ml respectively (P < 0.05) and DD at 8 hours after operation increased by 315.1 ng/ml as compared to 0 hour post-operation (P < 0.05). CONCLUSIONS: The pneumoperitoneum for laparoscopic cholecycstectomy may lead to postoperative hypercoagulation in the patients, and thereby may increase the risks for development of postoperative thrombosis; Patients may have risks for occurrence of thrombosis within 8 hours after the operation, to which attention should be paid in favor of preventing thrombosis. PMID- 25043075 TI - Impact of microbubble enhanced, pulsed, focused ultrasound on tumor circulation of subcutaneous VX2 cancer. AB - BACKGROUND: Intravascular microbubble-enhanced acoustic cavitation is capable of disrupting the vascular walls of capillaries and small vessels. This study was designed to investigate the impact of microbubble-enhanced, pulsed and focused ultrasound (MEUS) on the blood perfusion of subcutaneous VX2 tumors in rabbits. METHODS: Subcutaneous VX2 cancers in twenty New Zealand rabbits were treated by combining high-pressure amplitude, pulsed and focused therapeutic ultrasound (TUS) and intravenous microbubble injections. The TUS transducer was operated with a peak negative pressure of 4.6 MPa and a duty cycle of 0.41%. Controls were subcutaneous VX2 cancers treated with TUS or microbubbles only. Contrast-enhanced ultrasound (CEUS) and intravenous Evans Blue (EB) perfusion were performed to assess the tumor circulation. The tumor microvascular disruption was assessed by histological examination. RESULTS: CEUS showed that the tumor circulation almost vanished after MEUS treatment. The average peak grayscale value (GSV) of tumor CEUS dropped significantly from 84.1+/-22.4 to 15.8+/-10.8 in the MEUS-treated tumors but no significant GSV changes were found in tumors in the two control groups. The mean tumor EB content of the MEUS-treated tumors was significantly lower than that of the controls. Histological examination found scattered tumor microvascular disruption with intercellular edema after MEUS treatment. CONCLUSION: The tumor circulation of VX2 cancers can be arrested or significantly reduced by MEUS due to microvascular disruption. PMID- 25043076 TI - Outcomes of peripheral blood stem cell transplantation in patients from human leukocyte antigen matched or mismatched unrelated donors. AB - BACKGROUND: Allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) is an alternative treatment for many hematologic diseases due to lack of human leukocyte antigen (HLA)-identical sibling donors. This study aimed to evaluate the impact of the degree of the HLA match on the clinical efficacy of UR-PBSCT. METHODS: Patients who underwent UR-PBSCT from September 2003 to September 2012 were retrospectively investigated. They were divided into three groups according to high-resolution molecular typing. SPSS version 17.0 was used to analysis and compare the statistics of engraftment, incidence of GVHD, other complications and survival among the groups. RESULTS: One hundred and eleven patients received UR-PBSCT, 60 of them with an HLA matched donor (10/10), 36 of them with a one locus mismatched donor (9/10), and 15 of them with a two loci mismatched donor (8/10). Similar basic characteristics were found in the three groups. No differences were found in engraftment of myeloid cells or platelets in the three groups (P > 0.05). Two-year cumulative incidence of relapse, overall survival (OS) and disease-free survival (DFS) among those three groups were similar (P > 0.05). The cumulative incidence of 100-day III-IV aGVHD in the HLA matched group and the one HLA locus mismatched group were significantly lower than that in the two HLA loci mismatched group (3.3%, 8.6%, and 26.7%, P = 0.009). The occurrence rate of new pulmonary infections in the HLA matched group was lower than in the two HLA mismatched groups (26.67%, 52.78%, and 41.18%, P = 0.035). The cumulative incidence of 100-day and 2-year transplantation related mortality (TRM) in two HLA loci mismatched group was higher than in the HLA matched group and in the one HLA locus mismatched group, (8.4%, 11.8% and 33.3%, P = 0.016) and (12.3%, 18.7% and 47.5%, P = 0.002). CONCLUSIONS: HLA mismatch will not significantly impact the engraftment or 2-year survival after UR-PBSCT, but two mismatched HLA loci may increase the cumulative incidence of severe aGVHD and TRM. PMID- 25043077 TI - Autologous hematopoietic stem cell transplantation and conventional insulin therapy in the treatment of children with newly diagnosed type 1 diabetes: long term follow-up. AB - BACKGROUND: It has been indicated that autologous hematopoietic stem cell transplantation (AHST) is a promising treatment to adults with type 1 diabetes, however, the application of AHST therapy to children with type 1 diabetes still needs more data. The aim of this study was to assess the clinical effect of immune intervention combined with AHST and conventional insulin therapy in the treatment of children with newly diagnosed type 1 diabetes. METHODS: This 1:2 matched case-control study was comprised of 42 children who were newly diagnosed with type 1 diabetes in the Department of Endocrinology, Beijing Children's Hospital from 2009-2010. The case group included 14 patients, who were treated with AHST within the first 3 months after being diagnosed with diabetes at request of their parents during 2009-2010. The control group included 28 patients with newly diagnosed type 1 diabetes at the same period of hospitalization. We compared the baseline and follow-up data of them, including ketoacidosis onset, clinical variables (glycosylated hemoglobin (HbA1c), insulin dosage and serum C peptide). RESULTS: The clinical characteristics of the patients was comparable between the case group and the control group. At 6-12 months ((10.7+/-4.2) months) after AHST treatment, we found 11 patients in the case group did not stop the insulin therapy, three cases stopped insulin treatment for 2, 3 and 11 months, respectively. No diabetic ketoacidosis (DKA) occurred after transplantation in all the patients in the case group. HbA1c in the control group was significant lower than that in the case group (P < 0.01), while the insulin dosage and serum C-peptide were not significant different between the two groups (P > 0.05). In order to eliminate the honeymoon effect, we performed final follow up at the 3-5 years ((4.2+/-1.8) years) after AHST treatment, and found that HbA1c in the control group was still lower than that in the case group (P < 0.01); however, the insulin dosage and serum C-peptide were not significantly different between the two groups (P > 0.05). Moreover, the insulin dosage was not significant different from baseline to follow-up period in the case group. CONCLUSION: AHST treatment showed no advantage in effectiveness in children with newly diagnosed type 1 diabetes, both in insulin dose and long term blood glucose control. PMID- 25043078 TI - Comparison of Charlson's weighted index of comorbidities with the chronic health score for the prediction of mortality in septic patients. AB - BACKGROUND: Comorbidity is one of the most important determinants of short-term and long-term outcomes in septic patients. Charlson's weighted index of comorbidities (WIC) and the chronic health score (CHS), which is a component of the acute physiology and chronic health evaluation (APACHE) II, are two frequently-used measures of comorbidity. In this study, we assess the performance of WIC and CHS in predicting the hospital mortality of intensive care unit (ICU) patients with sepsis. METHODS: A total of 338 adult patients with sepsis were admitted to a multisystem ICU between October 2010 and August 2012. Clinical data were collected, including age, gender, underlying diseases, key predisposing causes, severity-of-sepsis, and hospital mortality. The APACHE II, CHS, acute physiology score (APS), sequential organ failure assessment (SOFA) and WIC scores were assessed within the first 24 hours of admission. Univariate and multiple Logistic regression analyses were used to compare the performance of WIC and CHS. The area under the receiver operating characteristic curve (AUC) was used to predict hospital mortality over classes of risk. RESULTS: Of all the enrolled patients, 224 patients survived and 114 patients died. The surviving patients had significantly lower WIC, CHS, APACHE II, and SOFA scores than the non-surviving patients (P < 0.05). Combining WIC or CHS with other administrative data showed that the hospital mortality was significantly associated with age, severe sepsis, key predisposing causes such as pneumonia, a history of underlying diseases such as hypertension and congestive cardiac failure, and WIC, CHS and APS scores (P < 0.05). The AUC for the hospital mortality were 0.564 (95% confidence interval (CI) 0.496-0.631) of CHS, 0.663 (95% CI 0.599-0.727) of WIC, 0.770 (95% CI 0.718 0.822) of APACHE II, 0.856 (95% CI 0.815-0.897) of the CHS combined with other administrative data, and 0.857 (95% CI 0.817-0.897) of the WIC combined with other administrative data. The diagnostic value of WIC was better than that of CHS (P = 0.0015). CONCLUSIONS: The WIC and CHS scores might be independent determinants for hospital mortality among ICU patients with sepsis. WIC might be an even better predictor of the mortality of septic patients with comorbidities than CHS. PMID- 25043079 TI - Effects of mildly increasing dialysis sodium removal on renin and sympathetic system in hemodialysis patients. AB - BACKGROUND: It has been argued that the benefits of reducing sodium loading may be offset by increased activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. This study aimed to investigate the long term effects of an increase in dialysis sodium removal on circulating RAAS and sympathetic system in hypertensive hemodialysis (HD) patients with "normal" post HD volume status. METHODS: Thirty hypertensive HD patients were enrolled in this pilot trial. After one month period of dialysis with standard dialysate sodium of 138 mmol/L, the patients were followed up for a four months period with dialysate sodium set at 136 mmol/L, without changes in instructions regarding dietary sodium control. During the period of study, the dry weight was adjusted monthly under the guidance of bioimpedance spectroscopy to maintain post-HD volume status in a steady state; 44-hour ambulatory blood pressure, plasma renin, angiotensin II (Ang II), aldosterone, and norepinephrine (NE) were measured. RESULTS: After four months of HD with low dialysate sodium of 136 mmol/L, 44-hour systolic and diastolic blood pressures (BPs) were significantly lower (-10 and -6 mmHg), in the absence of changes in antihypertensive medications. No significant changes were observed in plasma renin, Ang II, aldosterone, and NE concentrations. The post-HD volume parameters were kept constant. CONCLUSION: Mildly increasing dialysis sodium removal over 4 months can significantly improve BP control and does not activate circulating RAAS and sympathetic nervous system in hypertensive HD patients. PMID- 25043080 TI - Side effects and tolerability of post-exposure prophylaxis with zidovudine, lamivudine, and lopinavir/ritonavir: a comparative study with HIV/AIDS patients. AB - BACKGROUND: In the era of highly active antiretroviral therapy (HAART), the use of antiretrovirals as post-exposure prophylaxis (PEP) was the most important strategy for preventing occupational exposure to blood or fluids containing human immunodeficiency virus (HIV). The objective of this study was to retrospectively evaluate the tolerability, safety, and side effects of a HAART regimen containing three antiretroviral drugs, consisting of zidovudine, lamivudine, and lopinavir/ritonavir, in healthcare personnel (HCP) who experienced occupational exposure to HIV. METHODS: The tolerability, safety, and side effects in 26 HCPs who experienced PEP and in 27 HIV/AIDS patients with HAART regimen, AZT+3TC+Lpv/r, were evaluated between January 2010 and December 2012. RESULTS: The most frequent clinical side effect was fatigue (in 23 cases, 88.5%), and gastroenterological symptoms were the second most common side effects in HCP with PEP. Liver dysfunction was found in 10 cases (38.5%), while drug rash was found in 18 cases (69.2%) after PEP. The prevalence of side effects in HCPs who experienced PEP was higher than that in HIV/AIDS patients P < 0.05. One nurse (3.8%) experienced severe gastrointestinal symptoms, which led to withdrawal of PEP. No HIV infection was found during 6-month follow-up period. CONCLUSION: HCPs who received occupational PEP with triple-drug regimen, AZT+3TC+Lpv/r, experienced different side effects, and the tolerability and safety of PEP regimen were good in this cohort. PMID- 25043081 TI - Expressions of farnesoid X receptor and myeloid cell leukemia sequence 1 protein are associated with poor prognosis in patients with gallbladder cancer. AB - BACKGROUND: Farnesoid X receptor (FXR) regulates tumorigenesis, but its clinical significance in gallbladder cancer (GBC) remains unclear. This study investigated its clinical and prognostic significance in GBC patients, as well as its association with the anti-apoptotic protein, myeloid cell leukemia sequence 1 (MCL1) protein. METHODS: FXR and MCL1 expression in 42 primary GBC and 15 normal gallbladder tissues were analyzed by immunohistochemistry. The patients and samples were collected from Ren Ji Hospital from January 2005 to December 2010. Their association with clinicopathologic factors and prognosis, as well as the correlation between FXR and MCL1 protein expression were analyzed by statistical analyses. RESULTS: Compared with normal gallbladder tissues, FXR expression was decreased and MCL1 expression was increased in GBC, during progression of tumor node metastasis (TNM) stage. The Kaplan-Meier survival analysis showed that FXR low-expression and MCL1 over-expression were significantly associated with overall poor survival. Furthermore, multivariate analysis showed that FXR and MCL1 are both prognostic factors for GBC patients. FXR low-expression was significantly correlated with MCL1 over-expression. CONCLUSION: FXR might be a new molecular marker to predict the prognosis of patients with GBC and a novel therapeutic target. PMID- 25043082 TI - Mineral compositions in breast milk of healthy Chinese lactating women in urban areas and its associated factors. AB - BACKGROUND: Optimal mineral intakes are important for infant growth and development. However, data on mineral compositions of breast milk in Chinese women are scarce, and most were acquired before 1990. The objectives of this study were three-fold: (1) to investigate the mineral compositions of Chinese healthy mothers' breast milk in different lactation stages; (2) to explore correlations among mineral concentrations in breast milk; and (3) to explore the associated factors affecting mineral compositions in breast milk. METHODS: The inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze mineral concentrations in breast-milk of 444 healthy lactating women from three cities in China. A questionnaire was used to survey socio-demographic characteristics and pregnancy history. Food intakes by lactating women were measured using both food frequency questionnaire and one cycle of 24-hour dietary recall. RESULTS: Mineral compositions of breast milk varied in different regions. Concentrations of most minerals were higher in the first one or two months of lactation, and then decreased with time, except for magnesium and iron. Inter-mineral correlations existed among several minerals. The calcium-to-phosphorus ratio was above 2:1 in each lactation stage. Women with caesarean section had higher concentration of iodine in the transitional milk (349.9 ug/kg) compared to women with natural delivery (237.5 ug/kg, P < 0.001). Dietary mineral intakes, supplements, food intake frequencies in the recent 6 months, maternal age and maternal BMI did not show significant correlations with concentrations of milk minerals (all P > 0.05). CONCLUSIONS: Milk minerals decreased with time, and changed most rapidly in the first one or two months of lactation. Caesarean section might affect the iodine level in transitional milk. PMID- 25043083 TI - Are failures of anterior cruciate ligament reconstruction associated with steep posterior tibial slopes? A case control study. AB - BACKGROUND: Recently, increasing number of literature has identified the posterior tibial slope (PTS) as one of the risk factors of primary anterior cruciate ligament (ACL) injury. However, few studies concerning the association between failure of ACL reconstruction (ACLR) and PTS have been published. The objective of this study was to explore the association between the failure of ACLR and PTS at a minimum of two years follow-up. METHODS: Two hundred and thirty eight eligible patients from June 2009 to October 2010 were identified from our database. A total of 20 failure cases of ACLR and 20 randomly selected controls were included in this retrospective study. The demographic data and the results of manual maximum side-to-side difference with KT-1000 arthrometer at 30 degrees of knee flexion and pivot-shift test before the ACLR and at the final follow-up were collected. The medial and lateral PTSs were measured using the magnetic resonance imaging (MRI) scan, based on Hudek's measurement. A comparison of PTS between the two groups was performed. RESULTS: The overall failure rate of the present study was 8.4%. Of the 40 participants, the mean medial PTS was 4.1 degrees +/- 3.2 degrees and the mean lateral PTS was 4.6 degrees +/- 2.6 degrees . The medial PTS of the ACLR failure group was significantly steeper than the control group (3.5 degrees +/- 2.5 degrees vs. 6.1 degrees +/- 2.1 degrees , P = 0.000). Similarly, the lateral PTS of the ACLR failure group was significantly steeper than the control group (2.9 degrees +/- 2.1 degrees vs. 5.5 degrees +/- 3.0 degrees , P = 0.006). For medial PTS >= 5 degrees , the odds ratio of ACLR failure was 6.8 (P = 0.007); for lateral PTS >=5 degrees , the odds ratio of ACLR failure was 10.8 (P = 0.000). CONCLUSION: Both medial and lateral PTS were significantly steeper in failures of ACLR than the control group. Medial or lateral PTS >=5 degrees was a new risk factor of ACLR failure. PMID- 25043084 TI - Accuracy and complications of posterior C2 screw fixation using intraoperative three-dimensional fluoroscopy-based navigation. AB - BACKGROUND: The peculiar and highly variable C2 anatomy can make screw fixation more challenging and prone to potential vertebral artery or neurologic injury. Conventional C-arm fluoroscopy has several drawbacks. The aim of this research was to evaluate the accuracy of posterior C2 screw fixation using intraoperative three-dimensional fluoroscopy-based navigation (ITFN) and assess the perioperative complication rate related to screw placement. METHODS: A retrospective review identified patients who underwent operative management with C2 instruments using ITFN at our hospital between January 2006 and December 2012. Clinical data were obtained from medical records and final screw positions were graded according to a modified classification of Gertzbein and Robbins. Grade A and B screws were considered well positioned. RESULTS: The study included 99 patients (53 males and 46 females) who underwent posterior C2 screw fixation using ITFN. The mean Japan Orthopedic Association score improved from (6.7 +/- 1.9) points before surgery to (12.5 +/- 2.7) points at 6-month follow-up (z = +8.628, P < 0.01). The mean visual analogue scale improved from (4.1 +/- 1.2) points before surgery to (0.7 +/- 0.9) points at 6-month follow-up, with an improvement of 83.7% (z = 8.638, P < 0.01). Of the 196 screws analyzed using computed tomography and chart review, 126 transarticular, 64 pedicle, and 6 pars screws were placed with 82.5% (104/126), 89.1% (57/64), and 100% (6/6) accuracy (grade A), respectively; 98.5% (193/196) of screws were grade A or B (grade C, 1.5% (3/196)), and no neurologic injuries occurred. In normal C2 cases, 93 transarticulars and 47 pedicles were placed with high accuracy rates of 90.3% (84/93) and 93.6% (44/47) (grade A), respectively. However, in cases with C2 deformity, 33 transarticular, 17 pedicle, and 6 pars screws were placed with only 60.6% (20/33), 76.5% (13/17), and 100% (6/6) accuracy (grade A), respectively. CONCLUSION: ITFN is a safe, accurate, and effective tool for posterior C2 fixation. PMID- 25043085 TI - Profiles of and correlation between objective and subjective outcome assessments following open-door laminoplasty for cervical spondylotic myelopathy. AB - BACKGROUND: Open-door laminoplasty is widely used in the treatment of cervical spondylotic myelopathy (CSM). This study aimed to investigate the profiles of and correlation between objective and subjective short-term outcome assessments after open-door laminoplasty for CSM. METHODS: We retrospectively analyzed surgical outcomes in 129 consecutive CSM patients who underwent open-door laminoplasty in Peking University Third Hospital from February 2008 to November 2011. Both objective and subjective assessments were evaluated before surgery, 3 months after surgery, and 1 year after surgery. We then analyzed the profiles of and correlation between objective and subjective short-term outcomes. RESULTS: The Modified Japanese Orthopaedic Association (mJOA) score was significantly improved at 3 months (P < 0.01) and 1 year (P < 0.01) after surgery. Bivariate Logistic regression showed that sensory improvement contributed more to the recovery rate than motor function improvement at 3 months after surgery, while motor function contributed more to the recovery rate at 1 year after surgery. On the subjective assessment (the short form (SF)-36 ), there was no significant improvement at 3 months after surgery (P > 0.05), while physical function (PF), role-physical (RP), and social function (SF) were notably improved at 1 year after surgery (P < 0.01). Improved mJOA score correlated with improvements in PF, RP, bodily pain, general health (GH), vitality (VT), and SF (P < 0.05) at 3 months after surgery; PF, GH, VT, and SF were associated with improved mJOA scores at 1 year after surgery. CONCLUSIONS: Patients benefit from surgery by postoperative restitution of neurological function with early recovery of sensory function, followed by a gradual transition to motor function improvement. At the early stage of recovery, improvement in the mJOA score essentially correlated with improvements in the physical domains of the SF-36, while at the later stage, mJOA score improvement was associated with improvements in both mental and physical domains of the SF 36. PMID- 25043086 TI - Prognostic significance of gamma-H2AX in laryngeal squamous cell carcinoma after surgery. AB - BACKGROUND: The clinical significance of gamma-H2AX in laryngeal squamous cell carcinoma (LSCC) has not yet been established. This study was performed to assess the expression of nuclear gamma-H2AX in benign and malignant laryngeal lesions and to assess its clinicopathological significance. METHODS: A total of 70 LSCC tumor-normal tissue paired samples were evaluated for gamma-H2AX expression using immunohistochemical staining. Their expression was correlated with different clinicopathological parameters. RESULTS: Nuclear gamma-H2AX expression was frequently detected in LSCC tissues (P < 0.001). High nuclear gamma-H2AX levels were not associated with any clinicopathological characteristics of LSCC (P > 0.05). Univariate Kaplan-Meier analysis showed that positive nuclear gamma-H2AX expression was associated with a decreased overall survival (P = 0.017). Multivariate Cox regression analysis showed that nuclear gamma-H2AX expression was an independent risk factor for overall survival. CONCLUSION: The expression of nuclear gamma-H2AX might be closely related to the prognosis of LSCC. PMID- 25043087 TI - Trachoma rapid assessment in Shandong province of China. AB - BACKGROUND: This research aims at identifying relative interventions on trachoma and testing the effectiveness of control measures adopted by assessing its prevalence and related risk factors in Shandong province of China. METHODS: Trachoma rapid assessment (TRA) was conducted in 6 sub-districts selected from Shandong province based on primary high risk assessment. Active trachoma in children aged 1-9 years and environmental risk factors of trachoma (unclean faces, absence of running water, and absence of flush toilets) were assessed (TRA 1). Control measures were taken in endemic areas. A second TRA (TRA 2) was conducted after 12 months in the same 6 districts and findings of the two TRAs were compared. RESULTS: In TRA 1, we found trachoma in 3 sub-districts and the detection rate was 4% (95% CI: 0.39%-11.12%), 6% (95% CI: 1.18%-14.17%), and 6% (95% CI: 1.18%-14.17%) respectively. We could not find trachoma cases in TRA 2. Research data supports that children living with environmental risk factors face an increased risk to active trachoma. However, we could not find statistical evidence for this association, which may be caused by the limited data on prevalence. CONCLUSIONS: This research indicates that the TRA methodology is easy to assess trachoma and its related risk factors. Based on the results of this study, we have already achieved the goal of "elimination of trachoma" in Shandong province, as the detection rate of trachomatous inflamation follicular/trachomatous inflammation intense in 1-9-year-old children was less than 5%. PMID- 25043088 TI - Distinct properties and metabolic mechanisms of postresuscitation myocardial injuries in ventricular fibrillation cardiac arrest versus asphyxiation cardiac arrest in a porcine model. AB - BACKGROUND: The two most prevalent causes of sudden cardiac death are ventricular fibrillation cardiac arrest (VFCA) and asphyxiation cardiac arrest (ACA). Profound postresuscitation myocardial dysfunction has been demonstrated in both VFCA and ACA animal models. Our study aimed to characterize the two porcine models of cardiac arrest and postresuscitation myocardial metabolism dysfunction. METHODS: Thirty-two pigs were randomized into two groups. The VFCA group (n = 16) were subject to programmed electrical stimulation and the ACA group (n = 16) underwent endotracheal tube clamping to induce cardiac arrest (CA). Once induced, CA remained untreated for a period of 8 minutes. Two minutes following initiation of cardiopulmonary resuscitation (CPR), defibrillation was attempted until return of spontaneous circulation (ROSC) was achieved or animals died. To assess myocardial metabolism, (18)F-FluoroDeoxyGlucose Positron Emission Tomography was performed at baseline and 4 hours after ROSC. RESULTS: ROSC was 100% successful in VFCA and 50% successful in ACA. VFCA had better mean arterial pressure and cardiac output after ROSC than ACA. Arterial blood gas analysis indicated more detrimental metabolic disturbances in ACA compared with VFCA after ROSC (ROSC 0.5 hours, pH: 7.01 +/- 0.06 vs. 7.21 +/- 0.03, P < 0.01; HCO3(-): (15.83 +/- 2.31 vs. 20.11 +/- 1.83) mmol/L, P < 0.01; lactate: (16.22 +/- 1.76 vs. 5.84 +/- 1.44) mmol/L, P < 0.01). Myocardial metabolism imaging using Positron Emission Tomography demonstrated that myocardial injuries after ACA were more severe and widespread than after VFCA at 4 hours after ROSC (the maximum standardized uptake value of the whole left ventricular: 1.00 +/- 0.17 vs. 1.93 +/- 0.27, P < 0.01). Lower contents of myocardial energy metabolism enzymes (Na(+)-K(+)-ATPase enzyme activity, Ca(2+)- ATPase enzyme activity, superoxide dismutase and phosphodiesterase) were found in ACA relative to VFCA. CONCLUSIONS: Compared with VFCA, ACA causes more severe myocardium injury and metabolism hindrance, therefore they should be treated as different pathological entities. PMID- 25043089 TI - Decorin accelerates the liver regeneration after partial hepatectomy in fibrotic mice. AB - BACKGROUND: Considering the existence of a large number of liver cell degeneration and necrosis in fibrotic liver, liver function was damaged severely and could not effectively regenerate after partial hepatectomy (PHx). The aim of this study was to investigate whether decorin (DCN) could promote the liver regeneration after PHx in fibrotic mice. METHODS: Forty mice (5-week-old, Balb/c) were injected with CCl4 intraperitoneally and liver fibrosis model was established after 5 weeks. The survival mice were randomly divided into two groups: control group and DCN group. Then, we performed 70% PHx on all these mice and injected DCN or phosphate-buffered saline plus normal saline (NS) to each group, respectively, after surgery. Liver body weight ratio (LBR), quantitative real-time polymerase chain reaction, and immunohistochemistry were used to analyze liver regeneration and fibrosis degree in both groups, and to find out whether exogenous protein DCN could promote the regeneration of fibrosis liver after PHx. RESULTS: Expressions of a-smooth muscle actin (SMA) mRNA and LBR had significant increases in the DCN group at postoperative Day 3 (POD 3, P < 0.05). The protein expressions of CD31, a-SMA, and tumor necrosis factor (TNF)-a were higher in the DCN group than those in the control group by immunohistochemistry at POD 3 (P < 0.05). CONCLUSION: Exogenous protein DCN could promote liver regeneration after PHx in fibrotic mice. PMID- 25043090 TI - Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection. AB - BACKGROUND: OX40/OX40 ligand (OX40/OX40L) and programmed death-1/programmed death ligand-1 (PD-1/PD-L1) costimulatory signals play important roles in T cell induced immune responses. The aim of this study was to investigate the roles of OX40/OX40L and PD-1/PD-L1 costimulatory pathways in mouse islet allograft rejection. METHODS: Lentiviral vectors containing OX40L siRNA sequences and an adenovirus vector containing the PD-L1 gene were constructed. The streptozotocin induced model of diabetes was established in C57BL/6 (H-2(b)) mice. Diabetic C57BL/6 mice were randomly allocated into five groups: group 1, untreated control; group 2, Ad-EGFP treatment; group 3, Ad-PD-L1 treatment; group 4, OX40L RNAi-LV treatment; group 5, OX40L-RNAi-LV combined with Ad-PD-L1 treatment. Lentiviral vector and the adenovirus vector were injected, singly or combined, into the caudal vein one day before islet transplantation. The islets of DBA/2 (H 2(d)) mice were transplanted into the renal subcapsular space of the diabetic recipients. Recipient blood glucose and the survival time of the allografts were monitored. Antigen-specific mixed lymphocyte reaction was also evaluated. RESULTS: The recombinant lentiviral RNA interference vector OX40L-RNAi-LV reduced OX40L protein expression by 70%. The recombinant adenovirus vector Ad-PD-L1 increased PD-L1 protein expression in vivo in C57BL/6 recipient mice. Combined OX40L-RNAi-LV/Ad-PD-L1 treatment induced a synergistic protective effect in pancreatic islet allografts. Allograft survival time in the combined treatment group was (92.27+/-9.65) days, not only longer than that of the control ((6.51+/ 0.27) days) and Ad-EGFP groups ((7.09+/-0.13) days) (P < 0.01), but also significantly longer than that of Ad-PD-L1 and OX40L-RNAi-LV single treatment groups ((40.64+/-3.95) days and (55.14+/-5.48) days respectively, P < 0.01). The blood glucose concentration of recipient mice in the combined treatment group was also stable and kept within the normal range. Flow cytometry analysis showed that combined OX40L-RNAi-LV/Ad-PD-L1 treatment significantly decreased proliferation in an antigen-specific mixed lymphocyte reaction. After donor DBA/2 lymphocyte stimulation, 89.71% of lymphocytes from recipient combination treatment C57BL/6 mice were not split and proliferated. In contrast, after stimulation with third party Lewis rat lymphocytes, only 45.84% lymphocytes of C57BL/6 mice were not split and proliferated. CONCLUSIONS: This study demonstrates the successful construction of the recombinant lentivirus vector OX40L-RNAi-LV and adenovirus vector Ad-PD-L1 for the blockade of OX40/OX40L and activation of PD-1/PD-L1 costimulatory pathways simultaneously in pancreatic islet allografts in diabetic mice. Combination therapy with these two vectors resulted in inhibition of T cell activation, synergistically prolonging the survival time of pancreatic islet allografts. PMID- 25043091 TI - Effect of tacrolimus in idiopathic membranous nephropathy: a meta-analysis. AB - BACKGROUND: The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) are still controversial. Recent studies showed tacrolimus is effective in the treatment of IMN. To evaluate the efficacy and safety of tacrolimus (TAC) for IMN, we conducted a meta-analysis of published medical literatures. METHODS: Studies addressing the effect of tacrolimus in IMN were searched on PUBMED, EMBASE, The Cochrane Library, and ClinicalTrials.gov (March 2013). Trials comparing tacrolimus with corticosteroid versus control group (cyclophosphamide with corticosteroid) were included. The quality of the studies was assessed using Jadad method. Statistical analyses were performed using Review Manager 5.2 and the results were summarized by calculating the risk ratio (RR) for dichotomous data or the mean difference (MD) for continuous data with 95% confident interval (CI). RESULTS: A total of four studies (259 patients) were included. It was shown that therapy with tacrolimus plus corticosteroid had a higher complete remission rate compared to therapy with cyclophosplamide plus corticosteroid (RR = 1.53, 95% CI: 1.05-2.24, P < 0.05), but not significant on total remission, partial remission and adverse effects. Also, no significant alterations were observed in proteinuria and serum albumin level between the two groups. During the entire follow-up period, serum creatinine level remained stable in both groups without = 50% increase in its level. CONCLUSIONS: TAC is more effective than cyclophosphamide (CTX) by achieving complete remission in patients with IMN. Multi-ethnic RCTs are needed to evaluate its long-term efficacy and safety. PMID- 25043092 TI - Epicardial adipose tissue: the accomplice implicated in the genesis and maintenance of atrial fibrillation. AB - OBJECTIVE: The purpose of this review was to delineate our current knowledge of the close relationship between the abundance of epicardial adipose tissue (EAT) and the risk of all major cardiovascular disease, especially atrial fibrillation (AF). DATA SOURCES: The data analyzed in this review were mainly from articles reported in PubMed published from 1972 to 2014. STUDY SELECTION: Original articles and critical reviews relevant to EAT and AF were selected. RESULTS: EAT, a particular form of metabolically active visceral fat deposited around the heart, is being regarded as an important independent predictor of cardio metabolic diseases. EAT is composed of smaller adipocytes than other visceral fat depots and functioned like brown adipose tissue (BAT) to protect adjacent tissues. Improving the understanding of EAT in AF genesis and maintenance may contribute to prevent AF and reduce the complications associated with AF. CONCLUSION: The findings suggest that EAT associates with AF severity and the recurrence of AF after catheter ablation even after adjustment for AF risk factors, but the precise mechanisms are not fully elucidated. PMID- 25043094 TI - Pre-induction dexamethasone does not decrease postoperative nausea and vomiting after microvascular decompression for facial spasm. PMID- 25043093 TI - Application of third-party mediation for medical disputes: an introduction of Chinese experience. PMID- 25043095 TI - Metachronous multicentric giant cell tumor of bone with retroperitoneal metastasis. PMID- 25043096 TI - Inappropriate antidiuretic hormone secretion in a patient with pulmonary lymphoepithelioma like carcinoma. PMID- 25043097 TI - Difficulties in the clinical, radiological, and pathological diagnosis of a patient with dry cough and dyspnea. PMID- 25043098 TI - Goal directed fluid therapy with LiDCO(rapid) in a parturient with WPW syndrome and cardiac dysfunction undergoing emergent cesarean section. PMID- 25043099 TI - Pseudohypoaldosteronism type 1 secondary to vesicoureteral reflux: An endocrinologic emergency. PMID- 25043100 TI - Incidence rate of thyroid cancer in Neuquen (2001-2012). AB - During the past decades, an increasing incidence of thyroid cancer (TC) has been reported worldwide. In Argentina there is no national cancer registry, and its incidence has therefore not been established. The aim of our study was to determine the incidence of TC in the province of Neuquen and to compare it to that reported in the literature. The medical records of 229 patients admitted over a period of 12 years (2001 to 2012) were used for data analysis. Tumor size, age, sex, and histological type were evaluated. The study period was divided into four three-year periods, and differences in each of these features were analyzed. We found an incidence of 4.72/100,000 inhabitants/year, and almost all patients had papillary TC. TC was five times more common in females as compared to males (7.78 and 1.55 respectively). Mean tumor size was 22.2 +/- 1.1 mm. Tumor size was significantly greater in men (31.8 +/- 3.7 mm) than in women (20.4 +/- 1.0 mm). When grouped by three-year periods, a higher number of cases was found in the last one (47, 49, 49 and 84 respectively). As regards tumor distribution by size, there was a significant decrease in mean tumor size in the fourth period and an increase in the proportion of tumors <10mm. We report an increase in TC incidence in the Argentinean province of Neuquen which is similar to the overall increase reported in the international literature. PMID- 25043101 TI - Cervical adenopathy as first symptom of a neuroendocrine ampullary tumor. PMID- 25043102 TI - Occupational and military travel medicine. PMID- 25043103 TI - Prevalence and management of dementia in nursing home residents in Tunisia. PMID- 25043104 TI - Iridium-catalyzed H/D exchange: ligand complexes with improved efficiency and scope. AB - Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P-ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron-rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions. PMID- 25043105 TI - Mutual enhancement of differentiation of osteoblasts and osteocytes occurs through direct cell-cell contact. AB - There is increasing evidence that osteocytes regulate multiple aspects of bone remodeling through bi-directional communication with osteoblasts. This is potentially mediated through cell-cell contact via osteocytic dendritic processes, through the activity of secreted factors, or both. To test whether cell-cell contact affects gene expression patterns in osteoblasts and osteocytes, we used a co-culture system where calvarial osteoblasts and IDG-SW3 osteocytes were allowed to touch through a porous membrane, while still being physically separated to allow for phenotypic characterization. Osteoblast/osteocyte cell contact resulted in up-regulation of osteoblast differentiation genes in the osteoblasts, when compared to wells where no cell contact was allowed. Examination of osteocyte gene expression when in direct contact with osteoblasts also revealed increased expression of osteocyte-specific genes. These data suggest that physical contact mutually enhances both the osteoblastic and osteocytic character of each respective cell type. Interestingly, Gja1 (a gap junction protein) was increased in the osteoblasts only when in direct contact with the osteocytes, suggesting that Gja1 may mediate some of the effects of direct cell contact. To test this hypothesis, we treated the direct contact system with the gap junction inhibitor 18-alpha-glycyrrhetinic acid and found that Bglap expression was significantly inhibited. This suggests that osteocytes may regulate late osteoblast differentiation at least in part through Gja1. Identification of the specific factors involved in the enhancement of differentiation of both osteoblasts and osteocytes when in direct contact will uncover new biology concerning how these bone cells communicate. PMID- 25043106 TI - Birth of common shovelnose rays (Glaucostegus typus) under captive conditions. AB - The common shovelnose ray (Glaucostegus typus) is a poorly studied species of the Rhinobatidae family that occurs throughout the Indo-West Pacific. Although common in aquariums throughout the United States, there are currently no records of captive birth events. In 2013, a female common shovelnose ray housed at the Downtown Aquarium in Houston, Texas, USA gave birth to eleven pups. Although all pups were stillborn, this event demonstrates that it is possible to breed common shovelnose rays in a controlled environment. The single female and two male common shovelnose rays at the aquarium are of sexually mature size (between 206 and 240 cm total length, TL), demonstrate mating behaviors, and provide an excellent opportunity to investigate the reproductive biology of this species. Captive environmental conditions of the birth enclosure may be useful in replicating the birthing event in order to develop a breeding program that could potentially relieve collection pressures on wild populations of guitarfish given their vulnerable status. PMID- 25043107 TI - Multiple imputation methods for nonparametric inference on cumulative incidence with missing cause of failure. AB - We propose a nonparametric approach for cumulative incidence estimation when causes of failure are unknown or missing for some subjects. Under the missing at random assumption, we estimate the cumulative incidence function using multiple imputation methods. We develop asymptotic theory for the cumulative incidence estimators obtained from multiple imputation methods. We also discuss how to construct confidence intervals for the cumulative incidence function and perform a test for comparing the cumulative incidence functions in two samples with missing cause of failure. Through simulation studies, we show that the proposed methods perform well. The methods are illustrated with data from a randomized clinical trial in early stage breast cancer. PMID- 25043108 TI - Thrombosis of the torcular herophili in the fetus: a series of eight cases. AB - OBJECTIVE: The objective of this study was to describe the prenatal sonographic and magnetic resonance imaging (MRI) findings, antenatal course, and pregnancy outcome in fetuses diagnosed as having thrombosis of the torcular herophili. METHODS: Retrospective review of cases collected from five fetal medicine referral centers. RESULTS: Eight cases that were prenatally diagnosed by ultrasound between 22 and 32 weeks of gestation were reviewed. Seven cases were further evaluated with fetal MRI. Associated findings included torcular and superior sagittal sinus dilatation in all cases and ventriculomegaly in two (25%) cases. Serial sonographic follow-up scans demonstrated a favorable antenatal course with complete resolution before delivery in four (50%) cases. Postnatal follow-up from 6 months to 5 years revealed normal outcome in four (50%) infants, speech disabilities in three (38%), and mild neurodevelopmental delay in the remaining case (13%). CONCLUSIONS: Prenatal sonography is an effective method for diagnosing and monitoring thrombosis of the torcular herophili. As a complementary technique, fetal MRI can provide additional information to rule out cerebral parenchymal lesions secondary to hypoperfusion and associated brain malformations. According to our experience, the thrombus almost invariably resolves over time, although mild neurologic disabilities are frequent on long term follow-up. PMID- 25043121 TI - Structure-activity relationship studies of microbiologically active thiosemicarbazides derived from hydroxybenzoic acid hydrazides. AB - Forty-five derivatives of thiosemicarbazide were synthesized, and their antibacterial activity against Gram-positive and Gram-negative bacteria was evaluated. Some of the described compounds exhibited interesting activity against reference strains of Gram-positive bacteria, whereas only two derivatives had the ability to inhibit the growth of Gram-negative species (Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Proteus mirabilis ATCC 12453). The most potent antimicrobial activity was observed in the cases of salicylic acid hydrazide derivatives. The differences in activity inspired us to conduct conformational analysis using molecular mechanics level. The obtained results suggest that the molecule geometry, especially at the N4-terminus of thiosemicarbazide skeleton, determines the antibacterial activity. Unfortunately, in opposition to what we expected, only one of the tested compounds inhibited the activity of the topoIV enzyme, and none of them was active against DNA gyrase. PMID- 25043122 TI - White matter injury: Ischemic and nonischemic. AB - Ischemic pathologies of white matter (WM) include a large proportion of stroke and developmental lesions while multiple sclerosis (MS) is the archetype nonischemic pathology. Growing evidence suggests other important diseases including neurodegenerative and psychiatric disorders also involve a significant WM component. Axonal, oligodendroglial, and astroglial damage proceed via distinct mechanisms in ischemic WM and these mechanisms evolve dramatically with maturation. Axons may pass through four developmental stages where the pattern of membrane protein expression influences how the structure responds to ischemia; WM astrocytes pass through at least two and differ significantly in their ischemia tolerance from grey matter astrocytes; oligodendroglia pass through at least three, with the highly ischemia intolerant pre-oligodendrocyte (pre-Oli) stage linking the less sensitive precursor and mature phenotypes. Neurotransmitters play a central role in WM pathology at all ages. Glutamate excitotoxicity in WM has both necrotic and apoptotic components; the latter mediated by intracellular pathways which differ between receptor types. ATP excitotoxicity may be largely mediated by the P2X7 receptor and also has both necrotic and apoptotic components. Interplay between microglia and other cell types is a critical element in the injury process. A growing appreciation of the significance of WM injury for nonischemic neurological disorders is currently stimulating research into mechanisms; with curious similarities being found with those operating during ischemia. A good example is traumatic brain injury, where axonal pathology can proceed via almost identical pathways to those described during acute ischemia. PMID- 25043123 TI - Performance of density-functional tight-binding models in describing hydrogen bonded anionic-water clusters. AB - Density-functional tight-binding (DFTB) models are computationally efficient approximations to density-functional theory that have been shown to predict reliable structural and energetic properties for various systems. In this work, the reliability and accuracy of the self-consistent-charge DFTB model and its recent extension(s) in predicting the structures, binding energies, charge distributions, and vibrational frequencies of small water clusters containing polyatomic anions of the Hofmeister series (carbonate, sulfate, hydrogen phosphate, acetate, nitrate, perchlorate, and thiocyanate) have been carefully and systematically evaluated on the basis of high-level ab initio quantum chemistry [MP2/aug-cc-pVTZ and CCSD(T)/aug-cc-pVQZ] reference data. Comparison with available experimental data has also been made for further validation. The self-consistent-charge DFTB model, and even more so its recent extensions, are shown to properly account for the structural properties, energetics, intermolecular polarization, and spectral signature of hydrogen-bonding in anionic water clusters at a fraction of the computational cost of ab initio quantum-chemistry methods. This makes DFTB models candidates of choice for investigating much larger systems such as seeded water droplets, their structural properties, formation thermodynamics, and infrared spectra. PMID- 25043124 TI - An investigation of oxidative stress and antioxidant biomarkers during Greenshell mussel (Perna canaliculus) oocyte cryopreservation. AB - Oxidative damage to proteins and lipids, the enzymatic and nonenzymatic antioxidants' response, and the fertilization and development capability of Perna canaliculus oocytes were investigated at critical treatment steps in a previously published controlled-rate cryopreservation protocol. The cryoprotectant (CPA) from this protocol comprises 10% ethylene glycol (v:v) and 0.2 M trehalose (wt/vol) final concentration. Critical treatment steps included (1) seawater control, (2) CPA addition, (3) CPA addition followed by cooling to -6 degrees C, (4) CPA addition and cooling to -10 degrees C, and (5) CPA addition and cooling to -35 degrees C and immersion in liquid nitrogen (LN). The percentage of fertilized oocytes was 53.8 +/- 13.3% in the seawater control but was reduced to 26.0 +/- 15.6% after -35 degrees C + LN treatment, whereas development to D larvae was 21.0 +/- 6.4% in the seawater control reduced to 4.8 +/- 2.9% after cooling to -6 degrees C, and was zero at all the subsequent cooling steps. All oxidative damage biomarkers, protein carbonyls (PCs) and lipid hydroperoxides (LPs), and antioxidants, superoxide dismutase (SOD), catalase, glutathione peroxidase, percent reduced glutathione (%GSH), and total glutathione (defined as glutathione; reduced [GSH] plus glutathione disulphide; derived from two molecules of GSH [GSSG]) were measured over all treatments on unfertilized oocytes over a post-treatment recovery period of 0 to 240 minutes in seawater. An ANOVA showed that both treatment and post-treatment periods had significant effects on the concentrations of all biomarkers (P < 0.05). Protein carbonyls and LPs increased very little after CPA addition and cooling treatments, when compared with the seawater control, but large increases up to sixfold occurred between 0 and 240 minutes for the -35 degrees C + LN treatment. Concentrations of SOD, catalase, total glutathione, and %GSH at 0 minutes decreased by -31.2%, 26.9%, -21.9%, and -25.0%, respectively, between the seawater control and the -35 degrees C + LN treatment. In contrast, glutathione peroxidase concentrations at 0 minutes increased by 34.3% between the seawater control and the -35 degrees C + LN treatment. Although most biochemical biomarkers showed an increasing trend over time (0-240 minutes), total glutathione decreased in concentration over time in all treatments, with the greatest decrease after the -35 degrees C + LN treatment (-41.2%). Significant correlations between biomarkers and D-larvae yield were negative for LPs and positive for SOD, total glutathione, and %GSH (P < 0.05). This is the first report of an investigation using these oxidative stress biomarkers and antioxidant responses on mussel oocytes, and the results have proved useful in characterizing cellular injury during the cryopreservation process. PMID- 25043125 TI - Inhibition of myeloid cell leukemia-1: Association with sorafenib-induced apoptosis in human mucoepidermoid carcinoma cells and tumor xenograft. AB - BACKGROUND: The purpose of our study was to investigate the anticancer effect of sorafenib on mucoepidermoid carcinoma (MEC) and find its new molecular mechanism. METHODS: The apoptotic effects of sorafenib were performed using MTS assay, diamidino-phenylindole (DAPI) staining, Western blotting, reverse transcription polymerase chain reaction (RT-PCR), siRNA, and xenograft. RESULTS: Sorafenib had apoptotic effects on MC-3 and YD15 cells and decreased myeloid cell leukemia-1 (Mcl-1) through proteasome-dependent protein degradation and the inhibition of protein synthesis. Sorafenib significantly affected truncated bid (t-Bid) and siMcl-1 resulting in the upregulation of t-Bid to induce apoptosis. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was also blocked by sorafenib and a potent STAT3 inhibitor, cryptotanshinone clearly induced poly ADP-ribose polymerase (PARP) cleavage by inhibiting Mcl-1 and increasing t-Bid. Finally, administration of sorafenib significantly suppressed tumor growth and induced apoptosis in tumor xenograft model in association with downregulation of Mcl-1 without any side effects. CONCLUSION: Taken together, these findings suggest that sorafenib can be a good anticancer drug candidate for the treatment of MEC. PMID- 25043126 TI - Intraepidermal nerve fiber analysis using immunofluorescence with and without confocal microscopy. AB - INTRODUCTION: Intraepidermal nerve fiber (IENF) linear density is a reliable tool to detect small-fiber neuropathies. In immunofluorescence, the IENF count is performed typically by computer-assisted nerve tracing on confocal images. Alternatively, the count can be performed directly through the oculars of a standard epifluorescence microscope. We specifically compared measures obtained using the 2 methods. METHODS: We compared measures of IENF density in the same 50 skin samples using computer-assisted image analysis and direct count. RESULTS: There was excellent agreement between the 2 methods. Linear regression showed a slope between paired measures virtually equal to 1 (beta = 0.99). Bland-Altman analysis showed a mean difference (offset) between the measures of 0.46 +/- 0.91 fibers/mm. CONCLUSIONS: Direct observation with epifluorescence microscopy proved as reliable as the more time-consuming 3-dimensional computer-assisted analysis of confocal digital images for determining IENF density. PMID- 25043127 TI - NF-kappaB-inducing kinase is a key regulator of inflammation-induced and tumour associated angiogenesis. AB - Angiogenesis is essential during development and in pathological conditions such as chronic inflammation and cancer progression. Inhibition of angiogenesis by targeting vascular endothelial growth factor (VEGF) blocks disease progression, but most patients eventually develop resistance which may result from compensatory signalling pathways. In endothelial cells (ECs), expression of the pro-angiogenic chemokine CXCL12 is regulated by non-canonical nuclear factor (NF) kappaB signalling. Here, we report that NF-kappaB-inducing kinase (NIK) and subsequent non-canonical NF-kappaB signalling regulate both inflammation-induced and tumour-associated angiogenesis. NIK is highly expressed in endothelial cells (ECs) in tumour tissues and inflamed rheumatoid arthritis synovial tissue. Furthermore, non-canonical NF-kappaB signalling in human microvascular ECs significantly enhanced vascular tube formation, which was completely blocked by siRNA targeting NIK. Interestingly, Nik(-/-) mice exhibited normal angiogenesis during development and unaltered TNFalpha- or VEGF-induced angiogenic responses, whereas angiogenesis induced by non-canonical NF-kappaB stimuli was significantly reduced. In addition, angiogenesis in experimental arthritis and a murine tumour model was severely impaired in these mice. These studies provide evidence for a role of non-canonical NF-kappaB signalling in pathological angiogenesis, and identify NIK as a potential therapeutic target in chronic inflammatory diseases and tumour neoangiogenesis. PMID- 25043128 TI - Return to play for neurosurgical patients. AB - BACKGROUND: Concussion and sports-related cranial and spine injuries recently have garnered increased attention from the media, public, and sports' governing bodies. Although concussion has been well-studied, there are minimal data on return to play for structural neurosurgical lesions. OBJECTIVE: We aimed to study current neurosurgical practice on return to play for structural neurosurgical lesions in order to eventually establish guidelines for these athletes. METHODS: A survey was sent to all American Association of Neurological Surgeons members inviting them to submit information on athletes who presented with structural neurosurgical lesions. These included both operative and nonoperative lesions. Ten examples of relevant clinical scenarios were included. Neurosurgeons were surveyed about their practice of clearing these patients for return to play and about patient outcomes afterwards, including any clinical sequelae. Responses were tabulated and studied to search for trends in current practice. Nonstructural cases, such as concussion and cervical strain cases, were excluded. The Mann-Whitney U test was used to test for statistical difference in the time to return for spine versus cranial, instrumented versus noninstrumented spine, and pediatric versus adult cases. RESULTS: Ninety-eight respondents entered data on a total of 189 patients (118 surgical and 71 nonoperative/incidental). In the surgical category, 109 cases (41 cranial, 67 spine, and 1 peripheral nerve lesions) met inclusion criteria. There was a significant difference in time to return between spine (88% returned <=6 months) versus cranial (50% returned >6 months, P<0.001), noninstrumented (55% returned <=3 months) versus instrumented spine (92% returned >3 months, P=0.001), and adult (78% returned <=6 months) versus pediatric cases (52% returned >6 months, P=0.021). Fifty nonoperative/incidental cases met inclusion criteria; 94% of athletes returning to play with nonoperative lesions had no reported clinical sequelae. All nonsurgical and 81% of surgical respondents required deficit resolution before return to play. CONCLUSIONS: The results presented here are the first effort to study current practice on return to play for structural neurosurgical lesions. They establish an early foundation for neurosurgical guidelines on these patients. PMID- 25043129 TI - Nivulian-II a new milk clotting cysteine protease of Euphorbia nivulia latex. AB - Nivulian-II, new milk clotting cysteine protease has been purified from the latex of Euphorbia nivulia Buch.-Ham. Nivulian-II is a monomeric protein with an apparent molecular mass 43670.846 Da. It presents its optimum activity at pH 6.3 and temperature of 50 degrees C. The enzyme was strongly inhibited by common thiol-blocking reagents thereby indicating that it belongs to cysteine protease family. Nivulian-II is a type of glycoprotein and its pI is 3.4. The N-terminal amino acid sequence of Nivulian-II is DFPPNTCCCICC. This sequence showed relatively low homology with several other proteases of Euphorbian plants, suggesting that the isolated enzyme is a new cysteine protease. PMID- 25043130 TI - Partial structural characterization and antioxidant activity of a phenolic-xylan from Castanea sativa hardwood. AB - 4-O-Methylglucuronoxylans (MGX) were isolated from chestnut wood sawdust using two different procedures: chlorite delignification followed by the classical alkaline extraction step, and an unusual green chemistry process of delignification using phthalocyanine/H2O2 followed by a simple extraction with hot water. Antioxidant properties of both MGX were evaluated against the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) by electronic spin resonance (ESR). IC50 of water-extracted MGX was found to be less than 225 MUg mL(-1), in contrast with alkali-extracted MGX for which no radical scavenging was observed. Characterization of extracts by colorimetric assay, GC, LC-MS and NMR spectroscopy provided some clues to understanding structure-function relationships of MGX in connection with their antioxidant activity. PMID- 25043131 TI - Stabilization of antimicrobial silver nanoparticles by a polyhydroxyalkanoate obtained from mixed bacterial culture. AB - The incorporation of antimicrobials into polymer matrices is a promising technology in the food packaging and biomedical areas. Among the most widely used antimicrobials, silver nanoparticles (AgNPs) have emerged as one of the most researched technologies to prevent microbial outbreaks. However, it is known that AgNPs are rather unstable and present patterns of agglomeration that might limit their application. In this work, AgNPs were produced by chemical reduction in suspensions of an unpurified poly(3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV) which was previously obtained from a mixed culture fermentation using a synthetic medium mimicking fermented cheese whey. The synthesis of AgNPs was carried out within the unpurified PHBV suspension (in situ) and by physical mixing (mix). The stability of crystalline and spherical nanoparticles (7+/-3nm) obtained in situ was found to be stable during at least 40 days. The results suggest that the unpurified PHBV appears to be a very efficient capping agent, preventing agglomeration and, thereby, stabilizing successfully the silver nanoparticles. The in situ obtained AgNP-PHBV materials were also found to exhibit a strong antibacterial activity against Salmonella enterica at low concentration (0.1 1ppm). PMID- 25043132 TI - Perspectives on the production of polyhydroxyalkanoates in biorefineries associated with the production of sugar and ethanol. AB - Polyhydroxyalkanoates (PHA) are biodegradable and biocompatible bacterial thermoplastic polymers that can be obtained from renewable resources. The high impact of the carbon source in the final cost of this polymer has been one of the major limiting factors for PHA production and agricultural residues, mainly lignocellulosic materials, have gained attention to overcome this problem. In Brazil, production of 2nd generation ethanol from the glucose fraction, derived from sugarcane bagasse hydrolysate has been studied. The huge amounts of remaining xylose will create an opportunity for the development of other bioprocesses, generating new products to be introduced into a biorefinery model. Although PHA production from sucrose integrated to a 1G ethanol and sugar mill has been proposed in the past, the integration of the process of 2G ethanol in the context of a biorefinery will provide enormous amounts of xylose, which could be applied to produce PHA, establishing a second-generation of PHA production process. Those aspects and perspectives are presented in this article. PMID- 25043134 TI - Cataract surgery after diabetic vitrectomy. PMID- 25043133 TI - Association between brachial-ankle pulse wave velocity and the ratio of l arginine to asymmetric dimethylarginine in patients undergoing coronary angiography. AB - BACKGROUND: Endothelial dysfunction causes vasomotor dysregulation and vascular stiffening in addition to structural changes. By influencing NO synthesis, deficiency of l-arginine relative to asymmetric dimethylarginine (ADMA), which is an l-arginine derivative that acts as a competitive NO synthase inhibitor, may lead to the promotion of arterial stiffness. This study investigated the relationship between the l-arginine/ADMA ratio and brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness. METHODS AND RESULTS: This cross-sectional study enrolled 74 patients (62 men, 12 women; mean age, 67+/-10 years) undergoing elective coronary angiography. A total of 54 (73%) patients had coronary artery disease. Serum l-arginine and ADMA were measured by high performance liquid chromatography with fluorescence detection. The ratio of l arginine to ADMA and the serum l-arginine level was associated with baPWV in univariate regression analysis (l-arginine/ADMA ratio: beta=-0.323, p=0.005; l arginine: beta=-0.247, p=0.034). In addition, baPWV was related to blood hemoglobin concentration, hematocrit, brain natriuretic peptide level, symmetric dimethylarginine, renal function, blood pressure, and heart rate. In multivariate analysis, the l-arginine/ADMA ratio was a significant predictor of baPWV (beta= 0.310, p<0.001). In subgroup analyses, the l-arginine/ADMA ratio was associated with baPWV in elderly patients (n=46, beta=-0.359, p=0.004), and in younger patients (n=28, beta=-0.412, p=0.006). CONCLUSION: A low l-arginine/ADMA ratio may be associated with high baPWV in patients undergoing coronary angiography. PMID- 25043135 TI - Early non-invasive ventilation treatment for respiratory failure due to severe community-acquired pneumonia. AB - BACKGROUND AND AIMS: Severe community-acquired pneumonia (sCAP) have been as defined pneumonia requiring admission to the intensive care unit or carrying a high risk of death. Currently, the treatment of sCAP consists of antibiotic therapy and ventilator support. The use of invasive ventilation causes several complications as does admission to ICU. For this reason, non-invasive ventilation (NIV) has been used for acute respiratory failure to avoid endotracheal intubation. However, few studies have currently assessed the usefulness of NIV in sCAP. METHODS: We prospectively assessed 127 patients with sCAP and severe acute respiratory failure [oxygen arterial pressure/oxygen inspiratory fraction ratio (PaO2/FiO2) <250]. We defined successful NIV as avoidance of intubation and the achievement of PaO2/FiO2 >250 with spontaneous breathing. We assessed predictors of NIV failure and hospital mortality using univariate and multivariate analyses. RESULTS: NIV failed in 32 patients (25.1%). Higher chest X-ray score at admission, chest X-ray worsening, and a lower PaO2/FiO2 and higher alveolar arteriolar gradient (A-aDO2) after 1 h of NIV all independently predicted NIV failure. Higher lactate dehydrogenase and confusion, elevated blood urea, respiratory rate, blood pressure plus age >=65 years at admission, higher A-aDO2, respiratory rate and lower PaO2/FiO2 after 1 h of NIV and intubation rate were directly related to hospital mortality. CONCLUSIONS: Successful treatment is strongly related to less severe illness as well as to a good initial and sustained response to medical therapy and NIV treatment. Constant monitoring of these patients is mandatory. PMID- 25043136 TI - The importance of temperature on the neurovascular unit. AB - Therapeutic hypothermia is the only treatment that has been shown to be of benefit to infant's >= 36 weeks of gestation with hypoxic-ischemic encephalopathy. The evidence for the benefit is based on multiple, well-designed randomized clinical trials. Based on this data, the use of therapeutic hypothermia has been widely disseminated throughout the neonatal community. An important concept in hypoxic-ischemic brain injury is the functioning of the neurovascular unit which links neurons, non-neuronal cellular elements and the capillary endothelial cells to promote optimal barrier maintenance between the brain and systemic circulation, regulation of blood flow and neuro-immunologic functioning. Hypoxic-ischemic injury can trigger increased permeability of the blood-brain-barrier via molecular events within the neurovascular unit and initiate pathways to brain injury. In addition, exposure of the brain to cellular elements from the systemic circulation can further propagate the neuro inflammatory response. The influence of temperature on injury to the neurovascular unit has received relatively little attention. This review will focus on one component of the neurovascular unit, the blood-brain barrier and its constituents. Specifically, this review will address the effects of hypoxia ischemia and temperature on the neurovascular unit and potential knowledge gaps which may serve as areas for further investigation. PMID- 25043137 TI - Chondrocytes expressing intracellular collagen type II enter the cell cycle and co-express collagen type I in monolayer culture. AB - For autologous chondrocyte transplantation, articular chondrocytes are harvested from cartilage tissue and expanded in vitro in monolayer culture. We aimed to characterize with a cellular resolution the synthesis of collagen type II (COL2) and collagen type I (COL1) during expansion in order to further understand why these cells lose the potential to form cartilage tissue when re-introduced into a microenvironment that supports chondrogenesis. During expansion for six passages, levels of transcripts encoding COL2 decreased to <0.1%, whereas transcript levels encoding COL1 increased 370-fold as compared to primary chondrocytes. Flow cytometry for intracellular proteins revealed that chondrocytes acquired a COL2/COL1-double positive phenotype during expansion, and the COL2 positive cells were able to enter the cell cycle. While the fraction of COL2 positive cells decreased from 70% to <2% in primary chondrocytes to passage six cells, the fraction of COL1 positive cells increased from <1% to >95%. In parallel to the decrease of the fraction of COL2 positive cells, the cells' potential to form cartilage-like tissue in pellet cultures steadily decreased. Intracellular staining for COL2 enables for characterization of chondrocyte lineage cells in more detail with a cellular resolution, and it may allow predicting the effectiveness of expanded chondrocytes to form cartilage-like tissue. PMID- 25043138 TI - Discrimination between olfactory receptor agonists and non-agonists. AB - A joint approach combining free-energy calculations and calcium-imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular-dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non-agonists. This study constitutes a proof-of-principle for the computational deorphanization of olfactory receptors. PMID- 25043139 TI - Serial transverse enteroplasty to facilitate enteral autonomy in selected children with short bowel syndrome. AB - BACKGROUND: Serial transverse enteroplasty (STEP) was first described in 2003 as a method for lengthening and tapering of the bowel in short bowel syndrome. The aim of this multicentre study was to review the outcome of a Swedish cohort of children who underwent STEP. METHODS: All children who had a STEP procedure at one of the four centres of paediatric surgery in Sweden between September 2005 and January 2013 were included in this observational cohort study. Demographic details, and data from the time of STEP and at follow-up were collected from the case records and analysed. RESULTS: Twelve patients had a total of 16 STEP procedures; four children underwent a second STEP. The first STEP was performed at a median age of 5.8 (range 0.9-19.0) months. There was no death at a median follow-up of 37.2 (range 3.0-87.5) months and no child had small bowel transplantation. Seven of the 12 children were weaned from parenteral nutrition at a median of 19.5 (range 2.3-42.9) months after STEP. CONCLUSION: STEP is a useful procedure for selected patients with short bowel syndrome and seems to facilitate weaning from parenteral nutrition. At mid-term follow-up a majority of the children had achieved enteral autonomy. The study is limited by the small sample size and lack of a control group. PMID- 25043140 TI - All-organic microelectromechanical systems integrating specific molecular recognition--a new generation of chemical sensors. AB - Cantilever-type all-organic microelectromechanical systems based on molecularly imprinted polymers for specific analyte recognition are used as chemical sensors. They are produced by a simple spray-coating-shadow-masking process. Analyte binding to the cantilever generates a measurable change in its resonance frequency. This allows label-free detection by direct mass sensing of low molecular-weight analytes at nanomolar concentrations. PMID- 25043141 TI - Antibiotic dosing in critically ill patients with septic shock and on continuous renal replacement therapy: can we resolve this problem with pharmacokinetic studies and dosing guidelines? AB - Dosing antibiotics in critically ill patients to achieve therapeutic concentrations is a significant challenge. The presence of septic shock and prescription of continuous renal replacement therapy introduces further complexities for the clinician. Unfortunately, this is a dilemma encountered daily by intensivists. Although small pharmacokinetic studies are emerging to provide data to help address this problem, the variability in results from these studies is profound. As such, effective antibiotic dosing guidelines for critically ill patients who have septic shock and who receive continuous renal replacement therapy are not available. Dosing flowcharts and therapeutic drug monitoring represent the best available options for clinicians to optimize antibiotic dosing. PMID- 25043142 TI - Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. AB - Rhabdomyolysis, a clinical syndrome caused by damage to skeletal muscle and release of its breakdown products into the circulation, can be followed by acute kidney injury (AKI) as a severe complication. The belief that the AKI is triggered by myoglobin as the toxin responsible appears to be oversimplified. Better knowledge of the pathophysiology of rhabdomyolysis and following AKI could widen treatment options, leading to preservation of the kidney: the decision to initiate renal replacement therapy in clinical practice should not be made on the basis of the myoglobin or creatine phosphokinase serum concentrations. PMID- 25043143 TI - Adenoid cystic carcinoma of submandibular salivary gland with late metastases to lung and choroid: a case report and literature review. AB - PURPOSE: Adenoid cystic carcinoma (ACC) is a rare type of cancer that can exist in many body sites. Distant metastasis (DM) is one of the most common features of ACC, usually occurring several years after the initial diagnosis. Approximately half the patients with ACC are found to develop DM after initial treatment of the primary tumor. This report describes a case of ACC with late metastasis to the lung and choroid, which is extremely rare. MATERIALS AND METHODS: A 43-year-old female patient had a history of ACC of the submandibular salivary gland. Five years after total resection and postoperation radiotherapy, distant metastases were found in the left lung and left choroid by immunohistochemistry and imaging examinations. RESULTS: After radiotherapy of lesions of the lung and eye, the patient had a partial response and remained free of progression at almost 7 months. CONCLUSION: Although many metastatic sites have been reported, currently, there are only 6 cases in the literature on ACC metastasizing to the choroid. For those patients with metastatic ACC, although modality treatments, including chemotherapy and radiotherapy, are administered, most patients have continuous metastasis and have a fatal outcome. PMID- 25043144 TI - Maxillary posterior segmentation using an oscillating saw in Le Fort I posterior or superior movement without pterygomaxillary separation. AB - PURPOSE: Any remaining tuberosity or pterygoid plate frequently interferes with posterior or superior movement of the maxilla, if no pterygomaxillary separation is performed in low-level Le Fort I osteotomy. The objective of this report is to describe a technique for maxillary posterior segmentation using an oscillating saw in Le Fort I posterior or superior movement without pterygomaxillary separation and to present the authors' preliminary multicenter experience with this technique. MATERIALS AND METHODS: The authors retrospectively evaluated patients who underwent double-jaw surgery at 3 orthognathic surgery centers from May 2010 to December 2012. In all cases, the segmentation procedure was performed using an oscillating saw on a posterior or tuberosity area of the maxilla before downfracture obtained by leverage alone without pterygomaxillary separation, below or near the lower part of the pterygoid plate. RESULTS: In total, 1,231 patients (411 male and 820 female; mean age, 24.9 yr) were enrolled. Mean surgical time for the maxillary procedure was 55.9 minutes. None of the patients received a blood transfusion, and no significant soft or hard tissue complications clinically compromised the healing of the repositioned maxilla. Mean maxillary posterior and superior movements were 3.4 mm (range, 2.1 to 5.6 mm) and 4.0 mm (range, 1.3 to 5.6 mm), respectively. CONCLUSIONS: The preliminary results indicate that this maxillary posterior segmentation procedure using an oscillating saw in low-level stepped Le Fort I osteotomy can be completed safely and effectively for posterior or superior repositioning of the maxilla, with no need to disturb the integrity of the pterygoid plate. PMID- 25043145 TI - A case of oral plasmablastic lymphoma and review of current trends in oral manifestations associated with human immunodeficiency virus infection. AB - Plasmablastic lymphoma (PBL) is a rare and aggressive type of non-Hodgkin lymphoma that in 2000 was classified as a distinct type of lymphoma related to acquired immune deficiency syndrome by the World Health Organization after the first reports of the disease surfaced in 1997. PBL is strongly associated with human immunodeficiency virus (HIV) infection and often occurs within the oral cavity. Despite intensive chemotherapy regimens and combinational antiretroviral therapy, the prognosis of PBL in HIV-infected patients remains poor. This article describes a case of oral PBL and a literature review of current trends in oral manifestations associated with HIV infection. PMID- 25043146 TI - Optimizing third molar autotransplantation: applications of reverse-engineered surgical templates and rapid prototyping of three-dimensional teeth. AB - The success of autogenous tooth transplantation depends on the vitality of the periodontal ligament attached to the donor tooth, and its viability decreases when it is exposed extraorally. This report describes the case of a 16-year-old patient in whom a rapid prototyped tooth model was performed using cone-beam technology and a surgical template guide for autotransplantation as an effective technique for a critical time-based procedure. PMID- 25043148 TI - Acute toxicity, bioactivity, and enantioselective behavior with tissue distribution in rabbits of myclobutanil enantiomers. AB - The enantioselective bioactivity against pathogens (Cercospora arachidicola, Fulvia fulva, and Phytophthora infestans) and acute toxicity to Daphnia magna of the fungicide myclobutanil enantiomers were studied. The (+)-enantiomer in an antimicrobial activity test was about 1.79-1.96 times more active than the (-) enantiomer. In the toxicity assay, the calculated 24-h LC50 values of the (-) form, rac-form and (+)-form were 16.88, 13.17, and 11.91 mg/L, and the 48-h LC50 values were 10.15, 9.24, and 5.48 mg/L, respectively, showing that (+) myclobutanil was more toxic. Meanwhile, the enantioselective metabolism of myclobutanil enantiomers following a single intravenous (i.v.) administration was investigated in rabbits. Total plasma clearance value (CL) of the (+)-enantiomer was 1.68-fold higher than its antipode. Significant differences in pharmacokinetics parameters between the two enantiomers indicated that the high bioactive (+)-enantiomer was preferentially metabolized and eliminated in plasma. Consistent consequences were found in the tissues (liver, brain, heart, kidney, fat, and muscle), resulting in a relative enrichment of the low-activity (-) myclobutanil. These systemic assessments of the stereoisomers of myclobutanil cannot be used only to investigate environmental and biological behavior, but also have human health implications because of the long persistence of triazole fungicide and enantiomeric enrichment in mammals and humans. PMID- 25043147 TI - Epidemiology and impact of influenza in Mongolia, 2007-2012. AB - BACKGROUND: Mongolia's Health Service began to conduct surveillance for influenza in the 1970s. This surveillance has become more comprehensive over time and now includes 155 sentinel sites in Mongolia. In this study, we analyzed the epidemiological characteristics and impact of influenza using data from influenza surveillance in Mongolia. MATERIALS AND METHODS: The data were collected by the National Influenza Center, Mongolia (NIC). Incidence rates of influenza-like illness (ILI) and severe acute respiratory infections (sARI) were calculated as the proportion of the number of ILI and sARI cases to the total population in the studied areas. Nasopharyngeal samples were collected and tested using real-time reverse transcription polymerase chain reaction [(rt)-RT-PCR]. Selected samples negative for influenza were tested for other respiratory pathogens by multiplex rt-RT-PCR. RESULTS: Averages of 14.0 ILI and 0.8 sARI episodes per 100 population per year were observed during the five influenza seasons. The highest incidences of influenza associated with ILI and sARI were observed among children 0-4 years old. The number of ILI cases showed a clear seasonality, generally peaking between December and February. In contrast, sARI incidence peaked twice during each season. Influenza B was most prevalent during 2007-2008 and 2011-2012, influenza A (H3N2) during 2010-2011, seasonal A (H1N1) during 2008-2009, and A (H1N1) pdm09 during 2009-2010. CONCLUSIONS: Additional data on the epidemiology and impact of influenza including socioeconomic impact and vaccine effectiveness are required to develop a national influenza control policy, including a vaccination strategy. Our results provide useful data for developing such a policy. PMID- 25043149 TI - Energetic tuning by tRNA modifications ensures correct decoding of isoleucine and methionine on the ribosome. AB - Chemical modifications of tRNAs are critical for accurate translation of the genetic code on the ribosome. The discrimination between isoleucine (AUA) and methionine (AUG) codons depends on such modifications of the wobble position in isoleucine tRNA anticodon loops, in all kingdoms of life. Bacteria and archaea employ functionally similar lysine- and agmatine-conjugated cytidine derivatives to ensure decoding fidelity, but the thermodynamics underlying codon discrimination remains unknown. Here, we report structure-based computer simulations that quantitatively reveal the energetics of this decoding strategy in archaea. The results further show that the agmatidine modification confers tRNA specificity primarily by desolvation of the incorrect codon in the non cognate complex. Tautomerism is found to play no significant role in this decoding system as the usual amino form of the modified tRNA is by far the most stable. PMID- 25043150 TI - tert-Butyl nitrite mediated regiospecific nitration of (E)-azoarenes through palladium-catalyzed directed C-H activation. AB - An efficient protocol for the Pd-catalyzed regiospecific ortho-nitration of (E) azoarenes has been achieved for the first time using tBuONO as a nitrating agent under atmospheric oxygen. A series of both symmetrical and unsymmetrical azoarenes were nitrated efficiently by this procedure providing excellent chemo- and regioselectivity and compatibility with a broad array of functional groups. PMID- 25043151 TI - Characterization of the enterovirus 71 VP1 protein as a vaccine candidate. AB - Enterovirus 71 (EV71) is an important agent responsible for hand-foot-and-mouth disease (HFMD), which can cause severe neurological complications and death in children. However, there is no specific treatment for EV71 infection, and a safe and effective vaccine is needed urgently. In this study, an effective and economical method for the production of EV71-VP1 protein was developed, and the VP1 protein was evaluated in humoral and cellular immune responses as an EV71 vaccine. The results revealed that the VP1 protein induced high titers of cross neutralizing antibodies for different EV71 subtypes, and elicited significant splenocyte proliferation. The high levels of IFN-r and IL-10 showed the VP1 protein induced a mixed Th1 and Th2 immune response. Vaccinated female mice could confer protection in their neonatal offspring. Compared with the inactivated EV71, the VP1 protein elicited similar humoral and cellular responses, but the engineered protein is safer, less expensive and can be produced more efficiently. Therefore, EV71-VP1 protein can induce effective immunologic protection against EV71 and is an ideal candidate against EV71 infection. PMID- 25043152 TI - Preventive effects of ZPDC glycoprotein (24 kDa) on hepatotoxicity induced by mercury chloride in vitro and in vivo. AB - Mercury is a potent environmental contaminant that exerts toxic effect on various vital organs in the human body. Recently, we isolated glycoprotein from Zanthoxylum piperitum DC (ZPDC), which has antioxidant and anticancer effects. In the present study, we determined the preventive effects of ZPDC glycoprotein on hepatic damage induced by mercury chloride (HgCl2 ). We evaluated the activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), cyclo-oxygenase (COX-2), inducible nitric oxide synthetase (iNOS), and activator protein (AP-1) and the quantitative expressions of nuclear factor E2-related factor (Nrf2), heme oxygenase (HO-1), metallothionein (MT) and reduced glutathione (GSH) in mercury-chloride-exposed (50 MUM and 10 mg/kg body weight) primary cultured hepatocytes and ICR mice, using biochemical assays, radioactivity and immunoblot analysis. The results demonstrated that ZPDC glycoprotein decreased the levels of LDH, ALT, HO-1 and MT, whereas it increased the activities of hepatic antioxidant enzymes (SOD, CAT and GPx) and reduced GSH in mercury-chloride-exposed primary cultured hepatocytes. Also, it suppressed arachidonic acid release and expression of ERK, p38 MAPK, COX-2, iNOS, AP-1 and Nrf-2 in primary cultured hepatocytes and ICR mice exposed to mercury chloride. Collectively, ZPDC glycoprotein may have potential applications to prevent hepatotoxicity induced by mercury chloride. PMID- 25043154 TI - Toward enantioselective nano ultrahigh-performance liquid chromatography with Whelk-O1 chiral stationary phase. AB - In this study, a Whelk-O1 chiral stationary phase immobilized on 2.5 MUm silica particles was employed in nanoLC. Two nanocolumns (180 and 250 mm long, 75 MUm id) with a single polymeric organic monolithic outlet frit were packed under high pressure ultrasonic-assisted packing procedure. The monolithic outlet frit was prepared by thermal polymerization of methacrylate-based monomers affording high mechanical stability and high-pressure resistance. Very efficient enantioseparations with more than 70 000 plates/m were achieved in normal phase mode by eluting (+/-) acenaphthenol. Nanocolumns were also tested in RP mode by using on-line MS detection with nano-spray ESI ion source. Kinetic performances of columns in RP mode were comparable to those in normal phase-conditions. PMID- 25043153 TI - Phase III double-blind, placebo-controlled study of gabapentin for the prevention of delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, NCCTG N08C3 (Alliance). AB - BACKGROUND: Despite targeted antiemetics, data support an unmet need related to the management of delayed nausea and vomiting (NV). Promising pilot data informed this phase III trial evaluating gabapentin for delayed NV from highly emetogenic chemotherapy (HEC). METHODS: Participants were randomized to receive prophylactic treatment with 20 mg of dexamethasone and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by gabapentin 300 mg twice a day and dexamethasone (dex) or placebo and dex after HEC. Gabapentin/placebo was started the day of chemotherapy and continued through day 5 for the first chemotherapy cycle, whereas dex was titrated down on days 2-4. The primary end point was complete response (CR), defined as no emesis and no use of rescue medications on days 2-6, using an NV diary. The percentages of those in each group with a CR were compared by Fisher's exact test. RESULTS: Four hundred thirty patients were enrolled in this study. Forty-seven percent of patients in the gabapentin arm and 41% in the placebo arm had a CR (P = .23). Mean number of emesis episodes was <0.5 daily, and mean nausea severity was < 2 (mild). In both arms, patient satisfaction with NV control was greater than 8 (with 10 being perfectly satisfied). There were no significant differences in unwanted side effects. CONCLUSIONS: In this study, gabapentin did not significantly improve delayed NV. Patients were satisfied with the control of their nausea and vomiting irrespective of arm. The use of a 5HT3 RA and dexamethasone provided good control of nausea and vomiting for most patients. PMID- 25043155 TI - Outdoor time is associated with physical activity, sedentary time, and cardiorespiratory fitness in youth. AB - OBJECTIVE: To determine whether time spent outdoors was associated with increased moderate-to-vigorous physical activity (MVPA) and related health benefits in youth. STUDY DESIGN: We performed a cross-sectional study of 306 youth aged 13.6 +/- 1.4 years. The exposure of interest was self-reported time spent outdoors after school, stratified into three categories: none, some, and most/all of the time. The main outcome of interest was accelerometer-derived MVPA (Actical: 1500 to >6500 counts/min). Secondary outcomes included sedentary behavior, cardiorespiratory fitness, overweight status, and blood pressure. RESULTS: Among the 306 youth studied, those who reported spending most/all of their after-school time outdoors (n = 120) participated in more MVPA (61.0 +/- 24.3 vs 39.9 +/- 19.1 min/day; adjusted P < .001), were more likely to achieve the recommended minimum 60 min/day of MVPA (aOR 2.8; 95% CI, 1.3-6.4), spent less time in sedentary activities (539 +/- 97 min/day vs 610 +/- 146 min/day; adjusted P < .001), and had higher cardiorespiratory fitness (49 +/- 5 vs 45 +/- 6 mL/kg/min; adjusted P < .001) than youth who reported no time outdoors (n = 52). No differences in overweight/obesity or blood pressure were observed across the groups. CONCLUSIONS: Time spent outdoors is positively associated with MVPA and cardiorespiratory fitness in youth and negatively associated with sedentary behavior. Experimental trials are needed to determine whether strategies designed to increase time spent outdoors exert a positive influence on physical activity and fitness levels in youth. PMID- 25043156 TI - Efficacy of dipeptidyl-peptidase-4 inhibitors and impact on beta-cell function in Asian and Caucasian type 2 diabetes mellitus patients: A meta-analysis. AB - BACKGROUND: This work aimed to compare the efficacy of dipeptidyl peptidase-IV (DPP-4) inhibitors and their impact on beta-cell function in Asian and Caucasian patients with type 2 diabetes mellitus. METHODS: Databases were systematically searched and qualifying studies that compared DPP-4 inhibitors with other antidiabetic medications in type 2 diabetes were included. RESULTS: A total of 68 studies were included in the meta-analysis. Comparison of DPP-4 inhibitors with placebo in Asian patients showed a decrease in glycosylated hemoglobin (HbA1c ) favoring DPP-4 inhibitors (weighted mean difference [WMD], -0.81%; 95% confidence interval [CI], -0.95% to -0.68%; P < 0.001). Comparison of HbA1c changes between Asian and Caucasian patients showed a significant between-group difference of 0.18% (95% CI, -0.32% to -0.04%; P = 0.011) when compared with placebo. In Asian patients, the homeostatic model assessment for beta-cell function (HOMA-beta) was increased with DPP-4 inhibitors compared with placebo (WMD, 7.90; 95% CI, 4.29 to 11.51; P < 0.001), although to a lesser extent in Caucasian patients. Comparisons between Asian and Caucasian patients showed a significant between-group difference of -4.97 (95% CI, -9.86 to -0.09; P = 0.046) compared with placebo. Body weight increase with DPP-4 inhibitors compared with placebo was comparable in Asian and Caucasian studies (WMD, 0.37 kg and 0.45 kg and 95% CI, 0.04-0.69 and 0.27-0.62, respectively). CONCLUSIONS: The glucose-lowering efficacy of DPP-4 inhibitors was greater in Asian patients than in Caucasian patients, although the effect on beta-cell function was inferior in Asian patients. The effect of DPP-4 inhibitors on insulin resistance and body weight in Asian patients was comparable with that observed in Caucasian patients. PMID- 25043158 TI - Production of gamma-aminobutyric acid by microorganisms from different food sources. AB - BACKGROUND: gamma-Aminobutyric acid (GABA) is a potentially bioactive component of foods and pharmaceuticals. The aim of this study was screen lactic acid bacteria belonging to the Czech Collection of Microorganisms, and microorganisms (yeast and bacteria) from 10 different food sources for GABA production by fermentation in broth or plant and animal products. RESULTS: Under an aerobic atmosphere, very low selectivity of GABA production (from 0.8% to 1.3%) was obtained using yeast and filamentous fungi, while higher selectivity (from 6.5% to 21.0%) was obtained with bacteria. The use of anaerobic conditions, combined with the addition of coenzyme (pyridoxal-5-phosphate) and salts (CaCl2 , NaCl), led to the detection of a low concentration of GABA precursor. Simultaneously, using an optimal temperature of 33 degrees C, a pH of 6.5 and bacteria from banana (Pseudomonadaceae and Enterobacteriaceae families), surprisingly, a high selectivity of GABA was obtained. A positive impact of fenugreek sprouts on the proteolytic process and GABA production from plant material as a source of GABA precursor was identified. CONCLUSIONS: Lactic acid bacteria for the production of new plant and animal GABA-rich products from different natural sources containing GABA precursor can be used. PMID- 25043157 TI - Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer. AB - BACKGROUND: ERG rearrangements in localized prostate cancer can be detected with high sensitivity and specificity by immunohistochemistry (IHC). However, recent data suggest that ERG IHC may be less sensitive for ERG rearrangements in castration-resistant prostate cancer (CRPC). Thus, we sought to examine ERG protein expression in a cohort of rapid autopsy patients with lethal metastatic CRPC (mCRPC). METHODS: A tissue microarray (TMA) of tumor sites from these patients was evaluated for ERG, prostate-specific antigen (PSA), and androgen receptor (AR) expression by IHC and correlated with ERG rearrangement status by fluorescent in situ hybridization (FISH). IHC was scored as the product of tumor cell staining intensity (0-3) and percentage of cells positive (0-100) (overall product score range = 0-300). RESULTS: All 16 (100%) ERG rearrangement negative (ERG(neg) ) patients were also negative for ERG tumor cell expression (i.e., IHC product score = 0). Of the 10 ERG rearrangement positive (ERG(pos) ) patients, two (20%) were completely negative for ERG tumor cell expression, while eight (80%) had weak ERG expression (median IHC product score = 5-110). Of these eight ERG(pos) patients, five (63%) had at least one tumor site without any detectable ERG expression. For a given ERG(pos) patient, ERG expression varied both between and within tumor sites; AR and PSA expression also varied between tumor sites, and there was no significant correlation between ERG and AR or PSA expression. CONCLUSIONS: These data reveal frequent discordance between ERG IHC and ERG FISH in ERG(pos) patients from this unique cohort of heavily treated lethal mCRPC. PMID- 25043159 TI - Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography study with translocator protein 18 kDa radioligand, [18F] FEPPA. AB - The ability to quantify translocator protein 18 kDa (TSPO) in white matter (WM) is important to understand the role of neuroinflammation in neurological disorders with WM involvement. This article aims to extend the utility of TSPO imaging in WM using a second-generation radioligand, [18F]-FEPPA, and high resolution research tomograph (HRRT) positron emission tomography (PET) camera system. Four WM regions of interests (WM-ROI), relevant to the study of aging and neuroinflammatory diseases, were examined. The corpus callosum, cingulum bundle, superior longitudinal fasciculus, and posterior limb of internal capsule were delineated automatically onto subject's T1 -weighted magnetic resonance image using a diffusion tensor imaging-based WM template. The TSPO polymorphism (rs6971) stratified individuals to three genetic groups: high-affinity binders (HAB), mixed-affinity binders (MAB), and low-affinity binders. [18F]-FEPPA PET scans were acquired on 32 healthy subjects and analyzed using a full kinetic compartment analysis. The two-tissue compartment model showed moderate identifiability (coefficient of variation 15-19%) for [18F]-FEPPA total volume distribution (VT ) in WM-ROIs. Noise affects VT variability, although its effect on bias was small (6%). In a worst-case scenario, <=6% of simulated data did not fit reliably. A simulation of increased TSPO density exposed minimal effect on variability and identifiability of [18F]-FEPPA VT in WM-ROIs. We found no association between age and [18F]-FEPPA VT in WM-ROIs. The VT values were 15% higher in HAB than in MAB, although the difference was not statistically significant. This study provides evidence for the utility and limitations of [18F]-FEPPA PET to measure TSPO expression in WM. PMID- 25043160 TI - Cancer staging in outcomes assessment. AB - The T N M staging system created by a surgeon in the 1950s continues to be a major benchmark for assessing long-term outcomes in adult solid tumors. Although several major changes have occurred in this anatomical staging system, the tenets of TNM staging remain constant. Recently molecular markers and biologic modifiers have been added to this anatomical staging system to create a more robust outcomes tool. PMID- 25043161 TI - Bacterial pathogenesis: Pneumococci find a sugar daddy in influenza. PMID- 25043162 TI - Immune evasion: See no evil. PMID- 25043163 TI - Bacterial physiology: Flipping out over MurJ. PMID- 25043164 TI - Superficial siderosis of the central nervous system secondary to spinal ependymoma. AB - Superficial siderosis of the central nervous system is a syndrome caused by deposition of hemosiderin in the subpial layers of the central nervous system, occurring as a result of recurrent asymptomatic or symptomatic bleeding into the subarachnoid space. We report a rare case of superficial siderosis in a 33-year old man who presented with sensorineural hearing loss. The diagnosis of superficial siderosis on MRI brain studies led to further investigations with detection of a spinal ependymoma at L1-L2, compressing the cauda equina. Gross total resection of the tumor arrested the progression of the neurological deterioration. Our report underlies the importance of early diagnosis and surgical management, with imaging examination of the full neuroaxis to identify the source of bleeding, to halt disease progression and improve prognosis. PMID- 25043165 TI - Long-term efficacy and limitations of cyclophosphamide in myasthenia gravis. AB - Myasthenia gravis (MG) is a chronic autoimmune disorder with a fluctuating clinical course. The aim of immunotherapy is to bring about long-term remission. We evaluated the safety and efficacy of cyclophosphamide in generalized MG. We also highlight the limitations of cyclophosphamide therapy in inducing long-term remission. Data from 22 patients with generalized MG who received cyclophosphamide therapy were analyzed in terms of its safety and outcome. Twelve patients completed at least six pulses of intravenous cyclophosphamide therapy, and all improved symptomatically at 6 months. At 1 year, only seven patients reported sustained benefit and five had discontinued oral pyridostigmine. During a follow-up period of 56.67 months, all but one patient relapsed and required alternative immunomodulatory therapy. The average time to remission after the initiation of intravenous pulse cyclophosphamide (n=12) was 3.6 months (standard deviation [SD] 1.6 months, range 1-6 months), while the mean duration of remission was 20.3 months (SD 8.8 months, range 12-39 months). Forty-six adverse events were documented in 11 patients over 127 cyclophosphamide pulses. Most of the adverse events were managed symptomatically. In four patients, cyclophosphamide had to be discontinued due to adverse events. Intravenous pulse cyclophosphamide is effective in the management of MG; however remission may be short, necessitating long-term follow-up and alternative immunomodulation. Careful monitoring for adverse events should be mandatory. PMID- 25043166 TI - Gangliogliomas of the optic pathway. AB - Gangliogliomas involving the optic apparatus are rare, with only 23 cases described in the literature to our knowledge. Because of their location, they are resistant to gross total resection and command careful consideration of adjuvant treatment. Here, we review the existing literature describing these cases, along with our own additional patient. Most patients (91.3%) with optic gangliogliomas presented with progressive visual disturbances, and the majority were male (69.6%), as with gangliogliomas in general. Ophthalmological evaluation is warranted in these patients, followed by neurological imaging (preferably MRI). Screening for neurofibromatosis type 1 (NF1) is essential, as NF1 patients represent a disproportionate number of optic ganglioglioma cases (13.0%). Gross total resection should be attempted only if vision is beyond salvage, as this can be curative. Otherwise, when serviceable vision remains, subtotal resection with adjuvant radiation should be carried out when feasible. Despite treatment, the prognosis remains mixed, with roughly one-third of patients progressing. PMID- 25043167 TI - "Brain on fire": a new imaging sign. AB - Primary central nervous system (CNS) marginal zone B cell lymphoma is a rare condition. It has an indolent disease course and usually presents as a dural based lesion. We present a patient with non-dural-based, primary CNS marginal zone B cell lymphoma with an unusual imaging appearance, not previously described to our knowledge. PMID- 25043169 TI - When traveling--or making a germ line--packing in advance provides more options! PMID- 25043171 TI - The future of JAK inhibition in myelofibrosis and beyond. AB - The identification of aberrant JAK-STAT signaling in patients with myeloproliferative neoplasms has served as the basis for the development of a new class of targeted agents. Ruxolitinib, the first-in-class oral small molecule JAK1/2 inhibitor, has demonstrated clinical efficacy and shown a potential overall survival benefit in two randomized phase III clinical trials. However, this agent has not been associated with improvements in cytopenias, molecular remissions, or resolution of bone marrow fibrosis. Therefore, further translational research is needed to improve the understanding of the pathogenetic mechanisms driving this myeloid malignancy to ultimately address remaining unmet clinical needs. A number of novel JAK inhibitors are being evaluated in ongoing clinical trials and the full clinical potential of these newer agents remains incompletely understood. The use of JAK inhibition in combination therapy approaches, as well as mono- and combination therapies in the treatment of advanced forms of polycythemia vera are also under active investigation. This review will update the reader on the current understanding of oncogenic JAK-STAT pathway activity in the pathogenesis of myeloproliferative neoplasms and the current success and limitations of anti-JAK therapy. PMID- 25043172 TI - Removal of ammonia from landfill leachate by struvite precipitation with the use of low-cost phosphate and magnesium sources. AB - This paper presents a study concerning ammonia removal from landfill leachate by struvite precipitation with the use of waste phosphoric acid as the phosphate source. The results indicated that the Al(3+) ions present in the waste phosphoric acid significantly affected the struvite precipitation, and a removal ratio of ammonia close to that of pure phosphate salts could be achieved. Nevertheless, large amounts of NaOH were necessary to neutralize the H(+) present in the waste phosphoric acid. To overcome this problem, a low-cost magnesium source was proposed to be used as well as an alkali reagent in the struvite precipitation. The ammonia removal ratios were found to be 83%, with a remaining phosphate of 56 mg/L, by dosing the low-cost MgO in the Mg:N:P molar ratio of 3:1:1. An economic analysis showed that using waste phosphoric acid plus the low cost MgO could save chemical costs by 68% compared with the use of pure chemicals. Post-treatment employment of a biological anaerobic filter process demonstrated that the high concentration of Mg(2+) remaining in the effluent of the struvite precipitation has no inhibitory effect on the performance of the biological treatment. PMID- 25043173 TI - A revealed preference approach to valuing non-market recreational fishing losses from the Deepwater Horizon oil spill. AB - At an estimated 206 million gallons, the Deepwater Horizon (DWH) is the largest marine oil spill in the history of the United States. In this paper we develop a series of random utility models of site choice by saltwater anglers in the Southeast US and estimate monetary compensation for recreational losses due to the DWH oil spill. Heterogeneity in angler preferences is accounted for by using mixed logit models, and different compensation measures for shore-based, private boat, and for-hire anglers are estimated. Results indicate that willingness to pay for oil spill prevention varies by fishing mode and anglers fishing from shore and private boats exhibit heterogeneous preferences for oil spill avoidance. In addition, the total monetary compensation due to anglers is estimated at USD 585 million. PMID- 25043174 TI - Anaemia, a common but often unrecognized risk in diabetic patients: a review. AB - Anaemia in patients with diabetes, both type 1 and type 2, is a frequent clinical finding. The mechanisms of anaemia are multifactorial and often not very well understood. Iatrogenic causes, including oral antidiabetic drugs, ACE inhibitors and ARBs, and renal insufficiency are the major causes of anaemia in patients with type 2 diabetes. In patients with type 1, the cause is often an associated autoimmune disease, and screening for autoimmune gastritis, pernicious anaemia, Hashimoto's thyroiditis, coeliac disease and Addison's disease is recommended. Other rare causes - including G6PD deficiency, microangiopathic haemolytic anaemia and thiamine-responsive megaloblastic anaemia - should be suspected in young patients or when the classical causes are excluded. Early detection and recognition of the cause(s) of anaemia in patients with diabetes could help to prevent other clinical manifestations as well as the complications of diabetes. PMID- 25043175 TI - Tetradecacobalt(II)-containing 36-niobate [Co14(OH)16(H2O)8Nb36O106]20- and its photocatalytic H2 evolution activity. AB - A gigantic Co14-containing 36-niobate, Na12K8[Co14(OH)16(H2O)8Nb36O106]?71H2O (1), has been prepared by the hydrothermal method and structurally characterized. Polyanion [Co14(OH)16(H2O)8Nb36O106](20-) (1 a) comprises a central Co7 core, surrounded by another seven isolated Co(2+) ions and six Lindqvist-type (Nb6O19) hexaniobate fragments. This is the first example of a high-nuclear cobalt-cluster containing polyoxoniobate. The photocatalytic H2 evolution activity of Pt-loaded 1 was observed in methanol solution under irradiation using a 300 W Xe lamp. PMID- 25043176 TI - A staged thyroidectomy approach for gastric bypass patients. PMID- 25043177 TI - The SAGA histone deubiquitinase module controls yeast replicative lifespan via Sir2 interaction. AB - We have analyzed the yeast replicative lifespan of a large number of open reading frame (ORF) deletions. Here, we report that strains lacking genes SGF73, SGF11, and UBP8 encoding SAGA/SLIK complex histone deubiquitinase module (DUBm) components are exceptionally long lived. Strains lacking other SAGA/SALSA components, including the acetyltransferase encoded by GCN5, are not long lived; however, these genes are required for the lifespan extension observed in DUBm deletions. Moreover, the SIR2-encoded histone deacetylase is required, and we document both a genetic and physical interaction between DUBm and Sir2. A series of studies assessing Sir2-dependent functions lead us to propose that DUBm strains are exceptionally long lived because they promote multiple prolongevity events, including reduced rDNA recombination and altered silencing of telomere proximal genes. Given that ataxin-7, the human Sgf73 ortholog, causes the neurodegenerative disease spinocerebellar ataxia type 7, our findings indicate that the genetic and epigenetic interactions between DUBm and SIR2 will be relevant to neurodegeneration and aging. PMID- 25043179 TI - Contribution of aberrant GluK2-containing kainate receptors to chronic seizures in temporal lobe epilepsy. AB - Kainate is a potent neurotoxin known to induce acute seizures. However, whether kainate receptors (KARs) play any role in the pathophysiology of temporal lobe epilepsy (TLE) is not known. In TLE, recurrent mossy fiber (rMF) axons form abnormal excitatory synapses onto other dentate granule cells that operate via KARs. The present study explores the pathophysiological implications of KARs in generating recurrent seizures in chronic epilepsy. In an in vitro model of TLE, seizure-like activity was minimized in mice lacking the GluK2 subunit, which is a main component of aberrant synaptic KARs at rMF synapses. In vivo, the frequency of interictal spikes and ictal discharges was strongly reduced in GluK2(-/-) mice or in the presence of a GluK2/GluK5 receptor antagonist. Our data show that aberrant GluK2-containing KARs play a major role in the chronic seizures that characterize TLE and thus constitute a promising antiepileptic target. PMID- 25043178 TI - Genome-wide functional analysis reveals factors needed at the transition steps of induced reprogramming. AB - Although transcriptome analysis can uncover the molecular changes that occur during induced reprogramming, the functional requirements for a given factor during stepwise cell-fate transitions are left unclear. Here, we used a genome wide RNAi screen and performed integrated transcriptome analysis to identify key genes and cellular events required at the transition steps in reprogramming. Genes associated with cell signaling pathways (e.g., Itpr1, Itpr2, and Pdia3) constitute the major regulatory networks before cells acquire pluripotency. Activation of a specific gene set (e.g., Utf1 or Tdgf1) is important for mature induced pluripotent stem cell formation. Strikingly, a major proportion of RNAi targets (~ 53% to 70%) includes genes whose expression levels are unchanged during reprogramming. Among these non-differentially expressed genes, Dmbx1, Hnf4g, Nobox, and Asb4 are important, whereas Nfe2, Cdkn2aip, Msx3, Dbx1, Lzts1, Gtf2i, and Ankrd22 are roadblocks to reprogramming. Together, our results provide a wealth of information about gene functions required at transition steps during reprogramming. PMID- 25043180 TI - The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge. AB - The macrophage NLRC4 inflammasome drives potent innate immune responses against Salmonella by eliciting caspase-1-dependent proinflammatory cytokine production (e.g., interleukin-1beta [IL-1beta]) and pyroptotic cell death. However, the potential contribution of other cell types to inflammasome-mediated host defense against Salmonella was unclear. Here, we demonstrate that neutrophils, typically viewed as cellular targets of IL-1beta, themselves activate the NLRC4 inflammasome during acute Salmonella infection and are a major cell compartment for IL-1beta production during acute peritoneal challenge in vivo. Importantly, unlike macrophages, neutrophils do not undergo pyroptosis upon NLRC4 inflammasome activation. The resistance of neutrophils to pyroptotic death is unique among inflammasome-signaling cells so far described and allows neutrophils to sustain IL-1beta production at a site of infection without compromising the crucial inflammasome-independent antimicrobial effector functions that would be lost if neutrophils rapidly lysed upon caspase-1 activation. Inflammasome pathway modification in neutrophils thus maximizes host proinflammatory and antimicrobial responses during pathogen challenge. PMID- 25043181 TI - The extreme anterior domain is an essential craniofacial organizer acting through Kinin-Kallikrein signaling. AB - The extreme anterior domain (EAD) is a conserved embryonic region that includes the presumptive mouth. We show that the Kinin-Kallikrein pathway is active in the EAD and necessary for craniofacial development in Xenopus and zebrafish. The mouth failed to form and neural crest (NC) development and migration was abnormal after loss of function (LOF) in the pathway genes kng, encoding Bradykinin (xBdk), carboxypeptidase-N (cpn), which cleaves Bradykinin, and neuronal nitric oxide synthase (nNOS). Consistent with a role for nitric oxide (NO) in face formation, endogenous NO levels declined after LOF in pathway genes, but these were restored and a normal face formed after medial implantation of xBdk-beads into LOF embryos. Facial transplants demonstrated that Cpn function from within the EAD is necessary for the migration of first arch cranial NC into the face and for promoting mouth opening. The study identifies the EAD as an essential craniofacial organizer acting through Kinin-Kallikrein signaling. PMID- 25043182 TI - Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. AB - Embryo homing and implantation occur within a crypt (implantation chamber) at the antimesometrial (AM) pole along the uterus. The mechanism by which this is achieved is not known. Here, we show that villi-like epithelial projections from the main uterine lumen toward the AM pole at regularly spaced intervals that form crypts for embryo implantation were disrupted in mice with uterine loss or gain of function of Wnt5a, or loss of function of both Ror1 and Ror2. This disruption of Wnt5a-ROR signaling resulted in disorderly epithelial projections, crypt formation, embryo spacing, and impaired implantation. These early disturbances under abnormal Wnt5a-ROR signaling were reflected in adverse late pregnancy events, including defective decidualization and placentation, ultimately leading to compromised pregnancy outcomes. This study presents deeper insight regarding the formation of organized epithelial projections for crypt formation and embryo implantation for pregnancy success. PMID- 25043183 TI - Single-cell mass cytometry analysis of human tonsil T cell remodeling by varicella zoster virus. AB - Although pathogens must infect differentiated host cells that exhibit substantial diversity, documenting the consequences of infection against this heterogeneity is challenging. Single-cell mass cytometry permits deep profiling based on combinatorial expression of surface and intracellular proteins. We used this method to investigate varicella-zoster virus (VZV) infection of tonsil T cells, which mediate viral transport to skin. Our results indicate that VZV induces a continuum of changes regardless of basal phenotypic and functional T cell characteristics. Contrary to the premise that VZV selectively infects T cells with skin trafficking profiles, VZV infection altered T cell surface proteins to enhance or induce these properties. Zap70 and Akt signaling pathways that trigger such surface changes were activated in VZV-infected naive and memory cells by a T cell receptor (TCR)-independent process. Single-cell mass cytometry is likely to be broadly relevant for demonstrating how intracellular pathogens modulate differentiated cells to support pathogenesis in the natural host. PMID- 25043184 TI - Sox4 links tumor suppression to accelerated aging in mice by modulating stem cell activation. AB - Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4(cKO)) in stratified epithelia. Sox4(cKO) mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer. PMID- 25043185 TI - Silencing of the DNA mismatch repair gene MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase LSD1. AB - Silencing of MLH1 is frequently seen in sporadic colorectal cancers. We show here that hypoxia causes decreased histone H3 lysine 4 (H3K4) methylation at the MLH1 promoter via the action of the H3K4 demethylases LSD1 and PLU-1 and promotes durable long-term silencing in a pathway that requires LSD1. Knockdown of LSD1 or its corepressor, CoREST, also prevents the resilencing (and associated cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient reactivation by treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC). The results demonstrate that hypoxia is a driving force for silencing of MLH1 and that the LSD1/CoREST complex is necessary for this process. The results reveal a mechanism by which hypoxia promotes cancer cell evolution to drive malignant progression through epigenetic modulation. Our findings suggest that LSD1/CoREST acts as a colon cancer oncogene by epigenetically silencing MLH1 and also identify the LSD1/CoREST complex as a potential target for therapy. PMID- 25043186 TI - Cell-specific retrograde signals mediate antiparallel effects of angiotensin II on osmoreceptor afferents to vasopressin and oxytocin neurons. AB - Homeostatic control of extracellular fluid osmolality in rats requires a parallel excitation of vasopressin (VP) and oxytocin (OT) neurosecretory neurons by osmoreceptor afferents to regulate the amount of water and sodium in the urine under normal conditions. However, during decreased blood volume (hypovolemia), natriuresis is suppressed, whereas osmotically driven antidiuresis is enhanced to promote retention of isotonic fluid. Because Angiotensin II (Ang II) is released centrally to indicate hypovolemia, we hypothesized that Ang II can evoke a state dependent switch in circuit function. Here, we show that Ang II, a neuropeptide released centrally during hypovolemia, suppresses osmoreceptor-mediated synaptic excitation of OT neurons while potentiating excitation of VP neurons. Ang II does this by inducing cell-autonomous release of nitric oxide by VP neurons and endocannabinoids by OT neurons to respectively enhance and reduce glutamate release by osmoreceptor afferents. These findings indicate that peptide modulators such as Ang II can regulate synaptic communication to achieve a state dependent and target-specific modulation of circuit activity. PMID- 25043187 TI - A genome-scale resource for the functional characterization of Arabidopsis transcription factors. AB - Extensive transcriptional networks play major roles in cellular and organismal functions. Transcript levels are in part determined by the combinatorial and overlapping functions of multiple transcription factors (TFs) bound to gene promoters. Thus, TF-promoter interactions provide the basic molecular wiring of transcriptional regulatory networks. In plants, discovery of the functional roles of TFs is limited by an increased complexity of network circuitry due to a significant expansion of TF families. Here, we present the construction of a comprehensive collection of Arabidopsis TFs clones created to provide a versatile resource for uncovering TF biological functions. We leveraged this collection by implementing a high-throughput DNA binding assay and identified direct regulators of a key clock gene (CCA1) that provide molecular links between different signaling modules and the circadian clock. The resources introduced in this work will significantly contribute to a better understanding of the transcriptional regulatory landscape of plant genomes. PMID- 25043188 TI - Genome-wide translational changes induced by the prion [PSI+]. AB - Prions are infectious proteins that can adopt a structural conformation that is then propagated among other molecules of the same protein. [PSI(+)] is an aggregated conformation of the translational release factor eRF3. [PSI(+)] modifies cellular fitness, inducing various phenotypes depending on genetic background. However, the genes displaying [PSI(+)]-controlled expression remain unknown. We used ribosome profiling in isogenic [PSI(+)] and [psi(-)] strains to identify the changes induced by [PSI(+)]. We found 100 genes with stop codon readthrough events and showed that many stress-response genes were repressed in the presence of [PSI(+)]. Surprisingly, [PSI(+)] was also found to affect reading frame selection independently of its effect on translation termination efficiency. These results indicate that [PSI(+)] has a broader impact than initially anticipated, providing explanations for the phenotypic differences between [psi(-)] and [PSI(+)] strains. PMID- 25043189 TI - Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody. AB - Interleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor alpha chain (IL3Ralpha) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM CSF), IL-5, and IL-13 receptors, adopting unique "open" and classical "closed" conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas "open-like" IL3Ralpha mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a "double hit" cytokine receptor blockade. PMID- 25043191 TI - Fasting mediated increase in p-BAD(ser155) and p-AKT(ser473) in the prefrontal cortex of mice. AB - BAD-deficient mice and fasting have several common functional roles in seizures, beta-hydroxybutyrate (BHB) uptake in brain and alteration in counterregulatory hormonal regulation during hypoglycemia. Neuronal specific insulin receptor knockout (NIRKO) mice display impaired counterregulatory hormonal responses during hypoglycemia. In this study we investigated the fasting mediated expression of p-BAD(ser155) and p-AKT(ser473) in different regions of brain (prefrontal cortex, hippocampus, midbrain and hypothalamus). Fasting specifically increases p-BAD(ser155) and p-AKT(ser473) in prefrontal cortex and decreases in other regions of brain. Our results suggest that fasting may increase the uptake BHB by decreasing p-BAD(ser155) in the brain during hypoglycemia except prefrontal cortex and it uncovers specific functional area of p-BAD(ser155) and p AKT(ser473) that may regulates counter regulatory hormonal response. Overall in support with previous findings, fasting mediated hypoglycemia activates prefrontal cortex insulin signaling which influences the hypothalamic paraventricular nucleus mediated activation of sympathoadrenal hormonal responses. PMID- 25043192 TI - Expression profile of vesicular nucleotide transporter (VNUT, SLC17A9) in subpopulations of rat dorsal root ganglion neurons. AB - ATP plays an important role in the signal transduction between sensory neurons and satellite cells in dorsal root ganglia (DRGs). In primary cultured DRG neurons, ATP is known to be stored in lysosomes via a vesicular nucleotide transporter (VNUT), and to be released into the intercellular space through exocytosis. DRGs consist of large-, medium- and small-sized neurons, which play different roles in sensory transmission, but there is no information on the expression profiles of VNUT in DRG subpopulations. Here, we obtained detailed expression profiles of VNUT in isolated rat DRG tissues. On immunohistochemical analysis, VNUT was found in DRG neurons, and was predominantly expressed by the small- and medium-sized DRG ones, as judged upon visual inspection, and this was compatible with the finding that the number of VNUT-positive DRG neurons in IB4 positive cells was greater than that in NF200-positive ones. These results suggest that VNUT play a role in ATP accumulation in DRG neurons, especially in small- and medium-sized ones, and might be involved in ATP-mediated nociceptive signaling in DRGs. PMID- 25043190 TI - A comprehensive and high-resolution genome-wide response of p53 to stress. AB - Tumor suppressor p53 regulates transcription of stress-response genes. Many p53 targets remain undiscovered because of uncertainty as to where p53 binds in the genome and the fact that few genes reside near p53-bound recognition elements (REs). Using chromatin immunoprecipitation followed by exonuclease treatment (ChIP-exo), we associated p53 with 2,183 unsplit REs. REs were positionally constrained with other REs and other regulatory elements, which may reflect structurally organized p53 interactions. Surprisingly, stress resulted in increased occupancy of transcription factor IIB (TFIIB) and RNA polymerase (Pol) II near REs, which was reduced when p53 was present. A subset associated with antisense RNA near stress-response genes. The combination of high-confidence locations for p53/REs, TFIIB/Pol II, and their changes in response to stress allowed us to identify 151 high-confidence p53-regulated genes, substantially increasing the number of p53 targets. These genes composed a large portion of a predefined DNA-damage stress-response network. Thus, p53 plays a comprehensive role in regulating the stress-response network, including regulating noncoding transcription. PMID- 25043194 TI - Synthesis and Structural characterization of beta-ketoiminate-stabilized gallium hydrides for chemical vapor deposition applications. AB - Bis-beta-ketoimine ligands of the form [(CH2 )n {N(H)C(Me)?CHC(Me)?O}2 ] (L(n) H2 , n=2, 3 and 4) were employed in the formation of a range of gallium complexes [Ga(L(n) )X] (X=Cl, Me, H), which were characterised by NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction analysis. The beta-ketoimine ligands have also been used for the stabilisation of rare gallium hydride species [Ga(L(n) )H] (n=2 (7); n=3 (8)), which have been structurally characterised for the first time, confirming the formation of five-coordinate, monomeric species. The stability of these hydrides has been probed through thermal analysis, revealing stability at temperatures in excess of 200 degrees C. The efficacy of all the gallium beta-ketoiminate complexes as molecular precursors for the deposition of gallium oxide thin films by chemical vapour deposition (CVD) has been investigated through thermogravimetric analysis and deposition studies, with the best results being found for a bimetallic gallium methyl complex [L(3) {GaMe2 }2 ] (5) and the hydride [Ga(L(3) )H] (8). The resulting films (F5 and F8, respectively) were amorphous as-deposited and thus were characterised primarily by XPS, EDXA and SEM techniques, which showed the formation of stoichiometric (F5) and oxygen-deficient (F8) Ga2 O3 thin films. PMID- 25043195 TI - Intermolecular zero quantum coherences enable accurate temperature imaging in red bone marrow. AB - PURPOSE: Red bone marrow metastases are common in breast and prostate cancer patients, but those metastases are currently incurable. Recent developments show that hyperthermia could be a successful treatment for bone metastasis, but thermometry remains difficult or inaccurate in red marrow. METHOD: The technique evaluated in this study measures the evolution frequency of intermolecular zero quantum coherences (iZQCs) between fat and water. The iZQC evolution frequency was mapped linearly to temperature. The temperature accuracy and coherence lifetime of the iZQC method were evaluated against other thermometry methods that are based on localized spectroscopy and multiple gradient echo imaging. RESULTS: The temperature coefficient (alpha) was 9.8 +/- 0.7 ppb/ degrees C with the iZQC method and 2 +/- 7 ppb/ degrees C with traditional localized spectroscopy. CONCLUSION: Because the accuracy of thermometry is limited by the reproducibility of alpha between samples, iZQCs provide nearly a 10-fold accuracy improvement in red marrow (0.7 ppb/ degrees C for iZQCs versus 7 ppb/ degrees C for localized spectroscopy.) The iZQC technique in this study will for the first time allow accurate and quantitative thermal imaging of red marrow. Magn Reson Med, 2014. (c) 2014 Wiley Periodicals, Inc. Magn Reson Med 74:63-70, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25043193 TI - Dynamics and cellular localization of Bmp2, Bmp4, and Noggin transcription in the postnatal mouse skeleton. AB - Transcription of BMPs and their antagonists in precise spatiotemporal patterns is essential for proper skeletal development, maturation, maintenance, and repair. Nevertheless, transcriptional activity of these molecules in skeletal tissues beyond embryogenesis has not been well characterized. In this study, we used several transgenic reporter mouse lines to define the transcriptional activity of two potent BMP ligands, Bmp2 and Bmp4, and their antagonist, Noggin, in the postnatal skeleton. At 3 to 4 weeks of age, Bmp4 and Noggin reporter activity was readily apparent in most cells of the osteogenic or chondrogenic lineages, respectively, whereas Bmp2 reporter activity was strongest in terminally differentiated cells of both lineages. By 5 to 6 months, activity of the reporters had generally abated; however, the Noggin and Bmp2 reporters remained remarkably active in articular chondrocytes and persisted there indefinitely. We further found that endogenous Bmp2, Bmp4, and Noggin transcript levels in postnatal bone and cartilage mirrored the activity of their respective reporters in these tissues. Finally, we found that the activity of the Bmp2, Bmp4, and Noggin reporters in bone and cartilage at 3 to 4 weeks could be recapitulated in both osteogenic and chondrogenic culture models. These results reveal that Bmp2, Bmp4, and Noggin transcription persists to varying degrees in skeletal tissues postnatally, with each gene exhibiting its own cell type-specific pattern of activity. Illuminating these patterns and their dynamics will guide future studies aimed at elucidating both the causes and consequences of aberrant BMP signaling in the postnatal skeleton. PMID- 25043196 TI - Gelada feeding ecology in an intact ecosystem at Guassa, Ethiopia: Variability over time and implications for theropith and hominin dietary evolution. AB - Recent evidence suggests that several extinct primates, including contemporaneous Paranthropus boisei and Theropithecus oswaldi in East Africa, fed largely on grasses and sedges (i.e., graminoids). As the only living primate graminivores, gelada monkeys (Theropithecus gelada) can yield insights into the dietary strategies pursued by extinct grass- and sedge-eating primates. Past studies of gelada diet were of short duration and occurred in heavily disturbed ecosystems. We conducted a long-term study of gelada feeding ecology in an intact Afroalpine ecosystem at Guassa, Ethiopia. Geladas at Guassa consumed >=56 plant species, >=20 invertebrate species, one reptile species, and the eggs of one bird species over a 7-year period. The annual diet consisted of 56.8% graminoid parts, 37.8% forb parts, 2.8% invertebrates, and 2.6% other items, although geladas exhibited wide variability in diet across months at Guassa. Edible forbs were relatively scarce at Guassa but were strongly selected for by geladas. Tall graminoid leaf and tall graminoid seed head consumption correlated positively, and underground food item consumption correlated negatively, with rainfall over time. Geladas at Guassa consumed a species-rich diet dominated by graminoids, but unlike geladas in more disturbed habitats also ate a diversity of forbs and invertebrates along with occasional vertebrate prey. Although graminoids are staple foods for geladas, underground food items are important "fallback foods." We discuss the implications of our study, the first intensive study of the feeding ecology of the only extant primate graminivore, for understanding the dietary evolution of the theropith and hominin putative graminivores, Theropithecus oswaldi and Paranthropus boisei. PMID- 25043197 TI - Derivation of Phase 3 dosing for peginterferon lambda-1a in chronic hepatitis C, Part 1: Modeling optimal treatment duration and sustained virologic response rates. AB - Peginterferon lambda-1a (Lambda) is under clinical development for the treatment of chronic hepatitis B and C virus (HBV, HCV, respectively) infection. This is the first of two manuscripts detailing the pharmacodynamic derivation of Lambda dosing and treatment durations for Phase 3 studies in HCV, based on Phase 2 data. We describe here the derivation of a population model of Lambda exposure; the adaptation of a previously published viral dynamic model for Lambda treatment and host genotype, and its use to simulate sustained virologic responses (SVR). Lambda population pharmacokinetics was described by a one-compartment model with first-order absorption, and 33.0 L per day clearance with 47% interindividual (36% intra-individual) variability. Weight explained a negligible proportion of the variability. Based on SVR predictions, optimum treatment durations were 48 weeks for HCV genotypes 1 or 4 (SVR estimates for 120, 180, and 240 MUg Lambda: 58%, 54%, 47%, respectively) and 24 weeks for genotypes 2 or 3 (75%, 72%, 67%). SVR predictions for 240 MUg were lower due to dropout predictions. The SVR model established the optimum treatment duration for Phase 3 studies but did not differentiate between 120 and 180 MUg dosing. A companion manuscript describes dose selection based on exposure-response/safety modeling. PMID- 25043198 TI - Alterations in central motor representation increase over time in individuals with rotator cuff tendinopathy. AB - OBJECTIVE: To investigate whether rotator cuff tendinopathy leads to changes in central motor representation of a rotator cuff muscle, and to assess whether such changes are related to pain intensity, pain duration, and physical disability. METHODS: Using transcranial magnetic stimulation, motor representation of infraspinatus muscle was assessed bilaterally in patients with unilateral rotator cuff tendinopathy. RESULTS: Active motor threshold is significantly larger for the affected shoulder comparatively to the unaffected shoulder (n=39, p=0.01), indicating decreased corticospinal excitability on the affected side compared to unaffected side. Further, results suggest that this asymmetry in corticospinal excitability is associated with duration of pain (n=39; r=0.45; p=0.005), but not with pain intensity (n=39; r<0.03; p>0.43). In contrast with findings in other populations with musculoskeletal pain, no significant inter-hemispheric asymmetry was observed in map location (n=16; p-values ? 0.91), or in the amplitude of motor responses obtained at various stimulation intensities (n=16; p=0.83). CONCLUSION: Chronicity of pain, but not its intensity, appears to be a factor related to lower excitability of infraspinatus representation. SIGNIFICANCE: These results support the view that while cortical reorganization correlates with magnitude of pain in neuropathic pain syndromes, it could be more related to chronicity in the case of musculoskeletal disorders. PMID- 25043199 TI - Carbazole-BODIPY conjugates: design, synthesis, structure and properties. AB - A set of carbazole substituted BODIPYs 2a-2c were designed and synthesized by the Pd-catalysed Sonogashira cross-coupling reaction. The effects of variation in the donor strength of various carbazoles were investigated by photophysical, electrochemical and computational studies. The electronic absorption spectra of BODIPYs 2a and 2c show charge transfer bands, which show red shift in polar solvents. The BODIPYs 2a-2c are highly fluorescent in nonpolar solvents (emission from the localized state) and poorly fluorescent in polar solvents (emission from the charge transfer state). The photophysical and electrochemical studies reveal strong donor-acceptor interaction between carbazole and BODIPY and follows the order 2a > 2c > 2b. The computational calculations show good agreement with the experimental results. The single crystal structures of BODIPYs 2a-2c are reported, which exhibit interesting supramolecular interactions. The packing diagrams of 2a show a zigzag 3D structural arrangement, whereas 2b and 2c show complex 3D structural motifs. PMID- 25043200 TI - Role of the nitric oxide-soluble guanylyl cyclase pathway in obstructive airway diseases. AB - Nitric oxide (NO) is a gaseotransmitter, which is involved in many signaling processes in health and disease. Three enzymes generate NO from l-arginine, with citrulline formed as a by-product: neuronal NO synthase (nNOS or NOS1), endothelial NOS (eNOS or NOS3) and inducible NOS (iNOS or NOS2). NO is a ligand of soluble guanylyl cyclase (sGC), an intracellular heterodimer enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP). cGMP further activates protein kinase G that eventually reduces the smooth muscle tone in bronchi or vessels. Phosphodiesterase 5 (PDE5) degrades cGMP to GMP. However, NO reacts with superoxide anion (O2(-)), leading to formation of the pro inflammatory molecule peroxynitrite. Under physiological conditions, NO plays a homeostatic bronchoprotective role in healthy subjects. In obstructive airway diseases, NO can be beneficial by its bronchodilating effect, but could also be detrimental by the formation of peroxynitrite. Since asthma and COPD are associated with increased levels of exhaled NO, chronic inflammation and increased airway smooth muscle tone, the NO/sGC/cGMP pathway could be involved in these highly prevalent obstructive airway diseases. Here we review the involvement of NO, NO synthases, guanylyl cyclases, cGMP and phophodiesterase-5 in asthma and COPD and potential therapeutic approaches to modulate this pathway. PMID- 25043201 TI - Four new cembranoids from the soft coral Sarcophyton sp. PMID- 25043202 TI - Poly(ethylene imine) impurities induce n-doping reaction in organic (semi)conductors. AB - Volatile impurities contained in polyethyleneimine (PEI), and identified as ethyleneimine dimers and trimers, are reported. These N-based molecules show a strong reducing character, as demonstrated by the change in electrical conductivity of organic (semi)conductors exposed to the PEI vapor. The results prove that electron transfer rather than a dipole effect at the electrode interface is the origin of the work-function modification by the PEI-based layers. PMID- 25043203 TI - Chemical structure of the cell wall-associated polysaccharide of Bifidobacterium animalis subsp. lactis LKM512. AB - We have demonstrated that Bifidobacterium animalis subsp. lactis LKM512 had some probiotic properties in vivo and in vitro. To further understand their mechanisms, the chemical structure of the extracellular polysaccharide that constructs the cell envelope was determined. The strain was anaerobically cultured in MRS broth at 37 degrees C for 20 h, then the bacterial cells were harvested by centrifugation and washed. The cell wall-associated polysaccharide (CPS) was prepared from the cell wall component digested by lysozyme. The results of anion exchange and gel filtration chromatography showed that the polysaccharide was negatively charged and had a high molecular mass. The CPS was found to compose of galactopyranosyl, galactofuranosyl, glucopyranosyl and rhamnopyranosyl residues in the molar ratio of 1:1:1:3 by using methylation analysis with GC-MS and HPLC profiling. From the results of the structural characterization by 1 dimensional and 2 dimensional NMR spectroscopy, the polysaccharide was established to be a hexasaccharide repeating unit with the following structure: LKM512. PMID- 25043205 TI - Rationale for conducting a randomized trial to examine the efficacy of metformin in improving survival in cirrhosis: pleiotropic effects hypothesis. PMID- 25043204 TI - Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. AB - OBJECTIVE: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFkappaB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. METHODS: Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. RESULTS: We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFkappaB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. INTERPRETATION: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps. PMID- 25043206 TI - Box-Behnken design for optimum extraction of biogenetic chemicals from P. lanceolata with an energy audit (thermal * microwave * acoustic): a case study of HPTLC determination with additional specificity using on-line/off-line coupling with DAD/NIR/ESI-MS. AB - INTRODUCTION: The genus Pluchea comprises about 80 species distributed worldwide, out of them, only Pluchea lanceolata (DC.) Oliv. & Hiern, is used extensively in the traditional system of India. No chromatographic method is available for its quality. OBJECTIVES: To perform the energy audit for the extraction of biogenetic pentacyclic triterpene, its acetate and sterol from P. lanceolata utilising organic and four alternative solvents. Additionally to resolve the uncertainty of TLC determination, on-line/off-line coupling with a diode-array detector (DAD), and near-infrared (NIR) and electrospray ionisation (ESI) MS was introduced. METHODS: The extraction of taraxasterol (Tx), taraxasterol acetate (TxAc) and stigmasterol (St) from P. lanceolata was performed using three energy modes. The effects of different operating parameters were studied for optimum extraction yield using the design of experiments, that is, the central composite design and Box-Behnken design. In addition to the retention factor (Rf ) and visible spectral matching, two additional optical spectroscopic techniques, that is, NIR and ESI-MS, were applied for extended specificity. RESULTS: The method was developed for Tx, TxAc and St determination using HPTLC at 645 nm. The optimum extraction yield of targeted compounds was found to be higher with organic solvents than eco-friendly surfactants. The pulse ultrasonic assisted extraction (PUAE) has resulted in optimum extraction of compounds comparable to hot extraction. Both NIR and ESI-MS provided extended specificity in determination. CONCLUSION: The 5/1-PUAE was determined to be effective, reproducible, simple and energy efficient for the determination of Tx, TxAc and St in P. lanceolata. The offline coupling of NIR and ESI-MS with HPTLC led to considerable improvement in specificity. PMID- 25043207 TI - Single ventricle and single atrium with anomalous hepatic venous drainage and azygos continuation of inferior vena cava in an adult patient. AB - In a 37-year-old patient, ultrasonography showed and CT confirmed the presence of single ventricle, single atrium, azygos continuation of inferior vena cava, anomalous hepatic vein drainage, and persistent left superior vena cava. Such a constellation of cardiovascular anomalies is exceptionally diagnosed in adulthood. PMID- 25043208 TI - Elucidation of key aroma compounds in traditional dry fermented sausages using different extraction techniques. AB - BACKGROUND: The use of different extraction techniques - solid phase microextraction (SPME) and solvent assisted flavour evaporation (SAFE) - can deliver different aroma profiles and it is essential to determine which is most suitable to extract the aroma compounds from dry fermented sausages. RESULTS: Forty-five aroma-active compounds were detected by SPME and SAFE, with 11 of them reported for the first time as aroma compounds in dry fermented sausages: ethyl 3 hydroxy butanoate, trimethyl pyrazine, D-pantolactone, isobutyl hexanoate, ethyl benzoate, alpha-terpineol, ethyl 3-pyridinecarboxylate, benzothiazole, 2,3 dihydrothiophene, methyl eugenol, gamma-nonalactone. The aroma concentration and odour activity values (OAVs) were calculated. Flavour reconstitution analyses were performed using 20 odorants with OAVs above 1 obtained from the SAFE and SPME extracts to prepare the aroma model. CONCLUSION: SPME and SAFE techniques were complementary and necessary to reproduce the overall dry fermented sausage aroma. The final aroma model included the odorants from both extraction techniques (SPME and SAFE) but it was necessary to incorporate the compounds 2,4 decadienal (E,E), benzothiazole, methyl eugenol, alpha-terpineol, and eugenol to the final aroma model to evoked the fresh sausage aroma although a lowest cured meat aroma note was perceived. PMID- 25043209 TI - Association between baseline pulmonary status and interstitial lung disease in patients with non-small-cell lung cancer treated with erlotinib--a cohort study. AB - INTRODUCTION: Although interstitial lung disease (ILD) is a known serious adverse effect of epidermal growth factor receptor tyrosine kinase inhibitors, the risk factors for its development are poorly defined. To determine the risk factors for the development of drug-induced ILD and poor-prognosis (fatal) drug-induced ILD after erlotinib treatment, we assessed the baseline pulmonary status in patients with non-small cell lung cancer enrolled in a postmarketing clinical study of erlotinib. PATIENTS AND METHODS: In the present prospective cohort study, the baseline pulmonary status of all patients was evaluated using conventional or high-resolution computed tomography. The patients were monitored for the development of drug-induced ILD for 120 days after the start of treatment. All diagnoses of drug-induced ILD were confirmed by an independent ILD safety review committee. The risk factors were determined using logistic regression analysis. RESULTS: A total of 645 patients were enrolled, of whom 627 were evaluable. The committee confirmed the diagnoses of drug-induced ILD in 19 patients, 6 of whom had fatal outcomes. Multivariate logistic regression analysis revealed that pre existing ILD and limited residual normal lung were significant risk factors for the development of drug-induced ILD. An additional multivariate logistic regression analysis revealed that limited residual normal lung was a significant risk factor for the development of poor-prognosis (fatal) drug-induced ILD. CONCLUSION: Pre-existing ILD and the amount of residual normal lung (<= 50%) were identified as risk factors for the development of drug-induced ILD. The amount of residual normal lung (<= 50%) was identified as a risk factor for the development of poor-prognosis (fatal) drug-induced ILD. PMID- 25043210 TI - Diagnosis and predictive molecular analysis of non-small-cell lung cancer in the Africa-Middle East region: challenges and strategies for improvement. AB - The identification of tumor biomarkers provides information on the prognosis and guides the implementation of appropriate treatment in patients with many different cancer types. In non-small cell lung cancer (NSCLC), targeted treatment plans based on biomarker identification have already been used in the clinic. However, such predictive molecular testing is not currently a universally used practice. This is the case, in particular, in developing countries where lung cancer is increasingly prevalent. In September 2012 and November 2013, a committee of 16 lung cancer experts from Africa and the Middle East met to discuss key issues related to diagnosis and biomarker testing in NSCLC and the implementation of personalized medicine in the region. The committee identified current challenges for effective diagnosis and predictive analysis in Africa and the Middle East. Moreover, strategies to encourage the implementation of biomarker testing were discussed. A practical approach for the effective diagnosis and predictive molecular testing of NSCLC in these regions was derived. We present the key issues and recommendations arising from the meetings. PMID- 25043211 TI - Failure of hybrid therapy for the prevention of long-term recurrence of atrial fibrillation. AB - OBJECTIVES: To determine the long-term effectiveness of hybrid therapy in the control of atrial fibrillation (AF) as well as the differences in clinical outcomes between patients with antiarrhythmic drug atrial flutter (AAD-AFl), those with coexistent AFl and AF, and isolated AFl. METHODS: Four hundred eight patients who consecutively underwent cavotricuspid isthmus (CTI) ablation between 1998 and 2010 were followed for 5.9 years. Twenty-seven patients had AAD-AF1 (Group 1): they had AF but not AFl at baseline but on AAD therapy they showed typical AFl. They underwent CTI ablation and continued with AAD therapy, 96 patients had coexistent AF1 and AF at baseline (Group 2) and continued with AAD therapy at the discretion of their cardiologists and 284 patients had isolated AFl (Group 3). RESULTS: AF recurred in the majority of the AAD-AF1 patients (74%, incident density rate (IDR): 19.1/100 person-years). This incidence rate was similar to the recurrence rate of AF in patients with coexistent AFl and AF (59%, IDR: 19.2/100 person-years). The patients in Group 1 had a similar IDR of stroke as Group 2 and a slightly higher rate than Group 3. There were no significant differences in the IDR for death among Groups 1, 2 and 3. CONCLUSIONS: Hybrid therapy was not effective for long-term control of AF. The clinical outcomes (AF, stroke and death) were similar for AAD-AF1 patients and patients with coexistent AF and AFl. PMID- 25043213 TI - Cardiac tamponade, a medical concept known in medieval times. PMID- 25043212 TI - Health management in China. PMID- 25043214 TI - Cardiac adipose tissue is associated with coronary artery disease: a meta analysis. PMID- 25043215 TI - Coronary vasospasm is an unlikely cause of Takotsubo syndrome, although we should keep an open mind. AB - This viewpoint pertains to the still elusive pathophysiology of the Takotsubo syndrome (TTS), maintaining the position that this affliction is not the result of coronary vasospasm (CV) involving one or more coronary arteries. Although CV has been rarely encountered in the acute stage of TTS, or elicited via provocative testing in the subacute stage of the disease, it does not appear to be the cause of TTS as shown by the bulk of the published relevant literature. The author provides some speculations to explain the spontaneous appearance of CV, or its artificial elicitation, in some patients with TTS. However while we are striving to unravel the pathophysiology of TTS, we should keep an open mind about a possible role for CV in the causation of TTS. PMID- 25043216 TI - Early development of xanthoma and coronary disease in a young female with homozygous familial hypercholesterolemia. PMID- 25043217 TI - Diagnostic criteria for takotsubo syndrome: a call for consensus. PMID- 25043218 TI - Unexceptional occurrence of tricky ECG findings in patients having new Biotronik ICDs. PMID- 25043219 TI - Electrophysiological characteristics of left atrial diverticulum in patients with atrial fibrillation: electrograms, impedance and clinical implications. AB - BACKGROUND: Left atrial diverticulum (LAD) is not rare in patients with atrial fibrillation (AF). Recent reports focused on its morphology however data on its electrophysiological characteristics are lacking. Our study aims to investigate the electrogram and impedance features of LAD. METHODS: This study included 24 patients (mean age, 58.5 +/- 10.7 years) with LAD undergoing catheter ablation for AF and 24 gender-and-age-matched individuals without LAD as controls. A bipolar LAD electroanatomic map was acquired in sinus rhythm from all study participants. Points were acquired for diverticulum in the LAD group and for corresponding areas in the control group. Electrogram deflections were counted, bipolar voltage and impedance were measured for each point, and average ? impedance and highest ? impedance were calculated. RESULTS: A total of 234 points were collected in the two groups. In the LAD vs. control group, median (Q1, Q3) of electrogram deflections was 6 (5, 7) and 4 (4, 5) (P<0.0001), respectively, voltage was not significantly different (1.58 +/- 0.68 mV vs. 1.28 +/- 0.65 mV, P=0.10), and average ? impedance was significantly higher in the LAD group (19.5 +/- 9.0 Omega vs 3.9 +/- 1.7 Omega, P<0.0001). A cut-off value of 9.5 Omega for ? impedance predicted LAD with sensitivity, specificity, and positive and negative predictive values of 83.5%, 92.8%, 92.1% and 84.9%, respectively. CONCLUSIONS: Electrogram was more fractionated and impedance was higher at LAD than in corresponding areas without LAD, which might help to differentiate LAD during catheter ablation for AF. PMID- 25043220 TI - Mortality prediction models in acute respiratory failure treated with extracorporeal membrane oxygenation: it must be firstly designed for clinicians and beside use. PMID- 25043221 TI - Changing eating behaviours to treat childhood obesity in the community using Mandolean: the Community Mandolean randomised controlled trial (ComMando)--a pilot study. AB - BACKGROUND: Around one in five children in England is obese when they leave primary school. Thus far, it has not been demonstrated that primary care interventions to manage childhood obesity can achieve significant weight reduction. Training obese children to eat more slowly as an adjunct to other healthy lifestyle behaviour change has been shown to increase weight reduction in a hospital setting. OBJECTIVES: This pilot study aimed to test recruitment strategies, treatment adherence, clinic attendance and participants' experiences of using a device [Mandolean(r) (previously Mandometer(r), Mikrodidakt AB, Lund, Sweden)] to slow down speed of eating as an adjunct to dietary and activity advice in treating obesity in primary school-aged children. DESIGN: A two-arm, parallel, randomised controlled trial with a qualitative study embedded within the pilot. Randomisation occurred after informed consent and baseline measures were collected. Participants were randomised by the Bristol Randomised Trials Collaboration randomisation service with allocation stratified by hub and minimised by age of the child, gender, and baseline body mass index (BMI) standard deviation score (BMI z-value) of the child, and by BMI of the study parent (obese/not obese). SETTING: General practices across Bristol, North Somerset and South Gloucestershire primary care trusts. PARTICIPANTS: Children (BMI >= 95th percentile) aged 5-11 years and their families. INTERVENTION: Standard care comprised dietary and activity advice by trained practice nurses. Adjunctive Mandolean training (the intervention) educated participants to eat meals more slowly and to rate levels of fullness (satiety). Mandolean is a small computer device attached to a weighing scale that provides visual and oral feedback during meals while generating a visual representation of levels of satiety during the meal. Participants were encouraged to eat their main meal each day from the Mandolean. One parent was also given a Mandolean to use when eating with the child. OUTCOME MEASURES: Outcomes for the pilot were recruitment of 36 families to the trial in the 9-month pilot phase, that meals would be eaten at least five times a week off a Mandolean by 90% of patients randomised to the intervention arm, that 80% of patients in both arms would attend the weight management clinic appointment 3 months post randomisation and that > 60% of children using Mandolean would demonstrate a reduction in speed of eating from baseline within 3 months of randomisation. RESULTS: None of the criteria for progression to the main trial were reached. Despite numerous pathways being available for referral, only 21 (13 to standard care, eight to intervention arm; 58%) of the target 36 families were recruited in the pilot phase. Less than 20% of those randomised to Mandolean used the device at least five times a week. The > 60% target for slowing down of eating speed by 3 months was unmet. Attendance at the weight management clinic in general practice hubs for both arms of the study at 3 months was 44% against a target of 80%. CONCLUSIONS: This pilot trial failed to meet its objectives in terms of recruitment, treatment adherence, demonstration of a reduction in speed of eating in sufficient numbers of children, and attendance at follow-up appointments. Despite a high prevalence of childhood obesity in the geographical area and practices signing up for the trial, this study, like many others, demonstrates a failure of families to engage with and respond to primary care weight management interventions. We need to understand why the target population seems inured to the health message that childhood obesity is a significant health-care issue and identify the barriers to seeking help and then acting on positive health behaviour retraining. Only when we have fully understood the general public's perceptions of childhood obesity and have identified ways of engaging target populations can we hope to develop interventions that can work in a primary or community-based setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90561114. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 47. See the NIHR Journals Library website for further project information. PMID- 25043223 TI - Optimal experimental designs for accelerated failure time with Type I and random censoring. AB - Proportional Hazards models have been widely used to analyze survival data. In many cases survival data do not verify the assumption of proportional hazards. An alternative to the PH models with more relaxed conditions are Accelerated Failure Time models. These models are fairly commonly used in the field of manufacturing, but they are more and more frequent for modeling clinical trial data. They focus on the direct effect of the explanatory variables on the survival function allowing an easier interpretation of the effect of the corresponding covariates on the survival time. Optimal experimental designs are computed in this framework for Type I and random arrival. The results are applied to clinical models used to prevent tuberculosis in Ugandan adults infected with HIV. PMID- 25043222 TI - EUROGIN 2014 roadmap: differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection. AB - Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and <50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often, mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet, HPV-related cancer incidence at this site is several-fold higher than at either the anal canal or the penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age-specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts. PMID- 25043225 TI - Mechanism of crystalline self-assembly in aqueous medium: a combined cryo TEM/kinetic study. AB - Understanding the crystallization of organic molecules is a long-standing challenge. Herein, a mechanistic study on the self-assembly of crystalline arrays in aqueous solution is presented. The crystalline arrays are assembled from perylene diimide (PDI) amphiphiles bearing a chiral N-acetyltyrosine side group connected to the PDI aromatic core. A kinetic study of the crystallization process was performed using circular dichroism spectroscopy combined with time resolved cryogenic transmission electron microscopy (cryo-TEM) imaging of key points along the reaction coordinate, and molecular dynamics simulation of the initial stages of the assembly. The study reveals a complex self-assembly process starting from the formation of amorphous aggregates that are transformed into crystalline material through a nucleation-growth process. Activation parameters indicate the key role of desolvation along the assembly pathway. The insights from the kinetic study correlate well with the structural data from cryo-TEM imaging. Overall, the study reveals four stages of crystalline self-assembly: 1) collapse into amorphous aggregates; 2) nucleation as partial ordering; 3) crystal growth; and 4) fusion of smaller crystalline aggregates into large crystals. These studies indicate that the assembly process proceeds according to a two-step crystallization model, whereby initially formed amorphous material is reorganized into an ordered system. This process follows Ostwald's rule of stages, evolving through a series of intermediate phases prior to forming the final structure, thus providing an insight into the crystalline self-assembly process in aqueous medium. PMID- 25043224 TI - Animal models of allergic airways disease: where are we and where to next? AB - In a complex inflammatory airways disease such as asthma, abnormalities in a plethora of molecular and cellular pathways ultimately culminate in characteristic impairments in respiratory function. The ability to study disease pathophysiology in the setting of a functioning immune and respiratory system therefore makes mouse models an invaluable tool in translational research. Despite the vast understanding of inflammatory airways diseases gained from mouse models to date, concern over the validity of mouse models continues to grow. Therefore the aim of this review is twofold; firstly, to evaluate mouse models of asthma in light of current clinical definitions, and secondly, to provide a framework by which mouse models can be continually refined so that they continue to stand at the forefront of translational science. Indeed, it is in viewing mouse models as a continual work in progress that we will be able to target our research to those patient populations in whom current therapies are insufficient. PMID- 25043226 TI - Shedding and seroprevalence of pathogenic Leptospira spp. in sheep and cattle at a New Zealand Abattoir. AB - A cross-sectional study was carried out on sheep and cattle slaughtered at a New Zealand abattoir from September to November 2010 to investigate the supplier specific shedding rate, renal carriage rate and seroprevalence of leptospires. In the 2008/2009 season, this abattoir experienced three human leptospirosis cases from 20 staff, of which two were hospitalized. Urine, kidney and blood samples were collected from carcasses of 399 sheep (six suppliers, 17 slaughter lines) and 146 cattle (three suppliers, 22 slaughter lines). The urine and kidney samples were tested by quantitative real-time PCR (qPCR), while serum samples (from coagulated blood samples) were tested by microscopic agglutination test (MAT). In total, 27% (73/274; 95% CI: 18-37) of urine samples tested positive by qPCR. Species-specific shedding rates (prevalence of positive urine qPCR) were 31% (95% CI: 17-48) for sheep and 21% (95% CI: 14-30) for cattle. For 545 kidney samples tested, 145 were qPCR positive (27%; 95% CI: 17-39). The average prevalence of kidney qPCR positivity was 29% (95% CI: 17-45) for sheep and 21% (95% CI: 15-28) for cattle. Three hundred and thirty of 542 sampled sheep and cattle had antibodies against Leptospira borgpetersenii serovar Hardjobovis (Hardjobovis) and/or Leptospira interrogans serovar Pomona (Pomona), based on reciprocal MAT titre >=1 : 48 (overall seroprevalence of 61%; 95% CI: 48-73). Seroprevalence was 57% (95% CI: 40-72) for sheep and 73% (95% CI: 59-83) for cattle. Among the seropositive animals, 41% (70/170; 95% CI: 30-54) were shedding (tested positive by urine qPCR) and 42% (137/330; 95% CI: 30-54) had renal carriage (tested positive by kidney qPCR). Some risk management options for abattoirs or farms to prevent human leptospirosis infections include vaccination of maintenance hosts, the use of personal protective equipment, and the application of urine qPCR to detect shedding status of stock as surveillance and as an alert. PMID- 25043227 TI - Exploring the cost-effectiveness of a one-off screen for dementia (for people aged 75 years in England and Wales). AB - OBJECTIVE: This paper examines the numbers of people with dementia who could be diagnosed and the likely cost-effectiveness of a one-off screen for dementia for people aged 75 years in England and Wales. METHODS: The study uses static decision modelling to compare a one-off screen for dementia with a no-screen scenario. Estimates for the model were drawn from systematic reviews, high quality studies and government and administrative sources. A panel of experts also advised the study. RESULTS: An estimated 3514 people could be diagnosed as a result of screening, 2152 of whom would otherwise never receive a diagnosis. The study identified societal economic impact of between L3,649,794 (net costs) and L4,685,768 (net savings), depending on assumptions. CONCLUSIONS: Our analysis suggests that screening could be cost-effective, especially as treatments and social care interventions become more effective and if diagnosis by current routes remains low or occurs later than is optimal. This study was, however, limited by available evidence and a range of quality of life benefits, cost savings and potential harms could not be quantified. It was also beyond the scope of this study to consider dynamic factors such as repeat screening, mortality, disease trajectories or trends in the numbers of people with dementia. A larger study would be needed for this, involving more complex and innovative approaches to generating estimates for modelling. We did not compare population screening for people aged 75 years to other methods for increasing diagnosis rates. PMID- 25043228 TI - The bacterial metabolite 2-aminoacetophenone promotes association of pathogenic bacteria with flies. AB - Bacteria contaminate insects and secrete metabolites that may affect insect behaviour and potentially fitness through unknown mechanisms. Here we show that the 'grape-like' odorant 2-aminoacetophenone (2AA), secreted by Pseudomonas aeruginosa (a ubiquitous opportunistic human pathogen), facilitates attraction to food for several fly species including Musca domestica, Ceratitis capitata and Drosophila melanogaster. Constant feeding on 2AA increases the level of long-term colonization of the flies' intestine by P. aeruginosa. Odour perception is necessary for enhanced attraction to food containing 2AA, and expression in the Drosophila olfactory organs of odorant receptors Or49b and Or10a potentiates, while expression of Or85a inhibits, preference for 2AA. Our study shows that 2AA lures the flies to the bacterial source and increases the extent of colonization of the fly intestine by the bacteria that produce it, as a means to facilitate bacterial dissemination to new locations. PMID- 25043229 TI - How to compare biologic drugs. AB - This consensus document reviews the evidence on the evaluation of biological drugs. The main conclusions of the group are: a) the current evidence on biological comparisons is based on indirect comparisons and is generally unreliable and with important methodological limitations. Therefore, b) it is considered necessary to amend the regulatory directives in the sense of strongly favoring randomized non-inferiority studies comparing face to face the new biological treatment with current standards, avoiding trials versus placebo, c) A key element in this process will be determined by consensus among regulatory agencies, scientific societies, the pharmaceutical industry and health authorities regarding the clinical differences that should be considered relevant in each of the conditions tested. PMID- 25043230 TI - Model selection and diagnostics for joint modeling of survival and longitudinal data with crossing hazard rate functions. AB - Comparison of two hazard rate functions is important for evaluating treatment effect in studies concerning times to some important events. In practice, it may happen that the two hazard rate functions cross each other at one or more unknown time points, representing temporal changes of the treatment effect. Also, besides survival data, there could be longitudinal data available regarding some time dependent covariates. When jointly modeling the survival and longitudinal data in such cases, model selection and model diagnostics are especially important to provide reliable statistical analysis of the data, which are lacking in the literature. In this paper, we discuss several criteria for assessing model fit that have been used for model selection and apply them to the joint modeling of survival and longitudinal data for comparing two crossing hazard rate functions. We also propose hypothesis testing and graphical methods for model diagnostics of the proposed joint modeling approach. Our proposed methods are illustrated by a simulation study and by a real-data example concerning two early breast cancer treatments. PMID- 25043231 TI - Prenatal diagnosis of chromothripsis, with nine breaks characterized by karyotyping, FISH, microarray and whole-genome sequencing. PMID- 25043248 TI - Abstracts of the Medical Oncology Group of Australia Incorporated Annual Scientific Meeting, 6-8 August 2014, Sydney, Australia. PMID- 25043250 TI - A novel PLP1 frameshift mutation causing a milder form of Pelizaeus-Merzbacher disease. AB - BACKGROUND: Pelizaeus-Merzbacher disease (PMD), a hypomyelinating leukodystrophy, and the related but less severe allelic spastic paraplegia 2 (SPG2) are caused by mutations in the proteolipid protein 1 (PLP1) gene. Magnetic resonance imaging (MRI) is pivotal for diagnosing these disorders. The severity of PMD/SPG2 varies, and for a milder form of PMD, there have been some reports of near-normal findings in T1-weighted images but abnormal findings in T2-weighted images. PATIENT: We report the case of a 5-year-old boy diagnosed with a milder form of PMD caused by a novel PLP1 mutation in exon 3: c.300delC (p.I100IfsX13). He had delayed development from several months of age and was able to walk with support at 19 months in spite of the spasticity in his lower extremities. Hypomyelination was noted at 12 months by brain MRI. Motor nerve conduction studies showed decreased velocities with reduced amplitudes. Follow-up MRI at 1-year intervals from 18 months until 55 months of age showed gradual myelination progress. DISCUSSION: The single nucleotide deletion identified in this patient can cause a frameshift and premature termination of PLP1. Via the nonsense-mediated mRNA decay mechanism of this mutation will result in loss-of-function, leading to a milder form of PMD. The present case is compatible with previously reported cases of milder form of PMD. We incidentally identified progressive myelination in this patient by T1-weighted images obtained by serial MRI. This finding adds to our understanding of the pathological stages of a milder form of PMD. PMID- 25043251 TI - Genomic resources and genetic diversity of captive lesser kudu (Tragelaphus imberbis). AB - The lesser kudu (Tragelaphus imberbis) is a spiral-horned antelope native to northeastern Africa. Individuals kept in zoological gardens are suspected to be highly inbred due to few founder individuals and a small breeding stock. A morphological study suggested two distinct subspecies of the lesser kudu. However, subspecies designation and population structure in zoological gardens has not been analyzed using molecular markers. We analyzed one mitochondrial marker and two nuclear intron loci (total: 2,239 nucleotides) in 52 lesser kudu individuals. Of these, 48 individuals were bred in captivity and sampled from seven different zoos. The four remaining individuals were recently captured in Somalia and are currently held in the Maktoum zoo. Maternally inherited mitochondrial sequences indicate substantial amounts of genetic variation in the zoo populations, while the biparentally inherited intron sequences are, as expected, less variable. The analyzed individuals show 10 mitochondrial haplotypes with a maximal distance of 10 mutational steps. No prominent subspecies structure is detectable in this study. For further studies of the lesser kudu population genetics, we present microsatellite markers from a low coverage genome survey using 454 sequencing technology. PMID- 25043249 TI - Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. AB - The functional role of reactive astrocytes after stroke is controversial. To elucidate whether reactive astrocytes contribute to neurological recovery, we compared behavioral outcome, axonal remodeling of the corticospinal tract (CST), and the spatio-temporal change of chondroitin sulfate proteoglycan (CSPG) expression between wild-type (WT) and glial fibrillary acidic protein/vimentin double knockout (GFAP(-/-) Vim(-/-) ) mice subjected to Rose Bengal induced cerebral cortical photothrombotic stroke in the right forelimb motor area. A foot fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the CST axons. Compared with WT mice, the motor functional recovery and BDA-positive CST axonal length in the denervated side of the cervical gray matter were significantly reduced in GFAP(-/-) Vim(-/-) mice (n = 10/group, P < 0.01). Immunohistological data showed that in GFAP(-/-) Vim(-/-) mice, in which astrocytic reactivity is attenuated, CSPG expression was significantly increased in the lesion remote areas in both hemispheres, but decreased in the ischemic lesion boundary zone, compared with WT mice (n = 12/group, P < 0.001). Our data suggest that attenuated astrocytic reactivity impairs or delays neurological recovery by reducing CST axonal remodeling in the denervated spinal cord. Thus, manipulation of astrocytic reactivity post stroke may represent a therapeutic target for neurorestorative strategies. PMID- 25043252 TI - Immunoexpression of transforming growth factor beta and interferon gamma in radicular and dentigerous cysts. AB - INTRODUCTION: The aim of this study was to evaluate and compare the immunohistochemical expression of transforming growing factor beta (TGF-beta) and interferon gamma (IFN-gamma) between radicular cysts (RCs) and dentigerous cysts (DCs). METHODS: Twenty RCs and DCs were selected for analysis of the immunoexpression of TGF-beta and IFN-gamma in the epithelium and capsule. RESULTS: The cell reactivity of TGF-beta and IFN-gamma in the lining epithelium and capsule of RCs showed no significant differences when compared with DCs (P > .05). There was a tendency of a higher expression of TGF-beta in the capsule of DCs. CONCLUSIONS: Our results showed the presence of TGF-beta and IFN-gamma in RCs and DCs, supporting the hypothesis that both participate in the development of these lesions, where IFN-gamma usually plays a role in bone resorption, which is counterbalanced by the osteoprotective activity performed by TGF-beta. PMID- 25043253 TI - Red and blue shifted hydridic bonds. AB - By performing MP2/aug-cc-pVTZ ab initio calculations for a large set of dimer systems possessing a R-H hydridic bond involved in diverse types of intermolecular interactions (dihydrogen bonds, hydride halogen bonds, hydride hydrogen bonds, and charge-assisted hydride hydrogen bonds), we show that this is rather an elongation than a shortening that a hydride bond undergoes on interaction. Contrary to what might have been expected on the basis of studies in uniform electric field, this elongation is accompanied by a blue instead of red shift of the R-H stretching vibration frequency. We propose that the "additional" elongation of the R-H hydridic bond results from the significant charge outflow from the sigma bonding orbital of R-H that weakens this bond. The more standard red shift obtained for stronger complexes is explained by means of the Hermansson's formula and the particularly strong electric field produced by the H acceptor molecule. PMID- 25043254 TI - Allergic granulomatous skin reaction to electromyography needle. PMID- 25043255 TI - Reliability of a wellness inventory for use among adolescent females aged 12-14 years. AB - BACKGROUND: The wellness construct has application in a number of fields including education, healthcare and counseling, particularly with regard to female adolescents. The effective measurement of wellness in adolescents can assist researchers and practitioners in determining lifestyle behaviors in which they are lacking. Behavior change interventions can then be designed which directly aid in the promotion of these areas. METHODS: The 5-Factor Wellness Inventory (designed to measure the Indivisible Self model of wellness) is a popular instrument for measuring the broad aspects of wellness amongst adolescents. The instrument comprises 97 items contributing to 17 subscales, five dimension scores, four context scores, total wellness score, and a life satisfaction index. This investigation evaluated the test-retest (intra-rater) reliability of the 5F-Wel instrument in repeated assessments (seven days apart) among adolescent females aged 12-14 years. Percentages of exact agreement for individual items, and the number of respondents who scored within +/-5, +/-7.5 and +/-10 points for total wellness and the five summary dimension scores were calculated. RESULTS: Overall, 46 (95.8%) participants responded with complete data and were included in the analysis. Item agreement ranged from 47.8% to 100% across the 97 items (median 69.9%, interquartile range 60.9%-73.9%). The percentage of respondents who scored within +/-5, +/-7.5 and +/-10 points for total wellness at the re-assessment was 87.0%, 97.8% and 97.8% respectively. The percentage of respondents who scored within +/-5, +/-7.5 and +/-10 for the domain scores at the reassessment ranged between 54.3-76.1%, 78.3-95.7% and 89.1-95.7% respectively across the five dimensions. CONCLUSIONS: These findings suggest there was considerable variation in agreement between the two assessments on some individual items. However, the total wellness score and the five dimension summary scores remained comparatively stable between assessments. PMID- 25043257 TI - Abstracts of the 28th Annual Symposium of The Protein Society, July 27-30, 2014, San Diego, CA, USA. PMID- 25043259 TI - Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion. AB - Dietary gluten influences the development of type 1 diabetes in nonobese diabetic (NOD) mice and biobreeding rats, and has been shown to influence a wide range of immunological factors in the pancreas and gut. In the present study, the effects of gluten on NK cells were studied in vitro and in vivo. We demonstrated that gliadin increased direct cytotoxicity and IFN-gamma secretion from murine splenocytes and NK cells toward the pancreatic beta-cell line MIN6 cells. Additionally, stimulation of MIN6 cells led to a significantly increased proportion of degranulating C57BL/6 CD107a(+) NK cells. Stimulation of C57BL/6 pancreatic islets with gliadin significantly increased secretion of IL-6 more than ninefold. In vivo, the gluten-containing diet led to a higher expression of NKG2D and CD71 on NKp46(+) cells in all lymphoid organs in BALB/c and NOD mice compared with the gluten-free diet. Collectively, our data suggest that dietary gluten increases murine NK-cell activity against pancreatic beta cells. This mechanism may contribute to development of type 1 diabetes and explain the higher disease incidence associated with gluten intake in NOD mice. PMID- 25043256 TI - Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells. AB - BRCA2 mutations are significantly associated with early-onset breast cancer, and the tumour-suppressing function of BRCA2 has been attributed to its involvement in homologous recombination (HR)-mediated DNA repair. In order to identify additional functions of BRCA2, we generated BRCA2-knockout HCT116 human colorectal carcinoma cells. Using genome-wide microarray analyses, we have discovered a link between the loss of BRCA2 and the up-regulation of a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G. The over expression of IFN-related genes was confirmed in different human BRCA2(-/-) and mouse Brca2(-/-) tumour cell lines, and was independent of senescence and apoptosis. In isogenic wild-type BRCA2 cells, we observed over-expression of IFN related genes after treatment with DNA-damaging agents, and following ionizing radiation. Cells with endogenous DNA damage because of defective BRCA1 or RAD51 also exhibited over-expression of IFN-related genes. Transcriptional activity of the IFN-stimulated response element (ISRE) was increased in BRCA2 knockout cells, and the expression of BRCA2 greatly decreased IFNalpha-stimulated ISRE reporter activity, suggesting that BRCA2 directly represses the expression of IFN-related genes through the ISRE. Finally, the colony-forming capacity of BRCA2 knockout cells was significantly reduced in the presence of either IFNbeta or IFNgamma, suggesting that IFNs may have potential as therapeutic agents in cancer cells with BRCA2 mutations. The GEO Accession No. for microarray analysis is GSE54830. PMID- 25043260 TI - Biomechanical deficiencies in women with semitendinosus-gracilis anterior cruciate ligament reconstruction during drop jumps. AB - OBJECTIVE: To compare landing mechanics and neuromuscular recruitment strategies between women with semitendinosus-gracilis anterior cruciate ligament reconstruction (SG-ACLr) and noninjured women during double- and single-legged drop jumps. DESIGN: Cross-sectional biomechanical study. SETTING: Single university-based biomechanics laboratory. PARTICIPANTS: Fourteen women 1-5 years post-SG-ACLr and 16 noninjured women participated in this study. METHODS: After anthropometric measurements, warm-up, and familiarization procedures, participants performed 5 trials of a double- and single-legged drop jumps. MAIN OUTCOME MEASUREMENTS: Dynamic knee valgus was measured as the distance between knee joints during the landing phase of the double-leg drop jumps. Medial knee displacement was the outcome considered during the landing phase of the single leg drop jumps. For both drop jump tasks, neuromuscular recruitment was evaluated through rectified normalized electromyographic activity of the quadriceps and hamstrings (amplitude and latency), and quadriceps/hamstrings electromyographic co-contraction ratio. RESULTS: Although the SG-ACLr group demonstrated a tendency toward a greater dynamic knee valgus during both drop jumps, these differences did not reach statistical significance. EMG data revealed different neuromuscular strategies for each group, depending on the specific jump. CONCLUSIONS: These findings suggest that women with SG-ACLr have a tendency toward greater dynamic knee valgus that could predispose to additional knee injuries. Rehabilitation specialists need to be aware of existing kinematic and neuromuscular deficiencies years after SG-ACLr. Taking this into consideration will aid in prescribing appropriate interventions designed to prevent re-injury. PMID- 25043261 TI - Sensory and motor thresholds of transcutaneous electrical stimulation are influenced by gender and age. AB - BACKGROUND: Transcutaneous electrical stimulation (ES) is a therapeutic procedure used in rehabilitation. However, the effectiveness of it depends on sensory responses to pain and motor control in neuromuscular recruitment, considering the differences related to gender and age of the subjects treated, as well as the intensity and frequency of ES. OBJECTIVE: To determine the threshold of sensory perception (TSP) and the threshold of motor response (TMR) in young and elderly individuals of both genders. DESIGN: Randomized controlled clinical trial. SETTING: General community. PARTICIPANTS: Eighty volunteers with no history of systemic diseases were selected to participate in the study: 40 men and 40 women were subdivided by convenience sampling and age group into young male and female (age 21.6 +/- 2.4 years) groups as well as into elderly female and male groups (age 72.6 +/- 6.1 years). INTERVENTIONS: The participants received electrical stimulation (ES) at 5 and 50 Hz, with pulse durations of 20, 100, 400, 1000, and 3000 MUs applied on the flexor muscle bellies of the wrist and fingers. MAIN OUTCOME MEASURES: TSP was identified as the first sensation of increased current intensity and TMR as the minimum muscle contraction detected. The results were submitted to analysis of variance, followed by the Tukey's test, with a significance level of 5%. RESULTS: TSP was lower than TMR for all pulse durations, regardless of gender and age. In women, TSP was lower than that in young and elderly men at both frequencies. However, TSP was higher in elderly subjects than in younger subjects at 50 Hz for both genders. Age also affected the TMR, presenting higher thresholds in elderly subjects of both genders at 50 Hz; however the same occurred only in male subjects at 5 Hz. CONCLUSION: Age and gender interfere directly with ES. These variables should be considered during rehabilitation because they indicate that electrical stimulation in elderly women should be carefully performed, as they have lower thresholds than elderly men when polarized currents are used, and there is a risk of skin lesion because of their high thresholds. PMID- 25043262 TI - Melanization reaction products of shrimp display antimicrobial properties against their major bacterial and fungal pathogens. AB - Melanization is a rapid defense mechanism in invertebrates. The substrate specificity of phenoloxidases (POs) and the role of melanization reaction products were investigated in the black tiger shrimp, Penaeus monodon. Two PmPOs (PmproPO1 and PmproPO2) were found to display a substrate specificity towards monophenols and diphenols, and exhibit relatively weak activity against 5,6 dihydroxyindole (DHI). Systemic infection of the PmproPO1/2 co-silenced shrimp with the fungus, Fusarium solani, led to a significantly increased mortality, suggesting an important role of PmproPOs in shrimp's defense against fungal infection. Using L-DOPA, dopamine or DHI as a substrate, the melanization reaction products exhibited in vitro antimicrobial activities towards Gram negative bacteria (Vibrio harveyi and Vibrioparahaemolyticus) and Gram-positive bacteria (Bacillus subtilis), whereas the lower effect was detected against the fungus (F. solani). SEM analysis revealed the morphological changes and damage of cell membranes of V. harveyi and F. solani after treatment with shrimp melanization reaction products. Together, these findings demonstrate the crucial functions of the proPO system and the importance of melanization reaction products in the shrimp's immune defense. PMID- 25043263 TI - The Lepidopteran endoribonuclease-U domain protein P102 displays dramatically reduced enzymatic activity and forms functional amyloids. AB - Hemocytes of Heliothis virescens (F.) (Lepidoptera, Noctuidae) larvae produce a protein, P102, with a putative endoribonuclease-U domain. In previous works we have shown that P102 is involved in Lepidopteran immune response by forming amyloid fibrils, which catalyze and localize melanin deposition around non-self intruders during encapsulation, preventing harmful systemic spreading. Here we demonstrate that P102 belongs to a new class of proteins that, at least in Lepidoptera, has a diminished endoribonuclease-U activity probably due to the lack of two out of five catalytically essential residues. We show that the P102 homolog from Trichoplusia ni (Lepidoptera, Noctuidae) displays catalytic site residues identical to P102, a residual endoribonuclease-U activity and the ability to form functional amyloids. On the basis of these results as well as sequence and structural analyses, we hypothesize that all the Lepidoptera endoribonuclease-U orthologs with catalytic site residues identical to P102 form a subfamily with similar function. PMID- 25043264 TI - Effective connectivity of the posterior cingulate and medial prefrontal cortices relates to working memory impairment in schizophrenic and bipolar patients. AB - BACKGROUND: Schizophrenia (SZ) and bipolar I disorder (BD) share many overlapping clinical features, confounding the current diagnostic systems. Recent studies suggest the posterior cingulate (PCC) and medial prefrontal (MPFC) cortices that are involved in SZ and BD pathophysiology. However, the roles of PCC and MPFC in providing specific distinctive and shared neural substrates between these two disorders remain largely unknown. Examining the neurophysiologic mechanism of these diseases may help explain the clinical observations and differentiate the two disorders. METHODS: We used the Dynamic Casual Modeling (DCM), which is capable of eliciting hidden neuronal dynamics and reveal cross-regulation of multiple neuronal systems, to characterize the pattern of disrupted effective connectivity in the left PCC-MPFC circuit during working memory tasks in 36 SZ and 20 BD patients as well as 29 healthy controls. RESULTS: Compared to the healthy controls, both SZ and BD patient groups exhibited significant negative effective connectivity from the left MPFC to PCC. The negative effective connectivity was more remarkable in schizophrenic patients. Only patients with BD differed from healthy controls with positive effective connectivity from the left PCC to MPFC. CONCLUSIONS: Whole brain analysis revealed deactivation of the left PCC and MPFC across all patient groups. This study provides new insight that changes in effective connectivity of the left MPFC to left PCC circuit during working memory processing may be a core pathophysiological feature distinguishing SZ from BD. PMID- 25043265 TI - Existence of monomer and dimer forms of mGluR5, under reducing conditions in studies of postmortem brain in various psychiatric disorders. PMID- 25043266 TI - Nondisseminated histoplasmosis of the trachea. AB - Histoplasma capsulatum can rarely affect the trachea. We report the case of a 68 year-old woman with rheumatoid arthritis on immunosuppressive therapy who presented with fevers, worsening shortness of breath, nonproductive cough and subjective throat hoarseness and fullness. Chest computed tomography demonstrated no tracheal findings. Bronchoscopy found mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending seven centimeters distal to the vocal cords. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Silver staining and culture and wash of the tracheal biopsy revealed Histoplasma capsulatum. She was treated with oral itraconazole then briefly on intravenous amphotericin for rising Histoplasma urinary antigen levels. She continued treatment 24 months following diagnosis with minimal dyspnea. Histoplasma tracheitis has been proposed as an indicator of disseminated infection. However, our patient did not demonstrate other organ manifestations. Histoplasma tracheitis should be considered in a differential diagnosis of tracheal lesions even in the absence of systemic involvement. PMID- 25043268 TI - Development of a new method for sperm RNA purification in the chicken. AB - Currently RNA transcripts are being used as male fertility biomarker for many mammalian species, but research work on chicken is at halt because classical RNA isolation methods are not effective for chicken spermatozoa. Hence, attempts have been made to optimize RNA isolation protocol from chicken sperm by using different methods, and to confirm the presence of sperm-specific transcripts of PRM and PLCZ1. Semen samples were centrifuged at low speed for removing debris like uric acid. Further, 1mL diluted semen was gently placed over 40% PureSperm or 45%/90% Percoll, and centrifuged to remove somatic cells and immature diploid spermatocytes. RNA was isolated from sperm by using RNAzol or TRIzol reagent or RNeasy Micro kit with certain modification, and RNA quantity and quality were evaluated. RNA isolated by using RNAzol or RNeasy Micro Kit yielded good quantity and quality of RNA for downstream applications compared to TRIzol. 40% PureSperm was found effective in removing somatic cells. RT-PCR results showed that sperm RNA samples were negative for CD4 and PTPRC. All the sperm RNA samples were positive for PRM and PLCZ1, markers of sperm RNA. PMID- 25043269 TI - Chest tube template for free fibular flap osteotomies in mandibular reconstruction. PMID- 25043270 TI - Outside-in recrystallization of ZnS-Cu1.8 S hollow spheres with interdispersed lattices for enhanced visible light solar hydrogen generation. AB - For the first time an earth-abundant and nontoxic ZnS-Cu(1.8) S hybrid photocatalyst has been engineered with well-defined nanosheet hollow structures by a template-engaged method. In contrast to conventional surface coupling and loading, the unique outside-in recrystallization promotes co-precipitation of ZnS and Cu(1.8) S into homogeneous interdispersed lattices, hence forming a hybrid semiconductor with visible responsive photocatalytic activity. The as-derived ZnS Cu(1.8) S semiconductor alloy is tailored into a hierarchical hollow structure to provide readily accessible porous shells and interior spaces for effective ion transfer/exchange. Notably, this synergistic morphology, interface and crystal lattice engineering, aim towards the design of novel nanocatalysts for various sustainable environmental and energy applications. PMID- 25043271 TI - Anal acoustic reflectometry predicts the outcome of percutaneous nerve evaluation for faecal incontinence. AB - BACKGROUND: Sacral nerve stimulation (SNS) is effective for some patients with faecal incontinence. Before insertion of a costly implant, percutaneous nerve evaluation (PNE) is undertaken to identify patients likely to report success from SNS. The aim of this study was to determine whether variables of anal sphincter function measured by anal acoustic reflectometry (AAR) could predict the outcome of PNE for faecal incontinence. METHODS: Women with faecal incontinence undergoing PNE were recruited. AAR, followed by anal manometry, was performed on the day of surgery, immediately before PNE. The outcome of PNE was determined by bowel diary results and incontinence severity score. Patients with a successful PNE outcome were compared with those with an unsuccessful outcome; logistic regression analysis was used to identify any independent predictors of success. RESULTS: Fifty-two patients were recruited, of whom 32 (62 per cent) had a successful PNE outcome and 20 (38 per cent) an unsuccessful outcome. The AAR variable opening pressure was significantly greater in patients who subsequently had a successful PNE result compared with the pressure in patients who did not (28 versus 17 cmH2 O; P = 0.008). No difference was seen in the manometric equivalent, maximum resting pressure. Opening pressure was an independent predictor of success with an odds ratio of 1.08 (95 per cent confidence interval 1.01 to 1.16; P = 0.018). CONCLUSION: AAR is a sensitive test of sphincter function and can identify differences between patients who respond to PNE and those who do not. Opening pressure is an independent predictor of success in PNE, and may be of value in the selection of patients for this expensive treatment option. PMID- 25043272 TI - Room temperature homogeneous ductility of micrometer-sized metallic glass. AB - Homogeneous ductile flow of metallic glasses is observed at the micrometer scale. It is shown that this unusual deformation mode of an otherwise brittle material depends on both specimen size and applied loading rate. The results are explained by intrinsic length-scale effects of nanometer-sized defects, and provide a rationale for the long term debated brittle-to-ductile transition of amorphous metals. PMID- 25043273 TI - Safety of percutaneous tracheostomy in NeuroICU patients with intracranial pressure monitoring. PMID- 25043274 TI - Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2. AB - Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein we examined the expression profiles of long noncoding RNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one of these, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling, and the expression of stem cell-like properties of murine cells. Interestingly, we found that human lncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expression had a poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cell cycling, and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed that lncRNA-hPVT1 up regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and mass spectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. We confirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and that lncRNA-hPVT1 function depends on the presence of NOP2. CONCLUSION: Our study demonstrates that the expression of many lncRNAs is up-regulated in early liver development and that the fetal liver can be used to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cell cycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA hPVT1/NOP2 pathway may have beneficial effects on the treatment of HCC. PMID- 25043275 TI - Hybrid molecule from Farnesylthiosalicylic acid-diamine and phenylpropenoic acid as Ras-related signaling inhibitor with potent antitumor activities. AB - Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12 f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12 f dose-dependently induced SMMC-7721 cell apoptosis. Additionally, our observations demonstrated that 12 f inhibited both Ras-related signaling and phosphorylated NF-kappaB synergistically, which may be advantageous to the strong antitumor activities of 12 f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers. PMID- 25043276 TI - Use of fractional factorial design to study the compatibility of viral ribonucleoprotein gene segments of human H7N9 virus and circulating human influenza subtypes. AB - Avian H7N9 influenza viruses may pose a further threat to humans by reassortment with human viruses, which could lead to generation of novel reassortants with enhanced polymerase activity. We previously established a novel statistical approach to study the polymerase activity of reassorted vRNPs (Influenza Other Respir Viruses. 2013;7:969-78). Here, we report the use of this method to study recombinant vRNPs with subunits derived from human H1N1, H3N2, and H7N9 viruses. Our results demonstrate that some reassortant vRNPs with subunits derived from the H7N9 and other human viruses can have much higher polymerase activities than the wild-type levels. PMID- 25043278 TI - Safety and immunogenicity of a primary series of Sabin-IPV with and without aluminum hydroxide in infants. AB - BACKGROUND: An inactivated poliovirus vaccine (IPV) based on attenuated poliovirus strains (Sabin-1, -2 and -3) was developed for technology transfer to manufacturers in low- and middle-income countries in the context of the global polio eradication initiative. METHOD: Safety and immunogenicity of Sabin-IPV (sIPV) was evaluated in a double-blind, randomized, controlled, dose-escalation trial in the target population. Healthy infants (n=20/group) aged 56-63 days, received a primary series of three intramuscular injections with low-, middle- or high-dose sIPV with or without aluminum hydroxide or with the conventional IPV based on wild poliovirus strains (wIPV). Virus-neutralizing titers against both Sabin and wild poliovirus strains were determined before and 28 days after three vaccinations. RESULTS: The incidence of local and systemic reactions was comparable with the wIPV. Seroconversion rates after three vaccinations were 100% for type 2 and type 3 polioviruses (both Sabin and wild strains) and 95-100% for type 1 polioviruses. Median titers were high in all groups. Titers were well above the log2(titer) correlated with protection (=3) for all groups. Median titers for Sabin-2 were 9.3 (range 6.8-11.5) in the low-dose sIPV group, 9.2 (range 6.8-10.2) in the low-dose adjuvanted sIPV group and 9.8 (range 5.5-15.0) in the wIPV group, Median titers against MEF-1 (wild poliovirus type 2) were 8.2 (range 4.8-10.8) in the low-dose sIPV group, 7.3 (range 4.5-10.2) in the low-dose adjuvanted Sabin-IPV group and 10.3 (range 8.5-17.0) in the wIPV group. For all poliovirus types the median titers increased with increasing dose levels. CONCLUSION: sIPV and sIPV adjuvanted with aluminum hydroxide were immunogenic and safe at all dose levels, and comparable with the wIPV. EudraCTnr: 2011-003792-11, NCT01709071. PMID- 25043279 TI - Novel stereoselective high-performance liquid chromatographic method for simultaneous determination of guaifenesin and ketorolac enantiomers in human plasma. AB - A novel method was developed for the simultaneous determination of guaifenesin (GUA) and ketorolac tromethamine (KET) enantiomers in plasma samples. Since GUA probably increases the absorption of coadministered drugs (e.g., KET), it would be extremely important to monitor KET plasma levels for the purpose of dose adjustment with a subsequent decrease in the side effects. Enantiomeric resolution was achieved on a polysaccharide-based chiral stationary phase, amylose-2, as a chiral selector under the normal phase (NP) mode and using ornidazole (ORN) as internal standard. This innovative method has the advantage of the ease and reliability of sample preparation for plasma samples. Sample clean-up was based on simply using methanol for protein precipitation followed by direct extraction of drug residues using ethanol. Both GUA and KET enantiomers were separated using an isocratic mobile phase composed of hexane/isopropanol/trifluoroacetic acid, 85:15:0.05 v/v/v. Peak area ratios were linear over the range 0.05-20 ug/mL for the four enantiomers S (+) GUA, R (-) GUA, R (+) KET, and S (-) KET. The method was fully validated according to the International Conference on Harmonization (ICH) guidelines in terms of system suitability, specificity, accuracy, precision, robustness, and solution stability. Finally, this procedure was innovative to apply the rationale of developing a chiral high-performance liquid chromatography (HPLC) procedure for the simultaneous quantitative analysis of drug isomers in clinical samples. PMID- 25043277 TI - Phenotype of the anti-Rickettsia CD8(+) T cell response suggests cellular correlates of protection for the assessment of novel antigens. AB - The obligately intracellular bacteria Rickettsia infect endothelial cells and cause systemic febrile diseases that are potentially lethal. No vaccines are currently available and current knowledge of the effective immune response is limited. Natural and experimental rickettsial infections provide strong and cross protective cellular immunity if the infected individual survives the acute infection. Although resistance to rickettsial infections is attributed to the induction of antigen-specific T cells, particularly CD8(+) T cells, the identification and validation of correlates of protective cellular immunity against rickettsial infections, an important step toward vaccine validation, remains a gap in this field. Here, we show that after a primary challenge with Rickettsia typhi in the C3H mouse model, the peak of anti-Rickettsia CD8(+) T cell-mediated responses occurs 7 days post-infection (dpi), which coincides with the beginning of rickettsial clearance. At this time point, both effector-type and memory-type CD8(+) T cells are present, suggesting that 7 dpi is a valid time point for the assessment of CD8(+) T cell responses of mice previously immunized with protective antigens. Based on our results, we suggest four correlates of cellular protection for the assessment of protective rickettsial antigens: (1) production of IFN-gamma by antigen-experienced CD3(+)CD8(+)CD44(high) cells, (2) production of Granzyme B by CD27(low)CD43(low) antigen-experienced CD8(+) T cells, (3) generation of memory-type CD8(+) T cells [Memory Precursor Effector Cells (MPECs), as well as CD127(high)CD43(low), and CD27(high)CD43(low) CD8(+) T cells], and (4) generation of effector-like memory CD8(+) T cells (CD27(low)CD43(low)). We propose that these correlates could be useful for the general assessment of the quality of the CD8(+) T cell immune response induced by novel antigens with potential use in a vaccine against Rickettsia. PMID- 25043281 TI - Synthesis and properties of magnetic molecularly imprinted polymers based on multiwalled carbon nanotubes for magnetic extraction of bisphenol A from water. AB - Novel magnetic molecularly imprinted polymers based on multiwalled carbon nanotubes (MWNTs@MMIPs) with specific selectivity toward bisphenol A were synthesized using bisphenol A as the template molecule, methacrylic acid, and beta-cyclodextrin as binary functional monomers and ethylene glycol dimethacrylate as the cross-linker. The MWNTs@MMIPs were characterized by Fourier transform infrared, vibrating sample magnetometer, and transmission electron microscopy. Batch mode adsorption experiment was carried out to investigate the specific adsorption equilibrium and kinetics of the MWNTs@MMIPs. The MWNTs@MMIPs exhibited good affinity with a maximum adsorption capacity of 49.26 MUmol g(-1) and excellent selectivity toward bisphenol A. Combined with high-performance liquid chromatography analysis, the MWNTs@MMIPs were employed to extract bisphenol A in tap water, rain water, and lake water successfully with the recoveries of 89.8-95.4, 89.9-93.4, and 87.3-94.1%, respectively. PMID- 25043282 TI - Simultaneous determination of amantadine, rimantadine and memantine in chicken muscle using multi-walled carbon nanotubes as a reversed-dispersive solid phase extraction sorbent. AB - A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) method using multi-walled carbon nanotubes (MWCNTs) as a reversed-dispersive solid phase extraction (r-dSPE) material combined with ultra-high liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was developed for the simultaneous determination of amantadine, rimantadine and memantine in chicken muscle. The satisfactory separation of isomers (rimantadine and memantine) was obtained on an Acquity BEH C18 column (2.1 mm * 100 mm, 1.7 MUm) after optimization of mobile phase composition, column temperature and flow rate. The method involved an acetonitrile-based sample preparation and a dSPE clean-up procedure with MWCNTs material. Variations in the type and amount of MWCNTs, the pH value of the extract, the extraction time for MWCNTs, and the type of eluent were used to determine the optimal parameters for increasing the sample throughput and the sensitivity. The samples were quantified using amantadine-D15, rimantadine-D4 and memantine-D6 as the internal standards. Under the optimized conditions, recoveries of 96.8-104.6% and the values of coefficient of variation (CV) of 3.8 6.4% were obtained for the three drugs in chicken muscle at three spiked levels (0.5, 1.0 and 1.5 MUg/kg), and the decision limits (CCalpha) and detection capabilities (CCbeta) were 0.15-0.20 MUg/kg and 0.20-0.25 MUg/kg, respectively. Positive results were obtained from local supermarket using this method, and the concentrations obtained from the newly developed method compared well to the previously reported method. PMID- 25043283 TI - Enantioselective construction of quaternary stereogenic carbon atoms by the Lewis base catalyzed additions of silyl ketene imines to aldehydes. AB - Silyl ketene imines derived from a variety of alpha-branched nitriles have been developed as highly useful reagents for the construction of quaternary stereogenic centers via the aldol addition reaction. In the presence of SiCl4 and the catalytic action of a chiral phosphoramide, silyl ketene imines undergo extremely rapid and high yielding addition to a wide variety of aromatic aldehydes with excellent diastereo- and enantioselectivity. Of particular note are the high yields and selectivities obtained from electron-rich, electron-poor, and hindered aldehydes. Linear aliphatic aldehydes did react with good diastereo- and enantioselectivity in the presence of nBu4N(+)I(-), but branched aldehydes were much less reactive. Semiempirical calculations provided a rationalization of the observed diastereo- and enantioselectivity via open transitions states. PMID- 25043284 TI - Serum hepcidin levels in women infected with HIV-1 under antiviral therapy. AB - Accumulating data suggest that iron may have a role in the regulation of HIV infection. In the present study, we determined by radioimmunoassay the levels of hepcidin, a key regulator of iron homeostasis, in sera of 182 women infected with HIV-1 under highly active antiretroviral therapy (HAART). In the total cohort, hepcidin levels were lower in individuals infected with HIV than in controls (3.20 +/- 3.06 vs. 5.68 +/- 3.66 nmol/L, P = 0.009). Serum hepcidin concentrations were strongly correlated positively with iron, ferritin, urea, and uric acid. In the total cohort of patients with abnormal viral load and CD4 cell count <500 cells/mm(3) , a strong positive correlation was found between hepcidin and viral load. Hepcidin level was significantly higher in HIV-patients with high viremia than in patients with undetectable viral load. Iron level was significantly lower in HIV-patients with high viral load compared with patients with undetectable viral load. This study suggests that hepcidin controls serum iron, especially in response of iron utilization by HIV for viral replication. The possibility of using inhibitors of hepcidin expression as adjunct therapy for HIV-patients is discussed. PMID- 25043286 TI - Accuracy and precision of as-received implant torque wrenches. AB - STATEMENT OF PROBLEM: Previous implant torque evaluation did not determine if the target value fell within a confidence interval for the population mean of the test groups, disallowing determination of whether a specific type of wrench met a standardized goal value. PURPOSE: The purpose of this study was to measure both the accuracy and precision of 2 different configurations (spring style and peak break) of as-received implant torque wrenches and compare the measured values to manufacturer-stated values. MATERIAL AND METHODS: Ten wrenches from 4 manufacturers, representing a variety of torque-limiting mechanisms and specificity of use (with either a specific brand or universally with any brand of implant product). Drivers were placed into the wrench, and tightening torque was applied to reach predetermined values using a NIST-calibrated digital torque wrench. Five replications of measurement were made for each wrench and averaged to provide a single value from that instrument. The target torque value for each wrench brand was compared to the 95% confidence interval for the true population mean of measured values to see if it fell within the measured range. RESULTS: Only 1 wrench brand (Nobel Biocare) demonstrated the target torque value falling within the 95% confidence interval for the true population mean. For others, the targeted torque value fell above the 95% confidence interval (Straumann and Imtec) or below (Salvin Torq). CONCLUSIONS: Neither type of torque-limiting mechanism nor designation of a wrench to be used as a dedicated brand-only product or to be used as a universal product on many brands affected the ability of a wrench to deliver torque values where the true population mean included the target torque level. PMID- 25043285 TI - Pain experiences among a population-based cohort of current, former, and never regular smokers with lung and colorectal cancer. AB - BACKGROUND: Smoking and pain are prevalent and comorbid among patients with cancer. Limited work has compared pain experiences among current, former, and never (regular) smokers with lung and colorectal cancer. METHODS: We studied pain experiences of patients with lung (n = 2390) and colorectal (n = 2993) cancer participating in the multi-regional Cancer Care Outcomes Research and Surveillance study. We examined reports of pain, pain treatment, pain severity, and pain-related interference within each cancer group by smoking status, adjusting for demographic, psychosocial, and cancer characteristics. RESULTS: Among lung cancer patients, current smokers reported pain and receiving pain treatment more often than former smokers. Never smokers did not differ from current and former smokers on endorsement of pain; however, they reported pain treatment less often than their counterparts. Current smokers reported greater pain severity than former smokers after adjusting for other contributing factors; however, no differences were detected between current and never smokers. There were no differences in pain-related interference. Among colorectal cancer patients, current smokers reported pain and pain treatment more often than former and never smokers; however, the latter 2 groups did not differ. Current smokers also reported greater pain severity than never smokers after adjustments; however, no differences were detected between current and former smokers. An identical pattern of findings was observed for pain-related interference. CONCLUSIONS: Many smokers with lung and colorectal cancer experience pain following a cancer diagnosis. Future work should assess if comprehensive smoking cessation treatments that address pain can reduce pain and facilitate smoking cessation among patients with cancer. PMID- 25043287 TI - An alternative method for cementing laminate restorations with a micropulse toothbrush. AB - Because porcelain laminate veneers are fragile and thin, seating should be handled carefully, but complete seating is essential for a successful restoration. When a high-viscosity luting resin is chosen, high pressure will be needed to seat the veneer, which makes it possible to fracture the material with finger pressure. This technical report describes a straightforward and safe cementation technique for porcelain laminate veneers as well as for complete crown, inlay, and onlay restorations. PMID- 25043288 TI - Preprosthetic minor tooth movement with thermoplastic appliances and interproximal stripping: a clinical report. AB - This clinical report describes preprosthodontic minor tooth movement with serial thermoplastic appliances and interproximal stripping. A patient with rotated and labially tipped anterior teeth sought care with a request for improved appearance. The prosthodontic planning and treatment approach are discussed. PMID- 25043290 TI - A novel particle separation method based on induced-charge electro-osmotic flow and polarizability of dielectric particles. AB - A new microfluidic method of particle separation was proposed and studied theoretically in this paper. This method is based on the induced charge electro osmotic flow (ICEOF) and polarizability of dielectric particles. In this method, a pair of metal plates is embedded on the side channel walls to create a region of circulating flows under applied electric field. When a dielectric particle enters this region, the vortices produced by ICEOF around the particle will interact with the circulating flows produced by the metal plates. Such hydrodynamic interaction influences the particle's trajectory, and may result in the particle being trapped in the flow circulating zone or passing through this flow circulating zone. Because the hydrodynamic interaction is sensitive to the applied electric field, and the polarizability and the size of the particles, separation of different particles can be realized by controlling these parameters. Comparing with electrophoresis and dielectrophoresis methods, this strategy presented in this paper is simple and sensitive. PMID- 25043289 TI - Health-risk behaviors among high school athletes and preventive services provided during sports physicals. AB - INTRODUCTION: Preparticipation examinations (PPEs), or sports physicals, present opportunities for health care providers to identify and discuss common adolescent health-risk behaviors. We sought to examine the prevalence of health-risk behaviors among high school athletes and the proportion of providers who address these behaviors during PPEs. METHOD: For this descriptive study we used data from two statewide surveys: a survey of adolescents (n = 46,492) and a survey of nurse practitioners and physicians (n = 561). RESULTS: The most prevalent risk behaviors reported by student athletes were low levels of physical activity (70%), bullying perpetration (41%), and alcohol use (41%). Most providers (>=75%) addressed many common risk behaviors during PPEs but fewer addressed bullying, violence, and prescription drug use. Topics discussed differed by provider type and patient population. DISCUSSION: Many providers addressed critical threats to adolescent health during PPEs, but findings suggest potential disconnects between topics addressed during PPEs and behaviors of athletes. PMID- 25043292 TI - Effect of glycemic control on nocturnal arterial oxygen saturation: a case control study in type 2 diabetic patients. AB - BACKGROUND: There is growing evidence suggesting a deleterious effect of type 2 diabetes on lung function and sleep breathing. The aim of this case-control study was to evaluate whether or not an improvement in glycemic control could arrest or ameliorate nocturnal hypoxemia in type 2 diabetes. METHODS: Thirty patients with type 2 diabetes with HbA1c >=8% (cases) and 10 non-diabetic subjects were analyzed. Controls were closely matched to cases by age, gender, body mass index, and neck circumference. The nocturnal oxygen desaturation index (ODI) was calculated at baseline and 5 days after blood glucose improvement with pharmacological intervention. Four different oxygen desaturation thresholds (reductions in SaO2 >= 3%, 4%, 6%, and 8%) as indicators of hypoxemia severity (ODI-3%, ODI-4%, ODI-6%, ODI-8%) were used. RESULTS: At baseline, patients with diabetes showed a higher number of ODI-3%, ODI-4%, and ODI-6% in comparison with controls. A significant reduction in ODI-3% (29.7 [4.8-107.9] events per hour at baseline versus 24.6 [3.1-97.7] e/h at discharge, P < 0.001), ODI-4% (21.7 [1.6 79.3] versus 14.7 [0.3- 79.4], P = 0.003), ODI-6% (9.3 [0.3-71.8] versus 4.0 [0.0 73.7], P = 0.001), and ODI-8% (4.1 [0.0-64.3] versus 1.1 [0.0-69.8], P = 0.033) was observed in patients with diabetes after 5 days of follow-up. However, no changes in ODI events were observed in non-diabetic patients after the same period. No significant changes in weight were observed in either group. CONCLUSIONS: Glycemic control improvement significantly reduces the increased number of nocturnal oxygen desaturations that exist in type 2 diabetes. Although the mechanisms are not yet fully understood, the rapid effect without changes in body weight suggests a central mechanism involving respiratory center output. PMID- 25043291 TI - Honokiol activates reactive oxygen species-mediated cytoprotective autophagy in human prostate cancer cells. AB - BACKGROUND: Honokiol (HNK), derived from the bark of an oriental medicinal plant (Magnolia officinalis), is a promising anticancer agent with preclinical in vitro (PC-3 and LNCaP cells) and in vivo (PC-3 xenografts) efficacy against prostate cancer. However, the mechanisms affecting anticancer response to HNK are not fully understood. METHODS: Human (androgen-independent PC-3 and androgen responsive LNCaP) and murine (Myc-CaP) prostate cancer cells, and PC-3 tumor xenografts were used for various assays. Autophagy was assessed by transmission electron microscopy, immunofluorescence (LC3 puncta), and immunoblotting (LC3BII detection). Cell viability was determined by trypan blue assay. Apoptosis was quantitated by DNA fragmentation detection and Annexin V/propidium iodide assay. Reactive oxygen species (ROS) were detected by electron paramagnetic resonance spectrometry and flow cytometric/microscopic analysis of MitoSOX red fluorescence. RESULTS: Exposure of PC-3, LNCaP, and Myc-CaP cells to pharmacologic doses of HNK resulted in autophagy induction. The PC-3 tumor xenografts from HNK-treated mice contained higher levels of LC3BII protein compared with control tumors. Cell viability inhibition and apoptosis induction resulting from HNK exposure were significantly augmented by pharmacological inhibition of autophagy using 3-methyladenine as well as RNA interference of autophagy regulator ATG5. HNK-mediated increase in levels of LC3BII protein was partially but markedly diminished in the presence of antioxidants, including N acetylcysteine, polyethylene glycol-conjugated (PEG)-superoxide dismutase, and PEG-catalase. On the other hand, antioxidants had no impact on HNK-induced apoptosis. CONCLUSIONS: In conclusion, the present study demonstrates, for the first time, that HNK induces ROS-mediated cytoprotective autophagy in prostate cancer cells. PMID- 25043293 TI - Effect of the antioxidants composition in diet on the sensory and physical properties of frozen farmed Coho salmon (Oncorhynchus kisutch). AB - BACKGROUND: Great attention has been paid to the antioxidants present in farmed fish feeds, with the replacement of synthetic antioxidants by natural ones being a main objective. In the present study, Coho salmon (Oncorhynchus kisutch) was fed a conventional diet that was enriched with different kinds of antioxidants: synthetic antioxidants (butylated-hydroxy toluene and ethoxyquin; diet I), a tocopherols-rich mixture (diet II) and a tocopherols-rosemary extract mixture (diet III). A comparative study of the sensory and physical changes observed in the corresponding frozen products was undertaken. RESULTS: After 18 months at -18 degrees C, fish previously fed on diet I showed higher putrid and rancid odours and rancid taste scores, while lower mean typical odour and taste values were attained. Dripping and expressible moisture values obtained for diet II-fish were lower when compared with their counterparts belonging to the diet I; additionally, microstructure analysis revealed that Z-lines integration was better preserved in fish corresponding to diets II and III. CONCLUSION: Diet II has been recognised as being the most profitable to be employed to maintain the sensory and physical properties of the frozen product when long-term storage is considered. Further research is to be continued to optimise the natural antioxidants profile. PMID- 25043294 TI - Quantifying serotonin transporters by PET with [11C]-DASB before and after interferon-alpha treatment. AB - BACKGROUND: Interferon-alpha (IFN-alpha) therapy is frequently associated with disabling depression, fatigue, and related neuropsychiatric effects. Although depression in major depressive disorder is associated with low serotonin transporter binding, animal models suggest that IFN-associated mood effects are linked to increased presynaptic serotonin transporter binding. This study tested the hypotheses that IFN administration to human subjects increases presynaptic serotonin binding activity, and that this effect correlates with incident depression symptoms. METHODS: Positron emission tomography (PET) scans using [11C]-DASB were obtained for nine hepatitis C patients before and after IFN-alpha treatment for 8 weeks. Serotonin transporter binding was estimated using the likelihood estimation in graphical analysis (LEGA) model and measured as the volume of distribution (VT) divided by the free fraction of ligand (fP). Depression was measured with the Structured Clinical Interview for DSM-IV Diagnosis (SCID) and the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Compared to pre-IFN treatment values, changes in serotonin transporter binding and depression symptoms were not significant. There was no correlation between changes in serotonin transporter binding and depression symptoms. LIMITATIONS: The study is limited by small sample size, minimal effect on observed mood symptoms within the sample, and brief duration of follow-up. CONCLUSION: These findings do not support the hypothesis of an IFN-induced change in serotonin transporter function as the cause of incident depressive symptoms in patients treated with IFN-alpha. Additional study of these possible relationships should be of longer duration and include more subjects with more pronounced changes in mood. PMID- 25043295 TI - Overexpression of the Nek2 kinase in colorectal cancer correlates with beta catenin relocalization and shortened cancer-specific survival. AB - The serine/threonine kinase Nek2 (NIMA-related kinase 2) regulates centrosome separation and mitotic progression, with overexpression causing induction of aneuploidy in vitro. Overexpression may also enable tumour progression through effects upon Akt signalling, cell adhesion markers and the Wnt pathway. The objective of this study was to examine Nek2 protein expression in colorectal cancer (CRC). Nek2 protein expression was examined in a panel of CRC cell lines using Western blotting and immunofluorescence microscopy. Nek2 and beta-catenin expression were examined by immunohistochemistry in a series of resected CRC, as well as their matched lymph node and liver metastases, and correlated with clinicopathological characteristics. Nek2 protein expression in all CRC lines examined was higher than in the immortalised colonocyte line HCEC. Nek2 overexpression was present in 86.4% of resected CRC and was significantly associated with advancing AJCC tumour stage and shortened cancer-specific survival. Elevated Nek2 expression was maintained within all matched metastases from overexpressing primary tumours. Nek2 overexpression was significantly associated with lower tumour membranous beta-catenin expression and higher cytoplasmic and nuclear beta-catenin accumulation. These data support a role for Nek2 in CRC progression and confirm potential for Nek2 inhibition as a therapeutic avenue in CRC. PMID- 25043296 TI - Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. AB - Osteosarcoma (OS) is the most common cancer of bone. Parathyroid hormone (PTH) regulates calcium homeostasis and bone development, while the paracrine/autocrine PTH-related protein (PTHrP) has central roles in endochondral bone formation and bone remodeling. Using a murine OS model, we found that OS cells express PTHrP and the common PTH/PTHrP receptor (PTHR1). To investigate the role of PTHR1 signaling in OS cell behavior, we used shRNA to reduce PTHR1 expression. This only mildly inhibited proliferation in vitro, but markedly reduced invasion through collagen and reduced expression of RANK ligand (RANKL). Administration of PTH(1-34) did not stimulate OS proliferation in vivo but, strikingly, PTHR1 knockdown resulted in a profound growth inhibition and increased differentiation/mineralization of the tumors. Treatment with neutralizing antibody to PTHrP did not recapitulate the knockdown of PTHR1. Consistent with this lack of activity, PTHrP was predominantly intracellular in OS cells. Knockdown of PTHR1 resulted in increased expression of late osteoblast differentiation genes and upregulation of Wnt antagonists. RANKL production was reduced in knockdown tumors, providing for reduced homotypic signaling through the receptor, RANK. Loss of PTHR1 resulted in the coordinated loss of gene signatures associated with the polycomb repressive complex 2 (PRC2). Using Ezh2 inhibitors, we demonstrate that the increased expression of osteoblast maturation markers is in part mediated by the loss of PRC2 activity. Collectively these results demonstrate that PTHR1 signaling is important in maintaining OS proliferation and undifferentiated state. This is in part mediated by intracellular PTHrP and through regulation of the OS epigenome. PMID- 25043297 TI - DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1 mediated signaling pathway. AB - The DEAD-box RNA helicase DDX3 is a versatile protein involved in multiple steps of gene expression and various cellular signaling pathways. DDX3 mutations have been implicated in the wingless (Wnt) type of medulloblastoma. We show here that small interfering RNA-mediated DDX3 knockdown in various cell lines increased cell-cell adhesion but decreased cell-extracellular matrix adhesion. Moreover, DDX3 depletion suppressed cell motility and impaired directional migration in the wound-healing assay. Accordingly, DDX3-depleted cells exhibited reduced invasive capacities in vitro as well as reduced metastatic potential in mice. We also examined the mechanism underlying DDX3-regulated cell migration. DDX3 knockdown reduced the levels of both Rac1 and beta-catenin proteins, and consequentially downregulated the expression of several beta-catenin target genes. Moreover, we demonstrated that DDX3-regulated Rac1 mRNA translation, possibly through an interaction with its 5'-untranslated region, and affected beta-catenin protein stability in an Rac1-dependent manner. Taken together, our results indicate the DDX3-Rac1-beta-catenin regulatory axis in modulating the expression of Wnt/beta catenin target genes. Therefore, this report provides a mechanistic context for the role of DDX3 in Wnt-type tumors. PMID- 25043298 TI - Oncogenic role of Merlin/NF2 in glioblastoma. AB - Glioblastoma is the most common and aggressive primary brain tumor in adults, with a poor prognosis because of its resistance to radiotherapy and chemotherapy. Merlin/NF2 (moesin-ezrin-radixin-like protein/neurofibromatosis type 2) is a tumor suppressor found to be mutated in most nervous system tumors; however, it is not mutated in glioblastomas. Merlin associates with several transmembrane receptors and intracellular proteins serving as an anchoring molecule. Additionally, it acts as a key component of cell motility. By selecting sub populations of U251 glioblastoma cells, we observed that high expression of phosphorylated Merlin at serine 518 (S518-Merlin), NOTCH1 and epidermal growth factor receptor (EGFR) correlated with increased cell proliferation and tumorigenesis. These cells were defective in cell-contact inhibition with changes in Merlin phosphorylation directly affecting NOTCH1 and EGFR expression, as well as downstream targets HES1 (hairy and enhancer of split-1) and CCND1 (cyclin D1). Of note, we identified a function for S518-Merlin, which is distinct from what has been reported when the expression of Merlin is diminished in relation to EGFR and NOTCH1 expression, providing first-time evidence that demonstrates that the phosphorylation of S518-Merlin in glioblastoma promotes oncogenic properties that are not only the result of inactivation of the tumor suppressor role of Merlin but also an independent process implicating a Merlin-driven regulation of NOTCH1 and EGFR. PMID- 25043299 TI - TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells. AB - TIPE1 (tumor necrosis factor-alpha-induced protein 8-like 1 or TNFAIP8L1) is a newly identified member of the TIPE (TNFAIP8) family, which play roles in regulating cell death. However, the biologic functions of TIPE1 in physiologic and pathologic conditions are largely unknown. Here, we report the roles of TIPE1 in hepatocellular carcinoma (HCC). Evaluated by immunohistochemical staining, HCC tissues showed significantly downregulated TIPE1 expression compared with adjacent non-tumor tissues, which positively correlated with tumor pathologic grades and patient survival. Using a homograft tumor model in Balb/c mice, we discovered that TIPE1 significantly diminished the growth and tumor weight of murine liver cancer homografts. Consistently, TIPE1 inhibited both cell growth and colony formation ability of cultured HCC cell lines, which was further identified to be due to TIPE1-inducing apoptosis in a caspase-independent, necrostatin-1 (Nec-1)-insensitive manner. Furthermore, mechanistic investigations revealed that TIPE1 interacted with Rac1, and inhibited the activation of Rac1 and its downstream p65 and c-Jun N-terminal kinase pathway. Moreover, overexpression of constitutively active Rac1 partially rescued the apoptosis induced by TIPE1, and Rac1 knockdown significantly restored the deregulated cell growth induced by TIPE1 small interfering RNA. Our findings revealed that TIPE1 induced apoptosis in HCC cells by negatively regulating Rac1 pathway, and loss of TIPE1 might be a new prognostic indicator for HCC patients. PMID- 25043300 TI - DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1. AB - Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway. PMID- 25043301 TI - MACC1 supports human gastric cancer growth under metabolic stress by enhancing the Warburg effect. AB - Cancer cells mainly metabolize by glycolysis (the Warburg effect) and are better adapted to resist metabolic stress. Metastasis-associated in colon cancer-1 (MACC1) is an oncogene promoting gastric cancer (GC) growth and metastasis, and its expression positively correlates with GC progression. However, it is unknown why MACC1 elevates with GC progression and what is its role in cancer metabolism. In this study, we discovered that MACC1 expression was significantly upregulated via adenosine monophosphate-activated protein kinase signaling in response to glucose deprivation-induced metabolic stress. Clinical observation demonstrates that MACC1 expression was higher in advanced stage GC. MACC1 expression was proved to be positively correlated with the maximum standardized uptake value of (18)F-deoxyglucose in the patients, and MACC1 enhanced (18)F-deoxyglucose uptake in GC cells and the xenografts. The underlying mechanism was that MACC1 promoted the Warburg effect by upregulating the activities and expressions of a series of glycolytic enzymes, including hexokinase, pyruvate dehydrogenase kinase and lactate dehydrogenase, in GC cells. This metabolic shift enhanced cell viability and resistance to apoptosis by facilitating ATP generation, reducing the reactive oxygen species production and stabilizing the mitochondrial membrane potential. In contrast, MACC1-silenced or the Warburg effect-blocked GC cells were more vulnerable to metabolic stress. In conclusion, metabolic stress is one of the mechanisms that elevate MACC1 expression in GC, and MACC1 upregulation compensatively ensures GC growth against metabolic stress by facilitating the Warburg effect. PMID- 25043302 TI - Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor. AB - NF-kappaB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-kappaB1 as being necessary for cytotoxicity in response to DNA alkylation damage. Given the importance of damage induced cell death for the maintenance of genomic stability, we examined whether Nfkb1 acts as a tumor suppressor in the setting of alkylation damage. Hprt mutation analysis demonstrates that Nfkb1(-/-) cells accumulate more alkylator induced, but not ionizing radiation (IR)-induced, mutations than similarly treated wild-type cells. Subsequent in vivo tumor induction studies reveal that following alkylator treatment, but not IR, Nfkb1(-/-) mice develop more lymphomas than similarly treated Nfkb1(+/+) animals. Heterozygous mice develop lymphomas at an intermediate rate and retain functional p50 in their tumors, indicating that Nfkb1 acts in a haploinsufficient manner. Analysis of human cancers, including therapy-related myeloid neoplasms, demonstrates that NFKB1 mRNA expression is downregulated compared with control samples in multiple hematological malignancies. These data indicate that Nfkb1 is a haploinsufficient, pathway specific tumor suppressor that prevents the development of hematologic malignancy in the setting of alkylation damage. PMID- 25043303 TI - Phosphorylation of Dok1 by Abl family kinases inhibits CrkI transforming activity. AB - The Crk SH2/SH3 adaptor and the Abl nonreceptor tyrosine kinase were first identified as oncoproteins, and both can induce tumorigenesis when overexpressed or mutationally activated. We previously reported the surprising finding that inhibition or knockdown of Abl family kinases enhanced transformation of mouse fibroblasts by CrkI. Abl family inhibitors are currently used or are being tested for treatment of human malignancies, and our finding raised concerns that such inhibitors might actually promote the growth of tumors overexpressing CrkI. Here, we identify the Dok1 adaptor as the key effector for the enhancement of CrkI transformation by Abl inhibition. We show that phosphorylation of tyrosines 295 and 361 of Dok1 by Abl family kinases suppresses CrkI transforming activity, and that upon phosphorylation these tyrosines bind the SH2 domains of the Ras inhibitor p120 RasGAP. Knockdown of RasGAP resulted in a similar enhancement of CrkI transformation, consistent with a critical role for Ras activity. Imaging studies using a FRET sensor of Ras activation revealed alterations in the localization of activated Ras in CrkI-transformed cells. Our results support a model in which Dok1 phosphorylation normally suppresses localized Ras pathway activity in Crk-transformed cells via recruitment and/or activation of RasGAP, and that preventing this negative feedback mechanism by inhibiting Abl family kinases leads to enhanced transformation by Crk. PMID- 25043305 TI - Helicobacter pylori infection and stem cells at the origin of gastric cancer. AB - Helicobacter pylori infection is now recognized as the main and specific infectious cause of cancer in the world. It is responsible for gastric adenocarcinomas of both intestinal and diffuse types, which are the long-term consequences of the chronic infection of the gastric mucosa. Case-control studies have shown an association between the two, recognized as early as 1994 and further substantiated by interventional studies in which H. pylori eradication has led to the prevention of at least part of the gastric cancers. Experimental studies have highlighted the role of bone marrow-derived cells (BMDCs) and particularly mesenchymal stem cells, in the neoplastic process in about a quarter of the cases and possibly an epithelial-mesenchymal transition (EMT) in the other cases. Different studies have confirmed that chronic infection with H. pylori induces a chronic inflammation and subsequent damage of the gastric epithelial mucosa, leading to BMDC recruitment. Once recruited, these cells home and differentiate by cell-cell fusion with local gastric epithelial cells, bearing local stem cell failure and participating in tissue regeneration. The context of chronic infection and inflammation leads to an EMT and altered tissue regeneration and differentiation from both local epithelial stem cells and BMDC. EMT induces the emergence of CD44+ cells possessing mesenchymal and stem cell properties, resulting in metaplastic and dysplastic lesions to give rise, after additional epigenetic and mutational events, to the emergence of cancer stem cells (CSCs) and adenocarcinoma. PMID- 25043304 TI - Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors. AB - While DNA damage response pathways are well characterized in cancer cells, much less is known about their status in normal cells. These pathways protect tumour cells from DNA damage and replication stress and consequently present potential therapeutic targets. Here we characterize the response of human telomerase reverse transcriptase (hTERT)-immortalized normal human urothelial (NHU) and bladder cancer cell lines to agents that disrupt the DNA damage response. Effects of replication and DNA damage response inhibitors on cell cycle progression, checkpoint induction and apoptosis were analysed in hTERT-NHU and bladder cancer cell lines. The primary signalling cascade responding to replication stress in malignant cells (ataxia telangiectasia-mutated (ATM) and Rad3-related-checkpoint kinase 1 (ATR-CHK1)) is not activated in hTERT-NHU cells after treatment with a replication inhibitor and these cells do not depend upon CHK1 for protection from apoptosis during replication stress. Instead, ATM signalling is rapidly activated under these conditions. Intriguingly, an ATM inhibitor suppressed S-phase checkpoint activation after exposure to replication inhibitors and stopped entry of cells into S-phase indicating G1 checkpoint activation. Consistent with this, hTERT-NHU cells treated with the ATM inhibitor showed increased levels of cyclin dependent kinase inhibitor p19(INK4D), reduced levels of cyclin D1 and CDK4, and reduced phosphorylation of the retinoblastoma protein. In contrast, a bladder cancer cell line cotreated with ATM and replication inhibitors progressed more slowly through S phase and showed a marked increase in apoptosis. Taken together, our findings suggest that ATM and CHK1 signalling cascades have different roles in tumour and normal epithelial cells, confirming these as promising therapeutic targets. PMID- 25043306 TI - PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer. AB - Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy. PMID- 25043307 TI - The Gbeta5 protein regulates sensitivity to TRAIL-induced cell death in colon carcinoma. AB - Aberrant signaling via G protein-coupled receptors (GPCRs) is implicated in numerous diseases including colon cancer. The heterotrimeric G proteins transduce signals from GPCRs to various effectors. So far, the G protein subunit Gbeta5 has not been studied in the context of cancer. Here we demonstrate that Gbeta5 protects colon carcinoma cells from apoptosis induced by the death ligand TRAIL via different routes. The Gbeta5 protein (i) causes a decrease in the cell surface expression of the TRAIL-R2 death receptor, (ii) induces the expression of the anti-apoptotic protein XIAP and (iii) activates the NF-kappaB signaling pathway. The intrinsic resistance to TRAIL-triggered apoptosis of colon cancer cells is overcome by antagonization of Gbeta5. Based on these results, targeting of G proteins emerges as a novel therapeutic approach in the experimental treatment of colon cancer. PMID- 25043308 TI - PAX genes in childhood oncogenesis: developmental biology gone awry? AB - Childhood solid tumors often arise from embryonal-like cells, which are distinct from the epithelial cancers observed in adults, and etiologically can be considered as 'developmental patterning gone awry'. Paired-box (PAX) genes encode a family of evolutionarily conserved transcription factors that are important regulators of cell lineage specification, migration and tissue patterning. PAX loss-of-function mutations are well known to cause potent developmental phenotypes in animal models and underlie genetic disease in humans, whereas dysregulation and/or genetic modification of PAX genes have been shown to function as critical triggers for human tumorigenesis. Consequently, exploring PAX-related pathobiology generates insights into both normal developmental biology and key molecular mechanisms that underlie pediatric cancer, which are the topics of this review. PMID- 25043309 TI - Actin filament-associated protein 1 is required for cSrc activity and secretory activation in the lactating mammary gland. AB - Actin filament-associated protein 1 (AFAP1) is an adaptor protein of cSrc that binds to filamentous actin and regulates the activity of this tyrosine kinase to affect changes to the organization of the actin cytoskeleton. In breast and prostate cancer cells, AFAP1 has been shown to regulate cellular responses requiring actin cytoskeletal changes such as adhesion, invadopodia formation and invasion. However, a normal physiologic role for AFAP1 has remained elusive. In this study, we generated an AFAP1 knockout mouse model that establishes a novel physiologic role for AFAP1 in lactation. Specifically, these animals displayed a defect in lactation that resulted in an inability to nurse efficiently. Histologically, the mammary glands of the lactating knockout mice were distinguished by the accumulation of large cytoplasmic lipid droplets in the alveolar epithelial cells. There was a reduction in lipid synthesis and the expression of lipogenic genes without a corresponding reduction in the production of beta-casein, a milk protein. Furthermore, these defects were associated with histologic and biochemical signs of precocious involution. This study also demonstrated that AFAP1 responds to prolactin, a lactogenic hormone, by forming a complex with cSrc and becoming tyrosine phosphorylated. Taken together, these observations pointed to a defect in secretory activation. Certain characteristics of this phenotype mirrored the defect in secretory activation in the cSrc knockout mouse, but most importantly, the activity of cSrc in the mammary gland was reduced during early lactation in the AFAP1-null mouse and the localization of active cSrc at the apical surface of luminal epithelial cells during lactation was selectively lost in the absence of AFAP1. These data define, for the first time, the requirement of AFAP1 for the spatial and temporal regulation of cSrc activity in the normal breast, specifically for milk production. PMID- 25043310 TI - MicroRNA-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival. AB - Gastric cancer (GC) is one of the most common tumors and the molecular mechanism underlying its metastasis is still largely unclear. Here, we show that miR-25 was overexpressed in plasma and primary tumor tissues of GC patients with tumor node metastasis stage (III or IV) or lymph node metastasis. MiR-25 inhibition significantly decreased the metastasis, invasion and proliferation of GC cells in vitro, and reduced their capacity to develop distal pulmonary metastases and peritoneal dissemination in vivo. Furthermore, miR-25 repressed transducer of ERBB2, 1 (TOB1) expression by directly binding to TOB1-3'-UTR, and the inverse correlation was observed between the expressions of miR-25 and TOB1 mRNA in primary GC tissues. Moreover, the loss of TOB1 increased the metastasis, invasion and proliferation of GC cells, and the restoration of TOB1 led to suppressed metastasis, invasion and proliferation. The receiver operating characteristics analysis yielded an area under the curve value of 0.7325 in distinguishing the GC patients with death from those with survival. The analysis of optimal cutoff value revealed poor survival in GC patients with high plasma concentrations of miR-25 (>0.2333 amol/MUl). Taken together, miR-25 promotes GC progression by directly downregulating TOB1 expression, and may be a noninvasive biomarker for the prognosis of GC patients. PMID- 25043311 TI - Evaluation of the impact of persistent subepithelial corneal infiltrations on the visual performance and corneal optical quality after epidemic keratoconjunctivitis. AB - PURPOSE: Aim was to measure the effect of persistent subepithelial corneal infiltrates (SEIs) after epidemic keratoconjunctivitis (EKC) on visual performance and corneal optical quality. METHODS: We examined 53 patients divided into two groups. Patients with previous EKC constituted the study group (Group 1, n: 27). Healthy age matched subjects constituted the control group (Group 2, n: 26). Study group was subdivided into eyes with SEI (Group 1A, 40 eyes) and healthy fellow eyes (Group 1B, 14 eyes). Patients were submitted to a complete examination including high- and low-contrast visual acuities (HCVA, LCVA), corneal topography and aberrometry. RESULTS: The mean interval between epidemic conjunctivitis and examination was 7.25 +/- 5.63 months. Mean number of corneal infiltrates was 17.30 +/- 14.38. The mean HCVA and LCVA were significantly lower in the eyes with SEI than fellow eyes and control group (p = 0.001). LCVA value was also worse in the fellow eyes when compared to control (p = 0.048). Corneal topography values were significantly higher in the eyes with SEI from both fellow eyes and control group. During corneal aberrometry, the mean root mean square value of spheric aberration, irregular astigmatism and total aberration were significantly higher in SEI group when compared to fellow eyes and control group (p < 0.05). Total aberrations were higher than control subjects in the fellow eyes. Trefoil aberration was higher in SEI group only when compared to control subjects, while there was no significant difference in coma aberration values between the groups (p > 0.05). CONCLUSION: Results of this study suggested that visual performance is compromised in patients with EKC by aberrations and changes in topographic variables. PMID- 25043313 TI - Woodworking injuries: a comparative study of work-related and hobby-related accidents. AB - The primary objective of this study was to describe the injury characteristics and demographics of patients injured during woodworking activities, upon their arrival to the emergency department in a regional of France where this industry is prevalent. The secondary objective was to compare patient and injury characteristics for work-related and hobby-related accidents. A cohort of 87 patients who had suffered a woodworking accident over a two-year period was evaluated; 79 were available for follow-up. The context and circumstances of the accident, nature and location of the injuries and patient demographics were recorded. Hobby-related accidents accounted for two-thirds of the accidents (51/79). Most of the injured workers were either loggers (35%) or carpenters (46%). The hand was injured in 53 cases (67%). Work-related accidents resulted in significantly more serious consequences in terms of hospital stay, work stoppage, resumption of work or retraining than hobby-related accidents. For the workplace accidents, 86% occurred on new machines; more than 25% of the machines involved in accidents at home were over 15 years. Sixty-eight per cent of workers were wearing their safety gear, while only 31% of those injured during recreational woodworking wore the appropriate gear. Several elements of prevention should be improved: information about the need to maintain the equipment, protect the worker with suitable clothing, and learn which maneuvers are considered hazardous. Safety gear should be regularly inspected in the workplace. PMID- 25043312 TI - Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3 sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides. AB - TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI 400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described. PMID- 25043314 TI - Uptake and elimination kinetics of metals in soil invertebrates: a review. AB - Uptake and elimination kinetics of metals in soil invertebrates are a function of both soil and organism properties. This study critically reviewed metal toxicokinetics in soil invertebrates and its potential use for assessing bioavailability. Uptake and elimination rate constants of different metals are summarized. Invertebrates have different strategies for essential and non essential metals. As a consequence, different types of models must be applied to describe metal uptake and elimination kinetics. We discuss model parameters for each metal separately and show how they are influenced by exposure concentrations and by physiological properties of the organisms. Soil pH, cation exchange capacity, clay and organic matter content significantly affect uptake rates of non-essential metals in soil invertebrates. For essential metals, kinetics is hardly influenced by soil properties, but rather prone to physiological regulation mechanisms of the organisms. Our analysis illustrates that toxicokinetics can be a valuable measurement to assess bioavailability of soil bound metals. PMID- 25043315 TI - Enhanced hydrolytic stability of siliceous surfaces modified with pendant dipodal silanes. AB - Dipodal silanes possess two silicon atoms that can covalently bond to a surface. They offer a distinct advantage over conventional silanes commonly used for surface modification in terms of maintaining the integrity of surface coatings, adhesive primers, and composites in aqueous environments. New nonfunctional and functional dipodal silanes with structures containing "pendant" rather than "bridged" organofunctionality are introduced. The stability of surfaces in aqueous environments prepared from dipodal silanes with hydrophobic alkyl functionality is compared to the stability of similar surfaces prepared from the conventional silanes. In strongly acidic and brine environments, surfaces modified with dipodal silanes demonstrate markedly improved resistance to hydrolysis compared to surfaces prepared from conventional silanes. Pendant dipodal silanes exhibit greater stability than bridged dipodal silanes. The apparent equilibrium constant for the formation of silanol species by the hydrolysis of a disiloxane bond was determined as Kc = [SiOH](2)/[Si-O-Si][H2O] = 6+/-1*10(-5) and is helpful in understanding the enhanced hydrolytic stability of surfaces modified with dipodal silanes. PMID- 25043316 TI - Biopsies in oncology. AB - Imaging-guided percutaneous biopsies in patients in oncology provide an accurate diagnosis of malignant tumors. Percutaneous biopsy results are improved by correct use of sampling procedures. The risks of percutaneous biopsy are low and its complications are generally moderate. These risks can be reduced using aids such as blund tip introducers, hydrodissection and correct patient positioning. The multidisciplinary team meetings dialogue between oncologist, surgeon and radiologist correctly defines the indications in order to improve the treatment strategies. PMID- 25043317 TI - Prostate cancer: diagnosis, parametric imaging and standardized report. AB - Multiparametric MR of the prostate provides an extremely accurate diagnosis and offers an excellent negative predictive value for cancers which biopsies struggle to detect. Combined with biopsies they consolidate both positive and negative biopsy results and allow patients to be offered more appropriate treatments (active monitoring, radical treatment in full knowledge of the topography of the lesions involved, or local treatment, etc.). The investigation does not require advanced equipment and can be carried out in any MR centre although it needs to follow a technical protocol described in the European guidelines (ESUR 2012). Interpretation should be standardized to facilitate communication of clear and consistent information between practitioners. PMID- 25043318 TI - Distinguishing between adjustment disorder and depressive episode in clinical practice: the role of personality disorder. AB - BACKGROUND: There is significant symptomatic overlap between diagnostic criteria for adjustment disorder and depressive episode, commonly leading to diagnostic difficulty. Our aim was to clarify the role of personality in making this distinction. METHODS: We performed detailed assessments of features of personality disorder, depressive symptoms, social function, social support, life threatening experiences and diagnosis in individuals with clinical diagnoses of adjustment disorder (n=173) or depressive episode (n=175) presenting at consultation-liaison psychiatry services across 3 sites in Dublin, Ireland. RESULTS: Fifty six per cent of participants with adjustment disorder had likely personality disorder compared with 65% of participants with depressive episode. Compared to participants with depressive episode, those with adjustment disorder had fewer depressive symptoms; fewer problems with social contacts or stress with spare time; and more life events. On multi-variable testing, a clinical diagnosis of adjustment disorder (as opposed to depressive episode) was associated with lower scores for personality disorder and depressive symptoms, and higher scores for life-threatening experiences. LIMITATIONS: We used clinical diagnosis as the main diagnostic classification and generalisability may be limited to consultation-liaison psychiatry settings. CONCLUSIONS: Despite a substantial rate of likely personality disorder in adjustment disorder, the rate was even higher in depressive episode. Moreover, features of likely personality disorder are more strongly associated with depressive episode than adjustment disorder, even when other distinguishing features (severity of depressive symptoms, life-threatening experiences) are taken into account. PMID- 25043319 TI - Social Phobia symptoms across the adult lifespan. AB - BACKGROUND: This study investigated symptom patterns that might distinguish between individuals with and without a diagnosis of Social Phobia (SP) across the adult lifespan. METHODS: A sample of 5411 self-reported social worriers was derived from Wave 1 (2001 and 2002) of the U.S. National Epidemiological Survey of Alcohol and Related Conditions (NESARC). Participants were stratified into four age groups (18-29 years, 30-44 years, 45-64 years, 65-96 years), and further divided into two diagnostic groups (self-reported social worriers with and without a SP diagnosis). RESULTS: Binary logistic regression analyses revealed that a core set of symptoms was associated with SP across the adult lifespan. There were also successive reductions in the number of symptoms associated with SP in each age group, such that older adults endorsed numerically fewer SP symptoms. LIMITATIONS: Though our sample size is smaller than ideal for the nature of our analyses, the NESARC represents one of the largest existing clinical datasets we know of. CONCLUSIONS: Despite age-related reductions in symptom frequency, a core set of SP symptoms consistently distinguished between diagnostic groups, irrespective of age. PMID- 25043320 TI - DISC1-TSNAX and DAOA genes in major depression and citalopram efficacy. AB - BACKGROUND: Major depressive disorder (MDD) is a common disease with high morbidity and still unsatisfying treatment response. Both MDD pathogenesis and antidepressant effect are supposed to be strongly affected by genetic polymorphisms. Among promising candidate genes, distrupted in schizophrenia 1 (DISC1), translin-associated factor X (TSNAX) and D-amino acid oxidase activator (DAOA) were suggested since their regulator role in neurodevelopment, neuroplasticity and neurotransmission, and previous evidence of cross-involvement in major psychiatric diseases. METHODS: The present paper investigated the role of 13 SNPs within the reported genes in MDD susceptibility through a case-control (n=320 and n=150, respectively) study and in citalopram efficacy (n=157). Measures of citalopram efficacy were response (4th week) and remission (12th week). Pharmacogenetic findings were tested in the STAR(*)D genome-wide dataset (n=1892) for replication. RESULTS: Evidence of association among rs3738401 (DISC1), rs1615409 and rs766288 (TSNAX) and MDD was found (p=0.004, p=0.0019, and p=0.008, respectively). A trend of association between remission and DISC1 rs821616 and DAOA rs778294 was detected, and confirmation was found for rs778294 by repeated-measure ANOVA (p=0.0008). In the STAR(*)D a cluster of SNPs from 20 to 40Kbp from DISC1 findings in the original sample was associated with citalopram response, as well as rs778330 (12,325bp from rs778294). LIMITATIONS: Relatively small size of the original sample and focus on only three candidate genes. CONCLUSIONS: The present study supported a role of DISC1-TSNAX variants in MDD susceptibility. On the other hand, genetic regions around DAOA rs778294 and DISC1 rs6675281-rs1000731 may influence citalopram efficacy. PMID- 25043321 TI - Exercise or basic body awareness therapy as add-on treatment for major depression: a controlled study. AB - BACKGROUND: While physical exercise as adjunctive treatment for major depression has received considerable attention in recent years, the evidence is conflicting. This study evaluates the effects of two different add-on treatments: exercise and basic body awareness therapy. METHODS: Randomized controlled trial with two intervention groups and one control, including 62 adults on antidepressant medication, who fulfilled criteria for current major depression as determined by the Mini International Neuropsychiatric Interview. Interventions (10 weeks) were aerobic exercise or basic body awareness therapy (BBAT), compared to a single consultation with advice on physical activity. Primary outcome was depression severity, rated by a blinded assessor using the Montgomery Asberg Rating Scale (MADRS). Secondary outcomes were global function, cardiovascular fitness, self rated depression, anxiety and body awareness. RESULTS: Improvements in MADRS score (mean change=-10.3, 95% CI (-13.5 to -7.1), p=0.038) and cardiovascular fitness (mean change=2.4ml oxygen/kg/min, 95% CI (1.5 to 3.3), p=0.017) were observed in the exercise group. Per-protocol analysis confirmed the effects of exercise, and indicated that BBAT has an effect on self-rated depression. LIMITATIONS: The small sample size and the challenge of missing data. Participants' positive expectations regarding the exercise intervention need to be considered. CONCLUSIONS: Exercise in a physical therapy setting seems to have effect on depression severity and fitness, in major depression. Our findings suggest that physical therapy can be a viable clinical strategy to inspire and guide persons with major depression to exercise. More research is needed to clarify the effects of basic body awareness therapy. PMID- 25043322 TI - Relapse rates after psychotherapy for depression - stable long-term effects? A meta-analysis. AB - BACKGROUND: Depression is the most common mental disorder. Effective psychotherapeutic treatments for depression exist; however, data on their long term effectiveness beyond a time span of two years is still scarce. Our aim was to perform a meta-analysis, investigating (a) overall rates of relapse more than two years after psychotherapy (meta-analysis 1), and (b) if psychotherapy has more enduring effects than non-psychotherapeutic comparison conditions (e.g. pharmacotherapy, treatment as usual), again beyond a time span of two years post therapy (meta-analysis 2). METHODS: We searched electronic databases Medline, PsycINFO and the COCHRANE Library. Main selection criteria were (i) RCT of psychotherapy with follow-up interval of more than 2 years, (ii) primary diagnosis of depression, assessed by observer ratings, (iii) report of relapse at follow-up. RESULTS: We identified 11 studies, 6 of which included a non psychotherapeutic comparison condition. Together they comprised long-term data of 966 patients. Mean follow-up duration was 4.4 years. The overall relapse rate at long-term follow-up was 0.39 (95% CI 0.29, 0.50). Psychotherapy resulted in significantly less relapses (53.1% vs. 71.1%, OR 0.51; 95% CI 0.32, 0.82, p=0.005) than comparison treatments. This finding corresponded to a number needed to treat (NNT) of 5.55. LIMITATIONS: Results can only be preliminary as data was sparse and studies differed methodologically. Heterogeneity in the first meta analysis was high (I(2)=82%). Results indicated publication bias. CONCLUSIONS: The relapse rate more than two years after psychotherapy is relatively high, but significantly lower compared to non-psychotherapeutic treatments. Multiannual follow-ups should routinely be included in future psychotherapy RCTs. PMID- 25043323 TI - Cognitive performance and quality of life early in the course of bipolar disorder. AB - BACKGROUND: Several studies have reported cognitive functioning as a significant predictor of quality of life (QoL) in patients with established bipolar disorder (BD), in addition to mood symptoms. However, it is unclear whether cognitive functioning predicts QoL early in the course of illness. The purpose of this study was therefore to evaluate the relationship between mood and neuropsychological variables and self-reported QoL early in the course of BD. METHODS: Patients with BD-I (n=54) completed a neuropsychological battery and clinical assessment within 3 months of resolution of their first manic episode. QoL was assessed 6 months later using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Cognitive predictors of QoL were assessed through Pearson correlations and hierarchical multiple regression. RESULTS: After accounting for mood rating scores at the time of cognitive testing (DeltaR2=.27, p<.001), measures of sustained attention (DeltaR2=.08, p<.05), verbal memory (DeltaR2=.09, p<.01), working memory (DeltaR2=.06, p<.05), and executive functioning (DeltaR2=.08, p<.05) each predicted QoL when entered independently in separate regression models. When entered simultaneously, the cognitive domains explained 15% (R(2)=.42, p<.05) of the variance in QoL beyond mood. LIMITATIONS: Some aspects of QoL that are particularly important in BD may be missing as a result of using the Q-LES-Q, because the measure was not specifically developed to assess QoL in BD. CONCLUSIONS: In addition to mood symptoms, poorer cognitive functioning is a significant predictor of reduced QoL early in the course of BD. Recently diagnosed patients with BD may benefit from early cognitive-enhancing interventions to maintain or restore their QoL. PMID- 25043324 TI - Evolution and changing trends in surgery for benign parotid tumors. AB - OBJECTIVE/HYPOTHESIS: The ideal extent of surgical intervention for benign parotid tumors remains a matter of controversy. The aim of the study was to trace the development of surgical therapy in a large cohort, explore its changes in a single institution specializing in salivary gland pathologies over the last 12 years, and determine the extent to which a possible shift in the surgical therapy of parotid benign tumors toward less radical methods was correlated with a change in the incidence of facial palsy and Frey's syndrome. STUDY DESIGN: Retrospective clinical study. METHODS: A retrospective evaluation of the records for all patients treated for benign parotid tumors between 2000 and 2012 at a tertiary referral center was carried out. Surgical methods were classified into four groups: extracapsular dissection, partial superficial parotidectomy, superficial parotidectomy, and complete parotidectomy. RESULTS: A total of 1,624 patients were included in the study. Our analysis demonstrated an increase in the total number of parotidectomies for benign lesions from 71 (2000) to 184 (2012), mostly due to the increase in extracapsular dissections (from 9 to 123). Increased performance of less radical surgery was associated with a significantly decreased incidence of temporary and permanent facial palsies (from 22.8% to 9% and 9.8% to 5.9%, respectively) and Frey's syndrome (from 11.3% to 1.6%). CONCLUSIONS: One of the most controversial issues in the treatment of benign parotid tumors is the best therapeutic approach to be taken in such patients. Our study showed that increased performance of less radical surgery was associated with better functional outcomes. PMID- 25043325 TI - Disruption of redox homeostasis and histopathological alterations caused by in vivo intrastriatal administration of D-2-hydroxyglutaric acid to young rats. AB - High accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of patients affected by the inherited neurometabolic disorder D-2 hydroxyglutaric aciduria (D-2-HGA). Clinically, patients present neurological symptoms and basal ganglia injury whose pathophysiology is poorly understood. We investigated the ex vivo effects of intrastriatal administration of D-2-HG on important parameters of redox status in the striatum of weaning rats. D-2-HG in vivo administration increased malondialdehyde (MDA) and carbonyl formation (lipid and protein oxidative damage, respectively), as well as the production of reactive nitrogen species (RNS). D-2-HG also compromised the antioxidant defenses by decreasing reduced glutathione (GSH) concentrations, as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Increased amounts of oxidized glutathione (GSSG) with no significant alteration of total glutathione (tGS) were also found. Furthermore, D-2-HG-induced lipid oxidation and reduction of GSH concentrations and GPx activity were prevented by the N methyl-d-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) and the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME), suggesting the participation of NMDA receptors and nitric oxide derivatives in these effects. Creatine also impeded D-2-HG-elicited MDA increase, but did not change the D-2-HG-induced diminution of GSH and of the activities of SOD and GPx. We also found that DCFH oxidation and H2O2 production were not altered by D-2-HG, making unlikely an important role for reactive oxygen species (ROS) and reinforcing the participation of RNS in the oxidative damage and the reduction of antioxidant defenses provoked by this organic acid. Vacuolization, lymphocytic infiltrates and macrophages indicating brain damage were also observed in the striatum of rats injected with D-2-HG. The present data provide in vivo solid evidence that D-2-HG disrupts redox homeostasis and causes histological alterations in the rat striatum probably mediated by NMDA overstimulation and RNS production. It is therefore presumed that disturbance of redox status may contribute at least in part to the basal ganglia alterations characteristic of patients affected by D-2-HGA. PMID- 25043326 TI - Quantitative expression profiling in mouse spinal cord reveals changing relationships among channel and receptor mRNA levels across postnatal maturation. AB - Neural networks ultimately arrive at functional output via interaction of the excitability of individual neurons and their synaptic interactions. We investigated the relationships between voltage-gated ion channel and neurotransmitter receptor mRNA levels in mouse spinal cord at four different postnatal time points (P5, P11, P17, and adult) and three different adult cord levels (cervical, thoracic, and lumbosacral) using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our analysis and data visualization are novel in that we chose a focal group of voltage-gated channel subunits and transmitter receptor subunits, performed absolute quantitation of mRNA copy number for each gene from a sample, and used multiple correlation analyses and correlation matrices to detect patterns in correlated mRNA levels across all genes of interest. These correlation profiles suggest that postnatal maturation of the spinal cord includes changes among channel and receptor subunits that proceed from widespread co-regulation to more refined and distinct functional relationships. PMID- 25043327 TI - R-Ras contributes to LTP and contextual discrimination. AB - The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation long-term potentiation (HFS-LTP) via the activation of p38 Map kinase. Here, we show that R Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of the dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases. PMID- 25043328 TI - Root canal morphology of South asian Indian mandibular premolar teeth. AB - INTRODUCTION: The purpose of this study was to study the root canal morphology of South Asian Indian mandibular premolars using a tooth clearing technique. METHODS: Two hundred mandibular premolar teeth were collected from different dental schools and clinics in India. After pulp tissue removal and root canal staining with Indian ink, the specimens were decalcified with 5% nitric acid, dehydrated in ethyl alcohol, and subsequently cleared in methyl salicylate. RESULTS: Of the 200 mandibular premolars, 100 were first premolars and 100 were second premolars. Of the first premolars, 94% had a single root, whereas 6% were 2 rooted. Seventy-six percent had a single canal, 22% had 2 canals, and 2% had 3 canals. Eighty-two percent had a single apical foramen, 16% had 2 foramens, and 2% teeth had 3 apical foramens. Eighty percent of teeth had type I, 6% had type II, 10% had type IV, 2% had type V, and 2% teeth had type IX root canal anatomy. Of the 100 second premolars, 92% had a single root, whereas 8% teeth were 2 rooted and fused. Fifty-eight percent of teeth had a single canal, and 42% had two canals. Eighty-eight percent had a single apical foramen, and 12% had 2 foramens. Sixty-six percent had type I, 30% had type II, and 4% had type V root canal anatomy. CONCLUSIONS: A high prevalence of 2 canals was noted in the first and second premolars. Also, 20% of first premolars and 34% of second premolars had a root canal anatomy other than type I. PMID- 25043329 TI - Immunoexpression of interleukin 17 in apical periodontitis lesions. AB - INTRODUCTION: Interleukin (IL)-17 expression has been detected in apical periodontitis lesions, but its role in the disease process remains unclear. The present study compared the expression of IL-17 in periradicular cysts and granulomas and evaluated the association of this cytokine with clinical and radiographic findings. METHODS: Apical periodontitis lesions (18 cysts and 20 granulomas) were obtained from 38 patients subjected to periradicular surgery. Some clinical, radiographic, and cone-beam computed tomographic features were recorded. Silanized slides containing paraffin sections were used for the immunohistochemical reactions using anti-IL-17 antibody. Image analysis was performed using an optical microscope, and each sample was divided into 5 high power fields, which were evaluated for the expression of IL-17 in the epithelium and connective tissues. Results were evaluated for correlations with the lesion size and the occurrence of symptoms and sinus tract. RESULTS: Expression of IL-17 was significantly higher in cysts than in granulomas (P = .02). Among the periradicular cysts, a thin epithelium showed significantly increased labeling for IL-17 when compared with a hyperplastic epithelium (P = .003). IL-17 expression was usually associated with focal accumulations of polymorphonuclear leukocytes. No association of IL-17 expression with symptoms, sinus tract, or lesion size was observed (P > .05). CONCLUSIONS: The present study reinforces the notion that IL-17 may take part in the pathogenesis of apical periodontitis lesions. A role in the exacerbation of chronic inflammation and cyst formation is suspected. Further studies are required to shed light on the specific functions of IL-17 in periradicular inflammatory processes. PMID- 25043330 TI - Periapical status of non-root-filled teeth with resin composite, amalgam, or full crown restorations: a cross-sectional study of a Swedish adult population. AB - INTRODUCTION: Experimental studies show that dental pulp cells respond unfavorably to contact with resin composite restorative material. Hypothetically, in a random population, the frequency of apical periodontitis should be higher for teeth restored with resin composite than with amalgam. Therefore, the aim was to compare the periapical status of non-root-filled teeth restored with resin composite, amalgam, or laboratory-fabricated crowns in an adult Swedish population. METHODS: The subjects comprised 440 individuals from a randomly selected sample of 1,000 adult residents of a Swedish county. The type, material, and quality of the restorations were recorded for all non-root-filled teeth by clinical examination and intraoral clinical photographs. Periapical status was evaluated on panoramic radiographs. The association between periapical status and type, material, and quality of the restorations was analyzed using the chi-square test and logistic regression analysis. RESULTS: There was no significant difference in the frequency of apical periodontitis (AP) between teeth restored with resin composite or amalgam (1.3% and 1.1%, respectively). The frequency of AP for teeth restored with laboratory-fabricated crowns was significantly higher (6.3%). Regression analysis showed no association between AP and resin composite restorations but a significant association with laboratory-fabricated crowns. CONCLUSIONS: The results indicate that the risk of damage to the pulp-dentin complex from exposure to resin composite material and dentin bonding agents shown in experimental studies is not reflected in the clinical setting. However, in the study sample, AP was diagnosed in a significantly higher proportion of teeth restored with laboratory-fabricated crowns. PMID- 25043331 TI - A panoramic survey of air force basic trainees: how research translates into clinical practice. AB - INTRODUCTION: The purposes of this study were to examine the following in young adults residing in the United States: (1) the prevalence of teeth with root canal therapy (RCT) and teeth in need of RCT, (2) how frequently treatment practices associated with success as cited in the literature are found in posterior teeth with RCT, and (3) which treatment practices are associated with periradicular pathology. METHODS: Panoramic radiographs taken of all basic trainees entering the US Air Force in 2011 were evaluated in a 2-part review. A general survey of all radiographs was performed to determine the prevalence of teeth with and teeth in need of RCT. All panoramic radiographs that showed a posterior tooth with RCT were evaluated in detail to consider the presence and quality of cuspal coverage restorations, the quality of RCT, and the presence of periradicular pathology. RESULTS: A total of 35,811 panoramic images were evaluated. Ten percent of basic trainees had existing RCT, whereas 5% showed a need for RCT. The total number of posterior teeth with RCT was 3,455. Nearly half of these teeth had either no cuspal coverage or an unacceptable cuspal coverage restoration. Almost one third of the existing RCT was considered inadequate based on best treatment practices. Approximately 25% of teeth with RCT had periradicular pathology present. A strong correlation was found between the quality of RCT and the absence of periradicular pathology. Of RCT teeth deemed hopeless, 97.5% had no cuspal coverage restoration present. CONCLUSIONS: Factors cited in the literature as being associated with success are lacking in the dental treatment of young adults residing in the United States. PMID- 25043332 TI - A study of the root canal morphology of mandibular anterior teeth using cone-beam computed tomography in a Chinese subpopulation. AB - INTRODUCTION: The purpose of this study was to investigate the root canal configuration of the mandibular anterior teeth using cone-beam computed tomographic (CBCT) imaging in a Chinese subpopulation. METHODS: A total of 3,871 CBCT images of mandibular anterior teeth were collected from 648 patients who accepted CBCT projection as a preoperative assessment for implants or orthodontic treatment. The following items were recorded and evaluated: tooth position, root number, canal number, root canal type, the distance between the anatomic apex and the point at which the canal divided into 2 for mandibular anterior teeth with 2 root canals (excluding canines with 2 roots), and the distance between the 2 root canal orifices. The Fisher exact test was used to analyze the correlation between the number of root canals and tooth position. RESULTS: All of the incisors in this study had 1 root, and 1.32% of the canines had 2 roots. The prevalence of 2 root canals in the lateral incisors (354, 27.36%) was higher than that in the central incisors (202, 15.71%) (P < .05) and the canines (81, 6.27%) (P < .05). CONCLUSIONS: There is a high prevalence of 2 root canals in the mandibular anterior teeth of the studied Chinese subpopulation. This study provides detailed information about the root canal morphology of mandibular anterior teeth in a Chinese subpopulation. PMID- 25043333 TI - Fast GRAPPA reconstruction with random projection. AB - PURPOSE: To address the issue of computational complexity in generalized autocalibrating partially parallel acquisition (GRAPPA) when several calibration data are used. METHOD: GRAPPA requires fully sampled data for accurate calibration with increasing data needed for higher reduction factors to maintain accuracy, which leads to longer computational time, especially in a three dimensional (3D) setting and with higher channel count coils. Channel reduction methods have been developed to address this issue when massive array coils are used. In this study, the complexity problem was addressed from a different prospective. Instead of compressing to fewer channels, we propose the use of random projections to reduce the dimension of the linear equation in the calibration phase. The equivalence before and after the reduction is supported by the Johnson-Lindenstrauss lemma. The proposed random projection method can be integrated with channel reduction sequentially for even higher computational efficiency. RESULTS: Experimental results show that GRAPPA with random projection can achieve comparable image quality with much less computational time when compared with conventional GRAPPA without random projection. CONCLUSION: The proposed random projection method is able to reduce the computational time of GRAPPA, especially in a 3D setting, without compromising the image quality, or to improve the reconstruction quality by allowing more data for calibration when the computational time is a limiting factor. Magn Reson Med 74:71-80, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25043334 TI - Ancient human footprints in Ciur-Izbuc Cave, Romania. AB - In 1965, Ciur-Izbuc Cave in the Carpathian Mountains of Romania was discovered to contain about 400 ancient human footprints. At that time, researchers interpreted the footprints to be those of a man, woman and child who entered the cave by an opening which is now blocked but which was usable in antiquity. The age of the prints (~10-15 ka BP) was based partly on their association with cave bear (Ursus spelaeus) footprints and bones, and the belief that cave bears became extinct near the end of the last ice age. Since their discovery, the human and bear evidence and the cave itself have attracted spelunkers and other tourists, with the result that the ancient footprints are in danger of destruction by modern humans. In an effort to conserve the footprints and information about them and to reanalyze them with modern techiques, Ciur-Izbuc Cave was restudied in summer of 2012. Modern results are based on fewer than 25% of the originally described human footprints, the rest having been destroyed. It is impossible to confirm some of the original conclusions. The footprints do not cluster about three different sizes, and the number of individuals is estimated to be six or seven. Two cases of bears apparently overprinting humans help establish antiquity, and C 14 dates suggest a much greater age than originally thought. Unfortunately, insufficient footprints remain to measure movement variables such as stride length. However, detailed three-dimensional mapping of the footprints does allow a more precise description of human movements within the cave. PMID- 25043335 TI - Chloroplast-targeting protein expression in the oleaginous diatom Fistulifera solaris JPCC DA0580 toward metabolic engineering. AB - The chloroplast plays critical roles in lipid metabolism of microalgae, thus it is recognized as an attractive target of metabolic engineering to enhance biofuel production. It has been well known that recombinant protein expression in microalgal chloroplasts needs specific signal sequence which governs the transition manner of nuclear-encoded polypeptides within the subcellular compartments. However certain microalgae, including diatoms, have complex membrane systems surrounding the chloroplast, and thus chloroplast-targeting protein expression with the signal sequence has rarely been demonstrated except for a few model non-oleaginous diatoms. In this study, we performed recombinant green fluorescence protein (GFP) expression and transportation into the chloroplast of the oleaginous marine diatom, Fistulifera solaris JPCC DA0580. The signal sequence of ATP synthetase gamma subunit, which was predicted to localize in the chloroplast according to a bioinformatics analysis pipeline, was employed as a key factor of this technique. As a result, specific localization of GFP in the chloroplast was observed. It would be useful to engineer the lipid synthesis pathways existing in the chloroplast. Furthermore, intensive gathering of GFP in the rod-like structure was also detected, which has not been observed in model diatom studies. As comparing with electron microscopic observation, the structure was estimated to be a pyrenoid. PMID- 25043336 TI - Modulating betulinic acid production in Saccharomyces cerevisiae by managing the intracellular supplies of the co-factor NADPH and oxygen. AB - Betulinic acid is a plant derived triterpenoid with beneficial effects for anti tumor and anti-human immunodeficiency virus treatments. In Saccharomyces cerevisiae, we previously constructed the betulinic acid biosynthetic pathway, in which several enzymes function in a NADPH or oxygen-dependent manner. To seek whether the intracellular supply of the NADPH/oxygen of S. cerevisiae could be managed for improving betulinic acid production, the expressions of the mutated 2,3-butanediol dehydrogenase (mBDH1) and the yeast codon optimized Vitreoscilla hemoglobin (mvhb) were separately introduced into the betulinic acid forming yeast strain. The effect of these expressions on betulinic acid productivity was evaluated. Our results showed that the expression of mBDH1 and mvhb increased the concentration of betulinic acid to 1.5 and 3.2 times, respectively relative to the controls. Meanwhile, the growth property of these engineered yeast strains was also monitored. Though the mvhb expression greatly improved the production of betulinic acid but exerted a serious inhibition on yeast growth. However, it was possible to keep desirable yeast growth phenotype using an appropriate concentration of acetoin with the expression of mBDH1. The results of this study would provide a general reference to modulate the production of other triterpenoids in S. cerevisiae by managing the supplies of NADPH and oxygen. PMID- 25043337 TI - Population pharmacokinetic modeling and simulation to guide dose selection for RBP-7000, a new sustained-release formulation of risperidone. AB - RBP-7000 is a long-acting formulation of risperidone designed for once-monthly subcutaneous injection for the treatment of schizophrenia. The objective was to estimate clinically effective doses of RBP-7000 based on model simulations and on the comparison with other long-acting injectable antipsychotics. A population pharmacokinetic model of RBP-7000 was developed in 90 clinically stable schizophrenic patients having received single/repeated doses of 60, 90, or 120 mg. Model simulations were conducted to compare active moiety plasma exposure after repeated RBP-7000 administrations to the published data of long-acting risperidone injection (Risperdal(r) Consta(r)) at 25 and 50 mg, and of paliperidone palmitate (Invega(r) Sustenna(r)) at 50 and 100 mg equivalent paliperidone. Predictions of dopamine D2 receptor occupancy were derived from the simulated active moiety concentrations. Simulations showed similar active moiety plasma exposure at steady-state for 90 mg of RBP-7000 and 25 mg of long-acting risperidone. In comparison to risperidone, RBP-7000 reached effective concentrations immediately after the first administration. RBP-7000 at the doses of 60 and 90 mg provided similar active moiety plasma concentrations at steady state compared to 50 and 100 mg equivalent paliperidone, respectively. These findings provide guidance for dose selection in Phase III clinical trials and suggest potential benefits for RBP-7000 over competitors. PMID- 25043338 TI - Improvement of Aspergillus nidulans penicillin production by targeting AcvA to peroxisomes. AB - Aspergillus nidulans is able to synthesize penicillin and serves as a model to study the regulation of its biosynthesis. Only three enzymes are required to form the beta lactam ring tripeptide, which is comprised of l-cysteine, l-valine and l aminoadipic acid. Whereas two enzymes, AcvA and IpnA localize to the cytoplasm, AatA resides in peroxisomes. Here, we tested a novel strategy to improve penicillin production, namely the change of the residence of the enzymes involved in the biosynthesis. We tested if targeting of AcvA or IpnA (or both) to peroxisomes would increase the penicillin yield. Indeed, AcvA peroxisomal targeting led to a 3.2-fold increase. In contrast, targeting IpnA to peroxisomes caused a complete loss of penicillin production. Overexpression of acvA, ipnA or aatA resulted in 1.4, 2.8 and 3.1-fold more penicillin, respectively in comparison to wildtype. Simultaneous overexpression of all three enzymes resulted even in 6-fold more penicillin. Combination of acvA peroxisomal targeting and overexpression of the gene led to 5-fold increase of the penicillin titer. At last, the number of peroxisomes was increased through overexpression of pexK. A strain with the double number of peroxisomes produced 2.3 times more penicillin. These results show that penicillin production can be triggered at several levels of regulation, one of which is the subcellular localization of the enzymes. PMID- 25043340 TI - Elucidation of inorganic reaction mechanisms in ionic liquids: the important role of solvent donor and acceptor properties. AB - In this article, we focus on the important role of solvent donor and acceptor properties of ionic liquids in the elucidation of inorganic reaction mechanisms. For this purpose, mechanistic and structural studies on typical inorganic reactions, performed in ionic liquids, have been conducted. The presented systems range from simple complex-formation and ligand-substitution reactions to the activation of small molecules by catalytically active complexes. The data obtained for the reactions in ionic liquids are compared with those for the same reactions carried out in conventional solvents, and are discussed with respect to the donor and acceptor properties of the applied ionic liquids. The intention of this perspective is to gain more insight into the role of ILs as solvents and their interaction with metal ions and complexes in solution. PMID- 25043341 TI - Relativistic effects in the one-bond spin-spin coupling constants involving selenium. AB - One-bond spin-spin coupling constants involving selenium of seven different types, (1) J(Se,X), X = (1) H, (13) C, (15) N, (19) F, (29) Si, (31) P, and (77) Se, were calculated in the series of 14 representative compounds at the SOPPA(CCSD) level taking into account relativistic corrections evaluated both at the RPA and DFT levels of theory in comparison with experiment. Relativistic corrections were found to play a major role in the calculation of (1) J(Se,X) reaching as much as almost 170% of the total value of (1) J(Se,Se) and up to 60 70% for the rest of (1) J(Se,X). Scalar relativistic effects (Darwin and mass velocity corrections) by far dominate over spin-orbit coupling in the total relativistic effects for all (1) J(Se,X). Taking into account relativistic corrections at both random phase approximation and density functional theory levels essentially improves the agreement of theoretical results with experiment. The most 'relativistic' (1) J(Se,Se) demonstrates a marked Karplus-type dihedral angle dependence with respect to the mutual orientation of the selenium lone pairs providing a powerful tool for stereochemical analysis of selenoorganic compounds. PMID- 25043342 TI - Thermal or mechanical stimuli-induced photoluminescence color change of a molecular assembly composed of an amphiphilic anthracene derivative in water. AB - Molecular assemblies that change photoluminescence color in response to thermal or mechanical stimulation without dissociation into the monomeric states in water are described herein. A dumbbell-shaped amphiphilic compound forms micellar molecular assemblies in water and exhibits yellow photoluminescence derived from excimer formation of the luminescent core, which contains a 2,6 diethynylanthracene moiety. Annealing of the aqueous solution induces a photoluminescence color change from yellow to green (lambdaem, max =558->525 nm). The same photoluminescence color change is also achieved by rubbing the yellow photoluminescence-emitting molecular assemblies adsorbed on glass substrates with cotton wool in water. The observed green photoluminescence is ascribed to micelles that are distinct from the yellow-photoluminescence-emitting micelles, on the basis of transmission electron microscopy observations, atomic force microscopy observations, and dynamic light scattering measurements. We examined the relationship between the structure of the molecular assemblies and the photophysical properties of the anthracene derivative in water before and after thermal or mechanical stimulation and concluded that thermal or mechanical stimuli-induced slight changes of the molecular-assembled structures in the micelles result in the change in the photoluminescence color from yellow to green in water. PMID- 25043339 TI - Limited clinical utility of a genetic risk score for the prediction of fracture risk in elderly subjects. AB - It is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings, two genetic risk scores (GRS63 and GRS16) were developed. Our aim was to determine the clinical usefulness of these GRSs for the prediction of BMD, BMD change, and fracture risk in elderly subjects. We studied two male (Osteoporotic Fractures in Men Study [MrOS] US, MrOS Sweden) and one female (Study of Osteoporotic Fractures [SOF]) large prospective cohorts of older subjects, looking at BMD, BMD change, and radiographically and/or medically confirmed incident fractures (8067 subjects, 2185 incident nonvertebral or vertebral fractures). GRS63 was associated with BMD (?3% of the variation explained) but not with BMD change. Both GRS63 and GRS16 were associated with fractures. After BMD adjustment, the effect sizes for these associations were substantially reduced. Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared with those found using the corresponding weighted risk scores. Only minor improvements in C-statistics (AUC) for fractures were found when the GRSs were added to a base model (age, weight, and height), and no significant improvements in C-statistics were found when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models. GRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects. PMID- 25043343 TI - Mechanical force-driven growth of elongated bending TiO2 -based nanotubular materials for ultrafast rechargeable lithium ion batteries. AB - A stirring hydrothermal process that enables the formation of elongated bending TiO2 -based nanotubes is presented. By making use of its bending nature, the elongated TiO2 (B) nanotubular crosslinked-network anode electrode can cycle over 10 000 times in half cells while retaining a relatively high capacity (114 mA h g(-1)) at an ultra-high rate of 25 C (8.4 A g(-1)). PMID- 25043344 TI - Efficient free fatty acid production from woody biomass hydrolysate using metabolically engineered Escherichia coli. AB - Four engineered Escherichia coli strains, ML103(pXZ18), ML103(pXZ18Z), ML190(pXZ18) and ML190(pXZ18Z), were constructed to investigate free fatty acid production using hydrolysate as carbon source. These strains exhibited efficient fatty acid production when xylose was used as the sole carbon source. For mixed sugars, ML103 based strains utilized glucose and xylose sequentially under the carbon catabolite repression (CCR) regulation, while ML190 based strains, with ptsG mutation, used glucose and xylose simultaneously. The total free fatty acid concentration and yield of the strain ML190(pXZ18Z) based on the mixed sugar reached 3.64 g/L and 24.88%, respectively. Furthermore, when hydrolysate from a commercial plant was used as the carbon source, the strain ML190(pXZ18Z) can produce 3.79 g/L FFAs with a high yield of 21.42%. PMID- 25043345 TI - Quantitative response of nitrifying and denitrifying communities to environmental variables in a full-scale membrane bioreactor. AB - The abundance and transcription levels of specific gene markers of total bacteria, ammonia-oxidizing Betaproteobacteria, nitrite-oxidizing bacteria (Nitrospira-like) and denitrifiers (N2O-reducers) were analyzed using quantitative PCR (qPCR) and reverse-transcription qPCR during 9 months in a full scale membrane bioreactor treating urban wastewater. A stable community of N removal key players was developed; however, the abundance of active populations experienced sharper shifts, demonstrating their fast adaptation to changing conditions. Despite constituting a small percentage of the total bacterial community, the larger abundances of active populations of nitrifiers explained the high N-removal accomplished by the MBR. Multivariate analyses revealed that temperature, accumulation of volatile suspended solids in the sludge, BOD5, NH4(+) concentration and C/N ratio of the wastewater contributed significantly (23-38%) to explain changes in the abundance of nitrifiers and denitrifiers. However, each targeted group showed different responses to shifts in these parameters, evidencing the complexity of the balance among them for successful biological N-removal. PMID- 25043346 TI - Dual-fuel production from restaurant grease trap waste: bio-fuel oil extraction and anaerobic methane production from the post-extracted residue. AB - An effective way for restaurant grease trap waste (GTW) treatment to generate fuel oil and methane by the combination of physiological and biological processes was investigated. The heat-driven extraction could provide a high purity oil equivalent to an A-grade fuel oil of Japanese industrial standard with 81-93 wt% of extraction efficiency. A post-extracted residue was treated as an anaerobic digestion feedstock, and however, an inhibitory effect of long chain fatty acid (LCFA) was still a barrier for high-rate digestion. From the semi-continuous experiment fed with the residual sludge as a single substrate, it can be concluded that the continuous addition of calcium into the reactor contributed to reducing LCFA inhibition, resulting in the long-term stable operation over one year. Furthermore, the anaerobic reactor performed well with 70-80% of COD reduction and methane productivity under an organic loading rate up to 5.3g COD/L/d. PMID- 25043347 TI - Co-cultivation of Trichoderma reesei RutC30 with three black Aspergillus strains facilitates efficient hydrolysis of pretreated wheat straw and shows promises for on-site enzyme production. AB - Co-cultivation of fungi may be an excellent system for on-site production of cellulolytic enzymes in a single bioreactor. Enzyme supernatants from mixed cultures of Trichoderma reesei RutC30, with either the novel Aspergillus saccharolyticus AP, Aspergillus carbonarius ITEM 5010 or Aspergillus niger CBS 554.65 cultivated in solid-state fermentation were tested for avicelase, FPase, endoglucanase and beta-glucosidase activity as well as in hydrolysis of pretreated wheat straw. Around 30% more avicelase activity was produced in co cultivation of T. reesei and A. saccharolyticus than in T. reesei monoculture, suggesting synergistic interaction between those fungi. Fermentation broths of mixed cultures of T. reesei with different Aspergillus strains resulted in approx. 80% efficiency of hydrolysis which was comparable to results obtained using blended supernatants from parallel monocultures. This indicates that co cultivation of T. reesei with A. saccharolyticus or A. carbonarius could be a competitive alternative for monoculture enzyme production and a cheaper alternative to commercial enzymes. PMID- 25043348 TI - Feeding behavior and trophic relationship of earthworms and other predators in vermifiltration system for liquid-state sludge stabilization using fatty acid profiles. AB - The sludge reduction capability (VSS reduction) of vermifilter (VF) was 14.7% higher than that of conventional biofilter (BF) due to the fact that there was a net loss of biomass and energy when the food web in VF is extended. Therefore, feeding behavior and trophic relationship of earthworms and other predators (leeches, lymnaeidaes and limaxes) in VF were investigated using fatty acid (FA) profiles for the first time. Compared with BF biofilm, microbial community structure of VF biofilm got optimized by earthworms that the percentage of protozoa increased from 14.2% to 20.4%. Furthermore, analysis of specific microbial FAs composition in each predator suggested different trophic level of predators resulted from their selective ingestion of different microorganisms, and earthworms were at the second high trophic level in VF food web. Overall findings indicated earthworms modified microbial community and extended the food web of VF and thus enhanced the sludge reduction. PMID- 25043349 TI - Cloning and expression of two 9-cis-epoxycarotenoid dioxygenase genes during fruit development and under stress conditions from Malus. AB - There is now biochemical and genetic evidence that oxidative cleavage of cis epoxycarotenoids by 9-cis-epoxycarotenoid dioxygenase (NCED) is the critical step in the regulation of abscisic acid (ABA) synthesis in higher plants. To understand the expression characteristics of NCED during ABA biosynthesis in apple (Malus), two NCED genes cDNA sequence were cloned from Malus prunifolia using RT-PCR techniques, named MpNCED1 and MpNCED2. The two cDNA sequences have full-length open reading frame, encoding a polypeptide of 607 and 614 amino acids, respectively. Sequences analysis showed that the deduced two apple NCED proteins were highly homologous to other NCED proteins from different plant species. Real-time PCR analysis revealed MpNCED2 were expressed continuously during the whole period of apple fruit development with the pattern of "higher low-highest", while the expression of MpNCED1 clearly declined to a steady low level in the mid-later period of fruit development. Expression of the MpNCED2 increased under the drought stress, high temperature and low temperature strongly and rapidly, whereas expression of the MpNCED1 was detected in response to temperature stress, but did not detected under drought stress. These results revealed that MpNCED1 and MpNCED2 may play different roles in regulation of the ABA biosynthesis in fruit development and various stresses response. PMID- 25043351 TI - Reply: To PMID 24691835. PMID- 25043350 TI - A peek behind the curtain: peer review and editorial decision making at Stroke. AB - OBJECTIVE: A better understanding of the manuscript peer-review process could improve the likelihood that research of the highest quality is funded and published. To this end, we aimed to assess consistency across reviewers' recommendations, agreement between reviewers' recommendations and editors' final decisions, and reviewer- and editor-level factors influencing editorial decisions at the journal Stroke. METHODS: We analyzed all initial original contributions submitted to Stroke from January 2004 through December 2011. All submissions were linked to the final editorial decision (accept vs reject). We assessed the level of agreement between reviewers (intraclass correlation coefficient). We compared the initial editorial decision (accept, minor revision, major revision, and reject) across reviewers' recommendations. We performed a logistic regression analysis to identify reviewer- and editor-related factors associated with acceptance as the final decision. RESULTS: Of 12,902 original submissions to Stroke during the 8-year study period, the level of agreement between reviewers was between fair and moderate (intraclass correlation coefficient = 0.55, 95% confidence interval [CI] = 0.09-0.75). Likelihood of acceptance was <5% if at least 1 reviewer recommended a rejection. In the multivariate analysis, higher reviewer-assigned priority scores were related to greater odds of acceptance (odds ratio [OR] = 26.3, 95% CI = 23.2-29.8), whereas higher number of reviewers (OR = 0.54 per additional reviewer, 95% CI = 0.50-0.59) and suggestions for reviewers by authors versus no suggestions (OR = 0.83, 95% CI = 0.73-0.94) had lesser odds of acceptance. INTERPRETATION: This analysis of the peer-review process at Stroke identified several factors that might be targeted to improve the consistency and fairness of the overall process. PMID- 25043352 TI - Rapid determination of oligopeptides and amino acids in soybean protein hydrolysates using high-resolution mass spectrometry. AB - INTRODUCTION: Soybean protein hydrolysates (SPHs), especially oligopeptides, have shown a variety of functional properties, including immunomodulatory and anti oxidant effects. Soybean protein hydrolysate products have been used as functional ingredients in food, sports nutrition or clinical nutrition. However, the mixture is mostly undefined due to its complex nature, containing peptides and minor amino acids as well as small proteins. OBJECTIVES: To develop a specific and efficient method for the identification and structural characterisation of oligopeptides in SPHs, and to determine free amino acids in SPHs in the same analytical run, for evaluation of the chemical profile of SPH products. METHODS: Accurate mass spectrometry (MS) datasets of SPH samples were recorded on a high-performance liquid chromatography (HPLC) tandem high resolution (HR) MS system. Potential oligopeptides were tentatively characterised based on their elemental compositions and ring double bond equivalent (RDBE) values, as well as HRMS/MS data. The analytical method to determine amino acids was evaluated in terms of linearity, precision, apparent recovery and limits of detection and quantitation. RESULTS: In total, 186 oligopeptides spanning the mass range of m/z 200-1500 and three major free amino acids could be determined in SPH samples in a single sample injection. Ninety-nine oligopeptides were tentatively characterised. The sensitive and specific instrumental performances also permitted the determination of 19 amino acids with a limit of quantitation of <= 0.1 MUg/mL. CONCLUSION: The HPLC-HRMS technique has proven to be an advantageous tool for the rapid characterisation of oligopeptides and determination of amino acids in soybean protein hydrolysates. PMID- 25043353 TI - Rules, regs, and what's right. PMID- 25043354 TI - "Bad words": Tell Them to the Surrogate. PMID- 25043355 TI - Avoiding a slippery slope in PAD. PMID- 25043356 TI - Public health paternalism and "expenditure harm". PMID- 25043357 TI - The right to know genetic origins: a harmful value. PMID- 25043358 TI - The author replies. PMID- 25043359 TI - Fond of my patient. PMID- 25043360 TI - Death, state by state. PMID- 25043361 TI - Case study. Truly personalized medicine? Commentary. PMID- 25043362 TI - Logicality and regulatory ethics: lessons from the Bucharest early intervention project. PMID- 25043363 TI - When a blood donor has sickle cell trait: incidental findings and public health. AB - There are no national recommendations for routine screening for sickle cell trait, nor is there guidance on whether or how to notify donors that they might be tested or identified as having sickle cell trait. As a result, the organizations that collect blood have implemented variable policies about whether and how to inform prospective donors of the possible screening and discovery of this noncommunicable condition. The question of what they should do is related to the broader question of how to handle incidental and secondary findings. In a recent report, the Presidential Commission for the Study of Bioethical Issues outline a framework for handling such findings in the clinical, research, and direct-to-consumer contexts. While the commission's report did not directly address incidental and secondary findings in the public health context of blood donation, it made several overarching recommendations that apply in all contexts where such findings might arise. This essay outlines the special issues raised by discovering sickle cell trait in blood donation and considers the implications of the commission's framework for that problem. PMID- 25043364 TI - Have we asked too much of consent? PMID- 25043368 TI - The need for a neuroscience ELSI program. PMID- 25043369 TI - By and for the people. PMID- 25043370 TI - A comparative study of aroma-active compounds between dark and milk chocolate: relationship to sensory perception. AB - BACKGROUND: The most important aroma-active compounds of two types of chocolate and cocoa liquor used for their production were analysed by gas chromatography olfactometry-mass spectrometry (GC-O-MS) and aroma extract dilution analysis (AEDA). Furthermore, the relationship between odorants and sensory perception of chocolate was measured by quantitative analysis, sensory evaluation and correlation analysis. In addition, some chemicals were added to the original dark or milk chocolate to validate their roles in the aroma property of chocolate. RESULTS: A total of 32 major aroma-active compounds were identified in the chocolate with the flavour dilution factors of 27-729 by AEDA, including seven aldehydes, six pyrazines, three pyrroles, four carboxylic acids, four lactones, two alcohols, two ketones, one ester, one pyrone, one furan and one sulfur containing compound. Further quantitative analysis showed that dark chocolate had higher contents of pyrazine, pyrrole, carboxylic acids, alcohols and Strecker aldehydes, whereas the concentration of lactones, esters, long chain aldehydes and ketones were higher in the milk type. CONCLUSION: Differences in volatile composition and descriptive flavour attributes between the dark and milk chocolate were observed. The relationship between aroma-active compounds and sensory perception in the chocolate was verified. PMID- 25043371 TI - The biophysical, biochemical, and biological toolbox for tenogenic phenotype maintenance in vitro. AB - Tendon injuries constitute an unmet clinical need, with 3 to 5 million new incidents occurring annually worldwide. Tissue grafting and biomaterial-based approaches fail to provide environments that are conducive to regeneration; instead they lead to nonspecific cell adhesion and scar tissue formation, which collectively impair functionality. Cell based therapies may potentially recover native tendon function, if tenocyte trans-differentiation can be evaded and stem cell differentiation towards tenogenic lineage is attained. To this end, recreating an artificial in vivo tendon niche by engineering functional in vitro microenvironments is a research priority. Clinically relevant cell based therapies for tendon repair and regeneration could be created using tools that harness biophysical beacons (surface topography, mechanical loading), biochemical cues (oxygen tension), and biological signals (growth factors). PMID- 25043372 TI - Probiotics in patients with severe acute pancreatitis. PMID- 25043373 TI - Gamma glutamyltransferase, alanine aminotransferase and risk of cancer: systematic review and meta-analysis. AB - The prospective evidence for the associations of gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) with risk of cancer in the general population is uncertain. We conducted a systematic review and meta-analysis of published prospective observational studies evaluating the associations of baseline levels of GGT and ALT with risk of overall (incidence and/or mortality) and site specific cancers. Relevant studies were identified in a literature search of MEDLINE, EMBASE, Web of Science, reference lists of relevant studies to April 2014 and email contact with investigators. Study specific relative risks (RRs) were meta-analyzed using random effects models. Fourteen cohort studies with data on 1.79 million participants and 57,534 cancer outcomes were included. Comparing top versus bottom thirds of baseline circulating GGT levels, pooled RRs (95% confidence intervals) were 1.32 (1.15-1.52) for overall cancer, 1.09 (0.95-1.24) for cancers of the breast and female genital organs, 1.09 (1.02-1.16) for cancers of male genital organs, 1.94 (1.35-2.79) for cancers of digestive organs and 1.33 (0.94-1.89) for cancers of respiratory and intrathoracic organs. For ALT, corresponding RRs for overall cancer were 0.96 (0.94-0.99) and 1.65 (1.52-1.79) in European and Asian populations, respectively. There was an increased risk of cancers of the digestive organs 2.44 (1.23-4.84). The pooled RR for overall cancer per 5 U/L increment in GGT levels was 1.04 (1.03-1.05). Available observational data indicate a positive log-linear association of GGT levels with overall cancer risk. The positive association was generally evident for site specific cancers. There are geographical variations in the association of ALT and overall cancer. PMID- 25043374 TI - A novel segmentation-based algorithm for the quantification of magnified cells. AB - Cell segmentation and counting is often required in disciplines such as biological research and medical diagnosis. Manual counting, although still employed, suffers from being time consuming and sometimes unreliable. As a result, several automated cell segmentation and counting methods have been developed. A main component of automated cell counting algorithms is the image segmentation technique employed. Several such techniques were investigated and implemented in the present study. The segmentation and counting was performed on antibody stained brain tissue sections that were magnified by a factor of 40. Commonly used methods such as the circular Hough transform and watershed segmentation were analysed. These tests were found to over-segment and therefore over-count samples. Consequently, a novel cell segmentation and counting algorithm was developed and employed. The algorithm was found to be in almost perfect agreement with the average of four manual counters, with an intraclass correlation coefficient (ICC) of 0.8. PMID- 25043375 TI - The effect of temperature on the sensitivity of Daphnia magna to cyanobacteria is genus dependent. AB - In the present study, the authors investigated the effects of 6 different genera of cyanobacteria on multiple endpoints of Daphnia magna in a 21-d life table experiment conducted at 3 different temperatures (15 degrees C, 19 degrees C, and 23 degrees C). The specific aims were to test if the effect of temperature on Daphnia's sensitivity to cyanobacteria differed among different cyanobacteria and if the rank order from most to least harmful cyanobacteria to Daphnia reproduction changed or remained the same across the studied temperature range. Overall, the authors observed a decrease in harmful effects on reproduction with increasing temperature for Microcystis, Nodularia, and Aphanizomenon, and an increase in harmful effects with increasing temperature for Anabaena and Oscillatoria. No effect of temperature was observed on Daphnia sensitivity to Cylindrospermopsis. Harmful effects of Microcystis and Nodularia on reproduction appear to be mirrored by a decrease in length. On the other hand, harmful effects of Anabaena, Aphanizomenon, and Oscillatoria on reproduction were correlated with a decrease in intrinsic rate of natural increase, which was matched by a later onset of reproduction in exposures to Oscillatoria. In addition, the results suggest that the cyanobacteria rank order of harmfulness may change with temperature. Higher temperatures may increase the sensitivity of D. magna to the presence of some cyanobacteria (Anabaena and Oscillatoria) in their diet, whereas the harmful effects of others (Microcystis, Nodularia, and Aphanizomenon) may be reduced by higher temperatures. PMID- 25043376 TI - Highly luminescent and stable hydroxypyridinonate complexes: a step towards new curium decontamination strategies. AB - The photophysical properties, solution thermodynamics, and in vivo complex stabilities of Cm(III) complexes formed with multidentate hydroxypyridinonate ligands, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are reported. Both chelators were investigated for their ability to act as antenna chromophores for Cm(III), leading to highly sensitized luminescence emission of the metal upon complexation, with long lifetimes (383 and 196 MUs for 3,4,3-LI(1,2-HOPO) and 5 LIO(Me-3,2-HOPO), respectively) and remarkable quantum yields (45 % and 16 %, respectively) in aqueous solution. The bright emission peaks were used to probe the electronic structure of the 5f complexes and gain insight into ligand field effects; they were also exploited to determine the high (and proton-independent) stabilities of the corresponding Cm(III) complexes (log beta110 = 21.8(4) for 3,4,3-LI(1,2-HOPO) and log beta120 = 24.5(5) for 5-LIO(Me-3,2-HOPO)). The in vivo complex stability for both ligands was assessed by using (248) Cm as a tracer in a rodent model, which provided a direct comparison with the in vitro thermodynamic results and demonstrated the great potential of 3,4,3-LI(1,2-HOPO) as a therapeutic Cm(III) decontamination agent. PMID- 25043377 TI - Prenatal management and outcomes in mirror syndrome associated with twin-twin transfusion syndrome. AB - OBJECTIVE: The aim of this article is to investigate the prevalence, clinical presentation, prenatal management, and prognosis of mirror syndrome associated with twin-twin transfusion syndrome (TTTS) treated by amnioreduction or selective fetocide. METHOD: A retrospective study of twin pregnancies with TTTS was conducted. The prevalence of mirror syndrome, defined as severe maternal edema related to fetal hydrops and placental edema, was calculated for TTTS, and data on clinical characteristics, treatment, and outcomes of the patients were reviewed. RESULTS: We observed mirror syndrome in 4.85% (5/103) of pregnancies with TTTS and 26.32% (5/19) of pregnancies with TTTS Stage IV. Most cases (4/5) of mirror syndrome associated with TTTS were diagnosed before 24 weeks of gestation. The patients manifested edema, anemia, hemodilution, and hypoproteinemia (5/5); proteinuria (4/5); complicated postpartum hemorrhage (4/5); and pulmonary edema and congestive heart failure (2/5). Maternal hemoglobin, hematocrit, and plasma protein dropped after amnioreduction. The perinatal survival rate at 28 days was 28.57% (2/7), and only one infant born after selective feticide survived beyond 18 months. CONCLUSION: TTTS carries a high risk of mirror syndrome, a disease with significant materno-fetal mortality and morbidity. Amnioreduction alone or with selective feticide in mirror syndrome may transiently aggravate anemia and hemodilution and lead to severe maternal complications. (c) 2014 John Wiley & Sons, Ltd. PMID- 25043378 TI - Multicomponent intervention on enhancing dementia caregiver well-being and reducing behavioral problems among Hong Kong Chinese: a translational study based on REACH II. AB - OBJECTIVE: This study examined the effectiveness of a translated version of Resources for Enhancing Alzheimer's Caregiver Health (REACH) II in Hong Kong's service delivery context. METHOD: The localized intervention was adapted from REACH II with 12 individual-based sessions, which addressed multiple domains including disease education, safety, caregiver (CG) well-being, and care recipients' problem behavior. Two-hundred and one dementia family dyads completed the intervention. RESULTS: The efficacy of the intervention was demonstrated by the significant improvement in the perception of positive aspects of caregiving, reduction in depressive symptoms, subjective burden, bother and caregiving risks among CGs, and abatement in behavioral problems among care recipients. Treatment implementation was reflected from the high rate of adoption of each intervention component by interventionists and satisfactory reception from CGs. Promises in reach and adoption were demonstrated by the participation of 85 interventionists from 11 NGOs across 18 districts and CGs of a variety of demographic characteristics. DISCUSSION: This study is the first attempt to translate a highly successful evidence-based dementia CG intervention developed in the USA into the Hong Kong service delivery context. The current results echoed the success of REACH II. The values and challenges of translational research are discussed. PMID- 25043379 TI - Family-wide analysis of poly(ADP-ribose) polymerase activity. AB - The poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) protein family generates ADP-ribose (ADPr) modifications onto target proteins using NAD(+) as substrate. Based on the composition of three NAD(+) coordinating amino acids, the H-Y-E motif, each PARP is predicted to generate either poly(ADPr) (PAR) or mono(ADPr) (MAR). However, the reaction product of each PARP has not been clearly defined, and is an important priority since PAR and MAR function via distinct mechanisms. Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. We identify automodification sites on seven PARPs, and demonstrate that MAR and PAR generating PARPs modify similar amino acids, suggesting that the sequence and structural constraints limiting PARPs to MAR synthesis do not limit their ability to modify canonical amino-acid targets. In addition, we identify cysteine as a novel amino-acid target for ADP-ribosylation on PARPs. PMID- 25043381 TI - The 20th International AIDS Conference: where do we go from here? PMID- 25043380 TI - Maximizing the benefits of antiretroviral therapy for key affected populations. AB - INTRODUCTION: Scientific research has demonstrated the clinical benefits of earlier initiation of antiretroviral treatment (ART), and that ART can markedly reduce HIV transmission to sexual partners. Ensuring universal access to ART for those who need it has long been a core principle of the HIV response, and extending the benefits of ART to key populations is critical to increasing the impact of ART and the overall effectiveness of the HIV response. However, this can only be achieved through coordinated efforts to address political, social, legal and economic barriers that key populations face in accessing HIV services. DISCUSSION: Recent analyses show that HIV prevalence levels among key populations are far higher than among the general population, and they experience a range of biological and behavioural factors, and social, legal and economic barriers that increase their vulnerability to HIV and have resulted in alarmingly low ART coverage. World Health Organization 2014 consolidated guidance on HIV among key populations offers the potential for increased access to ART by key populations, following the same principles as for the general adult population. However, it should not be assumed that key populations will achieve greater access to ART unless stigma, discrimination and punitive laws, policies and practices that limit access to ART and other HIV interventions in many countries are addressed. CONCLUSIONS: Rights-based approaches and investments in critical enablers, such as supportive legal and policy environments, are essential to enable wider access to ART and other HIV interventions for key populations. The primary objective of ART should always be to treat the person living with HIV; prevention is an important, additional benefit. ART should be provided only with informed consent. The preventive benefits of treatment must not be used as a pretext for failure to provide other necessary HIV programming for key populations, including comprehensive harm reduction and other prevention interventions tailored to meet the needs of key populations. An end to AIDS is only possible if we overcome the barriers of criminalization, stigma and discrimination that remain key drivers of the HIV epidemics among key populations. PMID- 25043382 TI - Time-dependent tree-structured survival analysis with unbiased variable selection through permutation tests. AB - Incorporating time-dependent covariates into tree-structured survival analysis (TSSA) may result in more accurate prognostic models than if only baseline values are used. Available time-dependent TSSA methods exhaustively test every binary split on every covariate; however, this approach may result in selection bias toward covariates with more observed values. We present a method that uses unbiased significance levels from newly proposed permutation tests to select the time-dependent or baseline covariate with the strongest relationship with the survival outcome. The specific splitting value is identified using only the selected covariate. Simulation results show that the proposed time-dependent TSSA method produces tree models of equal or greater accuracy as compared to baseline TSSA models, even with high censoring rates and large within-subject variability in the time-dependent covariate. To illustrate, the proposed method is applied to data from a cohort of bipolar youths to identify subgroups at risk for self injurious behavior. PMID- 25043384 TI - Commercially available avian and mammalian whole prey diet items targeted for consumption by managed exotic and domestic pet felines: macronutrient, mineral, and long-chain fatty acid composition. AB - Whole prey diets encourage species-typical behaviors making them popular in the zoo and home setting for captive exotic and domestic felids, respectively. We evaluated macronutrient, mineral, and long-chain fatty acid composition of 20 whole prey items: mice (1-2, 10-13, 21-25, 30-40, and 150-180 days of age); rats (1-4, 10-13, 21-25, 33-42, and >60 days of age); rabbits (still born, 30-45 days, >65 days with skin, and >65 days of age with skin removed); chicken (1-3 days of age, ground adult); duck (ground adult); and quail (1-3, 21-40, and >60 days of age). Composition of whole prey was highly variable (15-40% DM, 34-75% CP, 10-60% fat, and 8-18% ash). A majority of whole prey samples (15/20) had at least one mineral or fatty acid below AAFCO [] or NRC [] minimum recommended concentrations for domestic cats (K, Na, Cl, Mg, Cu, Mn, and/or Zn; total fat, linolenic acid, arachidonic acid and/or EPA and DHA). These data identify potential nutrient deficiencies allowing for alterations in dietary formulation prior to long-term feeding. PMID- 25043383 TI - Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases. AB - Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease (PD). The inhibition of NOX2-generated superoxide has become an effective strategy for developing disease modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used, long-acting NOX2 inhibitor. However, due to its non-specificity for NOX2 and high cytotoxicity at standard doses (uM), DPI has been precluded from human studies. In this study, using ultra-low doses of DPI, we aimed to: (1) investigate whether these problems could be circumvented and (2) determine whether ultra-low doses of DPI were able to preserve its utility as a potent NOX2 inhibitor. We found that DPI at subpicomolar concentrations (10(-14) and 10(-13) M) displays no toxicity in primary midbrain neuron-glia cultures. More importantly, we observed that subpicomolar DPI inhibited phorbol myristate acetate (PMA)-induced activation of NOX2. The same concentrations of DPI did not inhibit the activities of a series of flavoprotein-containing enzymes. Furthermore, potent neuroprotective efficacy was demonstrated in a post-treatment study. When subpicomolar DPI was added to neuron-glia cultures pretreated with lipopolysaccharide, 1-methyl-4-phenylpyridinium or rotenone, it potently protected the dopaminergic neurons. In summary, DPI's unique combination of high specificity toward NOX2, low cytotoxicity and potent neuroprotective efficacy in post-treatment regimens suggests that subpicomolar DPI may be an ideal candidate for further animal studies and potential clinical trials. PMID- 25043385 TI - Optimal size selection of the classic laryngeal mask airway by tongue width-based method in male adults. AB - BACKGROUND: Proper size selection is crucial to the effective use of a laryngeal mask airway (LMA). The current choice of LMA size is based on body weight; in addition, the sex-based selection has also been suggested. However, the relationship between body weight, sex, and the dimension of hypopharynx where the LMA is positioned are inconsistent. Here we examined a tongue width-based method to determine the optimal size for the classic LMA (cLMA). METHODS: The enrolled patients had two different cLMA size selections, determined by both weight-based formula and tongue width-based method. Twenty-one male patients were studied. For the tongue width-based method, we made four rulers of different widths that corresponded to the four different cLMAs (Nos. 2.5, 3, 4, and 5) The patient was asked to open his mouth and protrude his tongue; the optimal size of cLMA was determined by the corresponding ruler which had the same tongue width of the patient. Two insertions with different-size cLMAs were randomly performed in every patient. Five parameters - frequency of insertion attempts, the presence of cuff in the mouth, end-tidal CO2 shown on monitor, oropharyngeal leak pressure, and fiberoptic score - were measured following each cLMA insertion. RESULTS: For all of the five measured parameters, the tongue width-based method was better than weight-based formula in determining optimal cLMA size selection. CONCLUSION: The tongue width-based method is a convenient and efficacious alternative for selecting an optimal cLMA size in male adults. PMID- 25043386 TI - Groove sign in eosinophilic fasciitis. PMID- 25043387 TI - Sexual and reproductive health and rights: a global development, health, and human rights priority. PMID- 25043388 TI - Coupled-cluster frozen-density embedding using resolution of the identity methods. AB - Frozen-density embedding (FDE) is combined with resolution of the identity (RI) Hartree-Fock and a RI-variant of a second-order approximate coupled-cluster singles and doubles (RI-CC2) to determine solvatochromic shifts for the lowest excitation energy of acetone and pyridazine, respectively, each solvated in different environments with total system sizes of about 2.5 nm diameter. The combination of FDE and RI-CC2 increases efficiency and enables the calculation of numerous snapshots with 100 to 300 molecules, also allowing for larger basis sets as well as diffuse functions needed for an accurate treatment of properties. The maximum errors in the solvatochromic shifts amount up to 0.2 eV, which are similar to other approximated studies in the literature. PMID- 25043389 TI - In vitro protection of biological macromolecules against oxidative stress and in vivo toxicity evaluation of Acacia nilotica (L.) and ethyl gallate in rats. AB - BACKGROUND: Recently, enormous research has been focused on natural bioactive compounds possessing potential antioxidant and anticancer properties using cell lines and animal models. Acacia nilotica (L.) is widely distributed in Asia, Africa, Australia and Kenya. The plant is traditionally used to treat mouth, ear and bone cancer. However, reports on Acacia nilotica (L.) Wild. Ex. Delile subsp. indica (Benth.) Brenan regarding its toxicity profile is limited. Hence in this study, we investigated the antioxidant capacity and acute toxicity of ethyl gallate, a phenolic antioxidant present in the A. nilotica (L.) leaf extract. METHODS: The antioxidant activity of ethyl gallate against Fenton's system (Fe3+/H2O2/ascorbic acid) generated oxidative damage to pBR322 DNA and BSA was investigated. We also studied the interaction of ethyl gallate to CT-DNA by wave scan and FTIR analysis. The amount of ethyl gallate present in the A. nilotica (L.) leaf extract was calculated using HPLC and represented in gram equivalence of ethyl gallate. The acute toxicity profile of ethyl gallate in the A. nilotica (L.) leaf extract was analyzed in albino Wistar rats. Measurement of liver and kidney function markers, total proteins and glucose were determined in the serum. Statistical analysis was done using statistical package for social sciences (SPSS) tool version 16.0. RESULTS: Ethyl gallate was found to be effective at 100 MUg/mL concentration by inhibiting the free radical mediated damage to BSA and pBR322 DNA. We also found that the interaction of ethyl gallate and A. nilotica (L.) leaf extract to CT-DNA occurs through intercalation. One gram of A. nilotica (L.) leaf extract was found to be equivalent to 20 mg of ethyl gallate through HPLC analysis. Based on the acute toxicity results, A. nilotica (L.) leaf extract and ethyl gallate as well was found to be non-toxic and safe. CONCLUSIONS: Results revealed no mortality or abnormal biochemical changes in vivo and the protective effect of A. nilotica (L.) leaf extract and ethyl gallate on DNA and protein against oxidative stress in vitro. Hence, A. nilotica (L.) leaf extract or ethyl gallate could be used as potential antioxidants with safe therapeutic application in cancer chemotherapy. PMID- 25043391 TI - Acute inflammatory demyelinating polyradiculopathy in Legionella pneumonia. PMID- 25043390 TI - Pathogenic role of the eight probably/possibly carcinogenic HPV types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer. AB - Eight HPV types (HPV26, 53, 66, 67, 68, 70, 73 and 82) that are phylogenetically closely related to 12 WHO-defined high-risk (HR) HPV have been rarely but consistently identified as single HPV infections in about 3% of cervical cancer (CxCa) tissues. Due to lack of biological data, these types are referred to as probable/possible (p) HR-HPV. To analyse their biological activity in direct comparison to HR-HPV types, we selected 55 formalin-fixed, paraffin-embedded (FFPE) CxCa tissues harbouring single pHR-HPV infections (2-13 cases per type) and 266 tissues harbouring single HR-HPV (7-40 cases per type) from a worldwide, retrospective, cross-sectional study. Single HPV infection was verified by two genotyping methods. Presence of type-specific spliced E6*I mRNA transcripts and expression of cellular proteins indicative of HPV transformation were assessed in all cases. In 55 CxCa tissues with pHR-HPV, E6*I mRNA expression was 100%; high p16(INK4a) , 98%; low pRb, 96%; low CyD1, 93%; and low p53, 84%. Compared to HPV16 tissues as a reference, individual frequencies of these five markers did not differ significantly, either for any of the eight pHR-HPV and the 11 other HR types individually or for the groups of pHR and HR types without HPV16. We conclude that the eight pHR-HPV types, when present as a single infection in CxCa, are biologically active and affect the same cellular pathways as any of the fully recognized carcinogenic HR-HPV types. Therefore we have provided molecular evidence of carcinogenicity for types currently classified as probably/possibly carcinogenic. Although this evidence is crucial for HPV-type carcinogenicity classification, per se it is not sufficient for inclusion of these HPV types into population-wide primary and secondary prevention programmes. Such decisions have to include careful estimation of effectiveness and cost-benefit analyses. PMID- 25043392 TI - pDCs efficiently process synthetic long peptides to induce functional virus- and tumour-specific T-cell responses. AB - Robust cell-mediated immunity is required for immune control of tumours and protection from viral infections, with both CD4(+) and CD8(+) T cells playing a pivotal role. Synthetic long peptides (SLPs) represent an attractive way to induce such combined responses, as they contain both class I and class II epitopes. The ability of plasmacytoid dendritic cells (pDCs) to cross-present SLPs has not yet been investigated; yet, pDCs play a critical role in shaping immune responses and have emerged as novel vectors for immunotherapy. Using overlapping 15-mer peptide pools covering the entire sequence of CMVpp65 and MelA, representing a viral disease (cytomegalovirus, CMV) and a tumour (melanoma), respectively, we showed that human pDCs can effectively process SLPs. Our results demonstrated that pDCs potently cross-present virus- and tumour derived SLPs and cross-prime broad-ranging, effective and long-lived CD4(+) and CD8(+) T-cell responses, triggering more efficient immune responses than short peptide loaded pDCs. This ability required intracellular processing by the proteasome and was enhanced by co-exposure to TLR7/9-L. Combining SLPs with pDCs represents a powerful immunotherapeutic strategy to elicit potent immune responses, which are required for clinical success in cancers and viral infections. PMID- 25043394 TI - Colistin, rifampicin, and meropenem administered as single agents in a model of pneumonia caused by a carbapenem-resistant Acinetobacter baumannii. PMID- 25043393 TI - Sepsis carries a high mortality among hospitalised adults in Malawi in the era of antiretroviral therapy scale-up: a longitudinal cohort study. AB - OBJECTIVE: To assess mortality risk among adults presenting to an African teaching hospital with sepsis and severe sepsis in a setting of high HIV prevalence and widespread ART uptake. METHODS: Prospective cohort study of adults (age >=16 years) admitted with clinical suspicion of severe infection between November 2008 and January 2009 to Queen Elizabeth Central Hospital, a 1250-bed government-funded hospital in Blantyre, Malawi. Demographic, clinical and laboratory information, including blood and cerebrospinal fluid cultures were obtained on admission. RESULTS: Data from 213 patients (181 with sepsis and 32 with severe sepsis; M:F = 2:3) were analysed. 161 (75.6%) patients were HIV positive. Overall mortality was 22%, rising to 50% amongst patients with severe sepsis. The mortality of all sepsis patients commenced on antiretroviral therapy (ART) within 90 days was 11/28 (39.3%) compared with 7/42 (16.7%) among all sepsis patients on ART for greater than 90 days (p = 0.050). Independent associations with death were hypoxia (OR = 2.4; 95% CI, 1.1-5.1) and systolic hypotension (OR 7.0; 95% CI: 2.4-20.4). CONCLUSIONS: Sepsis and severe sepsis carry high mortality among hospitalised adults in Malawi. Measures to reduce this, including early identification and targeted intervention in high-risk patients, especially HIV-positive individuals recently commenced on ART, are urgently required. PMID- 25043395 TI - Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero((r))). AB - OBJECTIVES: To assess the potential use of a protein-based meningococcal group B (MenB) vaccine (Bexsero((r))) in addition to antibiotic chemoprophylaxis for preventing secondary cases. METHODS: Published studies on the risk of secondary meningococcal infections were used to estimate the numbers needed to vaccinate (NNV) with Bexsero((r)) to prevent a secondary case in household and educational settings. RESULTS: Most secondary cases occur within a few days of diagnosis in the index case. Unlike conjugate vaccines, early protection offered after a single dose of Bexsero((r)) is likely to be low, particularly in young children, who are at higher risk of secondary infection. NNV was dependent on predicted meningococcal strain coverage, estimated onset of protection after one Bexsero((r)) dose and estimated vaccine efficacy. Even in the most favourable scenario where we assume the vaccine is administered within 4 days of the index case and prevents 90% of cases occurring after 14 days, the NNV for household contacts was >1000. NNV in educational settings was much higher. CONCLUSIONS: The estimated NNV should be taken into account when deciding policy to recommend Bexsero((r)) for close contacts of single cases in household or educational settings. Bexsero((r)) may have a protective role in clusters and outbreaks. PMID- 25043396 TI - Mitochondrial DNA haplogroups are associated with severe sepsis and mortality in patients who underwent major surgery. AB - OBJECTIVE: To analyse whether mitochondrial DNA (mtDNA) haplogroups are associated with severe sepsis and mortality after major surgery. METHODS: We performed a case-control study on 240 cardiac or abdominal surgery patients developing severe sepsis (Case-group) and 267 cardiac or abdominal surgery patients without severe sepsis and with systemic inflammatory response syndrome (SIRS, Control-group). Furthermore, a longitudinal substudy was performed for analysing the survival in septic patients. Only European white patients within the N macro-cluster were included. RESULTS: Case-group underwent cardiac surgery had lower frequencies of cluster HV (p = 0.005) and haplogroup H (p = 0.005) and higher frequencies of cluster JT (p = 0.028) than Control-group; but no significant differences were found for abdominal surgery. Besides, both cluster HV and haplogroup H were associated with decreased odds of severe sepsis (adjusted odds ratio (aOR) = 0.45 (95%CI = 0.25; 0.82); p = 0.009 and aOR = 0.48 (95%CI = 0.26; 0.87); p = 0.015, respectively) among patients underwent cardiac surgery. In Case-group, 45.4% (109/240) patients died with a survival median of 39 (95%CI = 31.4; 46.62) days. When the clusters were examined, 41% (55/134) patients within cluster HV died versus 71.4% (10/14) patients within cluster IWX (p = 0.018). Additionally, patients within cluster IWX had an increased risk of death (adjusted hazard ratio (aHR) = 2.22; (95%CI = 1.14; 4.34); p = 0.019). CONCLUSIONS: European mitochondrial haplogroups might be related to the onset of severe sepsis in patients who underwent major cardiac surgery, but not in patients underwent major abdominal surgery. Besides, mtDNA haplogroups could have influence on mortality in septic patients. PMID- 25043397 TI - Diagnostic value of suPAR in differentiating noncardiac pleural effusions from cardiac pleural effusions. AB - INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a newly discovered inflammatory biomarker. suPAR has not been previously studied in differentiating noncardiac pleural effusion (PF) from cardiac PF. The aim of our study was to assess the diagnostic value of suPAR in PF. METHODS: The concentration of PF-suPAR was measured by a commercialized enzyme-linked immunosorbent assay in a prospective cohort of 74 patients with PF, 18 patients with PF due to cardiac failure (CF) and 56 patients with noncardiac PF. The area under the curve quantified the overall diagnostic accuracy of the tests. RESULTS: The median pleural fluid suPAR level was found as 23 (5.4-102.8) ng/mL. The median PF-suPAR level in CF was significantly lower than that of noncardiac effusions [11.8 (5.4-28.9) ng/mL vs 26.7 (8.2-102.8) ng/mL, respectively, P < 0.001]. The area under the receiver operating characteristic curve was 0.878 (95% confidence interval: 0795-0.962, P < 0.001) for noncardiac pleural fluid suPAR. The sensitivity, specificity and positive predictive value of PF-suPAR for noncardiac effusions at the cutoff level of >=17.6 n/mL was 88%, 83% and 94%, respectively. The suPAR level in PF was found to correlate with all of the biochemical parameters of PF. CONCLUSIONS: suPAR is a potential new marker for the discrimination between cardiac and noncardiac PF. PMID- 25043398 TI - Glycosyl alkoxythioimidates as building blocks for glycosylation: a reactivity study. AB - Structural modifications of the leaving group of S-glycosyl O-methyl phenylcarbamothioates (SNea) involving change of substituents that express different electronic effects led to a better understanding of how the reactivity of these glycosyl donors can be modified by changing the structure of their leaving groups. Mechanistic studies involving the isolation of departed aglycones were indicative of the direct activation of both p-methoxy-SNea and p-nitro-SNea leaving groups via the anomeric sulfur rather than the remote nitrogen atom. The presence of an electron donating substituent (p-methoxy) has a strong effect on the nucleophilicity of the sulfur atom that becomes more susceptible toward the attack of thiophilic reagents, in particular. This key observation allowed to differentiate the reactivity levels of p-methoxy-SNea versus p-nitro-SNea and even unmodified SNea leaving groups. The reactivity difference observed in the series of SNea leaving groups is sufficient to be exploited in expeditious oligosaccharide synthesis via selective activation strategies. PMID- 25043399 TI - Online social networking services in the management of patients with diabetes mellitus: systematic review and meta-analysis of randomised controlled trials. AB - AIMS: Social networking services (SNS) can facilitate real-time communication and feedback of blood glucose and other physiological data between patients and healthcare professionals. This systematic review and meta-analysis aims to summarise the current evidence surrounding the role of online social networking services in diabetes care. METHODS: We performed a systematic literature review of the Medline, EMBASE and PsychINFO databases of all studies reporting HbA1c (glycated haemoglobin) as a measure of glycaemic control for social networking services in diabetes care. HbA1c, clinical outcomes and the type of technology used were extracted. Study quality and publication bias were assessed. RESULTS: SNS interventions beneficially reduced HbA1c when compared to controls, which was confirmed by sensitivity analysis. SNS interventions also significantly improved systolic and diastolic blood pressure, triglycerides and total cholesterol. Subgroup analysis according to diabetes type demonstrated that Type 2 diabetes patients had a significantly greater reduction in HbA1c than those with Type 1 diabetes. CONCLUSIONS: Online SNS provide a novel, feasible approach to improving glycaemic control, particularly in patients with Type 2 diabetes. Further mechanistic and cost-effectiveness studies are required to improve our understanding of SNS and its efficacy in diabetes care. PMID- 25043400 TI - Divergent pathways and competitive mechanisms of metathesis reactions between 3 arylprop-2-ynyl esters and aldehydes: an experimental and theoretical study. AB - Mechanistic studies of the reaction between 3-arylprop-2-ynyl esters and aldehydes catalyzed by BF3 ?Et2 O were performed by isotopic labeling experiments and quantum chemical calculations. The reactions are shown to proceed by either a classical alkyne-carbonyl metathesis route or an unprecedented addition rearrangement cascade. Depending on the structure of the starting materials and the reaction conditions, the products of these reactions can be Morita-Baylis Hillman (MBH) adducts that are unavailable by traditional MBH reactions or E- and Z-alpha,beta-unsaturated ketones. (18) O-Labeling studies suggested the existence of two different reaction pathways to the products. These pathways were further examined by quantum chemical calculations that employed the DFT(wB97XD)/6 311+G(2d,p) method, together with the conductor-like screening model for realistic solvation (COSMO-RS). By using the wB97XD functional, the accuracy of the computed data is estimated to be 1-2 kcal mol(-1) , shown by the careful benchmarking of various DFT functionals against coupled cluster calculations at the CCSD(T)/aug-cc-pVTZ level of theory. Indeed, most of the experimental data were reproduced and explained by theory and it was convincingly shown that the branching point between the two distinct mechanisms is the formation of the first intermediate on the reaction pathway: either the four-membered oxete or the six membered zwitterion. The deep mechanistic understanding of these reactions opens new synthetic avenues to chemically and biologically important alpha,beta unsaturated ketones. PMID- 25043402 TI - High dose of tigecycline for extremely resistant Gram-negative pneumonia: yes, we can. AB - Few antimicrobials are currently active to treat infections caused by extremely resistant Gram-negative bacilli (ERGNB), which represent a serious global public health concern. Tigecycline, which covers the majority of these ERGNB (with the exception of Pseudomonas aeruginosa), is not currently approved for hospital acquired pneumonia, and several meta-analyses have suggested an increased risk of death in patients receiving this antibiotic. Other studies suggest that the use of high-dose tigecycline may represent an alternative in daily practice. De Pascale and colleagues report that the clinical cure rate in patients with ventilator-associated pneumonia is significantly higher with a high dose of tigecycline than with the conventional dose, although mortality was unaffected. This high dose is safe; no patients required discontinuation or dose reduction. PMID- 25043401 TI - Long-term outcome after parathyroidectomy for lithium-induced hyperparathyroidism. AB - BACKGROUND: The accepted management of lithium-associated hyperparathyroidism (LiHPT) is open four-gland parathyroid exploration (OPTX). This approach has recently been the subject of controversy. A recent study has shown very high long term recurrence rates after OPTX, whereas some have promoted unilateral focused parathyroidectomy as appropriate management. The aim was to evaluate long-term outcomes after surgery for LiHPT and to assess the accuracy of preoperative imaging. METHODS: This was a retrospective cohort study that comprised all patients undergoing initial surgery for LiHPT between 1990 and 2013. The cumulative recurrence rate was calculated by the Kaplan-Meier method. The sensitivity and specificity of sestamibi scintigraphy and ultrasound imaging for identification of single-gland versus multigland disease was investigated using intraoperative assessment as reference. RESULTS: Of 48 patients, 45 had OPTX and three underwent focused parathyroidectomy. Multiglandular disease was documented in 27 patients and 21 had a single adenoma. The median follow-up was 5.9 (range 0.3-22) years and 16 patients died during follow-up. The 10-year cumulative recurrence rate was 16 (95 per cent confidence interval 2 to 29) per cent. No permanent complications occurred after primary surgery for LiHPT. Twenty-four patients had at least one preoperative ultrasound or sestamibi scan. For concordant sestamibi scintigraphy and ultrasound imaging, the sensitivity and specificity for identifying single-gland versus multigland disease was five of nine and five of eight respectively. CONCLUSION: Surgery provided a safe and effective management option for patients with LiHPT in this series, with a long term cure rate of well over 80 per cent. PMID- 25043403 TI - Controlled growth of single-crystal twelve-pointed graphene grains on a liquid Cu surface. AB - The controlled fabrication of single-crystal twelve-pointed graphene grains is demonstrated for the first time by ambient pressure chemical vapor deposition on a liquid Cu surface. An edge-diffusion limited mechanism is proposed. The highly controllable growth of twelve-pointed graphene grains presents an intriguing case for the fundamental study of graphene growth and should exhibit wide applications in graphene-based electronics. PMID- 25043404 TI - Epinephrine, vasopressin and steroids for in-hospital cardiac arrest: the right cocktail therapy? PMID- 25043405 TI - Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition. AB - Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin- or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling. CONCLUSION: Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients. PMID- 25043406 TI - Increasing mortality burden among adults with complex congenital heart disease. AB - BACKGROUND: Progress in management of congenital heart disease has shifted mortality largely to adulthood. However, adult survivors with complex congenital heart disease are not cured and remain at risk of premature death as young adults. Thus, our aim was to describe the evolution and mortality risk of adult patient cohorts with complex congenital heart disease. METHODS: Among 12,644 adults with congenital heart disease followed at a single center from 1980 to 2009, 176 had Eisenmenger syndrome, 76 had unrepaired cyanotic defects, 221 had atrial switch operations for transposition of the great arteries, 158 had congenitally corrected transposition of the great arteries, 227 had Fontan palliation, and 789 had repaired tetralogy of Fallot. We depict the 30-year evolution of these 6 patient cohorts, analyze survival probabilities in adulthood, and predict future number of deaths through 2029. RESULTS: Since 1980, there has been a steady increase in numbers of patients followed, except in cohorts with Eisenmenger syndrome and unrepaired cyanotic defects. Between 1980 and 2009, 308 patients in the study cohorts (19%) died. At the end of 2009, 85% of survivors were younger than 50 years. Survival estimates for all cohorts were markedly lower than for the general population, with important differences between cohorts. Over the upcoming two decades, we predict a substantial increase in numbers of deaths among young adults with subaortic right ventricles, Fontan palliation, and repaired tetralogy of Fallot. CONCLUSIONS: Anticipatory action is needed to prepare clinical services for increasing numbers of young adults at risk of dying from complex congenital heart disease. PMID- 25043407 TI - Direct asymmetric anti-Mannich-type reactions catalyzed by cinchona alkaloid derivatives. AB - A series of cinchona alkaloid derivatives were used to catalyze the asymmetric anti-Mannich-type reaction of 3-methyl-2-oxindole with N-tosyl aryl aldimines. The resulting anti-3,3-disubstituted 2-oxindole products were obtained in good yields (up to 92%) with high diastereo- and enantioselectivities (anti/syn up to 97:3 and 91% ee). PMID- 25043410 TI - Copper-mediated ortho-nitration of (hetero)arenecarboxylates. AB - Various (hetero)arenecarboxylic acids were converted to the corresponding Daugulis amides and nitrated selectively in the ortho-position in the presence of [CuNO3(PPh3)2] and AgNO2 at 50 degrees C. A microwave-assisted saponification allows regenerating the carboxylate group within minutes, which may then be removed tracelessly by protodecarboxylation, or substituted by aryl- or alkoxy groups via decarboxylative cross-coupling. PMID- 25043408 TI - Utility of snout wipe samples for influenza A virus surveillance in exhibition swine populations. AB - BACKGROUND: Sporadic influenza A virus (IAV) outbreaks in humans and swine have resulted from commingling of large numbers of people and pigs at agricultural fairs in the United States. Current antemortem IAV surveillance strategies in swine require collecting nasal swabs, which entails restraining pigs with snares. Restraint is labor-intensive for samplers, stressful for pigs, and displeasing to onlookers because pigs often resist and vocalize. OBJECTIVE: To evaluate the utility of snout wipes in exhibition swine as a method to make IAV surveillance efforts less intrusive, less labor-intensive, and more widely accepted among pig owners and exhibition officials. METHODS: Three materials (rayon/polyester gauze, cotton gauze, and Swiffer((r)) Sweeper dry cloths) were inoculated with IAV, and viral recoveries from these materials were quantified using qRT-PCR and TCID50 assays. In a field trial, paired cotton gauze snout wipes and gold standard polyester-tipped nasal swabs were collected from 553 pigs representing 29 agricultural fairs and the qualitative results of rRT-PCR and viral isolation were compared. RESULTS AND CONCLUSIONS: Viral recoveries from potential snout wipe materials ranged from 0.26 to 1.59 log10 TCID50 /ml less than that of the positive control in which no substrate was included; rayon/polyester gauze performed significantly worse than the other materials. In the field, snout wipes and nasal swabs had high levels of agreement for both rRT-PCR detection and virus isolation. Although further investigation and refinement of the sampling method is needed, results indicate that snout wipes will facilitate convenient and undisruptive IAV surveillance in pigs at agricultural fairs. PMID- 25043411 TI - Cancer incidence patterns among children and adolescents in Taiwan from 1995 to 2009: a population-based study. AB - BACKGROUND: Currently, little information is available on childhood cancer incidence rates in Eastern Asia. The objective of this study was to report the first population-based cancer surveillance of children and adolescents in Taiwan. METHODS: Data from the Taiwan Cancer Registry were examined for cancer frequencies and incidence rates among individuals ages birth to 19 years from 1995 to 2009. Types of cancers were grouped according to the International Classification of Childhood Cancer. Rates were compared by sex and age. For further comparisons with other countries, rates were age standardized to the 2000 world standard population in 5-year age groups. Trends in incidence rates also were evaluated. RESULTS: In total, 12,315 individuals were diagnosed with childhood cancers, for an age-standardized incidence rate (ASR) of 132.1 per million person-years from 1995 to 2009. The male-to-female incidence rate ratio was 1.19. Overall, leukemias were the most common cancer (ASR, 39.1 per million person-years), followed by central nervous system neoplasms (15.8 per million person-years), and lymphomas (15.3 per million person-years). During the 15-year study period, the incidence rates increased by 1% annually. Compared with other countries, the rate of hepatic tumors was 2 times greater in Taiwan. The rate of germ cell neoplasms in Taiwan was similar to that in the United States and was 1.3 to 1.9 times greater compared with Canada, Brazil, Israel, and Japan. CONCLUSIONS: Based on the current data, the observed increase in overall incidence rates was attributable only marginally to improvements in case ascertainment and diagnostic procedures. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in the background risk factors. PMID- 25043412 TI - Precedent of ideas and models in science: do we need a registry similar to patents? PMID- 25043417 TI - Synthesis of novel perphenylcarbamated beta-cyclodextrin based chiral stationary phases via thiol-ene click chemistry. AB - Novel cyclodextrin (CD) chiral stationary phases (CD-CSPs) with well-defined structure have been successfully synthesized by immobilization of mono/di(10 undecenoyl)-perphenylaminocarbonyl beta-CD on the 3-mercaptopropyl functionalized silica gel via thiol-ene click chemistry. The phenyl carbamate groups on the rims of CD extended the cavity of CD-CSPs, which facilitated the formation of inclusion complex with various types of racemic compounds under RP mode, and also improved the pi-pi stacking interaction, dipole-dipole interaction, and hydrogen bonding interaction with racemic compounds under normal phase mode. Fifteen racemic compounds were successfully separated on this CD-CSP with HPLC, and the chromatographic results also demonstrated that thiol-ene click chemistry affords a facile approach for preparation of CSPs. PMID- 25043416 TI - In vivo evidence of glutamate toxicity in multiple sclerosis. AB - OBJECTIVE: There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N-acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects. METHODS: We used multivoxel spectroscopy at 3T to longitudinally estimate Glu and NAA concentrations from large areas of normal-appearing white and gray matter (NAWM and GM) in MS patients (n = 343) with a mean follow-up time of 5 years. Using linear mixed-effects models, Glu was examined as a predictor of NAA decline, annualized percentage brain volume change, and evolution of clinical outcomes (Multiple Sclerosis Functional Composite [MSFC], Paced Auditory Serial Addition Test-3 [PASAT], and Expanded Disability Status Scale). Glu/NAA ratio was tested as a predictor of brain volume loss and clinical outcomes. RESULTS: Baseline Glu[NAWM] was predictive of accelerated longitudinal decline in NAA[GM] (-0.06mM change in NAA[GM] /yr for each unit increase in Glu; p = 0.004). The sustained elevation of Glu[NAWM] was predictive of a loss of 0.28mM/yr in NAA[NAWM] (p < 0.001) and 0.15mM/yr in NAA[GM] (p = 0.056). Each 10% increase in Glu/NAA[NAWM] was associated with a loss of 0.33% brain volume/yr (p = 0.001), 0.009 standard deviations/yr in MSFC z-score (p < 0.001), and 0.17 points/yr on the PASAT (p < 0.001). INTERPRETATION: These results indicate that higher Glu concentrations increase the rate of NAA decline, and higher Glu/NAA[NAWM] ratio increases the rate of decline of brain volume, MSFC, and PASAT. This provides evidence of a relationship between brain Glu and markers of disease progression in MS. PMID- 25043418 TI - Molecular evolution in the CREB1 signal pathway and a rare haplotype in CREB1 with genetic predisposition to schizophrenia. AB - CREB1 is a cAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We speculated that CSP has undergone positive selection during evolution of modern human and some genes that have undergone natural selection in the past may predispose to schizophrenia (SCZ) in modern time. Positive selection and association analysis were employed to explore the molecular evolution of CSP and association with schizophrenia. Our results showed a pan-ethnic selection event on NRG1 and CREB1, as confirmed in all 14 ethnic populations studied, which also suggested a selection process occurred before the "Out of Africa" scenario. Analysis of 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 SCZ patients and 1043 healthy individuals) showed an association of two SNPs (rs4379857, P = 0.009, OR [95% CI]: 1.200 [1.379-1.046]; rs2238751, P = 0.023, OR [95% CI]: 1.253 [1.522-1.032]) with SCZ. However, none of these significances survived after multiple testing corrections. Nonetheless, we observed an association of a rare CREB1 haplotype CCGGC (Bonferroni corrected P = 1.74 * 10(-5)) with SCZ. Our study showed that there was substantial population heterogeneity in genetic predisposition to SCZ, and different genes in the CSP pathway may predispose to SCZ in different populations. PMID- 25043419 TI - Identifying functional connections of the inner photoreceptors in Drosophila using Tango-Trace. AB - In Drosophila, the four inner photoreceptor neurons exhibit overlapping but distinct spectral sensitivities and mediate behaviors that reflect spectral preference. We developed a genetic strategy, Tango-Trace, that has permitted the identification of the connections of the four chromatic photoreceptors. Each of the four stochastically distributed chromatic photoreceptor subtypes make distinct connections in the medulla with four different TmY cells. Moreover, each class of TmY cells forms a retinotopic map in both the medulla and the lobula complex, generating four overlapping topographic maps that could carry different color information. Thus, the four inner photoreceptors transmit spectral information through distinct channels that may converge in both the medulla and lobula complex. These projections could provide an anatomic basis for color vision and may relay information about color to motion sensitive areas. Moreover, the Tango-Trace strategy we used may be applied more generally to identify neural circuits in the fly brain. PMID- 25043420 TI - Spatiotemporal dynamics underlying object completion in human ventral visual cortex. AB - Natural vision often involves recognizing objects from partial information. Recognition of objects from parts presents a significant challenge for theories of vision because it requires spatial integration and extrapolation from prior knowledge. Here we recorded intracranial field potentials of 113 visually selective electrodes from epilepsy patients in response to whole and partial objects. Responses along the ventral visual stream, particularly the inferior occipital and fusiform gyri, remained selective despite showing only 9%-25% of the object areas. However, these visually selective signals emerged ~100 ms later for partial versus whole objects. These processing delays were particularly pronounced in higher visual areas within the ventral stream. This latency difference persisted when controlling for changes in contrast, signal amplitude, and the strength of selectivity. These results argue against a purely feedforward explanation of recognition from partial information, and provide spatiotemporal constraints on theories of object recognition that involve recurrent processing. PMID- 25043422 TI - Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. AB - Interactions of adult neural stem cells (NSCs) with supportive vasculature appear critical for their maintenance and function, although the molecular details are still under investigation. Neurotrophin (NT)-3 belongs to the NT family of trophic factors, best known for their effects in promoting neuronal survival. Here we show that NT-3 produced and secreted by endothelial cells of brain and choroid plexus capillaries is required for the quiescence and long-term maintenance of NSCs in the mouse subependymal niche. Uptake of NT-3 from irrigating vasculature and cerebrospinal fluid (CSF) induces the rapid phosphorylation of endothelial nitric oxide (NO) synthase present in the NSCs, leading to the production of NO, which subsequently acts as a cytostatic factor. Our results identify a novel interaction between stem cells and vasculature/CSF compartments that is mediated by an unprecedented role of a neurotrophin and indicate that stem cells can regulate their own quiescence in response to endothelium-secreted molecules. PMID- 25043421 TI - Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus. AB - Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/ );2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent hydrocephalus. PMID- 25043423 TI - Weight loss effect of glucagon-like peptide-1 mimetics on obese/overweight adults without diabetes: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) benefit weight maintenance for diabetic patients. We performed a systematic review to evaluate its weight loss effect on obese/overweight patients without diabetes in randomized controlled trials (RCTs). METHODS: Literature updated to May 5, 2014 from Cochrane Library, MEDLINE, EMBASE and reference lists from relevant articles were identified. RCTs with GLP-1 mimetics treating obese/overweight adults without diabetes for at least 12 weeks were assessed. Studies lacking primary measurements were excluded. Three authors extracted data independently. Either fixed-effect or random-effect models were used to calculate weighted mean differences (WMDs), combined relative risks (RR) and 95% confidence interval (CI) in meta-analyses. Intertrial heterogeneity across studies was examined by I(2) and Q statistics. RESULTS: A total of 1345 individuals retrieved from eight studies were involved and all included trials were of mild-to-moderate bias risks. Participants in GLP-1RA groups achieved a larger weight loss than those in control groups (-2.85 kg, 95%CI -3.55 to -2.14), and liraglutide may work in a dose-dependent fashion. GLP-1RAs also reduced body mass index (BMI) and waist circumferences (WC) and benefited systolic blood pressure and triglyceride regulation. But GLP-1RAs were associated with increased nausea and vomiting events. CONCLUSIONS: GLP-1 mimetics induce a weight loss in addition to BMI and WC reduction in obese/overweight adults without diabetes. Further long-term randomized trials and basic studies are required to investigate the mechanisms. PMID- 25043424 TI - Canine prostate cancer cell line (Probasco) produces osteoblastic metastases in vivo. AB - BACKGROUND: In 2012, over 240,000 men were diagnosed with prostate cancer and over 28,000 died from the disease. Animal models of prostate cancer are vital to understanding its pathogenesis and developing therapeutics. Canine models in particular are useful due to their similarities to late-stage, castration resistant human disease with osteoblastic bone metastases. This study established and characterized a novel canine prostate cancer cell line that will contribute to the understanding of prostate cancer pathogenesis. METHODS: A novel cell line (Probasco) was derived from a mixed breed dog that had spontaneous prostate cancer. Cell proliferation and motility were analyzed in vitro. Tumor growth in vivo was studied by subcutaneous, intratibial, and intracardiac injection of Probasco cells into nude mice. Tumors were evaluated by bioluminescent imaging, Faxitron radiography, uCT, and histology. RT-PCR and genome-wide DNA copy number profiling were used to characterize the cell line. RESULTS: The Probasco cells grew in vitro (over 75 passages) and were tumorigenic in nude mice. Probasco cells expressed high levels of BMP2, CDH1, MYOF, FOLH1, RUNX2, and SMAD5 modest CXCL12, SLUG, and BMP, and no PTHrP mRNA. Following intracardiac injection, Probasco cells metastasized primarily to the appendicular skeleton, and both intratibial and intracardiac injections produced osteoblastic tumors in bone. Comparative genomic hybridization demonstrated numerous DNA copy number aberrations throughout the genome, including large losses and gains in multiple chromosomes. CONCLUSIONS: The Probasco prostate cancer cell line will be a valuable model to investigate the mechanisms of prostate cancer pathogenesis and osteoblastic bone metastases. PMID- 25043425 TI - Improvement of the antioxidant and hypolipidaemic effects of cowpea flours (Vigna unguiculata) by fermentation: results of in vitro and in vivo experiments. AB - BACKGROUND: The antioxidant capacity and hypolipidaemic effects of Vigna unguiculata, as well as their potential improvement by different fermentation and thermal processes were studied using in vitro and in vivo methods. RESULTS: Phenolic content and reducing capacity of legume acetone extract were significantly increased by different fermentation processes, and by the thermal treatment of fermented legume flours. TBARS inhibiting capacity was increased by fermentation but not by thermal treatment. A higher ability to decrease Cu(2+)/H2O2-induced electrophoretic mobility of LDL was found in fermented when compared to raw legume extracts, and a higher protective effect on short term metabolic status of HT-29 cells was found for raw and lactobacillus-fermented Vigna followed by naturally fermented Vigna extracts. Significant improvements in plasma antioxidant capacity and hepatic activity of antioxidant enzymes were observed in rats that consumed fermented legume flours when compared to the untreated legume or a casein-methionine control diet. In addition, liver weight and plasma levels of cholesterol and triglycerides were also positively affected by untreated or naturally fermented Vigna. CONCLUSION: V. unguiculata has demonstrated its potential as a functional food with interesting antioxidant and lipid lowering properties, which can be further augmented by fermentation processes associated or not to thermal processing. PMID- 25043427 TI - Volume-outcome disparities and informed consent: what should surgeons disclose? AB - It has been repeatedly shown that higher procedure volumes, by hospital and by physician, are associated with better outcomes. Buttressed by large-scale selective service purchasing, surgical care for many volume-sensitive operations has been regionalized. However, the implications of outcome disparity data for obtaining valid patient consent remain uncertain. When the first large scale outcome study appeared showing empirically that outcomes are volume-related, two prominent bioethicists promptly insisted that such information was material to a reasonable patient's decision whether and where to have a volume-sensitive operation and that surgeons at low-volume hospitals should disclose it. More recently, two surgical oncologists have reiterated that argument, most especially when patients are making decisions about pancreatic or esophageal resections. This proposal tantalizingly appeals to the concept of patient empowerment, supposedly showing appropriate respect for the patient's interest in self determination by having his surgeon (or physician), rather than others, outline for him personally the risks and benefits associated with surgical care delivered at different hospitals. But on the contrary, a surgeon's conducting a truthful, non-misleading, non-confusing informed consent discussion of statistical outcome disparities in the relentlessly shrinking time typically allowed for this conversation is unrealistic as a general requirement. The traditional approach to informed consent is simpler, less fraught and preferable. By law, a surgeon who is licensed to practice independently and who evidences willingness to examine and to offer an operation to a patient conveys (1) an implicit standard of care assurance, and (2) a fiduciary assurance. In other words, it goes without saying that the surgeon holds it out to the patient that s/he possesses the training and skill necessary to perform the offered service with reasonable skill and safety as measured by the applicable standard of care; that s/he will act in good faith and use his/her best medical judgment on the patient's behalf. Liability attaches when patient harm results from a surgeon's failure on either count. It also goes without saying that the surgeon extends similar assurances for care provided by trainees who are under his or her direct supervisory authority and control. The traditional theory of informed consent forestalls requiring desultory discussions of volume-outcome disparities and will be defended here. PMID- 25043426 TI - Evaluation of the sensitivity of the novel alpha4beta2* nicotinic acetylcholine receptor PET radioligand 18F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys. AB - OBJECTIVE: 18F-(-)-NCFHEB (also known as 18F-(-)-Flubatine) is a new radioligand to image alpha4beta2* nicotinic acetylcholine receptors in vivo with positron emission tomography (PET), with faster kinetics than previous radioligands such as 18F-2-F-A85380. The goal of this study was to assess the sensitivity of 18F-( )-NCFHEB-PET to increases in synaptic acetylcholine concentration induced by acetylcholinesterase inhibitors. METHODS: Two rhesus monkeys were scanned four times each on a Focus 220 scanner: first at baseline, then during two bolus plus infusions of physostigmine (0.06-0.28 mg/kg), and finally following a bolus injection of donepezil (0.25 mg/kg). The arterial input function and the plasma free fraction fP were measured. 18F-(-)-NCFHEB volume of distribution VT was estimated using the multilinear analysis MA1 and then normalized by plasma free fraction fP . RESULTS: 18F-(-)-NCFHEB fP was 0.89+/-0.04. At baseline, 18F-(-) NCFHEB VT /fP ranged from 7.9+/-1.3 mL plasma/cm3 tissue in the cerebellum to 34.3+/-8.4 mL plasma/cm3 tissue in the thalamus. Physostigmine induced a dose dependent reduction of 18F-(-)-NCFHEB VT /fP of 34+/-9% in the putamen, 32+/-8% in the thalamus, 25+/-8% in the cortex, and 23+/-10% in the hippocampus. With donepezil, 18F-(-)-NCFHEB VT /fP was reduced by 24+/-2%, 14+3% and 14+/-5%, 10+/ 6% in the same regions. CONCLUSION: 18F-(-)-NCFHEB can be used to detect changes in synaptic acetylcholine concentration and is a promising tracer to study acetylcholine dynamics with shorter scan durations than previous radioligands. PMID- 25043428 TI - Composition effect on intrinsic plasticity or brittleness in metallic glasses. AB - The high plasticity of metallic glasses is highly desirable for a wide range of novel engineering applications. However, the physical origin of the ductile/brittle behaviour of metallic glasses with various compositions and thermal histories has not been fully clarified. Here we have found that metallic glasses with compositions at or near intermetallic compounds, in contrast to the ones at or near eutectics, are extremely ductile and also insensitive to annealing-induced embrittlement. We have also proposed a close correlation between the element distribution features and the plasticity of metallic glasses by tracing the evolutions of the element distribution rearrangement and the corresponding potential energy change within the sliding shear band. These novel results provide useful and universal guidelines to search for new ductile metallic glasses at or near the intermetallic compound compositions in a number of glass-forming alloy systems. PMID- 25043429 TI - Students 4 Best Evidence: a new way of engaging the younger generation in evidence-based health care. PMID- 25043430 TI - Cognitive-behaviour therapy and schizophrenia. AB - People who experience debilitating psychotic symptoms that affect their everyday life are often, but not always, given a diagnosis of schizophrenia. Although the first line of treatment is medication, many people experience a suboptimal response and after the acute symptoms resolve they can continue to experience both hallucinations and delusions. These are generally termed residual symptoms and are the phenomena that cognitive-behavioural therapy for psychosis (CBTp) was originally devised to target. The success of CBTp in randomised controlled trials from the early 90s and evidence of cost-effectiveness has meant that many healthcare services across the world include CBTp in their treatment armamentaria. For instance, in the UK the National Institute for Health and Care Excellence guidance says that all individuals who have a diagnosis of schizophrenia should be given the option of a course of CBTp. Recently, however, the treatment effects have been re-examined, the targets widened and the premise that CBTp should be solely an adjunct to medication has been questioned. This article will describe and probe some of these changes and reflect on the development of psychological treatments for psychosis. PMID- 25043431 TI - Among untreated violent offenders with schizophrenia, persecutory delusions are associated with violent recidivism. PMID- 25043433 TI - Prognosis of a brief psychotic episode. PMID- 25043432 TI - Mental health problems in young people with experiences of homelessness and the relationship with health service use: a follow-up study. AB - BACKGROUND: Homeless young people represent one of the most vulnerable and underserved populations. OBJECTIVE: To assess the prevalence of psychiatric disorder and comorbidity among a UK sample, and examine the longitudinal relationship between psychiatric conditions and different types of health service use. METHODS: 90 young people with experiences of homelessness were interviewed using a full psychiatric assessment. Participants were followed up 8-12 months later and completed an interview that included information about recent health service use (mental health, emergency room, general practitioner, hospital for physical problems, drug or alcohol services). FINDINGS: The prevalence of psychiatric disorder (88% current; 93% lifetime) and psychiatric comorbidity (73%) was high and that of mental health service use low in comparison (31%). Mood disorders, psychosis and suicide risk were significantly associated with mental health service use (OR 5.21, 95% CI 1.64 to 16.58; OR 10.0, CI 1.58 to 94.58; OR 6.25, CI 1.82 to 21.43, respectively). Emergency department use was predicted by mood disorders (OR 5.19, CI 1.68 to 16.0), psychosis (OR 7.33, CI 1.24 to 43.29), anxiety disorder (OR 2.88, CI 1.04 to 7.97), high-suicide risk (OR 3.42, CI 1.86 to 13.67) and comorbidity (OR 1.41, CI 1.05 to 1.90). DISCUSSION AND CLINICAL IMPLICATIONS: The prevalence of psychiatric disorders in homeless young people was high and considerably higher than that reported for this age group in the general population. There is a need for improved uptake of services delivering longer term treatment of psychiatric problems among vulnerable groups of socially excluded young people. PMID- 25043434 TI - Relapse with oral antipsychotics versus long-acting injectable antipsychotics: new paradoxical findings. PMID- 25043436 TI - Comparing a 5-month trial of enhanced cognitive behavioural therapy to a 24-month trial of psychoanalytic psychotherapy for the treatment of bulimia nervosa. PMID- 25043437 TI - Dismantling mindfulness-based cognitive therapy for recurrent depression implicates lack of differential efficacy for mindfulness training. PMID- 25043438 TI - Reports of recovery in chronic fatigue syndrome may present less than meets the eye. PMID- 25043439 TI - The air temperature may affect ophthalmologic emergency attendances. PMID- 25043440 TI - Damage behavior and atomic migration in MgAl2O4 under an 80 keV scanning focused probe in a STEM. AB - With the dramatic improvement in the spatial resolution of scanning transmission electron microscopes over the past few decades, the tolerance of a specimen to the high-energy electron beam becomes the limiting factor for the quality of images and spectra obtained. Therefore, a deep understanding of the beam irradiation processes is crucial to extend the applications of electron microscopy. In this paper, we report the structural evolution of a selected oxide, MgAl2O4, under an 80 keV focused electron probe so that the beam irradiation process is not dominated by the knock-on mechanism. The formation of peroxyl bonds and the assisted atomic migration were studied using imaging and electron energy-loss spectroscopic techniques. PMID- 25043441 TI - Evaluation of heat-shock protein A2 (HSPA2) in male rats before and after varicocele induction. AB - Varicocele is a major cause of infertility and may impair spermatogenesis. This study evaluated the molecular consequences of varicocele on the induction of heat shock proteins, intracellular chaperones involved in stress responses, and of the ubiquitin-proteasome system, which is participates in the removal of defective sperm in the testis and epididymis. Wistar rats were randomly divided into three groups: surgically induced left varicocele, sham-operated, and untreated controls. Two months after surgery, we observed significantly reduced sperm parameters, DNA integrity, and protamine content in the sperm retrieved from the left epididymis compared to the right epididymis in the varicocele group, as well as compared to sperm retrieved from the left epididymis of the sham and control groups. According to Western blot analysis, we observed significantly higher HSPA2 expression in testicular tissue from the left testis compared to the right testis in the varicocele group or the left testis of the control group. Immunohistochemical analysis showed that expression of HSPA2 was higher in the round spermatid and sperm from the left varicocele compared to the control group. There was normally less HSPA2 expressed in the caput and corpus compared to the cauda of the epididymis in the control group, but this pattern was altered in the caput epididymis of the varicocele group. Levels of ubiquitination were also remarkably lower in the left testis of the varicocele group. Therefore, varicocele impacts expression of HSPA2 and ubiquitination. PMID- 25043442 TI - Surgery followed by radiosurgery: a deliberate valuable strategy in the treatment of intracranial meningioma. AB - OBJECTIVE: The aim of our study is to show that surgery followed by Gamma Knife Radiosurgery is an effective and safe combined treatment for the control of intracranial meningiomas located close to critical structures. MATERIALS AND METHODS: This retrospective study followed 31 patients with intracranial meningioma between 2005 and 2010. We included patients when initial therapeutic decision was deliberate subtotal surgical resection preparing a target for early postoperative GKR. Early MRI was performed to evaluate the tumor residual volume after surgical procedure. Annual MRI was performed to detect any tumor progression. RESULTS: The mean follow-up was 4.5 years. The mean margin dose was 14.5 Gy and the mean target volume was 2.4 cm3. The mean progression free survival after combined treatment was 4.4 years in the irradiated target volume and 3.9 years on the limit or remotely of irradiated target volume. Of all patients, we recorded 5 tumor progressions after combined treatment, in-field in 1 case and out-of-field in 4 cases. All tumor progressions were high-grade meningiomas. CONCLUSION: Surgery followed by radiosurgery is a safe and effective combined treatment for intracranial meningiomas. We recommend it in case of meningioma located close to critical structures for which it is safer to leave in place a tumor remnant to reduce morbidity. PMID- 25043443 TI - Effects of external cues on gait parameters of Parkinson's disease patients: a systematic review. AB - OBJECTIVES: A systematic review to evaluate the benefits of external cues on the gait of PD patients and their impact on the quality of life, freezing and psychomotor performance was performed. The types of cues that could lead to more significant gains were analyzed. METHODS: We searched for randomized clinical trials (RCTs) and quasi-randomized clinical trial (QRCTs) that assessed the influence of different external cues on gait, freezing, quality of life and psychomotor performance. RESULTS: Of 259 articles collected, seven (six RCTs and one QRCT) were included in the methodological quality criteria (two consider visual cues, two consider auditory cues, one considers verbal instructions, one considers combined cues and one considers sensory cues). All of the data regarding the methodology, interventions, population and bias were described. Cues generally led to a statistically significant improvement in the step and stride length, speed of gait, cadence and UPDRS. None of these studies assessed the quality of life, and one study analyzed freezing. CONCLUSION: Our review could show that external cues are effective for improving the gait parameters and psychomotor performance of PD patients. We need more studies to verify if the impact of this type of treatment could improve the quality of life of patients with PD. PMID- 25043446 TI - Outstanding chiroptical properties: a signature of enantiomerically pure alleno acetylenic macrocycles and monodisperse acyclic oligomers. AB - A second series of shape-persistent alleno-acetylenic macrocycles and monodisperse acyclic oligomers with conformationally less flexible backbones were synthesized in enantiomerically pure form by short, high-yielding routes starting from optically active 1,3-diethynylallenes. All seven stereoisomers-two pairs of enantiomers and three achiral stereoisomers-in the macrocyclic series were separated and configurationally assigned. The electronic circular dichroism (ECD) spectra of the D2 -symmetric, (P,P,P,P)- and (M,M,M,M)-configured macrocycles display remarkably intense chiroptical responses. A strong amplification of chirality is observed in the acyclic oligomeric series. Their preference for helical secondary structures of one handedness was supported by X-ray analysis and computational studies. This new set of data provides proof that outstanding ECD responses are a hallmark of alleno-acetylenic macrocyclic and acyclic oligomeric chromophores. PMID- 25043445 TI - Up-scaling clinician assisted internet cognitive behavioural therapy (iCBT) for depression: A model for dissemination into primary care. AB - Depression is a global health problem but only a minority of people with depression receive even minimally adequate treatment. Internet delivered automated cognitive behaviour therapy (iCBT) which is easily distributed and in which fidelity is guaranteed could be one solution to the problem of increasing coverage. In this review of iCBT for Major Depressive Disorder in adults, we address the concerns of clinicians in utilizing this technology by reviewing the research evidence with reference to efficacy and effectiveness and presenting a model for dissemination and uptake of iCBT into practice. This review includes studies of participants who would meet criteria for major depressive disorder who were supported as they learnt and implemented changes in thoughts, emotions and behaviours by using cognitive behaviour principles. We conclude that this form of treatment is effective and acceptable to both patients and clinicians. PMID- 25043444 TI - Clinical effectiveness and safety of tazobactam/piperacillin 4.5 g for the prevention of febrile infectious complication after prostate biopsy. AB - We investigated the clinical effectiveness and safety of tazobactam/piperacillin (TAZ/PIPC) in a 1:8 ratio, a beta-lactamase inhibitor with penicillin antibiotic, for the prevention of febrile infectious complication after prostate biopsy. Each patient received a single dose of TAZ/PIPC 4.5 g, 30 min before the biopsy in Group 1 or TAZ/PIPC 4.5 g twice, once 30 min before and once after the biopsy (just before discharge or 5 h after the biopsy), in Group 2. Estimation of efficacy was performed within 1-month after prostate biopsy. Clinical diagnosis of febrile infectious complication was based on a body temperature elevation greater than 38 degrees C. Infectious complication after prostate biopsy was detected in 2.5% (4/160 patients) in Group 1 and in 0.45% (2/442 patients) in Group 2. All of the patients with febrile infectious complication had risk factors: 5 patients had voiding disturbance, 2 patients had diabetes mellitus and 1 patient had steroid dosing. In group 1, 88 patients had at least one risk factor and 72 patients had no risk factors. Of the patients with a risk factor, 4 had febrile infectious complication after prostate biopsy, but there was no significant difference between the two groups. In group 2, 87 patients had at least one risk factor and 255 patients had no risk factors. The patients with a risk factor had febrile infectious complication significantly more frequently than did patients without a risk factor (P = 0.038). Therefore, TAZ/PIPC appears to be effective as preoperative prophylaxis against the occurrence of febrile infectious complication after prostate biopsy. PMID- 25043447 TI - Is scratch-cooking a cost-effective way to prepare healthy school meals with US Department of Agriculture foods? AB - BACKGROUND: Despite the resurgence of interest in scratch-cooking as a way to increase the quality and appeal of school meals, many school districts are concerned about the cost implications of switching to scratch-cooking. US Department of Agriculture (USDA) Foods are the single largest source of ingredients for school meals, and about half of USDA Foods are diverted for processing before being sent to the school district. OBJECTIVE: We aimed to determine whether school lunch entrees made in a district from basic or raw USDA Foods ingredients can be healthier and less expensive to prepare than those sent to external processors. DESIGN/SETTING: This cross-sectional study examined the relationship between the extent of scratch-cooking and the nutritional content and cost to prepare entrees. Information was gathered by interview with school foodservice personnel and from school foodservice records from a convenience sample of 10 school districts in California that employed varying degrees of scratch-cooking and is diverse in terms of geographic location and the sociodemographics of the student body. The sample included all elementary school lunch entrees that contain USDA Foods offered during October 2010 for a total sample of 146 entrees. STATISTICAL ANALYSES: Ordinary least squares regressions were used to test for statistically significant differences in cost and nutrient content of entrees according to the level of scratch-cooking. RESULTS: There was no significant relationship between total costs and level of scratch-cooking. Entrees with the highest scratch-cooking scores had significantly lower food costs, higher labor costs, and not significantly different total costs compared with entrees with no scratch-cooking. Nutrient content was not consistently associated with scratch-cooking, but scratch-cooked entrees did include a larger variety of non-fast-food-type entrees. CONCLUSIONS: The findings suggest that scratch-cooking can be a cost-effective way to expand the variety of healthy school lunches prepared with USDA Foods. PMID- 25043448 TI - Mastoidectomy performance assessment of virtual simulation training using final product analysis. AB - OBJECTIVES/HYPOTHESIS: The future development of integrated automatic assessment in temporal bone virtual surgical simulators calls for validation against currently established assessment tools. This study aimed to explore the relationship between mastoidectomy final-product performance assessment in virtual simulation and traditional dissection training. STUDY DESIGN: Prospective trial with blinding. METHODS: A total of 34 novice residents performed a mastoidectomy on the Visible Ear Simulator and on a cadaveric temporal bone. Two blinded senior otologists assessed the final-product performance using a modified Welling scale. The simulator gathered basic metrics on time, steps, and volumes in relation to the on-screen tutorial and collisions with vital structures. RESULTS: Substantial inter-rater reliability (kappa = 0.77) for virtual simulation and moderate inter-rater reliability (kappa = 0.59) for dissection final-product assessment was found. The simulation and dissection performance scores had significant correlation (P = .014). None of the basic simulator metrics correlated significantly with the final-product score except for number of steps completed in the simulator. CONCLUSIONS: A modified version of a validated final-product performance assessment tool can be used to assess mastoidectomy on virtual temporal bones. Performance assessment of virtual mastoidectomy could potentially save the use of cadaveric temporal bones for more advanced training when a basic level of competency in simulation has been achieved. LEVEL OF EVIDENCE: NA. PMID- 25043450 TI - Reconstruction of distal lower extremities defect using the free peroneal artery perforator vessel based flap. AB - Soft tissue defects of the distal lower extremities are challenging. The purpose of this paper is to present our experiences with the free peroneal artery perforator flap for the reconstruction of soft tissue defects of the distal lower extremity. Nine free peroneal artery perforator flaps were used to reconstruct soft tissue defects of the lower extremities between April 2006 and October 2011. All flaps were used for distal leg and foot reconstruction. Peroneal artery perforator flaps ranged in size from 2 cm * 4 cm to 6 cm * 12 cm. The length of the vascular pedicle ranged from 2 to 6 cm. Recipient vessels were: medial plantar vessels in seven cases, the dorsalis pedis vessel in one, metatarsal vessel in one. All flaps survived completely, a success rate of 100%. Advantages of this flap are that there is no need to sacrifice any main artery in the lower leg, and minimal morbidity at the donor site. This free perforator flap may be useful for patients with small to medium soft tissue defects of the distal lower extremities and feet. PMID- 25043449 TI - Eating habits modulate short term memory and epigenetical regulation of brain derived neurotrophic factor in hippocampus of low- and high running capacity rats. AB - Exercise capacity and dietary restriction (DR) are linked to improved quality of life, including enhanced brain function and neuro-protection. Brain derived neurotrophic factor (BDNF) is one of the key proteins involved in the beneficial effects of exercise on brain. Low capacity runner (LCR) and high capacity runner (HCR) rats were subjected to DR in order to investigate the regulation of BDNF. HCR-DR rats out-performed other groups in a passive avoidance test. BDNF content increased significantly in the hippocampus of HCR-DR groups compared to control groups (p<0.05). The acetylation of H3 increased significantly only in the LCR-DR group. However, chip-assay revealed that the specific binding between acetylated histone H3 and BNDF promoter was increased in both LCR-DR and HCR-DR groups. In spite of these increases in binding, at the transcriptional level only, the LCR DR group showed an increase in BDNF mRNA content. Additionally, DR also induced the activity of cAMP response element-binding protein (CREB), while the content of SIRT1 was not altered. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) was elevated in HCR-DR groups. But, based on the levels of nuclear respiratory factor-1 and cytocrome c oxidase, it appears that DR did not cause mitochondrial biogenesis. The data suggest that DR-mediated induction of BDNF levels includes chromatin remodeling. Moreover, DR does not induce mitochondrial biogenesis in the hippocampus of LCR/HCR rats. DR results in different responses to a passive avoidance test, and BDNF regulation in LCR and HCR rats. PMID- 25043451 TI - (G12D) NRAS and kinase-dead BRAF cooperate to drive naevogenesis and melanomagenesis. PMID- 25043452 TI - Trachoma. AB - Trachoma is the most common infectious cause of blindness. Repeated episodes of infection with Chlamydia trachomatis in childhood lead to severe conjunctival inflammation, scarring, and potentially blinding inturned eyelashes (trichiasis or entropion) in later life. Trachoma occurs in resource-poor areas with inadequate hygiene, where children with unclean faces share infected ocular secretions. Much has been learnt about the epidemiology and pathophysiology of trachoma. Integrated control programmes are implementing the SAFE Strategy: surgery for trichiasis, mass distribution of antibiotics, promotion of facial cleanliness, and environmental improvement. This strategy has successfully eliminated trachoma in several countries and global efforts are underway to eliminate blinding trachoma worldwide by 2020. PMID- 25043453 TI - Dixon-type and subtraction-type contrast-enhanced magnetic resonance angiography: A theoretical and experimental comparison of SNR and CNR. AB - PURPOSE: The purpose of this work is to compare the behavior of the signal-to noise ratio (SNR) and contrast-to-noise ratio (CNR) in contrast-enhanced MR angiography with background suppression performed by either a Dixon-type or subtraction-type method. THEORY AND METHODS: Theoretical expressions for the SNR and CNR for both background suppression techniques were derived. The theoretical Dixon:subtraction SNR and CNR ratios were compared to empirical ratios measured from phantom and in vivo studies for Dixon techniques utilizing one, two, and three echoes. Specifically, the SNR and CNR ratios were compared as the concentration of contrast material in the blood changed. RESULTS: Empirical measurements of the SNR and CNR ratios compared favorably with the ratios predicted by theory. As the contrast concentration was reduced, the SNR advantage of the Dixon techniques increased asymptotically. In the ideal case, the SNR improvement over subtraction contrast-enhanced MR angiography was at least twofold for one- and two-echo Dixon techniques and at least a factor of 6 for the three-echo Dixon technique. CONCLUSION: Expressions showing a contrast concentration-dependent SNR and CNR improvement of at least a factor of two when Dixon-type contrast-enhanced MR angiography is used in place of subtraction-type contrast-enhanced MR angiography were derived and validated with phantom and in vivo experiments. Magn Reson Med 74:81-92, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25043454 TI - Application of the Bang and Ramm age at death estimation method to two known-age archaeological assemblages. AB - The Bang and Ramm method uses root dentine translucency (RDT) length in sectioned or unsectioned teeth as a sole indicator of chronological age at death in adult human remains. The formulae have been tested on modern remains of known age and on modern and archaeological remains of unknown age. This is the first published study of the method on known-age archaeological specimens and tests whether RDT is a good indicator of chronological age in buried human remains. We applied the Bang and Ramm equations to two 18th and 19th century assemblages excavated from the crypt of Christ Church, Spitalfields, and the cemetery of All Hallows by the Tower. Translucency was defined by shining a light through the external unsectioned root surface and was measured from digital images of 583 and 83 nonmolar roots from 126 Spitalfields and 12 All Hallows individuals, respectively, aged 21-81 years. Average absolute difference between real age and estimated age was 10.7 years and 8.4 years for Spitalfields and All Hallows individuals, respectively, with 58% and 75% estimated within 10 years of known age, and 29% and 33% estimated within five years of known age. These estimations are comparable to results from other ageing methods applied to the Spitalfields collection. Ages from both populations were estimated largely to the middle ranges, with younger individuals overestimated and older individuals underestimated. This is a common occurrence when using inverse calibration, where age is treated as the dependent variable and the ageing feature as the independent variable. PMID- 25043455 TI - Association between urinary cadmium levels and prediabetes in the NHANES 2005 2010 population. AB - Evidence suggests an association between exposure to cadmium and dysglycemia. To investigate this matter, we examined the relationship between urinary cadmium and prediabetes in the cross sectional National Health and Nutrition Examination Survey (NHANES). NHANES participants for the years 2005 through 2010 aged >= 40 years were included in the analysis. Participants with nephropathy, overt diabetes, or missing required data were excluded. To assess the non-linear relationship between cadmium and Prediabetes, non-parametric logistic regression with B spline expansion of urinary cadmium/creatinine ratio was performed. This analysis revealed a complex non-linear association between higher cadmium levels and prediabetes. This relationship persisted, though with varying magnitudes across smoking groups (never smokers, moderate smokers, heavy smokers). In a conventional logistic regression analysis, this relationship was less evident with significantly increased OR for prediabetes was found in the highest quintile of urine cadmium compared to the lowest quintile in the overall population and in moderate smokers. In an age stratified analysis, a significant linear association was found only in the age groups 60-69 and >= 70. We conclude that there is a significant non-linear, complex relationship between urinary Cd levels, age, smoking habits and odds of prediabetes. PMID- 25043456 TI - Blood lead concentration and related factors in Korea from the 2008 National Survey for Environmental Pollutants in the Human Body. AB - This study evaluated blood lead concentrations in the Korean general population and the correlation between various exposure sources using data from the 2008 Korea National Survey for Environmental Pollutants in the Human Body (National Institute of Environmental Research, Korea). The general and occupational characteristics were gathered from 5136 participants who were 20 years of age and older using a structured questionnaire. Blood lead concentrations were analyzed using an atomic absorption spectrophotometer. Statistical analysis was performed using multiple linear regressions of the log lead concentrations to the independent variables such as age, gender, smoke, herbal medication and drug consumption, drinking water, and living area. Geometric mean (GM) blood lead concentrations in Korean adults were 19.7 MUg/l. The blood lead concentrations increased with age; the highest concentrations were found in the 50-69-year age group (p<0.001). Males were higher than in females (p<0.001). Current smokers and drinkers had higher concentrations than nonsmokers (p<0.001) and nondrinkers (p<0.001), respectively. People who took herbal medication and drug consumption were higher than those who did not (p<0.001). Education level was negatively associated with blood lead concentration (p<0.001). People living in or around industrial areas had elevated blood lead concentration (p<0.001). Family income was also negatively associated with lead concentration, but not significantly. For drinking water, the underground water (spring or well water) drinking group had higher concentrations than other types of water drinking groups, but not significantly (p=0.063). The blood lead concentrations by occupation were significant (p<0.034): the highest was in laborer and Agricultural-Fishery Forestry and the lowest in office workers. In women, blood lead concentrations tended to decrease with increasing delivery times, but not significantly. The blood lead concentration (GM) of the general adult population in Korea has decreased over time from 45.8 MUg/l (1999) to 19.7 MUg/l (2008). Although it is still higher than in other countries such as the United States and Canada, it is rapidly decreasing. Gender, age, smoking and alcohol drinking status, herbal medication and drug consumption, education level, living area and occupation were significantly related to the blood lead concentrations in Korea. PMID- 25043457 TI - A model measuring therapeutic inertia and the associated factors among diabetes patients: A nationwide population-based study in Taiwan. AB - This article presents an analysis conducted on the patterns related to therapeutic inertia with the aim of uncovering how variables at the patient level and the healthcare provider level influence the intensification of therapy when it is clinically indicated. A cohort study was conducted on 899,135 HbA1c results from 168,876 adult diabetes patients with poorly controlled HbA1c levels. HbA1c results were used to identify variations in the prescription of hypoglycemic drugs. Logistic regression and hierarchical linear models (HLMs) were used to determine how differences among healthcare providers and patient characteristics influence therapeutic inertia. We estimated that 38.5% of the patients in this study were subject to therapeutic inertia. The odds ratio of cardiologists choosing to intensify therapy was 0.708 times that of endocrinologists. Furthermore, patients in medical centers were shown to be 1.077 times more likely to be prescribed intensified treatment than patients in primary clinics. The HLMs presented results similar to those of the logistic model. Overall, we determined that 88.92% of the variation in the application of intensified treatment was at the within-physician level. Reducing therapeutic inertia will likely require educational initiatives aimed at ensuring adherence to clinical practice guidelines in the care of diabetes patients. PMID- 25043458 TI - Occurrence and quantitative microbial risk assessment of Cryptosporidium and Giardia in soil and air samples. AB - BACKGROUND: Cryptosporidium oocysts and Giardia cysts can be transmitted by the fecal-oral route and may cause gastrointestinal parasitic zoonoses. These zoonoses are common in rural zones due to the parasites being harbored in fecally contaminated soil. This study assessed the risk of illness (giardiasis and cryptosporidiosis) from inhaling and/or ingesting soil and/or airborne dust in Potam, Mexico. METHODS: To assess the risk of infection, Quantitative Microbial Risk Assessment (QMRA) was employed, with the following steps: (1) hazard identification, (2) hazard exposure, (3) dose-response, and (4) risk characterization. RESULTS: Cryptosporidium oocysts and Giardia cysts were observed in 52% and 57%, respectively, of total soil samples (n=21), and in 60% and 80%, respectively, of air samples (n=12). The calculated annual risks were higher than 9.9 * 10(-1) for both parasites in both types of sample. CONCLUSIONS: Soil and air inhalation and/or ingestion are important vehicles for these parasites. To our knowledge, the results obtained in the present study represent the first QMRAs for cryptosporidiosis and giardiasis due to soil and air inhalation/ingestion in Mexico. In addition, this is the first evidence of the microbial air quality around these parasites in rural zones. PMID- 25043460 TI - Cobalt orthosilicate as a new electrode material for secondary lithium-ion batteries. AB - Herein, cobalt orthosilicate (Co2SiO4, CSO) is presented as a new electrode material for rechargeable lithium-ion batteries. Orthorhombic alpha-Co2SiO4 (space group: Pbnm) was synthesized by a conventional solid-state method and subsequently characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM). To study the reversible lithium uptake and release, cyclic voltammetry (CV), in situ XRD, as well as ex situ X-ray photoelectron spectroscopy (XPS) and SEM analysis were performed. Based on these results a new reaction mechanism is proposed including the reversible formation of lithium silicate. In addition, the electrochemical performance of CSO-based electrodes was investigated by galvanostatic cycling, applying varying specific currents. Such electrodes revealed a good high rate capability and a highly reversible cycling behavior, providing a specific capacity exceeding 650 mAh g(-1) after 60 cycles. PMID- 25043459 TI - Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT Study. AB - Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high-resolution peripheral quantitative computed tomography (HR-pQCT) assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive teriparatide 20 ug daily (n = 31), denosumab 60 mg every 6 months (n = 33), or both (n = 30) for 12 months. In the teriparatide group, total volumetric bone mineral density (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1 +/- 2.2%) than both the denosumab (2.2 +/- 1.9%) and teriparatide groups (-0.3 +/- 1.9%) (p < 0.02 for both comparisons). Cortical vBMD decreased by 1.6 +/- 1.9% at the tibia and by 0.9 +/- 2.8% at the radius in the teriparatide group, whereas it increased in both other groups at both sites. Tibia cortical vBMD increased more in the combination group (1.5 +/- 1.5%) than both monotherapy groups (p < 0.04 for both comparisons). Cortical thickness did not change in the teriparatide group but increased in both other groups. The increase in cortical thickness at the tibia was greater in the combination group (5.4 +/- 3.9%) than both monotherapy groups (p < 0.01 for both comparisons). In the teriparatide group, radial cortical porosity increased by 20.9 +/- 37.6% and by 5.6 +/- 9.9% at the tibia but did not change in the other two groups. Bone stiffness and failure load, as estimated by finite element analysis, did not change in the teriparatide group but increased in the other two groups at both sites. Together, these findings suggest that the use of denosumab and teriparatide in combination improves HR-pQCT measures of bone quality more than either drug alone and may be of significant clinical benefit in the treatment of postmenopausal osteoporosis. PMID- 25043461 TI - Semisynthesis of a post-translationally modified protein by using chemical cleavage and activation of an expressed fusion polypeptide. AB - Herein, we describe a new semisynthetic strategy of a post-translationally modified protein in which the middle region is glycosylated. We designed a single plasmid coding for a fusion polypeptide, which can provide both an N-terminal alpha-thioester and a C-terminal cysteine peptide of a target glycoprotein by using chemical-cleavage and activation methods. The use of these resultant peptide derivatives resulted in the successful synthesis of N-glycosylated interleukin 13. PMID- 25043462 TI - A universal method for preparation of noble metal nanoparticle-decorated transition metal dichalcogenide nanobelts. AB - MoS2, TaS2, TiS2, WSe2 and TaSe2 nanobelts decorated with a PtAg alloy or Pt NPs have been successfully synthesized by etching 2D nanosheets under a mild reaction condition followed by a subsequent nanosheet-to-nanobelt transformation mediated by the PVP template. The PtAg-MoS2 hybrid nanobelt coated with PVP is used as the active material in a memory device, which exhibits hysteresis behavior with the function of dynamic random access memory. PMID- 25043463 TI - Client priorities and satisfaction with community pharmacies: the situation in Tehran. AB - BACKGROUND: Client satisfaction is an important criterion to evaluate pharmacy services. In addition, knowledge about client satisfaction can be helpful to identify strengths and weaknesses which can be used to improve health services. OBJECTIVE: The aim of this study was to assess clients' priorities and satisfaction with community pharmacy services in Tehran. SETTING: This study was conducted on clients visiting community pharmacies settled in Tehran, the capital city of Iran. METHOD: A cross-sectional descriptive study involving clients of community pharmacies was undertaken using a self-administrated anonymous questionnaire. Data were collected from 800 clients of 200 community pharmacies settled in 22 districts of Tehran. MAIN OUTCOMES MEASURE: Clients' satisfaction with four areas including community pharmacies physical space, relationship quality, consultation quality and other dimensions of service delivery, and clients' priorities about different issues related to community pharmacies. RESULTS: The study showed that client satisfaction regarding the four mentioned areas (relationship quality, physical space, consultation quality and other dimensions of service delivery) was more than the average of Likert scale (cut point = 3). However, satisfaction with consultations is not much higher than the mentioned cut point. Moreover, "observing courtesy and respect" and "computerized dispensing" showed the most and the least priority to respondents, respectively. CONCLUSION: According to the findings, it seems that a wide range of corrective actions can be performed to promote the level of client satisfaction especially in case of consultations. More importantly, clients' needs and priorities should be taken into account to select and prioritize these actions. PMID- 25043465 TI - Cost-effectiveness analysis of new drugs for chronic hepatitis C: the importance of updating utility values. PMID- 25043467 TI - Research misconduct involving noncompliance in human subjects research supported by the public health service: reconciling separate regulatory systems. PMID- 25043464 TI - PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. AB - OBJECTIVE: Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family-based approach that can detect robust associations with infrequent variants (minor allele frequency < 0.10). METHODS: We conducted a genome-wide association study in the Framingham Heart Study (discovery) and NIA-LOAD (National Institute on Aging-Late-Onset Alzheimer Disease) Study (replication) family-based cohorts using an approach that accounts for family structure and calculates a risk score for AD as the outcome. Links between the most promising gene candidate and AD pathogenesis were explored in silico as well as experimentally in cell-based models and in human brain. RESULTS: Genome-wide significant association was identified with a PLXNA4 single nucleotide polymorphism (rs277470) located in a region encoding the semaphorin-3A (SEMA3A) binding domain (meta-analysis p value [meta-P] = 4.1 * 10( 8) ). A test for association with the entire region was also significant (meta-P = 3.2 * 10(-4) ). Transfection of SH-SY5Y cells or primary rat neurons with full length PLXNA4 (TS1) increased tau phosphorylation with stimulated by SEMA3A. The opposite effect was observed when cells were transfected with shorter isoforms (TS2 and TS3). However, transfection of any isoform into HEK293 cells stably expressing amyloid beta (Abeta) precursor protein (APP) did not result in differential effects on APP processing or Abeta production. Late stage AD cases (n = 9) compared to controls (n = 5) had 1.9-fold increased expression of TS1 in cortical brain tissue (p = 1.6 * 10(-4) ). Expression of TS1 was significantly correlated with the Clinical Dementia Rating score (rho = 0.75, p = 2.2 * 10(-4) ), plaque density (rho = 0.56, p = 0.01), and Braak stage (rho = 0.54, p = 0.02). INTERPRETATION: Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform-specific effects on tau phosphorylation. PMID- 25043468 TI - Why guidance comes from the research community. Commentary. PMID- 25043469 TI - The irregular terrain of human subjects research regulations. Commentary. PMID- 25043470 TI - The third-party notification dilemma. Commentary. PMID- 25043471 TI - Parallel processes at the NIH. Commentary. PMID- 25043472 TI - Public trust and institutional culture. Commentary. PMID- 25043473 TI - The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. AB - How epithelial progenitor cells integrate local signals to balance expansion with differentiation during organogenesis is still little understood. Here, we provide evidence that the Hippo pathway effector Yap is a key regulator of this process in the developing lung. We show that when epithelial tubules are forming and branching, a nucleocytoplasmic shift in Yap localization marks the boundary between the airway and the distal lung compartments. At this transition zone, Yap specifies a transcriptional program that controls Sox2 expression and ultimately generates the airway epithelium. Without Yap, epithelial progenitors are unable to properly respond to local TGF-beta-induced cues and control levels and distribution of Sox2 to form airways. Yap levels and subcellular localization also markedly influence Sox2 expression and differentiation of adult airway progenitors. Our data reveal a role for the Hippo-Yap pathway in integrating growth-factor-induced cues in the developing and adult lung potentially key for homeostasis and regeneration repair. PMID- 25043475 TI - Is early treatment of disseminated intravascular coagulation beneficial in septic patients? PMID- 25043474 TI - Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. AB - Our understanding of how stem cells are regulated to maintain appropriate tissue size and architecture is incomplete. We show that Yap (Yes-associated protein 1) is required for the actual maintenance of an adult mammalian stem cell. Without Yap, adult airway basal stem cells are lost through their unrestrained differentiation, resulting in the simplification of a pseudostratified epithelium into a columnar one. Conversely, Yap overexpression increases stem cell self renewal and blocks terminal differentiation, resulting in epithelial hyperplasia and stratification. Yap overexpression in differentiated secretory cells causes them to partially reprogram and adopt a stem cell-like identity. In contrast, Yap knockdown prevents the dedifferentiation of secretory cells into stem cells. We then show that Yap functionally interacts with p63, the cardinal transcription factor associated with myriad epithelial basal stem cells. In aggregate, we show that Yap regulates all of the cardinal behaviors of airway epithelial stem cells and determines epithelial architecture. PMID- 25043476 TI - Long-term HPV type-specific risks of high-grade cervical intraepithelial lesions: a 14-year follow-up of a randomized primary HPV screening trial. AB - Quantitative knowledge of the long-term human papillomavirus (HPV) type-specific risks for high-grade cervical intraepithelial neoplasias Grades 2 and 3 (CIN2 and CIN3) is useful for estimating the effect of elimination of specific HPV types and clinical benefits of screening for specific HPV types. We estimated HPV type specific risks for CIN2 and CIN3 using a randomized primary HPV screening trial followed up for 14.6 years using comprehensive, nationwide registers. Poisson regression estimated cumulative incidences, population attributable proportions (PAR) and incidence rate ratios (IRRs) of high-grade lesions by baseline HPV type, with censoring at date of first CIN2/3 or last registered cytology. Multivariate analysis adjusted for coinfections. IRRs were highest during the first screening round, but continued to be high throughout follow-up (IRRs for CIN3 associated with high-risk (HR) HPV positivity were 226.9, 49.3, 17.7 and 10.3 during the first, second and third screening round and for >9 years of follow-up, respectively). Increased long-term risks were found particularly for HPV Types 16, 18 and 31 and for CIN3+ risks. HPV16/18/31/33 had 14-year cumulative incidences for CIN3+ above 28%, HPV35/45/52/58 had 14 year risks between 14% and 18% and HPV39/51/56/59/66/68 had risks <10%. HPV16 contributed to the greatest proportion of CIN2+ (first round PAR 36%), followed by Types 31, 52, 45 and 58 (7-11%). HPV16/18/31/33/45/52/58 together contributed 73.9% of CIN2+ lesions and all HR types contributed 86.9%. In summary, we found substantial differences in risks for CIN2 and CIN3 between different oncogenic HPV types. These differences may be relevant for both clinical management and design of preventive strategies. PMID- 25043478 TI - Protein tyrosine phosphatase receptor R and Z1 expression as independent prognostic indicators in oral squamous cell carcinoma. AB - BACKGROUND: The actions of tyrosine phosphorylation and dephosphorylation are controlled by tyrosine kinases and phosphatases. Although substantial previous data have revealed the role of several protein tyrosine phosphatases (PTPs) in various cancers, the function of protein tyrosine phosphatase receptor R (PTPRR) and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1) proteins in oral cavity squamous cell carcinoma (SCC) has not been studied to date. METHODS: The PTPRR and PTPRZ1 immunoreactivity in 67 formalin-fixed and paraffin-embedded oral cancer tissues at different stages were analyzed with the technique of immunohistochemistry (IHC). The presence of PTPRR in cancerous tissue was confirmed by Western blotting. RESULTS: The occurrence of PTPRR and PTPRZ1 proteins in the cancer specimens was more frequent in lower grade tumors. In addition, the association between the immunoreactivity of both examined proteins and improved patients survival was detected. Moreover, the PTPRR expression was found to be related to the absence of synchronous lymph node involvement. CONCLUSION: The above results indicate that the PTPRR and PTPRZ1 protein expression should be monitored in oral cancer for patients' prognostic stratification. PMID- 25043477 TI - The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. AB - The serotonin receptor 5-HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors that modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders. PMID- 25043479 TI - Detoxification of oxidative stress in glioma stem cells: mechanism, clinical relevance, and therapeutic development. AB - Neural oncogenesis is currently incurable and invariably lethal. The development of innovative treatments for this devastating cancer will require a deeper molecular understanding of how cancer cells survive, proliferate, and escape from current therapies. In high-grade gliomas (HGGs), glioma stem cells (GSCs) may causally contribute to tumor initiation and propagation, therapeutic resistance, and subsequent recurrence of tumors. Within a tumor mass, GSCs are enriched in a hypoxic niche in which the oxidative stress levels are substantially elevated. Paradoxically, however, recent studies suggest that GSCs appear to generate less reactive oxygen species (ROS), a chemical component responsible for elevation of oxidative stress levels. To date, molecular mechanisms for how GSCs reduce oxidative stress to allow preferential survival in hypoxic areas in tumors remains elusive. This review article summarizes recent studies on the role of ROS reducing enzymes, including peroxiredoxin 4, in detoxifying oxidative stress preferentially for GSCs in HGGs. In addition, the therapeutic potential of some of the recently identified antioxidant chemotherapeutic agents and avenues for future research in this area are discussed. PMID- 25043480 TI - The cytotoxic and genotoxic effects of metalaxy-M on earthworms (Eisenia fetida). AB - As the main optical isomer of metalaxyl, metalaxyl-M has been widely used worldwide in recent years because of its notable effect on the prevention and control of crop diseases. Together with the toxicity and degradation of metalaxyl M, the chemical has attracted the attention of researchers. The present study examined the toxic effects of metalaxyl-M on earthworms at 0 mg kg(-1) , 0.1 mg kg(-1) , 1 mg kg(-1) , and 3 mg kg(-1) on days 7, 14, 21 and 28 after exposure. The results showed that metalaxyl-M could cause an obvious increase in the production of reactive oxygen species (ROS) when the concentration was higher than 0.1 mg kg(-1) , which led to lipid peroxidation in earthworms. Metalaxyl-M can induce DNA damage in earthworms, and the level of DNA damage markedly increased with increasing the concentration of metalaxyl-M. Metalaxyl-M also has a serious influence on the activities of antioxidant enzymes, which results in irreversible oxidative damage in cells. The changes of these indicators all indicated that metalaxyl-M may cause cytotoxic and genotoxic effects on earthworms. PMID- 25043481 TI - Stereoselective aminoxylation of biradical titanium enolates with TEMPO. AB - A highly efficient and straightforward aminoxylation of titanium(IV) enolates from (S)-N-acyl-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-ones with TEMPO has been developed. A wide array of functional groups on the acyl moiety, including alkyl and aryl substituents, olefins, esters, or alpha-cyclopropyl, as well as alpha trifluoromethyl groups, are well tolerated. This transformation can therefore produce the alpha-aminoxylated adducts in excellent yields with high diastereomeric ratios (d.r.). In turn, parallel additions to the alpha,beta unsaturated N-acyl counterparts give the corresponding gamma-adducts with complete regioselectivity in moderate to good yields. Removal of the piperidinyl moiety or the chiral auxiliary converts the resultant adducts into enantiomerically pure alpha-hydroxy carboxyl derivatives, alcohols, or esters in high yields under mild conditions. Finally, a new mechanistic model based on the biradical character of the titanium(IV) enolates has been proposed. PMID- 25043482 TI - Interventions for older persons reporting memory difficulties: a randomized controlled pilot study. AB - OBJECTIVE: The objective of this study is to compare three different interventions for persons who report memory difficulties: health promotion, cognitive training, and a participation-centered course, using a single-blind, randomized controlled design. METHODS: Participants were 44 Israeli adults with memory complaints, aged 65 years or older. The main outcome variable was the Global Cognitive Score assessed using the MindStreams((r)) mild cognitive impairment assessment, a computerized cognitive assessment. The Mini-Mental State Examination and the self-report of memory difficulties were also utilized. To assess well-being, the UCLA Loneliness Scale-8 was used. Health was evaluated by self-report instruments. RESULTS: All three interventions resulted in significant improvement in cognitive function as measured by the computerized cognitive assessment. All approaches seemed to decrease loneliness. The only variable which showed a significant difference among the groups is the self-report of memory difficulties, in which the cognitive training group participants reported greater improvement than the other groups. CONCLUSION: Multiple approaches should be offered to older persons with memory complaints. The availability of diverse options would help fit the needs of a heterogeneous population. An educational media effort to promote the public's understanding of the efficacy of these multiple approaches is needed. PMID- 25043483 TI - Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children. AB - OBJECTIVES: The aim of this study was to compare the diagnostic accuracy of postmortem magnetic resonance (PMMR) imaging specifically for musculoskeletal pathology in fetuses and children, compared with conventional autopsy, with radiographic and histopathology assessment. METHODS: Institutional ethics approval and parental consent was obtained. A total of 400 cases underwent PMMR using a 1.5 T Siemens Avanto MR scanner before conventional autopsy. PMMR images and autopsy findings were reported blinded to the other data, respectively. RESULTS: A total of 400 cases were reported, with 277 (69%) fetuses (185 <=24 weeks' gestation and 92 >24 weeks' gestation) and 123 children (42 newborns aged <1 month, 53 infants <=12 months and 28 children <=16 years). Musculoskeletal (MSK) abnormalities were found at autopsy in 47/400 (11.7%). Overall sensitivity and specificity (with 95% confidence interval) of PMMR for MSK pathology were 51.1% (37.0, 65.0) and 98.2% (96.2, 99.2), with positive and negative predictive values of 79.3% (61.6, 90.2) and 93.8% (90.8, 95.9), respectively. Overall accuracy between PMMR and autopsy for MSK abnormalities was 92.7% (89.7, 94.9). In some cases, PMMR detected MSK abnormalities not routinely examined for or detected at traditional autopsy. CONCLUSION: Minimally invasive autopsy has good diagnostic accuracy for the exclusion of MSK abnormalities, but sensitivity is relatively poor. When PMMR is used with clinical examination and skeletal radiographs, all skeletal and soft tissue abnormalities of clinical significance are likely to be detected, even if not directly relevant to the cause of death. PMID- 25043485 TI - Survey of cosmetics for arsenic, cadmium, chromium, cobalt, lead, mercury, and nickel content. AB - As part of efforts to assess amounts of inorganic element contamination in cosmetics, the U.S. Food and Drug Administration contracted a private laboratory to determine the total content of seven potentially toxic or allergenic elements in 150 cosmetic products of 12 types (eye shadows, blushes, lipsticks, three types of lotions, mascaras, foundations, body powders, compact powders, shaving creams, and face paints). Samples were analyzed for arsenic, cadmium, chromium, cobalt, lead, and nickel by inductively coupled plasma-mass spectrometry and for mercury by cold vapor atomic fluorescence spectrometry. The methods used to determine the elements were tested for validity by using standard reference materials with matrices similar to the cosmetic types. The cosmetic products were found to contain median values of 0.21 mg/kg arsenic, 3.1 mg/kg chromium, 0.91 mg/kg cobalt, 0.85 mg/kg lead, and 2.7 mg/kg nickel. The median values for cadmium and mercury were below the limits of detection of the methods. The contract requirements, testing procedures, and findings from the survey are described. PMID- 25043484 TI - An intestinal commensal symbiosis factor controls neuroinflammation via TLR2 mediated CD39 signalling. AB - The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. The intestinal microbiome can influence host susceptibility to extra-intestinal autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for the human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through Toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39(+) CD4 T-cell subset by PSA. Ablation of CD39 signalling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3(+) CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination. PMID- 25043486 TI - Method for screening sunscreen cream formulations by determination of in vitro SPF and PA values using UV transmission spectroscopy and texture profile analysis. AB - Formulation of sunscreen products to obtain high values of sun protection factor (SPF) and protection from ultraviolet A (PA) is challenging work for cosmetic chemists. This study aimed to study factors affecting SPF and PA values using ultraviolet transmission spectroscopy as well as texture profiles of sunscreen formulations using 23 factorial designs. Results demonstrate that the correlation coefficient between the labeled SPF values of counter-brand sunscreen products and the in vitro SPF values was 0.901. In vitro SPF determination showed that the combination effect of phase volume ratio (PVR) and xanthan gum caused a significant increase to the SPF values of the formulations, whereas the interaction effect between PVR and stearic acid significantly decreased the SPF value. In addition, there was the interaction effect between xanthan gum and stearic acid leading to significant reduction of hardness, compressibility, and pH, but significantly increasing the adhesiveness. All tested factors did not significantly affect the cohesiveness of tested formulations. In conclusion, apart from sunscreen agents, the other ingredients also affected the SPF and PA values. The calculated SPF values range from 21 to 60. However, a selected formulation needs to be confirmed by the standard method of testing. In addition, the physical, chemical, and biological stability; shelf life; and sensory evaluation of all formulations need to be evaluated. PMID- 25043487 TI - Selection of fragrance for cosmetic cream containing olive oil. AB - Perceptions of essences for potential use in the development of a line of cosmetic emulsions containing olive oil were studied. Six cream samples prepared with six essences selected in a preliminary study were evaluated for overall liking and intention to purchase by a 63-women sample. A check-all-that-apply (CATA) question consisting of 32 terms was used to gather information about consumer perceptions of fragrance, affective associations, effects on the skin, price, target market, zones of application, and occasions of use. Hierarchical cluster analysis led to the identification of two consumer clusters with different frequency of use of face creams. The two clusters assigned different overall liking scores to the samples and used the CATA terms differently to describe them. A fragrance with jasmine as its principal note was selected for further development of cosmetic creams, as it was awarded the highest overall liking scores by respondents of the two clusters, and was significantly associated with cosmetic features including nourishing, moisturizing, softening, with a delicious and mild smell, and with a natural image, as well as being considered suitable for face and body creams. The use of CATA questions enabled the rapid identification of attributes associated by respondents with a cosmetic cream's fragrance, in addition to contributing relevant information for the definition of marketing and communication strategies. PMID- 25043488 TI - Effect of novel cyclohexane diester and benzene diester derivatives on melanogenesis. AB - In order to investigate potent whitening agents, we synthesized 15 cyclohexane diester derivatives and 15 benzene diester derivatives. To evaluate their structure-cytotoxicity relationships, we performed cell cytotoxicity tests on B16F10 mouse melanoma cells. To understand their whitening effects, melanin synthesis inhibitory activities in B16F10 cells and mushroom tyrosinase inhibitory activities were performed. In most cases, cell cytotoxicity was observed to be lower in 1,3-diester than in 1,2- and 1,4-diesters; when it came to the structural isomer of the side chain, all derivatives except the 1,2 cyclohexane diester derivatives showed lower cell cytotoxicity in the branch type of the side chain than in the linear type. Among the compounds evaluated, the compounds cyclohexane-1,3-diyl bis(decanoate), cyclohexane-1,4-diyl dioctanoate, and 1,3-phenylene bis (2-ethylhexanoate) emerged as potent melanin synthesis inhibitors. Our goal was to determine the expression levels of proteins involved in melanogenesis, Western blotting and RT-PCR showing that these compounds decreased tyrosinase, TRP-1, and TRP-2 while demonstrating significantly low cytotoxicity. PMID- 25043489 TI - Stability of urea in solution and pharmaceutical preparations. AB - The stability of urea in solution and pharmaceutical preparations was analyzed as a function of temperature (25 degrees -60 degrees C), pH (3.11-9.67), and initial urea concentration (2.5%-20%). This study was undertaken to (i) obtain more extensive, quantitative information relative to the degradation of urea in both aqueous and non-aqueous solutions and in pharmaceutical preparations, and (ii) test the effects of initial urea concentration, pH, buffer, and temperature values on urea degradation. The stability analysis shows that urea is more stable at the pH range of 4-8 and the stability of urea decreases by increase in temperature for all pH values. Within the experimental range of temperature and initial urea concentration values, the lowest urea degradation was found with lactate buffer pH 6.0. The urea decomposition rate in solution and pharmaceutical preparations shows the dependence of the initial urea concentrations. At higher initial urea concentrations, the rate of degradation is a decreasing function with time. This suggests that the reverse reaction is a factor in the degradation of concentrated urea solution. For non-aqueous solvents, isopropanol showed the best effort in retarding the decomposition of urea. Since the losses in urea is directly influenced by its stability at a given temperature and pH, the stability analysis of urea by the proposed model can be used to prevent the loss and optimize the operating condition for urea-containing pharmaceutical preparations. PMID- 25043490 TI - The first case of intersexuality in an African dwarf crocodile (Osteolaemus tetraspis). AB - To the authors knowledge this is the first case of intersexuality in an African dwarf crocodile (Osteolaemus tetraspis). An adult African dwarf crocodile with a male-typical phenotype lived at Zoo Duisburg in Germany for 10 years. It died in October 2012 despite intensive treatment as a result of terminal septicemia. After a detailed pathological examination the gonads were histologically confirmed as ovotestes. Half of the 22 extant species of crocodilians have been examined for occurrence of temperature dependent sex determination (TSD). In TSD reptiles, masculinizing temperatures yield 100% or a majority of males, whereas feminizing temperatures yield 100% or a majority of females. In the transition range of temperature (TRT), a mix of males, females and sometimes intersexes are obtained. However, the molecular mechanisms behind TSD and an explanation for the occurrence of intersexuality remain elusive. PMID- 25043491 TI - A marginalized two-part model for semicontinuous data. AB - In health services research, it is common to encounter semicontinuous data characterized by a point mass at zero followed by a right-skewed continuous distribution with positive support. Examples include health expenditures, in which the zeros represent a subpopulation of patients who do not use health services, while the continuous distribution describes the level of expenditures among health services users. Semicontinuous data are typically analyzed using two part mixture models that separately model the probability of health services use and the distribution of positive expenditures among users. However, because the second part conditions on a non-zero response, conventional two-part models do not provide a marginal interpretation of covariate effects on the overall population of health service users and non-users, even though this is often of greatest interest to investigators. Here, we propose a marginalized two-part model that yields more interpretable effect estimates in two-part models by parameterizing the model in terms of the marginal mean. This model maintains many of the important features of conventional two-part models, such as capturing zero inflation and skewness, but allows investigators to examine covariate effects on the overall marginal mean, a target of primary interest in many applications. Using a simulation study, we examine properties of the maximum likelihood estimates from this model. We illustrate the approach by evaluating the effect of a behavioral weight loss intervention on health-care expenditures in the Veterans Affairs health-care system. PMID- 25043492 TI - Functional requirement of dicer1 and miR-17-5p in reactive astrocyte proliferation after spinal cord injury in the mouse. AB - Reactive astrogliosis after spinal cord injury (SCI) contributes to glial scar formation that impedes axonal regeneration. The mechanisms underlying reactive astrocyte proliferation upon injury remain partially understood. MicroRNAs (miRNAs) function as a major class of post-transcriptional gene expression regulators that participate in many biological processes. However, miRNA function during reactive astrogliosis, particularly in injury-induced astrocyte proliferation, has not been carefully examined. In this study, we conditionally deleted Dicer1 gene encoding an enzyme that is required for mature miRNA generation, and examined the proliferative behavior of Dicer1-null reactive astrocytes in the transected mouse spinal cord. We found that injury-induced proliferation is blocked in Dicer1-null astrocytes. Previous reports indicate that miR-17-5p family members are upregulated during SCI. We therefore tested functional contribution of miR-17-5p to the proliferation of reactive astrocytes in vitro. Our results showed that a synthetic miR-17-5p mimic is able to rescue the proliferation defect of Dicer1-null astrocytes, while an antisense inhibitor of miR-17-5p blocked lipopolysaccharide-induced astrocytic proliferation. Similar results are also observed in leukemia inhibitory factor (LIF)-treated astroglial cultures suggesting that miR-17-5p particularly modulates reactive astrocyte proliferation initiated by LIF presumably via the JAK/STAT3 pathway. Furthermore, overexpression of miR-17-5p leads to decrease of several cell cycle regulators in cultured astroglia and astrocytoma cell line C6. Our conclusion is that miRNAs are indispensable to the injury-induced reactive astrocyte proliferation, and that miR-17-5p may be a major player regulating this pathological process by affecting cell cycle machinery. PMID- 25043493 TI - Mitral valve repair: an echocardiographic review: part 1. PMID- 25043494 TI - Staging accuracy of pancreatic cancer: comparison between non-contrast-enhanced and contrast-enhanced PET/CT. AB - PURPOSE: Our aim was to clarify the diagnostic impact of contrast-enhanced (CE) (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) for staging of pancreatic cancer compared to non-CE PET/CT. METHOD AND MATERIALS: Between April 2006 and November 2009, a total of 95 patients (age range, 36-83 years [mean age, 67]) with primary pancreatic cancer underwent (18)F-FDG PET/CT examinations. Diagnostic accuracy was compared between non-CE PET/CT and CE PET/CT. Images were analyzed visually and quantitatively by two blinded reviewers. Reference standard was histological examination in 48 patients (51%) and/or confirmation of an obvious progression in number and/or size of the lesions on follow-up CT examinations in 47 patients (49%). RESULTS: For T-staging, invasion of duodenum (n=20, 21%), mesentery (n=12, 13%), and retroperitoneum (n=13, 14%) was correctly diagnosed by both modalities. The ROC analyses revealed that the Az values of celiac artery (CA), common hepatic artery (CHA), splenic artery (SV), and superior mesenteric vein (SMV) invasion were significantly higher in the CE PET/CT group for both readers. Nodal metastasis was correctly diagnosed by CE PET/CT in 38 patients (88%) and by non-CE PET/CT in 45 patients (87%). Diagnostic accuracies of nodal metastasis in two modalities were similar. Using CE PET/CT, distant metastasis, scalene node metastasis, and peritoneal dissemination were correctly assigned in 39 patients (91%), while interpretation based on non-CE PET/CT revealed distant metastasis, scalene node metastasis, and peritoneal dissemination in 42 patients (81%). Diagnostic accuracy of distant metastasis, scalene node metastasis, and peritoneal dissemination with CE PET/CT was significantly higher than that of non-CE PET/CT (p<0.05). CONCLUSION: CE PET/CT allows a more precise assessment of distant metastasis, scalene node metastasis, and peritoneal dissemination in patients with pancreatic cancer. PMID- 25043495 TI - Usefulness of free-breathing readout-segmented echo-planar imaging (RESOLVE) for detection of malignant liver tumors: comparison with single-shot echo-planar imaging (SS-EPI). AB - PURPOSE: We aimed to clarify the usefulness of free-breathing readout-segmented echo-planar imaging (RESOLVE), which is multi-shot echo-planar imaging based on a 2D-navigator-based reacquisition technique, for detecting malignant liver tumor. MATERIALS AND METHODS: In 77 patients with malignant liver tumors, free-breathing RESOLVE and respiratory-triggered single-shot echo-planar imaging (SS-EPI) at 3-T MR unit were performed. We set a scan time up to approximately 5 min (300s) before examination, measured actual scan time and assessed (1) susceptibility and (2) motion artifacts in the right and left liver lobes (3, no artifact; 1, marked), and (3) detectability of malignant liver tumors (3, good; 1, poor) using a 3-point scale. RESULTS: The median actual scan time of RESOLVE/SS-EPI was 365/423s. The median scores of each factor in RESOLVE/SS-EPI were as following in this order: (1) 3/2 (right lobe); 3/3 (left lobe), (2) 2/3 (right lobe); 1/2 (left lobe), and (3) 3/3, respectively. Significant differences were noted between RESOLVE and SS-EPI in all evaluated factors (P<0.05) except for susceptibility of left lobe and detectability of the lesions. CONCLUSION: Despite the effect of motion artifacts, RESOLVE provides a comparable detectability of the lesion and the advantage of reducing scanning time compared with SS-EPI. PMID- 25043496 TI - Image and pathological changes after microwave ablation of breast cancer: a pilot study. AB - PURPOSE: To prospectively assess MR imaging evaluation of the ablation zone and pathological changes after microwave ablation (MWA) in breast cancer. MATERIALS AND METHODS: Twelve enrolled patients, diagnosed with non-operable locally advanced breast cancer (LABC), were treated by MWA and then neoadjuvant chemotherapy, followed by surgery. MR imaging was applied to evaluate the effect of MWA. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were applied to analyze the ablated area. RESULTS: All MWA procedures were performed successfully under local anesthesia. For a mean duration of 2.15 min, the mean largest, middle and smallest diameters in the ablated zone 24-h post ablation in MR imaging were 2.98 cm +/- 0.53, 2.51 cm +/- 0.41 and 2.23 cm +/- 0.41, respectively. The general shape of the ablation zone was close to a sphere. The ablated area became gradually smaller in MR imaging. No adverse effects related to MWA were noted in all 12 patients during and after MWA. HE staining could confirm the effect about 3 months after MWA, which was confirmed by TEM. CONCLUSIONS: 2 min MWA can cause an ablation zone with three diameters larger than 2 cm in breast cancer, which may be suitable for the local treatment of breast cancer up to 2 cm in largest diameter. However, the long-term effect of MWA in the treatment of small breast cancer should be determined in the future. PMID- 25043497 TI - Disrupted small world networks in patients without overt hepatic encephalopathy: a resting state fMRI study. AB - PURPOSE: To explore changes in functional connectivity and topological organization of brain functional networks in cirrhotic patients with minimal hepatic encephalopathy (MHE) and non hepatic encephalopathy (nonHE) and their relationship with clinical markers. MATERIALS AND METHODS: Resting-state functional MR imaging was acquired in 22 MHE, 29 nonHE patients and 33 healthy controls. Functional connectivity networks were obtained by computing temporal correlations between any pairs of 90 cortical and subcortical regions. Graph analysis measures were quantitatively assessed for each subject. One-way analysis of covariance was applied to identify statistical differences of functional connectivity and network parameters among three groups. Correlations between clinical markers, such as Child-Pugh scores, venous blood ammonia level, and number connection test type A (NCT-A)/digit symbol test (DST) scores, and connectivity/graph metrics were calculated. RESULTS: Thirty functional connectivities represented by edges were found to be abnormal (P<0.05, FDR corrected) in cirrhotic patients, in which 16 edges (53.3%) were related with sub cortical regions. MHE patients showed abnormal small-world attributes in the functional connectivity networks. Cirrhotic patients had significantly reduced nodal degree in 8 cortical regions and increased nodal centrality in 3 cortical regions. Twenty edges were correlated with either NCT-A or DST scores, in which 13 edges were related with sub-cortical regions. No correlation was found between Child-Pugh scores and graph theoretical measures in cirrhotic patients. CONCLUSION: Disturbances of brain functional connectivity and small world property loss are associated with neurocognitive impairment of cirrhotic patients. Reorganization of brain network occurred during disease progression from nonHE to MHE. PMID- 25043498 TI - Voxelwise meta-analysis of gray matter abnormalities in dementia with Lewy bodies. AB - BACKGROUND: Increasing neuroimaging studies have revealed brain gray matter (GM) atrophy by voxel-based morphometry (VBM) studies in patients with dementia with Lewy bodies (DLB) relative to healthy controls. However, the spatial localization of GM abnormalities reported in the existing studies is heterogeneous. Here, we aimed to investigate concurrence across VBM studies to help clarify the structural abnormalities underpinning this condition. METHODS: A systematic search for VBM studies of DLB patients and healthy controls published in PubMed database from January 2000 to March 2014 was conducted. A quantitative meta analysis of whole-brain VBM studies in DLB patients and healthy controls was performed by means of Anisotropic Effect Size version of Signed Differential Mapping (AES-SDM) software package. RESULTS: Seven studies comprising 218 DLB patients and 219 healthy controls were included in the present study. Compared to healthy subjects, the patients group showed consistent decreased GM in right lateral temporal/insular cortex and left lenticular nucleus/insular cortex. The results remained largely unchanged in the following jackknife sensitivity analyses. Meta-regression analysis indicated an increased probability of finding brain atrophy in left superior temporal gyrus in patients with lower MMSE scores. CONCLUSIONS: The present meta-analysis quantitatively demonstrates a characteristic pattern of GM alternations that contributed to the understanding of pathophysiology underlying DLB. Future studies will benefit from employing meta-analytical comparisons to other dementia subtypes with solid evidence to extend these findings. PMID- 25043500 TI - Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma. AB - Photodynamic therapy (PDT) is a new therapeutic approach for the palliative treatment of malignant bile duct obstruction. In this study, we designed photosensitizer-embedded self-expanding nonvascular metal stent (PDT-stent) which allows repeatable photodynamic treatment of cholangiocarcinoma without systemic injection of photosensitizer. Polymeric photosensitizer (pullulan acetate conjugated pheophorbide A; PPA) was incorporated in self-expanding nonvascular metal stent. Residence of PPA in the stent was estimated in buffer solution and subcutaneous implantation on mouse. Photodynamic activity of PDT-stent was evaluated through laserexposure on stent-layered tumor cell lines, HCT-116 tumor xenograft mouse models and endoscopic intervention of PDT-stent on bile duct of mini pigs. Photo-fluorescence imaging of the PDT-stent demonstrated homogeneous embedding of polymeric Pheo-A (PPA) on stent membrane. PDT-stent sustained its photodynamic activities at least for 2 month. And which implies repeatable endoscopic PDT is possible after stent emplacement. The PDT-stent after light exposure successfully generated cytotoxic singlet oxygen in the surrounding tissues, inducing apoptotic degradation of tumor cells and regression of xenograft tumors on mouse models. Endoscopic biliary in-stent photodynamic treatments on minipigs also suggested the potential efficacy of PDT-stent on cholangiocarcinoma. In vivo and in vitro studies revealed our PDT-stent, allows repeatable endoscopic biliary PDT, has the potential for the combination therapy (stent plus PDT) of cholangiocarcinoma. PMID- 25043501 TI - Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. AB - Despite dramatic progress in infertility treatments and assisted reproduction, no effective therapies exist for complete loss of uterine structure and/or function. For such patients, genetic motherhood is possible only through gestational surrogacy or uterine transplantation. However, many ethical, social, technical and safety challenges accompany such approaches. A theoretical alternative is to generate a bioartificial uterus, which requires engineering of uterine architecture and appropriate cellular constituents. Here, rat uteri decellularization by aortic perfusion with detergents produced an underlying extracellular matrix together with an acellular, perfusable vascular architecture. Uterine-like tissues were then regenerated and maintained in vitro for up to 10 d through decellularized uterine matrix (DUM) reseeding with adult and neonatal rat uterine cells and rat mesenchymal stem cells followed by aortic perfusion in a bioreactor. Furthermore, DUM placement onto a partially excised uterus yielded recellularization and regeneration of uterine tissues and achievement of pregnancy nearly comparable to the intact uterus. These results suggest that DUM could be used for uterine regeneration, and provides insights into treatments for uterine factor infertility. PMID- 25043499 TI - Including ligand-induced protein flexibility into protein tunnel prediction. AB - In proteins with buried active sites, understanding how ligands migrate through the tunnels that connect the exterior of the protein to the active site can shed light on substrate specificity and enzyme function. A growing body of evidence highlights the importance of protein flexibility in the binding site on ligand binding; however, the influence of protein flexibility throughout the body of the protein during ligand entry and egress is much less characterized. We have developed a novel tunnel prediction and evaluation method named IterTunnel, which includes the influence of ligand-induced protein flexibility, guarantees ligand egress, and provides detailed free energy information as the ligand proceeds along the egress route. IterTunnel combines geometric tunnel prediction with steered molecular dynamics in an iterative process to identify tunnels that open as a result of ligand migration and calculates the potential of mean force of ligand egress through a given tunnel. Applying this new method to cytochrome P450 2B6, we demonstrate the influence of protein flexibility on the shape and accessibility of tunnels. More importantly, we demonstrate that the ligand itself, while traversing through a tunnel, can reshape tunnels due to its interaction with the protein. This process results in the exposure of new tunnels and the closure of preexisting tunnels as the ligand migrates from the active site. PMID- 25043502 TI - Spider silk for xeno-free long-term self-renewal and differentiation of human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) can undergo unlimited self-renewal and have the capacity to differentiate into all somatic cell types, and are therefore an ideal source for the generation of cells and tissues for research and therapy. To realize this potential, defined cell culture systems that allow expansion of hPSCs and subsequent controlled differentiation, ideally in an implantable three dimensional (3D) matrix, are required. Here we mimic spider silk - Nature's high performance material - for the design of chemically defined 2D and 3D matrices for cell culture. The silk matrices do not only allow xeno-free long-term expansion of hPSCs but also differentiation in both 2D and 3D. These results show that biomimetic spider silk matrices enable hPSC culture in a manner that can be applied for experimental and clinical purposes. PMID- 25043504 TI - Boveri at 100: Boveri, chromosomes and cancer. AB - Microscopic studies of chromosomes in cells cultured from leukaemias and solid tumours have helped confirm the central tenet of Boveri's somatic mutation theory of cancer, namely that acquired chromosomal aberrations of susceptible target cells may cause their neoplastic transformation. Cancer cytogenetics - especially when used together with appropriate molecular genetic investigations of tumour parenchyma cells - offers diagnostic and prognostic information, insights into the clonal composition and evolution of neoplasms, and information about how the observed gains, losses and balanced relocations work pathogenetically. In the future, one may expect cancer cytogenetics to focus not only on how the various aberrations contribute to tumourigenesis, but also on why and how they occur, as well as on the biological meaning behind the polyclonality detected in several epithelial neoplasms. Finally, the study of different nuclear compartments during interphase may add to our understanding of how large-scale numerical and structural karyotypic aberrations may disturb normal controls of cell division and death to induce neoplastic transformation. PMID- 25043503 TI - Assessment of two different types of bias affecting the results of outcome-based evaluation in undergraduate medical education. AB - BACKGROUND: Estimating learning outcome from comparative student self-ratings is a reliable and valid method to identify specific strengths and shortcomings in undergraduate medical curricula. However, requiring students to complete two evaluation forms (i.e. one before and one after teaching) might adversely affect response rates. Alternatively, students could be asked to rate their initial performance level retrospectively. This approach might threaten the validity of results due to response shift or effort justification bias. METHODS: Two consecutive cohorts of medical students enrolled in a six-week cardio-respiratory module were enrolled in this study. In both cohorts, performance gain was estimated for 33 specific learning objectives. In the first cohort, outcomes calculated from ratings provided before (pretest) and after (posttest) teaching were compared to outcomes derived from comparative self-ratings collected after teaching only (thentest and posttest). In the second cohort, only thentests and posttests were used to calculate outcomes, but data collection tools differed with regard to item presentation. In one group, thentest and posttest ratings were obtained sequentially on separate forms while in the other, both ratings were obtained simultaneously for each learning objective. RESULTS: Using thentest ratings to calculate performance gain produced slightly higher values than using true pretest ratings. Direct comparison of then- and posttest ratings also yielded slightly higher performance gain than sequential ratings, but this effect was negligibly small. CONCLUSIONS: Given the small effect sizes, using thentests appears to be equivalent to using true pretest ratings. Item presentation in the posttest does not significantly impact on results. PMID- 25043505 TI - CD8+ MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis. AB - Recent findings indicate a pathogenic involvement of IL-17-producing CD8(+) T cells in multiple sclerosis (MS). IL-17 production has been attributed to a subset of CD8(+) T cells that belong to the mucosal-associated invariant T (MAIT) cell population. Here, we report a reduction of CD8(+) MAIT cells in the blood of MS patients compared with healthy individuals, which significantly correlated with IL-18 serum levels in MS patients. In vitro stimulation of peripheral blood mononuclear cells from healthy individuals and MS patients with IL-18 specifically activated CD8(+) MAIT cells. Moreover, IL-18 together with T-cell receptor stimulation induced, specifically on CD8(+) MAIT cells, an upregulation of the integrin very late antigen-4 that is essential for the infiltration of CD8(+) T cells into the CNS. Notably, we were able to identify CD8(+) MAIT cells in MS brain lesions by immunohistochemistry while they were almost absent in the cerebrospinal fluid (CSF). In summary, our findings indicate that an IL-18-driven activation of CD8(+) MAIT cells contributes to their CNS infiltration in MS, in turn leading to reduced CD8(+) MAIT-cell frequencies in the blood. Therefore, CD8(+) MAIT cells seem to play a role in the innate arm of immunopathology in MS. PMID- 25043506 TI - Neuromuscular fatigue of the knee extensors during repeated maximal intensity intermittent-sprints on a cycle ergometer. AB - INTRODUCTION: We studied the time course of neuromuscular fatigue during maximal intensity intermittent-sprint cycling. METHODS: Eight participants completed 10, 10-s sprints interspersed with 180 s of recovery. The power outputs were recorded for each sprint. Knee extensor maximum voluntary contraction (MVC) force, voluntary activation, and evoked contractile properties were recorded presprint, postsprint 5, and postsprint 10. RESULTS: Total work over the 10 sprints decreased significantly (P < 0.05) and could be described by 2 linear relationships from sprints 1-5 compared with sprints 6-10. Participants had significantly (P < 0.05) lower MVC and twitch forces postsprint 5 compared with presprint. MVC, voluntary activation, and twitch force were decreased (P < 0.05) postsprint 10 compared with postsprint 5. CONCLUSIONS: The maximal intermittent sprints induced neuromuscular fatigue. Neuromuscular fatigue in the first 5 sprints was mainly peripheral, whereas in the last 5 sprints it was both peripheral and central. PMID- 25043507 TI - Enthusiasm for induced pluripotent stem cell-based therapies in kidney regeneration. PMID- 25043508 TI - Saccade detection using a particle filter. AB - BACKGROUND: When healthy subjects track a moving target, "catch-up" saccades are triggered to compensate for the non-perfect tracking gain. The evaluation of the pursuit and/or saccade kinematics requires that saccade and pursuit components be separated from the eye movement trace. A similar situation occurs when analyzes eye movements of patients that could contain eye drifts between saccades. This task is especially difficult, because the range of saccadic amplitudes goes from microsaccades (less than 1 degrees ) to large exploratory saccades (40 degrees ). NEW METHOD: In this paper we proposed a new algorithm to detect saccades based on a particle filter. The new method suppresses the baseline velocity component linked to smooth pursuit (or to eye drifts) and thus permits a constant threshold during a trial despite the smooth pursuit behavior. It also accounts for a wide range of saccade amplitudes. RESULTS: The new method is validated with five different paradigms, microsaccades, microsaccades plus saccades with drift, linear target motion, non-linear target motion and free viewing. The sensitivity of the method to signal noise is analyzed. COMPARISON WITH EXISTING METHODS: Traditional saccade detection algorithms using a velocity (or acceleration or jerk) threshold can be inadequate because of the baseline velocity component linked to the smooth pursuit (especially if the target motion is non-linear, i.e. not constant velocity) or to eye drifts between saccades. CONCLUSIONS: The new method detects saccades in challenging situations involving eye movements between saccades (smooth pursuit and/or eye drifts) and unfiltered recordings. PMID- 25043509 TI - Customization, control, and characterization of a commercial haptic device for high-fidelity rendering of weak forces. AB - BACKGROUND: The emergence of commercial haptic devices offers new research opportunities to enhance our understanding of the human sensory-motor system. Yet, commercial device capabilities have limitations which need to be addressed. This paper describes the customization of a commercial force feedback device for displaying forces with a precision that exceeds the human force perception threshold. NEW METHOD: The device was outfitted with a multi-axis force sensor and closed-loop controlled to improve its transparency. Additionally, two force sensing resistors were attached to the device to measure grip force. Force errors were modeled in the frequency- and time-domain to identify contributions from the mass, viscous friction, and Coulomb friction during open- and closed-loop control. The effect of user interaction on system stability was assessed in the context of a user study which aimed to measure force perceptual thresholds. RESULTS: Findings based on 15 participants demonstrate that the system maintains stability when rendering forces ranging from 0-0.20 N, with an average maximum absolute force error of 0.041 +/- 0.013 N. Modeling the force errors revealed that Coulomb friction and inertia were the main contributors to force distortions during respectively slow and fast motions. COMPARISON WITH EXISTING METHODS: Existing commercial force feedback devices cannot render forces with the required precision for certain testing scenarios. Building on existing robotics work, this paper shows how a device can be customized to make it reliable for studying the perception of weak forces. CONCLUSIONS: The customized and closed-loop controlled device is suitable for measuring force perceptual thresholds. PMID- 25043510 TI - Relationship between radiological (X-ray/HRCT), spirometric and clinical findings in dental technicians' pneumoconiosis. AB - INTRODUCTION: Pneumoconiosis in dental technicians' has rarely been evaluated. OBJECTIVES: To evaluate clinical, functional and radiological impacts of exposure to dust on respiratory functions via chest X-ray (CXR), high-resolution computed tomography (HRCT) and spirometry in dental technicians. METHODS: Demographic data, respiratory symptoms, spirometry results, CXR and HRCT scans of 32 dental technicians were evaluated. The opacities on the radiological images were categorized based on their intensity. We investigated the relation of radiological scores with clinical, radiological and functional findings. RESULTS: The mean age of the study population was 31 +/- 9 years and mean employment duration was 14 +/- 9 years. Twenty-two (69%) technicians had a history of smoking. The most common symptom was phlegm, while dyspnea prevalence was higher in those with an elevated International Labour Office (ILO) profusion score (P < 0.01). Parenchymal opacities were determined in 10 (31%) technicians by CXR and in 22 (69%) technicians by HRCT (P < 0.01). There was a positive correlation between ILO profusion score and HRCT score (r = 0.765, P < 0.01). ILO profusion score and HRCT score showed positive correlation with employment duration (r = 0.599, P = 0.01; r = 0.514, P = 0.01, respectively), while exhibiting negative correlation with FVC (r = -0.509, P < 0.05; r = -0.627, P = 0.01 respectively), FVC% (r = -0.449, P < 0.05; r = -0.457, P < 0.05, respectively) and forced expiratory volume in 1 s (r = -0.473, P < 0.05; r = -0.598, P = 0.01, respectively). CONCLUSIONS: We believe that a combined approach including spirometry, CXR and HRCT modalities should be employed in demonstrating respiratory disorders associated with exposure to inorganic dusts in dental technicians. PMID- 25043511 TI - The prognostic value of concomitant assessment of NT-proCNP, C-reactive protein, procalcitonin and inflammatory cytokines in septic patients. PMID- 25043512 TI - A light-powered bio-capacitor with nanochannel modulation. AB - An artificial bio-capacitor system is established, consisting of the proton-pump protein proteorhodopsin and a modified alumina nanochannel, inspired by the capacitor-like behavior of plasma membranes realized through the cooperation of ion-pump and ion-channel proteins. Capacitor-like features of this simplified system are realized and identified, and the photocurrent duration time can be modulated by nanochannel modification to obtain favorable square-wave currents. PMID- 25043513 TI - It's not just the antibiotics, it's the treatment. AB - The recent study by Bloos and colleagues demonstrates that early initiation of antimicrobial therapy is not associated with improved survival in sepsis. We contend that these findings should not be surprising. This study is yet another part of the growing case against early and aggressive antimicrobial therapy and highlights the important roles resuscitation and source control play in the management of the septic patient. We suggest that, whenever possible, antimicrobial therapy should we withheld until objective evidence of infection has been obtained. PMID- 25043514 TI - Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. AB - There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (beta=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, beta=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;). PMID- 25043516 TI - Animal models, complications of trial protocols, and WAKE UP protocol. PMID- 25043515 TI - Molecular dynamics simulations of the auxin-binding protein 1 in complex with indole-3-acetic acid and naphthalen-1-acetic acid. AB - Auxin-binding protein 1 (ABP1) is suggested to be an auxin receptor which plays an important role in several processes in green plants. Maize ABP1 was simulated with the natural auxin indole-3-acetic acid (IAA) and the synthetic analog naphthalen-1-acetic acid (NAA), to elucidate the role of the KDEL sequence and the helix at the C-terminus. The KDEL sequence weakens the intermolecular interactions between the monomers but stabilizes the C-terminal helix. Conformational changes at the C-terminus occur within the KDEL sequence and are influenced by the binding of the simulated ligands. This observation helps to explain experimental findings on ABP1 interactions with antibodies that are modulated by the presence of auxin, and supports the hypothesis that ABP1 acts as an auxin receptor. Stable hydrogen bonds between the monomers are formed between Glu40 and Glu62, Arg10 and Thr97, Lys39, and Glu62 in all simulations. The amino acids Ile22, Leu25, Trp44, Pro55, Ile130, and Phe149 are located in the binding pocket and are involved in hydrophobic interactions with the ring system of the ligand. Trp151 is stably involved in a face to end interaction with the ligand. The calculated free energy of binding using the linear interaction energy approach showed a higher binding affinity for NAA as compared to IAA. Our simulations confirm the asymmetric behavior of the two monomers, the stronger interaction of NAA than IAA and offers insight into the possible mechanism of ABP1 as an auxin receptor. PMID- 25043517 TI - Testing devices for the prevention and treatment of stroke and its complications. AB - We are entering a challenging but exciting period when many new interventions may appear for stroke based on the use of devices. Hopefully these will lead to improved outcomes at a cost that can be afforded in most parts of the world. Nevertheless, it is vital that lessons are learnt from failures in the development of pharmacological interventions (and from some early device studies), including inadequate preclinical testing, suboptimal trial design and analysis, and underpowered studies. The device industry is far more disparate than that seen for pharmaceuticals; companies are very variable in size and experience in stroke, and are developing interventions across a wide range of stroke treatment and prevention. It is vital that companies work together where sales and marketing are not involved, including in understanding basic stroke mechanisms, prospective systematic reviews, and education of physicians. Where possible, industry and academics should also work closely together to ensure trials are designed to be relevant to patient care and outcomes. Additionally, regulation of the device industry lags behind that for pharmaceuticals, and it is critical that new interventions are shown to be safe and effective rather than just feasible. Phase IV postmarketing surveillance studies will also be needed to ensure that devices are safe when used in the 'real-world' and to pick up uncommon adverse events. PMID- 25043518 TI - Should DWI MRI be the primary screening test for stroke? AB - Patients presenting with focal neurological symptoms may suffer from ischemic stroke, intracerebral hemorrhage, or stroke mimics. Such patients are usually screened with a noncontrast-enhanced computed tomography to rule out hemorrhage and to detect early signs of ischemia. However, the sensitivity of noncontrast enhanced computed tomography for acute stroke is far inferior to that of diffusion-weighted magnetic resonance imaging and the latter is also very sensitive for identifying acute intracerebral hemorrhage. Most centers perform a magnetic resonance imaging stroke protocol that takes long to accomplish and may therefore delay therapy. Herein, we propose that a short diffusion-weighted imaging-only magnetic resonance imaging protocol can effectively differentiate ischemic stroke from intracerebral hemorrhage and stroke mimics and could therefore be used as the first line screening test for stroke. Adopting such a screening strategy will result in increased diagnostic accuracy and avoidance of unnecessary treatment of stroke mimics with thrombolysis but may come at the increased cost of performing a magnetic resonance imaging at the emergency department. Whether such a strategy will be cost effective or not remains to be tested in future studies. PMID- 25043519 TI - Use of appropriate statistical methods while conducting a meta-analysis. PMID- 25043520 TI - Identification of a novel RNF213 variant in a family with heterogeneous intracerebral vasculopathy. PMID- 25043521 TI - Doubling in use of alteplase in Australia between 2003 and 2009. PMID- 25043522 TI - Forcing open doors using images: ruptured aortic arch atheroma visualized by TEE in a stroke patient. PMID- 25043523 TI - Impact of ground- and excited-state aromaticity on cyclopentadiene and silole excitation energies and excited-state polarities. AB - A new qualitative model for estimating the properties of substituted cyclopentadienes and siloles in their lowest pipi* excited states is introduced and confirmed through quantum chemical calculations, and then applied to explain earlier reported experimental excitation energies. According to our model, which is based on excited-state aromaticity and antiaromaticity, siloles and cyclopentadienes are cross-hyperconjugated "aromatic chameleons" that adapt their electronic structures to conform to the various aromaticity rules in different electronic states (Huckel's rule in the pi(2) electronic ground state (S0) and Baird's rule in the lowest pipi* excited singlet and triplet states (S1 and T1)). By using pen-and-paper arguments, one can explain polarity changes upon excitation of substituted cyclopentadienes and siloles, and one can tune their lowest excitation energies by combined considerations of ground- and excited state aromaticity/antiaromaticity effects. Finally, the "aromatic chameleon" model can be extended to other monocyclic compound classes of potential use in organic electronics, thereby providing a unified view of the S0, T1, and S1 states of a range of different cyclic cross-pi-conjugated and cross hyperconjugated compound classes. PMID- 25043524 TI - Thermodynamic properties of the isomers of [HNOS], [HNO2 S], and [HNOS2 ] and the role of the central sulfur. AB - Simple hydrides of compounds containing N, S, and O are of significant interest due to the role that they play in atmospheric chemistry and in biological pathways. There is a lack of quantitative thermodynamic data on these compounds. We have used a reliable computational chemistry approach based on valence CCSD(T) calculations extrapolated to the complete basis set limit with additional corrections to predict the heats of formation and bond dissociation energies of such compounds. The results show that compounds with the ability of the central S atom to effectively expand its valency leads to more stable isomers and, as a consequence, that those with the NSO structural motif are thermochemically more stable than those with the SNO motif. In addition, S?O bonds are preferred over N?O bonds. PMID- 25043525 TI - Two pentasilahousanes fused together. AB - The organosilicon cluster 1 with two pentasilahousanes fused together was synthesized by the reduction of 1,1,3-trichlorocyclotetrasilane. This reaction involves dimerization and rearrangement of the silicon skeleton. The structure and properties of 1 were studied by X-ray crystallographic and spectroscopic analyses. PMID- 25043526 TI - The biologic effects of cigarette smoke on cancer cells. AB - Smoking is one of the largest preventable risk factors for developing cancer, and continued smoking by cancer patients is associated with increased toxicity, recurrence, risk of second primary cancer, and mortality. Cigarette smoke (CS) contains thousands of chemicals, including many known carcinogens. The carcinogenic effects of CS are well established, but relatively little work has been done to evaluate the effects of CS on cancer cells. In this review of the literature, the authors demonstrate that CS induces a more malignant tumor phenotype by increasing proliferation, migration, invasion, and angiogenesis and by activating prosurvival cellular pathways. Significant work is needed to understand the biologic effect of CS on cancer biology, including the development of model systems and the identification of critical biologic mediators of CS induced changes in cancer cell physiology. PMID- 25043527 TI - Quantitative analysis of hindered amine light stabilizers by CZE with UV detection and quadrupole TOF mass spectrometric detection. AB - The current work describes the development of a CZE method with quadrupole QTOF MS detection and UV detection for the quantitation of Cyasorb 3529, a common hindered amine light stabilizer (HALS), in polymer materials. Analysis of real polymer samples revealed that the oligomer composition of Cyasorb 3529 changes during processing, a fact hampering the development of a straightforward method for quantitation based on calibration with a Cyasorb 3529 standard. To overcome this obstacle in-depth investigations of the oligomer composition of this HALS using QTOF-MS and QTOF-MS/MS had to be performed whereby 22 new oligomer structures, in addition to the ten structures already described, were identified. Finally, a CZE method for quantitative analysis of this HALS was developed starting with a comprehensive characterization of a Cyasorb 3529 standard using CZE-QTOF-MS, subsequently allowing the correct assignment of most Cyasorb 3529 oligomers in an electropherogram with UV detection. Employing the latter detection technique and hexamethyl-melamine as internal standard, peak areas obtained for the melamine could be correlated with those from the triazine ring, the UV-absorbing unit present in the HALS. This approach finally allowed proper quantitation of the single oligomers of Cyasorb 3529, an imperative for the quantitative assessment of this HALS in real polymer samples. PMID- 25043528 TI - Prognostic significance of receptor for advanced glycation end products expression in hepatocellular carcinoma after hepatectomy. AB - BACKGROUND: The receptor for advanced glycation end products (RAGE) is recognized to be responsible for cancer progression in several human cancers. In this study, we investigated the clinical impact of RAGE expression in patients with hepatocellular carcinoma (HCC) after hepatectomy. MATERIALS AND METHODS: Sixty five consecutive patients who underwent initial hepatectomy for HCC were investigated. The relationships between immunohistochemical expression of RAGE and clinicopathologic features, clinical outcome (overall survival [OS], and disease-free survival [DFS]) were evaluated. RESULTS: The cytoplasmic expression of RAGE in HCC cells was observed in 46 patients (70.8%) and correlated with histologic grade (poorly differentiated versus moderately differentiated HCC, P = 0.021). Five-year OS in RAGE-positive and RAGE-negative groups were 72% and 94%, respectively, whereas 5-y DFS were 29% and 55%, respectively. There were significant differences between OS and DFS (P = 0.018 and 0.031, respectively). Multivariate analysis indicated that RAGE was an independent predictor for both OS and DFS (P = 0.048 and 0.032, respectively). CONCLUSIONS: Our data suggest for the first time a positive correlation between RAGE expression and poor therapeutic outcome. Furthermore, RAGE downregulation may provide a novel therapeutic target for HCC. PMID- 25043529 TI - Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer. AB - BACKGROUND: Photodynamic therapy (PDT) is a binary therapy using a drug and high energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery. METHODS: Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm(2) administered continuously over 24 h (10(-2) dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which <=33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed. RESULTS: Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm(2) and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm(2). None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm(2) over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules. CONCLUSIONS: The MTD of CLIPT was established at 50 J/cm(2) administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention. PMID- 25043530 TI - Success of elective cholecystectomy treatment plans after emergency department visit. AB - BACKGROUND: Differentiation between patients with acute cholecystitis and patients with severe biliary colic can be challenging. Patients with undiagnosed acute cholecystitis can incur repeat emergency department (ED) visits, which is resource intensive. METHODS: Billing records from 2000-2013 of all adults who visited the ED in the 30 d preceding their cholecystectomy were analyzed. Patients who were discharged from the ED and underwent elective cholecystectomy were compared with those who were discharged and returned to the ED within 30 d. T-tests, chi-square tests, and multivariable analysis were used as appropriate. RESULTS: From 2000-2013, 3138 patients (34%) presented to the ED within 30 d before surgery, 63% were women, mean age 51 y, and of those 1625 were directly admitted from the ED for cholecystectomy, whereas 1513 patients left the ED to return for an elective cholecystectomy. Patients who were discharged were younger (mean age 49 versus 54 y, P < 0.001) and had shorter ED stays (5.9 versus 7.2 h, P < 0.001) than the patients admitted immediately. Of the discharged patients, 303 (20%) returned to the ED within 30 d to undergo urgent cholecystectomy. Compared with patients with successful elective cholecystectomy after the ED visit, those who failed the pathway were more likely to have an American Society of Anesthesiologists score >=3 and were <40 or >=60 compared with the successful group. CONCLUSIONS: One in five patients failed the elective cholecystectomy pathway after ED discharge, leading to additional patient distress and use of resources. Further risk factor assessment may help design efficient care pathways. PMID- 25043531 TI - The expression and significance of dishevelled in human glioma. AB - BACKGROUND: The proto-oncogene dishevelled (Dvl) is a critical component of the Wnt/beta-catenin signaling pathway, and its elevated expression in various tumor types is associated with malignancy. However, a role for Dvl in glioma has not been explored. MATERIALS AND METHODS: To determine whether Dvl expression is elevated in human glioma, we examined the protein levels in 67 human glioma samples and 3 normal brain specimens by Western blotting and immunohistochemistry. To investigate a possible association of Dvl with the malignant phenotype in glioma, the correlation of the Dvl immunoreactivity score (IRS) with beta-catenin IRS, the tumor proliferation index (PI), and tumor invasion index (II) were determined for each sample. RESULTS: The Dvl IRS, beta catenin IRS, PI, and II increased significantly with the pathologic grade of glioma (P <0.001) with average scores of 3.46 +/- 3.45, 3.92 +/- 3.28, 30.93 +/- 17.92, and 20.43 +/- 11.79, respectively. Furthermore, the PI and II were significantly higher for the Dvl-positive group than the Dvl-negative group (P <0.001). Correlation analysis demonstrated that beta-catenin IRS, PI, and II were positively correlated with Dvl IRS. CONCLUSIONS: Dvl overexpression may contribute to the malignant proliferation and invasion of human glioma. PMID- 25043532 TI - Evaluation of percutaneous ultrasound-guided biopsies of solid mass lesions of the pancreas: a center's 10-year experience. AB - OBJECTIVE: To assess the efficacy and complication rates of percutaneous ultrasound (US)-guided pancreatic mass biopsy and to determine if location of the mass or method of biopsy affects efficacy. METHODS: Imaging, pathology, and clinical records of all patients undergoing percutaneous US-guided pancreatic mass sampling from January 2001 until November 2011 were reviewed. Of 88 pancreatic masses, 13 underwent fine needle aspiration (FNA) only, 60 underwent core needle biopsy only, and 15 underwent both. Diagnostic rate, sensitivity, specificity, accuracy, and positive predictive value and negative predictive value (NPV) based on location of the mass (head/neck vs. body/tail) and method of biopsy (core vs. FNA vs. combined) were determined. The final diagnosis was determined on the basis of follow-up imaging, clinical course, and/or surgical pathology. Complications were assessed by reviewing clinical notes and postprocedural imaging. RESULTS: The overall diagnostic rate, sensitivity, accuracy, and NPV of all 88 biopsies were 94%, 93%, 93%, and 57%, respectively. Five samples were nondiagnostic and considered false negatives. There were no false-positive biopsy results. No significant difference was observed in the diagnostic rate, sensitivity, accuracy, and NPV between core biopsies, FNAs, and combined core and FNA biopsies. Furthermore, no significant difference was found between head/neck and body/tail samplings. In 96.7% (85/88) of the cases, the procedure was uneventful. There were no major complications. CONCLUSIONS: Percutaneous US-guided sampling of pancreatic mass is safe and effective irrespective of location of the mass and method of biopsy. PMID- 25043533 TI - Hypoglossal canal invasion by glomus jugulare tumors: clinico-radiological correlation. AB - The aim of this retrospective study is to assess the rate at which glomus jugulare tumors invade the hypoglossal canal (HC) and to correlate computed tomography (CT) and magnetic resonance imaging (MRI) findings with the clinical evidence of cranial nerve (CN) XII dysfunction. CT and MRI imaging modalities of 31 patients were blindly reviewed by an attending neuroradiologist. Imaging studies identified involvement in 22 tumors (22/31, 71.0%). Thirteen of 22 patients (59.1%) had clinically evident CN XII symptoms. Accuracy rate was 76.7% (23/30) for MRI and 78.6% (11/14) for CT. MRI showed 100% sensitivity but had only 59% specificity and the specificity for CT was 66.7%. When radiologists elucidate HC involvement, it may alter the surgical approach and may lead to more focused/accurate clinical evaluation of tongue function. PMID- 25043534 TI - Evaluations of non-contrast enhanced MR venography with inflow inversion recovery sequence in diagnosing Budd-Chiari syndrome. AB - Non-contrast-enhanced (NCE) inflow inversion recovery magnetic resonance venography (MRV)and digital subtraction angiography (DSA) examination were carried out in 35 patients who were suspected of having Budd-Chiari syndrome (BCS). With DSA as the reference, NCE MRV got 100% in the diagnostic sensitivity, 67.8% in the specificity, 97.1% in the accuracy, 100% in the negative predictive value, and 96.9% in the positive predictive value. The consistency between NCE MRV and DSA in the depiction of IVC was excellent. NCE MRV is regarded as an alternative method in the diagnosis of BCS. PMID- 25043535 TI - Spontaneous migration of a portacath into the azygos vein with subsequent development of a tracheo-azygos fistula. AB - Subcutaneous venous port or 'portacath' devices are widely used, especially in oncology patients. Several potential complications of portacath devices have been well documented. We report a rare case of the spontaneous migration of the tip of a portacath into the azygos vein, with subsequent development of a tracheo-azygos fistula. This resulted in the patient receiving a dose of chemotherapy agent and saline directly into his lungs, which ultimately contributed to his death a few weeks later. To our knowledge, there have been only 10 previously reported cases of inadvertent intrathoracic (mediastinal, pleural or pulmonary) extravasation of chemotherapy agent as a result of central venous catheter malposition or perforation; this is the second reported case of extravasation of chemotherapy agent as a result of migration of a portacath device into the azygos vein. PMID- 25043536 TI - KLK3, PCA3, and TMPRSS2-ERG expression in the peripheral blood mononuclear cell fraction from castration-resistant prostate cancer patients and response to docetaxel treatment. AB - BACKGROUND: To monitor systemic disease activity, the potential of circulating tumor cells (CTCs) bears great promise. As surrogate for CTCs we measured KLK3, PCA3, and TMPRSS2-ERG messenger RNA (mRNA) in the peripheral blood mononuclear cell (PBMC) fraction from a castration-resistant prostate cancer (CRPC) patient cohort and three control groups. Moreover, biomarker response to docetaxel treatment was evaluated in the patient group. METHODS: Blood samples from 20 CRPC patients were analyzed at four different time points (prior to docetaxel treatment, at 9 weeks, 27 weeks, and 2 months after treatment). Blood was drawn once from three control groups (10 age-matched men, 10 men under 35 years of age, 12 women). All samples were analyzed for KLK3, PCA3, and TMPRSS2-ERG mRNA by using a quantitative nucleic acid amplification assay with gene-specific primers in the complementary DNA synthesis. RESULTS: At baseline, mRNA for KLK3 was detected in 17 (89%, 95% CI 76-100%), PCA3 in 10 (53%, 95% CI 30-75%), and TMPRSS2-ERG in seven of 19 evaluable patients (37%, 95% CI 15-59%). In contrast, the blood samples from all 32 healthy volunteers were reproducible negative for all markers. In response to docetaxel treatment, KLK3 levels decreased in 80% (95% CI 60-100%), PCA3 in 89% (95% CI 68-100%), and TMPRSS2-ERG in 86% (95% CI 60 100%) of patients. CONCLUSIONS: The feasibility of a highly sensitive modified nucleic acid amplification assay to assess KLK3, PCA3, and TMPRSS2-ERG mRNA in the PBMC fraction from CRPC patients was demonstrated. Moreover, response of these markers to systemic treatment was shown. PMID- 25043537 TI - The promise of perfect adult tissue repair and regeneration in mammals: Learning from regenerative amphibians and fish. AB - Regenerative medicine promises to greatly impact on human health by improving repair outcomes in a range of tissues and injury contexts. Successful therapies will rely on identifying both intrinsic and extrinsic biological circuits that control wound healing, proliferation, cell survival, and developmental cell fate. Animals such as the zebrafish and the salamander display powerful examples of near-perfect regeneration and scar-free healing in a range of injury contexts not attained in mammals. By studying regeneration in a range of highly regenerative species that maintain regenerative potential throughout life, many instructive and permissive factors have been identified that could assist in the development of regenerative therapies. This review highlights some of the recent observations in immune regulation, epigenetic regulation, stem cell mobilization, and regenerative signatures that have improved our understanding of the regenerative process. Potential opportunities in harnessing this knowledge for future translation into the clinic are discussed. PMID- 25043538 TI - [Introduction. Justification]. PMID- 25043539 TI - [Therapeutic targets in the treatment of dyslipidemia: HDL and non-HDL cholesterol]. AB - Atherogenic dyslipidemia (AD) consists of the combination of an increase in very low density lipoproteins (VLDL), which results in increased plasma triglyceride (TG) levels, with a reduction of levels of high-density lipoprotein bound cholesterol (HDL-C), also accompanied by a high proportion of small and dense LDL particles. AD is considered the main cause of the residual risk of experiencing cardiovascular disease (CVD), which is still presented by any patient on treatment with statins despite maintaining low-density lipoprotein bound cholesterol (LDL-C) levels below the values considered to be the objective. Non HDL cholesterol (non-HDL-c) reflects the number of atherogenic particles present in the plasma. This includes VLDL, intermediate density lipoproteins (IDL) and LDL. Non-HDL-c provides a better estimate of cardiovascular risk than LDL-c, especially in the presence of hypertriglyceridemia or AD. The European guidelines for managing dyslipidemia recommend that non-HDL-c values be less than 100 and 130 mg/dL for individuals with very high and high cardiovascular risk, respectively. However, these guidelines state that there is insufficient evidence to suggest that raising HDL-c levels incontrovertibly results in a reduction in CVD. Therefore, the guidelines do not set recommended HDL-c levels as a therapeutic objective. The guidelines, however, state that individuals with AD on treatment with statins could benefit from an additional reduction in their risk by using fibrates. PMID- 25043540 TI - [The combinations of statins and fibrates: pharmacokinetic and clinical implications]. AB - With mixed dyslipidemia of the atherogenic dyslipidemia type, once the LDL-c objectives have been achieved through statin treatment, there is often a residual risk, for which the addition of a fibrate is recommended. The combination of statins and fibrates has been limited by the possibility of drug interactions, which mostly result in myopathy. Interactions between statins and other drugs are caused by pharmacokinetic mechanisms, mainly by changing the metabolism of statins in the CYP450 enzyme system, in the hepatic glucuronidation pathway or in the transporters responsible for statin distribution in tissues. The most significant adverse eff ect of statins is myopathy, which can also be induced by fibrates and is more frequent when the 2 drugs (statins and fibrates) are combined. This adverse eff ect manifests clinically as myalgia, muscle weakness, increased CK levels and, in its most severe form, rhabdomyolysis. This interaction mainly aff ects gemfibrozil due to its specific action on the CYP450 enzyme system and that interferes with the hepatic glucuronidation of statins by using the same isoenzymes and with organic anion transporters in the liver. When combining statins, we should use other fibric acid derivatives, preferably fenofibrate. PMID- 25043541 TI - [The fixed combination of pravastatin and fenofibrate: what can it provide?]. AB - The treatment of patients with high cardiovascular risk and mixed hyperlipidemia is difficult due to multiple quantitative and qualitative lipid abnormalities. The priority is to reduce LDL-c levels, for which statins are the drug of choice. Despite the benefits of statins, the residual cardiovascular risk is very high in patients with atherogenic dyslipidemia. To reduce this risk, we also need to control non-HDL cholesterol levels, decreasing triglyceride levels and increasing HDL-c levels. To achieve these objectives and lifestyle changes, the use of combined therapy is often required. Fibrates are drugs that can be used in combination with statins to reduce this residual risk. Fenofibrate is well tolerated in combination with statins. The fixed combination of pravastatin/ fenofibrate has been shown to have complementary benefits in the atherogenic lipid profile in general. The combination is well tolerated and is indicated in patients with high risk and mixed hyperlipidemia who have controlled or are close to their objectives for LDL-c levels, using 40-mg pravastatin in monotherapy. The beneficial eff ect of the combination on LDL-c levels is minimal and is primarily observed in non-HDL cholesterol, triglycerides and HDL-c. The combination of pravastatin 40 and fenofibrate 160 can provide a considerable clinical benefit to patients with high risk and mixed atherogenic dyslipidemia, to patients with LDL c levels that are controlled or near the objectives for decreasing their residual risk of lipid origin and is especially useful for patients with type 2 diabetes, obesity and combined metabolic syndrome and familial hyperlipidemia. PMID- 25043543 TI - [Achievement of therapeutic objectives]. AB - Therapeutic objectives for patients with atherogenic dyslipidemia are achieved by improving patient compliance and adherence. Clinical practice guidelines address the importance of treatment compliance for achieving objectives. The combination of a fixed dose of pravastatin and fenofibrate increases the adherence by simplifying the drug regimen and reducing the number of daily doses. The good tolerance, the cost of the combination and the possibility of adjusting the administration to the patient's lifestyle helps achieve the objectives for these patients with high cardiovascular risk. PMID- 25043542 TI - [Efficacy studies]. AB - Pravafenix((r)) is a fixed-dose combination of 40mg of pravastatin and 160 mg of fenofibrate. The rationale behind the use of Pravafenix((r)) is based on the increased residual cardiovascular risk observed in high risk patients with hypertriglyceridemia and/or low HDL cholesterol levels despite treatment with statins in monotherapy. In this article, we review the available evidence on the clinical efficacy of Pravafenix((r)), which shows complementary benefits in the overall lipid profile of high risk patients with mixed dyslipidemia not controlled with 40-mg pravastatin or 20-mg simvastatin. PMID- 25043544 TI - [Combination of pravastatin and fenofibrate (Pravafenix (r)). Safety studies]. AB - Although LDL cholesterol is the primary treatment objective for reducing cardiovascular risk, the increase in triglyceride levels and the reduction of HDL cholesterol levels constitute the so-called residual cardiovascular risk. Treatment with statins combined with fibrates is an actual possibility for the treatment of overall cardiovascular risk. However, this combination is often associated with adverse eff ects, especially muscular and hepatic. Due to its pharmacological characteristics, the combination of pravastatin and fenofibrate can be effective and safe, with few adverse eff ects. In this review, we analyze the available safety studies and conclude that Pravafenix((r)) (the combination of 40-mg pravastatin and 160-mg fenofibrate) achieves complementary benefits on the overall atherogenic lipid profile, is well tolerated and has few adverse eff ects, which is similar to the monotherapy of each of its components. It remains to be seen whether this combination confers additional long-term benefits for patients treated with statins. PMID- 25043545 TI - [Indications for the combination of pravastatin and fenofibrate according to the type of dyslipidemia]. AB - The combination with fixed doses of pravastatin (40 mg) and fenofibrate (160 mg) offers a therapeutic alternative, especially in the comprehensive approach to mixed hyperlipidemia in patients with high cardiovascular risk of metabolic origin. It also ensures the efficacy and safety as a result of the evidence that supports the clinical benefit of both pravastatin in primary and secondary prevention and fenofibrate in patients with atherogenic dyslipidemia. This combination also has few adverse effects, which are similar in all cases to those produced by the isolated monotherapy of each of the drugs. Consequently, the possible indications for this combination include patients with mixed hyperlipidemia, patients with atherogenic dyslipidemia (increased triglyceride levels, reduced HDL-c levels and moderately increased LDL-c levels), patients with hypertriglyceridemia who need to reduce their LDL-c levels, patients with low HDL syndrome who also require a reduction in LDL-c levels, patients with moderate hypercholesterolemia who require an additional reduction of triglyceride levels and especially patients with high atherogenic metabolic risk who require an overall intervention for each of the lipid fractions. PMID- 25043546 TI - [Indications for the combination of pravastatin and fenofibrate according to the cardiovascular risk level. Common clinical situations]. AB - In diabetes, metabolic syndrome, some types of familial dyslipidemia, ischemic pathology of atheromatous origin and renal failure, the presence of mixed dyslipidemia is common. In other words, there is an excess of cholesterol and triglycerides, associated or not with HDL-c deficiency. These clinical conditions are associated with high to very high cardiovascular risk. It is appropriate when treating these conditions to achieve an overall control of lipid metabolism abnormalities, in terms of excess cholesterol carried by atherogenic lipoproteins (LDL-c and non-HDL-c) and triglyceride excess and deficit of HDL-c. To achieve this overall control is necessary to correct the potential causes of secondary dyslipidemia, improve lifestyle habits and use a drug from the statin family, and it is often necessary to combine a drug from the fibrate family. This combination has been shown to be effective and safe in the overall control of dyslipidemia and the cardiovascular risk prevention in patients at high risk. This combination has been shown to have a favorable eff ect in the population with diabetes and microangiopathy, both in the retina and in the glomerulus. For patients with moderate renal failure, the use of fibrates is controversial, and there are marked disagreements between the recommendations issued by various organizations and expert consensus groups. PMID- 25043547 TI - [Reasons for a combination]. PMID- 25043548 TI - Medullary thyroid carcinoma in a patient with MEN 1. PMID- 25043549 TI - Weak antilocalization effect and noncentrosymmetric superconductivity in a topologically nontrivial semimetal LuPdBi. AB - A large number of half-Heusler compounds have been recently proposed as three dimensional (3D) topological insulators (TIs) with tunable physical properties. However, no transport measurements associated with the topological surface states have been observed in these half-Heusler candidates due to the dominating contribution from bulk electrical conductance. Here we show that, by reducing the mobility of bulk carriers, a two-dimensional (2D) weak antilocalization (WAL) effect, one of the hallmarks of topological surface states, was experimentally revealed from the tilted magnetic field dependence of magnetoconductance in a topologically nontrivial semimetal LuPdBi. Besides the observation of a 2D WAL effect, a superconducting transition was revealed at Tc ~ 1.7 K in the same bulk LuPdBi. Quantitative analysis within the framework of a generalized BCS theory leads to the conclusion that the noncentrosymmetric superconductivity of LuPdBi is fully gapped with a possibly unconventional pairing character. The co existence of superconductivity and the transport signature of topological surface states in the same bulk alloy suggests that LuPdBi represents a very promising candidate as a topological superconductor. PMID- 25043550 TI - Structures of yeast 80S ribosome-tRNA complexes in the rotated and nonrotated conformations. AB - The structural understanding of eukaryotic translation lags behind that of translation on bacterial ribosomes. Here, we present two subnanometer resolution structures of S. cerevisiae 80S ribosome complexes formed with either one or two tRNAs and bound in response to an mRNA fragment containing the Kozak consensus sequence. The ribosomes adopt two globally different conformations that are related to each other by the rotation of the small subunit. Comparison with bacterial ribosome complexes reveals that the global structures and modes of intersubunit rotation of the yeast ribosome differ significantly from those in the bacterial counterpart, most notably in the regions involving the tRNA, small ribosomal subunit, and conserved helix 69 of the large ribosomal subunit. The structures provide insight into ribosome dynamics implicated in tRNA translocation and help elucidate the role of the Kozak fragment in positioning an open reading frame during translation initiation in eukaryotes. PMID- 25043551 TI - Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands. AB - The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles. PMID- 25043552 TI - Ocular components during the ages of ocular development. AB - PURPOSE: To determine the distribution of ocular biometric components and their correlation with age and sex during the ages of ocular development in a 6- to 18 year-old population in Iran. METHOD: In this cross-sectional study, which was performed in October 2012, multi-stage stratified cluster sampling was used to sample the study population from Dezful schools, a city in the southwest of Iran. Biometric examinations were done by an experienced optometrist using the LENSTAR/BioGraph (WaveLight AG, Erlangen, Germany). RESULTS: Among 864 selected students, 683 participated in the study (response rate: 79.1%); 377 participants (55.2%) were male, and the mean age of the participants was 12 +/- 3.4 years (range: 6-18 years). The mean and 95% confidence interval of axial length (AL) were 23.13 mm (22.93-23.33), anterior chamber depth (ACD) was 3.01 mm (2.96 3.06), lens thickness (LT) was 3.58 mm (3.55-3.61), central corneal thickness (CCT) was 549.33 mic (546.59-552.07), corneal radius (CR) was 7.77 mm (7.74 7.81), corneal diameter (CD) was 12.34 mm (12.31-12.38) and pupil diameter (PD) was 4.97 (4.91-5.03). Mean AL, ACD, CD and CR were significantly higher in boys, and mean LT was significantly higher in girls. AL and ACD increased, while LT decreased significantly with age. Myopia was associated with an increase in AL and ACD, and hyperopia was associated with an increase in LT and a decrease in ACD. CONCLUSION: This study evaluated the distribution of the biometric components of the eye during the ages of ocular development in an Iranian population. In this age range, the majority of the changes were observed in the AL and LT. PMID- 25043553 TI - Localization and characterization of val-opsin isoform-expressing cells in the brain of adult zebrafish. AB - In addition to vision, light information is used to regulate a range of animal physiology. Such nonimage-forming functions of light are mediated by nonvisual photoreceptors expressed in distinct neurons in the retina and the brain in most vertebrates. A nonvisual photoreceptor vertebrate ancient long opsin (VAL-opsin) possesses two functional isoforms in the zebrafish, encoded by valopa and valopb, which has received little attention. To delineate the neurochemical identities of valop cells and to test for colocalization of the valop isoforms, we used in situ hybridization to characterize the expression of the valop genes along with that of neurotransmitters and a neuropeptide known to be present at the sites of valop expression. Double labeling showed that the thalamic valop population coexpresses valopa and valopb. All the thalamic valop cells overlapped with a GABAergic cell mass that continues from the anterior nucleus to the intercalated thalamic nucleus. A novel valopa cell population found in the superior raphe was serotonergic in nature. A valopb cell population in the Edinger-Westphal nucleus was identified as containing thyrotropin-releasing hormone. Valopb cells localized in the hindbrain intermediate reticular formation were noncholinergic in nature (nonmotorneurons). Thus, the presence of valop cell populations in different brain regions with coexpression of neurotransmitters and neuropeptides and the colocalization of valop isoforms in the thalamic cell population indicate regulatory and functional complexity of VAL-opsin in the brain of the zebrafish. PMID- 25043554 TI - Significance of temporal changes on sexual dimorphism of cranial measurements of Indian population. AB - Revision of discriminant function formulae has always been advocated by anthropologist to take into account the changing pattern of sexual dimorphism due to temporal/secular changes. The present study aims to track temporal changes in cranial measurements of temporally distinct North Indian population and providing updated sex discriminating formulae. A total of 483 adult (20-65 years) crania representing contemporary and sub-recent populations collected from two medical colleges in North India. A total of 11 variables were measured to observe the changes in cranial dimension over time. Analysis of data demonstrated significant sexual and population (contemporary vs sub-recent sample) variations over time. The contemporary males and females exhibited larger cranial dimensions but it expressed less dimorphism than their predecessors. A trend toward brachycephalization was also observed in contemporary females. Maximum cranial length (84%) and biauricular breadth (79%) represent the most dimorphic variables for contemporary and sub-recent sample, respectively. The possible causes of such variations are discussed. PMID- 25043555 TI - Ultrasound-assisted extraction and characterization of hydrolytic and oxidative enzymes produced by solid state fermentation. AB - Ligninolytic and hydrolytic enzymes were produced with six selected fungi on flax substrate by solid state fermentation (SSF). The extracellular enzyme production of the organisms in two SSF media was evaluated by measuring the soluble protein concentration and the filter paper, endoxylanase, 1,4-beta-d-glucosidase, 1,4 beta-d-endoglucanase, polygalacturonase, lignin peroxidase, manganese peroxidase and laccase activities of the clear culture solutions produced by conventional extraction from the SSF materials. The SSF material of the best enzyme producer (Trichoderma virens TUB F-498) was further investigated to enhance the enzyme recovery by low frequency ultrasound treatment. Performance of both the original and ultrasound macerated crude enzyme mixtures was evaluated in degradation of the colored lignin-containing and waxy materials of raw linen fabric. Results proved that sonication (at 40%, 60% and 80% amplitudes, for 60min) did not result in reduction in the filter paper, lignin peroxidase and laccase activities of the crude enzyme solution, but has a significant positive effect on the efficiency of enzyme extraction from the SSF material. Depending on the parameters of sonication, the enzyme activities in the extracts obtained can be increased up to 129-413% of the original activities measured in the control extracts recovered by a common magnetic stirrer. Sonication also has an effect on both the enzymatic removal of the lignin-containing color materials and hydrophobic surface layer from the raw linen. PMID- 25043556 TI - Dependence of pulsed focused ultrasound induced thrombolysis on duty cycle and cavitation bubble size distribution. AB - In this study, we investigated the relationship between the efficiency of pulsed, focused ultrasound (FUS)-induced thrombolysis, the duty cycle (2.3%, 9%, and 18%) and the size distribution of cavitation bubbles. The efficiency of thrombolysis was evaluated through the degree of mechanical fragmentation, namely the number, mass, and size of clot debris particles. First, we found that the total number and mass of clot debris particles were highest when a duty cycle of 9% was used and that the mean diameter of clot debris particles was smallest. Second, we found that the size distribution of cavitation bubbles was mainly centered around the linear resonance radius (2.5MUm) of the emission frequency (1.2MHz) of the FUS transducer when a 9% duty cycle was used, while the majority of cavitation bubbles became smaller or larger than the linear resonance radius when a 2.3% or 18% duty cycle was used. In addition, the inertial cavitation dose from the treatment performed at 9% duty cycle was much higher than the dose obtained with the other two duty cycles. The data presented here suggest that there is an optimal duty cycle at which the thrombolysis efficiency and cavitation activity are strongest. They further indicate that using a pulsed FUS may help control the size distribution of cavitation nuclei within an active size range, which we found to be near the linear resonance radius of the emission frequency of the FUS transducer. PMID- 25043557 TI - Influence of acoustic pressure and bubble sizes on the coalescence of two contacting bubbles in an acoustic field. AB - In this study, the coalescence time between two contacting sub-resonance size bubbles was measured experimentally under an acoustic pressure ranging from 10kPa to 120kPa, driven at a frequency of 22.4kHz. The coalescence time obtained under sonication was much longer compared to that calculated by the film drainage theory for a free bubble surface without surfactants. It was found that under the influence of an acoustic field, the coalescence time could be probabilistic in nature, exhibiting upper and lower limits of coalescence times which are prolonged when both the maximum surface approach velocity and secondary Bjerknes force increases. The size of the two contacting bubbles is also important. For a given acoustic pressure, bubbles having a larger average size and size difference were observed to exhibit longer coalescence times. This could be caused by the phase difference between the volume oscillations of the two bubbles, which in turn affects the minimum film thickness reached between the bubbles and the film drainage time. These results will have important implications for developing film drainage theory to account for the effect of bubble translational and volumetric oscillations, bubble surface fluctuations and microstreaming. PMID- 25043558 TI - First evidence of Vasa expression in differentiating male germ cells of a reptile. PMID- 25043559 TI - Civil society and the Health and Social Care Act in England and Wales: theory and praxis for the twenty-first century. AB - In this paper we revisit the notion of civil society in the light of recent attempts to privatize health care in England via the passing of the Health and Social Care Act of 2013. This legislation promises a re-commodification of the National Health Service (NHS) in England. The Bill was bitterly contested during its passage through parliament, most vigorously in 2011. Much of the opposition occurred at a time of widespread, global rebellion, most notably in the 'Arab uprisings' and through the 'occupy movement'. Despite a plethora of protests, we argue, a non-porous boundary between what we call the 'protest sector' of civil society and the wider public sphere of the lifeworld has become apparent in England. A good deal of collective action, whether campaign-focused (like opposition to the Health and Social Care Bill) or more generalized (like rejections of corporate greed), has so far proved ineffective, at least in the short-term; no crisis of legitimation is apparent. We highlight a new 'class/command dynamic', leading to oligarchic rule, in the present era of financial capitalism. We use this health care case-study to re-examine the notion of civil society and its changing properties in what Castells calls a 'networked society'. The contribution ends with a discussion of the role of the sociologist re-civil society and the advocacy of both 'action' and 'foresight sociologies'. PMID- 25043560 TI - The role of civil society organizations in the institutionalization of indigenous medicine in Bolivia. AB - December 2013 marked a significant shift in Bolivia with the enactment of a law for the inclusion of indigenous doctors in the National Health System. This article traces the constellation of forces that led to the institutionalization of indigenous medicine in Bolivia. It identifies three factors contributing to this health policy change. The first factor is the crystallization of a strong indigenous movement fighting for the recognition of cultural rights through the foundation of civil society organizations. Second is the rise to power of Evo Morales, the first Latin American president of indigenous origin, who has promoted multicultural policies, formally supported through the promulgation of a new constitution. Lastly is the influence of the global acceptance of alternative medicine. Indigenous doctor organizations in Bolivia have been highly involved throughout the entire process of institutionalization and have played a crucial role in it. An analysis of the relationship between these civil society organizations and the Bolivian government reveals a strong partnership. This dynamic can be described in terms of Interdependence Theory, as each party relied on the other in the promotion and practice of the law to achieve the integration of indigenous medicine as part of the Bolivian Health System. PMID- 25043561 TI - [Prevalence and clinical characteristics of oral bony outgrowth in a Moroccan population]. AB - OBJECTIVES: Oral bony outgrowths (OBOs) are localized bony protuberances that arise from the cortical plate. Various types of OBOs have been described, the precise designation of which depends on anatomic location such as torus palatinus, torus mandibularis, buccal exostosis, or palatal exostosis. We had for aim to determine the prevalence and clinical characteristics of OBOs in a Moroccan population. METHODS: This cross-sectional study was conducted between March 15 and June 30, 2011 at the Rabat-Sale teaching hospital dental consultation and treatment center, in Morocco. Three hundred and fifty-three patients (160 female and 193 male patients), 11 to 82 years of age, were examined clinically and radiologically to determine the presence of OBO. RESULTS: Twenty four patients (6.8%) presented with OBOs. The prevalence for exostosis, torus mandibularis, torus palatinus, and associated OBOs was 3.1%, 2%, 0.8%, and 0.9% respectively. There was a significant difference (P=0,01) between the average age for patients presenting with OBO (43.2+/-12 years of age) and the average age for patients without any OBO (36.5+/-16 years of age). The prevalence of OBOs in female patients (7.3%) was higher than in male patients (6.3%) but the difference was not significant (P=0.439). Patients with occlusal parafunctional activity presented with significantly more OBO (P=0.016). DISCUSSION: The reported prevalence of OBO is extremely variable, according to age, gender, and ethnic group. The occurrence of OBO could be triggered by genetic factors associated with environmental factors. PMID- 25043562 TI - [Orthognathic surgery for patients with cleft lip and palate]. AB - Patients with cleft lip and palate frequently develop dento-facial deformity requiring orthognatic surgery. The origin of this deformity is therapeutic and surgeons are currently trying to prevent this iatrogenicity. The maxillary dento facial deformity in these patients is a retrognathia with infragnathia, associated with endognathia, obliquity of the occlusal plane, with deviation of the superior incisive midline in case of unilateral clefts. The difficulties in the treatment of these skeletal deformities are due to the palatal, labial, and pterygomaxillary scar tissue. Orthognathic surgery is most of the time bimaxillary with a 3-dimensional movement of the jaws including maxillary advancement. The aims of surgery are occlusal, esthetic, and functional improvement. The first step is gingivoperiosteoplasty (ideally performed during childhood), orthodontic treatment including, if necessary, transversal maxillary distraction to obtain enough space to replace the lateral incisor; extraction of premolars should be avoided if possible. Planning and performing the treatment are difficult for the orthodontist and for the surgeon. Maxillary advancement by distraction may be an interesting alternative to prevent partial relapse. Obtaining normal oro-facial functions are required for a stable result. These should be monitored after the primary treatment by the whole staff, surgeons, speech therapist, and orthodontists. Performing Le Fort 1 osteotomy is more difficult than in other patients because of scar fibrosis than needs to be released. PMID- 25043563 TI - Expression of EpCAM and prognosis in early-stage glottic cancer treated by radiotherapy. AB - OBJECTIVES/HYPOTHESIS: Treatment of head and neck squamous cell carcinoma (HNSCC) often requires radiotherapy, but relapse can occur. There is, therefore, an urgent need for the identification of a predictive novel biomarker for radiosensitivity. The epithelial cell adhesion molecule (EpCAM) has been shown to promote the transformation of malignant tumors, and EpCAM may have prognostic significance, but it is not known if EpCAM determines prognosis, especially with respect to radiotherapy. Therefore, we determined the incidence of the expression of EpCAM in HNSCC and analyzed the prognostic value in patients with early-stage glottic cancer treated with radiotherapy. STUDY DESIGN: Retrospective analysis. METHODS: All patients with HNSCCs examined in our hospital between January 2012 and February 2013 were analyzed prospectively for the expression of EpCAM. T1-2N0 glottic cancer patients who were primarily treated by radiation therapy between 1995 and 2008 were retrospectively investigated. Patients with or without local recurrence after radical radiation therapy were extracted. The relationship between local recurrence and histopathologic EpCAM expression was compared within these two groups. RESULTS: One hundred eighteen patients with HNSCCs from the nasopharynx, oropharynx, hypopharynx, larynx, oral cavity, paranasal cavity, unknown primary, and other sites were analyzed. Positive expression of EpCAM was noted in the oropharynx, hypopharynx, and larynx (72%, 90%, and 58%, respectively). Seventeen and 22 patients with or without local recurrence were extracted, respectively. There was no difference between two groups, with the exception of EpCAM expression. CONCLUSIONS: The expression of EpCAM in HNSCC was investigated. Patients with strong EpCAM expression were associated with local recurrence after primary radiation therapy. LEVEL OF EVIDENCE: NA PMID- 25043564 TI - Evaluation of a Brucella melitensis mutant deficient in O-polysaccharide export system ATP-binding protein as a rough vaccine candidate. AB - Rough Brucella mutants have been sought as vaccine candidates that do not interfere with the conventional serological diagnosis of brucellosis. In this study, a rough mutant of Brucella melitensis was generated by the disruption of the wzt gene, which encodes the O-polysaccharide (O-PS) export system ATP-binding protein. In vivo, the mutant 16MDeltawzt was attenuated and conferred a level of protection against B. melitensis 16M challenge similar to that conferred by the vaccine strain B. melitensis M5 in mice. In pregnant sheep, the mutant 16MDeltawzt did not induce abortion. In vitro, 16MDeltawzt was more susceptible to polymyxin B and complement-mediated killing than B. melitensis 16M was. Most importantly, although 16MDeltawzt had a rough phenotype, it was able to synthesize O-PS and did not induce detectable specific antibodies in sheep. These results suggested that 16MDeltawzt deserved to further systematic evaluation as a vaccine for target animal hosts due to its promising features. PMID- 25043565 TI - Benzothiophene or benzofuran bridges in diaryl ethenes: two-step access by pd catalyzed C-H activation and theoretical/experimental studies on their photoreactivity. AB - A series of terarylenes incorporating benzothiophene (BT)/benzofuran (BF) as the central ethene unit was synthesised by using sequential Pd-catalysed C-H activation reactions. This new methodology allows the easy modification of the nature of the pendant heteroarene groups. Diaryl ethene (DAE) derivatives with thiophene, thiazole, pyrrole, isoxazole and pyrazole rings were prepared. A large number of asymmetrical DAEs are easily accessible by this new method in both the BT and BF series. The study of their photochromic properties in solution revealed that the nature of the heteroarene and of the central unit drastically modify their photochromic behaviour. TD-DFT calculations were performed to assess the nature of the relevant excited states. PMID- 25043566 TI - Tamai zone I fingertip replantation: is external bleeding obligatory for survival of artery anastomosis-only replanted digits? AB - BACKGROUND: Distal fingertip replantation is associated with good functional and aesthetic results. Venous anastomosis is the most challenging procedure. For replantation with an artery anastomosis-only procedure (no venous anastomosis), some protocols have been designed to relieve venous congestion involve anticoagulation and the creation of wounds for persistent bleeding. This report presents the authors' experience of fingertip survival after artery anastomosis only replantation with no persistent external bleeding. METHODS: Twelve Tamai zone I fingertip total amputation patients who underwent artery anastomosis-only replantations were recruited from February 2009 to June 2012. Nerve repair was performed if identified. The patients were not subjected to conventional external bleeding methods. Both the blood color on pinprick and fingertip temperature difference between the replanted and uninjured digits were used as indicators of deteriorated venous congestion. RESULTS: The replanted digits of 11 patients survived. The only failed replant exhibited an average temperature difference of more than 6 degrees C compared with the uninjured digits and consistently exhibited darker blood during the pinprick test. All other replants exhibited average temperature differences of less than 6 degrees C. CONCLUSIONS: In these Tamai zone I artery anastomosis-only replantations, fingertips survived without the use of external bleeding method, indicating that external bleeding is probably not obligatory for survival of artery anastomosis-only replanted digits distal to Tamai zone I. An increasing temperature difference between the replanted and uninjured digits and darker blood on pinprick may be used as indicators of deteriorating congestion signs. PMID- 25043567 TI - Motivation and manipulation capacities of the blue and yellow macaw and the tufted capuchin: a comparative approach. AB - This study compared the motivation of the blue and yellow macaw (n=8) and the tufted capuchin (n=3) to manipulate objects that presented different features, their manipulative repertoires, and their ability to solve complex manipulation tasks. Results show that both species seem to be more motivated to manipulate objects that look like food items and that manipulative behavior may be considered as play behavior in the blue and yellow macaws, and would improve foraging motor skills. The tufted capuchins performed more different action styles than the macaws when manipulating objects, and performed substrate-use behavior - the object is put in relationship with a substrate - while the macaws did not. This is an interesting difference because these characteristics are supposed to be precursory of tool-use, behavior never observed in this macaw species. It may be due to the arboreal lifestyle of the macaw and its neophobic character that do not allow it to easily contact objects. Following the same method and using more individuals, further comparative studies should be conducted in order to test these hypotheses. Both species were able to solve complex manipulation tasks. PMID- 25043568 TI - Vocal output predicts territory quality in a Neotropical songbird. AB - Females who choose highly ornamented mates may gain resources that improve offspring production and survival. Studies have focused on the relationship between male quality and the complexity of sexual ornaments; however, less is known of the communicative content of courtship displays, and whether they indicate the quality of resources males can provide to mates. Here, we used blue black grassquits (Volatinia jacarina) to test the relationship between male display attributes and territory quality, measured as food availability. Our main hypothesis was that territory quality would be better predicted by dynamic displays than by static ornaments. During four breeding seasons in central Brazil, we quantified display song attributes (output and consistency) and the timing of nuptial molt. We measured territorial seed density, body condition, and ectoparasite infestation. We found a positive relationship between song output and territory seed density, suggesting this attribute provides a reliable indicator of territory quality. However, the timing of molt was unrelated to territory quality. Additionally, no other male attribute was associated with seed density. The link between song output and territory quality might reflect variation in male condition in response to territorial resources, or extra time males on higher quality territories have to invest in territorial defense. This article is part of a Special Issue entitled: Neotropical Behaviour. PMID- 25043569 TI - The promotion of a constructive macrophage phenotype by solubilized extracellular matrix. AB - The regenerative healing response of injured skeletal muscle is dependent upon a heterogeneous population of responding macrophages, which show a phenotypic transition from the pro-inflammatory M1 to the alternatively activated and constructive M2 phenotype. Biologic scaffolds derived from mammalian extracellular matrix (ECM) have been used for the repair and reconstruction of a variety of tissues, including skeletal muscle, and have been associated with an M2 phenotype and a constructive and functional tissue response. The mechanism(s) behind in-vivo macrophage phenotype transition in skeletal muscle and the enhanced M2:M1 ratio associated with ECM bioscaffold use in-vivo are only partially understood. The present study shows that degradation products from ECM bioscaffolds promote alternatively activated and constructive M2 macrophage polarization in-vitro, which in turn facilitates migration and myogenesis of skeletal muscle progenitor cells. PMID- 25043570 TI - Magnetic targeting of cardiosphere-derived stem cells with ferumoxytol nanoparticles for treating rats with myocardial infarction. AB - Stem cell transplantation is a promising therapeutic strategy for acute or chronic ischemic cardiomyopathy. A major limitation to efficacy in cell transplantation is the low efficiency of retention and engraftment, due at least in part to significant early "wash-out" of cells from coronary blood flow and heart contraction. We sought to enhance cell retention and engraftment by magnetic targeting. Human cardiosphere-derived stem cells (hCDCs) were labeled with FDA-approved ferumoxytol nanoparticles Feraheme((r)) (F) in the presence of heparin (H) and protamine (P). FHP labeling is nontoxic to hCDCs. FHP-labeled rat CDCs (FHP-rCDCs) were intracoronarily infused into syngeneic rats, with and without magnetic targeting. Magnetic resonance imaging, fluorescence imaging, and quantitative PCR revealed magnetic targeting increased cardiac retention of transplanted FHP-rCDCs. Neither infusion of FHP-rCDCs nor magnetic targeting exacerbated cardiac inflammation or caused iron overload. The augmentation of acute cell retention translated into more attenuated left ventricular remodeling and greater therapeutic benefit (ejection fraction) 3 weeks after treatment. Histology revealed enhanced cell engraftment and angiogenesis in hearts from the magnetic targeting group. FHP labeling is safe to cardiac stem cells and facilitates magnetically-targeted stem cell delivery into the heart which leads to augmented cell engraftment and therapeutic benefit. PMID- 25043572 TI - Active targeting of early and mid-stage atherosclerotic plaques using self assembled peptide amphiphile micelles. AB - Inflammatory cell adhesion molecules expressed by endothelial cells on the luminal surface of atherosclerotic plaques, such as vascular cell adhesion molecule-1 (VCAM-1), provide a rational target for diagnostic and therapeutic delivery vehicles. Therefore, the potential of using spherical, self-assembled micelles synthesized from VCAM-1 targeted peptide amphiphile molecules was examined for the ability to specifically bind to both early and mid-stage atherosclerotic plaques. In vitro, cells incubated with VCAM-1 targeted and dye labeled micelles show enhanced fluorescence signal as compared to cells incubated with a PEG micelle control. In vivo, VCAM-1 targeted and Cy7-labeled peptide amphiphile micelles were shown to specifically accumulate at atherosclerotic plaques in both early and mid-stage ApoE -/- mice through co-localization of Cy7 signal with anti-VCAM-1 antibody staining in fixed tissue. No specific accumulation was observed with a PEG micelle control. Histological analysis of excised tissue provided evidence for the in vivo biocompatibility of these micelle formulations as no tissue damage was observed. These results demonstrate that VCAM-1 targeted micelles have potential as a platform for targeted drug delivery to multiple stages of atherosclerotic plaque formation due to their established specificity and safety. PMID- 25043571 TI - ECM hydrogel coating mitigates the chronic inflammatory response to polypropylene mesh. AB - Polypropylene has been used as a surgical mesh material for several decades. This non-degradable synthetic polymer provides mechanical strength, a predictable host response, and its use has resulted in reduced recurrence rates for ventral hernia and pelvic organ prolapse. However, polypropylene and similar synthetic materials are associated with a chronic local tissue inflammatory response and dense fibrous tissue deposition. These outcomes have prompted variations in mesh design to minimize the surface area interface and increase integration with host tissue. In contrast, biologic scaffold materials composed of extracellular matrix (ECM) are rapidly degraded in-vivo and are associated with constructive tissue remodeling and minimal fibrosis. The objective of the present study was to assess the effects of an ECM hydrogel coating on the long-term host tissue response to polypropylene mesh in a rodent model of abdominal muscle injury. At 14 days post implantation, the ECM coated polypropylene mesh devices showed a decreased inflammatory response as characterized by the number and distribution of M1 macrophages (CD86+/CD68+) around mesh fibers when compared to the uncoated mesh devices. At 180 days the ECM coated polypropylene showed decreased density of collagen and amount of mature type I collagen deposited between mesh fibers when compared to the uncoated mesh devices. This study confirms and extends previous findings that an ECM coating mitigates the chronic inflammatory response and associated scar tissue deposition characteristic of polypropylene. PMID- 25043573 TI - Integrin alpha2beta1 targeted GdVO4:Eu ultrathin nanosheet for multimodal PET/MR imaging. AB - Multifunctional nanoprobes open exciting possibilities for accurate diagnosis and therapy. In this research, we developed a (64)Cu-labeled GdVO4:4%Eu two-dimension (2D) tetragonal ultrathin nanosheets (NSs) that simultaneously possess radioactivity, fluorescence, and paramagnetic properties for multimodal imaging. The carboxyl-functionalized Eu(3+)-doped GdVO4 NSs were synthesized by a facile solvothermal reaction, followed by ligand exchange with polyacrylic acid (PAA). With ultrathin thickness of ~5 nm and width of ~150 nm, the carboxyl functionalized NSs were further modified by DOTA chelator for (64)Cu labeling and Asp-Gly-Glu-Ala (DGEA) peptide for integrin alpha2beta1 targeting. After initial evaluation of the cytotoxicity and targeting capability with PC-3 cells, the obtained multifunctional nanoprobes ((64)Cu-DOTA-GdVO4:4%Eu-DGEA) were further explored for targeted positron emission tomography (PET) and T1-weighted magnetic resonance imaging (MRI) of PC-3 tumor (prostate cancer, high integrin alpha2beta1 expression) in vivo. Based on the strong fluorescence of the NSs, the particle distribution in mouse tissues was also determined by fluorescent microscopy. In summary, GdVO4:4%Eu NS is a potential multimodal multiscale nanoprobe that could not only be used for in vivo imaging, but also be tracked in cellular scale and ex vivo due to its fluorescent property. PMID- 25043574 TI - The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo. AB - Patients with melanoma may develop skin depigmentation spontaneously or following therapy, referred to as melanoma-associated leucoderma (MAL). As clinical presentation of MAL may precede primary/metastatic melanoma detection, recognition of MAL is important to prevent its misdiagnosis as vitiligo and the subsequent application of immunosuppressive treatment. To reveal the immunity involved in MAL development, we investigated the presence of antibody and T-cell immune responses directed against the melanocyte-differentiation-antigens MART-1 (Melan-A), tyrosinase and gp100 in patients with MAL, as compared to patients with vitiligo. Autoantibodies to gp100 and tyrosinase were commonly found in both diseases. Interestingly, MART-1 antibodies were only present in patients with MAL. Melanocyte antigen-specific T cells were found in all patients, with relatively more specific T cells in patients with active vitiligo. Although MAL and vitiligo may appear clinically similar, our results indicate that the humoral immune responses against MART-1 differ between these diseases, which can help to differentiate MAL from vitiligo. PMID- 25043575 TI - Improved SENSE imaging using accurate coil sensitivity maps generated by a global magnitude-phase fitting method. AB - PURPOSE: To develop a novel coil sensitivity processing technique that is able to reduce or eliminate aliasing artifacts and noise amplification in image-domain parallel imaging (i.e., SENSE). METHODS: Initial coil sensitivity maps were derived from the center k-space lines by a common self-calibration method. Then continuous trigonometric functions were used to fit both magnitude and phase maps of the self-calibrated coil sensitivity profile globally. Further, the global fitted coil sensitivity maps were adopted for SENSE reconstruction. Numerical simulations, as well as experiments on phantoms and human subjects were performed to evaluate and compare the effectiveness of this global magnitude-phase fitting approach with traditional local fitting methods. RESULTS: Both simulation and experimental results demonstrated that the proposed novel global fitting method was able to obtain accurate coil sensitivity profiles without Gibbs oscillations. The resultant SENSE images were improved substantially in terms of aliasing imaging artifacts. CONCLUSION: A global magnitude-phase fitting method for better estimation of accurate coil sensitivity maps was developed, and it was successfully used in producing high-quality parallel images. Magn Reson Med 74:217-224, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25043576 TI - Rationalizing the structural variability of the exocyclic amino groups in nucleobases and their metal complexes: cytosine and adenine. AB - The exocyclic amino groups of cytosine and adenine nucleobases are normally almost flat, with the N atoms essentially sp(2) hybridized and the lone pair largely delocalized into the heterocyclic rings. However, a change to marked pyramidality of the amino group (N then sp(3) hybridized, lone pair essentially localized at N) occurs during i) involvement of an amino proton in strong hydrogen bonding donor conditions or ii) with monofunctional metal coordination following removal of one of the two protons. PMID- 25043577 TI - Skeletal manifestations of stress in child victims of the Great Irish Famine (1845-1852): prevalence of enamel hypoplasia, Harris lines, and growth retardation. AB - The Great Irish Famine of 1845-1852 is among the worst food crises in human history. While numerous aspects of this period have been studied by generations of scholars, relatively little attention has so far been given to the physiological impact it is likely to have had on the people who suffered and succumbed to it. This study examines the prevalence of enamel hypoplasia, Harris lines, and growth retardation in the nonadult proportion of a skeletal population comprising victims of the Famine who died in the workhouse in the city of Kilkenny between 1847 and 1851. The frequency of enamel hypoplasia in these children does not appear to have increased as a consequence of famine, although this fact is likely to be a reflection of the osteological paradox. Harris lines and growth retardation; however, were very prevalent, and the manifestation and age-specific distribution of these may be indicators of the Famine experience. While there was no clear correlation in the occurrence of the assessed markers, the presence of cribra orbitalia displayed a significant relationship to enamel hypoplasia in 1- to 5-year-old children. While starvation, metabolic disorders and infectious diseases are likely to have greatly contributed to the manifestation of the markers, the psychosocial stress relating to institutionalization in the workhouse should not be underestimated as a substantial causative factor for skeletal stress in this population. PMID- 25043578 TI - Dissociation of early shock in takotsubo cardiomyopathy from either right or left ventricular systolic dysfunction. AB - BACKGROUND: Takotsubo cardiomyopathy (TTC) is often associated with hypotension and shock. However, development of hypotension/shock in TTC is not closely related to extent of left ventricular (LV) hypokinesis. We sought to determine whether additional right ventricular (RV) involvement in TTC might contribute to hypotension and shock development and thus to prolonged hospital stay (PHS). METHODS: We evaluated 102 consecutive TTC patients with acute transthoracic echocardiography (TTE) to detect RV hypokinesis. Correlates of hypotension, shock and PHS were identified by univariate and multivariate analyses. RESULTS: Of the 102 patients evaluated, 33% had RV hypokinesis but only 9% had extensive RV involvement. Within the first 24 hours of admission, severe hypotension (systolic blood pressure (SBP) <= 90 mmHg) occurred in 21% of the patients and shock (hypotension + peripheral organ hypo-perfusion) in 16.6% of cases. RV involvement was a univariate but not a multivariate correlate of either hypotension or shock and did not result in PHS. On the other hand, RV involvement predicted more extensive LV hypokinesis and LV systolic dysfunction. CONCLUSIONS: In TTC, RV hypokinesis occurs in approximately 33% of cases and correlates with more severe LV wall motion abnormality but not with development of hypotension or shock. These data therefore reinforce previous findings that hypotension/shock in TTC are not purely by impaired cardiac output. PMID- 25043579 TI - Questioning the benefits of statin therapy in older people without established cardiovascular disease. PMID- 25043580 TI - Extracorporeal-assisted rewarming in the management of accidental deep hypothermic cardiac arrest: a systematic review of the literature. AB - A systematic review of the literature surrounding the use of Extra-Corporeal Assisted Rewarming (ECAR) in patients presenting with deep hypothermia or hypothermic cardiac arrest was undertaken using a structured protocol. Thirty-one papers were deemed suitable for review, 13 of these were of sufficient quality to permit systematic data analysis. The primary outcome measure was survival to hospital discharge. The secondary outcome measure was functional neurological status at last follow-up. Analysis revealed a 67.7% survival to discharge and a 61.5% rate of good neurological recovery for patients presenting with pure hypothermic cardiac arrest. This was in marked contrast to a 23.4% survival and a 9.4% rate of good neurological outcome in those presenting with a mixed hypoxic/hypothermic arrest. Other data revealed a survival benefit for patients presenting with deep hypothermia without cardiac arrest treated with ECAR compared to those treated with conventional rewarming techniques. Hypoxic arrest, serum potassium > 10 mmol/L and presenting rhythm of asystole were found likely be significant predictors of poor outcome. Innovative reperfusion and rewarming strategies are also reviewed. PMID- 25043581 TI - The mitochondrion as a key regulator of ischaemic tolerance and injury. AB - Vascular pathologies pose a significant health problem because of their wide prevalence and high impact on the rate of mortality. Blockade of blood flow in major blood vessels leads to ischaemia associated with oxidative stress, where mitochondria act as a major source of reactive oxygen species (ROS). While low levels of ROS perform a necessary function in normal cellular signalling and metabolism, elevated levels under pathological conditions are detrimental both at the cell and organ level. While cellular oxygenation is necessary to maintain tissue viability, a key pathological occurrence when restoring blood flow to ischaemic tissues is the subsequent burst of ROS generation following reoxygenation, resulting in a cascade of ROS-induced ROS release. This oxygen 'paradox' is a constraint in clinical practice, that is, the need for rapid and maximal restoration of blood flow while at the same time minimising the harmful impact of reperfusion injury on damaged tissues. Mitochondria play a central role in many signalling pathways, including cardioprotection against ischaemic injury and ROS signalling, thus the main target of any anti-ischaemic protective or post injury therapeutic strategy should include mitochondria. At present, one of the most effective strategies that provide mitochondrial tolerance to ischaemia is ischaemic preconditioning. In addition, pharmacological preconditioning which mimics intrinsic natural protective mechanisms has proven effective at priming biological mechanisms to confront ischaemic damage. This review will discuss the role of mitochondria in contributing to acute ischaemia-reperfusion (IR) injury, and mechanisms of cardioprotection in respect to mitochondrial signalling pathways. PMID- 25043582 TI - Fluoroscopic ring of pannus within a mechanic mitral valve: a novel sign of calcified pannus infiltration. PMID- 25043583 TI - Awake extracorporeal membrane oxygenation (ECMO) as bridge to recovery after left main coronary artery occlusion: a promising concept of haemodynamic support in cardiogenic shock. AB - Cardiogenic shock following acute myocardial infarction is associated with high mortality rate. Different management concepts including fluid management, inotropic support, intra aortic balloon counterpulsation (IABP) and extracorporeal membrane oxygenation (ECMO) mainly in mechanically ventilated patients have been used as cornerstones of management. However, success rates have been disappointing. Few reports suggested that ECMO when performed under circumvention of mechanical ventilation, may offer some survival benefits. We herein present our experience with the use of veno-arterial ECMO as bridge to recovery in an awake and spontaneously breathing patient after left main coronary artery occlusion complicated by cardiogenic shock. PMID- 25043584 TI - An important amino acid in nucleoprotein contributes to influenza A virus replication by interacting with polymerase PB2. AB - The nucleoprotein (NP) of influenza A virus plays a critical role in the formation of viral ribonucleoprotein (vRNP) complex. However, it remains unclear which key residues in NP are associated with the assembly of vRNP and contribute to virus replication. Here, a highly conserved aspartic acid at residue 88 (D88) of NP was identified by molecular docking of NP with the Fv region of a broad spectrum anti-NP mAb 19C10 and further demonstrated to be an important residue contributes to the RNP activity, virus growth in MDCK cells and replication in lungs of infected mice by comparing recombinant wild-type A/WSN/1933 virus to the mutant virus that contains an alanine instead of aspartic acid at NP residue 88. D88 was also predicted to interact with PB2 by molecular docking and further verified by immunoprecipitation. These findings provide new information for understanding the interaction between NP and other polymerase subunits in virus replication. PMID- 25043585 TI - Conservation in China of a novel group of HCV variants dating to six centuries ago. AB - We characterized a novel group of HCV variants that are genetically related but distinct from each other belonging to genotype 6 (HCV-6). From 26 infected Austronesian-descended aborigines on Hainan Island, China, HCV sequences were determined followed by genetic analyses. Six nearly full-length genomes and 20 E1 sequences of HCV were obtained, which differ from each other and from all known HCV lineages by nucleotides above the intra-subtype level of 13%. Together with subtypes 6g and 6w, they constitute a phylogenetic group sharing a common ancestor dating from the end of the 12th century. CONCLUSION: Our data indicate the maintenance of an isolated HCV-6 indigenous circulation on Hainan Island at least for six centuries. PMID- 25043586 TI - Role of skin immune cells on the host susceptibility to mosquito-borne viruses. AB - Due to climate change and the propagation of competent arthropods worldwide, arboviruses have become pathogens of major medical importance. Early transmission to vertebrates is initiated by skin puncture and deposition of virus together with arthropod saliva in the epidermis and dermis. Saliva components have the capacity to modulate skin cell responses by enhancing and/or counteracting initial replication and establishment of systemic viral infection. Here, we review the nature of the cells targeted by arboviruses at the skin level and discuss the type of cellular responses elicited by these pathogens in light of the immunomodulatory properties of arthropod vector-derived salivary factors injected at the inoculation site. Understanding cutaneous arbovirus-host interactions may provide new clues for the design of future therapeutics. PMID- 25043587 TI - Characterization of S class gene segments of a newly isolated turkey arthritis reovirus. AB - We report on the complete characterization of S class gene segments of 12 newly isolated turkey arthritis reoviruses (TARVs) and compare it with that of a turkey enteric reovirus (TERV). Phylogenetic analysis of S2, S3 and S4 genome segments revealed grouping of all TARVs into two lineages while, on the basis of S1 genome segment, only one lineage was found. All TARVs had 95-100% nucleotide identity based on sigma C protein sequences (S1 segment) but varied from 90-100%, 88.9 100% and 88.7-100% on the basis of S2, S3, and S4 genome segments, respectively. Point mutations as well as possible re-assortments were observed in TARVs throughout the S class indicating the need for extensive epidemiological studies on these viruses in hatcheries and commercial farms, which would be useful in determining virus variation in the field. PMID- 25043588 TI - Divergent immune responses and disease outcomes in piglets immunized with inactivated and attenuated H3N2 swine influenza vaccines in the presence of maternally-derived antibodies. AB - Live-attenuated influenza virus (LAIV) prime-boost vaccination previously conferred protection against heterologous H3N2 swine influenza challenge, including in piglets with maternally derived antibodies (MDA). Conversely, a whole-inactivated virus (WIV) vaccine was associated with enhanced disease. This study was aimed at identifying immune correlates of cross-protection. Piglets with and without MDA received intramuscular adjuvanted WIV or intranasal LAIV, and were challenged with heterologous H3N2. WIV induced cross-reactive IgG, inhibited by MDA, and a moderate T cell response. LAIV elicited mucosal antibodies and T cells cross-reactive to the heterologous challenge strain. The presence of MDA at LAIV vaccination blocked lung and nasal antibody production, but did not interfere with T cell priming. Even without mucosal antibodies, MDA positive LAIV vaccinates were protected, indicating a likely role for T cells. Based on the data, one LAIV dose can induce cell-mediated immunity against antigenically divergent H3N2 influenza virus despite passive antibody interference with humoral immune responses. PMID- 25043590 TI - In vivo powering of pacemaker by breathing-driven implanted triboelectric nanogenerator. AB - The first application of an implanted triboelectric nanogenerator (iTENG) that enables harvesting energy from in vivo mechanical movement in breathing to directly drive a pacemaker is reported. The energy harvested by iTENG from animal breathing is stored in a capacitor and successfully drives a pacemaker prototype to regulate the heart rate of a rat. This research shows a feasible approach to scavenge biomechanical energy, and presents a crucial step forward for lifetime implantable self-powered medical devices. PMID- 25043589 TI - Three-dimensional reconstructions of the bacteriophage CUS-3 virion reveal a conserved coat protein I-domain but a distinct tailspike receptor-binding domain. AB - CUS-3 is a short-tailed, dsDNA bacteriophage that infects serotype K1 Escherichia coli. We report icosahedrally averaged and asymmetric, three-dimensional, cryo electron microscopic reconstructions of the CUS-3 virion. Its coat protein structure adopts the "HK97-fold" shared by other tailed phages and is quite similar to that in phages P22 and Sf6 despite only weak amino acid sequence similarity. In addition, these coat proteins share a unique extra external domain ("I-domain"), suggesting that the group of P22-like phages has evolved over a very long time period without acquiring a new coat protein gene from another phage group. On the other hand, the morphology of the CUS-3 tailspike differs significantly from that of P22 or Sf6, but is similar to the tailspike of phage K1F, a member of the extremely distantly related T7 group of phages. We conclude that CUS-3 obtained its tailspike gene from a distantly related phage quite recently. PMID- 25043592 TI - Synthesis and characterization of the ZnO/mpg-C3N4 heterojunction photocatalyst with enhanced visible light photoactivity. AB - The ZnO/mpg-C3N4 composite photocatalyst with high visible light activity was successfully synthesized by a facile solvothermal method and characterized by thermogravimetric analysis (TGA), X-ray diffraction (XRD), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM) and UV vis diffuse reflectance spectroscopy (DRS). The results indicated that ZnO particles dispersed uniformly on the mpg-C3N4 sheet. The photocatalytic activity of ZnO/mpg-C3N4 for photodegradation of MB was much higher than that of pure mpg C3N4 both under the visible light and simulated solar irradiation. The optimal ZnO content for the photocatalytic activity of the ZnO/mpg-C3N4 composites is 24.9%, which is almost 2.3 times as high as that of pure mpg-C3N4 under visible light, and 1.9 times higher than that under simulated solar irradiation. The enhancement in photocatalytic activity should be assigned to the effective separation and transfer of photogenerated charges coming from the well-matched overlapping band-structure between mpg-C3N4 and ZnO. Radical trap experiments show that both ZnO/mpg-C3N4 composites and mpg-C3N4 have the same photodegradation mechanism, and the holes are their main oxidative species for MB degradation. PMID- 25043591 TI - Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice. AB - Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase activating protein neurofibromin. Non-bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFbeta. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1(flox/flox) bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx (-/-) mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis. PMID- 25043593 TI - Geoenvironmental weathering/deterioration of landfilled MSWI-BA glass. AB - Municipal solid waste incineration bottom ash (MSWI-BA) glass serves as a matrix of assorted bottom ash (BA) compounds. Deterioration of the BA glass phases is quite important as they regulate the distribution of a series of toxic elements. This paper studied landfilled MSWI-BA samples from the mineralogical and geochemical viewpoint to understand the deterioration behavior of the BA glass phases as well as mechanisms involved. Bulk analysis by PXRD as well as micro scale analysis by optical microscopy and SEM/EDX was conducted for such purposes. The results revealed that dissolution of the BA glass phases has resulted in a deterioration layer of 10(0)-10(2)MUm thickness after years of disposal. This rapid weathering process is highly relevant to the specific glass characteristics and solution pH. The BA glass phases with more embedded compounds and cracks/fissures tend to be more vulnerable. Moreover, the generally alkaline pH in ash deposit favors a rapid disruption of the glass phase. The weathering products are mainly gel phases (including Al-Si gel, Ca-Al-Si gel, Fe-Al-Si gel etc.) with iron oxide/hydroxide as accessory products. Breakdown of the BA glass phases triggers chemical evolution of the embedded compounds. Based on all the findings above, a model is proposed to illustrate a general evolution trend for the landfilled MSWI-BA glass phases. PMID- 25043594 TI - Formation of polybrominated dibenzofurans (PBDFs) after heating of a salmon sample spiked with decabromodiphenyl ether (BDE-209). AB - Fish is a major source for the intake of polybrominated diphenyl ethers (PBDEs). However, fish is scarcely consumed without being cooked, and previous studies showed that the heating of salmon fillet contaminated with BDE-209 for longer periods of time was accompanied with the partial transformation of this brominated flame retardant. In this study, we heated salmon fillet spiked with BDE-209 and verified that this process was linked with the formation of polybrominated dibenzofurans (PBDFs) in the fish. Each minute of heating 1 g salmon fillet spiked with 200 ng BDE-209 generated about 0.5 0/00 PBDFs relative to the initial amount of the pre-dioxin BDE-209. This result of the chemical analysis by gas chromatography with mass spectrometry (GC/MS) was verified by means of an effect-directed bio-assay (DR CALUX). While unheated salmon with BDE 209 and heated salmon without BDE-209 were tested nontoxic, the bioanalytical response of fish linearly increased upon heating. We also found that PBDF formation did neither occur with BDE-47 nor when BDE-209 was heated in edible oil instead of salmon fillet. Due to the formation of PBDFs in this process, the consumption of heated, BDE-209 contaminated fish may add to the uptake of dioxin like compounds with our diet. PMID- 25043595 TI - Enhanced bioremediation of soil from Tianjin, China, contaminated with polybrominated diethyl ethers. AB - This work aimed to evaluate the effectiveness of nutrients, H2O2, and tourmaline on the bioremediation of fields where the soil was contaminated with polybrominated diethyl ethers (PBDEs). The results showed that 39.2, 38.3, and 48.1 % of total PBDE removal was observed in microcosms with the addition of nutrients, such as NaNO3, NH4Cl, and NH4NO3, respectively, compared to only 15.2 and 5.8 % of PBDE removal from soil with added Aspergillus niger and control soil, respectively, after 50 days of incubation. In addition, 50.8 and 56.5 % of total PBDE removal were observed in microcosms with 0.5 and 1 MUL H2O2. The addition of tourmaline increased total PBDE removal to 32.4 %. Significant increases in soil enzymatic activity with PBDE degraders and bacterial communities were observed using polymerase chain reaction (PCR)--denaturing gradient gel electrophoresis (DGGE). These observations suggested that the combination of inorganic nutrients with chemical, mineral, and biological treatment could improve the PBDE removal efficiency. However, the combination of H2O2 and biological treatment processes is the most efficient technology. This combination of technologies would not cause adverse effects on the subsequent bioremediation process. Therefore, this work offers a potential alternative for the remediation of soil contaminated with PBDE pollutants. PMID- 25043596 TI - Evaluation of HODE-15, FDE-15, CDE-15, and BDE-15 toxicity on adult and embryonic zebrafish (Danio rerio). AB - Diphenyl ether and its derivatives are widely used in the industry of spices, dyes, agrochemicals, and pharmaceuticals. Following the previous study, we selected 4,4'-dihydroxydiphenyl ether, 4,4'-difluorodiphenyl ether, 4,4' dichlorodiphenyl ether, and 4,4'-dibromodiphenyl ether as research objects. The LC50 (96 h) values for these compounds in adult zebrafish were determined with the acute test. Also, developmental toxicities of the four substances to zebrafish embryos were observed at 24, 48, 72, and 96 hpf. All the LC50 (96 h) values of these compounds were between 1 and 10 mg/L, suggesting that they all had moderate toxicity to adult zebrafish. The embryonic test demonstrated that with increasing doses, 4,4'-dihydroxydiphenyl ether decreased the hatching rate, while 4,4'-difluorodiphenyl ether, 4,4'-dichlorodiphenyl ether, and 4,4' dibromodiphenyl ether delayed the hatching time but had little effect on final hatchability at 96 hpf. All of these compounds inhibited larval growth, especially 4,4'-dihydroxydiphenyl ether. Exposure to these chemicals induced embryo yolk sac and pericardial edema. Spine deformation was visible in hatched larvae after 96 hpf 4,4'-dihydroxydiphenyl ether exposure, while tail curvature was observed for the halogenated compounds. The overall results indicated that 4,4'-dihydroxydiphenyl ether, 4,4'-difluorodiphenyl ether, 4,4'-dichlorodiphenyl ether, and 4,4'-dibromodiphenyl ether all had significant toxicity on adult and embryonic zebrafish. PMID- 25043597 TI - Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. AB - The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P < 0.001) during the study period. Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P < 0.05). CONCLUSIONS: The proportion of liver injury cases attributed to HDS in DILIN has increased significantly. Liver injury from nonbodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399-1408). PMID- 25043598 TI - Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates. AB - OBJECTIVE: We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. METHODS: Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C3 (n = 8) or placebo (n = 7) for 2 months starting 1 week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated nonhuman primate rating scale, kinematic analyses of peak upper extremity velocity, positron emission tomography imaging of 6-[(18) F]fluorodopa (FD; reflects dopa decarboxylase) and [(11) C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), ex vivo quantification of striatal dopamine, and stereologic counts of tyrosine hydroxylase-immunostained neurons in substantia nigra. RESULTS: After 2 months, C3 -treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 -treated animals developed any toxicity. INTERPRETATION: Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for Parkinson disease. PMID- 25043599 TI - A chloroplast-localized DEAD-box RNA helicaseAtRH3 is essential for intron splicing and plays an important role in the growth and stress response in Arabidopsis thaliana. AB - Although many DEAD-box RNA helicases (RHs) are targeted to chloroplasts, the functional roles of the majority of RHs are still unknown. Recently, the chloroplast-localized Arabidopsis thaliana AtRH3 has been demonstrated to play important roles in intron splicing, ribosome biogenesis, and seedling growth. To further understand the functional role of AtRH3 in intron splicing and growth and the stress response in Arabidopsis, the newly-generated artificial microRNA mediated knockdown plants as well as the previously characterized T-DNA tagged rh3-4 mutant were analyzed under normal and stress conditions. The rh3 mutants displayed retarded growth and pale-green phenotypes, and the growth of mutant plants was inhibited severely under salt or cold stress but marginally under dehydration stress conditions. Splicing of several intron-containing chloroplast genes was defective in the mutant plants. Importantly, splicing of ndhA and ndhB genes was severely inhibited in the mutant plants compared with the wild-type plants under salt or cold stress but not under dehydration stress conditions. Moreover, AtRH3 complemented the growth-defect phenotype of the RNA chaperone deficient Escherichia coli mutant and had the ability to disrupt RNA and DNA base pairs, indicating that AtRH3 possesses RNA chaperone activity. Taken together, these results demonstrate that AtRH3 plays a prominent role in the growth and stress response of Arabidopsis, and suggest that proper splicing of introns governed by RNA chaperone activity of AtRH3 is crucial for chloroplast function and the growth and stress response of plants. PMID- 25043600 TI - Noncoding origins of anthropoid traits and a new null model of transposon functionalization. AB - Little is known about novel genetic elements that drove the emergence of anthropoid primates. We exploited the sequencing of the marmoset genome to identify 23,849 anthropoid-specific constrained (ASC) regions and confirmed their robust functional signatures. Of the ASC base pairs, 99.7% were noncoding, suggesting that novel anthropoid functional elements were overwhelmingly cis regulatory. ASCs were highly enriched in loci associated with fetal brain development, motor coordination, neurotransmission, and vision, thus providing a large set of candidate elements for exploring the molecular basis of hallmark primate traits. We validated ASC192 as a primate-specific enhancer in proliferative zones of the developing brain. Unexpectedly, transposable elements (TEs) contributed to >56% of ASCs, and almost all TE families showed functional potential similar to that of nonrepetitive DNA. Three L1PA repeat-derived ASCs displayed coherent eye-enhancer function, thus demonstrating that the "gene battery" model of TE functionalization applies to enhancers in vivo. Our study provides fundamental insights into genome evolution and the origins of anthropoid phenotypes and supports an elegantly simple new null model of TE exaptation. PMID- 25043601 TI - Elevated CO2 alleviates high PAR and UV stress in the unicellular chlorophyte Dunaliella tertiolecta. AB - The effects of increased CO2 and irradiance on the physiological performance of the chlorophyte Dunaliella tertiolecta were studied at different PAR and UVR (UVA + UVB) irradiances, simulating the solar radiation at different depths, at present (390 ppmv, LC) and predicted CO2 levels for the year 2100 (1000 ppmv, HC). Elevated CO2 resulted in higher optimum and effective quantum yields (F(v)/F(m) and phiPSII, respectively), electron transport rates (ETR) and specific growth rates (MU). Cell stress was alleviated in HC with respect to LC as evidenced by a decrease in reactive oxygen species (ROS) accumulation. DNA damage showed a 42-fold increase in cyclobutane-pyrimidine dimer (CPD) formation under the highest irradiance (1100 MUmol quanta m(-2) s(-1)) in LC with respect to the lowest irradiance (200 MUmol quanta m(-2) s(-1)). Photolyase (CII-PCD-PL) gene expression was upregulated under HC resulting in a drastic decrease in CPD accumulation to only 25% with respect to LC. Proliferating cell nuclear antigen (PCNA) accumulation was always higher in HC and the accumulation pattern indicated its involvement in repair or growth depending on the irradiance dose. The repressor of silencing (ROS1) was only marginally involved in the response, suggesting that photoreactivation was the most relevant mechanism to overcome UVR damage. Our results demonstrate that future scenarios of global change result in alleviation of irradiance stress by CO2-induced photoprotection in D. tertiolecta. PMID- 25043603 TI - Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity. AB - Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy. PMID- 25043604 TI - Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. AB - PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI 400945 in patients with solid tumors, in particular those deficient in PTEN. PMID- 25043606 TI - Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk. AB - High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRP score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer. PMID- 25043607 TI - Unexpected transcellular protein crossover occurs during canonical DNA transfection. AB - Transfection of DNA has been invaluable for biological sciences, yet the effects upon membrane homeostasis are far from negligible. Here, we demonstrate that Neuro2A cells transfected using Lipofectamine LTX with the fluorescently coupled Botulinum serotype A holoenzyme (EGFP-LcA) cDNA express this SNAP25 protease that can, once translated, escape the transfected host cytosol and become endocytosed into untransfected cells, without its innate binding and translocation domains. Fluorescent readouts revealed moderate transfection rates (30-50%) while immunoblotting revealed a surprisingly total enzymatic cleavage of SNAP25; the transgenic protein acted beyond the confines of its host cell. Using intracellular dyes, no important cytotoxic effects were observed from reagent treatment alone, which excluded the possibility of membrane ruptures, though noticeably, intracellular acidic organelles were redistributed towards the plasma membrane. This drastic, yet frequently unobserved, change in protein permeability and endosomal trafficking following reagent treatment highlights important concerns for all studies using transient transfection. PMID- 25043608 TI - Late radiation-associated dysphagia with lower cranial neuropathy in long-term oropharyngeal cancer survivors: video case reports. AB - BACKGROUND: Lower cranial neuropathies are a late effect of radiotherapy (RT), typically reported in nasopharyngeal cancer survivors. Limited data examine these neuropathies after oropharyngeal cancer, particularly as it relates to late radiation-associated dysphagia (late-RAD). METHODS: Two cases were examined over 4 to 6 years. Late-RAD was assessed per MBS impairment profile (MBSImPTM(c)), Penetration-Aspiration Scale (PAS), Performance Status Scale for Head and Neck cancer (PSS-HN), and MD Anderson Dysphagia Inventory (MDADI). Neuropathies were examined via clinical examination and laryngeal videostroboscopy, and compared with trajectories of late-RAD. RESULTS: Media-enriched case reports describe the course of late-RAD and neuropathies in 2 cases after definitive RT +/- epidermal growth factor receptor-inhibitor for oropharyngeal cancer. Late-RAD was characterized by severe physiologic impairments per MBSImPTM(c) and decreased swallowing-related quality of life (QOL) per MDADI. Trajectories of late-RAD paralleled the progression or stability of neuropathies. CONCLUSION: Late-RAD with lower cranial neuropathies resulted in profound and persistent functional impairment. Rarely reported, late radiation-associated lower cranial neuropathies may be a major contributor to new-onset or progressive dysphagia in long-term oropharyngeal cancer survivors. PMID- 25043609 TI - Inhibition effect of glyphosate on the acute and subacute toxicity of cadmium to earthworm Eisenia fetida. AB - The acute and subacute toxicities of cadmium (Cd) to earthworm Eisenia fetida in the presence and absence of glyphosate were studied. Although Cd is highly toxic to E. fetida, the presence of glyphosate markedly reduced the acute toxicity of Cd to earthworm; both the mortality rate of the earthworms and the accumulation of Cd decreased with the increase of the glyphosate/Cd molar ratio. The subcellular distribution of Cd in E. fetida tissues showed that internal Cd was dominant in the intact cells fraction and the heat-stable proteins fraction. The presence of glyphosate reduced the concentration of Cd in all fractions, especially the intact cells. During a longer period of exposure, the weight loss of earthworm and the total Cd absorption was alleviated by glyphosate. Thus, the herbicide glyphosate can reduce the toxicity and bioavailability of Cd in the soil ecosystems at both short- and long-term exposures. PMID- 25043610 TI - Iron- and hemin-dependent gene expression of Porphyromonas gingivalis. AB - Although iron under anaerobic conditions is more accessible and highly reactive because of its reduced form, iron-dependent regulation is not well known in anaerobic bacteria. Here, we investigated iron- and hemin-dependent gene regulation in Porphyromonas gingivalis, an established periodontopathogen that primarily inhabits anaerobic pockets. Whole-genome microarrays of P. gingivalis genes were used to compare the levels of gene expression under iron-replete and iron-depleted conditions as well as under hemin-replete and hemin-depleted conditions. Under iron-depleted conditions, the expression of genes encoding proteins that participate in iron uptake and adhesion/invasion of host cells was increased, while that of genes encoding proteins involved in iron storage, energy metabolism, and electron transport was decreased. Interestingly, many of the genes with altered expression had no known function. Limiting the amount of hemin also resulted in a reduced expression of the genes encoding proteins involved in energy metabolism and electron transport. However, hemin also had a significant effect on many other biological processes such as oxidative stress protection and lipopolysaccharide synthesis. Overall, comparison of the data from iron-depleted conditions to those from hemin-depleted ones showed that although some regulation is through the iron derived from hemin, there also is significant distinct regulation through hemin only. Furthermore, our data showed that the molecular mechanisms of iron-dependent regulation are novel as the deletion of the putative Fur protein had no effect on the expression of iron-regulated genes. Finally, our functional studies demonstrated greater survivability of host cells in the presence of the iron-stressed bacterium than the iron-replete P. gingivalis cells. The major iron-regulated proteins encoded by PG1019-20 may play a role in this process as deletion of these sequences also resulted in reduced survival of the bacterium when grown with eukaryotic cells. Taken together, the results of this study demonstrated the utility of whole-genome microarray analysis for the identification of genes with altered expression profiles during varying growth conditions and provided a framework for the detailed analysis of the molecular mechanisms of iron and hemin acquisition, metabolism and virulence of P. gingivalis. PMID- 25043611 TI - A substrate-based approach to skeletal diversity from dicobalt hexacarbonyl (C1) alkynyl glycals by exploiting its combined Ferrier-Nicholas reactivity. AB - Novel substrates that combine dicobalt hexacarbonyl propargyl (Nicholas) and pyranose-derived allylic (Ferrier) cations have been generated by treatment of hexacarbonyldicobalt (C-1)-alkynyl glycals with BF3 (.) Et2 O. The study of these cations has resulted in the discovery of novel reaction pathways that have shown to be associated to the nature of O-6 substituent in the starting alkynyl glycals. Accordingly, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, can be obtained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, respectively. The use of a 6-O-allyl alkynyl glycal led to a suitable funtionalized oxepane able to experience an intramolecular Pauson-Khand cyclization leading to a single tricyclic derivative. PMID- 25043612 TI - Revisiting thyroid hormone treatment to prevent brain damage of prematurity. PMID- 25043613 TI - Solar steam generation by heat localization. AB - Currently, steam generation using solar energy is based on heating bulk liquid to high temperatures. This approach requires either costly high optical concentrations leading to heat loss by the hot bulk liquid and heated surfaces or vacuum. New solar receiver concepts such as porous volumetric receivers or nanofluids have been proposed to decrease these losses. Here we report development of an approach and corresponding material structure for solar steam generation while maintaining low optical concentration and keeping the bulk liquid at low temperature with no vacuum. We achieve solar thermal efficiency up to 85% at only 10 kW m(-2). This high performance results from four structure characteristics: absorbing in the solar spectrum, thermally insulating, hydrophilic and interconnected pores. The structure concentrates thermal energy and fluid flow where needed for phase change and minimizes dissipated energy. This new structure provides a novel approach to harvesting solar energy for a broad range of phase-change applications. PMID- 25043614 TI - Development of a practice guideline for optimal symptom relief for patients with pneumonia and dementia in nursing homes using a Delphi study. AB - OBJECTIVE: This study aimed to develop a practice guideline for a structured and consensus-based approach to relieve symptoms of pneumonia in patients with dementia in nursing homes. METHODS: A five-round Delphi study involving a panel consisting of 24 experts was conducted. An initial version of the practice guideline was developed with leading representatives of Dutch University Medical Centers with a department for elderly care medicine, based on existing guidelines for palliative care. The experts evaluated the initial version, after which we identified topics that reflected the main divergences. The experts rated their agreement with statements that addressed the main divergences on a 5-point Likert scale. Consensus was determined according to pre-defined criteria. The practice guideline was then revised according to the final decisions made by the project group and the representatives. RESULTS: The response rate for the expert panel was 67%. Main divergences included the applicability of guidelines for palliative care to patients with dementia and pneumonia in long-term care and the appropriateness of specific pharmacological treatment of dyspnea and coughing. Moderate consensus was reached for 80% of the statements. Major revisions included adding pharmacological treatment for coughing and recommending opioid rotation in the case of opioid-induced delirium. Two areas of divergent opinion remained: the usefulness of oxygen administration and treatment of rattling breath. The project group made the final decision in these areas. CONCLUSIONS: We developed a mostly consensus-based practice guideline for patients with dementia and pneumonia and mapped controversial issues for future investigation. PMID- 25043615 TI - Speckle tracking echocardiography in fetuses diagnosed with congenital diaphragmatic hernia. AB - OBJECTIVE: The aim of this study is to evaluate cardiac function in fetuses with congenital diaphragmatic hernia (CDH) using speckle tracking. METHOD: Case control study assessed cardiac contractility in consecutive fetuses with CDH. Controls were anatomically normal fetuses, adjusted for gestational age. Speckle tracking software calculated ventricular peak longitudinal velocity, displacement and strain. Pulmonary hypoplasia was assessed using observed/expected lung-to head ratio (O/E LHR). RESULTS: Thirty-eight fetuses with CDH (29 left and nine right) were evaluated at a mean gestational age of 26.9 +/- 2.5 weeks. In six fetuses, the acquired images were of insufficient quality (feasibility 83%). Velocity and displacement showed regional differences, as well as significant differences between the ventricular walls, similar to control fetuses. Strain measurements also demonstrated regional differences yet less uniformly arranged. In left CDH, we observed increased strain values in the left ventricle compared with controls (-18.7 +/- 7.2 vs -15.1 +/- 4.9). There was no correlation between strain values in the left ventricle and O/E LHR. In fetuses with right CDH, deformation analysis was not different from controls. CONCLUSIONS: In fetuses with CDH, no cardiac dysfunction could be detected despite the often concurrent hypoplasia of ipsilateral cardiac structures. In fetuses with left CDH, the decrease in ventricular size coincides with increased strain values in the free left ventricular wall. PMID- 25043616 TI - Mental health diversion courts: a two year recidivism study of a South Australian mental health court program. AB - The need to develop specialized judicial processes to deal with offenders with mental illnesses is now widely recognized and has led to the introduction of mental health court diversion programs around the world. At present, however, there is only limited evidence from which to assess the impact of these initiatives. This paper describes the South Australian model of diversion, with specific reference to the relationship between identified participant characteristics, program compliance rates, and re-offending outcomes. The results of a two-year recidivism study suggest that involvement with the program has a positive impact on recidivism, but that this is independent from the individual's level of success in the program. Lower risk offenders were more likely to achieve successful outcomes than those in the higher risk categories. The implications of these results, as well the factors that might inform the ongoing development of mental health court programs, are discussed. PMID- 25043617 TI - On the choice of degrees of freedom for testing gene-gene interactions. AB - In gene-gene interaction analysis using single nucleotide polymorphism (SNP) data, empty cells arise in the genotype contingency table more frequently than in single SNP association studies. Empty cells lead to unidentifiable regression coefficients in regression model fitting. It is unclear whether the degrees of freedom (d.f.) for testing interactions are reduced for such sparse contingency tables. Boolean Operation based Screening and Testing is an exhaustive gene-gene interaction search method in which a fixed d.f. of four (the most conservative choice) is used in the chi-squared null distribution for the likelihood ratio test for gene-gene interactions under a logistic regression model. In this paper, the choice of d.f. is investigated theoretically by introducing a decomposition of type I error. An adaptive method using the observed d.f. can be less conservative than the fixed d.f. method, thereby enhancing power. In simulated data, type I error rates for the adaptive method were usually better controlled under various scenarios for Gaussian linear regression and logistic regression, including prospective and retrospective sampling designs, as well as for artificial data that mimic actual genome-wide SNPs. When the adaptive method was applied to public datasets generated from simulations, it exhibited an improvement in power over the fixed method. PMID- 25043618 TI - Fcgamma receptors III and IV mediate tissue destruction in a novel adult mouse model of bullous pemphigoid. AB - Bullous pemphigoid (BP) and epidermolysis bullosa acquisita are subepidermal autoimmune blistering diseases mediated by autoantibodies against type XVII collagen (Col17) and Col7, respectively. For blister formation, Fc-mediated events, such as infiltration of inflammatory cells in the skin, complement activation, and release of proteases at the dermal-epidermal junction, are essential. Although in the neonatal passive transfer mouse model of BP, tissue destruction is mediated by Fcgamma receptors (FcgammaRs) I and III, the passive transfer model of epidermolysis bullosa acquisita completely depends on FcgammaRIV. To clarify this discrepancy, we developed a novel experimental model for BP using adult mice. Lesion formation was Fc mediated because gamma-chain deficient mice and mice treated with anti-Col17 IgG, depleted from its sugar moiety at the Fc portion, were resistant to disease induction. By the use of various FcgammaR-deficient mouse strains, tissue destruction was shown to be mediated by FcgammaRIV, FcgammaRIII, and FcgammaRIIB, whereas FcgammaRI was not essential. Furthermore, anti-inflammatory mediators in already clinically diseased mice can be explored in the novel BP model, because the pharmacological inhibition of FcgammaRIV and depletion of granulocytes abolished skin blisters. Herein, we extended our knowledge about the importance of FcgammaRs in experimental BP and established a novel BP mouse model suitable to study disease development over a longer time period and explore novel treatment strategies in a quasi-therapeutic setting. PMID- 25043619 TI - Angiopoietins promote ovarian cancer progression by establishing a procancer microenvironment. AB - Despite decades of research, the survival rate of ovarian cancer patients is largely unchanged. Current chemotherapeutic drugs are effective only transiently because patients with advanced disease eventually develop resistance. Thus, there is a pressing need for identifying novel therapeutic targets in ovarian cancer. Mounting evidence suggests that angiopoietins (Angpts) may play an essential role in cancer progression; however, the expression profiles and biological effects of Angpts on ovarian cancer remain largely unknown. Here, we show that, compared with their normal counterparts, expressions of Angpt1, Angpt2, and Angpt4 are increased in ovarian cancer cells and tissues and that human ovarian cancer cells also express the Angpt receptor Tie-2-receptor tyrosine kinase. We show that increased expression of Angpt1, Angpt2, or Angpt4 promotes intraperitoneal growth of ovarian cancers and shortens survival of the experimental mice. We further show, for the first time, that Angpts promote accumulation of cancer-associated fibroblasts and tumor angiogenesis in the ovarian cancer microenvironment, as well as enhance ovarian cancer cell proliferation and invasion in vivo. In addition, we establish a novel function of Angpts in promoting proliferation and invasion and inducing Tie-2 and extracellular signal-regulated kinase 1/2 activation in ovarian cancer-associated fibroblasts. Taken together, these data suggest that the Angpt-Tie-2 functional axis is an important player in ovarian cancer progression and an attractive target for ovarian cancer therapy. PMID- 25043620 TI - Mast cells protect against Pseudomonas aeruginosa-induced lung injury. AB - Pseudomonas aeruginosa, an opportunistic pathogen, is the leading cause of morbidity and mortality in immune-compromised individuals. Maintaining the integrity of the respiratory epithelium is critical for an effective host response to P. aeruginosa. Given the close spatial relationship between mast cells and the respiratory epithelium, and the importance of tightly regulated epithelial permeability during lung infections, we examined whether mast cells influence airway epithelial integrity during P. aeruginosa lung infection in a mouse model. We found that mast cell-deficient Kit(W-sh)/Kit(W-sh) mice displayed greatly increased epithelial permeability, bacterial dissemination, and neutrophil accumulation compared with wild-type animals after P. aeruginosa infection; these defects were corrected on reconstitution with mast cells. An in vitro Transwell co-culture model further demonstrated that a secreted mast cell factor decreased epithelial cell apoptosis and tumor necrosis factor production after P. aeruginosa infection. Together, our data demonstrate a previously unrecognized role for mast cells in the maintenance of epithelial integrity during P. aeruginosa infection, through a mechanism that likely involves prevention of epithelial apoptosis and tumor necrosis factor production. Our understanding of mechanisms of the host response to P. aeruginosa will open new avenues for the development of successful preventative and treatment strategies. PMID- 25043621 TI - Inferring the origin of rare fruit distillates from compositional data using multivariate statistical analyses and the identification of new flavour constituents. AB - BACKGROUND: In Serbia, delicatessen fruit alcoholic drinks are produced from autochthonous fruit-bearing species such as cornelian cherry, blackberry, elderberry, wild strawberry, European wild apple, European blueberry and blackthorn fruits. There are no chemical data on many of these and herein we analysed volatile minor constituents of these rare fruit distillates. Our second goal was to determine possible chemical markers of these distillates through a statistical/multivariate treatment of the herein obtained and previously reported data. RESULTS: Detailed chemical analyses revealed a complex volatile profile of all studied fruit distillates with 371 identified compounds. A number of constituents were recognised as marker compounds for a particular distillate. Moreover, 33 of them represent newly detected flavour constituents in alcoholic beverages or, in general, in foodstuffs. With the aid of multivariate analyses, these volatile profiles were successfully exploited to infer the origin of raw materials used in the production of these spirits. It was also shown that all fruit distillates possessed weak antimicrobial properties. CONCLUSION: It seems that the aroma of these highly esteemed wild-fruit spirits depends on the subtle balance of various minor volatile compounds, whereby some of them are specific to a certain type of fruit distillate and enable their mutual distinction. PMID- 25043623 TI - Plasmin administration during ex vivo lung perfusion ameliorates lung ischemia reperfusion injury. AB - BACKGROUND: Donor lung thrombus is considered a significant etiology for primary graft dysfunction (PGD). We hypothesized that thrombolysis in ex vivo lung perfusion (EVLP) before lung transplantation could alleviate ischemia-reperfusion injury (IRI), resulting in a decreased incidence of PGD. METHODS: Rats were divided into control (n = 5), non-plasmin (n = 7) and plasmin (n = 7) groups. In the non-plasmin and plasmin groups, cardiac arrest was induced by withdrawal of ventilation without heparinization. After 120 minutes of warm ischemia, the lungs were ventilated and flushed. Hearts and both lungs were excised en bloc. The lungs were perfused and ventilated in the EVLP for 30 minutes, and plasmin or placebo was administered on EVLP initiation. The lungs were then stored at 4 degrees C for 90 minutes and finally perfused with rat blood for 80 minutes. We assessed physiologic and histologic findings during reperfusion and the correlation between physiologic data during EVLP and after reperfusion. RESULTS: Physiologic results were better in the plasmin group than in the non-plasmin group. The plasmin group lungs had fewer signs of histologic injury. Caspase-3 and -7 activity in the plasmin group was lower in the non-plasmin group. Pulmonary vascular resistance (PVR) during EVLP correlated with that at the end of reperfusion. CONCLUSIONS: Plasmin administration during EVLP protected the donor lungs after reperfusion. We also found that several physiologic values in EVLP may be predictive markers of lung function after reperfusion. PMID- 25043622 TI - Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long distance neuronal integration. AB - Zebrafish maintain a greater capacity than mammals for central nervous system repair after injury. Understanding differences in regenerative responses between different vertebrate species may shed light on mechanisms to improve repair in humans. Quinolinic acid is an excitotoxin that has been used to induce brain injury in rodents for modeling Huntington's disease and stroke. When injected into the adult rodent striatum, this toxin stimulates subventricular zone neurogenesis and neuroblast migration to injury. However, most new neurons fail to survive and lesion repair is minimal. We used quinolinic acid to lesion the adult zebrafish telencephalon to study reparative processes. We also used conditional transgenic lineage mapping of adult radial glial stem cells to explore survival and integration of neurons generated after injury. Telencephalic lesioning with quinolinic acid, and to a lesser extent vehicle injection, produced cell death, microglial infiltration, increased cell proliferation, and enhanced neurogenesis in the injured hemisphere. Lesion repair was more complete with quinolinic acid injection than after vehicle injection. Fate mapping of her4 expressing radial glia showed injury-induced expansion of radial glial stem cells that gave rise to neurons which migrated to injury, survived at least 8 weeks and formed long-distance projections that crossed the anterior commissure and synapsed in the contralateral hemisphere. These findings suggest that quinolinic acid lesioning of the zebrafish brain stimulates adult neural stem cells to produce robust regeneration with long-distance integration of new neurons. This model should prove useful for elucidating reparative mechanisms that can be applied to restorative therapies for mammalian brain injury. PMID- 25043624 TI - No-clamp technique for pulmonary artery and venous anastomoses in lung transplantation. AB - BACKGROUND: Lung transplantation (LTx) is a complex surgical procedure conventionally performed with clamps on the recipient pulmonary artery (PA) and left atrial (LA) cuff, with or without cardiopulmonary bypass (CPB). The clamps may be awkward to apply and maintain on these structures, potentially causing injury and possibly compromising the quality of anastomosis. We describe a no clamp technique for performing these types of anastomoses. METHODS: A total of 184 LTx procedures performed under CPB were grouped depending on clamping of recipient PA and LA during anastomosis using either the "no-clamp" technique (Group 1, n = 41) or the conventional technique (Group 2, n = 143). Pre-operative donor and recipient demographics and baseline characteristics as well as post operative outcomes were compared. RESULTS: The demographics and pre-operative baseline characteristics of donors and recipients in both the groups were similar. Patients in Group 1 had a significantly shorter total ischemic time (p < 0.001), CPB time (p < 0.001), decreased incidence of post-LTx atrial fibrillation (p = 0.048), less need for blood and blood products transfusion, and fewer post LTx pulmonary infections (p = 0.038). No patient in any group had post-LTx stroke. Although the incidence of post-operative bronchiolitis obliterans syndrome (BOS) did not differ between the two groups (p = 0.638), patients in Group 1 had significantly better mid- and long-term survival (p = 0.013): 89.7% vs 80%, 89.7% vs 66.5% and 89.7% vs 62.2% at 1, 3 and 6 years after LTx, respectively. CONCLUSIONS: The no-clamp technique for anastomosis of PA and LA in LTx is feasible and safe. It may reduce warm ischemia time as well as CPB time, with improvement in post-LTx outcomes. It may also reduce the incidence of post LTx atrial arrhythmias. PMID- 25043625 TI - Anticoagulant-induced hemarthrosis presenting as anterior shoulder dislocation. AB - This is a case of nontraumatic shoulder pain initially diagnosed on x-ray as an anterior dislocation. The patient was on anticoagulants and, in actuality, had severe hemarthrosis that caused the subluxation. Attempts to reduce the dislocation in this situation might have resulted in worsening of the intra articular bleed. There has been only 1 similar reported case in the European Journal of Emergency Medicine in 2013 of a 53-year-old woman who was thought to have a nontraumatic anterior shoulder dislocation, and attempts were unsuccessful at reduction. Definitive therapy involved hemarthrosis aspiration. Others have reported spontaneous hemarthrosis due to anticoagulants; however, only 1 has reported an initial mistaken joint dislocation diagnosis. Nontraumatic hemarthrosis do occur in patients on anticoagulant therapy, and it is important to recognize that this can be misdiagnosed as a joint dislocation requiring reduction. In a patient who is on anticoagulants presenting with nontraumatic joint pain and anterior shoulder or possibly other dislocations on plain radiographs, it is pertinent to consider hemarthrosis. PMID- 25043626 TI - Epinephrine use and outcomes in anaphylaxis patients transported by emergency medical services. AB - BACKGROUND: Anaphylaxis is a potentially life-threatening allergic reaction that may require emergency medical system (EMS) transport. Fatal anaphylaxis is associated with delayed epinephrine administration. Patient outcome data to assess appropriateness of EMS epinephrine administration are sparse. OBJECTIVES: The objectives of this study are to (1) determine the frequency of epinephrine administration in EMS-transported patients with allergic complaints, (2) identify predictors of epinephrine administration, and (3) determine frequency of emergency department (ED) epinephrine administration after EMS transport. METHODS: A cohort study was conducted from over 5 years. A total of 59187 EMS transports of an Advanced Life Support (ALS) ambulance service were studied. RESULTS: One hundred and three patient transports for allergic complaints were analyzed. Fifteen patients received EMS epinephrine, and epinephrine was recommended for 2 additional patients who refused, for a total of 17 (17%) patients for whom epinephrine was administered or recommended. Emergency medical system epinephrine administration or recommendation was associated with venom as a trigger (29% vs 8%; odds ratio [OR], 4.70; 95% confidence interval [CI], 1.28 17.22; P = .013), respiratory symptoms (88% vs 52%; OR, 6.83; 95% CI, 1.47-31.71; P = .006), and fulfillment of anaphylaxis diagnostic criteria (82% vs 49%; OR, 3.50; 95% CI, 0.94-13.2; P = .0498). Four (4%) patients received epinephrine after ED arrival. CONCLUSION: Low rates of epinephrine administration were observed. The association of EMS administration of epinephrine with respiratory symptoms, fulfillment of anaphylaxis diagnostic criteria, and low rate of additional epinephrine administration in the ED suggest that ALS EMS administered epinephrine based on symptom severity. Additional studies of EMS anaphylaxis management including ED management and outcomes are needed. PMID- 25043627 TI - The prognostic factors of adult patients with hepatic portal venous gas in the ED. AB - OBJECTIVES: This study aimed to investigate the prognostic factors of adult patients with hepatic portal venous gas (HPVG) in the emergency department (ED) to facilitate clinical decision making by emergency physicians. METHODS: Data from adult patients with HPVG who visited our ED between December 2009 and December 2013 were analyzed. The computed tomographic scan images were reviewed, and the presence of HPVG with or without pneumatosis intestinalis (PI) was confirmed by a certified radiologist. The study end point was mortality or survival upon discharge. The factors associated with mortality were specifically analyzed with multiple logistic regression models. RESULTS: Among the total of 50 HPVG patients, the overall mortality rate was 56%. No deaths were observed among the patients with neither shock nor PI in the ED. Shock (odds ratio, 17.02; 95% confidence interval, 3.36-86.22) and PI (odds ratio, 5.14; 95% confidence interval, 1.03-25.67) were determined to be significant predictors of patient mortality after adjusting for age and sex. The mortality of the patients with both shock and PI was very high (84%). CONCLUSIONS: Early resuscitation should be initiated for the prevention of shock in adult patients with HPVG in the ED. To enhance the chance for survival, the prompt consultation of surgeons for emergency operations should be considered for adult ED patients exhibiting both shock and PI, which may indicate true ischemic bowel disease. PMID- 25043628 TI - Valsalva retinopathy and branch retinal artery occlusion after cardiopulmonary cerebral resuscitation. AB - We report a 53-year-old woman who had acute visual loss 10 days after cardiopulmonary cerebral resuscitation performance. Immediately after she had performed cardiopulmonary cerebral resuscitation, she developed floater symptoms in her left eye, which persisted for 2 hours, and she was diagnosed as having Valsalva retinopathy. Ten days later, she had an acute painless visual loss in the same eye (visual acuity 20/1000). On fundus examination, optic disk edema, peripapillary hemorrhage, and retinal artery occlusion were detected in the superior half of her left retina and she was diagnosed as having branch retinal artery occlusion. Four months later, her visual acuity had increased to 20/40; however, the inferior altitudinal visual field defect remained. To rule out cardiac associations of branch retinal artery occlusion, transesophageal echocardiography was performed and a patent foramen ovale on her atrial septum was detected. This case indicates a possible risk that emergency medical personnel could have medical problems while performing strenuous tasks to help other people. PMID- 25043629 TI - Compression stockings in ankle sprain: a multicenter randomized study. AB - OBJECTIVES: Ankle sprain is a frequently encountered traumatic injury in emergency departments and is associated with important health expenses. However, the appropriate care of this traumatic injury remains a matter of debate. We tested the hypothesis that compression stockings speed up recovery from ankle sprain. METHODS: Recent (<48 hours) cases of ankle sprain without other traumatic injury in patients aged between 18 and 55 years were included. Patients were randomly allocated to placebo Jersey or class II compression stockings (Venoflex; Thuasne, Levallois-Perret, France). The primary end point was the time to recovery of normal painless walking without requirement for analgesic drug. Secondary end points were time to return to sport activity, pain, analgesic consumption, and ankle edema (bimalleolar and midfoot circumferences). RESULTS: We randomized 126 patients and analyzed 117 patients (60 in the placebo group and 57 in the compression group). The median time to normal painless walking was not significantly decreased (P = .16). No significant differences were observed in pain, analgesic consumption, and bimalleloar and midfoot circumferences. No safety issue was reported. In the subgroup of patients with regular sport activity, the time to return to sport activity was shorter in patients treated with compression stockings (P = .02). CONCLUSIONS: Compression stockings failed to significantly modify the time to return to normal painless walking in ankle sprain. A beneficial effect was observed only in a subgroup of patients, as compression stockings significantly decreased the time to return to sport activity. PMID- 25043630 TI - DFT assessment of the spectroscopic constants and absorption spectra of neutral and charged diatomic species of group 11 and 14 elements. AB - The spectroscopic constants and absorption spectra of neutral and charged diatomic molecules of group 11 and 14 elements formulated as [M(2)](+/0/-) (M = Cu, Ag, Au), and [E(2)](+/0/-) (E = C, Si, Ge, Sn, Pb) have been calculated at the PBE0/Def2-QZVPP level of theory. The electronic and bonding properties of the diatomics have been analyzed by natural bond orbital analysis approach and topology analysis by the atoms in molecules method. Particular emphasis was given on the absorption spectra of the diatomic species, which were simulated by time dependent density functional theory calculations employing the hybrid Coulomb attenuating CAM-B3LYP density functional. The simulated absorption spectra of the [M(2)](+/0/-) (M = Cu, Ag, Au) and [E(2)](+/0/-) (E = C, Si, Ge, Sn, Pb) species are in close resemblance with the experimentally observed spectra whenever available. The neutral M(2) and E(2) diatomics strongly absorb in the ultraviolet region, given rise to UVC, UVA and in a few cases UVB absorptions. In a few cases, weak absorbion bands also occur in the visible region. The absorption bands have thoroughly been analyzed and assignments of the contributing principal electronic transitions associated to individual excitations have been made. PMID- 25043631 TI - "Employment and arthritis: making it work" a randomized controlled trial evaluating an online program to help people with inflammatory arthritis maintain employment (study protocol). AB - BACKGROUND: Arthritis and musculoskeletal conditions are the leading cause of long-term work disability (WD), an outcome with a major impact on quality of life and a high cost to society. The importance of decreased at-work productivity has also recently been recognized. Despite the importance of these problems, few interventions have been developed to reduce the impact of arthritis on employment. We have developed a novel intervention called "Making It Work", a program to help people with inflammatory arthritis (IA) deal with employment issues, prevent WD and improve at-work productivity. After favorable results in a proof-of-concept study, we converted the program to a web-based format for broader dissemination and improved accessibility. The objectives of this study are: 1) to evaluate in a randomized controlled trial (RCT) the effectiveness of the program at preventing work cessation and improving at-work productivity; 2) to perform a cost-utility analysis of the intervention. METHODS/DESIGN: 526 participants with IA will be recruited from British Columbia, Alberta, and Ontario in Canada. The intervention consists of a) 5 online group sessions; b) 5 web-based e-learning modules; c) consultations with an occupational therapist for an ergonomic work assessment and a vocational rehabilitation counselor. Questionnaires will be administered online at baseline and every 6 months to collect information about demographics, disease measures, costs, work-related risk factors for WD, quality of life, and work outcomes. Primary outcomes include at-work productivity and time to work cessation of > 6 months for any reason. Secondary outcomes include temporary work cessation, number of days missed from work per year, reduction in hours worked per week, quality adjusted life year for the cost utility analysis, and changes from baseline in employment risk factors. Analysis of Variance will evaluate the intervention's effect on at-work productivity, and multivariable Cox regression models will estimate the risk of work cessation associated with the intervention after controlling for risk factors for WD and other important predictors imbalanced at baseline. DISCUSSION: This program fills an important gap in arthritis health services and addresses an important and costly problem. Knowledge gained from the RCT will be useful to health care professionals, policy planners and arthritis stakeholders. TRIAL REGISTRATION: ClinicalTrials.gov NCT01852851; registered April 13, 2012; first participant randomized on July 6, 2013. PMID- 25043632 TI - Boveri at 100: cancer evolution, from preneoplasia to malignancy. AB - In the 100 years since the publication of Boveri's manuscript, 'Concerning the origin of human tumours', we have seen many advances in our understanding of how tumours originate, develop and progress. However, reading this article now, it is possible to find conclusions, or more often predictions, of what we now consider basic tenets of tumour biology. These include predicting the stochastic nature of the malignant change and that all tumours are necessarily of clonal origin, perhaps the basis of the modern concepts of field cancerization, of tumour heterogeneity and the clonal evolution of tumours. Modern researchers rarely refer to this paper, yet as a source of ideas it must rank amongst the landmarks in tumour biology of the last 100 years. PMID- 25043634 TI - Novel familial pathogenic mutation in gap junction protein, beta-1 gene (GJB1) associated with transient neurological deficits in a patient with X-linked Charcot-Marie-Tooth disease. PMID- 25043633 TI - Independent evolution of Fc- and Fab-mediated HIV-1-specific antiviral antibody activity following acute infection. AB - Fc-related antibody activities, such as antibody-dependent cellular cytotoxicity (ADCC), or more broadly, antibody-mediated cellular viral inhibition (ADCVI), play a role in curbing early SIV viral replication, are enriched in human long term infected nonprogressors, and could potentially contribute to protection from infection. However, little is known about the mechanism by which such humoral immune responses are naturally induced following infection. Here, we focused on the early evolution of the functional antibody response, largely driven by the Fc portion of the antibody, in the context of the evolving binding and neutralizing antibody response, which is driven mainly by the antibody-binding fragment (Fab). We show that ADCVI/ADCC-inducing responses in humans are rapidly generated following acute HIV-1 infection, peak at approximately 6 months postinfection, but decay rapidly in the setting of persistent immune activation, as Fab-related activities persistently increase. Moreover, the loss of Fc activity occurred in synchrony with a loss of HIV-specific IgG3 responses. Our data strongly suggest that Fc- and Fab-related antibody functions are modulated in a distinct manner following acute HIV infection. Vaccination strategies intended to optimally induce both sets of antiviral antibody activities may, therefore, require a fine tuning of the inflammatory response. PMID- 25043636 TI - Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler. AB - INTRODUCTION: A delivery device is the most important factor that determines the local/systemic bioavailability of inhaled corticosteroids. Dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs) are the most commonly used delivery devices for localized drug delivery to the airways. OBJECTIVE: This study was to compare the clinical equivalence of budesonide delivered by the Pulmicort Turbuhaler (DPI) and the Aeronide inhaler (pMDI). MATERIALS AND METHODS: The two inhalers were compared for their pharmaceutical equivalence and clinical equivalence. The in vitro test included the uniformity of the delivered dose and determination of the aerodynamic particle size of budesonide. The in vivo test was carried out in 36 patients with mild to moderate asthma. This was a randomized, single-blinded study conducted for a period of 3 months. This included assessment of the spirometric parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), forced expiratory flow 25-75% (FEF25-75)], the severity of asthma symptoms, adverse events, frequency of short-acting inhaled bronchodilator usage and measurement of urinary cortisol levels. RESULTS: The aerodynamic particle size was slightly different between the two inhalers (2.3 +/- 0.2 um for Pulmicort Turbuhaler and 2.2 +/- 0.2 um for Aeronide inhaler). Both inhalers passed the uniformity of delivered dose (95.4% and 97.4%) specified in the British Pharmacopoeia. There was no statistically significant difference observed between the two inhalers in terms of the spirometric parameters, symptom-free days, frequency of bronchodilator usage and the level of urinary cortisol. CONCLUSION: In addition to pharmaceutical equivalence, no clinical difference observed between the two budesonide inhalers. PMID- 25043635 TI - Probing structurally altered and aggregated states of therapeutically relevant proteins using GroEL coupled to bio-layer interferometry. AB - The ability of a GroEL-based bio-layer interferometry (BLI) assay to detect structurally altered and/or aggregated species of pharmaceutically relevant proteins is demonstrated. Assay development included optimizing biotinylated GroEL immobilization to streptavidin biosensors, combined with biophysical and activity measurements showing native and biotinylated GroEL are both stable and active. First, acidic fibroblast growth factor (FGF-1) was incubated under conditions known to promote (40 degrees C) and inhibit (heparin addition) molten globule formation. Heat exposed (40 degrees C) FGF-1 exhibited binding to GroEL biosensors, which was significantly diminished in the presence of heparin. Second, a polyclonal human IgG solution containing 6-8% non-native dimer showed an increase in higher molecular weight aggregates upon heating by size exclusion chromatography (SEC). The poly IgG solution displayed binding to GroEL-biosensors initially with progressively increased binding upon heating. Enriched preparations of the IgG dimers or monomers showed significant binding to GroEL biosensors. Finally, a thermally treated IgG1 monoclonal antibody (mAb) solution also demonstrated increased GroEL-biosensor binding, but with different kinetics. The bound complexes could be partially to fully dissociated after ATP addition (i.e., specific GroEL binding) depending on the protein, environmental stress, and the assay's experimental conditions. Transmission electron microscopy (TEM) images of GroEL-mAb complexes, released from the biosensor, also confirmed interaction of bound complexes at the GroEL binding site with heat-stressed mAb. Results indicate that the GroEL-biosensor-BLI method can detect conformationally altered and/or early aggregation states of proteins, and may potentially be useful as a rapid, stability-indicating biosensor assay for monitoring the structural integrity and physical stability of therapeutic protein candidates. PMID- 25043637 TI - Hepatitis C: the next 25years. AB - Excellent progress has been made in the field of hepatitis C since the discovery of the causative virus in 1989. Screening tests have been produced to protect the blood supply, along with diagnostics to aid therapeutic management, as well as the recent approval of highly effective small-molecule drugs targeting the viral life cycle, which, given in combination, can now cure the vast majority of patients. Future urgent priorities include facilitating the accessibility of these drugs to all of the world's estimated 170 million carriers before liver cancer and other end-stage liver diseases occur, as well as producing a vaccine to protect individuals at high risk of infection, such as intravenous drug users. Effective control of this viral infection is now clearly in sight. This article introduces a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." PMID- 25043638 TI - Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012-2013. AB - Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) is sporadic, often follows exposure to NAIs, but occasionally occurs in the absence of NAI pressure. The emergence and global spread in 2007/2008 of A(H1N1) influenza viruses showing clinical resistance to oseltamivir due to neuraminidase (NA) H275Y substitution, in the absence of drug pressure, warrants continued vigilance and monitoring for similar viruses. Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 11,387 viruses collected by WHO-recognized National Influenza Centres (NIC) between May 2012 and May 2013 to determine 50% inhibitory concentration (IC50) data for oseltamivir, zanamivir, peramivir and laninamivir. The data were evaluated using normalized IC50 fold-changes rather than raw IC50 data. Nearly 90% of the 11,387 viruses were from three WHO regions: Western Pacific, the Americas and Europe. Only 0.2% (n=27) showed highly reduced inhibition (HRI) against at least one of the four NAIs, usually oseltamivir, while 0.3% (n=39) showed reduced inhibition (RI). NA sequence data, available from the WHO CCs and from sequence databases (n=3661), were screened for amino acid substitutions associated with reduced NAI susceptibility. Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=18), A(H3N2) with NA E119V (n=3) or NA R292K (n=1) and B/Victoria-lineage with NA H273Y (n=2); amino acid position numbering is A subtype and B type specific. Overall, approximately 99% of circulating viruses tested during the 2012-2013 period were sensitive to all four NAIs. Consequently, these drugs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections. PMID- 25043639 TI - H1PVAT is a novel and potent early-stage inhibitor of poliovirus replication that targets VP1. AB - A novel small molecule, H1PVAT, was identified as a potent and selective inhibitor of the in vitro replication of all three poliovirus serotypes, whereas no activity was observed against other enteroviruses. Time-of-drug-addition studies revealed that the compound interfered with an early stage of virus replication. Four independently-selected H1PVAT-resistant virus variants uniformly carried the single amino acid substitution I194F in the VP1 capsid protein. Poliovirus type 1 strain Sabin, reverse-engineered to contain this substitution, proved to be completely insensitive to the antiviral effect of H1PVAT and was cross-resistant to the capsid-binding inhibitors V-073 and pirodavir. The VP1 I194F mutant had a smaller plaque phenotype than wild-type virus, and the amino acid substitution rendered the virus more susceptible to heat inactivation. Both for the wild-type and VP1 I194F mutant virus, the presence of H1PVAT increased the temperature at which the virus was inactivated, providing evidence that the compound interacts with the viral capsid, and that capsid stabilization and antiviral activity are not necessarily correlated. Molecular modeling suggested that H1PVAT binds with high affinity in the pocket underneath the floor of the canyon that is involved in receptor binding. Introduction of the I194F substitution in the model of VP1 induced a slight concerted rearrangement of the core beta-barrel in this pocket, which disfavors binding of the compound. Taken together, the compound scaffold, to which H1PVAT belongs, may represent another promising class of poliovirus capsid-binding inhibitors next to V-073 and pirodavir. Potent antivirals against poliovirus will be essential in the poliovirus eradication end-game. PMID- 25043641 TI - Prognostic impact of preoperative monocyte counts in patients with resected lung adenocarcinoma. AB - OBJECTIVES: Increasing evidence suggests that an elevated peripheral monocyte count at presentation predicts a poor prognosis in various types of malignancy, including malignant lymphoma. In lung adenocarcinoma, tumor-associated macrophages (TAMs) were reported to be associated with a poor prognosis. However, it is unknown if an elevated peripheral monocyte count is associated with a poor prognosis in lung adenocarcinoma. This study assessed the prognostic impact of the preoperative peripheral monocyte count in lung adenocarcinoma. MATERIALS AND METHODS: We retrospectively analyzed 302 consecutive patients with lung adenocarcinoma who received curative resection at Kitano Hospital. The receiver operating characteristic (ROC) curve for the peripheral monocyte count was used to determine the cut-off value. The relations between peripheral monocyte counts and clinicopathological factors were assessed. We also evaluated the impacts of possible prognostic factors including the preoperative peripheral monocyte count on survival, using the two-tailed log-rank test and Cox proportional hazards model. In addition, immunohistochemical staining for CD68 was performed to evaluate the monocytes in primary tumors. RESULTS: A peripheral monocyte count of 430mm(-3) was the optimal cut-off value for prognosis. An elevated peripheral monocyte count was significantly associated with sex, performance status, smoking history, chronic obstructive pulmonary disease and interstitial lung disease. The two-tailed log-rank test demonstrated that patients with an elevated peripheral monocyte count experienced a poorer recurrence-free survival (RFS) and overall survival (OS) (P=0.0063, P<0.0001, respectively). In the multivariate analysis an elevated peripheral monocyte count was shown to be an independent prognostic factor for the RFS and OS (HR: 1.765; 95% CI: 1.071-2.910; P=0.0258, HR: 4.339; 95% CI: 2.032-9.263; P=0.0001, respectively). Furthermore, numbers of the monocytes in primary tumors significantly correlated with peripheral monocyte counts (r=0.627, P<0.0001). CONCLUSION: The preoperative peripheral monocyte count is an important prognostic factor for patients with lung adenocarcinoma after curative resection. PMID- 25043640 TI - Polymorphisms of peroxisome proliferator-activated receptors and survival of lung cancer and upper aero-digestive tract cancers. AB - BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in several biological processes such as inflammation, cancer growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer outcomes. Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers. METHODS: 1212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) were followed for a median duration of 11 years. We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman - rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG - and investigated their associations with lung and UADT cancer survival using Cox regression. A semi-Bayesian shrinkage approach was used to reduce the potential for false positive findings when examining multiple associations. RESULTS: The variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR]=0.63, 95% confidence interval [CI]=0.42, 0.96) and UADT cancers (aHR=0.51, 95% CI=0.27, 0.99). Use of the semi Bayesian shrinkage approach yielded a posterior aHR for lung cancer of 0.66 (95% posterior limits=0.44, 0.98) and a posterior aHR for UADT cancers of 0.58 (95% posterior limits=0.33, 1.03). CONCLUSION: Our findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants. PMID- 25043642 TI - Multicenter phase II study evaluating docetaxel and cisplatin as neoadjuvant induction regimen prior to surgery or radiochemotherapy with docetaxel, followed by adjuvant docetaxel therapy in chemonaive patients with NSCLC stage II, IIIA and IIIB (TAX-AT 1.203 Trial). AB - OBJECTIVES: Neoadjuvant therapy with a platinum based doublet is an option in NSCLC patients with upfront resectable disease. However, the role of neoadjuvant induction in stages IIIA and IIIB and in initially not resectable patients is unclear. PATIENTS AND METHODS: In this phase II trial, 78 patients with locally advanced NSCLC, of whom 56 were considered not resectable at initial diagnosis, were treated with three neoadjuvant cycles of docetaxel and cisplatin and subjected to radical surgery if resectable. Definitive radiochemotherapy (RCT) using weekly docetaxel was the prespecified alternative if patients were not resectable at restaging. The primary objective was response to neoadjuvant induction. RESULTS: After induction, 36 (46%) were radically operated and 24 (31%) were treated with RCT. Overall, 32 patients (41%) completed the entire study plan. Partial response to induction therapy was observed in 43 patients (55%); furthermore, 19 of 56 initially not resectable cases (34%) became resectable upon induction. Median progression-free (PFS) and overall survival (OS) were 8.5 and 16.4 months for the whole cohort. Encouragingly, conversion to resectability was predictive for favorable outcome. On the other hand, patients who were not resectable at restaging and received RCT were characterized by a rather unfavorable prognosis (5-year and 10-year OS, whole cohort: 20% and 12%; RCT: 8% and 0%; surgery: 37% and 24%, respectively). CONCLUSION: Neoadjuvant induction with the doublet docetaxel/cisplatin and subsequent radical resection resulted in favorable survival. Of note, conversion to resectability was mandatory for the chance of cure in patients considered initially not resectable. PMID- 25043643 TI - Beta-lactam antibiotic dosing during continuous renal replacement therapy: how can we optimize therapy? AB - Correct antibiotic treatment is of utmost importance to treat infections in critically ill patients, not only in terms of spectrum and timing but also in terms of dosing. However, this is a real challenge for the clinician because the pathophysiology (such as shock, augmented renal clearance, and multiple organ dysfunction) has a major impact on the pharmacokinetics of hydrophilic antibiotics. The presence of extra-corporal circuits, such as continuous renal replacement therapy, may further complicate this difficult exercise. Standard dosing may result in inadequate concentrations, but unadjusted dosing regimens may lead to toxicity. Recent studies confirm the variability in concentrations, and the wide variation in dialysis techniques used certainly contributes to these findings. Well-designed clinical studies are needed to provide the data from which robust dosing guidance can be developed. In the meantime, non-adjusted dosing in the first 1 to 2 days of antibiotic therapy during continuous renal replacement therapy followed by dose reduction later on seems to be a prudent approach. PMID- 25043645 TI - A career forged in iron. PMID- 25043644 TI - Brain-kidney crosstalk. AB - Encephalopathy and altered higher mental functions are common clinical complications of acute kidney injury. Although sepsis is a major triggering factor, acute kidney injury predisposes to confusion by causing generalised inflammation, leading to increased permeability of the blood-brain barrier, exacerbated by hyperosmolarity and metabolic acidosis due to the retention of products of nitrogen metabolism potentially resulting in increased brain water content. Downregulation of cell membrane transporters predisposes to alterations in neurotransmitter secretion and uptake, coupled with drug accumulation increasing the risk of encephalopathy. On the other hand, acute brain injury can induce a variety of changes in renal function ranging from altered function and electrolyte imbalances to inflammatory changes in brain death kidney donors. PMID- 25043646 TI - Geometrical comparison of two protein structures using Wigner-D functions. AB - In this article, we develop a quantitative comparison method for two arbitrary protein structures. This method uses a root-mean-square deviation characterization and employs a series expansion of the protein's shape function in terms of the Wigner-D functions to define a new criterion, which is called a "similarity value." We further demonstrate that the expansion coefficients for the shape function obtained with the help of the Wigner-D functions correspond to structure factors. Our method addresses the common problem of comparing two proteins with different numbers of atoms. We illustrate it with a worked example. PMID- 25043647 TI - Baseline characteristics of the 4011 patients recruited into the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial. AB - BACKGROUND: High blood pressure is common in acute stroke and associated with a worse functional outcome. Many patients who present with acute stroke are taking prescribed antihypertensive therapy before their stroke. AIMS: ENOS tested whether lowering blood pressure and continuing pre-stroke antihypertensive therapy are each safe and effective. METHODS: This study is an international multi-centre prospective randomized single-blind blinded-endpoint parallel-group partial-factorial controlled trial of transdermal glyceryl trinitrate(a nitric oxide donor, given for seven-days) vs. no glyceryl trinitrate, and of continuing vs. stopping (temporarily for seven-days) pre-stroke antihypertensive drugs if relevant, inpatients with acute ischaemic stroke or intracerebral haemorrhage and high systolic blood pressure (140-220 mmHg). RESULTS: Recruitment ran from July 2001 to October 2013. Four thousand eleven patients [2097 (52.3%) in the continue/stop arm] were recruited from 173 sites across 23 countries in 5 continents (Asia 14%, Continental Europe 16%, UK 64%). Baseline characteristics include: mean age 70 (standard deviation 12) years; male 57%; mean time from stroke to recruitment 26 (13) h; mean severity (Scandinavian Stroke Scale) 34(13) of 58; mean blood pressure 167 (19)/90 (13) mmHg; ischaemic stroke 83%; and intracerebral haemorrhage 16%. The main trial results will be presented in May 2014. The results will also be presented in updated Cochrane systematic reviews and included in individual patient data meta-analyses of all relevant randomized controlled trials. CONCLUSION: ENOS is a large completed international trial of blood pressure management in acute stroke and includes patients representative of many stroke services worldwide. PMID- 25043648 TI - Re: Intrarenal and extrarenal autonomic nervous system redefined: A. Lusch, R. Leary, E. Heidari, M. A. Liss, Z. Okhunov, A. Perez-Lanzac De Lorca, J. Huang, J. Wikenheiser and J. Landman. J Urol 2014; 191: 1060-1065. PMID- 25043650 TI - Re: Safety and efficacy of testosterone replacement therapy in adolescents with Klinefelter syndrome: A. Mehta, T. Clearman and D. A. Paduch. J Urol 2014; 191: 1527-1531. PMID- 25043652 TI - Energy-efficient hydrogen separation by AB-type ladder-polymer molecular sieves. AB - Increases in hydrogen selectivity of more than 100% compared with the most selective ladder polymer of intrinsic microporosity (PIM) reported to date are achieved with self-polymerized A-B-type ladder monomers comprising rigid and three-dimensional 9,10-dialkyl-substituted triptycene moieties. The selectivities match those of materials commercially employed in hydrogen separation, but the gas permeabilities are 150-fold higher. This new polymer molecular sieve is also the most selective PIM for air separation. PMID- 25043653 TI - Oncologists and primary care physicians infrequently provide survivorship care plans. PMID- 25043654 TI - Continuous venovenous hemodiafiltration for hyperlactatemia caused by telbivudine in a patient with chronic hepatitis B: a case report and update review. AB - Although there have been reports on telbivudine-induced myopathy and creatine kinase (CK) elevation, few reports focus on its effect on hyperlactatemia in patients with chronic hepatitis B (CHB). Here we reported a case of hyperlactatemia during telbivudine treatment. A 26-year-old Chinese man had been receiving telbivudine for CHB since July 2011, with a CK level of 68 U/L before the antiviral therapy. After 3 months he felt muscular weakness in both upper and lower extremities. A check in the local clinic found his CK level was increased to 222 U/L (upper limit of normal 170 U/L). However, he did not visit his doctor or stop the telbivudine treatment until he felt myalgia throughout his body. By this time his CK level had increased to 4151 U/L. Even after the withdrawal of telbivudine, his myalgia was exacerbated and his CK level was decreased extremely slowly. His constant myolysis developed into hyperlactatemia and he finally recovered after successful venovenous hemodiafiltration. The findings in this patient suggest that telbivudine may lead to high CK levels and hyperlactatemia may occur if telbivudine is not discontinued immediately when CK levels are clearly increased. Moreover, we emphasized that serum CK and lactate levels should be monitored closely during treatment with telbivudine in patients with CHB. PMID- 25043655 TI - Highly functionalized and potent antiviral cyclopentane derivatives formed by a tandem process consisting of organometallic, transition-metal-catalyzed, and radical reaction steps. AB - A simple modular tandem approach to multiply substituted cyclopentane derivatives is reported, which succeeds by joining organometallic addition, conjugate addition, radical cyclization, and oxygenation steps. The key steps enabling this tandem process are the thus far rarely used isomerization of allylic alkoxides to enolates and single-electron transfer to merge the organometallic step with the radical and oxygenation chemistry. This controlled lineup of multiple electronically contrasting reactive intermediates provides versatile access to highly functionalized cyclopentane derivatives from very simple and readily available commodity precursors. The antiviral activity of the synthesized compounds was screened and a number of compounds showed potent activity against hepatitis C and dengue viruses. PMID- 25043657 TI - mTOR regulate EMT through RhoA and Rac1 pathway in prostate cancer. AB - Recently, an increasing number of studies have suggested that mTOR plays a critical role in the regulation of tumor cell motility, invasion and cancer metastasis. However, little is known about the signaling mechanisms in regulating epithelial-mesenchymal transition (EMT) of prostate cancer. In this study, we found that the expression levels of Raptor and Rictor in prostate cancer tissues were elevated, which may suggest that Raptor and Rictor signaling pathways are associated with prostate cancer progression and metastasis. Inhibition of mTORC1 or mTORC2 by knock down of Raptor or Rictor, respectively, migration and invasion of prostate cancer were attenuated. Furthermore, EMT, a characterized by the changed expression levels of various markers like E-cadherin, beta-catenin, N cadherin, and vimentin emergend following inhibition of Raptor or Rictor. Finally, the small GTPases (RhoA and Rac1) which were crucial regulatory proteins in cell migration and invasion were inactivited after downregulating Raptor and Rictor. These results suggest that mTOR regulate EMT at least in part by down regulation of RhoA and Rac1 signaling pathways. Our findings provide novel very attractive target strategies that the inhibition of mTOR signaling pathways may retard prostate cancer migration and invasion at early stages. PMID- 25043658 TI - An affine continuum mechanical model for cross-linked F-actin networks with compliant linker proteins. AB - Cross-linked actin networks are important building blocks of the cytoskeleton. In order to gain deeper insight into the interpretation of experimental data on actin networks, adequate models are required. In this paper we introduce an affine constitutive network model for cross-linked F-actin networks based on nonlinear continuum mechanics, and specialize it in order to reproduce the experimental behavior of in vitro reconstituted model networks. The model is based on the elastic properties of single filaments embedded in an isotropic matrix such that the overall properties of the composite are described by a free energy function. In particular, we are able to obtain the experimentally determined shear and normal stress responses of cross-linked actin networks typically observed in rheometer tests. In the present study an extensive analysis is performed by applying the proposed model network to a simple shear deformation. The single filament model is then extended by incorporating the compliance of cross-linker proteins and further extended by including viscoelasticity. All that is needed for the finite element implementation is the constitutive model for the filaments, the linkers and the matrix, and the associated elasticity tensor in either the Lagrangian or Eulerian formulation. The model facilitates parameter studies of experimental setups such as micropipette aspiration experiments and we present such studies to illustrate the efficacy of this modeling approach. PMID- 25043659 TI - The contribution of proteoglycans to the mechanical behavior of mineralized tissues. AB - It has been widely shown that proteoglycans (PG) and their glycosaminoglycan (GAG) side-chains form supramolecular aggregates that interconnect the collagenous network in connective tissues and play a significant role in regulating the mechanical behavior of the extracellular matrix, particularly in soft tissues. However, collective evidence of the mechanical participation of PGs and GAGs in mineralized tissues remains poorly explored in the literature. Here, we address this knowledge gap and discuss the participation of PGs on the biomechanics of mineralized tissues including dentine, cementum and bone. We review evidence suggesting that, on a microscale, PGs regulate the hydrostatic and osmotic pressure, as well as the poroelastic behavior of dentine and bone. On the nanoscale, we review the so-called sliding filament theory and intramolecular stretching of GAGs. We also discuss recent interpretations whereby folding and unfolding of the PG protein core, potentially in association with SIBLING proteins, may be a contributing factor to the mechanical behavior of mineralized tissues. Finally, we review in vitro and in vivo studies of mineralized tissues with targeted disruption or digestion of specific PG family members, which provide further insights into their relevance to the mechanical properties of load bearing hard tissues. In summary, this review brings forth collective evidence suggesting that PGs and GAGs, although less than 5% of the tissue matrix, may play a role in the mechanical behavior and durability of mineralized tissues. PMID- 25043660 TI - Cytology and human papillomavirus testing on cytobrushing samples from patients with head and neck squamous cell carcinoma. AB - BACKGROUND: The increasing incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) highlights the need for simple and effective tools to evaluate head and neck lesions and their HPV status. The main objective of the current study was to investigate the association between abnormal cytology and HPV infection, assessed on cytobrushing samples, and histologically confirmed HNSCC. Second, the authors attempted to investigate whether HPV status on cytobrushing samples reflected that of the tumoral tissue. METHODS: A total of 164 samples from HNSCC, nonmalignant lesions, or healthy mucosae of the oral cavity and oropharynx were collected by cytobrushing in PreservCyt solution and evaluated by liquid-based cytology and Linear Array HPV genotyping test. All the findings from the cytologic samples were compared with those from the corresponding histologic samples. RESULTS: Patients with abnormal cytology had a significantly higher risk of having an HNSCC (odds ratio [OR], 9.18; 95% confidence inteval [95% CI], 3.27-26.49). The association was stronger for oral cancer (OR, 10.86; 95% CI, 2.51-51.06) than oropharyngeal cancer (OR, 8.45; 95% CI, 1.62-49.82). HPV positivity in the oropharyngeal cytobrushing was associated with a nearly 5-fold higher risk of having abnormal cytology (OR, 4.57; 95% CI, 1.57-13.57) as well as histologically proven oropharyngeal cancer (OR, 5.09; 95% CI, 1.09-31.61). Comparing the HPV status on cytologic and corresponding histologic samples from patients with HNSCC, we found that 90.4% of the cases were concordant (kappa, 0.796). CONCLUSIONS: Abnormal brushing cytology is strongly associated with a diagnosis of HNSCC, whereas HPV positivity on cytobrushing samples is only associated with oropharyngeal cancer. HPV testing on cytobrushing samples represents a valid option for the assessment of HPV infection in patients with oropharyngeal cancer. PMID- 25043661 TI - A simple assay for quality binders to cucurbiturils. AB - A new approach towards the rapid identification of quality binders to cucurbiturils--those that combine high affinity with high selectivity for a particular homologue--was developed. The assay exploits macrocycle-specific optical fingerprints (colorimetric or fluorimetric) of carefully selected indicators dyes. The screening of a guest library revealed known (e.g., adamantane derivatives) and new (e.g., terpenes) quality binders. The predictive power of the assay was underpinned by the modeling of the involved thermodynamic equilibria. PMID- 25043662 TI - The effect of the biological variability of samples on Coomassie blue dye based fast staining for SDS-PAGE in nonfixed gels. AB - Fast-staining protocols based on the use of Coomassie blue dye for SDS-PAGE separated proteins, represent a quick and simple solution for protein visualization. It has been shown however, that in some cases a phenomenon of missing spots or spot discoloration may be observed in the proteome pattern when the standard fast-staining protocol is used. In this work, it is demonstrated that this occurrence is affected by the biological variability of samples, and therefore, cannot be observed in all samples. Moreover, it is demonstrated that the phenomenon is manifested exclusively in nonfixed gels, and that including a fixation step into the fast-staining protocol prevented this phenomenon. In conclusion, it has been demonstrated that standard Coomassie blue dye based fast staining for SDS-PAGE resolved proteins is affected by the biological variability of samples in nonfixed gels. PMID- 25043663 TI - Impaired mental simulation of specific past and future personal events in non depressed multiple sclerosis patients. AB - The aims of the present study were (i) to explore autobiographical memory and episodic future thought in multiple sclerosis (MS), using Levine's Autobiographical Interview; (ii) to investigate the influence of the Interview's high retrieval support condition (the specific probe phase) on MS patients' past and future simulations and (iii) to obtain the patients' estimations of their own difficulties, during the test, and in everyday life. To that end, we examined 39 non-depressed relapsing-remitting MS patients and 34 healthy subjects matched for gender, age and education level. The 73 participants underwent an adapted version of the Autobiographical Interview in two conditions: remembering and imagining personal events. The group of patients also underwent an extended neuropsychological baseline, including particularly, anterograde memory and executive functions. The results showed that the MS patients' scores on the baseline were mildly or not impaired. On the contrary, the Autobiographical Interview measure, i.e., the mean number of internal details, for each of the two phases of the test - free recall and specific probe - was significantly lower in simulated past and future events in comparison with the healthy controls. Within each group, autobiographical memory performance was superior to episodic future thought performance. A strong positive correlation was observed between past and future mental simulation scores in both groups. In conclusion, our results showed, for the first time, the co-occurrence of deficit of remembering the past and imagining the future in MS patients. They also showed more difficulty in imagining future events than remembering past events for both patients and normal controls. MS being a neurological condition very frequent in the young adult population, the clinical considerations of our study might be of interest. Indeed, they give rise to new insights on MS patients' daily life difficulties related to impaired mental simulation of personal events despite general abilities, including anterograde memory, only mildly or not impaired. PMID- 25043664 TI - Motor neuronopathy in Chediak-Higashi syndrome. AB - Chediak-Higashi syndrome is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, recurrent pyogenic infections and the presence of giant granules in many cells such as leucocytes (hallmark of the disease). Neurological symptoms are rare. We describe two sisters who presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one patient); biopsy of the sural nerve showed an abnormal endoneurial accumulation of lipofuscin granules. We discuss these two observations and compare them with the few case reports of neuropathy in Chediak-Higashi syndrome. PMID- 25043665 TI - Freezing of gait in Chinese patients with Parkinson disease. AB - A total of 474 Chinese Parkinson disease (PD) patients were evaluated to explore the prevalence and clinical correlates of freezing of gait (FOG) in this cross sectional study. Two hundred and twenty-one PD patients (46.62%) reported FOG (freezers). FOG occurred more frequently in older patients and patients with low limbs as the site of onset, longer disease duration and higher Hoehn and Yahr (H&Y) stage (P<0.05). After adjusting for confounding factors, the freezers had higher scores for the Unified PD Rating Scale (UPDRS) part III, Non-Motor Symptoms Scale (NMSS), PD Questionnaire 39 (PDQ-39), Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), and lower scores for the Mini-Mental status examination (MMSE), frontal assessment battery (FAB) and Montreal Cognitive Assessment (MoCA) compared with the non-freezers (P<0.05). The binary logistic regression analysis indicated that festination, falls, a high daily dose of levodopa, the use of a dopamine receptor agonist, a high H&Y stage, the severity of urinary symptoms and a high HAMD score were associated with FOG. FOG is a relatively common disabling symptom in Chinese PD patients. Patients that were older, or reported a longer disease duration, low limbs as the site of onset and a more severe disability were more likely to experience FOG. Non-motor symptoms, especially urinary symptoms and depression, may also be related to FOG. PMID- 25043666 TI - Pathological manifestation of difference in washout pattern of adrenal hyperplasia on dynamic CT. AB - INTRODUCTION: The relationship between the washout pattern and constituent cell in adrenal hyperplasia (AH) has not been fully investigated. The purpose of this study was to elucidate the radiological or pathological factors determining the washout pattern of AH on dynamic CT. METHODS: Ten patients with 14 surgically proven AHs were enrolled. Dynamic CT was scanned before (pre-contrast image) and 60 seconds (early phase) and 240 seconds (delayed phase) after administration of iodine contrast. The absolute percentage washout (APW) of each nodular lesion was calculated using the following formula: APW(%) = (TAearly-TAdelay)/(TAearly TApre) * 100, when TApre, TAearly and TAdelay were defined as tumour attenuation values of pre-contrast, early and delayed phases, respectively. Pathologically, the clear cell ratio (CCR) constituting each nodular lesion was qualitatively assessed. Regression analysis was performed to evaluate a correlation between each pair of CCR, TApre, (TAearly-TAdelay) and APW. RESULTS: There was a significant correlation between each pair of CCR, TApre and APW. CCR decreased as TApre increased (r = 0.81, P < 0.001). APW increased as CCR decreased (r = 0.80, P < 0.001) or as TApre increased (r = 0.74, P < 0.01). CONCLUSIONS: The key factors of washout pattern of AH on dynamic CT were CCR and TApre. The difference in constituent cell was associated with variability in APW of AH. PMID- 25043667 TI - Expression of phosphorylated-mTOR during the development of prostate cancer. AB - BACKGROUND: The PI3K pathway plays a significant role in the progression of prostate cancer (PCa) to an advanced stage. Mouse models suggest that the downstream effector molecule of the PI3K pathway, mTOR, is also important in the development of PCa, where it plays a pivotal role in forming precursor lesions such as high grade prostatic intraepithelial neoplasia (HGPIN). This study was conducted to determine the status of phosphorylated-mTOR (p-mTOR the activated state of mTOR) across the PCa progression model by looking at expression in normal prostate tissue, proliferative inflammatory atrophy (PIA), HGPIN, and PCa. METHODS: Expression of p-mTOR was evaluated by immunohistochemistry on tissue microarrays constructed from 120 archival formalin-fixed paraffin embedded radical prostatectomy tissue specimens. Levels of expression were recorded as the percentage of positive epithelial cells multiplied by the intensity of staining scored as 0-3. RESULTS: p-mTOR expression was found to increase across the progression model with mean staining in non-neoplastic samples of 40 compared to 98 in PIA, 107 in HGPIN, and 136 in cancer (P < 0.001), but without significant increase between HGPIN and PIA. Correlation of high p-mTOR expression with outcome in PCa showed a trend towards worse prognosis, but this was not statistically significant. CONCLUSIONS: This study demonstrates that p-mTOR signaling has a potential role in both the initiation and progression of PCa. These data provide support for further research into the possible use of rapamycin analogues in the treatment of PCa, and raise the possibility that mTOR might be a potential target for chemoprevention. PMID- 25043668 TI - Unraveling recombination rate evolution using ancestral recombination maps. AB - Recombination maps of ancestral species can be constructed from comparative analyses of genomes from closely related species, exemplified by a recently published map of the human-chimpanzee ancestor. Such maps resolve differences in recombination rate between species into changes along individual branches in the speciation tree, and allow identification of associated changes in the genomic sequences. We describe how coalescent hidden Markov models are able to call individual recombination events in ancestral species through inference of incomplete lineage sorting along a genomic alignment. In the great apes, speciation events are sufficiently close in time that a map can be inferred for the ancestral species at each internal branch - allowing evolution of recombination rate to be tracked over evolutionary time scales from speciation event to speciation event. We see this approach as a way of characterizing the evolution of recombination rate and the genomic properties that influence it. PMID- 25043669 TI - Soluble Expression of Bladder Cancer Biomarker Matrix Metalloproteinase 1. AB - BACKGROUND: Matrix metalloproteinase 1 (MMP1) has been shown as a novel unique biomarker of bladder cancer in urine. MMP1 can only be detected using conventional and time-consuming methods, such as ELISA and Western. Refolded MMP1 has been achieved and used in probe screen for many years, while there is no clinical application for MMP1 detection until now. Soluble expression of MMP1 is necessary in urine detection. METHODS: cDNA of MMP1 has been isolated from human embryonic kidney 293(HEK293) cells. The catalytic domain of MMP1 is expressed as fusion protein with Escherichia coli thioredoxin (TrxA). The 30 kDa recombinant proteins were purified by Ni-chelating chromatography. The activity of soluble MMP1 was determined and compared with refolded MMP1 by zymography. RESULTS: Compared with refolded MMP1, TrxA can increase the solubility of MMP1. The soluble MMP1 has the same protein sequences with refolded MMP1 and increased 1.54 fold of gelatin-degradation activities than refolded MMP1. CONCLUSION: Successfully soluble expression of MMP1 has been achieved by fusion expression and will make progress in discovering specific molecular probes against MMP1. PMID- 25043670 TI - Shared decision-making: applying a person-centered approach to tailored breast reconstruction information provides high satisfaction across a variety of breast reconstruction options. AB - BACKGROUND: A person-centered approach to co-decision-making using tailored information respects each woman's preferences and may heighten breast reconstruction satisfaction. METHODS: Women seeking breast reconstruction underwent initial and follow-up consultations wherein suitable options were discussed, and take-away material, balanced website links, and access to a nurse specialist and peer volunteers was provided. After reconstruction, the BRECON 31((c)) was administered and analyzed in three groups: autologous, alloplastic, and latissimus dorsi (LD)/implant. BRECON-31((c)) subscale scores were compared between the groups, and multiple regression used to determine if the type of reconstruction independently predicted satisfaction. RESULTS: One hundred twenty three of 176 (70%) women completed the questionnaire (43% autologous, 47% alloplastic, and 10% LD/implant reconstructions). The LD/implant group had a low rate of immediate reconstruction (8.3%, P = 0.04), and the highest rate of chemotherapy (91.7%, P = 0.002) and radiation (100%, P = 0.003). The alloplastic group had a high rate of bilateral reconstruction (86.8%, P = 0.01). All groups scored well on the self-image, arm concerns, intimacy, satisfaction, and expectations subscales. All groups scored moderately on the self-consciousness, appearance, and nipple subscales. The autologous group scored the lowest on recovery (51 vs. 68 and 65, P < 0.0001) and only moderately well on the abdomen subscale (67). Multiple regression analysis showed that satisfaction was not driven by type of reconstruction (P > 0.05). CONCLUSION: High satisfaction can be achieved using a person-centered approach by providing detailed information, appreciating each woman's unique features, and tailoring the reconstruction plan to the individual. Recovery remains a particular challenge, especially for women undergoing autologous reconstruction. PMID- 25043671 TI - Surprising prenatal toxicity of epidermal lipoxygenase-3. AB - Metabolites of the epidermal lipoxygenase-3 (eLOX-3) are involved in various metabolic pathways. Most unexpectedly, intra-amniotic delivery of eLOX-3 to mice at gestational day 14.5, both via an adenoviral vector and as recombinant protein, resulted in fetal growth restriction and intrauterine death. Periodic acid-Schiff staining and RT-PCR analysis of placentae from fetuses exposed to eLOX-3 indicated a lack of glycogen trophoblasts in the junctional zone. Placenta specific gene expression was altered. Thus, the observed prenatal toxicity of eLOX-3 could be due to a strong effect on placental development. PMID- 25043672 TI - High mobility group box 1 protein (HMGB-1): a pathogenic role in preeclampsia? AB - We evaluated whether preeclampsia is associated with elevated circulating levels of High mobility group box 1 protein (HMGB-1), a nuclear protein with proinflammatory effects when released extracellularly. We enrolled 48 women, 32 in third trimester pregnancy (16 with, 16 without preeclampsia), and 16 healthy non pregnant. In the peripheral blood of pregnant women, HMGB-1 concentration was assessed serially, before and after delivery. With or without preeclampsia, third trimester pregnancy was associated with elevated levels of HMGB-1. This elevation is exaggerated in preeclampsia. The source of HMGB-1 observed in these conditions is likely to involve tissues other than the placenta itself. PMID- 25043673 TI - Magnetoresistive performance and comparison of supermagnetic nanoparticles on giant magnetoresistive sensor-based detection system. AB - Giant magnetoresistive (GMR) biosensors have emerged as powerful tools for ultrasensitive, multiplexed, real-time electrical readout, and rapid biological/chemical detection while combining with magnetic particles. Finding appropriate magnetic nanoparticles (MNPs) and its influences on the detection signal is a vital aspect to the GMR bio-sensing technology. Here, we report a GMR sensor based detection system capable of stable and convenient connection, and real-time measurement. Five different types of MNPs with sizes ranging from 10 to 100 nm were investigated for GMR biosensing. The experiments were accomplished with the aid of DNA hybridization and detection architecture on GMR sensor surface. We found that different MNPs markedly affected the final detection signal, depending on their characteristics of magnetic moment, size, and surface based binding ability, etc. This work may provide a useful guidance in selecting or preparing MNPs to enhance the sensitivity of GMR biosensors, and eventually lead to a versatile and portable device for molecular diagnostics. PMID- 25043674 TI - Free fatty acids and IL-6 induce adipocyte galectin-3 which is increased in white and brown adipose tissues of obese mice. AB - Galectin-3 regulates immune cell function and clearance of advanced glycation end products. Galectin-3 is increased in serum of obese humans and mice and most studies suggest that this protein protects from inflammation in metabolic diseases. Current data show that galectin-3 is markedly elevated in the liver, subcutaneous and intra-abdominal fat depots of mice fed a high fat diet and ob/ob mice. Galectin-3 is also increased in brown adipose tissues of these animals and immunohistochemistry confirms higher levels in adipocytes. Raised galectin-3 in obese white adipocytes has been described in the literature and regulation of adipocyte galectin-3 by metabolites with a role in obesity has been analyzed. Galectin-3 is expressed in 3T3-L1 fibroblasts and human preadipocytes and is modestly induced in mature adipocytes. In 3T3-L1 adipocytes galectin-3 is localized in the cytoplasm and is also detected in cell supernatants. Glucose does not alter soluble galectin-3. Lipopolysaccharide has no effect while TNF reduces and IL-6 raises this lectin in cell supernatants. Palmitate and oleate modestly elevate soluble galectin-3. Differentiation of 3T3-L1 cells in the presence of 100 MUM and 200 MUM linoleate induces soluble galectin-3 and cellular levels are upregulated by the higher concentration. Current data suggest that free fatty acids and IL-6 increase galectin-3 in adipocytes and thereby may contribute to higher levels in obesity. PMID- 25043675 TI - Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease. AB - Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls->SMM->MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment. PMID- 25043677 TI - Impact of long-term soft contact lens wear on epithelial flap production and postoperative recovery in laser-assisted subepithelial keratomileusis. AB - PURPOSE: To investigate the impact and postoperative clinical recovery of long term soft contact lens wear on the epithelial flap made during laser-assisted subepithelial keratomileusis (LASEK). METHODS: In a prospective study, 371 patients (589 eyes) who underwent LASEK were divided into four groups (G1, G2, G3, G4) according to their length of soft contact lens wear. After the contact lens (CL) was removed 1 week after surgery, various symptoms - uncorrected visual acuity (UCVA), oedema of the corneal epithelium, spherical equivalent (SE) and haze degree - were recorded on day 1, and at 1 and 3 months postoperatively. RESULTS: There were no significant differences in corneal flap production among the first three groups that wore CLs, but various symptoms and UCVA were all different from the fourth group that did not wear CLs. There were statistically significant differences in oedema of corneal epithelium among the first three groups, and the degree of oedema was positively correlated with the CL wearing time. There were no significant differences in postoperative SE and haze in all four groups. CONCLUSIONS: Long-term soft CL wear can affect production of the epithelial flap and postoperative recovery, including various symptoms, oedema of the central corneal epithelium and visual acuity. In contrast, there was no effect of long-term CL wear on postoperative mean refractive spherical equivalent (MRSE) and haze. PMID- 25043679 TI - Inside the adolescent brain: a commentary on the Special Issue. PMID- 25043678 TI - Practical guideline for management of acute rhinosinusitis in Japan. PMID- 25043680 TI - The role of elective neck dissection in early stage buccal cancer. AB - OBJECTIVES/HYPOTHESIS: The benefits of elective neck dissection (END) in early stage tongue cancer have been widely discussed but are still controversial regarding early-stage buccal cancer. In this study, we evaluate the role of END and the treatment outcome in early-stage buccal cancer in an areca-quid endemic area. STUDY DESIGN: Retrospective case-control study. METHODS: One hundred seventy-three cT1-2N0M0 buccal cancer patients all staged by computed tomography or magnetic resonance imaging were recruited. A total of 151 patients received radical surgery with END, whereas 22 received observation (OBS). Adjuvant radiotherapy with or without chemotherapy was given in selected high-risk patients. RESULTS: The 5-year overall survival (OS) rates for cT1 lesions and cT2 lesions were 86.14% and 75.45%, respectively (P = .105). In the END group, the occult metastasis rate was 1.8% for cT1 lesions and 10.6% for cT2 lesions (P = .053). The 5-year neck control rate rates (P = .001) and disease-free survival rates (P = .0101) were significantly better in the END group compared to the OBS group but were not significant in OS (P = .689). Eighteen (10.41%) patients developed a second primary tumor (SPT), and five (2.89%) patients developed a third primary tumor. Ninety-four percent of SPTs were located within the oral cavity. CONCLUSIONS: END was suggested in T1-T2N0 buccal cancer to improve the neck control rate. In patients for whom END is not performed at the time of tumor excision, regular follow-up of neck status is necessary because the metastatic lesions are mostly salvageable and do not influence the OS. PMID- 25043676 TI - Dynamics of nascent and active zone ultrastructure as synapses enlarge during long-term potentiation in mature hippocampus. AB - Nascent zones and active zones are adjacent synaptic regions that share a postsynaptic density, but nascent zones lack the presynaptic vesicles found at active zones. Here dendritic spine synapses were reconstructed through serial section electron microscopy (3DEM) and EM tomography to investigate nascent zone dynamics during long-term potentiation (LTP) in mature rat hippocampus. LTP was induced with theta-burst stimulation, and comparisons were made with control stimulation in the same hippocampal slices at 5 minutes, 30 minutes, and 2 hours post-induction and to perfusion-fixed hippocampus in vivo. Nascent zones were present at the edges of ~35% of synapses in perfusion-fixed hippocampus and as many as ~50% of synapses in some hippocampal slice conditions. By 5 minutes, small dense-core vesicles known to transport active zone proteins moved into more presynaptic boutons. By 30 minutes, nascent zone area decreased, without significant change in synapse area, suggesting that presynaptic vesicles were recruited to preexisting nascent zones. By 2 hours, both nascent and active zones were enlarged. Immunogold labeling revealed glutamate receptors in nascent zones; however, average distances from nascent zones to docked presynaptic vesicles ranged from 170 +/- 5 nm in perfusion-fixed hippocampus to 251 +/- 4 nm at enlarged synapses by 2 hours during LTP. Prior stochastic modeling suggests that decrease in glutamate concentration reduces the probability of glutamate receptor activation from 0.4 at the center of release to 0.1 just 200 nm away. Thus, conversion of nascent zones to functional active zones likely requires the recruitment of presynaptic vesicles during LTP. PMID- 25043682 TI - Anatomy of anteromedial thigh perforators: CT-angiography study. AB - The anatomy of perforator for anteromedial thigh (AMT) flap is a very much debated issue. In this article, we report AMT perforator vascular anatomy by CT Angiography (CTA) evaluation of 68 consecutive healthy thighs. Perforators emergence, caliber, length, course, and source vessel in the central three fifth of the thigh were studied by a virtual coordinate system. A mean 4.94 +/- 1.75 perforators per thigh (average length, 2.6 +/- 0.99 cm) from superficial femoral artery (SFA) were found, emerging medial and lateral to sartorius muscle. A mean 0.4 +/- 0.74 perforators per thigh (average length, 2.45 +/- 0.97 cm) branched from rectus femoris artery, of which 80% were emerging lateral to sartorius muscle. A mean 0.62 +/- 0.91 perforators per thigh (average length, 3.1 +/- 1.23 cm) branched from an unnamed branch of SFA, of which 88% were emerging lateral to the sartorius muscle. Perforators' calibre was inferior to 1-5 mm in 177 perforators (51.6%), between 1.5 and 2 mm in 159 (46.7%), and over 2 mm in 7 (2%). The findings from this study show that AMT region is plenty of reliable perforators with overlapping fascial emergence but branching from three different source arteries. PMID- 25043681 TI - Contribution of body composition components and soft-tissue biochemical factors to genetic variation of body mass index (BMI) in an ethnically homogeneous population. AB - OBJECTIVES: Elevated BMI results from an excess of not only fat mass (FM) but also fat-free soft tissue mass (FFM). Both components of body soft tissue, FM, and FFM, are now considered as active endocrine organs. The major aim of this study was to explore the genetic architecture of BMI, considering genetic variations of its major soft tissue components, and the main biochemical factors associated with their corresponding metabolism: leptin, adiponectin, E-selectin, and insulin-like growth factor binding protein, IGFBP-1. METHODS: A total of 1,502 apparently healthy individuals (783 men, 719 women) from 359 ethnically homogeneous families were assessed anthropometrically for body composition. Model based quantitative genetic analyses were implemented to reveal genetic and shared environmental factors affecting the variation and covariation of the studied phenotypes. RESULTS: We found that inter-individual variation in BMI is strongly correlated with both body composition components (r > 0.92, P < 0.001). These correlations are caused by shared genetic and environmental factors that were interpreted to be a direct result of the intimate genetic and environmental correlations between FM and FFM. The latter were also significantly correlated with leptin, E-selectin, and IGFBP-1. However, whereas leptin displayed both genetic and environmental correlations with both FM and FFM, their correlations with E-selectin were caused only by common genes, and with IGFBP-1-only by a shared environment. CONCLUSIONS: This study clearly suggests that FM and FFM contributed almost equally to BMI variation, and provides evidence that this contribution is caused by common genetic as well as shared environmental and metabolic factors. PMID- 25043683 TI - Luminescent hybrid materials based on laponite clay. AB - The spectroscopic behavior of ionic Eu(3+) or Tb(3+) complexes of an aromatic carboxyl-functionalized organic salt as well as those of the hybrid materials derived from adsorption of the ionic complexes on Laponite clay are reported. X ray diffraction (XRD) patterns suggest that the complexes are mainly adsorbed on the outer surfaces of the Laponite disks rather than intercalated within the interlayer spaces. Photophysical data showed that the energy-transfer efficiency from the ligand to Eu(3+) ions in the hybrid material is increased remarkably with respect to the corresponding ionic complex. The hybrid material containing the Eu(3+) complex shows bright red emission from the prominent (5) D0 ->(7) F2 transition of Eu(3+) ions, and that containing the Tb(3+) complex exhibits bright green emission due to the dominant (5) D4 ->(7) F5 transition of Tb(3+) ions. PMID- 25043684 TI - Is there a diminishing return of prior glycaemic control? PMID- 25043685 TI - Effect of intensive diabetes treatment on albuminuria in type 1 diabetes: long term follow-up of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study. AB - BACKGROUND: Intensive diabetes treatment reduces the risk of developing albuminuria in individuals with type 1 diabetes. Effects on the long-term clinical course of kidney disease remain to be defined. We aimed to compare the long-term effects of intensive versus conventional treatment on incident albuminuria. METHODS: For this long-term follow-up study of the Diabetes Control and Complications Trial (DCCT) we assessed the effect of intensive diabetes treatment on albuminuria during 18 years after the completion of the trial. During the DCCT (1983-1993), 1441 participants with type 1 diabetes were randomly assigned to receive either intensive treatment (with the goal of achieving levels of glycaemia as close to the non-diabetic range as safely possible) or conventional treatment (aimed at prevention of symptoms of hyperglycaemia and hypoglycaemia). At the end of the DCCT, all participants were instructed in intensive treatment, and all participants were invited to join the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Mean HbA1c during the EDIC study was similar in the two groups of patients who differed in their treatment assignment during the DCCT. Albumin excretion rate was measured every other year during the EDIC study. Microalbuminuria was defined as an albumin excretion rate of 30 mg per 24 h or higher on two consecutive study visits and macroalbuminuria as an albumin excretion rate of 300 mg per day or higher. We estimated glomerular filtration rate from annual serum creatinine measurements throughout DCCT and the EDIC study. The DCCT is registered with ClinicalTrials.gov, number NCT00360815, and the EDIC study, with number NCT00360893. FINDINGS: During years 1-18 of EDIC, we noted 191 new cases of microalbuminuria (71 in the group receiving intensive treatment during DCCT and 120 in the group receiving conventional treatment during DCCT; risk reduction 45%, 95% CI 26-59) and 117 new cases of macroalbuminuria (31 intensive, 86 conventional; 61%, 41-74). At year 17-18 of EDIC, the prevalence of albumin excretion rate of 30 mg per 24 h or higher was 18.4% in participants assigned to intensive treatment during the DCCT, compared with 24.9% in participants assigned to conventional treatment (p=0.02). During years 1-18 of EDIC, we recorded 84 cases of sustained estimated glomerular filtration rate lower than 60 mL/min per 1.73m(2) (31 intensive, 53 conventional; risk reduction 44%, 95% CI 12-64). INTERPRETATION: In individuals with type 1 diabetes, intensive diabetes treatment yields durable renal benefits that persist for at least 18 years after its application. Ultimately, such benefits should result in fewer patients requiring renal replacement therapy. FUNDING: National Institute of Diabetes and Digestive and Kidney Disease. PMID- 25043686 TI - Post-transcriptional regulation of autophagy in C2C12 myotubes following starvation and nutrient restoration. AB - In skeletal muscle, autophagy is activated in multiple physiological and pathological conditions, notably through the transcriptional regulation of autophagy-related genes by FoxO3. However, recent evidence suggests that autophagy could also be regulated by post-transcriptional mechanisms. The purpose of the study was therefore to determine the temporal regulation of transcriptional and post-transcriptional events involved in the control of autophagy during starvation (4h) and nutrient restoration (4h) in C2C12 myotubes. Starvation was associated with an activation of autophagy (decrease in mTOR activity, increase in AMPK activity and Ulk1 phosphorylation on Ser467), an increase in autophagy flux (increased LC3B-II/LC3B-I ratio, LC3B-II level and LC3B-positive punctate), and an increase in the content of autophagy-related proteins (Ulk1, Atg13, Vps34, and Atg5-Atg12 conjugate). Our data also indicated that the content of autophagy-related proteins was essentially maintained when nutrient sufficiency was restored. By contrast, mRNA level of Ulk1, Atg5, Bnip3, LC3B and Gabarapl1 did not increase in response to starvation. Accordingly, binding of FoxO3 transcription factor on LC3B promoter was only increased at the end of the starvation period, whereas mRNA levels of Atrogin1/MAFbx and MuRF1, two transcriptional targets of FoxO involved in ubiquitin-proteasome pathway, were markedly increased at this time. Together, these data provide evidence that target genes of FoxO3 are differentially regulated during starvation and that starvation of C2C12 myotubes is associated with a post-transcriptional regulation of autophagy. PMID- 25043687 TI - Down-regulation of the P-glycoprotein relevant for multidrug resistance by intracellular acidification through the crosstalk of MAPK signaling pathways. AB - In our previous study, we have found that the tumor multidrug resistance mediated by P-glycoprotein could be reversed by sustained intracellular acidification through down-regulating the multidrug resistance gene 1 mRNA and P-glycoprotein expression. However, the molecular events linking the intracellular acidification and the regulation of P-glycoprotein remain unclear. In the present study, the molecular pathways involved in the regulation of P-glycoprotein expression by the intracellular acidification were investigated. We found that the P-glycoprotein expression was down-regulated by the intracellular acidification through inhibition of p38 mitogen-activated protein kinase (MAPK) and the activation of c Jun N-terminal kinase (JNK) in the resisitant K562/DOX cells. In the sensitive K562 and HL60 cell lines, the changes of the p38 MAPK expression after the acidification are not as obvious as that of K562/DOX cells, but the activation of extracellular signal-regulated kinase (ERK) is also observed, which indicates that the down-regulation of p38 MAPK by the intracellular acidification might be the resistant cell line specific. Blockade of ERK and JNK signaling by the inhibitors or RNA interference increased p38MAPK activities suggesting that cross talk within MAPKs is also important for this response. Our study provides the first direct evidence that the reversal of P-glycoprotein-mediated multidrug resistance by intracellular acidification is mediated by the crosstalk of MAPK signaling pathways. PMID- 25043688 TI - Hyperosmolarity induced by high glucose promotes senescence in human glomerular mesangial cells. AB - Hyperglycemia is involved in the diabetic complication of different organs and can elevate serum osmolarity. Here, we tested whether hyperosmolarity promoted by high glucose levels induces cellular senescence in renal cells. We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry. Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex. An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol. Intracellular mechanisms involved were analyzed in cultured human glomerular mesangial cells treated with 30 mM glucose or mannitol. After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated beta-galactosidase activity. Senescence was prevented when myo-inositol was added before treatment. High glucose or mannitol induced constitutive activation of Ras and ERK pathways which, in turn, were activated by oxidative stress. In summary, hyperosmolarity induced renal senescence, particularly in glomerular mesangial cells, increasing oxidative stress, which constitutively activated Ras-ERK 1/2 pathway. Cellular senescence could contribute to the organ dysfunction associated with diabetes. PMID- 25043689 TI - A g-factor metric for k-t-GRAPPA- and PEAK-GRAPPA-based parallel imaging. AB - PURPOSE: The aim of this work is to derive a theoretical framework for quantitative noise and temporal fidelity analysis of time-resolved k-space-based parallel imaging methods. THEORY: An analytical formalism of noise distribution is derived extending the existing g-factor formulation for nontime-resolved generalized autocalibrating partially parallel acquisition (GRAPPA) to time resolved k-space-based methods. The noise analysis considers temporal noise correlations and is further accompanied by a temporal filtering analysis. METHODS: All methods are derived and presented for k-t-GRAPPA and PEAK-GRAPPA. A sliding window reconstruction and nontime-resolved GRAPPA are taken as a reference. Statistical validation is based on series of pseudoreplica images. The analysis is demonstrated on a short-axis cardiac CINE dataset. RESULTS: The superior signal-to-noise performance of time-resolved over nontime-resolved parallel imaging methods at the expense of temporal frequency filtering is analytically confirmed. Further, different temporal frequency filter characteristics of k-t-GRAPPA, PEAK-GRAPPA, and sliding window are revealed. CONCLUSION: The proposed analysis of noise behavior and temporal fidelity establishes a theoretical basis for a quantitative evaluation of time-resolved reconstruction methods. Therefore, the presented theory allows for comparison between time-resolved parallel imaging methods and also nontime-resolved methods. Magn Reson Med 74:125-135, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25043690 TI - Reactions of diaryldibromodisilenes with N-heterocyclic carbenes: formation of formal bis-NHC adducts of silyliumylidene cations. AB - Reactions of stable 1,2-dibromodisilenes ((E)-Ar(Br)Si=Si(Br)Ar) with N heterocyclic carbenes (NHC) afforded NHC-arylbromosilylene adducts or bromide salts of the corresponding bis-NHC adducts of the formal arylsilyliumylidene cations ([ArSi:](+)). In some cases, an NHC was able to replace a bromide anion in the coordination sphere of the arylbromosilylene-NHC adduct. PMID- 25043691 TI - Midregional pro-adrenomedullin plasma concentrations are blunted in severe preeclampsia. AB - Levels of the peptide hormone adrenomedullin (AM) are elevated during normal pregnancy, but whether this differs during complications of pregnancy remains unresolved. AM can be quantified by measuring its pre-prohormone byproduct, midregional pro-adrenomedullin (MR-proADM). MR-proADM has shown prognostic value as a biomarker of heart failure, sepsis, and community-acquired pneumonia. Given the relevance of AM to pregnancy, we tested the hypothesis that MR-proADM provides a biomarker for preeclampsia. We find that MR-proADM plasma concentrations are blunted in severe preeclampsia and that MR-proADM is similarly effective as established biomarkers endoglin and placental growth factor at discriminating patients with severe preeclampsia from controls. PMID- 25043692 TI - Soluble endoglin production is upregulated by oxysterols but not quenched by pravastatin in primary placental and endothelial cells. AB - INTRODUCTION: Preeclampsia is a serious pregnancy complication. Soluble endoglin (sEng) is released from the placenta and contributes to the maternal endothelial dysfunction seen in preeclampsia. Recently oxysterols, which activate the Liver X Receptor (LXR), have been implicated in producing sEng, by upregulating matrix metalloproteinase-14 (MMP14; cleaves endoglin to produce sEng) and down regulating tissue inhibitor of metalloproteinase-3 (TIMP-3; inhibitor of MMP14). The functional experiments in that study were performed on JAR cells (human choriocarcinoma cell line) and placental explants. METHODS: We characterized LXR in severe preeclamptic placentas, and assessed whether oxysterols increase release of sEng from primary human umbilical vein endothelial cells (HUVECs), primary trophoblasts and placental explants. Given pravastatin is thought to block oxysterol production and inhibit the LXR, we examined whether pravastatin reduces sEng release. RESULTS: LXRalpha and beta were localized to the syncytiotrophoblast and villous tips and were significantly up-regulated in preeclamptic placenta. Oxysterols upregulated sEng production in HUVECs and placental explants although the increases were far more modest than that recently reported. Oxysterols did not upregulate sEng in primary trophoblasts. Furthermore, mRNA expression of MMP14 and TIMP-3 were not altered by oxysterols in any tissue. Surprisingly, pravastatin did not decrease oxysterol-induced upregulation of sEng. DISCUSSION: LXR is up-regulated in preeclamptic placenta. Oxysterols upregulate sEng production from human tissues, but the increase is modest, suggesting this may not be the main mechanism for the very significant elevations in sEng seen in preeclampsia. Pravastatin does not decrease sEng production. CONCLUSION: Oxysterols modestly up-regulate sEng production which is not quenched by pravastatin. PMID- 25043693 TI - Clinical and pathological associations of the activating RAC1 P29S mutation in primary cutaneous melanoma. AB - Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1(P29S) in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1(P29S) mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 P = 0.001), increased mitotic rate (OR=1.3 P = 0.03), ulceration (OR=2.4 P = 0.04), nodular subtype (OR=3.4 P = 0.004), and nodal disease at diagnosis (OR=3.3 P = 0.006). BRAF mutant tumors were also associated with nodal metastases (OR=1.9 P = 0.004), despite being thinner at diagnosis than BRAF WT (median 1.2 mm versus 1.6 mm, P < 0.001). Immunohistochemical analysis of 51 melanomas revealed that 47% were immunoreactive for RAC1. Melanomas were more likely to show RAC1 immunoreactivity if they were BRAF mutant (OR=5.2 P = 0.01). RAC1 may therefore be important in regulating the early migration of BRAF mutant tumors. RAC1 mutations are infrequent in primary melanomas but may accelerate disease progression. PMID- 25043694 TI - Vitamin D receptor signaling enhances locomotive ability in mice. AB - Bone fractures markedly reduce quality of life and life expectancy in elderly people. Although osteoporosis increases bone fragility, fractures frequently occur in patients with normal bone mineral density. Because most fractures occur on falling, preventing falls is another focus for reducing bone fractures. In this study, we investigated the role of vitamin D receptor (VDR) signaling in locomotive ability. In the rotarod test, physical exercise enhanced locomotive ability of wild-type (WT) mice by 1.6-fold, whereas exercise did not enhance locomotive ability of VDR knockout (KO) mice. Compared with WT mice, VDR KO mice had smaller peripheral nerve axonal diameter and disordered AChR morphology on the extensor digitorum longus muscle. Eldecalcitol (ED-71, ELD), an analog of 1,25(OH)2 D3 , administered to rotarod-trained C57BL/6 mice enhanced locomotor performance compared with vehicle-treated nontrained mice. The area of AChR cluster on the extensor digitorum longus was greater in ELD-treated mice than in vehicle-treated mice. ELD and 1,25(OH)2 D3 enhanced expression of IGF-1, myelin basic protein, and VDR in rat primary Schwann cells. VDR signaling regulates neuromuscular maintenance and enhances locomotive ability after physical exercise. Further investigation is required, but Schwann cells and the neuromuscular junction are targets of vitamin D3 signaling in locomotive ability. PMID- 25043695 TI - Shoulder injuries in rugby players: mechanisms, examination, and rehabilitation. AB - BACKGROUND: The sport of rugby is growing in popularity for players at the high school and collegiate levels. OBJECTIVE: This article will provided the sports therapist with an introduction to the management of shoulder injuries in rugby players. SUMMARY: Rugby matches results in frequent impacts and leveraging forces to the shoulder region during the tackling, scrums, rucks and maul components of the game. Rugby players frequently sustain contusion and impact injuries to the shoulder region, including injuries to the sternoclavicular, acromioclavicular (AC), and glenohumeral (GH) joints. Players assessed during practices and matches should be screened for signs of fracture, cervical spine and brachial plexus injuries. A three phase program will be proposed to rehabilitate players with shoulder instabilities using rugby specific stabilization, proprioception, and strengthening exercises. A plan for return to play will be addressed including position-specific activities. PMID- 25043696 TI - A biocultural study of the effects of maternal stress on mother and newborn health in the Democratic Republic of Congo. AB - The impact of stress on human health is a topic of wide-spread relevance and one that is particularly amenable to multidisciplinary investigation. Stress impacts both our psychological and physical health and, thus, may leave evidence on our psyche, our physical body and our genome. We are interested in the effect of extreme stressors, such as war, on health from the perspective of long-term and multigenerational effects. We integrate sociocultural, biological, and epigenetic data from the war-torn Democratic Republic of Congo (DRC). Between May and August, 2010, we measured sociocultural stress exposure among 25 mother-newborn dyads and we measured health outcomes in newborns. We also collected maternal venous blood, placental tissue, and umbilical cord blood to assay for methylation changes to test for a possible epigenetic mechanism that mediates the effects of stress on health. We provide a qualitative description of the wide range of stress exposures experienced by mothers in our study. As we have shown previously, maternal war stress is strongly associated with newborn birthweight and changes in newborn methylation at the glucocorticoid receptor NR3C1. New results presented here demonstrate that maternal war stress and birthweight are also associated with genome-wide changes in maternal methylation levels. In sum, these results suggest that stress may influence gene expression across a broad spectrum in the individual who directly experiences the stress, i.e., the mother, whereas potential heritable effects in the newborn may be focused on specific genes that are uniquely sensitive to environmental cues. PMID- 25043697 TI - Sn(IV) Schiff base complexes: triplet photosensitizers for photoredox reactions. AB - We present the synthesis and characterization of a series of four fluorescent Sn(iv) Schiff base complexes, which also possess long-lived triplet excited states. The complexes absorb visible light (lambdamax = 420 to 462 nm) and the optical properties are easily tunable without laborious synthetic elaboration. The triplet excited states are not luminescent, but can be observed and followed using nanosecond transient absorption spectroscopy. The lifetimes of the triplet excited states are on the order of 500 MUs-10 ms in PMMA matrices. The triplet state energies were estimated via energy transfer reactions with a series of organic triplet acceptors. In addition, the photoexcited complexes react with electron donors and acceptors in solution. These results demonstrate the potential for the development of photosensitizers based on main group elements with high spin orbit coupling constants. PMID- 25043698 TI - An efficient triple-junction polymer solar cell having a power conversion efficiency exceeding 11%. AB - Tandem solar cells have the potential to improve photon conversion efficiencies (PCEs) beyond the limits of single-junction devices. In this study, a triple junction tandem design is demonstrated by employing three distinct organic donor materials having bandgap energies ranging from 1.4 to 1.9 eV. Through optical modeling, balanced photon absorption rates are achieved and, thereby, the photo currents are matched among the three subcells. Accordingly, an efficient triple junction tandem organic solar cell can exhibit a record-high PCE of 11.5%. PMID- 25043699 TI - Cognitive decline and brain natriuretic peptide: how are they related? PMID- 25043700 TI - Co-metabolic degradation of diazo dye- reactive blue 160 by enriched mixed cultures BDN. AB - Mixed cultures BDN (BDN) proficient in decolourizing diazo dye-reactive blue 160 (RB160) consist of eight bacterial strains, was developed through culture enrichment method from soil samples contaminated with anthropogenic activities. The synthrophic interactions of BDN have led to complete decolourization and degradation of RB160 (100mg/L) within 4h along with co-metabolism of yeast extract (0.5%) in minimal medium. BDN microaerophilicaly decolourized even 1500mg/L of RB160 under high saline conditions (20g/L NaCl) at 37 degrees C and pH 7.0. BDN exhibited broad substrate specificity and decolourized 27 structurally different dyes. The reductase enzymes symmetrically cleaved RB160 and oxidative enzymes further metabolised the degraded products and five different intermediates were identified using FTIR, (1)HNMR and GC-MS. The phytotoxicity assay confirmed that intact RB160 was more toxic than dye degraded intermediates. The BDN was able to colonize and decolourized RB160 in soil model system in presence of indigenous miocroflora as well as in sterile soil without any amendment of additional nutrients, which signifies it useful and potential application in bioremediation. PMID- 25043702 TI - Complexation between polyallylammonium cations and polystyrenesulfonate anions: the effect of ionic strength and the electrolyte type. AB - Complexation between polyallylammonium cations and polystyrenesulfonate anions was investigated in aqueous solutions of binary 1 : 1 sodium electrolytes (NaX, X = F, Cl, Br, I, NO3, ClO4) by means of microcalorimetry, dynamic light scattering, electrokinetics and spectrophotometry. At lower molar ratios of monomer units charged polyelectrolyte complexes were formed. At molar ratios close to equivalence and at lower salt concentrations (c(NAX)/mol dm(-3) <= 0.1) flocculation occurred. The obtained precipitates contained approximately equimolar amounts of oppositely charged monomer units. At c(NAX)/mol dm(-3) >= 0.5 (X = NO3, ClO4) and in the case when the polycation was present in excess, the amount of positively charged monomer units in the precipitate was higher than that of negatively charged monomers (asymmetric neutralisation). In addition, the aggregation of positively charged complexes in concentrated solutions of all investigated electrolytes was noticed. The onset of aggregation was strongly anion specific. However, the aggregation of negatively charged complexes did not occur even at c(NaX) = 3 mol dm(-3). The composition of the insoluble products at equimolar ratio of monomer units and higher concentrations of NaNO3 and NaClO4 was dependent on the order of addition, indicating non-equilibrium interpolyelectrolyte neutralisation under all ionic conditions. At 25 degrees C and c(NaClO4) = 1 mol dm(-3) equilibrium was not reached after two months. In contrast, the supernatants showed no traces of free polyanion chains after being heated for a week at 60 degrees C. The pairing of monomer units was predominantly entropically driven, irrespective of the type of reaction products formed (polyelectrolyte complexes, precipitates) and the electrolyte type. The results obtained indicate that the overcharging is not an enthalpically demanding process. The calorimetric measurements also suggest that the strong influence of counteranions on the composition of the reaction product must be related to differences in ion distribution around polycations. However, despite rather similar energetics for complex and precipitate formation in the presence of various sodium salts a clear correlation of formation enthalpies with corresponding anion hydration enthalpies (Hofmeister series) was observed. Somewhat surprisingly, the titration calorimetry experiments have also revealed that the increase in electrolyte concentration affects the enthalpy of interpolyelectrolyte neutralisation negligibly. PMID- 25043701 TI - Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles. AB - Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1-immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1-expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF-conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A-containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. CONCLUSION: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA-laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. PMID- 25043703 TI - Intravenous mesenchymal stem cell therapy after recurrent laryngeal nerve injury: a preliminary study. AB - OBJECTIVES/HYPOTHESIS: Intravenous administration of mesenchymal stem cells (MSCs) has been recently shown to enhance functional recovery after stroke and spinal cord injury. The therapeutic properties of MSCs are attributed to their secretion of a variety of potent antiinflammatory and neurotrophic factors. We hypothesize that intravenous administration of MSCs after recurrent laryngeal nerve (RLN) injury in the rat may enhance functional recovery. STUDY DESIGN: Animal Research. METHODS: Twelve 250-gram Sprague-Dawley rats underwent a controlled crush injury to the left RLN. After confirming postoperative vocal fold immobility, each rat was intravenously infused with either green fluorescent protein-expressing MSCs or control media in a randomized and blinded fashion. Videolaryngoscopy was performed weekly. The laryngoscopy video recordings were reviewed and rated by a fellowship-trained laryngologist who remained blinded to the intervention using a 0 to 3 scale. RESULTS: At 1 week postinjury, the MSC infused group showed a trend for higher average functional recovery scores compared to the control group (2.2 vs 1.3), but it did not reach statistical significance (P value of 0.06). By 2 weeks, however, both groups exhibited complete return of function. CONCLUSIONS: These pilot data indicate that with complete nerve transection by crush injury of the RLN in rat, there is complete recovery of vocal fold mobility at 2 weeks. At 1 week postinjury, animals receiving intravenous infusion of MSCs showed a trend for greater functional recovery, suggesting a potential beneficial effect of MSCs; however, this did not reach statistical significance. Therefore, no definite conclusions can be drawn from these data and further study is required. LEVEL OF EVIDENCE: N/A. PMID- 25043704 TI - Hostility and substance use in relation to intimate partner violence and parenting among fathers. AB - Intimate partner violence (IPV) is a significant public health and economic problem, which also increases the risks for child maltreatment. One attribute that may contribute to both IPV and poor parenting is hostility. Moreover, the link between hostility and these outcomes may be mediated by substance use, such that more hostile individuals are at greater risk for using drugs and alcohol, leading them to engage in more aggressive and rejecting behavior toward their partners and children. We tested this possibility in sample of 132 fathers. Additionally, we explored whether hostility and substance use had interactive effects on IPV and parenting by examining moderated-mediation models. The results show that substance use mediated the relationship between hostility and all IPV and parenting outcomes. Furthermore, this mediated relationship was moderated by substance use level for parenting outcomes, but not IPV. In the case of parenting, the mediated path from hostility to aggressive and rejecting parenting only occurred for those high in substance use. Limitations and implications for prevention and treatment of IPV and aggressive and rejecting parenting are discussed. Aggr. Behav. 41:205-213, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25043705 TI - One-week intervention period led to improvements in glycemic control and reduction in DNA damage levels in patients with type 2 diabetes mellitus. AB - AIMS: Hyperglycemia leads to increased production of reactive oxygen species (ROS), which reduces cellular antioxidant defenses and induces several DNA lesions. We investigated the effects on DNA damage of a seven-day hospitalization period in patients with type 2 diabetes mellitus (T2DM) to achieve adequate blood glucose levels through dietary intervention and medication treatment, compared with non-diabetic individuals. METHODS: DNA damage levels were evaluated by the alkaline comet assay (with modified and without conventional use of hOGG1 enzyme, which detects oxidized DNA bases) for 10 patients and 16 controls. Real time PCR array method was performed to analyze the transcriptional expression of a set of 84 genes implicated in antioxidant defense and response to oxidative stress in blood samples from T2DM patients (n=6) collected before and after the hospitalization period. RESULTS: The seven-day period was sufficient to improve glycemic control and to significantly decrease (p<0.05) DNA damage levels in T2DM patients, although those levels were slightly higher than those in control subjects. We also found a tendency towards a decrease in the levels of oxidative DNA damage in T2DM patients after the hospitalization period. However, for all genes analyzed, a statistically significant difference in the transcriptional expression levels was not observed. CONCLUSIONS: The study demonstrated that although the transcriptional expression of the genes studied did not show significant alterations, one-week of glycemic control in hospital resulted in a significant reduction in DNA damage levels detected in T2DM patients, highlighting the importance of an adequate glycemic control. PMID- 25043706 TI - Cutaneous metastasis from lung cancer. Case report. AB - Lung cancer is the most common neoplasm diagnosed worldwide. Metastatic presentation of the disease is frequent. Apart from the usual sites of metastatic disease (bone, adrenals, liver, brain), a particular site for metastases is represented by skin. The case we report is about a 66 year-old man with cutaneous metastasis from lung cancer. A 66 year-old man, with a previous history of abdominal aortic aneurism, chronic obstructive pulmonary disease, cardiopathy, diabetes mellitus, was admitted to our institution for left lower lobe lung cancer. After accurate preoperative staging, patient underwent a thoracotomic left lower lobectomy. Histological examination revealed a squamocellular carcinoma: G2-3, pT2bN0. Patient underwent oncological evaluation for the scheduled follow up. After 6 months patient went back to our observation for the appearance of a skin nodule, firm, dischromic, painful and ulcerated, localized in right iliac fossa. Biopsies demonstrated the nodule to be squamocellular carcinoma. Patient underwent a CT scan of the abdomen and thorax, which revealed the absence of infiltration of the deep fascial and muscular planes by the neoplasm. Patient underwent surgical removal of the lesion. Final histological examination confirmed the lesion to be metastasis of squamocellular lung cancer. Metastases from lung cancer occur in about 2,5-7,5% of cases. Median survival for these patients is 2,9 months. The most common type of neoplasm, according to Japanese Authors, is adenocarcinoma followed by squamocellular carcinoma. Some studies demonstrated the adequacy of surgery followed by chemotherapy, in case of single lesion. In case of multiple cutaneous metastases, many Authors suggest only chemotherapy, although the ideal scheme hasn't been discovered yet. Cutaneous metastases from lung cancer are rare; however the appearance of skin lesions, in patients with a positive oncological history, requires much attention. Accurate evaluation of the patient is paramount in choosing the adequate therapeutic algorithm. KEY WORDS: Chemotherapy, Lung Cancer, Skin Metastases. PMID- 25043707 TI - Sodium lactate for fluid resuscitation: the preferred solution for the coming decades? AB - In a recent issue of Critical Care, 0.5 M sodium lactate infusion for 24 hours was reported to increase cardiac output in patients with acute heart failure. This effect was associated with a concomitant metabolic alkalosis and a negative water balance. Growing data strongly support the role of lactate as a preferential oxidizable substrate to supply energy metabolism leading to improved organ function (heart and brain especially) in ischemic conditions. Due to its sodium/chloride imbalance, this solution prevents hyperchloremic acidosis and limits fluid overload despite the obligatory high sodium load. Sodium lactate solution therefore shows many advantages and appears a very promising means for resuscitation of critically ill patients. Further studies are needed to establish the most appropriate dose and indications for sodium lactate infusion in order to prevent the occurrence of severe hypernatremia and metabolic alkalosis. PMID- 25043709 TI - Variability in secondary structure of 18S ribosomal RNA as topological marker for identification of Paramecium species. AB - Besides cytological and molecular applications, Paramecium is being used in water quality assessment and for determination of saprobic levels. An unambiguous identification of these unicellular eukaryotes is not only essential, but its ecological diversity must also be explored in the local environment. 18SrRNA genes of all the strains of Paramecium species isolated from waste water were amplified, cloned and sequenced. Phylogenetic comparison of the nucleotide sequences of these strains with 23 closely related Paramecium species from GenBank Database enabled identification of Paramecium multimicronucleatum and Paramecium jenningsi. Some isolates did not show significant close association with other Paramecium species, and because of their unique position in the phylogenetic tree, they were considered new to the field. In the present report, these isolates are being designated as Paramecium caudatum pakistanicus. In this article, secondary structure of 18SrRNA has also been analyzed as an additional and perhaps more reliable topological marker for species discrimination and for determining possible phylogenetic relationship between the ciliate species. On the basis of comparison of secondary structure of 18SrRNA of various isolated Paramacium strains, and among Paramecium caudatum pakistanicus, Tetrahymena thermophila, Drosophila melanogaster, and Homo sapiens, it can be deduced that variable regions are more helpful in differentiating the species at interspecific level rather than at intraspecific level. It was concluded that V3 was the least variable region in all the organisms, V2 and V7 were the longest expansion segments of D. melanogaster and there was continuous mutational bias towards G.C base pairing in H. sapiens. PMID- 25043708 TI - Mother and father socially desirable responding in nine countries: Two kinds of agreement and relations to parenting self-reports. AB - We assessed 2 forms of agreement between mothers' and fathers' socially desirable responding in China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand and the United States (N = 1110 families). Mothers and fathers in all 9 countries reported socially desirable responding in the upper half of the distribution, and countries varied minimally (but China was higher than the cross country grand mean and Sweden lower). Mothers and fathers did not differ in reported levels of socially desirable responding, and mothers' and fathers' socially desirable responding were largely uncorrelated. With one exception, mothers' and fathers' socially desirable responding were similarly correlated with self-perceptions of parenting, and correlations varied somewhat across countries. These findings are set in a discussion of socially desirable responding, cultural psychology and family systems. PMID- 25043711 TI - The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation. AB - Platelets are considered to have important functions in inflammatory processes and as actors in the innate immunity. Several studies have shown associations between cardiovascular disease and periodontitis, where the oral anaerobic pathogen Porphyromonas gingivalis has a prominent role in modulating the immune response. Porphyromonas gingivalis has been found in atherosclerotic plaques, indicating spreading of the pathogen via the circulation, with an ability to interact with and activate platelets via e.g. Toll-like receptors (TLR) and protease-activated receptors. We aimed to evaluate how the cysteine proteases, gingipains, of P. gingivalis affect platelets in terms of activation and chemokine secretion, and to further investigate the mechanisms of platelet bacteria interaction. This study shows that primary features of platelet activation, i.e. changes in intracellular free calcium and aggregation, are affected by P. gingivalis and that arg-gingipains are of great importance for the ability of the bacterium to activate platelets. The P. gingivalis induced a release of the chemokine RANTES, however, to a much lower extent compared with the TLR2/1-agonist Pam3 CSK4 , which evoked a time-dependent release of the chemokine. Interestingly, the TLR2/1-evoked response was abolished by a following addition of viable P. gingivalis wild-types and gingipain mutants, showing that both Rgp and Kgp cleave the secreted chemokine. We also demonstrate that Pam3 CSK4 -stimulated platelets release migration inhibitory factor and plasminogen activator inhibitor-1, and that also these responses were antagonized by P. gingivalis. These results supports immune-modulatory activities of P. gingivalis and further clarify platelets as active players in innate immunity and in sensing bacterial infections, and as target cells in inflammatory reactions induced by P. gingivalis infection. PMID- 25043712 TI - Acute sensitivity of white sturgeon (Acipenser transmontanus) and rainbow trout (Oncorhynchus mykiss) to copper, cadmium, or zinc in water-only laboratory exposures. AB - The acute toxicity of cadmium, copper, and zinc to white sturgeon (Acipenser transmontanus) and rainbow trout (Oncorhynchus mykiss) were determined for 7 developmental life stages in flow-through water-only exposures. Metal toxicity varied by species and by life stage. Rainbow trout were more sensitive to cadmium than white sturgeon across all life stages, with median effect concentrations (hardness-normalized EC50s) ranging from 1.47 ug Cd/L to 2.62 ug Cd/L with sensitivity remaining consistent during later stages of development. Rainbow trout at 46 d posthatch (dph) ranked at the 2nd percentile of a compiled database for Cd species sensitivity distribution with an EC50 of 1.46 ug Cd/L and 72 dph sturgeon ranked at the 19th percentile (EC50 of 3.02 ug Cd/L). White sturgeon were more sensitive to copper than rainbow trout in 5 of the 7 life stages tested with biotic ligand model (BLM)-normalized EC50s ranging from 1.51 ug Cu/L to 21.9 ug Cu/L. In turn, rainbow trout at 74 dph and 95 dph were more sensitive to copper than white sturgeon at 72 dph and 89 dph, indicating sturgeon become more tolerant in older life stages, whereas older trout become more sensitive to copper exposure. White sturgeon at 2 dph, 16 dph, and 30 dph ranked in the lower percentiles of a compiled database for copper species sensitivity distribution, ranking at the 3rd (2 dph), 5th (16 dph), and 10th (30 dph) percentiles. White sturgeon were more sensitive to zinc than rainbow trout for 1 out of 7 life stages tested (2 dph with an biotic ligand model-normalized EC50 of 209 ug Zn/L) and ranked in the 1st percentile of a compiled database for zinc species sensitivity distribution. PMID- 25043714 TI - Germanium quantum dots embedded in N-doping graphene matrix with sponge-like architecture for enhanced performance in lithium-ion batteries. AB - Germanium quantum dots embedded in a nitrogen-doped graphene matrix with a sponge like architecture (Ge/GN sponge) are prepared through a simple and scalable synthetic method, involving freeze drying to obtain the Ge(OH)4 /graphene oxide (GO) precursor and subsequent heat reduction treatment. Upon application as an anode for the lithium-ion battery (LIB), the Ge/GN sponge exhibits a high discharge capacity compared with previously reported N-doped graphene. The electrode with the as-synthesized Ge/GN sponge can deliver a capacity of 1258 mAh g(-1) even after 50 charge/discharge cycles. This improved electrochemical performance can be attributed to the pore memory effect and highly conductive N doping GN matrix from the unique sponge-like structure. PMID- 25043715 TI - Brain infection with Staphylococcus aureus leads to high extracellular levels of glutamate, aspartate, gamma-aminobutyric acid, and zinc. AB - Staphylococcal brain infections may cause mental deterioration and epileptic seizures, suggesting interference with normal neurotransmission in the brain. We injected Staphylococcus aureus into rat striatum and found an initial 76% reduction in the extracellular level of glutamate as detected by microdialysis at 2 hr after staphylococcal infection. At 8 hr after staphylococcal infection, however, the extracellular level of glutamate had increased 12-fold, and at 20 hr it had increased >30-fold. The extracellular level of aspartate and gamma aminobutyric acid (GABA) also increased greatly. Extracellular Zn(2+) , which was estimated at ~2.6 umol/liter in the control situation, was increased by 330% 1 2.5 hr after staphylococcal infection and by 100% at 8 and 20 hr. The increase in extracellular glutamate, aspartate, and GABA appeared to reflect the degree of tissue damage. The area of tissue damage greatly exceeded the area of staphylococcal infiltration, pointing to soluble factors being responsible for cell death. However, the N-methyl-D-aspartate receptor antagonist MK-801 ameliorated neither tissue damage nor the increase in extracellular neuroactive amino acids, suggesting the presence of neurotoxic factors other than glutamate and aspartate. In vitro staphylococci incubated with glutamine and glucose formed glutamate, so bacteria could be an additional source of infection-related glutamate. We conclude that the dramatic increase in the extracellular concentration of neuroactive amino acids and zinc could interfere with neurotransmission in the surrounding brain tissue, contributing to mental deterioration and a predisposition to epileptic seizures, which are often seen in brain abscess patients. PMID- 25043713 TI - GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis. AB - Progressive liver fibrosis is characterized by the deposition of collagen by activated hepatic stellate cells (HSCs). Activation of HSCs is a multiple receptor-driven process in which profibrotic signals are enhanced and antifibrotic pathways are suppressed. Here we report the discovery of a signalling platform comprising G protein subunit, Galphai and GIV, its guanine exchange factor (GEF), which serves as a central hub within the fibrogenic signalling network initiated by diverse classes of receptors. GIV is expressed in the liver after fibrogenic injury and is required for HSC activation. Once expressed, GIV enhances the profibrotic (PI3K-Akt-FoxO1 and TGFbeta-SMAD) and inhibits the antifibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favour of fibrosis, all via activation of Galphai. We also provide evidence that GIV may serve as a biomarker for progression of fibrosis after liver injury and a therapeutic target for arresting and/or reversing HSC activation during liver fibrosis. PMID- 25043716 TI - Nitric oxide and reactive species are modulated in the polyphenol-induced ductus arteriosus constriction in pregnant sheep. AB - OBJECTIVE: Because we have previously demonstrated the relation between polyphenol-rich foods (PRF) consumption and ductus arteriosus constriction, in this work, pregnant sheep were submitted to oral PRF intake for 14 days to understand how this process occurs. Fetal Doppler echocardiography, oxidative and inflammatory biomarkers and total polyphenol excretion were evaluated. RESULTS: The high polyphenol intake induced ductus arteriosus constriction by 71.6% increase in systolic (P = 0.001) and 57.8% in diastolic velocities (P = 0.002), and 18.9% decrease in pulsatility index (P = 0.033), along with 1.7-fold increase in total polyphenol excretion, 2.3-fold decrease in inflammatory mediator nitric oxide and following redox status changes (mean +/- standard deviation): higher protein carbonyls (1.09 +/- 0.09 and 1.49 +/- 0.31), catalase (0.69 +/- 0.39 and 1.44 +/- 0.33) and glutathione peroxidase (37.23 +/- 11.19 and 62.96 +/- 15.03) in addition to lower lipid damage (17.22 +/- 2.05 and 12.53 +/- 2.11) and nonprotein thiols (0.11 +/- 0.04 and 0.04 +/- 0.01) found before and after treatment, respectively. Ductal parameters correlated to NOx , catalase, glutathione peroxidase and protein carbonyl. CONCLUSION: Our results highlight the need to reduce maternal PRF intake in late pregnancy to prevent fetal duct constriction through NO-mediated vasoconstrictive action of polyphenols. PMID- 25043717 TI - Person-environment interaction in a new secure forensic state psychiatric hospital. AB - This study examined the person-environment interaction effects of environmental design on ward climate, safety, job satisfaction, and treatment outcomes within a new high security forensic psychiatric facility. Participants included male and female adult psychiatric inpatients and staff members at different security stages. Data were collected once before and twice after the experimental group moved into the new building. The control group remained in the same facilities. Contrary to expectations, the new building had limited effects on the measured variables. PMID- 25043718 TI - Assisted dying in dementia: a systematic review of the international literature on the attitudes of health professionals, patients, carers and the public, and the factors associated with these. AB - BACKGROUND: Assisted death and dementia is a controversial topic that, in recent years, has been subject to considerable clinical, ethical and political debate. OBJECTIVE: This paper reviews the international literature on attitudes towards assisted dying in dementia and considers the factors associated with these. DESIGN: A systematic literature search was conducted in Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica Database, PsychINFO and Web of Science between 1992 and August 2013. Electronic and hand searches identified 118 potential relevant studies. Eighteen studies met the full inclusion criteria and were screened using a quality assessment tool. RESULTS: Health professionals hold more restrictive views towards assisted dying, which appear less affected by their cultural background, than the public, patients and carers. However, opinions within each population vary according to dementia severity and issues of capacity, as well as differing according to factors such as age, ethnicity, gender and religion of those surveyed. There also appears to be a trend towards more accepting attitudes over time. CONCLUSIONS: Sociodemographic factors can influence attitudes towards assisted dying. The impact of these, however, may also differ according to the population surveyed. The findings from this review can contribute to current debates and inform clinical practice and future research in this area. PMID- 25043719 TI - A better alternative to stratified permuted block design for subject randomization in clinical trials. AB - Stratified permuted block randomization has been the dominant covariate-adaptive randomization procedure in clinical trials for several decades. Its high probability of deterministic assignment and low capacity of covariate balancing have been well recognized. The popularity of this sub-optimal method is largely due to its simplicity in implementation and the lack of better alternatives. Proposed in this paper is a two-stage covariate-adaptive randomization procedure that uses the block urn design or the big stick design in stage one to restrict the treatment imbalance within each covariate stratum, and uses the biased-coin minimization method in stage two to control imbalances in the distribution of additional covariates that are not included in the stratification algorithm. Analytical and simulation results show that the new randomization procedure significantly reduces the probability of deterministic assignments, and improve the covariate balancing capacity when compared to the traditional stratified permuted block randomization. PMID- 25043720 TI - Differing chemical compositions of three teas may explain their different effects on acute blood pressure in spontaneously hypertensive rats. AB - BACKGROUND: Heavy tea consumption is suggested to be unsuitable for hypertensive people. However, the bioactive substances in different varieties of tea leaves are very different. This study compares the effects of three Chinese teas - C. sinensis, C. ptilophylla and C. assamica var. kucha - on blood pressure (BP) and heart rate in spontaneously hypertensive rats (SHRs). RESULTS: Intragastric administration of C. sinensis extract led to an acute increase in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate in SHRs. However, C. ptilophylla and C. assamica var. kucha exerted no obvious influences on SBP, DBP or heart rate. Similar to the extract of C. sinensis, intragastric administration of caffeine also led to an acute increase in BP and heart rate in SHRs. In contrast, theobromine and theacrine - purine alkaloids predominantly contained in C. ptilophylla and C. assamica var. kucha, respectively - had no pressor effects. The effect of caffeine on BP was related to the regulation of plasma epinephrine and norepinephrine levels in SHRs. CONCLUSION: The different effects of C. sinensis, C. ptilophylla and C. assamica var. kucha on BP might be explained, at least partially, by the differences in the varieties and contents of purine alkaloids. PMID- 25043721 TI - Contribution of sodium channels to lamellipodial protrusion and Rac1 and ERK1/2 activation in ATP-stimulated microglia. AB - Microglia are motile resident immune cells of the central nervous system (CNS) that continuously explore their territories for threats to tissue homeostasis. Following CNS insult (e.g., cellular injury, infection, or ischemia), microglia respond to signals such as ATP, transform into an activated state, and migrate towards the threat. Directed migration is a complex and highly-coordinated process involving multiple intersecting cellular pathways, including signal transduction, membrane adhesion and retraction, cellular polarization, and rearrangement of cytoskeletal elements. We previously demonstrated that the activity of sodium channels contributes to ATP-induced migration of microglia. Here we show that TTX-sensitive sodium channels, specifically NaV 1.6, participate in an initial event in the migratory process, i.e., the formation in ATP-stimulated microglia of polymerized actin-rich membrane protrusions, lamellipodia, containing accumulations of Rac1 and phosphorylated ERK1/2. We also examined Ca(2+) transients in microglia and found that blockade of sodium channels with TTX produced a downward shift in the level of [Ca(2+) ]i during the delayed, slower recovery of [Ca(2+) ]i following ATP stimulation. These observations demonstrate a modulatory role of sodium channels on Ca(2+) transients in microglia that are likely to affect down-stream signaling cascades. Consistent with these observations, we demonstrate that ATP-induced microglial migration is mediated via Rac1 and ERK1/2, but not p38alpha/beta and JNK, dependent pathways, and that activation of both Rac1 and ERK1/2 is modulated by sodium channel activity. Our results provide evidence for a direct link between sodium channel activity and modulation of Rac1 and ERK1/2 activation in ATP stimulated microglia, possibly by regulating Ca(2+) transients. PMID- 25043722 TI - Genetic deletion of the GATA1-regulated protein alpha-synuclein reduces oxidative stress and nitric oxide synthase levels in mature erythrocytes. AB - alpha-Synuclein is highly expressed in neural tissue and during erythropoiesis, where the key erythroid regulator GATA1 has been found to modulate its expression. While specific alpha-synuclein (SNCA) mutations are known to cause autosomal dominant familial Parkinson's disease, its wild-type function remains under debate. To investigate the role of alpha-synuclein in murine hematopoiesis and erythropoiesis, we utilized Snca knock-out mice and analyzed erythroid compartments for maturation defects, in vivo erythrocyte survival, and erythrocyte-based reactive oxygen species (ROS) and nitric oxide synthase (NOS) levels. Our findings show that while bone marrow and spleen erythropoiesis and peripheral blood erythrocyte survival in Snca(-/-) mice was comparable to controls, the levels of ROS and of NOS-2 were significantly decreased in mature erythrocytes in these animals. These results indicate a role for alpha-synuclein in regulating oxidative stress in erythrocytes in vivo and could open new avenues for the investigation of its function in non-neural tissue. PMID- 25043723 TI - Cardiovascular regenerative therapeutics via synthetic paracrine factor modified mRNA. AB - The heart has a limited capacity for regeneration following injury. Recent strategies to promote heart regeneration have largely focused on autologous and allogeneic cell-based therapy, where the transplanted cells have been suggested to secrete unknown paracrine factors that are envisioned to promote endogenous repair and/or mobilization of endogenous heart progenitors. Here, we discuss the importance of paracrine mechanisms in facilitating replication of endogenous epicardial progenitor cells in the adult heart and signaling their subsequent reactivation and de novo differentiation into functional cell types such as endothelial cells and cardiomyocytes. Moreover, we discuss the use of a novel modified RNA technology in delivering such therapeutic paracrine factors into myocardium following injury. These studies suggest that modified mRNA may be a valuable experimental tool for the precise in vivo identification of paracrine factors and their downstream signaling that may promote heart repair, cardiac muscle replication, and/or heart progenitor mobilization. In addition, these studies lay the foundation for a new clinically tractable technology for a cell free approach to promote heart regeneration. PMID- 25043724 TI - Coarse-grained molecular dynamics simulations of protein-ligand binding. AB - Coarse-grained molecular dynamics (CGMD) simulations with the MARTINI force field were performed to reproduce the protein-ligand binding processes. We chose two protein-ligand systems, the levansucrase-sugar (glucose or sucrose), and LinB-1,2 dichloroethane systems, as target systems that differ in terms of the size and shape of the ligand-binding pocket and the physicochemical properties of the pocket and the ligand. Spatial distributions of the Coarse-grained (CG) ligand molecules revealed potential ligand-binding sites on the protein surfaces other than the real ligand-binding sites. The ligands bound most strongly to the real ligand-binding sites. The binding and unbinding rate constants obtained from the CGMD simulation of the levansucrase-sucrose system were approximately 10 times greater than the experimental values; this is mainly due to faster diffusion of the CG ligand in the CG water model. We could obtain dissociation constants close to the experimental values for both systems. Analysis of the ligand fluxes demonstrated that the CG ligand molecules entered the ligand-binding pockets through specific pathways. The ligands tended to move through grooves on the protein surface. Thus, the CGMD simulations produced reasonable results for the two different systems overall and are useful for studying the protein-ligand binding processes. PMID- 25043725 TI - Quantification of short and long asbestos fibers to assess asbestos exposure: a review of fiber size toxicity. AB - The fibrogenicity and carcinogenicity of asbestos fibers are dependent on several fiber parameters including fiber dimensions. Based on the WHO (World Health Organization) definition, the current regulations focalise on long asbestos fibers (LAF) (Length: L >= 5 MUm, Diameter: D < 3 MUm and L/D ratio > 3). However air samples contain short asbestos fibers (SAF) (L < 5 MUm). In a recent study we found that several air samples collected in buildings with asbestos containing materials (ACM) were composed only of SAF, sometimes in a concentration of >=10 fibers.L-1. This exhaustive review focuses on available information from peer review publications on the size-dependent pathogenetic effects of asbestos fibers reported in experimental in vivo and in vitro studies. In the literature, the findings that SAF are less pathogenic than LAF are based on experiments where a cut-off of 5 MUm was generally made to differentiate short from long asbestos fibers. Nevertheless, the value of 5 MUm as the limit for length is not based on scientific evidence, but is a limit for comparative analyses. From this review, it is clear that the pathogenicity of SAF cannot be completely ruled out, especially in high exposure situations. Therefore, the presence of SAF in air samples appears as an indicator of the degradation of ACM and inclusion of their systematic search should be considered in the regulation. Measurement of these fibers in air samples will then make it possible to identify pollution and anticipate health risk. PMID- 25043726 TI - Detection and quantitation of succinimide in intact protein via hydrazine trapping and chemical derivatization. AB - The formation of aspartyl succinimide is a common post-translational modification of protein pharmaceuticals under acidic conditions. We present a method to detect and quantitate succinimide in intact protein via hydrazine trapping and chemical derivatization. Succinimide, which is labile under typical analytical conditions, is first trapped with hydrazine to form stable hydrazide and can be directly analyzed by mass spectrometry. The resulting aspartyl hydrazide can be selectively derivatized by various tags, such as fluorescent rhodamine sulfonyl chloride that absorbs strongly in the visible region (570 nm). Our tagging strategy allows the labeled protein to be analyzed by orthogonal methods, including HPLC-UV-Vis, liquid chromatography mass spectrometry (LC-MS), and SDS PAGE coupled with fluorescence imaging. A unique advantage of our method is that variants containing succinimide, after derivatization, can be readily resolved via either affinity enrichment or chromatographic separation. This allows further investigation of individual factors in a complex protein mixture that affect succinimide formation. Some additional advantages are imparted by fluorescence labeling including the facile detection of the intact protein without proteolytic digestion to peptides; and high sensitivity, for example, without optimization, 0.41% succinimide was readily detected. As such, our method should be useful for rapid screening, optimization of formulation conditions, and related processes relevant to protein pharmaceuticals. PMID- 25043727 TI - Increased frequency and function of KIR2DL1-3+ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes. AB - The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1 positive and HIV-1-negative individuals were assessed (N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3(+) NK cells. Further analysis showed that KIR2DL1(+) NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1 homozygous individuals displayed increased proportions of KIR2DL2/3(+) NK cells. KIR2DL1-3(+) NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN-gamma and TNF-alpha production. These results identify a novel relationship between HLA-C and KIR2DL(+) NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection. PMID- 25043728 TI - The protective effects of vitamin C on the DNA damage, antioxidant defenses and aorta histopathology in chronic hyperhomocysteinemia induced rats. AB - The aim of this study was to investigate the protective effect of vitamin C towards hyperhomocysteinemia (hHcy) induced oxidative DNA damage using the comet assay. The increase in plasma homocysteine levels is an important risk factor for vascular and cardiovascular diseases through free radical production. This study was also conducted to investigate the histopathological changes in the thoracic aorta and the oxidant/antioxidant status in heart, liver and kidney tissues. Twenty-four adult male Wistar rats were divided as control, hHcy and hHcy+vitamin C group. Chronic hHcy was induced by oral administration of l-methionine (1g/kg/day) for 28 days. Vitamin C was given 150mg/kg/day within the specified days. DNA damage was measured by use of the comet assay in lymphocytes. Levels of malondialdehyde (MDA) and glutathione (GSH) as well as catalase (CAT) and superoxide dismutase (SOD) activities were determined in heart, liver and renal tissues. Results show that l-methionine administration significantly increased % Tail DNA and Mean Tail Moment in hHcy group as compared with other groups. Vitamin C treatment significantly decreased the high MDA levels and increased activity of antioxidant enzymes in tissues. Aortic diameter and thickness of aortic elastic laminae were significantly lower in hHcy+vitamin C group. Comet assay can be used for the assessment of primary DNA damage caused by hHcy. Histopathological findings showed that vitamin C may have a preventive effect in alleviating the negative effects of hHcy. Vitamin C might be useful in the prevention of endothelial dysfunction caused by hHcy. PMID- 25043729 TI - Deletion of forebrain glycine transporter 1 enhances conditioned freezing to a reliable, but not an ambiguous, cue for threat in a conditioned freezing paradigm. AB - Enhanced expression of Pavlovian aversive conditioning but not appetitive conditioning may indicate a bias in the processing of threatening or fearful events. Mice with disruption of glycine transporter 1 (GlyT1) in forebrain neurons exhibit such a bias, but they are at the same time highly sensitive to manipulations that hinder the development of the conditioned response (CR) suggesting that the mutation may modify higher cognitive processes that extract predictive information between environmental cues. Here, we further investigated the development of fear conditioning in forebrain neuronal GlyT1 knockout mice when the predictiveness of a tone stimulus for foot-shock was rendered ambiguous by interspersing [tone->no shock] trials in-between [tone->shock] trials during acquisition. The CR to the ambiguous tone CS (conditioned stimulus) was compared with that generated by an unambiguous CS that was always followed by the shock US (unconditioned stimulus) during acquisition. We showed that rendering the CS ambiguous as described significantly attenuated the CR in the mutants, but it was not sufficient to modify the CR in the control mice. It is concluded that disruption of GlyT1 in forebrain neurons does not increase the risk of forming spurious and potentially maladaptive fear associations. PMID- 25043730 TI - Acute serotonergic treatment changes the relation between anxiety and HPA-axis functioning and periaqueductal gray activation. AB - Serotonergic (5-HT) drugs are widely used in the clinical management of mood and anxiety disorders. However, it is reported that acute 5-HT treatment elicits anxiogenic-like behavior. Interestingly, the periaqueductal gray (PAG), a midbrain structure which regulates anxiety behavior - has robust 5-HT fibers and reciprocal connections with the hypothalamic-pituitary-adrenal (HPA) axis. Although the HPA axis and the 5-HT system are well investigated, the relationship between the stress hormones induced by 5-HT drug treatment and the PAG neural correlates of the behavior remain largely unknown. In this study, the effects of acute and chronic treatments with buspirone (BUSP) and escitalopram (ESCIT) on anxiety-related behaviors were tested in an open-field (OF). The treatment effects on PAG c-Fos immunoreactivity (c-Fos-ir) and corticosterone (CORT) concentration were measured in order to determine the neural-endocrine correlates of anxiety-related behaviors and drug treatments. Our results demonstrate that acute BUSP and ESCIT treatments induced anxiogenic behaviors with elevation of CORT compared to the baseline. A decrease of c-Fos-ir was found in the dorsomedial PAG region of both the treatment groups. Correlation analysis showed that the CORT were not associated with the OF anxiogenic behavior and PAG c-Fos ir. No significant differences were found in behaviors and CORT after chronic treatment. In conclusion, acute BUSP and ESCIT treatments elicited anxiogenic response with activation of the HPA axis and reduction of c-Fos-ir in the dorsomedial PAG. Although no correlation was found between the stress hormone and the PAG c-Fos-ir, this does not imply the lack of cause-and-effect relationship between neuroendocrine effects and PAG function in anxiety responses. These correlation studies suggest that the regulation of 5-HT system was probably disrupted by acute 5-HT treatment. PMID- 25043732 TI - Acute systemic rapamycin induces neurobehavioral alterations in rats. AB - Rapamycin is a drug with antiproliferative and immunosuppressive properties, widely used for prevention of acute graft rejection and cancer therapy. It specifically inhibits the activity of the mammalian target of rapamycin (mTOR), a protein kinase known to play an important role in cell growth, proliferation and antibody production. Clinical observations show that patients undergoing therapy with immunosuppressive drugs frequently suffer from affective disorders such as anxiety or depression. However, whether these symptoms are attributed to the action of the distinct compounds remains rather elusive. The present study investigated in rats neurobehavioral consequences of acute rapamycin treatment. Systemic administration of a single low dose rapamycin (3mg/kg) led to enhanced neuronal activity in the amygdala analyzed by intracerebral electroencephalography and FOS protein expression 90min after drug injection. Moreover, behavioral investigations revealed a rapamycin-induced increase in anxiety-related behaviors in the elevated plus-maze and in the open-field. The behavioral alterations correlated to enhanced amygdaloid expression of KLK8 and FKBP51, proteins that have been implicated in the development of anxiety and depression. Together, these results demonstrate that acute blockade of mTOR signaling by acute rapamycin administration not only causes changes in neuronal activity, but also leads to elevated protein expression in protein kinase pathways others than mTOR, contributing to the development of anxiety-like behavior. Given the pivotal role of the amygdala in mood regulation, associative learning, and modulation of cognitive functions, our findings raise the question whether therapy with rapamycin may induce alterations in patients neuropsychological functioning. PMID- 25043731 TI - Site-specific microinjection of Gaboxadol into the infralimbic cortex modulates ethanol intake in male C57BL/6J mice. AB - Extrasynaptic GABAA receptors, often identified as those containing both alpha4 and delta subunits, demonstrate super-sensitivity to GABA and are involved in tonic inhibitory processes regulating activity within mesolimbocortical circuitry. Rodent studies testing the effects of the delta-subunit selective agonist Gaboxadol (THIP) on alcohol consumption have produced mixed results. The goal of this study was to determine the role of extrasynaptic GABAA receptors located in the infralimbic cortex (ILC) in the alcohol consumption of male C57BL/6J (B6) mice. The ILC is of interest due to its demonstrated involvement in stress reactivity. Furthermore, alcohol exposure has been shown to interfere with extinction learning; impairments of which may be related to inflexible behavior (i.e., problematic alcohol consumption). Adult male B6 mice were bilaterally implanted with guide cannulas aimed at the ILC and were subsequently offered daily limited access to 20% ethanol or 5% sucrose for 7 days. Immediately prior to ethanol or sucrose access on day 7, mice were bilaterally injected with 50 or 100ng THIP (25 or 50ng per side respectively) or saline vehicle into the ILC. The highest dose of intra-ILC THIP (100ng/mouse) increased alcohol intake relative to vehicle controls, although control animals consumed relatively little ethanol following infusion. Intra-ILC THIP had no effect on sucrose consumption (p>0.05), suggesting that the effect of THIP was selective for ethanol consumption. Together, these findings suggest that THIP may have effectively prevented the decrease in ethanol intake on day 7 induced by the microinjection process, perhaps supporting a suggested role for the ILC in adaptive learning processes and behavioral flexibility. PMID- 25043733 TI - Antidepressant-like effect of the mGluR5 antagonist MTEP in an astroglial degeneration model of depression. AB - The glutamatergic predominance in the excitatory-inhibitory balance is postulated to be involved in the pathogenesis of depression. Such imbalance may be induced by astrocyte ablation which reduces glutamate uptake and increases glutamate level in the synaptic cleft. In the present study, we tried to ascertain whether astroglial degeneration in the prefrontal cortex could serve as an animal model of depression and whether inhibition of glutamatergic transmission by the mGluR5 antagonist MTEP could have antidepressant potential. Astrocytic toxins l-or dl alpha-aminoadipic acid (AAA), 100MUg/2MUl, were microinjected, bilaterally into the rat medial prefrontal cortex (PFC) on the first and second day of experiment. MTEP (10mg/kg) or imipramine (30mg/kg) were administered on the fifth day. Following administration of MTEP or imipramine the forced swim test (FST) was performed for assessment of depressive-like behavior. The brains were taken out for analysis on day eight. The astrocytic marker, glial fibrillary acidic protein (GFAP) was quantified in PFC by Western blot method and by stereological counting of immunohistochemically stained sections. Both l-AAA and dl-AAA induced a significant increase in immobility time in the FST. This effect was reversed by imipramine, which indicates depressive-like effects of these toxins. A significant decrease in GFAP (about 50%) was found after l-AAA. Both the behavioral and GFAP level changes were prevented by MTEP injection. The obtained results indicate that the degeneration of astrocytes in the PFC by l-AAA may be a useful animal model of depression and suggest antidepressant potential of MTEP. PMID- 25043734 TI - Effects of interval and continuous exercise training on autonomic cardiac function in COPD patients. AB - BACKGROUND AND AIM: Both interval (IT) and continuous (CT) exercise training results in an improvement of aerobic capacity in patients with chronic obstructive pulmonary disease (COPD); however, their effects on cardiac autonomic function remains unclear. The aim of our study was to evaluate the effect of a supervised CT vs IT on autonomic cardiac function in COPD patients. METHODS: COPD patients were divided into two different groups according to training modality (IT or CT). Autonomic cardiac dysfunction (ACD) was defined as a heart rate recovery lower than 12 bpm heart rate after the first minute of maximal exercise (HRR1 ) and an abnormal chronotropic response (CR) to exercise (<80%). RESULTS: A total of 29 patients {mean [standard deviation (SD)] age: 68 (8) years, %FEV1 : 42 (13) predicted} were trained (15 subjects in the CT group, 14 subjects in the IT group). After training, both groups increased peak oxygen consumption [mean difference DeltaVO2 peak: 156 mL/min (P = 0.04) on IT; and 210 mL/min (P = 0.01) on CT], HRR1 [IT, from 10.4 (5) to 13.8 (5) bpm (P = 0.04); and CT, from 14.3 (5) to 17.7 (5) bpm (P = 0.04)] and CR [IT, from 57% (22) to 81% (9) (P = 0.001); and CT, from 48% (28) to 73% (17) (P = 0.001)]. Sixteen patients showed ACD. Among these patients, HRR1 (P = 0.01 for IT and P = 0.04 for CT) and CR (P = 0.001 for IT and P = 0.002 for CT) were enhanced after training. CONCLUSIONS: Both IT and CT exercise training improve heart rate recovery and CR in COPD patients. These benefits could help to individualize exercise training. PMID- 25043735 TI - The diagnostic challenge of myocardial infarction in critically ill patients: do high-sensitivity troponin measurements add more clarity or more confusion? AB - In ICU settings, the diagnosis and treatment of acute myocardial infarction (AMI) are challenging, partly because cardiac troponin increase occurs frequently. In the previous issue of Critical Care, Ostermann and colleagues reported that myocardial infarction (MI), screened by plasma troponin and electrocardiography changes, is common and often clinically unrecognized in the ICU. Although the clinical significance of underdiagnosed MIs remains unclear, this approach may help to target and further investigate the at-risk population for appropriate therapy. PMID- 25043736 TI - The functional profile of the human amygdala in affective processing: insights from intracranial recordings. AB - The amygdala is suggested to serve as a key structure in the emotional brain, implicated in diverse affective processes. Still, the bulk of existing neuroscientific investigations of the amygdala relies on conventional neuroimaging techniques such as fMRI, which are very useful but subject to limitations. These limitations are particular to their temporal resolution, but also to their spatial precision at a very fine-grained level. Here, we review studies investigating the functional profile of the human amygdala using intracranial electroencephalography (iEEG), an invasive technique with high temporal and spatial precision. We conducted a systematic literature review of 47 iEEG studies investigating the human amygdala, and we focus on two content related domains and one process-related domain: (1) memory formation and retrieval; (2) affective processing; and (3) latency components. This review reveals the human amygdala to engage in invariant semantic encoding and recognition of specific objects and individuals, independent of context or visuospatial attributes, and to discriminate between familiar and novel stimuli. The review highlights the amygdala's role in emotion processing witnessed in differential treatment of social-affective facial cues, differential neuronal firing to relevant novel stimuli, and habituation to familiar affective stimuli. Overall, the review suggests the amygdala plays a key role in the processing of affective relevance. Finally, this review delineates effects on amygdala neuronal activity into three time latency windows (post-stimulus onset). The early window (~ 5 0-290 msec) subsumes effects respective to exogenous stimulus-driven affective processing of faces and emotion. The intermediate window (~ 270-470 msec) comprises effects related to explicit attention to novel task-relevant stimuli, irrespective of sensory modality. The late window (~ 600-1400 msec) subsumes effects from tasks soliciting semantic associations and working memory during affective processing. We juxtapose these iEEG data with current clinical topics relevant to amygdala activation and propose avenues for future investigation of the amygdala using iEEG methods. PMID- 25043737 TI - Comparative cognition for conservationists. AB - Every animal occupies a unique cognitive world based on its sensory capacities, and attentional and learning biases. Behaviour results from the interaction of this cognitive world with the environment. As humans alter environments, cognitive processes ranging from perceptual processes to learned behaviour govern animals' reactions. By harnessing animals' perceptual biases and applying insights from cognitive theory, we can purposefully alter cues to reduce maladaptive responses and shape behaviour. Despite the fundamental connection between cognition and behaviour, the breadth of cognitive theory is underutilised in conservation practice. Bridging these disciplines could augment existing conservation efforts targeting animal behaviour. We outline relevant principles of perception and learning, and develop a step-by-step process for applying aspects of cognition towards specific conservation issues. PMID- 25043738 TI - Engineering deamidation-susceptible asparagines leads to improved stability to thermal cycling in a lipase. AB - At high temperatures, protein stability is influenced by chemical alterations; most important among them is deamidation of asparagines. Deamidation kinetics of asparagines depends on the local sequence, solvent, pH, temperature, and the tertiary structure. Suitable replacement of deamidated asparagines could be a viable strategy to improve deamidation-mediated loss in protein properties, specifically protein thermostability. In this study, we have used nano RP-HPLC coupled ESI MS/MS approach to identify residues susceptible to deamidation in a lipase (6B) on heat treatment. Out of 15 asparagines and six glutamines in 6B, only five asparagines were susceptible to deamidation at temperatures higher than 75 degrees C. These five positions were subjected to site saturation mutagenesis followed by activity screen to identify the most suitable substitutions. Only three of the five asparagines were found to be tolerant to substitutions. Best substitutions at these positions were combined into a mutant. The resultant lipase (mutC) has near identical secondary structure and improved thermal tolerance as compared to its parent. The triple mutant has shown almost two-fold higher residual activity compared to 6B after four cycles at 90 degrees C. MutC has retained more than 50% activity even after incubation at 100 degrees C. Engineering asparagines susceptible to deamidation would be a potential strategy to improve proteins to withstand very high temperatures. PMID- 25043739 TI - Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration. AB - Liver cancer is the fifth most common cancer. A highly invasive surgical resection of the liver tumor is the main approach used to eliminate the tumor. Mechanisms that terminate liver regeneration when the liver reaches the original size are not known. The aims of this work were to generate an animal model that fails to stop liver regeneration after surgical resections and elucidate mechanisms that are involved in termination of liver regeneration. Because epigenetic control of liver function has been previously implicated in the regulation of liver proliferation, we generated C/EBPalpha-S193A knockin mice, which have alterations in formation of complexes of C/EBP family proteins with chromatin remodeling proteins. The C/EBPalpha-S193A mice have altered liver morphology and altered liver function leading to changes of glucose metabolism and blood parameters. Examination of the proliferative capacity of C/EBPalpha S193A livers showed that livers of S193A mice have a higher rate of proliferation after birth, but stop proliferation at the age of 2 months. These animals have increased liver proliferation in response to liver surgery as well as carbon tetrachloride (CCl4 )-mediated injury. Importantly, livers of C/EBPalpha-S193A mice fail to stop liver regeneration after surgery when livers reach the original, preresection, size. The failure of S193A livers to stop regeneration correlates with the epigenetic repression of key regulators of liver proliferation C/EBPalpha, p53, FXR, SIRT1, PGC1alpha, and TERT by C/EBPbeta-HDAC1 complexes. The C/EBPbeta-HDAC1 complexes also repress promoters of enzymes of glucose synthesis PEPCK and G6Pase. CONCLUSION: Proper cooperation of C/EBP and chromatin remodeling proteins is essential for the termination of liver regeneration after surgery and for maintenance of liver functions. PMID- 25043740 TI - Ultrasound-guided percutaneous tracheostomy: a feasible alternative for tetanus patients. PMID- 25043741 TI - Synthesis and evaluation of alpha-, beta-glucosidase inhibition of 1-N carboxamide-1-azafagomines and 5-epi-1-azafagomines. AB - 1-N-Carboxamide 1-azafagomines and 5-epi-1-azafagomines were obtained from 1 azafagomine and 5-epi-1-azafagomine. The hydroxyl groups and the N-2 pyridazine position were protected prior to reaction with different isocyanates to form ureas. Protective groups were removed leading to the target compounds in 18-23% global yields. Final compounds were tested towards alpha- and beta-glucosidases. PMID- 25043742 TI - No cost or safety advantage to robot-assisted radical prostatectomy compared with open-procedure surgery for patients with prostate cancer. PMID- 25043743 TI - Relationship between hospital volume and early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator. AB - BACKGROUND: There is controversy whether the annual number of acute ischemic stroke patients receiving stroke thrombolysis per hospital (hospital volume) is associated with outcomes in these patients. AIMS: The study aims to assess the relationship between hospital volume and early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator. METHODS: Patients with acute ischemic stroke treated with recombinant tissue plasminogen activator from July 1, 2010 to March 31, 2012 were identified in the Japanese Diagnosis Procedure Combination database. Hospital volume was categorized into three levels (low, medium, and high volume) to obtain approximately equal numbers of patients in each group. Primary outcomes were seven-day mortality and functional independence (modified Rankin Scale score of 0 to 2) at discharge. Univariate analyses and multivariate logistic regression analyses fitted with generalized estimating equations were performed. RESULTS: We identified 7476 eligible patients, including 2339 (31.3%) treated in low-volume hospitals (1-7 patients annually), 2670 (35.7%) in medium-volume hospitals (8-16 patients annually), and 2467 (33.0%) in high-volume hospitals (17-48 patients annually). Seven-day mortality and functional independence at discharge were comparable among the three hospital volume groups (P = 0.17 for seven-day mortality; P = 0.22 for functional independence at discharge). The comparability between groups persisted after multivariate adjustment. CONCLUSION: Hospital volume was not significantly associated with seven-day mortality or functional independence at discharge in acute ischemic stroke patients treated with recombinant tissue plasminogen activator in Japan. PMID- 25043744 TI - Computational design of protein antigens that interact with the CDR H3 loop of HIV broadly neutralizing antibody 2F5. AB - Rational design of proteins with novel binding specificities and increased affinity is one of the major goals of computational protein design. Epitope scaffolds are a new class of antigens engineered by transplanting viral epitopes of predefined structure to protein scaffolds, or by building protein scaffolds around such epitopes. Epitope-scaffolds are of interest as vaccine components to attempt to elicit neutralizing antibodies targeting the specified epitope. In this study we developed a new computational protocol, MultiGraft Interface, that transplants epitopes but also designs additional scaffold features outside the epitope to enhance antibody-binding specificity and potentially influence the specificity of elicited antibodies. We employed MultiGraft Interface to engineer novel epitope-scaffolds that display the known epitope of human immunodeficiency virus 1 (HIV-1) neutralizing antibody 2F5 and that also interact with the functionally important CDR H3 antibody loop. MultiGraft Interface generated an epitope-scaffold that bound 2F5 with subnanomolar affinity (K(D) = 400 pM) and that interacted with the antibody CDR H3 loop through computationally designed contacts. Substantial structural modifications were necessary to engineer this antigen, with the 2F5 epitope replacing a helix in the native scaffold and with 15% of the native scaffold sequence being modified in the design stage. This epitope-scaffold represents a successful example of rational protein backbone engineering and protein-protein interface design and could prove useful in the field of HIV vaccine design. MultiGraft Interface can be generally applied to engineer novel binding partners with altered specificity and optimized affinity. PMID- 25043745 TI - Transient CD15-positive endothelial phenotype in the human placenta correlates with physiological and pathological fetoplacental immaturity. AB - OBJECTIVE: Placental growth and villous maturation are critical parameters of placental function at the end of pregnancy. A failure in these processes leads to the development of placental dysfunction, as well as fetal and neonatal mortality and morbidity. The aim of the study was to determine the relevant diagnostic markers associated with pathological placental development. STUDY DESIGN: Forty tissue samples from normal placentas of different gestational age and 68 pathological term placentas with defective villous maturation (GDM, idiopathic IUFD, preeclamsia, HELLP syndrome) comprised the comparative immunohistochemical study (CD15, CD45 and CD34). Positive immunohistochemical reactions were quantitatively assessed in the chorionic plate and vessels of the villi of different histological type. RESULTS: Physiologically immature placentas of the first and second trimester and pathologically immature term placentas were characterized by marked endothelial CD15-immunostaining. A significant loss of CD15-positive endothelium of the placentas was associated with a physiological and accelerated villous maturity. A spatio-temporal correlation was shown for CD15+ endothelial cells (ECs) and the number of CD45+ stromal cells (SCs). A negative temporal correlation was shown for CD15+ ECs and CD15+ myelomonocytes in the fetal blood. CD34 expression in the ECs was stable during the pregnancy. CONCLUSION: A correlation between a transient CD15-positive endothelial phenotype and a physiological and pathological fetoplacental immaturity was demonstrated. Physiological and accelerated placental maturation was accompanied by a significant disappearance of CD15-positive endothelium. We propose that "immature" CD15+ endothelium is an important diagnostic marker of the physiological and pathological fetoplacental immaturity. PMID- 25043746 TI - Molecular parameters and transmembrane transport mechanism of imidazolium functionalized binols. AB - We describe the molecular parameters governing the transmembrane activity of imidazolium-functionalized anion transporters and present a detailed mechanistic study. These ionophores adopt a mobile-carrier mechanism for short methyl and butyl chains, a combined mobile-carrier/transmembrane-pore mechanism for octyl and dodecyl chains, and form transmembrane aggregates for hexadecyl chains. PMID- 25043747 TI - Carbon nanotube network ambipolar field-effect transistors with 10(8) on/off ratio. AB - Polymer wrapping is a highly effective method of selecting semiconducting carbon nanotubes and dispersing them in solution. Semi-aligned semiconducting carbon nanotube networks are obtained by blade coating, an effective and scalable process. The field-effect transistor (FET) performance can be tuned by the choice of wrapping polymer, and the polymer concentration modifies the FET transport characteristics, leading to a record on/off ratio of 10(8) . PMID- 25043748 TI - The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers. AB - Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue. PMID- 25043749 TI - FCR and bevacizumab treatment in patients with relapsed chronic lymphocytic leukemia. AB - BACKGROUND: Patients with relapsed chronic lymphocytic leukemia (CLL) often achieve response with chemoimmunotherapy but have short remission durations. Studies have shown that patients with CLL have increased angiogenesis in the microenvironment; levels of proangiogenic growth factors such as VEGF and/or angiopoietin-2 are also elevated. Increased angiogenesis correlates with poor outcome in CLL. Bevacizumab (B) is a humanized monoclonal antibody targeting VEGF A. METHODS: In this study, we analyzed whether a combination of bevacizumab with fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy (FCR-B) could improve outcomes in patients with relapsed CLL. Sixty-two patients were enrolled. The median age of the patients was 60 years (range, 31-84 years) and 40% had received >1 prior therapy for CLL. Sixty-one patients were evaluable for toxicity, and 57 were evaluable for response. Six cycles were planned; 36 patients (59%) completed >=4-6 cycles of the regimen. RESULTS: The overall response rate was 79%, with 13 (23%) complete remissions (CRs), 8 nodular partial remissions (14%), and 24 partial remissions (43%). The median progression-free survival and overall survival rates were 13.5 and 45 months, respectively. Grade 3 or 4 toxicities included febrile neutropenia (n = 40), infections (n = 21), thrombocytopenia (n = 18) and anemia (n = 9). CONCLUSIONS: Results with FCR-B were similar to those observed with an historical cohort of relapsed patients treated with FCR. PMID- 25043750 TI - Shape-anchored porous polymer monoliths for integrated online solid-phase extraction-microchip electrophoresis-electrospray ionization mass spectrometry. AB - We report a simple protocol for fabrication of shape-anchored porous polymer monoliths (PPMs) for on-chip SPE prior to online microchip electrophoresis (ME) separation and on-chip (ESI/MS). The chip design comprises a standard ME separation channel with simple cross injector and a fully integrated ESI emitter featuring coaxial sheath liquid channel. The monolith zone was prepared in situ at the injection cross by laser-initiated photopolymerization through the microchip cover layer. The use of high-power laser allowed not only maskless patterning of a precisely defined monolith zone, but also faster exposure time (here, 7 min) compared with flood exposure UV lamps. The size of the monolith pattern was defined by the diameter of the laser output (?500 MUm) and the porosity was geared toward high through-flow to allow electrokinetic actuation and thus avoid coupling to external pumps. Placing the monolith at the injection cross enabled firm anchoring based on its cross-shape so that no surface premodification with anchoring linkers was needed. In addition, sample loading and subsequent injection (elution) to the separation channel could be performed similar to standard ME setup. As a result, 15- to 23-fold enrichment factors were obtained already at loading (preconcentration) times as short as 25 s without sacrificing the throughput of ME analysis. The performance of the SPE-ME-ESI/MS chip was repeatable within 3.1% and 11.5% RSD (n = 3) in terms of migration time and peak height, respectively, and linear correlation was observed between the loading time and peak area. PMID- 25043751 TI - Oxidative cyclization reaction of 2-aryl-substituted cinnamates to form phenanthrene carboxylates by using MoCl5. AB - The oxidative cyclization reaction of 2-aryl cinnamates and derivatives thereof can be easily performed with MoCl5 as the oxidant. This powerful reagent allows oxidative coupling reactions for which other reagents fail. The best results are obtained when the 2-phenyl substituent of the cinnamate is equipped with two methoxy groups. Even iodo moieties in the bay region of phenanthrene are tolerated under the reaction conditions. If naphthalene moieties are involved, a rearrangement of the skeleton occurs, providing an elegant route to highly functionalized angular arenes. The cyclization is demonstrated for 15 example substrates with isolated yields of up to 99 % for the phenanthrene derivative. The broad scope of the reaction underlines the usefulness of MoCl5 and MoCl5 /TiCl4 in the oxidative coupling reaction. PMID- 25043752 TI - Increased interhemispheric resting-state in idiopathic generalized epilepsy with generalized tonic-clonic seizures: a resting-state fMRI study. AB - PURPOSE: The aim is to examine the resting state functional connectivity (RSFC) between the two hemispheres and its relationships with clinical characteristic in idiopathic generalized epilepsy with generalized tonic-clonic seizures only (IGE GTCS) patients using a technique called "voxel-mirrored homotopic connectivity (VMHC)". METHODS: The resting-state functional MRI (Rs-fMRI) was used to measure the RSFC in patients with IGE-GTC and age-gender matched healthy subjects. The between-group difference in interhemispheric RSFC was examined after the interhemispheric RSFC map was obtained by an automated VMHC approach. RESULTS: Compared to the controls, the IGE-GTCS patients showed significant increases in VMHC in the bilateral anterior cingulate and medial prefrontal gyrus. No areas showed decreased VMHC in patients. Moreover, the VMHC in bilateral thalamus, orbital frontal cortex as well as cerebellum showed significant negative correlations with the illness duration. CONCLUSIONS: The current findings provide preliminary evidence of increased interhemispheric RSFC in patients with IGE-GTCS during the interictal period. These VMHC deficits in these regions and the inverse relations between VMHC and clinical characteristic may play an important role in the pathophysiology of IGE-GTCS. Our study may contribute to the understanding of neuro-pathophysiological mechanism of epilepsy and psychosocial function impairments in patients with IGE-GTCS. PMID- 25043753 TI - The utility of 18F-fluorodeoxyglucose PET (FDG PET) in epilepsy surgery. AB - PURPOSE: To investigate the utility of 18F-fluorodeoxyglucose Positron Emission Tomography (FDG PET) in helping decision making for epilepsy surgery. METHODS: All patients with medically refractory focal epilepsy and MRI that was normal or discordant with clinical and EEG data underwent FDG PET. FDG PET scans were reported by two investigators blinded to clinical data using visual assessment aided by the semiquantitative assessment. All clinical, MRI and FDG PET data were reviewed in the multidisciplinary patient management conferences for the localization and further decisions, which were recorded in the electronic database. For this study, we reviewed the charts of all these patients to decide the usefulness of PET in further decision making. FDG PET was considered to be useful if led directly to surgery, helped in planning intracranial EEG or helped in excluding patients from further evaluation. RESULTS: 194 consecutive adult patients (median age, 32.5 years) underwent FDG PET; 158 had normal MRI, 12 had subtle MRI abnormalities and 24 had discordant non-invasive data. Final localization was temporal lobe epilepsy (TLE, n=64), frontal lobe epilepsy (FLE, n=66), temporal-plus epilepsy (n=26) and other extratemporal lobe epilepsies (ETE, n=38). PET scans were normal in 72 (37%) patients, showed unifocal hypometabolism in 98 (50.5%) and bilateral hypometabolism in 24 (12%) patients. The TLE group had a higher proportion of abnormal PET scans (67%) than FLE (52%) and ETE (61%). PET data were useful in 103 (53%) patients, more in TLE (63%) than FLE (38%) or ETE (50%). It led directly to surgery in 12 (6%) cases, helped in planning intracranial EEG in 67 (35%) patients and excluded 24 (12%) patients from further evaluation. Focal hypometabolism on FDG PET increased the odds of being selected for surgery or intracranial EEG by five fold [odds ratio, 5.1 (2.8 9.4); p<0.0001]. CONCLUSIONS: FDG PET scan can help decision making in 53% of presurgical patients with normal or discordant MRI. PET findings need to be evaluated in conjunction with other data. PMID- 25043754 TI - Increased risk of epilepsy among patients diagnosed with chronic osteomyelitis. AB - PURPOSE: Inflammatory processes, which raise the unsteadiness of brain neuron membrane potentials, might enhance the development of epilepsy. Inflammation is a substantial indicator of epilepsy risk. In this study, we evaluated whether chronic osteomyelitis (COM), a chronic inflammatory disease, increases epilepsy risk. MATERIALS AND METHODS: A Taiwanese national insurance claims dataset of more than 22 million enrollees was used to select 20,996 COM patients and 83,973 randomly selected age- and gender-matched controls to investigate epilepsy development over an 11-year follow-up period, starting on January 1, 2000 and ending on December 31, 2010. The epilepsy risk was analyzed using a Cox proportional hazards regression model. RESULTS: Comorbidities known to elevate epilepsy risk, including diabetes, hypertension, head injury, stroke, and cancer, were commonly noted in the COM cohort, which had considerably higher risk of epilepsy than did the control group. Comparing only those without comorbidities, COM patients still exhibited higher epilepsy risk than the control group did (adjusted hazard ratio [aHR]=3.87, 95% confidence interval [CI]: 3.01-4.98). The younger population exhibited an even greater risk (age <=39 years: aHR=6.10, 95% CI: 4.00-9.30; age >=65 years: aHR=1.66, 95% CI: 1.28-2.16). CONCLUSION: This is the first study linking COM to an increased risk in epilepsy development. The results demonstrated that COM is a significant predictor of epilepsy. Further study of COM patients, particularly young patients, is recommended to facilitate epilepsy prevention. PMID- 25043756 TI - Dihydrotestosterone enhances castration-resistant prostate cancer cell proliferation through STAT5 activation via glucocorticoid receptor pathway. AB - INTRODUCTION: We aimed to evaluate STAT5 expression and cell proliferation change after dihydrotestosterone (DHT) treatment in castration-resistant prostate cancer (CRPC) cells to elucidate the mechanism in relation to different androgen receptor (AR) expression status. METHODS: Using DU145, PC3, and LNCaP cells, cell viability assay and Western blot for phosphorylated STAT5 (p-STAT5) were done after DHT treatment at various concentrations. Endogenous levels of nuclear hormone receptor mRNA and protein were identified using real-time RT-PCR and Western blot. We treated the cells with RU486 and then glucocorticoid receptor (GR)-specific small interfering RNA (siRNA), to assess change in DHT-induced STAT5 activation. Immunofluorescence staining of DU145 cells with anti-GR and anti-pSTAT5 Ab before and after DHT treatment was done and visualized. RESULTS: DHT treatment enhanced STAT5 phosphorylation and promoted proliferation of all CRPC cells. Endogenous GR was identified strongly in DU145, weakly in PC3 but not in LNCaP cells. AR was identified strongly in LNCaP but not in DU145 cells. RU486 treatment abolished DHT-induced cell proliferation and STAT5 activation in both DU145 and PC3 cells but not in LNCaP cells. Similarly, GR-specific siRNA completely suppressed STAT5 activation. On immunofluorescence, activation of STAT5 and GR translocating into the nucleus after DHT treatment was confirmed. Immunoprecipitation confirmed direct complex formation between the GR and pSTAT5. CONCLUSION: In CRPC cells, DHT activated STAT5 enhancing cell proliferation. Activation was induced regardless of presence of AR and in cells devoid of AR, DHT used GR which formed direct complex with p-STAT5. PMID- 25043755 TI - Targeting cancer's weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model. AB - In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID- 25043757 TI - Using Novel Method to Detect Different Cancer-Cell Stages of Model Human Lung Carcinoma. AB - BACKGROUND: Synchrotron radiation infrared (SR-IR) microspectroscopy and SR-IR spectroscopic imaging are extremely valuable techniques for determining the molecular composition of biological and biomedical samples. In this work, SR-IR is applied in the study of the lung cancer cells in different cell cycles. METHODS: We use a novel synchrotron based radiation infrared system combined synchronized model human lung carcinoma to reveal its unique character pattern. RESULTS: After using SR-IR microspectroscopy, we discovered that the ratio of protein to lipid in G1 and G2 states is around 4.0 and 6.1, respectively. Moreover, for the DNA at the wavenumber position of 1225 cm(-1) , the intensity ratio of G2 state to G1 state is approximately 1.6. These data indicate that the cell in G1 state has more lipid composition to prepare for the DNA synthesis, but the cell in G2 state has more protein composition to prepare for the mitosis. The cell has larger DNA concentration in G2 state, which can be explained for the DNA synthesis. CONCLUSION: Through our research, we demonstrate that different growth state of cancer cell presenting unique functional groups concentration profiles and distribution via using SR-IR microspectrometry. These applications will provide another ways to improve modern cancer screening in the future. PMID- 25043758 TI - Foreign- vs US-born Asians and the association of type I uterine cancer. AB - OBJECTIVE: The purpose of this study was to determine the association of type I endometrioid uterine cancer in US-born vs immigrant Asian women. STUDY DESIGN: Data were obtained from the Surveillance, Epidemiology, and End Results Program from 2001-2009. Chi-squared, Kaplan-Meier, and binomial logistic regression analyses were used for statistics. RESULTS: Of 4834 Asian women with uterine cancer, 62% were US-born and 38% were immigrants. Of these women, 2972 (61%) had type I (grade 1 or 2, endometrioid histologic type) uterine cancer. Compared with patients with type II disease (grade 3, clear cell and serous histologic type), patients with type I disease were younger (age 55 vs 59 years; P < .01) and had lower stage disease (90% vs 71%; P < .01). US-born Asian women had a significantly higher proportion of type I uterine cancers in contrast to their immigrant counterparts (65% vs 56%; P < .01). Of all immigrants, the proportion of type I cancers was lowest in Japanese women followed by Chinese and Filipino women, respectively (48% vs 52% vs 58%; P < .01). The 5-year disease-specific survivals of US-born vs immigrant Asian women with type I cancer was 92% for both groups. Over 3 time periods (2001-2003, 2004-2006, and 2007-2009), there was an increase in type I cancers among US-born Asian women (61% to 65% to 68%; P < .01). CONCLUSION: US-born Asian women are more likely to be diagnosed with type I uterine cancer compared with immigrants. Over the study period, there was a trend towards an increase in type I cancers among US-born Asian women. PMID- 25043759 TI - American Society of Peritoneal Surface Malignancies opinion statement on defining expectations from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer. PMID- 25043761 TI - Structure-function analysis of peroxisomal ATP-binding cassette transporters using chimeric dimers. AB - ABCD1 and ABCD2 are two closely related ATP-binding cassette half-transporters predicted to homodimerize and form peroxisomal importers for fatty acyl-CoAs. Available evidence has shown that ABCD1 and ABCD2 display a distinct but overlapping substrate specificity, although much remains to be learned in this respect as well as in their capability to form functional heterodimers. Using a cell model expressing an ABCD2-EGFP fusion protein, we first demonstrated by proximity ligation assay and co-immunoprecipitation assay that ABCD1 interacts with ABCD2. Next, we tested in the pxa1/pxa2Delta yeast mutant the functionality of ABCD1/ABCD2 dimers by expressing chimeric proteins mimicking homo- or heterodimers. For further structure-function analysis of ABCD1/ABCD2 dimers, we expressed chimeric dimers fused to enhanced GFP in human skin fibroblasts of X linked adrenoleukodystrophy patients. These cells are devoid of ABCD1 and accumulate very long-chain fatty acids (C26:0 and C26:1). We checked that the chimeric proteins were correctly expressed and targeted to the peroxisomes. Very long-chain fatty acid levels were partially restored in transfected X-linked adrenoleukodystrophy fibroblasts regardless of the chimeric construct used, thus demonstrating functionality of both homo- and heterodimers. Interestingly, the level of C24:6 n-3, the immediate precursor of docosahexaenoic acid, was decreased in cells expressing chimeric proteins containing at least one ABCD2 moiety. Our data demonstrate for the first time that both homo- and heterodimers of ABCD1 and ABCD2 are functionally active. Interestingly, the role of ABCD2 (in homo- and heterodimeric forms) in the metabolism of polyunsaturated fatty acids is clearly evidenced, and the chimeric dimers provide a novel tool to study substrate specificity of peroxisomal ATP-binding cassette transporters. PMID- 25043762 TI - Structural insights into the low pH adaptation of a unique carboxylesterase from Ferroplasma: altering the pH optima of two carboxylesterases. AB - To investigate the mechanism for low pH adaptation by a carboxylesterase, structural and biochemical analyses of EstFa_R (a recombinant, slightly acidophilic carboxylesterase from Ferroplasma acidiphilum) and SshEstI (an alkaliphilic carboxylesterase from Sulfolobus shibatae DSM5389) were performed. Although a previous proteomics study by another group showed that the enzyme purified from F. acidiphilum contained an iron atom, EstFa_R did not bind to iron as analyzed by inductively coupled plasma MS and isothermal titration calorimetry. The crystal structures of EstFa_R and SshEstI were determined at 1.6 and 1.5-A resolutions, respectively. EstFa_R had a catalytic triad with an extended hydrogen bond network that was not observed in SshEstI. Quadruple mutants of both proteins were created to remove or introduce the extended hydrogen bond network. The mutation on EstFa_R enhanced its catalytic efficiency and gave it an alkaline pH optimum, whereas the mutation on SshEstI resulted in opposite effects (i.e. a decrease in the catalytic efficiency and a downward shift in the optimum pH). Our experimental results suggest that the low pH optimum of EstFa_R activity was a result of the unique extended hydrogen bond network in the catalytic triad and the highly negatively charged surface around the active site. The change in the pH optimum of EstFa_R happened simultaneously with a change in the catalytic efficiency, suggesting that the local flexibility of the active site in EstFa_R could be modified by quadruple mutation. These observations may provide a novel strategy to elucidate the low pH adaptation of serine hydrolases. PMID- 25043763 TI - Non-Markovianity and reservoir memory of quantum channels: a quantum information theory perspective. AB - Quantum technologies rely on the ability to coherently transfer information encoded in quantum states along quantum channels. Decoherence induced by the environment sets limits on the efficiency of any quantum-enhanced protocol. Generally, the longer a quantum channel is the worse its capacity is. We show that for non-Markovian quantum channels this is not always true: surprisingly the capacity of a longer channel can be greater than of a shorter one. We introduce a general theoretical framework linking non-Markovianity to the capacities of quantum channels and demonstrate how harnessing non-Markovianity may improve the efficiency of quantum information processing and communication. PMID- 25043760 TI - Protein dynamics control the progression and efficiency of the catalytic reaction cycle of the Escherichia coli DNA-repair enzyme AlkB. AB - A central goal of enzymology is to understand the physicochemical mechanisms that enable proteins to catalyze complex chemical reactions with high efficiency. Recent methodological advances enable the contribution of protein dynamics to enzyme efficiency to be explored more deeply. Here, we utilize enzymological and biophysical studies, including NMR measurements of conformational dynamics, to develop a quantitative mechanistic scheme for the DNA repair enzyme AlkB. Like other iron/2-oxoglutarate-dependent dioxygenases, AlkB employs a two-step mechanism in which oxidation of 2-oxoglutarate generates a highly reactive enzyme bound oxyferryl intermediate that, in the case of AlkB, slowly hydroxylates an alkylated nucleobase. Our results demonstrate that a microsecond-to-millisecond time scale conformational transition facilitates the proper sequential order of substrate binding to AlkB. Mutations altering the dynamics of this transition allow generation of the oxyferryl intermediate but promote its premature quenching by solvent, which uncouples 2-oxoglutarate turnover from nucleobase oxidation. Therefore, efficient catalysis by AlkB depends upon the dynamics of a specific conformational transition, establishing another paradigm for the control of enzyme function by protein dynamics. PMID- 25043765 TI - Specific spatial distribution of caspase-3 in normal lenses. AB - PURPOSE: To determine the distribution of active caspase-3 in rat eye lens epithelium. METHODS: In total, 120 sagittal sections from forty rats were assessed for active caspase-3 labelling using immunohistochemistry. Lens epithelial cells were counted, and the fraction of active caspase-3 labelled cells and their relative positions were identified in each section. RESULTS: Active caspase-3 is present in normal lens epithelium. The active caspase-3 expression was higher in the anterior pole of the lens. Probability of radial spatial distribution of labelling was fitted with a logistic model. The increase rate and the inflection point were estimated as CI (0.95) to 23 +/- 3 cells and 114 +/- 3 cells, respectively. CONCLUSION: The gradually decreasing active caspase-3 labelling from the anterior pole to the periphery suggests that active caspase-3 may be involved in normal protein turnover caused by, for example, incident light. PMID- 25043764 TI - Brain-derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo. AB - The neurotrophin receptor, TrkB receptor tyrosine kinase, is critical to central nervous system (CNS) function in health and disease. Elucidating the ligands mediating TrkB activation in vivo will provide insights into its diverse roles in the CNS. The canonical ligand for TrkB is brain-derived neurotrophic factor (BDNF). A diversity of stimuli also can activate TrkB in the absence of BDNF, a mechanism termed transactivation. Zinc, a divalent cation packaged in synaptic vesicles along with glutamate in axons of mammalian cortical neurons, can transactivate TrkB in neurons and heterologous cells in vitro. Yet the contributions of BDNF and zinc to TrkB activation in vivo are unknown. To address these questions, we conducted immunohistochemical (IHC) studies of the hippocampal mossy fiber axons and boutons using an antibody selective for pY816 of TrkB, a surrogate measure of TrkB activation. We found that conditional deletion of BDNF resulted in a reduction of pY816 in axons and synaptic boutons of hippocampal mossy fibers, thereby implicating BDNF in activation of TrkB in vivo. Unexpectedly, pY816 immunoreactivity was increased in axons but not synaptic boutons of mossy fibers in ZnT3 knockout mice that lack vesicular zinc. Marked increases of BDNF content were evident within the hippocampus of ZnT3 knockout mice and genetic elimination of BDNF reduced pY816 immunoreactivity in these mice, implicating BDNF in enhanced TrkB activation mediated by vesicular zinc depletion. These findings support the conclusion that BDNF but not vesicular zinc activates TrkB in hippocampal mossy fiber axons under physiological conditions. PMID- 25043766 TI - EEG activation by neuropsychological tasks in idiopathic generalized epilepsy of adolescence. AB - THE AIM OF THE STUDY: To evaluate the effects of neuropsychological activation (NPA) tasks on epileptiform discharges in adolescents with idiopathic generalized epilepsy (IGE) and their possible relationship to clinical epilepsy-related factors, also to compare the effects of the NPA to the habitual methods of electroencephalographic (EEG) activation. METHODS/SUBJECTS: Fifty-nine patients with IGE aged 14-17 years underwent baseline video-EEG recording with habitual activation procedures followed by NPA tasks, and sleep EEG after sleep deprivation on the next day. RESULTS: At least one task of NPA showed provocative effect in 18.6% of cases. There was no difference between the provocative effects of action-programming and thinking NPA task groups as well as among individual NPA tasks. The provocative effects of NPA tasks were more prevalent in photosensitive cases, especially the tasks of action-programming type (p=0.04). The provocative NPA effects showed no relationship to gender, age, age at seizure onset, duration of epilepsy, treatment status, presence of myoclonias, recent generalized tonic-clonic seizures, family history of epilepsy. The provocative effects of NPA were comparable to those of hyperventilation (23.7%) and intermittent light stimulation (30.5%) (p>0.05). CONCLUSIONS: Although the provocative effects NPA tasks on epileptiform discharges on EEG did not outweigh the effects of the habitual activation procedures, NPA activation might be helpful as an additional diagnostic tool in adolescents with IGE in selected cases when routine EEG is not informative enough or when sleep EEG is readily unavailable, also in photosensitive cases. It may also help in providing advice for patients on safety issues. PMID- 25043767 TI - Management of airway compromise following thyroid cyst hemorrhage after thrombolytic therapy. AB - The risk of hemorrhage after therapeutic administration of tissue plasminogen activator (tPA) is well known. Cases of postadministration hemorrhage have been reported within many organ systems. We present a case of a 62-year-old female with undiagnosed thyroid goiter who received tPA for acute ischemic stroke and developed acute airway compromise. The surgical airway response team was called due to inability to ventilate or intubate. An incision into the mass during attempted tracheotomy released colloid and blood, decompressing the airway and facilitating ventilation and intubation. Hemithyroidectomy for mass removal was delayed for 3 days to allow normalization of post-tPA coagulopathy. PMID- 25043768 TI - Body symmetry and physical strength in human males. AB - OBJECTIVES: Body symmetry and physical strength in males have been related to aspects of mate "quality"-women seem to prefer men who display both "good genes" (as indexed by high symmetry/developmental health) and fighting ability (as indexed by physical strength). Here we show that fluctuating asymmetry (FA) of the body and physical strength are negatively correlated. METHODS: Body FA (from 12 paired traits) and handgrip strength (HGS; a measure of muscular power and force) were measured in a sample of 69 heterosexual, right-handed men (18-42 years). RESULTS: There were positive correlations of body symmetry with HGS after controlling for the effect of body-mass-index. CONCLUSIONS: We conclude that in males, body symmetry and physical strength are correlated such that symmetric individuals tend to develop higher strength, which may contribute to their success in inter- and intra-sexual selection. PMID- 25043769 TI - 2-Acylpyrroles as mono-anionic O,N-chelating ligands in silicon coordination chemistry. AB - Kryptopyrrole (2,4-dimethyl-3-ethylpyrrole) was acylated with, for example, benzoyl chloride to afford 2-benzoyl-3,5-dimethyl-4-ethylpyrrole (L(1)H). With SiCl4 this ligand reacts under liberation of HCl and formation of the complex L(1)2SiCl2. In related reactions with HSiCl3 or H2SiCl2, the same chlorosilicon complex is formed under liberation of HCl and H2 or liberation of H2, respectively. The chlorine atoms of L(1)2SiCl2 can be replaced by fluoride and triflate using ZnF2 and Me3Si-OTf, respectively. The use of a supporting base (triethylamine) is required for the complexation of phenyltrichlorosilane and diphenyldichlorosilane. The complexes L(1)2SiCl2, L(1)2SiF2, L(1)2Si(OTf)2, L(1)2SiPhCl, and L(1)2SiPh2 exhibit various configurations of the octahedral silicon coordination spheres (i.e. cis or trans configuration of the monodentate substituents, different orientations of the bidentate chelating ligands relative to each other). Furthermore, cationic silicon complexes L(1)3Si(+) and L(1) SiPh(+) were synthesized by chloride abstraction with GaCl3. In contrast, reaction of L(1)2SiCl2 with a third equivalent of L(1)H in the presence of excess triethylamine produced a charge-neutral hexacoordinate Si complex with a new tetradentate chelating ligand which formed by Si-templated C-C coupling of two ligands L(1). PMID- 25043770 TI - An analysis of FDA-approved drugs for infectious disease: antibacterial agents. AB - Drugs targeting infectious diseases have greatly improved public health. A study to evaluate all US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals that the number of new agents targeting infectious disease peaked during the 1990s and declined rapidly thereafter. Molecules targeting bacterial pathogens represent the most common component of anti infectives followed by antivirals and antifungals. Focusing on antibacterial agents, an increase in new NMEs predominated from the 1960s through to the 1990s, dropping sharply thereafter. Obsolescence and resistance has eliminated one-third of these drugs. Consequently, the arsenal of antibiotics peaked in 2000 and is declining. Likewise, the number of organizations awarded at least one NME for a bacterial indication has declined to a level not seen in more than a half century. PMID- 25043771 TI - A case of brain and leptomeningeal metastases from urothelial carcinoma of the bladder. AB - Brain metastases are unusual from urethelial carcinoma of bladder and particularly the occurrence of leptomeningeal metastases is extremely rare, with few cases described in the literature. We present a case of a 45-year-old man with a rare brain metastases as the first metastatic manifestation secondary to urethelial carcinoma of bladder followed by leptomeningeal metastases without any other organ involvement. Eleven months after the diagnosis of high-grade urethelial carcinoma of bladder (T2N0M0), the patient was detected having brain metastases by MRI. FDG PET/CT images for the metastatic evaluation showed no abnormal FDG uptake elsewhere in the body except the brain. Histopathology examination from brain lesion demonstrated the cerebral lesion to be a metastatic urothelial carcinoma. Two months later, the patient was diagnosed to have leptomeningeal metastases by MRI. Our patient's condition gradually worsened, and he died 3 months after the diagnosis of leptomeningeal metastases. PMID- 25043772 TI - Crossed cerebellar diaschisis in cerebral toxoplasmosis demonstrated on 18F-FDG PET/CT. PMID- 25043773 TI - Pre-operative 68Ga-DOTANOC somatostatin receptor PET/CT imaging demonstrating multiple synchronous lesions in a patient with head and neck paraganglioma. AB - Paragangliomas, or glomus tumors, are neoplasms arising from extra-adrenal chromaffin tissue. They frequently cause symptoms by over-production of catecholamines with known predilection to multicentricity. We describe the case of a patient with bilateral carotid body tumor who underwent a preoperative 68Gallium labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1 NaI3-Octreotide (68Ga-DOTANOC) positron emission tomography/computed tomography (PET/CT) imaging for staging. This is a unique case in which multiple paraganglioma and pheochromocytoma were demonstrated in a single patient using 68Ga-DOTANOC PET/CT. PMID- 25043774 TI - Rare case of gall bladder neuroendocrine tumor: 18F-FDG and 68Ga-DOTANOC PET/CT findings. PMID- 25043775 TI - 18F-FDG PET/CT in worsening of Primary Sclerosing Cholangitis concomitant with improved Langerhans Cell Histiocytosis. PMID- 25043776 TI - 68Ga-DOTANOC PET/CT mimicking renal dynamic scan: lack of physiological uptake in the spleen of a newborn and the pituitary gland in congenital hyperinsulinism. PMID- 25043777 TI - Quality standards of the European Pharmacopoeia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The European Pharmacopoeia (Ph. Eur.) provides a legal and scientific reference for the quality control of medicines. It is legally binding in the 38 signatory parties of the Convention on the elaboration of a European Pharmacopoeia (37 member states and the European Union). MATERIALS AND METHODS: The requirements for a specific herbal drug are prescribed in the corresponding individual monograph and the relevant general monographs. Criteria for pesticides and heavy metals for example are defined in the general monograph on Herbal drugs. The Ph. Eur. also provides general methods including methods for determination of aflatoxins B1 and ochratoxin A. Screening methods for aristolochic acids are applied for herbal drugs that may be subject to adulteration or substitution with plant material containing aristolochic acids. CONCLUSION: The Ph. Eur. collaborate in many areas with the European Medicines Agency (EMA) to ensure close collaboration as regards the respective work programmes and approach. PMID- 25043778 TI - Quantitative evaluation of in vitro effects and interactions of active fractions in a Chinese medicinal formula (Yaotongning Capsule) on rat chondrocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yaotongning Capsule (YTNC) is a Traditional Chinese Medicinal (TCM) formula that has been demonstrated to be effective for osteoarthritis (OA) treatment in clinical use. Many compounds and 10 component medicinal materials (CMMs for short, i.e., the fundamental elements used in TCM formulas) in YTNC are challenging to study the pharmacological effects and interactions of the CMMs. Besides, it is difficult to know whether the YTNC formula is reasonable, and if YTNC formula could be improved without comparing YTNC with other TCM formulas of treating OA. Based on different combinations of the active fractions from the 10 CMMs of YTNC and eight additional herbs frequently used in the TCM formulas of treating OA, the present study evaluated systematically the in vitro effects of these active fractions and the interactions among the active fractions from YTNC on rat chondrocytes to find possible solutions of the above questions. MATERIALS AND METHODS: Based on the formulation of YTNC and the concept of combinatorial chemistry, the active fractions were applied to form the whole YTNC prescription (i.e., the combination of all YTNC active fractions and the extract of YTNC's vehicle), five disassembled formulas of YTNC (i.e., the combinations of some active fractions in YTNC) and 21 TCM samples consisted of different kinds of active fractions. The degenerated chondrocytes were induced with interleukin-1beta (IL-1beta), and then the half-effective concentration (EC50) value of the proliferation activity was analyzed to evaluate the 27 TCM samples. Nine samples were screened for the following evaluation on glycosaminoglycan (GAG) synthesis. Rat articular cartilage was obtained from six Sprague-Dawley rats (seven days of age), and then chondrocytes were isolated through enzymatic digestion with 0.2% Collagenase II. Proliferations of chondrocytes were examined through Cell Counting Kit-8 assay, when the intracellular levels of GAG were detected by 1,9-Dimethylmethylene blue staining. The interactions between the active fractions in YTNC were evaluated by comparing experimental EC50 values of the YTNC formulas with their additive EC50 values. The effects of every active fraction were estimated by comparing the EC50 values of the TCM sample containing the active fraction with that of the initial sample without the active fraction. RESULTS: The whole formula of YTNC was very good at promoting the proliferation and GAG synthesis among all the 27 TCM samples. The vehicle of YTNC (Chinese rice wine) strengthened the two activities of YTNC. Refer to promoting the proliferation in chondrocytes, Davallia mariesii flavonoids (not belong to YTNC) were more potent than Glycyrrhiza uralensis flavonoids in YTNC, while the saponins, volatile oils and polysaccharides of YTNC were more potent than those from the eight additional herbs. Some samples including fewer active fractions were as good as YTNC. The YTNC formula and its disassembled formulas exhibited good activities both in promoting the proliferation and GAG synthesis, and the whole formula was most potent among the six YTNC formulas. CONCLUSIONS: The YTNC formula is reasonable and has advantage in promoting the proliferation and GAG synthesis in IL-1beta induced chondrocytes. YTNC's vehicle Chinese rice wine plays an important role in strengthening the activity of YTNC. YTNC may have the potential activity on treating chondrocytes degeneration caused by OA. However, the formula still can be simplified based on the combination of alkaloids, flavonoids and 50% of saponins from Glycyrrhiza uralensis to improve its quality controllability and safety. The present study can be a quite purposeful work for developing new YTNC based formulas with maximal therapeutic efficacy and minimal adverse effects. PMID- 25043779 TI - High-resolution bacterial growth inhibition profiling combined with HPLC-HRMS-SPE NMR for identification of antibacterial constituents in Chinese plants used to treat snakebites. AB - ETHNOPHARMACOGICAL RELEVANCE: Bacterial infection is one of the main secondary infections caused by snakebite. The 88 plant species investigated in this study have been used as folk remedies for treatment of snakebite, and it is therefore the aim of this study to investigate whether the plants contain compounds with bacterial growth inhibition. MATERIALS AND METHODS: The water and ethanol extracts of 88 plant species were screened at 200 MUg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa for their antibacterial activity by micro-broth dilution assay. The most active extracts were fractionated into microplates using analytical-scale RP-HPLC, and subsequently growth inhibition was assessed for each well. The biochromatograms constructed from these assays were used to identify compounds responsible for antibacterial activity. The structures of five compounds were elucidated by HPLC HRMS-SPE-NMR. RESULTS: Crude extracts of Boehmeria nivea, Colocasia esculenta, Fagopyrum cymosum, Glochidion puberum, Melastoma dodecandrum, Polygonum bistorta, Polygonum cuspidatum and Sanguisorba officinalis showed MIC values below 200 MUg/mL against either Bacillus subtilis, Staphylococcus aureus, Escherichia coli or Pseudomonas aeruginosa. The biochromatograms demonstrated that tannins play a main role for the bacterial growth inhibition observed for all above-mentioned plants except for Polygonum cuspidatum. Furthermore, the high-resolution bacterial growth inhibition profiling combined with HPLC-HRMS-SPE-NMR allowed fast identification of three non-tannin active compounds, i.e., piceid, resveratrol and emodin from ethanol extract of Polygonum cuspidatum. CONCLUSION: The high-resolution bacterial growth inhibition profiling allowed fast pinpointing of constituents responsible for the bioactivity, e.g., either showing tannins being the main bacterial growth inhibitors as observed for the majority of the active plants, or combined with HPLC-HRMS-SPE-NMR for fast structural identification of non-tannin constituents correlated with antibacterial activity. PMID- 25043780 TI - The use of community herbal monographs to facilitate registrations and authorisations of herbal medicinal products in the European Union 2004-2012. AB - The provisions for the simplified registration of traditional herbal medicinal products in the European Union were introduced by Directive 2004/24/EC amending Directive 2001/83/EC (Chapter 2a) in 2004. Since implementation in the European member states until December 2012 a total of 1015 registrations (traditional use) and 514 authorisations (well-established use) have been granted for products containing substances/ preparations from about 200 different herbal drugs. The overall number of received applications with more than one third still under assessment suggests a further increase for the next years. This review summarises the main features of registered and authorised herbal medicinal products in the EU and evaluates available data against provisions of Directive 2004/24/EC and European standards established by the Committee on Herbal Medicinal Products at the European Medicines Agency. The supportive function of Community herbal monographs is described as regards availability and their use in national procedures, which is complemented by an analysis of specific future challenges from experiences made with the implementation of Directive 2004/24/EC so far. PMID- 25043781 TI - Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. AB - Since 2004 the regulatory framework within the European Union has a specific assessment procedure for herbal medicinal products, with a medicinal use based on traditional practice. The main requirement concerning the traditional use is focussed on the period of time for medical use: at least 30 years, including 15 years in the EU. In addition to requirements for quality and safety, an evaluation of pharmacological effects or efficacy based on long-standing use, is a main objective. "Traditional Use" however encompasses European, and non European traditional use. Outside the EU, the medicinal use of herbal substances, preparations, and combinations is well-known, with a long history, which is well documented in the different systems of medical practice. This has been addressed by WHO, but it has been acknowledged also by European Commission that herbal products from other systems of medicine, can be subject to the procedure for traditional herbal medicinal products. This paper will focus on the possibilities, restraints, and challenges of regulatory practice in the European Union regarding these category of medicinal products. PMID- 25043782 TI - Requirements on efficacy of herbal medicinal products. AB - Based on the regulatory requirements on efficacy documentation in the European Union, the herbal medicinal products have been grouped into the following sections: (i) Herbal medicinal products for which the efficacy is demonstrated by results of a "full" set of clinical trials that are in conformity with the relevant guidelines of the therapeutic area in question. This regulatory pathway to obtain a marketing authorisation for a new medicinal product (new chemical entity) is open to herbal medicinal products, but the examples are in reality few. (ii) Herbal medicinal products which have a "well-established medicinal use with a recognised efficacy and an acceptable level of safety" in the European Union. Results of new and product specific clinical trials are not required to obtain a marketing authorisation for products that fulfil these criteria, but a substantial clinical experience must be documented and sufficient scientific data on efficacy must be publicly available. (iii) "Traditional" herbal medicinal products, that do not fulfil the efficacy requirements for a marketing authorisation, but for which a medicinal use of at least 30 years including 15 years in the European Union can be documented. Traditional herbal medicinal products can only be registered with therapeutic indications that are considered safe for use without the supervision of a physician. After briefly reviewing the regulatory requirements on efficacy documentation of herbal medicinal products in the European Union, some concluding remarks on the past and future developments in the area are made. PMID- 25043783 TI - Regulation of traditional herbal medicinal products in Japan. AB - Kampo medicines are the main traditional herbal medicines in Japan and are classified as pharmaceuticals. They are based on ancient Chinese medicine and have evolved to the Japanese original style over a long period of time. Ethical Kampo formulations are prescribed in general practice by physician under the National Health Insurance reimbursement system. Over-the-counter (OTC) Kampo formulations can be purchased and used for self-medication in primary health care settings. Kampo medicines have a substantial role in the Japanese healthcare system. In the early 1970s, "The Internal Assignments on the Review for Approval of OTC Kampo Products", known as "210 OTC Kampo Formulae", was published by the Ministry of Health and Welfare (currently the Ministry of Health, Labour and Welfare). In 2008, "210 OTC Kampo Formulae" was revised and presented as "The Approval Standards for OTC Kampo Products" and now 294 Kampo formulae are listed in the standards. These products have had wide spread usage in Japan. Crude drugs and Kampo extracts have been listed in The Japanese Pharmacopoeia. Both The Approval Standards and The Quality Standards play a key role in regulation of Kampo products. "Application Guideline for Western Traditional Herbal Medicines as OTC Drugs" was published in 2007. Other ethnopharmaceuticals mostly from Europe could be approved as OTC drugs in Japan. PMID- 25043784 TI - Galanin activated Gi/o-proteins in human and rat central nervous systems. AB - The neuropeptide galanin (GAL) is involved in the control of hormone secretion, nociception, feeding behavior, attention, learning and memory. The anatomical localization of galanin receptors in the brain has been described using autoradiography and immunohistochemistry, but both techniques are limited by the availability of specific radioligands or antibodies. Functional autoradiography provides an alternative method by combining anatomical resolution and information of the activity mediated by G-protein coupled receptors. The present study analyzes the functional GAL receptors coupled to Gi/o-proteins in human and rat brain nuclei using [(35)S]GTPgammaS autoradiography. The results show the anatomical distribution of Gi/o-proteins activated by GAL receptors that trigger intracellular signaling mechanisms. The activity mediated by GAL receptors in human and rat brain showed a good correlation of the net stimulation in areas such as spinal cord, periaqueductal gray, putamen, CA3 layers of hippocampus, substantia nigra and diverse thalamic nuclei. The functional GAL receptors coupled to Gi/o-proteins showed a similar pattern for both species in most of the areas analyzed, but some discrete nuclei showed differences in the activity mediated by GAL, such as the ventroposteromedial thalamic nucleus, or areas that regulate learning and memory processes in the hippocampus. Taken into consideration the present results, the rat could be used as an experimental model for the study of the physiological role of GAL-mediated neurotransmission and the modulation of GAL receptors activity in the human CNS. PMID- 25043785 TI - Video-assisted patient education to modify behavior: a systematic review. AB - OBJECTIVE: To evaluate the efficacy of video-assisted patient education to modify behavior. METHODS: Fourteen databases were searched for articles published between January 1980 and October 2013, written in English or German. Behavioral change as main outcome had to be assessed by direct measurement, objective rating, or laboratory data. RESULTS: Ten of the 20 reviewed studies reported successful behavioral modification in the treatment group. We discerned three different formats to present the information: didactic presentation (objective information given as verbal instruction with or without figures), practice presentation (real people filmed while engaged in a specific practice), narrative presentation (real people filmed while enacting scenes). Seven of the ten studies reporting a behavioral change applied a practice presentation or narrative presentation format. CONCLUSION: The effectiveness of video-assisted patient education is a matter of presentation format. Videos that only provide spoken or graphically presented health information are inappropriate tools to modify patient behavior. Videos showing real people doing something are more effective. PRACTICE IMPLICATIONS: If researchers wish to improve a skill, a model patient enacting the behavior seems to be the best-suited presentation format. If researchers aim to modify a more complex behavior a narrative presentation format seems to be most promising. PMID- 25043786 TI - Metal nanoparticles and supramolecular macrocycles: a tale of synergy. AB - In this minireview, we summarize current research dealing with the combination of noble-metal nanoparticles and different families of supramolecular macrocycles (cyclodextrins, cucurbit[n]urils, calixarenes, and pillar[n]arenes). We intended to select relevant publications on the synthesis of noble-metal nanoparticles with macrocycles acting as capping agents or/and reducing agents, as well as on the post-synthetic metal-nanoparticle modification with macrocycles. We also discuss strategies in which supramolecular chemistry is applied to direct the self-assembly of nanoparticles and formation of polymer composites. We finally describe the main applications of these materials in various fields. PMID- 25043789 TI - Acta Ophthalmologica: History 1970-88. AB - This is my personal memories concerning the Nordic periodical Acta Ophthalmologica in the period 1970-88. Poul Braendstrup was scientific secretary for Acta 1950-70 and chief editor 1970-75. His many important scientific works and enormous work for Acta is described, but also personal topics are mentioned. Acta meetings in the Danish Ophthalmol Society (DOS) and in the Nordic ophtalmol. Congresses are discussed. A referee-system is established from 1976, but with political contra scientific motives. Only a few papers arrived to Acta. A catastrophe in 1978 is mentioned. The new secretary Ingelise Truberg did an enormous work for the next ten years. Erik Jorgensen (1928-90) was our printer, and from 1975 our idealistic publisher after Munksgaard. The economy became better and the number of papers of high quality increased. The relationship to the new Nordic periodical Oftalmolog was discussed in 1982. PMID- 25043790 TI - Past and present of corneal refractive surgery: a retrospective study of long term results after photorefractive keratectomy, and a prospective study of refractive lenticule extraction. PMID- 25043791 TI - Validation of the colour difference plot scoring system analysis of the 103 hexagon multifocal electroretinogram in the evaluation of hydroxychloroquine retinal toxicity. AB - PURPOSE: To evaluate sensitivity, specificity and reproducibility of colour difference plot analysis (CDPA) of 103 hexagon multifocal electroretinogram (mfERG) in detecting established hydroxychloroquine (HCQ) retinal toxicity. METHODS: Twenty-three patients taking HCQ were divided into those with and without retinal toxicity and were compared with a control group without retinal disease and not taking HCQ. CDPA with two masked examiners was performed using age-corrected mfERG responses in the central ring (Rc ; 0-5.5 degrees from fixation) and paracentral ring (Rp ; 5.5-11 degrees from fixation). An abnormal ring was defined as containing any hexagons with a difference in two or more standard deviations from normal (colour blue or black). RESULTS: Categorical analysis (ring involvement or not) showed Rc had 83% sensitivity and 93% specificity. Rp had 89% sensitivity and 82% specificity. Requiring abnormal hexagons in both Rc and Rp yielded sensitivity and specificity of 83% and 95%, respectively. If required in only one ring, they were 89% and 80%, respectively. In this population, there was complete agreement in identifying toxicity when comparing CDPA using Rp with ring ratio analysis using R5/R4 P1 ring responses (89% sensitivity and 95% specificity). Continuous analysis of CDPA with receiver operating characteristic analysis showed optimized detection (83% sensitivity and 96% specificity) when >=4 abnormal hexagons were present anywhere within the Rp ring outline. Intergrader agreement and reproducibility were good. CONCLUSIONS: Colour difference plot analysis had sensitivity and specificity that approached that of ring ratio analysis of R5/R4 P1 responses. Ease of implementation and reproducibility are notable advantages of CDPA. PMID- 25043792 TI - Ultrasound assessment of ocular vascular effects of repeated intravitreal injections of ranibizumab for wet age-related macular degeneration. AB - PURPOSE: Determine the effect of repeated intravitreal injections of ranibizumab (0.5 mg; 0.05 ml) on retrobulbar blood flow velocities (BFVs) using ultrasound imaging quantification in twenty patients with exudative age-related macular degeneration treated for 6 months. METHODS: Visual acuity (ETDRS), central macular thickness (OCT), peak-systolic, end-diastolic and mean-BFVs in central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries were measured before, 2 days, 3 weeks and 6 months after the first injection. Patients were examined monthly and received 1-5 additional injections depending on ophthalmologic examination results. RESULTS: Six months after the first injection, a significant increase in visual acuity 50.9 +/- 25.9 versus 44.4 +/- 21.7 (p < 0.01) and decrease in mean central macular thickness 267 +/- 74 versus 377 +/- 115 MUm (p < 0.001) were observed compared to baseline. Although mean BFVs decreased by 16%+/-3% in CRA and 20%+/-5% in TPCA (p < 0.001) 2 days after the first injection, no significant change was seen thereafter. Mean-BFVs in OA decreased by 19%+/-5% at week 3 (p < 0.001). However, the smallest number of injections (two injections) was associated with the longest time interval between the last injection and month 6 (20 weeks) and with the best return to baseline levels for mean-BFVs in CRA, suggesting that ranibizumab had reversible effects on native retinal vascular supply after its discontinuation. Moreover, a significant correlation between the number of injections and percentage of changes in mean-BFVs in CRA was observed at month 6 (R = 0.74, p < 0.001) unlike TPCA or OA. CONCLUSION: Ranibizumab could impair the native choroidal and retinal vascular networks, but its effect seems reversible after its discontinuation. PMID- 25043793 TI - A new and standardized method to sample and analyse vitreous samples by the Cellient automated cell block system. AB - PURPOSE: In this prospective study, a universal protocol for sampling and analysing vitreous material was investigated. Vitreous biopsies are difficult to handle because of the paucity of cells and the gelatinous structure of the vitreous. Histopathological analysis of the vitreous is useful in difficult uveitis cases to differentiate uveitis from lymphoma or infection and to define the type of cellular reaction. METHODS: Hundred consecutive vitreous samples were analysed with the Cellient tissue processor (Hologic). This machine is a fully automated processor starting from a specified container with PreservCyt (fixative fluid) with cells to paraffin. Cytology was compared with fixatives Cytolyt (contains a mucolyticum) and PreservCyt. Routine histochemical and immunostainings were evaluated. RESULTS: In 92% of the cases, sufficient material was found for diagnosis. In 14%, a Cytolyt wash was necessary to prevent clotting of the tubes in the Cellient due to the viscosity of the sample. In 23%, the diagnosis was an acute inflammation (presence of granulocytes); in 33%, chronic active inflammation (presence of T lymphocytes); in 33%, low-grade inflammation (presence of CD68 cells, without T lymphocytes); and in 3%, a malignant process. CONCLUSION: A standardized protocol for sampling and handling vitreous biopsies, fixing in PreservCyt and processing by the Cellient gives a satisfactory result in morphology, number of cells and possibility of immuno-histochemical stainings. The diagnosis can be established or confirmed in more than 90% of cases. PMID- 25043794 TI - A new classification paradigm of extracellular polymeric substances (EPS) in activated sludge: separation and characterization of exopolymers between floc level and microcolony level. AB - Extracellular polymeric substances (EPS) play a crucial role in the formation of activated sludge flocs. However, until now, the EPS are rather classified by the method used for extraction than by a theoretical consideration of their function and composition. In this paper, a new classification paradigm of EPS was proposed, which offered a novel approach to identify the role of EPS in the formation of activated sludge flocs. The current study gave an exploration to distinguish the EPS in the floc level (extra-microcolony polymers, EMPS) and in the microcolony level (extra-cellular polymers, ECPS). It was found that cation exchange resin treatment is efficient to disintegrate the flocs for EMPS extraction, however, inefficient to disaggregate the microcolonies for ECPS harvesting. A two-steps extraction strategy (cation exchange resin treatment followed by ultrasonication-high speed centrifugation treatment) was suggested to separate these two types of EPS in activated sludge flocs and the physicochemical characteristics of EMPS and ECPS were compared. The protein/polysaccharide ratio of ECPS was higher than that of EMPS and the molecular weight of proteins in EMPS and ECPS were found to be different. The ECPS contained higher molecular weight proteins and more hydrophobic substances than the EMPS contained. The result of excitation-emission matrix fluorescence spectroscopy analysis also showed that the EMPS and the ECPS have different fluorescent expressions and the components of EMPS were more diverse than that of ECPS. All results reported herein demonstrated that two different types of exopolymers exist in the activated sludge flocs and the inter-particle forces for aggregation of activated sludge flocs are not identical between the floc level and the microcolony level. It suggested that cation bridging interactions are more crucial in floc level flocculation, while the entanglement and hydrophobic interactions are more important in microcolony level cohesion. PMID- 25043795 TI - Enrichment of anodophilic nitrogen fixing bacteria in a bioelectrochemical system. AB - We demonstrated the ability of a bio-anode to fix dinitrogen (N2), and confirmed that diazotrophs can be used to treat N-deficient wastewater in a bioelectrochemical system (BES). A two-compartment BES was fed with an N deficient medium containing glucose for >200 days. The average glucose and COD removal at an anodic potential of +200 mV vs. Ag/AgCl was 100% and 76%, respectively. Glucose removal occurred via fermentation under open circuit (OC), with acetate as the key byproduct. Closing circuit remarkably reduced acetate accumulation, suggesting the biofilm could oxidise acetate under N-deficient conditions. Nitrogen fixation required an anode and glucose; removing either reduced N2 fixation significantly. This suggests that diazotroph utilised glucose directly at the anode or indirectly through syntrophic interaction of an N2 fixing fermenter and an anodophile. The enriched biofilm was dominated (68%) by the genus Clostridium, members of which are known to be electrochemically active and capable of fixing N2. PMID- 25043796 TI - Modified ADM1 for modelling an UASB reactor laboratory plant treating starch wastewater and synthetic substrate load tests. AB - A laboratory plant consisting of two UASB reactors was used for the treatment of industrial wastewater from the wheat starch industry. Several load tests were carried out with starch wastewater and the synthetic substrates glucose, acetate, cellulose, butyrate and propionate to observe the impact of changing loads on gas yield and effluent quality. The measurement data sets were used for calibration and validation of the Anaerobic Digestion Model No. 1 (ADM1). For a precise simulation of the detected glucose degradation during load tests with starch wastewater and glucose, it was necessary to incorporate the complete lactic acid fermentation into the ADM1, which contains the formation and degradation of lactate and a non-competitive inhibition function. The modelling results of both reactors based on the modified ADM1 confirm an accurate calculation of the produced gas and the effluent concentrations. Especially, the modelled lactate effluent concentrations for the load cases are similar to the measurements and justified by literature. PMID- 25043797 TI - Synergistic disinfection and removal of biofilms by a sequential two-step treatment with ozone followed by hydrogen peroxide. AB - Synergistic disinfection and removal of biofilms by ozone (O3) water in combination with hydrogen peroxide (H2O2) solution was studied by determining disinfection rates and observing changes of the biofilm structure in situ by confocal laser scanning microscopy (CLSM) using an established biofilm of Pseudomonas fluorescence. The sequential treatment with O3, 1.0-1.7 mg/L, followed by H2O2, 0.8-1.1%, showed synergistic disinfection effects, while the reversed treatment, first H2O2 followed by O3, showed only an additive effect. The decrease of synergistic disinfection effect by addition of methanol (CH3OH), a scavenger of hydroxyl radical (OH), into the H2O2 solution suggested generation of hydroxyl radicals on or in the biofilm by the sequential treatment with O3 followed by H2O2. The primary treatment with O3 increased disinfection rates of H2O2 in the secondary treatment, and the increase of O3 concentration enhanced the rates. The cold temperature of O3 water (14 degrees C and 8 degrees C) increased the synergistic effect, suggesting the increase of O3 adsorption and hydroxyl radical generation in the biofilm. CLSM observation showed that the sequential treatment, first with O3 followed by H2O2, loosened the cell connections and thinned the extracellular polysaccharides (EPS) in the biofilm. The hydroxyl radical generation in the biofilm may affect the EPS and biofilm structure and may induce effective disinfection with H2O2. This sequential treatment method may suggest a new practical procedure for disinfection and removal of biofilms by inorganic oxidants such as O3 and H2O2. PMID- 25043799 TI - Peripheral alpha-synuclein and Parkinson's disease. PMID- 25043798 TI - Genetic diversity in Puerto Rico and its implications for the peopling of the Island and the West Indies. AB - Puerto Rico and the surrounding islands rest on the eastern fringe of the Caribbean's Greater Antilles, located less than 100 miles northwest of the Lesser Antilles. Puerto Ricans are genetic descendants of pre-Columbian peoples, as well as peoples of European and African descent through 500 years of migration to the island. To infer these patterns of pre-Columbian and historic peopling of the Caribbean, we characterized genetic diversity in 326 individuals from the southeastern region of Puerto Rico and the island municipality of Vieques. We sequenced the mitochondrial DNA (mtDNA) control region of all of the samples and the complete mitogenomes of 12 of them to infer their putative place of origin. In addition, we genotyped 121 male samples for 25 Y-chromosome single nucleotide polymorphism and 17 STR loci. Approximately 60% of the participants had indigenous mtDNA haplotypes (mostly from haplogroups A2 and C1), while 25% had African and 15% European haplotypes. Three A2 sublineages were unique to the Greater Antilles, one of which was similar to Mesoamerican types, while C1b haplogroups showed links to South America, suggesting that people reached the island from the two distinct continental source areas. However, none of the male participants had indigenous Y-chromosomes, with 85% of them instead being European/Mediterranean and 15% sub-Saharan African in origin. West Eurasian Y chromosome short tandem repeat haplotypes were quite diverse and showed similarities to those observed in southern Europe, North Africa and the Middle East. These results attest to the distinct, yet equally complex, pasts for the male and female ancestors of modern day Puerto Ricans. PMID- 25043800 TI - The clinical spectrum of anxiety in Parkinson's disease. AB - Anxiety is common in Parkinson's disease (PD), and contributes to increased disability and poorer quality of life. In spite of its significant impact, the symptomatology, chronology, and neurobiology of anxiety in PD are all poorly understood, and this hinders accurate diagnosis and development of effective treatment strategies. This review investigates and updates literature related to the clinical spectrum of anxiety in PD. The reported prevalence of anxiety in PD varies considerably, with emerging interest in the frequency of the DSM-IV residual category of "Anxiety disorder, not otherwise specified" (Anxiety disorder NOS), which is observed in up to 25% of PD patients. By design, there are no standardized diagnostic criteria for Anxiety disorder NOS, because this is the category applied to individuals who do not meet diagnostic criteria for any other current anxiety disorder. Anxiety rating scales incompletely capture anxiety symptoms that relate specifically to PD symptoms and the complications arising from PD therapy. Consequently, these scales have been deemed inappropriate for use in PD, and there remains a need for the development of a new PD-specific anxiety scale. Research establishing accurate symptom profiles of anxiety in PD is sparse, although characterizing such symptomatology would likely improve clinical diagnosis and facilitate targeted treatment strategies. Research into the neurobiological and psychological underpinnings of anxiety in PD remains inconclusive. Anxiety can precede the onset of PD motor symptoms or can develop after a diagnosis of PD. Further investigations focused on the chronology of anxiety and its relationship to PD diagnosis are required. PMID- 25043801 TI - T cell mediated immunity to influenza: mechanisms of viral control. AB - Infection with influenza A virus (IAV) is a major cause of worldwide morbidity and mortality. Recent findings indicate that T cell immunity is key to limiting severity of disease arising from IAV infection, particularly in instances where antibody immunity is ineffective. As such, there is a need to understand better the mechanisms that mediate effective IAV-specific cellular immunity, especially given that T cell immunity must form an integral part of any vaccine designed to elicit crossreactive immunity against existing and new strains of influenza virus. Here, we review the current understanding of cellular immunity to IAV, highlighting recent findings that demonstrate important roles for both CD4+ and CD8+ T cell immunity in protection from IAV-mediated disease. PMID- 25043803 TI - Nickel oxide thin film from electrodeposited nickel sulfide thin film: peroxide sensing and photo-decomposition of phenol. AB - A novel non-enzymatic peroxide sensor has been constructed by using nickel oxide (NiO) thin films as sensing material, which were prepared by a two-step process: (i) electrodeposition of nickel sulfide (NiS) and (ii) thermal air oxidation of as-deposited NiS to NiO. The resultant material is highly porous and comprises interconnected nanofibers. UV-Vis spectroscopy, FTIR spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and field-emission scanning electron microscopy (FESEM) were used for a complete characterization of nanostructured NiO thin films. Cyclic voltammetry study shows that NiO/ITO electrode facilitates the oxidation of hydrogen peroxide and exhibits excellent catalytic activity towards its sensing. The amperometric study of NiO/ITO was carried out to determine the sensitivity, linear range, detection limit of the proposed sensor. The sensor exhibits prominent electrocatalytic activity toward the oxidation of H2O2 with a wide linear range and a low detection limit. The possible use of the synthesized NiO thin films as an effective photocatalyst for the decomposition of phenol is also discussed. PMID- 25043802 TI - Remote ischemic postconditioning alleviates cerebral ischemic injury by attenuating endoplasmic reticulum stress-mediated apoptosis. AB - Remote ischemic postconditioning (RIPostC) has been proved to protect the brain from stroke, but the precise mechanism remains not fully understood. In the present study, we aimed to investigate whether RIPostC attenuates cerebral ischemia-reperfusion injury by abating endoplasmic reticulum (ER) stress response. CHOP, a multifunctional transcription factor in ER stress, regulates the expression of genes related to apoptosis, such as Bim and Bcl-2. Male SD rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion, and RIPostC was induced by three cycles of 10 min ischemia and 10 min reperfusion on bilateral femoral arteries immediately after ischemia. CHOP siRNA (CHOPi) and control siRNA (Coni) were injected into the right lateral ventricle 30 min before the beginning of ischemia. RIPostC, CHOPi, or RIPostC + CHOPi application reduced infarct volume, improved the neurological function, and decreased cell apoptosis. RIPostC increased the protein level of glucose regulated protein 78 (GRP78) and decreased the protein level of phosphorylated EIF2alpha, caspase-12, and CHOP. Furthermore, the expression of CHOP, Bim and cleaved-caspase-3 was decreased, while Bcl-2 expression was increased in response to application of RIPostC, CHOPi, or RIPostC + CHOPi. In sum, RIPostC protects against ischemia-reperfusion brain injury in rats by attenuating ER stress response-induced apoptosis. PMID- 25043804 TI - Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities that are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. We used quantitative magnetic resonance (MR) imaging to study brain microstructure in DMD. METHODS: T1-weighted and diffusion tensor images were obtained on a 3T MR scanner from 30 patients and 22 age-matched controls (age = 8-18 years). All subjects underwent neuropsychological examination. Group comparisons on tissue volume and diffusion tensor imaging parameters were made between DMD patients and controls, and between 2 DMD subgroups that were classified according to predicted Dp140 isoform expression (DMD_Dp140(+) and DMD_Dp140(-) ). RESULTS: DMD patients had smaller total brain volume, smaller gray matter volume, lower white matter fractional anisotropy, and higher white matter mean and radial diffusivity than healthy controls. DMD patients also performed worse on neuropsychological examination. Subgroup analyses showed that DMD_Dp140(-) subjects contributed most to the gray matter volume differences and performed worse on information processing. INTERPRETATION: Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development. PMID- 25043805 TI - Inflammation and myocardial damage markers influence loss of residual renal function in peritoneal dialysis patients. AB - BACKGROUND: Residual renal function (RRF) has been identified as the most important component in dialysis adequacy and has a strong effect on clinical outcomes. This justifies any effort in understanding the mechanism behind the preservation or decline in RRF. The aim of this study was to analyze the possible association of components of cardio-renal syndrome with the rate of decline in RRF. METHODS: A retrospective cohort study was performed in a group of prevalent adult patients on continuous ambulatory peritoneal dialysis (CAPD). Patients were analyzed at baseline and after a 30-month follow-up. Evaluations included measurements of residual renal function, dialysis adequacy parameters, cardiovascular comorbidity, and measurements of biochemical markers of cardiovascular disease (CVD) and inflammation, as well as resting electrocardiography. RESULTS: We included 129 patients in the study who were divided into groups according to loss of RRF, considering the cut-off point as 100 mL/day of 24 h urine volume. At baseline, there were no differences between groups: patients who lost RRF showed low values of 24 h urine volume, higher levels of systolic blood pressure, N-terminal pro-brain natriuretic peptide (NT proBNP), C-reactive protein (CRP), IL-6, and low values of serum albumin. In the multivariate analysis, age, albumin, CRP, and NT-proBNP were significant risk factors for the loss of RRF. CONCLUSIONS: Data indicate a close relationship between heart and kidney function where chronic kidney disease (CKD) affects and is an effect of, heart function, indicative of a bi-directional influence that leads to a vicious cycle, promoting deleterious effects on both systems. PMID- 25043806 TI - A rare giant placental chorioangioma with favorable outcome: A case report and review of the literature. AB - We describe a rare giant placental chorioangioma in a patient who had a favorable outcome with close prenatal surveillance in a 28-year-old primigravida who was referred to our clinic for ultrasound evaluation of a suspected placental mass at 23 weeks' gestation. A detailed ultrasound scan revealed a well-circumscribed, echogenic lesion measuring 11.0 * 10.3 * 7.3 cm and protruding into the amniotic cavity. A diagnosis of placental chorioangioma was made and intensive prenatal surveillance was scheduled. A small-for-gestational age (2,325 g) but normal female neonate was delivered at 37 weeks by cesarean section and discharged from hospital on the second day of the delivery. A giant chorioangioma may not cause any adverse effect to the fetus and may not require any medication or invasive intervention. (c) 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:254-256, 2015. PMID- 25043807 TI - 13.8% Efficiency hybrid Si/organic heterojunction solar cells with MoO3 film as antireflection and inversion induced layer. AB - High reflection and low build-in electrical field hinder the power conversion efficiency (PCE) of planar n-Si/organic solar cells. Depositing a thin layer of MoO3 can improve the performance by creating an antireflection layer on the front surface as well as inducing an inversion layer in the Si. The as-processed device achieves a record PCE of 13.8%. PMID- 25043808 TI - Early, middle, or late administration of zoledronate alleviates spontaneous nociceptive behavior and restores functional outcomes in a mouse model of CFA induced arthritis. AB - This study was performed to evaluate whether early, middle, or late treatment of zoledronate, an approved bisphosphonate that blocks bone resorption, can reduce nociceptive behaviors in a mouse arthritis model. Arthritis was produced by repeated intra-articular knee injections of complete Freund's adjuvant (CFA). A dose-response curve with zoledronate (3, 30, 100, and 300 MUg/kg, i.p., day 4 to day 25, twice weekly for 3 weeks) was performed, and the most effective dose of zoledronate (100 MUg/kg, i.p.) was initially administered at different times of disease progression: day 4 (early), day 15 (middle), or day 21 (late) and continued until day 25 after the first CFA injection. Flinching of the injected extremity (spontaneous nociceptive behavior), vertical rearings and horizontal activity (functional outcomes), and knee edema were assessed. Zoledronate improved both functional outcomes and reduced flinching behavior. At day 25, the effect of zoledronate on flinching behavior and vertical rearings was greater in magnitude when it was given early or middle rather than late in the treatment regimen. Chronic zoledronate did not reduce knee edema in CFA-injected mice nor functional outcomes in naive mice by itself. These results suggest that zoledronate may have a positive effect on arthritis-induced nociception and functional disabilities. PMID- 25043809 TI - CIAPIN1 targets Na+/H+ exchanger 1 to mediate K562 chronic myeloid leukemia cells' differentiation via ERK1/2 signaling pathway. AB - CIAPIN1 (cytokine-induced antiapoptotic inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid differentiation remains unclear. In this study, we found depletion of CIAPIN1 by shRNAs led to granulocytic differentiation of K562 cells. Meanwhile, the decrease of NHE1 and up-regulation of phosphorylated ERK1/2 were observed after CIAPIN1 depletion. Interestingly, targeted inhibition of NHE1 further promoted the differentiation of K562 cells with CIAPIN1 silencing. Accordingly, ectopic expression of NHE1 reversed this phenotype. Furthermore, ERK1/2 inhibition with the chemical inhibitor, PD98059, abolished CIAPIN1 silencing-induced differentiation of K562 cells after NHE1 inhibition. Thus, our results revealed important mechanism that CIAPIN1 targeted NHE1 to mediate differentiation of K562 cells via ERK1/2 pathway. Our findings implied CIAPIN1 and NHE1 could be new targets in developing therapeutic strategies against leukemia. PMID- 25043810 TI - Evaluating for a geospatial relationship between radon levels and thyroid cancer in Pennsylvania. AB - OBJECTIVES/HYPOTHESIS: To determine whether there is an association between radon levels and the rise in incidence of thyroid cancer in Pennsylvania. STUDY DESIGN: Epidemiological study of the state of Pennsylvania. METHODS: We used information from the Pennsylvania Cancer Registry and the Pennsylvania Department of Energy. From the registry, information regarding thyroid incidence by county and zip code was recorded. Information regarding radon levels per county was recorded from the state. Poisson regression models were fit predicting county-level thyroid incidence and change as a function of radon/lagged radon levels. To account for measurement error in the radon levels, a Bayesian Model extending the Poisson models was fit. Geospatial clustering analysis was also performed. RESULTS: No association was noted between cumulative radon levels and thyroid incidence. In the Poisson modeling, no significant association was noted between county radon level and thyroid cancer incidence (P = .23). Looking for a lag between the radon level and its effect, no significant effect was seen with a lag of 0 to 6 years between exposure and effect (P = .063 to P = .59). The Bayesian models also failed to show a statistically significant association. A cluster of high thyroid cancer incidence was found in western Pennsylvania. CONCLUSIONS: Through a variety of models, no association was elicited between annual radon levels recorded in Pennsylvania and the rising incidence of thyroid cancer. However, a cluster of thyroid cancer incidence was found in western Pennsylvania. Further studies may be helpful in looking for other exposures or associations. PMID- 25043812 TI - Elasticity, viscosity, and orientational fluctuations of a lyotropic chromonic nematic liquid crystal disodium cromoglycate. AB - Using dynamic light scattering, we study orientational fluctuation modes in the nematic phase of a self-assembled lyotropic chromonic liquid crystal (LCLC) disodium cromoglycate and measure the Frank elastic moduli and viscosity coefficients. The elastic moduli of splay (K1) and bend (K3) are in the order of 10 pN while the twist modulus (K2) is an order of magnitude smaller. The splay constant K1 and the ratio K1/K3 both increase substantially as the temperature T decreases, which we attribute to the elongation of the chromonic aggregates at lower temperatures. The bend viscosity is comparable to that of thermotropic liquid crystals, while the splay and twist viscosities are several orders of magnitude larger. The temperature dependence of bend viscosity is weak. The splay and twist viscosities change exponentially with the temperature. In addition to the director modes, the fluctuation spectrum reveals an additional mode that is attributed to diffusion of structural defects in the column-like aggregates. PMID- 25043811 TI - Impulsive versus premeditated aggression in the prediction of violent criminal recidivism. AB - Past aggression is a potent predictor of future aggression and informs the prediction of violent criminal recidivism. However, aggression is a heterogeneous construct and different types of aggression may confer different levels of risk for future violence. In this prospective study of 91 adults in a pretrial diversion program, we examined (a) premeditated versus impulsive aggression in the prediction of violent recidivism during a one-year follow-up period, and (b) whether either type of aggression would have incremental validity in the prediction of violent recidivism after taking into account frequency of past general aggression. Findings indicate that premeditated, but not impulsive, aggression predicts violent recidivism. Moreover, premeditated aggression remained a predictor of recidivism even with general aggression frequency in the model. Results provide preliminary evidence that the assessment of premeditated aggression provides relevant information for the management of violent offenders. PMID- 25043813 TI - Percutaneous tracheostomy: it's time for a shared approach! PMID- 25043814 TI - A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. AB - The c-Jun NH(2)-terminal kinase (JNK) is a critical determinant of obesity associated inflammation and glucose intolerance. The upstream mechanisms controlling this pathway are still unknown. Here we report that the levels of the PB1 domain-containing adaptor NBR1 correlated with the expression of proinflammatory molecules in adipose tissue from human patients with metabolic syndrome, suggesting that NBR1 plays a key role in adipose-tissue inflammation. We also show that NBR1 inactivation in the myeloid compartment impairs the function, M1 polarization, and chemotactic activity of macrophages; prevents inflammation of adipose tissue; and improves glucose tolerance in obese mice. Furthermore, we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK. Together, these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose tissue inflammation in obesity. PMID- 25043815 TI - Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. AB - The activity of chaperone-mediated autophagy (CMA), a catabolic pathway for selective degradation of cytosolic proteins in lysosomes, decreases with age, but the consequences of this functional decline in vivo remain unknown. In this work, we have generated a conditional knockout mouse to selectively block CMA in liver. We have found that blockage of CMA causes hepatic glycogen depletion and hepatosteatosis. The liver phenotype is accompanied by reduced peripheral adiposity, increased energy expenditure, and altered glucose homeostasis. Comparative lysosomal proteomics revealed that key enzymes in carbohydrate and lipid metabolism are normally degraded by CMA and that impairment of their regulated degradation contributes to the metabolic abnormalities observed in CMA defective animals. These findings highlight the involvement of CMA in regulating hepatic metabolism and suggest that the age-related decline in CMA may have a negative impact on the energetic balance in old organisms. PMID- 25043816 TI - A switch from white to brown fat increases energy expenditure in cancer associated cachexia. AB - Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or beta-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients. PMID- 25043818 TI - The family experience of living with a person with amyotrophic lateral sclerosis: a qualitative study. AB - Living with a person with amyotrophic lateral sclerosis (ALS) is a complex and difficult experience. Most research involves only the primary caregiver and uses a quantitative approach. The aim of this study was to explore the experience of family members who live with ALS patients until their death. In-depth, semi structured interviews were conducted with 13 family members of ALS patients now deceased. Transcripts were analysed using interpretative phenomenological analysis. Three main themes were identified: "Meaning of ALS," including the peculiarity of ALS and its comparison with other illnesses, the explanation of ALS, emotions, coping strategies, personal change and difficult choices; "Family relationships," including centripetal vs. centrifugal forces, role changes, ALS as a family disease, ALS as a family solution, openness towards the outside world; and "Healthcare context," including access to services, information and humanization. One finding was that families of a person with ALS need more supportive interaction and information during the patients' illness and their end of-life. This study is an invitation to understand families' experience and subsequently help them to find new ways to cope with the situation. PMID- 25043819 TI - Osteogenic cell cultures cannot utilize exogenous sources of synthetic polyphosphate for mineralization. AB - Phosphate is critical for mineralization and deficiencies in the regulation of free phosphate lead to disease. Inorganic polyphosphates (polyPs) may represent a physiological source of phosphate because they can be hydrolyzed by biological phosphatases. To investigate whether exogenous polyP could be utilized for mineral formation, mineralization was evaluated in two osteogenic cell lines, Saos-2 and MC3T3, expressing different levels of tissue non-specific alkaline phosphatase (tnALP). The role of tnALP was further explored by lentiviral mediated overexpression in MC3T3 cells. When cells were cultured in the presence of three different phosphate sources, there was a strong mineralization response with beta-glycerophosphate (betaGP) and orthophosphate (Pi) but none of the cultures sustained mineralization in the presence of polyP (neither chain length 17-Pi nor 42-Pi). Even in the presence of mineralizing levels of phosphate, low concentrations of polyP (50 MUM) were sufficient to inhibit mineral formation. Energy-dispersive X-ray spectroscopy confirmed the presence of apatite-like mineral deposits in MC3T3 cultures supplemented with betaGP, but not in those with polyP. While von Kossa staining was consistent with the presence or absence of mineral, an unusual Alizarin staining was obtained in polyP-treated MC3T3 cultures. This staining pattern combined with low Ca:P ratios suggests the persistence of Ca-polyP complexes, even with high residual ALP activity. In conclusion, under standard culture conditions, exogenous polyP does not promote mineral deposition. This is not due to a lack of active ALP, and unless conditions that favor significant processing of polyP are achieved, its mineral inhibitory capacity predominates. PMID- 25043817 TI - The PPARalpha-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway. AB - The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Therefore, JNK causes decreased expression of PPARalpha target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARalpha target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARalpha-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver. PMID- 25043820 TI - Clinical outcome of relapsed or refractory burkitt lymphoma and mature B-cell lymphoblastic leukemia in children and adolescents. AB - PURPOSE: Despite the rapid improvement in survival rate from Burkitt lymphoma and mature B-cell lymphoblastic leukemia (B-ALL) in children, a small subset of patients do not respond to first-line chemotherapy or experience relapse (RL). Herein, we report the clinical characteristics and outcomes of these patients. MATERIALS AND METHODS: RL or refractory Burkitt lymphoma and mature B-ALL in 125 patients diagnosed from 1990 to 2009 were retrospectively analyzed. RESULTS: Nineteen patients experienced RL or progressive disease (PD). Among them, 12 patients had PD or RL less than six months after initial treatment and seven had late RL. Seven patients achieved complete response (CR), 11 had PD, and one had no more therapy. Six patients who achieved CR survived without evidence of disease and four of them underwent high-dose chemotherapy (HDC) followed by stem cell transplantation (SCT). However, 11 patients who failed to obtain CR eventually died of their disease. Five-year overall survival (OS) was 31.6+/ 10.7%. OS of patients with late RL was superior to that of patients with early RL (57.1+/-18.7%, vs. 16.7+/-10.8%, p=0.014). Achievement of CR after reinduction had significant OS (p < 0.001). OS for patients who were transplanted was superior (p < 0.01). In multivariate analysis, achievement of CR after reinduction chemotherapy showed an association with improved OS (p=0.05). CONCLUSION: Late RL and chemotherapy-sensitive patients have the chance to achieve continuous CR using HDC/SCT, whereas patients who are refractory to retrieval therapy have poor prognosis. Therefore, novel salvage strategy is required for improvement of survival for this small set of patients. PMID- 25043821 TI - Is Prophylactic Irradiation to Para-aortic Lymph Nodes in Locally Advanced Cervical Cancer Necessary? AB - PURPOSE: This study evaluated the efficacy of extended field irradiation (EFI) in patients with locally advanced cervical cancer without para-aortic nodal involvement. MATERIALS AND METHODS: A total of 203 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage, IB2-IIIB) treated with radiotherapy at Keimyung University Dongsan Medical Center from 1996 to 2010 were retrospectively analyzed. The median patient age was 59 years (range, 29 to 83 years). None of the patients had para-aortic node metastases. Of the 203 patients, 88 underwent EFI and 115 underwent irradiation of the pelvis only. Concurrent chemoradiotherapy (CCRT) was administered to 133 patients. EFI field was used for treatment of 26 patients who received radiotherapy alone and 62 who received CCRT. RESULTS: The median follow-up period was 60 months. The 2- and 5-year overall survival (OS) rates were 87.8% and 73.5%, respectively, and the 2- and 5-year disease-free survival rates were 81.7% and 75.0%, respectively, however, no survival differences were observed between the two treatment field groups. EFI tended to increase OS in the radiotherapy alone group, but not in the CCRT group. CONCLUSION: These findings suggest that EFI does not have a significant effect in patients with locally advanced cervical cancer, especially in patients receiving CCRT. Conduct of additional studies will be required in order to confirm these findings. PMID- 25043822 TI - Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-Label Study. AB - PURPOSE: To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain. MATERIALS AND METHODS: One hundred twenty cancer patients with pain (numeric rating scale [NRS] >= 4) and sleep disturbance (NRS >= 4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS:oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator's discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated. RESULTS: A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p < 0.01), worst pain NRS from 6.7 to 5.4 (p < 0.01), sleep disturbance NRS from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p = 0.001). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea. CONCLUSION: HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable. PMID- 25043823 TI - Surgical trials in head and neck oncology: Renaissance and revolution? PMID- 25043824 TI - Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache. AB - BACKGROUND: Triptans are only effective in terminating cluster headache (CH) attacks in 70-80% of patients. Pharmacogenetic aspects of the serotonin metabolism, specifically variation in the 5-HTTLPR may be involved. METHODS: Genetic association study in a well-defined cohort of 148 CH patients with information on drug response to triptans. CH was diagnosed according to the criteria of the International Headache Society. Genotypes of the 43-bp insdel (rs4795541) and A > G (rs25531) polymorphisms in the 5-HTTLPR promoter region were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between bi-allelic and tri-allelic genotypes and triptan non-response with genotype models. RESULTS: Mean age at study entry among patients was 44.6 +/- 10.5 years, 77.7% were men. The genotype distribution both for the bi-allelic and the tri-allelic polymorphism was in Hardy-Weinberg equilibrium. We did not find an association of the bi-allelic polymorphism with triptan non-response. While the effect estimates for the S variant of the tri-allelic polymorphisms suggested increased odds of triptan non-response in CH patients (multivariable-adjusted odds ratio [95% confidence interval]: L*L* genotype-reference; L*S* genotype-1.33 [0.53-3.32]; S*S* genotype-1.46 [0.54-3.98]), the results were not statistically significant. CONCLUSIONS: Data from our study do not indicate a role of bi-allelic and tri allelic genotypes of the 5-HTTLPR polymorphism in triptan non-response in CH. PMID- 25043825 TI - Effects of single and multiple applications of glyphosate or aminopyralid on simple constructed plant communities. AB - To determine effects of multiple applications of herbicides on small constructed plant communities, Prunella vulgaris L.var. lanceolata Fern, Festuca roemeri (Pavlick) Alexeev, Clarkia amoena (Lehm.) Nels., and Cynosurus echinatus L. were grown together in small field plots. Plants were treated with glyphosate at target concentrations of 0 * , 0.01 * , 0.1 * , and 0.2* a field application rate (FAR) of 1122 g ha(-1) active ingredient (a.i.) for 3 yr in 1 location, and for 2 yr in a second location. Plants also were treated with aminopyralid at 0 * , 0.037 * , 0.136 * , and 0.5* FAR of 123 g ha(-1) a.i. for 2 yr in 2 locations. Plants received 1, 2, or 3 applications of each herbicide each year. Species and community responses depended on herbicide concentration and number of applications. With glyphosate, plant volume (modified formula for a cone) tended to decrease for all species (especially C. echinatus), and the decreases generally became larger with more applications. Plant communities exposed to the 2 greatest concentrations initially differed from controls but then appeared to recover. With aminopyralid, C. amoena was essentially eliminated from the communities, especially at the 2 greatest FARs, whereas the other 3 species tended to have significant increases in volume, especially at the 2 smallest FARs. With aminopyralid, increasing numbers of applications produced variable results, and the plant community volume never tended to recover. PMID- 25043826 TI - Multistep pi dimerization of tetrakis(n-decyl)heptathienoacene radical cations: a combined experimental and theoretical study. AB - Radical cations of a heptathienoacene alpha,beta-substituted with four n-decyl side groups (D4T7(.) (+) ) form exceptionally stable pi-dimer dications already at ambient temperature (Chem. Comm. 2011, 47, 12622). This extraordinary pi dimerization process is investigated here with a focus on the ultimate [D4T7(.) (+) ]2 pi-dimer dication and yet-unreported transitory species formed during and after the oxidation. To this end, we use a joint experimental and theoretical approach that combines cyclic voltammetry, in situ spectrochemistry and spectroelectrochemistry, EPR spectroscopy, and DFT calculations. The impact of temperature, thienoacene concentration, and the nature and concentration of counteranions on the pi-dimerization process is also investigated in detail. Two different transitory species were detected in the course of the one-electron oxidation: 1) a different transient conformation of the ultimate [D4T7(.) (+) ]2 pi-dimer dications, the stability of which is strongly affected by the applied experimental conditions, and 2) intermediate [D4T7]2 (.) (+) pi-dimer radical cations formed prior to the fully oxidized [D4T7]2 (.) (+) pi-dimer dications. Thus, this comprehensive work demonstrates the formation of peculiar supramolecular species of heptathienoacene radical cations, the stability, nature, and structure of which have been successfully analyzed. We therefore believe that this study leads to a deeper fundamental understanding of the mechanism of dimer formation between conjugated aromatic systems. PMID- 25043827 TI - A one-dimensional optomechanical crystal with a complete phononic band gap. AB - Recent years have witnessed the boom of cavity optomechanics, which exploits the confinement and coupling of optical and mechanical waves at the nanoscale. Among their physical implementations, optomechanical (OM) crystals built on semiconductor slabs enable the integration and manipulation of multiple OM elements in a single chip and provide gigahertz phonons suitable for coherent phonon manipulation. Different demonstrations of coupling of infrared photons and gigahertz phonons in cavities created by inserting defects on OM crystals have been performed. However, the considered structures do not show a complete phononic bandgap, which should enable longer lifetimes, as acoustic leakage is minimized. Here we demonstrate the excitation of acoustic modes in a one dimensional OM crystal properly designed to display a full phononic bandgap for acoustic modes at 4 GHz. The modes inside the complete bandgap are designed to have high-mechanical Q-factors, limit clamping losses and be invariant to fabrication imperfections. PMID- 25043828 TI - Reduced expression of IA channels is associated with postischemic seizures in hyperglycemic rats. AB - Poststroke seizures are considered to be the major cause of epilepsy in the elderly. The mechanisms of poststroke seizures remain unclear. A history of diabetes mellitus has been identified as an independent predictor of acute poststroke seizures in stroke patients. The present study sought to reveal the mechanisms for the development of postischemic seizures under hyperglycemic conditions. Transient forebrain ischemia was produced in adult Wistar rats by using the four-vessel occlusion method. At the normal blood glucose level, seizures occurred in ~50% of rats after 25 min of ischemia. However, in rats with hyperglycemia, the incidence rate of postischemic seizures was significantly increased to 100%. The occurrence of postischemic seizures was not correlated with the severity of brain damage in hyperglycemic rats. Mannitol, an osmotic diuretic agent, could neither prevent postischemic seizures nor alleviate the exacerbated brain damage in the presence of hyperglycemia. K(+) channels play a critical role in controlling neuronal excitability. The expression of A-type K(+) channel subunit Kv4.2 in the hippocampus and the cortex was significantly reduced in hyperglycemic rats with seizures compared with those without seizures. These results suggest that the reduction of Kv4.2 expression could contribute to the development of postischemic seizures in hyperglycemia. PMID- 25043829 TI - Effects of 60 Hz sinusoidal magnetic field on in vitro establishment, multiplication, and acclimatization phases of Coffea arabica seedlings. AB - The influence of extremely low frequency electromagnetic fields on net photosynthesis, transpiration, photosynthetic pigment concentration, and gene expression of ribulose 1,5-bisphosphate carboxylase/oxygenase small subunit (RBCS1), during in vitro establishment, in vitro multiplication and acclimatization phases of coffee seedlings were investigated. Untreated coffee plants were considered as control, whereas treated plants were exposed to a 60 Hz sinusoidal magnetic field of 2 mT of magnetic induction during 3 min. This magnetic field was generated by an electromagnet, connected to a wave generator. The results revealed that magnetically treated plants showed a significant increase in net photosynthesis (85.4% and 117.9%, in multiplication and acclimatization phases, respectively), and in photosynthetic pigment concentration (66.6% for establishment phase, 79.9% for multiplication phase, and 43.8% for acclimatization phase). They also showed a differential RBCS1 gene expression (approximately twofold) and a decrease of transpiration rates in regard to their control plants. In conclusion, the findings suggest that the application of 60 Hz magnetic field to in vitro coffee plants may improve the seedlings quality by modifying some photosynthetic physiological and molecular processes, increasing their vigor, and ensuring better plant development in later stages. PMID- 25043830 TI - Jurors' views on the value and objectivity of mental health experts testifying in sexually violent predator trials. AB - Although psychologists and psychiatrists often testify in court, we know relatively little about the extent to which jurors value the testimony they hear from these experts. We surveyed 161 jurors who rendered opinions in 14 sex offender civil commitment trials after hearing testimony from psychologists and psychiatrists serving as expert witnesses. Most jurors reported that the experts they heard testify were honest, and they tended to attribute disagreements among experts to case complexity, as opposed to adversarial allegiance or bias. Most reported that hearing from the experts helped them make better decisions and that experts using risk assessment instruments could make more accurate predictions than those who did not. Jurors were, however, more skeptical about the ability of experts to accurately predict recidivism when they heard testimony from both prosecution and defense experts. Findings suggest that jurors value risk assessment testimony from experts, but that experts must think carefully about how to best make risk assessment instrument results accessible to jurors. PMID- 25043831 TI - A note on testing families of hypotheses using graphical procedures. AB - Regulatory guidelines for drug development suggest a strong control of the familywise error rate, when multiple hypotheses are simultaneously tested in confirmatory clinical trials. Accordingly, a variety of multiple test procedures exist for pharmaceutical trial applications, which are typically defined on a single structured family of null hypotheses. For some confirmatory clinical trials with multiple objectives, however, it is advantageous to address the arising multiplicity problems via grouped families of hypotheses. Graphical test procedures have been developed to construct, visualize, and perform multiple test procedures that are tailored to either a single or multiple families of structured hypotheses of interest. This note complements the existing literature by introducing a general algorithm to calculate adjusted p-values for any sequentially rejective graphical test procedure where the test procedures within the individual families of hypotheses are not necessarily graphical. PMID- 25043832 TI - Enhanced efficiency fertilisers: a review of formulation and nutrient release patterns. AB - Fertilisers are one of the most important elements of modern agriculture. The application of fertilisers in agricultural practices has markedly increased the production of food, feed, fuel, fibre and other plant products. However, a significant portion of nutrients applied in the field is not taken up by plants and is lost through leaching, volatilisation, nitrification, or other means. Such a loss increases the cost of fertiliser and severely pollutes the environment. To alleviate these problems, enhanced efficiency fertilisers (EEFs) are produced and used in the form of controlled release fertilisers and nitrification/urease inhibitors. The application of biopolymers for coating in EEFs, tailoring the release pattern of nutrients to closely match the growth requirement of plants and development of realistic models to predict the release pattern of common nutrients have been the foci of fertiliser research. In this context, this paper intends to review relevant aspects of new developments in fertiliser production and use, agronomic, economic and environmental drives for enhanced efficiency fertilisers and their formulation process and the nutrient release behaviour. Application of biopolymers and complex coacervation technique for nutrient encapsulation is also explored as a promising technology to produce EEFs. PMID- 25043833 TI - Comparison of imaging biomarkers for Alzheimer's disease: amyloid imaging with [18F]florbetapir positron emission tomography and magnetic resonance imaging voxel-based analysis for entorhinal cortex atrophy. AB - OBJECTIVE: We compared amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) in subjects clinically diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHC) in order to test how these imaging biomarkers represent cognitive decline in AD. METHODS: Fifteen OHC, 19 patients with MCI, and 19 patients with AD were examined by [(18)F]florbetapir PET to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI and the voxel-based specific regional analysis system for AD to calculate z-score as the degree of entorhinal cortex atrophy, and by mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive component--Japanese version (ADAS-Jcog) for cognitive functions. RESULTS: Both cutoff values for measuring AD-like levels of amyloid (1.099 for SUVR) and entorhinal cortex atrophy (1.60 for z-score) were well differentially diagnosed and clinically defined AD from OHC (84.2% for SUVR and 86.7% for z-score). Subgroup analysis based on beta-amyloid positivity revealed that z-score significantly correlated with MMSE (r = -0.626, p < 0.01) and ADAS Jcog (r = 0.691, p < 0.01) only among subjects with beta-amyloid. CONCLUSIONS: This is the first study to compare [(18)F]florbetapir PET and MRI voxel-based analysis of entorhinal cortex atrophy for AD. Both [(18)F]florbetapir PET and MRI detected changes in AD compared with OHC. Considering that entorhinal cortex atrophy correlated well with cognitive decline only among subjects with beta amyloid, [18F]florbetapir PET makes it possible to detect AD pathology in the early stage, whereas MRI morphometry for subjects with beta-amyloid provides a good biomarker to assess the severity of AD in the later stage. PMID- 25043835 TI - Clinical conversations about health: the impact of confidentiality in preventive adolescent care. AB - PURPOSE: To better understand how confidentiality impacts the delivery of preventive adolescent health care by examining adolescent and parent beliefs and the relationship between confidentiality and the number and subject matter of health topics discussed at the last visit. METHODS: This study represents a secondary analysis of nationally representative online survey data collected from adolescents aged 13-17 years (N = 504) and parents of adolescents aged 13-17 years (N = 500). Descriptive statistics were conducted on confidentiality variables of interest. Analysis of variance and Scheffe post hoc tests were computed to determine whether the mean number of topics discussed varied by level of confidential consultation provided. Associations between confidential consultation and health topics discussed at the last visit were examined using multivariate logistic regression. RESULTS: Approximately, half of both samples reported provision of confidential consultation. Eighty-nine percent of parents believed adolescents should be able to speak with providers alone, yet 61% preferred to be in examination room for the entire visit. Nearly half of all adolescents believed parental presence impacted conversation. Mean number of topics discussed was significantly higher when a visit was partially confidential (4.11 +/- 3.05; p = 0) versus when a visit was not confidential (2.76 +/- 2.68; p = 0). There were significant associations between confidential consultation and discussions about 8 of 11 health topics. CONCLUSIONS: Confidential consultation significantly impacts the number and subject matter of health topics discussed. A split-visit confidentiality model for adolescent preventive care visits may result in clinical conversations that address more topics. This arrangement may also appeal to parents who have mixed feelings about confidentiality. PMID- 25043834 TI - Gatekeeper training and access to mental health care at universities and colleges. AB - PURPOSE: Gatekeeper training (GKT) programs are an increasingly popular approach to addressing access to mental health care in adolescent and young adult populations. This study evaluates the effectiveness of a widely used GKT program, Mental Health First Aid, in college student populations. METHODS: A randomized control trial was conducted on 32 colleges and universities between 2009 and 2011. Campus residence halls were assigned to the intervention (Mental Health First Aid plus pre-existing trainings) or control condition (pre-existing trainings only) using matched pair randomization. The trainings were delivered to resident advisors (RAs). Outcome measures include service utilization, knowledge and attitudes about services, self-efficacy, intervention behaviors, and mental health symptoms. Data come from two sources: (1) surveys completed by the students (resident advisors and residents; N = 2,543), 2-3 months pre- and post intervention; and (2) utilization records from campus mental health centers, aggregated by residence. RESULTS: The training increases trainees' self-perceived knowledge (regression-adjusted effect size [ES] = .38, p < .001), self-perceived ability to identify students in distress (ES = .19, p = .01), and confidence to help (ES = .17, p = .04). There are no apparent effects, however, on utilization of mental health care in the student communities in which the trainees live. CONCLUSIONS: Although GKT programs are widely used to increase access to mental health care, these programs may require modifications to achieve their objectives. PMID- 25043836 TI - New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. PMID- 25043838 TI - A scientific and statistical analysis of accelerated aging for pharmaceuticals. Part 1: accuracy of fitting methods. AB - Three competing mathematical fitting models (a point-by-point estimation method, a linear fit method, and an isoconversion method) of chemical stability (related substance growth) when using high temperature data to predict room temperature shelf-life were employed in a detailed comparison. In each case, complex degradant formation behavior was analyzed by both exponential and linear forms of the Arrhenius equation. A hypothetical reaction was used where a drug (A) degrades to a primary degradant (B), which in turn degrades to a secondary degradation product (C). Calculated data with the fitting models were compared with the projected room-temperature shelf-lives of B and C, using one to four time points (in addition to the origin) for each of three accelerated temperatures. Isoconversion methods were found to provide more accurate estimates of shelf-life at ambient conditions. Of the methods for estimating isoconversion, bracketing the specification limit at each condition produced the best estimates and was considerably more accurate than when extrapolation was required. Good estimates of isoconversion produced similar shelf-life estimates fitting either linear or nonlinear forms of the Arrhenius equation, whereas poor isoconversion estimates favored one method or the other depending on which condition was most in error. PMID- 25043839 TI - Hypoxia in the intestine or solid tumors: a beneficial or deleterious alarm signal? AB - The transcription factor hypoxia inducible factors (HIF)-1 functions as a master regulator of oxygen homeostasis. There is increasing evidence that HIF has an essential role to prevent tissue damage in physiological and pathological situations in which cells are deprived of O2. Here, we review the effects of decreased oxygen supply on the innate and adaptive immune responses in the gut and in solid tumors in which the oxygenation profile correlates with the grade of inflammation. Data in the literature indicate that some tumors may co-opt immune mechanisms induced by HIF-1 to promote their survival and proliferation. By contrast, HIF-1 stabilization would have a beneficial effect in the intestinal tract as it would dampen inflammation and promote its resolution. Therefore, stabilization of HIF-1 in hypoxia may have opposite effects on the integrity of the host, depending on the tissue microenvironment. PMID- 25043840 TI - Comparison of metabolic substrates in alligators and several birds of prey. AB - On average, avian blood glucose concentrations are 1.5-2 times those of mammals of similar mass and high concentrations of insulin are required to lower blood glucose. Whereas considerable data exist for granivorous species, few data are available for plasma metabolic substrate and glucoregulatory hormone concentrations for carnivorous birds and alligators. Birds and mammals with carnivorous diets have higher metabolic rates than animals consuming diets with less protein whereas alligators have low metabolic rates. Therefore, the present study was designed to compare substrate and glucoregulatory hormone concentrations in several birds of prey and a phylogenetically close relative of birds, the alligator. The hypothesis was that the combination of carnivorous diets and high metabolic rates favored the evolution of greater protein and fatty acid utilization leading to insulin resistance and high plasma glucose concentrations in carnivorous birds. In contrast, it was hypothesized that alligators would have low substrate utilization attributable to a low metabolic rate. Fasting plasma substrate and glucoregulatory hormone concentrations were compared for bald eagles (Haliaeetus leucocephalus), great horned owls (Bubo virginianus), red-tailed hawks (Buteo jamaicensis), and American alligators (Alligator mississippiensis). Avian species had high circulating beta hydroxybutyrate (10-21 mg/dl) compared to alligators (2.81 +/- 0.16 mg/dl). In mammals high concentrations of this byproduct of fatty acid utilization are correlated with insulin resistance. Fasting glucose and insulin concentrations were positively correlated in eagles whereas no relationship was found between these variables for owls, hawks or alligators. Additionally, beta-hydroxybutyrate concentrations were low in alligators. Similar to carnivorous mammals, ingestion of a high protein diet may have favored the utilization of fatty acids and protein for energy thereby promoting the development of insulin resistance and gluconeogenesis-induced high plasma glucose concentrations during periods of fasting in birds of prey. PMID- 25043841 TI - Locomotion of free-swimming ghost knifefish: anal fin kinematics during four behaviors. AB - The maneuverability demonstrated by the weakly electric ghost knifefish (Apteronotus albifrons) is a result of its highly flexible ribbon-like anal fin, which extends nearly three-quarters the length of its body and is composed of approximately 150 individual fin rays. To understand how movement of the anal fin controls locomotion we examined kinematics of the whole fin, as well as selected individual fin rays, during four locomotor behaviors executed by free-swimming ghost knifefish: forward swimming, backward swimming, heave (vertical) motion, and hovering. We used high-speed video (1000 fps) to examine the motion of the entire anal fin and we measured the three-dimensional curvature of four adjacent fin rays in the middle of the fin during each behavior to determine how individual fin rays bend along their length during swimming. Canonical discriminant analysis separated all four behaviors on anal fin kinematic variables and showed that forward and backward swimming behaviors contrasted the most: forward behaviors exhibited a large anterior wavelength and posterior amplitude while during backward locomotion the anal fin exhibited both a large posterior wavelength and anterior amplitude. Heave and hover behaviors were defined by similar kinematic variables; however, for each variable, the mean values for heave motions were generally greater than for hovering. Individual fin rays in the middle of the anal fin curved substantially along their length during swimming, and the magnitude of this curvature was nearly twice the previously measured maximum curvature for ray-finned fish fin rays during locomotion. Fin rays were often curved into the direction of motion, indicating active control of fin ray curvature, and not just passive bending in response to fluid loading. PMID- 25043842 TI - A multisample model validation of the evidence-based practice questionnaire. AB - Evidence-based practice may be implemented more successfully if the barriers to its implementation have been previously identified. Many of the available instruments to measure these barriers have been validated in single samples or without confirmatory analyses. The objective of the study was to contrast the goodness of fit of two measurement models (24 items and 19 items) for the Spanish version of the Evidence-Based Practice Questionnaire (EBPQ) in a sample of 1,673 full-time registered nurses in 10 hospitals and 57 primary health care centers in the Spanish Public Health Service. The 19-item model performed better in all four subsamples. A hypothesis of strict invariance, with equal factor loadings, intercepts, and error variance in all contexts in which it was evaluated, was supported. Goodness-of-fit indices provided strong evidence of good fit according to standard cut-off criteria in a multisample confirmatory factor analysis. PMID- 25043843 TI - A low cost multi-level sampling device for synchronous aseptic collection of environmental water samples. AB - We describe a simple device for the aseptic collection of environmental water samples at high spatial resolution to depths of 50m. To demonstrate the utility of this technique we present geochemical and archaeal community data from samples collected throughout the water column of a stratified lake. PMID- 25043844 TI - Quantification of IgM molecular response by droplet digital PCR as a potential tool for the early diagnosis of sepsis. PMID- 25043845 TI - Increased serum leptin and resistin levels and increased carotid intima-media wall thickness in patients with psoriasis: is psoriasis associated with atherosclerosis? AB - BACKGROUND: Patients with psoriasis may have an increased risk of cardiovascular disease. OBJECTIVE: We sought to evaluate the potential association between subclinical atherosclerosis and psoriasis by measuring the intima-media wall thickness (IMT) of the common carotid artery (CCA) in patients with psoriasis and evaluating its correlation with serum leptin and resistin levels. METHODS: The mean IMT (MIMT) of the CCA and leptin, resistin, triglyceride (TG), and total cholesterol levels in serum were determined in 60 patients and 60 healthy sex- and age-matched control subjects. RESULTS: Compared with the healthy control subjects, patients with psoriasis had significantly higher MIMT of the CCA and higher levels of serum leptin, resistin, TG, and total cholesterol. In addition, MIMT of the CCA was positively correlated with serum leptin, resistin, TG, and total cholesterol levels in patients with psoriasis. LIMITATIONS: This was a cross-sectional single-center study, and we could not evaluate additional biomarkers such as adipokine or adiponectin because of our restricted facilities. CONCLUSION: Although serum leptin, resistin, TG, and total cholesterol levels and MIMT of the CCA were significantly increased in patients with psoriasis, MIMT of the CCA was also positively correlated with these biomarkers. Therefore, psoriasis could be an independent risk factor for subclinical atherosclerosis. PMID- 25043846 TI - Engineering of an isolated p110alpha subunit of PI3Kalpha permits crystallization and provides a platform for structure-based drug design. AB - PI3Kalpha remains an attractive target for the development of anticancer targeted therapy. A number of p110alpha crystal structures in complex with the nSH2-iSH2 fragment of p85 regulatory subunit have been reported, including a few small molecule co-crystal structures, but the utilization of this crystal form is limited by low diffraction resolution and a crystal packing artifact that partially blocks the ATP binding site. Taking advantage of recent data on the functional characterization of the lipid binding properties of p110alpha, we designed a set of novel constructs allowing production of isolated stable p110alpha subunit missing the Adapter Binding Domain and lacking or featuring a modified C-terminal lipid binding motif. While this protein is not catalytically competent to phosphorylate its substrate PIP2, it retains ligand binding properties as indicated by direct binding studies with a pan-PI3Kalpha inhibitor. Additionally, we determined apo and PF-04691502 bound crystal structures of the p110alpha (105-1048) subunit at 2.65 and 2.85 A, respectively. Comparison of isolated p110alpha(105-1048) with the p110alpha/p85 complex reveals a high degree of structural similarity, which validates suitability of this catalytically inactive p110alpha for iterative SBDD. Importantly, this crystal form of p110alpha readily accommodates the binding of noncovalent inhibitor by means of a fully accessible ATP site. The strategy presented here can be also applied to structural studies of other members of PI3KIA family. PMID- 25043847 TI - Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C. AB - The cost-effectiveness of noninvasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC). We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (quality-adjusted life-years; QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage>=F2; testing with liver biopsy and treating patients with >=F2; treat none; and treat all irrespective of fibrosis. We compared all NITs and tested the cost effectiveness using current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals. Treating all patients without any previous NIT was the most effective strategy and had an incremental cost effectiveness ratio (ICER) of L9,204 per additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective, compared to using an NIT to decide on treatment, with an ICER of L16,028 per QALY gained. The exploratory analysis to assess the possible effect on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the "treat all" strategy to remain the most cost-effective strategy would be L37,500. Above this threshold, the most cost-effective option would be noninvasive testing with magnetic resonance elastography (ICER=L9,189). CONCLUSIONS: Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries. PMID- 25043848 TI - miR-27a is up regulated and promotes inflammatory response in sepsis. AB - MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Dysregulation of miRNAs is common in sepsis. Through microRNA microarray and qRT-PCR we found that the levels of miR-27a, miR-153 and miR-143 are up regulated, while let-7a, miR-218 and miR-129-5p are down regulated in lungs of septic mice. Knocking down of miR-27a down regulates expression levels of TNF-alpha and IL-6 significantly via reducing the phosphorylation level of NF-kappaB p65 and inhibiting its DNA binding activity. Furthermore, neutralisation of miR-27a up regulates PPARgamma level, down regulates TNF-alpha expression, relieves pulmonary inflammation and promotes survival of septic mice, which demonstrates that miR-27a plays an important role in regulating inflammatory response in sepsis and provides a potential target for clinical sepsis research and treatment. PMID- 25043849 TI - Deregulated FOX genes in Hodgkin lymphoma. AB - FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFbeta- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets. PMID- 25043850 TI - Computational identification of post-translational modification-based nuclear import regulations by characterizing nuclear localization signal-import receptor interaction. AB - The binding affinity between a nuclear localization signal (NLS) and its import receptor is closely related to corresponding nuclear import activity. PTM-based modulation of the NLS binding affinity to the import receptor is one of the most understood mechanisms to regulate nuclear import of proteins. However, identification of such regulation mechanisms is challenging due to the difficulty of assessing the impact of PTM on corresponding nuclear import activities. In this study we proposed NIpredict, an effective algorithm to predict nuclear import activity given its NLS, in which molecular interaction energy components (MIECs) were used to characterize the NLS-import receptor interaction, and the support vector regression machine (SVR) was used to learn the relationship between the characterized NLS-import receptor interaction and the corresponding nuclear import activity. Our experiments showed that nuclear import activity change due to NLS change could be accurately predicted by the NIpredict algorithm. Based on NIpredict, we developed a systematic framework to identify potential PTM-based nuclear import regulations for human and yeast nuclear proteins. Application of this approach has identified the potential nuclear import regulation mechanisms by phosphorylation of two nuclear proteins including SF1 and ORC6. PMID- 25043851 TI - Implications of sea level rise scenarios on land use /land cover classes of the coastal zones of Cochin, India. AB - Physical responses of the coastal zones in the vicinity of Cochin, India due to sea level rise are investigated based on analysis of inundation scenarios. Quantification of potential habitat loss was made by merging the Land use/Land cover (LU/LC) prepared from the satellite imagery with the digital elevation model. Scenarios were generated for two different rates of sea level rise and responses of changes occurred were made to ascertain the vulnerability and loss in extent. LU/LC classes overlaid on 1 m and 2 m elevation showed that it was mostly covered by vegetation areas followed by water and urban zones. For the sea level rise scenarios of 1 m and 2 m, the total inundation zones were estimated to be 169.11 km(2) and 598.83 km(2) respectively using Geographic Information System (GIS). The losses of urban areas were estimated at 43 km(2) and 187 km(2) for the 1 m and 2 m sea level rise respectively which is alarming information for the most densely populated state of India. Quantitative comparison of other LU/LC classes showed significant changes under each of the inundation scenarios. The results obtained conclusively point that sea level rise scenarios will bring profound effects on the land use and land cover classes as well as on coastal landforms in the study region. Coastal inundation would leave ocean front and inland properties vulnerable. Increase in these water levels would alter the coastal drainage gradients. Reduction in these gradients would increase flooding attributable to rainstorms which could promote salt water intrusion into coastal aquifers and force water tables to rise. Changes in the coastal landforms associated with inundation generate concern in the background that the coastal region may continue to remain vulnerable in the coming decades due to population growth and development pressures. PMID- 25043852 TI - Configuration- and conformation-dependent electronic-structure variations in 1,4 disubstituted cyclohexanes enabled by a carbon-to-silicon exchange. AB - Cyclohexane, with its well-defined conformers, could be an ideal force-controlled molecular switch if it were to display substantial differences in electronic and optical properties between its conformers. We utilize sigma conjugation in heavier analogues of cyclohexanes (i.e. cyclohexasilanes) and show that 1,4 disubstituted cyclohexasilanes display configuration- and conformation-dependent variations in these properties. Cis- and trans-1,4 bis(trimethylsilylethynyl)cyclohexasilanes display a 0.11 V difference in their oxidation potentials (computed 0.11 V) and a 0.34 eV difference in their lowest UV absorption (computed difference between first excitations 0.07 eV). This is in stark contrast to differences in the corresponding properties of analogous all carbon cyclohexanes (computed 0.02 V and 0.03 eV, respectively). Moreover, the two chair conformers of the cyclohexasilane trans isomer display large differences in electronic-structure-related properties. This enables computational design of a mechanically force-controlled conductance switch with a calculated single-molecule ON/OFF ratio of 213 at zero-bias voltage. PMID- 25043853 TI - Big data and large sample size: a cautionary note on the potential for bias. AB - A number of commentaries have suggested that large studies are more reliable than smaller studies and there is a growing interest in the analysis of "big data" that integrates information from many thousands of persons and/or different data sources. We consider a variety of biases that are likely in the era of big data, including sampling error, measurement error, multiple comparisons errors, aggregation error, and errors associated with the systematic exclusion of information. Using examples from epidemiology, health services research, studies on determinants of health, and clinical trials, we conclude that it is necessary to exercise greater caution to be sure that big sample size does not lead to big inferential errors. Despite the advantages of big studies, large sample size can magnify the bias associated with error resulting from sampling or study design. PMID- 25043854 TI - Base motif recognition and design of DNA templates for fluorescent silver clusters by machine learning. AB - Discriminative base motifs within DNA templates for fluorescent silver clusters are identified using methods that combine large experimental data sets with machine learning tools for pattern recognition. Combining the discovery of certain multibase motifs important for determining fluorescence brightness with a generative algorithm, the probability of selecting DNA templates that stabilize fluorescent silver clusters is increased by a factor of >3. PMID- 25043855 TI - First report of the spectrum of delta-globin gene mutations in Omani subjects - identification of novel mutations. AB - INTRODUCTION: Both coinheritance of thalassemic delta-globin mutation and coexistence of iron deficiency anemia (IDA) tend to decrease HbA2 (alpha2 delta2 ) level and thereby poses a diagnostic conundrum in beta-thalassemia trait. METHODS: We retrospectively studied 78 Omani subjects, presenting with low HbA2 level by high-performance liquid chromatography (HPLC), and their DNA was sequenced for the presence of mutations in the delta-globin gene (HBD). In these subjects, their serum ferritin levels allowed evaluation of the degree of iron deficiency. RESULTS: Overall, six different delta-globin gene mutations were observed in 40 study subjects (51.3%) and IDA in 33 subjects, with the remaining five subjects showing normal HBD sequence and serum ferritin level. Among the subjects with delta-globin gene mutations, seven had an associated IDA confirmed by significantly low serum ferritin levels. Heterozygosity for the delta (+) cd27G-->T mutation (HbA2 -Yialousa; HBD: c.82G>T) was the most common abnormality observed (n = 26, 66.6%) followed by heterozygosity for HBD c.-118C->T (d -68 C >T) (n = 6, 15.4%), for cd16G-->C (n = 4, 10.3%), for cd98G-->A (n = 2, 5.1%), for cd142G-->C (n = 1, 2.6%), and for cd147G-->T (n = 1, 2.6%). CONCLUSIONS: These delta mutations exhibit low HbA2 either due to a shift in the HPLC position or due to their bona fide thalassemic feature. Two mutations, namely cd142 G-->C (GCC to CCC, Ala to Pro) and stop codon cd147 G-->T (stop to Leu with elongation of 15 amino acids), herein first reported are novel. Coexistence of IDA could lead to erroneous diagnostic interpretation unless it is specifically looked for. PMID- 25043856 TI - A pilot study on the effectiveness of a rose hip shell powder in patients suffering from chronic musculoskeletal pain. AB - We carried out a 3-month preliminary investigation on the effectiveness of a rose hip shell powder and its mechanism of action. Of 52 patients suffering from acute exacerbations of low back pain (n = 39) or knee pain (n = 13), 29 had participated earlier in the pilot study with the pseudofruit powder Litozin((r)) . After assessing the baseline values, patients were offered up to 20 g of a rose hip shell powder per day. Patients were encouraged to adjust the daily dose upwards or downwards according to their symptoms for the period of 3 months. The examination for possible effectiveness was by intention-to-treat analysis with last observation carried forward. There was no difference in any generic or disease-specific outcome variables between the patients consuming the rose hip shell powder and those consuming the pseudofruit powder Litozin((r)) in the previous surveillance study. A human protein array system and fractions from the rose powders were used to study their effect on cytokine expression in vitro. The data indicate that lipophilic rose hip fractions from the shell and the pseudofruit inhibit cytokine expression and that the shell powder may be the better starting material for a future rose hip extract prepared with a lipophilic solvent. PMID- 25043858 TI - Does adjuvant radiotherapy benefit patients with diffuse-type gastric cancer? Results from the Surveillance, Epidemiology, and End Results database. AB - BACKGROUND: Diffuse-type gastric cancer is observed in approximately one-third of gastric cancers, yet the optimal treatment remains controversial. In the recently published Intergroup 0116 trial, a subgroup analysis demonstrated a lack of a long-term survival benefit for adjuvant chemoradiation therapy among patients with diffuse-type gastric cancer. METHODS: The Surveillance, Epidemiology, and End Results registry database was queried for patients who were newly diagnosed with diffuse-type gastric cancer between 2002 and 2005 and underwent surgical resection with or without adjuvant radiotherapy (RT). Overall survival (OS) was analyzed by the Kaplan-Meier method. Cox proportional hazards models were used to investigate the association between adjuvant RT and OS, with and without adjusting for other factors. In addition, propensity score methods were used to control for the possible effects of measured confounders. RESULTS: A total of 1889 cases of surgically resected diffuse-type gastric cancer were included in the analysis; of these cases, 782 patients received adjuvant RT and 1107 did not receive RT. The median survival time was 30 months in the group treated with adjuvant RT versus 18 months in the group that did not receive RT with matched propensity scores (P<.001). The Cox model confirmed the improvement in OS in patients who received adjuvant RT (hazard ratio, 0.75; 95% confidence interval, 0.65-0.82 [P<.001]). CONCLUSIONS: The current population-based observational study suggested a potential survival benefit for adjuvant RT among patients with diffuse-type gastric cancer. The standard treatment will likely remain controversial until evidence becomes available from phase 3 randomized trials exclusively for patients with diffuse-type gastric cancer. PMID- 25043857 TI - Palmatine inhibits growth and invasion in prostate cancer cell: Potential role for rpS6/NFkappaB/FLIP. AB - Novel agents are desperately needed for improving the quality of life and 5-year survival to more than 30% for metastatic castrate-resistant prostate cancer. Previously we showed that Nexrutine, Phellodendron amurense bark extract, inhibits prostate tumor growth in vitro and in vivo. Subsequently using biochemical fractionation we identified butanol fraction contributes to the observed biological activities. We report here that palmatine, which is present in the butanol fraction, selectively inhibits growth of prostate cancer cells without significant effect on non-tumorigenic prostate epithelial cells. By screening receptor tyrosine kinases in a protein kinase array, we identified ribosomal protein S6, a downstream target of p70S6K and the Akt/mTOR signaling cascade as a potential target. We further show that palmatine treatment is associated with decreased activation of NFkappaB and its downstream target gene FLIP. These events led to inhibition of invasion. Similar results were obtained using parent extract Nexrutine (Nx) suggesting that palmatine either in the purified form or as one of the components in Nx is a potent cytotoxic agent with tumor invasion inhibitory properties. Synergistic inhibition of rpS6/NFkappaB/FLIP axis with palmatine may have therapeutic potential for the treatment of prostate cancer and possibly other malignancies with their constitutive activation. These data support a biological link between rpS6/NFkappaB/FLIP in mediating palmatine-induced inhibitory effects and warrants additional preclinical studies to test its therapeutic efficacy. PMID- 25043859 TI - Electronic transitions in conformationally controlled tetrasilanes with a wide range of SiSiSiSi dihedral angles. AB - Unlike pi-electron chromophores, the peralkylated n-tetrasilane sigma-electron chromophore resembles a chameleon in that its electronic spectrum changes dramatically as its silicon backbone is twisted almost effortlessly from the syn to the anti conformation (changing the SiSiSiSi dihedral angle omega from 0 to 180 degrees ). A combination of UV absorption, magnetic circular dichroism (MCD), and linear dichroism (LD) spectroscopy on conformationally controlled tetrasilanes 1-9, which cover fairly evenly the full range of angles omega, permitted a construction of an experimental correlation diagram for three to four lowest valence electronic states. The free chain tetrasilane n-Si4 Me10 (10), normally present as a mixture of three enantiomeric conformer pairs of widely different angles omega, has also been included in our study. The spectral trends are interpreted in terms of avoided crossings of 1B with 2B and 2A with 3A states, in agreement with SAC-CI calculations on the excited states of 1-7 and conformers of 10. PMID- 25043862 TI - Effectiveness of biatrial epicardial application of amiodarone-releasing adhesive hydrogel to prevent postoperative atrial fibrillation. AB - OBJECTIVE: Postoperative atrial fibrillation (POAF) is the most frequent complication arising after cardiac surgery, occurring in 30% of cases. Amiodarone is the most effective drug for prophylaxis and treatment. However, because of significant extracardiac side effects, only high-risk patients are eligible for prophylactic amiodarone therapy. We performed a randomized prospective study of 100 patients undergoing cardiac surgery with epicardial application of amiodarone releasing hydrogel to determine the effectiveness of preventing POAF. METHODS: After institutional review board approval, 100 patients, from January 2012 to July 2013, who had undergone cardiac surgery, were randomized to 2 equal groups. The study group received poly-based hydrogel with amiodarone sprayed diffusely over the epicardium. The control group underwent the procedure without the spray. Continuous telemetry monitored for POAF, and amiodarone levels in the atria, plasma, and tissue were measured postoperatively. Daily electrocardiographic parameters were measured until postoperative day 14. RESULTS: The incidence of POAF was significantly less in the study group, with 4 of 50 patients (8%) incurring atrial fibrillation compared with 13 of 50 patients (26%) in the control group (P < .01). The mean amiodarone concentrations in the atria (12.06 +/- 3.1) were significantly greater than those in the extracardiac tissues (1.32 +/- 0.9; P < .01). The plasma amiodarone levels remained below the detection limit (<8 MUg/mL) during the 14 days of follow-up. Bradycardia was observed less in the study group (76 +/- 29) than in the control group (93 +/- 18; P < .01). CONCLUSIONS: Epicardial application of amiodarone-releasing adhesive hydrogel is a less invasive, well-tolerated, quick, and effective therapeutic option for preventing POAF at minimal risk of extracardiac adverse side effects. PMID- 25043863 TI - Prediction of sinus rhythm in patients undergoing concomitant Cox maze procedure through a median sternotomy. AB - OBJECTIVE: One of the challenges that exists when discussing the Cox maze procedure for atrial fibrillation (AF) with patients is predicting the success for a given patient. The purpose of the present study was to develop a scoring system using well-established clinical factors to predict the probability of sinus rhythm (SR) after surgery. METHODS: The data from patients 1 and 2 years postoperatively were analyzed using logistic regression to predict SR, including the most accepted variables associated with failure (age, left atrium size, AF duration, AF type). Regression models were applied using hypothetical patients to examine the predicted probability of SR. RESULTS: The predictors of 1-year SR were a shorter AF duration and greater surgeon experience performing surgical ablation. The predictors at 2 years were a shorter AF duration and smaller left atrium. The 1-year prediction model applied to hypothetical data found a 1-cm increase in left atrial size associated with a 0.4% reduction in SR probability, a 5-year increase in AF duration associated with a 0.8% reduction, and a reduction by 50 cases of surgeon experience associated with a 1.0% reduction. The 2-year model found a 1-cm increase in left atrial size associated with a 1.0% reduction in SR probability, a 5-year increase in AF duration associated with a 0.8% reduction, and a reduction by 50 cases of experience associated with a 0.2% reduction. CONCLUSIONS: Our findings are the first step in establishing a risk scoring system to better predict the outcomes after surgical ablation for AF and improve the ability to discuss the risk and benefits with patients. PMID- 25043865 TI - Trends in use of off-pump coronary artery bypass grafting: Results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. AB - OBJECTIVES: Recent national trends in off-pump versus on-pump coronary artery bypass grafting have not been reported. METHODS: We analyzed data from the Society of Thoracic Surgeons Adult Cardiac Surgery Database regarding isolated primary coronary artery bypass grafting operations (N = 2,137,841; 1997-2012). The off-pump percentages were calculated in aggregate, by center, and by surgeon. On the basis of the 2007/2008 yearly off-pump volume, the analysis subgroups were "high" (center n > 200, surgeon n > 100), "intermediate" (center n = 50-200, surgeon n = 20-100), and "low" (center n = 1-49, surgeon n = 1-19). RESULTS: The use of off-pump procedures peaked in 2002 (23%) and again in 2008 (21%), followed by a progressive decline in off-pump frequency to 17% by 2012. After 2008, off pump rates declined among both high-volume and intermediate-volume centers and surgeons; little change was observed for low-volume centers or surgeons (off-pump rates = 10% since 2008). By the end of the study period, 84% of centers performed fewer than 50 off-pump cases per year, 34% of surgeons performed no off-pump operations, and 86% of surgeons performed fewer than 20 off-pump cases per year. Except for a higher (7.8%) conversion rate in 2003, the rate for conversions fluctuated approximately 6%. CONCLUSIONS: Enthusiasm for off-pump coronary artery bypass grafting has been tempered. The percentage of coronary artery bypass grafting operations performed off-pump has steadily declined over the last 5 years, and currently this technique is used in fewer than 1 in 5 patients who undergo surgical coronary revascularization. A minority of surgeons and centers continue to perform off-pump coronary artery bypass grafting in most of their patients. PMID- 25043866 TI - Homograft use in reoperative aortic root and proximal aortic surgery for endocarditis: A 12-year experience in high-risk patients. AB - OBJECTIVES: We examined the early and midterm outcomes of homograft use in reoperative aortic root and proximal aortic surgery for endocarditis and estimated the associated risk of postoperative reinfection. METHODS: From January 2001 to January 2014, 355 consecutive patients underwent reoperation of the proximal thoracic aorta. Thirty-nine patients (10.9%; mean age, 55.4 +/- 13.3 years) presented with active endocarditis; 30 (76.9%) had prosthetic aortic root infection with or without concomitant ascending and arch graft infection, and 9 (23.1%) had proximal ascending aortic graft infection with or without aortic valve involvement. Sixteen patients (41.0%) had genetically triggered thoracic aortic disease. Twelve patients (30.8%) had more than 1 prior sternotomy (mean, 2.4 +/- 0.6). RESULTS: Valved homografts were used to replace the aortic root in 29 patients (74.4%); nonvalved homografts were used to replace the ascending aorta in 10 patients (25.6%). Twenty-five patients (64.1%) required concomitant proximal arch replacement with a homograft, and 2 patients (5.1%) required a total arch homograft. Median cardiopulmonary bypass, cardiac ischemia, and circulatory arrest times were 186 (137-253) minutes, 113 (59-151) minutes, and 28 (16-81) minutes. Operative mortality was 10.3% (n = 4). The rate of permanent stroke was 2.6% (n = 1); 3 additional patients had transient neurologic events. One patient (1/35, 2.9%) returned with aortic valve stenosis 10 years after the homograft operation. During the follow-up period (median, 2.5 years; range, 1 month to 12.3 years), no reinfection was reported, and survival was 65.7%. CONCLUSIONS: This is one of the largest North American single-center series of homograft use in reoperations on the proximal thoracic aorta to treat active endocarditis. In this high-risk population, homograft tissue can be used with acceptable early and midterm survival and a low risk of reinfection. When necessary, homograft tissue may be extended into the distal ascending and transverse aortic arch, with excellent results. These patients require long-term surveillance for both infection and implant durability. PMID- 25043867 TI - Frozen elephant trunk with total arch replacement for type A aortic dissections: Does acuity affect operative mortality? AB - OBJECTIVE: We seek to compare the early outcomes of frozen elephant trunk with total aortic arch replacement using a 4-branched graft (the Sun procedure) in patients with acute and chronic type A aortic dissection (TAAD), identify the risk factors for operative mortality, and determine whether the acuity of TAAD significantly affects operative mortality. METHODS: We performed univariate and multivariate analyses of the clinical data from 803 patients with TAAD who underwent the Sun procedure. RESULTS: The operative mortality was 6.5% (52 of 803). The overall incidence of stroke and spinal cord injury was 2.0% (16 of 803) and 2.4% (19 of 803), respectively. Patients with acute TAAD had a greater incidence of operative death (8.1% vs 4.3%; P = .031), stroke (2.2% vs 0.6%; P = .046), and respiratory morbidities (20.8% vs 8.6%; P < .001). However, acuity was not identified as a risk factor for operative mortality (odds ratio [OR], 1.67; P = .152). The risk factors were previous cerebrovascular disease (OR, 7.01; P = .001); malperfusion of the brain (OR, 7.10; P = .002), kidneys (OR, 12.67; P = .005), spinal cord (OR, 22.79; P = .008), and viscera (OR 22.98; P = .002); concomitant extra-anatomic bypass (OR, 9.50; P < .001); and cardiopulmonary bypass time >180 minutes (OR, 1.01; P < .001). CONCLUSIONS: In this group of patients with type A dissection, acuity was not a risk factor for operative mortality after the Sun procedure. Patients with previous cerebrovascular disease; malperfusion of the brain, kidneys, spinal cord, and/or viscera; concomitant extra-anatomic bypass; and a longer cardiopulmonary bypass time (>180 minutes) were at greater risk of operative mortality. PMID- 25043869 TI - Serum Levels of Soluble Urokinase Plasminogen Activator Receptor in Infants with Late-onset Sepsis. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) has been studied in a variety of diseases. The aim of the study is to investigate the levels of suPAR in neonates with sepsis. METHODS: The infants enrolled to this prospective study were classified into four groups. Group 1, 2, and 3 were referred as the patient groups (40 infants), and group 4 was referred as control group (26 infants). Blood samples for whole blood count, C-reactive protein (CRP), suPAR and blood culture were obtained before initiating antimicrobial therapy, and two further samples were obtained on day 3 and at the end of the treatment for CRP and suPAR. RESULTS: The mean gestational ages of patient and control groups was similar. The median level of initial suPAR was 18.8 ng/mL (range 6.8-30.1 ng/mL) in the patient groups, and 6.0 ng/mL (range 3.7-10.8 ng/mL) in the control group (P < 0.001). A significant decrease in suPAR level was observed from the inclusion to the third day and end of the treatment (P < 0.001). The area under the curve (AUC) for suPAR is 0.959 (95% Cl: 0.919-0.999) and for CRP is 0.782 (95% Cl: 0.669-0.895). At a cut-off value of 11.3 ng/mL for suPAR the specificity was 100%, and the sensitivity was 82.5%. There was a positive correlation between laboratory values of CRP and suPAR (r: 0.359, P = 0.003). CONCLUSION: This is the first study that investigated the levels of suPAR in neonates and our results demonstrate that suPAR is a powerful marker of inflammation in infants with sepsis. PMID- 25043870 TI - Cell-free identification of novel N-myristoylated proteins from complementary DNA resources using bioorthogonal myristic acid analogues. AB - To establish a non-radioactive, cell-free detection system for protein N myristoylation, metabolic labeling in a cell-free protein synthesis system using bioorthogonal myristic acid analogues was performed. After Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) with a biotin tag, the tagged proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and blotted on a polyvinylidene fluoride (PVDF) membrane, and then protein N myristoylation was detected by enhanced chemiluminescence (ECL) using horseradish peroxidase (HRP)-conjugated streptavidin. The results showed that metabolic labeling in an insect cell-free protein synthesis system using an azide analogue of myristic acid followed by CuAAC with alkynyl biotin was the most effective strategy for cell-free detection of protein N-myristoylation. To determine whether the newly developed detection method can be applied for the detection of novel N-myristoylated proteins from complementary DNA (cDNA) resources, four candidate cDNA clones were selected from a human cDNA resource and their susceptibility to protein N-myristoylation was evaluated using the newly developed strategy. As a result, the products of three cDNA clones were found to be novel N-myristoylated protein, and myristoylation-dependent specific intracellular localization was observed for two novel N-myristoylated proteins. Thus, the metabolic labeling in an insect cell-free protein synthesis system using bioorthogonal azide analogue of myristic acid was an effective strategy to identify novel N-myristoylated proteins from cDNA resources. PMID- 25043871 TI - Spatiotemporal development of soaked protein crystal. AB - Crystal soaking is widely performed in biological crystallography. This paper reports time-resolved X-ray crystallographic and microtomographic analyses of tetragonal crystals of chicken egg-white lysozyme soaked in mother liquor containing potassium hexachloroplatinate. The microtomographic analysis showed that X-ray attenuation spread from the superficial layer of the crystal and then to the crystal core. The crystallographic analyses indicated that platinum sites can be classified into two groups from the temporal development of the electron densities. A soaking process consisting of binding-rate-driven and equilibrium driven layers is proposed to describe these results. This study suggests that the composition of chemical and structural species resulting from the soaking process varies depending on the position in the crystal. PMID- 25043873 TI - Update in intracranial pressure evaluation methods and translaminar pressure gradient role in glaucoma. AB - Glaucoma is one of the leading causes of blindness worldwide. Historically, it has been considered an ocular disease primary caused by pathological intraocular pressure (IOP). Recently, researchers have emphasized intracranial pressure (ICP), as translaminar counter pressure against IOP may play a role in glaucoma development and progression. It remains controversial what is the best way to measure ICP in glaucoma. Currently, the 'gold standard' for ICP measurement is invasive measurement of the pressure in the cerebrospinal fluid via lumbar puncture or via implantation of the pressure sensor into the brains ventricle. However, the direct measurements of ICP are not without risk due to its invasiveness and potential risk of intracranial haemorrhage and infection. Therefore, invasive ICP measurements are prohibitive due to safety needs, especially in glaucoma patients. Several approaches have been proposed to estimate ICP non-invasively, including transcranial Doppler ultrasonography, tympanic membrane displacement, ophthalmodynamometry, measurement of optic nerve sheath diameter and two-depth transcranial Doppler technology. Special emphasis is put on the two-depth transcranial Doppler technology, which uses an ophthalmic artery as a natural ICP sensor. It is the only method which accurately and precisely measures absolute ICP values and may provide valuable information in glaucoma. PMID- 25043874 TI - The use of heparin-impregnated sponges to remove dried blood clots and tissue remnants on microsurgical sutures. PMID- 25043872 TI - Risk factors for the requirement of surgical or endoscopic interventions during chemotherapy in patients with uncomplicated colorectal cancer and unresectable synchronous metastases. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to determine the risk factors for requirement of surgical or endoscopic interventions for complications caused by the primary tumor during chemotherapy in patients with unresectable metastatic colorectal cancer. METHODS: A total of 259 patients were diagnosed with uncomplicated colorectal cancer with unresectable metastatic disease and underwent chemotherapy as an initial treatment. Among them, 57 (22.0%) patients underwent palliative interventions because of complications caused by the primary tumor during chemotherapy, including bypass surgery or diverting enterostomy for 22 patients, insertion of colonic stent for 22, and resection of primary tumor for 13. RESULTS: Multivariate analysis revealed that rectal lesion (RR, 2.132; 95% CI, 1.080-4.210; P = 0.029) and tumor size larger than 5 cm (RR = 3.644, 95% CI = 1.923-6.902; P < 0.001) were significant risk factors for requirement of palliative intervention. Patients who had none of the risk factors showed better overall survival than those who had one or more (P = 0.021). CONCLUSIONS: Tumor location in rectum and tumor size larger than 5 cm were significant risk factors for the requirement of surgical or endoscopic interventions during chemotherapy for complications caused by the primary tumor in patients with unresectable metastatic colorectal cancer. PMID- 25043875 TI - [Requests for assisted reproduction formulated by same-sex couples consulting physicians in France]. AB - BACKGROUND, MATERIAL AND METHODS: In order to determine the characteristic features of requests for assisted reproduction formulated by same-sex couples consulting physicians in France, we conducted a study in collaboration with professional organizations, general practitioners, gynecologists and obstetricians who distributed an email questionnaire among their recruitment. RESULTS: In our sample, 191 physicians (71% of responders) reported that 1040 homosexual couples expressed desire to become parents in 2011-2012. Nearly all of the physicians (94%) reported that the couples sought assistance before participating in an assisted reproduction technology (ART) program in a foreign country, but 35% reported that advice was solicited concerning natural reproduction and 48.5% reported requests for advice concerning inseminations performed by the woman herself. Most of the physicians responded to all or part of the requests and 61% of those who had been consulted reported they had directly participated in preparing an ART program in a foreign country. Among the 270 physicians who participated in this study, 162 (60%) believed that ART should be assessable to homosexual couples in France, but less than half of them were in favor of reimbursement by the national health insurance fund. DISCUSSION: Although biased and non-representative, this study shows that assisted reproduction, with or without medical intervention, is a real-life phenomenon for many homosexual couples, and for many physicians, even before same-sex marriage became legal. PMID- 25043876 TI - [Record linkage of hospital discharge data and first health certificates: a test in the Val d'Oise]. AB - BACKGROUND: Our objective was to test the feasibility of an indirect linkage of data on births from health certificates (HC) with hospital discharge (HD) data. METHODS: The linkage was carried out for live births between April 1st and June 30th, 2011 in six of the nine maternity units in the district of Val d'Oise. The HC and HD had 3284 and 3550 births registered during this period, respectively. Linkage was conducted using variables available in both sources: number of fetuses, baby's birth date, gender, maternity unit of birth, maternal age, municipality of residence, gestational age and birth-weight. Two linkage methods were tested: a deterministic and a semi-deterministic method and a probabilistic approach. The latter method calculates a probability estimate for the strength of the relationship between two linked observations related to the discriminatory power and the error rate of the matched variables. For cases that were linked despite discordance on some of the matching variables, random samples of observations were checked against both HC and HD records to compute rates of false matches. RESULTS: The deterministic and semi-deterministic method linked 92.5% and 85.6% of observations in the HC and HD, respectively. The probabilistic method achieved a linkage rate of 99.6% for HC and 92.7% for HD. Cases only linked by the probabilistic method were more often preterm and had low birth weight. Cases matched using the probabilistic method only had an error rate of 0.4% with 95% CI [0.2-0.6%]. CONCLUSION: Common items in the HC and HD make it possible to achieve a high rate of linkage. The probabilistic method links more births and, in particular, those at higher risk, and error rates were low. PMID- 25043878 TI - Microdebrider complications in laryngologic and airway surgery. AB - OBJECTIVES/HYPOTHESIS: There is a paucity of experience in the published literature documenting complications of powered surgical instruments in laryngologic surgery. Our objective was to ascertain the nature of these complications from expert opinion and review of the literature, and to recommend strategies to decrease major complications. STUDY DESIGN: Review of the literature and an e-mail survey. METHODS: A literature review of microdebrider complications in laryngologic surgery was conducted using PubMed and Ovid (1985 to 2013), along with an analysis of a confidential e-mail survey of various surgeons in selected high-volume laryngologic centers. RESULTS: Powered instrumentation is frequently used in the operating room for larynx and airway surgery. The microdebrider can improve efficiency, lower costs, and shorten operative times. However, use of the microdebrider has the potential for serious complications in the larynx and airway. Great care must be taken when utilizing the microdebrider in laryngologic surgery. Significant complications including major vocal fold scar, airway compromise, severe hemorrhage, and unintentional tissue loss have occurred. CONCLUSIONS: The microdebrider is a popular and valuable tool for the otolaryngologist. A thorough knowledge of the instrument and its potential complications will improve surgical outcomes and may prevent complications. Awareness of the risks and surgeon experience with use of the microdebrider will allow the surgeon to successfully utilize this device in a safe and effective manner. LEVEL OF EVIDENCE: 5. PMID- 25043879 TI - The relationship between BMI and dietary intake of primary school children from a rural area of South Africa: The Ellisras longitudinal study. AB - OBJECTIVES: To investigate the relationship between dietary intake and BMI of primary school children from a rural area of South Africa cross-sectionally. Both under and over nutrition remain major health problems in South Africa. In rural areas, where especially undernutrition leads to child morbidity and mortality, determinants should be detected. METHODS: Data was used from 825 children (421 boys, 404 girls), aged 6-12 years, participating in the Ellisras Longitudinal Growth study. Height and weight were measured in accordance with the protocol of the International Society for the Advancement of Kinanthropometry. Internationally recommended cut-off points for body mass index (BMI) were used. Dietary intake was measured using the 24 h recall method. In general, boys and girls from Ellisras had dietary intake levels lower than or according to dietary guidelines. RESULTS: A singular linear regression model showed a significant association between monounsaturated fat and BMI. The multiple model demonstrated that total fat (B = 0.05, CI: 0.019-0.082), monounsaturated fat (B = -0.093, CI: 0.160 to -0.026) and polyunsaturated fat (B = 0.056, CI: 0.09-0.02) predict BMI. CONCLUSION: This study supports previous findings about BMI and dietary trends in rural areas of South Africa. Despite low fat intake of the subjects, this macronutrient appeared to predict BMI most strongly. More research is needed; however, to further examine how healthy their lifestyle is nowadays with respect to diet and into what extent the nutrition transition has reached this area. PMID- 25043880 TI - Natural product synthesis at the interface of chemistry and biology. AB - Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wohler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. PMID- 25043881 TI - Patients with low lying lymph nodes are at high risk for distant metastasis in oropharyngeal cancer. AB - PURPOSE: We sought to identify risk factors for distant metastasis (DM) in patients with oropharyngeal cancer (OPC) and perform a recursive partition analysis (RPA) to identify patients both at low and high risk for DM. METHODS: Our center treated 647 consecutive OPC patients with IMRT between 9/98 and 1/12. The following clinical features were used as prognostic factors: T Stage, N Stage, smoking history, tumor grade, tumor sub-site, the presence of a low lying (level IV or VB) lymph node (LLLN). A Cox model of the risk of DM was used to identify independent prognostic factors. RPA was used to identify patients at low, intermediate, and high risk for DM. RESULTS: The median follow-up time in living patients was 42.2months (range: 2-166). The primary OPC site was the tonsil in 296 patients, base of tongue in 315 patients, and soft palate or pharyngeal wall in 36 patients. For the entire cohort, the Kaplan-Meier estimate for 3year freedom from distant metastasis was 88.4%. A Cox model identified T Stage (p<0.001), N Stage (p=0.02), and LLLN (p=0.002) as independent predictors of DM. RPA identified patients at low, intermediate, and high risk of DM, with a 3-year freedom-from DM of 98%, 91.1%, and 65.4% respectively. CONCLUSION: The presence of a low lying lymph node is significantly associated with an increased risk of DM in OPC. RPA identified patients both at very low and very high risk for DM with information routinely obtained in clinic. PMID- 25043882 TI - The relative prognostic utility of standardized uptake value, gross tumor volume, and metabolic tumor volume in oropharyngeal cancer patients treated with platinum based concurrent chemoradiation with a pre-treatment [(18)F] fluorodeoxyglucose positron emission tomography scan. AB - OBJECTIVES: This study compared the relative prognostic utility of the Gross Tumor Volume (GTV), maximum Standardized Uptake Value (SUVmax), and Metabolic Tumor Volume (MTV) in a uniform cohort of oropharyngeal squamous cell carcinoma (OPSCC) patients treated with platinum-based concurrent chemoradiation therapy (CCRT). METHODS AND MATERIALS: One-hundred OPSCC with a pretreatment [(18)F] fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET CT) were treated with CCRT. Kaplan-Meier curves and Cox proportional hazard models were generated. RESULTS: When dichotomized by the median, a smaller MTV correlated with improved 5year locoregional control (LRC) (98.0% versus 87.0%, p=0.049), freedom from distant metastasis (FDM) (91.7% versus 65.0%, p=0.005), progression-free survival (PFS) (80.3% versus 56.7%, p=0.015), and overall survival (OS) (84.1% versus 57.8%, p=0.008), whereas a smaller GTV correlated with improved PFS (80.3% versus 57.4%, p=0.040) and OS (82.1% versus 60.1%, p=0.025). SUVmax failed to correlate with any outcome. On multivariate analysis, when adjusted for GTV, T-stage, and N-stage a smaller MTV remained independently correlated with improved FDM, PFS, and OS. GTV failed to reach significance in the multivariate model. CONCLUSIONS: A smaller MTV correlates with improved LRC, FDM, PFS, and OS in OPSCC patients undergoing platinum-based CCRT. PMID- 25043883 TI - Detection and typing of human papillomaviruses (HPV) in malignant, dysplastic, nondysplastic and normal oral epithelium by nested polymerase chain reaction, immunohistochemistry and transitional electron microscopy in patients of northern Greece. AB - OBJECTIVES: To evaluate the role of HPV in oral carcinogenesis, we examined the prevalence of HPV in malignant, potentially malignant and normal oral epithelium and studied the relation of HPV prevalence with other factors obtained from the patient's records. MATERIALS AND METHODS: Our material consisted of 291 tissue specimens from 258 individuals. From every individual formalin fixed and paraffin embedded tissues were examined by nested Polymerase Chain Reaction (NPCR) for the detection of HPV DNA and by immunohistochemistry (IHC) for the in situ detection of HPV L1 protein. Positive PCR products were sequenced in order to type HPVs. Also 33 fresh tissues were obtained, fixed and used to detect HPV particles by transitional electron microscopy (TEM). RESULTS: HPV was detected in 32.9% of the tissue specimens by NPCR, in 4.7% by immunohistochemistry and in 28.1% by TEM. In detail, by nested PCR HPV L1 DNA was detected in 40% of normal tissues, 40% of fibromas, 35.8% of non-dysplastic leukoplakias, 31.6% of dysplastic leukoplakias and 22.2% of oral squamous cell carcinomas. The HPV viral load of 96.5% of the samples was very low (1 viral copy per 10(2)-10(4) cells). HPV16 prevails in all histological groups in 89-100%. CONCLUSION: We conclude that HPV does not seem, from the specific sample examined, to play a substantial role in oral carcinogenesis. However, it cannot be excluded that HPV could be involved in oral carcinogenesis only in cases with high viral load or at early stages of carcinogenesis possibly through the hit-and-run mechanism. PMID- 25043884 TI - X-chromosome genetic association test accounting for X-inactivation, skewed X inactivation, and escape from X-inactivation. AB - X-chromosome inactivation (XCI) is the process in which one of the two copies of the X-chromosome in females is randomly inactivated to achieve the dosage compensation of X-linked genes between males and females. That is, 50% of the cells have one allele inactive and the other 50% of the cells have the other allele inactive. However, studies have shown that skewed or nonrandom XCI is a biological plausibility wherein more than 75% of cells have the same allele inactive. Also, some of the X-chromosome genes escape XCI, i.e., both alleles are active in all cells. Current statistical tests for X-chromosome association studies can either account for random XCI (e.g., Clayton's approach) or escape from XCI (e.g., PLINK software). Because the true XCI process is unknown and differs across different regions on the X-chromosome, we proposed a unified approach of maximizing likelihood ratio over all biological possibilities: random XCI, skewed XCI, and escape from XCI. A permutation-based procedure was developed to assess the significance of the approach. We conducted simulation studies to compare the performance of the proposed approach with Clayton's approach and PLINK regression. The results showed that the proposed approach has higher powers in the scenarios where XCI is skewed while losing some power in scenarios where XCI is random or XCI is escaped, with well-controlled type I errors. We also applied the approach to the X-chromosomal genetic association study of head and neck cancer. PMID- 25043886 TI - Peptides come round: using SICLOPPS libraries for early stage drug discovery. AB - Cyclic peptides are an emerging class of molecular therapeutics that are increasingly viewed as ideal backbones for modulation of protein-protein interactions. A split-intein based method, termed SICLOPPS, enables the rapid generation of genetically encoded cyclic peptide libraries of around a hundred million members. Here we review recent approaches using SICLOPPS for the discovery of bioactive compounds. PMID- 25043887 TI - Induction of the autophagy-associated gene MAP1S via PU.1 supports APL differentiation. AB - The PU.1 transcription factor is essential for myeloid development. We investigated if the microtubule-associated protein 1S (MAP1S) is a novel PU.1 target with a link to autophagy, a cellular recycling pathway. Comparable to PU.1, MAP1S expression was significantly repressed in primary AML blasts as compared to mature neutrophils. Accordingly, MAP1S expression was induced during neutrophil differentiation of CD34(+) progenitor and APL cells. Moreover, PU.1 bound to the MAP1S promoter and induced MAP1S expression during APL differentiation. Inhibiting MAP1S resulted in aberrant neutrophil differentiation and autophagy. Taken together, our findings implicate the PU.1-regulated MAP1S gene in neutrophil differentiation and autophagy control. PMID- 25043885 TI - De novo LINE-1 retrotransposition in HepG2 cells preferentially targets gene poor regions of chromosome 13. AB - Long interspersed nuclear elements (Line-1 or L1s) account for ~17% of the human genome. While the majority of human L1s are inactive, ~80-100 elements remain retrotransposition competent and mobilize through RNA intermediates to different locations within the genome. De novo insertions of L1s account for polymorphic variation of the human genome and disruption of target loci at their new location. In the present study, fluorescence in situ hybridization and DNA sequencing were used to characterize retrotransposition profiles of L1(RP) in cultured human HepG2 cells. While expression of synthetic L1(RP) was associated with full-length and truncated insertions throughout the entire genome, a strong preference for gene-poor regions, such as those found in chromosome 13 was observed for full-length insertions. These findings shed light into L1 targeting mechanisms within the human genome and question the putative randomness of L1 retrotransposition. PMID- 25043888 TI - Organochlorine (chlordecone) uptake by root vegetables. AB - Chlordecone, an organochlorine insecticide, continues to pollute soils in the French West Indies. The main source of human exposure to this pollutant is food. Root vegetables, which are staple foods in tropical regions, can be highly contaminated and are thus a very effective lever for action to reduce consumer exposure. We analyzed chlordecone contamination in three root vegetables, yam, dasheen and sweet potato, which are among the main sources of chlordecone exposure in food in the French West Indies. All soil types do not have the same potential for the contamination of root vegetables, allophanic andosols being two to ten times less contaminating than non-allophanic nitisols and ferralsols. This difference was only partially explained by the higher OC content in allophanic soils. Dasheen corms were shown to accumulate more chlordecone than yam and sweet potato tubers. The physiological nature of the root vegetable may explain this difference. Our results are in good agreement with the hypothesis that chlordecone uptake by root vegetables is based on passive and diffusive processes and limited by transport and dilution during growth. PMID- 25043890 TI - Refractive, anterior corneal and internal astigmatism in the pseudophakic eye. AB - PURPOSE: To evaluate the correlation between refractive astigmatism (RA) and anterior corneal astigmatism (ACA), and determine the internal astigmatism (IA) in 184 pseudophakic eyes. METHODS: The study was a prospective non-masked single centre study. Patients were examined 8 weeks after phacoemulsification with implantation of aspheric one-piece monofocal IOLs. Examination included autokeratometry and subjective refraction. All refractive data were converted to the corneal plane. The corneal refractive index, taken to be 1.376, was used to estimate the ACA. All astigmatisms were converted to net curvital and net torsional powers with the steeper corneal plane as the reference meridian. Curvital power is the force acting along a given meridian, and torsion is the power twisting the astigmatic direction out of that plane. The internal astigmatism (IA) was calculated as the difference between RA and ACA. RESULTS: For curvital powers, the refractive astigmatism (KP(Phi)RA ) could be described as a function of anterior corneal astigmatic magnitude (KP(Phi)ACA ) and direction alpha by the multiple linear regression equation: KP(Phi)RA = -0.09 + 0.61*KP(Phi)ACA + 0.33*cos2alpha, (r(2) = 0.59, p < 0.0001). The average internal astigmatism amounted to 0.47 D inclined 92 degrees relative to the steeper anterior corneal meridian. The magnitude of internal astigmatism depended on the angle alpha of the steeper anterior corneal meridian, averaging 0.86 D at 91 degrees for with-the-rule, 0.37 D at 95 degrees for oblique and 0.17 D at 97 degrees for against-the-rule corneal astigmatisms. CONCLUSIONS: The internal astigmatism varies as a function of the direction of the anterior steeper corneal meridian. In patient candidates to surgical correction of astigmatism, measuring only the curvature of the anterior corneal surface and neglecting that of the posterior corneal surface can lead to inaccurate evaluation of total corneal astigmatism. PMID- 25043889 TI - Defining utility and predicting outcome of cadaveric lower extremity bypass grafts in patients with critical limb ischemia. AB - OBJECTIVE: Despite poor long-term patency, acceptable limb salvage has been reported with cryopreserved saphenous vein bypass (CVB) for various indications. However, utility of CVB in patients with critical limb ischemia (CLI) remains undefined. The purpose of this analysis was to determine the role of CVB in CLI patients and to identify predictors of successful outcomes. METHODS: A retrospective review of all lower extremity bypass (LEB) procedures at a single institution was completed, and CVB in CLI patients were further analyzed. The primary end point was amputation-free survival. Secondary end points included primary patency and limb salvage. Life tables were used to estimate occurrence of end points. Cox regression analysis was used to determine predictors of limb salvage. RESULTS: From 2000 to 2012, 1059 patients underwent LEB for various indications, of whom 81 received CVB for either ischemic rest pain or tissue loss. Mean age (+/- standard deviation) was 66 +/- 10 years (male, 51%; diabetes, 51%; hemodialysis dependence, 12%), and 73% (n = 59) had history of failed ipsilateral LEB or endovascular intervention. None had sufficient autogenous conduit for even composite vein bypass. Infrainguinal CVB (infrapopliteal target, 96%; n = 78) was completed for multiple indications including Rutherford class 4 (42%; n = 34), class 5 (40%; n = 32), and class 6 (18%; n = 15). Eleven (14%) had CLI and concomitant graft infection (n = 8) or acute on chronic ischemia (n = 3). Intraoperative adjuncts (eg, profundaplasty, suprainguinal stent or bypass) were completed in 49% (n = 40) of cases. Complications occurred in 36% (n = 29), with 30-day mortality of 4% (n = 3). Median follow-up for CLI patients was 11.8 (interquartile range, 0.4-28.4) months with corresponding 1- and 3-year actuarial estimated survival (+/- standard error mean) of 84% +/- 4% and 62% +/- 6%. Primary patency of CVB for CLI was 27% +/- 6% and 17% +/- 6% at 1 and 3 years, respectively. Amputation-free survival was 43% +/- 6% and 23% +/- 6% at 1 and 3 years, respectively, and significantly higher for rest pain (59% +/- 9%, 36% +/- 10%) compared with tissue loss (31% +/- 7%, 14% +/- 7%; log-rank, P = .04). Freedom from major amputation after CVB for CLI was 57% +/- 6% and 43% +/- 7% at 1 and 3 years. Multivariable predictors of limb salvage for the CVB CLI cohort included postoperative warfarin (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2-0.8), dyslipidemia (HR, 0.4; 95% CI, 0.2-0.9), and rest pain (HR, 0.4; 95% CI, 0.2-0.9). Predictors of major amputation included graft infection (HR, 3.1; 95% CI, 1.1-9.0). CONCLUSIONS: In CLI patients with no autologous conduit and prior failed infrainguinal bypass, CVB outcomes are disappointing. CVB performs best in patients with rest pain, particularly those who can be anticoagulated with warfarin. However, it may be an acceptable option in patients with minor tissue loss or concurrent graft infection, but consideration should be weighed against the known natural history of nonrevascularized CLI and nonbiologic conduit alternatives, given potential cost implications. PMID- 25043891 TI - Comparison of aneuploidy, pregnancy and live birth rates between day 5 and day 6 blastocysts. AB - Comprehensive chromosome screening is typically used for aneuploidy analysis of blastocysts. It is believed that either day of blastocyst development is acceptable. Euploidy rates and outcomes were examined between day 5 and day 6 blastocysts in two studies. First, euploidy rates of day 5 and day 6 blastocysts were examined on a per-embryo and per-patient basis. Second, outcomes were compared when only euploid day 5 or day 6 blastocysts were transferred in a cryopreserved embryo transfer cycle. In cycles (n = 70) that had blastocysts biopsied on both day 5 and day 6, day 5 blastocysts had a higher chance of being euploid than day 6 blastocysts (125/229 [54.6%]) and (77/180 [42.8%]), respectively (P = 0.0231). Similarly, euploid rates in blastocysts from patients (n = 193) with day 5 biopsy, day 6 biopsy, or both, were significantly higher in day 5 (235/421 [55.8%]) compared with day 6 (184/413 [44.6%]) blastocysts (P = 0.0014). In the second study, 50 women (36.1 +/- 4.3 years) and 39 women (35.1 +/ 3.8 years) with only euploid day 5 or euploid day 6 blastocysts transferred during a cryopreserved embryo transfer had similar cycle outcomes. Although underpowered, these data suggest that euploid day 6 blastocysts are as capable of positive outcomes as their euploid day 5 counterparts. PMID- 25043892 TI - GnRH agonist and GnRH antagonist protocols: comparison of outcomes among good prognosis patients using national surveillance data. AB - Implantation and live birth rates resulting from IVF cycles using gonadotropin releasing hormone (GnRH) agonist and (GnRH) antagonist IVF protocols were compared among good-prognosis patients using the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System 2009 2010 data (n = 203,302 fresh, autologous cycles). Bivariable and multivariable analyses were conducted between cycles to compare outcomes. Cycles were restricted as follows: age younger than 35 years, maximum FSH less than 10 mIU/mL, first assisted reproduction technology cycle and FSH dose less than 3601 IU. A subgroup analysis including only elective single embryo transfer was also carried out. Among good-prognosis patients, the GnRH-agonist protocol was associated with a lower risk of cancellation before retrieval (4.3 versus 5.2%; P < 0.05) or transfer (5.5 versus 6.8%; P < 0.05), and a higher live birth rate per transfer (adjusted odds ratio [OR] 1.13, confidence interval [CI] 1.03 to 1.25) than the GnRH-antagonist group. Among the elective single embryo transfer group, the GnRH-agonist protocol was associated with a higher implantation rate (adjusted odds ratio [OR] 1.36, CI 1.08 to 1.73) and a higher live birth rate (adjusted OR 1.33, CI 1.07 to 1.66) compared with the GnRH-antagonist protocol. The GnRH-antagonist group had lower rates of ovarian hyperstimulation syndrome. Among good-prognosis patients, agonist protocols decreased cancellation risk and increased odds of implantation and live birth. Antagonist protocols may confer decreased risk of hyperstimulation. PMID- 25043893 TI - GnRHa trigger for final oocyte maturation: is HCG trigger history? AB - Since the introduction of the gonadotrophin-releasing hormone analogues (GnRHa) protocol, it has become possible to trigger final oocyte maturation with a bolus of GnRHa. This leads to a significant reduction or complete elimination of ovarian hyperstimulation syndrome compared with human chorionic gonadotrophin (HCG) trigger. Early trials showed a severe luteal phase insufficiency after GnRHa trigger despite the application of standard luteal phase support protocols. Subsequent research has led to modifications of the luteal phase support, resulting in reproductive outcome comparable to that seen after HCG trigger in normal- and high-responders. GnRHa trigger facilitates a tailored approach to subsequent luteal phase support, taking into account the ovarian response to stimulation. In the future, GnRHa is likely to be used for trigger in all women co-treated with GnRH antagonists. PMID- 25043894 TI - Development and glycoprotein composition of the perimicrovillar membrane in Triatoma (Meccus) pallidipennis (Hemiptera: Reduviidae). AB - Hemipterans and thysanopterans (Paneoptera: Condylognatha) differ from other insects by having an intestinal perimicrovillar membrane (PMM) which extends from the base of the microvilli to the intestinal lumen. The development and composition of the PMM in hematophagous Reduviidae depend on factors related to diet. The PMM may also allow the human parasite Trypanosoma cruzi, the etiological agent of human Chagas Disease, to establish and develop in this insect vector. We studied the PMM development in the Mexican vector of Chagas Disease, Triatoma (Meccus) pallidipennis. We describe changes in the midgut epithelial cells of insects in response to starvation, and at different times (10, 15 and 20 days) after bloodfeeding. In starved insects, the midguts showed epithelial cells closely connected to each other but apparently free of PMM with some regions being periodic acid-Schiff (PAS-Schiff) positive. In contrast, the PMM was evident and fully developed in the midgut region of insects 15 days after feeding. After this time, the PMM completely covered the microvilli and reached the midgut lumen. At 15 days following feeding the labeled PAS-Schiff increased in the epithelial apex, suggesting an increase in carbohydrates. Lectins as histochemical reagents show the presence of a variety of glycoconjugates including mannose, glucose, galactosamine, N-acetyl-galactosamine. Also present were N-acetyl-glucosamine and sialic acid which contribute to the successful establishment and replication or T. cruzi in its insect vectors. By means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM), the formation and structure of the PMM is confirmed at 15 days post feeding. Our results confirmed the importance of the feeding processes in the formation of the PMM and showed the nature of the biochemical composition of the vectors' intestine in this important Mexican vector of Chagas disease. PMID- 25043895 TI - Bilateral brachial plexopathy as the presenting symptom of giant cell arteritis. PMID- 25043896 TI - DNase I and proteinase K impair Listeria monocytogenes biofilm formation and induce dispersal of pre-existing biofilms. AB - Current sanitation methods in the food industry are not always sufficient for prevention or dispersal of Listeria monocytogenes biofilms. Here, we determined if prevention of adherence or dispersal of existing biofilms could occur if biofilm matrix components were disrupted enzymatically. Addition of DNase during biofilm formation reduced attachment (<50% of control) to polystyrene. Treatment of established 72h biofilms with 100MUg/ml of DNase for 24h induced incomplete biofilm dispersal, with <25% biofilm remaining compared to control. In contrast, addition of proteinase K completely inhibited biofilm formation, and 72h biofilms including those grown under stimulatory conditions-were completely dispersed with 100MUg/ml proteinase K. Generally-regarded-as-safe proteases bromelain and papain were less effective dispersants than proteinase K. In a time course assay, complete dispersal of L. monocytogenes biofilms from both polystyrene and type 304H food-grade stainless steel occurred within 5min at proteinase K concentrations above 25MUg/ml. These data confirm that both DNA and proteins are required for L. monocytogenes biofilm development and maintenance, and that these components of the biofilm matrix can be targeted for effective prevention and removal of biofilms. PMID- 25043897 TI - The ontogeny of nasal floor shape variation in extant humans. AB - Variation in nasal floor topography has generated both neontological and paleontological interest. Three categories of nasal floor shape (Franciscus: J Hum Evol 44 (2003) 699-727) have been used when analyzing this trait in extant humans and fossil Homo: flat, sloped, and depressed (or "bi-level"). Variation in the frequency of these configurations within and among extant and fossil humans has been well-documented (Franciscus: J Hum Evol 44 (2003) 699-727; Wu et al.: Anthropol Sci 120 (2012) 217-226). However, variation in this trait in Homo has been observed primarily in adults, with comparatively small subadult sample sizes and/or large age gradients that may not sufficiently track key ontogenetic changes. In this study, we investigate the ontogeny of nasal floor shape in a relatively large cross-sectional age sample of extant humans (n = 382) ranging from 4.0 months fetal to 21 years post-natal. Results indicate that no fetal or young infant individuals possess a depressed nasal floor, and that a depressed nasal floor, when present (ca. 21% of the sample), does not occur until 3.0 years postnatal. A canonical variates analysis of maxillary shape revealed that individuals with depressed nasal floors were also characterized by relatively taller anterior alveolar regions. This suggests that palate remodeling at about 3.0-3.5 years after birth, under the influence of tooth development, strongly influences nasal floor variation, and that various aspects of dental development, including larger crown/root size, may contribute to the development of a depressed nasal floor. These results in extant humans may help explain the high frequency of this trait found in Neandertal and other archaic Homo maxillae. PMID- 25043898 TI - The interaction of human microbial pathogens, particulate material and nutrients in estuarine environments and their impacts on recreational and shellfish waters. AB - Anthropogenic activities have increased the load of faecal bacteria, pathogenic viruses and nutrients in rivers, estuaries and coastal areas through point and diffuse sources such as sewage discharges and agricultural runoff. These areas are used by humans for both commercial and recreational activities and are therefore protected by a range of European Directives. If water quality declines in these zones, significant economic losses can occur. Identifying the sources of pollution, however, is notoriously difficult due to the ephemeral nature of discharges, their diffuse source, and uncertainties associated with transport and transformation of the pollutants through the freshwater-marine interface. Further, significant interaction between nutrients, microorganisms and particulates can occur in the water column making prediction of the fate and potential infectivity of human pathogenic organisms difficult to ascertain. This interaction is most prevalent in estuarine environments due to the formation of flocs (suspended sediment) at the marine-freshwater interface. A range of physical, chemical and biological processes can induce the co-flocculation of microorganisms, organic matter and mineral particles resulting in pathogenic organisms becoming potentially protected from a range of biotic (e.g. predation) and abiotic stresses (e.g. UV, salinity). These flocs contain and retain macro- and micro- nutrients allowing the potential survival, growth and transfer of pathogenic organisms to commercially sensitive areas (e.g. beaches, shellfish harvesting waters). The flocs can either be transported directly to the coastal environment or can become deposited in the estuary forming cohesive sediments where pathogens can survive for long periods. Especially in response to storms, these sediments can be subsequently remobilised releasing pulses of potential pathogenic organisms back into the water column leading to contamination of marine waters long after the initial contamination event occurred. Further work, however, is still required to understand and predict the potential human infectivity of pathogenic organisms alongside the better design of early warning systems and surveillance measures for risk assessment purposes. PMID- 25043899 TI - Reply: To PMID 24700511. PMID- 25043900 TI - Contrast-enhanced endoscopic ultrasonography can predict a higher malignant potential of gastrointestinal stromal tumors by visualizing large newly formed vessels. AB - BACKGROUND: The aim of this study was to elucidate the histologic and clinical implications of detection of intratumoral vessels on contrast-enhanced endoscopic ultrasonography (CE-EUS) in gastrointestinal stromal tumors (GISTs). METHODS: Thirteen patients with a GIST, all of whom were referred for surgery, underwent presurgical CE-EUS. The malignant potential, assessed according to the modified Fletcher risk classification system, and the histologic degree of angiogenesis were compared with the presence or absence of intratumoral vessels on CE-EUS. RESULTS: Of the six tumors with intratumoral vessels observed on CE-EUS, five were intermediate- or high-risk GISTs, and the remaining seven negative cases were categorized as very low risk or low risk. The presence of intratumoral vessels on CE-EUS was significantly correlated with a higher-risk classification (p = 0.005). On histologic examination, all GISTs having visualized vessels incorporated vessels of more than 500 MUm in diameter. The large intratumoral vessels of the five intermediate- or high-risk GISTs lacked elastic fibers, suggesting that they were neovascular in nature. These higher-risk tumors were also found, by immunohistochemical analysis, to have high expression of vascular endothelial growth factor. CONCLUSIONS: Intratumoral vessels observed in GISTs on CE-EUS are correlated with a higher degree of angiogenesis, resulting in higher malignant potential. PMID- 25043901 TI - High energy and power density capacitors from solution-processed ternary ferroelectric polymer nanocomposites. AB - Concurrent improvements in dielectric constant and breakdown strength are attained in a solution-processed ternary ferroelectric polymer nanocomposite incorporated with two-dimensional boron nitride nanosheets and zero-dimensional barium titanate nanoparticles that synergistically interact to enable a remarkable energy-storage capability, including large discharged energy density, high charge-discharge efficiency, and great power density. PMID- 25043902 TI - Z-cone model for the energy of an ordered foam. AB - We develop the Z-Cone Model, in terms of which the energy of a foam may be estimated. It is directly applicable to an ordered structure in which every bubble has Z identical neighbours. The energy (i.e. surface area) may be analytically related to liquid fraction. It has the correct asymptotic form in the limits of dry and wet foam, with prefactors dependent on Z. In particular, the variation of energy with deformation in the wet limit is consistent with the anomalous behaviour found by Morse and Witten [Europhysics Letters, 1993, 22, 549] and Lacasse et al. [Physical Review E, 54, 5436], with a prefactor Z/2. PMID- 25043903 TI - EGFR mutations and clinical outcomes of chemotherapy for advanced non-small cell lung cancer: a meta-analysis. AB - BACKGROUND: This meta-analysis was performed to assess whether epidermal growth factor receptor (EGFR) mutation status was associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy. METHOD: We systematically identified eligible articles investigating the effects of chemotherapy in patients with NSCLC stratified by EGFR mutation status. The summary risk ratio (RR) for ORR and hazard ratios (HRs) for both PFS and OS were calculated using the inverse variance formula of meta analysis. RESULTS: Identification for the current meta-analysis: 5 prospective studies (n=875) and 18 retrospective studies (n=1934) for ORR; 2 prospective studies (n=434) and 10 retrospective studies (n=947) for PFS; 2 prospective studies (n=438) and 7 retrospective studies (n=711) for OS. The ORR was significantly higher in patients with EGFR mutations in prospective studies (RR=1.42; 95% confidence interval [CI], 1.16-1.74; P=0.001), but not in retrospective studies (RR=1.12; 95% CI, 0.96-1.32; P=0.146). There was no obvious association between EGFR mutations and PFS both in prospective (HR=0.84; 95% CI: 0.65-1.09; P=0.197) and retrospective (HR=1.02; 95% CI: 0.87-1.18; P=0.838) studies. Association between EGFR mutations and OS was also not seen in prospective studies (HR=0.74; 95% CI: 0.27-2.05; P=0.566), but was seen in retrospective studies (HR=0.48; 95% CI: 0.33-0.72; P<0.001; I(2)=75.9%; P<0.001) with significant heterogeneity. CONCLUSION: EGFR mutations in advanced NSCLC may be associated with higher ORRs to chemotherapy, but may have nothing to do with PFS and OS. Further prospective studies are required to identify the influence of EGFR mutations on chemotherapy effects in advanced NSCLC. PMID- 25043904 TI - Calcineurin phosphatase as a negative regulator of fear memory in hippocampus: control on nuclear factor-kappaB signaling in consolidation and reconsolidation. AB - Protein phosphatases are important regulators of neural plasticity and memory. Some studies support that the Ca(2+) /calmodulin-dependent phosphatase calcineurin (CaN) is, on the one hand, a negative regulator of memory formation and, on the other hand, a positive regulator of memory extinction and reversal learning. However, the signaling mechanisms by which CaN exerts its action in such processes are not well understood. Previous findings support that CaN negatively regulate the nuclear factor kappaB (NF-kappaB) signaling pathway during extinction. Here, we have studied the role of CaN in contextual fear memory consolidation and reconsolidation in the hippocampus. We investigated the CaN control on the NF-kappaB signaling pathway, a key mechanism that regulates gene expression in memory processes. We found that post-training intrahippocampal administration of the CaN inhibitor FK506 enhanced memory retention one day but not two weeks after training. Accordingly, the inhibition of CaN by FK506 increased NF-kappaB activity in dorsal hippocampus. The administration of the NF kappaB signaling pathway inhibitor sulfasalazine (SSZ) impeded the enhancing effect of FK506. In line with our findings in consolidation, FK506 administration before memory reactivation enhanced memory reconsolidation when tested one day after re-exposure to the training context. Strikingly, memory was also enhanced two weeks after training, suggesting that reinforcement during reconsolidation is more persistent than during consolidation. The coadministration of SSZ and FK506 blocked the enhancement effect in reconsolidation, suggesting that this facilitation is also dependent on the NF-kappaB signaling pathway. In summary, our results support a novel mechanism by which memory formation and reprocessing can be controlled by CaN regulation on NF-kappaB activity. PMID- 25043905 TI - Effects of playing a violent video game as male versus female avatar on subsequent aggression in male and female players. AB - Previous research has shown that violent video games can increase aggression in players immediately after they play. The present research examines the effects of one subtle cue within violent video games that might moderate these effects whether the avatar is male or female. One common stereotype is that males are more aggressive than females. Thus, playing a violent video game as a male avatar, compared to a female avatar, should be more likely to prime aggressive thoughts and inclinations in players and lead to more aggressive behavior afterwards. Male and female university students (N = 242) were randomly assigned to play a violent video game as a male or female avatar. After gameplay, participants gave an ostensible partner who hated spicy food hot sauce to eat. The amount of hot sauce given was used to measure aggression. Consistent with priming theory, results showed that both male and female participants who played a violent game as a male avatar behaved more aggressively afterwards than those who played as female avatar. The priming effects of the male avatar were somewhat stronger for male participants than for female participants, suggesting that male participants identified more with the male avatar than did the female participants. These results are particularly noteworthy because they are consistent with another recent experiment showing that playing a violent game as an avatar with a different stereotypically aggressive attribute (black skin color) stimulates more aggression than playing as an avatar without the stereotypically aggressive attribute (Yang et al., 2014, Social Psychological and Personality Science). PMID- 25043906 TI - Vitamin D status in critically ill patients: the evidence is now bioavailable! PMID- 25043907 TI - Values and helping behavior: A study in four cultures. AB - Values are important factors in determining individuals' behaviours. Previous studies have examined the relations between values and helping behaviour, but usually in the context of a single culture. The current study examines the relations between personal value types and helping behaviour among university students (N = 722) in four cultures (Germany, Scotland-UK, Israel and Turkey). Across cultures, the value types of self-transcendence versus self-enhancement and conservation versus openness to change were positively related to helping. Specifically, self-transcendence values were positively related, and self enhancement and openness to change values negatively related, to helping behaviour. The correlations pattern did not differ significantly between cultures. PMID- 25043909 TI - Link between hippocampus' raised local and eased global intrinsic connectivity in AD. AB - BACKGROUND: The hippocampus (HP) is part of the default mode network (DMN), and both are key targets of Alzheimer's disease (AD). Because of widespread network degeneration, it has been suggested that increasing HP disconnection from the DMN may lead to progressive disinhibition of intra-HP synchronized activity. METHODS: To analyze HP local (i.e., within HP) and global (i.e., within DMN) intrinsic functional connectivity (local/global intrinsic functional connectivity [iFC]), healthy controls and patients with mild cognitive impairment and AD dementia were assessed by spatial high and normal resolution resting-state functional magnetic resonance imaging. RESULTS: Although patients' parietal local-iFC was reduced and positively correlated with reduced global-iFC within the DMN, HP local connectivity was progressively increased and negatively correlated with HP decreased global connectivity. Increased intra-HP connectivity was associated with impaired memory. CONCLUSION: Our result demonstrates a link between increased local and reduced global hippocampal connectivity in AD. Increased intra-HP synchrony may contribute to distinct symptoms such as memory impairment or more speculatively epileptic seizure. PMID- 25043908 TI - Insulin resistance predicts brain amyloid deposition in late middle-aged adults. AB - BACKGROUND: Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD. METHODS: Asymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal). RESULTS: In participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloid deposition. CONCLUSIONS: This is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD. PMID- 25043910 TI - Reactivated herpes simplex infection increases the risk of Alzheimer's disease. AB - BACKGROUND: Previous studies have suggested a link between herpes simplex virus (HSV) type 1 and the development of Alzheimer's disease (AD). METHODS: The present analysis included 3432 persons (53.9% women, mean age at inclusion 62.7 +/- 14.4 years) with a mean follow-up time of 11.3 years. The number of incident AD cases was 245. Serum samples were analyzed for anti-HSV antibodies (immunoglobulin (Ig)G and IgM) by enzyme-linked immunosorbent assays. RESULTS: The presence of anti-HSV IgG antibodies was not associated with an increased risk for AD, controlled for age and sex (hazard ratio, HR, 0.993, P = .979). However, the presence of anti-HSV IgM at baseline was associated with an increased risk of developing AD (HR 1.959, P = .012). CONCLUSION: Positivity for anti-HSV IgM, a sign of reactivated infection, was found to almost double the risk for AD, whereas the presence of anti-HSV IgG antibodies did not affect the risk. PMID- 25043912 TI - Rapid PCR protocols for forensic DNA typing on six thermal cycling platforms. AB - Rapid PCR protocols for the amplification of typing STR multiplexes were evaluated on six different thermal cyclers. Through the use of a faster DNA polymerase coupled with the use of rapid thermal cyclers the amplification cycling times were reduced down to as little as 14 min using PCR primers from the commercially available multiplex STR typing kit Identifiler. Previously described two-step and three-step thermal cycling protocols were evaluated for the six thermal cyclers on 95 unique single-source DNA extracts. CE characterization of the PCR products indicates good peak balance between loci (median values greater than 0.84), and N minus four stutter ratios on averages were 30 to 40% higher than for standard Identifiler PCR conditions. Nonspecific amplification artifacts were observed, but were not observed to migrate within the allele calling bins. With the exception of one locus (D18S51) in a single sample, genotyping results were concordant with manufacturer's recommended amplification conditions utilizing standard thermal cycling procedures. Assay conditions were robust enough to routinely amplify 250 to 500 pg of template DNA. This work describes the protocols for the rapid PCR amplification of STR multiplexes on various PCR thermal cyclers with the future intent to support validation for typing single source samples in a database laboratory. PMID- 25043911 TI - Protein kinase CK2 inhibition induces cell death via early impact on mitochondrial function. AB - CK2 (official acronym for casein kinase 2 or II) is a potent suppressor of apoptosis in response to diverse apoptotic stimuli-thus its molecular downregulation or activity inhibition results in potent induction of cell death. CK2 downregulation is known to impact mitochondrial apoptotic circuitry but the underlying mechanism(s) remain unclear. Utilizing prostate cancer cell lines subjected to CK2-specific inhibitors which cause loss of cell viability, we have found that CK2 inhibition in cells causes rapid early decrease in mitochondrial membrane potential (Deltapsim). Cells treated with the CK2 inhibitors TBB (4,5,6,7-tetrabromobenzotriazole) or TBCA (tetrabromocinnamic acid) demonstrate changes in Deltapsim which become apparent within 2 h, that is, significantly prior to evidence of activation of other mitochondrial apoptotic signals whose temporal expression ensues subsequent to loss of Deltapsim. Further, we have demonstrated the presence of CK2 in purified mitochondria and it appears that the effect on Deltapsim evoked by inhibition of CK2 may involve mitochondrial localized CK2. Results also suggest that alterations in Ca(2+) signaling may be involved in the CK2 mediated regulation of Deltapsim and mitochondrial permeability. Thus, we propose that a key mechanism of CK2 impact on mitochondrial apoptotic circuitry and cell death involves early loss of Deltapsim which may be a primary trigger for apoptotic signaling and cell death resulting from CK2 inhibition. PMID- 25043913 TI - Factors contributing to the duration of untreated psychosis. AB - BACKGROUND: Shortening the duration of untreated psychosis (DUP) - with the aim of improving the prognosis of psychotic disorders - requires an understanding of the causes of treatment delay. Current findings concerning several candidate risk factors of a longer DUP are inconsistent. Our aim was to identify factors contributing to DUP in a large sample that represents the treated prevalence of non-affective psychotic disorders. METHOD: Patients with a non-affective psychotic disorder were recruited from mental health care institutes from 2004 to 2008. Of the 1120 patients enrolled, 852 could be included in the present analysis. Examined candidate factors were gender, educational level, migration status, premorbid adjustment and age at onset of the psychotic disorder. DUP was divided into five ordinal categories: less than one month, one month to three months, three months to six months, six months to twelve months and twelve months and over. An ordinal logistic regression analysis was used to identify the risk factors of a longer DUP. RESULTS: Median DUP was less than one month (IQR 2). The factors migration status (p=0.028), age at onset of the psychotic disorder (p=0.003) and gender (p=0.034) were significantly associated with DUP in our analysis. CONCLUSION: First generation immigrant patients, patients with an early onset of their psychotic disorder and male patients seem at risk of a longer DUP. These findings can assist in designing specific interventions to shorten treatment delay. PMID- 25043914 TI - Methylated phenanthrenes are more potent than phenanthrene in a bioassay of human aryl hydrocarbon receptor (AhR) signaling. AB - Alkylated polycyclic aromatic hydrocarbons (APAHs) are abundant in petroleum, but data regarding their toxicological properties are limited. A survey of all monomethylated phenanthrene structures revealed that they were 2 times to 5 times more potent than phenanthrene for activation of human aryl hydrocarbon receptor in a yeast bioassay. Phenanthrenes with equatorial methyl groups had the greatest potency. The greater potency of the methylated phenanthrenes highlights the need for more toxicological data on APAHs. PMID- 25043915 TI - Beyond PEG2000: synthesis and functionalisation of monodisperse PEGylated homostars and clickable bivalent polyethyleneglycols. AB - A new strategy to access highly monodisperse, heterobifunctional linear polyethylenglycols (PEGs) has been designed. This was built around unidirectional, iterative chain extension of a 3-arm PEG homostar. A mono-(4,4' dimethoxytriphenylmethyl) octagol building block, DmtrO-EG8-OH, was constructed from tetragol. After six rounds of chain extension, the monodisperse homostar reached the unprecedented length of 56 monomers per arm (PEG2500). The unique architecture of the synthetic platform greatly assisted in facilitating and monitoring reaction completion, overcoming kinetic limitations, chromatographic purification of intermediates, and analytical assays. After chain terminal derivatisation, mild hydrogenolytic cleavage of the homostar hub provided heterobifunctional linear EG56 chains with a hydroxyl at one end, and either a toluene sulfonate, or a tert-butyl carboxylate ester at the other. A range of heterobifunctional, monodisperse PEGs was then prepared having useful cross linking functionalities (-OH, -COOH, -NH2, -N3) at both ends. A rapid preparation of polydisperse PEG homostars, free of multiply cross-linked chains, is also described. The above approach should be extendable to other high value oligomers and polymers. PMID- 25043916 TI - Elucidating how the saprophytic fungus Aspergillus nidulans uses the plant polyester suberin as carbon source. AB - BACKGROUND: Lipid polymers in plant cell walls, such as cutin and suberin, build recalcitrant hydrophobic protective barriers. Their degradation is of foremost importance for both plant pathogenic and saprophytic fungi. Regardless of numerous reports on fungal degradation of emulsified fatty acids or cutin, and on fungi-plant interactions, the pathways involved in the degradation and utilisation of suberin remain largely overlooked. As a structural component of the plant cell wall, suberin isolation, in general, uses harsh depolymerisation methods that destroy its macromolecular structure. We recently overcame this limitation isolating suberin macromolecules in a near-native state. RESULTS: Suberin macromolecules were used here to analyse the pathways involved in suberin degradation and utilisation by Aspergillus nidulans. Whole-genome profiling data revealed the complex degrading enzymatic machinery used by this saprophytic fungus. Initial suberin modification involved ester hydrolysis and omega-hydroxy fatty acid oxidation that released long chain fatty acids. These fatty acids were processed through peroxisomal beta-oxidation, leading to up-regulation of genes encoding the major enzymes of these pathways (e.g. faaB and aoxA). The obtained transcriptome data was further complemented by secretome, microscopic and spectroscopic analyses. CONCLUSIONS: Data support that during fungal growth on suberin, cutinase 1 and some lipases (e.g. AN8046) acted as the major suberin degrading enzymes (regulated by FarA and possibly by some unknown regulatory elements). Suberin also induced the onset of sexual development and the boost of secondary metabolism. PMID- 25043917 TI - Synthetic conantokin peptides potently inhibit N-methyl-D-aspartate receptor mediated currents of retinal ganglion cells. AB - Retinal ganglion cells (RGCs), which are the sole output neurons of the retina, express N-methyl-D-aspartate receptors (NMDARs), rendering these cells susceptible to glutamate excitotoxicity, with implications for loss of normal RGC excitatory responses in disorders such as glaucoma and diabetic retinopathy. Therefore, antagonists that inhibit NMDAR-mediated currents specifically by targeting the GluN2B component of the ion channel have the potential to serve as a basis for developing potential therapeutics. The roles of peptidic conantokins, which are potent brain neuronal NMDAR inhibitors, were studied. By using patch clamp whole-cell analyses in dissociated RGCs and retinal whole-mount RGCs, we evaluated the effects of synthetic conantokin-G (conG) and conantokin-T (conT), which are small gamma-carboxyglutamate-containing peptides, on NMDA-mediated excitatory responses in mouse RGCs. Both conG and conT inhibited the NMDA mediated currents of dark-adapted dissociated and whole-mount RGCs in a dose dependent, reversible, noncompetitive manner. Inhibition of NMDA-mediated steady state currents by NMDAR nonsubunit-selective conT was approximately threefold greater than GluN2B-selective conG or ifenprodil, demonstrating its potential ability to inhibit both GluN2A- and GluN2B-containing ion channels in RGCs. Because the extent of inhibition of NMDA-evoked currents by conG and the pharmacologic GluN2B-selective inhibitor ifenprodil were similar (40-45%) to that of the GluN2A-selective antagonist NVP-AAM0077, we conclude that the levels of GluN2A and GluN2B subunits are similar in RGCs. These results provide a novel basis for developing effective neuroprotective agents to aid in the prevention of undesired glutamatergic excitotoxicity in neurodegenerative diseases of the retina and demonstrate functional assembly of NMDARs in RGCs. PMID- 25043920 TI - Responding to information about children in adversity: ten years of a differential response model in Western Australia. AB - This article uses a comprehensive database about children in adversity collected over the 16-year period from 1990 to 2005 in the state of Western Australia. The focus of this interrogation is the effect of major changes in responses to information about children brought to the attention of the Western Australian statutory authority in a 10-year period during this 16 years. The initiative for these changes was termed New Directions, and its associated policy and practice changes were aimed at differentiating information expressing concerns about children and families from allegations of child maltreatment. They emphasized the provision of supportive and empowering services to families experiencing difficulties - a form of differential response to children in adversity. The article covers the period leading up to the policy and practice change and the 10 years during which these changes were implemented. It examines some effects of the new policy and comments on whether the changes resulted in missed opportunities to protect children from harm, which in turn, might have led to higher rates of re-reporting. The authors present an overall picture of the nature of the information accepted by the statutory authority and how the interpretation of that information might have affected subsequent outcomes for children. In doing so, it shows that the policy and consequential practice changes associated with a differential response mechanism had long lasting positive effects that, despite dire warnings, did not compromise the protection of the small group of children identified as requiring protective interventions. PMID- 25043919 TI - Benefit-risk assessment in a post-market setting: a case study integrating real life experience into benefit-risk methodology. AB - PURPOSE: Difficulties may be encountered when undertaking a benefit-risk assessment for an older product with well-established use but with a benefit-risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit-risk framework to assess the benefit-risk balance of warfarin for primary prevention of patients with atrial fibrillation. METHODS: We used the qualitative framework BRAT as the starting point of the benefit-risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi-criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making. RESULTS: Our benefit-risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit-risk balance is fairly robust to differences in preferences. The probability of a favourable benefit-risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data. In this case study, we identified major challenges related to the identification of relevant benefit-risk criteria and taking into account the diversity and quality of evidence available to inform the benefit-risk assessment. CONCLUSION: The main challenges in applying formal methods for medical benefit-risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large. PMID- 25043921 TI - Social support and child protection: Lessons learned and learning. AB - Social support has been a topic of research for nearly 50 years, and its applications to prevention and intervention have grown significantly, including programs advancing child protection. This article summarizes the central conclusions of the 1994 review of research on social support and the prevention of child maltreatment prepared for the U.S. Advisory Board on Child Abuse and Neglect, and surveys advances in the field since its publication. Among the lessons learned twenty years ago are (a) the diversity of the social support needs of at-risk families and their association with child endangerment, (b) the need to supplement the emotionally affirmative aspects of social support with efforts to socialize parenting practices and monitor child well-being, (c) the desirability of integrating formal and informal sources of social support for recipients, and (d) the importance of considering the complex recipient reactions to receiving support from others. The lessons we are now learning derive from research exploring the potential of online communication to enhance social support, the neurobiology of stress and its buffering through social support, and the lessons of evaluation research that are identifying the effective ingredients of social support interventions. PMID- 25043918 TI - The Warburg effect revisited--lesson from the Sertoli cell. AB - Otto Warburg observed that cancerous cells prefer fermentative instead of oxidative metabolism of glucose, although the former is in theory less efficient. Since Warburg's pioneering works, special attention has been given to this difference in cell metabolism. The Warburg effect has been implicated in cell transformation, immortalization, and proliferation during tumorigenesis. Cancer cells display enhanced glycolytic activity, which is correlated with high proliferation, and thus, glycolysis appears to be an excellent candidate to target cancer cells. Nevertheless, little attention has been given to noncancerous cells that exhibit a "Warburg-like" metabolism with slight, but perhaps crucial, alterations that may provide new directions to develop new and effective anticancer therapies. Within the testis, the somatic Sertoli cell (SC) presents several common metabolic features analogous to cancer cells, and a clear "Warburg-like" metabolism. Nevertheless, SCs actively proliferate only during a specific time period, ceasing to divide in most species after puberty, when they become terminally differentiated. The special metabolic features of SC, as well as progression from the immature but proliferative state, to the mature nonproliferative state, where a high glycolytic activity is maintained, make these cells unique and a good model to discuss new perspectives on the Warburg effect. Herein we provide new insight on how the somatic SC may be a source of new and exciting information concerning the Warburg effect and cell proliferation. PMID- 25043922 TI - Parents' behavior in response to infant crying: abusive head trauma education. AB - Abusive head trauma (AHT) is still too common, and probably underestimated. It is the leading cause of death from child abuse. Crying is thought to contribute to the act of shaking. Objectives of this study were to (a) assess parents' knowledge about infant crying, their ability to manage crying, and their knowledge about AHT; and (b) assess the feasibility and the impact of a simple educational intervention about crying and AHT with parents shortly after their child's birth. A short questionnaire was completed orally by the parents of 190 consecutive newborns in a maternity hospital at day 2 of life. Then, during the routine examination of the child, the pediatrician gave parents a short talk about infant crying and AHT, and a pamphlet. Finally, parents were contacted by phone at 6 weeks for the post-intervention questionnaire assessing their knowledge about crying and AHT. Among 202 consecutive births, parents of 190 children were included (266 parents; 70% mothers) over a 1-month period and answered the pre-intervention questionnaire. The intervention was feasible and easy to provide. Twenty-seven percent of mothers and 36% of fathers had never heard of AHT. At 6 weeks, 183 parents (68% of the sample; 80% mothers) answered the post-intervention questionnaire. Parents' knowledge improved significantly post-intervention. Parents found the intervention acceptable and useful. Health care professionals such as pediatricians or nurses could easily provide this brief talk to all parents during systematic newborn examination. PMID- 25043923 TI - Girls arrested for murder: an empirical analysis of 32 years of U.S. data by offender age groups. AB - Most studies on juvenile homicide offenders (JHOs) have used small samples and have concentrated on adolescent male offenders. As a result, little is known about the population of female juveniles arrested for murder. This study utilized the Supplementary Homicide Report (SHR) database to investigate age differences between younger (aged 6-12 years) and older (aged 13-17 years) females arrested for murder in the United States from 1976 to 2007. As predicted, six variables used to test seven hypotheses with respect to younger and older female JHOs in single victim incidents were significant (victim age, victim gender, victim offender relationship, murder weapon, offender count, and homicide circumstance). Regression analysis revealed that younger girls were seven times more likely than older girls to kill children aged 0-12 years. Girls aged 6-12 years were five times more likely than their teen counterparts to be involved in conflict-related homicides as opposed to crime-related homicides. Although approximately the same percentages of younger and older girls killed infants under the age of 1, the victims were significantly different for the two offender age groups. This article concludes with a discussion of our findings and directions for future research. PMID- 25043924 TI - Dietary patterns and cognitive decline in Taiwanese aged 65 years and older. AB - OBJECTIVE: This study examines the association between dietary patterns and cognitive decline in Taiwanese aged 65 years and older. METHODS: Data were from a population-based longitudinal study, the Taiwan Longitudinal Study of Aging, with a nationally representative sample. RESULTS: Nearly 2%, 8%, and 3% of participants had a western, traditional, and healthy dietary pattern, respectively. Western and traditional dietary patterns were negatively associated with subsequent short portable mental state questionnaire score over 4 and/or 8 years (all p < 0.05), whereas a healthy dietary pattern was not. Western dietary patterns significantly increased, by nearly threefold, the risk of subsequent cognitive decline over 8 years (adjusted odds ratio = 4.35, 95% confidence interval = 1.52-12.50, p < 0.05). For elders aged 65-74 years, a western dietary pattern was positively associated with increased, by eightfold, risk of cognitive decline over 8 years (adjusted odds ratio = 9.35, 95% confidence interval = 2.38 36.67, p < 0.05), whereas traditional and healthy dietary patterns were not. For elders aged >= 75 years, none of western, traditional, or healthy dietary patterns were associated with cognitive decline over 4 and 8 years. CONCLUSIONS: Dietary patterns correlate with cognitive function in Taiwanese aged 65 years and older and can predict the occurrence of subsequent cognitive decline. Western dietary pattern increases the risk of cognitive decline over 8 years. This study suggests that a diet that involves frequent consumption of meat/poultry and eggs and infrequent consumption of fish, beans/legumes, and vegetables and fruits may adversely affect cognitive function in older Taiwanese. PMID- 25043925 TI - Prevalence estimation subject to misclassification: the mis-substitution bias and some remedies. AB - We consider the problem of estimating the prevalence of a disease under a group testing framework. Because assays are usually imperfect, misclassification of disease status is a major challenge in prevalence estimation. To account for possible misclassification, it is usually assumed that the sensitivity and specificity of the assay are known and independent of the group size. This assumption is often questionable, and substitution of incorrect values of an assay's sensitivity and specificity can result in a large bias in the prevalence estimate, which we refer to as the mis-substitution bias. In this article, we propose simple designs and methods for prevalence estimation that do not require known values of assay sensitivity and specificity. If a gold standard test is available, it can be applied to a validation subsample to yield information on the imperfect assay's sensitivity and specificity. When a gold standard is unavailable, it is possible to estimate assay sensitivity and specificity, either as unknown constants or as specified functions of the group size, from group testing data with varying group size. We develop methods for estimating parameters and for finding or approximating optimal designs, and perform extensive simulation experiments to evaluate and compare the different designs. An example concerning human immunodeficiency virus infection is used to illustrate the validation subsample design. PMID- 25043926 TI - The neuroanatomy of prematurity: normal brain development and the impact of preterm birth. AB - Brain development is a complex process of micro- and macrostructural events that include neuronal and glial proliferation and migration, myelination, and organizational development of cortical layers and circuitry. Recent progress in understanding these processes has provided insight into the pathophysiology of brain injury and alterations of cerebral development in preterm infants. A key factor of abnormalities in the preterm infant is the maturational stage of the brain at the time of birth. This review summarizes current data on normal brain development, patterns of brain injury in the preterm infant, and the associated axonal/neuronal disturbances that occur in the setting of this injury, often termed encephalopathy of prematurity. PMID- 25043927 TI - Higher satisfaction with ethnographic edutainment using YouTube among medical students in Thailand. AB - PURPOSE: At present, transformative learning is one of the most important issues in medical education, since a conventional learning environment is prone to failure due to changing patterns among students. Ethnographic edutainment is a concept that consists of reward, competition, and motivation strategies that be used to effectively engage with learners. METHODS: A total 321 first-year medical students took part in ethnographic edutainment sessions in 2011. We defined four preset learning objectives and assigned a term group project using clouding technologies. Participatory evaluation was conducted to assess the delivery of and attitudes towards this method. RESULTS: Career lifestyles in the general population and expected real-life utilization of the final product were used as motivating factors, with competition and rewards provided through a short film contest. Nineteen out of twenty groups (95%) achieved all learning objectives. Females were more satisfied with this activity than males (P<0.001). We found statistically significant differences between lecture-based sessions and field visit sessions, as well as ethnographic edutainment activity sessions and other instructional approaches (P<0.01). The results were consistent in male and female groups. CONCLUSION: Ethnographic edutainment is well accepted, with higher satisfaction rates than other types of teaching. The concepts of health promotion and the social determinants of health can be learned through ethnographic edutainment activities, which might help train more humanized health professionals. PMID- 25043928 TI - Changes in flow experience among occupational therapy students: a 1-year longitudinal study. AB - PURPOSE: The purpose of this 1-year longitudinal study is to investigate the change in flow experience among occupational therapy students (OTS). METHODS: In December 2012, we prospectively recruited 97 OTS from the Department of Occupational Therapy, Kibi International University. To assess flow experience in daily life, we used the Flow Experience Checklist. RESULTS: The dataset included 87 OTS, of which 75 participated in the assessment at 1 year (follow-up rate, 86.2%). The mean age at baseline of 45 male and 30 female OTS was 19.59+/-1.1 years (range, 18 to 24 years). A comparison of the 'frequency of flow experience' showed significant differences between baseline values and those after 1 year (December 2013) among male OTS (P<0.05). CONCLUSION: The present results indicate that, for male OTS, the frequency of flow was significantly reduced after 1 year compared with baseline values. This finding suggests the need for further education to increase the frequency of flow among male OTS. PMID- 25043929 TI - Characterization of Phytophthora nicotianae isolates in southeast Spain and their detection and quantification through a real-time TaqMan PCR. AB - BACKGROUND: The soil-borne pathogens Phytophthora nicotianae and P. capsici are the causal agents of root and stem rot of many plant species. Although P. capsici was considered the causal agent in one of the main pepper production areas of Spain to date, evidence of the presence of P. nicotianae was found. We aimed to survey the presence of P. nicotianae and study the variability in its populations in this area in order to improve the management of Tristeza disease. RESULTS: A new specific primer and a TaqMan probe were designed based on the internal transcribed spacer regions of ribosomal DNA to detect and quantify P. nicotianae. Both morphological and molecular analysis showed its presence and confirmed it to be the causal agent of the Phytophthora disease symptoms in the studied area. The genetic characterization among P. nicotianae populations showed a low variability of genetic diversity among the isolates. Only isolates of the A2 mating type were detected. CONCLUSIONS: Not only is a specific and early detection of P. nicotianae essential but also the study of genetic variability among isolates for the appropriate management of the disease, above all, in producing areas with favorable conditions for the advance of the disease. PMID- 25043930 TI - Rituximab-cyclophosphamide-dexamethasone is highly effective in patients with monoclonal Ig deposit-related glomerulopathy and indolent non-Hodgkin lymphomas. AB - Indolent non-hodgkin lymphomas (iNHL) are a rare cause of monoclonal immunoglobulin deposits-related glomerulopathy (mIgGN). In patients with iNHL related mIgGN, whether treatment should include either single or a combination of drug(s) to target the malignant clone and renal inflammation remains elusive. In this retrospective study, we report a cohort of 14 patients with iNHL-related mIgGN (cryoglobulinemic glomerulonephritis [n = 5], membranous nephropathy [n = 3], membranoproliferative glomerulonephritis [n = 3], AL or AL/AH amyloidosis [n = 2], and Light Chain Deposits Disease [n = 1]) and who received a treatment combining rituximab, cyclophosphamide, and dexamethasone (RCD). After a mean follow-up of 18 +/- 4 months, nine patients (63%) had complete haematological response. Renal response was observed in 12 of the 14 patients (86%; complete response: n = 9; partial: n = 3). Estimated glomerular filtration rate increased from 47 +/- 7 to 63 +/- 8 mL/min/1.73 m(2) , and proteinuria decreased from 6.5 +/- 0.7 to 1.4 +/- 0.8 g/24 hr at one year. Following hematological relapse, renal relapse occurred in two patients suggesting sustained clonal eradication offers the best renal protection. Tolerance of RCD was good and the most frequent adverse event was pneumonia (3/14, 21%). RCD is a promising regimen for patients with iNHL and mIgGN, irrespective of glomerular pathologic pattern. Whether steroids can be avoided or minimized remains to be addressed. PMID- 25043931 TI - Real-time medication adherence monitoring intervention: test of concept in people living with HIV infection. PMID- 25043932 TI - Giving voice to cancer patients: assessing non-specific effects of an integrative oncology therapeutic program via short patient narratives. AB - OBJECTIVE: The aim of this study was to assess patient perspectives regarding non specific effects of a complementary medicine (CM) consultation and intervention within an integrative oncology setting. METHODS: Patients undergoing chemotherapy in a community-based oncology service were referred by oncology healthcare providers to an integrative oncology physician trained in CM-oriented supportive care. Assessment of concerns and well-being was made using the Measure Yourself Concerns and Wellbeing questionnaire, at baseline and after 3 months of CM treatments, which were designed to improve quality of life (QoL) outcomes. Patients were asked to describe the most important aspects of the integrative treatment process. Free-text narratives were examined using content analysis with ATLAS.Ti software for systematic coding. RESULTS: Of 152 patients' narratives analyzed, 44% reported an experience of patient-centered care, including CM practitioners' approach of togetherness, uniqueness, and the invoking of an internal process. CM practitioner approach was experienced within a context of an enhanced sense of confidence; gaining a different perspective; and acquiring emotional resilience and empowerment. CONCLUSIONS: Short patient narratives should be considered for patient-reported outcomes, expressing perspectives of both effects and experience of care. CM may promote patient QoL-related outcomes through non-specific effects, enhancing patient-centered care. The benefits of CM dependent on general therapeutic incidental aspects (i.e., common factors) warrant attention regarding non-specific components of treatment. PMID- 25043934 TI - Polymyxin B hemoperfusion: a mechanistic perspective. AB - Direct hemoperfusion therapy with polymyxin B immobilized fiber cartridge (PMX DHP) is an established strategy in the treatment of septic shock in Japan and parts of Western Europe. PMX-DHP is currently the subject of a pivotal North American randomized controlled trial (EUPHRATES) in patients with septic shock and confirmed endotoxemia, as measured by the endotoxin activity assay. The major mechanism of action of this therapy is the removal of circulating endotoxin. High affinity binding of circulating endotoxin by the PMX-DHP column may decrease circulating endotoxin levels by up to 90% after two standard treatments. Basic research has shown reductions in circulating cytokine levels and in renal tubular apoptosis. Clinical research has shown that PMX-DHP therapy results in hemodynamic improvements, improvements in oxygenation, renal function, and reductions in mortality. Further research is needed to further define additional patient populations with endotoxemia that may benefit from PMX-DHP therapy as well as to further elucidate dosing, timing, and additional information on mechanisms of action. This review will present the mechanistic rationale for this targeted strategy of endotoxin removal using PMX-DHP in endotoxemic septic patients, highlighting both the specific effects of the therapy and the evidence accumulated so far of clinical improvement following this therapy in terms of recovery of organ function. PMID- 25043935 TI - ALPPS and similar resection procedures in treating extensive hepatic metastases: our own experiences and critical discussion. AB - BACKGROUND: The combination of right sided portal vein ligation and hepatic parenchymal transection thus inducing a hypertrophy of the left or left lateral sector is an innovative treatment option in treating locally advanced hepatic tumors or hepatic metastases. The available published data regarding this procedure is weak. We analyzed our own data regarding tumor recurrence and complications. The data was then used to be critically analyzed using the available published literature. METHODS: We treated n = 5 patients with an ALPPS (associating liver partition and portal vein ligation for staged hepatectomy). The follow-up was 3 years. We analyzed the perioperative period, complications, mortality and oncological survival rate. RESULTS: In all patients (n = 5) a R0 resection was achieved. N = 1 patient died postoperatively. N = 1 patient died 6 month later due to a pulmonary embolism. N = 3 patients had a tumor recurrence within 6 months. CONCLUSION: Selected patients can be successfully treated by ALPPS in terms of an R0-resection. However, risk of tumor recurrence and rate of complications are high. PMID- 25043933 TI - Characterization of axons expressing the artemin receptor in the female rat urinary bladder: a comparison with other major neuronal populations. AB - Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family that has been strongly implicated in development and regeneration of autonomic nerves and modulation of nociception. Whereas other members of this family (GDNF and neurturin) primarily target parasympathetic and nonpeptidergic sensory neurons, the artemin receptor (GFRalpha3) is expressed by sympathetic and peptidergic sensory neurons that are also the primary sites of action of nerve growth factor, a powerful modulator of bladder nerves. Many bladder sensory neurons express GFRalpha3 but it is not known if they represent a specific functional subclass. Therefore, our initial aim was to map the distribution of GFRalpha3-immunoreactive (-IR) axons in the female rat bladder, using cryostat sections and whole wall thickness preparations. We found that GFRalpha3-IR axons innervated the detrusor, vasculature, and urothelium, but only part of this innervation was sensory. Many noradrenergic sympathetic axons innervating the vasculature were GFRalpha3-IR, but the noradrenergic innervation of the detrusor was GFRalpha3-negative. We also identified a prominent source of nonneuronal GFRalpha3-IR that is likely to be glial. Further characterization of bladder nerves revealed specific structural features of chemically distinct classes of axon terminals, and a major autonomic source of axons labeled with neurofilament 200, which is commonly used to identify myelinated sensory axons within organs. Intramural neurons were also characterized and quantified. Together, these studies reveal a diverse range of potential targets by which artemin could influence bladder function, nerve regeneration, and pain, and provide a strong microanatomical framework for understanding bladder physiology and pathophysiology. PMID- 25043936 TI - Adipose-derived stem cells versus bone marrow-derived stem cells for vocal fold regeneration. AB - OBJECTIVES/HYPOTHESIS: Vocal fold scarring presents therapeutic challenges. Recently, cell therapy with mesenchymal stromal cells has become a promising approach. The aim of this study was to compare the therapeutic potential of adipose-derived stem cells (ASC) with bone marrow-derived stem cells (BMSC) for vocal fold regeneration. STUDY DESIGN: Prospective animal experiments with controls. METHODS: The vocal folds of Sprague-Dawley rats were unilaterally injured. Two months after injury, rats were treated with a local injection of ASC (ASC group), BMSC (BMSC group), or saline (sham-treated group). The GFP-labeled ASC and BMSC were extracted from CAG-EGFP rats. Larynges were harvested for histological and immunohistochemical examinations 1 and 3 months posttransplantation and for quantitative real-time polymerase chain reaction (PCR) 1 month posttransplantation. RESULTS: After 1 month, no surviving cells from the transplant were detected. Histological examination showed significantly increased hyaluronic acid (HA) and decreased dense collagen deposition in both ASC and BMSC groups compared to shams 1 and 3 months after treatment. Real-time PCR revealed that hyaluronan synthase 1 (Has1) and Has2 were upregulated in only the ASC group compared with the sham-treated group. Fibroblast growth factor 2 (basic) (Fgf2), hepatocyte growth factor (Hgf) and Has3 were upregulated in both cell transplantation groups. ASC seemed to upregulate Hgf more than did BMSC. CONCLUSIONS: The regenerative effects of ASC and BMSC transplantation were found to be similar for the restoration. It is suggested that ASC might have more potential because of better recovery of HA, a superior antifibrotic effect, and the upregulation of Hgf. LEVEL OF EVIDENCE: N/A. PMID- 25043938 TI - Use of physiologically based pharmacokinetic models coupled with pharmacodynamic models to assess the clinical relevance of current bioequivalence criteria for generic drug products containing Ibuprofen. AB - Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venturesome for different drugs. A PBPK model constructed with Simcyp Simulator((r)) using reported biopharmaceutics parameters for ibuprofen was coupled with two published PD models: one for antipyresis and one for dental pain relief. Using products with doses of 400 mg and 10 mg/kg as "reference (R)" drug products, virtual products with doses of 280 mg and 7 mg/kg, respectively, could be interpreted as representing bioinequivalent test (T) drug products, as the point estimate for the ratios T/R are well below the bioequivalence limits. Despite being bioinequivalent in terms of PK, these lower doses were shown to be therapeutically equivalent to the higher doses because of the flat dose-response relationship of ibuprofen. Sensitivity analysis of the PBPK/PD models demonstrated that gastric emptying time, dissolution rate and small intestine pH are variables that influence ibuprofen PK, but do not seem to significantly affect its PD. It was concluded that current bioequivalent guidance might be unnecessarily restrictive for ibuprofen products. PMID- 25043937 TI - Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a. AB - Human monoclonal antibodies (HMAbs) with neutralizing capabilities constitute potential immune-based treatments or prophylaxis against hepatitis C virus (HCV). However, lack of cell culture-derived HCV (HCVcc) harboring authentic envelope proteins (E1/E2) has hindered neutralization investigations across genotypes, subtypes, and isolates. We investigated the breadth of neutralization of 10 HMAbs with therapeutic potential against a panel of 16 JFH1-based HCVcc-expressing patient-derived Core-NS2 from genotypes 1a (strains H77, TN, and DH6), 1b (J4, DH1, and DH5), 2a (J6, JFH1, and T9), 2b (J8, DH8, and DH10), 2c (S83), and 3a (S52, DBN, and DH11). Virus stocks used for in vitro neutralization analysis contained authentic E1/E2, with the exception of full-length JFH1 that acquired the N417S substitution in E2. The 50% inhibition concentration (IC50) for each HMAb against the HCVcc panel was determined by dose-response neutralization assays in Huh7.5 cells with antibody concentrations ranging from 0.0012 to 100 MUg/mL. Interestingly, IC50 values against the different HCVcc's exhibited large variations among the HMAbs, and only three HMAbs (HC-1AM, HC84.24, and AR4A) neutralized all 16 HCVcc recombinants. Furthermore, the IC50 values for a given HMAb varied greatly with the HCVcc strain, which supports the use of a diverse virus panel. In cooperation analyses, HMAbs HC84.24, AR3A, and, especially HC84.26, demonstrated synergistic effects towards the majority of the HCVcc's when combined individually with AR4A. CONCLUSION: Through a neutralization analysis of 10 clinically relevant HMAbs against 16 JFH1-based Core-NS2 recombinants from genotypes 1a, 1b, 2a, 2b, 2c, and 3a, we identified at least three HMAbs with potent and broad neutralization potential. The neutralization synergism obtained when pooling the most potent HMAbs could have significant implications for developing novel strategies to treat and control HCV. PMID- 25043939 TI - Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis. AB - BACKGROUND: The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-kappaB. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking. METHODS: The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS. RESULTS: We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development. CONCLUSIONS: Altogether, these data indicate that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS. PMID- 25043940 TI - Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients. AB - MAP1S (originally named C19ORF5) is a widely distributed homolog of neuronal specific MAP1A and MAP1B, and bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. Mitochondrion associated protein LRPPRC functions as an inhibitor for autophagy initiation to protect mitochondria from autophagy degradation. MAP1S and LRPPRC interact with each other and may collaboratively regulate autophagy although the underlying mechanism is yet unknown. Previously, we have reported that LRPPRC levels serve as a prognosis marker of patients with prostate adenocarcinomas (PCA), and that patients with high LRPPRC levels survive a shorter period after surgery than those with low levels of LRPPRC. MAP1S levels are elevated in diethylnitrosamine induced hepatocelular carcinomas in wildtype mice and the exposed MAP1S-deficient mice develop more malignant hepatocellular carcinomas. We performed immunochemical analysis to evaluate the co-relationship among the levels of MAP1S, LRPPRC, P62, and gamma-H2AX. Samples were collected from wildtype and prostate-specific PTEN-deficient mice, 111 patients with PCA who had been followed up for 10 years and 38 patients with benign prostate hyperplasia enrolled in hospitals in Guangzhou, China. The levels of MAP1S were generally elevated so the MAP1S-mediated autophagy was activated in PCA developed in either PTEN-deficient mice or patients than their respective benign tumors. The MAP1S levels among patients with PCA vary dramatically, and patients with low MAP1S levels survive a shorter period than those with high MAP1S levels. Levels of MAP1S in collaboration with levels of LRPPRC can serve as markers for prognosis of prostate cancer patients. PMID- 25043941 TI - European Association of Urology (@Uroweb) recommendations on the appropriate use of social media. AB - Social media use is becoming common in medical practice. Although primarily used in this context to connect physicians, social media allows users share information, to create an online profile, to learn and keep knowledge up to date, to facilitate virtual attendance at medical conferences, and to measure impact within a field. However, shared content should be considered permanent and beyond the control of its author, and typical boundaries, such as the patient-physician interaction, become blurred, putting both parties at risk. The European Association of Urology brought together a committee of stakeholders to create guidance on the good practice and standards of use of social media. These encompass guidance about defining an online profile; managing accounts; protecting the reputations of yourself and your organization; protecting patient confidentiality; and creating honest, responsible content that reflects your standing as a physician and your membership within this profession. PMID- 25043942 TI - Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients. AB - BACKGROUND: The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. OBJECTIVE: To assess prognostic factors in patients who received bacillus Calmette-Guerin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). RESULTS AND LIMITATIONS: With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age >= 70 yr, size >= 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients >= 70 yr with tumor size >= 3 cm and 13% otherwise. CONCLUSIONS: T1G3 patients >= 70 yr with tumors >= 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. PATIENT SUMMARY: Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guerin, there is a subgroup of T1G3 patients with age >= 70 yr, tumor size >= 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment. PMID- 25043944 TI - ABIM Maintenance of Certification 2014: navigating the challenges to find opportunities for success. PMID- 25043943 TI - Expansion of the APC superfamily of secondary carriers. AB - The amino acid-polyamine-organoCation (APC) superfamily is the second largest superfamily of secondary carriers currently known. In this study, we establish homology between previously recognized APC superfamily members and proteins of seven new families. These families include the PAAP (Putative Amino Acid Permease), LIVCS (Branched Chain Amino Acid:Cation Symporter), NRAMP (Natural Resistance-Associated Macrophage Protein), CstA (Carbon starvation A protein), KUP (K+ Uptake Permease), BenE (Benzoate:H+ Virginia Symporter), and AE (Anion Exchanger). The topology of the well-characterized human Anion Exchanger 1 (AE1) conforms to a UraA-like topology of 14 TMSs (12 alpha-helical TMSs and 2 mixed coil/helical TMSs). All functionally characterized members of the APC superfamily use cation symport for substrate accumulation except for some members of the AE family which frequently use anion:anion exchange. We show how the different topologies fit into the framework of the common LeuT-like fold, defined earlier (Proteins. 2014 Feb;82(2):336-46), and determine that some of the new members contain previously undocumented topological variations. All new entries contain the two 5 or 7 TMS APC superfamily repeat units, sometimes with extra TMSs at the ends, the variations being greatest within the CstA family. New, functionally characterized members transport amino acids, peptides, and inorganic anions or cations. Except for anions, these are typical substrates of established APC superfamily members. Active site TMSs are rich in glycyl residues in variable but conserved constellations. This work expands the APC superfamily and our understanding of its topological variations. PMID- 25043945 TI - Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. AB - The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided. PMID- 25043946 TI - Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells. AB - Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here, we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking, and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/ ) CTLs completely rescued lytic granule exocytosis, and vice versa, knockdown of MID1 inhibited exocytosis of lytic granules in WT CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity. PMID- 25043947 TI - Development of a sensitive LC-MS/MS method for simultaneous quantification of eleven constituents in rat serum and its application to a pharmacokinetic study of a Chinese medicine Shengmai injection. AB - A sensitive LC-MS/MS method was developed and validated for simultaneous quantification of 11 constituents, ginsenoside Rg1, Re, Rf, Rg2, Rb1, Rd, Rc, ophiopogonin D, schisandrin, schisandrol B and schizandrin B, in rat serum using digoxin as the internal standard (IS). The serum samples were pretreated and extracted with a two-step liquid-liquid extraction. Chromatographic separation was achieved on a C18 analytical column with a proper gradient elution using 0.02% acetic acid aqueous solution and 0.02% acetic acid-acetonitrile as mobile phase at a flow rate of 0.5 mL/min. MS detection was performed using multiple reaction monitoring via an electrospray ionization source. Good linearity was observed in the validated concentration range for every analyte (r(2) >=0.9929), and the lower limits of quantitation of the analytes were in the range of 0.044 1.190 ng/mL in rat serum. Intra- and inter-day precisions were <14.2%. The accuracy expressed as recovery was within the range of 85.1-112.8%. The extraction recoveries were >75.8%.The validated method was successfully applied to a pharmacokinetic study of all analytes in rats after single intravenous administration of Shengmai injection. PMID- 25043948 TI - Cardiac repolarization abnormalities among patients with various stages of chronic kidney disease. AB - BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of life-threatening cardiovascular arrhythmias. Although these arrhythmias are usually secondary to structural heart diseases that are commonly associated with CKD, a significant proportion of cases with sudden cardiac death have no obvious structural heart disease. This study aims to explore the relationship of cardiac repolarization in patients with CKD and worsening kidney function. HYPOTHESIS: There is cardiac repolarization abnormalities among patients with chronic kidney disease. METHODS: This was a retrospective, chart-review study of admissions or clinic visits to a university hospital between 2005 and 2010 by patients with a diagnosis of CKD. Inclusion criteria selected patients who had 12-lead surface electrocardiography (ECG), renal function tests within 24 hours, and transthoracic echocardiography within 6 months. Cases with a documented etiology for the corrected Qt (Qtc) interval prolongation including structural heart disease, QT prolonging drugs, or relevant disease conditions, were excluded. RESULTS: Our sample size was 154 ECGs. Two-thirds of patients with CKD had QTc interval prolongation, and about 20% had a QTc interval >500 ms. QTc interval was significantly different and increased with each successive stage of CKD using the Bazett (P < 0.006) or Fridericia (P = 0.03) formula. QTc interval correlated significantly with serum creatinine (P = 0.01). These finding were independent of age, gender, potassium, and calcium concentrations. CONCLUSIONS: The progression of CKD resulted in a significant delay of cardiac repolarization, independent of other risk factors. This effect may potentially increase the risk of sudden cardiac death, and may also increase the susceptibility of drug-induced arrhythmia. PMID- 25043949 TI - ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features. AB - Epithelioid hemangioma (EH) is a benign neoplasm with distinctive vasoformative features, which occasionally shows increased cellularity, cytologic atypia, and/or loco-regional aggressive growth, resulting in challenging differential diagnosis from malignant vascular neoplasms. Based on two intraosseous EH index cases with worrisome histologic features, such as the presence of necrosis, RNA sequencing was applied for possible fusion gene discovery and potential subclassification of a novel atypical EH subset. A ZFP36-FOSB fusion was detected in one case, while a WWTR1-FOSB chimeric transcript in the other, both were further validated by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). These abnormalities were then screened by FISH in 44 EH from different locations with seven additional EH revealing FOSB gene rearrangements, all except one being fused to ZFP36. Interestingly, 4/6 penile EH studied showed FOSB abnormalities. Although certain atypical histologic features were observed in the FOSB-rearranged EH, including solid growth, increased cellularity, mild to moderate nuclear pleomorphism, and necrosis in 3/9 cases, no overt sarcomatous areas were discerned to objectively separate the lesions from the fusion-negative EH. No patient has developed recurrence to date, but the follow-up was relatively limited and short to draw definitive conclusions regarding behavior. Although FOSB-rearranged EH do not show significant morphologic overlap with SERPINE1-FOSB fusion-positive pseudomyogenic hemangioendothelioma, FOSB oncogenic activation is emerging as an important event in these benign and intermediate groups of vascular tumors. PMID- 25043952 TI - The role of mitogen-activated protein kinase in cadmium-induced primary rat cerebral cortical neurons apoptosis via a mitochondrial apoptotic pathway. AB - Cadmium (Cd) is an extremely toxic metal capable of severely damaging several organs, including the brain. Studies have shown that Cd induces neuronal apoptosis partially by activating the mitogen-activated protein kinase (MAPK) pathways. However, the underlying mechanism of MAPK involving the mitochondrial apoptotic pathway in neurons remains unclear. In this study, primary rat cerebral cortical neurons were exposed to Cd, which significantly decreased cell viability and the B-cell lymphoma 2/Bcl-2 associate X protein (Bcl-2/Bax) ratio and increased the percentage of apoptotic cells, release of cytochrome c, cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP), and nuclear translocation of apoptosis-inducing factor (AIF). In addition, Cd induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK. Inhibition of ERK and JNK, but not p38 MAPK, partially protected the cells from Cd-induced apoptosis. ERK and JNK inhibition also blocked alteration of the Bcl-2/Bax ratio, release of cytochrome c, cleavages of caspase-3 and PARP, and nuclear translocation of AIF. Taken together, these data suggest that the ERK and JNK-mediated mitochondrial apoptotic pathways play important roles in Cd induced neuronal apoptosis. PMID- 25043953 TI - Is chromium pharmacologically relevant? AB - Recent research, combined with reanalysis of previous results, has revealed that chromium can no longer be considered an essential trace element. Clinical studies are ambiguous at best as to whether Cr has a pharmacological effect in humans. Observed effects of Cr on rodent models of insulin resistance and diabetes are best interpreted in terms of a pharmacological role for Cr. Studies on the effects of Cr on rat models of diabetes are reviewed herein and suggest Cr increases insulin sensitivity in peripheral tissues of the rodent models. The lack of effects in human studies may stem from humans receiving a comparably smaller dose than the rodent models. However, given the different responses to Cr in the rodent models, humans could potentially have different responses to Cr. PMID- 25043951 TI - Small molecule screening in context: lipid-catalyzed amyloid formation. AB - Islet Amyloid Polypeptide (IAPP) is a 37-residue hormone cosecreted with insulin by the beta-cells of the pancreas. Amyloid fiber aggregation of IAPP has been correlated with the dysfunction and death of these cells in type II diabetics. The likely mechanisms by which IAPP gains toxic function include energy independent cell membrane penetration and induction of membrane depolarization. These processes have been correlated with solution biophysical observations of lipid bilayer catalyzed acceleration of amyloid formation. Although the relationship between amyloid formation and toxicity is poorly understood, the fact that conditions promoting one also favor the other suggests related membrane active structural states. Here, a novel high throughput screening protocol is described that capitalizes on this correlation to identify compounds that target membrane active species. Applied to a small library of 960 known bioactive compounds, we are able to report identification of 37 compounds of which 36 were not previously reported as active toward IAPP fiber formation. Several compounds tested in secondary cell viability assays also demonstrate cytoprotective effects. It is a general observation that peptide induced toxicity in several amyloid diseases (such as Alzhiemer's and Parkinson's) involves a membrane bound, preamyloid oligomeric species. Our data here suggest that a screening protocol based on lipid-catalyzed assembly will find mechanistically informative small molecule hits in this subclass of amyloid diseases. PMID- 25043950 TI - High-density lipoprotein: a novel target for antirestenosis therapy. AB - Restenosis is an integral pathological process central to the recurrent vessel narrowing after interventional procedures. Although the mechanisms for restenosis are diverse in different pathological conditions, endothelial dysfunction, inflammation, vascular smooth muscle cell (SMC) proliferation, and myofibroblasts transition have been thought to play crucial role in the development of restenosis. Indeed, there is an inverse relationship between high-density lipoprotein (HDL) levels and risk for coronary heart disease (CHD). However, relatively studies on the direct assessment of HDL effect on restenosis are limited. In addition to involvement in the cholesterol reverse transport, many vascular protective effects of HDL, including protection of endothelium, antiinflammation, antithrombus actions, inhibition of SMC proliferation, and regulation by adventitial effects may contribute to the inhibition of restenosis, though the exact relationships between HDL and restenosis remain to be elucidated. This review summarizes the vascular protective effects of HDL, emphasizing the potential role of HDL in intimal hyperplasia and vascular remodeling, which may provide novel prophylactic and therapeutic strategies for antirestenosis. PMID- 25043954 TI - Are inhaled steroids beneficial on discharge from the emergency department for acute asthma? PMID- 25043955 TI - Preferred EEG brain states at stimulus onset in a fixed interstimulus interval equiprobable auditory Go/NoGo task: a definitive study. AB - This study examined the occurrence of preferred EEG phase states at stimulus onset in an equiprobable auditory Go/NoGo task with a fixed interstimulus interval, and their effects on the resultant event-related potentials (ERPs). We used a sliding short-time FFT decomposition of the EEG at Cz for each trial to assess prestimulus EEG activity in the delta, theta, alpha and beta bands. We determined the phase of each 2 Hz narrow-band contributing to these four broad bands at 125 ms before each stimulus onset, and for the first time, avoided contamination from poststimulus EEG activity. This phase value was extrapolated 125 ms to obtain the phase at stimulus onset, combined into the broad-band phase, and used to sort trials into four phase groups for each of the four broad bands. For each band, ERPs were derived for each phase from the raw EEG activity at 19 sites. Data sets from each band were separately decomposed using temporal Principal Components Analyses with unrestricted VARIMAX rotation to extract N1-1, PN, P2, P3, SW and LP components. Each component was analysed as a function of EEG phase at stimulus onset in the context of a simple conceptualisation of orthogonal phase effects (cortical negativity vs. positivity, negative driving vs. positive driving, waxing vs. waning). The predicted non-random occurrence of phase-defined brain states was confirmed. The preferred states of negativity, negative driving, and waxing were each associated with more efficient stimulus processing, as reflected in amplitude differences of the components. The present results confirm the existence of preferred brain states and their impact on the efficiency of brain dynamics in perceptual and cognitive processing. PMID- 25043956 TI - Analysis of the Xmn1-(G) gamma polymorphism in beta-thalassemia/hemoglobin E (HbE) and homozygous HbE patients with low and high levels of HbF. PMID- 25043957 TI - Physician alert: beware of counterfeit medical devices. PMID- 25043958 TI - All-polymer bulk heterojuction solar cells with 4.8% efficiency achieved by solution processing from a co-solvent. AB - All-polymer solar cells with 4.8% power conversion efficiency are achieved via solution processing from a co-solvent. The observed short-circuit current density of 10.5 mA cm(-2) and external quantum efficiency of 61.3% are also the best reported in all-polymer solar cells so far. The results demonstrate that processing the active layer from a co-solvent is an important strategy in achieving highly efficient all-polymer solar cells. PMID- 25043959 TI - The process-dependent impacts of dimethoate on the feeding behavior of rotifer. AB - Traditional toxicological studies usually depict the dose-effect relationship at the given exposure time while ignore how toxic effects vary during and after the exposure. In the present study, feeding depression of the rotifer Brachionus calyciflorus under the impact of dimethoate was evaluated not only in the exposure time but also in the post-exposure time. Both the filtration rates (F) and the ingestion rates (I) of the rotifers varied during the exposure period under any concentration of dimethoate. A three-stepwise stress was observed when the rotifers were exposed to 0.2 and 1.0 mg L(-1) of the pesticide respectively, whereas 1.8 mg L(-1) dimethoate caused only one-step stress on the rotifers during the whole period. In addition, although the feeding behaviors of the rotifers recovered after the exposure, two feeding rates both got even more depressed at 8h in the post-exposure time. The latent inhibition after exposure was related to the exposure concentrations and the exposure time. Our works indicated that the impact of dimethoate on the feeding behavior of the rotifers was highly process-dependent that caused the stepwise stress during the exposure period and the latent stress after the exposure. PMID- 25043960 TI - Degradation of chiral neonicotinoid insecticide cycloxaprid in flooded and anoxic soil. AB - Cycloxaprid (CYC), with two stereogenic centers from oxabridged ring, is a novel potent neonicotinoid insecticide. The investigation of relevant transformation products (TPs) is critical for the risk evaluation of CYC on environment impact and further regulatory decisions. In this study, stereoselective soil metabolism of CYC enantiomers was investigated using isotope labeling techniques. Liquid scintillation counting with LC-MS/MS was used to identify and quantify the major transformation products (TPs) of CYC enantiomers in four various soils under anoxic and flooded condition. Most of CYC had been transformed in four soils at 5d after treatment. Furthermore, CYC was found converted to a range of transformation products, which exhibited soil-specific dynamic changes. Cleavage of the oxabridged seven-member ring, reductive dechlorination in the chloropyridinyl and cleavage of C-N between the chloropyridinylmethyl and imidazalidine ring are the main transformation pathways of CYC. It is presumed that acidic condition may conduce to form the cleavage product of oxabridged seven-member ring. However, abiotic or biotic stereoselective persistence of TPs in all soils was not observed from the experimental data and may be attributed to the unstable oxabridged ring. PMID- 25043961 TI - Dissolution of three insensitive munitions formulations. AB - The US military fires live munitions during training. To save soldiers lives both during training and war, the military is developing insensitive munitions (IM) that minimize unintentional detonations. Some of the compounds in the IM formulation are, however, very soluble in water, raising environmental concerns about their fate and transport. We measured the dissolution of three of these IM formulations, IMX101, IMX104 and PAX21 using laboratory drip tests and studied the accompanying changes in particle structure using micro computed tomography. Our laboratory drip tests mimic conditions on training ranges, where spatially isolated particles of explosives scattered by partial detonations are dissolved by rainfall. We found that the constituents of these IM formulations dissolve sequentially and in the order predicted by their aqueous solubility. The order of magnitude differences in solubility among their constituents produce water solutions whose compositions and concentrations vary with time. For IMX101 and IMX104, that contain 3-nitro-1,2,4-triazol-5-one (NTO), the solutions also vary in pH. The good mass balances measured for the drip tests indicate that the formulations are not being photo-or bio-transformed under laboratory conditions. PMID- 25043962 TI - The future of antibiotics. AB - Antibiotic resistance continues to spread even as society is experiencing a market failure of new antibiotic research and development (R&D). Scientific, economic, and regulatory barriers all contribute to the antibiotic market failure. Scientific solutions to rekindle R&D include finding new screening strategies to identify novel antibiotic scaffolds and transforming the way we think about treating infections, such that the goal is to disarm the pathogen without killing it or modulate the host response to the organism without targeting the organism for destruction. Future economic strategies are likely to focus on 'push' incentives offered by public-private partnerships as well as increasing pricing by focusing development on areas of high unmet need. Such strategies can also help protect new antibiotics from overuse after marketing. Regulatory reform is needed to re-establish feasible and meaningful traditional antibiotic pathways, to create novel limited-use pathways that focus on highly resistant infections, and to harmonize regulatory standards across nations. We need new antibiotics with which to treat our patients. But we also need to protect those new antibiotics from misuse when they become available. If we want to break the cycle of resistance and change the current landscape, disruptive approaches that challenge long-standing dogma will be needed. PMID- 25043963 TI - Mono- and bis(pyrrolo)tetrathiafulvalene derivatives tethered to C60: synthesis, photophysical studies, and self-assembled monolayers. AB - A series of mono- (MPTTF) and bis(pyrrolo)tetrathiafulvalene (BPTTF) derivatives tethered to one or two C60 moieties was synthesized and characterized. The synthetic strategy for these dumbbell-shaped compounds was based on a 1,3-dipolar cycloaddition reaction between aldehyde-functionalized MPTTF/BPTTF derivatives, two different tailor-made amino acids, and C60. Electronic communication between the MPTTF/BPTTF units and the C60 moieties was studied by a variety of techniques including cyclic voltammetry and absorption spectroscopy. These solution-based studies indicated no observable electronic communication between the MPTTF/BPTTF units and the C60 moieties. In addition, femtosecond and nanosecond transient absorption spectroscopy revealed, rather surprisingly, that no charge transfer from the MPTTF/BPTTF units to the C60 moieties takes place on excitation of the fullerene moiety. Finally, it was shown that the MPTTF-C60 and C60-BPTTF-C60 dyad and triad molecules formed self-assembled monolayers on a Au(111) surface by anchoring to C60. PMID- 25043964 TI - An intermittent rocking platform for integrated expansion and differentiation of human pluripotent stem cells to cardiomyocytes in suspended microcarrier cultures. AB - The development of novel platforms for large scale production of human embryonic stem cells (hESC) derived cardiomyocytes (CM) becomes more crucial as the demand for CMs in preclinical trials, high throughput cardio toxicity assays and future regenerative therapeutics rises. To this end, we have designed a microcarrier (MC) suspension agitated platform that integrates pluripotent hESC expansion followed by CM differentiation in a continuous, homogenous process. Hydrodynamic shear stresses applied during the hESC expansion and CM differentiation steps drastically reduced the capability of the cells to differentiate into CMs. Applying vigorous stirring during pluripotent hESC expansion on Cytodex 1 MC in spinner cultures resulted in low CM yields in the following differentiation step (cardiac troponin-T (cTnT): 22.83+/-2.56%; myosin heavy chain (MHC): 19.30+/ 5.31%). Whereas the lower shear experienced in side to side rocker (wave type) platform resulted in higher CM yields (cTNT: 47.50+/-7.35%; MHC: 42.85+/-2.64%). The efficiency of CM differentiation is also affected by the hydrodynamic shear stress applied during the first 3days of the differentiation stage. Even low shear applied continuously by side to side rocker agitation resulted in very low CM differentiation efficiency (cTnT<5%; MHC<2%). Simply by applying intermittent agitation during these 3days followed by continuous agitation for the subsequent 9days, CM differentiation efficiency can be substantially increased (cTNT: 65.73+/-10.73%; MHC: 59.73+/-9.17%). These yields are 38.3% and 39.3% higher (for cTnT and MHC respectively) than static culture control. During the hESC expansion phase, cells grew on continuously agitated rocker platform as pluripotent cell/MC aggregates (166+/-88*10(5)MUm(2)) achieving a cell concentration of 3.74+/ 0.55*10(6)cells/mL (18.89+/-2.82 fold expansion) in 7days. These aggregates were further differentiated into CMs using a WNT modulation differentiation protocol for the subsequent 12days on a rocking platform with an intermittent agitation regime during the first 3days. Collectively, the integrated MC rocker platform produced 190.5+/-58.8*10(6) CMs per run (31.75+/-9.74 CM/hESC seeded). The robustness of the system was demonstrated by using 2 cells lines, hESC (HES-3) and human induced pluripotent stem cell (hiPSC) IMR-90. The CM/MC aggregates formed extensive sarcomeres that exhibited cross-striations confirming cardiac ontogeny. Functionality of the CMs was demonstrated by monitoring the effect of inotropic drug, Isoproterenol on beating frequency. In conclusion, we have developed a simple robust and scalable platform that integrates both hESC expansion and CM differentiation in one unit process which is capable of meeting the need for large amounts of CMs. PMID- 25043965 TI - Review on liver inflammation and antiinflammatory activity of Andrographis paniculata for hepatoprotection. AB - Till to date, the advancement of medical science and technology is still unable to provide inclusive treatment to liver inflammation caused by neither microbial invasion nor antibiotics nor environmental toxins. Therefore, this article provides the basic knowledge of liver inflammation up to the cellular level and its current medical treatment for inflammatory symptom suppression. Because of the adverse effects of drug treatment, people start looking for comprehensive alternative nowadays. Herbal medicine is believed to be the best of choice because it is being practiced until now for centuries. Although numerous herbal plants have been reported for their efficacies in liver protection, Andrographis paniculata is the most widely used herb for hepatoprotection, particularly in Ayurveda and traditional Chinese medicine. This review covers the significant observation on the biochemical responses due to the experimental induction of liver damage in vitro and in vivo using the marker compound of the herb, namely andrographolide and its derivatives. The standardized extract of A. paniculata with the right phytochemical composition of diterpenic labdanes is likely to have tremendous potential for the development of hepatoprotective medicine. This standardized herbal medicine may not provide immediate remedy, but it can be considered as a comprehensive therapy for liver inflammation. PMID- 25043966 TI - An examination of the association between chronic sleep restriction and electrocortical arousal in college students. AB - OBJECTIVE: The deleterious neurocognitive effects of laboratory-controlled short term sleep deprivation are well-known. The present study investigated neurocognitive changes arising from chronic sleep restriction outside the laboratory. METHODS: Sleep patterns of 24 undergraduates were tracked via actigraphy across a 15-week semester. At the semester beginning, at a midpoint, and a week before finals, students performed the Psychomotor Vigilance Test (PVT) and cortical arousal was measured via event-related potentials (ERP) and resting state electroencephalography (EEG). RESULTS: Average daily sleep decreased between Session 1 and Sessions 2 and 3. Calculated circadian rhythm measures indicated nighttime movement increased and sleep quality decreased from Sessions 1 and 2 to Session 3. Parallel to the sleep/activity measures, PVT reaction time increased between Session 1 and Sessions 2 and 3 and resting state alpha EEG reactivity magnitude and PVT-evoked P3 ERP amplitude decreased between Session 1 and Sessions 2 and 3. Cross-sectional regressions showed PVT reaction time was negatively associated with average daily sleep, alpha reactivity, and P3 changes; sleep/circadian measures were associated with alpha reactivity and/or P3 changes. CONCLUSIONS: Small, but persistent sleep deficits reduced cortical arousal and impaired vigilant attention. SIGNIFICANCE: Chronic sleep restriction impacts neurocognition in a manner similar to laboratory controlled sleep deprivation. PMID- 25043968 TI - Carboxylate switch between hydro- and carbopalladation pathways in regiodivergent dimerization of alkynes. AB - Experimental and theoretical investigation of the regiodivergent palladium catalyzed dimerization of terminal alkynes is presented. Employment of N heterocyclic carbene-based palladium catalyst in the presence of phosphine ligand allows for highly regio- and stereoselective head-to-head dimerization reaction. Alternatively, addition of carboxylate anion to the reaction mixture triggers selective head-to-tail coupling. Computational studies suggest that reaction proceeds via the hydropalladation pathway favoring head-to-head dimerization under neutral reaction conditions. The origin of the regioselectivity switch can be explained by the dual role of carboxylate anion. Thus, the removal of hydrogen atom by the carboxylate directs reaction from the hydropalladation to the carbopalladation pathway. Additionally, in the presence of the carboxylate anion intermediate, palladium complexes involved in the head-to-tail dimerization display higher stability compared to their analogues for the head-to-head reaction. PMID- 25043967 TI - The role of local ancestry adjustment in association studies using admixed populations. AB - Association analysis using admixed populations imposes challenges and opportunities for disease mapping. By developing some explicit results for the variance of an allele of interest conditional on either local or global ancestry and by simulation of recently admixed genomes we evaluate power and false positive rates under a variety of scenarios concerning linkage disequilibrium (LD) and the presence of unmeasured variants. Pairwise LD patterns were compared between admixed and nonadmixed populations using the HapMap phase 3 data. Based on the above, we showed that as follows: For causal variants with similar effect size in all populations, power is generally higher in a study using admixed population than using nonadmixed population, especially for highly differentiated SNPs. This gain of power is achieved with adjustment of global ancestry, which completely removes any cross-chromosome inflation of type I error rates, and addresses much of the intrachromosome inflation. If reliably estimated, adjusting for local ancestry precisely recovers the localization that could have been achieved in a stratified analysis of source populations. Improved localization is most evident for highly differentiated SNPs; however, the advantage of higher power is lost on exactly the same differentiated SNPs. In the real admixed populations such as African Americans and Latinos, the expansion of LD is not as dramatic as in our simulation. While adjustment for global ancestry is required prior to announcing a novel association seen in an admixed population, local ancestry adjustment may best be regarded as a localization tool not strictly required for discovery purposes. PMID- 25043969 TI - Short-term efficacy of intravitreal triamcinolone acetonide for bevacizumab resistant diabetic macular oedema. PMID- 25043970 TI - Selectivity of a lithium-recovery process based on LiFePO4. AB - The demand for lithium will increase in the near future to 713,000 tonnes per year. Although lake brines contribute to 80% of the production, existing methods for purification of lithium from this source are expensive, slow, and inefficient. A novel electrochemical process with low energy consumption and the ability to increase the purity of a brine solution to close to 98% with a single stage galvanostatic cycle is presented. PMID- 25043971 TI - Palliative radiotherapy at the end of life: a critical review. AB - When delivered with palliative intent, radiotherapy can help to alleviate a multitude of symptoms related to advanced cancer. In general, time to symptom relief is measured in weeks to months after the completion of radiotherapy. Over the past several years, an increasing number of studies have explored rates of radiotherapy use in the final months of life and have found variable rates of radiotherapy use. The optimal rate is unclear, but would incorporate anticipated efficacy in patients whose survival allows it and minimize overuse among patients with expected short survival. Clinician prediction has been shown to overestimate the length of survival in repeated studies. Prognostic indices can provide assistance with estimations of survival length and may help to guide treatment decisions regarding palliative radiotherapy in patients with potentially short survival times. This review explores the recent studies of radiotherapy near the end of life, examines general prognostic models for patients with advanced cancer, describes specific clinical circumstances when radiotherapy may and may not be beneficial, and addresses open questions for future research to help clarify when palliative radiotherapy may be effective near the end of life. PMID- 25043972 TI - Subtyping of triple-negative breast cancer: implications for therapy. AB - Triple-negative breast cancer (TNBC) is a heterogeneous disease; gene expression analyses recently identified 6 distinct TNBC subtypes, each of which displays a unique biology. Exploring novel approaches for the treatment of these subtypes is critical, especially because the median survival for women with metastatic TNBC is less than 12 months, and virtually all women with metastatic TNBC ultimately will die of their disease despite systemic therapy. To date, not a single targeted therapy has been approved for the treatment of TNBC, and cytotoxic chemotherapy remains the standard treatment. In this review, the authors discuss recent developments in subtyping TNBC and the current and upcoming therapeutic strategies being explored in an attempt to target TNBC. PMID- 25043973 TI - MicroRNA-340 as a modulator of RAS-RAF-MAPK signaling in melanoma. AB - microRNA (miRNA)-dependent regulation of gene expression is increasingly linked to development and progression of melanoma. In this study we evaluated the functions of miR-340 in human melanoma cells. Here, we show that miR-340 inhibits the tumorigenic phenotype of melanoma cells. We also found that miR-340 regulates RAS-RAF-Mitogen Activated Protein Kinase (MAPK) signaling by modulating the expression of multiple components of this pathway. Given the importance of MAPK signaling in melanoma, these results provide further insight into the pathogenesis of melanoma. PMID- 25043974 TI - Structural and biochemical analysis of a type II free methionine-R-sulfoxide reductase from Thermoplasma acidophilum. AB - Free methionine-R-sulfoxide reductase (fRMsr) enzymes only reduce the free form of methionine-R-sulfoxide and can be grouped into two types with respect to the number of conserved Cys residues in the active sites. In this work, the crystal structures of type II fRMsr from Thermoplasma acidophilum (TafRMsr), which contains two conserved Cys, have been determined in native form and in a complex with the substrate. The overall structure of TafRMsr consists of a central beta sheet encompassed by a two-alpha-helix bundle flanking on one side and one small alpha-helix on the other side. Based on biochemical and growth complementation assays, Cys(84) is demonstrated to be the catalytic Cys. The data also show that TafRMsr functions as an antioxidant protein. Structural analyses reveal insights into substrate recognition and orientation, conformational changes in the active site during substrate binding, and the role of active site residues in substrate binding. A model for the catalytic mechanism of type II TafRMsr is suggested, in which intramolecular disulfide bond formation is not involved. In addition, the biochemical, enzymatic, and structural properties of type II TafRMsr are compared with those of type I enzymes. PMID- 25043975 TI - Agaricus meleagris pyranose dehydrogenase: influence of covalent FAD linkage on catalysis and stability. AB - Pyranose dehydrogenase (PDH) is a monomeric flavoprotein belonging to the glucose methanol-choline (GMC) family of oxidoreductases. It catalyzes the oxidation of free, non-phosphorylated sugars to the corresponding keto sugars. The enzyme harbors an FAD cofactor that is covalently attached to histidine 103 via an 8alpha-N(3) histidyl linkage. Our previous work showed that variant H103Y was still able to bind FAD (non-covalently) and perform catalysis but steady-state kinetic parameters for several substrates were negatively affected. In order to investigate the impact of the covalent FAD attachment in Agaricus meleagris PDH in more detail, pre-steady-state kinetics, reduction potential and stability of the variant H103Y in comparison to the wild-type enzyme were probed. Stopped-flow analysis revealed that the mutation slowed down the reductive half-reaction by around three orders of magnitude whereas the oxidative half-reaction was affected only to a minor degree. This was reflected by a decrease in the standard reduction potential of variant H103Y compared to the wild-type protein. The existence of an anionic semiquinone radical in the resting state of both the wild type and variant H103Y was demonstrated using electron paramagnetic resonance (EPR) spectroscopy and suggested a higher mobility of the cofactor in the variant H103Y. Unfolding studies showed significant negative effects of the disruption of the covalent bond on thermal and conformational stability. The results are discussed with respect to the role of covalently bound FAD in catalysis and stability. PMID- 25043976 TI - Bone Morphogenetic Proteins: structure, biological function and therapeutic applications. AB - Bone Morphogenetic Proteins (BMPs) are multifunctional secreted cytokines, which belong to the TGF-beta superfamily. These glycoproteins act as a disulfide-linked homo- or heterodimers, being potent regulators of bone and cartilage formation and repair, cell proliferation during embryonic development and bone homeostasis in the adult. BMPs are promising molecules for tissue engineering and bone therapy. The present review discusses this family of proteins, their structure and biological function, their therapeutic applications and drawbacks, their effects on mesenchymal stem cells differentiation, and the cell signaling pathways involved in this process. PMID- 25043977 TI - Identification of important residues of insulin-like peptide 5 and its receptor RXFP4 for ligand-receptor interactions. AB - Insulin-like peptide 5 (INSL5) is an insulin/relaxin superfamily peptide involved in the regulation of glucose homeostasis by activating its receptor RXFP4, which can also be activated by relaxin-3 in vitro. To determine the interaction mechanism of INSL5 with its receptor RXFP4, we studied their electrostatic interactions using a charge-exchange mutagenesis approach. First, we identified three negatively charged extracellular residues (Glu100, Asp104 and Glu182) in human RXFP4 that were important for receptor activation by wild-type INSL5. Second, we demonstrated that two positively charged B-chain Arg residues (B13Arg and B23Arg) in human INSL5 were involved in receptor binding and activation. Third, we proposed probable electrostatic interactions between INSL5 and RXFP4: the B-chain central B13Arg of INSL5 interacts with both Asp104 and Glu182 of RXFP4, meanwhile the B-chain C-terminal B23Arg of INSL5 interacts with both Glu100 and Asp104 of RXFP4. The present electrostatic interactions between INSL5 and RXFP4 were similar to our previously identified interactions between relaxin 3 and RXFP4, but had subtle differences that might be caused by the different B chain C-terminal conformations of relaxin-3 and INSL5 because a dipeptide exchange at the B-chain C-terminus significantly decreased the activity of INSL5 and relaxin-3 to receptor RXFP4. PMID- 25043979 TI - Deciphering the cis-regulatory landscape of SOX9 implicated in craniofacial development and isolated Pierre Robin sequence. PMID- 25043980 TI - What identity crisis? Rapidly mutating Y-STRs facilitate differentiation of males. PMID- 25043981 TI - Drastic enhancement of catalytic activity via post-oxidation of a porous MnII triazolate framework. AB - Mn(III) is a powerful active site for catalytic oxidation of alkyl aromatics, but it can be only stabilized by macrocyclic chelating ligands such porphyrinates. Herein, by using benzobistriazolate as a rigid bridging ligand, a porous Mn(II) azolate framework with a nitrogen-rich coordinated environment similar to that of metalloporphyrins was synthesized, in which the Mn(II) ions can be post-oxidized to Mn(III) to achieve drastic increase of catalytic (aerobic) oxidation performance. PMID- 25043983 TI - Triple supermicrosurgical side-to-side lymphaticolymphatic anastomoses on a lymphatic vessel end-to-end anastomosed to a vein. PMID- 25043982 TI - Survival patterns in squamous cell carcinoma of the head and neck: pain as an independent prognostic factor for survival. AB - Survival outcomes in patients with squamous cell carcinoma of the head and neck (HNSCC) vary by extent of disease, behavioral factors, and socioeconomic factors. We assessed the extent to which pretreatment pain influences survival in 2,340 newly diagnosed patients with HNSCC, adjusting for disease stage, symptoms, pain medications, comorbidities, smoking, alcohol consumption, age, sex, and race/ethnicity. Patients rated their pain at presentation to the cancer center (0 = "no pain" and 10 = "pain as bad as you can imagine"). Survival time was calculated from the date of diagnosis to the date of death of any cause or last follow-up. Five-year overall survival was calculated for all the variables assessed in the study. Severe pain (>=7) was most prevalent among those with oral cancer (20.4%; pharynx = 18.8%; larynx = 16.1%) and significantly varied by tumor stage, fatigue severity, smoking status, comorbid lung disease, and race (all P < .05) across cancer diagnoses. Overall 5-year survival varied by pain for oral (severe pain = 31% vs nonsevere pain = 52%; P < .001) and pharyngeal cancer (severe pain = 33% vs nonsevere pain = 53%; P < .001). Multivariable analyses showed that pain persisted as an independent prognostic factor for survival. Pain reported prior to treatment should be considered in understanding survival outcomes in HNSCC patients. PERSPECTIVE: Pretreatment pain was an independent predictor of survival in a large sample of HNSCC patients even after accounting for tumor node metastasis stage, fatigue, age, race/ethnicity, smoking, and alcohol intake. Therefore, symptoms at presentation and before cancer treatment are important factors to be considered in understanding survival outcomes in HNSCC patients. PMID- 25043984 TI - Fibrous dysplasia and McCune-Albright syndrome: imaging for positive and differential diagnoses, prognosis, and follow-up guidelines. AB - PURPOSE: The radiologist plays a critical role at all steps of the management of patients with fibrous dysplasia (FD) and McCune-Albright syndrome (MAS). The development of a standardized approach to the management of FD/MAS is crucial given the low incidence and multiple clinical presentations of these conditions. Our aim was to develop recommendations for bone imaging in FD/MAS management. MATERIALS AND METHODS: The establishment of National Reference Centers in France as part of a Health Ministry program for orphan diseases has triggered the development of recommendations for the clinical management of FD/MAS. We used a well-established robust methodological approach involving an extensive literature review by a multidisciplinary working group (20 healthcare professionals) and scoring by a peer-review group (20 healthcare professionals different from the 20 previous ones). There were four phases: a systematic literature review, drafting of initial recommendations, peer-review of this initial draft, and drafting of the final recommendations. RESULTS: Fifty-seven specific recommendations are provided as key points for the diagnosis, prognosis, and follow-up of patients with FD/MAS. Issues of special interest are highlighted in the discussion, and areas in which future research is needed are identified. CONCLUSION: We believe the dissemination of these recommendations within the radiology community may facilitate communication between radiologists and other healthcare providers, thereby substantially improving the management of patients with these rare but potentially disabling conditions. PMID- 25043985 TI - Pharmaco-induced vasospasm therapy for acute lower gastrointestinal bleeding: a preliminary report. AB - PURPOSE: To report a novel technique and preliminary clinical outcomes in managing lower gastrointestinal bleeding (LGIB). MATERIALS AND METHODS: Eighteen LGIB patients (11 men and 7 women, mean age: 66.2 years) were treated with artificially induced vasospasm therapy by semi-selective catheterization technique. Epinephrine bolus injection was used to initiate the vascular spasm, and followed by a small dose vasopressin infusion (3-5 units/h) for 3h. The technical success, clinical success, recurrent bleeding and major complications of this study were evaluated and reported. RESULTS: Sixteen bleeders were in the superior mesenteric artery and 2 in the inferior mesenteric artery. All patients achieved successful immediate hemostasis. Early recurrent bleeding (<30 days) was found in 4 patients with local and new-foci re-bleeding in 2 (11.1%) each. Repeated vasospasm therapy was given to 3 patients, with clinical success in 2. Technical success for the 21 bleeding episodes was 100%. Lesion-based and patient based primary and overall clinical successes were achieved in 89.4% (17/19) and 77.7% (14/18), and 94.7% (18/19) and 88.8% (16/18), respectively. None of our patients had complications of bowel ischemia or other major procedure-related complications. The one year survival of our patients was 72.2 +/- 10.6%. CONCLUSIONS: Pharmaco-induced vasospasm therapy seems to be a safe and effective method to treat LGIB from our small patient-cohort study. Further evaluation with large series study is warranted. Considering the advanced age and complex medical problems of these patients, this treatment may be considered as an alternative approach for interventional radiologists in management of LGIB. PMID- 25043986 TI - Greater trochanter pain syndrome: a descriptive MR imaging study. AB - OBJECTIVE: Greater trochanter pain syndrome (GTPS) is a diverse clinical entity caused by a variety of underlying conditions. We sought to explore the impact of (1) hip morphology, namely the center-edge angle (CEa) and femoral neck-shaft (NSa) angle, (2) hip abductor tendon degeneration, (3) the dimensions of peritrochanteric edema and (4) bursitis, on the presence of GTPS, using MR imaging. MATERIALS AND METHODS: The presence of pain was prospectively assessed blindly by the senior author. CEa and NSa were blindly measured in 174 hip MR examinations, after completion of the clinical evaluation by another evaluator. The existence and dimensions of T2 hyperintensity of the peritrochanteric soft tissues, the existence and dimensions of bursae, as well as degeneration and tearing of gluteus tendons were also recorded. RESULTS: Out of 174 examinations, 91 displayed peritrochanteric edema (group A) and 34 bursitis, all with peritrochanteric edema (group B). A number of 78 patients from both A and B groups, showed gluteus medius tendon degeneration and one tendon tear. CEa of groups A and B were 6 degrees higher than those of normals (group C, P=0.0038). The mean age of normals was 16.6 years less than in group A and 19.8 years less than in group B (P<0.0001). Bursitis was associated with pain with a negative predictive value of 97% (P=0.0003). CONCLUSION: Acetabular morphology is associated with GTPS and the absence of bursitis was proved to be clinically relevant. Peritrochanteric edema alone was not associated with local pain. PMID- 25043987 TI - Isolated syndesmotic injury in acute ankle trauma: comparison of plain film radiography with 3T MRI. AB - OBJECTIVES: To determine cut-off values and the accuracy of plain film measurements for the detection of isolated syndesmotic injury after acute ankle trauma and to investigate MRI findings of concomitant ankle injury. METHODS: Eighty-four consecutive patients with absent fracture in plain film radiographs were prospectively evaluated for isolated syndesmotic injury after acute ankle trauma. The tibiofibular clear space (TFCS), the tibiofibular overlap (TFO), and the medial clear space (MCS) were independently assessed in plain radiographs by two readers. MRI performed at 3T within 24h served as the reference standard. MRI was evaluated for syndesmotic injury, using a four-scale grading system (0=normal syndesmosis, 1a=periligamentous edema, 1b=intraligamentous edema, 2=partial rupture, 3=complete rupture), and for concomitant ankle injury. Inter-observer variability for x-ray measurements was assessed using Bland-Altman diagrams. ROC analyses were performed to determine cut-off values and sensitivity and specificity for TFCS, TFO, and MCS. RESULTS: Eleven of 84 patients (13.1%) revealed syndesmotic injury (Grade 2 or 3) according to MRI. Between patients with and without syndesmotic injury significantly different measurements were obtained for TFCS (p=0.003) and MCS (p=0.04). ROC derived cut-off values were 5.3mm for TFCS, 2.8mm for TFO, and 2.8mm for MCS. Sensitivity and specificity was 82% and 75% for TFCS, 36% and 78% for TFO, and 73% and 59% for MCS. The bias and limits of agreement were -0.04 mm and [-1.54; 1.53] for TFCS, 0.8mm and [-2.5; 2.5] for TFO, and 0.05 mm and [-1.42; 1.43] for MCS. Patients with syndesmotic injury had a 5-fold increased risk of concomitant ankle injury (p=0.07). CONCLUSIONS: The determined cut-off values aid in the evaluation of syndesmotic integrity in patients with absent fracture in plain radiographs. In case of increased distances MRI is recommended to assess severity of SI and to reveal associated ankle injuries. PMID- 25043988 TI - Systematic review of nasogastric or nasojejunal decompression after gastrectomy for gastric cancer. AB - BACKGROUND: The aim of this meta-analysis was to evaluate the necessity of nasogastric or nasojejunal decompression after gastrectomy for gastric cancer. METHODS: Medline, Embase and the Cochrane Library were searched. Only prospective randomized controlled trials (RCTs) that compared subjects with and without nasogastric or nasojejunal decompression after gastrectomy were eligible in this meta-analysis. Time to flatus, time to first oral intake, length of hospital stay, reinsertion rate, anastomotic leakage, pulmonary complications, morbidity and mortality were evaluated. RESULTS: Eight studies finally fulfilled the inclusion criteria. This meta-analysis enrolled 1141 patients, 570 randomized to routine decompression and 571 randomized to no decompression. Time to first oral intake was significantly shorter in the non-decompression group (WMD = 0.53, 95% CI: 0.28 to 0.77; p < 0.001). Additionally, subjects with nasogastric or nasojejunal decompression experienced a longer hospital stay (p = 0.001). Time to flatus, anastomotic leakage, reinsertion rates, pulmonary complications, morbidity and mortality rates were similar between the two groups. CONCLUSION: Nasogastric or nasojejunal decompression does not facilitate the recovery of bowel function or reduce the risk of postoperative complications. Therefore, routine nasogastric or nasojejunal decompression is unnecessary after gastrectomy for gastric cancer. PMID- 25043990 TI - Refinements in nasolabial fold reconstruction for facial paralysis. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to describe a methodology for creation of a nasolabial fold in patients with facial paralysis and to report patient-reported outcome measures following this procedure. STUDY DESIGN: Retrospective case series. METHODS: All patients who underwent nasolabial fold modification at our institution since July 2010 were included in our analysis. Patient demographics and characteristics of their facial paralysis were noted. Preoperative Facial Clinimetric Evaluation scores were compared with postoperative scores to quantify outcomes. Pre- and postoperative photos were then presented to an observer for ratings of overall midfacial appearance. RESULTS: Thirty-one patients were included in the review. Most of the patients were male. The average onset of paralysis was 50 years, and the average age at time of surgery was 61 years. The majority of patients had flaccid paralysis, with 10% of patients having synkinesis. Most patients presented with complaints of oral incompetence or drooling and generalized facial asymmetry. Facial Clinimetric Evaluation scores (P < .004) and overall midfacial appearance (P < .05) improved significantly following surgery. CONCLUSIONS: The nasolabial fold is an important aesthetic component of the face commonly affected in patients with facial paralysis. We demonstrate quantitative improvement in quality of life scores and aesthetic appearance following nasolabial fold refinement and describe the procedure in depth. LEVEL OF EVIDENCE: 4. PMID- 25043989 TI - Differential circadian catecholamine and cortisol responses between healthy women with and without a parental history of hypertension. AB - OBJECTIVES: Previous studies suggest that otherwise healthy individuals who have a parental history of hypertension (PH+) have an accentuated reactive rise in catecholamines and cortisol to laboratory stressors as well as elevated plasma levels when compared with those with no parental history (PH-); however, few, if any, studies have evaluated whether parental history affects the responses of these hormones to changing environmental circumstances in everyday life. The purpose of this study was to compare urinary catecholamine (epinephrine and norepinephrine) and cortisol excretion and ambulatory blood pressures (BPs) across three daily microenvironments between women with and without a parental history of hypertension. METHODS: The women in the study (PH+, N = 62, age = 35.2 +/- 9.1; PH-, N = 72, age = 33.8 +/- 10.0) worked in clerical, technical, or professional positions at a major medical center in New York City. Urinary hormone excretion rates and ambulatory BP were measured across three daily microenvironments: work (11 am to 3 p.m.), home (approximately 6 p.m. to 10 p.m.), and during sleep (approximately 10 p.m. to 6 a.m.). History group comparisons by microenvironment were made using repeated-measures ANCOVA and ANOVA analyses. RESULTS: The results show that epinephrine excretion among PH+ women was 36% higher than PH- women (P < 0.008) over the entire day and that nocturnal cortisol excretion was also greater among PH+ women (P < 0.045). PH+ women also had statistically significantly higher systolic (4 mm Hg higher; P < 0.01) and diastolic (2 mm Hg higher, P < 0.03) BP when compared with PH- women across all daily microenvironments. CONCLUSION: These findings suggest that there may be genetically linked mechanisms which elevate tonic epinephrine levels and nocturnal cortisol levels that contribute to elevating circadian BP. PMID- 25043991 TI - Prevalence and viral load of oncogenic human papillomavirus (HPV) in pterygia in multi-ethnic patients in the Malay Peninsula. AB - PURPOSE: The aim of the study was to determine the prevalence of human papillomavirus (HPV) in primary and recurrent pterygia samples collected from different ethnic groups in the equatorial Malay Peninsula. METHODS: DNA was extracted from 45 specimens of freshly obtained primary and recurrent pterygia from patients and from 11 normal conjunctival swabs from volunteers with no ocular surface lesion as control. The presence of HPV DNA was detected by nested PCR. PCR-positive samples were subjected to DNA sequencing to determine the HPV genotypes. Real-time PCR with HPV16 and HPV18 type-specific TaqMan probes was employed to determine the viral DNA copy number. RESULTS: Of 45 pterygia samples with acceptable DNA quality, 29 (64.4%) were positive for HPV DNA, whereas all the normal conjunctiva swabs were HPV negative. Type 18 was the most prevalent (41.4% of positive samples) genotype followed by type 16 (27.6%). There was one case each of the less common HPV58 and HPV59. Seven of the samples harboured mixed infections of both HPV16 and HPV18. All the four known recurrent pterygia samples were HPV-positive, whereas the sole early-stage pterygium sample in the study was HPV-negative. There was no significant association between HPV-positive status with gender or age. A high proportion of patients from the Indian ethnic group (five of six) were HPV-positive, whereas the Malay patients were found to have higher HPV positivity than the Chinese. The viral load of HPV18 samples ranged between 2 * 10(2) and 3 * 10(4) copies per MUg, whereas the viral load of HPV16 specimen was 4 * 10(1) to 10(2) copies per MUg. CONCLUSION: This report describes for the first time the quantitative measurement of HPV viral DNA for pterygium samples. The high prevalence of oncogenic HPVs in our samples suggests a possible role for HPV in the pathogenesis of pterygia. Moreover, the relatively low HPV viral load is concordant with the premalignant nature of this ocular condition. PMID- 25043992 TI - The role of hepatic and splenic macrophages in E. coli-induced memory impairments in aged rats. AB - Bi-directional communication between the peripheral and central nervous systems has been extensively demonstrated. Aged rats exhibit a prolonged proinflammatory response in the hippocampus region of the brain following a peripheral bacterial infection, and this response in turn causes robust memory declines. Here we aimed to determine whether hepatic or splenic macrophages play a role in the maintenance of this central response. Proinflammatory cytokines measured in liver and spleen four days following an Escherichia coli infection revealed a potentiated proinflammatory response in liver, and to a lesser extent in spleen, in aged relative to young rats. To determine whether this potentiated response was caused by impaired bacterial clearance in these organs, E. coli colony forming units in liver and spleen were measured 4 days after infection, and there were no difference between young and aged rats in either organ. No E. coli was detected in the hippocampus, eliminating the possibility that the aged blood brain barrier allowed E. coli to enter the brain. Depletion of hepatic and splenic macrophages with clodronate-encapsulated liposomes effectively eliminated the proinflammatory response to E. coli at four days in both organs. However, this treatment failed to reduce the proinflammatory response in the hippocampus. Moreover, depletion of peripheral macrophages from liver and spleen did not prevent E. coli-induced memory impairment. These data strongly suggest that hepatic and splenic macrophages do not play a major role in the long-lasting maintenance of the proinflammatory response in the hippocampus of aged rats following a bacterial infection, or the memory declines that this response produces. PMID- 25043993 TI - Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression. AB - Both obesity and over-consumption of palatable high fat/high sugar "cafeteria" diets in rats has been shown to induce cognitive deficits in executive function, attention and spatial memory. Adult male Sprague-Dawley rats were fed a diet that supplemented standard lab chow with a range of palatable foods eaten by people for 8 weeks, or regular lab chow. Memory was assessed using a trace fear conditioning procedure, whereby a conditioned stimulus (CS) is presented for 10s and then 30s after its termination a foot shock (US) is delivered. We assessed freezing to the CS (flashing light) in a neutral context, and freezing in the context associated with footshock. A dissociation was observed between levels of freezing in the context and to the CS associated with footshock. Cafeteria diet fed rats froze less than control chow fed rats in the context associated with footshock (P<0.01), indicating that encoding of a hippocampus-dependent context representation was impaired in these rats. Conversely, cafeteria diet fed rats froze more (P<0.05) to the CS than chow fed rats, suggesting that when hippocampal function was compromised the cue was the best predictor of footshock, as contextual information was not encoded. Dorsal hippocampal mRNA expression of inflammatory and neuroplasticity markers was analysed at the end of the experiment, 10 weeks of diet. Of these, mRNA expression of reelin, which is known to be important in long term potentiation and neuronal plasticity, was significantly reduced in cafeteria diet fed rats (P=0.003). This implicates reductions in hippocampal plasticity in the contextual fear memory deficits seen in the cafeteria diet fed rats. PMID- 25043995 TI - The philosophy of M*A*S*H. PMID- 25043994 TI - Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury. AB - The aim of this study was to investigate the renoprotective activity of chlorogenic acid (CA) in a murine model of cisplatin (CP)-induced kidney injury. Male BALB/cN mice were gavaged daily with CA at 3, 10 and 30mg/kg for two successive days, 48h after intraperitoneal injection of CP (13mg/kg). On the fifth day, serum creatinine and blood urea nitrogen (BUN) levels were significantly increased in CP-intoxicated mice, which was recovered by CA. Renal oxidative stress, evidenced by increased 4-hydroxynonenal (4-HNE) expression, was significantly reduced with CA. Simultaneously, the overexpression of heme oxygenase 1 (HO-1) and cytochrome P450 E1 (CYP2E1) was attenuated. The inhibition of inflammatory response by CA was achieved through the reduction of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) expression. Additionally, CA significantly suppressed p53, Bax active caspase-3, cyclin D1 and microtubule-associated protein 1 light chain 3 isoform B (LC3B) expression, suggesting the inhibition of both apoptosis and autophagy. The expression of multidrug resistance-associated proteins (Mrp1 and Mrp2) increased and organic cation transporter 2 (Oct2) decreased by CP, protecting the kidneys from nephrotoxicity by reducing the burden of tubular cells. CA dose-dependently restored Mrp1, Mrp2 and Oct2 expression. The recovery of kidney tissue form CP injury was accompanied by increased proliferating nuclear cell antigen (PCNA) expression. The results of this study suggest that CA attenuates CP-induced kidney injury through suppression of oxidative stress, inflammation, apoptosis and autophagy, with the improvement in kidney regeneration. PMID- 25043996 TI - The immobilization of U(vi) on iron oxyhydroxides under various physicochemical conditions. AB - The immobilization of U(vi) at the solid-water interface is an important process affecting its transportation and migration in the environment, and is predominantly controlled by the sorption behavior of U(vi). In this study, U(vi) sorption on Fe(ii) and Fe(iii) oxyhydroxides prepared by a coprecipitation method was studied under a range of physicochemical conditions, including pH, ionic strength, presence of humic acid (HA) and temperature. The results showed that the sorption of U(vi) on iron oxyhydroxides is chemical, and that the principal rate limitation is due to intraparticle diffusion. The sorption of U(vi) on iron oxyhydroxides is strongly dependent on pH, but only weakly dependent on ionic strength through the entire pH range studied. Under acidic conditions, the presence of HA increases U(vi) sorption to a large degree, but an inhibiting effect on the sorption of U(vi) can be observed under alkaline conditions, due to the formation of soluble U(vi)-HA complexes. The sorption of U(vi) on iron oxyhydroxides is an endothermic process and favors high temperatures. The surface complexation model suggests three dominant monodentate inner-sphere complexes of [triple bond, length as m-dash]Fe(s)OUO2(+) (log K = 1.65), [triple bond, length as m-dash]Fe(w)OUO2OH(0) (log K = -8.00), and [triple bond, length as m dash]Fe(w)OUO2(CO3)2(3-) (log K = 17.50), contributing to U(vi) sorption on iron oxyhydroxides over the entire observed pH range. PMID- 25043997 TI - Lymphoma of the spermatic cord: sonographic appearance. AB - Primary lymphoma of the spermatic cord is a rare disease accounting for about 1.6% of primary spermatic cord tumors. We hereby present a new case in which color Doppler ultrasound (US), contrast-enhanced US, and MRI suggested a specific diagnosis that was subsequently confirmed pathologically. Color Doppler US revealed mostly hypoechoic, slighly hypervascular tissue surrounding the normal spermatic vessels, which was markedly hypervascular at contrast-enhanced US. MRI showed diffuse infiltration by homogeneously enhancing tissue surrounding the spermatic vessels hypointense to testis on T2-weighted images, isointense on T1 weighed images, lacking fat tissue, with relatively high signal intensity on diffusion-weighted images. PMID- 25043998 TI - Effects of dietary fracture toughness and dental wear on chewing efficiency in geladas (Theropithecus gelada). AB - Chewing efficiency has been associated with fitness in mammals, yet little is known about the behavioral, ecological, and morphological factors that influence chewing efficiency in wild animals. Although research has established that dental wear and food material properties independently affect chewing efficiency, few studies have addressed the interaction among these factors. We examined chewing efficiency, measured as mean fecal particle size, as a function of seasonal shifts in diet (and corresponding changes in food fracture toughness) in a single breeding population of a grazing primate, the gelada monkey, at Guassa, Ethiopia. We also measured dental topographic traits (slope, angularity, and relief index) and relative two- and three-dimensional shearing crest lengths in a cross sectional wear series of gelada molars. Chewing efficiency decreased during the dry season, a pattern corresponding to the consumption of foods with higher fracture toughness. Older individuals experienced the most pronounced decreases in chewing efficiency between seasons, implicating dental wear as a causal factor. This pattern is consistent with our finding that dental topographic metrics and three-dimensional relative shearing crest lengths were lowest at the last stage of wear. Integrating these lines of behavioral, ecological, and morphological evidence provides some of the first empirical support for the hypothesis that food fracture toughness and dental wear together contribute to chewing efficiency. Geladas have the highest chewing efficiencies measured thus far in primates, and may be analogous to equids in their emphasis on dental design as a means of particle size reduction in the absence of highly specialized digestive physiology. PMID- 25043999 TI - Top-down approach for nanophase reconstruction in bulk heterojunction solar cells. AB - "Top-Down" nanophase reconstruction via a post-additive soaking process is first presented with various BHJ binary composites. By simply rinsing as-cast BHJ films with a solvent mixture containing a few traces of a nanophase-control reagent such as 1,8-diiodooctane, oversized fullerene-rich clusters (>100 nm in dia meter) in the BHJ film are instataneously disassembled and entirely reorganized into finely intermixed donor/acceptor nanophases (ca. 10 nm) with a 3D compositional homogeneity, without surface segregation. PMID- 25044001 TI - Thin-slice T2 MRI imaging predicts vascular pathology in hemifacial spasm: a case control study. AB - Hemifacial spasm (HFS) is a condition that may severely reduce patients' quality of life. We sought to determine the sensitivity and specificity of thin-slice T2 magnetic resonance imaging (MRI) for detecting vascular compression in HFS patients. Prospective information was collected on 28 patients with HFS who presented to our center between March 2011 and March 2012 with thin-slice T2 MR imaging. The sensitivity and specificity for differentiating patients from controls were calculated. Sensitivities were 78.6% and 92.9% for the blinded radiologists and 75% for the partially blinded neurosurgeon. Specificities were 42.9% and 28.6% for the blinded radiologists and 75% for the partially blinded neurosurgeon. Magnetic resonance imaging of the facial nerve can guide clinicians in selecting patients who are good surgical candidates. Thin-slice T2 MRI should be viewed as supportive rather than diagnostic. PMID- 25044002 TI - Anti-N-methyl-D-aspartate receptor encephalitis with multiphasic demyelination. PMID- 25044003 TI - Graphene, a material for high temperature devices--intrinsic carrier density, carrier drift velocity, and lattice energy. AB - Heat has always been a killing matter for traditional semiconductor machines. The underlining physical reason is that the intrinsic carrier density of a device made from a traditional semiconductor material increases very fast with a rising temperature. Once reaching a temperature, the density surpasses the chemical doping or gating effect, any p-n junction or transistor made from the semiconductor will fail to function. Here, we measure the intrinsic Fermi level (|EF| = 2.93 kBT) or intrinsic carrier density (nin = 3.87 * 10(6) cm(-2)K(-2). T(2)), carrier drift velocity, and G mode phonon energy of graphene devices and their temperature dependencies up to 2400 K. Our results show intrinsic carrier density of graphene is an order of magnitude less sensitive to temperature than those of Si or Ge, and reveal the great potentials of graphene as a material for high temperature devices. We also observe a linear decline of saturation drift velocity with increasing temperature, and identify the temperature coefficients of the intrinsic G mode phonon energy. Above knowledge is vital in understanding the physical phenomena of graphene under high power or high temperature. PMID- 25044004 TI - Nonuniform growth and topological defects in the shaping of elastic sheets. AB - We demonstrate that shapes with zero Gaussian curvature, except at singularities, produced by the growth-induced buckling of a thin elastic sheet are the same as those produced by the Volterra construction of topological defects in which edges of an intrinsically flat surface are identified. With this connection, we study the problem of choosing an optimal pattern of growth for a prescribed developable surface, finding a fundamental trade-off between optimal design and the accuracy of the resulting shape which can be quantified by the length along which an edge should be identified. PMID- 25044005 TI - The role of moral commitment within the Investment Model. AB - The Investment Model (Rusbult, 1980) defines general commitment as a long-term orientation towards relationship maintenance and feelings of psychological attachment, influenced by satisfaction, quality of alternatives and intrinsic/extrinsic investments. We suggest the importance of additionally assessing moral commitment, defined by an intrapersonal predisposition to remain in the relationship (Johnson, 1991). We argue moral commitment's association to perceived intrinsic investments acting as internal barriers influencing general commitment and promoting relationship maintenance. A correlational study resorting to structural equation modelling showed that moral commitment predicted intrinsic investments, which in turn predicted general commitment (Model 1). No direct paths emerged from moral commitment to satisfaction or quality of alternatives (Model 2), nor it emerged as a fourth direct predictor of general commitment (Model 3). Results are discussed under relationships maintenance and dissolution frameworks. PMID- 25044006 TI - The hypocretin/orexin system: an increasingly important role in neuropsychiatry. AB - Hypocretins, also named as orexins, are excitatory neuropeptides secreted by neurons specifically located in lateral hypothalamus and perifornical areas. Orexinergic fibers are extensively distributed in various brain regions and involved in a number of physiological functions, such as arousal, cognition, stress, appetite, and metabolism. Arousal is the most important function of orexin system as dysfunction of orexin signaling leads to narcolepsy. In addition to narcolepsy, orexin dysfunction is associated with serious neural disorders, including addiction, depression, and anxiety. However, some results linking orexin with these disorders are still contradictory, which may result from differences of detection methods or the precision of tools used in measurements; strategies targeted to orexin system (e.g., antagonists to orexin receptors, gene delivery, and cell transplantation) are promising new tools for treatment of neuropsychiatric disorders, though studies are still in a stage of preclinical or clinical research. PMID- 25044000 TI - International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy. AB - OBJECTIVES: There are no international standards for relating fetal crown-rump length (CRL) to gestational age (GA), and most existing charts have considerable methodological limitations. The INTERGROWTH-21(st) Project aimed to produce the first international standards for early fetal size and ultrasound dating of pregnancy based on CRL measurement. METHODS: Urban areas in eight geographically diverse countries that met strict eligibility criteria were selected for the prospective, population-based recruitment, between 9 + 0 and 13 + 6 weeks' gestation, of healthy well-nourished women with singleton pregnancies at low risk of fetal growth impairment. GA was calculated on the basis of a certain last menstrual period, regular menstrual cycle and lack of hormonal medication or breastfeeding in the preceding 2 months. CRL was measured using strict protocols and quality-control measures. All women were followed up throughout pregnancy until delivery and hospital discharge. Cases of neonatal and fetal death, severe pregnancy complications and congenital abnormalities were excluded from the study. RESULTS: A total of 4607 women were enrolled in the Fetal Growth Longitudinal Study, one of the three main components of the INTERGROWTH-21(st) Project, of whom 4321 had a live singleton birth in the absence of severe maternal conditions or congenital abnormalities detected by ultrasound or at birth. The CRL was measured in 56 women at < 9 + 0 weeks' gestation; these were excluded, resulting in 4265 women who contributed data to the final analysis. The mean CRL and SD increased with GA almost linearly, and their relationship to GA is given by the following two equations (in which GA is in days and CRL in mm): mean CRL = -50.6562 + (0.815118 * GA) + (0.00535302 * GA(2) ); and SD of CRL = 2.21626 + (0.0984894 * GA). GA estimation is carried out according to the two equations: GA = 40.9041 + (3.21585 * CRL(0.5) ) + (0.348956 * CRL); and SD of GA = 2.39102 + (0.0193474 * CRL). CONCLUSIONS: We have produced international prescriptive standards for early fetal linear size and ultrasound dating of pregnancy in the first trimester that can be used throughout the world. PMID- 25044007 TI - Comparing translational population-PBPK modelling of brain microdialysis with bottom-up prediction of brain-to-plasma distribution in rat and human. AB - The prediction of brain extracellular fluid (ECF) concentrations in human is a potentially valuable asset during drug development as it can provide the pharmacokinetic input for pharmacokinetic-pharmacodynamic models. This study aimed to compare two translational modelling approaches that can be applied at the preclinical stage of development in order to simulate human brain ECF concentrations. A population-PBPK model of the central nervous system was developed based on brain microdialysis data, and the model parameters were translated to their corresponding human values to simulate ECF and brain tissue concentration profiles. In parallel, the PBPK modelling software Simcyp was used to simulate human brain tissue concentrations, via the bottom-up prediction of brain tissue distribution using two different sets of mechanistic tissue composition-based equations. The population-PBPK and bottom-up approaches gave similar predictions of total brain concentrations in both rat and human, while only the population-PBPK model was capable of accurately simulating the rat ECF concentrations. The choice of PBPK model must therefore depend on the purpose of the modelling exercise, the in vitro and in vivo data available and knowledge of the mechanisms governing the membrane permeability and distribution of the drug. PMID- 25044008 TI - Anatomical status of the human musculus uvulae and its functional implications. AB - In our ongoing series of anatomical studies to determine the three-dimensional architecture of the human velar muscles, we have previously reported on the palatopharyngeus. The present study deals with the musculus uvulae (MU), in which the positional relationships of its origin to the posterior nasal spine and the palatine aponeurosis, as well as the interrelation between its anatomical status and functions, have yet to be clarified. Macroscopic and microscopic examinations were performed on 25 and 2 cadavers, respectively. In the former, bilateral MUs and their adjacent structures were exposed mainly from the nasal aspect. In the latter, the soft palates embedded in paraffin were cut into frontal and sagittal sections and alternately processed with HE and Azan stains. The left and right MUs adjacent to each other were found to run longitudinally along the midline beneath the nasal aspect of velum. It was overlaid by glandular tissue that increased in amount as it coursed distally. After originating from the oral surface of palatine aponeurosis, it ran backward to cross above the sling formed by the levator veli palatini muscles of both sides and reached the tip of uvula with its muscle fibers intermingled with glandular tissue. Past studies have proposed three functions of MU to enhance the efficiency of velopharyngeal closure: space occupier, stiffness modifier, and velar extensor. All of the above described anatomical characteristics of MU could be explained as being adapted for these functions. This implies that MU is actively responsible for maintaining the velopharyngeal closure efficiency. PMID- 25044009 TI - Lead toxicity to Lemna minor predicted using a metal speciation chemistry approach. AB - In the present study, predictive measures for Pb toxicity and Lemna minor were developed from bioassays with 7 surface waters having varied chemistries (0.5 12.5 mg/L dissolved organic carbon, pH of 5.4-8.3, and water hardness of 8-266 mg/L CaCO3 ). As expected based on water quality, 10%, 20%, and 50% inhibitory concentration (IC10, IC20, and IC50, respectively) values expressed as percent net root elongation (%NRE) varied widely (e.g., IC20s ranging from 306 nM to >6920 nM total dissolved Pb), with unbounded values limited by Pb solubility. In considering chemical speciation, %NRE variability was better explained when both Pb hydroxides and the free lead ion were defined as bioavailable (i.e., f{OH} ) and colloidal Fe(III)(OH)3 precipitates were permitted to form and sorb metals (using FeOx as the binding phase). Although cause and effect could not be established because of covariance with alkalinity (p = 0.08), water hardness correlated strongly (r(2) = 0.998, p < 0.0001) with the concentration of total Pb in true solution ([Pb]T_True solution ). Using these correlations as the basis for predictions (i.e., [Pb]T_True solution vs water hardness and %NRE vs f{OH} ), IC20 and IC50 values produced were within a factor of 2.9 times and 2.2 times those measured, respectively. The results provide much needed effect data for L. minor and highlight the importance of chemical speciation in Pb-based risk assessments for aquatic macrophytes. PMID- 25044011 TI - Evolutionary implications of localization of the signaling scaffold protein parafusin to both cilia and the nucleus. AB - Parafusin (PFUS), a 63 kDa protein first discovered in the eukaryote Paramecium and known for its role in apicomplexan exocytosis, provides a model for the common origin of cellular systems employing scaffold proteins for targeting and signaling. PFUS is closely related to eubacterial rather than archeal phosphoglucomutases (PGM) - as we proved by comparison of their 88 sequences - but has no PGM activity. Immunofluorescence microscopy analysis with a PFUS specific peptide antibody showed presence of this protein around the base region of primary cilia in a variety of mammalian cell types, including mouse embryonic (MEFs) and human foreskin fibroblasts (hFFs), human carcinoma stem cells (NT-2 cells), and human retinal pigment epithelial (RPE) cells. Further, PFUS localized to the nucleus of fibroblasts, and prominently to nucleoli of MEFs. Localization studies were confirmed by Western blot analysis, showing that the PFUS antibody specifically recognizes a single protein of ca. 63 kDa in both cytoplasmic and nuclear fractions. Finally, immunofluorescence microscopy analysis showed that PFUS localized to nuclei and cilia in Paramecium. These results support the suggestion that PFUS plays a role in signaling between nucleus and cilia, and that the cilium and the nucleus both evolved around the time of eukaryotic emergence. We hypothesize that near the beginnings of eukaryotic cell evolution, scaffold proteins such as PFUS arose as peripheral membrane protein identifiers for cytoplasmic membrane trafficking and were employed similarly during the subsequent evolution of exocytic, nuclear transport, and ciliogenic mechanisms. PMID- 25044010 TI - Hereditary xerocytosis revisited. PMID- 25044012 TI - Effect of intragastric versus small intestinal delivery of enteral nutrition on the incidence of pneumonia in critically ill patients: a complementary meta analysis. PMID- 25044013 TI - Effect of lifestyle changes and atorvastatin administration on dyslipidemia in hemodialysis patients: a prospective study. AB - INTRODUCTION: Atherogenic dyslipidemia accelerates the development of cardiovascular complications and contributes to mortality of hemodialysis (HD) patients. OBJECTIVES: The aim of the study was to evaluate the effects of lifestyle changes followed by treatment with atorvastatin in dyslipidemic HD patients. PATIENTS AND METHODS: Dyslipidemic HD patients (n = 49) were enrolled into the prospective study. Forty-two patients completed a 21-week lifestyle intervention. In 34 patients, who continued to be dyslipidemic, atorvastatin was used for 14 weeks. After 4 weeks, the initial dose of atorvastatin of 10 mg/d was increased to 20 mg/d in dyslipidemic patients. RESULTS: The most pronounced effects of lifestyle changes were shown at 14 weeks and included significant differences in high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, salusin alpha, malondialdehyde-oxidized LDL, fructosamine, and monocyte CD36 expression. Immunoglobulin G anti-oxLDL showed the highest values at 21 weeks. Seven patients (16.7%) were nondyslipidemic at 21 weeks. In patients who continued to be dyslipidemic, LDL cholesterol and triglyceride levels significantly decreased, salusin alpha levels and CD36 expression increased, and dyslipidemia resolved in 59.4% of the patients following atorvastatin treatment. CONCLUSIONS: Lifestyle changes have selective efficacy in the treatment of dyslipidemia in HD patients, while atorvastatin (up to 20 mg/d) may be effective in about 60% of nonresponders to lifestyle changes. Lipid-lowering interventions affect plasma salusin alpha and monocyte CD36 expression. PMID- 25044014 TI - Lipopolysaccharide preconditioning facilitates M2 activation of resident microglia after spinal cord injury. AB - The inflammatory response following spinal cord injury (SCI) has both harmful and beneficial effects; however, it can be modulated for therapeutic benefit. Endotoxin/lipopolysaccharide (LPS) preconditioning, a well-established method for modifying the immune reaction, has been shown to attenuate damage induced by stroke and brain trauma in rodent models. Although such effects likely are conveyed by tissue-repairing functions of the inflammatory response, the mechanisms that control the effects have not yet been elucidated. The present study preconditioned C57BL6/J mice with 0.05 mg/kg of LPS 48 hr before inducing contusion SCI to investigate the effect of LPS preconditioning on the activation of macrophages/microglia. We found that LPS preconditioning promotes the polarization of M1/M2 macrophages/microglia toward an M2 phenotype in the injured spinal cord on quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Flow cytometric analyses reveal that LPS preconditioning facilitates M2 activation in resident microglia but not in infiltrating macrophages. Augmented M2 activation was accompanied by vascularization around the injured lesion, resulting in improvement in both tissue reorganization and functional recovery. Furthermore, we found that M2 activation induced by LPS preconditioning is regulated by interleukin-10 gene expression, which was preceded by the transcriptional activation of interferon regulatory factor (IRF)-3, as demonstrated by Western blotting and an IRF-3 binding assay. Altogether, our findings demonstrate that LPS preconditioning has a therapeutic effect on SCI through the modulation of M1/M2 polarization of resident microglia. The present study suggests that controlling M1/M2 polarization through endotoxin signal transduction could become a promising therapeutic strategy for various central nervous system diseases. (c) 2014 Wiley Periodicals, Inc. PMID- 25044017 TI - Characterization of functional reprogramming during osteoclast development using quantitative proteomics and mRNA profiling. AB - In addition to forming macrophages and dendritic cells, monocytes in adult peripheral blood retain the ability to develop into osteoclasts, mature bone resorbing cells. The extensive morphological and functional transformations that occur during osteoclast differentiation require substantial reprogramming of gene and protein expression. Here we employ -omic-scale technologies to examine in detail the molecular changes at discrete developmental stages in this process (precursor cells, intermediate osteoclasts, and multinuclear osteoclasts), quantitatively comparing their transcriptomes and proteomes. The data have been deposited to the ProteomeXchange with identifier PXD000471. Our analysis identified mitochondrial changes, along with several alterations in signaling pathways, as central to the development of mature osteoclasts, while also confirming changes in pathways previously implicated in osteoclast biology. In particular, changes in the expression of proteins involved in metabolism and redirection of energy flow from basic cellular function toward bone resorption appeared to play a key role in the switch from monocytic immune system function to specialized bone-turnover function. These findings provide new insight into the differentiation program involved in the generation of functional osteoclasts. PMID- 25044019 TI - A novel immuno-competitive capture mass spectrometry strategy for protein-protein interaction profiling reveals that LATS kinases regulate HCV replication through NS5A phosphorylation. AB - Mapping protein-protein interactions is essential to fully characterize the biological function of a protein and improve our understanding of diseases. Affinity purification coupled to mass spectrometry (AP-MS) using selective antibodies against a target protein has been commonly applied to study protein complexes. However, one major limitation is a lack of specificity as a substantial part of the proposed binders is due to nonspecific interactions. Here, we describe an innovative immuno-competitive capture mass spectrometry (ICC MS) method to allow systematic investigation of protein-protein interactions. ICC MS markedly increases the specificity of classical immunoprecipitation (IP) by introducing a competition step between free and capturing antibody prior to IP. Instead of comparing only one experimental sample with a control, the methodology generates a 12-concentration antibody competition profile. Label-free quantitation followed by a robust statistical analysis of the data is then used to extract the cellular interactome of a protein of interest and to filter out background proteins. We applied this new approach to specifically map the interactome of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) in a cellular HCV replication system and uncovered eight new NS5A-interacting protein candidates along with two previously validated binding partners. Follow-up biological validation experiments revealed that large tumor suppressor homolog 1 and 2 (LATS1 and LATS2, respectively), two closely related human protein kinases, are novel host kinases responsible for NS5A phosphorylation at a highly conserved position required for optimal HCV genome replication. These results are the first illustration of the value of ICC-MS for the analysis of endogenous protein complexes to identify biologically relevant protein-protein interactions with high specificity. PMID- 25044018 TI - Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline. AB - Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wild-type mice have hippocampus dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits, we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed robust and progressive up-regulation over time. This was confirmed by immunoblotting and histochemical analysis, which indicated that the increased levels of hippocampal extracellular matrix might limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance in old age. PMID- 25044021 TI - Inhaled insulin: a breath of fresh air? A review of inhaled insulin. AB - PURPOSE: Despite many advances in diabetes care over the last century, some elements of insulin therapy remain inadequate for optimal care of the patient with diabetes. There is a need for improved pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues to mimic physiologic insulin secretion. In addition, a major barrier to successful insulin therapy has been patient resistance. Alternative routes of insulin administration, including inhaled insulin, have been under investigation for several years. This review discusses the rationale for pulmonary delivery of insulin, compares previous inhaled insulin products, reviews the literature on the safety and efficacy of a current inhaled insulin formulation under investigation, and compares this product with other prandial insulin products. METHODS: English-language studies and reviews of inhaled insulin were searched in MEDLINE, the ClinicalTrials.gov registry (through May 2014), and the US Food and Drug Administration Website. FINDINGS: Inhaled insulin has several favorable characteristics due to pulmonary anatomy/physiology and the lack of injections. Pharmacokinetic and pharmacodynamic studies have shown a time-action profile suitable for prandial insulin use. Inhaled insulin seems to be safe and effective compared with other prandial insulin products and may be preferable to subcutaneous rapid-acting insulin analogues in terms of time-action profiles and rates of hypoglycemia. Small decreases in forced expiratory volume in 1 second (FEV1) have been shown with inhaled insulin, although this finding is not progressive over time and reverses with cessation of the medication. IMPLICATIONS: Although several inhaled insulin products have been under investigation, only one (Exubera((r)) [Nektar Therapeutics, San Carlos, California/Pfizer Inc, New York, New York]) was approved by the US Food and Drug Administration, and it was pulled from the market after only a short period of time. Technosphere((r)) insulin (MannKind Corporation, Valencia, California) is currently the only inhaled insulin that remains under investigation. A review of the past and present literature on inhaled insulin is pertinent in understanding the current status of inhaled insulin and its risks and benefits. The current literature suggests that inhaled insulin could be a valuable option for prandial insulin administration, with a favorable risk to benefit ratio in some patients. PMID- 25044020 TI - Progesterone receptor membrane component 1 is a functional part of the glucagon like peptide-1 (GLP-1) receptor complex in pancreatic beta cells. AB - Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic beta cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 beta cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1 induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in beta cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS. It was then found that PGRMC1 increased GLP-1-induced cAMP accumulation. PGRMC1 activation and GIIS induced by P4-BSA could be blocked by inhibition of adenylyl cyclase/EPAC signaling or the EGF receptor-PI3K signal transduction pathway. These data reveal a dual mechanism for PGRMC1-increased GIIS mediated through cAMP and EGF receptor signaling. In conclusion, we identified several novel GLP 1R interacting proteins. PGRMC1 expressed on the cell surface of beta cells was shown to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1. PMID- 25044023 TI - Sieving properties of end group-halogenated Pluronic polymer matrix in DNA separation under nondenaturing CE analysis. AB - CE-SSCP analysis is a well-established DNA separation method that is based on variations in mobility caused by sequence-induced differences in the conformation of single-stranded DNA. The resolution of CE-SSCP analysis was improved by using a Pluronic polymer matrix, and it has been successfully applied in various genetic analyses. Because the Pluronic polymer forms a micellar cubic structure in the capillary, it provides a stable internal structure for high-resolution CE SSCP analysis. We hypothesized that formation of micellar cubic structure is influenced by the end hydroxyl group of the Pluronic polymer, which affords structural stability through hydrogen bonding. To test this hypothesis, the hydroxyl group was halogenated to eliminate the hydrogen bonding without disturbing the polarity of polymer matrix. CE-SSCP resolution of two DNA fragments with a single base difference was significantly worse in the halogenated polymer matrices due to band broadening. The viscoelastic properties of control (which has hydroxyl group), chlorinated, and brominated F108 solution upon heating were also investigated by rheological experiments, and we found that gelation was significantly associated with resolution. In this series of experiments, the effect of the hydroxyl group in Pluronic polymer matrix on separation resolution of CE-SSCP analysis was demonstrated. PMID- 25044022 TI - Structural and functional vocal fold epithelial integrity following injury. AB - OBJECTIVES/HYPOTHESIS: An intact epithelium is an important part of vocal fold defense. Damage to the epithelium can compromise vocal fold homeostasis and protection of the host tissue from viral and bacterial invasion. Elucidating the effects of damage on epithelial architectural and barrier integrity provides insight into the role of epithelium in protecting vocal folds. Using an animal model, we evaluated the time course of structural and functional epithelial restoration following injury. STUDY DESIGN: Prospective, controlled animal study. METHODS: Forty rats underwent surgery to remove vocal fold mucosa unilaterally. Larynges were harvested at five time intervals between 3 to 90 days postinjury and were prepared for histological and permeability analyses. RESULTS: Rapid restoration of structural integrity was demonstrated by return of a multilayerd epithelium, intercellular junctions, and basement membrane at 5 days postinjury. Atypical epithelial permeability was observed up to 5 weeks postinjury. CONCLUSION: Restoration of epithelial barrier integrity lags epithelial structural restoration. Consequently, epithelial regeneration cannot be equated with return of functional barrier integrity. Rather, ongoing leakiness of regenerated epithelium indicates that vocal folds remain at risk for damage, pathogen invasion, and remodeling postinjury. LEVEL OF EVIDENCE: N/A. Laryngoscope, 124:2764-2769, 2014. PMID- 25044024 TI - Role of the sensorimotor cortex in Tourette syndrome using multimodal imaging. AB - Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most patients describe uncomfortable premonitory sensations preceding the tics and a subjective experience of increased sensitivity to tactile stimuli. These reports indicate that a sensory processing disturbance is an important component of TS together with motor phenomena. Thus, we focused our investigation on the role of the sensorimotor cortex (SMC) in TS using multimodal neuroimaging techniques. We measured the gamma-aminobutyric acid (GABA)+/Creatine (Cre) ratio in the SMC using GABA (1) H magnetic resonance spectroscopy. We recorded the baseline beta activity in the SMC using magnetoencephalography and correlated GABA+/Cre ratio with baseline beta band power. Finally, we examined the resting state functional connectivity (FC) pattern of the SMC using functional magnetic resonance imaging (fMRI). GABA+/Cre ratio in the SMC did not differ between patients and controls. Correlation between the baseline beta band power and GABA+/Cre ratio was abnormal in patients. The anterior insula showed increased FC with the SMC in patients. These findings suggest that altered limbic input to the SMC and abnormal GABA-mediated beta oscillations in the SMC may underpin some of the sensorimotor processing disturbances in TS and contribute to tic generation. PMID- 25044025 TI - Overexpression of DNAJB6 promotes colorectal cancer cell invasion through an IQGAP1/ERK-dependent signaling pathway. AB - DNAJB6 is a member of the heat shock protein 40 (Hsp40) family. We here investigated the clinical correlation and biological role of DNAJB6 overexpression in colorectal cancer (CRC). The expression of DNAJB6 protein was examined in 200 cases of colorectal adenocarcinomas by immunohistochemistry (IHC) technology. Gene transfection and RNA interference were performed to determine the effect of DNAJB6 expression on the invasion of CRC cells and to explore the underlying molecular mechanisms in vitro and in vivo. Overexpression of DNAJB6 was found in 39% (78/200) of the CRC tissues, especially in tumors at pT4 as compared with at pT1-3 (P = 0.02). A Kaplan-Meier survival analysis revealed a correlation between DNAJB6 expression and overall survival (OS) times (P = 0.003). Multivariate analysis confirmed that DNAJB6 overexpression was an independent prognostic factor for CRC (P = 0.002). RNA interference-mediated silencing of the DNAJB6 gene inhibited the invasion of CRC cells in vitro were accompanied by a significant reduction in the protein levels of IQ-domain GTPase activating protein 1 (IQGAP1) and phosphorylated ERK (pERK). An in vivo assay showed that inhibition of DNAJB6 expression decreased the lung metastases of CRC cells. IHC analysis of serial sections showed that there was a positive correlation between DNAJB6 and IQGAP1 expression in primary CRC tissues (P = 0.013). The data suggest that DNAJB6 plays an important oncogenic role in CRC cell invasion by up-regulating IQGAP1 and activating the ERK signaling pathway and that DNAJB6 may be used as a prognostic marker for CRC. PMID- 25044026 TI - Resolution and isolation of enantiomers of (+/-)-isoxsuprine using thin silica gel layers impregnated with L-glutamic acid, comparison of separation of its diastereomers prepared with chiral derivatizing reagents having L-amino acids as chiral auxiliaries. AB - Thin silica gel layers impregnated with optically pure l-glutamic acid were used for direct resolution of enantiomers of (+/-)-isoxsuprine in their native form. Three chiral derivatizing reagents, based on DFDNB moiety, were synthesized having l-alanine, l-valine and S-benzyl-l-cysteine as chiral auxiliaries. These were used to prepare diastereomers under microwave irradiation and conventional heating. The diastereomers were separated by reversed-phase high-performance liquid chromatography on a C18 column with detection at 340 nm using gradient elution with mobile phase containing aqueous trifluoroacetic acid and acetonitrile in different compositions and by thin-layer chromatography (TLC) on reversed phase (RP) C18 plates. Diastereomers prepared with enantiomerically pure (+)-isoxsuprine were used as standards for the determination of the elution order of diastereomers of (+/-)-isoxsuprine. The elution order in the experimental study of RP-TLC and RP-HPLC supported the developed optimized structures of diastereomers based on density functional theory. The limit of detection was 0.1 0.09 ug/mL in TLC while it was in the range of 22-23 pg/mL in HPLC and 11-13 ng/mL in RP-TLC for each enantiomer. The conditions of derivatization and chromatographic separation were optimized. The method was validated for accuracy, precision, limit of detection and limit of quantification. PMID- 25044027 TI - Gender differences in the long-term associations between posttraumatic stress disorder and depression symptoms: findings from the Detroit Neighborhood Health Study. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) and depression are known to be highly comorbid. However, previous findings regarding the nature of this comorbidity have been inconclusive. This study prospectively examined whether PTSD and depression are distinct constructs in an epidemiologic sample, as well as assessed the directionality of the PTSD-depression association across time. METHODS: Nine hundred and forty-two Detroit residents (males: n = 387; females: n = 555) were interviewed by phone at three time points, 1 year apart. At each time point, they were assessed for PTSD (using the PCL-C), depression (PHQ-9), trauma exposure, and stressful life events. RESULTS: First, a confirmatory factor analysis showed PTSD and depression to be two distinct factors at all three waves of assessments (W1, W2, and W3). Second, chi-square analysis detected significant differences between observed and expected rates of comorbidity at each time point, with significantly more no-disorder and comorbid cases, and significantly fewer PTSD only and depression only cases, than would be expected by chance alone. Finally, a cross-lagged analysis revealed a bidirectional association between PTSD and depression symptoms across time for the entire sample, as well as for women separately, wherein PTSD symptoms at an early wave predicted later depression symptoms, and vice versa. For men, however, only the paths from PTSD symptoms to subsequent depression symptoms were significant. CONCLUSIONS: Across time, PTSD and depression are distinct, but correlated, constructs among a highly exposed epidemiologic sample. Women and men differ in both the risk of these conditions, and the nature of the long-term associations between them. PMID- 25044028 TI - Antigenic relatedness defines Toll-like receptor 2 is crafted on ligand blueprint. AB - Toll-like receptors are located particularly on mammalian immune cells to recognize pathogen-associated molecules. Toll-like receptors are categorized on the basis of ligand specificity that includes Toll-like receptor 2 with affinity for bacterial porin, the major outer membrane protein. Here we show TLR2 antibody recognizes the monomer of porin, primarily a TLR2-ligand in Western blot, thus displaying relatedness of primary structures between the receptor and its ligand. Quantitative analysis revealed relatedness of the native porin molecule with TLR2 was as high as 71%, suggesting imprint of native porin trimer is mostly copied by the receptor crossing limits of primary structures. Flow cytometric analysis of TLR2 on HEK-293 cells shows the receptor and ligand also have common molecular patterns on surface, which is distinctively separate from regions assigned for putative TLR(*)ligand interaction. Molecular mimetic and specificity of TLR will caution investigators targeting TLR-ligands to develop adjuvants and vaccines. PMID- 25044029 TI - Metacognitive aspects influence subjective well-being in parents of children with cancer. AB - OBJECTIVE: Research suggests that metacognitive beliefs may be involved in psychological distress and even in the pathogenesis of emotional disorders. The present research is a first attempt to investigate how certain metacognitive aspects operate as favorable or adverse factors influencing subjective wellbeing (SWB) in the parents of children with cancer. METHOD: Thirty parents of children being treated for cancer completed questionnaires on their metacognitive beliefs (Metacognition Questionnaire), sensitivity to autobiographical memory, and self reported measures of positive and negative affect (Positive and Negative Affect Schedule). Results in the study group were compared with those obtained from 36 control parents of children being treated for acute, not life-threatening illnesses (hospitalized control group) and from 30 control parents of healthy children (healthy control group). RESULTS: Parents in both the study group and the hospitalized control group reported less SWB than the healthy control group. Most important, metacognitive aspects explained up to 77% of the variance in SWB in parents of children with cancer, as opposed to only 23% in hospitalized control group and 33% in the healthy control group. CONCLUSION: Differentmetacognitive aspects have a crucial role-both negative and positive inSWB of parents of children with cancer. It is suggested that the psychological support for parents copingwith a child suffering from oncological disease should assess such aspects and try to address them in clinical practice. PMID- 25044031 TI - Should hepatocellular carcinoma screening with ultrasound be recommended in hepatocellular carcinoma high-incidence areas? PMID- 25044030 TI - Validity of psoriatic arthritis and capture of disease modifying antirheumatic drugs in the health improvement network. AB - PURPOSE: The aims of this study are to examine the validity of diagnostic codes for psoriatic arthritis in The Health Improvement Network (THIN) and to examine the agreement between General Practitioner (GP) report and prescription records for disease modifying antirheumatic drugs (DMARDs). METHODS: Questionnaires were sent to the GPs of 100 randomly selected patients with at least one medical record code for psoriatic arthritis. The positive predictive value (PPV) for a GP confirmed diagnosis was calculated, and alternative algorithms were examined to determine which method resulted in the highest PPV. RESULTS: The PPV for a single code for psoriatic arthritis was 85% (95%CI: 75.8-91.7%). Adding a prescription for a DMARD increased the PPV to 91% but with a substantial loss in sensitivity. Agreement between GPs and prescription data for use of an oral DMARD was 69%. CONCLUSIONS: The diagnosis codes for psoriatic arthritis used in THIN are valid. All prescriptions for DMARDs may not be accounted for in THIN. PMID- 25044032 TI - An integrated physiology model to study regional lung damage effects and the physiologic response. AB - BACKGROUND: This work expands upon a previously developed exercise dynamic physiology model (DPM) with the addition of an anatomic pulmonary system in order to quantify the impact of lung damage on oxygen transport and physical performance decrement. METHODS: A pulmonary model is derived with an anatomic structure based on morphometric measurements, accounting for heterogeneous ventilation and perfusion observed experimentally. The model is incorporated into an existing exercise physiology model; the combined system is validated using human exercise data. Pulmonary damage from blast, blunt trauma, and chemical injury is quantified in the model based on lung fluid infiltration (edema) which reduces oxygen delivery to the blood. The pulmonary damage component is derived and calibrated based on published animal experiments; scaling laws are used to predict the human response to lung injury in terms of physical performance decrement. RESULTS: The augmented dynamic physiology model (DPM) accurately predicted the human response to hypoxia, altitude, and exercise observed experimentally. The pulmonary damage parameters (shunt and diffusing capacity reduction) were fit to experimental animal data obtained in blast, blunt trauma, and chemical damage studies which link lung damage to lung weight change; the model is able to predict the reduced oxygen delivery in damage conditions. The model accurately estimates physical performance reduction with pulmonary damage. CONCLUSIONS: We have developed a physiologically-based mathematical model to predict performance decrement endpoints in the presence of thoracic damage; simulations can be extended to estimate human performance and escape in extreme situations. PMID- 25044033 TI - Redesigning the type II' beta-turn in green fluorescent protein to type I': implications for folding kinetics and stability. AB - Both Type I' and Type II' beta-turns have the same sense of the beta-turn twist that is compatible with the beta-sheet twist. They occur predominantly in two residue beta-hairpins, but the occurrence of Type I' beta-turns is two times higher than Type II' beta-turns. This suggests that Type I' beta-turns may be more stable than Type II' beta-turns, and Type I' beta-turn sequence and structure can be more favorable for protein folding than Type II' beta-turns. Here, we redesigned the native Type II' beta-turn in GFP to Type I' beta-turn, and investigated its effect on protein folding and stability. The Type I' beta turns were designed based on the statistical analysis of residues in natural Type I' beta-turns. The substitution of the native "GD" sequence of i+1 and i+2 residues with Type I' preferred "(N/D)G" sequence motif increased the folding rate by 50% and slightly improved the thermodynamic stability. Despite the enhancement of in vitro refolding kinetics and stability of the redesigned mutants, they showed poor soluble expression level compared to wild type. To overcome this problem, i and i + 3 residues of the designed Type I' beta-turn were further engineered. The mutation of Thr to Lys at i + 3 could restore the in vivo soluble expression of the Type I' mutant. This study indicates that Type II' beta-turns in natural beta-hairpins can be further optimized by converting the sequence to Type I'. PMID- 25044034 TI - DNA methylation pattern of gene promoters of major neurotransmitter systems in older patients with schizophrenia with severe and mild cognitive impairment. AB - OBJECTIVE: To analyze, in older patients with schizophrenia, the methylation status of a set of genes associated with the pathophysiology of the disorder but including anatomical, clinical, and cognitive criteria in the experimental design that, in conjunction with the epigenetic status of specific genes, allows us to derive an integrative model. METHOD: This study included 29 human brain samples from older schizophrenic patients with severe and mild cognitive impairment. We administered a comprehensive battery of neurocognitive tests to determine the size of the impairment across different cognitive domains. We focused our study on the analysis of the methylation pattern of 19 genes of major neurotransmitter systems using methylation-specific PCR and bisulfite genomic sequencing. RESULTS: Our results highlight an absence of hypermethylation and hypomethylation in older patients with schizophrenia and in healthy controls, irrespective of the degree of the cognitive deficit measured in the neuropsychological assessment (Fisher's exact test; p<0.05). CONCLUSION: mRNA or protein expression level differences in genes of major neurotransmitter systems that are known to be altered in schizophrenia must be because of regulatory mechanisms other than the DNA methylation of its promoter regions, although our results highlight the idea that the analysis of the epigenetic mechanisms involved in schizophrenia represents a new approach that has the possibility of uncovering molecular mechanisms of dysregulated gene expression in this complex disorder. PMID- 25044036 TI - Interaction of double-stranded DNA with polymerized PprA protein from Deinococcus radiodurans. AB - Pleiotropic protein promoting DNA repair A (PprA) is a key protein that facilitates the extreme radioresistance of Deinococcus radiodurans. To clarify the role of PprA in the radioresistance mechanism, the interaction between recombinant PprA expressed in Escherichia coli with several double-stranded DNAs (i.e., super coiled, linear, or nicked circular dsDNA) was investigated. In a gel shift assay, the band shift of supercoiled pUC19 DNA caused by the binding of PprA showed a bimodal distribution, which was promoted by the addition of 1 mM Mg, Ca, or Sr ions. The dissociation constant of the PprA-supercoiled pUC19 DNA complex, calculated from the relative portions of shifted bands, was 0.6 MUM with Hill coefficient of 3.3 in the presence of 1 mM Mg acetate. This indicates that at least 281 PprA molecules are required to saturate a supercoiled pUC19 DNA, which is consistent with the number (280) of bound PprA molecules estimated by the UV absorption of the PprA-pUC19 complex purified by gel filtration. This saturation also suggests linear polymerization of PprA along the dsDNA. On the other hand, the bands of linear dsDNA and nicked circular dsDNA that eventually formed PprA complexes did not saturate, but created larger molecular complexes when the PprA concentration was >1.3 MUM. This result implies that DNA-bound PprA aids association of the termini of damaged DNAs, which is regulated by the concentration of PprA. These findings are important for the understanding of the mechanism underlying effective DNA repair involving PprA. PMID- 25044037 TI - Effective dosing of L-carnitine in the secondary prevention of cardiovascular disease: a systematic review and meta-analysis. AB - BACKGROUND: L-carnitine supplementation has been associated with a significant reduction in all-cause mortality, ventricular arrhythmia, and angina in the setting of acute myocardial infarction (MI). However, on account of strict homeostatic regulation of plasma L-carnitine concentrations, higher doses of L carnitine supplementation may not provide additional therapeutic benefits. This study aims to evaluate the effects of various oral maintenance dosages of L carnitine on all-cause mortality and cardiovascular morbidities in the setting of acute MI. METHODS: After a systematic review of several major electronic databases (PubMed, EMBASE, and the Cochrane Library) up to November 2013, a meta analysis of five controlled trials (n = 3108) was conducted to determine the effects of L-carnitine on all-cause mortality and cardiovascular morbidities in the setting of acute MI. RESULTS: The interaction test yielded no significant differences between the effects of the four daily oral maintenance dosages of L carnitine (i.e., 2 g, 3 g, 4 g, and 6 g) on all-cause mortality (risk ratio [RR] = 0.77, 95% CI [0.57-1.03], P = 0.08) with a statistically insignificant trend favoring the 3 g dose (RR = 0.48) over the lower 2 g dose (RR = 0.62), which was favored over the higher 4 g and 6 g doses (RR = 0.78, 0.78). There was no significant differences between the effects of the daily oral maintenance dosages of 2 g and 6 g on heart failure (RR = 0.53, 95% CI [0.25-1.13], P = 0.10), unstable angina (RR = 0.90, 95% CI [0.51-1.58], P = 0.71), or myocardial reinfarction (RR = 0.74, 95% CI [0.30-1.80], P = 0.50). CONCLUSIONS: There appears to be no significant marginal benefit in terms of all-cause mortality, heart failure, unstable angina, or myocardial reinfarction in the setting of acute MI for oral L-carnitine maintenance doses of greater or less than 3 g per day. PMID- 25044038 TI - XRF scanners as a quick screening tool for detecting toxic pollutant elements in sediments from Marin harbour in the Ria de Pontevedra (NW Spain). AB - X-ray fluorescence scanners, such as the ItraxTM Core Scanner (Itrax) (Cox Analytical Systems, Molndal, Sweden), provide high-resolution geochemical data within several hours. However, the semi-quantitative nature of these analysers has hampered their use to study pollution. This study explores Itrax's capabilities to detect trace metals, such as Hg and Cd, in the Ria de Pontevedra harbour (NW Spain). A set of Itrax detection levels were proposed for each metal after comparison with quantitative measurements obtained from Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) and Vapour Atomic Absorption Spectrometry (CVAAS) analyses. These quantitative data obtained after a sequential extraction were used to evaluate pollutant bioavailability and to determine metal pollution levels exhibiting Hg pollution. The reliability of inc/coh and Br/Cl ratios to assess the total organic matter variability was also evaluated. The results indicated that the Itrax is an efficient and fast option to monitor contamination, thereby avoiding laborious discrete analyses and reducing analytical cost and time. PMID- 25044035 TI - Quantitative susceptibility mapping (QSM): Decoding MRI data for a tissue magnetic biomarker. AB - In MRI, the main magnetic field polarizes the electron cloud of a molecule, generating a chemical shift for observer protons within the molecule and a magnetic susceptibility inhomogeneity field for observer protons outside the molecule. The number of water protons surrounding a molecule for detecting its magnetic susceptibility is vastly greater than the number of protons within the molecule for detecting its chemical shift. However, the study of tissue magnetic susceptibility has been hindered by poor molecular specificities of hitherto used methods based on MRI signal phase and T2* contrast, which depend convolutedly on surrounding susceptibility sources. Deconvolution of the MRI signal phase can determine tissue susceptibility but is challenged by the lack of MRI signal in the background and by the zeroes in the dipole kernel. Recently, physically meaningful regularizations, including the Bayesian approach, have been developed to enable accurate quantitative susceptibility mapping (QSM) for studying iron distribution, metabolic oxygen consumption, blood degradation, calcification, demyelination, and other pathophysiological susceptibility changes, as well as contrast agent biodistribution in MRI. This paper attempts to summarize the basic physical concepts and essential algorithmic steps in QSM, to describe clinical and technical issues under active development, and to provide references, codes, and testing data for readers interested in QSM. PMID- 25044039 TI - Out of sight but not out of mind: harmful effects of derelict traps in selected U.S. coastal waters. AB - There is a paucity of data in the published literature on the ecological and economic impacts of derelict fishing traps (DFTs) in coastal ecosystems. We synthesized results from seven NOAA-funded trap fisheries studies around the United States and determined that DFT-caused losses to habitat and harvestable annual catch are pervasive, persistent, and largely preventable. Based on this synthesis, we identified key gaps to fill in order to better manage and prevent DFTs. We conclude with suggestions for developing a U.S. DFT management strategy including: (1) targeting studies to estimate mortality of fishery stocks, (2) assessing the economic impacts of DFTs on fisheries, (3) collaborating with the fishing industry to develop solutions to ghost fishing, and (4) examining the regional context and challenges resulting in DFTs to find effective policy solutions to manage, reduce, and prevent gear loss. PMID- 25044040 TI - The effect of sand composition on the degradation of buried oil. AB - The potential effects of the mineralogical composition of sediment on the degradation of oil buried on sandy beaches were investigated. Toward that purpose, a laboratory experiment was carried out with sandy sediment collected along NW Iberian Peninsula beaches, tar-balls from the Prestige oil spill (NW Spain) and seawater. The results indicate that the mineralogical composition is important for the physical appearance of the oil (tar-balls or oil coatings). This finding prompted a reassessment of the current sequence of degradation for buried oil based on compositional factors. Moreover, the halo development of the oil coatings might be enhanced by the carbonate concentration of the sand. These findings open new prospects for future monitoring and management programs for oiled sandy beaches. PMID- 25044041 TI - Underwater noise emissions from a drillship in the Arctic. AB - Wideband sound recordings were made of underwater noise emitted by an active drillship, Stena Forth, working in 484 m of water in Baffin Bay, western Greenland. The recordings were obtained at thirty and one-hundred meters depth. Noise was recorded during both drilling and maintenance work at ranges from 500 m to 38 km. The emitted noise levels were highest during maintenance work with estimated source levels up to 190 dB re 1 MUPa (rms), while the source level during drilling was 184 dB re 1 MUPa (rms). There were spectral peaks discernible from the background noise to ranges of at least 38 km from the drillship with the main energy below 3 kHz. M-weighted sound pressure levels were virtually identical to broadband levels for low-frequency cetaceans and about 5 dB lower for high-frequency cetaceans. Signals from the dynamic positioning system were clearly detectable at ranges up to two km from the drillship. PMID- 25044042 TI - Phytoplankton dynamics in the Gulf of Aqaba (Eilat, Red Sea): a simulation study of mariculture effects. AB - The northern Gulf of Aqaba is an oligotrophic water body hosting valuable coral reefs. In the Gulf, phytoplankton dynamics are driven by an annual cycle of stratification and mixing. Superimposed on that fairly regular pattern was the establishment of a shallow-water fish-farm initiative that increased gradually until its activity was terminated in June 2008. Nutrient, water temperature, irradiation, phytoplankton data gathered in the area during the years 2007-2009, covering the peak of the fish-farm activity and its cessation, were analyzed by means of statistical analyses and ecological models of phytoplankton dynamics. Two datasets, one from an open water station and one next to the fish farms, were used. Results show that nutrient concentrations and, consequently, phytoplankton abundance and seasonal succession were radically altered by the pollution originating from the fish-farm in the sampling station closer to it, and also that the fish-farm might even have influenced the open water station. PMID- 25044043 TI - A Monte Carlo simulation based two-stage adaptive resonance theory mapping approach for offshore oil spill vulnerability index classification. AB - In this paper, a Monte Carlo simulation based two-stage adaptive resonance theory mapping (MC-TSAM) model was developed to classify a given site into distinguished zones representing different levels of offshore Oil Spill Vulnerability Index (OSVI). It consisted of an adaptive resonance theory (ART) module, an ART Mapping module, and a centroid determination module. Monte Carlo simulation was integrated with the TSAM approach to address uncertainties that widely exist in site conditions. The applicability of the proposed model was validated by classifying a large coastal area, which was surrounded by potential oil spill sources, based on 12 features. Statistical analysis of the results indicated that the classification process was affected by multiple features instead of one single feature. The classification results also provided the least or desired number of zones which can sufficiently represent the levels of offshore OSVI in an area under uncertainty and complexity, saving time and budget in spill monitoring and response. PMID- 25044044 TI - A baseline water quality assessment of the coastal reefs of Bonaire, Southern Caribbean. AB - Bonaire is considered to harbor some of the best remaining coral reefs of the Caribbean, but faces multiple pressures including eutrophication. We measured multiple water quality indicators twice annually, from November 2011 to May 2013, at 11 locations at the west coast of Bonaire. This study resulted in 834 data points. DIN concentrations ranged from below quantification to 2.69 MUmol/l, phosphate from below quantification to 0.16 MUmol/l, and chlorophyll-a from 0.02 to 0.42 MUg/l. Several indicators showed signs of eutrophication, with spatial and temporal effects. At southern and urban locations threshold levels of nitrogen were exceeded. This can be a result of brine leaching into sea from salt works and outflow of sewage water. Chlorophyll-a showed an increase in time, and phosphorus seemed to show a similar trend. These eutrophication indicators are likely to exceed threshold levels in near future if the observed trend continues. This is a cause for concern and action. PMID- 25044045 TI - Epilepsy of infancy with migrating focal seizures: six patients treated with bromide. AB - PURPOSE: We present six patients with epilepsy of infancy with migrating focal seizures (EIMFS) and provide a comprehensive evaluation of potassium bromide therapy. METHOD: Between February 1, 2007 and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. Potassium bromide was added to other antiepileptic drugs (AEDs) in doses ranging from 30 to 80 mg/kg/day. Plasma bromide concentration was monitored. A therapeutic bromide concentration between 75 and 125 mg/dL was considered to be ideal. RESULTS: Four of six children responded well to bromide. One of these patients became seizure free, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly seizures as well as axial hypotonia and severe language impairment. The fourth child responded well to bromide, having only weekly seizures and moderate psychomotor retardation. The patient who became seizure free improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus and hospital admission was not required. The remaining two patients did not respond well to bromide. Adverse effects were seen in three cases: vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. Adverse effects resolved with dose reduction. CONCLUSION: Early treatment with bromides should be considered in EIMFS to control the seizures and status epilepticus and to avoid progressive cognitive impairment. Potassium bromide is an old AED. Plasma concentration monitoring should be considered. PMID- 25044046 TI - A doping technique that suppresses undesirable H2 evolution derived from overall water splitting in the highly selective photocatalytic conversion of CO2 in and by water. AB - Photocatalytic conversion of CO2 to reduction products, such as CO, HCOOH, HCHO, CH3OH, and CH4, is one of the most attractive propositions for producing green energy by artificial photosynthesis. Herein, we found that Ga2O3 photocatalysts exhibit high conversion of CO2. Doping of Zn species into Ga2O3 suppresses the H2 evolution derived from overall water splitting and, consequently, Zn-doped, Ag modified Ga2O3 exhibits higher selectivity toward CO evolution than bare, Ag modified Ga2O3. We observed stoichiometric amounts of evolved O2 together with CO. Mass spectrometry clarified that the carbon source of the evolved CO is not the residual carbon species on the photocatalyst surface, but the CO2 introduced in the gas phase. Doping of the photocatalyst with Zn is expected to ease the adsorption of CO2 on the catalyst surface. PMID- 25044047 TI - Impact of metal ions in porphyrin-based applied materials for visible-light photocatalysis: key information from ultrafast electronic spectroscopy. AB - Protoporphyrin IX-zinc oxide (PP-ZnO) nanohybrids have been synthesized for applications in photocatalytic devices. High-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and steady-state infrared, absorption, and emission spectroscopies have been used to analyze the structural details and optical properties of these nanohybrids. Time-resolved fluorescence and transient absorption techniques have been applied to study the ultrafast dynamic events that are key to photocatalytic activities. The photocatalytic efficiency under visible-light irradiation in the presence of naturally abundant iron(III) and copper(II) ions has been found to be significantly retarded in the former case, but enhanced in the latter case. More importantly, femtosecond (fs) transient absorption data have clearly demonstrated that the residence of photoexcited electrons from the sensitizer PP in the centrally located iron moiety hinders ground-state bleach recovery of the sensitizer, affecting the overall photocatalytic rate of the nanohybrid. The presence of copper(II) ions, on the other hand, offers additional stability against photobleaching and eventually enhances the efficiency of photocatalysis. In addition, we have also explored the role of UV light in the efficiency of photocatalysis and have rationalized our observations from femtosecond- to picosecond-resolved studies. PMID- 25044048 TI - Potential changes to French recommendations about peri-prosthetic infections based on the international consensus meeting (ICMPJI). AB - BACKGROUND: Despite the large volume of studies on the prevention, diagnosis, and treatment of peri-prosthetic infections, surgical practice often rests on limited scientific evidence in this field. The vast International Consensus Meeting on Peri-prosthetic Joint Infection (ICMPJI) held in 2013 produced robust recommendations. HYPOTHESIS: French consensus conference recommendations show no major differences with ICMPJI recommendations. MATERIALS AND METHODS: The 207 recommendations developed by 300 experts at the ICMPJI were translated, and the translation was then examined by four reviewers, including 2 having participated in the consensus conference. The reviewers looked for any differences with French practices and recommendations. RESULTS: Twenty-three major differences or innovations were identified compared to French recommendations and standard practice. Among them, pre-operative screening for nasal or urinary micro organisms is performed routinely in France but should be reserved according to the ICMPJI for symptomatic patients and/or patients at high risk for infection. The ICMPJI emphasizes the role for the operating room environment as a vector for infection; more specifically, the operating lamp handle and suction cannula deserve close attention. A wound discharge persisting longer than 5-7 days requires irrigation and debridement. This procedure is effective only within the first 3 post-operative months and/or the first 3 weeks after symptom onset and must include exchange of all modular implants. The ICMPJI warns against both irrigation-debridement in fungal infections (suggesting two-stage prosthesis replacement) and one-stage replacement in patients with sinus tracts. The use of spacers (articulating at the knee) is recommended in the event of two-stage prosthesis replacement. DISCUSSION: The ICMPJI recommendations differed in many ways with French recommendations and standard practice. They can be expected to impact practices in France, although a point worth noting is that only 1 of the 207 recommendations received unanimous agreement by the conference experts (keeping operating room traffic to a minimum). PMID- 25044049 TI - A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities. AB - The vast majority of approved antidepressants and antipsychotics exhibit a complex pharmacology. The mechanistic understanding of how these psychotropic medications are related to adverse drug reactions (ADRs) is crucial for the development of novel drug candidates and patient adherence. This study aims to associate in vitro assessed binding affinity profiles (39 compounds, 24 molecular drug targets) and ADRs (n=22) reported in clinical trials of antidepressants and antipsychotics (n>59.000 patients) by the use of robust multivariate statistics. Orthogonal projection to latent structures (O-PLS) regression models with reasonable predictability were found for several frequent ADRs such as nausea, diarrhea, hypotension, dizziness, headache, insomnia, sedation, sleepiness, increased sweating, and weight gain. Results of the present study support many well-known pharmacological principles such as the association of hypotension and dizziness with alpha1-receptor or sedation with H1-receptor antagonism. Moreover, the analyses revealed novel or hardly investigated mechanisms for common ADRs including the potential involvement of 5-HT6-antagonism in weight gain, muscarinic receptor antagonism in dizziness, or 5-HT7-antagonism in sedation. To summarize, the presented study underlines the feasibility and value of a multivariate data mining approach in psychopharmacological development of antidepressants and antipsychotics. PMID- 25044050 TI - Complexity of oxytocin's effects in a chronic cocaine dependent population. AB - Behavioral and neuroplastic changes occurring in the development of addiction parallel those that occur in social bonding. This has led to speculation that drugs of abuse co-opt systems that subserve social attachment to shift attachment to drugs of abuse. Oxytocin, a neuropeptide that is important in social bonding, has been shown in rodents to decrease psychostimulant self-administration, locomotor activity, and conditioned place preference, it is unclear what role it may play in human drug addiction. In this double-blind, placebo-controlled crossover study, 23 cocaine-dependent inpatients in court-ordered treatment completed 4 task sessions measuring desire to use cocaine, cue-induced craving, monetary reward decisions and social cognition. Before each session, subjects administered 24 IU of intranasal oxytocin or placebo. Oxytocin increased desire to use cocaine and cue-induced excitability with no effect on cue-induced desire to use. Oxytocin also removed the effect of state anger on several measures of cue reactivity. Response to monetary reward increased under oxytocin and measures of social cognition worsened. The significant increase in the desire for drug and monetary reward as well as the significant decrease in measures of social cognition was small but warrant further study of the effect of oxytocin's effect in cocaine dependent subjects. The effect of oxytocin to modulate the relationship between state anger and cue reactivity should be explored further for potential therapeutic use of oxytocin in cocaine dependent patients. These findings are discussed in light of the human and rodent oxytocin literature. PMID- 25044052 TI - Influence of stimulant and non-stimulant drug treatment on driving performance in patients with attention deficit hyperactivity disorder: a systematic review. AB - Adults with Attention Deficit Hyperactivity Disorder (ADHD), especially teenagers and young adults, show important car driving impairments, including risky driving, accidents, fines and suspension of driver's license. We systematically reviewed the efficacy of stimulant and non-stimulant drugs on driving performance of ADHD patients. We searched several databases for randomized controlled trials (RCTs) published through March, 2013. Fifteen RCTs (the majority with crossover design) evaluated methylphenidate (MPH) immediate-release (MPH-IR), MPH osmotic controlled oral system (MPH-OROS), MPH transdermal system (MTS), extended-release mixed amphetamine salts (MAS-XR); atomoxetine (ATX) and lisdexamfetamine (LDX). Methods varied widely; including simulators and/or cars and different courses and scenarios. Various outcomes of driving performance, including a 'composite' or 'overall' driving score were considered. In general, stimulants improved driving performance in ADHD patients (either in RCTs conducted in simulators and/or cars). MPH-OROS improved driving performance compared with MAS-XR, placebo, or no drug conditions. Although MPH-OROS and MPH-IR produced similar improvements during the day, MPH-IR lost its efficacy in the evening. MAS-XR also improved driving performance, but worsened driving performance in the evening. MTS (one study) showed a positive effect, but drug compliance varied widely across patients. LDX had positive effect on driving (two studies with the same sample). Studies with ATX report conflicting results. Improvement was more consistent in teenagers and young adults. In general, treatment with psychostimulants or ATX in therapeutic dosages had no negative impact on driving performance of ADHD patients. To conclude, treatment with stimulants in therapeutic doses improves driving performance in ADHD patients, especially teenagers and young adults. PMID- 25044051 TI - The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes. AB - The variable length poly-T, rs10524523 ('523') located within the TOMM40 gene, was recently associated with several phenotypes of cognitive function. The short (S) allele is associated with later AD onset age and better cognitive performance, compared to the longer alleles (long and very-long (VL)). There is strong linkage disequilibrium between variants in the TOMM40 and APOE genes. In this study, we investigated the effect of '523' on cognitive performance in a sample of cognitively normal Jewish elderly with type 2 diabetes, a group at particularly high risk for cognitive impairment. Using a MANCOVA procedure, we compared homozygous carriers of the S/S allele (N=179) to carriers of the VL/VL allele (N=152), controlling for demographic and cardiovascular covariates. The S/S group performed better than the VL/VL group (p=0.048), specifically in the executive function (p=0.04) and episodic memory (p=0.050) domains. These results suggest that previous findings of an association of the TOMM40 short allele with better cognitive performance, independently from the APOE variant status, are pertinent to elderly with diabetes. PMID- 25044053 TI - Hydraulic "fracking": are surface water impacts an ecological concern? AB - Use of high-volume hydraulic fracturing (HVHF) in unconventional reservoirs to recover previously inaccessible oil and natural gas is rapidly expanding in North America and elsewhere. Although hydraulic fracturing has been practiced for decades, the advent of more technologically advanced horizontal drilling coupled with improved slickwater chemical formulations has allowed extensive natural gas and oil deposits to be recovered from shale formations. Millions of liters of local groundwaters are utilized to generate extensive fracture networks within these low-permeability reservoirs, allowing extraction of the trapped hydrocarbons. Although the technology is relatively standardized, the geographies and related policies and regulations guiding these operations vary markedly. Some ecosystems are more at risk from these operations than others because of either their sensitivities or the manner in which the HVHF operations are conducted. Generally, the closer geographical proximity of the susceptible ecosystem to a drilling site or a location of related industrial processes, the higher the risk of that ecosystem being impacted by the operation. The associated construction of roads, power grids, pipelines, well pads, and water-extraction systems along with increased truck traffic are common to virtually all HVHF operations. These operations may result in increased erosion and sedimentation, increased risk to aquatic ecosystems from chemical spills or runoff, habitat fragmentation, loss of stream riparian zones, altered biogeochemical cycling, and reduction of available surface and hyporheic water volumes because of withdrawal-induced lowering of local groundwater levels. The potential risks to surface waters from HVHF operations are similar in many ways to those resulting from agriculture, silviculture, mining, and urban development. Indeed, groundwater extraction associated with agriculture is perhaps a larger concern in the long term in some regions. Understanding the ecological impacts of these anthropogenic activities provides useful information for evaluations of potential HVHF hazards. Geographic information system-based modeling combined with strategic site monitoring has provided insights into the relative importance of these and other ecoregion and land-use factors in discerning potential HVHF impacts. Recent findings suggest that proper siting and operational controls along with strategic monitoring can reduce the potential for risks to aquatic ecosystems. Nevertheless, inadequate data exist to predict ecological risk at this time. The authors suggest considering the plausibility of surface water hazards associated with the various HVHF operations in terms of the ecological context and in the context of relevant anthropogenic activities. PMID- 25044054 TI - Environmental challenges in China: an introduction. PMID- 25044055 TI - Monitoring prognosis in severe traumatic brain injury. AB - The choice of disease-specific versus generic scales is common to many fields of medicine. In the area of traumatic brain injury, evidence is coming forward that disease-specific prognostic models and disease-specific scoring systems are preferable in the intensive care setting. In monitoring prognosis, the use of a calibration belt in validation studies potentially provides accurate and intuitively attractive insight into performance. This approach deserves further empirical evaluation of its added value as well as its limitations. PMID- 25044056 TI - Retinal projection to the pretectal nucleus lentiformis mesencephali in pigeons (Columba livia). AB - In birds, the nucleus of the basal optic root (nBOR) and the nucleus lentiformis mesencephali (LM) are retinal-recipient nuclei involved in the analysis of optic flow and the generation of the optokinetic response. The nBOR receives retinal input from displaced ganglion cells (DGCs), which are found at the margin of the inner nuclear and inner plexiform layers, rather than the ganglion cell layer. The LM receives afferents from retinal ganglion cells, but whether DGCs also project to LM remains unclear. To resolve this issue, we made small injections of retrograde tracer into LM and examined horizontal sections through the retina. For comparison, we also had cases with injections in nBOR, the optic tectum, and the anterior dorsolateral thalamus (the equivalent to the mammalian lateral geniculate nucleus). From all LM injections both retinal ganglion cells and DGCs were labeled. The percentage of DGCs, as a proportion of all labeled cells, varied from 2-28%, and these were not different in morphology or size compared to those labeled from nBOR, in which the proportion of DGCs was much higher (84 93%). DGCs were also labeled after injections into the anterior dorsolateral thalamus. The proportion was small (2-3%), and these DGCs were smaller in size than those projecting to the nBOR and LM. No DGCs were labeled from an injection in the optic tectum. Based on an analysis of size, we suggest that different populations of retinal ganglion cells are involved in the projections to LM, nBOR, the optic tectum, and the anterior dorsolateral thalamus. PMID- 25044057 TI - Sarcopenia in lung transplantation: a systematic review. AB - Lung transplant candidates and recipients have significant impairments in skeletal muscle mass, strength and function--individual measures of sarcopenia. Skeletal muscle dysfunction has been observed in the pre-transplant and post transplant period and could have an important effect on transplant outcomes. A systematic review was performed to characterize the techniques used to study sarcopenia and assess the level of impairment throughout the transplant process. Electronic databases were searched (inception to July 2013) for prospective studies measuring at least 1 element of sarcopenia (muscle mass, strength, or function) in lung transplant patients. Eighteen studies were included, and study quality was assessed using the Downs and Black scale. A variety of measurements were used to evaluate sarcopenia in 694 lung transplant patients. Muscle mass in 7 studies was assessed using bioelectrical impedance (n = 4), computed tomography or magnetic resonance imaging (n = 2), or skin folds (n = 1), and was significantly reduced. Quadriceps strength was examined in 14 studies with computerized dynamometer (n = 10) and hand-held dynamometer (n = 4). Quadriceps strength was reduced in the pre-transplant period (mean range, 49%-86% predicted; n = 455 patients), further reduced immediately after transplant (51%-72%, n = 126), and improved beyond 3 months after transplant (58%-101%, n = 164). Only 2 studies measured lower extremity function (sit-to-stand test). A multitude of measurement techniques have been used to assess individual measures of sarcopenia, with reduced muscle mass and quadriceps strength observed in the pre transplant and post-transplant period. Further standardization of measurement techniques is needed to assess the clinical effect of sarcopenia in lung transplantation. PMID- 25044058 TI - NIH Career Development Awards in Clinical and Translational Science Award institutions: distinguishing characteristics of top performing sites. AB - PURPOSE: To identify and disseminate the organizational characteristics of "top performing" National Institute of Health (NIH) Clinical and Translational Science Awards (CTSA) institutions in regards to career development, using the number of new K awards received per year to rank institutions and comparing these with non CTSA institutions. METHODS: The authors analyzed the organizational characteristics of all 61 CTSA institutions from 2006 to 2013 using the American Association of Medical Colleges Organizational Characteristics Database and K Award funding details using NIH RePORT. RESULTS: Five of the "top 10 performing" institutions are in the western region, and six out of the ten are public schools. Three of the "top 10 performing" institutions receive most of their K awards through two funding mechanisms-the K08 (mentored clinical scientist research award) and K23 (mentored patient-oriented research career development awards). Notably, these three institutions lack a KL2 program. CONCLUSION: The CTSA network of institutions is committed to developing the next generation of physician scientists in order to meet the pressing health needs of society. Educators and evaluators within this network may need to provide training to junior investigators beyond the traditional KL2 programs in order to advance their career development as physician scientists and clinical translational researchers. PMID- 25044059 TI - Micromorphology analysis and bond strength of two adhesives to Er,Cr:YSGG laser prepared vs. bur-prepared fluorosed enamel. AB - Preservation of enamel during composite veneer restorations of fluorosed teeth could be achieved by conservative preparation with Erbium lasers. This study evaluated the effect of fluorosed enamel preparation with Er,Cr:YSGG vs. conventional diamond bur on the micromorphology and bond strength of a self-etch and an etch-and-rinse adhesives. Er,Cr:YSGG laser or diamond bur preparation was performed on the flattened midbuccal surfaces of 70 extracted human premolars with moderate fluorosis (according to Thylstrup and Fejerskov index, TFI = 4-6). Adper Single Bond (SB) with acid etching for 20 or 40 s and Clearfil SE Bond (SEB) alone or with additional etching was applied in four laser groups. The same adhesive procedures were used in three bur groups except for 40 s of etching along with SB. After restoration, microshear bond strength was measured (MPa). Data were analyzed using ANOVA and Tamhane tests (alpha = 0.05). Six additional specimens were differently prepared and conditioned for scanning electron microscopy evaluation. The highest and lowest bond strengths were obtained for bur-prepared/SB (39.5) and laser-prepared/SEB (16.9), respectively, with a significant difference (P = 0.001). The different adhesive procedures used associated to two adhesives exhibited insignificantly lower bonding in laser prepared groups compared to bur-prepared ones (P > 0.05), with the exception of additional etching/SEB, which bonded significantly higher to bur-prepared (36.4) than to laser-prepared enamel (18.7, P = 0.04). Morphological analyses revealed a delicate etch pattern with exposed enamel prisms on laser-prepared fluorosed enamel after acid etching and less microretentive pattern after self-etching primer. The etch-and-rinse adhesive was preferred in the laser-prepared fluorosed enamel in terms of bonding performance. PMID- 25044060 TI - [(p-Cymene)RuCl2 ]2 : an efficient catalyst for highly regioselective allylic alkylations of chelated amino acid ester enolates. AB - Chelated amino acid ester enolates are excellent nucleophiles for ruthenium catalyzed allylic alkylations. Although [Cp*Ru(MeCN)3 ]PF6 was found to be the most reactive catalyst investigated, with the resulting allyl complexes reacting at temperatures as low as -78 degrees C, unfortunately the process took place with only moderate regio- and diastereoselectivity. In contrast, [(p-cymene)RuCl2 ]2 allowed allylations to be performed with a high degree of regioretention. Secondary allyl carboxylates with a terminal double bond were found to be the most reactive substrates, giving rise to the branched amino acids with perfect regioretention and chirality transfer. In this case, no isomerization of the Ru allyl complex formed in situ was observed, in contrast to the analogues palladium complexes. This isomerization-free protocol can also be used for the synthesis of (Z)-configured gamma,delta-unsaturated amino acid derivatives, starting from (Z) allylic substrates. Here, the more reactive phosphates were found to be superior to the carboxylates, providing the required amino acids in almost quantitative yield with perfect regio- and stereoretention. Therefore, the Ru-catalyzed allylation reactions are well positioned to overcome the drawbacks of Pd catalyzed processes. PMID- 25044062 TI - HSP70-hom gene polymorphisms modify the association of diethylhexyl phthalates with insulin resistance. AB - Recent studies suggest that diethylhexyl phthalates (DEHP) could contribute to the development of insulin resistance (IR) through oxidative stress, and that heat shock protein (HSP) could be related with the association between DEHP and IR. Therefore, we evaluated the effect modification of genetic polymorphisms of HSP70-hom, an oxidative stress related gene, on the relation between exposure to DEHP and IR. We obtained repeated blood and urine samples from 414 elderly female participants and measured urinary levels of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) as metabolites of DEHP. We also measured serum levels of fasting glucose and insulin, derived the homeostatic model assessment (HOMA) index to assess IR, and genotyped two HSP70-hom polymorphisms (rs2227956 and rs2075800). A mixed effect model and penalized regression spline were used to estimate the associations between DEHP exposure and IR by genetic polymorphisms. The molar sum of MEHHP and MEOHP (?DEHP) were significantly associated with HOMA (beta = 0.30, P = 0.022). When stratified by genotype at rs2227956, the relationship between ?DEHP and HOMA was statistically significant in participants with TT (beta = 0.32, P = 0.048) or TC (beta = 0.60, P = 0.008), while at rs2075800 there was a marginal association for the GA genotype (beta = 0.33, P = 0.097). When haplotypes were constituted across the two HSP70-hom polymorphisms (rs2227956 and rs2075800), the association was apparent only in participants with the T-A haplotype (beta = 0.39, P = 0.029). Our study suggests that HSP70-hom polymorphisms modify the association of DEHP with IR. PMID- 25044061 TI - Assessing model fit in joint models of longitudinal and survival data with applications to cancer clinical trials. AB - Joint models for longitudinal and survival data now have a long history of being used in clinical trials or other studies in which the goal is to assess a treatment effect while accounting for longitudinal assessments such as patient reported outcomes or tumor response. Compared to using survival data alone, the joint modeling of survival and longitudinal data allows for estimation of direct and indirect treatment effects, thereby resulting in improved efficacy assessment. Although global fit indices such as AIC or BIC can be used to rank joint models, these measures do not provide separate assessments of each component of the joint model. In this paper, we develop a novel decomposition of AIC and BIC (i.e., AIC = AICLong + AICSurv|Long and BIC = BICLong + BICSurv|Long) that allows us to assess the fit of each component of the joint model and in particular to assess the fit of the longitudinal component of the model and the survival component separately. Based on this decomposition, we then propose DeltaAICSurv and DeltaBICSurv to determine the importance and contribution of the longitudinal data to the model fit of the survival data. Moreover, this decomposition, along with DeltaAICSurv and DeltaBICSurv, is also quite useful in comparing, for example, trajectory-based joint models and shared parameter joint models and deciding which type of model best fits the survival data. We examine a detailed case study in mesothelioma to apply our proposed methodology along with an extensive set of simulation studies. PMID- 25044063 TI - Efforts to control prescription drug abuse: Why clinicians should be concerned and take action as essential advocates for rational policy. PMID- 25044064 TI - The xanthine oxidase-NFAT5 pathway regulates macrophage activation and TLR induced inflammatory arthritis. AB - NFAT5 (nuclear factor of activated T cells), a well-known osmoprotective factor, can be activated by isotonic stimuli such as Toll-like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO-ROS-p38 MAPK-NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO-derived ROS were selectively required for the TLR-induced NFAT5 activation and NFAT5 binding to the IL-6 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in BALB/c mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL-6 in splenic macrophages in C57BL/6 mice. Collectively, these data support a novel function of the XO-NFAT5 axis in macrophage activation and TLR-induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis. PMID- 25044065 TI - Highly efficient "on water" catalyst-free nucleophilic addition reactions using difluoroenoxysilanes: dramatic fluorine effects. AB - A remarkable fluorine effect on "on water" reactions is reported. The C?F???H?O interactions between suitably fluorinated nucleophiles and the hydrogen-bond network at the phase boundary of oil droplets enable the formation of a unique microstructure to facilitate on water catalyst-free reactions, which are difficult to realize using nonfluorinated substrates. Accordingly, a highly efficient on water, catalyst-free reaction of difluoroenoxysilanes with aldehydes, activated ketones, and isatylidene malononitriles was developed, thus leading to the highly efficient synthesis of a variety of alpha,alpha-difluoro beta-hydroxy ketones and quaternary oxindoles. PMID- 25044066 TI - Analyzing organic tea certification and traceability system within the Taiwanese tea industry. AB - BACKGROUND: We applied game theory to the organic tea certification process and traceability system used by the Taiwanese tea industry to elucidate the strategic choices made by tea farmers and organic tea certification agencies. Thus, this paper clarifies how relevant variables affect the organic certification process and traceability system used within the tea industry. RESULTS: The findings indicate that farmers who generate high revenues experience failures regarding tea deliveries, cash outflow, damage compensation, and quasi-rent. An additional problem included the high costs yielded when tea farmers colluded with or switched organic tea certification agencies. Furthermore, there could be decreasing levels of personal interest in planting non-organic tea and lowering the costs of planting organic tea and the managerial accounting costs of building comprehensive traceability systems; thus, the analysis yielded strong results and a superior equilibrium. CONCLUSION: This research is unprecedented, using an innovative model and providing a novel analysis structure for use in the tea industry. These results contribute to the field of literature and should serve as a valuable reference for members of the tea industry, government, and academia. PMID- 25044067 TI - Intravascular extension of papillary thyroid carcinoma to the internal jugular vein: A case report. AB - INTRODUCTION: Papillary thyroid cancer (PTC) is the most common thyroid malignancy and usually spreads via lymphatic system. PTC can sometimes show microscopic vascular invasion, but rarely causes tumour thrombus in the internal jugular vein (IJV) or other great veins of the neck. PRESENTATION OF CASE: We report a case of a 62-year-old female presented with symptomatic central neck mass. Clinical examination revealed a hard solitary right-sided thyroid nodule with ipsilateral cervical lymphadenopathy. Ultrasonography (US) confirmed the clinical diagnosis and visualised a dilated ipsilateral IJV. Fine-needle aspiration cytology revealed PTC cells so total thyroidectomy with right neck dissection was done. A tumour thrombus was discovered in the distended right IJV and was cleared successfully. The patient recovered well after the operation with no local or distant metastasis detected. DISCUSSION: Tumour vascular spread is observed in tumours with angio-invasive features including follicular carcinoma of the thyroid gland where great cervical veins can be affected. PTC commonly spreads to the lymph nodes and vascular spread via direct intravascular extension is extremely rare. Neck US has an important role in the diagnosis, and operators should attempt to detect signs of tumour thrombi in all patients with thyroid masses. Aggressive surgical treatment with vascular repair is recommended whenever possible to minimise the risk of potentially fatal complications of the intraluminal masses. CONCLUSION: Intravascular tumour extension of PTC is rare but with serious consequences. Diagnosis with neck US is possible but some cases are only discovered intraoperatively. Thrombectomy with vascular repair or reconstruction is usually possible. PMID- 25044068 TI - Recovery and patient satisfaction after cataract surgery. A one-year prospective follow-up study. PMID- 25044069 TI - Emotional intelligence and health-related quality of life in institutionalised Spanish older adults. AB - This study explores the relationship between emotional intelligence (EI) and health-related quality of life (HRQoL) in a sample of Spanish older adults who are institutionalised in long-term care (LTC) facilities. One hundred fifteen institutionalised individuals (47.82% women; 88.3 +/- 7.9 years) from southern Spain completed a set of questionnaires that included measures of EI, health and personality. Data were analysed via hierarchical regression. After controlling for personality and sociodemographic variables, the EI dimensions, emotional comprehension and emotional facilitation, accounted for part of the variance in several HRQoL facets. These dimensions could have an important role in the HRQoL of residents in LTC. Moreover, the use of a performance measure addresses the limitations of previous studies that have relied on self-report measures. These aspects underscore the importance of the results of this study. PMID- 25044070 TI - Trace element patterns in marine macroalgae. AB - Novel information on interspecific variation in trace element accumulation in seaweeds is provided. Concentrations and concentration factors (CFs) of a wide set of elements (As, Ba, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, Se, Sr, U, V and Zn) in 26 dominant macroalgae from the Gulf of Thessaloniki, Aegean Sea were determined and compared. Uni-and multivariate data analyses were applied. Phaeophyceae showed higher concentrations and CFs of As and Sr than Rhodophyta and Chlorophyta, indicating that the accumulation of these elements is closely related to species biochemical composition. Filamentous macroalgae displayed higher concentrations and CFs of several elements, particularly Cd, Co, Cr, Cu, Mn and V than sheet-like, coarsely-branched and/or thick-leathery macroalgae, irrespective of phylogenetic relationships, indicating that the accumulation of several elements is largely related to thallus morphology and growth strategy. On a species basis, Cystoseira spp. showed both the highest concentrations and CFs of As, Padina pavonica of Sr and U, Ceramium spp. of Mn, Ceramium and Cladophora species of Co and Cu, Cladophora prolifera of Cr and Polysiphonia deusta and Ulva clathrata of Cd. Se concentration in Ulva rigida correlated positively with seawater Se concentration, and As concentration in this species with sediment As concentration. Thereby, these seaweeds could be regarded as potential biomonitors for the respective elements. A literature review was performed and global element concentrations and CFs were presented for seaweeds from genera collected during this survey. The data presented can contribute to the interpretation of biomonitoring data and the design of biomonitoring programs for the protection and management of coastal environments. PMID- 25044071 TI - Nanoparticle growth in supported nickel catalysts during methanation reaction- larger is better. AB - A major cause of supported metal catalyst deactivation is particle growth by Ostwald ripening. Nickel catalysts, used in the methanation reaction, may suffer greatly from this through the formation of [Ni(CO)4 ]. By analyzing catalysts with various particle sizes and spatial distributions, the interparticle distance was found to have little effect on the stability, because formation and decomposition of nickel carbonyl rather than diffusion was rate limiting. Small particles (3-4 nm) were found to grow very large (20-200 nm), involving local destruction of the support, which was detrimental to the catalyst stability. However, medium sized particles (8 nm) remained confined by the pores of the support displaying enhanced stability, and an activity 3 times higher than initially small particles after 150 h. Physical modeling suggests that the higher [Ni(CO)4 ] supersaturation in catalysts with smaller particles enabled them to overcome the mechanical resistance of the support. Understanding the interplay of particle size and support properties related to the stability of nanoparticles offers the prospect of novel strategies to develop more stable nanostructured materials, also for applications beyond catalysis. PMID- 25044072 TI - A nurse-based strategy reduces heart failure morbidity in patients admitted for acute decompensated heart failure in Brazil: the HELEN-II clinical trial. AB - AIMS: Home-based interventions for heart failure (HF) patients might be particularly effective in middle-income countries, where social, cultural, and economic constraints limit the effectiveness of HF treatment outside the hospital environment. METHODS AND RESULTS: HELEN-II was a randomized clinical trial conducted in Brazil designed to evaluate the clinical efficacy of a nurse-based strategy, started after discharge following an acute decompensated HF (ADHF) admission. HELEN-II compares the efficacy of home visits and telephone reinforcement (n = 123) with that of the conventional strategy, which is based on medical follow-up (n = 129). The primary outcome was a composite endpoint of a first visit to the emergency department (<= 24 h), a hospital readmission (> 24 h), or all-cause death, assessed during the first 6 months of follow-up. Most enrolled subjects were middle-aged (62 +/- 13 years) males (63%) in NYHA functional class II-III (84%) with severe LV dysfunction (mean LVEF 29.6 +/- 9%). The primary composite endpoint was decreased by 27% in the interventional group (relative risk 0.73; 95% confidence interval 0.54-0.99; P = 0.049). At the end of follow-up, the rate of use of the standard-of-care HF medications was similar in both groups, except for the higher use of furosemide in the interventional group. Also, HF knowledge and self-care were significantly increased in the interventional group. CONCLUSIONS: A post-discharge, nurse-led management strategy significantly decreases the morbidity of ADHF patients in the public health system of a developing middle-income country. PMID- 25044073 TI - On the rotational intergrowth of hierarchical FAU/EMT zeolites. AB - A structural study of a hierarchical zeolite X, which is similar to the one first synthesized by Inayat et al.,12 was performed using transmission electron microscopy imaging and diffraction. Evidence is provided, by comparison to simulations, that this material is an intergrowth of FAU and EMT and a conceptual model is presented for the growth of the FAU material with a small fraction of EMT in an atypical morphology of assembled sheets with well-defined intersection angles. PMID- 25044074 TI - Transfer from high-shear batch to continuous twin screw wet granulation: a case study in understanding the relationship between process parameters and product quality attributes. AB - A twin screw to high-shear batch granulation technology switch was evaluated for a pharmaceutical development project. Differences in granule (particle size distribution and porosity) and tablet (dissolution) quality attributes were analysed for both continuous and batch technologies. Liquid to solid (L/S) ratio, screw configuration and screw speed parameters on the twin screw granulator were varied, with output granule and tablet properties characterised. L/S and screw configuration were found to influence the granule particle size distribution, porosity and tablet dissolution. At 0.15 L/S, the particle size distribution showed a significant proportion of ungranulated material in the output granule. As the L/S is increased, the level of ungranulated material decreased. An increase in L/S and the number of kneader elements caused a decrease in granule porosity and tablet dissolution. Twin screw and batch granulation technologies generated different granule properties (size and shape) at a constant L/S. A lower L/S in twin screw granulation was needed to achieve similar tablet attributes. It is concluded that differences in liquid addition and therefore initial granule nucleation caused differences in granule properties, which impacted tablet attributes and manufacturability. PMID- 25044075 TI - Impact of aging on spreading depolarizations induced by focal brain ischemia in rats. AB - Spreading depolarization (SD) contributes to the ischemic damage of the penumbra. Although age is the largest predictor of stroke, no studies have examined age dependence of SD appearance. We characterized the electrophysiological and hemodynamic changes in young (6 weeks old, n = 7), middle-aged (9 months old, n = 6), and old (2 years old, n = 7) male Wistar rats during 30 minutes of middle cerebral artery occlusion (MCAO), utilizing multimodal imaging through a closed cranial window over the ischemic cortex: membrane potential changes (with a voltage-sensitive dye), cerebral blood volume (green light reflectance), and cerebral blood flow (CBF, laser-speckle imaging) were observed. The initial CBF drop was similar in all groups, with a significant further reduction during ischemia in old rats (p < 0.01). Age reduced the total number of SDs (p < 0.05) but increased the size of ischemic area displaying prolonged SD (p < 0.01). The growth of area undergoing prolonged SDs positively correlated with the growth of ischemic core area (p < 0.01) during MCAO. Prolonged SDs and associated hypoperfusion likely compromise cortical tissue exposed to even a short focal ischemia in aged rats. PMID- 25044076 TI - Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice. AB - Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimer's disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid beta, the chronic LTG treatment reduced the cleavage of APP by beta-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF. PMID- 25044077 TI - A general method for preparing bridged organosilanes with pendant functional groups and functional mesoporous organosilicas. AB - New organosilica precursors containing two triethoxysilyl groups suitable for the organosilica material formation through the sol-gel process were designed and synthesised. These precursors display alkyne or azide groups for attaching targeted functional groups by copper-catalysed azide-alkyne cycloaddition (CuAAC) and can be used for the preparation of functional organosilicas following two strategies: 1) the functional group is first appended by CuAAC under anhydrous conditions, then the functional material is prepared by the sol-gel process; 2) the precursor is first subjected to the sol-gel process, producing porous, clickable bridged silsesquioxanes or periodic mesoporous organosilicas (PMOs), then the desired functional groups are attached by means of CuAAC. Herein, we show the feasibility of both approaches. A series of bridged bis(triethoxysilane)s with different pending organic moieties was prepared, demonstrating the compatibility of the first approach with many functional groups. In particular, we demonstrate that organic functional molecules bearing only one derivatisation site can be used to produce bridged organosilanes and bridged silsesquioxanes. In the second approach, clickable PMOs and porous bridged silsesquioxanes were prepared from the alkyne- or azide-containing precursors, and thereafter, functionalised with complementary model azide- or alkyne-containing molecules. These results confirmed the potential of this approach as a general methodology for preparing functional organosilicas with high loadings of functional groups. Both approaches give rise to a wide range of new functional organosilica materials. PMID- 25044078 TI - Selective estrogen receptor modulators, male hypogonadism, and infertility. PMID- 25044079 TI - Examining the temperature of embryo culture in in vitro fertilization: a randomized controlled trial comparing traditional core temperature (37 degrees C) to a more physiologic, cooler temperature (36 degrees C). AB - OBJECTIVE: To determine whether culture at a more physiologically cooler temperature, as suggested by limited human and animal data, would improve blastulation and pregnancy rates in human clinical IVF. DESIGN: Paired randomized controlled trial. SETTING: Academic. PATIENT(S): Infertile couples (n=52) with a female partner less than 42 years old with eight or more mature oocytes retrieved. INTERVENTION(S): Mature oocytes obtained from a single cohort of oocytes were randomly divided into two groups; one was cultured at 37 degrees C and the other at 36 degrees C from the time of ICSI to the time of embryo transfer or vitrification. Paired embryo transfers were accomplished by transferring one euploid embryo from each group. DNA fingerprinting was used as needed to determine the outcome for each embryo. MAIN OUTCOME MEASURE(S): Rate of development of expanded blastocysts suitable for transfer or vitrification (primary outcome), fertilization, aneuploidy, and sustained implantation. RESULT(S): A total of 805 mature oocytes were cultured; 399 at 36 degrees C and 406 at 37 degrees C. Paired analysis demonstrated a higher rate of usable blastocyst formation per zygote at 37 degrees C (48.4%) vs. at 36 degrees C (41.2%). Rates of fertilization, aneuploidy, and sustained implantation were equivalent. CONCLUSION(S): IVF culture at 36 degrees C does not improve clinically relevant parameters of embryo development or sustained implantation rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT01506089. PMID- 25044080 TI - Gonadotropin-releasing hormone agonists for the preservation of ovarian function among women with breast cancer who did not use tamoxifen after chemotherapy: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether concurrent use of GnRH agonists with chemotherapy preserves ovarian function in women with breast cancer who did not use tamoxifen. DESIGN: Systematic review and meta-analysis. SETTING: University-based hospitals. PATIENT(S): Premenopausal women with breast cancer treated with chemotherapy who did not receive tamoxifen. INTERVENTION(S): Randomization to concurrent GnRH agonists with chemotherapy or chemotherapy alone. MAIN OUTCOME MEASURE(S): Odds ratio (OR) of resumption of menses 1 year or more after chemotherapy. RESULT(S): Searches were conducted in PubMed, Scopus, Cochrane Trials Register, and the National Research Register through March 2014, and all randomized trials that reported resumption of menses 1 year or more after GnRH agonist with chemotherapy or chemotherapy alone among women with breast cancer who did not receive tamoxifen were included. Four studies were analyzed in the meta-analysis and included 252 patients (GnRH agonist with chemotherapy, n=131; chemotherapy alone, n=121). There was no significant difference in the rate of return of menses between the two groups (OR, 1.47; 95% confidence interval [0.60-3.62]). Heterogeneity among the trials was not significant (I2=16.6%). CONCLUSION(S): Concurrent GnRH agonists with chemotherapy may not preserve ovarian function in women with breast cancer. Furthermore, randomized data are limited regarding fertility after concurrent use of GnRH agonists with chemotherapy. PMID- 25044081 TI - Fertilizing potential of ejaculated human spermatozoa during in vitro semen bacterial infection. AB - OBJECTIVE: To assess the in vitro effect of three bacterial isolates (Escherichia coli, serotype O75:HNT, Staphylococcus haemolyticus, and Bacteroides ureolyticus) and/or leukocytes on sperm motility, subcellular changes in sperm plasma membranes, and sperm fertilizing potential. DESIGN: An in vitro model of semen bacterial infection. SETTING: Basic research laboratory. PATIENT(S): Healthy normozoospermic volunteers and healthy blood donors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sperm plasma membrane stability was evaluated with a LIVE/DEAD Sperm Viability Kit and with the merocyanine 540 (M540) test both performed using flow cytometry. An oxiSelect TBARS Assay Kit was used for quantitative measurement of malondialdehyde content. Functional ability of spermatozoa was assessed by hypo-osmotic swelling (HOS) test and sperm penetration assay (SPA). RESULT(S): The incubation of sperm with bacteria and/or leukocytes was associated with the reduction of their fertilizing potential demonstrated in both the HOS test and SPA, and this effect can be considered as a natural consequence of diminished motility and sperm membrane injury of lipid bilayers. Bacteroides ureolyticus demonstrated the most significant detrimental effect on sperm structure and function. CONCLUSION(S): Sperm motility and lipid sperm membrane status might be the earliest and the most sensitive indicators of sperm damage with negative consequences for male factor fertility, which can be attributed to both bacteria and leukocytes action. PMID- 25044082 TI - Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in recurrent pregnancy losses (RPL): possible participation of RAGE in RPL. AB - OBJECTIVE: To determine whether the soluble receptor for advanced glycation end products (sRAGE) and immune inflammatory markers are associated with recurrent pregnancy losses (RPL). DESIGN: Prospective case-control study. SETTING: University clinic. PATIENT(S): A total of 93 women (age 35.8+/-4.6 years) were enrolled including 63 women with three or more recurrent pregnancy losses (RPL), and age-matched fertile controls with a history of at least one live birth and no history of pregnancy losses (n=30). INTERVENTION(S): Peripheral blood collection. MAIN OUTCOME MEASURE(S): Assessment of anthropometric, metabolic, and inflammatory immune variables. RESULT(S): Levels of sRAGE were statistically significantly higher in RPL patients than in control patients (1,528.9+/-704.5 vs. 1,149.9+/-447.4 pg/mL). In the multivariate analysis, the levels of insulin, plasminogen activator inhibitor-1, the resistance index of the uterine radial artery, and the ratio of tumor necrosis factor-alpha/interleukin-10 producing T helper cells were statistically significantly associated with the serum sRAGE level. CONCLUSION(S): Elevated levels of serum sRAGE are associated with RPL. The soluble receptor for advanced glycation end products might contribute to RPL by reducing uterine blood flow and subsequently causing ischemia in the fetus via inflammatory and thrombotic reactions. PMID- 25044083 TI - Influence of follicle rupture and uterine contractions on intrauterine insemination outcome: a new predictive model. AB - OBJECTIVE: To correlate the detection of follicle rupture and the number of uterine contractions per minute with the outcome of IUI and to build a predictive model for the outcome of IUI including these parameters. DESIGN: Retrospective cohort study. SETTING: Fertility clinic. PATIENT(S): We analyzed data from 610 women who underwent homologous or donor double IUI from 2005 to 2010 and whose data of uterine contractions or follicle rupture were recorded. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate. RESULT(S): Nine hundred seventy nine IUI cycles were included. The detection of follicle rupture (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.30-3.01) and the number of uterine contractions per minute (OR, 1.67; 95% CI, 1.02-2.74) assessed after the second insemination procedure of a double IUI were positively correlated with the live birth rate. A multiple logistic regression model showed that sperm origin, maternal age, follicle count at hCG administration day, follicle rupture, and the number of uterine contractions observed after the second insemination procedure were significantly associated with the live-birth rate. CONCLUSION(S): Follicle rupture and uterine contractions are associated with the success of an IUI cycle. This may open new possibilities to improve the methodology of IUI. PMID- 25044084 TI - Assisted hatching: trends and pregnancy outcomes, United States, 2000-2010. AB - OBJECTIVE: To assess trends and outcomes of assisted hatching among assisted reproductive technology (ART) cycles. DESIGN: Retrospective cohort analysis using National ART Surveillance System (NASS) data. SETTING: U.S. fertility centers reporting to NASS. PATIENT(S): Fresh autologous noncanceled ART cycles conducted from 2000-2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, live-birth, miscarriage, multiple gestation. RESULT(S): Assisted hatching use statistically significantly increased in absolute number (from 25,724 to 35,518 cycles), percentages of day-3 (from 50.7% to 56.3%) and day-5 transfers (from 15.9% to 22.8%), and percentage of transfers among women >=38 years (from 17.8% to 21.8%) or women with >=2 prior ART cycles and no live birth(s) (from 4.3% to 7.4%). Both day-3 and day-5 cycles involving assisted hatching were associated with lower odds of implantation (adjusted odds ratios [aOR] 0.7 and 0.6, respectively), clinical pregnancy (aOR 0.8 and 0.7, respectively), live birth (aOR 0.8 and 0.7, respectively), and increased odds of miscarriage (aOR 1.4 and 1.4, respectively), as compared with cycles without assisted hatching. Assisted hatching was associated with lower odds of multiple gestation in day-5 cycles (aOR 0.8). In cycles for women with a "poor prognosis," the association of assisted hatching with pregnancy outcomes was not statistically significant. CONCLUSION(S): Assisted hatching use had an increasing trend but was not associated with improved pregnancy outcomes, even in poor prognosis patients. Prospective studies are needed to identify the patients who may benefit from assisted hatching. PMID- 25044086 TI - Comprehensive chromosome screening with synchronous blastocyst transfer: time for a paradigm shift. PMID- 25044085 TI - Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. AB - OBJECTIVE: To determine the effect of enclomiphene citrate in men with secondary hypogonadism. DESIGN: Phase II clinical trial. SETTING: Community dwelling men making visits to physician offices. PATIENT(S): Men with secondary hypogonadism. INTERVENTION(S): Oral administration of enclomiphene citrate or 1% topical T gel. MAIN OUTCOME MEASURE(S): Luteinizing hormone, FSH, T, and semen analysis. RESULT(S): Treatment with enclomiphene citrate resulted in increased morning serum T, E2, and LH levels similar to those obtained with a topical T gel in men with secondary hypogonadism. Follicle-stimulating hormone and LH were increased with enclomiphene, and sperm counts were conserved. CONCLUSION(S): Enclomiphene citrate reverses the two hallmarks of secondary hypogonadism, namely, low serum total T and low or inappropriately normal LH while preserving sperm production. CLINICAL TRIAL REGISTRATION NUMBER: NCT01270841 (ClinicalTrials.gov Identifier NCT01270841). PMID- 25044087 TI - Endometriosis in association with Herlyn-Werner-Wunderlich syndrome. AB - OBJECTIVE: To describe the clinical characteristics of patients with Herlyn Werner-Wunderlich syndrome (HWWS) and explore the relationship between an obstructive genital abnormality and pelvic endometriosis. DESIGN: Case series. SETTING: University hospital. PATIENT(S): A total of 94 women with Herlyn-Werner Wunderlich syndrome (HWWS). INTERVENTION(S): Retrospectively reviewed charts of patients diagnosed with HWWS and follow-up contact. MAIN OUTCOME MEASURE(S): Data for each patient regarding demographics, presenting symptoms, concomitant complications, and anatomic variations were obtained from operation notes and clinical records. RESULT(S): The occurrence of pelvic endometriosis was 19.15% (18/94) in patients with HWWS. All ovarian endometrial cysts (100%) occurred ipsilateral to the vaginal septum. Pelvic endometriosis was significantly more frequent in patients with complete hemivaginal obstructions (10/27, 37.0%) than those with incomplete obstructions (8/67, 11.9%). CONCLUSION(S): One-fifth of patients with HWWS were susceptible to pelvic endometriosis, and all of the ovarian endometriotic cysts were ipsilateral to the vaginal septum. Pelvic endometriosis in adolescents appeared to be related to the obstructed genital abnormality. Vaginal septum resection should be the first step in treatment and surgery has an important role in the treatment of endometriosis and pelvic adhesion. PMID- 25044088 TI - Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network. AB - OBJECTIVE: To determine consequences of lymphoma treatments on sperm characteristics and sperm DNA, and to evaluate predictors of sperm recovery. DESIGN: Multicenter prospective longitudinal study of patients analyzed before treatment and after 3, 6, 12, and 24 months. SETTING: University hospitals. PATIENT(S): Seventy-five Hodgkin lymphoma and non-Hodgkin lymphoma patients and a control group of 257 fertile men. INTERVENTION(S): Semen analyses, and sperm DNA and chromatin assessments. MAIN OUTCOME MEASURE(S): Comparisons of sperm characteristics before and after treatment. RESULT(S): Patients already had altered sperm characteristics before lymphoma treatment, with no identified risk factor. Sperm count, total sperm count, motility, and vitality decreased after treatment, with lowest values at 3 and 6 months. Twelve months after treatment, mean sperm count recovered to pretreatment values after doxorubicin, bleomycin, vinblastine, darcarbacine (ABVD) or ABVD+radiotherapy, but not after doxorubicin, cyclophosphamide, vincristine, prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, prednisone (MOPP) chemotherapies. It was noteworthy that 7% of patients remained azoospermic at 24 months. After 24 months, Kaplan-Meier estimates showed that more than 90% of patients will recover normal sperm count after ABVD or ABVD+radiotherapy vs. 61% for CHOP chemotherapies. In multivariate analyses including diagnosis and treatment protocol, only pretreatment total sperm count was related to recovery. Compared with a control group, lymphoma patients had higher sperm chromatin alterations and DNA fragmentation before any treatment. After treatment, DNA fragmentation assessed by TUNEL assay and sperm chromatin structure assay decreased from 3 and 6 months, respectively, while remaining higher than in the control group during follow-up. CONCLUSION(S): Lymphoma patients had altered sperm DNA and chromatin before treatment. Lymphoma treatment had damaging effects on spermatogenesis. These data on both the recovery period according to treatment modalities and the pre- and post-treatment chromatin status of sperm are useful tools for counseling patients wishing to conceive. PMID- 25044089 TI - Related impurities in peptide medicines. AB - Peptides are an increasingly important group of pharmaceuticals, positioned between classic small organic molecules and larger bio-molecules such as proteins. Currently, the peptide drug market is growing twice as fast as other drug markets, illustrating the increasing clinical as well as economical impact of this medicine group. Most peptides today are manufactured by solid-phase peptide synthesis (SPPS). This review will provide a structured overview of the most commonly observed peptide-related impurities in peptide medicines, encompassing the active pharmaceutical ingredients (API or drug substance) as well as the finished drug products. Not only is control of these peptide-related impurities and degradants critical for the already approved and clinically used peptide-drugs, these impurities also possess the capability of greatly influencing initial functionality studies during early drug discovery phases, possibly resulting in erroneous conclusions. The first group of peptide-related impurities is SPPS-related: deletion and insertion of amino acids are related to inefficient Fmoc-deprotection and excess use of amino acid reagents, respectively. Fmoc-deprotection can cause racemization of amino acid residues and thus diastereomeric impurities. Inefficient deprotection of amino acid side chains results into peptide-protection adducts. Furthermore, unprotected side chains can react with a variety of reagents used in the synthesis. Oxidation of amino acid side chains and dimeric-to-oligomeric impurities were also observed. Unwanted peptide counter ions such as trifluoroacetate, originating from the SPPS itself or from additional purification treatments, may also be present in the final peptide product. Contamination of the desired peptide product by other unrelated peptides was also seen, pointing out the lack of appropriate GMP. The second impurity group results from typical peptide degradation mechanisms such as beta-elimination, diketopiperazine, pyroglutamate and succinimide formation. These SPPS- and degradation-related impurity types can also found in the finished peptide drug products, which can additionally contain a third group of related impurities, i.e. the API-excipient degradation products. PMID- 25044090 TI - The isolation of antiprotozoal compounds from Libyan propolis. AB - Propolis is increasingly being explored as a source of biologically active compounds. Until now, there has been no study of Libyan propolis. Two samples were collected in North East Libya and tested for their activity against Trypanosoma brucei. Extracts from both samples had quite high activity. One of the samples was fractionated and yielded a number of active fractions. Three of the active fractions contained single compounds, which were found to be 13 epitorulosal, acetyl-13-epi-cupressic acid and 13-epi-cupressic acid, which have been described before in Mediterranean propolis. Two of the compounds had a minimum inhibitory concentration value of 1.56 ug/mL against T. brucei. The active fractions were also tested against macrophages infected with Leishmania donovani, and again moderate to strong activity was observed with the compounds having IC50 values in the range 5.1-21.9 ug/mL. PMID- 25044092 TI - Altered mental status in older adults with histamine2-receptor antagonists: a population-based study. AB - BACKGROUND: Standard doses of histamine2-receptor antagonists (H2RAs) may induce altered mental status in older adults, especially in those with chronic kidney disease (CKD). METHODS: Population-based cohort study of older adults who started a new H2RA between 2002 and 2011 was conducted. Ninety percent received the current standard H2RA dose in routine care. There was no significant difference in 27 baseline patient characteristics. The primary outcome was hospitalization with an urgent head computed tomography (CT) scan (proxy for altered mental status), and the secondary outcome was all-cause mortality also within 30days of a new H2RA prescription. RESULTS: Standard vs. low H2RA dose was associated with a higher risk of hospitalization with an urgent head CT scan (0.98% vs. 0.74%, absolute risk difference 0.24% [95% CI 0.11% to 0.36%], relative risk 1.33 [95% CI 1.12 to 1.58]). This risk was not modified by the presence of CKD (interaction P value=0.71). Standard vs. low H2RA dose was associated with a higher risk of mortality (1.07% vs.0.74%; absolute risk difference 0.34% [95% CI 0.20% to 0.46%], relative risk 1.46 [95% CI 1.23 to 1.73]). INTERPRETATION: Compared to a lower dose, initiation of the current standard dose of H2RA in older adults is associated with a small absolute increase in the 30-day risk of altered mental status (using neuroimaging as a proxy), even in the absence of CKD. This risk may be avoided by initiating older adults on low doses of H2RAs for gastroesophogeal reflux disease, and increasing dosing as necessary for symptom control. PMID- 25044093 TI - Thromboprophylaxis in patients with stroke: a delicate decision. PMID- 25044095 TI - Pulmonary embolism, where are the thrombi? PMID- 25044094 TI - A pragmatic triage system to reduce length of stay in medical emergency admission: feasibility study and health economic analysis. AB - BACKGROUND: Departments of Internal Medicine tend to treat patients on a first come first served basis. The effects of using triage systems are not known. METHODS: We studied a cohort in an Acute Medical Unit (AMU). A computer-assisted triage system using acute physiology, pre-existing illness and mobility identified five distinct risk categories. Management of the category of very low risk patients was streamlined by a dedicated Navigator. Main outcome parameters were length of hospital stay (LOS) and overall costs. Results were adjusted for the degree of frailty as measured by the Clinical Frailty Scale (CFS). A six month baseline phase and intervention phase were compared. RESULTS: 6764 patients were included: 3084 in the baseline and 3680 in the intervention phase. Patients with very low risk of death accounted for 40% of the cohort. The LOS of the 1489 patients with very low risk of death in the intervention group was reduced by a mean of 1.85days if compared with the 1276 patients with very low risk in the baseline cohort. This was true even after adjustment for frailty. Over the six month period the cost of care was reduced by L250,158 in very low patients with no increase in readmissions or 30day mortality. CONCLUSIONS: Implementation of an advanced triage system had a measurable impact on cost of care for patients with very low risk of death. Patients were safely discharged earlier to their own home and the intervention was cost-effective. PMID- 25044096 TI - cC1qR/CR and gC1qR/p33: observations in cancer. AB - The survival and growth of a primary tumor depends, by and large, on three major events: immune evasion, angiogenesis and metastasis. Tumor cells are "modified self", and as such express a plethora of modified surface antigens capable of inducing antibody production. Anti-tumor cell antibodies should, in theory, activate complement resulting in cell destruction. But this is not the case. Akin to many pathogenic microorganisms whose survival depends on evading the immune system, cancer cells have also evolved diverse mechanisms to prevent host mediated cell destruction by either retaining critical regulatory molecules or by hijacking host proteins to ensure their survival. Although immune evasion, angiogenesis and metastasis are complex biological processes involving a myriad of tumor associated proteins, enzymes, and cytokines, C1qRs can, nonetheless play an important role in all or part of these processes. Although both cC1qR/CR and gC1qR are expressed by all somatic cells, with the exception of red blood cells, both are highly upregulated on almost all types of tumors. It is not surprising therefore that blockade of C1qR on tumor cells inhibits their proliferation suggesting the significance of C1qRs in tumor growth and progression. Interestingly, the two C1q receptors: cC1qR/CR and gC1qR play a differential role in carcinogenesis. While gC1qR promotes tumor cell survival by enhancing angiogenesis and metastasis and also by contributing to the hypercoagulable and prothrombotic microenvironment, cC1qR/CR expression represents a pro-phagocytic "eat-me" signal through which cC1qR/CR expressing tumor cells are tagged for destruction by macrophages. The data accumulated to date therefore identify gC1qR and cC1qR/CR as potential targets for the design of either protein-based, antibody-based or chemical based therapeutic intervention that could be used to enhance conventional anti-cancer therapy. The inhibition of tumor cell proliferation by monoclonal antibody recognizing the C1q site on gC1qR, as well as the identification of agents such as anthracyclin that enhance cC1qR/CR expression on tumor cells, are indeed steps in the right direction. PMID- 25044097 TI - Restoration of MBL-deficiency: redefining the safety, efficacy and viability of MBL-substitution therapy. AB - MBL-deficiency is a commonly occurring deficiency of the innate immune system, affecting a substantial part of the population and has been extensively studied. MBL appears to function as a disease modifier. The role of MBL in different conditions is context-dependent. Many clinical studies show conflicting results, which can be partially explained by different definitions of MBL-deficiency, including phenotype- and genotype-based approaches. In this review we give an overview of literature of MBL, its role in different pathologies, diseases and patient populations. We review MBL replacement studies, and discuss the potential of MBL substitution therapy. We finally suggest that new MBL substitution trials should be conducted within a predefined patient population. MBL-deficiency should be based on serum levels and confirmed by genotyping. PMID- 25044098 TI - A polythiophene derivative with superior properties for practical application in polymer solar cells. AB - A polythiophene derivative called PDCBT, which has a backbone of thiophene units and just carboxylate functional groups to modulate its properties, exhibits properties superior to those of poly(3-hexylthiophene), the classic polythiophene derivative, when used as an electron donor in polymer solar cells (PSCs). The best device, based on PDCBT/PC71BM (1:1), develops a good power conversion efficiency of 7.2%. PMID- 25044099 TI - The clopidogrel conundrum. PMID- 25044100 TI - Clopidogrel, CYP2C19 and proton pump inhibitors: what we know and what it means. PMID- 25044101 TI - Miscibility and ordered structures of MgO-ZnO alloys under high pressure. AB - The MgxZn(1-x)O alloy system may provide an optically tunable family of wide band gap materials that can be used in various UV luminescences, absorption, lighting, and display applications. A systematic investigation of the MgO-ZnO system using ab initio evolutionary simulations shows that MgxZn(1-x)O alloys exist in ordered ground-state structures at pressures above about 6.5 GPa. Detailed enthalpy calculations for the most stable structures allowed us to construct the pressure composition phase diagram. In the entire composition, no phase transition from wurzite to rock-salt takes place with increasing Mg content. We also found two different slops occur at near x = 0.75 of Eg-x curves for different pressures, and the band gaps of high pressure ground-state MgxZn(1-x)O alloys at the Mg concentration of x > 0.75 increase more rapidly than x < 0.75. PMID- 25044102 TI - Cationic oligo(p-phenylene vinylene) materials for combating drug resistance of cancer cells by light manipulation. AB - An unconventional strategy that can be temporally and remotely activated with light to combat the drug resistance of cancer cells is developed. A cell-membrane anchored photosensitizer (OPV) is used to enhance anticancer drug uptake and restore toxicity in resistant cancer cells. This method recovers the activity of the already established anticancer drugs, and provides a new strategy for the development of light manipulation to combat anticancer resistance. PMID- 25044103 TI - Phase II study of the GI-4000 KRAS vaccine after curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, or G12V mutation. AB - INTRODUCTION: Patients with early-stage lung cancer have a high risk of recurrence despite multimodality therapy. KRAS-mutant lung adenocarcinomas are the largest genetically defined subgroup, representing 25% of patients. GI-4000 is a heat-killed recombinant Saccharomyces cerevisiae yeast-derived vaccine expressing mutant KRAS proteins. The present phase II study assessed the feasibility, immunogenicity, and safety of the GI-4000 vaccine in patients with early-stage, KRAS-mutant lung cancer. MATERIALS AND METHODS: Patients with stage I-III KRAS-mutant lung cancer who completed curative therapy were enrolled. The patients received the genotype matched GI-4000 vaccine for <= 3 years or until intolerance, disease recurrence, or death. The KRAS antigen T-cell response was assessed using the interferon-gamma enzyme-linked immunospot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response in >= 25% of patients. RESULTS: A total of 24 patients were enrolled over 28 months. No vaccine-related serious adverse events occurred. One patient withdrew consent because of pain at the injection site. The study met its primary endpoint, with 50% of patients developing an immune response to mutant KRAS. The median number of vaccinations received was 15 (range, 1-19). Ten patients experienced disease recurrence, and 6 died. Compared with the genotypically matched historical controls, the recurrence rates were equivalent but overall survival showed a favorable trend. CONCLUSION: GI-4000 was well tolerated and immunogenic when used as consolidation therapy in patients with stage I-III KRAS-mutant lung cancer. The patterns of recurrence and death observed in the present study can be used to design a randomized study of GI-4000 with overall survival as the primary endpoint. PMID- 25044104 TI - Prognostic significance of genotype and number of metastatic sites in advanced non-small-cell lung cancer. AB - BACKGROUND: TNM stage remains the most important prognostic factor in clinical practice. The 7th edition lung cancer staging system has not considered some important prognostic factors, such as the number of metastatic organ sites and the molecular biologic characterization. PATIENTS AND METHODS: Using driver gene alternation and tumor burden, advanced NSCLC cases were divided into 3 groups: M1 I group, epidermal growth factor (EGFR)-positive and/or anaplastic lymphoma kinase (ALK)-positive; MI-II, wild-type EGFR and ALK with intrathoracic metastasis or 1 distant metastatic organ with <= 3 metastasis lesions; and MI III, wild-type EGFR and ALK with 1 distant metastatic organ with > 3 metastasis lesions or multiple metastatic organs. Overall survival was comparable between the 7th edition staging system and our category of M descriptors. RESULTS: A total of 627 patients with stage IV NSCLC newly diagnosed at Guangdong Lung Cancer Institute between January 2009 and July 2012 were enrolled in the present study. The median overall survival (OS) was 22.2 (95% CI, 19.590-24.810), 15.5 (95% CI, 13.176-17.824), and 10.0 (95% CI, 8.033-11.967) months for M1-I, M1-II, and M1-III, respectively (P < .001). According to the 7th edition of the TNM staging system, the median OS of the M1a and M1b groups was 22.8 (95% CI, 19.484 26.116) and 13.7 (95% CI, 11.793-15.607) months, respectively (P < .001). The maximum of the absolute values of the M1 category for our study and the 7th TNM staging system was 5.881 and 5.089, respectively. CONCLUSION: Advanced NSCLC could potentially be further divided into 3 subgroups according to the genotype and number of metastatic organ sites and metastasis lesions. PMID- 25044105 TI - Validated spectrofluorimetric and spectrophotometric methods for the determination of brimonidine tartrate in ophthalmic solutions via derivatization with NBD-Cl. Application to stability study. AB - Two simple, selective and accurate methods were developed and validated for the determination of brimonidine tartrate (BT) in pure state and pharmaceutical formulations. Both methods are based on the coupling of the drug with 4-chloro-7 nitro-2,1,3-benzoxadiazole in borate buffer (pH 8.5) at 70 degrees C and measurement of the reaction product spectrophotometrically at 407 nm (method I) or spectrofluorimetrically at 528 nm upon excitation at 460 nm (method II). The calibration graphs were rectilinear over the concentration ranges of 1.0-16.0 and 0.1-4.0 ug/mL with lower detection limits of 0.21 and 0.03, and lower quantification limits of 0.65 and 0.09 ug/mL for methods I and II, respectively. Both methods were successfully applied to the analysis of commercial ophthalmic solution with mean recovery of 99.50 +/- 1.00 and 100.13 +/- 0.71%, respectively. Statistical analysis of the results obtained by the proposed methods revealed good agreement with those obtained using a comparison method. The proposed spectrofluorimetric method was extended to a stability study of BT under different ICH-outlined conditions such as alkaline, acidic, oxidative and photolytic degradation. Furthermore, the kinetics of oxidative degradation of the drug was investigated and the apparent first-order reaction rate constants, half life times and Arrhenius equation were estimated. The proposed methods are practical and valuable for routine applications in quality control laboratories for the analysis of BT. PMID- 25044106 TI - Estimating and testing pleiotropy of single genetic variant for two quantitative traits. AB - Along with the accumulated data of genetic variants and biomedical phenotypes in the genome era, statistical identification of pleiotropy is of growing interest for dissecting and understanding genetic correlations between complex traits. We proposed a novel method for estimating and testing pleiotropic effect of a genetic variant on two quantitative traits. Based on a covariance decomposition and estimation, our method quantifies pleiotropy as the portion of between-trait correlation explained by the same genetic variant. Unlike most multiple-trait methods that assess potential pleiotropy (i.e., whether a variant contributes to at least one trait), our method formulates a statistic that tests exact pleiotropy (i.e., whether a variant contributes to both of two traits). We developed two approaches (a regression approach and a bootstrapping approach) for such test and investigated their statistical properties, in comparison with other potential pleiotropy test methods. Our simulation shows that the regression approach produces correct P-values under both the complete null (i.e., a variant has no effect on both two traits) and the incomplete null (i.e., a variant has effect on only one of two traits), but requires large sample sizes to achieve a good power, when the bootstrapping approach has a better power and produces conservative P-values under the complete null. We demonstrate our method for detecting exact pleiotropy using a real GWAS dataset. Our method provides an easy to-implement tool for measuring, testing, and understanding the pleiotropic effect of a single variant on the correlation architecture of two complex traits. PMID- 25044107 TI - Flt3 ligand does not differentiate between Parkinsonian disorders. AB - BACKGROUND: Differential diagnosis of parkinsonian disorders is challenging because of overlapping symptoms, especially during early stages of disease. No validated biomarkers are available for early and accurate diagnosis of multiple system atrophy and other parkinsonian disorders. It has been reported that flt3 ligand levels in cerebrospinal fluid could clearly differentiate patients with Parkinson's disease from patients with multiple system atrophy, with 99% sensitivity and 95% specificity. METHODS: We measured flt3 ligand levels in cerebrospinal fluid of subjects with Parkinson's disease (n = 37), multiple system atrophy (n = 30), and progressive supranuclear palsy (n = 19). RESULTS: In our cohort, no significant difference was found in flt3 ligand levels between Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. CONCLUSIONS: Our results suggest that cerebrospinal fluid flt3 ligand levels do not differentiate between parkinsonian disorders. PMID- 25044108 TI - Drug encapsulation and release by mesoporous silica nanoparticles: the effect of surface functional groups. AB - Mesoporous silica nanoparticles (MSNPs) have been widely used as drug carriers for stimuli-responsive drug delivery. Herein, a catalysis screening technique was adopted for analyzing the effects of chain length, terminal group, and density of disulfide-appended functional ligands on the surface of MSNPs on drug-loading capacity and glutathione-triggered drug-release kinetics. The ligand with an intermediate length (5 carbon atoms) and a bulky terminal group (cyclohexyl) that complexes with thebeta-cyclodextrin ring showed the highest drug loading capacity as well as good release kinetics. In addition, decreasing the surface coverage of the functional ligands led to an enhancement in drug release. In vitro drug delivery experiments on a melanoma cell line (B16-F10) by using the functionalized MSNPs further supported the conclusion. The results obtained may serve as a general guide for developing more effective MSNP systems for drug delivery. PMID- 25044109 TI - Characterization of rat serum amyloid A4 (SAA4): a novel member of the SAA superfamily. AB - The serum amyloid A (SAA) family of proteins is encoded by multiple genes, which display allelic variation and a high degree of homology in mammals. The SAA1/2 genes code for non-glycosylated acute-phase SAA1/2 proteins, that may increase up to 1000-fold during inflammation. The SAA4 gene, well characterized in humans (hSAA4) and mice (mSaa4) codes for a SAA4 protein that is glycosylated only in humans. We here report on a previously uncharacterized SAA4 gene (rSAA4) and its product in Rattus norvegicus, the only mammalian species known not to express acute-phase SAA. The exon/intron organization of rSAA4 is similar to that reported for hSAA4 and mSaa4. By performing 5'- and 3'RACE, we identified a 1830 bases containing rSAA4 mRNA (including a GA-dinucleotide tandem repeat). Highest rSAA4 mRNA expression was detected in rat liver. In McA-RH7777 rat hepatoma cells, rSAA4 transcription was significantly upregulated in response to LPS and IL-6 while IL-1alpha/beta and TNFalpha were without effect. Luciferase assays with promoter-truncation constructs identified three proximal C/EBP-elements that mediate expression of rSAA4 in McA-RH7777 cells. In line with sequence prediction a 14-kDa non-glycosylated SAA4 protein is abundantly expressed in rat liver. Fluorescence microscopy revealed predominant localization of rSAA4-GFP-tagged fusion protein in the ER. PMID- 25044111 TI - Hypoxia induces FoxO3a-mediated dysfunction of blood-brain barrier. AB - The Forkhead box O 3a (FoxO3a), a transcription factor, is known to be involve in change of endothelial permeability. During hypoxia, blood-brain barrier (BBB) permeability is increased through degradation of vascular endothelium cadherin (VE-cadherin) and clsudin-5. The hypoxia also increased mRNA levels of matrix metalloproteinase (MMP)-3/9 and promoted translocation of FoxO3a into nucleus in endothelial cells. However, little is known about the role of FoxO3a in hypoxia induced BBB hyperpermeability. Here, we examined whether FoxO3a regulates hypoxia induced BBB permeability through induction of MMPs. The transfection of siFoxO3a suppressed hypoxia-induced BBB hyperpermeability. The transfection of siFoxO3a also inhibited hypoxia-induced degradation of VE-cadherin and claudin-5. In addition, the transfection of siFoxO3a reduced hypoxia-induced increase of MMP-3 mRNA levels. However, transfection of siFoxO3a did not inhibits transcription of MMP-9 induced by hypoxia. Taken together, our findings suggest that FoxO3a is involved in hypoxia-induced degradation of VE-cadherin and claudin-5 through induction of MMPs indirectly. PMID- 25044110 TI - Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells. AB - Regulatory T cells (Treg cells) are crucial for the maintenance of immunological tolerance, and it has been reported that Treg cells are enriched within the tumor micro-environment for immune evasion due to their immunosuppressive functions. To inhibit Treg cells functions, FoxP3, a lineage-specific transcription factor responsible for the differentiation and functions of Treg cells, was functionally targeted by a nucleus-transducible (nt) form of various FoxP3 functional subdomains. These nt modified domains can be delivered into the nucleus effectively and work as interactomic inhibitors via disruption of the endogenous FoxP3-mediated transcription complex. Among these domains, nt-FoxP3-FKH (Forkhead DNA binding domain) is most effective at restoring NFAT activity suppressed by FoxP3, and inhibiting the binding of endogenous FKH-containing proteins to FKH DNA binding sequences without influencing the viability and activation of T cells. The suppressive functions of TGF-beta-induced iTreg cells and thymus derived tTreg cells were substantially blocked by nt-FoxP3-FKH, accompanied with down-regulation of CTLA-4 surface expression and IL-10 secretion of Treg cells. In addition, nt-FoxP3-FKH upregulated the expression of IL-2 and IFN-gamma in Treg cells. Therefore, nt-FoxP3-FKH has the potential to be a novel therapeutic agent to modulate the immune-evasive tumor environment created by Treg cells without the need for genetic modifications. PMID- 25044112 TI - Comparative genomic and proteomic analyses of Clostridium acetobutylicum Rh8 and its parent strain DSM 1731 revealed new understandings on butanol tolerance. AB - Clostridium acetobutylicum strain Rh8 is a butanol-tolerant mutant which can tolerate up to 19g/L butanol, 46% higher than that of its parent strain DSM 1731. We previously performed comparative cytoplasm- and membrane-proteomic analyses to understand the mechanism underlying the improved butanol tolerance of strain Rh8. In this work, we further extended this comparison to the genomic level. Compared with the genome of the parent strain DSM 1731, two insertion sites, four deletion sites, and 67 single nucleotide variations (SNVs) are distributed throughout the genome of strain Rh8. Among the 67 SNVs, 16 SNVs are located in the predicted promoters and intergenic regions; while 29 SNVs are located in the coding sequence, affecting a total of 21 proteins involved in transport, cell structure, DNA replication, and protein translation. The remaining 22 SNVs are located in the ribosomal genes, affecting a total of 12 rRNA genes in different operons. Analysis of previous comparative proteomic data indicated that none of the differentially expressed proteins have mutations in its corresponding genes. Rchange Algorithms analysis indicated that the mutations occurred in the ribosomal genes might change the ribosome RNA thermodynamic characteristics, thus affect the translation strength of these proteins. Take together, the improved butanol tolerance of C. acetobutylicum strain Rh8 might be acquired through regulating the translational process to achieve different expression strength of genes involved in butanol tolerance. PMID- 25044113 TI - In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9. AB - Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy. PMID- 25044114 TI - Myogenin is a positive regulator of MEGF10 expression in skeletal muscle. AB - MEGF10 is known to function as a myogenic regulator of satellite cells in skeletal muscle. Mutations in MEGF10 gene cause a congenital myopathy called early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Despite its biological importance in muscle physiology, transcriptional regulation of the MEGF10 gene is unknown. Here, we characterized the 5' flanking region of the human MEGF10 gene and showed that the role of myogenic basic helix loop-helix factor (bHLH) myogenin in MEGF10 transcription in muscle cells. Myogenin was found to share a similar expression pattern with MEGF10 during muscle regeneration and to increase the promoter activity of the MEGF10 gene in C2C12 cells. Overexpression of myogenin led to upregulation of MEGF10 mRNA in C2C12 cells. Site-directed mutagenesis assays revealed that the conserved E-box element at the region -114/-108 serves as a myogenin-binding motif. Promoter enzyme immunoassays and chromatin immunoprecipitation analysis showed direct interaction between myogenin and the myogenin-binding motif in the MEGF10 promoter. Taken together, these results indicate that myogenin is a positive regulator in transcriptional regulation of MEGF10 in skeletal muscle. PMID- 25044115 TI - 5-(2-carboxyethenyl) isatin derivative induces G2/M cell cycle arrest and apoptosis in human leukemia K562 cells. AB - Our previous study successfully identified that the novel isatin derivative (E) methyl 3-(1-(4-methoxybenzyl)-2,3-dioxoindolin-5-yl) acrylate (HKL 2H) acts as an anticancer agent at an inhibitory concentration (IC50) level of 3nM. In this study, the molecular mechanism how HKL 2H induces cytotoxic activity in the human chronic myelogenous leukemia K562 cells was investigated. Flow cytometric analysis showed that the cells were arrested in the G2/M phase and accumulated subsequently in the sub-G1 phase in the presence of HKL 2H. HKL 2H treatment down regulated the expressions of CDK1 and cyclin B but up-regulated the level of phosphorylated CDK1. Annexin-V staining and the classic DNA ladder studies showed that HKL 2H induced the apoptosis of K562 cells. Our study further showed that HKL 2H treatment caused the dissipation of mitochondrial membrane potential, activated caspase-3 and lowered the Bcl-2/Bax ratio in K562 cells, suggesting that the HKL 2H-causing programmed cell death of K562 cells was caused via the mitochondrial apoptotic pathway. Taken together, our data demonstrated that HKL 2H, a 5-(2-carboxyethenyl) isatin derivative, notably induces G2/M cell cycle arrest and mitochondrial-mediated apoptosis in K562 cells, indicating that this compound could be a promising anticancer candidate for further investigation. PMID- 25044116 TI - Autophagy is induced by raptor degradation via the ubiquitin/proteasome system in granular corneal dystrophy type 2. AB - Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disorder that is caused by a point mutation in transforming growth factor-beta-induced gene-h3 (TGFBI), which encodes transforming growth factor-beta-induced protein (TGFBIp). Recently, we found that the autophagic clearance of mutant-TGFBIp is delayed in GCD2 corneal fibroblasts; however, any potential correlation between mutant TGFBIp turnover and autophagy-lysosome pathway remains unknown. Here, we report that mutant-TGFBIp is accumulated and that autophagy, a key clearance pathway for mutant-TGFBIp, is induced in primary cultured GCD2 homozygous (HO) and wild-type (WT) corneal fibroblasts that express exogenously introduced mutant-TGFBIp. Mutant-TGFBI colocalized with LC3-enriched cytosolic vesicles and cathepsin D in primary cultured GCD2 corneal fibroblasts. We also observed reduced levels of raptor (regulatory-associated protein of the mammalian target of rapamycin [mTOR]) in GCD2 corneal fibroblasts and WT corneal fibroblasts expressing mutant TGFBIp. Strikingly, treatment with MG132, a ubiquitin/proteasome system inhibitor, significantly increased the levels of both total and ubiquitinated raptor in GCD2 corneal fibroblasts. The levels of the autophagy marker LC3-II were also increased in WT corneal fibroblasts that were treated with shRNA against raptor. However, mutant-TGFBIp accumulated in autophagosomes or/and lysosomes in spite of the significant activation of basal autophagy in GCD2 corneal fibroblasts. These results suggest that an insufficient autophagy lysosome pathway might be responsible for the intracellular accumulation of mutant-TGFBIp during the pathogenesis of GCD2. PMID- 25044117 TI - Cilostazol prevents the degradation of collagen type II in human chondrocytes. AB - The alteration of extracellular matrix (ECM) in cartilage during the pathological development of Osteoarthritis (OA) changes the biomechanical environment of chondrocytes, which further drives the progression of the disease in the presence of inflammation. Healthy cartilage matrix mainly contains collagen type II, which is degraded by matrix metalloproteinase13 (MMP13), an important molecules responsible for joint damage in OA. Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5 yl)butoxy]-3,4-dihydro-2-(1H)-quinolinone) is a medication approved by the US Food and Drug Administration and used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease. In this study, we reported that cilostazol is able to suppress the degradation of type II collagen in human chondrocytes induced by IL-1beta. Mechanistically, cilostazol treatment leads to inhibiting the expression of IRF-1, thereby prevents the induction of MMP-13. Signal transducers and activator of transcription 1 (STAT1) has been reported to play an essential role in regulating the activation of IRF-1. Our results indicated that cilostazol suppresses the activation of STAT1 by mitigating the phosphorylation of STAT1 at Ser727 and tyrosine phosphorylation of STAT1 at position 701 (Tyr701). PMID- 25044118 TI - Orai-2 is localized on secretory granules and regulates antigen-evoked Ca2+ mobilization and exocytosis in mast cells. AB - The increase in intracellular Ca(2+) through the Ca(2+) channel is an indispensable step for the secretion of inflammatory mediators by mast cells. It was recently reported that Orai-1 is responsible for the Ca(2+) influx that is activated by depletion of stored Ca(2+). There are three isoforms of Orai: Orai 1, Orai-2, and Orai-3; however, isoforms other than Orai-1 are poorly understood. We found that Orai-2 is expressed and localized on secretory granules in RBL-2H3. Ca(2+) release from Ca(2+) store, induced by antigen stimulation, was significantly attenuated by knockdown of Orai-2, while that induced by thapsigargin was not affected. Furthermore, exocytotic release induced by antigen stimulation was inhibited in knockdown cells. This observation suggests a new role of Orai isoforms in secretory cells. PMID- 25044119 TI - The kinetics of thermal stress induced denaturation of Aquaporin 0. AB - Aquaporin 0 (AQP0) is an integral membrane protein that facilitates water transport and cellular adhesion in the lens. Its dysfunction has been associated with cataractogenesis. Our earlier studies showed AQP0 undergoes aggregation when subjected to thermal stress and this aggregation seems to have been facilitated by mechanical agitation brought about by gentle stirring. The purpose of this study is to determine the secondary structural changes that precede aggregation and the role that alpha-crystallin plays in inhibiting those structural changes. Detergent solubilized calf lens AQP0 was subjected to thermal stress at 50 degrees C for varying times. Secondary structural changes were measured by Circular Dichroism (CD) spectropolarimetry. Convex constraint analysis was used to deconvolute the CD spectra into pure component curves representing the secondary structural elements. Our results showed that under thermal stress, the alpha-helix content of AQP0 decreased from 50% to 7% with a concomitant increase from 0% to 52% in beta-sheet content. The time-dependent loss of alpha-helical structure and gain of beta-sheet structure appear to follow first-order kinetics with very similar values (~30min) suggesting a single transition. In the presence of alpha-crystallin, this conversion to beta-sheet is minimized, suggesting that the protein structure that binds to the molecular chaperone is mostly the alpha helical structure of AQP0. PMID- 25044120 TI - Isoform-specific proteasomal degradation of Rbfox3 during chicken embryonic development. AB - Rbfox3, a neuron-specific RNA-binding protein, plays an important role in neuronal differentiation during development. An isoform Rbfox3-d31, which excludes the 93-nucleotide cassette exon within the RNA recognition motif of chicken Rbfox3, has been previously identified. However, the cellular functions of Rbfox3-d31 remain largely unknown. Here we find that Rbfox3-d31 mRNA is highly expressed during the early developmental stages of the chicken embryo, while Rbfox3-d31 protein is barely detected during the same stage due to its rapid degradation mediated by the ubiquitin-proteasome pathway. Importantly, this degradation is specific to the Rbfox3-d31 isoform and it does not occur with full length Rbfox3. Furthermore, suppression of Rbfox3-d31 protein degradation with the proteasome inhibitor MG132 attenuates the splicing activity of another Rbfox family member Rbfox2 by altering the subcellular localization of Rbfox2. These results suggest that Rbfox3-d31 functions as a repressor for the splicing activity of the Rbfox family and its protein level is regulated in an isoform specific manner in vivo. PMID- 25044121 TI - Constitutive NF-kappaB activation and tumor-growth promotion by Romo1-mediated reactive oxygen species production. AB - Deregulation of nuclear factor-kappaB (NF-kappaB) and related pathways contribute to tumor cell proliferation and invasion. Mechanisms for constitutive NF-kappaB activation are not fully explained; however, the underlying defects appear to generate and maintain pro-oxidative conditions. In hepatocellular carcinoma (HCC) tissues, up-regulation of reactive oxygen species modulator 1 (Romo1) correlates positively with tumor size. In the present study, we showed that Romo1 expression is required to maintain constitutive nuclear DNA-binding activity of NF-kappaB and transcriptional activity through constitutive IkappaBalpha phosphorylation. Overexpression of Romo1 promoted p65 nuclear translocation and DNA-binding activity. We also show that Romo1 depletion suppressed anchorage-independent colony formation by HCC cells and suppressed tumor growth in vivo. Based on these findings, Romo1 may be a principal regulatory factor in the maintenance of constitutive NF-kappaB activation in tumor cells. In the interest of anti proliferative treatments for cancer, Romo1 may also present a productive target for drug development. PMID- 25044122 TI - Cervical cancer: is the wall crumbling? PMID- 25044123 TI - The microanatomy of spinal cord injury: a review. AB - Spinal cord injury is a highly prevalent condition associated with significant morbidity and mortality. The pathophysiology underlying it is extraordinarily complex and still not completely understood. We performed a comprehensive literature review of the pathophysiologic processes underlying spinal cord injury. The mechanisms underlying primary and secondary spinal cord injury are distinguished based on a number of factors and include the initial mechanical injury force, the vascular supply of the spinal cord which is associated with spinal cord perfusion, spinal cord autoregulation, and post-traumatic ischemia, and a complex inflammatory cascade involving local and infiltrating immunomodulating cells. This review illustrates the current literature regarding the pathophysiology behind spinal cord injury and outlines potential therapeutic options for reversing these mechanisms. PMID- 25044124 TI - Quasi-2D dynamic jamming in cornstarch suspensions: visualization and force measurements. AB - We report experiments investigating jamming fronts in a floating layer of cornstarch suspension. The suspension has a packing fraction close to jamming, which dynamically turns into a solid when impacted at a high speed. We show that the front propagates in both axial and transverse direction from the point of impact, with a constant ratio between the two directions of propagation of approximately 2. Inside the jammed solid, we observe an additional compression, which results from the increasing stress as the solid grows. During the initial growth of the jammed solid, we measure a force response that can be completely accounted for by added mass. Only once the jamming front reaches a boundary, the added mass cannot account for the measured force anymore. We do not, however, immediately see a strong force response as we would expect when compressing a jammed packing. Instead, we observe a delay in the force response on the pusher, which corresponds to the time it takes for the system to develop a close to uniform velocity gradient that spans the complete system. PMID- 25044125 TI - A neuronal gamma oscillatory signature during morphological unification in the left occipitotemporal junction. AB - Morphology is the aspect of language concerned with the internal structure of words. In the past decades, a large body of masked priming (behavioral and neuroimaging) data has suggested that the visual word recognition system automatically decomposes any morphologically complex word into a stem and its constituent morphemes. Yet the reliance of morphology on other reading processes (e.g., orthography and semantics), as well as its underlying neuronal mechanisms are yet to be determined. In the current magnetoencephalography study, we addressed morphology from the perspective of the unification framework, that is, by applying the Hold/Release paradigm, morphological unification was simulated via the assembly of internal morphemic units into a whole word. Trials representing real words were divided into words with a transparent (true) or a nontransparent (pseudo) morphological relationship. Morphological unification of truly suffixed words was faster and more accurate and additionally enhanced induced oscillations in the narrow gamma band (60-85 Hz, 260-440 ms) in the left posterior occipitotemporal junction. This neural signature could not be explained by a mere automatic lexical processing (i.e., stem perception), but more likely it related to a semantic access step during the morphological unification process. By demonstrating the validity of unification at the morphological level, this study contributes to the vast empirical evidence on unification across other language processes. Furthermore, we point out that morphological unification relies on the retrieval of lexical semantic associations via induced gamma band oscillations in a cerebral hub region for visual word form processing. PMID- 25044128 TI - Localized electric field induced transition and miniaturization of two-phase flow patterns inside microchannels. AB - Strategic application of external electrostatic field on a pressure-driven two phase flow inside a microchannel can transform the stratified or slug flow patterns into droplets. The localized electrohydrodynamic stress at the interface of the immiscible liquids can engender a liquid-dielectrophoretic deformation, which disrupts the balance of the viscous, capillary, and inertial forces of a pressure-driven flow to engender such flow morphologies. Interestingly, the size, shape, and frequency of the droplets can be tuned by varying the field intensity, location of the electric field, surface properties of the channel or fluids, viscosity ratio of the fluids, and the flow ratio of the phases. Higher field intensity with lower interfacial tension is found to facilitate the oil droplet formation with a higher throughput inside the hydrophilic microchannels. The method is successful in breaking down the regular pressure-driven flow patterns even when the fluid inlets are exchanged in the microchannel. The simulations identify the conditions to develop interesting flow morphologies, such as (i) an array of miniaturized spherical or hemispherical or elongated oil drops in continuous water phase, (ii) "oil-in-water" microemulsion with varying size and shape of oil droplets. The results reported can be of significance in improving the efficiency of multiphase microreactors where the flow patterns composed of droplets are preferred because of the availability of higher interfacial area for reactions or heat and mass exchange. PMID- 25044127 TI - SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. AB - Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UE(UA)) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UE(UA), suggesting that SUA decreased as a result of the increase in the UE(UA). The increase in UE(UA) was correlated with an increase in urinary D-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UE(UA) is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9DeltaN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and D-glucose. It was observed that the efflux of [(14) C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans stimulated by 10 mm D-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [(14) C]UA by oocytes was cis inhibited by 100 mm D-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UE(UA) could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. PMID- 25044129 TI - The association between sociodemographic characteristics and postpartum depression symptoms among Arab-Bedouin women in Southern Israel. AB - BACKGROUND: Prevalence rates of postpartum depression (PPD) are 10 to 20% among various populations. Little is known about the characteristics of PPD among populations experiencing cultural transition. This study aimed to assess PPD symptoms (PPDS) prevalence and to identify risk factors unique to Arab-Bedouin women in southern Israel. METHODS: The sample included 564 women who visited maternal and child health clinics. Sociodemographic characteristics were obtained using in-person interviews. PPDS were assessed using a validated Arabic translation of the Edinburgh Postnatal Depression Scale (EPDS). Prevalence of PPDS was estimated using the cut-off score of EPDS >=10; a more stringent cut-off score of EPDS >=13 was used to define women with moderate to severe PPDS. RESULTS: The prevalence of PPDS among women was 31%, of which 19.1% were assessed as having moderate to severe symptoms (EPDS >= 13). In a multivariate logistic regression, the variables associated with EPDS >=10 were having an ill-infant odds ratio (OR) = 3.9, lack of husband's support (OR = 2.6), history of emotional problems (OR = 3.2), low income (OR = 1.6), low level of education (OR = 1.6), high marital conflicts (OR = 1.5), and an unplanned pregnancy (OR = 1.5). CONCLUSION: In the generally understudied population of Arab-Bedouin women living in southern Israel, we found a high prevalence of PPDS. The unique risk factors described in our research can inform health care professionals in designing interventions for early detection and prevention of PPD. PMID- 25044130 TI - Out-of-sample validation for structured expert judgment of Asian carp establishment in Lake Erie. AB - Structured expert judgment (SEJ) is used to quantify the uncertainty of nonindigenous fish (bighead carp [Hypophthalmichthys nobilis] and silver carp [H. molitrix]) establishment in Lake Erie. The classical model for structured expert judgment model is applied. Forming a weighted combination (called a decision maker) of experts' distributions, with weights derived from performance on a set of calibration variables from the experts' field, exhibits greater statistical accuracy and greater informativeness than simple averaging with equal weights. New methods of cross validation are applied and suggest that performance characteristics relative to equal weighting could be predicted with a small number (1-2) of calibration variables. The performance-based decision maker is somewhat degraded on out-of-sample prediction, but remained superior to the equal weight decision maker in terms of statistical accuracy and informativeness. PMID- 25044132 TI - Mechanical properties and failure mechanisms of graphene under a central load. AB - By employing molecular dynamics simulations, the evolution of deformation of a monolayer graphene sheet under a central transverse loading are investigated. Dependence of mechanical responses on the symmetry (shape) of the loading domain, on the size of the graphene sheet, and on temperature, is determined. It is found that the symmetry of the loading domain plays a central role in fracture strength and strain. By increasing the size of the graphene sheet or increasing temperature, the tensile strength and fracture strain decrease. The results have demonstrated that the breaking force and breaking displacement are sensitive to both temperature and the symmetry of the loading domain. In addition, we find that the intrinsic strength of graphene under a central load is much smaller than that of graphene under a uniaxial load. By examining the deformation processes, two failure mechanisms are identified namely, brittle bond breaking and plastic relaxation. In the second mechanism, the Stone-Wales transformation occurs. PMID- 25044131 TI - Artemin augments survival and axon regeneration in axotomized retinal ganglion cells. AB - Artemin, a recently discovered member of the glial cell line-derived neurotrophic factor (GDNF) family, has neurotrophic effects on damaged neurons, including sympathetic neurons, dopamine neurons, and spiral ganglion neurons both in vivo and in vitro. However, its effects on retinal cells and its intracellular signaling remain relatively unexplored. During development, expression of GFRalpha3, a specific receptor for artemin, is strong in the immature retina and gradually decreases during maturation, suggesting a possible role in the formation of retinal connections. Optic nerve damage in mature rats causes levels of GFRalpha3 mRNA to increase tenfold in the retina within 3 days. GFRalpha3 mRNA levels continue to rise within the first week and then decline. Artemin, a specific ligand for GFRalpha3, has a neuroprotective effect on axotomized retinal ganglion cells (RGCs) in vivo and in vitro via activation of the extracellular signal-related kinase- and phosphoinositide 3-kinase-Akt signaling pathways. Artemin also has a substantial effect on axon regeneration in RGCs both in vivo and in vitro, whereas other GDNF family members do not. Therefore, artemin/GFRalpha3, but not other GDNF family members, may be of value for optic nerve regeneration in mature mammals. PMID- 25044133 TI - Site-specific dual labeling of proteins by using small orthogonal tags at neutral pH. AB - To expand the utility of proteinaceous FRET biosensors, we have developed a dual labeling approach based on two small bio-orthogonal tags: pyrroline-carboxy lysine (Pcl) and the S6 peptide. The lack of cross-reactivity between those tags enables site-specific two-color protein conjugation in a one-pot reaction. Moreover, Pcl/S6 dual-tagged proteins can be produced in both bacterial and mammalian expression systems, as demonstrated for Z domain and IgE-Fc, respectively. Both proteins could be efficiently dual-labeled with FRET compatible fluorescent dyes at neutral pH. In the case of IgE-Fc, the resulting conjugate enabled the monitoring of IgE binding to its high-affinity receptor FcepsilonRI, which is a key event in allergic disease. PMID- 25044134 TI - Self-healable electrically conducting wires for wearable microelectronics. AB - Electrically conducting wires play a critical role in the advancement of modern electronics and in particular are an important key to the development of next generation wearable microelectronics. However, the thin conducting wires can easily break during use, and the whole device fails to function as a result. Herein, a new family of high-performance conducting wires that can self-heal after breaking has been developed by wrapping sheets of aligned carbon nanotubes around polymer fibers. The aligned carbon nanotubes offer an effective strategy for the self-healing of the electric conductivity, whereas the polymer fiber recovers its mechanical strength. A self-healable wire-shaped supercapacitor fabricated from a wire electrode of this type maintained a high capacitance after breaking and self-healing. PMID- 25044135 TI - Spontaneous MRSA postcricoid abscess: a case report and literature review. AB - Laryngeal abscesses are rare but potentially life-threatening infections due to potential airway obstruction. Most abscesses occur in the epiglottis or preepiglottic space as a sequela of acute supraglottitis. Abscesses in the posterior larynx are extremely rare and typically due to instrumentation or trauma. Appropriate workup and management of the airway are essential for optimizing outcomes in these patients. We present an interesting case and our management of a spontaneous posterior laryngeal abscess due to methicillin resistant Staphlococcus aureus. PMID- 25044136 TI - A safe technique for in-the-bag intraocular lens implantation in pediatric cataract surgery. AB - PURPOSE: To describe a safe technique for in-the-bag intraocular lens (IOL) implantation in pediatric cataract patients who undergo lens aspiration with primary posterior capsulorhexis and anterior vitrectomy. METHODS: Sixty eyes of 45 consecutive patients with congenital/developmental cataract underwent lens aspiration with primary posterior continuous curvilinear capsulorhexis (PCCC) with anterior vitrectomy and in-the-bag IOL implantation using the described technique of IOL implantation using anterior capsule as support. RESULTS: All eyes had stable IOL at the end of surgery and none of the eyes had lens decentration/dislocation in posterior vitreous. CONCLUSIONS: Implantation of in the-bag IOL is difficult in children who undergo primary PCCC with anterior vitrectomy. Our technique of implanting IOL by pushing it against the back surface of anterior capsule is a safe method and results in no complications related to faulty IOL implantation. PMID- 25044137 TI - Effect of anti-VEGF treatment on choroidal thickness over time in patients with neovascular age-related macular degeneration. AB - PURPOSE: To evaluate change in subfoveal choroidal thickness (SCT) as measured by spectral-domain optical coherence tomography (SD-OCT) in patients with neovascular age-related macular degeneration (NVAMD) undergoing anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Patients with a diagnosis of NVAMD were retrospectively reviewed to identify those who had at least 12 months of follow-up. The SCT was manually measured from Bruch membrane to the choroid sclera junction at baseline and last follow-up. Only cases in which the choroid was fully visible were included in quantitative analyses. The SCT measurements were correlated with other characteristics including number and duration of treatments. RESULTS: Sixty eyes of 47 patients with a follow-up of 23.8 months (SD 7.3) met study inclusion criteria, and 49 eyes of 40 patients received anti VEGF treatment. Mean age was 83.7 years, and 52% were female. Treated eyes received a mean of 7.8 (SD 7.3) intravitreal anti-VEGF injections. The SCT at baseline was 126.7 MUm (SD 50.6) for untreated and 136.2 MUm (SD 57.6) for treated eyes. The SCT showed a decrease over time in both groups, with a mean rate of reduction of 6.0 MUm (p<0.0002) in treated eyes and 3.6 MUm (p = 0.3741) in untreated eyes. However, the change in SCT did not differ between the groups (p = 0.5113), and did not correlate with the number of re-treatments (p = 0.552), visual acuity at baseline (p = 0.618), or change in visual acuity over time (p = 0.429). CONCLUSIONS: Although choroidal thickness decreased over time in eyes with NVAMD, anti-VEGF therapy did not appear to accelerate or otherwise alter this decline. PMID- 25044138 TI - The effect of oral propranolol on intraocular pressure in infants with Sturge Weber syndrome glaucoma. AB - PURPOSE: To report the effect of oral propranolol on intraocular pressure (IOP) in infants newly diagnosed with unilateral Sturge-Weber syndrome (SWS) glaucoma receiving no other treatment. METHODS: This was a prospective, nonrandomized interventional case series. Four infants presenting with unilateral SWS glaucoma with no prior treatment were treated with oral propranolol at a dose of 2 mg/kg and followed thereafter. RESULTS: Propranolol had a temporary IOP-lowering effect in 3 of 4 children after 1 week of treatment. This effect diminished thereafter and 3 of 4 children required additional medical or surgical treatment. CONCLUSIONS: Oral propranolol has a temporary effect on IOP in SWS glaucoma and is not effective as a single treatment in this syndrome, yet can serve to delay surgical treatment for a short period of time. In one case, the glaucoma was well controlled on this medication. PMID- 25044139 TI - Meta-analysis of randomized controlled trials comparing latanoprost with other glaucoma medications in chronic angle-closure glaucoma. AB - PURPOSE: To evaluate the efficacy and safety of latanoprost compared with other glaucoma medications in the treatment of chronic angle-closure glaucoma (CACG) and to provide the basis for clinical medication. METHODS: Major literature databases were searched for randomized controlled trials (RCT) involving latanoprost among patients with CACG. Primary outcome measures were absolute changes in intraocular pressure (IOP) and incidence of ocular adverse events. Statistical analyses included the calculation of standardized mean difference (SMD) and relative risk (RR). The statistical analysis was performed using STATA version 12.0 software. RESULTS: Ten RCT involving 1096 patients were included in this meta-analysis. Analysis showed that latanoprost was not significantly different from other glaucoma medications in reducing IOP (SMD = 0.29, 95% confidence interval [CI] -0.02 to 0.59, p=0.069). Further subgroup analysis revealed that latanoprost was superior compared with timolol (SMD = 0.64, 95% CI 0.46 to 0.82, p<0.001) and marginally inferior to travoprost and bimatoprost (SMD = -0.19, 95% CI -0.35 to -0.02, p = 0.026). As for conjunctival hyperemia, latanoprost caused a higher proportion than timolol (RR = 2.36, 95% CI 1.27 to 4.37, p = 0.007). However, latanoprost was associated with lower incidence of conjunctival hyperemia (RR = 0.42, 95% CI 0.30 to 0.59, p<0.001), and with fewer occurrence of other ocular side effects (excluding conjunctival hyperemia) than travoprost and bimatoprost (RR = 0.61, 95% CI 0.48 to 0.78, p<0.001). CONCLUSIONS: Travoprost and bimatoprost are superior in IOP control than latanoprost, but latanoprost is better tolerated in patients with CACG. PMID- 25044140 TI - Late postoperative capsular block syndrome: a case series studied before and after Nd:YAG laser posterior capsulotomy. AB - PURPOSE: To evaluate the clinical characteristics of the unusual late postoperative capsular block syndrome (CBS) and the effect of Nd:YAG laser posterior capsulotomy on visual acuity and refractive error as well as its possible complications. METHODS: In this retrospective cohort study, 12 eyes of 11 patients with late CBS who had undergone Nd:YAG laser posterior capsulotomy were reviewed. A complete ophthalmic examination including Scheimpflug camera and anterior segment optical coherence tomography (AS-OCT) imaging had been performed before and after posterior capsulotomy. RESULTS: The mean time between cataract surgery and posterior capsulotomy was 4.7 +/- 1.5 years (range 3-9 years). Best corrected visual acuity increased in 11 cases (91.7%). Only one eye showed a 0.5 D hyperopic shift following posterior capsulotomy. There were no postlaser complications such as increased intraocular pressure (IOP), severe inflammation, cystoid macular edema, or retinal detachment. In all patients, the posterior capsule was vaulted posteriorly and could not be seen clearly. The AS-OCT confirmed CBS in the studied cases, demonstrating a distended capsular bag. Rotating Scheimpflug imaging examination showed the white substance located behind the intraocular lens (IOL). CONCLUSIONS: Late CBS is usually not accompanied by shallow anterior chamber, forward IOL displacement, or raised IOP. Nd:YAG laser posterior capsulotomy is a useful treatment and the prognosis of patients with this complication appears favorable. Furthermore, although AS-OCT measurements are easier to obtain than rotating Scheimpflug imaging examination, both are useful to visualize the distended capsular bag containing the white material and the IOL position. PMID- 25044141 TI - Vascular comorbidity in patients with low-tension glaucoma. AB - PURPOSE: To report vascular comorbidities, arterial hypertension (HT), ischemic heart disease (IHD), and diabetes mellitus (DM) in patients with low-tension glaucoma (LTG) with maximum intraocular pressure (IOP) of 18 mm Hg or less. Uniform criteria for glaucoma and the comorbidities were applied. METHODS: We reviewed records of 519 consecutive patients to whom the Finnish National Social Insurance Institution (FSII) had granted cost-free medication for the treatment of glaucoma. The FSII operates national health insurance, which is compulsory for all Finnish citizens. There were 344 patients with primary open-angle glaucoma (POAG) and 155 with exfoliative glaucoma (EG). Twenty cases were discarded for having other types of glaucoma. In the POAG group, there were 38 patients, with a median IOP of 16 mm Hg (range 12-18). We were masked to the systemic comorbidities when the registry provided us data on those to whom FSII had also granted cost-free medication for HT, IHD, or DM according to the uniform national criteria. RESULTS: None of the patients with LTG had exfoliation syndrome. There was a female predominance, 81%, compared to 68% in high-tension POAG. Hypertension had been diagnosed in 34%, which is the same as in high-tension POAG. A total of 24% had IHD, which is the same as in the Finnish population registry. Diabetes mellitus was present in only 5%. In all groups, patients with LTG with systemic comorbidity were markedly older than those without. CONCLUSIONS: In patients with LTG with median IOP 16 mm Hg (range 12-18), glaucomatous optic disc cupping and glaucomatous visual field defects probably developed independently of the systemic vascular comorbidity. However, the diagnostic criteria for HT, IHD, and DM used in the current study were based on the severity of stages set in the FSII system. PMID- 25044142 TI - Effectiveness of transscleral cyclophotocoagulation as adjuvant therapy for refractory glaucoma in keratoprosthesis patients. AB - PURPOSE: To evaluate the efficacy and safety of diode laser transscleral cyclophotocoagulation (DLTSC) as an adjuvant therapy to treat refractory glaucoma diagnosed before or after Moscow Eye Microsurgery Complex (MICOF) keratoprosthesis surgery. METHODS: Fifteen patients underwent unilateral DLTSC to treat refractory glaucoma diagnosed before or after undergoing MICOF keratoprosthesis surgery. The cause for keratoprosthesis was alkali burn in 8 patients (53.33%); thermal burn, sulfuric acid burn, and Steven-Johnson syndrome in 2 patients (13.33%) each; and ocular cicatricial pemphigoid in 1 patient (6.67%). Best-corrected visual acuity (BCVA), intraocular pressure (IOP), any medications, and adverse events were recorded before DLTSC and on postoperative day 7; months 1, 3, and 6; and every 6 months afterwards. RESULTS: The patients were followed up for an average of 13.15 +/- 9.35 months. The IOP was significantly less at postoperative months 6, 12, 24, and 36. There were no changes in BCVA after DLTSC. No significant changes in medication to treat ocular hypertension were prescribed. CONCLUSIONS: Diode laser transscleral cyclophotocoagulation is an effective treatment option for refractory glaucoma and can be used as a therapy adjuvant to keratoprosthesis. Long-term effects require further clinical observation. PMID- 25044143 TI - Intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks: a long-term follow-up study. AB - PURPOSE: To evaluate the safety and efficacy of intravitreal bevacizumab (IVB) to treat choroidal neovascularization (CNV) in patients with angioid streaks. METHODS: Retrospective chart review of 16 eyes of 10 patients treated with IVB for CNV secondary to angioid streaks between November 2005 and November 2011. Intravitreal bevacizumab was performed in all patients with a pro re nata regimen. Seven eyes received an additional photodynamic therapy and 1 eye argon laser photocoagulation. The diagnosis of CNV was confirmed by fluorescein angiography (FA) and indocyanine green (ICG) angiography; central macular thickness (CMT) was evaluated by optical coherence tomography. Outcome measures included changes in best-corrected visual acuity, retinal thickness, and degree of leakage on FA and ICG angiography. RESULTS: The median number of IVB was 2.5 (range 1-6) during a mean follow-up of 52 months (range 30-67). Risk of recurrence increased during the first 50 weeks; then it remained stable. In 6 of 16 eyes, the CNV was obliterated with a single injection. Increasing CNV reactivation corresponded with an increased number of injections. Final visual acuity was related to initial VA and not to number of injections or shorter follow-up. Previous treatments, CMT, or baseline CNV size were not related to final visual acuity. CONCLUSIONS: Intravitreal bevacizumab proved to be well tolerated in patients with CNV secondary to angioid streaks and in our small cohort IVB was efficacious for long-term follow-up. Larger series of patients are needed to confirm the effects of this treatment. PMID- 25044144 TI - Fluorescence sensing of amine vapors using a cationic conjugated polymer combined with various anions. AB - A series of conjugated cationic polymers, differentiated only by their accompanying counter-anions, was prepared and characterized. The choice of counter-anion (CA) was found to drastically impact the solubility of the polymers and their optical properties in solution and in the solid state. Fluorescent polymer thin films were found to be instantaneously quenched by volatile amines in the gas phase at low ppm concentrations, and a mini-array with CAs as variable elements was found to be able to differentiate amines with good fidelity. PMID- 25044145 TI - Syntheses, structures, and reactivities of two chalcogen-stabilized carbones. AB - Electronic effects on the central carbon atom of carbone, generated by the replacement of the S(IV) ligand of carbodisulfane (CDS) with other chalcogen ligands (Ph2 E, E=S or Se), were investigated. The carbones Ph2 E->C<-SPh2 (NMe) [E=S(1) or Se(2)] were synthesized from the corresponding salts, and their molecular structures and electronic properties were characterized. The carbone 2 is the first carbone containing selenium as the coordinated atom. DFT calculations revealed the electronic structures of 1 and 2, which have two lone pairs of electrons at the carbon center. The trend in HOMO energy levels, estimated by cyclic voltammetry measurements, for the carbones and CDS follows the order of 2>1>CDS. Analysis of a doubly protonated dication and trication complex revealed that the central carbon atom of 2 behaves as a four-electron donor. PMID- 25044146 TI - Control of solid catalysts down to the atomic scale: where is the limit? PMID- 25044147 TI - Sclerosing PEComa of the kidney: clinicopathologic analysis of 2 cases and review of the literature. PMID- 25044148 TI - A prognostic model including pre- and postsurgical variables to enhance risk stratification of primary mediastinal nonseminomatous germ cell tumors: the 27 year experience of a referral center. AB - BACKGROUND: Primary mediastinal germ cell tumors (PMGCTs) poorly benefit from chemotherapy and half of patients die because of disease progression. Enhancing the risk stratification might result in tailoring a more personalized treatment strategy from the time of diagnosis. PATIENTS AND METHODS: Between the years 1985 and 2012, 86 patients with PMGCT were treated at our center. Cox proportional hazards regression analysis was conducted in the population of nonseminomas to examine the prognostic effect of candidate factors on progression-free and OS. OS curves were compared using the Kaplan-Meier method and the log-rank test. RESULTS: Mean age was 29.8 years (range, 15-63 years). Twenty-five patients (29.1%) had lung and 8 (9.3%) liver, bone, or brain metastases. Twelve patients (13.9%) received upfront high-dose chemotherapy and 45 patients (52.3%) underwent surgery after chemotherapy. Cox analyses included 61 evaluable primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs). The final model of factors indicating a poor prognosis included the combination of surgery and histological response (overall P = .011) and lung metastases (hazard ratio, 3.03; 95% confidence interval, 1.12-8.15; P = .028). The model showed a bootstrap corrected Harrel c-statistic for OS of 0.66. A risk stratification model based on the combination of these factors and accounting for a 50% 5-year survival cutoff identified 2 groups (poor prognosis, n = 33 vs. good prognosis, n = 28) with distinct OS curves (P < .001). Preoperative serum tumor marker level was not associated with the final histology (P = .853, chi(2) test). Results were limited by small numbers. CONCLUSION: Patients with PMNSGCT included 2 subpopulations with distinct prognosis, and therapeutic improvements are needed for patients with poor-risk features. PMID- 25044149 TI - Antitumor efficacy in H22 tumor bearing mice and immunoregulatory activity on RAW 264.7 macrophages of polysaccharides from Talinum triangulare. AB - The aim of this paper was to study the antitumor and immunoregulatory activities of a polysaccharide (TTP) from Talinum triangulare. The molecular weight of TTP IV was 49.9 kDa. The monosaccharide composition analysis of TTP-IV revealed that it was a heteropolysaccharide consisting of rhamnose, arabinose, mannose and galactose with a molar ratio of 1.22 : 1.00 : 1.05 : 1.51. The results of the in vivo study showed that TTP (200 mg per kg bw) significantly inhibited the growth of tumor by 49.07% in H22-bearing Kunming mice. In vitro, the growth of primary murine macrophages was promoted by TTP in a dose- and time-dependent manner significantly. Besides, RAW 264.7 cells were activated by TTP to produce NO and the toxicity of RAW 264.7 supernatant was markedly enhanced in vitro. The levels of iNOS, TLR2, TLR4 and IL-1beta were obviously increased by TTP. Therefore, it is suggested that TTP can be utilized as a potent antitumor and immunoenhancing material in functional food. PMID- 25044150 TI - Adulteration and cultivation region identification of American ginseng using HPLC coupled with multivariate analysis. AB - American ginseng (Panax quinquefolius) is originally grown in North America. Due to price difference and supply shortage, American ginseng recently has been cultivated in northern China. Further, in the market, some Asian ginsengs are labeled as American ginseng. In this study, forty-three American ginseng samples cultivated in the USA, Canada or China were collected and 14 ginseng saponins were determined using HPLC. HPLC coupled with hierarchical cluster analysis and principal component analysis was developed to identify the species. Subsequently, an HPLC-linear discriminant analysis was established to discriminate cultivation regions of American ginseng. This method was successfully applied to identify the sources of 6 commercial American ginseng samples. Two of them were identified as Asian ginseng, while 4 others were identified as American ginseng, which were cultivated in the USA (3) and China (1). Our newly developed method can be used to identify American ginseng with different cultivation regions. PMID- 25044151 TI - Cationic permethylated 6-monoamino-6-monodeoxy-beta-cyclodextrin as chiral selector of dansylated amino acids in capillary electrophoresis. AB - The resolution power of permethylated 6-monoamino-6-monodeoxy-betaCD (PMMABCD) - a single isomer, cationic CD derivative - developed previously for chiral analyses in capillary electrophoresis was further studied here. Dansylated amino acids (Dns-AA) were chosen as amphoteric chiral model compounds. Changes in the resolutions of Dns-AAs by varying pH and selector concentrations were investigated and correlated with their structures and chemical properties (isoelectric point and lipophilicity). Maximal resolutions could be achieved at pH 6 or pH 4. The separations improved with increasing concentration of the selector. Baseline or substantially better resolution for 8 pairs of these Dns AAs could be achieved. Low CD concentration was enough for the separation of the most apolar Dns-AAs. Chiral discrimination ability of PMMABCD was demonstrated by the separation of an artificial mixture of 8 Dns-AA pairs. PMID- 25044160 TI - Exorhodopsin and melanopsin systems in the pineal complex and brain at early developmental stages of Atlantic halibut (Hippoglossus hippoglossus). AB - The complexity of the nonvisual photoreception systems in teleosts has just started to be appreciated, with colocalization of multiple photoreceptor types with unresolved functions. Here we describe an intricate expression pattern of melanopsins in early life stages of the marine flat fish Atlantic halibut (Hippoglossus hippoglossus), a period when the unpigmented brain is directly exposed to environmental photons. We show a refined and extensive expression of melanopsins in the halibut brain already at the time of hatching, long before the eyes are functional. We detect melanopsin in the habenula, suprachiasmatic nucleus, dorsal thalamus, and lateral tubular nucleus of first feeding larvae, suggesting conserved functions of the melanopsins in marine teleosts. The complex expression of melanopsins already at larval stages indicates the importance of nonvisual photoreception early in development. Most strikingly, we detect expression of both exorhodopsin and melanopsin in the pineal complex of halibut larvae. Double-fluorescence labeling showed that two clusters of melanopsin positive cells are located lateral to the central rosette of exorhodopsin positive cells. The localization of different photopigments in the pineal complex suggests that two parallel photoreceptor systems may be active. Furthermore, the dispersed melanopsin-positive cells in the spinal cord of halibut larvae at the time of hatching may be primary sensory cells or interneurons representing the first example of dispersed high-order photoreceptor cells. The appearance of nonvisual opsins early in the development of halibut provides an alternative model for studying the evolution and functional significance of nonvisual opsins. PMID- 25044161 TI - Evaluation of new guidelines for ROP screening in Sweden using SWEDROP - a national quality register. AB - PURPOSE: To investigate whether recent Swedish guidelines for Retinopathy of Prematurity (ROP) screening, that is, a gestational age (GA) at birth of <31 weeks (w), are applicable in a new national cohort of prematurely born infants. METHODS: SWEDROP is a national register for ROP, initiated in 2006. The present paper reports on data from the register on various aspects of screening for ROP in infants born between 2010 and 2011 and compares the results with those for a previously published cohort born between 2008 and 2009. RESULTS: During the study period, 1744 infants were screened for ROP. Mean GA was 28.4 w (22-31), and mean birth weight was 1239 g (382-2615). Screening started at postnatal age (PNA) 5.4 w (0.4-13.3) and postmenstrual age (PMA) 33.8 w (24.9-50.1) Mean number of examinations was 5.4 per infant (1-38). Mild (stages 1-2) and severe (>= stage 3) ROP was found in 15.4% and 8.7%, respectively. Treatment was performed in 4.2% (73/1744) of the infants, but in none with a GA of 30 weeks or more. The first treatment was performed at a mean PNA and PMA of 12.7 w (7.7-25.4) and 37.4 w (32.1-51.4), respectively. CONCLUSIONS: Recently introduced new guidelines for ROP screening in Sweden remain applicable. Reassuringly, in infants born between 2010 and 2011, incidence of ROP, frequency and timing of treatment, frequency and timing of examinations and national coverage of ROP screening remained almost identical to those for a previous cohort from 2008 to 2009. The two SWEDROP cohorts provide a basis for discussion among Swedish ophthalmologists and neonatologists on the question of further lowering the upper screening limit with 1 week. PMID- 25044162 TI - Symptoms of posttraumatic stress in Australian women with ovarian cancer. AB - OBJECTIVE: The aim of the study was to assess the prevalence and nature of symptoms of posttraumatic stress disorder (PTSD) in women with ovarian cancer. A further aim was to examine the demographic, medical and psychosocial factors associated with PTSD symptoms. METHOD: One hundred and eight women with ovarian cancer were assessed for PTSD, quality of life, depression, anxiety, posttraumatic growth, optimism, coping and social support. RESULTS: Clinically significant symptoms were experienced by 9.25% of participants for PTSD, 5.6% for depression and 13.9% for anxiety. Poorer quality of life was associated with total PTSD symptoms, and avoidance and intrusive symptoms. Depression was associated with avoidance and intrusive symptoms. Anxiety was associated with total, avoidance, intrusive and hyperarousal symptoms. Finally, coping by substance use/self-blame was associated with total, avoidance and hyperarousal PTSD symptoms. CONCLUSIONS: Levels of PTSD in women with ovarian cancer were equivalent to that of the general population. Poorer quality of life, depression, anxiety and maladaptive coping, characterised by avoidance, substance use and self-blame, were associated with increased symptoms of PTSD. PMID- 25044163 TI - Quantitative analysis of pancreatic echogenicity on transabdominal sonography: correlations with metabolic syndrome. AB - PURPOSE: To attempt a quantitative analysis of pancreatic echogenicity on transabdominal ultrasonography (US) and evaluate the correlation between pancreatic echogenicity and metabolic syndrome (MetS). METHODS: We retrospectively evaluated transabdominal sonograms from 286 subjects. Mean pancreatic body brightness, mean perihepatic fat brightness, and the pancreato perihepatic fat index (PPHFI) were measured, and reproducibility was analyzed using intraclass correlation coefficients. Associations between the PPHFI and MetS components were analyzed. The optimal PPHFI cutoff value to predict MetS was calculated. RESULTS: Reproducibility was good for mean pancreatic body brightness, mean perihepatic fat brightness, and PPHFI with intraclass correlation coefficients of 0.98, 0.95, and 0.95, respectively. Each MetS component showed a significant association with PPHFI. Waist circumference had the strongest association (r = 0.55, p < 0.0001). PPHFI was significantly higher in the MetS (+) group than the MetS (-) group (p < 0.0001), and PPHFI was an independent factor predicting MetS (p = 0.02; odds ratio, 2.89). The best PPHFI cutoff value to predict MetS was 1.97, with a relatively high negative predictive value of 94.1%. CONCLUSIONS: We quantitatively analyzed pancreatic echogenicity using the PPHFI on US and found that an increased PPHFI was significantly correlated with MetS. Because increased PPHFI on US may indicate MetS, radiologists and clinicians need to be aware of its implications. PMID- 25044164 TI - Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: definition of clinical and molecular spectrum and identification of new diagnostic scores. AB - Congenital Dyserythropoietic Anemia II (CDA II) is a rare hyporegenerative anemia of variable degree, whose causative gene is SEC23B. More than 60 causative mutations in 142 independent pedigrees have been described so far. However, the prevalence of the CDA II is probably underestimated, since its clinical spectrum was not yet well-defined and thus it is often misdiagnosed with more frequent clinically-related anemias. This study represents the first meta-analysis on clinical and molecular spectrum of CDA II from the largest cohort of cases ever described. We characterized 41 new cases and 18 mutations not yet associated to CDA II, thus expanding the global series to 205 cases (172 unrelated) and the total number of causative variants to 84. The 68.3% of patients are included in our International Registry of CDA II (Napoli, Italy). A genotype-phenotype correlation in three genotypic groups of patients was assessed. To quantify the degree of severity in each patient, a method based on ranking score was performed. We introduced a clinical index to easily discriminate patients with a well-compensated hemolytic anemia from those with ineffective erythropoiesis. Finally, the worldwide geographical distribution of SEC23B alleles highlighted the presence of multiple founder effects in different areas of the world. PMID- 25044165 TI - Metal-size influence in iso-selective lactide polymerization. AB - Iso-selective initiators for the ring-opening polymerization (ROP) of rac-lactide are rare outside of Group 13. We describe the first examples of highly iso selective lutetium initiators. The phosphasalen lutetium ethoxide complex shows excellent iso-selectivity, with a P(i) value of 0.81-0.84 at 298 K, excellent rates, and high degrees of polymerization control. Conversely, the corresponding La derivative exhibits moderate heteroselectivity (P(s)=0.74, 298 K). Thus, the choice of metal center is shown to be crucial in determining the level and mode of stereocontrol. The relative order of rates for the series of complexes is inversely related to metallic covalent radius: that is, La>Y>Lu. PMID- 25044166 TI - The application of a bilaminate skin substitute as a temporary coverage of a free flap pedicle. PMID- 25044167 TI - Pelvic floor muscle contractility: digital assessment vs transperineal ultrasound. AB - OBJECTIVES: A significant reduction in hiatal area and anteroposterior diameter can be induced by pelvic floor muscle contraction, and this has been demonstrated using three-dimensional/four-dimensional (3D/4D) transperineal ultrasound (TPS) in a small group of women. Our objective was to correlate pelvic floor muscle contractility using digital assessment with the change in TPS hiatus measurements during maximum pelvic floor muscle contraction. METHODS: Nulliparous pregnant women were recruited from the antenatal clinic. Pelvic floor muscle contractility was assessed by digital palpation using the validated Modified Oxford Scale (MOS). Subsequently, women underwent 3D/4D TPS. Measurements of the hiatal area and anteroposterior diameter were taken from the rendered ultrasound images at rest and at maximum contraction, and differences in measurements were expressed as percentages. Spearman's rank (rho) was used to assess the correlation. RESULTS: Four hundred and fifty-nine assessments were performed, of which 268 were from women at around 36 weeks' gestation, and 191 were from women following delivery at 3 months postpartum. The overall correlation between MOS and TPS was found to be rho = 0.47 for hiatal area (P < 0.001) and rho = 0.51 for hiatal anteroposterior diameter (P < 0.001). CONCLUSIONS: Digital palpation using MOS and TPS can both be used as tools to assess pelvic floor muscle contractility. Although MOS is a simple clinical tool without the need for any equipment, TPS can provide good visual biofeedback when training patients in pelvic floor muscle exercises. As TPS is non-intrusive, it may be the method of choice for some women. PMID- 25044169 TI - Cardiovascular and mortality risks in older Medicare patients treated with varenicline or bupropion for smoking cessation: an observational cohort study. AB - PURPOSE: To compare cardiovascular and mortality risks in elderly patients treated with varenicline or bupropion for smoking cessation. METHODS: Elderly Medicare beneficiaries were entered into new-user cohorts of varenicline or bupropion for smoking cessation and followed on therapy for primary outcomes of acute myocardial infarction (AMI), stroke, mortality, and a composite of any of these events. Secondary outcomes were unstable angina, coronary revascularization, and a composite of any primary or secondary outcome event. Propensity score stratification was used to adjust for baseline differences in potential confounding factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards, with bupropion as reference. RESULTS: In cohorts of 74 824 varenicline and 14 133 bupropion users, there were 164 AMI, 96 stroke, 87 death, 317 primary composite, and 814 secondary composite events while on therapy. The HRs (95%CI) were 0.79 (0.50-1.24) for AMI, 1.27 (0.63-2.55) for stroke, 0.58 (0.30-1.13) for death, 0.84 (0.58-1.23) for the primary composite, and 0.92 (0.73-1.14) for the secondary composite. The risk of AMI or the primary composite outcome did not differ in subgroups defined by age, diabetes status, or presence of underlying ischemic heart disease. Only 30% of patients remained on either study drug beyond their first prescription. CONCLUSION: Cardiovascular and mortality risks were not increased in older patients treated with varenicline compared with bupropion for smoking cessation. A potential increase in the risk of stroke with varenicline could not be excluded. Treatment persistence with either drug was low. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 25044168 TI - Multiple polymer architectures of human polyhomeotic homolog 3 sterile alpha motif. AB - The self-association of sterile alpha motifs (SAMs) into a helical polymer architecture is a critical functional component of many different and diverse array of proteins. For the Drosophila Polycomb group (PcG) protein Polyhomeotic (Ph), its SAM polymerization serves as the structural foundation to cluster multiple PcG complexes, helping to maintain a silenced chromatin state. Ph SAM shares 64% sequence identity with its human ortholog, PHC3 SAM, and both SAMs polymerize. However, in the context of their larger protein regions, PHC3 SAM forms longer polymers compared with Ph SAM. Motivated to establish the precise structural basis for the differences, if any, between Ph and PHC3 SAM, we determined the crystal structure of the PHC3 SAM polymer. PHC3 SAM uses the same SAM-SAM interaction as the Ph SAM sixfold repeat polymer. Yet, PHC3 SAM polymerizes using just five SAMs per turn of the helical polymer rather than the typical six per turn observed for all SAM polymers reported to date. Structural analysis suggested that malleability of the PHC3 SAM would allow formation of not just the fivefold repeat structure but also possibly others. Indeed, a second PHC3 SAM polymer in a different crystal form forms a sixfold repeat polymer. These results suggest that the polymers formed by PHC3 SAM, and likely others, are dynamic. The functional consequence of the variable PHC3 SAM polymers may be to create different chromatin architectures. PMID- 25044170 TI - Poikiloderma with neutropenia: genotype-ethnic origin correlation, expanding phenotype and literature review. AB - Poikiloderma with neutropenia (PN), is a rare genodermatosis associated with patognomic features of poikiloderma and permanent neutropenia. Three common recurrent mutations of related gene, USB1, were considered to be associated with three different ethnic origins. The most common recurrent mutation, c.531delA, has been detected in seven Caucasian patients in the literature. In this paper, we present review of all patients from the literature and report two additional patients of Turkish ancestry with the diagnosis of PN. The diagnosis of these two PN patients were made clinically and confirmed by molecular analysis which detected the most common recurrent mutation, c.531delA. Genotype-ethnic origin correlation hypothesis, therefore, has been strengthened with this result. Short stature in PN, is a common finding, which until now has never been treated with growth hormone (GH). One of our patients is the first patient with attempted treatment of short stature via GH administration. Finally, both of our patients had high-pitched voice and vocal cord nodules which might be considered as additional clinical findings not associated with PN before. PMID- 25044171 TI - Carbon accumulation of tropical peatlands over millennia: a modeling approach. AB - Tropical peatlands cover an estimated 440,000 km2 (~10% of global peatland area) and are significant in the global carbon cycle by storing about 40-90 Gt C in peat. Over the past several decades, tropical peatlands have experienced high rates of deforestation and conversion, which is often associated with lowering the water table and peat burning, releasing large amounts of carbon stored in peat to the atmosphere. We present the first model of long-term carbon accumulation in tropical peatlands by modifying the Holocene Peat Model (HPM), which has been successfully applied to northern temperate peatlands. Tropical HPM (HPMTrop) is a one-dimensional, nonlinear, dynamic model with a monthly time step that simulates peat mass remaining in annual peat cohorts over millennia as a balance between monthly vegetation inputs (litter) and monthly decomposition. Key model parameters were based on published data on vegetation characteristics, including net primary production partitioned into leaves, wood, and roots; and initial litter decomposition rates. HPMTrop outputs are generally consistent with field observations from Indonesia. Simulated long-term carbon accumulation rates for 11,000-year-old inland, and 5000-year-old coastal peatlands were about 0.3 and 0.59 Mg C ha(-1) yr(-1), and the resulting peat carbon stocks at the end of the 11,000-year and 5000-year simulations were 3300 and 2900 Mg C ha(-1), respectively. The simulated carbon loss caused by coastal peat swamp forest conversion into oil palm plantation with periodic burning was 1400 Mg C ha(-1) over 100 years, which is equivalent to ~2900 years of C accumulation in a hectare of coastal peatlands. PMID- 25044172 TI - Community-applied research of a traditional Chinese medicine rehabilitation scheme on Broca's aphasia after stroke: study protocol for a randomized controlled trial. AB - BACKGROUND: Aphasia is a common and severely disabling complication in stroke patients. It usually brings about lower rates of functional recovery, longer rehabilitation length of stay (LOS), and significantly poorer LOS efficiency (LOS Eff), resulting in higher rehabilitation costs compared to patients without aphasia. It also decreases the quality of life and increases the mortality of stroke patients. The evidence currently available suggests that the effect of acupuncture combined with language training for apoplectic aphasia is statistically better than speech and language therapy (SLT) alone, but there remains a lack of high-quality randomized controlled trials. Acupuncture combined with language training is relatively low-cost and especially suitable for community-based rehabilitation for aphasia patients after stroke, taking its medical and health facilities which are always deficient in manpower and material resources into account. The aim of the present study is to develop an effective standard therapeutic program for apoplectic aphasia in communities. METHODS/DESIGN: In a randomized controlled clinical trial with blinded assessment, 290 eligible patients with aphasia due to stroke will be randomly allocated into a control group or an experimental group. The course of this trial will comprise a 4-week intervention and a 12-week follow-up period. Five assessment points, including baseline, 2 and 4 weeks after treatment, 6 and 12 weeks after follow-up, are set to dynamically observe the changes of curative effects. Primary outcome measures are the differences in the score on both the China rehabilitation research center aphasia examination (CRRCAE) and Boston diagnostic aphasia examination - Chinese version (BDAE-C) after intervention and follow-up. The Modified Barthel Index (MBI), 36-Item Short Form Health Survey (SF 36), and results of blood oxygen level dependent-functional magnetic resonance imaging (BOLD-fMRI) examination are considered as the secondary outcome measures. Other outcomes will include rate of adverse events and economic effects. DISCUSSION: If the outcome is positive, this project will offer a low-cost appropriate technology for community health centers (CHCs) in the rehabilitation of aphasia patients after stroke, and could be implemented on a large scale, both in China and worldwide. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-13003703. Registration date: 18 October 2013. PMID- 25044175 TI - Nanorod and nanoparticle shells in concentration gradient core-shell lithium oxides for rechargeable lithium batteries. AB - The structure, electrochemistry, and thermal stability of concentration gradient core-shell (CGCS) particles with different shell morphologies were evaluated and compared. We modified the shell morphology from nanoparticles to nanorods, because nanorods can result in a reduced surface area of the shell such that the outer shell would have less contact with the corrosive electrolyte, resulting in improved electrochemical properties. Electron microscopy studies coupled with electron probe X-ray micro-analysis revealed the presence of a concentration gradient shell consisting of nanoparticles and nanorods before and after thermal lithiation at high temperature. Rietveld refinement of the X-ray diffraction data and the chemical analysis results showed no variations of the lattice parameters and chemical compositions of both produced CGCS particles except for the degree of cation mixing (or exchange) in Li and transition metal layers. As anticipated, the dense nanorods present in the shell gave rise to a high tap density (2.5 g cm(-3) ) with a reduced pore volume and surface area. Intimate contact among the nanorods is likely to improve the resulting electric conductivity. As a result, the CGCS Li[Ni0.60 Co0.15 Mn0.25 ]O2 with the nanorod shell retained approximately 85.5% of its initial capacity over 150 cycles in the range of 2.7 4.5 V at 60 degrees C. The charged electrode consisting of Li0.16 [Ni0.60 Co0.15 Mn0.25 ]O2 CGCS particles with the nanorod shell also displayed a main exothermic reaction at 279.4 degrees C releasing 751.7 J g(-1) of heat. Due to the presence of the nanorod shell in the CGCS particles, the electrochemical and thermal properties are substantially superior to those of the CGCS particles with the nanoparticle shell. PMID- 25044176 TI - Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency - a double-blind, randomized, placebo-controlled trial. AB - OBJECTIVES: Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes. MATERIALS/METHODS: A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 MUg daily for 2 weeks, 140 MUg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples. RESULTS: Serum-25(OH) vitamin D and serum-1,25(OH)2 vitamin D increased significantly after 12 weeks in the intervention group (p=0.01, p=0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p=0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass. CONCLUSIONS: Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes. PMID- 25044177 TI - The PI3K/p-Akt signaling pathway participates in calcitriol ameliorating podocyte injury in DN rats. AB - OBJECTIVES: The present study aimed to investigate the relationship between PI3K/p-Akt signaling pathway and podocyte impairment in DN rats as well as the protective effect of calcitriol. METHODS: SD rats were randomly divided into four groups: normal control (NC), normal treated with calcitriol (NC+VD), diabetic nephropathy (DN) and DN treated with calcitriol (DN+VD); all VD rats were treated with 0.1 MUg/kg/d calcitriol by gavage. DN model rats were established by intraperitoneal injections of streptozotocin (STZ). Rats were sacrificed after 18 weeks of treatments. RESULTS: In the present study, increased albuminuria was observed as early as 3 weeks of diabetes and continued to increase more than six fold throughout the length of the study (18 weeks). Expectedly, animals receiving the treatment with calcitriol was protected from this increase, lower about one third. Meanwhile, the expression of podocyte specific markers, including nephrin and podocin, together with PI3K/p-Akt was significantly decreased in DN rats, whereas calcitriol reversed these above changes accompanied by elevated the expression levels of VDR. Additionally, a positive correlation was observed between the expression levels of nephrin and VDR (r = 0.776, P < 0.05). Likewise, the expression of nephrin was positively correlated with both PI3K-p85 and p-Akt (r = 0.736, P < 0.05; r = 0.855, P < 0.05, respectively). CONCLUSION: PI3K/p-Akt signaling pathway participates in calcitriol ameliorating podocyte injury in DN rats. The manipulation of calcitriol might act as a promising therapeutic intervention for diabetic nephropathy. PMID- 25044178 TI - The influence of acid whey and mustard seed on lipid oxidation of organic fermented sausage without nitrite. AB - BACKGROUND: The influence of the addition of mustard seed and acid whey on the stability of nitrite-free organic fermented sausage during 90 days of vacuum storage was investigated by measuring primary and secondary products of lipid oxidation, changes in fatty acid composition and antioxidant capacity, as well as water activity. RESULTS: The native and autoclaved mustard seed with acid whey can be used in the composition of organic fermented sausage without nitrite with beneficial effect on pH, water activity, antioxidant capacity and oxidation stability during vacuum storage. The use of the combination of acid whey and mustard seed resulted in an effective decrease in pH of organic fermented sausage during fermentation. The inclusion of mustard seed to the sausage with acid whey significantly increased the capacity of stuffing to capture the radical cation ABTS. During the whole storage period the TBARS (thiobarbituric acid reactive substances) values of salted sausage samples with the addition of acid whey with combination of mustard seed were similar to the control sample with curing agent. CONCLUSION: In general, results suggest that mustard seed with combination of acid whey can be successfully applied to protect organic fermented sausages without nitrite from lipid oxidation. PMID- 25044179 TI - Tribbles homolog 3 expression in spermatogonial stem cells of rat testes. AB - Tribbles are a family of signal-regulating proteins shown to coordinate the action and the suppression of different pathways. Tribbles homolog 3 (Trib3), the best-studied member of the mammalian tribble family, has a key function in determining cell fate when responding to environmental challenges. Trib3 effects are also modulated by its direct interaction with other signaling molecules. We found that Trib3 is highly expressed in the early development of rat testis, at just the time when the gonocytes resume proliferation to give rise to A spermatogonia. Immunofluorescence staining of cross-sections of rat testis and cultured spermatogonial stem cells (SSCs) also confirmed that Trib3 is expressed in rat SSCs. PMID- 25044181 TI - Characterization of silica distribution in rice husk using Synchrotron Radiation uCT and its implications for archaeological interpretation. AB - This article reports the results of a pilot project using Synchrotron Radiation uCT (computer-aided tomography) to examine the distribution of silica within phytoliths from rice husks. Experiments indicate that computed tomography can be used to show how silica accumulates and is distributed in a distinctive zigzag pattern of long epidermal cells that are characteristic of phytoliths from rice husks. This method will help us to understand why the dry ashing method produced much more zigzag pattern of long cells phytoliths from rice husk than did the acid extraction method. Besides, the zigzag morphological pattern exhibited by long epidermal cells is characteristic of this species which makes it useful in the identification of rice husks from archaeological contexts and indicating heating process. PMID- 25044180 TI - Double trouble-Buffer selection and His-tag presence may be responsible for nonreproducibility of biomedical experiments. AB - The availability of purified and active protein is the starting point for the majority of in vitro biomedical, biochemical, and drug discovery experiments. The use of polyhistidine affinity tags has resulted in great increases of the efficiency of the protein purification process, but can negatively affect structure and/or activity measurements. Similarly, buffer molecules may perturb the conformational stability of a protein or its activity. During the determination of the structure of a Gcn5-related N-acetyltransferase (GNAT) from Pseudomonas aeruginosa (PA4794), we found that both HEPES and the polyhistidine affinity tag bind (separately) in the substrate-binding site. In the case of HEPES, the molecule induces conformational changes in the active site, but does not significantly affect enzyme activity. In contrast, the uncleaved His-tag does not induce major conformational changes but acts as a weak competitive inhibitor of peptide substrate. In two other GNAT enzymes, we observed that the presence of the His-tag had a strong influence on the activity of these proteins. The influence of protein preparation on functional studies may affect the reproducibility of experiments in other laboratories, even when changes between protocols seem at first glance to be insignificant. Moreover, the results presented here show how critical it is to adjust the experimental conditions for each protein or family of proteins, and investigate the influence of these factors on protein activity and structure, as they may significantly alter the effectiveness of functional characterization and screening methods. Thus, we show that a polyhistidine tag and the buffer molecule HEPES bind in the substrate binding site and influence the conformation of the active site and the activity of GNAT acetyltransferases. We believe that such discrepancies can influence the reproducibility of some experiments and therefore could have a significant "ripple effect" on subsequent studies. PMID- 25044188 TI - Living and dying with Parkinson's disease. PMID- 25044189 TI - Carbon monoxide-induced dynamic metal-surface nanostructuring. AB - Carbon monoxide is a ubiquitous molecule in surface science, materials chemistry, catalysis and nanotechnology. Its interaction with a number of metal surfaces is at the heart of major processes, such as Fischer-Tropsch synthesis or fuel-cell optimization. Recent works, coupling structural and nanoscale in situ analytic tools have highlighted the ability of metal surfaces and nanoparticles to undergo restructuring after exposure to CO under fairly mild conditions, generating nanostructures. This Minireview proposes a brief overview of recent examples of such nanostructuring, which leads to a discussion about the driving force in reversible and non-reversible situations. PMID- 25044191 TI - Enhancing youth tobacco surveillance to inform tobacco product regulation: findings from the 2012 National Youth Tobacco Survey. PMID- 25044190 TI - Why providers transfuse blood products outside recommended guidelines in spite of integrated electronic best practice alerts. AB - BACKGROUND: Best practice alerts (BPAs) provide clinical decision support (CDS) at the point of care to reduce unnecessary blood product transfusions, yet substantial transfusions continue outside of recommended guidelines. OBJECTIVE: To understand why providers order blood transfusions outside of recommended guidelines despite interruptive alerts. DESIGN: Retrospective review. SETTING: Tertiary care hospital. PARTICIPANTS: Inpatient healthcare providers. INTERVENTION: Provider-BPA interaction data were collected from January 2011 to August 2012 from the hospital electronic medical record. MEASUREMENTS: Provider (free-text) responses to blood transfusion BPA prompts were independently reviewed and categorized by 2 licensed physicians, with agreement assessed by chi(2) analysis and kappa scoring. RESULTS: Rationale for overriding blood transfusion BPAs was highly diverse, acute bleeding being the most common (>34%), followed by protocolized behaviors on specialty services (up to 26%), to "symptomatic" anemia (11%-12%). Many providers transfused in anticipation of surgical or procedural intervention (10%-15%) or imminent hospital discharge (2% 5%). Resident physicians represented the majority (55%) of providers interacting with BPAs. CONCLUSION: Providers interacting with BPAs (primarily residents and midlevel providers) often do not have the negotiating power to change ordering behavior. Protocolized behaviors, unlikely to be influenced by BPAs, are among the most commonly cited reasons for transfusing outside of guidelines. Symptomatic anemia is a common, albeit subjective, indication cited for blood transfusion. With a wide swath of individually uncommon rationales for transfusion behavior, secondary use of electronic medical record databases and integrated CDS tools are important to efficiently analyze common practice behaviors. PMID- 25044192 TI - Youth tobacco cessation: quitting intentions and past-year quit attempts. AB - BACKGROUND: Despite declining use of conventional tobacco products, youth use of non-cigarette tobacco has become prevalent; however, quitting behaviors remain largely unexplored. PURPOSE: To examine nationally representative data on quit intentions and past-year attempts to quit all tobacco use among current youth tobacco users. METHODS: In 2013, data were analyzed from the 2012 National Youth Tobacco Survey (NYTS). Weighted prevalence estimates of quit intentions and past year quit attempts for current youth tobacco users are presented. RESULTS: Prevalence of quit intentions and past-year attempts to quit all tobacco use were 52.8% and 51.5%, respectively, among current youth tobacco users. Among non mutually exclusive groups, current cigarette smokers had the highest prevalence of quit intentions (56.8%) and past-year quit attempts (52.5%), whereas current hookah users had the lowest prevalence of quit intentions (41.5%) and past-year quit attempts (43.7%). Quit intentions among black, non-Hispanics (65.0%) and Hispanics (60.4%) were significantly higher versus white, non-Hispanics (47.5%). Youth reporting parental advice against tobacco had significantly higher prevalence of quit intentions (56.7%) and past-year quit attempts (55.0%) than those not reporting parental advice. Youth who agreed all tobacco products are dangerous (58.5%) had significantly higher prevalence of quit intentions than those who disagreed (37.0%). CONCLUSIONS: Continued efforts are needed to better understand youth motivation for quitting all tobacco products. Public health messaging about the dangers of all tobacco and cessation efforts should be aimed at the full range of tobacco products, not just cigarettes, and tailored to meet the needs of youth polytobacco users. PMID- 25044193 TI - Cigar smoking among U.S. students: reported use after adding brands to survey items. AB - BACKGROUND: Among U.S. youth overall, cigars are the most commonly used tobacco product after cigarettes. However, youth who identify their products by brand names, not general terms like "cigar," may underreport use. PURPOSE: To examine changes in reported cigar (cigar, cigarillo, or little cigar) smoking among students following inclusion of cigar brand examples on the National Youth Tobacco Survey (NYTS). METHODS: Data from the 2011 and 2012 NYTS and National Survey on Drug Use and Health (NSDUH) were analyzed in 2013 to estimate ever and current cigar smoking, overall and by race/ethnicity. The 2012 NYTS included cigar brand examples (Black and Mild, Swisher Sweets, Dutch Masters, White Owl, Phillies Blunt) in the survey instructions and ever use question, but the 2011 NYTS and 2011 and 2012 NSDUH did not. RESULTS: NYTS ever cigar smoking was higher in 2012 (27.8%) than 2011 (19.5%) among black students overall. Current cigar smoking was 60%-70% higher among black females and students aged >= 17 years, in 2012 than 2011. For black females, current cigar smoking (11.5%) was two times greater than that of white females (4.3%) in 2012, whereas the prevalence among these subgroups was comparable in 2011. Similar changes were not observed among these subgroups in the 2011-2012 NSDUH. CONCLUSIONS: This study highlights the high burden of cigar use among U.S. youth and suggests that NYTS ascertainment of cigar smoking may have improved by including brands. Disparities in cigar smoking need to be addressed to prevent and reduce all youth tobacco use. PMID- 25044194 TI - Awareness and use of non-conventional tobacco products among U.S. students, 2012. AB - BACKGROUND: Increasing diversity of the tobacco product landscape, including electronic cigarettes (e-cigarettes), hookah, snus, and dissolvable tobacco products (dissolvables), raises concerns about the public health impact of these non-conventional tobacco products among youth. PURPOSE: This study assessed awareness, ever use, and current use of non-conventional tobacco products among U.S. students in 2012, overall and by demographic and tobacco use characteristics. METHODS: Data from the 2012 National Youth Tobacco Survey, a nationally representative survey of U.S. middle and high school students, were analyzed in 2013. Prevalence of awareness, ever use, and current use of e cigarettes, hookah, snus, and dissolvables were calculated overall and by sex, school level, race/ethnicity, and conventional tobacco product use, including cigarettes, cigars, or smokeless tobacco (chewing tobacco, snuff, or dip). RESULTS: Overall, 50.3% of students were aware of e-cigarettes; prevalence of ever and current use of e-cigarettes was 6.8% and 2.1%, respectively. Awareness of hookah was 41.2% among all students, and that of ever and current use were 8.9% and 3.6%, respectively. Overall awareness; ever; and current use of snus (32%, 5.3%, 1.7%, respectively) and dissolvables (19.3%, 2.0%, 0.7%, respectively) were generally lower than those of e-cigarettes or hookah. Conventional tobacco product users were more likely to be aware of and to use non conventional tobacco products. CONCLUSIONS: Many U.S. students are aware of and use non-conventional tobacco products. Evidence-based interventions should be implemented to prevent and reduce all tobacco use among youth. PMID- 25044195 TI - Symptoms of tobacco dependence among middle and high school tobacco users: results from the 2012 National Youth Tobacco Survey. AB - BACKGROUND: A growing body of evidence suggests that tobacco dependence symptoms can occur soon after smoking onset and with low levels of use. However, limited data are available nationally and among non-cigarette tobacco users. PURPOSE: To examine the prevalence and determinants of tobacco dependence symptoms among adolescent tobacco users in the 2012 National Youth Tobacco Survey, a nationally representative, school-based survey of U.S. middle and high school students. METHODS: Multivariate logistic regression was used to identify independent predictors of dependence symptoms among current users (i.e., past 30-day use) of cigarettes, cigars, or smokeless tobacco. Analyses were conducted in 2013 using SAS-callable SUDAAN, version 11 to account for the complex survey design. RESULTS: Prevalence of tobacco dependence symptoms ranged from 20.8% (95% CI=18.6, 23.1) of current tobacco users reporting wanting to use tobacco within 30 minutes of waking to 41.9% (95% CI=39.3, 44.5) reporting recent strong cravings. Reporting of dependence symptoms was most consistently associated with polytobacco use, higher frequency of use, earlier initiation age, and female gender. A 2-4-fold increase in the odds of symptom reporting was found in adolescents using tobacco products on as few as 3-5 days compared to those who only used it for 1-2 of the past 30 days. CONCLUSIONS: A substantial proportion of U.S. adolescent tobacco users, including those with low levels of use, report symptoms of tobacco dependence. These findings demonstrate the need for full implementation of evidence-based strategies to prevent both experimentation and progression to regular tobacco use among youth. PMID- 25044196 TI - Perceptions of the relative harm of cigarettes and e-cigarettes among U.S. youth. AB - BACKGROUND: Despite progress in reducing youth smoking, adolescents remain highly susceptible to tobacco use. Of concern is whether youth perceive electronic cigarettes (e-cigarettes) as a preferable alternative to conventional cigarettes. PURPOSE: To describe cigarette harm perception patterns among youth based on the frequency and intensity of cigarette smoking, and examine the relative harm perceptions of conventional versus e-cigarettes, using data from a large, nationally representative sample of U.S. youth. METHODS: Data from the 2012 National Youth Tobacco Survey (N=24,658) were analyzed in 2013 to identify patterns of cigarette harm perceptions. Multinomial logistic regression was conducted to identify associations between demographic and tobacco use characteristics and cigarette harm perception patterns. Logistic regression was conducted to examine the relationship between cigarette harm perceptions and the perception of e-cigarettes as less harmful than cigarettes for current, ever, and never cigarette smokers. RESULTS: The majority of youth (64.2%) perceived the harmfulness of cigarettes as dose-dependent. Approximately one in three students perceived e-cigarettes as less harmful than conventional cigarettes. Regardless of cigarette smoking status, ever users of e-cigarettes and those with "dose dependent" cigarette harm perceptions consistently were more likely to perceive e cigarettes as less harmful than conventional cigarettes. CONCLUSIONS: Many youth perceive tobacco use on a continuum of harm. Youth who perceive gradations in harm-both by frequency and intensity of cigarette use and by type of product-may be particularly susceptible to e-cigarette use. PMID- 25044197 TI - Exposure to tobacco coupons among U.S. middle and high school students. AB - BACKGROUND: Tobacco marketing contributes to increased tobacco use susceptibility and sustained use. There are limited data on youth exposure to tobacco coupons, a type of pro-tobacco promotion. PURPOSE: To explore channels through which youth report exposure to coupons and characteristics associated with this exposure. This may help inform efforts aimed at decreasing youth exposure to advertising and promotion. METHODS: Data from the 2012 National Youth Tobacco Survey were analyzed in 2013 to estimate the self-reported prevalence of U.S. middle and high school student exposure to coupons through various channels. Associations among exposure to coupons and demographics, tobacco use, living with a tobacco user, and receptivity to tobacco marketing were examined using multivariate logistic regression models. RESULTS: Approximately 13% of students reported exposure to tobacco coupons in the past 30 days through mail, digital communications, or tobacco packages. Prevalence was greatest among current tobacco users (34.0%) and those receptive to tobacco marketing (23.4%) compared to non-tobacco users (9.3%) and those not receptive to tobacco marketing (8.2%), respectively. Coupon exposure varied by sex, grade, and race/ethnicity. In adjusted models, current tobacco use (AOR=3.4, 95% CI=3.0, 3.9); living with a tobacco user (AOR=2.1, 95% CI=1.9, 2.4); and receptivity to tobacco marketing (AOR=2.3, 95% CI=2.0, 2.7) were independently associated with coupon exposure. CONCLUSIONS: Findings from this study indicate that despite restrictions on marketing to youth, youth are still being exposed to tobacco promotions such as coupons. Efforts to limit youth exposure may be valuable in reducing curiosity, susceptibility, and initiation. PMID- 25044198 TI - Self-reported exposure to tobacco warning labels among U.S. middle and high school students. AB - BACKGROUND: Warning labels on tobacco products are a means to communicate information about the negative health effects of tobacco use to current and potential users. Most tobacco use begins in early adolescence, making it particularly important to understand the degree to which warning labels reach adolescents. PURPOSE: To examine the extent to which youth report (1) seeing the current warnings on cigarettes and smokeless tobacco (SLT) products in the U.S. and (2) that seeing warnings makes them think about the health risks associated with tobacco use. METHODS: Exposure to warning labels on cigarettes and SLT, as well as the degree to which adolescents report thinking about health risks in response to warnings, was examined among U.S. middle and high school students using data from the 2012 National Youth Tobacco Survey (NYTS) and analyzed in 2013. RESULTS: Current data suggest that less than half of adolescents who saw a cigarette pack (46.9%) or SLT product (40.3%) reported seeing the warning label "most of the time" or "always." Among adolescents who reported seeing a warning, less than one third reported that cigarette (30.4%) or SLT (25.2%) warning labels made them think about health risks "a lot." These rates were even lower among current tobacco users (<14%). CONCLUSIONS: Current warning labels for cigarettes and SLT could be improved by implementing warnings that incorporate features that make them salient and more likely to evoke thoughts about health risks. PMID- 25044199 TI - Youth curiosity about cigarettes, smokeless tobacco, and cigars: prevalence and associations with advertising. AB - BACKGROUND: Curiosity about cigarettes is a reliable predictor of susceptibility to smoking and established use among youth. Related research has been limited to cigarettes, and lacks national-level estimates. Factors associated with curiosity about tobacco products, such as advertising, have been postulated but rarely tested. PURPOSE: To describe the prevalence of curiosity about cigarettes, smokeless tobacco, and cigars among youth and explore the association between curiosity and self-reported tobacco advertising exposure. METHODS: Data from the 2012 National Youth Tobacco Survey, a nationally representative survey of 24,658 students, were used. In 2013, estimates weighted to the national youth school population were calculated for curiosity about cigarettes, smokeless tobacco, and cigars among never users of any tobacco product. Associations between tobacco advertising and curiosity were explored using multivariable regressions. RESULTS: Curiosity about cigarettes (28.8%); cigars (19.5%); and smokeless tobacco (9.7%) was found, and many youth were curious about more than one product. Exposure to point-of-sale advertising (e.g., OR=1.35, 95% CI=1.19, 1.54 for cigarette curiosity); tobacco company communications (e.g., OR=1.70, 95% CI=1.38, 2.09 for cigarette curiosity); and tobacco products, as well as viewing tobacco use in TV/movies (e.g., OR=1.37, 95% CI=1.20, 1.58 for cigarette curiosity) were associated with curiosity about each examined tobacco product. CONCLUSIONS: Despite decreasing use of tobacco products, youth remain curious about them. Curiosity is associated with various forms of tobacco advertising. These findings suggest the importance of measuring curiosity as an early warning signal for potential future tobacco use and evaluating continued efforts to limit exposure to tobacco marketing among youth. PMID- 25044200 TI - Adapting to a changing tobacco landscape: research implications for understanding and reducing youth tobacco use. PMID- 25044201 TI - Teen tobacco use: research and regulatory gaps. PMID- 25044202 TI - Strategies to reduce youth tobacco use: opportunities for local government. PMID- 25044203 TI - Integrative assessment of selenium speciation, biogeochemistry, and distribution in a northern coldwater ecosystem. AB - For the past decade, considerable research has been conducted at a series of small lakes receiving treated liquid effluent containing elevated selenium (Se) from the Key Lake uranium (U) milling operation in northern Saskatchewan, Canada. Several studies related to this site, including field collections of water, sediment, and biota (biofilm and/or periphyton, invertebrates, fish, and birds), semicontrolled mesocosm and in situ caging studies, and controlled laboratory experiments have recently been published. The aim of the present investigation was to compile the site-specific information obtained from this multidisciplinary research into an integrative perspective regarding the influence of Se speciation on biogeochemical cycling and food web transfer of Se in coldwater ecosystems. Within lakes, approximately 50% of sediment Se was in the form of elemental Se, although this ranged from 0% to 81% among samples. This spatial variation in elemental Se was positively correlated with finer particles (less sand) and percent total organic C content in sediments. Other Se species detected in sediments included selenosulfides, selenite, and inorganic metal selenides. In contrast, the major Se form in sediment-associated biofilm and/or periphyton was an organoselenium species modeled as selenomethionine (SeMet), illustrating the critical importance of this matrix in biotransformation of inorganic Se to organoselenium compounds and subsequent trophic transfer to benthic invertebrates at the base of the food web. Detritus displayed a Se speciation profile intermediate between sediment and biofilm, with both elemental Se and SeMet present. In benthic detritivore (chironomid) larvae and emergent adults, and in foraging and predatory fishes, SeMet was the dominant Se species. The proportion of total Se present as a SeMet-like species displayed a direct nonlinear relationship with increasing whole-body Se in invertebrates and fishes, plateauing at approximately 70% to 80% of total Se as a SeMet-like species. In fish collected from reference lakes, a selenocystine-like species was the major Se species detected. Similar Se speciation profiles were observed using 21-day mesocosm and in situ caging studies with native small-bodied fishes, illustrating the efficient bioaccumulation of Se and use of these semicontrolled approaches for future research. A simplified conceptual model illustrating changes in Se speciation through abiotic and biotic components of lakes was developed, which is likely applicable to a wide range of northern industrial sites receiving elevated Se loading into aquatic ecosystems. PMID- 25044204 TI - Proteinticle/gold core/shell nanoparticles for targeted cancer therapy without nanotoxicity. AB - PGCS-NPs (40 nm) with excellent photo-thermal activity are developed, on the surface of which affibody peptides with specific affinity for EGFR and many small gold dots (1-3 nm) are densely presented. The IV-injected PGCS-NPs into EGFR expressing tumor-bearing mice successfully perform targeted and photothermal therapy of cancer. It seems that the small gold dots released from disassembled PGCS-NPs are easily removed and never cause in vivo toxicity problems. PMID- 25044205 TI - Development of new two-dimensional small molecules based on benzodifuran for efficient organic solar cells. AB - A new organic small molecule, DCA3TBDF, with a 2D benzo[1,2-b:4,5-b']difuran (BDF) moiety as the central core and octyl cyanoacetate units as the end-capped blocks, was designed and synthesized for solution-processed bulk heterojunction solar cells. DCA3TBDF possesses good solubility in common organic solvents such as toluene, CH2Cl2, chlorobenzene, and CHCl3 and good thermal stability with an onset decomposition temperature with 5% weight-loss occurring at 361 degrees C. The DCA3TBDF thin film showed a broad absorption at lambda=320-700 nm and high crystallinity. Small-molecule organic solar cells based on DCA3TBDF and [6,6] phenyl-C61-butyric acid methyl ester demonstrated promising power conversion efficiency with a high fill factor under the illumination of AM 1.5G (100 mW cm( 2)). PMID- 25044206 TI - Disease-specific health status as a predictor of mortality. PMID- 25044207 TI - Plasma antioxidant capacity in critical polytraumatized patients?: methods, severity, and anatomic location. PMID- 25044208 TI - Iodonium metathesis reactions. AB - A metathesis reaction occurs when a diaryliodonium triflate is heated with an aryl iodide, resulting in the formation of a new diaryliodonium triflate. PMID- 25044209 TI - Turmeric toxicity in A431 epidermoid cancer cells associates with autophagy degradation of anti-apoptotic and anti-autophagic p53 mutant. AB - The keratinocyte-derived A431 Squamous Cell Carcinoma cells express the p53R273H mutant, which has been reported to inhibit apoptosis and autophagy. Here, we show that the crude extract of turmeric (Curcuma longa), similarly to its bioactive component Curcumin, could induce both apoptosis and autophagy in A431 cells, and these effects were concomitant with degradation of p53. Turmeric and curcumin also stimulated the activity of mTOR, which notoriously promotes cell growth and acts negatively on basal autophagy. Rapamycin-mediated inhibition of mTOR synergized with turmeric and curcumin in causing p53 degradation, increased the production of autophagosomes and exacerbated cell toxicity leading to cell necrosis. Small-interference mediated silencing of the autophagy proteins BECLIN 1 or ATG7 abrogated the induction of autophagy and largely rescued p53 stability in Turmeric-treated or Curcumin-treated cells, indicating that macroautophagy was mainly responsible for mutant p53 degradation. These data uncover a novel mechanism of turmeric and curcumin toxicity in chemoresistant cancer cells bearing mutant p53. PMID- 25044210 TI - Mechanical downsizing of a gadolinium(III)-based metal-organic framework for anticancer drug delivery. AB - A Gd(III) -based porous metal-organic framework (MOF), Gd-pDBI, has been synthesized using fluorescent linker pDBI (pDBI=(1,4-bis(5-carboxy-1H benzimidazole-2-yl)benzene)), resulting in a three-dimensional interpenetrated structure with a one-dimensional open channel (1.9*1.2 nm) filled with hydrogen bonded water assemblies. Gd-pDBI exhibits high thermal stability, porosity, excellent water stability, along with organic-solvent and mild acid and base stability with retention of crystallinity. Gd-pDBI was transformed to the nanoscale regime (ca. 140 nm) by mechanical grinding to yield MG-Gd-pDBI with excellent water dispersibility (>90 min), maintaining its porosity and crystallinity. In vitro and in vivo studies on MG-Gd-pDBI revealed its low blood toxicity and highest drug loading (12 wt %) of anticancer drug doxorubicin in MOFs reported to date with pH-responsive cancer-cell-specific drug release. PMID- 25044211 TI - Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing. AB - There is strong evidence in the clinical literature to suggest that elevated lead (Pb) exposure impairs fracture healing. Since Pb has been demonstrated to inhibit bone formation, and Wnt signaling is an important anabolic pathway in chondrocyte maturation and endochondral ossification, we investigated the impact of Wnt therapy on Pb-exposed mice undergoing bone repair in a mouse tibial fracture model. We established that tibial fracture calluses from Pb-treated mice were smaller and contained less mineralized tissue than vehicle controls. This resulted in the persistence of immature cartilage in the callus and decreased beta-catenin levels. Reduction of beta-catenin protein was concurrent with systemic elevation of LRP5/6 antagonists DKK1 and sclerostin in Pb-exposed mice throughout fracture healing. beta-catenin stimulation by the GSK3 inhibitor BIO reversed these molecular changes and restored the amount of mineralized callus. Overall, Pb is identified as a potent inhibitor of endochondral ossification in vivo with correlated effects on bone healing with noted deficits in beta-catenin signaling, suggesting the Wnt/beta-catenin as a pivotal pathway in the influence of Pb on fracture repair. PMID- 25044212 TI - CCNB1 is a prognostic biomarker for ER+ breast cancer. AB - Identification of effective prognostic biomarkers and targets are of crucial importance to the management of breast cancer. CCNB1 (also known as CyclinB1) belongs to the highly conserved cyclin family and is significantly overexpressed in various cancer types. In this study, we demonstrated that CCNB1 had significant predictive power in distant metastasis free survival, disease free survival, recurrence free survival and overall survival of ER+ breast cancer patients. We also found that CCNB1 was closely associated with hormone therapy resistance. In addition, gene set enrichment analysis (GSEA) revealed that its expression was positively associated with genes overexpressed in endocrine therapy resistant samples. Finally, using CCNB1-Drug interaction network, we demonstrated the interactions between CCNB1 and several available cancer drugs. Overall, we suggest that CCNB1 is a biomarker for the prognosis of ER+ breast cancer and monitoring of hormone therapy efficacy. It is also a promising target for developing new strategies to prevent or even reverse hormone therapy resistance. Moreover, CCNB1 expression may help to monitor hormone therapy and to direct personalized therapies. Nevertheless, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed before its application in clinical settings. PMID- 25044214 TI - Ripple effect. PMID- 25044215 TI - Derivative emission spectrofluorimetry for the simultaneous determination of guaifenesin and phenylephrine hydrochloride in pharmaceutical tablets. AB - Rapid, simple and sensitive derivative emission spectrofluorimetric methods have been developed for the simultaneous analysis of binary mixtures of guaifenesin (GUA) and phenylephrine hydrochloride (PHE). The methods are based upon measurement of the native fluorescence intensity of the two drugs at lambdaex = 275 nm in methanolic solutions, followed by differentiation using first (D1) and second (D2) derivative techniques. The derivative fluorescence intensity concentration plots were rectilinear over a range of 0.1-2 ug/mL for both GUA and PHE. The limits of detection were 0.027 (D1, GUA), 0.025 (D2, GUA), 0.031 (D1, PHE) and 0.033 (D2, PHE) ug/mL and limits of quantitation were 0.089 (D1, GUA), 0.083 (D2, GUA), 0.095 (D1, PHE) and 0.097 (D2, PHE) ug/mL. The proposed derivative emission spectrofluorimetric methods (D1 and D2) were successfully applied for the determination of the two compounds in binary mixtures and tablets with high precision and accuracy. The proposed methods were fully validated as per ICH guidelines. PMID- 25044213 TI - Multivariate lesion-symptom mapping using support vector regression. AB - Lesion analysis is a classic approach to study brain functions. Because brain function is a result of coherent activations of a collection of functionally related voxels, lesion-symptom relations are generally contributed by multiple voxels simultaneously. Although voxel-based lesion-symptom mapping (VLSM) has made substantial contributions to the understanding of brain-behavior relationships, a better understanding of the brain-behavior relationship contributed by multiple brain regions needs a multivariate lesion-symptom mapping (MLSM). The purpose of this artilce was to develop an MLSM using a machine learning-based multivariate regression algorithm: support vector regression (SVR). In the proposed SVR-LSM, the symptom relation to the entire lesion map as opposed to each isolated voxel is modeled using a nonlinear function, so the intervoxel correlations are intrinsically considered, resulting in a potentially more sensitive way to examine lesion-symptom relationships. To explore the relative merits of VLSM and SVR-LSM we used both approaches in the analysis of a synthetic dataset. SVR-LSM showed much higher sensitivity and specificity for detecting the synthetic lesion-behavior relations than VLSM. When applied to lesion data and language measures from patients with brain damages, SVR-LSM reproduced the essential pattern of previous findings identified by VLSM and showed higher sensitivity than VLSM for identifying the lesion-behavior relations. Our data also showed the possibility of using lesion data to predict continuous behavior scores. PMID- 25044216 TI - Nonaqueous capillary electrophoresis of dextromethorphan and its metabolites. AB - This study deals with the nonaqueous capillary electrophoretic separation of dextromethorphan and its metabolites using a methanolic background electrolyte. The optimization of separation conditions was performed in terms of the resolution of dextromethorphan and dextrorphan and the effect of separation temperature, voltage, and the characteristics of the background electrolyte were studied. Complete separation of all analytes was achieved in 40 mM ammonium acetate dissolved in methanol. Hydrodynamic injection was performed at 3 kPa for 4 s. The separation voltage was 20 kV accompanied by a low electric current. The ultraviolet detection was performed at 214 nm, the temperature of the capillary was 25 degrees C. These conditions enabled the separation of four analytes plus the internal standard within 9 min. Further, the developed method was validated in terms of linearity, sensitivity, and repeatability. Rat liver perfusate samples were subjected to the nonaqueous capillary electrophoretic method to illustrate its applicability. PMID- 25044218 TI - Efficient conversion of polyamides to omega-hydroxyalkanoic acids: a new method for chemical recycling of waste plastics. AB - An efficient transformation of polyamides to omega-hydroxy alkanoic acids was achieved. Treatment of nylon-12 with supercritical MeOH in the presence of glycolic acid gave methyl omega-hydroxydodecanoate in 85% yield and the alcohol/alkene selectivity in the product was enhanced to up to 9.5:1. The use of (18)O-enriched acetic acid for the reaction successfully introduced an (18)O atom at the alcoholic OH group in the product. This strategy may provide a new and economical solution for the chemical recycling of waste plastics. PMID- 25044219 TI - Single-dose linezolid pharmacokinetics in critically ill patients with impaired renal function especially chronic hemodialysis patients. AB - BACKGROUND AND OBJECTIVE: Renal failure patients were treated with linezolid (LZD) for proven or suspected infections by multi-resistant Gram-positive cocci. The aim of this study was to determine if dose adjustment of LZD is needed as a function of renal impairment or not, especially that a significant component of LZD is eliminated unchanged in urine. METHODS: The single dose pharmacokinetics of LZD was investigated. Eighteen non-infected male subjects with various degrees of renal impairment ranged from normal to severe chronic impairment were enrolled, including end-stage renal disease (ESRD) patients maintained on hemodialysis (HD). LZD was administered as a single oral 600 mg dose, and blood samples were drawn at different times and analysed by a validated HPLC assay method. Plasma profiles were evaluated by non-compartmental and compartmental approaches. RESULTS AND DISCUSSION: A similar rate and extent of LZD absorption and elimination and comparable body exposure was observed in both healthy subjects and acute renal failure patients. The extent of LZD exposure was significantly increased by 3-fold in ESRD patients in their off-dialysis day. Furthermore, the t1/2 and MRT values were significantly increased by ~5- and 3 fold, respectively. The Vd /F values of LZD did not change with renal function. A significant decrease in CL/F by ~3-fold was observed in ESRD patients in their off-dialysis day however, CL/F was significantly increased by ~4-fold during HD. Approximately half of the administered LZD dose was removed during the HD session in these selected cohorts of ESRD patients. LZD was generally well tolerated. CONCLUSIONS: The dose of LZD did not need to be adjusted for patients with acute renal dysfunction or ESRD on HD. One of the twice-daily doses should be administered after the dialysis session because almost half of the LZD dose was substantially removed by HD. During the first three dialysis sessions of the treatment course, to avoid potentially ineffective therapy, a supplemental dose of LZD might be given if necessary or the dose of LZD should be administered 4 h before the beginning of the HD session. This was to keep LZD levels above the MIC for the organism causing the infection being treated. PMID- 25044220 TI - Protection of winter wheat against orange wheat blossom midge, Sitodiplosis mosellana (Gehin) (Diptera: Cecidomyiidae): efficacy of insecticides and cultivar resistance. AB - BACKGROUND: In 2012 and 2013, Sitodiplosis mosellana (Gehin) flights occurred during the susceptible phase of wheat development in Belgium. The protection against this midge afforded by various insecticides was assessed in infested fields on four winter wheat cultivars (susceptible or resistant, and early or late heading). RESULTS: The insecticides sprayed at the right time reduced the number of larvae in the ears by 44-96%, depending on the product. For Julius, the cultivar (cv.) most exposed to S. mosellana in 2013, the mean yield gain resulting from insecticide use was 1558 kg ha(-1) (18%). In the same year, insecticide use resulted in a yield gain of 780 kg ha(-1) (8%) for the cv. Lear, in spite of its resistance to this pest. The link between yield and number of larvae counted in the ears was a logarithmic relationship, suggesting an important reduction in yield, caused either by the damage inflicted by young larvae that died at the start of their development or by the activation of costly reactions in plants. CONCLUSION: The study showed that, in cases of severe attack, the timely application of insecticide treatments can protect wheat against S. mosellana, and that even resistant cultivars can benefit from these treatments. PMID- 25044221 TI - A historical perspective: Bernhard von Langenbeck German surgeon (1810-1887). AB - Bernhard von Langenbeck is undeniably one of the world's greatest surgeons and inventors. The influence which he exerted upon the practice of surgery, as apparent by the numerous surgical tools and 21 operations credited to his name, represents the notable contributions of this amazing man. Despite the tools and techniques which bear his name, the establishment of a surgical journal, and his role in co-founding the German Surgical Society, many attest that Bernhard von Langenbeck's greatest contribution to the professional field was the vast knowledge he imparted on his pupils. Commonly credited with training nearly every celebrated surgical operator of his time, von Langenbeck merits posthumous acknowledgement for his vast contributions to the field of medicine and surgery. PMID- 25044222 TI - Plant biomass fractionation meets catalysis. PMID- 25044224 TI - Preparation and properties of clickable amino analogues of the duocarmycins: factors that affect the efficiency of their fluorescent labelling of DNA. AB - Herein we report the synthesis of three DNA-alkylating amino analogues of the duocarmycins that carry an alkyne functional group suitable for copper-catalysed click chemistry. The alkyne-containing substituents are connected via a side chain position which projects away from the minor groove, and have only a small effect on DNA alkylation and cytotoxicity. The efficiency of click reactions with fluorophore azides was studied using alkylated ctDNA by analysing the adenine adducts produced after thermal depurination. Click reactions "on DNA" were sensitive to steric effects (tether length to the alkyne) and, surprisingly, to the nature of the fluorophore azide. With the best combination of click partners and reagents, adducts could be detected in the nuclei of treated cells by microscopy or flow cytometry, provided that an appropriate detergent (Triton X 100 and not Tween 20) was used for permeabilisation. The method is sensitive enough to detect adducts at physiologically relevant concentrations, and could have application in the development of nitro analogues of the duocarmycins as hypoxia-activated anticancer prodrugs. PMID- 25044223 TI - Structure and function of pseudoknots involved in gene expression control. AB - Natural RNA molecules can have a high degree of structural complexity but even the most complexly folded RNAs are assembled from simple structural building blocks. Among the simplest RNA elements are double-stranded helices that participate in the formation of different folding topologies and constitute the major fraction of RNA structures. One common folding motif of RNA is a pseudoknot, defined as a bipartite helical structure formed by base-pairing of the apical loop in the stem-loop structure with an outside sequence. Pseudoknots constitute integral parts of the RNA structures essential for various cellular activities. Among many functions of pseudoknotted RNAs is feedback regulation of gene expression, carried out through specific recognition of various molecules. Pseudoknotted RNAs autoregulate ribosomal and phage protein genes in response to downstream encoded proteins, while many metabolic and transport genes are controlled by cellular metabolites interacting with pseudoknotted RNA elements from the riboswitch family. Modulation of some genes also depends on metabolite induced messenger RNA (mRNA) cleavage performed by pseudoknotted ribozymes. Several regulatory pseudoknots have been characterized biochemically and structurally in great detail. These studies have demonstrated a plethora of pseudoknot-based folds and have begun uncovering diverse molecular principles of the ligand-dependent gene expression control. The pseudoknot-mediated mechanisms of gene control and many unexpected and interesting features of the regulatory pseudoknots have significantly advanced our understanding of the genetic circuits and laid the foundation for modulation of their outcomes. PMID- 25044226 TI - Impact of adverse left ventricular remodeling on sudden cardiac death in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Adverse left ventricular (LV) remodeling predicts heart failure symptoms and overt LV dysfunction in patients with hypertrophic cardiomyopathy (HCM), but its influence on the occurrence of sudden cardiac death (SCD) is unknown. The aim of this study was to investigate the effect of adverse LV remodeling on SCD risk in patients with HCM. HYPOTHESIS: Adverse LV remodeling increases SCD in HCM patients. METHODS: This study included 41 patients with HCM who experienced SCD; each case was matched with 3 controls based on age, gender, and time of first contact. In this population of 164 patients, predictors of SCD were identified using univariable and multivariable logistic regression and expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: Baseline characteristics, such as New York Heart Association (NYHA) class, systolic and diastolic left ventricular function, left ventricular wall thickness, left atrial size, atrial fibrillation, and established risk factors for SCD were similar in cases and controls. Independent predictors of SCD during follow-up (median follow up, 7.7 +/- 6.5 years) were: increase in NYHA class (OR: 8.7 [95% CI: 2.5-30.5], P = 0.001), decrease of fractional shortening (per % decrease, OR: 1.09 [95% CI: 1.03-1.14], P = 0.001), and decrease of diastolic function (OR: 3.5 [95% CI: 1.2 10.2], P = 0.02). CONCLUSIONS: This study shows that SCD risk in HCM increases when adverse remodeling occurs. Because cases and controls were similar at baseline, these findings emphasize the importance of vigilant follow-up of HCM patients and could aid clinical decision making concerning implantable cardioverter-defibrillator implantation, especially in patients with moderate risk for SCD. PMID- 25044225 TI - Differentiation of P19 embryonal carcinoma stem cells into insulin-producing cells promoted by pancreas-conditioned medium. AB - The ability of embryonal carcinoma )EC (stem cells to generate insulin-producing cells (IPCs) is still unknown. We examined the trophic effects of pancreas conditioned medium (PCM) on in vitro production of IPCs. Initially, P19 EC cells were characterized by the expression of stem cell markers, Oct3/4, Sox-2 and Nanog. To direct differentiation, P19-derived embryoid bodies (EBs) were induced by selection of nestin-positive cells and treatment with different concentrations of PCM. Morphological studies documented the presence of islet-like cell IPCs clusters. The differentiated cells were immunoreactive for beta cell-specific proteins, including insulin, proinsulin, C-peptide and insulin receptor-beta. The expression of genes related to pancreatic beta cell development and function (PDX 1, INS1, INS2, EP300 and CREB1) was confirmed by qPCR. During differentiation, the expression of EP300 and CREB1 increased by 2.5 and 3.1 times, respectively. In contrast, a sharp decrease in the expression of Oct3/4, Sox-2 and Nanog by 4, 1.5 and 1.5 times, respectively, was observed. The differentiated cells were functionally active, synthesizing and secreting insulin in a glucose-regulated manner. Network prediction highlighted crosstalk between PDX-1 transcription factor and INS2 ligand in IPC generation and revealed positive regulatory effects of EP300, CREB1, PPARA, EGR, KIT, GLP1R, and PKT2 on activation of PDX-1 and INS2. This is the first report of the induction of IPC differentiation from EC cells by using neonate mouse PCM. Since P19 EC cells are widely available, easily cultured without feeders and do not require special growth conditions, they would provide a valuable tool for studying pancreatic beta cell differentiation and development. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 25044228 TI - Graphitic silicon nitride: a metal-free ferromagnet with charge and spin current rectification. AB - As a first example, herein we show that g-Si(4)N(3) is expected to act as a metal free ferromagnet featuring both charge and spin current rectification simultaneously. Such rectification is crucial for envisioning devices that contain both logic and memory functionality on a single chip. The spin coherent quantum-transport calculations on g-Si(4)N(3) reveal that the chosen system is a unique molecular spin filter, the current-voltage characteristics of which is asymmetric in nature, which can create a perfect background for synchronous charge and spin current rectification. To shed light on this highly unusual in silico observation, we have meticulously inspected the bias-dependent modulation of the spin-polarized eigenstates. The results indicate that, whereas only the localized 2p orbitals of the outer-ring (OR) Si atoms participate in the transmission process in the positive bias, both OR Si and N atoms contribute in the reverse bias. Furthermore, we have evaluated the spin-polarized electron transfer rate in the tunneling regime, and the results demonstrate that the transfer rates are unequal in the positive and negative bias range, leading to the possible realization of a simultaneous logic-memory device. PMID- 25044227 TI - Pseudomonas aeruginosa biofilm growth inhibition on medical plastic materials by immobilized esterases and acylase. AB - Biofilms are matrix-encapsulated cell aggregates that cause problems in technical and health-related areas; for example, 65 % of all human infections are biofilm associated. This is mainly due to their ameliorated resistance against antimicrobials and immune systems. Pseudomonas aeruginosa, a biofilm-forming organism, is commonly responsible for nosocomial infections. Biofilm development is partly mediated by signal molecules, such as acyl-homoserine lactones (AHLs) in Gram-negative bacteria. We applied horse liver esterase, porcine kidney acylase, and porcine liver esterase; these can hydrolyze AHLs, thereby inhibiting biofilm formation. As biofilm infections are often related to foreign material introduced into the human body, we immobilized the enzymes on medical plastic materials. Biofilm formation was quantified by Crystal Violet staining and confocal laser scanning microscopy, revealing up to 97 % (on silicone), 54 % (on polyvinyl chloride), and 77 % (on polyurethane) reduced biomass after 68 h growth. PMID- 25044229 TI - Synthesis-enabled probing of mitosene structural space leads to improved IC50 over mitomycin C. AB - A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis-driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates. PMID- 25044231 TI - The future of therapygenetics: where will studies predicting psychological treatment response from genomic markers lead? PMID- 25044232 TI - Signaling added response-independent reinforcement to assess Pavlovian processes in resistance to change and relapse. AB - Behavioral momentum theory asserts Pavlovian stimulus-reinforcer relations govern the persistence of operant behavior. Specifically, resistance to conditions of disruption (e.g., extinction, satiation) reflects the relation between discriminative stimuli and the prevailing reinforcement conditions. The present study assessed whether Pavlovian stimulus-reinforcer relations govern resistance to disruption in pigeons by arranging both response-dependent and -independent food reinforcers in two components of a multiple schedule. In one component, discrete-stimulus changes preceded response-independent reinforcers, paralleling methods that reduce Pavlovian conditioned responding to contextual stimuli. Compared to the control component with no added stimuli preceding response independent reinforcement, response rates increased as discrete-stimulus duration increased (0, 5, 10, and 15 s) across conditions. Although resistance to extinction decreased as stimulus duration increased in the component with the added discrete stimulus, further tests revealed no effect of discrete stimuli, including other disrupters (presession food, intercomponent food, modified extinction) and reinstatement designed to control for generalization decrement. These findings call into question a straightforward conception that the stimulus reinforcer relations governing resistance to disruption reflect the same processes as Pavlovian conditioning, as asserted by behavioral momentum theory. PMID- 25044230 TI - Adult c-Kit(+) progenitor cells are necessary for maintenance and regeneration of olfactory neurons. AB - The olfactory epithelium houses chemosensory neurons, which transmit odor information from the nose to the brain. In adult mammals, the olfactory epithelium is a uniquely robust neuroproliferative zone, with the ability to replenish its neuronal and non-neuronal populations due to the presence of germinal basal cells. The stem and progenitor cells of these germinal layers, and their regulatory mechanisms, remain incompletely defined. Here we show that progenitor cells expressing c-Kit, a receptor tyrosine kinase marking stem cells in a variety of embryonic tissues, are required for maintenance of the adult neuroepithelium. Mouse genetic fate-mapping analyses show that embryonically, a c Kit(+) population contributes to olfactory neurogenesis. In adults under conditions of normal turnover, there is relatively sparse c-Kit(+) progenitor cell (ckPC) activity. However, after experimentally induced neuroepithelial injury, ckPCs are activated such that they reconstitute the neuronal population. There are also occasional non-neuronal cells found to arise from ckPCs. Moreover, the selective depletion of the ckPC population, utilizing temporally controlled targeted diphtheria toxin A expression, results in failure of neurogenesis after experimental injury. Analysis of this model indicates that most ckPCs reside among the globose basal cell populations and act downstream of horizontal basal cells, which can serve as stem cells. Identification of the requirement for olfactory c-Kit-expressing progenitors in olfactory maintenance provides new insight into the mechanisms involved in adult olfactory neurogenesis. Additionally, we define an important and previously unrecognized site of adult c Kit activity. PMID- 25044233 TI - Revisit frequency and its association with quality of care among diabetic patients: Translating Research Into Action for Diabetes (TRIAD). AB - OBJECTIVE: To describe patient and provider characteristics associated with outpatient revisit frequency and to examine the associations between the revisit frequency and the processes and intermediate outcomes of diabetes care. RESEARCH DESIGN AND METHODS: We analyzed data from Translating Research Into Action for Diabetes (TRIAD), a prospective, multicenter, observational study of diabetes care in managed care. RESULTS: Our analysis included 6040 eligible adult participants with type 2 diabetes (42.6% >=65 years of age, 54.1% female) whose primary care providers were the main provider of the participants' diabetes care. The median (interquartile range) revisit frequency was 4.0 (3.7, 6.0) visits per year. Being female, having lower education, lower income, more complex diabetes treatment, cardiovascular disease, higher Charlson comorbidity index, and impaired mobility were associated with higher revisit frequency. The proportion of participants who had annual assessments of HbA1c and LDL-cholesterol, foot examinations, advised or documented aspirin use, and influenza immunizations were higher for those with higher revisit frequency. The proportion of participants who met HbA1c (<9.5%) and LDL-cholesterol (<130 mg/dL) treatment goals were higher for those with a higher revisit frequency. The predicted probabilities of achieving more aggressive goals, HbA1c <8.5%, LDL-cholesterol <100mg/dL, and blood pressure <130/85 or even <140/90 mmHg were not associated with higher revisit frequency. CONCLUSIONS: Revisit frequency was highly variable and was associated with both sociodemographic characteristics and disease severity. A higher revisit frequency was associated with better processes of diabetes care, but the association with intermediate outcomes was less clear. PMID- 25044234 TI - Low-grade inflammation and endothelial dysfunction explain the association between retinopathy and left ventricular ejection fraction in men: an 8-year follow-up of the Hoorn Study. AB - PURPOSE: The aim of this study was to prospectively investigate the association of retinopathy with changes in left ventricular (LV) function. METHODS: Within the Hoorn Study, a population-based cohort study of diabetes in The Netherlands, retinal photography and echocardiography were performed in the year 2000 (baseline) and 2008 (follow-up). Retinopathy was graded according to the Eurodiab classification and further defined as absent or present retinopathy. LV systolic and diastolic functions were assessed by LV ejection fraction (%), LV mass (g/m(2.7)) and left atrial (LA) volume indices and the ratio of LV inflow (E) and early diastolic lengthening (e') velocities. Linear regression analyses stratified for sex were completed to investigate associations of retinopathy with changes in LV function in participants with impaired glucose metabolism and type 2 diabetes. RESULTS: One hundred forty-seven participants (58% men, mean age 66) were included in the study, of whom 13.6% were present with retinopathy at baseline. LV ejection fraction was similar among participants with and without retinopathy (60.2% versus 60.7%) at baseline. Eight years later, retinopathy was significantly associated with a lower LV ejection fraction (beta -8.0 95% CI 15.37 to -0.68) in men, independent of risk factors. Microvascular endothelial dysfunction ([ED] beta -4.87 95% CI -13.40 to 3.67) and low-grade inflammation ([LGI] beta -5.30 95% CI -13.72 to 3.12) both diminished the association. No significant associations between retinopathy and other LV function parameters were observed. CONCLUSION: Retinopathy was significantly associated with a lower LV ejection fraction in men but not in women. LGI and ED might explain the observed association. PMID- 25044235 TI - The association of oxidative stress and pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis. AB - AIMS: To investigate the relationship between oxidative stress and serum levels of pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis. METHODS: Seventy-three patients presenting to hospital with diabetic ketoacidosis or non-ketotic hyperglycemia were studied. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, total antioxidant capacity (TAC), 8-iso prostaglandin F2alpha (8-iso-prostaglandinF2alpha, 8-iso-PGF2alpha), tumor necrosis factor receptor-I (TNF-RI), interleukin -1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were measured in all patients. The patients were then given an intravenous infusion of insulin 0.1U * kg-1 * h-1, as well as fluids, symptomatic therapy and parenteral and intravenous nutrition. RESULTS CONCLUSION: Patients with hyperglycemic crises have significantly increased oxidative stress and dysregulated serum pro inflammatory cytokines that can be effectively treated by intensive insulin therapy. PMID- 25044237 TI - Variation in the position of the jugal medial ridge among lizards (reptilia: squamata): its functional and taxonomic significance. AB - The course of the medial ridge in the lizard jugal shows considerable morphological variation. There are four basic configurations: (1) the medial ridge is located ventral to mid-height on the suborbital process and anterior to mid-length on the postorbital process; (2) the medial ridge is located ventrally on the suborbital process (as above), but posteriorly on the postorbital process; (3) the medial ridge is located dorsally on the suborbital process and anteriorly on the postorbital process; and (4) the medial ridge is centrally located along the entire length of the jugal. Ancestral character state reconstruction shows that type 1 is plesiomorphic for Squamata regardless of the broad-scale phylogenetic topology. Type 3 is present in chamaeleonids and convergently in Anolis barbatus. Type 3 is a synapomorphy of the chamaeleonids. Type 2 is considered plesiomorphic for Anguidae, Heloderma and Xenosaurus, although it is independently modified in some extant members. These taxa form a clade in molecular phylogenies of Squamata, and the course of the medial ridge of the jugal therefore provides some measure of morphological support for this arrangement. The course of the medial ridge may be best explained by the position of the eye and by the angle of the jugal; its relations with other bony orbital structures (supraocular osteoderms, palpebral, supraorbital flanges) and the posterior extent of the maxilla are also discussed. PMID- 25044236 TI - Differential reduction in corneal nerve fiber length in patients with type 1 or type 2 diabetes mellitus. AB - AIM: To examine the relationship between corneal nerve fiber length (CNFL) and diabetic neuropathy (DN) status in patients with type 1 or type 2 diabetes mellitus (DM). METHODS: In this cross-sectional study, we examined 25 diabetic patients without DN, 10 patients with mild DN, 8 patients with severe DN, and 9 controls without diabetes. DN status was assigned based on a combination of clinical symptoms, signs, and electrophysiological testing. Patients underwent corneal confocal microscopy (CCM) of the sub-basal nerve plexus. Post-hoc analysis of the CCM images was performed to quantify the average CNFL, and ANOVA was used to assess for differences in CNFL. RESULTS: All 25 subjects without DN had type 1 DM, and subjects with DN had type 2 DM. Participants with severe DN had significantly lower CNFL (12.5+/-6.1mm/mm(2)) compared to controls (20.7+/ 2.2mm/mm(2)) (p=0.009). However, lower CNFL was also found in participants with type 1 DM who did not have DN (15.1+/-4.7mm/mm(2)) relative to controls (p=0.033). CONCLUSIONS: CCM of the sub-basal nerve plexus may be an indicator of early peripheral nerve degeneration in type 1 DM. Type of diabetes, in addition to degree of neuropathy, may influence the extent of corneal nerve damage. PMID- 25044238 TI - Development of C-N coupling using mechanochemistry: catalytic coupling of arylsulfonamides and carbodiimides. AB - Reported herein is the mechanochemical synthesis of sulfonyl guanidines, a family of molecules which are relevant as pharmaceuticals and herbicides, by direct coupling of sulfonamides and aromatic or aliphatic carbodiimides. Attempts to conduct the coupling in solution have either failed or given very low conversions, thus demonstrating mechanochemistry as the necessary component for the discovery of this synthetic strategy. PMID- 25044239 TI - Vicinal solvent effect on supramolecular gelation: alcohol controlled topochemical reaction and the toruloid nanostructure. AB - Although solvent is the major component of the gel, it still remains unclear how the solvent molecules take part in the formation of the gel nanostructures in many gels. In this study it was observed that the vicinal effect on gel formation as well as their nanostructures, that is, the vicinal solvent molecules to the gelator, determine the molecular packing and their subsequent structures and properties. A naphthylacryl-conjugated L-glutamide gelator was found to form organogels in various solvents and nanofiber structures. While the nanofibers from other solvents could not show any further reaction, the gel from the alcohol could undergo topochemical [2+2] cycloaddition under photoirradiation and resulted in toruloid nanostructures. Various pure alcohol solvents from methanol to pentanol were found to show a similar property. Interestingly, switching from a single alcohol solvent to mixed solvents of alcohol with miscible or immiscible non-alcohol solvents could still cause the same change, showing the vicinal effect of alcohol on controlling the molecular packing as well as the structural transformation. More interestingly, when nanofiber xerogel, obtained from non alcohol solvents, was exposed to alcohol vapor, the nanofiber was transferred into nanotoruloid. These results provide a new insight into the gelator-solvent interaction in soft gels. PMID- 25044240 TI - Design of fluorescent nanocapsules as ratiometric nanothermometers. AB - We have developed a novel design of optical nanothermometers that can measure the surrounding temperature in the range of 20-85 degrees C. The nanothermometers comprise two organic fluorophores encapsulated in a crosslinked polymethacrylate nanoshell. The role of the nanocapsule shell around the fluorophores is to form a well-defined and stable microenvironment to prevent other factors besides temperature from affecting the dyes' fluorescence. The two fluorophores feature different temperature-dependent emission profiles; a fluorophore with relatively insensitive fluorescence (rhodamine 640) serves as a reference whereas a sensitive fluorophore (indocyanine green) serves as a sensor. The sensitivity of the nanothermometers depends on the type of nanocapsule-forming lipid and is affected by the phase transition temperature. Both the fluorescence intensity and the fluorescence lifetime can be utilized to measure the temperature. PMID- 25044241 TI - Comparative epigenomics: defining and utilizing epigenomic variations across species, time-course, and individuals. AB - Epigenomic profiling, by revealing genome-wide distributions of epigenetic modifications, generated a large amount of structural information about the chromosomes. Epigenomic analysis has quickly become a big data science, posing tremendous challenges on its translation into knowledge. To meet this challenge, comparative analysis of epigenomes, dubbed comparative epigenomics, has emerged as an active research area. Here, we summarize the recent developments in comparative epigenomic analyses into three major directions, namely the comparisons across species, the time-course of a biological process, and individuals. We review the main ideas, methods, and findings in each direction, and discuss the implications to understanding the regulatory functions of the genomes. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. PMID- 25044242 TI - Contrasting above- and belowground sensitivity of three Great Plains grasslands to altered rainfall regimes. AB - Intensification of the global hydrological cycle with atmospheric warming is expected to increase interannual variation in precipitation amount and the frequency of extreme precipitation events. Although studies in grasslands have shown sensitivity of aboveground net primary productivity (ANPP) to both precipitation amount and event size, we lack equivalent knowledge for responses of belowground net primary productivity (BNPP) and NPP. We conducted a 2-year experiment in three US Great Plains grasslands--the C4-dominated shortgrass prairie (SGP; low ANPP) and tallgrass prairie (TGP; high ANPP), and the C3 dominated northern mixed grass prairie (NMP; intermediate ANPP)--to test three predictions: (i) both ANPP and BNPP responses to increased precipitation amount would vary inversely with mean annual precipitation (MAP) and site productivity; (ii) increased numbers of extreme rainfall events during high-rainfall years would affect high and low MAP sites differently; and (iii) responses belowground would mirror those aboveground. We increased growing season precipitation by as much as 50% by augmenting natural rainfall via (i) many (11-13) small or (ii) fewer (3-5) large watering events, with the latter coinciding with naturally occurring large storms. Both ANPP and BNPP increased with water addition in the two C4 grasslands, with greater ANPP sensitivity in TGP, but greater BNPP and NPP sensitivity in SGP. ANPP and BNPP did not respond to any rainfall manipulations in the C3 -dominated NMP. Consistent with previous studies, fewer larger (extreme) rainfall events increased ANPP relative to many small events in SGP, but event size had no effect in TGP. Neither system responded consistently above- and belowground to event size; consequently, total NPP was insensitive to event size. The diversity of responses observed in these three grassland types underscores the challenge of predicting responses relevant to C cycling to forecast changes in precipitation regimes even within relatively homogeneous biomes such as grasslands. PMID- 25044243 TI - Multiple treatments with L-3,4-dihydroxyphenylalanine modulate dopamine biosynthesis and neurotoxicity through the protein kinase A-transient extracellular signal-regulated kinase and exchange protein activation by cyclic AMP-sustained extracellular signal-regulated kinase signaling pathways. AB - Multiple treatments with L-3,4-dihydroxyphenylalanine (L-DOPA; 20 uM) induce neurite-like outgrowth and reduce dopamine biosynthesis in rat adrenal pheochromocytoma (PC) 12 cells. We therefore investigated the effects of multiple treatments with L-DOPA (MT-LD) on cell survival and death over a duration of 6 days by using PC12 cells and embryonic rat midbrain primary cell cultures. MT-LD (10 and 20 uM) decreased cell viability, and both types of cells advanced to the differentiation process at 4-6 days. MT-LD induced cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) phosphorylation and exchange protein activation by cAMP (Epac) expression at 1-3 days, which led to transient extracellular signal-regulated kinase (ERK1/2) phosphorylation in both cells. In these states, MT-LD activated cAMP-response element binding protein (CREB; Ser133) and tyrosine hydroxylase (Ser40) phosphorylation in PC12 cells, which led to an increase in intracellular dopamine levels. In contrast, MT-LD induced prolonged Epac expression at 4-5 days in both cells, which led to sustained ERK1/2 phosphorylation. In these states, the dopamine levels were decreased in PC12 cells. In addition, MT-LD induced c-Jun N-terminal kinase1/2 phosphorylation and cleaved caspase-3 expression at 4-6 days in both cells. These results suggest that MT-LD maintains cell survival via PKA-transient ERK1/2 activation, which stimulates dopamine biosynthesis. In contrast, at the later time period, MT-LD induces differentiation via both prolonged Epac and sustained ERK1/2 activation, which subsequently leads to the cell death process. Our data demonstrate that L DOPA can cause neurotoxicity by modulating the Epac-ERK pathways in neuronal and PC12 cells. PMID- 25044244 TI - Synthesis of triazole-linked homonucleoside polymers through topochemical azide alkyne cycloaddition. AB - There is a great deal of interest in developing stable modified nucleic acids for application in diverse fields. Phosphate-modified DNA analogues, in which the phosphodiester group is replaced with a surrogate group, are attractive because of their high stability and resistance to nucleases. However, the scope of conventional solution or solid-phase DNA synthesis is limited for making DNA analogues with unnatural linkages. Other limitations associated with conventional synthesis include difficulty in making larger polymers, poor yield, incomplete reaction, and difficult purification. To circumvent these problems, a single crystal-to-single-crystal (SCSC) synthesis of a 1,5-triazole-linked polymeric ssDNA analogue from a modified nucleoside through topochemical azide-alkyne cycloaddition (TAAC) is reported. This is the first solvent-free, catalyst-free synthesis of a DNA analogue that proceeds in quantitative yield and does not require any purification. PMID- 25044245 TI - Target cell limitation constrains chlamydial load in persistent infections: results from mathematical modelling applied to mouse genital tract infection data. AB - The interactions between chlamydial pathogens and their host contribute to the outcome of infection. Nonresolving infections in immunodeficient mice can provide insights into these mechanisms by allowing observation of a form of persistent infection. Using a mathematical model, we predict that in a nonresolving infection, the number of chlamydiae in the host will attain a stable equilibrium and that this equilibrium will be independent of the inoculum size. We test this hypothesis by infecting RAG(-/-) mice with 10(4)-10(7) inclusion-forming units (IFU) of Chlamydia muridarum and comparing the IFU levels at equilibrium. There were no statistically significant differences in equilibrium IFU levels between the reference group and other inoculation groups, supporting the hypothesis. Using the mathematical model, we estimated that at equilibrium just 3% of the chlamydiae infect a target cell. We predict that the equilibrium IFU level is highly sensitive to the rate of replenishment of healthy cells. The limitation of target cells is a key driver of infection dynamics, affecting both the peak of infection and the equilibrium level of persistent infections. Target cell limitation likely plays an important role in the dynamics of human infections as well. PMID- 25044246 TI - High-performance hole-extraction layer of sol-gel-processed NiO nanocrystals for inverted planar perovskite solar cells. AB - Hybrid organic/inorganic perovskite solar cells have been rapidly evolving with spectacular successes in both nanostructured and thin-film versions. Herein, we report the use of a simple sol-gel-processed NiO nanocrystal (NC) layer as the hole-transport layer in an inverted perovskite solar cell. The thin NiO NC film with a faceted and corrugated surface enabled the formation of a continuous and compact layer of well-crystallized CH3 NH3 PbI3 in a two-step solution process. The hole-extraction and -transport capabilities of this film interfaced with the CH3 NH3 PbI3 film were higher than those of organic PEDOT:PSS layers. The cell with a NiO NC film with a thickness of 30-40 nm exhibited the best performance, as a thinner layer led to a higher leakage current, whereas a thicker layer resulted in a higher series resistance. With the NiO film, we observed a cell efficiency of 9.11 %, which is by far the highest reported for planar perovskite solar cells based on an inorganic hole-extracting layer. PMID- 25044247 TI - Improving arithmetic performance with number sense training: an investigation of underlying mechanism. AB - A nonverbal primitive number sense allows approximate estimation and mental manipulations on numerical quantities without the use of numerical symbols. In a recent randomized controlled intervention study in adults, we demonstrated that repeated training on a non-symbolic approximate arithmetic task resulted in improved exact symbolic arithmetic performance, suggesting a causal relationship between the primitive number sense and arithmetic competence. Here, we investigate the potential mechanisms underlying this causal relationship. We constructed multiple training conditions designed to isolate distinct cognitive components of the approximate arithmetic task. We then assessed the effectiveness of these training conditions in improving exact symbolic arithmetic in adults. We found that training on approximate arithmetic, but not on numerical comparison, numerical matching, or visuo-spatial short-term memory, improves symbolic arithmetic performance. In addition, a second experiment revealed that our approximate arithmetic task does not require verbal encoding of number, ruling out an alternative explanation that participants use exact symbolic strategies during approximate arithmetic training. Based on these results, we propose that nonverbal numerical quantity manipulation is one key factor that drives the link between the primitive number sense and symbolic arithmetic competence. Future work should investigate whether training young children on approximate arithmetic tasks even before they solidify their symbolic number understanding is fruitful for improving readiness for math education. PMID- 25044248 TI - Working memory updating and the development of rule-guided behavior. AB - The transition from middle childhood into adolescence is marked by both increasing independence and also extensive change in the daily requirements of familial demands, social pressures, and academic achievement. To manage this increased complexity, children must develop the ability to use abstract rules that guide the choice of behavior across a range of circumstances. Here, we tested children through adults in a task that requires increasing levels of rule abstraction, while separately manipulating competition among alternatives in working memory. We found that age-related differences in rule-guided behavior can be explained in terms of improvement in rule abstraction, which we suggest involves a working memory updating mechanism. Furthermore, family socioeconomic status (SES) predicted change in rule-guided behavior, such that higher SES predicted better performance with development. We discuss these results within a working memory gating framework for abstract rule-guided behavior. PMID- 25044249 TI - PedBLIMP: extending linear predictors to impute genotypes in pedigrees. AB - Recently, Wen and Stephens (Wen and Stephens [2010] Ann Appl Stat 4(3):1158-1182) proposed a linear predictor, called BLIMP, that uses conditional multivariate normal moments to impute genotypes with accuracy similar to current state-of-the art methods. One novelty is that it regularized the estimated covariance matrix based on a model from population genetics. We extended multivariate moments to impute genotypes in pedigrees. Our proposed method, PedBLIMP, utilizes both the linkage-disequilibrium (LD) information estimated from external panel data and the pedigree structure or identity-by-descent (IBD) information. The proposed method was evaluated on a pedigree design where some individuals were genotyped with dense markers and the rest with sparse markers. We found that incorporating the pedigree/IBD information can improve imputation accuracy compared to BLIMP. Because rare variants usually have low LD with other single-nucleotide polymorphisms (SNPs), incorporating pedigree/IBD information largely improved imputation accuracy for rare variants. We also compared PedBLIMP with IMPUTE2 and GIGI. Results show that when sparse markers are in a certain density range, our method can outperform both IMPUTE2 and GIGI. PMID- 25044250 TI - Conformational transitions driven by pyridoxal-5'-phosphate uptake in the psychrophilic serine hydroxymethyltransferase from Psychromonas ingrahamii. AB - Serine hydroxymethyltransferase (SHMT) is a pyridoxal-5'-phosphate (PLP) dependent enzyme belonging to the fold type I superfamily, which catalyzes in vivo the reversible conversion of l-serine and tetrahydropteroylglutamate (H4PteGlu) to glycine and 5,10-methylenetetrahydropteroylglutamate (5,10-CH2 H4PteGlu). The SHMT from the psychrophilic bacterium Psychromonas ingrahamii (piSHMT) had been recently purified and characterized. This enzyme was shown to display catalytic and stability properties typical of psychrophilic enzymes, namely high catalytic activity at low temperature and thermolability. To gain deeper insights into the structure-function relationship of piSHMT, the three dimensional structure of its apo form was determined by X-ray crystallography. Homology modeling techniques were applied to build a model of the piSHMT holo form. Comparison of the two forms unraveled the conformation modifications that take place when the apo enzyme binds its cofactor. Our results show that the apo form is in an "open" conformation and possesses four (or five, in chain A) disordered loops whose electron density is not visible by X-ray crystallography. These loops contain residues that interact with the PLP cofactor and three of them are localized in the major domain that, along with the small domain, constitutes the single subunit of the SHMT homodimer. Cofactor binding triggers a rearrangement of the small domain that moves toward the large domain and screens the PLP binding site at the solvent side. Comparison to the mesophilic apo SHMT from Salmonella typhimurium suggests that the backbone conformational changes are wider in psychrophilic SHMT. PMID- 25044251 TI - Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. AB - OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression. PMID- 25044253 TI - Bladder cancer risk: Use of the PLCO and NLST to identify a suitable screening cohort. AB - PURPOSE: Bladder cancer (BC) screening is not accepted in part owing to low overall incidence. We used the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Cancer Screening Trial (NLST) to identify optimal high-risk populations most likely to benefit from screening. MATERIALS AND METHODS: Data were extracted from PLCO and NLST to stratify risk of BC by overall population, sex, race, age at inclusion, and smoking status. Incidence rates between groups were compared using chi-square test. RESULTS: BC was identified in 1,430/154,898 patients in PLCO and 439/53,173 patients in NLST. BCs were grade III/IV in 36.8% and 41.3%. Incidence rates were significantly higher in men than in women (PLCO: 1.4 vs. 0.31/1,000 person-years and NLST: 1.84 vs. 0.6/1,000 person-years, both P<0.0001). In proportional hazards models, male sex, higher age, and duration and intensity of smoking were associated with higher risk of BC (all P<0.0001). In men older than 70 years with smoking exposure of 30 pack-years (PY) and more, incidence rates were as high as 11.92 (PLCO) and 5.23 (NLST) (per 1,000 person-years). In current high-intensity smokers (>=50 PY), the sex disparity in incidence persists in both trials (0.78 vs. 2.99 per 1,000 person-years in PLCO and 1.12 vs. 2.65 per 1,000 person-years in NLST). CONCLUSIONS: Men older than 60 years with a smoking history of>30 PY had incidence rates of more than 2/1,000 person-years, which could serve as an excellent population for screening trials. Sex differences in the incidence of BC cannot be readily explained by the differences in exposure to tobacco, as sex disparity persisted regardless of smoking intensity. PMID- 25044252 TI - Serum biomarkers reflecting specific tumor tissue remodeling processes are valuable diagnostic tools for lung cancer. AB - Extracellular matrix (ECM) proteins, such as collagen type I and elastin, and intermediate filament (IMF) proteins, such as vimentin are modified and dysregulated as part of the malignant changes leading to disruption of tissue homeostasis. Noninvasive biomarkers that reflect such changes may have a great potential for cancer. Levels of matrix metalloproteinase (MMP) generated fragments of type I collagen (C1M), of elastin (ELM), and of citrullinated vimentin (VICM) were measured in serum from patients with lung cancer (n = 40), gastrointestinal cancer (n = 25), prostate cancer (n = 14), malignant melanoma (n = 7), chronic obstructive pulmonary disease (COPD) (n = 13), and idiopathic pulmonary fibrosis (IPF) (n = 10), as well as in age-matched controls (n = 33). The area under the receiver operating characteristics (AUROC) was calculated and a diagnostic decision tree generated from specific cutoff values. C1M and VICM were significantly elevated in lung cancer patients as compared with healthy controls (AUROC = 0.98, P < 0.0001) and other cancers (AUROC = 0.83 P < 0.0001). A trend was detected when comparing lung cancer with COPD+IPF. No difference could be seen for ELM. Interestingly, C1M and VICM were able to identify patients with lung cancer with a positive predictive value of 0.9 and an odds ratio of 40 (95% CI = 8.7-186, P < 0.0001). Biomarkers specifically reflecting degradation of collagen type I and citrullinated vimentin are applicable for lung cancer patients. Our data indicate that biomarkers reflecting ECM and IMF protein dysregulation are highly applicable in the lung cancer setting. We speculate that these markers may aid in diagnosing and characterizing patients with lung cancer. PMID- 25044254 TI - Metastatic small cell carcinoma of the prostate: Population-based analysis of patient characteristics and treatment paradigms. AB - INTRODUCTION: Small cell carcinoma of the prostate is a rare malignancy comprising<1% of prostate cancers. Little is known about population-based treatment patterns for metastatic small cell carcinoma of the prostate. We evaluated clinical characteristics, treatment patterns, and survival outcomes. METHODS: Using the National Cancer Database, we identified patients between 1998 and 2011 diagnosed with pure small cell carcinoma of the prostate as their only malignancy who presented with nodal involvement or distant metastasis. RESULTS: Treatment information was available for 379 patients. Of them, 122 (32.5%) underwent chemotherapy (CT) alone, 25 (6.7%) received hormonal therapy (androgen deprivation therapy) alone, 10 (2.7%) underwent radiation therapy alone, 3 (1%) underwent radical prostatectomy, and 167 (44.4%) underwent combination therapy. The 1- and 3-year survival rates were 35.3% and 4.4%, respectively. Those receiving any CT as part of their treatment had a median survival of 9.3 vs. 3.2 months for those not receiving it (P<0.001). Those receiving CT, androgen deprivation therapy, and radiation had a median survival of 15.1 vs. 7 months for those receiving CT alone (P<0.001). On multivariable analysis (controlling for age, Charlson comorbidity index, extent of metastasis, prostate-specific antigen level, and type of treatment), older age (hazard ratio [HR] = 3.87; 95% CI: 1.41 9.34; P = 0.007) and distant metastatic disease (HR = 7.17; 95% CI: 1.62-31.8; P = 0.010) increased risk of death, whereas receipt of CT (HR = 0.15; 95% CI: 0.05 0.44; P = 0.001) decreased risk of death. CONCLUSION: Men presenting with metastatic small cell carcinoma of the prostate have poor overall survival. Older patients and those presenting with distant metastases have an increased risk of death. It appears that patients receiving CT experience a modest survival benefit. The role of hormonal therapy in this population remains unclear. PMID- 25044256 TI - High early cardiovascular mortality after liver transplantation. AB - Cardiovascular disease (CVD) contributes to excessive long-term mortality after liver transplantation (LT); however, little is known about early postoperative CVD mortality in the current era. In addition, there is no model for predicting early postoperative CVD mortality across centers. We analyzed adult recipients of primary LT in the Organ Procurement and Transplantation Network (OPTN) database between February 2002 and December 2012 to assess the prevalence and predictors of early (30-day) CVD mortality, which was defined as death from arrhythmia, heart failure, myocardial infarction, cardiac arrest, thromboembolism, and/or stroke. We performed logistic regression with stepwise selection to develop a predictive model of early CVD mortality. Sex and center volume were forced into the final model, which was validated with bootstrapping techniques. Among 54,697 LT recipients, there were 1576 deaths (2.9%) within 30 days. CVD death was the leading cause of 30-day mortality (40.2%), and it was followed by infection (27.9%) and graft failure (12.2%). In a multivariate analysis, 9 significant covariates (6 recipient covariates, 2 donor covariates, and 1 operative covariate) were identified: age, preoperative hospitalization, intensive care unit status, ventilator status, calculated Model for End-Stage Liver Disease score, portal vein thrombosis, national organ sharing, donor body mass index, and cold ischemia time. The model showed moderate discrimination (C statistic = 0.66, 95% confidence interval = 0.63-0.68). In conclusion, we provide the first multicenter prognostic model for the prediction of early post-LT CVD death, the most common cause of early post-LT mortality in the current transplant era. However, evaluations of additional CVD-related variables not collected by the OPTN are needed in order to improve the model's accuracy and potential clinical utility. PMID- 25044255 TI - Simultaneous and independent tuning of RhoA and Rac1 activity with orthogonally inducible promoters. AB - The GTPases RhoA and Rac1 are key regulators of cell spreading, adhesion, and migration, and they exert distinct effects on the actin cytoskeleton. While RhoA classically stimulates stress fiber assembly and contraction, Rac1 promotes branched actin polymerization and membrane protrusion. These competing influences are reinforced by antagonistic crosstalk between RhoA and Rac1, which has complicated efforts to identify the specific mechanisms by which each GTPase regulates cell behavior. We therefore wondered whether RhoA and Rac1 are intrinsically coupled or whether they can be manipulated independently. To address this question, we placed constitutively active (CA) RhoA under a doxycycline-inducible promoter and CA Rac1 under an orthogonal cumate-inducible promoter, and we stably introduced both constructs into glioblastoma cells. We found that doxycycline addition increased RhoA activity without altering Rac1, and similarly cumate addition increased Rac1 activity without altering RhoA. Furthermore, co-expression of both mutants enabled high activation of RhoA and Rac1 simultaneously. When cells were cultured on collagen hydrogels, RhoA activation prevented cell spreading and motility, whereas Rac1 activation stimulated migration and dynamic cell protrusions. Interestingly, high activation of both GTPases induced a third phenotype, in which cells migrated at intermediate speeds similar to control cells but also aggregated into large, contractile clusters. In addition, we demonstrate dynamic and reversible switching between high RhoA and high Rac1 phenotypes. Overall, this approach represents a unique way to access different combinations of RhoA and Rac1 activity levels in a single cell and may serve as a valuable tool for multiplexed dissection and control of mechanobiological signals. PMID- 25044257 TI - The yeast Wickerhamomyces anomalus AS1 secretes a multifunctional exo-beta-1,3 glucanase with implications for winemaking. AB - A multifunctional exo-beta-1,3-glucanase (WaExg2) was purified from the culture supernatant of the yeast Wickerhamomyces anomalus AS1. The enzyme was identified by mass spectroscopic analysis of tryptic peptide fragments and the encoding gene WaEXG2 was sequenced. The latter codes for a protein of 427 amino acids, beginning with a probable signal peptide (17 aa) for secretion. The mature protein has a molecular mass of 47 456 Da with a calculated pI of 4.84. The somewhat higher mass of the protein in SDS-PAGE might be due to bound carbohydrates. Presumptive disulphide bridges confer a high compactness to the molecule. This explains the apparent smaller molecular mass (35 kDa) of the native enzyme determined by electrophoresis, whereas the unfolded form is consistent with the theoretical mass. Enzymatic hydrolysis of selected glycosides and glycans by WaExg2 was proved by TLC analysis of cleavage products. Glucose was detected as the sole hydrolysis product from laminarin, underlining that the enzyme acts as an exoglucanase. In addition, the enzyme efficiently hydrolysed small beta-linked glycosides (arbutin, esculin, polydatin, salicin) and disaccharides (cellobiose, gentiobiose). WaExg2 was active under typical wine related conditions, such as low pH (3.5-4.0), high sugar concentrations (up to 20% w/v), high ethanol concentrations (10-15% v/v), presence of sulphites (up to 2 mm) and various cations. Therefore, the characterized enzyme might have multiple uses in winemaking, to increase concentrations of sensory and bioactive compounds by splitting glycosylated precursors or to reduce viscosity by hydrolysis of glycan slimes. PMID- 25044258 TI - Prenatal diagnosis of isolated butterfly vertebra. PMID- 25044259 TI - Cross-cultural validation of Cancer Communication Assessment Tool in Korea. AB - BACKGROUND: Communication between cancer patients and caregivers is often suboptimal. The Cancer Communication Assessment Tool for Patient and Families (CCAT-PF) is a unique tool developed to measure congruence in patient-family caregiver communication employing a dyadic approach. We aimed to examine the cross-cultural applicability of the CCAT in the Korean healthcare setting. METHODS: Linguistic validation of the CCAT-PF was performed through a standard forward-backward translation process. Psychometric validation was performed with 990 patient-caregiver dyads recruited from 10 cancer centers. RESULTS: Mean scores of CCAT-P and CCAT-F were similar at 44.8 for both scales. Mean CCAT-PF score was 23.7 (8.66). Concordance of each items between patients and caregivers was low (weighted kappa values <0.20 for all items and Spearman's rho <0.18 for scale scores). Scale scores did not differ significantly across a variety of cancer types and stages. The CCAT-P or CCAT-F score was weakly associated with mental health and quality of life outcomes. The CCAT-PF was correlated weakly with both patient-perceived and caregiver-perceived family avoidance of cancer care scales. CONCLUSION: The CCAT-PF Korean version showed similar psychometric properties to the original English version in the assessment of communication congruence between cancer patient and family caregivers. PMID- 25044260 TI - Animal models are reliably mimicking human diseases? A morphological study that compares animal with human NAFLD. AB - Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological syndrome that includes a wide spectrum of morphological alterations. In research, animal models are crucial in evaluating not only the pathogenesis of NAFLD and its progression, but also the therapeutic effects of various agents. Investigations on the ultrastructural features of NAFLD in humans are not copious, due to the difficulty to obtain human samples and to the long time of NAFLD to evolve. Translational comparative studies on the reliability of animal models in representing the histopathologic picture as seen in humans are missing. To overcome this lack of investigations, we compared the ultrastructural NAFLD features of an animal model versus human. Sprague-Dawley rats were fed with a high fat diet (HFD) for 1-4 weeks, while control rats were fed with a standard diet. Human specimens were collected from patients with diagnosed fatty liver disease, undergoing liver biopsies or surgery. Rat and human samples were examined by light microscopy and by transmission and high resolution scanning electron microscopy. The present work demonstrated that NAFLD in animal model and in human, share overlapping ultrastructural features. In conclusion, animal HFD represent an appropriate tool in studying the pathogenesis of NAFLD. PMID- 25044261 TI - Core-shell NiFe2O4@TiO2 nanorods: an anode material with enhanced electrochemical performance for lithium-ion batteries. AB - Hierarchical porous core-shell NiFe2O4@TiO2 nanorods have been fabricated with the help of hydrothermal synthesis, chemical bath deposition, and a subsequent calcinating process. The nanorods with an average diameter of 48 nm and length of about 300-600 nm turn out have a highly uniform morphology and are composed of nanosized primary particles. Owing to the synergistic effect of individual constituents as well as the hierarchical porous structure, the novel core-shell NiFe2O4@TiO2 nanorods exhibit superior electrochemical performance when evaluated as anode materials for lithium-ion batteries. At the current density of 100 mA g( 1), the composite exhibits a reversible specific capacity of 1034 mAh g(-1) up to 100 charge-discharge cycles, which is much higher than the uncoated NiFe2O4 nanorods. Even when cycled at 2000 mA g(-1), the discharge capacity could still be maintained at 358 mAh g(-1). PMID- 25044262 TI - Identification and functional characterization of a peptidoglycan recognition protein from the cotton bollworm, Helicoverpa armigera. AB - Peptidoglycan recognition proteins (PGRPs) specifically bind to peptidoglycans, and play crucial roles as pattern recognition receptors (PRRs) in mediating innate immune responses. In this study, we identified and characterized a PGRP (HaPGRP-D) from the cotton bollworm, Helicoverpa armigera. Sequence analysis indicated that HaPGRP-D is an amidase-type PGRP. Expression of HaPGRP-D was upregulated in the hemocytes of H. armigera larvae after injecting Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus, or chromatography beads. To test the biological activity of HaPGRP-D, purified recombinant protein was prepared. Subsequent analysis showed that rHaPGRP-D (i) could bind and agglutinate Gram-negative E. coli and Gram-positive S. aureus in a zinc-dependent manner, (ii) functioned as an amidase to degrade peptidoglycans in the presence of Zn(2+) , (iii) strongly inhibited the growth of E. coli and S. aureus in the presence of Zn(2+) , (iv) could bind to the surface of hemocytes, (v) increased the phagocytosis of E. coli cells by hemocytes in vitro, and (vi) promoted hemocyte encapsulation on chromatography beads in vitro. These results suggest that HaPGRP-D plays important roles as PRR, amidase, and opsonin in H. armigera humoral and cellular immune responses. PMID- 25044264 TI - Predicted incorporation of non-native substrates by a polyketide synthase yields bioactive natural product derivatives. AB - The polyether ionophore monensin is biosynthesized by a polyketide synthase that delivers a mixture of monensins A and B by the incorporation of ethyl- or methyl malonyl-CoA at its fifth module. Here we present the first computational model of the fifth acyltransferase domain (AT5mon ) of this polyketide synthase, thus affording an investigation of the basis of the relaxed specificity in AT5mon , insights into the activation for the nucleophilic attack on the substrate, and prediction of the incorporation of synthetic malonic acid building blocks by this enzyme. Our predictions are supported by experimental studies, including the isolation of a predicted derivative of the monensin precursor premonensin. The incorporation of non-native building blocks was found to alter the ratio of premonensins A and B. The bioactivity of the natural product derivatives was investigated and revealed binding to prenyl-binding protein. We thus show the potential of engineered biosynthetic polyketides as a source of ligands for biological macromolecules. PMID- 25044265 TI - Increased epidermal growth factor in nasopharyngeal aspirates from infants with recurrent wheeze. AB - Airway remodeling is known to be a consequence of repeated injury and thought to be involved in early stage of asthma. We aimed to investigate the mediators associated with airway remodeling in recurrent early wheezers. Thirty-three infants, aged 2 years or less, admitted with exacerbation of wheezing were enrolled. All of them had experienced three or more episodes of wheezing before admission. They were categorized into two groups: those who had been hospitalized two or more times for severe wheezing (N = 19) and those who had only once or never been hospitalized (N = 14). Epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-beta1 levels in nasopharyngeal aspirates (NPA) collected on admission were measured. The difference between two patients groups divided based on their hospitalization history was assessed. We also examined these mediators in older asthmatic children (N = 15) admitted with exacerbation and their relationship with lung function parameters measured after stabilization. NPA EGF levels were significantly increased in recurrent early wheezers compared to controls. EGF, VEGF, and TGF-beta1 levels were significantly higher in those with a previous history of multiple hospitalizations than in those without. In older asthmatic children, EGF levels were related with age and duration of asthma, but showed an inverse correlation with forced expiratory volume in 1 sec and forced expiratory flow between 25% and 75% of vital capacity. Our study shows that there might be significant damage during exacerbation in wheezy infants as levels of the mediators, EGF, VEGF, and TGF-beta1 were higher in those who had been frequently hospitalized. It seems to suggest that those infants with severe recurrent wheezing might have chronic airway obstruction. PMID- 25044266 TI - Microbial invasion of dentinal tubules: a literature review and a new perspective. AB - Various features of endodontic microbiology have been investigated using various methods. The aim of the present study was to review the existing literature on endodontic microbiology in dentinal tubules, and to present the features of two cases with endodontic pathology. An electronic search was performed with a search string created ad hoc. Ex vivo and in vitro studies were included, recording the method of detection and characteristics of analyzed teeth. Twenty studies fulfilled the inclusion criteria. Seven of them were in vitro laboratory studies on teeth inoculated after extraction, while 13 were ex vivo studies on extracted, infected teeth. Endodontic bacteria were detected in dentinal tubules, both as single units and as biofilm aggregates. Two similar in vitro cases presented here corroborate the latter findings. A number of techniques have been utilized to observe bacteria in the dentinal tubule ecosystem. Dentinal tubules are favorable niches for microbial survival, either in the form of monomicrobial or polymicrobial communities. PMID- 25044267 TI - Developing a sustainable hip service in Cambodia. AB - OBJECTIVE: Initial report on establishment of a hip service in Phnom Penh, Cambodia at Children's Surgical Centre. We describe indications for total hip replacement (THR) and initial results. METHODS: A database was established to collect data and track patients for follow up. Initial data collected included; diagnosis, implant used, post-operative complications. As the service developed, pre- and postoperative Harris hip scores were included. RESULTS: High rate of avascular necrosis (AVN) as the initial diagnosis. Five years post initiation of the hip service, 95 patients have received 116 THRs; including 10 revisions, 12 bilateral procedures. Complications/failures requiring revision involved four prosthetic femoral neck fractures, two aseptic acetabular component, two late infections, one instability. One failure, a periprosthetic acetabular fracture, required removal of all prosthetics. Complications not requiring revision, included three post-op foot drops, three superficial wound infections, one Vancouver B1 periprosthetic femur fracture. Average age was 41. Overall implant survival is 85% at three years. DISCUSSION: AVN was the most common indication for THR: many patients had a history of hip trauma, and/or prolonged steroids from traditional healers for pain. Problems with specific implants were addressed by the company. A different stem is now routinely used, no further fractures have been reported. Acetabular loosening, thought to be due to poor technique, has been addressed by focused training. Infection rate is monitored, and microbiology resources are improving. CONCLUSION: Developing an affordable hip arthroplasty service in a country like Cambodia is challenging. Developing a local registry has helped to identify complications and modify techniques. PMID- 25044268 TI - Challenges and solutions in the fixation of a hip fracture in the presence of a contralateral ankylosed hip: a case report. AB - BACKGROUND: An intracapsular femoral neck fracture is a common orthopaedic presentation and requires expedient fixation in a young adult. This case demonstrates how patient-specific factors, namely an ankylosed contralateral hip, can make a common operation challenging. CASE DESCRIPTION: A 22-year-old man with osteogenesis imperfecta and multiple bony deformities was brought to A&E after being involved in a motor vehicle collision. Plain radiographs and clinical examination demonstrated a right intracapsular femoral neck fracture, ipsilateral femora vara and a contralateral ankylosed hip secondary to protrusio acetabuli. The intraoperative patient and fluoroscopic positioning were technically challenging. CLINICAL RELEVANCE: Preoperative literature review revealed no operative strategy or case report describing how best to perform closed reduction and internal fixation of a femoral neck fracture with a co-existing contralateral ankylosed hip joint. We hope our experience will aid other surgeons who find themselves in a similar clinical scenario. We will present the difficulties faced and the adaptations made to our surgical technique which we utilised to achieve an anatomical fixation. PMID- 25044269 TI - Hip arthroscopy for femoroacetabular impingement: a health economic analysis. AB - There has been a significant increase in use of hip arthroscopy for femoroacetabular impingement over the last 10 years. However, some care providers in the United Kingdom are not commissioning such an intervention due to cost constraints and lack of published cost effectiveness studies. A cost analysis for a prospective cohort of 58 patients undergoing hip arthroscopy for femoroacetabular impingement was performed. The short form 12 six dimension health utility score (SF12-6D) was used. This was recorded preoperatively and one year after surgery. Three time points (one, two, and 10 years) from operation were used to calculate the quality-adjusted-life-years (QALYs) gained. Predicted need for conversion to total hip replacement and diminishing gain with time (5% per year) was incorporated into the two- and 10-year models. The Scottish Tariff was used to assign the cost of surgery. The number of QALYs gained one year after surgery was 0.159, which equated to a cost per QALY of L19,335. This cost decreased to L10,118 per QALY gained at two years, and further still to L2,677 per QALY gained at 10 years. Multivariable regression analysis found that a worse preoperative SF12-6D was an independent predictor of greater QALYs gained one year after surgery (R2 = 0.51, p<0.001). At no point in time, from one year onwards, does hip arthroscopy for femoroacetabular impingement cost more than L20,000 per QALY, making it a cost-effective intervention according to the National Institute for Health and Clinical Excellence. PMID- 25044270 TI - Stem compatibility for cement-in-cement femoral revision: an in vitro study. AB - Cement-in-cement femoral component revision is a useful and commonly practised technique. Onerous and hazardous re-shaping of the original cement mantle is required if the new stem does not seat easily. Furthermore, without removing the entirety of the original cement mantle, the freedom to alter anteversion or leg length is difficult to predict preoperatively. We present data from in vitro experiments testing the compatibility of the top cemented stems according to UK registry figures (NJR 2013). This data augments preoperative planning by indicating which revision stems require minimal or no cement reshaping when being inserted into another stem's mantle. We also present the maximum shortening and anteversion that can be achieved without reshaping the original cement mantle. PMID- 25044271 TI - Cement brand and preparation effects cement-in-cement mantle shear strength. AB - Creating bi-laminar cement mantles as part of revision hip arthroplasty is well documented but there is a lack of data concerning the effect of cement brand on the procedure. The aim of this study was to compare the shear strength of bi laminar cement mantles using various combinations of two leading bone cement brands.Bi-laminar cement mantles were created using Simplex P with Tobramycin, and Palacos R+G: Simplex-Simplex (SS); Simplex-Palacos (SP); Palacos-Simplex (PS); and Palacos-Palacos (PP). Additionally, specimens were produced by rasping (R) the surface of the original mantle, or leaving it unrasped (U), leading to a total of eight groups (n = 10). Specimens were loaded in shear, at 0.1 mm/min, until failure, and the maximum shear strength calculated.The highest mean shear strength was found in the PSU and PSR groups (23.69 and 23.89 MPa respectively), and the lowest in the PPU group (14.70 MPa), which was significantly lower than all but two groups. Unrasped groups generally demonstrated greater standard error than rasped groups.In a further comparison to assess the effect of the new cement mantle brand, irrespective of the brand of the original mantle, Simplex significantly increased the shear strength compared to Palacos with equivalent preparation.It is recommended that the original mantle is rasped prior to injection of new cement, and that Simplex P with Tobramycin be used in preference to Palacos R+G irrespective of the existing cement type. Further research is needed to investigate more cement brands, and understand the underlying mechanisms relating to cement-in-cement procedures. PMID- 25044272 TI - MKP-1 is a target of miR-210 and mediate the negative regulation of miR-210 inhibitor on hypoxic hPASMC proliferation. AB - Chonic hypoxia, smooth muscle cell (SMC) proliferation and vascular remodeling are hallmark features of pathogenic pulmonary artery hypertension. MicroRNAs (miRNAs), endogenously expressed small noncoding RNAs, regulate gene expression at the post-transcriptional level. MiR-210 is considered a "master miRNA" in the control of diverse functions in hypoxic cells and tissues and has a cytoprotective function in pulmonary artery SMCs during hypoxic stress. MiR-210 is also upregulated in lung tissue of chonically hypoxic mice suffering from pulmonary hypertension. Jin et al. () showed that mice deficient in mitogen activated protein kinase phosphatase 1 (MKP-1) had severe hypoxia-induced pulmonary hypertension, so MKP-1 may be important in the progression of hypoxic pulmonary artery hypertension. We investigated the possible interactions between miR-210 and MKP-1 and the effect on cell proliferation in hypoxic human pulmonary artery SMCs (hPASMCs). miR-210 was significantly increased in cultured hPASMCs exposed to 1% O2 hypoxia for 48 h, as was MKP-1 mRNA and protein expression. Furthermore, inhibiting miR-210 expression increased MKP-1 mRNA and protein expression in hPASMCs and decreased cell proliferation under hypoxia. Conversely, overexpressing miR-210 prevented hypoxia-induced MKP-1 expression with no effect on cell proliferation. siRNA knockdown of MKP-1 abolished the miR-210-inhibition prevention of cell proliferation under hypoxia. MKP-1 is a target of miR-210 and could mediate the negative regulation of miR-210 inhibition on hypoxic hPASMCs. PMID- 25044273 TI - 1090 nm infrared radiation at close to threshold dose induces cataract with a time delay. AB - PURPOSE: To investigate whether infrared radiation (IRR)-induced cataract is instant or is associated with a time delay between the exposure and the onset of lens light scattering after an exposure to just above threshold dose. METHODS: Six-weeks-old albino Sprague-Dawley female rats were unilaterally exposed to 197 W/cm2 IRR at 1090 nm within the dilated pupil. In the first experiment, the animals were exposed with four exposure times of 5, 8, 13 and 20 second, respectively. At 24 hr after exposure, the light scattering in both exposed and contralateral not exposed lenses was measured. Based on the first experiment, four postexposure time groups were exposed unilaterally to 1090 nm IRR of 197 W/cm2 for 8 second. At 6, 18, 55 and 168 hr after exposure, the light scattering in both lenses was measured. RESULTS: A 197 W/cm2 IRR-induced light scattering in the lens with exposures of at least 8 second. Further, after exposure to IRR of 197 W/cm2 for 8 second, the light-scattering increase in the lens was delayed approximately 16 hr after the exposure. CONCLUSION: There is a time delay between the exposure and the onset of cataract after exposure to close to threshold dose implicating that either near IRR cataract is photochemical or there is a time delay in the biological expression of thermally induced damage. PMID- 25044274 TI - Intraneural pseudocyst (so-called ganglion) in an unusual retroperitoneal periadnexal location? AB - A case of an unusual unilocular cystic lesion of diameter 7 cm located retroperitoneally in the pelvis in close connection to the right adnexa of a 61 year-old woman is presented. Macroscopically, the lesion had a smooth outer and inner surface and was filled with translucent fluid. Histological examination revealed a fibrous and hyalinized wall which lacked a specific lining. Numerous nerve bundles in the cyst wall constituted the most conspicuous element of its histology possibly with some contribution of perineurial and/or mesothelial components. The morphology and immunohistochemistry speak for an intraneural pseudocyst sometimes called intraneural ganglion cyst which is rare in this location. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1357862917132314. PMID- 25044275 TI - Red blood cell transfusion: impact of an education program and a clinical guideline on transfusion practice. AB - BACKGROUND: Red blood cell (RBC) transfusion guidelines have been developed by professional societies. These guidelines recommend a restrictive RBC transfusion practice for most clinical populations. Despite the consistency of guidelines and limited evidence for RBC transfusion efficacy, there is variability in RBC transfusion practice. METHODS: A program was initiated in a tertiary medical center to align RBC transfusion practice with best-practice RBC transfusion guidelines. The program included an educational program, followed after 6 months by RBC transfusion decision support that included the approval of a best-practice RBC transfusion guideline by the hospital medical board and an RBC transfusion order form that included the guideline recommendations. RBC transfusion practice was followed over an 18-month period and compared with transfusion practice over the prior 18 months. The primary outcome variables were adult inpatient RBC units transfused, RBC units per admission, and RBC units per 100 patient-days. RESULTS: The mean RBC units transfused decreased with initiation of each component of the program: from 923 +/- 68 units to 852 +/- 40 (P = 0.025) with education and further to 690 +/- 52 (P < 0.0001) with the RBC transfusion decision support. Similarly, RBC transfusions per 100 patient-days fell from 10.56 +/- 0.80 to 9.69 +/- 0.49 (P = 0.02) and to 7.68 +/- 0.63 (P = 0.0001) during the 3 time periods. CONCLUSION: An education program coupled with institutional adoption of a best practice RBC transfusion guideline and RBC transfusion order set resulted in a reduction in total RBC units transfused. PMID- 25044277 TI - The miR-137 schizophrenia susceptibility variant rs1625579 does not predict variability in brain volume in a sample of schizophrenic patients and healthy individuals. AB - The micro RNA 137 (miR-137) variant rs1625579 has been identified as a genome wide significant risk variant for schizophrenia. miR-137 has an established role in neurodevelopment and may mediate cognitive dysfunction in schizophrenia. This role of miR-137 may be related to changes in brain morphology for risk-related genotypes; however this has not yet been delineated. Here we considered whether rs1625579 genotype was predictive of indices of brain structure in patients with schizophrenia and healthy controls. Structural magnetic resonance imaging (sMRI) data (i.e. 3T T1-TFE or 1.5T T1-MPRAGE) were acquired from 150 healthy controls and 163 schizophrenic patients. Two volumetric analyses that considered the impact of miR-137/rs1625579 genotype were carried out on sMRI data. In the first analysis, voxel based morphometry was employed to consider genotype-related variability in local grey and white matter across the entire brain volume. Our secondary analysis utilized the FIRST protocol in FSL to consider the volume of subcortical structures (i.e. bilateral accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus). Several brain regions in both analyses demonstrated the expected main effect of participant group (i.e. schizophrenics < controls), yet there were no regions where we observed an impact of rs1635579 genotype on brain volume. Our analyses suggest that the mechanism by which miR 137 confers risk for schizophrenia and impacts upon cognitive function may not be mediated by changes in local brain volume. However, it remains to be determined whether or not alternative measures of brain structure are related to these functions of miR-137. PMID- 25044276 TI - Dopamine-induced alpha-synuclein oligomers show self- and cross-propagation properties. AB - Amyloid aggregates of alpha-synuclein (alphaS) protein are the predominant species present within the intracellular inclusions called Lewy bodies in Parkinson's disease (PD) patients. Among various aggregates, the low-molecular weight ones broadly ranging between 2 and 30 mers are known to be the primary neurotoxic agents responsible for the impairment of neuronal function. Recent research has indicated that the neurotransmitter dopamine (DA) is one of the key physiological agents promoting and augmenting alphaS aggregation, which is thought to be a significant event in PD pathologenesis. Specifically, DA is known to induce the formation of soluble oligomers of alphaS, which in turn are responsible for inducing several important cellular changes leading to cellular toxicity. In this report, we present the generation, isolation, and biophysical characterization of five different dopamine-derived alphaS oligomers (DSOs) ranging between 3 and 15 mers, corroborating previously published reports. More importantly, we establish that these DSOs are also capable of replication by self propagation, which leads to the replication of DSOs upon interaction with alphaS monomers, a process similar to that observed in mammilian prions. In addition, DSOs are also able to cross-propagate amyloid-beta (Abeta) aggregates involved in Alzheimer's disease (AD). Interestingly, while self-propagation of DSOs occur with no net gain in protein structure, cross-propagation proceeds with an overall gain in beta-sheet conformation. These results implicate the involvement of DSOs in the progression of PD, and, in part, provide a molecular basis for the observed co-existence of AD-like pathology among PD patients. PMID- 25044278 TI - Sublethal effects induced by morphine to the freshwater biological model Dreissena polymorpha. AB - Opioids are considered as emerging contaminants in aquatic ecosystems, mainly due to their large illicit consume worldwide. Morphine (MOR) is the main opiate and it was commonly found at measurable concentrations in freshwaters. Even though its occurrence is well documented, just limited information is available regarding its hazard to nontarget organisms. The aim of this study was of the evaluation of sublethal effects induced by MOR to the freshwater bivalve Dreissena polymorpha. We exposed mussels to two MOR concentrations (0.05 ug/L and 0.5 ug/L) for 14 days and we investigated the sublethal effects by a suite of biomarkers. The Neutral Red Retention Assay (NRRA) was used as a test of cytotoxicity, while the oxidative stress was evaluated by the activity of antioxidant and detoxifying enzymes, namely catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), and by measuring the levels of lipid peroxidation (LPO) and protein carbonylation (PCC). The genetic damage was assessed by the Single Cell Gel Electrophoresis (SCGE) assay, the DNA diffusion assay and the micronucleus test (MN test). Finally, the filtration rate of D. polymorpha was evaluated in order to investigate possible physiological effects. Both tested concentrations reduced the lysosome membrane stability of bivalves, but only the highest MOR concentration induced significant changes in the activity of antioxidant enzymes (SOD, CAT, and GPx) and increase in lipid peroxidation levels. Slight increase in primary DNA fragmentation was noticed, while no fixed genetic damage and alterations of the filtering rate were found. PMID- 25044279 TI - Importance of the reversed halo sign for the diagnosis of angioinvasive pulmonary aspergillosis. PMID- 25044280 TI - Appraisal of lens opacity with mometasone furoate/formoterol fumarate combination in patients with COPD or asthma. AB - BACKGROUND: Long-term corticosteroid use may increase cataract risk. The Lens Opacities Classification System (LOCS) III ranked lens opacities as Class 1: 0.5 0.9 unit; Class 2: 1.0-1.4 units; or Class 3: >=1.5 units in clinical trials of combined mometasone furoate and formoterol (MF/F) administered by metered-dose inhaler (MDI). We examined retrospectively shifts in lenticular opacity in patients with chronic obstructive pulmonary disease (COPD) or asthma. METHODS: We analyzed pooled LOCS III data from two COPD studies and separately analyzed LOCS III data from an asthma study. COPD subjects were randomized to twice daily MF/F 200/10 MUg, MF/F 400/10 MUg, MF 400 MUg, F 10 MUg, and placebo; asthma subjects were randomized to MF/F 200/10 MUg, MF/F 400/10 MUg, fluticasone propionate/salmeterol (FP/S) 250/50 MUg, and FP/S 500/50 MUg. Lenticular opacity changes were analyzed post hoc for proportions of subjects with LOCS III grade increases >=0.5, >=1.0, or >=1.5 units at weeks 26 and 52. RESULTS: Proportions of subjects in the COPD studies with Class 1 (>=0.5 unit), 2 (>=1.0 unit), or 3 (>=1.5 units) increases in LOCS III at week 26 (N = 1675) ranged from 15.5 to 18.6%, 3.3-6.0%, and 0.9-2.2%, respectively. At week 52 (N = 1085), proportions of active-treated subjects with Class 1, 2, or 3 increases in LOCS III ranged from 26.6 to 28.9%, 6.3-10.7%, and 2.6-5.9%, respectively. Treatment differences in lenticular shifts were generally small and nonsignificant in the asthma study. CONCLUSION: No clinically relevant trends were observed in the LOCS III assessment of lenticular shifts during treatment of COPD and asthma patients, although further study may be needed to confirm the findings presented here. In these trials, MF/F effects on lens opacity were not observed. (Clinicaltrials.gov numbers: NCT00383435, NCT00383721, and NCT00379288.). PMID- 25044281 TI - Monosomal karyotype is an independent predictor of survival in patients with higher-risk myelodysplastic syndrome. AB - A monosomal karyotype (MK) correlates with poor survival in patients with acute myeloid leukemia, although whether this is also the case in patients with myelodysplastic syndrome (MDS) remains controversial. Some studies report a correlation between a MK and a worse survival, whereas others claim that this correlation arises because of a confounding effect between a MK and a complex karyotype (CK). To address this question, we analyzed the clinical data and karyotypes of 610 adults with MDS. A MK was identified in 60 patients, of whom 55 (92%) also fulfilled the criteria for a CK. Conversely, a CK was found in 85 patients, of whom 55 (65%) also had a MK. To determine the impact of a MK on survival, 464 patients who received nonintensive therapies for MDS were analyzed separately. Patients with a MK demonstrated worse survival than those without a MK in univariate analyses (median, 8 months [95% CI, 3-12 months] versus 83 months [63-103 months]; P < 0.001). This effect was observed predominately in the cohorts of higher-risk patients according to the Revised International Prognostic Scoring System and the World Health Organization Prognostic Scoring System (HR [hazard ratio] 3.94 [1.97-7.89]; P < 0.001 and 4.937 [2.45-9.94]; P < 0.001, respectively) and surpassed the impact of a CK in the final survival models. Our data suggest that the addition of MK as a binary variable could improve the predictive accuracy of current models to estimate the survival of patients with MDS. PMID- 25044282 TI - A sensitive multiplex real-time PCR panel for rapid diagnosis of viruses associated with porcine respiratory and reproductive disorders. AB - The objective of this study was to develop a multiplex real-time PCR panel using TaqMan probes for the detection and differentiation of porcine circovirus type 2 (PCV2), porcine reproductive and respiratory syndrome virus North American type (PRRSV-NA), pseudorabies virus (PRV), classical swine fever virus (CSFV), porcine parvovirus type 1 (PPV1) and Japanese encephalitis virus (JEV). Specific primer and probe combinations for PCV2, PRRSV, PRV, CSFV, PPV1 and JEV were selected within the conserved region of each viral genome. The multiplex real-time PCR panel which was run in two separate tubes was capable of specific detection of the six selected pig viruses, without cross-reactions with other non-targeted pig viruses. The detection limit of the assays was 10 copies/MUL for PCV2, PRV, CSFV and PRRSV and 100 copies/MUL for PPV and JEV. The two-tube multiplex real-time PCR panel showed 99.2% concordance with conventional PCR assays on 118 field samples. Overall, the multiplex real-time PCR panel provides a fast, specific, and sensitive diagnostic tool for detection of multiple viral pathogens in pigs and will be useful not only for diagnostics, or ecological, epidemiological and pathogenesis studies, but also for investigating host/virus or virus/virus interactions, particularly during coinfections. PMID- 25044283 TI - Sonographic appearance of a dermoid cyst (mature cystic teratoma) of the spleen. AB - Splenic dermoids are rare, with few published case reports and no ultrasound images in the English literature. We report the case of a 57-year-old woman with that diagnosis and illustrate it with ultrasound, CT, and pathology images. We discuss the differential diagnosis of solid splenic lesions. PMID- 25044284 TI - Can low-valent germanium chemistry be practiced under ambient conditions? A tale of a water-stable yet reactive germylene monochloride complex. AB - A germylene monochloride complex ((DPM)GeCl, 1) that is water stable was isolated for the first time. Interestingly, it reacts with cesium fluoride under ambient conditions (non-inert atmosphere and water-containing solvent) to afford water stable germylene monofluoride complex ((DPM)GeF, 2). Due to the usage of DPM (dipyrrinate) ligand, germylene monohalides 1 and 2 show fluorescence in the visible region at 555 and 538 nm, respectively. Compounds 1 and 2 are the first fluorescent germylene complexes and were characterized by multinuclear NMR spectroscopy. The structure of compound 1 was also proved by single crystal X-ray diffraction studies. PMID- 25044292 TI - Timing of events during deglutition after chemoradiation therapy for oropharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to determine if persistent changes in the duration of bolus movement through the pharynx and bolus movement coordination with pharyngeal swallowing gestures occur after treatment of oropharyngeal carcinoma with chemoradiation therapy. METHODS: The timing of bolus movement and coordination with swallowing gestures was evaluated in 30 patients using a modified barium swallowing study at least 1 year after completion of treatment. Patients were recruited irrespective of any swallowing complaints. The mean of each measure from the study subjects was compared to those from a group of age-matched controls. RESULTS: Bolus transit duration in the study population was unchanged compared with normal controls. Unlike normal controls, the patients were found to allow the bolus to arrive in the vallecula before the initiation of swallowing gestures that resulted in a swallow. Earlier opening of the upper esophageal sphincter was found for a 1-cc bolus (p = .004). For the 20 cc bolus size, the onset of hyoid and aryepiglottic fold elevation was delayed (p = .029 and .037, respectively). Gesture timing did not change to accommodate larger bolus sizes, as it normally does, resulting in a delay in airway protection for the 20-cc bolus. CONCLUSION: Patients are able to move a liquid bolus through the pharynx in a timely manner. However, patients are unable to modify swallowing gestures to safely protect the airway. PMID- 25044293 TI - Follow-up in early breast cancer--a surgical and radiological perceptive. PMID- 25044294 TI - A cyclization-rearrangement cascade for the synthesis of structurally complex chiral gold(I)-aminocarbene complexes. AB - A facile synthesis of chiral cyclic alkyl aminocarbene-gold(I) complexes from gold-free 1,7-enyne substrates was developed. The novel cyclization-rearrangement reaction sequence is triggered by the addition of (Me2S)AuCl to different 1,7 enynes and leads to structurally unique carbene-gold(I) complexes in high yields. These novel complexes are catalytically active and inhibit the proliferation of different human cancer cell lines. PMID- 25044295 TI - Temporal patterns of drug-eluting stent failure and its relationship with clinical outcomes. AB - OBJECTIVES: We investigated the temporal patterns of drug-eluting stents (DES) failure and its relationship with clinical outcomes in patients with DES failure. BACKGROUND: Time to DES failure is widely variable, but little information is available on the temporal patterns of DES failure and its impact on clinical outcomes. METHODS: The angiographic patterns of DES failure and clinical outcomes in 633 patients with 676 lesions who presented with their first instance of DES failure were analyzed. The primary outcome was all-cause death following treatment for DES failure. RESULTS: DES failure occurred in a median of 10.1 months after the index procedure. We identified 548 and 85 instances of DES restenosis (86.6%) and stent thrombosis (13.4%), respectively. Patients were divided into three groups according to the interval from the index procedure to DES failure: group 1 (early DES failure: <12 months), group 2 (late: 12-36 months), and group 3 (very late: >=36 months). Acute myocardial infarction was more common in patients who developed failure after >=12 months than patients with earlier presentations. Focal DES failure was more common in group 1, whereas nonfocal DES failure in groups 2 and 3. During follow-up after retreatment (median, 52.8 months), all-cause death was significantly higher in group 3 compared with group 1 (adjusted hazard ratio, 2.97; 95%CI, 1.31-6.74; P = 0.009). Similar findings were observed in terms of the rates of death or myocardial infarction. CONCLUSIONS: Late DES failure is more likely to progress to acute myocardial infarction, aggressive angiographic patterns, and worse outcomes following retreatment. PMID- 25044296 TI - Effects of pesticide exposure and the amphibian chytrid fungus on gray treefrog (Hyla chrysoscelis) metamorphosis. AB - Pesticides are detectable in most aquatic habitats and have the potential to alter host-pathogen interactions. The amphibian chytrid fungus, Batrachochytrium dendrobatidis (Bd), has been associated with amphibian declines around the world. However, Bd-associated declines are more prominent in some areas, despite nearly global distribution of Bd, suggesting other factors contribute to disease outbreaks. In a laboratory study, the authors examined the effects of 6 different isolates of Bd in the presence or absence of a pesticide (the insecticide carbaryl or the fungicide copper sulfate) to recently hatched Cope's gray treefrog (Hyla chrysoscelis) tadpoles reared through metamorphosis. The authors found the presence or absence of pesticides differentially altered the mass at metamorphosis of tadpoles exposed to different Bd isolates, suggesting that isolate could influence metamorphosis but not in ways expected based on origin of the isolate. Pesticide exposure had the strongest impact on metamorphosis of all treatment combinations. Whereas copper sulfate exposure reduced the length of the larval period, carbaryl exposure had apparent positive effects by increasing mass at metamorphosis and lengthening larval period, which adds to evidence that carbaryl can stimulate development in counterintuitive ways. The present study provides limited support to the hypothesis that pesticides can alter the response of tadpoles to isolates of Bd and that the insecticide carbaryl can alter developmental decisions. PMID- 25044297 TI - Targeted delivery of doxorubicin using a colorectal cancer-specific ssDNA aptamer. AB - Targeted drug delivery is particularly important in cancer treatment because many antitumor drugs are nonspecific and highly toxic to both cancerous and normal cells. The L33 aptamer is a single-stranded DNA (ssDNA) sequence that has the ability to recognize human colorectal cancer (CRC) cell line HCT116 specifically. In this study, we demonstrated that the L33 aptamer can selectively internalize into target HCT116 cells via receptor-mediated endocytosis. Based on this finding, we developed an aptamer-based drug delivery system using L33 as the carrier of the antitumor drug doxorubicin (Dox). The L33-Dox complex exhibited specific and high affinity (Kd = 14.3 +/- 2.2 nM) binding to HCT116 cells. The results of cytotoxicity assays revealed that the L33-Dox complex was capable of selectively delivering the drug to the target HCT116 cells and lowered the toxicity for nontarget CL187 cells. These findings indicate that the aptamer based targeted drug delivery system has the potential to be used in clinical settings and may overcome drug resistance to a certain extent because high drug dosages can be directed toward target cells. PMID- 25044298 TI - Selection of DNA-encoded small molecule libraries against unmodified and non immobilized protein targets. AB - The selection of DNA-encoded libraries against biological targets has become an important discovery method in chemical biology and drug discovery, but the requirement of modified and immobilized targets remains a significant disadvantage. With a terminal protection strategy and ligand-induced photo crosslinking, we show that iterated selections of DNA-encoded libraries can be realized with unmodified and non-immobilized protein targets. PMID- 25044299 TI - The role of microRNA in resistance to breast cancer therapy. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules with big implications in cancer. The abnormal expression of specific miRNAs has been linked to development of many cancer types. Dysregulated miRNAs play a significant role in proliferation, invasion, differentiation, apoptosis, and resistance of various cancer cells, and considered as oncogenes or tumor-suppressor genes. Findings have shown abnormal expression of specific miRNAs in breast tumors is a strong indication about the resistance to conventional cancer therapy methods. Acquired cancer resistance is a complex, multifactorial occurrence that requires various mechanisms and processes, however, recent studies have suggested that resistance may be linked to treatment-induced dysregulation of miRNAs. This dysregulation of miRNAs can affect the protein expression in cells, the ability for anti-cancer drugs to reach their targets within cells, and the apoptotic pathways. Controlling the expression of these miRNAs alters the resistant phenotype of breast cancer to a nonresistant one. This review focuses on the role of dysregulated miRNAs in breast cancer that are linked to resistance against chemo , radiation, hormone, and targeted therapies. Finally, the role of miRNAs in breast cancer metastasis is briefly discussed. PMID- 25044300 TI - Vitamin B1-catalyzed acetoin formation from acetaldehyde: a key step for upgrading bioethanol to bulk C4 chemicals. AB - The production of bulk chemicals and fuels from renewable biobased feedstocks is of significant importance for the sustainability of human society. The production of ethanol from biomass has dramatically increased and bioethanol also holds considerable potential as a versatile building block for the chemical industry. Herein, we report a highly selective process for the conversion of ethanol to C4 bulk chemicals, such as 2,3-butanediol and butene, via a vitamin B1 (thiamine) derived N-heterocyclic carbene (NHC)-catalyzed acetoin condensation as the key step to assemble two C2 acetaldehydes into a C4 product. The environmentally benign and cheap natural catalyst vitamin B1 demonstrates high selectivity (99%), high efficiency (97% yield), and high tolerance toward ethanol and water impurities in the acetoin reaction. The results enable a novel and efficient process for ethanol upgrading. PMID- 25044301 TI - Association between ligands and receptors related to the progression of early breast cancer in tumor epithelial and stromal cells. AB - BACKGROUND: Despite advances in the study of breast cancer (BC), it remains the second leading cause of mortality among women. BC is a heterogeneous system, mainly composed of tumor epithelial cells (TEpCs) and stromal cells (SCs); the interaction through the ligands and their receptors (Rs) plays a major role in BC progression. The aim of the present study was to evaluate the association between ligands, such as osteoprotegerin, tumor necrosis factor-related apoptosis inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand (RANKL), stromal cell-derived factor (SDF)-1, interleukin (IL)-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2), and their Rs in TEpC and spindle-shaped SCs not closely associated with the vasculature. PATIENTS AND METHODS: We studied the expression of all those factors in 63 primary tumors of untreated patients with BC with infiltrative ductal carcinoma (I/II stage) and 10 non-neoplastic tissues. The percentage of positive cells and the staining intensity were analyzed by immunohistochemistry. Mann-Whitney test and Spearman's rank correlation coefficient were used (P <= .05). RESULTS: We found a significant association between the expression of RANKL, IL-6, SDF-1, and CCL-2 in TEpC and the receptor activator of nuclear factor kappa B (RANK), IL-6R, C-X-C chemokine R type 4, and chemokine (C-C motif) R-2 (CCR-2) in spindle-shaped SC. The expression of TRAIL, RANKL, and CCL-2 in spindle-shaped SC also was associated with the expression of TRAIL-receptor 1, TRAIL-receptor 4, RANK, and CCR-2 in TEpC. CONCLUSIONS: Because the described ligands and Rs are implicated in BC progression, our results suggest that these factors could be involved in the crosstalk between TEpC and SC in the early stages of BC. PMID- 25044304 TI - Nonlinear imaging and spectroscopy of chiral metamaterials. AB - A chiral metamaterial produces both distinguishable linear and non-linear resonant features when probed with left and right circularly polarized light. The material demonstrates a linear transmission contrast of 0.5 between left and right circular polarizations and a 20* contrast between second-harmonic responses from the two incident polarizations. Non-linear and linear response images probed with circularly polarized light show strongly defined contrast. PMID- 25044305 TI - Evaluation of proximal joint kinematics and muscle strength following ACL reconstruction surgery in female athletes. AB - Despite the intense focus on outcomes following an anterior cruciate ligament (ACL) reconstruction, it is not yet known whether unresolved abnormal hip and trunk neuromuscular control exists. The purpose of this study was to compare trunk and hip kinematics during running, hip abductor and external rotator strength, and trunk control between females who had undergone an ACL reconstruction and healthy control participants. We compared 20 ACL reconstructed females to 20 healthy individuals, measuring abduction and external rotation strength, a trunk control test, and performed an instrumented gait evaluation during running. Comparisons between groups were made for non-sagittal peak hip angles, forward trunk lean, trunk ipsilateral lean at initial contact, trunk control and hip abduction, and external rotation strength. We found no significant differences in hip abduction (p = 0.25), hip external rotation strength (p = 0.63), peak hip adduction (p = 0.11) or hip internal rotation angle (p = 0.47). The ACL group did have a significantly greater ipsilateral trunk lean (p = 0.028), forward lean (p = 0.004), and had higher errors on the trunk stability test (p = 0.007). We found significant differences in trunk control, suggesting further attention should be devoted to this component of rehabilitation. PMID- 25044306 TI - A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States. AB - BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with health benefits throughout life and are obtained primarily through fish and fish oil supplements. Due to the growing popularity of dietary supplements, 47 commercial fish, krill, and algal oil supplements were analyzed for EPA, DHA, and other fatty acids. RESULTS: For fish- and krill-based supplements, the range of EPA was 81.8 to 454.6 mg g(-1) oil and DHA was 51.6 to 220.4 mg g(-1) oil. For algal oil supplements, EPA ranged from 7.7 to 151.1 mg g( 1) oil and DHA ranged from 237.8 to 423.5 mg g(-1) oil. The percentage of the stated label amount for EPA and DHA ranged from 66 to 184% and 62 to 184%, respectively. Only 10 supplements (21% of those tested) had at least 100% of the stated label amount of EPA, while 12 supplements (25% of those tested) had at least 100% of the stated amount of DHA. Over 70% of the supplements tested did not contain the stated label amount of EPA or DHA. CONCLUSIONS: These results indicate that the quality of fish oil supplements is not being adequately monitored by manufacturers or government agencies and increased testing is needed to ensure regulatory compliance. PMID- 25044307 TI - The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent. AB - Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism. PMID- 25044308 TI - Autophagy: an adaptive metabolic response to stress shaping the antitumor immunity. AB - Several environmental-associated stress conditions, including hypoxia, starvation, oxidative stress, fast growth and cell death suppression, modulate both cellular metabolism and autophagy to enable cancer cells to rapidly adapt to environmental stressors, maintain proliferation and evade therapies. It is now widely accepted that autophagy is essential to support cancer cell growth and metabolism and that metabolic reprogramming in cancer can also favor autophagy induction. Therefore, this complex interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets. As the regulation of the autophagic activity is related to metabolism, it is important to elucidate the exact molecular mechanism which drives it and the functional consequence of its activation in the context of cancer therapy. In this review, we will summarize the role of autophagy in shaping the cellular response to an abnormal tumor microenvironment and discuss some recent results on the molecular mechanism by which autophagy plays such a role in the context of the anti-tumor immune response. We will also describe how autophagy activation can behave as a double-edged sword, by activating the immune response in some circumstances, and impairing the anti-tumor immunity in others. These findings imply that defining the precise context-specific role for autophagy in cancer is critical to guide autophagy-based therapeutics which are becoming key strategies to overcome tumor resistance to therapies. PMID- 25044309 TI - Non-invasive in vivo tracking of fibrin degradation by fluorescence imaging. AB - Fibrin-based sealants consist of natural coagulation factors involved in the final phase of blood coagulation, during which fibrinogen is enzymatically converted by thrombin to form a solid-phase fibrin clot. For applications in tissue regeneration, a controlled process of matrix degradation within a certain period of time is essential for optimal wound healing. Hence, it is desirable to follow the kinetics of fibrinolysis at the application site. Non-invasive molecular imaging systems enable real-time tracking of processes in the living animal. In this study, a non-invasive fluorescence based imaging system was applied to follow and quantify site-specific degradation of fibrin sealant. To enable non-invasive tracking of fibrin in vivo, fibrin-matrix was labelled by incorporation of a fluorophore-conjugated fibrinogen component. Protein degradation and release of fluorescence were, in a first step, correlated in vitro. In vivo, fluorophore-labelled fibrin was subcutaneously implanted in mice and followed throughout the experiment using a multispectral imaging system. For the fluorescent fibrin, degradation correlated with the release of fluorescence from the clots in vitro. In vivo it was possible to follow and quantify implanted fibrin clots throughout the experiment, demonstrating degradation kinetics of approximately 16 days in the subcutaneous compartment, which was further confirmed by histological evaluation of the application site. PMID- 25044310 TI - How (not) to inform patients about drug use: use and effects of negations in Dutch patient information leaflets. AB - PURPOSE: Under EU regulations, patient information leaflets (PILs) are required to be clear and understandable. Negations (e.g., not, no) are a linguistic aspect that may impact PIL comprehension, yet go unmentioned in these regulations. We conducted two studies to determine (1) how negations are used in Dutch PILs (study 1) and (2) the effects of negations on readers (study 2). METHODS: Study 1 was a content analysis of 30 PILs of different brands of pollinosis drugs, half of which were freely available in drugstores and half only by physician prescription. We mapped negation use in PIL sections on 'proper usage' and 'potential side effects'. Study 2 was an experiment in which participants (N = 80, Mage = 33.19 years, SDage = 13.66; 76.3% female) were presented with one of two PIL texts on proper drug usage. Texts were identical except for the use of negations. After reading, participants answered questions about comprehension, PIL appreciation and medical adherence intentions. RESULTS: Study 1 demonstrates that negations are often used in PILs as 21.0% of clauses contain at least one negation. This number is higher in sections related to potential side effects than proper usage. Study 2 demonstrates that negations decrease both actual and subjective comprehension. Negations also decrease PIL appreciation and medical adherence intentions. The reduction in medical adherence intentions is driven by the decrease of subjective and not actual comprehension. CONCLUSIONS: In general, participants prefer PILs that contain clear and comprehensible language. To increase comprehensibility, PIL designers should refrain from using negations as much as possible. PMID- 25044311 TI - Nursing care of the super bariatric patient: challenges and lessons learned. AB - PURPOSE: The purpose of this article is to describe the care of a "super bariatric" patient. DESIGN AND METHODS: We used a case study approach to describe the complex interdisciplinary care challenges posed in the care of a super bariatric patient at a Veterans Administration Hospital in the Midwest. FINDINGS: Nurses and other healthcare providers discovered ways to provide high-quality patient-centered care under challenging conditions and also ensure the safety and well-being of nursing staff and other providers. CONCLUSIONS/CLINICAL RELEVANCE: An interdisciplinary, patient-centered approach with advance planning and coordination is necessary to ensure the delivery of safe, high-quality nursing care to veterans with complex health problems who are "super bariatric." PMID- 25044312 TI - Bis-pyrene-modified unlocked nucleic acids: synthesis, hybridization studies, and fluorescent properties. AB - Efficient synthesis of a building block for the incorporation of a bis-pyrene modified unlocked nucleic acid (UNA) into oligonucleotides (DNA*) was developed. The presence of bis-pyrene-modified UNA within a duplex leads to duplex destabilization that is more profound in DNA*/RNA and less distinct in DNA*/DNA duplexes. Nevertheless, the destabilization effect of bis-pyrene-modified UNA is weaker than that of unmodified UNA. Some oligonucleotides with bis-pyrene modified UNA incorporations displayed superior mismatch discrimination capabilities. UV/Vis absorption and molecular modeling studies indicate that the pyrene groups of bis-pyrene-modified UNA are located in the major groove of a duplex. Oligonucleotides containing two bis-pyrene-modified UNA monomers showed low pyrene monomer emission in bulge-containing duplexes, high pyrene monomer emission in fully matched duplexes, and 5-(pyrenyl)uracil:pyrene exciplex emission in the single-stranded form. Such fluorescent properties enable the application of bis-pyrene-modified UNA in the development of fluorescence probes for DNA/RNA detection and for detection of deletions at specific positions. PMID- 25044313 TI - Increase in testicular germ cell tumor incidence among Hispanic adolescents and young adults in the United States. AB - BACKGROUND: Although rising incidence rates of testicular germ cell tumors have been well documented in white men, relatively little is known about rates in men of Hispanic origin. In the current study, the authors compared germ cell tumor trends between men of Hispanic and non-Hispanic origin as a function of age at diagnosis. METHODS: Trends in testicular germ cell tumor incidence among white men were analyzed according to Hispanic ethnicity in 2 data sets of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, spanning from 1992 to 2010 and from 2000 to 2010 and sampling 15% and 28% of the United States population, respectively. Rates were age-adjusted to the year 2000 US standard population. RESULTS: Between 1992 and 2010, the annual incidence of testicular germ cell tumors among Hispanic whites ages 15 to 39 years increased 58%, from 7.18 cases per 100,000 in 1992 to 11.34 cases per 100,000 by 2010 (P<1 * 10(-9) ). Their incidence rates increased in metropolitan areas for both seminoma and nonseminoma subtypes and for all stages at diagnosis. During the same 19-year interval, incidence among non-Hispanic white young adults increased 7%, from 12.41 to 13.22 per 100,000. During the 2000 to 2010 interval, no significant trends were observed in incidence among non-Hispanic whites. CONCLUSIONS: There has been a recent substantial increase in testicular germ cell tumor incidence among Hispanic adolescents and young adults in the United States. Similar trends were not observed in non-Hispanic whites. PMID- 25044314 TI - Synthesis of pyrrolophenanthridine alkaloids based on C(sp3)-H and C(sp2)-H functionalization reactions. AB - Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C-H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp(3))-H functionalization followed by a Catellani reaction, including C(sp(2))-H functionalization. A one-pot reaction involving both C(sp(3))-H and C(sp(2))-H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups. PMID- 25044315 TI - Letter to the editor. Re: The perplexing paradox of paraquat: the case for host based susceptibility and postulated neurodegenerative effects. PMID- 25044316 TI - Response. PMID- 25044318 TI - Antiinflammatory, antioxidant, and immunological effects of Carum copticum L. and some of its constituents. AB - Carum copticum L. has been used traditionally for its various therapeutic effects. The plant contains various components such as thymol and carvacrol. Different therapeutic effects such as antifungal, antioxidant, antibacterial, antiparasitic, and antilipidemic were described for the plant and its constituents. Therefore, antiinflammatory, antioxidant, and immunological effects of C. copticum and its constituents, thymol and carvacrol, were discussed in the present review. Previous studies have shown potent antiinflammatory, antioxidant, and immunological effects for C. copticum and its constituents, thymol and carvacrol. Therefore, the plant and its constituents have therapeutic values in several inflammatory and immunological disorders as well as in the oxidative stress conditions. PMID- 25044319 TI - Reply to letter from I. Ekman, K. Swedberg, and M. Bohm. PMID- 25044321 TI - Cyclometalated mono- and dinuclear Ir(III) complexes with "click"-derived triazoles and mesoionic carbenes. AB - Orthometalation at Ir(III) centers is usually facile, and such orthometalated complexes often display intriguing electronic and catalytic properties. By using a central phenyl ring as C-H activation sites, we present here mono- and dinuclear Ir(III) complexes with "click"-derived 1,2,3-triazole and 1,2,3-triazol 5-ylidene ligands, in which the wingtip phenyl groups in the aforementioned ligands are additionally orthometalated and bind as carbanionic donors to the Ir(III) centers. Structural characterization of the complexes reveal a piano stool-type of coordination around the metal centers with the "click"-derived ligands bound either with C^N or C^C donor sets to the Ir(III) centers. Furthermore, whereas bond localization is observed within the 1,2,3-triazole ligands, a more delocalized situation is found in their 1,2,3-triazol-5-ylidene counterparts. All complexes were subjected to catalytic tests for the transfer hydrogenation of benzaldehyde and acetophenone. The dinuclear complexes turned out to be more active than their mononuclear counterparts. We present here the first examples of stable, isomer-pure, dinuclear cyclometalated Ir(III) complexes with poly-mesoionic-carbene ligands. PMID- 25044322 TI - Pigeons' delay discounting functions established using a concurrent-chains procedure. AB - Several studies have examined discounting by pigeons and rats using concurrent chains procedures, but the results have been inconsistent. None of these studies, however, has established that discounting functions derived from estimates of indifference points can be obtained with a concurrent-chains procedure, so their validity remains in doubt. The present study used a concurrent-chains procedure within sessions combined with an adjusting-amount procedure across sessions to determine the present, subjective values of food reinforcers to be obtained after a delay. Discounting was well described by the hyperbolic discounting function, suggesting that the concurrent-chains procedure and the more typical adjusting amount procedure are measuring the same process. Consistent with previous studies with rats and pigeons using adjusting-amount procedures, no significant effect of the amount of the delayed reinforcer on the degree of discounting was observed, suggesting that the amount effect may be unique to humans although consistent with the view that animals' choices are controlled by the relative, rather than the absolute, value of reinforcers. PMID- 25044323 TI - Effects of maturation and aging on the pressure-bearing region of the plantaris longus tendon of the bullfrog (Lithobates catesbeianus). AB - The plantaris longus tendon (PLT) in bullfrog develops a fibrocartilage-like tissue in the area that is functionally subject to compressive forces. The aim of this study was to analyze the modifications of the pressure-bearing region in bullfrog PLT with different ages (7, 180, and 1,080 days after the end of metamorphosis) using histomorphometric, ultrastructural and biochemical methods. Weak basophilia and cells with a fibroblastic phenotype were observed in the compression region at 7 days of age. On the other hand, a large area of intense tissue basophilia associated with a chondroblast-like cell population was noted at the other ages. Collagen fibers exhibited a three-dimensional network-like arrangement at all ages. The number of connective tissue cells increased between 7 and 180 days of age and was reduced in older animals. The 180-day-old animals presented a well-developed pericellular matrix rich in proteoglycans. The mean diameter of collagen fibrils increased from 7 to 180 days and was the same at 1,080 days. Glycosaminoglycan content was higher in 7-day-old animals. A higher amount of hydroxyproline was observed at 180 and 1,080 days. The swelling test showed a significant increase of wet weight in 7-day-old animals. In conclusion, the alterations that occur in the pressure-bearing of bullfrog PLT are the result of physiological alterations of the animal with the maturation and aging. PMID- 25044324 TI - Crystal structures of three representatives of a new Pfam family PF14869 (DUF4488) suggest they function in sugar binding/uptake. AB - Crystal structures of three members (BACOVA_00364 from Bacteroides ovatus, BACUNI_03039 from Bacteroides uniformis and BACEGG_00036 from Bacteroides eggerthii) of the Pfam domain of unknown function (DUF4488) were determined to 1.95, 1.66, and 1.81 A resolutions, respectively. The protein structures adopt an eight-stranded, calycin-like, beta-barrel fold and bind an endogenous unknown ligand at one end of the beta-barrel. The amino acids interacting with the ligand are not conserved in any other protein of known structure with this particular fold. The size and chemical environment of the bound ligand suggest binding or transport of a small polar molecule(s) as a potential function for these proteins. These are the first structural representatives of a newly defined PF14869 (DUF4488) Pfam family. PMID- 25044327 TI - One-pot synthesis of highly substituted polyheteroaromatic compounds by rhodium(III)-catalyzed multiple C-H activation and annulation. AB - A new method for the synthesis of highly substituted naphthyridine-based polyheteroaromatic compounds in high yields proceeds through rhodium(III) catalyzed multiple C-H bond cleavage and C-C and C-N bond formation in a one-pot process. Such highly substituted polyheteroaromatic compounds have attracted much attention because of their unique pi-conjugation, which make them suitable materials for organic semiconductors and luminescent materials. Furthermore, a possible mechanism, which involves multiple chelation-assisted ortho C-H activation, alkyne insertion, and reductive elimination, is proposed for this transformation. PMID- 25044326 TI - Missing genetic risk in neural tube defects: can exome sequencing yield an insight? AB - BACKGROUND: Neural tube defects (NTD) have a strong genetic component, with up to 70% of variance in human prevalence determined by heritable factors. Although the identification of causal DNA variants by sequencing candidate genes from functionally relevant pathways and model organisms has provided some success, alternative approaches are demanded. METHODS: Next generation sequencing platforms are facilitating the production of massive amounts of sequencing data, primarily from the protein coding regions of the genome, at a faster rate and cheaper cost than has previously been possible. These platforms are permitting the identification of variants (de novo, rare, and common) that are drivers of NYTD etiology, and the cost of the approach allows for the screening of increased numbers of affected and unaffected individuals from NTD families and in simplex cases. CONCLUSION: The next generation sequencing platforms represent a powerful tool in the armory of the genetics researcher to identify the causal genetic basis of NTDs. PMID- 25044328 TI - Aquatic risk assessment of pesticides in Latin America. AB - Latin America is anticipated to be a major growth market for agriculture and production is increasing with use of technologies such as pesticides. Reports of contamination of aquatic ecosystems by pesticides in Latin America have raised concerns about potential for adverse ecological effects. In the registration process of pesticides, all countries require significant data packages on aquatic toxicology and environmental fate. However, there are usually no specific requirements to conduct an aquatic risk assessment. To address this issue, the Society of Environmental Toxicology and Chemistry organized a workshop that brought together scientists from academia, government, and industry to review and elaborate on aquatic risk assessment frameworks that can be implemented into regulation of pesticides in Latin America. The workshop concluded that the international framework for risk assessments (protection goals, effects, and exposure assessments, risk characterization, and risk mitigation) is broadly applicable in Latin America but needs further refinement for the use in the region. Some of the challenges associated with these refinements are discussed in the article. It was recognized that there is potential for data sharing both within and outside of the region where conditions are similar. However, there is a need for research to compare local species and environmental conditions to those in other jurisdictions to be able to evaluate the applicability of data used in other countries. Development should also focus on human resources as there is a need to build local capacity and capability, and scientific collaboration and exchange between stakeholders in industry, government, and academia is also important. The meeting also emphasized that, although establishing a regionally relevant risk assessment framework is important, this also needs to be accompanied by enforcement of developed regulations and good management practices to help protect aquatic habitats. Education, training, and communication efforts are needed to achieve this. PMID- 25044325 TI - Nanoparticle approaches against bacterial infections. AB - Despite the wide success of antibiotics, the treatment of bacterial infections still faces significant challenges, particularly the emergence of antibiotic resistance. As a result, nanoparticle drug delivery platforms including liposomes, polymeric nanoparticles, dendrimers, and various inorganic nanoparticles have been increasingly exploited to enhance the therapeutic effectiveness of existing antibiotics. This review focuses on areas where nanoparticle approaches hold significant potential to advance the treatment of bacterial infections. These areas include targeted antibiotic delivery, environmentally responsive antibiotic delivery, combinatorial antibiotic delivery, nanoparticle-enabled antibacterial vaccination, and nanoparticle-based bacterial detection. In each area we highlight the innovative antimicrobial nanoparticle platforms and review their progress made against bacterial infections. PMID- 25044329 TI - Benjamin Hobson (1816-1873): his role in the absorption of western medicine and anatomy in Japan. PMID- 25044330 TI - Aerobic oxidation of alkylaromatics using a lipophilic N-hydroxyphthalimide: overcoming the industrial limit of catalyst solubility. AB - 4,4'-(4,4'-Isopropylidenediphenoxy)bis(N-hydroxyphthalimide), which is a new lipophilic analogue of N-hydroxyphthalimide, can act as an effective catalyst in the aerobic oxidation of alkylaromatics under reduced amounts of polar cosolvent. The catalyst was selected on the basis of an in-depth study of the influence that substituents on the aromatic ring of N-hydroxyphthalimide exert on determining the NO-H bond dissociation energy (BDE). BDE values for a range of model molecules are calculated by DFT and measured by EPR spectroscopy. The new catalyst can be successfully employed in the aerobic oxidation of cumene, ethylbenzene, and cyclohexylbenzene, affording, in all cases, good conversions and high selectivity for the corresponding hydroperoxide. The effect of solvent, catalyst, and temperature has also been investigated. PMID- 25044332 TI - Phenotypic alterations of regulatory T cells in autoimmune hepatitis: causal or associated with treatment and remission? PMID- 25044333 TI - Salinity affects the proteomics of rice roots and leaves. AB - While insights into the molecular mechanisms underlying salinity tolerance have been obtained from transcriptome and genome analysis, the molecules affected directly by salt and linking the extracellular stimulus to intracellular responses remain largely unknown. Protein alterations upon exogenous stimulus are vital in outlining differences that cannot otherwise be measured quantitatively. So proteomic analysis may reveal novel aspects of the plant protection mechanism from salinity. The pioneering work of Liu et al. (Proteomics 2014, 14, 1759-1775) found the differentially expressed proteins in rice roots and leaves after salt treatment, and these proteins may serve as marker group of rice resistant to salt stress. Metabolic pathways maintain cellular homeostasis and are very important for imparting stress tolerance in rice. PMID- 25044334 TI - Semiconductor and metallic core-shell nanostructures: synthesis and applications in solar cells and catalysis. AB - Nano-heterostructures have attracted great attention due to their extraordinary properties beyond those of their single-component counterparts. This review focuses on a specific type of hybrid structures: core-shell structures. In particular, we present and discuss the recent wet-chemical synthesis approaches for semiconductor and metallic core-shell nanostructures, and their relevant properties and potential applications in photovoltaics and catalysis, respectively. PMID- 25044331 TI - Combining diffusion tensor imaging and magnetic resonance spectroscopy to study reduced frontal white matter integrity in youths with family histories of substance use disorders. AB - Individuals with a family history of substance use disorder (FH+) show impaired frontal white matter as indicated by diffusion tensor imaging (DTI). This impairment may be due to impaired or delayed development of myelin in frontal regions, potentially contributing to this population's increased risk for developing substance use disorders. In this study, we examined high angular resolution DTI and proton magnetic resonance spectroscopy data from the anterior corona radiata were collected in 80 FH+ and 34 FH- youths (12.9 +/- 1.0 years old). White matter integrity indices included fractional anisotropy (FA), N acetylaspartate (NAA), and total choline (tCho). Lower FA suggests decreased myelination. Decreased NAA coupled with higher tCho suggests impaired build-up and maintenance of cerebral myelin and consequently greater breakdown of cellular membranes. We found FH+ youths had lower FA (P < 0.0001) and NAA (P = 0.017) and higher tCho (P = 0.04). FH density (number of parents and grandparents with substance use disorders) was negatively correlated with FA (P < 0.0001) and NAA (P = 0.011) and positively correlated with tCho (P = 0.001). FA was independently predicted by both FH density (P = 0.006) and NAA (P = 0.002), and NAA and tCho were both independent predictors of FH density (P < 0.001). Our finding of lower frontal FA in FH+ youths corresponding to lower NAA and increased tCho is consistent with delayed or impaired development of frontal white matter in FH+ youths. Longitudinal studies are needed to determine how these differences relate to substance use outcomes. PMID- 25044335 TI - Lysozyme and defense peptides as suppressors of phenoloxidase activity in Galleria mellonella. AB - The prophenoloxidase (proPO) cascade supplies quinones and other reactive compounds for melanin formation, protein cross-linking, hemolymph coagulation, and killing of microbial invaders as well as parasites. The high cytotoxicity of the generated compounds requires a strict control of the activation of the proPO system and phenoloxidase (PO) activity to minimize damage to host tissues and cells. The PO activity in hemolymph of Escherichia coli challenged Galleria mellonella larvae increased, with a temporal drop 1 h after the challenge, reaching the highest level 24 h after the challenge. In the present study, a potential role of G. mellonella defense peptides and lysozyme in controlling the proPO system was investigated. The effects of purified defense peptides (anionic peptides 1 and 2, cecropin D-like peptide, Galleria defensin, proline-rich peptides 1 and 2) and lysozyme were analyzed. Four compounds, namely lysozyme, Galleria defensin, proline-rich peptide 1, and anionic peptide 2, decreased the hemolymph PO activity considerably, whereas the others did not affect the enzyme activity level. Our results indicate that these hemolymph factors could play multiple and distinct roles in the insect immune response. PMID- 25044336 TI - Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge with Bacillus cereus G9241. AB - In the past decade, several Bacillus cereus strains have been isolated from otherwise healthy individuals who succumbed to bacterial pneumonia presenting symptoms resembling inhalational anthrax. One strain was indistinguishable from B. cereus G9241, previously cultured from an individual who survived a similar pneumonia-like illness and which was shown to possess a complete set of plasmid borne anthrax toxin-encoding homologs. The finding that B. cereus G9241 pathogenesis in mice is dependent on pagA1-derived protective antigen (PA) synthesis suggests that an anthrax toxin-based vaccine may be effective against this toxin-encoding B. cereus strain. Dunkin Hartley guinea pigs were immunized with protein- and DNA-based anthrax toxin-based vaccines, immune responses were evaluated and survival rates were calculated after lethal aerosol exposure with B. cereus G9241 spores. Each vaccine induced seroconversion with the protein immunization regimen eliciting significantly higher serum levels of antigen specific antibodies at the prechallenge time-point compared with the DNA-protein prime-boost immunization schedule. Complete protection against lethal challenge was observed in all groups with a detectable prechallenge serum titer of toxin neutralizing antibodies. For the first time, we demonstrated that the efficacy of fully defined anthrax toxin-based vaccines was protective against lethal B. cereus G9241 aerosol challenge in the guinea pig animal model. PMID- 25044337 TI - Flexible and robust methods for rare-variant testing of quantitative traits in trios and nuclear families. AB - Most rare-variant association tests for complex traits are applicable only to population-based or case-control resequencing studies. There are fewer rare variant association tests for family-based resequencing studies, which is unfortunate because pedigrees possess many attractive characteristics for such analyses. Family-based studies can be more powerful than their population-based counterparts due to increased genetic load and further enable the implementation of rare-variant association tests that, by design, are robust to confounding due to population stratification. With this in mind, we propose a rare-variant association test for quantitative traits in families; this test integrates the QTDT approach of Abecasis et al. [Abecasis et al., ] into the kernel-based SNP association test KMFAM of Schifano et al. [Schifano et al., ]. The resulting within-family test enjoys the many benefits of the kernel framework for rare variant association testing, including rapid evaluation of P-values and preservation of power when a region harbors rare causal variation that acts in different directions on phenotype. Additionally, by design, this within-family test is robust to confounding due to population stratification. Although within family association tests are generally less powerful than their counterparts that use all genetic information, we show that we can recover much of this power (although still ensuring robustness to population stratification) using a straightforward screening procedure. Our method accommodates covariates and allows for missing parental genotype data, and we have written software implementing the approach in R for public use. PMID- 25044338 TI - Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds coated with PhaP-RGD fusion protein promotes the proliferation and chondrogenic differentiation of human umbilical cord mesenchymal stem cells in vitro. AB - Human umbilical cord blood-derived mesenchymal stem cells (hUC-MSCs) have been widely used in tissue engineering. The aim of this study is to evaluate the ability of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) scaffolds coated with polyhydroxyalkanoate binding protein fused with arginyl-glycyl aspartic acid (PhaP-RGD) to promote the proliferation and chondrogenic differentiation of hUC-MSCs seeded on them. The PhaP-RGD fusion protein was expressed by Escherichia coli. PHBHHx films were coated with PhaP-RGD fusion protein and the physiochemical properties were examined. hUC-MSCs were seeded on PHBHHx films with or without PhaP-RGD precoating and tested for changes in morphology, viability, and chondrogenic differentiation. We found that PhaP-RGD coated PHBHHx films had similar surface morphology to uncoated PHBHHx. The water contact angle of the coated PHBHHx surface was lower than that of the uncoated surface (10.63 degrees vs. 98.69 degrees ). At 7 and 14 days after seeding, the PhaP-RGD-coated PHBHHx group showed greater numbers of viable cells compared to the uncoated PHBHHx group. The expression levels of aggrecan and collagen II were enhanced in the PhaP-RGD-coated PHBHHx group relative to the uncoated PHBHHx group. Histological analysis using toluidine blue staining showed elevated formation of proteoglycan producing chondrocytes in the PhaP-RGD-coated PHBHHx group. Additionally, the synthesis of proteoglycan and collagen was significantly enhanced within the PhaP-RGD constructs. Taken together, PhaP-RGD coating promotes the proliferation and chondrogenic differentiation of hUC-MSCs seeded on PHBHHx films. PhaP-RGD-coated PHBHHx may be a useful scaffold for cartilage tissue engineering. PMID- 25044340 TI - Effect of thermal annealing on the structural and optical properties of tris-(8 hydroxyquinoline)aluminum(III) (Alq3 ) films. AB - Tris-(8-hydroxyquionoline)aluminum (Alq3 ) was synthesized and coated on to a glass substrate using the dip coating method. The structural and optical properties of the Alq3 film after thermal annealing from 50 degrees C to 300 degrees C in 50 degrees steps was studied. The films have been prepared with 2 to 16 layers (42-324 nm). The thickness and thermal annealing of Alq3 films were optimized for maximum luminescence yield. The Fourier transform infrared spectrum confirms the formation of quinoline with absorption in the region 700 - 500/cm. Partial sublimation and decomposition of quinoline ion was observed with the Alq3 films annealed at 300 degrees C. The X-ray diffraction pattern of the Alq3 film annealed at 50 degrees C to 150 degrees C reveals the amorphous nature of the films. The Alq3 film annealed above 150 degrees C were crystalline nature. Film annealed at 150 degrees C exhibits a photoluminescence intensity maximum at 512 nm when excited at 390 nm. The Alq3 thin film deposited with 10 layers (220 nm) at 150 degrees C exhibited maximum luminescence yield. PMID- 25044339 TI - The biofilm matrix destabilizers, EDTA and DNaseI, enhance the susceptibility of nontypeable Hemophilus influenzae biofilms to treatment with ampicillin and ciprofloxacin. AB - Nontypeable Hemophilus influenzae (NTHi) is a Gram-negative bacterial pathogen that causes chronic biofilm infections of the ears and airways. The biofilm matrix provides structural integrity to the biofilm and protects biofilm cells from antibiotic exposure by reducing penetration of antimicrobial compounds into the biofilm. Extracellular DNA (eDNA) has been found to be a major matrix component of biofilms formed by many species of Gram-positive and Gram-negative bacteria, including NTHi. Interestingly, the cation chelator ethylenediaminetetra acetic acid (EDTA) has been shown to reduce the matrix strength of biofilms of several bacterial species as well as to have bactericidal activity against various pathogens. EDTA exerts its antimicrobial activity by chelating divalent cations necessary for growth and membrane stability and by destabilizing the matrix thus enhancing the detachment of bacterial cells from the biofilm. In this study, we have explored the role of divalent cations in NTHi biofilm development and stability. We have utilized in vitro static and continuous flow models of biofilm development by NTHi to demonstrate that magnesium cations enhance biofilm formation by NTHi. We found that the divalent cation chelator EDTA is effective at both preventing NTHi biofilm formation and at treating established NTHi biofilms. Furthermore, we found that the matrix destablilizers EDTA and DNaseI increase the susceptibility of NTHi biofilms to ampicillin and ciprofloxacin. Our observations indicate that DNaseI and EDTA enhance the efficacy of antibiotic treatment of NTHi biofilms. These observations may lead to new strategies that will improve the treatment options available to patients with chronic NTHi infections. PMID- 25044342 TI - A late appearance by the dopamine D-3 receptor. PMID- 25044341 TI - Towards reassigning the rare AGG codon in Escherichia coli. AB - The rare AGG codon in Escherichia coli has been reassigned to code non-canonical amino acids (ncAAs) by using the PylRS-tRNA(Pyl)(CCU) pair. When N(epsilon) alloc-lysine was used as a PylRS substrate, almost quantitative occupancy of N(epsilon) -alloc-lysine at an AGG codon site was achieved in minimal medium. ncAAs can be potentially incorporated at the AGG codon with varying efficiencies, depending on their activities towards corresponding enzymes. As AGG is a sense codon, the approach reported here resolves the typical low ncAA incorporation issue that has been associated with ncAA mutagenesis and therefore allows bulk preparation of proteins with site-selectively incorporated ncAAs for applications such as therapeutic protein production. PMID- 25044344 TI - Water encapsulation by nanomicelles. AB - Reported is the hydration of nanomicelles in the gas-phase using spectroscopic methods and quantum chemical calculations. A fine-tuning of the experimental conditions allowed formation of a propofol trimer and tetramer with a water molecule and to determine the structure of the aggregates. Their electronic and IR spectra were obtained using mass-resolved laser spectroscopy, together with the number of conformational isomers for each stoichiometry. Interpretation of the spectra in the light of high-level calculations allowed determination of the cluster's structure and demonstration that the trimer of propofol with a water molecule forms cyclic hydrogen-bond networks but, on the other hand, the tetramer is big enough to encapsulate the water molecule inside its hydrophilic core. Furthermore, these hydrated nanomicelles present an unusually high binding energy, thus reflecting their high stability and their capability to trap water inside. PMID- 25044343 TI - Syringotropic mycosis fungoides: clinical and histologic features, response to treatment, and outcome in 19 patients. AB - BACKGROUND: A rare variant of mycosis fungoides (MF), syringotropic MF (STMF) is characterized by a particular tropism of the lymphocytic infiltrate for the eccrine structures, and included in the follicular subtype of MF in the World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. OBJECTIVE: We sought to determine the clinicopathologic features and disease course of patients with STMF. METHODS: A retrospective study was conducted to identify patients with STMF from 1998 to 2013. RESULTS: Nineteen patients were included: 15 men and 4 women, mean age 55 years (range, 24-86). Most had multiple lesions (n=16, 84%) with associated alopecia (n=12, 63%) and/or punctuated aspect (n=12, 63%). Palms or soles were involved in 10 cases (53%). Folliculotropism was found in 13 cases (68%). After a median follow-up of 70 months (range, 2-140), 3 patients died, 1 from disease related death. The 5-year overall and disease-specific survival were 100%. The disease-specific survival was significantly higher than in 54 patients with folliculotropic MF without syringotropism (5-year disease-specific survival, 74%; 95% confidence interval, 58%-94%, P=.02). LIMITATIONS: Retrospective setting is a limitation. CONCLUSIONS: In the spectrum of adnexotropic MF, STMF appears as a distinct entity from follicular MF, with peculiar clinical characteristics and natural history. PMID- 25044345 TI - Clinical utility of locally-delivered collagen-based biodegradable tetracycline fibers in periodontal therapy: an in vivo study. AB - AIM: The purpose of the present investigation was to evaluate and compare the efficacy of resorbable collagen-based tetracycline fibers (Periodontal Plus AB fibers) given as an adjunct to scaling and root planing, with the clinical effects of scaling and root planning delivered as a monotherapy, in the treatment of chronic periodontitis. METHODS: A split-mouth design was used to conduct this study. Forty patients with periodontal pockets ranging from >= 5 mm to <= 7 mm, with minimum of two sites in two non-adjacent quadrants, were selected for the study. The treatment sites in each patient were randomly divided into the control and experimental groups. All of the selected sites were treated with scaling and root planning, and then collagen-based resorbable tetracycline fibers were placed adjunctively in the experimental sites at the same visit. Baseline and follow-up measurements in both treatment groups included plaque index, sulcus bleeding index, probing pocket depth, and relative attachment level. RESULTS: Although significant clinical benefits were obtained in both treatment groups, the adjunctive antimicrobial use of tetracycline fibers demonstrated better results compared to the control group over the 3-month observational period. CONCLUSIONS: The delivery of antimicrobial agent tetracycline in a collagen matrix was found to improve the benefits of scaling and root planing by a larger magnitude in patients with moderate-to-deep pockets. PMID- 25044346 TI - Taming gold(I)-counterion interplay in the de-aromatization of indoles with allenamides. AB - A careful interplay between the pi electrophilicity of a cationic Au(I) center and the basicity of the corresponding counterion allowed for the chemo- and regioselective inter- as well as intramolecular de-aromatization of 2,3 disubstituted indoles with allenamides. The silver-free bifunctional Lewis acid/Bronsted base complex [{2,4-(tBu)2C6H3O}3PAuTFA] assisted the formation of a range of densely functionalized indolenines under mild conditions. PMID- 25044347 TI - Effects of high-severity fire drove the population collapse of the subalpine Tasmanian endemic conifer Athrotaxis cupressoides. AB - Athrotaxis cupressoides is a slow-growing and long-lived conifer that occurs in the subalpine temperate forests of Tasmania, a continental island to the south of Australia. In 1960-1961, human-ignited wildfires occurred during an extremely dry summer that killed many A. cupressoides stands on the high plateau in the center of Tasmania. That fire year, coupled with subsequent regeneration failure, caused a loss of ca. 10% of the geographic extent of this endemic Tasmanian forest type. To provide historical context for these large-scale fire events, we (i) collected dendroecological, floristic, and structural data, (ii) documented the postfire survival and regeneration of A. cupressoides and co-occurring understory species, and (iii) assessed postfire understory plant community composition and flammability. We found that fire frequency did not vary following the arrival of European settlers, and that A. cupressoides populations were able to persist under a regime of low-to-mid severity fires prior to the 1960 fires. Our data indicate that the 1960 fires were (i) of greater severity than previous fires, (ii) herbivory by native marsupials may limit seedling survival in both burned and unburned A. cupressoides stands, and (iii) the loss of A. cupressoides populations is largely irreversible given the relatively high fuel loads of postfire vegetation communities that are dominated by resprouting shrubs. We suggest that the feedback between regeneration failure and increased flammability will be further exacerbated by a warmer and drier climate causing A. cupressoides to contract to the most fire-proof landscape settings. PMID- 25044349 TI - The scaffold protein IscU retains a structured conformation in the Fe-S cluster assembly complex. AB - IscU and IscS are two essential proteins in the machine responsible for the biogenesis of iron-sulfur clusters, prosthetic groups that are involved in several essential functions. The scaffold protein IscU is the temporary acceptor of the cluster that results when the protein forms a 110 kDa complex with the desulfurase IscS. In the absence of zinc, which stabilises the folded state, IscU is present in solution in equilibrium between a structured and an unstructured form. It has been suggested that IscS preferentially binds unstructured IscU, although crystal structures indicate otherwise. To learn more about the IscS-IscU complex, we have used advanced solution NMR techniques to observe directly the state of fold of IscS-bound IscU. We present unambiguous evidence that IscU is folded in the complex and that the unstructured form does not bind to IscS. Our data correlate with several observations and explain an IscU-related pathology. PMID- 25044350 TI - Photodegradation of the antihistamine cetirizine in natural waters. AB - The photodegradation rate of the anti-histamine cetirizine (Zyrtec(r)) was investigated in various water matrices. The average observed first-order photodegradation rate coefficient (kobs ), obtained by linear regression of the logarithmic-transformed cetirizine concentrations versus irradiation time in simulated sunlight, was 0.024 h(-1) (n = 6; standard deviation +/- 0.004) in deionized water corresponding to a half-life of approximately 30 h. There was no statistical difference in the kobs of cetirizine photodegradation in coastal seawater compared with deionized water or deionized water amended with dissolved chromophoric organic matter. The quantum yield of cetirizine photodegradation decreased dramatically with increasing wavelength and decreasing energy of incoming radiation, with the average value ranging from 5.28 * 10(-4) to 6.40 * 10(-3) in the ultraviolet wavelength range (280-366 nm). The activation energy of cetirizine photodegradation was 10.3 kJ mol(-1) with an observed increase in cetirizine photodegradation as temperature increased. This is a significant environmental factor influencing half-life and an important consideration, given that cetirizine has been detected in wastewater and receiving waters from different locations globally. PMID- 25044348 TI - Analysis of diazofluorene DNA binding and damaging activity: DNA cleavage by a synthetic monomeric diazofluorene. AB - The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies. PMID- 25044352 TI - Laser mass spectrometry with circularly polarized light: circular dichroism of cold molecules in a supersonic gas beam. AB - An experiment on chiral molecules that combines circular dichroism (CD) spectroscopy, mass-selective detection by laser mass spectrometry (MS), and cooling of molecules by using a supersonic beam is presented. The combination of the former two techniques (CD-laser-MS) is a new method to investigate chiral molecules and is now used by several research groups. Cooling in a supersonic beam supplies a substantial increase in spectroscopic resolution, a feature that has not yet been used in CD spectroscopy. In the experiments reported herein, a large variation in the electronic CD of carbonyl 3-methylcyclopentanone was observed depending on the excited vibrational modes in the n -> pi* transition. This finding should be of interest for the detection of chiral molecules and for the theoretical understanding of the CD of vibronic bands. It is expected that this effect will show up in other chiral carbonyls because the n -> pi* transition is typical for the carbonyl group. PMID- 25044351 TI - Emerging approaches in predictive toxicology. AB - Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. PMID- 25044353 TI - Obesity and bronchial obstruction in impulse oscillometry at age 5-7 years in a prospective post-bronchiolitis cohort. AB - BACKGROUND AND AIMS: Obesity has been linked with asthma symptoms, need for asthma treatment and reduced lung function but not with increased bronchial reactivity in children. The aim of this study was to evaluate the association between previous or current weight status and current lung function and bronchial reactivity to exercise at early school age. METHODS: Ninety-nine children hospitalized for bronchiolitis at the age of less than 6 months were studied with impulse oscillometry (IOS) at the mean age of 6.3 years. Data on birth weight and weight gain in infancy before hospitalization were collected during hospitalization. Current weight and height data were transformed into age- and sex-specific height-related body mass index z scores (zBMI) using the Finnish national population-based weight and height data as reference. RESULTS: Some significant though only low or modest correlations were found between current zBMI and baseline, post-exercise and post-bronchodilator IOS values in adjusted linear regression analysis. Seven obese children by zBMI had higher post bronchodilator airway impedance (Zrs) and resistance (Rrs) at 5 Hz and lower post bronchodilator frequency dependency of resistance (dRrs/df) than normal weight children. There were no significant differences in responses to exercise or to bronchodilators between currently obese or overweight children and normal weight children. Birth weight less than 3,000 g was associated with larger exercise induced changes in Zrs and Rrs at 5 Hz, and in reactance (Xrs) at 5 Hz, than those with birth weight more than 3,000 g. CONCLUSIONS: Preliminary evidence was found that obesity may be associated with airway obstruction, but not with bronchial hyper-reactivity. PMID- 25044354 TI - Consecutive cervical length measurements as a predictor of preterm cesarean section in complete placenta previa. AB - BACKGROUND: To evaluate whether consecutive cervical length measurements can predict preterm cesarean section in women with complete placenta previa. METHODS: Seventy-one women with complete placenta previa were retrospectively categorized into women who delivered preterm due to massive hemorrhage (the preterm cesarean section group, n = 28) and those delivered at term (the control group, n = 43). Maternal characteristics, delivery outcomes, and cervical lengths serially measured at least every 2 weeks from 24 weeks' gestation until delivery were compared. The relationship between cervical length and preterm cesarean section was analyzed. RESULTS: Cervical length gradually decreased with advancing gestational age. After 26 weeks' gestation, this decrease was significantly more rapid in the preterm cesarean section group. Cervical length before cesarean section in the preterm cesarean section group was significantly shorter than that in the control group. Just before cesarean section, 71.4% of the preterm cesarean section group presented with cervical lengths of <=35 mm, whereas only 34.9% of the control group had cervical lengths of <=35 mm (odds ratio 4.67, 95% confidence interval 1.66-13.10, p = 0.006). CONCLUSIONS: In women with complete placenta previa, decrease in cervical length to <=35 mm was associated with increased risk of preterm cesarean section due to massive hemorrhage. PMID- 25044355 TI - Weight gain after orthotopic liver transplantation: is nonalcoholic fatty liver disease cirrhosis a risk factor for greater weight gain? AB - Posttransplant weight gain is common after orthotopic liver transplantation. We sought to determine the extent of weight gain at 5 years after transplantation in patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis versus patients with other types of cirrhosis (non-NAFLD). We studied 126 liver transplants performed between 2005 and 2007 at Saint Luc Hospital, University of Montreal. Seventeen of the 126 patients (13.5%) had NAFLD cirrhosis. Ascites volume was difficult to assess, so we used the body mass index (BMI) at 3 months as the reference BMI. All patients gained weight after transplantation, but BMI increased significantly more and earlier among the NAFLD patients [4.8 versus 1.5 kg/m(2) at 1 year (P = 0.001), 5.0 versus 2.3 kg/m(2) at 2 years (P = 0.01), and 5.6 versus 2.6 kg/m(2) at 5 years (P = 0.009)] in comparison with non-NAFLD patients in unadjusted analyses. The greatest BMI increase over time was investigated with univariate and multivariate logistic regression analyses. The BMI increase was divided into tertiles for each period of time observed. The greatest BMI increase over time was defined as the top tertile of BMI increase. After adjustments for potential confounders (ie, total cholesterol, diabetes, and length of hospital stay), NAFLD was no longer associated with a risk of a greater BMI increase [odds ratio (OR) = 3.73 at 1 year (P = 0.11), OR = 2.15 at 2 years (P = 0.34), and OR = 2.87 at 5 years (P = 0.30)]. These findings suggest the need for multidisciplinary, early, and close weight monitoring for all patients. All patients could benefit from pretransplant counseling regarding weight gain and its consequences. PMID- 25044356 TI - Simultaneous determination of atropine, scopolamine, and anisodamine from Hyoscyamus niger L. in rat plasma by high-performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetics study. AB - In order to investigate the pharmacokinetics of tropane alkaloids in Hyoscyamus niger L., a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry method for the simultaneous determination of atropine, scopolamine, and anisodamine in rat plasma is developed and fully validated, using homatropine as an internal standard. The separation of the four compounds was carried out on a BDS Hypersil C18 column using a mobile phase consisting of acetonitrile and water (containing 10 mmol ammonium acetate). Calibration curves were linear from 0.2 to 40 ng/mL for atropine, scopolamine, and from 0.08 to 20 ng/mL for anisodamine. The precision of three analytes was <5.89% and the accuracy was between -1.04 to 2.94%. This method is successfully applied to rat pharmacokinetics analysis of the three tropane alkaloids after oral administration of H. niger extract. The maximum concentration of these three tropane alkaloids was reached within 15 min, and the maximum concentrations were 31.36 +/- 7.35 ng/mL for atropine, 49.94 +/- 2.67 ng/mL for scopolamine, and 2.83 +/- 1.49 ng/mL for anisodamine. The pharmacokinetic parameters revealed areas under the curve of 22.76 +/- 5.80, 16.80 +/- 3.08, and 4.31 +/- 1.21 ng/h mL and mean residence times of 2.08 +/- 0.55, 1.19 +/- 0.45, and 3.28 +/- 0.78 h for atropine, scopolamine, and anisodamine, respectively. PMID- 25044357 TI - Improvement of trospium-specific absorption models for fasted and fed states in humans. AB - The purpose of this study was to mechanistically interpret the oral absorption pattern of trospium in fasted and fed states by means of gastrointestinal simulation technology. A drug absorption model was built on the basis of experimental data. According to the generated model, low permeability across the intestinal epithelium, delayed gastric emptying time and a prolonged residence time in the small intestine are the key factors governing trospium absorption in the fasted state. Furthermore, in silico modelling provided a plausible explanation of the pronounced reduction in the oral bioavailability of trospium when administered with food. The simulation results support the decreased dissolution in viscous medium, and the reduced drug permeability in the fed state as the predominant mechanisms for the food effect on trospium absorption. PMID- 25044358 TI - Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. AB - In Western countries, gene alterations involving the CRLF2-JAK signaling pathway are identified in approximately 50-60% of patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial. IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (~2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients. We confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries (~50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8-CRLF2-positive patients than in P2RY8-CRLF2 negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but not in P2RY8-CRLF2-positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS-ALL patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients. PMID- 25044359 TI - Unzipping of small diameter stents: an in vitro study. AB - OBJECTIVE: The purpose of this study was to determine if small-diameter stents can be unzipped in vitro. BACKGROUND: Small-diameter stents can relieve stenosis in infant blood vessels. As the child grows, refractory stenosis may result. If an implanted stent can be intentionally fractured along its length-"unzipped," it can be redilated to the eventual adult vessel diameter. METHODS: Stents of diameters <=6 mm were dilated using angioplasty balloons until they fractured. The change in length-diameter (dL/dD ratio), and the yield-point-force (sigmay ) for each stent was calculated. RESULTS: Thirty-four coronary (CS), 11 biliary, and 10 nitinol peripheral stents (median diameter = 4, 5, and 6 mm; range = 2.75 4.5, 4-6, 6 mm, respectively) were tested. Stainless-steel (SS) CS unzipped predictably at twice their nominal diameter with minimal shortening (n = 24, median dL/dD = 0.4). Nitinol stents fractured in a disorganized fashion. The remaining stents unzipped, had disorganized fractures, and shortened significantly (dL/dD>1). A dL/dD ratio of<1 had a strong, positive correlation with the ability to unzip (Pearson rho = 0.94). By multivariate regression analysis, SS alloy, and closed-cell design were found to be significant predictors (P < 0.05) for unzipping. Optimal cut-off points for stents to unzip included, strut-thickness = 112 um, alloy-density = 7.7 g/cm(3) , dL/dD ratio = 0.12 and sigmay = 108Mpa (Youden's index = 0.8, 0.4, 0.8, and 0.5, respectively). CONCLUSIONS: Stainless-steel, coronary stents of a closed-cell design unzip at twice their nominal diameter without significant shortening when serially dilated. This study may encourage the implantation of small stents in infant blood vessels and aid in selection of appropriate stent type. PMID- 25044360 TI - Development of multifunctional metabolic synergists to suppress the evolution of resistance against pyrethroids in insects that blood feed on humans. AB - BACKGROUND: Pyrethroids are the insecticides of choice when exposure to humans is likely, such as occurs in vector and public-health-related control programs. Unfortunately, the pyrethroids share a common resistance mechanism with dichlorodiphenyltrichloroethane (DDT), knockdown resistance (kdr), and prior extensive use of DDT has predisposed the pyrethroids to cross-resistance via kdr. Given the widespread occurrence of kdr, the use of synergists with pyrethroids is considered to be prudent to guard against the selection of multiply resistant insects. RESULTS: 3-Phenoxybenzyl hexanoate (PBH) was synthesized as a multifunctional pyrethroid synergist that, besides being a surrogate substrate for sequestration/hydrolytic carboxylesterases, now also functions as a substrate for oxidative xenobiotic metabolism. The addition of PBH to permethrin-treated females of the ISOP450 strain of Culex pipiens quinquefasciatus resulted in a threefold increase in synergism, as judged by the synergistic ratio. Similarly, PBH synergized the action of deltamethrin sixfold on females of the common bed bug, Cimex lectularius, and was 2.8-fold more synergistic than piperonyl butoxide (PBO). CONCLUSIONS: PBH synergized the action of both type I and type II pyrethroids in a mosquito vector (Cx. p. quinquefasciatus) and in a public-health pest, C. lectularius, respectively, indicating a broad spectrum of action on blood-feeding insects. PBH appears to have residual properties similar to permethrin and is itself non-toxic, unlike PBO, and therefore should be compatible with existing pyrethroid formulations used for insecticide-treated nets and home/residential sprays. PMID- 25044361 TI - Comparison of lipids, fatty acids and volatile compounds of various kumquat species using HS/GC/MS/FID techniques. AB - BACKGROUND: Kumquat (Fortunella spp.) is one of the important fruit species that has been introduced into Turkey recently. It is well adapted to the Mediterranean region in Turkey. Early research of kumquat was started on adaptation and pomological traits, and only a few studies have been concerned with chemical content. After understanding the health benefits of kumquat fruits farmers started their plantations in Turkey. Thus in this study the fruits of five kumquat species - Fortunella margarita (Lour.) Swingle, F. crassifolia Swingle, F. obovata Hort. ex Tanaka, F. hindsii (Champ. ex Benth.) Swingle, and limequat [Citrus aurantifolia * F. japonica (Thumb.)] - were compared based on their lipids, fatty acids and volatile profiles. The lipids, fatty acids and volatile profiles were determined by using gas chromatography with flame ionisation detection (GC/FID) and headspace gas chromatography mass spectrometry (HS-GC/MS) techniques. Volatile constituents of kumquat fruits were isolated by a headspace method. RESULTS: The total lipid content (%) of kumquat species ranged from 0.26% to 0.37%. The polyunsaturated fatty acids were detected in a higher amount compared to the monounsaturated fatty acids and saturated fatty acids, respectively. The headspace technique led to the identification of 39 compounds and among a total of 39 constituents identified, d-limonene was the most abundant compound, comprising 67.78-88.72%. The results indicated that kumquats are rich in dietary and health benefits. CONCLUSION: Thirty-nine compounds were identified and terpenes were the major chemical group in all kumquat genotypes. Esters, alcohols, aldehydes and ketones were also detected. The present study revealed that the kumquat fruits have a valuable levels of health beneficial chemo preventive effects and genotypes varied based on their lipid, fatty acids and volatile constituents. PMID- 25044362 TI - Reply to Hughes et al.: Impact of cleaning and other interventions on the reduction of hospital-acquired Clostridium difficile infections in two hospitals in England assessed using a breakpoint model. PMID- 25044363 TI - Carbolithiation of chloro-substituted alkynes: a new access to vinyl carbenoids. AB - The intramolecular carbolithiation of a series of chloro-substituted alkynes leads to exocyclic alkylidene carbenoids of which both nucleophilic and electrophilic characters can be drove. A sole stereoselective 5-exo-dig addition takes place, probably because of a strong and persisting Li-Cl interaction arising before the transition state. PMID- 25044364 TI - Appearance of the endometrium at saline contrast sonohysterography in the luteal phase of the menstrual cycle: a prospective observational study. AB - OBJECTIVE: To describe the ultrasonographic morphology of the endometrium at saline contrast sonohysterography (SCSH) performed in the luteal phase of the menstrual cycle in women 20-38 years of age with regular menstrual cycles. METHODS: The study included 26 women (median age 33 (range, 20-38) years) with regular menstrual cycles referred for hysterosalpingo-contrast sonography (HyCoSy) as part of infertility work-up (n = 19) or before donor insemination in lesbian couples (n = 7). SCSH and HyCoSy were performed 6-10 days after a positive luteinizing hormone (LH) urinary self-test. Three-dimensional (3D) ultrasound volumes of the uterus were saved with and without saline in the uterine cavity. The results presented are based on offline analysis of the 3D volumes. RESULTS: Median endometrial thickness was 10.4 (range, 6.0-17.3) mm. Twelve (46%; 95% CI, 27-65%) of the 26 women had endometrial folds at SCSH. The number of folds varied between 1 and 6 (median 3). Endometrial thickness was similar in women with and without endometrial folds (median endometrial thickness 10.7 (range, 6.0-17.3) mm vs 10.1 (range, 6.1-14.4) mm; P = 0.257), and the amount of saline in the uterine cavity did not differ between the two groups (median 8.6 (range, 5.2-12.9) mm vs 7.1 (range, 3.2-13.3) mm; P = 0.527). In two women with endometrial folds at two-dimensional (2D) or 3D-SCSH, focal endometrial pathology (polyp) was suspected, but hysteroscopically resected endometrium showed normal histology. CONCLUSIONS: One should avoid performing SCSH in the luteal phase of the menstrual cycle, not only because there may be a fertilized ovum in the genital tract but also because endometrial folds are common in this phase and may lead to overdiagnosis of focal endometrial pathology, such as polyps. If, for some reason, SCSH is performed in the luteal phase and the results are equivocal, the procedure should be repeated in the follicular phase. PMID- 25044365 TI - Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients. AB - Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo- and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable. PMID- 25044366 TI - Biodegradable nanofibrous polymeric substrates for generating elastic and flexible electronics. AB - Biodegradable nanofibrous polymeric substrates are used to fabricate suturable, elastic, and flexible electronics and sensors. The fibrous microstructure of the substrate makes it permeable to gas and liquid and facilitates the patterning process. As a proof-of-principle, temperature and strain sensors are fabricated on this elastic substrate and tested in vitro. The proposed system can be implemented in the field of bioresorbable electronics and the emerging area of smart wound dressings. PMID- 25044368 TI - Tailoring intermolecular interactions for efficient room-temperature phosphorescence from purely organic materials in amorphous polymer matrices. AB - Herein we report a rational design strategy for tailoring intermolecular interactions to enhance room-temperature phosphorescence from purely organic materials in amorphous matrices at ambient conditions. The built-in strong halogen and hydrogen bonding between the newly developed phosphor G1 and the poly(vinyl alcohol) (PVA) matrix efficiently suppresses vibrational dissipation and thus enables bright room-temperature phosphorescence (RTP) with quantum yields reaching 24%. Furthermore, we found that modulation of the strength of halogen and hydrogen bonding in the G1-PVA system by water molecules produced unique reversible phosphorescence-to-fluorescence switching behavior. This unique system can be utilized as a ratiometric water sensor. PMID- 25044369 TI - Lithium chloride promotes the odontoblast differentiation of hair follicle neural crest cells by activating Wnt/beta-catenin signaling. AB - The Wnt/beta-catenin signalling pathway contributes to the maintenance of pluripotency and partial reprogramming of stem cells. Postnatal neural crest cells (NCCs) can differentiate into odontoblast-like cells due to their multi potential property, but further endeavors need to be made to promote odontogenic differentiation of hair follicle neural crest cells (hfNCCs). This study investigated whether the Wnt pathway activator lithium chloride (LiCl) promotes odontoblast differentiation of hfNCCs. Change of proliferation, beta-catenin and pluripotency markers of hfNCCs were examined after treatment with LiCl. An in vitro odontoblast differentiation model of hfNCCs was built using dental cell conditioned media (DC-CM). The effects of LiCl on odontoblast differentiation of hfNCCs showed that proliferation and expression of beta-catenin in the cytosolic and nuclear compartments were increased in the LiCl-treated hfNCCs, and the pluripotency marks, Oct4, Klf4, Sox2 and Nanog, were more highly expressed in the LiCl-treated group than in the control group. The odontoblast markers such as DSP, DMP1 and Runx2, could be detected in hfNCCs induced by DC-CM, but in LiCl treated group all three markers had stronger expression. Expression of beta catenin in the nuclear of LiCl-treated hfNCCs induced by DC-CM was higher than in the other groups. The data indicate that the Wnt pathway activator LiCl can promote proliferation and odontoblast differentiation of hfNCCs, and chemical approaches are of benefit in obtaining more desirable seed cell types for cell based therapies. PMID- 25044367 TI - Noncoding RNAs and the borders of heterochromatin. AB - Eukaryotic genomes contain long stretches of repetitive DNA sequences, which are the preferred sites for the assembly of heterochromatin structures. The formation of heterochromatin results in highly condensed chromosomal domains that limit the accessibility of DNA to the transcription and recombination machinery to maintain genome stability. Heterochromatin has the tendency to spread, and the formation of boundaries that block heterochromatin spreading is required to maintain stable gene expression patterns. Recent work has suggested that noncoding RNAs (ncRNAs) are involved in regulating boundary formation in addition to their well established roles in chromatin regulation. Here, we present a review of our current understanding of the involvement of ncRNA at the boundaries of heterochromatin, highlighting their mechanisms of action in different settings. PMID- 25044370 TI - Spatiotemporal characteristics of electrocortical brain activity during mental calculation. AB - Mental calculation is a complex mental procedure involving a frontoparietal network of brain regions. Functional MRI (fMRI) studies have revealed interesting characteristics of these regions, but the precise function of some areas remains elusive. In the present study, we used electrocorticographic (ECoG) recordings to chronometrically assess the neuronal processes during mental arithmetic. A calculation task was performed during presurgical 3T fMRI scanning and subsequent ECoG monitoring. Mental calculation induced an increase in fMRI blood oxygen level dependent signal in prefrontal, parietal and lower temporo-occipital regions. The group-fMRI result was subsequently used to cluster the implanted electrodes into anatomically defined regions of interest (ROIs). We observed remarkable differences in high frequency power profiles between ROIs, some of which were closely associated with stimulus presentation and others with the response. Upon stimulus presentation, occipital areas were the first to respond, followed by parietal and frontal areas, and finally by motor areas. Notably, we demonstrate that the fMRI activation in the middle frontal gyrus/precentral gyrus is associated with two subfunctions during mental calculation. This finding reveals the significance of the temporal dynamics of neural ensembles within regions with an apparent uniform function. In conclusion, our results shed more light on the spatiotemporal aspects of brain activation during a mental calculation task, and demonstrate that the use of fMRI data to cluster ECoG electrodes is a useful approach for ECoG group analysis. PMID- 25044371 TI - Conversion of toluene and water to methylcyclohexane and oxygen using niobium doped strontium titanate photoelectrodes. AB - Methylcyclohexane (MCH) is regarded as a promising hydrogen carrier that enables hydrogen to be harnessed as an alternate fuel source, which paves the way to a clean-energy future. A photoelectrochemical (PEC) system with a Nb:SrTiO3 photoelectrode for oxygen evolution from an aqueous electrolyte and a Pt/C electrode for toluene (TL) hydrogenation to MCH was investigated under UV irradiation. A Nb:SrTiO3 single-crystal electrode and an ionomer/Pt/C membrane electrode assembly (MEA) were used as the photoanode and cathode, respectively. A steady-state current density of 0.12 mA cm(-2) was observed for the two-electrode system without any bias voltage for >2 h, and a Faradaic efficiency of 97% was obtained for MCH production from TL. This is the first demonstration of the production of MCH from TL and water using only light energy. This means that light energy was converted directly into MCH from TL and water without any electricity. The PEC properties of the devices are discussed. PMID- 25044372 TI - Outcomes associated with fractional flow-guided revascularization: a meta analysis. AB - BACKGROUND: Deferral of revascularization for abnormal but nonischemic lesions is usually recommended; however, the long-term outcome of this approach is not well known. HYPOTHESIS: Deferral of nonischemic lesions will be associated with a low frequency of adverse events. METHODS: A PubMed search of the MEDLINE database identified studies that reported clinical outcomes among patients who had fractional flow reserve-guided revascularization. We further categorized studies into 2 subgroups: left main and non-left main coronary artery lesions. Baseline demographics and clinical outcome data were extracted by 3 independent reviewers. Fixed and random effects summary risk ratios were constructed using Mantel Haenszel and DerSimonian-Laird models, respectively. The primary outcome was the composite of death, myocardial infarction, and revascularization. RESULTS: From 741 potential studies, 17 were included in the meta-analysis (n = 2975 participants), 8 in the left main subgroup (n = 595) and 9 studies (n = 2380) in non-left main subgroup. In the left main subgroup, the incidence of the composite outcome was 15.3% in the no-ischemia/deferral group vs 14.3% in the ischemia/revascularization group (risk ratio [RR] = 1.13, 95% confidence interval [CI]: 0.76-1.68, P = 0.54, I(2) = 3.7%). In the non-left main subgroup, the incidence of the composite outcome was 9.2% in the no-ischemia/deferral group vs 18.8% in the ischemia/revascularization group (RR = 0.42, 95% CI: 0.34-0.52, P < 0.0001, I(2) = 20.7%). CONCLUSIONS: Patients with left main coronary disease had a relatively high incidence of adverse cardiovascular events, which was similar in both the deferral and revascularization groups. In patients with non-left main disease, ischemia was associated with worse outcomes despite revascularization. PMID- 25044373 TI - Remote sulfonamido group enhances reactivity and selectivity for asymmetric Michael addition of nitroalkanes to alpha,beta-unsaturated aldehydes. AB - The pyrrolidine-camphorsulfonamide-based catalyst 1 a catalyzes the enantioselective conjugate addition of nitroalkanes to alpha,beta-unsaturated aldehydes in the presence of five equivalents of water in iPrOH to give the corresponding chiral Michael adducts in good yields and high enantioselectivities (up to 99% ee) with a catalyst loading as low as 1 mol%. PMID- 25044374 TI - Effect of tempol on redox homeostasis and stress tolerance in mimetically aged Drosophila. AB - We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol, a membrane permeable antioxidant, affects the type and magnitude of oxidative damage and stress tolerance through mimetic aging process in Drosophila. Drosophila colonies were randomly divided into three groups: (1) no D galactose, no tempol; (2) D-galactose without tempol; (3) D-galactose, but with tempol. Mimetic aging was induced by d-galactose administration. The tempol administered flies received tempol at the concentration of 0.2% in addition to d galactose. Thiobarbituric acid reacting substance (TBARS) concentrations, advanced oxidation protein products (AOPPs), Cu,Zn-superoxide dismutase (Cu,Zn SOD), sialic acid (SA) were determined. Additionally, stress tolerances were tested. Mimetically aged group without tempol led to a significant decrease in tolerance to heat, cold, and starvation (P < 0.05), but tempol was used for these parameters. The Cu,Zn-SOD activity and SA concentrations were lower in both mimetically aged and tempol-administered Drosophila groups compared to control (P < 0.05), whereas there were no significantly difference between mimetically aged and tempol-administered groups. Mimetically aged group without tempol led to a significant increase in tissue TBARS and AOPPs concentrations (P < 0.05). Coadministration of tempol could prevent these alterations. Scavenging ROS using tempol also restores redox homeostasis in mimetically aged group. Tempol partly restores age-related oxidative injury and increases stress tolerance. PMID- 25044375 TI - Affinity maturation of Cry1Aa toxin to the Bombyx mori cadherin-like receptor by directed evolution based on phage display and biopanning selections of domain II loop 2 mutant toxins. AB - Directed evolution of a Cry1Aa toxin using phage display and biopanning was performed to generate an increased binding affinity to the Bombyx mori cadherin like receptor (BtR175). Three mutant toxins (371 WGLA374 , 371 WPHH374 , 371 WRPQ374 25) with 16-, 16-, and 50-fold higher binding affinities, respectively, for BtR175 were selected from a phage library containing toxins with mutations in domain II loop 2. However, the observed toxicities of the three mutants against B. mori larvae and cultured cells expressing the BtR175 toxin-binding region did not increase, suggesting that increased binding affinity to cadherins does not contribute to the insecticidal activity. Affinity maturation of a Cry toxin to a receptor via directed evolution was relatively simple to achieve, and seems to have potential for generating a toxin with increased insecticidal activity. PMID- 25044376 TI - Effect of weather on back pain: results from a case-crossover study. AB - OBJECTIVE: To investigate the influence of various weather conditions on risk of low back pain. METHODS: We conducted a case-crossover study in primary care clinics in Sydney, Australia. A total of 993 consecutive patients with a sudden, acute episode of back pain were recruited from October 2011 to November 2012. Following the pain onset, demographic and clinical data about the back pain episode were obtained for each participant during an interview. Weather parameters (temperature, relative humidity, air pressure, wind speed, wind gust, wind direction, and precipitation) were obtained from the Australian Bureau of Meteorology for the entire study period. Weather exposures in the case window (time when participants first noticed their back pain) were compared to exposures in 2 control time windows (same time duration, 1 week and 1 month before the case window). RESULTS: Temperature, relative humidity, air pressure, wind direction, and precipitation showed no association with onset of back pain. Higher wind speed (odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.04-1.32], P = 0.01 for an increase of 11 km/hour) and wind gust (OR 1.14 [95% CI 1.02-1.28], P = 0.02 for an increase of 14 km/hour) increased the odds of pain onset. CONCLUSION: Weather parameters that have been linked to musculoskeletal pain such as temperature, relative humidity, air pressure, and precipitation do not increase the risk of a low back pain episode. Higher wind speed and wind gust speed provided a small increase in risk of back pain, and although this reached statistical significance, the magnitude of the increase was not clinically important. PMID- 25044377 TI - Short-term outcomes of seniors aged 80 years and older with acute illness: hospitalist care by geriatricians and other internists compared. AB - BACKGROUND: Although acute geriatric units have improved the outcomes of hospitalized seniors, it is uncertain as to whether hospitalist care by geriatricians outside of these units confers similar benefit. OBJECTIVE: To determine whether hospitalist care by geriatricians reduces short-term mortality and readmission, and length of stay (LOS) for seniors aged 80 years and older with acute medical illnesses compared with care by other internists. DESIGN: Retrospective cohort study using administrative and chart review data on demographic, admission-related, and clinical information of hospital episodes. SETTING: General internal medicine department of an acute-care hospital in Singapore from 2005 to 2008. PATIENTS: Seniors aged 80 years and older with specific focus on 2 subgroups with premorbid functional impairment and acute geriatric syndromes. INTERVENTION: Hospitalist care by geriatricians compared with care by other internists. MEASURES: Hospital mortality, 30-day mortality or readmission, and LOS. RESULTS: For 1944 hospital episodes (intervention: 968, control: 976), there was a nonsignificant trend toward lower hospital mortality (15.5% vs 16.9%) but not 30-day mortality or readmission, or LOS for care by geriatricians compared with care by other internists. A marginally stronger trend toward lower hospital mortality for care by geriatricians among those with acute geriatric syndromes (20.2% vs 23.1%) was observed. Similar treatment effects were found after adjustment for demographic, admission-related, and clinical factors. CONCLUSIONS: For seniors aged 80 years and over with acute medical illness, hospitalist care by geriatricians did not significantly reduce short-term mortality, readmission, or LOS, compared with care by other internists. PMID- 25044378 TI - One-step, room-temperature synthesis of glutathione-capped iron-oxide nanoparticles and their application in in vivo T1-weighted magnetic resonance imaging. AB - The room-temperature, aqueous-phase synthesis of iron-oxide nanoparticles (IO NPs) with glutathione (GSH) is reported. The simple, one-step reduction involves GSH as a capping agent and tetrakis(hydroxymethyl)phosphonium chloride (THPC) as the reducing agent; GSH is an anti-oxidant that is abundant in the human body while THPC is commonly used in the synthesis of noble-metal clusters. Due to their low magnetization and good water-dispersibility, the resulting GSH-IO NPs, which are 3.72 +/- 0.12 nm in diameter, exhibit a low r2 relaxivity (8.28 mm(-1) s(-1)) and r2/r1 ratio (2.28)--both of which are critical for T1 contrast agents. This, together with the excellent biocompatibility, makes these NPs an ideal candidate to be a T1 contrast agent. Its capability in cellular imaging is illustrated by the high signal intensity in the T1-weighted magnetic resonance imaging (MRI) of treated HeLa cells. Surprisingly, the GSH-IO NPs escape ingestion by the hepatic reticuloendothelial system, enabling strong vascular enhancement at the internal carotid artery and superior sagittal sinus, where detection of the thrombus is critical for diagnosing a stroke. Moreover, serial T1- and T2-weighted time-dependent MR images are resolved for a rat's kidneys, unveiling detailed cortical-medullary anatomy and renal physiological functions. The newly developed GSH-IO NPs thus open a new dimension in efforts towards high performance, long-circulating MRI contrast agents that have biotargeting potential. PMID- 25044379 TI - PPG peptide nucleic acids that promote DNA guanine quadruplexes. AB - Recent studies have shown that guanine-rich (G-rich) sequences with the potential to form quadruplexes might play a role in normal transcription as well as overexpression of oncogenes. Chemical tools that allow examination of the specific roles of G-quadruplex formation in vivo, and their association with gene regulation will be essential to understanding the functions of these quadruplexes and might lead to beneficial therapies. Properly designed peptide nucleic acids (PNAs) can invade G-rich DNA duplexes and induce the formation of a G-quadruplex in the free DNA strand. Replacing guanines in the PNA sequence with pyrazolo[3,4 d]pyrimidine guanine (PPG) nucleobases eliminates G-quadruplex formation with PNA and promotes invasion of the target DNA. PMID- 25044380 TI - Failure analysis of clinical trials to test the amyloid hypothesis. PMID- 25044382 TI - Elemental F2 with transannular dienes: regioselectivities and mechanisms. AB - Three reaction paths, namely, molecule-induced homolytic, free radical, and electrophilic, were modeled computationally at the MP2 level of ab initio theory and studied experimentally for the reaction of F2 with the terminal dienes of bicyclo[3.3.1]nonane series. The addition of fluorine is accompanied by transannular cyclization to the adamantane derivatives in which strong evidence for the electrophilic mechanism both in nucleophilic (acetonitrile) and non nucleophilic (CFCl3 , CHCl3 ) solvents were found. The presence of KF in CFCl3 and CHCl3 facilitates the addition and substantially reduces the formation of tar products. PMID- 25044383 TI - Pentoxifylline does not alter the concentration of hepcidin in chronic kidney disease patients undergoing hemodialysis. AB - INTRODUCTION: Anemia is a frequent condition in patients with chronic kidney disease due to a reduction in the production of erythropoietin. Patients with inflammation respond less well to treatment with erythropoietin, possibly because the increased production of hepcidin reduces the availability of iron for hematopoiesis. Some studies suggest that pentoxifylline has anti-inflammatory properties and could be used as adjuvant therapy in the treatment of anemia. OBJECTIVE: The aim of this study was to analyze the effect of pentoxifylline on serum hepcidin in chronic hemodialysis patients with inflammation. METHODS: 71 adult patients on hemodialysis with C-reactive protein (CRP) >=0.5 mg/dl in screening tests; patients were randomized to the treatment group (oral pentoxifylline 400 mg/thrice-weekly) or the control group for 3 months follow-up. RESULTS: During the study, a decrease in hemoglobin, transferrin saturation, and hepcidin was observed in both groups. However, these reductions were related to the time and not to the drug. There was no difference in the concentrations of CRP, ferritin, and albumin over time in either group. CONCLUSIONS: The use of this amount of pentoxifylline did not modify the serum levels of hepcidin in this population. PMID- 25044384 TI - Transfer of low-molecular weight single-stranded DNA through the membrane of a high-flux dialyzer. AB - PURPOSE: Microbial contamination is often present in dialysate used for hemodialysis. Small single-stranded bacterial DNA sequences are capable of activating human inflammatory pathways, through mechanisms that include the Toll like-receptor 9, and dialysis patients frequently show severe inflammation. Since these molecules have been found in dialysate and in patients' bloodstreams, we studied the potential of low-molecular weight DNA sequences, of the same structure as found in bacteria, to cross from the dialyzer circuit to the blood circuit of a dialysis filter. METHODS: The mass transfer of DNA fragments across a high-flux dialyzer was evaluated with an in vitro dialysis model, in both conventional dialysis and pure convection mode. Measurement of DNA was performed by HPLC. RESULTS: In dialysis mode, these mass transfer coefficients were calculated for different single-stranded DNA chain lengths: 5-bases = 28.5%, 9 bases = 20.5%, 20-bases = 9.4%, 35-bases = 2.4%, 50-bases and 100-bases, no transfer detected. In convection mode, these sieving coefficients were calculated: 5-bases = 1.0, 9-bases = 1.0, 20-bases = 0.68, 35-bases = 0.40, 50 bases = 0.17, 100-bases, no convective transfer detected. The physical size of DNA molecules could be the major factor that influences their movement through dialyzer pores. CONCLUSIONS: This study establishes that significant transfer across the dialyzer may occur with single-stranded DNA in the size range of 20 bases or less. These findings need to be confirmed with an in vitro whole blood model and with clinical investigations. Previous studies have described the clinical benefits of achieving high-purity dialysate. Precautions are warranted to minimize the presence of these DNA compounds in fluids utilized for hemodialysis treatment. PMID- 25044385 TI - Six-minute walk distance predicts VO2 (max) in patients supported with continuous flow left ventricular assist devices. AB - BACKGROUND: Six-minute walk distance (6MWD) and maximal oxygen uptake (VO2 max ) are used as prognostic tools in patients with heart failure (HF). Whether these tests provide similar information in the LVAD population is not known. METHODS: Eight patients supported with VentrAssist rotary blood pump LVADs, underwent three days of testing that included 6MWD and VO2 max at normal, high or low speeds, generating twenty-four paired results. RESULTS: The mean 6MWD was 438 (+/ 90 SD) m and the mean VO2 (max) was 14.12 (+/-1.87) ml/kg/min. There was a modest correlation between VO2 (max) and 6MWD (r = 0.56 p = 0.004), which improved (r = 0.72 p = 0.002) when patients with higher resting Pro BNP levels and larger left ventricular end diastolic diameters (LVEDD) were excluded. CONCLUSIONS: 6MWD is correlated with VO2 (max) in LVAD supported patients, with higher correlations in patients with better underlying cardiac function. PMID- 25044386 TI - From histology and imaging data to models for in-stent restenosis. AB - The implantation of stents has been used to treat coronary artery stenosis for several decades. Although stenting is successful in restoring the vessel lumen and is a minimally invasive approach, the long-term outcomes are often compromised by in-stent restenosis (ISR). Animal models have provided insights into the pathophysiology of ISR and are widely used to evaluate candidate drug inhibitors of ISR. Such biological models allow the response of the vessel to stent implantation to be studied without the variation of lesion characteristics encountered in patient studies.This paper describes the development of complementary in silico models employed to improve the understanding of the biological response to stenting using a porcine model of restenosis. This includes experimental quantification using microCT imaging and histology and the use of this data to establish numerical models of restenosis. Comparison of in silico results with histology is used to examine the relationship between spatial localization of fluid and solid mechanics stimuli immediately post-stenting. Multi-scale simulation methods are employed to study the evolution of neointimal growth over time and the variation in the extent of neointimal hyperplasia within the stented region. Interpretation of model results through direct comparison with the biological response contributes to more detailed understanding of the pathophysiology of ISR, and suggests the focus for follow-up studies.In conclusion we outline the challenges which remain to both complete our understanding of the mechanisms responsible for restenosis and translate these models to applications in stent design and treatment planning at both population based and patient-specific levels. PMID- 25044387 TI - Bioengineered vascular scaffolds: the state of the art. AB - To date, there is increasing clinical need for vascular substitutes due to accidents, malformations, and ischemic diseases. Over the years, many approaches have been developed to solve this problem, starting from autologous native vessels to artificial vascular grafts; unfortunately, none of these have provided the perfect vascular substitute. All have been burdened by various complications, including infection, thrombogenicity, calcification, foreign body reaction, lack of growth potential, late stenosis and occlusion from intimal hyperplasia, and pseudoaneurysm formation. In the last few years, vascular tissue engineering has emerged as one of the most promising approaches for producing mechanically competent vascular substitutes. Nanotechnologies have contributed their part, allowing extraordinarily biostable and biocompatible materials to be developed. Specifically, the use of electrospinning to manufacture conduits able to guarantee a stable flow of biological fluids and guide the formation of a new vessel has revolutionized the concept of the vascular substitute. The electrospinning technique allows extracellular matrix (ECM) to be mimicked with high fidelity, reproducing its porosity and complexity, and providing an environment suitable for cell growth. In the future, a better knowledge of ECM and the manufacture of new materials will allow us to "create" functional biological vessels - the base required to develop organ substitutes and eventually solve the problem of organ failure. PMID- 25044388 TI - HeartWare LVAD implantation in a patient with a rare ARVD: Carvajal syndrome. AB - Carvajal syndrome is a variant of Naxos disease characterized by a predominant left ventricular involvement, wooly or curly hair, and palmoplantar keratoderma or similar skin disorders. We describe the clinical and therapeutic course of a 14-year old boy affected by this syndrome, in whom a progressive biventricular failure developed at 13 years of age. The patient was hospitalized in the pediatric department 3 months earlier after the onset of cardiac arrhythmias and he critically worsened with signs and symptoms of biventricular cardiac failure. Over massive inotropic agent infusion, the patient was transferred to our intensive-care-unit in order to be haemodinamically stabilized with a ventricular assist device (VAD) and thereafter transplanted. PMID- 25044389 TI - Evaluation of decellularized extracellular matrix of skeletal muscle for tissue engineering. AB - OBJECTIVE: We evaluated the effectiveness of enzyme-detergent methods on cell removal of mouse skeletal muscle tissue and assessed the biocompatibility of the decellularized tissues by an animal model. METHODS: The mouse latissimus dorsi (LD) muscles underwent decellularization with different enzyme-detergent mixtures (trypsin-Triton X-100, trypsin-sodium dodecyl sulfate (SDS), trypsin-Triton X-100 SDS). The effectiveness of decellularization was assessed by histology and DNA assay. The content in collagen and glycosaminoglycan was measured. The biomechanical property was evaluated in uniaxial tensile tests. For biocompatibility, the decellularized muscle specimens were implanted in situ and the tissue samples were retrieved at day 10, 20, and 30, to evaluate the host graft inflammatory reaction. RESULTS: Extensive washing of the mouse LD muscles with an enzyme-detergent mixture (trypsin and Triton X-100) can yield an intact matrix devoid of cells, depleted of more than 93% nuclear component and exhibiting comparable biomechanical properties with native tissue. In addition, we observed increased infiltration of inflammatory cells into the scaffold initially, and the presence of M1 (CD68)-phenotype mononuclear cells 10 days after implantation, which decreased gradually until day 30. CONCLUSIONS: The enzyme-detergent method can serve as an effective method for cell removal of mouse skeletal muscle. In short-term follow-up, the implanted scaffolds revealed mild inflammation with fibrotic tissue formation. The decellularized extracelluar matrix developed herein is shown to be feasible for further long-term study for detailed information about muscle regeneration, innervation, and angiogenesis in vivo. PMID- 25044390 TI - Indium acetate toxicity in male reproductive system in rats. AB - Indium, a rare earth metal characterized by high plasticity, corrosion resistance, and a low melting point, is widely used in the electronics industry, but has been reported to be an environmental pollutant and a health hazard. We designed a study to investigate the effects of subacute exposure of indium compounds on male reproductive function. Twelve-week old male Sprague-Dawley rats were randomly divided into test and control groups, and received weekly intraperitoneal injections of indium acetate (1.5 mg/kg body weight) and normal saline, respectively, for 8 weeks. Serum indium levels, cauda epididymal sperm count, motility, morphology, chromatin DNA structure, mitochondrial membrane potential, oxidative stress, and testis DNA content were investigated. The indium acetate-treated group showed significant reproductive toxicity, as well as an increased percentage of sperm morphology abnormality, chromatin integrity damage, and superoxide anion generation. Furthermore, positive correlations among sperm morphology abnormalities, chromatin DNA damage, and superoxide anion generation were also noted. The results of this study demonstrated the toxic effect of subacute low-dose indium exposure during the period of sexual maturation on male reproductive function in adulthood, through an increase in oxidative stress and sperm chromatin DNA damage during spermiogenesis, in a rodent model. PMID- 25044391 TI - Nickel-catalyzed cross-coupling of functionalized difluoromethyl bromides and chlorides with aryl boronic acids: a general method for difluoroalkylated arenes. AB - Transition-metal-catalyzed difluoroalkylation of aromatics remains challenging despite the importance of difluoroalkylated arenes in medicinal chemistry. Herein, the first successful example of nickel-catalyzed difluoroalkylation of aryl boronic acids is described. The reaction allows access to a variety of functionalized difluoromethyl bromides and chlorides, and paves the way to highly cost-efficient synthesis of a wide range of difluoroalkylated arenes. The notable features of this protocol are its high generality, excellent functional-group compatibility, low-cost nickel-catalyst, and practicality for gram-scale production, thus providing a facile method for applications in drug discovery and development. PMID- 25044392 TI - Effect of the readmission primary diagnosis and time interval in heart failure patients: analysis of English administrative data. AB - AIMS: To compare the predictors of unplanned readmission by primary diagnosis and time since discharge in heart failure (HF) patients. METHODS AND RESULTS: We used national hospital administrative data for England to analyse unplanned readmission by primary diagnosis (HF and non-HF) at 7, 30, 90, 182, and 365 days after the index discharge. A total of 84 212 adult patients had their first HF admission between April 2008 and March 2010; 14 104 (16.8%) died during the index admission and were excluded. Of the remaining 70 108, half were readmitted and 28.7% died during 1 year from discharge (overall mortality rate of 40.6%). Patients had an average of three co-morbidities. Hierarchical logistic regression showed that arrhythmias [odds ratio (OR) = 1.13] and valvular disease (OR = 1.12) had significantly higher odds only for HF readmission; dementia (OR = 1.29), stroke (OR = 1.29), and mental health conditions (OR = 1.25) had higher odds only for non-HF. Ischaemic heart disease, renal disease, and chronic lung disease predicted both. Same-day discharge occurred for 6% of patients and was strongly associated with higher readmission for HF at 7 days, less so thereafter, and not for non-HF after 7 days. Other relationships changed little between 7 and 365 days. Prior outpatient non-attendance was associated with 5-10% higher odds of any readmission per appointment missed. CONCLUSION: In HF patients, some predictors of readmission for HF, especially some common co-morbidities, differ from those for non-HF. In contrast, the time since discharge made little difference to the results. PMID- 25044393 TI - An unusual case of infective endocarditis involving a right coronary artery to superior vena cava fistula. AB - Coronary artery fistulas (CAFs) are rare and mostly congenital anomalous connections between a coronary artery and a cardiac chamber or great vessel. Most CAFs are small, asymptomatic, and found incidentally during cardiac imaging. However, they can lead to serious complications including myocardial infarction, congestive heart failure, arrhythmias, or fistula rupture. CAFs have been associated with infective endocarditis, but to our knowledge, this complication has never been reported involving an isolated CAF to an otherwise anatomically normal great vessel. We report the first case of this complication in a 49-year old man with a presumed streptococcus vegetation found within an isolated large, tortuous CAF connecting the right coronary artery to the superior vena cava. After completing antibiotic treatment, transcatheter closure of the CAF was performed. Since then, the patient has remained symptom-free. This case demonstrates that CAF closure is feasible following CAF-associated endocarditis, and that closure may represent a viable strategy for reducing risk of recurrent infection. PMID- 25044394 TI - Pheromone responsiveness is regulated by components of the Gpr1p-mediated glucose sensing pathway in Saccharomyces cerevisiae. AB - Many fungi have evolved mechanisms to assess environmental nutrient availability prior to the energy-intensive process of mating. In this study, we examined one such system in Saccharomyces cerevisiae, involving a glucose-sensing pathway mediated by Gpr1p and the pheromone-induced mating pathway. Initially we observed that the mating pathway in MATa cells is sensitive to environmental glucose depletion. This phenomenon can be partially reversed with a high glucose spike, but not with the addition of low levels of glucose. Deletion of the low-affinity glucose receptor, Gpr1p, eliminated this glucose-induced recovery of pheromone responsiveness. We then determined the impact of GPR1 deletion on the mating pathway and observed that, in all end points studied, the mating pathway response to pheromone is reduced in the absence of Gpr1p. Similarly, elimination of the Galpha for Gpr1p, Gpa2p, resulted in reduction in pheromone sensitivity in all assays studied. The negative effect of removing Gpr1p on mating pathway activation could be recovered by overexpressing the mating receptor, Ste2p. Furthermore, Ste2p levels are reduced in the absence of glucose and GPR1. These data suggest that activity of the GPCR-mediated mating pathway in S. cerevisiae is modulated by extracellular glucose concentrations through the only other GPCR in MATa cells, Gpr1p. PMID- 25044395 TI - N-acyl derivatives of 4-phenoxyaniline as neuroprotective agents. AB - Neuronal cell death is the main cause behind the progressive loss of brain function in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death-promoting factors into the cytosol have been revealed as the "point of no return" in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro-apoptotic Bcl-2 family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N-acyl-substituted derivatives of 4 phenoxyaniline that were screened for their potential to attenuate Bid-mediated neurotoxicity. These compounds provided significant protection against glutamate- and Bid-induced toxicity in cultured neurons. Substitution of the amino group in the 4-phenoxyaniline scaffold with 4-piperidine carboxylic acid and N hydroxyethyl-4-piperidine carboxylic acid yielded compounds that displayed significant neuroprotective activity at concentrations as low as 1 MUM. Furthermore, findings of a tBid-overexpression assay and real-time measurements of cell impedance support the hypothesis that these compounds indeed address the Bid protein. PMID- 25044396 TI - Direct optical generation of long-range charge-transfer states in organic photovoltaics. AB - Direct optical excitation of long-range charge-transfer (CT) states in organic photovoltaics is shown to be feasible, a fact that is ascribed to the very low but non-vanishing oscillator strength of each individual transition and the much higher density of states (DOS) as compared with their short-range counterparts. This finding provides a new framework to interpret the low-energy absorption spectra of photovoltaic devices and to correlate this property with the optoelectronic conversion process in working devices. PMID- 25044397 TI - Non-invasive prenatal testing for fetal aneuploidies in the first trimester of pregnancy. AB - OBJECTIVES: To evaluate the feasibility of non-invasive prenatal testing (NIPT) of maternal plasma samples collected from pregnant Chinese women in early gestation, between 8 + 0 and 12 + 6 weeks' gestation. METHODS: In this pilot study, 212 women with high-risk pregnancies were recruited at a single Chinese Hospital. Fetal aneuploidies associated with chromosomes 21, 18, 13, X and Y were detected by massively parallel sequencing of maternal plasma DNA samples. Invasive prenatal diagnosis by either chorionic villus sampling or amniocentesis and then karyotyping was offered to all women to confirm both positive and negative NIPT results. Fetal DNA fraction was also determined in male pregnancies, by the relative percentage of Y-chromosome sequences. All confirmed NIPT-negative pregnancies were followed up to birth and neonates were clinically evaluated for any symptoms of chromosomal disease. RESULTS: Autosomal aneuploidies trisomy 21 (n = 2), 18 (n = 1) and 13 (n = 1) were detected by NIPT and confirmed by amniocentesis and karyotyping. There were one false-positive 45,X sample and two false-negative samples associated with fetal karyotypes 47,XXY and 45,X[16]/47,XXX[14]. In the 100 male pregnancies, the median fetal DNA fraction was 8.54% and there was a trend towards an increasing fetal fraction from 8 + 0 to 12 + 6 weeks' gestation. The majority (95%) of pregnancies had a fetal DNA fraction > 4%, which is generally the limit for accurate aneuploidy detection by NIPT. Across this early gestational time period, there was a weak inverse relationship (R(2) = 0.186) between fetal DNA fraction and maternal weight. CONCLUSIONS: NIPT is highly reliable and accurate when applied to maternal DNA samples collected from pregnant women in the first trimester between 8 + 0 and 12 + 6 weeks. PMID- 25044398 TI - Increasing the maximum achievable strain of a covalent polymer gel through the addition of mechanically invisible cross-links. AB - Hydrogels and organogels made from polymer networks are widely used in biomedical applications and soft, active devices for which the ability to sustain large deformations is required. The strain at which polymer networks fracture is typically improved through the addition of elements that dissipate energy, but these materials require extra work to achieve a given, desired level of deformation. Here, the addition of mechanically "invisible" supramolecular crosslinks causes substantial increases in the ultimate gel properties without incurring the added energetic costs of dissipation. PMID- 25044399 TI - Ellagic acid antiinflammatory and antiapoptotic potential mediate renoprotection in cisplatin nephrotoxic rats. AB - Ellagic acid (EA) renoprotective effect against cisplatin (CIS)-induced nephrotoxicity remains elusive. Therefore, male Sprague-Dawley rats received CIS alone or EA (10 and 30 mg/kg, p.o.) for 5 days before and after CIS injection. CIS increased serum levels of blood urea nitrogen, creatinine, gamma-glutamyl transferase, and reduced those of albumin and total protein. It also raised serum endothelin-1, as well as serum and renal nitric oxide, tumor necrosis factor alpha, and monocyte chemoattractant protein-1. CIS enhanced the renal caspase-3, hemeoxygenase (HO)-1, nuclear factor-kappaB, and inducible nitric oxide. EA hampered CIS-induced nephrotoxicity manifested by an enhancement of the glomerular filtration rate which was associated by the reduction of inflammatory mediators and the apoptotic marker in the serum and/or kidney. The present study discloses that EA suppresses HO-1 and, its renoprotection is also linked to its anti-inflammatory and antiapoptotic properties, as well as the reduction of nitric oxide and endothelin-1. PMID- 25044400 TI - Effect of social support and donation-related concerns on ambivalence of living liver donor candidates. AB - Ambivalence in the decision-making process for living liver donors has the potential to result in their experiencing a negative mental status. To promote donor candidates' well-being, it is important to study the factors related to ambivalence. Thus, the aim of this study was to explore the ambivalence of living liver donor candidates and to investigate the effect of social support and donation-related concerns on their ambivalence. A cross-sectional design was used. In total, 100 living liver donor candidates who underwent a preoperative evaluation between April and October 2009 were recruited for the study. Participants completed a self-administered questionnaire that contained items related to ambivalence, donation-related concerns, and social support. The mean score for ambivalence was 3.14 (standard deviation = 1.8), and the median was 3. Only 7% of the study sample reported no ambivalence during the assessment stage. Ambivalence was positively correlated with donation-related concerns (physical concerns, r = 0.39; psychosocial concerns, r = 0.43; financial concerns, r = 0.29) and negatively correlated with social support (r = -0.16 to -0.33). Those with psychosocial concerns had significantly worse ambivalence (beta = 0.29, P = 0.03), but social support mitigated ambivalence (beta = -0.34, P = 0.01). When intimacy and social support were included in the model, the effect of psychosocial concerns on ambivalence became nonsignificant (beta = 0.24, P = 0.08). Ambivalence is common among living liver donor candidates, but instrumental social support can mediate the negative effect of donation-related concerns. Recommendations include providing appropriate social support to minimize donation-related concerns and, thus, to reduce the ambivalence of living liver candidates. PMID- 25044401 TI - A simple and sensitive turn-on fluorescence probe for detection of cetyltrimethylammonium bromide in aqueous samples. AB - The interaction of acid (PTCA) with cetyltrimethylammonium bromide (CTAB) has been studied by fluorescence spectroscopy. The fluorescence of PTCA can be greatly enhanced by the addition of CTAB, due to the formation a fluorescent supramolecular compound. Under optimum conditions, the enhancement intensity of fluorescence was proportional to the concentration of CTAB over a range of 0-4.5 umol L(-1) . Its detection limit was 0.057 umol L(-1) , which was lower than reported previously. Compared with other methods that have been reported to determine CTAB, this method has high sensitivity, stability and wide linear range and it can be used satisfactorily for the determination of CTAB in aqueous samples. PMID- 25044402 TI - Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease. AB - In a 6-month double-blind, placebo-controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON-time without increasing dyskinesia. Further long-term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON-time over 24 months. Other efficacy endpoints included change in ON-time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2-year, controlled study of add-on safinamide in mid-to-late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON-time (without troublesome dyskinesia), OFF-time, activities of daily living, motor symptoms, quality of life, and symptoms of depression. PMID- 25044403 TI - MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1. AB - Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR-200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA-MB-231 and BT549) vs. two representative luminal cancer cells (MCF-7 and BT474). The results revealed practically lower expression of miR-200c in the two basal cancer cell lines and higher expression of miR-200c in luminal cancer cells compared to the normal breast epithelial cell line MCF-10A. Ectopic expression of miR-200c in MDA-MB-231 cells inhibited irradiation-induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR-200c involved in irradiation-induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR 200c vs. UBQLN1 and LC3. These results indicate that the identified miR 200c/UBQLN1-mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy. PMID- 25044404 TI - Contrasting soil microbial community functional structures in two major landscapes of the Tibetan alpine meadow. AB - The grassland and shrubland are two major landscapes of the Tibetan alpine meadow, a region very sensitive to the impact of global warming and anthropogenic perturbation. Herein, we report a study showing that a majority of differences in soil microbial community functional structures, measured by a functional gene array named GeoChip 4.0, in two adjacent shrubland and grassland areas, were explainable by environmental properties, suggesting that the harsh environments in the alpine grassland rendered niche adaptation important. Furthermore, genes involved in labile carbon degradation were more abundant in the shrubland than those of the grassland but genes involved in recalcitrant carbon degradation were less abundant, which was conducive to long-term carbon storage and sequestration in the shrubland despite low soil organic carbon content. In addition, genes of anerobic nitrogen cycling processes such as denitrification and dissimilatory nitrogen reduction were more abundant, shifting soil nitrogen cycling toward ammonium biosynthesis and consequently leading to higher soil ammonium contents. We also noted higher abundances of stress genes responsive to nitrogen limitation and oxygen limitation, which might be attributed to low total nitrogen and higher water contents in the shrubland. Together, these results provide mechanistic knowledge about microbial linkages to soil carbon and nitrogen storage and potential consequences of vegetation shifts in the Tibetan alpine meadow. PMID- 25044406 TI - Reply: To PMID 24623375. PMID- 25044405 TI - Production of IgG autoantibody requires expression of activation-induced deaminase in early-developing B cells in a mouse model of SLE. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of pathogenic IgG antinuclear antibodies. Pathogenic IgG autoantibody production requires B-cell activation, leading to the production of activation induced deaminase (AID) and class switching of IgM genes to IgG. To understand how and when B cells are activated to produce these IgG autoantibodies, we studied cells from 564Igi, a mouse model of SLE. 564Igi mice develop a disease profile closely resembling that found in human SLE patients, including the presence of IgG antinucleic acid Abs. We have generated 564Igi mice that conditionally express an activation-induced cytidine deaminase transgene (Aicda(tg) ), either in all B cells or only in mature B cells. Here, we show that class-switched pathogenic IgG autoantibodies were produced only in 564Igi mice in which AID was functional in early-developing B cells, resulting in loss of tolerance. Furthermore, we show that the absence of AID in early-developing B cells also results in increased production of self-reactive IgM, indicating that AID, through somatic hypermutation, contributes to tolerance. Our results suggest that the pathophysiology of clinical SLE might also be dependent on AID expression in early-developing B cells. PMID- 25044407 TI - Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats. AB - We have shown recently that acute administration of ethanol modulates the expression of brain-derived neurotrophic factor (BDNF) in several rat brain areas known to be involved in the development of addiction to ethanol and other drugs of abuse, suggesting that BDNF may be a factor contributing to the neuroadaptive changes set in motion by ethanol exposure. The purpose of the present study was to further clarify the role of BDNF in reinforcement from ethanol and in the development of addiction to ethanol by specifying the effect of acute administration of ethanol (1.5 or 3.0 g/kg i.p.) on the expression profile of BDNF mRNA in the ventral tegmental area and in the terminal areas of the mesolimbic dopamine pathway in the brain of alcohol-preferring AA and alcohol avoiding ANA rats, selected for high and low voluntary ethanol intake, respectively. The level of BDNF mRNA expression was higher in the amygdala and ventral tegmental area of AA than in those of ANA rats, and there was a trend for a higher level in the nucleus accumbens. In the amygdala and hippocampus, a biphasic change in the BDNF mRNA levels was detected: the levels were decreased at 3 and 6h but increased above the basal levels at 24h. Furthermore, there was a difference between the AA and ANA lines in the effect of ethanol, the ANA rats showing an increase in BDNF mRNA levels while such a change was not seen in AA rats. These findings suggest that the innate levels of BDNF expression may play a role in the mediation of the reinforcing effects of ethanol and in the control of ethanol intake. PMID- 25044408 TI - Estrogen, but not progesterone, induces the activity of nitric oxide synthase within the medial preoptic area in female rats. AB - The control of gonadotropin-releasing hormone (GnRH) secretion depends on the action of ovarian steroids and several substances, including nitric oxide (NO). NO in the medial preoptic area (MPOA) stimulates the proestrus surge of luteinizing hormone (LH). We studied the effect of estrogen (Tamoxifen-TMX) and progesterone (RU-486) antagonists on mRNA and protein expression of NO synthase (NOS), the enzyme that produces NO, as well as its activity within MPOA. Female rats received s.c. injections of TMX (3mg/animal) on first and second days of the estrous cycle (9 am), RU-486 (2mg/animal) on first, second, (8 am and 5 pm) and third days of the estrous cycle (8 am) or oil (controls) and were killed on the third day (5 pm). Real time-PCR and western blotting were performed to study NOS mRNA and protein expressions. The NOS activity was indirectly assessed by measuring the conversion from [(14)C]-L-arginine into [(14)C]-L-citrulline. TMX significantly decreased neuronal NOS (nNOS) mRNA expression (90%), and the activity of NOS, but did not alter nNOS protein expression. Also, TMX significantly decreased LH, FSH, estrogen and progesterone plasma levels. RU-486 nor affected NOS mRNA and protein expressions neither the NOS activity in the MPOA, but reduced FSH levels. The nitrergic system in the MPOA can be stimulated by estrogen whereas TMX decreased NOS activity and mRNA expression. In conclusion, the involvement of the nitrergic system in the MPOA to induce the surge of LH on proestrus depends on the estrogen action to stimulate the mRNA nNOS expression and the activity of nNOS but it does not seem to depend on progesterone action. PMID- 25044409 TI - Rapid and sensitive profiling and quantification of the human cell line proteome by LC-MS/MS without prefractionation. AB - In this paper, we demonstrate a rapid and reproducible 1D LC-MS/MS workflow for fast quantitative proteomic research. We have optimized the LC-MS/MS conditions, including digestion and gradient conditions, sample loading amount, and MS parameter settings. As a result, we were able to obtain twice as many protein identifications compared with the LC-MS/MS conditions before optimization. More than 4500 protein groups and 50 000 peptides were identified in less than 8 h without any fractionation. This 1D workflow was then applied to the analysis of the MLN4924 treated/untreated human umbilical vein endothelial cell (HUVEC) samples with label-free quantification. In these experiments, a total of 179 proteins showed a statistically significant expression change after the MLN4924 treatment. Functional analysis showed that these proteins are associated with cell death and survival; gene expression; cell cycle; and DNA replication, recombination, and repair. PMID- 25044410 TI - Human protein kinase CK2 phosphorylates matrix metalloproteinase 2 and inhibits its activity. AB - Matrix metalloproteinase 2 (MMP-2) is involved in cancer development and is overexpressed in a variety of malignant tumors. MMP-2 activity is controlled mainly by transcription, proteolytic activation, and inhibition by endogenous inhibitors. It had previously been demonstrated that MMP-2 activity is also regulated by phosphorylation at several sites by protein kinase C. Here we demonstrate, by means of bioinformatics and biochemical and cellular assays, that protein kinase CK2 also acts as a modulator of MMP-2 activity. CK2 down-regulates MMP-2 in vitro, and inhibition of CK2 in human fibrosarcoma cells results in up regulation of MMP-2. The discovery of the crosstalk between MMP-2 and CK2 opens the possibility of new combined anticancer therapies. PMID- 25044411 TI - Genome-wide association and network analysis of lung function in the Framingham Heart Study. AB - Single nucleotide polymorphisms have been found to be associated with pulmonary function using genome-wide association studies. However, lung function is a complex trait that is likely to be influenced by multiple gene-gene interactions besides individual genes. Our goal is to build a cellular network to explore the relationship between pulmonary function and genotypes by combining SNP level and network analyses using longitudinal lung function data from the Framingham Heart Study. We analyzed 2,698 genotyped participants from the Offspring cohort that had an average of 3.35 spirometry measurements per person for a mean length of 13 years. Repeated forced expiratory volume in one second (FEV1 ) and the ratio of FEV1 to forced vital capacity (FVC) were used as outcomes. Data were analyzed using linear-mixed models for the association between lung function and alleles by accounting for the correlation among repeated measures over time within the same subject and within-family correlation. Network analyses were performed using dmGWAS and validated with data from the Third Generation cohort. Analyses identified SMAD3, TGFBR2, CD44, CTGF, VCAN, CTNNB1, SCGB1A1, PDE4D, NRG1, EPHB1, and LYN as contributors to pulmonary function. Most of these genes were novel that were not found previously using solely SNP-level analysis. These novel genes are involving the transforming growth factor beta (TGFB)-SMAD pathway, Wnt/beta catenin pathway, etc. Therefore, combining SNP-level and network analyses using longitudinal lung function data is a useful alternative strategy to identify risk genes. PMID- 25044413 TI - Carfilzomib and pomalidomide: recent advances in the treatment of multiple myeloma. AB - Multiple myeloma is a hematologic malignancy characterized by plasma cell clonal expansion as well as end-organ damage due to increased levels of monoclonal proteins in both the plasma and urine. The clinical syndrome is characterized by hypercalcemia, renal insufficiency, anemia, and bone involvement that leads to pathologic fractures. This progressive disease can result in significant patient morbidity and mortality. Despite advances with treatment options and autologous stem cell transplantation, multiple myeloma remains incurable. Current front-line therapies include proteasome inhibitors, immunomodulators, anthracyclines, and steroids. Due to the advent of the immunomodulatory agents thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, overall survival in patients with multiple myeloma has improved greatly. However, once patients progress through front-line therapy and have relapsed or refractory disease, treatment options have historically been very limited. Carfilzomib, a second generation proteasome inhibitor, has shown impressive response rates as a single agent in the relapsed and refractory patient setting; this includes patients who are refractory to previous bortezomib therapy. In addition, a third-generation immunomodulator, pomalidomide, has also shown promising results in a similar patient population, including those patients who have been shown to be refractory to lenalidomide and bortezomib. Adverse effects of both of these medications have been considered tolerable in the relapsed or refractory population, especially considering the benefits that have been shown. Continuing clinical research will reveal the utility of these agents in combination regimens or in a front-line setting for patients with multiple myeloma. PMID- 25044414 TI - An all-halogen bonding rotaxane for selective sensing of halides in aqueous media. AB - The synthesis and anion binding properties of the first rotaxane host system to bind and sense anions purely through halogen bonding, is described. Through a combination of polarized iodotriazole and iodotriazolium halogen bond donors, a three-dimensional cavity is created for anion binding. This rotaxane incorporates a luminescent rhenium(I) bipyridyl metal sensor motif within the macrocycle component, thus enabling optical study of the anion binding properties. The rotaxane topology was confirmed by single-crystal X-ray structural analysis, demonstrating halogen bonding between the electrophilic iodine atoms and chloride anions. In 50% H2O/CH3CN solvent mixtures the rotaxane host exhibits strong binding affinity and selectivity for chloride, bromide, and iodide over a range of oxoanions. PMID- 25044412 TI - Not miR-ly micromanagers: the functions and regulatory networks of microRNAs in mammalian skin. AB - The microRNA (miRNA) pathway is a widespread mechanism of post-transcriptional gene regulation in eukaryotic cells. In animals, each miRNA species can regulate hundreds of protein-coding genes, resulting in pervasive functions for miRNAs in numerous cellular processes. Since the identification of the first mammalian miRNA, the function of miRNAs in mammals has been a topic of great interest, both because of the versatile roles of miRNAs in biological systems, as well as the clinical potential of these regulatory RNAs. With well-defined cell lineages and the availability of versatile tools for both in vivo and in vitro studies, mammalian skin has emerged as an important system in which to examine miRNAs' functions in adult tissues. In this review, we discuss recent insights into the functions and regulatory networks of miRNAs in mammals, with a specific focus on murine skin development as a model system. We first introduce functional analyses of the miRNA biogenesis pathway in the skin, then highlight the functions of individual miRNAs in skin development, followed by an examination of miRNA roles in skin stress responses. We finish with a discussion of miRNA regulatory networks and emphasize future challenges and emerging technologies that permit the genome-wide study of miRNA functions and regulatory mechanisms in mammalian skin. PMID- 25044415 TI - Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols. AB - Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in childhood. Genetically, it is characterized by the presence of an IG-MYC translocation which is supposed to be an initiating but not sufficient event in Burkitt lymphomagenesis. In a recent whole-genome sequencing study of four cases, we showed that the gene encoding the ras homolog family member A (RHOA) is recurrently mutated in pediatric BL. Here, we analyzed RHOA by Sanger sequencing in a cohort of 101 pediatric B-cell lymphoma patients treated according to Non Hodgkin's Lymphoma Berlin-Frankfurt-Munster (NHL-BFM) study protocols. Among the 78 BLs in this series, an additional five had RHOA mutations resulting in a total incidence of 7/82 (8.5%) with c.14G>A (p.R5Q) being present in three cases. Modeling the mutational effect suggests that most of them inactivate the RHOA protein. Thus, deregulation of RHOA by mutation is a recurrent event in Burkitt lymphomagenesis in children. PMID- 25044416 TI - Scaling up experimental ocean acidification and warming research: from individuals to the ecosystem. AB - Understanding long-term, ecosystem-level impacts of climate change is challenging because experimental research frequently focuses on short-term, individual-level impacts in isolation. We address this shortcoming first through an interdisciplinary ensemble of novel experimental techniques to investigate the impacts of 14-month exposure to ocean acidification and warming (OAW) on the physiology, activity, predatory behaviour and susceptibility to predation of an important marine gastropod (Nucella lapillus). We simultaneously estimated the potential impacts of these global drivers on N. lapillus population dynamics and dispersal parameters. We then used these data to parameterize a dynamic bioclimatic envelope model, to investigate the consequences of OAW on the distribution of the species in the wider NE Atlantic region by 2100. The model accounts also for changes in the distribution of resources, suitable habitat and environment simulated by finely resolved biogeochemical models, under three IPCC global emissions scenarios. The experiments showed that temperature had the greatest impact on individual-level responses, while acidification had a similarly important role in the mediation of predatory behaviour and susceptibility to predators. Changes in Nucella predatory behaviour appeared to serve as a strategy to mitigate individual-level impacts of acidification, but the development of this response may be limited in the presence of predators. The model projected significant large-scale changes in the distribution of Nucella by the year 2100 that were exacerbated by rising greenhouse gas emissions. These changes were spatially heterogeneous, as the degree of impact of OAW on the combination of responses considered by the model varied depending on local environmental conditions and resource availability. Such changes in macro-scale distributions cannot be predicted by investigating individual-level impacts in isolation, or by considering climate stressors separately. Scaling up the results of experimental climate change research requires approaches that account for long term, multiscale responses to multiple stressors, in an ecosystem context. PMID- 25044417 TI - Prospects for the control of apple leaf midge Dasineura mali (Diptera: Cecidomyiidae) by mass trapping with pheromone lures. AB - BACKGROUND: Apple leaf midge, Dasineura mali (Kieffer), poses quarantine issues for some apple export markets because larvae occasionally pupate in the stem end and calyx of fruit. Pheromone-baited oil-filled containers were used in 1 ha orchard plots to trap adult male D. mali in order to test the potential for mass trapping to reduce populations. RESULTS: Mass-trapped plots had 97% fewer adult males in pheromone traps and 48% fewer larvae per shoot in the second D. mali generation compared with untreated areas. Oil traps caught on average 900 000 D. mali per plot over 11 weeks during the second and third generations. Catches averaged 9200 per trap at plot corners. By comparison, catches were 51% lower 10 25 m away along borders, 80% lower at the midpoint of borders and 95% lower >7 m from plot edges. Fruit infestation was low (four out of 8000 apples). CONCLUSION: The attractiveness of the pheromone, monophagous habit and low mobility of D. mali enhance the prospects for successful mass trapping. Countering this are high populations, multivoltinism and aspects of mating behaviour. Mass trapping would probably have been more effective had it been in place season long and conducted over successive years. It needs refinements and more study before becoming a feasible control option for D. mali. PMID- 25044418 TI - Primary cell cultures for understanding rat epididymal inflammation. AB - Treatment-induced epididymal inflammation and granuloma formation is only an occasional problem in preclinical drug development, but it can effectively terminate the development of that candidate molecule. Screening for backup molecules without that toxicity must be performed in animals (generally rats) that requires at least 2 to 3 weeks of in vivo exposure, a great deal of specially synthesized candidate compound, and histologic examination of the target tissues. We instead hypothesized that these treatments induced proinflammatory gene expression, and so used mixed-cell cultures from the rat epididymal tubule to monitor the induction of proinflammatory cytokines. Cells were exposed for 24 hr and then cytotoxicity was evaluated with the MTS assay and mRNA levels of Interleukin-6 (IL-6) and growth-related oncogene (GRO) were measured. We found that compounds that were more toxic in vivo stimulated a greater induction of IL-6 and GRO mRNA levels in vitro. By relating effective concentrations in vitro with the predicted C(eff), we could rank compounds by their propensity to induce inflammation in rats in vivo. This method allowed the identification of several compounds with very low inflammatory induction in vitro. When tested in rats, the compounds produced small degrees of inflammation at an acceptable margin (approximately 20*), and have progressed into further development. PMID- 25044420 TI - Photoreversible assembly-disassembly of a polymeric structure by using an azobenzene photoswitch and Al3+ ions. AB - A nonmacrocyclic azobenzene-based photochromic receptor in its E isomer forms an extended polymeric assembly with Al(3+) ions. Exposure of the E form to UV light at lambda = 366 nm causes a disassembly of the polymeric structure due to the change in the molecular geometry of the ligand. The linear polymeric structure was regenerated on exposure to visible light. PMID- 25044419 TI - Enhancing the stiffness of collagen hydrogels for delivery of encapsulated chondrocytes to articular lesions for cartilage regeneration. AB - This study investigated a dual crosslinking paradigm, consisting of (a) photocrosslinking with Rose Bengal (RB) and green light followed by (b) chemical crosslinking with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and N hydroxysuccinimide (NHS) to enhance collagen gel stiffness. In group 1, 50 MUL collagen constructs of 2% (w/v) type I collagen containing 10 MUM RB were allowed to gel spontaneously at 37 degrees C. In group 2, the spontaneous gels were exposed to green light (532 nm). In group 3, the photochemically crosslinked gels were subsequently treated with a 1-h exposure to 33 mM EDC/6 mM NHS. Samples (n = 18) were subjected to 0.08% (w/v) collagenase digestion, and the storage modulus of samples was measured by rheometry. Viability of encapsulated chondrocytes was measured by live/dead assay. Chondrocytes were >= 95% viable in all constructs at 10 days in vitro. Resistance to collagenase digestion increased as; spontaneous gels (2 h) < photochemical gels (3-4 h) < dual crosslinked gels (>24 h). The storage modulus of dual-crosslinked constructs was increased 5-fold over both photocrosslinked and spontaneous gels. As the dual crosslinking paradigm did not reduce encapsulated chondrocyte viability, these crosslinked collagen hydrogels could be a useful tool for the practical delivery of encapsulated chondrocytes to articular defects. PMID- 25044422 TI - Imidazole-based small molecules that promote neurogenesis in pluripotent cells. AB - Reported herein are two imidazole-based small molecules, termed neurodazine (Nz) and neurodazole (Nzl), which induce neuronal differentiation of pluripotent P19 cells. Their ability to induce neurogenesis of P19 cells is comparable to that of retinoic acid. However, Nz and Nzl were found to be more selective neurogenesis inducers than retinoic acid owing to their unique ability to suppress astrocyte differentiation of P19 cells. Our results also show that Nz and Nzl promote production of physiologically active neurons because P19-cell-derived neurons induced by these substances have functional glutamate responsiveness. The present study suggests that Nz and Nzl could serve as important chemical tools to induce formation of specific populations of neuronal cell types from pluripotent cells. PMID- 25044423 TI - Evaluation of the effect of curcumin capsules on glyburide therapy in patients with type-2 diabetes mellitus. AB - This study aimed to assess the possible beneficial effects of curcumin capsules as lipid-lowering effects and as a permeability glycoprotein (P-gp) inhibitor on the pharmacokinetics and pharmacodynamics of glyburide and as a P-gp substrate with glyburide in patients with type-2 diabetes mellitus. Open-label, randomized control trial was carried out for 11 days on eight type-2 diabetic patients on glyburide therapy. On the first day of the study, following the administration of 5 mg of glyburide, blood samples were collected from the patients at various time intervals ranging from 0.5 to 24 h. Blood sampling was repeated on the 11th day of the study, after treating the patients with curcumin for ten consecutive days. Glyburide concentrations changed at the second hour, Cmax was unchanged, the glucose levels were decreased, Area Under first Movement Curre (AUMC) was increased, and no patient has experienced the hypoglycaemia. The low-density lipoprotein, very-low-density lipoprotein and triglycerides were decreased significantly, and the high-density lipoprotein content increased. The co administration of curcumin capsules with glyburide may be beneficial to the patients in better glycaemic control. The lipid lowering and antidiabetic properties of the curcumin show as a potential future drug molecule. PMID- 25044424 TI - Thermoelectric tin selenide: the beauty of simplicity. PMID- 25044425 TI - Isolation and identification of two unknown impurities from the raw material of clindamycin hydrochloride. AB - Clindamycin hydrochloride belongs to the antibiotic family of lincomycin. It has the same antibacterial spectrum as lincomycin, but the antibacterial activity is four to eight times stronger than that of lincomycin. There have been some adverse reactions in clinical use of clindamycin hydrochloride and its finished drug products. The impurities in drugs are directly related to their safety. In this study, two unknown impurities were isolated from the raw material of clindamycin hydrochloride through various chromatographic methods. Their structures were identified as clindamycin isomer (impurity 1) and dehydroclindamycin (impurity 2) by mass spectrometry and NMR spectroscopy. Both of them were found for the first time. The two impurities exhibit a similar but lower antibacterial activity compared with clindamycin hydrochloride. PMID- 25044426 TI - Highlights of topic "Surgical management of perihilar cholangiocarcinoma". PMID- 25044427 TI - Advisory comment to Oncological benefit of preoperative endoscopic biliary drainage in patients with hilar cholangiocarcinoma. PMID- 25044428 TI - To whom goes the kidney? PMID- 25044430 TI - High correlation between oxidation loci on graphene oxide. AB - Recent experiments have shown the coexistence of both large unoxidized and oxidized regions on graphene oxide (GO), but the underlying mechanism for the formation of the GO atomic structure remains unknown. Now, using density functional calculations, 52 oxidation pathways for local pyrene structures on GO were identified, and a kinetic profile for graphene oxidation with a high correlation between oxidation loci was proposed, which is different from the conventional view, which entails a random distribution of oxidation loci. The high correlation is an essential nature of graphene oxidation processes and can be attributed to three crucial effects: 1) breaking of delocalized pi bonds, 2) steric hindrance, and 3) hydrogen-bond formation. This high correlation leads to the coexistence of both large unoxidized and oxidized regions on GO. Interestingly, even in oxidized regions on GO, some small areas of sp(2) hybridized domains, similar to "islands", can persist because of steric effects. PMID- 25044431 TI - Orientation-controlled single-molecule junctions. AB - The conductivity of a single aromatic ring, perpendicular to its plane, is determined using a new strategy under ambient conditions and at room temperature by a combination of molecular assembly, scanning tunneling microscopy (STM) imaging, and STM break junction (STM-BJ) techniques. The construction of such molecular junctions exploits the formation of highly ordered structures of flat oriented mesitylene molecules on Au(111) to enable direct tip/pi contacts, a result that is not possible by conventional methods. The measured conductance of Au/pi/Au junction is about 0.1 G(o) , two orders of magnitude higher than the conductance of phenyl rings connected to the electrodes by standard anchoring groups. Our experiments suggest that long-range ordered structures, which hold the aromatic ring in place and parallel to the surface, are essential to increase probability of the formation of orientation-controlled molecular junctions. PMID- 25044429 TI - Response and adaptation of Escherichia coli to suppression of the amber stop codon. AB - Some extant organisms reassign the amber stop codon to a sense codon through evolution, and suppression of the amber codon with engineered tRNAs has been exploited to expand the genetic code for incorporating non-canonical amino acids (ncAAs) in live systems. However, it is unclear how the host cells respond and adapt to such amber suppression. Herein we suppressed the amber codon in Escherichia coli with an orthogonal tRNA/synthetase pair and cultured the cells under such a pressure for about 500 generations. We discovered that E. coli quickly counteracted the suppression with transposon insertion to inactivate the orthogonal synthetase. Persistent amber suppression evading transposon inactivation led to global proteomic changes with a notable up-regulation of a previously uncharacterized protein (YdiI) for which we identified an unexpected function of expelling plasmids. These results should be valuable for understanding codon reassignment in genetic code evolution and for improving the efficiency of ncAA incorporation. PMID- 25044432 TI - Biomechanics and functional distortion of the human mandible. AB - The reaction to the use of finite element analysis (FEA) in the study of the human body has been particularly enthusiastic. Of equal and challenging complexity is the investigation of load/stress distribution and morphological distortion of the human mandible under functional loads. Furthermore, the mandible also impacts directly on body function and esthetics, playing a vital role, such as mastication and speech. The application of FEA to the biomechanical investigation of the oral systems, such as human teeth and mandibular bone remodeling, began in the early 1970s. The clinical significance of jaw deformation is unknown. The primary concern is that deformation might result in an ill-fitting superstructure or the creation of harmful strains in the patient implant complex. Although mandibular implant treatment has a high success rate, the possibility of failure caused by these dimensional changes and the related micromotion cannot be ignored. PMID- 25044433 TI - Laccase-mediator system for alcohol oxidation to carbonyls or carboxylic acids: toward a sustainable synthesis of profens. AB - By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration. PMID- 25044434 TI - Differentiation of organic and non-organic winter wheat cultivars from a controlled field trial by crystallization patterns. AB - BACKGROUND: There is a need for authentication tools in order to verify the existing certification system. Recently, markers for analytical authentication of organic products were evaluated. Herein, crystallization with additives was described as an interesting fingerprint approach which needs further evidence, based on a standardized method and well-documented sample origin. RESULTS: The fingerprint of wheat cultivars from a controlled field trial is generated from structure analysis variables of crystal patterns. Method performance was tested on factors such as crystallization chamber, day of experiment and region of interest of the patterns. Two different organic treatments and two different treatments of the non-organic regime can be grouped together in each of three consecutive seasons. When the k-nearest-neighbor classification method was applied, approximately 84% of Runal samples and 95% of Titlis samples were classified correctly into organic and non-organic origin using cross-validation. CONCLUSION: Crystallization with additive offers an interesting complementary fingerprint method for organic wheat samples. When the method is applied to winter wheat from the DOK trial, organic and non-organic treated samples can be differentiated significantly based on pattern recognition. Therefore crystallization with additives seems to be a promising tool in organic wheat authentication. PMID- 25044435 TI - Selective stabilization of abasic site-containing DNA by insertion of sterically demanding biaryl ligands. AB - Biaryl derivatives that consist of one DNA-intercalating unit and a sterically demanding component exhibit a specific behavior towards abasic site-containing DNA (AP-DNA) as determined by thermal DNA denaturation experiments, spectrometric titrations and CD spectroscopic analysis. Specifically, these ligands strongly stabilize AP-DNA towards dissociation, whereas they do not or only marginally affect the melting temperature of regular duplex DNA. PMID- 25044436 TI - Chlorine-free pyrotechnics: copper(I) iodide as a "green" blue-light emitter. AB - The generation of blue-light-emitting pyrotechnic formulations without the use of chlorine-containing compounds is reported. Suitable blue-light emission has been achieved through the generation of molecular emitting copper(I) iodide. The most optimal copper(I) iodide based blue-light-emitting formulation was found to have performances exceeding those of chlorine-containing compositions, and was found to be insensitive to various ignition stimuli. PMID- 25044437 TI - Molecular recognition of two 2,4-syn-functionalized (S)-glutamate analogues by the kainate receptor GluK3 ligand binding domain. AB - The kainate receptors are the least studied subfamily of ionotropic glutamate receptors. These receptors are thought to have a neuromodulatory role and have been associated with a variety of disorders in the central nervous system. This makes kainate receptors interesting potential drug targets. Today, structures of the ligand binding domain (LBD) of the kainate receptor GluK3 are only known in complex with the endogenous agonist glutamate, the natural product kainate, and two synthetic agonists. Herein we report structures of GluK3 LBD in complex with two 2,4-syn-functionalized (S)-glutamate analogues to investigate their structural potential as chemical scaffolds. Similar binding affinities at GluK3 were determined for the 2-(methylcarbamoyl)ethyl analogue (Ki =4.0 MUM) and the 2 (methoxycarbonyl)ethyl analogue (Ki =1.7 MUM), in agreement with the similar positioning of the compounds within the binding pocket. As the binding affinity is similar to that of glutamate, this type of Cgamma substituent could be used as a scaffold for introduction of even larger substituents reaching into unexplored binding site regions to achieve subtype selectivity. PMID- 25044438 TI - A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs. AB - Genotype imputation is a critical technique for following up genome-wide association studies. Efficient methods are available for dealing with the probabilistic nature of imputed single nucleotide polymorphisms (SNPs) in population-based designs, but not for family-based studies. We have developed a new analytical approach (FBATdosage), using imputed allele dosage in the general framework of family-based association tests to bridge this gap. Simulation studies showed that FBATdosage yielded highly consistent type I error rates, whatever the level of genotype uncertainty, and a much higher power than the best guess genotype approach. FBATdosage allows fast linkage and association testing of several million of imputed variants with binary or quantitative phenotypes in nuclear families of arbitrary size with arbitrary missing data for the parents. The application of this approach to a family-based association study of leprosy susceptibility successfully refined the association signal at two candidate loci, C1orf141-IL23R on chromosome 1 and RAB32-C6orf103 on chromosome 6. PMID- 25044439 TI - Inhibition of JNK3 promotes apoptosis induced by BH3 mimetic S1 in chemoresistant human ovarian cancer cells. AB - Previous studies have suggested that the novel BH3 mimetic S1 could induce apoptosis in diverse tumor cell lines through endoplasmic reticulum (ER) stress or mitochondrial cell death pathways. The activation of c-Jun N-terminal kinase (JNK) through inositol requiring enzyme-1 (IRE1) is closely connected to ER stress-induced apoptosis. However, the role of JNK is complex, as there are different JNK subtypes and the function of each subtype is still not entirely clear. Here we found that the mRNA expression of JNK3 was continuously high in S1 treated human ovarian cancer SKOV3/DDP cells using a human unfolded protein response (UPR) pathway PCR array. Pharmacological inhibition of JNK3 increased cell sensitivity to apoptosis induced by S1. Furthermore, inhibition of JNK3 induced accumulation of both acidic compartment and p62, and upregulated ROS production. Our results suggest that JNK3 plays a pro-survival role during ER stress through preventing the block of autophagic flux and reducing oxidative stress in SKOV3/DDP cells. Inhibition of JNK3 may be a potential method to enhance the killing effect of the Bcl-2 inhibitor S1. PMID- 25044440 TI - Left atrial volume predicts abnormal exercise left ventricular filling pressure. AB - AIMS: Latent heart failure at rest can be observed in a number of patients upon exercise. Considering left atrial (LA) remodelling as the reflection of the cumulative effects of the LV filling pressure (FP) over time, our aim was to investigate whether the LA volume would predict abnormal exercise LVFP. METHODS AND RESULTS: Ninety patients (58.6 +/- 10.8 years, 74 men) underwent exercise echocardiography. The LA maximal volume was measured by the Simpson method and indexed to body surface area. LVFP was assessed by the ratio between early peak diastolic velocities of mitral inflow and the septal annular mitral plane (E/e'). Exercise E/e' >13 was used as a threshold to define abnormal LVFP. Indexed LA volume was correlated with E/e' at rest (r = 0.37, P = 0.003), but the correlation was better with exercise E/e' (r = 0.54, P < 0.0001). In multivariate analysis, age, LV end-diastolic volume index, LVEF, and exercise E/e' were the independent determinants of LA volume index (R(2) = 0.47, P < 0.0001). Eleven patients had exercise E/e' >13; compared with the rest of the population, these patients were older and achieved a milder effort. LA volume index >33 mL/m(2) predicted an abnormal exercise LVFP with a 91% sensitivity and a 78% specificity. None of the patients with an LA volume index <26 mL/m(2) (n = 31, 34%) had an exercise E/e' >13. CONCLUSION: Exercise LVFP is a determinant of LA size. LA volume index seems to be helpful for predicting abnormal exercise LVFP. The potential use of LA remodelling to identify the patients benefitting most from exercise echocardiography should be investigated in larger studies. PMID- 25044441 TI - Fluorine as a hydrogen-bond acceptor: experimental evidence and computational calculations. AB - Hydrogen-bonding interactions play an important role in many chemical and biological systems. Fluorine acting as a hydrogen-bond acceptor in intermolecular and intramolecular interactions has been the subject of many controversial discussions and there are different opinions about it. Recently, we have proposed a correlation between the propensity of fluorine to be involved in hydrogen bonds and its (19)F NMR chemical shift. We now provide additional experimental and computational evidence for this correlation. The strength of hydrogen-bond complexes involving the fluorine moieties CH2F, CHF2, and CF3 was measured and characterized in simple systems by using established and novel NMR methods and compared to the known hydrogen-bond complex formed between acetophenone and p fluorophenol. Implications of these results for (19)F NMR screening are analyzed in detail. Computed values of the molecular electrostatic potential at the different fluorine atoms and the analysis of the electron density topology at bond critical points correlate well with the NMR results. PMID- 25044442 TI - Utilization of triptans in Sweden; analyses of over the counter and prescription sales. AB - PURPOSE: To enable easier access to triptans, the drug of choice for moderate to severe migraine, some countries have made triptans available without prescription, that is, over the counter (OTC). Concern has been raised about this. The aim of this study was to describe the utilization pattern of triptans in Sweden before and after the OTC switch. METHODS: Wholesaler and aggregated sales data from all Swedish pharmacies 1991 to 2011 and patient identity data on dispensed prescriptions 2007 and 2011 from the Swedish National Prescribed Drug Register were used to investigate volume and expenditure of triptans. The databases contain complete data for all drugs sold in Sweden or dispensed to all Swedish inhabitants (9.5 million in 2012). RESULTS: Volumes of triptans have increased to 7.0 million defined daily doses (DDD) on prescriptions and 0.7 million DDDs OTC in 2011. Prescriptions were dispensed to 10.0 and 10.1 per 1000 inhabitants in 2007 and 2011, respectively. Although half of those dispensed triptans in 2007 were not in 2011, the incidence remained stable at 2.8 patients per thousand person-years. In 2011, the 10% of the heaviest users accounted for 44% and 48% of dispensed triptans in women and men, respectively. CONCLUSIONS: Triptans OTC and the volumes dispensed on prescription have increased as has the DDD per patient purchasing triptans on prescription. However, the number of patient's dispensed triptans on prescription has remained stable. A concern is that almost half of prescribed triptans are purchased by 10% of the users. PMID- 25044443 TI - Hinokitiol induces autophagy in murine breast and colorectal cancer cells. AB - Hinokitiol is found in the heartwood of cupressaceous plants and possesses several biological activities. Hinokitiol may play an important role in anti inflammation and antioxidant processes, making it potentially useful in therapies for inflammatory-mediated disease. Previously, the suppression of tumor growth by hinokitiol has been shown to occur through apoptosis. Programmed cell death can also occur through autophagy, but the mechanism of hinokitiol-induced autophagy in tumor cells is poorly defined. We used an autophagy inhibitor (3 methyladenine) to demonstrate that hinokitiol can induce cell death via an autophagic pathway. Further, we suggest that hinokitiol induces autophagy in a dose-dependent manner. Markers of autophagy were increased after tumor cells were treated with hinokitiol. In addition, immunoblotting revealed that the levels of phosphoprotein kinase B (P-AKT), phosphomammalian target of rapamycin (P-mTOR), and phospho-p70 ribosomal s6 kinase (P-p70S6K) in tumor cells were decreased after hinokitiol treatment. In conclusion, our results indicate that hinokitiol induces the autophagic signaling pathway via downregulation of the AKT/mTOR pathway. Therefore, our findings show that hinokitiol may control tumor growth by inducing autophagic signaling. PMID- 25044444 TI - HAb18G/CD147 is involved in TGF-beta-induced epithelial-mesenchymal transition and hepatocellular carcinoma invasion. AB - Epithelial-mesenchymal transition (EMT) induced by the transforming growth factor beta (TGF-beta) is involved in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, a member of the immunoglobulin family, plays an important role in tumor invasion and metastasis. HAb18G/CD147 promotes EMT of hepatocytes through TGF-beta signaling and is transcriptionally regulated by Slug. We investigated the role of HAb18G/CD147 in TGF-beta-induced EMT in HCC invasion. Two human HCC cell lines, SMMC-7721 and HepG2, were used to determine the role of HAb18G/CD147 in EMT. Upregulation of HAb18G/CD147 induced by the high doses of TGF-beta1 in SMMC-7721 (5 ng/mL) and HepG2 cells (10 ng/mL) (P < 0.05). CD147 upregulation was coupled with upregulation of Snail1 and Slug. CD147 knockout significantly decreased the expression of N-cadherin and vimentin, and colony formation ability of SMMC-7721 cells. TGF-beta1 enhanced the migration capacity of SMMC-7721 cells, which was markedly attenuated by CD147 knockdown. Thus, HAb18G/CD147 is involved in TGF-beta-induced EMT and HCC invasion. PMID- 25044445 TI - Intravenous antibiotic durations for common bacterial infections in children: when is enough enough? AB - Durations of intravenous antibiotic therapy for bacterial infections in hospitalized children sometimes extend well beyond clinical recovery and are often the primary determinants of length of stay. These durations, however, are not always based on solid evidence. Moreover, fixed durations are invariant to important individual factors. We review guidelines and the available evidence for durations of intravenous antibiotic therapy for meningitis, bacteremia, urinary tract infection, and osteomyelitis, conditions where intravenous antibiotics often extend beyond resolution of clinical symptoms. We propose a framework for the duration of therapy that is intended to serve as a guide when standards of care are either nonexistent, dated, conflicting, or contrary to evidence from published studies. This framework incorporates patient-centered factors such as severity of infection, response to therapy, ease of intravenous access, harms and costs of ongoing intravenous treatment, and family preferences. PMID- 25044446 TI - Oxidized HDL induces cytotoxic effects: implications for atherogenic mechanism. AB - Atherosclerosis can be considered as an inflammatory disease and oxidized low density lipoprotein (oxLDL) is a critical factor in atherogenesis. Although high density lipoprotein (HDL) is generally an antiatherogenic lipoprotein, this property can be compromised by functional impairment mainly due to oxidative modification. As such, understanding the proatherogenic properties exerted by oxidized-HDL (oxHDL) becomes more important. This study was focused on examining the role of oxHDL as a proatherogenic agent, using oxLDL as a positive control. The comparative toxicity of oxHDL and oxLDL having same range of malondialdehyde, to monocytes was evaluated. After treatment, markers for oxidative stress, inflammation, and cytotoxicity were quantitated. The results showed that like oxLDL, oxHDL induced significant oxidative stress, cytotoxicity, and release of TNF -alpha and MMP-9 in monocytes/macrophages, but was less potent than oxLDL in promoting these proatherogenic effects. Further, the effects of oxHDL for the enhanced formation of MMP-9 were found to be mediated by NADPH oxidase/ROS JNK/ERK pathway, as one mechanism. PMID- 25044448 TI - Modified dual guide catheter ("ping-pong") technique to treat left internal mammary artery graft perforation. AB - Perforation of a left internal mammary artery (LIMA) graft during percutaneous coronary intervention is a rare event. We report a case of mid-LIMA perforation treated by a polytetrafluoroethylene-covered stent using a modification of the dual catheter ("ping pong") technique. We propose that use of this modification when possible will further improve safety of treating a perforation. PMID- 25044447 TI - Soluble CD163 is associated with noninvasive measures of liver fibrosis in hepatitis C virus- and hepatitis C virus/human immunodeficiency virus-infected women. PMID- 25044449 TI - Small noncoding RNAs and male infertility. AB - Small noncoding RNAs (ncRNAs) are a novel class of gene regulators that modulate gene expression at transcriptional, post-transcriptional, and epigenetic levels, and they play crucial roles in almost all cellular processes in eukaryotes. Recent studies have indicated that several types of small noncoding RNAs, including microRNAs (miRNAs), endo-small interference RNAs (endo-siRNAs), and Piwi-interacting RNAs (piRNAs), are expressed in the male germline and are required for spermatogenesis in animals. In this review, we summarize the recent knowledge of these small noncoding RNAs in male germ cells and their biological functions and mechanisms of action in animal spermatogenesis. PMID- 25044451 TI - The microbiome in early life: self-completion and microbiota protection as health priorities. AB - This minireview considers the benefits of refocusing attention away from treating the patient as a mammalian human to managing the complete patient: a majority microbial superorganism. Under the "completed self" model for formation of the human-microbial superorganism, the single, most pivotal sign in distinguishing a life course of health versus that filled with disease is self-completion (i.e., seeding of the minority mammalian human by the majority microbial portion of the symbiont). From a disease prevention perspective, microbial seeding at birth and subsequent nurturing of the microbiota are significant steps to reduce the risk of both noncommunicable diseases (e.g., type 1 diabetes) and certain infectious diseases. Management of the microbiome during pregnancy, birth, and shortly thereafter appears to be the most significant critical window for healthy superorganism formation. However, the bolus for microbiota seeding at birth and the nurturing process are subject to environmental influences and disruption, such as exposure to toxic chemicals and drugs, infections, and other physical and psychological stressors. Additionally, childhood and adult corrective measures, such as fecal transplantation and administration of prebiotics and probiotics, while potentially useful, may have limitations that are yet to be fully defined. This minireview considers (1) basic features of management of the microbiome to facilitate self-completion, (2) protection of the microbiota from environmental hazards, and (3) the benefits of using a superorganism focus for health management beginning with pregnancy and extending throughout childhood and adult life. PMID- 25044452 TI - Graphene field effect transistors with mica as gate dielectric layers. AB - Chemical vapor deposited monolayer graphene is transferred onto atomically flat and ultra-thin muscovite mica to study the transport characteristics of graphene with a test structure of mica-based graphene field effect transistor (GFET). The transfer curve of the 24 nm mica-based GFET shows an effective carrier mobility of 2748 cm(2)/Vs and a transconductance of 3.36 MUS, a factor of 2 and 7 larger than those values obtained from 40 nm SiO2 based GFET, respectively. The results demonstrate that mica is an excellent gate dielectric material due to its high dielectric constant, high dielectric strength, and atomically flat surface. PMID- 25044450 TI - Generalizability of established prostate cancer risk variants in men of African ancestry. AB - Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 * 10(-26) ) and rs6983561 (p = 1.1 * 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 * 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 * 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry. PMID- 25044453 TI - Functional interplay between protein arginine methyltransferases in Trypanosoma brucei. AB - Arginine methylation is a common posttranslational modification that has far reaching cellular effects. Trypanosoma brucei is an early-branching eukaryote with four characterized protein arginine methyltransferases (PRMTs), one additional putative PRMT, and over 800 arginine methylated proteins, suggesting that arginine methylation has widespread impacts in this organism. While much is known about the activities of individual T. brucei PRMTs (TbPRMTs), little is known regarding how TbPRMTs function together in vivo. In this study, we analyzed single and selected double TbPRMT knockdowns for the impact on expression of TbPRMTs and global methylation status. Repression of TbPRMT1 caused a decrease in asymmetric dimethylarginine and a marked increase in monomethylarginine that was catalyzed by TbPRMT7, suggesting that TbPRMT1 and TbPRMT7 can compete for the same substrate. We also observed an unexpected and strong interdependence between TbPRMT1 and TbPRMT3 protein levels. This finding, together with the observation of similar methyl landscape profiles in TbPRMT1 and TbPRMT3 repressed cells, strongly suggests that these two enzymes form a functional complex. We show that corepression of TbPRMT6/7 synergistically impacts growth of procyclic-form T. brucei. Our findings also implicate the actions of noncanonical, and as yet unidentified, PRMTs in T. brucei. Together, our studies indicate that TbPRMTs display a functional interplay at multiple levels. PMID- 25044459 TI - In vivo monitoring of intracellular chloroplast movements in intact leaves of C4 plants using two-photon microscopy. AB - Dynamic changes in the spatial distribution of chloroplasts are essential for optimizing photosynthetic capacity under changing light conditions. Light-induced movement of chloroplasts has been widely investigated, but most studies were conducted on isolated tissues or protoplasts. In this study, a two-photon microscopy (TPM) system was adapted to monitor the intracellular 3-dimensional (3D) movements of chloroplasts in intact leaves of plants during dark to light transitions. The TPM imaging was based on autofluorescence of chlorophyll generated by a femto-second Ti:Sapphire laser. All chloroplasts did not exhibit the same motion in response to irradiation variation. In the sub-epidermal mesophyll cells, chloroplasts generally moved away from the surface following blue light treatment, however many chloroplasts did not show any movement. Such spatial heterogeneity in chloroplast motility underlines the importance of monitoring intracellular orientation and movement of individual chloroplasts across intact leaves. Our investigation shows that the 3D imaging of chloroplasts using TPM can help to understand the changes in local photosynthetic capacity in intact leaves under changing environmental conditions. PMID- 25044460 TI - Experimental test and life estimation of the OLED at normal working stress based on the luminance degradation model. AB - In order to accurately acquire the life time information for the organic light emitting diode (OLED), an experiment based on the normal stress life test was carried out to gain the data for the luminance degradation tests. The luminance degradation model of OLED was established based on the Weibull function and the least square method. Combined with luminance degradation data, Weibull parameters were estimated, the qualitative and the quantitative relationship between the initial luminance and the OLED life was obtained, and the life estimation of the product was achieved. Numerical results show that the test scheme is feasible, the luminance degradation model proves to be reliable for the OLED life estimation, and the fitting accuracy is very high by comparison with the test data fluctuation. Moreover, the real life time of the OLED is measured, which can verify the validity of the assumptions used in accelerated life test methods and provide manufacturers and customers with significant guidelines. PMID- 25044461 TI - Quantitative proteomic study of myocardial mitochondria in urea transporter B knockout mice. AB - In previous research, we showed that 16-week-old urea transporter B (UT-B) null mice have an atrial-ventricular conduction block, and hypothesized myocardial mitochondrial dysfunction. To investigate the mechanism of this block, we examined the proteomic differences in the myocardial mitochondria of UT-B null and wild-type mice with nanoscale LC-MS/MS. Of 26 proteins clearly downregulated in the UT-B null mice, 15 are involved in complexes I, III, IV, and V of the respiratory chain, which would strongly reduce the activity of the electron transport chain. Excess electrons from complexes I and III pass directly to O2 to generate ROS and deplete ROS-scavenging enzymes. Myocardial intracellular ROS were significantly higher in UT-B null mice than in wild-type mice (p < 0.01), constituting an important cause of oxidative stress injury in the myocardia of UT B null mice. The mitochondrial membrane potential (DeltaPsim) was also lower in UT-B null mice than in wild-type mice (p < 0.05), causing oxidative phosphorylation dysfunction of complex V and insufficient ATP in the myocardial cells of UT-B null mice. HADHA (a trifunctional protein) and HSP60 were also downregulated in the UT-B null myocardial mitochondria. These results confirm that mitochondrial dysfunction underlies the pathogenesis of the atrial ventricular conduction block in UT-B null mice. PMID- 25044462 TI - New trifluoromethylated derivatives of metal nitride clusterfullerenes: Sc3N@I(h) C80 (CF3)14 and Sc3N@D(5h)-C80 (CF3)16. AB - Trifluoromethylated derivatives of Sc3N@I(h)-C80 and Sc3N@D(5h)-C80 were synthesized by the reaction with CF3I at 440 degrees C. HPLC separation of the mixture of Sc3N@D(5h)-C80(CF3)n derivatives resulted in isolation and X-ray structure determination of Sc3N@D(5h)-C80(CF3)16, which represents a precursor of the known Sc3N@D(5h)-C80(CF3)18. Among the CF3 derivatives of Sc3N@I(h)-C80, two new isomers of Sc3N@I(h)-C80(CF3)14 (Sc-14-VI and Sc-14-VII) were isolated by HPLC, and their molecular structures were determined by X-ray diffraction, thus enabling a comprehensive comparison of altogether seven isomers. Two types of addition patterns with different orientations of the Sc3N cluster relative to the I(h)-C80 fullerene cage were established. In particular, Sc-14-VII represents a direct precursor of the known Sc3N@I(h)-C80(CF3)16-II. All molecular structures exhibit an ordered position of a Sc3N cluster inside the fullerene C80 cage. PMID- 25044466 TI - 1q gain is a frequent finding in preoperatively treated Wilms tumors, but of limited prognostic value for risk stratification in the SIOP2001/GPOH trial. PMID- 25044467 TI - Applying a framework for landscape planning under climate change for the conservation of biodiversity in the Finnish boreal forest. AB - Conservation strategies are often established without consideration of the impact of climate change. However, this impact is expected to threaten species and ecosystem persistence and to have dramatic effects towards the end of the 21st century. Landscape suitability for species under climate change is determined by several interacting factors including dispersal and human land use. Designing effective conservation strategies at regional scales to improve landscape suitability requires measuring the vulnerabilities of specific regions to climate change and determining their conservation capacities. Although methods for defining vulnerability categories are available, methods for doing this in a systematic, cost-effective way have not been identified. Here, we use an ecosystem model to define the potential resilience of the Finnish forest landscape by relating its current conservation capacity to its vulnerability to climate change. In applying this framework, we take into account the responses to climate change of a broad range of red-listed species with different niche requirements. This framework allowed us to identify four categories in which representation in the landscape varies among three IPCC emission scenarios (B1, low; A1B, intermediate; A2, high emissions): (i) susceptible (B1 = 24.7%, A1B = 26.4%, A2 = 26.2%), the most intact forest landscapes vulnerable to climate change, requiring management for heterogeneity and resilience; (ii) resilient (B1 = 2.2%, A1B = 0.5%, A2 = 0.6%), intact areas with low vulnerability that represent potential climate refugia and require conservation capacity maintenance; (iii) resistant (B1 = 6.7%, A1B = 0.8%, A2 = 1.1%), landscapes with low current conservation capacity and low vulnerability that are suitable for restoration projects; (iv) sensitive (B1 = 66.4%, A1B = 72.3%, A2 = 72.0%), low conservation capacity landscapes that are vulnerable and for which alternative conservation measures are required depending on the intensity of climate change. Our results indicate that the Finnish landscape is likely to be dominated by a very high proportion of sensitive and susceptible forest patches, thereby increasing uncertainty for landscape managers in the choice of conservation strategies. PMID- 25044468 TI - Dissipation behaviour, processing factors and risk assessment for metalaxyl in greenhouse-grown cucumber. AB - BACKGROUND: Cucumber is widely cultivated in Iran, and the application of systemic and protective fungicides is the main choice of disease treatment, particularly in greenhouse-grown systems. In this research, cucumber fruits were harvested at 1 h to 25 days after the last application to determine the residue and dissipation behaviour of metalaxyl. The effects of peeling and storage (at 3 degrees C for 4 days) on metalaxyl residue reduction were also assessed. Samples were extracted by the QuEChERS procedure then analysed using liquid chromatography-tandem mass spectrometry. RESULTS: The dissipation of metalaxyl residues approximately fitted a first-order kinetic model, obtaining half-life values of 2.2 and 3.8 days and preharvest interval values of 5.2 and 12.5 days at the recommended dose (2 kg ha(-1) ) and double (4 kg ha(-1) ) dose respectively. The processing factor values for peeling and storage were 0.50 and 0.93 respectively, showing that storage had little effect on residue reduction compared with peeling. CONCLUSION: The higher content of metalaxyl residues in flesh showed its penetration from the skin into the flesh. The results provided more understanding of fungicide distribution as well as the effective role of peeling in reducing residues in cucumber fruits. PMID- 25044469 TI - Novel nanofiber-based material for endovascular scaffolds. AB - Conventional collagen-based heart valves eventually fail because of insufficient replacement of graft material by host tissue. In this study, type I collagen was blended with silk fibroin and the synthetic elastic polymer poly (glycerol sebacate) (PGS) in varying proportions to create multifunctional electrospun nanofibrous materials tailored for use as endovascular scaffolds such as heart valve replacement. Depending on the blended material the elastic moduli ranged from 2.3 to 5.0 Mpa; tensile stresses ranged from 0.8 to 1.5 Mpa; and strains ranged from 30% to 70%. Electrospun materials with a weight ratio of 4.5:4.5:1 (collagen, fibroin, and PGS) (termed PFC mats) were the most similar to native heart valves. In vitro degradation of PFC mats was 0.01% per week. Endothelial cells adhered to, proliferated, and formed cell-cell junctions on PFC mats. Compared with collagen hydrogels and electrospun collagen mats respectively 220 290% less platelet adhesion was observed for PFC mats. The study demonstrates that PFC material has superior mechanical properties, low degradation, and reduced thrombogenic potential and suggests that further investigation of this biomaterial for cardiovascular applications is warranted. PMID- 25044470 TI - Zirconium allyl complexes as participants in zirconocene-catalyzed alpha-olefin polymerizations. AB - In a search for the hitherto elusive catalyst resting state(s) of zirconocene based olefin polymerization catalysts, a combination of UV/Vis and NMR spectrometric methods reveals that polymer-carrying cationic Zr allyl complexes make up about 90 % of the total catalyst concentration. Other catalyst species that take part in the polymerization process have to be generated from this allyl pool into which they appear to relapse rather frequently. PMID- 25044471 TI - Enantioselective assembly of a ruthenium(II) polypyridyl complex into a double helix. AB - Evolution can increase the complexity of matter by self-organization into helical architectures, the best example being the DNA double helix. One common aspect, apparently shared by most of these architectures, is the presence of covalent bonds within the helix backbone. Here, we report the unprecedented crystal structures of a metal complex that self-organizes into a continuous double helical structure, assembled by non-covalent building blocks. Built up solely by weak stacking interactions, this alternating tread stairs-like double helical assembly mimics the DNA double helix structure. Starting from a racemic mixture in aqueous solution, the ruthenium(II) polypyridyl complex forms two polymorphic structures of a left-handed double helical assembly of only the Lambda enantiomer. The stacking of the helices is different in both polymorphs: a crossed woodpile structure versus a parallel columnar stacking. PMID- 25044472 TI - Regioselective glucuronidation of the isoflavone calycosin by human liver microsomes and recombinant human UDP-glucuronosyltransferases. AB - Hepatic conjugation plays important roles in systemic exposure and drug interactions of flavonoids. In the present study, the hepatic metabolism of calycosin, a major isoflavone from Astragali Radix, was characterized and the regioselectivity in the predominant glucuronidation pathway was first delineated in human liver microsomes (HLMs) and a panel of recombinant human UDP glucuronosyltransferases (UGTs). Calycosin underwent major glucuronidation and minor oxidation and sulfation in human liver subcellular fractions. The major glucuronide (G2) of calycosin was isolated and identified as calycosin 3' glucuronide by NMR analysis, and thus, the minor glucuronide (G1) was tentatively assigned as calycosin 7-glucuronide. The formations of both glucuronides in HLMs fit typical Michaelis-Menten kinetics. HLMs exhibited higher affinity (Km, G2 12.37+/-1.20 MUM vs G1 40.90+/-5.51 MUM) and velocity (Vmax, G2 5.39+/-0.13 nmol/min/mg protein vs G1 2.80+/-0.13 nmol/min/mg protein) on G2 formation, leading to the intrinsic clearance of calycosin via 3'-glucuronidation 6 times that through 7-glucuronidation. UGT1A1, 1A3 and 1A10 showed activities on both 3' OH and 7-OH, whereas UGT1A7, 1A8, 1A9, and 2B7 were only capable of catalyzing 3' OH glucuronidation of calycosin. Among them, UGT1A9 exhibited the highest activity (Clint, 2169.50 MUL/min/mg protein) for 3'-glucuronide formation followed by UGT1A7 (Clint, 396.38 MUL/min/mg protein). UGT1A1 showed the highest activity towards 7-OH glucuronidation (Clint, 224.34 MUL/min/mg protein), which was comparable to its activity on 3'-OH glucuronidation (Clint, 203.82 MUL/min/mg protein). Propofol (UGT1A9 inhibitor) produced a complete inhibition of 3' glucuronide formation accompanied by an increase of 7-glucuronide in HLMs, while bilirubin (UGT1A1 inhibitor) only partially (~60%) inhibited the 7-OH glucuronidation. These findings demonstrated the regioselective glucuronidation at the 3'-OH of the isoflavone calycosin in HLMs and shed light on potential drug interactions of calycosin with other UGT1A9 substrates. PMID- 25044473 TI - Sequential evolution of cortical activity and effective connectivity of swallowing using fMRI. AB - Swallowing consists of a hierarchical sequence of primary motor and somatosensory processes. The temporal interplay of different phases is complex and clinical disturbances frequent. Of interest was the temporal interaction of the swallowing network. Time resolution optimized functional magnetic resonance imaging was used to describe the temporal sequence of representation sites of swallowing and their functional connectivity. Sixteen young healthy volunteers were investigated who swallowed 2 ml of water 20 times per run with a repetition time for functional imaging of 514 ms. After applying the general linear model approach to identify activation magnitude in preselected regions of interest repeated measures analysis of variance (rmANOVA) was used to detect relevant effects on lateralization, time, and onset. Furthermore, dynamic causal modeling (DCM) was applied to uncover where the input enters the model and the way in which the cortical regions are connected. The temporal analysis revealed a successive activation starting at the premotor cortex, supplementary motor area (SMA), and bilateral thalamus, followed by the primary sensorimotor cortex, the posterior insula, and cerebellum and culminating with activation in the pons shortly before subsiding. The rmANOVA revealed that activation was lateralized initially to the left hemisphere and gradually moved to the right hemisphere over time. The group random effects DCM analysis resulted in a most likely model that consisted of inputs to SMA and M1S1, bidirectionally connected, and a one-way connection from M1S1 to the posterior insula. PMID- 25044476 TI - The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4+ T-cell compartment. AB - Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4(+) T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4(+) T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features. PMID- 25044474 TI - Contribution of each Trp residue toward the intrinsic fluorescence of the Gialpha1 protein. AB - Gialpha1 is the inhibitory G-protein that, upon activation, reduces the activity of adenylyl cyclase. Comparison of the crystal structures of Gialpha1 bound to GDP*AMF or GTPgammaS with that of the inactive, GPD-bound protein indicates that a conformational change occurs in the activation step centered on three switch regions. The contribution of each tryptophan residue (W211 in the switch II region, W131 in the alpha-helical domain, and W258 in the GTPase domain) toward the intrinsic protein fluorescence was evaluated by using W211F, W131F, and W258F mutants. All three tryptophan residues contributed significantly toward the emission spectra regardless of the conformation. When activated by either GDP*AMF or GTPgammaS, the observed maximal-fluorescence scaled according to the solvent accessibilities of the tryptophan residues, calculated from molecular dynamics simulations. In the GDP*AMF and GTPgammaS, but not in the GDP, conformations, the residues W211 and R208 are in close proximity and form a pi-cation interaction that results in a red shift in the emission spectra of WT, and W131F and W258F mutants, but a blue shift for the W211F mutant. The observed shifts did not show a relationship with the span of the W211-R208 bridge, but rather with changes in the total interaction energies. Trypsin digestion of the active conformations only occurred for the W211F mutant indicating that the electrostatic pi-cation interaction blocks access to R208, which was consistent with the molecular dynamics simulations. We conclude that solvent accessibility and interaction energies account for the fluorescence features of Gialpha1 . PMID- 25044477 TI - Polymer nanoparticle hydrogels with autonomous affinity switching for the protection of proteins from thermal stress. AB - We report a new material design concept for synthetic, thermally responsive poly(N-isopropylacrylamide)-based copolymer nanoparticle (NP) hydrogels, which protect proteins from thermal stress. The NP hydrogels bind and protect a target enzyme from irreversible activity loss upon exposure to heat but "autonomously" release the enzyme upon subsequent cooling of the solution. Incorporation of the optimized amount of negatively charged and hydrophobic comonomers to the NP hydrogels was key to achieve these desired functions. As the NP hydrogels do not show a strong affinity for the enzyme at room temperature, they can remain in solution without adversely affecting enzymatic activity or they can be removed by filtration to leave the enzyme in solution. The results demonstrate the promise of this approach for improving the thermal tolerance of proteins. PMID- 25044479 TI - Poly(dimethylsiloxane)-supported ionogels with a high ionic liquid loading. AB - The immiscibility of poly(dimethylsiloxane) (PDMS) and ionic liquids (ILs) was overcome to create PDMS-supported IL gels (ionogels) with IL loadings of up to 80% by mass through a simple sol-gel reaction at room temperature. By stirring a mixture of a functionalized PDMS oligomer, formic acid, and an IL (or lithium-in IL solution), a resin was formed that could be cast to create a freestanding, flexible ionogel. PDMS-supported ionogels exhibited favorable ionic conductivity (ca. 3 mS cm(-1)) and excellent mechanical behavior (elastic modulus: ca. 60 kPa; fatigue life: >5000 cycles; mechanically stable at temperatures up to 200 degrees C). The activation energy of ionic conductivity was shown to be nearly identical for the ionogel and the neat IL, in contrast to ionogel systems wherein the scaffold material is miscible with the IL. This similarity indicates that IL/scaffold chemical interactions are key to the understanding of ionogel electrical performance, especially at elevated temperatures. PMID- 25044481 TI - Protein arginine N-methyltransferase substrate preferences for different neta substituted arginyl peptides. AB - Protein arginine N-methyltransferases (PRMTs) catalyze methyl-group transfer from S-adenosyl-L-methionine onto arginine residues in proteins. In this study, modifications were introduced at the guanidine moiety of a peptidyl arginine residue to investigate how changes to the PRMT substrate can modulate enzyme activity. We found that peptides bearing Neta-hydroxy or Neta-amino substituted arginine showed higher apparent kcat values than for the monomethylated substrate when using PRMT1, whereas this catalytic preference was not observed for PRMT4 and PRMT6. Methylation by compromised PRMT1 variants E153Q and D51N further supports the finding that the N-hydroxy substitution facilitates methyl transfer by tuning the reactivity of the guanidine moiety. In contrast, Neta-nitro and Neta-canavanine substituted substrates inhibit PRMT activity. These findings demonstrate that methylation of these PRMT substrates is dependent on the nature of the modification at the guanidine moiety. PMID- 25044480 TI - STATs profiling reveals predominantly-activated STAT3 in cholangiocarcinoma genesis and progression. AB - BACKGROUND: We investigated the aberrant expression of the STAT family in humans and liver fluke (Opisthorchis viverrini, Ov)-induced hamster cholangiocarcinoma (CCA) tissues. METHODS: The expression and phosphorylation of STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 in human hamster CCA tissues were immunohistochemistry-profiled. Localizations of STAT5 in macrophages and lipopolysaccharide (LPS)-induced macrophage-conditioned media mediated STAT3 activation in CCA cells were demonstrated. RESULTS: The expressions of STAT 1-4 and 6 were detected in the cytoplasm of hyperplastic bile ducts and tumor cells, whereas STAT5a and STAT5b were observed in macrophages and connective tissues surrounding tumor, respectively. The expressions of STAT3 and STAT5b were significantly observed in tumors with a poorer histological differentiation. STAT3 expression was significantly associated with shorter survival of CCA patients and was predominately activated in CCA cell lines. In the CCA-hamsters, STATs expression was gradually increased along the carcinogenesis, especially at 30 days post-infection in which the inflammatory response was markedly observed, showing the correlation between the inflammation and STATs activation. Moreover, LPS-induced macrophage-conditioned media could mediate STAT3 activation in CCA cells. CONCLUSIONS: STAT3 is the major STAT, which plays roles in the inflammation that contributes to CCA carcinogenesis and progression and may serve as a marker for a poor prognosis of CCA. PMID- 25044482 TI - Is there an ideal cutoff for alpha-fetoprotein as an exclusion criterion for liver transplantation? PMID- 25044483 TI - Replicating an expanded genetic alphabet in cells. AB - Recent advances in synthetic biology have made it possible to replicate an unnatural base pair in living cells. This study highlights the technologies developed to create a semisynthetic organism with an expanded genetic alphabet and the potential challenges of moving forward. PMID- 25044484 TI - Protein adsorption behavior and immunoglobulin separation with a mixed-mode resin based on p-aminohippuric acid. AB - p-Aminohippuric acid is a newly developed ligand for mixed-mode chromatography with a commercial resin name of Nuvia cPrime. In this study, bovine immunoglobulin G and bovine serum albumin were used as two model proteins, and the adsorption isotherms with Nuvia cPrime were investigated under different pH and salt concentrations. The results showed that pH had a strong but different influence on the adsorption of these two proteins. The adsorption capacity for bovine immunoglobulin G and BSA was 170.4 and 28.1 mg/g at pH 6.0, respectively. Different salts also showed varying effects on the protein adsorption. Moreover, the adsorption and elution behaviors of the two proteins in a column were determined under varying pH and salt concentrations. An optimized process showed that feedstock loaded under pH 6.0 with 0.8 M (NH4)2SO4 and eluted under pH 8.0 with 1.0 M NaCl could effectively purify bovine immunoglobulin G from feedstock containing BSA. The purity of bovine immunoglobulin G could reach 99.8% and the recovery was 92.7%. The results demonstrated that the control of pH and salt addition during the loading and elution processes were two key factors in improving separation efficiency with Nuvia cPrime resin. PMID- 25044485 TI - Synthesis of the heparin-based anticoagulant drug fondaparinux. AB - Fondaparinux, a synthetic pentasaccharide based on the heparin antithrombin binding domain, is an approved clinical anticoagulant. Although it is a better and safer alternative to pharmaceutical heparins in many cases, its high cost, which results from the difficult and tedious synthesis, is a deterrent for its widespread use. The chemical synthesis of fondaparinux was achieved in an efficient and concise manner from commercially available D-glucosamine, diacetone alpha-D-glucose, and penta-O-acetyl-D-glucose. The method involves suitably functionalized building blocks that are readily accessible and employs shared intermediates and a series of one-pot reactions that considerably reduce the synthetic effort and improve the yield. PMID- 25044486 TI - Self-perceived oral health and periodontal parameters in chronic periodontitis patients with and without rheumatoid arthritis. AB - AIM: It is hypothesized that self-perceived oral health and periodontal status are worse in chronic periodontitis (CP) patients with rheumatoid arthritis (RA) compared to CP patients without RA. The aim of the present study was to assess self-perceived oral health and periodontal parameters in CP patients with and without RA. METHODS: Fifty CP patients with RA and 50 CP patients without RA were included. Information regarding sociodemographic characteristics and self perceived oral symptoms were collected using a questionnaire. Periodontal parameters (plaque index, bleeding on probing, probing depth, clinical attachment loss, number of missing teeth, and marginal bone loss) were recorded. RESULTS: There was no significant difference in socioeconomic status, education status, self-perceived oral symptoms, and periodontal parameters among CP patients with and without RA. CONCLUSIONS: Self-perceived oral health and periodontal parameters are mainly governed by the intensity of CP, and the role of RA in this context seems to be rather secondary. PMID- 25044488 TI - Phenothiazinedioxide-conjugated sensitizers and a dual-TEMPO/iodide redox mediator for dye-sensitized solar cells. AB - Metal-free dyes containing a phenothiazinedioxide entity in the spacer were synthesized. The best conversion efficiency (7.47%) of the dye-sensitized solar cell (DSSC) by using new sensitizers with chenodeoxycholic acid as a co-adsorbent and the I(-) /I3 (-) electrolyte reached over 90% of that of the standard N719 based cell (8.10%). A new type of ionic liquid containing the nitroxide radical (N-O(.) ) and iodide was successfully synthesized and applied to the DSSCs. If the I(-) /I3 (-) electrolyte was replaced with a dual redox electrolyte, that is, a TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) derivative with a dangling imidazolium iodide entity, the cell exhibited a high open-circuit voltage of 0.85 V and a cell efficiency of 8.36%. PMID- 25044489 TI - Efficient synthesis of eight-membered nitrogen heterocycles from o-propargylic oximes by rhodium-catalyzed cascade reactions. AB - Azocine derivatives were successfully synthesized from O-propargylic oximes by means of a Rh-catalyzed 2,3-rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines. PMID- 25044487 TI - Ligand modification transforms a catalase mimic into a water oxidation catalyst. AB - The catalytic reactivity of the high-spin Mn(II) pyridinophane complexes [(Py2NR2)Mn(H2O)2](2+) (R=H, Me, tBu) toward O2 formation is reported. With small macrocycle N-substituents (R=H, Me), the complexes catalytically disproportionate H2O2 in aqueous solution; with a bulky substituent (R=tBu), this catalytic reaction is shut down, but the complex becomes active for aqueous electrocatalytic H2O oxidation. Control experiments are in support of a homogeneous molecular catalyst and preliminary mechanistic studies suggest that the catalyst is mononuclear. This ligand-controlled switch in catalytic reactivity has implications for the design of new manganese-based water oxidation catalysts. PMID- 25044490 TI - Asymmetric synthesis of highly substituted beta-lactones through oxidative carbene catalysis with LiCl as cooperative Lewis acid. AB - The reaction of enals with beta-diketones, beta-ketoesters, and malonates bearing a beta-oxyalkyl substituent at the alpha-position by oxidative NHC catalysis to provide highly substituted beta-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two C?C bond formations and one C?O bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade. PMID- 25044491 TI - Insight into the interactions between novel coumarin derivatives and human A3 adenosine receptors. AB - A study focused on the discovery of new chemical entities based on the 3 arylcoumarin scaffold was performed with the aim of finding new adenosine receptor (AR) ligands. Thirteen synthesized compounds were evaluated by radioligand binding (A1, A2A, and A3) and adenylyl cyclase activity (A2B) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A3 AR ligands, with 3-(4' methylphenyl)-8-(2-oxopropoxy)coumarin (12) being the most potent (Ki =634 nM). None of the compounds showed affinity for the A2B receptor, while four compounds were found to be nonselective AR ligands for the other three subtypes. Docking simulations were carried out to identify the hypothetical binding mode and to rationalize the interaction of these types of coumarin derivatives with the binding site of the three ARs to which binding was observed. The results allowed us to conclude that the 3-arylcoumarin scaffold composes a novel and promising class of A3 AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates. PMID- 25044492 TI - Bone signaling in middle ear development: a genome-wide differential expression analysis. AB - Common middle ear diseases may affect bone behavior in the middle ear air cell system. To understand this pathologic pneumatization, the normal development of bone in the middle ear should be investigated. The objective of this study was to analyze gene expression of bone-related signaling factors and gene sets in the developing middle ear. Microarray technology was used to identify bone-related genes and gene sets, which were differentially expressed between the lining tissue of adult (quiescent) bulla and young (resorbing/forming) bulla. Data were analyzed using tools of bioinformatics and expression levels of selected genes were validated using quantitative polymerase chain reaction. The candidate gene products were compared with previously published data on middle ear bone metabolism. No differentially expressed genes were found on the outer surface of bulla. On the inner lining a total of 260 genes were identified of which 22 genes were involved in bone metabolism. Gene set analysis revealed five enriched bone related gene sets. The identified differentially expressed bone-related mRNAs and gene sets are of potential significance in the normally developing bulla. These factors and gene sets may also play important roles during pathologic pneumatization of the middle ear air cell system in common middle ear diseases. In addition, this study suggests that the control of growth rate and wall thickness from resorptive as well as formative signals all originate from the inner lining cells of the bulla wall. PMID- 25044493 TI - Symptoms of anxiety and depression and risk of heart failure: the HUNT Study. AB - AIMS: Symptoms of anxiety and depression often co-exist with cardiovascular disease, yet little is known about the prospective risk for heart failure (HF) in people with symptoms of depression and anxiety. We aimed to study these prospective associations using self-reported symptoms of anxiety, depression, and mixed symptoms of anxiety and depression (MSAD) in a large population sample. METHODS AND RESULTS: In the second wave of the Nord-Trondelag Health Study (HUNT 2, 1995-1997), Norway, baseline data on symptoms of anxiety and depression, socio demographic variables, health status including cardiovascular risk factors, and common chronic somatic diseases were registered for 62,567 adults, men and women, free of known HF. The cohort was followed for incident HF from baseline throughout 2008. A total of 1499 cases of HF occurred during a mean follow-up of 11.3 years (SD = 2.9), identified either in hospital registers or by the National Cause of Death Registry. There was no excess risk for future HF associated with symptoms of anxiety or MSAD at baseline. For depression, the multi-adjusted hazard ratios for HF were 1.07 (0.87-1.30) for moderate symptoms and 1.41 (1.07 1.87) for severe symptoms (P for trend 0.026). Established cardiovascular risk factors, acute myocardial infarction (AMI) prior to baseline, and adjustment for incident AMI as a time-dependent covariate during follow-up had little influence on the estimates. CONCLUSION: Symptoms of depression, but not symptoms of anxiety or MSAD, were associated with increased risk for HF in a dose-response manner. The increased risk could not be fully explained by cardiovascular or socio economic risk factors, or by co-morbid AMI. PMID- 25044494 TI - The Effectiveness of Health Screening. AB - Using a matched insurant-general practitioner panel data set, we estimate the effect of a general health-screening program on individuals' health status and health-care cost. To account for selection into treatment, we use regional variation in the intensity of exposure to supply-determined screening recommendations as an instrumental variable. We find that screening participation increases inpatient and outpatient health-care costs up to 2 years after treatment substantially. In the medium run, we find cost savings in the outpatient sector, whereas in the long run, no statistically significant effects of screening on either health-care cost component can be discerned. In sum, screening participation increases health-care cost. Given that we do not find any statistically significant effect of screening participation on insurants' health status (at any point in time), we do not recommend a general health-screening program. However, given that we find some evidence for cost-saving potential for the sub-sample of younger insurants, we suggest more targeted screening programs. PMID- 25044495 TI - Oxidative stress modulation by Rosmarinus officinalis in creosote-induced hepatotoxicity. AB - Coal tar is a significant product generated from coal pyrolysis. Coal tar can be utilized as raw materials for various industries. It is also a type of raw material from which phenols, naphthalenes, and anthracene can be extracted. The present study was designed to investigate the possibility of coal tar creosote to induce oxidative stress and biochemical perturbations in rat liver and the role of rosemary (Rosmarinus officinalis) in ameliorating its toxic effects. Male Wister Albino rats were randomly divided into four groups of seven each, group I served as control; group II treated with rosemary (10 mL of water extract/kg BW for 21 days), group III received coal tar creosote (200 mg/4 mL olive oil/kg BW for 3 days), and group IV treated with both rosemary and coal tar creosote. The administration of coal tar creosote significantly caused elevation in lipid peroxidation (LPO) and reduction in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST). A significant decrease in reduced glutathione (GSH) content was also observed. Liver aminotransferases aspartate transaminase (AST) and alanine transaminase (ALT)] and alkaline phosphatase (AlP) were significantly decreased while lactate dehydrogenase (LDH) was increased. Rosemary pretreatment to coal tar creosote-treated rats decreased LPO level and normalized GPx, GR, SOD, CAT, and GST activities, while GSH content was increased. Also, liver AST, ALT, AlP, and LDH were maintained near normal level due to rosemary treatment. In conclusion, rosemary has beneficial effects and could be able to antagonize coal tar creosote toxicity. PMID- 25044496 TI - Sensitisation of human lung adenocarcinoma A549 cells to radiotherapy by Nimotuzumab is associated with enhanced apoptosis and cell cycle arrest in the G2/M phase. AB - The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and maintenance of cancers, making it a possible therapeutic target for cancer treatment. Nimotuzumab (h-R3), a humanised monoclonal antibody against EGFR, sensitises human lung adenocarcinoma A549 cells to radiotherapy. We have investigated the underlying molecular mechanism by treating A549 cells with Nimotuzumab (100 MUg/mL) alone or in combination with a single dose of 2 Gy irradiation, and analysing apoptosis and cell cycle distribution by flow cytometry. Nimotuzumab significantly enhanced radiation-induced apoptosis of A549 cells as evidenced by increased cell apoptosis (7.15 +/- 0.30%) compared with the control group (1.08 +/- 0.25%), Nimotuzumab alone group (4.89 +/- 0.30%) and irradiation alone group (5.90 +/- 0.15%). Combining Nimotuzumab with irradiation significantly arrested cells in the G2/M phase (43. +/- 0.36%) compared radiotherapy alone (18.7 +/- 0.35%) and single Nimotuzumab treatment (27.2 +/- 0.17%). A combination of Nimotuzumab with radiation increased apoptosis and G2/M phase arrest in human lung adenocarcinoma A549 cells, suggesting potential development of combinatorial therapy of Nimotuzumab with radiotherapy for lung cancer. PMID- 25044497 TI - Toxicological study and oxidative stress evaluation for safety assessment of xylanase preparations in Wistar rats. AB - Acute and 90-day subchronic oral toxicity studies were conducted to establish the safety evaluation of xylanases preparations. A potential oxidative stress evaluation was also performed through testing the generation of oxidative radicals, depletion of antioxidants via oxidative modification of lipids, proteins and DNA of organ cells. During the subchronic oral toxicity study, no mortality was observed, obvious treatment-related clinical signs and urinalysis parameters were in normal range. Differences in some hematological parameters, biochemistry, relative organ weight, and histopathology examinations between the treated group and the control group were not judged to be adverse. Our results indicated that the no-observed-adverse-effect level for xylanases was 1,500 TXU/kg/day and the plasma antioxidant assays showed that these xylanases did not produce free-radicals nor oxidative injuries. On the basis of the bacterial reverse mutation assay data, it is concluded that the expressed xylanase in Pichia pastoris do not present any mutagenic potential when tested in relevant genotoxicological assays. PMID- 25044498 TI - Management of anomalous circumflex coronary artery from the neo-pulmonary artery in an adolescent following neonatal arterial switch operation. AB - A 15-year-old male with transposition of the great arteries presented with exertional chest pain. He was found to have a circumflex coronary artery from the neo-pulmonary artery that had not been transferred during his arterial switch operation. The circumflex coronary artery, fed through collaterals from a re implanted single coronary artery, resulted in coronary steal. This report describes a management pathway to treat this rare anomaly. PMID- 25044499 TI - Novel roles of the CCR4-NOT complex. AB - The CCR4-NOT complex is a multi-subunit protein complex evolutionarily conserved across eukaryotes which regulates several aspects of gene expression. A fascinating model is emerging in which this complex acts as a regulation platform, controlling gene products 'from birth to death' through the coordination of different cellular machineries involved in diverse cellular functions. Recently the CCR4-NOT functions have been extended to the control of the innate immune response through the regulation of interferon signaling. Thus, a more comprehensive picture of how CCR4-NOT allows the rapid adaptation of cells to external stress, from transcription to mRNA and protein decay, is presented and discussed here. Overall, CCR4-NOT permits the efficient and rapid adaptation of cellular gene expression in response to changes in environmental conditions and stimuli. PMID- 25044500 TI - Engineering enzyme-cleavable hybrid click capsules with a pH-sheddable coating for intracellular degradation. AB - The engineering of layer-by-layer (LbL) hybrid click capsules that are responsive to biological stimuli is reported. The capsules comprise a pH-sheddable, non cross-linked outer coating that protects enzyme-cleavable inner layers. Upon cellular uptake, the outer coating is released and the capsules are enzymatically degraded. In vitro cell degradation results in rapid capsule degradation (10 min) upon cellular internalization. PMID- 25044501 TI - Construction and characterization of stable, constitutively expressed, chromosomal green and red fluorescent transcriptional fusions in the select agents, Bacillus anthracis, Yersinia pestis, Burkholderia mallei, and Burkholderia pseudomallei. AB - Here, we constructed stable, chromosomal, constitutively expressed, green and red fluorescent protein (GFP and RFP) as reporters in the select agents, Bacillus anthracis, Yersinia pestis, Burkholderia mallei, and Burkholderia pseudomallei. Using bioinformatic approaches and other experimental analyses, we identified P0253 and P1 as potent promoters that drive the optimal expression of fluorescent reporters in single copy in B. anthracis and Burkholderia spp. as well as their surrogate strains, respectively. In comparison, Y. pestis and its surrogate strain need two chromosomal copies of cysZK promoter (P2cysZK) for optimal fluorescence. The P0253-, P2cysZK-, and P1-driven GFP and RFP fusions were first cloned into the vectors pRP1028, pUC18R6KT-mini-Tn7T-Km, pmini-Tn7-gat, or their derivatives. The resultant constructs were delivered into the respective surrogates and subsequently into the select agent strains. The chromosomal GFP- and RFP-tagged strains exhibited bright fluorescence at an exposure time of less than 200 msec and displayed the same virulence traits as their wild-type parental strains. The utility of the tagged strains was proven by the macrophage infection assays and lactate dehydrogenase release analysis. Such strains will be extremely useful in high-throughput screens for novel compounds that could either kill these organisms, or interfere with critical virulence processes in these important bioweapon agents and during infection of alveolar macrophages. PMID- 25044503 TI - A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32. AB - A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13 q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 * 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13 q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population. PMID- 25044502 TI - The bioactivity of cartilage extracellular matrix in articular cartilage regeneration. AB - Cartilage matrix is a promising material for cartilage regeneration given the evidence supporting its chondroinductive character. The "raw materials" of cartilage matrix can serve as building blocks and signals for tissue regeneration. These matrices can be created by chemical or physical processing: physical methods disrupt cellular membranes and nuclei but may not fully remove all cell components and DNA, whereas chemical methods combined with physical methods are effective in fully decellularizing such materials. It is important to delineate between the sources of the cartilage matrix, that is, derived from matrix in vitro or from native tissue, and then to further characterize the cartilage matrix based on the processing method, decellularization or devitalization. With these distinctions, four types of cartilage matrices exist: decellularized native cartilage (DCC), devitalized native cartilage (DVC), decellularized cell-derived matrix (DCCM), and devitalized cell-derived matrix (DVCM). One currently marketed cartilage matrix device is decellularized, although trends in patents suggest additional decellularized products may be available in the future. To identify the most relevant source and processing for cartilage matrix, testing needs to include targeting the desired application, optimizing delivery of the material, identify relevant FDA regulations, assess availability of materials, and immunogenic properties of the product. PMID- 25044504 TI - Design of highly sensitive phosphorescence sensor for determination of procaterol hydrochloride based on inhibition of KClO3 oxidation fluorescein isothiocyanate. AB - Procaterol hydrochloride (Prh) can inhibit KClO3 oxidation of fluorescein isothiocyanate (FITC) to form a non-phosphorescent compound, which causes room temperature phosphorescence (RTP) of FITC in the system to enhance sharply the linear relationship between ?Ip and the Prh content. Thus, a rapid response and highly sensitive phosphorescence sensor for the determination of Prh has been developed based on the inhibiting effect of Prh on KClO3 oxidation of FITC. This simple, high sensitivity (detection limit (LD) calculated by 3Sb /k was 0.019 fg/spot, sample volume 0.40 ul, corresponding concentration 4.8 * 10(-14) g ml( 1) ) and selective sensor with a wide linear range (0.080-11.20 g/spot) has been applied to detect Prh in blood samples, and the results were consistent with those obtained by high-performance liquid chromatography (HPLC). Simultaneously, the mechanism of the phosphorescence sensor for the detection of Prh was also investigated using infrared spectroscopy. PMID- 25044505 TI - Gel-based mass spectrometric analysis of hippocampal transmembrane proteins using high resolution LTQ Orbitrap Velos Pro. AB - Membrane proteins (MPs) play diverse important roles for physical interactions, cell communication, molecular transport, and signal transduction. Membrane proteins comprise approximately 25~35% of the genome in living organisms, but there are difficulties in the analysis at the protein chemical level, in particular due to low abundance and limited solubility. Sequence information on membrane proteins and their complexes would be beneficial to elucidate their function. Proteins were extracted from pooled whole mouse brains, enriched membrane fractions were prepared using either two commercially available kits or 6-aminocaproic acid under denaturing or native conditions followed by gel-based proteomic approaches using blue native (BN-) and SDS-PAGE with subsequent in-gel digestion with several proteases, chymotrypsin, trypsin followed by nano-LC-ESI MS/MS analysis on LTQ Orbitrap Velos Pro. By combining three different extraction methods and two separation methods, 28.39% of proteins were identified as either "integral" or "anchored/integral" MPs based on UniProtKB database searches. MPs with more than six transmembrane domains (TMDs) were identified more efficiently from BN-PAGE separation although a higher number of proteins was identified from SDS-PAGE separation. Comparative analysis of MPs containing TMDs via gel-based LC MS/MS using BN-PAGE and SDS-PAGE may be useful to increase the number of identified membrane proteins in brain. All MS data have been deposited in the ProteomeXchange with identifier PXD000311 (http://proteomecentral.proteomexchange.org/dataset/PXD000311). PMID- 25044506 TI - Eight year follow-up of an epidemic of sirenomelia in Cali, Colombia. PMID- 25044507 TI - Spatial and body-size dependent response of marine pelagic communities to projected global climate change. AB - Temperature, oxygen, and food availability directly affect marine life. Climate models project a global warming of the ocean's surface (~+3 degrees C), a de oxygenation of the ocean's interior (~-3%) and a decrease in total marine net primary production (~-8%) under the 'business as usual' climate change scenario (RCP8.5). We estimated the effects of these changes on biological communities using a coupled biogeochemical (PISCES)--ecosystems (APECOSM) model forced by the physical outputs of the last generation of the IPSL-CM Earth System Model. The APECOSM model is a size-structured bio-energetic model that simulates the 3D dynamical distributions of three interactive pelagic communities (epipelagic, mesopelagic, and migratory) under the effects of multiple environmental factors. The PISCES-APECOSM model ran from 1850 to 2100 under historical forcing followed by RCP8.5. Our RCP8.5 simulation highlights significant changes in the spatial distribution, biomass, and maximum body-size of the simulated pelagic communities. Biomass and maximum body-size increase at high latitude over the course of the century, reflecting the capacity of marine organisms to respond to new suitable environment. At low- and midlatitude, biomass and maximum body-size strongly decrease. In those regions, large organisms cannot maintain their high metabolic needs because of limited and declining food availability. This resource reduction enhances the competition and modifies the biomass distribution among and within the three communities: the proportion of small organisms increases in the three communities and the migrant community that initially comprised a higher proportion of small organisms is favored. The greater resilience of small body size organisms resides in their capacity to fulfill their metabolic needs under reduced energy supply and is further favored by the release of predation pressure due to the decline of large organisms. These results suggest that small body-size organisms might be more resilient to climate change than large ones. PMID- 25044509 TI - Improving the mechanical properties of collagen-based membranes using silk fibroin for corneal tissue engineering. AB - Although collagen with outstanding biocompatibility has promising application in corneal tissue engineering, the mechanical properties of collagen-based scaffolds, especially suture retention strength, must be further improved to satisfy the requirements of clinical applications. This article describes a toughness reinforced collagen-based membrane using silk fibroin. The collagen silk fibroin membranes based on collagen [silk fibroin (w/w) ratios of 100:5, 100:10, and 100:20] were prepared by using silk fibroin and cross-linking by 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide. These membranes were analyzed by scanning electron microscopy and their optical property, and NaCl and tryptophan diffusivity had been tested. The water content was found to be dependent on the content of silk fibroin, and CS10 membrane (loading 10 wt % of silk fibroin) performed the optimal mechanical properties. Also the suture experiments have proved CS10 has high suture retention strength, which can be sutured in rabbit eyes integrally. Moreover, the composite membrane proved good biocompatibility for the proliferation of human corneal epithelial cells in vitro. Lamellar keratoplasty shows that CS10 membrane promoted complete epithelialization in 35 +/- 5 days, and their transparency is restored quickly in the first month. Corneal rejection reaction, neovascularization, and keratoconus are not observed. The composite films show potential for use in the field of corneal tissue engineering. PMID- 25044510 TI - Evidence of dihydrogen bonding of a chiral amine-borane complex in solution by VCD spectroscopy. AB - IR and vibrational circular dichroism (VCD) spectra of a chiral amine-borane in solution are investigated. By comparison of experimental and calculated spectra, unique VCD spectral signatures, which can be attributed to the formation of dihydrogen-bonded dimers in solution, are identified for the first time. These VCD features are highly sensitive to the specific dihydrogen-bonding topologies utilized by the chiral amine-borane subunits and thus provide direct structural information of these dihydrogen-bonded species in solution. Differences in the dihydrogen binding arrangements in solution and in solid state are also revealed. PMID- 25044511 TI - Enantioselective biomimetic total syntheses of kuwanons I and J and brosimones A and B. AB - The first enantioselective total syntheses of prenylflavonoid Diels-Alder natural products (-)-kuwanon I, (+)-kuwanon J, (-)-brosimone A, and (-)-brosimone B have been accomplished from a common intermediate based on a concise synthetic strategy. Key elements of the synthesis include a biosynthesis-inspired asymmetric Diels-Alder cycloaddition mediated by a chiral ligand/boron Lewis acid, as well as a process involving regioselective Schenck ene reaction, reduction, and dehydration to realize a biomimetic dehydrogenation for generation of the required diene precursor. Furthermore, a remarkable tandem inter /intramolecular asymmetric Diels-Alder cycloaddition process was applied for the synthesis of (-)-brosimone A. PMID- 25044513 TI - Field dissipation of four personal care products in biosolids-amended soils in North China. AB - The present study investigated the dissipation behaviors of 4 typical personal care products (PCPs)-triclocarban (TCC), triclosan (TCS), tonalide (AHTN), and galaxolide (HHCB)- in soils amended with biosolids under field conditions in North China. The results showed that the 4 target compounds were detected in all biosolids-amended soils at levels of a few nanograms per gram to thousands of nanograms per gram (dry wt). The residual concentrations of the 4 PCPs were found in the following order: TCC > TCS > AHTN > HHCB. Significant dissipation of the 4 PCPs was observed in the biosolids-amended soils, with half-lives ranging from 26 d to 133 d. Furthermore, repeated biosolids applications and a higher biosolids application rate could lead to higher accumulation of the 4 PCPs in the agricultural soils. Based on the detected concentrations in the field trial and limited ecotoxicity data, high risks to soil organisms are expected for TCC, whereas low to medium risks are expected in most cases for AHTN, HHCB, and TCS. PMID- 25044512 TI - Preparation and characterization of the 'research chemical' diphenidine, its pyrrolidine analogue, and their 2,2-diphenylethyl isomers. AB - Substances with the diphenylethylamine nucleus represent a recent addition to the product catalog of dissociative agents sold as 'research chemicals' on the Internet. Diphenidine, i.e. 1-(1,2-diphenylethyl)piperidine (1,2-DEP), is such an example but detailed analytical data are less abundant. The present study describes the synthesis of diphenidine and its most obvious isomer, 1-(2,2 diphenylethyl)piperidine (2,2-DEP), in order to assess the ability to differentiate between them. Preparation and characterization were also extended to the two corresponding pyrrolidine analogues 1-(1,2-diphenylethyl)- and 1-(2,2 diphenylethyl)pyrrolidine, respectively. Analytical characterizations included high-resolution electrospray mass spectrometry (HR-ESI-MS), liquid chromatography ESI-MS/MS, gas chromatography ion trap electron and chemical ionization MS, nuclear magnetic resonance spectroscopy (NMR) and infrared spectroscopy. Differentiation between the two isomeric pairs was possible under GC-(EI/CI)-MS conditions and included the formation of distinct iminium ions, such as m/z 174 for 1,2-DEP and m/z 98 for 2,2-DEP, respectively. The pyrrolidine counterparts demonstrated similar phenomena including the expected mass difference of 14 Da due to the lack of one methylene unit in the ring. Two samples obtained from an Internet vendor provided confirmation that diphenidine was present in both samples, concurring with the product label. Finally, it was confirmed that diphenidine (30 MUM) reduced N-methyl-D-aspartate-mediated field excitatory postsynaptic potentials (NMDA-fEPSPs) to a similar extent to that of ketamine (30 MUM) when using rat hippocampal slices. The appearance of 1,2- diphenylethylamines appears to reflect the exploration of alternatives to arylcyclohexylamine-type substances, such as methoxetamine, PCP and PCPy-based analogues that also show NMDA receptor activity as demonstrated here for diphenidine. PMID- 25044515 TI - The ketimide ligand is not just an inert spectator: heteroallene insertion reactivity of an actinide-ketimide linkage in a thorium carbene amide ketimide complex. AB - The ketimide anion R2C=N(-) is an important class of chemically robust ligand that binds strongly to metal ions and is considered ideal for supporting reactive metal fragments due to its inert spectator nature; this contrasts with R2N(-) amides that exhibit a wide range of reactivities. Here, we report the synthesis and characterization of a rare example of an actinide ketimide complex [Th(BIPM(TMS)){N(SiMe3)2}(N=CPh2)] [2, BIPM(TMS)=C(PPh2NSiMe3)2]. Complex 2 contains Th=C(carbene), Th-N(amide) and Th-N(ketimide) linkages, thereby presenting the opportunity to probe the preferential reactivity of these linkages. Importantly, reactivity studies of 2 with unsaturated substrates shows that insertion reactions occur preferentially at the Th-N(ketimide) bond rather than at the Th=C(carbene) or Th-N(amide) bonds. This overturns the established view that metal-ketimide linkages are purely inert spectators. PMID- 25044514 TI - Oxidative DNA damage in disease--insights gained from base excision repair glycosylase-deficient mouse models. AB - Cellular components, including nucleic acids, are subject to oxidative damage. If left unrepaired, this damage can lead to multiple adverse cellular outcomes, including increased mutagenesis and cell death. The major pathway for repair of oxidative base lesions is the base excision repair pathway, catalyzed by DNA glycosylases with overlapping but distinct substrate specificities. To understand the role of these glycosylases in the initiation and progression of disease, several transgenic mouse models have been generated to carry a targeted deletion or overexpression of one or more glycosylases. This review summarizes some of the major findings from transgenic animal models of altered DNA glycosylase expression, especially as they relate to pathologies ranging from metabolic disease and cancer to inflammation and neuronal health. PMID- 25044516 TI - Graphene oxides prepared by Hummers', Hofmann's, and Staudenmaier's methods: dramatic influences on heavy-metal-ion adsorption. AB - Graphene oxide (GO), an up-and-coming material rich in oxygenated groups, shows much promise in pollution management. GO is synthesised using several synthetic routes, and the adsorption behaviour of GO is investigated to establish its ability to remove the heavy-metal pollutants of lead and cadmium ions. The GO is synthesised by Hummers' (HU), Hofmann's (HO) and Staudenmaier's (ST) methodologies. Characterisation of GO is performed before and after adsorption experiments to investigate the structure-function relationship by using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Scanning electron microscopy coupled with elemental detection spectroscopy is used to investigate morphological changes and heavy-metal content in the adsorbed GO. The filtrate, collected after adsorption, is analysed by inductively coupled plasma mass spectrometry, through which the efficiency and adsorption capacity of each GO for heavy-metal-ion removal is obtained. Spectroscopic analysis and characterisation reveal that the three types of GO have different compositions of oxygenated carbon functionalities. The trend in the affinity towards both Pb(II) and Cd(II) is HU GO>HO GO>ST GO. A direct correlation between the number of carboxyl groups present and the amount of heavy-metal ions adsorbed is established. The highest efficiency and highest adsorption capacity of heavy metal ions is achieved with HU, in which the relative abundance of carboxyl groups is highest. The embedded systematic study reveals that carboxyl groups are the principal functionality responsible for heavy-metal-ion removal in GO. The choice of synthesis methodology for GO has a profound influence on heavy-metal ion adsorption. A further enrichment of the carboxyl groups in GO will serve to enhance the role of GO as an adsorbent for environmental clean-up. PMID- 25044518 TI - Stereocontrolled synthesis of 1,5-stereogenic centers through three-carbon homologation of boronic esters. AB - Allylic pinacol boronic esters are stable toward 1,3-borotropic rearrangement. We developed a Pd(II)-mediated isomerization process that gives di- or trisubstituted allylic boronic esters with high E selectivity. The combination of this method with lithiation-borylation enables the synthesis of carbon chains that bear 1,5-stereogenic centers. The utility of this method has been demonstrated in a formal synthesis of (+)-jasplakinolide. PMID- 25044519 TI - Microarray-based identification of lectins for the purification of human urinary extracellular vesicles directly from urine samples. AB - As cellular-derived vesicles largely maintain the biomolecule composition of their original tissue, exosomes, which are found in nearly all body fluids, have enormous potential as clinical disease markers. A major bottleneck in the development of exosome-based diagnostic assays is the challenging purification of these vesicles; this requires time-consuming and instrument-based procedures. We employed lectin arrays to identify potential lectins as probes for affinity-based isolation of exosomes from the urinary matrix. We found three lectins that showed specific interactions to vesicles and no (or only residual) interaction with matrix proteins. Based on these findings a bead-based method for lectin-based isolation of exosomes from urine was developed as a sample preparation step for exosome-based biomarker research. PMID- 25044520 TI - Reply: To PMID 24734314. PMID- 25044522 TI - Electrochemical energy conversion: past, present, and future. PMID- 25044521 TI - Ultra high performance liquid chromatography with photodiode array detector and quadrupole time-of-flight tandem mass spectrometry coupled with discriminant analysis to evaluate Angelicae pubescentis radix from different regions. AB - A rapid and effective method was developed for the qualitative and quantitative analysis of the major chemical constituents in Angelicae pubescentis radix by ultra high performance liquid chromatography with photodiode array detection and quadrupole time-of-flight tandem mass spectrometry. The chromatographic separation was achieved on an ACQUITY UHPLC BEH C18 column (2.1 * 100 mm, 1.7 MUm). Nine phenolic acids, 30 coumarins, bisabolangelone, and adenosine were identified by quadrupole time-of-flight tandem mass spectrometry. All calibration curves exhibited good linearity (r > 0.9996) within the linear ranges. The relative standard deviation calculated for intraday and interday precision, stability, and accuracy were <5%. The mean recovery ranged from 95.8 to 106%. The overall limits of detection and quantification were 0.025-0.160 and 0.100-0.560 MUg/mL, respectively. Discriminant analysis was investigated as a method for evaluating the quality of the samples with 100% correction in their classification. The results demonstrated that the developed method could successfully be used to differentiate samples from different regions and could be a helpful tool for detection and confirmation of the quality of traditional Chinese medicines. PMID- 25044525 TI - Recent progress in research on high-voltage electrolytes for lithium-ion batteries. AB - Developing a stable and safe electrolyte that works at voltages as high as 5 V is a formidable challenge in present Li-ion-battery research because such high voltages are beyond the electrochemical stability of the conventional carbonate based solvents available. In the past few years, extensive efforts have been carried out by the research community toward the exploration of high-voltage electrolytes. In this review, recent progress in the study of several promising high-voltage electrolyte systems, as well as their recipes, electrochemical performance, electrode compatibility, and characterization methods, are summarized and reviewed. These new electrolyte systems include high-voltage film forming additives and new solvents, such as sulfones, ionic liquids, nitriles, and fluorinated carbonates. It appears to be very difficult to find a good high voltage (~5 V) electrolyte with a single-component solvent at the present stage. Using mixed fluorinated-carbonate solvents and additives are two realistic solutions for practical applications in the near term, while sulfones, nitriles, ionic liquids and solid-state electrolyte/polymer electrolytes are promising candidates for the next generation of high-voltage electrolyte systems. PMID- 25044526 TI - Sodium vanadium oxide: a new material for high-performance symmetric sodium-ion batteries. AB - Room-temperature sodium-ion batteries have the potential to become the technology of choice for large-scale electrochemical energy storage because of the high sodium abundance and low costs. However, not many materials meet the performance requirements for practical applications. Here, we report a novel sodium-ion battery electrode material, Na(2.55)V(6)O(16)?0.6 H(2)O, that shows significant capacities and stabilities at high current rates up to 800 mA g(-1). X-ray photoelectron spectroscopy measurements are carried out to better understand the underlying reactions. Moreover, due to the different oxidation states of vanadium, this material can also be employed in a symmetric full cell, which would decrease production costs even further. For these full cells, capacity and stability tests are conducted using various cathode:anode mass ratios. PMID- 25044527 TI - In situ quantification and visualization of lithium transport with neutrons. AB - A real-time quantification of Li transport using a nondestructive neutron method to measure the Li distribution upon charge and discharge in a Li-ion cell is reported. By using in situ neutron depth profiling (NDP), we probed the onset of lithiation in a high-capacity Sn anode and visualized the enrichment of Li atoms on the surface followed by their propagation into the bulk. The delithiation process shows the removal of Li near the surface, which leads to a decreased coulombic efficiency, likely because of trapped Li within the intermetallic material. The developed in situ NDP provides exceptional sensitivity in the temporal and spatial measurement of Li transport within the battery material. This diagnostic tool opens up possibilities to understand rates of Li transport and their distribution to guide materials development for efficient storage mechanisms. Our observations provide important mechanistic insights for the design of advanced battery materials. PMID- 25044528 TI - Nanostructured manganese oxides as highly active water oxidation catalysts: a boost from manganese precursor chemistry. AB - We present a facile synthesis of bioinspired manganese oxides for chemical and photocatalytic water oxidation, starting from a reliable and versatile manganese(II) oxalate single-source precursor (SSP) accessible through an inverse micellar molecular approach. Strikingly, thermal decomposition of the latter precursor in various environments (air, nitrogen, and vacuum) led to the three different mineral phases of bixbyite (Mn2 O3 ), hausmannite (Mn3 O4 ), and manganosite (MnO). Initial chemical water oxidation experiments using ceric ammonium nitrate (CAN) gave the maximum catalytic activity for Mn2 O3 and MnO whereas Mn3 O4 had a limited activity. The substantial increase in the catalytic activity of MnO in chemical water oxidation was demonstrated by the fact that a phase transformation occurs at the surface from nanocrystalline MnO into an amorphous MnOx (1= 70 years of age with HF. Patients were divided into three baseline pre-treatment SBP categories (<110, 110-130, and >130 mmHg). In addition, we evaluated the influence of SBP (<= 130 and > 130 mmHg) on patients with LVEF <40% vs. >= 40%. Low baseline SBP was associated with worse clinical outcomes irrespective of treatment group, both in patients with reduced EF and in those with preserved EF. Nebivolol had similar benefits irrespective of baseline SBP: the hazard ratio (HR) for primary outcome of all-cause mortality or cardiovascular hospitalization in the three SBP categories for nebivolol vs. placebo was 0.85 [95% confidence interval (CI) 0.50-1.45], 0.79 (95% CI 0.61 1.01), and 0.88 (95% CI 0.72-1.07), respectively (P for interaction = 0.61). Similar results were obtained for the secondary endpoint of all-cause mortality. There was no significant interaction for the effects of nebivolol by baseline SBP stratified by LVEF. CONCLUSIONS: Elderly HF patients with lower SBP have a worse outcome than those with higher SBP, but nebivolol appears to be safe and well tolerated, with similar benefits on the composite outcome of death or cardiovascular hospital admission irrespective of baseline SBP and LVEF. PMID- 25044536 TI - Acoustical and anatomical determination of sound production and transmission in West Indian (Trichechus manatus) and Amazonian (T. inunguis) manatees. AB - West Indian (Trichechus manatus) and Amazonian (T. inunguis) manatees are vocal mammals, with most sounds produced for communication between mothers and calves. While their hearing and vocalizations have been well studied, the actual mechanism of sound production is unknown. Acoustical recordings and anatomical examination were used to determine the source of sound generation. Recordings were performed on live captive manatees from Puerto Rico, Cuba and Colombia (T. manatus) and from Peru (T. inunguis) to determine focal points of sound production. The manatees were recorded using two directional hydrophones placed on the throat and nasal region and an Edirol-R44 digital recorder. The average sound intensity level was analyzed to evaluate the sound source with a T test: paired two sample for means. Anatomical examinations were conducted on six T. manatus carcasses from Florida and Puerto Rico. During necropsies, the larynx, trachea, and nasal areas were dissected, with particular focus on identifying musculature and soft tissues capable of vibrating or constricting the airway. From the recordings we found that the acoustical intensity was significant (P < 0.0001) for both the individuals and the pooled manatees in the ventral throat region compared to the nasal region. From the dissection we found two raised areas of tissue in the lateral walls of the manatee's laryngeal lumen that are consistent with mammalian vocal folds. They oppose each other and may be able to regulate airflow between them when they are adducted or abducted by muscular control of arytenoid cartilages. Acoustic and anatomical evidence taken together suggest vocal folds as the mechanism for sound production in manatees. PMID- 25044537 TI - Birth weight and academic achievement in childhood. AB - Research has shown that birth weight has a lasting impact on later-life outcomes such as educational attainment and earnings. This paper examines the role of health at birth in determining academic achievement in childhood, which may provide the link between birth weight and adult outcomes. Using three waves of the Child Development Supplement of the Panel Study of Income Dynamics data over 1997-2007, we build on the literature by employing the fetal growth rate as a proxy for net nutritional intake in utero and propose a nested error-component two-stage least squares estimator that draws on internal instruments from alternative dimensions of the multilevel panel data set. In particular, this alternative estimator allows us to exploit the information on children with no siblings in the sample, which comprise over 40% of the observations in our sample, as well as to obtain coefficient estimates for the time-invariant variables such as race and maternal education. This would not be feasible with the usual mother fixed effects estimation. We obtain modest but significant effects of both birth weight and the fetal growth rate on math and reading scores, with the effects concentrated in the low birth weight range. Infant health measures appear to explain little of the well-documented racial disparity in test scores. PMID- 25044538 TI - Silica-carrying particulate matter enhances Bjerkandera adusta-induced murine lung eosinophilia. AB - Bjerkandera adusta (B. adusta) causes fungus-associated chronic cough. However, the inflammatory response is not yet fully understood. Recently, B. adusta was identified in Asian sand dust (ASD) aerosol. This study investigated the enhancing effects of ASD on B. adusta-induced lung inflammation. B. adusta was inactivated by formalin. ASD was heated to remove toxic organic substances. ICR mice were intratracheally instilled with saline, B. adusta 0.2 ug, or B. adusta 0.8 ug with or without heated ASD 0.1 mg (H-ASD), four times at 2-week intervals. Two in vitro experiments were conducted to investigate any enhancing effects using bone marrow-derived macrophages (BMDM) from Toll-like receptor (TLR) knockout mice and ICR mice. Co-exposure to H-ASD and B. adusta, especially at high doses, caused eosinophil infiltration, proliferation of goblet cells in the airway, and fibrous thickening of the subepithelial layer, and remarkable increases in expression of Th2 cytokines and eosinophil-related cytokine and chemokine expression in bronchoalveolar lavage fluid. In the in vitro study using BMDM from wild-type, TLR2-/-, and TLR4-/- mice, the TLR-signaling pathway for cytokine production caused by B. adusta was predominantly TLR2 rather than TLR4. H-ASD increased the expression of NF-kappaB and cytokine production by B. adusta in BMDM from ICR mice. The results suggest that co-exposure to H-ASD and B. adusta caused aggravated lung eosinophilia via remarkable increases of pro inflammatory mediators. The aggravation of inflammation may be related, at least in part, to the activation of the TLR2-NF-kappaB signaling pathway in antigen presenting cells by H-ASD. PMID- 25044540 TI - Improved nuclear delivery of antisense 2'-Ome RNA by conjugation with the histidine-rich peptide H5WYG. AB - BACKGROUND: Antisense oligonucleotides are promising medicines for treating various diseases, although their efficiency still requires high doses. Their delivery in the cytosol and nucleus to reach their mRNA targets would increase their efficiency at the same time as reducing the dose. METHODS: We conjugated the histidine-rich peptide H5WYG (GLFHAIAHFIHGGWHGLIHGWYG) at the 5'-end of the RNase H-incompetent antisense 2'-O-methyl-phosphodiester oligonucleotide (2'-Ome RNA705) targeting aberrant splicing of luciferase pre-mRNA in HeLa pLuc705 cells. H5WYG was also conjugated with 2'-Ome-RNA705 labelled by fluorescein at the 3' end. Then, H5WYG-2'-Ome-RNA705 conjugate and 2'-Ome-RNA705 were formulated with lipofectamine to favor their uptake in HeLa pLuc705 cells. RESULTS: Confocal microscopy showed that, after 4 h and overnight incubation, the presence of fluorescein-labelled 2'-Ome-RNA705 in the cytosol and nucleus was enhanced when the oligonucleotide was conjugated with H5WYG. We found that H5WYG-2'-Ome-RNA705 increased the splicing redirection and restoration of a functional luciferase mRNA. Luciferase activity and luciferase mRNA levels in these cells were 6.6- and two-fold higher, respectively, with H5WYG-2'-Ome-RNA705 than with 2'-Ome-RNA705. CONCLUSIONS: The results of the present study show that the conjugation of 2'-Ome antisense RNA to peptide H5WYG is a good strategy for improving its cytosol delivery, accumulation in the nucleus and antisense activity. PMID- 25044539 TI - Epigallocatechin-3-gallate suppresses the lipid deposition through the apoptosis during differentiation in bovine bone marrow mesenchymal stem cells. AB - Epigallocatechin gallate (EGCG), a major component of tea, has known effects on obesity, fatty liver, and obesity-related cancer. We explored the effects of EGCG on the differentiation of bovine mesenchymal stem cells (BMSCs, which are multipotent) in a dose- and time-dependent manner. Differentiating BMSCs were exposed to various concentrations of EGCG (0, 10, 50, 100, and 200 uM) for 2, 4, and 6 days. BMSCs were cultured in Dulbecco's modified Eagle's medium (DMEM)/high glucose medium with adipogenic inducers for 6 days, and the expression levels of various genes involved in adipogenesis were measured using real-time polymerase chain reaction (PCR) and Western blotting. We assessed apoptosis by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining of control and EGCG-exposed cells. We found that EGCG significantly suppressed fat deposition and cell viability (P < 0.05). The mRNA and protein levels of various adipogenic factors were measured. Expression of the genes encoding peroxisome proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein alpha (CEBPA), fatty acid-binding protein 4 (FABP4), and stearoyl-CoA desaturase (SCD) were diminished by EGCG during adipogenic differentiation (P < 0.05). We also found that EGCG lowered the expression levels of the adipogenic proteins encoded by these genes (P < 0.05). EGCG induced apoptosis during adipogenic differentiation (P < 0.05). Thus, exposure to EGCG potentially inhibits adipogenesis by triggering apoptosis; the data suggest that EGCG inhibits adipogenic differentiation in BMSCs. PMID- 25044541 TI - Utilization of nanoparticles as X-ray contrast agents for diagnostic imaging applications. AB - Among all the diagnostic imaging modalities, X-ray imaging techniques are the most commonly used owing to their high resolution and low cost. The improvement of these techniques relies heavily on the development of novel X-ray contrast agents, which are molecules that enhance the visibility of internal structures within the body in X-ray imaging. To date, clinically used X-ray contrast agents consist mainly of small iodinated molecules that might cause severe adverse effects (e.g. allergies, cardiovascular diseases and nephrotoxicity) in some patients owing to the large and repeated doses that are required to achieve good contrast. For this reason, there is an increasing interest in the development of alternative X-ray contrast agents utilizing elements with high atomic numbers (e.g. gold, bismuth, ytterbium and tantalum), which are well known for exhibiting high absorption of X-rays. Nanoparticles (NPs) made from these elements have been reported to have better imaging properties, longer blood circulation times and lower toxicity than conventional iodinated X-ray contrast agents. Additionally, the combination of two or more of these elements into a single carrier allows for the development of multimodal and hybrid contrast agents. Herein, the limitations of iodinated X-ray contrast agents are discussed and the parameters that influence the efficacy of X-ray contrast agents are summarized. Several examples of the design and production of both iodinated and iodine-free NP-based X-ray contrast agents are then provided, emphasizing the studies performed to evaluate their X-ray attenuation capabilities and their toxicity in vitro and in vivo. PMID- 25044542 TI - Biopsy of a complicated right atrial mass using CARTO 3-dimensional electro anatomic mapping. AB - We report the successful biopsy of a right atrial fatty mass using CARTO 3 dimensional electro-anatomic mapping fused with cardiac MRI. Fluoroscopic guidance within the cardiac chambers lacks precision and therefore risks geographical miss of the intended target and cardiac perforation. CARTO mapping fused with cardiac MRI facilitated precise navigation of the bioptome thereby ensuring a successful biopsy of the intended tissue while minimizing the risks of inadvertent trauma to adjacent tissue. PMID- 25044543 TI - Biological effects of paenilamicin, a secondary metabolite antibiotic produced by the honey bee pathogenic bacterium Paenibacillus larvae. AB - Paenibacillus larvae is the etiological agent of American Foulbrood (AFB) a world wide distributed devastating disease of the honey bee brood. Previous comparative genome analysis and more recently, the elucidation of the bacterial genome, provided evidence that this bacterium harbors putative functional nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) and therefore, might produce nonribosomal peptides (NRPs) and polyketides (PKs). Such biosynthesis products have been shown to display a wide-range of biological activities such as antibacterial, antifungal or cytotoxic activity. Herein we present an in silico analysis of the first NRPS/PKS hybrid of P. larvae and we show the involvement of this cluster in the production of a compound named paenilamicin (Pam). For the characterization of its in vitro and in vivo bioactivity, a knock-out mutant strain lacking the production of Pam was constructed and subsequently compared to wild-type species. This led to the identification of Pam by mass spectrometry. Purified Pam-fractions showed not only antibacterial but also antifungal and cytotoxic activities. The latter suggested a direct effect of Pam on honey bee larval death which could, however, not be corroborated in laboratory infection assays. Bee larvae infected with the non-producing Pam strain showed no decrease in larval mortality, but a delay in the onset of larval death. We propose that Pam, although not essential for larval mortality, is a virulence factor of P. larvae influencing the time course of disease. These findings are not only of significance in elucidating and understanding host-pathogen interactions but also within the context of the quest for new compounds with antibiotic activity for drug development. PMID- 25044544 TI - Directing stem cell differentiation by changing the molecular mobility of supramolecular surfaces. AB - Polymer surfaces with a wide range of hydrated surface mobility are developed by a simple deposition method with supramolecular block copolymers. The morphologies of adhering stem cells are greatly dependent on the surface mobility of polymers, and this induces significant changes in the cytoskeletal signaling pathway to direct the downstream stem cell differentiation. PMID- 25044546 TI - Graphene field-effect transistor and its application for electronic sensing. AB - Graphene, because of its excellent mechanical, electrical, chemical, physical properties, sparked great interest to develop and extend its applications. Particularly, graphene based field-effect transistors (GFETs) present exciting and bright prospects for sensing applications due to their greatly higher sensitivity and stronger selectivity. This Review highlights a selection of important topics pertinent to GFETs and their application in electronic sensors. This article begins with a description of the fabrications and characterizations of GFETs, and then introduces the new developments in physical, chemical, and biological electronic detection using GFETs. Finally, several perspective and current challenges of GFETs development are presented, and some proposals are suggested for further development and exploration. PMID- 25044545 TI - Removal of cleavage slow points from affinity tags used in the IMAC purification of recombinant proteins. AB - The complete enzymatic removal of affinity tags from tagged recombinant proteins is often required but can be challenging when slow points for cleavage exist. This study documents a general approach to remove N-terminal tags from recombinant proteins specifically designed to be efficiently captured by IMAC resins. In particular, site-directed mutagenesis procedures have been used to modify the amino acid sequence of metal binding tags useful in IMAC purifications of recombinant proteins with the objective to increase cleavage efficiency with the exopeptidase, dipeptidyl aminopeptidase 1. These tags were specifically developed for application with borderline metal ions, such as Ni(2+) or Cu(2+) ions, chelated to the immobilized ligands, 1,4,7-triazacyclononane (tacn) and its analogs. Due to the ability to control cleavage site structure and accessibility via site directed mutagenesis methods, these procedures offer considerable scope to obtain recombinant proteins with authentic native N-termini, thus avoiding any impact on structural stability, humoral and cellular immune responses, or other biological functions. Collectively, these IMAC-based methods provide a practical alternative to other procedures for the purification of recombinant proteins with tag removal. Overall, this approach is essentially operating as an integrated down-stream purification capability. PMID- 25044547 TI - Psychological Well-Being and Anticipated Positive Personal Events: Their Relationship to Depression. AB - Well-being is now defined in a number of multicomponent ways. One approach to defining well-being-psychological well-being (PWB; Ryff, )-encompasses six dimensions of positive functioning. This study's first aim was to compare PWB self-report scores from a group of depressed participants (N = 26) with a non depressed group (N = 26). The second aim was to examine anticipated well-being, specifically, how the positive events people anticipate in the future are seen as being related to various aspects of their well-being. Participants completed the self-report scales of PWB and a task which elicited events participants were looking forward to in the future and their thoughts about what was good about those events. Responses about the value of the events were independently coded for the presence of the six PWB dimensions. The depressed group scored significantly lower on all dimensions of self-reported PWB than the control group, with particularly marked deficits on environmental mastery and self acceptance. For anticipated events, positive relations with others was the most commonly present aspect of PWB in participants' responses about what was good about the events. The frequency of PWB dimensions present in participants' responses was similar between the two groups with the exception of the depressed group having more self-acceptance related responses and fewer positive relationship responses. The well-established lack of positive anticipation found in depressed individuals is likely to mean a diminished resource for a wide range of aspects of well-being but especially positive relationships with others. KEY PRACTITIONER MESSAGE: The treatment of depression is thought to be more effective when it enhances psychological well-being as well as reducing dysfunction. In the present study, all dimensions of psychological well-being were lower in depressed participants with particularly marked deficits in environmental mastery and self acceptance, suggesting that these may be particularly important treatment targets. People with depression show specific deficits in being able to anticipate future positive events. The present study suggests that anticipated well-being linked to positive relationships with other people may be particularly impacted by the lack of anticipated future events found in depression. PMID- 25044548 TI - Polygenic scores associated with educational attainment in adults predict educational achievement and ADHD symptoms in children. AB - The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale. PMID- 25044549 TI - Preparation of carbon quantum dots based on starch and their spectral properties. AB - A simple method for the synthesis of water-soluble carbon quantum dots (CQDs) has been developed based on chemical oxidation of starch. The structures and optical properties of the CQDs were characterized by ultraviolet-visible (UV-Vis) spectroscopy, photoluminescence spectroscopy (PL) and transmission electron microscopy. The CQDs were found to emit bright blue fluorescence and disperse uniformly. The effects of ambient temperature, light and pH on the properties of CQDs were studied. The CQDs exhibited good chemical stability, good photostability and pH sensitivity. Furthermore, the interaction between CQDs and bovine serum albumin (BSA) was investigated. PMID- 25044550 TI - Characterization of the proteinaceous skeletal organic matrix from the precious coral Corallium konojoi. AB - The Japanese red and pink corals are known to be precious because of their commercial value resulting from their use in ornaments, jewelry, and medicine. Precious corals are very interesting models for biomineralization studies and possess two different skeletal structures: an axial skeleton and an endoskeleton (sclerites). Although it has long been known that the organic matrix proteins existing in coral skeletons are critical for the oriented precipitation of CaCO3 crystals, these proteins in moderate deep-sea Japanese precious corals remain uncharacterized. Therefore, in this study, we performed skeletal whole proteome analyses using 1D and 2D electrophoresis, nano-LC, and MALDI-TOF-TOF MS. We identified a total of 147 functional coral skeletal organic matrix proteins (120 from the sclerites and 36 from the axial skeleton), including two calcium-binding calmodulin. Among the organic matrix proteins identified, nine key proteins are highly typical and common in both skeletons. Strong glycosylation activity, which is essential for skeletal formation in calcifying organisms, was detected in both skeletons. This work demonstrates unique biomineralization-related proteins in precious corals and provides the first description of the major proteinaceous components of CaCO3 minerals in precious corals, enabling the comparative investigation of biocalcification in other octocorals. PMID- 25044551 TI - The historical Coffin-Lowry syndrome family revisited: identification of two novel mutations of RPS6KA3 in three male patients. AB - Coffin-Lowry syndrome (CLS) is a rare X-linked dominant disorder characterized by intellectual disability, craniofacial abnormalities, short stature, tapering fingers, hypotonia, and skeletal malformations. CLS is caused by mutations in the Ribosomal Protein S6 Kinase, 90 kDa, Polypeptide 3 (RPS6KA3) gene located at Xp22.12, which encodes Ribosomal S6 Kinase 2 (RSK2). Here we analyzed RPS6KA3 in three unrelated CLS patients including one from the historical Coffin-Lowry syndrome family and found two novel mutations. To date, over 140 mutations in RPS6KA3 have been reported. However, the etiology of the very first familial case, which was described in 1971 by Lowry with detailed phenotype and coined the term CLS, has remained unknown. More than 40 years after the report, we succeeded in identifying deposited fibroblast cells from one patient of this historic family and found a novel heterozygous 216 bp in-frame deletion, encompassing exons 15 and 16 of RPS6KA3. Drop episodes in CLS patients were reported to be associated with truncating mutations deleting the C-terminal kinase domain (KD), and only one missense mutation and one single basepair duplication involving the C-terminal KD of RSK2 in the patients with drop episode have been reported thus far. Here we report the first in-frame deletion in C-terminal KD of RPS6KA3 in a CLS patient with drop episodes. PMID- 25044552 TI - The effects of changing climate on faunal depth distributions determine winners and losers. AB - Changing climate is predicted to impact all depths of the global oceans, yet projections of range shifts in marine faunal distributions in response to changing climate seldom evaluate potential shifts in depth distribution. Marine ectotherms' thermal tolerance is limited by their ability to maintain aerobic metabolism (oxygen- and capacity-limited tolerance), and is functionally associated with their hypoxia tolerance. Shallow-water (<200 m depth) marine invertebrates and fishes demonstrate limited tolerance of increasing hydrostatic pressure (pressure exerted by the overlying mass of water), and hyperbaric (increased pressure) tolerance is proposed to depend on the ability to maintain aerobic metabolism, too. Here, we report significant correlation between the hypoxia thresholds and the hyperbaric thresholds of taxonomic groups of shallow water fauna, suggesting that pressure tolerance is indeed oxygen limited. Consequently, it appears that the combined effects of temperature, pressure and oxygen concentration constrain the fundamental ecological niches (FENs) of marine invertebrates and fishes. Including depth in a conceptual model of oxygen- and capacity-limited FENs' responses to ocean warming and deoxygenation confirms previous predictions made based solely on consideration of the latitudinal effects of ocean warming (e.g. Cheung et al., 2009), that polar taxa are most vulnerable to the effects of climate change, with Arctic fauna experiencing the greatest FEN contraction. In contrast, the inclusion of depth in the conceptual model reveals for the first time that temperate fauna as well as tropical fauna may experience substantial FEN expansion with ocean warming and deoxygenation, rather than FEN maintenance or contraction suggested by solely considering latitudinal range shifts. PMID- 25044553 TI - Growth, cell cycle progression, and morphology of 3T3 cells following fibroin microsphere ingestion. AB - Cellular uptake of microspheres may cause physiological stress and toxicity. In this report, we investigated the effect of cellular uptake of fibroin microspheres on the growth, cell cycle progression, and morphology of 3T3 cells. The microspheres were prepared by physical cross-linking of fibroin molecules without any chemical modification. Fluorescent microspheres are comprised of fluorescein isothiocyanate-dextran core and fibroin shell. More than 90% of cells were determined to be fluorescence-positive following 24-h incubation with fluorescent microspheres (0.17 mg/mL). Microsphere localization in the cytoplasm was demonstrated using confocal and transmission electron microscopy. Cellular uptake of microspheres did not influence cellular viability, but microsphere concentrations above 0.1 mg/mL resulted in decreased cell proliferation. The proliferation inhibition was attributed to G2 /M phase delay in cell cycle progression and S-phase delay at higher microsphere concentrations (0.33 mg/mL). Although flow cytometry light-scattering data raised the possibility of morphological changes, Coulter counter analysis confirmed no significant size differences between cells incubated with and without microspheres. Accordingly, fibroin microspheres can be a potential vehicle for intracytoplasmic delivery of cargos, without affecting cell viability. PMID- 25044554 TI - Highly electron-deficient and air-stable conjugated thienylboranes. AB - Introduced herein is a series of conjugated thienylboranes, which are inert to air and moisture, and even resist acids and strong bases. X-ray analyses reveal a coplanar arrangement of the thiophene rings, an arrangement which facilitates p pi conjugation through the boron atoms despite the presence of highly bulky 2,4,6 tri-tert-butylphenyl (Mes*) or 2,4,6-tris(trifluoromethyl)phenyl ((F)Mes) groups. Short B???F contacts, which lead to a pseudotrigonal bipyramidal geometry in the (F)Mes species, have been further studied by DFT and AIM analysis. In contrast to the Mes* groups, the highly electron-withdrawing (F) Mes groups do not diminish the Lewis acidity of boron toward F(-) anions. These compounds can be lithiated or iodinated under electrophilic conditions without decomposition, thus offering a promising route to larger conjugated structures with electron-acceptor character. PMID- 25044555 TI - Dating archaeological copper/bronze artifacts by using the voltammetry of microparticles. AB - A method for dating copper/bronze archaeological objects aged in atmospheric environments is proposed based on the specific signals for cuprite and tenorite corrosion products measured through the voltammtry of microparticles method. The tenorite/cuprite ratio increased with the corrosion time and fitted to a potential law that yielded a calibration curve usable for dating purposes. PMID- 25044556 TI - DOCK2 is critical for CD8(+) TCR(-) graft facilitating cells to enhance engraftment of hematopoietic stem and progenitor cells. AB - CD8(+) TCR(-) graft facilitating cells (FCs) enhance engraftment of hematopoietic stem cells (HSCs) in allogeneic and syngeneic recipients. The mechanisms by which FCs promote HSC engraftment and tolerance induction have not been fully elucidated. Here, we provide data to support a critical role for dedicator of cytokinesis 2 (DOCK2) in multiple aspects of FCs function. DOCK2(-/-) FCs exhibit compromised facilitative function in vivo as evidenced by the loss of engraftment enhancing capability for c-Kit(+) Sca-1(+) lineage(-) (KSL) cells, and compromised ability to promote KSL cell homing and lodgment in hematopoietic niche. Deletion of DOCK2 abrogates the ability of FCs to induce differentiation of naive CD4(+) CD25(-) T cells into FoxP3(+) regulatory T cells and interleukin 10-producing type 1 regulatory T cells in vitro. Moreover, DOCK2(-/-) FCs are unable to promote survival of KSL cells when cocultured with KSL cells. DOCK2(-/ ) FCs also exhibit compromised migration to stroma-derived factor-1 in vitro and impaired homing to the bone marrow in vivo. In conclusion, our results demonstrate that DOCK2 is critical for FCs to maintain its immunomodulatory function and exert its trophic effects on KSL cells. These findings may have direct clinical relevance to promote HSC engraftment for treatment of autoimmunity, hemoglobinopathies, and to induce transplantation tolerance. PMID- 25044557 TI - Quantifying cobalt in doping control urine samples--a pilot study. AB - Since first reports on the impact of metals such as manganese and cobalt on erythropoiesis were published in the late 1920s, cobaltous chloride became a viable though not widespread means for the treatment of anaemic conditions. Today, its use is de facto eliminated from clinical practice; however, its (mis)use in human as well as animal sport as an erythropoiesis-stimulating agent has been discussed frequently. In order to assess possible analytical options and to provide relevant information on the prevalence of cobalt use/misuse among athletes, urinary cobalt concentrations were determined by inductively coupled plasma-mass spectrometry (ICP-MS) from four groups of subjects. The cohorts consisted of (1) a reference population with specimens of 100 non-elite athletes (not being part of the doping control system), (2) a total of 96 doping control samples from endurance sport athletes, (3) elimination study urine samples collected from six individuals having ingested cobaltous chloride (500 ug/day) through dietary supplements, and (4) samples from people supplementing vitamin B12 (cobalamin) at 500 ug/day, accounting for approximately 22 ug of cobalt. The obtained results demonstrated that urinary cobalt concentrations of the reference population as well as the group of elite athletes were within normal ranges (0.1 2.2 ng/mL). A modest but significant difference between these two groups was observed (Wilcoxon rank sum test, p < 0.01) with the athletes' samples presenting slightly higher urinary cobalt levels. The elimination study urine specimens yielded cobalt concentrations between 40 and 318 ng/mL during the first 6 h post administration, and levels remained elevated (>22 ng/mL) up to 33 h. Oral supplementation of 500 ug of cobalamin did not result in urinary cobalt concentrations > 2 ng/mL. Based on these pilot study data it is concluded that measuring the urinary concentration of cobalt can provide information indicating the use of cobaltous chloride by athletes. Additional studies are however required to elucidate further factors potentially influencing urinary cobalt levels. PMID- 25044558 TI - Synthesis of the highly glycosylated hydrophilic motif of extensins. AB - Extensin, the structural motif of plant extracellular matrix proteins, possesses a unique highly glycosylated, hydrophilic, and repeating Ser1Hyp4 pentapeptide unit, and has been proposed to include post-translational hydroxylation at proline residue and subsequent oligo-L-arabinosylations at all of the resultant hydroxyprolines as well as galactosylation at serine residue. Reported herein is the stereoselective synthesis of one of the highly glycosylated motifs, Ser(Galp1)-Hyp(Araf4)-Hyp(Araf4)-Hyp(Araf3)-Hyp(Araf1). The synthesis has been completed by the application of 2-(naphthyl)methylether-mediated intramolecular aglycon delivery to the stereoselective construction of the Ser(Galp1) and Hyp(Araf(n)) fragments as the key step, as well as Fmoc solid-phase peptide synthesis for the backbone pentapeptide. PMID- 25044560 TI - Do Ni/Cu and Cu/Ni alloys have different catalytic performances towards water-gas shift? A density functional theory investigation. AB - Density functional calculations were preformed to investigate whether adding Ni into a Cu surface (denoted as Cu/Ni) or adding Cu into a Ni surface (Ni/Cu) is more efficient for catalyzing the water-gas shift (WGS)? The reactions of water dissociation and monoxide dissociation were selected to assess the activity and selectivity towards WGS, respectively. Our results show that Ni-atom modification of surfaces is thermodynamically favorable for both reactions. Kinetically, compared with pure Cu, water dissociation is greatly facilitated on Ni-modified surfaces, and the activity is insensitive to the Ni concentration; however, monoxide dissociation is not well-promoted on one Ni-atom-modified surfaces, but two Ni-atom modification can notably decrease the dissociation barriers. Overall, on the basis of these results, we conclude that 1) the catalytic performance of bimetallic metals is superior to monometallic ones; 2) at the same Ni concentration on the surface, Cu/Ni and Ni/Cu alloys have almost the same performance towards WGS; and 3) to acquire high WGS performance, the surface Ni atoms should either be low in concentration or highly dispersed. PMID- 25044559 TI - Selective apheresis of C-reactive protein: a new therapeutic option in myocardial infarction? AB - BACKGROUND: There is substantial evidence that C-reactive protein (CRP) mediates secondary damage of the myocardium after acute myocardial infarction (AMI). The aim of this animal trial in pigs was to specifically deplete CRP from porcine plasma after AMI and to study possible beneficial effects of the reduced CRP concentration on the infarcted area. METHODS: Ten pigs received balloon catheter induced myocardial infarction. CRP was depleted from five animals utilizing a new specific CRP-adsorber, five animals served as controls. The area of infarction was analyzed by cardiovascular magnetic resonance imaging on day 1 and day 14 after AMI. Porcine CRP levels were determined by ELISA. RESULTS: CRP-apheresis resulted in a mean reduction of the CRP levels up to 48.3%. The area of infarction was significantly reduced by 30 +/- 6% (P = 0.003) within 14 days in the treatment group, whereas it increased by 19 +/- 11% (P = 0.260) in the controls. Fourteen days after infarction, the infarcted area revealed compact, transmural scars in the controls, whereas animals receiving CRP-apheresis showed spotted scar morphology. In the interventional group, a significantly higher left ventricular ejection fraction (LVEF) was observed after 14 days as compared to the controls (57.6 +/- 2.4% vs. 46.4 +/- 2.7%; P = 0.007). CONCLUSIONS: In a pig model for AMI, we observed that selective CRP-apheresis significantly reduces CRP levels and the volume of the infarction zone after AMI. Additionally, it changes the morphology of the scars and preserves cardiac output (LVEF). PMID- 25044562 TI - Metal-free dihydrogen oxidation by a borenium cation: a combined electrochemical/frustrated Lewis pair approach. AB - In order to use H2 as a clean source of electricity, prohibitively rare and expensive precious metal electrocatalysts, such as Pt, are often used to overcome the large oxidative voltage required to convert H2 into 2 H(+) and 2 e(-). Herein, we report a metal-free approach to catalyze the oxidation of H2 by combining the ability of frustrated Lewis pairs (FLPs) to heterolytically cleave H2 with the in situ electrochemical oxidation of the resulting borohydride. The use of the NHC-stabilized borenium cation [(IiPr2)(BC8H14)](+) (IiPr2=C3H2(NiPr)2, NHC=N-heterocyclic carbene) as the Lewis acidic component of the FLP is shown to decrease the voltage required for H2 oxidation by 910 mV at inexpensive carbon electrodes, a significant energy saving equivalent to 175.6 kJ mol(-1). The NHC-borenium Lewis acid also offers improved catalyst recyclability and chemical stability compared to B(C6F5)3, the paradigm Lewis acid originally used to pioneer our combined electrochemical/frustrated Lewis pair approach. PMID- 25044564 TI - Comparing living donor and deceased donor liver transplantation: A matched national analysis from 2007 to 2012. AB - A complete evaluation of living donor liver transplantation (LDLT) in the United States has been difficult because of the persistent low volume and the lack of adequate comparisons with deceased donor liver transplantation (DDLT). Recent reports have suggested outcomes equivalent to those for DDLT, but these studies did not adjust for differences in recipient selection. From a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 14,282 patients at 62 centers who underwent DDLT from 2007 to 2012 and 715 patients at 35 centers who underwent LDLT during the same period. Then, we performed 1:1 propensity score matching for 708 LDLT recipients based on age, Model for End-Stage Liver Disease (MELD) score, and pretransplant patient status. The median follow-up was 2 years. Compared with DDLT recipients, LDLT recipients were more likely to be white (84.5% versus 72.2%) and female (41.1% versus 31.7%), to have lower MELD scores (15 versus 19), and to be classified preoperatively as independent (65.3% versus 46.7%) and not hospitalized (91.3% versus 78.4%). The posttransplant length of stay (LOS), in hospital mortality, costs, and survival were similar between the groups, but LDLT recipients were more likely to be readmitted within 30 days (44.9% versus 37.1%, P = 0.001). After matching, the difference in 30-day readmission rates persisted (45.1% versus 33.8%, P = 0.001), but there were no differences in the LOS, costs, patient survival, or graft survival. This national report shows that LDLT is associated with higher readmission rates in comparison with DDLT, but the results are comparable for other key patient metrics. PMID- 25044563 TI - Low/no calorie sweetened beverage consumption in the National Weight Control Registry. AB - OBJECTIVE: The aim of this cross-sectional study was to evaluate prevalence of and strategies behind low/no calorie sweetened beverage (LNCSB) consumption in successful weight loss maintainers. METHODS: An online survey was administered to 434 members of the National Weight Control Registry (NWCR, individuals who have lost >=13.6 kg and maintained weight loss for > 1 year). RESULTS: While few participants (10%) consume sugar-sweetened beverages on a regular basis, 53% regularly consume LNCSB. The top five reasons for choosing LNCSB were for taste (54%), to satisfy thirst (40%), part of routine (27%), to reduce calories (22%) and to go with meals (21%). The majority who consume LNCSB (78%) felt they helped control total calorie intake. Many participants considered changing patterns of beverage consumption to be very important in weight loss (42%) and maintenance (40%). Increasing water was by far the most common strategy, followed by reducing regular calorie beverages. CONCLUSIONS: Regular consumption of LNCSB is common in successful weight loss maintainers for various reasons including helping individuals to limit total energy intake. Changing beverage consumption patterns was felt to be very important for weight loss and maintenance by a substantial percentage of successful weight loss maintainers in the NWCR. PMID- 25044565 TI - Synthesis of the human milk oligosaccharide lacto-N-tetraose in metabolically engineered, plasmid-free E. coli. AB - Human milk oligosaccharides (HMOs) constitute the third most abundant solid component of human milk. HMOs have been demonstrated to show positive effects on the infant's well-being. Despite numerous studies, more physiological analyses of single compounds are needed to fully elucidate these effects. Although being one of the most abundant core structures in human milk, the HMO lacto-N-tetraose (LNT) is not available at reasonable prices. In this study, we demonstrate the construction of the first E. coli strain capable of producing LNT in vivo. The strain was constructed by chromosomally integrating the genes lgtA and wbgO, encoding beta-1,3-N-acetylglucosaminyltransferase and beta-1,3 galactosyltransferase. In shake-flask cultivations, the strain yielded a total concentration of 219.1+/-3.5 mg L(-1) LNT (LNT in culture broth and the cell pellet). After recovery of LNT, structural analysis by NMR spectroscopy confirmed the molecule structure. PMID- 25044566 TI - Advances in chiral separations of small peptides by capillary electrophoresis and chromatography. AB - Many chemical and biological processes are controlled by the stereochemistry of small polypeptides (di-, tri-, tetra-, penta-, hexapeptides, etc). The biological importance of peptide stereoisomers is of great value. Therefore, the chiral resolution of peptides is an important issue in biological and medicinal sciences and drug industries. The chiral resolutions of peptide racemates have been discussed with the use of capillary electrophoresis and chromatographic techniques. The various chiral selectors used were polysaccharides, cyclodextrins, Pirkle types, macrocyclic antibiotics, crown ethers, imprinted polymers, etc. The stereochemistry of dipeptides is also discussed. Besides, efforts are made to explain the chiral recognition mechanisms, which will be helpful in understanding existing and developing new stereoselective analyses. Future perspectives of enantiomeric resolution are also predicted. Finally, the review concludes with the demand of enantiomeric resolution of all naturally occurring and synthetic peptides. PMID- 25044567 TI - Electrochemical Energy Conversion: Past, Present, and Future. PMID- 25044568 TI - Paving the way for using Li2S batteries. AB - In this work, a novel lithium-sulfur battery was developed comprising Li2S as the cathode, lithium metal as the anode and polysulfide-based solution as the electrolyte. The electrochemical performances of these Li2S-based cells strongly depended upon the nature of the electrolytes. In the presence of the conventional electrolyte that consisted of lithium bis(trifluoromethanesulfonyl)-imide (LiTFSI) salt dissolved in a solvent combination of dimethoxyethane (DME)/1,3 dioxolane (DOL), the Li/Li2S cells showed sluggish kinetics, which translated into poor cycling and capacity retention. However, when using small amounts of polysulfides in the electrolyte along with a shuttle inhibitor the Li2S cathode was efficiently activated in the cell with the generation of over 1000 mAh g(-1) capacity and good cycle life. PMID- 25044569 TI - Palladium-catalyzed carbonylative alpha-arylation of 2-oxindoles with (hetero)aryl bromides: efficient and complementary approach to 3-acyl-2 oxindoles. AB - An efficient Pd-catalyzed carbonylative alpha-arylation of 2-oxindoles with aryl and heteroaryl bromides for the one-step synthesis of 3-acyl-2-oxindoles has been developed. This reaction proceeds efficiently under mild conditions and is complementary to the more common oxindole forming reactions. The transformation only requires a mild base and provides good to excellent yields even with heteroaromatic substrates. Employing a near stoichiometric amount of (13) COgen, the methodology was easily extended to [(13) C] acyl labeling. The general applicability of the reaction conditions was demonstrated in the synthesis of a structure related to the pharmaceutically active 3-acyl-2-oxindoles, tenidap. PMID- 25044570 TI - Visual displays that directly interface and provide read-outs of molecular states via molecular graphics processing units. AB - The monitoring of molecular systems usually requires sophisticated technologies to interpret nanoscale events into electronic-decipherable signals. We demonstrate a new method for obtaining read-outs of molecular states that uses graphics processing units made from molecular circuits. Because they are made from molecules, the units are able to directly interact with molecular systems. We developed deoxyribozyme-based graphics processing units able to monitor nucleic acids and output alphanumerical read-outs via a fluorescent display. Using this design we created a molecular 7-segment display, a molecular calculator able to add and multiply small numbers, and a molecular automaton able to diagnose Ebola and Marburg virus sequences. These molecular graphics processing units provide insight for the construction of autonomous biosensing devices, and are essential components for the development of molecular computing platforms devoid of electronics. PMID- 25044571 TI - First stabilization of 14-electron rhodium(I) complexes by hemichelation. AB - Hemichelation is emerging as a new mode of coordination where non-covalent interactions crucially contribute to the cohesion of electron-unsaturated organometallic complexes. This study discloses an unprecedented demonstration of this concept to a Group 9 metal, that is, Rh(I). The syntheses of new 14-electron Rh(I) complexes were achieved by choosing the anti-[(eta(6):eta(6) fluorenyl){Cr(CO)3}2] anion as the ambiphilic hemichelating ligand, which was treated with [{Rh(nbd)Cl}2] (nbd=norbornadiene) and [{Rh(CO)2Cl}2]. The new T shaped Rh(I) hemichelates were characterized by analytical and structural methods. Investigations using the methods of the DFT and electron-density topology analysis (NCI region analysis, QTAIM theory) confirmed the closed-shell, non-covalent and attractive characters of the interaction between the Rh(I) center and the proximal Cr(CO)3 moiety. This study shows that, by appropriate tuning of the electronic properties of the ambiphilic ligand, truly coordination unsaturated Rh(I) complexes can be synthesized in a manageable form. PMID- 25044573 TI - First systematic plant proteomics workshop in Botany Department, University of Delhi: transferring proteomics knowledge to next-generation researchers and students. AB - International Plant Proteomics Organization (INPPO) outlined ten initiatives to promote plant proteomics in each and every country. With greater emphasis in developing countries, one of those was to "organize workshops at national and international levels to train manpower and exchange information". This third INPPO highlights covers the workshop organized for the very first time in a developing country, India, at the Department of Botany in University of Delhi on December 26-30, 2013 titled - "1(st) Plant Proteomics Workshop / Training Program" under the umbrella of INPPO India-Nepal chapter. Selected 20 participants received on-hand training mainly on gel-based proteomics approach along with manual booklet and parallel lectures on this and associated topics. In house, as well as invited experts drawn from other Universities and Institutes (national and international), delivered talks on different aspects of gel-based and gel-free proteomics. Importance of gel-free proteomics approach, translational proteomics, and INPPO roles were presented and interactively discussed by a group of three invited speakers Drs. Ganesh Kumar Agrawal (Nepal), Randeep Rakwal (Japan), and Antonio Masi (Italy). Given the output of this systematic workshop, it was proposed and thereafter decided to be organized every alternate year; the next workshop will be held in 2015. Furthermore, possibilities on providing advanced training to those students / researchers / teachers with basic knowledge in proteomics theory and experiments at national and international levels were discussed. INPPO is committed to generating next generation trained manpower in proteomics, and it would only happen by the firm determination of scientists to come forward and do it. PMID- 25044578 TI - Small alterations in cobinamide structure considerably influence sGC activation. AB - Specially designed B-ring-modified cobalamin derivatives were synthesized and tested as potential activators of soluble guanylyl cyclase (sGC). Herein, we disclose the influence of substituents at the c- and d-positions in hydrophilic and hydrophobic cobyrinic acid derivatives on their capacities to activate sGC. The presence of the amide group at c-/d-position in cobyrinic acid derivatives strongly influence the level of sGC activation. Removal of the d-position altogether has a profound effect for hydrophobic compounds. In contrast, little differences were observed in hydrophilic ones. PMID- 25044581 TI - Morphometric examination of the equine adult and foal lung. AB - To understand the mechanisms of airway inflammation associated with equine diseases such as Rhodococcus equi infection, we must identify baseline "normal" structural characteristics of the horse lung. To develop a detailed understanding of the morphology of the horse lung, we adapted and applied stereological methods to the lungs from healthy adult horses (N = 4) and 1-day (N = 5) and 30-day (N = 5) old foals. The left lung was fixed in situ by intrabronchial instillation of glutaraldehyde/paraformaldehyde fixative at 25 cm H2 O column and sampled using a fractionator design followed by embedding in glycol methacrylate. The lung was characterized into parenchyma and non-parenchyma, where median parenchymal density was 81.0% in 1-day-old foals, 84.4% in 30-day-old foals and 93.7% in adult lungs. The median volume density of alveolar airspace per lung was 45.9% in 1-day-old, 55.5% in 30-day and 66.9% in adult horse lungs. The median alveolar surface area increased with age, from 205.3 m(2) , 258.2 m(2) , and 629.9 m(2) in 1-day-old foals, 30-day-old foals, and adults, respectively. While the median alveolar surface density decreased with age, the mean linear intercept (mean free distance within acinar airspaces) increased with age. Alveolar surface area was greater than endothelial surface area within each lung. The ratio between alveolar and endothelial surface density remains unchanged with age. The median endothelium surface area was 106.2 m(2) in 1-day, 147.5 m(2) in 30-day, and 430 m(2) in adult lungs. The data suggest the foal lung is functionally developed and postnatal lung development and remodelling is driven by alveolar expansion paralleled with angiogenesis. PMID- 25044582 TI - Drug Launch Timing and International Reference Pricing. AB - This paper analyzes the timing decisions of pharmaceutical firms to launch a new drug in countries involved in international reference pricing. We show three important features of launch timing when all countries refer to the prices in all other countries and in all previous periods of time. First, there is no withdrawal of drugs in any country and in any period. Second, whenever the drug is sold in a country, it is also sold in all countries with larger willingness to pay. Third, there is no strict incentive to delay the launch of a drug in any country. We then show that the first and third results continue to hold when the countries only refer to the prices of a subset of all countries in a transitive way and in any period. We also show that the second result continues to hold when the reference is on the last period prices only. Last, we show that the seller's profits increase as the sets of reference countries decrease with respect to inclusion. PMID- 25044583 TI - Ex vivo gene delivery to synovium using foamy viral vectors. AB - BACKGROUND: Gene transfer technologies have the potential to fundamentally improve current therapies for arthritic conditions, although this is essentially dependent on safe and efficient vector systems. The foamy virus (FV)-based vectors have many safety features that favour their use in the treatment of arthritis. In the present study, we investigated the use of safe prototype foamy viral vectors (FVV) for indirect gene delivery to articular tissues. METHODS: We generated recombinant FVV encoding enhanced green fluorescent protein (EGFP) or human interleukin 1 receptor antagonist protein (IL1RA) cDNA under the control of the spleen focus forming virus U3 promoter and explored their transgene expression profile following ex vivo gene delivery to knee joints of Wistar and athymic nude rats. RESULTS: FVV efficiently transduced primary rat synovial fibroblasts using the EGFP and the IL1RA transgene in vitro. FVV-mediated IL1RA expression was functional in blocking IL1 effects in vitro. After the transplantation of FVV transduced synovial fibroblasts, the intra-articular transgene expression in Wistar rats was initially high and declined after approximately 3 weeks for both transgenes. By contrast, FVV-mediated expression of EGFP and IL1RA persisted for at least 12 weeks at high levels in immunocompromised nude rats. FVV-meditated gene delivery was well tolerated by all animals without extra-articular transgene expression, arguing for the safety of this approach. CONCLUSIONS: Our results indicate that FVV are capable of efficient ex vivo gene transfer to synovium and merit further investigation as a means to provide long-term intra-articular transgene expression for arthritis treatment. PMID- 25044584 TI - Diabetes mellitus: influences on cancer risk. AB - Diabetes mellitus and cancer are common conditions, and their co-diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2-1.5-fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non-Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti-diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre-existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes. PMID- 25044585 TI - Three new and other limonoids from the hexane extract of Melia azedarach fruits and their cytotoxic activities. AB - A defatted fraction obtained from the hexane extract of the fruits of Melia azedarach L. (chinaberry tree; Meliaceae) exhibited cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines with IC50 values in the range of 2.9-21.9 MUg/ml. Three new limonoids, 3 deacetyl-4'-demethylsalannin (5), 3-deacetyl-28-oxosalannin (14), and 1 detigloylohchinolal (17), along with 16 known limonoids, 1-4, 6-13, 15, 16, 18, and 19, and one known triterpenoid, 20, were isolated from the fraction. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. These compounds were evaluated for their cytotoxic activities against the four cancer cell lines mentioned above. 3-Deacetyl-4'-demethyl-28-oxosalannin (16), which exhibited potent cytotoxicity against AZ521 (IC50 3.2 MUM) cells, induced typical apoptotic cell death in AZ521 cells upon evaluation of the apoptosis-inducing activity by flow cytometry. This work provided, furthermore, valuable information on the structural features of limonoids of the fruits and/or seeds of Melia azedarach and related Meliaceae plants, M. toosendan and Azadirachta indica. PMID- 25044587 TI - Phytochemical diversity of the essential oils of Mexican Oregano (Lippia graveolens Kunth) populations along an Edapho-climatic gradient. AB - Mexican oregano (Lippia graveolens) is an important aromatic plant, mainly used as flavoring and usually harvested from non-cultivated populations. Mexican oregano essential oil showed important variation in the essential-oil yield and composition. The composition of the essential oils extracted by hydrodistillation from 14 wild populations of L. graveolens growing along an edaphoclimatic gradient was evaluated. Characterization of the oils by GC-FID and GC/MS analyses allowed the identification of 70 components, which accounted for 89-99% of the total oil composition. Principal component and hierarchical cluster analyses divided the essential oils into three distinct groups with contrasting oil compositions, viz., two phenolic chemotypes, with either carvacrol (C) or thymol (T) as dominant compounds (contents >75% of the total oil composition), and a non phenolic chemotype (S) dominated by oxygenated sesquiterpenes. While Chemotype C was associated with semi-arid climate and shallower and rockier soils, Chemotype T was found for plants growing under less arid conditions and in deeper soils. The plants showing Chemotype S were more abundant in subhumid climate. High-oil yield individuals (>3%) were identified, which additionally presented high percentages of either carvacrol or thymol; these individuals are of interest, as they could be used as parental material for scientific and commercial breeding programs. PMID- 25044586 TI - Toxicity of thiophenes from Echinops transiliensis (Asteraceae) against Aedes aegypti (Diptera: Culicidae) larvae. AB - Structure?activity relationships of nine thiophenes, 2,2': 5',2"-terthiophene (1), 2-chloro-4-[5-(penta-1,3-diyn-1-yl)thiophen-2-yl]but-3-yn-1-yl acetate (2), 4-(2,2'-bithiophen-5-yl)but-3-yne-1,2-diyl diacetate (3), 4-[5-(penta-1,3-diyn-1 yl)thiophen-2-yl]but-3-yne-1,2-diyl diacetate (4), 4-(2,2'-bithiophen-5-yl)-2 hydroxybut-3-yn-1-yl acetate (5), 2-hydroxy-4-[5-(penta-1,3-diyn-1-yl)thiophen-2 yl]but-3-yn-1-yl acetate (6), 1-hydroxy-4-[5-(penta-1,3-diyn-1-yl)thiophen-2 yl]but-3-yn-2-yl acetate (7), 4-(2,2'-bithiophen-5-yl)but-3-yne-1,2-diol (8), and 4-[5-(penta-1,3-diyn-1-yl)thiophen-2-yl]but-3-yne-1,2-diol (9), isolated from the roots of Echinops transiliensis, were studied as larvicides against Aedes aegypti. Structural differences among compounds 3, 5, and 8 consisted in differing AcO and OH groups attached to C(3") and C(4"), and resulted in variations in efficacy. Terthiophene 1 showed the highest activity (LC50 , 0.16 MUg/ml) among compounds 1-9, followed by bithiophene compounds 3 (LC50 , 4.22 MUg/ml), 5 (LC50 , 7.45 MUg/ml), and 8 (LC50 , 9.89 MUg/ml), and monothiophene compounds 9 (LC50 , 12.45 MUg/ml), 2 (LC50 , 14.71 MUg/ml), 4 (LC50 , 17.95 MUg/ml), 6 (LC50 , 18.55 MUg/ml), and 7 (LC50 , 19.97 MUg/ml). These data indicated that A. aegypti larvicidal activities of thiophenes increase with increasing number of thiophene rings, and the most important active site in the structure of thiophenes could be the tetrahydro-thiophene moiety. In bithiophenes, 3, 5, and 8, A. aegypti larvicidal activity increased with increasing number of AcO groups attached to C(3") or C(4"), indicating that AcO groups may play an important role in the larvicidal activity. PMID- 25044588 TI - Essential-oil composition of Daucus carota ssp. major (Pastinocello Carrot) and nine different commercial varieties of Daucus carota ssp. sativus fruits. AB - The chemical composition of the essential oils obtained by hydrodistillation from the pastinocello carrot, Daucus carota ssp. major (Vis.) Arcang. (flowers and achenes), and from nine different commercial varieties of D. carota L. ssp. sativus (achenes) was investigated by GC/MS analyses. Selective breeding over centuries of a naturally occurring subspecies of the wild carrot, D. carota L. ssp. sativus, has produced the common garden vegetable with reduced bitterness, increased sweetness, and minimized woody core. On the other hand, the cultivation of the pastinocello carrot has been abandoned, even if, recently, there has been renewed interest in the development of this species, which risks genetic erosion. The cultivated carrot (D. carota ssp. sativus) and the pastinocello carrot (D. carota ssp. major) were classified as different subspecies of the same species. This close relationship between the two subspecies urged us to compare the chemical composition of their essential oils, to evaluate the differences. The main essential-oil constituents isolated from the pastinocello fruits were geranyl acetate (34.2%), alpha-pinene (12.9%), geraniol (6.9%), myrcene (4.7%), epi-alpha-bisabolol (4.5%), sabinene (3.3%), and limonene (3.0%). The fruit essential oils of the nine commercial varieties of D. carota ssp. sativus were very different from that of pastinocello, as also confirmed by multivariate statistical analyses. PMID- 25044589 TI - Suppression of Inflammatory cytokine production by ar-Turmerone isolated from Curcuma phaeocaulis. AB - Rhizomes of Curcuma phaeocaulis Valeton (Zingiberaceae) have traditionally been used for controlling inflammatory conditions. Numerous studies have aimed to isolate and characterize the bioactive constituents of C. phaeocaulis. It has been reported that its anti-inflammatory properties are a result of cyclooxygenase-2 inhibition; however, its effect on the T-cell function remains to be elucidated. In this study, four known sesquiterpenoids, viz., ar-turmerone (TM), germacrone (GM), (+)-(4S,5S)-germacrone-4,5-epoxide (GE), and curzerenone (CZ), were isolated from C. phaeocaulis rhizomes and evaluated for their effects on the CD4(+) T-cell function. While GM, GE, and CZ had no effect on the activation of splenic T cells or CD4(+) T cells, TM suppressed the interferon (IFN)-gamma production, without affecting the interleukin (IL)-4 expression. TM also decreased the expression of IL-2 in CD4(+) T cells, but did not change their cell-division rates upon stimulation. These results suggest that TM, a major constituent of C. phaeocaulis rhizomes selectively exerts potent anti inflammatory effects via suppression of the inflammatory cytokines IFN-gamma and IL-2. PMID- 25044590 TI - Leaf n-alkanes as characters differentiating coastal and continental Juniperus deltoides populations from the Balkan Peninsula. AB - The composition of the cuticular n-alkanes isolated from the leaves of nine populations of Juniperus deltoides R.P.Adams from continental and coastal areas of the Balkan Peninsula was characterized by GC-FID and GC/MS analyses. In the leaf waxes, 14 n-alkane homologues with chain-lengths ranging from C22 to C35 were identified. n-Tritriacontane (C33 ) was dominant in the waxes of all populations, but variations between the populations in the contents of all n alkanes were observed. Several statistical methods (ANOVA, principal component, discriminant, and cluster analyses) were used to investigate the diversity and variability of the cuticular-leaf-n-alkane patterns of the nine J. deltoides populations. This is the first report on the n-alkane composition for this species. The multivariate statistical analyses evidenced a high correlation of the leaf-n-alkane pattern with the geographical distribution of the investigated samples, differentiating the coastal from the continental populations of this taxon. PMID- 25044591 TI - Seven new sesquiterpenoids from the fruits of Schisandra sphenanthera. AB - Fractionation of the EtOH extract from the fruits of Schisandra sphenanthera resulted in the isolation of seven new sesquiterpenoids, 1-7, in addition to the known metabolites 8-23. Among them, schiscupatetralin A (1) possesses an unprecedented structure with a C?C bond between cuparenol and tetralin. The isolated new compounds were evaluated for their anti-HSV-1 and anti-inflammatory activities. The results revealed that compound 4 exhibited anti-HSV-1 activity, while compound 6 showed a significant anti-inflammatory activity. PMID- 25044592 TI - Electrophysiology investigation of Trichogin GA IV activity in planar lipid membranes reveals ion channels of well-defined size. AB - Trichogin GA IV, an antimicrobial peptaibol, exerts its function by augmenting membrane permeability, but the molecular aspects of its pore-forming mechanism are still debated. Several lines of evidence indicate a 'barrel-stave' channel structure, similar to that of alamethicin, but the length of a trichogin helix is too short to span a normal bilayer. Herein, we present electrophysiology measurements in planar bilayers, showing that trichogin does form channels of a well-defined size (R=4.2?10(9) Omega; corresponding at least to a trimeric aggregate) that span the membrane and allow ion diffusion, but do not exhibit voltage-dependent rectification, unlike those of alamethicin. PMID- 25044593 TI - Halogenated metabolites isolated from Penicillium citreonigrum. AB - Three chromone analogs, 1-3, a chlorinated alkaloid sclerotioramine (4), together with two 11-noreremophilane-type sesquiterpenes with a conjugated enolic OH group and a brominated one, 5 and 6, respectively, were isolated from Penicillium citreonigrum (HQ738282). Compounds 1, 5, and 6 were new. Biological tests revealed that 4 exhibited a significant activity (IC50 7.32 MUg/ml), and 6 showed a moderate activity (IC50 16.31 MUg/ml) in vitro against HepG2 cell line, and 4 also displayed an activity comparable to that of acarbose against alpha glucosidase. PMID- 25044594 TI - New derivatives of nonactic and homononactic acids from Bacillus pumilus derived from Breynia fruticosa. AB - Six new nonactic and homononactic acid derivatives, ethyl homononactate (1), ethyl nonactate (2), homononactyl homononactate (6), ethyl homononactyl nonactate (7), ethyl homononactyl homononactate (8), and ethyl nonactyl nonactate (9), as well as four known compounds, homononactic acid (3), nonactic acid (4), homononactyl nonactate (5), and bishomononactic acid (10), were isolated from culture broth of Bacillus pumilus derived from Breynia fruticosa. The structures of new compounds were elucidated by spectroscopic analysis and chemical methods. The optical purities of 1-6 were determined by HPLC/MS after treatment with L phenylalanine methyl ester. The dimeric compounds 5-9 showed weak cytotoxic activities against five human cancer cell lines (IC50 19-100 MUg/ml). PMID- 25044595 TI - New isocoumarins from a cold-adapted fungal strain mucor sp. and their developmental toxicity to zebrafish embryos. AB - Three new isocoumarin derivatives, mucorisocoumarins A-C (1-3, resp.), together with seven known compounds, 4-10, were isolated from the cold-adapted fungal strain Mucor sp. (No. XJ07027-5). The structures of the new compounds were identified by detailed IR, MS, and 1D- and 2D-NMR analyses. It was noteworthy that compounds 1, 2, 4, and 5 were successfully resolved by chiral HPLC, indicating that 1-7 should exist as enantiomers. In an embryonic developmental toxicity assay using a zebrafish model, compound 3 produced developmental abnormalities in the zebrafish embryos. This is the first report of isocoumarins with developmental toxicity to zebrafish embryos. PMID- 25044596 TI - Bioactive 9,11-secosteroids from Gorgonian Subergorgia suberosa collected from the South China sea. AB - Five new 9,11-secosteroids 1, 2, and 4-6, and seven known analogs, 3 and 7-12, with the same steroid skeleton, (5alphaH)-3beta,6alpha,11-trihydroxy-9,11 secocholest-7-en-9-one, were isolated from the South China Sea gorgonian Subergorgia suberosa. Among them, 2/3 and 4/5 are C(24)-epimeric mixtures, and 6/7 is an (E)/(Z) mixture of (C(24)?C(28)). Their structures and relative configurations were elucidated by using comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of the steroidal nucleus was established by the modified Mosher method applied to 10 and on the basis of a common biogenesis for all of these compounds. All isolated compounds, 1-12, and five synthetic acetylated derivatives, 12a-12e, were evaluated for their cytotoxicities in vitro. Compounds 4/5, 11, 12, and 12b-12d showed cytotoxic activities against K562 cell line with the IC50 values ranging from 1.09 to 8.12 MUM. PMID- 25044597 TI - Recurrent syncope after left atrial appendage occlusion. AB - We present the case of a 72-year-old woman with permanent atrial fibrillation and contraindication to long-term oral anticoagulant therapy who underwent left atrial appendage (LAA) occlusion. A 24-mm Amplatzer Cardiac Plug (St Jude Medical) device was deployed. The inferior part of the external disc of the device appeared to be over the posterior leaflet of the mitral valve but no significant mitral stenosis or mitral regurgitation was detected before deployment. After the procedure the patient suffered several syncopes when she tried to stand up. A transesophageal echocardiography (TEE) was performed and no significant differences on the device position were detected, it was not possible to perform the TEE in a stand-up position due to the patient symptoms (hypotension, tachycardia, dizziness, and loss of consciousness). After discussion with the surgical team, surgical removal of the device and surgical exclusion of LAA was performed. The symptoms disappeared and the patient was discharged. In the best of our knowledge, this is the first time that recurrent syncope has been described as a complication of LAA occlusion. PMID- 25044598 TI - The relationship between perceived health and physical activity indoors, outdoors in built environments, and outdoors in nature. AB - BACKGROUND: A body of evidence shows that both physical activity and exposure to nature are connected to improved general and mental health. Experimental studies have consistently found short term positive effects of physical activity in nature compared with built environments. This study explores whether these benefits are also evident in everyday life, perceived over repeated contact with nature. The topic is important from the perspectives of city planning, individual well-being, and public health. METHODS: National survey data (n = 2,070) from Finland was analysed using structural regression analyses. Perceived general health, emotional well-being, and sleep quality were regressed on the weekly frequency of physical activity indoors, outdoors in built environments, and in nature. Socioeconomic factors and other plausible confounders were controlled for. RESULTS: Emotional well-being showed the most consistent positive connection to physical activity in nature, whereas general health was positively associated with physical activity in both built and natural outdoor settings. Better sleep quality was weakly connected to frequent physical activity in nature, but the connection was outweighed by other factors. CONCLUSION: The results indicate that nature provides an added value to the known benefits of physical activity. Repeated exercise in nature is, in particular, connected to better emotional well being. PMID- 25044599 TI - Mechanisms involved in Escherichia coli and Serratia marcescens removal during activated sludge wastewater treatment. AB - Wastewater treatment reduces environmental contamination by removing gross solids and mitigating the effects of pollution. Treatment also reduces the number of indicator organisms and pathogens. In this work, the fates of two coliform bacteria, Escherichia coli and Serratia marcescens, were analyzed in an activated sludge process to determine the main mechanisms involved in the reduction of pathogenic microorganisms during wastewater treatment. These bacteria, modified to express green fluorescent protein, were inoculated in an activated sludge unit and in batch systems containing wastewater. The results suggested that, among the different biological factors implied in bacterial removal, bacterivorous protozoa play a key role. Moreover, a representative number of bacteria persisted in the system as free-living or embedded cells, but their distribution into liquid or solid fractions varied depending on the bacterium tested, questioning the real value of bacterial indicators for the control of wastewater treatment process. Additionally, viable but nonculturable cells constituted an important part of the bacterial population adhered to solid fractions, what can be derived from the competition relationships with native bacteria, present in high densities in this environment. These facts, taken together, emphasize the need for reliable quantitative and qualitative analysis tools for the evaluation of pathogenic microbial composition in sludge, which could represent an undefined risk to public health and ecosystem functions when considering its recycling. PMID- 25044601 TI - A multistep photothermic-driven drug release system using wire-framed Au nanobundles. AB - Here, wire-framed Au nanobundles (WNBs), which consist of randomly oriented and mutually connected Au wires to form a bundle shape, are synthesized. In contrast to conventional nanoparticles (spheres, rods, cubes, and stars), which exhibit nanostructure only on the surface, cross-sectional view image shows that WNBs have nanostructures in a whole volume. By using this specific property of WNBs, an externally controllable multistep photothermic-driven drug release (PDR) system is demonstrated for in vivo cancer treatment. In contrast to conventional nanoparticles that encapsulate a drug on their surface, WNBs preserve the drug payload in the overall inner volume, providing a drug loading capacity sufficient for cancer therapy. An improved in vivo therapeutic efficacy of PDR therapy is also demonstrated by delivering sufficient amount of drugs to the target tumor region. PMID- 25044602 TI - Humanized antibody neutralizing 2009 pandemic H1N1 virus. AB - The 2009 pandemic H1N1 S-OIV (swine origin influenza A virus) caused noticeable morbidity and mortality worldwide. In addition to vaccine and antiviral drug therapy, the use of influenza virus neutralizing monoclonal antibodies (MAbs) for treatment purposes is a viable alternative. We previously reported the isolation of a high affinity, potently neutralizing murine MAb MA2077 against 2009 pandemic H1N1 virus. We describe here the humanization of MA2077 and its expression in a mammalian cell line. Six complementarity-determining regions (CDRs) of MA2077 were grafted onto the human germline variable regions; along with six and eight back mutations in the framework of heavy and light chains, respectively, pertaining to the vernier zone and interchain packing residues to promote favorable CDR conformation and facilitate antigen binding. The full length humanized antibody, 2077Hu2, expressed in CHO-K1 cells, showed high affinity to hemagglutinin protein (KD = 0.75 +/- 0.32 nM) and potent neutralization of pandemic H1N1 virus (IC50 = 0.17 MUg/mL), with marginally higher IC50 as compared to MA2077 (0.08 MUg/mL). In addition, 2077Hu2 also retained the epitope specificity for the "Sa" antigenic site on pandemic HA. To the best of our knowledge, this is the first report of a humanized neutralizing antibody against pandemic H1N1 virus. PMID- 25044603 TI - Folic acid functionalized surface highlights 5-methylcytosine-genomic content within circulating tumor cells. AB - Although the detection of methylated cell free DNA represents one of the most promising approaches for relapse risk assessment in cancer patients, the low concentration of cell-free circulating DNA constitutes the biggest obstacle in the development of DNA methylation-based biomarkers from blood. This paper describes a method for the measurement of genomic methylation content directly on circulating tumor cells (CTC), which could be used to deceive the aforementioned problem. Since CTC are disease related blood-based biomarkers, they result essential to monitor tumor's stadiation, therapy, and early relapsing lesions. Within surface's bio-functionalization and cell's isolation procedure standardization, the presented approach reveals a singular ability to detect high 5-methylcytosine CTC-subset content in the whole CTC compound, by choosing folic acid (FA) as transducer molecule. Sensitivity and specificity, calculated for FA functionalized surface (FA-surface), result respectively on about 83% and 60%. FA surface, allowing the detection and characterization of early metastatic dissemination, provides a unique advance in the comprehension of tumors progression and dissemination confirming the presence of CTC and its association with high risk of relapse. This functionalized surface identifying and quantifying high 5-methylcytosine CTC-subset content into the patient's blood lead significant progress in cancer risk assessment, also providing a novel therapeutic strategy. PMID- 25044605 TI - Working on the Edge: Stresses and Rewards of Work in a Front-line Mental Health Service. AB - This study sought to investigate frontline mental health professionals' perceptions of work stress and the rewards and demands associated with their work. Locally known as 'linkworkers', and from a variety of professional backgrounds, these staff worked mainly in general practice settings. Individual interviews were conducted with nine linkworkers, and the interview transcripts were analysed thematically. The main themes identified were the following: demands, coping, individual resilience, ownership and creativity, boundaries, secure base and service philosophy and ethos. Themes, categories and sub categories were presented and discussed with seven of the linkworkers in two focus groups. Focus group transcripts were analysed, and additional themes of recognizing limitations, disillusionment and the dilemma of setting boundaries were identified. These themes overlapped with those previously identified but were associated with service changes over time. The themes of ownership and creativity and service philosophy and ethos are significant, not only in relation to their impact on individual linkworkers but also in terms of their relevance for establishing and maintaining morale, engagement and a reflective culture within a service. The relevance of this work to accessible and newly developing mental health services is considered. KEY PRACTITIONER MESSAGE: Supporting and listening to staff and allowing time for informal contact are valued by staff and enable the provision of empathic, compassionate services. Without space for reflection, staff groups may be vulnerable to the development and effects of unhelpful organizational defences, which reduce the effectiveness, quality and efficiency of caring services and increase perceived workplace stress. Services which foster staff engagement, ownership and creativity and employ "bottom up" approaches to service development are valued by staff and appear to increase staff morale and capacity to cope adaptively to change. PMID- 25044604 TI - Aberrant parietal cortex developmental trajectories in girls with Turner syndrome and related visual-spatial cognitive development: a preliminary study. AB - Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 +/- 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors. PMID- 25044606 TI - Posttranslational modifications of human histone H3: an update. AB - Histone proteins, the fundamental components of chromatin, are highly conserved proteins that present in eukaryotic nuclei. They organize genomic DNA to form nucleosomes, the basic units of chromatin. PTMs of histones play essential roles in many biological processes, such as chromatin condensation, gene expression, cell differentiation, and apoptosis. With the advancement of proteomic technology, a growing number of histone PTMs have been identified, including ADP ribosylation, biotinylation, citrullination, crotonylation, O-GlcNAcylation, glutathionylation, succinylation, and so on. Because of the fast growing list of these PTMs in just a few years, the functions of these marks are being studied intensively. As histone H3 has the most number of PTMs among the histone members, in this review, we would like to present the overall concepts of the more familiar PTMs as well as discussing all the recently identified yet less well known PTMs on human histone H3. PMID- 25044607 TI - Global herbicide resistance challenge. PMID- 25044608 TI - Whole ARX gene duplication is compatible with normal intellectual development. AB - We report here on four males from three families carrying de novo or inherited small Xp22.13 duplications including the ARX gene detected by chromosomal microarray analysis (CMA). Two of these males had normal intelligence. Our report suggests that, unlike other XLMR genes like MECP2 and FMR1, the presence of an extra copy of the ARX gene may not be sufficient to perturb its developmental functions. ARX duplication does not inevitably have detrimental effects on brain development, in contrast with the effects of ARX haploinsufficiency. The abnormal phenotype ascribed to the presence of an extra copy in some male patients may have resulted from the effect of another, not yet identified, chromosomal or molecular anomaly, alone or in association with ARX duplication. PMID- 25044609 TI - A global assessment of forest surface albedo and its relationships with climate and atmospheric nitrogen deposition. AB - We present a global assessment of the relationships between the short-wave surface albedo of forests, derived from the MODIS satellite instrument product at 0.5 degrees spatial resolution, with simulated atmospheric nitrogen deposition rates (Ndep ), and climatic variables (mean annual temperature Tm and total annual precipitation P), compiled at the same spatial resolution. The analysis was performed on the following five forest plant functional types (PFTs): evergreen needle-leaf forests (ENF); evergreen broad-leaf forests (EBF); deciduous needle-leaf forests (DNF); deciduous broad-leaf forests (DBF); and mixed-forests (MF). Generalized additive models (GAMs) were applied in the exploratory analysis to assess the functional nature of short-wave surface albedo relations to environmental variables. The analysis showed evident correlations of albedo with environmental predictors when data were pooled across PFTs: Tm and Ndep displayed a positive relationship with forest albedo, while a negative relationship was detected with P. These correlations are primarily due to surface albedo differences between conifer and broad-leaf species, and different species geographical distributions. However, the analysis performed within individual PFTs, strengthened by attempts to select 'pure' pixels in terms of species composition, showed significant correlations with annual precipitation and nitrogen deposition, pointing toward the potential effect of environmental variables on forest surface albedo at the ecosystem level. Overall, our global assessment emphasizes the importance of elucidating the ecological mechanisms that link environmental conditions and forest canopy properties for an improved parameterization of surface albedo in climate models. PMID- 25044610 TI - Biofilm formation on titanium implants counteracted by grafting gallium and silver ions. AB - Biofilm-associated infections remain the leading cause of implant failure. Thanks to its established biocompatibility and biomechanical properties, titanium has become one of the most widely used materials for bone implants. Engineered surface modifications of titanium able to thwart biofilm formation while endowing a safe anchorage to eukaryotic cells are being progressively developed. Here surfaces of disks of commercial grade 2 titanium for bone implant were grafted with gallium and silver ions by anodic spark deposition. Scanning electron microscopy of the surface morphology and energy dispersive X-ray spectroscopy were used for characterization. Gallium-grafted titanium was evaluated in comparison with silver-grafted titanium for both in vivo and in vitro antibiofilm properties and for in vitro compatibility with human primary gingival fibroblasts. Surface-modified materials showed: (i) homogeneous porous morphology, with pores of micrometric size; (ii) absence of cytotoxic effects; (iii) ability to support in vitro the adhesion and spreading of gingival fibroblasts; and (iv) antibiofilm properties. Although both silver and gallium exhibited in vitro strong antibacterial properties, in vivo gallium was significantly more effective than silver in reducing number and viability of biofilm bacteria colonies. Gallium-based treatments represent promising titanium antibiofilm coatings to develop new bone implantable devices for oral, maxillofacial, and orthopedic applications. PMID- 25044611 TI - Organic chemistry as a language and the implications of chemical linguistics for structural and retrosynthetic analyses. AB - Methods of computational linguistics are used to demonstrate that a natural language such as English and organic chemistry have the same structure in terms of the frequency of, respectively, text fragments and molecular fragments. This quantitative correspondence suggests that it is possible to extend the methods of computational corpus linguistics to the analysis of organic molecules. It is shown that within organic molecules bonds that have highest information content are the ones that 1) define repeat/symmetry subunits and 2) in asymmetric molecules, define the loci of potential retrosynthetic disconnections. Linguistics-based analysis appears well-suited to the analysis of complex structural and reactivity patterns within organic molecules. PMID- 25044612 TI - Enzymetically regulating the self-healing of protein hydrogels with high healing efficiency. AB - Enzyme-mediated self-healing of dynamic covalent bond-driven protein hydrogels was realized by the synergy of two enzymes, glucose oxidase (GOX) and catalase (CAT). The reversible covalent attachment of glutaraldehyde to lysine residues of GOX, CAT, and bovine serum albumin (BSA) led to the formation and functionalization of the self-healing protein hydrogel system. The enzyme mediated protein hydrogels exhibit excellent self-healing properties with 100% recovery. The self-healing process was reversible and effective with an external glucose stimulus at room temperature. PMID- 25044613 TI - Stressful life events and binge eating disorder. AB - Although there is evidence about the role played by stressful life events (SE) in the pathogenesis of eating disorders, few studies to date have explored this problem in binge eating disorder (BED). The aim of the present study was to examine SE preceding the onset of BED. A retrospective interview-based design was used to compare 107 patients with BED and 107 patients with bulimia nervosa (BN), matched for duration of illness. Compared with patients with BN, those with BED reported a greater number of traumatic events in the 6 months preceding onset, revealing more often three types of events: bereavement, separation from a family member and accidents. The presence of SE before onset showed a dose-response relationship with the severity of psychopathology at the time of referral for treatment. Study of SE in patients with BED may be important for better understanding of the pathogenetic pathway to this disorder and to provide adequate treatment. PMID- 25044614 TI - Development, optimization, and validation of a novel extraction procedure for the removal of opiates from human hair's surface. AB - Room temperature ionic liquids (ILs) have proved to be efficient extraction media for several systems, and their ability to capture volatile compounds from the atmosphere is well established. We report herein a contactless extraction procedure for the removal of opiate drugs from the surface of human hair. The compounds were chosen as a model drug, particularly due to their low volatility. Equal amounts of IL and hair (about 100 mg) were introduced in a customized Y shaped vial, and the process occurred simply by heating. After testing several ILs, some of them (e.g. 1-methyl-3-ethanol-imidazolium tetrafluoroborate, phenyl trimethyl-ammonium triflate or bis(dimethyl) diheptylguanidinium iodide) showed extraction efficiencies higher than 80% for the two studied compounds, morphine and 6-monoacetylmorphine. Using the design of experiments (DOE) approach as an optimization tool, and bearing in mind the hygroscopic properties of the ILs (in particular, 1-methyl-3-ethanol-imidazolium tetrafluoroborate), the process was optimized concerning the following variables: temperature (50-120 oC), extraction time (8-24 h), IL amount (50-200 mg) and water content of the IL (0.01-60%). This study not only provided the optimum conditions for the process (120 oC, 16 h, 100 mg of IL containing 40% of water), but has also showed that the water content of the IL represents the variable with the most significant effect on the extraction efficiency. Finally, we validated our method through the comparison of the results obtained by treating hair samples with the described procedure to those obtained using a standard washing method and criteria for positivity. PMID- 25044615 TI - A polyphenylene support for Pd catalysts with exceptional catalytic activity. AB - We describe a solid polyphenylene support that serves as an excellent platform for metal-catalyzed reactions that are normally carried out under homogeneous conditions. The catalyst is synthesized by palladium-catalyzed Suzuki coupling which directly results in formation of palladium nanoparticles confined to a porous polyphenylene network. The composite solid is in turn highly active for further Suzuki coupling reactions, including non-activated substrates that are challenging even for molecular catalysts. PMID- 25044616 TI - Computational reference data for the photochemistry of cyclobutane pyrimidine dimers. AB - The cis-syn cyclobutane pyrimidine dimer is one of the major classes of carcinogenic UV-induced DNA photoproducts. In this work, diverse high-level quantum-chemical methods were used to determine the spectroscopic properties of neutral (singlet and triplet) and charged (cation and anion) species of thymine dimers. Maps of potential energy, charge distribution, electron affinity, and ionization potential of the thymidine dimers were computed along the two dimerization coordinates for neutral and charged species, as well as for the singlet excited state. This set of data aims at providing consistent results computed with the same methods as for photodamage and repair. Based on these results, several different photo-, heat-, and charge-induced mechanisms of dimerization and repair are characterized and discussed. Additionally, a new stable dimer with methylmethylidene-hexahydropyrimidine structure was found in the S0 state. PMID- 25044617 TI - Apheresis training for nurses and physicians around the World. AB - A training program for apheresis nurses in leukocyte collection and therapeutic apheresis was developed by the Joint Task Force for Apheresis Education and Certification. This is a modular program with theoretical and practical information and knowledge. On request of the Indonesian authorities, in the capital of Indonesia Jakarta, a certification course for apheresis nurses/operators based on the training program described above was organized in December 2013. The course existed of themes related to apheresis, such as hematology, anatomy, physiology, calculations, adverse events, basics of apheresis, nursing aspects, quality, collection of cells for cellular therapies, pediatrics, and therapeutic collections (cell reductions and exchange procedures). A pretest and post-test regarding the knowledge and judgment in the themes described was taken in Bahasa Indonesia or in English. In total, 38 apheresis nurses and 32 physicians participated in the course. In the post-test, the nurses scored in a mean 72/100 and the physicians 77/100 (nurses vs. physicians: P = 0.005), which was significantly better than the results of the pretest (54/100 and 53/100, respectively (P < 0.0001 for both). In conclusion, with this course, 38 apheresis nurses/operators proved a significant increase of knowledge in the theory behind apheresis. This educational program provides an approach to educate and certificate apheresis nurses. It is also shown that also for physicians working in the field of apheresis, this course is of use increasing their knowledge regarding apheresis. PMID- 25044618 TI - Oxygen enhanced lung MRI by simultaneous measurement of T1 and T2 * during free breathing using ultrashort TE. AB - PURPOSE: To provide a robust method for the simultaneous quantification of T1 and T2 * in the human lung during free breathing. Breathing pure oxygen accelerates T1 and T2 * relaxation in the lung. While T1 shortening reflects an increased amount of dissolved molecular oxygen in lung tissue, T2 * shortening shows an increased concentration of oxygen in the alveolar gas. Therefore, both parameters reflect different aspects of the oxygen uptake and provide complementary lung functional information. MATERIALS AND METHODS: A segmented inversion recovery Look-Locker multiecho sequence based on a multiecho 2D ultrashort TE (UTE) was employed for simultaneous T1 and T2 * quantification. The radial projections follow a modified golden angle ordering, allowing for respiratory self-gating and thus the reconstruction of a series of differently T1 and T2 *-weighted images in arbitrary breathing states. The method was evaluated in nine healthy volunteers while breathing room air and pure oxygen, with two volunteers examined at five oxygen concentrations. RESULTS: Relative differences of DeltaT1 between 7.9% and 12.7% and of DeltaT2 * between 13.2% and 6.0% were found. CONCLUSION: The proposed method provides inherently coregistered, quantitative T1 and T2 * maps in both expiration and inspiration from a single measurement acquired during free breathing and is thus well suited for clinical application. PMID- 25044619 TI - Reversible supramolecular assembly at specific DNA sites: nickel-promoted bivalent DNA binding with designed peptide and bipyridyl-bis(benzamidine) components. AB - At specific DNA sites, nickel(II) salts promote the assembly of designed components, namely a bis(histidine)-modified peptide that is derived from a bZIP transcription factor and a bis(benzamidine) unit that is equipped with a bipyridine. This programmed supramolecular system with emergent properties reproduces some key characteristics of naturally occurring DNA-binding proteins, such as bivalence, selectivity, responsiveness to external agents, and reversibility. PMID- 25044621 TI - Reframing the impact of combined heart-liver allocation on liver transplant wait list candidates. AB - Simultaneous heart-liver (H-L) transplantation, although rare, has become more common in the United States. When the primary organ is a heart or liver, patients receiving an offer for the primary organ automatically receive the second, nonprimary organ from that donor. This policy raises issues of equity, such as whether liver transplantation alone candidates bypassed by H-L recipients are disadvantaged. No prior published analyses have addressed this issue, and few methods have been developed as means of measuring the impact of such allocation policies. We analyzed Organ Procurement and Transplantation Network match run data from 2007 to 2013 to determine whether this combined organ allocation policy disadvantages bypassed liver transplant wait-list candidates in a clinically meaningful way. Among 65 H-L recipients since May 2007, 42 had substantially higher priority for the heart versus the liver, and these 42 bypassed 268 liver alone candidates ranked 1 to 10 on these match runs. Bypassed patients had a lower risk of wait-list removal for death or clinical deterioration in comparison with controls selected by the match Model for End-Stage Liver Disease (MELD) score [hazard ratio (HR) = 0.56, 95% confidence interval (CI) = 0.40-0.79] and a risk similar to that of controls selected by the laboratory MELD score (HR = 0.91, 95% CI = 0.63-1.33) or on match runs of similar graft quality (HR = 0.97, 95% CI = 0.73-1.37). The waiting time from bypass to subsequent transplantation was significantly longer among bypassed candidates versus controls on match runs of similar graft quality [median: 87 days (interquartile range = 27-192 days) versus 24 days (interquartile range = 5-79 days), P < 0.001]. Although transplantation was delayed, liver transplant wait-list candidates bypassed by H L recipients did not have excess mortality in comparison with 3 sets of matched controls. These analytic methods serve as a starting point for considering other potential approaches to evaluating the impact of multiorgan transplant allocation policies. PMID- 25044620 TI - An abnormal lymphatic phenotype is associated with subcutaneous adipose tissue deposits in Dercum's disease. AB - OBJECTIVE: Investigational, near-infrared fluorescence (NIRF) lymphatic imaging was used to assess lymphatic architecture and contractile function in participants diagnosed with Dercum's disease, a rare, poorly understood disorder characterized by painful lipomas in subcutaneous adipose tissues. METHODS: After informed consent and as part of an FDA-approved feasibility study to evaluate lymphatics in diseases in which their contribution has been implicated, three women diagnosed with Dercum's disease and four control subjects were imaged. Each participant received multiple intradermal and subcutaneous injections of indocyanine green (ICG, total dose <=400 ug) in arms, legs, and/or trunk. Immediately after injection, ICG was taken up by the lymphatics and NIRF imaging was conducted. RESULTS: The lymphatics in the participants with Dercum's disease were intact and dilated, yet sluggishly propelled lymph when compared to control lymphatics. Palpation of regions containing fluorescent lymphatic pathways revealed tender, fibrotic, tubular structures within the subcutaneous adipose tissue that were associated with painful nodules, and, in some cases, masses of fluorescent tissue indicating that some lipomas may represent tertiary lymphoid tissues. CONCLUSIONS: These data support the hypothesis that Dercum's disease may be a lymphovascular disorder and suggest a possible association between abnormal adipose tissue deposition and abnormal lymphatic structure and function. PMID- 25044622 TI - Selective retention of basic compounds by metal aquo-ion affinity chromatography. AB - A novel metal aquo-ion affinity chromatography has been developed for the analysis of basic compounds using heat-treated silica gel containing hydrated metal cations (metal aquo-ions) as the packing material. The packing materials of the metal aquo-ion affinity chromatography were prepared by the immobilization of a single metal component such as Fe(III), Al(III), Ag(I), and Ni(II) on silica gel followed by extensive heat treatment. The immobilized metals form aquo-ions to present cation-exchange ability for basic analytes and the cation-exchange ability for basic analytes depends on pKa of the immobilized metal species. In the present study, to evaluate the retention characteristics of metal aquo-ion affinity chromatography, the on-line solid-phase extraction of drugs was investigated. Obtained data clearly evidence the selective retention capability of metal aquo-ion affinity chromatography for basic analytes with sufficient capacity. PMID- 25044623 TI - Molecular design of an environmentally sensitive fluorescent nucleoside, 3-deaza 2'-deoxyadenosine derivative: distinguishing thymine by probing the DNA minor groove. AB - An environmentally sensitive fluorescent nucleoside containing a 3-deazaadenine skeleton has been developed, and its photophysical properties were investigated. Newly developed C3-naphthylethynylated 3-deaza-2'-deoxyadenosine ((3nz) A, 1) exhibited dual fluorescence emission from an intramolecular charge-transfer state and a locally excited state, depending upon molecular coplanarity. DNA probes containing 1 clearly discriminated a perfectly matched thymine base on the complementary strand by a distinct change in emission wavelength. PMID- 25044624 TI - Dephasing and dissipation in a source-drain model of light-harvesting systems. AB - The energy transport process in natural-light-harvesting systems is investigated by solving the time-dependent Schrodinger equation for a source-network-drain model incorporating the effects of dephasing and dissipation, owing to coupling with the environment. In this model, the network consists of electronically coupled chromophores, which can host energy excitations (excitons) and are connected to source channels, from which the excitons are generated, thereby simulating exciton creation from sunlight. After passing through the network, excitons are captured by the reaction centers and converted into chemical energy. In addition, excitons can reradiate in green plants as photoluminescent light or be destroyed by nonphotochemical quenching (NPQ). These annihilation processes are described in the model by outgoing channels, which allow the excitons to spread to infinity. Besides the photoluminescent reflection, the NPQ processes are the main outgoing channels accompanied by energy dissipation and dephasing. From the simulation of wave-packet dynamics in a one-dimensional chain, it is found that, without dephasing, the motion remains superdiffusive or ballistic, despite the strong energy dissipation. At an increased dephasing rate, the wave packet motion is found to switch from superdiffusive to diffusive in nature. When a steady energy flow is injected into a site of a linear chain, exciton dissipation along the chain, owing to photoluminescence and NPQ processes, is examined by using a model with coherent and incoherent outgoing channels. It is found that channel coherence leads to suppression of dissipation and multiexciton super-radiance. With this method, the effects of NPQ and dephasing on energy transfer in the Fenna-Matthews-Olson complex are investigated. The NPQ process and the photochemical reflection are found to significantly reduce the energy transfer efficiency in the complex, whereas the dephasing process slightly enhances the efficiency. The calculated absorption spectrum reproduces the main features of the measured counterpart. As a comparison, the exciton dynamics are also studied in a linear chain of pigments and in a multiple-ring system of light harvesting complexes II (LH2) from purple bacteria by using the Davydov D1 ansatz. It is found that the exciton transport shows superdiffusion characteristics in both the chain and the LH2 rings. PMID- 25044625 TI - In reference to "the value of resident presentations at scientific meetings". PMID- 25044626 TI - Synthesis of potassium-modified graphitic carbon nitride with high photocatalytic activity for hydrogen evolution. AB - Potassium-modified graphitic carbon nitride (K-g-C3N4) nanosheets are synthesized by a facile KCl-template method that holds the advantage of easy removal of residual template. A combination of XRD, X-ray photoelectron spectroscopy, and inductively coupled plasma analyses are utilized to characterize the obtained resultant K-g-C3N4 architectures, which are composed of nanosheets of variable thickness (<10 nm). Photocatalytic hydrogen evolution experiments under visible light irradiation showed that K-g-C3N4 nanosheets have high photocatalytic activities (up to about thirteen times higher than that of pure g-C3 N4 ) as well as good stability (no reduction in activity within 16 h); both features emanate from their unique structural characteristics. These results illustrate the viability of this methodology for the facile synthesis of efficient heterogeneous photocatalysts for potential commercial applications. PMID- 25044627 TI - Bonding nature of local structural motifs in amorphous GeTe. AB - Despite its simple chemical constitution and unparalleled technological importance, the phase-change material germanium telluride (GeTe) still poses fundamental questions. In particular, the bonding mechanisms in amorphous GeTe have remained elusive to date, owing to the lack of suitable bond-analysis tools. Herein, we introduce a bonding indicator for amorphous structures, dubbed "bond weighted distribution function" (BWDF), and we apply this method to amorphous GeTe. The results underline a peculiar role of homopolar Ge-Ge bonds, which locally stabilize tetrahedral fragments but not the global network. This atom resolved (i.e., chemical) perspective has implications for the stability of amorphous "zero bits" and thus for the technologically relevant resistance-drift phenomenon. PMID- 25044628 TI - Cooperative, reversible self-assembly of covalently pre-linked proteins into giant fibrous structures. AB - We demonstrate a simple bioconjugate polymer system that undergoes reversible self-assembling into extended fibrous structures, reminiscent of those observed in living systems. It is comprised of green fluorescent protein (GFP) molecules linked into linear oligomeric strands through click step growth polymerization with dialkyne poly(ethylene oxide) (PEO). Confocal microscopy, atomic force microscopy, and dynamic light scattering revealed that such strands form high persistence length fibers, with lengths reaching tens of micrometers, and uniform, sub-100 nm widths. We ascribe this remarkable and robust form of self assembly to the cooperativity arising from the known tendency of GFP molecules to dimerize through localized hydrophobic patches and from their covalent pre linking with flexible PEO. Dissipative particle dynamics simulations of a coarse grained model of the system revealed its tendency to form elongated fibrous aggregates, suggesting the general nature of this mode of self-assembly. PMID- 25044629 TI - A supramolecular sorting hat: stereocontrol in metal-ligand self-assembly by complementary hydrogen bonding. AB - A combination of self-complementary hydrogen bonding and metal-ligand interactions allows stereocontrol in the self-assembly of prochiral ligand scaffolds. A unique, non-tetrahedral M4L6 structure is observed upon multicomponent self-assembly of 2,7-diaminofluorenol with 2-formylpyridine and Fe(ClO4)2. The stereochemical outcome of the assembly is controlled by self complementary hydrogen bonding between both individual ligands and a suitably sized counterion as template. This hydrogen-bonding-mediated stereoselective metal-ligand assembly allows the controlled formation of nonsymmetric discrete cage structures from previously unexploited ligand scaffolds. PMID- 25044630 TI - Indolicidin targets duplex DNA: structural and mechanistic insight through a combination of spectroscopy and microscopy. AB - Indolicidin (IR13), a 13-residue antimicrobial peptide from the cathelicidin family, is known to exhibit a broad spectrum of antimicrobial activity against various microorganisms. This peptide inhibits bacterial DNA synthesis resulting in cell filamentation. However, the precise mechanism remains unclear and requires further investigation. The central PWWP motif of IR13 provides a unique structural element that can wrap around, and thus stabilize, duplex B-type DNA structures. Replacements of the central Trp-Trp pair with Ala-Ala, His-His, or Phe-Phe residues in the PxxP motif significantly affects the ability of the peptide to stabilize duplex DNA. Results of microscopy studies in conjunction with spectroscopic data confirm that the DNA duplex is stabilized by IR13, thereby inhibiting DNA replication and transcription. In this study we provide high-resolution structural information on the interaction between indolicidin and DNA, which will be beneficial for the design of novel therapeutic antibiotics based on peptide scaffolds. PMID- 25044631 TI - The effects of age on the morphometry of the cervical spinal cord and spinal column in adult rats: an MRI-based study. AB - Rat models are commonly used to investigate the pathophysiological pathways and treatment outcomes after spinal cord injury (SCI). The high incidence of fall induced SCI in older adults has created a need for aging models of SCI in rats to investigate potential age-related differences in SCI severity and outcomes. The aims of this study were to determine the influences of age and vertebral level on the geometries of the cervical spinal cord and spinal column in a rat model. Three young (3 months) and three aged (12 months) Fischer 344 rats were imaged in a high field (7 T) small-animal magnetic resonance imaging system. All spinal cord geometry variables (including depth, width, and axial cross-sectional area) and one spinal canal variable (depth) were significantly larger in the aged specimens by an average of 8.1%. There were main effects of vertebral level on all spinal cord variables and four spinal canal variables with values generally larger at C4 as compared to C6 (average increases ranged from 5.7% to 12.9% in spinal cord measures and 5.4% to 6.8% in spinal canal measures). High inter-rater reliability between two measurers was observed with a mean intraclass correlation of 0.921 and percent difference of 0.9% across all variables measured. This study clearly demonstrates that cervical spinal cord geometry changes between the ages of 3 and 12 months in Fischer 344 rats. This information can aid in the planning and interpretation of studies that use a rat model to investigate the influence of age on cervical SCI. PMID- 25044632 TI - How Do Smokers Respond to Cigarette Taxes? Evidence from China's Cigarette Industry. AB - This paper examines how Chinese smokers respond to tax-driven cigarette price increases by estimating a discrete choice model of demand for differentiated products, using annual nationwide brand-level cigarette sales data in China from 2005 to 2010. We allow for substitution between different cigarette brands and also incorporate key features of rational addiction theory into the model. Results show that the average own-price elasticity of demand for cigarettes at the brand level is -0.807, and the overall price elasticity of cigarettes at the market level is -0.488 in China. We find tax-induced substitution toward low price cigarettes as well as high-tar cigarettes and that tax hikes encourage within-class substitution more than across-class substitution. These results have important policy implications for the potential effects of cigarette taxation. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25044633 TI - The risk for diabetic nephropathy is low in young adults in a 17-year follow-up from the Diabetes Incidence Study in Sweden (DISS). Older age and higher BMI at diabetes onset can be important risk factors. AB - AIMS: The main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years). METHODS: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes. RESULTS: After median 17 years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m2), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing diabetic nephropathy between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05 1.12 per 1 mmHg increase) were associated with DN. CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow-up was a risk marker for later development of diabetic nephropathy. PMID- 25044636 TI - Clinical and molecular characteristics of Chinese patients with X-linked lymphoproliferative syndrome type 1. AB - BACKGROUND: X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inherited, life-threatening immunodeficiency disorder caused by mutations in SH2D1A gene. It affect approximately two to three males per million. Fewer than 10 cases with definite gene mutations have been reported in Chinese mainland and no rapid diagnosis method has been established. PROCEDURE: We determined the clinical and molecular characteristics of five patients with XLP1. The SH2D1A gene were amplified by PCR and sequenced, the SAP expression was analyzed by flow cytometry. RESULTS: Two patients had novel SH2D1A mutations and three had mutations that have been previously reported. Three patients presented with fulminant infectious mononucleosis or hemophagocytic lymphohistiocytosis and one presented with lymphoma. Null or decreased SAP expression on PBMCs was noted. The remaining patient presented with unique, recurrent, nonfulminant infectious mononucleosis and bimodal intracellular SAP protein expression. CONCLUSIONS: The overall molecular characteristics and clinical phenotypes of Chinese patients with XLP1 matched previous reports. The unique bimodal intracellular SAP protein expression indicated the presence of some residual SAP-positive T cells that are able to respond to persistent Epstein-Barr virus infection and could explain the relatively mild clinical phenotype of this patient. PMID- 25044635 TI - Bioabsorbable polymer-coated sirolimus-eluting stent implantation preserves coronary vasomotion: A DESSOLVE II trial sub-study. AB - OBJECTIVES: We studied coronary vasomotion in patients treated with the Mistent((r)) absorbable polymer sirolimus-eluting stent (APSES) and in patients implanted with the Endeavor((r)) zotarolimus-eluting stent (ZES). BACKGROUND: First generation (1st-gen) drug-eluting stents (DES) induce persistent vasomotor dysfunction in the treated coronary artery. It is unknown whether and to what extent the implantation of an absorbable polymer DES impairs coronary vasomotion. METHODS: This sub-study of the DESSOLVE II trial included 19 APSES Mistent((r)) and 10 ZES Endeavor((r)) patients. Incremental atrial pacing and quantitative coronary angiography were used to assess vasomotion proximal and distal to the stent and in a reference segment at 9 months after implantation. Percent changes in vessel diameter with pacing versus baseline were calculated and compared. Vasomotor response of the APSES group was also compared with changes observed in a historical group of 17 patients implanted with a 1st-gen sirolimus-eluting stent (SES). RESULTS: Normal vasomotion (vasodilatation) was preserved and of comparable magnitude in the APSES and in the ZES group both proximally (P = 0.34) and distally (P = 0.38) to the stent. This finding was not observed in the 1st gen SES group showing marked pacing-induced vasoconstriction at both stent edges (P < 0.05 vs. APSES). The results were practically unchanged after excluding patients with absolute changes in vessel diameter <3% between baseline and maximal pacing. CONCLUSIONS: The implantation of an absorbable polymer sirolimus eluting stent is associated with preserved coronary vasomotion, comparable to that observed after implantation of the Endeavor((r)) ZES, and distinct from 1st gen SES which induce coronary vasomotor dysfunction. PMID- 25044634 TI - Vitamin K catabolite inhibition of ovariectomy-induced bone loss: structure activity relationship considerations. AB - SCOPE: The potential benefit of vitamin K as a therapeutic in osteoporosis is controversial and the vitamin K regimen being used clinically (45 mg/day) employs doses that are many times higher than required to ensure maximal gamma carboxylation of the vitamin K-dependent bone proteins. We therefore tested the hypothesis that vitamin K catabolites, 5-carbon (CAN5C) and 7-carbon carboxylic acid (CAN7C) aliphatic side-chain derivatives of the naphthoquinone moiety exert an osteotrophic role consistent with the treatment of osteoporosis. METHODS AND RESULTS: Osteoblast-like MG63 cell cultures were challenged with lipopolysaccharide and the levels of interleukin-6, an osteoclastogenic cytokine, measured with and without catabolites; low concentrations of CAN7C significantly inhibited interleukin-6 release, but CAN5C did not. In models of bone loss induced by ovariectomy or sciatic neurectomy in C57BL/6 mice, we found that the rarer CAN7C catabolite markedly restricted ovariectomy-induced bone loss and possibly limited sciatic neurectomy-induced bone loss. CAN7C activity depends on a free carboxylic acid and its particular side-chain structure. CONCLUSION: These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite. PMID- 25044637 TI - Low testosterone syndrome protects subjects with high cardiovascular risk burden from major adverse cardiovascular events. AB - The role of testosterone (T) in the cardiovascular (CV) health of men is controversial. Some data suggest that hypogonadism is associated with CV mortality but not morbidity, however, recent evidence shows that hypogonadal subjects treated with T replacement therapy have a higher incidence of new CV events. The aim of this study is to analyse whether gonadal status might predict new CV event incidence according to a patient's previous history of CV events, in a cohort of subjects complaining of sexual dysfunction. A consecutive series of 1687 patients was followed-up for a mean time of 4.3 +/- 2.6 years for new occurrence of CV events, detecting 139 events. Hypogonadism (total T < 12 nmol/L) was not associated with an increased incidence of new CV events in the entire cohort. However, when considering patients with a previous history of CV events, hypogonadism was associated with a reduced risk of new CV events, even after adjusting for confounders (hazard ratios - HR = 0.498 [0.240; 0.996]; p = 0.049), whereas no relationship was observed in subjects free of previous CV events. Similar results were observed when reduced testis volume (TV) was considered as a predictor of new CV events in subjects with previous CV events (HR = 0.486 [0.257; 0.920]; p = 0.027). In patients with a history of previous CV events, but not in those without previous CV events, having both low T and low TV was associated with a lower incidence of new CV events as compared with subjects with only one or none of these conditions, even after adjusting for confounders (HR = 0.514 [0.306; 0.864]; p for trend < 0.02). Notably, CV risk estimated with risk engines based on traditional risk factors was not different between hypogonadal and eugonadal subjects. In conclusion, hypogonadism could be interpreted as a protective mechanism in unhealthy conditions, such as previous CV events, to avoid fatherhood and spare energy. PMID- 25044638 TI - Degradable hyaluronic acid/protamine sulfate interpolyelectrolyte complexes as miRNA-delivery nanocapsules for triple-negative breast cancer therapy. AB - Metastatic relapse is a leading cause of cancer-associated death and one of the major obstacles for effective therapy against triple-negative breast cancer. To address this problem, a miRNA-delivering nanocapsule technology based on hyaluronic acid (HA)/protamine sulfate (PS) interpolyelectrolyte complexes (HP IPECs) is developed for efficient encapsulation and intracellular delivery microRNA-34a (miR-34a), which is a potent endogenous tumor suppressor of breast cancer. The nanocapsules are successfully generated through a self-assembly approach mediated by an electrostatic interaction. In vitro and in vivo experiments illustrate that miR-34a can be efficiently encapsulated into HP-IPECs and delivered into breast cancer cells or breast cancer tissues. Nanocomplex assisted delivery of miR-34a induces cell apoptosis and suppresses migration, proliferation, and tumor growth of breast cancer cells via targeting CD44 and a Notch-1-signaling pathway. The obtained results suggest that HP-IPECs have a great potential as a biodegradable vector for microRNA-based therapy against triple-negative breast cancer. PMID- 25044639 TI - Chromosomal integration of hyaluronic acid synthesis (has) genes enhances the molecular weight of hyaluronan produced in Lactococcus lactis. AB - Microbial production of hyaluronic acid (HA) is an attractive substitute for extraction of this biopolymer from animal tissues. Natural producers such as Streptococcus zooepidemicus are potential pathogens; therefore, production of HA by recombinant bacteria that are generally recognized as safe (GRAS) organisms is a viable alternative that is being extensively explored. However, plasmid-based expression systems for HA production by recombinant bacteria have the inherent disadvantage of reduced productivity because of plasmid instability. To overcome this problem, the HA synthesis genes (hasA-hasB and hasA-hasB-hasC) from has operon of S. zooepidemicus were integrated into the chromosome of Lactococcus lactis by site-directed, double-homologous recombination developing strains VRJ2AB and VRJ3ABC. The chromosomal integration stabilized the genes and obviated the instability observed in plasmid-expressed recombinant strains. The genome integrated strains produced higher molecular weight (3.5-4 million Dalton [MDa]) HA compared to the plasmid-expressed strains (2 MDa). High molecular weight HA was produced when the intracellular concentration of uridine diphosphate N acetylglucosamine (UDP-GlcNAc) and uridine diphosphate-glucuronic acid (UDP GlcUA) was almost equal and hasA to hasB ratio was low. This work suggests an optimal approach to obtain high molecular weight HA in recombinant strains. PMID- 25044640 TI - ZnO nanowire arrays exhibit cytotoxic distinction to cancer cells with different surface charge density: cytotoxicity is charge-dependent. AB - Using distinct ZnO NW arrays to provide positively charged surface, charge effect on cytotoxicity is investigated. 1-D structure of ZnO NWs is the main factor leads to apoptosis accompanied by ROS enrichment and GSH depletion, and electrostatic interaction between positively charged ZnO NWs and negatively charged cells make important contribution to the degree of ZnO NW arrays damaging cell membrane. PMID- 25044641 TI - Performance of super-SILAC based quantitative proteomics for comparison of different acute myeloid leukemia (AML) cell lines. AB - As a direct consequence of the high diversity of the aggressive blood cancer acute myeloid leukemia (AML), proteomic samples from patients are strongly heterogeneous, rendering their accurate relative quantification challenging. In the present study, we investigated the benefits of using a super-SILAC mix of AML derived cell lines as internal standard (IS) for quantitative shotgun studies. The Molm-13, NB4, MV4-11, THP-1, and OCI-AML3 cell lines were selected for their complementarity with regard to clinical, cytogenetic, and molecular risk factors used for prognostication of AML patients. The resulting IS presents a high coverage of the AML proteome compared to single cell lines allied with high technical reproducibility, thus enabling its use for AML patient comparison. This was confirmed by comparing the protein regulation between the five cell lines and by applying the IS to patient material; hence, we were able to reproduce specific functional regulations known to be related to disease progression and molecular genetic abnormalities. The MS proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository with the dataset identifier PXD000441. PMID- 25044642 TI - Heavy hitting: Using water to label humans. AB - Monitoring protein dynamics, compared to measuring static protein expression profiles taken with snapshot evaluations, have recently been the focus of proteomics studies examining tissue or blood samples where time course changes occur. Using deuterium oxide ((2) H2 O) to label amino acids is a useful method to monitor protein turnover rates. The synthesis rate for individual proteins is calculated from the rate of (2) H incorporation into specific proteins analyzed by high resolution MS. In this issue, Wang and colleagues measured the plasma protein turnover dynamics in healthy humans by in vivo (2) H2 O labeling [Wang, D. et al., Proteomics Clin. Appl. 2014, 8, 610-619]. The authors developed and validated a safe and accessible (2) H2 O administration protocol to record the turnover dynamics of 542 plasma proteins using MS. Their study demonstrates a promising new way to evaluate plasma protein dynamics in clinical trials where such knowledge could help for prognosis and evaluating treatment efficacy. PMID- 25044643 TI - Sap-feeding insects on forest trees along latitudinal gradients in northern Europe: a climate-driven patterns. AB - Knowledge of the latitudinal patterns in biotic interactions, and especially in herbivory, is crucial for understanding the mechanisms that govern ecosystem functioning and for predicting their responses to climate change. We used sap feeding insects as a model group to test the hypotheses that the strength of plant-herbivore interactions in boreal forests decreases with latitude and that this latitudinal pattern is driven primarily by midsummer temperatures. We used a replicated sampling design and quantitatively collected and identified all sap feeding insects from four species of forest trees along five latitudinal gradients (750-1300 km in length, ten sites in each gradient) in northern Europe (59 to 70 degrees N and 10 to 60 degrees E) during 2008-2011. Similar decreases in diversity of sap-feeding insects with latitude were observed in all gradients during all study years. The sap-feeder load (i.e. insect biomass per unit of foliar biomass) decreased with latitude in typical summers, but increased in an exceptionally hot summer and was independent of latitude during a warm summer. Analysis of combined data from all sites and years revealed dome-shaped relationships between the loads of sap-feeders and midsummer temperatures, peaking at 17 degrees C in Picea abies, at 19.5 degrees C in Pinus sylvestris and Betula pubescens and at 22 degrees C in B. pendula. From these relationships, we predict that the losses of forest trees to sap-feeders will increase by 0-45% of the current level in southern boreal forests and by 65-210% in subarctic forests with a 1 degrees C increase in summer temperatures. The observed relationships between temperatures and the loads of sap-feeders differ between the coniferous and deciduous tree species. We conclude that climate warming will not only increase plant losses to sap-feeding insects, especially in subarctic forests, but can also alter plant-plant interactions, thereby affecting both the productivity and the structure of future forest ecosystems. PMID- 25044645 TI - Insights into the regulatory domain of cystathionine Beta-synthase: characterization of six variant proteins. AB - Cystathionine beta-synthase (CBS) catalyzes the formation of cystathionine from homocysteine and serine. CBS is allosterically activated by S-adenosylmethionine (SAM), which binds to its C-terminal regulatory domain. Mutations in this domain lead to variants with high residual activity but lacking SAM activation. We characterized six C-terminal CBS variants (p.P427L, p.D444N, p.V449G, p.S500L, p.K523Sfs*18, and p.L540Q). To understand the effect of C-terminal mutations on the functional/structural properties of CBS, we performed dynamic light scattering, differential scanning fluorimetry, limited proteolysis, enzymatic characterization, and determination of SAM-binding affinity. Kinetic data confirm that the enzymatic function of these variants is not impaired. Although lacking SAM activation, the p.P427L and p.S500L were able to bind SAM at a lower extent than the wild type (WT), confirming that SAM binding and activation can be two independent events. At the structural level, the C-terminal variants presented various effects, either showing catalytic core instability and increased susceptibility toward aggregation or presenting with similar or higher stability than the WT. Our study highlights as the common feature to the C-terminal variants an impaired binding of SAM and no increase in enzymatic activity with physiological concentrations of the activator, suggesting the loss of regulation by SAM as a potential pathogenic mechanism. PMID- 25044646 TI - Membrane deformation by neolectins with engineered glycolipid binding sites. AB - Lectins are glycan-binding proteins that are involved in the recognition of glycoconjugates at the cell surface. When binding to glycolipids, multivalent lectins can affect their distribution and alter membrane shapes. Neolectins have now been designed with controlled number and position of binding sites to decipher the role of multivalency on avidity to a glycosylated surface and on membrane dynamics of glycolipids. A monomeric hexavalent neolectin has been first engineered from a trimeric hexavalent bacterial lectin, From this neolectin template, 13 different neolectins with a valency ranging from 0 to 6 were designed, produced, and analyzed for their ability to bind fucose in solution, to attach to a glycosylated surface and to invaginate glycolipid-containing giant liposomes. Whereas the avidity only depends on the presence of at least two binding sites, the ability to bend and invaginate membranes critically depends on the distance between two adjacent binding sites. PMID- 25044644 TI - Design and biocompatibility of endovascular aneurysm filling devices. AB - The rupture of an intracranial aneurysm, which can result in severe mental disabilities or death, affects approximately 30,000 people in the United States annually. The traditional surgical method of treating these arterial malformations involves a full craniotomy procedure, wherein a clip is placed around the aneurysm neck. In recent decades, research and device development have focused on new endovascular treatment methods to occlude the aneurysm void space. These methods, some of which are currently in clinical use, utilize metal, polymeric, or hybrid devices delivered via catheter to the aneurysm site. In this review, we present several such devices, including those that have been approved for clinical use, and some that are currently in development. We present several design requirements for a successful aneurysm filling device and discuss the success or failure of current and past technologies. We also present novel polymeric-based aneurysm filling methods that are currently being tested in animal models that could result in superior healing. PMID- 25044647 TI - Using the population-shift mechanism to rationally introduce "Hill-type" cooperativity into a normally non-cooperative receptor. AB - Allosteric cooperativity, which nature uses to improve the sensitivity with which biomolecular receptors respond to small changes in ligand concentration, could likewise be of use in improving the responsiveness of artificial biosystems. Thus motivated, we demonstrate here the rational design of cooperative molecular beacons, a widely employed DNA sensor, using a generalizable population-shift approach in which we engineer receptors that equilibrate between a low-affinity state and a high-affinity state exposing two binding sites. Doing so we achieve cooperativity within error of ideal behavior, greatly steepening the beacon's binding curve relative to that of the parent receptor. The ability to rationally engineer cooperativity should prove useful in applications such as biosensors, synthetic biology and "smart" biomaterials, in which improved responsiveness is of value. PMID- 25044648 TI - Measurement of iron in serum and EDTA plasma for screening of blood transfusion in sports. PMID- 25044650 TI - Image-contrast technology based on the electrochemiluminescence of porous silicon and its application in fingerprint visualization. AB - The electrochemiluminescence (ECL) of porous silicon (pSi) has attracted great interest for its potential application in display technology and chemical sensors. In this study, we found that pSi with a different surface chemistry displayed an apparently different dynamic ECL process. An image-contrast technology was established on the basis of the intrinsic mechanism of the ECL dynamic process. As a proof of principle, the visualization of latent fingerprints (LFPs) and in situ detection of TNT in fingerprints was demonstrated by using the ECL-based image-contrast technology. PMID- 25044651 TI - The diverse manifold of electronic states generated by a single carbon defect in a graphene sheet: multireference calculations using a pyrene defect model. AB - Detailed calculations have been performed on the electronic states occurring in a single vacancy defect model based on pyrene from which one of the central carbon atoms has been removed. Complete active space self-consistent field and multireference configuration interaction with singles and doubles calculations have been performed using the 6-31G and 6-31G* basis sets. Two types of defect geometries have been defined: 1) The unrelaxed defect structure based on pyrene and 2) a relaxed structure. In total 12 electronic states have been computed for the unrelaxed structure at C2v symmetry, comprising four singlets, triplets and quintets each. The lowest six states are formed from singlet and triplet states and appear in a rather narrow gap of ~0.6 eV. The lowest quintet state is found 1.43 eV above the (3) B1 ground state. As predicted from Jahn-Teller distortions, a C?C bond is formed between dangling carbon bonds in the (1, 3) B1 states, leading to the formation of a five-membered ring. The (1, 3) A2 states show initial repulsive behavior along the bond formation coordinate until an avoided crossing is reached by which these states are furnished with C?C bonding character so that finally also in these cases a C?C bond is established. Linear interpolation curves between the initial unrelaxed defect structure and the final optimized structure are used to give an overview of the evolution of electronic states and the occurrence of avoided crossings. Out-of-plane structures are investigated with special emphasis on the carbon atom containing a dangling bond in the relaxed structure. Unpaired electron densities are used to characterize the electronic structure of the different states. PMID- 25044652 TI - Highly enantioselective rhodium(I)-catalyzed carbonyl carboacylations initiated by C-C bond activation. AB - The lactone motif is ubiquitous in natural products and pharmaceuticals. The Tishchenko disproportionation of two aldehydes, a carbonyl hydroacylation, is an efficient and atom-economic access to lactones. However, these reaction types are limited to the transfer of a hydride to the accepting carbonyl group. The transfer of alkyl groups enabling the formation of C?C bonds during the ester formation would be of significant interest. Reported herein is such asymmetric carbonyl carboacylation of aldehydes and ketones, thus affording complex bicyclic lactones in excellent enantioselectivities. The rhodium(I)-catalyzed transformation is induced by an enantiotopic C?C bond activation of a cyclobutanone and the formed rhodacyclic intermediate reacts with aldehyde or ketone groups to give highly functionalized lactones. PMID- 25044653 TI - Optimization of intra-voxel incoherent motion imaging at 3.0 Tesla for fast liver examination. AB - BACKGROUND: Optimization of multi b-values MR protocol for fast intra-voxel incoherent motion imaging of the liver at 3.0 Tesla. METHODS: A comparison of four different acquisition protocols were carried out based on estimated IVIM (DSlow , DFast , and f) and ADC-parameters in 25 healthy volunteers. The effects of respiratory gating compared with free breathing acquisition then diffusion gradient scheme (simultaneous or sequential) and finally use of weighted averaging for different b-values were assessed. An optimization study based on Cramer-Rao lower bound theory was then performed to minimize the number of b values required for a suitable quantification. The duration-optimized protocol was evaluated on 12 patients with chronic liver diseases RESULTS: No significant differences of IVIM parameters were observed between the assessed protocols. Only four b-values (0, 12, 82, and 1310 s.mm(-2) ) were found mandatory to perform a suitable quantification of IVIM parameters. DSlow and DFast significantly decreased between nonadvanced and advanced fibrosis (P < 0.05 and P < 0.01) whereas perfusion fraction and ADC variations were not found to be significant. CONCLUSION: Results showed that IVIM could be performed in free breathing, with a weighted-averaging procedure, a simultaneous diffusion gradient scheme and only four optimized b-values (0, 10, 80, and 800) reducing scan duration by a factor of nine compared with a nonoptimized protocol. Preliminary results have shown that parameters such as DSlow and DFast based on optimized IVIM protocol can be relevant biomarkers to distinguish between nonadvanced and advanced fibrosis. PMID- 25044654 TI - Progression and reversal of coronary and mesenteric vascular dysfunction associated with obesity. AB - OBJECTIVE: The purpose of this study was to examine progression and reversal of microvascular complications when rats were fed a high fat diet. METHODS: Sprague Dawley rats 10 weeks of age were fed a diet containing 45% kcal fat for up to 32 weeks. Blood pressure and heart rate was measured by telemetry. Vascular reactivity of aorta and small coronary and mesenteric vessels was determined after 8, 16, 24, and 32 weeks on diet. RESULTS: There was a modest increase in weight and blood pressure in high fat fed rats. Sodium nitroprusside (SNP) induced relaxation of coronary arteries was potentiated after 8 weeks on high fat diet, however, this enhanced response was not observed after 16, 24, or 32 weeks of diet. Acetylcholine (Ach) mediated relaxation was attenuated after 16, 24, and 32 weeks of high fat diet in coronary arteries; however, in aorta and mesenteric arteries, Ach-mediated response was not altered until 32 weeks on high fat diet. Reversing the high fat diet for 8 weeks resulted in partial recovery of metabolic parameters; however endothelial function in coronary arteries remained impaired. CONCLUSIONS: These studies indicate that high fat diet promotes progressive impairment of coronary vascular function that is difficult to reverse. PMID- 25044655 TI - A novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). AB - Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis. PMID- 25044656 TI - Supersonic molecular beam experiments on surface chemical reactions. AB - The interaction of a molecule and a surface is important in various fields, and in particular in complex systems like biomaterials and their related chemistry. However, the detailed understanding of the elementary steps in the surface chemistry, for example, stereodynamics, is still insufficient even for simple model systems. In this Personal Account, I review our recent studies of chemical reactions on single-crystalline Cu and Si surfaces induced by hyperthermal oxygen molecular beams and by oriented molecular beams, respectively. Studies of oxide formation on Cu induced by hyperthermal molecular beams demonstrate a significant role of the translational energy of the incident molecules. The use of hyperthermal molecular beams enables us to open up new chemical reaction paths specific for the hyperthermal energy region, and to develop new methods for the fabrication of thin films. On the other hand, oriented molecular beams also demonstrate the possibility of understanding surface chemical reactions in detail by varying the orientation of the incident molecules. The steric effects found on Si surfaces hint at new ways of material fabrication on Si surfaces. Controlling the initial conditions of incoming molecules is a powerful tool for finely monitoring the elementary step of the surface chemical reactions and creating new materials on surfaces. PMID- 25044657 TI - Magnetic graphene oxide as adsorbent for the determination of polycyclic aromatic hydrocarbon metabolites in human urine. AB - Detection of monohydroxy polycyclic aromatic hydrocarbons metabolites in urine is an advisable and valid method to assess human environmental exposure to polycyclic aromatic hydrocarbons. In this work, novel Fe3O4/graphene oxide composites were prepared and their application in the magnetic solid-phase extraction of monohydroxy polycyclic aromatic hydrocarbons in urine was investigated by coupling with liquid chromatography and mass spectrometry. In the hybrid material, superparamagnetic Fe3O4 nanoparticles provide fast separation to simplify the analytical process and graphene oxide provides a large functional surface for the adsorption. The prepared magnetic nanocomposites were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and vibrating sample magnetometry. The experimental conditions were optimized systematically. Under the optimal conditions, the recoveries of these compounds were in the range of 98.3-125.2%, the relative standard deviations ranged between 6.8 and 15.5%, and the limits of detection were in the range of 0.01-0.15 ng/mL. The simple, quick, and affordable method was successfully used in the analysis of human urinary monohydroxy polycyclic aromatic hydrocarbons in two different cities. The results indicated that the monohydroxy polycyclic aromatic hydrocarbons level in human urine can provide useful information for environmental exposure to polycyclic aromatic hydrocarbons. PMID- 25044659 TI - Adsorption of large hydrocarbons on coinage metals: a van der Waals density functional study. AB - The adsorption of organic molecules onto the close-packed facets of coinage metals is studied, and how accurately adsorption heights can be described by using recent advances of the van der Waals density functional (vdWDF), with optPBE/vdWDF, optB86b/vdWDF, vdWDF2, and rev/vdWDF2 functionals is illustrated. The adsorption of two prototypical aromatic hydrocarbons is investigated, and the calculated adsorption heights are compared to experimental literature values from normal incident X-ray standing wave absorption and a state-of-the-art semi empirical method. It is shown that both the optB86b/vdWDF and rev/vdWDF2 functionals describe adsorption heights with an accuracy of 0.1 A, compared to experimental values, and are concluded as reliable methods of choice for related systems. PMID- 25044658 TI - Comparative effectiveness of medical and surgical therapy on olfaction in chronic rhinosinusitis: a prospective, multi-institutional study. AB - BACKGROUND: Evidence comparing the impact of medical and surgical management of chronic rhinosinusitis on olfactory function is limited. This study evaluates olfactory outcomes in patients who failed initial medical management and elect either continued medical management or endoscopic sinus surgery (ESS) followed by medical management. METHODS: Adult subjects were prospectively enrolled into a nonrandomized, multi-institutional cohort. Baseline characteristics, quality-of life and objective clinical findings were collected along with 2 quality-of-life disease-specific measures, the Rhinosinusitis Disability Index (RSDI) and Sinonasal Outcome Test (SNOT-22). The primary outcome measure was the posttreatment change (>=6 months) in the Brief Smell Identification Test (B-SIT). Bivariate and multivariate analyses compared B-SIT changes by treatment type while controlling for baseline cofactors. RESULTS: Subjects (n = 280) were enrolled between March 2011 and May 2013. Baseline B-SIT scores (mean +/- standard deviation) were comparable between medical and surgical treatment groups (8.8 +/- 3.2 vs 9.0 +/- 3.2; p = 0.703). Subjects with baseline impaired olfaction (n = 83; 29.6%) experienced B-SIT improvement in both the medical (n = 17; 2.3 +/- 2.8; p = 0.005) and surgical (n = 66; 2.1 +/- 3.0; p < 0.001) cohort. A total of 38.6% of subjects with impaired olfaction return to normal olfaction at follow-up with no difference identified between treatment modalities (p = 0.803). Multivariate analyses identified prior surgery as a predictor of less improvement regardless of treatment modality in patients with baseline impaired olfaction. Average changes in B-SIT scores were comparable between treatment groups (p > 0.050). CONCLUSION: Subjects electing ESS experienced gains in olfaction comparable to subjects electing continued medical management. Further study with larger sample size and more sensitive measures of olfaction are needed to determine differences between treatment groups. PMID- 25044660 TI - Increasing the reaction rate of hydroxynitrile lyase from Hevea brasiliensis toward mandelonitrile by copying active site residues from an esterase that accepts aromatic esters. AB - The natural substrate of hydroxynitrile lyase from rubber tree (HbHNL, Hevea brasiliensis) is acetone cyanohydrin, but synthetic applications usually involve aromatic cyanohydrins such as mandelonitrile. To increase the activity of HbHNL toward this unnatural substrate, we replaced active site residues in HbHNL with the corresponding ones from esterase SABP2 (salicylic acid binding protein 2). Although this enzyme catalyzes a different reaction (hydrolysis of esters), its natural substrate (methyl salicylate) contains an aromatic ring. Three of the eleven single-amino-acid-substitution variants of HbHNL reacted more rapidly with mandelonitrile. The best was HbHNL-L121Y, with a kcat 4.2 times higher and high enantioselectivity. Site-saturation mutagenesis at position 121 identified three other improved variants. We hypothesize that the smaller active site orients the aromatic substrate more productively. PMID- 25044661 TI - Porous anionic indium-organic framework with enhanced gas and vapor adsorption and separation ability. AB - A three-dimensional microporous anionic metal-organic framework (MOF) (Et4N)3[In3(TATB)4] (FJI-C1, H3TATB=4,4',4''-s-triazine-2,4,6-triyltribenzoic acid) with large unit cell volume has been synthesized. Assisted by the organic cation group Et4N in the pores of the compound, FJI-C1 not only shows high adsorption uptakes of C2 and C3 hydrocarbons, but also exhibits highly selective separation of propane, acetylene, ethane, and ethylene from methane at room temperature. Furthermore, it also exhibits high separation selectivity for propane over C2 hydrocarbons and acetylene can be readily separated from their C2 hydrocarbons mixtures at low pressure due to the high selectivity for C2H2 in comparison to C2H4 and C2H6. In addition, FJI-C1 with hydrophilic internal pores surfaces shows highly efficient adsorption separation of polar molecules from nonpolar molecules. Notably, it exhibits high separation selectivity for benzene over cyclohexane due to the pi-pi interactions between benzene molecules and s triazine rings of the porous MOF. PMID- 25044662 TI - "CLASSIC NMR": an in-situ NMR strategy for mapping the time-evolution of crystallization processes by combined liquid-state and solid-state measurements. AB - A new in-situ NMR strategy (termed CLASSIC NMR) for mapping the evolution of crystallization processes is reported, involving simultaneous measurement of both liquid-state and solid-state NMR spectra as a function of time. This combined strategy allows complementary information to be obtained on the evolution of both the solid and liquid phases during the crystallization process. In particular, as crystallization proceeds (monitored by solid-state NMR), the solution state becomes more dilute, leading to changes in solution-state speciation and the modes of molecular aggregation in solution, which are monitored by liquid-state NMR. The CLASSIC NMR experiment is applied here to yield new insights into the crystallization of m-aminobenzoic acid. PMID- 25044664 TI - Submicron imaging of soft-tissues using low-dose phase-contrast x-ray synchrotron microtomography with an iodine contrast agent. PMID- 25044665 TI - Tobacco Control Policies and Sudden Infant Death Syndrome in Developed Nations. AB - This paper estimates the effects of higher cigarette prices and smoke-free policies on the prevalence of Sudden Infant Death Syndrome (SIDS). Using a panel of developed countries over a 20 year period, we find that higher cigarette prices are associated with reductions in the prevalence of SIDS. However, we find no evidence that smoke-free policies are associated with declines in SIDS. PMID- 25044666 TI - Point-of-care blood glucose measurement errors overestimate hypoglycaemia rates in critically ill patients. AB - BACKGROUND: Hypoglycaemia is associated with morbidity and mortality in critically ill patients, and many hospitals have programmes to minimize hypoglycaemia rates. Recent studies have established the hypoglycaemic patient day as a key metric and have published benchmark inpatient hypoglycaemia rates on the basis of point-of-care blood glucose data even though these values are prone to measurement errors. METHODS: A retrospective, cohort study including all patients admitted to Harborview Medical Center Intensive Care Units (ICUs) during 2010 and 2011 was conducted to evaluate a quality improvement programme to reduce inappropriate documentation of point-of-care blood glucose measurement errors. Laboratory Medicine point-of-care blood glucose data and patient charts were reviewed to evaluate all episodes of hypoglycaemia. RESULTS: A quality improvement intervention decreased measurement errors from 31% of hypoglycaemic (<70 mg/dL) patient-days in 2010 to 14% in 2011 (p < 0.001) and decreased the observed hypoglycaemia rate from 4.3% of ICU patient-days to 3.4% (p < 0.001). Hypoglycaemic events were frequently recurrent or prolonged (~40%), and these events are not identified by the hypoglycaemic patient-day metric, which also may be confounded by a large number of very low risk or minimally monitored patient days. CONCLUSIONS: Documentation of point-of-care blood glucose measurement errors likely overestimates ICU hypoglycaemia rates and can be reduced by a quality improvement effort. The currently used hypoglycaemic patient-day metric does not evaluate recurrent or prolonged events that may be more likely to cause patient harm. The monitored patient-day as currently defined may not be the optimal denominator to determine inpatient hypoglycaemic risk. PMID- 25044668 TI - Chronic total occlusion percutaneous coronary intervention case selection and techniques for the antegrade-only operator. AB - Coronary chronic total occlusions (CTO) remain a difficult lesion subset to treat. Although CTOs are present at coronary angiography in 15-20% of patients, only a small fraction of eligible patients will be offered percutaneous treatment. Recent publications from centers with dedicated CTO programs using the full range of antegrade and retrograde techniques suggest success rates in the range of 90% even when little anatomic exclusion are used. However, many patients with clinically appropriate CTO targets have simpler anatomy that can predictably be managed without the selected skills and equipment. The purpose of this review is to provide skilled percutaneous coronary intervention operators who have not specialized in complex retrograde CTO techniques, an algorithm for the selection and antegrade management of appropriate CTO cases. Core equipment and techniques are discussed. PMID- 25044667 TI - Deuterium-labeled phylloquinone fed to alpha-tocopherol-injected rats demonstrates sensitivity of low phylloquinone-containing tissues to menaquinone-4 depletion. AB - SCOPE: The influence of excess alpha-tocopherol (alpha-T) on tissue depletion of phylloquinone (PK) and menaquinone-4 (MK-4) was evaluated. METHODS AND RESULTS: Rats (n = 5 per group) were fed deuterium-labeled PK (2 MUmol/kg diet) for 17 days, thereby labeling the conversion from deuterium-labeled PK to d4-MK-4. Then they were injected subcutaneously daily for the last 7 days with saline, vehicle, or alpha-T (100 mg/kg body weight). alpha-T injections (i) increased alpha-T concentrations by tenfold in liver, doubled them in plasma and most tissues, but they were unchanged in brain; (ii) increased the alpha-T metabolite, carboxyethyl hydroxychromanol (alpha-CEHC) concentrations: >25-fold in liver and kidney, tenfold in plasma and lung, and 50-fold in heart; brain contained detectable alpha-CEHC (0.26 +/- 0.03 nmol/g) only in alpha-T-injected animals; and (iii) depleted most tissues' vitamin K. Compared with vehicle-injected rats, brains from alpha-T rats contained half the total vitamin K (10.3 +/- 0.5 versus 21 +/- 2 pmol/g, p = 0.0002) and one-third the d4-MK-4 (5.8 +/- 0.5 versus 14.6 +/- 1.7 pmol/g, p = 0.0002). Tissues with high PK concentrations (liver, 21-30 pmol/g and heart, 28-50 pmol/g) were resistant to K depletion. CONCLUSION: We propose that alpha-T-dependent vitamin K depletion is likely mediated at an intermediate step in MK-4 production; thus, tissues with high PK are unaffected. PMID- 25044669 TI - Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: a report from the Children's Oncology Group. AB - BACKGROUND: Hepatoblastoma is a malignancy of young children. Low birth weight is associated with significantly increased risk of hepatoblastoma and neonatal medical exposures are hypothesized as contributors. This study represents the largest case-control study of hepatoblastoma to date and aimed to define the role of neonatal exposures in hepatoblastoma risk among low birth weight children. PROCEDURE: Incident hepatoblastoma cases who were born <2,500 g (N = 60), diagnosed between 2000 and 2008, were identified through the Children's Oncology Group. Controls were recruited through state birth registries (N = 51). Neonatal medical exposures were abstracted from medical records. Subjects from the Vermont Oxford Network were used for further comparisons, as were existing reports on neonatal medical exposures. RESULTS: Case-control comparisons were hindered by poor matching within birth weight strata. Cases were smaller and received more aggressive neonatal treatment compared to controls, and reflected high correlation levels between birth weight and treatments. Similar difficulty was encountered when comparing cases to Vermont Oxford Network subjects; cases were smaller and required more aggressive neonatal therapy. Furthermore, it appears hepatoblastoma cases were exposed to a greater number of diagnostic X-rays than in case series previously reported in the neonatal literature. CONCLUSIONS: This study presents the largest case series of hepatoblastoma in <2,500 g birth weight infants with accompanying neonatal medical exposure data. Findings confirm that birth weight is highly correlated with exposure intensity, and neonatal exposures are themselves highly correlated, which hampers the identification of a causal exposure among hepatoblastoma cases. Experimental models or genetic susceptibility testing may be more revealing of etiology. PMID- 25044670 TI - Impact of cigarette smoking on histone (H2B) to protamine ratio in human spermatozoa and its relation to sperm parameters. AB - Smoking is strongly associated with abnormalities in histone-to-protamine transition and with alteration of protamine expression in human spermatozoa. A proper protamine to histone ratio is, however, essential for sperm chromatin maturity and DNA integrity. Alterations in these sperm nuclear proteins were observed in infertile men. The present prospective study is aimed at evaluating the possible relationship among smoking, semen quality and the histone-to protamine transition ratio in mature spermatozoa. Histone H2B and protamine 1 (P1) and 2 (P2) were quantified using acid-urea polyacrylamide gel electrophoresis in the spermatozoa of 35 smokers and 19 non-smokers. Levels of lipid peroxidation marker malondialdehyde (MDA) were measured in seminal plasma by thiobarbituric acid assay. Cotinine concentrations were determined in seminal plasma using an enzyme-linked immunosorbent assay. Histone H2B levels in smokers (292.27 +/- 58.24 ng/10(6)) were significantly higher (p = 0.001) than that of non-smokers (109.1 +/- 43.70 ng/10(6)), besides, a significant difference (p > 0.0001) was found for the P1 and P2 ratio between smokers (1.71 +/- 0.071) and non-smokers (1.05 +/- 0.033). The H2B/(H2B+P1 + P2) ratio (0.29 +/- 0.71) of smokers were significantly higher (p = <0.0001) than that of non-smokers (0.12 +/ 0.01). The concentrations of MDA (MUm) (7.13 +/- 1.15) and cotinine (ng/mL) (60.44 +/- 31.32) in seminal plasma of smokers were significantly higher (p = 0.001) than those in the samples of the non-smoker group (4.42 +/- 1.16 and 2.01 +/- 2.84 respectively). In addition, smokers showed significantly (p <= 0.002) lower sperm count, motility (p = 0.018), vitality (p = 0.009) and membrane integrity (p = 0.0001) than non-smokers. These results reveal that patients who smoke possess a higher proportion of spermatozoa with an alteration of the histone to protamine ratio than patients who do not smoke, and suggest that cigarette smoking may inversely affect male fertility. PMID- 25044671 TI - A LecA ligand identified from a galactoside-conjugate array inhibits host cell invasion by Pseudomonas aeruginosa. AB - Lectin LecA is a virulence factor of Pseudomonas aeruginosa involved in lung injury, mortality, and cellular invasion. Ligands competing with human glycoconjugates for LecA binding are thus promising candidates to counteract P. aeruginosa infections. We have identified a novel divalent ligand from a focused galactoside(Gal)-conjugate array which binds to LecA with very high affinity (Kd = 82 nM). Crystal structures of LecA complexed with the ligand together with modeling studies confirmed its ability to chelate two binding sites of LecA. The ligand lowers cellular invasiveness of P. aeruginosa up to 90 % when applied in the range of 0.05-5 MUM. Hence, this ligand might lead to the development of drugs against P. aeruginosa infection. PMID- 25044673 TI - Size-selective DNA separation: recovery spectra help determine the sodium chloride (NaCl) and polyethylene glycol (PEG) concentrations required. AB - In the presence of sodium chloride (NaCl), DNA fragments can be size-selectively separated by varying the final concentration of polyethylene glycol (PEG). This separation strategy in combination with the use of paramagnetic particles provides a valuable platform for achieving the desired DNA size interval, which is important in automated library preparation for high-throughput DNA sequencing. Here, we report the establishment of recovery spectra of DNA fragments that enable the determination of suitable NaCl and PEG concentrations for size selective separation. Firstly, at a given NaCl concentration, the recovery equation was obtained by fitting the DNA recovery ratios versus the PEG concentrations using the logistic function to determine the required parameters. Secondly, the slope function of the recovery equation was achieved by deducing its first derivative. Therefore, the recovery spectrum can be generated using the slope function based on those parameters. According to the recovery spectra of different length DNA fragments, suitable NaCl and PEG concentrations can be determined, respectively, by calculating their resolution values and recovery ratios. The strategy was effectively applied to the size-selective separation of 532-, 400-, and 307-bp fragments at the selected reagent concentrations with recoveries of 96.9, 64.7, and 85.9%, respectively. Our method enables good predictions of NaCl and PEG concentrations for size-selective DNA separation. PMID- 25044672 TI - An investigation of positive and inverted hemodynamic response functions across multiple visual areas. AB - Recent studies have demonstrated significant regional variability in the hemodynamic response function (HRF), highlighting the difficulty of correctly interpreting functional MRI (fMRI) data without proper modeling of the HRF. The focus of this study was to investigate the HRF variability within visual cortex. The HRF was estimated for a number of cortical visual areas by deconvolution of fMRI blood oxygenation level dependent (BOLD) responses to brief, large-field visual stimulation. Significant HRF variation was found across visual areas V1, V2, V3, V4, VO-1,2, V3AB, IPS-0,1,2,3, LO-1,2, and TO-1,2. Additionally, a subpopulation of voxels was identified that exhibited an impulse response waveform that was similar, but not identical, to an inverted version of the commonly described and modeled positive HRF. These voxels were found within the retinotopic confines of the stimulus and were intermixed with those showing positive responses. The spatial distribution and variability of these HRFs suggest a vascular origin for the inverted waveforms. We suggest that the polarity of the HRF is a separate factor that is independent of the suppressive or activating nature of the underlying neuronal activity. Correctly modeling the polarity of the HRF allows one to recover an estimate of the underlying neuronal activity rather than discard the responses from these voxels on the assumption that they are artifactual. We demonstrate this approach on phase-encoded retinotopic mapping data as an example of the benefits of accurately modeling the HRF during the analysis of fMRI data. PMID- 25044675 TI - Effects of free carriers on piezoelectric nanogenerators and piezotronic devices made of GaN nanowire arrays. AB - This study investigates the role of carrier concentration in semiconducting piezoelectric single-nanowire nanogenerators (SNWNGs) and piezotronic devices. Unintentionally doped and Si-doped GaN nanowire arrays with various carrier concentrations, ranging from 10(17) (unintentionally doped) to 10(19) cm(-3) (heavily doped), are synthesized. For SNWNGs, the output current of individual nanowires starts from a negligible level and rises to the maximum of ~50 nA at a doping concentration of 5.63 * 10(18) cm(-3) and then falls off with further increase in carrier concentration, due to the competition between the reduction of inner resistance and the screening effect on piezoelectric potential. For piezotronic applications, the force sensitivity based on the change of the Schottky barrier height works best for unintentionally doped nanowires, reaching 26.20 +/- 1.82 meV nN(-1) and then decreasing with carrier concentration. Although both types of devices share the same Schottky diode, they involve different characteristics in that the slope of the current-voltage characteristics governs SNWNG devices, while the turn-on voltage determines piezotronic devices. It is demonstrated that free carriers in piezotronic materials can influence the slope and turn-on voltage of the diode characteristics concurrently when subjected to strain. This work offers a design guideline for the optimum doping concentration in semiconductors for obtaining the best performance in piezotronic devices and SNWNGs. PMID- 25044674 TI - Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. AB - OBJECTIVE: To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection. METHODS: International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5 adapted) or 4 of 5 of the remaining items (4/5-adapted) were present. RESULTS: The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels >=500 ng/ml discriminated best between MAS and systemic infections. CONCLUSION: The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA. PMID- 25044676 TI - Comprehensive proteomic analysis of a Chinese 2-herb formula (Astragali Radix and Rehmanniae Radix) on mature endothelial cells. AB - Endothelial cells are crucially involved in wound healing angiogenesis, restoring blood flow to wound tissues. Our previous study demonstrated that the Chinese 2 herb formula (NF3) possesses significant wound healing effect in diabetic foot ulcer rats with promising in vitro proangiogenic effects on human umbilical vein endothelial cells (HUVEC). Here, we present the comparative global proteome analysis of NF3-treated HUVEC in static or scratch conditions, screening the comprehensive molecular targets in governing the proangiogenic response in wound healing. Our results suggest plasminogen activator inhibitor-1, specifically down regulated in static condition and Annexin A1 and Annexin A2, up-regulated in scratch condition, as principal proteins responsible for the proangiogenesis in wound healing. We also identified a panel of cytoskeleton regulatory proteins in static and scratch condition, mediating the migratory behavior of NF3-treated HUVEC. The key proteins in static state include myosin regulatory light polypeptide 9, SPAST, tropomyosin (TPM)2, and Vimentin while that in scratch state contained prelamin-A/C, TPM1, TPM2, and Vimentin. In addition, NF3 was shown to regulate transcription and translation, cell-cell interaction, and ROS defense in HUVEC. Proliferation and migration assays further confirmed the identified principal proteins plasminogen activator inhibitor-1 and Annexin A2 which are responsible for NF3-induced proangiogenesis of HUVEC in wound healing. This is the first study on the global proteome expression of NF3-treated HUVEC with the identification of the differences at the molecular level, between static and scratch conditions involved in wound healing angiogenesis. PMID- 25044677 TI - Asymmetric changes of growth and reproductive investment herald altitudinal and latitudinal range shifts of two woody species. AB - Ongoing changes in global climate are altering ecological conditions for many species. The consequences of such changes are typically most evident at the edge of the geographical distribution of a species, where range expansions or contractions may occur. Current demographical status at geographical range limits can help us to predict population trends and their implications for the future distribution of the species. Thus, understanding the comparability of demographical patterns occurring along both altitudinal and latitudinal gradients would be highly informative. In this study, we analyse the differences in the demography of two woody species through altitudinal gradients at their southernmost distribution limit and the consistency of demographical patterns at the treeline across a latitudinal gradient covering the complete distribution range. We focus on Pinus sylvestris and Juniperus communis, assessing their demographical structure (density, age and mortality rate), growth, reproduction investment and damage from herbivory on 53 populations covering the upper, central and lower altitudes as well as the treeline at central latitude and northernmost and southernmost latitudinal distribution limits. For both species, populations at the lowermost altitude presented older age structure, higher mortality, decreased growth and lower reproduction when compared to the upper limit, indicating higher fitness at the treeline. This trend at the treeline was generally maintained through the latitudinal gradient, but with a decreased growth at the northern edge for both species and lower reproduction for P. sylvestris. However, altitudinal and latitudinal transects are not directly comparable as factors other than climate, including herbivore pressure or human management, must be taken into account if we are to understand how to infer latitudinal processes from altitudinal data. PMID- 25044678 TI - Microporous calcium phosphate ceramics driving osteogenesis through surface architecture. AB - The presence of micropores in calcium phosphate (CaP) ceramics has shown its important role in initiating inductive bone formation in ectopic sites. To investigate how microporous CaP ceramics trigger osteoinduction, we optimized two biphasic CaP ceramics (i.e., BCP-R and BCP-S) to have the same chemical composition, equivalent surface area per volume, comparable protein adsorption, similar ion (i.e., calcium and phosphate) exchange and the same surface mineralization potential, but different surface architecture. In particular, BCP R had a surface roughness (Ra) of 325.4 +/- 58.9 nm while for BCP-S it was 231.6 +/- 35.7 nm. Ceramic blocks with crossing or noncrossing channels of 250, 500, 1000, and 2000 um were implanted in paraspinal muscle of dogs for 12 weeks. The percentage of bone volume in the channels was not affected by the type of pores (i.e., crossing vs. closed) or their size, but it was greatly influenced by the ceramic type (i.e., BCP-R vs. BCP-S). Significantly, more bone was formed in the channels of BCP-R than in those of BCP-S. Since the two CaP ceramics differed only in their surface architecture, the results hereby demonstrate that microporous CaP ceramics may induce ectopic osteogenesis through surface architecture. PMID- 25044679 TI - Oikopleura dioica culturing made easy: a low-cost facility for an emerging animal model in EvoDevo. AB - The genome sequencing and the development of RNAi knockdown technologies in the urochordate Oikopleura dioica are making this organism an attractive emergent model in the field of EvoDevo. To succeed as a new animal model, however, an organism needs to be easily and affordably cultured in the laboratory. Nowadays, there are only two facilities in the world capable to indefinitely maintain Oikopleura dioica, one in the SARS institute (Bergen, Norway) and the other in the Osaka University (Japan). Here, we describe the setup of a new facility in the University of Barcelona (Spain) in which we have modified previously published husbandry protocols to optimize the weekly production of thousands of embryos and hundreds of mature animals using the minimum amount of space, human resources, and technical equipment. This optimization includes novel protocols of cryopreservation and solid cultures for long-term maintenance of microalgal stocks-Chaetoceros calcitrans, Isochrysis sp., Rhinomonas reticulate, and Synechococcus sp.-needed for Oikopleura dioica feeding. Our culture system maintains partially inbred lines healthy with similar characteristics to wild animals, and it is easily expandable to satisfy on demand the needs of any laboratory that may wish to use Oikopleura dioica as a model organism. PMID- 25044681 TI - An extra-large-pore zeolite with intersecting 18-, 12-, and 10-membered ring channels. AB - Zeolites with extra-large pores have attracted great attention because of their important applications such as in hydrocracking, catalysis, and separation of large molecules. Despite much progress has been made during the past decades, the synthesis of these materials remains a big challenge. A new extra-large-pore zeolite NUD-1 (Nanjing University Du's group zeolite no. 1) is synthesized by using an approach based on supramolecular self-assemblies of small aromatic organic cations as structure-directing agents. NUD-1 possesses interconnecting 18 , 12-, and 10-membered ring channels, built from the same building units as those of ITQ-33 and ITQ-44. There coexist single 3-membered ring, double-3-membered ring and double-4-membered ring secondary building units in NUD-1, which have not been seen in any other zeolites. PMID- 25044680 TI - Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families. AB - Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes. PMID- 25044682 TI - Three-dimensional scaffolds of carbonized polyacrylonitrile for bone tissue regeneration. AB - Carbon-based materials have been extensively studied for stem cell culture. However, difficulties associated with engineering pure carbon materials into 3D scaffolds have hampered applications in tissue engineering and regenerative medicine. Carbonized polyacrylonitrile (cPAN) could be a promising alternative, as cPAN is a highly ordered carbon isomorph that resembles the graphitic structure and can be easily processed into 3D scaffolds. Despite the notable features of cPAN, application of cPAN in tissue engineering and regenerative medicine have not been explored. This study, for the first time, demonstrates the fabrication of microporous 3D scaffolds of cPAN and excellent osteoinductivity of cPAN, suggesting utility of 3D cPAN scaffolds as synthetic bone graft materials. The combination of excellent processability and unique bioactive properties of cPAN may lead to future applications in orthopedic regenerative medicine. PMID- 25044683 TI - Micelle bound structure and DNA interaction of brevinin-2-related peptide, an antimicrobial peptide derived from frog skin. AB - Brevinin-2-related peptide (BR-II), a novel antimicrobial peptide isolated from the skin of frog, Rana septentrionalis, shows a broad spectrum of antimicrobial activity with low haemolytic activity. It has also been shown to have antiviral activity, specifically to protect cells from infection by HIV-1. To understand the active conformation of the BR-II peptide in membranes, we have investigated the interaction of BR-II with the prokaryotic and eukaryotic membrane-mimetic micelles such as sodium dodecylsulfate (SDS) and dodecylphosphocholine (DPC), respectively. The interactions were studied using fluorescence and circular dichroism (CD) spectroscopy. Fluorescence experiments revealed that the N terminus tryptophan residue of BR-II interacts with the hydrophobic core of the membrane mimicking micelles. The CD results suggest that interactions with membrane-mimetic micelles induce an alpha-helix conformation in BR-II. We have also determined the solution structures of BR-II in DPC and SDS micelles using NMR spectroscopy. The structural comparison of BR-II in the presence of SDS and DPC micelles showed significant conformational changes in the residues connecting the N-terminus and C-terminus helices. The ability of BR-II to bind DNA was elucidated by agarose gel retardation and fluorescence experiments. The structural differences of BR-II in zwitterionic versus anionic membrane mimics and the DNA binding ability of BR-II collectively contribute to the general understanding of the pharmacological specificity of this peptide towards prokaryotic and eukaryotic membranes and provide insights into its overall antimicrobial mechanism. PMID- 25044684 TI - Photothermal conversion of CO2 into CH4 with H2 over Group VIII nanocatalysts: an alternative approach for solar fuel production. AB - The photothermal conversion of CO2 provides a straightforward and effective method for the highly efficient production of solar fuels with high solar-light utilization efficiency. This is due to several crucial features of the Group VIII nanocatalysts, including effective energy utilization over the whole range of the solar spectrum, excellent photothermal performance, and unique activation abilities. Photothermal CO2 reaction rates (mol h(-1) g(-1)) that are several orders of magnitude larger than those obtained with photocatalytic methods (MUmol h(-1) g(-1)) were thus achieved. It is proposed that the overall water-based CO2 conversion process can be achieved by combining light-driven H2 production from water and photothermal CO2 conversion with H2. More generally, this work suggests that traditional catalysts that are characterized by intense photoabsorption will find new applications in photo-induced green-chemistry processes. PMID- 25044685 TI - Effect of the cationic surfactant moiety on the structure of water entrapped in two catanionic reverse micelles created from ionic liquid-like surfactants. AB - The behavior of water entrapped in reverse micelles (RMs) formed by two catanionic ionic liquid-like surfactants, benzyl-n-hexadecyldimethylammonium 1,4 bis-2-ethylhexylsulfosuccinate (AOT-BHD) and cetyltrimethylammonium 1,4-bis-2 ethylhexylsulfosuccinate (AOT-CTA), was investigated by using dynamic (DLS) and static (SLS) light scattering, FTIR, and (1)H NMR spectroscopy techniques. To the best of our knowledge, this is the first report in which AOT-CTA has been used to create RMs and encapsulate water. DLS and SLS results revealed the formation of RMs in benzene and the interaction of water with the RM interface. From FTIR and (1)H NMR spectroscopy data, a difference in the magnitude of the water-catanionic surfactant interaction at the interface is observed. For the AOT-BHD RMs, a strong water-surfactant interaction can be invoked whereas for AOT-CTA this interaction seems to be weaker. Consequently, more water molecules interact with the interface in AOT-BHD RMs with a completely disrupted hydrogen-bond network, than in AOT-CTA RMs in which the water structure is partially preserved. We suggest that the benzyl group present in the BHD(+) moiety in AOT-BHD is responsible for the behavior of the catanionic interface in comparison with the interface created in AOT-CTA. These results show that a simple change in the cationic component in the catanionic surfactant promotes remarkable changes in the RMs interface with interesting consequences, in particular when using the systems as nanoreactors. PMID- 25044686 TI - Treating cell culture media with UV irradiation against adventitious agents: minimal impact on CHO performance. AB - Sterility of cell culture media is an important concern in biotherapeutic processing. In large scale biotherapeutic production, a unit contamination of cell culture media can have costly effects. Ultraviolet (UV) irradiation is a sterilization method effective against bacteria and viruses while being non thermal and non-adulterating in its mechanism of action. This makes UV irradiation attractive for use in sterilization of cell culture media. The objective of this study was to evaluate the effect of UV irradiation of cell culture media in terms of chemical composition and the ability to grow cell cultures in the treated media. The results showed that UV irradiation of commercial cell culture media at relevant disinfection doses impacted the chemical composition of the media with respect to several carboxylic acids, and to a minimal extent, amino acids. The cumulative effect of these changes, however, did not negatively influence the ability to culture Chinese Hamster Ovary cells, as evaluated by cell viability, growth rate, and protein titer measurements in simple batch growth compared with the same cells cultured in control media exposed to visible light. PMID- 25044687 TI - Multi-parametric (mp) MRI of prostatic ductal adenocarcinoma. AB - BACKGROUND: Prostatic ductal adenocarcinoma (DCa) is an aggressive variant of conventional adenocarcinoma (CCa) with mixed DCa and CCa tumors comprising up to 5% of all prostate cancers. DCa may be underestimated on T2-weighted (T2W) MRI. This study assessed the mp-MRI appearance of DCa as compared with CCa. METHODS: With research ethics board approval, we identified 38 patients who underwent mp MRI (T2W, DWI, and DCE) and radical prostatectomy (RP) between 2012 and 2014. Eight DCa in 8 patients and 39 CCa tumor foci in 30 consecutive patients were identified. Tumor volume, apparent diffusion coefficient (ADC;10(-3) mm(2) /s), and time-signal intensity (SI) curves were calculated. Parametric data were compared using the Kruskal-Wallis test and univariate regression. Time-SI curves were compared using the chi-square test. RESULTS: Tumor volumes were: 1.62(+/ 1.02) for DCa, 1.03(+/-0.54) for Gleason 9, 0.88(+/-0.93) for Gleason 7/8, and 0.26(+/-0.14) mL for Gleason 6. There was no difference in size between DCa and Gleason 9 (P = 0.22); however, DCa were larger than Gleason 7/8 (P = 0.03) and Gleason 6 (P = 0.003) tumors. ADC values were: 0.789(+/-0.22) for DCa, 1.01(+/ 0.19) for Gleason 9, 0.992(+/-0.23) for Gleason 7/8 and 1.389(+/-0.41) 10(-3) mm(2) /s for Gleason 6 tumors. There was no difference in ADC between DCa and Gleason 9 (P = 0.14) or Gleason 7/8 (P = 0.055) tumors. There was a difference in ADC for DCa and Gleason >=7 CCa compared to Gleason 6 tumors, (P < 0.001 and P = 0.012). All DCa demonstrated type III time-SI curves. Gleason >= 7 tumors demonstrated type II/III curves. Gleason 6 tumors demonstrated Type I/II time-SI curves. There was no difference in curve type between groups, (P = 0.18). CONCLUSION: Although DCa mimics Gleason score 3 + 3 = 6 tumor at T2W MRI; DCa resembles Gleason >=7 CCa on mp-MRI. PMID- 25044689 TI - Skin-resident CD4+ T cells express NK receptors: lessons from skin pathologies. PMID- 25044690 TI - Sirt1 rescues the obesity induced by insulin-resistant constitutively-nuclear FoxO1 in POMC neurons of male mice. AB - OBJECTIVE: The hypothalamus is the brain center that controls the energy balance. Anorexigenic proopiomelanocortin (POMC) neurons and orexigenic AgRP neurons in the arcuate nucleus of the hypothalamus plays critical roles in energy balance regulation. FoxO1 is a transcription factor regulated by insulin signaling that is deacetylated by Sirt1, a nicotinamide adenine dinucleotide- (NAD(+) -) dependent deacetylase. Overexpression of insulin-resistant constitutively-nuclear FoxO1 (CN-FoxO1) in POMC neurons leads to obesity, whereas Sirt1 overexpression in POMC neurons leads to leanness. Whether overexpression of Sirt1 in POMC neurons could rescue the obesity caused by insulin-resistant CN-FoxO1 was tested here. METHODS: POMC neuron-specific CN-FoxO1/Sirt1 double-KI (DKI) mice were analyzed. RESULTS: The obese phenotype of CN-FoxO1 KI mice was rescued in male DKI mice. Reduced O2 consumption, increased adiposity, and fewer POMC neurons observed in CN-FoxO1 mice were rescued in male DKI mice without affecting food intake and locomotor activity. Sirt1 overexpression decreased FoxO1 acetylation and protein levels without affecting its nuclear localization in mouse embryonic fibroblasts and hypothalamic N41 cells. CONCLUSIONS: Sirt1 rescues the obesity induced by insulin-resistant CN-FoxO1 in POMC neurons of male mice by decreasing FoxO1 protein through deacetylation. Sirt1 ameliorates obesity caused by a genetic model of central insulin resistance. PMID- 25044691 TI - Dissecting the differentiation process of the preplacodal ectoderm in zebrafish. AB - BACKGROUND: The preplacodal region (PPR) is a region of specialized ectoderm at the border of neural and nonneural ectoderm (NNE). Coordinated Bmp, Fgf, and Wnt signals are known to drive PPR development; however, the underlying mechanism is unknown. RESULTS: We identified key components involved in PPR differentiation. The mesoderm/marginal Wnts at the early gastrula stage trigger differentiation by allowing the adjacent NNE border cells to start adopting caudal PPR fates; otherwise, the development of caudal PPR identity is hindered due to the persistent presence of gata3 mRNA. The caudal PPR fate dominates when foxi1 expression is enhanced at the late gastrula stage, and depleting Foxi1 after 6 hours postfertilization (hpf) reduces the otic-epibranchial placodal domain. When the Gata3 level is manipulated at the fertilized egg stage or near 6 hpf, the lens is always affected. In establishing PPR polarity, both Gata3 and Foxi1 inhibit Bmp signaling, whereas Foxi1 inhibits, but Gata3 enhances, Fgf sensitivity of the PPR cells. CONCLUSIONS: Our study reveals that in zebrafish, (1) the PPR at the shield stage may enter a developmental state when the PPR cells preferentially adopt a particular placodal fate and (2) a network of genetically linked factors, including Wnt/beta-catenin, Fgfr, Bmp, Gata3, and Foxi1, direct the process of PPR differentiation. PMID- 25044692 TI - Radiographic evaluation of stillbirth: what does it contribute? AB - Despite advances in perinatal care, stillbirth is relatively common (1/160 births) and frequently remains unexplained. Most recent protocols for etiologic evaluation of stillbirth either omit radiography or reserve it for infants with obvious skeletal disproportion. Over the past 30 years, the Wisconsin Stillbirth Service Program has collected radiographic images from 2,032 stillbirths and second trimester losses, of which about 25% (517) showed abnormalities. Review of these images by a medical geneticist showed that radiographs yielded a diagnosis in 45% of the infants with abnormalities (11.5% of all radiographs obtained) and were critical, yielding a diagnosis that would otherwise have been missed or incomplete in 1.5% of the total infants. The probability of a diagnosis was not significantly different between miscarriages <20 weeks and stillbirths. Diagnoses were mainly fetal, most commonly sporadic birth defects, idiopathic hydrops, chromosome abnormalities, and skeletal dysplasias, but chorioamnionitis with fetal sepsis, complications of twinning, and cord accidents were also diagnosed radiographically. Radiographs may help direct the use of newer technologies such as chromosomal microarray or gene sequencing. Limiting radiographs to infants with obvious skeletal disproportion would have resulted in many of these diagnoses, including 4/24 skeletal dysplasias, being overlooked. We recommend at least an anterior/posterior babygram film as part of the permanent record of all second trimester losses and stillbirths. PMID- 25044693 TI - Model study of the photochemical rearrangement pathways of 1,2,4-oxadiazole. AB - The mechanisms of photochemical isomerization reactions are investigated theoretically by using a model system of 1,2,4- oxadiazole with the CAS(14,9)/6 311G(d) and MP2-CAS-(14,9)/ 6-311++G(3df,3pd)//CAS(14,9)/6-311G(d) methods. Three reaction pathways are examined, including 1) the direct mechanism, 2) the ring contraction-ring expansion mechanism, and 3) the internal cyclization isomerization mechanism, which lead to two types of photoisomers. The theoretical findings suggest that conical intersections play a crucial role in the photorearrangement of 1,2,4-oxadiazoles. These model investigations also indicate that the preferred reaction route for 1,2,4-oxadiazole, which leads to phototransposition products, is as follows: reactant -> Franck-Condon region -> conical intersection -> photoproduct. In other words, the direct mechanism is a one-step process that has no barrier. These theoretical results agree with the available experimental observations. PMID- 25044694 TI - The nasoseptal flap for reconstruction of the medial and inferior orbit. AB - BACKGROUND: Endoscopic endonasal orbital surgery may result in large orbital defects that mandate reconstruction to minimize the risk of diplopia and enophthalmos. The purpose of this study is to determine whether the nasoseptal flap can provide adequate coverage of maximal orbital defects. METHODS: This was an anatomic cadaveric study. Morphometric measurements were completed in 5 cadaveric orbits to determine the dimensions of an orbital defect comprising the entire lamina papyracea and the orbital floor. The dimensions of a planned nasoseptal flap were then calculated and an appropriately sized flap was harvested to verify complete coverage of the defect. RESULTS: The mean +/- standard deviation (SD) medial orbital defect was a depth of 47.3 mm +/- 2.52, height of 13.67 mm +/- 2.73, and width of 13.33 mm +/- 1.03 for the orbital floor. The mean flap dimensions were a width of 55 +/- 6.16 mm, height of 48 +/- 4.47 mm, and depth of 70 +/- 3.54 mm. In all cases, the harvested flap adequately covered the orbital defect. These dimensions correlated with flap incisions subtending the mucocutaneous junction anteriorly, the inferior meatus laterally, the attachment of the middle turbinate superiorly, and the choanal arch posteriorly. CONCLUSION: Endoscopic orbital approaches may result in large orbital defects with significant orbital fat herniation and extraocular muscle exposure. Immediate vascularized flap reconstruction of the orbit may help to limit the attendant morbidity including diplopia and enophthalmos. This study is the first to demonstrate the feasibility of the nasoseptal flap for the reconstruction of maximal orbital defects. PMID- 25044696 TI - An innovative approach for highly selective direct conversion of CO2 into propanol using C2H4 and H2. AB - Multifunctional catalysts are developed for converting CO2 with C2H4 and H2 into propanol. Au nanoparticles (NP) supported on TiO2 are found to facilitate this reaction. The activity and selectivity strongly depend on NP size, which can be tuned by the method of Au deposition and by promoting with K. The promoter improves the selectivity to propanol. Under optimized reaction conditions (2 MPa, 473 K, and CO2/H2/C2H4=1:1:1), CO2 is continuously converted into propanol with a near-to-100% selectivity. Catalytic tests as well as mechanistic studies by in situ FTIR and temporal analysis of products with isotopic tracers allow the overall reaction scheme to be determined. Propanol is formed through a sequence of reactions starting with reverse water-gas shift to reduce CO2 to CO, which is further consumed in the hydroformylation of ethylene to propanal. The latter is finally hydrogenated to propanol, while propanol hydrogenation to propane is suppressed. PMID- 25044695 TI - Ion-pair cloud-point extraction: a new method for the determination of water soluble vitamins in plasma and urine. AB - A novel, simple, and effective ion-pair cloud-point extraction coupled with a gradient high-performance liquid chromatography method was developed for determination of thiamine (vitamin B1 ), niacinamide (vitamin B3 ), pyridoxine (vitamin B6 ), and riboflavin (vitamin B2 ) in plasma and urine samples. The extraction and separation of vitamins were achieved based on an ion-pair formation approach between these ionizable analytes and 1-heptanesulfonic acid sodium salt as an ion-pairing agent. Influential variables on the ion-pair cloud point extraction efficiency, such as the ion-pairing agent concentration, ionic strength, pH, volume of Triton X-100, extraction temperature, and incubation time have been fully evaluated and optimized. Water-soluble vitamins were successfully extracted by 1-heptanesulfonic acid sodium salt (0.2% w/v) as ion-pairing agent with Triton X-100 (4% w/v) as surfactant phase at 50 degrees C for 10 min. The calibration curves showed good linearity (r(2) > 0.9916) and precision in the concentration ranges of 1-50 MUg/mL for thiamine and niacinamide, 5-100 MUg/mL for pyridoxine, and 0.5-20 MUg/mL for riboflavin. The recoveries were in the range of 78.0-88.0% with relative standard deviations ranging from 6.2 to 8.2%. PMID- 25044697 TI - 2'-Bispyrene-modified 2'-O-methyl RNA probes as useful tools for the detection of RNA: synthesis, fluorescent properties, and duplex stability. AB - The synthesis and properties two series of new 2'-O-methyl RNA probes, each containing a single insertion of a 2'-bispyrenylmethylphosphorodiamidate derivative of a nucleotide (U, C, A, and G), are described. As demonstrated by UV melting studies, the probes form stable complexes with model RNAs and DNAs. Significant increases (up to 21-fold) in pyrene excimer fluorescence intensity were observed upon binding of most of the probes with complementary RNAs, but not with DNAs. The fluorescence spectra are independent of the nature of the modified nucleotides. The nucleotides on the 5'-side of the modified nucleotide have no effect on the fluorescence spectra, whereas the natures of the two nucleotides on the 3'-side are important: CC, CG, and UC dinucleotide units on the 3'-side of the modified nucleotide provide the maximum increases in excimer fluorescence intensity. This study suggests that these 2'-bispyrene-labeled 2'-O-methyl RNA probes might be useful tools for detection of RNAs. PMID- 25044698 TI - Liquid organic hydrogen carriers: surface science studies of carbazole derivatives. AB - We review recent results towards a molecular understanding of the adsorption and dehydrogenation of carbazole-derived liquid organic hydrogen carriers on platinum and palladium single crystals and on Al2 O3 -supported Pt and Pd nanoparticles. By combining synchrotron-based high-resolution X-ray photoelectron spectroscopy, infrared reflection-absorption spectroscopy, advanced molecular beam methods and temperature-programmed desorption spectroscopy, detailed insights into the reaction mechanism are obtained. On Pt(111), dehydrogenation of perhydro-N ethylcarbazole, H12 -NEC, starts with activation of the hydrogen atoms at the pyrrole unit, yielding H8 -NEC as the first stable reaction intermediate at ~340 K, followed by further dehydrogenation to NEC at ~380 K. Above 390 K, dealkylation starts, yielding carbazole as an undesired byproduct. On small supported Pt particles, the dealkylation sets in at lower temperatures, due to the higher reactivity of low-coordinated sites, while on larger particles with (111) facets a reactivity as on the flat surface is observed. Carbazole derivatives with ethyl, propyl and butyl chains show an overall very similar reactivity, both on Pt(111) and on Pt nanoparticles. When comparing the dealkylation behavior of H12 -NEC on Pt(111) and Pt nanoparticles to that on Pd(111) and Pd nanoparticles, we find a higher reactivity for the Pd systems. PMID- 25044699 TI - Synthesis and duplex-stabilizing properties of fluorinated N methanocarbathymidine analogues locked in the C3'-endo conformation. AB - The efficient synthesis, antiviral activity, and duplex-stabilizing properties of both isomers of the 2'-fluoro analogue of Northern methanocarbathymidine (N-MCT), 2 and 3, are reported. We show that 2'-F incorporation on the N-MCT scaffold has a strong stabilizing effect on duplex thermal stability. PMID- 25044700 TI - Controllable synthesis of wurtzite Cu(2)ZnSnS(4) nanocrystals by hot-injection approach and growth mechanism studies. AB - Wurtzite Cu2 ZnSnS4 (WZ-CZTS) has been controllably synthesized through a hot injection route. The crystal-growth mechanism of WZ-CZTS has been investigated by using time-dependent XRD patterns, TEM images, and absorption spectra analysis, and revealed that WZ-CZTS nucleated and grew from monoclinic Cu7 S4 nanocrystals through phase transformation of Cu7 S4 to WZ-CZTS within 5 min. The synthesis processes are dependent on precursor concentration, reaction temperature, reaction time, organic ligand, and sulfur source and have been studied in detail. It was revealed that the width of the WZ-CZTS nanocrystals was mainly controlled by the precursor concentration, which determines the diameter of Cu7 S4 . The length could be regulated by the ratio of dodecanethiol (DDT) to oleylamine (OLA) and reaction time. PMID- 25044701 TI - An integrative examination of general personality dysfunction in a large community sample. AB - Recently, the severity of general personality dysfunction has gained broad interest in personality disorder (PD) research. We analysed data of 511 participants aged 20-41 years from a comprehensive psychiatric survey in the general population of Zurich, Switzerland. We added the trait-scores from all DSM IV PDs, as assessed by a self-report questionnaire, to provide a measure of general personality dysfunction. Adjusting for the Big Five personality domains as a proxy for stylistic PD elements, this composite PD score exhibited strong associations with neuroticism and schizotypy. General personality dysfunction additionally revealed a moderate detrimental association with psychosocial functioning and a strong effect on coping resources, on heavy drinking and drug use and on most psychopathological syndromes. Of particular interest is the strong association with total psychopathological distress and co-occurrence of multiple disorders, suggesting that increasing PD severity relates to the degree of global impairment independent of specific PD traits. Discussed herein are implications for public mental health policies, classification, conceptualization and treatment of PDs. PMID- 25044702 TI - Efficacy of acarbose in different geographical regions of the world: analysis of a real-life database. AB - BACKGROUND: Alpha-glucosidase inhibitors are recommended in some international guidelines as first-line, second-line and third-line treatment options but are not used worldwide due to perceived greater effectiveness in Asians than Caucasians. METHODS: Data from ten post-marketing non-interventional studies using acarbose, the most widely used alpha-glucosidase inhibitor, from 21 countries, provinces and country groups were pooled. Effects on glycated hemoglobin (HbA1c ) were analysed for four major ethnicity/region groups (European Caucasians and Asians from East, Southeast and South Asia) to identify differences in the response to acarbose. RESULTS: The safety and efficacy populations included 67 682 and 62 905 patients, respectively. Mean HbA1c in the total population decreased by 1.12 +/- 1.31% at the 3-month visit from 8.4% at baseline (p < 0.0001). Reductions in HbA1c , fasting plasma glucose and post prandial plasma glucose were greater in patients with higher baseline values. Acarbose was well tolerated, with few episodes of hypoglycemia (0.03%) and gastrointestinal adverse events (2.76%). Data from 30 730 Caucasians from Europe and Asians from three major regions of Asia with non-missing gender/age information and baseline/3-month HbA1c data were analysed by multivariable analyses of covariance. After adjustment for relevant baseline confounding factors, Southeast and East Asians had slightly better responses to acarbose than South Asians and European Caucasians; however, the differences were small. CONCLUSIONS: Acarbose was effective in both European Caucasians and Asians; however, after adjustment for baseline confounding factors, significant small differences in response favoured Southeast and East Asians. PMID- 25044703 TI - Serum vitamin D levels and hypogonadism in men. AB - There is inconsistent evidence on a possible association of vitamin D and androgen levels in men. We therefore aim to investigate the association of 25 hydroxyvitamin D (25(OH)D) with androgen levels in a cohort of middle-aged men. This cross-sectional study included 225 men with a median (interquartile range) age of 35 (30-41) years. We measured 25(OH)D, total testosterone (TT) and SHBG concentrations. Hypogonadism was defined as TT <10.4 nmol/L. We found no significant correlation of 25(OH)D and androgen levels. Furthermore, androgen levels were not significantly different across 25(OH)D quintiles. The overall prevalence of hypogonadism was 21.5% and lowest in men within 25(OH)D quintile 4 (82-102 nmol/L). We found a significantly increased risk of hypogonadism in men within the highest 25(OH)D quintile (>102 nmol/L) compared to men in quintile 4 (reference) in crude (OR 5.10, 1.51-17.24, p = 0.009) as well as in multivariate adjusted analysis (OR 9.21, 2.27-37.35, p = 0.002). We found a trend towards increased risk of hypogonadism in men within the lowest 25(OH)D quintile (<=43.9 nmol/L). In conclusion, our data suggest that men with very high 25(OH)D levels (>102 nmol/L) might be at an increased risk of hypogonadism. Furthermore, we observed a trend towards increased risk of hypogonadism in men with very low vitamin D levels indicating a U-shaped association of vitamin D levels and hypogonadism. With respect to risk of male hypogonadism, our results suggest optimal serum 25(OH)D concentrations of 82-102 nmol/L. PMID- 25044705 TI - Orthotopic Wilms tumor xenografts derived from cell lines reflect limited aspects of tumor morphology and clinical characteristics. AB - BACKGROUND: Wilms tumor (WT) is a pediatric tumor of the kidney, the treatment of which includes heavy chemotherapy. Affected children would likely benefit from more targeted therapies with limited side effects. Establishment of relevant orthotopic WT xenografts is important to better understand mechanisms of WT growth and for preclinical drug testing. PROCEDURE: Here we established and characterized orthotopic xenografts from WT cell lines WiT49, CCG-99-11, and WT CLS1 to ascertain in what aspects each of them recapitulated WT histology, immunophenotype, invasion, and metastatic spread. RESULTS: WiT49 xenografts recapitulated near triphasic WTs with clear WT1 staining and anaplastic features, but with tumor restricted to the kidney. On the contrary both CCG-99-11 and WT CLS1 xenografts conveyed metastatic disease. CCG-99-11 showed a blastemal phenotype whereas WT-CLS1 xenografts did not properly reflect any specific WT subtype. CONCLUSIONS: From the three tested cell lines, orthotopic WiT49 xenografts best reflect the triphasic pattern of classical WT. PMID- 25044704 TI - Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention. AB - SCOPE: Epidemiological studies provide evidence that consumption of cruciferous vegetables, like broccoli, can reduce the risk of cancer development. Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that induces anti-proliferative and pro-apoptotic responses in prostate cancer cells, but not in normal prostate cells. The mechanisms responsible for this cancer specific cytotoxicity remain unclear. METHODS AND RESULTS: We utilized RNA sequencing and determined the transcriptomes of normal prostate epithelial cells, androgen-dependent prostate cancer cells, and androgen-independent prostate cancer cells treated with SFN. SFN treatment dynamically altered gene expression and resulted in distinct transcriptome profiles depending on prostate cell line. SFN also down-regulated the expression of genes that were up-regulated in prostate cancer cells. Network analysis of genes altered by SFN treatment revealed that the transcription factor Specificity protein 1 (Sp1) was present in an average of 90.5% of networks. Sp1 protein was significantly decreased by SFN treatment in prostate cancer cells and Sp1 may be an important mediator of SFN induced changes in expression. CONCLUSION: Overall, the data show that SFN alters gene expression differentially in normal and cancer cells with key targets in chemopreventive processes, making it a promising dietary anti-cancer agent. PMID- 25044707 TI - UV excited-state photoresponse of biochromophore negative ions. AB - Members of the green fluorescent protein (GFP) family may undergo irreversible phototransformation upon irradiation with UV light. This provides clear evidence for the importance of the higher-energy photophysics of the chromophore, which remains essentially unexplored. By using time-resolved action and photoelectron spectroscopy together with high-level electronic structure theory, we directly probe and identify higher electronically excited singlet states of the isolated para- and meta-chromophore anions of GFP. These molecular resonances are found to serve as a doorway for very efficient electron detachment in the gas phase. Inside the protein, this band is found to be resonant with the quasicontinuum of a solvated electron, thus enhancing electron transfer from the GFP to the solvent. This suggests a photophysical pathway for photoconversion of the protein, where GFP resonant photooxidation in solution triggers radical redox reactions inside these proteins. PMID- 25044708 TI - Selective reductive coupling of nitro compounds with aldehydes to nitrones in H2 using carbon-supported and -decorated platinum nanoparticles. AB - Nitrones were synthesized in high yields directly from nitro compounds, aldehydes, and H2 using carbon-decorated platinum nanoparticles. The high selectivity for nitrone synthesis contrasts that of common supported metal catalysts and corresponds to an increase from roughly 6 to 97%. The catalytic performance is tuned by precise control of the structure of the active sites and the characteristics of the support. PMID- 25044706 TI - Regulation of early cartilage destruction in inflammatory arthritis by death receptor 3. AB - OBJECTIVE: To investigate the role of death receptor 3 (DR-3) and its ligand tumor necrosis factor-like molecule 1A (TL1A) in the early stages of inflammatory arthritis. METHODS: Antigen-induced arthritis (AIA) was generated in C57BL/6 mice deficient in the DR-3 gene (DR3(-/-) ) and their DR3(+/+) (wild-type) littermates by priming and intraarticular injection of methylated bovine serum albumin. The joints were sectioned and analyzed histochemically for damage to cartilage and expression of DR3, TL1A, Ly-6G (a marker for neutrophils), the gelatinase matrix metalloproteinase 9 (MMP-9), the aggrecanase ADAMTS-5, and the neutrophil chemoattractant CXCL1. In vitro production of MMP-9 was measured in cultures from fibroblasts, macrophages, and neutrophils following the addition of TL1A and other proinflammatory stimuli. RESULTS: DR3 expression was up-regulated in the joints of wild-type mice following generation of AIA. DR3(-/-) mice were protected against cartilage damage compared with wild-type mice, even at early time points prior to the main accumulation of Teff cells in the joint. Early protection against AIA in vivo correlated with reduced levels of MMP-9. In vitro, neutrophils were major producers of MMP-9, while neutrophil numbers were reduced in the joints of DR3(-/-) mice. However, TL1A neither induced MMP-9 release nor affected the survival of neutrophils. Instead, reduced levels of CXCL1 were observed in the joints of DR3(-/-) mice. CONCLUSION: DR-3 drives early cartilage destruction in the AIA model of inflammatory arthritis through the release of CXCL1, maximizing neutrophil recruitment to the joint and leading to enhanced local production of cartilage-destroying enzymes. PMID- 25044709 TI - 6-Hydroxybenzothiophene ketones: potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) owing to favorable molecule geometry and conformational preorganization. AB - The inhibition of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which catalyzes the conversion of estrone into the potent estrogen receptor agonist estradiol (E2), is discussed as a novel therapeutic approach for the treatment of estrogen-dependent diseases. Because the reduction of E2 would be basically limited to the target tissues, this approach is expected to cause fewer side effects than the currently employed antihormonal therapies. Recently, we reported on 6-hydroxybenzothiazole ketones as a new class of 17beta-HSD1 inhibitors with a notable activity/selectivity profile. In an attempt to further optimize these parameters, we modified the benzothiazole core by a systematic bioisosteric replacement. Thus, we were able to identify a new 6-hydroxybenzothiophene derivative that displayed stronger inhibition of 17beta-HSD1 (IC50 =13 nM) and that was also more selective than a benzothiazole analog. Using ab initio calculations, we found that the higher potency of the 6-hydroxybenzothiophene derivative was probably due to more favorable conformational preorganization of the scaffold for binding to the enzyme. PMID- 25044710 TI - Comparison of scanning electron microscopy and optical coherence tomography for imaging of coronary bifurcation stents. AB - BACKGROUND: Optical coherence tomography (OCT) is a new intracoronary imaging modality that has excellent resolution and image quality and has been used to image neointimal coverage after stent implantation. OCT has been compared to histologic, intravascular ultrasound, and scanning electron microscopy (SEM) studies. However, OCT has not been compared with SEM for imaging stent coverage over side branches. OBJECTIVE: The aim of this study was to compare OCT with SEM in imaging neointimal coverage over stent struts bridging coronary side-branch ostia. METHODS: Using a balloon-overstretch in-stent restenosis model, we deployed 38 everolimus-eluting stents across coronary bifurcations in nine pigs. We performed OCT immediately after stenting and 4 weeks later; SEM was performed after euthanizing the pigs. OCT images of each stent were compared to the corresponding SEM image. RESULTS: We analyzed OCT frames (n=111) for strut-level neointimal coverage and compared them to corresponding SEM images. The concordance correlation coefficient was 0.809 (95%CI; 0.734-0.864) and 0.951 (95%CI; 0.930-0.966) for covered and uncovered struts, respectively. CONCLUSIONS: In a non-atherosclerotic pig model, we showed strong agreement between OCT and SEM in imaging coverage of stent struts bridging side-branch ostia. PMID- 25044711 TI - Emotion perception and executive control interact in the salience network during emotionally charged working memory processing. AB - Processing of emotional stimuli can either hinder or facilitate ongoing working memory (WM); however, the neural basis of these effects remains largely unknown. Here we examined the neural mechanisms of these paradoxical effects by implementing a novel emotional WM task in an fMRI study. Twenty-five young healthy participants performed an N-back task with fearful and neutral faces as stimuli. Participants made more errors when performing 0-back task with fearful versus neutral faces, whereas they made fewer errors when performing 2-back task with fearful versus neutral faces. These emotional impairment and enhancement on behavioral performance paralleled significant interactions in distributed regions in the salience network including anterior insula (AI) and dorsal cingulate cortex (dACC), as well as in emotion perception network including amygdala and temporal-occipital association cortex (TOC). The dorsal AI (dAI) and dACC were more activated when comparing fearful with neutral faces in 0-back task. Contrarily, dAI showed reduced activation, while TOC and amygdala showed stronger responses to fearful as compared to neutral faces in the 2-back task. These findings provide direct neural evidence to the emerging dual competition model suggesting that the salience network plays a critical role in mediating interaction between emotion perception and executive control when facing ever changing behavioral demands. PMID- 25044712 TI - Structural integrity, immunogenicity and biomechanical evaluation of rabbit decelluarized tracheal matrix. AB - Decellularization techniques have been widely used as an alternative strategy to produce matrices for organ reconstruction. This study investigated the impact of a detergent-enzymatic decellularization protocol on the extracellular matrix integrity, mechanical properties, and biocompatibility of decellularized tracheal matrices from rabbits. The tracheas of New Zealand white rabbits were decellularized using a modified detergent-enzymatic method (DEM). Antigenicity, cellularity, glycosaminoglycan content, DNA content, histoarchitecture, and mechanical properties were monitored during processing. The surface ultrastructure of the matrix was examined by scanning electron microscopy (SEM). Bioengineered and control tracheas were then implanted in major histocompatibility complex-unmatched rats (xenograft) heterotopically for 7, 15, and 30 days. Structural and functional analysis was performed after transplantation. The results showed that seven cycles of decellularization removed most of the cells and eliminated antigenicity. Histological and molecular biology analysis demonstrated that most of the cellular components and nuclear material were removed. SEM analysis revealed that the decellularized matrices retained the hierarchical structure of the native trachea, and biomechanical tests showed that decellularization did not significantly influence the mechanical properties. Seven, 15 and 30 days after implantation, decreased (p < 0.01) inflammatory reactions were observed in the xenograft models for decellularized matrices compared with control tracheas. No increases in IgM or IgG content were observed in rats that received bioengineered tracheas. In conclusion, this work suggests that seven cycles of the DEM generates a bioengineered rabbit tracheal matrix that is structurally and mechanically similar to native trachea. PMID- 25044713 TI - Peptides derived from the copper-binding region of lysyl oxidase exhibit antiangiogeneic properties by inhibiting enzyme activity: an in vitro study. AB - Despite the rigorous research on abnormal angiogenesis, there is a persistent need for the development of new and efficient therapies against angiogenesis related diseases. The role of Lysyl oxidase (LOX) in angiogenesis and cancer has been established in prior studies. Copper is known to induce the synthesis of LOX, and hence regulates its activity. Hypoxia-induced metastasis is dependent on LOX expression and activity. It has been believed that the inhibition of LOX would be a therapeutic strategy to inhibit angiogenesis. To explore this, we designed peptides (M peptides) from the copper-binding region of LOX and hypothesized them to modulate LOX. The peptides were characterized, and their copper-binding ability was confirmed by mass spectrometry. The M peptides were found to reduce the levels of intracellular copper when the cells were co-treated with copper. The peptides showed promising effect on aortic LOX, recombinant human LOX and LOX produced by human umbilical vein endothelial cells (HUVECs). The study also explores the effect of these peptides on copper and hypoxia stimulated angiogenic response in HUVECs. It was found that the M peptides inhibited copper/hypoxia-induced LOX activity and inhibited stimulated HUVEC tube formation and migration. This clearly indicated the potential of M peptides in inhibiting angiogenesis, highlighting their role in the formulation of drugs for the same. PMID- 25044714 TI - Proteomic investigation of Vibrio alginolyticus challenged Caenorhabditis elegans revealed regulation of cellular homeostasis proteins and their role in supporting innate immune system. AB - Caenorhabditis elegans has been the preferred model system for many investigators to study pathogenesis. In the present investigation, regulation of C. elegans proteome was explored against V. alginolyticus infection using quantitative proteomics approach. Proteins were separated using 2D-DIGE and the differentially regulated proteins were identified using PMF and MALDI TOF/TOF analysis. The results thus obtained were validated using Western blotting for candidate proteins. The corresponding transcriptional regulation was quantified subsequently using real-time PCR. Interaction network for candidate proteins was predicted using search tool for the retrieval of interacting genes/proteins (STRING) and functional validation was performed using respective mutant strains. Out of the 25 proteins identified, 21 proteins appeared to be upregulated while four were downregulated. Upregulated proteins included those involved in stress response (PDI-2, HSP-6), immune-response (protein kinase -18, GST-8) and energy production (ATP-2) while proteins involved in structural maintenance (IFB-2) and lipid metabolism (SODH-1) were downregulated. The roles of these players in the host system during Vibrio infection was analyzed in vivo using wild type and mutant C. elegans. Survival assays using mutants lacking pdi-2, ire-1, and xbp-1 displayed enhanced susceptibility to V. alginolyticus. Cellular stress generated by V. alginolyticus was determined using ROS assay. This is the first report of proteome changes in C. elegans against V. alginolyticus challenge and highlights the significance of unfolded protein response (UPR) pathway during bacterial infection. PMID- 25044715 TI - ROFRET: a molecular-scale fluorescent probe displaying viscosity-enhanced intramolecular Forster energy transfer. AB - The fluorescent probe ROFRET contains a Bodipy molecular rotor connected through a short triazole-based spacer to a fully alkylated Bodipy. Forster resonance energy transfer takes place from the rotor to the other Bodipy, and is enhanced to a limiting value as the viscosity of the solvent increases. Time-resolved spectroscopy and steady-state studies are consistent with both forward and reverse energy transfer, and delayed fluorescence. PMID- 25044716 TI - Preparation of Keggin-type phosphomolybdate by a one-step solid-state reaction at room temperature and its application in protein adsorption. AB - Keggin-type phosphomolybdate ((C19H42N)3PMo12O40) is prepared by a one-step solid state reaction at room temperature and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and elemental analysis. The as-prepared phosphomolybdate is demonstrated to be an efficient adsorbent for proteins. In this particular case, the selective adsorption of neutral protein hemoglobin is achieved. While under the same conditions virtually no adsorption of acidic and basic proteins, represented by bovine serum albumin and cytochrome c, are observed. A solid-phase extraction procedure is developed for the selective isolation of hemoglobin. At pH 6, a sorption efficiency of 91.4% is achieved for 100 MUg/mL hemoglobin in 1.0 mL solution by using 5.0 mg of the phosphomolybdate. The adsorption behavior of hemoglobin fits well with a Langmuir adsorption model, corresponding to a theoretical adsorption capacity of 55.86 mg/g. The retained hemoglobin could be readily recovered by using a 60 mmol/L imidazole solution at pH 7, giving rise to a recovery of 64.7%. The practical application of phosphomolybdate for protein adsorption is demonstrated by the selective isolation of hemoglobin from human whole blood followed by a sodium dodecyl sulfate polyacrylamide gel electrophoresis assay. PMID- 25044718 TI - Proteomic approaches to sexual development mediated by antheridiogen in the fern Blechnum spicant L. AB - This report is intended to compare proteomic profiles between female and male gametophytes of Blechnum spicant L. For this purpose, female gametophytes were obtained from spores germinated on Murashige and Skoog medium (1962), and the male ones by culturing 30-day-old gametophytes on the same medium supplemented with extract derived from mature gametophytes, which exhibits anteridiogen effect. Proteins were extracted using the phenolic method, and after two dimensional gel electrophoresis, 581 spots were detected in Coomassie stained gels within the 3-11 pH range and 10-100 kDa Mr ranges. Quantitative and qualitative differences in spot intensity between both types of gametophytes were found. The induction of male gametophytes by antheridiogens was correlated to a global increase in stress and defence-related pathways, which affect flavonoid signaling and cell division, while reducing protein biosynthesis, photosynthesis, and other energy-related pathways, reflecting how stressed are the gametophytes during the induction process. This is the first proteomic study that examines proteins associated to sexual development in the gametophyte of the fern B. spicant. PMID- 25044717 TI - Anti-obesity and pro-diabetic effects of hemochromatosis. AB - OBJECTIVE: Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, and on the interaction of weight and iron overload on diabetes risk. Therefore, the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls was examined. METHODS: Chart reviews were performed on a cohort of adults (age >=40, N = 101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N = 32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. RESULTS: Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. CONCLUSIONS: High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. PMID- 25044719 TI - Delineating the phenotype of 1p36 deletion in adolescents and adults. AB - 1p36 deletion is the most common telomeric deletion syndrome, with an incidence of 1/5,000-1/10,000. A variety of clinical complications have been reported including seizures, hypotonia, heart malformations, cardiomyopathy, vision problems, and hearing loss. Approximately 90% are reported to have severe to profound intellectual disability and 75% to have absent expressive language. Little is known about long-term outcomes. The current literature suggests a poor prognosis for most patients. This study attempted to assess medical conditions and function of adolescent and adult patients with 1p36 deletion. A survey was distributed through three support groups to identify patients >12 years of age to assess functional status and medical problems in older patients with 1p36 deletion syndrome. 40 patients were identified between 12 and 46 years old. Among our survey sample, medical complications including seizures, hypotonia, structural heart defects, hearing loss, and vision problems, were similar to previous reports. However, functional skills were better than anticipated, with an overwhelming majority reported to independently sit, walk, and receive the majority of nutrition orally. Forty-four percent were reported to use complex speech abilities. While medical problems in patients with 1p36 deletion were similar to those that have been previously reported, we also demonstrated these same concerns persist into adolescence and adulthood. Additionally, patients were reported to have better functional skills than anticipated. Thus, quality of life and level of function appear to be better than anticipated from previous studies. (c) 2014 Wiley Periodicals, Inc. PMID- 25044722 TI - Synthesis and biochemical characterization of tricyclothymidine triphosphate (tc TTP). AB - Tricyclo-DNA (tc-DNA) is a conformationally restricted oligonucleotide analogue that exhibits promising properties as a robust antisense agent. Here we report on the synthesis and biochemical characterization of tc-TTP, the triphosphate of a tc-DNA nucleoside containing the base thymine. Tc-TTP turned out to be a substrate for the Vent (exo(-) ) DNA polymerase, a polymerase that allows for multiple incorporations of tc-T nucleotides under primer extension reaction conditions. However, the substrate acceptance is rather low, as also observed for other sugar-modified analogues. Tc-TTP and tc-nucleotide-containing templates do not sustain enzymatic polymerization under physiological conditions; this indicates that tc-DNA-based antisense agents will not enter natural metabolic pathways that lead to long-term toxicity. PMID- 25044723 TI - Ruthenium-catalyzed oxidative transformations of terminal alkynes to ketenes by using tethered sulfoxides: access to beta-lactams and cyclobutanones. AB - The oxidation of in situ generated Ru vinylidenes to ketenes is realized with tethered sulfoxides. The result is a Ru-catalyzed oxidative transformation of terminal alkynes to highly valuable ketenes. Moreover, the ketenes generated here were shown to undergo characteristic ketene [2+2] cycloaddition reactions with tethered alkenes and external imines, yielding synthetically versatile bicyclic cyclobutanones and beta-lactams, respectively. PMID- 25044720 TI - Analysis of centromere signal patterns in breast cancer cells with chromosomal instability using image cytometry combined with centromere fluorescence in situ hybridization. AB - Fluorescence in situ hybridization (FISH) with centromeric probes is a method used to detect chromosomal instability (CIN), a hallmark of most cancers. However, no studies thus far have investigated the relationship between centromeric FISH signals and the cell cycle in cancer cells. In this study, the chromosome content in each cell cycle phase was evaluated with respect to the number of centromeric FISH signals in two breast cancer cell lines and eight surgically resected breast cancer specimens using image cytometry. Variations in chromosome number were detected at each phase of the cell cycle but were not associated with proliferative capacity in the cell lines. Furthermore, the chromosome doubling frequency differed in each cell line and clinical specimen. These results reveal two aspects of centromeric FISH signal variation in breast cancers that exhibit CIN, and suggest that chromosome doubling is a remarkable occurrence that may increase the heterogeneity of tumors. PMID- 25044724 TI - Efficient total synthesis of bioactive natural products: a personal record. AB - In this account, we have highlighted our most recent works towards the total synthesis of bioactive natural products, which have resulted in the development of several novel synthetic methods. Inspired and guided by strategies based on diversity-oriented synthesis, we have successfully applied the novel synthetic methodologies developed in our lab to the total synthesis of a diverse collection of structurally challenging targets. We have also documented the evolution of these synthetic strategies. The total syntheses described in this account have been organized from the perspective of different molecules whilst still alluding to the parallel synthetic strategies involved. PMID- 25044725 TI - A fluorescent nucleic acid nanodevice quantitatively images elevated cyclic adenosine monophosphate in membrane-bound compartments. AB - cAMPhor: In the presence of cAMP, cAMPhor folds into a structure that binds DFHBI (green), increasing its fluorescence, while Alexa 647 (red) functions as a normalizing dye. It can thus be used to spatially image cAMP quantitatively in membrane-bound compartments.